WO2024046409A1 - Heterocyclic compound, preparation method therefor, and pharmaceutical use thereof - Google Patents

Heterocyclic compound, preparation method therefor, and pharmaceutical use thereof Download PDF

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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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French (fr)
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/en

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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
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    • 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
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    • 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

The present invention relates to a heterocyclic compound, a preparation method therefor, and a pharmaceutical use thereof. Specifically, the present invention relates to a heterocyclic compound as shown in general formula (I), a preparation method therefor, a pharmaceutical composition containing the compound, and a use of the heterocyclic compound as a therapeutic agent, especially a use as a Nav inhibitor and a use in preparation of drugs for treating and/or alleviating pain and pain-related diseases. The groups in general formula (I) are as defined in the description.

Description

杂环类化合物、其制备方法及其在医药上的应用Heterocyclic compounds, their preparation methods and their applications in medicine 技术领域Technical field
本公开属于医药领域，涉及一种杂环类化合物、其制备方法及其在医药上的应用。特别地，本公开涉及通式(I)所示的杂环类化合物、其制备方法及含有该类化合物的药物组合物，以及其作为Nav抑制剂的用途和其在制备治疗和/或减轻疼痛和疼痛相关疾病的药物中的用途。The present disclosure belongs to the field of medicine and relates to a heterocyclic compound, its preparation method and its application in medicine. In particular, 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.
背景技术Background technique
疼痛是一种复杂的生理心理活动，是临床上最常见的症状之一。国际疼痛研究协会将疼痛定义为“一种令人不快的感觉和情绪上的感受，伴有实质上的或潜在的组织损伤，它是一种主观感受。”疼痛可以作为一种警戒信号，提醒机体注意潜在的危险，对机体正常的生命活动具有不可或缺的保护作用。同时，疼痛也是一种常见的临床症状，在引发疼痛的外界刺激消失后，强烈或持久的疼痛会造成生理功能的紊乱，严重影响生命体的生活质量。统计数据显示，全世界约五分之一的人患有中度至重度慢性疼痛。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. The body's attention to potential dangers plays an indispensable protective role in the body's normal life activities. At the same time, pain is also a common clinical symptom. After the external stimulus that caused the pain disappears, strong or long-lasting pain 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.
疼痛起源于周围神经系统的伤害感受器。这是一种游离的神经末梢，广泛分布于全身的皮肤、肌肉、关节和内脏组织中，它可以将感受到的热的、机械的或化学的刺激转化为神经冲动(动作电位)并经由传入神经纤维传递到其位于背根神经节(dorsal root ganglia，DRG)的胞体部分，最终传递到高级神经中枢，引起痛觉。而神经元中动作电位的产生和传导又依赖于细胞膜上的电压门控钠通道(voltage-gated sodium channels，Nav)。当细胞膜去极化时，钠离子通道激活，通道打开，引起钠离子内流，使细胞膜进一步去极化，导致动作电位的产生。因此，抑制异常的钠离子通道活动有助于疼痛的治疗、缓解。Pain originates from nociceptors in the peripheral nervous system. This is a kind of free nerve ending, which is widely distributed in the skin, muscles, joints and visceral tissues of the whole body. It can convert the thermal, mechanical or chemical stimulation it feels into nerve impulses (action potentials) and transmit them through The incoming nerve fibers are transmitted to the cell body part located in the dorsal root ganglion (DRG), and finally transmitted to the higher nerve center, causing pain. 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是一类跨膜离子通道蛋白。这些蛋白由分子量260kD的α亚基和分子量为30-40kD的β亚基组成。根据α亚基的不同可以分为9种亚型，Navl.l～Nav1.9。不同亚型表现出不同的组织分布和电生理、药理学特征(Rush A.M.,et al.J.Physiol.2007,579,1–14)。根据能否被纳摩尔河豚毒素(tetrodotoxin，TTX)有效抑制，钠离子通道被分为TTX敏感型(TTX-S)和TTX不敏感型(TTX-R)。其中，Nav1.1、Nav1.2、Nav1.3和Nav1.7为TTX-S型，编码基因位于人类染色体2q23-24，它们在神经元中大量表达。Nav1.5、Nav1.8和Nav1.9为TTX-R型，编码基因位于人类染色体3p21-24。其中，Nav1.5主要存在于心肌细胞中，Nav 1.8、Nav l.9存在于外周神经系统(GoldinA.L.,et al.Annu.Rev.Physiol.2001,63,871–894)。Nav1.4和Nav1.6都为TTX-S型，分别在骨骼肌和中枢神经系统中大量存在(Fozzard H.A.,et al.Physiol.Rev.1996,76,887–926)。局部麻醉药利多卡因通过抑制Nav来止痛。而非选择性的Nav抑制剂，例如拉莫三嗪，拉科酰胺，美西律已经成功地用于治疗 慢性疼痛。Nav is a type of transmembrane ion channel protein. These proteins are composed of an α subunit with a molecular weight of 260 kD and a β subunit with a molecular weight of 30-40 kD. According to the different α 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). Among them, 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. Among them, Nav1.5 mainly exists in cardiomyocytes, and Nav 1.8 and Nav 1.9 exist in the peripheral nervous system (GoldinA.L., et al. Annu. Rev. Physiol. 2001, 63, 871-894). Both 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为TTX-R型，编码基因为SCN10A，主要存在于三叉神经节神经元和DRG神经元中，具有慢速失活、迅速恢复的电生理特征(Dib-Hajj S.D.,et al.Annu.Rev.Neurosci.2010,33,325–347)。在表达Nav 1.8的神经元内，动作电位的上升主要由Nav1.8电流构成。在研究神经性疼痛的一些模型中，神经损伤会使Nav1.8在轴突和神经元胞体中的表达水平上升(Sleeper A.A.,et al.J.Neurosci.2000,20,7279–7289)。使用Nav1.8反义寡核苷酸在降低Nav1.8表达的同时可以明显地缓解疼痛(Yoshimura N.,et al.J.Neurosci.2001,21,8690-8696)。大鼠爪内注射角叉菜胶(carrageenan)后，DRG神经元中Nav1.8的表达有所上升(Tanaka M.,et al.G.NeuroReport 1998,9,967–972)。Nav1.8敲除小鼠不能表现出正常的内脏炎症痛(Kerr B.J.,et al.NeuroReport 2001,12,3077–3080)。人类的Nav1.8基因产生功能增益突变后，会导致外周神经痛(Faber C.G.,et al.Proc.Natl.Acad.Sci.USA2012,109,19444–19449)。根据一系列动物实验以及人类基因证据，选择性抑制Nav1.8具有成为新型镇痛疗法的潜力，可以用于炎性疼痛，神经疼痛，手术后疼痛，癌痛等多种疼痛类型的治疗。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). The use of Nav1.8 antisense oligonucleotides can significantly relieve pain while reducing Nav1.8 expression (Yoshimura N., et al. J. Neurosci. 2001, 21, 8690-8696). 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. Acad. Sci. USA 2012, 109, 19444–19449). According to a series of animal experiments and human genetic evidence, selective inhibition of Nav1.8 has the potential to become a new analgesic therapy, which can be used to treat inflammatory pain, neuralgia, post-surgical pain, cancer pain and other types of pain.
临床中使用的Nav抑制剂由于缺乏亚型选择性，能够抑制表达在心脏和中枢神经系统中的钠离子通道，因此治疗窗口较窄，应用范围受到限制。Nav1.8主要分布在外周神经系统，所以选择性地抑制Nav1.8可以有效地减少副作用。因此，有必要开发活性更高，选择性更好，药代动力学性质更佳，副作用更少的Nav1.8抑制剂。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.
已公开的Nav1.8抑制剂化合物的专利申请包括WO2015089361A1、WO2021113627A1、WO2022129281 A1、WO2022121517A1、WO2019014352A1、WO2022256622A1、WO2022256676A1、WO2022256679A1、WO2022256842A1和WO2022256702A1。Published patent applications for Nav1.8 inhibitor compounds include WO2015089361A1, WO2021113627A1, WO2022129281 A1, WO2022121517A1, WO2019014352A1, WO2022256622A1, WO2022256676A1, WO2022256679 A1, WO2022256842A1 and WO2022256702A1.
发明内容Contents of the invention
本公开的目的在于提供一种通式(I)所示的化合物或其可药用的盐：
The purpose of this disclosure is to provide a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof:
其中：in:
环Cy选自多环环烷基、多环杂环基、多环芳基和多环杂芳基；Ring Cy is selected from polycyclic cycloalkyl, polycyclic heterocyclyl, polycyclic aryl and polycyclic heteroaryl;
RA选自氢原子、卤素、羟基、氰基、烷基、烷氧基、卤代烷基、卤代烷氧基、 羟烷基、羟烷氧基、烯基、-NR3R4、-亚烷基-NR3R4、-O-亚烷基-NR3R4、-C(＝NR5)R6、-C(O)NR3R4、-C(O)R6、-S(O)vNR3R4、-NR5S(O)vR6、-S(O)vR6、-S(＝NR5)(O)R6、＝NR5、＝CR7R8、-NR5C(O)R6、-NR5C(O)NR3R4、-P(O)R7R8、-C(O)NR5NR3R4、-C(＝NR5)NR3R4、-C(O)C(O)NR3R4、-S(＝NR5)NR3R4、-S(＝NR5)R6、环烷基、杂环基、芳基、杂芳基、-O-亚烷基-杂芳基和-O-亚烷基-杂环基，其中，所述的烯基、亚烷基、环烷基、杂环基、芳基和杂芳基各自独立地任选被1个或多个R01所取代；R A is selected from hydrogen atom, halogen, hydroxyl, cyano group, alkyl group, alkoxy group, haloalkyl group, haloalkoxy group, Hydroxyalkyl, hydroxyalkoxy, alkenyl, -NR 3 R 4 , -alkylene-NR 3 R 4 , -O-alkylene-NR 3 R 4 , -C(=NR 5 )R 6 , -C(O)NR 3 R 4 , -C(O)R 6 , -S(O) v NR 3 R 4 , -NR 5 S(O) v R 6 , -S(O) v R 6 , - S(=NR 5 )(O)R 6 , =NR 5 , =CR 7 R 8 , -NR 5 C(O)R 6 , -NR 5 C(O)NR 3 R 4 , -P(O)R 7 R 8 , -C(O)NR 5 NR 3 R 4 , -C(＝NR 5 )NR 3 R 4 , -C(O)C(O)NR 3 R 4 , -S(＝NR 5 )NR 3 R 4 , -S(=NR 5 )R 6 , cycloalkyl, heterocyclyl, aryl, heteroaryl, -O-alkylene-heteroaryl and -O-alkylene-heterocyclyl , wherein the alkenyl, alkylene, cycloalkyl, heterocyclyl, aryl and heteroaryl groups are each independently optionally substituted by one or more R 01 ;
各个RB相同或不同，且各自独立地选自卤素、羟基、氨基、氰基、氧代基、烷基、烷氧基、卤代烷基、卤代烷氧基、烯基、环烷基、杂环基、芳基和杂芳基；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;
R3、R4和R5相同或不同，且各自独立地选自氢原子、烷基、烷氧基、烯基、炔基、NR20R21、C(O)NR20R21、NR22C(O)R23、C(O)R23、C(O)OR23、OC(O)R23、S(O)vR23、S(O)vOR23、OS(O)vR23、S(O)vNR20R21、OR23、环烷基、杂环基、芳基和杂芳基；其中，所述的烷基、环烷基、杂环基、芳基和杂芳基各自独立地任选被1个或多个R01所取代；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 Each aryl group is independently optionally substituted by 1 or more R 01 ;
或R3、R4及与其相连的氮原子一起形成杂环基；所述杂环基任选被1个或多个R01所取代；Or 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 ;
R6、R7和R8相同或不同，且各自独立地选自氢原子、卤素、烷基、烷氧基、卤代烷基、卤代烷氧基、羟烷基、烯基、炔基、NR20R21、C(O)NR20R21、NR22C(O)R23、C(O)R23、C(O)OR23、OC(O)R23、S(O)vR23、S(O)vOR23、OS(O)vR23、S(O)vNR20R21、OR23、环烷基、杂环基、芳基和杂芳基；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;
各个R01相同或不同，且各自独立地选自卤素、羟基、氰基、氧代基、氨基、-NH烷基、-N(烷基)2、乙酰基、烷基、烯基、炔基、烷氧基、卤代烷基、卤代烷氧基、羟烷基、环烷基、杂环基、芳基和杂芳基；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;
各个R20、R21、R22和R23相同或不同，且各自独立地选自氢原子、烷基、烷氧基、烯基、炔基、环烷基、杂环基、芳基和杂芳基；所述的烷基、烷氧基、烯基、炔基、环烷基、杂环基、芳基和杂芳基各自独立地任选被选自卤素、羟基、氰基、氨基、烷基、烷氧基、卤代烷基、卤代烷氧基和羟烷基中的一个或多个所取代；Each of 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’选自氢原子、烷基、卤代烷基、羟烷基、环烷基和杂环基；R' is selected from hydrogen atoms, alkyl groups, haloalkyl groups, hydroxyalkyl groups, cycloalkyl groups and heterocyclyl groups;
X为O或S；X is O or S;
Ra和Rb相同或不同，且各自独立地选自氢原子、卤素、羟基、氰基、氨基、烷基、烯基、炔基、烷氧基、卤代烷基、卤代烷氧基、羟烷基、环烷基、杂环基、环烷基氧基和杂环基氧基；所述的环烷基、杂环基、环烷基氧基和杂环基氧基各组独立地任选被1个或多个R02所取代；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 ;
Rc和Rd相同或不同，且各自独立地选自氢原子、卤素、羟基、氰基、氨基、烷基、烯基、炔基、烷氧基、卤代烷基、卤代烷氧基、羟烷基、环烷基、杂环基、环烷基氧基和杂环基氧基；所述的环烷基、杂环基、环烷基氧基和杂环基氧基各 组独立地任选被1个或多个R02所取代；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 ;
或，Ra、Rb及与其相连的碳原子一起形成环烷基或杂环基；或，Rc、Rd及与其相连的碳原子一起形成环烷基或杂环基；其中，所述的环烷基或杂环基各自独立地任选被1个或多个R02所取代；Or, R a , R b and the carbon atoms connected to them together form a cycloalkyl or heterocyclic group; or, R c , R d and the carbon atoms connected to them together form a cycloalkyl or heterocyclic group; wherein, the The cycloalkyl or heterocyclyl groups are each independently optionally substituted by 1 or more R 02 ;
Re选自氢原子、卤素、羟基、氰基、氨基、烷基、烷氧基、卤代烷基、卤代烷氧基和羟烷基；R e is selected from hydrogen atoms, halogen, hydroxyl, cyano, amino, alkyl, alkoxy, haloalkyl, haloalkoxy and hydroxyalkyl;
各个R02相同或不同，且各自独立地选自卤素、羟基、氰基、氧代基、氨基、酰胺基、烷基、烯基、炔基、烷氧基、卤代烷基、卤代烷氧基、羟烷基、环烷基、杂环基、芳基和杂芳基；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;
X1为CRX1或N；X 1 is CR X1 or N;
X2为CRX2或N；X 2 is CR X2 or N;
X3为CRX3或N；X 3 is CR X3 or N;
X4为CRX4或N；X 4 is CR X4 or N;
X5为CRX5或N；X 5 is CR X5 or N;
条件是，X1、X2、X3、X4和X5不同时为N；The condition is that X 1 , X 2 , X 3 , X 4 and X 5 are not N at the same time;
RX1、RX2、RX3、RX4和RX5相同或不同，且各自独立地选自氢原子、卤素、羟基、氰基、氨基、酰胺基、硝基、烷基、烯基、炔基、烷氧基、卤代烷基、卤代烷氧基、羟烷基、环烷基、杂环基、-O-(CH2)n-环烷基、-O-(CH2)s-杂环基、芳基和杂芳基；其中，所述的环烷基、杂环基、芳基和杂芳基各自独立地任选被1个或多个R03所取代； 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 ;
各个R03相同或不同，且各自独立地选自卤素、羟基、氰基、氧代基、氨基、酰胺基、烷基、烯基、炔基、烷氧基、卤代烷基、卤代烷氧基、羟烷基、环烷基、杂环基、芳基和杂芳基；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选自0、1和2；v is selected from 0, 1 and 2;
n选自0、1、2、3、4和5；n is selected from 0, 1, 2, 3, 4 and 5;
s选自0、1、2、3、4和5；且，s is selected from 0, 1, 2, 3, 4 and 5; and,
r选自0、1、2、3、4和5。r is selected from 0, 1, 2, 3, 4 and 5.
本公开的目的在于提供一种通式(I)所示的化合物或其可药用的盐：
The purpose of this disclosure is to provide a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof:
其中： in:
环Cy选自多环环烷基、多环杂环基、多环芳基和多环杂芳基；Ring Cy is selected from polycyclic cycloalkyl, polycyclic heterocyclyl, polycyclic aryl and polycyclic heteroaryl;
RA选自氢原子、卤素、羟基、氰基、烷基、烷氧基、卤代烷基、卤代烷氧基、羟烷基、羟烷氧基、烯基、-NR3R4、-亚烷基-NR3R4、-O-亚烷基-NR3R4、-C(＝NR5)R6、-C(O)NR3R4、-C(O)R6、-S(O)vNR3R4、-NR5S(O)vR6、-S(O)vR6、-S(＝NR5)(O)R6、环烷基、杂环基、芳基、杂芳基、-O-亚烷基-杂芳基和-O-亚烷基-杂环基，其中，所述的烯基、亚烷基、环烷基、杂环基、芳基和杂芳基各自独立地任选被1个或多个R01所取代；R A is selected from hydrogen atom, halogen, hydroxyl, cyano, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, hydroxyalkoxy, alkenyl, -NR 3 R 4 , -alkylene -NR 3 R 4 , -O-alkylene-NR 3 R 4 , -C(=NR 5 )R 6 , -C(O)NR 3 R 4 , -C(O)R 6 , -S(O ) v NR 3 R 4 , -NR 5 S(O) v R 6 , -S(O) v R 6 , -S(=NR 5 )(O)R 6 , cycloalkyl group, heterocyclyl group, aryl group , heteroaryl, -O-alkylene-heteroaryl and -O-alkylene-heterocyclyl, wherein the alkenyl, alkylene, cycloalkyl, heterocyclyl, aryl and Each heteroaryl group is independently optionally substituted by 1 or more R 01 ;
各个RB相同或不同，且各自独立地选自卤素、羟基、氨基、氰基、氧代基、烷基、烷氧基、卤代烷基、卤代烷氧基、烯基、环烷基、杂环基、芳基和杂芳基；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;
R3、R4和R5相同或不同，且各自独立地选自氢原子、烷基、环烷基、杂环基、芳基和杂芳基；其中，所述的烷基、环烷基、杂环基、芳基和杂芳基各自独立地任选被1个或多个R01所取代；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 ;
或R3、R4及与其相连的氮原子一起形成杂环基；所述杂环基任选被1个或多个R01所取代；Or 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 ;
R6选自烷基、烷氧基、卤代烷基、卤代烷氧基、羟烷基、环烷基、杂环基、芳基和杂芳基；R 6 is selected from alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;
各个R01相同或不同，且各自独立地选自卤素、羟基、氰基、氧代基、氨基、-NH烷基、-N(烷基)2、乙酰基、烷基、烯基、炔基、烷氧基、卤代烷基、卤代烷氧基、羟烷基、环烷基、杂环基、芳基和杂芳基；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’选自氢原子、烷基、卤代烷基、羟烷基、环烷基和杂环基；R' is selected from hydrogen atoms, alkyl groups, haloalkyl groups, hydroxyalkyl groups, cycloalkyl groups and heterocyclyl groups;
X为O或S；X is O or S;
Ra和Rb相同或不同，且各自独立地选自氢原子、卤素、羟基、氰基、氨基、烷基、烯基、炔基、烷氧基、卤代烷基、卤代烷氧基、羟烷基、环烷基、杂环基、环烷基氧基和杂环基氧基；所述的环烷基、杂环基、环烷基氧基和杂环基氧基任选被1个或多个R02所取代；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 ;
条件是，Ra和Rb不同时为氢；The condition is that R a and R b are not hydrogen at the same time;
Rc和Rd相同或不同，且各自独立地选自氢原子、卤素、羟基、氰基、氨基、烷基、烯基、炔基、烷氧基、卤代烷基、卤代烷氧基、羟烷基、环烷基、杂环基、环烷基氧基和杂环基氧基；所述的环烷基、杂环基、环烷基氧基和杂环基氧基任选被1个或多个R02所取代；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 ;
或，Ra、Rb及与其相连的碳原子一起形成环烷基或杂环基；或，Rc、Rd及与其相连的碳原子一起形成环烷基或杂环基；其中，所述的环烷基或杂环基各自独立地任选被1个或多个R02所取代；Or, R a , R b and the carbon atoms connected to them together form a cycloalkyl or heterocyclic group; or, R c , R d and the carbon atoms connected to them together form a cycloalkyl or heterocyclic group; wherein, the The cycloalkyl or heterocyclyl groups are each independently optionally substituted by 1 or more R 02 ;
Re选自氢原子、卤素、羟基、氰基、氨基、烷基、烷氧基、卤代烷基、卤代烷氧基和羟烷基；R e is selected from hydrogen atoms, halogen, hydroxyl, cyano, amino, alkyl, alkoxy, haloalkyl, haloalkoxy and hydroxyalkyl;
各个R02相同或不同，且各自独立地选自卤素、羟基、氰基、氧代基、氨基、 酰胺基、烷基、烯基、炔基、烷氧基、卤代烷基、卤代烷氧基、羟烷基、环烷基、杂环基、芳基和杂芳基；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;
X1为CRX1或N；X 1 is CR X1 or N;
X2为CRX2或N；X 2 is CR X2 or N;
X3为CRX3或N；X 3 is CR X3 or N;
X4为CRX4或N；X 4 is CR X4 or N;
X5为CRX5或N；X 5 is CR X5 or N;
条件是，X1、X2、X3、X4和X5不同时为N；The condition is that X 1 , X 2 , X 3 , X 4 and X 5 are not N at the same time;
RX1、RX2、RX3、RX4和RX5相同或不同，且各自独立地选自氢原子、卤素、羟基、氰基、氨基、酰胺基、硝基、烷基、烯基、炔基、烷氧基、卤代烷基、卤代烷氧基、羟烷基、环烷基、杂环基、-O-(CH2)n-环烷基、-O-(CH2)s-杂环基、芳基和杂芳基；其中，所述的环烷基、杂环基、芳基和杂芳基各自独立地任选被1个或多个R03所取代； 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 ;
各个R03相同或不同，且各自独立地选自卤素、羟基、氰基、氧代基、氨基、酰胺基、烷基、烯基、炔基、烷氧基、卤代烷基、卤代烷氧基、羟烷基、环烷基、杂环基、芳基和杂芳基；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选自0、1和2；v is selected from 0, 1 and 2;
n选自0、1、2、3、4和5；n is selected from 0, 1, 2, 3, 4 and 5;
s选自0、1、2、3、4和5；且，s is selected from 0, 1, 2, 3, 4 and 5; and,
r选自0、1、2、3、4和5。r is selected from 0, 1, 2, 3, 4 and 5.
在本公开一些实施方案中，所述的通式(I)所示的化合物或其可药用的盐，其中X1为N，X2为CRX2，X3为CRX3，X4为CRX4，X5为CRX5；或X2为N，X1为CRX1，X3为CRX3，X4为CRX4，X5为CRX5；或X3为N，X1为CRX1，X2为CRX2，X4为CRX4，X5为CRX5；或X1为N，X3为N，X2为CRX2，X4为CRX4，X5为CRX5；或X2为N，X4为N，X1为CRX1，X3为CRX3，X5为CRX5；或X1为CRX1，X2为CRX2，X3为CRX3，X4为CRX4，X5为CRX5；RX1、RX2、RX3、RX4和RX5如通式(I)所定义；优选地，X1为CRX1，X2为CRX2，X3为CRX3，X4为CRX4，X5为CRX5；RX1、RX2、RX3、RX4和RX5如通式(I)所定义；更优选地，X1为CRX1，X2为CRX2，X3为CRX3，X4为CH，X5为CH；RX1、RX2和RX3相同或不同，且各自独立地选自氢原子、卤素、C1-6烷基、C1-6烷氧基、卤代C1-6烷基、卤代C1-6烷氧基、C1-6羟烷基、3至8元环烷基、4至7元杂环基、3至8元环烷基氧基和4至7元杂环基氧基；所述3至8元环烷基、4至7元杂环基、3至8元环烷基氧基和4至7元杂环基氧基各自独立地任选被1个或多个R03所取代；R03如通式(I)所定义；最优选地，X1为CRX1，X2为CRX2，X3为CRX3，X4为CH，X5为CH；RX1、RX2和RX3相同或不同，且各自独立地选自氢原子、卤素、C1-6烷基、C1-6烷氧基、卤代C1-6烷基和卤代C1-6烷氧基。 In some embodiments of the present disclosure, 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 ; or X 1 is CR X1 , X 2 is CR X2 , X 3 is CR X3 , X 4 is CR X4 , X5 is CR _ _ _ _ _ _ _ _ _ , X 4 is CR X4 , X 5 is CR X5 ; R X2 , X3 is CR X3 , X4 is CH, X5 is CH ; R -6 alkoxy, halogenated C 1-6 alkyl, halogenated C 1-6 alkoxy, C 1-6 hydroxyalkyl, 3 to 8 -membered cycloalkyl, 4 to 7-membered heterocyclyl, 3 to 8-membered cycloalkyloxy and 4 to 7-membered heterocyclyloxy; the 3 to 8-membered cycloalkyl, 4 to 7-membered heterocyclyl, 3 to 8-membered cycloalkyloxy and 4 to 7 Each heterocyclyloxy group is independently optionally substituted by one or more R 03 ; R 03 is as defined by the general formula (I); most preferably, X 1 is CR X1 , X 2 is CR X2 , and X 3 is CR X3 , X 4 is CH, and X 5 is CH ; R Oxygen, halogenated C 1-6 alkyl and halogenated C 1-6 alkoxy.
在本公开一些实施方案中，所述的通式(I)所示的化合物或其可药用的盐，其为通式(II)所示的化合物或其可药用的盐：
In some embodiments of the present disclosure, 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:
其中：in:
Ra和Rb不同，且各自独立地选自氢原子、卤素、羟基、氰基、氨基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6烷氧基、卤代C1-6烷基、卤代C1-6烷氧基、C1-6羟烷基、3至10元环烷基、3至10元杂环基、3至10元环烷基氧基和3至10元杂环基氧基；所述的3至10元环烷基、3至10元杂环基、3至10元环烷基氧基和3至10元杂环基氧基任选被1个或多个R02所取代；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 ;
Rc和Rd不同，且各自独立地选自氢原子、卤素、羟基、氰基、氨基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6烷氧基、卤代C1-6烷基、卤代C1-6烷氧基、C1-6羟烷基、3至10元环烷基、3至10元杂环基、3至10元环烷基氧基和3至10元杂环基氧基；所述的3至10元环烷基、3至10元杂环基、3至10元环烷基氧基和3至10元杂环基氧基任选被1个或多个R02所取代；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 ;
环Cy、RA、RB、R’、X、RX1、RX2、RX3、R02和r如通式(I)中所定义。Rings Cy, RA , RB , R', X, RX1 , RX2 , RX3 , R02 and r are as defined in general formula (I).
在本公开一些实施方案中，所述的通式(I)或通式(II)所示的化合物或其可药用的盐，其为通式(II-1)所示的化合物或其可药用的盐：
In some embodiments of the present disclosure, 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:
其中，R’、X、Ra、Rb、Rc、Rd、RX1、RX2和RX3如通式(II)中所定义。Among them, R', X, Ra, Rb , Rc , Rd, RX1 , RX2 and RX3 are as defined in the general formula (II ) .
在本公开一些实施方案中，所述的通式(I)或通式(II)所示的化合物或其可药用的盐，其为通式(III)所示的化合物或其可药用的盐：
In some embodiments of the present disclosure, 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:
其中，环A为苯基或5或6元杂芳基； Among them, ring A is phenyl or 5- or 6-membered heteroaryl;
Q1为C或N；Q 1 is C or N;
Q2选自CRA、N、NR”和C(O)；Q3选自CRaa、CHRaa、N、NR”和O；Y选自CRaa、CHRaa、N、NR”和O；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;
---为单键或双键；--- is a single bond or a double bond;
Raa相同或不同，且各自独立地选自氢原子、卤素、羟基、氨基、氰基、烷基、烷氧基、卤代烷基、卤代烷氧基、烯基、环烷基、杂环基、芳基和杂芳基；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”相同或不同，且各自独立地选自氢原子、烷基、烷氧基、卤代烷基、卤代烷氧基、环烷基、杂环基、芳基和杂芳基；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;
y为0或1；p为0或1；y is 0 or 1; p is 0 or 1;
R’、X、Ra、Rb、Rc、Rd、RX1、RX2、RX3、RB和RA如通式(II)中所定义。R' , X, R a , R b , R c , R d , RX1 , RX2 , R
在本公开一些实施方案中，所述的通式(I)所示的化合物或其可药用的盐，其中选自Ra、Rb、Rc、Rd和X如通式(I)所定义；优选地，选自 X、Ra、Rb、Rc和Rd如通式(II)中所定义；进一步优选地，选自X为O或S，Ra和Rb不同，且各自独立地选自氢原子、卤素、C1-6烷基、C1-6烷氧基、卤代C1-6烷基、卤代C1-6烷氧基和3至10元环烷基，Rc和Rd不同，且各自独立地选自氢原子、卤素、C1-6烷基、C1-6烷氧基、卤代C1-6烷基、卤代C1-6烷氧基和3至10元环烷基；最优选地，为Ra和Rb不同，且各自独立地选自氢原子、C1-6烷基和C1-6卤代烷基，Rc和Rd不同，且各自独立地选自氢原子、C1-6烷基和C1-6卤代烷基； In some embodiments of the present disclosure, 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, for R a and R b are different, and each is independently selected from a hydrogen atom, C 1-6 alkyl group, and C 1-6 haloalkyl group. R c and R d are different, and each is independently selected from a hydrogen atom, C 1-6 Alkyl and C 1-6 haloalkyl;
在一些实施方案中，为Ra和Rb相同或不同，且各自独立地选自氢原子、卤素、C1-6烷基、卤代C1-6烷基和3至10元环烷基；Rc和Rd不同，且各自独立地选自氢原子、卤素、C1-6烷基、卤代C1-6烷基和3至10元环烷基；In some embodiments, for 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;
在一些实施方案中，为Ra和Rb不同，且各自独立地选自氢原子、卤素、C1-6烷基、卤代C1-6烷基和3至10元环烷基；Rc和Rd相同或不同，且各自独立地选自氢原子、卤素、C1-6烷基、卤代C1-6烷基和3至10元环烷基。In some embodiments, for 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.
在本公开一些实施方案中，所述的通式(I)或通式(II)所示的化合物或其可药用的盐，其中环Cy选自5至20元稠环烷基、5至20元稠杂环基、8至14元多环芳基和7至14元多环杂芳基；在一些实施方案中，环Cy为8至14元多环杂芳基；优选地，环Cy为9至10元双环杂芳基。In some embodiments of the present disclosure, 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.
在本公开一些实施方案中，所述的通式(I)或通式(II)所示的化合物或其可药用的盐，其中环Cy表示为环A和环B相同或不同，且各自独立地选自3至12元环烷基、3至12元杂环基、6至10元芳基和5至14元杂芳基，*端与-C(O)NR’-连接，在化合价允许的范围内RA和RB连接至环A和环B的任意位置；优选地，环Cy表示为环A为苯基或5或6元杂芳基，环B选自3至10元环烷基、3至10元杂环基、苯基和5或6元杂芳基，*端与-C(O)NR’-连接，在化合价允许的范围内RA和RB连接至环A和环B的任意位置；进一步优选地，环Cy表示为环A为苯基或5或6元杂芳基，环B选自5或6元环烷基、5或6元杂环基、苯基和5或6元杂芳基，*端与-C(O)NR’-连接，在化合价允许的范围内RA和RB连接至环A和环B的任意位置；更进一步优选地，环Cy表示为环A和环B相同或不同，且各自独立地为苯基或5或6元杂芳基，*端与-C(O)NR’-连接，在化合价允许的范围内RA和RB连接至环A和环B的任意位置；In some embodiments of the present disclosure, 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 B within the range allowed by the chemical valency; further preferably, ring Cy is expressed as Ring A is phenyl or 5- or 6-membered heteroaryl, ring B is selected from 5- or 6-membered cycloalkyl, 5- or 6-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 B within the range allowed by the chemical valency; further preferably, ring Cy is expressed as Ring A and Ring B are the same or different, and each is independently a phenyl group or a 5- or 6-membered heteroaryl group. The * end is connected to -C(O)NR'-, and R A and R B are connected within the range allowed by the chemical valency. To any position of Ring A and Ring B;
在一些实施方案中，环Cy表示为环A为苯基或5或6元杂芳基，环B为5或6元杂芳基，*端与-C(O)NR’-连接，在化合价允许的范围内RA和RB 连接至环A和环B的任意位置；更优选地，环Cy选自 *端与-C(O)NR’-连接，在化合价允许的范围内RA和RB连接至环Cy的任意位置；最优选地，环Cy选自 *端与-C(O)NR’-连接，在化合价允许的范围内RA和RB连接至环Cy的任意位置。In some embodiments, 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.
在本公开一些实施方案中，所述的通式(I)或通式(II)所示的化合物或其可药用的盐，其中环Cy为环A为苯基或5或6元杂芳基；Q1为C或N，Q2选自CH、CH2、N、NH和C(O)；Q3选自CH、CH2、N、NH和O；Y选自CH、CH2、N、NH和O；---为单键或双键；y为0或1；*端与-C(O)NR’-连接，在化合价允许的范围内RA和RB连接至环Cy的任意位置。In some embodiments of the present disclosure, 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.
在本公开一些实施方案中，所述的通式(I)或通式(II)所示的化合物或其可药用的盐，其中环Cy选自 In some embodiments of the present disclosure, the compound represented by general formula (I) or general formula (II) or a pharmaceutically acceptable salt thereof, wherein ring Cy is selected from
在一些实施方案中，环Cy选自 *端与-C(O)NR’-连接，在化合价允许的范围内RA和RB连接至环Cy的任意位置；在一些实施方案中，环Cy选自 *端与-C(O)NR’-连接，在化合价允许的范围内RA和RB连接至环Cy的任意位置；在一些实施方案中，环Cy选自 In some embodiments, 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
在一些实施方案中，环Cy选自 In some embodiments, Ring Cy is selected from
在一些实施方案中，环Cy选自 在一些实施方案中，Cy为*端与-C(O)NR’-连接，在化合价允许的范围内RA和RB连接至环Cy的任意位置。In some embodiments, 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.
在本公开一些实施方案中，所述的通式(I)或通式(II)所示的化合物或其可药用的盐，其中环Cy表示为环A为5元杂芳基，环B为5或6元杂环基或5或6元杂芳基，*端与-C(O)NR’-连接，RA为羟基或氨基。In some embodiments of the present disclosure, 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.
在本公开一些实施方案中，所述的通式(I)或通式(II)所示的化合物或其可药用的盐，其中环Cy中所含杂原子数量不超过5，优选不超过4，更优选不超过3。In some embodiments of the present disclosure, 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.
在本公开一些实施方案中，所述的通式(I)、(II)或(III)所示的化合物或其可药用的盐，其中RA选自氢原子、羟基、C1-6羟烷基、C1-6羟烷氧基、-NR3R4、-C1-6亚烷基-NR3R4、-O-C1-6亚烷基-NR3R4、3至10元环烷基、3至10元杂环基、6至10元芳基、5至14元杂芳基、-O-C1-6亚烷基-5至14杂芳基和-O-C1-6亚烷基-3至10元杂环基，其中，所述的C1-6亚烷基、3至10元环烷基、3至10元杂环基、6至10元芳基和5至14元杂芳基各自独立地任选被1个或多个R01所取代；R01、R3和R4如通式(I)所定义；In some embodiments of the present disclosure, 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 Each heteroaryl group is independently optionally substituted by one or more R 01 ; R 01 , R 3 and R 4 are as defined by general formula (I);
优选地，RA选自氢原子、羟基、C1-6羟烷基、C1-6羟烷氧基、-NR3R4、-C1-6亚烷基-NR3R4和-O-C1-6亚烷基-NR3R4，所述的C1-6亚烷基任选被1个或多个R01所取代；R01、R3和R4如通式(I)所定义；进一步优选地，RA选自羟基、氨基、C1-6烷氧基、C1-6羟烷基和C1-6羟烷氧基；更优选地，RA为羟基或氨基；最优选地，RA为羟基；Preferably, 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;
在一些实施方案中，RA为氢原子、羟基或氨基，优选为氢原子或羟基；在一些实施方案中，RA选自氢原子、卤素、羟基和氨基；在一些实施方案中，RA选自氢原子、卤素、羟基、氨基和＝NH；在一些实施方案中，RA为氢原子。In some embodiments, R A is a hydrogen atom, a hydroxyl group or an amino group, preferably a hydrogen atom or a hydroxyl group; in some embodiments, R A is selected from a hydrogen atom, a halogen, a hydroxyl group and an amino group; in some embodiments, R A Selected from hydrogen atoms, halogens, hydroxyl, amino groups, and =NH; in some embodiments, RA is a hydrogen atom.
在本公开一些实施方案中，所述的通式(I)、(II)或(III)所示的化合物或其可药用的盐，其中各个RB相同或不同，且各自独立地选自卤素、羟基、氨基、C1-6烷基、C1-6烷氧基、卤代C1-6烷基和卤代C1-6烷氧基；优选地，各个RB相同或不同，且各自独立地选自卤素、羟基、C1-6烷基和卤代C1-6烷基；In some embodiments of the present disclosure, 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, 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;
在一些实施方案中，各个RB相同或不同，且各自独立地选自氧代基、卤素、 C1-6烷基和卤代C1-6烷基；优选地，各个RB相同或不同，且各自独立地选自氧代基、卤素和C1-6烷基；更优选地，各个RB相同或不同，且各自独立地选自氧代基和C1-6烷基；在一些实施方案中，各个RB相同或不同，且各自独立地选自卤素、C1-6烷基和卤代C1-6烷基；在一些实施方案中，各个RB相同或不同，且各自独立地为卤素或C1-6烷基。In some embodiments, 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.
在本公开一些实施方案中，所述的通式(I)、(II)或(III)所示的化合物或其可药用的盐，其中各个RB相同或不同，且各自独立地选自卤素、C1-6烷基和卤代C1-6烷基，且r选自0、1和2。In some embodiments of the present disclosure, 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.
在本公开一些实施方案中，所述的通式(I)或通式(II)所示的化合物或其可药用的盐，其中选自 W为N或CRW；W1、W2和W3中的一者为CRA，余下的两者各自独立地为N或CR1B；W4和W5中的一者为CRA，另一者为N或CR2B；W6选自O、S和NR3B；W7、W8、W9和W10中的一者为CRA，余下的三者各自独立地为N或CR4B，且W7、W8、W9和W10中至少有一个为N；W11和W12相同或不同，且各自独立地为N或CR5B；W13和W14相同或不同，且各自独立地为N或CR6B；W17、W18、W19和W20中的一者为CRA，余下的三者各自独立地为N或CR7B；W15为N或CR8B，W16选自O、S和NR9B；各个R1B、R2B、R4B、R5B、R6B、R7B、R8B、RW和R0相同或不同，且各自独立地选自氢原子、卤素、C1-6烷基和卤代C1-6烷基；R3B和R9B相同或不同，且各自独立地选自氢原子、C1-6烷基和卤代C1-6烷基；RA如通式(I)所定义；In some embodiments of the present disclosure, 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 15 is N or CR 8B , W 16 Selected from O, S and NR 9B ; each R 1B , R 2B , R 4B , R 5B , R 6B , R 7B , R 8B , R W and R 0 are the same or different, and each is independently selected from hydrogen atoms, halogens , C 1-6 alkyl and halogenated C 1-6 alkyl; R 3B and R 9B are the same or different, and each is independently selected from a hydrogen atom, C 1-6 alkyl and halogenated C 1-6 alkyl ; R A is as defined by general formula (I);
优选地，选自 W为N或CH； W1、W2和W3中的一者为CRA，余下的两者各自独立地为N或CR1B；W4和W5中的一者为CRA，另一者为N或CR2B；W6选自O、S和NR3B；W13和W14相同或不同，且各自独立地为N或CR6B；W15为N或CR8B，W16选自O、S和NR9B；W17、W18、W19和W20中的一者为CRA，余下的三者各自独立地为N或CR7B；各个R1B、R0、R2B、R6B、R7B和R8B相同或不同，且各自独立地选自氢原子、卤素、C1-6烷基和卤代C1-6烷基；R9B和R3B各自独立地为氢原子或C1-6烷基；RA如通式(I)所定义；Preferably, 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 independently a hydrogen atom or C 1-6 alkyl; R A is as defined by general formula (I);
进一步优选地，选自 RA如通式(I)所定义；Further preferably, Selected from R A is as defined by general formula (I);
更进一步优选地，选自RA如通式(I)所定义；最优选地，选自 More preferably, Selected from R A is as defined by general formula (I); most preferably, Selected from
在本公开一些实施方案中，所述的通式(I)或通式(II)所示的化合物或其可药用的盐，其中选自 W21和W22各自独立地为N或CR5b；W23为N或CR6b；W24选自O、S和NR7b；各个R1b、R2b、R3b、R4b、R5b和R6b相同或不同，且各自 独立地选自氢原子、卤素、C1-6烷基和卤代C1-6烷基；R7b选自氢原子、C1-6烷基和卤代C1-6烷基；t选自0、1和2，p选自0、1和2，且t和p不同时为0；优选地，选自 In some embodiments of the present disclosure, 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
在一些实施方案中，选自 W、W1、W2、W3和R0如式(C3)中所定义，W4、W5和W6如式(C4)中所定义，W13、W14、W17、W18、W19和W20如式(C8)中所定义，W15和W16如式(C11)中所定义，W21、W22、R1b、W2b、R3b、W4b、t和p如式(C13-3)中所定义；优选地，选自 其中，W13、W14、W17、W18、W19和W20如式(C8)中所定义，W15和W16如式(C11)中所定义，W21、W22、R1b、W2b、R3b、W4b、t和p如式(C13-3)中所定义；更优选地，为 其中，W13、W14、W17、W18、W19和W20如式(C8)中所定义， W15和W16如式(C11)中所定义；进一步优选地，为 W13、RA、R6B和R7B如式(C8)中所定义，W15和R9B如式(C11)中所定义。In some embodiments, Selected from W, W 1 , W 2 , W 3 and R 0 are as defined in formula (C3), W 4 , W 5 and W 6 are as defined in formula (C4), 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 , W 18 , W 19 and W 20 are as defined in formula (C8), W 15 and W 16 are as defined in formula (C11); further preferably, for W 13 , RA , R 6B and R 7B are as defined in formula (C8), and W 15 and R 9B are as defined in formula (C11).
在本公开一些实施方案中，所述的式(C8-1)所示的化合物或其可药用的盐，其中W13为N或CR6B，R6B选自氢原子、卤素和C1-6烷基；优选地，W13为N或CH；更优选为N。In some embodiments of the present disclosure, the compound represented by formula (C8-1) or a pharmaceutically acceptable salt thereof, wherein W 13 is N or CR 6B , R 6B is selected from hydrogen atoms, halogens and C 1- 6 alkyl; preferably, W 13 is N or CH; more preferably, it is N.
在本公开一些实施方案中，所述的式(C11-2)所示的化合物或其可药用的盐，其中W15为N或CR8B，R8B选自氢原子、卤素和C1-6烷基；优选地，W15为N或CH；更优选为CH。In some embodiments of the present disclosure, the compound represented by formula (C11-2) or a pharmaceutically acceptable salt thereof, wherein W 15 is N or CR 8B , R 8B is selected from hydrogen atoms, halogens and C 1- 6 alkyl; preferably, W 15 is N or CH; more preferably, it is CH.
在本公开一些实施方案中，所述的通式(I)或(II)所示的化合物或其可药用的盐，其中为环A为苯基或5或6元杂芳基；Q1为C或N；Q2选自CRA、N、NR”和C(O)；Q3选自CRaa、CHRaa、N、NR”和O；Y选自CRaa、CHRaa、N、NR”和O；---为单键或双键；In some embodiments of the present disclosure, 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;
Raa相同或不同，且各自独立地选自氢原子、卤素、羟基、氨基、氰基、烷基、烷氧基、卤代烷基、卤代烷氧基、烯基、环烷基、杂环基、芳基和杂芳基；R”相同或不同，且各自独立地选自氢原子、烷基、烷氧基、卤代烷基、卤代烷氧基、环烷基、杂环基、芳基和杂芳基；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;
y为0或1；p为0或1；RB和RA如通式(I)中所定义。y is 0 or 1; p is 0 or 1; R B and R A are as defined in general formula (I).
在本公开一些实施方案中，所述的通式(III)所示的化合物或其可药用的盐或片段(A1)、(A2)，其中选自苯基、吡啶基、吡咯基、吡唑基和咪唑基；优选地，选自 In some embodiments of the present disclosure, the compound represented by the general formula (III) or its pharmaceutically acceptable salt or fragment (A1), (A2), wherein Selected from phenyl, pyridyl, pyrrolyl, pyrazolyl and imidazolyl; preferably, Selected from
更优选选自*端与-C(O)NR’-连接，#端与Y连接，+端与Q2相连。More preferably selected from The * terminal is connected to -C(O)NR'-, the # terminal is connected to Y, and the + terminal is connected to Q 2 .
在本公开一些实施方案中，所述的通式(III)所示的化合物或其可药用的盐或式(A1)、(A2)，其中选自RA如通式(I)中所定义；优选地，为RA选自卤素、羟基和氨基。In some embodiments of the present disclosure, the compound represented by general formula (III) or a pharmaceutically acceptable salt thereof or formula (A1), (A2), wherein Selected from R A is as defined in general formula (I); preferably, for R A is selected from halogen, hydroxyl and amino.
在本公开一些实施方案中，所述的通式(III)所示的化合物或其可药用的盐或式(A1)、(A2)，其中Y选自CRaa、CH2、N和O，Raa如通式(III)中所定义；优选为CH或CH2。In some embodiments of the present disclosure, the compound represented by the general formula (III) or its pharmaceutically acceptable salt or formula (A1), (A2), wherein Y is selected from CR aa , CH 2 , N and O , R aa is as defined in general formula (III); preferably CH or CH 2 .
在本公开一些实施方案中，所述的通式(III)所示的化合物或其可药用的盐或片段(A1)、(A2)，其中p为0。In some embodiments of the present disclosure, the compound represented by the general formula (III) or its pharmaceutically acceptable salt or fragment (A1), (A2), wherein p is 0.
在本公开一些实施方案中，所述的通式(I)或(II)所示的化合物或其可药用的盐，其中选自 RC为氢原子或RB，RA、RB和r如通式(I)中所定义；In some embodiments of the present disclosure, 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);
在一些实施方案中，选自 RC为氢原子或RB，RA和RB如通式(I)中所定义；In some embodiments, Selected from R C is a hydrogen atom or R B , R A and R B are as defined in general formula (I);
在一些实施方案中，选自 RA如通式(I)中所定义；在一些实施方案中，选自 In some embodiments, Selected from RA is as defined in general formula (I); in some embodiments, Selected from
优选地，RA选自卤素、羟基和-NR3R4，R3和R4相同或不同，且各自独立地为氢原子或C1-6烷基；各个RB相同或不同，且各自独立地选自卤素、C1-6烷基和卤代C1-6烷基，且r选自0、1和2；*端与-C(O)NR’-连接；Preferably, 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'-;
在一些实施方案中，选自 In some embodiments, Selected from
在一些实施方案中，选自 在一些实施方案中，为 In some embodiments, Selected from In some embodiments, for
在本公开一些实施方案中，所述的通式(I)或(II)所示的化合物或其可药用的盐，其中选自 RA选自氢原子、羟基、氨基、C1-6烷氧基、C1-6羟烷基和C1-6羟烷氧基(优选为氢原子、羟基或氨基)，*端与-C(O)NR’-连接；优选地，选自 RA选自氢原子、羟基、氨基、C1-6烷氧基、C1-6羟烷基和C1-6羟烷氧基(优选为氢原子、羟基或氨基)，*端与-C(O)NR’-连接。In some embodiments of the present disclosure, 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.
在本公开一些实施方案中，所述的式(C2)或(C3)所示的化合物或其可药用的盐，其中W为CRW，RW选自氢原子、卤素和C1-6烷基；优选为CH。In some embodiments of the present disclosure, the compound represented by formula (C2) or (C3) or a pharmaceutically acceptable salt thereof, wherein W is CR W , R W is selected from hydrogen atoms, halogens and C 1-6 Alkyl; preferably CH.
在本公开一些实施方案中，所述的式(C1)、(C2)或(C3)所示的化合物或其可药用的盐，其中W2为CRA，W1和W3各自独立地为N或CR1B；RA选自羟基、氨基、C1-6烷氧基、C1-6羟烷基和C1-6羟烷氧基，R1B选自氢原子、卤素和C1-6烷基；优选地，W2为CRA，W1和W3均为N；或，W2为CRA，W1为N，W3为CR1B；或，W2为CRA，W3为N，W1为CR1B；RA选自羟基、氨基、C1-6羟烷基和C1-6羟烷氧基，R1B为氢原子、卤素和C1-6烷基；优选地，W2为CRA，W1和W3均为N；RA选自羟基、氨基、C1-6羟烷基和C1-6羟烷氧基。In some embodiments of the present disclosure, the compound represented by formula (C1), (C2) or (C3) or a pharmaceutically acceptable salt thereof, wherein W 2 is CRA , W 1 and W 3 are each independently is N or CR 1B ; 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 ; Preferably, W 2 is CRA , W 1 and W 3 are both N; R A is selected from hydroxyl, amino, C 1-6 hydroxyalkyl and C 1-6 hydroxyalkoxy.
在本公开一些实施方案中，所述的式(C4)或(C5)所示的化合物或其可药用的盐，其中R0选自氢原子、卤素和C1-6烷基，W5为CRA，W4为N，W6为NR3B；RA选自羟基、氨基、C1-6烷氧基、C1-6羟烷基和C1-6羟烷氧基，R3B为氢原子或C1-6烷基；优选地，R0为氢原子，W5为CRA，W4为N，W6为NH；RA为羟基或氨基。In some embodiments of the present disclosure, 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.
在本公开一些实施方案中，所述的式(C8)、(C9)或(C10)所示的化合物或其可药用的盐，其中W13为N，且W14为CR6B；或，W14为N，且W13为CR6B；或，W13和W14均为CR6B，R6B选自氢原子、卤素和C1-6烷基；优选地，W13为N，且W14为CR6B；R6B选自氢原子、卤素和C1-6烷基；更优选地，W13为N，且W14为CH。In some embodiments of the present disclosure, 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.
在本公开一些实施方案中，所述的式(C8)、(C9)或(C10)所示的化合物或其可药用的盐，其中W13为N，且W14为CH；或，W14为N，且W13为CH；或，W13和W14均为CH。In some embodiments of the present disclosure, the compound represented by formula (C8), (C9) or (C10) or a pharmaceutically acceptable salt thereof, wherein W 13 is N, and W 14 is CH; or, W 14 is N, and W 13 is CH; or, both W 13 and W 14 are CH.
在本公开一些实施方案中，所述的式(C8)、(C9)、(C10)、(C11)、(C11-1)或(C12)所示的化合物或其可药用的盐，其中W17、W18、W19和W20中的一者为CRA，一者为N，余下的两者均为CR7B，R7B选自氢原子、卤素和C1-6烷基，RA如通式(I)所定义；优选地，W17、W18、W19和W20中的一者为CRA，一者为N，余下的两者均为CH，RA选自羟基、氨基、C1-6烷氧基、C1-6羟烷基和C1-6羟烷氧基；优选地，W17、W18、W19和W20中的一者为CRA，一者为N，余下的两者均为CH，RA为羟基或氨基。In some embodiments of the present disclosure, 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.
在本公开一些实施方案中，所述的式(C8)、(C9)、(C10)或(C11-1)所示的化合 物或其可药用的盐，其中W17为CRA，W19为CR7B，W18和W20中的一者为N，另一者为CR7B，RA选自羟基、氨基、C1-6羟烷基和C1-6羟烷氧基，R7B选自氢原子、卤素和C1-6烷基；优选地，W17为CRA，W18为N，W19和W20均为CR7B，RA选自羟基、氨基、C1-6羟烷基和C1-6羟烷氧基，R7B选自氢原子、卤素和C1-6烷基；更优选地，W17为CRA，W18为N，W19和W20均为CH，RA选自羟基、氨基、C1-6羟烷基和C1-6羟烷氧基。In some embodiments of the present disclosure, 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 hydroxyalkoxy.
在本公开一些实施方案中，所述的式(C11)或(C12)所示的化合物或其可药用的盐，其中W20为CRA，W19为N，W17和W18均为CR7B，RA选自羟基、氨基、C1-6羟烷基和C1-6羟烷氧基，R7B选自氢原子、卤素和C1-6烷基；优选地，W20为CRA，W19为N，W17和W18均为CH，RA选自羟基、氨基、C1-6羟烷基和C1-6羟烷氧基。In some embodiments of the present disclosure, 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.
在本公开一些实施方案中，所述的式(C11)、(C11-1)或(C12)所示的化合物或其可药用的盐，其中W15为N或CR8B，W16为NR9B，R8B选自氢原子、卤素和C1-6烷基，R9B为氢原子或C1-6烷基；优选地，W15为N或CH，W16为NH；更优选地，W15为CH，W16为NH。In some embodiments of the present disclosure, the compound represented by formula (C11), (C11-1) or (C12) or a pharmaceutically acceptable salt thereof, wherein W 15 is N or CR 8B and W 16 is NR 9B , R 8B is selected from hydrogen atom, halogen and C 1-6 alkyl group, R 9B is a hydrogen atom or C 1-6 alkyl group; preferably, W 15 is N or CH, W 16 is NH; more preferably, W 15 is CH and W 16 is NH.
在本公开一些实施方案中，所述的式(C1)至(C12)、(C11-1)、(C11-2)或(C8-1)所示的化合物或其可药用的盐，其中RA选自羟基、氨基、C1-6羟烷基和C1-6羟烷氧基；优选地，RA为羟基或氨基；最优选地，RA为羟基。In some embodiments of the present disclosure, the compound represented by formula (C1) to (C12), (C11-1), (C11-2) or (C8-1) or a pharmaceutically acceptable salt thereof, wherein RA is selected from hydroxyl, amino, C 1-6 hydroxyalkyl and C 1-6 hydroxyalkoxy; preferably, RA is hydroxyl or amino; most preferably, RA is hydroxyl.
在本公开一些实施方案中，所述的式(C1)至(C12)、(C11-1)、(C11-2)或(C8-1)所示的化合物或其可药用的盐，其中各个R1B、R2B、R4B、R5B、R6B、R7B、R8B、RW和R0在每次出现时相同或不同，且各自独立地选自氢原子、卤素或C1-6烷基；优选地，R1B、R2B、R4B、R5B、R6B、R7B、R8B、RW和R0在每次出现时均为氢原子。In some embodiments of the present disclosure, 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.
在本公开一些实施方案中，所述的式(C1)至(C12)、(C11-1)、(C11-2)或(C8-1)所示的化合物或其可药用的盐，其中R3B和R9B在每次出现时相同或不同，且各自独立地为氢原子或C1-6烷基；优选地，R3B和R9B在每次出现时均为氢原子。In some embodiments of the present disclosure, 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.
在本公开一些实施方案中，所述的式(C13-1)、(C13-2)或(C13-3)所示的化合物或其可药用的盐，其中W21为N，且W22为CR5b；或，W22为N，且W21为CR5b；或，W21和W22均为CR5b，R5b选自氢原子、卤素和C1-6烷基；优选地，W21为N，且W22为CR5b；R5b选自氢原子、卤素和C1-6烷基；更优选地，W21为N，且W22为CH。In some embodiments of the present disclosure, the compound represented by formula (C13-1), (C13-2) or (C13-3) or a pharmaceutically acceptable salt thereof, wherein W 21 is N, and W 22 is CR 5b ; or, W 22 is N, and W 21 is CR 5b ; or, W 21 and W 22 are both CR 5b , and R 5b is selected from hydrogen atoms, halogens and C 1-6 alkyl groups; preferably, W 21 is N, and W 22 is CR 5b ; R 5b is selected from hydrogen atom, halogen and C 1-6 alkyl group; more preferably, W 21 is N, and W 22 is CH.
在本公开一些实施方案中，所述的式(C13-1)、(C13-2)或(C13-3)所示的化合物或其可药用的盐，其中W21为N，且W22为CH；或，W22为N，且W21为CH；或，W21和W22均为CH。In some embodiments of the present disclosure, the compound represented by formula (C13-1), (C13-2) or (C13-3) or a pharmaceutically acceptable salt thereof, wherein W 21 is N, and W 22 is CH; or, W 22 is N, and W 21 is CH; or, W 21 and W 22 are both CH.
在本公开一些实施方案中，所述的式(C14-1)或(C14-2)所示的化合物或其可药用的盐，其中W23为N或CR6b，W24为NR7b，R6b选自氢原子、卤素和C1-6烷基，R7b为氢原子或C1-6烷基；优选地，W23为N或CH，W24为NH；更优选地，W23 为CH，W24为NH。In some embodiments of the present disclosure, 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.
在本公开一些实施方案中，所述的式(C13-1)、(C13-2)、(C13-3)、(C14-1)或(C14-2)所示的化合物或其可药用的盐，其中t为0或1，且q为1或2；优选地，t为0，且q为1或2。In some embodiments of the present disclosure, the compound represented by formula (C13-1), (C13-2), (C13-3), (C14-1) or (C14-2) or a pharmaceutically acceptable compound thereof A salt where t is 0 or 1 and q is 1 or 2; preferably, t is 0 and q is 1 or 2.
在本公开一些实施方案中，所述的式(C13-1)、(C13-2)、(C13-3)、(C14-1)或(C14-2)所示的化合物或其可药用的盐，其中各个R1b、R2b、R3b、R4b、R5b和R6b在每次出现时相同或不同，且各自独立地选自氢原子、卤素和C1-6烷基，R7b选自氢原子、C1-6烷基和卤代C1-6烷基；优选地，R1b、R2b、R3b、R4b、R5b、R6b和R7b在每次出现时均为氢原子。In some embodiments of the present disclosure, 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.
在本公开一些实施方案中，所述的通式(I)、(II)、(II-1)或(III)所示的化合物或其可药用的盐，其中Ra选自氢原子、卤素、C1-6烷基、C1-6烷氧基、卤代C1-6烷基、卤代C1-6烷氧基、C1-6羟烷基、3至10元环烷基和3至10元杂环基；优选地，Ra选自氢原子、卤素、C1-6烷基和卤代C1-6烷基；进一步优选地，Ra为C1-6烷基或卤代C1-6烷基；最优选地，Ra为CH3或CF3；In some embodiments of the present disclosure, 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 ;
在一些实施方案中，Ra为C1-6烷基；优选地，Ra为CH3。In some embodiments, Ra is C 1-6 alkyl; preferably, Ra is CH 3 .
在本公开一些实施方案中，所述的通式(I)、(II)、(II-1)或(III)所示的化合物或其可药用的盐，其中Rb选自氢原子、卤素、C1-6烷基、C1-6烷氧基、卤代C1-6烷基、卤代C1-6烷氧基、C1-6羟烷基、3至10元环烷基和3至10元杂环基；优选地，Rb选自氢原子、卤素、C1-6烷基和卤代C1-6烷基；进一步优选地，Rb为C1-6烷基或卤代C1-6烷基；最优选地，Rb为CH3或CF3；In some embodiments of the present disclosure, 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 ;
在一些实施方案中，Rb为卤代C1-6烷基；优选地，Rb为CF3。In some embodiments, R b is haloC 1-6 alkyl; preferably, R b is CF 3 .
在本公开一些实施方案中，所述的通式(I)、(II)、(II-1)或(III)所示的化合物或其可药用的盐，其中Rc选自氢原子、卤素、C1-6烷基、C1-6烷氧基、卤代C1-6烷基、卤代C1-6烷氧基、C1-6羟烷基、3至10元环烷基和3至10元杂环基；优选地，Rc选自氢原子、卤素、C1-6烷基和卤代C1-6烷基；进一步优选地，Rc为氢原子或C1-6烷基；更进一步优选地，Rc为氢原子或CH3；最优选地，Rc为氢原子。In some embodiments of the present disclosure, the compound represented by the general formula (I), (II), (II-1) or (III) or a pharmaceutically acceptable salt thereof, wherein R c 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 c is selected from hydrogen atom, halogen, C 1-6 alkyl group and halogenated C 1-6 alkyl group; further preferably, R c is a hydrogen atom or C 1 -6 alkyl; further preferably, R c is a hydrogen atom or CH 3 ; most preferably, R c is a hydrogen atom.
在本公开一些实施方案中，所述的通式(I)、(II)、(II-1)或(III)所示的化合物或其可药用的盐，其中Rd选自氢原子、卤素、C1-6烷基、C1-6烷氧基、卤代C1-6烷基、卤代C1-6烷氧基、C1-6羟烷基、3至10元环烷基和3至10元杂环基；优选地，Rd选自氢原子、卤素、C1-6烷基和卤代C1-6烷基；更优选地，Rd为氢原子或C1-6烷基；进一步优选地，Rd为氢原子或CH3；在一些实施方案中，Rd为C1-6烷基；在一些实施方案中，Rd为CH3。In some embodiments of the present disclosure, the compound represented by the general formula (I), (II), (II-1) or (III) or a pharmaceutically acceptable salt thereof, wherein R d 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 d is selected from hydrogen atom, halogen, C 1-6 alkyl group and halogenated C 1-6 alkyl group; more preferably, R d is a hydrogen atom or C 1 -6 alkyl; further preferably, R d is a hydrogen atom or CH 3 ; in some embodiments, R d is C 1-6 alkyl; in some embodiments, R d is CH 3 .
在本公开一些实施方案中，所述的通式(I)所示的化合物或其可药用的盐，其中Re选自氢原子、卤素、羟基、氰基和C1-6烷基；优选地，Re为氢原子。In some embodiments of the present disclosure, 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.
在本公开一些实施方案中，所述的通式(I)所示的化合物或其可药用的盐，其中Ra和Rb相同或不同，且各自独立地选自氢原子、C1-6烷基和卤代C1-6烷基；优 选地，Ra和Rb相同或不同，且各自独立地为C1-6烷基或卤代C1-6烷基；进一步优选地，Ra为C1-6烷基，且Rb为卤代C1-6烷基，最优选地，Ra为CH3，且Rb为CF3。In some embodiments of the present disclosure, 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 Optionally, 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 .
在本公开一些实施方案中，所述的通式(II)、(II-1)或(III)所示的化合物或其可药用的盐，其中Ra和Rb不同，且各自独立地选自氢原子、C1-6烷基和卤代C1-6烷基；优选地，Ra和Rb不同，且各自独立地为C1-6烷基或卤代C1-6烷基；进一步优选地，Ra为C1-6烷基，且Rb为卤代C1-6烷基，最优选地，Ra为CH3，且Rb为CF3；In some embodiments of the present disclosure, 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 ;
在一些实施方案中，Ra为卤代C1-6烷基，且Rb为C1-6烷基；优选地，Ra为CF3，且Rb为CH3。In some embodiments, R a is haloC 1-6 alkyl, and R b is C 1-6 alkyl; preferably, R a is CF 3 , and R b is CH 3 .
在本公开一些实施方案中，所述的通式(I)所示的化合物或其可药用的盐，其中Ra和Rb相同或不同，且各自独立地选自氢原子、CH3和CF3；在一些实施方案中，Ra和Rb相同或不同，且各自独立地为C1-6烷基；在一些实施方案中，Ra和Rb相同或不同，且各自独立地为卤代C1-6烷基。In some embodiments of the present disclosure, 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.
在本公开一些实施方案中，所述的通式(II)、(II-1)或(III)所示的化合物或其可药用的盐，其中Ra和Rb不同，且各自独立地选自氢原子、CH3和CF3；在一些实施方案中，Ra和Rb不同，且各自独立地为C1-6烷基；在一些实施方案中，Ra和Rb不同，且各自独立地为卤代C1-6烷基。In some embodiments of the present disclosure, 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, CH 3 and CF 3 ; in some embodiments, R a and R b are different, and each is independently C 1-6 alkyl; in some embodiments, R a and R b are different, and Each independently represents a halogenated C 1-6 alkyl group.
在本公开一些实施方案中，所述的通式(I)、(II)、(II-1)或(III)所示的化合物或其可药用的盐，其中Ra为卤代C1-6烷基，Rb为氢原子；在一些实施方案中，Ra为氢原子，Rb为卤代C1-6烷基；在一些实施方案中，Ra为氢原子，Rb为C1-6烷基；在一些实施方案中，Ra为C1-6烷基，Rb为氢原子。In some embodiments of the present disclosure, 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.
在本公开一些实施方案中，所述的通式(I)所示的化合物或其可药用的盐，其中Rc和Rd相同或不同，且各自独立地选自氢原子、C1-6烷基和3至6元环烷基；优选地，Rc和Rd相同或不同，且各自独立地为氢原子或C1-6烷基；进一步优选地，Rc为氢原子，且Rd为C1-6烷基；最优选地，Rc为氢原子，且Rd为CH3。In some embodiments of the present disclosure, 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 .
在本公开一些实施方案中，所述的通式(II)、(II-1)或(III)所示的化合物或其可药用的盐，其中Rc和Rd不同，且各自独立地选自氢原子、C1-6烷基和3至6元环烷基；优选地，Rc和Rd不同，且各自独立地为氢原子或C1-6烷基；进一步优选地，Rc为氢原子，且Rd为C1-6烷基；最优选地，Rc为氢原子，且Rd为CH3；在一些实施方案中，Rc和Rd不同，且各自独立地为氢原子或CH3。In some embodiments of the present disclosure, 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 .
在本公开一些实施方案中，所述的通式(I)、(II)、(II-1)或(III)所示的化合物或其可药用的盐，其中Rc为C1-6烷基，且Rd为氢原子；或Rc为CH3，且Rd为氢原子；在一些实施方案中，Rc为3至10元环烷基(优选为环丙基)，Rd为氢原子；在一些实施方案中，Rc为氢原子，Rd为3至10元环烷基(优选为环丙基)。In some embodiments of the present disclosure, 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).
在本公开一些实施方案中，所述的通式(I)所示的化合物或其可药用的盐，其中Rc和Rd相同或不同，且各自独立地为氢原子或CH3；在一些实施方案中，Rc和Rd均为氢原子。 In some embodiments of the present disclosure, 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.
在本公开一些实施方案中，所述的通式(I)、(II)、(II-1)或(III)所示的化合物或其可药用的盐，其中X为O。In some embodiments of the present disclosure, the compound represented by the general formula (I), (II), (II-1) or (III) or a pharmaceutically acceptable salt thereof, wherein X is O.
在本公开一些实施方案中，所述的通式(I)、(II)、(II-1)或(III)所示的化合物或其可药用的盐，其中R’为氢原子或C1-6烷基；优选地，R’为氢原子。In some embodiments of the present disclosure, the compound represented by the general formula (I), (II), (II-1) or (III) or a pharmaceutically acceptable salt thereof, wherein R' is a hydrogen atom or C 1-6 alkyl; preferably, R' is a hydrogen atom.
在本公开一些实施方案中，所述的通式(I)、(II)、(II-1)或(III)所示的化合物或其可药用的盐，其中R3和R4相同或不同，且各自独立地选自氢原子、C1-6烷基、卤代C1-6烷基和C1-6羟烷基；优选地，R3和R4相同或不同，且各自独立地为氢原子或C1-6烷基；进一步优选地，R3和R4均为氢原子。In some embodiments of the present disclosure, 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.
在本公开一些实施方案中，所述的通式(I)、(II)、(II-1)或(III)所示的化合物或其可药用的盐，其中R5选自氢原子、C1-6烷基、卤代C1-6烷基和C1-6羟烷基；优选地，R5为氢原子或C1-6烷基；进一步优选地，R5为氢原子。In some embodiments of the present disclosure, the compound represented by the general formula (I), (II), (II-1) or (III) or a pharmaceutically acceptable salt thereof, wherein R 5 is selected from a hydrogen atom, C 1-6 alkyl, halogenated C 1-6 alkyl and C 1-6 hydroxyalkyl; preferably, R 5 is a hydrogen atom or C 1-6 alkyl; further preferably, R 5 is a hydrogen atom.
在本公开一些实施方案中，所述的通式(I)、(II)、(II-1)或(III)所示的化合物或其可药用的盐，其中R6选自C1-6烷基、卤代C1-6烷基和C1-6羟烷基；优选地，R6为C1-6烷基；最优选地，R6为CH3。In some embodiments of the present disclosure, the compound represented by the general formula (I), (II), (II-1) or (III) or a pharmaceutically acceptable salt thereof, wherein R 6 is selected from C 1- 6 alkyl, halogenated C 1-6 alkyl and C 1-6 hydroxyalkyl; preferably, R 6 is C 1-6 alkyl; most preferably, R 6 is CH 3 .
在本公开一些实施方案中，所述的通式(I)、(II)、(II-1)或(III)所示的化合物或其可药用的盐，其中RX1选自氢原子、卤素、羟基、C1-6烷基、C1-6烷氧基、卤代C1-6烷基、卤代C1-6烷氧基、3至6元环烷基、4至7元杂环基、3至6元环烷基氧基和4至7元杂环基氧基，所述的3至6元环烷基、4至7元杂环基、3至6元环烷基氧基和4至7元杂环基氧基各自独立地任选被1个或多个R03所取代，各个R03相同或不同，且各自独立地选自卤素、C1-6烷基和卤代C1-6烷基；优选地，RX1选自羟基、C1-6烷氧基和卤代C1-6烷氧基；进一步优选地，RX1为C1-6烷氧基；最优选地，RX1为甲氧基。In some embodiments of the present disclosure, the compound represented by the general formula (I), (II), (II-1) or (III) or a pharmaceutically acceptable salt thereof, wherein R X1 is selected from a hydrogen atom, Halogen, hydroxyl, C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkyl, halogenated C 1-6 alkoxy, 3 to 6-membered cycloalkyl, 4 to 7-membered Heterocyclyl, 3 to 6-membered cycloalkyloxy and 4 to 7-membered heterocyclyloxy, the 3 to 6-membered cycloalkyl, 4 to 7-membered heterocyclyl, 3 to 6-membered cycloalkyl 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 1-6 alkyl; preferably, R X1 is selected from hydroxyl, C 1-6 alkoxy and halogenated C 1-6 alkoxy; further preferably, R ; Most preferably, R X1 is methoxy.
在本公开一些实施方案中，所述的通式(I)、(II)、(II-1)或(III)所示的化合物或其可药用的盐，其中RX2选自氢原子、卤素、C1-6烷基、C1-6烷氧基、卤代C1-6烷基、卤代C1-6烷氧基、3至6元环烷基和4至7元杂环基；优选地，RX2选自氢原子、卤素、C1-6烷基和卤代C1-6烷基；进一步优选地，RX2为卤素；最优选地，RX2为氟原子。In some embodiments of the present disclosure, the compound represented by the general formula (I), (II), (II-1) or (III) or a pharmaceutically acceptable salt thereof, wherein R Halogen, C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkyl, halogenated C 1-6 alkoxy, 3 to 6 - membered cycloalkyl and 4 to 7-membered heterocycle group ; preferably , R
在本公开一些实施方案中，所述的通式(I)、(II)、(II-1)或(III)所示的化合物或其可药用的盐，其中RX3选自氢原子、卤素、C1-6烷基、C1-6烷氧基、卤代C1-6烷基、卤代C1-6烷氧基、3至6元环烷基和4至7元杂环基；优选地，RX3选自氢原子、卤素、C1-6烷基和卤代C1-6烷基；进一步优选地，RX3为卤素；最优选地，RX3为氟原子。In some embodiments of the present disclosure, the compound represented by the general formula (I), (II), (II-1) or (III) or a pharmaceutically acceptable salt thereof, wherein R Halogen, C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkyl, halogenated C 1-6 alkoxy, 3 to 6 - membered cycloalkyl and 4 to 7-membered heterocycle group ; preferably , R
在本公开一些实施方案中，所述的通式(I)所示的化合物或其可药用的盐，其中RX4和RX5各自独立地选自氢原子、卤素、C1-6烷基、C1-6烷氧基、卤代C1-6烷基和卤代C1-6烷氧基；优选地，RX4和RX5均为氢原子。In some embodiments of the present disclosure, 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.
在本公开一些实施方案中，所述的通式(I)、(II)、(II-1)或(III)所示的化合物或 其可药用的盐，其中n选自0、1、2和3；优选地，n为0或1，进一步优选地n为0。In some embodiments of the present disclosure, the compound represented by the general formula (I), (II), (II-1) or (III) or Its pharmaceutically acceptable salt, wherein n is selected from 0, 1, 2 and 3; preferably, n is 0 or 1, and further preferably n is 0.
在本公开一些实施方案中，所述的通式(I)、(II)、(II-1)或(III)所示的化合物或其可药用的盐，其中s选自0、1、2和3；优选地，s为0或1，进一步优选地s为0。In some embodiments of the present disclosure, the compound represented by the general formula (I), (II), (II-1) or (III) or a pharmaceutically acceptable salt thereof, wherein s is selected from 0, 1, 2 and 3; preferably, s is 0 or 1, and further preferably s is 0.
在本公开一些实施方案中，所述的通式(I)、(II)或(II-1)所示的化合物或其可药用的盐，r选自0、1和2；优选地，r为0或1，最优选地，r为0。In some embodiments of the present disclosure, in the compound represented by general formula (I), (II) or (II-1) or a pharmaceutically acceptable salt thereof, r is selected from 0, 1 and 2; preferably, r is 0 or 1, most preferably r is 0.
在本公开一些实施方案中，所述的通式(I)、(II)、(II-1)或(III)所示的化合物或其可药用的盐，v为1或2；优选地，v为2。In some embodiments of the present disclosure, the compound represented by the general formula (I), (II), (II-1) or (III) or a pharmaceutically acceptable salt thereof, v is 1 or 2; preferably , v is 2.
在本公开一些实施方案中，所述的通式(II)所示的化合物或其可药用的盐，其中，Ra为C1-6烷基；Rb为卤代C1-6烷基；Rc为氢原子；Rd为C1-6烷基；X为O；In some embodiments of the present disclosure, 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’为氢原子或C1-6烷基；环Cy为*端与-C(O)NR’-连接，在化合价允许的范围内RA和RB连接至环Cy的任意位置；RA为羟基或氨基；RX1为C1-6烷氧基；RX2为卤素；RX3为卤素；r为0。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.
在本公开一些实施方案中，所述的通式(II)所示的化合物或其可药用的盐，其中，Ra为C1-6烷基；Rb为卤代C1-6烷基；Rc为氢原子；Rd为C1-6烷基；X为O；R’为氢原子或C1-6烷基；选自 RA为氢原子、羟基或氨基，*端与-C(O)NR’-连接；RX1为C1-6烷氧基；RX2为卤素；RX3为卤素。In some embodiments of the present disclosure, 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.
在本公开一些实施方案中，所述的通式(II)所示的化合物或其可药用的盐，其中，Ra为C1-6烷基；Rb为卤代C1-6烷基；Rc为氢原子；Rd为C1-6烷基；RX1为C1-6烷氧基；RX2为卤素；RX3为卤素；X为O；R’为氢原子或C1-6烷基；选自 RC为氢原子或RB，RA选自卤素、羟基和-NR3R4，R3和R4相同或不同，且各自独立地为氢原子或C1-6烷基；各个RB相同或不同，且各自独立地选自卤素、C1-6烷基和卤代C1-6烷基，且r选自0、1和2；*端与-C(O)NR’-连接。In some embodiments of the present disclosure, 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 selected from 0, 1 and 2; * end is connected to -C(O)NR'- .
在本公开一些实施方案中，所述的通式(II)所示的化合物或其可药用的盐，其中，Ra为CH3；Rb为CF3；Rc为氢原子；Rd为CH3；RX1为甲氧基；RX2为卤素；RX3为卤素；X为O；R’为氢原子；选自 In some embodiments of the present disclosure, 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
表A本公开的典型化合物包括但不限于：










Table A Typical compounds of the present disclosure include, but are not limited to:










本公开的另一方面涉及通式(I-A)所示的化合物或其盐，
Another aspect of the present disclosure relates to compounds represented by general formula (IA) or salts thereof,
其中，R9为C1-6烷基； Among them, R 9 is C 1-6 alkyl;
环Cy、RB、R’、X、Ra、Rb、Rc、Rd、Re、X1、X2、X3、X4、X5和r如通式(I)中所定义。Ring Cy, R B , R', X, R a , R b , R c , R d , Re , X 1 , X 2 , X 3 , X 4 , definition.
本公开的另一方面涉及通式(II-A)所示的化合物或其盐，
Another aspect of the present disclosure relates to a compound represented by general formula (II-A) or a salt thereof,
其中，R9为C1-6烷基；Among them, R 9 is C 1-6 alkyl;
环Cy、RB、R’、X、Ra、Rb、Rc、Rd、RX1、RX2、RX3和r如通式(II)中所定义。Rings Cy, RB , R' , X, Ra, Rb, Rc, Rd, RX1, RX2 , RX3 and r are as defined in general formula (II).
本公开的另一方面涉及通式(II-1A)所示的化合物或其盐，
Another aspect of the present disclosure relates to a compound represented by general formula (II-1A) or a salt thereof,
其中，in,
R11、R12和R13均为氨基保护基，优选为Boc；R 11 , R 12 and R 13 are all amino protecting groups, preferably Boc;
R’、X、Ra、Rb、Rc、Rd、RX1、RX2和RX3如通式(II-1)中所定义。R', X, Ra , Rb , Rc , Rd , R
表B本公开的典型中间体化合物包括但不限于：


Table B Typical intermediate compounds of the present disclosure include, but are not limited to:


本公开另一方面涉及一种制备上述通式(I)所示的化合物或其可药用的盐的方法，该方法包括：
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:
通式(Ia)所示的化合物或其盐与通式(Ib)所示的化合物或其盐进行缩合反应得到通式(I)所示的化合物或其可药用的盐，其中，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,
R10为卤素(优选为氯原子)或OH；R 10 is halogen (preferably chlorine atom) or OH;
环Cy、RA、RB、R’、Ra、Rb、Rc、Rd、Re、X、X1、X2、X3、X4、X5和r如通式(I)中所定义。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.
本公开的另一方面涉及一种制备上述通式(I)所示的化合物或其可药用的盐的方法，该方法包括：
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:
通式(I-A)所示的化合物或其盐发生氨解或水解反应得到通式(I)所示的化合物或其可药用的盐，其中，The compound represented by general formula (I-A) or a salt thereof undergoes an ammonolysis or hydrolysis reaction to obtain a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof, wherein,
RA为羟基或氨基；R9为C1-6烷基；R A is hydroxyl or amino; R 9 is C 1-6 alkyl;
环Cy、RB、R’、Ra、Rb、Rc、Rd、Re、X、X1、X2、X3、X4、X5和r如通式(I)中所定义。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.
本公开的另一方面涉及一种制备上述通式(II)所示的化合物或其可药用的盐的方法，该方法包括：
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:
通式(IIa)所示的化合物或其盐与通式(Ib)所示的化合物或其盐进行缩合反应得到通式(II)所示的化合物或其可药用的盐，其中，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,
R10为卤素(优选为氯原子)或OH；R 10 is halogen (preferably chlorine atom) or OH;
环Cy、RA、RB、R’、Ra、Rb、Rc、Rd、X、RX1、RX2、RX3和r如通式(II)中所定义。Rings Cy, RA , RB , R' , Ra, Rb , Rc , Rd , X, RX1 , RX2 , RX3 and r are as defined in general formula (II).
本公开的另一方面涉及一种制备上述通式(II)所示的化合物或其可药用的盐的方法，该方法包括：
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:
通式(II-A)所示的化合物或其盐发生氨解或水解反应得到通式(II)所示的化合物或其可药用的盐，其中，The compound represented by general formula (II-A) or a salt thereof undergoes an ammonolysis or hydrolysis reaction to obtain a compound represented by general formula (II) or a pharmaceutically acceptable salt thereof, wherein,
RA为羟基或氨基；R9为C1-6烷基；R A is hydroxyl or amino; R 9 is C 1-6 alkyl;
环Cy、RB、R’、X、Ra、Rb、Rc、Rd、RX1、RX2、RX3和r如通式(II)中所定义。 Rings Cy, RB , R' , X, Ra, Rb, Rc, Rd, RX1, RX2 , RX3 and r are as defined in general formula (II).
本公开的另一方面涉及一种制备上述通式(II-1)所示的化合物或其可药用的盐的方法，该方法包括：
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:
通式(II-1A)所示的化合物或其盐脱去氨基保护基得到通式(II-1)所示的化合物或其可药用的盐，其中，The compound represented by the general formula (II-1A) or a salt thereof is removed from the amino protecting group to obtain a compound represented by the general formula (II-1) or a pharmaceutically acceptable salt thereof, wherein,
R11、R12和R13均为氨基保护基，优选为Boc；R 11 , R 12 and R 13 are all amino protecting groups, preferably Boc;
R’、X、Ra、Rb、Rc、Rd、RX1、RX2和RX3如通式(II-1)中所定义。R', X, Ra , Rb , Rc , Rd , R
本公开的另一方面涉及一种制备上述通式(III)所示的化合物或其可药用的盐的方法，该方法包括：
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:
通式(IIa)所示的化合物或其盐与通式(IIIb)所示的化合物或其盐(优选为盐酸盐或三氟乙酸盐)进行缩合反应得到通式(III)所示的化合物或其可药用的盐，其中，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,
其中，R10为卤素(优选为氯原子)或OH；Wherein, R 10 is halogen (preferably chlorine atom) or OH;
R’、X、Ra、Rb、Rc、Rd、RX1、RX2、RX3、RB、p、环A、Q1、Q2、Q3、---、Y、Raa和y如通式(III)中所定义。 R ', X , R a , R b , R c , R d , R X1 , R aa and y are as defined in general formula (III).
本公开的另一方面涉及一种药物组合物，所述药物组合物含有本公开通式(I)、(II)、(II-1)、(III)或表A中所示的化合物或其可药用的盐，以及一种或多种药学上可接受的载体、稀释剂或赋形剂。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.
本公开进一步涉及通式(I)、(II)、(II-1)、(III)或表A中所示的化合物或其可药用的盐、或包括其的药物组合物在制备抑制电压门控钠通道的药物中的用途；优选地，所述电压门控钠通道为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 inhibitory voltage Use of gated sodium channels in drugs; preferably, the voltage-gated sodium channel is Nav1.8.
本公开进一步涉及通式(I)、(II)、(II-1)、(III)或表A中所示的化合物或其可药用的盐、或包括其的药物组合物在制备用于治疗和/或预防由电压门控钠通道介导的疾病或病症的药物中的用途，优选地，所述电压门控钠通道为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. Preferably, the voltage-gated sodium channel is Nav1.8.
本公开进一步涉及通式(I)、(II)、(II-1)、(III)或表A中所示的化合物或其可药用的盐、或包括其的药物组合物在制备治疗和/或减轻疼痛和疼痛相关疾病、多发性硬化症、夏-马-图三氏综合症、失禁、病理咳嗽或心律失常的药物中的用途；优 选地，所述疼痛选自慢性疼痛、急性疼痛、炎性疼痛、癌症疼痛、术后疼痛、神经性疼痛、肌肉骨骼痛、原发性疼痛、肠痛和特发性疼痛；所述术后疼痛优选选自拇囊炎切除术疼痛、疝修补术疼痛和腹部整形术疼痛。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 Optionally, 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.
本公开进一步涉及一种抑制电压门控钠通道的方法，其包括给予所需患者通式(I)、(II)、(II-1)、(III)或表A所示的化合物或其可药用的盐、或包括其的药物组合物；优选地，所述电压门控钠通道为Nav1.8。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. Pharmaceutically acceptable salts, or pharmaceutical compositions including the same; preferably, the voltage-gated sodium channel is Nav1.8.
本公开进一步涉及一种治疗和/或预防由电压门控钠通道介导的疾病或病症的方法，其包括给予所需患者通式(I)、(II)、(II-1)、(III)或表A所示的化合物或其可药用的盐、或包括其的药物组合物；优选地，所述电压门控钠通道为Nav1.8。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.
本公开进一步涉及一种治疗和/或减轻疼痛和疼痛相关疾病、多发性硬化症、夏-马-图三氏综合症、失禁、病理咳嗽和心律失常的方法，其包括给予所需患者通式(I)、(II)、(II-1)、(III)或表A所示的化合物或其可药用的盐、或包括其的药物组合物；优选地，所述疼痛选自慢性疼痛、急性疼痛、炎性疼痛、癌症疼痛、术后疼痛、神经性疼痛、肌肉骨骼痛、原发性疼痛、肠痛和特发性疼痛；所述术后疼痛优选选自拇囊炎切除术疼痛、疝修补术疼痛和腹部整形术疼痛。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.
本公开进一步涉及一种通式(I)、(II)、(II-1)、(III)或表A所示的化合物或其可药用的盐、或包括其的药物组合物，其用作药物。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.
本公开进一步涉及一种通式(I)、(II)、(II-1)、(III)或表A所示的化合物或其可药用的盐、或包括其的药物组合物，其用于抑制电压门控钠通道；优选地，所述电压门控钠通道为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 inhibiting voltage-gated sodium channels; preferably, the voltage-gated sodium channel is Nav1.8.
本公开进一步涉及一种通式(I)、(II)、(II-1)、(III)或表A所示的化合物或其可药用的盐、或包括其的药物组合物，其用于治疗和/或预防由电压门控钠通道介导的疾病或病症；优选地，所述电压门控钠通道为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.
本公开进一步涉及一种通式(I)、(II)、(II-1)、(III)或表A所示的化合物或其可药用的盐、或包括其的药物组合物，其用于治疗和/或预防疼痛和疼痛相关疾病、多发性硬化症、夏-马-图三氏综合症、失禁、病理咳嗽或心律失常；优选地，所述疼痛选自慢性疼痛、急性疼痛、炎性疼痛、癌症疼痛、神经性疼痛、肌肉骨骼痛、原发性疼痛、肠痛和特发性疼痛；所述术后疼痛优选选自拇囊炎切除术疼痛、疝修补术疼痛和腹部整形术疼痛。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 the treatment and/or prevention of pain and pain-related diseases, multiple sclerosis, Schein-Marie-Touch syndrome, incontinence, pathological cough or arrhythmia; preferably, 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.
本公开所述的疾病或病症是通过抑制电压门控钠通道来治疗和/或预防的疾病或病症；优选地，所述电压门控钠通道为Nav1.8。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.
优选地，本公开所述的由电压门控钠通道介导的疾病或病症为疼痛和疼痛相关疾病、多发性硬化症、夏-马-图三氏综合症、失禁或心律失常；优选地，所述疼痛选自慢性疼痛、急性疼痛、炎性疼痛、癌症疼痛、神经性疼痛、肌肉骨骼痛、原发性疼痛、肠痛和特发性疼痛。Preferably, 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.
本公开中所述的神经性疼痛优选选自三叉神经痛、疱疹后神经痛、糖尿病性 神经痛、痛性HIV相关性感觉神经痛、灼伤综合症、截肢术后疼痛、脊髓损伤后疼痛、幻痛、痛性神经瘤、创伤性神经瘤、莫顿(Morton)神经瘤、神经挤压损伤、脊管狭窄、腕管综合症、神经根痛、坐骨神经痛、神经撕脱伤、臂丛撕脱伤、复杂性区域疼痛综合征、药物疗法引起的神经痛、癌症化学疗法引起的神经痛、抗逆转录病毒疗法引起的神经痛、原发性小纤维神经病变、原发性感觉神经痛和三叉自主神经性头痛。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.
本公开中所述的肌肉骨骼痛优选选自骨关节炎疼痛、背痛、冷痛、灼烧疼痛和牙痛。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.
本公开中所述的肠痛优选选自发炎性肠病疼痛、克罗恩病疼痛或间质性膀胱炎疼痛。Intestinal pain described in the present disclosure is preferably selected from inflammatory bowel disease pain, Crohn's disease pain or interstitial cystitis pain.
本公开中所述的炎性疼痛优选选自类风湿性关节炎疼痛和外阴痛。The inflammatory pain described in this disclosure is preferably selected from the group consisting of rheumatoid arthritis pain and vulvodynia.
本公开中所述的特发性疼痛包括纤维肌痛。Idiopathic pain as described in this disclosure includes fibromyalgia.
本公开中所述急性疼痛包括急性术后疼痛。Acute pain as used in this disclosure includes acute postoperative pain.
本公开中所述术后疼痛包括关节置换疼痛、软组织手术疼痛、拇囊炎切除术疼痛、疝修补术疼痛和腹部整形术疼痛；优选选自拇囊炎切除术疼痛、疝修补术疼痛和腹部整形术疼痛。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.
所述神经性疼痛为糖尿病性周围神经痛或小纤维神经痛。The neuropathic pain is diabetic peripheral neuralgia or small fiber neuralgia.
本公开所述的疾病或病症选自急性疼痛、慢性疼痛、神经性疼痛、炎性疼痛、关节炎、偏头痛、丛集性头痛、三叉神经痛、疱疹性神经痛、一般神经痛、癫痫症、癫痫症疾患、神经退行性病症、精神病症、焦虑症、抑郁症、躁郁症、肌强直、心律失常、运动障碍、神经内分泌病症、共济失调、多发性硬化症、肠易激综合征、失禁、病理性咳嗽、内脏疼痛、骨关节炎疼痛、疱疹后神经痛、糖尿病性神经病、神经根疼痛、坐骨神经痛、背痛、头痛、颈痛、严重疼痛、顽固性疼痛、伤害感受性疼痛、爆发性疼痛、手术后疼痛、癌症疼痛、中风、大脑缺血、创伤性脑损伤、肌萎缩性侧索硬化症、应激诱导性心绞痛、运动诱导性心绞痛、心悸、高血压或异常胃肠运动。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.
本公开中所述疼痛和疼痛相关疾病选自股骨癌症疼痛、非恶性慢性骨痛、类风湿性关节炎、骨关节炎、椎管狭窄、神经性腰痛、肌筋膜疼痛综合征、肌肉纤维疼痛、颞下颌关节疼痛、慢性内脏疼痛、腹痛、胰脏疼痛、IBS疼痛、慢性和急性头痛、偏头痛、紧张性头痛、从集性头痛、慢性和急性神经性疼痛、疱疹后神经痛、糖尿病性神经病、HIV相关神经病、三叉神经痛、恰克-马利-杜斯神经病、遗传性感觉神经病、周围神经损伤、疼痛性神经瘤、异位近端和远端放电、神经根病变、化学疗法诱导性神经性疼痛、放射疗法诱导性神经性疼痛、乳房切除后疼痛、中枢性疼痛、脊髓损伤疼痛、中风后疼痛、丘脑疼痛、复杂性局部疼痛综合征、幻痛、幻肢痛、顽固性疼痛、急性疼痛、急性手术后疼痛、急性肌肉骨骼痛、关节疼痛、机械性下背痛、颈痛、肌腱炎、损伤性疼痛、运动疼痛、急性内 脏疼痛、肾盂肾炎、阑尾炎、胆囊炎、肠梗阻、疝气、胸痛、心脏疼痛、骨盆疼痛、肾绞痛、急性分娩疼痛、产痛、剖腹产疼痛、急性炎性疼痛、烧伤性疼痛、创伤性疼痛、急性间歇性疼痛、子宫内膜异位、急性带状疱疹疼痛、镰状细胞贫血、急性胰脏炎、爆发性疼痛、口面部疼痛、鼻窦炎疼痛、牙齿疼痛、多发性硬化症(MS)疼痛、抑郁症中的疼痛、麻疯病疼痛、白塞氏病(Behcet's disease)疼痛、痛性肥胖症、静脉炎性疼痛、格林-巴利疼痛(Guillain-Barre pain)、腿痛和趾动症、哈格伦德综合征(Haglund syndrome)、红斑性肢痛、法布里病疼痛(Fabry's disease pain)、膀胱和泌尿生殖疾病、尿失禁、病理性咳嗽、高反应性膀胱、疼痛性膀胱综合征、间质性膀胱炎(IC)、前列腺炎、I型复杂性局部疼痛综合征(CRPS)、II型复杂性局部疼痛综合征(CRPS)、广泛性疼痛、阵发性剧痛、瘙痒症、耳鸣或绞痛诱导性疼痛。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, appendicitis, cholecystitis, intestinal obstruction, hernia, chest pain, heart pain, pelvic pain, renal colic, acute labor pain, labor pain, caesarean section pain, acute inflammatory pain, burn pain, traumatic pain , acute intermittent pain, endometriosis, acute herpes zoster pain, sickle cell anemia, acute pancreatitis, breakthrough pain, orofacial pain, sinusitis pain, dental pain, multiple sclerosis (MS) Pain, pain in depression, leprosy pain, Behcet's disease pain, painful obesity, phlebitis pain, Guillain-Barre pain, leg pain and toe movements syndrome, Haglund syndrome, erythromelalgia, Fabry's disease pain, bladder and genitourinary disorders, urinary incontinence, pathological cough, hyperresponsive bladder, painful bladder syndrome, interstitial cystitis (IC), prostatitis, complex regional pain syndrome type I (CRPS), complex regional pain syndrome type II (CRPS), generalized pain, paroxysmal severe pain, pruritus symptoms, tinnitus, or colic-induced pain.
本公开所述的疾病或病症选自急性疼痛、亚急性和慢性疼痛、伤害性疼痛、神经性疼痛、炎性疼痛、伤害性疼痛、关节炎、偏头痛、丛集性头痛、三叉神经痛、疱疹性神经痛、一般神经痛、癫痫、癫痫病症、神经退行性病症、精神病症、焦虑、抑郁、躁郁症、肌强直、心律失常、运动障碍、神经退行性疾病、内分泌失调、共济失调、多发性硬化症和肠易激综合征的中枢神经性疼痛、失禁、病理性咳嗽、内脏痛、骨关节炎疼痛、带状疱疹后神经痛、糖尿病神经病变、神经根痛、坐骨神经痛、背痛、非特异性慢性背痛、头部疼痛、颈部疼痛、中度疼痛、重度疼痛、顽固性疼痛、伤害性疼痛、突破性疼痛、术后疼痛、癌症疼痛(包括慢性癌症疼痛和突破性癌症疼痛)、中风(例如中风后中枢神经性疼痛)、颈椎扭伤相关疾病、脆性骨折、脊柱骨折、强直性脊柱炎、天疱疮、雷诺氏病、硬皮病、系统性红斑狼疮、大疱性表皮松解症、痛风、幼年特发性关节炎、风湿性多肌痛、坏疽性脓皮病、慢性广泛性疼痛、弥漫性特发性骨骼肥厚、椎间盘退变/突出疼痛、神经根病、小关节综合征、背部手术失败综合征、烧伤、腕管综合征、佩吉特病疼痛、椎管狭窄、椎间盘炎、横贯性脊髓炎、埃勒斯-当洛斯综合征、法布里病、肥大细胞增多症、神经纤维瘤病、眼部神经性疼痛、结节病、脊椎峡部裂、脊椎滑脱、化疗引起的口腔粘膜炎、夏科神经性骨关节病、颞下颌关节紊乱、关节置换术疼痛、非心源性胸痛、阴部痛、肾绞痛、胆道疾病、血管性腿部溃疡、帕金森病疼痛、阿尔茨海默病疼痛、脑缺血、创伤性脑损伤、肌萎缩性侧索硬化症、应激诱发的心绞痛、运动诱发的心绞痛、心悸、高血压或胃肠动力异常。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 ), stroke (e.g. post-stroke central neuropathic pain), cervical sprain-related disorders, fragility fractures, spinal fractures, ankylosing spondylitis, pemphigus, Raynaud's disease, scleroderma, systemic lupus erythematosus, bullous epidermis Lysis, gout, juvenile idiopathic arthritis, polymyalgia rheumatica, pyoderma gangrenosum, chronic widespread pain, diffuse idiopathic skeletal hypertrophy, disc degeneration/herniation pain, radiculopathy, small Joint syndrome, failed back surgery syndrome, burns, carpal tunnel syndrome, Paget's disease pain, spinal stenosis, discitis, transverse myelitis, Ehlers-Danlos syndrome, Fabry disease, hypertrophy Cytosis, neurofibromatosis, ocular neuropathic pain, sarcoidosis, spondylolysis, spondylolisthesis, chemotherapy-induced oral mucositis, Charcot neuroarthropathy, temporomandibular joint disorders, joint replacement pain , noncardiac chest pain, pudendal pain, renal colic, biliary tract disease, vascular leg ulcers, Parkinson's disease pain, Alzheimer's disease pain, cerebral ischemia, traumatic brain injury, amyotrophic lateral sclerosis disease, stress-induced angina, exercise-induced angina, palpitations, hypertension, or abnormal gastrointestinal motility.
可将活性化合物制成适合于通过任何适当途径给药的形式，通过常规方法使用一种或多种药学上可接受的载体来配制本公开的组合物。因此，本公开的活性化合物可以配制成用于口服给药、注射(例如静脉内、肌肉内或皮下)给药，吸入或吹入给药的各种剂型。本公开的化合物也可以配制成例如片剂、硬或软胶囊、水性或油性混悬液、乳剂、注射液、可分散性粉末或颗粒、栓剂、锭剂或糖浆等剂型。 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.
作为一般性指导，本公开的活性化合物优选是以单位剂量的方式，或者是以患者可以以单剂自我给药的方式。本公开化合物或组合物的单位剂量的表达方式可以是片剂、胶囊、扁囊剂、瓶装药水、药粉、颗粒剂、锭剂、栓剂、再生药粉或液体制剂。合适的单位剂量可以是0.1～1000mg。As a general guide, 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.
本公开的药物组合物除活性化合物外，可含有一种或多种辅料，所述辅料选自以下成分：填充剂(稀释剂)、粘合剂、润湿剂、崩解剂或赋形剂等。根据给药方法的不同，组合物可含有0.1至99重量％的活性化合物。In addition to the active compound, 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. Depending on the method of administration, the composition may contain from 0.1 to 99% by weight of active compound.
在一些实施方案中，所述的药物组合物的单位剂量为0.001mg-1000mg。In some embodiments, the unit dosage of the pharmaceutical composition is 0.001 mg-1000 mg.
在某些实施方案中，基于组合物的总重量，所述的药物组合物含有0.01-99.99％的前述化合物或其可药用的盐或其同位素取代物。在某些实施方案中，所述的药物组合物含有0.1-99.9％的前述化合物或其可药用的盐或其同位素取代物。在某些实施方案中，所述的药物组合物含有0.5％-99.5％的前述化合物或其可药用的盐或其同位素取代物。在某些实施方案中，所述的药物组合物含有1％-99％的前述化合物或其可药用的盐或其同位素取代物。在某些实施方案中，所述的药物组合物含有2％-98％的前述化合物或其可药用的盐或其同位素取代物。In certain embodiments, 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.
在某些实施方案中，基于组合物的总重量，所述的药物组合物含有0.01％-99.99％的药学上可接受的赋形剂。在某些实施方案中，所述的药物组合物含有0.1％-99.9％的药学上可接受的赋形剂。在某些实施方案中，所述的药物组合物含有0.5％-99.5％的药学上可接受的赋形剂。在某些实施方案中，所述的药物组合物含有1％-99％的药学上可接受的赋形剂。在某些实施方案中，所述的药物组合物含有2％-98％的药学上可接受的赋形剂。片剂含有活性成分和用于混合的适宜制备片剂的无毒的可药用的赋形剂。这些赋形剂可以是惰性赋形剂、造粒剂、崩解剂、粘合剂和润滑剂。这些片剂可以不包衣或可通过掩盖药物的味道或在胃肠道中延迟崩解和吸收，因而在较长时间内提供缓释作用的已知技术将其包衣。In certain embodiments, 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.
也可用其中活性成分与惰性固体稀释剂或其中活性成分与水溶性载体或油溶媒混合的软明胶胶囊提供口服制剂。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.
水混悬液含有活性物质和用于混合的适宜制备水悬浮液的赋形剂。此类赋形剂是悬浮剂、分散剂或湿润剂。水混悬液也可以含有一种或多种防腐剂、一种或多种着色剂、一种或多种矫味剂和一种或多种甜味剂。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.
油混悬液可通过使活性成分悬浮于植物油，或矿物油配制而成。油悬浮液可含有增稠剂。可加入上述的甜味剂和矫味剂，以提供可口的制剂。可通过加入抗氧化剂保存这些组合物。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.
本公开的药物组合物也可以是水包油乳剂的形式。油相可以是植物油，或矿物油或其混合物。适宜的乳化剂可以是天然产生的磷脂，乳剂也可以含有甜味剂、矫味剂、防腐剂和抗氧剂。此类制剂也可含有缓和剂、防腐剂、着色剂和抗氧剂。Pharmaceutical 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.
本公开的药物组合物可以是无菌注射水溶液形式。可以使用的可接受的溶媒 或溶剂有水、林格氏液和等渗氯化钠溶液。无菌注射制剂可以是其中活性成分溶于油相的无菌注射水包油微乳可通过局部大量注射，将注射液或微乳注入患者的血流中。或者，最好按可保持本公开化合物恒定循环浓度的方式给予溶液和微乳。为保持这种恒定浓度，可使用连续静脉内递药装置。这种装置的实例是Deltec CADD-PLUS.TM.5400型静脉注射泵。Pharmaceutical 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. Alternatively, solutions and microemulsions are preferably administered in a manner that maintains constant circulating concentrations of the compounds of the present disclosure. To maintain this constant concentration, continuous intravenous drug delivery devices can be used. An example of such a device is the Deltec CADD-PLUS.TM. 5400 intravenous pump.
本公开的药物组合物可以是用于肌内和皮下给药的无菌注射水或油混悬液的形式。可按已知技术，用上述那些适宜的分散剂或湿润剂和悬浮剂配制该混悬液。无菌注射制剂也可以是在肠胃外可接受的无毒稀释剂或溶剂中制备的无菌注射溶液或混悬液。此外，可方便地用无菌固定油作为溶剂或悬浮介质。为此目的，可使用任何调和固定油。此外，脂肪酸也可以制备注射剂。Pharmaceutical 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. In addition, sterile fixed oil can be conveniently used as the solvent or suspending medium. For this purpose, any blend of fixed oils can be used. In addition, fatty acids are also prepared as injectables.
可按用于直肠给药的栓剂形式给予本公开化合物。可通过将药物与在普通温度下为固体但在直肠中为液体，因而在直肠中会溶化而释放药物的适宜的无刺激性赋形剂混合来制备这些药物组合物。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.
可通过加入水来制备水混悬的可分散粉末和颗粒给予本公开化合物。可通过将活性成分与分散剂或湿润剂、悬浮剂或一种或多种防腐剂混合来制备这些药物组合物。Compounds 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.
如本领域技术人员所熟知的，药物的给药剂量依赖于多种因素，包括但并非限定于以下因素：所用具体化合物的活性、疾病的严重性、患者的年龄、患者的体重、患者的健康状况、患者的行为、患者的饮食、给药时间、给药方式、排泄的速率、药物的组合等；另外，最佳的治疗方式如治疗的模式、化合物的日用量或可药用的盐的种类可以根据传统的治疗方案来验证。As is well known to those skilled in the art, 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.
术语说明Terminology
除非有相反陈述，在说明书和权利要求书中使用的术语具有下述含义。Unless stated to the contrary, the terms used in the specification and claims have the following meanings.
术语“烷基”指饱和的直链或带有支链的脂肪族烃基，其具有1至20个(例如1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19或20个)碳原子(即C1-20烷基)。所述烷基优选具有1至12个碳原子的烷基(即C1-12烷基)，更优选具有1至6个碳原子的烷基(即C1-6烷基)。非限制性的实例包括：甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基、正戊基、1,1-二甲基丙基、1,2-二甲基丙基、2,2-二甲基丙基、1-乙基丙基、2-甲基丁基、3-甲基丁基、正己基、1-乙基-2-甲基丙基、1,1,2-三甲基丙基、1,1-二甲基丁基、1,2-二甲基丁基、2,2-二甲基丁基、1,3-二甲基丁基、2-乙基丁基、2-甲基戊基、3-甲基戊基、4-甲基戊基、2,3-二甲基丁基、正庚基、2-甲基己基、3-甲基己基、4-甲基己基、5-甲基己基、2,3-二甲基戊基、2,4-二甲基戊基、2,2-二甲基戊基、3,3-二甲基戊基、2-乙基戊基、3-乙基戊基、正辛基、2,3-二甲基己基、2,4-二甲基己基、2,5-二甲基己基、2,2-二甲基己基、3,3-二甲基己基、4,4-二甲基己基、2-乙基己基、 3-乙基己基、4-乙基己基、2-甲基-2-乙基戊基、2-甲基-3-乙基戊基、正壬基、2-甲基-2-乙基己基、2-甲基-3-乙基己基、2,2-二乙基戊基、正癸基、3,3-二乙基己基、2,2-二乙基己基，及其各种支链异构体等。烷基可以是取代的或非取代的，当被取代时，其可以在任何可使用的连接点被取代，取代基优选选自D原子、卤素、烷氧基、卤代烷基、卤代烷氧基、环烷基氧基、杂环基氧基、羟基、羟烷基、氰基、氨基、硝基、环烷基、杂环基、芳基和杂芳基中的一个或多个。The term "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, 5-methylhexyl, 2,3-dimethylpentyl, 2,4-dimethylpentyl, 2,2-di Methylpentyl, 3,3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl , 2,5-dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-nonyl, 2-methyl-2-ethylhexyl , 2-methyl-3-ethylhexyl, 2,2-diethylpentyl, n-decyl, 3,3-diethylhexyl, 2,2-diethylhexyl, and various branched chains Isomers etc. 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.
术语“亚烷基”指二价烷基，其中烷基如上所定义，其具有1至20个(例如1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19或20个)碳原子(即C1-20亚烷基)。所述亚烷基优选具有1至12个碳原子的亚烷基(即C1-12亚烷基)，更优选具有1至6个碳原子的亚烷基(即C1-6亚烷基)。非限制性的实例包括：-CH2-、-CH(CH3)-、-C(CH3)2-、-CH2CH2-、-CH(CH2CH3)-、-CH2CH(CH3)-、-CH2C(CH3)2-、-CH2CH2CH2-、-CH2CH2CH2CH2-等。亚烷基可以是取代的或非取代的，当被取代时，其可以在任何可使用的连接点被取代，取代基优选选自D原子、卤素、烷氧基、卤代烷基、卤代烷氧基、环烷基氧基、杂环基氧基、羟基、羟烷基、氰基、氨基、硝基、环烷基、杂环基、芳基和杂芳基中的一个或多个。The term "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.
术语“烯基”指分子中含有至少一个碳碳双键的烷基，其中烷基的定义如上所述，其具有2至12个(例如2、3、4、5、6、7、8、9、10、11或12个)碳原子(即C2-12烯基)。所述烯基优选具有2至6个碳原子的烯基(即C2-6烯基)。非限制性的实例包括：乙烯基、丙烯基、异丙烯基、丁烯基等。烯基可以是取代的或非取代的，当被取代时，其可以在任何可使用的连接点被取代，取代基优选选自D原子、烷氧基、卤素、卤代烷基、卤代烷氧基、环烷基氧基、杂环基氧基、羟基、羟烷基、氰基、氨基、硝基、环烷基、杂环基、芳基和杂芳基中的一个或多个。The term "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.
术语“炔基”指分子中含有至少一个碳碳三键的烷基，其中烷基的定义如上所述，其具有2至12个(例如2、3、4、5、6、7、8、9、10、11或12个)碳原子(即C2-12炔基)。所述炔基优选具有2至6个碳原子的炔基(即C2-6炔基)。非限制性的实例包括：乙炔基、丙炔基、丁炔基、戊炔基、己炔基等。炔基可以是取代的或非取代的，当被取代时，其可以在任何可使用的连接点被取代，取代基优选选自D原子、烷氧基、卤素、卤代烷基、卤代烷氧基、环烷基氧基、杂环基氧基、羟基、羟烷基、氰基、氨基、硝基、环烷基、杂环基、芳基和杂芳基中的一个或多个。The term "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.
术语“烷氧基”指-O-(烷基)，其中烷基的定义如上所述。非限制性的实例包括：甲氧基、乙氧基、丙氧基和丁氧基等。烷氧基可以是取代的或非取代的，当被取代时，其可以在任何可使用的连接点被取代，取代基优选选自D原子、卤素、烷氧基、卤代烷基、卤代烷氧基、环烷基氧基、杂环基氧基、羟基、羟烷基、氰 基、氨基、硝基、环烷基、杂环基、芳基和杂芳基中的一个或多个。The term "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.
术语“环烷基”指饱和或部分不饱和的单环全碳环(即单环环烷基)或多环系统(即多环环烷基)，其具有3至20个(例如3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19或20个)环原子(即3至20元环烷基)。所述环烷基优选具有3至12个环原子的环烷基(即3至12元环烷基)，更优选具有3至10个环原子的环烷基(即3至10元环烷基)或具有3至8个环原子的环烷基(即3至8元环烷基)，最优选具有3至6个环原子的环烷基(即3至6元环烷基)或具有5或6个环原子的环烷基(即5或6元环烷基)。The term "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. a 3 to 6 membered cycloalkyl group) or a cycloalkyl group having 5 to 6 ring atoms Or cycloalkyl group with 6 ring atoms (i.e. 5 or 6 membered cycloalkyl group).
所述的单环环烷基，非限制性的实例包括：环丙基、环丁基、环戊基、环戊烯基、环己基、环己烯基、环己二烯基、环庚基、环庚三烯基和环辛基等。Non-limiting examples of the monocyclic cycloalkyl include: cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, and cycloheptyl , cycloheptatrienyl and cyclooctyl, etc.
所述的多环环烷基包括：螺环烷基、稠环烷基和桥环烷基。The polycyclic cycloalkyl group includes: spirocycloalkyl group, fused cycloalkyl group and bridged cycloalkyl group.
术语“螺环烷基”指环之间共用一个碳原子(称螺原子)的多环系统，其环内可以含有一个或多个双键，或其环内可以含有一个或多个选自氮、氧和硫的杂原子(所述的氮可任选被氧化，即形成氮氧化物；所述的硫可任选被氧代，即形成亚砜或砜，但不包括-O-O-、-O-S-或-S-S-)，条件是至少含有一个全碳环且连接点在该全碳环上，其具有5至20个(例如5、6、7、8、9、10、11、12、13、14、15、16、17、18、19或20个)环原子(即5至20元螺环烷基)。所述螺环烷基优选具有6至14个环原子的螺环烷基(即6至14元螺环烷基)，更优选具有7至10个环原子的螺环烷基(即7至10元螺环烷基)。所述螺环烷基包括单螺环烷基和多螺环烷基(如双螺环烷基等)，优选单螺环烷基或双螺环烷基，更优选3元/4元、3元/5元、3元/6元、4元/4元、4元/5元、4元/6元、5元/3元、5元/4元、5元/5元、5元/6元、5元/7元、6元/3元、6元/4元、6元/5元、6元/6元、6元/7元、7元/5元或7元/6元单螺环烷基。非限制性的实例包括：The term "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. 5 to 20 membered spirocycloalkyl). 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. 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 yuan/6 yuan Single spirocycloalkyl. Non-limiting examples include:
其连接点可在任意位置； Its connection point can be at any position;
等。 wait.
术语“稠环烷基”指环之间共享毗邻的两个碳原子的多环系统，其为单环环烷基与一个或多个单环环烷基稠合，或者单环环烷基与杂环基、芳基或杂芳基中的一个或多个稠合，其中连接点在单环环烷基上，其环内可以含有一个或多个双键，且具有5至20个(例如5、6、7、8、9、10、11、12、13、14、15、16、17、18、19或20个)环原子(即5至20元稠环烷基)。所述稠环烷基优选具有6至14个环原子的稠环烷基(即6至14元稠环烷基)，更优选具有7至10个环原子的稠环烷基(即7至10元稠环烷基)。所述稠环烷基包括双环稠环烷基和多环稠 环烷基(如三环稠环烷基、四环稠环烷基等)，优选双环稠环烷基或三环稠环烷基，更优选3元/4元、3元/5元、3元/6元、4元/4元、4元/5元、4元/6元、5元/3元、5元/4元、5元/5元、5元/6元、5元/7元、6元/3元、6元/4元、6元/5元、6元/6元、6元/7元、7元/5元或7元/6元双环稠环烷基。非限制性的实例包括：其连接点可在任意位置；等。The term "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. 5 to 20 membered fused ring alkyl group). 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 any position; wait.
术语“桥环烷基”指环之间共用两个不直接连接的碳原子的全碳多环系统，其环内可以含有一个或多个双键，且具有5至20个(例如5、6、7、8、9、10、11、12、13、14、15、16、17、18、19或20个)碳原子(即5至20元桥环烷基)。所述桥环烷基优选具有6至14个碳原子的桥环烷基(即6至14元桥环烷基)，更优选具有7至10个碳原子的桥环烷基(即7至10元桥环烷基)。所述桥环烷基包括双环桥环烷基和多环桥环烷基(如三环桥环烷基、四环桥环烷基等)，优选双环桥环烷基或三环桥环烷基。非限制性的实例包括：The term "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:
其连接点可在任意位置。 Its connection point can be anywhere.
环烷基可以是取代的或非取代的，当被取代时，其可以在任何可使用的连接点被取代，取代基优选选自D原子、卤素、烷基、烷氧基、卤代烷基、卤代烷氧基、环烷基氧基、杂环基氧基、羟基、羟烷基、氧代基、氰基、氨基、硝基、环烷基、杂环基、芳基和杂芳基中的一个或多个。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 One of oxygen, cycloalkyloxy, heterocyclyloxy, hydroxyl, hydroxyalkyl, oxo, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl or more.
术语“杂环基”指饱和或部分不饱和的单环杂环(即单环杂环基)或多环杂环系统(即多环杂环基)，其环内至少含有一个(例如1、2、3或4个)选自氮、氧和硫的杂原子(所述的氮可任选被氧化，即形成氮氧化物；所述的硫可任选被氧代，即形成亚砜或砜，但不包括-O-O-、-O-S-或-S-S-)，且具有3至20个(例如3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19或20个)环原子(即3至20元杂环基)。所述杂环基优选具有3至12个环原子的杂环基(即3至12元杂环基)或具有3至10个环原子的杂环基(即3至10元杂环基)；进一步优选具有3至8个环原子的杂环基(即3至8元杂环基)；更优选具有4至7个环原子的杂环基(即4至7元杂环基)；更优选具有3至6个环原子的杂环基(即3至6元杂环基)；最优选具有5或6个环原子的杂环基(即5或6元杂环基)。 The term "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. 3 to 20 membered heterocyclyl). 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. 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).
所述的单环杂环基，非限制性的实例包括：吡咯烷基、四氢吡喃基、1,2,3,6-四氢吡啶基、哌啶基、哌嗪基、吗啉基、硫代吗啉基和高哌嗪基等。Non-limiting examples of the monocyclic heterocyclyl include: pyrrolidinyl, tetrahydropyranyl, 1,2,3,6-tetrahydropyridyl, piperidinyl, piperazinyl, morpholinyl , thiomorpholinyl and homopiperazinyl, etc.
所述的多环杂环基包括螺杂环基、稠杂环基和桥杂环基。The polycyclic heterocyclyl group includes spiroheterocyclyl group, fused heterocyclyl group and bridged heterocyclyl group.
术语“螺杂环基”指环之间共用一个原子(称螺原子)的多环杂环系统，其环内可以含有一个或多个双键，且其环内至少含有一个(例如1、2、3或4个)选自氮、氧和硫的杂原子(所述的氮可任选被氧化，即形成氮氧化物；所述的硫可任选被氧代，即形成亚砜或砜，但不包括-O-O-、-O-S-或-S-S-)，条件是至少含有一个单环杂环基且连接点在该单环杂环基上，其具有5至20个(例如5、6、7、8、9、10、11、12、13、14、15、16、17、18、19或20个)环原子(即5至20元螺杂环基)。所述螺杂环基优选具有6至14个环原子的螺杂环基(即6至14元螺杂环基)，更优选具有7至10个环原子的螺杂环基(即7至10元螺杂环基)。所述螺杂环基包括单螺杂环基和多螺杂环基(如双螺杂环基等)，优选单螺杂环基或双螺杂环基，更优选3元/4元、3元/5元、3元/6元、4元/4元、4元/5元、4元/6元、5元/3元、5元/4元、5元/5元、5元/6元、5元/7元、6元/3元、6元/4元、6元/5元、6元/6元、6元/7元、7元/5元或7元/6元单螺杂环基。非限制性的实例包括：The term "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). 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. 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 yuan/6 yuan Single spiroheterocyclyl. Non-limiting examples include:
等。 wait.
术语“稠杂环基”指环之间共享毗邻的两个原子的多环杂环系统，其环内可以含有一个或多个双键，且其环内至少含有一个(例如1、2、3或4个)选自氮、氧和硫的杂原子(所述的氮可任选被氧化，即形成氮氧化物；所述的硫可任选被氧代，即形成亚砜或砜，但不包括-O-O-、-O-S-或-S-S-)，其为单环杂环基与一个或多个单环杂环基稠合，或者单环杂环基与环烷基、芳基或杂芳基中的一个或多个稠合，其中连接点在单环杂环基上，且具有5至20个(例如5、6、7、8、9、10、11、12、13、14、15、16、17、18、19或20个)环原子(即5至20元稠杂环基)。所述稠杂环基优选具有6至14个环原子的稠杂环基(即6至14元稠杂环基)，更优选具有7至10个环原子的稠杂环基(即7至10元稠杂环基)。所述稠杂环基包括双环和多环稠杂环基(如三环稠杂环基、四环稠杂环基等)，优选双环稠杂环基或三环稠杂环基，更优选3元/4元、3元/5元、3元/6元、4元/4元、4元/5元、4元/6元、5元/3元、5元/4元、5元/5元、5元/6元、5元/7元、6元/3元、6元/4元、6元/5元、6元/6元、6元/7元、7元/5元或7元/6元双环稠杂环基。非限制性的实例包括： The term "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. One or more of the radicals are fused, wherein the point of attachment is on the monocyclic heterocyclyl radical, and there are 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. 5 to 20 membered fused heterocyclyl). 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. Non-limiting examples include:
等。 wait.
术语“桥杂环基”指环之间共用两个不直接连接的原子的多环杂环系统，其环内可以含有一个或多个双键，并且其环内至少含有一个(例如1、2、3或4个)选自氮、氧和硫的杂原子(所述的氮可任选被氧化，即形成氮氧化物；所述的硫可任选被氧代，即形成亚砜或砜，但不包括-O-O-、-O-S-或-S-S-)，其具有5至20个(例如5、6、7、8、9、10、11、12、13、14、15、16、17、18、19或20个)环原子(即5至20元桥杂环基)。所述桥杂环基优选具有6至14个环原子的桥杂环基(即6至14元桥杂环基)，更优选具有7至10个环原子的桥杂环基(即7至10元桥杂环基)。根据组成环的数目可以分为双环桥杂环基和多环桥杂环基(如三环桥杂环基、四环桥杂环基等)，优选双环桥杂环基或三环桥杂环基。非限制性的实例包括：The term "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. 5 to 20 membered bridged heterocyclyl). 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). According to the number of constituent rings, it can be divided into bicyclic bridged heterocyclyl and polycyclic bridged heterocyclyl (such as tricyclic bridged heterocyclyl, tetracyclic bridged heterocyclyl, etc.), preferably bicyclic bridged heterocyclyl or tricyclic bridged heterocyclyl. base. Non-limiting examples include:
等。 wait.
杂环基可以是取代的或非取代的，当被取代时，其可以在任何可使用的连接点被取代，取代基优选选自D原子、卤素、烷基、烷氧基、卤代烷基、卤代烷氧基、环烷基氧基、杂环基氧基、羟基、羟烷基、氧代基、氰基、氨基、硝基、环烷基、杂环基、芳基和杂芳基中的一个或多个。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. One of oxygen, cycloalkyloxy, heterocyclyloxy, hydroxyl, hydroxyalkyl, oxo, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl or more.
术语“芳基”指具有共轭的π电子体系的单环全碳芳环(即单环芳基)或多环芳环系统(即多环芳基)，其具有6至14个(例如6、7、8、9、10、11、12、13或14个)环原子(即6至14元芳基)。所述芳基优选具有6至10个环原子的芳基(即6至10元芳基)。所述的单环芳基，例如苯基。所述的多环芳基，优选8至14元多环芳基，非限制性的实例包括：萘基、蒽基、菲基等。所述多环芳基还包括苯基与杂环基或环烷基中的一个或多个稠合，或萘基与杂环基或环烷基中的一个或多个稠合，其中连接点在苯基或萘基上，并且在这种情况下，环原子个数继续表示多环芳环系统中的环原子个数，非限制性的实例包括： The term "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 π 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:
等。 wait.
芳基可以是取代的或非取代的，当被取代时，其可以在任何可使用的连接点被取代，取代基优选选自D原子、卤素、烷基、烷氧基、卤代烷基、卤代烷氧基、环烷基氧基、杂环基氧基、羟基、羟烷基、氧代基、氰基、氨基、硝基、环烷基、杂环基、芳基和杂芳基中的一个或多个。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.
术语“杂芳基”指具有共轭的π电子体系的单环杂芳环(即单环杂芳基)或多环杂芳环系统(即多环杂芳基)，其环内至少含有一个(例如1、2、3或4个)选自氮、氧和硫的杂原子(所述的氮可任选被氧化，即形成氮氧化物；所述的硫可任选被氧代，即形成亚砜或砜，但不包括-O-O-、-O-S-或-S-S-)，其具有5至14个(例如5、6、7、8、9、10、11、12、13或14个)环原子(即5至14元杂芳基)。所述杂芳基优选具有5至10个环原子的杂芳基(即5至10元杂芳基)，更优选具有5或6个环原子的杂芳基(即5或6元杂芳基)。The term "heteroaryl" refers to a monocyclic heteroaromatic ring (i.e., monocyclic heteroaryl) or a polycyclic heteroaromatic ring system (i.e., polycyclic heteroaryl) with a conjugated π 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. Forms sulfoxides or sulfones, but not -O-O-, -O-S-, or -S-S-), which have 5 to 14 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 ) ring atoms (i.e. 5 to 14 membered heteroaryl). 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). ).
所述的单环杂芳基，非限制性的实例包括：呋喃基、噻吩基、噻唑基、异噻唑基、噁唑基、异噁唑基、噁二唑基、噻二唑基、咪唑基、吡唑基、三唑基、四唑基、呋咱基、吡咯基、N-烷基吡咯基、吡啶基、嘧啶基、吡啶酮基、N-烷基吡啶酮(如等)、吡嗪基、哒嗪基等。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.
所述的多环杂芳基，优选7至14元多环杂芳基或8至14元多环杂芳基，更优选9至10元双环杂芳基；非限制性的实例包括：吲哚基、吲唑基、喹啉基、异喹啉基、喹喔啉基、酞嗪基、苯并咪唑基、苯并噻吩基、喹唑啉基、苯并噻唑基、咔唑基等。所述多环杂芳基还包括单环杂芳基与一个或多个芳基稠合，其中连接点在芳香环上，并且在这种情况下，环原子个数继续表示多环杂芳环系统中的环原子个数。所述多环杂芳基还包括单环杂芳基与环烷基或杂环基中的一个或多个稠合，其中连接点在单环杂芳环上，并且在这种情况下，环原子个数继续表示多环杂芳环系统中的环原子个数。非限制性的实例包括：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:
等。 wait.
杂芳基可以是取代的或非取代的，当被取代时，其可以在任何可使用的连接点被取代，取代基优选选自D原子、卤素、烷基、烷氧基、卤代烷基、卤代烷氧基、环烷基氧基、杂环基氧基、羟基、羟烷基、氰基、氨基、硝基、环烷基、杂环基、芳基和杂芳基中的一个或多个。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. One or more of oxy, cycloalkyloxy, heterocyclyloxy, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.
术语“氨基保护基”是指为了使分子其它部位进行反应时氨基保持不变，在氨基上引入的易于脱去的基团。非限制性的实例包括：(三甲基硅)乙氧基甲基、四氢吡喃基、叔丁氧羰基(Boc)、苄氧羰基(Cbz)、笏甲氧羰基(Fmoc)、烯丙氧羰基(Alloc)、三甲基硅乙氧羰基(Teoc)、甲氧羰基、乙氧羰基、邻苯二甲酰基(Pht)、对甲苯磺酰基(Tos)、三氟乙酰基(Tfa)、三苯甲基(Trt)、2,4-二甲氧基苄基(DMB)、对甲氧基苄基(PMB)、乙酰基、苄基、烯丙基、对甲氧苄基等。The term "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.
术语“羟基保护基”是指在羟基上引入的易于脱去的基团，用于阻断或保护羟基而在化合物的其它官能团上进行反应。非限制性的实例包括：三甲基硅基(TMS)、三乙基硅基(TES)、三异丙基硅基(TIPS)、叔丁基二甲基硅基(TBS)、叔丁基二甲基硅基(TBDMS)、叔丁基二苯基硅基(TBDPS)、甲基、叔丁基、烯丙基、苄基、甲氧基甲基(MOM)、乙氧基乙基、2-四氢吡喃基(THP)、甲酰基、乙酰基、苯甲酰基、对硝基苯甲酰基等。The term "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.
术语“炔基保护基”是指为了使分子其它部位进行反应时乙炔或末端炔烃中的活泼氢保持不变，在炔基上引入的易于脱去的基团。非限制性的实例包括：三甲基硅基(TMS)、三乙基硅基(TES)、叔丁基二甲基硅基(TBS)、三异丙基硅基(TIPS)、叔丁基二甲基硅基(TBDMS)、叔丁基二苯基硅基(TBDPS)、甲基、叔丁基、烯丙基、苄基、甲氧基甲基(MOM)、乙氧基乙基、2-四氢吡喃基(THP)、甲酰基、乙酰基、苯甲酰基、对硝基苯甲酰基等。The term "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.
术语“环烷基氧基”指环烷基-O-，其中环烷基如上所定义。The term "cycloalkyloxy" refers to cycloalkyl-O-, where cycloalkyl is as defined above.
术语“杂环基氧基”指杂环基-O-，其中杂环基如上所定义。The term "heterocyclyloxy" refers to heterocyclyl-O-, wherein heterocyclyl is as defined above.
术语“芳基氧基”指芳基-O-，其中芳基如上所定义。The term "aryloxy" refers to aryl-O-, where aryl is as defined above.
术语“杂芳基氧基”指杂芳基-O-，其中杂芳基如上所定义。The term "heteroaryloxy" refers to heteroaryl-O-, where heteroaryl is as defined above.
术语“烷硫基”指烷基-S-，其中烷基如上所定义。The term "alkylthio" refers to alkyl-S-, where alkyl is as defined above.
术语“卤代烷基”指烷基被一个或多个卤素取代，其中烷基如上所定义。 The term "haloalkyl" refers to an alkyl group substituted with one or more halogens, where alkyl is as defined above.
术语“卤代烷氧基”指烷氧基被一个或多个卤素取代，其中烷氧基如上所定义。The term "haloalkoxy" refers to an alkoxy group substituted with one or more halogens, where alkoxy is as defined above.
术语“氘代烷基”指烷基被一个或多个氘原子取代，其中烷基如上所定义。The term "deuterated alkyl" refers to an alkyl group substituted with one or more deuterium atoms, wherein alkyl is as defined above.
术语“羟烷基”指烷基被一个或多个羟基取代，其中烷基如上所定义。The term "hydroxyalkyl" refers to an alkyl group substituted with one or more hydroxyl groups, where alkyl is as defined above.
术语“羟烷氧基”指烷氧基被一个或多个羟基取代，其中烷氧基如上所定义。The term "hydroxyalkoxy" refers to an alkoxy group substituted with one or more hydroxyl groups, where alkoxy is as defined above.
术语“甲叉基”指＝CH2。The term "methylene" refers to = CH2 .
术语“卤素”指氟、氯、溴或碘。The term "halogen" refers to fluorine, chlorine, bromine or iodine.
术语“羟基”指-OH。The term "hydroxy" refers to -OH.
术语“巯基”指-SH。The term "mercapto" refers to -SH.
术语“氨基”指-NH2。The term "amino" refers to -NH2 .
术语“氰基”指-CN。The term "cyano" refers to -CN.
术语“硝基”指-NO2。The term "nitro" refers to -NO2 .
术语“氧代”或“氧代基”指“＝O”。The term "oxo" or "oxo" refers to "=O".
术语“羰基”指C＝O。The term "carbonyl" refers to C=O.
术语“乙酰基”指-C(O)CH3。The term "acetyl" refers to -C(O) CH3 .
术语“酰胺基”指-C(O)NH2。The term "amide" refers to -C(O) NH2 .
术语“羧基”指-C(O)OH。The term "carboxy" refers to -C(O)OH.
术语“羧酸酯基”指-C(O)O(烷基)、-C(O)O(环烷基)、(烷基)C(O)O-或(环烷基)C(O)O-，其中烷基和环烷基如上所定义。The term "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.
本公开化合物可以存在特定的立体异构体形式。术语“立体异构体”是指结构相同但原子在空间中的排列不同的异构体。其包括顺式和反式(或Z和E)异构体、(-)-和(+)-异构体、(R)-和(S)-对映异构体、非对映异构体、(D)-和(L)-异构体、互变异构体、阻转异构体、构象异构体及其混合物(如外消旋体、非对映异构体的混合物)。本公开化合物中的取代基可以存在另外的不对称原子。所有这些立体异构体以及它们的混合物，均包括在本公开的范围内。可以通过手性合成、手性试剂或者其他常规技术制备光学活性的(-)-和(+)-异构体、(R)-和(S)-对映异构体以及(D)-和(L)-异构体。本公开某化合物的一种异构体，可以通过不对称合成或者手性助剂来制备，或者，当分子中含有碱性官能团(如氨基)或酸性官能团(如羧基)时，与适当的光学活性的酸或碱形成非对映异构体的盐，然后通过本领域所公知的常规方法进行非对映异构体拆分，得到纯的异构体。此外，对映异构体和非对映异构体的分离通常是通过色谱法完成。Compounds of the present disclosure may exist in specific stereoisomeric forms. The term "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. All such stereoisomers, as well as mixtures thereof, are included within the scope of this disclosure. 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.
本公开所述化合物的化学结构中，键表示未指定构型，即如果化学结构中存在手性异构体，键可以为或者同时包含 两种构型。本公开所述化合物的化学结构中，键并未指定构型，即可以为Z构型或E构型，或者同时包含两种构型。对于所有的碳-碳双键，即使仅命名了一个构型，Z型和E型均包括在内。 In the chemical structure of the compounds described in this disclosure, 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. In the chemical structure of the compounds described in this disclosure, 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.
本公开所述化合物的化学结构中，连接至化合物的立体异构中心的键 如中，表示立体异构中心的相对构型；其中，实施例1化合物1a为1b-1和1b-2的混合物。In the chemical structure of the compounds described in this disclosure, 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.
本公开的化合物可以以不同的互变异构体形式存在，并且所有这样的形式包含在本公开的范围内。术语“互变异构体”或“互变异构体形式”是指平衡存在并且容易从一种异构形式转化为另一种异构形式的结构异构体。其包括所有可能的互变异构体，即以单一异构体的形式或以所述互变异构体的任意比例的混合物的形式存在。非限制性的实例包括：酮-烯醇、亚胺-烯胺、内酰胺-内酰亚胺等。内酰胺-内酰亚胺的平衡实例如下所示：
The compounds of the present disclosure may exist in different tautomeric forms, and all such forms are included within the scope of the present disclosure. The term "tautomer" or "tautomeric form" 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:
如当提及吡唑基时，应理解为包括如下两种结构中的任何一种或两种互变异构体的混合物：
When referring to pyrazolyl, it should be understood to include either one of the following two structures or a mixture of two tautomers:
所有的互变异构形式在本公开的范围内，且化合物的命名不排除任何互变异构体。All tautomeric forms are within the scope of the present disclosure, and the naming of a compound does not exclude any tautomeric form.
本公开的化合物包括其化合物的所有合适的同位素衍生物。术语“同位素衍生物”是指至少一个原子被具有相同原子序数但原子质量不同的原子替代的化合物。可引入到本公开化合物中的同位素的实例包括氢、碳、氮、氧、磷、硫、氟、氯、溴和碘等的稳定和放射性的同位素，例如分别为2H(氘，D)、3H(氚，T)、11C、13C、14C、15N、17O、18O、32p、33p、33S、34S、35S、36S、18F、36Cl、82Br、123I、124I、125I、129I和131I等，优选氘。The compounds of the present disclosure include all suitable isotopic derivatives of the compounds thereof. The term "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. Examples of 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. 3 H (tritium, T), 11 C, 13 C, 14 C, 15 N, 17 O, 18 O, 32 p, 33 p, 33 S, 34 S, 35 S, 36 S, 18 F , 36 Cl, 82 Br, 123 I, 124 I, 125 I, 129 I and 131 I, etc., preferably deuterium.
相比于未氘代药物，氘代药物有降低毒副作用、增加药物稳定性、增强疗效、延长药物生物半衰期等优势。本公开的化合物的所有同位素组成的变换，无论放射性与否，都包括在本公开的范围之内。与碳原子连接的各个可用的氢原子可独 立地被氘原子替换，其中氘的替换可以是部分或完全的，部分氘的替换是指至少一个氢被至少一个氘替换。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.
本公开的化合物，当其一个位置被特别地指定为“氘”或“D”时，该位置应理解为氘的丰度比氘的天然丰度(其为0.015％)大至少1000倍(即至少15％的氘掺入)。在一些实施方案中，每个被指定的氘原子的氘的丰度比氘的天然丰度大至少1000倍(即至少15％的氘掺入)。在一些实施方案中，每个被指定的氘原子的氘的丰度比氘的天然丰度大至少2000倍(即至少30％的氘掺入)。在一些实施方案中，每个被指定的氘原子的氘的丰度比氘的天然丰度大至少3000倍(即至少45％的氘掺入)。在一些实施方案中，每个被指定的氘原子的氘的丰度比氘的天然丰度大至少3340倍(即至少50.1％的氘掺入)。在一些实施方案中，每个被指定的氘原子的氘的丰度比氘的天然丰度大至少3500倍(即至少52.5％的氘掺入)。在一些实施方案中，每个被指定的氘原子的氘的丰度比氘的天然丰度大至少4000倍(即至少60％的氘掺入)。在一些实施方案中，每个被指定的氘原子的氘的丰度比氘的天然丰度大至少4500倍(即至少67.5％的氘掺入)。在一些实施方案中，每个被指定的氘原子的氘的丰度比氘的天然丰度大至少5000倍(即至少75％的氘掺入)。在一些实施方案中，每个被指定的氘原子的氘的丰度比氘的天然丰度大至少5500倍(即至少82.5％的氘掺入)。在一些实施方案中，每个被指定的氘原子的氘的丰度比氘的天然丰度大至少6000倍(即至少90％的氘掺入)。在一些实施方案中，每个被指定的氘原子的氘的丰度比氘的天然丰度大至少6333.3倍(即至少95％的氘掺入)。在一些实施方案中，每个被指定的氘原子的氘的丰度比氘的天然丰度大至少6466.7倍(即至少97％的氘掺入)。在一些实施方案中，每个被指定的氘原子的氘的丰度比氘的天然丰度大至少6600倍(即至少99％的氘掺入)。在一些实施方案中，每个被指定的氘原子的氘的丰度比氘的天然丰度大至少6633.3倍(即至少99.5％的氘掺入)。Compounds of the present disclosure, 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). In some embodiments, 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). In some embodiments, 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). In some embodiments, 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). In some embodiments, 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). In some embodiments, 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).
“任选地”或“任选”是指随后所描述的事件或环境可以但不必然发生，其包括该事件或环境发生或不发生两种情形。例如“任选地(任选)被卤素或者氰基取代的烷基”包括烷基被卤素或者氰基取代的情形和烷基不被卤素和氰基取代的情形。"Optionally" or "optionally" means that the subsequently described event or circumstance may but does not necessarily occur, which includes both the occurrence or non-occurrence of the event or circumstance. For example, "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.
“取代”或“取代的”指基团中的一个或多个氢原子，优选1～6个，更优选1～3个氢原子彼此独立地被相应数目的取代基取代。本领域技术人员能够在不付出过多努力的情况下(通过实验或理论)确定可能或不可能的取代。例如，具有游离氢的氨基或羟基与具有不饱和键的碳原子(如烯)结合时可能是不稳定的。"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). For example, 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.
“药物组合物”表示含有一种或多种本文所述化合物或其可药用的盐与其他化学组分的混合物，以及其他组分例如药学上可接受的载体和赋形剂。药物组合物的目的是促进对生物体的给药，利于活性成分的吸收进而发挥生物活性。"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.
“可药用的盐”是指本公开化合物的盐，可选自无机盐或有机盐。这类盐用于 哺乳动物体内时具有安全性和有效性，且具有应有的生物活性。可以在化合物的最终分离和纯化过程中，或通过使合适的基团与合适的碱或酸反应来单独制备。通常用于形成药学上可接受的盐的碱包括无机碱，例如氢氧化钠和氢氧化钾，以及有机碱，例如氨。通常用于形成药学上可接受的盐的酸包括无机酸以及有机酸。"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.
本文所用的术语“药学上可接受的”是指这些化合物、材料、组合物和/或剂型，在合理的医学判断范围内，适用于与患者组织接触而没有过度毒性、刺激性、过敏反应或其他问题或并发症，具有合理的获益/风险比，并且对预期的用途是有效。The term "pharmaceutically acceptable" as used herein 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.
本文所使用的，单数形式的“一个”、“一种”和“该”包括复数引用，反之亦然，除非上下文另外明确指出。As used herein, the singular forms "a," "an," and "the" include plural references and vice versa unless the context clearly dictates otherwise.
当将术语“约”应用于诸如pH、浓度、温度等参数时，表明该参数可以变化±10％，并且有时更优选地在±5％之内。如本领域技术人员将理解的，当参数不是关键时，通常仅出于说明目的给出数字，而不是限制。When the term "about" is applied to a parameter such as pH, concentration, temperature, etc., it is intended that the parameter may vary by ±10%, and is sometimes more preferably within ±5%. As those skilled in the art will appreciate, when a parameter is not critical, numbers are generally given for purposes of illustration only and not limitation.
本公开化合物的合成方法Synthetic methods of compounds of the present disclosure
为了完成本公开的目的，本公开采用如下技术方案：In order to achieve the purpose of this disclosure, this disclosure adopts the following technical solutions:
方案一Option One
本公开提供通式(I)所示的化合物或其可药用的盐的制备方法，该方法包括：
The present disclosure provides a method for preparing a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof, which method includes:
通式(Ia)所示的化合物或其盐与通式(Ib)所示的化合物或其盐在碱性条件下进行缩合反应得到通式(I)所示的化合物或其可药用的盐，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 ,
R10为卤素(优选氯原子)或OH；R 10 is halogen (preferably chlorine atom) or OH;
其中，当R10为OH时，该反应在缩合剂的存在下发生；Wherein, when R 10 is OH, the reaction occurs in the presence of a condensing agent;
环Cy、RA、RB、R’、Ra、Rb、Rc、Rd、Re、X、X1、X2、X3、X4、X5和r如通式(I)中所定义。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.
方案二Option II
本公开提供通式(I)所示的化合物或其可药用的盐的制备方法，该方法包括：
The present disclosure provides a method for preparing a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof, which method includes:
通式(I-A)所示的化合物或其盐在胺化剂存在下发生氨解反应得到通式(I)所示的化合物或其可药用的盐，其中，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,
RA为氨基，R9为C1-6烷基；进一步当溶剂中含水时，通式(I-A)所示的化合物或其盐同时还发生水解反应得到通式(I)所示的化合物或其可药用的盐，此时RA为羟基或氨基；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;
或通式(I-A)所示的化合物或其盐在碱性条件下发生水解反应得到通式(I)所示的化合物或其可药用的盐，其中，R9为C1-6烷基，RA为羟基；Or the compound represented by the general formula (IA) or a salt thereof undergoes a hydrolysis reaction under alkaline conditions to obtain a compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof, wherein R 9 is a C 1-6 alkyl group , R A is hydroxyl;
环Cy、RB、R’、Ra、Rb、Rc、Rd、Re、X、X1、X2、X3、X4、X5和r如通式(I)中所定义。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.
方案三third solution
本公开提供通式(II)所示的化合物或其可药用的盐的制备方法，该方法包括：
The present disclosure provides a method for preparing a compound represented by general formula (II) or a pharmaceutically acceptable salt thereof, which method includes:
通式(IIa)所示的化合物或其盐与通式(Ib)所示的化合物或其盐在碱性条件下进行缩合反应得到通式(II)所示的化合物或其可药用的盐，其中，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,
R10为卤素(优选氯原子)或OH；R 10 is halogen (preferably chlorine atom) or OH;
其中，当R10为OH时，该反应在缩合剂的存在下发生；Wherein, when R 10 is OH, the reaction occurs in the presence of a condensing agent;
环Cy、RA、RB、R’、Ra、Rb、Rc、Rd、X、RX1、RX2、RX3和r如通式(II)中所定义。Rings Cy, RA , RB , R' , Ra, Rb , Rc , Rd , X, RX1 , RX2 , RX3 and r are as defined in general formula (II).
方案四Option 4
本公开提供通式(II)所示的化合物或其可药用的盐的制备方法，该方法包括：
The present disclosure provides a method for preparing a compound represented by general formula (II) or a pharmaceutically acceptable salt thereof, which method includes:
通式(II-A)所示的化合物或其盐在胺化剂存在下发生氨解反应得到通式(II)所示的化合物或其可药用的盐，其中，The compound represented by general formula (II-A) or a salt thereof undergoes an aminolysis reaction in the presence of an aminating agent to obtain a compound represented by general formula (II) or a pharmaceutically acceptable salt thereof, wherein,
RA为氨基，R9为C1-6烷基；进一步当溶剂中含水时，通式(II-A)所示的化合物或其盐同时还发生水解反应得到通式(II)所示的化合物或其可药用的盐，此时RA为羟基或氨基；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). The compound or its pharmaceutically acceptable salt, in which case R A is hydroxyl or amino;
或通式(II-A)所示的化合物或其盐在碱性条件下发生水解反应得到通式(II)所示的化合物或其可药用的盐，其中，R9为C1-6烷基，RA为羟基；Or the compound represented by general formula (II-A) or a salt thereof undergoes a hydrolysis reaction under alkaline conditions to obtain a compound represented by general formula (II) or a pharmaceutically acceptable salt thereof, wherein R 9 is C 1-6 Alkyl group, R A is hydroxyl;
环Cy、RB、R’、X、Ra、Rb、Rc、Rd、RX1、RX2、RX3和r如通式(II)中所定义。Rings Cy, RB , R' , X, Ra, Rb, Rc, Rd, RX1, RX2 , RX3 and r are as defined in general formula (II).
方案五Option five
本公开提供通式(II-1)所示的化合物或其可药用的盐的制备方法，该方法包括：
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:
通式(II-1A)所示的化合物或其盐在酸性条件下脱去氨基保护基得到通式(II-1)所示的化合物或其可药用的盐，其中，The compound represented by general formula (II-1A) or a salt thereof is removed from the amino protecting group under acidic conditions to obtain a compound represented by general formula (II-1) or a pharmaceutically acceptable salt thereof, wherein,
R11、R12和R13均为氨基保护基，优选为Boc；R 11 , R 12 and R 13 are all amino protecting groups, preferably Boc;
R’、X、Ra、Rb、Rc、Rd、RX1、RX2和RX3如通式(II-1)中所定义。R', X, Ra , Rb , Rc , Rd , R
方案六Option six
本公开提供通式(III)所示的化合物或其可药用的盐的制备方法，该方法包括：
The present disclosure provides a method for preparing a compound represented by general formula (III) or a pharmaceutically acceptable salt thereof, which method includes:
通式(IIa)所示的化合物或其盐与通式(IIIb)所示的化合物或其盐(优选为盐酸盐或三氟乙酸盐)在碱性条件下进行缩合反应得到通式(III)所示的化合物或其可药用的盐，其中，The compound represented by general formula (IIa) or a salt thereof and the compound represented by general formula (IIIb) or a salt thereof (preferably hydrochloride or trifluoroacetate) are subjected to a condensation reaction under alkaline conditions to obtain the general formula ( III) The compound or a pharmaceutically acceptable salt thereof, wherein,
其中，R10为卤素(优选为氯原子)或OH；Wherein, R 10 is halogen (preferably chlorine atom) or OH;
当R10为OH时，该反应在缩合剂的存在下发生；When R 10 is OH, this reaction occurs in the presence of a condensing agent;
R’、X、Ra、Rb、Rc、Rd、RX1、RX2、RX3、RB、p、环A、Q1、Q2、Q3、---、Y、Raa和y如通式(III)中所定义。 R ', X , R a , R b , R c , R d , R X1 , R aa and y are as defined in general formula (III).
以上合成方案中的缩合反应，当R10为卤素时，所述缩合反应任选在催化剂存 在下进行，所述催化剂优选4-二甲氨基吡啶。In the condensation reaction in the above synthesis scheme, when R 10 is halogen, the condensation reaction may be carried out in the presence of a catalyst. The catalyst is preferably 4-dimethylaminopyridine.
以上合成方案中提供碱性条件的试剂包括有机碱和无机碱类，所述的有机碱类包括但不限于三乙胺、N,N-二异丙基乙胺(DIPEA)、正丁基锂、二异丙基氨基锂、醋酸钾、叔丁醇钠、叔丁醇钾、四丁基氟化铵、四丁基氟化铵的四氢呋喃溶液或1,8-二氮杂二环十一碳-7-烯，所述的无机碱类包括但不限于氢化钠、磷酸钾、碳酸钠、醋酸钠、醋酸钾、碳酸钾、碳酸铯、氢氧化钠、氢氧化锂、氨水、氟化铯和氢氧化钾。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.
以上合成方案中进行缩合反应时，提供碱性条件的试剂优选三乙胺或N,N-二异丙基乙胺；当R10为OH时，提供碱性条件的试剂优选为N,N-二异丙基乙胺。以上合成方案中发生水解反应时，提供碱性条件的试剂为上述有机碱和无机碱类的水溶液，优选为DIPEA的水溶液。When performing a condensation reaction in the above synthesis scheme, 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. When the hydrolysis reaction occurs in the above synthesis scheme, 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.
上述反应中所述的缩合剂包括但不限于1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐、N,N'-二环己基碳化二亚胺、N,N'-二异丙基碳二酰亚胺、O-苯并三氮唑-N,N,N',N'-四甲基脲四氟硼酸酯、1-羟基苯并三唑、1-羟基-7-偶氮苯并三氮唑、O-苯并三氮唑-N,N,N',N'-四甲脲六氟磷酸酯、O-(7-氮杂苯并三氮唑-1-基)-N,N,N’,N’-四甲基脲六氟磷酸酯(HATU)、2-(7-氧化苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯、苯并三氮唑-1-基氧基三(二甲基氨基)磷鎓六氟磷酸盐或六氟磷酸苯并三唑-1-基-氧基三吡咯烷基磷；优选为HATU。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 hexafluorophosphate, benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate or benzotriazol-1-yl-oxyhexafluorophosphate tripyrrolidinylphosphonium; preferably HATU.
上述合成方案中，提供酸性条件的试剂包括但不限于氯化氢、氯化氢的1,4-二氧六环溶液、盐酸的1,4-二氧六环溶液、三氟乙酸、甲酸、乙酸、盐酸、浓硫酸、甲磺酸、硝酸、磷酸、对苯甲磺酸、Me3SiCl和TMSOTf，优选为三氟乙酸。In the above synthesis scheme, 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.
上述反应中所述的胺化剂包括但不限于：液氨、氨水、尿素、铵盐(NH3的来源)、氨的1,4-二氧六环及有机胺；优选为氨的1,4-二氧六环。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.
上述步骤的反应优选在溶剂中进行，所用的溶剂包括但不限于：吡啶、乙二醇二甲醚、醋酸、甲醇、乙醇、乙腈、正丁醇、甲苯、四氢呋喃、二氯甲烷、石油醚、乙酸乙酯、正己烷、二甲基亚砜、1,4-二氧六环、水、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、1,2-二溴乙烷及其混合物。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.
具体实施方式Detailed ways
以下结合实施例用于进一步描述本公开，但这些实施例并非限制着本公开的范围。The following examples are used to further describe the present disclosure, but these examples do not limit the scope of the present disclosure.
实施例Example
化合物的结构是通过核磁共振(NMR)或/和质谱(MS)来确定的。NMR位移(δ)以10-6(ppm)的单位给出。NMR的测定是用Bruker AVANCE-400核磁仪或Bruker AVANCE NEO 500M，测定溶剂为氘代二甲基亚砜(DMSO-d6)、氘代氯仿(CDCl3)、氘代甲醇(CD3OD)，内标为四甲基硅烷(TMS)。 The structure of the compound is determined by nuclear magnetic resonance (NMR) or/and mass spectrometry (MS). NMR shifts (δ) 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的测定用Agilent 1200/1290 DAD-6110/6120 Quadrupole MS液质联用仪(生产商：Agilent，MS型号：6110/6120 Quadrupole MS)，waters ACQuity UPLC-QD/SQD(生产商：waters，MS型号：waters ACQuity Qda Detector/waters SQ Detector)，THERMO Ultimate 3000-Q Exactive(生产商：THERMO，MS型号：THERMO Q Exactive)。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).
高效液相色谱法(HPLC)分析使用Agilent HPLC 1200DAD、Agilent HPLC1200VWD和Waters HPLC e2695-2489高效液相色谱仪。High performance liquid chromatography (HPLC) analysis used Agilent HPLC 1200DAD, Agilent HPLC1200VWD and Waters HPLC e2695-2489 high performance liquid chromatography.
手性HPLC分析测定使用Agilent 1260 DAD高效液相色谱仪。Chiral HPLC analysis was performed using an Agilent 1260 DAD high performance liquid chromatograph.
高效液相制备使用Waters 2545-2767、Waters 2767-SQ Detecor2、Shimadzu LC-20AP和Gilson GX-281制备型色谱仪。High-performance liquid phase preparation uses Waters 2545-2767, Waters 2767-SQ Detecor2, Shimadzu LC-20AP and Gilson GX-281 preparative chromatographs.
手性制备使用Shimadzu LC-20AP制备型色谱仪。Chiral preparation uses Shimadzu LC-20AP preparative chromatograph.
CombiFlash快速制备仪使用Combiflash Rf200(TELEDYNE ISCO)。CombiFlash rapid preparation instrument uses Combiflash Rf200 (TELEDYNE ISCO).
薄层层析硅胶板使用烟台黄海HSGF254或青岛GF254硅胶板，薄层色谱法(TLC)使用的硅胶板采用的规格是0.15mm～0.2mm，薄层层析分离纯化产品采用的规格是0.4mm～0.5mm。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.
硅胶柱色谱法一般使用烟台黄海硅胶200～300目硅胶为载体。Silica gel column chromatography generally uses Yantai Huanghai Silica Gel 200~300 mesh silica gel as the carrier.
激酶平均抑制率及IC50值的测定用NovoStar酶标仪(德国BMG公司)。The average kinase inhibition rate and IC 50 value were measured using NovoStar microplate reader (BMG Company, Germany).
本公开的已知的起始原料可以采用或按照本领域已知的方法来合成，或可购买自ABCR GmbH&Co.KG，Acros Organics，Aldrich Chemical Company，韶远化学科技(Accela ChemBio Inc)、达瑞化学品等公司。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.
实施例中无特殊说明，反应均能够在氩气氛或氮气氛下进行。There are no special instructions in the examples, and the reactions can be carried out under an argon atmosphere or a nitrogen atmosphere.
氩气氛或氮气氛是指反应瓶连接一个约1L容积的氩气或氮气气球。Argon atmosphere or nitrogen atmosphere means that the reaction bottle is connected to an argon or nitrogen balloon with a volume of about 1L.
氢气氛是指反应瓶连接一个约1L容积的氢气气球。The hydrogen atmosphere refers to the reaction bottle connected to a hydrogen balloon with a volume of about 1L.
加压氢化反应使用Parr 3916EKX型氢化仪和清蓝QL-500型氢气发生器或HC2-SS型氢化仪。The pressurized hydrogenation reaction uses Parr 3916EKX hydrogenator and Clear Blue QL-500 hydrogen generator or HC2-SS hydrogenator.
氢化反应通常抽真空，充入氢气，反复操作3次。The hydrogenation reaction is usually evacuated, filled with hydrogen, and repeated three times.
微波反应使用CEM Discover-S 908860型微波反应器。The microwave reaction uses CEM Discover-S 908860 microwave reactor.
实施例中无特殊说明，溶液是指水溶液。There is no special explanation in the examples, and the solution refers to an aqueous solution.
实施例中无特殊说明，反应的温度为室温，为20℃～30℃。There are no special instructions in the examples. The reaction temperature is room temperature, which is 20°C to 30°C.
实施例中的反应进程的监测采用薄层色谱法(TLC)，反应所使用的展开剂，纯化化合物采用的柱层析的洗脱剂的体系和薄层色谱法的展开剂体系包括：A：二氯甲烷/甲醇体系，B：正己烷/乙酸乙酯体系，C：石油醚/乙酸乙酯体系，溶剂的体积比根据化合物的极性不同而进行调节，也可以加入少量的三乙胺和醋酸等碱性或酸性试剂进行调节。The reaction progress in the embodiment is monitored by thin layer chromatography (TLC). 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.
实施例1-P1和实施例1-P2Example 1-P1 and Example 1-P2
(2R,3S,4S,5R)-3-(3,4-二氟-2-甲氧基苯基)-4,5-二甲基-N-(7-氧代-6,7-二氢吡唑并 [1,5-c]嘧啶-3-基)-5-(三氟甲基)四氢呋喃-2-甲酰胺1-P1(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-N-(7-oxo-6,7-di Hydropyrazolo [1,5-c]pyrimidin-3-yl)-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide 1-P1
(2R,3S,4S,5R)-N-(7-氨基吡唑并[1,5-c]嘧啶-3-基)-3-(3,4-二氟-2-甲氧基苯基)-4,5-二甲基-5-(三氟甲基)四氢呋喃-2-甲酰胺1-P2
(2R,3S,4S,5R)-N-(7-aminopyrazolo[1,5-c]pyrimidin-3-yl)-3-(3,4-difluoro-2-methoxyphenyl )-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide 1-P2
第一步first step
(2R,3S,4S,5R)-3-(3,4-二氟-2-甲氧基苯基)-4,5-二甲基-5-(三氟甲基)四氢呋喃-2-羧酸1b-1(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxy Acid 1b-1
(2S,3R,4R,5S)-3-(3,4-二氟-2-甲氧基苯基)-4,5-二甲基-5-(三氟甲基)四氢呋喃-2-羧酸1b-2(2S,3R,4R,5S)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxy Acid 1b-2
rac-(2R,3S,4S,5R)-3-(3,4-二氟-2-甲氧基苯基)-4,5-二甲基-5-(三氟甲基)四氢呋喃-2-羧酸1a(12g，33.87mmol，采用专利申请“WO2021113627”中说明书第231页实施例3公开的方法制备而得)经手性柱拆分(Waters SFC 150，色谱柱：DAICEL40*250mm,10μm；流动相A：Supercritical CO2，流动相B：IPA)，梯度配比：A:B为90:10，流速：120mL/min)得到标题产物1b-1(5.5g，产率：45.8％) 和1b-2(5.08g，产率：42.3％)。rac-(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2 -Carboxylic acid 1a (12g, 33.87mmol, prepared by the method disclosed in Example 3 on page 231 of the specification in patent application "WO2021113627") was resolved by chiral column (Waters SFC 150, chromatographic column: DAICEL 40*250mm, 10μm; mobile phase A: Supercritical CO2, mobile phase B: IPA), gradient ratio: A:B is 90:10, flow rate: 120mL/min) to obtain the title product 1b-1 (5.5g, yield :45.8%) and 1b-2 (5.08g, yield: 42.3%).
单一构型化合物(较短保留时间)1b-1(5.5g，产率：45.8％)：Single configuration compound (shorter retention time) 1b-1 (5.5g, yield: 45.8%):
MS m/z(ESI):353.2[M-1]。MS m/z(ESI):353.2[M-1].
手性HPLC分析：保留时间2.414分钟，纯度：99％(色谱柱：DAICEL100*3mm，3μm；流动相A：Supercritical CO2，流动相B：IPA(0.1％DEA))，梯度配比：流动相A：60％-95％，流速：1.5mL/min)。Chiral HPLC analysis: retention time 2.414 minutes, purity: 99% (Column: DAICEL 100*3mm, 3μm; 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).
单一构型化合物(较长保留时间)1b-2(5.08g，产率：42.3％)：Single configuration compound (longer retention time) 1b-2 (5.08g, yield: 42.3%):
MS m/z(ESI):353.2[M-1]。MS m/z(ESI):353.2[M-1].
手性HPLC分析：保留时间2.724分钟，纯度：99％(色谱柱：DAICEL100*3mm，3μm；流动相A：Supercritical CO2，流动相B：IPA(0.1％DEA))，梯度配比：流动相A：60％-95％，流速：1.5mL/min)。Chiral HPLC analysis: retention time 2.724 minutes, purity: 99% (Column: DAICEL 100*3mm, 3μm; 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).
第二步Step 2
7-(甲硫基)吡唑并[1,5-c]嘧啶-3-羧酸乙酯1e7-(Methylthio)pyrazolo[1,5-c]pyrimidine-3-carboxylic acid ethyl ester 1e
将(E)-3-(二甲氨基)-2-(2-(甲硫基)嘧啶-4-基)丙烯酸乙酯1c(5g，18.7mmol，采用文献“Journal of Chemical Information and Modeling,2021,vol.61,#1,p.467–480”公开的方法制备而得)溶于二氯甲烷(50mL)中，冰浴滴加2,4,6-三甲基苯磺酰羟胺1d(5.47g，25.43mmol，上海瀚鸿)的二氯甲烷(50mL)溶液，搅拌反应3小时，反应液中加入饱和碳酸氢钠溶液(50mL)，用二氯甲烷萃取(50mL×3)，合并有机相，用无水硫酸钠干燥，过滤除去干燥剂后减压浓缩，残余物用高效液相制备色谱法纯化(Waters-2545，色谱柱：YMC Triart-Exrs C18,30*150mm,5μm；流动相：水相(10mmol/L碳酸氢铵)和乙腈，梯度配比：乙腈30％-45％，流速：30mL/min)得到标题化合物1e(140mg，产率：3％)。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. The residue was purified by high performance liquid phase preparative chromatography (Waters-2545, chromatographic column: YMC Triart-Exrs C18, 30*150mm, 5μm; mobile phase : aqueous phase (10 mmol/L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 30%-45%, flow rate: 30 mL/min) to obtain the title compound 1e (140 mg, yield: 3%).
MS m/z(ESI):238.2[M+1]。MS m/z(ESI):238.2[M+1].
第三步third step
7-(甲硫基)吡唑并[1,5-c]嘧啶-3-羧酸1f7-(Methylthio)pyrazolo[1,5-c]pyrimidine-3-carboxylic acid 1f
将化合物1e(130mg，547μmol)溶于四氢呋喃/甲醇/水(1/1/0.5)的混合溶剂(5mL)中，加入氢氧化锂(115mg，2.74mmol)，搅拌反应3小时，反应液中加水稀释，用乙酸乙酯萃取(5mL×3)，合并有机相，用无水硫酸钠干燥，过滤除去干燥剂后减压浓缩即得到粗品标题化合物1f(100mg)，产品不经纯化直接用于下一步反应。MS m/z(ESI):210.2[M+1]。Compound 1e (130 mg, 547 μmol) was dissolved in a mixed solvent (5 mL) of tetrahydrofuran/methanol/water (1/1/0.5), lithium hydroxide (115 mg, 2.74 mmol) was added, and the reaction was stirred for 3 hours. Water was added to the reaction solution. Dilute, extract with ethyl acetate (5mL One step reaction. MS m/z(ESI):210.2[M+1].
第四步the fourth step
(7-(甲硫基)吡唑并[1,5-c]嘧啶-3-基)氨基甲酸叔丁酯1g(7-(Methylthio)pyrazolo[1,5-c]pyrimidin-3-yl)carbamic acid tert-butyl ester 1g
将化合物1f(100mg，478μmol)溶于叔丁醇(0.2mL)和甲苯(5mL)，加入叠氮磷酸二苯酯(DPPA)(127.8mg，525.7μmol)，三乙胺(144mg，1.42mmol)，90℃搅拌反应16小时，反应液冷却至室温，减压浓缩，残余物用硅胶柱色谱法以洗脱剂体系A纯化得到标题化合物1g(8mg，5.97％)。 Compound 1f (100 mg, 478 μmol) was dissolved in tert-butanol (0.2 mL) and toluene (5 mL), and diphenylphosphoryl azide (DPPA) (127.8 mg, 525.7 μmol) and triethylamine (144 mg, 1.42 mmol) were added. , the reaction was stirred at 90° C. for 16 hours. The reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent system A to obtain 1 g of the title compound (8 mg, 5.97%).
MS m/z(ESI):281.2[M+1]。MS m/z(ESI):281.2[M+1].
第五步the fifth step
7-(甲硫基)吡唑并[1,5-c]嘧啶-3-胺盐酸盐1h7-(Methylthio)pyrazolo[1,5-c]pyrimidin-3-amine hydrochloride 1h
将化合物1g(8mg，28μmol)溶于1mL二氯甲烷中，加入0.5mL 4M HCl二氧六环溶液，搅拌反应3小时，反应液减压浓缩即得到粗品标题化合物1h(5mg)，不经纯化，直接用于下一步反应。Dissolve 1g of compound (8mg, 28μmol) in 1mL of methylene chloride, add 0.5mL of 4M HCl dioxane solution, stir and react for 3 hours, and concentrate the reaction solution under reduced pressure to obtain the crude title compound 1h (5mg) without purification , used directly for the next reaction.
MS m/z(ESI):181.2[M+1]。MS m/z(ESI):181.2[M+1].
第六步Step 6
(2R,3S,4S,5R)-3-(3,4-二氟-2-甲氧基苯基)-4,5-二甲基-N-(7-(甲硫基)吡唑并[1,5-c]嘧啶-3-基)-5-(三氟甲基)四氢呋喃-2-甲酰胺1i(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-N-(7-(methylthio)pyrazolo [1,5-c]pyrimidin-3-yl)-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide 1i
将化合物1h(5mg，27μmol)，化合物1b-1(13mg，36μmol)溶于0.5mL N,N-二甲基甲酰胺中，冰浴下加入N,N-二异丙基乙胺(14mg，110μmol)和O-(7-氮杂苯并三氮唑-1-基)-N,N,N’,N’-四甲基脲六氟磷酸酯(HATU)(16mg，44μmol)，保持温度反应1小时，反应液减压浓缩，残余物用硅胶柱色谱法以洗脱体系A纯化得到标题化合物1i(10mg，产率：52.7％)。Compound 1h (5 mg, 27 μmol) and compound 1b-1 (13 mg, 36 μmol) were dissolved in 0.5 mL N,N-dimethylformamide, and N,N-diisopropylethylamine (14 mg, 110 μmol) and O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethylurea hexafluorophosphate (HATU) (16 mg, 44 μmol), maintaining temperature The reaction was carried out for 1 hour, and the reaction solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using elution system A to obtain the title compound 1i (10 mg, yield: 52.7%).
MS m/z(ESI):517.2[M+1]。MS m/z(ESI):517.2[M+1].
第七步Step 7
(2R,3S,4S,5R)-3-(3,4-二氟-2-甲氧基苯基)-4,5-二甲基-N-(7-(甲磺酰基)吡唑并[1,5-c]嘧啶-3-基)-5-(三氟甲基)四氢呋喃-2-甲酰胺1j(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-N-(7-(methanesulfonyl)pyrazolo [1,5-c]pyrimidin-3-yl)-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide 1j
将化合物1i(10mg，19.3μmol)溶于二氯甲烷(0.5mL)，加入间氯过氧苯甲酸(10mg，57.9μmol，上海泰坦)，搅拌反应2小时，反应液减压浓缩即得粗品标题化合物1j(20mg)，产物不经纯化，直接用于下步反应。Compound 1i (10 mg, 19.3 μmol) was dissolved in dichloromethane (0.5 mL), m-chloroperoxybenzoic acid (10 mg, 57.9 μmol, Shanghai Titan) was added, and the reaction was stirred for 2 hours. The reaction solution was concentrated under reduced pressure to obtain the crude product title. Compound 1j (20 mg), the product was directly used in the next reaction without purification.
MS m/z(ESI):549.2[M+1]。MS m/z(ESI):549.2[M+1].
第八步Step 8
(2R,3S,4S,5R)-3-(3,4-二氟-2-甲氧基苯基)-4,5-二甲基-N-(7-氧代-6,7-二氢吡唑并[1,5-c]嘧啶-3-基)-5-(三氟甲基)四氢呋喃-2-甲酰胺1-P1(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-N-(7-oxo-6,7-di Hydropyrazolo[1,5-c]pyrimidin-3-yl)-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide 1-P1
(2R,3S,4S,5R)-N-(7-氨基吡唑并[1,5-c]嘧啶-3-基)-3-(3,4-二氟-2-甲氧基苯基)-4,5-二甲基-5-(三氟甲基)四氢呋喃-2-甲酰胺1-P2(2R,3S,4S,5R)-N-(7-aminopyrazolo[1,5-c]pyrimidin-3-yl)-3-(3,4-difluoro-2-methoxyphenyl )-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide 1-P2
将化合物1j(10mg，18.2μmol)加入10mL 0.4M氨的1,4-二氧六环溶液(含少量水)，搅拌反应1小时，反应液减压浓缩，残余物用高效液相制备色谱法纯化(Waters-2545，色谱柱：YMC Triart-Exrs C18,30*150mm，5μm；流动相：水相(10mmol/L碳酸氢铵)和乙腈，梯度配比：乙腈30％-45％，流速：30mL/min)得到标题化合物1-P1(2mg，22.59％)和化合物1-P2(2mg，22.5％)。Compound 1j (10 mg, 18.2 μmol) was added to 10 mL of 0.4 M ammonia solution in 1,4-dioxane (containing a small amount of water), and the reaction was stirred for 1 hour. The reaction solution was concentrated under reduced pressure, and the residue was subjected to high-performance liquid phase preparative chromatography. Purification (Waters-2545, column: YMC Triart-Exrs C18, 30*150mm, 5μm; mobile phase: water phase (10mmol/L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 30%-45%, flow rate: 30 mL/min) to obtain the title compound 1-P1 (2 mg, 22.59%) and compound 1-P2 (2 mg, 22.5%).
化合物1-P1:Compound 1-P1:
MS m/z(ESI):487.2[M+1]。MS m/z(ESI):487.2[M+1].
1H NMR(500MHz,MeOD):δ8.19(s,1H),7.16(ddd,1H),7.02(dd,2H),6.59(d,1H), 5.13(d,1H),4.33(dd,1H),4.02(d,3H),2.82(p,1H),1.69(s,3H),0.90-0.75(m,3H)。化合物1-P2: 1 H NMR (500MHz, MeOD): δ8.19(s,1H),7.16(ddd,1H),7.02(dd,2H),6.59(d,1H), 5.13(d,1H),4.33(dd,1H),4.02(d,3H),2.82(p,1H),1.69(s,3H),0.90-0.75(m,3H). Compound 1-P2:
MS m/z(ESI):486.2[M+1]。MS m/z(ESI):486.2[M+1].
1H NMR(500MHz,MeOD):δ8.19(s,1H),7.40(d,1H),7.17(ddd,1H),7.06-6.97(m,1H),6.82(d,1H),5.14(d,1H),4.34(dd,1H),4.02(d,3H),2.82(p,1H),1.70(s,3H),0.89-0.77(m,3H)。 1 H NMR (500MHz, MeOD): δ8.19(s,1H),7.40(d,1H),7.17(ddd,1H),7.06-6.97(m,1H),6.82(d,1H),5.14( d,1H),4.34(dd,1H),4.02(d,3H),2.82(p,1H),1.70(s,3H),0.89-0.77(m,3H).
实施例2Example 2
(2R,3S,4S,5R)-N-(2-氨基-[1,2,4]三唑并[1,5-a]吡啶-7-基)-3-(3,4-二氟-2-甲氧基苯基)-4,5-二甲基-5-(三氟甲基)四氢呋喃-2-甲酰胺2
(2R,3S,4S,5R)-N-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-3-(3,4-difluoro -2-Methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide 2
第一步first step
(7-溴-[1,2,4]三唑并[1,5-a]吡啶-2-基)(叔丁氧基羰基)氨基甲酸叔丁酯2b(7-Bromo-[1,2,4]triazolo[1,5-a]pyridin-2-yl)(tert-butoxycarbonyl)carbamic acid tert-butyl ester 2b
将7-溴-[1,2,4]三唑并[1,5-a]吡啶-2-胺2a(1g，4.71mmol，上海韶远)溶于二氯甲烷(25mL)，甲醇(10mL)和四氢呋喃(10mL)的混合溶剂中，加入二碳酸二叔丁酯(1.2g，5.5mmol，上海韶远)，搅拌反应24小时，反应液过滤，滤液减压浓缩，残余物溶于乙酸乙酯(30mL)中，用水洗涤，有机相用无水硫酸钠干燥，过滤除去干燥剂后减压浓缩，残余物用硅胶柱色谱法以洗脱体系A纯化得到标题化合物2b(500mg，产率：25％)。Dissolve 7-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-amine 2a (1g, 4.71mmol, Shaoyuan, Shanghai) in dichloromethane (25mL), methanol (10mL ) and tetrahydrofuran (10 mL), add di-tert-butyl dicarbonate (1.2 g, 5.5 mmol, Shaoyuan, Shanghai), stir and react for 24 hours, filter the reaction solution, and concentrate the filtrate under reduced pressure. The residue is dissolved in ethyl acetate. ester (30 mL), washed with water, the organic phase was dried over anhydrous sodium sulfate, filtered to remove the desiccant and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with elution system A to obtain the title compound 2b (500 mg, yield: 25%).
MS m/z(ESI):212.9[M-199]。MS m/z(ESI):212.9[M-199].
第二步Step 2
(叔丁氧基羰基)(7-((叔丁氧基羰基)氨基)-[1,2,4]三唑并[1,5-a]吡啶-2-基)氨基甲酸叔丁酯2c(tert-butoxycarbonyl)(7-((tert-butoxycarbonyl)amino)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)carbamate 2c
将化合物2b(500mg，1.21mmol)溶于1,4-二氧六环(10mL)，加入氨基甲酸叔丁酯(180mg，1.54mmol，上海韶远)，甲烷磺酸(2-二环己基膦-3,6-二甲氧基-2',4',6'-三异丙基-1,1'-联苯)(2'-氨基-1,1'-联苯基-2-基)钯(II)(BrettPhos Pd G3)(50mg，55.16μmol，sigma)，碳酸铯(800mg，2.4mmol)，氮气置换，100℃反应3小时，反应液 降至室温，过滤，滤液减压浓缩，残余物用硅胶柱色谱法以洗脱体系A纯化得到标题化合物2c(300mg，产率：55％)。Compound 2b (500 mg, 1.21 mmol) was dissolved in 1,4-dioxane (10 mL), tert-butyl carbamate (180 mg, 1.54 mmol, Shanghai Shaoyuan), methane sulfonic acid (2-dicyclohexylphosphine) were added -3,6-Dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl) (2'-amino-1,1'-biphenyl-2-yl ) Palladium (II) (BrettPhos Pd G3) (50 mg, 55.16 μmol, sigma), cesium carbonate (800 mg, 2.4 mmol), nitrogen replacement, reaction at 100°C for 3 hours, reaction solution The mixture was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using elution system A to obtain the title compound 2c (300 mg, yield: 55%).
MS m/z(ESI):450.2[M+1]。MS m/z(ESI):450.2[M+1].
第三步third step
[1,2,4]三唑并[1,5-a]吡啶-2,7-二胺二(2,2,2-三氟乙酸)盐2d[1,2,4]Triazolo[1,5-a]pyridine-2,7-diaminebis(2,2,2-trifluoroacetic acid) salt 2d
将化合物2c(100mg，222.4μmol)溶于二氯甲烷(5mL)，加入5mL三氟醋酸(1mL)，搅拌反应1小时，反应液减压浓缩即得到粗品标题化合物2d(83mg)，不经纯化，直接用于下一步反应。Compound 2c (100 mg, 222.4 μmol) was dissolved in dichloromethane (5 mL), 5 mL of trifluoroacetic acid (1 mL) was added, and the reaction was stirred for 1 hour. The reaction solution was concentrated under reduced pressure to obtain the crude title compound 2d (83 mg) without purification. , used directly for the next reaction.
MS m/z(ESI):150.2[M+1]。MS m/z(ESI):150.2[M+1].
第四步the fourth step
(2R,3S,4S,5R)-N-(2-氨基-[1,2,4]三唑并[1,5-a]吡啶-7-基)-3-(3,4-二氟-2-甲氧基苯基)-4,5-二甲基-5-(三氟甲基)四氢呋喃-2-甲酰胺2(2R,3S,4S,5R)-N-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-3-(3,4-difluoro -2-Methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide 2
将化合物1b-1(21mg，29μmol)，粗品化合物2d(30mg，79.8μmol)溶于2mL N,N-二甲基甲酰胺中，冰浴下加入N,N-二异丙基乙胺(25mg，193μmol)和O-(7-氮杂苯并三氮唑-1-基)-N,N,N’,N’-四甲基脲六氟磷酸酯(HATU)(34mg，89μmol)，保持温度反应2小时，反应液用高效液相制备色谱法纯化(Waters-2545，色谱柱：YMC Triart-Exrs C18,30*150mm，5μm；流动相：水相(10mmol/L碳酸氢铵)和乙腈，梯度配比：乙腈35％-45％，流速：30mL/min)得到标题化合物2(2.5mg，产率：8.6％)。Compound 1b-1 (21 mg, 29 μmol) and crude compound 2d (30 mg, 79.8 μmol) were dissolved in 2 mL N,N-dimethylformamide, and N,N-diisopropylethylamine (25 mg) was added under ice bath. , 193 μmol) and O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethylurea hexafluorophosphate (HATU) (34 mg, 89 μmol), maintained React at room temperature for 2 hours, and the reaction solution is purified by high-performance liquid phase preparative chromatography (Waters-2545, chromatographic column: YMC Triart-Exrs C18, 30*150mm, 5μm; mobile phase: aqueous phase (10mmol/L ammonium bicarbonate) and acetonitrile , gradient ratio: acetonitrile 35%-45%, flow rate: 30mL/min) to obtain the title compound 2 (2.5mg, yield: 8.6%).
MS m/z(ESI):486.2[M+1]。MS m/z(ESI):486.2[M+1].
1H NMR(500MHz,DMSO-d6):δ10.53(s,1H),8.43-8.41(m,1H),7.74-7.73(m,1H),7.20-7.11(m,2H),7.01-6.99(m,1H),5.91(s,2H),5.09-5.01(m,1H),4.27-4.25(m,1H),3.95(s,3H),2.79-2.76(m,1H),1.60(s,3H),0.74-0.72(m,3H)。 1 H NMR (500MHz, DMSO-d 6 ): δ10.53(s,1H),8.43-8.41(m,1H),7.74-7.73(m,1H),7.20-7.11(m,2H),7.01- 6.99(m,1H),5.91(s,2H),5.09-5.01(m,1H),4.27-4.25(m,1H),3.95(s,3H),2.79-2.76(m,1H),1.60( s,3H),0.74-0.72(m,3H).
实施例3Example 3
(2R,3S,4S,5R)-N-(2-氨基-1H-苯并[d]咪唑-5-基)-3-(3,4-二氟-2-甲氧基苯基)-4,5-二甲基-5-(三氟甲基)四氢呋喃-2-甲酰胺3

(2R,3S,4S,5R)-N-(2-amino-1H-benzo[d]imidazol-5-yl)-3-(3,4-difluoro-2-methoxyphenyl)- 4,5-Dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide 3

第一步first step
2-(双(叔丁氧基羰基)氨基)-6-硝基-1H-苯并[d]咪唑-1-羧酸叔丁酯3b2-(Bis(tert-butoxycarbonyl)amino)-6-nitro-1H-benzo[d]imidazole-1-carboxylic acid tert-butyl ester 3b
将6-硝基-1H-苯并[d]咪唑-2-胺3a(1g，5.6mmol，上海瀚鸿)溶于四氢呋喃(50mL)中，加入二碳酸二叔丁酯(4g，18.3mmol)和4-二甲氨基吡啶(100mg，0.82mmol)，搅拌反应3小时，反应液过滤，滤液减压浓缩，残余物溶于乙酸乙酯(30mL)，用水洗涤，有机相用无水硫酸钠干燥，过滤除去干燥剂后减压浓缩，残余物用硅胶柱色谱法以洗脱体系B纯化得到标题化合物3b(1.2g，产率：44％)。Dissolve 6-nitro-1H-benzo[d]imidazole-2-amine 3a (1g, 5.6mmol, Shanghai Hanhong) in tetrahydrofuran (50mL), and add di-tert-butyl dicarbonate (4g, 18.3mmol) and 4-dimethylaminopyridine (100 mg, 0.82 mmol), stirred for 3 hours, the reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The residue was dissolved in ethyl acetate (30 mL), washed with water, and the organic phase was dried over anhydrous sodium sulfate. , filtered to remove the drying agent and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using elution system B to obtain the title compound 3b (1.2 g, yield: 44%).
第二步Step 2
6-氨基-2-(双(叔丁氧基羰基)氨基)-1H-苯并[d]咪唑-1-羧酸叔丁酯3c6-Amino-2-(bis(tert-butoxycarbonyl)amino)-1H-benzo[d]imidazole-1-carboxylic acid tert-butyl ester 3c
将化合物3b(400mg，836μmol)溶于甲醇(5mL)和四氢呋喃(5mL)中，加入10％钯碳催化剂(湿)(100mg)，氢气氛围下，搅拌反应14小时，反应液过滤，滤液减压浓缩即得到粗品标题化合物3c(300mg)。Compound 3b (400 mg, 836 μmol) was dissolved in methanol (5 mL) and tetrahydrofuran (5 mL), 10% palladium on carbon catalyst (wet) (100 mg) was added, and the reaction was stirred for 14 hours under a hydrogen atmosphere. The reaction liquid was filtered, and the filtrate was decompressed. Concentration gave crude title compound 3c (300 mg).
第三步third step
2-(双(叔丁氧基羰基)氨基)-5-((2R,3S,4S,5R)-3-(3,4-二氟-2-甲氧基苯基)-4,5-二甲基-5-(三氟甲基)四氢呋喃-2-甲酰胺)-1H-苯并[d]咪唑-1-羧酸叔丁酯3d2-(Bis(tert-butoxycarbonyl)amino)-5-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5- Dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide)-1H-benzo[d]imidazole-1-carboxylic acid tert-butyl ester 3d
将化合物1b-1(20mg，56.4μmol)，粗品化合物3c(35mg，78μmol)溶于2mL N,N-二甲基甲酰胺中，冰浴下加入N,N-二异丙基乙胺(25mg，193μmol)和O-(7-氮杂苯并三氮唑-1-基)-N,N,N’,N’-四甲基脲六氟磷酸酯(HATU)(28mg，73.6μmol)，保持温度反应2小时，反应液减压浓缩，残余物用硅胶柱色谱法以洗脱剂体系B纯化得到标题化合物3d(21mg，产率：47％)。Compound 1b-1 (20 mg, 56.4 μmol) and crude compound 3c (35 mg, 78 μmol) were dissolved in 2 mL N,N-dimethylformamide, and N,N-diisopropylethylamine (25 mg) was added under ice bath. , 193 μmol) and O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethylurea hexafluorophosphate (HATU) (28 mg, 73.6 μmol), The temperature was maintained for 2 hours, and the reaction solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent system B to obtain the title compound 3d (21 mg, yield: 47%).
MS m/z(ESI):785.2[M+1]。MS m/z(ESI):785.2[M+1].
第四步the fourth step
(2R,3S,4S,5R)-N-(2-氨基-1H-苯并[d]咪唑-5-基)-3-(3,4-二氟-2-甲氧基苯基)-4,5-二甲基-5-(三氟甲基)四氢呋喃-2-甲酰胺3(2R,3S,4S,5R)-N-(2-amino-1H-benzo[d]imidazol-5-yl)-3-(3,4-difluoro-2-methoxyphenyl)- 4,5-Dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide 3
将化合物3d(20mg，25.4μmol)溶于二氯甲烷(2mL)，加入2mL三氟醋酸(1mL)，搅拌反应0.5小时，反应液减压浓缩，残余物用高效液相制备色谱法纯化(Waters-2545，色谱柱：YMC Triart-Exrs C18，30*150mm,5μm；流动相：水相(10mmol/L碳酸氢铵)和乙腈，梯度配比：乙腈35％-45％，流速：30mL/min)得到标题化合物3(3mg，产率：24％)。 Compound 3d (20 mg, 25.4 μmol) was dissolved in dichloromethane (2 mL), 2 mL of trifluoroacetic acid (1 mL) was added, and the reaction was stirred for 0.5 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by high-performance liquid phase preparative chromatography (Waters -2545, column: YMC Triart-Exrs C18, 30*150mm, 5μm; mobile phase: aqueous phase (10mmol/L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 35%-45%, flow rate: 30mL/min ) to obtain the title compound 3 (3 mg, yield: 24%).
MS m/z(ESI):485.2[M+1]。MS m/z(ESI):485.2[M+1].
1H NMR(500MHz,DMSO-d6):δ10.65(br,1H),9.99(s,1H),7.50(s,1H),7.22-7.11(m,2H),7.05-6.96(m,2H),6.12(s,2H),5.10-4.96(m,1H),4.31-4.21(m,1H),3.96(s,3H),2.80-2.68(m,1H),1.59(s,3H),0.76-0.72(m,3H)。 1 H NMR (500MHz, DMSO-d 6 ): δ10.65(br,1H),9.99(s,1H),7.50(s,1H),7.22-7.11(m,2H),7.05-6.96(m, 2H),6.12(s,2H),5.10-4.96(m,1H),4.31-4.21(m,1H),3.96(s,3H),2.80-2.68(m,1H),1.59(s,3H) ,0.76-0.72(m,3H).
实施例4Example 4
(2R,3S,4S,5R)-3-(3,4-二氟-2-甲氧基苯基)-4,5-二甲基-N-(1-氧代-1,2-二氢吡咯并[1,2-a]吡嗪-6-基)-5-(三氟甲基)四氢呋喃-2-甲酰胺4
(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-N-(1-oxo-1,2-di Hydropyrrolo[1,2-a]pyrazin-6-yl)-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide 4
第一步first step
6-溴-1-氯吡咯并[1,2-a]吡嗪4b6-Bromo-1-chloropyrrolo[1,2-a]pyrazine 4b
将1-氯吡咯并[1,2-a]吡嗪4a(1.53g，10mmol，上海毕得)溶于四氢呋喃(30mL)中，冰浴下加入二溴海因(1.41g，5mmol)，保持温度反应1小时，反应液中加入乙酸乙酯稀释，用饱和碳酸氢钠溶液洗涤，有机相减压浓缩，残余物用硅胶柱色谱法以洗脱体系B纯化得到标题化合物4b(1.86g，产率：80％)。Dissolve 1-chloropyrrolo[1,2-a]pyrazine 4a (1.53g, 10mmol, Shanghai Bide) in tetrahydrofuran (30mL), add dibromohydantoin (1.41g, 5mmol) under ice bath, and keep The reaction solution was reacted at room temperature for 1 hour. The reaction solution was diluted with ethyl acetate, washed with saturated sodium bicarbonate solution, and the organic phase was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with elution system B to obtain the title compound 4b (1.86g, product rate: 80%).
MS m/z(ESI):230.9[M+1]。MS m/z(ESI):230.9[M+1].
第二步Step 2
6-溴吡咯并[1,2-a]吡嗪-1(2H)-酮4c6-Bromopyrrolo[1,2-a]pyrazin-1(2H)-one 4c
将化合物4b(1.74g，7.5mmol)溶于甲醇(15mL)中，加入浓盐酸(15mL)，80℃下搅拌反应2小时，反应液降至室温，用碳酸氢钠中和后减压浓缩，残余物用硅胶柱色谱法以洗脱体系B纯化得到标题化合物4c(1.48g，产率：92％)。Compound 4b (1.74g, 7.5mmol) was dissolved in methanol (15mL), concentrated hydrochloric acid (15mL) was added, and the reaction was stirred at 80°C for 2 hours. The reaction solution was cooled to room temperature, neutralized with sodium bicarbonate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using elution system B to obtain the title compound 4c (1.48 g, yield: 92%).
MS m/z(ESI):213.0[M+1]。MS m/z(ESI):213.0[M+1].
第三步third step
6-((二苯基亚甲基)氨基)吡咯并[1,2-a]吡嗪-1(2H)-酮4d6-((Diphenylmethylene)amino)pyrrolo[1,2-a]pyrazin-1(2H)-one 4d
将化合物4c(427mg，2mmol)溶于甲苯(11mL)中，加入二苯甲酮亚胺(727mg，4mmol，上海韶远)，三(二亚苄基丙酮)二钯(184mg，201μmol，上海泰坦)，4,5-双二苯基膦-9,9-二甲基氧杂蒽(230mg，401μmol，上海泰坦)，叔丁醇钠(578mg， 6mmol)，氮气置换，100℃搅拌反应16小时，反应液降至室温后减压浓缩，残余物用硅胶柱色谱法以洗脱体系B纯化得到标题化合物4d(550mg，产率：87.5％)。Compound 4c (427 mg, 2 mmol) was dissolved in toluene (11 mL), benzophenone imine (727 mg, 4 mmol, Shanghai Shaoyuan), tris(dibenzylideneacetone) dipalladium (184 mg, 201 μmol, Shanghai Titan) were added ), 4,5-bisdiphenylphosphine-9,9-dimethylxanthene (230mg, 401μmol, Shanghai Titan), sodium tert-butoxide (578mg, 6 mmol), replaced with nitrogen, and stirred for 16 hours at 100°C. The reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using elution system B to obtain the title compound 4d (550 mg, yield: 87.5%).
MS m/z(ESI):314.0[M+1]。MS m/z(ESI):314.0[M+1].
第四步the fourth step
6-氨基吡咯并[1,2-a]吡嗪-1(2H)-酮4e6-Aminopyrrolo[1,2-a]pyrazin-1(2H)-one 4e
将化合物4d(40mg，127μmol)溶于1mL甲醇中，加入0.2mL 4M盐酸1,4-二氧六环溶液，搅拌反应1.5小时，反应液用饱和碳酸氢钠溶液中和后减压浓缩，即得到粗品标题化合物4e(19mg)，产物不经纯化，直接用于下一步反应。Dissolve compound 4d (40mg, 127μmol) 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.
MS m/z(ESI):150.2[M+1]。MS m/z(ESI):150.2[M+1].
第五步the fifth step
(2R,3S,4S,5R)-3-(3,4-二氟-2-甲氧基苯基)-4,5-二甲基-N-(1-氧代-1,2-二氢吡咯并[1,2-a]吡嗪-6-基)-5-(三氟甲基)四氢呋喃-2-甲酰胺4(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-N-(1-oxo-1,2-di Hydropyrrolo[1,2-a]pyrazin-6-yl)-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide 4
将化合物1b-1(35mg，100μmol)，粗品化合物4e(30mg，201μmol)溶于2mL N,N-二甲基甲酰胺中，冰浴下加入N,N-二异丙基乙胺(65mg，501μmol)和O-(7-氮杂苯并三氮唑-1-基)-N,N,N’,N’-四甲基脲六氟磷酸酯(HATU)(57mg，150μmol)，保持温度反应2小时，反应液用高效液相制备色谱法纯化(Waters-2545，色谱柱：YMC Triart-Exrs C18，30*150mm，5μm；流动相：水相(10mmol/L碳酸氢铵)和乙腈，梯度配比：乙腈30％-45％，流速：30mL/min)得到标题化合物4(8mg，产率：16％)。Compound 1b-1 (35 mg, 100 μmol) and crude compound 4e (30 mg, 201 μmol) were dissolved in 2 mL of N,N-dimethylformamide, and N,N-diisopropylethylamine (65 mg, 501 μmol) and O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethylurea hexafluorophosphate (HATU) (57 mg, 150 μmol), maintaining temperature React for 2 hours, and the reaction solution is purified by high performance liquid phase preparative chromatography (Waters-2545, chromatographic column: YMC Triart-Exrs C18, 30*150mm, 5μm; mobile phase: aqueous phase (10mmol/L ammonium bicarbonate) and acetonitrile, Gradient ratio: acetonitrile 30%-45%, flow rate: 30 mL/min) to obtain the title compound 4 (8 mg, yield: 16%).
MS m/z(ESI):486.2[M+1]。MS m/z(ESI):486.2[M+1].
1H NMR(500MHz,MeOD):δ7.18(t,1H),7.05(d,1H),7.00(q,1H),6.85(d,1H),6.57(d,1H),6.48(d,1H),5.16(d,1H),4.32(q,1H),4.00(s,3H),2.84-2.78(m,1H),1.69(s,3H),0.84(d,3H)。 1 H NMR (500MHz, MeOD): δ7.18(t,1H),7.05(d,1H),7.00(q,1H),6.85(d,1H),6.57(d,1H),6.48(d, 1H),5.16(d,1H),4.32(q,1H),4.00(s,3H),2.84-2.78(m,1H),1.69(s,3H),0.84(d,3H).
实施例5Example 5
(2R,3S,4S,5R)-3-(3,4-二氟-2-甲氧基苯基)-4,5-二甲基-N-(7-氧代-6,7-二氢-1H-吡咯并[2,3-c]吡啶-3-基)-5-(三氟甲基)四氢呋喃-2-甲酰胺5

(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-N-(7-oxo-6,7-di Hydrogen-1H-pyrrolo[2,3-c]pyridin-3-yl)-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide 5

第一步first step
7-甲氧基-3-硝基-1H-吡咯并[2,3-c]吡啶5b7-methoxy-3-nitro-1H-pyrrolo[2,3-c]pyridine 5b
将7-甲氧基-1H-吡咯并[2,3-c]吡啶5a(1g，6.7mmol，上海毕得)溶于浓硫酸(5mL)中，冰浴下分批加入硝酸钾(820mg，8.1mmol)，保持温度反应2小时，反应液中倒入冰水中，有黄色固体析出，过滤，滤饼用水洗涤，干燥后即得到粗品标题化合物5b(1g)，产物不经纯化，直接用于下一步反应。Dissolve 7-methoxy-1H-pyrrolo[2,3-c]pyridine 5a (1g, 6.7mmol, Shanghai Bide) in concentrated sulfuric acid (5mL), and add potassium nitrate (820mg) in batches under ice bath. 8.1mmol), keep the temperature for 2 hours, pour ice water into the reaction solution, a yellow solid will precipitate, filter, wash the filter cake with water, and dry it to obtain the crude title compound 5b (1g). The product is directly used without purification. Next reaction.
MS m/z(ESI):194.2[M+1]。MS m/z(ESI):194.2[M+1].
第二步Step 2
3-硝基-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮5c3-nitro-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one 5c
将化合物5b(200mg，1mmol)溶于2mL 4M盐酸1,4-二氧六环溶液，100℃搅拌反应16小时，反应液降至室温，有黄色固体析出，过滤，滤饼用乙醇洗涤，干燥后即得到粗品标题化合物5c(100mg)，产物不经纯化，直接用于下一步反应。Dissolve compound 5b (200 mg, 1 mmol) in 2 mL of 4M hydrochloric acid 1,4-dioxane solution. Stir and react at 100°C for 16 hours. The reaction solution cools to room temperature and a yellow solid precipitates. Filter and wash the filter cake with ethanol and dry. Afterwards, the crude title compound 5c (100 mg) was obtained. The product was directly used in the next reaction without purification.
MS m/z(ESI):180.1[M+1]。MS m/z(ESI):180.1[M+1].
第三步third step
3-氨基-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮5d3-Amino-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one 5d
将化合物5c(50mg，279μmol)溶于5mL异丙醇，加入雷尼镍(100mg)和1mL水合肼，85℃搅拌反应2小时，反应液降至室温后过滤，滤液减压浓缩即得到粗品标题化合物5d(40mg)，产物不经纯化，直接用于下一步反应。Dissolve compound 5c (50 mg, 279 μmol) in 5 mL of isopropanol, add Raney nickel (100 mg) and 1 mL of hydrazine hydrate, stir and react at 85°C for 2 hours, filter the reaction solution after cooling to room temperature, and concentrate the filtrate under reduced pressure to obtain the crude product title Compound 5d (40 mg), the product was directly used in the next reaction without purification.
MS m/z(ESI):150.1[M+1]。MS m/z(ESI):150.1[M+1].
第四步the fourth step
(2R,3S,4S,5R)-3-(3,4-二氟-2-甲氧基苯基)-4,5-二甲基-N-(7-氧代-6,7-二氢-1H-吡咯并[2,3-c]吡啶-3-基)-5-(三氟甲基)四氢呋喃-2-甲酰胺5(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-N-(7-oxo-6,7-di Hydrogen-1H-pyrrolo[2,3-c]pyridin-3-yl)-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide 5
将化合物1b-1(40mg，112.9μmol)，粗品化合物5d(40mg，268.1μmol)溶于2mL N,N-二甲基甲酰胺中，冰浴下加入N,N-二异丙基乙胺(50mg，386μmol)和O-(7-氮杂苯并三氮唑-1-基)-N,N,N’,N’-四甲基脲六氟磷酸酯(HATU)(70mg，184μmol)，保持温度反应2小时，反应液用高效液相制备色谱法纯化(Waters-2545，色谱柱：YMC Triart-Exrs C18，30*150mm，5μm；流动相：水相(10mmol/L碳酸氢铵)和乙腈，梯度配比：乙腈30％-45％，流速：30mL/min)得到标题化合物5(12mg， 产率：21％)。Compound 1b-1 (40 mg, 112.9 μmol) and crude compound 5d (40 mg, 268.1 μmol) were dissolved in 2 mL of N,N-dimethylformamide, and N,N-diisopropylethylamine ( 50 mg, 386 μmol) and O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethylurea hexafluorophosphate (HATU) (70 mg, 184 μmol), The temperature was maintained for 2 hours, and the reaction solution was purified by high-performance liquid phase preparative chromatography (Waters-2545, chromatographic column: YMC Triart-Exrs C18, 30*150mm, 5 μm; mobile phase: aqueous phase (10mmol/L ammonium bicarbonate) and Acetonitrile, gradient ratio: acetonitrile 30%-45%, flow rate: 30mL/min) to obtain the title compound 5 (12mg, Yield: 21%).
MS m/z(ESI):486.2[M+1]。MS m/z(ESI):486.2[M+1].
1H NMR(500MHz,DMSO-d6):δ11.76(br,1H),10.94-10.90(m,1H),10.20(br,1H),7.58(s,1H),7.19-7.12(m,2H),6.90-6.85(m,1H),6.59-6.55(m,1H),5.16-5.12(m,1H),4.28-4.24(m,1H),3.95(s,3H),2.78-2.74(m,1H),1.59(s,3H),0.76-0.72(m,3H)。 1 H NMR (500MHz, DMSO-d 6 ): δ11.76(br,1H),10.94-10.90(m,1H),10.20(br,1H),7.58(s,1H),7.19-7.12(m, 2H),6.90-6.85(m,1H),6.59-6.55(m,1H),5.16-5.12(m,1H),4.28-4.24(m,1H),3.95(s,3H),2.78-2.74( m,1H),1.59(s,3H),0.76-0.72(m,3H).
实施例6Example 6
(2R,3S,4S,5R)-3-(3,4-二氟-2-甲氧基苯基)-4,5-二甲基-N-(7-氧代-4,7-二氢吡唑并[1,5-a]嘧啶-3-基)-5-(三氟甲基)四氢呋喃-2-甲酰胺6
(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-N-(7-oxo-4,7-di Hydropyrazolo[1,5-a]pyrimidin-3-yl)-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide 6
第一步first step
3-氨基吡唑并[1,5-a]嘧啶-7(4H)-酮6b3-Aminopyrazolo[1,5-a]pyrimidine-7(4H)-one 6b
将3-硝基吡唑并[1,5-a]嘧啶-7-酚6a(5mg，27.7μmol，采用专利申请“US006099593A”中说明书第6页实施例2公开的方法制备而得)溶于1mL甲醇和1mL四氢呋喃，加入10％钯碳催化剂(湿)(5mg)，氢气置换，搅拌反应16小时，反应液过滤，滤液减压浓缩即得到粗品标题化合物6b(4mg)，产物不经纯化，直接用于下一步反应。3-Nitropyrazolo[1,5-a]pyrimidine-7-phenol 6a (5 mg, 27.7 μmol, prepared by the method disclosed in Example 2 on page 6 of the patent application "US006099593A") was dissolved in 1mL methanol and 1mL tetrahydrofuran, add 10% palladium carbon catalyst (wet) (5mg), replace with hydrogen, stir and react for 16 hours, filter the reaction solution, and concentrate the filtrate under reduced pressure to obtain the crude title compound 6b (4mg). The product is not purified. used directly for the next reaction.
MS m/z(ESI):151.1[M+1]。MS m/z(ESI):151.1[M+1].
第二步Step 2
(2R,3S,4S,5R)-3-(3,4-二氟-2-甲氧基苯基)-4,5-二甲基-N-(7-氧代-4,7-二氢吡唑并[1,5-a]嘧啶-3-基)-5-(三氟甲基)四氢呋喃-2-甲酰胺6(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-N-(7-oxo-4,7-di Hydropyrazolo[1,5-a]pyrimidin-3-yl)-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide 6
将化合物1b-1(12mg，33.8μmol)，粗品化合物6b(4mg，26.6μmol)溶于0.5mL N,N-二甲基甲酰胺中，冰浴下加入N,N-二异丙基乙胺(13mg，101.6μmol)和O-(7-氮杂苯并三氮唑-1-基)-N,N,N’,N’-四甲基脲六氟磷酸酯(HATU)(75mg，40.6μmol)，保持温度反应2小时，反应液用高效液相制备色谱法纯化(Waters-2545，色谱柱：YMC Triart-Exrs C18，30*150mm，5μm；流动相：水相(10mmol/L碳酸氢铵)和乙腈，梯度配比：乙腈30％-45％，流速：30mL/min)得到标题化合物6(5mg，产率：30.3％)。Dissolve compound 1b-1 (12 mg, 33.8 μmol) and crude compound 6b (4 mg, 26.6 μmol) in 0.5 mL N,N-dimethylformamide, and add N,N-diisopropylethylamine under ice bath (13 mg, 101.6 μmol) and O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethylurea hexafluorophosphate (HATU) (75 mg, 40.6 μmol), keep the temperature for 2 hours, and the reaction solution is purified by high performance liquid phase preparative chromatography (Waters-2545, chromatographic column: YMC Triart-Exrs C18, 30*150mm, 5μm; mobile phase: water phase (10mmol/L hydrogen carbonate ammonium) and acetonitrile, gradient ratio: acetonitrile 30%-45%, flow rate: 30 mL/min) to obtain the title compound 6 (5 mg, yield: 30.3%).
MS m/z(ESI):487.2[M+1]。MS m/z(ESI):487.2[M+1].
1H NMR(500MHz,CD3OD):δ7.94(s,1H),7.78(d,1H),7.25-7.14(m,1H),7.00(q, 1H),5.82(d,1H),5.16(d,1H),4.31(dd,1H),4.02(t,3H),2.83(t,1H),1.71(s,3H),0.83(d,3H)。 1 H NMR (500MHz, CD 3 OD): δ7.94(s,1H),7.78(d,1H),7.25-7.14(m,1H),7.00(q, 1H),5.82(d,1H),5.16(d,1H),4.31(dd,1H),4.02(t,3H),2.83(t,1H),1.71(s,3H),0.83(d,3H ).
实施例7Example 7
(2R,3S,4S,5R)-3-(3,4-二氟-2-甲氧基苯基)-4,5-二甲基-N-(7-氧代-4,5,6,7-四氢吡唑并[1,5-c]嘧啶-3-基)-5-(三氟甲基)四氢呋喃-2-甲酰胺7
(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-N-(7-oxo-4,5,6 ,7-Tetrahydropyrazolo[1,5-c]pyrimidin-3-yl)-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide 7
第一步first step
(E)-3-(2-甲氧基乙烯基)-4-硝基-1-(四氢-2H-吡喃-2-基)-1H吡唑7b(E)-3-(2-Methoxyvinyl)-4-nitro-1-(tetrahydro-2H-pyran-2-yl)-1H pyrazole 7b
将(甲氧基甲基)三苯基氯化膦(1.51g，4.4mmol，上海韶远)溶于四氢呋喃(20mL)，冰浴下加入叔丁醇钾(996.5mg，8.9mmol)，保持温度搅拌反应0.5小时，加入4-硝基-1-(四氢-2H-吡喃-2-基)-1H-吡唑-3-甲醛7a(1.0g，4.45mmol，采用专利申请“WO2020150545”中说明书第107页Scheme 22公开的方法制备而得)，自然恢复室温反应5小时，反应液中加入水，用乙酸乙酯萃取(25mL×3)，合并有机相，用无水硫酸钠干燥，过滤除去干燥剂后减压浓缩，残余物用硅胶柱色谱法以洗脱剂体系B纯化得到标题化合物7b(600mg，产率：53.3％)。Dissolve (methoxymethyl)triphenylphosphine chloride (1.51g, 4.4mmol, Shanghai Shaoyuan) in tetrahydrofuran (20mL), add potassium tert-butoxide (996.5mg, 8.9mmol) under ice bath, and maintain the temperature Stir the reaction for 0.5 hours, add 4-nitro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-3-carbaldehyde 7a (1.0g, 4.45mmol, adopted from the patent application "WO2020150545" Prepared by the method disclosed in Scheme 22 on page 107 of the instruction manual), naturally return to room temperature and react for 5 hours. Add water to the reaction solution, extract with ethyl acetate (25mL×3), combine the organic phases, dry with anhydrous sodium sulfate, and filter The desiccant was removed and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent system B to obtain the title compound 7b (600 mg, yield: 53.3%).
MS m/z(ESI):254.2[M+1]。MS m/z(ESI):254.2[M+1].
第二步Step 2
2-(4-硝基-1H-吡唑-3-基)乙醛盐酸盐7c2-(4-nitro-1H-pyrazol-3-yl)acetaldehyde hydrochloride 7c
将化合物7b(150mg，5923μmol)溶于四氢呋喃(2mL)，加入6M盐酸(1mL)，60℃搅拌反应3小时，反应液减压浓缩即得到粗品标题化合物7c(100mg)，不经纯化，直接用于下一步反应。 Compound 7b (150 mg, 5923 μmol) was dissolved in tetrahydrofuran (2 mL), 6 M hydrochloric acid (1 mL) was added, and the reaction was stirred at 60°C for 3 hours. The reaction solution was concentrated under reduced pressure to obtain the crude title compound 7c (100 mg), which was directly used without purification. react in the next step.
MS m/z(ESI):154.2[M-1]。MS m/z(ESI):154.2[M-1].
第三步third step
N-(4-甲氧基苄基)-2-(4-硝基-1H-吡唑-3-基)乙-1-胺7dN-(4-methoxybenzyl)-2-(4-nitro-1H-pyrazol-3-yl)ethyl-1-amine 7d
将粗品化合物7c(114.9mg，599.7μmol)溶于甲醇(8mL)，加入对甲氧基苄胺(164.6mg，1.29mmol)，搅拌反应1小时，加入硼氢化钠(66.6mg，1.8mmol)，搅拌反应1小时，反应液减压浓缩，残余物用硅胶柱色谱法以洗脱剂体系A纯化得到标题化合物7d(25mg，产率：15％)。Dissolve crude compound 7c (114.9 mg, 599.7 μmol) in methanol (8 mL), add p-methoxybenzylamine (164.6 mg, 1.29 mmol), stir and react for 1 hour, add sodium borohydride (66.6 mg, 1.8 mmol), The reaction was stirred for 1 hour, and the reaction solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent system A to obtain the title compound 7d (25 mg, yield: 15%).
MS m/z(ESI):277.2[M+1]。MS m/z(ESI):277.2[M+1].
第四步the fourth step
6-(4-甲氧基苄基)-3-硝基-5,6-二氢吡唑并[1,5-c]嘧啶-7(4H)-酮7e6-(4-methoxybenzyl)-3-nitro-5,6-dihydropyrazolo[1,5-c]pyrimidin-7(4H)-one 7e
将化合物7d(60mg，217.1μmol)溶于乙腈(5mL)，加入N,N-羰基二咪唑(CDI)(52.81mg，325.7μmol)和三乙胺(65.92mg，651.4μmol)，搅拌反应2小时，反应液减压浓缩，残余物用硅胶柱色谱法以洗脱剂体系B纯化得到标题化合物7e(28mg，产率：42％)。Dissolve compound 7d (60 mg, 217.1 μmol) in acetonitrile (5 mL), add N,N-carbonyldiimidazole (CDI) (52.81 mg, 325.7 μmol) and triethylamine (65.92 mg, 651.4 μmol), and stir for 2 hours. , the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using eluent system B to obtain the title compound 7e (28 mg, yield: 42%).
MS m/z(ESI):303.2[M+1]。MS m/z(ESI):303.2[M+1].
第五步the fifth step
3-氨基-6-(4-甲氧基苄基)-5,6-二氢吡唑并[1,5-c]嘧啶-7(4H)-酮7f3-amino-6-(4-methoxybenzyl)-5,6-dihydropyrazolo[1,5-c]pyrimidin-7(4H)-one 7f
将化合物7e(12mg，39.7μmol)溶于甲醇(1mL)和四氢呋喃(1mL)，加入10％钯碳加氢催化剂(干)(10mg)，氢气置换，搅拌反应14小时，反应液过滤，滤液减压浓缩即得到粗品标题化合物7f(10mg)，不经纯化，直接用于下一步。Dissolve compound 7e (12 mg, 39.7 μmol) in methanol (1 mL) and tetrahydrofuran (1 mL), add 10% palladium carbon hydrogenation catalyst (dry) (10 mg), replace with hydrogen, stir and react for 14 hours, filter the reaction solution, and reduce the filtrate to Concentrate under pressure to obtain the crude title compound 7f (10 mg), which was used directly in the next step without purification.
MS m/z(ESI):273.2[M+1]。MS m/z(ESI):273.2[M+1].
第六步Step 6
3-氨基-5,6-二氢吡唑并[1,5-c]嘧啶-7(4H)-酮7g3-Amino-5,6-dihydropyrazolo[1,5-c]pyrimidin-7(4H)-one 7g
将粗品化合物7f(10mg，36.7μmol)溶于二氯甲烷(1mL)，冰浴下加入三氟乙酸(0.25mL)和三氟甲磺酸(0.25mL)，保持温度搅拌反应2小时，反应液用饱和碳酸氢钠溶液调节pH＝8后减压浓缩，残余物中加入二氯甲烷/甲醇(V/V＝9/1)的混合溶剂洗涤，过滤，滤液减压浓缩即得到粗品标题化合物7g(5mg)，不经纯化，直接用于下一步。Dissolve crude compound 7f (10 mg, 36.7 μmol) in dichloromethane (1 mL), add trifluoroacetic acid (0.25 mL) and trifluoromethanesulfonic acid (0.25 mL) under ice bath, maintain the temperature and stir for 2 hours, and the reaction solution Adjust pH=8 with saturated sodium bicarbonate solution and then concentrate under reduced pressure. Add a mixed solvent of methylene chloride/methanol (V/V=9/1) to the residue to wash, filter, and concentrate the filtrate under reduced pressure to obtain 7g of the crude title compound. (5mg), was used directly in the next step without purification.
MS m/z(ESI):153.2[M+1]。MS m/z(ESI):153.2[M+1].
第七步Step 7
(2R,3S,4S,5R)-3-(3,4-二氟-2-甲氧基苯基)-4,5-二甲基-N-(7-氧代-4,5,6,7-四氢吡唑(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-N-(7-oxo-4,5,6 ,7-Tetrahydropyrazole
并[1,5-c]嘧啶-3-基)-5-(三氟甲基)四氢呋喃-2-甲酰胺7And[1,5-c]pyrimidin-3-yl)-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide 7
将化合物1b-1(10mg，28μmol)，粗品化合物7g(5mg，32.8μmol)溶于2mL N,N-二甲基甲酰胺中，冰浴下加入N,N-二异丙基乙胺(10.9mg，84.6μmol)和O-(7-氮杂苯并三氮唑-1-基)-N,N,N’,N’-四甲基脲六氟磷酸酯(HATU)(12.8mg，33.8μmol)，保持温度反应2小时，反应液用高效液相制备色谱法纯化(Waters-2545，色 谱柱：YMC Triart-Exrs C18，30*150mm，5μm；流动相：水相(10mmol/L碳酸氢铵)和乙腈，梯度配比：乙腈35％-45％，流速：30mL/min)得到标题化合物7(3mg，产率：21％)。Compound 1b-1 (10 mg, 28 μmol) and crude compound 7g (5 mg, 32.8 μmol) were dissolved in 2 mL of N,N-dimethylformamide, and N,N-diisopropylethylamine (10.9 mg, 84.6 μmol) and O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethylurea hexafluorophosphate (HATU) (12.8 mg, 33.8 μmol), the temperature was maintained for 2 hours, and the reaction solution was purified by high performance liquid phase preparative chromatography (Waters-2545, color Column: YMC Triart-Exrs C18, 30*150mm, 5μm; mobile phase: water phase (10mmol/L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 35%-45%, flow rate: 30mL/min) to obtain the title Compound 7 (3 mg, yield: 21%).
MS m/z(ESI):489.2[M+1]。MS m/z(ESI):489.2[M+1].
1H NMR(500MHz,CD3OD):δ7.81(s,1H),7.13(ddd,1H),6.98(td,1H),5.07(d,1H),4.26(dd,1H),3.99(d,3H),3.49(t,2H),2.96(t,2H),2.78(p,1H),1.66(s,3H),0.81(dq,3H)。 1 H NMR (500MHz, CD 3 OD): δ7.81(s,1H),7.13(ddd,1H),6.98(td,1H),5.07(d,1H),4.26(dd,1H),3.99( d,3H),3.49(t,2H),2.96(t,2H),2.78(p,1H),1.66(s,3H),0.81(dq,3H).
实施例8Example 8
(2R,3S,4S,5R)-3-(3,4-二氟-2-甲氧基苯基)-4,5-二甲基-N-(1-氧代-1,2,3,4-四氢吡咯并[1,2-c]嘧啶-5-基)-5-(三氟甲基)四氢呋喃-2-甲酰胺8
(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-N-(1-oxo-1,2,3 ,4-tetrahydropyrro[1,2-c]pyrimidin-5-yl)-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide 8
第一步first step
(3-溴-1H-吡咯-2-基)甲醇8b(3-Bromo-1H-pyrrol-2-yl)methanol 8b
将3-溴-1H-吡咯-2-羧酸甲酯8a(8g，39.2mmol，南京药石)溶于四氢呋喃(150mL)，冰浴下滴加2.5M氢化铝锂的四氢呋喃溶液(24mL)，自然恢复室温搅拌反应2小时，冰浴下反应液中加入十水硫酸钠淬灭，过滤，滤液减压浓缩即得到粗品标题化合物8b(5g)，不经纯化，直接用于下一步。Dissolve 3-bromo-1H-pyrrole-2-carboxylic acid methyl ester 8a (8g, 39.2mmol, Nanjing Yaoshi) in tetrahydrofuran (150mL), add 2.5M lithium aluminum hydride in tetrahydrofuran (24mL) dropwise in an ice bath, and naturally Return to room temperature and stir the reaction for 2 hours. Add sodium sulfate decahydrate to the reaction solution in an ice bath to quench, filter, and concentrate the filtrate under reduced pressure to obtain crude title compound 8b (5g), which is used directly in the next step without purification.
MS m/z(ESI):174.0[M-1]。MS m/z(ESI):174.0[M-1].
第二步Step 2
3-溴-1H-吡咯-2-甲醛8c 3-Bromo-1H-pyrrole-2-carbaldehyde 8c
将粗品化合物8b(5g，28.4mmol)溶于二氯甲烷(100mL)，加入二氧化锰(24.7g，284.1mmol)，搅拌反应16小时，反应液过滤，滤液减压浓缩即得到粗品标题化合物8c(4g)，不经纯化，直接用于下一步。Dissolve crude compound 8b (5g, 28.4mmol) in dichloromethane (100mL), add manganese dioxide (24.7g, 284.1mmol), stir and react for 16 hours, filter the reaction solution, and concentrate the filtrate under reduced pressure to obtain crude title compound 8c. (4g), was used directly in the next step without purification.
MS m/z(ESI):172.0[M-1]。MS m/z(ESI):172.0[M-1].
第三步third step
3-溴-1-对甲苯磺酰基-1H-吡咯-2-甲醛8d3-Bromo-1-p-toluenesulfonyl-1H-pyrrole-2-carbaldehyde 8d
将氢化钠(766.3mg，20mmol，60％纯度)混悬于四氢呋喃(150mL)，加入粗品化合物8c(2.9g，16.7mmol)，搅拌30分钟后加入对甲苯磺酰氯(3.5g，18.35mmol)，搅拌反应14小时，反应液中加入饱和氯化铵溶液淬灭，用乙酸乙酯萃取(30mL×3)，合并有机相，用饱和氯化钠溶液洗涤，无水硫酸钠干燥，过滤除去干燥剂后减压浓缩，残余物用硅胶柱色谱法以洗脱剂体系B纯化得到标题化合物8d(5.1g，产率：93.2％)。Suspend sodium hydride (766.3 mg, 20 mmol, 60% purity) in tetrahydrofuran (150 mL), add crude compound 8c (2.9 g, 16.7 mmol), stir for 30 minutes, and then add p-toluenesulfonyl chloride (3.5 g, 18.35 mmol). Stir the reaction for 14 hours, add saturated ammonium chloride solution to the reaction solution to quench, extract with ethyl acetate (30mL×3), combine the organic phases, wash with saturated sodium chloride solution, dry over anhydrous sodium sulfate, filter to remove the desiccant After concentration under reduced pressure, the residue was purified by silica gel column chromatography using eluent system B to obtain the title compound 8d (5.1 g, yield: 93.2%).
MS m/z(ESI):328.1[M+1]。MS m/z(ESI):328.1[M+1].
第四步the fourth step
(E)-3-溴-2-(2-甲氧基乙烯基)-1-对甲苯磺酰基-1H-吡咯8e(E)-3-Bromo-2-(2-methoxyvinyl)-1-p-toluenesulfonyl-1H-pyrrole 8e
将(甲氧基甲基)三苯基氯化膦(4.17g，12.1mmol，上海韶远)溶于四氢呋喃(150mL)，冰浴下加入叔丁醇钾(1.36g，12.1mmol)，保持温度搅拌反应0.5小时，加入化合物8d(2g，6.09mmol)，自然恢复室温反应14小时，反应液中加入水淬灭，用乙酸乙酯萃取(25mL×3)，合并有机相，用无水硫酸钠干燥，过滤除去干燥剂后减压浓缩，残余物用硅胶柱色谱法以洗脱剂体系B纯化得到标题化合物8e(1.4g，产率：64％)。Dissolve (methoxymethyl)triphenylphosphine chloride (4.17g, 12.1mmol, Shanghai Shaoyuan) in tetrahydrofuran (150mL), add potassium tert-butoxide (1.36g, 12.1mmol) under ice bath, and maintain the temperature Stir the reaction for 0.5 hours, add compound 8d (2g, 6.09mmol), and naturally return to room temperature to react for 14 hours. Add water to the reaction solution to quench, extract with ethyl acetate (25mL×3), combine the organic phases, and use anhydrous sodium sulfate. Dry, filter to remove the desiccant and concentrate under reduced pressure. The residue is purified by silica gel column chromatography using eluent system B to obtain the title compound 8e (1.4 g, yield: 64%).
MS m/z(ESI):356.2[M+1]。MS m/z(ESI):356.2[M+1].
第五步the fifth step
2-(3-溴-1-对甲苯磺酰基-1H-吡咯-2-基)乙醛8f2-(3-Bromo-1-p-toluenesulfonyl-1H-pyrrol-2-yl)acetaldehyde 8f
将化合物8e(1.4g，3.93mmol)溶于四氢呋喃(30mL)，加入浓盐酸(3mL)，搅拌反应1小时，反应液用饱和碳酸氢钠溶液调节pH至中性，乙酸乙酯萃取(25mL×3)，合并有机相，用无水硫酸钠干燥，过滤除去干燥剂后减压浓缩即得到粗品标题化合物8f(1.3g)，不经纯化，直接用于下一步反应。Compound 8e (1.4g, 3.93mmol) was dissolved in tetrahydrofuran (30mL), concentrated hydrochloric acid (3mL) was added, and the reaction was stirred for 1 hour. The pH of the reaction solution was adjusted to neutral with saturated sodium bicarbonate solution, and extracted with ethyl acetate (25mL× 3), combine the organic phases, dry over anhydrous sodium sulfate, filter to remove the desiccant and concentrate under reduced pressure to obtain crude title compound 8f (1.3g), which is directly used in the next reaction without purification.
MS m/z(ESI):340.0[M-1]。MS m/z(ESI):340.0[M-1].
第六步Step 6
2-(3-溴-1-对甲苯磺酰基-1H-吡咯-2-基)-N-(4-甲氧基苄基)乙-1-胺8g2-(3-Bromo-1-p-toluenesulfonyl-1H-pyrrol-2-yl)-N-(4-methoxybenzyl)ethyl-1-amine 8g
将粗品化合物8f(1g，2.92mmol)溶于甲醇(30mL)，加入对甲氧基苄胺(601mg，4.38mmol，上海韶远)，搅拌反应1小时，加入氰基硼氢化钠(275mg，4.38mmol)，搅拌反应14小时，反应液减压浓缩，残余物用硅胶柱色谱法以洗脱剂体系B纯化得到标题化合物8g(466mg，产率：34.4％)。Dissolve crude compound 8f (1g, 2.92mmol) in methanol (30mL), add p-methoxybenzylamine (601mg, 4.38mmol, Shanghai Shaoyuan), stir for 1 hour, and add sodium cyanoborohydride (275mg, 4.38 mmol), the reaction was stirred for 14 hours, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using eluent system B to obtain 8g of the title compound (466 mg, yield: 34.4%).
MS m/z(ESI):463.2[M+1]。 MS m/z(ESI):463.2[M+1].
第七步Step 7
2-(3-溴-1H-吡咯-2-基)-N-(4-甲氧基苄基)乙烷-1-胺8h2-(3-Bromo-1H-pyrrol-2-yl)-N-(4-methoxybenzyl)ethane-1-amine 8h
将化合物8g(466mg，1mmol)溶于四氢呋喃(10mL)，冰浴下加入甲醇钠甲醇溶液(50％)(1.1g，10mmol)，自然恢复室温搅拌反应4小时，反应液用2N盐酸调节pH至中性，乙酸乙酯萃取(25mL×3)，合并有机相，用无水硫酸钠干燥，过滤除去干燥剂后减压浓缩，残余物用硅胶柱色谱法以洗脱剂体系B纯化得到标题化合物8h(287mg，产率：92％)。Dissolve compound 8g (466mg, 1mmol) in tetrahydrofuran (10mL), add sodium methoxide methanol solution (50%) (1.1g, 10mmol) in an ice bath, naturally return to room temperature and stir for 4 hours, and adjust the pH of the reaction solution to 2N hydrochloric acid. Neutral, extracted with ethyl acetate (25mL×3), combined the organic phases, dried over anhydrous sodium sulfate, filtered to remove the desiccant and concentrated under reduced pressure, the residue was purified by silica gel column chromatography using eluent system B to obtain the title compound 8h (287mg, yield: 92%).
MS m/z(ESI):309.2[M+1]。MS m/z(ESI):309.2[M+1].
第八步Step 8
5-溴-2-(4-甲氧基苄基)-3,4-二氢吡咯并[1,2-c]嘧啶-1(2H)-酮8i5-Bromo-2-(4-methoxybenzyl)-3,4-dihydropyrro[1,2-c]pyrimidin-1(2H)-one 8i
将化合物8h(287mg，928.2μmol)溶于四氢呋喃(20mL)，加入N,N-羰基二咪唑(CDI)(451.5mg，2.8mmol)，搅拌30分钟后，加入氢化钠(106.7mg，2.8mmol，60％纯度)，继续搅拌反应14小时，反应液中加入水淬灭，减压浓缩，残余物用硅胶柱色谱法以洗脱剂体系B纯化得到标题化合物8i(126mg，产率：40.5％)。Compound 8h (287 mg, 928.2 μmol) was dissolved in tetrahydrofuran (20 mL), N, N-carbonyldiimidazole (CDI) (451.5 mg, 2.8 mmol) was added, and after stirring for 30 minutes, sodium hydride (106.7 mg, 2.8 mmol, 60% purity), continue to stir the reaction for 14 hours, add water to the reaction solution to quench, and concentrate under reduced pressure. The residue is purified by silica gel column chromatography with eluent system B to obtain the title compound 8i (126 mg, yield: 40.5%) .
MS m/z(ESI):335.2[M+1]。MS m/z(ESI):335.2[M+1].
第九步Step 9
5-((二苯基亚甲基)氨基)-2-(4-甲氧基苄基)-3,4-二氢吡咯并[1,2-c]嘧啶-1(2H)-酮8j5-((Diphenylmethylene)amino)-2-(4-methoxybenzyl)-3,4-dihydropyrro[1,2-c]pyrimidin-1(2H)-one 8j
将化合物8i(40mg，119.3μmol)，二苯甲酮亚胺(43.2mg，238.6μmol)溶于甲苯(10mL)，加入三(二亚苄基丙酮)钯(10.92mg，11.9μmol，上海泰坦)，4,5-双二苯基膦-9,9-二甲基氧杂蒽(13.8mg，23.9μmol，上海泰坦)和叔丁醇钠(34.4mg，358μmol)，氮气置换，100℃搅拌反应14小时，反应液减压浓缩，残余物用硅胶柱色谱法以洗脱剂体系B纯化得到标题化合物8j(44mg，产率：84.6％)。Compound 8i (40 mg, 119.3 μmol) and benzophenone imine (43.2 mg, 238.6 μmol) were dissolved in toluene (10 mL), and tris(dibenzylideneacetone)palladium (10.92 mg, 11.9 μmol, Shanghai Titan) was added. , 4,5-bisdiphenylphosphine-9,9-dimethylxanthene (13.8 mg, 23.9 μmol, Shanghai Titan) and sodium tert-butoxide (34.4 mg, 358 μmol), nitrogen replacement, stirring reaction at 100°C After 14 hours, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using eluent system B to obtain the title compound 8j (44 mg, yield: 84.6%).
MS m/z(ESI):436.2[M+1]。MS m/z(ESI):436.2[M+1].
第十步Step 10
5-((二苯基亚甲基)氨基)-3,4-二氢吡咯并[1,2-c]嘧啶-1(2H)-酮8k5-((Diphenylmethylene)amino)-3,4-dihydropyrro[1,2-c]pyrimidin-1(2H)-one 8k
将化合物8j(20mg，45.9μmol)溶于二氯甲烷(1mL)，冰浴下加入三氟乙酸(0.2mL)和三氟甲磺酸(0.3mL)，保持温度搅拌反应2小时，反应液用饱和碳酸氢钠溶液调节pH＝8后减压浓缩，残余物中加入二氯甲烷/甲醇(V/V＝9/1)的混合溶剂洗涤，过滤，滤液减压浓缩即得到粗品标题化合物8k(14mg)，不经纯化，直接用于下一步。Compound 8j (20 mg, 45.9 μmol) was dissolved in dichloromethane (1 mL), trifluoroacetic acid (0.2 mL) and trifluoromethanesulfonic acid (0.3 mL) were added under ice bath, and the temperature was maintained with stirring for 2 hours. The reaction solution was The saturated sodium bicarbonate solution was adjusted to pH=8 and then concentrated under reduced pressure. A mixed solvent of methylene chloride/methanol (V/V=9/1) was added to the residue to wash, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude title compound 8k ( 14 mg) and was used directly in the next step without purification.
MS m/z(ESI):316.2[M+1]。MS m/z(ESI):316.2[M+1].
第十一步Step 11
5-氨基-3,4-二氢吡咯并[1,2-c]嘧啶-1(2H)-酮8l5-amino-3,4-dihydropyrro[1,2-c]pyrimidin-1(2H)-one 8l
将化合物8k(14mg，44.4μmol)溶于甲醇(1mL)，加入0.3mL 4M盐酸1,4-二氧六环溶液，搅拌反应2小时，反应液用饱和碳酸氢钠溶液调节pH＝8，乙酸乙酯萃取(5mL×2)，合并有机相，用无水硫酸钠干燥，过滤除去干燥剂后减压浓缩 即得到粗品标题化合物8l(6mg)，不经纯化，直接用于下一步。Dissolve compound 8k (14 mg, 44.4 μmol) 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.
MS m/z(ESI):152.2[M+1]。MS m/z(ESI):152.2[M+1].
第十二步Step 12
(2R,3S,4S,5R)-3-(3,4-二氟-2-甲氧基苯基)-4,5-二甲基-N-(1-氧代-1,2,3,4-四氢吡咯(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-N-(1-oxo-1,2,3 ,4-Tetrahydropyrrole
并[1,2-c]嘧啶-5-基)-5-(三氟甲基)四氢呋喃-2-甲酰胺8And[1,2-c]pyrimidin-5-yl)-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide 8
将化合物1b-1(20mg，56μmol)，粗品化合物8l(8.5mg，56μmol)溶于2mL N,N-二甲基甲酰胺中，冰浴下加入N,N-二异丙基乙胺(22mg，269μmol)和O-(7-氮杂苯并三氮唑-1-基)-N,N,N’,N’-四甲基脲六氟磷酸酯(HATU)(25.7mg，67.7μmol)，保持温度反应2小时，反应液用高效液相制备色谱法纯化(Waters-2545，色谱柱：YMC Triart-Exrs C18，30*150mm，5μm；流动相：水相(10mmol/L碳酸氢铵)和乙腈，梯度配比：乙腈35％-45％，流速：30mL/min)得到标题化合物8(1.5mg，产率：5.4％)。Compound 1b-1 (20 mg, 56 μmol) and crude compound 8l (8.5 mg, 56 μmol) were dissolved in 2 mL N,N-dimethylformamide, and N,N-diisopropylethylamine (22 mg) was added under ice bath. , 269 μmol) and O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethylurea hexafluorophosphate (HATU) (25.7 mg, 67.7 μmol) , keep the temperature for 2 hours, and the reaction solution is purified by high-performance liquid phase preparative chromatography (Waters-2545, chromatographic column: YMC Triart-Exrs C18, 30*150mm, 5μm; mobile phase: aqueous phase (10mmol/L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 35%-45%, flow rate: 30 mL/min) to obtain the title compound 8 (1.5 mg, yield: 5.4%).
MS m/z(ESI):488.2[M+1]。MS m/z(ESI):488.2[M+1].
1H NMR(500MHz,CD3OD):δ7.15-7.10(m,2H),7.01-6.96(m,1H),6.28(d,1H),5.06(d,,1H),4.29-4.26(m,1H),4.02(d,3H),3.43-3.41(m,2H),2.79(t,3H),1.67(s,3H),0.83-0.78(m,3H)。 1 H NMR (500MHz, CD 3 OD): δ7.15-7.10(m,2H),7.01-6.96(m,1H),6.28(d,1H),5.06(d,,1H),4.29-4.26( m,1H),4.02(d,3H),3.43-3.41(m,2H),2.79(t,3H),1.67(s,3H),0.83-0.78(m,3H).
实施例9Example 9
(2R,3S,4S,5R)-3-(3,4-二氟-2-甲氧基苯基)-4,5-二甲基-N-(3-氧代-2,3-二氢-1H-吡咯并[1,2-c]咪唑-7-基)-5-(三氟甲基)四氢呋喃-2-甲酰胺9
(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-N-(3-oxo-2,3-di Hydrogen-1H-pyrrolo[1,2-c]imidazol-7-yl)-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide 9
第一步first step
1-(3-溴-1H-吡咯-2-基)-N-(4-甲氧基苄基)甲胺9a1-(3-bromo-1H-pyrrol-2-yl)-N-(4-methoxybenzyl)methanamine 9a
将化合物8c(441mg，2.53mmol)溶于甲醇(20mL)，加入对甲氧基苄胺(414mg，3mmol，上海毕得)，乙酸(152mg，2.53mmol)和醋酸硼氢化钠(1.07g，5.06mmol)，搅拌反应14小时，反应液减压浓缩，残余物用硅胶柱色谱法以洗脱剂体系B纯化得到标题化合物9a(544mg，产率：72.7％)。Compound 8c (441 mg, 2.53 mmol) was dissolved in methanol (20 mL), and p-methoxybenzylamine (414 mg, 3 mmol, Shanghai Bide), acetic acid (152 mg, 2.53 mmol) and sodium borohydride acetate (1.07 g, 5.06 mmol), the reaction was stirred for 14 hours, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using eluent system B to obtain the title compound 9a (544 mg, yield: 72.7%).
MS m/z(ESI):295.2[M+1]。MS m/z(ESI):295.2[M+1].
第二步 Step 2
(2R,3S,4S,5R)-3-(3,4-二氟-2-甲氧基苯基)-4,5-二甲基-N-(3-氧代-2,3-二氢-1H-吡咯(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-N-(3-oxo-2,3-di Hydrogen-1H-pyrrole
并[1,2-c]咪唑-7-基)-5-(三氟甲基)四氢呋喃-2-甲酰胺9And[1,2-c]imidazol-7-yl)-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide 9
采用实施例8中的合成路线第八步至第十二步，将第八步原料化合物8h替换为化合物9a得到标题化合物9(1mg，产率：9.35％)。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.
MS m/z(ESI):474.2[M+1]。MS m/z(ESI):474.2[M+1].
1H NMR(500MHz,CD3OD):δ7.15-7.09(m,1H),7.02-6.96(m,2H),6.33(d,1H),5.01(d,1H),4.51(d,1H),4.26(dd,2H),4.01(d,3H),2.79(t,2H),1.66(s,3H),0.83-0.78(m,3H)。 1 H NMR (500MHz, CD 3 OD): δ7.15-7.09(m,1H),7.02-6.96(m,2H),6.33(d,1H),5.01(d,1H),4.51(d,1H ),4.26(dd,2H),4.01(d,3H),2.79(t,2H),1.66(s,3H),0.83-0.78(m,3H).
实施例10Example 10
(2R,3S,4S,5R)-3-(3,4-二氟-2-甲氧基苯基)-4,5-二甲基-N-(1-氧代-1,2-二氢吡咯并[1,2-c]嘧啶-5-基)-5-(三氟甲基)四氢呋喃-2-甲酰胺10
(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-N-(1-oxo-1,2-di Hydropyrrolo[1,2-c]pyrimidin-5-yl)-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide 10
第一步first step
5-((二苯亚甲基)氨基)-2-(甲氧基甲基)吡咯并[1,2-c]嘧啶-1(2H)-酮10b5-((Diphenylidene)amino)-2-(methoxymethyl)pyrrolo[1,2-c]pyrimidin-1(2H)-one 10b
将5-溴-2-(甲氧甲基)吡咯并[1,2-c]嘧啶-1(2H)-酮10a(500mg，1.9mmol，采用文献“Journal of the Chemical Society.Perkin Transactions 1(2001),2002,#4,p.471-475”公开的方法制备而得)，二苯甲酮亚胺704.9mg，3.88mmol)溶于甲苯(10mL)，加入三(二亚苄基丙酮)钯(178mg，194.4μmol)，4,5-双二苯基膦-9,9-二甲基氧杂蒽(224.8mg，388.9μmol)和叔丁醇钠(560.7mg，5.83mmol)，氮气置换，100℃搅拌反应14小时，反应液减压浓缩，残余物用硅胶柱色谱法以洗脱剂体系B纯化得到标题化合物10b(375mg，产率：53.9％)。5-bromo-2-(methoxymethyl)pyrrolo[1,2-c]pyrimidin-1(2H)-one 10a (500 mg, 1.9 mmol, using the literature "Journal of the Chemical Society.Perkin Transactions 1( 2001), 2002, #4, p.471-475"), benzophenone imine 704.9 mg, 3.88 mmol) was dissolved in toluene (10 mL), and tris(dibenzylideneacetone) was added Palladium (178 mg, 194.4 μmol), 4,5-bisdiphenylphosphine-9,9-dimethylxanthene (224.8 mg, 388.9 μmol) and sodium tert-butoxide (560.7 mg, 5.83 mmol), nitrogen replacement , the reaction was stirred at 100°C for 14 hours, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using eluent system B to obtain the title compound 10b (375 mg, yield: 53.9%).
MS m/z(ESI):358.2[M+1]。MS m/z(ESI):358.2[M+1].
第二步 Step 2
5-氨基-2-(甲氧基甲基)吡咯并[1,2-c]嘧啶-1(2H)-酮10c5-amino-2-(methoxymethyl)pyrrolo[1,2-c]pyrimidin-1(2H)-one 10c
将化合物10b(90mg，251.8μmol)溶于四氢呋喃(2mL)，加入1M盐酸(0.5mL)和水(0.2mL)，搅拌反应2小时，反应液用饱和碳酸氢钠溶液调节pH＝8，乙酸乙酯萃取(5mL×2)，合并有机相，用无水硫酸钠干燥，过滤除去干燥剂后减压浓缩即得到粗品标题化合物10c(50mg)，不经纯化，直接用于下一步。Compound 10b (90 mg, 251.8 μmol) was dissolved in tetrahydrofuran (2 mL), 1 M hydrochloric acid (0.5 mL) and water (0.2 mL) were added, and the reaction was stirred for 2 hours. The reaction solution was adjusted to pH=8 with saturated sodium bicarbonate solution, and ethyl acetate was added. Ester extraction (5 mL × 2), combined organic phases, dried over anhydrous sodium sulfate, filtered to remove the desiccant and concentrated under reduced pressure to obtain crude title compound 10c (50 mg), which was used directly in the next step without purification.
MS m/z(ESI):194.2[M+1]。MS m/z(ESI):194.2[M+1].
第三步third step
(2R,3S,4S,5R)-3-(3,4-二氟-2-甲氧基苯基)-N-(2-(甲氧基甲基)-1-氧代-1,2-二氢吡咯并[1,2-c]嘧啶-5-基)-4,5-二甲基-5-(三氟甲基)四氢呋喃-2-甲酰胺10d(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-N-(2-(methoxymethyl)-1-oxo-1,2 -Dihydropyrro[1,2-c]pyrimidin-5-yl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide 10d
将化合物1b-1(91mg，258.8μmol)，粗品化合物10c(50mg，258.8μmol)溶于2mL N,N-二甲基甲酰胺中，冰浴下加入N,N-二异丙基乙胺(100mg，776μmol)和O-(7-氮杂苯并三氮唑-1-基)-N,N,N’,N’-四甲基脲六氟磷酸酯(HATU)(118mg，310μmol)，保持温度反应2小时，反应液反应液减压浓缩，残余物用硅胶柱色谱法以洗脱剂体系A纯化得到标题化合物10d(135mg，98.5％)。Compound 1b-1 (91 mg, 258.8 μmol) and crude compound 10c (50 mg, 258.8 μmol) were dissolved in 2 mL of N,N-dimethylformamide, and N,N-diisopropylethylamine ( 100 mg, 776 μmol) and O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethylurea hexafluorophosphate (HATU) (118 mg, 310 μmol), The temperature was maintained for 2 hours, and the reaction solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent system A to obtain the title compound 10d (135 mg, 98.5%).
MS m/z(ESI):530.2[M+1]。MS m/z(ESI):530.2[M+1].
第四步the fourth step
(2R,3S,4S,5R)-3-(3,4-二氟-2-甲氧基苯基)-4,5-二甲基-N-(1-氧代-1,2-二氢吡咯并[1,2-c]嘧啶-5-基)-5-(三氟甲基)四氢呋喃-2-甲酰胺10(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-N-(1-oxo-1,2-di Hydropyrrolo[1,2-c]pyrimidin-5-yl)-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide 10
将化合物10d(80mg，151.1μmol)溶于2M的盐酸异丙醇溶液(4mL)，80℃搅拌反应2小时，反应液减压浓缩，残余物用高效液相制备色谱法纯化(Waters-2545，色谱柱：YMC Triart-Exrs C18，30*150mm，5μm；流动相：水相(10mmol/L碳酸氢铵)和乙腈，梯度配比：乙腈30％-45％，流速：30mL/min)得到标题化合物10(1mg，产率：1.3％)。Compound 10d (80 mg, 151.1 μmol) was dissolved in 2M hydrochloric acid isopropyl alcohol solution (4 mL), and the reaction was stirred at 80°C for 2 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by high-performance liquid phase preparative chromatography (Waters-2545, Chromatographic column: YMC Triart-Exrs C18, 30*150mm, 5μm; mobile phase: aqueous phase (10mmol/L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 30%-45%, flow rate: 30mL/min) to obtain the title Compound 10 (1 mg, yield: 1.3%).
MS m/z(ESI):486.2[M+1]。MS m/z(ESI):486.2[M+1].
1H NMR(500MHz,CD3OD):δ7.47(s,1H),7.17(ddd,1H),7.01(td,1H),6.81(d,1H),6.66(d,1H),6.41(d,1H),5.11(d,1H),4.33(dd,1H),4.02(d,3H),2.81(p,1H),1.69(s,3H),0.86-0.82(m,3H)。 1 H NMR (500MHz, CD 3 OD): δ7.47(s,1H),7.17(ddd,1H),7.01(td,1H),6.81(d,1H),6.66(d,1H),6.41( d,1H),5.11(d,1H),4.33(dd,1H),4.02(d,3H),2.81(p,1H),1.69(s,3H),0.86-0.82(m,3H).
实施例11Example 11
(2R,3S,4S,5R)-3-(3,4-二氟-2-甲氧基苯基)-4,5-二甲基-N-(5-氧代-5,6-二氢咪唑并[1,5-c]嘧啶-1-基)-5-(三氟甲基)四氢呋喃-2-甲酰胺11

(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-N-(5-oxo-5,6-di Hydroimidazo[1,5-c]pyrimidin-1-yl)-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide 11

第一步first step
2-((二苯基亚甲基)氨基)-2-(2-(甲硫基)嘧啶-4-基)乙酸乙酯11b2-((Diphenylmethylene)amino)-2-(2-(methylthio)pyrimidin-4-yl)acetate 11b
将2-((二苯基亚甲基)氨基)乙酸乙酯(3.66g，13.7mmol，上海韶远)溶于二甲亚砜(30mL)，冰浴下分批加入氢化钠(955mg，24.9mmol，60％purity)，保持温度反应1小时，加入4-氯-2-(甲硫基)嘧啶11a(2.0g，12.4mmol，上海毕得)的二甲亚砜(5mL)溶液，搅拌反应14小时，反应液中加入50mL水，用乙酸乙酯萃取(50mL×3)，合并有机相，用饱和氯化钠溶液洗涤，无水硫酸钠干燥，过滤除去干燥剂后减压浓缩，残余物用硅胶柱色谱法以洗脱体系B纯化得到标题化合物11b(2.2g，产率：45.1％)。Dissolve 2-((diphenylmethylene)amino)ethyl acetate (3.66g, 13.7mmol, Shaoyuan, Shanghai) in dimethyl sulfoxide (30mL), and add sodium hydride (955mg, 24.9 mmol, 60% purity), maintain the temperature and react for 1 hour, add a solution of 4-chloro-2-(methylthio)pyrimidine 11a (2.0g, 12.4mmol, Shanghai Bid) in dimethyl sulfoxide (5mL), and stir the reaction For 14 hours, add 50 mL of water to the reaction solution, extract with ethyl acetate (50 mL Purification using silica gel column chromatography with elution system B gave the title compound 11b (2.2 g, yield: 45.1%).
MS m/z(ESI):392.2[M+1]。MS m/z(ESI):392.2[M+1].
第二步Step 2
2-氨基-2-(2-(甲硫基)嘧啶-4-基)乙酸乙酯11c2-Amino-2-(2-(methylthio)pyrimidin-4-yl)acetate 11c
将化合物11b(2.2g，5.6mmol)溶于四氢呋喃(20mL)，加入浓盐酸(4mL)，搅拌反应1小时，反应液减压浓缩，残余物中加入饱和碳酸氢钠溶液，用二氯甲烷萃取(30mL×3)，合并有机相，用饱和氯化钠溶液洗涤，无水硫酸钠干燥，过滤除去干燥剂后减压浓缩，残余物用硅胶柱色谱法以洗脱体系B纯化得到标题化合物11c(1.1g，产率：86％)。Compound 11b (2.2g, 5.6mmol) was dissolved in tetrahydrofuran (20mL), concentrated hydrochloric acid (4mL) was added, and the reaction was stirred for 1 hour. The reaction solution was concentrated under reduced pressure. A saturated sodium bicarbonate solution was added to the residue, and extracted with dichloromethane. (30 mL (1.1 g, yield: 86%).
MS m/z(ESI):228.2[M+1]。MS m/z(ESI):228.2[M+1].
第三步third step
2-甲酰胺基-2-(2-(甲硫基)嘧啶-4-基)乙酸乙酯11d2-Carboxamido-2-(2-(methylthio)pyrimidin-4-yl)acetate 11d
将甲酸(2mL)和醋酸酐(2mL)混合，50℃反应1小时，降至室温后滴加入化合物11c(1.1g，4.8mmol)的二氯甲烷溶液(20mL)中，搅拌反应2小时，反应液减压浓缩，残余物用硅胶柱色谱法以洗脱体系B纯化得到标题化合物11d(1.1g，产率： 89％)。Mix formic acid (2mL) and acetic anhydride (2mL) and react at 50°C for 1 hour. After cooling to room temperature, add compound 11c (1.1g, 4.8mmol) dropwise into a dichloromethane solution (20mL) and stir for 2 hours. The liquid was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with elution system B to obtain the title compound 11d (1.1g, yield: 89%).
MS m/z(ESI):256.2[M+1]。MS m/z(ESI):256.2[M+1].
第四步the fourth step
5-(甲硫基)咪唑并[1,5-c]嘧啶-1-羧酸乙酯11e5-(Methylthio)imidazo[1,5-c]pyrimidine-1-carboxylic acid ethyl ester 11e
将化合物11d(1.1g，4.3mmol)溶于1,4-二氧六环(20mL)，加入三氯氧磷(3mL)，110℃反应1小时，反应液冷却至室温后减压浓缩，残余物用碳酸氢钠水溶液调节pH＝7-8，二氯甲烷萃取(30mL×3)，合并有机相，用饱和氯化钠溶液洗涤，无水硫酸钠干燥，过滤除去干燥剂后减压浓缩，残余物用硅胶柱色谱法以洗脱体系B纯化得到标题化合物11e(820mg，产率：80％)。Compound 11d (1.1g, 4.3mmol) was dissolved in 1,4-dioxane (20mL), phosphorus oxychloride (3mL) was added, and the reaction was carried out at 110°C for 1 hour. The reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue Adjust pH=7-8 with sodium bicarbonate aqueous solution, extract with dichloromethane (30mL×3), combine the organic phases, wash with saturated sodium chloride solution, dry over anhydrous sodium sulfate, filter to remove the desiccant and concentrate under reduced pressure. The residue was purified by silica gel column chromatography using elution system B to obtain the title compound 11e (820 mg, yield: 80%).
MS m/z(ESI):238.2[M+1]。MS m/z(ESI):238.2[M+1].
第五步the fifth step
5-氧代-5,6-二氢咪唑并[1,5-c]嘧啶-1-甲酸乙酯11f5-Oxo-5,6-dihydroimidazo[1,5-c]pyrimidine-1-carboxylic acid ethyl ester 11f
将化合物11e(800mg，3.37mmol)溶于四氢呋喃(10mL)和水(10mL)，加入氢氧化锂(283mg，6.74mmol)，搅拌反应2小时，用2M盐酸调节pH＝7左右，析出固体，过滤，滤饼水洗干燥后即得到粗品标题化合物11f(390mg)，不经纯化，直接用于下一步反应。Dissolve compound 11e (800 mg, 3.37 mmol) in tetrahydrofuran (10 mL) and water (10 mL), add lithium hydroxide (283 mg, 6.74 mmol), stir the reaction for 2 hours, adjust the pH to about 7 with 2M hydrochloric acid, precipitate a solid, and filter , the filter cake was washed and dried to obtain the crude title compound 11f (390 mg), which was directly used in the next reaction without purification.
MS m/z(ESI):208.2[M+1]。MS m/z(ESI):208.2[M+1].
第六步Step 6
5-氧代-5,6-二氢咪唑并[1,5-c]嘧啶-1-甲酸11g5-Oxo-5,6-dihydroimidazo[1,5-c]pyrimidine-1-carboxylic acid 11g
将粗品化合物11f(1g，4.8mmol)溶于四氢呋喃(20mL)和水(5mL)，加入氢氧化锂(497mg，11.8mmol)，回流反应3小时，反应液降至室温后减压浓缩除去大部分溶剂，用2M盐酸调节pH＝7左右，析出固体，过滤，滤饼水洗干燥后即得到粗品标题化合物11g(590mg)，不经纯化，直接用于下一步反应。Dissolve crude compound 11f (1g, 4.8mmol) in tetrahydrofuran (20mL) and water (5mL), add lithium hydroxide (497mg, 11.8mmol), and react under reflux for 3 hours. After the reaction solution cools to room temperature, it is concentrated under reduced pressure to remove most of it. As a solvent, adjust the pH to about 7 with 2M hydrochloric acid, precipitate a solid, filter, and wash and dry the filter cake to obtain 11 g (590 mg) of the crude title compound, which is directly used in the next step of the reaction without purification.
MS m/z(ESI):180.2[M+1]。MS m/z(ESI):180.2[M+1].
第七步Step 7
(5-氧代-5,6-二氢咪唑并[1,5-c]嘧啶-1-基)氨基甲酸叔丁酯11h(5-Oxo-5,6-dihydroimidazo[1,5-c]pyrimidin-1-yl)carbamic acid tert-butyl ester 11h
将粗品化合物11g(500mg，2.79mmol)溶于叔丁醇(5mL)和甲苯(10mL)，加入叠氮磷酸二苯酯(1.02g，4.19mmol，上海韶远)，三乙胺(848mg，8.38mmol)，氮气置换，90℃反应14小时，反应液减压浓缩，残余物用硅胶柱色谱法以洗脱体系A纯化得到标题化合物11h(300mg,产率：42.94％)。Dissolve 11g of the crude compound (500mg, 2.79mmol) in tert-butanol (5mL) and toluene (10mL), add diphenylphosphoryl azide (1.02g, 4.19mmol, Shaoyuan, Shanghai), triethylamine (848mg, 8.38 mmol), nitrogen replacement, reaction at 90°C for 14 hours, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using elution system A to obtain the title compound 11h (300 mg, yield: 42.94%).
MS m/z(ESI):251.2[M+1]。MS m/z(ESI):251.2[M+1].
第八步Step 8
1-氨基咪唑并[1,5-c]嘧啶-5(6H)-酮2,2,2-三氟乙酸盐11i1-Aminoimidazo[1,5-c]pyrimidin-5(6H)-one 2,2,2-trifluoroacetate 11i
化合物11h(230mg，919μmol)溶于三氟乙酸(2mL)，搅拌反应3小时，反应液减压浓缩即得到粗品标题化合物11i(230mg)，不经纯化，直接用于下一步反应。MS m/z(ESI):151.2[M+1]。 Compound 11h (230 mg, 919 μmol) was dissolved in trifluoroacetic acid (2 mL), and the reaction was stirred for 3 hours. The reaction solution was concentrated under reduced pressure to obtain the crude title compound 11i (230 mg), which was directly used in the next reaction without purification. MS m/z(ESI):151.2[M+1].
第九步Step 9
(2R,3S,4S,5R)-3-(3,4-二氟-2-甲氧基苯基)-4,5-二甲基-N-(5-氧代-5,6-二氢咪唑并[1,5-c]嘧啶-1-基)-5-(三氟甲基)四氢呋喃-2-甲酰胺11(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-N-(5-oxo-5,6-di Hydroimidazo[1,5-c]pyrimidin-1-yl)-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide 11
将化合物1b-1(150mg，423μmol)，粗品化合物11i(113mg，426.3μmol)溶于5mL N,N-二甲基甲酰胺中，冰浴下加入N,N-二异丙基乙胺(274mg，2.1mmol)和O-(7-氮杂苯并三氮唑-1-基)-N,N,N’,N’-四甲基脲六氟磷酸酯(HATU)(242mg，636.4μmol)，保持温度反应2小时，反应液用高效液相制备色谱法纯化(Waters-2545，色谱柱：YMC Triart-Exrs C18，30*150mm，5μm；流动相：水相(10mmol/L碳酸氢铵)和乙腈，梯度配比：乙腈30％-45％，流速：30mL/min)得到标题化合物11(25mg，产率：12.1％)。Compound 1b-1 (150 mg, 423 μmol) and crude compound 11i (113 mg, 426.3 μmol) were dissolved in 5 mL of N,N-dimethylformamide, and N,N-diisopropylethylamine (274 mg was added under ice bath , 2.1mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethylurea hexafluorophosphate (HATU) (242mg, 636.4μmol) , keep the temperature for 2 hours, and the reaction solution is purified by high-performance liquid phase preparative chromatography (Waters-2545, chromatographic column: YMC Triart-Exrs C18, 30*150mm, 5μm; mobile phase: aqueous phase (10mmol/L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 30%-45%, flow rate: 30 mL/min) to obtain the title compound 11 (25 mg, yield: 12.1%).
MS m/z(ESI):487.2[M+1]。MS m/z(ESI):487.2[M+1].
1H NMR(500MHz,DMSO-d6):δ11.07(br,1H),10.55(br,1H),8.30(s,1H),7.23-7.19(m,2H),6.66-6.64(m,1H),6.52-6.51(m,1H),5.16-5.14(m,1H),4.25-4.21(m,1H),3.95(s,3H),2.78-2.72(m,1H),1.60(s,3H),0.73-0.71(m,3H)。 1 H NMR (500MHz, DMSO-d 6 ): δ11.07(br,1H),10.55(br,1H),8.30(s,1H),7.23-7.19(m,2H),6.66-6.64(m, 1H),6.52-6.51(m,1H),5.16-5.14(m,1H),4.25-4.21(m,1H),3.95(s,3H),2.78-2.72(m,1H),1.60(s, 3H),0.73-0.71(m,3H).
实施例12Example 12
(2R,3S,4S,5R)-N-(7-氯-1H-吡咯并[2,3-c]吡啶-3-基)-3-(3,4-二氟-2-甲氧基苯基)-4,5-二甲基-5-(三氟甲基)四氢呋喃-2-甲酰胺12
(2R,3S,4S,5R)-N-(7-chloro-1H-pyrrolo[2,3-c]pyridin-3-yl)-3-(3,4-difluoro-2-methoxy Phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide 12
第一步first step
7-氯-3-硝基-1H-吡咯并[2,3-c]吡啶12a7-Chloro-3-nitro-1H-pyrrolo[2,3-c]pyridine 12a
将化合物5c(1g，5.58mmol)溶于三氯氧磷(10mL)，加入N,N-二异丙基乙胺(2g，15.47mmol)，100℃搅拌反应2小时，反应液降至室温后过滤，滤饼用乙酸乙酯洗涤，干燥后即得到粗品标题化合物12a(800mg)，不经纯化，直接用于下一步。Compound 5c (1g, 5.58mmol) was dissolved in phosphorus oxychloride (10mL), N,N-diisopropylethylamine (2g, 15.47mmol) was added, and the reaction was stirred at 100°C for 2 hours, and the reaction solution was cooled to room temperature. After filtration, the filter cake was washed with ethyl acetate and dried to obtain the crude title compound 12a (800 mg), which was used directly in the next step without purification.
MS m/z(ESI):198.2[M+1]。MS m/z(ESI):198.2[M+1].
第二步Step 2
7-氯-1H-吡咯并[2,3-c]吡啶-3-胺12b7-Chloro-1H-pyrrolo[2,3-c]pyridin-3-amine 12b
将粗品化合物12a(100mg，506.12μmol)溶于四氢呋喃(5mL)和乙醇(5mL)， 加入铁粉(300mg，5.37mmol)和2mL饱和氯化铵溶液，70℃搅拌反应2小时，反应液趁热过滤，滤液减压浓缩即得到粗品标题化合物12b(50mg)，不经纯化，直接用于下一步。Crude compound 12a (100 mg, 506.12 μmol) 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.
MS m/z(ESI):168.2[M+1]。MS m/z(ESI):168.2[M+1].
第三步third step
(2R,3S,4S,5R)-N-(7-氯-1H-吡咯并[2,3-c]吡啶-3-基)-3-(3,4-二氟-2-甲氧基苯基)-4,5-二甲基-5-(三氟甲基)四氢呋喃-2-甲酰胺12(2R,3S,4S,5R)-N-(7-chloro-1H-pyrrolo[2,3-c]pyridin-3-yl)-3-(3,4-difluoro-2-methoxy Phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide 12
将化合物1b-1(40mg，112.9μmol)，粗品化合物12b(50mg，298μmol)溶于2mL N,N-二甲基甲酰胺中，冰浴下加入N,N-二异丙基乙胺(50mg，386μmol)和O-(7-氮杂苯并三氮唑-1-基)-N,N,N’,N’-四甲基脲六氟磷酸酯(HATU)(65mg，171μmol)，保持温度反应2小时，反应液用高效液相制备色谱法纯化(Waters-2545，色谱柱：YMC Triart-Exrs C18，30*150mm，5μm；流动相：水相(10mmol/L碳酸氢铵)和乙腈，梯度配比：乙腈30％-45％，流速：30mL/min)得到标题化合物12(12mg，产率：21％)。Compound 1b-1 (40 mg, 112.9 μmol) and crude compound 12b (50 mg, 298 μmol) were dissolved in 2 mL N,N-dimethylformamide, and N,N-diisopropylethylamine (50 mg) was added under ice bath. , 386 μmol) and O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethylurea hexafluorophosphate (HATU) (65 mg, 171 μmol), maintained React at room temperature for 2 hours, and the reaction solution is purified by high-performance liquid phase preparative chromatography (Waters-2545, chromatographic column: YMC Triart-Exrs C18, 30*150mm, 5μm; mobile phase: aqueous phase (10mmol/L ammonium bicarbonate) and acetonitrile , gradient ratio: acetonitrile 30%-45%, flow rate: 30 mL/min) to obtain the title compound 12 (12 mg, yield: 21%).
MS m/z(ESI):504.2[M+1]。MS m/z(ESI):504.2[M+1].
1H NMR(500MHz,DMSO-d6):δ11.89(s,1H),10.50(s,1H),7.98-7.90(m,2H),7.70(s,1H),7.21-7.12(m,2H),5.18-5.12(m,1H),4.31-4.27(m,1H),3.95(s,3H),2.78-2.74(m,1H),1.60(s,3H),0.76-0.72(m,3H)。 1 H NMR (500MHz, DMSO-d 6 ): δ11.89(s,1H),10.50(s,1H),7.98-7.90(m,2H),7.70(s,1H),7.21-7.12(m, 2H),5.18-5.12(m,1H),4.31-4.27(m,1H),3.95(s,3H),2.78-2.74(m,1H),1.60(s,3H),0.76-0.72(m, 3H).
实施例13Example 13
(2R,3S,4S,5R)-3-(3,4-二氟-2-甲氧基苯基)-N-(7-氟-1H-吡咯并[2,3-c]吡啶-3-基)-4,5-二甲基-5-(三氟甲基)四氢呋喃-2-甲酰胺13
(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-N-(7-fluoro-1H-pyrrolo[2,3-c]pyridine-3 -yl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide 13
第一步first step
7-氟-1H-吡咯并[2,3-c]吡啶13b7-Fluoro-1H-pyrrolo[2,3-c]pyridine 13b
将2-氟-3-硝基吡啶13a(5g，35.2mmol，上海毕得)溶于四氢呋喃(20mL)，-78℃ 下滴加1M乙烯基溴化镁的四氢呋喃溶液(105mL)，缓慢升至-20℃反应2小时，反应液中加入饱和氯化铵溶液淬灭反应，乙酸乙酯萃取(50mL×2)，合并有机相，用无水硫酸钠干燥，过滤除去干燥剂后减压浓缩，残余物用硅胶柱色谱法以洗脱剂体系B纯化得到标题化合物13b(800mg，产率：16.7％)。Dissolve 2-fluoro-3-nitropyridine 13a (5g, 35.2mmol, Shanghai Bide) in tetrahydrofuran (20mL), -78°C Add 1M vinyl magnesium bromide solution in tetrahydrofuran (105mL) dropwise, slowly rise to -20°C and react for 2 hours. Add saturated ammonium chloride solution to the reaction solution to quench the reaction, extract with ethyl acetate (50mL×2), and combine The organic phase was dried over anhydrous sodium sulfate, filtered to remove the desiccant and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent system B to obtain the title compound 13b (800 mg, yield: 16.7%).
MS m/z(ESI):137.2[M+1]。MS m/z(ESI):137.2[M+1].
第二步Step 2
7-氟-3-硝基-1H-吡咯并[2,3-c]吡啶13c7-Fluoro-3-nitro-1H-pyrrolo[2,3-c]pyridine 13c
将化合物13b(200mg，1.47mmol)溶于浓硫酸(5mL)，0℃下分批加入硝酸钾(150mg，1.48mmol)，保持温度继续反应反应2小时，反应液中加入水，搅拌30分钟，过滤，滤饼用水洗涤，干燥后即得到粗品标题化合物13c(100mg)，不经纯化，直接用于下一步。Dissolve compound 13b (200 mg, 1.47 mmol) in concentrated sulfuric acid (5 mL), add potassium nitrate (150 mg, 1.48 mmol) in batches at 0°C, maintain the temperature and continue the reaction for 2 hours, add water to the reaction solution, and stir for 30 minutes. After filtration, the filter cake was washed with water and dried to obtain the crude title compound 13c (100 mg), which was used directly in the next step without purification.
MS m/z(ESI):182.2[M+1]。MS m/z(ESI):182.2[M+1].
第三步third step
7-氟-1H-吡咯并[2,3-c]吡啶-3-胺13d7-Fluoro-1H-pyrrolo[2,3-c]pyridin-3-amine 13d
将粗品化合物13c(20mg，110.42μmol)溶于四氢呋喃(2mL)和甲醇(2mL)，加入10％钯碳催化剂(10mg)，氢气置换，搅拌反应2小时，过滤，滤液减压浓缩即得到粗品标题化合物13d(20mg)，不经纯化，直接用于下一步。Dissolve crude compound 13c (20 mg, 110.42 μmol) in tetrahydrofuran (2 mL) and methanol (2 mL), add 10% palladium carbon catalyst (10 mg), replace with hydrogen, stir and react for 2 hours, filter, and concentrate the filtrate under reduced pressure to obtain the crude title product Compound 13d (20 mg) was used directly in the next step without purification.
MS m/z(ESI):152.2[M+1]。MS m/z(ESI):152.2[M+1].
第四步the fourth step
(2R,3S,4S,5R)-3-(3,4-二氟-2-甲氧基苯基)-N-(7-氟-1H-吡咯并[2,3-c]吡啶-3-基)-4,5-二甲基-5-(三氟甲基)四氢呋喃-2-甲酰胺13(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-N-(7-fluoro-1H-pyrrolo[2,3-c]pyridine-3 -yl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide 13
将化合物1b-1(30mg，84.6μmol)，粗品化合物13d(20mg，132μmol)溶于2mL N,N-二甲基甲酰胺中，冰浴下加入N,N-二异丙基乙胺(33mg，255μmol)和O-(7-氮杂苯并三氮唑-1-基)-N,N,N’,N’-四甲基脲六氟磷酸酯(HATU)(100mg，262μmol)，保持温度反应2小时，反应液用高效液相制备色谱法纯化(Waters-2545，色谱柱：YMC Triart-Exrs C18，30*150mm，5μm；流动相：水相(10mmol/L碳酸氢铵)和乙腈，梯度配比：乙腈30％-45％，流速：30mL/min)得到标题化合物13(5mg，产率：12％)。Compound 1b-1 (30 mg, 84.6 μmol) and crude compound 13d (20 mg, 132 μmol) were dissolved in 2 mL of N,N-dimethylformamide, and N,N-diisopropylethylamine (33 mg was added under ice bath , 255 μmol) and O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethylurea hexafluorophosphate (HATU) (100 mg, 262 μmol), maintained React at room temperature for 2 hours, and the reaction solution is purified by high-performance liquid phase preparative chromatography (Waters-2545, chromatographic column: YMC Triart-Exrs C18, 30*150mm, 5μm; mobile phase: aqueous phase (10mmol/L ammonium bicarbonate) and acetonitrile , gradient ratio: acetonitrile 30%-45%, flow rate: 30mL/min) to obtain the title compound 13 (5 mg, yield: 12%).
MS m/z(ESI):488.2[M+1]。MS m/z(ESI):488.2[M+1].
1H NMR(500MHz,DMSO-d6):δ7.89(s,1H),7.64-7.63(m,1H),7.50-7.47(m,1H),7.18-7.15(m,1H),7.02-6.97(m,1H),5.18-5.12(m,1H),4.38-4.35(m,1H),4.01(s,3H),2.83-2.80(m,1H),1.69(s,3H),0.86-0.83(m,3H)。 1 H NMR (500MHz, DMSO-d 6 ): δ7.89(s,1H),7.64-7.63(m,1H),7.50-7.47(m,1H),7.18-7.15(m,1H),7.02- 6.97(m,1H),5.18-5.12(m,1H),4.38-4.35(m,1H),4.01(s,3H),2.83-2.80(m,1H),1.69(s,3H),0.86- 0.83(m,3H).
实施例14Example 14
(2R,3S,4S,5R)-3-(3,4-二氟-2-甲氧基苯基)-4,5-二甲基-N-(3-氧代-2,3-二氢异噁唑并[4,5-b]吡啶-7-基)-5-(三氟甲基)四氢呋喃-2-甲酰胺14
(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-N-(3-oxo-2,3-di Hydroisoxazolo[4,5-b]pyridin-7-yl)-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide 14
第一步first step
3-(苄氧基)-4-((叔丁氧基羰基)氨基)吡啶甲酸甲酯14bMethyl 3-(benzyloxy)-4-((tert-butoxycarbonyl)amino)pyridinecarboxylate 14b
将3-(苄氧基)-4-溴吡啶甲酸甲酯14a(1.8g，5.58mmol，采用文献“[Journal of Medicinal Chemistry,2020,vol.63,#14,p.7491-7507”公开的方法制备而得)，氨基甲酸叔丁酯(1.97g，16.8mmol，上海泰坦)溶于1,4-二氧六环(50mL)，加入三(二亚苄基丙酮)二钯(512mg，559μmol)，2,2’-双(二苯基膦)-1,1’-联萘(647mg，1.1mmol)，碳酸铯(4.56g，14mmol)，115℃搅拌反应2小时，反应液冷却至室温，过滤，滤液减压浓缩，残余物用硅胶柱色谱法以洗脱剂体系B纯化得到标题化合物14b(2g，产率：99.8％)。3-(Benzyloxy)-4-bromopicolinate methyl ester 14a (1.8g, 5.58mmol, using the method disclosed in the literature "[Journal of Medicinal Chemistry, 2020, vol. 63, #14, p. 7491-7507" Prepared by the method), tert-butyl carbamate (1.97g, 16.8mmol, Shanghai Titan) was dissolved in 1,4-dioxane (50mL), and tris(dibenzylideneacetone)dipalladium (512mg, 559μmol) was added ), 2,2'-bis(diphenylphosphine)-1,1'-binaphthyl (647mg, 1.1mmol), cesium carbonate (4.56g, 14mmol), stir and react at 115°C for 2 hours, and cool the reaction solution to room temperature , filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent system B to obtain the title compound 14b (2g, yield: 99.8%).
MS m/z(ESI):359.2[M+1]。MS m/z(ESI):359.2[M+1].
第二步Step 2
4-((叔丁氧基羰基)氨基)-3-羟基吡啶甲酸甲酯14cMethyl 4-((tert-butoxycarbonyl)amino)-3-hydroxypyridinecarboxylate 14c
将化合物14b(2g，5.58mmol)溶于40mL甲醇，加入10％钯碳催化剂(湿)(1.2g)，氢气置换，搅拌反应4小时，反应液过滤，滤液减压浓缩即得到粗品标题化合物14c(1.42g)，产物不经纯化，直接用于下一步反应。Dissolve compound 14b (2g, 5.58mmol) in 40mL methanol, add 10% palladium on carbon catalyst (wet) (1.2g), replace with hydrogen, stir and react for 4 hours, filter the reaction solution, and concentrate the filtrate under reduced pressure to obtain the crude title compound 14c (1.42g), the product was directly used in the next reaction without purification.
MS m/z(ESI):269.1[M+1]。MS m/z(ESI):269.1[M+1].
第三步third step
(3-羟基-2-(羟基氨基甲酰基)吡啶-4-基)氨基甲酸叔丁酯14d(3-Hydroxy-2-(hydroxycarbamoyl)pyridin-4-yl)carbamic acid tert-butyl ester 14d
将粗品化合物14c(1.42g，5.29mmol)溶于25mL乙醇，加入50％羟胺水溶液(3.49g，52.9mmol)，搅拌反应16小时，反应液中加入水，搅拌10分钟后过滤，滤饼干燥后即得到粗品标题化合物14d(1.03g)，产物不经纯化，直接用于下一步反应。Dissolve crude compound 14c (1.42g, 5.29mmol) in 25mL ethanol, add 50% hydroxylamine aqueous solution (3.49g, 52.9mmol), stir for 16 hours, add water to the reaction solution, stir for 10 minutes, filter, and dry the filter cake. The crude title compound 14d (1.03g) was obtained. The product was directly used in the next reaction without purification.
MS m/z(ESI):270.1[M+1]。 MS m/z(ESI):270.1[M+1].
第四步the fourth step
(3-氧代-2,3-二氢异噁唑并[4,5-b]吡啶-7-基)氨基甲酸叔丁酯14e(3-Oxo-2,3-dihydroisoxazolo[4,5-b]pyridin-7-yl)carbamic acid tert-butyl ester 14e
将化合物14d(900mg，3.34mmol)，三乙胺(406mg，4.01mmol)溶于四氢呋喃(25mL)，-78℃滴加氯化亚砜(438mg，3.68mmol)，自然恢复室温搅拌反应0.5小时，反应液加入乙酸乙酯稀释，饱和氯化钠溶液洗涤，有机相用无水硫酸钠干燥，过滤除去干燥剂后减压浓缩，即得到粗品标题化合物14e(839mg)，产物不经纯化，直接用于下一步反应。Compound 14d (900mg, 3.34mmol) and triethylamine (406mg, 4.01mmol) were dissolved in tetrahydrofuran (25mL), thionyl chloride (438mg, 3.68mmol) was added dropwise at -78°C, and the reaction was allowed to return to room temperature with stirring for 0.5 hours. The reaction solution was diluted with ethyl acetate and washed with saturated sodium chloride solution. The organic phase was dried with anhydrous sodium sulfate, filtered to remove the desiccant and concentrated under reduced pressure to obtain crude title compound 14e (839 mg). The product was directly used without purification. react in the next step.
MS m/z(ESI):252.2[M+1]。MS m/z(ESI):252.2[M+1].
第五步the fifth step
7-氨基异噁唑并[4,5-b]吡啶-3(2H)-酮盐酸盐14f7-Aminoisoxazolo[4,5-b]pyridin-3(2H)-one hydrochloride 14f
将粗品化合物14e(800mg，3.18mmol)溶于30mL 4M盐酸1,4-二氧六环溶液，搅拌反应14小时，反应液减压浓缩即得到粗品标题化合物14f(410mg)，不经纯化，直接用于下一步。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.
MS m/z(ESI):152.2[M+1]。MS m/z(ESI):152.2[M+1].
第六步Step 6
(2R,3S,4S,5R)-3-(3,4-二氟-2-甲氧基苯基)-4,5-二甲基-N-(3-氧代-2,3-二氢异噁唑并[4,5-b]吡啶-7-基)-5-(三氟甲基)四氢呋喃-2-甲酰胺14(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-N-(3-oxo-2,3-di Hydroisoxazolo[4,5-b]pyridin-7-yl)-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide 14
将化合物1b-1(500mg，1.41mmol)溶于二氯甲烷(10mL)，冰浴下加入草酰氯(360mg，2.83mmol)和1滴N,N-二甲基甲酰胺，恢复室温反应1小时，反应液减压浓缩，残余物溶于N,N-二甲基甲酰胺(5mL)，加入N,N-二异丙基乙胺(1.38g，10.67mmol)，4-二甲氨基吡啶(265mg，2.15mmol)，冰浴下加入粗品化合物14f(400mg，2.13mmol，上海瀚泓)，搅拌反应14小时，反应液减压浓缩，用高效液相制备色谱法纯化(Waters-2545，色谱柱：YMC Triart-Exrs C18，30*150mm，5μm；流动相：水相(10mmol/L碳酸氢铵)和乙腈，梯度配比：乙腈35％-45％，流速：30mL/min)得到标题化合物14(55mg，产率：5.29％)。Dissolve compound 1b-1 (500 mg, 1.41 mmol) in dichloromethane (10 mL), add oxalyl chloride (360 mg, 2.83 mmol) and 1 drop of N, N-dimethylformamide under ice bath, and return to room temperature for 1 hour. , the reaction solution was concentrated under reduced pressure, the residue was dissolved in N,N-dimethylformamide (5mL), N,N-diisopropylethylamine (1.38g, 10.67mmol), 4-dimethylaminopyridine ( 265 mg, 2.15 mmol), add crude compound 14f (400 mg, 2.13 mmol, Shanghai Hanhong) under ice bath, stir and react for 14 hours, concentrate the reaction solution under reduced pressure, and purify with high performance liquid chromatography (Waters-2545, chromatographic column : YMC Triart-Exrs C18, 30*150mm, 5μm; mobile phase: aqueous phase (10mmol/L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 35%-45%, flow rate: 30mL/min) to obtain the title compound 14 (55 mg, yield: 5.29%).
MS m/z(ESI):488.2[M+1]。MS m/z(ESI):488.2[M+1].
1H NMR(500MHz,CDCl3):δ9.07(bs,1H),8.23(d,1H),7.12(d,1H),7.08-7.05(m,1H),6.88(q,1H),5.07(d,1H),4.13(dd,1H),3.97(s,3H),2.77-2.71(m,1H),1.67(s,3H),0.77(d,3H)。 1 H NMR (500MHz, CDCl 3 ): δ9.07(bs,1H),8.23(d,1H),7.12(d,1H),7.08-7.05(m,1H),6.88(q,1H),5.07 (d,1H),4.13(dd,1H),3.97(s,3H),2.77-2.71(m,1H),1.67(s,3H),0.77(d,3H).
实施例15Example 15
(2R,3S,4S,5R)-3-(3,4-二氟-2-甲氧基苯基)-4,5-二甲基-N-(8-氧代-5,6,7,8-四氢-1,7-萘啶-4-基)-5-(三氟甲基)四氢呋喃-2-甲酰胺15

(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-N-(8-oxo-5,6,7 ,8-tetrahydro-1,7-naphthyridin-4-yl)-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide 15

第一步first step
4-(双(叔丁氧基羰基)氨基)-3-甲基吡啶甲酸甲酯15bMethyl 4-(bis(tert-butoxycarbonyl)amino)-3-methylpyridinecarboxylate 15b
将4-氨基-3-甲基吡啶甲酸甲酯15a(1.5g，9.02mmol，采用文献“Heterocycles,2013,vol.87,#6,p.1279-1287”公开的方法制备而得)，二碳酸二叔丁酯(5.9g，27.03mmol)，三乙胺(4.56g，45.06mmol)，4-二甲氨基吡啶(1.11g，9.01mmol)溶于二氯甲烷(40mL)，搅拌反应14小时，反应液减压浓缩，残余物用硅胶柱色谱法以洗脱剂体系B纯化得到标题化合物15b(1.25g，产率：37.8％)。4-Amino-3-methylpicolinate methyl ester 15a (1.5g, 9.02mmol, prepared by the method disclosed in the document "Heterocycles, 2013, vol.87, #6, p.1279-1287"), 2 Di-tert-butyl carbonate (5.9g, 27.03mmol), triethylamine (4.56g, 45.06mmol), 4-dimethylaminopyridine (1.11g, 9.01mmol) were dissolved in dichloromethane (40mL), and the reaction was stirred for 14 hours. , the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using eluent system B to obtain the title compound 15b (1.25 g, yield: 37.8%).
MS m/z(ESI):367.2[M+1]。MS m/z(ESI):367.2[M+1].
第二步Step 2
4-(双(叔丁氧基羰基)氨基)-3-(溴甲基)吡啶甲酸甲酯15cMethyl 4-(bis(tert-butoxycarbonyl)amino)-3-(bromomethyl)picolinate 15c
将化合物15b(1.25g，3.41mmol)溶于四氯化碳(30mL)，加入N-溴代丁二酰亚胺(729mg，4.10mmol)，偶氮二异丁腈(56mg，341.03μmol)，100℃反应14小时，反应液冷却至室温，加入饱和硫代硫酸钠溶液淬灭，用二氯甲烷(20mL×3)萃取，合并有机相，用无水硫酸钠干燥，过滤除去干燥剂后减压浓缩，残余物用硅胶柱色谱法以洗脱剂体系B纯化得到标题化合物15c(1.28g，产率：84.2％)。Compound 15b (1.25g, 3.41mmol) was dissolved in carbon tetrachloride (30mL), and N-bromosuccinimide (729mg, 4.10mmol) and azobisisobutyronitrile (56mg, 341.03μmol) were added. React at 100°C for 14 hours, cool the reaction solution to room temperature, add saturated sodium thiosulfate solution to quench, extract with dichloromethane (20mL×3), combine the organic phases, dry over anhydrous sodium sulfate, filter to remove the desiccant and reduce The mixture was concentrated under pressure, and the residue was purified by silica gel column chromatography using eluent system B to obtain the title compound 15c (1.28 g, yield: 84.2%).
MS m/z(ESI):445.2[M+1]。MS m/z(ESI):445.2[M+1].
第三步third step
4-(双(叔丁氧基羰基)氨基)-3-(氰基甲基)吡啶甲酸甲酯15dMethyl 4-(bis(tert-butoxycarbonyl)amino)-3-(cyanomethyl)picolinate 15d
将化合物15c(1.28g，2.87mmol)溶于乙腈(20mL)，加入氟化铯(2.18g，14.35mmol)，三甲基氰硅烷(1.42g，14.31mmol)，50℃搅拌反应14小时，反应液冷却至室温，过滤，滤液减压浓缩，残余物用硅胶柱色谱法以洗脱剂体系B纯化得到标题化合物15d(417mg，产率：37％)。Compound 15c (1.28g, 2.87mmol) was dissolved in acetonitrile (20mL), cesium fluoride (2.18g, 14.35mmol) and trimethylsilyl cyanide (1.42g, 14.31mmol) were added, and the reaction was stirred at 50°C for 14 hours. The liquid was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent system B to obtain the title compound 15d (417 mg, yield: 37%).
MS m/z(ESI):392.2[M+1]。MS m/z(ESI):392.2[M+1].
第四步the fourth step
(叔丁氧基羰基)(8-氧代-5,6,7,8-四氢-1,7-萘啶-4-基)氨基甲酸叔丁酯15e(tert-butoxycarbonyl)(8-oxo-5,6,7,8-tetrahydro-1,7-naphthyridin-4-yl)carbamate 15e
将化合物15d(417mg，1.06mmol)溶于甲醇(10mL)，0℃加入硼氢化钠(242mg，6.4mmol)，缓慢加入六水合氯化钴(153mg，643.04μmol，国药)，搅拌反应14小时，反应液减压浓缩，残余物溶于乙酸乙酯(30mL)中，用水洗涤，有机相用无水 硫酸钠干燥，过滤除去干燥剂后减压浓缩，即得到粗品标题化合物15e(200mg)，产物不经纯化，直接用于下一步反应。Compound 15d (417 mg, 1.06 mmol) was dissolved in methanol (10 mL), sodium borohydride (242 mg, 6.4 mmol) was added at 0°C, cobalt chloride hexahydrate (153 mg, 643.04 μmol, Sinopharm) was slowly added, and the reaction was stirred for 14 hours. The reaction solution was concentrated under reduced pressure, and the residue was dissolved in ethyl acetate (30 mL), washed with water, and the organic phase was washed with anhydrous water. Dry over sodium sulfate, remove the desiccant by filtration, and concentrate under reduced pressure to obtain the crude title compound 15e (200 mg). The product was directly used in the next reaction without purification.
MS m/z(ESI):364.2[M+1]。MS m/z(ESI):364.2[M+1].
第五步the fifth step
4-氨基-6,7-二氢-1,7-萘啶-8(5H)-酮15f4-Amino-6,7-dihydro-1,7-naphthyridin-8(5H)-one 15f
将粗品化合物15e(200mg，550μmol)加入4M氯化氢的1,4-二氧六环溶液(5mL)，搅拌反应14小时，反应液减压浓缩，残余物用高效液相制备色谱法纯化(Waters-2545，色谱柱：YMC Triart-Exrs C18，30*150mm，5μm；流动相：水相(10mmol/L碳酸氢铵)和乙腈，梯度配比：乙腈30％-40％，流速：30mL/min)得到标题化合物15f(20mg，产率：22％)。Crude compound 15e (200 mg, 550 μmol) was added to 4M hydrogen chloride in 1,4-dioxane solution (5 mL), and the reaction was stirred for 14 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by high-performance liquid phase preparative chromatography (Waters- 2545, column: YMC Triart-Exrs C18, 30*150mm, 5μm; mobile phase: aqueous phase (10mmol/L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 30%-40%, flow rate: 30mL/min) The title compound 15f (20 mg, yield: 22%) was obtained.
MS m/z(ESI):164.2[M+1]。MS m/z(ESI):164.2[M+1].
第六步Step 6
(2R,3S,4S,5R)-3-(3,4-二氟-2-甲氧基苯基)-4,5-二甲基-N-(8-氧代-5,6,7,8-四氢-1,7-萘啶-4-基)-5-(三氟甲基)四氢呋喃-2-甲酰胺15(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-N-(8-oxo-5,6,7 ,8-tetrahydro-1,7-naphthyridin-4-yl)-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide 15
将化合物1b-1(45mg，127μmol)，化合物15f(20mg，128μmol)溶于2mL N,N-二甲基甲酰胺中，冰浴下加入N,N-二异丙基乙胺(164mg，1.26mmol)和O-(7-氮杂苯并三氮唑-1-基)-N,N,N’,N’-四甲基脲六氟磷酸酯(HATU)(77mg，202μmol)，保持温度反应2小时，反应液用高效液相制备色谱法纯化(Waters-2545，色谱柱：YMC Triart-Exrs C18，30*150mm，5μm；流动相：水相(10mmol/L碳酸氢铵)和乙腈，梯度配比：乙腈35％-45％，流速：30mL/min)得到标题化合物15(4mg，产率：6.3％)。Compound 1b-1 (45mg, 127μmol) and compound 15f (20mg, 128μmol) were dissolved in 2mL N,N-dimethylformamide, and N,N-diisopropylethylamine (164mg, 1.26 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethylurea hexafluorophosphate (HATU) (77 mg, 202 μmol), maintaining temperature React for 2 hours, and the reaction solution is purified by high performance liquid phase preparative chromatography (Waters-2545, chromatographic column: YMC Triart-Exrs C18, 30*150mm, 5μm; mobile phase: aqueous phase (10mmol/L ammonium bicarbonate) and acetonitrile, Gradient ratio: acetonitrile 35%-45%, flow rate: 30 mL/min) to obtain the title compound 15 (4 mg, yield: 6.3%).
MS m/z(ESI):500.2[M+1]。MS m/z(ESI):500.2[M+1].
1H NMR(500MHz,CDCl3):δ7.89(s,1H),7.05(s,1H),6.81(dd,1H),6.58(s,1H),5.88-5.60(m,1H),4.84(d,1H),4.65(s,2H),4.10(d,1H),3.96(s,3H),3.55(s,2H),2.67(t,1H),1.57(s,3H),0.75(d,3H)。 1 H NMR (500MHz, CDCl 3 ): δ7.89(s,1H),7.05(s,1H),6.81(dd,1H),6.58(s,1H),5.88-5.60(m,1H),4.84 (d,1H),4.65(s,2H),4.10(d,1H),3.96(s,3H),3.55(s,2H),2.67(t,1H),1.57(s,3H),0.75( d,3H).
实施例16Example 16
(2R,3S,4S,5R)-3-(3,4-二氟-2-甲氧基苯基)-4,5-二甲基-N-(5-氧代-2,3,4,5-四氢苯并[f][1,4]氧杂氮杂卓-7-基)-5-(三氟甲基)四氢呋喃-2-甲酰胺16
(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-N-(5-oxo-2,3,4 ,5-Tetrahydrobenzo[f][1,4]oxazepine-7-yl)-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide 16
第一步first step
7-氨基-3,4-二氢苯并[f][1,4]氧杂氮杂卓-5(2H)-酮16b7-Amino-3,4-dihydrobenzo[f][1,4]oxaazepine-5(2H)-one 16b
将7-硝基-3,4-二氢苯并[f][1,4]氧杂氮杂卓-5(2H)-酮16a(30mg，144.1μmol，采用专利申请“WO2007004959”中说明书第34页实施例9公开的方法制备而得)溶于甲醇(4mL)，加入10％钯碳加氢催化剂(干)(15mg)，氢气置换，搅拌反应14小时，反应液过滤，滤液减压浓缩即得到粗品标题化合物16b(25mg)，不经纯化，直接用于下一步。7-Nitro-3,4-dihydrobenzo[f][1,4]oxaazepine-5(2H)-one 16a (30 mg, 144.1 μmol, was prepared using the instructions in the patent application "WO2007004959" Prepared by the method disclosed in Example 9 on page 34) was dissolved in methanol (4 mL), added 10% palladium carbon hydrogenation catalyst (dry) (15 mg), replaced with hydrogen, stirred for 14 hours, the reaction liquid was filtered, and the filtrate was concentrated under reduced pressure The crude title compound 16b (25 mg) was obtained, which was used directly in the next step without purification.
MS m/z(ESI):179.2[M+1]。MS m/z(ESI):179.2[M+1].
第二步Step 2
(2R,3S,4S,5R)-3-(3,4-二氟-2-甲氧基苯基)-4,5-二甲基-N-(5-氧代-2,3,4,5-四氢苯并[f][1,4]氧杂氮杂卓-7-基)-5-(三氟甲基)四氢呋喃-2-甲酰胺16(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-N-(5-oxo-2,3,4 ,5-Tetrahydrobenzo[f][1,4]oxazepine-7-yl)-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide 16
将化合物1b-1(45mg，127.5μmol)溶于3mL N,N-二甲基甲酰胺中，冰浴下加入N,N-二异丙基乙胺(57.7mg，446.3μmol)和O-(7-氮杂苯并三氮唑-1-基)-N,N,N’,N’-四甲基脲六氟磷酸酯(HATU)(72.7mg，191.3μmol)，保持温度搅拌10分钟后加入粗品化合物16b(25mg，140.3μmol)，继续保持温度反应2小时，反应液用高效液相制备色谱法纯化(Waters-2545，色谱柱：YMC Triart-Exrs C18，30*150mm，5μm；流动相：水相(10mmol/L碳酸氢铵)和乙腈，梯度配比：乙腈35％-42％，流速：30mL/min)得到标题化合物16(15mg，产率：22.8％)。Compound 1b-1 (45 mg, 127.5 μmol) was dissolved in 3 mL N,N-dimethylformamide, and N,N-diisopropylethylamine (57.7 mg, 446.3 μmol) and O-( 7-Azabenzotriazol-1-yl)-N,N,N',N'-tetramethylurea hexafluorophosphate (HATU) (72.7mg, 191.3μmol), after stirring for 10 minutes while maintaining temperature Add crude compound 16b (25 mg, 140.3 μmol) and continue to maintain the temperature for 2 hours. The reaction solution is purified by high performance liquid phase preparative chromatography (Waters-2545, chromatographic column: YMC Triart-Exrs C18, 30*150mm, 5 μm; 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%).
MS m/z(ESI):515.2[M+1]。MS m/z(ESI):515.2[M+1].
1H NMR(500MHz,CD3OD):δ7.89(d,1H),7.71(dd,1H),7.13(t,1H),6.99(dd,2H),5.03(d,1H),4.36-4.26(m,3H),3.99(t,3H),3.41(d,2H),2.78(t,1H),1.66(s,3H),0.81(d,3H)。 1 H NMR (500MHz, CD 3 OD): δ7.89(d,1H),7.71(dd,1H),7.13(t,1H),6.99(dd,2H),5.03(d,1H),4.36- 4.26(m,3H),3.99(t,3H),3.41(d,2H),2.78(t,1H),1.66(s,3H),0.81(d,3H).
实施例17Example 17
(2R,3S,4S,5R)-3-(3,4-二氟-2-甲氧基苯基)-N-(3'-亚氨基螺[环丙烷-1,1'-异吲哚啉]-6'-基)-4,5-二甲基-5-(三氟甲基)四氢呋喃-2-甲酰胺2,2,2-三氟乙酸盐17-p1(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-N-(3'-iminospiro[cyclopropane-1,1'-isoindole Phenolin]-6'-yl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide 2,2,2-trifluoroacetate 17-p1
(2R,3S,4S,5R)-3-(3,4-二氟-2-甲氧基苯基)-N-(3'-亚氨基螺[环丙烷-1,1'-异吲哚啉]-5'-基)-4,5-二甲基-5-(三氟甲基)四氢呋喃-2-甲酰胺2,2,2-三氟乙酸盐17-p2
(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-N-(3'-iminospiro[cyclopropane-1,1'-isoindole Phenolin]-5'-yl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide 2,2,2-trifluoroacetate 17-p2
第一步first step
(2R,3S,4S,5R)-N-(3,4-二氰基苯基)-3-(3,4-二氟-2-甲氧基苯基)-4,5-二甲基-5-(三氟甲基)四氢呋喃-2-甲酰胺17b(2R,3S,4S,5R)-N-(3,4-dicyanophenyl)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl -5-(Trifluoromethyl)tetrahydrofuran-2-carboxamide 17b
将化合物1b-1(1.25g，3.52mmol)溶于二氯甲烷(30mL)，冰浴下加入草酰氯(1.33g，10.5mmol)和5滴N,N-二甲基甲酰胺，保持温度反应1小时，反应液减压浓缩，残余物溶于二氯甲烷(5mL)，冰浴下加入N,N-二异丙基乙胺(1.36g，10.5mmol)，4-二甲氨基吡啶(2mg，16.2μmol)，4-氨基邻苯二甲腈17a(400mg，2.13mmol，上海韶远)，搅拌反应14小时，反应液减压浓缩，残余物用硅胶柱色谱法以洗脱剂体系B纯化得到标题化合物17b(900mg，产率：53.7％)。Dissolve compound 1b-1 (1.25g, 3.52mmol) in dichloromethane (30mL), add oxalyl chloride (1.33g, 10.5mmol) and 5 drops of N,N-dimethylformamide under ice bath, and maintain the temperature for reaction. After 1 hour, the reaction solution was concentrated under reduced pressure, and the residue was dissolved in dichloromethane (5 mL). N,N-diisopropylethylamine (1.36 g, 10.5 mmol) and 4-dimethylaminopyridine (2 mg) were added under ice bath. , 16.2 μmol), 4-aminophthalonitrile 17a (400 mg, 2.13 mmol, Shaoyuan, Shanghai), stir and react for 14 hours, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system B The title compound 17b (900 mg, yield: 53.7%) was obtained.
MS m/z(ESI):480.2[M+1]。MS m/z(ESI):480.2[M+1].
第二步Step 2
(2R,3S,4S,5R)-3-(3,4-二氟-2-甲氧基苯基)-N-(3'-亚氨基螺[环丙烷-1,1'-异吲哚啉]-6'-基)-4,5-二甲基-5-(三氟甲基)四氢呋喃-2-甲酰胺2,2,2-三氟乙酸盐17-p1(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-N-(3'-iminospiro[cyclopropane-1,1'-isoindole Phenolin]-6'-yl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide 2,2,2-trifluoroacetate 17-p1
(2R,3S,4S,5R)-3-(3,4-二氟-2-甲氧基苯基)-N-(3'-亚氨基螺[环丙烷-1,1'-异吲哚啉]-5'-基)-4,5-二甲基-5-(三氟甲基)四氢呋喃-2-甲酰胺2,2,2-三氟乙酸盐17-p2(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-N-(3'-iminospiro[cyclopropane-1,1'-isoindole Phenolin]-5'-yl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide 2,2,2-trifluoroacetate 17-p2
将化合物17b(200mg，417.2μmol)溶于乙醚(5mL)中，-78℃下加入钛酸四异丙酯(261mg，918.3μmol，上海泰坦)，滴加2.0M乙基溴化镁的四氢呋喃溶液(690.3μL)，0℃搅拌反应1小时后恢复室温反应16小时，反应液中加入甲醇淬灭，过滤，滤液减压浓缩，残余物用高效液相制备色谱法纯化(Waters-2545，色谱柱：YMC Triart-Exrs C18，30*150mm，5μm；流动相：流动相：水相(1‰三氟醋酸)和乙腈，梯度配比：乙腈30％-42％，流速：30mL/min)得到标题化合物(15mg，产率：5.7％)，(15mg，产率：5.7％)。Compound 17b (200 mg, 417.2 μmol) was dissolved in diethyl ether (5 mL), tetraisopropyl titanate (261 mg, 918.3 μmol, Shanghai Titan) was added at -78°C, and 2.0 M ethyl magnesium bromide in tetrahydrofuran was added dropwise. (690.3 μL), stirred at 0°C for 1 hour and then returned to room temperature for 16 hours. Methanol was added to the reaction solution to quench it, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by HPLC preparative chromatography (Waters-2545, chromatographic column : YMC Triart-Exrs C18, 30*150mm, 5μm; mobile phase: mobile phase: water phase (1‰ trifluoroacetic acid) and acetonitrile, gradient ratio: acetonitrile 30%-42%, flow rate: 30mL/min) to get the title Compound (15 mg, yield: 5.7%), (15 mg, yield: 5.7%).
单一构型化合物(较短保留时间)：(15mg，产率：5.7％)。Single configuration compound (shorter retention time): (15 mg, yield: 5.7%).
MS m/z(ESI):510.2[M+1]。MS m/z(ESI):510.2[M+1].
HPLC分析：保留时间1.835分钟，纯度：95％(色谱柱：HALOC18，2.7μm，3.0*30mm；流动相：水(1‰甲酸)，乙腈，梯度配比：乙腈10％-95％)。HPLC analysis: retention time 1.835 minutes, purity: 95% (column: HALO C18, 2.7μm, 3.0*30mm; mobile phase: water (1‰ formic acid), acetonitrile, gradient ratio: acetonitrile 10%-95%).
1H NMR(500MHz,CD3OD):δ8.57(d,1H),7.73(dd,1H),7.35(d,1H),7.17-7.13(m,1H),7.01-6.95(m,1H),5.10(d,1H),4.33(dd,1H),4.10(d,3H),2.82-2.76(m,1H),1.83-1.80(m,2H),1.71-1.69(m,2H),1.68(s,3H),0.83(d,3H)。 1 H NMR (500MHz, CD 3 OD): δ8.57(d,1H),7.73(dd,1H),7.35(d,1H),7.17-7.13(m,1H),7.01-6.95(m,1H ),5.10(d,1H),4.33(dd,1H),4.10(d,3H),2.82-2.76(m,1H),1.83-1.80(m,2H),1.71-1.69(m,2H), 1.68(s,3H),0.83(d,3H).
单一构型化合物(较长保留时间)：(15mg，产率：5.7％)。Single configuration compound (longer retention time): (15 mg, yield: 5.7%).
MS m/z(ESI):510.2[M+1]。MS m/z(ESI):510.2[M+1].
HPLC分析：保留时间2.057分钟，纯度：98％(色谱柱：HALOC18，2.7μm，3.0*30mm；流动相：水(1‰甲酸)，乙腈，梯度配比：乙腈10％-95％)。HPLC analysis: retention time 2.057 minutes, purity: 98% (column: HALO C18, 2.7μm, 3.0*30mm; mobile phase: water (1‰ formic acid), acetonitrile, gradient ratio: acetonitrile 10%-95%).
1H NMR(500MHz,CD3OD):δ8.02(d,1H),7.77(d,1H),7.71(dd,1H),7.14-7.10(m,1H),6.99-6.94(m,1H),5.09(d,1H),4.33-4.29(m,1H),4.00-3.99(m,3H),2.82-2.76(m,1H),1.83-1.80(m,2H),1.68-1.66(m,2H),1.65(s,3H),0.81(d,3H)。 1 H NMR (500MHz, CD 3 OD): δ8.02(d,1H),7.77(d,1H),7.71(dd,1H),7.14-7.10(m,1H),6.99-6.94(m,1H ),5.09(d,1H),4.33-4.29(m,1H),4.00-3.99(m,3H),2.82-2.76(m,1H),1.83-1.80(m,2H),1.68-1.66(m ,2H),1.65(s,3H),0.81(d,3H).
实施例18 Example 18
(2R,3S,4S,5R)-3-(3,4-二氟-2-甲氧基苯基)-N-(cis-(1R,2S)-2-氟-1-羟基-2,3-二氢-1H-茚-5-基)-4,5-二甲基-5-(三氟甲基)四氢呋喃-2-甲酰胺(顺式异构体混合物)18-p1(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-N-(cis-(1R,2S)-2-fluoro-1-hydroxy-2, 3-Dihydro-1H-inden-5-yl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (cis isomer mixture) 18-p1
(2R,3S,4S,5R)-3-(3,4-二氟-2-甲氧基苯基)-N-(trans-(1S,2S)-2-氟-1-羟基-2,3-二氢-1H-茚-5-基)-4,5-二甲基-5-(三氟甲基)四氢呋喃-2-甲酰胺(反式异构体混合物)18-p2
(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-N-(trans-(1S,2S)-2-fluoro-1-hydroxy-2, 3-Dihydro-1H-inden-5-yl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (trans isomer mixture) 18-p2
第一步first step
(1-氧代-2,3-二氢-1H-茚-5-基)氨基甲酸叔丁酯18b(1-Oxo-2,3-dihydro-1H-inden-5-yl)carbamic acid tert-butyl ester 18b
将5-氯-2,3-二氢-1H-茚-1-酮18a(1g，6mmol，上海韶远)溶于1,4-二氧六环(11mL)中，加入氨基甲酸叔丁酯(843.7mg，7.2mmol，上海韶远)，醋酸钯(67.4mg，300μmol，上海泰坦)，2-二环己基磷-2,4,6-三异丙基联苯(285.7mg，600μmol，上海泰坦)，碳酸铯(4.9g，15mmol)，氮气置换，100℃搅拌反应2小时，反应液降至室温后过滤，滤液减压浓缩，残余物用硅胶柱色谱法以洗脱体系B纯化得到标题化合物18b(1.4g，产率：94.3％)。Dissolve 5-chloro-2,3-dihydro-1H-inden-1-one 18a (1g, 6mmol, Shaoyuan, Shanghai) in 1,4-dioxane (11mL), and add tert-butyl carbamate (843.7mg, 7.2mmol, Shanghai Shaoyuan), palladium acetate (67.4mg, 300μmol, Shanghai Titan), 2-dicyclohexylphosphonium-2,4,6-triisopropylbiphenyl (285.7mg, 600μmol, Shanghai Titan), cesium carbonate (4.9g, 15mmol), nitrogen replacement, stirring reaction at 100°C for 2 hours, the reaction solution was filtered after cooling to room temperature, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using elution system B to obtain the title Compound 18b (1.4 g, yield: 94.3%).
MS m/z(ESI):248.2[M+1]。MS m/z(ESI):248.2[M+1].
第二步Step 2
5-氨基-2-氟-2,3-二氢-1H-茚-1-酮18c5-amino-2-fluoro-2,3-dihydro-1H-inden-1-one 18c
将化合物18b(110mg，444.8μmol)溶于甲醇(3mL)中，加入1-氯甲基-4-氟-1,4-二氮杂双环[2.2.2]辛烷二(四氟硼酸)盐(315.1mg，889.6μmol)，70℃搅拌反应48小时，反应液降至室温后减压浓缩，残余物用硅胶柱色谱法以洗脱体系B纯化得到标题化合物18c(48mg，产率：65.3％)。Compound 18b (110 mg, 444.8 μmol) was dissolved in methanol (3 mL), and 1-chloromethyl-4-fluoro-1,4-diazabicyclo[2.2.2]octanebis(tetrafluoroborate) salt was added (315.1 mg, 889.6 μmol), the reaction was stirred at 70°C for 48 hours, the reaction solution was cooled to room temperature and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography using elution system B to obtain the title compound 18c (48 mg, yield: 65.3% ).
MS m/z(ESI):166.2[M+1]。MS m/z(ESI):166.2[M+1].
第三步 third step
(2R,3S,4S,5R)-3-(3,4-二氟-2-甲氧基苯基)-N-(cis-(1R,2S)-2-氟-1-羟基-2,3-二氢-1H-茚-5-基)-4,5-二甲基-5-(三氟甲基)四氢呋喃-2-甲酰胺(顺式混合物)18-p1(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-N-(cis-(1R,2S)-2-fluoro-1-hydroxy-2, 3-Dihydro-1H-inden-5-yl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (cis mixture) 18-p1
(2R,3S,4S,5R)-3-(3,4-二氟-2-甲氧基苯基)-N-(trans-(1S,2S)-2-氟-1-羟基-2,3-二氢-1H-茚-5-基)-4,5-二甲基-5-(三氟甲基)四氢呋喃-2-甲酰胺(反式混合物)18-p2(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-N-(trans-(1S,2S)-2-fluoro-1-hydroxy-2, 3-Dihydro-1H-inden-5-yl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (trans mixture) 18-p2
将化合物1b-1(200mg，564.5μmol)，化合物18c(93.2mg，564.5μmol)溶于2mL N,N-二甲基甲酰胺中，冰浴下加入N,N-二异丙基乙胺(73mg，564.5μmol)和O-(7-氮杂苯并三氮唑-1-基)-N,N,N’,N’-四甲基脲六氟磷酸酯(HATU)(257.6mg，677.4μmol)，恢复室温反应0.5小时，反应液中加入水，用乙酸乙酯萃取(10mL×3)，合并有机相，用无水硫酸钠干燥，过滤，滤液减压浓缩后溶于甲醇(5mL)，加入硼氢化钠(60.6mg，564.5μmol)，搅拌反应1小时后加入饱和氯化铵溶液淬灭，用乙酸乙酯萃取(10mL×3)，合并有机相，用无水硫酸钠干燥，过滤，滤液减压浓缩，残余物用高效液相制备色谱法纯化(Waters-2545，色谱柱：YMC Triart-Exrs C18，30*150mm，5μm；流动相：水相(10mmol/L碳酸氢铵)和乙腈，梯度配比：乙腈35％-45％，流速：30mL/min)得到标题化合物(24.4mg，产率：8.5％)，(5.6mg，产率：2％)。Compound 1b-1 (200 mg, 564.5 μmol) and compound 18c (93.2 mg, 564.5 μmol) were dissolved in 2 mL of N,N-dimethylformamide, and N,N-diisopropylethylamine ( 73 mg, 564.5 μmol) and O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethylurea hexafluorophosphate (HATU) (257.6 mg, 677.4 μmol), return to room temperature and react for 0.5 hours. Add water to the reaction solution, extract with ethyl acetate (10mL×3), combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure and dissolve in methanol (5mL) , add sodium borohydride (60.6 mg, 564.5 μmol), stir the reaction for 1 hour, add saturated ammonium chloride solution to quench, extract with ethyl acetate (10 mL × 3), combine the organic phases, dry over anhydrous sodium sulfate, and filter , the filtrate was concentrated under reduced pressure, and the residue was purified by high-performance liquid phase preparative chromatography (Waters-2545, chromatographic column: YMC Triart-Exrs C18, 30*150mm, 5μm; mobile phase: aqueous phase (10mmol/L ammonium bicarbonate) and Acetonitrile, gradient ratio: acetonitrile 35%-45%, flow rate: 30 mL/min) to obtain the title compound (24.4 mg, yield: 8.5%), (5.6 mg, yield: 2%).
顺式(cis)异构体混合物或反式(trans)异构体混合物(较短保留时间)(24.4mg，产率：8.5％)：cis (cis) isomer mixture or trans (trans) isomer mixture (shorter retention time) (24.4 mg, yield: 8.5%):
MS m/z(ESI):504.2[M+1]。MS m/z(ESI):504.2[M+1].
HPLC分析：保留时间2.57分钟，纯度：97％(色谱柱：ACQUITYC18,1.7μm，2.1*50mm；流动相：水(1‰甲酸)，乙腈，梯度配比：乙腈10％-95％)。1H NMR(500MHz,CD3OD):δ7.50(s,1H),7.40(dd,1H),7.33(d,1H),7.15-7.12(m,1H),7.01-6.93(m,1H),5.29-5.11(m,1H),5.07-4.92(m,2H),4.30(dd,1H),3.98(d,3H),3.15-3.00(m,2H),2.78(q,1H),1.66(s,3H),0.93-0.76(m,3H)。HPLC analysis: retention time 2.57 minutes, purity: 97% (Column: ACQUITY C18, 1.7μm, 2.1*50mm; mobile phase: water (1‰ formic acid), acetonitrile, gradient ratio: acetonitrile 10%-95%). 1 H NMR (500MHz, CD 3 OD): δ7.50(s,1H),7.40(dd,1H),7.33(d,1H),7.15-7.12(m,1H),7.01-6.93(m,1H ),5.29-5.11(m,1H),5.07-4.92(m,2H),4.30(dd,1H),3.98(d,3H),3.15-3.00(m,2H),2.78(q,1H), 1.66(s,3H),0.93-0.76(m,3H).
顺式异构体混合物或反式异构体混合物(较长保留时间)(5.6mg，产率：2％)：Mixture of cis isomers or mixture of trans isomers (longer retention time) (5.6 mg, yield: 2%):
MS m/z(ESI):504.2[M+1]。MS m/z(ESI):504.2[M+1].
HPLC分析：保留时间2.62分钟，纯度：94％(色谱柱：ACQUITYC18，1.7μm，2.1*50mm；流动相：水(1‰甲酸)，乙腈，梯度配比：乙腈10％-95％)。1H NMR(500MHz,CD3OD):δ7.50(d,1H),7.41(dd,1H),7.32(d,1H),7.15-7.12(m,1H),7.05-6.91(m,1H),5.07-5.00(m,2H),4.30(dd,1H),3.99(d,3H),3.03-2.89(m,1H),2.78(q,1H),2.19(t,1H),2.08-1.99(m,1H),1.66(s,3H),0.82-0.81(m,3H)。HPLC analysis: retention time 2.62 minutes, purity: 94% (Column: ACQUITY C18, 1.7μm, 2.1*50mm; mobile phase: water (1‰ formic acid), acetonitrile, gradient ratio: acetonitrile 10%-95%). 1 H NMR (500MHz, CD 3 OD): δ7.50(d,1H),7.41(dd,1H),7.32(d,1H),7.15-7.12(m,1H),7.05-6.91(m,1H) ),5.07-5.00(m,2H),4.30(dd,1H),3.99(d,3H),3.03-2.89(m,1H),2.78(q,1H),2.19(t,1H),2.08- 1.99(m,1H),1.66(s,3H),0.82-0.81(m,3H).
实施例19Example 19
(2R,3S,4S,5R)-3-(3,4-二氟-2-甲氧基苯基)-4,5-二甲基-N-(5-甲基-7-氧代-6,7-二氢-1H-吡咯并[2,3-c]吡啶-3-基)-5-(三氟甲基)四氢呋喃-2-甲酰胺19
(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-N-(5-methyl-7-oxo- 6,7-Dihydro-1H-pyrrolo[2,3-c]pyridin-3-yl)-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide 19
第一步first step
7-甲氧基-5-甲基-1H-吡咯并[2,3-c]吡啶19b7-methoxy-5-methyl-1H-pyrrolo[2,3-c]pyridine 19b
将7-氯-5-甲基-1H-吡咯并[2,3-c]吡啶19a(4g，24mmol，采用专利申请“US2007185154”中说明书第9页的实施例P1公开的方法制备而得)，30％甲醇钠甲醇溶液(40mL)混合，微波110℃反应4小时，反应液冷却至室温后加入饱和氯化铵溶液，用乙酸乙酯萃取(50mL×2)，合并有机相，用无水硫酸钠干燥，过滤，滤液减压浓缩，残余物用硅胶柱色谱法以洗脱剂体系B纯化得到标题化合物19b(1.1g，28.2％)。7-Chloro-5-methyl-1H-pyrrolo[2,3-c]pyridine 19a (4g, 24mmol, prepared by the method disclosed in Example P1 on page 9 of the specification in the patent application "US2007185154") , 30% sodium methoxide methanol solution (40mL) was mixed, and the microwave was reacted at 110°C for 4 hours. After the reaction solution was cooled to room temperature, saturated ammonium chloride solution was added, extracted with ethyl acetate (50mL×2), the organic phases were combined, and anhydrous Dry over sodium sulfate, filter, and concentrate the filtrate under reduced pressure. The residue is purified by silica gel column chromatography using eluent system B to obtain the title compound 19b (1.1 g, 28.2%).
MS m/z(ESI):163.2[M+1]。MS m/z(ESI):163.2[M+1].
第二步Step 2
7-甲氧基-5-甲基-3-硝基-1H-吡咯并[2,3-c]吡啶19c7-methoxy-5-methyl-3-nitro-1H-pyrrolo[2,3-c]pyridine 19c
将化合物19b(1.1g，6.78mmol)溶于浓硫酸(10mL)中，冰浴下分批加入硝酸钾(686mg，6.78mmol)，保持温度反应2小时，反应液中倒入冰水中，用2M氢氧化钠溶液调节pH至中性，乙酸乙酯萃取(30mL×2)，合并有机相，用无水硫酸钠干燥，过滤，滤液减压浓缩，残余物用高效液相制备色谱法纯化(Waters-2545，色谱柱：YMC Triart-Exrs C18，30*150mm，5μm；流动相：水相(10mmol/L碳酸氢铵)和乙腈，梯度配比：乙腈30％-40％，流速：30mL/min)得到标题化合物19c(300mg，产率：21.3％)。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, 5μm; 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%).
第三步third step
5-甲基-3-硝基-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮19d5-Methyl-3-nitro-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one 19d
将化合物19c(180mg，1.35mmol)溶于3mL 1,4-二氧六环和3mL浓盐酸，85℃搅拌反应4小时，反应液降至室温后过滤，滤饼用水洗涤并干燥后即得到粗品标题化合物19d(261mg)，产物不经纯化，直接用于下一步反应。 Compound 19c (180 mg, 1.35 mmol) was dissolved in 3 mL of 1,4-dioxane and 3 mL of concentrated hydrochloric acid. The reaction was stirred at 85°C for 4 hours. The reaction solution was filtered after cooling to room temperature. The filter cake was washed with water and dried to obtain the crude product. The title compound 19d (261 mg) was used directly in the next reaction without purification.
MS m/z(ESI):194.0[M+1]。MS m/z(ESI):194.0[M+1].
第四步the fourth step
3-氨基-5-甲基-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮19e3-amino-5-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one 19e
将粗品化合物19d(261mg，1.35mmol)溶于异丙醇(3mL)，加入雷尼镍(230mg)和水合肼(1.5mL)，85℃搅拌反应2小时，反应液降至室温后过滤，滤液减压浓缩即得到粗品标题化合物19e(220mg)，产物不经纯化，直接用于下一步反应。Dissolve the crude compound 19d (261 mg, 1.35 mmol) in isopropanol (3 mL), add Raney nickel (230 mg) and hydrazine hydrate (1.5 mL), stir and react at 85°C for 2 hours, filter the reaction solution after cooling to room temperature, and filter the filtrate. Concentrate under reduced pressure to obtain the crude title compound 19e (220 mg). The product was directly used in the next reaction without purification.
MS m/z(ESI):163.9[M+1]。MS m/z(ESI):163.9[M+1].
第五步the fifth step
(2R,3S,4S,5R)-3-(3,4-二氟-2-甲氧基苯基)-4,5-二甲基-N-(5-甲基-7-氧代-6,7-二氢-1H-吡咯并[2,3-c]吡啶-3-基)-5-(三氟甲基)四氢呋喃-2-甲酰胺19(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-N-(5-methyl-7-oxo- 6,7-Dihydro-1H-pyrrolo[2,3-c]pyridin-3-yl)-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide 19
将化合物1b-1(131mg，369.77μmol)，粗品化合物19e(50mg，306.4μmol)溶于2mL N,N-二甲基甲酰胺中，加入N,N-二异丙基乙胺(199mg，1.53mmol)和50％1-丙基磷酸环酐的乙酸乙酯溶液(391mg，614mmol，上海毕得)，搅拌反应2小时，反应液过滤，滤液用高效液相制备色谱法纯化(Waters-2545，色谱柱：YMC Triart-Exrs C18，30*150mm，5μm；流动相：水相(10mmol/L碳酸氢铵)和乙腈，梯度配比：乙腈35％-45％，流速：30mL/min)得到标题化合物19(80mg，产率：52.2％)。Compound 1b-1 (131 mg, 369.77 μmol) and crude compound 19e (50 mg, 306.4 μmol) were dissolved in 2 mL of N,N-dimethylformamide, and N,N-diisopropylethylamine (199 mg, 1.53 mmol) and 50% 1-propylphosphoric acid cyclic anhydride in ethyl acetate solution (391 mg, 614 mmol, Shanghai Bide), stirred for 2 hours, the reaction liquid was filtered, and the filtrate was purified by high performance liquid phase preparative chromatography (Waters-2545, Chromatographic column: YMC Triart-Exrs C18, 30*150mm, 5μm; mobile phase: aqueous phase (10mmol/L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 35%-45%, flow rate: 30mL/min) to obtain the title Compound 19 (80 mg, yield: 52.2%).
MS m/z(ESI):500.2[M+1]。MS m/z(ESI):500.2[M+1].
1H NMR(500MHz,CD3OD):δ7.60(s,1H),7.16-7.13(m,1H),7.01-6.96(m,1H),6.34(s,1H),5.12(d,1H),4.33(dd,1H),4.00-3.99(m,3H),2.82-2.75(m,1H),2.28(s,3H),1.67(s,3H),0.83(d,3H)。 1 H NMR (500MHz, CD 3 OD): δ7.60(s,1H),7.16-7.13(m,1H),7.01-6.96(m,1H),6.34(s,1H),5.12(d,1H ),4.33(dd,1H),4.00-3.99(m,3H),2.82-2.75(m,1H),2.28(s,3H),1.67(s,3H),0.83(d,3H).
生物学评价biological evaluation
测试例1、本公开化合物对Nav1.8抑制活性的测定Test Example 1. Determination of Nav1.8 inhibitory activity of compounds of the present disclosure
实验的目的是为了调查化合物在离体实验中对Nav1.8离子通道的影响，Nav1.8离子通道稳定地表达在HEK293细胞上。在Nav1.8电流稳定后，比较化合物应用前后Nav1.8电流的大小，可以得到化合物对Nav1.8离子通道的影响。The purpose of the experiment was to investigate the effect of compounds on Nav1.8 ion channels in in vitro experiments. 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.
1实验材料及仪器1Experimental materials and instruments
1)膜片钳放大器：patch clamp PC-505B(WARNER instruments)/MultiClamp700A(Axon instrument)1) Patch clamp amplifier: patch clamp PC-505B (WARNER instruments)/MultiClamp700A (Axon instruments)
2)数模转换器：Digidata 1440A(Axon CNS)/Digidata 1550A(Axon instruments)2) Digital-to-analog converter: Digidata 1440A (Axon CNS)/Digidata 1550A (Axon instruments)
3)微操控仪：MP-225(SUTTER instrument)3) Microcontroller: MP-225 (SUTTER instrument)
4)倒置显微镜：TL4(Olympus)4) Inverted microscope: TL4 (Olympus)
5)玻璃微电极拉制仪：PC-10(NARISHIGE)5) Glass microelectrode drawing instrument: PC-10 (NARISHIGE)
6)微电极玻璃毛细管：B12024F(武汉微探科学仪器有限公司)6) Microelectrode glass capillary: B12024F (Wuhan Weitan Scientific Instrument Co., Ltd.)
7)二甲基亚砜(DMSO)D2650(Sigma-Aldrich) 7) Dimethyl sulfoxide (DMSO) D2650 (Sigma-Aldrich)
8)TTX AF3014(Affix Scientific)8)TTX AF3014(Affix Scientific)
2实验步骤2 Experimental steps
2.1化合物配制2.1 Compound preparation
配制细胞内外液的化合物除用于酸碱滴定的NaOH和KOH外，均从Sigma(St.Louis,MO)公司购买。细胞外液(mM)为:NaCl，137；KCl，4；CaCl2，1.8；MgCl2，1；HEPES，10；葡萄糖，10；pH 7.4(NaOH滴定)。细胞内液(mM)为天冬氨酸，140；MgCl2，2；EGTA，11；HEPES，10；pH 7.2(CsOH滴定)。所有测试化合物和对照化合物溶液均含1μM TTX。The compounds for preparing intracellular and intracellular fluids were all purchased from Sigma (St. Louis, MO), except for NaOH and KOH used for acid-base titration. Extracellular fluid (mM) 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 μM TTX.
测试化合物的保存浓度为9mM，溶于二甲基亚砜(DMSO)。测试当天再溶于细胞外液，配制成要求浓度。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.
2.2手动膜片钳测试过程2.2 Manual patch clamp testing process
1)化合物配制成指定浓度的溶液后，按浓度从低到高顺序将药液依次加入各个管道，并对各个管道进行标记。1) After the compound is prepared into a solution with a specified concentration, the solution is added to each pipeline in order from low to high concentration, and each pipeline is marked.
2)将细胞转移到灌流槽中，电极内施加正压，将电极尖端接触到细胞，抽气装置三通阀调成三通状态，然后对电极施加负压，使得电极与细胞形成高阻封接。继续施加负压，使得细胞膜破裂，形成电流通路。2) Transfer the cells to the perfusion tank, apply positive pressure to the electrode, touch the tip of the electrode to the cells, adjust the three-way valve of the air extraction device to the three-way state, and then apply negative pressure to the electrode to form a high-resistance seal between the electrode and the cells. catch. Continuing to apply negative pressure causes the cell membrane to rupture and create a current path.
3)待细胞破膜电流稳定后，依次进行不同的浓度的灌注。若电流稳定至少一分钟即可换下一个浓度进行灌流。每个浓度灌流时间不超过五分钟。3) After the cell membrane-breaking current is stable, perform perfusion with different concentrations in sequence. If the current is stable for at least one minute, you can change to the next concentration for perfusion. The perfusion time for each concentration should not exceed five minutes.
4)清洗灌流槽。按药液浓度从高到低进行冲洗，每个浓度药液冲洗20s。最后用细胞外液冲洗1min。4) Clean the perfusion tank. Flush according to the concentration of the medicinal solution from high to low, and rinse with each concentration of medicinal solution for 20 seconds. Finally, rinse with extracellular fluid for 1 min.
2.3测试电压方程(resting)及结果2.3 Test voltage equation (resting) and results
将细胞钳制在-80mV，然后用持续10毫秒方波去极化到10mV，以得到Nav1.8电流。这一程序每5秒重复一次。检测方波引发的最大电流，待其稳定后，灌流测试化合物，当反应稳定后，计算阻断的强度。Cells were clamped at -80 mV and then depolarized to 10 mV with a square wave lasting 10 ms to obtain Nav1.8 currents. This procedure is repeated every 5 seconds. The maximum current induced by the square wave is detected. After it stabilizes, the test compound is perfused. When the reaction is stable, the intensity of the blockage is calculated.
3.数据分析3.Data analysis
资料将存于计算机系统做分析。资料采集和分析将用pCLAMP 10(Molecular Devices,Union City,CA),管理人员将审查分析结果。电流稳定指的是电流随时间变化在有限的范围内。电流稳定后的大小用来计算化合物在此溶度的作用。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.
本公开化合物对Nav1.8的抑制活性通过以上的试验进行测定，测得的IC50值见表1。The inhibitory activity of the compounds of the present disclosure on Nav1.8 was measured through the above test, and the measured IC 50 values are shown in Table 1.
表1、本公开化合物对Nav1.8通道活性抑制的IC50

Table 1. IC 50 of the compounds of the present disclosure inhibiting Nav1.8 channel activity

结论：本公开中的化合物对Nav1.8通道活性具有明显的抑制效果。Conclusion: The compounds in the present disclosure have significant inhibitory effects on Nav1.8 channel activity.
测试例2、药代动力学评价Test example 2, pharmacokinetic evaluation
一、SD大鼠试验1. SD rat test
1、摘要1. Abstract
以SD大鼠为受试动物，应用LC/MS/MS法测定了SD大鼠灌胃(i.g.)给予实施例化合物后不同时刻血浆中的药物浓度。研究本公开化合物在SD大鼠体内的药代动力学行为，评价其药动学特征。Using SD rats as the test animals, 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.
2、试验方案2. Test plan
2.1试验药品2.1 Experimental drugs
实施例5化合物。Example 5 Compounds.
2.2试验动物2.2 Experimental animals
SD大鼠4只，雌雄各半，由维通利华实验动物技术有限公司提供。禁食一夜后分别灌胃给药。Four SD rats, half male and half female, were provided by Vitong Lever Experimental Animal Technology Co., Ltd. After fasting overnight, they were administered intragastrically.
2.3药物配制2.3 Drug Preparation
分别称取一定量的实施例化合物，加5％DMSO+5％吐温80+90％生理盐水，配制成0.2mg/mL无色澄明溶液。Weigh a certain amount of the example compounds respectively, add 5% DMSO + 5% Tween 80 + 90% physiological saline to prepare a 0.2 mg/mL colorless and clear solution.
2.4给药2.4 Administration
给药剂量为2mg/kg，给药体积为10.0mL/kg。The dosage is 2 mg/kg, and the dosage volume is 10.0 mL/kg.
3、操作3. Operation
于给药前及给药后0.25、0.5、1.0、2.0、4.0、6.0、8.0、11.0、24.0小时，由眼眶采血0.2mL，置EDTA-K2抗凝试管中，10000rpm离心1分钟(4℃)，1小时内分离血浆，-20℃保存待测。采血至离心过程在冰浴条件下操作。给药后2小时进食。Before and 0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0, 11.0, and 24.0 hours after administration, 0.2 mL of blood was collected from the orbit, placed in an EDTA-K2 anticoagulant test tube, and centrifuged at 10000 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.
测定不同浓度的药物给药后SD大鼠血浆中的待测化合物含量：取给药后各时刻的SD大鼠血浆样品25μL，250μL含内标乙腈溶液(SHR3162 100ng/ml)涡旋混合，并在3700rpm下离心10分钟。上清液与水1:1混合后，取上清液0.5μL进行LC/MS/MS分析。Determine the content of the test compound in the plasma of SD rats after administration of different concentrations of drugs: Take 25 μL of SD rat plasma samples at each time after administration, and 250 μL of acetonitrile solution containing internal standard (SHR3162 100ng/ml), vortex and mix. Centrifuge at 3700 rpm for 10 minutes. After the supernatant was mixed with water at a ratio of 1:1, 0.5 μL of the supernatant was taken for LC/MS/MS analysis.
4、药代动力学参数结果4. Pharmacokinetic parameter results
表2、本公开化合物在SD大鼠体内的药代动力学参数

Table 2. Pharmacokinetic parameters of the disclosed compounds in SD rats

结论：本公开化合物在SD大鼠体内血药浓度高，暴露量高，生物利用度高，具有明显的药代动力学优势。Conclusion: The disclosed compound has high blood concentration, high exposure, and high bioavailability in SD rats, and has obvious pharmacokinetic advantages.
二、小鼠试验2. Mouse test
1、摘要1. Abstract
以CD-1小鼠为受试动物，应用LC/MS/MS法测定了CD-1小鼠灌胃(i.g.)给予实施例化合物后不同时刻血浆中的药物浓度。研究本公开化合物在CD-1小鼠体内的药代动力学行为，评价其药动学特征。Using CD-1 mice as test animals, 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.
2、试验方案2. Test plan
2.1试验药品2.1 Experimental drugs
实施例5和实施例1-P1化合物。Example 5 and Example 1-P1 compounds.
2.2试验动物2.2 Experimental animals
CD-1小鼠18只，雄性，由维通利华实验动物技术有限公司提供。平均分成2组，分别灌胃给药。18 CD-1 mice, male, were provided by Vitong Lever Laboratory Animal Technology Co., Ltd. Divide into 2 groups evenly and administer intragastric administration respectively.
2.3药物配制2.3 Drug Preparation
分别称取一定量的实施例化合物，加25％PEG400+75％(10％TPGS+1％HPMC K100LV)，配制成10mg/mL溶液(实施例1-P1：白色混悬液；实施例5：无色微不透明溶液)。Weigh a certain amount of the example compounds respectively, add 25% PEG400+75% (10% TPGS+1% HPMC K100LV), and prepare a 10 mg/mL solution (Example 1-P1: white suspension; Example 5: Colorless slightly opaque solution).
2.4给药2.4 Administration
给药剂量为100mg/kg，给药体积为10.0mL/kg。The dosage is 100 mg/kg, and the dosage volume is 10.0 mL/kg.
3、操作3. Operation
于给药前及给药后0.25、0.5、1.0、2.0、4.0、6.0、8.0、11.0、24.0小时，由眼眶采血0.1mL，置EDTA-K2抗凝试管中，10000rpm离心1分钟(4℃)，1小时内分离血浆，-20℃保存待测。采血至离心过程在冰浴条件下操作。给药后2小时进食。Before and 0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0, 11.0, and 24.0 hours after administration, 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.
测定不同浓度的药物给药后CD-1小鼠血浆中的待测化合物含量：取给药后各时刻的CD-1小鼠血浆样品20μL，250μL含内标乙腈溶液(实施例1-P1：维拉帕米100ng/ml；实施例5：甲苯磺丁脲100ng/ml)涡旋混合，并在3700rpm下离心15分钟。实施例5的上清液与水(1:1)混合后，取上清液1μL进行LC/MS/MS分析；Determine the content of the test compound in the plasma of CD-1 mice after administration of different concentrations of drugs: Take 20 μL of CD-1 mouse plasma samples at each time after administration, and 250 μL of acetonitrile solution containing internal standard (Example 1-P1: Verapamil 100ng/ml; Example 5: Tolbutamide 100ng/ml) vortex and mix, and centrifuge at 3700 rpm for 15 minutes. After mixing the supernatant of Example 5 with water (1:1), take 1 μL of the supernatant for LC/MS/MS analysis;
实施例1-P1组取120μL上清液与50μL水混合物，取上清液3μL进行LC/MS/MS分析。Example 1-P1 group took a mixture of 120 μL of supernatant and 50 μL of water, and took 3 μL of the supernatant for LC/MS/MS analysis.
4、药代动力学参数结果4. Pharmacokinetic parameter results
表3、本公开化合物在CD-1小鼠体内的药代动力学参数
Table 3. Pharmacokinetic parameters of the disclosed compounds in CD-1 mice
结论：本公开化合物在CD-1小鼠体内血药浓度高，暴露量高，清除率低，具有明显的药代动力学优势。 Conclusion: The disclosed compound has high blood concentration, high exposure, and low clearance rate in CD-1 mice, and has obvious pharmacokinetic advantages.

Claims (21)

  1. 一种通式(I)所示的化合物或其可药用的盐：
    A compound represented by general formula (I) or a pharmaceutically acceptable salt thereof:
    其中：in:
    环Cy选自多环环烷基、多环杂环基、多环芳基和多环杂芳基；Ring Cy is selected from polycyclic cycloalkyl, polycyclic heterocyclyl, polycyclic aryl and polycyclic heteroaryl;
    RA选自氢原子、卤素、羟基、氰基、烷基、烷氧基、卤代烷基、卤代烷氧基、羟烷基、羟烷氧基、烯基、-NR3R4、-亚烷基-NR3R4、-O-亚烷基-NR3R4、-C(＝NR5)R6、-C(O)NR3R4、-C(O)R6、-S(O)vNR3R4、-NR5S(O)vR6、-S(O)vR6、-S(＝NR5)(O)R6、＝NR5、＝CR7R8、-NR5C(O)R6、-NR5C(O)NR3R4、-P(O)R7R8、-C(O)NR5NR3R4、-C(＝NR5)NR3R4、-C(O)C(O)NR3R4、-S(＝NR5)NR3R4、-S(＝NR5)R6、环烷基、杂环基、芳基、杂芳基、-O-亚烷基-杂芳基和-O-亚烷基-杂环基，其中，所述的烯基、亚烷基、环烷基、杂环基、芳基和杂芳基各自独立地任选被1个或多个R01所取代；R A is selected from hydrogen atom, halogen, hydroxyl, cyano, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, hydroxyalkoxy, alkenyl, -NR 3 R 4 , -alkylene -NR 3 R 4 , -O-alkylene-NR 3 R 4 , -C(=NR 5 )R 6 , -C(O)NR 3 R 4 , -C(O)R 6 , -S(O ) v NR 3 R 4 , -NR 5 S(O) v R 6 , -S(O) v R 6 , -S(＝NR 5 )(O)R 6 , ＝NR 5 , ＝CR 7 R 8 , -NR 5 C(O)R 6 , -NR 5 C(O)NR 3 R 4 , -P(O)R 7 R 8 , -C(O)NR 5 NR 3 R 4 , -C(＝NR 5 )NR 3 R 4 , -C(O)C(O)NR 3 R 4 , -S(=NR 5 )NR 3 R 4 , -S(=NR 5 )R 6 , cycloalkyl group, heterocyclyl group, Aryl, heteroaryl, -O-alkylene-heteroaryl and -O-alkylene-heterocyclyl, wherein the alkenyl, alkylene, cycloalkyl, heterocyclyl, aromatic The radical and heteroaryl are each independently optionally substituted by 1 or more R 01 ;
    各个RB相同或不同，且各自独立地选自卤素、羟基、氨基、氰基、氧代基、烷基、烷氧基、卤代烷基、卤代烷氧基、烯基、环烷基、杂环基、芳基和杂芳基；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;
    R3、R4和R5相同或不同，且各自独立地选自氢原子、烷基、烷氧基、烯基、炔基、NR20R21、C(O)NR20R21、NR22C(O)R23、C(O)R23、C(O)OR23、OC(O)R23、S(O)vR23、S(O)vOR23、OS(O)vR23、S(O)vNR20R21、OR23、环烷基、杂环基、芳基和杂芳基；其中，所述的烷基、环烷基、杂环基、芳基和杂芳基各自独立地任选被1个或多个R01所取代；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 Each aryl group is independently optionally substituted by 1 or more R 01 ;
    或R3、R4及与其相连的氮原子一起形成杂环基；所述杂环基任选被1个或多个R01所取代；Or 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 ;
    R6、R7和R8相同或不同，且各自独立地选自氢原子、卤素、烷基、烷氧基、卤代烷基、卤代烷氧基、羟烷基、烯基、炔基、NR20R21、C(O)NR20R21、NR22C(O)R23、C(O)R23、C(O)OR23、OC(O)R23、S(O)vR23、S(O)vOR23、OS(O)vR23、S(O)vNR20R21、OR23、环烷基、杂环基、芳基和杂芳基；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;
    各个R01相同或不同，且各自独立地选自卤素、羟基、氰基、氧代基、氨基、-NH烷基、-N(烷基)2、乙酰基、烷基、烯基、炔基、烷氧基、卤代烷基、卤代烷氧基、羟烷基、环烷基、杂环基、芳基和杂芳基； 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;
    各个R20、R21、R22和R23相同或不同，且各自独立地选自氢原子、烷基、烷氧基、烯基、炔基、环烷基、杂环基、芳基和杂芳基；所述的烷基、烷氧基、烯基、炔基、环烷基、杂环基、芳基和杂芳基各自独立地任选被选自卤素、羟基、氰基、氨基、烷基、烷氧基、卤代烷基、卤代烷氧基和羟烷基中的一个或多个所取代；Each of 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’选自氢原子、烷基、卤代烷基、羟烷基、环烷基和杂环基；R' is selected from hydrogen atoms, alkyl groups, haloalkyl groups, hydroxyalkyl groups, cycloalkyl groups and heterocyclic groups;
    X为O或S；X is O or S;
    Ra和Rb相同或不同，且各自独立地选自氢原子、卤素、羟基、氰基、氨基、烷基、烯基、炔基、烷氧基、卤代烷基、卤代烷氧基、羟烷基、环烷基、杂环基、环烷基氧基和杂环基氧基；所述的环烷基、杂环基、环烷基氧基和杂环基氧基各自独立地任选被1个或多个R02所取代；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 each independently optionally substituted by 1 Replaced by one or more R 02 ;
    Rc和Rd相同或不同，且各自独立地选自氢原子、卤素、羟基、氰基、氨基、烷基、烯基、炔基、烷氧基、卤代烷基、卤代烷氧基、羟烷基、环烷基、杂环基、环烷基氧基和杂环基氧基；所述的环烷基、杂环基、环烷基氧基和杂环基氧基各自独立地任选被1个或多个R02所取代；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 each independently optionally substituted by 1 Replaced by one or more R 02 ;
    或，Ra、Rb及与其相连的碳原子一起形成环烷基或杂环基；或，Rc、Rd及与其相连的碳原子一起形成环烷基或杂环基；其中，所述的环烷基或杂环基各自独立地任选被1个或多个R02所取代；Or, R a , R b and the carbon atoms connected to them together form a cycloalkyl or heterocyclic group; or, R c , R d and the carbon atoms connected to them together form a cycloalkyl or heterocyclic group; wherein, the The cycloalkyl or heterocyclyl groups are each independently optionally substituted by 1 or more R 02 ;
    Re选自氢原子、卤素、羟基、氰基、氨基、烷基、烷氧基、卤代烷基、卤代烷氧基和羟烷基；R e is selected from hydrogen atoms, halogen, hydroxyl, cyano, amino, alkyl, alkoxy, haloalkyl, haloalkoxy and hydroxyalkyl;
    各个R02相同或不同，且各自独立地选自卤素、羟基、氰基、氧代基、氨基、酰胺基、烷基、烯基、炔基、烷氧基、卤代烷基、卤代烷氧基、羟烷基、环烷基、杂环基、芳基和杂芳基；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;
    X1为CRX1或N；X 1 is CR X1 or N;
    X2为CRX2或N；X 2 is CR X2 or N;
    X3为CRX3或N；X 3 is CR X3 or N;
    X4为CRX4或N；X 4 is CR X4 or N;
    X5为CRX5或N；X 5 is CR X5 or N;
    条件是，X1、X2、X3、X4和X5不同时为N；The condition is that X 1 , X 2 , X 3 , X 4 and X 5 are not N at the same time;
    RX1、RX2、RX3、RX4和RX5相同或不同，且各自独立地选自氢原子、卤素、羟基、氰基、氨基、酰胺基、硝基、烷基、烯基、炔基、烷氧基、卤代烷基、卤代烷氧基、羟烷基、环烷基、杂环基、-O-(CH2)n-环烷基、-O-(CH2)s-杂环基、芳基和杂芳基；其中，所述的环烷基、杂环基、芳基和杂芳基各自独立地任选被1个或多个R03所取代； 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 ;
    各个R03相同或不同，且各自独立地选自卤素、羟基、氰基、氧代基、氨基、酰胺基、烷基、烯基、炔基、烷氧基、卤代烷基、卤代烷氧基、羟烷基、环烷基、 杂环基、芳基和杂芳基；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选自0、1和2；v is selected from 0, 1 and 2;
    n选自0、1、2、3、4和5；n is selected from 0, 1, 2, 3, 4 and 5;
    s选自0、1、2、3、4和5；且，s is selected from 0, 1, 2, 3, 4 and 5; and,
    r选自0、1、2、3、4和5。r is selected from 0, 1, 2, 3, 4 and 5.
  2. 根据权利要求1所述的通式(I)所示的化合物或其可药用的盐，其为通式(II)所示的化合物或其可药用的盐：
    The compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, which is a compound represented by the general formula (II) or a pharmaceutically acceptable salt thereof:
    其中：in:
    Ra和Rb不同，且各自独立地选自氢原子、卤素、羟基、氰基、氨基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6烷氧基、卤代C1-6烷基、卤代C1-6烷氧基、C1-6羟烷基、3至10元环烷基、3至10元杂环基、3至10元环烷基氧基和3至10元杂环基氧基；所述的3至10元环烷基、3至10元杂环基、3至10元环烷基氧基和3至10元杂环基氧基任选被1个或多个R02所取代；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 ;
    Rc和Rd不同，且各自独立地选自氢原子、卤素、羟基、氰基、氨基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6烷氧基、卤代C1-6烷基、卤代C1-6烷氧基、C1-6羟烷基、3至10元环烷基、3至10元杂环基、3至10元环烷基氧基和3至10元杂环基氧基；所述的3至10元环烷基、3至10元杂环基、3至10元环烷基氧基和3至10元杂环基氧基任选被1个或多个R02所取代；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 ;
    环Cy、RA、RB、R’、X、RX1、RX2、RX3、R02和r如权利要求1中所定义。Rings Cy, RA , RB , R', X, RX1 , RX2 , RX3 , R02 and r are as defined in claim 1.
  3. 根据权利要求1或2所述的通式(I)所示的化合物或其可药用的盐，其中环Cy选自 The compound represented by general formula (I) according to claim 1 or 2 or a pharmaceutically acceptable salt thereof, wherein ring Cy is selected from
    优选地，环Cy选自 更优选为*端与-C(O)NR’-连接，在化合价允许的范围内RA和RB连接至环Cy的任意位置。Preferably, ring Cy is selected from More preferably 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.
  4. 根据权利要求1至3中任一所述的通式(I)所示的化合物或其可药用的盐，其中选自 RC为氢原子或RB，RA和RB如权利要求1中所定义；The compound represented by general formula (I) according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof, wherein Selected from R C is a hydrogen atom or R B , R A and R B are as defined in claim 1;
    优选选自 Preferably selected from
    更优选选自 最优选为 More preferably selected from Most preferably
  5. 根据权利要求1至4中任一所述的通式(I)所示的化合物或其可药用的盐，其中Ra为C1-6烷基；优选地，Ra为CH3。The compound represented by general formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 4, wherein R a is a C 1-6 alkyl group; preferably, R a is CH 3 .
  6. 根据权利要求1至5中任一所述的通式(I)所示的化合物或其可药用的盐，其中Rb为卤代C1-6烷基；优选地，Rb为CF3。The compound represented by general formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 5, wherein R b is a halo C 1-6 alkyl group; preferably, R b is CF 3 .
  7. 根据权利要求1至6中任一所述的通式(I)所示的化合物或其可药用的盐，其中Rc为氢原子，且Rd为C1-6烷基；优选地，Rc为氢原子，且Rd为CH3。The compound represented by general formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 6, wherein R c is a hydrogen atom, and R d is a C 1-6 alkyl group; preferably, R c is a hydrogen atom, and R d is CH 3 .
  8. 根据权利要求1至7中任一项所述的通式(I)所示的化合物或其可药用的盐，其中X为O。The compound represented by general formula (I) according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, wherein X is O.
  9. 根据权利要求1至8中任一项所述的通式(I)所示的化合物或其可药用的盐，其中RA选自氢原子、卤素、羟基、氨基和＝NH；优选地，RA为氢原子、羟基或氨基；更优选地，RA为氢原子。The compound represented by general formula (I) according to any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof, wherein R A is selected from hydrogen atoms, halogens, hydroxyl, amino and =NH; Preferably, RA is a hydrogen atom, hydroxyl group or amino group; more preferably, RA is a hydrogen atom.
  10. 根据权利要求1至9中任一项所述的通式(I)所示的化合物或其可药用的盐， 其中R’为氢原子。The compound represented by general formula (I) according to any one of claims 1 to 9 or a pharmaceutically acceptable salt thereof, where R' is a hydrogen atom.
  11. 根据权利要求1至10中任一项所述的通式(I)所示的化合物或其可药用的盐，其中各个RB相同或不同，且各自独立地选自氧代基、卤素和C1-6烷基；优选地，各个RB相同或不同，且各自独立地为卤素或C1-6烷基。The compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 10, wherein each R B is the same or different, and each is independently selected from the group consisting of oxo, halogen and C 1-6 alkyl; preferably, each R B is the same or different, and each is independently halogen or C 1-6 alkyl.
  12. 根据权利要求1至11中任一项所述的通式(I)所示的化合物或其可药用的盐，其中RX1为C1-6烷氧基；优选地，RX1为甲氧基。The compound represented by general formula (I) according to any one of claims 1 to 11 or a pharmaceutically acceptable salt thereof, wherein R X1 is C 1-6 alkoxy; preferably, R X1 is methoxy base.
  13. 根据权利要求1至12中任一项所述的通式(I)所示的化合物或其可药用的盐，其中RX2为卤素；优选地，RX2为氟原子。The compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 12, wherein R X2 is a halogen; preferably, R X2 is a fluorine atom.
  14. 根据权利要求1至13中任一项所述的通式(I)所示的化合物或其可药用的盐，其中RX3为卤素；优选地，RX3为氟原子。The compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 13, wherein R X3 is a halogen; preferably, R X3 is a fluorine atom.
  15. 根据权利要求1至14中任一项所述的通式(I)所示的化合物或其可药用的盐，其选自如下化合物：


    The compound represented by general formula (I) according to any one of claims 1 to 14 or a pharmaceutically acceptable salt thereof, which is selected from the following compounds:


  16. 一种通式(II-A)或通式(II-1A)所示的化合物或其盐：
    A compound represented by general formula (II-A) or general formula (II-1A) or a salt thereof:
    其中，in,
    R9为C1-6烷基；R 9 is C 1-6 alkyl;
    R11、R12和R13均为氨基保护基，优选为Boc；R 11 , R 12 and R 13 are all amino protecting groups, preferably Boc;
    环Cy、RB、R’、X、Ra、Rb、Rc、Rd、RX1、RX2、RX3和r如权利要求2中所定义。Rings Cy, R B , R ′ , X, Ra , R b , R c , R d , R
  17. 化合物或其盐，其选自如下化合物：
    Compound or salt thereof, which is selected from the following compounds:
  18. 一种制备通式(II)所示的化合物或其可药用的盐的方法，该方法包括：
    A method for preparing a compound represented by general formula (II) or a pharmaceutically acceptable salt thereof, the method comprising:
    通式(II-A)所示的化合物或其盐发生氨解或水解反应得到通式(II)所示的化合物或其可药用的盐，其中， The compound represented by general formula (II-A) or a salt thereof undergoes an ammonolysis or hydrolysis reaction to obtain a compound represented by general formula (II) or a pharmaceutically acceptable salt thereof, wherein,
    RA为羟基或氨基；R9为C1-6烷基；R A is hydroxyl or amino; R 9 is C 1-6 alkyl;
    环Cy、RB、R’、X、Ra、Rb、Rc、Rd、RX1、RX2、RX3和r如权利要求2中所定义。Rings Cy, R B , R ′ , X, Ra , R b , R c , R d , R
  19. 一种药物组合物，所述药物组合物含有根据权利要求1至15中任一项所述的化合物或其可药用的盐，以及一种或多种药学上可接受的载体、稀释剂或赋形剂。A pharmaceutical composition containing a compound according to any one of claims 1 to 15 or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents or excipient.
  20. 根据权利要求1至15中任一项所述的化合物或其可药用的盐或根据权利要求19所述的药物组合物在制备抑制电压门控钠通道的药物中的用途；优选地，所述电压门控钠通道为Nav1.8。The use of the compound according to any one of claims 1 to 15 or a pharmaceutically acceptable salt thereof or the pharmaceutical composition according to claim 19 in the preparation of a medicine that inhibits voltage-gated sodium channels; preferably, the The voltage-gated sodium channel is Nav1.8.
  21. 根据权利要求1至15中任一项所述的化合物或其可药用的盐或根据权利要求19所述的药物组合物在制备治疗和/或减轻疼痛和疼痛相关疾病、多发性硬化症、夏-马-图三氏综合症、失禁、病理咳嗽或心律失常的药物中的用途；优选地，所述疼痛选自慢性疼痛、急性疼痛、炎性疼痛、癌症疼痛、术后疼痛、神经性疼痛、肌肉骨骼痛、原发性疼痛、肠痛和特发性疼痛；所述术后疼痛优选选自拇囊炎切除术疼痛、疝修补术疼痛和腹部整形术疼痛。 The compound according to any one of claims 1 to 15 or a pharmaceutically acceptable salt thereof or the pharmaceutical composition according to claim 19 is used in the preparation of treating and/or alleviating pain and pain-related diseases, multiple sclerosis, Use in medicines for Schaumburg-Marie-Touche syndrome, incontinence, pathological cough or arrhythmia; preferably, the pain is selected from chronic pain, acute pain, inflammatory pain, cancer pain, postoperative pain, neuropathic pain Pain, musculoskeletal pain, primary pain, intestinal pain and idiopathic pain; the postoperative pain is preferably selected from the group consisting of bunionectomy pain, hernia repair pain and abdominoplasty pain.
PCT/CN2023/116053 2022-08-31 2023-08-31 Heterocyclic compound, preparation method therefor, and pharmaceutical use thereof WO2024046409A1 (en)

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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 (en) * 2010-05-11 2011-11-16 江苏恒瑞医药股份有限公司 5,5-disubstituted-2-iminopyrrolidine derivatives, preparation method thereof, and medical applications thereof
CN108349968A (en) * 2015-07-28 2018-07-31 维奥梅生物科学私人有限公司 Antibacterial therapy agent and prophylactic
US20180289706A1 (en) * 2017-04-06 2018-10-11 Janssen Pharmaceutica Nv 2,4-diaminopyrimidine derivatives as histamine h4 modulators
CN111065383A (en) * 2017-07-11 2020-04-24 沃泰克斯药物股份有限公司 Carboxamides useful as sodium channel modulators
CN114945566A (en) * 2019-12-06 2022-08-26 沃泰克斯药物股份有限公司 Substituted tetrahydrofurans as sodium channel modulators
WO2022256702A1 (en) * 2021-06-04 2022-12-08 Vertex Pharmaceuticals Incorporated Substituted tetrahydrofuran-2-carboxamides as modulators of sodium channels
WO2022256679A1 (en) * 2021-06-04 2022-12-08 Vertex Pharmaceuticals Incorporated N-(hydroxyalkyl (hetero)aryl) tetrahydrofuran carboxamide analogs as modulators of sodium channels

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 (en) * 2010-05-11 2011-11-16 江苏恒瑞医药股份有限公司 5,5-disubstituted-2-iminopyrrolidine derivatives, preparation method thereof, and medical applications thereof
CN108349968A (en) * 2015-07-28 2018-07-31 维奥梅生物科学私人有限公司 Antibacterial therapy agent and prophylactic
US20180289706A1 (en) * 2017-04-06 2018-10-11 Janssen Pharmaceutica Nv 2,4-diaminopyrimidine derivatives as histamine h4 modulators
CN111065383A (en) * 2017-07-11 2020-04-24 沃泰克斯药物股份有限公司 Carboxamides useful as sodium channel modulators
CN114945566A (en) * 2019-12-06 2022-08-26 沃泰克斯药物股份有限公司 Substituted tetrahydrofurans as sodium channel modulators
WO2022256702A1 (en) * 2021-06-04 2022-12-08 Vertex Pharmaceuticals Incorporated Substituted tetrahydrofuran-2-carboxamides as modulators of sodium channels
WO2022256679A1 (en) * 2021-06-04 2022-12-08 Vertex Pharmaceuticals Incorporated N-(hydroxyalkyl (hetero)aryl) tetrahydrofuran carboxamide analogs as modulators of sodium channels

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