WO2024041613A1 - 杂环类化合物、其制备方法及其在医药上的应用 - Google Patents

杂环类化合物、其制备方法及其在医药上的应用 Download PDF

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Publication number
WO2024041613A1
WO2024041613A1 PCT/CN2023/114740 CN2023114740W WO2024041613A1 WO 2024041613 A1 WO2024041613 A1 WO 2024041613A1 CN 2023114740 W CN2023114740 W CN 2023114740W WO 2024041613 A1 WO2024041613 A1 WO 2024041613A1
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group
alkyl
cycloalkyl
alkoxy
general formula
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English (en)
French (fr)
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李心
陈阳
沈峰
贺峰
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Shanghai Hengrui Pharmaceutical Co Ltd
Jiangsu Hengrui Pharmaceutical Co Ltd
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Shanghai Hengrui Pharmaceutical Co Ltd
Jiangsu Hengrui Pharmaceutical Co Ltd
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Priority to US19/105,401 priority Critical patent/US20260055088A1/en
Priority to JP2025510376A priority patent/JP2025529841A/ja
Priority to KR1020257006465A priority patent/KR20250052383A/ko
Priority to EP23856701.0A priority patent/EP4578852A4/en
Priority to CN202380055347.3A priority patent/CN119585260A/zh
Priority to AU2023328112A priority patent/AU2023328112A1/en
Publication of WO2024041613A1 publication Critical patent/WO2024041613A1/zh
Priority to MX2025001995A priority patent/MX2025001995A/es
Anticipated expiration legal-status Critical
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    • A—HUMAN NECESSITIES
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    • 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]
    • 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
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
    • A61K31/341—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide not condensed with another ring, e.g. ranitidine, furosemide, bufetolol, muscarine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/4025—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil not condensed and containing further heterocyclic rings, e.g. cromakalim
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    • 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
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    • 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
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/513—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
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    • C07D307/04—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C07D307/18—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • 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
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    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
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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. 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.
  • Both Nav1.4 and Nav1.6 are TTX-S types, which are abundant in skeletal muscle and central nervous system respectively.
  • the local anesthetic lidocaine provides pain relief by inhibiting Nav.
  • Non-selective Nav inhibitors such as lamotrigine, lacosamide, and mexiletine, have been successfully used to treat 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. 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 Nav1.8 expression levels in axons and neuronal cell bodies. The use of Nav1.8 antisense oligonucleotides can significantly relieve pain while reducing Nav1.8 expression. After intrapaw injection of carrageenan in rats, the expression of Nav1.8 in DRG neurons increased. Nav1.8 knockout mice do not exhibit normal visceral inflammatory pain.
  • Gain-of-function mutations in the human Nav1.8 gene can cause peripheral neuralgia. 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.
  • 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 WO2021113627A1, WO2022256622A1, WO2022256676A1, WO2022256679A1, WO2022256842A1 and WO2022256702A1.
  • Ring A is phenyl or 6-membered heteroaryl
  • Cy is a cycloalkyl group or a heterocyclic group, and the cycloalkyl group and the heterocyclic group are each independently selected from the group consisting of deuterium atoms, halogens, hydroxyl groups, cyano groups, oxo groups, amino groups, -NH alkyl groups, - N (alkyl) 2 , acetyl, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl Substituted by one or more substituents;
  • Each R 3 , R 4 and R 5 are the same or different, and each is independently selected from a hydrogen atom, an alkyl group, a deuterated alkyl group, an alkoxy group, a deuterated alkoxy group, an alkenyl group, an 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, Alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally substituted by 1 or more R 01 ;
  • R 3 and R 4 together with the nitrogen atom to which they are connected form a heterocyclic group; the heterocyclic group is optionally substituted by one or more R 01 ;
  • Each of R 6 , R 7 and R 8 is the same or different, and each is independently selected from a hydrogen atom, an alkyl group, an alkoxy group, a haloalkyl group, a deuterated alkyl group, a haloalkoxy group, a deuterated alkoxy group, and a hydroxyalkyl group.
  • R 6a , R 7a and R 8a is the same or different, and each is independently selected from a hydrogen atom, a deuterium atom, a halogen, a hydroxyl group, a cyano group, an amino group, -NH alkyl group, -N (alkyl) 2 , acetyl group, Alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;
  • R' is selected from a hydrogen atom, an alkyl group, a haloalkyl group, a deuterated alkyl group, an alkoxy group, a deuterated alkoxy group, a hydroxyalkyl group, a cycloalkyl group and a heterocyclyl group;
  • X is O or S
  • R a and R b are the same or different, and are each independently selected from a hydrogen atom, a deuterium atom, a halogen, a hydroxyl group, a cyano group, an amino group, an alkyl group, a deuterated alkyl group, an alkenyl group, an alkynyl group, an alkoxy group, and a deuterated group.
  • R c and R d are the same or different, and are each independently selected from a hydrogen atom, a deuterium atom, a halogen, a hydroxyl, a cyano group, an amino group, an alkyl group, an alkenyl group, an alkynyl group, an alkoxy group, a haloalkyl group, and a deuterated alkyl group.
  • haloalkoxy deuterated alkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, cycloalkyloxy and heterocyclyloxy; the alkyl, alkoxy, alkenyl, alkynyl , cycloalkyl, heterocyclyl, cycloalkyloxy and heterocyclyloxy are optionally substituted by 1 or more R 02 ;
  • R a and R b together with the carbon atoms to which they are connected form a cycloalkyl or heterocyclic group; or, R c and R d to the carbon atoms to which they are connected together form a cycloalkyl or heterocyclic group; wherein, the ring
  • the alkyl or heterocyclyl groups are each independently optionally substituted by 1 or more R 02 ;
  • R e is selected from a hydrogen atom, a deuterium atom, a halogen, a hydroxyl group, a cyano group, an amino group, an alkyl group, an alkoxy group, a haloalkyl group, a haloalkoxy group, a deuterated alkyl group, a deuterated alkoxy group and a hydroxyalkyl group;
  • Each R 02 is the same or different, and each is independently selected from deuterium atom, halogen, hydroxyl, cyano group, oxo group, amino group, amide group, alkyl group, alkenyl group, alkynyl group, alkoxy group, haloalkyl group, haloalkoxy group base, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;
  • Each R 20 , R 21 and R 22 are the same or different, and each is independently selected from a hydrogen atom, an alkyl group, a deuterated alkyl group, an alkoxy group, a deuterated alkoxy group, an alkenyl group, an alkynyl group, a cycloalkyl group, Heterocyclyl, aryl and heteroaryl; the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups are each independently selected from deuterium Substituted with one or more of atom, halogen, hydroxyl, cyano, amino, alkyl, alkoxy, haloalkyl, haloalkoxy and hydroxyalkyl;
  • Each R 23 is the same or different, and each is independently selected from a hydrogen atom, an alkyl group, a deuterated alkyl group, an alkoxy group, a deuterated alkoxy group, an alkenyl group, an alkynyl group, a cycloalkyl group, a heterocyclyl group, and an aryl group.
  • alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups are each independently selected from the group consisting of deuterium atoms, halogens, hydroxyl groups, Substituted with one or more of cyano, amino, alkyl, alkoxy, haloalkyl, haloalkoxy and hydroxyalkyl;
  • 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
  • X 1 , X 2 , X 3 , X 4 and X 5 are not N at the same time;
  • RX1 , R _ _ alkynyl, alkoxy, haloalkyl, deuterated alkyl, haloalkoxy, deuterated alkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, -O-(CH 2 ) n -cycloalkyl , -O-(CH 2 ) s -heterocyclyl, aryl and heteroaryl; wherein, the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and Each heteroaryl group is independently optionally substituted by 1 or more R 03 ;
  • Each R 03 is the same or different, and each is independently selected from deuterium atom, halogen, hydroxyl, cyano group, oxo group, amino group, amide group, alkyl group, alkenyl group, alkynyl group, alkoxy group, haloalkyl group, haloalkoxy group base, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;
  • Each v is the same or different, and each is independently 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 A is phenyl or 6-membered heteroaryl
  • Cy is a cycloalkyl group or a heterocyclic group, and the cycloalkyl group and the heterocyclic group are each independently selected from the group consisting of deuterium atoms, halogens, hydroxyl groups, cyano groups, oxo groups, amino groups, -NH alkyl groups, - N (alkyl) 2 , acetyl, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl Substituted by one or more substituents;
  • Each R 3 , R 4 and R 5 are the same or different, and each is independently selected from a hydrogen atom, an alkyl group, an alkenyl group, an 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, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aromatic
  • the radical and heteroaryl are each independently optionally substituted by 1 or more R 01 ;
  • R 3 and R 4 together with the nitrogen atom to which they are connected form a heterocyclic group; the heterocyclic group is optionally substituted by one or more R 01 ;
  • Each R 6 , R 7 and R 8 are 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 hydroxyalkyl group, an alkenyl group, an 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, cycloalkylalkyl, heterocyclylalkyl, aryl and Heteroaryl; the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocycly
  • R 6a , R 7a and R 8a is the same or different, and each is independently selected from a hydrogen atom, a deuterium atom, a halogen, a hydroxyl group, a cyano group, an amino group, -NH alkyl group, -N (alkyl) 2 , acetyl group, 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 a hydrogen atom, a deuterium atom, a halogen, a hydroxyl, a cyano group, an amino group, an alkyl group, an alkenyl group, an alkynyl group, an alkoxy group, a haloalkyl group, a haloalkoxy group, Hydroxyalkyl, cycloalkyl, Heterocyclyl, cycloalkyloxy and heterocyclyloxy; the cycloalkyl, heterocyclyl, cycloalkyloxy and heterocyclyloxy are optionally substituted by one 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 are optionally substituted by one or more Replaced by R 02 ;
  • R a and R b together with the carbon atoms to which they are connected form a cycloalkyl or heterocyclic group; or, R c and R d to the carbon atoms to which they are connected together form a cycloalkyl or heterocyclic group; wherein, the ring
  • the alkyl or heterocyclyl groups are each independently optionally substituted by 1 or more R 02 ;
  • R e is selected from a hydrogen atom, a deuterium atom, a halogen, a hydroxyl group, a cyano group, an amino group, an alkyl group, an alkoxy group, a haloalkyl group, a haloalkoxy group and a hydroxyalkyl group;
  • Each R 02 is the same or different, and each is independently selected from deuterium atom, halogen, hydroxyl, cyano group, oxo group, amino group, amide group, alkyl group, alkenyl group, alkynyl group, alkoxy group, haloalkyl group, haloalkoxy group base, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;
  • Each R 20 , R 21 and R 22 are 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 heterocyclyl group, an aryl group and a heteroaryl group;
  • the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups are each independently selected from the group consisting of halogen, hydroxyl, cyano, amino, alkyl, Substituted with one or more of alkoxy, haloalkyl, haloalkoxy and hydroxyalkyl;
  • Each 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 heterocyclyl group, an aryl group and a heteroaryl group; the alkyl group, Alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally selected from the group consisting of halogen, hydroxyl, cyano, amino, alkyl, alkoxy, haloalkyl , substituted by one or more of haloalkoxy and hydroxyalkyl;
  • 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
  • X 1 , X 2 , X 3 , X 4 and X 5 are not N at the same time;
  • RX1 , R _ _ Alkynyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, -O-(CH 2 ) n -cycloalkyl, -O-(CH 2 ) s -hetero Cyclic groups, aryl groups and heteroaryl groups; wherein, the cycloalkyl groups, heterocyclic groups, aryl groups and heteroaryl groups 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 deuterium atom, halogen, hydroxyl, cyano group, oxo group, amino group, amide group, alkyl group, alkenyl group, alkynyl group, alkoxy group, haloalkyl group, haloalkoxy group base, hydroxyalkyl group, Cycloalkyl, heterocyclyl, aryl and heteroaryl;
  • Each v is the same or different, and each is independently 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 A is phenyl or 6-membered heteroaryl
  • Cy is a cycloalkyl group or a 3- to 4-membered heterocyclic group, and each of the cycloalkyl group or a 3- to 4-membered heterocyclic group is independently selected from deuterium atoms, halogens, hydroxyl groups, cyano groups, oxo groups, Amino, -NH alkyl, -N (alkyl) 2 , acetyl, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, Substituted with one or more substituents in aryl and heteroaryl;
  • Each R 3 , R 4 and R 5 are the same or different, and each is independently selected from a hydrogen atom, an alkyl group, an alkenyl group, an 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 , NR 22 S(O) v R 23 , OR 23 , cycloalkyl, heterocyclyl, aryl and heteroaryl; wherein, the alkyl, alkenyl, alkynyl , cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally substituted by 1 or more R 01 ;
  • R 3 and R 4 together with the nitrogen atom to which they are connected form a heterocyclic group; the heterocyclic group is optionally substituted by one or more R 01 ;
  • R 6 , R 7 and R 8 is the same or different, and each is independently selected from hydrogen atom, alkyl group, alkoxy group, halogen Alkyl group, haloalkoxy group, hydroxyalkyl 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 , NR 22 S( O) v R 23 , OR 23 , cycloalkyl, heterocyclyl, cycloalkylalkyl, heterocyclylalkyl, aryl and heteroaryl; the alkyl, alkoxy, alkenyl, alkyne A group, a cycloalkyl group,
  • Each R 01 is the same or different, and each is independently selected from deuterium atom, halogen, hydroxyl, cyano group, oxo group, 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 a hydrogen atom, a deuterium atom, a halogen, a hydroxyl, a cyano group, an amino group, an alkyl group, an alkenyl group, an alkynyl group, an alkoxy group, a haloalkyl group, a haloalkoxy group, Hydroxyalkyl, cycloalkyl, heterocyclyl, cycloalkyloxy and heterocyclyloxy; the cycloalkyl, heterocyclyl, cycloalkyloxy and heterocyclyloxy are optionally replaced by 1 Replaced by one 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 are optionally substituted by one or more Replaced by R 02 ;
  • R a and R b together with the carbon atoms to which they are connected form a cycloalkyl or heterocyclic group; or, R c and R d to the carbon atoms to which they are connected together form a cycloalkyl or heterocyclic group; wherein, the ring
  • the alkyl or heterocyclyl groups are each independently optionally substituted by 1 or more R 02 ;
  • R e is selected from a hydrogen atom, a deuterium atom, a halogen, a hydroxyl group, a cyano group, an amino group, an alkyl group, an alkoxy group, a haloalkyl group, a haloalkoxy group and a hydroxyalkyl group;
  • Each R 02 is the same or different, and each is independently selected from deuterium atom, halogen, hydroxyl, cyano group, oxo group, amino group, amide group, alkyl group, alkenyl group, alkynyl group, alkoxy group, haloalkyl group, haloalkoxy group base, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;
  • Each R 20 , R 21 and R 22 are 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 heterocyclyl group, an aryl group and a heteroaryl group;
  • the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups are each independently selected from the group consisting of halogen, hydroxyl, cyano, amino, alkyl, Substituted with one or more of alkoxy, haloalkyl, haloalkoxy and hydroxyalkyl;
  • Each 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 heterocyclyl group, an aryl group and a heteroaryl group; the alkyl group, Alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally selected from the group consisting of halogen, hydroxyl, cyano, amino, alkyl, Substituted with one or more of alkoxy, haloalkyl, haloalkoxy and hydroxyalkyl;
  • 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
  • X 1 , X 2 , X 3 , X 4 and X 5 are not N at the same time;
  • RX1 , R _ _ Alkynyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, -O-(CH 2 ) n -cycloalkyl, -O-(CH 2 ) s -hetero Cyclic groups, aryl groups and heteroaryl groups; wherein, the cycloalkyl groups, heterocyclic groups, aryl groups and heteroaryl groups 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 deuterium atom, halogen, hydroxyl, cyano group, oxo group, amino group, amide group, alkyl group, alkenyl group, alkynyl group, alkoxy group, haloalkyl group, haloalkoxy group base, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;
  • Each v is the same or different, and each is independently 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 A is phenyl or 6-membered heteroaryl
  • Each R A is the same or different, and each is independently selected from halogen, hydroxyl, cyano, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, hydroxyalkoxy, alkenyl, -NR 3 R 4.
  • Cy is a cycloalkyl group or a 3- to 4-membered heterocyclic group, and each of the cycloalkyl group or a 3- to 4-membered heterocyclic group is independently selected from the group consisting of halogen, hydroxyl, cyano, oxo, amino, - NH alkyl, -N(alkyl) 2 , acetyl, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and Substituted by one or more substituents in the heteroaryl group;
  • 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 and R 4 together with the nitrogen atom to which they are connected 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 a hydrogen atom, an alkyl group, an alkoxy group, a haloalkyl group, a haloalkoxy group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclyl group, and a cycloalkyl group.
  • aryl group is independently optionally selected from halogen, hydroxy, cyano, oxo, amino, -NH alkyl, -N(alkyl) 2 , acetyl, alkyl, alkenyl, alkynyl, alkoxy Substituted with one or more substituents of base, haloalkyl, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;
  • R 01 is each independently selected from halogen, hydroxyl, cyano, oxo, amino, -NH alkyl, -N(alkyl) 2 , acetyl, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl base, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;
  • R' is selected from hydrogen atoms, alkyl groups, haloalkyl groups, hydroxyalkyl groups, cycloalkyl groups and heterocyclic 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 a and R b together with the carbon atoms to which they are connected form a cycloalkyl or heterocyclic group; or, R c and R d to the carbon atoms to which they are connected together form a cycloalkyl or heterocyclic group; wherein, the ring
  • the alkyl or heterocyclyl groups are each independently optionally substituted by 1 or more R 02 ;
  • R e is selected from hydrogen atom, halogen, hydroxyl, cyano, amino, alkyl, alkoxy, haloalkyl, halogen alkoxy and hydroxyalkyl;
  • R 02 is each 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
  • 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 ;
  • R 03 is each independently selected from halogen, hydroxyl, cyano, oxo, amino, amide, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, 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 A is phenyl or 6-membered heteroaryl
  • Each R A is the same or different, and each is independently selected from halogen, hydroxyl, cyano, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, hydroxyalkoxy, alkenyl, -NR 3 R 4. -Alkylene-NR 3 R 4 .
  • 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 and R 4 together with the nitrogen atom to which they are connected 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, alkyl group, alkoxy group, haloalkyl group, haloalkoxy group, hydroxyalkyl group, cycloalkyl group, heterocyclyl group, aryl group and heteroaryl;
  • R 01 is each independently selected from halogen, hydroxyl, cyano, oxo, amino, -NH alkyl, -N(alkyl) 2 , acetyl, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl base, 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 a and R b together with the carbon atoms to which they are connected form a cycloalkyl or heterocyclic group; or, R c and R d to the carbon atoms to which they are connected together form a cycloalkyl or heterocyclic group; wherein, the ring
  • the alkyl or heterocyclyl groups are each independently optionally substituted by 1 or more R 02 ;
  • R e is selected from hydrogen atoms, halogen, hydroxyl, cyano, amino, alkyl, alkoxy, haloalkyl, haloalkoxy and hydroxyalkyl;
  • R 02 is each 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
  • 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 ;
  • R 03 is each independently selected from halogen, hydroxyl, cyano, oxo, amino, amide, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, 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 A is phenyl or 6-membered heteroaryl
  • Each R A is the same or different, and each is independently selected from halogen, hydroxyl, cyano, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, hydroxyalkoxy, alkenyl, -NR 3 R 4.
  • 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 and R 4 together with the nitrogen atom to which they are connected 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, alkyl group, alkoxy group, haloalkyl group, haloalkoxy group, hydroxyalkyl group, cycloalkyl group, heterocyclyl group, aryl group and heteroaryl;
  • R 01 is each independently selected from halogen, hydroxyl, cyano, oxo, amino, -NH alkyl, -N(alkyl) 2 , acetyl, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl base, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;
  • R' is selected from hydrogen atoms, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl and heterocyclyl;
  • 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 a and R b together with the carbon atoms to which they are connected form a cycloalkyl or heterocyclic group; or, R c and R d to the carbon atoms to which they are connected together form a cycloalkyl or heterocyclic group; wherein, the ring
  • the alkyl or heterocyclyl groups are each independently optionally substituted by 1 or more R 02 ;
  • R e is selected from hydrogen atoms, halogen, hydroxyl, cyano, amino, alkyl, alkoxy, haloalkyl, haloalkoxy and hydroxyalkyl;
  • R 02 is each 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
  • 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 1 or replaced by multiple R 03 ;
  • R 03 is each independently selected from halogen, hydroxyl, cyano, oxo, amino, amide, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, 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 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 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 wherein Selected from R a , R b , R c , R d and X are as defined by general formula (I); 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; further preferably, for R a and R b are different, and each is independently selected from a hydrogen atom, C 1-6
  • the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof wherein 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;
  • the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof wherein 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.
  • 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 A, RA , 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') or a pharmaceutically acceptable salt thereof. Salt used:
  • R 3a is selected from hydrogen atom, alkyl group, haloalkyl group, hydroxyalkyl group, OR 6 , cycloalkyl group and heterocyclic group; the alkyl group, cycloalkyl group and heterocyclic group are each independently selected. From one or more of halogen, hydroxyl, cyano, oxo, amino, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, cycloalkyl and heterocyclyl Substituted by substituents;
  • r-1 is 0, 1, 2, 3 or 4;
  • 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-1 is 0, 1, 2, 3 or 4;
  • 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:
  • t is selected from 0, 1, 2, 3 and 4;
  • Rings A, R', Ra , Rb , Rc , Rd , X, RX1 , RX2 and RX3 are as defined in general formula (II).
  • the compound represented by general formula (I), (II) or (III) or a pharmaceutically acceptable salt thereof is a compound represented by general formula (III-1) or Its medicinal salts:
  • t is selected from 0, 1, 2, 3 and 4;
  • Rings A, R', Ra , Rb , Rc , Rd , X, RX1 , RX2 and RX3 are as defined in general formula (II).
  • the compound represented by general formula (I) or (II) or a pharmaceutically acceptable salt thereof is a compound represented by general formula (IV) or a pharmaceutically acceptable salt thereof :
  • R 1A and R 2A are the same or different, and each is independently a hydrogen atom or RA ;
  • R 3A is RA ;
  • R a , R b , R c , R d , R X1 , R X2 , R X3 , R' and R A are as defined in general formula (II).
  • the compound represented by general formula (I) or (II) or a pharmaceutically acceptable salt thereof is a compound represented by general formula (IV) or a pharmaceutically acceptable salt thereof :
  • R 1A and R 2A are the same or different, and each is independently a hydrogen atom or RA ;
  • the compound represented by general formula (I) or (II) or a pharmaceutically acceptable salt thereof is a compound represented by general formula (IV) or a pharmaceutically acceptable salt thereof :
  • R a , R b , R c , R d are as in the general formula ( As defined in I); preferably, R a , R b , R c , R d are as defined in general formula (II).
  • the compound represented by general formula (I) or (II) or a pharmaceutically acceptable salt thereof is a compound represented by general formula (IV) or a pharmaceutically acceptable salt thereof :
  • R a , R b , R c , R d R X1 , R X2 , R X3 , R', R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 01 and v
  • Ra, Rb , Rc , Rd are as defined in general formula (II).
  • the compound represented by the general formula (IV) or a pharmaceutically acceptable salt thereof wherein R 3A is selected from hydroxyl, amino, C 1-6 alkyl, C 1-6 alkoxy group, C 1-6 hydroxyalkyl group, C 1-6 hydroxyalkoxy group, -C 1-6 alkylene group -NH 2 , -OC 1-6 alkylene group -NH 2 , -NR 5 C(O) NR 3 R 4 , -C(O)NR 5 -OR 6 , 3 to 8 membered cycloalkyl, 3 to 8 membered heterocyclyl, phenyl, 5 or 6 membered heteroaryl and -OC 1-6 alkylene -5 or 6-membered heteroaryl, the C 1-6 alkylene group, 3 to 8 membered cycloalkyl group, 3 to 8 membered heterocyclyl group, phenyl and 5 or 6 membered heteroaryl group are each independently optional Selected to be substituted by
  • R 3A is selected from amino, C 1-6 hydroxyalkyl, C 1-6 hydroxyalkoxy, -C 1-6 alkylene-NH 2 , -NR 5 C(O)NR 3 R 4 , -C(O)NR 5 -OR 6 , 3 to 8-membered cycloalkyl and 5 or 6-membered heteroaryl, the C 1-6 alkylene group, 3 to 8-membered cycloalkyl and 5 or 6-membered heteroaryl
  • the 6-membered heteroaryl groups are each independently optionally substituted by one or more R 01 , and each R 01 is independently selected from halogen, hydroxyl, cyano, oxo, amino, -NH C 1-6 alkyl, -N(C 1-6 alkyl) 2 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, halogenated C 1-6 alkyl, Halogenated C 1-6 alkoxy,
  • R 3A is selected from amino, C 1-6 hydroxyalkyl, C 1-6 hydroxyalkoxy, -C 1-6 alkylene-NH 2 , -NR 5 C(O)NR 3 R 4 , -C(O)NR 5 -OR 6 , 3 to 6-membered cycloalkyl and 5 or 6-membered heteroaryl, the C 1-6 alkylene group, 3 to 6-membered cycloalkyl and 5 or 6-membered heteroaryl
  • the 6-membered heteroaryl groups are each independently optionally substituted by one or more R 01 , and R 01 is each independently selected from hydroxyl, cyano, amino, C 1-6 alkyl and C 1-6 hydroxyalkyl, R 3 , R 4 , R 5 and R 6 are the same or different, and each is independently a hydrogen atom or a C 1-6 alkyl group; in some embodiments, R 3A is selected from amino, C 1-6 hydroxyalkyl, NR 5 C(O)NR 3 R
  • R 01 is selected from hydroxyl, cyano group, amino and C 1-6 hydroxyalkyl group.
  • Each R G and RN are the same. or different, and each is independently a hydrogen atom or a C 1-6 alkyl group, t is selected from 0, 1, 2 and 3, u1 is selected from 0, 1 and 2, u2 is selected from 0, 1, 2 and 3, u3 Selected from 1, 2 and 3;
  • R 3A is selected from amino, In some embodiments, R 3A is selected from
  • R 3A is selected from amino
  • the compound represented by the general formula (IV) or a pharmaceutically acceptable salt thereof wherein R 3A is selected from C 1-6 hydroxyalkyl, C 1-6 hydroxyalkoxy, -NR 3 R 4 , -C 1-6 alkylene -NR 3 R 4 , -NR 5 C(O)R 6 , -NR 5 C(O)NR 3 R 4 , -C(O)NR 5 - OR 6 , 3 to 10-membered cycloalkyl, 3 to 10-membered heterocyclyl and 5 or 6-membered heteroaryl, the C 1-6 alkylene, 3 to 10-membered cycloalkyl, 3 to 10-membered heteroaryl
  • the ring group and the 5- or 6-membered heteroaryl group are each independently optionally substituted by one or more R 01
  • R 01 is each independently selected from hydroxyl, cyano, C 1-6 alkyl and C 1-6 hydroxyl Alkyl group, R 3 and R 4 are the same
  • R 3A is selected from C 1-6 hydroxyalkyl, C 1-6 hydroxyalkoxy, -C 1-6 alkylene-NH 2 , -C(O)NR 5 -OR 6 , 3 to 6 membered cycloalkyl and 5 or 6 membered heteroaryl, the C 1-6 alkylene group, 3 to 6 membered cycloalkyl and 5 or 6 membered heteroaryl are each independently optionally substituted by 1 or Substituted with multiple R 01 , each R 01 is independently selected from hydroxyl, cyano, C 1-6 alkyl and C 1-6 hydroxyalkyl, R 5 and R 6 are the same or different, and each is independently a hydrogen atom Or C 1-6 alkyl; in some embodiments, R 3A is -C 1-6 alkylene-NH 2 or -C(O)NR 5 -OR 6 , the C 1-6 alkylene is either Selected to be substituted by one or more R 01 , each R 01 is independently selected from
  • the compound represented by general formula (I), (II) or (IV) or a pharmaceutically acceptable salt thereof is a compound represented by general formula (V) or a pharmaceutically acceptable salt thereof.
  • R A4 is selected from hydrogen atoms, hydroxyl groups, alkyl groups and hydroxyalkyl groups; u1 is selected from 0, 1, 2 and 3, u2 is selected from 0, 1, 2 and 3;
  • R a , R b , R c , R d are as in the general formula ( As defined in I); preferably, R a , R b , R c , R d are as defined in general formula (II).
  • the compound represented by general formula (I), (II), (IV) or (V) or a pharmaceutically acceptable salt thereof is of general formula (V-1) or The compound represented by (V-2) or a pharmaceutically acceptable salt thereof:
  • the compound represented by general formula (I), (II) or a pharmaceutically acceptable salt thereof is a compound represented by general formula (VI') or a pharmaceutically acceptable salt thereof Salt:
  • Q is selected from CR 5A , N and N + -O - ;
  • R 5A is R 1A ;
  • R 1A , R 2A , R', R a , R b , R c , R d , R X1 , R X2 , R X3 , R 3 , R 4 and R 5 are as defined in general formula (IV).
  • the compound represented by the general formula (I), (II), (VI') or a pharmaceutically acceptable salt thereof is represented by the general formula (VI'-1) Compound or pharmaceutically acceptable salt thereof:
  • Q is selected from CR 5A , N and N + -O - ;
  • R 5A is R 1A ;
  • R C is R 23 or OR 23 ;
  • R 1A , R 2A , R', R a , R b , R c , R d , R X1 , R X2 , R X3 , R 3 , R 5 and R 23 are as defined in general formula (IV).
  • the compound represented by the general formula (VI'-1) or a pharmaceutically acceptable salt thereof wherein R C is selected from C 1-8 alkyl, C 1-8 alkoxy and 3 to 10 membered cyclic alkyloxy; in some embodiments, R is C 1-8 alkoxy; in some embodiments, R is isopropoxy or n-hexyloxy.
  • the compound represented by the general formula (I), (II), (II'), (IV), (VI') or a pharmaceutically acceptable salt thereof is of the general formula The compound shown in (VI) or a pharmaceutically acceptable salt thereof:
  • R 3a is selected from hydrogen atom, alkyl group, haloalkyl group, hydroxyalkyl group, OR 6 , cycloalkyl group and heterocyclic group; the alkyl group, cycloalkyl group and heterocyclic group are each independently selected. From one or more of halogen, hydroxyl, cyano, oxo, amino, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, cycloalkyl and heterocyclyl Substituted by substituents;
  • R 1A , R 2A , R', R a , R b , R c , R d , R X1 , R X2 , R X3 , R 4 , R 5 and R 6 are as defined in general formula (IV).
  • the compound represented by the general formula (II') or (VI) or a pharmaceutically acceptable salt thereof wherein R 3a is selected from hydrogen atom, C 1-6 alkyl, halogenated C 1-6 alkyl, C 1-6 hydroxyalkyl, OR 6 , 3 to 6-membered cycloalkyl and 3 to 6-membered cycloalkyl C 1-6 alkyl, R 6 is selected from hydrogen atom, C 1- 6 alkyl, 3 to 6 membered cycloalkyl and 3 to 6 membered cycloalkyl C 1-6 alkyl;
  • R 3a is selected from hydrogen atom, C 1-6 alkyl, C 1-6 alkoxy and 3 to 6 membered cycloalkyl; in some embodiments, R 3a is selected from hydrogen atom, C 1-6 alkyl and C 1-6 alkoxy; in some embodiments, R 3a is selected from a hydrogen atom, C 1-6 alkyl and 3 to 6 membered cycloalkyl; in some embodiments, R 3a Is a hydrogen atom or C 1-6 alkyl group;
  • R 3a is selected from the group consisting of hydrogen atoms, methyl, ethyl, methoxy and cyclopropyl groups; in some embodiments, R 3a is selected from the group consisting of hydrogen atoms, methyl, ethyl and cyclopropyl groups; In some embodiments, R 3a is a hydrogen atom; in some embodiments, R 3a is selected from a hydrogen atom, methyl, ethyl, hydroxyl, methoxy, deuterated methoxy, cyclopropyl,
  • the compound represented by the general formula (I), (II), (II-1) or a pharmaceutically acceptable salt thereof is a compound represented by the general formula (VII') or its pharmaceutically acceptable salt:
  • Q is selected from CR 5A , N and N + -O - ;
  • R 5A is R 1A ;
  • R 1A , R 2A , R', R a , R b , R c , R d , R X1 , R X2 , R X3 , R 3 , R 4 and R 5 are as defined in general formula (IV).
  • the compound represented by the general formula (I), (II), (II-1), (IV) or (VII') or a pharmaceutically acceptable salt thereof is a general Compounds represented by formula (VII) or pharmaceutically acceptable salts thereof:
  • R 1A , R 2A , R', R a , R b , R c , R d , R X1 , R X2 , R X3 , R 3 , R 4 and R 5 are as defined in the general formula (IV).
  • the compound represented by general formula (I), (II) or a pharmaceutically acceptable salt thereof is a compound represented by general formula (VIII) or a pharmaceutically acceptable salt thereof :
  • Q is selected from CR 5A , N and N + -O - ;
  • R 5A is R 1A ;
  • R a is selected from 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 and 3 to 10 membered heterocyclyl; in some embodiments, R is selected from hydrogen atom, halogen, C 1-6 alkyl and halogenated C 1-6 alkyl ; In some embodiments, R a is C 1-6 alkyl or halo C 1-6 alkyl; in some embodiments, R a is CH 3 or CF 3 ;
  • R a is C 1-6 alkyl; in some embodiments, R a is selected from CH 3 , deuterated methyl, and CF 3 ; in some embodiments, R a is CH 3 or deuterium Substitute methyl; in some embodiments, R a is CH 3 .
  • R b is selected from 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 and 3 to 10 membered heterocyclyl; in some embodiments, R b is selected from hydrogen atom, halogen, C 1-6 alkyl and halogenated C 1-6 alkyl ; In some embodiments, R b is C 1-6 alkyl or halo C 1-6 alkyl; in some embodiments, R b is selected from CH 3 , deuterated
  • R c is selected from 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 and 3 to 10-membered heterocyclyl; preferably, R c is selected from hydrogen atom, halogen, C 1-6 alkyl and halogenated C 1-6 alkyl; more preferably Specifically, R c is a hydrogen atom or a C 1-6 alkyl group; most preferably, R c is a hydrogen atom or CH 3 ; in some embodiment
  • R d is selected from hydrogen atom, halogen, C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkyl, halo C 1-6 alkoxy, C 1-6 Hydroxyalkyl, 3 to 10-membered cycloalkyl and 3 to 10-membered heterocyclyl; preferably, R d is selected from hydrogen atom, halogen, C 1-6 alkyl and halogenated C 1-6 alkyl; more preferably Specifically, R d is a hydrogen atom or a C 1-6 alkyl group; further preferably, R d is a hydrogen atom or CH 3 ; in some embodiments,
  • 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 haloC 1-6 alkyl; in some embodiments, R a and R b are the same or different, and each is independently C 1-6 alkyl or halo C 1-6 alkyl; in In some embodiments, R a is C 1-6 alkyl, and R b is haloC 1-6 alkyl; in some embodiments, R a is CH 3 , and R b is CF 3 ;
  • R a and R b are the same or different, and each is independently selected from a hydrogen atom, CH 3 , deuterated methyl, and CF 3 ; in some embodiments, R a and R b are the same or different, And each is independently selected from hydrogen atoms, CH 3 and CF 3 ;
  • R a and R b are the same or different, and each is independently C 1-6 alkyl; in some embodiments, R a and R b are the same or different, and each is independently C halo. 1-6 alkyl.
  • Ra and Rb are different and each is independently selected from hydrogen atoms, CH3 , deuterated methyl, and CF3 ; in some embodiments, Ra and Rb are different and each is independently selected from the group consisting of hydrogen atoms, CH3, deuterated methyl , and CF3; Selected from hydrogen atoms, CH 3 and CF 3 ;
  • R a and R b are different, and each is independently a C 1-6 alkyl; in some embodiments, R a and R b are different, and each is independently a haloC 1-6 alkyl. base.
  • R a is a hydrogen atom
  • R b is a halogenated C 1-6 alkyl group
  • R a is a hydrogen atom
  • R b is a C 1-6 alkyl group
  • R a is a C 1-6 alkyl group
  • 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; in some embodiments, R c and R d are the same or different, and each is independently a hydrogen atom or C 1-6 alkyl group; in some embodiments, R c is a hydrogen atom, and R d is a C 1-6 alkyl group; in some embodiments, R c is a hydrogen atom, and R d is CH 3 ;
  • Rc and Rd are the same or different, and are each independently selected from hydrogen atoms, CH3 , and deuterated methyl; in some embodiments, Rc and Rd are the same or different, and are each independently selected is a hydrogen atom or CH3 ; in some embodiments, Rc and Rd are both hydrogen atoms.
  • Rc and Rd are different, and each is independently selected from a hydrogen atom, CH3 , and deuterated methyl; in some embodiments, Rc and Rd are different, and each is independently a hydrogen atom. or CH 3 .
  • the compound represented by the general formula (I), (II), (II'), (II-1), (III) or (III-1) or a pharmaceutically acceptable compound thereof salt wherein ring A is a 6-membered heteroaryl; preferably, ring A is selected from pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl and triazinyl; further preferably, ring A is pyridyl or pyrimidinyl ;More preferably, Ring A is Most preferably The * terminal is connected to -NR', The end is connected to RA ;
  • Ring A is selected from phenyl, pyridyl, and pyrimidinyl; in some embodiments, Ring A is selected from In some embodiments, Ring A is selected from In some embodiments, Ring A is selected from In some embodiments, Ring A is selected from In some embodiments, Ring A is In some embodiments, Ring A is The * terminal is connected to -NR', end is connected to RA ; in some embodiments, loop A is selected from * terminal is connected with -NR', The end is connected to an RA .
  • the compound represented by general formula (I) or (II) or a pharmaceutically acceptable salt thereof, Selected from R A and r are as defined by general formula (I); preferably, Selected from R A and r are as defined by general formula (I); further preferably, Selected from R A is as defined by general formula (I); more preferably, for R A is as defined by general formula (I); most preferably, for R A is as defined by general formula (I).
  • R A is selected from F, Cl, amino, cyano,
  • R A is selected from F, Cl, amino, cyano,
  • R A is selected from F, Cl, amino,
  • R A is selected from amino
  • R A is selected from amino
  • RA is selected from
  • RA is selected from
  • RA is selected from In some embodiments, RA is selected from
  • RA is selected from
  • RA is selected from
  • RA is selected from In some embodiments, RA is selected from In some embodiments, RA is selected from In some embodiments, RA is In some embodiments, RA is In some embodiments, RA is In some embodiments, RA is In some embodiments, RA is In some embodiments, RA is In some embodiments, RA is in some embodiments, RA is selected from RA.
  • RA is selected from In some embodiments, RA is In some embodiments, RA is In some embodiments, RA is In some embodiments, RA is In some embodiments, RA is selected from RA.
  • RA is -C(O)-C(O)-NR 3 R 4 , R 3 and R 4 are as defined in Formula (I); in some embodiments, RA is - C(O)-C(O)-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;
  • R 3 , R 4 , R 5 and R 6 are the same or different, And each is independently a hydrogen atom or a C 1-6 alkyl group.
  • each R 01 is independently selected from halogen, hydroxyl, cyano, oxo, amino, -NH C 1-6 alkyl, -N(C 1-6 alkyl) 2 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, halo C 1-6 alkyl, halo C 1-6 alkoxy, C 1 -6 hydroxyalkyl, 3 to 10 membered cycloalkyl, 3 to 10 membered heterocyclyl, 6 to 10 membered aryl and 5 to 14 membered heteroaryl, R 3 , R 4 , R 5 and R 6 are as follows: As defined in formula (
  • R A is selected from amino, C 1-6 hydroxyalkyl, C 1-6 hydroxyalkoxy, -C 1-6 alkylene-NH 2 , -NR 5 C(O)NR 3 R 4 , -C(O)NR 5 -OR 6 , 3 to 6-membered cycloalkyl and 5 or 6-membered heteroaryl, the C 1-6 alkylene group, 3 to 6-membered cycloalkyl and 5 or 6-membered heteroaryl
  • the 6-membered heteroaryl groups are each independently optionally substituted by one or more R 01 , and R 01 is each independently selected from hydroxyl, cyano, amino, C 1-6 alkyl and C 1-6 hydroxyalkyl, R 3 , R 4 , R 5 and R 6 are the same or different, and each is independently a hydrogen atom or a C 1-6 alkyl group;
  • R A is selected from amino, C 1-6 hydroxyalkyl, NR 5 C(O)NR 3 R 4 , Among them, G 1 is a nitrogen atom or CR G , G 2 is a nitrogen atom or CRG , R A4 is a hydrogen atom, a hydroxyl group, a C 1-6 alkyl group and a C 1-6 hydroxyalkyl group, R 3 , R 4 , R 5 and R 6 are the same or different, and each is independently Hydrogen atom or C 1-6 alkyl group, R 01 is each independently selected from hydroxyl, cyano group, amino and C 1-6 hydroxyalkyl group, each R G and R N are the same or different, and each is independently a hydrogen atom or C 1-6 alkyl, t is selected from 0, 1, 2 and 3, u1 is selected from 0, 1, 2 and 3, u2 is selected from 0, 1, 2 and 3, u3 is selected from 1, 2 and 3;
  • R A is selected from amino
  • RA is selected from
  • R A is selected from C 1-6 hydroxyalkyl, C 1-6 hydroxyalkoxy, -C 1-6 alkylene-NH 2 , -C(O)NR 5 -OR 6 , 3 to 6 membered cycloalkyl and 5 or 6 membered heteroaryl, the C 1-6 alkylene, 3 to 6 membered cycloalkyl and 5 or 6 membered heteroaryl are optionally replaced by 1 or more R 01 substituted, R 01 is each independently selected from hydroxyl, cyano, C 1-6 alkyl and C 1-6 hydroxyalkyl, R 5 and R 6 are the same or different, and each is independently a hydrogen atom or C 1 -6 alkyl; in some embodiments, R A is -C 1-6 alkylene-NH 2 or -C(O)NR 5 -OR 6 , the C 1-6 alkylene optionally replaced by 1 Substituted by one or more R 01 , each R 01 is independently selected from hydroxyl and C 1-6 1-6 1-6
  • R A is a 3- to 6-membered cycloalkyl group or a 5- or 6-membered heteroaryl group, each of which is independently optionally substituted by 1 or multiple R 01 substituted, each R 01 is independently selected from hydroxyl, cyano, amino, C 1-6 alkyl and C 1-6 hydroxyalkyl; in some embodiments, R A is 3 to 6 yuan Cycloalkyl or 5-membered heteroaryl, the 3- to 6-membered cycloalkyl and 5-membered heteroaryl are each independently optionally substituted by one or more R 01 , and R 01 is each independently selected from hydroxyl, Cyano, amino, C 1-6 alkyl, and C 1-6 hydroxyalkyl; in some embodiments, R A is selected from G 1 is a nitrogen atom or CR G , G 2 is a nitrogen atom or CR G , R 01 is selected from hydroxyl, cyano, amino and C 1-6 hydroxyalkyl, each R G and R
  • RA are the same or different, and each is independently selected from hydroxy, amino, -C 1-6 alkylene-NH 2 , -OC 1-6 alkylene-NH 2 , C 1-6 Alkoxy, C 1-6 hydroxyalkyl, C 1-6 hydroxyalkoxy, 3 to 8 membered cycloalkyl, 4 to 7 membered heterocyclyl, phenyl, 5 or 6 membered heteroaryl and -OC 1-6 alkylene-5 or 6-membered heteroaryl, wherein the C 1-6 alkylene, 3 to 8-membered cycloalkyl, 4 to 7-membered heterocyclyl, phenyl and 5 or 6
  • Each heteroaryl group is independently optionally substituted by one or more R 01 ;
  • R 01 is each independently selected from halogen, hydroxyl, cyano, oxo, amino, -NHC 1-6 alkyl, -N (C 1-6 alkyl) 2 , C 1-6 alkyl, C 2-6
  • R A are the same or different, and each is independently selected from amino, C 1-6 hydroxyalkyl, C 1-6 hydroxyalkoxy, phenyl, and 5- or 6-membered heteroaryl, Phenyl and 5- or 6-membered heteroaryl are each independently optionally substituted by one or more R 01 ;
  • R 01 is each independently selected from halogen, hydroxyl, cyano, oxo, amino, -NHC 1- 6 alkyl, -N(C 1-6 alkyl) 2 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, 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, 6 to 10 membered aryl and 5 to 14 membered hetero Aryl; in some embodiments, R A are the same or different, and each
  • the compound represented by general formula (I) or (II) or a pharmaceutically acceptable salt thereof wherein for Each R B is the same or different, and each is independently selected from halogen, hydroxyl, cyano, amino, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyl and heterocyclyl; the alkyl, Alkoxy, cycloalkyl and heterocyclyl are each independently optionally selected from the group consisting of halogen, hydroxyl, cyano, amino, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyl and heterocyclyl one or more of Substituted; p is 0, 1, 2, 3 or 4; Ring A and R A are as defined in general formula (I);
  • R B is selected from halogen, hydroxyl, C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkyl and halo C 1-6 alkoxy; p is selected from 0, 1 and 2 , Ring A is selected from phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl and R A is as defined by general formula (I); more preferably, for R B is selected from halogen, hydroxyl, C 1-6 alkyl and halogenated C 1-6 alkyl; p is 0 or 1, ring A is selected from phenyl, pyridyl and pyrimidinyl; R A is selected from amino, C 1-6 hydroxyalkyl, C 1-6 hydroxyalkoxy, phenyl and 5- or 6-membered heteroaryl, the phenyl and 5- or 6-membered heteroaryl are each independently optionally substituted by 1 or more Replaced by R 01 ,
  • each R B is the same or different, and each independently is halogen; in some embodiments, R B is F.
  • each R B is the same or different, and each is independently selected from halogen, C 1-6 alkyl, and C 1-6 alkoxy; and/or p is 0 or 1; in some implementations In the scheme, each R B is the same or different, and each is independently a halogen, and/or p is 0 or 1.
  • p is 0 or 1; in some embodiments, p is 0; in some embodiments, p is 1.
  • the compound represented by general formula (I) or (II) or a pharmaceutically acceptable salt thereof, in for R 1A and R 2A are the same or different, and are each independently selected from hydrogen atom, halogen, hydroxyl, amino, C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkyl, halogenated C 1-6 alkoxy, C 1-6 hydroxyalkyl and C 1-6 hydroxyalkoxy;
  • R 1A and R 2A are the same or different, and each is independently selected from a hydrogen atom, halogen, hydroxyl, amino, C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1- 6 alkyl, halogenated C 1-6 alkoxy, C 1-6 hydroxyalkyl and C 1-6 hydroxyalkoxy;
  • R 3A is selected from hydroxyl, amino, C 1-6 alkyl, C 1-6 Alkoxy, C 1-6 hydroxyalkyl, C 1-6 hydroxyalkoxy, -C 1-6 alkylene-NH 2 , -OC 1-6 alkylene-NH 2 , phenyl, 5 or 6-membered heteroaryl and -OC 1-6 alkylene-5 or 6-membered heteroaryl, the C 1-6 alkylene, phenyl and 5- or 6-membered heteroaryl are each independently optionally substituted by 1 Substituted by one or more R 01 ; each R 01 is independently selected from halogen, hydroxyl,
  • R 1A and R 2A are the same or different, and each is independently selected from hydrogen atom, halogen, C 1-6 alkyl and halogenated C 1-6 alkyl;
  • R 3A is selected from hydroxyl, amino, C 1- 6 alkoxy, C 1-6 hydroxyalkyl, C 1-6 hydroxyalkoxy, -C 1-6 alkylene-NH 2 , -OC 1-6 alkylene-NH 2 , phenyl, 5 Or 6-membered heteroaryl and -OC 1-6 alkylene-5 or 6-membered heteroaryl, the C 1-6 alkylene, phenyl and 5- or 6-membered heteroaryl are each independently optionally Substituted by one or more R 01 ; each R 01 is independently selected from halogen, hydroxyl, cyano, oxo, amino, -NH C 1-6 alkyl, -N(C 1-6 alkyl) 2 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkyl
  • R 3A is selected from amino
  • R 3A is selected from amino
  • R 3A is selected from
  • R 3A is selected from
  • R 3A is selected from
  • R 3A is selected from
  • R 3A is selected from
  • R 3A is selected from In some embodiments, R 3A is In some embodiments, R 3A is In some embodiments, R 3A is In some embodiments, R 3A is
  • R 3A is -C(O)-C(O)-NR 3 R 4 , R 3 and R 4 are as defined in Formula (I); in some embodiments, R 3A is - C(O)-C(O)-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;
  • R 3 , R 4 , R 5 and R 6 are the same or different, And each is independently a hydrogen atom or a C 1-6 alkyl group.
  • R3 is selected from a hydrogen atom, C 1-6 alkyl, halo C 1-6 alkyl, C 1-6 hydroxyalkyl, 3 to 6 membered cycloalkyl, and 3 to 6 membered ring Alkyl C 1-6 alkyl; in some embodiments, R 3 is selected from a hydrogen atom, C 1-6 alkyl and 3 to 6 membered cycloalkyl; in some embodiments, R 3 is selected from a hydrogen atom, methyl, ethyl and cyclopropyl; in some embodiments, R 3 is ethyl or cyclopropyl;
  • R 3 is a 3- to 6-membered cycloalkyl group; in some embodiments, R 3 is a hydrogen atom or a C 1-6 alkyl group; in some embodiments, R 3 is selected from a hydrogen atom, C 1-6 alkyl, OR 23 , 3 to 6 membered cycloalkyl and C(O)OR 23 , R 23 is as defined in general formula (I); in some embodiments, R 3 is selected from hydrogen atom, C 1-6 alkyl, OR 23 , 3 to 6-membered cycloalkyl and C(O)OR 23 , R 23 is a hydrogen atom or C 1-8 alkyl;
  • R 3 is selected from hydrogen atom, C 1-6 alkyl group, C 1-6 alkoxy group, 3 to 6 membered cycloalkyl group and C(O)OR 23 , R 23 is as in the general formula (I );
  • R 3 is selected from hydrogen atom, C 1-6 alkyl, C 1-6 alkoxy, 3 to 6 membered cycloalkyl, and C(O)OR 23 , R 23 is a hydrogen atom or C 1-8 alkyl;
  • R3 is selected from a hydrogen atom, methyl, ethyl, hydroxyl, methoxy, cyclopropyl, In some embodiments, R is selected from a hydrogen atom, methyl, ethyl, methoxy, cyclopropyl, In some embodiments, R is selected from a hydrogen atom, methyl, ethyl, hydroxyl, methoxy, deuterated methoxy, cyclopropyl,
  • R 3 is a hydrogen atom; in some embodiments, R 3 is methyl; in some embodiments, R 3 is ethyl; in some embodiments, R 3 is hydroxyl; in some embodiments, R 3 is hydroxyl; In some embodiments, R 3 is methoxy; in some embodiments, R 3 is cyclopropyl; in some embodiments, R 3 is C(O)OR 23 and R 23 is C 1-8 alkyl.
  • R 4 is a hydrogen atom or C 1-6 alkyl, in some embodiments, R 4 is a hydrogen atom or methyl; in some embodiments, R 4 is a hydrogen atom; in some embodiments, R 4 is C 1-6 alkyl; in In some embodiments, R 4 is methyl or ethyl.
  • R 3 is selected from a hydrogen atom, C 1-6 alkyl, OR 23 and C(O)OR 23 , R 23 is as defined in general formula (I); and/or R 4 is a hydrogen atom; in some embodiments, R 3 is selected from a hydrogen atom , hydroxyl, C 1-6 alkyl, C 1-6 alkoxy, deuterated C 1-6 alkoxy, -O-3 to 6-membered cycloalkyl and C(O)OR 23 , R 23 is C 1-8 alkyl; and/or R 4 is a hydrogen atom; in some embodiments, R 3 is selected from a hydrogen atom, methyl, ethyl, hydroxyl, methoxy
  • R 23 is selected from a hydrogen atom, C 1-8 alkyl, deuterated C 1-6 alkyl, halo C 1-8 alkyl and C 1-8 hydroxyalkyl; in some embodiments, R 23 is selected from hydrogen atom, C 1-8 Alkyl, haloC 1-8 alkyl, and C 1-8 hydroxyalkyl; in some embodiments, R 23 is selected from a hydrogen atom, C 1-8 alkyl, and deuterated C 1-6 alkyl; in In some embodiments, R 23 is selected from hydrogen atom, methyl, deuterated methyl, cyclopropyl, isopropyl and n-hexyl; in some embodiments, R 23 is
  • R 5 is selected from hydrogen atom, C 1-6 alkyl, OR 23 , 3 to 6 membered cycloalkyl and C(O)OR 23 , R 23 is as defined in general formula (I);
  • R5 is selected from a hydrogen atom, a deuterium atom, a C 1-6 alkyl group, a deuterated C 1-6 alkyl group, a C 1-6 alkoxy group, a deuterated C 1-6 alkoxy group, 3 to 6-membered cycloalkyl, -O-3 to 6-membered cycloalkyl and C(O)OR 23 , R 23 is a hydrogen atom or C 1-8 alkyl; in some embodiments, R 5 is selected from hydrogen Atom, hydroxyl group, C 1-6 alkyl group, C 1-6 alkoxy group, deuterated C 1-6 alkoxy group, -O-3 to 6-membered cycloalkyl group and C(O)OR 23 , R 23 is C 1-8 alkyl; in some embodiments, R 5 is selected from hydrogen atom, C 1-6 alkyl, C 1-6 alkoxy, deuterated C 1-6 alkoxy, -O-3 to 6-membered ring alkyl
  • R5 is selected from a hydrogen atom, a deuterium atom, a methyl group, a deuterated methyl group, a hydroxyl group, a methoxy group, a deuterated methoxy group, a cyclopropyl group, an -O-cyclopropyl group, In some embodiments , R 5 is selected from hydrogen atom, methyl group, hydroxyl group, methoxy group, OCD 3 , In some embodiments, R5 is selected from a hydrogen atom, methyl, hydroxyl, methoxy, deuterated methoxy, -O-cyclopropyl, In some embodiments, R5 is hydroxyl or methoxy;
  • R 5 is methyl; in some embodiments, R 5 is deuterated methyl; in some embodiments, R 5 is hydroxyl; in some embodiments, R 5 is methoxy; In some embodiments, R 5 is deuterated methoxy; in some embodiments, R 5 is OCD 3 ; in some embodiments, R 5 is cyclopropyl or -O-cyclopropyl; in some embodiments, R 5 is OCD 3
  • R 5 is In some embodiments, R 5 is selected from a hydrogen atom, methyl, hydroxyl, methoxy, deuterated methoxy, and -O-cyclopropyl; in some embodiments, R 5 is selected from a hydrogen atom, methyl , hydroxyl and methoxy.
  • R 5 is a hydrogen atom
  • R 4 is a hydrogen atom
  • R 3 is selected from a hydrogen atom, methyl, ethyl, hydroxyl, methoxy, deuterated methoxy, cyclopropyl
  • R 3 and R 4 are both hydrogen atoms
  • R 5 is selected from a hydrogen atom, a deuterium atom, a methyl group, a deuterated methyl group, a hydroxyl group, a methoxy group, a deuterated methoxy group, a cyclopropyl group, -O-cyclopropyl,
  • the compound represented by the general formula (I), (II), (II'), (IV), (VI) or a pharmaceutically acceptable salt thereof wherein R 3a and R 4 are all hydrogen atoms, and R 5 is selected from hydrogen atom, deuterium atom, methyl group, deuterated methyl group, hydroxyl group, methoxy group, deuterated methoxy group, cyclopropyl group, -O-cyclopropyl group, Or R 5 is a hydrogen atom, R 4 is a hydrogen atom, and R 3a is selected from a hydrogen atom, methyl, ethyl, hydroxyl, methoxy, deuterated methoxy, cyclopropyl, In some embodiments, R 3a and R 4 are both hydrogen atoms, and R 5 is selected from a hydrogen atom, a deuterium atom, a methyl group, a deuterated methyl group, a hydroxyl group, a methoxy group, a de
  • R 6 is selected from a hydrogen atom, C 1-6 alkyl, haloC 1-6 alkyl, C 1-6 alkoxy, haloC 1-6 alkoxy, C 1- 6 hydroxyalkyl, 3 to 6 membered cycloalkyl, and 3 to 6 membered cycloalkyl C 1-6 alkyl; in some embodiments, R 6 is selected from C 1-6 alkyl, 3 to 6 membered cycloalkyl and 3 to 6 membered cycloalkyl C 1-6 alkyl; in some embodiments, R 6 is C 1-6 alkyl or 3 to 6 membered cycloalkyl C 1-6 alkyl; in some embodiments , R 6 is CH 3 or In some embodiments, R6 is a hydrogen atom;
  • R 6 is selected from a hydrogen atom, a C 1-6 alkyl group, a deuterated C 1-6 alkyl group, and a 3- to 6-membered cycloalkyl group; in some embodiments, R 6 is selected from a hydrogen atom, Methyl, deuterated methyl, and cyclopropyl; in some embodiments, R is selected from a hydrogen atom, methyl, and deuterated methyl; in some embodiments, R is a hydrogen atom or a methyl group.
  • R 7 and R 8 are the same or Different, and each is independently selected from hydrogen atom, C 1-6 alkyl group, halogenated C 1-6 alkyl group and C 1-6 hydroxyalkyl group; preferably, R 7 and R 8 are each independently a hydrogen atom or C 1-6 alkyl; further preferably, R 7 and R 8 are each independently C 1-6 alkyl; most preferably, R 7 and R 8 are both CH 3 ; in some embodiments, R 7 and R 8 is the same or different, and each is independently C 1-6 alkyl or amino; in some embodiments, R 7 and R 8 are the same or different, and each is independently methyl or amino; in some embodiments, , R 7 is methyl
  • R 01 is each independently selected from Halogen, hydroxyl, cyano, oxo, amino, -NH alkyl, -N (alkyl) 2 , C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1 -6 haloalkoxy, C 1-6 hydroxyalkyl, 3 to 6 membered cycloalkyl and 3 to 6 membered heterocyclyl; in some embodiments, R 01 is each independently selected from halogen, hydroxyl, cyano, Oxo, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, and C 1-6 haloalkoxy; in some
  • R X1 is hydroxyl; in some embodiments, R X1 is In some embodiments, R X1 is selected from hydroxyl, methoxy, deuterated methoxy, and In some embodiments, R In some embodiments, R X1 is deuterated methoxy; in some embodiments, R X1 is OCD 3 .
  • 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.
  • the compound represented by general formula (I) or (II) or a pharmaceutically acceptable salt thereof wherein r is selected from 0, 1 and 2; preferably, r is 1; in In some embodiments, r is 2.
  • 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 and R b are different, and each is independently C 1-6 alkyl or halo C 1-6 alkyl; R c and R d are different, and each is independently a hydrogen atom or C 1-6 alkyl; X is O; R' is a hydrogen atom or C 1-6 alkyl; Ring A is Pyridyl or pyrimidinyl; R A is selected from amino, R X1 is C 1-6 alkoxy; R X2 is halogen; R X3 is halogen; and r is 1.
  • the compound represented by the general formula (II) or a pharmaceutically acceptable salt thereof wherein R a is a C 1-6 alkyl group and R b is a halogenated C 1-6 alkyl group.
  • Base R c is a hydrogen atom, and R d is a C 1-6 alkyl group, R' is a hydrogen atom, and X is O; for R A is selected from amino group, R X1 is C 1-6 alkoxy; R X2 is halogen; R X3 is 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 and R b is a halogenated C 1-6 Alkyl group, R c is a hydrogen atom, and R d is a C 1-6 alkyl group, R' is a hydrogen atom, X is O; Ring A is a pyridyl or pyrimidinyl group; r-1 is 0; R 5 is a hydrogen atom ; R 3a is selected from hydrogen atom, C 1-6 alkyl group and C 1-6 alkoxy group; R 4 is a hydrogen atom or methyl group; R X1 is C 1-6 alkoxy group; R X2 is halogen; R X3 For halogen.
  • the compound represented by the general formula (II-1) or a pharmaceutically acceptable salt thereof wherein R a is a C 1-6 alkyl group and R b is a halogenated C 1- 6 alkyl, R c is a hydrogen atom, and R d is a C 1-6 alkyl group, R' is a hydrogen atom, X is O; Ring A is a pyridyl or pyrimidinyl group; r-1 is 0; R 5 is hydrogen Atom; R 3 is selected from hydrogen atom, C 1-6 alkyl group and 3 to 6-membered cycloalkyl group; R 4 is a hydrogen atom or methyl group; R X1 is C 1-6 alkoxy group; R X2 is halogen; R X3 is halogen.
  • the compound represented by the general formula (IV) or a pharmaceutically acceptable salt thereof wherein R a is CH 3 , R b is CF 3 , R c is a hydrogen atom, and R d is CH 3 , R' is a hydrogen atom, R 1A and R 2A are both hydrogen atoms; R 3A is selected from R X1 is a methoxy group; R X2 is a fluorine atom; R X3 is a fluorine atom.
  • the compound represented by the general formula (IV) or a pharmaceutically acceptable salt thereof wherein R a is a C 1-6 alkyl group and R b is a halogenated C 1-6 alkyl group.
  • base R c is a hydrogen atom, and R d is a C 1-6 alkyl group, R' is a hydrogen atom, R 1A and R 2A are both hydrogen atoms;
  • R 3A is selected from R X1 is C 1-6 alkoxy;
  • R X2 is halogen;
  • R X3 is halogen.
  • the compound represented by the general formula (IV) or a pharmaceutically acceptable salt thereof wherein R a is a C 1-6 alkyl group and R b is a halogenated C 1-6 alkyl group.
  • base R c is a hydrogen atom, and R d is a C 1-6 alkyl group, R' is a hydrogen atom, R 1A and R 2A are both hydrogen atoms;
  • R X1 is C 1- 6 alkoxy group;
  • R X2 is halogen;
  • R X3 is halogen.
  • the compound represented by the general formula (IV) or a pharmaceutically acceptable salt thereof wherein R a is a C 1-6 alkyl group and R b is a halogenated C 1-6 alkyl group.
  • base R c is a hydrogen atom, and R d is a C 1-6 alkyl group, R' is a hydrogen atom, R 1A and R 2A are both hydrogen atoms;
  • R 3A is selected from R X1 is C 1-6 alkoxy;
  • R X2 is halogen;
  • R X3 is halogen.
  • the compound represented by the general formula (VI) or a pharmaceutically acceptable salt thereof wherein R a is a C 1-6 alkyl group and R b is a halogenated C 1-6 alkyl group.
  • base R c is a hydrogen atom, and R d is a C 1-6 alkyl group, R' is a hydrogen atom, R 1A and R 2A are both hydrogen atoms;
  • R 5 is a hydrogen atom;
  • R 3a is selected from hydrogen atoms, C 1 -6 alkyl and C 1-6 alkoxy;
  • R 4 is a hydrogen atom or methyl;
  • R X1 is C 1-6 alkoxy;
  • R X2 is halogen;
  • R X3 is halogen.
  • the compound represented by the general formula (VII) or a pharmaceutically acceptable salt thereof wherein R a is a C 1-6 alkyl group and R b is a halogenated C 1-6 alkyl group.
  • base R c is a hydrogen atom, and R d is a C 1-6 alkyl group, R' is a hydrogen atom, R 1A and R 2A are both hydrogen atoms;
  • R 5 is a hydrogen atom;
  • R 3 is selected from hydrogen atoms, C 1 -6 alkyl and 3 to 6-membered cycloalkyl;
  • R 4 is a hydrogen atom or a methyl group;
  • 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 (VI') or a pharmaceutically acceptable salt thereof wherein R a is a C 1-6 alkyl group and R b is a halogenated C 1-6 Alkyl group, R c is a hydrogen atom, and R d is a C 1-6 alkyl group, R' is a hydrogen atom, R X1 is a C 1-6 alkoxy group; R X2 is a halogen; R X3 is a halogen; R 1A and R 2A are all hydrogen atoms; Q is selected from CR 5A , N and N + -O - ; R 5A is halogen; R 3 is selected from hydrogen atoms, methyl, ethyl, methoxy, cyclopropyl, R 4 is a hydrogen atom or a methyl group; R 5 is a hydrogen atom.
  • the compound represented by the general formula (VIII) or a pharmaceutically acceptable salt thereof wherein X is O; R a is a C 1-6 alkyl group, and R b is a haloC 1-6 alkyl group, R c is a hydrogen atom, and R d is a C 1-6 alkyl group, R' is a hydrogen atom, R X1 is a C 1-6 alkoxy group; R X2 is a halogen; R X3 is a halogen; R 1A and R 2A are both hydrogen atoms; Q is selected from CR 5A , N and N + -O - ; R 5A is halogen; R 3 is selected from hydrogen atoms, methyl, ethyl, methoxy, cyclopropyl, R 4 is a hydrogen atom or methyl group.
  • 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, and R d is CH 3 ; R X1 is selected from hydroxyl, methoxy and R X2 is F, R X3 is F; X is O, R' is a hydrogen atom; for Each R B is the same or different, and each is independently a halogen, p is 0 or 1; Ring A is selected from The * terminal is connected to -NR', The end is connected to R A ;
  • R A is selected from F, Cl, amino, cyano,
  • 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, and R d is CH 3 ; R X1 is selected from hydroxyl, methoxy, deuterated methoxy and R X2 is F, R X3 is F; X is O, R' is a hydrogen atom; for R B is F, p is 0 or 1; ring A is The * terminal is connected to -NR', terminal is connected to R A ; R A is selected from
  • the compound represented by the general formula (VI') or a pharmaceutically acceptable salt thereof wherein R a is CH 3 , R b is CF 3 , R c is a hydrogen atom, and R d is CH 3 ; R X1 is selected from hydroxyl, methoxy and R X2 is F , R _ _ _ Atom, methyl, ethyl, hydroxyl, methoxy, cyclopropyl, R 4 is a hydrogen atom or a methyl group; R 5 is a hydrogen atom.
  • the compound represented by the general formula (VI') or a pharmaceutically acceptable salt thereof wherein R a is CH 3 , R b is CF 3 , R c is a hydrogen atom, and R d is CH 3 ; R X1 is selected from hydroxyl, methoxy, deuterated methoxy and R X2 is F , R _ _ R 5 is selected from hydrogen atom, deuterium atom, methyl group, deuterated methyl group, hydroxyl group, methoxy group, deuterated methoxy group, cyclopropyl group, -O-cyclopropyl group,
  • the compound represented by the general formula (VI') or a pharmaceutically acceptable salt thereof wherein R a is CH 3 , R b is CF 3 , R c is a hydrogen atom, and R d is CH 3 ; R X1 is selected from hydroxyl, methoxy and R X2 is F , R _ _ _ , R 4 is a hydrogen atom; R 5 is selected from a hydrogen atom, methyl, hydroxyl, methoxy, deuterated methoxy, -O-cyclopropyl,
  • the compound represented by the general formula (IV) or a pharmaceutically acceptable salt thereof wherein R a is CH 3 , R b is CF 3 , R c is a hydrogen atom, and R d is CH 3 ; R X1 is selected from hydroxyl, methoxy and R X2 is F, R X3 is F; R' is a hydrogen atom; R 1A and R 2A are both hydrogen atoms; R 3A is
  • the compound represented by general formula (IV) or a pharmaceutically acceptable salt thereof In, R a is CH 3 , R b is CF 3 , R c is a hydrogen atom, R d is CH 3 ; R X1 is selected from hydroxyl, methoxy and R X2 is F, R X3 is F; R' is a hydrogen atom; R 1A and R 2A are both hydrogen atoms; R A is
  • 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 (IIA') or salts thereof,
  • Ring A, RA , R', X, Ra, Rb, Rc, Rd, RX1, RX2 , RX3 and r - 1 are as defined in the general formula (II').
  • Another aspect of the present disclosure relates to a compound represented by general formula (IIa') or a salt thereof,
  • R* is selected from hydroxyl, alkoxy and halogen
  • Another aspect of the present disclosure relates to a compound represented by general formula (IIIA) or a salt thereof,
  • t is selected from 0, 1, 2, 3 and 4;
  • R 12 and R 13 are the same or different, and are each independently selected from a hydrogen atom, an alkyl group, a cycloalkyl group and a phenyl group; preferably, R 12 and R 13 are the same or different, and are each independently selected from a hydrogen atom, C 1-6 alkyl and 5 or 6-membered cycloalkyl; most preferably, R 12 and R 13 are both CH 3 ;
  • Rings A, R', Ra , Rb , Rc , Rd , X, RX1 , RX2 and RX3 are as defined in general formula (III).
  • Another aspect of the present disclosure relates to a compound represented by general formula (IIIA-1) or a salt thereof,
  • t is selected from 0, 1, 2, 3 and 4;
  • R 12 and R 13 are the same or different, and are each independently selected from a hydrogen atom, an alkyl group, a cycloalkyl group and a phenyl group; preferably, R 12 and R 13 are the same or different, and are each independently selected from a hydrogen atom, C 1-6 alkyl and 5 or 6-membered cycloalkyl; most preferably, R 12 and R 13 are both CH 3 ;
  • Rings A, R', R a , R b , R c , R d , X, R X1 , R X2 and R X3 are as defined in general formula (III-1).
  • Another aspect of the present disclosure relates to compounds represented by general formula (IVA') or salts thereof,
  • R 1A , R 2A , R', R a , R b , R c , R d , R X1 , R X2 and R X3 are as defined in the general formula (IV).
  • Another aspect of the present disclosure relates to compounds represented by general formula (IVa') or salts thereof,
  • R* is selected from hydroxyl, alkoxy and halogen
  • R 1A , R 2A , R ′ , Ra , R b , R c , R d , R X1 , R X2 and R X3 are as defined in general formula (IV).
  • Another aspect of the present disclosure relates to a compound represented by general formula (VII'A) or a salt thereof,
  • R* is selected from hydroxyl, alkoxy and halogen
  • R 1A , R 2A , R', R a , R b , R c , R d , R X1 , R X2 and R X3 are as defined in general formula (VII').
  • Another aspect of the present disclosure relates to compounds represented by general formula (VIIIA) or salts thereof,
  • R L is selected from halogen, hydroxyl and alkoxy
  • R1A , R2A , R', X, Ra, Rb, Rc, Rd, RX1 , RX2 and RX3 are as defined in general formula (VIII).
  • 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 A, R A , 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 (I) or a pharmaceutically acceptable salt thereof, which method includes:
  • the compound represented by the general formula (IA') or a salt thereof reacts with the compound represented by the general formula (IB') or a salt thereof (preferably a hydrochloride) to obtain a compound represented by the general formula (I) or a pharmaceutically acceptable compound thereof of salt, among which,
  • r is 1, 2, 3, 4 or 5; r-1 is 0, 1, 2, 3 or 4;
  • R A is as defined in the general formula (I); Ring A, R', R a , R b , R c , R d , Re, X, X 1 , X 2 , X 3 , X 4 , X 5 , R 3 , R 4 , R 5 and R 6 are as defined in general formula (I).
  • 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;
  • Ring A, RA , 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 is 1, 2, 3, 4 or 5; r-1 is 0, 1, 2, 3 or 4;
  • R 3 and R 4 are both hydrogen atoms; the remaining R A is as defined in general formula (II);
  • Rings A, R', R a , R b , R c , R d , X, R X1 , R X2 , R X3 and R 5 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:
  • the compound represented by the general formula (IIA') or a salt thereof reacts with the compound represented by the general formula (IB') or a salt thereof (preferably a hydrochloride) to obtain a compound represented by the general formula (II) or a pharmaceutically acceptable compound thereof of salt, among which,
  • r is 1, 2, 3, 4 or 5; r-1 is 0, 1, 2, 3 or 4;
  • R A is as defined in general formula (II);
  • Rings A, R', Ra, Rb , Rc , Rd, X, RX1 , RX2 , RX3 , R3 , R4 , R5 and R6 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:
  • the above-mentioned amine is selected from HNR 5 -OR 6 , HNR 5 -NR 3 R 4 and HNR 5 -alkylene-Cy;
  • R* is selected from hydroxyl, alkoxy and halogen
  • At least one R A in general formula (II) is selected from -C(O)NR 5 -OR 6 , -C(O)NR 5 -NR 3 R 4 and -C(O)NR 5 -alkylene-Cy; The remaining R A is as defined in general formula (II);
  • r is 1, 2, 3, 4 or 5; r-1 is 0, 1, 2, 3 or 4;
  • the method further includes the step of removing the protecting group;
  • the amino protecting group is preferably Boc;
  • 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 3a and R 4 are both hydrogen atoms
  • 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 reacts with the compound represented by the general formula (II'B) or a salt thereof (preferably a hydrochloride) to obtain a compound represented by the general formula (II') or its salt.
  • Medicinal salt of which,
  • R 5 is a hydrogen atom
  • 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 10 is halogen (preferably chlorine atom) or OH;
  • 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:
  • the compound represented by the general formula (IIa') or a salt thereof reacts with the compound represented by the general formula (II-1B) or a salt thereof (preferably a hydrochloride) to obtain a compound represented by the general formula (II-1) or a salt thereof.
  • Medicinal salts of which,
  • R* is selected from hydroxyl, alkoxy and halogen
  • the method further includes the step of removing the protecting group;
  • the amino protecting group is preferably Boc;
  • 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:
  • the compound represented by the general formula (IIa) or a salt thereof undergoes a condensation reaction with the compound represented by the general formula (II-1b) or a salt thereof (preferably a hydrochloride) to obtain a compound represented by the general formula (II-1) or Its medicinal salts, of which,
  • R 10 is halogen (preferably chlorine atom) or OH;
  • 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:
  • R 12 and R 13 are the same or different, and are each independently selected from a hydrogen atom, an alkyl group, a cycloalkyl group and a phenyl group; preferably, R 12 and R 13 are the same or different, and are each independently selected from a hydrogen atom, C 1-6 alkyl and 5 or 6-membered cycloalkyl; most preferably, R 12 and R 13 are both CH 3 ;
  • Rings A, R', X, Ra , Rb , Rc , Rd, RX1 , RX2 , RX3 and t are as defined in general formula (III).
  • Another aspect of the present disclosure relates to a method for preparing the compound represented by the above general formula (III-1) or a pharmaceutically acceptable salt thereof, which method includes:
  • R 12 and R 13 are the same or different, and are each independently selected from a hydrogen atom, an alkyl group, a cycloalkyl group and a phenyl group; preferably, R 12 and R 13 are the same or different, and are each independently selected from a hydrogen atom, C 1-6 alkyl and 5 or 6-membered cycloalkyl; most preferably, R 12 and R 13 are both CH 3 ;
  • Ring A, R', X, Ra , Rb , Rc , Rd , RX1 , RX2 , RX3 and t are as defined in general formula (III-1).
  • Another aspect of the present disclosure relates to a method for preparing the compound represented by the above general formula (IV) or a pharmaceutically acceptable salt thereof, which method includes:
  • R 10 is halogen (preferably chlorine atom) or OH;
  • R a , R b , R c , R d , R X1 , R X2 , R X3 , R', R 1A , R 2A and R 3A are as defined in general formula (IV).
  • Another aspect of the present disclosure relates to a method for preparing the compound represented by the above general formula (IV) or a pharmaceutically acceptable salt thereof, which method includes:
  • R 3 and R 4 are both hydrogen atoms
  • R 1A , R 2A , R ′ , Ra , R b , R c , R d , R X1 , R X2 , R X3 and R 5 are as defined in general formula (IV).
  • Another aspect of the present disclosure relates to a method for preparing the compound represented by the above general formula (IV) or a pharmaceutically acceptable salt thereof, which method includes:
  • the compound represented by the general formula (IVA') or a salt thereof reacts with the compound represented by the general formula (IB') or a salt thereof (preferably a hydrochloride) to obtain a compound represented by the general formula (IV) or a pharmaceutically acceptable compound thereof of salt, among which,
  • R 1A , R 2A , R', R a , R b , R c , R d , R X1 , R X2 , R X3 , R 3 , R 4 , R 5 and R 6 are as defined in the general formula (IV) .
  • Another aspect of the present disclosure relates to a method for preparing the compound represented by the above general formula (IV) or a pharmaceutically acceptable salt thereof, which method includes:
  • the above-mentioned amine is selected from HNR 5 -OR 6 , HNR 5 -NR 3 R 4 and HNR 5 -alkylene-Cy;
  • R* is selected from hydroxyl, alkoxy and halogen
  • R 3A is selected from -C(O)NR 5 -OR 6 , -C(O)NR 5 -NR 3 R 4 and -C(O)NR 5 -alkylene-Cy;
  • the method further includes the step of removing the protecting group;
  • the amino protecting group is preferably Boc;
  • R 1A , R 2A , R', R a , R b , R c , R d , R X1 , R X2 , R X3 , R 3 , R 4 , R 5 , R 6 and Cy are as in the general formula (IV) defined.
  • Another aspect of the present disclosure relates to a method for preparing the compound represented by the above general formula (V) or a pharmaceutically acceptable salt thereof, which method includes:
  • the compound represented by the general formula (IVa) or a salt thereof undergoes a condensation reaction with the compound represented by the general formula (Vb) or a salt thereof to obtain a compound represented by the general formula (V) or a pharmaceutically acceptable salt thereof, wherein,
  • R W1 is a hydrogen atom or an amino protecting group (preferably tert-butylsulfinyl), R W2 is a hydrogen atom or a hydroxyl protecting group (preferably TBS);
  • the preparation method further includes the step of removing the protecting group
  • R 10 is halogen (preferably chlorine atom) or OH;
  • R a , R b , R c , R d , R X1 , R X2 , R X3 , R', R 1A , R 2A , R A4 , u1 and u2 are as defined in the general formula (V).
  • Another aspect of the present disclosure relates to a method for preparing a compound represented by the above general formula (V-1) or (V-2) or a pharmaceutically acceptable salt thereof, which method includes:
  • the compound represented by the general formula (IVa) or a salt thereof undergoes a condensation reaction with the compound represented by the general formula (V-1b) or a salt thereof to obtain a compound represented by the general formula (V-1) or a pharmaceutically acceptable salt thereof, or,
  • the compound represented by the general formula (IVa) or a salt thereof undergoes a condensation reaction with the compound represented by the general formula (V-2b) or a salt thereof to obtain a compound represented by the general formula (V-2) or a pharmaceutically acceptable salt thereof, in,
  • R W1 is a hydrogen atom or an amino protecting group (preferably tert-butylsulfinyl), R W2 is a hydrogen atom or a hydroxyl protecting group (preferably TBS);
  • the preparation method further includes the step of removing the protecting group
  • R 10 is halogen (preferably chlorine atom) or OH;
  • R a , R b , R c , R d , R X1 , R X2 , R X3 , R', R 1A , R 2A , R A4 , u1 and u2 are as defined in the general formula (V-1).
  • Another aspect of the present disclosure relates to a method for preparing a compound represented by the above general formula (V-1) or (V-2) or a pharmaceutically acceptable salt thereof, which method includes:
  • R W1 is an amino protecting group, and the amino protecting group is preferably Boc;
  • R a , R b , R c , R d , R X1 , R X2 , R X3 , R', R 1A , R 2A , R A4 , u1 and u2 are as defined in the general formula (V-1).
  • Another aspect of the present disclosure relates to a method for preparing the compound represented by the above general formula (VI') or a pharmaceutically acceptable salt thereof, which method includes:
  • the compound represented by the general formula (IVa) or a salt thereof undergoes a condensation reaction with the compound represented by the general formula (VI'B) or a salt thereof (preferably a hydrochloride) to obtain a compound represented by the general formula (VI') or a salt thereof.
  • Medicinal salts of which,
  • R 10 is halogen (preferably chlorine atom) or OH;
  • R', R a , R b , R c , R d , R X1 , R X2 , R X3 , R 1A , R 2A , Q, R 3 , R 4 and R 5 are as defined in the general formula (VI') .
  • Another aspect of the present disclosure relates to a method for preparing the compound represented by the above general formula (VI') or a pharmaceutically acceptable salt thereof, which method includes:
  • the compound represented by general formula (VI'A) or a salt thereof reacts with NH 2 -R 5 or a salt thereof (preferably hydrochloride) to obtain a compound represented by general formula (VI') or a pharmaceutically acceptable salt thereof, in,
  • R 3 and R 4 are both hydrogen atoms
  • R', R a , R b , R c , R d , R X1 , R X2 , R X3 , R 1A , R 2A , Q and R 5 are as defined in the general formula (VI').
  • Another aspect of the present disclosure relates to a method for preparing the compound represented by the above general formula (VI') or a pharmaceutically acceptable salt thereof, which method includes:
  • the compound represented by the general formula (VI'A) or a salt thereof reacts with the compound represented by the general formula (IB') or a salt thereof (preferably a hydrochloride) to obtain a compound represented by the general formula (VI') or a salt thereof.
  • Medicinal salt of which,
  • R 5 is a hydrogen atom
  • R', R a , R b , R c , R d , R X1 , R X2 , R X3 , R 1A , R 2A , Q, R 3 and R 4 are as defined in general formula (VI').
  • Another aspect of the present disclosure relates to a method for preparing the compound represented by the above general formula (VI'-1) or a pharmaceutically acceptable salt thereof, which method includes:
  • R 10 is halogen (preferably chlorine atom) or OH;
  • R', R a , R b , R c , R d , R X1 , R X2 , R X3 , R 1A , R 2A , Q, R 3 , R 5 and R C are as in the general formula (VI'-1) defined.
  • Another aspect of the present disclosure relates to a method for preparing the compound represented by the above general formula (VI'-1) or a pharmaceutically acceptable salt thereof, which method includes:
  • the compound represented by the general formula (VI'A) or a salt thereof reacts with the compound represented by the general formula (VI-1B') or a salt thereof (preferably a hydrochloride) to obtain a compound represented by the general formula (VI'-1) Compounds or pharmaceutically acceptable salts thereof, wherein,
  • R 5 is a hydrogen atom
  • Another aspect of the present disclosure relates to a method for preparing the compound represented by the above general formula (VI'-1) or a pharmaceutically acceptable salt thereof, which method includes:
  • the compound represented by the general formula (VI') or a salt thereof reacts with the compound represented by the general formula (VI'-1b) or a salt thereof to obtain the general formula (VI'-1 ) or a pharmaceutically acceptable salt thereof, wherein,
  • R 4 is a hydrogen atom
  • R 10 is halogen (preferably chlorine) or OH
  • R', R a , R b , R c , R d , R X1 , R X2 , R X3 , R 1A , R 2A , Q, R 3 , R 5 and R C are as in the general formula (VI'-1) defined.
  • Another aspect of the present disclosure relates to a method for preparing the compound represented by the above general formula (VI) or a pharmaceutically acceptable salt thereof, which method includes:
  • the compound represented by the general formula (IVA') or a salt thereof reacts with NH 2 -R 5 or a salt thereof (preferably the hydrochloride) to obtain a compound represented by the general formula (VI) or a pharmaceutically acceptable salt thereof, wherein,
  • R 3a and R 4 are both hydrogen atoms
  • R 1A , R 2A , R′, R a , R b , R c , R d , R X1 , R X2 , R X3 and R 5 are as defined in general formula (VI).
  • Another aspect of the present disclosure relates to a method for preparing the compound represented by the above general formula (VI) or a pharmaceutically acceptable salt thereof, which method includes:
  • the compound represented by the general formula (IVA') or a salt thereof reacts with the compound represented by the general formula (II'B) or a salt thereof (preferably a hydrochloride) to obtain a compound represented by the general formula (VI) or a pharmaceutically acceptable compound thereof salt used, among which,
  • R 5 is a hydrogen atom
  • R 1A , R 2A , R', R a , R b , R c , R d , R X1 , R X2 , R X3 , R 3a and R 4 are as defined in general formula (VI).
  • Another aspect of the present disclosure relates to a method for preparing the compound represented by the above general formula (VI) or a pharmaceutically acceptable salt thereof, which method includes:
  • the compound represented by the general formula (IVa) or a salt thereof undergoes a condensation reaction with the compound represented by the general formula (VIb) or a salt thereof (preferably a hydrochloride) to obtain a compound represented by the general formula (VI) or a pharmaceutically acceptable compound thereof of salt, among which,
  • R 10 is halogen (preferably chlorine atom) or OH;
  • R', R a , R b , R c , R d , R X1 , R X2 , R X3 , R 1A , R 2A , R 3a , R 4 and R 5 are as defined in general formula (VI).
  • Another aspect of the present disclosure relates to a method for preparing the compound represented by the above general formula (VII') or a pharmaceutically acceptable salt thereof, which method includes:
  • R 10 is halogen (preferably chlorine atom) or OH;
  • R', R a , R b , R c , R d , R X1 , R X2 , R X3 , R 1A , R 2A , Q, R 3 , R 4 and R 5 are as defined in the general formula (VII') .
  • Another aspect of the present disclosure relates to a method for preparing the compound represented by the above general formula (VII') or a pharmaceutically acceptable salt thereof, which method includes:
  • the compound represented by the general formula (VII') or a salt thereof undergoes an amidation reaction with the compound represented by the general formula (II-1B) or a salt thereof (preferably a hydrochloride) to obtain a compound represented by the general formula (VII') or a pharmaceutically acceptable salt thereof, wherein,
  • R* is selected from hydroxyl, alkoxy and halogen
  • the method further includes the step of removing the protecting group;
  • the amino protecting group is preferably Boc;
  • R', R a , R b , R c , R d , R X1 , R X2 , R X3 , R 1A , R 2A , Q, R 3 , R 4 and R 5 are as defined in the general formula (VII') .
  • Another aspect of the present disclosure relates to a method for preparing the compound represented by the above general formula (VII) or a pharmaceutically acceptable salt thereof, which method includes:
  • the compound represented by the general formula (IVa') or a salt thereof undergoes an amidation reaction with the compound represented by the general formula (II-1B) or a salt thereof (preferably the hydrochloride) to obtain a compound represented by the general formula (VII) or its medicinal salt,
  • R* is selected from hydroxyl, alkoxy and halogen
  • the method further includes the step of removing the protecting group;
  • the amino protecting group is preferably Boc;
  • R 1A , R 2A , R', R a , R b , R c , R d , R X1 , R X2 , R X3 , R 3 , R 4 and R 5 are as defined in the general formula (VII).
  • Another aspect of the present disclosure relates to a method for preparing the compound represented by the above general formula (VII) or a pharmaceutically acceptable salt thereof, which method includes:
  • the compound represented by the general formula (IVa) or a salt thereof undergoes a condensation reaction with the compound represented by the general formula (VIIb) or a salt thereof (preferably a hydrochloride) to obtain a compound represented by the general formula (VII) or a pharmaceutically acceptable compound thereof of salt, among which,
  • R 10 is halogen (preferably chlorine atom) or OH;
  • R', R a , R b , R c , R d , R X1 , R X2 , R X3 , R 1A , R 2A , R 3 , R 4 and R 5 are as defined in general formula (VII).
  • Another aspect of the present disclosure relates to a method for preparing the compound represented by the above general formula (VIII) or a pharmaceutically acceptable salt thereof, which method includes:
  • the compound represented by the general formula (IIa) or a salt thereof undergoes a condensation reaction with the compound represented by the general formula (VIIIB) or a salt thereof (preferably a hydrochloride) to obtain a compound represented by the general formula (VIII) or a pharmaceutically acceptable compound thereof of salt, among which,
  • R 10 is halogen (preferably chlorine atom) or OH;
  • Another aspect of the present disclosure relates to a method for preparing the compound represented by the above general formula (VIII) or a pharmaceutically acceptable salt thereof, which method includes:
  • the compound represented by the general formula (VIIIA) or a salt thereof undergoes an urethane exchange reaction with the compound represented by the general formula (IB') or a salt thereof (preferably a hydrochloride) to obtain a compound represented by the general formula (VIII) or a salt thereof.
  • Medicinal salts of which,
  • R L is alkoxy
  • R 4 is an amino protecting group
  • the amidation reaction also includes the step of removing the amino protecting group.
  • Another aspect of the present disclosure relates to a method for preparing the above general formula (II), (II'), (II-1), (III), (III-1), (IV), (V), (V-1 ), (V-2), (VI), (VII), (VI'), (VI'-1), (VII') or (VIII) or a pharmaceutically acceptable salt thereof,
  • the method includes: general formula (II), (II'), (II-1), (III), (III-1), (IV), (V) in which R X1 is an alkoxy group or a cycloalkoxy group.
  • Another aspect of the present disclosure relates to a pharmaceutical composition containing the general formula (I), (II), (II'), (II-1), (III), (III-1) of the present disclosure. ), (IV), (V), (V-1), (V-2), (VI), (VII), (VI'), (VI'-1), (VII'), (VIII) Or a compound shown in Table A or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients.
  • the present disclosure further relates to general formulas (I), (II), (II'), (II-1), (III), (III-1), (IV), (V), (V-1), ( V-2), (VI), (VII), (VI'), (VI'-1), (VII'), (VIII) or a compound shown in Table A or a pharmaceutically acceptable salt thereof, or Use of a pharmaceutical composition including the same in the preparation of drugs that inhibit voltage-gated sodium channels; preferably, the voltage-gated sodium channel is Nav1.8.
  • the present disclosure further relates to general formulas (I), (II), (II'), (II-1), (III), (III-1), (IV), (V), (V-1), ( V-2), (VI), (VII), (VI'), (VI'-1), (VII'), (VIII) or a compound shown in Table A or a pharmaceutically acceptable salt thereof, or Use of a pharmaceutical composition comprising the same in the preparation of a medicament 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 general formulas (I), (II), (II'), (II-1), (III), (III-1), (IV), (V), (V-1), ( V-2), (VI), (VII), (VI'), (VI'-1), (VII'), (VIII) or a compound shown in Table A or a drug thereof Salts used, or pharmaceutical compositions comprising them, in the preparation of medicaments for the treatment and/or alleviation of pain and pain-related diseases, multiple sclerosis, Schaumburg-Touchen syndrome, incontinence, pathological cough or cardiac arrhythmias.
  • 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 the group consisting of bunionectomy pain, hernia repair pain and abdominoplasty pain.
  • the present disclosure further relates to a method of inhibiting voltage-gated sodium channels, comprising administering to a patient in need thereof general formula (I), (II), (II'), (II-1), (III), (III-1 ), (IV), (V), (V-1), (V-2), (VI), (VII), (VI'), (VI'-1), (VII'), (VIII) Or the 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 preventing a disease or condition mediated by voltage-gated sodium channels, comprising administering to a patient in need thereof general formula (I), (II), (II'), (II- 1), (III), (III-1), (IV), (V), (V-1), (V-2), (VI), (VII), (VI'), (VI'- 1), (VII'), (VIII) or the 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 preventing pain and pain-related disorders, multiple sclerosis, Schaumburg-Touche syndrome, incontinence, pathological cough or cardiac arrhythmia, comprising administering to a patient in need thereof the general formula (I), (II), (II'), (II-1), (III), (III-1), (IV), (V), (V-1), (V-2), ( VI), (VII), (VI'), (VI'-1), (VII'), (VIII) or the compound shown in Table A or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition including the same;
  • 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 general formula (I), (II), (II'), (II-1), (III), (III-1), (IV), (V), (V-1) , (V-2), (VI), (VII), (VI'), (VI'-1), (VII'), (VIII) or the compound shown in Table A or a pharmaceutically acceptable salt thereof, Or a pharmaceutical composition comprising the same, which is used as a medicament; preferably, it is used as a medicament that inhibits the activity of voltage-gated sodium channels.
  • the present disclosure further relates to a general formula (I), (II), (II'), (II-1), (III), (III-1), (IV), (V), (V-1) , (V-2), (VI), (VII), (VI'), (VI'-1), (VII'), (VIII) or the compound shown in Table A or a pharmaceutically acceptable salt thereof, Or a pharmaceutical composition including the same, which is used to inhibit voltage-gated sodium channels; preferably, the voltage-gated sodium channel is Nav1.8.
  • the present disclosure further relates to a general formula (I), (II), (II'), (II-1), (III), (III-1), (IV), (V), (V-1) , (V-2), (VI), (VII), (VI'), (VI'-1), (VII'), (VIII) or the compound shown in Table A or a pharmaceutically acceptable salt thereof, Or a pharmaceutical composition comprising the same for use as a voltage-gated sodium channel inhibitor.
  • the present disclosure further relates to a general formula (I), (II), (II'), (II-1), (III), (III-1), (IV), (V), (V-1) , (V-2), (VI), (VII), (VI'), (VI'-1), (VII'), (VIII) or the compound shown in Table A or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same for use as a medicament for the treatment and/or prevention of diseases or conditions mediated by voltage-gated sodium channels.
  • the present disclosure further relates to a general formula (I), (II), (II'), (II-1), (III), (III-1), (IV), (V), (V-1), (V-2), (VI), (VII), (VI'), (VI'-1), (VII'), (VIII) or the compound shown in Table A or its Pharmaceutically acceptable salts, or pharmaceutical compositions including them, are used to treat and/or prevent 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 general formula (I), (II), (II'), (II-1), (III), (III-1), (IV), (V), (V-1) , (V-2), (VI), (VII), (VI'), (VI'-1), (VII'), (VIII) or the compound shown in Table A or a pharmaceutically acceptable salt thereof, Or a pharmaceutical composition comprising the same for the treatment and/or prevention of pain and pain-related diseases, multiple sclerosis, Schaumburg-Touchen syndrome, incontinence, pathological cough or cardiac arrhythmia; preferably, said 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 postoperative pain is preferably selected from bunionectomy Pain, hernia repair pain, and abdominoplasty 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 the group consisting of trigeminal neuralgia, post-herpetic neuralgia, diabetic neuralgia, painful HIV-related sensory neuralgia, burn syndrome, post-amputation pain, post-spinal cord injury pain, phantom pain Pain, painful neuroma, traumatic neuroma, Morton's neuroma, nerve crush injury, spinal stenosis, carpal tunnel syndrome, radicular pain, sciatica, nerve avulsion injury, brachial plexus avulsion Injury, complex regional pain syndrome, pharmacotherapy-induced neuralgia, cancer chemotherapy-induced neuralgia, antiretroviral therapy-induced neuralgia, primary small fiber neuropathy, primary sensory neuralgia, and trigeminal Autonomic headache; preferably, the neuropathic pain is selected from postherpetic neuralgia, small fiber neuralgia, diabetic neuralgia or idiopathic small fiber neuralgia.
  • 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 disease or condition described in the present disclosure is selected from the group consisting of acute pain, chronic pain, neuropathic pain, inflammatory pain, arthritis, migraine, cluster headache, trigeminal neuralgia, herpetic neuralgia, general neuralgia, epilepsy disorders, epilepsy disorders, neurodegenerative disorders, psychosis, anxiety disorders, depression, bipolar disorder, myotonia, cardiac arrhythmias, movement disorders, neuroendocrine disorders, ataxia, multiple sclerosis, irritable bowel syndrome symptoms, 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 , breakthrough pain, post-operative pain, cancer pain, stroke, cerebral ischemia, traumatic brain injury, amyotrophic lateral sclerosis, stress-induced angina, exercise-induced angina, palpitations, hypertension, or abnormal gastrointestinal sports
  • 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, traumatic pain, movement pain, acute visceral pain, pyelonephritis, appendicitis
  • 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 pain 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% of the drug Scientifically acceptable excipients.
  • compositions described in this disclosure may be selected from inorganic or organic salts.
  • Tablets contain the active ingredient in admixture with nontoxic pharmaceutically acceptable excipients suitable for the manufacture of tablets.
  • 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 vehicles or solvents that may be used are 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 administered depends on a variety of factors, including, but not limited to, the activity of the specific compound used, the severity of the disease, the age of the patient, the patient's Body weight, patient's health status, patient's behavior, patient's diet, administration time, administration method, excretion rate, drug combination, etc.; in addition, the best treatment method such as treatment mode, daily dosage of the compound may
  • the types of medicinal salts can be verified according to 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). No 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, One or more of cycloalkyloxy, heterocyclyloxy, hydroxyl, hydroxyalkyl, cyano, 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 preferably has a cycloalkyl group with 3 to 12 ring atoms (ie, a 3 to 12-membered cycloalkyl group) and a cycloalkyl group with 3 to 10 ring atoms (ie, a 3 to 10-membered cycloalkyl group), and more Cycloalkyl groups having 3 to 8 ring atoms (ie, 3 to 8 membered cycloalkyl groups) are preferred, and cycloalkyl groups having 3 to 6 ring atoms (ie, 3 to 6 membered cycloalkyl groups) are most preferred.
  • 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 rings 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 oxidized, that is, to form sulfoxide or sulfone, but does not include -OO-, -OS - or -SS-), the condition is that it contains at least one all-carbon ring and the connection point 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 polyspirocycloalkyl group (such as a double spirocycloalkyl group, etc.), preferably a single spirocycloalkyl group or a double spirocycloalkyl 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-membere
  • 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 and polycyclic fused cycloalkyl (such as tricyclic fused cycloalkyl, tetracyclic fused cycloalkyl, etc.), preferably bicyclic fused cycloalkyl or tricyclic fused cycloalkyl , 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
  • connection point can be at any position
  • 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 -O-O-, -O-S- or -S-S-), and having 3 to 20 (e.g.
  • the heterocyclyl group is preferably a heterocyclyl group having 3 to 12 ring atoms (i.e. a 3 to 12 membered heterocyclyl group); further preferably a heterocyclyl group having 3 to 10 ring atoms (i.e. a 3 to 10 membered heterocyclyl group) ) and a heterocyclyl group having 3 to 8 ring atoms (i.e. a 3 to 8 membered heterocyclyl group); more preferably a heterocyclyl group having 4 to 7 ring atoms (i.e.
  • a 4 to 7 membered heterocyclyl group more preferably Heterocyclyl having 3 to 6 ring atoms (i.e. 3 to 6 membered heterocyclyl); most preferably heterocyclyl having 5 or 6 ring atoms (i.e. 5 or 6 membered heterocyclyl) or having 3 to 4 Heterocyclyl group with 3 ring atoms (i.e. 3 to 4 membered heterocyclyl group).
  • 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) 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 oxidized, that is, to form sulfoxide or sulfone, but does not include -OO-, -OS - or -SS-), which is a monocyclic heterocyclyl group fused with one or more monocyclic heterocyclyl groups, or a monocyclic heterocyclyl group with one or more of cycloalkyl, aryl or heteroaryl groups Condensed, wherein the point of attachment is on the monocyclic heterocyclyl group 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
  • 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. Oxygen, cycloalkyloxy, heterocyclyloxy, hydroxyl, hydroxyalkyl, oxo, cyano, amino, nitro, cyclo One or more of alkyl, heterocyclyl, aryl and heteroaryl.
  • 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.
  • Non-limiting examples of the polycyclic aromatic group 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.
  • Non-limiting examples of the polycyclic heteroaryl include: indolyl, indazolyl, quinolyl, isoquinolyl, quinoxalinyl, phthalazinyl, benzimidazolyl, benzothiophene base, 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), tert-butylsulfinyl, tris Fluoroacetyl (Tfa), trichloroacetyl, trityl (Trt), 2,4-dimethoxybenzyl (DMB), p-methoxybenzyl (PMB), ace
  • 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.
  • cycloalkylalkyl refers to an alkyl group substituted by one or more cycloalkyl groups, where cycloalkyl and alkyl are as defined above.
  • heterocyclylalkyl refers to an alkyl group substituted by one or more heterocyclyl groups, where heterocyclyl and alkyl are as defined above.
  • alkoxyalkyl refers to an alkyl group substituted with one or more alkoxy groups, where alkoxy and alkyl are as defined above.
  • 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.
  • deuterated methyl refers to a methyl group substituted with one or more deuterium atoms, such as CHD2 , CH2D and CD3 ; preferably CD3 .
  • deuterated methoxy refers to -O-deuterated methyl, deuterated methyl being as defined above, such as OCD3 .
  • 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, - and (S)-enantiomers, diastereomers, (D)- and (L)-isomers, tautomers, atropisomers, conformational isomers and their Mixtures (such as 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 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 Z and E forms are included; bonds If the configuration is not specified, it can be either the Z configuration or the E configuration, or both.
  • the bond to the stereogenic center of the compound or 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 an enamine-imine equilibrium is shown below:
  • Amidines also known as iminoamides, are compounds in which the carbonyl oxygen atom in the amide molecule is replaced by an imino group.
  • the imino and amino groups of the amidine can transform into each other to form tautomers.
  • the tautomerization of the amidine The structure is as follows:
  • 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 connected to a carbon atom can be independently 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 alkyl is not substituted by halogen or cyano. situation.
  • 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 safe and effective when used 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 A, R A , 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 (I) or a pharmaceutically acceptable salt thereof, which method includes:
  • the compound represented by the general formula (IA') or a salt thereof reacts with the compound represented by the general formula (IB') or a salt thereof (preferably a hydrochloride) in the presence of thioglycolic acid and a base to obtain the general formula (I ) or a pharmaceutically acceptable salt thereof, wherein,
  • r is 1, 2, 3, 4 or 5; r-1 is 0, 1, 2, 3 or 4;
  • R A is as defined in general formula (I);
  • Ring A, R', Ra, Rb , Rc , Rd , Re , X, X1 , X2 , X3 , X4 , X5 , R3 , R4 , R5 and R6 are as follows As defined in general formula (I).
  • 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;
  • R 10 when R 10 is OH, the reaction occurs in the presence of a condensing agent or oxalyl chloride, preferably in the presence of a condensing agent;
  • Ring A, R A , R', R a , R b , R c , R d , X, R X1 , R X2 , R X3 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:
  • the compound represented by general formula (IIA') or a salt thereof reacts with the compound represented by general formula (IB') or a salt thereof (preferably hydrochloride) in the presence of thioglycolic acid and a base to obtain general formula (II ) or a pharmaceutically acceptable salt thereof, wherein,
  • r is 1, 2, 3, 4 or 5; r-1 is 0, 1, 2, 3 or 4;
  • R A is as defined in general formula (II);
  • Rings A, R', Ra, Rb , Rc , Rd, X, RX1 , RX2 , RX3 , R3 , R4 , R5 and R6 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:
  • the above-mentioned amine is selected from HNR 5 -OR 6 , HNR 5 -NR 3 R 4 and HNR 5 -alkylene-Cy;
  • R* is selected from hydroxyl, alkoxy and halogen
  • At least one R A in general formula (II) is selected from -C(O)NR 5 -OR 6 , -C(O)NR 5 -NR 3 R 4 and -C(O)NR 5 -alkylene-Cy;
  • R A is as defined in general formula (II);
  • r is 1, 2, 3, 4 or 5; r-1 is 0, 1, 2, 3 or 4;
  • the method further includes the step of removing the protecting group;
  • the amino protecting group is preferably Boc;
  • the present disclosure provides a method for preparing a compound represented by the general formula (II) or a pharmaceutically acceptable salt thereof.
  • the method includes: a compound represented by the general formula (II) in which R The pharmaceutically acceptable salt undergoes a dealkylation or decycloalkyl reaction under acidic conditions to obtain a compound represented by the general formula (II) in which R X1 is -OH or a pharmaceutically acceptable salt thereof.
  • 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 NH 2 -R 5 or a salt thereof (preferably the hydrochloride) undergo a pinner reaction in the presence of a catalyst to obtain the compound represented by the general formula (II) or a drug thereof salt used,
  • r is 1, 2, 3, 4 or 5; r-1 is 0, 1, 2, 3 or 4;
  • R 3 and R 4 are both hydrogen atoms
  • R A is as defined in general formula (II);
  • Rings A, R', R a , R b , R c , R d , X, R X1 , R X2 , R X3 and R 5 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 5 is a hydrogen atom
  • 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 10 is halogen (preferably a chlorine atom) or OH; when R 10 is OH, the reaction occurs in the presence of a condensing agent or oxalyl chloride, preferably in the presence of a condensing agent;
  • the present disclosure provides a method for preparing a compound represented by the general formula (II') or a pharmaceutically acceptable salt thereof.
  • the method includes: a compound represented by the general formula (II') in which R X1 is an alkoxy group or a cycloalkoxy group. Or its pharmaceutically acceptable salt undergoes dealkylation or decycloalkyl reaction under acidic conditions to obtain a compound represented by the general formula (II') in which R X1 is -OH, or a pharmaceutically acceptable salt thereof.
  • 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 3a and R 4 are both hydrogen atoms
  • 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* is selected from hydroxyl, alkoxy and halogen
  • the method further includes the step of removing the protecting group;
  • the amino protecting group is preferably Boc;
  • 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 10 is halogen (preferably a chlorine atom) or OH; when R 10 is OH, the reaction occurs in the presence of a condensing agent or oxalyl chloride, preferably in the presence of a condensing agent;
  • the present disclosure provides a method for preparing a compound represented by the general formula (II-1) or a pharmaceutically acceptable salt thereof.
  • the method includes: R X1 is an alkoxy group or a cycloalkoxy group represented by the general formula (II-1)
  • the compound or a pharmaceutically acceptable salt thereof undergoes a dealkylation or decycloalkyl reaction under acidic conditions to obtain a compound represented by the general formula (II-1) in which R X1 is -OH or a pharmaceutically acceptable salt thereof.
  • 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 12 and R 13 are the same or different, and are each independently selected from a hydrogen atom, an alkyl group, a cycloalkyl group and a phenyl group; preferably, R 12 and R 13 are the same or different, and are each independently selected from a hydrogen atom, C 1-6 alkyl and 5 or 6-membered cycloalkyl; most preferably, R 12 and R 13 are both CH 3 ;
  • Rings A, R', R a , R b , R c , R d , X, R X1 , R X2 , R X3 and t are as defined in general formula (III).
  • the present disclosure provides a method for preparing a compound represented by general formula (III) or a pharmaceutically acceptable salt thereof.
  • the method includes: a compound represented by general formula (III) in which R The pharmaceutically acceptable salt undergoes a dealkylation or decycloalkyl reaction under acidic conditions to obtain a compound represented by the general formula (III) in which R X1 is -OH or a pharmaceutically acceptable salt thereof.
  • the present disclosure provides a method for preparing a compound represented by general formula (III-1) or a pharmaceutically acceptable salt thereof, which method includes:
  • R 12 and R 13 are the same or different, and are each independently selected from a hydrogen atom, an alkyl group, a cycloalkyl group and a phenyl group; preferably, R 12 and R 13 are the same or different, and are each independently selected from a hydrogen atom, C 1-6 alkyl and 5 or 6-membered cycloalkyl; most preferably, R 12 and R 13 are both CH 3 ;
  • Ring A, R', R a , R b , R c , R d , X, R X1 , R X2 , R X3 and t are as defined in general formula (III-1).
  • the present disclosure provides a method for preparing a compound represented by the general formula (III-1) or a pharmaceutically acceptable salt thereof, which method includes: R X1 is an alkoxy group or a cycloalkoxy group represented by the general formula (III-1)
  • R X1 is an alkoxy group or a cycloalkoxy group represented by the general formula (III-1)
  • the compound or a pharmaceutically acceptable salt thereof undergoes a dealkylation or decycloalkyl reaction under acidic conditions to obtain a compound represented by the general formula (III-1) in which R X1 is -OH or a pharmaceutically acceptable salt thereof.
  • the present disclosure provides a method for a compound represented by general formula (IV) or a pharmaceutically acceptable salt thereof, which method includes:
  • R 10 is halogen (preferably chlorine atom) or OH;
  • R 10 when R 10 is OH, the reaction occurs in the presence of a condensing agent or oxalyl chloride, preferably in the presence of a condensing agent;
  • R a , R b , R c , R d , R X1 , R X2 , R X3 , R', R 1A , R 2A and R 3A are as defined in general formula (IV).
  • the present disclosure provides a method for a compound represented by general formula (IV) or a pharmaceutically acceptable salt thereof, which method includes:
  • the compound represented by general formula (IVA') or a salt thereof reacts with the compound represented by general formula (IB') or a salt thereof (preferably hydrochloride) in the presence of a catalyst to obtain a compound represented by general formula (IV) or its medicinal salt,
  • the compound represented by the general formula (IVA') or a salt thereof reacts with the compound represented by the general formula (IB') or a salt thereof (preferably a hydrochloride) in the presence of thioglycolic acid and a base to obtain the general formula (IV ) or a pharmaceutically acceptable salt thereof, wherein,
  • R 1A , R 2A , R', R a , R b , R c , R d , R X1 , R X2 , R X3 , R 3 , R 4 , R 5 and R 6 are as defined in the general formula (IV) .
  • the present disclosure provides a method for a compound represented by general formula (IV) or a pharmaceutically acceptable salt thereof, which method includes:
  • the compound represented by the general formula (IVa') or a salt thereof and an amine or a salt thereof undergo amidation reaction under alkaline conditions to obtain the compound represented by the general formula (IV) or a pharmaceutically acceptable compound thereof salt, among which,
  • the above-mentioned amine is selected from HNR 5 -OR 6 , HNR 5 -NR 3 R 4 and HNR 5 -alkylene-Cy;
  • R* is selected from hydroxyl, alkoxy and halogen
  • R 3A is selected from -C(O)NR 5 -OR 6 , -C(O)NR 5 -NR 3 R 4 and -C(O)NR 5 -alkylene-Cy;
  • the method further includes the step of removing the protecting group;
  • the amino protecting group is preferably Boc;
  • R 1A , R 2A , R', R a , R b , R c , R d , R X1 , R X2 , R X3 , R 3 , R 4 , R 5 , R 6 and Cy are as in the general formula (IV) defined.
  • the present disclosure provides a method for a compound represented by the general formula (IV) or a pharmaceutically acceptable salt thereof.
  • the method includes: a compound represented by the general formula (IV) in which R The pharmaceutically acceptable salt undergoes a dealkylation or decycloalkyl reaction under acidic conditions to obtain a compound represented by the general formula (IV) in which R X1 is -OH or a pharmaceutically acceptable salt thereof.
  • the present disclosure provides a method for a compound represented by general formula (IV) or a pharmaceutically acceptable salt thereof, which method includes:
  • the compound represented by the general formula (IVA') or a salt thereof reacts with NH 2 -R 5 or a salt thereof (preferably hydrochloride) in the presence of a catalyst to obtain a compound represented by the general formula (IV) or a pharmaceutically acceptable compound thereof Salt,
  • R 1A , R 2A , R ′ , Ra , R b , R c , R d , R X1 , R X2 , R X3 and R 5 are as defined in general formula (IV).
  • the present disclosure provides a method for a compound represented by general formula (V) or a pharmaceutically acceptable salt thereof, which method includes:
  • the compound represented by the general formula (IVa) or a salt thereof undergoes a condensation reaction with the compound represented by the general formula (Vb) or a salt thereof to obtain a compound represented by the general formula (V) or a pharmaceutically acceptable salt thereof, wherein,
  • R W1 is a hydrogen atom or an amino protecting group (preferably tert-butylsulfinyl), R W2 is a hydrogen atom or a hydroxyl protecting group (preferably TBS);
  • the preparation method further includes the step of removing the protecting group under acidic conditions after the condensation reaction;
  • R 10 is halogen (preferably a chlorine atom) or OH; when R 10 is OH, the reaction occurs in the presence of a condensing agent or oxalyl chloride, preferably in the presence of a condensing agent;
  • R a , R b , R c , R d , R X1 , R X2 , R X3 , R', R 1A , R 2A , R A4 , u1 and u2 are as defined in the general formula (V).
  • the present disclosure provides a method for a compound represented by the general formula (V) or a pharmaceutically acceptable salt thereof.
  • the method includes: a compound represented by the general formula (V) in which R The pharmaceutically acceptable salt undergoes a dealkylation or decycloalkyl reaction under acidic conditions to obtain a compound represented by the general formula (V) in which R X1 is -OH or a pharmaceutically acceptable salt thereof.
  • the present disclosure provides a method for a compound represented by general formula (V-1) or (V-2) or a pharmaceutically acceptable salt thereof, which method includes:
  • R W1 is a hydrogen atom or an amino protecting group (preferably tert-butylsulfinyl), R W2 is a hydrogen atom or a hydroxyl protecting group (preferably TBS);
  • the preparation method further includes the step of removing the protecting group under acidic conditions after the condensation reaction;
  • R 10 is halogen (preferably a chlorine atom) or OH; when R 10 is OH, the reaction occurs in the presence of a condensing agent or oxalyl chloride, preferably in the presence of a condensing agent;
  • R a , R b , R c , R d , R X1 , R X2 , R X3 , R', R 1A , R 2A , R A4 , u1 and u2 are as defined in the general formula (V-1).
  • the present disclosure provides a method for a compound represented by general formula (V-1) or (V-2) or a pharmaceutically acceptable salt thereof.
  • the method includes: R X1 is an alkoxy group or a cycloalkoxy group of the general formula (V).
  • R X1 is an alkoxy group or a cycloalkoxy group of the general formula (V)
  • the compound represented by -1) or (V-2) or a pharmaceutically acceptable salt thereof undergoes a dealkylation or decycloalkyl reaction under acidic conditions to obtain the general formula (V-1) or ((V-1) or () in which R X1 is -OH.
  • the compound represented by V-2) or a pharmaceutically acceptable salt thereof is a pharmaceutically acceptable salt thereof.
  • the present disclosure provides a method for a compound represented by general formula (V-1) or (V-2) or a pharmaceutically acceptable salt thereof, which method includes:
  • R W1 is an amino protecting group, and the amino protecting group is preferably Boc;
  • R a , R b , R c , R d , R X1 , R X2 , R X3 , R', R 1A , R 2A , R A4 , u1 and u2 are as defined in the general formula (V-1).
  • the present disclosure provides a method for a compound represented by general formula (VI') or a pharmaceutically acceptable salt thereof, which method includes:
  • R 10 is halogen (preferably a chlorine atom) or OH; when R 10 is OH, the reaction occurs in the presence of a condensing agent or oxalyl chloride, preferably in the presence of a condensing agent;
  • R', R a , R b , R c , R d , R X1 , R X2 , R X3 , R 1A , R 2A , Q, R 3 , R 4 and R 5 are as defined in the general formula (VI') .
  • the present disclosure provides a method for a compound represented by general formula (VI') or a pharmaceutically acceptable salt thereof, which method includes:
  • the compound represented by the general formula (VI'A) or a salt thereof reacts with the compound represented by the general formula (IB') or a salt thereof (preferably the hydrochloride) to obtain a compound represented by the general formula (VI') or Its medicinal salts, of which,
  • R 5 is a hydrogen atom
  • R', R a , R b , R c , R d , R X1 , R X2 , R X3 , R 1A , R 2A , Q, R 3 and R 4 are as defined in general formula (VI').
  • the present disclosure provides a method for a compound represented by general formula (VI') or a pharmaceutically acceptable salt thereof, which method includes: a compound represented by general formula (VI') in which R X1 is an alkoxy group or a cycloalkoxy group, or The pharmaceutically acceptable salt thereof undergoes a dealkylation or decycloalkyl reaction under acidic conditions to obtain a compound represented by the general formula (VI') in which R X1 is -OH or a pharmaceutically acceptable salt thereof.
  • the present disclosure provides a method for a compound represented by general formula (VI') or a pharmaceutically acceptable salt thereof, which method includes:
  • the compound represented by the general formula (VI'A) or a salt thereof reacts with NH 2 -R 5 or a salt thereof (preferably the hydrochloride) to obtain a compound represented by the general formula (VI') or a pharmaceutically acceptable compound thereof salt, among them,
  • R 3 and R 4 are both hydrogen atoms
  • R', R a , R b , R c , R d , R X1 , R X2 , R X3 , R 1A , R 2A , Q and R 5 are as defined in the general formula (VI').
  • the present disclosure provides a method for a compound represented by general formula (VI'-1) or a pharmaceutically acceptable salt thereof, which method includes:
  • R 10 is halogen (preferably a chlorine atom) or OH; when R 10 is OH, the reaction occurs in the presence of a condensing agent or oxalyl chloride, preferably in the presence of a condensing agent;
  • R', R a , R b , R c , R d , R X1 , R X2 , R X3 , R 1A , R 2A , Q, R 3 , R 5 and R C are as in the general formula (VI'-1) defined.
  • the present disclosure provides a method for a compound represented by general formula (VI'-1) or a pharmaceutically acceptable salt thereof, which method includes:
  • the compound represented by the general formula (VI'A) or a salt thereof reacts with the compound represented by the general formula (VI-1B') or a salt thereof (preferably a hydrochloride) to obtain the compound represented by the general formula (VI'-1)
  • the compound or pharmaceutically acceptable salt thereof wherein,
  • R 5 is a hydrogen atom
  • the present disclosure provides a method for a compound represented by general formula (VI'-1) or a pharmaceutically acceptable salt thereof, which method includes:
  • R 4 is a hydrogen atom
  • R 10 is halogen (preferably chlorine) or OH; when R 10 is OH, the reaction occurs in the presence of a condensing agent or oxalyl chloride, preferably in the presence of a condensing agent;
  • R', R a , R b , R c , R d , R X1 , R X2 , R X3 , R 1A , R 2A , Q, R 3 , R 5 and R C are as in the general formula (VI'-1) defined.
  • the present disclosure provides a method for the compound represented by the general formula (VI'-1) or a pharmaceutically acceptable salt thereof.
  • the method includes: R The compound shown or a pharmaceutically acceptable salt thereof undergoes a dealkylation or decycloalkyl reaction under acidic conditions to obtain a compound represented by the general formula (VI'-1) in which R X1 is -OH or a pharmaceutically acceptable salt thereof .
  • the present disclosure provides a method for the compound represented by general formula (VI) or a pharmaceutically acceptable salt thereof, which method includes:
  • R 5 is a hydrogen atom
  • R 1A , R 2A , R', R a , R b , R c , R d , R X1 , R X2 , R X3 , R 3a and R 4 are as defined in general formula (VI).
  • the present disclosure provides a method for the compound represented by general formula (VI) or a pharmaceutically acceptable salt thereof, which method includes:
  • R 10 is halogen (preferably a chlorine atom) or OH; when R 10 is OH, the reaction occurs in the presence of a condensing agent or oxalyl chloride, preferably in the presence of a condensing agent;
  • R', R a , R b , R c , R d , R X1 , R X2 , R X3 , R 1A , R 2A , R 3a , R 4 and R 5 are as defined in general formula (VI).
  • the present disclosure provides a method for a compound represented by general formula (VI) or a pharmaceutically acceptable salt thereof.
  • the method includes: a compound represented by general formula (VI) in which R The pharmaceutically acceptable salt undergoes a dealkylation or decycloalkyl reaction under acidic conditions to obtain a compound represented by the general formula (VI) in which R X1 is -OH or a pharmaceutically acceptable salt thereof.
  • the present disclosure provides a method for the compound represented by general formula (VI) or a pharmaceutically acceptable salt thereof, which method includes:
  • R 3a and R 4 are both hydrogen atoms
  • R 1A , R 2A , R′, R a , R b , R c , R d , R X1 , R X2 , R X3 and R 5 are as defined in general formula (VI).
  • the present disclosure provides a method for a compound represented by general formula (VII') or a pharmaceutically acceptable salt thereof, which method includes:
  • R 10 is halogen (preferably a chlorine atom) or OH; when R 10 is OH, the reaction occurs in the presence of a condensing agent or oxalyl chloride, preferably in the presence of a condensing agent;
  • R', Ra, Rb , Rc , Rd , RX1 , RX2 , RX3 , R1A , R2A , R3 , R4 and R5 are as defined in the general formula (VII').
  • the present disclosure provides a method for a compound represented by general formula (VII') or a pharmaceutically acceptable salt thereof, which method includes:
  • R* is selected from hydroxyl, alkoxy and halogen
  • the method further includes the step of removing the protecting group;
  • the amino protecting group is preferably Boc;
  • R', R a , R b , R c , R d , R X1 , R X2 , R X3 , R 1A , R 2A , Q, R 3 , R 4 and R 5 are as defined in the general formula (VII') .
  • the present disclosure provides a method for a compound represented by general formula (VII') or a pharmaceutically acceptable salt thereof, which method includes: a compound represented by general formula (VII') in which R X1 is an alkoxy group or a cycloalkoxy group, or The pharmaceutically acceptable salt thereof undergoes a dealkylation or decycloalkyl reaction under acidic conditions to obtain a compound represented by the general formula (VII') in which R X1 is -OH or a pharmaceutically acceptable salt thereof.
  • the present disclosure provides a method for the compound represented by general formula (VII) or a pharmaceutically acceptable salt thereof, which method includes:
  • R* is selected from hydroxyl, alkoxy and halogen
  • the method further includes the step of removing the protecting group;
  • the amino protecting group is preferably Boc;
  • R 1A , R 2A , R', R a , R b , R c , R d , R X1 , R X2 , R X3 , R 3 , R 4 and R 5 are as defined in general formula (VII).
  • the present disclosure provides a method for the compound represented by general formula (VII) or a pharmaceutically acceptable salt thereof, which method includes:
  • R 10 is halogen (preferably a chlorine atom) or OH; when R 10 is OH, the reaction occurs in the presence of a condensing agent or oxalyl chloride, preferably in the presence of a condensing agent;
  • R', R a , R b , R c , R d , R X1 , R X2 , R X3 , R 1A , R 2A , R 3 , R 4 and R 5 are as defined in general formula (VII).
  • the present disclosure provides a method for a compound represented by general formula (VII) or a pharmaceutically acceptable salt thereof.
  • the method includes: a compound represented by general formula (VII) in which R The pharmaceutically acceptable salt undergoes a dealkylation or decycloalkyl reaction under acidic conditions to obtain a compound represented by the general formula (VII) in which R X1 is -OH or a pharmaceutically acceptable salt thereof.
  • the present disclosure provides a method for a compound represented by general formula (VIII) or a pharmaceutically acceptable salt thereof, which method includes:
  • R 10 is halogen (preferably a chlorine atom) or OH; when R 10 is OH, the reaction occurs in the presence of a condensing agent or oxalyl chloride, preferably in the presence of a condensing agent;
  • the present disclosure provides a method for a compound represented by general formula (VIII) or a pharmaceutically acceptable salt thereof, which method includes:
  • the compound represented by the general formula (VIIIA) or a salt thereof undergoes an urethane exchange reaction with the compound represented by the general formula (IB') or a salt thereof (preferably a hydrochloride) to obtain a compound represented by the general formula (VIII) or a salt thereof.
  • Medicinal salts of which,
  • R L is alkoxy
  • the present disclosure provides a method for a compound represented by general formula (VIII) or a pharmaceutically acceptable salt thereof.
  • the method includes: a compound represented by general formula (VIII) in which R The pharmaceutically acceptable salt undergoes a dealkylation or decycloalkyl reaction under acidic conditions to obtain a compound represented by the general formula (VIII) in which R X1 is -OH or a pharmaceutically acceptable salt thereof.
  • the above-mentioned pinner reaction is based on the pinner amidine synthesis method.
  • the specific mechanism is: the raw material cyano compound undergoes an alcoholysis reaction with an alcohol solvent under the catalysis of a catalyst to form an imide ester, and then reacts with an amine or ammonia to form an amidine.
  • the catalyst described in the above pinner reaction can be an acid catalyst or an alkali catalyst.
  • the acid catalyst is an organic acid or an inorganic acid, including but not limited to hydrochloric acid, hydrogen chloride gas, thioglycolic acid, N-acetyl cysteine, etc., preferably thioglycolic acid; alkali
  • the catalyst is an organic base or an inorganic base, including but not limited to sodium methoxide, sodium ethoxide, sodium triethoxide, Ethylamine, N,N-diisopropylethylamine, N,N-diisopropylethylenediamine, etc., preferably N,N-diisopropylethylamine or sodium methoxide, and more preferably sodium methoxide.
  • ammonia used in the above-mentioned aminolysis reaction is liquid ammonia, ammonia water or ammonium salt, etc., preferably ammonium chloride; the amine used in the aminolysis reaction is an organic amine.
  • the above-mentioned alcohol solvents include but are not limited to methanol, ethanol, isopropyl alcohol, n-butanol, etc.
  • the reagents that provide acidic conditions in the above synthesis scheme include organic acids and inorganic acids.
  • the organic acids include but are not limited to trifluoroacetic acid, formic acid, acetic acid, methanesulfonic acid, p-toluenesulfonic acid, Me 3 SiCl and TMSOTf;
  • the inorganic acids include but are not limited to hydrogen chloride, HCl ⁇ dioxane solution, hydrochloric acid dioxane solution, hydrochloric acid, sulfuric acid, nitric acid and phosphoric acid; preferably HCl ⁇ dioxane solution or hydrochloric acid dioxane solution; the above
  • the reagent that provides acidic conditions in the dealkylation or decycloalkyl reaction in the synthesis scheme is preferably a Lewis acid, such as BBr 3 , ALCl 3 , etc., preferably BBr 3 .
  • 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, and N,N-diisopropylamine.
  • 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, hydrogen Lithium oxide, cesium fluoride and potassium hydroxide; preferably triethylamine or N,N-diisopropylethylamine; when R 10 is halogen, the reagent providing alkaline conditions is preferably triethylamine, when R 10 is When OH is used, the reagent that provides alkaline conditions is preferably N,N-diisopropyle

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Abstract

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

Description

杂环类化合物、其制备方法及其在医药上的应用 技术领域
本公开属于医药领域，涉及一种杂环类化合物、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。
背景技术
疼痛是一种复杂的生理心理活动，是临床上最常见的症状之一。国际疼痛研究协会将疼痛定义为“一种令人不快的感觉和情绪上的感受，伴有实质上的或潜在的组织损伤，它是一种主观感受。”疼痛可以作为一种警戒信号，提醒机体注意潜在的危险，对机体正常的生命活动具有不可或缺的保护作用。同时，疼痛也是一种常见的临床症状，在引发疼痛的外界刺激消失后，强烈或持久的疼痛会造成生理功能的紊乱，严重影响生命体的生活质量。统计数据显示，全世界约五分之一的人患有中度至重度慢性疼痛。
疼痛起源于周围神经系统的伤害感受器。这是一种游离的神经末梢，广泛分布于全身的皮肤、肌肉、关节和内脏组织中，它可以将感受到的热的、机械的或化学的刺激转化为神经冲动(动作电位)并经由传入神经纤维传递到其位于背根神经节(dorsal root ganglia，DRG)的胞体部分，最终传递到高级神经中枢，引起痛觉。而神经元中动作电位的产生和传导又依赖于细胞膜上的电压门控钠通道(voltage-gated sodium channels，Nav)。当细胞膜去极化时，钠离子通道激活，通道打开，引起钠离子内流，使细胞膜进一步去极化，导致动作电位的产生。因此，抑制异常的钠离子通道活动有助于疼痛的治疗、缓解。
Nav是一类跨膜离子通道蛋白。这些蛋白由分子量260kD的α亚基和分子量为30-40kD的β亚基组成。根据α亚基的不同可以分为9种亚型，Navl.l～Nav1.9。不同亚型表现出不同的组织分布和电生理、药理学特征。根据能否被纳摩尔河豚毒素(tetrodotoxin，TTX)有效抑制，钠离子通道被分为TTX敏感型(TTX-S)和TTX不敏感型(TTX-R)。其中，Nav1.1、Nav1.2、Nav1.3和Nav1.7为TTX-S型，编码基因位于人类染色体2q23-24，它们在神经元中大量表达。Nav1.5、Nav1.8和Nav1.9为TTX-R型，编码基因位于人类染色体3p21-24。其中，Nav1.5主要存在于心肌细胞中，Nav 1.8、Nav l.9存在于外周神经系统。Nav1.4和Nav1.6都为TTX-S型，分别在骨骼肌和中枢神经系统中大量存在。局部麻醉药利多卡因通过抑制Nav来止痛。而非选择性的Nav抑制剂，例如拉莫三嗪，拉科酰胺，美西律已经成功地用于治疗慢性疼痛。
Nav1.8为TTX-R型，编码基因为SCN10A，主要存在于三叉神经节神经元和DRG神经元中，具有慢速失活、迅速恢复的电生理特征。在表达Nav 1.8的神经元内，动作电位的上升主要由Nav1.8电流构成。在研究神经性疼痛的一些模型中，神经损伤会使Nav1.8在轴突和神经元胞体中的表达水平上升。使用Nav1.8反义寡核苷酸在降低Nav1.8表达的同时可以明显地缓解疼痛。大鼠爪内注射角叉菜胶(carrageenan)后，DRG神经元中Nav1.8的表达有所上升。Nav1.8敲除小鼠不能表现出正常的内脏炎症痛。人类的Nav1.8基因产生功能增益突变后，会导致外周神经痛。根据一系列动物实验以及人类基因证据，选择性抑制Nav1.8具有成为新型镇痛疗法的潜力，可以用于炎性疼痛，神经疼痛，手术后疼痛，癌痛等多种疼痛类型的治疗。
临床中使用的Nav抑制剂由于缺乏亚型选择性，能够抑制表达在心脏和中枢神经系统中的钠离子通道，因此治疗窗口较窄，应用范围受到限制。Nav1.8主要分布在外周神经系统，所以选择性地抑制Nav1.8可以有效地减少副作用。因此，有必要开发活性更高，选择性更好，药代动力学性质更佳，副作用更少的Nav1.8抑制剂。
已公开的Nav1.8抑制剂化合物的专利申请包括WO2021113627A1、WO2022256622A1、WO2022256676A1、WO2022256679A1、WO2022256842A1和WO2022256702A1。
发明内容
本公开的目的在于提供一种通式(I)所示的化合物或其可药用的盐：
其中：
环A为苯基或6元杂芳基；
各个RA相同或不同，且各自独立地选自氘原子、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、烷氧基烷基、烯基、炔基、-NR3R4、-亚烷基-NR3R4、-O-亚烷基-NR3R4、-C(＝NR5)R6、-S(O)vNR3R4、-NR5S(O)vR6、-S(O)vR6、-S(＝NR5)(O)R6、-NR5C(O)R6、-NR5C(O)NR3R4、-C(O)NR5-OR6、-P(O)R7R8、-C(O)NR5-NR3R4、-C(＝NR5)NR5-OR6、-C(O)NR5-亚烷基-Cy、-C(＝NR5)NR3R4、-C(O)-C(O)-NR3R4、-S(＝NR5)NR3R4、-S(＝NR5)R6、-S(＝NR5)(O)NR3R4、-Si(O)NR3R4、-Si(R6)3、-OR6、环烷基、杂环基、芳基、杂芳基、环烷基烷基、杂环基烷基、-C(O)- 环烷基、-C(O)-杂环基、-亚烷基-O-亚烷基-环烷基、-亚烷基-O-环烷基、-O-亚烷基-杂芳基和-O-亚烷基-杂环基，其中，所述的烷基、烷氧基、烷氧基烷基、烯基、炔基、亚烷基、环烷基、杂环基、芳基、杂芳基、环烷基烷基和杂环基烷基各自独立地任选被1个或多个R01所取代；
Cy为环烷基或杂环基，所述的环烷基和杂环基各自独立地任选被选自氘原子、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、芳基和杂芳基中的一个或多个取代基所取代；
各个R3、R4和R5相同或不同，且各自独立地选自氢原子、烷基、氘代烷基、烷氧基、氘代烷氧基、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、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1个或多个R01所取代；
或R3、R4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；
各个R6、R7和R8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、氘代烷基、卤代烷氧基、氘代烷氧基、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、环烷基烷基、杂环基烷基、芳基和杂芳基；所述的烷基、烷氧基、烯基、炔基、环烷基、杂环基、环烷基烷基、杂环基烷基、芳基和杂芳基各自独立地任选被选自一个或多个R01所取代；
各个R01相同或不同，且各自独立地选自氘原子、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、杂芳基、＝CR7aR8a、-NR3R4、-亚烷基-NR3R4、-O-亚烷基-NR3R4、-C(＝NR5)R6、-S(O)vNR3R4、-NR5S(O)vR6、-S(O)vR6、-S(＝NR5)(O)R6、-NR5C(O)R6、-NR5C(O)NR3R4、-C(O)NR5-OR6、-P(O)R7R8、-C(O)NR5-NR3R4、-C(＝NR5)NR5-OR6、-C(O)NR5-亚烷基-Cy、-C(＝NR5)NR3R4、-C(O)-C(O)-NR3R4、-S(＝NR5)NR3R4、-S(＝NR5)R6、-S(＝NR5)(O)NR3R4、-Si(O)NR3R4、-OR6、-Si(R6a)3、-O-亚烷基-杂芳基和-O-亚烷基-杂环基；所述的烷基、烯基、炔基、烷氧基、亚烷基、环烷基、杂环基、芳基和杂芳基各自独立地任选被选自氘原子、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、芳基和杂芳基中的一个或多个取代基所取代；
各个R6a、R7a和R8a相同或不同，且各自独立地选自氢原子、氘原子、卤素、羟基、氰基、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；
R’选自氢原子、烷基、卤代烷基、氘代烷基、烷氧基、氘代烷氧基、羟烷基、环烷基和杂环基；
X为O或S；
Ra和Rb相同或不同，且各自独立地选自氢原子、氘原子、卤素、羟基、氰基、氨基、烷基、氘代烷基、烯基、炔基、烷氧基、氘代烷氧基、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；所述的烷基、烷氧基、烯基、炔基、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；
条件是，Ra和Rb不同时为氢；
Rc和Rd相同或不同，且各自独立地选自氢原子、氘原子、卤素、羟基、氰基、氨基、烷基、烯基、炔基、烷氧基、卤代烷基、氘代烷基、卤代烷氧基、氘代烷氧基、羟烷基、环烷基、杂环基、环烷基氧基和杂环基氧基；所述的烷基、烷氧基、烯基、炔基、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；
或，Ra、Rb与其相连的碳原子一起形成环烷基或杂环基；或，Rc、Rd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；
Re选自氢原子、氘原子、卤素、羟基、氰基、氨基、烷基、烷氧基、卤代烷基、卤代烷氧基、氘代烷基、氘代烷氧基和羟烷基；
各个R02相同或不同，且各自独立地选自氘原子、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；
各个R20、R21和R22相同或不同，且各自独立地选自氢原子、烷基、氘代烷基、烷氧基、氘代烷氧基、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氘原子、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中的一个或多个所取代；
各个R23相同或不同，且各自独立地选自氢原子、烷基、氘代烷基、烷氧基、氘代烷氧基、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氘原子、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中的一个或多个所取代；
X1为CRX1或N；
X2为CRX2或N；
X3为CRX3或N；
X4为CRX4或N；
X5为CRX5或N；
X1、X2、X3、X4和X5不同时为N；
RX1、RX2、RX3、RX4和RX5相同或不同，且各自独立地选自氢原子、氘原子、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、氘代烷基、卤代烷氧基、氘代烷氧基、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，且各自独立地选自氘原子、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；
各个v相同或不同，且各自独立地选自0、1和2；
n选自0、1、2、3、4和5；
s选自0、1、2、3、4和5；且，
r选自0、1、2、3、4和5；
条件是，不为
本公开的目的在于提供一种通式(I)所示的化合物或其可药用的盐：
其中：
环A为苯基或6元杂芳基；
各个RA相同或不同，且各自独立地选自氘原子、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、烷氧基烷基、烯基、炔基、-NR3R4、-亚烷基-NR3R4、-O-亚烷基-NR3R4、-C(＝NR5)R6、-S(O)vNR3R4、-NR5S(O)vR6、-S(O)vR6、-S(＝NR5)(O)R6、-NR5C(O)R6、-NR5C(O)NR3R4、-C(O)NR5-OR6、-P(O)R7R8、-C(O)NR5-NR3R4、-C(＝NR5)NR5-OR6、-C(O)NR5-亚烷基-Cy、-C(＝NR5)NR3R4、-C(O)-C(O)-NR3R4、-S(＝NR5)NR3R4、-S(＝NR5)R6、-S(＝NR5)(O)NR3R4、-Si(O)NR3R4、-Si(R6)3、-OR6、环烷基、杂环基、芳基、杂芳基、环烷基烷基、杂环基烷基、-C(O)-环烷基、-C(O)-杂环基、-亚烷基-O-亚烷基-环烷基、-亚烷基-O-环烷基、-O-亚烷基-杂芳基和-O-亚烷基-杂环基，其中，所述的烷基、烷氧基、烷氧基烷基、烯基、炔基、亚烷基、环烷基、杂环基、芳基、杂芳基、环烷基烷基和杂环基烷基各自独立地任选被1个或多个R01所取代；
Cy为环烷基或杂环基，所述的环烷基和杂环基各自独立地任选被选自氘原子、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、芳基和杂芳基中的一个或多个取代基所取代；
各个R3、R4和R5相同或不同，且各自独立地选自氢原子、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；其中，所述的烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基各自独立地任选被1个或多个R01所取代；
或R3、R4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；
各个R6、R7和R8相同或不同，且各自独立地选自氢原子、烷基、烷氧基、卤代烷基、卤代烷氧基、羟烷基、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、环烷基烷基、杂环基烷基、芳基和杂芳基；所述的烷基、烷氧基、烯基、炔基、环烷基、杂环基、环烷基烷基、杂环基烷基、芳基和杂芳基各自独立地任选被选自一个或多个R01所取代；
各个R01相同或不同，且各自独立地选自氘原子、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、杂芳基、＝CR7aR8a、-NR3R4、-亚烷基-NR3R4、-O-亚烷基-NR3R4、-C(＝NR5)R6、-S(O)vNR3R4、-NR5S(O)vR6、-S(O)vR6、-S(＝NR5)(O)R6、-NR5C(O)R6、-NR5C(O)NR3R4、-C(O)NR5-OR6、-P(O)R7R8、-C(O)NR5-NR3R4、-C(＝NR5)NR5-OR6、-C(O)NR5-亚烷基-Cy、-C(＝NR5)NR3R4、-C(O)-C(O)-NR3R4、-S(＝NR5)NR3R4、-S(＝NR5)R6、-S(＝NR5)(O)NR3R4、-Si(O)NR3R4、-OR6、-Si(R6a)3、-O-亚烷基-杂芳基和-O-亚烷基-杂环基；所述的烷基、烯基、炔基、烷氧基、亚烷基、环烷基、杂环基、芳基和杂芳基各自独立地任选被一个或多个选自氘原子、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、芳基和杂芳基的取代基所取代；
各个R6a、R7a和R8a相同或不同，且各自独立地选自氢原子、氘原子、卤素、羟基、氰基、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；
R’选自氢原子、烷基、卤代烷基、羟烷基、环烷基和杂环基；
X为O或S；
Ra和Rb相同或不同，且各自独立地选自氢原子、氘原子、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；
条件是，Ra和Rb不同时为氢；
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；
或，Ra、Rb与其相连的碳原子一起形成环烷基或杂环基；或，Rc、Rd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；
Re选自氢原子、氘原子、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；
各个R02相同或不同，且各自独立地选自氘原子、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；
各个R20、R21和R22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；
各个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；
X1为CRX1或N；
X2为CRX2或N；
X3为CRX3或N；
X4为CRX4或N；
X5为CRX5或N；
X1、X2、X3、X4和X5不同时为N；
RX1、RX2、RX3、RX4和RX5相同或不同，且各自独立地选自氢原子、氘原子、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；
各个R03相同或不同，且各自独立地选自氘原子、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；
各个v相同或不同，且各自独立地选自0、1和2；
n选自0、1、2、3、4和5；
s选自0、1、2、3、4和5；且，
r选自0、1、2、3、4和5；
条件是，不为
本公开的目的在于提供一种通式(I)所示的化合物或其可药用的盐：
其中：
环A为苯基或6元杂芳基；
各个RA相同或不同，且各自独立地选自氘原子、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、炔基、-NR3R4、-亚烷基-NR3R4、-O-亚烷基-NR3R4、-C(＝NR5)R6、-S(O)vNR3R4、-NR5S(O)vR6、-S(O)vR6、-S(＝NR5)(O)R6、-NR5C(O)R6、-NR5C(O)NR3R4、-C(O)NR5-OR6、-P(O)R7R8、-C(O)NR5-NR3R4、-C(＝NR5)NR5-OR6、-C(O)NR5-亚烷基-Cy、-C(＝NR5)NR3R4、-C(O)-C(O)-NR3R4、-S(＝NR5)NR3R4、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、炔基、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；
Cy为环烷基或3至4元杂环基，所述的环烷基或3至4元杂环基各自独立地任选被选自氘原子、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、芳基和杂芳基中的一个或多个取代基所取代；
各个R3、R4和R5相同或不同，且各自独立地选自氢原子、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、NR22S(O)vR23、OR23、环烷基、杂环基、芳基和杂芳基；其中，所述的烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基各自独立地任选被1个或多个R01所取代；
或R3、R4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；
各个R6、R7和R8相同或不同，且各自独立地选自氢原子、烷基、烷氧基、卤 代烷基、卤代烷氧基、羟烷基、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、NR22S(O)vR23、OR23、环烷基、杂环基、环烷基烷基、杂环基烷基、芳基和杂芳基；所述的烷基、烷氧基、烯基、炔基、环烷基、杂环基、环烷基烷基、杂环基烷基、芳基和杂芳基各自独立地任选被选自氘原子、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、芳基和杂芳基中的一个或多个取代基所取代；
各个R01相同或不同，且各自独立地选自氘原子、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；
R’选自氢原子、烷基、卤代烷基、羟烷基、环烷基和杂环基；
X为O或S；
Ra和Rb相同或不同，且各自独立地选自氢原子、氘原子、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；
条件是，Ra和Rb不同时为氢；
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；
或，Ra、Rb与其相连的碳原子一起形成环烷基或杂环基；或，Rc、Rd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；
Re选自氢原子、氘原子、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；
各个R02相同或不同，且各自独立地选自氘原子、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；
各个R20、R21和R22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；
各个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；
X1为CRX1或N；
X2为CRX2或N；
X3为CRX3或N；
X4为CRX4或N；
X5为CRX5或N；
X1、X2、X3、X4和X5不同时为N；
RX1、RX2、RX3、RX4和RX5相同或不同，且各自独立地选自氢原子、氘原子、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；
各个R03相同或不同，且各自独立地选自氘原子、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；
各个v相同或不同，且各自独立地选自0、1和2；
n选自0、1、2、3、4和5；
s选自0、1、2、3、4和5；且，
r选自0、1、2、3、4和5；
条件是，不为
本公开的目的在于提供一种通式(I)所示的化合物或其可药用的盐：
其中：
环A为苯基或6元杂芳基；
各个RA相同或不同，且各自独立地选自卤素、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、-S(O)vNR3R4、-NR5S(O)vR6、-S(O)vR6、-S(＝NR5)(O)R6、-NR5C(O)R6、-NR5C(O)NR3R4、-C(O)NR5-OR6、-P(O)R7R8、-C(O)NR5-NR3R4、-C(＝NR5)NR5-OR6、-C(O)NR5-亚烷基-Cy、-C(＝NR5)NR3R4、-C(O)-C(O)-NR3R4、 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；
Cy为环烷基或3至4元杂环基，所述的环烷基或3至4元杂环基各自独立地任选被选自卤素、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、芳基和杂芳基中的一个或多个取代基所取代；
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；
或R3、R4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；
R6、R7和R8相同或不同，且各自独立地选自氢原子、烷基、烷氧基、卤代烷基、卤代烷氧基、羟烷基、环烷基、杂环基、环烷基烷基、杂环基烷基、芳基和杂芳基；所述的烷基、烷氧基、环烷基、杂环基、环烷基烷基、杂环基烷基、芳基和杂芳基各自独立地任选被选自卤素、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、芳基和杂芳基中的一个或多个取代基所取代；
R01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；
R’选自氢原子、烷基、卤代烷基、羟烷基、环烷基和杂环基；
X为O或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；
条件是，Ra和Rb不同时为氢；
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；
或，Ra、Rb与其相连的碳原子一起形成环烷基或杂环基；或，Rc、Rd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；
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；
R02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；
X1为CRX1或N；
X2为CRX2或N；
X3为CRX3或N；
X4为CRX4或N；
X5为CRX5或N；
X1、X2、X3、X4和X5不同时为N；
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；
R03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；
v选自0、1和2；
n选自0、1、2、3、4和5；
s选自0、1、2、3、4和5；且，
r选自0、1、2、3、4和5；
条件是，不为
本公开的目的在于提供一种通式(I)所示的化合物或其可药用的盐：
其中：
环A为苯基或6元杂芳基；
各个RA相同或不同，且各自独立地选自卤素、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、-S(O)vNR3R4、-NR5S(O)vR6、-S(O)vR6、-S(＝NR5)(O)R6、-NR5C(O)R6、-NR5C(O)NR3R4、-C(O)NR5-OR6、-P(O)R7R8、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；
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；
或R3、R4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；
R6、R7和R8相同或不同，且各自独立地选自氢原子、烷基、烷氧基、卤代烷基、卤代烷氧基、羟烷基、环烷基、杂环基、芳基和杂芳基；
R01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；
R’选自氢原子、烷基、卤代烷基、羟烷基、环烷基和杂环基；
X为O或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；
条件是，Ra和Rb不同时为氢；
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；
或，Ra、Rb与其相连的碳原子一起形成环烷基或杂环基；或，Rc、Rd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；
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；
R02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；
X1为CRX1或N；
X2为CRX2或N；
X3为CRX3或N；
X4为CRX4或N；
X5为CRX5或N；
X1、X2、X3、X4和X5不同时为N；
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；
R03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；
v选自0、1和2；
n选自0、1、2、3、4和5；
s选自0、1、2、3、4和5；且，
r选自0、1、2、3、4和5；
条件是，不为
本公开的目的在于提供一种通式(I)所示的化合物或其可药用的盐：
其中：
环A为苯基或6元杂芳基；
各个RA相同或不同，且各自独立地选自卤素、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、-S(O)vNR3R4、-NR5S(O)vR6、-S(O)vR6、-S(＝NR5)(O)R6、-P(O)R7R8、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；
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；
或R3、R4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；
R6、R7和R8相同或不同，且各自独立地选自氢原子、烷基、烷氧基、卤代烷基、卤代烷氧基、羟烷基、环烷基、杂环基、芳基和杂芳基；
R01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；R’选自氢原子、烷基、卤代烷基、羟烷基、环烷基和杂环基；
X为O或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；
条件是，Ra和Rb不同时为氢；
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；
或，Ra、Rb与其相连的碳原子一起形成环烷基或杂环基；或，Rc、Rd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；
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；
R02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；
X1为CRX1或N；
X2为CRX2或N；
X3为CRX3或N；
X4为CRX4或N；
X5为CRX5或N；
X1、X2、X3、X4和X5不同时为N；
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；
R03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；
v选自0、1和2；
n选自0、1、2、3、4和5；
s选自0、1、2、3、4和5；且，
r选自0、1、2、3、4和5；
条件是，不为
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。
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各自独立地选自卤素、羟基、氰基、氧代基、氨基、C1-6烷基、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、6至10元芳基和5至14元杂芳基；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。
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；进一步优选地，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。
在本公开一些实施方案中，所述的通式(I)所示的化合物或其可药用的盐，其中为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；
在一些实施方案中，所述的通式(I)所示的化合物或其可药用的盐，其中为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。
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：
其中：
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；
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；
环A、RA、R’、X、RX1、RX2、RX3、R02和r如通式(I)中所定义。
在本公开一些实施方案中，所述的通式(I)或通式(II)所示的化合物或其可药用的盐，其为通式(II’)所示的化合物或其可药用的盐：
其中，R3a选自氢原子、烷基、卤代烷基、羟烷基、OR6、环烷基和杂环基；所述的烷基、环烷基和杂环基各自独立地任选被选自卤素、羟基、氰基、氧代基、氨基、烷基、烯基、炔基、烷氧基、卤代烷基、卤代烷氧基、羟烷基、环烷基和杂环基中的一个或多个取代基所取代；
r-1为0、1、2、3或4；
环A、RA、R’、X、Ra、Rb、Rc、Rd、RX1、RX2、RX3、R4、R5和R6如通式(II)中所定义。
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：
其中，r-1为0、1、2、3或4；
环A、RA、R’、X、Ra、Rb、Rc、Rd、RX1、RX2、RX3、R3、R4和R5如通式(II)中所定义。
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：
其中，t选自0、1、2、3和4；
环A、R’、Ra、Rb、Rc、Rd、X、RX1、RX2和RX3如通式(II)中所定义。
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，其为通式(III-1)所示的化合物或其可药用的盐：
其中，t选自0、1、2、3和4；
环A、R’、Ra、Rb、Rc、Rd、X、RX1、RX2和RX3如通式(II)中所定义。
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，其为通式(IV)所示的化合物或其可药用的盐：
其中，R1A与R2A相同或不同，且各自独立地为氢原子或RA；
R3A为RA；
Ra、Rb、Rc、Rd、RX1、RX2、RX3、R’和RA如通式(II)中所定义。
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，其为通式(IV)所示的化合物或其可药用的盐：
其中，R1A与R2A相同或不同，且各自独立地为氢原子或RA；
R3A选自F、Cl、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、炔基、-NR3R4、-亚烷基-NR3R4、-O-亚烷基-NR3R4、-C(＝NR5)R6、-S(O)vNR3R4、-NR5S(O)vR6、-S(O)vR6、-S(＝NR5)(O)R6、-NR5C(O)R6、-NR5C(O)NR3R4、-C(O)NR5-OR6、-P(O)R7R8、-C(O)NR5-NR3R4、-C(＝NR5)NR5-OR6、-C(O)NR5-亚烷基-Cy、-C(＝NR5)NR3R4、-C(O)-C(O)-NR3R4、-S(＝NR5)NR3R4、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、炔基、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；
Ra、Rb、Rc、Rd、RX1、RX2、RX3、R’、RA、R3、R4、R5、R6、R7、R8、R01和v如通式(II)中所定义。
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，其为通式(IV)所示的化合物或其可药用的盐：
其中，R1A与R2A相同或不同，且各自独立地选自氢原子、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、-S(O)vNR3R4、-NR5S(O)vR6、-S(O)vR6、-S(＝NR5)(O)R6、-NR5C(O)R6、-NR5C(O)NR3R4、-P(O)R7R8、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；
R3A选自卤素、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、-S(O)vNR3R4、-NR5S(O)vR6、-S(O)vR6、-S(＝NR5)(O)R6、-NR5C(O)R6、-NR5C(O)NR3R4、-C(O)NR5-OR6、-P(O)R7R8、-C(O)NR5-NR3R4、-C(＝NR5)NR5-OR6、-C(O)NR5-亚烷基-Cy、-C(＝NR5)NR3R4、-C(O)-C(O)-NR3R4、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；
Ra、Rb、Rc、Rd、RX1、RX2、RX3、R’、R3、R4、R5、R6、R7、R8、R01和v如通式(I)中所定义；优选地，Ra、Rb、Rc、Rd如通式(II)中所定义。
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，其为通式(IV)所示的化合物或其可药用的盐：
其中，R1A与R2A相同或不同，且各自独立地选自氢原子、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、-S(O)vNR3R4、-NR5S(O)vR6、-S(O)vR6、-S(＝NR5)(O)R6、-NR5C(O)R6、-NR5C(O)NR3R4、-P(O)R7R8、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；
R3A选自卤素、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、-S(O)vNR3R4、-NR5S(O)vR6、-S(O)vR6、-S(＝NR5)(O)R6、-NR5C(O)R6、-NR5C(O)NR3R4、-C(O)NR5-OR6、-P(O)R7R8、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；
Ra、Rb、Rc、Rd、RX1、RX2、RX3、R’、R3、R4、R5、R6、R7、R8、R01和v 如通式(I)中所定义；优选地，Ra、Rb、Rc、Rd如通式(II)中所定义。
在本公开一些实施方案中，所述的通式(IV)所示的化合物或其可药用的盐，其中R3A选自羟基、氨基、C1-6烷基、C1-6烷氧基、C1-6羟烷基、C1-6羟烷氧基、-C1-6亚烷基-NH2、-O-C1-6亚烷基-NH2、-NR5C(O)NR3R4、-C(O)NR5-OR6、3至8元环烷基、3至8元杂环基、苯基、5或6元杂芳基和-O-C1-6亚烷基-5或6元杂芳基，所述C1-6亚烷基、3至8元环烷基、3至8元杂环基、苯基和5或6元杂芳基各自独立地任选被1个或多个R01所取代；R01各自独立地选自卤素、羟基、氰基、氧代基、氨基、-NH C1-6烷基、-N(C1-6烷基)2、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、6至10元芳基和5至14元杂芳基，R3、R4、R5和R6如通式(I)中所定义；
在一些实施方案中，R3A选自氨基、C1-6羟烷基、C1-6羟烷氧基、-C1-6亚烷基-NH2、-NR5C(O)NR3R4、-C(O)NR5-OR6、3至8元环烷基和5或6元杂芳基，所述C1-6亚烷基、3至8元环烷基和5或6元杂芳基各自独立地任选被1个或多个R01所取代，R01各自独立地选自卤素、羟基、氰基、氧代基、氨基、-NH C1-6烷基、-N(C1-6烷基)2、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、6至10元芳基和5至14元杂芳基，R3、R4、R5和R6如通式(I)中所定义；
在一些实施方案中，R3A选自氨基、C1-6羟烷基、C1-6羟烷氧基、-C1-6亚烷基-NH2、-NR5C(O)NR3R4、-C(O)NR5-OR6、3至6元环烷基和5或6元杂芳基，所述C1-6亚烷基、3至6元环烷基和5或6元杂芳基各自独立地任选被1个或多个R01所取代，R01各自独立地选自羟基、氰基、氨基、C1-6烷基和C1-6羟烷基，R3、R4、R5和R6相同或不同，且各自独立地为氢原子或C1-6烷基；在一些实施方案中，R3A选自氨基、C1-6羟烷基、 NR5C(O)NR3R4、 其中，G1为氮原子或CRG，G2为氮原子或CRG，RA4选自氢原子、羟基、C1-6烷基和C1-6羟烷基，R3、R4、R5和R6相同或不同，且各自独立地为氢原子或C1-6烷基，R01选自羟基、氰基、氨基和C1-6羟烷基，各个RG和RN相同或不同，且各自独立地为氢原子或C1-6烷基，t选自0、1、2和3，u1选自0、1和2，u2选自0、1、2和3，u3选自1、2和3；
在一些实施方案中，R3A选自氨基、 在一些实施方案中，R3A选自
在实施方案中，R3A选自氨基、
在本公开一些实施方案中，所述的通式(IV)所示的化合物或其可药用的盐，其中R3A选自C1-6羟烷基、C1-6羟烷氧基、-NR3R4、-C1-6亚烷基-NR3R4、-NR5C(O)R6、-NR5C(O)NR3R4、-C(O)NR5-OR6、3至10元环烷基、3至10元杂环基和5或6元杂芳基，所述C1-6亚烷基、3至10元环烷基、3至10元杂环基和5或6元杂芳基各自独立地任选被1个或多个R01所取代，R01各自独立地选自羟基、氰基、C1-6烷基和C1-6羟烷基，R3和R4相同或不同，且各自独立地为氢原子或C1-6烷基；R5和R6相同或不同，且各自独立地为氢原子或C1-6烷基；
在一些实施方案中，R3A选自C1-6羟烷基、C1-6羟烷氧基、-C1-6亚烷基-NH2、-C(O)NR5-OR6、3至6元环烷基和5或6元杂芳基，所述C1-6亚烷基、3至6元环烷基和5或6元杂芳基各自独立地任选被1个或多个R01所取代，R01各自独立地选自羟基、氰基、C1-6烷基和C1-6羟烷基，R5和R6相同或不同，且各自独立地为氢原子或C1-6烷基；在一些实施方案中，R3A为-C1-6亚烷基-NH2或-C(O)NR5-OR6，所述C1-6亚烷基任选被1个或多个R01所取代，R01各自独立地选自羟基和C1-6羟烷基，R5和R6相同或不同，且各自独立地为氢原子或C1-6烷基。
在本公开一些实施方案中，所述的通式(I)、(II)或(IV)所示的化合物或其可药用的盐，其为通式(V)所示的化合物或其可药用的盐：
其中，
R1A与R2A相同或不同，且各自独立地选自氢原子、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、-S(O)vNR3R4、-NR5S(O)vR6、-S(O)vR6、-S(＝NR5)(O)R6、-P(O)R7R8、-NR5C(O)R6、-NR5C(O)NR3R4、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；
RA4选自氢原子、羟基、烷基和羟烷基；u1选自0、1、2和3，u2选自0、1、2和3；
Ra、Rb、Rc、Rd、RX1、RX2、RX3、R’、R3、R4、R5、R6、R7、R8、R01和v如通式(I)中所定义；优选地，Ra、Rb、Rc、Rd如通式(II)中所定义。
在本公开一些实施方案中，所述的通式(I)、(II)、(IV)或(V)所示的化合物或其可药用的盐，其为通式(V-1)或(V-2)所示的化合物或其可药用的盐：
其中，Ra、Rb、Rc、Rd、RX1、RX2、RX3、R’、R1A、R2A、RA4、u1和u2如通式(V)中所定义。
在本公开一些实施方案中，所述的通式(V)、(V-1)或(V-2)所示的化合物或其可药用的盐，其中，RA4选自氢原子、C1-6烷基和C1-6羟烷基；优选为氢原子。
在本公开一些实施方案中，所述的通式(V)、(V-1)或(V-2)所示的化合物或其可药用的盐，其中，u1选自0、1和2，且u2选自0、1和2；优选地，u1为0或1，且u2为0或1；更优选地，u1为0，且u2为1。
在本公开一些实施方案中，所述的通式(V)、(V-1)或(V-2)所示的化合物或其可药用的盐，其中，RA4为氢原子，u1选自0、1和2，且u2选自0、1和2。
在本公开一些实施方案中，所述的通式(I)、(II)所示的化合物或其可药用的盐，其为通式(VI’)所示的化合物或其可药用的盐：
其中，Q选自CR5A、N和N+-O-；
R5A为R1A；
R1A、R2A、R’、Ra、Rb、Rc、Rd、RX1、RX2、RX3、R3、R4和R5如通式(IV)中所定义。
在本公开一些实施方案中，所述的通式(I)、(II)、(VI’)所示的化合物或其可药用的盐，其为通式(VI’-1)所示的化合物或其可药用的盐：
其中，
Q选自CR5A、N和N+-O-；
R5A为R1A；
RC为R23或OR23；
R1A、R2A、R’、Ra、Rb、Rc、Rd、RX1、RX2、RX3、R3、R5和R23如通式(IV)中所定义。
在本公开一些实施方案中，所述的通式(VI’-1)所示的化合物或其可药用的盐，其中RC选自C1-8烷基、C1-8烷氧基和3至10元环烷基氧基；在一些实施方案中，RC为C1-8烷氧基；在一些实施方案中，RC为异丙氧基或正己基氧基。
在本公开一些实施方案中，所述的通式(I)、(II)、(II’)、(IV)、(VI’)所示的化合物或其可药用的盐，其为通式(VI)所示的化合物或其可药用的盐：
其中，R3a选自氢原子、烷基、卤代烷基、羟烷基、OR6、环烷基和杂环基；所述的烷基、环烷基和杂环基各自独立地任选被选自卤素、羟基、氰基、氧代基、氨基、烷基、烯基、炔基、烷氧基、卤代烷基、卤代烷氧基、羟烷基、环烷基和杂环基中的一个或多个取代基所取代；
R1A、R2A、R’、Ra、Rb、Rc、Rd、RX1、RX2、RX3、R4、R5和R6如通式(IV)中所定义。
在本公开一些实施方案中，所述的通式(II’)或(VI)所示的化合物或其可药用的盐，其中R3a选自氢原子、C1-6烷基、卤代C1-6烷基、C1-6羟烷基、OR6、3至6元环烷基和3至6元环烷基C1-6烷基，R6选自氢原子、C1-6烷基、3至6元环烷基和3至6元环烷基C1-6烷基；
在一些实施方案中，R3a选自氢原子、C1-6烷基、C1-6烷氧基和3至6元环烷基；在一些实施方案中，R3a选自氢原子、C1-6烷基和C1-6烷氧基；在一些实施方案中，R3a选自氢原子、C1-6烷基和3至6元环烷基；在一些实施方案中，R3a为氢原子或C1-6烷基；
在一些实施方案中，R3a选自氢原子、甲基、乙基、甲氧基和环丙基；在一些实施方案中，R3a选自氢原子、甲基、乙基和环丙基；在一些实施方案中，R3a为氢原子；在一些实施方案中，R3a选自氢原子、甲基、乙基、羟基、甲氧基、氘代甲氧基、环丙基、
在本公开一些实施方案中，所述的通式(I)、(II)、(II-1)所示的化合物或其可药用的盐，其为通式(VII’)所示的化合物或其可药用的盐：
其中，Q选自CR5A、N和N+-O-；
R5A为R1A；
R1A、R2A、R’、Ra、Rb、Rc、Rd、RX1、RX2、RX3、R3、R4和R5如通式(IV)中所定义。
在本公开一些实施方案中，所述的通式(I)、(II)、(II-1)、(IV)或(VII’)所示的化合物或其可药用的盐，其为通式(VII)所示的化合物或其可药用的盐：
其中，R1A、R2A、R’、Ra、Rb、Rc、Rd、RX1、RX2、RX3、R3、R4和R5如通式(IV)中所定义。
在本公开一些实施方案中，所述的通式(I)、(II)所示的化合物或其可药用的盐，其为通式(VIII)所示的化合物或其可药用的盐：
其中，Q选自CR5A、N和N+-O-；
R5A为R1A；
R1A、R2A、R’、X、Ra、Rb、Rc、Rd、RX1、RX2、RX3、R3和R4如通式(IV)中所定义。
在本公开一些实施方案中，所述的通式(VI’)、(VI’-1)、(VII’)、(VIII)所示的化合物或其可药用的盐，其中Q为N或CR5A，R5A为R1A，R1A如通式(IV)中所定义；在一些实施方案中，Q为N；在一些实施方案中，Q为CR5A，R5A为R1A，R1A如通式(IV)中所定义；在一些实施方案中，Q为N或CF。
在本公开一些实施方案中，所述的通式(VI’)、(VI’-1)、(VII’)、(VIII)所示的化合物或其可药用的盐，其中R5A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6元环烷基和3至6元杂环基；在一些实施方案中，R5A选自氢原子、卤素、C1-6烷基和卤代C1-6烷基；在一些实施方案中，R5A为卤素；在一些实施方案中，R5A为F。
在本公开一些实施方案中，所述的通式(IV)、(V)、(V-1)、(V-2)、(VI)、(VII)、(VI’)、(VI’-1)、(VII’)、(VIII)所示的化合物或其可药用的盐，其中R1A和R2A相同或不同，且各自独立地选自氢原子、卤素、羟基、氨基、C1-6烷基、C1-6烷氧基、卤代C1-6烷基、卤代C1-6烷氧基、C1-6羟烷基和C1-6羟烷氧基；优选地，R1A和R2A相同或不同，且各自独立地选自氢原子、卤素、C1-6烷基和C1-6羟烷基；更优选地，R1A和R2A均为氢原子。
在本公开一些实施方案中，所述的通式(I)、(II)、(II’)、(II-1)、(III)、(III-1)、(IV)、(V)、(V-1)、(V-2)、(VI)、(VII)、(VI’)、(VI’-1)、(VII’)、(VIII)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；在一些实施方案中，Ra选自氢原子、卤素、C1-6烷基和卤代C1-6烷基；在一些实施方案中，Ra为C1-6烷基或卤代C1-6烷基；在一些实施方案中，Ra为CH3或CF3；
在一些实施方案中，Ra为C1-6烷基；在一些实施方案中，Ra选自CH3、氘代甲基和CF3；在一些实施方案中，Ra为CH3或氘代甲基；在一些实施方案中，Ra为CH3。
在本公开一些实施方案中，所述的通式(I)、(II)、(II’)、(II-1)、(III)、(III-1)、(IV)、(V)、(V-1)、(V-2)、(VI)、(VII)、(VI’)、(VI’-1)、(VII’)、(VIII)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；在一些实施方案中，Rb选自氢原子、卤素、C1-6烷基和卤代C1-6烷基；在一些实施方案中，Rb为C1-6烷基或卤代C1-6烷基；在一些实施方案中，Rb选自CH3、氘代甲基和CF3；在一些实施方案中，Rb为CH3或CF3；在一些实施方案中，Rb为卤代C1-6烷基；在一些实施方案中，Rb为CF3。
在本公开一些实施方案中，所述的通式(I)、(II)、(II’)、(II-1)、(III)、(III-1)、(IV)、(V)、(V-1)、(V-2)、(VI)、(VII)、(VI’)、(VI’-1)、(VII’)、(VIII)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；更优选地，Rc为氢原子或C1-6烷基；最优选地，Rc为氢原子或CH3；在一些实施方案中，Rc选自氢原子、CH3、氘代甲基和CF3。
在本公开一些实施方案中，所述的通式(I)、(II)、(II’)、(II-1)、(III)、(III-1)、(IV)、(V)、(V-1)、(V-2)、(VI)、(VII)、(VI’)、(VI’-1)、(VII’)、(VIII)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选自氢原子、CH3、氘代甲基和CF3；在一些实施方案中，Rd选自氢原子、CH3和CD3。
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；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烷基或卤代C1-6烷基；在一些实施方案中，Ra为C1-6烷基，且Rb为卤代C1-6烷基；在一些实施方案中，Ra为CH3，且Rb为CF3；
在一些实施方案中，Ra和Rb相同或不同，且各自独立地选自氢原子、CH3、氘代甲基和CF3；在一些实施方案中，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。
在本公开一些实施方案中，所述的通式(II)、(II’)、(II-1)、(III)、(III-1)、(IV)、(V)、(V-1)、(V-2)、(VI)、(VII)、(VII)、(VI’)、(VI’-1)、(VII’)、(VIII)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；
在一些实施方案中，Ra和Rb不同，且各自独立地选自氢原子、CH3、氘代甲基和CF3；在一些实施方案中，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。
在本公开一些实施方案中，所述的通式(I)、(II)、(II’)、(II-1)、(III)、(III-1)、(IV)、(V)、(V-1)、(V-2)、(VI)、(VII)、(VI’)、(VI’-1)、(VII’)、(VIII)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为卤代C1-6烷基，且Rb为C1-6烷基；在一些实施方案中，Ra为CF3，且Rb为CH3；
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。
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；在一些实施方案中，Rc和Rd相同或不同，且各自独立地为氢原子或C1-6烷基；在一些实施方案中，Rc为氢原子，且Rd为C1-6烷基；在一些实施方案中，Rc为氢原子，且Rd为CH3；
在一些实施方案中，Rc和Rd相同或不同，且各自独立地选自氢原子、CH3和氘代甲基；在一些实施方案中，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。
在本公开一些实施方案中，所述的通式(II)、(II’)、(II-1)、(III)、(III-1)、(IV)、(V)、(V-1)、(V-2)、(VI)、(VII)、(VI’)、(VI’-1)、(VII’)、(VIII)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；在一些实施方案中，Rc和Rd不同，且各自独立地为氢原子或C1-6烷基；在一些实施方案中，Rc为氢原子，且Rd为C1-6烷基；在一些实施方案中，Rc为氢原子，且Rd为CH3；
在一些实施方案中，Rc和Rd不同，且各自独立地选自氢原子、CH3和氘代甲基；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。
在本公开一些实施方案中，所述的通式(I)、(II)、(II’)、(II-1)、(III)、(III-1)、(IV)、(V)、(V-1)、(V-2)、(VI)、(VII)、(VI’)、(VI’-1)、(VII’)、(VIII)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；在一些实施方案中，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)。
在本公开一些实施方案中，所述的通式(I)、(II)、(II’)、(II-1)、(III)、(III-1)、(IV)、(V)、(V-1)、(V-2)、(VI)、(VII)、(VI’)、(VI’-1)、(VII’)、(VIII)所示的化合物或其可药用的盐，其中Ra为C1-6烷基，和/或Rb为卤代C1-6烷基，和/或Rc为氢原子，和/或Rd为C1-6烷基；在一些实施方案中，Ra为CH3，和/或Rb为CF3，和/或Rc为氢原子，和/或Rd为CH3。
在本公开一些实施方案中，所述的通式(I)、(II)、(II’)、(II-1)、(III)、(III-1)、(VIII)所示的化合物或其可药用的盐，其中X为O。
在本公开一些实施方案中，所述的通式(I)、(II)、(II’)、(II-1)、(III)、(III-1)、(IV)、(V)、(V-1)、(V-2)、(VI)、(VII)、(VI’)、(VI’-1)、(VII’)、(VIII)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。
在本公开一些实施方案中，所述的通式(I)、(II)、(II’)、(II-1)、(III)、(III-1)、(IV)、(V)、(V-1)、(V-2)、(VI)、(VII)、(VI’)、(VI’-1)、(VII’)、(VIII)所示的化合物或其可药用的盐，其中X为O，和/或R’为氢原子。
在本公开一些实施方案中，所述的通式(I)、(II)、(II’)、(II-1)、(III)或(III-1)所示的化合物或其可药用的盐，其中环A为6元杂芳基；优选地，环A选自吡啶基、嘧啶基、吡嗪基、哒嗪基和三嗪基；进一步优选地，环A为吡啶基或嘧啶基；更优选地，环A为最优选为其中*端与-NR’连接，端与RA连接；
在一些实施方案中，环A选自苯基、吡啶基和嘧啶基；在一些实施方式中，环A选自在一些实施方式中，环A选自 在一些实施方式中，环A选自在一些实施方式中，环A选自在一些实施方式中， 环A为在一些实施方式中，环A为其中*端与-NR’连接，端与RA连接；在一些实施方式中，环A选自*端与-NR’连接，端与一个RA连接。
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，选自 RA和r如通式(I)所定义；优选地，选自 RA和r如通式(I)所定义；进一步优选地，选自 RA如通式(I)所定义；更优选地，为RA如通式(I)所定义；最优选地，为RA如通式(I)所定义。
在本公开一些实施方案中，所述的通式(I)、(II)、(II’)、(II-1)、(IV)所示的化合物或其可药用的盐，其中RA选自C1-6羟烷基、C1-6羟烷氧基、-NR3R4、-C1-6亚烷基-NR3R4、-NR5C(O)R6、-NR5C(O)NR3R4、-C(O)NR5-OR6、3至10元环烷基、3至10元杂环基和5或6元杂芳基，所述C1-6亚烷基、3至10元环烷基、3至10元杂环基和5或6元杂芳基各自独立地任选被1个或多个R01所取代，R01各自独立地选自卤素、羟基、氰基、氧代基、氨基、-NH C1-6烷基、-N(C1-6烷基)2、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、6至10元芳基和5至14元杂芳基，R3、R4、R5和R6如通式(I)中所定义；在一些实施方案中，RA选自氨基、
在一些实施方案中，RA选自F、Cl、氨基、氰基、
在一些实施方案中，RA选自F、Cl、氨基、氰基、
在一些实施方案中，RA选自F、Cl、氨基、
在一些实施方案中，RA选自氨基、
在一些实施方案中，RA选自氨基、
在一些实施方案中，RA选自
在一些实施方案中，RA选自
在一些实施方案中，RA选自 在一些实施方案中，RA选自
在一些实施方案中，RA选自
在一些实施方案中，RA选自
在一些实施方案中，RA选自 在一些实施方案中，RA选自 在一些实施方案中，RA为在一些实施方案中，RA为在一些实施方案中，RA为在一些实施方案中，RA为 在一些实施方案中，RA为
在一些实施方案中，RA选自 在一些实施方案中，RA为在一些实施方案中，RA为 在一些实施方案中，RA为在一些实施方案中，RA为
在一些实施方案中，RA选自-C(O)NR5-OR6、-C(O)NR5-NR3R4、-C(＝NR5)NR5-OR6、-C(O)NR5-亚烷基-Cy、-C(＝NR5)NR3R4和-C(O)-C(O)-NR3R4， 所述亚烷基任选被1个或多个R01所取代，Cy、R3、R4、R5、R6和R01如通式(I)中所定义；在一些实施方案中，RA选自-C(O)NR5-NR3R4、-C(＝NR5)NR5-OR6、-C(O)NR5-亚烷基-Cy、-C(O)NR5-O-亚烷基-环烷基、-C(＝NR5)NR3R4和-C(O)-C(O)-NR3R4，所述亚烷基和环烷基任选被1个或多个R01所取代，Cy、R3、R4、R5、R6和R01如通式(I)中所定义；在一些实施方案中，RA为-C(O)NR5-NR3R4或-C(＝NR5)NR3-OR6，R3、R4、R5和R6如通式(I)中所定义；在一些实施方案中，RA为-C(O)NR5-NR3R4，R3、R4和R5如通式(I)中所定义；在一些实施方案中，RA为-C(＝NR5)NR3-OR6，R3、R5和R6如通式(I)中所定义；在一些实施方案中，RA为-C(＝NR5)NR3R4，R3、R4和R5如通式(I)中所定义；在一些实施方案中，RA为-C(＝NR5)NR3R4，R3、R4和R5相同或不同，且各自独立地选自氢原子、C1-6烷基和3至6元环烷基；
在一些实施方案中，RA为-C(O)-C(O)-NR3R4，R3和R4如通式(I)中所定义；在一些实施方案中，RA为-C(O)-C(O)-NR3R4，R3和R4相同或不同，且各自独立地为氢原子或C1-6烷基；
在一些实施方案中，RA为-C(O)NR5-NR3R4或-C(＝NR5)NR3-OR6，R3、R4、R5和R6相同或不同，且各自独立地为氢原子或C1-6烷基。
在本公开一些实施方案中，所述的通式(I)、(II)、(II’)或(II-1)所示的化合物或其可药用的盐，其中RA选自氨基、C1-6羟烷基、C1-6羟烷氧基、-C1-6亚烷基-NH2、-NR5C(O)NR3R4、-C(O)NR5-OR6、3至8元环烷基和5或6元杂芳基，所述C1-6亚烷基、3至8元环烷基和5或6元杂芳基各自独立地任选被1个或多个R01所取代，R01各自独立地选自卤素、羟基、氰基、氧代基、氨基、-NH C1-6烷基、-N(C1-6烷基)2、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、6至10元芳基和5至14元杂芳基，R3、R4、R5和R6如通式(I)中所定义；
在一些实施方案中，RA选自氨基、C1-6羟烷基、C1-6羟烷氧基、-C1-6亚烷基-NH2、-NR5C(O)NR3R4、-C(O)NR5-OR6、3至6元环烷基和5或6元杂芳基，所述C1-6亚烷基、3至6元环烷基和5或6元杂芳基各自独立地任选被1个或多个R01所取代，R01各自独立地选自羟基、氰基、氨基、C1-6烷基和C1-6羟烷基，R3、R4、R5和R6相同或不同，且各自独立地为氢原子或C1-6烷基；
在一些实施方案中，RA选自氨基、C1-6羟烷基、 NR5C(O)NR3R4、其中，G1为氮原子或CRG，G2 为氮原子或CRG，RA4为氢原子、羟基、C1-6烷基和C1-6羟烷基，R3、R4、R5和R6相同或不同，且各自独立地为氢原子或C1-6烷基，R01各自独立地选自羟基、氰基、氨基和C1-6羟烷基，各个RG和RN相同或不同，且各自独立地为氢原子或C1-6烷基，t选自0、1、2和3，u1选自0、1、2和3，u2选自0、1、2和3，u3选自1、2和3；
在一些实施方案中，RA选自氨基、 在一些实施方案中，RA选自
在一些实施方案中，RA选自C1-6羟烷基、C1-6羟烷氧基、-C1-6亚烷基-NH2、-C(O)NR5-OR6、3至6元环烷基和5或6元杂芳基，所述C1-6亚烷基、3至6元环烷基和5或6元杂芳基任选被1个或多个R01所取代，R01各自独立地选自羟基、氰基、C1-6烷基和C1-6羟烷基，R5和R6相同或不同，且各自独立地为氢原子或C1-6烷基；在一些实施方案中，RA为-C1-6亚烷基-NH2或-C(O)NR5-OR6，所述C1-6亚烷基任选被1个或多个R01所取代，R01各自独立地选自羟基和C1-6羟烷基，R5和R6相同或不同，且各自独立地为氢原子或C1-6烷基；在一些实施方案中，RA选自
在一些实施方案中，RA为3至6元环烷基或5或6元杂芳基，所述3至6元环烷基和5或6元杂芳基各自独立地任选被1个或多个R01所取代，R01各自独立地选自羟基、氰基、氨基、C1-6烷基和C1-6羟烷基；在一些实施方案中，RA为3至6元环烷基或5元杂芳基，所述3至6元环烷基和5元杂芳基各自独立地任选被1个或多个R01所取代，R01各自独立地选自羟基、氰基、氨基、C1-6烷基和C1-6羟烷基；在一些实施方案中，RA选自G1为氮原子或CRG，G2为氮原子或CRG，R01选自羟基、氰基、氨基和C1-6羟烷基，各个RG和RN相同或不同，且各自独立地为氢原子或C1-6烷基；u3为1或2；
在一些实施方案中，各个RA相同或不同，且各自独立地选自氟原子、氯原子、羟基、氰基、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、C1-6羟烷氧基、-NR3R4、-C1-6亚烷基-NR3R4、-O-C1-6亚烷基-NR3R4、-C(＝NR5)R6、-S(O)vNR3R4、-NR5S(O)vR6、-S(＝NR5)(O)R6、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各自独立地选自卤素、羟基、氰基、氧代基、氨基、-NHC1-6烷基、-N(C1-6烷基)2、乙酰基、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、6至10元芳基和5至14元杂芳基；R3、R4、R5、R6和v如通式(I)所定义；
在一些实施方案中，RA相同或不同，且各自独立地选自羟基、氨基、-C1-6亚烷基-NH2、-O-C1-6亚烷基-NH2、C1-6烷氧基、C1-6羟烷基、C1-6羟烷氧基、3至8元环烷基、4至7元杂环基、苯基、5或6元杂芳基和-O-C1-6亚烷基-5或6元杂芳基，其中，所述的C1-6亚烷基、3至8元环烷基、4至7元杂环基、苯基和5或6元杂芳基各自独立地任选被1个或多个R01所取代；R01各自独立地选自卤素、羟基、氰基、氧代基、氨基、-NHC1-6烷基、-N(C1-6烷基)2、C1-6烷基、C2-6烯基、C2-6炔基、C1-6烷氧基、卤代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、6至10元芳基和5至14元杂芳基；
在一些实施方案中，RA相同或不同，且各自独立地选自氨基、C1-6羟烷基、C1-6羟烷氧基、苯基和5或6元杂芳基，所述苯基和5或6元杂芳基各自独立地任选被1个或多个R01所取代；R01各自独立地选自卤素、羟基、氰基、氧代基、氨基、-NHC1-6烷基、-N(C1-6烷基)2、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、6至10元芳基和5至14元杂芳基；在一些实施方案中，RA相同或不同，且各自独立地选自氨基、 在一些实施方案中，RA为
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，其中为各个RB相同或不同，且各自独立地选自卤素、羟基、氰基、氨基、烷基、烷氧基、卤代烷基、卤代烷氧基、环烷基和杂环基；所述的烷基、烷氧基、环烷基和杂环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、环烷基和杂环基中的一个或多个 所取代；p为0、1、2、3或4；环A和RA如通式(I)中所定义；
优选地，为RB选自卤素、羟基、C1-6烷基、C1-6烷氧基、卤代C1-6烷基和卤代C1-6烷氧基；p选自0、1和2，环A选自苯基、吡啶基、嘧啶基、吡嗪基、哒嗪基和RA如通式(I)所定义；更优选地，为RB选自卤素、羟基、C1-6烷基和卤代C1-6烷基；p为0或1，环A选自苯基、吡啶基和嘧啶基；RA选自氨基、C1-6羟烷基、C1-6羟烷氧基、苯基和5或6元杂芳基，所述苯基和5或6元杂芳基各自独立地任选被1个或多个R01所取代，R01如通式(I)所定义。
在本公开一些实施方案中，各个RB相同或不同，且各自独立地为卤素；在一些实施方案中，RB为F。
在本公开一些实施方案中，各个RB相同或不同，且各自独立地选自卤素、C1-6烷基和C1-6烷氧基；和/或p为0或1；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，和/或p为0或1。
在本公开一些实施方案中，p为0或1；在一些实施方式中，p为0；在一些实施方式中，p为1。
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R1A、R2A和R3A相同或不同，且各自独立地选自氢原子、氟原子、氯原子、羟基、氰基、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、C1-6羟烷氧基、-NR3R4、-C1-6亚烷基-NR3R4、-O-C1-6亚烷基-NR3R4、-C(＝NR5)R6、-S(O)vNR3R4、-NR5S(O)vR6、-S(O)vR6、-S(＝NR5)(O)R6、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、R4、R5、R6和v如通式(I)所定义。
在本公开一些实施方案中，所述的通式(I)、(II)、(II’)、(II-1)所示的化合物或其可药用的盐，其中RA选自卤素、羟基、C1-6烷基、C1-6烷氧基、卤代C1-6烷基和卤代C1-6烷氧基。
在本公开一些实施方案中，所述的通式(II’)或(II-1)所示的化合物或其可药用的盐，其中r-1为0、1或2；在一些实施方案中r-1为0；在一些实施方案中r-1为1。
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R1A和R2A相同或不同，且各自独立地选自氢原子、卤素、羟基、氨基、C1-6烷基、C1-6烷氧基、卤代C1-6烷基、卤代C1-6烷氧基、C1-6羟烷基和C1-6羟烷氧基；R3A选自卤素、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、-S(O)vNR3R4、-NR5S(O)vR6、-S(O)vR6、-S(＝NR5)(O)R6、-NR5C(O)R6、-NR5C(O)NR3R4、-C(O)NR5-OR6、-P(O)R7R8、-C(O)NR5-NR3R4、-C(＝NR5)NR5-OR6、-C(O)NR5-亚烷基-Cy、-C(＝NR5)NR3R4、-C(O)-C(O)-NR3R4、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；R01、R3、R4、R5、R6和v如通式(I)所定义；
在一些实施方案中，R1A和R2A相同或不同，且各自独立地选自氢原子、卤素、羟基、氨基、C1-6烷基、C1-6烷氧基、卤代C1-6烷基、卤代C1-6烷氧基、C1-6羟烷基和C1-6羟烷氧基；R3A选自羟基、氨基、C1-6烷基、C1-6烷氧基、C1-6羟烷基、C1-6羟烷氧基、-C1-6亚烷基-NH2、-O-C1-6亚烷基-NH2、苯基、5或6元杂芳基和-O-C1-6亚烷基-5或6元杂芳基，所述C1-6亚烷基、苯基和5或6元杂芳基各自独立地任选被1个或多个R01所取代；R01各自独立地选自卤素、羟基、氰基、氧代基、氨基、-NH C1-6烷基、-N(C1-6烷基)2、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、6至10元芳基和5至14元杂芳基；
优选地，R1A和R2A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；R3A选自羟基、氨基、C1-6烷氧基、C1-6羟烷基、C1-6羟烷氧基、-C1-6亚烷基-NH2、-O-C1-6亚烷基-NH2、苯基、5或6元杂芳基和-O-C1-6亚烷基-5或6元杂芳基，所述C1-6亚烷基、苯基和5或6元杂芳基各自独立地任选被1个或多个R01所取代；R01各自独立地选自卤素、羟基、氰基、氧代基、氨基、-NH C1-6烷基、-N(C1-6烷基)2、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、6至10元芳基和5至14元杂芳基。
在本公开一些实施方案中，所述的通式(I)、(II)或(IV)所示的化合物或其可药用的盐，其中R3A选自F、Cl、氨基、
在一些实施方案中，R3A选自氨基、
在一些实施方案中，R3A选自氨基、
在一些实施方案中，R3A选自
在一些实施方案中，R3A选自
在一些实施方案中，R3A选自
在一些实施方案中，R3A选自
在一些实施方案中，R3A选自
在一些实施方案中，R3A选自 在一些实施方案中，R3A为在一些实施方案中，R3A为在一些实施方案中，R3A为在一些实施方案中，R3A为
在一些实施方案中，R3A选自-C(O)NR5-OR6、-C(O)NR5-NR3R4、-C(＝NR5)NR5-OR6、-C(O)NR5-亚烷基-Cy、-C(＝NR5)NR3R4和-C(O)-C(O)-NR3R4，所述亚烷基任选被1个或多个R01所取代，Cy、R3、R4、R5、R6和R01如通式(I)中所定义；在一些实施方案中，R3A选自-C(O)NR5-NR3R4、-C(＝NR5)NR5-OR6、 -C(O)NR5-亚烷基-Cy、-C(O)NR5-O-亚烷基-环烷基、-C(＝NR5)NR3R4和-C(O)-C(O)-NR3R4，所述亚烷基任选被1个或多个R01所取代，Cy、R3、R4、R5、R6和R01如通式(I)中所定义；在一些实施方案中，R3A为-C(O)NR5-NR3R4或-C(＝NR5)NR3-OR6，R3、R4、R5和R6如通式(I)中所定义；在一些实施方案中，R3A为-C(O)NR5-NR3R4，R3、R4和R5如通式(I)中所定义；在一些实施方案中，R3A为-C(＝NR5)NR3-OR6，R3、R5和R6如通式(I)中所定义；
在一些实施方案中，R3A为-C(＝NR5)NR3R4，R3、R4和R5如通式(I)中所定义；在一些实施方案中，R3A为-C(＝NR5)NR3R4，R3、R4和R5相同或不同，且各自独立地选自氢原子、C1-6烷基和3至6元环烷基；
在一些实施方案中，R3A为-C(O)-C(O)-NR3R4，R3和R4如通式(I)中所定义；在一些实施方案中，R3A为-C(O)-C(O)-NR3R4，R3和R4相同或不同，且各自独立地为氢原子或C1-6烷基；
在一些实施方案中，R3A为-C(O)NR5-NR3R4或-C(＝NR5)NR3-OR6，R3、R4、R5和R6相同或不同，且各自独立地为氢原子或C1-6烷基。
在本公开一些实施方案中，所述的通式(I)、(II)、(II’)、(II-1)或(IV)所示的化合物或其可药用的盐，其中Cy为3至6元环烷基，所述的3至6元环烷基任选被选自卤素、C1-6烷基、卤代C1-6烷基、C1-6烷氧基、卤代C1-6烷氧基、羟基、氨基、氰基和3至6元环烷基中的一个或多个取代基所取代；在一些实施方案中，Cy为环丙基，其任选被选自卤素、C1-6烷基、卤代C1-6烷基、C1-6烷氧基、卤代C1-6烷氧基、羟基、氰基和3至6元环烷基中的一个或多个取代基所取代；在一些实施方案中，Cy为在一些实施方案中，Cy选自环丙基、环丁基和环戊基，所述的环丙基、环丁基和环戊基任选被选自卤素、C1-6烷基、卤代C1-6烷基、C1-6烷氧基、卤代C1-6烷氧基和羟基中的一个或多个取代基所取代。
在本公开一些实施方案中，所述的通式(I)、(II)、(II’)、(II-1)、(IV)、(V)、(V-1)、(V-2)、(VI)、(VII)、(VI’)、(VI’-1)、(VII’)、(VIII)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。
在本公开一些实施方案中，所述的通式(I)、(II)、(II’)、(II-1)、(IV)、(V)、(V-1)、(V-2)、(VI)、(VII)、(VI’)、(VI’-1)、(VII’)、(VIII)所示的化合物或其可药用的盐，其中R3选自氢原子、C1-6烷基、卤代C1-6烷基、C1-6羟烷基、3至6元环烷基和3至6元环烷基C1-6烷基；所述的C1-6烷基和3至6元环烷基各自独立地任选被选自卤素、羟基、氧代基、C1-6烷基和C1-6烷氧基中的一个或多个所取代；
在一些实施方案中，R3选自氢原子、C1-6烷基、卤代C1-6烷基、C1-6羟烷基、3至6元环烷基和3至6元环烷基C1-6烷基；在一些实施方案中，R3选自氢原子、 C1-6烷基和3至6元环烷基；在一些实施方案中，R3选自氢原子、甲基、乙基和环丙基；在一些实施方案中，R3为乙基或环丙基；
在一些实施方案中，R3为3至6元环烷基；在一些实施方案中，R3为氢原子或C1-6烷基；在一些实施方案中，R3选自氢原子、C1-6烷基、OR23、3至6元环烷基和C(O)OR23，R23如通式(I)中所定义；在一些实施方案中，R3选自氢原子、C1-6烷基、OR23、3至6元环烷基和C(O)OR23，R23为氢原子或C1-8烷基；
在一些实施方案中，R3选自氢原子、C1-6烷基、C1-6烷氧基、3至6元环烷基和C(O)OR23，R23如通式(I)中所定义；
在一些实施方案中，R3选自氢原子、C1-6烷基、C1-6烷氧基、3至6元环烷基和C(O)OR23，R23为氢原子或C1-8烷基；
在一些实施方案中，R3选自氢原子、甲基、乙基、羟基、甲氧基、环丙基、 在一些实施方案中，R3选自氢原子、甲基、乙基、甲氧基、环丙基、在一些实施方案中，R3选自氢原子、甲基、乙基、羟基、甲氧基、氘代甲氧基、环丙基、
在一些实施方案中，R3为氢原子；在一些实施方案中，R3为甲基；在一些实施方案中，R3为乙基；在一些实施方案中，R3为羟基；在一些实施方案中，R3为甲氧基；在一些实施方案中，R3为环丙基；在一些实施方案中，R3为C(O)OR23，R23为C1-8烷基。
在本公开一些实施方案中，所述的通式(I)、(II)、(II’)、(II-1)、(IV)、(V)、(V-1)、(V-2)、(VI)、(VII)、(VI’)、(VI’-1)、(VII’)、(VIII)所示的化合物或其可药用的盐，其中R4为氢原子或C1-6烷基，在一些实施方案中，R4为氢原子或甲基；在一些实施方案中，R4为氢原子；在一些实施方案中，R4为C1-6烷基；在一些实施方案中，R4为甲基或乙基。
在本公开一些实施方案中，所述的通式(I)、(II)、(II’)、(II-1)、(IV)、(V)、(V-1)、(V-2)、(VI)、(VII)、(VI’)、(VI’-1)、(VII’)、(VIII)所示的化合物或其可药用的盐，其中R3选自氢原子、C1-6烷基、OR23和C(O)OR23，R23如通式(I)中所定义；和/或R4为氢原子；在一些实施方案中，R3选自氢原子、羟基、C1-6烷基、C1-6烷氧基、氘代C1-6烷氧基、-O-3至6元环烷基和C(O)OR23，R23为C1-8烷基；和/或R4为氢原子；在一些实施方案中，R3选自氢原子、甲基、乙基、羟基、甲氧基、环丙基、 和/或R4为氢原子。
在本公开一些实施方案中，所述的通式(I)、(II)、(II’)、(II-1)、(IV)、(V)、(V-1)、(V-2)、(VI)、(VII)、(VI’)、(VI’-1)、(VII’)、(VIII)所示的化合物或其可药用的盐，其中R20和R21相同或不同，且各自独立地选自氢原子、C1-8烷基、卤代C1-8烷基和C1-8羟烷基；在一些实施方案中，R20和R21相同或不同，且各自独立地为氢原子或C1-8烷基；在一些实施方案中，R20为氢原子，R21为C1-8烷基；在一些实施方案中，R20为氢原子，R21为正己基。
在本公开一些实施方案中，所述的通式(I)、(II)、(II’)、(II-1)、(IV)、(V)、(V-1)、(V-2)、(VI)、(VII)、(VI’)、(VI’-1)、(VII’)、(VIII)所示的化合物或其可药用的盐，其中R23选自氢原子、C1-8烷基、氘代C1-6烷基、卤代C1-8烷基和C1-8羟烷基；在一些实施方案中，R23选自氢原子、C1-8烷基、卤代C1-8烷基和C1-8羟烷基；在一些实施方案中，R23选自氢原子、C1-8烷基和氘代C1-6烷基；在一些实施方案中，R23选自氢原子、甲基、氘代甲基、环丙基、异丙基和正己基；在一些实施方案中，R23为C1-8烷基；在一些实施方案中，R23为氢原子或甲基；在一些实施方案中，R23选自氢原子、甲基和氘代甲基；在一些实施方案中，R23为异丙基或正己基。
在本公开一些实施方案中，所述的通式(I)、(II)、(II’)、(II-1)、(IV)、(V)、(V-1)、(V-2)、(VI)、(VII)、(VI’)、(VI’-1)、(VII’)、(VIII)所示的化合物或其可药用的盐，其中R22为氢原子或C1-6烷基；在一些实施方案中，R22为氢原子。
在本公开一些实施方案中，所述的通式(I)、(II)、(II’)、(II-1)、(III)、(III-1)、(IV)、(V)、(V-1)、(V-2)、(VI)、(VII)、(VI’)、(VI’-1)、(VII’)、(VIII)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；在一些实施方案中，R5为氢原子；
在一些实施方案中，R5选自氢原子、C1-6烷基、OR23、3至6元环烷基和C(O)OR23，R23如通式(I)中所定义；
在一些实施方案中，R5选自氢原子、氘原子、C1-6烷基、氘代C1-6烷基、C1-6烷氧基、氘代C1-6烷氧基、3至6元环烷基、-O-3至6元环烷基和C(O)OR23，R23为氢原子或C1-8烷基；在一些实施方案中，R5选自氢原子、羟基、C1-6烷基、C1-6烷氧基、氘代C1-6烷氧基、-O-3至6元环烷基和C(O)OR23，R23为C1-8烷基；在一些实施方案中，R5选自氢原子、C1-6烷基、C1-6烷氧基、氘代C1-6烷氧基、-O-3至6元环烷基和C(O)OR23，R23为C1-8烷基；在一些实施方案中，R5为羟基或C1-6烷氧基；
在一些实施方案中，R5选自氢原子、氘原子、甲基、氘代甲基、羟基、甲氧基、氘代甲氧基、环丙基、-O-环丙基、在一些实施方案 中，R5选自氢原子、甲基、羟基、甲氧基、OCD3、在一些实施方案中，R5选自氢原子、甲基、羟基、甲氧基、氘代甲氧基、-O-环丙基、在一些实施方案中，R5为羟基或甲氧基；
在一些实施方案中，R5为甲基；在一些实施方案中，R5为氘代甲基；在一些实施方案中，R5为羟基；在一些实施方案中，R5为甲氧基；在一些实施方案中，R5为氘代甲氧基；在一些实施方案中，R5为OCD3；在一些实施方案中，R5为环丙基或-O-环丙基；在一些实施方案中，R5为在一些实施方案中，R5选自氢原子、甲基、羟基、甲氧基、氘代甲氧基和-O-环丙基；在一些实施方案中，R5选自氢原子、甲基、羟基和甲氧基。
在本公开一些实施方案中，所述的通式(I)、(II)、(II’)、(II-1)、(IV)、(VI)、(VII)、(VI’)、(VI’-1)、(VII’)所示的化合物或其可药用的盐，其中R3和R4均为氢原子，R5选自氢原子、氘原子、甲基、氘代甲基、羟基、甲氧基、氘代甲氧基、环丙基、-O-环丙基、或R5为氢原子，R4为氢原子，R3选自氢原子、甲基、乙基、羟基、甲氧基、氘代甲氧基、环丙基、在一些实施方案中，R3和R4均为氢原子，R5选自氢原子、氘原子、甲基、氘代甲基、羟基、甲氧基、氘代甲氧基、环丙基、-O-环丙基、
在本公开一些实施方案中，所述的通式(I)、(II)、(II’)、(IV)、(VI)所示的化合物或其可药用的盐，其中R3a和R4均为氢原子，R5选自氢原子、氘原子、甲基、氘代甲基、羟基、甲氧基、氘代甲氧基、环丙基、-O-环丙基、或R5为氢原子，R4为氢原子，R3a选自氢原子、甲基、乙基、羟基、甲氧基、氘代甲氧基、环丙基、在一些实施方案中，R3a和R4均为氢原子，R5选自氢原子、氘原子、甲基、氘代甲基、羟基、甲氧基、氘代甲氧基、环丙基、-O-环丙基、
在本公开一些实施方案中，所述的通式(I)、(II)、(II’)、(II-1)、(III)、(III-1)、(IV)、(V)、(V-1)、(V-2)、(VI)、(VII)、(VI’)、(VI’-1)、(VII’)、(VIII)所示的化合物或其可药用的盐，其中R6选自氢原子、C1-6烷基、卤代C1-6烷基和C1-6羟烷基；优选地，R6为氢原子或C1-6烷基；进一步优选地，R6为C1-6烷基；最优选地，R6为CH3；
在一些实施方案中，R6选自氢原子、C1-6烷基、卤代C1-6烷基、C1-6烷氧基、卤代C1-6烷氧基、C1-6羟烷基、3至6元环烷基和3至6元环烷基C1-6烷基；在一些实施方案中，R6选自C1-6烷基、3至6元环烷基和3至6元环烷基C1-6烷基；在一些实施方案中，R6为C1-6烷基或3至6元环烷基C1-6烷基；在一些实施方案中，R6为CH3或在一些实施方案中，R6为氢原子；
在一些实施方案中，R6选自氢原子、C1-6烷基、氘代C1-6烷基和3至6元环烷基；在一些实施方案中，R6选自氢原子、甲基、氘代甲基和环丙基；在一些实施方案中，R6选自氢原子、甲基和氘代甲基；在一些实施方案中，R6为氢原子或甲基。
在本公开一些实施方案中，所述的通式(I)、(II)、(II’)、(II-1)、(IV)、(V)、(V-1)、(V-2)、(VI)、(VII)、(VI’)、(VI’-1)、(VII’)、(VIII)所示的化合物或其可药用的盐，其中R7和R8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，R7和R8各自独立地为氢原子或C1-6烷基；进一步优选地，R7和R8各自独立地为C1-6烷基；最优选地，R7和R8均为CH3；在一些实施方案中，R7和R8相同或不同，且各自独立地为C1-6烷基或氨基；在一些实施方案中，R7和R8相同或不同，且各自独立地为甲基或氨基；在一些实施方案中，R7为甲基，R8为氨基。
在本公开一些实施方案中，所述的通式(I)、(II)、(II’)、(II-1)、(IV)、(V)、(V-1)、(V-2)、(VI)、(VII)、(VI’)、(VI’-1)、(VII’)、(VIII)所示的化合物或其可药用的盐，其中R01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、C1-6烷基、C1-6烷氧基、C1-6卤代烷基、C1-6卤代烷氧基、C1-6羟烷基、3至6元环烷基和3至6元杂环基；在一些实施方案中，R01各自独立地选自卤素、羟基、氰基、氧代基、C1-6烷基、C1-6烷氧基、C1-6卤代烷基和C1-6卤代烷氧基；在一些实施方案中，R01各自独立地选自卤素、羟基、氧代基、C1-6烷基和C1-6烷氧基；在一些实施方案中，R01为氘原子。
在本公开一些实施方案中，所述的通式(I)、(II)、(II’)、(II-1)、(III)、(III-1)、(IV)、(V)、(V-1)、(V-2)、(VI)、(VII)、(VI’)、(VI’-1)、(VII’)、(VIII)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，R03 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；
在一些实施方案中，RX1选自羟基、C1-6烷氧基和3至6元环烷基氧基；在一些实施方案中，RX1选自羟基、甲氧基和在一些实施方案中，RX1为羟基；在一些实施方案中，RX1为在一些实施方案中，RX1选自羟基、甲氧基、氘代甲氧基和在一些实施方案中，RX1选自羟基、甲氧基、OCD3和在一些实施方案中，RX1为氘代甲氧基；在一些实施方案中，RX1为OCD3。
在本公开一些实施方案中，所述的通式(I)、(II)、(II’)、(II-1)、(III)、(III-1)、(IV)、(V)、(V-1)、(V-2)、(VI)、(VII)、(VI’)、(VI’-1)、(VII’)、(VIII)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。
在本公开一些实施方案中，所述的通式(I)、(II)、(II’)、(II-1)、(III)、(III-1)、(IV)、(V)、(V-1)、(V-2)、(VI)、(VII)、(VI’)、(VI’-1)、(VII’)、(VIII)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。
在本公开一些实施方案中，所述的通式(I)、(II)、(II’)、(II-1)、(III)、(III-1)、(IV)、(V)、(V-1)、(V-2)、(VI)、(VII)、(VI’)、(VI’-1)、(VII’)、(VIII)所示的化合物或其可药用的盐，其中RX1、RX2和RX3相同或不同，且各自独立地选自氢原子、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元环烷基氧基和3至6元杂环基氧基；在一些实施方案中，RX1、RX2和RX3相同或不同，且各自独立地选自卤素、羟基、C1-6烷氧基和3至6元环烷基氧基；在一些实施方案中，RX1、RX2和RX3相同或不同，且各自独立地选自F、羟基、甲氧基和
在本公开一些实施方案中，所述的通式(I)、(II)、(II’)、(II-1)、(III)、(III-1)、(IV)、(V)、(V-1)、(V-2)、(VI)、(VII)、(VI’)、(VI’-1)、(VII’)、(VIII)所示的化合物或其可药用的盐，其中RX1选自羟基、C1-6烷氧基和3至6元环烷基氧基，和/或RX2为卤素，和/或RX3为卤素；在一些实施方案中，RX1选自羟基、甲氧基和和/或RX2为F，和/或RX3为F。
在本公开一些实施方案中，所述的通式(I)所示的化合物或其可药用的盐，其中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。
在本公开一些实施方案中，所述的通式(I)、(II)、(II’)、(II-1)、(III)、(III-1)、(IV)、(V)、(V-1)、(V-2)、(VI)、(VII)、(VI’)、(VI’-1)、(VII’)、(VIII)所示的化合物或其可药用的盐，其中R7a和R8a相同或不同，且各自独立地选自氢原子、C1-6烷基和卤素；在一些实施方案中，R7a和R8a相同或不同，且各自独立地为氢原子或F。
在本公开一些实施方案中，所述的通式(I)、(II)、(II’)、(II-1)、(III)、(III-1)、(IV)、(V)、(V-1)、(V-2)、(VI)、(VII)、(VI’)、(VI’-1)、(VII’)、(VIII)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。
在本公开一些实施方案中，所述的通式(I)、(II)、(II’)、(II-1)、(III)、(III-1)、(IV)、(V)、(V-1)、(V-2)、(VI)、(VII)、(VI’)、(VI’-1)、(VII’)、(VIII)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。
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r选自0、1和2；优选地，r为1；在一些实施方案中，r为2。
在本公开一些实施方案中，所述的通式(I)、(II)、(II’)、(II-1)、(IV)、(V)、(V-1)、(V-2)、(VI)、(VII)、(VI’)、(VI’-1)、(VII’)、(VIII)所示的化合物或其可药用的盐，v为1或2；优选地，v为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和Rb不同，且各自独立地为C1-6烷基或卤代C1-6烷基；Rc和Rd不同，且各自独立地为氢原子或C1-6烷基；X为O；R’为氢原子或C1-6烷基；环A为吡啶基或嘧啶基；RA选自氨基、 RX1为C1-6烷氧基；RX2为卤素；RX3为卤素；且r为1。
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，且Rd为C1-6烷基，R’为氢原子，X为O；为RA选自氨基、 RX1为C1-6烷氧基；RX2为卤素；RX3为卤素。
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，且Rd为C1-6烷基，R’为氢原子，X为O；环A为吡啶基或嘧啶基；r-1为0；R5为氢原子；R3a选自氢原子、C1-6烷基和C1-6烷氧基；R4为氢原子或甲基；RX1为C1-6烷氧基；RX2为卤素；RX3为卤素。
在本公开一些实施方案中，所述的通式(II-1)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，且Rd为C1-6烷基，R’为氢原子，X为O；环A为吡啶基或嘧啶基；r-1为0；R5为氢原子；R3选自氢原子、C1-6烷基和3至6元环烷基；R4为氢原子或甲基；RX1为C1-6烷氧基；RX2为卤素；RX3为卤素。
在本公开一些实施方案中，所述的通式(IV)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，且Rd为CH3，R’为氢原子，R1A和R2A均为氢原子；R3A选自 RX1为甲氧基；RX2为氟原子；RX3为氟原子。
在本公开一些实施方案中，所述的通式(IV)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，且Rd为C1-6烷基，R’为氢原子，R1A和R2A均为氢原子；R3A选自 RX1为C1-6烷氧基；RX2为卤素；RX3为卤素。
在本公开一些实施方案中，所述的通式(IV)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，且Rd为C1-6烷基，R’为氢原子，R1A和R2A均为氢原子；R3A为-C(O)NR5-NR3R4或-C(＝NR5)NR3-OR6，R3、R4、R5和R6相同或不同，且各自独立地为氢原子或C1-6烷基；RX1为C1-6烷氧基；RX2为卤素；RX3为卤素。
在本公开一些实施方案中，所述的通式(IV)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，且Rd为C1-6烷基，R’为氢原子，R1A和R2A均为氢原子；R3A为-C(＝NR5)NR3R4，R3、R4和R5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；RX1为C1-6烷氧基；RX2为卤素；RX3为卤素。
在本公开一些实施方案中，所述的通式(IV)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，且Rd为C1-6烷基，R’为氢原子，R1A和R2A均为氢原子；R3A选自 RX1为C1-6烷氧基；RX2为卤素；RX3为卤素。
在本公开一些实施方案中，所述的通式(VI)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，且Rd为C1-6烷基，R’为氢原子，R1A和R2A均为氢原子；R5为氢原子；R3a选自氢原子、C1-6烷基和C1-6烷氧基；R4为氢原子或甲基；RX1为C1-6烷氧基；RX2为卤素；RX3为卤素。
在本公开一些实施方案中，所述的通式(VII)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，且Rd为C1-6烷基，R’为氢原子，R1A和R2A均为氢原子；R5为氢原子；R3选自氢原子、C1-6烷基和3至6元环烷基；R4为氢原子或甲基；RX1为C1-6烷氧基；RX2为卤素；RX3为卤素。
在本公开一些实施方案中，所述的通式(VI’)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，且Rd为C1-6烷基，R’为氢原子，RX1为C1-6烷氧基；RX2为卤素；RX3为卤素；R1A和R2A均为氢原子；Q选自CR5A、N和N+-O-；R5A为卤素；R3选自氢原子、甲基、乙基、甲氧基、环丙基、R4为氢原子或甲基；R5为氢原子。
在本公开一些实施方案中，所述的通式(VIII)所示的化合物或其可药用的盐，其中，X为O；Ra为C1-6烷基，Rb为卤代C1-6烷基，Rc为氢原子，且Rd为C1-6烷基，R’为氢原子，RX1为C1-6烷氧基；RX2为卤素；RX3为卤素；R1A和R2A均为氢原子；Q选自CR5A、N和N+-O-；R5A为卤素；R3选自氢原子、甲基、乙基、甲氧基、环丙基、R4为氢原子或甲基。
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选自羟基、甲氧基和 RX2为F，RX3为F；X为O，R’为氢原子；为各个RB相同或不同，且各自独立地为卤素，p为0或1；环A选自 其中*端与-NR’连接，端与RA连接；
RA选自F、Cl、氨基、氰基、
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选自羟基、甲氧基、氘代甲氧基和RX2为F，RX3为F；X为O，R’为氢原子；为RB为F，p为0或1；环A为其中*端与-NR’连接，端与RA连接；RA选自
在本公开一些实施方案中，所述的通式(VI’)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选自羟基、甲氧基和RX2为F，RX3为F；R’为氢原子；R1A和R2A均为氢原子；Q选自CR5A、N和N+-O-；R5A为卤素；R3选自氢原子、甲基、乙基、羟基、甲氧基、环丙基、 R4为氢原子或甲基；R5为氢原子。
在本公开一些实施方案中，所述的通式(VI’)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选自羟基、甲氧基、氘代甲氧基和RX2为F，RX3为F；R’为氢原子；R1A和R2A均为氢原子；Q为N或CR5A；R5A为F；R3为氢原子，R4为氢原子；R5选自氢原子、氘原子、甲基、氘代甲基、羟基、甲氧基、氘代甲氧基、环丙基、-O-环丙基、
在本公开一些实施方案中，所述的通式(VI’)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选自羟基、甲氧基和RX2为F，RX3为F；R’为氢原子；R1A和R2A均为氢原子；Q选自CR5A、N和N+-O-；R5A为F；R3为氢原子，R4为氢原子；R5选自氢原子、甲基、羟基、甲氧基、氘代甲氧基、-O-环丙基、
在本公开一些实施方案中，所述的通式(IV)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选自羟基、甲氧基和RX2为F，RX3为F；R’为氢原子；R1A和R2A均为氢原子；R3A为
在本公开一些实施方案中，所述的通式(IV)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选自羟基、甲氧基和RX2为F，RX3为F；R’为氢原子；R1A和R2A均为氢原子；RA为
表A本公开的典型化合物包括但不限于：



















本公开的另一方面涉及通式(IIA’)所示的化合物或其盐，
其中，环A、RA、R’、X、Ra、Rb、Rc、Rd、RX1、RX2、RX3和r-1如通式(II’)中所定义。
本公开的另一方面涉及通式(IIa’)所示的化合物或其盐，
其中，R*选自羟基、烷氧基和卤素；
环A、RA、R’、X、Ra、Rb、Rc、Rd、RX1、RX2、RX3和r-1如通式(II’)中所定义。
本公开的另一方面涉及通式(IIIA)所示的化合物或其盐，
其中，t选自0、1、2、3和4；
R12和R13相同或不同，且各自独立地选自氢原子、烷基、环烷基和苯基；优选地，R12和R13相同或不同，且各自独立地选自氢原子、C1-6烷基和5或6元环烷基；最优选地，R12和R13均为CH3；
环A、R’、Ra、Rb、Rc、Rd、X、RX1、RX2和RX3如通式(III)中所定义。
本公开的另一方面涉及通式(IIIA-1)所示的化合物或其盐，
其中，t选自0、1、2、3和4；
R12和R13相同或不同，且各自独立地选自氢原子、烷基、环烷基和苯基；优选地，R12和R13相同或不同，且各自独立地选自氢原子、C1-6烷基和5或6元环烷基；最优选地，R12和R13均为CH3；
环A、R’、Ra、Rb、Rc、Rd、X、RX1、RX2和RX3如通式(III-1)中所定义。
本公开的另一方面涉及通式(IVA’)所示的化合物或其盐，
其中，R1A、R2A、R’、Ra、Rb、Rc、Rd、RX1、RX2和RX3如通式(IV)中所定义。
本公开的另一方面涉及通式(IVa’)所示的化合物或其盐，
其中，R*选自羟基、烷氧基和卤素；
R1A、R2A、R’、Ra、Rb、Rc、Rd、RX1、RX2和RX3如通式(IV)中所定义。
本公开的另一方面涉及通式(VI’A)所示的化合物或其盐，
其中，Q、R1A、R2A、R’、Ra、Rb、Rc、Rd、RX1、RX2和RX3如通式(VI’)中所 定义。
本公开的另一方面涉及通式(VII’A)所示的化合物或其盐，
其中，R*选自羟基、烷氧基和卤素；
Q、R1A、R2A、R’、Ra、Rb、Rc、Rd、RX1、RX2和RX3如通式(VII’)中所定义。
本公开的另一方面涉及通式(VIIIA)所示的化合物或其盐，
其中，RL选自卤素、羟基和烷氧基；
Q、R1A、R2A、R’、X、Ra、Rb、Rc、Rd、RX1、RX2和RX3如通式(VIII)中所定义。
表B本公开的典型中间体化合物包括但不限于：







本公开另一方面涉及一种制备上述通式(I)所示的化合物或其可药用的盐的方法，该方法包括：
通式(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，
R10为卤素(优选为氯原子)或OH；
环A、RA、R’、Ra、Rb、Rc、Rd、Re、X、X1、X2、X3、X4、X5和r如通式(I)中所定义。
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：
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(优选为盐酸盐)反应得到通式(I)所示的化合物或其可药用的盐，其中，
通式(I)中至少一个RA为-C(＝NH)NR5-OR6或-C(＝NH)NR3R4；
r为1、2、3、4或5；r-1为0、1、2、3或4；
余下的RA如通式(I)中所定义；环A、R’、Ra、Rb、Rc、Rd、Re、X、X1、X2、X3、X4、X5、R3、R4、R5和R6如通式(I)中所定义。
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：
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，
R10为卤素(优选为氯原子)或OH；
环A、RA、R’、Ra、Rb、Rc、Rd、X、RX1、RX2、RX3和r如通式(II)中所定义。
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：
通式(IIA’)所示的化合物或其盐与NH2-R5或其盐(优选为盐酸盐)反应得到通式(II)所示的化合物或其可药用的盐，其中，
通式(II)中至少一个RA为-C(＝NR5)NR3R4；
r为1、2、3、4或5；r-1为0、1、2、3或4；
R3和R4均为氢原子；余下的RA如通式(II)中所定义；
环A、R’、Ra、Rb、Rc、Rd、X、RX1、RX2、RX3和R5如通式(II)中所定义。
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：
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(优选为盐酸盐)反应得到通式(II)所示的化合物或其可药用的盐，其中，
通式(II)中至少一个RA为-C(＝NH)NR5-OR6或-C(＝NH)NR3R4；
r为1、2、3、4或5；r-1为0、1、2、3或4；
余下的RA如通式(II)中所定义；
环A、R’、Ra、Rb、Rc、Rd、X、RX1、RX2、RX3、R3、R4、R5和R6如通式(II)中所定义。
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：
通式(IIa’)所示的化合物或其盐与胺或其盐(优选为盐酸盐)发生酰胺化反应得到通式(II)所示的化合物或其可药用的盐，其中，
上述的胺选自HNR5-OR6、HNR5-NR3R4和HNR5-亚烷基-Cy；
R*选自羟基、烷氧基和卤素；
通式(II)中至少一个RA选自-C(O)NR5-OR6、-C(O)NR5-NR3R4和-C(O)NR5-亚烷基-Cy；余下的RA如通式(II)中所定义；
r为1、2、3、4或5；r-1为0、1、2、3或4；
当氨基含保护基时，所述方法还包括脱去保护基的步骤；氨基保护基优选为Boc；
环A、R’、X、Ra、Rb、Rc、Rd、RX1、RX2、RX3、R3、R4、R5、R6和Cy如通式(II)中所定义。
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：
通式(IIA’)所示的化合物或其盐与NH2-R5或其盐(优选为盐酸盐)反应得到通式(II’)所示的化合物或其可药用的盐，其中，
R3a和R4均为氢原子；
环A、RA、R’、X、Ra、Rb、Rc、Rd、RX1、RX2、RX3、R5和r-1如通式(II’)中所定义。
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：
通式(IIA’)所示的化合物或其盐与通式(II’B)所示的化合物或其盐(优选为盐酸盐)反应得到通式(II’)所示的化合物或其可药用的盐，其中，
R5为氢原子；
环A、RA、R’、X、Ra、Rb、Rc、Rd、RX1、RX2、RX3、R3a、R4和r-1如通式(II’)中所定义。
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：
通式(IIa)所示的化合物或其盐与通式(II’b)所示的化合物或其盐(优选为盐酸盐)发生缩合反应得到通式(II’)所示的化合物或其可药用的盐，其中，
R10为卤素(优选为氯原子)或OH；
环A、RA、R’、X、Ra、Rb、Rc、Rd、RX1、RX2、RX3、R3a、R4、R5和r-1如 通式(II’)中所定义。
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：
通式(IIa’)所示的化合物或其盐与通式(II-1B)所示的化合物或其盐(优选为盐酸盐)反应得到通式(II-1)所示的化合物或其可药用的盐，其中，
R*选自羟基、烷氧基和卤素；
当氨基含保护基时，所述方法还包括脱去保护基的步骤；氨基保护基优选为Boc；
环A、RA、R’、X、Ra、Rb、Rc、Rd、RX1、RX2、RX3、R3、R4、R5和r-1如通式(II-1)中所定义。
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：
通式(IIa)所示的化合物或其盐与通式(II-1b)所示的化合物或其盐(优选为盐酸盐)发生缩合反应得到通式(II-1)所示的化合物或其可药用的盐，其中，
R10为卤素(优选为氯原子)或OH；
环A、RA、R’、X、Ra、Rb、Rc、Rd、RX1、RX2、RX3、R3、R4、R5和r-1如通式(II-1)中所定义。
本公开的另一方面涉及一种制备上述通式(III)所示的化合物或其可药用的盐的方法，该方法包括：
通式(IIIA)所示的化合物或其盐发生水解反应得到通式(III)所示的化合物或其可药用的盐，其中，
R12和R13相同或不同，且各自独立地选自氢原子、烷基、环烷基和苯基；优选地，R12和R13相同或不同，且各自独立地选自氢原子、C1-6烷基和5或6元环烷基；最优选地，R12和R13均为CH3；
环A、R’、X、Ra、Rb、Rc、Rd、RX1、RX2、RX3和t如通式(III)中所定义。
本公开的另一方面涉及一种制备上述通式(III-1)所示的化合物或其可药用的盐的方法，该方法包括：
通式(IIIA-1)所示的化合物或其盐发生水解反应得到通式(III-1)所示的化合物或其可药用的盐，其中，
R12和R13相同或不同，且各自独立地选自氢原子、烷基、环烷基和苯基；优选地，R12和R13相同或不同，且各自独立地选自氢原子、C1-6烷基和5或6元环烷基；最优选地，R12和R13均为CH3；
环A、R’、X、Ra、Rb、Rc、Rd、RX1、RX2、RX3和t如通式(III-1)中所定义。
本公开的另一方面涉及一种制备上述通式(IV)所示的化合物或其可药用的盐的方法，该方法包括：
通式(IVa)所示的化合物或其盐与通式(IVb)所示的化合物或其盐发生缩合反应 得到通式(IV)所示的化合物或其可药用的盐，其中，
R10为卤素(优选为氯原子)或OH；
Ra、Rb、Rc、Rd、RX1、RX2、RX3、R’、R1A、R2A和R3A如通式(IV)中所定义。
本公开的另一方面涉及一种制备上述通式(IV)所示的化合物或其可药用的盐的方法，该方法包括：
通式(IVA’)所示的化合物或其盐与NH2-R5或其盐(优选为盐酸盐)反应得到通式(IV)所示的化合物或其可药用的盐，其中，
R3A为-C(＝NR5)NR3R4；
R3和R4均为氢原子；
R1A、R2A、R’、Ra、Rb、Rc、Rd、RX1、RX2、RX3和R5如通式(IV)中所定义。
本公开的另一方面涉及一种制备上述通式(IV)所示的化合物或其可药用的盐的方法，该方法包括：
通式(IVA’)所示的化合物或其盐与通式(IB’)所示的化合物或其盐(优选为盐酸盐)反应得到通式(IV)所示的化合物或其可药用的盐，其中，
R3A为-C(＝NH)NR5-OR6或-C(＝NH)NR3R4；
R1A、R2A、R’、Ra、Rb、Rc、Rd、RX1、RX2、RX3、R3、R4、R5和R6如通式(IV)中所定义。
本公开的另一方面涉及一种制备上述通式(IV)所示的化合物或其可药用的盐的方法，该方法包括：
通式(IVa’)所示的化合物或其盐与胺或其盐(优选为盐酸盐)发生酰胺化反应得到通式(IV)所示的化合物或其可药用的盐，其中，
上述的胺选自HNR5-OR6、HNR5-NR3R4和HNR5-亚烷基-Cy；
R*选自羟基、烷氧基和卤素；
R3A选自-C(O)NR5-OR6、-C(O)NR5-NR3R4和-C(O)NR5-亚烷基-Cy；
当氨基含保护基时，所述方法还包括脱去保护基的步骤；氨基保护基优选为Boc；
R1A、R2A、R’、Ra、Rb、Rc、Rd、RX1、RX2、RX3、R3、R4、R5、R6和Cy如通式(IV)中所定义。
本公开的另一方面涉及一种制备上述通式(V)所示的化合物或其可药用的盐的方法，该方法包括：
通式(IVa)所示的化合物或其盐与通式(Vb)所示的化合物或其盐发生缩合反应得到通式(V)所示的化合物或其可药用的盐，其中，
RW1为氢原子或氨基保护基(优选为叔丁基亚磺酰基)，RW2为氢原子或羟基保护基(优选为TBS)；
当RW1为氨基保护基和/或RW2为羟基保护基时，所述制备方法还包括脱去保护基的步骤；
R10为卤素(优选为氯原子)或OH；
Ra、Rb、Rc、Rd、RX1、RX2、RX3、R’、R1A、R2A、RA4、u1和u2如通式(V)中所定义。
本公开的另一方面涉及一种制备上述通式(V-1)或(V-2)所示的化合物或其可药用的盐的方法，该方法包括：
通式(IVa)所示的化合物或其盐与通式(V-1b)所示的化合物或其盐发生缩合反应得到通式(V-1)所示的化合物或其可药用的盐，或，
通式(IVa)所示的化合物或其盐与通式(V-2b)所示的化合物或其盐发生缩合反应得到通式(V-2)所示的化合物或其可药用的盐，其中，
RW1为氢原子或氨基保护基(优选为叔丁基亚磺酰基)，RW2为氢原子或羟基保护基(优选为TBS)；
当RW1为氨基保护基和/或RW2为羟基保护基时，所述制备方法还包括脱去保护基的步骤；
R10为卤素(优选为氯原子)或OH；
Ra、Rb、Rc、Rd、RX1、RX2、RX3、R’、R1A、R2A、RA4、u1和u2如通式(V-1)中所定义。
本公开的另一方面涉及一种制备上述通式(V-1)或(V-2)所示的化合物或其可药用的盐的方法，该方法包括：
通式(V-1A)所示的化合物或其盐发生脱保护反应得到通式(V-1)所示的化合物 或其可药用的盐，
通式(V-2A)所示的化合物或其盐发生脱保护反应得到通式(V-2)所示的化合物或其可药用的盐，其中，
RW1为氨基保护基，所述氨基保护基优选为Boc；
Ra、Rb、Rc、Rd、RX1、RX2、RX3、R’、R1A、R2A、RA4、u1和u2如通式(V-1)中所定义。
本公开的另一方面涉及一种制备上述通式(VI’)所示的化合物或其可药用的盐的方法，该方法包括：
通式(IVa)所示的化合物或其盐与通式(VI’B)所示的化合物或其盐(优选为盐酸盐)发生缩合反应得到通式(VI’)所示的化合物或其可药用的盐，其中，
R10为卤素(优选为氯原子)或OH；
R’、Ra、Rb、Rc、Rd、RX1、RX2、RX3、R1A、R2A、Q、R3、R4和R5如通式(VI’)中所定义。
本公开的另一方面涉及一种制备上述通式(VI’)所示的化合物或其可药用的盐的方法，该方法包括：
通式(VI’A)所示的化合物或其盐与NH2-R5或其盐(优选为盐酸盐)反应得到通式(VI’)所示的化合物或其可药用的盐，其中，
R3和R4均为氢原子；
R’、Ra、Rb、Rc、Rd、RX1、RX2、RX3、R1A、R2A、Q和R5如通式(VI’)中所定义。
本公开的另一方面涉及一种制备上述通式(VI’)所示的化合物或其可药用的盐的方法，该方法包括：
通式(VI’A)所示的化合物或其盐与通式(IB’)所示的化合物或其盐(优选为盐酸盐)反应得到通式(VI’)所示的化合物或其可药用的盐，其中，
R5为氢原子；
R’、Ra、Rb、Rc、Rd、RX1、RX2、RX3、R1A、R2A、Q、R3和R4如通式(VI’)中所定义。
本公开的另一方面涉及一种制备上述通式(VI’-1)所示的化合物或其可药用的盐的方法，该方法包括：
通式(IVa)所示的化合物或其盐与通式(VI’-1B)所示的化合物或其盐(优选为盐酸盐)发生缩合反应得到通式(VI’-1)所示的化合物或其可药用的盐，其中，
R10为卤素(优选为氯原子)或OH；
R’、Ra、Rb、Rc、Rd、RX1、RX2、RX3、R1A、R2A、Q、R3、R5和RC如通式(VI’-1)中所定义。
本公开的另一方面涉及一种制备上述通式(VI’-1)所示的化合物或其可药用的盐的方法，该方法包括：
通式(VI’A)所示的化合物或其盐与通式(VI-1B’)所示的化合物或其盐(优选为盐酸盐)反应得到通式(VI’-1)所示的化合物或其可药用的盐，其中，
R5为氢原子；
R’、Ra、Rb、Rc、Rd、RX1、RX2、RX3、R1A、R2A、Q、R3和RC如通式(VI’-1) 中所定义。
本公开的另一方面涉及一种制备上述通式(VI’-1)所示的化合物或其可药用的盐的方法，该方法包括：
通式(VI’)所示的化合物或其盐(优选为三氟乙酸盐)与通式(VI’-1b)所示的化合物或其盐发生酰胺化反应得到通式(VI’-1)所示的化合物或其可药用的盐，其中，
R4为氢原子；
R10为卤素(优选为氯)或OH；
R’、Ra、Rb、Rc、Rd、RX1、RX2、RX3、R1A、R2A、Q、R3、R5和RC如通式(VI’-1)中所定义。
本公开的另一方面涉及一种制备上述通式(VI)所示的化合物或其可药用的盐的方法，该方法包括：
通式(IVA’)所示的化合物或其盐与NH2-R5或其盐(优选为盐酸盐)反应得到通式(VI)所示的化合物或其可药用的盐，其中，
R3a和R4均为氢原子；
R1A、R2A、R’、Ra、Rb、Rc、Rd、RX1、RX2、RX3和R5如通式(VI)中所定义。
本公开的另一方面涉及一种制备上述通式(VI)所示的化合物或其可药用的盐的方法，该方法包括：
通式(IVA’)所示的化合物或其盐与通式(II’B)所示的化合物或其盐(优选为盐酸盐)反应得到通式(VI)所示的化合物或其可药用的盐，其中，
R5为氢原子；
R1A、R2A、R’、Ra、Rb、Rc、Rd、RX1、RX2、RX3、R3a和R4如通式(VI)中所定义。
本公开的另一方面涉及一种制备上述通式(VI)所示的化合物或其可药用的盐的方法，该方法包括：
通式(IVa)所示的化合物或其盐与通式(VIb)所示的化合物或其盐(优选为盐酸盐)发生缩合反应得到通式(VI)所示的化合物或其可药用的盐，其中，
R10为卤素(优选为氯原子)或OH；
R’、Ra、Rb、Rc、Rd、RX1、RX2、RX3、R1A、R2A、R3a、R4和R5如通式(VI)中所定义。
本公开的另一方面涉及一种制备上述通式(VII’)所示的化合物或其可药用的盐的方法，该方法包括：
通式(IVa)所示的化合物或其盐与通式(VII’B)所示的化合物或其盐(优选为盐酸盐)发生缩合反应得到通式(VII’)所示的化合物或其可药用的盐，其中，
R10为卤素(优选为氯原子)或OH；
R’、Ra、Rb、Rc、Rd、RX1、RX2、RX3、R1A、R2A、Q、R3、R4和R5如通式(VII’)中所定义。
本公开的另一方面涉及一种制备上述通式(VII’)所示的化合物或其可药用的盐的方法，该方法包括：
通式(VII’)所示的化合物或其盐与通式(II-1B)所示的化合物或其盐(优选为盐酸盐)发生酰胺化反应得到通式(VII’)所示的化合物或其可药用的盐，其中，
R*选自羟基、烷氧基和卤素；
当氨基含保护基时，所述方法还包括脱去保护基的步骤；氨基保护基优选为Boc；
R’、Ra、Rb、Rc、Rd、RX1、RX2、RX3、R1A、R2A、Q、R3、R4和R5如通式(VII’)中所定义。
本公开的另一方面涉及一种制备上述通式(VII)所示的化合物或其可药用的盐的方法，该方法包括：
通式(IVa’)所示的化合物或其盐与通式(II-1B)所示的化合物或其盐(优选为盐酸盐)发生酰胺化反应得到通式(VII)所示的化合物或其可药用的盐，
R*选自羟基、烷氧基和卤素；
当氨基含保护基时，所述方法还包括脱去保护基的步骤；氨基保护基优选为Boc；
其中，R1A、R2A、R’、Ra、Rb、Rc、Rd、RX1、RX2、RX3、R3、R4和R5如通式(VII)中所定义。
本公开的另一方面涉及一种制备上述通式(VII)所示的化合物或其可药用的盐的方法，该方法包括：
通式(IVa)所示的化合物或其盐与通式(VIIb)所示的化合物或其盐(优选为盐酸盐)发生缩合反应得到通式(VII)所示的化合物或其可药用的盐，其中，
R10为卤素(优选为氯原子)或OH；
R’、Ra、Rb、Rc、Rd、RX1、RX2、RX3、R1A、R2A、R3、R4和R5如通式(VII)中所定义。
本公开的另一方面涉及一种制备上述通式(VIII)所示的化合物或其可药用的盐的方法，该方法包括：
通式(IIa)所示的化合物或其盐与通式(VIIIB)所示的化合物或其盐(优选为盐酸盐)发生缩合反应得到通式(VIII)所示的化合物或其可药用的盐，其中，
R10为卤素(优选为氯原子)或OH；
R’、X、Ra、Rb、Rc、Rd、RX1、RX2、RX3、R1A、R2A、Q、R3和R4如通式(VIII)中所定义。
本公开的另一方面涉及一种制备上述通式(VIII)所示的化合物或其可药用的盐的方法，该方法包括：
通式(VIIIA)所示的化合物或其盐与通式(IB’)所示的化合物或其盐(优选为盐酸盐)发生氨酯交换反应得到通式(VIII)所示的化合物或其可药用的盐，其中，
RL为烷氧基；
R’、X、Ra、Rb、Rc、Rd、RX1、RX2、RX3、R1A、R2A、Q、R3和R4如通式(VIII) 中所定义。
在本公开的一些实施方案中，所述通式(VIII)所示的化合物或其可药用的盐的制备方法，其中RL为C1-6烷氧基；优选为甲氧基或乙氧基。
在本公开的一些实施方案中，所述通式(II)、(II-1)、(IV)或(VII)所示的化合物或其可药用的盐的制备方法，其中R*选自羟基、C1-6烷氧基和卤素；在一些实施方案中，R*选自羟基、甲氧基、乙氧基和氯；在一些实施方案中，R*为羟基。
在本公开的一些实施方案中，所述通式(II)、(II-1)、(IV)或(VII)所示的化合物或其可药用的盐的制备方法，其中R4选自氢原子、C1-6烷基和氨基保护基，当R4为氨基保护基时，所述酰胺化反应之后还包括脱去氨基保护基的步骤。
本公开的另一方面涉及一种制备上述通式(II)、(II’)、(II-1)、(III)、(III-1)、(IV)、(V)、(V-1)、(V-2)、(VI)、(VII)、(VI’)、(VI’-1)、(VII’)或(VIII)所示的化合物或其可药用的盐的方法，该方法包括：RX1为烷氧基或环烷氧基的通式(II)、(II’)、(II-1)、(III)、(III-1)、(IV)、(V)、(V-1)、(V-2)、(VI)、(VII)、(VI’)、(VI’-1)、(VII’)或(VIII)所示的化合物或其可药用的盐发生去烷基反应或去环烷基反应得到RX1为-OH的通式(II)、(II’)、(II-1)、(III)、(III-1)、(IV)、(V)、(V-1)、(V-2)、(VI)、(VII)、(VI’)、(VI’-1)、(VII’)或(VIII)所示的化合物或其可药用的盐。
本公开的制备上述通式(II)、(II’)、(II-1)、(III)、(III-1)、(IV)、(V)、(V-1)、(V-2)、(VI)、(VII)、(VI’)、(VI’-1)、(VII’)或(VIII)所示的化合物或其可药用的盐的方法，其中，RX1选自甲氧基、氘代甲氧基和在一些实施方案中，RX1为甲氧基或
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’)、(II-1)、(III)、(III-1)、(IV)、(V)、(V-1)、(V-2)、(VI)、(VII)、(VI’)、(VI’-1)、(VII’)、(VIII)或表A中所示的化合物或其可药用的盐，以及一种或多种药学上可接受的载体、稀释剂或赋形剂。
本公开进一步涉及通式(I)、(II)、(II’)、(II-1)、(III)、(III-1)、(IV)、(V)、(V-1)、(V-2)、(VI)、(VII)、(VI’)、(VI’-1)、(VII’)、(VIII)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。
本公开进一步涉及通式(I)、(II)、(II’)、(II-1)、(III)、(III-1)、(IV)、(V)、(V-1)、(V-2)、(VI)、(VII)、(VI’)、(VI’-1)、(VII’)、(VIII)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。
本公开进一步涉及通式(I)、(II)、(II’)、(II-1)、(III)、(III-1)、(IV)、(V)、(V-1)、(V-2)、(VI)、(VII)、(VI’)、(VI’-1)、(VII’)、(VIII)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、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。
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’)、(II-1)、(III)、(III-1)、(IV)、(V)、(V-1)、(V-2)、(VI)、(VII)、(VI’)、(VI’-1)、(VII’)、(VIII)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。
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’)、(II-1)、(III)、(III-1)、(IV)、(V)、(V-1)、(V-2)、(VI)、(VII)、(VI’)、(VI’-1)、(VII’)、(VIII)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。
本公开进一步涉及一种治疗和/或预防疼痛和疼痛相关疾病、多发性硬化症、夏-马-图三氏综合症、失禁、病理咳嗽或心律失常的方法，其包括给予所需患者通式(I)、(II)、(II’)、(II-1)、(III)、(III-1)、(IV)、(V)、(V-1)、(V-2)、(VI)、(VII)、(VI’)、(VI’-1)、(VII’)、(VIII)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。
本公开进一步涉及一种通式(I)、(II)、(II’)、(II-1)、(III)、(III-1)、(IV)、(V)、(V-1)、(V-2)、(VI)、(VII)、(VI’)、(VI’-1)、(VII’)、(VIII)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；优选地，其用作抑制电压门控钠通道活性的药物。
本公开进一步涉及一种通式(I)、(II)、(II’)、(II-1)、(III)、(III-1)、(IV)、(V)、(V-1)、(V-2)、(VI)、(VII)、(VI’)、(VI’-1)、(VII’)、(VIII)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。
本公开进一步涉及一种通式(I)、(II)、(II’)、(II-1)、(III)、(III-1)、(IV)、(V)、(V-1)、(V-2)、(VI)、(VII)、(VI’)、(VI’-1)、(VII’)、(VIII)或表A所示的化合物或其可药用的盐、或包括其的药物组合物，其用作电压门控钠通道抑制剂。
本公开进一步涉及一种通式(I)、(II)、(II’)、(II-1)、(III)、(III-1)、(IV)、(V)、(V-1)、(V-2)、(VI)、(VII)、(VI’)、(VI’-1)、(VII’)、(VIII)或表A所示的化合物或其可药用的盐、或包括其的药物组合物，其用作治疗和/或预防由电压门控钠通道介导的疾病或病症的药物。
本公开进一步涉及一种通式(I)、(II)、(II’)、(II-1)、(III)、(III-1)、(IV)、(V)、 (V-1)、(V-2)、(VI)、(VII)、(VI’)、(VI’-1)、(VII’)、(VIII)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。
本公开进一步涉及一种通式(I)、(II)、(II’)、(II-1)、(III)、(III-1)、(IV)、(V)、(V-1)、(V-2)、(VI)、(VII)、(VI’)、(VI’-1)、(VII’)、(VIII)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。
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。
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。
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；优选地，所述神经性疼痛选自带状疱疹后神经痛、小纤维神经痛、糖尿病性神经痛或特发性小纤维神经痛。
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。
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。
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。
本公开中所述的特发性疼痛包括纤维肌痛。
本公开中所述急性疼痛包括急性术后疼痛。
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。
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。
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。
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。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。
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。
本公开的药物组合物除活性化合物外，可含有一种或多种辅料，所述辅料选自以下成分：填充剂(稀释剂)、粘合剂、润湿剂、崩解剂或赋形剂等。根据给药方法的不同，组合物可含有0.1至99重量％的活性化合物。
在一些实施方案中，所述的药物组合物的单位剂量为0.001mg-1000mg。
在某些实施方案中，基于组合物的总重量，所述的药物组合物含有0.01-99.99％的前述化合物或其可药用的盐或其同位素取代物。在某些实施方案中，所述的药物组合物含有0.1-99.9％的前述化合物或其可药用的盐或其同位素取代物。在某些实施方案中，所述的药物组合物含有0.5％-99.5％的前述化合物或其可药用的盐或其同位素取代物。在某些实施方案中，所述的药物组合物含有1％-99％的前述化合物或其可药用的盐或其同位素取代物。在某些实施方案中，所述的药物组合物含有2％-98％的前述化合物或其可药用的盐或其同位素取代物。
在某些实施方案中，基于组合物的总重量，所述的药物组合物含有0.01％-99.99％的药学上可接受的赋形剂。在某些实施方案中，所述的药物组合物含有0.1％-99.9％的药学上可接受的赋形剂。在某些实施方案中，所述的药物组合物含有0.5％-99.5％的药学上可接受的赋形剂。在某些实施方案中，所述的药物组合物含有1％-99％的药学上可接受的赋形剂。在某些实施方案中，所述的药物组合物含有2％-98％的药 学上可接受的赋形剂。
本公开中所述化合物可药用盐可选自无机盐或有机盐。
片剂含有活性成分和用于混合的适宜制备片剂的无毒的可药用的赋形剂。这些赋形剂可以是惰性赋形剂、造粒剂、崩解剂、粘合剂和润滑剂。这些片剂可以不包衣或可通过掩盖药物的味道或在胃肠道中延迟崩解和吸收，因而在较长时间内提供缓释作用的已知技术将其包衣。
也可用其中活性成分与惰性固体稀释剂或其中活性成分与水溶性载体或油溶媒混合的软明胶胶囊提供口服制剂。
水混悬液含有活性物质和用于混合的适宜制备水悬浮液的赋形剂。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。
油混悬液可通过使活性成分悬浮于植物油，或矿物油配制而成。油悬浮液可含有增稠剂。可加入上述的甜味剂和矫味剂，以提供可口的制剂。可通过加入抗氧化剂保存这些组合物。
本公开的药物组合物也可以是水包油乳剂的形式。油相可以是植物油，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。
本公开的药物组合物可以是无菌注射水溶液形式。可以使用的可接受的溶媒或溶剂有水、林格氏液和等渗氯化钠溶液。无菌注射制剂可以是其中活性成分溶于油相的无菌注射水包油微乳可通过局部大量注射，将注射液或微乳注入患者的血流中。或者，最好按可保持本公开化合物恒定循环浓度的方式给予溶液和微乳。为保持这种恒定浓度，可使用连续静脉内递药装置。这种装置的实例是Deltec CADD-PLUS.TM.5400型静脉注射泵。
本公开的药物组合物可以是用于肌内和皮下给药的无菌注射水或油混悬液的形式。可按已知技术，用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。
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。
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。
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。
术语说明
除非有相反陈述，在说明书和权利要求书中使用的术语具有下述含义。
术语“烷基”指饱和的直链或带有支链的脂肪族烃基，其具有1至20个(例如1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19或20个)碳原子(即C1-20烷基)。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。
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。
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。
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。
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。
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)和3至10个环原子的环烷基(即3至10元环烷基)，更优选具有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)。
所述的单环环烷基，非限制性的实例包括：环丙基、环丁基、环戊基、环戊烯基、环己基、环己烯基、环己二烯基、环庚基、环庚三烯基和环辛基等。
所述的多环环烷基包括：螺环烷基、稠环烷基和桥环烷基。
术语“螺环烷基”指环之间共用一个碳原子(称螺原子)的多环系统，其环内可以含有一个或多个双键，或其环内可以含有一个或多个选自氮、氧和硫的杂原子(所述的氮可任选被氧化，即形成氮氧化物；所述的硫可任选被氧代，即形成亚砜或砜，但不包括-O-O-、-O-S-或-S-S-)，条件是至少含有一个全碳环且连接点在该全碳环上，其具有5至20个(例如5、6、7、8、9、10、11、12、13、14、15、16、17、18、19或20个)环原子(即5至20元螺环烷基)。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：
其连接点可在任意位置；
等。
术语“稠环烷基”指环之间共享毗邻的两个碳原子的多环系统，其为单环环烷基与一个或多个单环环烷基稠合，或者单环环烷基与杂环基、芳基或杂芳基中的一个或多个稠合，其中连接点在单环环烷基上，其环内可以含有一个或多个双键，且具有5至20个(例如5、6、7、8、9、10、11、12、13、14、15、16、17、18、19或20个)环原子(即5至20元稠环烷基)。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。
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：
其连接点可在任意位置。
环烷基可以是取代的或非取代的，当被取代时，其可以在任何可使用的连接点被取代，取代基优选选自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。
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)；进一步优选具有3至10个环原子的杂环基(即3至10元杂环基)和具有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)或具有3至4个环原子的杂环基(即3至4元杂环基)。
所述的单环杂环基，非限制性的实例包括：吡咯烷基、四氢吡喃基、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。
所述的多环杂环基包括螺杂环基、稠杂环基和桥杂环基。
术语“螺杂环基”指环之间共用一个原子(称螺原子)的多环杂环系统，其环内可以含有一个或多个双键，且其环内至少含有一个(例如1、2、3或4个)选自氮、氧和硫的杂原子(所述的氮可任选被氧化，即形成氮氧化物；所述的硫可任选被氧代，即形成亚砜或砜，但不包括-O-O-、-O-S-或-S-S-)，条件是至少含有一个单环杂环基且连接点在该单环杂环基上，其具有5至20个(例如5、6、7、8、9、10、11、12、13、14、15、16、17、18、19或20个)环原子(即5至20元螺杂环基)。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：
等。
术语“稠杂环基”指环之间共享毗邻的两个原子的多环杂环系统，其环内可以含有一个或多个双键，且其环内至少含有一个(例如1、2、3或4个)选自氮、 氧和硫的杂原子(所述的氮可任选被氧化，即形成氮氧化物；所述的硫可任选被氧代，即形成亚砜或砜，但不包括-O-O-、-O-S-或-S-S-)，其为单环杂环基与一个或多个单环杂环基稠合，或者单环杂环基与环烷基、芳基或杂芳基中的一个或多个稠合，其中连接点在单环杂环基上，且具有5至20个(例如5、6、7、8、9、10、11、12、13、14、15、16、17、18、19或20个)环原子(即5至20元稠杂环基)。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：
等。
术语“桥杂环基”指环之间共用两个不直接连接的原子的多环杂环系统，其环内可以含有一个或多个双键，并且其环内至少含有一个(例如1、2、3或4个)选自氮、氧和硫的杂原子(所述的氮可任选被氧化，即形成氮氧化物；所述的硫可任选被氧代，即形成亚砜或砜，但不包括-O-O-、-O-S-或-S-S-)，其具有5至20个(例如5、6、7、8、9、10、11、12、13、14、15、16、17、18、19或20个)环原子(即5至20元桥杂环基)。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：
等。
杂环基可以是取代的或非取代的，当被取代时，其可以在任何可使用的连接点被取代，取代基优选选自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。
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，非限制性的实例包括：萘基、蒽基、菲基等。所述多环芳基还包括苯基与杂环基或环烷基中的一个或多个稠合，或萘基与杂环基或环烷基中的一个或多个稠合，其中连接点在苯基或萘基上，并且在这种情况下，环原子个数继续表示多环芳环系统中的环原子个数，非限制性的实例包括：
等。
芳基可以是取代的或非取代的，当被取代时，其可以在任何可使用的连接点被取代，取代基优选选自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。
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)。
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。
所述的多环杂芳基，非限制性的实例包括：吲哚基、吲唑基、喹啉基、异喹啉基、喹喔啉基、酞嗪基、苯并咪唑基、苯并噻吩基、喹唑啉基、苯并噻唑基、咔唑基等。所述多环杂芳基还包括单环杂芳基与一个或多个芳基稠合，其中连接点在芳香环上，并且在这种情况下，环原子个数继续表示多环杂芳环系统中的环原子个数。所述多环杂芳基还包括单环杂芳基与环烷基或杂环基中的一个或多个稠合，其中连接点在单环杂芳环上，并且在这种情况下，环原子个数继续表示多环杂芳环系统中的环原子个数。非限制性的实例包括：
等。
杂芳基可以是取代的或非取代的，当被取代时，其可以在任何可使用的连接点被取代，取代基优选选自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。
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)、叔丁基亚磺酰基、三氟乙酰基(Tfa)、三氯乙酰基、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。
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。
术语“环烷基烷基”指烷基被一个或多个环烷基取代，其中环烷基、烷基如上所定义。
术语“杂环基烷基”指烷基被一个或多个杂环基取代，其中杂环基、烷基如上所定义。
术语“烷氧基烷基”指烷基被一个或多个烷氧基取代，其中烷氧基、烷基如上所定义。
术语“环烷基氧基”指环烷基-O-，其中环烷基如上所定义。
术语“杂环基氧基”指杂环基-O-，其中杂环基如上所定义。
术语“芳基氧基”指芳基-O-，其中芳基如上所定义。
术语“杂芳基氧基”指杂芳基-O-，其中杂芳基如上所定义。
术语“烷硫基”指烷基-S-，其中烷基如上所定义。
术语“卤代烷基”指烷基被一个或多个卤素取代，其中烷基如上所定义。
术语“卤代烷氧基”指烷氧基被一个或多个卤素取代，其中烷氧基如上所定义。
术语“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。
术语“羟烷基”指烷基被一个或多个羟基取代，其中烷基如上所定义。
术语“羟烷氧基”指烷氧基被一个或多个羟基取代，其中烷氧基如上所定义。
术语“甲叉基”指＝CH2。
术语“氘代甲基”指甲基一个或多个氘原子取代，如CHD2、CH2D和CD3；优选CD3。
术语“氘代甲氧基”指-O-氘代甲基，氘代甲基如上所定义，如OCD3。
术语“卤素”指氟、氯、溴或碘。
术语“羟基”指-OH。
术语“巯基”指-SH。
术语“氨基”指-NH2。
术语“氰基”指-CN。
术语“硝基”指-NO2。
术语“氧代”或“氧代基”指“＝O”。
术语“羰基”指C＝O。
术语“乙酰基”指-C(O)CH3。
术语“酰胺基”指-C(O)NH2。
术语“羧基”指-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。
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、-和(S)-对映异构体、非对映异构体、(D)-和(L)-异构体、互变异构体、阻转异构体、构象异构体及其混合物(如外消旋体、非对映异构体的混合物)。本公开化合物中的取代基可以存在另外的不对称原子。所有这些立体异构体以及它们的混合物，均包括在本公开的范围内。可以通过手性合成、手性试剂或者其他常规技术制备光学活性的(-)-和(+)-异构体、(R)-和(S)-对映异构体以及(D)-和(L)-异构体。本公开某化合物的一种异构体，可以通过不对称合成或者手性助剂来制备，或者，当分子中含有碱性官能团(如氨基)或酸性官能团(如羧基)时，与适当的光学活性的酸或碱形成非对映异构体的盐，然后通过本领域所公知的常规方法进行非对映异构体拆分，得到纯的异构体。此外，对映异构体和非对映异构体的分离通常是通过色谱法完成。
本公开所述化合物的化学结构中，键表示未指定构型，即如果化学结构中存在手性异构体，键可以为或者同时包含 两种构型。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；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。
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 或如中，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。
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。烯胺-亚胺的平衡实例如下所示：
“脒”(amidines)，又称亚氨酰胺(iminoamide)，酰胺分子中羰基氧原子被亚氨基取代的化合物，脒的亚氨基和氨基可互相转化形成互变异构体，脒的互变异构如下所示：
如当提及吡唑基时，应理解为包括如下两种结构中的任何一种或两种互变异构体的混合物：
所有的互变异构形式在本公开的范围内，且化合物的命名不排除任何互变异构体。
本公开的化合物包括其化合物的所有合适的同位素衍生物。术语“同位素衍生物”是指至少一个原子被具有相同原子序数但原子质量不同的原子替代的化合物。可引入到本公开化合物中的同位素的实例包括氢、碳、氮、氧、磷、硫、氟、氯、溴和碘等的稳定和放射性的同位素，例如分别为2H(氘，D)、3H(氚，T)、11C、13C、14C、15N、17O、18O、32p、33p、33S、34S、35S、36S、18F、36Cl、82Br、123I、124I、125I、129I和131I等，优选氘。
相比于未氘代药物，氘代药物有降低毒副作用、增加药物稳定性、增强疗效、延长药物生物半衰期等优势。本公开的化合物的所有同位素组成的变换，无论放射性与否，都包括在本公开的范围之内。与碳原子连接的各个可用的氢原子可独立地被氘原子替换，其中氘的替换可以是部分或完全的，部分氘的替换是指至少一个氢被至少一个氘替换。
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)。
“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。
“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。
“药物组合物”表示含有一种或多种本文所述化合物或其可药用的盐与其他化学组分的混合物，以及其他组分例如药学上可接受的载体和赋形剂。药物组合物的目的是促进对生物体的给药，利于活性成分的吸收进而发挥生物活性。
“可药用的盐”是指本公开化合物的盐，可选自无机盐或有机盐。这类盐用于哺乳动物体内时具有安全性和有效性，且具有应有的生物活性。可以在化合物的最终分离和纯化过程中，或通过使合适的基团与合适的碱或酸反应来单独制备。通常用于形成药学上可接受的盐的碱包括无机碱，例如氢氧化钠和氢氧化钾，以及有机碱，例如氨。通常用于形成药学上可接受的盐的酸包括无机酸以及有机酸。
本文所用的术语“药学上可接受的”是指这些化合物、材料、组合物和/或剂型，在合理的医学判断范围内，适用于与患者组织接触而没有过度毒性、刺激性、过敏反应或其他问题或并发症，具有合理的获益/风险比，并且对预期的用途是有效。
本文所使用的，单数形式的“一个”、“一种”和“该”包括复数引用，反之亦然，除非上下文另外明确指出。
当将术语“约”应用于诸如pH、浓度、温度等参数时，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。
本公开化合物的合成方法
为了完成本公开的目的，本公开采用如下技术方案：
方案一
本公开提供通式(I)所示的化合物或其可药用的盐的制备方法，该方法包括：
通式(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，
R10为卤素(优选氯原子)或OH；
其中，当R10为OH时，该反应在缩合剂的存在下发生；
环A、RA、R’、Ra、Rb、Rc、Rd、Re、X、X1、X2、X3、X4、X5和r如通式(I)中所定义。
方案一-1
本公开提供通式(I)所示的化合物或其可药用的盐的制备方法，该方法包括：
通式(IA’)所示的化合物或其盐与通式(IB’)所示的化合物或其盐(优选为盐酸盐)在催化剂存在下发生pinner反应得到通式(I)所示的化合物或其可药用的盐，
优选地，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(优选为盐酸盐)在巯基乙酸和碱存在下反应得到通式(I)所示的化合物或其可药用的盐，其中，
通式(I)中至少一个RA为-C(＝NH)NR5-OR6或-C(＝NH)NR3R4；
r为1、2、3、4或5；r-1为0、1、2、3或4；
余下的RA如通式(I)中所定义；
环A、R’、Ra、Rb、Rc、Rd、Re、X、X1、X2、X3、X4、X5、R3、R4、R5和R6如通式(I)中所定义。
方案二
本公开提供通式(II)所示的化合物或其可药用的盐的制备方法，该方法包括：
通式(IIa)所示的化合物或其盐与通式(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，
R10为卤素(优选氯原子)或OH；
其中，当R10为OH时，该反应在缩合剂或草酰氯的存在下发生，优选在缩合剂的存在下发生；
环A、RA、R’、Ra、Rb、Rc、Rd、X、RX1、RX2、RX3和r如通式(II)中所定义。
方案二-1
本公开提供通式(II)所示的化合物或其可药用的盐的制备方法，该方法包括：
通式(IIA’)所示的化合物或其盐与通式(IB’)所示的化合物或其盐(优选为盐酸盐)在催化剂存在下发生pinner反应得到通式(II)所示的化合物或其可药用的盐，
优选地，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(优选为盐酸盐)在巯基乙酸和碱存在下反应得到通式(II)所示的化合物或其可药用的盐，其中，
通式(II)中至少一个RA为-C(＝NH)NR5-OR6或-C(＝NH)NR3R4；
r为1、2、3、4或5；r-1为0、1、2、3或4；
余下的RA如通式(II)中所定义；
环A、R’、Ra、Rb、Rc、Rd、X、RX1、RX2、RX3、R3、R4、R5和R6如通式(II)中所定义。
方案二-2
本公开提供通式(II)所示的化合物或其可药用的盐的制备方法，该方法包括：
通式(IIa’)所示的化合物或其盐与胺或其盐(优选为盐酸盐)发生酰胺化反应得到通式(II)所示的化合物或其可药用的盐，其中，
上述的胺选自HNR5-OR6、HNR5-NR3R4和HNR5-亚烷基-Cy；
R*选自羟基、烷氧基和卤素；
通式(II)中至少一个RA选自-C(O)NR5-OR6、-C(O)NR5-NR3R4和-C(O)NR5-亚烷基-Cy；
余下的RA如通式(II)中所定义；
r为1、2、3、4或5；r-1为0、1、2、3或4；
当氨基含保护基时，所述方法还包括脱去保护基的步骤；氨基保护基优选为 Boc；
环A、R’、X、Ra、Rb、Rc、Rd、RX1、RX2、RX3、R3、R4、R5、R6和Cy如通式(II)中所定义。
方案二-3
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：RX1为烷氧基或环烷氧基的通式(II)所示的化合物或其可药用的盐在酸性条件下发生去烷基或去环烷基反应得到RX1为-OH的通式(II)所示的化合物或其可药用的盐。
方案二-4
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：
通式(IIA’)所示的化合物或其盐与NH2-R5或其盐(优选为盐酸盐)在催化剂存在下发生pinner反应得到通式(II)所示的化合物或其可药用的盐，
通式(II)中至少一个RA为-C(＝NR5)NR3R4；
r为1、2、3、4或5；r-1为0、1、2、3或4；
R3和R4均为氢原子；
余下的RA如通式(II)中所定义；
环A、R’、Ra、Rb、Rc、Rd、X、RX1、RX2、RX3和R5如通式(II)中所定义。
方案二-A
本公开提供通式(II’)所示的化合物或其可药用的盐的制备方法，该方法包括：
通式(IIA’)所示的化合物或其盐与通式(II’B)所示的化合物或其盐(优选为盐酸盐)在催化剂存在下发生pinner反应得到通式(II’)所示的化合物或其可药用的盐，其中，
R5为氢原子；
环A、RA、R’、X、Ra、Rb、Rc、Rd、RX1、RX2、RX3、R3a、R4和r-1如通式(II’)中所定义。
方案二-A1
本公开提供通式(II’)所示的化合物或其可药用的盐的制备方法，该方法包括：
通式(IIa)所示的化合物或其盐与通式(II’b)所示的化合物或其盐(优选为盐酸盐)在碱性条件下发生缩合反应得到通式(II’)所示的化合物或其可药用的盐，其中，
R10为卤素(优选为氯原子)或OH；当R10为OH时，该反应在缩合剂或草酰氯的存在下发生，优选在缩合剂的存在下发生；
环A、RA、R’、X、Ra、Rb、Rc、Rd、RX1、RX2、RX3、R3a、R4、R5和r-1如通式(II’)中所定义。
方案二-A2
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：RX1为烷氧基或环烷氧基的通式(II’)所示的化合物或其可药用的盐在酸性条件下发生去烷基或去环烷基反应得到RX1为-OH的通式(II’)所示的化合物或其可药用的盐。
方案二-A3
本公开提供通式(II’)所示的化合物或其可药用的盐的制备方法，该方法包括：
通式(IIA’)所示的化合物或其盐与NH2-R5或其盐(优选为盐酸盐)在催化剂存在下发生pinner反应得到通式(II’)所示的化合物或其可药用的盐，其中，
R3a和R4均为氢原子；
环A、RA、R’、X、Ra、Rb、Rc、Rd、RX1、RX2、RX3、R5和r-1如通式(II’)中所定义。
方案二-B
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：
通式(IIa’)所示的化合物或其盐与通式(II-1B)所示的化合物或其盐(优选为盐酸盐)在碱性条件下发生酰胺化反应得到通式(II-1)所示的化合物或其可药用的盐，其中，
R*选自羟基、烷氧基和卤素；
当氨基含保护基时，所述方法还包括脱去保护基的步骤；氨基保护基优选为Boc；
环A、RA、R’、X、Ra、Rb、Rc、Rd、RX1、RX2、RX3、R3、R4、R5和r-1如通式(II-1)中所定义。
方案二-B1
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：
通式(IIa)所示的化合物或其盐与通式(II-1b)所示的化合物或其盐(优选为盐酸盐)在碱性条件下发生缩合反应得到通式(II-1)所示的化合物或其可药用的盐，其中，
R10为卤素(优选为氯原子)或OH；当R10为OH时，该反应在缩合剂或草酰氯的存在下发生，优选在缩合剂的存在下发生；
环A、RA、R’、X、Ra、Rb、Rc、Rd、RX1、RX2、RX3、R3、R4、R5和r-1如通式(II-1)中所定义。
方案二-B2
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：RX1为烷氧基或环烷氧基的通式(II-1)所示的化合物或其可药用的盐在酸性条件下发生去烷基或去环烷基反应得到RX1为-OH的通式(II-1)所示的化合物或其可药用的盐。
方案三
本公开提供通式(III)所示的化合物或其可药用的盐的制备方法，该方法包括：
通式(IIIA)所示的化合物或其盐在酸性条件下水解得到通式(III)所示的化合物或其可药用的盐，其中，
R12和R13相同或不同，且各自独立地选自氢原子、烷基、环烷基和苯基；优选地，R12和R13相同或不同，且各自独立地选自氢原子、C1-6烷基和5或6元环烷基；最优选地，R12和R13均为CH3；
环A、R’、Ra、Rb、Rc、Rd、X、RX1、RX2、RX3和t如通式(III)中所定义。
方案三-1
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：RX1为烷氧基或环烷氧基的通式(III)所示的化合物或其可药用的盐在酸性条件下发生去烷基或去环烷基反应得到RX1为-OH的通式(III)所示的化合物或其可药用的盐。
方案四
本公开提供通式(III-1)所示的化合物或其可药用的盐的制备方法，该方法包括：
通式(IIIA-1)所示的化合物或其盐在酸性条件下水解得到通式(III-1)所示的化合物或其可药用的盐，其中，
R12和R13相同或不同，且各自独立地选自氢原子、烷基、环烷基和苯基；优选地，R12和R13相同或不同，且各自独立地选自氢原子、C1-6烷基和5或6元环烷基；最优选地，R12和R13均为CH3；
环A、R’、Ra、Rb、Rc、Rd、X、RX1、RX2、RX3和t如通式(III-1)中所定义。
方案四-1
本公开提供通式(III-1)所示的化合物或其可药用的盐的制备方法，该方法包括：RX1为烷氧基或环烷氧基的通式(III-1)所示的化合物或其可药用的盐在酸性条件下发生去烷基或去环烷基反应得到RX1为-OH的通式(III-1)所示的化合物或其可药用的盐。
方案五
本公开的提供通式(IV)所示的化合物或其可药用的盐的方法，该方法包括：
通式(IVa)所示的化合物或其盐与通式(IVb)所示的化合物或其盐在碱性条件下发生缩合反应得到通式(IV)所示的化合物或其可药用的盐，其中，
R10为卤素(优选为氯原子)或OH；
其中，当R10为OH时，该反应在缩合剂或草酰氯的存在下发生，优选在缩合剂的存在下发生；
Ra、Rb、Rc、Rd、RX1、RX2、RX3、R’、R1A、R2A和R3A如通式(IV)中所定义。
方案五-1
本公开的提供通式(IV)所示的化合物或其可药用的盐的方法，该方法包括：
通式(IVA’)所示的化合物或其盐与通式(IB’)所示的化合物或其盐(优选为盐酸盐)在催化剂存在下反应得到通式(IV)所示的化合物或其可药用的盐，
优选地，通式(IVA’)所示的化合物或其盐与通式(IB’)所示的化合物或其盐(优选为盐酸盐)在巯基乙酸和碱存在下反应得到通式(IV)所示的化合物或其可药用的盐，其中，
R3A为-C(＝NH)NR5-OR6或-C(＝NH)NR3R4；
R1A、R2A、R’、Ra、Rb、Rc、Rd、RX1、RX2、RX3、R3、R4、R5和R6如通式(IV)中所定义。
方案五-2
本公开的提供通式(IV)所示的化合物或其可药用的盐的方法，该方法包括：
通式(IVa’)所示的化合物或其盐与胺或其盐(优选为盐酸盐)在碱性条件下发生酰胺化反应得到通式(IV)所示的化合物或其可药用的盐，其中，
上述的胺选自HNR5-OR6、HNR5-NR3R4和HNR5-亚烷基-Cy；
R*选自羟基、烷氧基和卤素；
R3A选自-C(O)NR5-OR6、-C(O)NR5-NR3R4和-C(O)NR5-亚烷基-Cy；
当氨基含保护基时，所述方法还包括脱去保护基的步骤；氨基保护基优选为Boc；
R1A、R2A、R’、Ra、Rb、Rc、Rd、RX1、RX2、RX3、R3、R4、R5、R6和Cy如通式(IV)中所定义。
方案五-3
本公开的提供通式(IV)所示的化合物或其可药用的盐的方法，该方法包括：RX1为烷氧基或环烷氧基的通式(IV)所示的化合物或其可药用的盐在酸性条件下发生去烷基或去环烷基反应得到RX1为-OH的通式(IV)所示的化合物或其可药用的盐。
方案五-4
本公开的提供通式(IV)所示的化合物或其可药用的盐的方法，该方法包括：
通式(IVA’)所示的化合物或其盐与NH2-R5或其盐(优选为盐酸盐)在催化剂存在下反应得到通式(IV)所示的化合物或其可药用的盐，
R3A为-C(＝NR5)NR3R4；
R1A、R2A、R’、Ra、Rb、Rc、Rd、RX1、RX2、RX3和R5如通式(IV)中所定义。
方案六
本公开提供通式(V)所示的化合物或其可药用的盐的方法，该方法包括：
通式(IVa)所示的化合物或其盐与通式(Vb)所示的化合物或其盐发生缩合反应得到通式(V)所示的化合物或其可药用的盐，其中，
RW1为氢原子或氨基保护基(优选为叔丁基亚磺酰基)，RW2为氢原子或羟基保护基(优选为TBS)；
当RW1为氨基保护基和/或RW2为羟基保护基时，所述制备方法还包括在缩合反应之后于酸性条件下脱去保护基的步骤；
R10为卤素(优选为氯原子)或OH；当R10为OH时，该反应在缩合剂或草酰氯的存在下发生，优选在缩合剂的存在下发生；
Ra、Rb、Rc、Rd、RX1、RX2、RX3、R’、R1A、R2A、RA4、u1和u2如通式(V)中所定义。
方案六-1
本公开提供通式(V)所示的化合物或其可药用的盐的方法，该方法包括：RX1为烷氧基或环烷氧基的通式(V)所示的化合物或其可药用的盐在酸性条件下发生去烷基或去环烷基反应得到RX1为-OH的通式(V)所示的化合物或其可药用的盐。
方案七
本公开提供通式(V-1)或(V-2)所示的化合物或其可药用的盐的方法，该方法包括：
通式(IVa)所示的化合物或其盐与通式(V-1b)所示的化合物或其盐在碱性条件下发生缩合反应得到通式(V-1)所示的化合物或其可药用的盐，或，
通式(IVa)所示的化合物或其盐与通式(V-2b)所示的化合物或其盐在碱性条件 下发生缩合反应得到通式(V-2)所示的化合物或其可药用的盐，其中，
RW1为氢原子或氨基保护基(优选为优选为叔丁基亚磺酰基)，RW2为氢原子或羟基保护基(优选为TBS)；
当RW1为氨基保护基和/或RW2为羟基保护基时，所述制备方法还包括在缩合反应之后于酸性条件下脱去保护基的步骤；
R10为卤素(优选为氯原子)或OH；当R10为OH时，该反应在缩合剂或草酰氯的存在下发生，优选在缩合剂的存在下发生；
Ra、Rb、Rc、Rd、RX1、RX2、RX3、R’、R1A、R2A、RA4、u1和u2如通式(V-1)中所定义。
方案七-1
本公开提供通式(V-1)或(V-2)所示的化合物或其可药用的盐的方法，该方法包括：RX1为烷氧基或环烷氧基的通式(V-1)或(V-2)所示的化合物或其可药用的盐在酸性条件下发生去烷基或去环烷基反应得到RX1为-OH的通式(V-1)或(V-2)所示的化合物或其可药用的盐。
方案八
本公开提供通式(V-1)或(V-2)所示的化合物或其可药用的盐的方法，该方法包括：
通式(V-1A)所示的化合物或其盐在酸性条件下发生脱保护反应得到通式(V-1)所示的化合物或其可药用的盐，
通式(V-2A)所示的化合物或其盐在酸性条件下发生脱保护反应得到通式(V-2)所示的化合物或其可药用的盐，其中，
RW1为氨基保护基，所述氨基保护基优选为Boc；
Ra、Rb、Rc、Rd、RX1、RX2、RX3、R’、R1A、R2A、RA4、u1和u2如通式(V-1)中所定义。
方案九-A1
本公开提供通式(VI’)所示的化合物或其可药用的盐的方法，该方法包括：
通式(IVa)所示的化合物或其盐与通式(VI’B)所示的化合物或其盐(优选为盐酸盐)在碱性条件下发生缩合反应得到通式(VI’)所示的化合物或其可药用的盐，其中，
R10为卤素(优选为氯原子)或OH；当R10为OH时，该反应在缩合剂或草酰氯的存在下发生，优选在缩合剂的存在下发生；
R’、Ra、Rb、Rc、Rd、RX1、RX2、RX3、R1A、R2A、Q、R3、R4和R5如通式(VI’)中所定义。
方案九-A2
本公开提供通式(VI’)所示的化合物或其可药用的盐的方法，该方法包括：
通式(VI’A)所示的化合物或其盐与通式(IB’)所示的化合物或其盐(优选为盐酸盐)发生pinner反应得到通式(VI’)所示的化合物或其可药用的盐，其中，
R5为氢原子；
R’、Ra、Rb、Rc、Rd、RX1、RX2、RX3、R1A、R2A、Q、R3和R4如通式(VI’)中所定义。
方案九-A3
本公开提供通式(VI’)所示的化合物或其可药用的盐的方法，该方法包括：RX1为烷氧基或环烷氧基的通式(VI’)所示的化合物或其可药用的盐在酸性条件下发生去烷基或去环烷基反应得到RX1为-OH的通式(VI’)所示的化合物或其可药用的盐。
方案九-A4
本公开提供通式(VI’)所示的化合物或其可药用的盐的方法，该方法包括：
通式(VI’A)所示的化合物或其盐与NH2-R5或其盐(优选为盐酸盐)发生pinner反应得到通式(VI’)所示的化合物或其可药用的盐，其中，
R3和R4均为氢原子；
R’、Ra、Rb、Rc、Rd、RX1、RX2、RX3、R1A、R2A、Q和R5如通式(VI’)中所定义。
方案九-A-A1
本公开提供通式(VI’-1)所示的化合物或其可药用的盐的方法，该方法包括：
通式(IVa)所示的化合物或其盐与通式(VI’-1B)所示的化合物或其盐(优选为盐酸盐)在碱性条件下发生缩合反应得到通式(VI’-1)所示的化合物或其可药用的盐，其中，
R10为卤素(优选为氯原子)或OH；当R10为OH时，该反应在缩合剂或草酰氯的存在下发生，优选在缩合剂的存在下发生；
R’、Ra、Rb、Rc、Rd、RX1、RX2、RX3、R1A、R2A、Q、R3、R5和RC如通式(VI’-1)中所定义。
方案九-A-A2
本公开提供通式(VI’-1)所示的化合物或其可药用的盐的方法，该方法包括：
通式(VI’A)所示的化合物或其盐与通式(VI-1B’)所示的化合物或其盐(优选为盐酸盐)发生pinner反应得到通式(VI’-1)所示的化合物或其可药用的盐，其中，
R5为氢原子；
R’、Ra、Rb、Rc、Rd、RX1、RX2、RX3、R1A、R2A、Q、R3和RC如通式(VI’-1)中所定义。
方案九-A-A3
本公开提供通式(VI’-1)所示的化合物或其可药用的盐的方法，该方法包括：
通式(VI’)所示的化合物或其盐(优选三氟乙酸盐)与通式(VI’-1b)所示的化合物或其盐(优选为盐酸盐)在碱性条件下发生酰胺化反应得到通式(VI’-1)所示的化合物或其可药用的盐，其中，
R4为氢原子；
R10为卤素(优选为氯)或OH；当R10为OH时，该反应在缩合剂或草酰氯的存在下发生，优选在缩合剂的存在下发生；
R’、Ra、Rb、Rc、Rd、RX1、RX2、RX3、R1A、R2A、Q、R3、R5和RC如通式(VI’-1)中所定义。
方案九-A-A4
本公开提供通式(VI’-1)所示的化合物或其可药用的盐的方法，该方法包括：RX1为烷氧基或环烷氧基的通式(VI’-1)所示的化合物或其可药用的盐在酸性条件下发生去烷基或去环烷基反应得到RX1为-OH的通式(VI’-1)所示的化合物或其可药用的盐。
方案九
本公开提供通式(VI)所示的化合物或其可药用的盐的方法，该方法包括：
通式(IVA’)所示的化合物或其盐与通式(II’B)所示的化合物或其盐(优选为盐酸盐)在催化剂存在下发生pinner反应得到通式(VI)所示的化合物或其可药用的盐，其中，
R5为氢原子；
R1A、R2A、R’、Ra、Rb、Rc、Rd、RX1、RX2、RX3、R3a和R4如通式(VI)中所定义。
方案九-1
本公开提供通式(VI)所示的化合物或其可药用的盐的方法，该方法包括：
通式(IVa)所示的化合物或其盐与通式(VIb)所示的化合物或其盐(优选为盐酸盐)在碱性条件下发生缩合反应得到通式(VI)所示的化合物或其可药用的盐，其中，
R10为卤素(优选为氯原子)或OH；当R10为OH时，该反应在缩合剂或草酰氯的存在下发生，优选在缩合剂的存在下发生；
R’、Ra、Rb、Rc、Rd、RX1、RX2、RX3、R1A、R2A、R3a、R4和R5如通式(VI)中所定义。
方案九-2
本公开提供通式(VI)所示的化合物或其可药用的盐的方法，该方法包括：RX1为烷氧基或环烷氧基的通式(VI)所示的化合物或其可药用的盐在酸性条件下发生去烷基或去环烷基反应得到RX1为-OH的通式(VI)所示的化合物或其可药用的盐。
方案九-3
本公开提供通式(VI)所示的化合物或其可药用的盐的方法，该方法包括：
通式(IVA’)所示的化合物或其盐与NH2-R5或其盐(优选为盐酸盐)在催化剂存在下发生pinner反应得到通式(VI)所示的化合物或其可药用的盐，其中，
R3a和R4均为氢原子；
R1A、R2A、R’、Ra、Rb、Rc、Rd、RX1、RX2、RX3和R5如通式(VI)中所定义。
方案十-A1
本公开提供通式(VII’)所示的化合物或其可药用的盐的方法，该方法包括：
通式(IVa)所示的化合物或其盐与通式(VII’B)所示的化合物或其盐(优选为盐酸盐)在碱性条件下发生缩合反应得到通式(VII’)所示的化合物或其可药用的盐，其中，
R10为卤素(优选为氯原子)或OH；当R10为OH时，该反应在缩合剂或草酰氯的存在下发生，优选在缩合剂的存在下发生；
R’、Ra、Rb、Rc、Rd、RX1、RX2、RX3、R1A、R2A、R3、R4和R5如通式(VII’)中所定义。
方案十-A2
本公开提供通式(VII’)所示的化合物或其可药用的盐的方法，该方法包括：
通式(VII’)所示的化合物或其盐与通式(II-1B)所示的化合物或其盐(优选为盐酸盐)在碱性条件下发生缩合反应得到通式(VII’)所示的化合物或其可药用的盐，其中，
R*选自羟基、烷氧基和卤素；
当氨基含保护基时，所述方法还包括脱去保护基的步骤；氨基保护基优选为Boc；
R’、Ra、Rb、Rc、Rd、RX1、RX2、RX3、R1A、R2A、Q、R3、R4和R5如通式(VII’)中所定义。
方案十-A3
本公开提供通式(VII’)所示的化合物或其可药用的盐的方法，该方法包括：RX1为烷氧基或环烷氧基的通式(VII’)所示的化合物或其可药用的盐在酸性条件下发生去烷基或去环烷基反应得到RX1为-OH的通式(VII’)所示的化合物或其可药用的盐。
方案十
本公开提供通式(VII)所示的化合物或其可药用的盐的方法，该方法包括：
通式(IVa’)所示的化合物或其盐与通式(II-1B)所示的化合物或其盐(优选为盐酸盐)在碱性条件下发生酰胺化反应得到通式(VII)所示的化合物或其可药用的盐，
其中，R*选自羟基、烷氧基和卤素；
当氨基含保护基时，所述方法还包括脱去保护基的步骤；氨基保护基优选为Boc；
R1A、R2A、R’、Ra、Rb、Rc、Rd、RX1、RX2、RX3、R3、R4和R5如通式(VII)中所定义。
方案十-1
本公开提供通式(VII)所示的化合物或其可药用的盐的方法，该方法包括：
通式(IVa)所示的化合物或其盐与通式(VIIb)所示的化合物或其盐(优选为盐酸盐)在碱性条件下发生缩合反应得到通式(VII)所示的化合物或其可药用的盐，其中，
R10为卤素(优选为氯原子)或OH；当R10为OH时，该反应在缩合剂或草酰氯的存在下发生，优选在缩合剂的存在下发生；
R’、Ra、Rb、Rc、Rd、RX1、RX2、RX3、R1A、R2A、R3、R4和R5如通式(VII)中所定义。
方案十-2
本公开提供通式(VII)所示的化合物或其可药用的盐的方法，该方法包括：RX1为烷氧基或环烷氧基的通式(VII)所示的化合物或其可药用的盐在酸性条件下发生去烷基或去环烷基反应得到RX1为-OH的通式(VII)所示的化合物或其可药用的盐。
方案十一-1
本公开提供通式(VIII)所示的化合物或其可药用的盐的方法，该方法包括：
通式(IIa)所示的化合物或其盐与通式(VIIIB)所示的化合物或其盐(优选为盐酸盐)在碱性条件下发生缩合反应得到通式(VIII)所示的化合物或其可药用的盐，其中，
R10为卤素(优选为氯原子)或OH；当R10为OH时，该反应在缩合剂或草酰氯的存在下发生，优选在缩合剂的存在下发生；
R’、X、Ra、Rb、Rc、Rd、RX1、RX2、RX3、R1A、R2A、Q、R3和R4如通式(VIII)中所定义。
方案十一-2
本公开提供通式(VIII)所示的化合物或其可药用的盐的方法，该方法包括：
通式(VIIIA)所示的化合物或其盐与通式(IB’)所示的化合物或其盐(优选为盐酸盐)发生氨酯交换反应得到通式(VIII)所示的化合物或其可药用的盐，其中，
RL为烷氧基；
R’、X、Ra、Rb、Rc、Rd、RX1、RX2、RX3、R1A、R2A、Q、R3和R4如通式(VIII)中所定义。
方案十一-3
本公开提供通式(VIII)所示的化合物或其可药用的盐的方法，该方法包括：RX1为烷氧基或环烷氧基的通式(VIII)所示的化合物或其可药用的盐在酸性条件下发生去烷基或去环烷基反应得到RX1为-OH的通式(VIII)所示的化合物或其可药用的盐。
上述的pinner反应依据为pinner脒合成法，具体机理为：原料氰基化合物在催化剂催化下与醇溶剂发生醇解反应生成亚氨酯，再与胺或氨发生胺解或氨解反应生成脒。
上述pinner反应所述的催化剂可以为酸催化剂或碱催化剂，酸催化剂为有机酸或无机酸，包括但不限于盐酸、氯化氢气体、巯基乙酸和N-乙酰半胱氨酸等，优选巯基乙酸；碱催化剂为有机碱或无机碱，包括但不限于甲醇钠、乙醇钠、三 乙胺、N,N-二异丙基乙胺、N,N-二异丙基乙二胺等，优选N,N-二异丙基乙胺或甲醇钠，进一步优选甲醇钠。
上述氨解反应所用的氨为液氨、氨水或铵盐等，优选氯化铵；胺解反应所用的胺为有机胺。
上述醇溶剂包括但不限于甲醇、乙醇、异丙醇和正丁醇等。
以上合成方案中提供酸性条件的试剂包括有机酸和无机酸，所述的有机酸包括但不限于三氟乙酸、甲酸、乙酸、甲磺酸、对甲苯磺酸、Me3SiCl和TMSOTf；所述的无机酸包括但不限于氯化氢、HCl·二氧六环溶液、盐酸二氧六环溶液、盐酸、硫酸、硝酸和磷酸；优选为HCl·二氧六环溶液或盐酸二氧六环溶液；上述合成方案中的去烷基或去环烷基反应中提供酸性条件的试剂优选为路易斯酸，如BBr3、ALCl3等，优选为BBr3。
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、N,N-二异丙基乙二胺、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、氟化铯和氢氧化钾；优选三乙胺或N,N-二异丙基乙胺；当R10为卤素时，提供碱性条件的试剂优选为三乙胺，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，该缩合反应优选在缩合剂存在下进行，缩合剂如下所定义；上述合成方案一-1、二-1和五-1中的碱优选为N,N-二异丙基乙胺。
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。
上述合成方案中的缩合反应，当R10为卤素时，该缩合反应任选在催化剂存在下进行，所述催化剂优选为4-二甲氨基吡啶。
上述合成方案中的酰胺化反应，当R*为羟基时，该反应任选在缩合剂存在下进行；所述缩合剂如上所定义。
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。
附图说明
图1实施例16化合物的H-N HSQC谱图；
图2实施例16化合物的H-N HMBC谱图；
图3实施例16化合物在大鼠切口疼痛模型中的镇痛药效；
图4实施例16化合物在大鼠切口疼痛模型中体重的影响；
图5实施例32化合物在大鼠切口疼痛模型中的镇痛药效；
图6实施例32化合物在大鼠切口疼痛模型中体重的影响。
具体实施方式
以下结合实施例用于进一步描述本公开，但这些实施例并非限制着本公开的范围。
实施例
化合物的结构是通过核磁共振(NMR)或/和质谱(MS)来确定的。NMR位移(δ)以10-6(ppm)的单位给出。NMR的测定是用Bruker AVANCE-400核磁仪或Bruker AVANCE NEO 500M，测定溶剂为氘代二甲基亚砜(DMSO-d6)、氘代氯仿(CDCl3)、氘代甲醇(CD3OD)，内标为四甲基硅烷(TMS)。
MS的测定用Agilent 1200/1290 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)
高效液相色谱法(HPLC)分析使用Agilent HPLC 1200DAD、Agilent HPLC 1200VWD和Waters HPLC e2695-2489高效液相色谱仪。
手性HPLC分析测定使用Agilent 1260 DAD高效液相色谱仪。
高效液相制备使用Waters 2545-2767、Waters 2767-SQ Detecor2、Shimadzu LC-20AP和Gilson GX-281制备型色谱仪。
手性制备使用Shimadzu LC-20AP制备型色谱仪。
CombiFlash快速制备仪使用Combiflash Rf200(TELEDYNE ISCO)。
薄层层析硅胶板使用烟台黄海HSGF254或青岛GF254硅胶板，薄层色谱法(TLC)使用的硅胶板采用的规格是0.15mm～0.2mm，薄层层析分离纯化产品采用的规格是0.4mm～0.5mm。
硅胶柱色谱法一般使用烟台黄海硅胶200～300目硅胶为载体。
激酶平均抑制率及IC50值的测定用NovoStar酶标仪(德国BMG公司)。
本发明的已知的起始原料可以采用或按照本领域已知的方法来合成，或可购买自ABCR GmbH&Co.KG，Acros Organics，Aldrich Chemical Company，韶远化学 科技(Accela ChemBio Inc)、达瑞化学品等公司。
实施例中无特殊说明，反应均能够在氩气氛或氮气氛下进行。
氩气氛或氮气氛是指反应瓶连接一个约1L容积的氩气或氮气气球。
氢气氛是指反应瓶连接一个约1L容积的氢气气球。
加压氢化反应使用Parr 3916EKX型氢化仪和清蓝QL-500型氢气发生器或HC2-SS型氢化仪。
氢化反应通常抽真空，充入氢气，反复操作3次。
微波反应使用CEM Discover-S 908860型微波反应器。
实施例中无特殊说明，溶液是指水溶液。
实施例中无特殊说明，反应的温度为室温，为20℃～30℃。
实施例中的反应进程的监测采用薄层色谱法(TLC)，反应所使用的展开剂，纯化化合物采用的柱层析的洗脱剂的体系和薄层色谱法的展开剂体系包括：A：二氯甲烷/甲醇体系，B：正己烷/乙酸乙酯体系，C：石油醚/乙酸乙酯体系，溶剂的体积比根据化合物的极性不同而进行调节，也可以加入少量的三乙胺和醋酸等碱性或酸性试剂进行调节。
实施例1
(2R,3S,4S,5R)-N-(2-氨基嘧啶-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1
第一步
(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
(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
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Example 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：超临界CO2，流动相B：IPA)，梯度配比：A:B：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％)。
MS m/z(ESI):353.2[M-1]。
单一构型化合物(较短保留时间)1b-1(5.5g，产率：45.8％)
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：超临界CO2，流动相B：IPA(0.1％DEA))，梯度配比：流动相A：60％-95％，流速：1.5mL/min)。
单一构型化合物(较长保留时间)1b-2(5.08g，产率：42.3％)。
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：超临界CO2，流动相B：IPA(0.1％DEA))，梯度配比：流动相A：60％-95％，流速：1.5mL/min)。
第二步
(2R,3S,4S,5R)-N-(2-氨基嘧啶-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1
将化合物1b-1(22mg，62μmol)，2,5-二氨基嘧啶1c(10.3mg，93μmol，上海毕得)溶解在1mL N,N-二甲基甲酰胺中，冰浴下加入N,N-二异丙基乙胺(24mg，186μmol)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)(28.3mg，74μmol)，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1(8mg，产率：28.8％)。
MS m/z(ESI):447.2[M+1]。
1H NMR(500MHz,CD3OD):δ8.39(s,2H),7.13(ddd,1H),6.98(td,1H),5.05(d,1H),4.26(dd,1H),3.99(d,3H),2.78(p,1H),1.68-1.64(m,3H),0.80(dq,3H)。
实施例2
(2R,3S,4S,5R)-3-(3,4-二氟-2-甲氧基苯基)-N-(2-((R)-2,3-二羟基丙氧基)吡啶-4-基)-4,5-二甲基-5-(三氟甲基)四氢呋喃-2-甲酰胺2
第一步
(S)-(+)-2-((2,2-二甲基-1,3-二氧杂戊环烷-4-基)甲氧基)吡啶-4-胺2c
将(S)-(+)-(2,2-二甲基-1,3-二氧杂戊环烷-4-基)甲醇2b(616mg，4.66mmol，上海韶远)溶于10mL无水N,N-二甲基甲酰胺中，冰浴下加入氢化钠(199mg，5mmol，60％purity)，保持温度反应1小时后加入2-氯-4-氨基吡啶2a(200mg，1.55mmol，上海毕得)，160℃搅拌反应10小时，反应液降至室温，加入水淬灭，用二氯甲烷萃取(30mL×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35％-45％，流速：30mL/min)得到标题化合物2c(140mg，产率：40％)。
MS m/z(ESI):225.2[M+1]。
第二步
(2R,3S,4S,5R)-3-(3,4-二氟-2-甲氧基苯基)-N-(2-((S)-2,2-二甲基-1,3-二氧杂戊环烷-4-基)甲氧基)吡啶-4-基)-4,5-二甲基-5-(三氟甲基)四氢呋喃-2-甲酰胺2d
将化合物1b-1(20mg，56.43μmol)溶于二氯甲烷(0.8mL)，冰浴下加入草酰氯(14.3mg，112μmol)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，残余物溶于二氯甲烷(1mL)，加入化合物2c(15.2mg，67.7μmol)，三乙胺(22.8mg，225.8μmol)和4-二甲氨基吡啶(1.4mg，11.2μmol)，搅拌反应1小时，反应液减压浓缩即得粗品标题化合物2d(31mg)，产物不经纯化，直接用于下步反应。
MS m/z(ESI):561.2[M+1]。
第三步
(2R,3S,4S,5R)-3-(3,4-二氟-2-甲氧基苯基)-N-(2-((R)-2,3-二羟基丙氧基)吡啶-4-基)-4,5-二甲基-5-(三氟甲基)四氢呋喃-2-甲酰胺2
将粗品化合物2d(30mg，53.5μmol)溶于二氯甲烷(1mL)，加入4M HCl二氧六环溶液(0.5mL)，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2(2mg，产率：7％)。
MS m/z(ESI):521.2[M+1]。
1H NMR(500MHz,CD3OD):δ8.00(dd,1H),7.41(d,1H),7.30(d,1H),7.17(dd,1H),7.00(td,1H),5.07(s,1H),4.25(dd,1H),4.05-3.84(m,5H),3.64(qd,2H),2.80(t,1H),2.21(t,1H),1.66(s,3H),0.83(dt,3H)。
实施例3
(2R,3S,4S,5R)-3-(3,4-二氟-2-甲氧基苯基)-N-(2-(2-羟基丙-2-基)吡啶-4-基)-4,5-二甲基-5-(三氟甲基)四氢呋喃-2-甲酰胺3
将化合物1b-1(20mg，56μmol)，2-(4-氨基吡啶-2-基)丙-2-醇3a(12.9mg，84.6μmol，上海韶远)溶于1mL N,N-二甲基甲酰胺中，冰浴下加入N,N-二异丙基乙胺(22mg，169μmol)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)(26mg，68μmol)，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3(4mg，产率：14.5％)。
MS m/z(ESI):489.2[M+1]。
1H NMR(500MHz,CD3OD):δ8.34(d,1H),7.90(d,1H),7.58(dd,1H),7.12(ddd,1H),6.98(td,1H),5.07(d,1H),4.32(dd,1H),4.00(d,3H),2.79(p,1H),1.66(d,3H),1.51(s,6H),0.81(dt,3H)。
实施例4-1或实施例4-2
(2R,3S,4S,5R)-3-(3,4-二氟-2-甲氧基苯基)-4,5-二甲基-N-(2-(2-甲基-2H-四唑-5-基)吡啶-4-基)-5-(三氟甲基)四氢呋喃-2-甲酰胺4-1或
(2R,3S,4S,5R)-3-(3,4-二氟-2-甲氧基苯基)-4,5-二甲基-N-(2-(1-甲基-1H-四唑-5-基)吡啶-4-基)-5-(三氟甲基)四氢呋喃-2-甲酰胺4-2
第一步
4-叠氮-2-(2H-四唑-5-基)吡啶4b
将4-溴吡啶-2-甲腈4a(1g，5.46mmol，上海韶远)，叠氮化钠(535mg，8.22mmol)溶于N,N-二甲基甲酰胺(25mL)中，加入氯化铵(1.0g，18.7mmol)，120℃搅拌反应4小时，反应液冷却至室温，倒入水中，用乙酸乙酯萃取(15mL×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4b(1g)，产品不经纯化直接用于下一步反应。
MS m/z(ESI):189.2[M+1]。
第二步
4-叠氮-2-(2-甲基-2H-四唑-5-基)吡啶4c-1和
4-叠氮-2-(1-甲基-1H-四唑-5-基)吡啶4c-2的混合物
将化合物4b(1g，5.3149mmol)溶于N,N-二甲基甲酰胺(20mL)，加入氢氧化钾(900mg，16mmol)和碘甲烷(1g，7mmol)，搅拌反应16小时，反应液过滤，滤液中加入水，用乙酸乙酯萃取(15mL×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标题化合物4c-1和4c-2的粗品混合物(1g)，产品不经纯化直接用于下一步反应。
MS m/z(ESI):203.2[M+1]。
第三步
2-(2-甲基-2H-四唑-5-基)吡啶-4-胺4d-1
2-(1-甲基-1H-四唑-5-基)吡啶-4-胺4d-2
将化合物4c-1和4c-2的粗品混合物(400mg，1.97mmol)溶于甲醇(20mL)，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，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(40mg，30mg，产率：11.4％，8.6％)。
MS m/z(ESI):177.2[M+1]。
单一构型化合物(较短保留时间)(30mg，产率：8.6％)
HPLC分析：保留时间0.54分钟，纯度：99％(色谱柱：ACQUITYC18,1.7μm，2.1*50mm；流动相：水(10mM碳酸氢铵)，乙腈，梯度配比：乙腈10％-95％)。
单一构型化合物(较长保留时间)(40mg，产率：11.4％)
HPLC分析：保留时间0.81分钟，纯度：92％(色谱柱：ACQUITYC18，1.7μm，2.1*50mm；流动相：水(10mM碳酸氢铵)，乙腈，梯度配比：乙腈10％-95％)。
第四步
(2R,3S,4S,5R)-3-(3,4-二氟-2-甲氧基苯基)-4,5-二甲基-N-(2-(2-甲基-2H-四唑-5-基)吡啶-4-基)-5-(三氟甲基)四氢呋喃-2-甲酰胺4-1或
(2R,3S,4S,5R)-3-(3,4-二氟-2-甲氧基苯基)-4,5-二甲基-N-(2-(1-甲基-1H-四唑-5-基)吡啶-4-基)-5-(三氟甲基)四氢呋喃-2-甲酰胺4-2
将化合物1b-1(20mg，56.43μmol)溶于二氯甲烷(2mL)，冰浴下加入草酰氯(40mg，315μmol)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，残余物溶于二氯甲烷(3mL)，加入三乙胺(40mg，395μmol)，-10℃滴加化合物4d-1,4d-2中较长保留时间对应的化合物的(15.2mg，67.7μmol)二氯甲烷溶液(1mL)，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4-1或4-2(4mg，产率：13.8％)。
MS m/z(ESI):513.2[M+1]。
1H NMR(500MHz,DMSO-d6):δ10.87(s,1H),8.69-8.67(m,1H),8.58-8.56(m,1H),7.88-7.84(m,1H),7.23-7.15(m,2H),5.18-5.13(m,1H),4.40(s,3H),4.31-4.23(m,1H),3.96(s,3H),2.83-2.74(m,1H),1.63(s,3H),0.76-0.72(m,3H)。
实施例4-1或实施例4-2
(2R,3S,4S,5R)-3-(3,4-二氟-2-甲氧基苯基)-4,5-二甲基-N-(2-(2-甲基-2H-四唑-5-基)吡啶-4-基)-5-(三氟甲基)四氢呋喃-2-甲酰胺4-1或
(2R,3S,4S,5R)-3-(3,4-二氟-2-甲氧基苯基)-4,5-二甲基-N-(2-(1-甲基-1H-四唑-5-基) 吡啶-4-基)-5-(三氟甲基)四氢呋喃-2-甲酰胺4-2
第一步
4-叠氮-2-(2H-四唑-5-基)吡啶4b
将4-溴吡啶-2-甲腈4a(1g，5.46mmol，上海韶远)，叠氮化钠(535mg，8.22mmol)溶于N,N-二甲基甲酰胺(25mL)中，加入氯化铵(1.0g，18.7mmol)，120℃搅拌反应4小时，反应液冷却至室温，倒入水中，用乙酸乙酯萃取(15mL×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4b(1g)，产品不经纯化直接用于下一步反应。
MS m/z(ESI):189.2[M+1]。
第二步
4-叠氮-2-(2-甲基-2H-四唑-5-基)吡啶4c-1和
4-叠氮-2-(1-甲基-1H-四唑-5-基)吡啶4c-2的混合物
将化合物4b(1g，5.3149mmol)溶于N,N-二甲基甲酰胺(20mL)，加入氢氧化钾(900mg，16mmol)和碘甲烷(1g，7mmol)，搅拌反应16小时，反应液过滤，滤液中加入水，用乙酸乙酯萃取(15mL×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标题化合物4c-1和4c-2的粗品混合物(1g)，产品不经纯化直接用于下一步反应。
MS m/z(ESI):203.2[M+1]。
第三步
2-(2-甲基-2H-四唑-5-基)吡啶-4-胺4d-1
2-(1-甲基-1H-四唑-5-基)吡啶-4-胺4d-2
将化合物4c-1和4c-2的粗品混合物(400mg，1.97mmol)溶于甲醇(20mL)，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，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(40mg，30mg，产率：11.4％，8.6％)。
MS m/z(ESI):177.2[M+1]。
单一构型化合物(较短保留时间)(30mg，产率：8.6％)
HPLC分析：保留时间0.54分钟，纯度：99％(色谱柱：ACQUITYC18，1.7μm，2.1*50mm；流动相：水(10mM碳酸氢铵)，乙腈，梯度配比：乙腈10％-95％)。
单一构型化合物(较长保留时间)(40mg，产率：11.4％)
HPLC分析：保留时间0.81分钟，纯度：92％(色谱柱：ACQUITYC18，1.7μm，2.1*50mm；流动相：水(10mM碳酸氢铵)，乙腈，梯度配比：乙腈10％-95％)。
第四步
(2R,3S,4S,5R)-3-(3,4-二氟-2-甲氧基苯基)-4,5-二甲基-N-(2-(2-甲基-2H-四唑-5-基)吡啶-4-基)-5-(三氟甲基)四氢呋喃-2-甲酰胺4-1或
(2R,3S,4S,5R)-3-(3,4-二氟-2-甲氧基苯基)-4,5-二甲基-N-(2-(1-甲基-1H-四唑-5-基)吡啶-4-基)-5-(三氟甲基)四氢呋喃-2-甲酰胺4-2
将化合物1b-1(20mg，56.43μmol)溶于二氯甲烷(2mL)，冰浴下加入草酰氯(40mg，315μmol)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，残余物溶于二氯甲烷(3mL)，加入三乙胺(40mg，395μmol)，-10℃滴加化合物4d-1,4d-2中较短保留时间对应的化合物的(15.2mg，67.7μmol)二氯甲烷溶液(1mL)，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4-1或4-2(3mg，产率：10.3％)。
MS m/z(ESI):513.2[M+1]。
1H NMR(500MHz,DMSO-d6):δ10.80(s,1H),8.61-8.57(m,1H),8.52-8.51(m,1H),7.75-7.71(m,1H),7.22-7.16(m,2H),5.16-5.13(m,1H),4.43(s,3H),4.29-4.25(m,1H),3.95(s,3H),2.77-2.74(m,1H),1.61(s,3H),0.74-0.72(m,3H)。
实施例5
4-((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)-N-甲氧基吡啶甲酰胺5
第一步
4-((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)吡啶甲酸甲酯5a
将化合物1b-1(50mg，141.1μmol)溶于二氯甲烷(5mL)，冰浴下加入草酰氯(36mg，282μmol)和1滴N,N-二甲基甲酰胺，自然恢复室温反应1小时，反应液减压浓缩，残余物溶于二氯甲烷(5mL)，加入三乙胺(72mg，711μmol)，4-二甲氨基吡啶(3.5mg，28.2μmol)，冰浴下加入4-氨基吡啶-2-甲酸甲酯(30mg，197.6μmol)，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体系B纯化得到标题化合物5a(30mg，产率：43.5％)。
MS m/z(ESI):489.2[M+1]。
第二步
4-((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)-N-甲氧基吡啶甲酰胺5
将化合物5a(20mg，40.9μmol)溶于四氢呋喃(0.5mL)，加入甲氧基胺盐酸盐(6.84mg，81.9μmol，上海泰坦)，冰浴下滴加1M双三甲基硅基胺基锂的四氢呋喃溶液(0.2mL)，保持温度反应1小时，反应液中加入饱和氯化铵溶液淬灭，用乙酸乙酯萃取(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，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5(3mg，产率：14.5％)。
MS m/z(ESI):504.2[M+1]。
1H NMR(500MHz,CD3OD):δ8.48(d,1H),8.25(d,1H),7.90(dd,1H),7.14(dd,1H),7.00(q,1H),5.10(d,1H),4.35(dd,1H),4.02(d,3H),3.83(s,3H),2.82(p,1H),1.68(s,3H),0.87-0.80(m,3H)。
实施例6
(2R,3S,4S,5R)-N-(2-(1-氨基-2-羟乙基)吡啶-4-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6(非对映异构体混合物)
第一步
(2-(2-((叔丁基二甲基硅基)氧基)-1-((叔丁基亚磺酰基)氨基)乙基)吡啶-4-基)氨基甲酸叔丁酯6c(外消旋体)
将0.8mL 2.5M正丁基锂的正己烷溶液加入四氢呋喃(10mL)中，-78℃滴加(2-溴吡啶-4-基)氨基甲酸叔丁酯6b(250mg，915μmol，采用文献“Dalton Transactions,2016,vol.45,#32,p.128–7-12813”公开的方法制备而得)的四氢呋喃溶液(2mL)，保持温度反应1小时，加入N-(2-((叔丁基二甲基硅基)氧基)乙亚基)-2-甲基丙烷-2-亚磺酰胺6a(250mg，56.43μmol，采用专利申请“WO2008132502”中说明书第89页Intermediate 25公开的方法制备而得)的四氢呋喃溶液(2mL)，保持温度搅拌反应2小时，-78℃加入饱和氯化钠溶液淬灭，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6c(170mg，外消旋体，产率：40％)。
MS m/z(ESI):472.2[M+1]。
第二步
N-(1-(4-氨基吡啶-2-基)-2-((叔丁基二甲基硅基)氧基)乙基)-2-甲基丙烷-2-亚磺酰胺6d(外消旋体)
将化合物6c(132mg，280μmol)溶于二氯甲烷(3mL)，加入1mL三氟醋酸，搅拌反应3小时，反应液减压浓缩，残余物溶于二氯甲烷，用饱和碳酸氢钠溶液洗涤，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6d(104mg，外消旋体)，不经纯化，直接用于下一步反应。
MS m/z(ESI):372.2[M+1]。
第三步
(2R,3S,4S,5R)-N-(2-(2-((叔丁基二甲基硅基)氧基)-1-((叔丁基亚磺酰基)氨基)乙基) 吡啶-4-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6e(非对映异构体混合物)
将化合物1b-1(354mg，284μmol)溶于二氯甲烷(3mL)，冰浴下加入草酰氯(71mg，560μmol)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，残余物溶于二氯甲烷(3mL)，冰浴下加入化合物6d(104mg，280μmol)，N,N-二异丙基乙二胺(110mg，851μmol)，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体系A纯化得到标题化合物6e(150mg，非对映异构体混合物，产率：75％)。
MS m/z(ESI):708.2[M+1]。
第四步
(2R,3S,4S,5R)-N-(2-(1-氨基-2-羟乙基)吡啶-4-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6(非对映异构体混合物)
将化合物6e(150mg，212μmol)溶于二氯甲烷(2mL)，加入4M盐酸二氧六环溶液(5mL)，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(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)纯化得到标题化合物6(3mg，非对映异构体混合物，产率：2.9％)。
MS m/z(ESI):490.2[M+1]。
1H NMR(500MHz,CD3OD):δ8.72-8.18(m,1H),7.69(s,2H),7.13(ddd,1H),7.06-6.92(m,1H),5.08(d,1H),4.32(dd,1H),4.00(d,3H),3.86-3.54(m,2H),2.80(t,1H),1.66(s,3H),1.30(s,1H),0.88-0.71(m,3H)。
实施例6-1或实施例6-2
(2R,3S,4S,5R)-N-(2-((S)-1-氨基-2-羟乙基)吡啶-4-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6-1或
(2R,3S,4S,5R)-N-(2-((R)-1-氨基-2-羟乙基)吡啶-4-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6-2

第一步
(1-(4-((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-甲酰胺基)吡啶-2-基)-2-羟乙基)氨基甲酸叔丁酯6f(非对映异构体混合物)
将化合物6(190mg，388.2μmol)溶于二氯甲烷(6mL)，加入二碳酸二叔丁酯(85mg，388.2μmol)，搅拌反应14小时，反应液减压浓缩得到粗品标题化合物6f(230mg，非对映异构体混合物)。
MS m/z(ESI):590.2[M+1]。
第二步
((S)-(1-(4-((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-甲酰胺基)吡啶-2-基)-2-羟乙基)氨基甲酸叔丁酯6f-1
((R)-(1-(4-((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-甲酰胺基)吡啶-2-基)-2-羟乙基)氨基甲酸叔丁酯6f-2
将化合物6f(230mg)经手性柱拆分(Gilson 281，色谱柱：CHIRALPAK IE,20*250mm,10μm；流动相A：正己烷，流动相B：乙醇，梯度配比：A:B：90:10，流速：20mL/min))纯化得到标题化合物(65mg，114mg，产率：28.4％，49.8％)。
非对映异构体混合物6f手性HPLC分析方法：Agilent 1260DAD，色谱柱：CHIRALPAK IE，250*4.6mm，5μm；流动相：正己烷和乙醇(含0.1％二乙胺)，梯度配比：A:B：90:10，流速：1.0mL/min。
单一构型化合物(较短保留时间)：6.447min，(65mg，产率：28.4％)。
MS m/z(ESI):590.2[M+1]。
单一构型化合物(较长保留时间)：8.484min，(114mg，产率：49.8％)。
MS m/z(ESI):590.2[M+1]。
第三步
(2R,3S,4S,5R)-N-(2-((S)-1-氨基-2-羟乙基)吡啶-4-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6-1或
(2R,3S,4S,5R)-N-(2-((R)-1-氨基-2-羟乙基)吡啶-4-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6-2
将化合物6f-1，6f-2中较短保留时间对应的化合物(65mg，110μmol)溶于二氯甲烷(4mL)，加入4M盐酸的1,4-二氧六环溶液(2mL)，反应1小时后，减压浓缩，残余物用高效液相色谱法(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)纯化得到标题化合物6-1或6-2(37.6mg，产率：69.6％)。
MS m/z(ESI):490.2[M+1]。
1H NMR(500MHz,CD3OD):δ8.71-8.07(m,1H),7.68(s,2H),7.11(ddd,1H),6.97(td,1H),5.06(d,1H),4.30(dd,1H),3.98(d,3H),3.89-3.52(m,2H),2.78(p,1H),1.64(s,3H),1.30(d,1H),0.80(dt,3H)。
实施例6-1或实施例6-2
(2R,3S,4S,5R)-N-(2-((S)-1-氨基-2-羟乙基)吡啶-4-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6-1或
(2R,3S,4S,5R)-N-(2-((R)-1-氨基-2-羟乙基)吡啶-4-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6-2
第一步
(1-(4-((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-甲酰胺基)吡啶-2-基)-2-羟乙基)氨基甲酸叔丁酯6f(非对映异构体混合物)
将化合物6(190mg，388.2μmol)溶于二氯甲烷(6mL)，加入二碳酸二叔丁酯(85mg，388.2μmol)，搅拌反应14小时，反应液减压浓缩得到粗品标题化合物6f(230mg，非对映异构体混合物)。
MS m/z(ESI):590.2[M+1]。
第二步
((S)-(1-(4-((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-甲酰胺基)吡啶-2-基)-2-羟乙基)氨基甲酸叔丁酯6f-1
((R)-(1-(4-((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-甲酰胺基)吡啶-2-基)-2-羟乙基)氨基甲酸叔丁酯6f-2
将化合物6f(230mg)经手性柱拆分(Gilson 281，色谱柱：CHIRALPAK IE,20*250mm,10μm；流动相A：正己烷，流动相B：乙醇，梯度配比：A:B：90:10，流速：20mL/min))纯化得到标题化合物(65mg，114mg，产率：28.4％，49.8％)。非对映异构体混合物6f手性HPLC分析方法：Agilent 1260 DAD，色谱柱：CHIRALPAK IE，250*4.6mm，5μm；流动相：正己烷和乙醇(含0.1％二乙胺)，梯度配比：A:B：90:10，流速：1.0mL/min。
单一构型化合物(较短保留时间)：6.447min，(65mg，产率：28.4％)。
MS m/z(ESI):590.2[M+1]。
单一构型化合物(较长保留时间)：8.484min，(114mg，产率：49.8％)。
MS m/z(ESI):590.2[M+1]。
第三步
(2R,3S,4S,5R)-N-(2-((S)-1-氨基-2-羟乙基)吡啶-4-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6-1或
(2R,3S,4S,5R)-N-(2-((R)-1-氨基-2-羟乙基)吡啶-4-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6-2
将化合物6f-1,6f-2中较长保留时间对应的化合物(114mg，193μmol)溶于二氯甲烷(4mL)，加入4M盐酸的1,4-二氧六环溶液(2mL)，反应1小时后，减压浓缩，残余物用高效液相色谱法(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)纯化得到标题化合物6-1或6-2(33.3mg，产率：61.7％)。
MS m/z(ESI):490.2[M+1]。
1H NMR(500MHz,CD3OD):δ8.37(s,1H),7.66(s,2H),7.11(ddd,1H),6.97(td,1H),5.06(d,1H),4.30(dd,1H),3.98(d,3H),3.87-3.53(m,2H),2.78(p,1H),1.64(s,3H),1.30(d,1H),0.80(dt,3H)。
实施例7
(2R,3S,4S,5R)-N-(2-(2H-四唑-5-基)吡啶-4-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7
第一步
(2R,3S,4S,5R)-N-(2-氰基吡啶-4-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7b
将化合物1b-1(50mg，141μmol)溶于二氯甲烷(10mL)，冰浴下加入草酰氯(40mg，315μmol)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，残余物溶于二氯甲烷(3mL)，加入N,N-二异丙基乙胺(60mg，464μmol)，冰浴下滴加4-氨基吡啶-2-甲腈7a(30mg，251μmol，上海瀚泓)的二氯甲烷溶液(1mL)，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7b(45mg，产率：70％)。
MS m/z(ESI):456.2[M+1]。
第二步
(2R,3S,4S,5R)-N-(2-(2H-四唑-5-基)吡啶-4-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7
将化合物7b(20mg，44μmol)，叠氮化钠(30mg，461mmol)溶于N,N-二甲基甲酰胺(2mL)中，加入氯化铵(10mg，187μmol)，110℃搅拌反应4小时，反应液冷却至室温，倒入水中，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，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7(12mg，产率：54％)。
MS m/z(ESI):499.2[M+1]。
1H NMR(500MHz,DMSO-d6):δ10.80(s,1H),8.63-8.57(m,1H),8.48-8.45(m,1H),7.80(s,1H),7.25-7.05(m,3H),5.16-5.12(m,1H),4.31-4.21(m,1H),3.96(s,3H),2.80-2.68(m,1H),1.63(s,3H),0.76-0.72(m,3H)。
实施例8
(2R,3S,4S,5R)-N-(2-(1-氰基环丙基)吡啶-4-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8
采用实施例1中的合成路线，将第二步原料化合物1c替换为1-(4-氨基吡啶-2-基)环丙烷-1-甲腈盐酸盐(采用专利申请“CN111196804”中说明书第107页的实施例98公开的方法制备而得)得到标题化合物8(5mg，产率：4.6％)。
MS m/z(ESI):496.2[M+1]。
1H NMR(500MHz,CD3OD):δ8.33(d,1H),7.99(d,1H),7.58(dd,1H),7.13(ddd,1H),7.00(td,1H),5.08(d,1H),4.34(dd,1H),4.02(d,3H),2.81(t,1H),1.74(dt,4H),1.68(s,3H),0.83(dq,3H)。
实施例9
(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)-N-(2-脲基吡啶-4-基)四氢呋喃-2-甲酰胺9
第一步
(2R,3S,4S,5R)-N-(2-溴吡啶-4-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9a
将化合物1b-1(100mg，282.2μmol)溶于二氯甲烷(5mL)，冰浴下加入草酰氯(72mg，564μmol)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，残余物溶于二氯甲烷(5mL)，加入三乙胺(143mg，1.4mmol)和4-二甲氨基吡啶(100mg，282.2μmol)，冰浴下滴加2-溴-4-氨基吡啶(50mg，289μmol)二氯甲 烷溶液(1mL)，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体系B纯化得到标题化合物9a(90mg，产率：62.6％)。
MS m/z(ESI):509.2[M+1]。
第二步
(2R,3S,4S,5R)-N-(2-氨基吡啶-4-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9b
将化合物9a(45mg，88.3μmol)和尿素(43.2mg，166.6μmol)溶于1,4-二氧六环(5mL)，加入三(二亚苄基丙酮)钯(10mg，11μmol，上海泰坦)，4,5-双二苯基膦-9,9-二甲基氧杂蒽(10mg，17μmol，上海泰坦)和碳酸铯(60mg，184μmol)，氮气置换，105℃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A纯化得到标题化合物9b(39mg，产率：99％)。
MS m/z(ESI):446.2[M+1]。
第三步
(2R,3S,4S,5R)-3-(3,4-二氟-2-甲氧基苯基)-4,5-二甲基-N-(2-(3-(2,2,2-三氯乙酰基)脲基)吡啶-4-基)-5-(三氟甲基)四氢呋喃-2-甲酰胺9c
将化合物9b(39mg，87.5μmol)溶于四氢呋喃中，冰浴下加入三氯乙酰基异氰酸酯(19.84mg，105.1μmol，TCI)，保持温度反应20分钟，反应液减压浓缩即得到粗品标题化合物9c(50mg)，不经纯化，直接用于下一步。
MS m/z(ESI):633.2[M+1]。
第四步
(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)-N-(2-脲基吡啶-4-基)四氢呋喃-2-甲酰胺9
将化合物9c(50mg，78.9μmol)溶于7M氨甲醇溶液(2mL)，搅拌反应10分钟，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9(4mg，产率：10.3％)。MS m/z(ESI):489.2[M+1]。
1H NMR(500MHz,CD3OD):δ8.10(d,1H),7.54(d,1H),7.17(dd,1H),7.12(ddd,1H),6.99(td,1H),5.07(dd,1H),4.37-4.29(m,1H),4.01(d,3H),2.80(p,1H),1.67(s,3H),0.83(dq,3H)。
实施例10
(2R,3S,4S,5R)-3-(3,4-二氟-2-甲氧基苯基)-4,5-二甲基-N-(2-(2-氧代四氢嘧啶-1(2H)-基)吡啶-4-基)-5-(三氟甲基)四氢呋喃-2-甲酰胺10
第一步
(3-((4-硝基吡啶-2-基)氨基)丙基)氨基甲酸叔丁酯10c
将2-氯-4-硝基吡啶10a(1g，5.46mmol，上海韶远)，(3-氨基丙基)氨基甲酸叔丁酯10b(1.73g，9.93mmol，上海毕得)溶于N,N-二甲基甲酰胺(25mL)中，加入N,N-二异丙基乙胺(2.58g，19.96mmol)，110℃搅拌反应4小时，反应液冷却至室温，倒入水中，用乙酸乙酯萃取(30mL×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体系B纯化得到标题化合物10c(300mg，产率：10.1％)。
MS m/z(ESI):297.2[M+1]。
第二步
N1-(4-硝基吡啶-2-基)丙烷-1,3-二胺2,2,2-三氟乙酸盐10d
将化合物10c(300mg，1.01mol)溶于二氯甲烷(3mL)，加入3mL三氟醋酸，搅拌反应3小时，反应液减压浓缩，残余物溶于二氯甲烷，用饱和碳酸氢钠溶液洗涤，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10d(224mg)，不经纯化，直接用于下一步反应。
MS m/z(ESI):197.2[M+1]。
第三步
N2-(3-氨基丙基)吡啶-2,4-二胺2,2,2-三氟乙酸盐10e
将粗品化合物10d(224mg，722.04μmol)溶于甲醇(5mL)，加入10％钯碳催化剂(湿)(70mg)，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10e(189mg)，不经纯化，直接用于下一步反应。
MS m/z(ESI):167.2[M+1]。
第四步
1-(4-氨基吡啶-2-基)四氢嘧啶-2(1H)-酮10f
将粗品化合物10e(189mg，674μmol)溶于5mL四氢呋喃中，加入N,N-二异丙基乙胺(441mg，3.4mmol)和N,N-羰基二咪唑(CDI)(185mg，1.14mmol)，回流反应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35％-45％，流速：30mL/min)得到标题化合物10f(15mg，产率：6.8％)。
MS m/z(ESI):192.2[M+1]。
第五步
(2R,3S,4S,5R)-3-(3,4-二氟-2-甲氧基苯基)-4,5-二甲基-N-(2-(2-氧代四氢嘧啶-1(2H)-基)吡啶-4-基)-5-(三氟甲基)四氢呋喃-2-甲酰胺10
将化合物1b-1(50mg，141.4μmol)溶于二氯甲烷(3mL)，冰浴下加入草酰氯(17mg，134μmol)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，残余物溶于二氯甲烷(3mL)，加入N,N-二异丙基乙胺(43mg，332.7μmol)，4-二甲氨基吡啶(8mg，65μmol)，化合物10f(15mg，78μmol)，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10(3mg，产率：8.6％)。MS m/z(ESI):529.2[M+1]。
1H NMR(500MHz,DMSO-d6):δ10.59(s,1H),8.18(d,1H),8.01(d,1H),7.41(dd,1H),7.20-7.15(m,1H),7.11-7.08(m,1H),6.87-6.85(m,1H),5.08(d,1H),4.23(dd,1H),3.95(s,3H),3.83-3.80(m,2H),3.21-3.18(m,2H),2.79-2.73(m,1H),1.92-1.87(m,2H),1.58(s,3H),0.71(d,3H)。
实施例11
(2R,3S,4S,5R)-N-(2-乙酰氨基吡啶-4-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11
第一步
N-(4-((二苯基亚甲基)氨基)吡啶-2-基)乙酰胺11b
将N-(4-溴吡啶-2-基)乙酰胺11a(500mg，2.32mmol，上海韶远)，二苯甲酮亚胺(510mg，2.81mmol)溶于1,4-二氧六环(20mL)，加入三(二亚苄基丙酮)钯(220mg，240mmol)，4,5-双二苯基膦-9,9-二甲基氧杂蒽(250mg，432mmol)和碳酸铯(2.1g，6.44mmol)，氮气置换，100℃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11b(430mg，产率：58.6％)。
MS m/z(ESI):316.2[M+1]。
第二步
N-(4-氨基吡啶-2-基)乙酰胺11c
将化合物11b(200mg，634.18μmol)溶于浓盐酸(5mL)，搅拌反应30分钟，反应液减压浓缩，残余物中加入乙酸乙酯(5mL)，搅拌30分钟，过滤，滤饼干燥即得到粗品标题化合物11c(100mg)，不经纯化，直接用于下一步反应。
MS m/z(ESI):152.2[M+1]。
第三步
(2R,3S,4S,5R)-N-(2-乙酰氨基吡啶-4-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11
将化合物1b-1(50mg，141μmol)，粗品化合物11c(50mg，266μmol)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(55mg，425.5μmol)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)(80mg，210μmol)，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11(4mg，产率：5.8％)。
MS m/z(ESI):488.2[M+1]。
1H NMR(500MHz,DMSO-d6):δ10.70(s,1H),10.42(s,1H),8.25(s,1H),8.16(d,1H),7.51-7.46(m,1H),7.19(q,1H),7.14-7.08(m,1H),5.09(d,1H),4.25(dd,1H),3.96(d,3H),2.77(p,1H),2.08(s,3H),1.59(s,3H),0.73(d,3H)。
实施例12
(2R,3S,4S,5R)-3-(3,4-二氟-2-甲氧基苯基)-N-(2-(肼基羰基)吡啶-4-基)-4,5-二甲基-5-(三氟甲基)四氢呋喃-2-甲酰胺12

第一步
4-((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)吡啶甲酸12a
将化合物5a(700mg，1.43mmol)溶于甲醇(5mL)和水(5mL)，加入一水合氢氧化锂(400mg，1.43mmol)，搅拌反应1小时，反应液减压浓缩，加入水稀释，用1M盐酸调节pH至3-4，过滤，滤饼水洗并干燥后即得到粗品标题化合物12a(650mg)，产品不经纯化直接用于下一步反应。
MS m/z(ESI):473.1[M-1]。
第二步
2-(4-((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)吡啶甲酰基)肼-1-羧酸叔丁酯12b
将化合物12a(50mg，105.4μmol)，肼基甲酸叔丁酯(16mg，93μmol，上海毕得)溶解在1mL N,N-二甲基甲酰胺中，冰浴下加入N,N-二异丙基乙胺(41mg，317.2μmol)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)(61mg，160.4μmol)，保持温度反应14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12b(55mg，产率：88％)。MS m/z(ESI):589.2[M+1]。
第三步
(2R,3S,4S,5R)-3-(3,4-二氟-2-甲氧基苯基)-N-(2-(肼基羰基)吡啶-4-基)-4,5-二甲基-5-(三氟甲基)四氢呋喃-2-甲酰胺12
将化合物12b(50mg，105.4μmol)溶于二氯甲烷(5mL)，加入4M氯化氢的1,4-二氧六环溶液(3mL)，搅拌反应1小时，反应液减压浓缩，残余物溶于甲醇中，加入固体碳酸钾中和，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％-45％，流速：30mL/min)得到标题化合物12(20mg，产率：48.2％)。
MS m/z(ESI):489.2[M+1]。
1H NMR(500MHz,DMSO-d6):δ10.76(s,1H),9.82(s,1H),8.47(s,1H),8.24(s,1H),7.82(s,1H),7.17(brs,2H),5.11(d,1H),4.54(s,2H),4.26(t,1H),3.93(s,3H),2.78(t,1H),1.62(s,3H),0.74(s,3H)。
实施例13
4-((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)-N-(吡咯烷-1-基)吡啶甲酰胺13
将化合物12a(50mg，105.4μmol)，1-氨基吡咯烷盐酸盐(25.9mg，210.9μmol，上海毕得)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(68.1mg，527μmol)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)(80.2mg，210.8μmol)，保持温度反应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35％-45％，流速：30mL/min)得到标题化合物13(12mg，产率：22％)。
MS m/z(ESI):543.2.2[M+1]。
1H NMR(500MHz,CDCl3):δ8.63(d,2H),8.40(d,1H),8.19-8.17(m,1H),7.86(s,1H),7.24-7.07(m,1H),7.05-6.90(m,1H),5.00(d,1H),4.08-4.04(m,1H),4.00(s,3H),3.01(t,4H),2.76-2.73(m,1H),1.96-1.94(m,4H),1.69(s,3H),0.79(d,3H)。
实施例14
(2R,3S,4S,5R)-3-(3,4-二氟-2-甲氧基苯基)-4,5-二甲基-N-(2-(吡唑烷-1-羰基)吡啶-4-基)-5-(三氟甲基)四氢呋喃-2-甲酰胺14

将化合物12a(50mg，105.4μmol)，吡唑烷二盐酸盐(30.5mg，210.9μmol，上海韶远)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(68.1mg，527μmol)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)(80.2mg，210.8μmol)，保持温度反应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35％-45％，流速：30mL/min)得到标题化合物14(10mg，产率：18％)。
MS m/z(ESI):529.2[M+1]。
1H NMR(500MHz,CDCl3):δ8.56-8.47(m,2H),7.82-7.77(m,1H),7.08-7.05(m,1H),6.93-6.89(m,1H),5.00(d,1H),4.08-4.04(m,1H),4.00(s,3H),3.78-3.75(m,1H),3.21-3.09(m,2H),2.76-2.73(m,1H),2.23-2.01(m,3H),1.67(s,3H),0.89-0.87(m,2H),0.79(d,3H)。
实施例15
(2R,3S,4S,5R)-3-(3,4-二氟-2-甲氧基苯基)-N-(2-(异噁唑烷-2-羰基)吡啶-4-基)-4,5-二甲基-5-(三氟甲基)四氢呋喃-2-甲酰胺15
将化合物12a(50mg，105.4μmol)，异噁唑烷盐酸盐(23.1mg，210.7μmol，上海韶远)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(54.5mg，421.6μmol)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)(80.2mg，210.8μmol)，保持温度反应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35％-45％，流速：30mL/min)得到标题化合物15(10mg，产率：18％)。
MS m/z(ESI):530.2[M+1]。
1H NMR(500MHz,CDCl3):δ8.53(s,1H),7.97(d,2H),7.26-7.09(m,1H),6.92-6.87(m,1H),5.05(d,1H),4.41-4.04(m,6H),4.00(s,3H),2.77-2.74(m,1H),2.44-2.39(m,2H),1.68(s,3H),0.80-0.77(m,3H)。
实施例16
(2R,3S,4S,5R)-3-(3,4-二氟-2-甲氧基苯基)-N-(2-((Z)-(N’-甲氧基甲脒基)吡啶-4-基)-4,5-二甲基-5-(三氟甲基)四氢呋喃-2-甲酰胺16
将化合物7b(100mg，219.6μmol)溶于10mL异丙醇中，加入N,N-二异丙基乙胺(85.1mg，658.8μmol)和巯基乙酸(40.5mg，439μmol，上海毕得)，甲氧基胺盐酸盐(55mg，658.8μmol)，80℃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35％-45％，流速：30mL/min)得到标题化合物16(10mg，产率：18％)。
MS m/z(ESI):503.2[M+1]。
1H NMR(500MHz,DMSO-d6):δ10.69(s,1H),8.44(d,1H),8.11(d,1H),7.72(dd,1H),7.18(dt,2H),6.07(s,1H),5.09(d,1H),4.25(dd,1H),3.96(d,3H),3.79(d,3H),2.78(t,1H),2.01(q,1H),1.61(s,3H),0.73(d,3H)；
实施例16化合物的H-N HSQC谱图见图1；H-N HMBC谱图见图2。
实施例17
4-(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-N-((1-羟基环丙基)甲基)吡啶甲酰胺17

将化合物12a(51.5mg，108.6μmol)，1-(氨基甲基)环丙醇(19mg，217.3μmol，上海韶远)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(42mg，326μmol)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)(80.6mg，217.2μmol)，保持温度反应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35％-45％，流速：30mL/min)得到标题化合物17(12mg，产率：20.3％)。
MS m/z(ESI):544.2[M+1]。
1H NMR(500MHz,CDCl3):δ8.79(s,2H),8.47(d,1H),8.27(d,1H),8.03(s,1H),7.08-7.05(m,1H),6.94-6.89(m,1H),5.04(d,1H),4.10-4.06(m,1H),4.00(s,3H),3.62(t,2H),2.76(t,2H),1.70(s,3H),0.91-0.88(m,2H),0.79(d,3H),0.69-0.66(m,2H)。
实施例18
N-(环丙基甲氧基)-4-((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)吡啶甲酰胺18
将化合物12a(50mg，105.4μmol)，O-环丙基甲基羟胺盐酸盐(26mg，210.7μmol，上海韶远)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(68.1mg，527μmol)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)(80.2mg，210.8μmol)，保持温度反应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35％-45％，流速：30mL/min)得到标题化合物18(10mg，产率：26％)。
MS m/z(ESI):544.2[M+1]。
1H NMR(500MHz,CDCl3):δ10.23(s,1H),8.61(s,1H),8.40(d,1H),8.15-8.13(m,1H),7.86(s,1H),7.09-7.05(m,1H),6.93-6.88(m,1H),5.01(d,1H),4.08-4.05(m,1H),4.00(s,3H),3.87(d,2H),2.75(t,1H),1.69(s,3H),0.89-0.86(m,1H),0.80-0.78(m,3H),0.65-0.61(m,2H),0.36-0.33(m,2H)。
实施例19
(2R,3S,4S,5R)-3-(3,4-二氟-2-甲氧基苯基)-4,5-二甲基-N-(2-(2-甲基肼-1-羰基)吡啶-4-基)-5-(三氟甲基)四氢呋喃-2-甲酰胺19
第一步
2-(4-((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)吡啶甲酰基)-1-甲基肼-1-羧酸叔丁酯19a
将化合物12a(40mg，84.3μmol)，1-叔丁氧基羰基-1-甲基肼(15mg，102.6μmol，上海韶远)溶解在4mL N,N-二甲基甲酰胺中，冰浴下加入N,N-二异丙基乙胺(33mg，255.3μmol)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)(42mg，110.4μmol)，保持温度反应14小时，反应液中加入水，用二氯甲烷萃取(10mL×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19a(50mg)。
MS m/z(ESI):603.2[M+1]。
第二步
(2R,3S,4S,5R)-3-(3,4-二氟-2-甲氧基苯基)-4,5-二甲基-N-(2-(2-甲基肼-1-羰基)吡啶-4-基)-5-(三氟甲基)四氢呋喃-2-甲酰胺19
将化合物19a(50mg，82.9μmol)溶于二氯甲烷(5mL)，加入三氟乙酸(3mL)，搅拌反应1小时，反应液减压浓缩，残余物溶于二氯甲烷中，用饱和碳酸氢钠溶液中和，二氯甲烷萃取(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，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19(30mg，产率：71.9％)。
MS m/z(ESI):503.2[M+1]。
1H NMR(500MHz,DMSO-d6):δ10.74(s,1H),10.12(s,1H),8.49(d,1H),8.25(s,1H),7.84(d,1H),7.21-7.14(m,2H),5.11(d,2H),4.26(t,1H),3.96(s,3H),2.80-2.75 (m,1H),2.53(s,3H),1.61(s,3H),0.74(d,3H)。
实施例20
(2R,3S,4S,5R)-N-(2-甲脒基吡啶-4-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20
将化合物7b(85mg，186.6μmol)溶于2mL甲醇中，加入甲醇钠(10mg，185.1μmol)和氯化铵(20mg，373.9μmol)，70℃反应6小时，反应液冷却至室温后过滤，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20(9mg，产率：10.2％)。MS m/z(ESI):473.2[M+1]。
1H NMR(500MHz,DMSO-d6):δ8.48(d,1H),8.36(s,1H),7.79(dd,1H),7.17(dd,2H),5.12(d,1H),4.26(dd,1H),3.96(d,3H),2.78(p,1H),1.61(s,3H),0.76-0.71(m,3H)。
实施例21
(2R,3S,4S,5R)-3-(3,4-二氟-2-甲氧基苯基)-4,5-二甲基-N-(2-((Z)-N’-甲基甲脒基)吡啶-4-基)-5-(三氟甲基)四氢呋喃-2-甲酰胺21
将化合物7b(60mg，131.7μmol)溶于5mL异丙醇中，加入N,N-二异丙基乙 胺(51mg，395.2μmol)和巯基乙酸(24.3mg，263.6μmol，上海毕得)，甲胺盐酸盐(26.7mg，395.3μmol)，80℃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35％-45％，流速：30mL/min)得到标题化合物21(20mg，产率：31.2％)。
MS m/z(ESI):487.2[M+1]。
1H NMR(500MHz,CDCl3):δ8.45(d,1H),8.40(s,1H),8.28(d,1H),7.13(s,1H),6.92(q,1H),5.05(d,1H),4.14(dd,1H),4.01(d,3H),3.19(s,3H),2.77(p,1H),1.74(s,3H),0.85-0.77(m,3H)。
实施例22
(2R,3S,4S,5R)-3-(3,4-二氟-2-甲氧基苯基)-N-(2-(2-乙基肼-1-羰基)吡啶-4-基)-4,5-二甲基-5-(三氟甲基)四氢呋喃-2-甲酰胺22
采用实施例13中的合成路线，将原料化合物1-氨基吡咯烷盐酸盐替换为化合物乙肼盐酸盐(上海毕得)得到标题化合物22。
MS m/z(ESI):517.2[M+1]。
1H NMR(500MHz,CD3OD)δ8.48(d,1H),8.25(s,1H),7.89(d,1H),7.20-7.12(m,1H),6.98-6.93(m,1H),5.08(d,1H),4.33(t,1H),4.00(s,3H),2.94(q,2H),2.80(p,1H),1.66(s,3H),1.14(t,3H),0.82(d,3H)。
实施例23
(2R,3S,4S,5R)-N-(2-(2-环丙基肼-1-羰基)吡啶-4-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23
采用实施例13中的合成路线，将原料化合物1-氨基吡咯烷盐酸盐替换为化合物环丙基肼盐酸盐得到标题化合物23(10mg，产率：15.7％)。
MS m/z(ESI):529.2[M+1]。
1H NMR(500MHz,CD3OD):δ8.50(d,1H),8.26(d,1H),7.90(dd,1H),7.14(ddd,1H),7.00(td,1H),5.10(d,1H),4.35(dd,1H),4.02(d,3H),2.82(p,1H),2.69(tt,1H),1.68(d,3H),0.84(dq,3H),0.64-0.57(m,2H),0.57-0.49(m,2H)。
实施例24
(2R,3S,4S,5R)-3-(3,4-二氟-2-甲氧基苯基)-N-(2-(2,2-二甲基肼-1-羰基)吡啶-4-基)-4,5-二甲基-5-(三氟甲基)四氢呋喃-2-甲酰胺24
采用实施例13中的合成路线，将原料化合物1-氨基吡咯烷盐酸盐替换为化合物1,1-二甲基肼盐酸盐得到标题化合物24(5mg，产率：23％)。
MS m/z(ESI):517.2[M+1]。
1H NMR(500MHz,CD3OD):δ8.49(d,1H),8.25(d,1H),7.92(dd,1H),7.14(ddd,1H),7.05-6.96(m,1H),5.10(d,1H),4.34(dd,1H),4.01(d,3H),2.86-2.75(m,1H),2.67(s,6H),1.68(s,3H),0.87-0.78(m,3H)。
实施例25
(2R,3S,4S,5R)-N-(5-(2-氨基-2-氧代乙酰基)-1H-吡咯-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25
第一步
2-(4-硝基-1H-吡咯-2-基)-2-氧代乙酰胺25b
-5℃下将浓硝酸(4mL)加入醋酸酐(10mL)中，升至0℃，搅拌30分钟后降至-50℃，加入2-氧代-2-(1H-吡咯-2-基)乙酰胺25a(1.5g，10.86mmol，采用文献“Organic and Biomolecular Chemistry,2009,vol.7,#10,p.2187-2194”公开的方法制备而得)的氯仿溶液(4mL)，缓慢升至-30℃搅拌反应1小时，反应液倒入水(100mL)中，用饱和碳酸钠溶液调节pH至中性，氯仿萃取(30mL×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体系A纯化得到标题化合物25b(236mg，产率：11.8％)。
MS m/z(ESI):182.0[M-1]。
第二步
2-(4-氨基-1H-吡咯-2-基)-2-氧代乙酰胺25c
将化合物25b(80mg，436.8μmol)溶于甲醇(10mL)，加入10％钯碳催化剂(湿)(10mg)，氢气氛围下，搅拌反应3小时，反应液过滤，滤液减压浓缩，即得到粗品标题化合物25c(69mg)，不经纯化，直接用于下一步反应。
MS m/z(ESI):154.2[M+1]。
第三步
(2R,3S,4S,5R)-N-(5-(2-氨基-2-氧代乙酰基)-1H-吡咯-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25
将化合物1b-1(80mg，225.8μmol)，粗品化合物25c(69mg，450.6μmol)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(29mg，225μmol)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)(85mg，225.8μmol)，恢复室温搅拌反应30分钟，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25(2.5mg，产率：2.2％)。
MS m/z(ESI):490.0[M+1]。
1H NMR(500MHz,CD3OD):δ7.59(d,1H),7.41(s,1H),7.18-7.12(m,1H),7.02-6.96(m,1H),5.02(d,1H),4.27(dd,1H),4.00(s,3H),2.82-2.75(m,1H),1.67(s,3H),1.40-1.32(d,3H),0.86-0.80(m,1H)。
实施例26
(2R,3S,4S,5R)-N-(2-(2-氨基-2-氧代乙酰基)吡啶-4-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-甲酰胺三氟乙酸盐26
第一步
(2R,3S,4S,5R)-3-(3,4-二氟-2-甲氧基苯基)-N-(2-碘吡啶-4-基)-4,5-二甲基-5-(三氟甲基)四氢呋喃-2-甲酰胺26b
将化合物1b-1(500mg，1.41mmol)溶于二氯甲烷(10mL)，冰浴下加入草酰氯(628mg，4.94mmol)和5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，残余物溶于二氯甲烷(10mL)，加入N,N-二异丙基乙胺(913mg，7.06mmol)，冰浴下加入2-碘吡啶-4-胺26a(342mg，1.55mol，药明康德)和4-二甲氨基吡啶(174 mg，1.41mmol)，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26b(680mg，产率：86.6％)。
MS m/z(ESI):557.2[M+1]。
第二步
2-(4-((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-甲酰胺基)吡啶-2-基)-2-氧代乙酸乙酯26c
将化合物26b(680mg，1.22mmol)溶于四氢呋喃(15mL)，氮气氛围和冰浴下加入1M异丙基溴化镁的四氢呋喃溶液(6.2mL)，恢复室温反应1小时，冰浴下加入草酸二乙酯(1.79g，12.2mmol)，恢复室温继续反应2小时，反应结束，反应液中加入饱和氯化铵溶液淬灭，用乙酸乙酯萃取(20mL×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A纯化得到标题化合物26c(340mg，产率：52.4％)。
MS m/z(ESI):531.2[M+1]。
第三步
(2R,3S,4S,5R)-N-(2-(2-氨基-2-氧代乙酰基)吡啶-4-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-甲酰胺三氟乙酸盐26
将化合物26c(340mg，640.9μmol)溶于7M氨甲醇溶液(10mL)，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：Welch Xtimate Prep C18,30*250mm,5μm；流动相：水相(0.1％三氟乙酸)和乙腈，梯度配比：乙腈30％-65％，流速：30mL/min)得到标题化合物26(108mg，产率：27.3％)。
MS m/z(ESI):502.2[M+1]。
1H NMR(500MHz,CD3OD):δ8.54(d,1H),8.39(d,1H),8.20(dd,1H),7.12(t,1H),6.98(q,1H),5.16(d,1H),4.35(t,1H),4.00(d,3H),2.84-2.78(m,1H),1.66(s,3H),0.83(d,3H)。
实施例27
(2R,3S,4S,5R)-N-(3-甲脒基-4-氟苯基)-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27
第一步
(2R,3S,4S,5R)-N-(3-氰基-4-氟苯基)-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27b
将化合物1b-1(260mg，734μmol)溶于二氯甲烷(12mL)，冰浴下加入草酰氯(279.7mg，2.2mmol)和2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，残余物溶于二氯甲烷(5mL)，加入N,N-二异丙基乙胺(284mg，2.2mmol)，冰浴下滴加5-氨基-2-氟苯甲腈27a(100mg，734.6μmol，采用文献“Bioorganic and Medicinal Chemistry Letters,2006,vol.16,#19,p.5176-5182”公开的方法制备而得)和催化量的4-二甲氨基吡啶，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27b(165mg，产率：47.5％)。
MS m/z(ESI):473.2[M+1]。
第二步
(2R,3S,4S,5R)-N-(3-甲脒基-4-氟苯基)-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27
将化合物27b(83mg，175.7μmol)溶于2mL甲醇中，加入甲醇钠(28.5mg，527μmol)，35℃反应1小时后加入氯化铵(37.6mg，702.7μmol)，70℃反应2小时，反应液冷却至室温后过滤，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27(8mg，产率：9％)。
MS m/z(ESI):490.2[M+1]。
1H NMR(500MHz,DMSO-d6):δ10.39(s,2H),7.80(dd,1H),7.69(dt,1H),7.28-7.04(m,4H),5.06(d,1H),4.24(dd,1H),3.95(d,3H),2.76(t,1H),2.06-1.94(m,1H),1.60(s,3H),0.78-0.62(m,3H)。
实施例28
((4-((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-甲酰胺基)吡啶-2-基)(氨亚基)甲基)氨基甲酸己酯28
第一步
(2R,3S,4S,5R)-N-(2-甲脒基吡啶-4-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2,2,2-三氟乙酸盐28a
将化合物7b(2.8g，6.15mmol)溶于甲醇(60mL)中，加入甲醇钠(333mg，6.16mmol)，35℃反应5小时后加入氯化铵(658mg，12.3mmol)，70℃反应1.5小时，反应液冷却至室温后过滤，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：Welch Xtimate Prep C18，30*250mm，5μm；流动相：水相(0.1％三氟乙酸)和乙腈，梯度配比：乙腈35％-65％，流速：30mL/min)得到标题化合物28a(650mg，产率：18％)。
MS m/z(ESI):473.2[M+1]。
第二步
((4-((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-甲酰胺基)吡啶-2-基)(氨亚基)甲基)氨基甲酸己酯28
将化合物28a(100mg，170.5μmol)溶于四氢呋喃(3mL)，加入N,N-二异丙基乙胺(66.1mg，511.5μmol)，氯甲酸正己酯(33.6mg，204.62μmol，上海泰坦)，搅拌反应20分钟后减压浓缩，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35％-45％，流速：30mL/min)得到标题化合物28(46mg，产率：44.9％)。
MS m/z(ESI):601.1[M+1]。
1H NMR(500MHz,CD3OD):δ8.55(d,1H),8.32(s,1H),8.02(d,1H),7.15(t,1H),7.00(q,1H),5.10(d,1H),4.35(t,1H),4.18(t,2H),4.02(s,3H),2.90-2.73(m,1H),1.71(d,5H),1.46-1.34(m,6H),0.94(q,3H),0.84(d,3H)。
实施例29
((4-((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-甲酰胺基)吡啶-2-基)(氨亚基)甲基)氨基甲酸异丙酯29
将化合物28a(57mg，97.19μmol)溶于四氢呋喃(3mL)，加入N,N-二异丙基乙胺(37.6mg，291.5μmol)，氯甲酸异丙酯(14.3mg，116.6μmol，上海泰坦)，搅拌 反应20分钟后减压浓缩，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35％-45％，流速：30mL/min)得到标题化合物29(28mg，产率：51.5％)。
MS m/z(ESI):559.2[M+1]。
1H NMR(500MHz,CD3OD):δ8.55(d,1H),8.31(d,1H),8.02(dd,1H),7.15(ddd,1H),7.00(td,1H),5.10(d,1H),5.01(q,1H),4.35(dd,1H),4.02(d,3H),2.82(p,1H),1.69(s,3H),1.34(d,6H),0.84(dq,3H)。
实施例30
((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-甲酰胺基)-2-氟苯基)(氨亚基)甲基)氨基甲酸己酯30
采用实施例28中的合成路线第二步，将原料化合物28a替换为化合物27得到标题化合物30(145mg，产率：76.6％)。
MS m/z(ESI):617.2[M+1]。
1H NMR(500MHz,CD3OD):δ7.85(dd,1H),7.79(dt,1H),7.20(t,1H),7.15(ddd,1H),6.99(q,1H),5.06(d,1H),4.31(dd,1H),4.13(t,2H),4.01(d,3H),2.80(p,1H),1.69(d,5H),1.49-1.32(m,6H),1.05-0.91(m,3H),0.83(dt,3H)。
实施例31
((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-甲酰胺基)-2-氟苯基)(氨亚基)甲基)氨基甲酸异丙酯31
采用实施例29的合成路线，将原料化合物28a替换为化合物27得到标题化合物31。
MS m/z(ESI):576.2[M+1]。
实施例32
(2R,3S,4S,5R)-3-(3,4-二氟-2-甲氧基苯基)-N-(2-((Z)-(N’-羟基甲脒基)吡啶-4-基)-4,5-二甲基-5-(三氟甲基)四氢呋喃-2-甲酰胺32
将化合物7b(200mg，439.2μmol)溶于甲醇(4mL)，加入盐酸羟胺(61mg，877.8μmol)和N,N-二异丙基乙胺(60mg，464.2μmol)，搅拌反应1.5小时，反应液减压浓缩，残余物溶于二氯甲烷，依次用水，饱和氯化钠溶液洗涤，有机相减压浓缩，残余物用硅胶柱色谱法以洗脱体系A纯化得到标题化合物32(160mg，产率：74.6％)。
MS m/z(ESI):489.0[M+1]。
1H NMR(500MHz,CDCl3):δ8.61(s,1H),8.46(d,1H),7.87(dd,1H),7.83(d,1H),7.09(ddd,1H),6.92(td,1H),5.75(s,2H),5.02(d,1H),4.10(dd,1H),4.01(d,3H),2.76(p,1H),1.68(s,3H),0.80(dq,3H)。
实施例33
(2R,3S,4S,5R)-3-(3,4-二氟-2-羟基苯基)-N-(2-((Z)-(N’-甲氧基甲脒基)吡啶-4-基)-4,5-二甲基-5-(三氟甲基)四氢呋喃-2-甲酰胺33
将化合物16(1.5g，3mmol)溶于二氯甲烷(15mL)，冰浴下加入三溴化硼(8.8g，6mmol，17％二氯甲烷溶液)，自然恢复室温反应16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33(185mg，产率：12.7％)。
MS m/z(ESI):489.0[M+1]。
1H NMR(500MHz,DMSO-d6):δ10.70(s,1H),10.47(s,1H),8.44(d,1H),8.11(d,1H),7.72(dd,1H),7.06-6.99(m,1H),6.91-6.82(m,1H),6.07(s,2H),5.08(d,1H),4.25(dd,1H),3.79(s,3H),2.84(p,1H),1.60(s,3H),0.75-0.68(m,3H)。
实施例34
(2R,3S,4S,5R)-3-(2-环丁氧基-3,4-二氟苯基)-N-(2-((Z)-(N’-甲氧基氨基甲酰)吡啶-4-基)-4,5-二甲基-5-(三氟甲基)四氢呋喃-2-甲酰胺34
第一步
(2R,3S,4S,5R)-3-(3,4-二氟-2-羟基苯基)-4,5-二甲基-5-(三氟甲基)四氢呋喃-2-羧酸甲酯34a
将化合物1b-1(1.0g，2.8mmol)溶于二氯甲烷(20mL)中，0℃时加入1M三溴化硼的二氯甲烷溶液(8.5mL)，恢复室温搅拌反应2小时，反应液中加入甲醇(10mL)淬灭，减压浓缩即得到粗品标题化合物34a(1g)，不经纯化，直接用于下一步反应。MS m/z(ESI):353.0[M-1]。
第二步
(2R,3S,4S,5R)-3-(2-环丁氧基-3,4-二氟苯基)-4,5-二甲基-5-(三氟甲基)四氢呋喃-2-羧酸甲酯34b
将粗品化合物34a(600mg，1.7mmol)溶于N,N-二甲基乙酰胺(20mL)，加入溴代环丁烷(2.28g，16.9mmol，上海韶远)，碳酸铯(2.76g，8.5mmol)，碘化钾(282mg，1.7mmol)，80℃反应7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体系C纯化得到标题化合物34b(440mg，产率：63.6％)
第三步
(2R,3S,4S,5R)-3-(2-环丁氧基-3,4-二氟苯基)-4,5-二甲基-5-(三氟甲基)四氢呋喃-2- 羧酸34c
将化合物34b(440mg，1.1mmol)溶于四氢呋喃(5mL)，冰浴下加入一水合氢氧化锂(175mg，4.2mmol)的水溶液(4.2mL)，恢复室温反应2小时，反应液减压浓缩，加入水稀释，用1M盐酸调节pH至3，乙酸乙酯萃取(10mL×3)，合并有机相，用无水硫酸钠干燥，过滤，除去干燥剂后滤液减压浓缩即得到粗品标题化合物34c(420mg)，产品不经纯化，直接用于下一步反应。
MS m/z(ESI):393.3[M-1]。
第四步
(2R,3S,4S,5R)-N-(2-氰基吡啶-4-基)-3-(2-环丁氧基-3,4-二氟苯基)-4,5-二甲基-5-(三氟甲基)四氢呋喃-2-甲酰胺34d
将粗品化合物34c(420mg，1.1mmol)溶于二氯甲烷(5mL)，冰浴下加入草酰氯(406mg，3.2mmol)和1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)，加入N,N-二异丙基乙胺(413mg，3.2mmol)，化合物7a(254mg，2.1mmol)，搅拌反应16小时，反应液减压浓缩，残余物用硅胶柱色谱法以洗脱体系B纯化得到标题化合物34d(480mg，产率：91％)。
MS m/z(ESI):496.1[M+1]。
第五步
(2R,3S,4S,5R)-3-(2-环丁氧基-3,4-二氟苯基)-N-(2-((Z)-(N’-甲氧基氨基甲酰)吡啶-4-基)-4,5-二甲基-5-(三氟甲基)四氢呋喃-2-甲酰胺34
将化合物34d(100mg，221.8μmol)溶于3mL异丙醇中，加入巯基乙酸(38mg，412.5μmol)，甲氧基胺盐酸盐(51mg，610.6μmol)，N,N-二异丙基乙胺(79mg，611.2μmol)，80℃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35％-45％，流速：30mL/min)得到标题化合物34(70mg，产率：63.9％)。
MS m/z(ESI):543.2[M+1]。
1H NMR(500MHz,CD3OD):δ8.42(d,1H),8.09(d,1H),7.71(dd,1H),7.12-7.08(m,1H),6.98-6.92(m,1H),5.05(d,1H),4.71-4.65(m,1H),4.36(dd,1H),3.86(s,3H),2.82-2.76(m,1H),2.44-2.36(m,1H),2.35-2.28(m,1H),2.27-2.20(m,1H),2.19-2.12(m,1H),1.80-1.71(m,1H),1.67(s,3H),1.59-1.49(m,1H),0.81(d,3H)。
实施例35
4-((2R,3S,4S,5R)-3-(2-环丁氧基-3,4-二氟苯基)-4,5-二甲基-5-(三氟甲基)四氢呋喃-2-甲酰胺)-N-甲氧基吡啶甲酰胺35
采用实施例5中的合成路线，将第一步原料化合物1b-1替换为化合物34c得到标题化合物35(30mg，产率：41.6％)。
MS m/z(ESI):544.2[M+1]。
1H NMR(500MHz,CD3OD):δ8.46(d,1H),8.23(d,1H),7.88(dd,1H),7.12-7.08(m,1H),6.98-6.93(m,1H),5.06(d,1H),4.72-4.65(m,1H),4.38(dd,1H),3.81(s,3H),2.83-2.77(m,1H),2.43-2.37(m,1H),2.34-2.29(m,1H),2.28-2.21(m,1H),2.20-2.12(m,1H),1.80-1.71(m,1H),1.67(s,3H),1.59-1.50(m,1H),0.81(d,3H)。
实施例36
(2R,3S,4S,5R)-3-(2-环丁氧基-3,4-二氟苯基)-N-(2-((Z)-(N’-羟基甲脒基)吡啶-4-基)-4,5-二甲基-5-(三氟甲基)四氢呋喃-2-甲酰胺36
将化合物34d(100mg，210.8μmol)溶于甲醇(3mL)，加入盐酸羟胺(29mg，417.3μmol)和N,N-二异丙基乙胺(27mg，208.9μmol)，搅拌反应1.5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30％-40％，流速：30mL/min)得到标题化合物36(80mg，产率：75％)。
MS m/z(ESI):527.3[M-1]。
1H NMR(500MHz,CD3OD):δ8.42(d,1H),8.02(d,1H),7.73(dd,1H),7.12-7.08(m,1H),6.97-6.92(m,1H),5.04(d,1H),4.71-4.65(m,1H),4.36(dd,1H),2.83-2.76(m,1H),2.43-2.36(m,1H),2.35-2.28(m,1H),2.27-2.20(m,1H),2.19-2.12(m,1H),1.80-1.71(m,1H),1.67(s,3H),1.59-1.49(m,1H),0.81(d,3H)。
实施例37
(2R,3S,4S,5R)-3-(3,4-二氟-2-甲氧基苯基)-N-(2-((Z)-(N’-甲氧基-d3)甲脒基)吡啶-4- 基)-4,5-二甲基-5-(三氟甲基)四氢呋喃-2-甲酰胺37
将化合物32(102mg，208.8μmol)溶于N,N-二甲基甲酰胺(1mL)，加入一水合氢氧化锂(8.8mg，208.8μmol)的水溶液(0.1mL)，搅拌1小时后，加入氘代碘甲烷37a(36.3mg，250.6μmol，安耐吉)的N,N-二甲基甲酰胺(1mL)溶液，搅拌0.5小时后，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37(15mg，产率：14.2％)。
MS m/z(ESI):506.3[M+1]。
1H NMR(500MHz,DMSO-d6):δ10.68(s,1H),8.44(d,1H),8.10(d,1H),7.71(dd,1H),7.24-7.08(m,2H),6.06(s,2H),5.08(d,1H),4.24(dd,1H),3.95(d,3H),2.77(t,1H),1.60(s,3H),0.80-0.64(m,3H)。
实施例38
(2R,3S,4S,5R)-N-(2-(1-氨基环丙基)吡啶-4-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38
将化合物7b(80mg，175.7μmol)溶于四氢呋喃(10mL)，加入钛酸四异丙酯(100mg，351.8μmol，上海韶远)，搅拌10分钟后滴加1M乙基溴化镁的四氢呋喃溶液(0.75mL)，搅拌反应0.5小时，加入饱和氯化铵溶液淬灭，用乙酸乙酯萃取(5 mL×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30％-42％，流速：30mL/min)得到标题化合物38(10mg，产率：11.7％)。
MS m/z(ESI):484.4[M-1]。
1H NMR(500MHz,CDCl3):δ8.52-8.36(m,2H),7.65(s,1H),7.25-7.24(m,1H),7.10-7.06(m,1H),6.93-6.88(m,1H),5.01-4.99(m,1H),4.14-4.06(m,1H),4.01(s,3H),2.76-2.71(m,1H),2.00(br,2H),1.68(s,3H),1.35-1.24(m,2H),1.15-1.10(m,2H),0.85-0.72(m,3H)。
实施例39
(2R,3S,4S,5R)-3-(3,4-二氟-2-甲氧基苯基)-N-(2-(2-羟基-2-(1-羟基环丙基)乙氧基)吡啶-4-基)-4,5-二甲基-5-(三氟甲基)四氢呋喃-2-甲酰胺39(非对映异构体混合物)
第一步
(±)-3-((叔丁基二苯基硅基)氧基)-2-羟基丙酸乙酯39b
将(±)-2,3-二羟基丙酸乙酯39a(1g，7.5mmol，采用文献“Synthesis,2016,vol.48,#21,art.no.SS-2016-H0270-PSP,p.3696-3700”中公开的方法制备而得)溶于二氯甲烷(20mL)，加入咪唑(761.3mg，11.2mmol)，叔丁基二苯基氯硅烷(2.5g，9mmol)，搅拌反应2小时，反应液冷却至室温后减压浓缩，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39b(2.2g，产率：79.2％)。
第二步
(±)-1-(2-((叔丁基二苯基硅基)氧基)-1-羟乙基)环丙烷-1-醇39c
将化合物39b(2.2g，5.9mmol)溶于四氢呋喃(50mL)，加入钛酸四异丙酯(1.68g，5.9mmol)，冰浴下滴加2M乙基溴化镁的四氢呋喃溶液(8.9mL)，自然恢复室温搅拌反应3小时，反应液减压浓缩，残余物溶于二氯甲烷(50mL)，倒入饱和氯化铵水溶液(50mL)中，搅拌30分钟后过滤，滤饼用二氯甲烷洗涤，收集滤液，分离有机相，有机相用饱和氯化钠溶液洗涤，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39c(550mg，产率：26.1％)。
MS m/z(ESI):355.2[M-1]。
第三步
(±)-叔丁基((5,5-二甲基-4,6-二氧杂螺[2.4]庚-7-基)甲氧基)二苯基硅烷39d
将化合物39c(550mg，1.5mmol)，2,2-二甲氧基丙烷(482mg，4.6mmol，上海泰坦)，对甲苯磺酸(26.6mg，154.2μmol)溶于丙酮(10mL)，搅拌反应16小时，反应液减压浓缩，残余物用硅胶柱色谱法以洗脱剂体系B纯化得到标题化合物39d(500mg，产率：81.7％)。
第四步
(±)-(5,5-二甲基-4,6-二氧杂螺[2.4]庚-7-基)甲醇39e
将化合物39d(500mg，1.3mmol)溶于四氢呋喃(10mL)，加入四丁基氟化铵(284mg，1.3mmol)，搅拌反应2小时，反应液减压浓缩即得到粗品标题化合物39e(200mg)，产品不经纯化直接用于下一步反应。
第五步
(±)-2-((5,5-二甲基-4,6-二氧杂螺[2.4]庚-7-基)甲氧基)吡啶-4-胺39f
将粗品化合物39e(115mg，727μmol)溶于N-甲基吡咯烷酮(5mL)中，冰浴下加入氢化钠(40mg，1mmol，纯度60％)，恢复室温搅拌反应1小时后滴加2-氯-4-氨基吡啶(35mg，272μmol，上海韶远)的N-甲基吡咯烷酮(5ml)溶液，升温至160℃，反应3小时，反应液降至室温，加入水稀释，用乙酸乙酯萃取(15mL×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30％-42％，流速：30mL/min)得到标题化合物39f(8mg，产率：11.7％)。
MS m/z(ESI):251.3[M+1]。
第六步
(2R,3S,4S,5R)-3-(3,4-二氟-2-甲氧基苯基)-N-(2-((5,5-二甲基-4,6-二氧杂螺[2.4]庚-7-基)甲氧基)吡啶-4-基)-4,5-二甲基-5-(三氟甲基)四氢呋喃-2-甲酰胺39g(非对映异构体混合物)
将化合物1b-1(20mg，56.5μmol)溶于二氯甲烷(1mL)，冰浴下加入草酰氯(14.3mg，113μmol)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，残余物溶于二氯甲烷(1mL)，冰浴下加入39f(14mg，56μmol)，4-二甲氨基吡啶(1.4mg，11μmol)，N,N-二异丙基乙胺(22mg，169.4μmol)，搅拌反应2小时，反应液减压浓缩即得到粗品标题化合物39g(30mg)，产品不经纯化直接用于下一步反应。
MS m/z(ESI):587.5[M+1]。
第七步
(2R,3S,4S,5R)-3-(3,4-二氟-2-甲氧基苯基)-N-(2-(2-羟基-2-(1-羟基环丙基)乙氧基)吡啶-4-基)-4,5-二甲基-5-(三氟甲基)四氢呋喃-2-甲酰胺39(非对映异构体混合物)
将粗品化合物39g(30mg，51.1μmol)溶于二氯甲烷(1mL)，冰浴下加入4M氯化氢的1,4-二氧六环溶液(0.5mL)，搅拌反应0.5小时，反应液用饱和碳酸钠溶液调节pH至中性，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39(非对映异构体混合物，7mg，产率：25％)。
MS m/z(ESI):545.4[M-1]。
1H NMR(500MHz,CD3OD):δ7.99(d,1H),7.25(d,1H),7.16(dd,1H),7.12(ddd,1H),7.00(td,1H),5.06(d,1H),4.56(dd,1H),4.34(ddd,2H),4.01(d,3H),3.61(dd,1H),2.86-2.74(m,1H),1.67(s,3H),0.87-0.78(m,3H),0.68(dt,4H)。
实施例40
(2R,3S,4S,5R)-N-(2-(1-甲酰胺基环丙基)吡啶-4-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40
第一步
1-(4-氨基吡啶-2-基)环丙烷-1-甲酰胺40b
将(2-(1-氰基环丙基)吡啶-4-基)氨基甲酸叔丁酯40a(50mg，192.8μmol，采用专利申请“CN111196804A”中说明书第107页的实施例98公开的方法制备而得)溶于浓硫酸(0.25mL)，搅拌反应16小时，反应液用4N氢氧化钠溶液调pH至中性，加入N,N-二甲基甲酰胺(0.5mL)稀释，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(10 mmol/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40b(20mg，产率58.5％)。
MS m/z(ESI):178.0[M+1]。
第二步
(2R,3S,4S,5R)-N-(2-(1-甲酰胺基环丙基)吡啶-4-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40
将化合物1b-1(50mg，141.4μmol)溶于二氯甲烷(1mL)，冰浴下加入草酰氯(53.7mg，423.4μmol)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，残余物溶于二氯甲烷(3mL)，冰浴下加入N,N-二异丙基乙胺(91.2mg，705.6μmol)，4-二甲氨基吡啶(1.7mg，14μmol)，化合物40b(30mg，169.3μmol)，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40(4mg，产率：5.5％)。
MS m/z(ESI):512.4[M-1]。
1H NMR(500MHz,CD3OD):δ8.39(d,1H),7.74(d,1H),7.65(dd,1H),7.13(dd,1H),7.00(q,1H),5.08(d,1H),4.33(dd,1H),4.02(d,3H),2.81(p,1H),1.67(s,3H),1.56(q,2H),1.24(q,2H),0.86-0.80(m,3H)。
实施例41
(2R,3S,4S,5R)-N-(2-(氨基(甲基)膦氧爪基)吡啶-4-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41(非对映异构体混合物)
第一步
(4-((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-甲酰胺基)吡啶-2-基)(甲基)亚膦酸乙酯41a(非对映异构体混合物)
称取甲基亚膦酸二乙酯(31.8mg，233.7μmol，上海麦克林)，0下℃加入水(4.2mg，233.7μmol)，搅拌反应16小时后加入化合物26b(100mg，179,8μmol)，N,N-二异丙基乙胺(69.7mg，539.3μmol)，1,1'-二(二苯膦基)二茂铁二氯化钯(II)(13.2mg， 8μmol)和甲苯(1mL)，氮气置换，105℃反应4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41a(80mg，产率：83％)。
MS m/z(ESI):537.4[M+1]。
第二步
(2R,3S,4S,5R)-N-(2-(氨基(甲基)膦氧爪基)吡啶-4-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41(非对映异构体混合物)
将化合物41a(60mg，111.9μmol)溶于四氢呋喃(1mL)，冰浴下加入1M双(三甲基硅基)氨基锂的四氢呋喃溶液(1mL)，保持温度反应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30％-45％，流速：30mL/min)得到标题化合物41(非对映异构体混合物，2mg，产率：3.5％)。
MS m/z(ESI):508.4[M+1]。
1H NMR(500MHz,CD3OD):δ8.61(d,1H),8.22(dd,1H),7.87(dt,1H),7.14(t,1H),7.06-6.96(m,1H),5.10(d,1H),4.34(dd,1H),4.01(d,3H),2.88-2.75(m,1H),1.72(d,3H),1.68(s,3H),0.84(dt,3H)。
实施例42
(2R,3S,4S,5R))-N-(2-(1-氨基-2-(环丙基甲氧基)乙基)吡啶-4-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42(非对映异构体混合物)
第一步
((2,2-二乙氧基乙氧基)甲基)环丙烷42c
将氢化钠(2.38g，59.5mmol，纯度60％)混于四氢呋喃(40mL)，冰浴下，滴加2,2-二乙氧基乙醇42b(5g，37.2mmol，上海泰坦)的四氢呋喃(40mL)溶液，滴完后恢复室温反应1小时，加入溴甲基环丙烷42a(7.54g，55.9mmol，南京药石)的四氢呋喃(40mL)溶液和碘化钠(56mg，372.6μmol)，80℃反应4天，反应液降至室温后过滤，滤液减压浓缩后溶于二氯甲烷(100mL)，用饱和氯化钠溶液洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩即得到粗品标题化合物42c(5.1g)，产品不经纯化直接用于下一步反应。
第二步
2-(环丙基甲氧基)乙醛42d
将粗品化合物42c(1g，5.3mmol)溶于四氢呋喃(16mL)，加入2M硫酸溶液(8mL)，搅拌反应1小时后加热至60℃反应1小时，反应液降至室温后用碳酸氢钠调节pH至中性，乙酸乙酯萃取(20mL×3)，合并有机相，用无水硫酸钠干燥，过滤，滤液减压浓缩，残余物用硅胶柱色谱法以洗脱剂体系B纯化得到标题化合物42d(570mg，产率：94％)。
第三步
N-(2-(环丙基甲氧基)乙亚基)-2-甲基丙烷-2-亚磺酰胺42f
将化合物42d(0.57g，5mmol)和2-甲基丙烷-2-亚磺酰胺42e(605.2mg，5mmol，上海毕得)溶于二氯甲烷(10mL)，加入无水硫酸铜(2g，12,5mmol)，氮气置换，搅拌反应16小时，反应液过滤，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42f(750mg，产率：69％)。
MS m/z(ESI):218.4[M+1]。
第四步
(±)-(2-(1-((叔丁基亚磺酰基)氨基)-2-(环丙基甲氧基)乙基)吡啶-4-基)氨基甲酸叔丁酯42h
(2-溴吡啶-4-基)氨基甲酸叔丁酯42g(439.9mg，1.6,mmol，上海乐研)溶于四氢呋喃(10mL)，-78℃下缓慢滴加2.5M正丁基锂的正己烷溶液(1.4mL)，保持温度反应1小时后加入化合物42f(0.35g，1.6mmol)的四氢呋喃溶液(2mL)，-78℃下继续反应3小时，反应液中加入饱和氯化铵溶液，用乙酸乙酯萃取(15mL×3)，合并有机相，用无水硫酸钠干燥，过滤，滤液减压浓缩，残余物用硅胶柱色谱法以洗脱剂体系B纯化得到标题化合物42h(450mg，产率：67.9％)。
MS m/z(ESI):412.4[M+1]。
第五步
(±)-N-(1-(4-氨基吡啶-2-基)-2-(环丙基甲氧基)乙基)-2-甲基丙烷-2-亚磺酰胺2,2,2-三氟乙酸盐42i
将化合物42h(75mg，182.2μmol)溶于二氯甲烷(1.3mL)，冰浴下加入三氟醋酸(0.5mL)，恢复室温反应1.5小时，反应液减压浓缩即得到粗品标题化合物42i (77mg)，产品不经纯化直接用于下一步反应。
MS m/z(ESI):312.4[M+1]。
第六步
(2R,3S,4S,5R)-N-(2-(1-((叔丁基亚磺酰基)氨基)-2-(环丙基甲氧基)乙基)吡啶-4-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42j(非对映异构体混合物)
将化合物1b-1(57.9mg，163.4μmol)溶于二氯甲烷(2mL)，冰浴下加入草酰氯(51.9mg，408.6μmol)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，残余物溶于二氯甲烷(2mL)备用。
将粗品化合物42i(77mg，181μmol)溶于二氯甲烷(4mL)，冰浴下加入N,N-二异丙基乙胺(211.2mg，1.6mmol)，4-二甲氨基吡啶(4mg，32.6μmol)，滴加上述备用溶液，恢复室温搅拌反应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42j(10mg，产率：9.4％)。
MS m/z(ESI):648.4[M+1]。
第七步
(2R,3S,4S,5R)-N-(2-(1-氨基-2-(环丙基甲氧基)乙基)吡啶-4-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42(非对映异构体混合物)
将化合物42j(10mg，15.4μmol)溶于二氯甲烷(1.5mL)，加入4M氯化氢的1,4-二氧六环溶液(0.2mL)，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42(非对映异构体混合物，2mg，产率：23.8％)。
MS m/z(ESI):544.2[M+1]。
1H NMR(500MHz,CD3OD):δ8.40(d,1H),7.74(d,1H),7.61(dd,1H),7.14(t,1H),7.00(q,1H),5.09(d,1H),4.33(dd,1H),4.14(dd,1H),4.01(d,3H),3.73(dd,1H),3.60(dd,1H),3.31(d,2H),2.21(t,1H),1.68(s,3H),1.01(d,1H),0.88-0.80(m,3H),0.52-0.43(m,2H),0.17(q,2H)。
实施例43
4-((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-甲酰胺基)-2-((Z)-N'-羟基甲脒基)吡啶1-氧化物43

第一步
2-氰基-4-((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-甲酰胺基)吡啶1-氧化物43a
将化合物7b(300mg，658.8μmol)溶于氯仿(6mL)，加入间氯过氧苯甲酸(268mg，1.3mmol，纯度85％)，65℃搅拌反应16小时，反应液降至室温，用硅胶柱色谱法以洗脱剂体系A纯化得到标题化合物43a(105mg，产率：33.8％)。
MS m/z(ESI):472.2[M+1]。
第二步
4-((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-甲酰胺基)-2-((Z)-N'-羟基甲脒基)吡啶1-氧化物43
将化合物43a(100mg，212.1μmol)溶于甲醇(2mL)，依次加入羟胺盐酸盐(30mg，431.7μmol)和N,N-二异丙基乙胺(30mg,，232.1μmol)，45℃搅拌反应1.5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30％-40％，流速：30mL/min)得到标题化合物43(45mg，产率：42％)。
MS m/z(ESI):505.1[M+1]。
1H NMR(500MHz,DMSO-d6):δ10.71(s,1H),10.16(s,1H),8.21(d,1H),8.19(d,1H),7.69(dd,1H),7.22-7.10(m,2H),6.78(s,2H),5.07(d,1H),4.24(dd,1H),3.95(d,3H),2.76(p,1H),1.60(s,3H),0.73(dd,3H)。
实施例44
4-((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-甲酰胺基)-2-((Z)-N'-甲氧基甲脒基)吡啶1-氧化物44
将化合物43a(412mg，874μmol)溶于异丙醇(8mL)，加入甲氧基胺盐酸盐(219mg，2.6mmol)，巯基乙酸(161mg，1.7mmol)和N,N-二异丙基乙胺(339mg，2.6mmol)，85℃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％-40％，流速：30mL/min)得到标题化合物44(207mg，产率：45.6％)。
MS m/z(ESI):519.2[M+1]。
1H NMR(500MHz,DMSO-d6):δ10.79(s,1H),8.21(d,1H),8.12(d,1H),7.77(dd,1H),7.22-7.11(m,2H),7.10-7.00(m,2H),5.08(d,1H),4.24(dd,1H),3.96(t,3H),3.78(d,3H),2.77(p,1H),1.60(s,3H),0.72(d,3H)。
实施例45
(2R,3S,4S,5R)-N-(2-((Z)-(N'-环丙氧基甲脒基)吡啶-4-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45
采用实施例16的合成路线，将原料化合物甲氧基胺盐酸盐替换为O-环丙基羟胺盐酸盐(采用文献“Organic and biomolecular chemistry,2020,vol.18,#17,p.3281-3287”公开的方法制备而得)得到标题化合物45(3mg，产率：5％)。
MS m/z(ESI):529.1[M+1]。
1H NMR(500MHz,CDCl3):δ8.55(s,1H),8.44(d,1H),8.02(dd,1H),7.73(d,1H),7.10(t,1H),6.93(q,1H),5.57(s,2H),5.02(d,1H),4.15-3.96(m,5H),2.77(p,1H),1.72(s,3H),0.90(t,1H),0.84-0.79(m,4H),0.71(q,2H)。
实施例46
2-甲脒基-4-((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-甲酰胺基)吡啶1-氧化物2,2,2-三氟乙酸盐46
将化合物43a(100mg，212.1μmol)溶于四氢呋喃(1mL)中，加入1M双三甲基硅基胺基锂(636.4μL)，搅拌反应30分钟，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(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46(2.8mg，产率：1.4％)。
MS m/z(ESI):489.4[M+1]。
1H NMR(500MHz,CD3OD):δ8.41(dd,2H),7.92(dd,1H),7.14(t,1H),7.01(t,1H),5.36(s,1H),4.33(dd,1H),4.02(d,3H),2.82(t,1H),1.68(s,3H),0.84(d,3H)。
实施例47
(2R,3S,4S,5R)-3-(3,4-二氟-2-甲氧基苯基)-N-(2-(1-羟基环丙基)吡啶-4-基)-4,5-二甲基-5-(三氟甲基)四氢呋喃-2-甲酰胺47
第一步
(2R,3S,4S,5R)-N-(2-(1-((叔丁基二甲基硅基)氧基)环丙基)吡啶-4-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47b
将化合物1b-1(80mg，225.8μmol)溶于二氯甲烷(3mL)，冰浴下加入草酰氯(60mg，472.7μmol)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，残余物溶于二氯甲烷(3mL)，加入N,N-二异丙基乙胺(60mg，464.2μmol)，4-二甲氨基吡啶(12mg，97.4μmol)，2-(1-((叔丁基二甲基硅基)氧基)环丙基)吡啶-4-胺47a(65mg，245.8μmol，采用专利申请“WO2022053022”中说明书第196页的实施例169公开的方法制备而得)，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体系B纯化得到标题化合物47b(25mg，产率：18.4％)。
MS m/z(ESI):601.3[M+1]。
第二步
(2R,3S,4S,5R)-3-(3,4-二氟-2-甲氧基苯基)-N-(2-(1-羟基环丙基)吡啶-4-基)-4,5-二甲基-5-(三氟甲基)四氢呋喃-2-甲酰胺47
将化合物47b(30mg，49.9μmol)溶于四氢呋喃(2mL)，加入1M四丁基氟化 胺的四氢呋喃溶液(2mL)，搅拌反应30分钟，反应液加入乙酸乙酯稀释，水洗后分离有机相，减压浓缩，残余物用高效液相制备色谱法纯化(Waters-2545，色谱柱：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47(5mg，产率：20.5％)。
MS m/z(ESI):487.1[M+1]。
1H NMR(500MHz,CD3OD):δ8.29-8.28(m,1H),7.76-7.75(m,1H),7.48-7.46(m,1H),7.14-7.12(m,1H),7.11-6.97(m,1H),5.08-5.06(m,1H),4.33-4.29(m,1H),4.00(s,3H),2.81-2.78(m,1H),1.66(s,3H),1.23-1.22(m,2H),1.10-1.08(m,2H),0.83-0.80(m,3H)。
生物学评价
测试例1、本公开化合物对Nav1.8抑制活性的测定
实验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。
1实验材料及仪器
1)膜片钳放大器：patch clamp PC-505B(WARNER instruments)/MultiClamp 700A(Axon instrument)
2)数模转换器：Digidata 1440A(Axon CNS)/Digidata 1550A(Axon instruments)
3)微操控仪：MP-225(SUTTER instrument)
4)倒置显微镜：TL4(Olympus)
5)玻璃微电极拉制仪：PC-10(NARISHIGE)
6)微电极玻璃毛细管：B12024F(武汉微探科学仪器有限公司)
7)二甲基亚砜(DMSO)D2650(Sigma-Aldrich)
8)TTX AF3014(Affix Scientific)
2实验步骤
2.1化合物配制
配制细胞内外液的化合物除用于酸碱滴定的NaOH和KOH外，均从Sigma(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。
测试化合物的保存浓度为9mM，溶于二甲基亚砜(DMSO)。测试当天再溶于细胞外液，配制成要求浓度。
2.2手动膜片钳测试过程
1)化合物配制成指定浓度的溶液后，按浓度从低到高顺序将药液依次加入各个管道，并对各个管道进行标记。
2)将细胞转移到灌流槽中，电极内施加正压，将电极尖端接触到细胞，抽气装置三通阀调成三通状态，然后对电极施加负压，使得电极与细胞形成高阻封接。继续施加负压，使得细胞膜破裂，形成电流通路。
3)待细胞破膜电流稳定后，依次进行不同的浓度的灌注。若电流稳定至少一分钟即可换下一个浓度进行灌流。每个浓度灌流时间不超过五分钟。
4)清洗灌流槽。按药液浓度从高到低进行冲洗，每个浓度药液冲洗20s。最后用细胞外液冲洗1min。
2.3测试电压方程(resting)及结果
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。
3.数据分析
资料将存于计算机系统做分析。资料采集和分析将用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。
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。
表1、本公开化合物对Nav1.8通道活性抑制的IC50

结论：本公开中的化合物对Nav1.8通道活性具有明显的抑制效果。
测试例2：药代动力学评价
一、SD大鼠试验
1、摘要
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。
2、试验方案
2.1试验药品
化合物16、32和38。
2.2试验动物
化合物16和32：SD大鼠4只，雄性，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。
化合物38：SD大鼠2只，雄性，由浙江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。
2.3药物配制
化合物16和32：分别称取一定量的受试化合物，加5％DMSO+5％吐温80+90％生理盐水，配制成0.2mg/mL无色澄明溶液。
化合物38：分别称取一定量的受试化合物，加25％PEG400+75％(10％TPGS+1％HPMC K100LV)，配制成5mg/mL无色澄明溶液。
2.4给药
化合物16和32：给药剂量为2mg/kg，给药体积为10.0mL/kg。
化合物38：给药剂量为50mg/kg，给药体积为10.0mL/kg。
3、操作
于给药前及给药后0.25、0.5、1.0、2.0、4.0、6.0、8.0、11.0、24.0小时，由眼眶采血0.2mL，置EDTA-K2抗凝试管中，10000rpm离心1分钟(4℃)，1小时内分离血浆，干冰保存待测。采血至离心过程在冰浴条件下操作。给药后2小时进食。
化合物16和32：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，加入200μL含内标(维拉帕米100ng/ml)的乙腈涡旋混合，并在3700rpm下离心10分钟。取上清液0.1μL进行LC/MS/MS分析。
化合物38：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，加入200μL含内标(地塞米松100ng/ml)的乙腈涡旋混合，并在4000rpm下离心15分钟。取上清液1μL进行LC/MS/MS分析。
4、药代动力学参数结果
表2、本公开化合物的药代动力学参数
结论：本公开化合物在SD大鼠体内血药浓度高，暴露量高，具有明显的药代动力学优势。
二、C57小鼠试验
1、摘要
以C57小鼠为受试动物，应用LC/MS/MS法测定了C57小鼠灌胃(i.g.)/静脉注射(i.v.)给予本公开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C57小鼠体内的药代动力学行为，评价其药动学特征。
2、试验方案
2.1试验药品
化合物16和化合物32。
2.2试验动物
C57小鼠36只，雌雄各半，平均分成4组，9只一组，每组每个时间点3只小鼠，由维通利华实验动物技术有限公司提供，生产许可证SCXK(浙)2019-0001，SCXK(京)2019-0006，分别灌胃及静脉注射给药。
2.3药物配制
分别称取一定量的受试化合物，加5％DMSO+5％吐温80+90％生理盐水，配制成0.1mg/mL无色澄明溶液(灌胃给药组)和0.1mg/mL无色澄明溶液(静脉注射给药组)。
2.4给药
灌胃给药组：给药剂量为2.0mg/kg，给药体积为20mL/kg。
静脉注射给药组：给药剂量为1.0mg/kg，给药体积为10mL/kg。
3.操作
灌胃给药组：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，-80℃保存待测。采血至离心过程在冰浴条件下操作。
静脉注射给药组：于给药前及给药后5分钟，0.25、0.5、1.0、2.0、4.0、8.0、11.0、24小时采血，处理同灌胃给药组。
测定不同浓度的药物给药后C57小鼠血浆中的待测化合物含量：化合物16：取给药后各时刻的C57小鼠血浆样品20μL，每个样品加入200μL含100ng/ml的喜树碱(内标)的乙腈沉淀蛋白质，涡旋混合5分钟，并在3700rpm下离心10分钟。取50μL上清液，加入100μL水，涡旋5分钟，进样1μL进行LC/MS/MS分析。化合物32：取给药后各时刻的C57小鼠血浆样品20μL，每个样品加入200μL含维拉帕米(内标20ng/mL)的乙腈沉淀蛋白质，涡旋混合5分钟，并在3700rpm下离心10分钟。取90μL上清液，加入90μL水，涡旋5分钟，进样0.1μL进行LC/MS/MS分析。
4、药代动力学参数结果
表3、本公开化合物的药代动力学参数
结论：本公开化合物在C57小鼠体内血药浓度高，暴露量大，清除率低，生物利用度较高，具有药代动力学优势。三、CD-1小鼠试验
1、摘要
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.)给予本公开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。
2、试验方案
2.1试验药品
化合物38。
2.2试验动物
CD-1小鼠9只，雄性，每个时间点3只小鼠，由维通利华实验动物技术有限公司提供(许可证：SCXK(浙)2019-0001)，分别灌胃给药。
2.3药物配制
分别称取一定量的受试化合物，加25％PEG400+75％(10％TPGS+1％HPMC K100LV)，配制成10mg/mL微黄悬浮溶液。
2.4给药
给药剂量为100mg/kg，给药体积为10mL/kg。
3.操作
灌胃给药组：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，-80℃保存待测。采血至离心过程在冰浴条件下操作。
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，每个样品加入200μL含内标(地塞米松100ng/ml)的乙腈沉淀蛋白质，涡旋混合5分钟，并在4000rpm下离心15分钟。取40μL上清液，加入120μL水，涡旋5分钟，进样0.5μL进行LC/MS/MS分析。
4、药代动力学参数结果
表4、本公开化合物的药代动力学参数
结论：本公开化合物在CD-1小鼠体内血药浓度高，暴露量高，具有明显的药代动力学优势。
四、犬试验
1、摘要
以犬为受试动物，应用LC/MS/MS法测定了犬灌胃(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犬体内的药代动力学行为，评价其药动学特征。
2、试验方案
2.1试验药品
实施例43化合物。
2.2试验动物
犬4只，雌雄各半，由潍坊圣诺实验动物养殖有限公司(许可证：SCXK(京)2020-0009)和北京协尔鑫生物资源研究所有限责任公司(许可证：SCXK(鲁)20230001)提供。禁食一夜后分别灌胃给药。
2.3药物配制
分别称取一定量的实施例化合物，加5％DMSO+20％PG+20％PEG400+55％生理盐水，配制成0.4mg/mL无色澄明溶液。
2.4给药
给药剂量为2mg/kg，给药体积为10.0mL/kg。
3、操作
于给药前及给药后0.25、0.5、1.0、2.0、4.0、6.0、8.0、11.0、24.0、48.0、72小时，由前肢静脉采血0.5mL，置EDTA-K2抗凝试管中，10000rpm离心1分钟(4℃)，1小时内分离血浆，干冰保存待测。采血至离心过程在冰浴条件下操作。给药后2小时进食。
测定不同浓度的药物给药后犬血浆中的待测化合物含量：取给药后各时刻的犬血浆样品50μL，250μL含内标乙腈(拉贝洛尔1ug/ml)涡旋混合，并在3700rpm下离心10分钟。取上清液0.5μL进行LC/MS/MS分析。
4、药代动力学参数结果
表5、本公开化合物在犬体内的药代动力学参数
结论：本公开化合物在犬体内血药浓度高，暴露量高，半衰期长，清除率低，具有明显的药代动力学优势。
测试例3本公开化合物的溶解度
1、实验材料
试剂：二甲亚砜(色谱纯，Sigma-Aldrich，货号472301-4X4L)、乙醇(色谱纯，CNW，货号4.016362.4000)、乙腈(色谱纯，FISHER，货号A998-4)、NaH2PO4·2H2O(分析纯，国药集团化学试剂有限公司，货号20040717)、乙酸铵(色谱纯，ALADDIN，货号17836-250G)、FaSSIF/FeSSIF/FaSSGF粉末(Biorelevant，货号FFF02)、FaSSIF缓冲浓缩液(Biorelevant，货号FASBUF)、FeSSIF缓冲浓缩液(Biorelevant，货号FESBUF)和超纯水(ELGA CHORUS实验室超纯水机自 制)。
仪器：Agilent 1200 DAD液相色谱仪(美国安捷伦公司)
2、材料配制
2.1 FassIF溶液的配制
FaSSIF溶液：称取2.0825g FaSSIF介质溶液和48.055g超纯水于50mL烧杯中，再向其中加入0.112g FaSSIF/FeSSIF/FaSSGF粉末，搅拌溶解后静置平衡2小时后使用(溶液应在48小时内使用)。
2.2 FessIF溶液的配制
FeSSIF溶液：称取4.0705g FeSSIF介质溶液和45.97g超纯水于50mL烧杯中，再向其中加入0.56g FaSSIF/FeSSIF/FaSSGF粉末，搅拌溶解即得(溶液应在48小时内使用)。
3、实验步骤
在FassIF溶液和FessIF溶液中的溶解测试。
3.1精密称取适量待测化合物用DMSO作为溶剂，配制10mM储备液。精密量取10μL储备液(浓度10mM，溶解在DMSO中)与990μL有机混合溶剂(通常为DMSO：乙腈：乙醇＝1:1:1)于2mL样品瓶中，混匀，得到澄清的100μM样品溶液，用0.22μm的有机相微孔滤膜过滤，取续滤液作为参比溶液。
3.2溶解1mg待测样品至900μL FassIF溶液(或FessIF溶液)，强力混合(不易分散的块状固体需超声分散)，平行配制溶液两份；在37℃恒温振荡器中振摇24小时后，在12000rpm离心30min，上清液作为样品溶液，转移至液相色谱分析。
4、实验结果
溶解度(μM)＝样品的峰面积/参比的峰面积×参比溶液浓度(μM)×样品溶液稀释倍数。
取两次测量值的平均值作为最终在FassIF溶液和FessIF溶液中的溶解度。
表6、本公开化合物的溶解度。
结论：本公开化合物在FassIF和FessIF溶液中均具有很好的溶解度。
测试例4药效试验
1、实验目的
评价本公开化合物在大鼠切口疼痛模型中抑制大鼠疼痛的镇痛药效。
2、实验药品
实施例16和实施例32化合物。
采用25％PEG400+75％(10％TPGS+1％HPMC K100LV)溶液。
3、实验方法和实验材料
3.1实验动物和饲养条件
实验动物：SD大鼠，购自北京维通利华实验动物有限公司(许可证号码:SCXK(浙)2019-0001)，购入时体重约180g。
饲养条件：5只/笼饲养，12/12小时光/暗周期调节，温度23±1℃恒温，湿度50至60％，自由进食进水。
3.2动物分组
SD大鼠适应性饲养后，分组如下：
注：one dose为只给药1次；i.g.为灌胃给药。
3.3实验方法：
取SD大鼠，体重170-190g，9只，用电子触觉测量仪测定机械疼痛阈值。然后进行切口疼痛手术，手术时用舒泰麻醉(舒泰-50，250mg，溶解后用生理盐水稀释到50ml，200g体重注射2ml)后，用10号手术刀片在左后爪足底中部切开1cm长的切口，通过皮肤和筋膜，用3-0无菌丝手术缝合线缝合皮肤。受伤部位用青霉素消毒，动物放回原处过夜恢复。手术恢复过夜后，口服灌胃给药，大鼠给药后5h(手术后24h左右)后用电子触觉测量仪测定机械疼痛阈值。
3.4数据统计
使用Excel统计软件记录数据：平均值以avg计算；SD值以STDEV计算；SEM值以STDEV/SQRT(每组动物数)计算；采用GraphPad Prism软件作图，采用one-way ANOVA和t-test对数据进行统计学分析。
阈值升高百分比(％)＝[(Gt-G0)/G0]×100(％)，其中Gt为给药组足底疼痛阈值，G0为溶媒组足底疼痛阈值。
4、结果
实施例16化合物在大鼠切口疼痛模型中的镇痛药效如图3和表7所示，体重影响见图4；实施例32化合物在大鼠切口疼痛模型中的镇痛药效如图5和表7所示，体重影响见图6。
表7、本公开化合物在大鼠切口疼痛模型中的镇痛药效

注：one dose为只给药1次；i.g.为灌胃给药。
5、结论
正常大鼠(体重170-190g)触痛阈值为26.2±1.6gf，溶媒对照组为10.0±0.7gf。实施例16化合物在200、100、50mg/kg触痛阈值分别为22.3、14.9、10.8gf，触痛阈值比溶媒对照组分别明显升高122％(p＜0.001)、49％(p＜0.05)、7％。200mg/kg的触痛阈值明显高于100mg/kg触痛阈值(p＜0.01)，100mg/kg的触痛阈值明显高于50mg/kg触痛阈值(p＜0.05)，镇痛作用具有明显的剂量依赖性，且给药对大鼠体重没有影响。
正常大鼠(体重170-190g)触痛阈值为26.3±0.8gf，溶媒对照组为10.4±0.9gf。实施例32化合物在200、100、30mg/kg触痛阈值分别为22.4、22.3、12.0gf，触痛阈值比溶媒对照组分别明显升高114％(p＜0.001)、114％(p＜0.001)、15％。200mg/kg的触痛阈值与100mg/kg触痛阈值相当，镇痛药效达到饱和，100mg/kg的触痛阈值明显高于30mg/kg触痛阈值(p＜0.01)，镇痛作用具有明显的剂量依赖性，且给药对大鼠体重没有影响。

Claims (24)

  1. 一种通式(I)所示的化合物或其可药用的盐：
    其中：
    环A为苯基或6元杂芳基；
    各个RA相同或不同，且各自独立地选自氘原子、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、烷氧基烷基、烯基、炔基、-NR3R4、-亚烷基-NR3R4、-O-亚烷基-NR3R4、-C(＝NR5)R6、-S(O)vNR3R4、-NR5S(O)vR6、-S(O)vR6、-S(＝NR5)(O)R6、-NR5C(O)R6、-NR5C(O)NR3R4、-C(O)NR5-OR6、-P(O)R7R8、-C(O)NR5-NR3R4、-C(＝NR5)NR5-OR6、-C(O)NR5-亚烷基-Cy、-C(＝NR5)NR3R4、-C(O)-C(O)-NR3R4、-S(＝NR5)NR3R4、-S(＝NR5)R6、-S(＝NR5)(O)NR3R4、-Si(O)NR3R4、-Si(R6)3、-OR6、环烷基、杂环基、芳基、杂芳基、环烷基烷基、杂环基烷基、-C(O)-环烷基、-C(O)-杂环基、-亚烷基-O-亚烷基-环烷基、-亚烷基-O-环烷基、-O-亚烷基-杂芳基和-O-亚烷基-杂环基，其中，所述的烷基、烷氧基、烷氧基烷基、烯基、炔基、亚烷基、环烷基、杂环基、芳基、杂芳基、环烷基烷基和杂环基烷基各自独立地任选被1个或多个R01所取代；
    Cy为环烷基或杂环基，所述的环烷基和杂环基各自独立地任选被选自氘原子、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、芳基和杂芳基中的一个或多个取代基所取代；
    各个R3、R4和R5相同或不同，且各自独立地选自氢原子、烷基、氘代烷基、烷氧基、氘代烷氧基、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、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1个或多个R01所取代；
    或R3、R4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；
    各个R6、R7和R8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、氘代烷基、卤代烷氧基、氘代烷氧基、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、环烷基烷基、杂环基烷基、芳基和杂芳基；所述的烷基、烷氧基、烯基、炔基、环烷基、杂环基、环烷基烷基、杂环基烷基、芳基和杂芳基各自独立地任选被选自一个或多个R01所取代；
    各个R01相同或不同，且各自独立地选自氘原子、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、杂芳基、＝CR7aR8a、-NR3R4、-亚烷基-NR3R4、-O-亚烷基-NR3R4、-C(＝NR5)R6、-S(O)vNR3R4、-NR5S(O)vR6、-S(O)vR6、-S(＝NR5)(O)R6、-NR5C(O)R6、-NR5C(O)NR3R4、-C(O)NR5-OR6、-P(O)R7R8、-C(O)NR5-NR3R4、-C(＝NR5)NR5-OR6、-C(O)NR5-亚烷基-Cy、-C(＝NR5)NR3R4、-C(O)-C(O)-NR3R4、-S(＝NR5)NR3R4、-S(＝NR5)R6、-S(＝NR5)(O)NR3R4、-Si(O)NR3R4、-OR6、-Si(R6a)3、-O-亚烷基-杂芳基和-O-亚烷基-杂环基；所述的烷基、烯基、炔基、烷氧基、亚烷基、环烷基、杂环基、芳基和杂芳基各自独立地任选被选自氘原子、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、芳基和杂芳基中的一个或多个取代基所取代；
    各个R6a、R7a和R8a相同或不同，且各自独立地选自氢原子、氘原子、卤素、羟基、氰基、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；
    R’选自氢原子、烷基、卤代烷基、氘代烷基、烷氧基、氘代烷氧基、羟烷基、环烷基和杂环基；
    X为O或S；
    Ra和Rb相同或不同，且各自独立地选自氢原子、氘原子、卤素、羟基、氰基、氨基、烷基、氘代烷基、烯基、炔基、烷氧基、氘代烷氧基、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；所述的烷基、烷氧基、烯基、炔基、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取代；
    条件是，Ra和Rb不同时为氢；
    Rc和Rd相同或不同，且各自独立地选自氢原子、氘原子、卤素、羟基、氰基、氨基、烷基、烯基、炔基、烷氧基、卤代烷基、氘代烷基、卤代烷氧基、氘代烷氧基、羟烷基、环烷基、杂环基、环烷基氧基和杂环基氧基；所述的烷基、烷氧基、烯基、炔基、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；
    或，Ra、Rb与其相连的碳原子一起形成环烷基或杂环基；或，Rc、Rd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；
    Re选自氢原子、氘原子、卤素、羟基、氰基、氨基、烷基、烷氧基、卤代烷基、卤代烷氧基、氘代烷基、氘代烷氧基和羟烷基；
    各个R02相同或不同，且各自独立地选自氘原子、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；
    各个R20、R21和R22相同或不同，且各自独立地选自氢原子、烷基、氘代烷基、烷氧基、氘代烷氧基、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氘原子、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中的一个或多个所取代；
    各个R23相同或不同，且各自独立地选自氢原子、烷基、氘代烷基、烷氧基、氘代烷氧基、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氘原子、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中的一个或多个所取代；
    X1为CRX1或N；
    X2为CRX2或N；
    X3为CRX3或N；
    X4为CRX4或N；
    X5为CRX5或N；
    X1、X2、X3、X4和X5不同时为N；
    RX1、RX2、RX3、RX4和RX5相同或不同，且各自独立地选自氢原子、氘原子、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、氘代烷基、卤代烷氧基、氘代烷氧基、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，且各自独立地选自氘原子、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；
    各个v相同或不同，且各自独立地选自0、1和2；
    n选自0、1、2、3、4和5；
    s选自0、1、2、3、4和5；且，
    r选自0、1、2、3、4和5；
    条件是，不为
  2. 根据权利要求1所述的化合物或其可药用的盐，其为通式(II)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、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；
    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；
    环A、RA、R’、X、RX1、RX2、RX3、R02和r如权利要求1中所定义。
  3. 根据权利要求1或2所述的化合物或其可药用的盐，其中环A选自 其中*端与-NR’连接，端与RA连接。
  4. 根据权利要求1至3中任一项所述的化合物或其可药用的盐，其中RA选自F、Cl、氨基、氰基、 优选地，RA选自 更优选为
  5. 根据权利要求1或2所述的化合物或其可药用的盐，其为通式(IV)所示的化合物或其可药用的盐：
    其中，R1A与R2A相同或不同，且各自独立地为氢原子或RA；
    R3A为RA；
    Ra、Rb、Rc、Rd、RX1、RX2、RX3、R’和RA如权利要求2中所定义。
  6. 根据权利要求1或2所述的化合物或其可药用的盐，其为通式(VI’)所示的化合物或其可药用的盐：
    其中，Q选自CR5A、N和N+-O-；
    R5A为R1A；
    R1A、R2A、R’、Ra、Rb、Rc、Rd、RX1、RX2、RX3、R3、R4和R5如权利要求5中所定义。
  7. 根据权利要求1至3、5和6中任一项所述的化合物或其可药用的盐，其中R3选自氢原子、C1-6烷基、OR23和C(O)OR23，R23如通式(I)中所定义；和/或R4为氢原子；优选地，R3选自氢原子、羟基、C1-6烷基、C1-6烷氧基、氘代C1-6烷氧基、-O-3至6元环烷基和C(O)OR23，R23为C1-8烷基；和/或R4为氢原子；更优选地，R3选自氢原子、甲基、乙基、羟基、甲氧基、环丙基、和/或R4为氢原子；最优选地，R3和R4均为氢原子。
  8. 根据权利要求1至3、5、6和7中任一项所述的化合物或其可药用的盐，其中R5选自氢原子、C1-6烷基、OR23、3至6元环烷基和C(O)OR23，R23如权利要求1中所定义；优选地，R5选自氢原子、羟基、C1-6烷基、C1-6烷氧基、氘代C1-6烷氧基、-O-3至6元环烷基和C(O)OR23，R23为C1-8烷基；更优选地，R5为羟基或C1-6烷氧基；最优选地，R5为羟基或甲氧基。
  9. 根据权利要求1至3和5至8中任一项所述的化合物或其可药用的盐，其中R5选自氢原子、甲基、羟基、甲氧基、氘代甲氧基、-O-环丙基、 优选地，R5选自氢原子、甲基、羟基、甲氧基、氘代甲氧基和-O-环丙基。
  10. 根据权利要求1至9中任一项所述的化合物或其可药用的盐，其中Ra为C1-6烷基；优选地，Ra为CH3。
  11. 根据权利要求1至10中任一项所述的化合物或其可药用的盐，其中Rb为卤代C1-6烷基；优选地Rb为CF3。
  12. 根据权利要求1至11中任一项所述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。
  13. 根据权利要求1至12中任一项所述的化合物或其可药用的盐，其中R’为氢原子。
  14. 根据权利要求1至13中任一项所述的化合物或其可药用的盐，其中RX1选自羟基、C1-6烷氧基和3至6元环烷基氧基；优选地，RX1选自羟基、甲氧基和更优选地，RX1为甲氧基。
  15. 根据权利要求1至14中任一项所述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。
  16. 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，其中RX3为卤素；优选地，RX3为氟原子。
  17. 化合物或其可药用的盐，其选自如下化合物：






  18. 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(VI’A)所示的化合物或其盐：
    其中，Q、R1A、R2A、R’、Ra、Rb、Rc、Rd、RX1、RX2和RX3如权利要求6中所定义。
  19. 化合物或其盐，其选自如下化合物：


  20. 一种制备通式(I)所示的化合物或其可药用的盐的方法，该方法包括：
    通式(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，
    R10为卤素(优选为氯原子)或OH；
    环A、RA、R’、Ra、Rb、Rc、Rd、Re、X、X1、X2、X3、X4、X5和r如权利要求1中所定义。
  21. 一种制备通式(VI’)所示的化合物或其可药用的盐的方法，该方法包括：
    通式(VI’A)所示的化合物或其盐与NH2-R5或其盐(优选为盐酸盐)反应得到通式(VI’)所示的化合物或其可药用的盐，其中，
    R3和R4均为氢原子；
    R’、Ra、Rb、Rc、Rd、RX1、RX2、RX3、R1A、R2A、Q和R5如权利要求6中所定义。
  22. 一种药物组合物，所述药物组合物含有根据权利要求1至17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。
  23. 根据权利要求1至17中任一项所述的化合物或其可药用的盐或根据权利要求22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。
  24. 根据权利要求1至17中任一项所述的化合物或其可药用的盐或根据权利要求22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。
PCT/CN2023/114740 2022-08-24 2023-08-24 杂环类化合物、其制备方法及其在医药上的应用 Ceased WO2024041613A1 (zh)

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KR1020257006465A KR20250052383A (ko) 2022-08-24 2023-08-24 헤테로시클릭계 화합물, 이의 제조 방법 및 이의 의학적 응용
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WO2024217557A1 (zh) * 2023-04-19 2024-10-24 武汉人福创新药物研发中心有限公司 取代的四氢呋喃作为Nav1.8抑制剂
WO2025090465A1 (en) 2023-10-23 2025-05-01 Vertex Pharmaceuticals Incorporated Heteroaryl compounds for the treatment of pain
WO2025092901A1 (en) * 2023-11-01 2025-05-08 Insilico Medicine Ip Limited Novel compounds as modulators of sodium channels and uses thereof
WO2025092922A1 (en) * 2023-11-02 2025-05-08 Iongen Therapeutics Co., Ltd. Compounds, compositions and methods thereof
CN120040429A (zh) * 2024-02-23 2025-05-27 山东盛迪医药有限公司 一种取代四氢呋喃衍生物的结晶形式及其用途
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WO2025108301A1 (zh) * 2023-11-21 2025-05-30 武汉熙瑞医药科技有限公司 一种含呋喃环的化合物、其药物组合物及其应用
CN120058686A (zh) * 2024-02-23 2025-05-30 山东盛迪医药有限公司 一种取代四氢呋喃化合物的可药用盐、其结晶形式及用途
WO2025131100A1 (zh) * 2023-12-21 2025-06-26 武汉熙瑞医药科技有限公司 一种含苯环的多环化合物、其药物组合物及其应用
WO2025131099A1 (zh) * 2023-12-21 2025-06-26 武汉熙瑞医药科技有限公司 一种含苯环的多环化合物、其药物组合物及其应用
WO2025209562A1 (zh) * 2024-04-03 2025-10-09 武汉人福创新药物研发中心有限公司 作为Nav1.8抑制剂的四氢呋喃吡啶酮类化合物
WO2025218764A1 (zh) * 2024-04-19 2025-10-23 广州市联瑞制药有限公司 作为电压门控钠通道抑制剂的化合物及其应用
WO2025223193A1 (zh) * 2024-04-23 2025-10-30 安润医药科技（苏州）有限公司 作钠通道调节剂的酰胺衍生物及其用途
WO2025252186A1 (zh) * 2024-06-07 2025-12-11 济川药业集团有限公司 一种用作电压门控钠通道抑制剂的杂环类化合物及其药物组合物、药物制剂和应用
WO2025252109A1 (zh) * 2024-06-04 2025-12-11 成都苑东生物制药股份有限公司 一种取代四氢呋喃类衍生物、其制备方法及用途
WO2026006674A1 (en) 2024-06-28 2026-01-02 Vertex Pharmaceuticals Incorporated Heteroaryl compounds for the treatment of pain
WO2026030525A1 (en) 2024-07-31 2026-02-05 Vertex Pharmaceuticals Incorporated Zilvetrigine dosage forms and dosing regimens for treating pain

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WO2024188367A1 (zh) * 2023-03-10 2024-09-19 西藏海思科制药有限公司 一种四氢呋喃衍生物及其在医药上的应用
WO2024217557A1 (zh) * 2023-04-19 2024-10-24 武汉人福创新药物研发中心有限公司 取代的四氢呋喃作为Nav1.8抑制剂
WO2025090465A1 (en) 2023-10-23 2025-05-01 Vertex Pharmaceuticals Incorporated Heteroaryl compounds for the treatment of pain
WO2025092901A1 (en) * 2023-11-01 2025-05-08 Insilico Medicine Ip Limited Novel compounds as modulators of sodium channels and uses thereof
WO2025092922A1 (en) * 2023-11-02 2025-05-08 Iongen Therapeutics Co., Ltd. Compounds, compositions and methods thereof
WO2025108301A1 (zh) * 2023-11-21 2025-05-30 武汉熙瑞医药科技有限公司 一种含呋喃环的化合物、其药物组合物及其应用
WO2025131099A1 (zh) * 2023-12-21 2025-06-26 武汉熙瑞医药科技有限公司 一种含苯环的多环化合物、其药物组合物及其应用
WO2025131100A1 (zh) * 2023-12-21 2025-06-26 武汉熙瑞医药科技有限公司 一种含苯环的多环化合物、其药物组合物及其应用
CN120058686A (zh) * 2024-02-23 2025-05-30 山东盛迪医药有限公司 一种取代四氢呋喃化合物的可药用盐、其结晶形式及用途
CN120040429B (zh) * 2024-02-23 2026-03-31 山东盛迪医药有限公司 一种取代四氢呋喃衍生物的结晶形式及其用途
CN120040430A (zh) * 2024-02-23 2025-05-27 山东盛迪医药有限公司 一种取代四氢呋喃衍生物的可药用盐、其结晶形式及用途
CN120058685A (zh) * 2024-02-23 2025-05-30 山东盛迪医药有限公司 一种取代四氢呋喃化合物的结晶形式及其制备方法
CN120040431A (zh) * 2024-02-23 2025-05-27 山东盛迪医药有限公司 一种取代四氢呋喃衍生物的可药用盐、其结晶形式及用途
CN120040429A (zh) * 2024-02-23 2025-05-27 山东盛迪医药有限公司 一种取代四氢呋喃衍生物的结晶形式及其用途
CN120058684A (zh) * 2024-02-23 2025-05-30 山东盛迪医药有限公司 一种取代四氢呋喃化合物的结晶形式及其制备方法
WO2025209562A1 (zh) * 2024-04-03 2025-10-09 武汉人福创新药物研发中心有限公司 作为Nav1.8抑制剂的四氢呋喃吡啶酮类化合物
WO2025218764A1 (zh) * 2024-04-19 2025-10-23 广州市联瑞制药有限公司 作为电压门控钠通道抑制剂的化合物及其应用
WO2025223193A1 (zh) * 2024-04-23 2025-10-30 安润医药科技（苏州）有限公司 作钠通道调节剂的酰胺衍生物及其用途
WO2025252109A1 (zh) * 2024-06-04 2025-12-11 成都苑东生物制药股份有限公司 一种取代四氢呋喃类衍生物、其制备方法及用途
WO2025252186A1 (zh) * 2024-06-07 2025-12-11 济川药业集团有限公司 一种用作电压门控钠通道抑制剂的杂环类化合物及其药物组合物、药物制剂和应用
WO2026006674A1 (en) 2024-06-28 2026-01-02 Vertex Pharmaceuticals Incorporated Heteroaryl compounds for the treatment of pain
WO2026030525A1 (en) 2024-07-31 2026-02-05 Vertex Pharmaceuticals Incorporated Zilvetrigine dosage forms and dosing regimens for treating pain

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