WO2024088409A1 - 一种含氮杂环化合物、其药学上可接受的盐及其制备方法与应用 - Google Patents

一种含氮杂环化合物、其药学上可接受的盐及其制备方法与应用 Download PDF

Info

Publication number
WO2024088409A1
WO2024088409A1 PCT/CN2023/127300 CN2023127300W WO2024088409A1 WO 2024088409 A1 WO2024088409 A1 WO 2024088409A1 CN 2023127300 W CN2023127300 W CN 2023127300W WO 2024088409 A1 WO2024088409 A1 WO 2024088409A1
Authority
WO
WIPO (PCT)
Prior art keywords
group
independently
alkyl
membered
membered heterocycloalkyl
Prior art date
Application number
PCT/CN2023/127300
Other languages
English (en)
French (fr)
Inventor
陈德恒
贾海飞
申华琼
赵乐乐
Original Assignee
纽欧申医药(上海)有限公司
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 纽欧申医药(上海)有限公司 filed Critical 纽欧申医药(上海)有限公司
Publication of WO2024088409A1 publication Critical patent/WO2024088409A1/zh

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/397—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having four-membered rings, e.g. azetidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/50—Pyridazines; Hydrogenated pyridazines
    • A61K31/5025—Pyridazines; Hydrogenated pyridazines ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • the present invention relates to a nitrogen-containing heterocyclic compound, a pharmaceutically acceptable salt thereof, and a preparation method and application thereof.
  • Muscarinic receptors belong to G protein-coupled receptors and are a type of acetylcholine receptor. There are five subtypes of M receptors, of which M1, M3, and M5 are coupled to Gq proteins, activate phospholipase C, and increase intracellular calcium levels. M2 and M4 are coupled to Gi proteins, inhibit adenylate cyclase, and reduce cAMP levels. M1 receptors are distributed in the central nervous system, digestive tract, and lymphoid tissues. As the main subtype of M receptors, they can regulate cell excitability and cholinergic transmission at the same time. M4 receptors are mainly located in the cortex, hippocampus, and striatum, and play an important role in controlling dopamine release and motor activity, but do not regulate important peripheral physiological functions (Neuropharmacology 2018, 136, 362).
  • M receptor agonists have been widely studied as therapeutic drugs for mental illness by many scientific research institutions and drug development companies.
  • the M1/M4 receptor agonist Xanomeline was used in a Phase II clinical trial for the treatment of Alzheimer's disease in the 1990s.
  • the patient's cognitive function was improved after treatment with the drug, but there were relatively serious toxic side effects in the periphery and digestive tract.
  • KarXT composed of Xanomeline and the M1 receptor antagonist trospium chloride, is a drug developed by Karuna to treat schizophrenia.
  • M receptor positive allosteric modulator has been one of the research hotspots in the field of mental illness in recent years.
  • the M1 receptor positive allosteric modulator TAK-071 significantly improved the mice's deficits in memory cognition, social ability, and sensorimotor gating (Neurosci Lett 2021, 764, 136240). This compound is used to treat Parkinson's syndrome.
  • Phase II clinical trials of M1 receptor positive allosteric modulator MK-7622 are ongoing. Phase II clinical trials are underway to evaluate its efficacy in treating Alzheimer's disease (ACS Med Chem Lett 2018, 9, 652).
  • the present invention provides a nitrogen-containing heterocyclic compound, a pharmaceutically acceptable salt thereof, and a preparation method and application thereof.
  • the compound of the present invention can be used as a positive allosteric modulator of muscarinic receptors.
  • the compound of the present invention can treat M receptor-mediated (or M receptor-related) diseases.
  • the present invention provides a compound represented by formula I or a pharmaceutically acceptable salt thereof:
  • n is a natural number from 0 to 3;
  • n is a natural number from 0 to 3; m and n are not 0 at the same time;
  • k is a natural number from 0 to 3;
  • X 1 , X 2 , X 3 , X 4 and X 5 are independently -CR 1 -, N, O, S, or chemical bonds;
  • RN-1 is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy or 3-7 membered cycloalkyl, wherein the C 1 -C 6 alkyl and C 1 -C 6 alkoxy are optionally independently substituted by 1, 2, 3 or 4 RN-2 ;
  • each R N-2 is independently halogen
  • Y and Z are independently carbonyl (CO), -(CR 2 R 3 ) r - or a chemical bond; r is a natural number of 0 to 5;
  • Each W is independently a carbonyl group (CO), -O-, -(CR 4 R 5 )-, -NR 6 - or a chemical bond;
  • Each R 1 is independently hydrogen, halogen, cyano, hydroxyl, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 alkylthio, 3-7 membered cycloalkyl, 3-7 membered heterocycloalkyl or -NR 1-1 R 1-2 , wherein the C 1 -C 6 alkylthio, C 1 -C 6 alkyl and C 1 -C 6 alkoxy are optionally independently substituted by 1, 2, 3 or 4 R a ; or two R 1 and the atoms to which they are connected form a 3-7 membered cycloalkyl or 3-7 membered heterocycloalkyl;
  • Each Ra is independently halogen, cyano, hydroxyl, C1 - C3 alkyl, C1 - C6 alkoxy or -NR1-4R1-5 ; or, two Ra and the atoms to which they are connected form a 3-7 membered cycloalkyl or 3-7 membered heterocycloalkyl;
  • R 1-1 and R 1-2 are independently hydrogen or C 1 -C 6 alkyl, wherein the C 1 -C 6 alkyl is optionally independently substituted by 1, 2, 3 or 4 R b ; or, R 1-1 and R 1-2 and the atoms to which they are attached form a 3-7 membered heterocycloalkyl, wherein the 3-7 membered heterocycloalkyl is arbitrarily substituted by 1, 2, 3 or 4 R b-2 ;
  • Each R b is independently halogen, cyano, hydroxyl, C 1 -C 6 alkoxy, 3-7 membered cycloalkyl, 3-7 membered heterocycloalkyl, C 1 -C 3 alkyl and NR 1-1-1 R 1-2-1 , wherein the 3-7 membered cycloalkyl, 3-7 membered heterocycloalkyl and C 1 -C 3 alkyl are optionally independently substituted by 1, 2, 3 or 4 R b-1 ;
  • Each R b-1 is independently halogen, hydroxyl or cyano
  • Each R b-2 is independently halogen, C 1 -C 6 alkyl or cyano;
  • R 1-4 and R 1-5 are independently hydrogen or C 1 -C 3 alkyl, wherein the C 1 -C 3 alkyl is optionally independently substituted by 1, 2, 3 or 4 R 1-4-1 ; or, R 1-4 and R 1-5 , together with the atoms to which they are attached, form a 3-7 membered heterocycloalkyl;
  • R 1-1-1 and R 1-2-1 are independently hydrogen or C 1 -C 3 alkyl, wherein the C 1 -C 3 alkyl is optionally substituted independently with 1, 2, 3 or 4 R 1-1-1-1 ;
  • R 1-4-1 and R 1-1-1-1 is independently halogen, hydroxyl or cyano;
  • R2 and R3 are independently hydrogen, halogen, cyano, hydroxyl, C1 - C6 alkoxy or NR2-1R2-2 ; or R2 and R3 , together with the atoms to which they are connected, form a 3-7 membered cycloalkyl or 3-7 membered heterocycloalkyl;
  • R 2-1 and R 2-2 are independently hydrogen or C 1 -C 6 alkyl, wherein the C 1 -C 6 alkyl is optionally independently substituted by 1, 2, 3 or 4 R d ; or, R 2-1 and R 2-2 and the atoms to which they are connected form a 3-7 membered heterocycloalkyl;
  • Each R d is independently halogen, cyano, hydroxy, C 1 -C 6 alkoxy, 3-7 membered cycloalkyl, 3-7 membered heterocycloalkyl or C 1 -C 3 alkyl;
  • R 4 , R 5 and R 6 are independently hydrogen, halogen, cyano, hydroxyl, C 1 -C 6 alkoxy, C 1 -C 6 alkyl or NR 4-1 R 4-2 , wherein the C 1 -C 6 alkyl is optionally independently substituted by 1, 2, 3 or 4 Re ;
  • Each Re is independently halogen, cyano, hydroxy, C 1 -C 3 alkyl, C 1 -C 3 alkoxy or -NR 4-4 R 4-5 ;
  • R 4-1 and R 4-2 are independently hydrogen or C 1 -C 6 alkyl, wherein the C 1 -C 6 alkyl is optionally independently substituted by 1, 2, 3 or 4 R f ; or, R 4-1 and R 4-2 and the atoms to which they are attached form a 3-7 membered heterocycloalkyl;
  • Each R f is independently halogen, cyano, hydroxy, 3- to 7-membered cycloalkyl, 3- to 7-membered heterocycloalkyl, C 1 -C 3 alkyl, C 1 -C 3 alkoxy or -NR 4-1-1 R 4-2-1 ;
  • R 4-4 and R 4-5 are independently hydrogen or C 1 -C 3 alkyl; or R 4 and R 5 together with the atoms to which they are attached form a 3-7 membered cycloalkyl or a 3-7 membered heterocycloalkyl;
  • R 4-1-1 and R 4-2- are independently hydrogen or C 1 -C 3 alkyl
  • t is a natural number from 0 to 3;
  • u is a natural number from 0 to 3;
  • E is a carbonyl group, -NHCO-, or chemical bond
  • F is a carbonyl group, -O-, -NH- or chemical bonds
  • R8 and R9 are independently hydrogen, halogen, cyano, hydroxyl or C1 - C6 alkyl, wherein the C1 - C6 alkyl is optionally independently substituted by 1, 2, 3 or 4 Rg ; or R8 and R9 and the atoms to which they are connected form a 3-7 membered cycloalkyl or 3-7 membered heterocycloalkyl;
  • Each Rg is independently halogen, cyano, hydroxy, C1 - C3 alkyl or C1 - C3 alkoxy;
  • B is a 3- to 7-membered cycloalkyl group, a 4- to 6-membered heterocycloalkyl group, a 6- to 10-membered aryl group, or a 5- to 12-membered heteroaryl group; wherein the 3- to 7-membered cycloalkyl group, the 4- to 6-membered heterocycloalkyl group, the 6- to 10-membered aryl group, and the 5- to 12-membered heteroaryl group are optionally independently substituted by 1, 2, or 3 R i ;
  • Each R i is independently hydrogen, halogen, hydroxyl, C 1 -C 3 alkyl, 3-7 membered cycloalkyl, 3-7 membered heterocycloalkyl, cyano, -NR 11-1 R 11- 2 , -OR 11-3 or -SR 11-4 ; wherein the C 1 -C 3 alkyl is optionally independently substituted by 1, 2, 3 or 4 R i-1 , or two R i on the same atom and the atom to which they are connected form a 3-7 membered cycloalkyl or 3-7 membered heterocycloalkyl; or two adjacent R i and the atom to which they are connected form a 3-7 membered cycloalkyl or 3-7 membered heterocycloalkyl (wherein the 3-7 membered cycloalkyl or 3-7 membered heterocycloalkyl forms a cyclic ring with B);
  • Each R i-1 is independently C 1 -C 3 alkyl, halogen, cyano or hydroxyl;
  • R 11-1 and R 11-2 are independently hydrogen, C 1 -C 3 alkyl, 3-7 membered cycloalkyl or 3-7 membered heterocycloalkyl; or, R 11-1 and R 11-2 and the atoms to which they are connected form a 3-7 membered cycloalkyl or 3-7 membered heterocycloalkyl;
  • R 11-3 and R 11-4 are independently C 1 -C 3 alkyl, 3-7 membered cycloalkyl or 3-7 membered heterocycloalkyl;
  • R 11-1 , R 11-2 , R 11-3 and R 11-4 the C 1 -C 3 alkyl, 3- to 7-membered cycloalkyl and 3- to 7-membered heterocycloalkyl are optionally independently substituted by 1, 2 or 3 R i-2 ;
  • Each R i-2 is independently C 1 -C 3 alkyl, 3-7 membered cycloalkyl, 3-7 membered heterocycloalkyl, halogen, cyano or hydroxyl;
  • D is hydrogen, halogen, cyano, hydroxyl, C 1 -C 6 alkyl, 3-7 membered cycloalkyl, 3-7 membered heterocycloalkyl, 6-10 membered aryl or 5-12 membered heteroaryl; wherein the C 1 -C 6 alkyl, 3-7 membered cycloalkyl, 3-7 membered heterocycloalkyl, 6-10 membered aryl and 5-12 membered heteroaryl are optionally and independently substituted by 1, 2 or 3 R j ;
  • Each R j is independently hydrogen, halogen, cyano, hydroxyl, C 1 -C 3 alkyl, 3-7 membered cycloalkyl, 3-7 membered heterocycloalkyl, -NR 12-1 R 12- 2 , -OR 12-3 or -SR 12-4 ; the C 1 -C 3 alkyl, 3-7 membered cycloalkyl and 3-7 membered heterocycloalkyl are optionally independently substituted by 1, 2 or 3 R k ;
  • R 12-1 , R 12-2 , R 12-3 and R 12-4 are independently hydrogen, C 1 -C 3 alkyl, 3-7 membered cycloalkyl or 3-7 membered heterocycloalkyl; wherein C 1 -C 3 alkyl, 3-7 membered cycloalkyl and 3-7 membered heterocycloalkyl are optionally independently substituted by 1, 2 or 3 R k-1 ; or, R 12-1 and R 12-2 and the atoms connected thereto form a 3-7 membered heterocycloalkyl;
  • Each R k is independently halogen, cyano, hydroxy, C 1 -C 3 alkyl, 3-7 membered cycloalkyl or 3-7 membered heterocycloalkyl;
  • Each R k-1 is independently halogen, cyano, hydroxy, C 1 -C 3 alkyl, 3- to 7-membered cycloalkyl or 3- to 7-membered heterocycloalkyl;
  • E is -NHCO- or a chemical bond
  • F is -O-, -NH- or a chemical bond
  • E is a carbonyl group
  • F is -NH-
  • B is a 4- to 7-membered cycloalkyl group, a 6- to 10-membered aryl group, a 5- to 12-membered heteroaryl group, or a 4- to 6-membered heterocycloalkyl group substituted by 1, 2 or 3 R i , wherein two R i on the same atom and the atom to which they are attached form a 3- to 7-membered cycloalkyl group or a 3- to 7-membered heterocycloalkyl group; or, two adjacent R i and the atom to which they are attached form a 3- to 7-membered cycloalkyl group or a 3- to 7-membered heterocycloalkyl group (wherein the 3- to 7-membered cycloalkyl group or the 3- to 7-membered heterocycloalkyl group and B form a cyclic ring); wherein the 4- to 7-membered cycloalkyl group,
  • A When A is When L is a carbonyl group, u is a natural number of 1 to 3, and B is a 4- to 6-membered heterocycloalkyl group, and the 4- to 6-membered heterocycloalkyl group is optionally substituted independently by 1, 2 or 3 R i ;
  • the heteroatom is one or more of N, O and S, and the number of the heteroatoms is 1 to 5.
  • certain groups have the following definitions, and the definitions of the unmentioned groups are as described in any embodiment of the present invention (hereinafter referred to as "in a certain embodiment”, “in some embodiments”, “in a certain embodiment” or “in a preferred embodiment” in this paragraph).
  • n is a natural number from 0 to 3;
  • n is a natural number from 0 to 3; m and n are not 0 at the same time;
  • k is a natural number from 0 to 3;
  • X 1 , X 2 , X 3 , X 4 and X 5 are independently -CR 1 -, N, O, S, or chemical bonds;
  • RN-1 is hydrogen or C 1 -C 6 alkyl, C 1 -C 6 alkoxy or 3-7 membered cycloalkyl, wherein the C 1 -C 6 alkyl and C 1 -C 6 alkoxy are optionally independently substituted by 1, 2, 3 or 4 RN-2 ;
  • each R N-2 is independently halogen
  • Y and Z are independently carbonyl (CO), -(CR 2 R 3 ) r - or a chemical bond; r is a natural number of 0 to 5;
  • Each W is independently a carbonyl group (CO), -O-, -(CR 4 R 5 )-, -NR 6 - or a chemical bond;
  • Each R 1 is independently hydrogen, halogen, cyano, hydroxyl, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, 3-7 membered cycloalkyl, 3-7 membered heterocycloalkyl or -NR 1-1 R 1-2 , wherein the C 1 -C 6 alkyl and C 1 -C 6 alkoxy are optionally independently substituted by 1, 2, 3 or 4 R a ; or two R 1 and the atoms to which they are connected form a 3-7 membered cycloalkyl or 3-7 membered heterocycloalkyl;
  • Each Ra is independently halogen, cyano, hydroxyl, C1 - C3 alkyl, C1 - C6 alkoxy or -NR1-4R1-5 ; or, two Ras and the atoms to which they are attached form a 3-7-membered cycloalkyl or 3-7-membered heterocycloalkyl;
  • R1-1 and R1-2 are independently hydrogen or C1 - C6 alkyl, wherein the C1 - C6 alkyl is optionally independently substituted by 1, 2, 3 or 4 Rb ; or, R1-1 and R1-2 and the atoms to which they are attached form a 3-7-membered heterocycloalkyl ;
  • Each R b is independently halogen, cyano, hydroxyl, C 1 -C 6 alkoxy, 3-7 membered cycloalkyl, 3-7 membered heterocycloalkyl, C 1 -C 3 alkyl and NR 1-1-1 R 1-2-1 , wherein the 3-7 membered cycloalkyl, 3-7 membered heterocycloalkyl and C 1 -C 3 alkyl are optionally independently substituted by 1, 2, 3 or 4 R b-1 ;
  • Each R b-1 is independently halogen, hydroxyl or cyano
  • R 1-4 and R 1-5 are independently hydrogen or C 1 -C 3 alkyl, wherein the C 1 -C 3 alkyl is optionally independently substituted by 1, 2, 3 or 4 R 1-4-1 ; or, R 1-4 and R 1-5 , together with the atoms to which they are attached, form a 3-7 membered heterocycloalkyl;
  • R 1-1-1 and R 1-2-1 are independently hydrogen or C 1 -C 3 alkyl, wherein the C 1 -C 3 alkyl is optionally substituted independently with 1, 2, 3 or 4 R 1-1-1-1 ;
  • R 1-4-1 and R 1-1-1-1 is independently halogen, hydroxyl or cyano;
  • R2 and R3 are independently hydrogen, halogen, cyano, hydroxyl, C1 - C6 alkoxy or NR2-1R2-2 ; or R2 and R3 , together with the atoms to which they are connected, form a 3-7 membered cycloalkyl or 3-7 membered heterocycloalkyl;
  • R 2-1 and R 2-2 are independently hydrogen or C 1 -C 6 alkyl, wherein the C 1 -C 6 alkyl is optionally independently substituted by 1, 2, 3 or 4 R d ; or, R 2-1 and R 2-2 and the atoms to which they are attached form a 3-7 membered heterocycloalkyl;
  • Each R d is independently halogen, cyano, hydroxy, C 1 -C 6 alkoxy, 3-7 membered cycloalkyl, 3-7 membered heterocycloalkyl or C 1 -C 3 alkoxy. base;
  • R 4 , R 5 and R 6 are independently hydrogen, halogen, cyano, hydroxyl, C 1 -C 6 alkoxy, C 1 -C 6 alkyl or NR 4-1 R 4-2 , wherein the C 1 -C 6 alkyl is optionally independently substituted by 1, 2, 3 or 4 Re ;
  • Each Re is independently halogen, cyano, hydroxy, C 1 -C 3 alkyl, C 1 -C 3 alkoxy or -NR 4-4 R 4-5 ;
  • R 4-1 and R 4-2 are independently hydrogen or C 1 -C 6 alkyl, wherein the C 1 -C 6 alkyl is optionally independently substituted by 1, 2, 3 or 4 R f ; or, R 4-1 and R 4-2 and the atoms to which they are attached form a 3-7 membered heterocycloalkyl;
  • Each R f is independently halogen, cyano, hydroxy, 3- to 7-membered cycloalkyl, 3- to 7-membered heterocycloalkyl, C 1 -C 3 alkyl, C 1 -C 3 alkoxy or -NR 4-1-1 R 4-2-1 ;
  • R 4-4 and R 4-5 are independently hydrogen or C 1 -C 3 alkyl; or R 4 and R 5 together with the atoms to which they are attached form a 3-7 membered cycloalkyl or a 3-7 membered heterocycloalkyl;
  • R 4-1-1 and R 4-2- are independently hydrogen or C 1 -C 3 alkyl
  • t is a natural number from 0 to 3;
  • u is a natural number from 0 to 3;
  • E is a carbonyl group, -NHCO-, or a chemical bond
  • F is a carbonyl group, -O-, -NH- or a chemical bond
  • R8 and R9 are independently hydrogen, halogen, cyano, hydroxyl or C1 - C6 alkyl, wherein the C1 - C6 alkyl is optionally independently substituted by 1, 2, 3 or 4 Rg ; or R8 and R9 and the atoms to which they are connected form a 3-7 membered cycloalkyl or 3-7 membered heterocycloalkyl;
  • Each Rg is independently halogen, cyano, hydroxy, C1 - C3 alkyl or C1 - C3 alkoxy;
  • B is a 3- to 7-membered cycloalkyl group, a 4- to 6-membered heterocycloalkyl group, a 6- to 10-membered aryl group, or a 5- to 12-membered heteroaryl group; wherein the 3- to 7-membered cycloalkyl group, the 4- to 6-membered heterocycloalkyl group, the 6- to 10-membered aryl group, and the 5- to 12-membered heteroaryl group are optionally independently substituted by 1, 2, or 3 R i ;
  • Each R i is independently hydrogen, halogen, hydroxyl, C 1 -C 3 alkyl, 3-7 membered cycloalkyl, 3-7 membered heterocycloalkyl, cyano, -NR 11-1 R 11- 2 , -OR 11-3 or -SR 11-4 ; wherein the C 1 -C 3 alkyl is optionally independently substituted by 1, 2, 3 or 4 R i-1 , or two R i on the same atom and the atom to which they are connected form a 3-7 membered cycloalkyl or 3-7 membered heterocycloalkyl; or two adjacent R i and the atom to which they are connected form a 3-7 membered cycloalkyl or 3-7 membered heterocycloalkyl (wherein the 3-7 membered cycloalkyl or 3-7 membered heterocycloalkyl forms a cyclic ring with B);
  • Each R i-1 is independently C 1 -C 3 alkyl, halogen, cyano or hydroxyl;
  • R 11-1 and R 11-2 are independently hydrogen, C 1 -C 3 alkyl, 3-7 membered cycloalkyl or 3-7 membered heterocycloalkyl; or, R 11-1 and R 11-2 and the atoms to which they are connected form a 3-7 membered cycloalkyl or 3-7 membered heterocycloalkyl;
  • R 11-3 and R 11-4 are independently C 1 -C 3 alkyl, 3-7 membered cycloalkyl or 3-7 membered heterocycloalkyl;
  • R 11-1 , R 11-2 , R 11-3 and R 11-4 the C 1 -C 3 alkyl, 3- to 7-membered cycloalkyl and 3- to 7-membered heterocycloalkyl are optionally independently substituted by 1, 2 or 3 R i-2 ;
  • Each R i-2 is independently C 1 -C 3 alkyl, 3-7 membered cycloalkyl, 3-7 membered heterocycloalkyl, halogen, cyano or hydroxyl;
  • D is hydrogen, halogen, cyano, hydroxyl, C 1 -C 6 alkyl, 3-7 membered cycloalkyl, 3-7 membered heterocycloalkyl, 6-10 membered aryl or 5-12 membered wherein the C 1 -C 6 alkyl, 3-7 membered cycloalkyl, 3-7 membered heterocycloalkyl, 6-10 membered aryl and 5-12 membered heteroaryl are optionally and independently substituted by 1, 2 or 3 R j ;
  • Each R j is independently hydrogen, halogen, cyano, hydroxyl, C 1 -C 3 alkyl, 3-7 membered cycloalkyl, 3-7 membered heterocycloalkyl, -NR 12-1 R 12- 2 , -OR 12-3 or -SR 12-4 ; the C 1 -C 3 alkyl, 3-7 membered cycloalkyl and 3-7 membered heterocycloalkyl are optionally independently substituted by 1, 2 or 3 R k ;
  • R 12-1 , R 12-2 , R 12-3 and R 12-4 are independently hydrogen, C 1 -C 3 alkyl, 3-7 membered cycloalkyl or 3-7 membered heterocycloalkyl; wherein C 1 -C 3 alkyl, 3-7 membered cycloalkyl and 3-7 membered heterocycloalkyl are optionally independently substituted by 1, 2 or 3 R k-1 ; or, R 12-1 and R 12-2 and the atoms connected thereto form a 3-7 membered heterocycloalkyl;
  • Each R k is independently halogen, cyano, hydroxy, C 1 -C 3 alkyl, 3-7 membered cycloalkyl or 3-7 membered heterocycloalkyl;
  • Each R k-1 is independently halogen, cyano, hydroxy, C 1 -C 3 alkyl, 3- to 7-membered cycloalkyl or 3- to 7-membered heterocycloalkyl;
  • E is -NHCO- or a chemical bond
  • F is -O-, -NH- or a chemical bond
  • E is a carbonyl group
  • F is -NH-
  • B is a 4- to 7-membered cycloalkyl group, a 6- to 10-membered aryl group, a 5- to 12-membered heteroaryl group, or a 4- to 6-membered heterocycloalkyl group substituted by 1, 2 or 3 R i , wherein two R i on the same atom and the atom to which they are attached form a 3- to 7-membered cycloalkyl group or a 3- to 7-membered heterocycloalkyl group; or, two adjacent R i and the atom to which they are attached form a 3- to 7-membered cycloalkyl group or a 3- to 7-membered heterocycloalkyl group (wherein the 3- to 7-membered cycloalkyl group or the 3- to 7-membered heterocycloalkyl group and B form a cyclic ring); wherein the 4- to 7-membered cycloalkyl group,
  • A When A is When L is a carbonyl group, u is a natural number of 1 to 3, and B is a 4- to 6-membered heterocycloalkyl group, and the 4- to 6-membered heterocycloalkyl group is optionally substituted independently by 1, 2 or 3 R i ;
  • the heteroatom is N, O or S, and the number of heteroatoms is 1 to 5; or, in the 3- to 7-membered heterocycloalkyl, 4- to 6-membered heterocycloalkyl and 5- to 12-membered heteroaryl, the heteroatom is one or more of N, O and S, and the number of heteroatoms is 1 to 5.
  • m is preferably a natural number of 0 to 3, such as 0, 1, 2 or 3, and further such as 1, 2 or 3.
  • n is preferably a natural number of 1 to 3, such as 1, 2 or 3, and also such as 1 or 2.
  • n 1
  • X1 is N
  • X2 , X3 and X4 are -CR1-
  • Y and Z are independently -( CH2 )-
  • m and n are 2
  • Rj is trifluoromethyl
  • m is 1.
  • k is preferably a natural number from 0 to 3, such as 0, 1, 2 or 3, and further such as 1, 2 or 3.
  • r is preferably a natural number from 0 to 5, such as 0, 1, 2, 3, 4 or 5, and also such as 1 or 2.
  • r is 1.
  • r is a natural number from 0 to 3, such as 1 or 2.
  • R N-1 is C 1 -C 6 alkyl.
  • R N-1 is hydrogen, C 1 -C 6 alkyl or 3-7 membered cycloalkyl.
  • each W is independently -(CR 4 R 5 )-, -O-, -NR 6 - or a chemical bond.
  • each W is independently -(CR 4 R 5 )-, -NR 6 - or a chemical bond.
  • Y and Z are independently carbonyl (CO) or -(CR 2 R 3 ) r -.
  • Y and Z are independently -(CR 2 R 3 ) r -.
  • each R 1 is independently hydrogen, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 alkylthio, 3-7 membered cycloalkyl, 3-7 membered heterocycloalkyl or -NR 1-1 R 1-2 .
  • each R 1 is independently C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 alkylthio or -NR 1-1 R 1-2 .
  • each R 1 is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 alkylthio, 3-7 membered cycloalkyl, 3-7 membered heterocycloalkyl or -NR 1-1 R 1-2 , for example, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 alkylthio or -NR 1-1 R 1-2 .
  • each R 1 is independently hydrogen, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 alkylthio, 3-7 membered cycloalkane
  • the invention also provides a C 1 -C 6 alkylthio group, a C 1 -C 6 alkyl group and a C 1 -C 6 alkoxy group, wherein the C 1 -C 6 alkylthio group, the C 1 -C 6 alkyl group and the C 1 -C 6 alkoxy group are optionally independently substituted by 1, 2, 3 or 4 R a .
  • each R 1 is independently hydrogen, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, 3- to 7-membered cycloalkyl, 3- to 7-membered heterocycloalkyl, or -NR 1-1 R 1-2 .
  • each R 1 is independently C 1 -C 6 alkyl.
  • each R 1 is independently C 1 -C 6 alkyl or C 1 -C 6 alkoxy.
  • R 1-1 and R 1-2 are independently hydrogen or C 1 -C 6 alkyl; or, R 1-1 and R 1-2 and the atoms to which they are attached form a 3-7 membered heterocycloalkyl; for example, R 1-1 and R 1-2 and the atoms to which they are attached form a 3-7 membered heterocycloalkyl.
  • each R1 is independently C1 - C6 alkyl, C1 - C6 alkoxy, C1- C6 alkylthio, 3-7 membered heterocycloalkyl or -NR1-1R1-2 .
  • R 1 when X 2 is independently -CR 1 -, R 1 (at X 2 ) is C 1 -C 6 alkyl or C 1 -C 6 alkoxy.
  • each R 1 is independently halogen or 3-7 membered cycloalkyl.
  • each R1 is independently C1 - C6 alkyl or 3-7 membered heterocycloalkyl.
  • each Ra is independently hydroxy, C1 - C3 alkoxy or NR1-4R1-5 .
  • each Ra is independently halogen, hydroxy, C1 - C6 alkoxy or -NR1-4R1-5 , for example, each Ra is independently hydroxy, C1 - C6 alkoxy or -NR1-4R1-5 , for example, hydroxy.
  • each R b is independently hydroxy, 3- to 7-membered cycloalkyl, 3- to 7-membered heterocycloalkyl, C 1 -C 3 alkyl, C 1 -C 3 alkoxy, or NR 1-1-1 R 1-2-1 .
  • each R b is independently hydroxyl, 3-7 membered cycloalkyl or C 1 -C 3 alkyl.
  • each R b is independently hydroxyl or 3-7 membered cycloalkyl.
  • each R b is independently a 3- to 7-membered cycloalkyl group.
  • R b-1 is independently hydroxyl.
  • each R b-1 is independently hydroxyl.
  • each R b-2 is independently halogen or C 1 -C 6 alkyl.
  • R 1-4 and R 1-5 are independently C 1 -C 3 alkyl.
  • each R 1-4-1 is independently halogen.
  • R 1-4-1 is halogen
  • R 2 and R 3 are independently hydrogen or NR 2-1 R 2-2 .
  • R2 and R3 are independently hydrogen.
  • R 2-1 and R 2-2 are independently hydrogen or C 1 -C 6 alkyl, such as hydrogen.
  • R 4 , R 5 and R 6 are independently hydrogen.
  • R 4 , R 5 and R 6 are independently hydrogen or NR 4-1 R 4-2 .
  • R 4-1 and R 4-2 are independently hydrogen.
  • Re is -NR4-4R4-5 .
  • R 4-4 and R 4-5 are independently hydrogen or C 1 -C 3 alkyl.
  • E is a carbonyl group, -NHCO- or chemical bond.
  • E is a carbonyl group or a chemical bond.
  • E is carbonyl
  • t 0.
  • F is -NH-, -O- or a chemical bond.
  • F is a carbonyl group, -O-, -NH- or chemical bond.
  • F is a chemical bond
  • R8 and R9 are independently hydrogen or C1 - C6 alkyl; or R8 and R9, together with the atoms to which they are attached, form a 3-7 membered cycloalkyl or a 3-7 membered heterocycloalkyl.
  • R8 and R9 are independently hydrogen or C1 - C6 alkyl, or R8 and R9 together with the atoms to which they are attached form a 3-7 membered cycloalkyl.
  • R8 and R9 are independently C1 - C6 alkyl; or R8 and R9 , together with the atoms to which they are attached, form a 3-7 membered cycloalkyl or a 3-7 membered heterocycloalkyl.
  • B is a 4- to 6-membered heterocycloalkyl, a 6- to 10-membered aryl or a 5- to 12-membered heteroaryl, wherein the 5- to 12-membered heteroaryl, the 6- to 10-membered aryl and the 4- to 6-membered heterocycloalkyl are optionally independently substituted by 1, 2 or 3 R i .
  • B is a 4- to 6-membered heterocycloalkyl group or a 5- to 12-membered heteroaryl group, wherein the 5- to 12-membered heteroaryl group and the 4- to 6-membered heterocycloalkyl group are optionally independently substituted by 1, 2 or 3 R i .
  • B is a 4- to 6-membered heterocycloalkyl group, wherein the 4- to 6-membered heterocycloalkyl group is optionally substituted independently by 1, 2 or 3 R i ;
  • D is hydrogen, halogen, cyano, hydroxyl, C 1 -C 6 alkyl group, 3-7 membered cycloalkyl group, 3-7 membered heterocycloalkyl group, wherein the C 1 -C 6 alkyl group, 3-7 membered cycloalkyl group, 3-7 membered heterocycloalkyl group is optionally substituted independently by 1, 2 or 3 R j ; preferably, D is hydrogen or C 1 -C 6 alkyl group.
  • B is azetidinyl (e.g. ).
  • each Rj is independently -OR12-3 or -SR12-4 .
  • R i is hydrogen, halogen, hydroxyl or C 1 -C 3 alkyl; or, two R i and the atoms to which they are connected form a 3-7 membered cycloalkyl or 3-7 membered heterocycloalkyl.
  • each R i is independently hydrogen, halogen, hydroxyl or C 1 -C 3 alkyl; or, two R i and the atoms to which they are connected form a 3-7 membered cycloalkyl, for example, R i is hydrogen or C 1 -C 3 alkyl, for example C 1 -C 3 alkyl. In one embodiment, R i is hydrogen.
  • D is hydrogen, C 1 -C 6 alkyl or 5- to 12-membered heteroaryl; wherein the C 1 -C 6 alkyl and 5- to 12-membered heteroaryl are optionally and independently substituted by 1, 2 or 3 R j .
  • D is hydrogen, 3-7 membered cycloalkyl, C 1 -C 6 alkyl or 5-6 membered heteroaryl, wherein the C 1 -C 6 alkyl and 5-6 membered heteroaryl are optionally independently substituted by 1, 2 or 3 R j .
  • D is a 5- to 12-membered heteroaryl group; wherein the 5- to 12-membered heteroaryl group is optionally substituted independently by 1, 2 or 3 R j .
  • D is a 5- to 6-membered heteroaryl group; wherein the 5- to 6-membered heteroaryl group is optionally substituted independently by 1, 2 or 3 R j .
  • D is a 6-membered heteroaryl group (e.g. ); wherein the 6-membered heteroaryl is optionally independently substituted by 1, 2 or 3 R j .
  • D when D is a five-membered heteroaryl group, the five-membered heteroaryl group is Each R 1 is independently a C 1 -C 6 alkyl group or a C 1 -C 6 alkoxy group.
  • R j is halogen, C 1 -C 3 alkyl, OR 12-3 or SR 12-4 .
  • each R j is independently C 1 -C 3 alkyl, OR 12-3 or SR 12-4 , and the C 1 -C 3 alkyl is optionally independently substituted with 1, 2 or 3 R k .
  • each R j is independently OR 12-3 or SR 12-4 .
  • each R j is independently halogen, C 1 -C 3 alkyl, OR 12-3 or SR 12-4 .
  • each R j is independently hydrogen, halogen, C 1 -C 3 alkyl, 3-7 membered cycloalkyl, -OR 12-3 or -SR 12-4 .
  • each R j is independently hydrogen, halogen, C 1 -C 3 alkyl, 3-7 membered cycloalkyl, -OR 12-3 or -SR 12-4 ; the C 1 -C 3 alkyl and 3-7 membered cycloalkyl are optionally independently substituted by 1, 2 or 3 R k .
  • R j is OR 12-3 .
  • each Rj is independently OR12-3 .
  • R j is halogen or C 1 -C 3 alkyl.
  • each R j is independently halogen or C 1 -C 3 alkyl.
  • each R1 is independently C1 - C6 alkyl and C1 - C6 alkoxy
  • each Rj is independently halogen, 3-7 membered cycloalkyl, OCH2CF3 , or SR 12-4 .
  • each Rj is independently OR 12-3 or SR 12-4 .
  • R 1 is independently 3-7 membered heterocycloalkyl or -NR 1-1 R 1-2
  • each R j is independently OR 12-3 or SR 12-4 .
  • R 12-3 and R 12-4 are independently C 1 -C 3 alkyl.
  • R 12-3 and R 12-4 are independently C 1 -C 3 alkyl; wherein the C 1 -C 3 alkyl is optionally independently substituted by 1, 2 or 3 R k-1 .
  • R 12-1 , R 12-2 , R 12-3 and R 12-4 are independently C 1 -C 3 alkyl.
  • each R k is independently halogen.
  • R k is independently halogen
  • each R k-1 is independently halogen.
  • R k-1 is independently halogen.
  • the heteroatom is N, O or S, and the number of the heteroatoms is 1 to 3.
  • the heteroatom is N, O or S, and the number of the heteroatoms is 1 to 5.
  • the heteroatom is N, O or S, and the number of the heteroatoms is 1 to 3.
  • the heteroatom is selected from 1, 2 or 3 of N, O or S, and the number of heteroatoms is 1, 2 or 3.
  • the 3- to 7-membered heterocycloalkyl group is a 3- to 6-membered heterocycloalkyl group, wherein the heteroatoms are, for example, one or two of N and O, and the number of the heteroatoms is, for example, one or two.
  • the 4- to 6-membered heterocycloalkyl group is a 4-membered heterocycloalkyl group
  • the heteroatom is, for example, one or two of N and O, and the number of the heteroatom is, for example, one.
  • the 5- to 6-membered heteroaryl group is a 6-membered heteroaryl group
  • the heteroatom is, for example, one or two of N and O, and the number of the heteroatom is, for example, one.
  • the 5- to 12-membered heteroaryl group is a 5- to 10-membered heterocycloalkyl group, wherein the heteroatoms are, for example, one or two of N and O, and the number of the heteroatoms is, for example, one.
  • the C 1 -C 6 alkyl group is preferably a C 1 -C 3 alkyl group, such as a methyl group, an ethyl group, a n-propyl group or an isopropyl group, and another example is a methyl group, an ethyl group or an isopropyl group.
  • the C 1 -C 6 alkoxy group is preferably a C 1 -C 3 alkoxy group, such as a methoxy group, an ethoxy group, a n-propoxy group or an isopropoxy group.
  • the 3- to 7-membered cycloalkyl group is preferably a 3- to 6-membered cycloalkyl group, such as cyclopropane, cyclobutane or cyclopentane.
  • the halogen is F, Cl, Br or I, such as F or Cl.
  • the halogen is F, Cl, Br or I, for example F or Cl, and for example Cl.
  • the C 1 -C 6 alkyl group is preferably a C 1 -C 3 alkyl group, such as a methyl group, an ethyl group, a n-propyl group or an isopropyl group, and another example is a methyl group, an ethyl group or an isopropyl group.
  • the C1 - C6 alkoxy group is preferably a C1 - C3 alkoxy group, such as a methoxy group, an ethoxy group, a n-propoxy group or Isopropoxy, for example, methoxy or ethoxy.
  • the C 1 -C 6 alkylthio group is preferably a C 1 -C 3 alkylthio group, such as methylthio, ethylthio, n-propylthio or isopropylthio, and for example, methylthio.
  • the 3- to 7-membered cycloalkyl group is preferably a 3- to 6-membered cycloalkyl group, such as a cyclopropyl group, a cyclobutyl group or a cyclopentyl group, and also such as a cyclopropyl group or a cyclobutyl group.
  • the 3- to 7-membered heterocycloalkyl is preferably a 3- to 6-membered heterocycloalkyl; the heteroatom in the 3- to 6-membered heterocycloalkyl is preferably N or O; the number of heteroatoms in the 3- to 6-membered heterocycloalkyl is preferably 1 or 2; the 3- to 6-membered heterocycloalkyl is more preferably a 4-membered heterocycloalkyl, for example
  • the 3- to 7-membered heterocycloalkyl is preferably a 3- to 6-membered heterocycloalkyl; the heteroatom in the 3- to 6-membered heterocycloalkyl is preferably N or O; the number of heteroatoms in the 3- to 6-membered heterocycloalkyl is preferably 1 or 2; the 3- to 6-membered heterocycloalkyl is more preferably a 4-membered heterocycloalkyl, for example
  • the halogen is preferably F, Cl, Br or I, such as F or Cl, and also such as F.
  • the C1 - C3 alkyl group is preferably methyl, ethyl, n-propyl or isopropyl.
  • the C1 - C6 alkoxy group is preferably a C1 - C3 alkoxy group, such as a methoxy group, an ethoxy group, a n-propoxy group or an isopropoxy group, and also a methoxy group.
  • the 3- to 7-membered heterocycloalkyl is preferably a 3- to 6-membered heterocycloalkyl; the heteroatom in the 3- to 6-membered heterocycloalkyl is preferably N or O; the number of heteroatoms in the 3- to 6-membered heterocycloalkyl is preferably 1 or 2; the 3- to 6-membered heterocycloalkyl is more preferably a 4-membered heterocycloalkyl, for example
  • the 3- to 7-membered cycloalkyl group is preferably a 3- to 6-membered cycloalkyl group, such as cyclopropane, cyclobutane or cyclopentane.
  • the C 1 -C 6 alkyl group is preferably a C 1 -C 3 alkyl group, such as methyl, ethyl, n-propyl or isopropyl, such as methyl or ethyl (eg methyl).
  • the 3- to 7-membered heterocycloalkyl is preferably a 3- to 6-membered heterocycloalkyl; the heteroatom in the 3- to 6-membered heterocycloalkyl is preferably N or O; the number of heteroatoms in the 3- to 6-membered heterocycloalkyl is preferably 1 or 2; the 3- to 6-membered heterocycloalkyl is, for example, a 4-membered heterocycloalkyl, for example
  • the halogen is preferably F, Cl, Br or I, such as F or Cl.
  • the C 1 -C 6 alkoxy group is preferably a C 1 -C 3 alkoxy group, such as methoxy, ethoxy, n-propoxy or Isopropyloxy.
  • the 3- to 7-membered cycloalkyl group is preferably a 3- to 6-membered cycloalkyl group, such as cyclopropane, cyclobutane or cyclopentane, and also such as cyclopropane.
  • the 3- to 7-membered heterocycloalkyl is preferably a 3- to 6-membered heterocycloalkyl; the heteroatom in the 3- to 6-membered heterocycloalkyl is preferably N or O; and the number of heteroatoms in the 3- to 6-membered heterocycloalkyl is preferably 1 or 2.
  • the C 1 -C 3 alkyl group is preferably methyl, ethyl, n-propyl or isopropyl, for example methyl.
  • the halogen is preferably F, Cl, Br or I, such as F or Cl.
  • the halogen is preferably F, Cl, Br or I, such as F.
  • the C 1 -C 6 alkyl group is preferably a C 1 -C 3 alkyl group, such as methyl, ethyl, n-propyl or isopropyl, and also such as methyl (e.g. ).
  • the C 1 -C 3 alkyl group is preferably methyl, ethyl, n-propyl or isopropyl, for example methyl, ethyl or n-propyl, for example methyl.
  • the 3- to 7-membered heterocycloalkyl is preferably a 3- to 6-membered heterocycloalkyl; the heteroatom in the 3- to 6-membered heterocycloalkyl is preferably N or O; the number of heteroatoms in the 3- to 6-membered heterocycloalkyl is preferably 1 or 2; the 3- to 6-membered heterocycloalkyl is more preferably a 4-membered heterocycloalkyl, for example
  • the C 1 -C 3 alkyl group is preferably a methyl group, an ethyl group, a n-propyl group or an isopropyl group.
  • the halogen is preferably F, Cl, Br or I, for example F or Cl, and for example F.
  • the halogen is preferably F, Cl, Br or I, such as F or Cl.
  • the C 1 -C 6 alkoxy group is preferably a C 1 -C 3 alkoxy group, such as a methoxy group, an ethoxy group, a n-propoxy group or an isopropoxy group.
  • the 3- to 7-membered cycloalkyl group is preferably a 3- to 6-membered cycloalkyl group, such as cyclopropane, cyclobutane or cyclopentane.
  • the 3-7 membered heterocycloalkyl is preferably a 3-6 membered heterocycloalkyl; the heteroatom in the 3-6 membered heterocycloalkyl is preferably N or O; the number of heteroatoms in the 3-6 membered heterocycloalkyl is preferably 1 or 2.
  • the C 1 -C 6 alkyl group is preferably a C 1 -C 3 alkyl group, such as methyl, ethyl, n-propyl or isopropyl, such as methyl or ethyl.
  • the 3- to 7-membered heterocycloalkyl is preferably a 3- to 6-membered heterocycloalkyl; the heteroatom in the 3- to 6-membered heterocycloalkyl is preferably N or O; and the number of heteroatoms in the 3- to 6-membered heterocycloalkyl is preferably 1 or 2.
  • the halogen is preferably F, Cl, Br or I, such as F or Cl.
  • the C 1 -C 6 alkoxy group is preferably a C 1 -C 3 alkoxy group, such as a methoxy group, an ethoxy group, a n-propoxy group or an isopropoxy group.
  • the 3- to 7-membered cycloalkyl group is preferably a 3- to 6-membered cycloalkyl group, such as cyclopropane, cyclobutane or cyclopentane.
  • the 3- to 7-membered heterocycloalkyl group is preferably a 3- to 6-membered heterocycloalkyl group; the heteroatom of the 3- to 7-membered heterocycloalkyl group is preferably N or O, and the number of heteroatoms of the 3- to 6-membered heterocycloalkyl group is preferably 1 or 2.
  • the C 1 -C 3 alkyl group is preferably methyl, ethyl, n-propyl or isopropyl.
  • the halogen is preferably F, Cl, Br or I, such as F or Cl.
  • the C 1 -C 6 alkoxy group is preferably a C 1 -C 3 alkoxy group, such as a methoxy group, an ethoxy group, a n-propoxy group or an isopropoxy group.
  • the C 1 -C 6 alkyl group is preferably a C 1 -C 3 alkyl group, such as methyl, ethyl, n-propyl or isopropyl.
  • the halogen is preferably F, Cl, Br or I, such as F or Cl.
  • the C 1 -C 3 alkyl group is preferably methyl, ethyl, n-propyl or isopropyl.
  • the C 1 -C 3 alkoxy group is preferably a methoxy group, an ethoxy group, a n-propoxy group or an isopropoxy group.
  • the C 1 -C 6 alkyl group is preferably a C 1 -C 3 alkyl group, such as methyl, ethyl, n-propyl or isopropyl.
  • the 3- to 7-membered heterocycloalkyl is preferably a 3- to 6-membered heterocycloalkyl; the heteroatom in the 3- to 6-membered heterocycloalkyl is preferably N or O; and the number of heteroatoms in the 3- to 6-membered heterocycloalkyl is preferably 1 or 2.
  • the halogen is preferably F, Cl, Br or I, such as F or Cl.
  • the 3- to 7-membered cycloalkyl group is preferably a 3- to 6-membered cycloalkyl group, such as cyclopropane, cyclobutane or cyclopentane.
  • the 3- to 7-membered heterocycloalkyl is preferably a 3- to 6-membered heterocycloalkyl; the heteroatom in the 3- to 6-membered heterocycloalkyl is preferably N or O; and the number of heteroatoms in the 3- to 6-membered heterocycloalkyl is preferably 1 or 2.
  • the C 1 -C 3 alkyl group is preferably methyl, ethyl, n-propyl or isopropyl.
  • the C 1 -C 3 alkoxy group is preferably a methoxy group, an ethoxy group, a n-propoxy group or an isopropoxy group.
  • the C 1 -C 3 alkyl group is preferably methyl, ethyl, n-propyl or isopropyl.
  • t is a natural number from 0 to 3, such as 0, 1, 2 or 3, and further such as 0, 1 or 2, such as 0.
  • u is a natural number from 0 to 3, such as 0, 1, 2 or 3, and further such as 0, 1 or 2, such as 1.
  • the halogen is preferably F, Cl, Br or I, such as F or Cl.
  • the C 1 -C 6 alkyl group is preferably a C 1 -C 3 alkyl group, such as methyl, ethyl, n-propyl or isopropyl, and also such as methyl.
  • the 3-7 membered cycloalkyl group is preferably a 3-6 membered cycloalkyl group, such as cyclopropane, cyclobutane or cyclopentane, and also such as cyclopropane.
  • the 3- to 7-membered heterocycloalkyl is preferably a 3- to 6-membered heterocycloalkyl; the heteroatom in the 3- to 6-membered heterocycloalkyl is preferably N or O; the number of heteroatoms in the 3- to 6-membered heterocycloalkyl is preferably 1 or 2, and the 3- to 6-membered heterocycloalkyl is preferably For example, a 4-membered heterocycloalkyl group, or oxetane.
  • the halogen is preferably F, Cl, Br or I, such as F or Cl.
  • the C1 - C3 alkyl group is preferably methyl, ethyl, n-propyl or isopropyl, for example methyl.
  • the C1 - C3 alkoxy group is preferably a methoxy group, an ethoxy group, a n-propoxy group or an isopropoxy group.
  • the 3- to 7-membered cycloalkyl group is preferably a 3- to 6-membered cycloalkyl group, such as a cyclopropane group, a cyclobutane group or a cyclopentane group.
  • the 4- to 7-membered cycloalkyl group is preferably a 3- to 6-membered cycloalkyl group, such as a cyclobutane group or a cyclopentane group.
  • the 4- to 6-membered heterocycloalkyl is preferably a 4-membered heterocycloalkyl, a 5-membered heterocycloalkyl or a 6-membered heterocycloalkyl; the heteroatom in the 4-membered heterocycloalkyl, the 5-membered heterocycloalkyl and the 6-membered heterocycloalkyl is preferably N; the number of heteroatoms in the 4- to 6-membered heterocycloalkyl is preferably 1 or 2, for example, the 4- to 6-membered heterocycloalkyl is a 4-membered nitrogen heterocycloalkyl (for example ) or a 5-membered nitrogen heterocycloalkyl group (e.g. ).
  • the 6-10 membered aryl group is preferably a phenyl group or a naphthyl group, such as a phenyl group.
  • the halogen is preferably F, Cl, Br or I, for example F or Cl, and for example F.
  • the C 1 -C 3 alkyl group is preferably methyl, ethyl, n-propyl or isopropyl, and is also methyl.
  • the 3-7 membered cycloalkyl is preferably a 3-6 membered cycloalkyl, such as cyclopropane, cyclobutane or cyclopentane, and for example, cyclopropane or cyclobutane, for example, cyclopropane.
  • the 3- to 7-membered heterocycloalkyl is preferably a 3- to 6-membered heterocycloalkyl; the heteroatom in the 3- to 6-membered heterocycloalkyl is preferably N or O; and the number of heteroatoms in the 3- to 6-membered heterocycloalkyl is preferably 1 or 2.
  • the halogen is preferably F, Cl, Br or I, such as F or Cl.
  • the C 1 -C 3 alkyl group is preferably methyl, ethyl, n-propyl or isopropyl.
  • the C 1 -C 3 alkyl group is, for example, methyl, ethyl, n-propyl or isopropyl.
  • the 3- to 7-membered cycloalkyl group may be a 3- to 6-membered cycloalkyl group, such as a cyclopropyl group, a cyclobutyl group or a cyclopentyl group.
  • the 3- to 7-membered heterocycloalkyl is preferably a 3- to 6-membered heterocycloalkyl; the heteroatom in the 3- to 6-membered heterocycloalkyl is preferably N or O; and the number of heteroatoms in the 3- to 6-membered heterocycloalkyl is preferably 1 or 2.
  • the 3- to 7-membered cycloalkyl group is preferably a 3- to 6-membered cycloalkyl group, such as a cyclopropyl group, a cyclobutyl group or a cyclopentyl group.
  • the 3- to 7-membered heterocycloalkyl is preferably a 3- to 6-membered heterocycloalkyl; the heteroatom in the 3- to 6-membered heterocycloalkyl is preferably N or O; and the number of heteroatoms in the 3- to 6-membered heterocycloalkyl is preferably 1 or 2.
  • the halogen is preferably F, Cl, Br or I, such as F or Cl.
  • the C 1 -C 3 alkyl group is preferably methyl, ethyl, n-propyl or isopropyl.
  • the 3- to 7-membered cycloalkyl group is preferably a 3- to 6-membered cycloalkyl group, such as a cyclopropane group, a cyclobutane group or a cyclopentane group. alkyl.
  • the 3- to 7-membered heterocycloalkyl is preferably a 3- to 6-membered heterocycloalkyl; the heteroatom in the 3- to 6-membered heterocycloalkyl is preferably N or O; and the number of heteroatoms in the 3- to 6-membered heterocycloalkyl is preferably 1 or 2.
  • the halogen is preferably F, Cl, Br or I, such as F or Cl.
  • the C 1 -C 6 alkyl group is preferably a C 1 -C 3 alkyl group, such as methyl, ethyl, n-propyl or isopropyl, and also such as methyl.
  • the 3- to 7-membered cycloalkyl group is preferably a 3- to 6-membered cycloalkyl group, such as a cyclopropane group, a cyclobutane group or a cyclopentane group, such as a cyclopropane group.
  • the 6-10 membered aryl group is phenyl or naphthyl.
  • the halogen is preferably F, Cl, Br or I, such as F or Cl, and also such as F.
  • the C 1 -C 3 alkyl group is preferably methyl, ethyl, n-propyl or isopropyl, such as methyl, ethyl or isopropyl, and is preferably methyl.
  • the 3- to 7-membered cycloalkyl group is preferably a 3- to 6-membered cycloalkyl group, such as cyclopropane, cyclobutane or cyclopentane, and also such as cyclopropane.
  • the 3- to 7-membered heterocycloalkyl is preferably a 3- to 6-membered heterocycloalkyl; the heteroatom in the 3- to 6-membered heterocycloalkyl is preferably N or O; and the number of heteroatoms in the 3- to 6-membered heterocycloalkyl is preferably 1 or 2.
  • the C 1 -C 3 alkyl group is preferably methyl, ethyl, n-propyl or isopropyl, for example methyl or ethyl, for example methyl, ethyl or isopropyl.
  • the 3- to 7-membered cycloalkyl group is preferably a 3- to 6-membered cycloalkyl group, such as cyclopropyl, cyclobutyl or cyclopentyl.
  • the 3- to 7-membered heterocycloalkyl is preferably a 3- to 6-membered heterocycloalkyl; the heteroatom in the 3- to 6-membered heterocycloalkyl is preferably N or O; and the number of heteroatoms in the 3- to 6-membered heterocycloalkyl is preferably 1 or 2.
  • the halogen is preferably F, Cl, Br or I, such as F or Cl, and also such as F.
  • the C 1 -C 3 alkyl group is preferably methyl, ethyl, n-propyl or isopropyl.
  • the 3- to 7-membered cycloalkyl group is preferably a 3- to 6-membered cycloalkyl group, such as cyclopropane, cyclobutane or cyclopentane.
  • the 3- to 7-membered heterocycloalkyl is preferably a 3- to 6-membered heterocycloalkyl; the heteroatom in the 3- to 6-membered heterocycloalkyl is preferably N or O; and the number of heteroatoms in the 3- to 6-membered heterocycloalkyl is preferably 1 or 2.
  • the halogen is preferably F, Cl, Br or I, such as F or Cl, and also such as F.
  • the C 1 -C 3 alkyl group is preferably methyl, ethyl, n-propyl or isopropyl, for example methyl.
  • the 3- to 7-membered cycloalkyl group is preferably a 3- to 6-membered cycloalkyl group, such as cyclopropane, cyclobutane or cyclopentane.
  • the 3- to 7-membered heterocycloalkyl is preferably a 3- to 6-membered heterocycloalkyl; the heteroatom in the 3- to 6-membered heterocycloalkyl is preferably N or O; and the number of heteroatoms in the 3- to 6-membered heterocycloalkyl is preferably 1 or 2.
  • the compound represented by Formula I is a compound represented by Formula I-1, a compound represented by Formula I-2, a compound represented by Formula I-3, a compound represented by Formula I-4, or a compound represented by Formula I-5;
  • X6 is N or CH
  • X1 , Ri , X2 , X3 , X4 , X5 , Y, Z, m, n, E, Rj , R1 , B, D, W, k, F, u, R8 and R9 are as described in any one of the present invention.
  • the compound represented by formula I-1 is a compound represented by formula I-1-1, a compound represented by formula I-1-2, a compound represented by formula I-1-3, or a compound represented by formula I-1-4;
  • R 1 , R j , Z, n, X 6 , X 2 and X 4 are as described in any one of the present invention.
  • the compound represented by formula I-5 is a compound represented by formula I-5-1;
  • R 1 , R 8 , R 9 and R j are as described in any one of the present invention.
  • the compound represented by formula I-4 is a compound represented by formula I-4-1;
  • B is as described in any one of the present invention.
  • X 1 , X 2 , X 3 , X 4 and X 5 are independently -CR 1 -, N, O, S, or a chemical bond, and the number of heteroatoms in X 1 , X 2 , X 3 , X 4 and X 5 is 0, 1, 2 or 3.
  • X 1 , X 2 , X 3 , X 4 and X 5 are independently -CR 1 -, N, S, or a chemical bond, and the number of heteroatoms in X 1 , X 2 , X 3 , X 4 and X 5 is 1 or 2.
  • X1 and X3 are independently N; X4 and X2 are independently -CR1- .
  • X2 and X3 are independently N; X4 and X1 are independently -CR1- .
  • X1 and X4 are independently N; X2 and X3 are independently -CR1- .
  • X 1 , X 2 , X 3 and X 4 are independently -CR 1 - or N; and the number of heteroatoms is 0, 1 or 2.
  • Y and Z are independently carbonyl (CO) or -(CR 2 R 3 ) r -; r is 1, R 2 and R 3 are independently H, -(CH 2 )-, -(NHCH 2 )-, -(NHCH 2 CH 2 )- or
  • the heteroatom in the 5-membered heterocycloalkyl is N, and the number of heteroatoms is 1.
  • e is independently 0, 1 or 2, for example
  • the heteroatom in the 5-membered heterocycloalkyl is N, and the number of heteroatoms is 1.
  • the number of heteroatoms is 1, for example e is independently 0, 1, 2 or 3, for example
  • the heteroatom in the 6-membered heterocycloalkyl is N and the number of heteroatoms is 1.
  • e is independently 0, 1, 2 or 3, for example
  • the heteroatom in the 6-membered heterocycloalkyl is N and the number of heteroatoms is 1.
  • the heteroatom in the 7-membered heterocycloalkyl is N, and the number of heteroatoms is 1.
  • e is independently 0, 1, 2 or 3
  • the heteroatom in the 7-membered heterocycloalkyl is N, and the number of heteroatoms is 1.
  • the heteroatom in the 5-membered heterocycloalkyl is N, and the number of heteroatoms is 1.
  • the heteroatom in the 5-membered heterocycloalkyl is N, and the number of heteroatoms is 1.
  • the heteroatom in the 6-membered heterocycloalkyl is N, and the number of heteroatoms is 1.
  • X 1 , X 2 , X 3 , X 4 and X 5 are independently -CR 1 -, N, S, or a chemical bond, and the number of heteroatoms in X 1 , X 2 , X 3 , X 4 and X 5 is 0, 1 or 2.
  • C-(W) k - where C is C is a 5-membered heteroaryl, a 6-membered heteroaryl or a phenyl group; preferably, the heteroatom in the 5-membered heteroaryl is N, and the number of heteroatoms is 1 or 2, or the heteroatom in the 6-membered heteroaryl is N, and the number of heteroatoms is 1, for example, C is a pyridyl, a phenyl or
  • W is -O-, -CH 2 - or -NH-.
  • the 5-12 membered heteroaryl is preferably a 5-6 membered heteroaryl, a phenyl and a 5-6 membered heteroaryl, a 5-7 membered cycloalkyl and a phenyl group, a 5-7 membered cycloalkyl and a 5-6 membered heteroaryl, a 5-6 membered heteroaryl and a 5-6 membered heteroaryl, a 5-7 membered heterocycloalkyl and a 5-6 membered heteroaryl, or a 5-7 membered heterocycloalkyl and a 5-6 membered aryl; further preferably a 5-6 membered heteroaryl, a phenyl and a 5-6 membered heteroaryl, a 5-6 membered heteroaryl and a 5-6 membered heteroaryl, a 5-7 membered heterocycloalkyl and a 5-6 membered heteroaryl, or a 5-7 membered
  • the heteroatom in the 4-6 membered heterocycloalkyl is N, and the number of heteroatoms is 1, for example e is independently 0, 1, 2 or 3, for example
  • the heteroatom in the 4-6 membered heterocycloalkyl is N, and the number of heteroatoms is 1, for example
  • B is a 4-6 membered heterocycloalkyl substituted by 2 R i , and two R i on the same atom and the atom connected thereto form a 3-7 membered cycloalkyl, and the 3-7 membered cycloalkyl is preferably a 3-6 membered cycloalkyl.
  • B is a 4-membered heterocycloalkyl or a 5-membered heterocycloalkyl, and two R i form a 3-4 membered cycloalkyl.
  • B is
  • B is a 4-6 membered heterocycloalkyl substituted by 2 R i , and two R i on the same atom and the atom connected thereto form a 3-7 membered cycloalkyl, and the 3-7 membered cycloalkyl is preferably a 3-6 membered cycloalkyl.
  • B is a 4 membered heterocycloalkyl, and two R i form a 3-4 membered cycloalkyl.
  • B is
  • B is a 4-6 membered heterocycloalkyl substituted by 2 R i , and two R i on the same atom and the atom connected thereto form a 3-7 membered cycloalkyl, and the 3-7 membered cycloalkyl is preferably a 3-6 membered cycloalkyl.
  • B is a 5 membered heterocycloalkyl, and two R i form a 3-4 membered cycloalkyl.
  • B is
  • B is a 4-6 membered heterocycloalkyl substituted by two R i ortho-substituted groups, and two adjacent R i and the atoms to which they are connected form a 3-7 membered cycloalkyl group (wherein the 3-7 membered cycloalkyl group and B form a cycloalkyl group), and the 3-7 membered cycloalkyl group is preferably a 3-6 membered cycloalkyl group.
  • B is 5-membered heterocycloalkyl, two R i and the atoms to which they are attached form a 3-membered cycloalkyl, and if B is
  • B is a 5-membered heteroaryl group, wherein the heteroatom in the 5-membered heteroaryl group is N and/or S, and the number of heteroatoms is 1 or 2, for example
  • B is a 5-membered heteroaryl group, wherein the heteroatom in the 5-membered heteroaryl group is N or S, and the number of heteroatoms is 1 or 2, for example
  • B is a 6-membered heteroaryl group, wherein the heteroatom in the 6-membered heteroaryl group is N, and the number of heteroatoms is 1 or 2, for example
  • the 6-10 membered aryl group is, for example, phenyl.
  • B is a phenyl 5-membered heterocycloalkyl group, wherein the heteroatom in the 5-membered heterocycloalkyl group is N, and the number of heteroatoms is 1, for example e is independently 0, 1, 2 or 3, for example
  • B is a phenyl 5-membered heterocycloalkyl group, wherein the heteroatom in the 5-membered heterocycloalkyl group is N, and the number of heteroatoms is 1, for example
  • B is a phenyl 6-membered heteroaryl group, wherein the heteroatom in the 6-membered heteroaryl group is N, and the number of heteroatoms is 1 or 2, for example
  • B is a phenyl 6-membered heterocycloalkyl, wherein the heteroatom in the 6-membered heterocycloalkyl is N and/or O, and the heteroatom
  • the number of sub-items is 1 or 2, for example
  • B is a phenyl 6-membered heterocycloalkyl group, wherein the heteroatom in the 6-membered heterocycloalkyl group is N or O, and the number of heteroatoms is 1 or 2, for example
  • B is a 6-membered heteroaryl group and a 5-membered heteroaryl group, wherein the heteroatom in the 6-membered heteroaryl group is N, and the number of heteroatoms is 1.
  • the heteroatom in the 5-membered heteroaryl group is N or S, and the number of heteroatoms is 1.
  • B is a 6-membered heteroaryl and a 6-membered heterocycloalkyl, wherein the heteroatom in the 6-membered heteroaryl is N and the number of heteroatoms is 1.
  • the heteroatom in the 6-membered heterocycloalkyl is O and the number of heteroatoms is 1.
  • the 5-12 membered heteroaryl is preferably a 5-6 membered heteroaryl, a phenyl and a 5-6 membered heteroaryl, a 5-7 membered cycloalkyl and a phenyl, a 5-7 membered cycloalkyl and a 5-6 membered heteroaryl, a 5-6 membered heteroaryl and a 5-6 membered heteroaryl, a 5-7 membered heterocycloalkyl and a 5-6 membered heteroaryl, or a 5-7 membered heterocycloalkyl and a 5-6 membered aryl; further preferably a 5-6 membered heteroaryl, a phenyl and a 5-6 membered heteroaryl, a 5-7 membered cycloalkyl and a 5-6 membered heteroaryl, a 5-6 membered heteroaryl and a 5-6 membered heteroaryl, a 5-7 membered heterocycloalkyl and
  • the 5- to 12-membered heteroaryl group is a 5- to 6-membered heteroaryl group, a phenyl 5- to 6-membered heteroaryl group, a 5- to 7-membered cycloalkyl 5- to 6-membered heteroaryl group, a 5- to 6-membered heteroaryl group, a 5- to 6-membered heteroaryl group, a 5- to 7-membered heterocycloalkyl 5- to 6-membered heteroaryl group, or a 5- to 7-membered heterocycloalkyl phenyl group, wherein the heteroatoms in the 5- to 6-membered heteroaryl group and the 5- to 7-membered heterocycloalkyl group are preferably selected from one, two or three of N, O and S, and the number of heteroatoms is preferably one, two or three.
  • the 5- to 6-membered heteroaryl group is preferably a 5-membered heteroaryl group or a 6-membered heteroaryl group.
  • D is hydrogen, methyl, ethyl, isopropyl, cyclopropyl or trifluoromethyl.
  • D is a 6-membered heteroaryl group, wherein the heteroatom in the 6-membered heteroaryl group is N, and the number of heteroatoms is 1 or 2, for example e is independently 0, 1, 2 or 3, for example
  • D is a 6-membered heteroaryl group, wherein the heteroatom in the 6-membered heteroaryl group is N, and the number of heteroatoms is 1 or 2, for example
  • D is a 5-membered heteroaryl group, wherein the heteroatom in the 5-membered heteroaryl group is one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3, for example
  • D is a 5-membered heteroaryl group, wherein the heteroatom in the 5-membered heteroaryl group is N and/or S, and the number of heteroatoms is 1, 2 or 3, for example
  • D is a 5-membered heteroaryl group, wherein the heteroatom in the 5-membered heteroaryl group is N or S, and the number of heteroatoms is 1, 2 or 3, for example
  • D is a 6-membered heteroaryl and a 5-membered heterocycloalkyl, wherein the heteroatom in the 6-membered heteroaryl is N and the number of heteroatoms is 1, and preferably, the heteroatom in the 5-membered heterocycloalkyl is N or O and the number of heteroatoms is 1, for example e is independently 0, 1, 2 or 3, for example
  • D is a 6-membered heteroaryl and a 5-membered heterocycloalkyl, wherein the heteroatom in the 6-membered heteroaryl is N, and the number of heteroatoms is
  • the heteroatom in the 5-membered heterocycloalkyl group is N or O, and the number of heteroatoms is 1, for example
  • D is a 6-membered heteroaryl group and a 5-membered cycloalkyl group, wherein the heteroatom in the 6-membered heteroaryl group is N and the number of heteroatoms is 1, for example e is independently 0, 1, 2 or 3, for example
  • D is a 6-membered heteroaryl group and a 5-membered cycloalkyl group, wherein the heteroatom in the 6-membered heteroaryl group is N and the number of heteroatoms is 1, for example
  • D is a phenyl 5-membered heteroaryl group, wherein the heteroatom in the 5-membered heteroaryl group is N and/or S, and the number of heteroatoms is 2, for example e is independently 0, 1, 2 or 3, for example
  • D is a 5-6 membered heteroaryl group and a 5-6 membered heteroaryl group, wherein the heteroatom in the 5-6 membered heteroaryl group is N and/or S, and the number of heteroatoms is 1, 2 or 3, for example e is independently 0, 1, 2 or 3.
  • D is a 5-6 membered heteroaryl and a 5-6 membered heterocycloalkyl, wherein the heteroatom in the 5-6 membered heteroaryl is N, and the number of heteroatoms is 1, 2 or 3.
  • the heteroatom in the 5-6 membered heterocycloalkyl is O, and the number of heteroatoms is 1, 2 or 3.
  • e is independently 0, 1, 2 or 3.
  • D is a phenyl 5- to 6-membered heterocycloalkyl group, wherein the heteroatom in the 5- to 6-membered heterocycloalkyl group is one or more of O, N and O, and the number of the heteroatoms is 1, 2 or 3, for example e is independently 0, 1, 2 or 3.
  • D is a phenyl 5- to 6-membered heteroaryl group, wherein the heteroatom in the 5- to 6-membered heteroaryl group is N, and the number of heteroatoms is 1 , 2 or 3, e.g. e is independently 0, 1, 2 or 3.
  • It is preferably a 6-membered heteroaryl and a 5-membered heterocycloalkyl, wherein the heteroatom in the 6-membered heteroaryl is N and the number of heteroatoms is 2, for example e is independently 0, 1 or 2, for example
  • It is preferably a 6-membered heteroaryl and a 5-membered heterocycloalkyl, wherein the heteroatom in the 6-membered heteroaryl is N and the number of heteroatoms is 2, for example
  • It is preferably a 6-membered heteroaryl and a 7-membered heterocycloalkyl, wherein the heteroatom in the 6-membered heteroaryl is N and the number of heteroatoms is 1 or 2, for example
  • E is preferably a carbonyl group
  • F is a chemical bond
  • t is 0, and u is 1.
  • B is preferably a 4-membered heterocycloalkyl group, wherein the heteroatom in the 4-membered heterocycloalkyl group is N, and the number of heteroatoms is 1 or 2, for example
  • D is preferably a 6-membered heteroaryl group, wherein the heteroatom in the 6-membered heteroaryl group is N, and the number of heteroatoms is 1 or 2, for example
  • n is a natural number from 0 to 3;
  • n is a natural number from 0 to 3; m and n are not 0 at the same time;
  • k is a natural number from 0 to 3;
  • X 1 , X 2 , X 3 , X 4 and X 5 are independently -CR 1 -, N, S, or chemical bonds;
  • R N-1 is hydrogen, C 1 -C 6 alkyl or 3-7 membered cycloalkyl
  • Y and Z are independently carbonyl (CO) or -(CR 2 R 3 ) r -; r is a natural number of 0 to 5;
  • Each W is independently -O-, -(CR 4 R 5 )-, -NR 6 - or a chemical bond;
  • Each R 1 is independently hydrogen, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 alkylthio, 3-7 membered cycloalkyl, 3-7 membered heterocycloalkyl or -NR 1-1 R 1-2 , wherein the C 1 -C 6 alkylthio, C 1 -C 6 alkyl and C 1 -C 6 alkoxy are optionally independently substituted by 1, 2, 3 or 4 R a ;
  • Each Ra is independently halogen, hydroxy, C1 - C6 alkoxy or -NR1-4R1-5 ;
  • R 1-1 and R 1-2 are independently hydrogen or C 1 -C 6 alkyl, wherein the C 1 -C 6 alkyl is optionally independently substituted by 1, 2, 3 or 4 R b ; or, R 1-1 and R 1-2 and the atoms to which they are attached form a 3-7 membered heterocycloalkyl, wherein the 3-7 membered heterocycloalkyl is arbitrarily substituted by 1, 2, 3 or 4 R b-2 ;
  • Each R b is independently hydroxy, 3-7 membered cycloalkyl or C 1 -C 3 alkyl;
  • Each R b-2 is independently halogen or C 1 -C 6 alkyl
  • R 1-4 and R 1-5 are independently hydrogen or C 1 -C 3 alkyl, wherein the C 1 -C 3 alkyl is optionally independently substituted by 1, 2, 3 or 4 R 1-4-1 ; or, R 1-4 and R 1-5 , together with the atoms to which they are attached, form a 3-7 membered heterocycloalkyl;
  • Each R 1-4-1 is independently halogen
  • R 2 and R 3 are independently hydrogen or NR 2-1 R 2-2 ;
  • R 2-1 and R 2-2 are independently hydrogen or C 1 -C 6 alkyl
  • R 4 , R 5 and R 6 are independently hydrogen or NR 4-1 R 4-2 ;
  • R 4-1 and R 4-2 are independently hydrogen
  • t is a natural number from 0 to 3;
  • u is a natural number from 0 to 3;
  • E is a carbonyl group, -NHCO- or chemical bond
  • F is a carbonyl group, -O-, -NH- or chemical bonds
  • R8 and R9 are independently hydrogen or C1 - C6 alkyl, or R8 and R9, together with the atoms to which they are attached, form a 3- to 7-membered cycloalkyl or a 3- to 7-membered heterocycloalkyl;
  • B is a 4- to 6-membered heterocycloalkyl, a 6- to 10-membered aryl or a 5- to 12-membered heteroaryl; wherein the 4- to 6-membered heterocycloalkyl, the 6- to 10-membered aryl and the 5- to 12-membered heteroaryl are optionally independently substituted by 1, 2 or 3 R i ;
  • Each R i is independently hydrogen, halogen, hydroxyl or C 1 -C 3 alkyl; or, two R i on the same atom and the atom to which they are connected form a 3-7 membered cycloalkyl; or, two adjacent R i and the atom to which they are connected form a 3-7 membered cycloalkyl;
  • D is hydrogen, C 1 -C 6 alkyl or 5- to 12-membered heteroaryl; wherein the C 1 -C 6 alkyl and 5- to 12-membered heteroaryl are optionally independently substituted by 1, 2 or 3 R j ;
  • Each R j is independently hydrogen, halogen, C 1 -C 3 alkyl, 3-7 membered cycloalkyl, -OR 12-3 or -SR 12-4 ; the C 1 -C 3 alkyl and 3-7 membered cycloalkyl are optionally independently substituted by 1, 2 or 3 R k ;
  • R 12-3 and R 12-4 are independently C 1 -C 3 alkyl; wherein the C 1 -C 3 alkyl is optionally independently substituted by 1, 2 or 3 R k-1 ;
  • Each R k is independently halogen
  • Each R k-1 is independently halogen
  • the heteroatom is one or more of N, O and S, and the number of the heteroatoms is 1 to 3.
  • n is a natural number from 0 to 3;
  • n is a natural number from 0 to 3; m and n are not 0 at the same time;
  • k is a natural number from 0 to 3;
  • X 1 , X 2 , X 3 , X 4 and X 5 are independently -CR 1 -, N, S, or chemical bonds;
  • R N-1 is C 1 -C 6 alkyl
  • Y and Z are independently carbonyl (CO) or -(CR 2 R 3 ) r -; r is a natural number of 0 to 5;
  • Each W is independently -(CR 4 R 5 )-, -NR 6 - or a chemical bond;
  • Each R 1 is independently hydrogen, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 alkylthio, 3-7 membered cycloalkyl, 3-7 membered heterocycloalkyl or -NR 1-1 R 1-2 , wherein the C 1 -C 6 alkylthio, C 1 -C 6 alkyl and C 1 -C 6 alkoxy are optionally independently substituted by 1, 2, 3 or 4 R a ;
  • Each Ra is independently hydroxy, C1 - C6 alkoxy or -NR1-4R1-5 ;
  • R 1-1 and R 1-2 are independently hydrogen or C 1 -C 6 alkyl, wherein the C 1 -C 6 alkyl is optionally independently substituted by 1, 2, 3 or 4 R b ; or, R 1-1 and R 1-2 and the atoms to which they are connected form a 3-7 membered heterocycloalkyl, wherein the 3-7 membered heterocycloalkyl is arbitrarily substituted by 1, 2, 3 or 4 R b-2 ;
  • Each R b is independently a 3- to 7-membered cycloalkyl group
  • Each R b-2 is independently halogen or C 1 -C 6 alkyl
  • R 1-4 and R 1-5 are independently C 1 -C 3 alkyl
  • R 2 and R 3 are independently hydrogen or NR 2-1 R 2-2 ;
  • R 2-1 and R 2-2 are independently hydrogen
  • R 4 , R 5 and R 6 are independently hydrogen
  • t is a natural number from 0 to 3;
  • u is a natural number from 0 to 3;
  • E is a carbonyl group, -NHCO- or chemical bond
  • R 8 and R 9 are independently hydrogen or C 1 -C 6 alkyl, or R 8 and R 9 and the atoms to which they are attached form a 3-7 membered cycloalkyl;
  • B is a 4- to 6-membered heterocycloalkyl, a 6- to 10-membered aryl or a 5- to 12-membered heteroaryl; wherein the 4- to 6-membered heterocycloalkyl, the 6- to 10-membered aryl and the 5- to 12-membered heteroaryl are optionally independently substituted by 1, 2 or 3 R i ;
  • Each R i is independently hydrogen, halogen, hydroxyl or C 1 -C 3 alkyl; or, two R i on the same atom and the atom to which they are connected form a 3-7 membered cycloalkyl;
  • D is hydrogen, C 1 -C 6 alkyl or 5- to 12-membered heteroaryl; wherein the C 1 -C 6 alkyl and 5- to 12-membered heteroaryl are optionally independently substituted by 1, 2 or 3 R j ;
  • Each R j is independently hydrogen, halogen, C 1 -C 3 alkyl, 3-7 membered cycloalkyl, -OR 12-3 or -SR 12-4 ; the C 1 -C 3 alkyl and 3-7 membered cycloalkyl are optionally independently substituted by 1, 2 or 3 R k ;
  • R 12-3 and R 12-4 are independently C 1 -C 3 alkyl; wherein the C 1 -C 3 alkyl is optionally independently substituted by 1, 2 or 3 R k-1 ;
  • Each R k is independently halogen
  • Each R k-1 is independently halogen
  • the heteroatom is one or more of N, O and S, and the number of the heteroatoms is 1 to 3.
  • n is a natural number from 1 to 3;
  • n is a natural number from 1 to 3;
  • k is a natural number from 1 to 3;
  • X 1 , X 2 , X 3 , X 4 and X 5 are independently -CR 1 -, N, O, S, or a chemical bond, and the number of heteroatoms in X 1 , X 2 , X 3 , X 4 and X 5 is 0, 1, 2 or 3;
  • R N-1 is hydrogen or C 1 -C 6 alkyl
  • Y and Z are independently carbonyl (CO) or -(CR 2 R 3 ) r -; r is a natural number of 1 to 2;
  • Each W is independently -O-, -(CR 4 R 5 )-, -NR 6 - or a chemical bond;
  • Each R 1 is independently hydrogen, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, 3-7 membered cycloalkyl, 3-7 membered heterocycloalkyl or -NR 1- 1 R 1-2 , wherein the C 1 -C 6 alkyl and C 1 -C 6 alkoxy are optionally independently substituted by 1, 2, 3 or 4 R a ;
  • Each Ra is independently hydroxy, C1 - C3 alkoxy or NR1-4R1-5 ;
  • R 1-1 and R 1-2 are independently hydrogen or C 1 -C 6 alkyl, wherein the C 1 -C 6 alkyl is optionally independently substituted by 1, 2, 3 or 4 R b ; or, R 1-1 and R 1-2 and the atoms to which they are attached form a 3-7 membered heterocycloalkyl;
  • Each R b is independently hydroxy, 3-7 membered cycloalkyl, 3-7 membered heterocycloalkyl, C 1 -C 3 alkyl, C 1 -C 3 alkoxy or NR 1-1-1 R 1-2- 1 , wherein the 3-7 membered cycloalkyl, 3-7 membered heterocycloalkyl and C 1 -C 3 alkyl are optionally independently substituted by 1, 2, 3 or 4 R b- 1 ;
  • Each R b-1 is independently hydroxyl
  • R 1-4 and R 1-5 are independently hydrogen or C 1 -C 3 alkyl; wherein the C 1 -C 3 alkyl is optionally independently substituted by 1, 2, 3 or 4 R 1-4-1 ; or, R 1-4 and R 1-5 form a 3-7 membered heterocycloalkyl with the atoms to which they are attached;
  • Each R 1-4-1 is independently halogen
  • R 1-1-1 and R 1-2-1 are independently hydrogen or C 1 -C 3 alkyl
  • R 2 and R 3 are independently hydrogen or NR 2-1 R 2-2 ;
  • R 2-1 and R 2-2 are independently hydrogen or C 1 -C 6 alkyl
  • R 4 , R 5 and R 6 are independently hydrogen
  • t is a natural number from 0 to 2;
  • u is a natural number from 0 to 2;
  • E is a carbonyl group, -NHCO- or a chemical bond
  • F is -O-, -NH- or a chemical bond
  • R8 and R9 are independently hydrogen or C1 - C6 alkyl; or R8 and R9, together with the atoms to which they are connected, form a 3-7 membered cycloalkyl or a 3-7 membered heterocycloalkyl;
  • B is a 4- to 6-membered heterocycloalkyl, a 6- to 10-membered aryl or a 5- to 12-membered heteroaryl; wherein the 5- to 12-membered heteroaryl, the 6- to 10-membered aryl and the 4- to 6-membered heterocycloalkyl are optionally independently substituted by 1, 2 or 3 R i ;
  • Each R i is independently hydrogen, hydroxyl, halogen or C 1 -C 3 alkyl; or, two R i and the atoms to which they are connected form a 3-7-membered cycloalkyl or 3-7-membered heterocycloalkyl; or, two adjacent R i and the atoms to which they are connected form a 3-7-membered cycloalkyl or 3-7-membered heterocycloalkyl (wherein, the 3-7-membered cycloalkyl or 3-7-membered heterocycloalkyl forms a cyclic ring with B);
  • D is hydrogen, 3-7 membered cycloalkyl, C 1 -C 6 alkyl or 5-12 membered heteroaryl; wherein the C 1 -C 6 alkyl and 5-12 membered heteroaryl are optionally independently substituted by 1, 2 or 3 R j ;
  • each R j is independently halogen, C 1 -C 3 alkyl, -OR 12-3 or -SR 12-4 ; said C 1 -C 3 alkyl is optionally substituted independently with 1, 2 or 3 R k ; each R k is independently halogen;
  • R 12-3 and R 12-4 are independently C 1 -C 3 alkyl; the C 1 -C 3 alkyl is optionally independently substituted by 1, 2 or 3 R k ; each R k is independently halogen;
  • the heteroatom is N, O or S, and the number of the heteroatoms is 1 to 3; or, in the 3- to 7-membered heterocycloalkyl, 4- to 6-membered heterocycloalkyl and 5- to 12-membered heteroaryl, the heteroatom is one or more of N, O and S, and the number of the heteroatoms is 1 to 3.
  • n is a natural number from 1 to 3;
  • n is a natural number from 1 to 3;
  • X 1 , X 2 , X 3 and X 4 are independently -CR 1 -, N, S, or a chemical bond, and the number of heteroatoms in X 1 , X 2 , X 3 , X 4 and X 5 is 1 or 2;
  • R N-1 is C 1 -C 6 alkyl
  • Y and Z are independently carbonyl (CO) or -(CR 2 R 3 ) r -; r is a natural number of 1 to 2;
  • Each R 1 is independently hydrogen, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, 3-7 membered cycloalkyl, 3-7 membered heterocycloalkyl or -NR 1- 1 R 1-2 , wherein the C 1 -C 6 alkyl and C 1 -C 6 alkoxy are optionally independently substituted by 1, 2, 3 or 4 R a ;
  • Each Ra is independently hydroxy, C1 - C3 alkoxy or NR1-4R1-5 ;
  • R 1-1 and R 1-2 are independently hydrogen or C 1 -C 6 alkyl, wherein the C 1 -C 6 alkyl is optionally independently substituted by 1, 2, 3 or 4 R b ; or, R 1-1 and R 1-2 and the atoms to which they are attached form a 3-7 membered heterocycloalkyl;
  • Each R b is independently hydroxy, 3-7 membered cycloalkyl, 3-7 membered heterocycloalkyl, C 1 -C 3 alkyl, C 1 -C 3 alkoxy or NR 1-1-1 R 1-2- 1 , wherein the 3-7 membered cycloalkyl, 3-7 membered heterocycloalkyl and C 1 -C 3 alkyl are optionally independently substituted by 1, 2, 3 or 4 R b- 1 ;
  • Each R b-1 is independently hydroxyl
  • R 1-4 and R 1-5 are independently hydrogen or C 1 -C 3 alkyl, wherein the C 1 -C 3 alkyl is optionally independently substituted by 1, 2, 3 or 4 R 1-4-1 ; or, R 1-4 and R 1-5 , together with the atoms to which they are attached, form a 3-7 membered heterocycloalkyl;
  • R 1-1-1 and R 1-2-1 are independently hydrogen or C 1 -C 3 alkyl
  • R 1-4-1 is halogen
  • R2 and R3 are independently hydrogen
  • t is a natural number from 0 to 2;
  • u is a natural number from 0 to 2;
  • E is a carbonyl group or a chemical bond
  • F is -O-, -NH- or a chemical bond
  • R 8 and R 9 are independently C 1 -C 6 alkyl, or R 8 and R 9 and the atoms to which they are connected form a 3-7 membered cycloalkyl or a 3-7 membered heterocycloalkyl;
  • B is a 4- to 6-membered heterocycloalkyl or a 5- to 12-membered heteroaryl; wherein the 5- to 12-membered heteroaryl and the 4- to 6-membered heterocycloalkyl are optionally independently substituted by 1, 2 or 3 R i ;
  • Each R i is independently hydrogen, hydroxyl, halogen or C 1 -C 3 alkyl; or, two R i and the atoms to which they are connected form a 3-7-membered cycloalkyl or 3-7-membered heterocycloalkyl; or, two adjacent R i and the atoms to which they are connected form a 3-7-membered cycloalkyl or 3-7-membered heterocycloalkyl (wherein, the 3-7-membered cycloalkyl or 3-7-membered heterocycloalkyl forms a cyclic ring with B);
  • D is hydrogen, 3-7 membered cycloalkyl, C 1 -C 6 alkyl or 5-6 membered heteroaryl; wherein the C 1 -C 6 alkyl and 5-6 membered heteroaryl are optionally independently substituted by 1, 2 or 3 R j ;
  • Each R j is independently halogen or C 1 -C 3 alkyl; said C 1 -C 3 alkyl is optionally independently substituted with 1, 2 or 3 R k ; each R k is independently halogen;
  • the heteroatom is N, O or S, and the number of the heteroatoms is 1 to 3; or, in the 3- to 7-membered heterocycloalkyl, 4- to 6-membered heterocycloalkyl, 5- to 6-membered heteroaryl and 5- to 12-membered heteroaryl, the heteroatom is one or more of N, O and S, and the number of the heteroatoms is 1 to 3.
  • n is a natural number from 1 to 2;
  • n is a natural number from 1 to 2;
  • k is a natural number from 1 to 3;
  • X 1 , X 2 , X 3 , X 4 and X 5 are independently -CR 1 -, N, O, S, or chemical bonds, and the number of heteroatoms in X 1 , X 2 , X 3 , X 4 and X 5 is 0, 1, 2 or 3;
  • R N-1 is C 1 -C 6 alkyl
  • Each W is independently -(CR 4 R 5 )-, -O-, -NR 6 - or a chemical bond;
  • Y and Z are independently carbonyl (CO) or -(CR 2 R 3 ) r -; r is a natural number of 1 to 2;
  • Each R 1 is independently hydrogen, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, 3-7 membered cycloalkyl, 3-7 membered heterocycloalkyl or -NR 1- 1 R 1-2 , wherein the C 1 -C 6 alkyl and C 1 -C 6 alkoxy are optionally independently substituted by 1, 2, 3 or 4 R a ;
  • Each Ra is independently hydroxy, C1 - C3 alkoxy or NR1-4R1-5 ;
  • R 1-1 and R 1-2 are independently hydrogen or C 1 -C 6 alkyl, wherein the C 1 -C 6 alkyl is optionally independently substituted by 1, 2, 3 or 4 R b ; or, R 1-1 and R 1-2 and the atoms to which they are attached form a 3-7 membered heterocycloalkyl;
  • Each R b is independently hydroxy, 3-7 membered cycloalkyl, 3-7 membered heterocycloalkyl, C 1 -C 3 alkyl, C 1 -C 3 alkoxy or NR 1-1-1 R 1-2- 1 , wherein the 3-7 membered cycloalkyl, 3-7 membered heterocycloalkyl and C 1 -C 3 alkyl are optionally independently substituted by 1, 2, 3 or 4 R b- 1 ;
  • Each R b-1 is independently hydroxyl
  • R 1-4 and R 1-5 are independently hydrogen or C 1 -C 3 alkyl, wherein the C 1 -C 3 alkyl is optionally independently substituted by 1, 2, 3 or 4 R 1-4-1 ; or, R 1-4 and R 1-5 , together with the atoms to which they are attached, form a 3-7 membered heterocycloalkyl;
  • R 1-1-1 and R 1-2-1 are independently hydrogen or C 1 -C 3 alkyl
  • Each R 1-4-1 is independently halogen
  • R 2 and R 3 are independently hydrogen or NR 2-1 R 2-2 ;
  • R 2-1 and R 2-2 are independently hydrogen or C 1 -C 6 alkyl
  • R 4 , R 5 and R 6 are independently hydrogen; L is
  • t is a natural number from 0 to 2;
  • u is a natural number from 0 to 2;
  • E is a carbonyl group, -NHCO- or a chemical bond
  • F is -O-, -NH- or a chemical bond
  • R8 and R9 are independently hydrogen or C1 - C6 alkyl; or R8 and R9, together with the atoms to which they are connected, form a 3-7 membered cycloalkyl or a 3-7 membered heterocycloalkyl;
  • B is a 4- to 6-membered heterocycloalkyl, a 6- to 10-membered aryl or a 5- to 12-membered heteroaryl; wherein the 5- to 12-membered heteroaryl, the 6- to 10-membered aryl and the 4- to 6-membered heterocycloalkyl are optionally independently substituted by 1, 2 or 3 R i ;
  • Each R i is independently hydrogen, hydroxyl, halogen or C 1 -C 3 alkyl; or, two R i and the atoms to which they are connected form a 3-7-membered cycloalkyl or 3-7-membered heterocycloalkyl; or, two adjacent R i and the atoms to which they are connected form a 3-7-membered cycloalkyl or 3-7-membered heterocycloalkyl (wherein, the 3-7-membered cycloalkyl or 3-7-membered heterocycloalkyl forms a cyclic ring with B);
  • D is hydrogen, C 1 -C 6 alkyl or 5- to 12-membered heteroaryl; wherein the C 1 -C 6 alkyl and 5- to 12-membered heteroaryl are optionally independently substituted by 1, 2 or 3 R j ;
  • each R j is independently halogen, C 1 -C 3 alkyl, OR 12-3 or SR 12-4 ; said C 1 -C 3 alkyl is optionally substituted independently with 1, 2 or 3 R k ; each R k is independently halogen;
  • R 12-3 and R 12-4 are independently C 1 -C 3 alkyl, wherein the C 1 -C 3 alkyl is optionally independently substituted by 1, 2 or 3 R k-1 ; each R k-1 is independently halogen; in the 3- to 7-membered heterocycloalkyl, 4- to 6-membered heterocycloalkyl and 5- to 12-membered heteroaryl, the heteroatom is N, O or S, and the number of the heteroatoms is 1 to 3; or, in the 3- to 7-membered heterocycloalkyl, 4- to 6-membered heterocycloalkyl and 5- to 12-membered heteroaryl, the heteroatom is one or more of N, O and S, and the number of the heteroatoms is 1 to 3.
  • n 1;
  • n 1;
  • X 1 , X 2 , X 3 and X 4 are independently -CR 1 - or N, and the number of heteroatoms in X 1 , X 2 , X 3 and X 4 is 2;
  • Y and Z are independently -(CR 2 R 3 ) r -; r is 1;
  • Each R 1 is independently C 1 -C 6 alkyl (eg methyl) or C 1 -C 6 alkoxy (eg methoxy);
  • R2 and R3 are independently hydrogen
  • u 1;
  • E is a carbonyl group
  • B is a 4- to 6-membered heterocycloalkyl group; wherein the 4- to 6-membered heterocycloalkyl group is optionally substituted independently by 1, 2 or 3 R i ;
  • each R i is independently hydrogen
  • D is a 5- to 12-membered heteroaryl group; wherein the 5- to 12-membered heteroaryl group is optionally independently substituted by 1, 2 or 3 R j (eg, 1);
  • Each Rj is independently -OR 12-3 ;
  • R 12-3 is C 1 -C 3 alkyl (eg, ethyl or isopropyl); the C 1 -C 3 alkyl is optionally substituted independently by 1, 2 or 3 R k ; each R k is independently halogen (eg, F);
  • the heteroatom is N, O or S, and the number of heteroatoms is 1 to 3; or, in the 4- to 6-membered heterocycloalkyl and 5- to 12-membered heteroaryl, the heteroatom is one or more of N, O and S, and the number of heteroatoms is 1 to 3;
  • A When A is When L is a carbonyl group, u is a natural number of 1 to 3, and B is a 4- to 6-membered heterocycloalkyl group, which is optionally independently substituted by 1, 2 or 3 R i .
  • n 1;
  • n 1;
  • X2 and X3 are N;
  • X 1 and X 4 are independently -CR 1 -;
  • Y and Z are independently -(CR 2 R 3 ) r -; r is 1;
  • Each R 1 is independently hydrogen, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, 3-7 membered cycloalkyl, 3-7 membered heterocycloalkyl or -NR 1- 1 R 1-2 ; wherein the C 1 -C 6 alkyl and C 1 -C 6 alkoxy are optionally independently substituted by 1, 2, 3 or 4 R a ;
  • R 1-1 and R 1-2 are independently hydrogen or C 1 -C 6 alkyl; or, R 1-1 and R 1-2 and the atoms to which they are connected form a 3-7 membered heterocycloalkyl;
  • Each Ra is independently hydroxy, C1 - C6 alkoxy or NR1-4R1-5 ;
  • R 1-4 and R 1-5 are independently hydrogen or C 1 -C 3 alkyl
  • R2 and R3 are independently hydrogen
  • u 1;
  • E is a carbonyl group
  • B is a 4- to 6-membered heterocycloalkyl group; wherein the 4- to 6-membered heterocycloalkyl group is optionally substituted independently by 1, 2 or 3 R i ;
  • Each R i is independently hydrogen, halogen, hydroxyl or C 1 -C 3 alkyl
  • D is a 5- to 12-membered heteroaryl group; wherein the 5- to 12-membered heteroaryl group is optionally independently substituted by 1, 2 or 3 R j ; preferably, D is a 5- to 6-membered heteroaryl group; wherein the 5- to 6-membered heteroaryl group is optionally independently substituted by 1, 2 or 3 R j ; in the 5- to 6-membered heteroaryl group, the heteroatoms are selected from 1, 2 or 3 of N, S and O, and the number of heteroatoms is 1, 2 or 3;
  • Each R j is independently H, halogen, C 1 -C 3 alkyl, OR 12-3 or SR 12-4 ; wherein the C 1 -C 3 alkyl is optionally independently substituted with 1, 2 or 3 R k ;
  • R 12-3 and R 12-4 are independently C 1 -C 3 alkyl; the C 1 -C 3 alkyl is optionally substituted independently by 1, 2 or 3 R k-1 ;
  • Each R k is independently halogen or C 1 -C 3 alkyl
  • Each R k-1 is independently halogen or C 1 -C 3 alkyl
  • the heteroatom is one or more of N, O and S, and the number of the heteroatoms is 1 to 3.
  • n 1;
  • n 1;
  • X1 and X3 are N;
  • X 2 and X 4 are independently -CR 1 -;
  • Y and Z are independently -(CR 2 R 3 ) r -; r is 1;
  • Each R 1 is independently hydrogen, halogen, cyano, hydroxyl, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 alkylthio, 3-7 membered cycloalkyl, 3-7 membered heterocycloalkyl or -NR 1-1 R 1-2 ; wherein the C 1 -C 6 alkyl, C 1 -C 6 alkoxy and C 1 -C 6 alkylthio are optionally independently substituted by 1, 2, 3 or 4 R a ;
  • R 1-1 and R 1-2 are independently hydrogen or C 1 -C 6 alkyl; or, R 1-1 and R 1-2 and the atoms to which they are connected form a 3-7 membered heterocycloalkyl;
  • Each Ra is independently hydroxy, C1 - C6 alkoxy or NR1-4R1-5 ;
  • R 1-4 and R 1-5 are independently hydrogen or C 1 -C 3 alkyl
  • R2 and R3 are independently hydrogen
  • u 1;
  • E is a carbonyl group
  • B is a 4- to 6-membered heterocycloalkyl group; wherein the 4- to 6-membered heterocycloalkyl group is optionally substituted independently by 1, 2 or 3 R i ;
  • Each R i is independently hydrogen, halogen, hydroxyl or C 1 -C 3 alkyl; or, two R i and the atoms to which they are connected form a 3-7 membered cycloalkyl;
  • D is a 5- to 12-membered heteroaryl group; wherein the 5- to 12-membered heteroaryl group is optionally independently substituted by 1, 2 or 3 R j ; preferably, D is a 5- to 6-membered heteroaryl group; wherein the 5- to 6-membered heteroaryl group is optionally independently substituted by 1, 2 or 3 R j ; in the 5- to 6-membered heteroaryl group, the heteroatoms are selected from 1, 2 or 3 of N, S and O, and the number of heteroatoms is 1, 2 or 3;
  • Each R j is independently hydrogen, halogen, cyano, hydroxyl, C 1 -C 3 alkyl, 3-7 membered cycloalkyl, 3-7 membered heterocycloalkyl, -NR 12-1 R 12- 2 , -OR 12-3 or -SR 12-4 ; wherein the C 1 -C 3 alkyl, 3-7 membered cycloalkyl and 3-7 membered heterocycloalkyl are optionally independently substituted by 1, 2 or 3 R k ;
  • R 12-1 , R 12-2 , R 12-4 and R 12-3 are independently C 1 -C 3 alkyl; the C 1 -C 3 alkyl is optionally independently substituted by 1, 2 or 3 R k-1 ;
  • Each R k is independently halogen or C 1 -C 3 alkyl
  • Each R k-1 is independently halogen or C 1 -C 3 alkyl
  • heteroatom is one or more of N, O and S,
  • the number of heteroatoms is 1 to 3.
  • each R 1 is independently hydrogen, methyl, Ethyl, Chlorine, Methoxy, Isopropyl, Amino,
  • each R 1 is independently hydrogen, methyl, Ethyl, Chlorine, Methoxy, Isopropyl, Amino group (-NH 2 ), Trifluoromethyl, or methylthio.
  • each R 1 is independently methyl
  • L is -(CH 2 )-, -(CH 2 ) 2 -, Preferably, L is in Indicates connected to A.
  • L is -(CH 2 )-, -(CH 2 ) 2 -, Preferably, L is in Indicates connected to A.
  • B is
  • D is hydrogen, methyl, Ethyl, isopropyl, cyclopropyl, trifluoromethyl or
  • D is N
  • D is hydrogen, methyl, Ethyl, isopropyl, cyclopropyl, trifluoromethyl or
  • the compound represented by formula I is any of the following compounds:
  • the present invention also provides a method for preparing the compound represented by the above formula I, which can be prepared by any of the following schemes:
  • Z is halogen (e.g., chlorine or bromine), TsO-, hydroxyl, methoxy, ethoxy, n-propoxy or isopropoxy; preferably, Z is hydroxyl, methoxy, ethoxy, n-propoxy or isopropoxy;
  • A, L, B, D, X 1 , X 2 , X 3 , X 4 , Y and m are as described in any one of the present invention.
  • the present invention also provides a method for preparing the compound represented by the above formula I, which can be prepared by the following scheme:
  • Z, A, L, B, and D are as described in any one of the present invention.
  • the present invention also provides a pharmaceutical composition, which comprises a therapeutically effective amount of substance A and pharmaceutical excipients; the substance A is the compound represented by the above formula I or a pharmaceutically acceptable salt thereof.
  • the present invention also provides an application of a substance A in the preparation of a muscarinic receptor positive allosteric modulator, wherein the substance A is the compound represented by the above formula I or a pharmaceutically acceptable salt thereof or the above pharmaceutical composition.
  • the present invention also provides a use of a substance A in the preparation of a drug, wherein the drug is used to treat and/or prevent a muscarinic receptor-mediated disease, wherein the substance A is a compound represented by the above formula I or a pharmaceutically acceptable salt thereof or the above pharmaceutical composition; preferably, the disease is Parkinson's disease, Alzheimer's disease, Huntington's disease, schizophrenia, drug addiction or pain.
  • the present invention also provides an application of substance A in the preparation of a medicine, wherein the medicine is used to treat Parkinson's disease, Alzheimer's disease, Huntington's disease, schizophrenia, drug addiction or pain.
  • the positive and progressive effects of the present invention are that the compounds of the present invention can be used as positive allosteric modulators of muscarinic receptors, and the compounds of the present invention can treat M receptor (muscarinic receptor) mediated (or M receptor related) diseases.
  • M receptor muscarinic receptor
  • CH3O- refers to an alkoxy group
  • middle refers to the site through which the structural fragment is connected to the rest of the molecule.
  • pharmaceutically acceptable means relatively non-toxic, safe, and suitable for use by patients.
  • pharmaceutically acceptable salt refers to a salt obtained by reacting a compound with a pharmaceutically acceptable acid or base.
  • a base addition salt can be obtained by contacting the compound with a sufficient amount of a pharmaceutically acceptable base in a suitable inert solvent.
  • Pharmaceutically acceptable base addition salts include, but are not limited to, lithium salts, sodium salts, potassium salts, calcium salts, aluminum salts, magnesium salts, zinc salts, bismuth salts, ammonium salts, and diethanolamine salts.
  • an acid addition salt can be obtained by contacting the compound with a sufficient amount of a pharmaceutically acceptable acid in a suitable inert solvent.
  • the pharmaceutically acceptable acid includes inorganic acids, organic acids (e.g., trifluoroacetic acid, hydrochloric acid, formic acid).
  • organic acids e.g., trifluoroacetic acid, hydrochloric acid, formic acid.
  • pharmaceutical excipients refers to all substances contained in pharmaceutical preparations other than active pharmaceutical ingredients, which are generally divided into two categories: excipients and additives. For details, please refer to the “Pharmacopoeia of the People's Republic of China (2020 Edition)” and Handbook of Pharmaceutical Excipients (Paul J Sheskey, Bruno C Hancock, Gary P Moss, David J Goldfarb, 2020, 9th Edition).
  • treating refers to removing the cause or alleviating the symptoms.
  • prevention refers to reducing the risk of developing a disease.
  • patient refers to any animal, usually a mammal, such as a human, that needs to be treated or prevented. Mammals include, but are not limited to, cows, horses, sheep, pigs, cats, dogs, mice, rats, rabbits, guinea pigs, monkeys, humans, etc.
  • therapeutically effective amount refers to the amount of a compound administered to a patient that is sufficient to effectively treat a disease.
  • the therapeutically effective amount will vary depending on the type of compound, the type of disease, the severity of the disease, the age of the patient, etc., but can be adjusted by those skilled in the art as appropriate.
  • a group B substituted by one or more groups A means that one or more hydrogen atoms in the group B are independently replaced by a group A.
  • groups A appear at the same time, unless otherwise specified, their definitions are independent of each other and do not affect each other.
  • halogen refers to fluorine, chlorine, bromine or iodine.
  • alkyl refers to a linear or branched, saturated, monovalent hydrocarbon group having a specified number of carbon atoms.
  • Alkyl includes, but is not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl.
  • alkyl-O- the definition of alkyl is as described above.
  • alkyl-O- include C 1 -C 6 alkyl-O- or C 1 -C 4 alkyl-O-, and more specifically CH 3 -O-, CH 3 CH 2 -O-, CH 3 CH 2 CH 2 -O- or CH 3 CH(CH 3 )-O-, etc.
  • Rx-O- the definition of Rx is as described in their respective corresponding definitions, for example, the definition of cycloalkyl in "cycloalkyl-O-" is as described in the following "cycloalkyl".
  • alkyl-S- the definition of alkyl is as described above.
  • alkyl-S- include C 1 -C 6 alkyl-S- or C 1 -C 4 alkyl-S-, and more specifically CH 3 -S-, CH 3 CH 2 -S-, CH 3 CH 2 CH 2 -S- or CH 3 CH(CH 3 )-S-, etc.
  • Rx-S- the definition of Rx is as described in their respective corresponding definitions, for example, the definition of cycloalkyl in "cycloalkyl-S-" is as described in the following "cycloalkyl".
  • alkoxy refers to an oxygen atom attached to one end of an alkyl group as a linker, forming "alkyl-O-".
  • alkyl-O- The definition of "alkyl-O-" is As mentioned above.
  • alkylthio refers to a sulfur atom attached to one end of an alkyl group as a linker, forming “alkyl-S-,” wherein “alkyl-S-” is as defined above.
  • heteroaryl refers to a cyclic, unsaturated, monovalent group having a specified number of ring atoms (e.g., 5-12, 5-10, or 5-6 members), a specified number of heteroatoms (e.g., 1, 2, or 3), and a specified type of heteroatom (one or more of N, O, and S), which has aromatic character.
  • cycloalkyl means a saturated carbocyclic substituent, and it can be connected to the rest of the molecule through any suitable carbon atom by a single bond; C3 - C7 cycloalkyl having 3 to 7 carbon atoms, preferably C3 -C6 cycloalkyl having 3 to 6 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, etc.
  • aryl refers to a cyclic, unsaturated, monovalent hydrocarbon group having a specified number of carbon atoms (eg, C 6 -C 10 ). Examples of aryl groups include, but are not limited to, phenyl or naphthyl.
  • heteroaryl refers to a cyclic or unsaturated monovalent group with a specified number of ring atoms (e.g., 5-10 members, 5-6 members), a specified number of heteroatoms (e.g., 1, 2 or 3), a specified heteroatom type (one or more of N, O and S), which is monocyclic or polycyclic, and (at least one ring/each ring) has aromatic properties.
  • the heteroaryl group is connected to the rest of the molecule through a carbon atom or a heteroatom; the heteroaryl group is connected to the rest of the molecule through a ring with heteroatoms or a ring without heteroatoms; the heteroaryl group is connected to the rest of the molecule through a ring with aromatic properties or a ring without aromatic properties.
  • the key is a solid wedge. and dotted wedge key To indicate the absolute configuration of a stereocenter, a wavy line is used between the atom and its substituent. When connected, it means or a mixture thereof.
  • the reagents and raw materials used in the present invention are commercially available.
  • Boc tert-butyloxycarbonyl.
  • DBU 1,8-diazabicyclo[5.4.0]undec-7-ene.
  • NBS N-bromosuccinimide
  • DIEA N,N-diisopropylethylamine.
  • DMSO dimethyl sulfoxide
  • HATU 2-(7-Azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate.
  • LiHMDS Lithium bis(trimethylsilyl)amide.
  • NCS N-chlorosuccinimide
  • A-4 (1.0 g, 3.5 mmol) was dissolved in tetrahydrofuran (20 mL) and water (4 mL), and lithium hydroxide (0.22 g, 5.2 mmol) was added and stirred at room temperature for 2 hours. The pH of the reaction solution was adjusted to 7, water (50 mL) was added, and lyophilized to obtain a crude product containing intermediate A, which was directly used in the next reaction.
  • G-2 (4.00 g, 11.9 mmol) and potassium carbonate (4.9 g, 35.8 mmol) were added to tetrahydrofuran (4 mL), and a tetrahydrofuran solution of 4-methoxybenzylamine (1.64 g, 11.9 mmol) was added dropwise at room temperature, and stirring was continued at room temperature for 1 hour.
  • the reaction solution was filtered and concentrated under reduced pressure to obtain a crude product containing the target compound, which was purified by silica gel column chromatography (petroleum ether/ethyl acetate, 9/1, v/v) to obtain G-3.
  • G-3 400 mg, 1.29 mmol
  • methylboronic acid 116 mg, 1.93 mmol
  • potassium carbonate 535 mg, 3.87 mmol
  • [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium 189 mg, 0.26 mmol
  • 1,4-dioxane 3 mL
  • X-1 (900 mg, 4.68 mmol) was dissolved in 1,4-dioxane (40 mL), X-2 (1.8 g, 5.61 mmol) was added, and the mixture was heated to 90 °C and stirred for 18 hours. After the reaction solution was cooled to room temperature, water (50 mL) was added to dilute it, and ethyl acetate (50 mL ⁇ 3) was used for extraction.
  • AA-1 (1.4 g, 12.2 mmol) was dissolved in DMF (30 mL), cooled to 0 °C, sodium hydride (60%, 910 mg, 22.8 mmol) was added, stirred for 30 minutes, and then O-1 (2.0 g, 15.2 mmol) was added and stirred at room temperature for 18 hours.
  • AA-2 400 mg, 1.77 mmol
  • A-2 (254 mg, 1.77 mmol) were dissolved in DMSO (15 mL), TEA (1.08 g, 10.6 mmol) and cesium fluoride (404 mg, 2.66 mmol) were added, and the temperature was raised to 100 ° C and stirred for 10 hours. After the reaction solution was cooled to room temperature, saturated ammonium chloride solution (50 mL) was added, and ethyl acetate (50 mL ⁇ 3) was used for extraction.
  • AI-1 (90 mg, 0.35 mmol) was dissolved in tetrahydrofuran (2 mL) and water (1 mL), and lithium hydroxide monohydrate (18 mg, 0.42mmol), stirred at room temperature for 3 hours. After the reaction, the pH of the reaction solution was adjusted to 5 with dilute hydrochloric acid (1mol/L), concentrated under reduced pressure and freeze-dried to obtain a crude product containing intermediate AI, which was directly used in the next reaction.
  • G-4 500 mg, 1.73 mmol
  • cyclopropylboronic acid (296 mg, 3.45 mmol)
  • potassium carbonate (596 mg, 4.31 mmol)
  • [1,1'-bis(diphenylphosphino)ferrocene] palladium dichloride (253 mg, 0.35 mmol) were added to 1,4-dioxane (6 mL), heated to 100 ° C and stirred for 12 hours under nitrogen protection.
  • reaction solution was cooled to room temperature, filtered, diluted with water (30 mL), extracted with ethyl acetate (30 mL ⁇ 3), the organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product containing the target compound, which was purified by silica gel column chromatography (petroleum ether/ethyl acetate, 2/3, v/v) to obtain AK-1.
  • AK-1 300 mg, 1.02 mmol
  • trifluoroacetic acid 4 mL
  • the reaction solution was cooled to room temperature and concentrated under reduced pressure to obtain the trifluoroacetate salt containing the intermediate AK, which was directly used in the next step.
  • G-4 (200 mg, 0.69 mmol), methanesulfonic acid (tricyclohexylphosphine) (2-amino-1,1-biphenyl-2-yl) palladium (45 mg, 0.07 mmol), potassium phosphate (513 mg, 2.42 mmol), ethylboric acid (153 mg, 2.07 mmol) were added to toluene (5 mL) and water (1 mL), and the mixture was heated to 100 °C and stirred for 12 hours under nitrogen protection.
  • methanesulfonic acid tricyclohexylphosphine
  • ethylboric acid 153 mg, 2.07 mmol
  • reaction solution was cooled to room temperature, diluted with water (20 mL), extracted with ethyl acetate (20 mL ⁇ 3), the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product containing the target compound, which was purified by silica gel column chromatography (petroleum ether/ethyl acetate, 2/3, v/v) to obtain AO-1.
  • AO-1 150 mg, 0.53 mmol
  • trifluoroacetic acid 4 mL
  • the reaction solution was cooled to room temperature and concentrated under reduced pressure to obtain the trifluoroacetate salt containing the intermediate AO, which was directly used in the next step.
  • reaction solution was cooled to room temperature, diluted with water (20 mL), extracted with ethyl acetate (20 mL ⁇ 3), the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product containing the target compound, which was purified by silica gel column chromatography (dichloromethane/methanol, 9/1, v/v) to obtain AP-1.
  • AP-1 150 mg, 0.50 mmol
  • trifluoroacetic acid 4 mL
  • the reaction solution was cooled to room temperature and concentrated under reduced pressure to obtain the trifluoroacetate containing the intermediate AP, which was directly used in the next step.
  • AR-1 (1.00 g, 2.89 mmol) was dissolved in dichloromethane (6 mL), trifluoroacetic acid (2 mL) was added, and the mixture was stirred at room temperature for 3 hours. The reaction solution was concentrated under reduced pressure to obtain a crude product containing the intermediate AR, which was directly used in the next step.
  • reaction solution was concentrated under reduced pressure to obtain a crude product containing the target compound, which was purified by preparative high performance liquid chromatography (chromatographic column: Waters-Xbridge-C18, 10 ⁇ m, 19*250 mm, mobile phase: acetonitrile-10 mmol/L ammonium bicarbonate aqueous solution, gradient: 32-62%, retention time: 9 min) to obtain compound 47.
  • chromatographic column Waters-Xbridge-C18, 10 ⁇ m, 19*250 mm
  • mobile phase acetonitrile-10 mmol/L ammonium bicarbonate aqueous solution, gradient: 32-62%, retention time: 9 min
  • reaction solution was concentrated under reduced pressure to obtain a crude product containing the target compound, which was purified by preparative high performance liquid chromatography (chromatographic column: Waters-Xbridge-C18, 10 ⁇ m, 19*250 mm, mobile phase: acetonitrile-10 mmol/L ammonium bicarbonate aqueous solution, gradient: 9-39%, retention time: 9 min) to obtain compound 50.
  • chromatographic column Waters-Xbridge-C18, 10 ⁇ m, 19*250 mm
  • mobile phase acetonitrile-10 mmol/L ammonium bicarbonate aqueous solution, gradient: 9-39%, retention time: 9 min
  • reaction solution was concentrated under reduced pressure to obtain a crude product containing the target compound, which was purified by preparative high performance liquid chromatography (chromatographic column: Waters-Xbridge-C18, 10 ⁇ m, 19*250 mm, mobile phase: acetonitrile-10 mmol/L ammonium bicarbonate aqueous solution, gradient: 22-52%, retention time: 9 min) to obtain compound 51.
  • chromatographic column Waters-Xbridge-C18, 10 ⁇ m, 19*250 mm
  • mobile phase acetonitrile-10 mmol/L ammonium bicarbonate aqueous solution, gradient: 22-52%, retention time: 9 min
  • reaction solution was concentrated under reduced pressure to obtain a crude product containing the target compound, which was purified by preparative high performance liquid chromatography (chromatographic column: Waters-Xbridge-C18, 10 ⁇ m, 19*250 mm, mobile phase: acetonitrile-10 mmol/L ammonium bicarbonate aqueous solution, gradient: 17-47%, retention time: 9 min) to obtain compound 56.
  • chromatographic column Waters-Xbridge-C18, 10 ⁇ m, 19*250 mm
  • mobile phase acetonitrile-10 mmol/L ammonium bicarbonate aqueous solution, gradient: 17-47%, retention time: 9 min
  • reaction solution was concentrated under reduced pressure to obtain a crude product containing the target compound, which was purified by preparative high performance liquid chromatography (chromatographic column: Waters-Xbridge-C18, 10 ⁇ m, 19*250 mm, mobile phase: acetonitrile-10 mmol/L ammonium bicarbonate aqueous solution, gradient: 26-56%, retention time: 9 min) to obtain compound 67.
  • chromatographic column Waters-Xbridge-C18, 10 ⁇ m, 19*250 mm
  • mobile phase acetonitrile-10 mmol/L ammonium bicarbonate aqueous solution, gradient: 26-56%, retention time: 9 min
  • reaction solution was concentrated under reduced pressure to obtain a crude product containing the target compound, which was purified by preparative high performance liquid chromatography (chromatographic column: Waters-Xbridge-C18, 10 ⁇ m, 19*250 mm, mobile phase: acetonitrile-10 mmol/L ammonium bicarbonate aqueous solution, gradient: 25-55%, retention time: 9 min) to obtain compound 68.
  • chromatographic column Waters-Xbridge-C18, 10 ⁇ m, 19*250 mm
  • mobile phase acetonitrile-10 mmol/L ammonium bicarbonate aqueous solution, gradient: 25-55%, retention time: 9 min
  • reaction solution was concentrated under reduced pressure to obtain a crude product containing the target compound, which was purified by preparative high performance liquid chromatography (chromatographic column: Waters-Xbridge-C18, 10 ⁇ m, 19*250 mm, mobile phase: acetonitrile-10 mmol/L ammonium bicarbonate aqueous solution, gradient: 35-65%, retention time: 9 min) to obtain compound 98.
  • chromatographic column Waters-Xbridge-C18, 10 ⁇ m, 19*250 mm
  • mobile phase acetonitrile-10 mmol/L ammonium bicarbonate aqueous solution, gradient: 35-65%, retention time: 9 min
  • reaction solution was concentrated under reduced pressure to obtain a crude product containing the target compound, which was purified by preparative high performance liquid chromatography (chromatographic column: Waters-Xbridge-C18, 10 ⁇ m, 19*250 mm, mobile phase: acetonitrile-10 mmol/L ammonium bicarbonate aqueous solution, gradient: 31-61%, retention time: 9 min) to obtain compound 110.
  • chromatographic column Waters-Xbridge-C18, 10 ⁇ m, 19*250 mm
  • mobile phase acetonitrile-10 mmol/L ammonium bicarbonate aqueous solution, gradient: 31-61%, retention time: 9 min
  • reaction solution was concentrated under reduced pressure to obtain a crude product containing the target compound, which was purified by preparative high performance liquid chromatography (chromatographic column: Waters-Xbridge-C18, 10 ⁇ m, 19*250 mm, mobile phase: acetonitrile-10 mmol/L ammonium bicarbonate aqueous solution, gradient: 34-64%, retention time: 9 min) to obtain compound 111.
  • chromatographic column Waters-Xbridge-C18, 10 ⁇ m, 19*250 mm
  • mobile phase acetonitrile-10 mmol/L ammonium bicarbonate aqueous solution, gradient: 34-64%, retention time: 9 min
  • reaction solution was concentrated under reduced pressure to obtain a crude product containing the target compound, which was purified by preparative high performance liquid chromatography (chromatographic column: Waters-Xbridge-C18, 10 ⁇ m, 19*250 mm, mobile phase: acetonitrile-10 mmol/L ammonium bicarbonate aqueous solution, gradient: 32-62%, retention time: 9 min) to obtain compound 116.
  • chromatographic column Waters-Xbridge-C18, 10 ⁇ m, 19*250 mm
  • mobile phase acetonitrile-10 mmol/L ammonium bicarbonate aqueous solution, gradient: 32-62%, retention time: 9 min
  • Embodiment 123 is a diagrammatic representation of Embodiment 123.
  • reaction solution was cooled, it was diluted with water (50 mL), extracted with ethyl acetate (50 mL ⁇ 3), and the organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product containing the target compound, which was purified by preparative high performance liquid chromatography (chromatographic column: Waters-Xbridge-C18-10 ⁇ m-19*250mm, mobile phase: acetonitrile-10mmol/L ammonium bicarbonate aqueous solution, gradient: 16-46%, retention time: 10min) to obtain compound 124.
  • chromatographic column Waters-Xbridge-C18-10 ⁇ m-19*250mm
  • mobile phase acetonitrile-10mmol/L ammonium bicarbonate aqueous solution, gradient: 16-46%, retention time: 10min
  • reaction solution was diluted with water (50 mL), extracted with ethyl acetate (50 mL ⁇ 3), and the organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product containing the target compound, which was purified by preparative high performance liquid chromatography (chromatographic column: Waters-Xbridge-C18-10 ⁇ m-19*250mm, mobile phase: acetonitrile-10mmol/L ammonium bicarbonate aqueous solution, gradient: 5-95%, retention time: 10min) to obtain compound 131.
  • chromatographic column Waters-Xbridge-C18-10 ⁇ m-19*250mm
  • mobile phase acetonitrile-10mmol/L ammonium bicarbonate aqueous solution, gradient: 5-95%, retention time: 10min
  • the intermediate G-4 (500 mg, 1.60 mmol) was dissolved in methanol (20 mL), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (127 mg, 0.17 mmol) and TEA (524 mg, 5.18 mmol) were added.
  • the reaction system was replaced with carbon monoxide three times and then heated to 70°C and stirred for 18 hours.
  • the reaction solution was filtered, the filtrate was concentrated under reduced pressure, and purified by silica gel column chromatography (petroleum ether/ethyl acetate, 1/4, v/v) to obtain 132-1.
  • the activity of compounds against M4 receptor was determined using the FLIPR CALCIUM 6ASSAY KIT kit using a stably transfected cell line expressing the human M4 receptor (M4-G ⁇ 15-CHO).

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Neurosurgery (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Epidemiology (AREA)
  • Psychiatry (AREA)
  • Psychology (AREA)
  • Hospice & Palliative Care (AREA)
  • Addiction (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

本发明公开一种含氮杂环化合物、其药学上可接受的盐及其制备方法与应用。本发明提供了一种式I所示的化合物或其药学上可接受的盐。本发明化合物可作为毒蕈碱受体正向变构调节剂，发明化合物可治疗M受体介导的(或M受体相关的)疾病。

Description

一种含氮杂环化合物、其药学上可接受的盐及其制备方法与应用
本申请要求申请日为2022/10/28的中国专利申请202211339268.9的优先权，本申请引用上述中国专利申请的全文。
本申请要求申请日为2022/12/26的中国专利申请202211686868.2的优先权，本申请引用上述中国专利申请的全文。
本申请要求申请日为2023/02/08的中国专利申请202310099794.0的优先权，本申请引用上述中国专利申请的全文。
本申请要求申请日为2023/03/01的中国专利申请202310186197.1的优先权，本申请引用上述中国专利申请的全文。
本申请要求申请日为2023/03/17的中国专利申请202310263463.6的优先权，本申请引用上述中国专利申请的全文。
本申请要求申请日为2023/06/16的中国专利申请202310719553.1的优先权，本申请引用上述中国专利申请的全文。
本申请要求申请日为2023/10/23的中国专利申请202311378324.4的优先权，本申请引用上述中国专利申请的全文。
技术领域
本发明涉及一种含氮杂环化合物、其药学上可接受的盐及其制备方法与应用。
背景技术
毒蕈碱受体(Muscarinic receptor,M受体)属于G蛋白偶联受体，是乙酰胆碱受体的一种。M受体有五种亚型，其中M1、M3、M5与Gq蛋白偶联，激活磷脂酶C，增加细胞内钙水平。M2、M4与Gi蛋白偶联，抑制腺苷酸环化酶，降低cAMP水平。M1受体在中枢、消化道、淋巴组织中均有分布，作为M受体的主要亚型，能同时调节细胞兴奋性和胆碱能传递。M4受体主要位于皮质、海马、纹状体中，在控制多巴胺释放和运动活动中起重要作用，但并不调节重要的外周生理功能(Neuropharmacology 2018,136,362)。
M受体激动剂用作精神疾病的治疗药物已经被众多科研机构和药物研发企业广泛研究。例如,M1/M4受体激动剂占诺美林在九十年代开展过治疗阿尔兹海默症的临床Ⅱ期试验,该药物治疗后病人的认知功能得到了提高，但是在外周及消化道存在比较严重的毒副作用。占诺美林和M1受体拮抗剂曲司氯铵组成的KarXT是由Karuna开发的治疗精神分裂症药物。最新的临床二期研究表明,相比于安慰剂组,KarXT治疗组的阳性与阴性症状量表(PANSS)评分有显著改善,达到了主要终点,但依旧存在着外周胆碱能副作用(N Engl J Med 2021,384,717)。
M受体正向变构调节剂(Positive Allosteric Modulator,PAM)是精神疾病领域近年来的研究热点之一。在精神分裂症遗传小鼠模型中,M1受体正向变构调节剂TAK-071显著改善了小鼠在记忆认知、社交能力和感觉运动门控方面的缺陷(Neurosci Lett 2021,764,136240),该化合物用于治疗帕金森综合 征的临床II期试验正在进行中。另一M1受体正向变构调节剂MK-7622正在开展临床II期试验,评估其用于治疗阿尔兹海默症的药效(ACS Med Chem Lett 2018,9,652)。在临床Ⅰb试验招募的精神分裂症患者中,由Cerevel公司开发的M4受体正向变构调节剂CVL-231能显著降低患者的PANSS总评分，同时,常见不良反应与安慰剂组相似,并且未报道锥体外系不良反应。相比于传统的M受体正构激动剂,正向变构调节剂在外周和中枢方面的潜在风险更低,在维持药效的同时可能产生的毒副作用更小。因此,作用于变构调节口袋是靶向M受体治疗精神疾病的新方向。具备良好成药性、体内药效和安全性的M受体正向变构调节剂有较大的开发价值和市场前景。
发明内容
本发明提供了一种含氮杂环化合物、其药学上可接受的盐及其制备方法与应用。本发明化合物可作为毒蕈碱受体正向变构调节剂。发明化合物可治疗M受体介导的(或M受体相关的)疾病。
本发明提供了一种式I所示的化合物或其药学上可接受的盐：
其中，为
m为0～3的自然数；
n为0～3的自然数；m和n不同时为0；
k为0～3的自然数；
X1、X2、X3、X4和X5独立地为-CR1-、N、O、S、或化学键；
RN-1为氢、C1-C6烷基、C1-C6烷氧基或3～7元环烷基，其中所述C1-C6烷基和C1-C6烷氧基任选独立地被1个、2个、3个或4个RN-2取代；
各个RN-2独立地为卤素；
Y和Z独立地为羰基(CO)、-(CR2R3)r-或化学键；r为0～5的自然数；
各个W独立地为羰基(CO)、-O-、-(CR4R5)-、-NR6-或化学键；
各个R1独立地为氢、卤素、氰基、羟基、C1-C6烷基、C1-C6烷氧基、C1-C6烷硫基、3～7元环烷基、3～7元杂环烷基或-NR1-1R1-2，其中，所述C1-C6烷硫基、C1-C6烷基和C1-C6烷氧基任选独立地被1个、2个、3个或4个Ra取代；或者两个R1和与其相连的原子形成3～7元环烷基或3～7元杂环烷基；
各个Ra独立地为卤素、氰基、羟基、C1-C3烷基、C1-C6烷氧基或-NR1-4R1-5；或者，两个Ra和与其连接的原子形成3～7元环烷基或3～7元杂环烷基；
R1-1和R1-2独立地为氢或C1-C6烷基，其中所述C1-C6烷基任选独立地被1个、2个、3个或4个Rb取代；或者，R1-1和R1-2与其相连的原子形成3～7元杂环烷基，其中，所述3～7元杂环烷基任性地被1个、2个、3个或4个Rb-2取代；
各个Rb独立地为卤素、氰基、羟基、C1-C6烷氧基、3～7元环烷基、3～7元杂环烷基、C1-C3烷基和NR1-1-1R1-2-1，其中，所述3～7元环烷基、3～7元杂环烷基和C1-C3烷基任选独立地被1个、2个、3个或4个Rb-1取代；
各个Rb-1独立地为卤素、羟基或氰基；
各个Rb-2独立地为卤素、C1-C6烷基或氰基；
R1-4和R1-5独立地为氢或C1-C3烷基，其中所述C1-C3烷基任选独立地被1个、2个、3个或4个R1-4-1取代；或者，R1-4和R1-5与其相连的原子形成3～7元杂环烷基；
R1-1-1和R1-2-1独立地为氢或C1-C3烷基，其中所述C1-C3烷基任选独立地被1个、2个、3个或4个R1-1-1-1取代；
各个R1-4-1和R1-1-1-1独立地为卤素、羟基或氰基；
R2和R3独立地为氢、卤素、氰基、羟基、C1-C6烷氧基或NR2-1R2-2；或者R2和R3与其相连的原子形成3～7元环烷基或3～7元杂环烷基；
R2-1和R2-2独立地为氢或C1-C6烷基，其中，所述C1-C6烷基任选独立地被1个、2个、3个或4个Rd取代；或者，R2-1和R2-2与其相连的原子形成3～7元杂环烷基；
各个Rd独立地为卤素、氰基、羟基、C1-C6烷氧基、3～7元环烷基、3～7元杂环烷基或C1-C3烷基；
R4、R5和R6独立地为氢、卤素、氰基、羟基、C1-C6烷氧基、C1-C6烷基或NR4-1R4-2，其中，所述C1-C6烷基任选独立地被1个、2个、3个或4个Re取代；
各个Re独立地为卤素、氰基、羟基、C1-C3烷基、C1-C3烷氧基或-NR4-4R4-5；
R4-1和R4-2独立地为氢或C1-C6烷基，其中所述C1-C6烷基任选独立地被1个、2个、3个或4个Rf取代；或者，R4-1和R4-2与其相连的原子形成3～7元杂环烷基；
各个Rf独立地为卤素、氰基、羟基、3～7元环烷基、3～7元杂环烷基、C1-C3烷基、C1-C3烷氧基或-NR4-1-1R4-2-1；
R4-4和R4-5独立地为氢或C1-C3烷基；或者R4和R5与其相连的原子形成3～7元环烷基或3～7元杂环烷基；
R4-1-1和R4-2-独立地为氢或C1-C3烷基；
L为
t为0～3的自然数；
u为0～3的自然数；
E为羰基、-NHCO-、或化学键；
F为羰基、-O-、-NH-或化学键；
R8和R9独立地为氢、卤素、氰基、羟基或C1-C6烷基，其中，所述C1-C6烷基任选独立地被1个、2个、3个或4个Rg取代；或者R8和R9与其相连的原子形成3～7元环烷基或3～7元杂环烷基；
各个Rg独立地为卤素、氰基、羟基、C1-C3烷基或C1-C3烷氧基；
B为3～7元环烷基、4～6元杂环烷基、6～10元芳基或5～12元杂芳基；其中，所述3～7元环烷基、4～6元杂环烷基、6～10元芳基和5～12元杂芳基任选独立地被1个、2个或3个Ri取代；
各个Ri独立地为氢、卤素、羟基、C1-C3烷基、3～7元环烷基、3～7元杂环烷基、氰基、-NR11-1R11- 2、-OR11-3或-SR11-4；其中，所述C1-C3烷基任选独立地被1个、2个、3个或4个Ri-1取代，或者，两个同一原子上的Ri和与其相连的原子形成3～7元环烷基或3～7元杂环烷基；或者，两个相邻的Ri与其相连的原子形成3～7元环烷基或3～7元杂环烷基(其中，3～7元环烷基或3～7元杂环烷基与B形成并环)；
各个Ri-1独立地为C1-C3烷基、卤素、氰基或羟基；
R11-1和R11-2独立地为氢、C1-C3烷基、3～7元环烷基或3～7元杂环烷基；或者，R11-1和R11-2与其相连地原子形成3～7元环烷基或3～7元杂环烷基；
R11-3和R11-4独立地为C1-C3烷基、3～7元环烷基或3～7元杂环烷基；
R11-1、R11-2、R11-3和R11-4中，所述C1-C3烷基、3～7元环烷基和3～7元杂环烷基任选独立地被1个、2个或3个Ri-2取代；
各个Ri-2独立地为C1-C3烷基、3～7元环烷基、3～7元杂环烷基、卤素、氰基或羟基；
D为氢、卤素、氰基、羟基、C1-C6烷基、3～7元环烷基、3～7元杂环烷基、6～10元芳基或5～12元杂芳基；其中，所述C1-C6烷基、3～7元环烷基、3～7元杂环烷基、6～10元芳基和5～12元杂芳基任选独立地被1个、2个或3个Rj取代；
各个Rj独立地为氢、卤素、氰基、羟基、C1-C3烷基、3～7元环烷基、3～7元杂环烷基、-NR12-1R12- 2、-OR12-3或-SR12-4；所述C1-C3烷基、3～7元环烷基和3～7元杂环烷基任选独立地被任选独立地被1个、2个或3个Rk取代；
R12-1、R12-2、R12-3和R12-4独立地为氢、C1-C3烷基、3～7元环烷基或3～7元杂环烷基；其中，C1-C3烷基、3～7元环烷基和3～7元杂环烷基任选独立地被1个、2个或3个Rk-1取代；或者，R12-1与R12- 2和与其相连的原子形成3～7元杂环烷基；
各个Rk独立地为卤素、氰基、羟基、C1-C3烷基、3～7元环烷基或3～7元杂环烷基；
各个Rk-1独立地为卤素、氰基、羟基、C1-C3烷基、3～7元环烷基或3～7元杂环烷基；
当A为X1、X2和X3为CR1时，所述式I所示化合物满足如下任一条件：
(1)E为-NHCO-或化学键，F为-O-、-NH-或化学键，
(2)E为羰基，F为-NH-，
(3)L为-(CH2)-、-(CH2)2-、
(4)当E或F为羰基时，B为4～7元环烷基、6～10元芳基、5～12元杂芳基、被1个、2个或3个Ri取代的4～6元杂环烷基，其中，两个同一原子上的Ri和与其相连的原子形成3～7元环烷基或3～7元杂环烷基；或者，两个相邻的Ri与其相连的原子形成3～7元环烷基或3～7元杂环烷基(其中，3～7元环烷基或3～7元杂环烷基与B形成并环)；其中，所述4～7元环烷基、6～10元芳基和5～12元杂芳基任选独立地被1个、2个或3个Ri取代，
(5)为
当A为时，X1、X2和X4中杂原子数为1个或2个；
当A为且L为羰基时，u为1～3的自然数，B为4～6元杂环烷基，所述4～6元杂环烷基任选独立地被1个、2个或3个Ri取代；
所述3～7元杂环烷基、4～6元杂环烷基和5～12元杂芳基中，杂原子为N、O和S中一种或多种，杂原子数为1～5个。
某一方案中，所述式I所示的化合物或其药学上可接受的盐中，某些基团具有如下定义，未提及的基团的定义如本发明中任一方案所述(本段内容以下简称为“某一方案中”、“一些方案中”、“某一实施方案中”或“某一优选方案中”)。
某一方案中，
其中，为
m为0～3的自然数；
n为0～3的自然数；m和n不同时为0；
k为0～3的自然数；
X1、X2、X3、X4和X5独立地为-CR1-、N、O、S、或化学键；
RN-1为氢或C1-C6烷基、C1-C6烷氧基或3～7元环烷基，其中所述C1-C6烷基和C1-C6烷氧基任选独立地被1个、2个、3个或4个RN-2取代；
各个RN-2独立地为卤素；
Y和Z独立地为羰基(CO)、-(CR2R3)r-或化学键；r为0～5的自然数；
各个W独立地为羰基(CO)、-O-、-(CR4R5)-、-NR6-或化学键；
各个R1独立地为氢、卤素、氰基、羟基、C1-C6烷基、C1-C6烷氧基、3～7元环烷基、3～7元杂环烷基或-NR1-1R1-2，其中，所述C1-C6烷基和C1-C6烷氧基任选独立地被1个、2个、3个或4个Ra取代；或者两个R1和与其相连的原子形成3～7元环烷基或3～7元杂环烷基；
各个Ra独立地为卤素、氰基、羟基、C1-C3烷基、C1-C6烷氧基或-NR1-4R1-5；或者，两个Ra和与其连接的原子形成3～7元环烷基或3～7元杂环烷基；R1-1和R1-2独立地为氢或C1-C6烷基，其中所述C1-C6烷基任选独立地被1个、2个、3个或4个Rb取代；或者，R1-1和R1-2与其相连的原子形成3～7元杂环烷基；
各个Rb独立地为卤素、氰基、羟基、C1-C6烷氧基、3～7元环烷基、3～7元杂环烷基、C1-C3烷基和NR1-1-1R1-2-1，其中，所述3～7元环烷基、3～7元杂环烷基和C1-C3烷基任选独立地被1个、2个、3个或4个Rb-1取代；
各个Rb-1独立地为卤素、羟基或氰基；
R1-4和R1-5独立地为氢或C1-C3烷基，其中所述C1-C3烷基任选独立地被1个、2个、3个或4个R1-4-1取代；或者，R1-4和R1-5与其相连的原子形成3～7元杂环烷基；
R1-1-1和R1-2-1独立地为氢或C1-C3烷基，其中所述C1-C3烷基任选独立地被1个、2个、3个或4个R1-1-1-1取代；
各个R1-4-1和R1-1-1-1独立地为卤素、羟基或氰基；
R2和R3独立地为氢、卤素、氰基、羟基、C1-C6烷氧基或NR2-1R2-2；或者R2和R3与其相连的原子形成3～7元环烷基或3～7元杂环烷基；
R2-1和R2-2独立地为氢或C1-C6烷基，其中所述C1-C6烷基任选独立地被1个、2个、3个或4个Rd取代；或者，R2-1和R2-2与其相连的原子形成3～7元杂环烷基；
各个Rd独立地为卤素、氰基、羟基、C1-C6烷氧基、3～7元环烷基、3～7元杂环烷基或C1-C3烷 基；
R4、R5和R6独立地为氢、卤素、氰基、羟基、C1-C6烷氧基、C1-C6烷基或NR4-1R4-2，其中，所述C1-C6烷基任选独立地被1个、2个、3个或4个Re取代；
各个Re独立地为卤素、氰基、羟基、C1-C3烷基、C1-C3烷氧基或-NR4-4R4-5；
R4-1和R4-2独立地为氢或C1-C6烷基，其中所述C1-C6烷基任选独立地被1个、2个、3个或4个Rf取代；或者，R4-1和R4-2与其相连的原子形成3～7元杂环烷基；
各个Rf独立地为卤素、氰基、羟基、3～7元环烷基、3～7元杂环烷基、C1-C3烷基、C1-C3烷氧基或-NR4-1-1R4-2-1；
R4-4和R4-5独立地为氢或C1-C3烷基；或者R4和R5与其相连的原子形成3～7元环烷基或3～7元杂环烷基；
R4-1-1和R4-2-独立地为氢或C1-C3烷基；
L为
t为0～3的自然数；
u为0～3的自然数；
E为羰基、-NHCO-、或化学键；
F为羰基、-O-、-NH-或化学键；
R8和R9独立地为氢、卤素、氰基、羟基或C1-C6烷基，其中，所述C1-C6烷基任选独立地被1个、2个、3个或4个Rg取代；或者R8和R9与其相连的原子形成3～7元环烷基或3～7元杂环烷基；
各个Rg独立地为卤素、氰基、羟基、C1-C3烷基或C1-C3烷氧基；
B为3～7元环烷基、4～6元杂环烷基、6～10元芳基或5～12元杂芳基；其中，所述3～7元环烷基、4～6元杂环烷基、6～10元芳基和5～12元杂芳基任选独立地被1个、2个或3个Ri取代；
各个Ri独立地为氢、卤素、羟基、C1-C3烷基、3～7元环烷基、3～7元杂环烷基、氰基、-NR11-1R11- 2、-OR11-3或-SR11-4；其中，所述C1-C3烷基任选独立地被1个、2个、3个或4个Ri-1取代，或者，两个同一原子上的Ri和与其相连的原子形成3～7元环烷基或3～7元杂环烷基；或者，两个相邻的Ri与其相连的原子形成3～7元环烷基或3～7元杂环烷基(其中，3～7元环烷基或3～7元杂环烷基与B形成并环)；
各个Ri-1独立地为C1-C3烷基、卤素、氰基或羟基；
R11-1和R11-2独立地为氢、C1-C3烷基、3～7元环烷基或3～7元杂环烷基；或者，R11-1和R11-2与其相连地原子形成3～7元环烷基或3～7元杂环烷基；
R11-3和R11-4独立地为C1-C3烷基、3～7元环烷基或3～7元杂环烷基；
R11-1、R11-2、R11-3和R11-4中，所述C1-C3烷基、3～7元环烷基和3～7元杂环烷基任选独立地被1个、2个或3个Ri-2取代；
各个Ri-2独立地为C1-C3烷基、3～7元环烷基、3～7元杂环烷基、卤素、氰基或羟基；
D为氢、卤素、氰基、羟基、C1-C6烷基、3～7元环烷基、3～7元杂环烷基、6～10元芳基或5～12 元杂芳基；其中，所述C1-C6烷基、3～7元环烷基、3～7元杂环烷基、6～10元芳基和5～12元杂芳基任选独立地被1个、2个或3个Rj取代；
各个Rj独立地为氢、卤素、氰基、羟基、C1-C3烷基、3～7元环烷基、3～7元杂环烷基、-NR12-1R12- 2、-OR12-3或-SR12-4；所述C1-C3烷基、3～7元环烷基和3～7元杂环烷基任选独立地被任选独立地被1个、2个或3个Rk取代；
R12-1、R12-2、R12-3和R12-4独立地为氢、C1-C3烷基、3～7元环烷基或3～7元杂环烷基；其中，C1-C3烷基、3～7元环烷基和3～7元杂环烷基任选独立地被1个、2个或3个Rk-1取代；或者，R12-1与R12- 2和与其相连的原子形成3～7元杂环烷基；
各个Rk独立地为卤素、氰基、羟基、C1-C3烷基、3～7元环烷基或3～7元杂环烷基；
各个Rk-1独立地为卤素、氰基、羟基、C1-C3烷基、3～7元环烷基或3～7元杂环烷基；
当A为X1、X2和X3为CR1时，所述式I所示化合物满足如下任一条件：
(1)E为-NHCO-或化学键，F为-O-、-NH-或化学键，
(2)E为羰基，F为-NH-，
(3)L为-(CH2)-、-(CH2)2-、
(4)当E或F为羰基时，B为4～7元环烷基、6～10元芳基、5～12元杂芳基、被1个、2个或3个Ri取代的4～6元杂环烷基，其中，两个同一原子上的Ri和与其相连的原子形成3～7元环烷基或3～7元杂环烷基；或者，两个相邻的Ri与其相连的原子形成3～7元环烷基或3～7元杂环烷基(其中，3～7元环烷基或3～7元杂环烷基与B形成并环)；其中，所述4～7元环烷基、6～10元芳基和5～12元杂芳基任选独立地被1个、2个或3个Ri取代，
(5)为
当A为时，X1、X2和X4中杂原子数为1个或2个；
当A为且L为羰基时，u为1～3的自然数，B为4～6元杂环烷基，所述4～6元杂环烷基任选独立地被1个、2个或3个Ri取代；
所述3～7元杂环烷基、4～6元杂环烷基和5～12元杂芳基中，杂原子为N、O或S，杂原子数为1～5个；或者，所述3～7元杂环烷基、4～6元杂环烷基和5～12元杂芳基中，杂原子为N、O和S中一种或多种，杂原子数为1～5个。
某一方案中，m优选为0～3的自然数，例如0、1、2或3，还例如1、2或3。
某一方案中，n优选为1～3的自然数，例如1、2或3，又如1或2。
某一方案中，n为1。
某一方案中，当X1为N，X2、X3和X4为-CR1-时，Y和Z独立地为-(CH2)-，m和n为2，Rj为三氟甲基。
某一方案中，为
某一方案中，为
某一方案中，m为1。
某一方案中，k优选为0～3的自然数，例如0、1、2或3，又如1、2或3。
某一方案中，r优选为0～5的自然数，例如0、1、2、3、4或5，又如1或2。
某一方案中，r为1。
某一方案中，r为0-3的自然数，例如1或2。
某一方案中，RN-1为C1-C6烷基。
某一方案中，RN-1为氢、C1-C6烷基或3～7元环烷基。
某一方案中，各个W独立地为-(CR4R5)-、-O-、-NR6-或化学键。
某一方案中，各个W独立地为-(CR4R5)-、-NR6-或化学键。
某一方案中，Y和Z独立地为羰基(CO)或-(CR2R3)r-。
某一方案中，Y和Z独立地为-(CR2R3)r-。
某一方案中，各个R1独立地为氢、卤素、C1-C6烷基、C1-C6烷氧基、C1-C6烷硫基、3～7元环烷基、3～7元杂环烷基或-NR1-1R1-2。
某一方案中，各个R1独立地为C1-C6烷基、C1-C6烷氧基、C1-C6烷硫基或-NR1-1R1-2。
某一方案中，各个R1独立地为氢、C1-C6烷基、C1-C6烷氧基、C1-C6烷硫基、3～7元环烷基、3～7元杂环烷基或-NR1-1R1-2，例如，C1-C6烷基、C1-C6烷氧基、C1-C6烷硫基或-NR1-1R1-2。
某一方案中，各个R1独立地为氢、卤素、C1-C6烷基、C1-C6烷氧基、C1-C6烷硫基、3～7元环烷 基、3～7元杂环烷基或-NR1-1R1-2，其中，所述C1-C6烷硫基、C1-C6烷基和C1-C6烷氧基任选独立地被1个、2个、3个或4个Ra取代。
某一方案中，各个R1独立地为氢、卤素、C1-C6烷基、C1-C6烷氧基、3～7元环烷基、3～7元杂环烷基或-NR1-1R1-2。
某一方案中，各个R1独立地为C1-C6烷基。
某一方案中，各个R1独立地为C1-C6烷基或C1-C6烷氧基。
某一方案中，R1-1和R1-2独立地为氢或C1-C6烷基；或者，R1-1和R1-2与其相连的原子形成3～7元杂环烷基；例如R1-1和R1-2与其相连的原子形成3～7元杂环烷基。
某一方案中，当X1和X3独立地为N；X4和X2独立地为-CR1-时，各个R1独立地为C1-C6烷基、C1-C6烷氧基、C1-C6烷硫基、3～7元杂环烷基或-NR1-1R1-2。
某一方案中，当X2独立地为-CR1-时，R1(X2处)为C1-C6烷基或C1-C6烷氧基。
某一方案中，当D为嘧啶基时，各个R1独立地为卤素或3～7元环烷基。
某一方案中，当X2和X3独立地为N；X4和X1独立地为-CR1-时，各个R1独立地为C1-C6烷基或3～7元杂环烷基。
某一方案中，各个Ra独立地为羟基、C1-C3烷氧基或NR1-4R1-5。
某一方案中，各个Ra独立地为卤素、羟基、C1-C6烷氧基或-NR1-4R1-5，例如各个Ra独立地为羟基、C1-C6烷氧基或-NR1-4R1-5，又如羟基。
某一方案中，各个Rb独立地为羟基、3～7元环烷基、3～7元杂环烷基、C1-C3烷基、C1-C3烷氧基或NR1-1-1R1-2-1。
某一方案中，各个Rb独立地为羟基、3～7元环烷基或C1-C3烷基，例如各个Rb独立地为羟基、3～7元环烷基。
某一方案中，各个Rb独立地为3～7元环烷基。
某一方案中，Rb-1独立地为羟基。
某一方案中，各个Rb-1独立地为羟基。
某一方案中，各个Rb-2独立地为卤素、C1-C6烷基。
某一方案中，R1-4和R1-5独立地为C1-C3烷基。
某一方案中，各个R1-4-1独立地为卤素。
某一方案中，R1-4-1为卤素。
某一方案中，R2和R3独立地为氢或NR2-1R2-2。
某一方案中，R2和R3独立地为氢。
某一方案中，R2-1和R2-2独立地为氢或C1-C6烷基，例如氢。
某一方案中，R4、R5和R6独立地为氢。
某一方案中，R4、R5和R6独立地为氢或NR4-1R4-2。
某一方案中，R4-1和R4-2独立地为氢。
某一方案中，Re为-NR4-4R4-5。
某一方案中，R4-4和R4-5独立地为氢或C1-C3烷基。
某一方案中，E为羰基、-NHCO-或化学键。
某一方案中，E为羰基或化学键。
某一方案中，E为羰基。
某一方案中，t为0。
某一方案中，F为-NH-、-O-或化学键。
某一方案中，F为羰基、-O-、-NH-或化学键。
某一方案中，F为化学键。
某一方案中，R8和R9独立地为氢或C1-C6烷基；或者R8和R9与其相连的原子形成3～7元环烷基或3～7元杂环烷基。
某一方案中，R8和R9独立地为氢或C1-C6烷基，或者R8和R9与其相连的原子形成3～7元环烷基。
某一方案中，R8和R9独立地为C1-C6烷基；或者R8和R9与其相连的原子形成3～7元环烷基或3～7元杂环烷基。
某一方案中，B为4～6元杂环烷基、6～10元芳基或5～12元杂芳基，其中，所述5～12元杂芳基、6～10元芳基和4～6元杂环烷基任选独立地被1个、2个或3个Ri取代。
某一方案中，B为4～6元杂环烷基或5～12元杂芳基，其中，所述5～12元杂芳基和4～6元杂环烷基任选独立地被1个、2个或3个Ri取代。
某一方案中，B为4～6元杂环烷基，其中，所述4～6元杂环烷基任选独立地被1个、2个或3个Ri取代；
某一方案中，当B为6～10元芳基或5～12元杂芳基时，D为氢、卤素、氰基、羟基、C1-C6烷基、3～7元环烷基、3～7元杂环烷基，其中，所述C1-C6烷基、3～7元环烷基、3～7元杂环烷基任选独立地被1个、2个或3个Rj取代；优选地，D为氢、C1-C6烷基。
某一方案中，当X2和X3独立地为N；X4和X1独立地为-CR1-时，B为氮杂环丁烷基(例如)。
某一方案中，当X1和X3(或X2和X4)为-CR1-，R1为C1-C6烷基时，各个Rj独立地为-OR12-3或-SR12-4。
某一方案中，Ri为氢、卤素、羟基或C1-C3烷基；或者，两个Ri和与其相连地原子形成3～7元环烷基或3～7元杂环烷基。
某一方案中，各个Ri独立地为氢、卤素、羟基或C1-C3烷基；或者，两个Ri和与其相连地原子形成3～7元环烷基，例如，Ri为氢或C1-C3烷基，例如C1-C3烷基。某一方案中，Ri为氢。
某一方案中，D为氢、C1-C6烷基或5～12元杂芳基；其中，所述C1-C6烷基和5～12元杂芳基任选独立地被1个、2个或3个Rj取代。
某一方案中，D为氢、3～7元环烷基、C1-C6烷基或5～6元杂芳基，其中，所述C1-C6烷基和5～6元杂芳基任选独立地被1个、2个或3个Rj取代。
某一方案中，D为5～12元杂芳基；其中，所述5～12元杂芳基任选独立地被1个、2个或3个Rj取代。
某一方案中，D为5～6元杂芳基；其中，所述5～6元杂芳基任选独立地被1个、2个或3个Rj取代。
某一方案中，当X2和X3独立地为N；X4和X1独立地为-CR1-时，D为6元杂芳基(例如)；其中，所述6元杂芳基任选独立地被1个、2个或3个Rj取代。
某一方案中，当D为五元杂芳基时，所述五元杂芳基为各个R1独立地为C1-C6烷基或C1-C6烷氧基。
某一方案中，Rj为卤素、C1-C3烷基、OR12-3或SR12-4。
某一方案中，各个Rj独立地为C1-C3烷基、OR12-3或SR12-4，所述C1-C3烷基任选独立地被任选独立地被1个、2个或3个Rk取代，优选地，各个Rj独立地为OR12-3或SR12-4。
某一方案中，各个Rj独立地为卤素、C1-C3烷基、OR12-3或SR12-4。
某一方案中，各个Rj独立地为氢、卤素、C1-C3烷基、3～7元环烷基、-OR12-3或-SR12-4。
某一方案中，各个Rj独立地为氢、卤素、C1-C3烷基、3～7元环烷基、-OR12-3或-SR12-4；所述C1-C3烷基和3～7元环烷基任选独立地被任选独立地被1个、2个或3个Rk取代。
某一方案中，Rj为OR12-3。
某一方案中，各个Rj独立地为OR12-3。
某一方案中，Rj为卤素或C1-C3烷基。
某一方案中，各个Rj独立地为卤素或C1-C3烷基。
某一方案中，当X1和X3独立地为N；X4和X2独立地为-CR1-，各个R1独立地为C1-C6烷基和C1-C6烷氧基时，各个Rj独立地为卤素、3～7元环烷基、OCH2CF3、 或SR12-4。
某一方案中，当为时，各个Rj独立地为OR12-3或SR12-4。
某一方案中，当X1或X4为-CR1-，R1独立地为3～7元杂环烷基或-NR1-1R1-2时，各个Rj独立地为OR12-3或SR12-4。
某一方案中，R12-3和R12-4独立地为C1-C3烷基。
某一方案中，R12-3和R12-4独立地为C1-C3烷基；其中，所述C1-C3烷基任选独立地被1个、2个或3个Rk-1取代。
某一方案中，R12-1、R12-2、R12-3和R12-4独立地为C1-C3烷基。
某一方案中，各个Rk独立地为卤素。
某一方案中，Rk独立地为卤素。
某一方案中，各个Rk-1独立地为卤素。
某一方案中，Rk-1独立地为卤素。
某一方案中，所述3～7元杂环烷基、4～6元杂环烷基和5～12元杂芳基中，杂原子为N、O或S，杂原子数为1～3个。
某一方案中，所述3～7元杂环烷基、4～6元杂环烷基和5～12元杂芳基中，杂原子为N、O或S，杂原子数为1～5个。
某一方案中，所述3～7元杂环烷基、4～6元杂环烷基、5～6元杂芳基和5～12元杂芳基中，杂原子为N、O或S，杂原子数为1～3个。
某一方案中，所述3～7元杂环烷基、4～6元杂环烷基、5～6元杂芳基和和5～12元杂芳基中，杂原子选自N、O或S中1种、2种或3种，杂原子数为1个、2个或3个。
某一方案中，所述3～7元杂环烷基为3-6元杂环烷基，杂原子例如为N和O中1种或2种，杂原子数例如为1个或2个。
某一方案中，所述4～6元杂环烷基为4元杂环烷基，杂原子例如为N和O中1种或2种，杂原子数例如为1个。
某一方案中，所述5～6元杂芳基为6元杂芳基，杂原子例如为N和O中1种或2种，杂原子数例如为1个。
某一方案中，所述5～12元杂芳基为5-10元杂环烷基，杂原子例如为N和O中1种或2种，杂原子数例如为1个。
某一方案中，当A为X1、X2和X3为CR1时，所述式I所示化合物中，E或F为
某一方案中，RN-1中，所述C1-C6烷基优选为C1-C3烷基，例如甲基、乙基、正丙基或异丙基，又如为甲基、乙基或异丙基。
某一方案中，RN-1中，所述C1-C6烷氧基优选为C1-C3烷氧基，例如甲氧基、乙氧基、正丙氧基或异丙氧基。
某一方案中，RN-1中，所述3～7元环烷基优选为3～6元环烷基，例如环丙烷基、环丁烷基或环戊烷基。
某一方案中，RN-2中，所述卤素为F、Cl、Br或I，例如F或Cl。
某一方案中，R1中，所述卤素为F、Cl、Br或I，例如F或Cl，又如为Cl。
某一方案中，R1中，所述C1-C6烷基优选为C1-C3烷基，例如甲基、乙基、正丙基或异丙基，又如为甲基、乙基或异丙基。
某一方案中，R1中，所述C1-C6烷氧基优选为C1-C3烷氧基，例如甲氧基、乙氧基、正丙氧基或 异丙氧基，又如为甲氧基或乙氧基。
某一方案中，R1中，所述C1-C6烷硫基优选为C1-C3烷硫基，例如甲硫基、乙硫基、正丙硫基或异丙硫基，又如为甲硫基。
某一方案中，R1中，所述3～7元环烷基优选为3～6元环烷基，例如环丙烷基、环丁烷基或环戊烷基，又如环丙烷基或环丁烷基。
某一方案中，R1中，所述3～7元杂环烷基优选为3～6元杂环烷基；所述3～6元杂环烷基中杂原子优选为N或O；所述3～6元杂环烷基中杂原子数优选为1个或2个；所述3～6元杂环烷基更优选为4元杂环烷基，例如
某一方案中，R1中，所述3～7元杂环烷基优选为3～6元杂环烷基；所述3～6元杂环烷基中杂原子优选为N或O；所述3～6元杂环烷基中杂原子数优选为1个或2个；所述3～6元杂环烷基更优选为4元杂环烷基，例如
某一方案中，Ra中，所述卤素为优选F、Cl、Br或I，例如F或Cl，又如F。
某一方案中，Ra中，所述C1-C3烷基优选为甲基、乙基、正丙基或异丙基。
某一方案中，Ra中，所述C1-C6烷氧基优选为C1-C3烷氧基，例如甲氧基、乙氧基、正丙氧基或异丙氧基，又如甲氧基。
某一方案中，Ra中，所述3～7元杂环烷基优选为3～6元杂环烷基；所述3～6元杂环烷基中杂原子优选为N或O；所述3～6元杂环烷基中杂原子数优选为1个或2个；所述3～6元杂环烷基更优选为4元杂环烷基，例如
某一方案中，Ra中，所述3～7元环烷基优选为3～6元环烷基，例如环丙烷基、环丁烷基或环戊烷基。
某一方案中，R1-1和R1-2中，所述C1-C6烷基优选为C1-C3烷基，例如甲基、乙基、正丙基或异丙基，又如甲基或乙基(例如甲基)。
某一方案中，R1-1和R1-2中，所述3～7元杂环烷基优选为3～6元杂环烷基；所述3～6元杂环烷基中杂原子优选为N或O；所述3～6元杂环烷基中杂原子数优选为1个或2个；所述3～6元杂环烷基例如4元杂环烷基，又如
某一方案中，Rb中，所述卤素优选为F、Cl、Br或I，例如F或Cl。
某一方案中，Rb中，所述C1-C6烷氧基优选为C1-C3烷氧基，例如甲氧基、乙氧基、正丙氧基或 异丙氧基。
某一方案中，Rb中，所述3～7元环烷基优选为3～6元环烷基，例如环丙烷基、环丁烷基或环戊烷基，又如环丙烷基。
某一方案中，Rb中，所述3～7元杂环烷基优选为3～6元杂环烷基；所述3～6元杂环烷基中杂原子优选为N或O；所述3～6元杂环烷基中杂原子数优选为1个或2个。
某一方案中，Rb中，所述C1-C3烷基优选为甲基、乙基、正丙基或异丙基，例如甲基。
某一方案中，Rb-1中，所述卤素优选为F、Cl、Br或I，例如F或Cl。
某一方案中，Rb-2中，所述卤素优选为F、Cl、Br或I，例如F。
某一方案中，Rb-2中，所述C1-C6烷基优选为C1-C3烷基，例如甲基、乙基、正丙基或异丙基，又如甲基(例如)。
某一方案中，R1-4和R1-5中，所述C1-C3烷基优选为甲基、乙基、正丙基或异丙基，例如甲基、乙基或正丙基，又如甲基。
某一方案中，R1-4和R1-5中，所述3～7元杂环烷基优选为3～6元杂环烷基；所述3～6元杂环烷基中杂原子优选为N或O；所述3～6元杂环烷基中杂原子数优选为1个或2个；所述3～6元杂环烷基更优选为4元杂环烷基，例如
某一方案中，R1-1-1和R1-2-1中，所述C1-C3烷基优选为甲基、乙基、正丙基或异丙基。
某一方案中，R1-4-1和R1-1-1-1中，所述卤素优选为F、Cl、Br或I，例如F或Cl，又如为F。
某一方案中，R2和R3中，所述卤素优选为F、Cl、Br或I，例如F或Cl。
某一方案中，R2和R3中，所述C1-C6烷氧基优选为C1-C3烷氧基，例如甲氧基、乙氧基、正丙氧基或异丙氧基。
某一方案中，R2和R3中，所述3～7元环烷基优选为3～6元环烷基，例如环丙烷基、环丁烷基或环戊烷基。
某一方案中，R2和R3中，所述3～7元杂环烷基优选为3～6元杂环烷基；所述3～6元杂环烷基中杂原子优选为N或O；所述3～6元杂环烷基中杂原子数优选为1个或2个。
某一方案中，R2-1和R2-2中，所述C1-C6烷基优选为C1-C3烷基，例如甲基、乙基、正丙基或异丙基，又如甲基或乙基。
某一方案中，R2-1与R2-2中，所述3～7元杂环烷基优选为3～6元杂环烷基；所述3～6元杂环烷基中杂原子优选为N或O；所述3～6元杂环烷基中杂原子数优选为1个或2个。
某一方案中，Rd中，所述卤素优选为F、Cl、Br或I，例如F或Cl。
某一方案中，Rd中，所述C1-C6烷氧基优选为C1-C3烷氧基，例如甲氧基、乙氧基、正丙氧基或异丙氧基。
某一方案中，Rd中，所述3～7元环烷基优选为3～6元环烷基，例如环丙烷基、环丁烷基或环戊烷基。
某一方案中，Rd中，所述3～7元杂环烷基优选为3～6元杂环烷基；所述3～7元杂环烷基的杂原子优选为N或O，所述3～6元杂环烷基的杂原子数优选为1个或2个。
某一方案中，Rd中，所述C1-C3烷基优选为甲基、乙基、正丙基或异丙基。
某一方案中，R4、R5和R6中，所述卤素优选为F、Cl、Br或I，例如F或Cl。
某一方案中，R4、R5和R6中，所述C1-C6烷氧基优选为C1-C3烷氧基，例如甲氧基、乙氧基、正丙氧基或异丙氧基。
某一方案中，R4、R5和R6中，所述C1-C6烷基优选为C1-C3烷基，例如甲基、乙基、正丙基或异丙基。
某一方案中，Re中，所述卤素优选为F、Cl、Br或I，例如F或Cl。
某一方案中，Re中，所述C1-C3烷基优选为甲基、乙基、正丙基或异丙基。
某一方案中，Re中，所述C1-C3烷氧基优选为甲氧基、乙氧基、正丙氧基或异丙氧基。
某一方案中，R4-1和R4-2中，所述C1-C6烷基优选为C1-C3烷基，例如甲基、乙基、正丙基或异丙基。
某一方案中，R4-1与R4-2中，所述3～7元杂环烷基优选为3～6元杂环烷基；所述3～6元杂环烷基中杂原子优选为N或O；所述3～6元杂环烷基中杂原子数优选为1个或2个。
某一方案中，Rf中，所述卤素优选为F、Cl、Br或I，例如F或Cl。
某一方案中，Rf中，所述3～7元环烷基优选为3～6元环烷基，例如环丙烷基、环丁烷基或环戊烷基。
某一方案中，Rf中，所述3～7元杂环烷基优选为3～6元杂环烷基；所述3～6元杂环烷基中杂原子优选为N或O；所述3～6元杂环烷基中杂原子数优选为1个或2个。
某一方案中，Rf中，所述C1-C3烷基优选为甲基、乙基、正丙基或异丙基。
某一方案中，Rf中，所述C1-C3烷氧基优选为甲氧基、乙氧基、正丙氧基或异丙氧基。
某一方案中，R4-4和R4-5中，所述C1-C3烷基优选为甲基、乙基、正丙基或异丙基。
某一方案中，t为0～3的自然数，例如0、1、2或3，还例如0、1或2，例如0。
某一方案中，u为0～3的自然数，例如0、1、2或3，还例如0、1或2，例如1。
某一方案中，R8和R9中，所述卤素优选为F、Cl、Br或I，例如F或Cl。
某一方案中，R8和R9中，所述C1-C6烷基优选为C1-C3烷基，例如甲基、乙基、正丙基或异丙基，又如甲基。
某一方案中，R8和R9中，所述3～7元环烷基优选为3～6元环烷基，例如环丙烷基、环丁烷基或环戊烷基，又如环丙烷基。
某一方案中，R8和R9中，所述3～7元杂环烷基优选为3～6元杂环烷基；所述3～6元杂环烷基中杂原子优选为N或O；所述3～6元杂环烷基中杂原子数优选为1个或2个，所述3～6元杂环烷基例 如4元杂环烷基，又如为氧杂环丁烷。
某一方案中，Rg中，所述卤素优选为F、Cl、Br或I，例如F或Cl。
某一方案中，Rg中，所述C1-C3烷基优选为甲基、乙基、正丙基或异丙基，例如甲基。
某一方案中，Rg中，所述C1-C3烷氧基优选为甲氧基、乙氧基、正丙氧基或异丙氧基。
某一方案中，B中，所述3～7元环烷基优选为3～6元环烷基，例如环丙烷基、环丁烷基或环戊烷基。
某一方案中，B中，所述4～7元环烷基优选为3～6元环烷基，例如环丁烷基或环戊烷基。
某一方案中，B中，所述4～6元杂环烷基优选为4元杂环烷基、5元杂环烷基或6元杂环烷基；所述4元杂环烷基、5元杂环烷基和6元杂环烷基中杂原子优选为N；所述4～6元杂环烷基中杂原子数优选为1个或2个，例如，所述4～6元杂环烷基为4元氮杂环烷基(例如)或5元氮杂环烷基(例如)。
某一方案中，B中，所述6～10元芳基优选为苯基或萘基，例如苯基。
某一方案中，Ri中，所述卤素优选为F、Cl、Br或I，例如F或Cl，又如为F。
某一方案中，Ri中，所述C1-C3烷基优选为甲基、乙基、正丙基或异丙基，又如为甲基。
某一方案中，Ri中，所述3～7元环烷基优选为3～6元环烷基，例如环丙烷基、环丁烷基或环戊烷基，又如为环丙烷基或环丁烷基，例如环丙烷基。
某一方案中，Ri中，所述3～7元杂环烷基优选为3～6元杂环烷基；所述3～6元杂环烷基中杂原子优选为N或O；所述3～6元杂环烷基中杂原子数优选为1个或2个。
某一方案中，Ri-1中，所述卤素优选为F、Cl、Br或I，例如F或Cl。
某一方案中，Ri-1中，所述C1-C3烷基优选为甲基、乙基、正丙基或异丙基。
某一方案中，R11-1、R11-2、R11-3和R11-4中，所述C1-C3烷基例如甲基、乙基、正丙基或异丙基。
某一方案中，R11-3和R11-4中，所述3～7元环烷基可为3～6元环烷基，例如环丙烷基、环丁烷基或环戊烷基。
某一方案中，R11-3和R11-4中，所述3～7元杂环烷基优选为3～6元杂环烷基；所述3～6元杂环烷基中杂原子优选为N或O；所述3～6元杂环烷基中杂原子数优选为1个或2个。
某一方案中，R11-1和R11-2中，所述3～7元环烷基优选为3～6元环烷基，例如环丙烷基、环丁烷基或环戊烷基。
某一方案中，R11-1和R11-2中，所述3～7元杂环烷基优选为3～6元杂环烷基；所述3～6元杂环烷基中杂原子优选为N或O；所述3～6元杂环烷基中杂原子数优选为1个或2个。
某一方案中，Ri-2中，所述卤素优选为F、Cl、Br或I，例如F或Cl。
某一方案中，Ri-2中，所述C1-C3烷基优选为甲基、乙基、正丙基或异丙基。
某一方案中，Ri-2中，所述3～7元环烷基优选为3～6元环烷基，例如环丙烷基、环丁烷基或环戊 烷基。
某一方案中，Ri-2中，所述3～7元杂环烷基优选为3～6元杂环烷基；所述3～6元杂环烷基中杂原子优选为N或O；所述3～6元杂环烷基中杂原子数优选为1个或2个。
某一方案中，D中，所述卤素优选为F、Cl、Br或I，例如F或Cl。
某一方案中，D中，所述C1-C6烷基优选为C1-C3烷基，例如甲基、乙基、正丙基或异丙基，又如甲基。
某一方案中，D中，所述3～7元环烷基优选为3～6元环烷基，例如环丙烷基、环丁烷基或环戊烷基，例如环丙烷基。
某一方案中，D中，所述6～10元芳基为苯基或萘基。
某一方案中，Rj中，所述卤素优选为F、Cl、Br或I，例如F或Cl，又如F。
某一方案中，Rj中，所述C1-C3烷基优选为甲基、乙基、正丙基或异丙基，又如甲基、乙基或异丙基，优选为甲基。
某一方案中，Rj中，所述3～7元环烷基优选为3～6元环烷基，例如环丙烷基、环丁烷基或环戊烷基，又如环丙烷基。
某一方案中，Rj中，所述3～7元杂环烷基优选为3～6元杂环烷基；所述3～6元杂环烷基中杂原子优选为N或O；所述3～6元杂环烷基中杂原子数优选为1个或2个。
某一方案中，R12-1、R12-2、R12-3和R12-4中，所述C1-C3烷基优选为甲基、乙基、正丙基或异丙基，例如甲基或乙基，又如甲基、乙基或异丙基。
某一方案中，R12-1、R12-2、R12-3和R12-4中，所述3～7元环烷基优选为3～6元环烷基，例如环丙烷基、环丁烷基或环戊烷基。
某一方案中，R12-1、R12-2、R12-3和R12-4中，所述3～7元杂环烷基优选为3～6元杂环烷基；所述3～6元杂环烷基中杂原子优选为N或O；所述3～6元杂环烷基中杂原子数优选为1个或2个。
某一方案中，Rk中，所述卤素优选为F、Cl、Br或I，例如F或Cl，又如F。
某一方案中，Rk中，所述C1-C3烷基优选为甲基、乙基、正丙基或异丙基。
某一方案中，Rk中，所述3～7元环烷基优选为3～6元环烷基，例如环丙烷基、环丁烷基或环戊烷基。
某一方案中，Rk中，所述3～7元杂环烷基优选为3～6元杂环烷基；所述3～6元杂环烷基中杂原子优选为N或O；所述3～6元杂环烷基中杂原子数优选为1个或2个。
某一方案中，Rk-1中，所述卤素优选为F、Cl、Br或I，例如F或Cl，又如F。
某一方案中，Rk-1中，所述C1-C3烷基优选为甲基、乙基、正丙基或异丙基，例如甲基。
某一方案中，Rk-1中，所述3～7元环烷基优选为3～6元环烷基，例如环丙烷基、环丁烷基或环戊烷基。
某一方案中，Rk-1中，所述3～7元杂环烷基优选为3～6元杂环烷基；所述3～6元杂环烷基中杂原子优选为N或O；所述3～6元杂环烷基中杂原子数优选为1个或2个。
一些方案中，所述式I所示的化合物为式I-1所示的化合物、式I-2所示的化合物、式I-3所示的化合物、式I-4所示的化合物或式I-5所示的化合物；
其中，X6为N或CH，X1、Ri、X2、X3、X4、X5、Y、Z、m、n、E、Rj、R1、B、D、W、k、F、u、R8和R9如本发明任一项所述。
一些方案中，所述式I-1所示的化合物为式I-1-1所示化合物、式I-1-2所示化合物、式I-1-3所示化合物或式I-1-4所示化合物；
其中，R1、Rj、Z、n、X6、X2和X4如本发明任一项所述。
一些方案中，所述式I-5所示的化合物为式I-5-1所示化合物；
其中，R1、R8、R9和Rj如本发明任一项所述。
一些方案中，所述式I-4所示的化合物为式I-4-1所示化合物；
其中，B如本发明任一项所述。
某一方案中，X1、X2、X3、X4和X5独立地为-CR1-、N、O、S、或化学键，且X1、X2、X3、X4和X5中杂原子数为0、1、2或3个。
某一方案中，X1、X2、X3、X4和X5独立地为-CR1-、N、S、或化学键，且X1、X2、X3、X4和X5中杂原子数为1或2个。
某一方案中，X1和X3独立地为N；X4和X2独立地为-CR1-。
某一方案中，X2和X3独立地为N；X4和X1独立地为-CR1-。
某一方案中，X1和X4独立地为N；X2和X3独立地为-CR1-。
一些方案中，中，X1、X2、X3和X4独立地为-CR1-或N；杂原子数为0个、1个或2个。
一些方案中，中，Y和Z独立地为羰基(CO)或-(CR2R3)r-；r为1，R2和R3独立地为H、-(CH2)-、-(NHCH2)-、-(NHCH2CH2)-或
一些方案中，中，m为2，n为2，Y和Z独立地为-(CR2R3)r-；r为1，R2和R3独立地为H。
一些方案中，为苯基并5元杂环烷基，其中，所述5元杂环烷基中杂原子为N，杂原子数为1个，例如e独立地为1、2或3，又如
一些方案中，为苯基并5元杂环烷基，其中，所述5元杂环烷基中杂原子为N，杂原子数为1个，例如
一些方案中，为苯基并7元杂环烷基，其中，所述7元杂环烷基中杂原子为N，杂原子数为1或2个，例如e独立地为0、1、2或3，又例如
一些方案中，为苯基并7元杂环烷基，其中，所述7元杂环烷基中杂原子为N，杂原子数为1或2个，例如
一些方案中，为6元杂芳基并5元杂环烷基，其中，所述6元杂芳基中杂原子为N，杂原子数为1或2个，优选地，所述5元杂环烷基中杂原子为N，杂原子数为1个，例如 e独立地为0、1或2，又例如
一些方案中，为6元杂芳基并5元杂环烷基，其中，所述6元杂芳基中杂原子为N，杂原子数为1或2个，优选地，所述5元杂环烷基中杂原子为N，杂原子数为1个，例如
一些方案中，为6元杂芳基并5元杂环烷基，其中，所述6元杂芳基中杂原子为N，杂原子数为2个，优选地，所述5元杂环烷基中杂原子为N，杂原子数为1个，例如 e独立地为0、1或2。
一些方案中，为6元杂芳基并5杂环烷基，其中，所述6元杂芳基中杂原子为N， 杂原子数为1个，例如e独立地为0、1、2或3，又例如
一些方案中，为6元杂芳基并5杂环烷基，其中，所述6元杂芳基中杂原子为N，杂原子数为1个，例如
一些方案中，为6元杂芳基并6元杂环烷基，其中，所述6元杂芳基中杂原子为N，杂原子数为1个，优选地，所述6元杂环烷基中杂原子为N，杂原子数为1个，例如e独立地为0、1、2或3，又例如
一些方案中，为6元杂芳基并6元杂环烷基，其中，所述6元杂芳基中杂原子为N，杂原子数为1个，优选地，所述6元杂环烷基中杂原子为N，杂原子数为1个，例如
一些方案中，为6元杂芳基并7元杂环烷基，其中，所述6元杂芳基中杂原子为N，杂原子数为1个或2个，优选地，所述7元杂环烷基中杂原子为N，杂原子数为1个，例如e独立地为0、1、2或3、
一些方案中，为6元杂芳基并7元杂环烷基，其中，所述6元杂芳基中杂原子为N，杂原子数为1个或2个，优选地，所述7元杂环烷基中杂原子为N，杂原子数为1个，例如
一些方案中，为5元杂芳基并5元杂环烷基，其中，所述5元杂芳基中杂原子为N或S，杂原子数为1个或2个，优选地，所述5元杂环烷基中杂原子为N，杂原子数为1个，例如
一些方案中，为5元杂芳基并5元杂环烷基，其中，所述5元杂芳基中杂原子为N和/或S，杂原子数为1个或2个，优选地，所述5元杂环烷基中杂原子为N，杂原子数为1个，例如
一些方案中，为5元杂芳基并6元杂环烷基，其中，所述5元杂芳基中杂原子为N，杂原子数为1个或2个，优选地，所述6元杂环烷基中杂原子为N，杂原子数为1个，例如 又例如
一些方案中，为5元杂芳基并6元杂环烷基，其中，所述5元杂芳基中杂原子为N，杂原子数为1个，优选地，所述6元杂环烷基中杂原子为N，杂原子数为1个，例如又例如
一些方案中，为5元杂芳基并6元杂环烷基，其中，所述5元杂芳基中杂原子为N，杂原子数为1个，优选地，所述6元杂环烷基中杂原子为N，杂原子数为1个，例如
一些方案中，中，X1、X2、X3、X4和X5独立地为-CR1-、N、S、或化学键，且X1、X2、X3、X4和X5中杂原子数为0、1或2个。
一些方案中，为C-(W)k-,其中，C为C为5元杂芳基、6元杂芳基或苯基；优选地，所述5元杂芳基中杂原子为N，杂原子数为1个或2个，或者所述6元杂芳基中杂原子为N，杂原子数为1个，例如所述C为吡啶基、苯基或
一些方案中，中，W为-O-、-CH2-或-NH-。
一些方案中，B中，所述5～12元杂芳基优选为5～6元杂芳基、苯基并5～6元杂芳基、5～7元环烷基并苯基、5～7元环烷基并5～6元杂芳基、5～6元杂芳基并5～6元杂芳基、5～7元杂环烷基并5～6元杂芳基或5～7元杂环烷基并5～6元芳基；进一步优选为5～6元杂芳基、苯基并5～6元杂芳基、5～6元杂芳基并5～6元杂芳基、5～7元杂环烷基并5～6元杂芳基或5～7元杂环烷基并苯基。
一些方案中，B中，所述4～6元杂环烷基中杂原子为N，杂原子数为1个，例如 e独立地为0、1、2或3，又例如
一些方案中，B中，所述4～6元杂环烷基中杂原子为N，杂原子数为1个，例如
一些方案中，B为被2个Ri取代的4～6元杂环烷基，两个同一原子上的Ri和与其相连地原子形成3～7元环烷基，所述3～7元环烷基优选为3～6元环烷基，例如B为4元杂环烷基或5元杂环烷基，两个Ri形成3～4元环烷基，又如B为
一些方案中，B为被2个Ri取代的4～6元杂环烷基，两个同一原子上的Ri和与其相连地原子形成3～7元环烷基，所述3～7元环烷基优选为3～6元环烷基，例如B为4元杂环烷基，两个Ri形成3～4元环烷基，又如B为
一些方案中，B为被2个Ri取代的4～6元杂环烷基，两个同一原子上的Ri和与其相连地原子形成3～7元环烷基，所述3～7元环烷基优选为3～6元环烷基，例如B为5元杂环烷基，两个Ri形成3～4元环烷基，又如B为
一些方案中，B为被2个Ri邻位取代的4～6元杂环烷基，两个相邻的Ri与其相连的原子形成3～7元环烷基(其中，3～7元环烷基与B形成并环)，所述3～7元环烷基优选为3～6元环烷基，例如B为 5元杂环烷基，两个Ri与其相连的原子形成3元环烷基，又如B为
一些方案中，B为5元杂芳基，其中，所述5元杂芳基中杂原子为N和/或S，杂原子数为1个或2个，例如
一些方案中，B为5元杂芳基，其中，所述5元杂芳基中杂原子为N或S，杂原子数为1个或2个，例如
一些方案中，B为6元杂芳基，其中，所述6元杂芳基中杂原子为N，杂原子数为1个或2个，例如
一些方案中，B中，所述6～10元芳基，例如苯基。
一些方案中，B为苯基并5元杂环烷基，其中，所述5元杂环烷基中杂原子为N，杂原子数为1个，例如e独立地为0、1、2或3，又例如
一些方案中，B为苯基并5元杂环烷基，其中，所述5元杂环烷基中杂原子为N，杂原子数为1个，例如
一些方案中，B为苯基并6元杂芳基，其中，所述6元杂芳基中杂原子为N，杂原子数为1或2个，例如
一些方案中，B为苯基并6元杂环烷基，其中，所述6元杂环烷基中杂原子为N和/或O，杂原 子数为1或2个，例如
一些方案中，B为苯基并6元杂环烷基，其中，所述6元杂环烷基中杂原子为N或O，杂原子数为1或2个，例如
一些方案中，B为6元杂芳基并5元杂芳基，其中，所述6元杂芳基中杂原子为N，杂原子数为1个，优选地，所述5元杂芳基中杂原子为N或S，杂原子数为1个，例如
一些方案中，B为6元杂芳基并6元杂环烷基，其中，所述6元杂芳基中杂原子为N，杂原子数为1个，优选地，所述6元杂环烷基中杂原子为O，杂原子为1个，例如
一些方案中，D中，所述5～12元杂芳基优选为5～6元杂芳基、苯基并5～6元杂芳基、5～7元环烷基并苯基、5～7元环烷基并5～6元杂芳基、5～6元杂芳基并5～6元杂芳基、5～7元杂环烷基并5～6元杂芳基或5～7元杂环烷基并5～6元芳基；进一步优选为5～6元杂芳基、苯基并5～6元杂芳基、5～7元环烷基并5～6元杂芳基、5～6元杂芳基并5～6元杂芳基、5～7元杂环烷基并5～6元杂芳基或5～7元杂环烷基并苯基。
一些方案中，D中，所述5～12元杂芳基为5～6元杂芳基、苯基并5～6元杂芳基、5～7元环烷基并5～6元杂芳基、5～6元杂芳基并5～6元杂芳基、5～7元杂环烷基并5～6元杂芳基或5～7元杂环烷基并苯基，其中，所述5～6元杂芳基和5～7元杂环烷基中，杂原子优选选自N、O和S中1种，2种或3种，杂原子数优选为1个、2个或3个。
一些方案中，D中，所述5～6元杂芳基优选为5元杂芳基或6元杂芳基。
一些方案中，D为氢、甲基、乙基、异丙基、环丙基或三氟甲基。
一些方案中，D为6元杂芳基，其中，所述6元杂芳基中杂原子为N，杂原子数为1个或2个，例如e独立地为0、1、2或3，又例如
一些方案中，D为6元杂芳基，其中，所述6元杂芳基中杂原子为N，杂原子数为1个或2个，例如
一些方案中，D为5元杂芳基，其中，所述5元杂芳基中杂原子为N、O和S中一种或多种，杂原子数为1个、2个或3个，例如
一些方案中，D为5元杂芳基，其中，所述5元杂芳基中杂原子为N和/或S，杂原子数为1个、2个或3个，例如
一些方案中，D为5元杂芳基，其中，所述5元杂芳基中杂原子为N或S，杂原子数为1个、2个或3个，例如
一些方案中，D为6元杂芳基并5元杂环烷基，其中，所述6元杂芳基中杂原子为N，杂原子数为1个，优选地，所述5元杂环烷基中杂原子为N或O，杂原子数为1个，例如e独立地为0、1、2或3，又例如
一些方案中，D为6元杂芳基并5元杂环烷基，其中，所述6元杂芳基中杂原子为N，杂原子数 为1个，优选地，所述5元杂环烷基中杂原子为N或O，杂原子数为1个，例如
一些方案中，D为6元杂芳基并5元环烷基，其中，所述6元杂芳基中杂原子为N，杂原子数为1个，例如e独立地为0、1、2或3，又例如
一些方案中，D为6元杂芳基并5元环烷基，其中，所述6元杂芳基中杂原子为N，杂原子数为1个，例如
一些方案中，D为苯基并5元杂芳基，其中，所述5元杂芳基中杂原子为N和/或S，杂原子数为2个，例如为e独立地为0、1、2或3，又例如
一些方案中，D为5-6元杂芳基并5-6元杂芳基，其中，所述5-6元杂芳基中杂原子为N和/或S，杂原子数为1个、2个或3个，例如e独立地为0、1、2或3。
一些方案中，D为5-6元杂芳基并5～6元杂环烷基，其中，所述5-6元杂芳基中杂原子为N，杂原子数为1个、2个或3个，优选地，所述5-6元杂环烷基中杂原子为O，杂原子为1个、2个或3个，例如e独立地为0、1、2或3。
一些方案中，D为苯基并5～6元杂环烷基，其中，所述5-6元杂环烷基中杂原子为O、N和O中一种或多种，杂原子为1个、2个或3个，例如e独立地为0、1、2或3。
一些方案中，D为苯基并5～6元杂芳基，其中，所述5-6元杂芳基中杂原子为N，杂原子数为1 个、2个或3个，例如e独立地为0、1、2或3。
某一实施方案中，优选为6元杂芳基并5元杂环烷基，其中，所述六元杂芳基中杂原子为N，杂原子数为2个，例如 e独立地为0、1或2，又例如
某一实施方案中，优选为6元杂芳基并5元杂环烷基，其中，所述六元杂芳基中杂原子为N，杂原子数为2个，例如
某一实施方案中，优选为6元杂芳基并7元杂环烷基，其中，所述6元杂芳基中杂原子为N，杂原子数为1个或2个，例如
某一实施方案中，L中，E优选为羰基，F为化学键，t为0，u为1。
某一实施方案中，B优选为4元杂环烷基，其中，所述4元杂环烷基中杂原子为N，杂原子数为1个或2个，例如
某一实施方案中，D优选为6元杂芳基，其中，所述6元杂芳基中杂原子为N，杂原子数为1个或2个，例如
某一优选方案中，所述式I所示的化合物或其药学上可接受的盐中，
其中，为
m为0～3的自然数；
n为0～3的自然数；m和n不同时为0；
k为0～3的自然数；
X1、X2、X3、X4和X5独立地为-CR1-、N、S、或化学键；
RN-1为氢、C1-C6烷基或3～7元环烷基；
Y和Z独立地为羰基(CO)或-(CR2R3)r-；r为0～5的自然数；
各个W独立地为-O-、-(CR4R5)-、-NR6-或化学键；
各个R1独立地为氢、卤素、C1-C6烷基、C1-C6烷氧基、C1-C6烷硫基、3～7元环烷基、3～7元杂环烷基或-NR1-1R1-2，其中，所述C1-C6烷硫基、C1-C6烷基和C1-C6烷氧基任选独立地被1个、2个、3个或4个Ra取代；
各个Ra独立地为卤素、羟基、C1-C6烷氧基或-NR1-4R1-5；
R1-1和R1-2独立地为氢或C1-C6烷基，其中所述C1-C6烷基任选独立地被1个、2个、3个或4个Rb取代；或者，R1-1和R1-2与其相连的原子形成3～7元杂环烷基，其中，所述3～7元杂环烷基任性地被1个、2个、3个或4个Rb-2取代；
各个Rb独立地为羟基、3～7元环烷基或C1-C3烷基；
各个Rb-2独立地为卤素或C1-C6烷基；
R1-4和R1-5独立地为氢或C1-C3烷基，其中所述C1-C3烷基任选独立地被1个、2个、3个或4个R1-4-1取代；或者，R1-4和R1-5与其相连的原子形成3～7元杂环烷基；
各个R1-4-1独立地为卤素；
R2和R3独立地为氢或NR2-1R2-2；
R2-1和R2-2独立地为氢或C1-C6烷基；
R4、R5和R6独立地为氢或NR4-1R4-2；
R4-1和R4-2独立地为氢；
L为
t为0～3的自然数；
u为0～3的自然数；
E为羰基、-NHCO-或化学键；
F为羰基、-O-、-NH-或化学键；
R8和R9独立地为氢或C1-C6烷基，或者R8和R9与其相连的原子形成3～7元环烷基或3～7元杂环烷基；
B为4～6元杂环烷基、6～10元芳基或5～12元杂芳基；其中，所述4～6元杂环烷基、6～10元芳基和5～12元杂芳基任选独立地被1个、2个或3个Ri取代；
各个Ri独立地为氢、卤素、羟基或C1-C3烷基；或者，两个同一原子上的Ri和与其相连的原子形成3～7元环烷基；或者，两个相邻的Ri与其相连的原子形成3～7元环烷基；
D为氢、C1-C6烷基或5～12元杂芳基；其中，所述C1-C6烷基和5～12元杂芳基任选独立地被1个、2个或3个Rj取代；
各个Rj独立地为氢、卤素、C1-C3烷基、3～7元环烷基、-OR12-3或-SR12-4；所述C1-C3烷基和3～7元环烷基任选独立地被任选独立地被1个、2个或3个Rk取代；
R12-3和R12-4独立地为C1-C3烷基；其中，所述C1-C3烷基任选独立地被1个、2个或3个Rk-1取代；
各个Rk独立地为卤素；
各个Rk-1独立地为卤素；
所述3～7元杂环烷基、4～6元杂环烷基和5～12元杂芳基中，杂原子为N、O和S中一种或多种，杂原子数为1～3个。
某一优选方案中，所述式I所示的化合物或其药学上可接受的盐中，
其中，为
m为0～3的自然数；
n为0～3的自然数；m和n不同时为0；
k为0～3的自然数；
X1、X2、X3、X4和X5独立地为-CR1-、N、S、或化学键；
RN-1为C1-C6烷基；
Y和Z独立地为羰基(CO)或-(CR2R3)r-；r为0～5的自然数；
各个W独立地为-(CR4R5)-、-NR6-或化学键；
各个R1独立地为氢、卤素、C1-C6烷基、C1-C6烷氧基、C1-C6烷硫基、3～7元环烷基、3～7元杂环烷基或-NR1-1R1-2，其中，所述C1-C6烷硫基、C1-C6烷基和C1-C6烷氧基任选独立地被1个、2个、3个或4个Ra取代；
各个Ra独立地为羟基、C1-C6烷氧基或-NR1-4R1-5；
R1-1和R1-2独立地为氢或C1-C6烷基，其中，所述C1-C6烷基任选独立地被1个、2个、3个或4个Rb取代；或者，R1-1和R1-2与其相连的原子形成3～7元杂环烷基，其中，所述3～7元杂环烷基任性地被1个、2个、3个或4个Rb-2取代；
各个Rb独立地为3～7元环烷基；
各个Rb-2独立地为卤素或C1-C6烷基；
R1-4和R1-5独立地为C1-C3烷基；
R2和R3独立地为氢或NR2-1R2-2；
R2-1和R2-2独立地为氢；
R4、R5和R6独立地为氢；
L为
t为0～3的自然数；
u为0～3的自然数；
E为羰基、-NHCO-或化学键；
F为化学键；
R8和R9独立地为氢或C1-C6烷基，或者R8和R9与其相连的原子形成3～7元环烷基；
B为4～6元杂环烷基、6～10元芳基或5～12元杂芳基；其中，所述4～6元杂环烷基、6～10元芳基和5～12元杂芳基任选独立地被1个、2个或3个Ri取代；
各个Ri独立地为氢、卤素、羟基或C1-C3烷基；或者，两个同一原子上的Ri和与其相连的原子形成3～7元环烷基；
D为氢、C1-C6烷基或5～12元杂芳基；其中，所述C1-C6烷基和5～12元杂芳基任选独立地被1个、2个或3个Rj取代；
各个Rj独立地为氢、卤素、C1-C3烷基、3～7元环烷基、-OR12-3或-SR12-4；所述C1-C3烷基和3～7元环烷基任选独立地被任选独立地被1个、2个或3个Rk取代；
R12-3和R12-4独立地为C1-C3烷基；其中，所述C1-C3烷基任选独立地被1个、2个或3个Rk-1取代；
各个Rk独立地为卤素；
各个Rk-1独立地为卤素；
所述3～7元杂环烷基、4～6元杂环烷基和5～12元杂芳基中，杂原子为N、O和S中一种或多种，杂原子数为1～3个。
某一优选方案中，所述式I所示的化合物或其药学上可接受的盐中，
其中，为
m为1～3的自然数；
n为1～3的自然数；
k为1～3的自然数；
X1、X2、X3、X4和X5独立地为-CR1-、N、O、S、或化学键，且X1、X2、X3、X4和X5中杂原子数为0、1、2或3个；
RN-1为氢或C1-C6烷基；
Y和Z独立地为羰基(CO)或-(CR2R3)r-；r为1～2的自然数；
各个W独立地为-O-、-(CR4R5)-、-NR6-或化学键；
各个R1独立地为氢、卤素、C1-C6烷基、C1-C6烷氧基、3～7元环烷基、3～7元杂环烷基或-NR1- 1R1-2，其中，所述C1-C6烷基和C1-C6烷氧基任选独立地被1个、2个、3个或4个Ra取代；
各个Ra独立地为羟基、C1-C3烷氧基或NR1-4R1-5；
R1-1和R1-2独立地为氢或C1-C6烷基，其中所述C1-C6烷基任选独立地被1个、2个、3个或4个Rb取代；或者，R1-1和R1-2与其相连的原子形成3～7元杂环烷基；
各个Rb独立地为羟基、3～7元环烷基、3～7元杂环烷基、C1-C3烷基、C1-C3烷氧基或NR1-1-1R1-2- 1，其中，所述3～7元环烷基、3～7元杂环烷基和C1-C3烷基任选独立地被1个、2个、3个或4个Rb- 1取代；
各个Rb-1独立地为羟基；
R1-4和R1-5独立地为氢或C1-C3烷基；其中所述C1-C3烷基任选独立地被1个、2个、3个或4个R1-4-1取代；或者，R1-4和R1-5与其相连的原子形成3～7元杂环烷基；
各个R1-4-1独立地为卤素；
R1-1-1和R1-2-1独立地为氢或C1-C3烷基；
R2和R3独立地为氢或NR2-1R2-2；
R2-1和R2-2独立地为氢或C1-C6烷基；
R4、R5和R6独立地为氢；
L为
t为0～2的自然数；
u为0～2的自然数；
E为羰基、-NHCO-或化学键；
F为-O-、-NH-或化学键；
R8和R9独立地为氢或C1-C6烷基；或者R8和R9与其相连的原子形成3～7元环烷基或3～7元杂环烷基；
B为4～6元杂环烷基、6～10元芳基或5～12元杂芳基；其中，所述5～12元杂芳基、6～10元芳基和4～6元杂环烷基任选独立地被1个、2个或3个Ri取代；
各个Ri独立地为氢、羟基、卤素或C1-C3烷基；或者，两个Ri和与其相连地原子形成3～7元环烷基或3～7元杂环烷基；或者，两个相邻的Ri与其相连的原子形成3～7元环烷基或3～7元杂环烷基(其中，3～7元环烷基或3～7元杂环烷基与B形成并环)；
D为氢、3～7元环烷基、C1-C6烷基或5～12元杂芳基；其中，所述C1-C6烷基和5～12元杂芳基任选独立地被1个、2个或3个Rj取代；
各个Rj独立地为卤素、C1-C3烷基、-OR12-3或-SR12-4；所述C1-C3烷基任选独立地被1个、2个或3个Rk取代；各个Rk独立地为卤素；
R12-3和R12-4独立地为C1-C3烷基；所述C1-C3烷基任选独立地被1个、2个或3个Rk取代；各个Rk独立地为卤素；
所述3～7元杂环烷基、4～6元杂环烷基和5～12元杂芳基中，杂原子为N、O或S，杂原子数为1～3个；或者，所述3～7元杂环烷基、4～6元杂环烷基和5～12元杂芳基中，杂原子为N、O和S中一种或多种，杂原子数为1～3个。
某一优选方案中，所述式I所示的化合物或其药学上可接受的盐中，
其中，为
m为1～3的自然数；
n为1～3的自然数；
X1、X2、X3和X4独立地为-CR1-、N、S、或化学键，且X1、X2、X3、X4和X5中杂原子数为1或2个；
RN-1为C1-C6烷基；
Y和Z独立地为羰基(CO)或-(CR2R3)r-；r为1～2的自然数；
各个R1独立地为氢、卤素、C1-C6烷基、C1-C6烷氧基、3～7元环烷基、3～7元杂环烷基或-NR1- 1R1-2，其中，所述C1-C6烷基和C1-C6烷氧基任选独立地被1个、2个、3个或4个Ra取代；
各个Ra独立地为羟基、C1-C3烷氧基或NR1-4R1-5；
R1-1和R1-2独立地为氢或C1-C6烷基，其中所述C1-C6烷基任选独立地被1个、2个、3个或4个Rb取代；或者，R1-1和R1-2与其相连的原子形成3～7元杂环烷基；
各个Rb独立地为羟基、3～7元环烷基、3～7元杂环烷基、C1-C3烷基、C1-C3烷氧基或NR1-1-1R1-2- 1，其中，所述3～7元环烷基、3～7元杂环烷基和C1-C3烷基任选独立地被1个、2个、3个或4个Rb- 1取代；
各个Rb-1独立地为羟基；
R1-4和R1-5独立地为氢或C1-C3烷基，其中所述C1-C3烷基任选独立地被1个、2个、3个或4个R1-4-1取代；或者，R1-4和R1-5与其相连的原子形成3～7元杂环烷基；
R1-1-1和R1-2-1独立地为氢或C1-C3烷基；
R1-4-1为卤素；
R2和R3独立地为氢；
L为
t为0～2的自然数；
u为0～2的自然数；
E为羰基或化学键；
F为-O-、-NH-或化学键；
R8和R9独立地为C1-C6烷基，或者R8和R9与其相连的原子形成3～7元环烷基或3～7元杂环烷基；
B为4～6元杂环烷基或5～12元杂芳基；其中，所述5～12元杂芳基和4～6元杂环烷基任选独立地被1个、2个或3个Ri取代；
各个Ri独立地为氢、羟基、卤素或C1-C3烷基；或者，两个Ri和与其相连地原子形成3～7元环烷基或3～7元杂环烷基；或者，两个相邻的Ri与其相连的原子形成3～7元环烷基或3～7元杂环烷基(其中，3～7元环烷基或3～7元杂环烷基与B形成并环)；
D为氢、3～7元环烷基、C1-C6烷基或5～6元杂芳基；其中，所述C1-C6烷基和5～6元杂芳基任选独立地被1个、2个或3个Rj取代；
各个Rj独立地为卤素或C1-C3烷基；所述C1-C3烷基任选独立地被1个、2个或3个Rk取代；各个Rk独立地为卤素；
所述3～7元杂环烷基、4～6元杂环烷基、5～6元杂芳基和5～12元杂芳基中，杂原子为N、O或S，杂原子数为1～3个；或者，所述3～7元杂环烷基、4～6元杂环烷基、5～6元杂芳基和5～12元杂芳基中，杂原子为N、O和S中一种或多种，杂原子数为1～3个。
某一优选方案中，所述式I所示的化合物或其药学上可接受的盐中，
其中，为
m为1～2的自然数；
n为1～2的自然数；
k为1～3的自然数；
X1、X2、X3、X4和X5独立地为-CR1-、N、O、S、或化学键，且X1、X2、X3、X4和X5中杂原子数为0、1、2或3个；
RN-1为C1-C6烷基；
各个W独立地为-(CR4R5)-、-O-、-NR6-或化学键；Y和Z独立地为羰基(CO)或-(CR2R3)r-；r为1～2的自然数；
各个R1独立地为氢、卤素、C1-C6烷基、C1-C6烷氧基、3～7元环烷基、3～7元杂环烷基或-NR1- 1R1-2，其中，所述C1-C6烷基和C1-C6烷氧基任选独立地被1个、2个、3个或4个Ra取代；
各个Ra独立地为羟基、C1-C3烷氧基或NR1-4R1-5；
R1-1和R1-2独立地为氢或C1-C6烷基，其中所述C1-C6烷基任选独立地被1个、2个、3个或4个Rb取代；或者，R1-1和R1-2与其相连的原子形成3～7元杂环烷基；
各个Rb独立地为羟基、3～7元环烷基、3～7元杂环烷基、C1-C3烷基、C1-C3烷氧基或NR1-1-1R1-2- 1，其中，所述3～7元环烷基、3～7元杂环烷基和C1-C3烷基任选独立地被1个、2个、3个或4个Rb- 1取代；
各个Rb-1独立地为羟基；
R1-4和R1-5独立地为氢或C1-C3烷基，其中所述C1-C3烷基任选独立地被1个、2个、3个或4个R1-4-1取代；或者，R1-4和R1-5与其相连的原子形成3～7元杂环烷基；
R1-1-1和R1-2-1独立地为氢或C1-C3烷基；
各个R1-4-1独立地为卤素；
R2和R3独立地为氢或NR2-1R2-2；
R2-1和R2-2独立地为氢或C1-C6烷基；
R4、R5和R6独立地为氢；L为
t为0～2的自然数；
u为0～2的自然数；
E为羰基、-NHCO-或化学键；
F为-O-、-NH-或化学键；
R8和R9独立地为氢或C1-C6烷基；或者R8和R9与其相连的原子形成3～7元环烷基或3～7元杂环烷基；
B为4～6元杂环烷基、6～10元芳基或5～12元杂芳基；其中，所述5～12元杂芳基、6～10元芳基和4～6元杂环烷基任选独立地被1个、2个或3个Ri取代；
各个Ri独立地为氢、羟基、卤素或C1-C3烷基；或者，两个Ri和与其相连地原子形成3～7元环烷基或3～7元杂环烷基；或者，两个相邻的Ri与其相连的原子形成3～7元环烷基或3～7元杂环烷基(其中，3～7元环烷基或3～7元杂环烷基与B形成并环)；
D为氢、C1-C6烷基或5～12元杂芳基；其中，所述C1-C6烷基和5～12元杂芳基任选独立地被1个、2个或3个Rj取代；
各个Rj独立地为卤素、C1-C3烷基、OR12-3或SR12-4；所述C1-C3烷基任选独立地被1个、2个或3个Rk取代；各个Rk独立地为卤素；
R12-3和R12-4独立地为C1-C3烷基，其中，所述C1-C3烷基任选独立地被1个、2个或3个Rk-1取代；各个Rk-1独立地为卤素；所述3～7元杂环烷基、4～6元杂环烷基和5～12元杂芳基中，杂原子为N、O或S，杂原子数为1～3个；或者，所述3～7元杂环烷基、4～6元杂环烷基和5～12元杂芳基中，杂原子为N、O和S中一种或多种，杂原子数为1～3个。
某一优选方案中，所述式I所示的化合物或其药学上可接受的盐中，
其中，为
m为1；
n为1；
X1、X2、X3和X4独立地为-CR1-或N，且X1、X2、X3和X4中杂原子数为2个；
Y和Z独立地为-(CR2R3)r-；r为1；
各个R1独立地为C1-C6烷基(例如甲基)或C1-C6烷氧基(例如甲氧基)；
R2和R3独立地为氢；
L为
t为0；
u为1；
E为羰基；
F为化学键；
B为4～6元杂环烷基；其中，所述4～6元杂环烷基任选独立地被1个、2个或3个Ri取代；
各个Ri独立地为氢；
D为5～12元杂芳基；其中，所述5～12元杂芳基任选独立地被1个、2个或3个Rj(例如1个)取代；
各个Rj独立地为-OR12-3；
R12-3为C1-C3烷基(例如乙基或异丙基)；所述C1-C3烷基任选独立地被1个、2个或3个Rk取代；各个Rk独立地为卤素(例如F)；
所述4～6元杂环烷基和5～12元杂芳基中，杂原子为N、O或S，杂原子数为1～3个；或者，所述4～6元杂环烷基和5～12元杂芳基中，杂原子为N、O和S中一种或多种，杂原子数为1～3个；
当A为时，X1、X2和X4中杂原子数为1个或2个；
当A为且L为羰基时，u为1～3的自然数，B为4～6元杂环烷基，所述4～6元杂环烷基任选独立地被1个、2个或3个Ri取代。
某一优选方案中，所述式I所示的化合物或其药学上可接受的盐中，
其中，为
m为1；
n为1；
X2和X3为N；
X1和X4独立地为-CR1-；
Y和Z独立地为-(CR2R3)r-；r为1；
各个R1独立地为氢、卤素、C1-C6烷基、C1-C6烷氧基、3～7元环烷基、3～7元杂环烷基或-NR1- 1R1-2；其中，所述C1-C6烷基和C1-C6烷氧基任选独立地被1个、2个、3个或4个Ra取代；
R1-1和R1-2独立地为氢或C1-C6烷基；或者，R1-1和R1-2与其相连的原子形成3～7元杂环烷基；
各个Ra独立地为羟基、C1-C6烷氧基或NR1-4R1-5；
R1-4和R1-5独立地为氢或C1-C3烷基；
R2和R3独立地为氢；
L为
t为0；
u为1；
E为羰基；
F为化学键；
B为4～6元杂环烷基；其中，所述4～6元杂环烷基任选独立地被1个、2个或3个Ri取代；
各个Ri独立地为氢、卤素、羟基或C1-C3烷基；
D为5～12元杂芳基；其中，所述5～12元杂芳基任选独立地被1个、2个或3个Rj取代；优选地，D为5～6元杂芳基；其中，所述5～6元杂芳基任选独立地被1个、2个或3个Rj取代；所述5～6元杂芳基中，杂原子选自N、S和O中1种、2种或3种，杂原子数为1个、2个或3个；
各个Rj独立地为H、卤素、C1-C3烷基、OR12-3或SR12-4；其中，所述C1-C3烷基任选独立地被任选独立地被1个、2个或3个Rk取代；
R12-3和R12-4独立地为C1-C3烷基；所述C1-C3烷基任选独立地被1个、2个或3个Rk-1取代；
各个Rk独立地为卤素或C1-C3烷基；
各个Rk-1独立地为卤素或C1-C3烷基；
所述3～7元杂环烷基、4～6元杂环烷基和5～12元杂芳基中，杂原子为N、O和S中的一种或多种，杂原子数为1～3个。
某一优选方案中，所述式I所示的化合物或其药学上可接受的盐中，
其中，为
m为1；
n为1；
X1和X3为N；
X2和X4独立地为-CR1-；
Y和Z独立地为-(CR2R3)r-；r为1；
各个R1独立地为氢、卤素、氰基、羟基、C1-C6烷基、C1-C6烷氧基、C1-C6烷硫基、3～7元环烷基、3～7元杂环烷基或-NR1-1R1-2；其中，所述C1-C6烷基、C1-C6烷氧基和C1-C6烷硫基任选独立地被1个、2个、3个或4个Ra取代；
R1-1和R1-2独立地为氢或C1-C6烷基；或者，R1-1和R1-2与其相连的原子形成3～7元杂环烷基；
各个Ra独立地为羟基、C1-C6烷氧基或NR1-4R1-5；
R1-4和R1-5独立地为氢或C1-C3烷基；
R2和R3独立地为氢；
L为
t为0；
u为1；
E为羰基；
F为化学键；
B为4～6元杂环烷基；其中，所述4～6元杂环烷基任选独立地被1个、2个或3个Ri取代；
各个Ri独立地为氢、卤素、羟基或C1-C3烷基；或者，两个Ri和与其相连地原子形成3～7元环烷基；
D为5～12元杂芳基；其中，所述5～12元杂芳基任选独立地被1个、2个或3个Rj取代；优选地，D为5～6元杂芳基；其中，所述5～6元杂芳基任选独立地被1个、2个或3个Rj取代；所述5～6元杂芳基中，杂原子选自N、S和O中1种、2种或3种，杂原子数为1个、2个或3个；
各个Rj独立地为氢、卤素、氰基、羟基、C1-C3烷基、3～7元环烷基、3～7元杂环烷基、-NR12-1R12- 2、-OR12-3或-SR12-4；其中，所述C1-C3烷基、3～7元环烷基和3～7元杂环烷基任选独立地被1个、2个或3个Rk取代；
R12-1、R12-2、R12-4和R12-3独立地为C1-C3烷基；所述C1-C3烷基任选独立地被1个、2个或3个Rk-1取代；
各个Rk独立地为卤素或C1-C3烷基；
各个Rk-1独立地为卤素或C1-C3烷基；
所述3～7元杂环烷基、4～6元杂环烷基和5～12元杂芳基中，杂原子为N、O和S中一种或多种， 杂原子数为1～3个。
某一方案中，各个R1独立地为氢、甲基、乙基、氯、 甲氧基、异丙基、氨基、
某一方案中，各个R1独立地为氢、甲基、乙基、氯、 甲氧基、异丙基、氨基(-NH2)、 三氟甲基、或甲硫基。
优选地，各个R1独立地为甲基、
某一方案中，为
优选地，为
某一方案中，为
某一方案中，L为-(CH2)-、-(CH2)2-、 较佳地，L为 其中表示与A相连。
优选地，L为
某一方案中，L为-(CH2)-、-(CH2)2-、 较佳地，L为 其中表示与A相连。
某一方案中，B为
某一方案中，B为
优选地，B为
某一方案中，B为
某一方案中，D为氢、甲基、 乙基、异丙基、环丙基、三氟甲基或
优选地，D为
某一方案中，D为氢、甲基、 乙基、异丙基、环丙基、三氟甲基或
某一方案中，所述式I所示的化合物为如下任一化合物：
本发明还提供了一种上述式I所示的化合物的制备方法，其可由如下任一方案制备得到：
方案(a):有机溶剂中，催化剂存在下，式II所示的化合物与式III所示的化合物发生如下所示的缩合反应，得到式I所示的化合物；
方案(b):有机溶剂中，催化剂存在下，式IV所示的化合物与式V所示的化合物发生如下所示的缩合反应，得到式I所示的化合物；
方案(C):有机溶剂中，催化剂存在下，式VI所示的化合物与式VII所示的化合物发生如下所示的环化反应，得到式I所示的化合物；
其中，Z为卤素(例如氯或溴)、TsO-、羟基、甲氧基、乙氧基、正丙氧基或异丙氧基；优选地，Z为羟基、甲氧基、乙氧基、正丙氧基或异丙氧基；
A、L、B、D、X1、X2、X3、X4、Y和m如本发明任一项所述。
本发明还提供了一种上述式I所示的化合物的制备方法，其可由如下方案制备得到：
方案(D):有机溶剂中，催化剂存在下，式VIII所示的化合物与式VIIII所示的化合物发生如下所示的环化反应，得到式I所示的化合物；
其中，Z、A、L、B、D如本发明任一项所述。
本发明还提供了一种药物组合物，其包含治疗有效量的物质A和药用辅料；所述物质A为上述的式I所示的化合物或其药学上可接受的盐。
本发明还提供了一种物质A在制备毒蕈碱受体正向变构调节剂中的应用，所述物质A为上述的式I所示的化合物或其药学上可接受的盐或上述药物组合物。
本发明还提供了一种物质A在制备药物中的应用，所述药物用于治疗和/或预防毒蕈碱受体介导的疾病，所述物质A为上述的式I所示的化合物或其药学上可接受的盐或上述药物组合物；优选地，所述疾病为帕金森病、阿尔兹海默症、亨廷顿舞蹈症、精神分裂症、药物成瘾或疼痛。
本发明还提供了一种物质A在制备药物中的应用，所述药物用于治疗帕金森病、阿尔兹海默症、亨廷顿舞蹈症、精神分裂症、药物成瘾或疼痛。
本发明的积极进步效果在于：本发明化合物可作为毒蕈碱受体正向变构调节剂，本明化合物可治疗M受体(毒蕈碱受体)介导的(或M受体相关的)疾病。
术语解释：
术语“-”是指该基团通过该位点与分子其余部分相连。例如，“CH3O-”是指烷氧基。
术语(中的)是指该结构片段通过该位点与分子其余部分相连。
术语“药学上可接受”是指相对无毒、安全、适合于患者使用。
术语“药学上可接受的盐”是指化合物与药学上可接受的酸或碱反应得到的盐。当化合物中含有相对酸性的官能团时，可以通过在合适的惰性溶剂中用足量的药学上可接受的碱与化合物接触的方式获得碱加成盐。药学上可接受的碱加成盐包括但不限于：锂盐、钠盐、钾盐、钙盐、铝盐、镁盐、锌盐、铋盐、铵盐、二乙醇胺盐。当化合物中含有相对碱性的官能团时，可以通过在合适的惰性溶剂中用足量的药学上可接受的酸与化合物接触的方式获得酸加成盐。所述药学上可接受的酸包括无机酸、有机酸(例如三氟乙酸、盐酸、甲酸)。具体可参见Handbook of Pharmaceutical Salts:Properties,Selection,and Use(P.Heinrich Stahl,Camille G.Wermuth,2011,2nd Revised Edition)，例如甲酸盐。
术语“药用辅料”是指除活性药物成分以外，包含在药物制剂中的所有物质，一般分为赋形剂和附加剂两大类。具体可参见《中华人民共和国药典(2020年版)》、Handbook of Pharmaceutical Excipients(Paul J Sheskey,Bruno C Hancock,Gary P Moss,David J Goldfarb,2020,9th Edition)。
术语“治疗”是指消除病因或缓解症状。
术语“预防”是指降低发生疾病的风险。
术语“患者”是指需要接受治疗或预防疾病的任何动物，通常是哺乳动物，例如人类。哺乳动物包括但不限于：牛、马、羊、猪、猫、狗、小鼠、大鼠、家兔、豚鼠、猴、人类等。
术语“治疗有效量”是指给予患者的、足以有效治疗疾病的化合物的量。治疗有效量将根据化合物种类、疾病种类、疾病的严重度、患者的年龄等变化，但可由本领域技术人员视情况调整。
表述“被一个或多个基团A取代的基团B”是指基团B中的一个或多个氢原子独立地被基团A替代。当同时出现多个A基团时，如无特别说明，它们的定义互相独立、互不影响。
术语“卤素”是指氟、氯、溴或碘。
术语“氧代基”是指＝O，氧原子替代同一原子上的两个氢，例如，亚甲基(-(CH2-)被氧代后为羰基(-C(＝O)-)。
术语“烷基”是指具有指定碳原子数的、直链或支链的、饱和的一价烃基。例如，C1-C6烷基(C1-6烷基)或C4-C20烷基(C4-20烷基)，优选C1-C4烷基(C1-4烷基)或C9-C15烷基(C1-6烷基)。烷基包括但不限于：甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基。
术语“烷基-O-”中，烷基的定义如上所述。烷基-O-的实例如C1-C6烷基-O-或C1-C4烷基-O-，更例如：CH3-O-、CH3CH2-O-、CH3CH2CH2-O-或CH3CH(CH3)-O-等。同样地，本申请中其余“Rx-O-”形式的表述，Rx的定义均为其各自对应的定义所述，例如“环烷基-O-”中环烷基的定义如下述“环烷基”所述。
术语“烷基-S-”中，烷基的定义如上所述。烷基-S-的实例如C1-C6烷基-S-或C1-C4烷基-S-，更例如：CH3-S-、CH3CH2-S-、CH3CH2CH2-S-或CH3CH(CH3)-S-等。同样地，本申请中其余“Rx-S-”形式的表述，Rx的定义均为其各自对应的定义所述，例如“环烷基-S-”中环烷基的定义如下述“环烷基”所述。
术语“烷氧基”是指氧原子连接在烷基一端作为连接键，形成“烷基-O-”。其中，“烷基-O-”的定义 如上所述。
术语“烷硫基”是指硫原子连接在烷基一端作为连接键，形成“烷基-S-”。其中，“烷基-S-”的定义如上所述。
术语“杂芳基”是指具有指定环原子数(例如，5-12元、5-10元或5-6元)的、指定杂原子数(例如，1个、2个或3个)的、指定杂原子种类(N、O和S中的一种或多种)的、环状的、不饱和的一价基团，其具有芳香性。
术语“杂环烷基”是指具有指定环原子数(例如4-12元、4-10元、3-7元、6-10元、4-7元、5-6元)的、指定杂原子数(例如1个、2个或3个)的、指定杂原子种类或杂原子基团(N、O、S、S(＝O)和S(＝O)2中的一种或多种)的饱和杂环烷基或部分不饱和的单环或多环(例如双环、三环或更多环的桥环、并环(稠环)或螺环体系)杂环基。
术语“环烷基”意指饱和的碳环取代基，且其可经由任何适宜的碳原子通过单键与分子的其余部分连接；具有3至7个碳原子的C3-C7环烷基，优选具有3至6个碳原子的C3-C6环烷基，例如环丙基、环丁基、环戊基或环己基等。
术语“芳基”是指具有指定碳原子数(例如，C6-C10)的、环状的、不饱和的一价烃基。芳基的例子包括但不限于：苯基或萘基。
术语“杂芳基”是指具有指定环原子数(例如，5～10元，5-6元)的、指定杂原子数(例如，1个、2个或3个)的、指定杂原子种类(N、O和S中的一种或多种)的、环状的或不饱和的一价基团，其为单环或多环，(至少一个环/每个环均)具有芳香性。杂芳基通过碳原子或杂原子与分子其余部分相连；杂芳基通过具有杂原子的环或不具有杂原子的环与分子其余部分相连；杂芳基通过具有芳香性的环或不具有芳香性的环与分子其余部分相连。
除非另有说明，用楔形实线键和楔形虚线键表示一个立体中心的绝对构型，当原子与其取代基之间用波浪线连接时，则表示或其混合物。
在不违背本领域常识的基础上，上述各优选条件，可任意组合，即得本发明各较佳实例。
本发明所用试剂和原料均市售可得。
缩略词：
PMB：4-甲氧基苄基。
Boc：叔丁氧羰基。
DBU：1,8-二氮杂双环[5.4.0]十一碳-7-烯。
NBS：N-溴代丁二酰亚胺。
DIEA：N,N-二异丙基乙胺。
DMF：N,N-二甲基甲酰胺。
Et：乙基。
Me：甲基。
i-Pr：异丙基。
DMSO：二甲基亚砜。
HATU：2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯。
PyBOP：1H-苯并三唑-1-基氧三吡咯烷基六氟磷酸盐。
TEA三乙胺。
LiHMDS二(三甲基硅基)氨基锂。
NCS：N-氯代丁二酰亚胺。
具体实施方式
下面通过实施例的方式进一步说明本发明，但并不因此将本发明限制在所述实施例范围之中。下列实施例中未注明具体条件的实验方法，按照常规方法和条件，或按照商品说明书选择。
中间体A
合成路线：
第一步
将A-1(5.0g,20.5mmol)溶解在二氯甲烷(10mL)和三氟乙酸(10mL)中,在室温下搅拌2小时。将反应液减压浓缩后得到A-2的三氟乙酸盐。1H NMR(400MHz,DMSO-d6)δ4.13-3.91(m,4H),3.83-3.66(m,2H),3.11-3.03(m,1H),2.74-2.63(m,2H),1.19-1.13(m,3H).ESI-MS理论计算值C7H14NO2[M+H]+＝144.1,实测值144.2。
第二步
将A-2的三氟乙酸盐(5.0g,19.4mmol)和A-3(6.0g,33.5mmol)溶解在二甲基亚砜(10mL)中,依次加入三乙胺(13.4g,132.2mmol)和氟化铯(5.0g,33.0mmol)后升温至80℃下搅拌18小时。将反应液倒入饱和氯化铵溶液(20mL)中，加入二氯甲烷(50mL×1)萃取。有机相用无水硫酸钠干燥、过滤、减压浓缩得到含有目标化合物的粗产品,经硅胶柱层析纯化(石油醚/乙酸乙酯,3/2,v/v)得到A-4。1H NMR(400MHz,DMSO-d6)δ8.21(d,J＝5.64Hz,1H),6.70(d,J＝2.28Hz,1H),6.53-6.48(m,1H),4.17-4.04(m,4H),3.70-3.67(m,2H),3.10-3.01(m,1H),2.76-2.72(m,2H),1.21-1.17(m,3H).ESI-MS理论计算值C13H16F3N2O2[M+H]+＝289.1,实测值289.2。
第三步
将A-4(1.0g,3.5mmol)溶解在四氢呋喃(20mL)和水(4mL)中,加入氢氧化锂(0.22g,5.2mmol)后在室温下搅拌2小时。将反应液pH调至7，加入水(50mL)，冻干，得到含有中间体A的粗产品,直接用于下一步反应。1H NMR(400MHz,DMSO-d6)δ8.25(d,J＝5.64Hz,1H),6.72(d,J＝2.26Hz,1H),6.55(dd,J＝5.64,2.26Hz,1H),4.20-4.12(m,2H),3.74-3.64(m,2H),3.14-3.04(m,1H),2.54-2.50(m,2H).ESI-MS理论计算值C11H11F3N2O2[M+H]+＝261.1,实测值261.0。
中间体G
合成路线：
第一步
将G-1(2.0g,11.3mmol)、NBS(4.2g,23.7mmol)、偶氮二异丁腈(370mg,2.26mmol)依次加入到四氯化碳(25mL)中,反应体系在氮气保护下升温至80℃搅拌16小时。反应液冷却至室温,过滤,减压浓缩得到的油状物用乙酸乙酯(20mL)稀释,饱和硫代硫酸钠溶液(15mL×2)洗涤,无水硫酸钠干燥,过滤,减压浓缩得到含有目标化合物的粗产品,经硅胶柱层析纯化(石油醚/乙酸乙酯,9/1,v/v)得到G-2。ESI-MS理论计算值C6H5Br2Cl2N2[M+H]+＝332.8,实测值332.0。
第二步
将G-2(4.00g,11.9mmol)、碳酸钾(4.9g,35.8mmol)加入到四氢呋喃(4mL)中,在室温下滴加4-甲氧基苄胺的四氢呋喃溶液(1.64g,11.9mmol),继续在室温下搅拌1小时。反应液过滤,减压浓缩得到含有目标化合物的粗产品,经硅胶柱层析纯化(石油醚/乙酸乙酯,9/1,v/v)得到G-3。ESI-MS理论计算值C14H14Cl2N3O[M+H]+＝310.0,实测值310.0。
第三步
将G-3(400mg,1.29mmol)、甲基硼酸(116mg,1.93mmol)、碳酸钾(535mg,3.87mmol)、[1,1'-双(二苯基膦)二茂铁]二氯化钯(189mg,0.26mmol)、1,4-二氧六环(3mL)加入到10mL微波管中,在氮气保护下升温至90℃搅拌18小时。反应液冷却至室温,过滤,加水(15mL)稀释,用乙酸乙酯(5mL×3)萃取,合并有机相,饱和食盐水(20mL)洗涤,无水硫酸钠干燥、过滤,减压浓缩得到含有目标化合物的粗产品,经硅胶柱层析纯化(石油醚/乙酸乙酯,9/1,v/v)得到G-4。ESI-MS理论计算C15H17ClN3O[M+H]+＝290.1,实测值290.0。
第四步
将G-4(130mg,0.45mmol)、杂氮环丁烷(2mL)加入到10mL微波管中,升温至90℃搅拌16小时。反应液冷却至室温,加水(15mL)稀释,用乙酸乙酯(5mL×3)萃取,合并有机相,饱和食盐水(20mL)洗涤,无水硫酸钠干燥、过滤,减压浓缩得到含有目标化合物的粗产品,经硅胶柱层析纯化(石油醚/乙酸乙酯,4/1,v/v)得到G-5。ESI-MS理论计算值C18H23N4O[M+H]+＝311.2,实测值311.2。
第五步
将G-5(120mg,0.39mmol)、三氟乙酸(2mL)加入到5mL微波管中,升温至100℃搅拌8小 时。反应液冷却至室温,加水(15mL)稀释,用饱和碳酸氢钠溶液调节pH至8,用乙酸乙酯(5mL×3)萃取,合并有机相,饱和食盐水(20mL)洗涤,无水硫酸钠干燥、过滤,减压浓缩得到中间体G,直接用于下一步反应。ESI-MS理论计算值C10H15N4[M+H]+＝191.1,实测值191.1。
中间体I
合成路线：
第一步
将G-3(1.5g,4.84mmol)、1,1'-双(二苯基膦)二茂铁]二氯化钯(710mg,0.97mmol)、碳酸钾(2.0g,14.5mmol)、F-2(1.21g,9.67mmol)和1,4-二氧六环(10mL)中,在氮气保护下升温至90℃搅拌18小时。反应液冷却至室温,减压浓缩得到含有目标化合物的粗产品,经硅胶柱层析纯化(石油醚/乙酸乙酯,4/1,v/v)得到I-1。ESI-MS理论计算值C16H20N3O[M+H]+＝270.2,实测值270.1。
第二步
将I-1(120mg,0.45mmol)、三氟乙酸(2mL)加入到5mL微波管中,升温至90℃搅拌8小时。反应液冷却至室温,减压浓缩得到含有中间体I的三氟乙酸盐,直接用于下一步反应。ESI-MS理论计算值C8H12N3[M+H]+＝150.1,实测值150.1。
中间体O
合成路线：
第一步
将O-1(2.0g,15.2mmol)溶解在DMF(20mL)中,依次加入O-2(1.52g,15.2mmol)和氢化钠(60％,1.82g,45.6mmol),升温至60℃搅拌18小时。冷却后向反应液中缓慢加入饱和氯化铵溶液(50mL),乙酸乙酯萃取(70mL×3),合并有机相,用饱和食盐水洗涤(150mL),无水硫酸钠干燥、过滤、减压浓缩得到含有目标化合物的粗产品,经硅胶柱层析纯化(石油醚/乙酸乙酯,4/1,v/v)得到O-3。1H NMR(400MHz,DMSO-d6)δ8.21(d,J＝5.50Hz,1H),7.26(dd,J＝5.50,1.76Hz,1H),7.22(d,J＝1.74Hz,1H),5.09-4.96(m,2H).
第二步
将O-3(650mg,3.07mmol)溶解在DMSO(6mL)中,依次加入中间体A-2(1.1g,3.07mmol)、TEA(1.86g,18.4mmol)、氟化铯(700mg,4.02mmol),升温至100℃搅拌18小时。冷却后向反应液中加入水(30mL),二氯甲烷萃取(30mL×3),合并有机相,用饱和食盐水洗涤(100mL),无水硫酸钠干燥、过滤、减压浓缩得到含有目标化合物的粗产品,经硅胶柱层析纯化(石油醚/乙酸乙酯,4/1,v/v) 得到O-4。1H NMR(400MHz,DMSO-d6)δ7.76(d,J＝5.76Hz,1H),6.14(dd,J＝5.80,1.98Hz,1H),5.77(d,J＝1.96Hz,1H),4.93-4.84(m,2H),4.10-4.01(m,4H),3.61-3.56(m,2H),3.05-2.97(m,1H),2.74-2.68(m,2H),1.20-1.16(m,3H).ESI-MS理论计算值C14H18F3N2O3[M+H]+＝319.1,实测值319.1。
第三步
将O-4(150mg,0.47mmol)溶解在四氢呋喃(4mL)和水(1mL)中,加入氢氧化锂(29mg,0.71mmol),升温至60℃搅拌1小时。冷却后用盐酸(1mol/L)调节反应液pH至7,加水冻干得到含有中间体O的粗产品,直接用于下一步反应。1H NMR(400MHz,DMSO-d6)δ7.73(d,J＝5.80Hz,1H),6.10(dd,J＝5.76,1.98Hz,1H),5.72(d,J＝1.96Hz,1H),4.92-4.84(m,2H),4.01-3.96(m,2H),3.54-3.50(m,2H),2.98-2.88(m,1H),2.35-2.32(m,2H).ESI-MS理论计算值C12H14F3N2O3[M+H]+＝291.1,实测值291.1。
中间体P
合成路线：
第一步
将P-1(500mg,3.72mmol)和A-2(585mg,4.09mmol)溶解在DMSO(5mL)中,加入TEA(1.50g,14.90mmol)和氟化铯(152mg,3.72mmol),升温至100℃搅拌18小时。向反应液中加入饱和氯化铵溶液(20mL),二氯甲烷(20mL×3)萃取,合并有机相,用饱和食盐水洗涤(50mL),无水硫酸钠干燥、过滤、减压浓缩得到含有目标化合物的粗产品,经硅胶柱层析纯化(石油醚/乙酸乙酯,1/1,v/v)得到P-2。1H NMR(400MHz,Chloroform-d)δ4.35-4.27(m,2H),4.19-4.12(m,2H),3.90-3.82(m,2H),3.30-3.17(m,1H),2.73(d,J＝7.84Hz,2H),2.42(s,3H),1.26(t,J＝7.78Hz,3H).ESI-MS理论计算值C10H16N3O2S[M+H]+＝242.1,实测值242.0。
第二步
将P-2(200mg,0.83mmol)溶解在甲醇(2mL)和水(1mL)中,加入氢氧化锂一水合物(35mg,0.83mmol),在室温下搅拌3小时。反应结束后,用稀盐酸(1mol/L)将反应液的pH调至5,减压浓缩后冻干得到含有中间体P的粗产品,直接用于下一步反应。1H NMR(400MHz,Chloroform-d)δ4.39-4.29(m,2H),3.97-3.86(m,2H),3.35-3.22(m,1H),2.78(d,J＝8.00Hz,2H),2.44(s,3H).ESI-MS理论计算值C8H12N3O2S[M+H]+＝214.1,实测值214.0。
中间体Q
合成路线：
第一步
将Q-2(726mg,3.24mmol)溶解在四氢呋喃(20mL)中,冷却至0℃后加入氢化钠(60％,130mg,3.24mmol),搅拌1小时,再加入Q-1(500mg,2.70mmol)在室温下搅拌18小时。反应结束后,用饱和氯化铵溶液(5mL)淬灭,乙酸乙酯萃取(20mL×3)萃取,合并有机相,用饱和食盐水洗涤(50mL),无水硫酸钠干燥、过滤、减压浓缩得到含有目标化合物的粗产品,经硅胶柱层析纯化(石油醚/乙酸乙酯,4/1,v/v)得到Q-3。1H NMR(400MHz,Chloroform-d)δ5.69-5.63(m,1H),5.06-5.01(m,0.3H),4.81-4.76(m,0.7H),4.68-4.50(m,2H),4.15-4.03(m,2H),1.40-1.36(m,12H),1.24-1.15(m,3H).
第二步
将Q-3(500mg,1.96mmol)溶解在甲醇(10mL)中,加入湿钯碳(10％,450mg),反应体系用氢气置换三次后在室温下搅拌1小时。将反应液过滤,滤液减压浓缩,得到Q-4。1H NMR(400MHz,Chloroform-d)δ4.47-4.35(m,0.6H),4.13(q,J＝7.14Hz,2H),4.06-3.87(m,1.4H),3.52-3.48(m,1H),3.02-2.87(m,0.6H),2.61-2.53(m,2H),2.45-2.40(m,0.4H)1.44(s,9H),1.40(d,J＝6.20Hz,1.2H),1.27-1.23(m,4.8H).
第三步
将Q-4(250mg,0.97mmol)溶解在二氯甲烷(5mL)中,加入三氟乙酸(3mL),在室温下搅拌1小时。将反应液减压浓缩得到含有Q-5的粗产品,直接用于下一步反应。ESI-MS理论计算值C8H16NO2[M+H]+＝158.1,实测值158.1。
第四步
将Q-5的三氟乙酸盐(140mg,0.89mmol)和A-3(173mg,0.95mmol)溶解在二甲基亚砜(5mL)中,依次加入TEA(385mg,3.80mmol)和氟化铯(144mg,0.95mmol),升温至100℃下搅拌18小时。将反应液倒入水(20mL)中，加入二氯甲烷(20mL×3)萃取,合并有机相,用饱和食盐水洗涤(50mL),无水硫酸钠干燥、过滤、减压浓缩得到含有目标化合物的粗产品,经硅胶柱层析纯化(石油醚/乙酸乙酯,2/3,v/v)得到Q-6。1H NMR(400MHz,DMSO-d6)δ8.23-8.19(m,1H),6.72(s,1H),6.58(d,J＝5.84Hz,1H),4.53(t,J＝7.24Hz,0.6H),4.23-3.88(m,2.4H),3.77-3.73(m,0.6H),3.51-3.47(m,0.4H),3.18-3.09(m,1H),2.74-2.69(m,3H),1.46(d,J＝6.16Hz,1H),1.31(d,J＝6.52Hz,2H),1.21-1.18(m,3H).ESI-MS理论计算值C14H18F3N2O2[M+H]+＝303.1,实测值303.1。
第五步
将Q-6(180mg,0.57mmol)溶解在四氢呋喃(4mL)和水(1mL)中,加入氢氧化锂一水合物(38mg,0.89mmol),在室温下搅拌3小时。反应结束后,用稀盐酸(1mol/L)将反应液的pH调至5, 加水冻干得到含有中间体Q的粗产品,直接用于下一步反应。ESI-MS理论计算值C12H14F3N2O2[M+H]+＝275.1,实测值275.0。
中间体S
合成路线：
第一步
将S-2(4.54g,61.3mmol)溶解在四氢呋喃(120mL)中,冷却至-78℃,缓慢滴加LiHMDS的四氢呋喃溶液(1.0mol/L,64.3mL,64.3mmol),搅拌10分钟,再加入S-1(10g,58.4mmol),搅拌15分钟。反应体系升温至0℃再搅拌2小时,加入冰水(100mL),乙酸乙酯(100mL×2)萃取,合并有机相,无水硫酸钠干燥、过滤,减压浓缩得到含有S-3的粗产品,直接用于下一步反应。ESI-MS理论计算值C11H20NO5[M-56+H]+＝190.1,实测值190.1。
第二步
将S-3(2.0g,8.15mmol)溶解在二氯甲烷(20mL)中,加入三氟乙酸(20mL),在室温下搅拌3小时。将反应液减压浓缩得到S-4的三氟乙酸盐,直接用于下一步反应。ESI-MS理论计算值C6H12NO3[M+H]+＝146.1,实测值146.2。
第三步
将S-4的三氟乙酸盐(2.0g,13.8mmol)和A-3(2.49g,13.8mmol)溶解在二甲基亚砜(10mL)中,依次加入TEA(5.58g,55.11mmol)和氟化铯(2.1g,13.8mmol),升温至100℃下搅拌18小时。将反应液倒入水(80mL)中，加入二氯甲烷(50mL×3)萃取,合并有机相,用饱和食盐水洗涤(100mL),无水硫酸钠干燥、过滤、减压浓缩得到含有目标化合物的粗产品,经硅胶柱层析纯化(石油醚/乙酸乙酯,3/7,v/v)得到S-5。1H NMR(400MHz,DMSO-d6)δ8.22(d,J＝5.68Hz,1H),6.76(d,J＝2.26Hz,1H),6.62-6.51(m,1H),6.03(s,1H),4.16-4.10(m,2H),3.90-3.85(m,2H),3.60(s,3H),2.82(s,2H).ESI-MS理论计算值C12H14F3N2O3[M+H]+＝291.1,实测值291.1。
第四步
将S-5(130mg,0.45mmol)溶解在四氢呋喃(2mL)和水(0.2mL)中,加入氢氧化锂一水合物(28mg,0.68mmol),在室温下搅拌2小时。反应结束后,用稀盐酸(1mol/L)将反应液的pH调至5,加水冻干得到含有中间体S的粗产品,直接用于下一步反应。ESI-MS理论计算值C11H12F3N2O3[M+H]+＝277.1,实测值277.0。
中间体U
合成路线：
第一步
将U-1(1.0g,5.90mmol)和二氧化锰(6.66g,76.65mmol)加到二氯甲烷(15mL)中,在25℃下搅拌8小时。反应液经硅藻土过滤,滤液减压浓缩得到U-2,直接用于下一步反应。1H NMR(400MHz,Chloroform-d)δ8.74-8.66(m,1H),7.51(d,J＝5.06Hz,1H),3.24-3.17(m,2H),2.88-2.80(m,2H).ESI-MS理论计算值C8H7ClNO[M+H]+＝168.0,实测值168.0。
第二步
将U-2(1.1g,6.56mmol)溶解在二氯甲烷(15mL)中,在0℃下加入二乙胺基三氟化硫(3.7g,22.97mmol),升至室温搅拌18小时。向反应液中加入饱和碳酸氢钠溶液(20mL),二氯甲烷(20mL×1)萃取,合并有机相,无水硫酸钠干燥、过滤、减压浓缩得到含有目标化合物的粗产品,经硅胶柱层析纯化(石油醚/乙酸乙酯,7/3,v/v)得到U-3。1H NMR(400MHz,Chloroform-d)δ8.55(d,J＝5.24Hz,1H),7.39(d,J＝5.22Hz,1H),3.12-3.02(m,2H),2.76-2.61(m,2H).ESI-MS理论计算值C8H7ClF2N[M+H]+＝190.0,实测值190.0。
第三步
将化合物U-3(300mg,1.58mmol)和A-2(249mg,1.74mmol)溶解在DMSO(10mL)中,加入TEA(641mg,6.33mmol)和氟化铯(240mg,1.58mmol),升温至70℃搅拌18小时。反应液冷却至室温后,加入饱和氯化铵溶液(50mL),乙酸乙酯(40mL×3)萃取,合并有机相,饱和食盐水(100mL)洗涤,无水硫酸钠干燥、过滤、减压浓缩得到含有目标化合物的粗产品,经硅胶柱层析纯化(石油醚/乙酸乙酯,3/7,v/v)得到U-4。1H NMR(400MHz,Chloroform-d)δ8.24(d,J＝5.58Hz,1H),6.15(d,J＝5.60Hz,1H),4.36-4.30(m,2H),4.16(q,J＝7.12Hz,2H),3.88-3.81(m,2H),3.20-3.09(m,1H),3.03-2.96(m,2H),2.71(d,J＝7.78Hz,2H),2.62-2.48(m,2H),1.27(t,J＝7.06Hz,3H).ESI-MS理论计算值C15H19F2N2O2[M+H]+＝297.1,实测值297.1。
第四步
将U-4(70mg,0.24mmol)溶解在四氢呋喃(2mL)和水(0.4mL)中,加入氢氧化锂一水合物(10mg,0.24mmol),在室温下搅拌3小时。反应结束后,用稀盐酸(1mol/L)将反应液的pH调至5,加水冻干得到含有中间体U的粗产品,直接用于下一步反应。ESI-MS理论计算值C13H15F2N2O2[M+H]+＝269.1,实测值269.1。
中间体V
合成路线：
第一步
将化合物V-1(100mg,0.55mmol)和A-2(157mg,0.55mmol)溶解在DMSO(5mL)中,加入TEA(221mg,2.19mmol)和氟化铯(80mg,0.55mmol),升温至100℃搅拌18小时。反应液冷却至室温后,加入饱和氯化铵溶液(20mL),乙酸乙酯(15mL×3)萃取,合并有机相,饱和食盐水(30mL)洗涤,无水硫酸钠干燥、过滤、减压浓缩得到含有目标化合物的粗产品,经硅胶柱层析纯化(石油醚/乙酸乙酯,2/3,v/v)得到V-2。1H NMR(400MHz,Chloroform-d)δ8.24(d,J＝5.70Hz,1H),6.23(d,J＝5.86Hz,1H),4.35-4.27(m,2H),4.19-4.12(m,2H),3.97-3.72(m,2H),3.14-3.22(m,1H),2.72(d,J＝7.76Hz,2H),1.28-1.24(m,3H).ESI-MS理论计算值C12H15F3N3O2[M+H]+＝290.3,实测值290.2。
第二步
将V-2(80mg,0.28mmol)溶解在四氢呋喃(2mL)和水(0.4mL)中,加入氢氧化锂一水合物(18mg,0.41mmol),在室温下搅拌2小时。反应结束后,用稀盐酸(1mol/L)将反应液的pH调至5,加水冻干得到含有中间体V的粗产品,直接用于下一步反应。ESI-MS理论计算值C10H11F3N3O2[M+H]+＝262.1,实测值262.0。
中间体X
合成路线：
第一步
将X-1(900mg,4.68mmol)溶解在1,4-二氧六环(40mL)中,加入X-2(1.8g,5.61mmol)后升温至90℃搅拌18小时。反应液冷却至室温后,加入水(50mL)稀释,乙酸乙酯(50mL×3)萃取,合并有机相,无水硫酸钠干燥、过滤、减压浓缩得到含有目标化合物的粗产品,经硅胶柱层析纯化(石油醚/乙酸乙酯,1/0,v/v)得到X-3。1H NMR(400MHz,Chloroform-d)δ8.52(d,J＝5.34Hz,1H),7.58(d,J＝1.82Hz,1H),7.32(dd,J＝5.30,1.84Hz,1H).
第二步
将X-3(100mg,0.47mmol)和A-2(201mg,0.70mmol)溶解在DMSO(3mL)中,加入TEA(142mg,1.40mmol)和氟化铯(71mg,0.47mmol),升温至100℃搅拌18小时。反应液冷却至室温后,加入饱和氯化铵溶液(10mL),二氯甲烷(15mL×3)萃取,合并有机相,饱和食盐水(30mL)洗涤,无水硫酸钠干燥、过滤、减压浓缩得到含有目标化合物的粗产品,经硅胶柱层析纯化(石油醚/乙酸乙酯,7/3,v/v)得到X-4。ESI-MS理论计算值C13H14F3N2O2S[M+H]+＝321.1,实测值321.1。
第三步
将X-4(150mg,2.50mmol)溶解在四氢呋喃(3mL)和水(1mL)中,加入氢氧化锂一水合物(30mg,0.70mmol),升温至40℃搅拌2小时。反应结束后,用稀盐酸(1mol/L)将反应液的pH调至5,加水冻干得到含有中间体X的粗产品,直接用于下一步反应。ESI-MS理论计算值C11H12F3N2O2S[M+H]+＝293.1,实测值293.1。
中间体AA
合成路线：
第一步
将AA-1(1.4g,12.2mmol)溶解在DMF(30mL)中,冷却至0℃后加入氢化钠(60％,910mg,22.8mmol),搅拌30分钟,再加入O-1(2.0g,15.2mmol)在室温下搅拌18小时。反应结束后,用饱和氯化铵溶液(150mL)淬灭,乙酸乙酯萃取(150mL×3)萃取,合并有机相,用饱和食盐水洗涤(300mL),无水硫酸钠干燥、过滤、减压浓缩得到含有目标化合物的粗产品,经硅胶柱层析纯化(石油醚/乙酸乙酯,19/1,v/v)得到AA-2。1H NMR(400MHz,DMSO-d6)δ8.21(d,J＝5.50Hz,1H),7.25(dd,J＝5.54,1.78Hz,1H),7.16(d,J＝1.80Hz,1H),5.95-5.86(m,1H),1.45(d,J＝6.68Hz,3H).
第二步
将AA-2(400mg,1.77mmol)和A-2(254mg,1.77mmol)溶解在DMSO(15mL)中,加入TEA(1.08g,10.6mmol)和氟化铯(404mg,2.66mmol),升温至100℃搅拌10小时。反应液冷却至室温后,加入饱和氯化铵溶液(50mL),乙酸乙酯(50mL×3)萃取,合并有机相,饱和食盐水(100mL)洗涤,无水硫酸钠干燥、过滤、减压浓缩得到含有目标化合物的粗产品,经硅胶柱层析纯化(石油醚/乙酸乙酯,3/17,v/v)得到AA-3。1H NMR(400MHz,Chloroform-d)δ7.75(d,J＝5.74Hz,1H),6.12(dd,J＝5.82,1.98Hz,1H),5.87-5.80(m,1H),5.73(d,J＝1.96Hz,1H),4.10-4.01(m,4H),3.62-3.54(m,2H),3.07-2.97(m,1H),2.70(d,J＝7.70Hz,2H),1.38(d,J＝6.54Hz,3H),1.18(t,J＝7.10Hz,3H).ESI-MS理论计算值C15H20F3N2O3[M+H]+＝333.1,实测值333.1。
第三步
将AA-3(350mg,1.05mmol)溶解在四氢呋喃(2mL)和水(0.4mL)中,加入氢氧化锂一水合物(66mg,1.58mmol),在室温下搅拌2小时。反应结束后,用稀盐酸(1mol/L)将反应液的pH调至5,过滤,固体用水(3mL)洗涤,干燥后得到中间体AA,直接用于下一步反应。ESI-MS理论计算值C13H16F3N2O3[M+H]+＝305.1,实测值305.1。
中间体AB
合成路线：
第一步
将AB-1(208mg,1.82mmol)溶解在DMF(4mL)中,冷却至0℃后加入氢化钠(60％,137mg,3.43mmol),搅拌30分钟,再加入O-1(300mg,2.28mmol)在室温下搅拌18小时。反应结束后,用饱和氯化铵溶液(30mL)淬灭,乙酸乙酯萃取(30mL×3)萃取,合并有机相,用饱和食盐水洗涤(100mL),无水硫酸钠干燥、过滤、减压浓缩得到含有目标化合物的粗产品,经硅胶柱层析纯化(石油醚/乙酸乙酯,19/1,v/v)得到AB-2。1H NMR(400MHz,DMSO-d6)δ8.21(d,J＝5.50Hz,1H),7.25(dd,J＝5.58,1.76Hz,1H),7.16(d,J＝1.74Hz,1H),5.93-5.85(m,1H),1.45(d,J＝6.68Hz,3H).
第二步
将AB-2(200mg,0.89mmol)和A-2(317mg,2.22mmol)溶解在DMSO(5mL)中,加入TEA(538mg,5.32mmol)和氟化铯(202mg,1.33mmol),升温至100℃搅拌10小时。反应液冷却至室温后,加入饱和氯化铵溶液(20mL),乙酸乙酯(20mL×3)萃取,合并有机相,饱和食盐水(50mL)洗涤,无水硫酸钠干燥、过滤、减压浓缩得到含有目标化合物的粗产品,经硅胶柱层析纯化(石油醚/乙酸乙酯,3/17,v/v)得到AB-3。ESI-MS理论计算值C15H20F3N2O3[M+H]+＝333.1,实测值333.0。
第三步
将AB-3(100mg,0.30mmol)溶解在四氢呋喃(2mL)和水(0.4mL)中,加入氢氧化锂一水合物(10mg,0.45mmol),在室温下搅拌2小时。反应结束后,用稀盐酸(1mol/L)将反应液的pH调至5,过滤,固体用水(3mL)洗涤,干燥后得到中间体AB,直接用于下一步反应。ESI-MS理论计算值C13H16F3N2O3[M+H]+＝305.1,实测值305.0。
中间体AI
合成路线：
第一步
将Q-5(109mg,0.69mmol)和P-1(112mg,0.83mmol)溶解在DMSO(5mL)中,加入TEA(280mg,2.77mmol)和氟化铯(105mg,0.69mmol),升温至70℃搅拌18小时。向反应液中加入饱和氯化铵溶液(20mL),乙酸乙酯(20mL×3)萃取,合并有机相,用饱和食盐水洗涤(50mL),无水硫酸钠干燥、过滤、减压浓缩得到含有目标化合物的粗产品,经硅胶柱层析纯化(石油醚/乙酸乙酯,4/1,v/v)得到AI-1。ESI-MS理论计算值C11H18N3O2S[M+H]+＝256.1,实测值256.1。
第二步
将AI-1(90mg,0.35mmol)溶解在四氢呋喃(2mL)和水(1mL)中,加入氢氧化锂一水合物(18 mg,0.42mmol),在室温下搅拌3小时。反应结束后,用稀盐酸(1mol/L)将反应液的pH调至5,减压浓缩后冻干得到含有中间体AI的粗产品,直接用于下一步反应。ESI-MS理论计算值C9H14N3O2S[M+H]+＝228.1,实测值228.0。
中间体AK
合成路线：
第一步
将G-4(500mg,1.73mmol)、环丙基硼酸(296mg,3.45mmol)、碳酸钾(596mg,4.31mmol)、[1,1'-双(二苯基膦)二茂铁]二氯化钯(253mg,0.35mmol)加入到1,4-二氧六环(6mL)中,在氮气保护下升温至100℃搅拌12小时。反应液冷却至室温,过滤,加水(30mL)稀释,用乙酸乙酯(30mL×3)萃取,合并有机相,饱和食盐水(50mL)洗涤,无水硫酸钠干燥、过滤,减压浓缩得到含有目标化合物的粗产品,经硅胶柱层析纯化(石油醚/乙酸乙酯,2/3,v/v)得到AK-1。1H NMR(400MHz,DMSO-d6)δ7.30(d,J＝8.60Hz,2H),6.92(d,J＝8.62Hz,2H),4.03-4.00(m,2H),3.91-3.88(m,2H),3.85(s,2H),3.75(s,3H),2.44(s,3H),1.99-1.95(m,1H),1.12-1.08(m,2H),1.00-0.95(m,2H).ESI-MS理论计算C18H22N3O[M+H]+＝296.2,实测值296.1。
第二步
将AK-1(300mg,1.02mmol)、三氟乙酸(4mL)加入到微波管中,升温至90℃搅拌10小时。反应液冷却至室温,减压浓缩得到含有中间体AK的三氟乙酸盐,直接用于下一步反应。ESI-MS理论计算值C10H14N3[M+H]+＝176.1,实测值176.0。
中间体AO
合成路线：
第一步
将G-4(200mg,0.69mmol)、甲烷磺酸(三环己基膦)(2-氨基-1,1-联苯-2-基)钯(45mg,0.07mmol)、磷酸钾(513mg,2.42mmol)、乙基硼酸(153mg,2.07mmol)加入到甲苯(5mL)和水(1mL)中,在氮气保护下升温至100℃搅拌12小时。反应液冷却至室温,加水(20mL)稀释,用乙酸乙酯(20mL×3)萃取、合并有机相、无水硫酸钠干燥、减压浓缩得到含有目标化合物的粗产品,经硅胶柱层析纯化(石油醚/乙酸乙酯,2/3,v/v)得到AO-1。1H NMR(400MHz,DMSO-d6)δ7.29(d,J＝8.54Hz,2H),6.92(d,J＝8.52Hz,2H),3.96-3.85(m,6H),3.75(s,3H),2.80(q,J＝7.58Hz,2H),2.47(s,3H),1.20(t,J＝7.58 Hz,3H).ESI-MS理论计算值C17H22N3O[M+H]+＝284.2,实测值284.1。
第二步
将AO-1(150mg,0.53mmol)、三氟乙酸(4mL)加入到微波管中,升温至90℃搅拌10小时。反应液冷却至室温,减压浓缩得到含有中间体AO的三氟乙酸盐,直接用于下一步反应。ESI-MS理论计算值C9H14N3[M+H]+＝164.1,实测值164.0。
中间体AP
合成路线：
第一步
将G-3(200mg,0.64mmol)、甲烷磺酸(三环己基膦)(2-氨基-1,1-联苯-2-基)钯(42mg,0.06mmol)、磷酸钾(479mg,2.26mmol)、乙基硼酸(285mg,3.87mmol)加入到甲苯(5mL)和水(1mL)中,在氮气保护下升温至100℃搅拌18小时。反应液冷却至室温,加水(20mL)稀释,用乙酸乙酯(20mL×3)萃取、合并有机相、无水硫酸钠干燥、减压浓缩得到含有目标化合物的粗产品,经硅胶柱层析纯化(二氯甲烷/甲醇,9/1,v/v)得到AP-1。1H NMR(400MHz,DMSO-d6)δ7.31(d,J＝8.60Hz,2H),6.91(d,J＝8.62Hz,2H),3.95(s,3H),3.85(s,2H),3.75(s,4H),2.80(q,J＝7.58Hz,4H),1.21(t,J＝7.60Hz,6H).ESI-MS理论计算值C18H24N3O[M+H]+＝298.2,实测值298.1。
第二步
将AP-1(150mg,0.50mmol)、三氟乙酸(4mL)加入到微波管中,升温至90℃搅拌10小时。反应液冷却至室温,减压浓缩得到含有中间体AP的三氟乙酸盐,直接用于下一步反应。ESI-MS理论计算值C10H16N3[M+H]+＝178.1,实测值178.0。
中间体AR
合成路线：
第一步
将中间体I(800mg,5.36mmol)和中间体AC-1(1.15g,5.36mmol)溶解在DMF(10mL)中,加入DIEA(2.08g,16.1mmol),在室温下搅拌30分钟,再加入HATU(3.06g,8.04mmol),继续在室温下搅拌1小时。反应结束后,用水(100mL)稀释,乙酸乙酯萃取(80mL×3)萃取,合并有机相,用饱和食盐水洗涤(150mL),无水硫酸钠干燥、过滤、减压浓缩得到含有目标化合物的粗产品,经硅胶柱层析纯化(二氯甲烷/甲醇,4/1,v/v)得到AR-1。ESI-MS理论计算值C18H27N4O3[M+H]+＝347.3,实 测值347.2。
第二步
将AR-1(1.00g,2.89mmol)溶解在二氯甲烷(6mL)中,加入三氟乙酸(2mL),在室温下搅拌3小时。将反应液减压浓缩得到含有中间体AR的粗产品,直接用于下一步反应。ESI-MS理论计算值C13H19N4O[M+H]+＝247.2,实测值247.1。
产物的制备合成
实施例12
合成路线：
第一步
将中间体G(50mg,0.26mmol)、HATU(149.9mg,0.39mmol)、DIEA(0.13mL,0.79mmol)、中间体A(136.8mg,0.53mmol)加入四氢呋喃(2mL)中,在室温下搅拌3小时。反应液过滤,减压浓缩得到含有目标化合物的粗产品,经制备高效液相色谱纯化(色谱柱:Waters-Xbridge-C18-10μm-19*250mm,流动相:乙腈-10mmol/L碳酸氢铵水溶液,梯度:20-50％,保留时间:9min)得到化合物12。1H NMR(400MHz,DMSO-d6)δ8.21(d,J＝5.66Hz,1H),6.74-6.70(m,1H),6.56-6.51(m,1H),4.88-4.84(m,1H),4.81-4.77(m,1H),4.66-4.61(m,1H),4.58-4.55(m,1H),4.19-4.14(m,2H),4.13-4.08(m,4H),3.73-3.65(m,2H),3.17-3.06(m,1H),2.89-2.80(m,2H),2.40(s,3H),2.38-2.29(m,2H).ESI-MS理论计算值C21H24F3N6O[M+H]+＝433.2,实测值433.2。
实施例24
合成路线：
第一步
将中间体I的三氟乙酸盐(100mg,0.67mmol)和中间体A(262mg,1.01mmol)溶解在四氢呋喃(4mL)中,加入DIEA(260mg,2.01mmol)和HATU(382mg,1.01mmol),在室温下搅拌3小时。将反应液减压浓缩得到含有目标化合物的粗产品，经制备高效液相色谱纯化(色谱柱:Waters-Xbridge C18 10μm,19*250mm,流动相:乙腈-10mmol/L碳酸氢铵水溶液,梯度:17-47％,保留时间:9min)得到化合物24。1H NMR(400MHz,DMSO-d6)δ8.21(d,J＝5.66Hz,1H),6.72(d,J＝2.24Hz,1H),6.54(dd,J＝5.66,2.24Hz,1H),4.95-4.90(m,2H),4.76-4.69(m,2H),4.22-4.15(m,2H),3.75-3.68(m,2H),3.17- 3.10(m,1H),2.90-2.82(m,2H),2.57-2.52(m,6H).ESI-MS理论计算值C19H21F3N5O[M+H]+＝392.2,实测值392.2。
实施例47
合成路线：
第一步
将中间体G(30mg,0.16mmol)和中间体O(45mg,0.16mmol)溶解在DMF(5mL)中,加入DIEA(122mg,0.95mmol),在室温下搅拌30分钟,再加入HATU(72mg,0.19mmol),继续在室温下搅拌1小时。将反应液减压浓缩得到含有目标化合物的粗产品,经制备高效液相色谱纯化(色谱柱:Waters-Xbridge-C18,10μm,19*250mm,流动相:乙腈-10mmol/L碳酸氢铵水溶液,梯度:32-62％,保留时间:9min)得到化合物47。1H NMR(400MHz,DMSO-d6)δ7.76(d,J＝5.78Hz,1H),6.17-6.13(m,1H),5.79(t,J＝1.86Hz,1H),4.94-4.77(m,4H),4.64-4.56(m,2H),4.14-4.06(m,6H),3.65-3.56(m,2H),3.13-3.02(m,1H),2.85-2.82(m,2H),2.40(s,3H),2.41-2.33(m,2H).ESI-MS理论计算值C22H26F3N6O2[M+H]+＝463.2,实测值463.2。
实施例50
合成路线：
第一步
将中间体G(30mg,0.16mmol)和中间体P(41mg,0.19mmol)溶解在DMF(5mL)中,加入DIEA(62mg,0.47mmol),在室温下搅拌30分钟,再加入HATU(90mg,0.24mmol),继续在室温下搅拌2小时。将反应液减压浓缩得到含有目标化合物的粗产品,经制备高效液相色谱纯化(色谱柱:Waters-Xbridge-C18,10μm,19*250mm,流动相:乙腈-10mmol/L碳酸氢铵水溶液,梯度:9-39％,保留时间:9min)得到化合物50。1H NMR(400MHz,DMSO-d6)δ4.85-4.74(m,2H),4.65-4.51(m,2H),4.25-4.20(m,2H),4.15-4.07(m,4H),3.83-3.76(m,2H),3.25-3.15(m,1H),2.92-2.84(m,2H),2.40(s,3H),2.38-2.31(m,2H),2.28(s,3H).ESI-MS理论计算值C18H24N7OS[M+H]+＝386.2,实测值386.2。
实施例51
合成路线：
第一步
将中间体G(30mg,0.16mmol)和中间体Q(43mg,0.11mmol)溶解在DMF(3mL)中,加入DIEA(122mg,0.95mmol),在室温下搅拌30分钟,再加入HATU(72mg,0.19mmol),继续在室温下搅拌2小时。将反应液减压浓缩得到含有目标化合物的粗产品,经制备高效液相色谱纯化(色谱柱:Waters-Xbridge-C18,10μm,19*250mm,流动相:乙腈-10mmol/L碳酸氢铵水溶液,梯度:22-52％,保留时间:9min)得到化合物51。1H NMR(400MHz,DMSO-d6)δ8.20(d,J＝5.70Hz,1H),6.70(s,1H),6.58(d,J＝5.64Hz,1H),4.92-4.84(m,2H),4.66-4.51(m,3H),4.15-4.02(m,4H),4.01-3.96(m,1H),3.76-3.71(m,1H),3.24-3.20(m,1H),2.89-2.77(m,2H),2.42(s,3H),2.39-2.34(m,2H),1.37-1.34(m,3H).ESI-MS理论计算值C22H26F3N6O[M+H]+＝447.2,实测值447.1。
实施例56
合成路线：
第一步
将中间体T(20mg,0.11mmol)和中间体S(29mg,0.11mmol)溶解在DMF(3mL)中,加入DIEA(55mg,0.42mmol),在室温下搅拌30分钟,再加入HATU(48mg,0.13mmol),继续在室温下搅拌1小时。将反应液减压浓缩得到含有目标化合物的粗产品,经制备高效液相色谱纯化(色谱柱:Waters-Xbridge-C18,10μm,19*250mm,流动相:乙腈-10mmol/L碳酸氢铵水溶液,梯度:17-47％,保留时间:9min)得到化合物56。1H NMR(400MHz,DMSO-d6)δ8.22(d,J＝5.68Hz,1H),6.76(t,J＝2.52Hz,1H),6.58-6.56(m,1H),5.93-5.90(m,1H),4.91-4.82(m,2H),4.65-4.57(m,2H),4.19-4.15(m,2H),4.13-4.09(m,4H),3.90-3.87(m,2H),2.92-2.88(m,2H),2.41-2.39(m,3H),2.36-2.32(m,2H).ESI-MS理论计算值C21H24F3N6O2[M+H]+＝449.2,实测值449.1。
实施例67
合成路线：
第一步
将中间体I的三氟乙酸盐(80mg,0.54mmol)和中间体O(156mg,0.54mmol)溶解在DMF(5mL)中,加入DIEA(209mg,1.62mmol),在室温下搅拌30分钟,再加入HATU(265mg,0.70mmol),继续在室温下搅拌1小时。将反应液减压浓缩得到含有目标化合物的粗产品,经制备高效液相色谱纯化(色谱柱:Waters-Xbridge-C18,10μm,19*250mm,流动相:乙腈-10mmol/L碳酸氢铵水溶液,梯度:26-56％,保留时间:9min)得到化合物67。1H NMR(400MHz,DMSO-d6)δ7.76(d,J＝5.78Hz,1H),6.15(dd,J＝5.82,1.94Hz,1H),5.78(d,J＝1.94Hz,1H),5.01-4.77(m,4H),4.71-4.68(m,2H),4.11-4.06(m,2H),3.63-3.58(m,2H),3.13-3.05(m,1H),2.84(d,J＝7.62Hz,2H),2.55-2.53(m,6H).ESI-MS理论计算值C20H23F3N5O2[M+H]+＝422.2,实测值422.2。
实施例68
合成路线：
第一步
将中间体I的三氟乙酸盐(54mg,0.36mmol)和中间体X(70mg,0.24mmol)溶解在DMF(5mL)中,加入DIEA(93mg,0.72mmol),在室温下搅拌30分钟,再加入HATU(128mg,0.34mmol),继续在室温下搅拌1小时。将反应液减压浓缩得到含有目标化合物的粗产品,经制备高效液相色谱纯化(色谱柱:Waters-Xbridge-C18,10μm,19*250mm,流动相:乙腈-10mmol/L碳酸氢铵水溶液,梯度:25-55％,保留时间:9min)得到化合物68。1H NMR(400MHz,DMSO-d6)δ8.10(d,J＝5.72Hz,1H),6.59(d,J＝2.18Hz,1H),6.40(dd,J＝5.76,2.18Hz,1H),4.93-4.91(m,2H),4.70-4.67(m,2H),4.17-4.11(m,2H),3.69-3.65(m,2H),3.15-3.09(m,1H),2.86(d,J＝7.68Hz,2H),2.55-2.53(m,6H).ESI-MS理论计算值C19H21F3N5OS[M+H]+＝424.1,实测值424.1。
实施例89
合成路线：
第一步
将中间体I的三氟乙酸盐(49mg,0.33mmol)和中间体AB(100mg,0.33mmol)溶解在DMF(5mL)中,加入DIEA(127mg,0.99mmol),在室温下搅拌30分钟,再加入HATU(175mg,0.46mmol),继续在室温下搅拌1小时。将反应液减压浓缩得到含有目标化合物的粗产品,经制备高效液相色谱纯化(色谱柱:Waters-Xbridge-C18,10μm,19*250mm,流动相:乙腈-10mmol/L碳酸氢铵水溶液,梯度:35-65％,保留时间:11min)得到化合物89。1H NMR(400MHz,DMSO-d6)δ7.75(d,J＝5.80Hz,1H), 6.15-6.12(m,1H),5.87-5.78(m,1H),5.75-5.73(m,1H),4.93-4.90(m,2H),4.71-4.68(m,2H),4.10-4.06(m,2H),3.64-3.58(m,2H),3.12-3.05(m,1H),2.85-2.82(m,2H),2.55-2.53(m,6H),1.38(d,J＝6.50Hz,3H).ESI-MS理论计算值C21H25F3N5O2[M+H]+＝436.2,实测值436.2。
实施例98
合成路线：
第一步
将中间体AK(73mg,0.41mmol)和中间体O(80mg,0.28mmol)溶解在DMF(5mL)中,加入DIEA(142mg,1.10mmol),在室温下搅拌30分钟,再加入HATU(136mg,0.36mmol),继续在室温下搅拌1小时。将反应液减压浓缩得到含有目标化合物的粗产品,经制备高效液相色谱纯化(色谱柱:Waters-Xbridge-C18,10μm,19*250mm,流动相:乙腈-10mmol/L碳酸氢铵水溶液,梯度:35-65％,保留时间:9min)得到化合物98。1H NMR(400MHz,DMSO-d6)δ7.77(d,J＝5.76Hz,1H),6.16(dd,J＝5.80,1.96Hz,1H),5.79(d,J＝1.94Hz,1H),5.06-5.03(m,1H),4.95-4.86(m,3H),4.79-4.69(m,2H),4.09(t,J＝8.04Hz,2H),3.65-3.58(m,2H),3.14-3.05(m,1H),2.88-2.83(m,2H),2.53(s,3H),2.11-2.01(m,1H),1.18-1.13(m,2H),1.09-1.04(m,2H).ESI-MS理论计算值C22H25F3N5O2[M+H]+＝448.2,实测值448.2。
实施例110
合成路线：
第一步
将中间体AO(59mg,0.36mmol)和中间体O(70mg,0.24mmol)溶解在DMF(5mL)中,加入DIEA(94mg,0.72mmol),在室温下搅拌30分钟,再加入HATU(119mg,0.31mmol),继续在室温下搅拌1小时。将反应液减压浓缩得到含有目标化合物的粗产品,经制备高效液相色谱纯化(色谱柱:Waters-Xbridge-C18,10μm,19*250mm,流动相:乙腈-10mmol/L碳酸氢铵水溶液,梯度:31-61％,保留时间:9min)得到化合物110。1H NMR(400MHz,DMSO-d6)δ7.76(d,J＝5.84Hz,1H),6.15(dd,J＝5.80,1.96Hz,1H),5.78(d,J＝1.94Hz,1H),5.02-4.85(m,4H),4.74-4.67(m,2H),4.11-4.05(m,2H),3.64-3.57(m,2H),3.12-3.04(m,1H),2.90-2.82(m,4H),2.55(s,3H),1.26(t,J＝7.54Hz,3H).ESI-MS理论计算值C21H25F3N5O2[M+H]+＝436.2,实测值436.2。
实施例111
合成路线：
第一步
将中间体AP(70mg,0.39mmol)和中间体O(115mg,0.39mmol)溶解在DMF(5mL)中,加入DIEA(153mg,1.18mmol),在室温下搅拌30分钟,再加入HATU(195mg,0.51mmol),继续在室温下搅拌1小时。将反应液减压浓缩得到含有目标化合物的粗产品,经制备高效液相色谱纯化(色谱柱:Waters-Xbridge-C18,10μm,19*250mm,流动相:乙腈-10mmol/L碳酸氢铵水溶液,梯度:34-64％,保留时间:9min)得到化合物111。1H NMR(400MHz,DMSO-d6)δ7.76(d,J＝5.78Hz,1H),6.15(dd,J＝5.82,1.94Hz,1H),5.78(d,J＝1.92Hz,1H),4.97-4.83(m,4H),4.73-4.70(m,2H),4.10-4.06(m,2H),3.64-3.57(m,2H),3.13-3.05(m,1H),2.91-2.83(m,6H),1.27(t,J＝7.54Hz,6H).ESI-MS理论计算值C22H27F3N5O2[M+H]+＝450.2,实测值450.2。
实施例116
合成路线：
第一步
将中间体I(66mg,0.44mmol)和中间体AA(90mg,0.30mmol)溶解在DMF(5mL)中,加入DIEA(115mg,0.89mmol),在室温下搅拌30分钟,再加入HATU(169mg,0.44mmol),继续在室温下搅拌1小时。将反应液减压浓缩得到含有目标化合物的粗产品,经制备高效液相色谱纯化(色谱柱:Waters-Xbridge-C18,10μm,19*250mm,流动相:乙腈-10mmol/L碳酸氢铵水溶液,梯度:32-62％,保留时间:9min)得到化合物116。1H NMR(400MHz,DMSO-d6)δ7.76(d,J＝5.80Hz,1H),6.13(dd,J＝5.84,2.00Hz,1H),5.87-5.80(m,1H),5.74(d,J＝1.96Hz,1H),4.93-4.90(m,2H),4.71-4.68(m,2H),4.12-4.03(m,2H),3.64-3.55(m,2H),3.14-3.03(m,1H),2.86-2.82(m,2H),2.58-2.52(m,6H),1.38(d,J＝6.50Hz,3H).ESI-MS理论计算值C21H25F3N5O2[M+H]+＝436.2,实测值436.2。
实施例123
合成路线：
第一步
将中间体G(33mg,0.17mmol)、HATU(78mg,0.20mmol)、DIEA(66mg,0.51mmol)、中间体O(50mg,0.17mmol)加入DMF(5mL)中,在室温下搅拌3小时。反应液过滤,减压浓缩得到含有目标化合物的粗产品,经制备高效液相色谱纯化(色谱柱:Waters-Xbridge-C18-10μm-19*250mm,流动相:乙腈-10mmol/L碳酸氢铵水溶液,梯度:30-60％,保留时间:10min)得到化合物123。1H NMR(400MHz,DMSO-d6)δ7.76(d,J＝5.78Hz,1H),6.14(dd,J＝5.78,1.82Hz,1H),5.78(d,J＝1.884Hz,1H),4.95-4.76(m,4H),4.65-4.57(m,2H),4.13-4.05(m,6H),3.61-3.58(m,2H),3.12-3.01(m,1H),2.84-2.81(m,2H),2.40-2.32(m,5H).ESI-MS理论计算值C22H26F3N6O2[M+H]+＝463.2,实测值463.0。
实施例124
合成路线：
第一步
将中间体AR(67mg,0.27mmol)、124-1(50mg,0.27mmol)、TEA(83mg,0.82mmol)、氟化铯(62mg,0.42mmol)加到DMSO(5mL)中,在100℃下搅拌10小时。反应液冷却后加水(50mL)稀释,乙酸乙酯(50mL×3)萃取,合并有机相,用饱和食盐水(100mL)洗涤,无水硫酸钠干燥、减压浓缩得到含有目标化合物的粗产品,经制备高效液相色谱纯化(色谱柱:Waters-Xbridge-C18-10μm-19*250mm,流动相:乙腈-10mmol/L碳酸氢铵水溶液,梯度:16-46％,保留时间:10min)得到化合物124。1H NMR(400MHz,DMSO-d6)δ8.27(d,J＝6.02Hz,1H),6.59(d,J＝6.02Hz,1H),4.93-4.89(m,2H),4.71-4.68(m,2H),4.29-4.23(m,2H),3.85-3.77(m,2H),3.17-3.07(m,1H),2.89-2.86(m,2H),2.55-2.53(m,6H).ESI-MS理论计算值C18H20F3N6O[M+H]+＝393.2,实测值393.2。
实施例125
合成路线：
第一步
将中间体AR(80mg,0.32mmol)、125-1(70mg,0.32mmol)、甲烷磺酸(2-二环己基膦基-2',4',6'-三-异丙基-1,1'-联苯基)(2'-氨基-1,1'-联苯-2-基)钯(28mg,0.03mmol)、碳酸铯(317mg,0.97mmol)加到1,4-二氧六环(5mL)中,在氮气保护下升温至100℃搅拌18小时。反应液冷却后减压浓缩得到含有目标化合物的粗产品,经制备高效液相色谱纯化(色谱柱:Waters-Xbridge-C18-10μm-19*250mm,流动相:乙腈-10mmol/L碳酸氢铵水溶液,梯度:18-48％,保留时间:10min)得到化合物125。1H NMR(400MHz,DMSO-d6)δ9.25(s,1H),7.89(d,J＝8.62Hz,1H),7.02(d,J＝2.18Hz,1H),6.68(dd,J＝8.62, 2.24Hz,1H),4.94-4.92(m,2H),4.72-4.69(m,2H),4.10-4.05(m,2H),3.60-3.56(m,2H),3.16-3.03(m,1H),2.88-2.84(m,2H),2.55(s,3H),2.53(s,3H).ESI-MS理论计算值C20H22N5OS[M+H]+＝380.2,实测值380.0。
实施例126
合成路线：
第一步
将中间体AR(65mg,0.26mmol)、126-1(50mg,0.26mmol)、氟化铯(60mg,0.40mmol)、TEA(80mg,0.79mmol)加到DMSO(5mL)中,反应液冷却后加水(50mL)稀释,乙酸乙酯(50mL×3)萃取,合并有机相,用饱和食盐水(100mL)洗涤,无水硫酸钠干燥、减压浓缩得到含有目标化合物的粗产品,经制备高效液相色谱纯化(色谱柱:Waters-Xbridge-C18-10μm-19*250mm,流动相:乙腈-10mmol/L碳酸氢铵水溶液,梯度:15-45％,保留时间:10min)得到化合物126。1H NMR(400MHz,DMSO-d6)δ8.11(d,J＝5.50Hz,1H),6.28(d,J＝5.58Hz,1H),4.94-4.91(m,2H),4.70-4.67(m,2H),4.32-4.28(m,2H),3.86-3.82(m,2H),3.09-2.98(m,3H),2.87-2.84(m,2H),2.56-2.53(m,8H).ESI-MS理论计算值C21H24F2N5O[M+H]+＝400.2,实测值400.2。
实施例127
合成路线：
第一步
将中间体AR(106mg,0.43mmol)、127-1(100mg,0.43mmol)、碳酸铯(351mg,1.08mmol)加到DMF(3mL)中,反应液冷却后加水(50mL)稀释,乙酸乙酯(50mL×3)萃取,合并有机相,用饱和食盐水(100mL)洗涤,无水硫酸钠干燥、减压浓缩得到含有目标化合物的粗产品,经制备高效液相色谱纯化(色谱柱:Waters-Xbridge-C18-10μm-19*250mm,流动相:乙腈-10mmol/L碳酸氢铵水溶液,梯度:25-55％,保留时间:10min)得到化合物127。1H NMR(400MHz,DMSO-d6)δ7.70(s,1H),4.92-4.89(m,2H),4.71-4.68(m,2H),4.28-4.21(m,2H),3.84-3.78(m,2H),3.22-3.16(m,1H),2.91-2.88(m,2H),2.56-2.53(m,6H).ESI-MS理论计算值C17H19F3N5OS[M+H]+＝398.1,实测值398.1。
实施例128
合成路线：
第一步
将中间体I(26mg,0.17mmol)、HATU(78mg,0.20mmol)、DIEA(66mg,0.51mmol)、中间体X(50mg,0.17mmol)加入DMF(5mL)中,在室温下搅拌3小时。反应液过滤,减压浓缩得到含有目标化合物的粗产品,经制备高效液相色谱纯化(色谱柱:Waters-Xbridge-C18-10μm-19*250mm,流动相:乙腈-10mmol/L碳酸氢铵水溶液,梯度:20-50％,保留时间:10min)得到化合物128。1H NMR(400MHz,DMSO-d6)δ8.10(d,J＝5.72Hz,1H),6.59(d,J＝2.20Hz,1H),6.40(dd,J＝5.72,2.22Hz,1H),4.93-4.90(m,2H),4.70-4.67(m,2H),4.16-4.12(m,2H),3.68-3.64(m,2H),3.17-3.03(m,1H),2.88-2.85(m,2H),2.55-2.52(m,6H).ESI-MS理论计算值C19H21F3N5OS[M+H]+＝424.1,实测值424.1。
实施例129
合成路线：
第一步
将中间体I(26mg,0.17mmol)、HATU(78mg,0.20mmol)、DIEA(66mg,0.51mmol)、中间体O(50mg,0.17mmol)加入DMF(5mL)中,在室温下搅拌3小时。反应液过滤,减压浓缩得到含有目标化合物的粗产品,经制备高效液相色谱纯化(色谱柱:Waters-Xbridge-C18-10μm-19*250mm,流动相:乙腈-10mmol/L碳酸氢铵水溶液,梯度:37-47％,保留时间:10min)得到化合物129。1H NMR(400MHz,DMSO-d6)δ7.76(d,J＝5.80Hz,1H),6.15(dd,J＝5.78,1.98Hz,1H),5.78(d,J＝1.96Hz,1H),4.99-4.83(m,4H),4.71-4.68(m,2H),4.10-4.06(m,2H),3.62-3.59(m,2H),3.12-3.05(m,1H),2.86-2.83(m,2H),2.56-2.53(m,6H).ESI-MS理论计算值C20H23F3N5O2[M+H]+＝422.2,实测值422.0。
实施例130
合成路线：
第一步
将中间体AR(65mg,0.26mmol)、130-1(50mg,0.26mmol)、氟化铯(60mg,0.40mmol)、TEA(80mg,0.79mmol)加到DMSO(5mL)中,反应液冷却后加水(50mL)稀释,乙酸乙酯(50mL×3)萃取, 合并有机相,用饱和食盐水(100mL)洗涤,无水硫酸钠干燥、减压浓缩得到含有目标化合物的粗产品,经制备高效液相色谱纯化(色谱柱:Waters-Xbridge-C18-10μm-19*250mm,流动相:乙腈-10mmol/L碳酸氢铵水溶液,梯度:18-45％,保留时间:9min)得到化合物130。1H NMR(400MHz,DMSO-d6)δ4.93-4.89(m,2H),4.72-4.68(m,2H),4.38-4.32(m,2H),3.96-3.88(m,2H),3.29-3.18(m,1H),2.92-2.88(m,2H),2.55-2.52(m,6H).ESI-MS理论计算值C16H18F3N6OS[M+H]+＝399.1,实测值399.1。
实施例131
合成路线：
第一步
将中间体AR(67mg,0.27mmol)、131-1(50mg,0.27mmol)、TEA(83mg,0.82mmol)、氟化铯(42mg,0.27mmol)加到DMSO(5mL)中,在70℃下搅拌18小时。反应液冷却后加水(50mL)稀释,乙酸乙酯(50mL×3)萃取,合并有机相,用饱和食盐水(100mL)洗涤,无水硫酸钠干燥、减压浓缩得到含有目标化合物的粗产品,经制备高效液相色谱纯化(色谱柱:Waters-Xbridge-C18-10μm-19*250mm,流动相:乙腈-10mmol/L碳酸氢铵水溶液,梯度:5-95％,保留时间:10min)得到化合物131。1H NMR(400MHz,DMSO-d6)δ8.63(d,J＝2.80Hz,1H),6.91(d,J＝2.80Hz,1H),4.92-4.90(m,2H),4.70-4.68(m,2H),4.32-4.28(m,2H),3.87-3.80(m,2H),3.20-3.10(m,1H),2.89-2.86(m,2H),2.55-2.52(m,6H).ESI-MS理论计算值C18H20F3N6O[M+H]+＝393.2,实测值392.9。
实施例132
合成路线：
第一步
将中间体G-4(500mg,1.60mmol)溶解在甲醇(20mL)中,加入[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(127mg,0.17mmol)、TEA(524mg,5.18mmol),反应体系用一氧化碳置换三次后升温至70℃搅拌18小时。将反应液过滤,滤液减压浓缩,经硅胶柱层析纯化(石油醚/乙酸乙酯,1/4,v/v)得到132-1。ESI-MS理论计算值C17H20N3O3[M+H]+＝314.1,实测值314.0。
第二步
将132-1(200mg,0.64mmol)溶解在四氢呋喃(10mL)中,在0℃下缓慢加入硼氢化锂(14mg,0.64mmol),在室温下搅拌1小时。将反应液用水(30mL)淬灭,用二氯甲烷(20mL×3)萃取,合并有机相,无水硫酸钠干燥、过滤、减压浓缩,经硅胶柱层析纯化(石油醚/乙酸乙酯,1/4,v/v)得到132-2。ESI-MS理论计算值C16H20N3O2[M+H]+＝286.2,实测值286.2。
第三步
将132-2(100mg,0.35mmol)、三氟乙酸(2mL)加入到5mL微波管中,升温至90℃搅拌8小时。反应液冷却至室温,减压浓缩得到含有132-3的粗产品,直接用于下一步反应。ESI-MS理论计算值C8H12N3O[M+H]+＝166.1,实测值166.1。
第四步
将132-3(56mg,0.34mmol)、HATU(98mg,0.26mmol)、DIEA(66mg,0.51mmol)、中间体O(50mg,0.17mmol)加入DMF(5mL)中,在室温下搅拌3小时。反应液过滤,减压浓缩得到含有目标化合物的粗产品,经制备高效液相色谱纯化(色谱柱:Waters-Xbridge-C18-10μm-19*250mm,流动相:乙腈-10mmol/L碳酸氢铵水溶液,梯度:5-95％,保留时间:10min)得到化合物132。1H NMR(400MHz,MeOD-d4)δ7.74-7.71(m,1H),6.14-6.12(m,1H),5.82-5.75(m,1H),5.12-5.10(m,1H),4.97-4.89(m,4H),4.82-4.78(m,1H),4.74-4.68(m,2H),4.19-4.14(m,2H),3.73-3.64(m,2H),3.26-3.08(m,1H),2.95-2.91(m,2H),2.65(s,3H).ESI-MS理论计算值C20H23F3N5O3[M+H]+＝438.2,实测值437.9。
活性测试1化合物对M4受体的PAM活性评价
实验目的：
利用表达人源M4受体的稳转系细胞(M4-Gα15-CHO)，通过FLIPR CALCIUM 6ASSAY KIT试剂盒测定化合物对M4受体的活性。
实验材料：

实验仪器:
细胞处理：
1.本研究采用了稳定表达M4-Gα15受体的CHO细胞系,分别表达人的CHRM4和GNA15基因；
2.细胞处理：M4-Gα15-CHO细胞在含有10％胎牛血清、0.4mg/mL潮霉素B、0.8mg/mL遗传霉素G418的F-12培养基中培养,培养温度为37℃,二氧化碳浓度为5％。除去旧培养基并用磷酸盐缓冲液洗一次,然后加入1mL胰蛋白酶溶液,37℃孵育2分钟左右。当细胞从皿底脱离,加入约5mL 37℃预热的完全培养基。将细胞悬液用吸管轻轻吹打使聚集的细胞分离。将细胞悬液转移至无菌的离心管中,离心5分钟(1000转/分钟)。
实验操作：
1.细胞铺板：消化收集M4-Gα15-CHO细胞,经重悬计数后接种至384孔细胞板,接种密度为：1.2×104cells/25μL/孔。然后将细胞板置于于37℃,5％CO2培养箱培养约20小时；
2. 24h后按照FLIPR CALCIUM 6ASSAY KIT试剂盒说明准备上样缓冲液：冻融其中Component A至室温,用检测缓冲液和丙磺舒溶液将其稀释得到上样缓冲液,置于室温备用；
3.将细胞板中培养基去除,迅速向每孔中加入35μL上样缓冲液,离心后将细胞板置于37℃条件下避光孵育120分钟；
4.配制待测化合物工作液,并转移5μL至相应细胞孔内,置于37℃条件下避光孵育30分钟；
5.配制30nM乙酰胆碱激动剂工作液,并转移20μL/孔至384孔上样板内；
6.将细胞板、上样板及枪头放至FLIPR仪器相应位置,利用FLIPR将步骤5中稀释好的10μL激动剂加入各实验孔中,并在515nm-575nm波长下收集数据；
7.通过信号值与化合物浓度作图,用GraphPad Prism软件非线性回归方法进行曲线拟合及EC50计算。
检测缓冲液和上样缓冲液的配制：
1.将0.5mol/L 2-(4-(2-羟乙基)哌嗪)乙磺酸缓冲液与Hank’s平衡盐溶液(pH 7.4)混合,体积比为1:24,配制为检测缓冲液。将10mL检测缓冲液加入到一瓶冻干粉形式的CALCIUM 6 ASSAY KIT Component A中,分装冻存于-20℃；
2.用1mol/L氢氧化钠溶液溶解丙磺舒粉末,使其最终浓度为250mol/L。将检测缓冲液、冻融的Component A和丙磺舒溶液按照体积比44:5:1混合,配制成上样缓冲液。
实验结果：
实验结论:
实验样品(化合物)由相应实施例制得，结果如上表所示，本申请化合物在该试验体系中，对M4受体显示出激动活性。
活性测试2化合物在小鼠体内药代动力学性质评价
实验目的：
评价本发明实施例所得化合物在CD-1小鼠体内的药代动力学性质。
实验材料：
实验操作：
以标准方案测试化合物静脉注射和口服给药后啮齿类动物的药代动力学特征。实验中候选化合物用指定溶媒配置成澄清溶液或混悬液,分别给予三只小鼠单次静脉注射及口服给药。静脉注射和口服给药的溶媒均为5％二甲基亚砜+95％(10％聚乙二醇(15)-羟基硬脂酸酯水溶液)。收集24小时内全血样 品至商品化的EDTA2K抗凝管中,离心得到上层血浆样品,加入含内标的乙腈溶液沉淀蛋白,离心取上清液加入等体积的水,再离心后取上清液进样,以LCMS/MS分析方法定量分析血药浓度、计算药代动力学参数。
实验方法：
实验结果：
实验结论:
供试品由相应实施例制得，结果显示，本申请化合物具有良好的药代动力学性质。
活性测试3化合物在大鼠体内药代动力学性质评价
实验目的：
评价本发明实施例所得化合物在SD大鼠体内的药代动力学性质。
实验材料：
实验操作：
以标准方案测试化合物静脉注射和口服给药后啮齿类动物的药代动力学特征。实验中候选化合物用指定溶媒配置成澄清溶液或混悬液,分别给予三只大鼠单次静脉注射及口服给药。静脉注射的溶媒为5％二甲基亚砜+95％(10％聚乙二醇(15)-羟基硬脂酸酯水溶液)，口服给药的溶媒为5％二甲基亚砜+95％(10％聚乙二醇(15)-羟基硬脂酸酯水溶液)或0.5％甲基纤维素+0.2吐温80+99.3％水。收集24小时内全血样品至商品化的EDTA2K抗凝管中,离心得到上层血浆样品,加入含内标的乙腈溶液沉淀蛋 白,离心取上清液加入等体积的水,再离心后取上清液进样,以LCMS/MS分析方法定量分析血药浓度、计算药代动力学参数。
供试品由相应实施例制得，本申请部分化合物生物利用度在80％以上，清除率不高于16mL/min/kg，半衰期T1/2在2hr-10hr之间，药时曲线下面积AUC0-last在5000-50000hr*ng/mL之间，本申请化合物具有良好的药代动力学性质。
活性测试4化合物在犬体内药代动力学性质评价
实验目的：
评价本发明实施例化合物在比格犬体内的药代动力学性质。
实验材料：
实验操作：
以标准方案测试化合物静脉注射和口服给药后比格犬的药代动力学特征。实验中候选化合物用指定溶媒配置成澄清溶液或混悬液,分别给予两只比格犬单次静脉注射及口服给药。静脉注射的溶媒为5％二甲基亚砜+95％(10％聚乙二醇(15)-羟基硬脂酸酯水溶液)，口服给药的溶媒为0.5％甲基纤维素+0.2％吐温80+99.3％水。收集24小时内全血样品至商品化的EDTA2K抗凝管中,离心得到上层血浆样品,加入含内标的乙腈溶液沉淀蛋白,离心取上清液加入等体积的水,再离心后取上清液进样,以LCMS/MS分析方法定量分析血药浓度、计算药代动力学参数。
供试品由相应实施例制得，本申请部分化合物生物利用度在80％以上，清除率不高于16mL/min/kg，半衰期T1/2在2hr-10hr之间，药时曲线下面积AUC0-last在2000-20000hr*ng/mL之间，本申请化合物表现出良好的药代动力学性质。
活性测试5化合物在小鼠前脉冲抑制模型中的药效评价
实验目的：
评价本发明实施例在C57小鼠前脉冲抑制模型中的药效。
实验材料：
实验操作：
动物在给药前根据体重随机分成4组,每组10只,第1组为溶媒对照组、第2组为造模组、第3和4组为给药组。第1组和第2组动物灌胃给予溶媒C,第3组动物按照剂量5毫克/千克灌胃给予本 申请化合物,第4组动物按照剂量10毫克/千克灌胃给予本申请化合物。30分钟后,第1组动物腹腔注射溶媒B(生理盐水),第2、3、4组动物按照剂量0.3毫克/千克腹腔注射地亚平(MK-801),30分钟后置于前脉冲抑制试验箱开始实验,由仪器记录动物的反应期峰值。首先，设置前脉冲抑制试验箱参数背景噪音为67分贝,将动物轻轻置于束缚笼内适应10分钟；随后,设置实验前参数：5分钟内给予动物5次120分贝随机刺激；正式实验参数：实验开始时,对动物实施10次震惊刺激：120分贝、81+120分贝分别5次,平均刺激间隔时间选择7～21秒随机功能；整个实验过程中保持67分贝的背景噪音。动物的前脉冲抑制百分率＝1-[(81+120分贝刺激时的反应期峰值)/120分贝刺激时的反应期峰值]×100％。
供试品由相应实施例制得，观察到小鼠前脉冲抑制百分率约为40％-80％，本申请部分化合物能够有效逆转MK-801对小鼠前脉冲抑制功能造成的损伤,在C57小鼠前脉冲抑制模型中展现出良好的体内药效。
活性测试6化合物在小鼠强迫游泳模型中的药效评价
实验目的：
评价本发明实施例在C57小鼠强迫游泳模型中的药效。
实验材料：
实验操作：
动物在给药前根据体重随机分成4组,每组8只,第1组为溶媒对照组、第2组至第4组为给药组。第1组动物灌胃给予溶媒C,第2组至第4组动物分别按照剂量2、5、10毫克/千克灌胃给予本申请化合物。给药结束后将动物放回原饲养笼。1小时后,将动物从饲养笼中轻轻取出,安抚1-3分钟待动物不紧张的时候,将动物单个放入高40厘米，直径13厘米、水深26厘米、水温23℃的玻璃圆筒中,然后打开分析软件自动记录4分钟内动物的强迫游泳不动时间。
供试品由相应实施例制得，观察到小鼠不动时间约为50s-150s，本申请部分化合物能够显著减少强迫游泳小鼠的不动时间,在C57小鼠强迫游泳模型中展现出良好的抗抑郁药效。
活性测试7化合物在小鼠悬尾模型中的药效评价
实验目的：
评价本发明实施例在C57小鼠悬尾模型中的药效。
实验材料：
实验操作：
动物在给药前根据体重随机分成2组,每组8只,第1组为溶媒对照组、第2组为给药组。第1组动物灌胃给予溶媒C,第2组动物按照剂量5毫克/千克灌胃给予本申请化合物。给药结束后将动物放回原饲养笼。1小时后,将动物从饲养笼中轻轻取出,安抚1-3分钟待动物不紧张的时候,用医用胶带缠绕动物尾尖部1/3处,使其悬于悬尾箱内,打开分析软件自动记录4分钟内动物的不动时间。供试品由相应实施例制得，观察到小鼠不动时间在150s以内，本申请部分化合物在C57小鼠悬尾模型中展现出良好的抗抑郁药效。

Claims (13)

  1. 一种式I所示的化合物或其药学上可接受的盐，
    其中，为
    m为1；
    n为1；
    X2和X3为N；
    X1和X4独立地为-CR1-；
    Y和Z独立地为-(CR2R3)r-；r为1；
    各个R1独立地为氢、卤素、C1-C6烷基、C1-C6烷氧基、3～7元环烷基、3～7元杂环烷基或-NR1- 1R1-2；其中，所述C1-C6烷基和C1-C6烷氧基任选独立地被1个、2个、3个或4个Ra取代；
    R1-1和R1-2独立地为氢或C1-C6烷基；或者，R1-1和R1-2与其相连的原子形成3～7元杂环烷基；
    各个Ra独立地为羟基、C1-C6烷氧基或NR1-4R1-5；
    R1-4和R1-5独立地为氢或C1-C3烷基；
    R2和R3独立地为氢；
    L为
    t为0；
    u为1；
    E为羰基；
    F为化学键；
    B为4～6元杂环烷基；其中，所述4～6元杂环烷基任选独立地被1个、2个或3个Ri取代；
    各个Ri独立地为氢、卤素、羟基或C1-C3烷基；
    D为5～12元杂芳基；其中，所述5～12元杂芳基任选独立地被1个、2个或3个Rj取代；
    各个Rj独立地为H、卤素、C1-C3烷基、OR12-3或SR12-4；其中，所述C1-C3烷基任选独立地被任选独立地被1个、2个或3个Rk取代；
    R12-3和R12-4独立地为C1-C3烷基；所述C1-C3烷基任选独立地被1个、2个或3个Rk-1取代；
    各个Rk独立地为卤素或C1-C3烷基；
    各个Rk-1独立地为卤素或C1-C3烷基；
    所述3～7元杂环烷基、4～6元杂环烷基和5～12元杂芳基中，杂原子为N、O和S中的一种或多 种，杂原子数为1～3个。
  2. 如权利要求1所述式I所示的化合物或其药学上可接受的盐，其特征在于，其满足如下一个或多个条件；
    (1)R1中，所述卤素为F、Cl、Br或I，例如F或Cl，又如为Cl；
    (2)R1中，所述C1-C6烷基为C1-C3烷基，例如甲基、乙基、正丙基或异丙基，又如为甲基、乙基或异丙基；
    (3)R1中，所述C1-C6烷氧基为C1-C3烷氧基，例如甲氧基、乙氧基、正丙氧基或异丙氧基，又如为甲氧基或乙氧基；
    (4)R1中，所述3～7元环烷基为3～6元环烷基，例如环丙烷基、环丁烷基或环戊烷基，又如环丙烷基；
    (5)R1中，所述3～7元杂环烷基为3～6元杂环烷基；所述3～6元杂环烷基中杂原子优选为N或O；所述3～6元杂环烷基中杂原子数优选为1个或2个；所述3～6元杂环烷基更优选为4元杂环烷基，例如
    (6)Ra中，所述C1-C6烷氧基为C1-C3烷氧基，例如甲氧基、乙氧基、正丙氧基或异丙氧基，又如甲氧基；
    (7)R1-1和R1-2中，所述C1-C6烷基为C1-C3烷基，例如甲基、乙基、正丙基或异丙基，又如甲基或乙基，优选为甲基；
    (8)R1-1和R1-2中，所述3～7元杂环烷基为3～6元杂环烷基；所述3～6元杂环烷基中杂原子优选为N或O；所述3～6元杂环烷基中杂原子数优选为1个或2个；所述3～6元杂环烷基例如4元杂环烷基，又如
    (9)R1-4和R1-5中，所述C1-C3烷基为甲基、乙基、正丙基或异丙基，例如甲基、乙基或正丙基，又如甲基；
    (10)B中，所述4～6元杂环烷基为4元杂环烷基、5元杂环烷基或6元杂环烷基；所述4元杂环烷基、5元杂环烷基和6元杂环烷基中杂原子优选为N；所述4～6元杂环烷基中杂原子数优选为1个或2个；例如，所述4～6元杂环烷基为4元氮杂环烷基或5元氮杂环烷基，所述4元氮杂环烷基可为所述5元氮杂环烷基可为
    (11)Ri中，所述卤素为F、Cl、Br或I，例如F或Cl，又如为F；
    (12)Ri中，所述C1-C3烷基为甲基、乙基、正丙基或异丙基，例如为甲基；
    (13)Rj中，所述卤素为F、Cl、Br或I，例如F或Cl，又如F；
    (14)Rj中，所述C1-C3烷基为甲基、乙基、正丙基或异丙基，例如甲基、乙基或异丙基，又如甲基；
    (15)R12-3和R12-4中，所述C1-C3烷基为甲基、乙基、正丙基或异丙基，例如甲基或乙基；
    (16)Rk中，所述卤素为F、Cl、Br或I，例如F或Cl，又如F；
    (17)Rk中，所述C1-C3烷基为甲基、乙基、正丙基或异丙基；
    (18)Rk-1中，所述卤素为F、Cl、Br或I，例如F或Cl，又如F；
    (19)Rk-1中，所述C1-C3烷基为甲基、乙基、正丙基或异丙基，例如甲基。
  3. 如权利要求1所述式I所示的化合物或其药学上可接受的盐，其特征在于，其满足如下一个或多个条件；
    (1)各个R1独立地为C1-C6烷基、3～7元环烷基或-NR1-1R1-2；其中，所述C1-C6烷基任选独立地被1个、2个、3个或4个Ra取代；例如，各个R1独立地为氢、C1-C6烷基、3～7元环烷基或-NR1-1R1-2；优选地，各个R1独立地为C1-C6烷基；
    (2)各个Ra独立地为羟基、C1-C3烷氧基或NR1-4R1-5，例如羟基；
    (3)R1-1和R1-2与其相连的原子形成3～7元杂环烷基；
    (4)各个Ri独立地为氢、羟基或C1-C3烷基，例如氢；
    (5)各个Rj独立地为H、卤素、C1-C3烷基、OR12-3或SR12-4；其中，所述C1-C3烷基任选独立地被任选独立地被1个、2个或3个Rk取代；例如，各个Rj独立地为H、卤素、C1-C3烷基、OR12-3或SR12-4；又如，各个Rj独立地为C1-C3烷基、-OR12-3或-SR12-4，优选地，各个Rj独立地为-OR12-3；进一步优选地，Rj为卤素或C1-C3烷基；
    (6)各个Rk独立地为卤素；
    (7)各个Rk-1独立地为卤素；
    (8)D为5-6元杂芳基；其中，所述5-6元杂芳基任选独立地被1个、2个或3个Rj取代；所述5-6元杂芳基例如为
    (9)所述3～7元杂环烷基、4～6元杂环烷基、5～6元杂芳基和5～12元杂芳基中，杂原子选自N、O或S中1种、2种或3种，杂原子数为1个、2个或3个，例如，所述3～7元杂环烷基、4～6元杂环烷基和5～12元杂芳基中，杂原子为N、O或S，杂原子数为1～3个。
  4. 如权利要求1～3任一项所述式I所示的化合物或其药学上可接受的盐，其特征在于，所述式I所示的化合物为式I-3所示的化合物；
    其中，R1、Ri、X2、X3、X4和D如权利要求1～3中 任一项所述。
  5. 如权利要求1所述式I所示的化合物或其药学上可接受的盐，其特征在于，所述式I所示的化合物为式I-1-4所示化合物；
    X6为C或N；
    其中，R1、Ri和Rj如权利要求1所述。
  6. 如权利要求1所述式I所示的化合物或其药学上可接受的盐，其特征在于，其满足如下一个或多个条件；
    (1)B中，所述4～6元杂环烷基中杂原子为N，杂原子数为1个，例如 e独立地为0、1、2或3，又例如
    (2)D中，所述5～12元杂芳基为5～6元杂芳基、苯基并5～6元杂芳基或5～7元环烷基并苯基；
    优选地，所述式I所示的化合物满足如下一个或多个条件：
    (a)D为6元杂芳基，其中，所述6元杂芳基中杂原子为N，杂原子数为1个或2个，例如e独立地为0、1、2或3，又例如
    (b)D为5元杂芳基，其中，所述5元杂芳基中杂原子为N、S和O中一种或多种，杂原子数为1个、2个或3个，例如为 又如，所述5元杂芳基中杂原子为N和/或S，杂原子数为1个、2个或3个，再如，所述5元杂芳基中杂原子为N或S，杂原子数为1个、2个或3个，优选为
    (c)D为6元杂芳基并5元环烷基，其中，所述6元杂芳基中杂原子为N，杂原子数为1个，例如e独立地为0、1、2或3，又例如
    (d)所述D为苯基并5元杂芳基，其中，所述5元杂芳基中杂原子为N和/或S，杂原子数为2个，例如为e独立地为0、1、2或3，又例如
  7. 如权利要求1所述式I所示的化合物或其药学上可接受的盐，其特征在于，所述式I所示的化合物为如下任一方案：
    方案一：
    其中，为
    m为1；
    n为1；
    X2和X3为N；
    X1和X4独立地为-CR1-；
    Y和Z独立地为-(CR2R3)r-；r为1；
    各个R1独立地为C1-C6烷基、3～7元环烷基或-NR1-1R1-2；其中，所述C1-C6烷基任选独立地被1个、2个、3个或4个Ra取代；R1-1和R1-2与其相连的原子形成3～7元杂环烷基；
    各个Ra独立地为羟基；
    R2和R3独立地为氢；
    L为
    t为0；
    u为1；
    E为羰基；
    F为化学键；
    B为4～6元杂环烷基；其中，所述4～6元杂环烷基任选独立地被1个、2个或3个Ri取代；
    各个Ri独立地为氢、羟基或C1-C3烷基；
    D为5～12元杂芳基；其中，所述5～12元杂芳基任选独立地被1个、2个或3个Rj取代；
    各个Rj独立地为H、卤素、C1-C3烷基、OR12-3或SR12-4；其中，所述C1-C3烷基任选独立地被任选独立地被1个、2个或3个Rk取代；
    R12-3和R12-4独立地为C1-C3烷基；所述C1-C3烷基任选独立地被1个、2个或3个Rk-1取代；
    各个Rk独立地为卤素；
    各个Rk-1独立地为卤素；
    所述3～7元杂环烷基、4～6元杂环烷基和5～12元杂芳基中，杂原子为N、O和S中的一种或多种，杂原子数为1～3个；
    方案二：
    其中，为
    m为1；
    n为1；
    X2和X3为N；
    X1和X4独立地为-CR1-；
    Y和Z独立地为-(CR2R3)r-；r为1；
    各个R1独立地为C1-C6烷基、3～7元环烷基或-NR1-1R1-2；其中，所述C1-C6烷基任选独立地被1个、2个、3个或4个Ra取代；R1-1和R1-2与其相连的原子形成3～7元杂环烷基；所述3～7元杂环烷基中，杂原子选自N、O和S中1种、2种或3种，杂原子数为1个、2个或3个；
    各个Ra独立地为羟基；
    R2和R3独立地为氢；
    L为
    t为0；
    u为1；
    E为羰基；
    F为化学键；
    B为4～6元杂环烷基；其中，所述4～6元杂环烷基任选独立地被1个、2个或3个Ri取代；所述 4～6元杂环烷基中，杂原子选自N、O和S中1种、2种或3种，杂原子数为1个、2个或3个；
    各个Ri独立地为氢、羟基或C1-C3烷基；
    D为5～6元杂芳基；其中，所述5～6元杂芳基任选独立地被1个、2个或3个Rj取代；所述5～6元杂芳基中，杂原子选自N、O和S中1种、2种或3种，杂原子数为1个、2个或3个；
    各个Rj独立地为H、卤素、C1-C3烷基、OR12-3或SR12-4；其中，所述C1-C3烷基任选独立地被任选独立地被1个、2个或3个Rk取代；
    R12-3和R12-4独立地为C1-C3烷基；所述C1-C3烷基任选独立地被1个、2个或3个Rk-1取代；
    各个Rk独立地为卤素；
    各个Rk-1独立地为卤素。
  8. 如权利要求1所述式I所示的化合物或其药学上可接受的盐，其特征在于，其满足如下一个或多个条件：
    (1)各个R1独立地为甲基、乙基、优选地，各个R1独立地为甲基、
    (2)为 例如，为
    (3)L为较佳地，L为其中表示与A相连；
    (4)B为优选地，B为
    (5)D为
    例如，D为 优选地，D为
  9. 如权利要求1所述式I所示的化合物或其药学上可接受的盐，其特征在于，其为如下任一化合物

  10. 本发明提供了一种如权利要求1～9任一项所述式I所示的化合物或其药学上可接受的盐的制备方法，其特征在于，其为如下任一方案：
    方案(a):有机溶剂中，催化剂存在下，式II所示的化合物与式III所示的化合物发生如下所示的缩合反应，得到式I所示的化合物；
    方案(D):有机溶剂中，催化剂存在下，式VIII所示的化合物与式VIIII所示的化合物发生如下所示的环化反应，得到式I所示的化合物；
    其中，Z为卤素、TsO-、羟基、甲氧基、乙氧基、正丙氧基或异丙氧基；所述卤素例如为氯或溴；优选地，Z为羟基、甲氧基、乙氧基、正丙氧基或异丙氧基；
    A、L、B和D如权利要求1～9任一项所述。
  11. 一种药物组合物，其特征在于，其包含治疗有效量的物质A和药用辅料；所述物质A为如权 利要求1～9任一项所述式I所示的化合物或其药学上可接受的盐。
  12. 一种物质A在制备毒蕈碱受体正向变构调节剂中的应用，所述物质A为如权利要求1～9任一项所述式I所示的化合物或其药学上可接受的盐或如权利要求11所述的药物组合物。
  13. 一种物质A在制备药物中的应用，所述药物用于治疗和/或预防毒蕈碱受体介导的疾病，所述物质A为如权利要求1～9任一项所述式I所示的化合物或其药学上可接受的盐或如权利要求11所述的药物组合物；优选地，所述疾病为帕金森病、阿尔兹海默症、亨廷顿舞蹈症、精神分裂症或药物成瘾。
PCT/CN2023/127300 2022-10-28 2023-10-27 一种含氮杂环化合物、其药学上可接受的盐及其制备方法与应用 WO2024088409A1 (zh)

Applications Claiming Priority (14)

Application Number Priority Date Filing Date Title
CN202211339268 2022-10-28
CN202211339268.9 2022-10-28
CN202211686868.2 2022-12-26
CN202211686868 2022-12-26
CN202310099794.0 2023-02-08
CN202310099794 2023-02-08
CN202310186197 2023-03-01
CN202310186197.1 2023-03-01
CN202310263463.6 2023-03-17
CN202310263463 2023-03-17
CN202310719553.1 2023-06-16
CN202310719553 2023-06-16
CN202311378324 2023-10-23
CN202311378324.4 2023-10-23

Publications (1)

Publication Number Publication Date
WO2024088409A1 true WO2024088409A1 (zh) 2024-05-02

Family

ID=90798952

Family Applications (2)

Application Number Title Priority Date Filing Date
PCT/CN2023/127300 WO2024088409A1 (zh) 2022-10-28 2023-10-27 一种含氮杂环化合物、其药学上可接受的盐及其制备方法与应用
PCT/CN2023/127298 WO2024088408A1 (zh) 2022-10-28 2023-10-27 一种含氮杂环化合物、其药学上可接受的盐及其制备方法与应用

Family Applications After (1)

Application Number Title Priority Date Filing Date
PCT/CN2023/127298 WO2024088408A1 (zh) 2022-10-28 2023-10-27 一种含氮杂环化合物、其药学上可接受的盐及其制备方法与应用

Country Status (2)

Country Link
CN (2) CN117946113A (zh)
WO (2) WO2024088409A1 (zh)

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102015687A (zh) * 2008-02-28 2011-04-13 阿斯利康(瑞典)有限公司 毒蕈碱性受体激动剂、其组合物、其治疗方法以及其制备方法177
US20120040978A1 (en) * 2009-04-20 2012-02-16 Merck Sharp & Dohme Corp. Heterocyclic Fused Cinnoline M1 Receptor Positive Allosteric Modulators
US20170081332A1 (en) * 2014-05-16 2017-03-23 Takeda Pharmaceutical Company Limited Nitrogen-containing heterocyclic compound
WO2018112840A1 (en) * 2016-12-22 2018-06-28 Merck Sharp & Dohme Corp. 6, 5-fused heteroaryl piperidine ether allosteric modulators of the m4 muscarinic acetylcholine receptor
CN113727758A (zh) * 2019-03-01 2021-11-30 锐新医药公司 双环杂环基化合物及其用途

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB2285977B (en) * 1994-01-24 1998-05-27 Du Pont Merck Pharma Novel azetidine antipsychotic drugs
RU2016150326A (ru) * 2014-07-08 2018-08-08 ВАЙВ ХЕЛТКЕР ЮКей ЛИМИТЕД Производные изоиндолина для применения в лечении вирусной инфекции
HUE054857T2 (hu) * 2016-07-01 2021-10-28 Pfizer 5,7-dihidro-pirrolo-piridinszármazékok neurológiai és neurodegeneratív betegségek kezelésére
HUE060914T2 (hu) * 2017-06-22 2023-04-28 Pfizer Dihidro-pirrolo-piridin származékok
JP2023502445A (ja) * 2019-11-22 2023-01-24 エフ．ホフマン－ラ ロシュ アーゲー ピロリジン誘導体

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102015687A (zh) * 2008-02-28 2011-04-13 阿斯利康(瑞典)有限公司 毒蕈碱性受体激动剂、其组合物、其治疗方法以及其制备方法177
US20120040978A1 (en) * 2009-04-20 2012-02-16 Merck Sharp & Dohme Corp. Heterocyclic Fused Cinnoline M1 Receptor Positive Allosteric Modulators
US20170081332A1 (en) * 2014-05-16 2017-03-23 Takeda Pharmaceutical Company Limited Nitrogen-containing heterocyclic compound
WO2018112840A1 (en) * 2016-12-22 2018-06-28 Merck Sharp & Dohme Corp. 6, 5-fused heteroaryl piperidine ether allosteric modulators of the m4 muscarinic acetylcholine receptor
CN113727758A (zh) * 2019-03-01 2021-11-30 锐新医药公司 双环杂环基化合物及其用途

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
HU GUO-QIANG: "Recent Progress in Selective Muscarinic Agonists", PROGRESS IN PHARMACEUTICAL SCIENCES, vol. 25, no. 6, 30 December 2001 (2001-12-30), pages 326 - 330, XP093162781 *

Also Published As

Publication number Publication date
CN117946113A (zh) 2024-04-30
WO2024088408A1 (zh) 2024-05-02
CN117946112A (zh) 2024-04-30

Similar Documents

Publication Publication Date Title
AU2019262144B2 (en) RIP1 inhibitory compounds and methods for making and using the same
WO2021218110A1 (zh) 一类苯并噻唑基联芳基类化合物、制备方法和用途
EP3331879B1 (en) Benzazole compounds and methods for making and using the compounds
KR20210006407A (ko) Rip1 억제 화합물 및 이를 제조하고 사용하는 방법
TW202110837A (zh) 氫化吡啶并嘧啶類衍生物、其製備方法及其在醫藥上的應用
WO2019006126A1 (en) KINASE INHIBITORS AND METHODS OF MAKING AND USING THEM
CN111094288A (zh) 具有mgat-2抑制活性的稠合环衍生物
JP2023508097A (ja) タンパク質分解剤化合物の製造方法及び使用
WO2013154163A1 (ja) 新規５－アリール－１，２－チアジナン誘導体
TW202202492A (zh) ３－氮雜二環烷基衍生物及包含其之醫藥組成物
WO2021244634A1 (zh) 咪唑并吡啶类化合物及其用途
TW202344252A (zh) 一種喜樹鹼衍生物，基於其的抗體－藥物偶聯物和藥物組成物，及其應用
TW202110831A (zh) 吡啶酮類衍生物、其製備方法及其在醫藥上的應用
CN114230512A (zh) 芳香乙烯类化合物、其制备方法、中间体、药物组合物及其应用
TW202115036A (zh) 橋雜環基取代的嘧啶類化合物及其製備方法和醫藥用途
WO2024088409A1 (zh) 一种含氮杂环化合物、其药学上可接受的盐及其制备方法与应用
WO2019129114A1 (zh) 吲哚胺2,3-双加氧酶抑制剂以及它们在医学上的应用
WO2022247770A1 (zh) 一种含氮杂环化合物、其制备方法及应用
WO2022166923A1 (zh) 苯基二氢嘧啶类化合物及其应用
CN113773273B (zh) 苯并异噻唑类化合物及其制备方法和用途
TWI839738B (zh) 含氮雜環化合物、其製備方法及應用
CN114790164B (zh) 一种取代的异吲哚啉-1,3-二酮类pde4抑制剂及其药物用途
CN114105977B (zh) 雌激素受体调节剂化合物及其用途
WO2022052926A1 (zh) 芳香乙烯类化合物、其制备方法、中间体、药物组合物及其应用
WO2023141852A1 (zh) Cdk2抑制剂及其制备方法和用途

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 23881984

Country of ref document: EP

Kind code of ref document: A1