WO2022135567A1 - 一类含哒嗪的化合物及其医药用途 - Google Patents

一类含哒嗪的化合物及其医药用途 Download PDF

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WO2022135567A1
WO2022135567A1 PCT/CN2021/141211 CN2021141211W WO2022135567A1 WO 2022135567 A1 WO2022135567 A1 WO 2022135567A1 CN 2021141211 W CN2021141211 W CN 2021141211W WO 2022135567 A1 WO2022135567 A1 WO 2022135567A1
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alkyl
deuterium
halogen
cycloalkyl
substituents
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PCT/CN2021/141211
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English (en)
French (fr)
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余健
庞夏明
李云飞
张芳
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上海拓界生物医药科技有限公司
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Priority to CN202180074215.6A priority Critical patent/CN116390914A/zh
Publication of WO2022135567A1 publication Critical patent/WO2022135567A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—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
    • A61K31/501—Pyridazines; Hydrogenated pyridazines not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D237/00—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings
    • C07D237/02—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings
    • C07D237/06—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D237/10—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D237/14—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D237/00—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings
    • C07D237/02—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings
    • C07D237/06—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D237/10—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D237/20—Nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings

Definitions

  • the present disclosure relates to the field of medicine, in particular to a class of pyridazine-containing compounds and their medicinal uses.
  • NOD-like receptor protein 3 is a protein-coding gene that belongs to nucleotide-binding and oligomerization domain-like receptors (NLRs) ) family, also known as "pyodomain-containing protein 3" (Inoue et al, Immunology, 2013, 139, 11-18). This gene encodes a protein that contains a pyridine domain, a nucleotide-binding site domain (NBD), and a leucine-rich repeat (LRR) motif.
  • NLRs nucleotide-binding and oligomerization domain-like receptors
  • LRR leucine-rich repeat
  • NLRP3 interacts with adaptor proteins, apoptosis-associated speck-like protein (ASC), and zymogen-1 to form the NLRP3 inflammasome. Subsequently, activation of the NLRP3 inflammasome leads to the release of the inflammatory cytokines IL-1b and IL-18, and when dysregulated NLRP3
  • the present disclosure provides a compound of formula I or a pharmaceutically acceptable salt thereof,
  • R 2 and R 3 together with the atoms to which they are attached form a 5-6 membered cyclic hydrocarbon, phenyl, heterocycle or heteroaromatic ring optionally substituted with one or more substituents selected from: Deuterium, halogen, -OH, -NH 2 , -CN, oxo, C 1-6 alkyl, -OC 1-6 alkyl and C 3-6 cycloalkyl, the C 1-6 alkyl, - OC 1-6 alkyl and C 3-6 cycloalkyl are optionally further substituted with one or more deuterium or halogen;
  • R 4 , R 5 , R 6 and R 7 are independently selected from hydrogen, deuterium, halogen, -OH, -NH 2 and the following groups optionally substituted with one or more substituents: C 1-6 alkyl, -OC 1-6 alkyl, -SC 1-6 alkyl, C 3-6 cycloalkyl and C 3-6 cycloalkylmethylene, the substituents are selected from: deuterium, halogen, -OH, - NH2 and -CN;
  • R 6 and R 7 together with the atoms to which they are attached form a 5-6 membered cyclic hydrocarbon, 5-6 membered heterocycle, phenyl, 5-6 membered heteroaryl optionally substituted with one or more substituents
  • the substituent is selected from: deuterium, halogen, -OH, -NH 2 , -CN, oxo, C 1-6 alkyl, -OC 1-6 alkyl and C 3-6 cycloalkyl, the C 1-6 alkyl, -OC 1-6 alkyl and C 3-6 cycloalkyl are optionally further substituted by one or more deuterium or halogen;
  • R 4 , R 5 are independently selected from hydrogen, deuterium, halogen, - OH, -NH 2 and the following groups optionally substituted by one or more substituents: C 1-6 alkyl, -OC 1-6 alkyl, -SC 1-6 alkyl, C 3-6 cycloalkane and C 3-6
  • R3 and R4 together with the atoms to which they are attached form a 5-6 membered cyclic hydrocarbon, phenyl, heterocycle or heteroaromatic ring optionally substituted with one or more substituents selected from: Deuterium, halogen, -NH 2 , -CN, C 1-6 alkyl, -OC 1-6 alkyl and C 3-6 cycloalkyl, the C 1-6 alkyl, -OC 1-6 alkyl and C 3-6 cycloalkyl is optionally further substituted with one or more deuterium or halogen;
  • R 2 , R 5 , R 6 and R 7 are independently selected from hydrogen, deuterium, halogen, -OH, -NH 2 and any Select the following groups substituted by one or more substituents: C 1-6 alkyl, -OC 1-6 alkyl, -SC 1-6 alkyl, C 3-6 cycloalkyl and C 3-6 cyclo Alkylmethylene, the substituents are selected from:
  • R4 and R5 together with the atoms to which they are attached form a 5-6 membered cyclic hydrocarbon, phenyl, heterocycle or heteroaromatic ring optionally substituted with one or more substituents selected from: Deuterium, halogen, -OH, -NH 2 , -CN, oxo, C 1-6 alkyl, -OC 1-6 alkyl and C 3-6 cycloalkyl, the C 1-6 alkyl, - OC 1-6 alkyl and C 3-6 cycloalkyl are optionally further substituted with one or more deuterium or halogen;
  • R 2 , R 3 , R 6 and R 7 are independently selected from hydrogen, deuterium, halogen, -OH , -NH 2 and the following groups optionally substituted by one or more substituents: C 1-6 alkyl, -OC 1-6 alkyl, -SC 1-6 alkyl, C 3-6 cycloalkyl and C 3-6 cycloalkyl
  • R6 and R7 together with the atoms to which they are attached form a 5-6 membered cyclic hydrocarbon, 5-6 membered heterocycle, phenyl, 5-6 membered optionally substituted with one or more substituents Heteroaryl, the substituents being selected from: deuterium, halogen, -OH, -NH 2 , -CN, oxo, C 1-6 alkyl, -OC 1-6 alkyl and C 3-6 cycloalkyl , the C 1-6 alkyl, -OC 1-6 alkyl and C 3-6 cycloalkyl are optionally further substituted by one or more deuterium or halogen;
  • R 2 , R 3 , R 4 and R 5 are independent is selected from the group consisting of hydrogen, deuterium, halogen, -OH , -NH and the following groups optionally substituted with one or more substituents: C 1-6 alkyl, -OC 1-6 alkyl, -SC 1- 6
  • Z is O or -NH-(CH2)n-, and n is an integer selected from 0-3;
  • R 8a and R 8b are independently selected from hydrogen, deuterium or the following groups optionally substituted with one or more substituents: C 1-4 alkyl, C 3-6 cycloalkyl and C 3-6 cycloalkyl methylene, the substituents being selected from: deuterium, halogen, -NH 2 , -OH, -CN, C 1-4 alkyl, C 1-4 alkoxy, C 3-6 cycloalkyl and C 3 -6 cycloalkylmethylene, the above-mentioned substituents are optionally further substituted by one or more deuterium or halogen;
  • R6 and R7 together with the atoms to which they are attached form an unsubstituted 5-6 membered cyclic hydrocarbon, R1 is methyl or methoxy, and Z is -NH-, R8 is not aryl.
  • R 2 and R 3 together with the atoms to which they are attached form a 5-6 membered cyclic hydrocarbon, phenyl, heterocycle or heteroaromatic ring optionally substituted with one or more substituents selected from: Deuterium, halogen, -OH, -NH 2 , -CN, oxo, C 1-6 alkyl, -OC 1-6 alkyl and C 3-6 cycloalkyl, the C 1-6 alkyl, - OC 1-6 alkyl and C 3-6 cycloalkyl are optionally further substituted with one or more deuterium or halogen;
  • R 4 , R 5 , R 6 and R 7 are independently selected from hydrogen, deuterium, halogen, -OH , -NH 2 and the following groups optionally substituted by one or more substituents: C 1-6 alkyl, -OC 1-6 alkyl, -SC 1-6 alkyl, C 3-6 cycloalkyl and C 3-6 cycloalkyl
  • R3 and R4 together with the atoms to which they are attached form a 5-6 membered cyclic hydrocarbon, phenyl, heterocycle or heteroaromatic ring optionally substituted with one or more substituents selected from: Deuterium, halogen, -NH 2 , -CN, C 1-6 alkyl, -OC 1-6 alkyl and C 3-6 cycloalkyl, the C 1-6 alkyl, -OC 1-6 alkyl and C 3-6 cycloalkyl is optionally further substituted with one or more deuterium or halogen;
  • R 2 , R 5 , R 6 and R 7 are independently selected from hydrogen, deuterium, halogen, -OH, -NH 2 and any Select the following groups substituted by one or more substituents: C 1-6 alkyl, -OC 1-6 alkyl, -SC 1-6 alkyl, C 3-6 cycloalkyl and C 3-6 cyclo Alkylmethylene, the substituents are selected from:
  • R4 and R5 together with the atoms to which they are attached form a 5-6 membered cyclic hydrocarbon, phenyl, heterocycle or heteroaromatic ring optionally substituted with one or more substituents selected from: Deuterium, halogen, -OH, -NH 2 , -CN, oxo, C 1-6 alkyl, -OC 1-6 alkyl and C 3-6 cycloalkyl, the C 1-6 alkyl, - OC 1-6 alkyl and C 3-6 cycloalkyl are optionally further substituted with one or more deuterium or halogen;
  • R 2 , R 3 , R 6 and R 7 are independently selected from hydrogen, deuterium, halogen, -OH , -NH 2 and the following groups optionally substituted by one or more substituents: C 1-6 alkyl, -OC 1-6 alkyl, -SC 1-6 alkyl, C 3-6 cycloalkyl and C 3-6 cycloalkyl
  • R6 and R7 together with the atoms to which they are attached form a 5-6 membered cyclic hydrocarbon, 5-6 membered heterocycle, phenyl, 5-6 membered optionally substituted with one or more substituents Heteroaryl, the substituents being selected from: deuterium, halogen, -OH, -NH 2 , -CN, oxo, C 1-6 alkyl, -OC 1-6 alkyl and C 3-6 cycloalkyl , the C 1-6 alkyl, -OC 1-6 alkyl and C 3-6 cycloalkyl are optionally further substituted by one or more deuterium or halogen;
  • R 2 , R 3 , R 4 and R 5 are independent is selected from the group consisting of hydrogen, deuterium, halogen, -OH , -NH and the following groups optionally substituted with one or more substituents: C 1-6 alkyl, -OC 1-6 alkyl, -SC 1- 6
  • Z is O or -NH-(CH2)n-, and n is an integer selected from 0-3;
  • R 8a and R 8b are independently selected from hydrogen, deuterium or the following groups optionally substituted with one or more substituents: C 1-4 alkyl, C 3-6 cycloalkyl and C 3-6 cycloalkyl methylene, the substituents being selected from: deuterium, halogen, -NH 2 , -OH, -CN, C 1-4 alkyl, C 1-4 alkoxy, C 3-6 cycloalkyl and C 3 -6 cycloalkylmethylene, the above-mentioned substituents are optionally further substituted by one or more deuterium or halogen;
  • R6 and R7 together with the atoms to which they are attached form an unsubstituted 5-6 membered cyclic hydrocarbon, R1 is methyl or methoxy, and Z is -NH-, R8 is not aryl.
  • R 2 and R 3 together with the atoms to which they are attached form a 5-6 membered cyclic hydrocarbon, heterocyclic or heteroaromatic ring optionally substituted with one or more substituents selected from: deuterium, halogen , -OH, -NH 2 , -CN, oxo, C 1-6 alkyl, -OC 1-6 alkyl and C 3-6 cycloalkyl, the C 1-6 alkyl, -OC 1- 6 alkyl and C 3-6 cycloalkyl are optionally further substituted with one or more deuterium or halogen;
  • R 4 , R 5 , R 6 and R 7 are independently selected from hydrogen, deuterium, halogen, -OH, -NH 2 and the following groups optionally substituted with one or more substituents: C 1-6 alkyl, -OC 1-6 alkyl, -SC 1-6 alkyl, C 3-6 cycloalkyl, and C 3 -6 cycloalkylmethylene,
  • R 3 and R 4 together with the atoms to which they are attached form a 5-6 membered cyclic hydrocarbon, phenyl optionally substituted with one or more substituents selected from: deuterium, halogen, -NH 2 , -CN, C 1-6 alkyl, -OC 1-6 alkyl and C 3-6 cycloalkyl, the C 1-6 alkyl, -OC 1-6 alkyl and C 3-6 cycloalkane radicals are optionally further substituted with one or more deuterium or halogen;
  • R 2 , R 5 , R 6 and R 7 are independently selected from hydrogen, deuterium, halogen, -OH, -NH 2 and optionally substituted by one or more The following groups substituted by radicals: C 1-6 alkyl, -OC 1-6 alkyl, -SC 1-6 alkyl, C 3-6 cycloalkyl and C 3-6 cycloalkylmethylene, so The substituent is selected from: deuterium, hal
  • R 4 and R 5 together with the atoms to which they are attached form a 5-6 membered cyclic hydrocarbon, phenyl group optionally substituted by one or more substituents selected from: deuterium, halogen, -OH, -NH 2 , -CN, oxo, C 1-6 alkyl, -OC 1-6 alkyl and C 3-6 cycloalkyl, the C 1-6 alkyl, -OC 1-6 alkyl and C 3-6 cycloalkyl is optionally further substituted with one or more deuterium or halogen;
  • R 2 , R 3 , R 6 and R 7 are independently selected from hydrogen, deuterium, halogen, -OH, -NH 2 and optionally The following groups substituted with one or more substituents: C 1-6 alkyl, -OC 1-6 alkyl, -SC 1-6 alkyl, C 3-6 cycloalkyl and C 3-6 cycloalkane methylene, the substituents are selected from
  • R6 and R7 together with the atoms to which they are attached form a 5-6 membered cyclic hydrocarbon, 5-6 membered heterocycle, phenyl optionally substituted with one or more substituents, the substituents Selected from: deuterium, halogen, -OH, -NH 2 , -CN, oxo, C 1-6 alkyl, -OC 1-6 alkyl and C 3-6 cycloalkyl, the C 1-6 alkyl radicals, -OC 1-6 alkyl and C 3-6 cycloalkyl are optionally further substituted with one or more deuterium or halogen;
  • R 2 , R 3 , R 4 and R 5 are independently selected from hydrogen, deuterium, halogen , -OH, -NH 2 and the following groups optionally substituted by one or more substituents: C 1-6 alkyl, -OC 1-6 alkyl, -SC 1-6 alkyl, C 3-6 Cycloalkyl and C
  • Z is O or -NH-(CH2)n-, and n is an integer selected from 0-3;
  • R 8a and R 8b are independently selected from hydrogen, deuterium or the following groups optionally substituted with one or more substituents: C 1-4 alkyl, C 3-6 cycloalkyl and C 3-6 cycloalkyl methylene, the substituents being selected from: deuterium, halogen, -NH 2 , -OH, -CN, C 1-4 alkyl, C 1-4 alkoxy, C 3-6 cycloalkyl and C 3 -6 cycloalkylmethylene, the above-mentioned substituents are optionally further substituted by one or more deuterium or halogen;
  • R6 and R7 together with the atoms to which they are attached form an unsubstituted 5-6 membered cyclic hydrocarbon, R1 is methyl or methoxy, and Z is -NH-, R8 is not aryl.
  • R 2 and R 3 together with the atoms to which they are attached form a 5-6 membered cyclic hydrocarbon, heterocyclic or heteroaromatic ring optionally substituted with one or more substituents selected from: deuterium, halogen , -OH, -NH 2 , -CN, oxo, C 1-6 alkyl, -OC 1-6 alkyl and C 3-6 cycloalkyl, the C 1-6 alkyl, -OC 1- 6 alkyl and C 3-6 cycloalkyl are optionally further substituted with one or more deuterium or halogen;
  • R 4 , R 5 , R 6 and R 7 are independently selected from hydrogen, deuterium, halogen, -OH, -NH 2 and the following groups optionally substituted with one or more substituents: C 1-6 alkyl, -OC 1-6 alkyl, -SC 1-6 alkyl, C 3-6 cycloalkyl, and C 3 -6 cycloalkylmethylene,
  • R 3 and R 4 together with the atoms to which they are attached form a 5-6 membered cyclic hydrocarbon, phenyl optionally substituted with one or more substituents selected from: deuterium, halogen, -NH 2 , -CN, C 1-6 alkyl, -OC 1-6 alkyl and C 3-6 cycloalkyl, the C 1-6 alkyl, -OC 1-6 alkyl and C 3-6 cycloalkane radicals are optionally further substituted with one or more deuterium or halogen;
  • R 2 , R 5 , R 6 and R 7 are independently selected from hydrogen, deuterium, halogen, -OH, -NH 2 and optionally substituted by one or more The following groups substituted by radicals: C 1-6 alkyl, -OC 1-6 alkyl, -SC 1-6 alkyl, C 3-6 cycloalkyl and C 3-6 cycloalkylmethylene, so The substituent is selected from: deuterium, hal
  • R4 and R5 together with the atoms to which they are attached form a 5-6 membered cyclic hydrocarbon optionally substituted with one or more substituents selected from: deuterium, halogen, -OH, -NH2 , -CN, oxo, C 1-6 alkyl, -OC 1-6 alkyl and C 3-6 cycloalkyl, the C 1-6 alkyl, -OC 1-6 alkyl and C 3- 6 Cycloalkyl is optionally further substituted with one or more deuterium or halogen;
  • R 2 , R 3 , R 6 and R 7 are independently selected from hydrogen, deuterium, halogen, -OH, -NH 2 and optionally substituted by one or The following groups substituted with multiple substituents: C 1-6 alkyl, -OC 1-6 alkyl, -SC 1-6 alkyl, C 3-6 cycloalkyl and C 3-6 cycloalkylmethylene base, the substituent is selected from: deuterium,
  • R6 and R7 together with the atoms to which they are attached form a 5-6 membered cyclic hydrocarbon, 5-6 membered heterocycle, phenyl optionally substituted with one or more substituents, the substituents Selected from: deuterium, halogen, -OH, -NH 2 , -CN, oxo, C 1-6 alkyl, -OC 1-6 alkyl and C 3-6 cycloalkyl, the C 1-6 alkyl radicals, -OC 1-6 alkyl and C 3-6 cycloalkyl are optionally further substituted with one or more deuterium or halogen;
  • R 2 , R 3 , R 4 and R 5 are independently selected from hydrogen, deuterium, halogen , -OH, -NH 2 and the following groups optionally substituted by one or more substituents: C 1-6 alkyl, -OC 1-6 alkyl, -SC 1-6 alkyl, C 3-6 Cycloalkyl and C
  • Z is O or -NH-(CH2)n-, and n is an integer selected from 0-3;
  • R 8a and R 8b are independently selected from hydrogen, deuterium or the following groups optionally substituted with one or more substituents: C 1-4 alkyl, C 3-6 cycloalkyl and C 3-6 cycloalkyl methylene, the substituents being selected from: deuterium, halogen, -NH 2 , -OH, -CN, C 1-4 alkyl, C 1-4 alkoxy, C 3-6 cycloalkyl and C 3 -6 cycloalkylmethylene, the above-mentioned substituents are optionally further substituted by one or more deuterium or halogen;
  • R6 and R7 together with the atoms to which they are attached form an unsubstituted 5-6 membered cyclic hydrocarbon, R1 is methyl or methoxy, and Z is -NH-, R8 is not aryl.
  • R 2 and R 3 together with the atoms to which they are attached form a 5-6 membered cyclic hydrocarbon, heterocyclic or heteroaromatic ring optionally substituted with one or more substituents selected from: deuterium, halogen , -OH, -NH 2 , -CN, oxo, C 1-6 alkyl, -OC 1-6 alkyl and C 3-6 cycloalkyl, the C 1-6 alkyl, -OC 1- 6 alkyl and C 3-6 cycloalkyl are optionally further substituted with one or more deuterium or halogen;
  • R 4 , R 5 , R 6 and R 7 are independently selected from hydrogen, deuterium, halogen, -OH, -NH 2 and the following groups optionally substituted with one or more substituents: C 1-6 alkyl, -OC 1-6 alkyl, -SC 1-6 alkyl, C 3-6 cycloalkyl, and C 3 -6 cycloalkylmethylene,
  • R3 and R4 together with the atoms to which they are attached form a 5-6 membered cyclic hydrocarbon optionally substituted with one or more substituents selected from: deuterium, halogen, -NH2 , -CN , C 1-6 alkyl, -OC 1-6 alkyl and C 3-6 cycloalkyl, the C 1-6 alkyl, -OC 1-6 alkyl and C 3-6 cycloalkyl are optional further substituted with one or more deuterium or halogen;
  • R 2 , R 5 , R 6 and R 7 are independently selected from hydrogen, deuterium, halogen, -OH, -NH 2 and optionally substituted with one or more substituents
  • R4 and R5 together with the atoms to which they are attached form a 5-6 membered cyclic hydrocarbon optionally substituted with one or more substituents selected from: deuterium, halogen, -OH, -NH2 , -CN, oxo, C 1-6 alkyl, -OC 1-6 alkyl and C 3-6 cycloalkyl, the C 1-6 alkyl, -OC 1-6 alkyl and C 3- 6 Cycloalkyl is optionally further substituted with one or more deuterium or halogen;
  • R 2 , R 3 , R 6 and R 7 are independently selected from hydrogen, deuterium, halogen, -OH, -NH 2 and optionally substituted by one or The following groups substituted with multiple substituents: C 1-6 alkyl, -OC 1-6 alkyl, -SC 1-6 alkyl, C 3-6 cycloalkyl and C 3-6 cycloalkylmethylene base, the substituent is selected from: deuterium,
  • R and R together with the atoms to which they are attached form a 5-6 membered cyclic hydrocarbon or heterocycle optionally substituted with one or more substituents selected from the group consisting of: deuterium, halogen, - OH, -NH 2 , -CN, oxo, C 1-6 alkyl, -OC 1-6 alkyl and C 3-6 cycloalkyl, the C 1-6 alkyl, -OC 1-6 alkane and C 3-6 cycloalkyl are optionally further substituted with one or more deuterium or halogen;
  • R 2 , R 3 , R 4 and R 5 are independently selected from hydrogen, deuterium, halogen, -OH, -NH 2 and The following groups optionally substituted with one or more substituents: C 1-6 alkyl, -OC 1-6 alkyl, -SC 1-6 alkyl, C 3-6 cycloalkyl and C 3-6 Cycloalkylmethylene, the substituents are
  • Z is O or -NH-(CH2)n-, and n is an integer selected from 0-3;
  • R 8a and R 8b are independently selected from hydrogen, deuterium or the following groups optionally substituted with one or more substituents: C 1-4 alkyl, C 3-6 cycloalkyl and C 3-6 cycloalkyl methylene, the substituents being selected from: deuterium, halogen, -NH 2 , -OH, -CN, C 1-4 alkyl, C 1-4 alkoxy, C 3-6 cycloalkyl and C 3 -6 cycloalkylmethylene, the above-mentioned substituents are optionally further substituted by one or more deuterium or halogen;
  • R6 and R7 together with the atoms to which they are attached form an unsubstituted 5-6 membered cyclic hydrocarbon, R1 is methyl or methoxy, and Z is -NH-, R8 is not aryl.
  • R1 is -OH.
  • R 1 is -OC 1-6 alkyl, preferably -OCH 3 or -OCH 2 CH 3 , more preferably -OCH 3 .
  • R 1 is C 1-6 alkyl optionally substituted with one or more -OH, preferably -CH 2 OH or -CH 2 CH 2 OH, more preferably -CH 2 OH.
  • R1 is -NH2 .
  • R and R together with the atoms to which they are attached form a 5-6 membered cyclic hydrocarbon optionally substituted with one or more substituents selected from the group consisting of: deuterium, halogen, -OH, -NH 2 , -CN, oxo, C 1-6 alkyl, -OC 1-6 alkyl and C 3-6 cycloalkyl, the C 1-6 alkyl, -OC 1-6 alkyl and C 3-6 cycloalkyl is optionally further substituted with one or more deuterium or halogen;
  • R 4 , R 5 , R 6 and R 7 are independently selected from hydrogen, deuterium, halogen, -OH, -NH 2 and the following groups optionally substituted with one or more substituents: C 1-6 alkyl, -OC 1-6 alkyl, -SC 1-6 alkyl, C 3-6 cycloalkyl, C 3-6 cycloalkylmethylene, the substituents are selected from: deuterium, halogen, -OH, - NH2 and -CN.
  • the compound of formula I is:
  • R 9a is independently selected from hydrogen, deuterium, halogen, -OH, -NH 2 , -CN, oxo, C 1-6 alkyl, -OC 1-6 alkyl and C 3-6 cycloalkyl, the C 1-6 alkyl, -OC 1-6 alkyl and C 3-6 cycloalkyl are optionally further substituted with one or more deuterium or halogen; m is an integer selected from 0-8.
  • the compound of formula I is selected from:
  • the compound of formula I is selected from the group consisting of formula II'-a, II'-b, II'-c, II'-d, II'-f, II'-g, II'-k, II'- l and II'-m compounds; preferably from compounds of formula II'-a, II'-c, II'-d, II'-k, II'-l and II'-m; more preferably from formula II'-a , II'-d, II'-k and II'-m compounds; most preferably compounds of formula II'-a or II'-k.
  • R 2 and R 3 together with the atoms to which they are attached form a 5-6 membered cyclic hydrocarbon optionally substituted with one or more substituents selected from: deuterium, halogen, -OH , -NH 2 , -CN, oxo, C 1-6 alkyl, -OC 1-6 alkyl and C 3-6 cycloalkyl, the C 1-6 alkyl, -OC 1-6 alkyl and C 3-6 cycloalkyl is optionally further substituted with one or more deuterium or halogen;
  • R6 and R7 together with the atoms to which they are attached form phenyl, 5-6 membered heteroaryl optionally substituted with one or more substituents selected from: deuterium, halogen, -OH, -NH2 , -CN, oxo, C 1-6 alkyl, -OC 1-6 alkyl and C 3-6 cycloalkyl, the C 1-6 alkyl, -OC 1-6 alkyl and C 3- 6Cycloalkyl is optionally further substituted with one or more deuterium or halogen;
  • R 4 , R 5 are independently selected from hydrogen, deuterium, halogen, -OH, -NH 2 and the following groups optionally substituted with one or more substituents: C 1-6 alkyl, -OC 1-6 alkane group, C 3-6 cycloalkyl and C 3-6 cycloalkylmethylene, the substituents are selected from: deuterium, halogen, -OH, -NH2 and -CN.
  • R and R together with the atoms to which they are attached form a 5-6 membered cyclic hydrocarbon; preferably the 5-6 membered cyclic hydrocarbon is cyclopentyl or cyclohexyl; the cyclopentyl or cyclohexyl optionally substituted with a substituent selected from hydrogen, deuterium, halogen, -OH, C 1-6 alkyl, halogenated C 1-6 alkyl;
  • R 6 and R 7 together with the atoms to which they are attached form a phenyl, 5-6 membered heteroaryl; preferably the 5-6 membered heteroaryl is pyridine; the phenyl or 5-6 membered heteroaryl is optionally Replaced by a substituent selected from hydrogen, deuterium, halogen, -OH, C 1-6 alkyl, and halogenated C 1-6 alkyl;
  • R 4 , R 5 are independently selected from hydrogen, deuterium, halogen, -OH, -NH 2 and the following groups optionally substituted with one or more substituents: C 1-6 alkyl, -OC 1-6 alkane group, C 3-6 cycloalkyl and C 3-6 cycloalkylmethylene, the substituents are selected from: deuterium, halogen, -OH, -NH 2 and -CN; preferably R 4 , R 5 independently selected from hydrogen, deuterium, halogen, -OH, C 1-6 alkyl, haloC 1-6 alkyl; more preferably R 4 , R 5 are independently selected from hydrogen or deuterium.
  • R 2 and R 3 together with the atoms to which they are attached form a 5-6 membered heterocycle optionally substituted with one or more substituents selected from: deuterium, halogen, -OH , -NH 2 , -CN, oxo, C 1-6 alkyl, -OC 1-6 alkyl and C 3-6 cycloalkyl, the C 1-6 alkyl, -OC 1-6 alkyl and C 3-6 cycloalkyl is optionally further substituted with one or more deuterium or halogen;
  • R 4 , R 5 , R 6 and R 7 are independently selected from hydrogen, deuterium, halogen, -OH, -NH 2 and the following groups optionally substituted with one or more substituents: C 1-6 alkyl, -OC 1-6 alkyl, -SC 1-6 alkyl, C 3-6 cycloalkyl, C 3-6 cycloalkylmethylene, the substituents are selected from: deuterium, halogen, -OH, - NH2 and -CN.
  • the 5-6 membered heterocycle is a 5-6 membered S-containing heterocycle.
  • the compound of formula I is selected from:
  • R 9b is selected from hydrogen, deuterium, halogen, -OH, -NH 2 , -CN, oxo, C 1-6 alkyl, -OC 1-6 alkyl and C 3-6 cycloalkyl, the C 1 -6 alkyl, -OC 1-6 alkyl and C 3-6 cycloalkyl are optionally further substituted with one or more deuterium or halogen;
  • R 9c is selected from the group consisting of hydrogen, deuterium, C 1-6 alkyl and C 3-6 cycloalkyl, optionally further substituted by one or more deuterium or halogen Substituted; p is an integer selected from 0-6.
  • the compound of formula I is selected from:
  • the compound of formula I is selected from the group consisting of formula III'-a, III'-b, III'-c, III'-d, III'-f, III'-g, III'-h, and III'- i compounds; preferably compounds of formula III'-a, III'-b, III'-c, III'-f, III'-g and III'-h; more preferably selected from formula III'-a, III'-c , III'-f and III'-h compounds; most preferably compounds of formula III'-a or III'-f.
  • R 2 and R 3 together with the atoms to which they are attached form a 5-6 membered heteroaromatic ring optionally substituted with one or more substituents selected from the group consisting of: deuterium, halogen, - OH, -NH 2 , -CN, C 1-6 alkyl, -OC 1-6 alkyl and C 3-6 cycloalkyl, the C 1-6 alkyl, -OC 1-6 alkyl and C 3-6 Cycloalkyl is optionally further substituted with one or more deuterium or halogen;
  • R 4 , R 5 , R 6 and R 7 are independently selected from hydrogen, deuterium, halogen, -OH, -NH 2 and the following groups optionally substituted with one or more substituents: C 1-6 alkyl, -OC 1-6 alkyl, -SC 1-6 alkyl, C 3-6 cycloalkyl, C 3-6 cycloalkylmethylene, the substituents are selected from: deuterium, halogen, -OH, - NH2 and -CN.
  • the 5-6 membered heteroaromatic ring is a 5-membered S-containing heteroaromatic ring.
  • the compound of formula I is selected from:
  • R 9d is selected from hydrogen, deuterium, halogen, -OH, -NH 2 , -CN, C 1-6 alkyl, -OC 1-6 alkyl and C 3-6 cycloalkyl, the C 1-6 alkyl radicals, -OC 1-6 alkyl and C 3-6 cycloalkyl are optionally further substituted with one or more deuterium or halogen;
  • R 9e is selected from the group consisting of hydrogen, deuterium, C 1-6 alkyl and C 3-6 cycloalkyl optionally further substituted by one or more deuterium or halogen Substituted; q is an integer selected from 0-3.
  • the compound of formula I is selected from:
  • the compound of formula I is selected from the group consisting of formula IV'-a, IV'-b, IV'-c, IV'-d, IV'-e, IV'-f, IV'-g, IV'- h, IV'-i, IV'-j, IV'-k and IV'-l compounds; preferably selected from Formula IV'-a, IV'-b, IV'-c, IV'-d, IV'-g , IV'-h, IV'-i and IV'-j compounds; more preferably from formula IV'-a, IV'-d, IV'-g and IV'-j compounds; most preferably formula IV'-a or IV'-g compounds.
  • Formula II-a, Formula II-b, Formula II'-a to II'-q, Formula III-a to III-p, Formula III'a to III'-r, Formula IV-a To IV-n and formulas IV'-a to IV'-p, R 4 , R 5 , R 6 and R 7 are independently selected from hydrogen, deuterium, halogen and the following optionally substituted with one or more substituents Group: C 1-6 alkyl, C 3-6 cycloalkyl and C 3-6 cycloalkylmethylene, the substituents are deuterium or halogen.
  • R and R are independently selected from hydrogen, deuterium, and halogen, and R and R are independently selected from hydrogen, deuterium, halogen, and C optionally substituted with one or more deuterium or halogen. -6 alkyl.
  • R 4 , R 5 and R 7 are each hydrogen and R 6 is methyl; alternatively, R 4 , R 6 and R 7 are each hydrogen and R 5 is methyl.
  • R3 and R4 together with the atoms to which they are attached form a 5-6 membered cyclic hydrocarbon optionally substituted with one or more substituents selected from: deuterium, halogen, C1 -6 alkyl and C 3-6 cycloalkyl, optionally further substituted with one or more deuterium or halogen;
  • R 2 , R 5 , R 6 and R 7 are independently selected from hydrogen, deuterium, halogen, -OH, -NH 2 and the following groups optionally substituted with one or more substituents: C 1-6 alkyl, -OC 1-6 alkyl, -SC 1-6 alkyl, C 3-6 cycloalkyl, C 3-6 cycloalkylmethylene, the substituents are selected from: deuterium, halogen, -OH, - NH2 and -CN.
  • the compound of formula I is selected from:
  • the compound of formula I is selected from compounds of formulae V-a, V-b, V-c, V-d, V-f, V-g, V-k, V-l and V-m; preferably from compounds of formula V-a, V-c, V-d, V-k, V-l and V-m; more preferably from Compounds of formula V-a, V-d, V-k and V-m; most preferably compounds of formula V-a or V-k.
  • R 2 , R 5 , R 6 , and R 7 are independently selected from hydrogen, deuterium, halogen, and the following groups optionally substituted with one or more substituents: C 1-6 alkyl, C 3-6 cycloalkyl and C 3-6 cycloalkylmethylene, the substituents are deuterium or halogen.
  • R and R are independently selected from hydrogen , deuterium, and halogen, and R and R are independently selected from hydrogen, deuterium, halogen, and C optionally substituted with one or more deuterium or halogen. -6 alkyl.
  • R 2 , R 5 and R 7 are each hydrogen and R 6 is methyl; alternatively, R 2 , R 6 and R 7 are each hydrogen and R 5 is methyl.
  • R4 and R5 together with the atoms to which they are attached form a 5-6 membered cyclic hydrocarbon optionally substituted with one or more substituents selected from: deuterium, halogen, oxo , C 1-6 alkyl and C 3-6 cycloalkyl, said C 1-6 alkyl and C 3-6 cycloalkyl are optionally further substituted with one or more deuterium or halogen;
  • R 2 , R 3 , R 6 and R 7 are independently selected from hydrogen, deuterium, halogen, -OH, -NH 2 and the following groups optionally substituted with one or more substituents: C 1-6 alkyl, -OC 1-6 alkyl, -SC 1-6 alkyl, C 3-6 cycloalkyl, C 3-6 cycloalkylmethylene, the substituents are selected from: deuterium, halogen, -OH, - NH2 and -CN;
  • the compound of formula I is selected from:
  • the compound of formula I is selected from the group consisting of formula VI-a, VI-b, VI-c, VI-d, VI-e, VI-h, VI-i, VI-j, VI-k, and VI- l compound; preferably a compound of formula VI-a, VI-b, VI-c, VI-h, VI-i and VI-j; more preferably a compound of formula VI-a or VI-h.
  • R 2 , R 3 , R 6 and R 7 are independently selected from hydrogen, deuterium, halogen and the following optionally substituted with one or more substituents Group: C 1-6 alkyl, C 3-6 cycloalkyl and C 3-6 cycloalkylmethylene, the substituents are deuterium or halogen.
  • R and R are independently selected from hydrogen , deuterium, and halogen, and R and R are independently selected from hydrogen, deuterium, halogen, and C optionally substituted with one or more deuterium or halogen. -6 alkyl.
  • R 2 and R 7 are each hydrogen, R 3 is trifluoromethyl, and R 6 is methyl; alternatively, R 2 and R 7 are each hydrogen, R 3 is chloro, and R 6 is methyl .
  • R4 and R5 together with the atom to which they are attached form a phenyl group optionally substituted with one or more substituents selected from the group consisting of: deuterium, halogen, oxo, C1-6alkane and C 3-6 cycloalkyl, said C 1-6 alkyl and C 3-6 cycloalkyl are optionally further substituted with one or more deuterium or halogen;
  • R 2 , R 3 , R 6 and R 7 are independently selected from hydrogen, deuterium, halogen, -OH, -NH 2 and the following groups optionally substituted with one or more substituents: C 1-6 alkyl, -OC 1-6 alkyl, -SC 1-6 alkyl, C 3-6 cycloalkyl, C 3-6 cycloalkylmethylene, the substituents are selected from: deuterium, halogen, -OH, - NH2 and -CN;
  • R 2 , R 3 , R 6 and R 7 are independently selected from hydrogen, deuterium, halogen, -OH, -NH 2 , C 1-6 alkyl, -OC 1-6 alkyl;
  • R 2 , R 3 , R 6 and R 7 are independently selected from hydrogen, deuterium, halogen, -OH, -NH 2 , C 1-6 alkyl, -OC 1-6 alkyl;
  • R2, R3 , R6 and R7 are independently selected from hydrogen or deuterium.
  • the compound of formula I is selected from:
  • R 18b is independently selected from hydrogen, deuterium, halogen, -OH, -NH 2 and the following groups optionally substituted with one or more substituents: C 1-6 alkyl, -OC 1-6 alkyl, C 3-6 cycloalkyl, C 3-6 cycloalkylmethylene, the substituents are selected from: deuterium, halogen, -OH, -NH 2 and -CN; preferably R 18b is hydrogen.
  • R 2 , R 5 , R 6 and R 7 are independently selected from hydrogen, deuterium, halogen, -OH, -NH 2 and the following groups optionally substituted with one or more substituents: C 1-6 alkyl, -OC 1-6 alkyl, -SC 1-6 alkyl, C 3-6 cycloalkyl, C 3-6 cycloalkylmethylene, the substituents are selected from: deuterium, halogen, -OH, - NH2 and -CN;
  • R 2 , R 5 , R 6 and R 7 are independently selected from hydrogen, deuterium, halogen, -OH, -NH 2 , C 1-6 alkyl, -OC 1-6 alkyl;
  • R 2 , R 5 or R 7 are independently selected from hydrogen, deuterium, halogen, -OH, -NH 2 , C 1-6 alkyl, -OC 1-6 alkyl; R 6 is selected from C 1-6 alkyl;
  • R2 and R7 are independently selected from hydrogen or deuterium and R6 is methyl.
  • the compound of formula I is selected from:
  • R 18a is independently selected from hydrogen, deuterium, halogen, -OH, -NH 2 and the following groups optionally substituted with one or more substituents: C 1-6 alkyl, -OC 1-6 alkyl, C 3-6 cycloalkyl, C 3-6 cycloalkylmethylene, the substituents are selected from: deuterium, halogen, -OH, -NH 2 and -CN;
  • R 18a is independently selected from hydrogen, deuterium, halogen, -OH, -NH 2 or C 1-6 alkyl, -OC 1-6 alkyl; more preferably R 18a is hydrogen.
  • R6 and R7 together with the atoms to which they are attached form a 5-6 membered cyclic hydrocarbon optionally substituted with one or more substituents selected from: deuterium, halogen, C1 -6 alkyl, -OC 1-6 alkyl and C 3-6 cycloalkyl, the C 1-6 alkyl, -OC 1-6 alkyl and C 3-6 cycloalkyl are optionally further replaced by a or more deuterium or halogen substitution;
  • R 2 , R 3 , R 4 and R 5 are independently selected from hydrogen, deuterium, halogen, -OH, -NH 2 and the following groups optionally substituted with one or more substituents : C 1-6 alkyl, -OC 1-6 alkyl, -SC 1-6 alkyl, C 3-6 cycloalkyl, C 3-6 cycloalkylmethylene, the substituents are selected from: Deuterium, halogen, -OH , -NH and -CN
  • R 2 , R 4 and R 5 are independently selected from hydrogen, deuterium, C 1-6 alkyl and halogen, and R 3 is selected from trifluoromethyl, cyclopropyl, -S-trifluoromethyl;
  • R2, R4 and R5 are independently selected from hydrogen or deuterium and R3 is selected from trifluoromethyl.
  • the compound of formula I is selected from:
  • the compound of formula I is selected from compounds of formulae VII-a, VII-b, VII-c, VII-g, VII-h, and VII-i; preferably from the group consisting of formulae VII-a, VII-b, VII- g and VII-h compounds; more preferably compounds of formula VII-a or VII-g; most preferably compounds of formula VII-g.
  • R6 and R7 together with the atoms to which they are attached form a 5-6 membered heterocycle optionally substituted with one or more substituents selected from the group consisting of: deuterium, halogen, oxo , C 1-6 alkyl, -OC 1-6 alkyl and C 3-6 cycloalkyl, the C 1-6 alkyl, -OC 1-6 alkyl and C 3-6 cycloalkyl are optional is further substituted with one or more deuterium or halogen;
  • R 2 , R 3 , R 4 and R 5 are independently selected from hydrogen, deuterium, halogen, -OH, -NH 2 and the following groups optionally substituted with one or more substituents: C 1-6 alkyl, -OC 1-6 alkyl, -SC 1-6 alkyl, C 3-6 cycloalkyl, C 3-6 cycloalkylmethylene, the substituents are selected from: deuterium, halogen, -OH, - NH2 and -CN.
  • the compound of formula I is selected from:
  • R 9f is independently selected from deuterium, halogen, oxo, C 1-6 alkyl, -OC 1-6 alkyl and C 3-6 cycloalkyl, the C 1-6 alkyl, -OC 1-6 Alkyl and C3-6cycloalkyl are optionally further substituted with one or more deuterium or halogen;
  • R 9g is selected from hydrogen, deuterium, C 1-6 alkyl and C 3-6 cycloalkyl, optionally further substituted by one or more deuterium or halogen Substituted; r is an integer selected from 0-6.
  • the compound of formula I is selected from:
  • the compound of formula I is selected from the group consisting of formula VIII'-a, VIII'-c, VIII'-d, VIII'-f, VIII'-g, VIII'-j, VIII'-k, VIII'- l and VIII'-m compounds; preferably from compounds of formulae VIII'-a, VIII'-c, VIII'-d, VIII'-f, VIII'-g, VIII'-j and VIII'-l; more preferably from Compounds of formula VIII'-a, VIII'-c, VIII'-d and VIII'-j; most preferably compounds of formula VIII'-a or VIII'-d.
  • R 2 , R 3 , R 4 and R 5 are independently selected from hydrogen, deuterium, halogen, -OH, -NH 2 and the following groups optionally substituted with one or more substituents: C 1-6 alkyl, -OC 1-6 alkyl, -SC 1-6 alkyl, C 3-6 cycloalkyl, C 3-6 cycloalkylmethylene, the substituents are selected from: deuterium, halogen, -OH, - NH2 and -CN.
  • the compound of formula I is selected from:
  • R 9k is independently selected from deuterium, halogen, oxo, C 1-6 alkyl, -OC 1-6 alkyl and C 3-6 cycloalkyl, the C 1-6 alkyl, -OC 1-6 Alkyl and C3-6cycloalkyl are optionally further substituted with one or more deuterium or halogen;
  • R 9k is independently selected from deuterium, halogen, oxo, C 1-6 alkyl, -OC 1-6 alkyl.
  • R 2 , R 3 , R 4 and R are independently selected from hydrogen, deuterium, halogen and the following groups optionally substituted with one or more substituents: C 1-6 alkyl, C 3-6 cycloalkyl and C 3-6 cycloalkyl methylene, the substituent is deuterium or halogen; more preferably R 9k is independently selected from deuterium, halogen, oxo, halo-C 1-6 alkyl, halo-OC 1-6 alkyl; most preferably R 9k is independently selected from deuterium, halogen, C 1-6 alkyl, -OC 1-6 alkyl.
  • R and R are independently selected from hydrogen , deuterium, and halogen, and R and R are independently selected from hydrogen, deuterium, halogen, and C optionally substituted with one or more deuterium or halogen. -6 alkyl.
  • R 2 and R 4 are each hydrogen, R 3 is trifluoromethyl or chlorine, and R 5 is hydrogen, halogen or methyl; preferably R 2 , R 4 and R 5 are each hydrogen, and R 3 is trifluoromethyl.
  • R and R together with the atoms to which they are attached form a 5-6 membered heteroaryl optionally substituted with one or more substituents selected from the group consisting of: deuterium, halogen, oxygen generation, C 1-6 alkyl, -OC 1-6 alkyl and C 3-6 cycloalkyl, the C 1-6 alkyl, -OC 1-6 alkyl and C 3-6 cycloalkyl are any Optionally, it is further substituted by one or more deuterium or halogen; preferably, the 5-6-membered heteroaryl group is pyridine;
  • R 2 , R 3 , R 4 and R 5 are independently selected from hydrogen, deuterium, halogen, -OH, -NH 2 and the following groups optionally substituted with one or more substituents: C 1-6 alkyl, -OC 1-6 alkyl, -SC 1-6 alkyl, C 3-6 cycloalkyl, C 3-6 cycloalkylmethylene, the substituents are selected from: deuterium, halogen, -OH, - NH2 and -CN.
  • R and R together with the atoms to which they are attached form a 5-6 membered heteroaryl group containing 1-2 heteroatoms optionally substituted with one or more substituents the substitution The group is selected from: deuterium, halogen, C 1-6 alkyl, -OC 1-6 alkyl and C 3-6 cycloalkyl, the C 1-6 alkyl, -OC 1-6 alkyl and C 3 -6 Cycloalkyl is optionally further substituted with one or more deuterium or halogen; the heteroatom is selected from oxygen, nitrogen, sulfur, preferably the heteroatom is selected from nitrogen.
  • the compound of formula I is selected from:
  • the X is selected from an oxygen atom or a sulfur atom;
  • the R 18c is selected from deuterium, halogen, C 1-6 alkyl, -OC 1-6 alkyl and C 3-6 cycloalkyl, the C 1-6 Alkyl, -OC 1-6 alkyl and C 3-6 cycloalkyl are optionally further substituted with one or more halogens; preferably R 18c is independently selected from deuterium, halogen, C 1-6 alkyl, -OC 1 -6 alkyl;
  • a is selected from an integer of 0-3; preferably a is selected from an integer of 0-1; more preferably a is 0;
  • a compound of formula Xa, Xb, Xc, Xd, Xe, Xf, Xg, Xh, Xi, or a pharmaceutically acceptable salt thereof wherein R 2 , R 3 , R 4 and R 5 are independently is selected from the group consisting of hydrogen, deuterium, halogen, and optionally substituted with one or more substituents: C1-6 alkyl, C3-6 cycloalkyl, and C3-6 cycloalkylmethylene, where Said substituent is deuterium or halogen.
  • a compound of formula Xa, Xb, Xc, Xd, Xe, Xf, Xg, Xh, Xi, or a pharmaceutically acceptable salt thereof wherein R and R are independently selected from hydrogen , deuterium and Halogen, R3 and R5 are independently selected from hydrogen, deuterium, halogen and C1-6 alkyl optionally substituted with one or more deuterium or halogen.
  • a compound of formula Xa, Xb, Xc, Xd, Xe, Xf, Xg, Xh, Xi, or a pharmaceutically acceptable salt thereof wherein R 2 and R 4 are each hydrogen, and R 3 is three Fluoromethyl or chlorine, R 5 is hydrogen or methyl; preferably R 2 , R 4 and R 5 are each hydrogen, and R 3 is trifluoromethyl.
  • the present disclosure also provides a compound of formula I' or a pharmaceutically acceptable salt thereof,
  • R 13 is selected from the following groups optionally substituted with one or more substituents: C 2-6 alkyl, -SC 1-6 alkyl and C 3-6 cycloalkyl, the substituents being selected from deuterium, Halogen and -OH.
  • R 15 , R 16 and R 17 are independently selected from hydrogen, deuterium, halogen, -OH, -NH 2 and C 1-6 alkyl , optionally by one or more of the following Substituent substitution of: deuterium, halogen, -OH, -NH2 and -CN;
  • Z is O or -NH-(CH2)n-, and n is an integer selected from 0-3;
  • R 8a and R 8b are independently selected from hydrogen, deuterium, or the following groups optionally substituted with one or more substituents: C 1-4 alkyl, C 3-6 cycloalkyl, C 3-6 cycloalkyl Methylene, the substituents are selected from: deuterium, halogen, -NH 2 , -OH, -CN, C 1-4 alkyl, C 1-4 alkoxy, C 3-6 cycloalkyl or C 3 -6 cycloalkylmethylene, the above substituents are optionally further substituted with one or more deuterium or halogen.
  • R 13 is selected from ethyl, n-propyl, isopropyl and n-butyl, preferably ethyl;
  • R 13 is -S-CF 3 .
  • R 13 is selected from:
  • R 11 is -OH.
  • R 11 is -NH 2 .
  • R 11 is -OC 1-6 alkyl optionally substituted with deuterium or halogen; preferably methoxy or ethoxy; more preferably methoxy.
  • R 11 is -CH 2 OH.
  • R 15 , R 16 and R 17 are independently selected from hydrogen, deuterium, fluoro and methyl.
  • the present disclosure also provides a compound of formula I" or a pharmaceutically acceptable salt thereof,
  • R 23 is selected from chlorine or C 1-6 alkyl optionally substituted with one or more deuterium or halogen;
  • R 25 , R 26 and R 27 are independently selected from hydrogen, deuterium, halogen, -OH, -NH 2 and C 1-6 alkyl optionally selected by one or more of the following Substituent substitution of: deuterium, halogen, -OH, -NH2 and -CN;
  • Z is O or -NH-(CH2)n-, and n is an integer selected from 0-3;
  • R 8a and R 8b are independently selected from hydrogen, deuterium, or the following groups optionally substituted with one or more substituents: C 1-4 alkyl, C 3-6 cycloalkyl, C 3-6 cycloalkyl Methylene, the substituents are selected from: deuterium, halogen, -NH 2 , -OH, -CN, C 1-4 alkyl, C 1-4 alkoxy, C 3-6 cycloalkyl or C 3 -6 cycloalkylmethylene, the above-mentioned substituents are optionally further substituted by one or more deuterium or halogen;
  • R 21 is not methoxy.
  • R 21 is -NH 2 .
  • R 21 is -OC 1-6 alkyl optionally substituted with deuterium or halogen; preferably methoxy or ethoxy; more preferably methoxy.
  • R 21 is -CH 2 OH.
  • R 23 is C 1-6 alkyl optionally substituted with one or more fluorine, preferably trifluoromethyl.
  • R 23 is chloro
  • R 25 , R 26 and R 27 are independently selected from hydrogen, deuterium, fluoro and methyl.
  • Z is O.
  • Z is -NH-(CH2)n-, and n is an integer selected from 0-2; n is preferably 0 or 1; more preferably n is 0.
  • R 8a and R 8b are independently selected from hydrogen, deuterium and the following groups optionally substituted with one or more substituents: C 1-4 alkyl, C 3-6 cycloalkyl and C 3-6 cycloalkyl Methylene, the substituents are selected from: deuterium, halogen, -NH 2 , -OH, -CN, C 1-4 alkyl, C 1-4 alkoxy, C 3-6 cycloalkyl or C 3 -6 cycloalkylmethylene, the above substituents are optionally further substituted with one or more deuterium or halogen.
  • R 8 is selected from:
  • R 10a is selected from hydrogen, deuterium, halogen, oxo, -OH, -NH 2 , -COOH, -CN, C 1-4 alkyl and C 3-6 cycloalkyl, the C 1-4 alkyl or C 3-6 cycloalkyl is optionally further substituted with one or more deuterium, halogen or -OH;
  • R 10b is selected from the group consisting of hydrogen, deuterium, C 1-4 alkyl and C 3-6 cycloalkyl , optionally further substituted by one or more deuterium or halogen Substituted; s is an integer selected from 0-15.
  • R 8 is selected from:
  • R 8 is preferably
  • R 8a and R 8b are independently selected from hydrogen, deuterium and the following groups optionally substituted with one or more substituents: C 1-4 alkyl, C 3-6 cycloalkyl and C 3-6 cycloalkyl Methylene, the substituents are selected from: deuterium, halogen, -NH 2 , -OH, -CN, C 1-4 alkyl, C 1-4 alkoxy, C 3-6 cycloalkyl or C 3 -6 cycloalkylmethylene, the above substituents are optionally further substituted with one or more deuterium or halogen.
  • R 8 is selected from:
  • R 10d is selected from the group consisting of hydrogen, deuterium, C 1-4 alkyl and C 3-6 cycloalkyl optionally further substituted by one or more deuterium or halogen Substituted; t is an integer selected from 0-7.
  • R 8 is selected from:
  • R 8 is selected from C 3-8 cycloalkyl optionally substituted with one or more substituents selected from deuterium, halogen, -OH, -NH2 , -CN and C1-4 alkyl optionally further substituted with one or more deuterium, halogen or -OH.
  • R 8 is selected from:
  • R 10e , R 10f , R 10e′ , R 10f′ are independently selected from hydrogen, deuterium, halogen, -OH, and C 1-4 alkyl optionally further modified by one or more Deuterium, halogen or -OH substitution.
  • R 8 is selected from:
  • R 10e , R 10e' are independently selected from hydrogen, deuterium, halogen, -OH and C 1-4 alkyl optionally further substituted with one or more deuterium, halogen or -OH .
  • R 8 is selected from:
  • R 8a and R 8b are independently selected from hydrogen, deuterium and the following groups optionally substituted with one or more substituents: C 1-4 alkyl, C 3-6 cycloalkyl and C 3-6 cycloalkyl Methylene, the substituents are selected from: deuterium, halogen, -NH 2 , -OH, -CN, C 1-4 alkyl, C 1-4 alkoxy, C 3-6 cycloalkyl or C 3 -6 cycloalkylmethylene, the above substituents are optionally further substituted with one or more deuterium or halogen.
  • R 8 is selected from:
  • R 10g is selected from hydrogen, deuterium, halogen, -NH 2 , -OH, -CN, -NH-C 1-4 alkyl and -N(C 1-4 alkyl) 2 , the C 1-4 alkyl Optionally substituted with one or more of deuterium, halogen or -OH.
  • the present disclosure provides a compound or a pharmaceutically acceptable salt thereof selected from the group consisting of:
  • the present disclosure provides a compound or a pharmaceutically acceptable salt thereof selected from the group consisting of:
  • the present disclosure also provides an isotopic substitution of the aforementioned compound, preferably, the isotopic substitution is a deuterium atom substitution
  • the present disclosure also provides a pharmaceutical composition, comprising the compound described in the first to third aspects or a pharmaceutically acceptable salt thereof or the isotopic substitution described in the fourth aspect, and at least one pharmaceutically acceptable carrier, diluent or excipient.
  • the unit dose of the pharmaceutical composition is 0.001 mg-1000 mg.
  • the pharmaceutical composition contains 0.01-99.99% of the aforementioned compound or a pharmaceutically acceptable salt thereof, based on the total weight of the composition. In certain embodiments, the pharmaceutical composition contains 0.1-99.9% of the aforementioned compound or a pharmaceutically acceptable salt thereof. In certain embodiments, the pharmaceutical composition contains 0.5%-99.5% of the compound or a pharmaceutically acceptable salt thereof. In certain embodiments, the pharmaceutical composition contains 1%-99% of the compound or a pharmaceutically acceptable salt thereof. In certain embodiments, the pharmaceutical composition contains 2%-98% of the compound or a pharmaceutically acceptable salt thereof.
  • the present disclosure also provides use of a compound of the first, second or third aspect, or a pharmaceutically acceptable salt thereof, as a medicament.
  • the present disclosure also provides the compounds of the first, second or third aspects or their pharmaceutically acceptable salts, or the isotopic substitutions of the fourth aspect or the pharmaceutical compositions of the fifth aspect in the preparation of treatment Use in the medicament of a disease associated with NLRP3 activity.
  • the present disclosure also provides a method of preventing and/or treating a patient with a disease associated with NLRP3 activity by administering to the patient a therapeutically effective amount of a compound of the first, second or third aspect or a pharmaceutically acceptable amount thereof Use a salt, or the isotopic substitution of the fourth aspect, or the pharmaceutical composition of the fifth aspect.
  • the present disclosure also provides a compound according to the first, second or third aspect, or a pharmaceutically acceptable salt thereof, or the isotopic substitution or the third aspect for preventing or treating a disease associated with NLRP3 activity.
  • the pharmaceutical composition of the fifth aspect is also provided.
  • the present disclosure also provides a method of preventing and/or treating a patient of a disease associated with NLRP3 activity by administering to the patient a therapeutically effective amount of the aforementioned compound or a pharmaceutically acceptable salt thereof, or the aforementioned pharmaceutical composition.
  • Diseases associated with NLRP3 activity include inflammasome-related diseases, immune diseases, inflammatory diseases, autoimmune diseases, and/or autoinflammatory diseases.
  • the present disclosure also provides the compounds of the first, second or third aspects or pharmaceutically acceptable salts thereof, or the isotopic substitutions of the fourth aspect or the pharmaceutical compositions of the fifth aspect in the preparation of the treatment of inflammasomes.
  • the present disclosure also provides the compounds of the first, second or third aspects or pharmaceutically acceptable salts thereof, or the isotopic substitutions of the fourth aspect or the pharmaceutical compositions of the fifth aspect in the preparation of the treatment of inflammasomes.
  • the present disclosure also provides a compound according to the first, second or third aspect for treating an inflammasome-related disease, an immune disease, an inflammatory disease, an autoimmune disease and/or an autoinflammatory disease or A pharmaceutically acceptable salt thereof, or the isotopic substitution of the fourth aspect or the pharmaceutical composition of the fifth aspect.
  • the present disclosure also provides a method of treating and/or preventing a patient with inflammasome-related disease, immune disease, inflammatory disease, autoimmune disease, and/or autoinflammatory disease by administering to the patient a therapeutically effective amount
  • a patient with inflammasome-related disease, immune disease, inflammatory disease, autoimmune disease, and/or autoinflammatory disease by administering to the patient a therapeutically effective amount
  • the aforementioned compound or a pharmaceutically acceptable salt thereof, or the aforementioned pharmaceutical composition is administered to the patient a therapeutically effective amount
  • the aforementioned compound or a pharmaceutically acceptable salt thereof, or the aforementioned pharmaceutical composition are examples of treating and/or preventing a patient with inflammasome-related disease, immune disease, inflammatory disease, autoimmune disease, and/or autoinflammatory disease.
  • the inflammasome-related disease, immune disease, inflammatory disease, autoimmune disease and/or autoinflammatory disease may be specifically selected from: autoinflammatory fever syndrome (such as cold pyridine-related periodic syndrome), Squamous cell anemia, systemic lupus erythematosus, liver-related diseases (eg, chronic liver disease, viral hepatitis, nonalcoholic steatohepatitis, alcoholic steatohepatitis, alcoholic liver disease), inflammatory arthritis-related diseases (eg, gout) , chondrocalcification, osteoarthritis, rheumatoid arthritis, acute or chronic arthritis), kidney-related diseases (eg, hyperoxaluria, lupus nephritis, hypertensive nephropathy, hemodialysis-related inflammation, type I or type II Diabetes and its complications (eg, nephropathy, retinopathy), neuroinflammation-related diseases (eg, brain infection, acute injury, multiple sclerosis, Alzheimer's disease, and neuro
  • the compounds described in the present disclosure are expected to increase the AUC or Cmax in blood by oral administration of 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100% and even higher.
  • Y is selected from fluorine, chlorine, bromine and iodine; preferably Y is selected from fluorine, chlorine and bromine; more preferably Y is selected from chlorine;
  • R 6 , R 7 , Z, R 8 are as defined in formula I;
  • the compound acts as an intermediate.
  • R and R together with the atoms to which they are attached form a 5-6 membered cyclic hydrocarbon, 5-6 membered heterocycle, phenyl, 5-6 membered optionally substituted with one or more substituents A membered heteroaryl group, the substituents being selected from: deuterium, halogen, -OH, -NH 2 , -CN, oxo, C 1-6 alkyl, -OC 1-6 alkyl and C 3-6 cycloalkane base, the C 1-6 alkyl, -OC 1-6 alkyl and C 3-6 cycloalkyl are optionally further substituted with one or more deuterium or halogen;
  • R 2 , R 3 , R 4 and R 5 are independently selected from hydrogen, deuterium, halogen, -OH, -NH 2 and the following groups optionally substituted with one or more substituents: C 1-6 alkyl, -OC 1-6 alkyl, -SC 1-6 alkyl, C 3-6 cycloalkyl and C 3-6 cycloalkylmethylene, the substituents are selected from: deuterium, halogen, -OH, - NH2 and -CN.
  • the pharmaceutically acceptable salts of the compounds described in the present disclosure are selected from inorganic salts or organic salts, and the compounds described in the present disclosure can react with acidic or basic substances to form corresponding salts.
  • the compounds of the present disclosure may exist in specific geometric or stereoisomeric forms.
  • This disclosure contemplates all such compounds, including cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers isomers, (D)-isomers, (L)-isomers, and racemic and other mixtures thereof, such as enantiomerically or diastereomerically enriched mixtures, all of which belong to within the scope of this disclosure.
  • Additional asymmetric carbon atoms may be present in substituents such as alkyl. All such isomers, as well as mixtures thereof, are included within the scope of this disclosure.
  • tautomer or "tautomeric form” refers to structural isomers of different energies that are interconvertible via a low energy barrier.
  • proton tautomers also known as proton tautomers
  • proton transfer such as keto-enol and imine-enamine, lactam-lactam isomerizations .
  • An example of a lactam-lactam equilibrium is between A and B as shown below.
  • the compounds of the present disclosure may be asymmetric, eg, have one or more stereoisomers. Unless otherwise specified, all stereoisomers include, such as enantiomers and diastereomers.
  • Compounds of the present disclosure containing asymmetric carbon atoms can be isolated in optically pure or racemic forms. Optically pure forms can be resolved from racemic mixtures or synthesized by using chiral starting materials or chiral reagents.
  • Optically active (R)- and (S)-isomers can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If one enantiomer of a compound of the present disclosure is desired, it can be prepared by asymmetric synthesis or derivatization with a chiral auxiliary, wherein the resulting mixture of diastereomers is separated and the auxiliary group is cleaved to provide pure desired enantiomer.
  • a diastereomeric salt is formed with an appropriate optically active acid or base, followed by conventional methods known in the art
  • the diastereoisomers were resolved and the pure enantiomers recovered.
  • separation of enantiomers and diastereomers is usually accomplished by the use of chromatography employing a chiral stationary phase, optionally in combination with chemical derivatization (eg, from amines to amino groups) formate).
  • the present disclosure also includes certain isotopically-labeled compounds of the present disclosure which are identical to those described herein, but wherein one or more atoms are replaced by an atom having an atomic weight or mass number different from that normally found in nature.
  • isotopes that can be incorporated into the compounds of the present disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine, such as 2H, 3H , 11C , 13C , 14C , 13 , respectively N, 15 N, 15 O, 17 O, 18 O, 31 P, 32 P, 35 S, 18 F, 123 I, 125 I and 36 Cl and the like.
  • deuterium when a position is specifically designated as deuterium (D), the position is understood to have an abundance of deuterium (ie, at least 1000 times greater than the natural abundance of deuterium (which is 0.015%)) % of deuterium incorporated).
  • Exemplary compounds having natural abundance greater than deuterium may be at least 1000 times more abundant deuterium, at least 2000 times more abundant deuterium, at least 3000 times more abundant deuterium, at least 4000 times more abundant deuterium, at least 4000 times more abundant 5000 times more abundant deuterium, at least 6000 times more abundant deuterium or more abundant deuterium.
  • the present disclosure also includes compounds of formula (I) in various deuterated forms.
  • Each available hydrogen atom attached to a carbon atom can be independently replaced by a deuterium atom.
  • Those skilled in the art can refer to relevant literature to synthesize the compound of formula (I) in deuterated form.
  • Commercially available deuterated starting materials can be used in the preparation of deuterated forms of compounds of formula (I), or they can be synthesized using conventional techniques using deuterated reagents including, but not limited to, deuterated borane, trideuterated Borane tetrahydrofuran solution, deuterated lithium aluminum hydride, deuterated iodoethane and deuterated iodomethane, etc.
  • C 1-6 alkyl optionally substituted by halogen or cyano means that halogen or cyano may but need not be present, and the description includes the case where the alkyl is substituted by halogen or cyano and the case where the alkyl is not substituted by halogen and cyano substitution.
  • the bond Indicates an unspecified configuration, i.e. if a chiral isomer exists in the chemical structure, the bond can be or both Two configurations.
  • the present invention encompasses all isomers such as tautomers, rotamers, geometric isomers, diastereomers isomers, racemates and enantiomers.
  • “Pharmaceutical composition” means a mixture containing one or more of the compounds described herein, or a physiologically pharmaceutically acceptable salt or prodrug thereof, with other chemical components, and other components such as physiologically pharmaceutically acceptable carriers and excipients Form.
  • the purpose of the pharmaceutical composition is to facilitate the administration to the organism, facilitate the absorption of the active ingredient and then exert the biological activity.
  • “Pharmaceutically acceptable excipient” includes, but is not limited to, any adjuvant, carrier, excipient, glidant, sweetener, diluent that has been approved by the U.S. Food and Drug Administration as acceptable for use in humans or livestock animals agents, preservatives, dyes/colorants, flavoring agents, surfactants, wetting agents, dispersing agents, suspending agents, stabilizers, isotonic agents, solvents or emulsifiers.
  • Alkyl refers to saturated aliphatic hydrocarbon groups, including straight and branched chain groups of 1 to 20 carbon atoms. An alkyl group containing 1 to 6 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl and various branched chain isomers, etc.
  • the alkyl group may be substituted or unsubstituted, and when substituted, the substituent may be substituted at any available point of attachment, preferably one or more of the following groups, independently selected from halogen, Deuterium, hydroxyl, oxo, nitro, cyano, C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyloxy, C 2-6 alkynyloxy, C 3-6 cycloalkane base, 3- to 6-membered heterocycloalkyl, C 5-8 cycloalkenyl, C 3-6 cycloalkoxy, 3- to 6-membered heterocycloalkoxy, C 5-8 cycloalkenyloxy, C 6- 10 -aryl or 5- to 6-membered heteroaryl, the C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyloxy, C 2-6 alkynyloxy, C 3-6 ring Alkyl, 3- to 6-membered heterocycloalkyl,
  • Cycloalkyl or “cyclohydrocarbon” refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, the cycloalkyl ring containing 3 to 20 carbon atoms, preferably 3 to 8 carbon atoms.
  • Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, and the like; polycyclic cycloalkyl groups include spiro Ring, fused and bridged cycloalkyl groups.
  • the cycloalkyl ring can be fused to an aryl, heteroaryl or heterocycloalkyl ring, wherein the ring linked to the parent structure is a cycloalkyl, non-limiting examples include indanyl, tetrahydronaphthalene base, benzocycloheptyl, etc.
  • cycloalkyl can be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups, which are independently selected from deuterium, alkyl, alkenyl, alkyne group, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkane Oxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl or carboxylate.
  • groups which are independently selected from deuterium, alkyl, alkenyl, alkyne group, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl,
  • Heterocyclyl or “heterocycle” refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon group containing from 3 to 20 ring atoms, one or more of which are selected from nitrogen, oxygen, or S (O) heteroatoms of m (where m is an integer from 0 to 2), excluding ring moieties of -OO-, -OS- or -SS-, the remaining ring atoms being carbon.
  • m is an integer from 0 to 2
  • it contains 3 to 12 ring atoms, of which 1 to 4 are heteroatoms; more preferably 3 to 7 ring atoms.
  • Non-limiting examples of monocyclic heterocycloalkyl include pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, piper pyridyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, etc.
  • Polycyclic heterocycloalkyl groups include spiro, fused and bridged ring heterocycloalkyl groups.
  • Non-limiting examples of "heterocycloalkyl" include:
  • Heterocycloalkyl can be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from groups such as halogen, deuterium, hydroxy, oxo, nitro, cyano base, C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyloxy, C 2-6 alkynyloxy, C 3-6 cycloalkyl, 3- to 6-membered heterocycloalkyl, C 5-8 cycloalkenyl, C 3-6 cycloalkoxy, 3- to 6-membered heterocycloalkoxy, C 5-8 cycloalkenyloxy, C 6-10 aryl or 5- to 6-membered heteroaryl , the C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyloxy, C 2-6 alkynyloxy, C 3-6 cycloalkyl, 3- to 6-membered heterocycloalkyl , C 5-8 cycl
  • the heterocyclyl ring can be fused to an aromatic ring, a heteroaromatic ring, or a cyclic hydrocarbon, wherein the ring attached to the parent structure is a heterocyclyl, non-limiting examples of which include:
  • Aryl or “aromatic ring” refers to a 6- to 14-membered all-carbon monocyclic or fused polycyclic (ie, rings that share adjacent pairs of carbon atoms) groups having a conjugated pi-electron system, preferably 6 to 12 elements such as phenyl and naphthyl.
  • Aryl may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from halogen, deuterium, hydroxyl, oxo, nitro, cyano, C1 -6 alkyl, C 1-6 alkoxy, C 2-6 alkenyloxy, C 2-6 alkynyloxy, C 3-6 cycloalkyl, 3- to 6-membered heterocycloalkyl, C 5-8 cycloalkenyl, C 3-6 cycloalkoxy, 3- to 6-membered heterocycloalkoxy, C 5-8 cycloalkenyloxy, C 6-10 aryl or 5- to 6-membered heteroaryl, the C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyloxy, C 2-6 alkynyloxy, C 3-6 cycloalkyl, 3- to 6-membered heterocycloalkyl, C 5- 8 -cycloalkenyl, C 3-6 cycl
  • the aryl ring may be fused to a heteroaromatic ring, a heterocyclic ring or a cyclic hydrocarbon, wherein the ring linked to the parent structure is an aryl ring, non-limiting examples of which include:
  • Heteroaryl or “heteroaromatic ring” refers to a heteroaromatic system comprising 1 to 4 heteroatoms, 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur and nitrogen.
  • the heteroaryl group is preferably 6- to 12-membered, more preferably 5- or 6-membered.
  • Non-limiting examples thereof include: imidazolyl, furyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, pyrrolyl, tetrazolyl, pyridyl, pyrimidinyl, thiadiazole, pyrazine, and many more.
  • nitrogen-containing heteroaryl groups include, but are not limited to, pyrrolyl, piperazinyl, pyrimidinyl, imidazolyl, pyridazinyl, pyrazinyl, tetrazolyl, triazolyl, pyridyl, pyrazolyl, oxa azolyl or thiazolyl, etc.
  • Heteroaryl groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from halogen, deuterium, hydroxy, oxo, nitro, cyano , C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyloxy, C 2-6 alkynyloxy, C 3-6 cycloalkyl, 3- to 6-membered heterocycloalkyl, C 5-8 cycloalkenyl, C 3-6 cycloalkoxy, 3- to 6-membered heterocycloalkoxy, C 5-8 cycloalkenyloxy, C 6-10 aryl or 5- to 6-membered heteroaryl, The C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyloxy, C 2-6 alkynyloxy, C 3-6 cycloalkyl, 3- to 6-membered heterocycloalkyl, C 5-8 cycloalkenyl, C
  • the heteroaryl ring can be fused to an aromatic ring, a heterocycle or a cyclic hydrocarbon, wherein the ring linked to the parent structure is a heteroaryl ring, non-limiting examples of which include:
  • Halogen refers to fluorine, chlorine, bromine or iodine.
  • Substituted with one or more A, B means that it may be substituted with single or multiple substituents. When substituted by a plurality of substituents, it may be a plurality of the same substituents, or a combination of one or a plurality of different substituents.
  • the structures of the compounds were determined by nuclear magnetic resonance (NMR) or/and mass spectrometry (MS). NMR shifts ([delta]) are given in units of 10<" 6 > (ppm). NMR was measured by Bruker AVANCE-400 nuclear magnetic instrument, and the solvent was deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated chloroform (CDCl 3 ), deuterated methanol (CD 3 OD), and the internal standard was four Methylsilane (TMS). The spatial configuration of the optical isomers (isomers) of the compounds can be further confirmed by means of measuring single crystal parameters.
  • NMR nuclear magnetic resonance
  • MS mass spectrometry
  • HPLC was measured using Waters ACQUITY ultra high performance LC, Shimadzu LC-20A systems, Shimadzu LC-2010HT series or Agilent Agilent 1200 LC high pressure liquid chromatograph (ACQUITY UPLC BEH C18 1.7UM 2.1X50MM column, Ultimate XB-C18 3.0* 150mm chromatographic column or Xtimate C18 2.1*30mm chromatographic column).
  • MS was measured with a Waters SQD2 mass spectrometer, scanned in positive/negative ion mode, and the mass scanning range was 100-1200.
  • Chiral HPLC analysis and determination using Chiralpak IC-3 100 ⁇ 4.6mm I.D., 3um, Chiralpak AD-3 150 ⁇ 4.6mm I.D., 3um, Chiralpak AD-3 50 ⁇ 4.6mm I.D., 3um, Chiralpak AS-3 150 ⁇ 4.6mm I.D., 3um, Chiralpak AS-3 100 ⁇ 4.6mm I.D., 3 ⁇ m, ChiralCel OD-3 150 ⁇ 4.6mm I.D., 3um, Chiralcel OD-3 100 ⁇ 4.6mm I.D., 3 ⁇ m, ChiralCel OJ-H 150 ⁇ 4.6mm I.D., 5um, Chiralcel OJ-3 150 ⁇ 4.6mm I.D., 3um chromatographic column;
  • the thin layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate, the size of the silica gel plate used for thin layer chromatography (TLC) is 0.15mm ⁇ 0.2mm, and the size of the TLC separation and purification products is 0.4mm ⁇ 0.5mm.
  • the flash column purification system used Combiflash Rf150 (TELEDYNE ISCO) or Isolara one (Biotage).
  • Forward column chromatography generally uses Yantai Huanghai silica gel 100-200 mesh, 200-300 mesh or 300-400 mesh silica gel as the carrier, or use Changzhou Santai pre-packed pre-packed ultra-pure normal phase silica gel column (40-63 ⁇ m, 60, 12 g ,, 25g, 40g, 80g or other specifications).
  • Reversed-phase column chromatography generally uses Changzhou Santai pre-packed ultra-pure C18 silica gel column (20-45 ⁇ m, 40g, 80g, 120g, 220g or other specifications).
  • the high-pressure column purification system uses Waters AutoP, in conjunction with Waters XBridge BEH C18 OBD Prep Column, 5 ⁇ m, 19mm X 150mm or Atlantis T3 OBD Prep Column, 5 ⁇ m, 19mm X 150mm.
  • the chiral preparative column uses DAICEL CHIRALPAK IC (250mm*30mm, 10um) or Phenomenex-Amylose-1 (250mm*30mm, 5um).
  • the known starting materials in the present disclosure can be synthesized by using or according to methods known in the art, or can be purchased from Shanghai Titan Technology, ABCR GmbH & Co.KG, Acros Organics, Aldrich Chemical Company, Shaoyuan Chemical Technology (Accela ChemBio Inc), Darui Chemicals and other companies.
  • Argon or nitrogen atmosphere means that the reaction flask is connected to an argon or nitrogen balloon with a volume of about 1 L.
  • Hydrogen atmosphere means that the reaction flask is connected to a hydrogen balloon with a volume of about 1 L.
  • the pressure hydrogenation reaction uses Parr 3916EKX hydrogenation apparatus and Qinglan QL-500 hydrogen generator or HC2-SS hydrogenation apparatus.
  • the hydrogenation reaction is usually evacuated and filled with hydrogen, and the operation is repeated 3 times.
  • the microwave reaction used a CEM Discover-S 908860 microwave reactor.
  • the solution refers to an aqueous solution.
  • reaction temperature is room temperature, which is 20°C to 30°C.
  • Step 1 Synthesis of (R)-4-chloro-N-(1-methylpiperidin-3-yl)-5,6,7,8-tetrahydrophthalazin-1-amine (Compound 1c)
  • Step 2 (R)-2-(4-((1-Methylpiperidin-3-yl)amino)-5,6,7,8-tetrahydrophthalazin-1-yl)-5-(tris Synthesis of Fluoromethyl)phenol (Compound 1)
  • Compound 2 was prepared according to the method described in Example 1 starting from 2a.
  • Compound 3 was prepared according to the method described in Example 1 using 3a as starting material.
  • compound 4 was prepared according to the method described in step 2 in Example 1.
  • compound 5 was prepared according to the method described in Example 4.
  • Compound 6 was prepared according to the method described in Example 4 using compound 6a as starting material.
  • Compound 7d was prepared according to the method described in Example 4, starting from compound 7b.
  • Compound 9 was prepared according to the method described in Example 4 starting from compound 9a.
  • compound 10b was prepared according to the method described in step 2 of Example 4.
  • Compound 10 was prepared according to the method described in Example 7 using compound 10c as starting material.
  • Compound 11 was prepared according to the method described in Example 7, starting from compound 11c.
  • Compound 12 was prepared according to the method described in Example 7 using compound 12a as starting material.
  • Compound 13 was prepared according to the method described in Example 7 using compound 13a as starting material.
  • Compound 14b was prepared according to the method described in Example 4, step 2, starting from compound 14a.
  • compound 14 was prepared according to the method described in step 2 of Example 1.
  • Compound 15 was prepared according to the method described in Example 14 starting from 3a.
  • Compound 16 was prepared according to the method described in Example 1 starting from 16c.
  • Compound 17 was prepared according to the method described in Example 7 starting from 7c.
  • Compound 18 was prepared according to the method described in Example 7 starting from 18b.
  • Compound 19c was prepared according to the method described in Example 1 using 19a as starting material.
  • Compound 20 was prepared according to the method described in Example 2 starting from 2b.
  • Compound 21 was prepared according to the method described in Example 14 starting from 21a.
  • compound 26 was prepared according to the method described in Example 16.
  • compound 27 was prepared according to the method described in Example 4.
  • compound 28 was prepared according to the method described in Example 18.
  • compound 29 was prepared according to the method described in Example 18.
  • compound 30 was prepared according to the method described in Example 18.
  • compound 32 was prepared according to the method described in Example 19.
  • Compound 35 was prepared according to the method described in Example 15 starting from compound 16d.
  • Compound 36 was prepared according to the method described in compound 19 starting from compounds 4d and 19a.
  • Compound 37 was prepared according to the method described in Example 4 starting from compound 14b.
  • Compound 38 was prepared according to the method described in Example 15 starting from 22c.
  • Compound 41 was prepared according to the method described in compound 18 starting from compound 18c.
  • Compound 44 was prepared according to the method described in Example 15 starting from compound 15a.
  • Compound 45 was prepared according to the method described in Example 15 starting from compound 24b.
  • Compound 46 was prepared according to the method described in Example 15 starting from compound 15a.
  • Compound 47 was prepared according to the method described in Example 15 starting from compound 16d.
  • Compound 48 was prepared according to the method described in Example 15 starting from compound 2b.
  • PBMCs were isolated from human blood by density gradient centrifugation, washed twice with PBS containing 2% FBS (300g for 8 minutes). Monocytes were then isolated from PBMCs using a human pan-monocyte isolation kit and an LS column. Cells were stained with CD14-FITC for 30 min at 4°C and FACS was run on a BD FACSVerse to analyze the purity of pan-monocytes. Count and adjust the cell density to 2.5x105 cells/ml. Cells were seeded into 96-well plates at 2.5x104 monocytes/100 mL suspension/well. Incubate overnight at 5% CO2 , 37°C.
  • Test compounds are pre-titrated so that all titration points, including DMSO control wells, contain 0.1% DMSO.
  • the medium was removed and monocytes were pretreated (by adding 150 mL of compound (diluted in serum-free 1640 medium) or DMSO to the respective wells and incubating at 37°C for 0.5 hours in 5% CO2 ).
  • Cells were then treated (by adding 25 mL of 1640 (serum-free) solution containing 700 ng/mL LPS (final concentration of 100 ng/mL), incubating for 3.5 hours at 37°C in 5% CO 2 ).
  • test product 3. Weigh an appropriate amount of the test product, dissolve it in 10% DMA/33% PEG400/57% Water (V/V/V), vortex, ultrasonic, and prepare the required drug preparation for intravenous administration . An appropriate amount of the test product was weighed, dissolved in 0.5% HPMC 0.1% Tween in water, vortexed, and ultrasonicated to prepare the required preparation for oral administration.

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Abstract

一类含哒嗪的化合物及其医药用途。具体而言，式I所示的化合物或其可药用盐，该类化合物或其可药用盐具有NLRP3炎性体抑制活性，可用于治疗或预防NLRP3相关疾病。

Description

一类含哒嗪的化合物及其医药用途 技术领域
本公开涉及医药领域，具体涉及一类含哒嗪的化合物及其医药用途。
背景技术
NOD样受体蛋白3(NOD-like receptor protein 3,NLRP3)是一种蛋白编码基因，该蛋白属于核苷酸结合和寡聚化域样受体(nucleotide-binding and oligomerization domain-like receptors,NLRs)家族，也被称为“含脓素域蛋白3”(Inoue et al，Immunology，2013，139，11-18)。该基因编码一种蛋白，该蛋白包含一个吡啶结构域，一个核苷酸结合位点结构域(NBD)和一个富含亮氨酸的重复(LRR)基序。通过响应无菌的炎性危险信号，NLRP3与衔接蛋白、凋亡相关斑点样蛋白(ASC)以及酶原-1相互作用，形成NLRP3炎性体。之后，NLRP3炎性体的激活导致炎性细胞因子IL-1b和IL-18的释放，而当NLRP3炎性体的激活失调时，则会驱动许多疾病的发生。
研究表明，NLRP3炎性体的激活与多类疾病相关，包括：炎性体相关疾病、免疫性疾病、炎症性疾病、自身免疫性疾病和自身炎症性疾病。因此，需要提供新的NLRP3炎性体通路抑制剂，来为上述疾病的治疗提供新的可选方式。
发明内容
第一方面，本公开提供式I化合物或其可药用盐，
Figure PCTCN2021141211-appb-000001
其中，R 1选自氢、氘、卤素、-OH、-NH 2、-CN和任选被一个或多个取代基取代的以下基团：C 1-6烷基、-O-C 1-6烷基、-NHC(＝O)-C 1-6烷基和-(C＝O)NH-C 1-6烷基，所述取代基选自：氘、卤素、-OH、-NH 2和-CN；
R 2、R 3、R 4、R 5、R 6和R 7：
(a)R 2和R 3与其连接的原子一起形成任选被一个或多个取代基取代的5-6元的环烃、苯基、杂环或杂芳环，所述取代基选自：氘、卤素、-OH、-NH 2、-CN、氧代、C 1-6烷基、-O-C 1-6烷基和C 3-6环烷基，所述C 1-6烷基、-O-C 1-6烷基和C 3-6环烷基任选进一步被一个或多个氘或卤素取代；
R 4、R 5、R 6和R 7独立地选自氢、氘、卤素、-OH、-NH 2和任选被一个或多个 取代基取代的以下基团：C 1-6烷基、-O-C 1-6烷基、-S-C 1-6烷基、C 3-6环烷基和C 3-6环烷基亚甲基，所述取代基选自：氘、卤素、-OH、-NH 2和-CN；
或R 6和R 7与其连接的原子一起形成任选被一个或多个取代基取代的5-6元的环烃、5-6元的杂环、苯基、5-6元杂芳基，所述取代基选自：氘、卤素、-OH、-NH 2、-CN、氧代、C 1-6烷基、-O-C 1-6烷基和C 3-6环烷基，所述C 1-6烷基、-O-C 1-6烷基和C 3-6环烷基任选进一步被一个或多个氘或卤素取代；R 4、R 5独立地选自氢、氘、卤素、-OH、-NH 2和任选被一个或多个取代基取代的以下基团：C 1-6烷基、-O-C 1-6烷基、-S-C 1-6烷基、C 3-6环烷基和C 3-6环烷基亚甲基，所述取代基选自：氘、卤素、-OH、-NH 2和-CN；
(b)R 3和R 4与其连接的原子一起形成任选被一个或多个取代基取代的5-6元的环烃、苯基、杂环或杂芳环，所述取代基选自：氘、卤素、-NH 2、-CN、C 1-6烷基、-O-C 1-6烷基和C 3-6环烷基，所述C 1-6烷基、-O-C 1-6烷基和C 3-6环烷基任选进一步被一个或多个氘或卤素取代；R 2、R 5、R 6和R 7独立地选自氢、氘、卤素、-OH、-NH 2和任选被一个或多个取代基取代的以下基团：C 1-6烷基、-O-C 1-6烷基、-S-C 1-6烷基、C 3-6环烷基和C 3-6环烷基亚甲基，所述取代基选自：氘、卤素、-OH、-NH 2和-CN；
(c)R 4和R 5与其连接的原子一起形成任选被一个或多个取代基取代的5-6元的环烃、苯基、杂环或杂芳环，所述取代基选自：氘、卤素、-OH、-NH 2、-CN、氧代、C 1-6烷基、-O-C 1-6烷基和C 3-6环烷基，所述C 1-6烷基、-O-C 1-6烷基和C 3-6环烷基任选进一步被一个或多个氘或卤素取代；R 2、R 3、R 6和R 7独立地选自氢、氘、卤素、-OH、-NH 2和任选被一个或多个取代基取代的以下基团：C 1-6烷基、-O-C 1-6烷基、-S-C 1-6烷基、C 3-6环烷基和C 3-6环烷基亚甲基，所述取代基选自：氘、卤素、-OH、-NH 2和-CN；
或者，(d)R 6和R 7与其连接的原子一起形成任选被一个或多个取代基取代的5-6元的环烃、5-6元的杂环、苯基、5-6元杂芳基，所述取代基选自：氘、卤素、-OH、-NH 2、-CN、氧代、C 1-6烷基、-O-C 1-6烷基和C 3-6环烷基，所述C 1-6烷基、-O-C 1-6烷基和C 3-6环烷基任选进一步被一个或多个氘或卤素取代；R 2、R 3、R 4和R 5独立地选自氢、氘、卤素、-OH、-NH 2和任选被一个或多个取代基取代的以下基团：C 1-6烷基、-O-C 1-6烷基、-S-C 1-6烷基、C 3-6环烷基和C 3-6环烷基亚甲基，所述取代基选自：氘、卤素、-OH、-NH 2和-CN；
Z为O或-NH-(CH2)n-，n为选自0-3的整数；
R 8选自任选被一个或多个取代基取代的芳基、杂芳基、杂环基、C 3-8环烷基、C 1-6烷基和-O-C 1-6烷基，所述取代基选自氘、卤素、氧代、-OR 8a、-SR 8a、-C(＝O)R 8a、-OC(＝O)R 8a、-C(＝O)OR 8a、-C(＝O)NR 8aR 8b、-NR 8aR 8b、-NR 8aC(＝O)R 8b、-NR 8aS(＝O) 2R 8b、-S(＝O) 2R 8a、-S(＝O) 2NR 8aR 8b、-CN、-NO 2、C 1-4烷基和C 3-6环烷基，所述C 1-4烷基 或C 3-6环烷基任选进一步被一个或多个的氘、卤素或-OH取代；
R 8a和R 8b独立地选自氢、氘或任选被一个或多个取代基取代的以下基团：C 1-4烷基、C 3-6环烷基和C 3-6环烷基亚甲基，所述取代基选自：氘、卤素、-NH 2、-OH、-CN、C 1-4烷基、C 1-4烷氧基、C 3-6环烷基和C 3-6环烷基亚甲基，上述取代基任选进一步被一个或多个的氘或卤素取代；
当R 6和R 7与其连接的原子一起形成未取代的5-6元环烃，R 1为甲基或甲氧基，且Z为-NH-时，R 8不为芳基。
在一些实施方案中，R 1选自氢、氘、卤素、-OH、-NH 2、-CN和任选被一个或多个取代基取代的以下基团：C 1-6烷基、-O-C 1-6烷基、-NHC(＝O)-C 1-6烷基和-(C＝O)NH-C 1-6烷基，所述取代基选自：氘、卤素、-OH、-NH 2和-CN；
R 2、R 3、R 4、R 5、R 6和R 7：
(a)R 2和R 3与其连接的原子一起形成任选被一个或多个取代基取代的5-6元的环烃、苯基、杂环或杂芳环，所述取代基选自：氘、卤素、-OH、-NH 2、-CN、氧代、C 1-6烷基、-O-C 1-6烷基和C 3-6环烷基，所述C 1-6烷基、-O-C 1-6烷基和C 3-6环烷基任选进一步被一个或多个氘或卤素取代；R 4、R 5、R 6和R 7独立地选自氢、氘、卤素、-OH、-NH 2和任选被一个或多个取代基取代的以下基团：C 1-6烷基、-O-C 1-6烷基、-S-C 1-6烷基、C 3-6环烷基和C 3-6环烷基亚甲基，所述取代基选自：氘、卤素、-OH、-NH 2和-CN；
(b)R 3和R 4与其连接的原子一起形成任选被一个或多个取代基取代的5-6元的环烃、苯基、杂环或杂芳环，所述取代基选自：氘、卤素、-NH 2、-CN、C 1-6烷基、-O-C 1-6烷基和C 3-6环烷基，所述C 1-6烷基、-O-C 1-6烷基和C 3-6环烷基任选进一步被一个或多个氘或卤素取代；R 2、R 5、R 6和R 7独立地选自氢、氘、卤素、-OH、-NH 2和任选被一个或多个取代基取代的以下基团：C 1-6烷基、-O-C 1-6烷基、-S-C 1-6烷基、C 3-6环烷基和C 3-6环烷基亚甲基，所述取代基选自：氘、卤素、-OH、-NH 2和-CN；
(c)R 4和R 5与其连接的原子一起形成任选被一个或多个取代基取代的5-6元的环烃、苯基、杂环或杂芳环，所述取代基选自：氘、卤素、-OH、-NH 2、-CN、氧代、C 1-6烷基、-O-C 1-6烷基和C 3-6环烷基，所述C 1-6烷基、-O-C 1-6烷基和C 3-6环烷基任选进一步被一个或多个氘或卤素取代；R 2、R 3、R 6和R 7独立地选自氢、氘、卤素、-OH、-NH 2和任选被一个或多个取代基取代的以下基团：C 1-6烷基、-O-C 1-6烷基、-S-C 1-6烷基、C 3-6环烷基和C 3-6环烷基亚甲基，所述取代基选自：氘、卤素、-OH、-NH 2和-CN；
或者，(d)R 6和R 7与其连接的原子一起形成任选被一个或多个取代基取代的5-6元的环烃、5-6元的杂环、苯基、5-6元杂芳基，所述取代基选自：氘、卤素、-OH、-NH 2、-CN、氧代、C 1-6烷基、-O-C 1-6烷基和C 3-6环烷基，所述C 1-6烷基、 -O-C 1-6烷基和C 3-6环烷基任选进一步被一个或多个氘或卤素取代；R 2、R 3、R 4和R 5独立地选自氢、氘、卤素、-OH、-NH 2和任选被一个或多个取代基取代的以下基团：C 1-6烷基、-O-C 1-6烷基、-S-C 1-6烷基、C 3-6环烷基和C 3-6环烷基亚甲基，所述取代基选自：氘、卤素、-OH、-NH 2和-CN；
Z为O或-NH-(CH2)n-，n为选自0-3的整数；
R 8选自任选被一个或多个取代基取代的芳基、杂芳基、杂环基、C 3-8环烷基、C 1-6烷基和-O-C 1-6烷基，所述取代基选自氘、卤素、氧代、-OR 8a、-SR 8a、-C(＝O)R 8a、-OC(＝O)R 8a、-C(＝O)OR 8a、-C(＝O)NR 8aR 8b、-NR 8aR 8b、-NR 8aC(＝O)R 8b、-NR 8aS(＝O) 2R 8b、-S(＝O) 2R 8a、-S(＝O) 2NR 8aR 8b、-CN、-NO 2、C 1-4烷基和C 3-6环烷基，所述C 1-4烷基或C 3-6环烷基任选进一步被一个或多个的氘、卤素或-OH取代；
R 8a和R 8b独立地选自氢、氘或任选被一个或多个取代基取代的以下基团：C 1-4烷基、C 3-6环烷基和C 3-6环烷基亚甲基，所述取代基选自：氘、卤素、-NH 2、-OH、-CN、C 1-4烷基、C 1-4烷氧基、C 3-6环烷基和C 3-6环烷基亚甲基，上述取代基任选进一步被一个或多个的氘或卤素取代；
当R 6和R 7与其连接的原子一起形成未取代的5-6元环烃，R 1为甲基或甲氧基，且Z为-NH-时，R 8不为芳基。
在一些实施方案中，R 1选自氢、氘、卤素、-OH、-NH 2、-CN和任选被一个或多个取代基取代的以下基团：C 1-6烷基、-O-C 1-6烷基、-NHC(＝O)-C 1-6烷基和-(C＝O)NH-C 1-6烷基，所述取代基选自：氘、卤素、-OH、-NH 2和-CN；
R 2、R 3、R 4、R 5、R 6和R 7：
(a)R 2和R 3与其连接的原子一起形成任选被一个或多个取代基取代的5-6元的环烃、杂环或杂芳环，所述取代基选自：氘、卤素、-OH、-NH 2、-CN、氧代、C 1-6烷基、-O-C 1-6烷基和C 3-6环烷基，所述C 1-6烷基、-O-C 1-6烷基和C 3-6环烷基任选进一步被一个或多个氘或卤素取代；R 4、R 5、R 6和R 7独立地选自氢、氘、卤素、-OH、-NH 2和任选被一个或多个取代基取代的以下基团：C 1-6烷基、-O-C 1-6烷基、-S-C 1-6烷基、C 3-6环烷基和C 3-6环烷基亚甲基，所述取代基选自：氘、卤素、-OH、-NH 2和-CN；
(b)R 3和R 4与其连接的原子一起形成任选被一个或多个取代基取代的5-6元的环烃、苯基，所述取代基选自：氘、卤素、-NH 2、-CN、C 1-6烷基、-O-C 1-6烷基和C 3-6环烷基，所述C 1-6烷基、-O-C 1-6烷基和C 3-6环烷基任选进一步被一个或多个氘或卤素取代；R 2、R 5、R 6和R 7独立地选自氢、氘、卤素、-OH、-NH 2和任选被一个或多个取代基取代的以下基团：C 1-6烷基、-O-C 1-6烷基、-S-C 1-6烷基、C 3-6环烷基和C 3-6环烷基亚甲基，所述取代基选自：氘、卤素、-OH、-NH 2和-CN；
(c)R 4和R 5与其连接的原子一起形成任选被一个或多个取代基取代的5-6元的环烃、苯基，所述取代基选自：氘、卤素、-OH、-NH 2、-CN、氧代、C 1-6烷 基、-O-C 1-6烷基和C 3-6环烷基，所述C 1-6烷基、-O-C 1-6烷基和C 3-6环烷基任选进一步被一个或多个氘或卤素取代；R 2、R 3、R 6和R 7独立地选自氢、氘、卤素、-OH、-NH 2和任选被一个或多个取代基取代的以下基团：C 1-6烷基、-O-C 1-6烷基、-S-C 1-6烷基、C 3-6环烷基和C 3-6环烷基亚甲基，所述取代基选自：氘、卤素、-OH、-NH 2和-CN；
或者，(d)R 6和R 7与其连接的原子一起形成任选被一个或多个取代基取代的5-6元的环烃、5-6元的杂环、苯基，所述取代基选自：氘、卤素、-OH、-NH 2、-CN、氧代、C 1-6烷基、-O-C 1-6烷基和C 3-6环烷基，所述C 1-6烷基、-O-C 1-6烷基和C 3-6环烷基任选进一步被一个或多个氘或卤素取代；R 2、R 3、R 4和R 5独立地选自氢、氘、卤素、-OH、-NH 2和任选被一个或多个取代基取代的以下基团：C 1-6烷基、-O-C 1-6烷基、-S-C 1-6烷基、C 3-6环烷基和C 3-6环烷基亚甲基，所述取代基选自：氘、卤素、-OH、-NH 2和-CN；
Z为O或-NH-(CH2)n-，n为选自0-3的整数；
R 8选自任选被一个或多个取代基取代的芳基、杂芳基、杂环基、C 3-8环烷基、C 1-6烷基和-O-C 1-6烷基，所述取代基选自氘、卤素、氧代、-OR 8a、-SR 8a、-C(＝O)R 8a、-OC(＝O)R 8a、-C(＝O)OR 8a、-C(＝O)NR 8aR 8b、-NR 8aR 8b、-NR 8aC(＝O)R 8b、-NR 8aS(＝O) 2R 8b、-S(＝O) 2R 8a、-S(＝O) 2NR 8aR 8b、-CN、-NO 2、C 1-4烷基和C 3-6环烷基，所述C 1-4烷基或C 3-6环烷基任选进一步被一个或多个的氘、卤素或-OH取代；
R 8a和R 8b独立地选自氢、氘或任选被一个或多个取代基取代的以下基团：C 1-4烷基、C 3-6环烷基和C 3-6环烷基亚甲基，所述取代基选自：氘、卤素、-NH 2、-OH、-CN、C 1-4烷基、C 1-4烷氧基、C 3-6环烷基和C 3-6环烷基亚甲基，上述取代基任选进一步被一个或多个的氘或卤素取代；
当R 6和R 7与其连接的原子一起形成未取代的5-6元环烃，R 1为甲基或甲氧基，且Z为-NH-时，R 8不为芳基。
在一些实施方案中，R 1选自氢、氘、卤素、-OH、-NH 2、-CN和任选被一个或多个取代基取代的以下基团：C 1-6烷基、-O-C 1-6烷基、-NHC(＝O)-C 1-6烷基和-(C＝O)NH-C 1-6烷基，所述取代基选自：氘、卤素、-OH、-NH 2和-CN；
R 2、R 3、R 4、R 5、R 6和R 7：
(a)R 2和R 3与其连接的原子一起形成任选被一个或多个取代基取代的5-6元的环烃、杂环或杂芳环，所述取代基选自：氘、卤素、-OH、-NH 2、-CN、氧代、C 1-6烷基、-O-C 1-6烷基和C 3-6环烷基，所述C 1-6烷基、-O-C 1-6烷基和C 3-6环烷基任选进一步被一个或多个氘或卤素取代；R 4、R 5、R 6和R 7独立地选自氢、氘、卤素、-OH、-NH 2和任选被一个或多个取代基取代的以下基团：C 1-6烷基、-O-C 1-6烷基、-S-C 1-6烷基、C 3-6环烷基和C 3-6环烷基亚甲基，所述取代基选自：氘、卤素、-OH、-NH 2和-CN；
(b)R 3和R 4与其连接的原子一起形成任选被一个或多个取代基取代的5-6元的环烃、苯基，所述取代基选自：氘、卤素、-NH 2、-CN、C 1-6烷基、-O-C 1-6烷基和C 3-6环烷基，所述C 1-6烷基、-O-C 1-6烷基和C 3-6环烷基任选进一步被一个或多个氘或卤素取代；R 2、R 5、R 6和R 7独立地选自氢、氘、卤素、-OH、-NH 2和任选被一个或多个取代基取代的以下基团：C 1-6烷基、-O-C 1-6烷基、-S-C 1-6烷基、C 3-6环烷基和C 3-6环烷基亚甲基，所述取代基选自：氘、卤素、-OH、-NH 2和-CN；
(c)R 4和R 5与其连接的原子一起形成任选被一个或多个取代基取代的5-6元的环烃，所述取代基选自：氘、卤素、-OH、-NH 2、-CN、氧代、C 1-6烷基、-O-C 1-6烷基和C 3-6环烷基，所述C 1-6烷基、-O-C 1-6烷基和C 3-6环烷基任选进一步被一个或多个氘或卤素取代；R 2、R 3、R 6和R 7独立地选自氢、氘、卤素、-OH、-NH 2和任选被一个或多个取代基取代的以下基团：C 1-6烷基、-O-C 1-6烷基、-S-C 1-6烷基、C 3-6环烷基和C 3-6环烷基亚甲基，所述取代基选自：氘、卤素、-OH、-NH 2和-CN；
或者，(d)R 6和R 7与其连接的原子一起形成任选被一个或多个取代基取代的5-6元的环烃、5-6元的杂环、苯基，所述取代基选自：氘、卤素、-OH、-NH 2、-CN、氧代、C 1-6烷基、-O-C 1-6烷基和C 3-6环烷基，所述C 1-6烷基、-O-C 1-6烷基和C 3-6环烷基任选进一步被一个或多个氘或卤素取代；R 2、R 3、R 4和R 5独立地选自氢、氘、卤素、-OH、-NH 2和任选被一个或多个取代基取代的以下基团：C 1-6烷基、-O-C 1-6烷基、-S-C 1-6烷基、C 3-6环烷基和C 3-6环烷基亚甲基，所述取代基选自：氘、卤素、-OH、-NH 2和-CN；
Z为O或-NH-(CH2)n-，n为选自0-3的整数；
R 8选自任选被一个或多个取代基取代的芳基、杂芳基、杂环基、C 3-8环烷基、C 1-6烷基和-O-C 1-6烷基，所述取代基选自氘、卤素、氧代、-OR 8a、-SR 8a、-C(＝O)R 8a、-OC(＝O)R 8a、-C(＝O)OR 8a、-C(＝O)NR 8aR 8b、-NR 8aR 8b、-NR 8aC(＝O)R 8b、-NR 8aS(＝O) 2R 8b、-S(＝O) 2R 8a、-S(＝O) 2NR 8aR 8b、-CN、-NO 2、C 1-4烷基和C 3-6环烷基，所述C 1-4烷基或C 3-6环烷基任选进一步被一个或多个的氘、卤素或-OH取代；
R 8a和R 8b独立地选自氢、氘或任选被一个或多个取代基取代的以下基团：C 1-4烷基、C 3-6环烷基和C 3-6环烷基亚甲基，所述取代基选自：氘、卤素、-NH 2、-OH、-CN、C 1-4烷基、C 1-4烷氧基、C 3-6环烷基和C 3-6环烷基亚甲基，上述取代基任选进一步被一个或多个的氘或卤素取代；
当R 6和R 7与其连接的原子一起形成未取代的5-6元环烃，R 1为甲基或甲氧基，且Z为-NH-时，R 8不为芳基。
在一些实施方案中，其中，R 1选自氢、氘、卤素、-OH、-NH 2、-CN和任选被一个或多个取代基取代的以下基团：C 1-6烷基、-O-C 1-6烷基、-NHC(＝O)-C 1-6烷基和-(C＝O)NH-C 1-6烷基，所述取代基选自：氘、卤素、-OH、-NH 2和-CN；
R 2、R 3、R 4、R 5、R 6和R 7：
(a)R 2和R 3与其连接的原子一起形成任选被一个或多个取代基取代的5-6元的环烃、杂环或杂芳环，所述取代基选自：氘、卤素、-OH、-NH 2、-CN、氧代、C 1-6烷基、-O-C 1-6烷基和C 3-6环烷基，所述C 1-6烷基、-O-C 1-6烷基和C 3-6环烷基任选进一步被一个或多个氘或卤素取代；R 4、R 5、R 6和R 7独立地选自氢、氘、卤素、-OH、-NH 2和任选被一个或多个取代基取代的以下基团：C 1-6烷基、-O-C 1-6烷基、-S-C 1-6烷基、C 3-6环烷基和C 3-6环烷基亚甲基，所述取代基选自：氘、卤素、-OH、-NH 2和-CN；
(b)R 3和R 4与其连接的原子一起形成任选被一个或多个取代基取代的5-6元的环烃，所述取代基选自：氘、卤素、-NH 2、-CN、C 1-6烷基、-O-C 1-6烷基和C 3-6环烷基，所述C 1-6烷基、-O-C 1-6烷基和C 3-6环烷基任选进一步被一个或多个氘或卤素取代；R 2、R 5、R 6和R 7独立地选自氢、氘、卤素、-OH、-NH 2和任选被一个或多个取代基取代的以下基团：C 1-6烷基、-O-C 1-6烷基、-S-C 1-6烷基、C 3-6环烷基和C 3-6环烷基亚甲基，所述取代基选自：氘、卤素、-OH、-NH 2和-CN；
(c)R 4和R 5与其连接的原子一起形成任选被一个或多个取代基取代的5-6元的环烃，所述取代基选自：氘、卤素、-OH、-NH 2、-CN、氧代、C 1-6烷基、-O-C 1-6烷基和C 3-6环烷基，所述C 1-6烷基、-O-C 1-6烷基和C 3-6环烷基任选进一步被一个或多个氘或卤素取代；R 2、R 3、R 6和R 7独立地选自氢、氘、卤素、-OH、-NH 2和任选被一个或多个取代基取代的以下基团：C 1-6烷基、-O-C 1-6烷基、-S-C 1-6烷基、C 3-6环烷基和C 3-6环烷基亚甲基，所述取代基选自：氘、卤素、-OH、-NH 2和-CN；
或者，(d)R 6和R 7与其连接的原子一起形成任选被一个或多个取代基取代的5-6元的环烃或杂环，所述取代基选自：氘、卤素、-OH、-NH 2、-CN、氧代、C 1-6烷基、-O-C 1-6烷基和C 3-6环烷基，所述C 1-6烷基、-O-C 1-6烷基和C 3-6环烷基任选进一步被一个或多个氘或卤素取代；R 2、R 3、R 4和R 5独立地选自氢、氘、卤素、-OH、-NH 2和任选被一个或多个取代基取代的以下基团：C 1-6烷基、-O-C 1-6烷基、-S-C 1-6烷基、C 3-6环烷基和C 3-6环烷基亚甲基，所述取代基选自：氘、卤素、-OH、-NH 2和-CN；
Z为O或-NH-(CH2)n-，n为选自0-3的整数；
R 8选自任选被一个或多个取代基取代的芳基、杂芳基、杂环基、C 3-8环烷基、C 1-6烷基和-O-C 1-6烷基，所述取代基选自氘、卤素、氧代、-OR 8a、-SR 8a、-C(＝O)R 8a、-OC(＝O)R 8a、-C(＝O)OR 8a、-C(＝O)NR 8aR 8b、-NR 8aR 8b、-NR 8aC(＝O)R 8b、-NR 8aS(＝O) 2R 8b、-S(＝O) 2R 8a、-S(＝O) 2NR 8aR 8b、-CN、-NO 2、C 1-4烷基和C 3-6环烷基，所述C 1-4烷基或C 3-6环烷基任选进一步被一个或多个的氘、卤素或-OH取代；
R 8a和R 8b独立地选自氢、氘或任选被一个或多个取代基取代的以下基团：C 1-4烷基、C 3-6环烷基和C 3-6环烷基亚甲基，所述取代基选自：氘、卤素、-NH 2、-OH、-CN、C 1-4烷基、C 1-4烷氧基、C 3-6环烷基和C 3-6环烷基亚甲基，上述取代基任选进 一步被一个或多个的氘或卤素取代；
当R 6和R 7与其连接的原子一起形成未取代的5-6元环烃，R 1为甲基或甲氧基，且Z为-NH-时，R 8不为芳基。
在一些实施方案中，R 1选自卤素、-OH、-NH 2、-CN和任选被一个或多个取代基取代的以下基团：C 1-6烷基、-O-C 1-6烷基、-NHC(＝O)-C 1-6烷基和-(C＝O)NH-C 1-6烷基，所述取代基选自：氘、卤素、-OH、-NH 2和-CN。
在一些实施方案中，R 1选自-OH、-NH 2和任选被一个或多个取代基取代的以下基团：C 1-6烷基、-O-C 1-6烷基和-NHC(＝O)-C 1-6烷基，所述取代基选自：氘、卤素、-OH、-NH 2和-CN。
在一些实施方案中，R 1选自-OH、-NH 2和任选被一个或多个-OH取代的以下基团：C 1-6烷基、-O-C 1-6烷基和-NHC(＝O)-C 1-6烷基。
在一个实施方案中，R 1为-OH。
在一些实施方案中，R 1为-O-C 1-6烷基，优选为-OCH 3或-OCH 2CH 3，更优选为-OCH 3。
在一些实施方案中，R 1为任选被一个或多个-OH取代的C 1-6烷基，优选为-CH 2OH或-CH 2CH 2OH，更优选为-CH 2OH。
在一个实施方案中，R 1为-NH 2。
在一些实施方案中，R 1为任选被一个或多个-OH取代的-NHC(＝O)-C 1-6烷基，优选为-NH 2C(＝O)CH 3。
在一些实施方案中，R 2和R 3与其连接的原子一起形成任选被一个或多个取代基取代的5-6元的环烃，所述取代基选自：氘、卤素、-OH、-NH 2、-CN、氧代、C 1-6烷基、-O-C 1-6烷基和C 3-6环烷基，所述C 1-6烷基、-O-C 1-6烷基和C 3-6环烷基任选进一步被一个或多个氘或卤素取代；
R 4、R 5、R 6和R 7独立地选自氢、氘、卤素、-OH、-NH 2和任选被一个或多个取代基取代的以下基团：C 1-6烷基、-O-C 1-6烷基、-S-C 1-6烷基、C 3-6环烷基、C 3-6环烷基亚甲基，所述取代基选自：氘、卤素、-OH、-NH 2和-CN。
在一些实施方案中，式I化合物为：
Figure PCTCN2021141211-appb-000002
R 9a独立地选自氢、氘、卤素、-OH、-NH 2、-CN、氧代、C 1-6烷基、-O-C 1-6烷基和C 3-6环烷基，所述C 1-6烷基、-O-C 1-6烷基和C 3-6环烷基任选进一步被一个或多个氘或卤素取代；m为选自0-8的整数。
在一些实施方案中，式I化合物选自：
Figure PCTCN2021141211-appb-000003
在一些实施方案中，式I化合物选自式II’-a、II’-b、II’-c、II’-d、II’-f、II’-g、II’-k、II’-l和II’-m化合物；优选自式II’-a、II’-c、II’-d、II’-k、II’-l和II’-m化合物；更优选自式II’-a、II’-d、II’-k和II’-m化合物；最优选为式II’-a或II’-k化合物。
在另一些实施方案中，R 2和R 3与其连接的原子一起形成任选被一个或多个取 代基取代的5-6元的环烃，所述取代基选自：氘、卤素、-OH、-NH 2、-CN、氧代、C 1-6烷基、-O-C 1-6烷基和C 3-6环烷基，所述C 1-6烷基、-O-C 1-6烷基和C 3-6环烷基任选进一步被一个或多个氘或卤素取代；
R 6和R 7与其连接的原子一起形成任选被一个或多个取代基取代的苯基、5-6元杂芳基，所述取代基选自：氘、卤素、-OH、-NH 2、-CN、氧代、C 1-6烷基、-O-C 1-6烷基和C 3-6环烷基，所述C 1-6烷基、-O-C 1-6烷基和C 3-6环烷基任选进一步被一个或多个氘或卤素取代；
R 4、R 5独立地选自氢、氘、卤素、-OH、-NH 2和任选被一个或多个取代基取代的以下基团：C 1-6烷基、-O-C 1-6烷基、C 3-6环烷基和C 3-6环烷基亚甲基，所述取代基选自：氘、卤素、-OH、-NH 2和-CN。
在一些实施方案中R 2和R 3与其连接的原子一起形成5-6元的环烃；优选所述5-6元的环烃为环戊基或环己基；所述环戊基或环己基任选被选自氢、氘、卤素、-OH、C 1-6烷基、卤代C 1-6烷基的取代基所取代；
R 6和R 7与其连接的原子一起形成苯基、5-6元杂芳基；优选所述5-6元杂芳基为吡啶；所述苯基或5-6元杂芳基任选被选自氢、氘、卤素、-OH、C 1-6烷基、卤代C 1-6烷基的取代基所取代；
R 4、R 5独立地选自氢、氘、卤素、-OH、-NH 2和任选被一个或多个取代基取代的以下基团：C 1-6烷基、-O-C 1-6烷基、C 3-6环烷基和C 3-6环烷基亚甲基，所述取代基选自：氘、卤素、-OH、-NH 2和-CN；优选R 4、R 5独立地选自氢、氘、卤素、-OH、C 1-6烷基、卤代C 1-6烷基；更优选R 4、R 5独立地选自氢或氘。
在另一些实施方案中，R 2和R 3与其连接的原子一起形成任选被一个或多个取代基取代的5-6元的杂环，所述取代基选自：氘、卤素、-OH、-NH 2、-CN、氧代、C 1-6烷基、-O-C 1-6烷基和C 3-6环烷基，所述C 1-6烷基、-O-C 1-6烷基和C 3-6环烷基任选进一步被一个或多个氘或卤素取代；
R 4、R 5、R 6和R 7独立地选自氢、氘、卤素、-OH、-NH 2和任选被一个或多个取代基取代的以下基团：C 1-6烷基、-O-C 1-6烷基、-S-C 1-6烷基、C 3-6环烷基、C 3-6环烷基亚甲基，所述取代基选自：氘、卤素、-OH、-NH 2和-CN。
在一些实施方案中，所述5-6元的杂环为5-6元的含S杂环。
在一些实施方案中，式I化合物选自：
Figure PCTCN2021141211-appb-000004
Figure PCTCN2021141211-appb-000005
R 9b选自氢、氘、卤素、-OH、-NH 2、-CN、氧代、C 1-6烷基、-O-C 1-6烷基和C 3-6环烷基，所述C 1-6烷基、-O-C 1-6烷基和C 3-6环烷基任选进一步被一个或多个氘或卤素取代；
R 9c选自氢、氘、C 1-6烷基和C 3-6环烷基，所述C 1-6烷基和C 3-6环烷基任选进一步被一个或多个氘或卤素取代；p为选自0-6的整数。
在一些实施方案中，式I化合物选自：
Figure PCTCN2021141211-appb-000006
Figure PCTCN2021141211-appb-000007
在一些实施方案中，式I化合物选自式III’-a、III’-b、III’-c、III’-d、III’-f、III’-g、III’-h和III’-i化合物；优选自式III’-a、III’-b、III’-c、III’-f、III’-g和III’-h化合物；更优选自式III’-a、III’-c、III’-f和III’-h化合物；最优选为式III’-a或III’-f化合物。
在另一些实施方案中，R 2和R 3与其连接的原子一起形成任选被一个或多个取代基取代的5-6元的杂芳环，所述取代基选自：氘、卤素、-OH、-NH 2、-CN、C 1-6烷基、-O-C 1-6烷基和C 3-6环烷基，所述C 1-6烷基、-O-C 1-6烷基和C 3-6环烷基任选进一步被一个或多个氘或卤素取代；
R 4、R 5、R 6和R 7独立地选自氢、氘、卤素、-OH、-NH 2和任选被一个或多个取代基取代的以下基团：C 1-6烷基、-O-C 1-6烷基、-S-C 1-6烷基、C 3-6环烷基、C 3-6环烷基亚甲基，所述取代基选自：氘、卤素、-OH、-NH 2和-CN。
在一些实施方案中，所述5-6元的杂芳环为5元含S杂芳环。
在一些实施方案中，式I化合物选自：
Figure PCTCN2021141211-appb-000008
Figure PCTCN2021141211-appb-000009
R 9d选自氢、氘、卤素、-OH、-NH 2、-CN、C 1-6烷基、-O-C 1-6烷基和C 3-6环烷基，所述C 1-6烷基、-O-C 1-6烷基和C 3-6环烷基任选进一步被一个或多个氘或卤素取代；
R 9e选自氢、氘、C 1-6烷基和C 3-6环烷基，所述C 1-6烷基和C 3-6环烷基任选进一步被一个或多个氘或卤素取代；q为选自0-3的整数。
在一些实施方案中，式I化合物选自：
Figure PCTCN2021141211-appb-000010
Figure PCTCN2021141211-appb-000011
在一些实施方案中，式I化合物选自式IV’-a、IV’-b、IV’-c、IV’-d、IV’-e、IV’-f、IV’-g、IV’-h、IV’-i、IV’-j、IV’-k和IV’-l化合物；优选自式IV’-a、IV’-b、IV’-c、IV’-d、IV’-g、IV’-h、IV’-i和IV’-j化合物；更优选自式IV’-a、IV’-d、IV’-g和IV’-j化合物；最优选式IV’-a或IV’-g化合物。
在一些实施方案中，式II-a、式II-b、式II’-a至II’-q、式III-a至III-p、式III’a至III’-r、式IV-a至IV-n以及式IV’-a至IV’-p中，R 4、R 5、R 6和R 7独立地选自氢、氘、卤素和任选被一个或多个取代基取代的以下基团：C 1-6烷基、C 3-6环烷基和C 3-6环烷基亚甲基，所述取代基为氘或卤素。
在一些实施方案中，R 4和R 7独立地选自氢、氘和卤素，R 5和R 6独立地选自氢、氘、卤素和任选被一个或多个氘或卤素取代的C 1-6烷基。
在一些实施方案中，R 4、R 5和R 7分别为氢，R 6为甲基；或者，R 4、R 6和R 7分别为氢，R 5为甲基。
在另一些实施方案中，R 3和R 4与其连接的原子一起形成任选被一个或多个取代基取代的5-6元的环烃，所述取代基选自：氘、卤素、C 1-6烷基和C 3-6环烷基，所述C 1-6烷基和C 3-6环烷基任选进一步被一个或多个氘或卤素取代；
R 2、R 5、R 6和R 7独立地选自氢、氘、卤素、-OH、-NH 2和任选被一个或多个取代基取代的以下基团：C 1-6烷基、-O-C 1-6烷基、-S-C 1-6烷基、C 3-6环烷基、C 3-6环烷基亚甲基，所述取代基选自：氘、卤素、-OH、-NH 2和-CN。
在一些实施方案中，式I化合物选自：
Figure PCTCN2021141211-appb-000012
Figure PCTCN2021141211-appb-000013
在一些实施方案中，式I化合物选自式V-a、V-b、V-c、V-d、V-f、V-g、V-k、V-l和V-m化合物；优选自式V-a、V-c、V-d、V-k、V-l和V-m化合物；更优选自式V-a、V-d、V-k和V-m化合物；最优选为式V-a或V-k化合物。
在一些实施方案中，式V-a至V-q化合物中，R 2、R 5、R 6和R 7独立地选自氢、氘、卤素和任选被一个或多个取代基取代的以下基团：C 1-6烷基、C 3-6环烷基和C 3-6环烷基亚甲基，所述取代基为氘或卤素。
在一些实施方案中，R 2和R 7独立地选自氢、氘和卤素，R 5和R 6独立地选自氢、氘、卤素和任选被一个或多个氘或卤素取代的C 1-6烷基。
在一些实施方案中，R 2、R 5和R 7分别为氢，R 6为甲基；或者，R 2、R 6和R 7分别为氢，R 5为甲基。
在另一些实施方案中，R 4和R 5与其连接的原子一起形成任选被一个或多个取代基取代的5-6元的环烃，所述取代基选自：氘、卤素、氧代、C 1-6烷基和C 3-6环烷基，所述C 1-6烷基和C 3-6环烷基任选进一步被一个或多个氘或卤素取代；
R 2、R 3、R 6和R 7独立地选自氢、氘、卤素、-OH、-NH 2和任选被一个或多个取代基取代的以下基团：C 1-6烷基、-O-C 1-6烷基、-S-C 1-6烷基、C 3-6环烷基、C 3-6环烷基亚甲基，所述取代基选自：氘、卤素、-OH、-NH 2和-CN；
在一些实施方案中，式I化合物选自：
Figure PCTCN2021141211-appb-000014
Figure PCTCN2021141211-appb-000015
在一些实施方案中，式I化合物选自式VI-a、VI-b、VI-c、VI-d、VI-e、VI-h、VI-i、VI-j、VI-k和VI-l化合物；优选自式VI-a、VI-b、VI-c、VI-h、VI-i和VI-j化合物；更优选为式VI-a或VI-h化合物。
在一些实施方案中，式VI-a至VI-l化合物中，R 2、R 3、R 6和R 7独立地选自氢、氘、卤素和任选被一个或多个取代基取代的以下基团：C 1-6烷基、C 3-6环烷基和C 3-6环烷基亚甲基，所述取代基为氘或卤素。
在一些实施方案中，R 2和R 7独立地选自氢、氘和卤素，R 3和R 6独立地选自氢、氘、卤素和任选被一个或多个氘或卤素取代的C 1-6烷基。
在一些实施方案中，R 2和R 7分别为氢，R 3为三氟甲基，R 6为甲基；或者，R 2和R 7分别为氢，R 3为氯，R 6为甲基。
在一些实施方案中，R 4和R 5与其连接的原子一起形成任选被一个或多个取代基取代的苯基，所述取代基选自：氘、卤素、氧代、C 1-6烷基和C 3-6环烷基，所述C 1-6烷基和C 3-6环烷基任选进一步被一个或多个氘或卤素取代；
R 2、R 3、R 6和R 7独立地选自氢、氘、卤素、-OH、-NH 2和任选被一个或多个取代基取代的以下基团：C 1-6烷基、-O-C 1-6烷基、-S-C 1-6烷基、C 3-6环烷基、C 3-6环烷基亚甲基，所述取代基选自：氘、卤素、-OH、-NH 2和-CN；
优选R 2、R 3、R 6和R 7独立地选自氢、氘、卤素、-OH、-NH 2、C 1-6烷基、-O-C 1-6烷基；
更优选R 2、R 3、R 6和R 7独立地选自氢、氘、卤素、-OH、-NH 2、C 1-6烷基、 -O-C 1-6烷基；
最优选R 2、R 3、R 6和R 7独立地选自氢或氘。
在一些实施方案中，式I化合物选自：
Figure PCTCN2021141211-appb-000016
R 18b独立地选自氢、氘、卤素、-OH、-NH 2和任选被一个或多个取代基取代的以下基团：C 1-6烷基、-O-C 1-6烷基、C 3-6环烷基、C 3-6环烷基亚甲基，所述取代基选自：氘、卤素、-OH、-NH 2和-CN；优选R 18b为氢。
在一些实施方案中，R 3和R 4与其连接的原子一起形成任选被一个或多个取代基取代的苯基，所述取代基选自：氘、卤素、C 1-6烷基和C 3-6环烷基，所述C 1-6烷基和C 3-6环烷基任选进一步被一个或多个氘或卤素取代；
R 2、R 5、R 6和R 7独立地选自氢、氘、卤素、-OH、-NH 2和任选被一个或多个取代基取代的以下基团：C 1-6烷基、-O-C 1-6烷基、-S-C 1-6烷基、C 3-6环烷基、C 3-6环烷基亚甲基，所述取代基选自：氘、卤素、-OH、-NH 2和-CN；
优选R 2、R 5、R 6和R 7独立地选自氢、氘、卤素、-OH、-NH 2、C 1-6烷基、-O-C 1-6烷基；
更优选R 2、R 5或R 7独立地选自氢、氘、卤素、-OH、-NH 2、C 1-6烷基、-O-C 1-6烷基；R 6选自C 1-6烷基；
最优选R 2、R 5和R 7独立地选自氢或氘，R 6为甲基。
在一些实施方案中，式I化合物选自：
Figure PCTCN2021141211-appb-000017
R 18a独立地选自氢、氘、卤素、-OH、-NH 2和任选被一个或多个取代基取代的以下基团：C 1-6烷基、-O-C 1-6烷基、C 3-6环烷基、C 3-6环烷基亚甲基，所述取代基选自：氘、卤素、-OH、-NH 2和-CN；
优选R 18a独立地选自氢、氘、卤素、-OH、-NH 2或C 1-6烷基、-O-C 1-6烷基；更优选R 18a为氢。
在另一些实施方案中，R 6和R 7与其连接的原子一起形成任选被一个或多个取代基取代的5-6元的环烃，所述取代基选自：氘、卤素、C 1-6烷基、-O-C 1-6烷基和 C 3-6环烷基，所述C 1-6烷基、-O-C 1-6烷基和C 3-6环烷基任选进一步被一个或多个氘或卤素取代；R 2、R 3、R 4和R 5独立地选自氢、氘、卤素、-OH、-NH 2和任选被一个或多个取代基取代的以下基团：C 1-6烷基、-O-C 1-6烷基、-S-C 1-6烷基、C 3-6环烷基、C 3-6环烷基亚甲基，所述取代基选自：氘、卤素、-OH、-NH 2和-CN；
优选R 2、R 4和R 5独立地选自氢、氘、C 1-6烷基和卤素，R 3选自三氟甲基、环丙基、-S-三氟甲基；
更优选R 2、R 4和R 5独立地选自氢或氘，R 3选自三氟甲基。
在一些实施方案中，式I化合物选自：
Figure PCTCN2021141211-appb-000018
在一些实施方案中，式I化合物选自式VII-a、VII-b、VII-c、VII-g、VII-h和VII-i化合物；优选自式VII-a、VII-b、VII-g和VII-h化合物；更优选为式VII-a或VII-g化合物；最优选为式VII-g化合物。
在另一些实施方案中，R 6和R 7与其连接的原子一起形成任选被一个或多个取代基取代的5-6元的杂环，所述取代基选自：氘、卤素、氧代、C 1-6烷基、-O-C 1-6烷基和C 3-6环烷基，所述C 1-6烷基、-O-C 1-6烷基和C 3-6环烷基任选进一步被一个或多个氘或卤素取代；
R 2、R 3、R 4和R 5独立地选自氢、氘、卤素、-OH、-NH 2和任选被一个或多个取代基取代的以下基团：C 1-6烷基、-O-C 1-6烷基、-S-C 1-6烷基、C 3-6环烷基、C 3-6环烷基亚甲基，所述取代基选自：氘、卤素、-OH、-NH 2和-CN。
在一些实施方案中，式I化合物选自：
Figure PCTCN2021141211-appb-000019
R 9f独立地选自氘、卤素、氧代、C 1-6烷基、-O-C 1-6烷基和C 3-6环烷基，所述C 1-6烷基、-O-C 1-6烷基和C 3-6环烷基任选进一步被一个或多个氘或卤素取代；
R 9g选自氢、氘、C 1-6烷基和C 3-6环烷基，所述C 1-6烷基和C 3-6环烷基任选进一步被一个或多个氘或卤素取代；r为选自0-6的整数。
在一些实施方案中，式I化合物选自：
Figure PCTCN2021141211-appb-000020
Figure PCTCN2021141211-appb-000021
在一些实施方案中，式I化合物选自式VIII’-a、VIII’-c、VIII’-d、VIII’-f、VIII’-g、VIII’-j、VIII’-k、VIII’-l和VIII’-m化合物；优选自式VIII’-a、VIII’-c、VIII’-d、VIII’-f、VIII’-g、VIII’-j和VIII’-l化合物；更优选自式VIII’-a、VIII’-c、VIII’-d和VIII’-j化合物；最优选为式VIII’-a或VIII’-d化合物。
在一些实施方案中，其中，R 6和R 7与其连接的原子一起形成任选被一个或多个取代基取代的苯环，所述取代基选自：氘、卤素、氧代、C 1-6烷基、-O-C 1-6烷基和C 3-6环烷基，所述C 1-6烷基、-O-C 1-6烷基和C 3-6环烷基任选进一步被一个或多个氘或卤素取代；
R 2、R 3、R 4和R 5独立地选自氢、氘、卤素、-OH、-NH 2和任选被一个或多个取代基取代的以下基团：C 1-6烷基、-O-C 1-6烷基、-S-C 1-6烷基、C 3-6环烷基、C 3-6环烷基亚甲基，所述取代基选自：氘、卤素、-OH、-NH 2和-CN。
在一些实施方案中，式I化合物选自：
Figure PCTCN2021141211-appb-000022
R 9k独立地选自氘、卤素、氧代、C 1-6烷基、-O-C 1-6烷基和C 3-6环烷基，所述C 1-6烷基、-O-C 1-6烷基和C 3-6环烷基任选进一步被一个或多个氘或卤素取代；
优选R 9k独立地选自氘、卤素、氧代、C 1-6烷基、-O-C 1-6烷基。在一些实施方案中，式VII-a至VII-k、VII’-a、式VIII-a至VIII-g以及式VIII’-a至VIII’-m化合物中，R 2、R 3、R 4和R 5独立地选自氢、氘、卤素和任选被一个或多个取代基取代的以下基团：C 1-6烷基、C 3-6环烷基和C 3-6环烷基亚甲基，所述取代基为氘或卤素；更优选R 9k独立地选自氘、卤素、氧代、卤代C 1-6烷基、卤代-O-C 1-6烷基；最优选R 9k独立地选自氘、卤素、C 1-6烷基、-O-C 1-6烷基。
在一些实施方案中，R 2和R 4独立地选自氢、氘和卤素，R 3和R 5独立地选自氢、氘、卤素和任选被一个或多个氘或卤素取代的C 1-6烷基。
在一些实施方案中，R 2和R 4分别为氢，R 3为三氟甲基或氯，R 5为氢、卤素或甲基；优选R 2、R 4和R 5分别为氢，R 3为三氟甲基。
在一些实施方案中，其中，R 6和R 7与其连接的原子一起形成任选被一个或多个取代基取代的5-6元杂芳基，所述取代基选自：氘、卤素、氧代、C 1-6烷基、-O-C 1-6烷基和C 3-6环烷基，所述C 1-6烷基、-O-C 1-6烷基和C 3-6环烷基任选进一步被一个或多个氘或卤素取代；优选所述5-6元杂芳基为吡啶；
R 2、R 3、R 4和R 5独立地选自氢、氘、卤素、-OH、-NH 2和任选被一个或多个取代基取代的以下基团：C 1-6烷基、-O-C 1-6烷基、-S-C 1-6烷基、C 3-6环烷基、C 3-6环烷基亚甲基，所述取代基选自：氘、卤素、-OH、-NH 2和-CN。
在一些实施方案中，其中，R 6和R 7与其连接的原子一起形成任选被一个或多个取代基取代的包含1-2个杂原子的5-6元的杂芳基，所述取代基选自：氘、卤素、C 1-6烷基、-O-C 1-6烷基和C 3-6环烷基，所述C 1-6烷基、-O-C 1-6烷基和C 3-6环烷基任选进一步被一个或多个氘或卤素取代；所述杂原子选自氧原子、氮原子、硫原子，优选所述杂原子选自氮原子。
在一些实施方案中，式I化合物选自：
Figure PCTCN2021141211-appb-000023
所述X选自氧原子或硫原子；所述R 18c选自氘、卤素、C 1-6烷基、-O-C 1-6烷基和C 3-6环烷基，所述C 1-6烷基、-O-C 1-6烷基和C 3-6环烷基任选进一步被一个或多个卤素取代；优选R 18c独立地选自氘、卤素、C 1-6烷基、-O-C 1-6烷基；
a选自0-3的整数；优选a选自0-1的整数；更优选a为0；
Z、R 2、R 3、R 4、R 5、R 8如式I中定义。
在一些实施方案中，如式X-a、X-b、X-c、X-d、X-e、X-f、X-g、X-h、X-i所示的化合物或其可药用盐，其中R 18c独立地选自氘、卤素、C 1-6烷基、-O-C 1-6烷基。
在一些实施方案中，如式X-a、X-b、X-c、X-d、X-e、X-f、X-g、X-h、X-i所示的化合物或其可药用盐，其中R 2、R 3、R 4和R 5独立地选自氢、氘、卤素和任选被一个或多个取代基取代的以下基团：C 1-6烷基、C 3-6环烷基和C 3-6环烷基亚甲基，所述取代基为氘或卤素。
在一些实施方案中，如式X-a、X-b、X-c、X-d、X-e、X-f、X-g、X-h、X-i所示的化合物或其可药用盐，其中R 2和R 4独立地选自氢、氘和卤素，R 3和R 5独立地选自氢、氘、卤素和任选被一个或多个氘或卤素取代的C 1-6烷基。
在一些实施方案中，如式X-a、X-b、X-c、X-d、X-e、X-f、X-g、X-h、X-i所示的化合物或其可药用盐，其中R 2和R 4分别为氢，R 3为三氟甲基或氯，R 5为氢或甲基；优选R 2、R 4和R 5分别为氢，R 3为三氟甲基。
本公开还提供式I’化合物或其可药用盐，
Figure PCTCN2021141211-appb-000024
其中，R 11选自-OH、-NH 2、-CN、-O-C 1-6烷基、-C 1-6烷基-OH或-NHC(＝O)-C 1-6烷基，所述C 1-6烷基任选被一个或多个选自如下的取代基取代：氘、卤素、-OH、-NH 2和-CN；
R 13选自任选被一个或多个取代基取代的以下基团：C 2-6烷基、-S-C 1-6烷基和C 3-6环烷基，所述取代基选自氘、卤素和-OH。
R 15、R 16和R 17独立地选自氢、氘、卤素、-OH、-NH 2和C 1-6烷基，所述C 1-6烷基任选被一个或多个选自如下的取代基取代：氘、卤素、-OH、-NH 2和-CN；
Z为O或-NH-(CH2)n-，n为选自0-3的整数；
R 8选自任选被一个或多个取代基取代的芳基、杂芳基、杂环基、C 3-8环烷基、C 1-6烷基或-O-C 1-6烷基，所述取代基选自氘、卤素、氧代、-OR 8a、-SR 8a、-C(＝O)R 8a、-OC(＝O)R 8a、-C(＝O)OR 8a、-C(＝O)NR 8aR 8b、-NR 8aR 8b、-NR 8aC(＝O)R 8b、-NR 8aS(＝O) 2R 8b、-S(＝O) 2R 8a、-S(＝O) 2NR 8aR 8b、-CN、-NO 2、C 1-4烷基或C 3-6环烷基，所述C 1-4烷基或C 3-6环烷基任选进一步被一个或多个的氘、卤素或-OH取代；
R 8a和R 8b独立地选自氢、氘或任选被一个或多个取代基取代的以下基团：C 1-4烷基、C 3-6环烷基、C 3-6环烷基亚甲基，所述取代基选自：氘、卤素、-NH 2、-OH、-CN、C 1-4烷基、C 1-4烷氧基、C 3-6环烷基或C 3-6环烷基亚甲基，上述取代基任选进一步被一个或多个的氘或卤素取代。
在一些实施方案中，R 13选自乙基、正丙基、异丙基和正丁基，优选为乙基；
在一个实施方案中，R 13为-S-CF 3。
在一些实施方案中，R 13选自：
Figure PCTCN2021141211-appb-000025
Figure PCTCN2021141211-appb-000026
优选
Figure PCTCN2021141211-appb-000027
更优选
Figure PCTCN2021141211-appb-000028
Figure PCTCN2021141211-appb-000029
最优选为
Figure PCTCN2021141211-appb-000030
在一个实施方案中，R 11为-OH。
在一个实施方案中，R 11为-NH 2。
在一些实施方案中，R 11为任选被氘或卤素取代的-O-C 1-6烷基；优选为甲氧基或乙氧基；更优选为甲氧基。
在一个实施方案中，R 11为-CH 2OH。
在一些实施方案中，R 11为任选被氘或卤素取代的-NHC(＝O)-C 1-6烷基；优选为-NHC(＝O)-CH 3。
在一些实施方案中，R 15、R 16和R 17独立地选自氢、氘、氟和甲基。
本公开还提供式I”化合物或其可药用盐，
Figure PCTCN2021141211-appb-000031
其中，R 21选自-NH 2、-O-C 1-6烷基、-C 1-6烷基-OH或-NHC(＝O)-C 1-6烷基，所述C 1-6烷基任选被一个或多个选自如下的取代基取代：氘、卤素、-OH、-NH 2和-CN；
R 23选自氯或任选被一个或多个氘或卤素取代的C 1-6烷基；
R 25、R 26和R 27独立地选自氢、氘、卤素、-OH、-NH 2和C 1-6烷基，所述C 1-6烷基任选被一个或多个选自如下的取代基取代：氘、卤素、-OH、-NH 2和-CN；
Z为O或-NH-(CH2)n-，n为选自0-3的整数；
R 8选自任选被一个或多个取代基取代的芳基、杂芳基、杂环基、C 3-8环烷基、C 1-6烷基或-O-C 1-6烷基，所述取代基选自氘、卤素、氧代、-OR 8a、-SR 8a、-C(＝O)R 8a、-OC(＝O)R 8a、-C(＝O)OR 8a、-C(＝O)NR 8aR 8b、-NR 8aR 8b、-NR 8aC(＝O)R 8b、-NR 8aS(＝O) 2R 8b、-S(＝O) 2R 8a、-S(＝O) 2NR 8aR 8b、-CN、-NO 2、C 1-4烷基或C 3-6环烷基，所述C 1-4烷基或C 3-6环烷基任选进一步被一个或多个的氘、卤素或-OH取代；
R 8a和R 8b独立地选自氢、氘或任选被一个或多个取代基取代的以下基团：C 1-4烷基、C 3-6环烷基、C 3-6环烷基亚甲基，所述取代基选自：氘、卤素、-NH 2、-OH、-CN、C 1-4烷基、C 1-4烷氧基、C 3-6环烷基或C 3-6环烷基亚甲基，上述取代基任选进一步被一个或多个的氘或卤素取代；
并且，当R 23为甲基时，R 21不为甲氧基。
在一个实施方案中，R 21为-NH 2。
在一些实施方案中，R 21为任选被氘或卤素取代的-O-C 1-6烷基；优选为甲氧基或乙氧基；更优选为甲氧基。
在一个实施方案中，R 21为-CH 2OH。
在一些实施方案中，R 21为任选被氘或卤素取代的-NHC(＝O)-C 1-6烷基；优选为-NHC(＝O)-CH 3。
在一些实施方案中，R 23为任选被一个或多个氟取代的C 1-6烷基，优选为三氟甲基。
在一个实施方案中，R 23为氯。
在一些实施方案中，R 25、R 26和R 27独立地选自氢、氘、氟和甲基。
在一些实施方案中，前述本公开的化合物中，Z为O。
在一些实施方案中，前述本公开的化合物中，Z为-NH-(CH2)n-，n为选自0-2的整数；n优选为0或1；n更优选为0。
在一些实施方案中，前述本公开的化合物中，R 8选自任选被一个或多个取代基取代的5-10元杂环基，所述取代基选自氘、卤素、氧代、-OR 8a、-SR 8a、-C(＝O)R 8a、-OC(＝O)R 8a、-C(＝O)OR 8a、-C(＝O)NR 8aR 8b、-NR 8aR 8b、-NR 8aC(＝O)R 8b、-NR 8aS(＝O) 2R 8b、-S(＝O) 2R 8a、-S(＝O) 2NR 8aR 8b、-CN、-NO 2、C 1-4烷基和C 3-6环烷基，所述C 1-4烷基或C 3-6环烷基任选进一步被一个或多个的氘、卤素或-OH取代；
R 8a和R 8b独立地选自氢、氘和任选被一个或多个取代基取代的以下基团：C 1-4烷基、C 3-6环烷基和C 3-6环烷基亚甲基，所述取代基选自：氘、卤素、-NH 2、-OH、-CN、C 1-4烷基、C 1-4烷氧基、C 3-6环烷基或C 3-6环烷基亚甲基，上述取代基任选进一步被一个或多个的氘或卤素取代。
在一些实施方案中，R 8选自：
Figure PCTCN2021141211-appb-000032
R 10a选自氢、氘、卤素、氧代、-OH、-NH 2、-COOH、-CN、C 1-4烷基和C 3-6环烷基，所述C 1-4烷基或C 3-6环烷基任选进一步被一个或多个的氘、卤素或-OH取代；
R 10b选自氢、氘、C 1-4烷基和C 3-6环烷基，所述C 1-4烷基和C 3-6环烷基任选进一步被一个或多个氘或卤素取代；s为选自0-15的整数。
在一些实施方案中，R 8选自：
Figure PCTCN2021141211-appb-000033
Figure PCTCN2021141211-appb-000034
优选
Figure PCTCN2021141211-appb-000035
Figure PCTCN2021141211-appb-000036
更优选为
Figure PCTCN2021141211-appb-000037
最优选为
Figure PCTCN2021141211-appb-000038
在一些实施方案中，R 8为
Figure PCTCN2021141211-appb-000039
优选为
Figure PCTCN2021141211-appb-000040
在另一些实施方案中，前述本公开的化合物中，R 8选自任选被一个或多个取代基取代的芳基或杂芳基，所述取代基选自氘、卤素、氧代、-OR 8a、-SR 8a、-C(＝O)R 8a、-OC(＝O)R 8a、-C(＝O)OR 8a、-C(＝O)NR 8aR 8b、-NR 8aR 8b、-NR 8aC(＝O)R 8b、-NR 8aS(＝O) 2R 8b、-S(＝O) 2R 8a、-S(＝O) 2NR 8aR 8b、-CN、-NO 2、C 1-4烷基和C 3-6环烷基，所述C 1-4烷基或C 3-6环烷基任选进一步被一个或多个的氘、卤素或-OH取代；
R 8a和R 8b独立地选自氢、氘和任选被一个或多个取代基取代的以下基团：C 1-4烷基、C 3-6环烷基和C 3-6环烷基亚甲基，所述取代基选自：氘、卤素、-NH 2、-OH、-CN、C 1-4烷基、C 1-4烷氧基、C 3-6环烷基或C 3-6环烷基亚甲基，上述取代基任选进一步被一个或多个的氘或卤素取代。
在一些实施方案中，R 8选自：
Figure PCTCN2021141211-appb-000041
R 10c选自氢、氘、卤素、-OH、-NH 2、-COOH、-CN、-C(＝O) 2NH 2、-S(＝O) 2NH 2、C 1-4烷基和C 3-6环烷基，所述C 1-4烷基或C 3-6环烷基任选进一步被一个或多个的氘、卤素或-OH取代；
R 10d选自氢、氘、C 1-4烷基和C 3-6环烷基，所述C 1-4烷基和C 3-6环烷基任选进一步被一个或多个氘或卤素取代；t为选自0-7的整数。
在一些实施方案中，R 8选自：
Figure PCTCN2021141211-appb-000042
优选
Figure PCTCN2021141211-appb-000043
更优选为
Figure PCTCN2021141211-appb-000044
Figure PCTCN2021141211-appb-000045
在另一些实施方案中，前述本公开的化合物中，R 8选自任选被一个或多个取代基取代的C 3-8环烷基，所述取代基选自氘、卤素、-OH、-NH 2、-CN和C 1-4烷基，所述C 1-4烷基任选进一步被一个或多个的氘、卤素或-OH取代。
在一些实施方案中，R 8选自：
Figure PCTCN2021141211-appb-000046
R 10e、R 10f、R 10e’、R 10f’独立地选自氢、氘、卤素、-OH和C 1-4烷基，所述C 1-4烷基任选进一步被一个或多个的氘、卤素或-OH取代。
在一些实施方案中，R 8选自：
Figure PCTCN2021141211-appb-000047
R 10e、R 10e’独立地选自氢、氘、卤素、-OH和C 1-4烷基，所述C 1-4烷基任选进一步被一个或多个的氘、卤素或-OH取代。
在一些实施方案中，R 8选自：
Figure PCTCN2021141211-appb-000048
优选
Figure PCTCN2021141211-appb-000049
更优选为
Figure PCTCN2021141211-appb-000050
在另一些实施方案中，前述本公开的化合物中，R 8选自任选被一个或多个取代基取代的C 2-6烷基，所述取代基选自氘、卤素、-OR 8a、-SR 8a、-C(＝O)R 8a、-OC(＝O)R 8a、-C(＝O)OR 8a、-C(＝O)NR 8aR 8b、-NR 8aR 8b、-NR 8aC(＝O)R 8b、-NR 8aS(＝O) 2R 8b、-S(＝O) 2R 8a、-S(＝O) 2NR 8aR 8b、-CN、-NO 2、C 1-4烷基和C 3-6环烷基，所述C 1-4烷基或C 3-6环烷基任选进一步被一个或多个的氘、卤素或-OH取代；
R 8a和R 8b独立地选自氢、氘和任选被一个或多个取代基取代的以下基团：C 1-4烷基、C 3-6环烷基和C 3-6环烷基亚甲基，所述取代基选自：氘、卤素、-NH 2、-OH、-CN、C 1-4烷基、C 1-4烷氧基、C 3-6环烷基或C 3-6环烷基亚甲基，上述取代基任选进一步被一个或多个的氘或卤素取代。
在一些实施方案中，R 8选自：
Figure PCTCN2021141211-appb-000051
R 10g选自氢、氘、卤素、-NH 2、-OH、-CN、-NH-C 1-4烷基和-N(C 1-4烷基) 2，所述C 1-4烷基任选被一个或多个的氘、卤素或-OH取代。
第二方面，本公开该提供选自如下的化合物或其可药用盐：
Figure PCTCN2021141211-appb-000052
Figure PCTCN2021141211-appb-000053
第三方面，本公开该提供选自如下的化合物或其可药用盐：
Figure PCTCN2021141211-appb-000054
Figure PCTCN2021141211-appb-000055
第四方面，本公开还提供一种在前所述的化合物的同位素取代物，优选地，所述的同位素取代为氘原子取代
第五方面，本公开还提供一种药物组合物，包含第一至第三方面所述的化合物或其可药用盐或第四方面所述的同位素取代物，和至少一种药学上可接受的载体、稀释剂或者赋形剂。
在一些实施方案中，所述的药物组合物的单位剂量为0.001mg-1000mg。
在某些实施方案中，基于组合物的总重量，所述的药物组合物含有0.01-99.99％的前述化合物或其可药用的盐。在某些实施方案中，所述的药物组合物含有0.1-99.9％的前述化合物或其可药用的盐。在某些实施方案中，所述的药物组合物含有0.5％-99.5％的化合物或其可药用的盐。在某些实施方案中，所述的药物组合物含有1％-99％的化合物或其可药用的盐。在某些实施方案中，所述的药物组合物含有2％-98％的化合物或其可药用的盐。
本公开还提供第一、第二或第三方面所述的化合物或其可药用盐作为药物的用途。
第六方面，本公开还提供第一、第二或第三方面所述的化合物或其可药用盐，或第四方面所述的同位素取代物或第五方面所述药物组合物在制备治疗与NLRP3活性相关的疾病的药物中的用途。
本公开还提供一种预防和/或治疗与NLRP3活性相关的疾病的患者的方法，其通过向所述患者施用治疗有效量的第一、第二或第三方面所述的化合物或其可药用盐，或第四方面所述的同位素取代物，或第五方面所述药物组合物。
本公开还提供一种用于预防或治疗与NLRP3活性相关的疾病的第一、第二或第三方面所述的化合物或其可药用盐，或第四方面所述的同位素取代物或第五方面所述药物组合物。
本公开还提供一种预防和/或治疗与NLRP3活性相关的疾病的患者的方法，其通过向所述患者施用治疗有效量的前述化合物或其可药用盐、或前述药物组合物。
NLRP3活性相关的疾病包括炎性体相关疾病、免疫性疾病、炎症性疾病、自身免疫性疾病和/或自身炎症性疾病。
本公开还提供第一、第二或第三方面所述的化合物或其可药用盐，或第四方面所述的同位素取代物或第五方面所述药物组合物在制备治疗炎性体相关疾病、免疫性疾病、炎症性疾病、自身免疫性疾病和/或自身炎症性疾病的药物中的用途。
本公开还提供第一、第二或第三方面所述的化合物或其可药用盐，或第四方面所述的同位素取代物或第五方面所述药物组合物在制备治疗炎性体相关疾病、免疫性疾病、炎症性疾病、自身免疫性疾病和/或自身炎症性疾病的药物中的用途。
本公开还提供一种用于治疗治疗炎性体相关疾病、免疫性疾病、炎症性疾病、自身免疫性疾病和/或自身炎症性疾病的第一、第二或第三方面所述的化合物或其可药用盐，或第四方面所述的同位素取代物或第五方面所述药物组合物。
本公开还提供一种治疗和/或预防炎性体相关疾病、免疫性疾病、炎症性疾病、自身免疫性疾病和/或自身炎症性疾病患者的方法，其通过向所述患者施用治疗有效量的前述化合物或其可药用盐、或前述药物组合物。所述炎性体相关疾病、免 疫性疾病、炎症性疾病、自身免疫性疾病和/或自身炎症性疾病可具体选自：自身炎症发热综合征(如冷吡啉相关周期性综合征)，镰状细胞性贫血症，系统性红斑狼疮，肝脏相关疾病(如慢性肝病、病毒性肝炎、非酒精性脂肪性肝炎、酒精性脂肪性肝炎、酒精性肝病)，炎症性关节炎相关疾病(如痛风、软骨钙化病、骨关节炎、类风湿关节炎、急性或慢性关节炎)，肾脏相关疾病(如高草酸尿症、狼疮性肾炎、高血压性肾病、血液透析相关炎症、I型或II型糖尿病和其并发症(如肾病、视网膜病))，神经炎症相关疾病(如脑部感染、急性损伤、多发性硬化症，阿尔茨海默氏病和神经退行性疾病)，心血管及代谢相关紊乱或疾病(如降低心血管疾病风险(CvRR)、动脉粥样硬化、I型和II型糖尿病以及相关并发症、外周动脉疾病(PAD)、急性心力衰竭和高血压)，伤口愈合，疤痕形成，炎性皮肤疾病(例如痤疮、化脓性汗腺炎)，哮喘，结节病，年龄相关性黄斑变性，与癌症有关的疾病/病症(例如骨髓增生性肿瘤、白血病、骨髓增生异常综合症(MDS)、骨髓纤维化、肺癌、结肠癌)。
在一些实施方案中，本公开所述的化合物相比于化合物R1或化合物R2或化合物R3经口服血液中的AUC或C max预期可提高10％、20％、30％、40％、50％、60％、70％、80％、90％、100％甚至更高。
本公开还提供如下所示的化合物，
Figure PCTCN2021141211-appb-000056
Y选自氟、氯、溴和碘；优选Y选自氟、氯和溴；更优选Y选自氯；
R 6、R 7、Z、R 8如式I中所定义；
在某些实施方案中，该化合物作为中间体。
在一些实施方案中，R 6和R 7与其连接的原子一起形成任选被一个或多个取代基取代的5-6元的环烃、5-6元的杂环、苯基、5-6元杂芳基，所述取代基选自：氘、卤素、-OH、-NH 2、-CN、氧代、C 1-6烷基、-O-C 1-6烷基和C 3-6环烷基，所述C 1-6烷基、-O-C 1-6烷基和C 3-6环烷基任选进一步被一个或多个氘或卤素取代；
R 2、R 3、R 4和R 5独立地选自氢、氘、卤素、-OH、-NH 2和任选被一个或多个取代基取代的以下基团：C 1-6烷基、-O-C 1-6烷基、-S-C 1-6烷基、C 3-6环烷基和C 3-6环烷基亚甲基，所述取代基选自：氘、卤素、-OH、-NH 2和-CN。
本公开中所述化合物可药用盐选自无机盐或有机盐，本公开所述化合物可与酸性或碱性物质反应成相应盐。
另一方面，本公开化合物可以存在特定的几何或立体异构体形式。本公开设想所有的这类化合物，包括顺式和反式异构体、(-)-和(+)-对对映体、(R)-和(S)-对映体、非对映异构体、(D)-异构体、(L)-异构体，及其外消旋混合物和其他混合物， 例如对映异构体或非对映体富集的混合物，所有这些混合物都属于本公开的范围之内。烷基等取代基中可存在另外的不对称碳原子。所有这些异构体以及它们的混合物，均包括在本公开的范围之内。
另外，本公开的化合物和中间体还可以以不同的互变异构体形式存在，并且所有这样的形式包含于本公开的范围内。术语“互变异构体”或“互变异构体形式”是指可经由低能垒互变的不同能量的结构异构体。例如，质子互变异构体(也称为质子转移互变异构体)包括经由质子迁移的互变，如酮-烯醇及亚胺-烯胺、内酰胺-内酰亚胺异构化。内酰胺-内酰亚胺平衡实例是在如下所示的A和B之间。
Figure PCTCN2021141211-appb-000057
本发明中的所有化合物可以被画成A型或B型。所有的互变异构形式在本发明的范围内。化合物的命名不排除任何互变异构体。
本公开化合物可以是不对称的，例如，具有一个或多个立体异构体。除非另有说明，所有立体异构体都包括，如对映异构体和非对映异构体。本公开的含有不对称碳原子的化合物可以以光学活性纯的形式或外消旋形式被分离出来。光学活性纯的形式可以从外消旋混合物拆分，或通过使用手性原料或手性试剂合成。
可以通过的手性合成或手性试剂或者其他常规技术制备光学活性的(R)-和(S)-异构体以及D和L异构体。如果想得到本公开某化合物的一种对映体，可以通过不对称合成或者具有手性助剂的衍生作用来制备，其中将所得非对映体混合物分离，并且辅助基团裂开以提供纯的所需对映异构体。或者，当分子中含有碱性官能团(如氨基)或酸性官能团(如羧基)时，与适当的光学活性的酸或碱形成非对映异构体的盐，然后通过本领域所公知的常规方法进行非对映异构体拆分，然后回收得到纯的对映体。此外，对映异构体和非对映异构体的分离通常是通过使用色谱法完成的，所述色谱法采用手性固定相，并任选地与化学衍生法相结合(例如由胺生成氨基甲酸盐)。
本公开还包括一些与本文中记载的那些相同的，但一个或多个原子被原子量或质量数不同于自然中通常发现的原子量或质量数的原子置换的同位素标记的本公开化合物。可结合到本公开化合物的同位素的实例包括氢、碳、氮、氧、磷、硫、氟、碘和氯的同位素，诸如分别为 2H、 3H、 11C、 13C、 14C、 13N、 15N、 15O、 17O、 18O、 31P、 32P、 35S、 18F、 123I、 125I和 36Cl等。
除另有说明，当一个位置被特别地指定为氘(D)时，该位置应理解为具有大于氘的天然丰度(其为0.015％)至少1000倍的丰度的氘(即，至少10％的氘 掺入)。示例中化合物的具有大于氘的天然丰度可以是至少1000倍的丰度的氘、至少2000倍的丰度的氘、至少3000倍的丰度的氘、至少4000倍的丰度的氘、至少5000倍的丰度的氘、至少6000倍的丰度的氘或更高丰度的氘。本公开还包括各种氘化形式的式(I)化合物。与碳原子连接的各个可用的氢原子可独立地被氘原子替换。本领域技术人员能够参考相关文献合成氘化形式的式(I)化合物。在制备氘代形式的式(I)化合物时可使用市售的氘代起始物质，或它们可使用常规技术采用氘代试剂合成，氘代试剂包括但不限于氘代硼烷、三氘代硼烷四氢呋喃溶液、氘代氢化锂铝、氘代碘乙烷和氘代碘甲烷等。
“任选地”或“任选”是指意味着随后所描述的事件或环境可以但不必发生，该说明包括该事件或环境发生或不发生的场合。例如“任选的被卤素或者氰基取代的C 1-6烷基”是指卤素或者氰基可以但不必须存在，该说明包括烷基被卤素或者氰基取代的情形和烷基不被卤素和氰基取代的情形。
本发明所述化合物的化学结构中，键
Figure PCTCN2021141211-appb-000058
表示未指定构型，即如果化学结构中存在手性异构体，键
Figure PCTCN2021141211-appb-000059
可以为
Figure PCTCN2021141211-appb-000060
或者同时包含
Figure PCTCN2021141211-appb-000061
Figure PCTCN2021141211-appb-000062
两种构型。虽然为简便起见将全部上述结构式画成某些异构体形式，但是本发明可以包括所有的异构体，如互变异构体、旋转异构体、几何异构体、非对映异构体、外消旋体和对映异构体。
术语解释：
“药物组合物”表示含有一种或多种本文所述化合物或其生理学上可药用的盐或前体药物与其他化学组分的混合物，以及其他组分例如生理学可药用的载体和赋形剂。药物组合物的目的是促进对生物体的给药，利于活性成分的吸收进而发挥生物活性。
“可药用赋形剂”包括但不限于任何已经被美国食品和药物管理局批准对于人类或家畜动物使用可接受的任何助剂、载体、赋形剂、助流剂、甜味剂、稀释剂、防腐剂、染料/着色剂、增香剂、表面活性剂、润湿剂、分散剂、助悬剂、稳定剂、等渗剂、溶剂或乳化剂。
“烷基”指饱和的脂族烃基团，包括1至20个碳原子的直链和支链基团。含有1至6个碳原子的烷基。非限制性实施例包括甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基、正戊基、1,1-二甲基丙基、1,2-二甲基丙基、2,2-二甲基丙基及其各种支链异构体等。如无特殊说明，烷基可以是取代的或未取代的，当被取代时，取代基可以在任何可使用的连接点上被取代，优选一个或多个以下基团，独立地选自卤素、氘、羟基、氧代、硝基、氰基、C 1-6烷基、C 1-6烷氧基、C 2-6烯氧基、C 2-6炔氧基、C 3-6环烷基、3至6元杂环烷基、C 5-8环烯基、C 3-6环烷氧基、3至6元杂环烷氧基、C 5-8环烯氧基、C 6-10芳基或5至6元杂芳基， 所述C 1-6烷基、C 1-6烷氧基、C 2-6烯氧基、C 2-6炔氧基、C 3-6环烷基、3至6元杂环烷基、C 5-8环烯基、C 3-6环烷氧基、3至6元杂环烷氧基、C 5-8环烯氧基、C 6-10芳基或5至6元杂芳基任选被一个或多个选自卤素、氘、羟基、氧代、硝基、氰基所取代。
“环烷基”或“环烃”指饱和或部分不饱和的单环或多环环状烃取代基，环烷基环包含3至20个碳原子，优选包含3至8个碳原子。单环环烷基的非限制性实例包括环丙基、环丁基、环戊基、环戊烯基、环己基、环己烯基、环己二烯基等；多环环烷基包括螺环、稠环和桥环的环烷基。
所述环烷基环可以稠合于芳基、杂芳基或杂环烷基环上，其中与母体结构连接在一起的环为环烷基，非限制性实例包括茚满基、四氢萘基、苯并环庚烷基等。如无特殊说明，环烷基可以是任选取代的或非取代的，当被取代时，取代基优选为一个或多个以下基团，其独立地选自氘、烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、氧代基、羧基或羧酸酯基。
“杂环基”或“杂环”指饱和或部分不饱和单环或多环环状烃基团，其包含3至20个环原子，其中一个或多个环原子为选自氮、氧或S(O) m(其中m是整数0至2)的杂原子，但不包括-O-O-、-O-S-或-S-S-的环部分，其余环原子为碳。优选包含3至12个环原子，其中1～4个是杂原子；更优选包含3至7个环原子。单环杂环烷基的非限制性实例包括吡咯烷基、咪唑烷基、四氢呋喃基、四氢噻吩基、二氢咪唑基、二氢呋喃基、二氢吡唑基、二氢吡咯基、哌啶基、哌嗪基、吗啉基、硫代吗啉基、高哌嗪基等。多环杂环烷基包括螺环、稠环和桥环的杂环烷基。“杂环烷基”非限制性实例包括：
Figure PCTCN2021141211-appb-000063
Figure PCTCN2021141211-appb-000064
等等。
杂环烷基可以是任选取代的或非取代的，当被取代时，取代基优选为一个或多个以下基团，其独立地选自如卤素、氘、羟基、氧代、硝基、氰基、C 1-6烷基、C 1-6烷氧基、C 2-6烯氧基、C 2-6炔氧基、C 3-6环烷基、3至6元杂环烷基、C 5-8环烯基、C 3-6环烷氧基、3至6元杂环烷氧基、C 5-8环烯氧基、C 6-10芳基或5至6元杂芳基，所述C 1-6烷基、C 1-6烷氧基、C 2-6烯氧基、C 2-6炔氧基、C 3-6环烷基、3至6元杂环烷基、C 5-8环烯基、C 3-6环烷氧基、3至6元杂环烷氧基、C 5-8环烯氧基、C 6-10芳基或5至6元杂芳基任选被一个或多个选自卤素、氘、羟基、氧代、硝基、氰基所取代。
所述杂环基环可以稠合于芳环、杂芳环或环烃上，其中与母体结构连接在一起的环为杂环基，其非限制性实例包括：
Figure PCTCN2021141211-appb-000065
等。
“芳基”或“芳环”指具有共轭的π电子体系的6至14元全碳单环或稠合多环(也就是共享毗邻碳原子对的环)基团，优选为6至12元，例如苯基和萘基。
芳基可以是取代的或非取代的，当被取代时，取代基优选为一个或多个以下基团，其独立地选自卤素、氘、羟基、氧代、硝基、氰基、C 1-6烷基、C 1-6烷氧基、C 2-6烯氧基、C 2-6炔氧基、C 3-6环烷基、3至6元杂环烷基、C 5-8环烯基、C 3-6环烷氧基、3至6元杂环烷氧基、C 5-8环烯氧基、C 6-10芳基或5至6元杂芳基，所述C 1-6烷基、C 1-6烷氧基、C 2-6烯氧基、C 2-6炔氧基、C 3-6环烷基、3至6元杂环烷基、C 5-8环烯基、C 3-6环烷氧基、3至6元杂环烷氧基、C 5-8环烯氧基、C 6-10芳基或5至6元杂芳基任选被一个或多个选自卤素、氘、羟基、氧代、硝基、氰基所取代。
所述芳基环可以稠合于杂芳环、杂环或环烃上，其中与母体结构连接在一起的环为芳基环，其非限制性实例包括：
Figure PCTCN2021141211-appb-000066
“杂芳基”或“杂芳环”指包含1至4个杂原子、5至14个环原子的杂芳族体系，其中杂原子选自氧、硫和氮。杂芳基优选为6至12元，更优选为5元或6元。例如。其非限制性实例包括：咪唑基、呋喃基、噻吩基、噻唑基、吡唑基、噁唑基、吡咯基、四唑基、吡啶基、嘧啶基、噻二唑、吡嗪，
Figure PCTCN2021141211-appb-000067
等等。
含有氮原子的杂芳基的示例包括但不限于吡咯基、哌嗪基、嘧啶基、咪唑基、哒嗪基、吡嗪基、四唑基、三唑基、吡啶基、吡唑基、噁唑基或噻唑基等。
杂芳基可以是任选取代的或非取代的，当被取代时，取代基优选为一个或多个以下基团，其独立地选自卤素、氘、羟基、氧代、硝基、氰基、C 1-6烷基、C 1-6烷氧基、C 2-6烯氧基、C 2-6炔氧基、C 3-6环烷基、3至6元杂环烷基、C 5-8环烯基、C 3-6环烷氧基、3至6元杂环烷氧基、C 5-8环烯氧基、C 6-10芳基或5至6元杂芳基，所述C 1-6烷基、C 1-6烷氧基、C 2-6烯氧基、C 2-6炔氧基、C 3-6环烷基、3至6元杂环烷基、C 5-8环烯基、C 3-6环烷氧基、3至6元杂环烷氧基、C 5-8环烯氧基、C 6-10芳基或5至6元杂芳基任选被一个或多个选自卤素、氘、羟基、氧代、硝基、氰基所取代。
所述杂芳基环可以稠合于芳环、杂环或环烃上，其中与母体结构连接在一起的环为杂芳基环，其非限制性实例包括：
Figure PCTCN2021141211-appb-000068
“卤素”指氟、氯、溴或碘。
“被一个或多个A、B……取代”是指可以被单个或多个取代基取代。当被多个取代基取代时，可以是复数个相同取代基，也可以是一个或复数个不同取代基的组合。
具体实施方式
以下结合实施例进一步描述本公开中，但这些实施例并非限制本公开中的范围。
本公开中实施例中未注明具体条件的实验方法，通常按照常规条件，或按照原料或商品制造厂商所建议的条件。未注明具体来源的试剂，为市场购买的常规试剂。
化合物的结构是通过核磁共振(NMR)或/和质谱(MS)来确定的。NMR位移(δ)以10 -6(ppm)的单位给出。NMR的测定是用Bruker AVANCE-400核磁仪，测定溶剂为氘代二甲基亚砜(DMSO-d 6)，氘代氯仿(CDCl 3)，氘代甲醇(CD 3OD)，内标为四甲基硅烷(TMS)。化合物的光学异构体(异构体)空间构型可进一步通过测量单晶参数的方式确认。
HPLC的测定使用Waters ACQUITY ultra high performance LC、Shimadzu LC-20A systems、Shimadzu LC-2010HT series或安捷伦Agilent 1200 LC高压液相 色谱仪(ACQUITY UPLC BEH C18 1.7UM 2.1X50MM色谱柱、Ultimate XB-C18 3.0*150mm色谱柱或Xtimate C18 2.1*30mm色谱柱)。
MS的测定用Waters SQD2质谱仪，以正/负离子模式扫描，质量扫描范围为100～1200。
手性HPLC分析测定使用Chiralpak IC-3 100×4.6mm I.D.，3um、Chiralpak AD-3 150×4.6mm I.D.，3um、Chiralpak AD-3 50×4.6mm I.D.，3um、Chiralpak AS-3 150×4.6mm I.D.，3um、Chiralpak AS-3 100×4.6mm I.D.，3μm、ChiralCel OD-3 150×4.6mm I.D.，3um、Chiralcel OD-3 100×4.6mm I.D.，3μm、ChiralCel OJ-H 150×4.6mm I.D.，5um、Chiralcel OJ-3 150×4.6mm I.D.，3um色谱柱；
薄层层析硅胶板使用烟台黄海HSGF254或青岛GF254硅胶板，薄层色谱法(TLC)使用的硅胶板采用的规格是0.15mm～0.2mm，薄层层析分离纯化产品采用的规格是0.4mm～0.5mm。
快速柱纯化系统使用Combiflash Rf150(TELEDYNE ISCO)或者Isolara one(Biotage)。
正向柱层析一般使用烟台黄海硅胶100～200目、200～300目或300～400目硅胶为载体，或者使用常州三泰预填预填超纯正相硅胶柱(40-63μm，60，12g,，25g，40g，80g或其他规格)。
反相柱层析一般使用常州三泰预填超纯C18硅胶柱(20-45μm，
Figure PCTCN2021141211-appb-000069
40g，80g，120g，220g或其他规格)。
高压柱纯化系统使用Waters AutoP，配合使用Waters XBridge BEH C18 OBD Prep Column，
Figure PCTCN2021141211-appb-000070
5μm，19mm X 150mm或者Atlantis T3 OBD Prep Column，
Figure PCTCN2021141211-appb-000071
5μm，19mm X 150mm。
手性制备柱使用DAICEL CHIRALPAK IC(250mm*30mm,10um)或Phenomenex-Amylose-1(250mm*30mm,5um)。
本公开中的已知的起始原料可以采用或按照本领域已知的方法来合成，或可购买自上海泰坦科技，ABCR GmbH&Co.KG，Acros Organics，Aldrich Chemical Company，韶远化学科技(Accela ChemBio Inc)、达瑞化学品等公司。
实施例中无特殊说明，反应能够均在氩气氛或氮气氛下进行。
氩气氛或氮气氛是指反应瓶连接一个约1L容积的氩气或氮气气球。
氢气氛是指反应瓶连接一个约1L容积的氢气气球。
加压氢化反应使用Parr 3916EKX型氢化仪和清蓝QL-500型氢气发生器或HC2-SS型氢化仪。
氢化反应通常抽真空，充入氢气，反复操作3次。
微波反应使用CEM Discover-S 908860型微波反应器。
实施例中无特殊说明，溶液是指水溶液。
实施例中无特殊说明，反应的温度为室温，为20℃～30℃。
实施例1
(R)-2-(4-((1-甲基哌啶-3-基)氨基)-5,6,7,8-四氢酞嗪-1-基)-5-(三氟甲基)苯酚
Figure PCTCN2021141211-appb-000072
步骤1：(R)-4-氯-N-(1-甲基哌啶-3-基)-5,6,7,8-四氢酞嗪-1-胺(化合物1c)的合成
Figure PCTCN2021141211-appb-000073
将化合物1a(100mg,0.492mmol)，化合物1b(56.23mg,0.492mmol)和二异丙基乙胺(0.24mL,1.48mmol)混合于NMP中，混合物在180℃下微波充分反应。冷却至室温后，加入1M的氢氧化钠淬灭反应，混合物用二氯甲烷萃取，分液，合并的有机相通过盐水洗，用无水硫酸钠干燥后过滤。滤液在真空中浓缩得到粗品，粗品通过快速柱层析(淋洗剂：0-10％甲醇的二氯甲烷)进行纯化，得到化合物1c(30mg，收率19.5％)。
LCMS:t R＝0.575min in 5-95AB_1min_220&254_Agilent.M ES-MS m/z 281.1[M+H] +.
步骤2：(R)-2-(4-((1-甲基哌啶-3-基)氨基)-5,6,7,8-四氢酞嗪-1-基)-5-(三氟甲基)苯酚(化合物1)的合成
Figure PCTCN2021141211-appb-000074
将化合物1c(15mg,0.053mmol)，化合物1d(17.60mg,0.085mmol)和1M的碳酸氢钠溶液(0.13mL)混合于二氧六烷(1mL)中，在氮气下加入四三苯基磷钯(12.35mg,0.011mmol)，混合物在氮气下160℃下微波充分反应。冷却至室温后，在真空中浓缩，得到粗品。用反相制备HPLC[柱:Boston Prime C18 150*30mm*5um,20-60％(A:水0.05％氨水v/v,B:乙腈)，流速:30mL/min]对粗品进行纯化后冻干，得到化合物1(5.1mg，收率23.7％)。
LCMS:tR＝3.140min in 0-95CD_7MIN.M(Waters Xbridge C18 30*2.0mm,3.5um)ES-MS m/z 407.2[M+H]+.
1H NMR：(400MHz,DMSO-d6)δ＝7.41-7.15(m,3H),3.89(br d,J＝15.3Hz,1H),3.97-3.80(m,1H),3.51-3.37(m,7H),2.56-2.51(m,3H),2.47-2.25(m,3H), 2.15-1.51(m,3H),1.30-1.11(m,2H)
实施例2
(R)-2-(4-((1-甲基哌啶-3-基)氨基)-6,7-二氢-5H-环戊烷[d]哒嗪-1-基)-5-(三氟甲基)苯酚
Figure PCTCN2021141211-appb-000075
以2a为起始原料，参照实施例1中描述的方法制备化合物2。
LCMS:t R＝3.75min in 0-95CD_7MIN.M(Waters Xbridge C18 30*2.0mm,3.5um)ES-MS m/z 393.2[M+H]+。
1H NMR:(400MHz,DMSO-d 6)δppm 13.52(br s,1H),7.75(br d,J＝8.4Hz,1H),7.22(br s,2H),6.35(br d,J＝7.6Hz,1H),4.29-4.19(m,1H),3.11(br t,J＝7.2Hz,2H),2.94(br d,J＝8.8Hz,1H),2.78(br t,J＝7.2Hz,2H),2.69-2.60(m,1H),2.18(s,3H),2.12-2.01(m,2H),1.96-1.81(m,3H),1.75-1.66(m,1H),1.62-1.49(m,1H),1.44-1.30(m,1H).
实施例3
(R)-2-(4-((1-甲基哌啶-3-基)氨基)邻苯二甲嗪-1-基)-5-(三氟甲基)苯酚
Figure PCTCN2021141211-appb-000076
以3a为起始原料，参照实施例1中描述的方法制备化合物3。
LCMS:t R＝1.027min in 10-80AB_4min_220&254_Shimadzu.lcm(Chromolith Flash RP-C18 25-3mm),MS(ESI)m/z＝403.2[M+H]+.
1H NMR:(400MHz,CDCl 3)δppm 8.88(br s,1H),8.15(d,J＝8.4Hz,1H),7.96(t,J＝7.6Hz,1H),7.84(t,J＝7.6Hz,1H),7.69(d,J＝8.0Hz,1H),7.39(s,1H),7.24(d,J＝8.4Hz,1H),5.12(br,1H),3.87-3.67(m,1H),3.66-3.53(m,1H),3.14-3.03(m, 1H),2.94-2.80(m,4H),2.77(br,1H),2.57-2.43(m,1H),2.36(br,1H),1.89(br,1H),1.81-1.70(m,1H).
实施例4
(R)-5-(4-甲基-6-((1-甲基哌啶-3-基)氨基)哒嗪-3-基)-2,3-二氢-1H-茚-4-醇
Figure PCTCN2021141211-appb-000077
步骤1：(化合物4c)的合成
Figure PCTCN2021141211-appb-000078
将化合物4a(250mg,1.173mmol)，化合物4b(1.520mL,5.867mmol)和醋酸钾(345.45mg,3.520mmol)混合于二氧六烷(6mL)中，在氮气下加入Pd(dppf)Cl 2·CH 2Cl 2(96.76mg,0.117mmol)，混合物在氮气下90℃下搅拌充分反应。冷却至室温后，加入水(15mL)稀释，混合物用乙酸乙酯(20mL x 2)萃取，分液，合并的有机相通过盐水(30mL x 3)洗，用无水硫酸钠干燥后过滤。滤液在真空中浓缩得到粗品，粗品通过快速柱层析(淋洗剂：0-20％乙酸乙酯的正己烷)进行纯化，得到化合物4c(170mg，收率55.7％)。
1H NMR(400MHz,CDCl 3)δppm 7.92(s,1H),7.44(d,J＝7.6Hz,1H),6.82(d,J＝7.2Hz,1H),2.93-2.88(m,4H),2.11-2.06(m,2H),1.36(s,12H).
步骤2：(化合物4f)的合成
Figure PCTCN2021141211-appb-000079
将化合物4d(200mg,1.227mmol)，化合物4e(168.12mg,1.472mmol)和二异丙基乙胺混合于NMP(2mL)中，混合物在120℃下微波充分反应。冷却至室温后，加入水(10mL)稀释，混合物用二氯甲烷(10mL x 3)萃取，分液，合并的有机相通过盐水(5mL x 3)洗，用无水硫酸钠干燥后过滤。滤液在真空中浓缩得到粗品，通过快速柱层析(淋洗剂：0-10％甲醇的二氯甲烷)进行纯化，得到化合物4f(80mg，收率27.1％)。
步骤3：(化合物4)的合成
Figure PCTCN2021141211-appb-000080
以化合物4c和化合物4f为起始原料，参照实施例1中步骤2中描述的方法制备化合物4。
LCMS:t R＝2.8min in 10-80CD_7min_220&254_Shimadzu.lcm ES-MS m/z 339.2(M+H) +.
1H NMR(400MHz,DMSO-d6)δppm 9.71(s,1H),7.02(d,J＝8.0Hz,1H),6.78(d,J＝7.6Hz,1H),6.72(s,1H),6.61(d,J＝8.0Hz,1H),4.04(s,1H),2.90-2.84(m,4H),2.18(s,3H),2.08(s,3H),2.04-2.02(m,3H),1.89-1.77(m,2H),1.45-1.64(m,2H),1.23-1.33(m,2H).
实施例5
(R)-3-(4-甲基-6-((1-甲基哌啶-3-基)氨基)哒嗪-3-基)萘-2-醇
Figure PCTCN2021141211-appb-000081
以化合物5a为原料，参照实施例4中描述的方法制备化合物5。
1H NMR(400MHz,DMSO-d6)δppm 8.22(s,1H),7.82(d,J＝8.0Hz,1H),7.72(d,J＝8Hz,2H),7.42(t,J＝7.4Hz,1H),7.29(t,J＝7.4Hz,1H),7.24(s,1H),6.71(s,1H),6.65(d,J＝8.0Hz,1H),4.06(s,1H),2.94(br,1H),2.60-2.55(m,1H),2.47-2.41(m,1H),2.33(s,1H),2.09(s,1H),1.87-1.84(m,1H),1.72-1.75(m,1H),1.60-1.56(m,1H),1.37-1.42(m,1H).
实施例6
(R)-6-(4-甲基-6-((1-甲基哌啶-3-基)氨基)哒嗪-3-基)-2,3-二氢-1H-茚-5-醇
Figure PCTCN2021141211-appb-000082
Figure PCTCN2021141211-appb-000083
以化合物6a为起始原料，参照实施例4中描述的方法制备化合物6。
LCMS:t R＝2.9min in 10-80CD_7min_220&254_Shimadzu.lcm ES-MS m/z 339.2(M+H) +.
1H NMR(400MHz,DMSO-d6)δppm 9.47(s,1H),6.97(s,1H),6.76(s,1H),6.65(s,1H),6.50(d,J＝8.0Hz,1H),4.08-3.95(m,1H),2.80(br,5H),2.17(s,3H),2.07-1.97(m,6H),1.85(br,3H),1.70(br,1H),1.53(br,1H),1.27(br,1H)
实施例7
4-(4-甲基-6-((R)-1-甲基哌啶-3-基)氨基)哒嗪-3-基)-2,3-二氢-1H-茚-5-醇
Figure PCTCN2021141211-appb-000084
步骤1：(化合物7b)的合成
Figure PCTCN2021141211-appb-000085
将化合物7a(100mg,0.415mmol)和锌粉(271mg,4.15mmol)混合于醋酸(2mL)中，混合物在100℃下搅拌充分反应。冷却至室温后，加入水(20mL)稀释，混合物用乙酸乙酯(20mLx3)萃取，分液，合并的有机相通过盐水(20mL)洗，用无水硫酸钠干燥后过滤。滤液在真空中浓缩得到粗品，通过快速柱层析(淋洗剂：10-20％乙酸乙酯的石油醚)进行纯化，得到化合物7b(40mg，收率34.0％)。
1H NMR:(400MHz,CDCl 3)δppm 7.09(d,J＝8.0Hz,1H),6.70(d,J＝8.4Hz,1H),3.88(s,3H),2.96(q,J＝7.2Hz,4H),2.15-2.06(m,2H).步骤2：(化合物7d)的合成
Figure PCTCN2021141211-appb-000086
以化合物7b为起始原料，参照实施例4中描述的方法制备化合物7d。
LCMS:t R＝2.973min in 0-30AB_7min_220&254_Shimadzu.lcm ES-MS m/z＝353.2[M+H] +.
1H NMR: 1H NMR(400MHz,CDCl 3)δppm 7.23-7.18(m,1H),6.87-6.74(m,2H),3.75(s,1H),3.71-3.71(m,1H),3.71(s,2H),2.93-2.86(m,4H),2.60-2.46(m,4H),2.42-2.32(m,3H),2.07-2.01(m,3H),1.99(s,3H),1.90-1.72(m,2H),1.26(br t,J＝7.2Hz,1H).
步骤3：(化合物7)的合成
Figure PCTCN2021141211-appb-000087
将化合物7d(30mg,0.085mmol)的二氯甲烷(2mL)溶液冷却至-78℃，滴加三溴化硼(213mg,0.85mmol)，混合物升至室温搅拌搅拌充分反应。加入甲醇(2mL)淬灭反应，在真空下除去溶剂得到粗品，通过反相制备HPLC(Column Boston Prime C18 150*30mm*5um；Condition water(0.05％ammonia hydroxide v/v)-ACN；Begin B 40；End B 70；FlowRate(ml/min))纯化获得化合物7(5.8mg，收率20.1％)。
LCMS:t R＝4.403min in 0-60CD_7min_220&254_Shimadzu.lcm,MS(ESI)m/z＝339.3[M+H] +.
1H NMR:(400MHz,CD 3OD)δppm 7.08(d,J＝8.0Hz,1H),6.76(s,1H),6.68(d,J＝8.0Hz,1H),4.12(dt,J＝4.6,9.2Hz,1H),3.17-3.02(m,1H),2.92-2.83(m,2H),2.79(br dd,J＝8.0,16.4Hz,2H),2.33(d,J＝2.1Hz,4H),2.20(br d,J＝6.4Hz,2H),2.04(d,J＝0.8Hz,6H),1.90-1.78(m,1H),1.78-1.64(m,1H),1.45-1.41(m,1H).
实施例8
(R)-6-(2-(二氟甲基)-4-(三氟甲基)苯基)-5-甲基-N-(1-甲基哌啶-3-基)哒嗪-3-胺
Figure PCTCN2021141211-appb-000088
步骤1：(化合物8b)的合成
Figure PCTCN2021141211-appb-000089
将化合物8a(3.0g,11.86mmol)溶于二氯甲烷(30mL)，加入DAST(3.82g, 23.7mmol)，混合物在室温搅拌充分反应。反应加入水(50mL)淬灭，加入二氯甲烷(50mL)稀释，分液，有机相饱和碳酸氢钠溶液(30mL)洗，分离的有机相通过无水硫酸钠干燥后过滤。滤液在真空中浓缩得到得到化合物8b(3.10g，收率95.1％)。
1H NMR(400MHz,CDCl 3)Shift＝7.92(s,1H),7.77(d,J＝8.3Hz,1H),7.59(d,J＝8.3Hz,1H),6.92(t,J＝54.4Hz,1H)
步骤2：(化合物8)的合成
Figure PCTCN2021141211-appb-000090
以化合物8b为原料，参照实施例4中描述的方法制备化合物8。
LCMS:t R＝2.25min in 5-95AB_7min_220&254_Agilent.M ES-MS m/z 362.2[M+H] +.
1H NMR(400MHz,CDCl 3)Shift＝8.61(s,1H),8.05(s,1H),7.79(d,J＝7.9Hz,1H),7.43(d,J＝8.1Hz,1H),7.68(t,J＝55.4Hz,1H),6.72(s,1H),4.46(br s,2H),3.03-2.73(m,2H),2.48(s,4H),2.24-1.87(m,5H),1.82-1.66(m,2H)
实施例9
(R)-3-(4-甲基-6-((1-甲基哌啶-3-基)氨基)哒嗪-3-基)萘-2-醇
Figure PCTCN2021141211-appb-000091
以化合物9a为起始原料，参照实施例4中描述的方法制备化合物9。
LCMS:t R＝2.76min in 10-80CD_7min_220&254_Shimadzu.lcm ES-MS m/z349.2[M+H] +.
实施例10
(R)-1-(6-((1-甲基哌啶-3-基)氨基)哒嗪-3-基)萘-2-醇
Figure PCTCN2021141211-appb-000092
步骤1(化合物10b)的合成
Figure PCTCN2021141211-appb-000093
以化合物10a为起始原料，参照实施例4步骤2中描述的方法制备化合物10b。
1H NMR:(400MHz,CDCl 3)δppm 7.35(d,J＝9.2Hz,1H),6.93(d,J＝9.2Hz,1H),4.00-3.94(m,1H),2.79-2.75(m,1H),2.49-2.47(m,1H),2.16(s,3H),2.06-2.03(m,1H),1.93-1.90(m,1H),1.77-1.75(m,1H),1.69-1.67(m,1H),1.54-1.49(m,1H),1.28-1.21(m,1H).
步骤2(化合物10)的合成
Figure PCTCN2021141211-appb-000094
以化合物10c为起始原料，参照实施例7中描述的方法制备化合物10。
LCMS:ES-LCMS m/z 335.2[M+H] +.
1H NMR:(400MHz,CDCl 3)δppm 7.90(d,J＝8.4Hz,1H),7.85-7.74(m,3H),7.43(t,J＝7.2Hz,1H),7.37-7.33(m,1H),7.30(d,J＝9.2Hz,1H),6.89(br d,J＝9.2Hz,1H),4.34(br s,1H),2.83-2.51(m,3H),2.36(br s,3H),1.89(br s,5H),1.26(br s,1H).
实施例11
rac-(R)-2-(4-甲基-6-((1-甲基哌啶-3-基)氨基)哒嗪-3-基)-5-((三氟甲基)硫代)苯酚
Figure PCTCN2021141211-appb-000095
步骤1(化合物11b)的合成
Figure PCTCN2021141211-appb-000096
将化合物11a(2g,10.0mmol)混合于50％的硫酸(40mL)中，混合物冷却至-5℃，滴加亚硝酸钠(759mg,11mmol)溶液(20mL)，保持温度，然后加入硫氰酸亚铜(,20mmol)和硫氰酸钾(20mmol)，最终的混合物在0℃下搅拌充分反应。过滤，收集滤饼溶于乙酸乙酯(50mL)，用盐水(30mL)洗，用无水硫酸钠干燥后过滤。滤液在真空中浓缩得到粗品，通过快速柱层析(淋洗剂：2-10％乙酸乙酯的石油醚)进行纯化，得到化合物11b(0.5g，收率20.7％)。
1H NMR:(400MHz,CDCl 3)δppm 7.59(d,J＝8.0Hz,1H),7.04-6.98(m,2H),3.95(s,3H).
步骤2(化合物11c)的合成
Figure PCTCN2021141211-appb-000097
将三氟乙酸钾(374mg,2.46mmol)，氯化亚铁(78mg,0.61mmol)和化合物11b(500mg,2.05mmol)混合于DMF(5mL)中，混合物在氮气氛围下140℃下搅拌充分反应。加入水(20mL)稀释，混合物用乙酸乙酯(20mLx3)萃取，分液，合并的有机相通过盐水(20mLx3)洗，用无水硫酸钠干燥后过滤。滤液在真空中浓缩得到粗品，通过快速柱层析(淋洗剂：0-3％乙酸乙酯的石油醚)进行纯化，得到化合物11c(40mg，收率34.0％)。
1H NMR:(400MHz,DMSO-d 6)δppm 7.76(d,J＝8.4Hz,1H),7.39(d,J＝1.6Hz,1H),7.24(dd,J＝1.6,8.0Hz,1H),3.91(s,3H).
步骤3(化合物11)的合成
Figure PCTCN2021141211-appb-000098
以化合物11c为起始原料，参照实施例7中描述的方法制备化合物11。
LCMS:t R＝1.161min in 10-80AB_7min_220&254_Shimadzu.lcm；MS(ESI) m/z＝399.2[M+H] +.
1H NMR:(400MHz,CDCl 3)δppm 8.58(s,1H),7.48(d,J＝8.0Hz,1H),7.42-7.37(m,J＝1.5Hz,1H),7.17(d,J＝8.4Hz,1H),6.85(s,1H),4.56(br s,1H),3.09(br s,2H),2.79(br s,2H),2.55(br s,3H),2.46(s,4H),1.82-1.63(m,J＝14.9Hz,2H),1.26(s,1H).
实施例12
(R)-3-羟基-4-(4-甲基-6-((1-甲基哌啶-3-基)氨基)哒嗪-3-基)苯甲酸
Figure PCTCN2021141211-appb-000099
以化合物12a为起始原料，参照实施例7中描述的方法制备化合物12。
LCMS:ES-LCMS m/z 343.1[M+H] +.
1H NMR:(400MHz,DMSO-d 6)δppm 13.97(br s,1H),8.08(s,1H),7.87(d,J＝8.4Hz,1H),7.44-7.36(m,2H),6.21(br d,J＝7.6Hz,1H),4.24(br d,J＝8.4Hz,1H),2.92(br d,J＝7.6Hz,2H),2.61(br s,2H),2.23(s,3H),2.19(s,3H),1.97-1.90(m,2H),1.86(br s,1H),1.73-1.67(m,1H),1.62-1.53(m,1H),1.48-1.39(m,1H).
实施例13
(R)-4-(4-甲基-6-((1-甲基哌啶-3-基)氨基)哒嗪-3-基)吡啶-3-醇
Figure PCTCN2021141211-appb-000100
Figure PCTCN2021141211-appb-000101
以化合物13a为起始原料，参照实施例7中描述的方法制备化合物13。
1H NMR:(400MHz,CDCl 3)δ＝8.48(s,1H),8.16(d,J＝5.2Hz,1H),7.35(d,J＝5.2Hz,1H),6.67(s,1H),5.57(br s,1H),4.20(br s,1H),2.55(br s,2H),2.49(s,3H),2.30(s,3H),2.24-2.18(m,1H),1.91-1.52(m,6H).
实施例14
5-(6-((1s，3s)-3-羟基-3-甲基环丁基)氨基)-4-甲基哒嗪-3-基)-2,3-二氢-1H-茚-4-醇
Figure PCTCN2021141211-appb-000102
步骤1(化合物14b)的合成
以化合物14a为起始原料，参照实施例4步骤2中描述的方法制备化合物14b。
LCMS:t R＝0.4min in 5-95AB_1min_220&254_Agilent.M ES-MS m/z 228.1[M+H] +.
1H NMR:(400MHz,CDCl 3)δppm 7.03(s,1H),4.42(br s,1H),4.28(br s,1H),3.87(br s,1H),2.73(br s,2H),2.44(s,3H),2.20-2.16(m,2H),1.46(s,3H).
步骤2(化合物14)的合成
以化合物14b为起始原料，参照实施例1步骤2中描述的方法制备化合物14。
LCMS:t R＝2.761min in 0-95CD_7MIN.M(Waters Xbridge C18 30*2.0mm,3.5um)ES-MS m/z 326.2[M+H] +.
1H NMR:(400MHz,DMSO-d 6)δppm 9.70(br s,1H),7.01(d,J＝7.6Hz,1H),6.95(d,J＝6.8Hz,1H),6.77(d,J＝7.6Hz,1H),6.64(s,1H),4.99(s,1H),3.97-3.85 (m,1H),2.89-2.82(m,4H),2.45-2.37(m,2H),2.09(s,3H),2.07-1.99(m,2H),1.98-1.90(m,2H),1.28(s,3H).
实施例15
2-(4-((1s，3s)-3-羟基-3-甲基环丁基)氨基)邻苯二甲嗪-1-基)-5-(三氟甲基)苯酚
Figure PCTCN2021141211-appb-000103
以3a为起始原料，参照实施例14中描述的方法制备化合物15。
LCMS:t R＝2.415min in 0-95CD_7MIN.M(Waters Xbridge C18 30*2.0mm,3.5um)ES-MS m/z 390.1[M+H] +.
1H NMR:(400MHz,DMSO-d 6)δppm 10.34(br s,1H),8.42(d,J＝8.4Hz,1H),7.89-7.82(m,1H),7.77(t,J＝7.2Hz,1H),7.62(br d,J＝5.6Hz,1H),7.50(d,J＝7.8Hz,1H),7.43(d,J＝8.0Hz,1H),7.32-7.24(m,2H),5.00(s,1H),4.31-4.14(m,1H),2.46(br d,J＝2.8Hz,2H),2.22-2.13(m,2H),1.33(s,3H).
实施例16
2-(4-((1s，3s)-3-羟基-3-甲基环丁基)氨基)-5,7-二氢糠醛[3,4-d]哒嗪-1-基)-5-(三氟甲基)苯酚
Figure PCTCN2021141211-appb-000104
步骤1(化合物16b)的合成
Figure PCTCN2021141211-appb-000105
将化合物16a(1g,11.6mmol)和碳酸钾(0.16g,1.16mmol)混合于四氢吡咯(0.95mL,11.6mmol)中，混合物在0℃下搅拌充分反应，过滤，滤液在真空中浓缩得到化合物16b(1.5g，收率92.8％)。
LCMS:ES-LCMS m/z 140.1[M+H] +.
步骤2(化合物16c)的合成
Figure PCTCN2021141211-appb-000106
将化合物16b(300mg,2.16mmol)和3,6-二氯四嗪(325g,2.16mmol)混合于二氯甲烷(5mL)中，混合物在0℃下搅拌充分反应，加入水(5mL)稀释，混合物用二氯甲烷(5mLx3)萃取，分液，合并的有机相通过盐水(5mL)洗，用无水硫酸钠干燥后过滤。滤液在真空中浓缩得到粗品，通过快速柱层析(淋洗剂：0-20％乙酸乙酯的石油醚)进行纯化，得到化合物16c(70mg，收率15.3％)。
LCMS:t R＝0.568min in 5-95AB_1min_220&254_Agilent.M ES-MS m/z 191.0(M+H)+
1H NMR:(400MHz,CDCl 3)δppm 5.24(s,4H)
步骤3(化合物16)的合成
Figure PCTCN2021141211-appb-000107
以16c为起始原料，参照实施例1中描述的方法制备化合物16。
1H NMR(400MHz,DMSO-d 6)δ＝8.14(s,1H),7.47(br d,J＝8.0Hz,1H),7.26-7.22(m,2H),6.88(br d,J＝7.0Hz,1H),5.26(br s,2H),4.97(br s,2H),4.30(br s,1H),2.33(br s,3H),2.15-1.88(m,4H),1.77(br s,1H),1.61(br d,J＝12.0Hz,1H),1.38(br d,J＝12.3Hz,1H),1.23(br s,2H).
实施例17
4-(4-甲基-6-((R)-1-甲基哌啶-3-基)氨基)哒嗪-3-基)-2,3-二氢-1H-茚-5-醇
Figure PCTCN2021141211-appb-000108
以7c为起始原料，参照实施例7中描述的方法制备化合物17。
LCMS:ES-LCMS m/z 339.2[M+H] +.
实施例18
(R)-5-环丙基-2-(4-甲基-6-((1-甲基哌啶-3-基)氨基)哒嗪-3-基)苯酚
Figure PCTCN2021141211-appb-000109
步骤1(化合物18b)的合成
Figure PCTCN2021141211-appb-000110
将化合物18a(500mg,1.6mmol)，环丙基硼酸(505mg,5.87mmol)和碳酸钾(883mg,6.39mmol)混合于二氧六烷(10mL)和水(5mL)中，在氮气下加入Pd(dppf)Cl 2·CH 2Cl 2(65.9mg,0.080mmol)，混合物在氮气下120℃下搅拌充分反应。冷却至室温后，加入乙酸乙酯(20mL)稀释，有机相通过盐水(30mL)洗，用无水硫酸钠干燥后过滤。滤液在真空中浓缩得到化合物18b粗品。直接用于下一步。
步骤2(化合物18)的合成
Figure PCTCN2021141211-appb-000111
以18b为起始原料，参照实施例7中描述的方法制备化合物18。
LCMS:ES-LCMS m/z 339.3[M+H] +.
1H NMR(400MHz,CDCl 3)δ＝7.20(d,J＝8.0Hz,1H),6.73(d,J＝8.0Hz,1H),6.69(s,1H),6.63(br s,1H),4.32(br s,1H),2.95-2.45(m,4H),2.41(s,3H),2.36-2.19(m,1H),2.05(s,3H),1.98-1.92(m,1H),1.88-1.54(m,4H),1.05-0.95(m,2H),0.81-0.71(m,2H).
实施例19
rac-(R)-2-(4-(1-(2-羟乙基)哌啶-3-基)氨基)-5,6,7,8-四氢邻苯二甲嗪-1-基)-5-(三氟甲基)苯酚
Figure PCTCN2021141211-appb-000112
步骤1(化合物19c)的合成
Figure PCTCN2021141211-appb-000113
以19a为起始原料，参照实施例1中描述的方法制备化合物19c。
LCMS:ES-LCMS m/z 493.3[M+H] +.
步骤2(化合物19d)的合成
Figure PCTCN2021141211-appb-000114
将化合物19c(180mg,0.365mmol)溶于盐酸二氧六烷溶液(2mL)中，混合物在室温下搅拌充分反应。在真空中浓缩得到化合物19d的盐酸盐(220mg，收率92.0％)。
LCMS:ES-LCMS m/z 393.3[M+H] +.
步骤3(化合物19)的合成
Figure PCTCN2021141211-appb-000115
将化合物19d(20mg,0.05mmol)和二异丙基乙胺(0.017mL,0.10mmol)溶于乙腈(2mL)中，加入溴乙醇(6.37mg,0.05mmol)，混合物在70℃下搅拌充分反应，在真空中浓缩得到粗品，通过反相制备HPLC纯化获得化合物19(2.9mg，收率12.9％)。
LCMS:ES-LCMS m/z 437.2[M+H] +.
1H NMR(400MHz,CD 3OD)δ＝7.37(d,J＝7.8Hz,1H),7.24(d,J＝8.0Hz,1H),7.18(s,1H),4.71-4.60(m,2H),3.80-3.55(m,4H),3.06(br d,J＝7.3Hz,2H),2.55-2.44(m,4H),2.21-2.07(m,2H),2.03-1.84(m,4H),1.83-1.70(m,3H).
实施例20
rac-3-氟-2-(4-((R)-1-甲基哌啶-3-基)氨基)-6,7-二氢-5H-环戊烷[d]哒嗪-1-基)苯酚
Figure PCTCN2021141211-appb-000116
以2b为起始原料，参照实施例2中描述的方法制备化合物20。
LCMS:t R＝0.719min in 5-95AB_1min_220&254_Agilent.M ES-MS m/z 343.1[M+H] +.
1H NMR(400MHz,CD 3OD)Shift＝7.26(dt,J＝6.8,8.3Hz,1H),6.78-6.66(m,2H),4.48-4.38(m,1H),3.09(br s,1H),2.88(t,J＝7.5Hz,2H),2.80(t,J＝7.7Hz,2H),2.70(br s,1H),2.36(s,3H),2.31(br d,J＝13.1Hz,2H),2.15(quin,J＝7.7Hz,2H),2.00(br s,1H),1.92-1.81(m,1H),1.79-1.68(m,1H),1.57(br s,1H)
实施例21
5-(6-((1s，3s)-3-羟基-3-甲基环丁基)氨基)-4,5-二甲基哒嗪-3-基)-2,3-二氢-1H-茚-4-醇
Figure PCTCN2021141211-appb-000117
以21a为起始原料，参照实施例14中描述的方法制备化合物21。
LCMS:t R＝0.774min in 5-95AB_1min_220&254_Agilent.M ES-MS m/z 340.2[M+H] +.
1H NMR(400MHz,CDCl 3)Shift＝7.05(d,J＝7.8Hz,1H),6.81(d,J＝7.8Hz,1H),4.62(br s,1H),4.41-4.24(m,1H),2.97(td,J＝7.4,19.0Hz,4H),2.75(ddd,J＝2.8,7.4,9.9Hz,2H),2.35(s,3H),2.18-2.06(m,8H),1.47(s,3H)
实施例22
2-(5-((1s，3s)-3-羟基-3-甲基环丁基)氨基)吡啶[2,3-d]哒嗪-8-基)-5-(三氟甲基)苯酚(化合物22)
Figure PCTCN2021141211-appb-000118
2-(8-((1s，3s)-3-羟基-3-甲基环丁基)氨基)吡啶基[2,3-d]哒嗪-5-基)-5-(三氟甲基)苯酚(化合物23)
Figure PCTCN2021141211-appb-000119
Figure PCTCN2021141211-appb-000120
以22a为起始原料，参照实施例15中描述的方法制备化合物22、23。
化合物22
1H NMR:(400MHz,CD 3OD)δppm 9.08(m,1H),8.00(d,J＝8.0Hz,1H),7.80(dd,J＝8.0,4.4Hz,1H),7.58(d,J＝8.0Hz,1H),7.31(d,J＝8.0Hz,1H),7.26(s,1H),4.39-4.31(m,1H),2.72-2.67(m,2H),2.27-2.21(m,2H),1.45(s,3H).
化合物23
1H NMR:(400MHz,CD 3OD)δppm 9.15(br s,1H),8.80(dd,J＝8.4,2.4Hz,1H),8.49(d,J＝8.0Hz,1H),7.89(d,J＝8.4Hz,1H),7.22(d,J＝6.8Hz,1H),4.34-4.26(m,1H),2.71-2.66(m,2H),2.27-2.22(m,2H),1.46(s,3H).
实施例23
2-(4-((1s，3s)-3-羟基-3-甲基环丁基)氨基)吡啶[3,4-d]哒嗪-1-基)-5-(三氟甲基)苯酚(化合物24)
Figure PCTCN2021141211-appb-000121
2-(1-((1s，3s)-3-羟基-3-甲基环丁基)氨基)吡啶[3,4-d]哒嗪-4-基)-5-(三氟甲基)苯酚
Figure PCTCN2021141211-appb-000122
Figure PCTCN2021141211-appb-000123
以化合物24a为原料，参照实施例15中描述的方法制备化合物24、25。
化合物24
1H NMR:(400MHz,CD 3OD)δppm 9.70(br s,1H),8.84(d,J＝6.0Hz,1H),7.58(d,J＝7.6Hz,1H),7.47(d,J＝5.6Hz,1H),7.32(d,J＝8.0Hz,1H),7.26(s,1H),4.39-4.31(m,1H),2.72-2.67(m,2H),2.29-2.24(m,2H),1.46(s,3H).
化合物25
1H NMR:(400MHz,CD 3OD)δppm 8.91(m,2H),8.21(d,J＝5.6Hz,1H),7.62(d,J＝8.0Hz,1H),7.34(d,J＝8.0Hz,1H),7.28(s,1H),4.35-4.27(m,1H),2.71-2.66(m,2H),2.28-2.23(m,2H),1.45(s,3H).
实施例24
2-(4-((1s，3s)-3-羟基-3-甲基环丁基)氨基)-5,7-二氢糠醛[3,4-d]哒嗪-1-基)-5-(三氟甲基)苯酚
Figure PCTCN2021141211-appb-000124
以化合物16c为原料，参照实施例16中描述的方法制备化合物26。
1H NMR(400MHz,CD 3OD)Shift＝7.42(d,J＝8.4Hz,1H),7.21-7.20(m,2H),5.39(t,J＝3.2Hz,2H),5.05(t,J＝3.2Hz,2H),4.19(m,1H),2.61(m,2H),2.14(m,2H),1.43(s,3H).
实施例25
(R)-2-(4-甲基-6-((1-甲基哌啶-3-基)氨基)哒嗪-3-基)-5,6,7,8-四氢萘-1-醇
Figure PCTCN2021141211-appb-000125
步骤1：(化合物27b)的合成
Figure PCTCN2021141211-appb-000126
将化合物27a(1.0g,6.17mmol)溶于DMF(6mL)，加入NBS(0.99g,5.55mmol)，混合物在室温搅拌充分反应。反应加入二氯甲烷(10mL)和饱和氯化钠溶液(10mL)稀释，分液，有机相用水洗，分离的有机相通过无水硫酸钠干燥后过滤。滤液在真空中浓缩得到粗品，通过反相快速柱层析(淋洗剂：0-60％乙腈的水)进行纯化，得到化合物27b(680mg，收率45.7％)。
步骤2：(化合物27c)的合成
Figure PCTCN2021141211-appb-000127
将化合物27b(300mg,1.24mmol)溶于三氟乙酸()和三乙基硅烷()的混合溶剂中，混合物在90℃下搅拌充分反应。混合物直接旋干溶剂，加入二氯甲烷(10mL)和饱和碳酸氢钠溶液(10mL)稀释，分液，有机相用饱和氯化钠溶液洗，分离的有机相通过无水硫酸钠干燥后过滤。滤液在真空中浓缩得到粗品，通过快速柱层析(淋洗剂：10％二氯甲烷的石油醚)进行纯化，得到化合物27c(200mg，收率70.8％)。
步骤3：(化合物27)的合成
Figure PCTCN2021141211-appb-000128
以化合物27c为原料，参照实施例4中描述的方法制备化合物27。
1H NMR(400MHz,CD 3OD)Shift＝7.00(d,J＝8.0Hz,1H),6.81(s,1H),6.69(d,J＝8.0Hz,1H),4.18(m,1H),2.96(m,1H),2.77(t,J＝5.6Hz,2H),2.69(t,J＝5.8Hz,2H),2.56(m,5H),2.20(m,4H),2.03(m,1H),1.98(m,1H),1.85-1.79(m,5H),1.61(m,2H).
实施例26
5-环丙基-2-(6-((1s，3s)-3-羟基-3-甲基环丁基)氨基)-4-甲基哒嗪-3-基)苯酚
Figure PCTCN2021141211-appb-000129
以化合物18c为原料，参照实施例18中描述的方法制备化合物28。
LCMS:t R＝2.657min in 5-95AB_7min_220&254_Agilent.M ES-MS m/z 326.1[M+H] +.
1H NMR(400MHz,CD 3OD)Shift＝7.10(d,J＝7.6Hz,1H),6.74(s,1H),6.69(d,J＝7.6Hz,1H),6.63(s,1H),4.05-3.98(m,1H),2.62-2.57(m,2H),2.16(s,3H),2.08-2.03(m,2H),1.91-1.87(m,1H),1.41(s,3H),1.01-0.98(m,2H),0.72-0.69(m,2H).
实施例27
Figure PCTCN2021141211-appb-000130
5-环丙基-2-(6-((1s，3s)-3-羟基-3-甲基环丁基)氨基)-4,5-二甲基哒嗪-3-基)苯酚
Figure PCTCN2021141211-appb-000131
以化合物18c为原料，参照实施例18中描述的方法制备化合物29。
LCMS:t R＝0.57min in 5-95AB_1.5min_220&254_Agilent.M ES-MS m/z 340.2[M+H] +.
1H NMR(400MHz,CD 3OD)Shift＝7.07(d,J＝7.6Hz,1H),6.68(d,J＝7.6Hz,1H),6.63(s,1H),4.19-4.09(m,1H),2.64-2.59(m,2H),2.18(s,3H),2.15-2.08(m,5H),1.90(m,1H),1.42(s,3H),1.01-0.98(m,2H),0.72-0.70(m,2H).
实施例28
5-环丙基-2-(4-((1s，3s)-3-羟基-3-甲基环丁基)氨基)邻苯二甲嗪-1-基)苯酚
Figure PCTCN2021141211-appb-000132
以化合物18c为原料，参照实施例18中描述的方法制备化合物30。
LCMS:t R＝3.11min in 5-95AB_7min_220&254_Agilent.M ES-MS m/z 362.2[M+H] +.
1H NMR(400MHz,CD 3OD)Shift＝8.27(d,J＝8.0Hz,1H),7.86(t,J＝7.6Hz,1H),7.79(t,J＝7.6Hz,1H),7.72(d,J＝8.0Hz,1H),7.24(d,J＝7.6Hz,1H),6.75(d,J＝8.0Hz,1H),6.71(s,1H),4.35-4.27(m,1H),2.71-2.66(m,2H),2.26-2.22(m,2H),1.94(m,1H),1.46(s,3H),1.04-1.00(m,2H),0.77-0.74(m,2H).
实施例29
5-(4-((1s，3s)-3-羟基-3-甲基环丁基)氨基)邻苯二甲嗪-1-基)-2,3-二氢-1H-茚-4-醇
Figure PCTCN2021141211-appb-000133
Figure PCTCN2021141211-appb-000134
以化合物15a为原料，参照实施例14中描述的方法制备化合物31。
LCMS:t R＝0.81min in 5-95AB_1.5min_220&254_Agilent.M ES-MS m/z 362.2[M+H] +.
1H NMR(400MHz,DMSO-d 6)Shift＝9.47(br,1H),8.42(d,J＝7.6Hz,1H),7.86(t,J＝7.2Hz,1H),7.79(t,J＝7.2Hz,1H),7.65(d,J＝7.6Hz,1H),7.55(d,J＝6.4Hz,1H),7.10(d,J＝7.6Hz,1H),6.86(d,J＝7.6Hz,1H),5.00(s,1H),2.94(t,J＝7.4Hz,2H),2.88(t,J＝7.4Hz,1H),2.21-2.18(m,2H),2.10-2.06(m,2H),3.16(br,4H).
实施例30
rac-(R)-2-(4-(1-(2-羟乙基)哌啶-3-基)氨基)-5,7-二氢糠醛[3,4-d]哒嗪-1-基)-5-(三氟甲基)苯酚
Figure PCTCN2021141211-appb-000135
以化合物16c为原料，参照实施例19中描述的方法制备化合物32。
1H NMR(400MHz,CD 3OD)δ＝8.50(s,1H),7.43(d,J＝8.5Hz,1H),7.27-7.16(m,2H),5.36(t,J＝3.0Hz,2H),5.05(br s,2H),4.55-4.44(m,1H),3.80(t,J＝5.5Hz,2H),3.50(br d,J＝10.8Hz,1H),3.13(br s,1H),3.01-2.83(m,2H),2.76-2.64(m,1H),2.59(br s,1H),2.09(br d,J＝8.8Hz,1H),2.03-1.93(m,1H),1.92-1.79(m,1H),1.74-1.55(m,1H).
实施例31
3-氟-2-(4-((1s，3s)-3-羟基-3-甲基环丁基)氨基)吡啶[3,4-d]哒嗪-1-基)-5-(三氟甲基)苯酚(化合物33)
Figure PCTCN2021141211-appb-000136
3-氟-2-(1-((1s，3s)-3-羟基-3-甲基环丁基)氨基)吡啶[3,4-d]哒嗪-4-基)-5-(三氟甲基)苯酚(化合物34)
Figure PCTCN2021141211-appb-000137
以化合物24b和24c为起始原料，按照实施例15中描述的方法制备化合物33和34。
化合物33
1H-NMR:(400MHz,METHANOL-d4)Shift＝9.71(s,1H),8.84(d,J＝5.7Hz,1H),7.38(d,J＝5.5Hz,1H),7.05(s,1H),7.01(br d,J＝8.8Hz,1H),4.36(quin,J＝7.8Hz,1H),2.78-2.61(m,2H),2.34-2.20(m,2H),1.45(s,3H).
化合物34
1H-NMR:(400MHz,METHANOL-d4)Shift＝8.93(d,J＝5.8Hz,1H),8.83(s,1H),8.24(d,J＝6.1Hz,1H),7.12(br s,2H),4.34(br d,J＝8.3Hz,1H),2.75-2.64(m,3H),2.28(br d,J＝8.6Hz,3H),1.45(s,3H).
实施例32
3-氟-2-(4-((R)-1-甲基哌啶-3-基)氨基)-5,7-二氢糠醛[3,4-d]哒嗪-1-基)-5-(三氟甲基)苯酚
Figure PCTCN2021141211-appb-000138
Figure PCTCN2021141211-appb-000139
以化合物16d为起始原料，参照实施例15中描述的方法制备化合物35。
1H-NMR:(400MHz,CD 3OD)δ＝7.08-6.96(m,2H),5.10-5.04(m,2H),4.65-4.56(m,2H),3.68-3.60(m,1H),3.01-2.86(m,1H),2.56-2.45(m,3H),2.43-2.30(m,1H),2.15-2.01(m,1H),1.97-1.90(m,1H),1.86-1.74(m,1H),1.65-1.53(m,1H),1.40-1.24(m,2H).
实施例33
rac-(R)-5-环丙基-2-(6-((1-(2-羟乙基)哌啶-3-基)氨基)-4-甲基哒嗪-3-基)苯酚
Figure PCTCN2021141211-appb-000140
以化合物4d和19a为原料，参照化合物19中描述的方法制备化合物36。
1H NMR:(400MHz,CD 3OD)δ＝8.50(s,1H),7.88(s,1H),7.63(d,J＝8.3Hz,1H),6.65(d,J＝8.0Hz,1H),6.62(s,1H),4.52-4.40(m,1H),3.83(t,J＝5.4Hz,2H),3.57(br d,J＝10.0Hz,1H),3.28-3.19(m,1H),3.12-2.95(m,2H),2.83(br t,J＝10.4Hz,1H),2.75(br t,J＝10.8Hz,1H),2.28(s,3H),2.09(br d,J＝12.0Hz,1H),2.05-1.97(m,1H),1.95-1.83(m,2H),1.79-1.67(m,1H),1.03-0.94(m,2H),0.74-0.67(m,2H).
实施例34
7-氟-5-(6-((1s，3s)-3-羟基-3-甲基环丁基)氨基)-4-甲基哒嗪-3-基)-2,3-二氢-1H-茚-4-醇
Figure PCTCN2021141211-appb-000141
以化合物14b为起始原料，参照实施例4中描述的方法制备化合物37。
1H NMR:(400MHz,CD 3OD)δ＝6.79(d,J＝9.2Hz,1H),6.77(s,1H),4.01(penta,J＝7.8Hz,1H),2.99(t,J＝7.6Hz,2H),2.94(t,J＝7.6Hz,2H),2.61-2.58(m,2H),2.21-2.18(m,5H),2.06-2.03(m,2H),1.42(s,3H).
实施例35
5-(8-((1s，3s)-3-羟基-3-甲基环丁基)氨基)吡啶基[2,3-d]哒嗪-5-基)-2,3-二氢-1H-茚-4-醇
Figure PCTCN2021141211-appb-000142
以22c为起始原料，参照实施例15中描述的方法制备化合物38。
1H NMR:(400MHz,DMSO-d6)δ＝9.39(br,1H),9.10(dd,J＝8.4,1.2Hz,1H),8.02(d,J＝8.4Hz,1H),7.86(d,J＝8.4Hz,1H),7.52(d,J＝7.2Hz,1H),7.14(d,J＝7.6Hz,1H),6.88(d,J＝7.6Hz,1H),5.00(s,1H),4.36-4.26(m,1H),2.93(t,J＝7.2Hz,2H),2.88(t,J＝7.2Hz,2H),2.32-2.22(m,2H),2.18-2.08(m,2H),1.33(s,3H).
实施例36
5-(4-((1s，3s)-3-羟基-3-甲基环丁基)氨基)吡啶[3,4-d]哒嗪-1-基)-2,3-二氢-1H-茚-4-醇(化合物39)
Figure PCTCN2021141211-appb-000143
5-(1-((1s，3s)-3-羟基-3-甲基环丁基)氨基)吡啶[3,4-d]哒嗪-4-基)-2,3-二氢-1H-茚-4-醇(化合物40)
Figure PCTCN2021141211-appb-000144
以24b和24c为起始原料，参照实施例15中描述的方法制备化合物39和40。
化合物39。
1H NMR:(400MHz,CD 3OD)δppm 9.05(br s,1H),8.90(d,J＝5.6Hz,1H),8.21(d,J＝5.6Hz,1H),7.24(d,J＝7.6Hz,1H),6.97(d,J＝7.6Hz,1H),4.01(penta,J＝7.8Hz,1H),3.01(t,J＝7.6Hz,2H),2.70(t,J＝7.6Hz,2H),2.70-2.61(m,2H),2.26-2.17(m,4H),1.42(s,3H).
化合物40
1H NMR:(400MHz,CD 3OD)δppm 9.69(s,1H),8.85(d,J＝5.6Hz,1H),7.64(d,J＝5.6Hz,1H),7.21(d,J＝7.6Hz,1H),6.92(d,J＝7.6Hz,1H),4.35(penta,J＝7.8Hz,1H),3.01(t,J＝7.6Hz,2H),2.96(t,J＝7.6Hz,2H),2.71-2.61(m,2H),2.28-2.16(m,4H),1.47(s,3H).
实施例37
5-环丙基-2-(4-((1s，3s)-3-羟基-3-甲基环丁基)氨基)吡啶基[3,4-d]哒嗪-1-基)苯酚
Figure PCTCN2021141211-appb-000145
Figure PCTCN2021141211-appb-000146
以化合物18c为原料，参照化合物18中描述的方法制备化合物41。
1H NMR(400MHz,CD 3OD)δppm 9.70(s,1H),8.86(d,J＝5.7Hz,1H),7.57(d,J＝5.6Hz,1H),7.28(d,J＝7.8Hz,1H),6.79(br d,J＝7.8Hz,1H),6.73(s,1H),5.43-5.43(m,1H),4.34(quin,J＝7.8Hz,1H),2.76-2.65(m,2H),2.35-2.23(m,2H),2.02-1.90(m,1H),1.08-0.99(m,2H),0.81-0.70(m,2H).
实施例38
2-(4-((1s，3s)-3-羟基-3-甲基环丁基)氨基)-7,8-二氢-5H-吡喃并[3,4-d]哒嗪-1-基)-5-(三氟甲基)苯酚(化合物42)
Figure PCTCN2021141211-appb-000147
2-(1-((1s，3s)-3-羟基-3-甲基环丁基)氨基)-7,8-二氢-5H-吡喃并[3,4-d]哒嗪-4-基)-5-(三氟甲基)苯酚(化合物43)
Figure PCTCN2021141211-appb-000148
以42a为起始原料，参照实施例15中描述的方法制备化合物42和43。
化合物42
1H NMR:(400MHz,CD 3OD)δppm 7.40(d,J＝7.6Hz,1H),7.24(d,J＝7.6Hz,1H),4.48(s,2H),4.21(penta,J＝7.6Hz,1H),4.02(t,J＝7.6Hz,2H),2.68-2.56(m,4H),2.16-2.02(m,2H),1.43(s,3H).
化合物43
1H NMR:(400MHz,CD 3OD)δppm 7.42(d,J＝7.6Hz,1H),7.23(d,J＝7.6Hz,1H),4.61(s,2H),4.19(penta,J＝7.6Hz,1H),3.89(t,J＝7.6Hz,2H),2.70-2.58(m,4H),2.14-2.00(m,2H),1.41(s,3H).
实施例39
3-氟-2-(4-((1s，3s)-3-羟基-3-甲基环丁基)氨基)邻苯二甲嗪-1-基)-5-(三氟甲基)苯酚
Figure PCTCN2021141211-appb-000149
以化合物15a为起始原料，参照实施例15中描述的方法制备化合物44。
1H-NMR:(400MHz,DMSO-d6)δ＝10.78(br,1H),8.48(d,J＝8.0Hz,1H),7.90(t,J＝7.8Hz,1H),7.81(t,J＝7.7Hz,1H),7.36(d,J＝8.0Hz,1H),7.27(d,J＝7.6Hz,1H),7.17(s,1H),5.05(s,1H),4.28-4.22(m,1H),2.28-2.20(m,2H),1.34(s,3H).
实施例40
2-(4-((1s，3s)-3-羟基-3-甲基环丁基)氨基)吡啶[3,4-d]哒嗪-1-基)-3-甲基-5-(三氟甲基)苯酚
Figure PCTCN2021141211-appb-000150
Figure PCTCN2021141211-appb-000151
以化合物24b为起始原料，参照实施例15中描述的方法制备化合物45。
1H-NMR:(400MHz,DMSO-d6)δ＝9.81(s,1H),8.81(d,J＝5.2Hz,1H),8.08(d,J＝6.4Hz,1H),7.20(s,1H),7.13-7.03(m,2H),5.05(br s,1H),4.49-4.15(m,1H),2.52-2.52(m,2H),2.26(br t,J＝9.2Hz,1H),2.16(br t,J＝10.0Hz,1H),1.99(s,3H),1.35(s,3H).
实施例41
2-(4-((1s，3s)-3-羟基-3-甲基环丁基)氨基)邻苯二甲嗪-1-基)-3-甲基-5-(三氟甲基)苯酚
Figure PCTCN2021141211-appb-000152
以化合物15a为起始原料，参照实施例15中描述的方法制备化合物46。
1H-NMR:(400MHz,CD 3OD)δ＝8.39(d,J＝8.4Hz,1H),7.97-7.87(m,1H),7.86-7.78(m,1H),7.42(d,J＝8.0Hz,1H),7.17(s,1H),7.08(s,1H),4.39-4.22(m,1H),2.76-2.63(m,2H),2.36-2.20(m,2H),2.06(s,3H),1.45(s,3H).
实施例42
3-甲基-2-(4-((R)-1-甲基哌啶-3-基)氨基)-5,7-二氢糠醛[3,4-d]哒嗪-1-基)-5-(三氟甲基)苯酚
Figure PCTCN2021141211-appb-000153
Figure PCTCN2021141211-appb-000154
以化合物16d为起始原料，参照实施例15中描述的方法制备化合物47。
1H-NMR:(400MHz,DMSO-d6)δ＝8.16(s,1H),7.12(s,1H),7.05(s,1H),6.50(br d,J＝6.9Hz,1H),4.95(br s,2H),4.81(br s,1H),4.69(br s,1H),4.29(br s,1H),3.13-3.01(m,1H),2.78-2.63(m,1H),2.26(s,3H),2.08(s,3H),1.94(br d,J＝12.8Hz,2H),1.75(br d,J＝13.9Hz,1H),1.59(br d,J＝12.1Hz,1H),1.34(br d,J＝11.4Hz,1H).
实施例43
3-氟-2-(4-((R)-1-甲基哌啶-3-基)氨基)-6,7-二氢-5H-环戊烷[d]哒嗪-1-基)-5-(三氟甲基)苯酚
Figure PCTCN2021141211-appb-000155
以化合物2b为起始原料，参照实施例15中描述的方法制备化合物48。
LCMS:ES-LCMS m/z 411.3[M+H] +。
实施例44
3-氟-2-(4-((R)-1-(2-羟乙基)哌啶-3-基)氨基)-5,7-二氢糠醛[3,4-d]哒嗪-1-基)-5-(三氟甲基)苯酚
Figure PCTCN2021141211-appb-000156
Figure PCTCN2021141211-appb-000157
以化合物32a为原料，参照实施例19中描述的方法制备化合物49。
LCMS:ES-LCMS m/z 443.3[M+H] +。
实施例45
(R)-2-(4-((1-甲基哌啶-3-基)氨基)-7,8-二氢-5H-吡喃并[3,4-d]哒嗪-1-基)-5-(三氟甲基)苯酚(化合物50)
Figure PCTCN2021141211-appb-000158
(R)-2-(1-((1-甲基哌啶-3-基)氨基)-7,8-二氢-5H-吡喃并[3,4-d]哒嗪-4-基)-5-(三氟甲基)苯酚(化合物51)
Figure PCTCN2021141211-appb-000159
以化合物42c为原料，参照化合物16中描述的方法制备化合物50和51。
化合物50：LCMS:ES-LCMS m/z 409.3[M+H] +.
化合物51：LCMS:ES-LCMS m/z 409.3[M+H] +.
实施例46
(R)-2-(4-(1-(2-羟乙基)哌啶-3-基)氨基)-7,8-二氢-5H-吡喃并[3,4-d]哒嗪-1-基)-5-(三氟甲基)苯酚(化合物52)
Figure PCTCN2021141211-appb-000160
(R)-2-(1-(2-羟乙基)哌啶-3-基)氨基)-7,8-二氢-5H-吡喃并[3,4-d]哒嗪-4-基)-5-(三氟甲基)苯酚(化合物53)
Figure PCTCN2021141211-appb-000161
以化合物16c为原料，参照化合物32中描述的方法制备化合物52和53。
化合物52：LCMS:ES-LCMS m/z 439.3[M+H] +.
化合物53：LCMS:ES-LCMS m/z 439.3[M+H] +.
生物学评价
以下结合测试例进一步描述解释本公开中，但这些测试例并非意味着限制本公开中的范围。
实验例1在人类单核细胞中的NLRP3炎症体抑制活性测定
1.实验仪器和试剂
1.1实验仪器
Plate washer:BioTek 405 Select 405TSUS Microplate Washer 96 and 384 Well w/Ultrasonic(6025)(BioTek,cat#405TSUS)
Plate reader:PerkinElmer 2104 EnVision Multilabel Plate Readers
1.2实验试剂
试剂 供应商
人IL-1b ELISA试剂盒 BD
青霉素/链霉素 Gibco
RPMI1640培养基 Gibco
HEPES Gibco
FBS Gibco
脂多糖 Sigma
潮霉素B Client
Normocin Client
ATP Sigma
96孔板，Elisa Greiner
96孔板 Corning
化合物R1
Figure PCTCN2021141211-appb-000162
化合物R2
Figure PCTCN2021141211-appb-000163
化合物R3
Figure PCTCN2021141211-appb-000164
化合物R1、R2、R3通过报道文献(WO2020234715)一致的方法合成
2.实验方案
第1天：通过密度梯度离心从人体血液中分离PBMC，用含有2％FBS的PBS清洗PBMC两次(300g离心8分钟)。然后使用人类泛单核细胞分离试剂盒和LS柱将单核细胞从PBMC中分离。细胞在4℃下与CD14-FITC染色30分钟，FACS在BD FACSVerse上运行，以分析泛单核细胞的纯度。计数并调整细胞密度至2.5x10 5细胞/毫升。将细胞种至96孔板中，2.5x10 4单核细胞/100mL悬浮液/孔。在5％CO 2,37℃，孵育过夜。
第2天：预滴定测试化合物，使所有滴定点，包括DMSO对照孔包含0.1％的DMSO。去除培养基，预处理单核细胞(通过将150mL化合物(在无血清1640培养基中稀释)或DMSO添加到各自的孔中，在5％的CO 2，37℃下孵育0.5小时)。然后处理细胞(通过加入含有700ng/mL LPS(最终浓度为100ng/mL)的1640(无血清)溶液25mL，在37℃下5％CO 2中孵育3.5小时)。在3.5小时的孵育结束时，刺激细胞(加入25mL的40mM ATP(最终浓度将是5mM)处理45分钟)。将80mL的上清转移到新板中，并在-80℃下储存。
第3天：根据制造商的说明将上清溶液稀释20倍用于人类单核细胞IL-1b ELISA。
第3-4天：ELISA实验
1)第3天：在板中加入100mL/孔捕获抗体(用包被缓冲液稀释)。密封板，并在4℃下孵育过夜。
2)第4天：吸掉孔中液体，每次用300uL/≥洗缓冲液洗3次。最后一次洗涤后，将板反转过来，在吸水纸上吸干，以去除任何残留缓冲液。
3)在板中加入试验稀释液，≥200uL/孔。在室温中孵育1小时。
4)吸干/洗涤，如步骤2。
5)用试验稀释液制备标准和样品稀释液。
6)将每个标准品、样品和对照加入对应的孔中，100mL/孔。密封板并在室温中 孵育2小时。
7)吸干/洗涤如步骤2，但要洗涤5次。
8)将检测抗体用试验稀释液稀释，加入孔中，100mL/孔。
9)密封板并在室温中孵育1小时。
10)吸干/洗涤如步骤2，但要洗涤5次。
11)将酶试剂用试验稀释液稀释，并加入孔中，100mL/孔。密封板并在室温中孵育30分钟。
12)吸干/洗涤，使用30秒-1分钟的浸泡步骤，共洗7次。
13)在每个孔中加入100mL的底物溶液。在黑暗中室温下孵育板(无板密封剂)30分钟。
14)向每孔添加50mL终止溶液。
15)在停止反应后30分钟内通过仪器Envision读取450nm的吸收值。如果波长校正可用，则从吸收度450nm中减去570nm的吸收度。
3.实验结果
Figure PCTCN2021141211-appb-000165
Figure PCTCN2021141211-appb-000166
*稳定实验条件后，进行n次检测结果的均值。
实验例2大鼠药代动力学实验方案
1、健康成年SD大鼠，SPF级，雄性，3只，6-8周龄；体重200-300克。
2、所需设备：HPLC-MS、分析天平、动物体重秤、磁力搅拌器、冷冻离心机、单道手动移液器等。
3、称取适量供试品，溶于10％DMA/33％PEG400/57％Water(V/V/V)中，经旋涡，超声，配成所需的给药制剂，用于静脉给药。称取适量供试品，溶于0.5％HPMC 0.1％Tween in water中，经旋涡，超声，配成所需的给药制剂，用于口服给药。
4、动物饲养于大鼠笼中，开试验前一天开始禁食(不少于10h)不禁水；给药前称重，根据体重，计算给药量。给药当天静脉注射或口服灌胃给药一次。
5、采血时间点，静脉组：给药后0.083、0.25、0.5、1、2、4、8和24h。口服组：给药后0.25、0.5、1、2、4、8和24h。
6、经颈静脉采血，约0.20mL/时间点，K 2-EDTA抗凝，采集后放置冰上。血液样本采集后于1小时之内离心分离血浆(离心条件：6800g/分钟，6分钟，2-8℃)。采集的血浆样本在分析前存放于-80℃冰箱内，分析后剩余血浆样本继续存放于-80℃冰箱。
7、生物分析，进行血浆药物浓度-时间曲线绘制时，BLQ均记为0。进行药代参数计算时，给药前的浓度按照0计算；Cmax之前的BLQ(包括“No peak”)按照0计算；Cmax之后出现的BLQ(包括“No peak”)一律不参与计算。通过不同时间点的血药浓度数据，运用WinNonlin计算药代动力学参数，如AUC(0-t)，T1/2，Cmax，Tmax和MRT等。

Claims (64)

  1. 式I化合物或其可药用盐，
    Figure PCTCN2021141211-appb-100001
    其中，R 1选自氢、氘、卤素、-OH、-NH 2、-CN和任选被一个或多个取代基取代的以下基团：C 1-6烷基、-O-C 1-6烷基、-NHC(＝O)-C 1-6烷基和-(C＝O)NH-C 1-6烷基，所述取代基选自：氘、卤素、-OH、-NH 2和-CN；
    R 2、R 3、R 4、R 5、R 6和R 7：
    (a)R 2和R 3与其连接的原子一起形成任选被一个或多个取代基取代的5-6元的环烃、苯基、杂环或杂芳环，所述取代基选自：氘、卤素、-OH、-NH 2、-CN、氧代、C 1-6烷基、-O-C 1-6烷基和C 3-6环烷基，所述C 1-6烷基、-O-C 1-6烷基和C 3-6环烷基任选进一步被一个或多个氘或卤素取代；
    R 4、R 5、R 6和R 7独立地选自氢、氘、卤素、-OH、-NH 2和任选被一个或多个取代基取代的以下基团：C 1-6烷基、-O-C 1-6烷基、-S-C 1-6烷基、C 3-6环烷基和C 3-6环烷基亚甲基，所述取代基选自：氘、卤素、-OH、-NH 2和-CN；
    或R 6和R 7与其连接的原子一起形成任选被一个或多个取代基取代的5-6元的环烃、5-6元的杂环、苯基、5-6元杂芳基，所述取代基选自：氘、卤素、-OH、-NH 2、-CN、氧代、C 1-6烷基、-O-C 1-6烷基和C 3-6环烷基，所述C 1-6烷基、-O-C 1-6烷基和C 3-6环烷基任选进一步被一个或多个选自氘或卤素的取代基所取代；R 4、R 5独立地选自氢、氘、卤素、-OH、-NH 2和任选被一个或多个取代基取代的以下基团：C 1-6烷基、-O-C 1-6烷基、-S-C 1-6烷基、C 3-6环烷基和C 3-6环烷基亚甲基，所述取代基选自：氘、卤素、-OH、-NH 2和-CN；
    (b)R 3和R 4与其连接的原子一起形成任选被一个或多个取代基取代的5-6元的环烃、苯基、杂环或杂芳环，所述取代基选自：氘、卤素、-NH 2、-CN、C 1-6烷基、-O-C 1-6烷基和C 3-6环烷基，所述C 1-6烷基、-O-C 1-6烷基和C 3-6环烷基任选进一步被一个或多个氘或卤素取代；R 2、R 5、R 6和R 7独立地选自氢、氘、卤素、-OH、-NH 2和任选被一个或多个取代基取代的以下基团：C 1-6烷基、-O-C 1-6烷基、-S-C 1-6烷基、C 3-6环烷基和C 3-6环烷基亚甲基，所述取代基选自：氘、卤素、-OH、-NH 2和-CN；
    (c)R 4和R 5与其连接的原子一起形成任选被一个或多个取代基取代的5-6元的环烃、苯基、杂环或杂芳环，所述取代基选自：氘、卤素、-OH、-NH 2、-CN、氧代、C 1-6烷基、-O-C 1-6烷基和C 3-6环烷基，所述C 1-6烷基、-O-C 1-6烷基和C 3-6 环烷基任选进一步被一个或多个氘或卤素取代；R 2、R 3、R 6和R 7独立地选自氢、氘、卤素、-OH、-NH 2和任选被一个或多个取代基取代的以下基团：C 1-6烷基、-O-C 1-6烷基、-S-C 1-6烷基、C 3-6环烷基和C 3-6环烷基亚甲基，所述取代基选自：氘、卤素、-OH、-NH 2和-CN；
    或者，(d)R 6和R 7与其连接的原子一起形成任选被一个或多个取代基取代的5-6元的环烃、5-6元的杂环、苯基、5-6元杂芳基，所述取代基选自：氘、卤素、-OH、-NH 2、-CN、氧代、C 1-6烷基、-O-C 1-6烷基和C 3-6环烷基，所述C 1-6烷基、-O-C 1-6烷基和C 3-6环烷基任选进一步被一个或多个氘或卤素取代；R 2、R 3、R 4和R 5独立地选自氢、氘、卤素、-OH、-NH 2和任选被一个或多个取代基取代的以下基团：C 1-6烷基、-O-C 1-6烷基、-S-C 1-6烷基、C 3-6环烷基和C 3-6环烷基亚甲基，所述取代基选自：氘、卤素、-OH、-NH 2和-CN；
    Z为O或-NH-(CH 2)n-，n为选自0-3的整数；
    R 8选自任选被一个或多个取代基取代的芳基、杂芳基、杂环基、C 3-8环烷基、C 1-6烷基和-O-C 1-6烷基，所述取代基选自氘、卤素、氧代、-OR 8a、-SR 8a、-C(＝O)R 8a、-OC(＝O)R 8a、-C(＝O)OR 8a、-C(＝O)NR 8aR 8b、-NR 8aR 8b、-NR 8aC(＝O)R 8b、-NR 8aS(＝O) 2R 8b、-S(＝O) 2R 8a、-S(＝O) 2NR 8aR 8b、-CN、-NO 2、C 1-4烷基和C 3-6环烷基，所述C 1-4烷基或C 3-6环烷基任选进一步被一个或多个的氘、卤素或-OH取代；
    R 8a和R 8b独立地选自氢、氘或任选被一个或多个取代基取代的以下基团：C 1-4烷基、C 3-6环烷基和C 3-6环烷基亚甲基，所述取代基选自：氘、卤素、-NH 2、-OH、-CN、C 1-4烷基、C 1-4烷氧基、C 3-6环烷基和C 3-6环烷基亚甲基，上述取代基任选进一步被一个或多个的氘或卤素取代；
    当R 6和R 7与其连接的原子一起形成未取代的5-6元环烃，R 1为甲基或甲氧基，且Z为-NH-时，R 8不为芳基。
  2. 根据权利要求1所述化合物或其可药用盐，
    Figure PCTCN2021141211-appb-100002
    其中，R 1选自氢、氘、卤素、-OH、-NH 2、-CN和任选被一个或多个取代基取代的以下基团：C 1-6烷基、-O-C 1-6烷基、-NHC(＝O)-C 1-6烷基和-(C＝O)NH-C 1-6烷基，所述取代基选自：氘、卤素、-OH、-NH 2和-CN；
    R 2、R 3、R 4、R 5、R 6和R 7：
    (a)R 2和R 3与其连接的原子一起形成任选被一个或多个取代基取代的5-6元的环烃、杂环或杂芳环，所述取代基选自：氘、卤素、-OH、-NH 2、-CN、氧代、 C 1-6烷基、-O-C 1-6烷基和C 3-6环烷基，所述C 1-6烷基、-O-C 1-6烷基和C 3-6环烷基任选进一步被一个或多个氘或卤素取代；R 4、R 5、R 6和R 7独立地选自氢、氘、卤素、-OH、-NH 2和任选被一个或多个取代基取代的以下基团：C 1-6烷基、-O-C 1-6烷基、-S-C 1-6烷基、C 3-6环烷基和C 3-6环烷基亚甲基，所述取代基选自：氘、卤素、-OH、-NH 2和-CN；
    (b)R 3和R 4与其连接的原子一起形成任选被一个或多个取代基取代的5-6元的环烃、苯基，所述取代基选自：氘、卤素、-NH 2、-CN、C 1-6烷基、-O-C 1-6烷基和C 3-6环烷基，所述C 1-6烷基、-O-C 1-6烷基和C 3-6环烷基任选进一步被一个或多个氘或卤素取代；R 2、R 5、R 6和R 7独立地选自氢、氘、卤素、-OH、-NH 2和任选被一个或多个取代基取代的以下基团：C 1-6烷基、-O-C 1-6烷基、-S-C 1-6烷基、C 3-6环烷基和C 3-6环烷基亚甲基，所述取代基选自：氘、卤素、-OH、-NH 2和-CN；
    (c)R 4和R 5与其连接的原子一起形成任选被一个或多个取代基取代的5-6元的环烃、苯基，所述取代基选自：氘、卤素、-OH、-NH 2、-CN、氧代、C 1-6烷基、-O-C 1-6烷基和C 3-6环烷基，所述C 1-6烷基、-O-C 1-6烷基和C 3-6环烷基任选进一步被一个或多个氘或卤素取代；R 2、R 3、R 6和R 7独立地选自氢、氘、卤素、-OH、-NH 2和任选被一个或多个取代基取代的以下基团：C 1-6烷基、-O-C 1-6烷基、-S-C 1-6烷基、C 3-6环烷基和C 3-6环烷基亚甲基，所述取代基选自：氘、卤素、-OH、-NH 2和-CN；
    或者，(d)R 6和R 7与其连接的原子一起形成任选被一个或多个取代基取代的5-6元的环烃、5-6元的杂环、苯基，所述取代基选自：氘、卤素、-OH、-NH 2、-CN、氧代、C 1-6烷基、-O-C 1-6烷基和C 3-6环烷基，所述C 1-6烷基、-O-C 1-6烷基和C 3-6环烷基任选进一步被一个或多个氘或卤素取代；R 2、R 3、R 4和R 5独立地选自氢、氘、卤素、-OH、-NH 2和任选被一个或多个取代基取代的以下基团：C 1-6烷基、-O-C 1-6烷基、-S-C 1-6烷基、C 3-6环烷基和C 3-6环烷基亚甲基，所述取代基选自：氘、卤素、-OH、-NH 2和-CN；
    Z为O或-NH-(CH2)n-，n为选自0-3的整数；
    R 8选自任选被一个或多个取代基取代的芳基、杂芳基、杂环基、C 3-8环烷基、C 1-6烷基和-O-C 1-6烷基，所述取代基选自氘、卤素、氧代、-OR 8a、-SR 8a、-C(＝O)R 8a、-OC(＝O)R 8a、-C(＝O)OR 8a、-C(＝O)NR 8aR 8b、-NR 8aR 8b、-NR 8aC(＝O)R 8b、-NR 8aS(＝O) 2R 8b、-S(＝O) 2R 8a、-S(＝O) 2NR 8aR 8b、-CN、-NO 2、C 1-4烷基和C 3-6环烷基，所述C 1-4烷基或C 3-6环烷基任选进一步被一个或多个的氘、卤素或-OH取代；
    R 8a和R 8b独立地选自氢、氘或任选被一个或多个取代基取代的以下基团：C 1-4烷基、C 3-6环烷基和C 3-6环烷基亚甲基，所述取代基选自：氘、卤素、-NH 2、-OH、-CN、C 1-4烷基、C 1-4烷氧基、C 3-6环烷基和C 3-6环烷基亚甲基，上述取代基任选进一步被一个或多个的氘或卤素取代；
    当R 6和R 7与其连接的原子一起形成未取代的5-6元环烃，R 1为甲基或甲氧基，且Z为-NH-时，R 8不为芳基。
  3. 根据权利要求1所述化合物或其可药用盐，
    Figure PCTCN2021141211-appb-100003
    其中，R 1选自氢、氘、卤素、-OH、-NH 2、-CN和任选被一个或多个取代基取代的以下基团：C 1-6烷基、-O-C 1-6烷基、-NHC(＝O)-C 1-6烷基和-(C＝O)NH-C 1-6烷基，所述取代基选自：氘、卤素、-OH、-NH 2和-CN；
    R 2、R 3、R 4、R 5、R 6和R 7：
    (a)R 2和R 3与其连接的原子一起形成任选被一个或多个取代基取代的5-6元的环烃、杂环或杂芳环，所述取代基选自：氘、卤素、-OH、-NH 2、-CN、氧代、C 1-6烷基、-O-C 1-6烷基和C 3-6环烷基，所述C 1-6烷基、-O-C 1-6烷基和C 3-6环烷基任选进一步被一个或多个氘或卤素取代；R 4、R 5、R 6和R 7独立地选自氢、氘、卤素、-OH、-NH 2和任选被一个或多个取代基取代的以下基团：C 1-6烷基、-O-C 1-6烷基、-S-C 1-6烷基、C 3-6环烷基和C 3-6环烷基亚甲基，所述取代基选自：氘、卤素、-OH、-NH 2和-CN；
    (b)R 3和R 4与其连接的原子一起形成任选被一个或多个取代基取代的5-6元的环烃、苯基，所述取代基选自：氘、卤素、-NH 2、-CN、C 1-6烷基、-O-C 1-6烷基和C 3-6环烷基，所述C 1-6烷基、-O-C 1-6烷基和C 3-6环烷基任选进一步被一个或多个氘或卤素取代；R 2、R 5、R 6和R 7独立地选自氢、氘、卤素、-OH、-NH 2和任选被一个或多个取代基取代的以下基团：C 1-6烷基、-O-C 1-6烷基、-S-C 1-6烷基、C 3-6环烷基和C 3-6环烷基亚甲基，所述取代基选自：氘、卤素、-OH、-NH 2和-CN；
    (c)R 4和R 5与其连接的原子一起形成任选被一个或多个取代基取代的5-6元的环烃，所述取代基选自：氘、卤素、-OH、-NH 2、-CN、氧代、C 1-6烷基、-O-C 1-6烷基和C 3-6环烷基，所述C 1-6烷基、-O-C 1-6烷基和C 3-6环烷基任选进一步被一个或多个氘或卤素取代；R 2、R 3、R 6和R 7独立地选自氢、氘、卤素、-OH、-NH 2和任选被一个或多个取代基取代的以下基团：C 1-6烷基、-O-C 1-6烷基、-S-C 1-6烷基、C 3-6环烷基和C 3-6环烷基亚甲基，所述取代基选自：氘、卤素、-OH、-NH 2和-CN；
    或者，(d)R 6和R 7与其连接的原子一起形成任选被一个或多个取代基取代的5-6元的环烃、5-6元的杂环、苯基，所述取代基选自：氘、卤素、-OH、-NH 2、-CN、氧代、C 1-6烷基、-O-C 1-6烷基和C 3-6环烷基，所述C 1-6烷基、-O-C 1-6烷基和C 3-6环烷基任选进一步被一个或多个氘或卤素取代；R 2、R 3、R 4和R 5独立地选自氢、 氘、卤素、-OH、-NH 2和任选被一个或多个取代基取代的以下基团：C 1-6烷基、-O-C 1-6烷基、-S-C 1-6烷基、C 3-6环烷基和C 3-6环烷基亚甲基，所述取代基选自：氘、卤素、-OH、-NH 2和-CN；
    Z为O或-NH-(CH2)n-，n为选自0-3的整数；
    R 8选自任选被一个或多个取代基取代的芳基、杂芳基、杂环基、C 3-8环烷基、C 1-6烷基和-O-C 1-6烷基，所述取代基选自氘、卤素、氧代、-OR 8a、-SR 8a、-C(＝O)R 8a、-OC(＝O)R 8a、-C(＝O)OR 8a、-C(＝O)NR 8aR 8b、-NR 8aR 8b、-NR 8aC(＝O)R 8b、-NR 8aS(＝O) 2R 8b、-S(＝O) 2R 8a、-S(＝O) 2NR 8aR 8b、-CN、-NO 2、C 1-4烷基和C 3-6环烷基，所述C 1-4烷基或C 3-6环烷基任选进一步被一个或多个的氘、卤素或-OH取代；
    R 8a和R 8b独立地选自氢、氘或任选被一个或多个取代基取代的以下基团：C 1-4烷基、C 3-6环烷基和C 3-6环烷基亚甲基，所述取代基选自：氘、卤素、-NH 2、-OH、-CN、C 1-4烷基、C 1-4烷氧基、C 3-6环烷基和C 3-6环烷基亚甲基，上述取代基任选进一步被一个或多个的氘或卤素取代；
    当R 6和R 7与其连接的原子一起形成未取代的5-6元环烃，R 1为甲基或甲氧基，且Z为-NH-时，R 8不为芳基。
  4. 根据权利要求1所述化合物或其可药用盐，
    其中，R 1选自氢、氘、卤素、-OH、-NH 2、-CN和任选被一个或多个取代基取代的以下基团：C 1-6烷基、-O-C 1-6烷基、-NHC(＝O)-C 1-6烷基和-(C＝O)NH-C 1-6烷基，所述取代基选自：氘、卤素、-OH、-NH 2和-CN；
    R 2、R 3、R 4、R 5、R 6和R 7：
    (a)R 2和R 3与其连接的原子一起形成任选被一个或多个取代基取代的5-6元的环烃、杂环或杂芳环，所述取代基选自：氘、卤素、-OH、-NH 2、-CN、氧代、C 1-6烷基、-O-C 1-6烷基和C 3-6环烷基，所述C 1-6烷基、-O-C 1-6烷基和C 3-6环烷基任选进一步被一个或多个氘或卤素取代；R 4、R 5、R 6和R 7独立地选自氢、氘、卤素、-OH、-NH 2和任选被一个或多个取代基取代的以下基团：C 1-6烷基、-O-C 1-6烷基、-S-C 1-6烷基、C 3-6环烷基和C 3-6环烷基亚甲基，所述取代基选自：氘、卤素、-OH、-NH 2和-CN；
    (b)R 3和R 4与其连接的原子一起形成任选被一个或多个取代基取代的5-6元的环烃，所述取代基选自：氘、卤素、-NH 2、-CN、C 1-6烷基、-O-C 1-6烷基和C 3-6环烷基，所述C 1-6烷基、-O-C 1-6烷基和C 3-6环烷基任选进一步被一个或多个氘或卤素取代；R 2、R 5、R 6和R 7独立地选自氢、氘、卤素、-OH、-NH 2和任选被一个或多个取代基取代的以下基团：C 1-6烷基、-O-C 1-6烷基、-S-C 1-6烷基、C 3-6环烷基和C 3-6环烷基亚甲基，所述取代基选自：氘、卤素、-OH、-NH 2和-CN；
    (c)R 4和R 5与其连接的原子一起形成任选被一个或多个取代基取代的5-6 元的环烃，所述取代基选自：氘、卤素、-OH、-NH 2、-CN、氧代、C 1-6烷基、-O-C 1-6烷基和C 3-6环烷基，所述C 1-6烷基、-O-C 1-6烷基和C 3-6环烷基任选进一步被一个或多个氘或卤素取代；R 2、R 3、R 6和R 7独立地选自氢、氘、卤素、-OH、-NH 2和任选被一个或多个取代基取代的以下基团：C 1-6烷基、-O-C 1-6烷基、-S-C 1-6烷基、C 3-6环烷基和C 3-6环烷基亚甲基，所述取代基选自：氘、卤素、-OH、-NH 2和-CN；
    或者，(d)R 6和R 7与其连接的原子一起形成任选被一个或多个取代基取代的5-6元的环烃或杂环，所述取代基选自：氘、卤素、-OH、-NH 2、-CN、氧代、C 1-6烷基、-O-C 1-6烷基和C 3-6环烷基，所述C 1-6烷基、-O-C 1-6烷基和C 3-6环烷基任选进一步被一个或多个氘或卤素取代；R 2、R 3、R 4和R 5独立地选自氢、氘、卤素、-OH、-NH 2和任选被一个或多个取代基取代的以下基团：C 1-6烷基、-O-C 1-6烷基、-S-C 1-6烷基、C 3-6环烷基和C 3-6环烷基亚甲基，所述取代基选自：氘、卤素、-OH、-NH 2和-CN；
    Z为O或-NH-(CH2)n-，n为选自0-3的整数；
    R 8选自任选被一个或多个取代基取代的芳基、杂芳基、杂环基、C 3-8环烷基、C 1-6烷基和-O-C 1-6烷基，所述取代基选自氘、卤素、氧代、-OR 8a、-SR 8a、-C(＝O)R 8a、-OC(＝O)R 8a、-C(＝O)OR 8a、-C(＝O)NR 8aR 8b、-NR 8aR 8b、-NR 8aC(＝O)R 8b、-NR 8aS(＝O) 2R 8b、-S(＝O) 2R 8a、-S(＝O) 2NR 8aR 8b、-CN、-NO 2、C 1-4烷基和C 3-6环烷基，所述C 1-4烷基或C 3-6环烷基任选进一步被一个或多个的氘、卤素或-OH取代；
    R 8a和R 8b独立地选自氢、氘或任选被一个或多个取代基取代的以下基团：C 1-4烷基、C 3-6环烷基和C 3-6环烷基亚甲基，所述取代基选自：氘、卤素、-NH 2、-OH、-CN、C 1-4烷基、C 1-4烷氧基、C 3-6环烷基和C 3-6环烷基亚甲基，上述取代基任选进一步被一个或多个的氘或卤素取代；
    当R 6和R 7与其连接的原子一起形成未取代的5-6元环烃，R 1为甲基或甲氧基，且Z为-NH-时，R 8不为芳基。
  5. 根据权利要求1-4中任一所述化合物或其可药用盐，其中，R 1选自卤素、-OH、-NH 2、-CN和任选被一个或多个取代基取代的以下基团：C 1-6烷基、-O-C 1-6烷基、-NHC(＝O)-C 1-6烷基和-(C＝O)NH-C 1-6烷基，所述取代基选自：氘、卤素、-OH、-NH 2和-CN；
    优选R 1选自-OH、-NH 2和任选被一个或多个取代基取代的以下基团：C 1-6烷基、-O-C 1-6烷基和-NHC(＝O)-C 1-6烷基，所述取代基选自：氘、卤素、-OH、-NH 2和-CN；
    更优选R 1选自-OH、-NH 2和任选被一个或多个-OH取代的以下基团：C 1-6烷基、-O-C 1-6烷基和-NHC(＝O)-C 1-6烷基。
  6. 根据权利要求5所述化合物或其可药用盐，其中，R 1为-OH。
  7. 根据权利要求1-6任一所述化合物或其可药用盐，其中，R 2和R 3与其连接的原子一起形成任选被一个或多个取代基取代的5-6元的环烃，所述取代基选自：氘、卤素、-OH、-NH 2、-CN、氧代、C 1-6烷基、-O-C 1-6烷基和C 3-6环烷基，所述C 1-6烷基、-O-C 1-6烷基和C 3-6环烷基任选进一步被一个或多个氘或卤素取代；
    R 4、R 5、R 6和R 7独立地选自氢、氘、卤素、-OH、-NH 2和任选被一个或多个取代基取代的以下基团：C 1-6烷基、-O-C 1-6烷基、-S-C 1-6烷基、C 3-6环烷基、C 3-6环烷基亚甲基，所述取代基选自：氘、卤素、-OH、-NH 2和-CN。
  8. 根据权利要求7所述化合物或其可药用盐，其中，式I化合物为：
    Figure PCTCN2021141211-appb-100004
    R 9a独立地选自氢、氘、卤素、-OH、-NH 2、-CN、氧代、C 1-6烷基、-O-C 1-6烷基和C 3-6环烷基，所述C 1-6烷基、-O-C 1-6烷基和C 3-6环烷基任选进一步被一个或多个氘或卤素取代；
    m为选自0-8的整数；优选m为选自0-3的整数；更优选m选自0-1的整数。
  9. 根据权利要求7所述化合物或其可药用盐，其中，式I化合物选自：
    Figure PCTCN2021141211-appb-100005
    Figure PCTCN2021141211-appb-100006
  10. 根据权利要求9所述化合物或其可药用盐，其中，式I化合物选自式II’-a、II’-b、II’-c、II’-d、II’-f、II’-g、II’-k、II’-l和II’-m化合物；优选自式II’-a、II’-c、II’-d、II’-k、II’-l和II’-m化合物；更优选自式II’-a、II’-d、II’-k和II’-m化合物；最优选为式II’-a或II’-k化合物。
  11. 根据权利要求7-10任一所述化合物或其可药用盐，其中，R 4、R 5、R 6和R 7独立地选自氢、氘、卤素和任选被一个或多个取代基取代的以下基团：C 1-6烷基、C 3-6环烷基和C 3-6环烷基亚甲基，所述取代基为氘或卤素；
    优选R 4和R 5独立地选自氢、氘和卤素，R 6和R 7独立地选自氢、氘、卤素和任选被一个或多个氘或卤素取代的C 1-6烷基；
    更优选R 4和R 7独立地选自氢、氘和卤素，R 5和R 6独立地选自氢、氘、卤素和任选被一个或多个氘或卤素取代的C 1-6烷基。
  12. 根据权利要求11所述化合物或其可药用盐，其中，R 4、R 5和R 7分别为氢，R 6为甲基；或者，R 4、R 6和R 7分别为氢，R 5为甲基。
  13. 根据权利要求1-6任一所述化合物或其可药用盐，其中
    R 2和R 3与其连接的原子一起形成任选被一个或多个取代基取代的5-6元的环烃，所述取代基选自：氘、卤素、-OH、-NH 2、-CN、氧代、C 1-6烷基、-O-C 1-6烷基和C 3-6环烷基，所述C 1-6烷基、-O-C 1-6烷基和C 3-6环烷基任选进一步被一个或多个选自氘或卤素的取代基取代；
    R 6和R 7与其连接的原子一起形成任选被一个或多个取代基取代的苯基、5-6元杂芳基，所述取代基选自：氘、卤素、-OH、-NH 2、-CN、氧代、C 1-6烷基、-O-C 1-6烷基和C 3-6环烷基，所述C 1-6烷基、-O-C 1-6烷基和C 3-6环烷基任选进一步被一个或多个选自氘或卤素的取代基取代；
    R 4、R 5独立地选自氢、氘、卤素、-OH、-NH 2和任选被一个或多个取代基取代的以下基团：C 1-6烷基、-O-C 1-6烷基、C 3-6环烷基和C 3-6环烷基亚甲基，所述取代基选自：氘、卤素、-OH、-NH 2和-CN。
  14. 根据权利要求1-6任一所述化合物或其可药用盐，R 2和R 3与其连接的原子一起形成5-6元的环烃；优选所述5-6元的环烃为环戊基或环己基；所述环戊基或环己基任选被选自氢、氘、卤素、-OH、C 1-6烷基、卤代C 1-6烷基的取代基所取代；
    R 6和R 7与其连接的原子一起形成苯基、5-6元杂芳基；优选所述5-6元杂芳基为吡啶；所述苯基或5-6元杂芳基任选被选自氢、氘、卤素、-OH、C 1-6烷基、卤代C 1-6烷基的取代基所取代；
    R 4、R 5独立地选自氢、氘、卤素、-OH、-NH 2和任选被一个或多个取代基取代的以下基团：C 1-6烷基、-O-C 1-6烷基、C 3-6环烷基和C 3-6环烷基亚甲基，所述取代基选自：氘、卤素、-OH、-NH 2和-CN；优选R 4、R 5独立地选自氢、氘、卤素、-OH、C 1-6烷基、卤代C 1-6烷基；更优选R 4、R 5独立地选自氢或氘。
  15. 根据权利要求1-6任一所述化合物或其可药用盐，其中，R 3和R 4与其连接的原子一起形成任选被一个或多个取代基取代的5-6元的环烃，所述取代基选自：氘、卤素、C 1-6烷基和C 3-6环烷基，所述C 1-6烷基和C 3-6环烷基任选进一步被一个或多个氘或卤素取代；
    R 2、R 5、R 6和R 7独立地选自氢、氘、卤素、-OH、-NH 2和任选被一个或多个取代基取代的以下基团：C 1-6烷基、-O-C 1-6烷基、-S-C 1-6烷基、C 3-6环烷基、C 3-6环烷基亚甲基，所述取代基选自：氘、卤素、-OH、-NH 2和-CN。
  16. 根据权利要求15所述化合物或其可药用盐，其中，式I化合物选自：
    Figure PCTCN2021141211-appb-100007
  17. 根据权利要求16所述化合物或其可药用盐，其中，式I化合物选自式V-a、V-b、V-c、V-d、V-f、V-g、V-k、V-l和V-m化合物；优选自式V-a、V-c、V-d、V-k、V-l和V-m化合物；更优选自式V-a、V-d、V-k和V-m化合物；最优选为式V-a或V-k化合物。
  18. 根据权利要求15-17任一所述化合物或其可药用盐，其中，R 2、R 5、R 6和R 7独立地选自氢、氘、卤素和任选被一个或多个取代基取代的以下基团：C 1-6烷基、C 3-6环烷基和C 3-6环烷基亚甲基，所述取代基为氘或卤素；
    优选R 2和R 7独立地选自氢、氘和卤素，R 5和R 6独立地选自氢、氘、卤素和任选被一个或多个氘或卤素取代的C 1-6烷基。
  19. 根据权利要求18所述化合物或其可药用盐，其中，R 2、R 5和R 7分别为氢，R 6为甲基；或者，R 2、R 6和R 7分别为氢，R 5为甲基。
  20. 根据权利要求1-12任一所述化合物或其可药用盐，其中，R 4和R 5与其连接的原子一起形成任选被一个或多个取代基取代的5-6元的环烃，所述取代基选自：氘、卤素、氧代、C 1-6烷基和C 3-6环烷基，所述C 1-6烷基和C 3-6环烷基任选进一步被一个或多个氘或卤素取代；
    R 2、R 3、R 6和R 7独立地选自氢、氘、卤素、-OH、-NH 2和任选被一个或多个取代基取代的以下基团：C 1-6烷基、-O-C 1-6烷基、-S-C 1-6烷基、C 3-6环烷基、C 3-6环烷基亚甲基，所述取代基选自：氘、卤素、-OH、-NH 2和-CN。
  21. 根据权利要求20所述化合物或其可药用盐，其中，式I化合物选自：
    Figure PCTCN2021141211-appb-100008
  22. 根据权利要求21所述化合物或其可药用盐，其中，式I化合物选自式VI-a、VI-b、VI-c、VI-d、VI-e、VI-h、VI-i、VI-j、VI-k和VI-l化合物；优选自式VI-a、VI-b、VI-c、VI-h、VI-i和VI-j化合物；更优选为式VI-a或VI-h化合物。
  23. 根据权利要求20-22任一所述化合物或其可药用盐，其中，R 2、R 3、R 6和R 7独立地选自氢、氘、卤素和任选被一个或多个取代基取代的以下基团：C 1-6烷基、C 3-6环烷基和C 3-6环烷基亚甲基，所述取代基为氘或卤素；
    优选R 2和R 7独立地选自氢、氘和卤素，R 3和R 6独立地选自氢、氘、卤素和任选被一个或多个氘或卤素取代的C 1-6烷基。
  24. 根据权利要求23所述化合物或其可药用盐，其中，R 2和R 7分别为氢，R 3为三氟甲基，R 6为甲基；或者，R 2和R 7分别为氢，R 3为氯，R 6为甲基。
  25. 根据权利要求1-6任一所述化合物或其可药用盐，其中，R 4和R 5与其连接的原子一起形成任选被一个或多个取代基取代的苯基，所述取代基选自：氘、卤素、氧代、C 1-6烷基和C 3-6环烷基，所述C 1-6烷基和C 3-6环烷基任选进一步被一个或多个氘或卤素取代；
    R 2、R 3、R 6和R 7独立地选自氢、氘、卤素、-OH、-NH 2和任选被一个或多个取代基取代的以下基团：C 1-6烷基、-O-C 1-6烷基、-S-C 1-6烷基、C 3-6环烷基、C 3-6环烷基亚甲基，所述取代基选自：氘、卤素、-OH、-NH 2和-CN；
    优选R 2、R 3、R 6和R 7独立地选自氢、氘、卤素、-OH、-NH 2、C 1-6烷基、-O-C 1-6烷基；
    更优选R 2、R 3、R 6和R 7独立地选自氢、氘、卤素、-OH、-NH 2、C 1-6烷基、-O-C 1-6烷基；
    最优选R 2、R 3、R 6和R 7独立地选自氢或氘。
  26. 根据权利要求25所述化合物或其可药用盐，其中，式I化合物选自：
    Figure PCTCN2021141211-appb-100009
    R 18b独立地选自氢、氘、卤素、-OH、-NH 2和任选被一个或多个取代基取代的以下基团：C 1-6烷基、-O-C 1-6烷基、C 3-6环烷基、C 3-6环烷基亚甲基，所述取代基 选自：氘、卤素、-OH、-NH 2和-CN；
    优选R 18b独立地选自氢、氘、卤素、-OH、C 1-6烷基、-O-C 1-6烷基、卤代C 1-6烷基、卤代-O-C 1-6烷基；
    更优选R 18b为氢。
  27. 根据权利要求1-6任一所述化合物或其可药用盐，其中，R 3和R 4与其连接的原子一起形成任选被一个或多个取代基取代的苯基，所述取代基选自：氘、卤素、C 1-6烷基和C 3-6环烷基，所述C 1-6烷基和C 3-6环烷基任选进一步被一个或多个氘或卤素取代；
    R 2、R 5、R 6和R 7独立地选自氢、氘、卤素、-OH、-NH 2和任选被一个或多个取代基取代的以下基团：C 1-6烷基、-O-C 1-6烷基、-S-C 1-6烷基、C 3-6环烷基、C 3-6环烷基亚甲基，所述取代基选自：氘、卤素、-OH、-NH 2和-CN；
    优选R 2、R 5、R 6和R 7独立地选自氢、氘、卤素、-OH、-NH 2、C 1-6烷基、-O-C 1-6烷基；
    更优选R 2、R 5或R 7独立地选自氢、氘、卤素、-OH、-NH 2、C 1-6烷基、-O-C 1-6烷基；R 6选自C 1-6烷基；
    最优选R 2、R 5和R 7独立地选自氢或氘，R 6为甲基。
  28. 根据权利要求27所述化合物或其可药用盐，其中，式I化合物选自：
    Figure PCTCN2021141211-appb-100010
    R 18a独立地选自氢、氘、卤素、-OH、-NH 2和任选被一个或多个取代基取代的以下基团：C 1-6烷基、-O-C 1-6烷基、C 3-6环烷基、C 3-6环烷基亚甲基，所述取代基选自：氘、卤素、-OH、-NH 2和-CN；
    优选R 18a独立地选自氢、氘、卤素、-OH、C 1-6烷基、-O-C 1-6烷基、卤代C 1-6烷基、卤代-O-C 1-6烷基；
    更优选R 18a为氢。
  29. 根据权利要求1-6任一所述化合物或其可药用盐，其中，R 6和R 7与其连接的原子一起形成任选被一个或多个取代基取代的5-6元的环烃，所述取代基选自：氘、卤素、C 1-6烷基、-O-C 1-6烷基和C 3-6环烷基，所述C 1-6烷基、-O-C 1-6烷基和C 3-6环烷基任选进一步被一个或多个氘或卤素取代；
    R 2、R 3、R 4和R 5独立地选自氢、氘、卤素、-OH、-NH 2和任选被一个或多个取代基取代的以下基团：C 1-6烷基、-O-C 1-6烷基、-S-C 1-6烷基、C 3-6环烷基、C 3-6环烷基亚甲基，所述取代基选自：氘、卤素、-OH、-NH 2和-CN；
    优选R 2、R 4和R 5独立地选自氢、氘、C 1-6烷基和卤素，R 3选自三氟甲基、环丙基、-S-三氟甲基；
    更优选R 2、R 4和R 5独立地选自氢或氘，R 3选自三氟甲基。
  30. 根据权利要求29所述化合物或其可药用盐，其中，式I化合物选自：
    Figure PCTCN2021141211-appb-100011
  31. 根据权利要求30所述化合物或其可药用盐，其中，式I化合物选自式VII-a、VII-b、VII-c、VII-g、VII-h和VII-i化合物；优选自式VII-a、VII-b、VII-g和VII-h化合物；更优选为式VII-a或VII-g化合物；最优选为式VII-g化合物。
  32. 根据权利要求1-6任一所述化合物或其可药用盐，其中，R 6和R 7与其连接的原子一起形成任选被一个或多个取代基取代的5-6元的杂环，所述取代基选自： 氘、卤素、氧代、C 1-6烷基、-O-C 1-6烷基和C 3-6环烷基，所述C 1-6烷基、-O-C 1-6烷基和C 3-6环烷基任选进一步被一个或多个氘或卤素取代；
    优选所述5-6元的杂环含1-2个选自氧原子或氮原子的杂原子；更优选所述5-6元的杂环含1氧原子；
    R 2、R 3、R 4和R 5独立地选自氢、氘、卤素、-OH、-NH 2和任选被一个或多个取代基取代的以下基团：C 1-6烷基、-O-C 1-6烷基、-S-C 1-6烷基、C 3-6环烷基、C 3-6环烷基亚甲基，所述取代基选自：氘、卤素、-OH、-NH 2和-CN。
  33. 根据权利要求32所述化合物或其可药用盐，其中，式I化合物选自：
    Figure PCTCN2021141211-appb-100012
    R 9f独立地选自氘、卤素、氧代、C 1-6烷基、-O-C 1-6烷基和C 3-6环烷基，所述C 1-6烷基、-O-C 1-6烷基和C 3-6环烷基任选进一步被一个或多个氘或卤素取代；
    R 9g选自氢、氘、C 1-6烷基和C 3-6环烷基，所述C 1-6烷基和C 3-6环烷基任选进一步被一个或多个氘或卤素取代；r为选自0-6的整数。
  34. 根据权利要求33所述化合物或其可药用盐，其中，式I化合物选自：
    Figure PCTCN2021141211-appb-100013
  35. 根据权利要求34所述化合物或其可药用盐，其中，式I化合物选自式VIII’-a、VIII’-c、VIII’-d、VIII’-f、VIII’-g、VIII’-j、VIII’-k、VIII’-l和VIII’-m化合物；优选自式VIII’-a、VIII’-c、VIII’-d、VIII’-f、VIII’-g、VIII’-j和VIII’-l化合物；更优选自式VIII’-a、VIII’-c、VIII’-d和VIII’-j化合物；最优选为式VIII’-a或VIII’-d化合物。
  36. 根据权利要求1-6任一所述化合物或其可药用盐，其中，R 6和R 7与其连接的原子一起形成任选被一个或多个取代基取代的苯环，所述取代基选自：氘、卤素、氧代、C 1-6烷基、-O-C 1-6烷基和C 3-6环烷基，所述C 1-6烷基、-O-C 1-6烷基和 C 3-6环烷基任选进一步被一个或多个氘或卤素取代；
    R 2、R 3、R 4和R 5独立地选自氢、氘、卤素、-OH、-NH 2和任选被一个或多个取代基取代的以下基团：C 1-6烷基、-O-C 1-6烷基、-S-C 1-6烷基、C 3-6环烷基、C 3-6环烷基亚甲基，所述取代基选自：氘、卤素、-OH、-NH 2和-CN。
  37. 根据权利要求36所述化合物或其可药用盐，其中，式I化合物选自：
    Figure PCTCN2021141211-appb-100014
    R 9k独立地选自氘、卤素、氧代、C 1-6烷基、-O-C 1-6烷基和C 3-6环烷基，所述C 1-6烷基、-O-C 1-6烷基和C 3-6环烷基任选进一步被一个或多个氘或卤素取代；
    优选R 9k独立地选自氘、卤素、氧代、卤代C 1-6烷基、卤代-O-C 1-6烷基；更优选R 9k独立地选自氘、卤素、C 1-6烷基、-O-C 1-6烷基。
  38. 根据权利要求29-37任一所述化合物或其可药用盐，其中，R 2、R 3、R 4和R 5独立地选自氢、氘、卤素和任选被一个或多个取代基取代的以下基团：C 1-6烷基、C 3-6环烷基和C 3-6环烷基亚甲基，所述取代基为氘或卤素；
    优选R 2和R 4独立地选自氢、氘和卤素，R 3和R 5独立地选自氢、氘、卤素和任选被一个或多个氘或卤素取代的C 1-6烷基。
  39. 根据权利要求38所述化合物或其可药用盐，其中，R 2和R 4分别为氢，R 3为三氟甲基或氯，R 5为氢、卤素或甲基；优选R 2、R 4和R 5分别为氢，R 3为三氟甲基。
  40. 根据权利要求1-6任一所述化合物或其可药用盐，其中，R 6和R 7与其连接的原子一起形成任选被一个或多个取代基取代的5-6元杂芳基，所述取代基选自：氘、卤素、氧代、C 1-6烷基、-O-C 1-6烷基和C 3-6环烷基，所述C 1-6烷基、-O-C 1-6烷基和C 3-6环烷基任选进一步被一个或多个选自氘或卤素的取代基所取代；优选所述的5-6元杂芳基为吡啶；
    R 2、R 3、R 4和R 5独立地选自氢、氘、卤素、-OH、-NH 2和任选被一个或多个取代基取代的以下基团：C 1-6烷基、-O-C 1-6烷基、-S-C 1-6烷基、C 3-6环烷基、C 3-6环烷基亚甲基，所述取代基选自：氘、卤素、-OH、-NH 2和-CN。
  41. 根据权利要求40所述化合物或其可药用盐，其中，R 6和R 7与其连接的原子一起形成任选被一个或多个取代基取代的包含1-2个杂原子的5-6元的杂芳基，所述取代基选自：氘、卤素、C 1-6烷基、-O-C 1-6烷基和C 3-6环烷基，所述C 1-6烷基、-O-C 1-6烷基和C 3-6环烷基任选进一步被一个或多个氘或卤素取代；所述杂原子选自氧原子、氮原子、硫原子，优选所述杂原子选自氮原子。
  42. 根据权利要求40所述化合物或其可药用盐，其中，式I化合物选自：
    Figure PCTCN2021141211-appb-100015
    所述X选自氧原子或硫原子；所述R 18c选自氘、卤素、C 1-6烷基、-O-C 1-6烷基和C 3-6环烷基，所述C 1-6烷基、-O-C 1-6烷基和C 3-6环烷基任选进一步被一个或多个卤素取代；优选R 18c独立地选自氘、卤素、C 1-6烷基、-O-C 1-6烷基；更优选R 18c为氢；
    a选自0-3的整数；优选a选自0-1的整数；更优选a为0；
    Z、R 2、R 3、R 4、R 5、R 8如权利要求1中定义。
  43. 根据权利要求40-42任一所述化合物或其可药用盐，其中，R 2、R 3、R 4和R 5独立地选自氢、氘、卤素和任选被一个或多个取代基取代的以下基团：C 1-6烷基、C 3-6环烷基和C 3-6环烷基亚甲基，所述取代基为氘或卤素；
    优选R 2和R 4独立地选自氢、氘和卤素，R 3和R 5独立地选自氢、氘、卤素和 任选被一个或多个氘或卤素取代的C 1-6烷基。
  44. 根据权利要求40-42任一所述化合物或其可药用盐，其中，R 2和R 4分别为氢，R 3为三氟甲基或氯，R 5为氢或甲基；优选R 2、R 4和R 5分别为氢，R 3为三氟甲基。
  45. 式I’化合物或其可药用盐，
    Figure PCTCN2021141211-appb-100016
    其中，R 11选自-OH、-NH 2、-CN、-O-C 1-6烷基、-C 1-6烷基-OH或-NHC(＝O)-C 1-6烷基，所述C 1-6烷基任选被一个或多个选自如下的取代基取代：氘、卤素、-OH、-NH 2和-CN；优选R 11为-OH或卤代C 1-6烷基；更优选R 11为-OH或二氟甲基；最优选R 11为-OH；
    R 13选自任选被一个或多个取代基取代的以下基团：C 2-6烷基、-S-C 1-6烷基和C 3-6环烷基，所述取代基选自氘、卤素和-OH；
    R 15、R 16和R 17独立地选自氢、氘、卤素、-OH、-NH 2和C 1-6烷基，所述C 1-6烷基任选被一个或多个选自如下的取代基取代：氘、卤素、-OH、-NH 2和-CN；
    Z为O或-NH-(CH2)n-，n为选自0-3的整数；
    R 8选自任选被一个或多个取代基取代的芳基、杂芳基、杂环基、C 3-8环烷基、C 1-6烷基或-O-C 1-6烷基，所述取代基选自氘、卤素、氧代、-OR 8a、-SR 8a、-C(＝O)R 8a、-OC(＝O)R 8a、-C(＝O)OR 8a、-C(＝O)NR 8aR 8b、-NR 8aR 8b、-NR 8aC(＝O)R 8b、-NR 8aS(＝O) 2R 8b、-S(＝O) 2R 8a、-S(＝O) 2NR 8aR 8b、-CN、-NO 2、C 1-4烷基或C 3-6环烷基，所述C 1-4烷基或C 3-6环烷基任选进一步被一个或多个的氘、卤素或-OH取代；
    R 8a和R 8b独立地选自氢、氘或任选被一个或多个取代基取代的以下基团：C 1-4烷基、C 3-6环烷基、C 3-6环烷基亚甲基，所述取代基选自：氘、卤素、-NH 2、-OH、-CN、C 1-4烷基、C 1-4烷氧基、C 3-6环烷基或C 3-6环烷基亚甲基，上述取代基任选进一步被一个或多个的氘或卤素取代。
  46. 根据权利要求45所述化合物或其可药用盐，其中，R 13选自乙基、正丙基、异丙基和正丁基，优选为乙基；
    或R 13为-S-CF 3。
  47. 根据权利要求45所述化合物或其可药用盐，其中，R 13选自：
    Figure PCTCN2021141211-appb-100017
    Figure PCTCN2021141211-appb-100018
    优选
    Figure PCTCN2021141211-appb-100019
    更优选
    Figure PCTCN2021141211-appb-100020
    Figure PCTCN2021141211-appb-100021
    最优选为
    Figure PCTCN2021141211-appb-100022
  48. 根据权利要求45-47任一所述化合物或其可药用盐，其中，R 15、R 16和R 17独立地选自氢、氘、氟和甲基。
  49. 根据权利要求1-48任一所述化合物或其可药用盐，其中，Z为O。
  50. 根据权利要求1-48任一所述化合物或其可药用盐，其中，Z为-NH-(CH2)n-，n为选自0-2的整数；n优选为0或1；n更优选为0。
  51. 根据权利要求1-50任一所述化合物或其可药用盐，其中，R 8选自任选被一个或多个取代基取代的5-10元杂环基，所述取代基选自氘、卤素、氧代、-OR 8a、-SR 8a、-C(＝O)R 8a、-OC(＝O)R 8a、-C(＝O)OR 8a、-C(＝O)NR 8aR 8b、-NR 8aR 8b、-NR 8aC(＝O)R 8b、-NR 8aS(＝O) 2R 8b、-S(＝O) 2R 8a、-S(＝O) 2NR 8aR 8b、-CN、-NO 2、C 1-4烷基和C 3-6环烷基，所述C 1-4烷基或C 3-6环烷基任选进一步被一个或多个的氘、卤素或-OH取代；
    R 8a和R 8b独立地选自氢、氘和任选被一个或多个取代基取代的以下基团：C 1-4烷基、C 3-6环烷基和C 3-6环烷基亚甲基，所述取代基选自：氘、卤素、-NH 2、-OH、-CN、C 1-4烷基、C 1-4烷氧基、C 3-6环烷基或C 3-6环烷基亚甲基，上述取代基任选进一步被一个或多个的氘或卤素取代。
  52. 根据权利要求51所述化合物或其可药用盐，其中，R 8选自：
    Figure PCTCN2021141211-appb-100023
    R 10a选自氢、氘、卤素、氧代、-OH、-NH 2、-COOH、-CN、C 1-4烷基和C 3-6环烷基，所述C 1-4烷基或C 3-6环烷基任选进一步被一个或多个的氘、卤素或-OH取代；
    R 10b选自氢、氘、C 1-4烷基和C 3-6环烷基，所述C 1-4烷基和C 3-6环烷基任选进一步被一个或多个氘或卤素取代；s为选自0-15的整数。
  53. 根据权利要求52所述化合物或其可药用盐，其中，R 8选自：
    Figure PCTCN2021141211-appb-100024
    Figure PCTCN2021141211-appb-100025
    优选
    Figure PCTCN2021141211-appb-100026
    Figure PCTCN2021141211-appb-100027
    更优选为
    Figure PCTCN2021141211-appb-100028
    最优选为
    Figure PCTCN2021141211-appb-100029
  54. 根据权利要求53所述化合物或其可药用盐，其中，R 8为
    Figure PCTCN2021141211-appb-100030
    优选为
    Figure PCTCN2021141211-appb-100031
  55. 根据权利要求1-50任一所述化合物或其可药用盐，其中，R 8选自任选被一个或多个取代基取代的C 3-8环烷基，所述取代基选自氘、卤素、-OH、-NH 2、-CN和C 1-4烷基，所述C 1-4烷基任选进一步被一个或多个的氘、卤素或-OH取代。
  56. 根据权利要求54所述化合物或其可药用盐，其中，R 8选自：
    Figure PCTCN2021141211-appb-100032
    R 10e、R 10f、R 10e’、R 10f’独立地选自氢、氘、卤素、-OH和C 1-4烷基，所述C 1-4烷基任选进一步被一个或多个的氘、卤素或-OH取代；
    优选R 8选自：
    Figure PCTCN2021141211-appb-100033
    R 10e、R 10e’独立地选自氢、氘、卤素、-OH和C 1-4烷基，所述C 1-4烷基任选进一步被一个或多个的氘、卤素或-OH取代。
  57. 根据权利要求54所述化合物或其可药用盐，其中，R 8选自：
    Figure PCTCN2021141211-appb-100034
    优选
    Figure PCTCN2021141211-appb-100035
    更优选为
    Figure PCTCN2021141211-appb-100036
  58. 根据权利要求1-50中任一项所述化合物或其可药用盐，其中，R 8选自：
    Figure PCTCN2021141211-appb-100037
    R 10g选自氢、氘、卤素、-NH 2、-OH、-CN、-NH-C 1-4烷基和-N(C 1-4烷基) 2，所述C 1-4烷基任选被一个或多个的氘、卤素或-OH取代。
  59. 式I所示化合物或其可药用盐，其选自：
    Figure PCTCN2021141211-appb-100038
    Figure PCTCN2021141211-appb-100039
    Figure PCTCN2021141211-appb-100040
    Figure PCTCN2021141211-appb-100041
  60. 一种根据权利要求1-58中任一项所示的化合物的同位素取代物，优选地，所述的同位素取代为氘原子取代。
  61. 一种药物组合物，包含权利要求1-58所述的化合物或其可药用盐或权利要求59所述的同位素取代物，和至少一种药学上可接受的载体、稀释剂或者赋形剂。
  62. 权利要求1-58所述的化合物或其可药用盐，权利要求59所述的同位素取代物，或权利要求60所述的药物组合物在制备治疗与NLRP3活性相关的疾病的药物中的用途。
  63. 权利要求1-58所述的化合物或其可药用盐，权利要求59所述的同位素取代物，或权利要求60所述的药物组合物在制备治疗炎性体相关疾病、免疫性疾病、炎症性疾病、自身免疫性疾病和/或自身炎症性疾病的药物中的用途。
  64. 一种化合物
    Figure PCTCN2021141211-appb-100042
    Y选自氟、氯、溴和碘；优选Y选自氟、氯和溴；更优选Y选自氯；
    R 6、R 7、Z、R 8如权利要求1中所定义。
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DATABASE REGISTRY 4 May 2007 (2007-05-04), ANONYMOUS: "/1 -(C) FILE REGISTRY RN -934264-83-2 REGISTRY ED -Entered STN: 04 May 2007 CN -1-Phthalazinamine, 7-methoxy-4-(4-methoxyphenyl)-N-4-piperidinyl- (CA INDEX NAME)", XP055946367, retrieved from STN Database accession no. 934264-83-2 *
DATABASE REGISTRY 5 December 2013 (2013-12-05), ANONYMOUS: "RN 1488322-94-6", XP055945954, retrieved from STN Database accession no. 1488322-94-6 *
DATABASE REGISTRY 6 September 2002 (2002-09-06), ANONYMOUS: "/1 -(C) FILE REGISTRY RN -447431-24-5 REGISTRY ED -Entered STN: 06 Sep 2002 CN -1-Phthalazinamine, N,4-bis(4-fluorophenyl)- (CA INDEX NAME)", XP055946297, retrieved from STN Database accession no. 447431-24-5 *
DATABASE REGISTRY 7 February 2003 (2003-02-07), ANONYMOUS: "/1 -(C) FILE REGISTRY RN -487025-40-1 REGISTRY ED -Entered STN: 07 Feb 2003 CN -Benzamide, 4-[[4-(4-hydroxyphenyl)-1-phthalazinyl]amino]- (CA INDEX NAME)", XP055946369, retrieved from STN Database accession no. 487025-40-1 *

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WO2023275366A1 (en) * 2021-07-02 2023-01-05 Astrazeneca Ab Nlrp3 inflammasome inhibitors
US11970463B2 (en) 2021-07-02 2024-04-30 Astrazeneca Ab Compounds and their use
WO2023003002A1 (ja) * 2021-07-21 2023-01-26 アステラス製薬株式会社 縮環ピリダジン化合物
WO2023028534A1 (en) * 2021-08-25 2023-03-02 Ptc Therapeutics, Inc. Inhibitors of nlrp3
WO2023051761A1 (zh) * 2021-09-30 2023-04-06 成都奥睿药业有限公司 一类取代杂芳酞嗪衍生物的药学用途及其制备方法
WO2023066377A1 (zh) * 2021-10-22 2023-04-27 索智生物科技（浙江）有限公司 一种含氮化合物、其制备方法及应用
US11618751B1 (en) 2022-03-25 2023-04-04 Ventus Therapeutics U.S., Inc. Pyrido-[3,4-d]pyridazine amine derivatives useful as NLRP3 derivatives
WO2023186020A1 (en) * 2022-03-31 2023-10-05 Hangzhou Highlightll Pharmaceutical Co., Ltd Nlrp3 inflammasome inhibitors
WO2023194964A1 (en) * 2022-04-07 2023-10-12 Takeda Pharmaceutical Company Limited Fused pyridazine derivatives as nlrp3 inhibitors
WO2024006559A1 (en) * 2022-07-01 2024-01-04 Neumora Therapeutics, Inc. Modulators of nlrp3 inflammasome and related products and methods
WO2024012551A1 (zh) * 2022-07-14 2024-01-18 南京明德新药研发有限公司 氘取代的哒嗪苯并噻吩化合物及其应用
WO2024013395A1 (en) * 2022-07-14 2024-01-18 Ac Immune Sa Pyrrolotriazine and imidazotriazine derivatives as modulators of the nlrp3 inflammasome pathway
WO2024027723A1 (zh) * 2022-08-01 2024-02-08 南京明德新药研发有限公司 哒嗪类化合物的晶型、盐型、组合物及其制备方法
WO2024028782A1 (en) 2022-08-03 2024-02-08 Novartis Ag Nlrp3 inflammasome inhibitors
CN116789674A (zh) * 2022-08-24 2023-09-22 杭州高光制药有限公司 Nlrp3炎性小体抑制剂
CN116789674B (zh) * 2022-08-24 2024-05-24 杭州高光制药有限公司 Nlrp3炎性小体抑制剂
WO2024090469A1 (ja) * 2022-10-26 2024-05-02 アステラス製薬株式会社 縮環ピリダジン誘導体

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