WO2024169895A1 - 一种抑制nlrp3的化合物及制备方法和应用 - Google Patents

一种抑制nlrp3的化合物及制备方法和应用 Download PDF

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WO2024169895A1
WO2024169895A1 PCT/CN2024/076764 CN2024076764W WO2024169895A1 WO 2024169895 A1 WO2024169895 A1 WO 2024169895A1 CN 2024076764 W CN2024076764 W CN 2024076764W WO 2024169895 A1 WO2024169895 A1 WO 2024169895A1
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alkyl
membered
group
cycloalkyl
deuterium
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French (fr)
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杜鑫明
马君君
陈道兴
王绍晖
陈斌
张佩宇
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Shenzhen Zhongge Biological Technology Co Ltd
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Shenzhen Zhongge Biological Technology Co Ltd
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Priority to JP2025547508A priority patent/JP2026508178A/ja
Priority to EP24756268.9A priority patent/EP4667468A1/en
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    • A—HUMAN NECESSITIES
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    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
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    • A—HUMAN NECESSITIES
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    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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    • C—CHEMISTRY; METALLURGY
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D237/00—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings
    • C07D237/26—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings condensed with carbocyclic rings or ring systems
    • C07D237/28—Cinnolines
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    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
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    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
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    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/04—Ortho-condensed systems
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    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Definitions

  • the present invention relates to a compound for inhibiting NLRP3, and a preparation method and application thereof.
  • the NLRP3 inflammasome is a multi-protein polymer complex composed of NLRP3, apoptosis-associated speck-like protein containing a CARD (ASC) and caspase-1 precursor.
  • the activation of the NLRP3 inflammasome requires two steps, namely initiation (first signal) and activation (second signal).
  • first signal activates the nuclear transcription factor NF- ⁇ B, which in turn upregulates the transcription of inflammasome-related components, including inactive NLRP3 and IL-1 ⁇ precursor.
  • the second signal promotes the conversion of inactive NLRP3 to activated NLRP3.
  • ASC and pro-caspase-1 are recruited to form the inflammasome.
  • the inflammasome promotes the self-cleavage of pro-caspase-1 into the activated form of Caspase-1.
  • Caspase-1 induces Gasdermin D (GSDMD) to cut and further form holes in the cell membrane, triggering cell death, namely pyroptosis.
  • GDMD Gasdermin D
  • Caspase-1 induces cell pyroptosis while promoting the secretion of IL-1 ⁇ and IL-18, regulating the body's inflammatory response.
  • NLRP3 inflammasome can lead to the occurrence of a variety of diseases, such as the hereditary diseases Cryopyrin-associated periodic syndrome (CAPS) caused by NLRP3 acquired mutations, familial cold autoinflammatory syndrome (FCAS), Muckle-Wells syndrome, and neonatal-onset multisystem inflammatory disease (NOMID).
  • CPS hereditary diseases Cryopyrin-associated periodic syndrome
  • FCAS familial cold autoinflammatory syndrome
  • NOMID neonatal-onset multisystem inflammatory disease
  • NLRP3 inflammasomes are also involved in the occurrence of a variety of complex diseases, such as diseases of the central nervous system (Alzheimer's disease, brain infection, multiple sclerosis, amyotrophic lateral sclerosis and Parkinson's disease), lung diseases (asthma, idiopathic pulmonary fibrosis); metabolic disorders (type II diabetes and related complications, atherosclerosis, obesity and gout), liver diseases (chronic liver disease, non-alcoholic steatohepatitis, viral hepatitis and cirrhosis), kidney diseases (acute and chronic kidney injury), inflammatory bowel disease (IBD), other autoimmune diseases (rheumatoid arthritis, suppurative hidradenitis, systemic lupus erythematosus) and tumors (colorectal cancer, lung cancer, myeloproliferative neoplasms, leukemia, myelodysplastic syndrome (MDS), myelofibrosis). Therefore,
  • the present invention provides a compound with a bicyclic fused ring mother core as an NLRP3 inhibitor, and the compound provided by the present invention has better drugability.
  • the present invention provides a compound of formula I, or an enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, nitrogen oxide, metabolite, or a pharmaceutically acceptable salt, ester, solvate, hydrate, isotope-labeled compound (preferably a deuterated compound), or prodrug thereof;
  • Ring A and Ring B are each independently selected from: 5-6 membered heteroaryl, 5-6 membered heterocyclyl, phenyl;
  • Ring C is selected from: 6-10 membered aryl, 5-10 membered heteroaryl, phenyl and 4-7 membered cycloalkyl, phenyl and 4-7 membered heterocyclyl, 5-6 membered heteroaryl and 4-7 membered cycloalkyl, 5-6 membered heteroaryl and 4-7 membered heterocyclyl, 4-7 membered cycloalkyl, 4-7 membered heterocyclyl;
  • each R c is independently selected from the group consisting of hydrogen, deuterium, halogen, hydroxy, amino, cyano, C 1-6 alkoxy, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 haloalkoxy, hydroxyC 1-6 alkyl, C 1-6 alkoxy-C 1-6 alkyl, R c1 S(O) 2 -, -(CH 2 ) s -N(R c1 )(R c2 ), 3-6 membered cycloalkyl, 3-6 membered heterocyclyl, phenyl, one or more halogen-substituted phenyl or one or more hydroxy-substituted phenyl, 5-6 membered heteroaryl, wherein the 3-6 membered cycloalkyl, 3-6 membered heterocyclyl, phenyl, 5-6 membered heteroaryl are optionally substituted with 1, 2 or 3 substituents selected from the group consisting of
  • two R c may form together with the C atom to which they are attached a 3-6 membered cycloalkyl, a 4-7 membered heterocyclyl, a 6 membered aryl or a 5-6 membered heteroaryl, wherein the 3-6 membered cycloalkyl, the 4-7 membered heterocyclyl, the 6 membered aryl or the 5-6 membered heteroaryl may be optionally substituted with 1, 2 or 3 substituents selected from deuterium, halogen, hydroxyl, amino, cyano, C 1-6 alkoxy, C 1-6 alkyl, C 1-6 haloalkyl;
  • L 2 is selected from the group consisting of bonds, -NR 6 -, -O-, -S-, -NR 6 -(CR 7 R 8 ) b -, -(CR 7 R 8 ) b -NR 6 -, -O-(CR 7 R 8 ) b -, -(CR 7 R 8 ) b -O-, -S-(CR 7 R 8 ) b -, -(CR 7 R 8 ) b -S-;
  • R 2 , R 5 , R 6 , R 9 and R 10 is independently selected from the group consisting of hydrogen, deuterium, C 1-6 alkyl;
  • R 3 , R 4 , R 7 and R 8 is independently selected from the group consisting of hydrogen, deuterium, halogen, oxo, hydroxyl, amino, C 1-6 alkyl;
  • R c1 and R c2 are independently selected from: hydrogen, C 1-6 alkyl, C 1-6 haloalkoxy, C 3-6 cycloalkyl or 4-7 membered heterocyclyl;
  • R c3 is selected from hydrogen, deuterium, C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, wherein the C 1-6 alkyl and C 3-6 cycloalkyl are arbitrarily substituted with 1, 2 or 3 substituents selected from deuterium, halogen, hydroxy, amino, cyano, oxo, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 1-6 alkoxy-C 1-6 alkyl, -NH(C 1-6 alkyl), -N(C 1-6 alkyl)(C 1-6 alkyl);
  • R c4 is selected from hydrogen, deuterium, C 1-6 alkyl
  • Rc5 and Rc6 are selected from hydrogen, deuterium, C1-6 alkyl, C3-6 cycloalkyl, or Rc5 and Rc6 together with the nitrogen atom to which they are attached form a 4-6 membered heterocyclic group, wherein the C1-6 alkyl, C3-6 cycloalkyl and 4-6 membered heterocyclic group are arbitrarily substituted with 1, 2 or 3 substituents selected from deuterium, halogen, hydroxyl, amino, cyano, oxo, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C1-6 haloalkoxy, C1-6 alkoxy- C1-6 alkyl, -NH( C1-6 alkyl), -N( C1-6 alkyl)( C1-6 alkyl);
  • R c7 and R c8 are selected from hydrogen, deuterium, C 1-6 alkyl, or R c7 and R c8 together with the C atom to which they are attached form a 3-6 membered cycloalkyl;
  • R c9 is selected from 3-6 membered heterocyclic groups, wherein the heterocyclic groups are optionally substituted by 1, 2 or 3 groups selected from hydrogen, deuterium and C 1-6 alkyl;
  • R 11 is selected from the group consisting of: hydrogen, deuterium, C 1-6 alkyl, 3-6 membered monocyclic heterocyclic group;
  • each a and b are independently 1, 2, 3 or 4;
  • Each s, n, m and p are independently selected from: 0, 1, 2, 3 or 4;
  • the condition is Not hydrogen, C 1-6 alkyl.
  • the groups involved in Ring A and Ring B Selected from the following groups:
  • Each of M 1 , M 2 , M 3 , M 4 , U 1 , and U 2 is independently selected from: CH, N;
  • Each of U 3 , U 4 , U 5 and U 6 is independently selected from the group consisting of CH 2 , NH, O and S.
  • the groups involved in Ring A and Ring B Selected from the following groups:
  • Each of M 1 , M 2 , M 3 , M 4 , U 1 , and U 2 is independently selected from: CH, N;
  • Each of U 3 , U 4 , U 5 and U 6 is independently selected from the group consisting of CH 2 , NH, O and S.
  • the groups involved in Ring A and Ring B Selected from the following groups:
  • Each of M 1 , M 2 , M 3 , M 4 , M 5 , M 6 , U 1 , and U 2 is independently selected from: CH, N;
  • Each of U 3 , U 4 , U 5 and U 6 is independently selected from the group consisting of CH 2 , NH, O and S.
  • the compounds of the present invention have a structure shown in Formula VIII-3 or VIII-4:
  • R 1 is not the following group:
  • R1 is not the following group:
  • R 1 is not the following group:
  • the groups involved in Ring A and Ring B Selected from the following groups, wherein the following bicyclic groups represent ring A and ring B from left to right or represent ring A and ring B from right to left:
  • Rab are each independently selected from the group consisting of hydrogen, deuterium, halogen, hydroxyl, amino, cyano, oxo, methyl, ethyl, propyl, isopropyl, and butyl;
  • k is independently selected from: 0, 1, 2, 3 or 4.
  • the groups involved in Ring A and Ring B Selected from the following groups, wherein the following bicyclic groups represent ring A and ring B from left to right or represent ring A and ring B from right to left:
  • Rab are each independently selected from the group consisting of hydrogen, deuterium, halogen, hydroxyl, amino, cyano, oxo, methyl, ethyl, propyl, isopropyl, and butyl;
  • k is independently selected from: 0, 1, 2, 3 or 4.
  • the groups involved in Ring A and Ring B Selected from the following groups, wherein the following bicyclic groups represent ring A and ring B from left to right or represent ring A and ring B from right to left:
  • the groups involved in Ring A and Ring B Selected from the following groups, wherein the following bicyclic groups represent ring A and ring B from left to right or represent ring A and ring B from right to left:
  • Ring C is selected from: 6-10 membered aryl, 5-6 membered heteroaryl, phenyl and 5-6 membered heteroaryl, phenyl and 4-6 membered cycloalkyl, phenyl and 4-6 membered heterocyclyl, 5-6 membered heteroaryl and 5-6 membered heteroaryl, 5-6 membered heteroaryl and 4-6 membered cycloalkyl, 5-6 membered heteroaryl and 4-6 membered heterocyclyl, 5-6 membered cycloalkyl, 5-6 membered heterocyclyl.
  • ring C is selected from: 6-10 membered aryl, 5-6 membered heteroaryl, phenyl 5-6 membered heteroaryl, phenyl 4-6 membered cycloalkyl, phenyl 4-6 membered heterocyclyl, nitrogen-containing 6 membered heteroaryl and 5-6 membered heteroaryl, nitrogen-containing 6 membered heteroaryl and 4-6 membered cycloalkyl, nitrogen-containing 6 membered heteroaryl and 4-6 membered heterocyclyl, 5-6 membered cycloalkyl, 5-6 membered heterocyclyl.
  • the group involved in ring C Selected from the following groups:
  • ring C1 and C2 are each independently selected from: phenyl, 5-membered heteroaryl, 6-membered heteroaryl, 4-membered heterocyclyl, 5-membered heterocyclyl, 6-membered heterocyclyl, 4-membered cycloalkyl, 5-membered cycloalkyl, 6-membered cycloalkyl; preferably, ring C1 and C2 are each independently selected from: phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyrrolyl, furanyl, thienyl, imidazolyl, oxazolyl, thiazolyl, triazolyl, 2,3-dihydrofuranyl, 2,3-dihydrothienyl, 2,3-dihydropyrrolyl, 2,3-dihydrodioxinyl, cyclobutyl, cyclopentyl, cyclohexyl;
  • E 1 , E 2 , E 3 , E 4 and E 5 are each independently selected from the group consisting of CH 2 , O, S and NH, provided that at least one of E 1 , E 2 , E 3 , E 4 and E 5 is NH and together they form a stable ring.
  • the group involved in ring C Selected from the following groups:
  • R c and n have the definitions described in the present invention.
  • the group involved in ring C Selected from the following groups:
  • each Ra and Rb is independently selected from the group consisting of hydrogen, deuterium, fluorine, chlorine, bromine, hydroxyl, amino, cyano, oxo, methyl, ethyl, trifluoromethyl, methoxy, n-propyl, isopropyl, dimethylamino, and acetyl.
  • each R c is independently selected from: hydrogen, deuterium, fluorine, chlorine, bromine, hydroxyl, amino, cyano, C 1-4 alkoxy, C 1-4 haloalkoxy, C 1-4 alkyl, C 1-4 haloalkyl, hydroxyC 1-4 alkyl, C 1-4 alkoxy-C 1-2 alkyl, R c1 S(O) 2 -, -(CH 2 ) s -N(R c1 )(R c2 ), 3-6 membered cycloalkyl, 3-6 membered heterocyclyl, phenyl, wherein the phenyl is optionally substituted with 1, 2, or 3 substituents selected from deuterium, halogen, hydroxyl, amino, cyano, C 1-6 alkyl, C 1-6 haloalkyl, and C 1-6 alkoxy;
  • two R c may form together with the C atom to which they are attached a 3-6 membered cycloalkyl, a 4-7 membered heterocyclyl, a 6 membered aryl or a 5-6 membered heteroaryl, wherein the 3-6 membered cycloalkyl, the 4-7 membered heterocyclyl, the 6 membered aryl or the 5-6 membered heteroaryl may be optionally substituted with 1, 2 or 3 substituents selected from deuterium, halogen, hydroxyl, amino, cyano, C 1-6 alkoxy, C 1-6 alkyl, C 1-6 haloalkyl;
  • each R c is independently selected from: hydrogen, deuterium, fluorine, chlorine, bromine, hydroxyl, amino, cyano, C 1-4 alkoxy, C 1-4 haloalkoxy, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 hydroxyalkyl, C 1-4 alkoxy-C 1-2 alkyl, -(CH 2 ) s -N(R c1 )(R c2 ), 3-6 membered cycloalkyl, 3-6 membered heterocyclyl, phenyl, phenyl substituted with one or more halogens, or phenyl substituted with one or more hydroxyl groups; or, two R c can be taken together with the C atom to which they are attached to form a 3-6 membered cycloalkyl, 4-7 membered heterocyclyl, 6 membered aryl, or 5-6 membered heteroaryl, and the 3-6 membered cycloal
  • each R c is independently selected from: fluoro, chloro, bromo, hydroxy, amino, cyano, methoxy, ethoxy, isopropoxy, methylamino, ethylamino, isopropylamino, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, trifluoromethyl, difluoromethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, trifluoromethoxy, difluoromethoxy, hydroxymethyl, aminoethyl, methoxymethyl, methoxyethyl, ethoxymethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentenyl, cyclobutenyl, cyclohexenyl, oxetanyl, phenyl, 4-chloro-phen
  • R 2 , R 5 and R 6 is independently selected from the group consisting of hydrogen, deuterium, methyl, ethyl, propyl, isopropyl;
  • R 3 , R 4 , R 7 and R 8 is independently selected from the group consisting of hydrogen, deuterium, oxo, hydroxy, amino, methyl, ethyl, propyl, isopropyl;
  • Each a and b is independently 1 or 2.
  • L 2 is selected from the group consisting of a bond, -NR 6 -, -NR 6 -(CR 7 R 8 ) b -, -O-, and -S-.
  • each of s, n, m and p is independently selected from: 0, 1, 2 or 3.
  • R 1 is selected from: 3-6 membered cycloalkyl, 3-6 membered monocyclic heterocyclyl or 6-11 membered bicyclic heterocyclyl
  • the 3-6 membered cycloalkyl, 3-6 membered monocyclic heterocyclyl or 6-11 membered bicyclic heterocyclyl is further optionally substituted by 1, 2 or 3 substituents selected from hydrogen, deuterium, halogen, hydroxy, oxo, C
  • R c3 is selected from C 1-6 alkyl, C 3-6 cycloalkyl, and the C 1-6 alkyl and C 3-6 cycloalkyl are further optionally substituted with 1, 2, or 3 substituents selected from deuterium, halogen, hydroxy, amino, cyano, oxo, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 1-6 alkoxy-C 1-6 alkyl, -NH(C 1-6 alkyl), -N(C 1-6 alkyl)(C 1-6 alkyl);
  • Rc5 and Rc6 are selected from H, deuterium, C1-6 alkyl, C3-6 cycloalkyl, and the C1-6 alkyl and C3-6 cycloalkyl are further optionally substituted with 1, 2 or 3 substituents selected from deuterium, halogen, hydroxy, amino, cyano, oxo, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C1-6 haloalkoxy, C1-6 alkoxy- C1-6 alkyl, -NH( C1-6 alkyl), -N( C1-6 alkyl)( C1-6 alkyl).
  • R 1 is selected from: cyclopentane, cyclohexane, azetidine, tetrahydropyrrole, piperidine, morpholine, piperazine
  • R 1 is selected from: tetrahydropyrrole, piperidine, morpholine, piperazine
  • R 1 is selected from:
  • the compounds of the present invention have the structure shown in Formula II;
  • Ring B, Ring C, L 1 , L 2 , Ra , R b , R c , n, m, p, R 1 , M 1 , M 2 , M 3 , and M 4 have the same definitions as described in the present invention.
  • the compounds of the present invention have the structure shown in Formula III;
  • Ring B, L 1 , L 2 , Ra , R b , R c , n, m, p, R 1 , M 1 , M 2 , M 3 and M 4 have the same definitions as described in the present invention.
  • the compounds of the present invention have a structure shown in Formula IV-1, IV-2, IV-3, IV-4, IV-5, IV-6, IV-7, IV-8, IV-9 or IV-10;
  • Ring C, L1 , L2 , Ra , Rb , Rc , n, m, p, R1 , M1 , M2 , M3 , M4 , M5 , M6 , U1 , U3 , U4 and U5 have the same meanings as described in the present invention.
  • the compounds of the present invention have the structure shown in Formula IV-1.
  • the compounds of the present invention have the structure shown in Formula IV-2.
  • the compounds of the present invention have the structure shown in Formula IV-3.
  • the compounds of the present invention have the structure shown in Formula IV-4.
  • the compounds of the present invention have the structure shown in Formula IV-5.
  • the compounds of the present invention have the structure shown in Formula IV-6.
  • the compounds of the present invention have the structure shown in Formula IV-7.
  • the compounds of the present invention have the structure shown in Formula IV-8.
  • the compounds of the present invention have the structure shown in Formula IV-9.
  • the compounds of the present invention have the structure shown in Formula IV-10.
  • the compounds of the present invention have a structure shown in Formula V-1, V-2, V-3, V-4, V-5, V-6, V-7, V-8, V-9 or V-10;
  • L1 , L2 , Ra , Rb , Rc , n, m, p, R1 , M1 , M2 , M3 , M4 , M5 , M6 , U1 , U3 , U4 and U5 have the same definitions as described in the present invention.
  • the compounds of the present invention have the structure shown in Formula V-1.
  • the compounds of the present invention have the structure shown in Formula V-2.
  • the compounds of the present invention have the structure shown in Formula V-3.
  • the compounds of the present invention have the structure shown in Formula V-4.
  • the compounds of the present invention have the structure shown in Formula V-5.
  • the compounds of the present invention have the structure shown in Formula V-6.
  • the compounds of the present invention have the structure shown in Formula V-7.
  • the compounds of the present invention have the structure shown in Formula V-8.
  • the compounds of the present invention have the structure shown in Formula V-9.
  • n1 is 0, 1, 2 or 3
  • L1 , L2 , Ra , Rb , Rc , m, p, R1 , M1 , M2 , M3 , M4 , M5 , M6 , U1 , U3 , U4 and U5 are defined as described herein.
  • the compounds of the present invention have the structure shown in Formula VI-1.
  • the compounds of the present invention have the structure shown in Formula VI-2.
  • the compounds of the present invention have the structure shown in Formula VI-3.
  • the compounds of the present invention have the structure shown in Formula VI-4.
  • the compounds of the present invention have the structure shown in Formula VI-5.
  • the compounds of the present invention have the structure shown in Formula VI-6.
  • the compounds of the present invention have the structure shown in Formula VI-8.
  • the compounds of the present invention have the structure shown in Formula VI-9.
  • the compounds of the present invention have the structure shown in Formula VI-10.
  • the compounds of the present invention have a structure shown in Formula VII-1, VII-2, VII-3, VII-4, VII-5, VII-6, VII-7, VII-8, VII-9 or VII-10;
  • n2 is 0, 1 or 2
  • L1 , L2 , Ra , Rb , Rc , m, p, R1 , M1 , M2 , M3 , M4 , U1 , U3 , U4 and U5 are defined as described in the present invention.
  • the compounds of the present invention have the structure shown in Formula VII-1.
  • the compounds of the present invention have the structure shown in Formula VII-2.
  • the compounds of the present invention have the structure shown in Formula VII-3.
  • the compounds of the present invention have the structure shown in Formula VII-4.
  • the compounds of the present invention have the structure shown in Formula VII-5.
  • the compounds of the present invention have the structure shown in Formula VII-6.
  • the compounds of the present invention have the structure shown in Formula VII-7.
  • the compounds of the present invention have the structure shown in Formula VII-8.
  • the compounds of the present invention have the structure shown in Formula VII-9.
  • the compounds of the present invention have the structure shown in Formula VII-10.
  • the compounds of the present invention have a structure shown in Formula VIII-1, VIII-2, VIII-3, VIII-4, VIII-5, VIII-6, VIII-7, VIII-8, VIII-9, VIII-10, VIII-11 or VIII-12:
  • Ra , Rb , Rc , m, n, p, L1 , L2 and R1 have the same definitions as described in the present invention.
  • the compounds of the present invention have the structure shown in Formula VIII-1.
  • the compounds of the present invention have the structure shown in Formula VIII-2.
  • the compounds of the present invention have the structure shown in Formula VIII-3.
  • the compounds of the present invention have the structure shown in Formula VIII-4.
  • the compounds of the present invention have the structure shown in Formula VIII-5.
  • the compounds of the present invention have the structure shown in Formula VIII-6.
  • the compounds of the present invention have the structure shown in Formula VIII-7.
  • the compounds of the present invention have the structure shown in Formula VIII-8.
  • the compounds of the present invention have the structure shown in Formula VIII-9.
  • the compounds of the present invention have the structure shown in Formula VIII-10.
  • the compounds of the present invention have the structure shown in Formula VIII-11.
  • the compounds of the present invention have the structure shown in Formula VIII-12.
  • the compounds of the present invention have the structure shown in Formula IX-1, IX-2, IX-3, IX-4, IX-5 or IX-6:
  • Ra , Rb , L1 , L2 , R1 , m and p have the same definitions as described in the present invention.
  • the compounds of the present invention have the structure shown in Formula IX-1.
  • the compounds of the present invention have the structure shown in Formula IX-2.
  • the compounds of the present invention have the structure shown in Formula IX-3.
  • the compounds of the present invention have the structure shown in Formula IX-4.
  • the compounds of the present invention have the structure shown in Formula IX-5.
  • the compounds of the present invention have the structure shown in Formula IX-6.
  • the compounds of the present invention have a structure shown in Formula VIII-1 or VIII-2:
  • Each Rcn is independently selected from the group consisting of hydrogen, deuterium, halogen, hydroxy, amino, cyano, C1-6 alkoxy, C1-6 alkyl, C1-6 haloalkyl, C1-6 haloalkoxy, hydroxyC1-6 alkyl, C1-6 alkoxy- C1-6 alkyl, -( CH2 ) s - N ( Rc1 )( Rc2 ), 3-6 membered cycloalkyl, 3-6 membered heterocyclyl, phenyl, 5-6 membered heteroaryl, wherein the 3-6 membered cycloalkyl, 3-6 membered heterocyclyl, phenyl, 5-6 membered heteroaryl
  • the membered heteroaryl is optionally substituted with 1, 2, or 3 substituents selected from deuterium, halogen, hydroxy, amino, cyano, C 1-6 alkyl, C 1-6 haloalkyl, and C 1-6 alkoxy;
  • two Rcn may form together with the C atom to which they are attached a 3-6 membered cycloalkyl, a 4-7 membered heterocyclyl, a 6 membered aryl or a 5-6 membered heteroaryl, wherein the 3-6 membered cycloalkyl, the 4-7 membered heterocyclyl, the 6 membered aryl or the 5-6 membered heteroaryl may be optionally substituted with 1, 2 or 3 substituents selected from deuterium, halogen, hydroxyl, amino, cyano, C1-6 alkoxy, C1-6 alkyl, C1-6 haloalkyl;
  • each R cn is independently selected from: hydrogen, deuterium, halogen, hydroxyl, amino, cyano, C 1-6 alkoxy, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 haloalkoxy, hydroxyC 1-6 alkyl, C 1-6 alkoxy-C 1-6 alkyl, -(CH 2 ) s -N(R c1 )(R c2 ), 3-6 membered cycloalkyl, 3-6 membered heterocyclyl, phenyl, one or more halogen-substituted phenyl or one or more hydroxy-substituted phenyl;
  • two Rcn may form, together with the C atoms to which they are attached, a 3-6 membered cycloalkyl or a 4-7 membered heterocyclyl;
  • L 2 is selected from the group consisting of bonds, -NR 6 -, -O-, -S-, -NR 6 -(CR 7 R 8 ) b -, -(CR 7 R 8 ) b -NR 6 -, -O-(CR 7 R 8 ) b -, -(CR 7 R 8 ) b -O-, -S-(CR 7 R 8 ) b -, -(CR 7 R 8 ) b -S-;
  • R 2 , R 5 , R 6 , R 9 and R 10 is independently selected from the group consisting of hydrogen, deuterium, C 1-6 alkyl;
  • R 3 , R 4 , R 7 and R 8 is independently selected from the group consisting of hydrogen, deuterium, halogen, oxo, hydroxyl, amino, C 1-6 alkyl;
  • R c1 and R c2 are independently selected from: hydrogen, C 1-6 alkyl, C 1-6 haloalkoxy, C 3-6 cycloalkyl or 4-7 membered heterocyclyl;
  • R c3 is selected from hydrogen, deuterium, C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, and the C 3-6 cycloalkyl is further substituted with 1, 2, or 3 substituents selected from deuterium, hydroxyl, halogen, and C 1-6 alkyl;
  • R c4 is selected from hydrogen, deuterium, C 1-6 alkyl
  • Rc5 and Rc6 are selected from hydrogen, deuterium, C1-6 alkyl, C1-6 haloalkyl, C3-6 cycloalkyl, or Rc5 and Rc6 together with the N atom to which they are attached form a 4-6 membered heterocyclic group, and the C3-6 cycloalkyl and 4-6 membered heterocyclic group are further substituted with 1, 2 or 3 substituents selected from deuterium, hydroxyl, halogen, C1-6 alkyl;
  • R 11 is selected from the group consisting of: hydrogen, deuterium, C 1-6 alkyl, 3-6 membered monocyclic heterocyclic group;
  • each a and b are independently 1, 2, 3 or 4;
  • Each m is 0 or 1;
  • Each p is 0, 1 or 2;
  • Each s and n are independently selected from 0, 1, 2, 3 or 4;
  • the compounds of the present invention have the structure shown in Formula VIII-1:
  • Ra and Rb are each independently selected from hydrogen, deuterium, F, Cl, Br, cyano, methyl, ethyl, trifluoromethyl, methoxy, dimethylamino, acetyl; preferably, Ra and Rb are each independently selected from hydrogen, deuterium, F, Cl, Br, methyl, ethyl; more preferably, Ra and Rb are each independently selected from hydrogen, deuterium, methyl.
  • each Rcn is independently selected from: hydrogen, deuterium, fluorine, chlorine, bromine, hydroxyl, amino, cyano, C1-4 alkoxy, C1-4 haloalkoxy, C1-4 alkyl, C1-4 haloalkyl, hydroxylC1-4 alkyl, C1-4 alkoxy- C1-2 alkyl, -(CH2) s -N( Rc1 )( Rc2 ), 3-6 membered cycloalkyl, 3-6 membered heterocyclyl, phenyl, said 3-6 membered cycloalkyl, 3-6 membered heterocyclyl, phenyl is optionally substituted with 1 , 2 , or 3 substituents selected from deuterium, halogen, hydroxyl, amino, cyano, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy ; or, two Rcn may be taken together with the C atom to which they are attached to form a 3-6 membered
  • each Rcn is independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, hydroxyl, amino, cyano, C 1-4 alkoxy, C 1-4 haloalkoxy, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 hydroxyalkyl, C 1-4 alkoxy-C 1-2 alkyl, -(CH 2 ) s -N(R c1 )(R c2 ), 3-6 membered cycloalkyl, 3-6 membered heterocyclyl, phenyl, one or more halogen-substituted phenyl or one or more hydroxy-substituted phenyl, or two R cn may form together with the C atom to which they are attached a 3-6 membered cycloalkyl or a 4-7 membered heterocyclyl;
  • each Rcn is independently selected from: fluoro, chloro, bromo, hydroxy, amino, cyano, methoxy, ethoxy, isopropoxy, methylamino, ethylamino, isopropylamino, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, difluoromethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, trifluoromethoxy, difluoromethoxy, hydroxymethyl, aminoethyl, methoxymethyl, methoxyethyl, ethoxymethyl, cyclopropyl, cyclobutyl, cyclopentyl, oxetanyl, phenyl, 4-chloro-phenyl, 2-chloro-4-fluoro-phenyl, 4-hydroxyphenyl, cyclobutylamino, Alternatively, two Rcn together with the C atom
  • each R cn is independently selected from the group consisting of fluoro, chloro, bromo, hydroxy, methoxy, ethoxy, methyl, ethyl, trifluoromethyl, difluoromethyl, trifluoromethoxy, difluoromethoxy.
  • each R 2 is independently selected from the group consisting of hydrogen, deuterium, and C 1-4 alkyl; each R 3 and R 4 is independently selected from the group consisting of hydrogen, deuterium, halogen, hydroxyl, and C 1-4 alkyl.
  • R 1 is selected from: C 1-3 alkyl, NHR 11 -C( ⁇ O)-, 3-10 membered cycloalkyl, 3-6 membered monocyclic heterocyclyl, 6-11 membered bicyclic heterocyclyl, 6-10 membered aryl, 5-10 membered heteroaryl; wherein the C 1-3 alkyl, 3-10 membered cycloalkyl, 3-6 membered monocyclic heterocyclyl, 6-11 membered bicyclic heterocyclyl, 6-10 membered aryl, 5-10 membered heteroaryl are each independently substituted by 1, 2, or 3 members selected from deuterium, halogen, hydroxyl, oxo, cyano, C 1-6 alkyl, C 1-6 alkoxy, -(CH 2 ) s -O(R c1 ), -(CH 2 ) s -N(R c1 )(R c2 ), C 3-6 cycloalkyl,
  • R 1 is selected from the group consisting of: methyl, isopropyl, pyrrolidine, tetrahydrofuran, tetrahydrothiophene, tetrahydrothiopyran, tetrahydropyran, thietane, oxetane, azetidine, piperidine, morpholine, piperazine, cyclobutane, cyclopentane, cyclohexane, n-heptane, phenyl, pyridine, pyrimidine, pyrrole, imidazole, oxazole, isoxazole, thiazole, pyrazole, furan, triazole, wherein the methyl, isopropyl, pyrrolidine, tetrahydrofuran, tetrahydrothiophene, tetrahydrothiopyran, tetrahydropyran, thietane, o
  • the compounds of the present invention have a structure shown in Formula X-1 or X-2:
  • Ring C is selected from: 6-10 membered aryl, 5-10 membered heteroaryl, phenyl and 4-7 membered cycloalkyl, phenyl and 4-7 membered heterocyclyl, 5-6 membered heteroaryl and 4-7 membered cycloalkyl, 5-6 membered heteroaryl and 4-7 membered heterocyclyl, 4-7 membered cycloalkyl, 4-7 membered heterocyclyl;
  • each R cn is independently selected from the group consisting of hydrogen, deuterium, halogen, hydroxy, amino, cyano, C 1-6 alkoxy, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 haloalkoxy, hydroxyC 1-6 alkyl, C 1-6 alkoxy-C 1-6 alkyl, R c1 S(O) 2 -, -(CH 2 ) s -N(R c1 )(R c2 ), 3-6 membered cycloalkyl, 3-6 membered heterocyclyl, phenyl, 5-6 membered heteroaryl, said 3-6 membered cycloalkyl, 3-6 membered heterocyclyl, phenyl, 5-6 membered heteroaryl are optionally substituted with 1, 2, or 3 substituents selected from the group consisting of deuterium, halogen, hydroxy, amino, cyano, C 1-6 alkyl, C 1-6 haloalkyl,
  • two Rcn may form together with the C atom to which they are attached a 3-6 membered cycloalkyl, a 4-7 membered heterocyclyl, a 6 membered aryl or a 5-6 membered heteroaryl, wherein the 3-6 membered cycloalkyl, the 4-7 membered heterocyclyl, the 6 membered aryl or the 5-6 membered heteroaryl may be optionally substituted with 1, 2 or 3 substituents selected from deuterium, halogen, hydroxyl, amino, cyano, C1-6 alkoxy, C1-6 alkyl, C1-6 haloalkyl;
  • L 2 is selected from the group consisting of bonds, -NR 6 -, -O-, -S-, -NR 6 -(CR 7 R 8 ) b -, -(CR 7 R 8 ) b -NR 6 -, -O-(CR 7 R 8 ) b -, -(CR 7 R 8 ) b -O-, -S-(CR 7 R 8 ) b -, -(CR 7 R 8 ) b -S-;
  • R 2 , R 5 , R 6 , R 9 and R 10 is independently selected from the group consisting of hydrogen, deuterium, C 1-6 alkyl;
  • R 3 , R 4 , R 7 and R 8 is independently selected from the group consisting of hydrogen, deuterium, halogen, oxo, hydroxyl, amino, C 1-6 alkyl;
  • R1 is selected from: 3-10 membered cycloalkyl, 3-6 membered monocyclic heterocyclic group, 6-11 membered bicyclic heterocyclic group, 6-10 membered aryl, 5-10 membered
  • R c1 and R c2 are independently selected from: hydrogen, C 1-6 alkyl, C 1-6 haloalkoxy, C 3-6 cycloalkyl or 4-7 membered heterocyclyl;
  • R c3 is selected from C 1-6 alkyl, C 3-6 cycloalkyl, and the C 1-6 alkyl and C 3-6 cycloalkyl are further optionally substituted with 1, 2, or 3 substituents selected from deuterium, halogen, hydroxy, amino, cyano, oxo, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 1-6 alkoxy-C 1-6 alkyl, -NH(C 1-6 alkyl), -N(C 1-6 alkyl)(C 1-6 alkyl);
  • Rc5 and Rc6 are selected from H, deuterium, C1-6 alkyl, C3-6 cycloalkyl, or Rc5 and Rc6 together with the N atom to which they are attached form a 4-6 membered heterocyclyl, wherein the C1-6 alkyl, C3-6 cycloalkyl and 4-6 membered heterocyclyl are further optionally substituted with 1, 2 or 3 substituents selected from deuterium, halogen, hydroxyl, amino, cyano, oxo, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C1-6 haloalkoxy, C1-6 alkoxy- C1-6 alkyl, -NH( C1-6 alkyl), -N( C1-6 alkyl)( C1-6 alkyl);
  • each a and b are independently 1, 2, 3 or 4;
  • Each m is 0 or 1;
  • Each p is 0, 1 or 2;
  • Each s and n are independently selected from 0, 1, 2, 3 or 4;
  • the compounds of the present invention have a structure shown in Formula VIII-3 or VIII-4:
  • each R cn is independently selected from the group consisting of hydrogen, deuterium, halogen, hydroxy, amino, cyano, C 1-6 alkoxy, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 haloalkoxy, hydroxyC 1-6 alkyl, C 1-6 alkoxy-C 1-6 alkyl, R c1 -S (O) 2 -, -(CH 2 ) s -N(R c1 )(R c2 ), 3-6 membered cycloalkyl, 3-6 membered heterocyclyl, phenyl, 5-6 membered heteroaryl, said 3-6 membered cycloalkyl, 3-6 membered heterocyclyl, phenyl, 5-6 membered heteroaryl are optionally substituted with 1, 2, or 3 substituents selected from the group consisting of deuterium, halogen, hydroxy, amino, cyano, C 1-6 alkyl, C 1-6 haloalky
  • two Rcn may form together with the C atom to which they are attached a 3-6 membered cycloalkyl, a 4-7 membered heterocyclyl, a 6 membered aryl or a 5-6 membered heteroaryl, wherein the 3-6 membered cycloalkyl, the 4-7 membered heterocyclyl, the 6 membered aryl or the 5-6 membered heteroaryl may be optionally substituted with 1, 2 or 3 substituents selected from deuterium, halogen, hydroxyl, amino, cyano, C1-6 alkoxy, C1-6 alkyl, C1-6 haloalkyl;
  • L 2 is selected from the group consisting of bonds, -NR 6 -, -O-, -S-, -NR 6 -(CR 7 R 8 ) b -, -(CR 7 R 8 ) b -NR 6 -, -O-(CR 7 R 8 ) b -, -(CR 7 R 8 ) b -O-, -S-(CR 7 R 8 ) b -, -(CR 7 R 8 ) b -S-;
  • R 2 , R 5 , R 6 , R 9 and R 10 is independently selected from the group consisting of hydrogen, deuterium, C 1-6 alkyl;
  • R 3 , R 4 , R 7 and R 8 is independently selected from the group consisting of hydrogen, deuterium, halogen, oxo, hydroxyl, amino, C 1-6 alkyl;
  • R c1 and R c2 are independently selected from: hydrogen, C 1-6 alkyl, C 1-6 haloalkoxy, C 3-6 cycloalkyl or 4-7 membered heterocyclyl;
  • R c3 is selected from C 1-6 alkyl, C 3-6 cycloalkyl, and the C 1-6 alkyl and C 3-6 cycloalkyl are further optionally substituted with 1, 2, or 3 substituents selected from deuterium, halogen, hydroxy, amino, cyano, oxo, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 1-6 alkoxy-C 1-6 alkyl, -NH(C 1-6 alkyl), -N(C 1-6 alkyl)(C 1-6 alkyl);
  • Rc5 and Rc6 are selected from H, deuterium, C1-6 alkyl, C3-6 cycloalkyl, or Rc5 and Rc6 together with the N atom to which they are attached form a 4-6 membered heterocyclyl, wherein the C1-6 alkyl, C3-6 cycloalkyl and 4-6 membered heterocyclyl are further optionally substituted with 1, 2 or 3 substituents selected from deuterium, halogen, hydroxyl, amino, cyano, oxo, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C1-6 haloalkoxy, C1-6 alkoxy- C1-6 alkyl, -NH( C1-6 alkyl), -N( C1-6 alkyl)( C1-6 alkyl);
  • R 11 is selected from the group consisting of: hydrogen, deuterium, C 1-6 alkyl, 3-6 membered monocyclic heterocyclic group;
  • each a and b are independently 1, 2, 3 or 4;
  • Each m is 0 or 1;
  • Each p is 0, 1 or 2;
  • Each s and n is independently selected from 0, 1, 2, 3 or 4.
  • the compound has a structure shown in Formula VIII-3:
  • Ra and Rb are each independently selected from hydrogen, deuterium, F, Cl, Br, cyano, methyl, ethyl, trifluoromethyl, methoxy, 1-hydroxyethyl-1-yl, methylamino, dimethylamino, acetyl, 3-hydroxyazetidinyl; preferably, Ra and Rb are each independently selected from hydrogen, deuterium, F, Cl, Br, methyl, ethyl; more preferably, Ra and Rb are each independently selected from hydrogen, deuterium, methyl.
  • each Rcn is independently selected from the group consisting of hydrogen, deuterium, fluorine, chlorine, bromine, hydroxyl, amino, cyano, C1-4 alkoxy, C1-4 haloalkoxy, C1-4 alkyl, C1-4 haloalkyl, hydroxyC1-4 alkyl, C1-4 alkoxy- C1-2 alkyl, Rc1 - S(O) 2- , -(CH2) s -N( Rc1 )( Rc2 ), 3-6 membered cycloalkyl, 3-6 membered heterocyclyl, phenyl, 5-6 membered heteroaryl, said 3-6 membered cycloalkyl, 3-6 membered heterocyclyl, phenyl, 5-6 membered heteroaryl are optionally substituted with 1, 2 , or 3 substituents selected from the group consisting of deuterium, halogen, hydroxyl, amino, cyano, C1-6 alkyl, C1-6 haloalkyl, C
  • 3-6 membered cycloalkyl, 4-7 membered heterocyclyl, 6 membered aryl or 5-6 membered heteroaryl may be optionally substituted with 1-3 substituents selected from deuterium, halogen, hydroxy, amino, cyano, C 1-6 alkoxy, C 1-6 alkyl, C 1-6 haloalkyl;
  • each Rcn is independently selected from: hydrogen, deuterium, fluorine, chlorine, bromine, hydroxyl, amino, cyano, C1-4 alkoxy, C1-4 haloalkoxy , C1-4 alkyl, C1-4 haloalkyl, hydroxyC1-4 alkyl, C1-4 alkoxy- C1-2 alkyl, Rc1 -S(O) 2- , -(CH2) s -N( Rc1 )( Rc2 ), 3-6 membered cycloalkyl, 3-6 membered heterocyclyl, phenyl, phenyl substituted with one or more halogens, or phenyl substituted with one or more hydroxyl groups, or two Rcn can be taken together with the C atom to which they are attached to form a 3-6 membered cycloalkyl, a 4-7 membered heterocyclyl, a 6 membered aryl, or a 5-6 membered heteroaryl, and the 3-6
  • each Rcn is independently selected from: fluoro, chloro, bromo, hydroxy, amino, cyano, methoxy, ethoxy, isopropoxy, methylamino, ethylamino, isopropylamino, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, trifluoromethyl, difluoromethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, trifluoromethoxy, difluoromethoxy, hydroxymethyl, aminoethyl, methoxymethyl, methoxyethyl, ethoxymethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentenyl, cyclobutenyl, cyclohexenyl, oxetanyl, phenyl, 4-chloro-phen
  • each R cn is independently selected from the group consisting of fluoro, chloro, bromo, hydroxy, cyano, methoxy, ethoxy, methyl, ethyl, trifluoromethyl, difluoromethyl, trifluoromethoxy, and difluoromethoxy.
  • L2 is selected from a bond, -NR6- , -O-, -S-, -NR6- ( CR7R8 ) b1- , -(CR7R8)b1-NR6-, -O-(CR7R8 )b1-, -(CR7R8 ) b1 - O- , -S-(CR7R8)b1- , - ( CR7R8 ) b1 - S- , wherein b1 is 1 or 2.
  • L 2 is selected from a bond, -NR 6 -, -NR 6 -(CR 7 R 8 ) b1 -, -(CR 7 R 8 ) b1 -NR 6 -, wherein b1 is 1 or 2.
  • L 2 is selected from -NR 6 -, -NR 6 -(CR 7 R 8 ) b1 -, -(CR 7 R 8 ) b1 -NR 6 -, wherein b1 is 1.
  • L 2 is selected from -NH-, -NH-(CR 7 R 8 )-.
  • L 2 is selected from -NH-, -NH-CH 2 -.
  • R 1 is selected from: cyclopentane, cyclohexane, azetidine, tetrahydropyrrole, piperidine, morpholine, piperazine
  • R1 is selected from the group consisting of: tetrahydropyrrole, piperidine, morpholine, piperazine,
  • R1 is selected from the group consisting of: tetrahydropyrrole, piperidine, morpholine, piperazine,
  • R 1 is selected from:
  • R 1 is selected from:
  • the compound has a structure shown in Formula VIII-8 or VIII-12:
  • R 1 , L 1 , Ra , R b , R c , L 2 , m, n and p are as defined above.
  • each R c is independently selected from: hydrogen, deuterium, halogen, hydroxyl, cyano, C 1-6 alkoxy, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 1-6 alkoxy-C 1-6 alkyl, R c1 S(O) 2 -, 3-6 membered cycloalkyl, 3-6 membered heterocyclyl, phenyl, 5-6 membered heteroaryl, wherein the 3-6 membered cycloalkyl, 3-6 membered heterocyclyl, phenyl, 5-6 membered heteroaryl are optionally substituted with 1, 2, or 3 substituents selected from deuterium, halogen, hydroxyl, amino, cyano, C 1-6 alkyl, C 1-6 haloalkyl, and C 1-6 alkoxy;
  • two R c may form together with the C atom to which they are attached a 3-6 membered cycloalkyl, a 4-7 membered heterocyclyl, a 6 membered aryl or a 5-6 membered heteroaryl, wherein the 3-6 membered cycloalkyl, the 4-7 membered heterocyclyl, the 6 membered aryl or the 5-6 membered heteroaryl may be optionally substituted with 1, 2 or 3 substituents selected from deuterium, halogen, hydroxyl, amino, cyano, C 1-6 alkoxy, C 1-6 alkyl, C 1-6 haloalkyl;
  • L 2 is selected from a bond, -NR 6 -, -O-, -S-;
  • Ra , Rb , Rc , Rc1 , R6 , R1 , L1 , n, m and p are as defined above.
  • the compound has a structure shown in Formula VIII-8:
  • R 1 , L 1 , Ra , R b , R c , L 2 , m, n and p are as defined above.
  • R 1 is a 3-6 membered monocyclic heterocyclyl
  • the R 1 is selected from pyrrole, piperidine, morpholine, piperazine, and 1,4-oxathiacyclohexane
  • R 1 is selected from:
  • the compounds of the present invention have the structure shown in Formula VIII-9:
  • R 1 , L 1 , Ra , R b , R c , L 2 , m, n, and p are as defined above; provided that:
  • the R 1 is selected from:
  • the compounds of the invention have the following structure:
  • the compounds of the invention have the following structure:
  • the compounds of the invention have the following structure:
  • the compounds of the invention have the following structure:
  • the compounds of the invention have the following structure:
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of the compound described in the present invention, or its enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, nitrogen oxide, metabolite or its pharmaceutically acceptable salt, ester, solvate, hydrate, isotope-labeled compound (preferably deuterated) or prodrug.
  • the present invention provides a combination comprising a therapeutically effective amount of a compound of the present invention or its enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, nitrogen oxide, metabolite or a pharmaceutically acceptable salt, ester, solvate, hydrate, isotope-labeled compound (preferably deuterated) or prodrug, and one or more therapeutic agents.
  • one or more therapeutic agents are independently selected from farnesoid X receptor (FXR) agonists; anti-fat degeneration agents; anti-fibrotic agents; JAK inhibitors; checkpoint inhibitors; chemotherapy, radiotherapy and surgery; urate-lowering therapy; anabolic agents and cartilage regeneration therapy; IL-17 blockers; complement inhibitors; Bruton’s tyrosine kinase inhibitors (BTK inhibitors); Toll-like receptor inhibitors (TLR7/8 inhibitors); CAR-T therapies; antihypertensive agents; cholesterol-lowering agents; leukotriene A4 hydrolase (LTAH4) inhibitors; SGLT2 inhibitors; beta2-agonists; anti-inflammatory agents; nonsteroidal anti-inflammatory drugs (“NSAIDs”); acetylsalicylic acid agents (ASA); regenerative therapy therapies; cystic fibrosis therapies; and atherosclerosis therapies.
  • FXR farnesoid X receptor
  • the present invention provides a compound of the present invention, or its enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, nitrogen oxide, metabolite or a pharmaceutically acceptable salt, ester, solvate, hydrate, isotope-labeled compound (preferably deuterated) or prodrug, or a combination of the present invention, for use as a medicine.
  • the present invention provides a compound of the present invention, or an enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, nitrogen oxide, metabolite or a pharmaceutically acceptable salt, ester, solvate, hydrate, isotope-labeled compound (preferably deuterated) or prodrug thereof, for use in the treatment of the following diseases or disorders, in which NLRP3 signaling contributes to the pathology, and/or symptoms, and/or progression of the disease or disorder.
  • the present invention provides a method for treating the following diseases or disorders, in which NLRP3 signaling contributes to the pathology, and/or symptoms, and/or progression of the disease or disorder, the method comprising administering a therapeutically effective amount of a compound of the present invention, or an enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, nitrogen oxide, metabolite or a pharmaceutically acceptable salt, ester, solvate, hydrate, isotope or prodrug thereof.
  • the present invention provides a compound of the present invention, or its enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, nitrogen oxide, metabolite or pharmaceutically acceptable salt, ester, solvate, hydrate, isotope-labeled compound (preferably deuterated) or prodrug, for use in the preparation of a drug for the treatment of the following diseases or disorders, in which NLRP3 signaling contributes to the pathology, and/or symptoms, and/or progression of the disease or disorder.
  • the present invention is used for the compounds for use according to the present invention or the methods of treatment according to the present invention, wherein the disease or disorder is selected from: an inflammasome-related disease/disorder, an immune disease, an inflammatory disease, an autoimmune disease, or an autoinflammatory disease, for example, an autoinflammatory fever syndrome (e.g., cryptopyrin-associated periodic syndrome), a liver-related disease/disorder (e.g., chronic liver disease, viral hepatitis, non-alcoholic steatohepatitis (NASH), alcoholic steatohepatitis, and alcoholic liver disease), an inflammatory arthritis-related disorder (e.g., gout, pseudogout (chondrocalcinosis), osteoarthritis, rheumatoid arthritis, joint diseases such as acute and chronic joint diseases), a kidney-related disease (e.g., hyperoxaluria, lupus nephritis, type I/type II diabetes and related complications (e.g., ne
  • the present invention provides a method of inhibiting NLRP3 inflammasome activity in a subject in need thereof, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of the present invention, or its enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, nitrogen oxide, metabolite, or a pharmaceutically acceptable salt, ester, solvate, hydrate, isotope or prodrug thereof.
  • the present invention relates to methods for preparing, separating and purifying compounds shown in formula I, II, III, IV-1, IV-2, IV-3, IV-4, IV-5, IV-6, IV-7, IV-8, V-1, V-2, V-3, V-4, V-5, V-6, V-7, V-8, VI-1, VI-2, VI-3, VI-4, VI-5, VI-6, VI-7, VI-8, VII-1, VII-2, VII-3, VII-4, VII-5, VII-6, VII-7, VII-8, VIII-1, VIII-2, VIII-3, VIII-4, VIII-5, VIII-6, VIII-7, VIII-8, IX-1, IX-2, IX-3, IX-4, IX-5, and IX-6.
  • any embodiment of any aspect of the present invention may be combined with other embodiments as long as they do not appear
  • any technical feature can be applied to the technical features in other embodiments as long as there is no contradiction between them.
  • subject refers to an animal. Typically, the animal is a mammal. Subjects, for example, also refer to primates (e.g., humans, male or female), cattle, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds, etc. In certain embodiments, the subject is a primate. In other embodiments, the subject is a human.
  • primates e.g., humans, male or female
  • the subject is a primate. In other embodiments, the subject is a human.
  • patient refers to humans (including adults and children) or other animals. In some embodiments, “patient” refers to humans.
  • substituents When substituents are described by conventional chemical formulas written from left to right, the substituents also include chemically equivalent substituents that would result if the formula were written from right to left. For example, -CH2O- is equivalent to -OCH2- .
  • enantiomers refers to two non-superimposable isomers of a compound that are mirror images of each other.
  • diastereoisomer refers to stereoisomers that have two or more chiral neutrals and whose molecules are not mirror images of each other. Diastereoisomers have different physical properties, such as melting points, boiling points, spectral properties and reactivity. Diastereomeric mixtures can be separated by high resolution analytical procedures such as electrophoresis and chromatography, for example HPLC.
  • racemate refers to an equimolar mixture of two enantiomers devoid of optical activity.
  • tautomer or "tautomeric form” refers to structural isomers of different energies that are interconvertible via a low energy barrier. If tautomerism is possible (such as in solution), tautomerism can be achieved. chemical equilibrium.
  • proton tautomers also called prototropic tautomers
  • Valence tautomers include interconversions through the reorganization of some bonding electrons.
  • keto-enol tautomerism is the interconversion of pentane-2,4-dione and 4-hydroxypent-3-en-2-one tautomers.
  • tautomerism is phenol-keto tautomerism.
  • a specific example of phenol-keto tautomerism is the interconversion of pyridine-4-ol and pyridine-4(1H)-one tautomers.
  • the hydrogen on the 1-nitrogen atom on the imidazole ring can be transferred to the 3-nitrogen atom, and the two forms of the imidazole ring are tautomers, that is, the groups containing imidazole rings in this article exist in tautomerism, such as and are tautomers; and and Unless otherwise indicated, all tautomeric forms of the compounds of the present invention are within the scope of the present invention.
  • stereoisomers refers to compounds that have identical chemical constitution, but differ in the way the atoms or groups are arranged in space. Stereoisomers include enantiomers, diastereomers, conformational isomers (rotamers), geometric isomers (cis/trans isomers), atropisomers, and the like.
  • the prefixes d and l or (+) and (-) are the signs used to specify the rotation of plane polarized light caused by the compound, where (-) or l indicates that the compound is levorotatory.
  • Compounds prefixed with (+) or d are dextrorotatory.
  • a specific stereoisomer is an enantiomer and a mixture of such isomers is called an enantiomeric mixture.
  • a 50:50 mixture of enantiomers is called a racemic mixture or a racemate and may occur when there is no stereoselectivity or stereospecificity in a chemical reaction or process.
  • any asymmetric atom (e.g., carbon, etc.) of the compounds disclosed herein can exist in a racemic or enantiomerically enriched form, such as in the (R)-, (S)-, or (R,S)-configuration.
  • each asymmetric atom has at least 50% enantiomeric excess, at least 60% enantiomeric excess, at least 70% enantiomeric excess, at least 80% enantiomeric excess, at least 90% enantiomeric excess, at least 95% enantiomeric excess, or at least 99% enantiomeric excess in terms of the (R)- or (S)-configuration.
  • the compounds of the invention may exist in the form of one of the possible isomers or a mixture thereof, such as a racemate and a diastereomeric mixture (depending on the number of asymmetric carbon atoms).
  • Optically active (R)- or (S)-isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. If the compound contains a double bond, the substituents may be in the E or Z configuration; if the compound contains a disubstituted cycloalkyl group, the cycloalkyl substituents may be in the cis or trans configuration.
  • Any resulting mixture of stereoisomers can be separated into the pure or substantially pure geometric isomers, enantiomers, diastereomers on the basis of the differences in the constituent physicochemical properties, for example, by chromatography and/or fractional crystallization.
  • racemate of the final product or intermediate obtained can be separated into optical antipodes by known methods by methods familiar to those skilled in the art, such as by separation of the diastereoisomeric salts obtained thereof.
  • the racemic product can also be separated by chiral chromatography, such as high performance liquid chromatography (HPLC) using a chiral adsorbent.
  • HPLC high performance liquid chromatography
  • enantiomers can be prepared by asymmetric synthesis, for example, see Jacques, et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Principles of Asymmetric Synthesis (2nd Ed. Robert E.
  • nitrogen oxide means that when a compound contains several amine functional groups, one or more nitrogen atoms can be oxidized to form an N-oxide.
  • Special examples of N-oxides are N-oxides of tertiary amines or N-oxides of nitrogen atoms of nitrogen-containing heterocyclic rings.
  • the corresponding amines can be treated with oxidizing agents such as hydrogen peroxide or peracids (e.g. peroxycarboxylic acids) to form N-oxides (see Advanced Organic Chemistry, Wiley Interscience, 4th edition, Jerry March, pages).
  • oxidizing agents such as hydrogen peroxide or peracids (e.g. peroxycarboxylic acids) to form N-oxides (see Advanced Organic Chemistry, Wiley Interscience, 4th edition, Jerry March, pages).
  • N-oxides can be prepared by the method of L. W. Deady (Syn. Comm. 1977, 7, 509-514), wherein, for example, the amine compound is reacted
  • metabolite refers to a product obtained by the metabolism of a specific compound or its salt in vivo.
  • the metabolite of a compound can be identified by techniques known in the art, and its activity can be characterized by experimental methods as described in the present invention. Such products can be obtained by administering the compound through oxidation, reduction, hydrolysis, amidation, deamidation, esterification, defatting, enzymatic cleavage, etc.
  • the present invention includes metabolites of compounds, including metabolites produced by contacting the compounds of the present invention with mammals for a period of time.
  • pharmaceutically acceptable means that the substance or composition must be chemically and/or toxicologically compatible with the other ingredients of the formulation and/or the mammals treated therewith.
  • pharmaceutically acceptable refers to those approved by federal regulatory agencies or national governments or listed in the U.S. Pharmacopoeia or other generally recognized pharmacopeias for use in animals, particularly humans.
  • pharmaceutically acceptable salt refers to organic salts and inorganic salts of the compounds of the present invention.
  • Pharmaceutically acceptable salts are well known in the art, as described in S.M.Berge et al., J.Pharmaceutical Sciences, 66: 1-19, 1977.
  • Pharmaceutically acceptable salts include salts formed between compounds and acids, including but not limited to inorganic acid salts (such as hydrochlorides, hydrobromides, phosphates, sulfates, nitrates, perchlorates) and organic acid salts (such as acetates, glycolates, oxalates, maleates, tartrates, citrates, succinates, fumarates, mandelates, sulfosalicylate), or other methods described in books and literature, such as ion exchange methods, to obtain these salts.
  • inorganic acid salts such as hydrochlorides, hydrobromides, phosphates, sulfates, nitrates, perchlorates
  • organic acid salts such as acetates, glycolates, oxalates, maleates, tartrates, citrates, succinates, fumarates, mandelates, sulfosalicylate
  • More pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, cyclopentylpropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, oleate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate
  • Pharmaceutically acceptable salts also include salts formed from compounds and bases, including but not limited to, inorganic base salts (such as alkali metal salts, alkaline earth metal salts, ammonium salts and N+(C1-4 alkyl)4 salts), alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like.
  • inorganic base salts such as alkali metal salts, alkaline earth metal salts, ammonium salts and N+(C1-4 alkyl)4 salts
  • alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like.
  • the present invention also contemplates quaternary ammonium salts formed by compounds of any group containing N. Water-soluble or oil-soluble or dispersed products can be obtained by quaternization.
  • Pharmaceutically acceptable salts further include appropriate, non-toxic ammonium, quaternary ammonium salts and amine cations formed by counter-balancing ions, such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, C1-8 sulfonates and aromatic sulfonates.
  • Organic base salts e.g., primary, secondary, and tertiary amine salts, substituted amines (including naturally occurring substituted amines, cyclic amines, basic ion exchange resins) salts
  • certain organic amine salts include, for example, isopropylamine salts, benzathine salts, cholinate salts, diethanolamine salts, diethylamine salts, lysine salts, meglumine salts, piperazine salts, and tromethamine salts.
  • Pharmaceutically acceptable acid addition salts can be formed by the action of the compounds of the present invention with inorganic acids or organic acids
  • pharmaceutically acceptable base addition salts can be formed by the action of the compounds of the present invention with inorganic bases or organic bases.
  • the pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound, alkaline or acidic part using conventional chemical methods. In general, such salts can be prepared by reacting the free acid form of these compounds with a stoichiometric amount of a suitable base (such as hydroxides, carbonates, bicarbonates, etc. of Na, Ca, Mg or K), or by reacting the free base form of these compounds with a stoichiometric amount of a suitable acid.
  • a suitable base such as hydroxides, carbonates, bicarbonates, etc. of Na, Ca, Mg or K
  • solvate refers to an association formed by one or more solvent molecules and the compound of the present invention.
  • the solvent can be water, acetic acid, ether, isopropyl ether, petroleum ether, ethyl formate, ethyl acetate, isopropyl acetate, n-propyl acetate, isobutyl acetate, n-butyl acetate, methyl tert-butyl ether (MTBE), n-heptane, a mixed solvent of ethanol and water in a volume ratio of 10:90 to 90:10, acetone, methyl isobutyl ketone, acetonitrile, benzene, chloroform, carbon tetrachloride, dichloromethane, dimethyl sulfoxide, 1,4-dioxane, ethanol, ethyl acetate, ethylene glycol, n-butanol, tert-butanol , sec-but
  • hydrate refers to an association of one or more water molecules with a compound of the present invention.
  • the compounds disclosed in the present invention can also be obtained in the form of their hydrates or in the form of containing their solvents (e.g., ethanol, DMSO, etc.) for their crystallization.
  • their solvents e.g., ethanol, DMSO, etc.
  • the compounds disclosed in the present invention can inherently or by design form solvates with pharmaceutically acceptable solvents (including water); therefore, the present invention is intended to include both solvated and unsolvated forms.
  • esters is represented by the formula -OC(O)R or -C(O)OR, wherein R can be an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl or heteroaryl group as described herein.
  • isotopically labeled compound means that the compounds of the present invention are labeled with an isotope. They are identical to those compounds described herein except for the fact that one or more atoms are replaced by atoms having an atomic mass or mass number different from the natural common atomic mass or mass number.
  • isotopes that may also be introduced into the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, such as 2 H, 3 H, 13 C, 14 C, 15 N, 16 O, 17 O, 31 P, 32 P, 36 S, 18 F, and 37 Cl.
  • the compounds of the present invention comprising the aforementioned isotopes and/or other isotopes of other atoms and pharmaceutically acceptable salts of the compounds are all included within the scope of the present invention.
  • Isotope-labeled compounds of the present invention such as radioactive isotopes, such as 3 H and 14 C are incorporated into the compounds of the present invention and can be used for drug and/or substrate tissue distribution analysis. Due to ease of preparation and detection, tritiated, i.e., 3 H, and carbon-14, i.e., 14 C, isotopes are particularly preferred.
  • substitution with isotopes with larger mass numbers, such as deuterium, i.e., 2 H, can provide some greater therapeutic advantages of metabolic stability, such as increased in vivo half-life or reduced dosage requirements. Therefore, it may be preferred in some cases.
  • isotopic enrichment factor used in the present invention refers to the ratio between the isotopic abundance and the natural abundance of a specified isotope.
  • a substituent of a compound of the invention is designated as deuterium
  • the compound has an isotopic enrichment factor for each designated deuterium atom of at least 3500 (52.5% deuterium incorporation at each designated deuterium atom), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium incorporation), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation).
  • Pharmaceutically acceptable solvates according to the invention include those wherein the solvent of crystallization may be isotopically substituted, for example D2O, acetone-d6, DMSO-d6.
  • prodrug refers to a compound that is converted into a compound of formula (I) in vivo. Such conversion is affected by the hydrolysis of the prodrug in the blood or the conversion of the prodrug into the parent structure by enzymes in the blood or tissues.
  • the prodrug compounds of the present invention may be esters.
  • esters that can be used as prodrugs include phenyl esters, aliphatic (C1-24) esters, acyloxymethyl esters, carbonates, carbamates and amino acid esters.
  • a compound in the present invention contains a hydroxyl group, which can be acylated to obtain a compound in the form of a prodrug.
  • prodrug forms include phosphate esters, such as these phosphate ester compounds that are obtained by phosphorylation of the hydroxyl group on the parent.
  • phosphate esters such as these phosphate ester compounds that are obtained by phosphorylation of the hydroxyl group on the parent.
  • prodrugs please refer to the following. The following literature: Higuchi et al., Pro-drugs as Novel Delivery Systems, Vol. 14, ACSSymposium Series; Roche et al., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987; Rautio et al., Prodrugs: Design and Clinical Applications, Nature Reviews Drug Discovery, 2008, 7, 255-270, and Hecker et al., Prodrugs of Phos Phates and Phosphonates, J. Med. Chem., 2008, 51, 2328-2345.
  • C1-6 alkyl specifically refers to the independently disclosed methyl, ethyl, C3 alkyl, C4 alkyl, C5 alkyl and C6 alkyl.
  • linking substituents are described.
  • the Markush variable listed for that group should be understood as a linking group.
  • the Markush group definition for that variable lists “alkyl” or “aryl”, it should be understood that the "alkyl” or “aryl” represents an alkylene group or an arylene group, respectively, that is connected.
  • heteroatom refers to O, S, N, P and Si, including any oxidation state of S, N and P; primary, secondary, tertiary amines and quaternary ammonium salts; or the hydrogen on the nitrogen atom in the heterocyclic ring is substituted, for example, N (such as N in 3,4-dihydro-2H-pyrrolyl), NH (such as NH in pyrrolidinyl) or NRT (such as NRT in N-substituted pyrrolidinyl, RT is a substituent on N).
  • N such as N in 3,4-dihydro-2H-pyrrolyl
  • NH such as NH in pyrrolidinyl
  • NRT such as NRT in N-substituted pyrrolidinyl, RT is a substituent on N.
  • the compounds composed thereof conform to the covalent rules and composition rules of organic compounds, that is, the compounds containing multiple heteroatoms should exclude compounds that do not conform to the covalent rules and composition rules of organic compounds.
  • heterocyclyl or “heterocycle” means a monovalent or polyvalent monocyclic, bicyclic or tricyclic ring system containing carbon atoms and heteroatoms.
  • the heteroatoms have the meanings as described herein.
  • the bicyclic or tricyclic ring system may be a spirocyclic, bridged or fused ring, for example, a bicyclic system includes a cyclospirobicyclic, a bridged bicyclic or a fused bicyclic.
  • Saturated or partially unsaturated heterocyclyls may be fully saturated or contain one or more degrees of unsaturation, but may not have an aromatic ring.
  • the heterocyclyl group is a 3-6 membered ring, such as a 3-6 membered saturated or partially unsaturated heterocyclyl (2-6 carbon atoms and 1-3 heteroatoms selected from N, O, P, S, where S or P is optionally substituted by one or more oxygen atoms to give groups such as SO, SO2 , PO, PO2 ).
  • the saturated or partially unsaturated heterocyclic group is selected from: saturated monocyclic heterocyclic group, saturated bicyclic heterocyclic group, saturated tricyclic heterocyclic group, partially unsaturated monocyclic heterocyclic group, partially unsaturated bicyclic heterocyclic group, partially unsaturated tricyclic heterocyclic group.
  • Bicyclic heterocyclic group refers to heterocyclic group of bicyclic system, for example, bicyclic heterocyclic system includes cyclospiro bicyclic heterocyclic ring, bridged bicyclic heterocyclic ring, condensed bicyclic heterocyclic ring.
  • Monocyclic heterocyclic group refers to heterocyclic group of monocyclic system.
  • 5-6 member heterocyclic group refers to heterocyclic group with 5-6 ring atoms.
  • 4-7 member heterocyclic group refers to heterocyclic group with 4-7 ring atoms.
  • 3-6 member heterocyclic group refers to heterocyclic group with 3-6 ring atoms.
  • cycloalkyl refers to a monocyclic, bicyclic or tricyclic ring system containing carbon atoms, which is monovalent or polyvalent. Saturated or partially unsaturated cycloalkyl groups may be fully saturated or contain one or more degrees of unsaturation, but none of the aromatic rings may be present. In one embodiment, the cycloalkyl group contains 3-6 carbon atoms, such as C 3 -C 6 saturated or partially unsaturated cycloalkyl groups. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentenyl, cyclohexenyl, and the like.
  • the saturated or partially unsaturated cycloalkyl group is selected from: saturated monocyclic cycloalkyl, saturated bicyclic cycloalkyl, saturated tricyclic cycloalkyl, partially unsaturated monocyclic cycloalkyl, partially unsaturated bicyclic cycloalkyl, partially unsaturated tricyclic cycloalkyl.
  • Bicyclic cycloalkyl groups refer to cycloalkyl groups of bicyclic ring systems, for example, bicyclic cycloalkyl systems include cyclospiro bicyclic cycloalkyl, bridged bicyclic cycloalkyl, fused bicyclic cycloalkyl.
  • Monocyclic cycloalkyl groups refer to cycloalkyl groups of monocyclic ring systems.
  • the 4-7-membered cycloalkyl group refers to a cycloalkyl group having 4 to 7 ring atoms.
  • the 3-6-membered cycloalkyl group refers to a cycloalkyl group having 3 to 6 ring atoms.
  • heteroaryl refers to a monocyclic, bicyclic and tricyclic aromatic system containing 5-10 ring atoms.
  • heteroaryl can be used interchangeably with the term “heteroaromatic ring” or “heteroaromatic compound”.
  • the heteroaryl group is a heteroaryl group consisting of 5-10 atoms containing 1, 2, 3 or 4 heteroatoms independently selected from O, S and N, i.e., a 5-10-membered heteroaryl group;
  • the heteroaryl group is a heteroaryl group consisting of 5-8 atoms containing 1, 2, 3 or 4 heteroatoms independently selected from O, S and N, i.e., a 5-8-membered heteroaryl group;
  • the heteroaryl group is a heteroaryl group consisting of 5-7 atoms containing 1, 2, 3 or 4 heteroatoms independently selected from O, S and N, i.e., a 5-7-membered heteroaryl group.
  • the heteroaryl group is a heteroaryl group consisting of 5-6 atoms containing 1, 2, 3 or 4 heteroatoms independently selected from O, S and N, i.e., a 5-6 membered heteroaryl group; In some embodiments, the heteroaryl group is a heteroaryl group consisting of 5 atoms containing 1, 2, 3 or 4 heteroatoms independently selected from O, S and N, i.e., a 5-membered heteroaryl group; In some embodiments, the heteroaryl group is a heteroaryl group consisting of 6 atoms containing 1, 2, 3 or 4 heteroatoms independently selected from O, S and N, i.e., a 6-membered heteroaryl group.
  • aryl refers to a monocyclic, bicyclic, or tricyclic aromatic carbon ring system.
  • aryl can be used interchangeably with the term “aromatic ring” or "aromatic ring”.
  • 6-10 membered aryl refers to an aromatic group containing 6-10 ring atoms. Examples include, but are not limited to, phenyl, naphthyl, etc.
  • halogen and halo refer to fluorine (F), chlorine (Cl), bromine (Br) or iodine (I).
  • amino refers to -NH2 .
  • hydroxy refers to -OH.
  • cyano refers to -CN.
  • nitro refers to -NO2 .
  • alkyl refers to a saturated, straight-chain or branched monovalent hydrocarbon group containing carbon atoms.
  • the alkyl group contains 1-6 carbon atoms, i.e., C 1 -C 6 alkyl; in another embodiment, the alkyl group contains 1-4 carbon atoms, i.e., C 1 -C 4 alkyl; in another embodiment, the alkyl group contains 1-3 carbon atoms, i.e., C 1 -C 3 alkyl.
  • alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl, n-pentyl, n-hexyl and the like.
  • alkoxy means an alkyl group attached to the rest of the molecule via an oxygen atom, wherein the alkyl group has the meaning as described herein.
  • the alkoxy group contains 1-6 carbon atoms, i.e., C 1 -C 6 alkoxy; in another embodiment, the alkoxy group contains 1-4 carbon atoms, i.e., C 1 -C 4 alkoxy; in yet another embodiment, the alkoxy group contains 1-3 carbon atoms, i.e., C 1 -C 3 alkoxy.
  • alkylamino means an alkyl group attached to the rest of the molecule via a nitrogen atom, wherein the alkyl group has the meaning as described herein.
  • the alkylamino group is a monoalkylamino group, represented by "alkyl-NH-”.
  • the alkylamino group is a dialkylamino group, represented by "(alkyl) 2 N-”.
  • the alkylamino group contains 1-6 carbon atoms, i.e., C 1 -C 6 alkylamino; in another embodiment, the alkylamino group contains 1-4 carbon atoms, i.e., C 1 -C 4 alkylamino; in yet another embodiment, the alkylamino group contains 1-3 carbon atoms, i.e., C 1 -C 3 alkylamino.
  • haloalkyl means that the hydrogen on the alkyl group is replaced by one or more halogens (F, Cl, Br);
  • hydroxyalkyl means that the hydrogen on the alkyl group is replaced by one or more hydroxyl (OH);
  • aminoalkyl means that the hydrogen on the alkyl group is replaced by one or more amino (NH 2 ).
  • One or more halophenyls means phenyl is substituted with 1, 2, 3, 4 or 5 halogens.
  • the halogen has the definition as described herein.
  • One or more halophenyls is also represented as phenyl substituted with one or more halogens.
  • One or more hydroxyl groups substituted with phenyl means that phenyl is substituted with 1, 2, 3, 4 or 5 hydroxyl groups.
  • the hydroxyl group has the definition as described herein.
  • phenyl and 4-7-membered cycloalkyl means phenyl fused and the cycloalkyl with 4-7 ring atoms described in the present invention
  • 5-6-membered heteroaryl and 4-7-membered cycloalkyl means heteroaryl fused with 5-6 ring atoms described in the present invention and cycloalkyl with 4-7 ring atoms described in the present invention.
  • C1-6alkoxy - C1-6alkyl means that C1-6alkoxy is connected to the rest of the molecule through C1-6alkylene
  • hydroxyC1-6alkyl means that hydroxy is connected to the rest of the molecule through C1-6alkylene .
  • the substituent R is connected to the central ring by a bond to form a ring system (as shown in the figure below), which means that the substituent R is limited to any substitutable or any reasonable position on the A ring.
  • formula f represents any possible position on the A ring that can be substituted, as shown in formulas f1 - f4 :
  • the substituent R is a ring system formed by connecting multiple rings with a bond (as shown in the figure below), which means that the substituent R can be substituted at any substitutable or any reasonable position on the A ring and the B ring.
  • formula e represents any possible substituted position on the A ring, as shown in formula e 1 -e 7 :
  • a substituent is connected to a central ring by a bond to form a ring system, such as (R x ) n , which means that n substituents R x can be substituted at any substitutable position on the ring.
  • formula a means that a benzene ring can be substituted by n R x .
  • substituted refers to one or more hydrogen atoms on a specific group being replaced by a specific substituent.
  • the specific substituent is a substituent described above, or a substituent appearing in the embodiments.
  • a substituted group may have a substituent selected from a specific group at any substitutable site of the group, and the substituent may be the same or different at each position, i.e., each substitution is independent of each other. It will be appreciated by those skilled in the art that the combinations of substituents contemplated by the present invention are those that are stable or chemically feasible.
  • the groups involved in ring A and ring B are It refers to a fused structure formed by ring A and ring B sharing a ring edge (i.e., ring A and ring B form a fused bicyclic ring), for example
  • substituents means connecting to the corresponding groups from left to right, for example, formula I
  • R c is selected from C 1-6 alkoxy-C 1-6 alkyl, it means that the C 1-6 alkoxy is connected to the C 1-6 alkyl, and the C 1-6 alkyl is further connected to the ring C.
  • the present invention provides a compound having a structure as shown in Formula I or its enantiomers, diastereomers, racemates, tautomers, stereoisomers, geometric isomers, nitrogen oxides, metabolites or pharmaceutically acceptable salts, esters, solvates, hydrates, isotope-labeled compounds (preferably deuterated compounds) or prodrugs;
  • Ring A, Ring B, Ring C, L 1 , L 2 , Ra , R b , R c , n, m, p and R 1 have the same definitions as described in the present invention.
  • the present invention provides a compound having a structure shown in Formula II,
  • Ring B, Ring C, L 1 , L 2 , Ra , R b , R c , n, m, p, R 1 , M 1 , M 2 , M 3 , and M 4 have the same definitions as described in the present invention.
  • the present invention provides a compound having a structure shown in Formula III,
  • Ring B, L 1 , L 2 , Ra , R b , R c , n, m, p, R 1 , M 1 , M 2 , M 3 and M 4 have the same definitions as described in the present invention.
  • the present invention provides a compound having a structure shown in Formula IV-1, IV-2, IV-3, IV-4, IV-5, IV-6, IV-7 or IV-8;
  • Ring C, L1 , L2 , Ra , Rb , Rc , n, m, p, R1 , M1 , M2 , M3 , M4 , M5 , M6 , U1 , U3 , U4 and U5 have the same meanings as described in the present invention.
  • the present invention provides a compound having a structure shown in Formula V-1, V-2, V-3, V-4, V-5, V-6, V-7 or V-8;
  • L1 , L2 , Ra , Rb , Rc , n, m, p, R1 , M1 , M2 , M3 , M4 , M5 , M6 , U1 , U3 , U4 and U5 have the same definitions as described in the present invention.
  • the present invention provides a compound having a structure shown in Formula VI-1, VI-2, VI-3, VI-4, VI-5, VI-6, VI-7 or VI-8;
  • n1 is 0, 1, 2 or 3
  • L1 , L2 , Ra , Rb , Rc , n, m, p, R1 , M1 , M2 , M3 , M4 , M5 , M6 , U1 , U3 , U4 and U5 have the same meanings as described in the present invention.
  • the compounds of the present invention have the structure shown in Formula VII-1, VII-2, VII-3, VII-4, VII-5 or VII-6;
  • L 1 , L 2 , Ra , R b , m, p, R 1 , M 1 , M 2 , M 3 , M 4 , M 5 , and U 1 have the same definitions as described in the present invention.
  • the compounds of the present invention have a structure shown in Formula VIII-1, VIII-2, VIII-3, VIII-4, VIII-5, VIII-6, VIII-7 or VIII-8:
  • R c , n, L 1 , L 2 , R 1 , Ra , R b , m and n have the same definitions as described in the present invention.
  • the compounds of the present invention have the structure shown in Formula IX-1, IX-2, IX-3, IX-4, IX-5 or IX-6:
  • L 1 , L 2 , and R 1 have the definitions as described in the present invention
  • Rab are each independently selected from the group consisting of hydrogen, deuterium, halogen, hydroxy, amino, cyano, oxo, methyl, ethyl, propyl, isopropyl, and butyl;
  • k is independently selected from: 0, 1, 2 or 3.
  • compositions and methods of administration are provided.
  • the present invention relates to a pharmaceutical composition, which comprises the compound of the present invention or its enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, nitrogen oxide, metabolite or its pharmaceutically acceptable salt, ester, solvate, hydrate, isotope-labeled compound or prodrug; and a pharmaceutically acceptable carrier or diluent.
  • pharmaceutical composition refers to a mixture of one or more compounds described herein or their physiologically/pharmaceutically acceptable salts or prodrugs with other chemical components, such as physiologically/pharmaceutically acceptable carriers and diluents, and further excipients such as excipients, binders, fillers, and additional therapeutic agents such as antidiabetic agents, antihyperglycemic agents, antiobesity agents, antihypertensive agents, antiplatelet agents, antiatherosclerotic agents, or lipid-lowering agents.
  • additional therapeutic agents such as antidiabetic agents, antihyperglycemic agents, antiobesity agents, antihypertensive agents, antiplatelet agents, antiatherosclerotic agents, or lipid-lowering agents.
  • the purpose of a pharmaceutical composition is to facilitate the administration of a compound to an organism.
  • carrier includes any solvent, dispersion medium, coating material, surfactant, antioxidant, preservative (e.g., antibacterial agent, antifungal agent), isotonic agent, salt, drug stabilizer, binder, excipient, dispersant, lubricant, sweetener, flavoring agent, coloring agent, or a combination thereof, which carriers are known to those skilled in the art (such as Remington's Pharmaceutical Sciences, 18th Ed. Mack Printing Company, 1990, pp. 1289-1329). Except insofar as any conventional carrier is incompatible with the active ingredient, its use in the therapeutic or pharmaceutical compositions is contemplated.
  • the present invention also relates to pharmaceutical compositions comprising as active ingredients a compound of formula I, II, III, IV-1, IV-2, IV-3, IV-4, IV-5, IV-6, IV-7, IV-8, V-1, V-2, V-3, V-4, V-5, V-6, V-7, V-8, VI-1, VI-2, VI-3, VI-4, VI-5, VI-6, VI-7, VI-8, VII-1, VII-2, VII-3, VII-4, VII-5, VII-6, VII-7, VII-8, VIII-1, VIII-2, VIII-3, VIII-4, VIII-5, VIII-6, VIII-7, VIII-8, IX-1, IX-2, IX-3, IX-4, IX-5, IX-6, or a pharmaceutically acceptable salt thereof, which can be used, in particular, for the treatment of neoplastic diseases, in particular cancer, as described herein.
  • the composition can be formulated for non-parenteral administration, such as nasal, oral, rectal, pulmonary, vaginal, sublingual, topical, transdermal, ophthalmic, or especially for oral administration, for example in the form of oral solid dosage forms, such as granules, pills, powders, tablets, film-coated tablets or sugar-coated tablets, effervescent tablets, hard and soft capsules or hydroxypropylmethylcellulose (HPMC) capsules (suitably coated), orally disintegrating tablets, oral solutions, lipid emulsions or suspensions, or for parenteral administration, such as intravenous, intramuscular or subcutaneous, intrathecal, intradermal or epidural administration to mammals, especially humans, for example in the form of solutions, lipid emulsions or suspensions containing microparticles or nanoparticles.
  • These compositions can contain the active ingredient alone, or preferably, together with a pharmaceutically acceptable carrier.
  • Fillers such as lactose, cellulose, mannitol, sorbitol, calcium phosphate, starch or its derivatives, binders Excipients such as cellulose, starch, polyvinyl pyrrolidone or its derivatives, glidants such as talc, stearic acid or its salts, and flow agents such as fumed silicon dioxide can be used as such excipients for formulation and Manufacture of oral solid dosage forms such as granules, pills, powders, tablets, film-coated or sugar-coated tablets, effervescent tablets, hard or HPMC capsules or orally disintegrating tablets.
  • Suitable excipients for soft capsules are, for example, vegetable oils, waxes, fats, semisolid and liquid polyols and the like.
  • Suitable excipients for the production of oral solutions, lipid emulsions or suspensions are, for example, water, alcohols, polyols, sucrose, invert sugar, glucose and the like.
  • Suitable excipients for parenteral formulations are, for example, water, alcohols, polyols, glycerol, vegetable oils, lecithin, surfactants and the like.
  • the pharmaceutical preparations may contain preservatives, solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavorings, salts for varying the osmotic pressure, buffers, masking agents or antioxidants.
  • the pharmaceutical preparations may also contain other therapeutically valuable substances.
  • the dosage can vary within a wide range and, of course, will be in accordance with individual requirements in each particular case.
  • a daily dosage of about 1 to 1000 mg of a compound of formula (I) per person should be appropriate, although the above lower or upper limits may also be exceeded when necessary.
  • the compounds of formula I, II, III, IV-1, IV-2, IV-3, IV-4, IV-5, IV-6, IV-7, IV-8, V-1, V-2, V-3, V-4, V-5, V-6, V-7, V-8, VI-1, VI-2, VI-3, VI-4, VI-5, VI-6, VI-7, VI-8, VII-1, VII-2, VII-3, VII-4, VII-5, VII-6, VII-7, VII-8, VIII-1, VIII-2, VIII-3, VIII-4, VIII-5, VIII-6, VIII-7, VIII-8, IX-1, IX-2, IX-3, IX-4, IX-5, IX-6 can also be used in combination with one or more other pharmacologically active compounds, which other compounds are also effective To combat the same disease, preferably using different modes of action, or to reduce or prevent possible undesirable side effects of compounds of formula I, II, III, IV-1, IV-2, IV-3, IV-4, IV-5, IV-6, IV-7, IV-8, V-1, V-2, V-3, V-4, V-5, V-6, V
  • the term "pharmaceutically acceptable carrier” refers to a substance that can be used to prepare or use a pharmaceutical composition, and includes, for example, suitable diluents, solvents, dispersion media, surfactants, antioxidants, preservatives, isotonic agents, buffers, emulsifiers, absorption delaying agents, salts, drug stabilizers, binders, excipients, disintegrants, lubricants, wetting agents, sweeteners, flavoring agents, dyes, and combinations thereof, as known to those skilled in the art (see, for example, Remington The Science and Practice of Pharmacy, 22nd ed., Pharmaceutical Press, 2013, pp. 1049-1070).
  • terapéuticaally effective amount of a compound of the present invention refers to an amount of a compound of the present invention that will cause a biological or medical response in a subject (e.g., a reduction or inhibition of enzyme or protein activity, or an improvement in symptoms, relief of symptoms, slowing or delaying disease progression, or prevention of disease, etc.).
  • the term "therapeutically effective amount” refers to an amount of a compound of the present invention that, when administered to a subject, effectively (1) at least partially alleviates, inhibits, prevents and/or improves (i) a condition, disorder or disease mediated by NLRP3, or (ii) associated with NLRP3 activity, or (iii) characterized by the activity (normal or abnormal) of NLRP3; or (2) reduces or inhibits the activity of NLRP3; or (3) reduces or inhibits the expression of NLRP3.
  • the term "therapeutically effective amount" of a compound of the present invention refers to an amount that, when administered to a cell, or tissue, or non-cellular biological material or medium, effectively at least partially reduces or inhibits the activity of NLRP3; or at least partially reduces or inhibits the expression of NLRP3.
  • treatment or “treating” as used herein in the context of treating a disease or disorder generally relates to treatment and therapy of humans or animals (e.g., in veterinary applications), wherein some desired therapeutic effects are obtained, e.g., inhibiting the progression of a disease or disorder, and including reducing the rate of progression, stopping the rate of progression, alleviating the symptoms of a disease or disorder, improving a disease or disorder, and curing a disease or disorder.
  • Treatment as a preventive measure i.e., prevention
  • treatment includes prevention of cancer, reducing the incidence of cancer, alleviating cancer symptoms, etc.
  • inhibiting NLRP3 or inhibiting the NLRP3 inflammasome pathway comprises reducing the ability of NLRP3 or the NLRP3 inflammasome pathway to induce the production of IL-1 ⁇ and/or IL-18. This can be achieved by mechanisms including, but not limited to, inactivating, destabilizing NLRP3, and/or altering the distribution of NLRP3.
  • prevent refers to prophylactic treatment of the disease or disorder; or delaying the onset or progression of the disease or disorder.
  • NLRP3 is meant to include, but is not limited to, nucleic acids, polynucleotides, oligonucleotides, sense and antisense polynucleotide chains, complementary sequences, peptides, polypeptides, proteins, homologous and/or orthologous NLRP molecules, isoforms, precursors, mutants, variants, derivatives, splice variants, alleles, different species, and active fragments thereof.
  • the structures of the compounds were determined by nuclear magnetic resonance ( 1 H-NMR, 13 C-NMR or/and 19 F-NMR).
  • 1 H-NMR, 13 C-NMR, 19 F-NMR chemical shifts ( ⁇ ) are given in parts per million (ppm).
  • 1 H-NMR, 13 C-NMR, 19 F-NMR measurements were performed using a Bruker Ultrashield-400 NMR spectrometer and a Bruker Avance III HD 600 NMR spectrometer.
  • the measurement solvent is deuterated chloroform (CDCl 3 ), deuterated methanol (CD 3 OD or MeOH-d 4 ) or deuterated dimethyl sulfoxide (DMSO-d6).
  • TMS (0 ppm) or chloroform (7.25 ppm) is used as the reference standard.
  • s single peak
  • d doublet, double peak
  • t triplet, triple peak
  • m multiplet, multiple peak
  • br broadened, broad peak
  • dd doublet of doublets, double double peak
  • dt doublet of triplets, double triple peak
  • td triplet of doublets, triple double peak
  • brs (broadened singlet, broad single peak).
  • the coupling constant J is expressed in Hertz (Hz).
  • LC-MS Liquid chromatography-mass spectrometry
  • the thin layer chromatography silica gel plate uses Qingdao GF254 silica gel plate, TLC uses 0.15-0.20 mm, and preparative thin layer chromatography uses 0.4 mm-0.5 mm.
  • Column chromatography generally uses Qingdao silica gel 200-300 mesh silica gel as a carrier.
  • the starting materials in the examples of the present invention are all known and commercially available, or can be synthesized using or according to literature data reported in the art.
  • the optimal reaction conditions may vary with the specific reactants or solvents used, but these conditions may be determined by conventional optimization procedures. In some cases, the order in which the following reaction schemes and/or reaction steps are carried out may be changed to promote the reaction or to avoid the formation of unwanted by-products.
  • the functional groups present in various positions of the molecule must be compatible with the proposed reagents and reactions. Such restrictions on substituents compatible with the reaction conditions are obvious to those skilled in the art, and then alternative methods must be used. In addition, in some reactions mentioned herein, it may be necessary or desirable to protect any sensitive groups in the compound, and it is assumed that such protecting groups (PG) are in appropriate positions when necessary.
  • protecting groups can be used according to standard practices well known in the art (for explanation, see Greene T.W, Wuts P.G.M, Protective Groups in Organic Synthesis, 5th edition, Publisher: John Wiley & Sons, 2014).
  • the protecting groups may be removed at any convenient stage in the synthesis using conventional techniques well known in the art, or may be removed in a subsequent reaction step or work-up.
  • DIPEA N,N-diisopropylethylamine
  • DCM/TFA 1:1: a mixed solution of dichloromethane and trifluoroacetic acid in a volume ratio of 1:1
  • XPhos Pd G3 methanesulfonate (2-dicyclohexylphosphino-2',4',6'-tri-isopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II)
  • SPhos Pd G3 methanesulfonate (2-dicyclohexylphosphino-2',6'-dimethoxy-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II)
  • CDI N,N'-Carbonyldiimidazole
  • Formula I-1-1 undergoes cyclization reaction to obtain compound formula I-1-2, and formula I-1-2 undergoes coupling reaction to obtain compound I-1, wherein X is halogen, and M 1 , M 2 , M 3 , Ra , R c , L 1 , R 1 , m, and n are defined as described in the above embodiments.
  • FIG1 and FIG2 show the pharmacological effects of compound 111 of the present application and Yangshen compound on the iodoacetic acid-induced SD rat knee osteoarthritis model.
  • Step 1) At room temperature, compound 12-1 (3.0 g, 18.29 mmol, Bid), triethylamine (5.07 mL, 36.59 mmol), and anhydrous dichloromethane (15 mL) were added to a 100 mL three-necked flask in sequence. After being fully mixed, the mixture was cooled to 0°C in an ice-water bath, and a dichloromethane solution (15 mL) of chloroacetyl chloride (1.60 mL, 20.12 mmol) was slowly added dropwise. The reaction solution was stirred at 20°C for 16 hours. LCMS monitored the reaction of the raw materials.
  • Step 2) At room temperature, compound 12-2 (600 mg, 2.50 mmol) and N,N-dimethylformamide (6 mL) were added to a 40 mL IKA bottle in sequence, and then triethylamine (1.04 mL, 7.49 mmol) and 1-ethylpiperidin-3-amine hydrochloride (534.16 mg, 3.24 mmol, Leyan) were added to the reaction bottle.
  • the reaction solution was stirred at 60°C for 5 hours.
  • LCMS monitored the reaction of the raw materials. 10 mL of saturated sodium chloride solution was added to the reaction solution, and then extracted twice with 10 mL of tetrahydrofuran.
  • Step 3) At room temperature, compound 12-3 (400 mg, 2.50 mmol) and dimethyl sulfoxide (4 mL) were added to a 40 mL IKA bottle in sequence, and then DIPEA (0.60 mL, 3.61 mmol) was added to the reaction bottle, and the reaction solution was stirred at 130°C for 3 hours.
  • Step 4) At room temperature, add compound 12-4 (90.0 mg, 0.300 mmol), intermediate M-1 (137 mg, 0.520 mmol), Xphos PdG3 (25.8 mg, 0.030 mmol), potassium phosphate (258 mg, 1.22 mmol), dioxane (2 mL), water (0.2 mL) to an 8 mL single-mouth bottle. The reaction was reacted at 80 ° C for 1 hour.
  • Step 5) At room temperature, add compound 12-5, dichloromethane (1 mL), and trifluoroacetic acid (1 mL) to an 8 mL single-mouth bottle. The reaction was carried out at 25°C for 3 hours. The reaction solution was spin-dried. The residue was purified by high performance liquid chromatography (Waters-SunFire-C18-10 ⁇ m-19*250mm; mobile phase: water (containing 10mmol/L formic acid) and acetonitrile, gradient ratio: acetonitrile 23%-48%, flow rate: 30mL/min) to obtain compound 12.
  • Step 1) At room temperature, compound 2-2 (200.0 mg, 1.30 mmol) and N,N-dimethylformamide (5 mL) were added to a 40 mL IKA bottle in sequence, and then cesium carbonate (636.0 mg, 1.95 mmol) and compound 3-chloro-7H-pyrrolo[2,3-c]pyridazine (442.88 mg, 1.56 mmol, Bid) were added to the reaction bottle. The reaction solution was stirred at 100°C for 2 hours. LCMS monitored the reaction of the raw materials. 20 mL of water was added to the reaction solution, and then extracted twice with 50 mL of ethyl acetate.
  • Step 3) At 25°C, compound 11-2 (45.0 mg, 0.100 mmol) and hydrochloric acid/dioxane solution (2.0 mL, 4.0 M) were added to a 25 mL single-mouth bottle, and the reaction was stirred at 25°C for 1 hour. The reaction solution was spin-dried. The crude product was purified by preparation (Waters-SunFire-C18-10 ⁇ m-19*250 mm; mobile phase: water (containing 10 mmol/L formic acid) and acetonitrile, gradient ratio: acetonitrile 23%-48%, flow rate: 30 mL/min) to obtain compound 11.
  • LC-MS m/z 405.1 [M+H] + .
  • Step 1) Compound 5-1 (1.00 g, 6.28 mmol) and compound 5-1a (1.14 g, 5.85 mmol) were added to EtOH (10 mL) at room temperature and refluxed overnight. The reaction system was directly concentrated, and the residue was purified by column chromatography (0-3% methanol/dichloromethane) to obtain compound 5-2. LC-MS: m/z: 283.8 (M+H) + .
  • Step 2) A solution of compound 5-2 (250 mg, 1.04 mmol) in aqueous ammonia (10 mL, 28%) was stirred at 50°C for 5 hours. The reaction solution was evaporated to dryness under reduced pressure, ethyl acetate (3 mL) and petroleum ether (6 mL) were added to the residue, stirred for 2 hours, and then the mixture was filtered to obtain compound 5-3 (150 mg).
  • Step 4) At room temperature, trifluoroacetic acid (1 mL, 13.42 mmol) was added to a solution of compound 5-4 (120 mg, 0.30 mmol) in dichloromethane (1 mL). The reaction was stirred at 25°C for 2 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by high performance liquid chromatography (Waters-SunFire-C18-10 ⁇ m-19*250 mm; mobile phase: water (containing 10 mmol/L formic acid) and acetonitrile, gradient ratio: acetonitrile 23%-48%, flow rate: 30 mL/min) to obtain compound 5.
  • LC-MS m/z: 351.1 (M+H) + .
  • Step 3) At 25°C, compound 9-3 (70 mg, 0.13 mmol), dichloromethane (1 mL), and trifluoroacetic acid (1 mL, 0.670 mmol) were added to a 25 mL single-mouth bottle and stirred at room temperature for 1 hour.
  • the reaction solution was spin-dried and prepared by (Waters-SunFire-C18-10 ⁇ m-19*250 mm; mobile phase: water (containing 10 mmol/L formic acid) and acetonitrile, gradient ratio: acetonitrile 23%-48%, flow rate: 30 mL/min) to obtain compound 9.
  • LC-MS m/z 377.1 [M+H] + .
  • Step 1) Add trifluoroacetic acid (1 mL, 13.42 mmol) to a solution of compound 9-2 (360 mg, 1.07 mmol) in dichloromethane (5 mL). Stir the reaction at 25°C for 3 hours, and concentrate the reaction solution to obtain compound 10-1.
  • Step 2) A solution of compound 10-1 (360 mg, 1.44 mmol) and acetaldehyde (0.54 mL, 3.06 mmol) in methanol (1 mL) was stirred at 25 ° C for 1 hour. Then sodium cyanoborohydride (191.2 mg, 3.06 mmol) was added and the reaction was stirred at 25 ° C for 18 hours. Ethyl acetate (50 ml) and water (50 ml) were added to the reaction solution for extraction.
  • Step 3) At room temperature, compound 10-2 (150 mg, 0.57 mmol), intermediate M-1 (226 mg, 0.86 mmol), potassium phosphate (481 mg, 2.27 mmol), dioxane (2 mL) and water (0.2 mL) were added to a three-necked flask, nitrogen was replaced three times, XPhos PdG3 (48 mg, 0.06 mmol) was added, and nitrogen was replaced three times. The reaction solution was heated to 80 ° C, stirred for 1 hour, and slowly returned to room temperature.
  • Step 4) At 25°C, trifluoroacetic acid (1.0 mL) was added to a solution of compound 10-3 (60.0 mg, 0.130 mmol) in dichloromethane (1.0 mL), and the reaction was stirred at room temperature for 2 hours. The reaction solution was spin-dried, and the crude product was purified by preparation (Waters-SunFire-C18-10 ⁇ m-19*250 mm; mobile phase: water (containing 10 mmol/L formic acid) and acetonitrile, gradient ratio: acetonitrile 23%-48%, flow rate: 30 mL/min) to obtain compound 10.
  • LC-MS m/z 405.1 [M+H] + .
  • Step 1) At room temperature, compound 14-1 (2.00 g, 10.6 mmol), methanol (10 mL) and water (10 mL) were added to a 250 mL single-mouth bottle and stirred, and cyanogen bromide (2.33 mL, 31.74 mmol) was added. The reaction solution was stirred at 70 ° C for 3 hours under a nitrogen atmosphere. Water was added to the reaction solution, extracted with ethyl acetate (50 mL ⁇ 3), washed with saturated brine (20 mL ⁇ 1), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (0-5% methanol/dichloromethane) to obtain compound 14-2. LC-MS: m/z: 213.9 (M+H) + .
  • Step 2) At room temperature, compound 14-2 (100 mg, 0.47 mmol), 1,4-dioxane (5 mL) and water (1 mL) were added to a 50 mL single-mouth bottle and stirred, and intermediate M-1 (123 mg, 0.470 mmol) was added, potassium carbonate (193 mg, 1.40 mmol) and [1,1'-bis(diphenylphosphino)ferrocene] dichloropalladium dichloromethane complex (38.2 mg, 0.05 mmol) were added, and the reaction solution was stirred at 80 ° C for 2 hours under a nitrogen atmosphere, and water was added to the reaction solution, extracted with ethyl acetate (50 mL ⁇ 3), washed with saturated brine (20 mL ⁇ 1), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (0-5% methanol/dichloromethane) to obtain compound 14-3.
  • Step 3) At room temperature, compound 12-3 (100 mg, 0.28 mmol) was added to a 50 mL single-mouth bottle, and dichloromethane (2 mL) and TFA (2 mL) were added and stirred. The reaction solution was stirred at room temperature for 2 hours.
  • the crude product was purified by high performance liquid chromatography (Waters-SunFire-C18-10 ⁇ m-19*250 mm; mobile phase: water (containing 10 mmol/L formic acid) and acetonitrile, gradient ratio: acetonitrile 23%-48%, flow rate: 30 mL/min) to prepare compound 14.
  • Step 1) At 0°C, slowly add bis(trimethylsilyl)amide lithium (0.64mL, 0.64mmol, 1M) to a THF (1mL) solution of compound 3-1 (50.0mg, 0.320mmol, synthesis method reference: WO2021018858A1), stir the reaction at 0°C for 1 hour, add compound 3-1a (40.8mg, 0.320mmol, Bid), and stir the reaction at room temperature for 3 hours.
  • LCMS detected that the reaction was complete, saturated ammonium chloride solution (2mL) was added to the reaction solution to quench the reaction, ethyl acetate (2mL) was extracted 3 times, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and spin-dried.
  • LC-MS , m/z 247.1[M+H] + .
  • Step 2) At room temperature, compound 3-2a (26.7 mg, 0.120 mmol, synthesis method reference: US20200361898A1, page 39 synthesis of intermediate B005), potassium carbonate (33.6 mg, 0.240 mmol), Pd (dtbpf) Cl 2 (7.85 mg, 0.01 mmol) were added to a solution of compound 3-2 (30.0 mg, 0.120 mmol) in acetone (0.5 mL) and water (0.5 mL), and the reaction was carried out in a microwave reactor at 120 ° C for 30 minutes.
  • the reaction solution was evaporated to dryness under reduced pressure, and the residue was extracted 3 times with dichloromethane (1 mL), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and spin-dried.
  • the crude product was prepared by (Waters-SunFire-C18-10 ⁇ m-19*250 mm; mobile phase: water (containing 10 mmol/L formic acid) and acetonitrile, gradient ratio: acetonitrile 23%-48%, flow rate: 30 mL/min) to obtain compound 3.
  • LC-MS m/z 387.3 [M+H] + .
  • Step 1) At room temperature, compound 2-1 (1.03 mL, 7.74 mmol, Bid) and pyridine (10 mL) were added to a 40 mL LIKA bottle in sequence, and p-toluenesulfonyl chloride (1.62 g, 8.51 mmol) was added after thorough mixing.
  • the reaction solution was stirred at 25 ° C for 16 hours.
  • LCMS monitored the reaction of the raw materials.
  • the reaction solution was concentrated into a dark red mud by vacuum rotary evaporation, and then 10 mL of ethanol was added and shaken evenly to obtain a dark red suspension, which was concentrated again by vacuum rotary evaporation. Add ethanol and concentrate, and repeat three times to obtain a slightly reddish white solid.
  • Step 2) At room temperature, add compound 3-chloro-5H-pyrrolo[3,2-c]pyridazine (1.30 g, 8.47 mmol, preparation method reference: WO2022121914A1, page 73 Synthesis of compound 25c) to a 100 mL single-mouth bottle, dissolve in dimethylformamide (20 mL), and then add cesium carbonate (11.0 g, 33.9 mmol) and compound 2-2 (5.28 g, 18.62 mmol) to the reaction bottle. The reaction solution was stirred at 100 ° C for 6 hours.
  • Step 3) At room temperature, compound 2-3 (90.0 mg, 0.340 mmol), compound M-1 (90.0 mg, 0.340 mmol), potassium phosphate (289 mg, 1.36 mmol) and dioxane (2 mL) were added to a 25 mL three-necked flask, and water (0.2 mL) was stirred evenly, XPhos PdG3 (29 mg, 0.03 mmol) was added, and the system was replaced with nitrogen 3 times. The reaction solution was stirred at 80 ° C for 1 hour. The reaction solution was cooled to room temperature, water (10 mL) was added, and ethyl acetate (5 mL ⁇ 3) was extracted.
  • Step 4) At room temperature, add 2-5 (60 mg, 0.13 mmol) and dichloromethane (1 mL) to a 25 mL single-mouth bottle and stir evenly, add trifluoroacetic acid (1 mL), and stir the reaction solution at room temperature for 2 hours. Add saturated sodium bicarbonate aqueous solution to the reaction solution and adjust the pH to 7-8. The mixture was extracted three times with dichloromethane (5 mL), the organic phases were combined, washed with saturated brine (8 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure.
  • Step 1) Compound 4-1 (1.00 g, 6.97 mmol, Bid) and compound 4-1a (1.50 g, 7.66 mmol, Bid) were added to ethanol (10 mL) at room temperature and refluxed overnight. The reaction system was directly concentrated, and the residue was purified by column chromatography (0-3% methanol/dichloromethane) to obtain compound 4-2. LC-MS: m/z: 240.1 [M+H] + .
  • Step 2) At room temperature, compound 3-2a (97.4 mg, 0.440 mmol, synthesis method reference: US20200361898A1, synthesis of intermediate B005 on page 39), Pd(dtbpf)Cl 2 (28.6 mg, 0.040 mmol) and potassium carbonate (122 mg, 0.890 mmol) were added to a solution of compound 4-2 in acetonitrile (0.5 mL) and water (0.5 mL), and the reaction was carried out in a microwave reactor at 120°C for 40 minutes.
  • the reaction solution was concentrated, the residue was mixed with water (5 mL), extracted 3 times with dichloromethane (5 mL), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and spin-dried.
  • the residue was purified by preparative purification (Waters-SunFire-C18-10 ⁇ m-19*250 mm; mobile phase: water (containing 10 mmol/L formic acid) and acetonitrile, gradient ratio: acetonitrile 23%-48%, flow rate: 30 mL/min) to obtain compound 4.
  • LC-MS m/z 352.3 [M+H] + .
  • Step 1) Add N,N'-carbonyldiimidazole (1.29 g, 7.98 mmol) to a solution of compound 1-1 (1000 mg, 5.32 mmol, Bid) in tetrahydrofuran (10 mL) at room temperature. Stir the reaction at 70°C for 3 hours. Then filter the mixture to obtain compound 6-1.
  • Step 3) Add compound 6-3 (481 mg, 5.38 mmol) and N-methylmorpholine (0.35 mL, 3.23 mmol) to a solution of compound 6-2 (250 mg, 1.08 mmol) in N-methylpyrrolidone (4 mL). Stir the reaction at 100 °C for 18 hours. The reaction solution was purified by C18 liquid chromatography (eluent: 17% acetonitrile aqueous solution) to obtain compound 6-4. LC-MS: m/z: 284.9 [M+H] + .
  • Step 5 At room temperature, trifluoroacetic acid (1 mL) was added to a solution of compound 6-5 (60 mg, 0.14 mmol) in dichloromethane (2 mL). The reaction was stirred at 25°C for 1 hour. The reaction solution was concentrated under reduced pressure and the residue was purified by high performance liquid chromatography (Waters- SunFire-C18-10 ⁇ m-19*250 mm; mobile phase: water (containing 10 mmol/L formic acid) and acetonitrile, gradient ratio: acetonitrile 23%-48%, flow rate: 30 mL/min) to prepare compound 6.
  • LC-MS m/z: 381.1 [M+H] + .
  • Step 1) At room temperature, add compound 13-1 (50.0 mg, 0.290 mmol), compound M-1 (132 mg, 0.500 mmol), Xphos Pd G3 (49.92 mg, 0.06 mmol), potassium phosphate (250 mg, 1.18 mmol), dioxane (2 mL), and water (0.2 mL) to an 8 mL single-mouth bottle.
  • the reaction was carried out under nitrogen protection at 80 ° C for 1 hour.
  • Step 2) At room temperature, compound 13-2 was dissolved in dichloromethane (1 mL) in an 8 mL single-mouth bottle, and trifluoroacetic acid (1 mL) was added. The reaction was allowed to react at 25°C for 0.5 hours. The reaction solution was spin-dried. The residue was purified by high performance liquid chromatography (Waters-SunFire-C18-10 ⁇ m-19*250mm; mobile phase: water (containing 10mmol/L formic acid) and acetonitrile, gradient ratio: acetonitrile 23%-48%, flow rate: 30mL/min) to obtain the title compound) 13.
  • LC-MS m/z: 310.1 [M+H] + .
  • Step 1) At room temperature, compound M-1 (73.9 mg, 0.280 mmol), potassium carbonate (0.56 mL, 0.56 mmol, 1M aqueous solution), SPhos Pd G3 (24.1 mg, 0.03 mmol) were added to a solution of compound 7-1 (50.0 mg, 0.280 mmol) in dioxane/water (1.0 mL/0.2 mL). The system was replaced with nitrogen three times and the reaction was stirred at 90 ° C for 3 hours.
  • reaction solution was diluted with water (5 mL), extracted three times with ethyl acetate (5 mL), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and dried to obtain a crude compound 7-2, which was directly used in the next step without further purification.
  • Step 2) At room temperature, trifluoroacetic acid (1 mL) was added to a solution of compound 7-2 (45.0 mg, 0.120 mmol) in dichloromethane (3 mL), and the reaction was stirred at room temperature for 2 hours. The reaction solution was evaporated to dryness under reduced pressure, and the residue was purified by preparative purification (Waters-SunFire-C18-10 ⁇ m-19*250 mm; mobile phase: water (containing 10 mmol/L formic acid) and acetonitrile, gradient ratio: acetonitrile 23%-48%, flow rate: 30 mL/min) to obtain compound 7.
  • Step 1) At room temperature, add compound 8-1 (3.58 g, 18.9 mmol, Bid) to a single-mouth bottle, then add methanol (35 mL), add cyanogen bromide (2.01 g, 18.9 mmol) to the rapidly stirred reaction solution, and react at 50°C for 2 hours after the addition. After the reaction system returns to room temperature, add saturated sodium bicarbonate solution (200 mL) to the reaction system, and filter after the solid precipitates. The filter cake is washed with water (20 mL ⁇ 3) and dried to obtain compound 8-2.
  • Step 2) At room temperature, add compound 8-2 (100 mg, 0.470 mmol), compound M-1 (248 mg, 0.940 mmol), Pd(dppf)Cl 2 (34.4 mg, 0.050 mmol), potassium carbonate (260 mg, 1.88 mmol), dioxane (2 mL), and water (0.2 mL) to a single-mouth bottle.
  • the reaction was carried out under nitrogen protection at 80°C for 1 hour.
  • Dichloromethane (10 mL) was added to the reaction solution, diluted with water (5 mL), separated, extracted with dichloromethane (5 mL) 3 times, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and spin-dried to obtain a crude compound 8-3.
  • Step 3) At room temperature, compound 8-3 (145 mg, 0.410 mmol), dichloromethane (3 mL), and trifluoroacetic acid (1.5 mL) were added to a single-mouth bottle. The reaction was allowed to react at 25°C for 1 hour. The reaction solution was evaporated to dryness under reduced pressure. The residue was prepared and purified (Waters-SunFire-C18-10 ⁇ m-19*250 mm; mobile phase: water (containing 10 mmol/L formic acid) and acetonitrile, gradient ratio: acetonitrile 23%-48%, flow rate: 30 mL/min) to obtain compound 8.
  • Step 1) A mixture of compound 1-1 (500 mg, 2.66 mmol), cyanogen bromide (282 mg, 2.66 mmol), methanol (5 mL) and water (5 mL) was stirred at 50°C for 3 hours at room temperature. The obtained mixture was distilled under reduced pressure, ethyl acetate (10 mL) and petroleum ether (10 mL) were added to the residue, stirred for 2 hours, and then the mixture was filtered to obtain compound 1-2.
  • Step 2) At room temperature, di-tert-butyl dicarbonate (799 mg, 3.66 mmol), triethylamine (0.78 mL, 5.63 mmol) and 4-dimethylaminopyridine (1.03 g, 8.45 mmol) were added to a solution of compound 1-2 (600 mg, 2.82 mmol) in tetrahydrofuran (3 mL). The reaction was stirred at 25 ° C for 18 hours. Ethyl acetate (50 ml) and water (50 ml) were added to the reaction solution for extraction.
  • Step 4) At room temperature, trifluoroacetic acid (1 mL) was added to a solution of compound 1-5 (80 mg, 0.23 mmol) in dichloromethane (1 mL). The reaction was stirred at 25°C for 2 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by high performance liquid chromatography (Waters-SunFire-C18-10 ⁇ m-19*250mm; mobile phase: water (containing 10mmol/L formic acid) and acetonitrile, gradient ratio: acetonitrile 23%-48%, flow rate: 30mL/min) to obtain compound 1.
  • LC-MS m/z: 309.1 [M+H] + .
  • Step 3) Compound 111-4 (1.70 g, 4.11 mmol) was dissolved in dichloromethane (10 mL), trifluoroacetic acid (10 mL) was added, the reaction solution was stirred at 25°C for 3 hours, and the reaction solution was concentrated under reduced pressure to obtain compound 111-5.
  • Step 5) Compound 111-6 (1.15 g, 3.24 mmol) and compound M-1 (1.71 g, 6.48 mmol) were dissolved in dioxane (30 mL) and water (6 mL), and 1,1-bis(diphenylphosphine)diferropalladium dichloride (236 mg, 0.320 mmol, adamas) and potassium carbonate (1.78 g, 12.6 mmol) were added. The reaction was replaced with nitrogen three times, and stirred for 18 hours at 80 ° C in a nitrogen atmosphere. After the reaction was completed, water (50 mL) was added to the reaction solution, and extracted with dichloromethane (50 mL ⁇ 2).
  • Step 6): Dissolve compound 111-7 (1.26 g, 2.29 mmol) in hydrochloric acid/dioxane solution (12 mL, 4 M) and react The reaction mixture was stirred at 25°C for 2 hours. The reaction mixture was filtered to obtain a filter cake, which was dissolved in methanol (3 mL) and dichloromethane (20 mL), and extracted with saturated sodium bicarbonate solution (20 mL). The organic phase was dried over anhydrous sodium sulfate, filtered to remove the desiccant, and the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (dichloromethane/methanol 100/1 to 5/10) to obtain compound 111. MS m/z (ESI): 451.2 [M+1] + .
  • Step 3 Compound 247-2 (50.0 mg, 0.09 mmol) was dissolved in dichloromethane (3 mL), trifluoroacetic acid (3 mL) was added, and the reaction was stirred at room temperature for 2 hours. The reaction solution was directly concentrated under reduced pressure, and the residue was purified by high performance liquid chromatography (Waters-2545, chromatographic column: SharpSil-TC18, 30*150 mm, 5 ⁇ m; mobile phase: water (containing 10 mmol/L formic acid) and acetonitrile, gradient ratio: acetonitrile 38%-45%, flow rate: 30 mL/min) to obtain compound 247. MS m/z (ESI): 505.3 [M+1] +.
  • Step 1) Compound 248-1 (70.0 mg, 0.32 mmol) was dissolved in dichloromethane (3 mL), triethylamine (98.3 mg, 0.97 mmol) and isobutyryl chloride (44.8 mg, 0.42 mmol, Bid) were added at 0°C, and the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was added to a saturated sodium bicarbonate solution (15 ml), and extracted with dichloromethane (10 mL ⁇ 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered to remove the desiccant, and the filtrate was concentrated under reduced pressure. The residue was directly used as the raw material for the next step without purification to obtain compound 248-2. MS m/z (ESI): 231.2 [M-55] +.
  • Step 2) Compound 248-2 (140 mg, 0.49 mmol) was dissolved in dichloromethane (3 mL), trifluoroacetic acid (3 mL) was added, and the mixture was stirred at room temperature for 1.5 hours. The reaction solution was directly concentrated under reduced pressure to obtain compound 248-3. The residue was directly used as the raw material for the next step without purification. MS m/z (ESI): 187.2 [M+1] +.
  • Step 5 Compound 248-5 (50.0 mg, 0.10 mmol) was dissolved in dichloromethane (2 mL), trifluoroacetic acid (2 mL) was added, and the reaction was stirred at room temperature for 2 hours. The reaction solution was directly concentrated under reduced pressure, and the residue was purified by high performance liquid chromatography (Waters-2545, chromatographic column: SharpSil-TC18, 30*150 mm, 5 ⁇ m; mobile phase: water (containing 10 mmol/L formic acid) and acetonitrile, gradient ratio: acetonitrile 38%-45%, flow rate: 30 mL/min) to obtain compound 248. MS m/z (ESI): 479.3 [M+1] +.
  • Step 3 Compound 249-2 (50.0 mg, 0.09 mmol) was dissolved in dichloromethane (2 mL), trifluoroacetic acid (2 mL) was added, and the reaction was stirred at room temperature for 2 hours, and the reaction solution was directly concentrated under reduced pressure. The residue was purified by high performance liquid chromatography (Waters-2545, chromatographic column: SharpSil-TC18, 30*150 mm, 5 ⁇ m; mobile phase: water (containing 10 mmol/L formic acid) and acetonitrile, gradient ratio: acetonitrile 38%-45%, flow rate: 30 mL/min) to obtain compound 249. MS m/z (ESI): 487.4 [M+1] +.
  • Step 2) Compound 250-1 (50.0 mg, 0.14 mmol) was dissolved in a mixed solution of 1,4-dioxane (3 mL) and water (0.6 mL), M-1 (71.5 mg, 0.27 mmol), potassium carbonate (56.2 mg, 0.41 mmol) and 1,1'-bis(diphenylphosphino)ferrocenepalladium dichloride (9.91 mg, 0.01 mmol) were added, nitrogen was replaced three times, and the reaction was stirred at 80°C for 12 hours. Water (10 mL) was added to the reaction solution, and ethyl acetate was extracted (10 mL ⁇ 3).
  • Step 3) Compound 250-2 (50.0 mg, 0.10 mmol) was dissolved in dichloromethane (2 mL), trifluoroacetic acid (2 mL) was added, and the mixture was stirred at room temperature for 2 hours.
  • the reaction solution was directly concentrated under reduced pressure, and the residue was purified by high performance liquid chromatography (Waters-2545, chromatographic column: SharpSil-TC18, 30*150 mm, 5 ⁇ m; mobile phase: water (containing 10 mmol/L formic acid) and acetonitrile.
  • the product was purified by HPLC (gradient ratio: acetonitrile 38%-45%, flow rate: 30 mL/min) to obtain compound 250.
  • Step 1) Compound 253-1 (209 mg, 1.13 mmol, Bid) was dissolved in a dioxane-water solution (5/1, 5 mL), and compound 111-6 (200 mg, 0.56 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (41.2 mg, 0.06 mmol), potassium carbonate (312 mg, 2.25 mmol), the system was replaced with nitrogen three times, the reaction was stirred at 80 ° C for 2 hours, the reaction solution was diluted with water (5 mL), extracted with ethyl acetate (5 mL) three times, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and dried.
  • Step 1) Compound 254-1 (120 mg, 0.72 mmol, Bid), compound 111-6 (154 mg, 0.43 mmol) were dissolved in dioxane (5 mL) and water (1 mL), and 1,1-bis(diphenylphosphine)diferronichloridopalladium (52.9 mg, 0.07 mmol, adamas) and potassium carbonate (199 mg, 1.45 mmol) were added. The reaction was replaced with nitrogen three times, and stirred at 80 ° C for 18 hours in a nitrogen atmosphere. After the reaction was completed, water (20 mL) was added to the reaction solution, and extracted with dichloromethane (20 mL ⁇ 2).
  • Step 1) Compound 252-1 (500 mg, 2.16 mmol, prepared by the method disclosed in intermediate 20-3 on page 66 of the specification of patent application "WO 2022/166890Al”) and chloromethyl methyl ether (0.25 mL, 3.27 mmol) were dissolved in dichloromethane (10 mL), and N,N-diisopropylethylamine (0.72 mL, 4.3 mmol) was added. The reaction solution was stirred at 25°C for 18 hours, and water (50 mL) was added to the reaction solution. Ethyl acetate was extracted (50 mL ⁇ 3), the organic phases were combined, washed with saturated brine, and the organic phase was dried over anhydrous sodium sulfate.
  • Step 2) Compound 252-2 (300 mg, 1.10 mmol) was dissolved in anhydrous tetrahydrofuran, and n-butyl lithium (0.57 mL, 2.33 mmol, 2.5 M) was added at -40°C. After the reaction solution was stirred at -40°C for half an hour, isopropanol pinacol borate (0.45 mL, 2.20 mmol) was added, and the reaction was continued at 25°C for 2 hours. Ice water (20 mL) was added to the reaction solution, and ethyl acetate was extracted (20 mL ⁇ 3). The organic phases were combined and washed with saturated brine, and the organic phase was dried over anhydrous sodium sulfate.
  • Step 3) Compound 252-3 (200 mg, 0.62 mmol) and compound 111-6 (155 mg, 0.44 mmol) were dissolved in dioxane (5 mL) and water (1 mL), and 1,1-bis(diphenylphosphine)diferropalladium dichloride (45.7 mg, 0.06 mmol, adamas) and potassium carbonate (172 mg, 1.25 mmol) were added. The reaction was replaced with nitrogen three times, and stirred for 18 hours at 80 ° C in a nitrogen atmosphere. After the reaction was completed, water (50 mL) was added to the reaction solution, and extracted with ethyl acetate (50 mL ⁇ 2).
  • Step 4) Compound 252-4 (80 mg, 0.17 mmol) was dissolved in dichloromethane (4 mL), and trifluoroacetic acid (1 mL) was added. The reaction solution was stirred at 25 ° C for 2 hours. After the reaction was completed, it was concentrated under reduced pressure, and the residue was purified by high performance liquid chromatography (Gilson_306_1741, chromatographic column: Waters-SunFire-C18-10 ⁇ m-19*250mm; mobile phase: water (containing 10mmol/L formic acid) and acetonitrile, gradient ratio: acetonitrile 46%-95%, flow rate: 25mL/min) to obtain compound 252. MS m/z (ESI): 425.2 [M+1] +.
  • dichloromethane 10 mL
  • Step 2) Compound 251-2 (300 mg, 1.17 mmol) was dissolved in anhydrous tetrahydrofuran, and n-butyl lithium (0.93 mL, 2.33 mmol, 2.5 M hexane solution) was added at -78 ° C. After the reaction solution was stirred at -78 ° C for 1 hour, isopropanol pinacol borate (0.38 mL, 1.87 mmol) was added, and the reaction was continued at -78 ° C for 1 hour.
  • Step 3) Compound 251-3 (230 mg, 0.76 mmol) and compound 111-6 (188 mg, 0.53 mmol) were dissolved in dioxane (5 mL) and water (1 mL), and 1,1-bis(diphenylphosphine)diferronichloridopalladium (55.3 mg, 0.08 mmol, adamas) and potassium carbonate (209 mg, 1.51 mmol) were added. The reaction was replaced with nitrogen three times, and stirred at 80 ° C for 18 hours in a nitrogen atmosphere. After the reaction was completed, water (50 mL) was added to the reaction solution, and extracted with ethyl acetate (50 mL ⁇ 2).
  • Step 4) Compound 251-4 (130 mg, 0.29 mmol) was dissolved in dichloromethane (2 mL), and trifluoroacetic acid (2 mL) was added. The reaction solution was stirred at 25 ° C for 2 hours. After the reaction was completed, it was concentrated under reduced pressure, and the residue was purified by high performance liquid chromatography (Gilson_306_1741, chromatographic column: Waters-SunFire-C18-10 ⁇ m-19*250mm; mobile phase: water (containing 10mmol/L formic acid) and acetonitrile, gradient ratio: acetonitrile 46%-95%, flow rate: 25mL/min) to obtain compound 251.
  • Step 1) Compound 255-1 (1.00 g, 3.26 mmol, prepared by the method disclosed in Journal of Agricultural and Food Chemistry (1995), 43 (3), 804-8) was added to tetrahydrofuran (15 mL), stirred evenly, replaced with nitrogen three times, the reaction solution was cooled to -70 ° C, and n-butyl lithium (1.60 mL, 3.91 mmol, 2.5 M tetrahydrofuran solution) was slowly added, and the temperature was controlled below -65 ° C. The reaction solution was stirred for 30 minutes, and triisopropyl borate (0.92 g, 4.88 mmol) was slowly added. After the addition was completed, the reaction solution was slowly heated to room temperature and stirred at room temperature for 18 hours.
  • Step 2) Compound 255-2 (500 mg, 0.92 mmol) and compound 111-6 (100 mg, 0.28 mmol) were dissolved in dioxane (5 mL) and water (1 mL), and 1,1-bis(diphenylphosphine)diferronichloridopalladium (67.2 mg, 0.09 mmol, adamas) and potassium carbonate (254 mg, 1.84 mmol) were added. The reaction was replaced with nitrogen three times, and stirred for 18 hours at 80 ° C in a nitrogen atmosphere. After the reaction was completed, water (50 mL) was added to the reaction solution, and extracted with ethyl acetate (50 mL ⁇ 2).
  • Step 3 Compound 255-3 (160 mg, 0.22 mmol) was dissolved in methanol (15 mL), and 10% wet palladium carbon (20 mg, adamas) was added. The reaction solution was stirred for 18 hours under a hydrogen atmosphere. After the reaction was completed, the palladium carbon was filtered off, the filtrate was concentrated under reduced pressure, and the residue was purified by high performance liquid chromatography (Gilson_306_1741, chromatographic column: Waters-SunFire-C18-10 ⁇ m-19*250mm; mobile phase: water (containing 10mmol/L formic acid) and acetonitrile, gradient ratio: acetonitrile 46%-95%, flow rate: 25mL/min) to obtain compound 255. MS m/z(ESI):413.3[M+1]+.
  • Step 1) Cyclopropylcarbonyl chloride (126 ⁇ L, 1.39 mmol) was added to a solution containing compound 248-1 (150 mg, 0.69 mmol, Bid), triethylamine (192 ⁇ L, 1.39 mmol) and dichloromethane (1 mL) at 0°C.
  • the reaction solution was stirred at 25°C for 0.5 hours, then water (20 mL) was added, and ethyl acetate (20 mL ⁇ 2) was extracted.
  • the organic phases were combined and washed with saturated brine, and the organic phases were dried over anhydrous sodium sulfate. After filtering to remove the desiccant, the filtrate was concentrated under reduced pressure to obtain compound 257-1.
  • Step 2) Compound 257-1 (190 mg, 0.67 mmol) was dissolved in dichloromethane (2 mL), trifluoroacetic acid (1 mL) was added, the reaction solution was stirred at 25° C. for 1 hour, and the reaction solution was concentrated under reduced pressure to obtain compound 257-2.
  • Step 3) Potassium carbonate (277 mg, 2.00 mmol) was added to a solution of 111-2 (156 mg, 0.67 mmol), 257-2 (123 mg, 0.67 mmol), and acetonitrile (3 mL). The reaction solution was stirred at 25 ° C for 18 hours. Then water (20 mL) was added, and ethyl acetate (20 mL ⁇ 3) was extracted. The organic phases were combined and washed with saturated brine. The organic phase was dried over anhydrous sodium sulfate. After filtering to remove the desiccant, the filtrate was concentrated under reduced pressure.
  • Step 5 Trifluoroacetic acid (1 mL) was added to a solution of 257-4 (100 mg, 0.19 mmol) and dichloromethane (3 mL). The mixture was stirred at 25°C for 18 hours. The reaction solution was concentrated under reduced pressure and purified by high performance liquid chromatography (Waters-2545, column: Waters-SunFire-C18-10 ⁇ m-19*250 mm; mobile phase: water (containing 10 mmol/L formic acid) and acetonitrile, gradient ratio: acetonitrile 42%-52%, flow rate: 25 mL/min) to obtain compound 257. MS m/z (ESI): 477.0 [M+1] + .
  • Step 1) At room temperature, compound 248-1 (80.0 mg, 0.37 mmol, Leyan) and triethylamine (110 mg, 1.09 mmol) were added to dichloromethane (2 mL) and stirred evenly. Cooled to 0 ° C in an ice bath, methylsulfonyl chloride (64.0 mg, 0.56 mmol) was slowly added, and the temperature was slowly raised to room temperature and reacted for 2 hours. Water (10 mL) was added to the reaction solution, extracted with dichloromethane (5 mL ⁇ 3), the organic phase was dried with saturated brine and anhydrous sodium sulfate, and the solvent was removed under reduced pressure. No purification is required and it is directly used in the next step reaction. Compound 258-1 is obtained. MS m/z (ESI): 195.0 [M-100] +.
  • Step 2) At room temperature, compound 258-1 (120 mg, 0.41 mmol) was added to dichloromethane (1 mL) and stirred evenly, trifluoroacetic acid (1 mL) was slowly added, and the mixture was reacted at room temperature for 1 hour. The reaction solution was decompressed to remove the solvent and was directly used in the next step without purification to obtain compound 258-2.
  • Step 4) At room temperature, compound 258-3 (110 mg, 0.28 mmol), M-1 (124 mg, 0.47 mmol), potassium carbonate (118 mg, 0.85 mmol) and [1,1'-bis(diphenylphosphino)ferrocene] palladium dichloride (41.0 mg, 0.06 mmol) were added to dioxane (3 mL) and water (0.3 mL) and stirred evenly, replaced with nitrogen three times, and heated to 80 ° C for 2 hours.
  • reaction solution was cooled to room temperature, added to water (20 mL), extracted with ethyl acetate (6 mL ⁇ 3), and the organic phase was dried with saturated brine and anhydrous sodium sulfate, and the solvent was removed under reduced pressure.
  • Step 5 At room temperature, compound 258-4 (50.0 mg, 0.09 mmol) was added to dichloromethane (1 mL) and stirred evenly, trifluoroacetic acid (1 mL) was slowly added, and the reaction was carried out at room temperature for 1 hour. The reaction solution was decompressed to remove the solvent. The residue was purified by high performance liquid chromatography (Gilson_306_1741, chromatographic column: Waters-SunFire-C18-10 ⁇ m-19*250mm; mobile phase: water (containing 0.1% formic acid) and acetonitrile, gradient ratio: acetonitrile 33%-67%, flow rate: 25 mL/min) to obtain compound 258. MS m/z (ESI): 487.2 [M+1] +.
  • Step 1) At room temperature, compound 248-1 (100 mg, 0.46 mmol, Bid) and triethylamine (0.200 mL, 1.39 mmol) were added to dichloromethane (2 mL) and stirred evenly. The mixture was cooled to 0°C in an ice bath, and cyclopropanesulfonyl chloride (0.10 mL, 0.92 mmol, Bid) was slowly added. After the addition, the mixture was slowly heated to room temperature and reacted for 18 hours. Water (10 mL) was added to the reaction solution, and the mixture was extracted with dichloromethane (5 mL ⁇ 3).
  • Step 2) At room temperature, add 260-1 (130 mg, 0.41 mmol) to dichloromethane (1 mL) and stir evenly, slowly add trifluoroacetic acid (1 mL), and react at room temperature for 1 hour. The reaction solution is decompressed to remove the solvent. No purification is required and it can be directly used in the next step to obtain compound 260-2.
  • Step 3) At room temperature, compound 111-2 (75 mg, 0.32 mmol), compound 260-2 (85.0 mg, 0.39 mmol) and potassium carbonate (133 mg, 0.96 mmol) were added to acetonitrile (3 mL), stirred evenly, and the reaction solution was heated to 70 ° C and reacted for 2 hours. The reaction solution was cooled and filtered, and the filter cake was washed with dichloromethane (5 mL ⁇ 3), and the solvent was removed under reduced pressure. No purification is required and it can be directly used in the next step. Compound 260-3 is obtained. MS m/z (ESI): 419.0 [M+1] +.
  • Step 5 At room temperature, compound 260-4 (50 mg, 0.09 mmol) was added to dichloromethane (1 mL) and stirred evenly, trifluoroacetic acid (1 mL) was slowly added, and the reaction was carried out at room temperature for 1 hour. The reaction solution was decompressed to remove the solvent, and the residue was subjected to high performance liquid chromatography (Gilson_306_1741, chromatographic column: Waters-SunFire-C18-10 ⁇ m-19*250mm; mobile phase: water (containing 0.1% formic acid) and acetonitrile, gradient ratio: acetonitrile 35%-65%, flow rate: 25 mL/min) to obtain compound 260. MS m/z (ESI): 513.0 [M+1] +.
  • Step 1) Ethylsulfonyl chloride (44.0 ⁇ L, 0.46 mmol, Leyan) was added to a solution containing compound 248-1 (50.0 mg, 0.23 mmol, Bid), triethylamine (64.0 ⁇ L, 0.46 mmol) and dichloromethane (1 mL) at 0°C.
  • the reaction solution was stirred at 25°C for 0.5 hours, then water (20 mL) was added, and ethyl acetate (20 mL ⁇ 2) was extracted.
  • the organic phases were combined and washed with saturated brine.
  • the organic phase was dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure to obtain compound 259-1.
  • Step 2) Compound 128-1 (70 mg, 0.23 mmol) was dissolved in dichloromethane (2 mL), trifluoroacetic acid (0.5 mL) was added, the reaction solution was stirred at 25°C for 1 hour, and the reaction solution was concentrated under reduced pressure to obtain compound 259-2.
  • Step 3) Potassium carbonate (145 mg, 1.05 mmol) was added to a solution of 111-2 (82.0 mg, 0.35 mmol), 259-2 (73.0 mg, 0.35 mmol), and acetonitrile (5 mL). The reaction solution was stirred at 25 ° C for 18 hours. Then water (20 mL) was added, and ethyl acetate (20 mL ⁇ 3) was extracted. The organic phases were combined and washed with saturated brine. The organic phase was dried over anhydrous sodium sulfate. After filtering to remove the desiccant, the filtrate was concentrated under reduced pressure.
  • Step 5) Add trifluoroacetic acid (1 mL) to a solution of 259-4 (80.0 mg, 0.15 mmol) and dichloromethane (3 mL). Stir at 25°C for 18 hours.
  • the reaction solution was concentrated under reduced pressure and chromatographed by high performance liquid chromatography (Waters-2545, column: Waters-SunFire-C18-10 ⁇ m-19*250 mm; mobile phase: water (containing 10 mmol/L formic acid) and acetonitrile, gradient ratio: acetonitrile
  • the product was purified by HPLC (45%-55% nitrile, flow rate: 25 mL/min) to give compound 259.
  • Step 1) Compound 420-1 (1.00 g, 4.67 mmol, prepared by the method disclosed in intermediate 33 on page 84 of the specification of patent application "WO2014198594A1" and cuprous chloride (0.320 g, 3.27 mmol, Bid) were dissolved in concentrated hydrochloric acid (12 mL), and a solution of sodium nitrite (0.520 g, 7.48 mmol, Bid) in water (1 mL) was added at 5 ° C. After stirring the reaction solution at 5 ° C for 1 hour, the reaction solution was slowly poured into a saturated sodium bicarbonate aqueous solution (50 mL), and the mixture was diluted with dichloromethane (20 mL).
  • Step 2) Compound 420-2 (100 mg, 0.430 mmol), compound A (104 mg, 0.560 mmol), potassium carbonate (178 mg, 1.29 mmol) and 1,1-bis(diphenylphosphine)dichloropalladium(II) (31.5 mg, 40 ⁇ mol, Bid) were dissolved in dioxane (2.5 mL) and water (0.5 mL). The reaction solution was heated to 80 ° C under a nitrogen atmosphere and reacted for 2 hours. The reaction solution was diluted with dichloromethane (5 mL) and water (5 mL), and after the aqueous phase was separated, it was extracted with dichloromethane (5 mL ⁇ 3).
  • Step 3) Compound 420-3 (100 mg, 0.430 mmol) was dissolved in morpholine (1 mL). The mixture was heated to 200 ° C using a microwave and reacted at this temperature for 30 minutes. The reaction solution was poured into water (5 mL). The aqueous phase was extracted with dichloromethane (5 mL ⁇ 3). The combined organic phase was washed with saturated brine (5 mL) and dried over anhydrous sodium sulfate. After filtering to remove the desiccant, the filtrate was concentrated under reduced pressure.
  • Step 1) Compound 439-2 (150 mg, 360 ⁇ mol) was dissolved in dioxane (6 mL), and (R)-4-Boc-3-morpholinemethylamine (156 mg, 720 ⁇ mol, Leyan), 4,5-bis(diphenylphosphino)-9,9-dimethyloxanthene (41.6 mg, 72.0 ⁇ mol), tert- Sodium butoxide (69.1 mg, 720 ⁇ mol) and tris(dibenzylideneacetone)dipalladium (65.9 mg, 72.0 ⁇ mol) were added, nitrogen was replaced three times, and the reaction solution was poured into water (20 mL) after stirring at 100°C for 2 hours.
  • Step 2) Compound 419-1 (100 mg, 181 ⁇ mol) was dissolved in dichloromethane (2 mL), and hydrogen chloride/dioxane (4 mL, 4 M) was added. After stirring at room temperature for 1 hour, the reaction solution was directly concentrated under reduced pressure, and the residue was directly used as the raw material for the next step without purification to obtain compound 419-2.
  • Step 3 Compound 419-2 (60 mg, 147 ⁇ mol) was dissolved in dichloromethane (5 mL), triethylamine (44.6 mg, 441 ⁇ mol) and acetic anhydride (15.0 mg, 147 ⁇ mol) were added at 0°C, and the mixture was stirred at 0°C for 30 minutes.
  • the reaction solution was mixed with an aqueous sodium bicarbonate solution (10 mL), extracted with dichloromethane (20 mL ⁇ 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure.
  • Step 1) At room temperature, compound 424-5 (50 mg, 120 ⁇ mol), (R)-4-Boc-3-morpholinemethylamine (26 mg, 120 ⁇ mol, Leyan), tris(dibenzylideneacetone)dipalladium (11 mg, 12.0 ⁇ mol), sodium tert-butoxide (34 mg, 360 ⁇ mol) and 4,5-bis(diphenylphosphino-9,9-dimethylxanthene) (7.0 mg, 12.0 ⁇ mol) were added to dioxane (2 mL) and stirred evenly, replaced with nitrogen three times, heated to 80 ° C for 3 hours, and the reaction solution was added to water (20 mL) for dilution, extracted with ethyl acetate (6 mL ⁇ 3), the organic phases were combined, washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure.
  • Step 2 Trifluoroacetic acid (1 mL) was added to a solution containing 425-1 (50 mg, 180 ⁇ mol) and dichloromethane (2 mL). The reaction was stirred at 25°C for 1 hour. The reaction solution was concentrated under reduced pressure to obtain compound 425-2, which was used directly in the next step without purification. MS m/z (ESI): 423.4 [M+1] + ;
  • Step 3) Compound 425-2 (30 mg, 71 ⁇ mol), triethylamine (8.0 mg, 79 ⁇ mol) and acetic anhydride (7.0 mg, 69 ⁇ mol) were dissolved in dichloromethane (2 mL). The reaction solution was stirred at 25 ° C for 2 hours, the reaction solution was mixed with dichloromethane (10 mL) and water (5 mL), and after the aqueous phase was separated, it was extracted with dichloromethane (5 mL ⁇ 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure.
  • Step 4) Compound 425-3 (40 mg, 79 ⁇ mol) and potassium carbonate (17 mg, 180 ⁇ mol) were dissolved in methanol (2 mL). The resulting mixture was heated to 60°C and stirred for 2 hours. The reaction solution was mixed with dichloromethane (10 mL) and water (5 mL). After the aqueous phase was separated, it was extracted with dichloromethane (5 mL ⁇ 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure.
  • Step 1) Sodium methoxide methanol solution (12 mL, 30% methanol solution) was added to a methanol (220 mL) solution of compound 451-1 (10.0 g, 64.8 mmol, Anaiji), and the mixture was stirred for 30 minutes under a nitrogen atmosphere at 25 ° C. The mixture was then cooled to 0 ° C, and liquid bromine (3.33 mL, 64.8 mmol) was added. The reaction solution was stirred for 2 hours under a nitrogen atmosphere at 0 ° C. The reaction solution was concentrated under reduced pressure, the residue was mixed with water (100 mL), filtered, and the filter cake was collected and dried under vacuum to obtain compound 451-2. MS m/z (ESI): 233.0 [M + 1] + ;
  • Step 2 Raney nickel (3.00 g) was added to a solution of compound 451-2 (6.00 g, 25.7 mmol) in methanol (60 mL), and the mixture was stirred at 25° C. under a hydrogen atmosphere (1 atm) for 3 hours, filtered, and the filtrate was concentrated to obtain compound 451-3.
  • Step 4) Under a nitrogen atmosphere at 0°C, thionyl chloride (0.90 mL, 12.4 mmol) and N,N-dimethylformamide (0.80 mL, 10.3 mmol) were added to a solution of 451-4 (1.00 g, 4.08 mmol) in dichloromethane (15 mL), and the mixture was stirred for reaction at 25°C under a nitrogen atmosphere for 1 hour.
  • the reaction solution was diluted with ethyl acetate (50 mL) and poured into water (20 mL), the organic phase was washed with brine (20 mL ⁇ 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound 451-5.
  • Step 6) Compound 451-6 (430 mg, 1.01 mmol) was dissolved in dioxane (4 mL), and hydrogen chloride/dioxane (4 mL, 4 M) was added. The reaction solution was stirred at 25° C. for 3 hours, and the reaction solution was concentrated under reduced pressure to obtain compound 451-7. MS m/z (ESI): 328.8 [M+1] + ;
  • Step 7) Compound 451-7 (430 mg, 1.31 mmol) was dissolved in dichloromethane (10 mL), triethylamine (0.55 mL, 3.94 mmol) was added, and the reaction was stirred at 0°C for 10 minutes. Acetic anhydride (0.13 mL, 1.38 mmol) was added to the reaction solution, and the reaction was continued at 25°C for 15 minutes. Water (50 mL) was added to the reaction solution, and dichloromethane (50 mL ⁇ 3) was used for extraction. The organic phases were combined and washed with saturated brine (50 mL).
  • Step 9) Compound 451-9 (150 mg, 0.29 mmol) was dissolved in a hydrogen chloride/dioxane solution (4 mL, 4 M), and the reaction solution was stirred at 25°C for 2 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by high performance liquid chromatography (A: 0.1% formic acid/water, B: acetonitrile, chromatographic column: Waters-SunFire-C18-10 ⁇ m-19*250mm; mobile phase: water (containing 0.1% formic acid) and acetonitrile, gradient ratio: acetonitrile 32%-48%, flow rate: 25 mL/min) to obtain compound 451. MS m/z (ESI): 465.7 [M+1] + ;
  • Step 1) Compound 451-8 (130 mg, 0.352 mmol) and compound 253-1 (164 mg, 0.882 mmol, Bid) were dissolved in dioxane (5 mL) and water (1 mL), and 1,1-bis(diphenylphosphino)ferrocenepalladium dichloride (25.7 mg, 0.04 mmol, adamas) and potassium carbonate (195 mg, 1.41 mmol) were added. The reaction was replaced with nitrogen three times, and stirred at 80°C for 18 hours in a nitrogen atmosphere. After the reaction was completed, water (20 mL) was added to the reaction solution, and extracted with dichloromethane (20 mL ⁇ 2).
  • Step 1) At room temperature, a mixture of compound 444-1 and compound 444-1A (200 mg, 479 ⁇ mol) was added to (R)-4-Boc-3-morpholinemethylamine (1.08 g, 5.0 mmol, Leyan), microwave heated to 190°C, and reacted for 30 minutes. Cooled to room temperature, water (15 mL) was added, extracted with dichloromethane/methanol (10/1, 5 mL ⁇ 3), the organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a mixture of compound 453-1 and compound 453-1A.
  • Step 3) At room temperature, add a mixture of compound 453-2 and compound 453-2A (150 mg, 367 ⁇ mol) to dichloromethane (3 mL), add triethylamine (148 mg, 1.47 mmol), stir evenly, slowly add acetic anhydride (45.0 mg, 440 ⁇ mol), and react at room temperature for 3 hours. The solvent was removed under reduced pressure, dichloromethane (15 mL) and water (5 mL) were added, and aqueous sodium bicarbonate solution (5 mL) was added and stirred for 5 minutes, allowed to stand, and separated.
  • aqueous phase was extracted with dichloromethane (5 mL ⁇ 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure.
  • the residue was purified by high performance liquid chromatography (Gilson_306_1741, chromatographic column: Waters-SunFire-C18-10 ⁇ m-19*250mm; mobile phase: water (containing 10mmol/L formic acid) and acetonitrile, gradient ratio: acetonitrile 30%-70%, flow rate: 25mL/min) to obtain compound 453.
  • Step 1) Compound 454-1 (16.0 g, 40.7 mmol, prepared by the method disclosed in the third step intermediate on page 94 of the specification of patent application "WO2023159148A2" was dissolved in methanol (60 mL), and 10% wet palladium carbon (500 The resulting mixture was stirred under a hydrogen atmosphere (1 atm) for 18 hours, filtered, and the filtrate was concentrated to obtain compound 454-2.
  • Step 2) Compound 439-2 (100 mg, 0.241 mmol), 454-2 (93 mg, 0.361 mmol), tris(dibenzylideneacetone)dipalladium (21.9 mg, 0.025 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethyloxanthene (27.7 mg, 0.051 mmol) and sodium tert-butoxide (46.7 mg, 0.481 mmol, Bid) were mixed with dioxane (3 mL), and the resulting mixture was heated to 100 ° C. under a nitrogen atmosphere, reacted for 2 hours, cooled, and the reaction mixture was mixed with dichloromethane (5 mL) and water (5 mL).
  • Step 3 Compound 454-3 (100 mg, 0.21 mmol) was dissolved in a hydrogen chloride/dioxane solution (4 mL, 4 M), and the reaction solution was stirred at 25°C for 2 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by high performance liquid chromatography (A: 0.1% formic acid/water, B: acetonitrile, chromatographic column: Waters-SunFire-C18-10 ⁇ m-19*250mm; mobile phase: water (containing 0.1% formic acid) and acetonitrile, gradient ratio: acetonitrile 32%-48%, flow rate: 25 mL/min) to obtain compound 454. MS m/z (ESI): 437.7 [M+1] + ;
  • Step 2) At room temperature, a mixture of compound 455-1 and compound 455-1A (100 mg, 208 ⁇ mol) was added to hydrogen chloride/dioxane (2 mL, 4 M) and reacted at room temperature for 1 hour. The mixture was concentrated under reduced pressure to remove the solvent. The residue was purified by high performance liquid chromatography (Gilson_306_1741, chromatographic column: Waters-SunFire-C18-10 ⁇ m-19*250 mm; mobile phase: water (containing 10 mmol/L formic acid) and acetonitrile, gradient ratio: acetonitrile 20%-80%, flow rate: 25 mL/min) to obtain compound 455.
  • Gel_306_1741 chromatographic column: Waters-SunFire-C18-10 ⁇ m-19*250 mm
  • mobile phase water (containing 10 mmol/L formic acid) and acetonitrile, gradient ratio: acetonitrile 20%-80%, flow rate: 25 mL/min
  • Step 1) At room temperature, compound 424-5 (150 mg, 350 ⁇ mol), compound 454-2 (90 mg, 350 ⁇ mol), tris(dibenzylideneacetone)dipalladium (32 mg, 30.0 ⁇ mol), sodium tert-butoxide (100 mg, 1.04 mmol) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (21 mg, 30.0 ⁇ mol) were added to dioxane (2 mL) and stirred evenly. The mixture was replaced with nitrogen three times. The resulting mixture was heated to 80 ° C. and reacted for 3 hours. The reaction mixture was then mixed with water (20 mL) and extracted with ethyl acetate (6 mL ⁇ 3).
  • Step 2) At room temperature, compound 456-1 (20 mg, 30.0 ⁇ mol) was added to a 50 mL single-mouth bottle, and hydrogen chloride/dioxane solution (2 mL, 4 M) was added and stirred. The reaction solution was stirred at room temperature for 1.5 hours, concentrated under reduced pressure, and the residue was purified by high performance liquid chromatography (A: 0.1% formic acid/water, B: acetonitrile, chromatographic column: Waters-SunFire-C18-10 ⁇ m-19*250 mm; mobile phase: water (containing 0.1% formic acid) and acetonitrile, gradient ratio: acetonitrile 32%-48%, flow rate: 25 mL/min) to prepare compound 456. MS m/z (ESI): 451.2 [M+1] + ;
  • Step 1) After mixing a mixture of 443-4 and 443-4A (200 mg, 0.460 mmol) and (R)-4-Boc-3-morpholinemethylamine (1.00 g, 4.64 mmol, Bid), the reaction solution was stirred at 170 ° C in a microwave for 1 hour. The reaction solution was mixed with dichloromethane (10 mL) and water (2 mL), and after the aqueous phase was separated, it was extracted with dichloromethane (2 mL ⁇ 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure.
  • Step 2) Dissolve the mixture of 457-1 and 457-1A (164 mg, 0.390 mmol) and triethylamine (0.161 mL, 1.16 mmol) in dichloromethane (2 mL). Slowly add acetyl chloride (79.3 mg, 0.780 mmol) dropwise to the reaction solution at 0°C. The reaction mixture was reacted at this temperature for 1 hour. The reaction mixture was concentrated under reduced pressure to obtain a mixture of compounds 457-2 and 457-2A. MS m/z (ESI): 507.5 [M+H] + ;
  • Step 3) Dissolve the mixture 457-2 and 457-2A (197 mg, 0.390 mmol) in methanol (3 mL) and water (0.3 mL), and add potassium carbonate (107 mg, 0.780 mmol). The reaction solution was reacted at 25°C for 1 hour. The reaction solution was concentrated under reduced pressure to remove the solvent. The residue was adjusted to pH 7-8 with dilute hydrochloric acid (1.0 M), then extracted with dichloromethane (5 mL ⁇ 3), and the combined organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure.
  • the fluorescent probe used in this test is compound NP3-301 from Journal of Molecular Biology (2021) 433, 167309, which was synthesized independently based on the reference.
  • His6-Flag-TEV-NLRP3 (134-1036) protein was custom expressed by ChemPartner (Shanghai).
  • 1X assay buffer composition 50 mM Hepes, pH 7.4, 150 mM NaCl, 2.5 mM MgCl 2 , 0.005% Tween-20, 1 mM TCEP, 100 ⁇ M ATP.
  • A means IC50 ⁇ 100nM
  • B means 100nM ⁇ IC50 ⁇ 500nM
  • C means 500nM ⁇ IC50 ⁇
  • D means IC50>1000nM.
  • This experiment used the PerkinElmer AlphaLISA_human_IL1 ⁇ kit (AL220C/F).
  • the detection buffer was RPMI-1640+10FBS.
  • AlphaLISA Immunoassay Buffer, AlphaLISAAnti-IL1 ⁇ Acceptor beads, Streptavidin(SA)-coated Donor beads, and Biotinylated Antibody Anti-IL1 ⁇ were all included in the kit.
  • Table 2 Test results of IC 50 experiments using THP-1 cells to detect NLRP3 inhibitors
  • A represents IC50 ⁇ 50 nM
  • B represents 50 nM ⁇ IC50 ⁇ 100 nM
  • C represents 100 nM ⁇ IC50 ⁇ 500 nM
  • D represents IC50 ⁇ 500 nM.
  • liver microsome solution Take 18.75 ⁇ L of 20 mg/mL HLM, RLM, MLM, DLM, MOLM (final concentration: 0.5 mg/ml) in a 96-well plate;
  • the slope was calculated based on the LN value of the compound concentration percentage and time as the coordinate axis, and the residual content of the compound after incubation with liver microsomes was calculated based on the slope and the formula.
  • the compounds of the present invention showed good stability in liver microsomes of different species, and the test results of representative compounds (residual content after 45 minutes of incubation of the test compound with liver microsomes) are shown in Table 3.
  • the compound, liver microsomes and different CYP subtype enzyme substrates were incubated in a 37°C water bath, the amount of substrate metabolites generated was measured, and the inhibitory effect of the disclosed compound on CYP enzymes was evaluated based on the IC50 value.
  • iii Sample incubation. Take 1 ⁇ L of each concentration of compound and CYP subtype enzyme inhibitor in a 96-deep well plate (A-gen: P-1.0-RD-96-S), add 169 ⁇ L 0.05 mg/mL liver microsome (BioIVT, IHG) phosphate buffer solution (CYP2C19 uses 0.2 mg/mL liver microsomes), mix well and place in a 37°C shaking water bath (Shanghai Jinghong Experimental Equipment Co., Ltd., DK-500) for pre-incubation for 15 minutes.
  • A-gen P-1.0-RD-96-S
  • CYP2C19 uses 0.2 mg/mL liver microsomes
  • CYP1A2 20 min
  • CYP2C9 10 min
  • CYP2C19 10 min
  • CYP2D6 10 min
  • CYP3A4-Testosterone 10 min
  • CYP3A4-Midazolam 5 min.
  • the inhibitory effect of the compound on each P450 enzyme in human liver microsomes was calculated as the percentage of metabolite formation reduction compared to the non-inhibitory control (i.e., blank DMSO).
  • the compounds disclosed herein have weak inhibitory effects on the enzyme activities of CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4.
  • the test results of representative compounds are shown in Table 6.
  • the inhibitory effect of the compound on the hERG ion channel was detected by manual patch clamp electrophysiological method, and the cardiac safety was evaluated according to the single concentration inhibition rate or IC50 size of the compound.
  • the cells used in this experiment are HEK293 cell lines transfected with hERG cDNA and stably expressing hERG channels (#60187, provided by BPS, P3-P23 generations are used for experimental research).
  • Cell culture is cultured in a medium containing the following components: MEM medium, 10% (v/v) inactivated fetal bovine serum, 1mM sodium pyruvate, 500 ⁇ g geneticin, 0.1mM non-essential amino acids, 100U penicillin-streptomycin.
  • HEK293 hERG cells are grown in culture flasks containing the above culture medium and cultured in an incubator at 37°C and 5% CO 2.
  • HEK293 hERG cells are transferred to glass cell slides pretreated with 0.05mg/ml poly-lysine (PDL), placed in 48-well plates at a number of 1 ⁇ 10 4 cells, and grown in the same culture medium and culture conditions.
  • PDL poly-lysine
  • the components of the extracellular solution used in the hERG assay are as follows (mM): 145 NaCl, 4 KCl, 2 CaCl 2 , 1 MgCl 2 , 10 glucose, and 10 HEPES (pH adjusted to 7.40 using NaOH).
  • the components of the intracellular solution are as follows (mM): 130 KCl, 2 MgCl 2 , 5 EGTA, 10 HEPES and 5 Na 2 ATP (pH adjusted to 7.25 using KOH).
  • the following concentrations (30, 10, 3, 1, 0.3 and 0.1 ⁇ M) were tested.
  • the stock solution was first diluted with DMSO in a gradient dilution manner to 10, 3, 1, 0.3 and 0.1 mM, and then diluted with extracellular fluid to the final ⁇ M test concentration.
  • the final concentration of DMSO in each concentration of compound solution was between 0.1% and 0.3%. All compound solutions were routinely sonicated for 5 to 10 minutes and fully shaken to ensure complete dissolution of the compound, and all test solutions were mixed by rotation for at least 10 minutes.
  • the electrophysiological experiment used a manual patch clamp system (HEKA EPC-10 signal amplifier and digital conversion system, purchased from HEKA Electronics, Germany) to record the whole-cell current.
  • the specific test method is described as follows: A round glass slide with HEK293 cells stably expressing hERG channels growing on the surface is placed in an electrophysiological recording tank under an inverted microscope. The recording tank is continuously perfused with extracellular fluid (approximately 1 ml per minute).
  • the experimental process uses conventional whole-cell patch clamp current recording technology. Unless otherwise specified, the experiments are performed at normal room temperature ( ⁇ 25°C). The cells are clamped at a voltage of -80mV.
  • the cell clamping voltage is depolarized to +30mV to activate the hERG potassium channel, and then clamped to -50mV after 5 seconds to eliminate inactivation and generate tail current.
  • the peak value of the tail current is used as the value of the hERG current size.
  • mice were selected as test animals, and the LC-MS/MS method was used to quantitatively determine the drug concentration in the plasma of mice at different time points after intravenous injection or oral administration of the test compound to evaluate the pharmacokinetic characteristics of the test drug in mice.
  • ICR mice male, 15-35 g, 5-10 weeks old, Shanghai Xipu-Bikai Experimental Animal Co., Ltd.
  • the clear solution of the test compound was injected into ICR mice via the tail vein (without fasting, vehicle: 5% DMSO/10% Solutol/85% Saline), and was administered to ICR mice by gavage (fasting for 10-14h).
  • ICR mice For intravenous administration, blood was collected from the submandibular venous plexus at 0.033, 0.083, 0.25, 0.5, 1, 2, 4, 8, and 24h after administration, and placed in an EDTA-K2 anticoagulant tube (Jiangsu Kangjian Medical Supplies Co., Ltd.), mixed, and centrifuged at 2-8°C, 6800g for 6 minutes to obtain plasma;
  • EDTA-K2 anticoagulant tube Jiangsu Kangjian Medical Supplies Co., Ltd.
  • the blood drug concentration was determined by LC-MS/MS, and the pharmacokinetic software Phoenix WinNonlinTM Version 7.0 (Pharsight, USA) was used to calculate the relevant pharmacokinetic parameters by the non-compartmental linear logarithmic trapezoidal method.
  • the compounds disclosed in the present invention have good pharmacokinetic characteristics in mice.
  • the test results of representative compounds are shown in Table 8.
  • SD male rats were selected as test animals, and the LC-MS/MS method was used to quantitatively determine the drug concentration in the plasma of rats at different time points after intravenous injection or oral administration of the test compound to evaluate the pharmacokinetic characteristics of the test drug in rats.
  • the clear solution of the test compound was injected into SD rats (without fasting) via the tail vein (vehicle: 5% DMSO/10% Solutol/85% Saline), and was administered orally into SD rats (without fasting for 10-14 hours, free access to water) (vehicle: 5% DMSO/10% Solutol/85% Saline).
  • the intravenous administration was performed at 0.033, 0.083, 0.25, 0.5, 1, 2, Blood was collected from the jugular vein at 4, 8, and 24 hours, placed in an EDTA-K2 anticoagulant tube (Jiangsu Kangjian Medical Supplies Co., Ltd.), mixed, and centrifuged at 2-8°C, 6800g for 6 minutes to obtain plasma; oral gavage was performed at 0.083, 0.25, 0.5, 1, 2, 4, 6, 8, and 24 hours after administration. Blood was collected from the jugular vein and placed in an anticoagulant tube (Jiangsu Kangjian Medical Supplies Co., Ltd.) with EDTA-K2 added, mixed, and centrifuged at 2-8°C, 6800g for 6 minutes to obtain plasma.
  • the blood drug concentration was determined by LC-MS/MS, and Phoenix WinNonlinTM Version 7.0 (Pharsight, USA) pharmacokinetic software was used to calculate the relevant pharmacokinetic parameters by the non-compartmental model linear logarithmic trapezoidal method.
  • the compounds disclosed herein have good pharmacokinetic characteristics in rats, and the test results of representative compounds are shown in Table 9.
  • MCC950 Yangshen compound
  • MIA iodoacetic acid
  • the experiments used male SD rats, 4 weeks old.
  • the model induction began after the experimental animals adapted to the animal environment for 7 days.
  • Day 0 The rats were anesthetized, the hair around the left knee joint was removed, and the skin was disinfected.
  • the left leg was flexed 90° to expose the patellar platform.
  • the depression in the middle of the platform was touched by hand to find the femoral condyle, patella and ligament.
  • the syringe needle was inserted from the bottom of the patella on both sides of the patellar ligament in the direction of the femoral condyle. When a clear sense of emptiness was felt, 50 ⁇ L of iodoacetic acid solution was injected.
  • Day 7 The rats were divided into groups according to the width of the knee joint on the induced side.
  • the groups were: normal control group (healthy control without modeling, 5% DMSO + 10% Solutol + 85% Saline), model blank control group (5% DMSO + 10% Solutol + 85% Saline), MCC950 30 mg/kg, and compound 111 30 mg/kg of the present invention.
  • the normal control group and the model blank control group were orally administered with the vehicle (5% DMSO + 10% Solutol + 85% Saline) once a day, and the other groups were orally administered with the corresponding compounds once a day until the end of the administration on Day 42.
  • the knee joint width and body weight of the rats were measured once on Day 7, 14, 21, 28, 35, and 42.

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Abstract

本发明提供了一种化合物作为NLRP3抑制剂，其具有新颖的双环稠环母核。本发明进一步涉及其制备方法、含有其的药物组合物和药物、以及其在由NLRP3介导的疾病和障碍的治疗中的用途。

Description

一种抑制NLRP3的化合物及制备方法和应用
相关申请的引用
本申请要求2023年02月14日提交的中国专利申请CN202310139999.7、2023年05月31日提交的中国专利申请CN202310644402.4、2023年06月14日提交的中国专利申请CN202310705888.8、2024年01月12日提交的中国专利申请CN202410056683.6的优先权，通过援引加入的方式将上述专利申请的内容整体并入本申请，并用于所有目的。
技术领域
本发明涉及一种抑制NLRP3的化合物及制备方法和应用。
背景技术
NLRP3炎性小体是一种多蛋白聚合复合物，由NLRP3、凋亡相关斑点样蛋白(apoptosis-associated speck-like protein containing a CARD,ASC)和半胱氨酸天冬氨酸蛋白酶-1前体(Procaspase-1)组成。NLRP3炎性小体的激活需要两个步骤，即引发(第一信号)和激活(第二信号)。首先，第一信号活化核转录因子NF-κB，进而上调炎性小体相关组分的转录，包括非活性NLRP3和IL-1β前体。第二信号促进非活化的NLRP3转变为活化的NLRP3，NLRP3活化后招募ASC与pro-caspase-1，三者形成炎症小体。该小体促进pro-caspase-1自剪切成活化形式Caspase-1，Caspase-1诱导Gasdermin D(GSDMD)进行切割，并进一步在细胞膜上成孔，引发细胞死亡，即细胞焦亡(Pyroptosis)。Caspase-1诱导细胞焦亡的同时，促进IL-1β和IL-18分泌，调控机体的炎症反应。
研究表明，NLRP3炎性小体的异常激活会导致多种疾病的发生，如NLRP3获得性突变导致的遗传性疾病Cryopyrin蛋白相关周期性综合征(CAPS)、家族性寒冷型自身炎症综合征(FCAS)、Muckle-Wells综合征、新生儿发病的多系统炎症性疾病(NOMID)。另外，NLRP3炎性小体也参与多种复杂疾病的发生，如中枢神经系统的疾病(阿尔茨海默病、脑感染、多发性硬化症、肌萎缩性侧索硬化症和帕金森病)、肺部疾病(哮喘、肺部特发性纤维化)；代谢障碍(II型糖尿病及相关并发症、动脉粥样硬化、肥胖症和痛风)、肝脏疾病(慢性肝病、非酒精性脂肪肝炎、病毒性肝炎和肝硬化)、肾疾病(急性和慢性肾损伤)、炎症性肠病(IBD)、其他自身免疫性疾病(类风湿性关节炎、化脓性汗腺炎、系统性红斑狼疮)和肿瘤(大肠癌、肺癌、骨髓增生性肿瘤、白血病、骨髓发育不良症候群(MDS)、骨髓纤维化)。因此，NLRP3炎性小体作为重要的潜在靶标对多种疾病均具有重要的治疗价值。
当前尚无靶向NLRP3炎性小体的药物分子上市，未满足的市场需求明显。迄今为止已开发并进入临床试验的化合物包括Dapansutrile(Olatec)、IFM-2427(IFM/Novartis)、ZYIL-1(Zydus Lifesciences)、VTX-2735(Zomagen Biosciences/Ventyx Biosciences)等。这些化合物大多为磺酰脲类小分子NLRP3抑制剂化合物MCC950的衍生物，存在结构种类较为单一、半衰期短、不易透过血脑脊液屏障等缺点，因此，开发出新一代的具有较高活性、成药性更好的NLRP3炎症小体小分子抑制剂十分必要。
发明内容
为了解决现有技术中存在的上述技术问题之一，本发明提供了一种双环稠环母核的化合物作为NLRP3抑制剂，本发明提供的化合物具有更优良的成药性。
一方面，本发明提供了一种式I所示的化合物，或其对映异构体、非对映异构体、消旋体、互变异构体、立体异构体、几何异构体、氮氧化物、代谢产物或其药学上可接受的盐、酯、溶剂化物、水合物、同位素标记化合物(优选氘代物)或前药；
其中与环A相连接，与环B相连接；
环A和环B各自独立地选自：5-6元杂芳基、5-6元杂环基、苯基；
环C选自：6-10元芳基、5-10元杂芳基、苯基并4-7元环烷基、苯基并4-7元杂环基、5-6元杂芳基并4-7元环烷基、5-6元杂芳基并4-7元杂环基、4-7元环烷基、4-7元杂环基；
各Rc独立地选自：氢、氘、卤素、羟基、氨基、氰基、C1-6烷氧基、C1-6烷基、C1-6卤代烷基、C1-6卤代烷氧基、羟基C1-6烷基、C1-6烷氧基-C1-6烷基、Rc1S(O)2-、-(CH2)s-N(Rc1)(Rc2)、3-6元环烷基、3-6元杂环基、苯基、一个或多个卤素取代的苯基或一个或多个羟基取代苯基、5-6元杂芳基，所述3-6元环烷基、3-6元杂环基、苯基、5-6元杂芳基任选地被1、2、3个选自氘、卤素、羟基、氨基、氰基、C1-6烷基、C1-6卤代烷基、C1-6烷氧基的取代基所取代；
或者，两个Rc可与其所连接的C原子一起形成3-6元环烷基、4-7元杂环基、6元芳基或5-6元杂芳基，所述3-6元环烷基、4-7元杂环基、6元芳基或5-6元杂芳基可任选地被1、2、3个选自氘、卤素、羟基、氨基、氰基、C1-6烷氧基、C1-6烷基、C1-6卤代烷基的取代基所取代；
各Ra和Rb独立地选自：氢、氘、卤素、羟基、氨基、氰基、氧代、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C1-6烷氧基-C1-6烷基、C1-6卤代烷氧基、羟基-C1-6烷基、-NH(C1-6烷基)、-N(C1-6烷基)(C1-6烷基)、-C(＝O)-(C1-6烷基)、任选地被羟基取代的3-6元杂环基；
L1选自：键、C3-6亚环烷基、-NR2-、-O-、-S-、-C(＝O)-、-(CR3R4)a-、-NR2-(CR3R4)a-、-(CR3R4)a-NR2-、-O-(CR3R4)a-、-(CR3R4)a-O-、-S-(CR3R4)a-、-(CR3R4)a-S-、-C(＝O)-(CR3R4)a-、-(CR3R4)a-C(＝O)-、-(CR3R4)a-(CR9＝CR10)-、-(CR9＝CR10)-(CR3R4)a-、-C(＝O)-O-、-O-C(＝O)-、-C(＝O)-NR2-、-(CR3R4)a-C(＝O)-NR2-、-NR2-C(＝O)-、-(CR3R4)a-NR2-C(＝O)-、-S(＝O)2-NR2-、-NR2-S(＝O)2-、-NR2-(CR3R4)a-C(＝O)-、-C(＝O)-(CR3R4)a-NR2-、-NR2-(CR3R4)a-C(＝O)-NR5-、-NR2-C(＝O)-(CR3R4)a-NR5-、-C(＝S)-NR2-、-NR2-C(＝S)-；
L2选自键、-NR6-、-O-、-S-、-NR6-(CR7R8)b-、-(CR7R8)b-NR6-、-O-(CR7R8)b-、-(CR7R8)b-O-、-S-(CR7R8)b-、-(CR7R8)b-S-；
各R2、R5、R6、R9和R10各自独立地选自：氢、氘、C1-6烷基；
各R3、R4、R7和R8各自独立地选自：氢、氘、卤素、氧代、羟基、氨基、C1-6烷基；
R1选自：氢、羟基、氨基、羧基、C1-6烷基、C1-6烷氧基、NHR11-C(＝O)-、C1-6烷基-C(＝O)-O-、C1-6烷基-O-C(＝O)-、3-10元环烷基(优选3-6元环烷基)、3-6元单环杂环基、6-11元双环杂环基、6-10元芳基、5-10元杂芳基；其中所述氨基、C1-6烷基、C1-6烷氧基、NHR11-C(＝O)-、C1-6烷基-C(＝O)-O-、C1-6烷基-O-C(＝O)-、3-10元环烷基(优选3-6元环烷基)、3-6元单环杂环基、6-11元双环杂环基、6-10元芳基、5-10元杂芳基各自独立地任意地被1、2、3个选自氢、氘、卤素、羟基、氧代、氰基、C1-6烷基、羟基C1-6烷基、C1-6卤代烷基、C1-6烷氧基、-(CH2)s-O(Rc1)、-(CH2)s-N(Rc1)(Rc2)、C3-6环烷基、3-6元单环杂环基、5-6元杂芳基、-C(＝O)-Rc3、-S(O)-Rc3、-S(O)2-Rc3、-C(＝O)O-Rc3、-CH2-C(＝O)O-Rc4、-N(Rc4)-C(＝O)-Rc3、-CH2-N(Rc4)-C(＝O)-Rc4、-C(＝O)-N(Rc6)(Rc5)、-CH2-C(＝O)-N(Rc4)(Rc4)、-N(Rc4)- C(＝O)-N(Rc6)(Rc5)、-P(＝O)Rc5Rc6、-CRc7Rc8-CN、-(CH2)s-Rc9的取代基进一步取代；
各Rc1和Rc2独立地选自：氢、C1-6烷基、C1-6卤代烷氧基、C3-6环烷基或4-7元杂环基；
Rc3选自氢、氘、C1-6烷基、C1-6卤代烷基、C3-6环烷基，所述C1-6烷基和C3-6环烷基任意地被1、2、3个选自氘、卤素、羟基、氨基、氰基、氧代、C1-6烷基、C1-6烷氧基、C1-6卤代烷基、C1-6卤代烷氧基、C1-6烷氧基-C1-6烷基、-NH(C1-6烷基)、-N(C1-6烷基)(C1-6烷基)的取代基所取代；
Rc4选自氢、氘、C1-6烷基；
Rc5和Rc6选自氢、氘、C1-6烷基、C3-6环烷基，或者Rc5和Rc6与其所连接的N原子一起形成4-6元杂环基，所述C1-6烷基、C3-6环烷基和4-6元杂环基任意地被1、2、3个选自氘、卤素、羟基、氨基、氰基、氧代、C1-6烷基、C1-6烷氧基、C1-6卤代烷基、C1-6卤代烷氧基、C1-6烷氧基-C1-6烷基、-NH(C1-6烷基)、-N(C1-6烷基)(C1-6烷基)的取代基所取代；
Rc7和Rc8选自氢、氘、C1-6烷基，或者Rc7和Rc8与其所连接的C原子一起形成3-6元环烷基；
Rc9选自3-6元杂环基，所述杂环基任选地被1、2、3个选自氢、氘、C1-6烷基取代；
R11选自：氢、氘、C1-6烷基、3-6元单环杂环基；
各a和b各自独立地为1、2、3或4；
各s、n、m和p各自独立地选自：0、1、2、3或4；
条件是不是氢、C1-6烷基。
在一些实施例中，环A和环B涉及的基团选自如下基团：

各M1、M2、M3、M4、U1、U2各自独立地选自：CH、N；
各U3、U4、U5、U6各自独立地选自：CH2、NH、O、S。
在一些实施例中，环A和环B涉及的基团选自如下基团：
各M1、M2、M3、M4、U1、U2各自独立地选自：CH、N；
各U3、U4、U5、U6各自独立地选自：CH2、NH、O、S。
在一些实施例中，环A和环B涉及的基团选自如下基团：


各M1、M2、M3、M4、M5、M6、U1、U2各自独立地选自：CH、N；
各U3、U4、U5、U6各自独立地选自：CH2、NH、O、S。
在一些实施例中，本发明化合物具有式VIII-3或VIII-4所示的结构：
其中，R1选自：羟基、氨基、羧基、C1-6烷基、C1-6烷氧基、NHR11-C(＝O)-、C1-6烷基-C(＝O)-O-、C1-6烷基-O-C(＝O)-、3-10元环烷基、3-6元单环杂环基、6-11元双环杂环基、6-10元芳基、5-10元杂芳基；其中所述氨基、C1-6烷基、C1-6烷氧基、NHR11-C(＝O)-、C1-6烷基-C(＝O)-O-、C1-6烷基-O-C(＝O)-、3-10元环烷基、3-6元单环杂环基、6-11元双环杂环基、6-10元芳基、5-10元杂芳基各自独立地任意地被1、2、3个选自氢、氘、卤素、羟基、氧代、氰基、C1-6烷基、羟基C1-6烷基、C1-6卤代烷基、C1-6烷氧基、-(CH2)s-O(Rc1)、-(CH2)s-N(Rc1)(Rc2)、C3-6环烷基、3-6元单环杂环基、5-6元杂芳基、-CRc7Rc8-CN、-(CH2)s-Rc9的取代基进一步取代；Rcn如上述Rc所定义；
条件是同时满足下列1)～45)：
1)当为L2为键，m＝p＝0或Ra＝Rb＝H，以及L1为-NH-的同时，R1不为如下基团：
2)当为L2为键，m＝p＝0或Ra＝Rb＝H，以及L1为-NH-CH2-的同时，R1不为如下基团：
3)当为L2为键，m＝p＝0或Ra＝Rb＝H，以及L1为键的同时，R1 不为如下基团：
4)当为L2为键，m＝p＝0或Ra＝Rb＝H，以及L1为-NH-的同时，R1不为如下基团：
5)当为L2为键，m＝p＝0或Ra＝Rb＝H，以及L1为键的同时，R1 不为如下基团：
6)当为L2为键，m＝p＝0或Ra＝Rb＝H，以及L1为-NH-CH2-的同时，R1不为如下基团：
7)当为L2为键，m＝p＝0或Ra＝Rb＝H，以及L1为-CH2-的同时，R1不为如下基团：
8)当为L2为键，为以及L1为-NH-的同时，R1不为如下基团：
9)当为L2为键，m＝p＝0或Ra＝Rb＝H，以及L1为-NH-的同时，R1不为如下基团：
10)当为L2为键，m＝p＝0或Ra＝Rb＝H，以及L1为-NH-的同时，R1不为如下基团：
11)当为L2为键，m＝p＝0或Ra＝Rb＝H，以及L1为-NH-的同时，R1不为如下基团：
12)当为L2为键，m＝p＝0或Ra＝Rb＝H，以及L1为-NH-的同时，R1不为如下基团：
13)当为L2为键，m＝p＝0或Ra＝Rb＝H，以及L1为-NH-的同时，R1不为如下基团：
14)当为L2为键，m＝p＝0或Ra＝Rb＝H，以及L1为-NH-的同时，R1不为如下基团：
15)当为L2为键，m＝p＝0或Ra＝Rb＝H，以及L1为-NH-的同时，R1不为如下基团：
16)当为L2为键，m＝p＝0或Ra＝Rb＝H，以及L1为-NH-的同时， R1不为如下基团：
17)当为L2为键，m＝p＝0或Ra＝Rb＝H，以及L1为-NH-的同时，R1不为如下基团：
18)当为L2为键，m＝p＝0或Ra＝Rb＝H，以及L1为-NH-的同时，R1不为如下基团：
19)当为L2为键，m＝p＝0或Ra＝Rb＝H，以及L1为-NH-的同时，R1不为如下基团：
20)当为L2为键，m＝p＝0或Ra＝Rb＝H，以及L1为-NH-的同时，R1不为如下基团：
21)当为L2为键，m＝p＝0或Ra＝Rb＝H，以及L1为-NH-的同时，R1不为如下基团：
22)当为L2为键，m＝p＝0或Ra＝Rb＝H，以及L1为-NH-的同时， R1不为如下基团：
23)当为L2为键，m＝p＝0或Ra＝Rb＝H，以及L1为-NH-的同时，R1不为如下基团：
24)当为L2为键，m＝p＝0或Ra＝Rb＝H，以及L1为-NH-的同时，R1不为如下基团：
25)当为L2为键，m＝p＝0或Ra＝Rb＝H，以及L1为-NH-的同时，R1不为如下基团：
26)当为L2为键，m＝p＝0或Ra＝Rb＝H，以及L1为-NH-的同时，R1不为如下基团：
27)当为L2为键，m＝p＝0或Ra＝Rb＝H，以及L1为-NH-的同时，R1不为如下基团：
28)当为L2为键，为以及L1 为-NH-的同时，R1不为如下基团：
29)当为L2为键，m＝p＝0或Ra＝Rb＝H，以及L1为-NH-的同时，R1不为如下基团：
30)当为L2为键，m＝p＝0或Ra＝Rb＝H，以及L1为-NH-的同时，R1不为如下基团：
31)当为L2为键，m＝p＝0或Ra＝Rb＝H，以及L1为-NH-的同时，R1不为如下基团：
32)当为为以及L1为-NH-的同时，R1不为如下基团：
33)当为L2为键，m＝p＝0或Ra＝Rb＝H，以及L1为-NH-的同时，R1不为如下基团：
34)当为L2为键，m＝p＝0或Ra＝Rb＝H，以及L1为-NH-的同时， R1不为如下基团：
35)当为L2为键，m＝p＝0或Ra＝Rb＝H，以及L1为-NH-的同时，R1不为如下基团：
36)当为L2为键，m＝p＝0或Ra＝Rb＝H，以及L1为-NH-的同时，R1不为如下基团：
37)当为L2为键，m＝p＝0或Ra＝Rb＝H，以及L1为-NH-的同时，R1不为如下基团：
38)当为L2为键，m＝p＝0或Ra＝Rb＝H，以及L1为-NH-的同时，R1不为如下基团：
39)当为L2为键，m＝p＝0或Ra＝Rb＝H，以及L1为-NH-的同时，R1不为如下基团：
40)当为L2为键，m＝p＝0或Ra＝Rb＝H，以及L1为键的同时，R1不为如下基团：
41)当为L2为键，为以及L1为键的同时，R1不为如下基团：
42)当为L2为键，L1为-NH-，以及R1为的同时，不为如下基团：
43)当为L2为键，L1为-NH-，以及R1为的同时， 不为如下基团：
44)当为L2为键，m＝p＝0或Ra＝Rb＝H，以及L1为键的同时，R1不为如下基团：
45)不是
在一些实施例中，环A和环B涉及的基团选自如下基团，其中，以下双环基团从左向右表示环A和环B或从右向左表示环A和环B：

其中，Rab各自独立地选自：氢、氘、卤素、羟基、氨基、氰基、氧代、甲基、乙基、丙基、异丙基、丁基；
k各自独立地选自：0、1、2、3或4。
在一些实施例中，环A和环B涉及的基团选自如下基团，其中，以下双环基团从左向右表示环A和环B或从右向左表示环A和环B：

其中，Rab各自独立地选自：氢、氘、卤素、羟基、氨基、氰基、氧代、甲基、乙基、丙基、异丙基、丁基；
k各自独立地选自：0、1、2、3或4。
在一些实施例中，环A和环B涉及的基团选自如下基团，其中，以下双环基团从左向右表示环A和环B或从右向左表示环A和环B：

在一些实施例中，环A和环B涉及的基团选自如下基团，其中，以下双环基团从左向右表示环A和环B或从右向左表示环A和环B：

在一些实施例中，环C选自：6-10元芳基、5-6元杂芳基、苯基并5-6元杂芳基、苯基并4-6元环烷基、苯基并4-6元杂环基、5-6元杂芳基并5-6元杂芳基、5-6元杂芳基并4-6元环烷基、5-6元杂芳基并4-6元杂环基、5-6元环烷基、5-6元杂环基。
在一些实施例中，环C选自：6-10元芳基、5-6元杂芳基、苯基并5-6元杂芳基、苯基并4-6元环烷基、苯基并4-6元杂环基、含氮6元杂芳基并5-6元杂芳基、含氮6元杂芳基并4-6元环烷基、含氮6元杂芳基并4-6元杂环基、5-6元环烷基、5-6元杂环基。
在一些实施例中，环C涉及的基团选自以下基团：

其中，环C1和C2各自独立地选自：苯基、5元杂芳基、6元杂芳基、4元杂环基、5元杂环基、6元杂环基、4元环烷基、5元环烷基、6元环烷基；优选地，环C1和C2各自独立地选自：苯基、吡啶基、嘧啶基、吡嗪基、吡咯基、呋喃基、噻吩基、咪唑基、噁唑基、噻唑基、三氮唑基、2,3-二氢呋喃基、2,3-二氢噻吩基、2,3-二氢吡咯基、2,3-二氢二噁英基、环丁基、环戊基、环己基；
E1、E2、E3、E4和E5各自独立地选自：CH2、O、S、NH，条件是，E1、E2、E3、E4和E5中至少一个为NH，且一起组成稳定的环。
在一些实施例中，环C涉及的基团选自以下基团：

其中，Rc、n具有本发明所述的定义。
在一些实施例中，环C涉及的基团选自以下基团：


在一些实施例中，各Ra和Rb独立地选自：氢、氘、氟、氯、溴、羟基、氨基、氰基、氧代、甲基、乙基、三氟甲基、甲氧基、正丙基、异丙基、二甲胺基、乙酰基。
在一些实施例中，各Rc独立地选自：氢、氘、氟、氯、溴、羟基、氨基、氰基、C1-4烷氧基、C1-4卤代烷氧基、C1-4烷基、C1-4卤代烷基、羟基C1-4烷基、C1-4烷氧基-C1-2烷基、Rc1S(O)2-、-(CH2)s-N(Rc1)(Rc2)、3-6元环烷基、3-6元杂环基、苯基，所述苯基任选地被1、2、3个选自氘、卤素、羟基、氨基、氰基、C1-6烷基、C1-6卤代烷基、C1-6烷氧基的取代基所取代；
或者，两个Rc可与其所连接的C原子一起形成3-6元环烷基、4-7元杂环基、6元芳基或5-6元杂芳基，所述3-6元环烷基、4-7元杂环基、6元芳基或5-6元杂芳基可任选地被1、2、3个选自氘、卤素、羟基、氨基、氰基、C1-6烷氧基、C1-6烷基、C1-6卤代烷基的取代基所取代；
在一些实施例中，各Rc独立地选自：氢、氘、氟、氯、溴、羟基、氨基、氰基、C1-4烷氧基、C1-4卤代烷氧基、C1-4烷基、C1-4卤代烷基、C1-4羟基烷基、C1-4烷氧基-C1-2烷基、-(CH2)s-N(Rc1)(Rc2)、3-6元环烷基、3-6元杂环基、苯基、一个或多个卤素取代的苯基或一个或多个羟基取代苯基；或者，两个Rc可与其所连接的C原子一起形成3-6元环烷基、4-7元杂环基、6元芳基或5-6元杂芳基，所述3-6元环烷基、4-7元杂环基、6元芳基或5-6元杂芳基可任选地被1、2、3个选自氘、卤素、羟基、氨基、氰基、C1-6烷氧基、C1-6烷基、C1-6卤代烷基的取代基所取代；
在一些实施例中，各Rc独立地选自：氟、氯、溴、羟基、氨基、氰基、甲氧基、乙氧基、异丙氧基、甲氨基、乙氨基、异丙氨基、甲基、乙基、正丙基、异丙基、正丁基、异丁基、三氟甲基、二氟甲基、2,2,2-三氟乙基、五氟乙基、三氟甲氧基、二氟甲氧基、羟甲基、氨基乙基、甲氧基甲基、甲氧基乙基、乙氧基甲基、环丙基、环丁基、环戊基、环己基、环戊烯基、环丁烯基、环己烯基、氧杂环丁基、苯基、4-氯-苯基、2-氯-4-氟-苯基、4-羟基苯基、4-甲基-苯基、4-氟-苯基、吡啶基、环丁基氨基、甲磺酰基；或者，两个Rc与其所连接的C原子一起形成环戊烯基、2,3-二氢呋喃基、环丁烯基、噻吩基、1,4-二氧六环 基、吡啶基、环戊-1,3-二烯基、苯基、二噁烯基。
在一些实施例中，
各R2、R5和R6各自独立地选自：氢、氘、甲基、乙基、丙基、异丙基；
各R3、R4、R7和R8各自独立地选自：氢、氘、氧代、羟基、氨基、甲基、乙基、丙基、异丙基；
各a和b各自独立地为1或2。
在一些实施例中，
L1选自：键、-NR2-、-O-、-S-、-C(＝O)-、-NR2-(CR3R4)a-、-(CR3R4)a-NR2-、-O-(CR3R4)a-、-(CR3R4)a-O-、-S-(CR3R4)a-、-(CR3R4)a-S-，其中a为1或2；
L2选自：键、-NR6-、-NR6-(CR7R8)b-、-O-、-S-。
在一些实施例中，各s、n、m和p各自独立地选自：0、1、2或3。
在一些实施例中，
R1选自：氢、羟基、氨基、羧基、C1-4烷基、C1-4烷氧基、NHR11-C(＝O)-、C1-4烷基-C(＝O)-O-、C1-4烷基-O-C(＝O)-、3-6元环烷基、3-6元单环杂环基、6-11元螺双环杂环基、6-11元桥双环杂环基、6-11元稠双环杂环基、苯基、萘基、5-10元杂芳基；其中所述氨基、C1-4烷基、C1-4烷氧基、NHR11-C(＝O)-、C1-4烷基-C(＝O)-O-、C1-4烷基-O-C(＝O)-、3-6元环烷基、3-6元单环杂环基、6-11元螺双环杂环基、6-11元桥双环杂环基、6-11元稠双环杂环基、苯基、萘基、5-10元杂芳基各自独立地任意地被1、2、3个选自氢、氘、卤素、羟基、氨基、氧代、C1-4烷基、羟基C1-4烷基、C1-4卤代烷基、C1-4烷氧基、C3-6环烷基、3-6元单环杂环基、-C(＝O)-Rc3、-S(O)-Rc3、-S(O)2-Rc3、-C(＝O)O-Rc3、-CH2-C(＝O)O-Rc4、-N(Rc4)-C(＝O)-Rc3、-CH2-N(Rc4)-C(＝O)-Rc4、-C(＝O)-N(Rc6)(Rc5)、-CH2-C(＝O)-N(Rc4)(Rc4)、-N(Rc4)-C(＝O)-N(Rc6)(Rc5)、-P(＝O)Rc5Rc6、-CRc7Rc8-CN、-(CH2)s-Rc9的取代基进一步取代；其中R11选自：氢、氘、C1-4烷基、3-6元单环杂环基。
在一些实施例中，
R1选自：R1选自：氢、羟基、氨基、羧基、甲基、乙基、正丙基、异丙基、甲氧基、乙氧基、正丙氧基、异丙氧基、NH2-C(＝O)-、CH3NH-C(＝O)-、CH3CH2NH-C(＝O)-、CH3-C(＝O)-O-、CH3CH2-C(＝O)-O-、CH3-O-C(＝O)-、CH3CH2-O-C(＝O)-、环丙基、环丁基、环戊基、环己基、氮杂环丁基、氧杂环丁基、四氢呋喃基、吡咯烷基、哌啶基、哌嗪基、吗啉基、1,4-二氧六环基、四氢-2H-吡喃基、苯基、萘基、吡啶基、嘧啶基、吡嗪基、吡咯基、呋喃基、噻吩基、咪唑基、吡唑基、噁唑基、异噁唑基、噻唑基、异噻唑基、噻二唑基、三氮唑基、喹啉基、异喹啉基，或选自下列基团：

其中所述甲基、乙基、正丙基、异丙基、甲氧基、乙氧基、正丙氧基、异丙氧基、NH2-C(＝O)-、CH3NH-C(＝O)-、CH3CH2NH-C(＝O)-、CH3-C(＝O)-O-、CH3CH2-C(＝O)-O-、CH3-O-C(＝O)-、CH3CH2-O-C(＝O)-、环丙基、环丁基、环戊基、环己基、氮杂环丁基、氧杂环丁基、四氢呋喃基、吡咯烷基、哌啶基、哌嗪基、吗啉基、1,4-二氧六环基、四氢-2H-吡喃基、苯基、萘基、吡啶基、嘧啶基、吡嗪基、吡咯基、呋喃基、噻吩基、咪唑基、吡唑基、噁唑基、异噁唑基、噻唑基、异噻唑基、噻二唑基、三氮唑基、喹啉基、异喹啉基、 各自独立地任意地被1、2、3个选自氢、氘、卤素、羟基、氨基、氧代、甲基、乙基、正丙基、异丙基、3-6元单环杂环基、-C(＝O)-Rc3、-S(O)-Rc3、-S(O)2-Rc3、-C(＝O)O-Rc3、-N(Rc4)-C(＝O)-Rc3、-CH2-N(Rc4)-C(＝O)-Rc4、-C(＝O)-N(Rc6)(Rc5)、-N(Rc4)-C(＝O)-N(Rc6)(Rc5)、-P(＝O)Rc5Rc6、-CRc7Rc8-CN的取代基进一步取代。
在一些实施例中，其中R1选自：3-6元环烷基、3-6元单环杂环基或6-11元双环杂环基， 所述3-6元环烷基、3-6元单环杂环基或6-11元双环杂环基被1或2个选自-C(＝O)-Rc3、-S(＝O)-Rc3、-S(＝O)2-Rc3、-C(＝O)-NRc6Rc5、-P(＝O)Rc5Rc6的取代基所取代，并且所述3-6元环烷基、3-6元单环杂环基或6-11元双环杂环基还任选被1、2、3个选自氢、氘、卤素、羟基、氧代、C1-6烷基、C1-6烷氧基、C1-6烷氧基-C1-6烷基(优选C1-6烷氧基-C1-4烷基)、-(CH2)s-N(Rc1)(Rc2)、C3-6环烷基、3-6元单环杂环基的取代基所取代；
Rc3选自C1-6烷基、C3-6环烷基，所述C1-6烷基和C3-6环烷基进一步任选被1、2、3个选自氘、卤素、羟基、氨基、氰基、氧代、C1-6烷基、C1-6烷氧基、C1-6卤代烷基、C1-6卤代烷氧基、C1-6烷氧基-C1-6烷基、-NH(C1-6烷基)、-N(C1-6烷基)(C1-6烷基)的取代基所取代；
Rc5和Rc6选自H、氘、C1-6烷基、C3-6环烷基，所述C1-6烷基和C3-6环烷基进一步任选被1、2、3个选自氘、卤素、羟基、氨基、氰基、氧代、C1-6烷基、C1-6烷氧基、C1-6卤代烷基、C1-6卤代烷氧基、C1-6烷氧基-C1-6烷基、-NH(C1-6烷基)、-N(C1-6烷基)(C1-6烷基)的取代基所取代。
在一些实施例中，其中R1选自：环戊烷、环己烷、氮杂环丁烷、四氢吡咯、哌啶、吗啉、哌嗪、 所述环戊烷、环己烷、氮杂环丁烷、四氢吡咯、哌啶、吗啉、哌嗪、 被1或2个选自-C(＝O)-Rc3、-S(＝O)-Rc3、-S(＝O)2-Rc3、-C(＝O)-NRc5Rc6、-P(＝O)Rc5Rc6的取代基所取代，并且所述环戊烷、环己烷、氮杂环丁烷、四氢吡咯、哌啶、吗啉、哌嗪、 还任选被1、2、3个选自氢、氘、卤素、羟基、氧代、 C1-6烷基、C1-6烷氧基、C1-6烷氧基-C1-6烷基(优选C1-6烷氧基-C1-4烷基)、-(CH2)s-N(Rc1)(Rc2)、C3-6环烷基、3-6元单环杂环基的取代基所取代。
在一些实施例中，其中R1选自：四氢吡咯、哌啶、吗啉、哌嗪、 所述四氢吡咯、哌啶、吗啉、哌嗪、被1或2个选自-C(＝O)-Rc3、-S(＝O)-Rc3、-S(＝O)2-Rc3、-C(＝O)-NRc5Rc6、-P(＝O)Rc5Rc6的取代基所取代，并且所述四氢吡咯、哌啶、吗啉或哌嗪还任选被1、2、3个选自氢、氘、卤素、羟基、氧代、C1-6烷基、C1-6烷氧基、-(CH2)s-N(Rc1)(Rc2)、C3-6环烷基、C1-6烷氧基-C1-6烷基(优选C1-6烷氧基-C1-4烷基)、3-6元单环杂环基的取代基所取代。
在一些实施例中，其中R1选自：四氢吡咯、哌啶、吗啉或哌嗪，所述四氢吡咯、哌啶、吗啉或哌嗪被1个选自-C(＝O)-Rc3、-S(＝O)2-Rc3、-P(＝O)Rc5Rc6的取代基所取代，并且所述四氢吡咯、哌啶、吗啉或哌嗪还任选被1或2个选自氘、卤素、羟基、C1-6烷基、C1-6烷氧基、C1-6烷氧基-C1-6烷基(优选C1-6烷氧基-C1-4烷基)的取代基所取代。
在一些实施例中，其中R1选自：
在一些实施例中，本发明化合物具有式II所示的结构；
其中，环B、环C、L1、L2、Ra、Rb、Rc、n、m、p、R1、M1、M2、M3、M4具有如本发明所述的定义。
在一些实施例中，本发明化合物具有式III所示的结构；
其中，环B、L1、L2、Ra、Rb、Rc、n、m、p、R1、M1、M2、M3、M4具有如本发明所述的定义。
在一些实施例中，本发明化合物具有式IV-1、IV-2、IV-3、IV-4、IV-5、IV-6、IV-7、IV-8、IV-9或IV-10所示的结构；
其中，环C、L1、L2、Ra、Rb、Rc、n、m、p、R1、、M1、M2、M3、M4、M5、M6、U1、U3、U4、U5具有如本发明所述的定义。
在一些实施例中，本发明化合物具有式IV-1所示的结构。
在一些实施例中，本发明化合物具有式IV-2所示的结构。
在一些实施例中，本发明化合物具有式IV-3所示的结构。
在一些实施例中，本发明化合物具有式IV-4所示的结构。
在一些实施例中，本发明化合物具有式IV-5所示的结构。
在一些实施例中，本发明化合物具有式IV-6所示的结构。
在一些实施例中，本发明化合物具有式IV-7所示的结构。
在一些实施例中，本发明化合物具有式IV-8所示的结构。
在一些实施例中，本发明化合物具有式IV-9所示的结构。
在一些实施例中，本发明化合物具有式IV-10所示的结构。
在一些实施例中，本发明化合物具有式V-1、V-2、V-3、V-4、V-5、V-6、V-7、V-8、V-9或V-10所示的结构；
其中，L1、L2、Ra、Rb、Rc、n、m、p、R1、M1、M2、M3、M4、M5、M6、U1、U3、U4、U5具有如本发明所述的定义。
在一些实施例中，本发明化合物具有式V-1所示的结构。
在一些实施例中，本发明化合物具有式V-2所示的结构。
在一些实施例中，本发明化合物具有式V-3所示的结构。
在一些实施例中，本发明化合物具有式V-4所示的结构。
在一些实施例中，本发明化合物具有式V-5所示的结构。
在一些实施例中，本发明化合物具有式V-6所示的结构。
在一些实施例中，本发明化合物具有式V-7所示的结构。
在一些实施例中，本发明化合物具有式V-8所示的结构。
在一些实施例中，本发明化合物具有式V-9所示的结构。
在一些实施例中，本发明化合物具有式V-10所示的结构。
在一些实施例中，本发明化合物具有式VI-1、VI-2、VI-3、VI-4、VI-5、VI-6、VI-7、VI-8、VI-9或VI-10所示的结构；
其中n1为0、1、2或3，L1、L2、Ra、Rb、Rc、m、p、R1、M1、M2、M3、M4、M5、M6、U1、U3、U4、U5具有如本发明所述的定义。
在一些实施例中，本发明化合物具有式VI-1所示的结构。
在一些实施例中，本发明化合物具有式VI-2所示的结构。
在一些实施例中，本发明化合物具有式VI-3所示的结构。
在一些实施例中，本发明化合物具有式VI-4所示的结构。
在一些实施例中，本发明化合物具有式VI-5所示的结构。
在一些实施例中，本发明化合物具有式VI-6所示的结构。
在一些实施例中，本发明化合物具有式VI-7所示的结构。
在一些实施例中，本发明化合物具有式VI-8所示的结构。
在一些实施例中，本发明化合物具有式VI-9所示的结构。
在一些实施例中，本发明化合物具有式VI-10所示的结构。
在一些实施例中，本发明化合物具有式VII-1、VII-2、VII-3、VII-4、VII-5、VII-6、VII-7、VII-8、VII-9或VII-10所示的结构；
其中n2为0、1或2，L1、L2、Ra、Rb、Rc、m、p、R1、M1、M2、M3、M4、U1、U3、U4、U5具有如本发明所述的定义。
在一些实施例中，本发明化合物具有式VII-1所示的结构。
在一些实施例中，本发明化合物具有式VII-2所示的结构。
在一些实施例中，本发明化合物具有式VII-3所示的结构。
在一些实施例中，本发明化合物具有式VII-4所示的结构。
在一些实施例中，本发明化合物具有式VII-5所示的结构。
在一些实施例中，本发明化合物具有式VII-6所示的结构。
在一些实施例中，本发明化合物具有式VII-7所示的结构。
在一些实施例中，本发明化合物具有式VII-8所示的结构。
在一些实施例中，本发明化合物具有式VII-9所示的结构。
在一些实施例中，本发明化合物具有式VII-10所示的结构。
在一些实施例中，本发明化合物具有式VIII-1、VIII-2、VIII-3、VIII-4、VIII-5、VIII-6、VIII-7、VIII-8、VIII-9、VIII-10、VIII-11或VIII-12所示的结构：
其中，Ra、Rb、Rc、m、n、p、L1、L2、R1具有如本发明所述的定义。
在一些实施例中，本发明化合物具有式VIII-1所示的结构。
在一些实施例中，本发明化合物具有式VIII-2所示的结构。
在一些实施例中，本发明化合物具有式VIII-3所示的结构。
在一些实施例中，本发明化合物具有式VIII-4所示的结构。
在一些实施例中，本发明化合物具有式VIII-5所示的结构。
在一些实施例中，本发明化合物具有式VIII-6所示的结构。
在一些实施例中，本发明化合物具有式VIII-7所示的结构。
在一些实施例中，本发明化合物具有式VIII-8所示的结构。
在一些实施例中，本发明化合物具有式VIII-9所示的结构。
在一些实施例中，本发明化合物具有式VIII-10所示的结构。
在一些实施例中，本发明化合物具有式VIII-11所示的结构。
在一些实施例中，本发明化合物具有式VIII-12所示的结构。
在一些实施例中，本发明化合物具有式IX-1、IX-2、IX-3、IX-4、IX-5或IX-6所示的结构：
其中，Ra、Rb、L1、L2、R1、m、p具有如本发明所述的定义。
在一些实施例中，本发明化合物具有式IX-1所示的结构。
在一些实施例中，本发明化合物具有式IX-2所示的结构。
在一些实施例中，本发明化合物具有式IX-3所示的结构。
在一些实施例中，本发明化合物具有式IX-4所示的结构。
在一些实施例中，本发明化合物具有式IX-5所示的结构。
在一些实施例中，本发明化合物具有式IX-6所示的结构。
在一些实施例中，本发明化合物具有式VIII-1或VIII-2所示的结构：
各Rcn独立地选自：氢、氘、卤素、羟基、氨基、氰基、C1-6烷氧基、C1-6烷基、C1-6卤代烷基、C1-6卤代烷氧基、羟基C1-6烷基、C1-6烷氧基-C1-6烷基、-(CH2)s-N(Rc1)(Rc2)、3-6元环烷基、3-6元杂环基、苯基、5-6元杂芳基，所述3-6元环烷基、3-6元杂环基、苯基、5-6 元杂芳基任选地被1、2、3个选自氘、卤素、羟基、氨基、氰基、C1-6烷基、C1-6卤代烷基、C1-6烷氧基的取代基所取代；
或者，两个Rcn可与其所连接的C原子一起形成3-6元环烷基、4-7元杂环基、6元芳基或5-6元杂芳基，所述3-6元环烷基、4-7元杂环基、6元芳基或5-6元杂芳基可任选地被1、2、3个选自氘、卤素、羟基、氨基、氰基、C1-6烷氧基、C1-6烷基、C1-6卤代烷基的取代基所取代；
优选地，各Rcn独立地选自：氢、氘、卤素、羟基、氨基、氰基、C1-6烷氧基、C1-6烷基、C1-6卤代烷基、C1-6卤代烷氧基、羟基C1-6烷基、C1-6烷氧基-C1-6烷基、-(CH2)s-N(Rc1)(Rc2)、3-6元环烷基、3-6元杂环基、苯基、一个或多个卤素取代的苯基或一个或多个羟基取代苯基；
或者，两个Rcn可与其所连接的C原子一起形成3-6元环烷基或4-7元杂环基；
各Ra和Rb独立地选自：氢、氘、卤素、羟基、氨基、氰基、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C1-6烷氧基-C1-6烷基、C1-6卤代烷氧基、羟基-C1-6烷基、-NH(C1-6烷基)、-N(C1-6烷基)(C1-6烷基)、-C(＝O)-(C1-6烷基)、任选地被羟基取代的3-6元杂环基；
优选地，各Ra和Rb独立地选自：氢、氘、卤素、羟基、氨基、氰基、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、-NH2、-NH(C1-6烷基)、-N(C1-6烷基)(C1-6烷基)、-C(＝O)-(C1-6烷基)；
L1选自：键、C3-6亚环烷基、-NR2-、-O-、-S-、-C(＝O)-、-(CR3R4)a-、-NR2-(CR3R4)a-、-(CR3R4)a-NR2-、-O-(CR3R4)a-、-(CR3R4)a-O-、-S-(CR3R4)a-、-(CR3R4)a-S-、-C(＝O)-(CR3R4)a-、-(CR3R4)a-C(＝O)-、-(CR3R4)a-(CR9＝CR10)-、-(CR9＝CR10)-(CR3R4)a-、-C(＝O)-O-、-O-C(＝O)-、-C(＝O)-NR2-、-(CR3R4)a-C(＝O)-NR2-、-NR2-C(＝O)-、-(CR3R4)a-NR2-C(＝O)-、-S(＝O)2-NR2-、-NR2-S(＝O)2-、-NR2-(CR3R4)a-C(＝O)-、-C(＝O)-(CR3R4)a-NR2-、-NR2-(CR3R4)a-C(＝O)-NR5-、-NR2-C(＝O)-(CR3R4)a-NR5-、-C(＝S)-NR2-、-NR2-C(＝S)-；
L2选自键、-NR6-、-O-、-S-、-NR6-(CR7R8)b-、-(CR7R8)b-NR6-、-O-(CR7R8)b-、-(CR7R8)b-O-、-S-(CR7R8)b-、-(CR7R8)b-S-；
各R2、R5、R6、R9和R10各自独立地选自：氢、氘、C1-6烷基；
各R3、R4、R7和R8各自独立地选自：氢、氘、卤素、氧代、羟基、氨基、C1-6烷基；
R1选自：氢、羟基、氨基、羧基、C1-6烷基、C1-6烷氧基、NHR11-C(＝O)-、C1-6烷基-C(＝O)-O-、C1-6烷基-O-C(＝O)-、3-10元环烷基、3-6元单环杂环基、6-11元双环杂环基、6-10元芳基、5-10元杂芳基；其中所述氨基、C1-6烷基、C1-6烷氧基、NHR11-C(＝O)-、C1-6烷基-C(＝O)-O-、C1-6烷基-O-C(＝O)-、3-10元环烷基、3-6元单环杂环基、6-11元双环杂环基、6-10元芳基、5-10元杂芳基各自独立地任意地被1、2、3个选自氢、氘、卤素、羟基、氧代、氰基、C1-6烷基、羟基C1-6烷基、C1-6卤代烷基、C1-6烷氧基、-(CH2)s-O(Rc1)、-(CH2)s-N(Rc1)(Rc2)、C3-6环烷基、3-6元单环杂环基、5-6元杂芳基、-C(＝O)-Rc3、-S(O)-Rc3、-S(O)2-Rc3、-C(＝O)O-Rc3、-N(Rc4)-C(＝O)-Rc3、-C(O)-N(Rc6)(Rc5)、-CH2-C(＝O)-N(Rc4)(Rc4)、-N(Rc4)-C(＝O)-N(Rc6)(Rc5)的取代基进一步取代；
各Rc1和Rc2独立地选自：氢、C1-6烷基、C1-6卤代烷氧基、C3-6环烷基或4-7元杂环基；
Rc3选自氢、氘、C1-6烷基、C1-6卤代烷基、C3-6环烷基，所述C3-6环烷基任意地被1、2、3个选自氘、羟基、卤素、C1-6烷基的取代基进一步取代；
Rc4选自氢、氘、C1-6烷基；
Rc5和Rc6选自氢、氘、C1-6烷基、C1-6卤代烷基、C3-6环烷基，或者Rc5和Rc6与其所连接的N原子一起形成4-6元杂环基，所述C3-6环烷基和4-6元杂环基任意地被1、2、3个选自氘、羟基、卤素、C1-6烷基的取代基进一步取代；
R11选自：氢、氘、C1-6烷基、3-6元单环杂环基；
各a和b各自独立地为1、2、3或4；
各m为0或1；
各p为0、1或2；
各s、n各自独立地选自0、1、2、3或4；
条件是同时满足下列1)和2)：
1)不是H、甲基、乙基、CHF2、Boc；
2)不是
在一些实施例中，本发明的化合物具有式VIII-1所示的结构：
在一些实施例中，其中L2为键。
在一些实施例中，其中Ra和Rb各自独立地选自氢、氘、F、Cl、Br、氰基、甲基、乙基、三氟甲基、甲氧基、二甲胺基、乙酰基；优选地，Ra和Rb各自独立地选自氢、氘、F、Cl、Br、甲基、乙基；更优选地，Ra和Rb各自独立地选自氢、氘、甲基。
在一些实施例中，其中各Rcn独立地选自：氢、氘、氟、氯、溴、羟基、氨基、氰基、C1-4烷氧基、C1-4卤代烷氧基、C1-4烷基、C1-4卤代烷基、羟基C1-4烷基、C1-4烷氧基-C1-2烷基、-(CH2)s-N(Rc1)(Rc2)、3-6元环烷基、3-6元杂环基、苯基，所述3-6元环烷基、3-6元杂环基、苯基任选地被1、2、3个选自氘、卤素、羟基、氨基、氰基、C1-6烷基、C1-6卤代烷基、C1-6烷氧基的取代基所取代；，或者，两个Rcn可与其所连接的C原子一起形成3-6元环烷基、4-7元杂环基或5-6元杂芳基；
在一些实施例中，其中各Rcn独立地选自：氢、氘、氟、氯、溴、羟基、氨基、氰基、 C1-4烷氧基、C1-4卤代烷氧基、C1-4烷基、C1-4卤代烷基、C1-4羟基烷基、C1-4烷氧基-C1-2烷基、-(CH2)s-N(Rc1)(Rc2)、3-6元环烷基、3-6元杂环基、苯基、一个或多个卤素取代的苯基或一个或多个羟基取代苯基，或者，两个Rcn可与其所连接的C原子一起形成3-6元环烷基或4-7元杂环基；
在一些实施例中，其中各Rcn独立地选自：氟、氯、溴、羟基、氨基、氰基、甲氧基、乙氧基、异丙氧基、甲氨基、乙氨基、异丙氨基、甲基、乙基、正丙基、异丙基、三氟甲基、二氟甲基、2,2,2-三氟乙基、五氟乙基、三氟甲氧基、二氟甲氧基、羟甲基、氨基乙基、甲氧基甲基、甲氧基乙基、乙氧基甲基、环丙基、环丁基、环戊基、氧杂环丁基、苯基、4-氯-苯基、2-氯-4-氟-苯基、4-羟基苯基、环丁基氨基、或者，两个Rcn与其所连接的C原子一起形成环戊基或四氢呋喃基；
在一些实施例中，其中各Rcn独立地选自：氟、氯、溴、羟基、甲氧基、乙氧基、甲基、乙基、三氟甲基、二氟甲基、三氟甲氧基、二氟甲氧基。
在一些实施例中，其中选自
在一些实施例中，其中选自
在一些实施例中，其中L1选自：键、C3-6亚环烷基、-NR2-、-O-、-S-、-C(＝O)-、-(CR3R4)a-、-NR2-(CR3R4)a-、-(CR3R4)a-NR2-、-O-(CR3R4)a-、-(CR3R4)a-O-、-S-(CR3R4)a-、-(CR3R4)a-S-、-C(＝O)-(CR3R4)a-、-(CR3R4)a-C(＝O)-、-(CR3R4)a-(CR9＝CR10)-、-(CR9＝CR10)-(CR3R4)a-、-C(＝O)-O-、-O-C(＝O)-、-C(＝O)-NR2-、-(CR3R4)a-C(＝O)-NR2-、-NR2-C(＝O)-、-(CR3R4)a-NR2-C(＝O)-、-S(＝O)2-NR2-、-NR2-S(＝O)2-、-NR2-(CR3R4)a-C(＝O)-、-C(＝O)-(CR3R4)a-NR2-。
在一些实施例中，其中L1选自：键、C3-6亚环烷基、-C(＝O)-、-(CR3R4)a-、-(CR3R4)a-(CR9＝CR10)-、-(CR3R4)a-C(＝O)-NR2-、-(CR3R4)a-NR2-C(＝O)-。
在一些实施例中，其中各R2各自独立地选自：氢、氘、C1-4烷基；各R3、R4各自独立地选自：氢、氘、卤素、羟基、C1-4烷基。
在一些实施例中，其中L1选自：键、亚甲基、-C(＝O)-、亚环丙基、亚正丙基、亚正丁基、亚乙基、
在一些实施例中，其中L1选自：键、亚甲基、-C(＝O)-、亚环丙基。
在一些实施例中，其中R1选自：C1-6烷基、C1-6烷氧基、NHR11-C(＝O)-、C1-6烷基-C(＝O)-O-、C1-6烷基-O-C(＝O)-、3-10元环烷基、3-6元单环杂环基、6-11元双环杂环基、6-10元芳基、5-10元杂芳基；其中所述C1-6烷基、C1-6烷氧基、C1-6烷基-C(＝O)-O-、C1-6烷基-O-C(＝O)-、3-10元环烷基、3-6元单环杂环基、6-11元双环杂环基、6-10元芳基、5-10元杂芳基各自独立地任意地被1、2、3个选自氢、氘、卤素、羟基、氧代、氰基、C1-6烷基、C1-6烷氧基、-(CH2)s-O(Rc1)、-(CH2)s-N(Rc1)(Rc2)、C3-6环烷基、3-6元单环杂环基、-C(＝O)-Rc3、-S(O)-Rc3、-S(O)2-Rc3、-C(＝O)O-Rc3、-N(Rc4)-C(＝O)-Rc3、-C(O)-N(Rc6)(Rc5)、-N(Rc4)-C(＝O)-N(Rc6)(Rc5)的取代基进一步取代。
在一些实施例中，其中R1选自：C1-3烷基、NHR11-C(＝O)-、3-10元环烷基、3-6元单环杂环基、6-11元双环杂环基、6-10元芳基、5-10元杂芳基；其中所述C1-3烷基、3-10元环烷基、3-6元单环杂环基、6-11元双环杂环基、6-10元芳基、5-10元杂芳基各自独立地任意地被1、2、3个选自氘、卤素、羟基、氧代、氰基、C1-6烷基、C1-6烷氧基、-(CH2)s-O(Rc1)、-(CH2)s-N(Rc1)(Rc2)、C3-6环烷基、3-6元单环杂环基、-C(＝O)-Rc3、-S(O)2-Rc3、-C(＝O)O-Rc3、- N(Rc4)-C(＝O)-Rc3、-C(O)-N(Rc6)(Rc5)、-N(Rc4)-C(＝O)-N(Rc6)(Rc5)的取代基进一步取代。
在一些实施例中，其中R1选自：甲基、乙基、异丙基、吡咯烷、四氢呋喃、四氢噻吩、四氢噻喃、四氢吡喃、硫杂环丁烷、氧杂环丁烷、氮杂环丁烷、哌啶、吗啉、哌嗪、环丁烷、环戊烷、环己烷、正庚烷、苯基、吡啶、嘧啶、吡咯、咪唑、噁唑、异噁唑、噻唑、吡唑、呋喃、三唑、-C(＝O)-NH2、 其中所述甲基、乙基、异丙基、吡咯烷、四氢呋喃、四氢噻吩、四氢噻喃、四氢吡喃、硫杂环丁烷、氧杂环丁烷、氮杂环丁烷、哌啶、吗啉、哌嗪、环丁烷、环戊烷、环己烷、正庚烷、苯基、吡啶、嘧啶、吡咯、咪唑、噁唑、异噁唑、噻唑、吡唑、呋喃、三唑、 各自独立地任意地被1、2、3个选自氘、卤素、羟基、氧代、氰基、C1-6烷基、C1-6烷氧基、-(CH2)s-O(Rc1)、-(CH2)s-N(Rc1)(Rc2)、C3-6环烷基、3-6元单环杂环基、-C(＝O)-Rc3、-S(O)2-Rc3、-C(＝O)O-Rc3、-N(Rc4)-C(＝O)-Rc3、-C(O)-N(Rc6)(Rc5)、-N(Rc4)-C(＝O)-N(Rc6)(Rc5)的取代基进一步取代。
在一些实施例中，其中R1选自：甲基、异丙基、吡咯烷、四氢呋喃、四氢噻吩、四氢噻喃、四氢吡喃、硫杂环丁烷、氧杂环丁烷、氮杂环丁烷、哌啶、吗啉、哌嗪、环丁烷、环戊烷、环己烷、正庚烷、苯基、吡啶、嘧啶、吡咯、咪唑、噁唑、异噁唑、噻唑、吡唑、呋喃、三唑，其中所述甲基、异丙基、吡咯烷、四氢呋喃、四氢噻吩、四氢噻喃、四氢吡喃、硫杂环丁烷、氧杂环丁烷、氮杂环丁烷、哌啶、吗啉、哌嗪、环丁烷、环戊烷、环己烷、正庚烷、苯基、吡啶、嘧啶、吡咯、咪唑、噁唑、异噁唑、噻唑、吡唑、呋喃、三唑各自独立地任意地被1、2、3个选自氘、卤素、羟基、氧代、氰基、C1-6烷基、C1-6烷氧基、-(CH2)s-O(Rc1)、-(CH2)s-N(Rc1)(Rc2)、C3-6环烷基、3-6元单环杂环基、-C(＝O)-Rc3、-S(O)2-Rc3、-C(＝O)O-Rc3、-N(Rc4)-C(＝O)-Rc3、-C(O)-N(Rc6)(Rc5)、-N(Rc4)-C(＝O)-N(Rc6)(Rc5)的取代基进一步取代。
在一些实施例中，其中-L1-R1选自
在一些实施例中，其中-L1-R1选自
在一些实施例中，其中-L1-R1选自
在一些实施例中，本发明化合物具有式X-1或X-2所示的结构：
环C选自：6-10元芳基、5-10元杂芳基、苯基并4-7元环烷基、苯基并4-7元杂环基、5-6元杂芳基并4-7元环烷基、5-6元杂芳基并4-7元杂环基、4-7元环烷基、4-7元杂环基；
各Rcn独立地选自：氢、氘、卤素、羟基、氨基、氰基、C1-6烷氧基、C1-6烷基、C1-6卤代烷基、C1-6卤代烷氧基、羟基C1-6烷基、C1-6烷氧基-C1-6烷基、Rc1S(O)2-、-(CH2)s-N(Rc1)(Rc2)、3-6元环烷基、3-6元杂环基、苯基、5-6元杂芳基，所述3-6元环烷基、3-6元杂环基、苯基、5-6元杂芳基任选地被1、2、3个选自氘、卤素、羟基、氨基、氰基、C1-6烷基、C1-6卤代烷基、C1-6烷氧基的取代基所取代；
或者，两个Rcn可与其所连接的C原子一起形成3-6元环烷基、4-7元杂环基、6元芳基或5-6元杂芳基，所述3-6元环烷基、4-7元杂环基、6元芳基或5-6元杂芳基可任选地被1、2、3个选自氘、卤素、羟基、氨基、氰基、C1-6烷氧基、C1-6烷基、C1-6卤代烷基的取代基所取代；
各Ra和Rb独立地选自：氢、氘、卤素、羟基、氨基、氰基、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C1-6烷氧基-C1-6烷基、C1-6卤代烷氧基、羟基-C1-6烷基、-NH(C1-6烷基)、-N(C1-6烷基)(C1-6烷基)、-C(＝O)-(C1-6烷基)、任选地被羟基取代的3-6元杂环烷基；
L1选自：键、C3-6亚环烷基、-NR2-、-O-、-S-、-C(＝O)-、-(CR3R4)a-、-NR2-(CR3R4)a-、-(CR3R4)a-NR2-、-O-(CR3R4)a-、-(CR3R4)a-O-、-S-(CR3R4)a-、-(CR3R4)a-S-、-C(＝O)-(CR3R4)a-、-(CR3R4)a-C(＝O)-、-(CR3R4)a-(CR9＝CR10)-、-(CR9＝CR10)-(CR3R4)a-、-C(＝O)-O-、-O-C(＝O)-、-C(＝O)-NR2-、-(CR3R4)a-C(＝O)-NR2-、-NR2-C(＝O)-、-(CR3R4)a-NR2-C(＝O)-、-S(＝O)2-NR2-、-NR2-S(＝O)2-、-NR2-(CR3R4)a-C(＝O)-、-C(＝O)-(CR3R4)a-NR2-、-NR2-(CR3R4)a-C(＝O)-NR5-、-NR2-C(＝O)-(CR3R4)a-NR5-、-C(＝S)-NR2-、-NR2-C(＝S)-；
L2选自键、-NR6-、-O-、-S-、-NR6-(CR7R8)b-、-(CR7R8)b-NR6-、-O-(CR7R8)b-、-(CR7R8)b-O-、-S-(CR7R8)b-、-(CR7R8)b-S-；
各R2、R5、R6、R9和R10各自独立地选自：氢、氘、C1-6烷基；
各R3、R4、R7和R8各自独立地选自：氢、氘、卤素、氧代、羟基、氨基、C1-6烷基；
R1选自：3-10元环烷基、3-6元单环杂环基、6-11元双环杂环基、6-10元芳基、5-10元 杂芳基，所述3-10元环烷基、3-6元单环杂环基、6-11元双环杂环基、6-10元芳基、5-10元杂芳基被1或2个选自-C(＝O)-Rc3、-S(＝O)-Rc3、-S(＝O)2-Rc3、-C(＝O)-NRc5Rc6、-P(＝O)Rc5Rc6的取代基所取代，并且所述3-10元环烷基、3-6元单环杂环基、6-11元双环杂环基、6-10元芳基、5-10元杂芳基还任选被1、2、3个选自氢、氘、卤素、羟基、氧代、氰基、C1-6烷基、羟基C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C1-6烷氧基-C1-6烷基、-(CH2)s-N(Rc1)(Rc2)、C3-6环烷基、3-6元单环杂环基的取代基所取代；
各Rc1和Rc2独立地选自：氢、C1-6烷基、C1-6卤代烷氧基、C3-6环烷基或4-7元杂环基；
Rc3选自C1-6烷基、C3-6环烷基，所述C1-6烷基和C3-6环烷基进一步任选被1、2、3个选自氘、卤素、羟基、氨基、氰基、氧代、C1-6烷基、C1-6烷氧基、C1-6卤代烷基、C1-6卤代烷氧基、C1-6烷氧基-C1-6烷基、-NH(C1-6烷基)、-N(C1-6烷基)(C1-6烷基)的取代基所取代；
Rc5和Rc6选自H、氘、C1-6烷基、C3-6环烷基，或者Rc5和Rc6与其所连接的N原子一起形成4-6元杂环基，所述C1-6烷基、C3-6环烷基和4-6元杂环基进一步任选被1、2、3个选自氘、卤素、羟基、氨基、氰基、氧代、C1-6烷基、C1-6烷氧基、C1-6卤代烷基、C1-6卤代烷氧基、C1-6烷氧基-C1-6烷基、-NH(C1-6烷基)、-N(C1-6烷基)(C1-6烷基)的取代基所取代；
各a和b各自独立地为1、2、3或4；
各m为0或1；
各p为0、1或2；
各s、n各自独立地选自0、1、2、3或4；
条件是：不是
在一些实施例中，本发明化合物具有式VIII-3或VIII-4所示的结构：
各Rcn独立地选自：氢、氘、卤素、羟基、氨基、氰基、C1-6烷氧基、C1-6烷基、C1-6卤代烷基、C1-6卤代烷氧基、羟基C1-6烷基、C1-6烷氧基-C1-6烷基、Rc1-S(O)2-、-(CH2)s-N(Rc1)(Rc2)、3-6元环烷基、3-6元杂环基、苯基、5-6元杂芳基，所述3-6元环烷基、3-6元杂环基、苯基、5-6元杂芳基任选地被1、2、3个选自氘、卤素、羟基、氨基、氰基、C1-6烷基、C1-6卤代烷基、C1-6烷氧基的取代基所取代；
或者，两个Rcn可与其所连接的C原子一起形成3-6元环烷基、4-7元杂环基、6元芳基或5-6元杂芳基，所述3-6元环烷基、4-7元杂环基、6元芳基或5-6元杂芳基可任选地被1、2、3个选自氘、卤素、羟基、氨基、氰基、C1-6烷氧基、C1-6烷基、C1-6卤代烷基的取代基所取代；
各Ra和Rb独立地选自：氢、氘、卤素、羟基、氨基、氰基、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C1-6烷氧基-C1-6烷基、C1-6卤代烷氧基、羟基-C1-6烷基、-NH(C1-6烷基)、-N(C1-6烷基)(C1-6烷基)、-C(＝O)-(C1-6烷基)、任选地被羟基取代的3-6元杂环烷基；
L1选自：键、C3-6亚环烷基、-NR2-、-O-、-S-、-C(＝O)-、-(CR3R4)a-、-NR2-(CR3R4)a-、-(CR3R4)a-NR2-、-O-(CR3R4)a-、-(CR3R4)a-O-、-S-(CR3R4)a-、-(CR3R4)a-S-、-C(＝O)-(CR3R4)a-、-(CR3R4)a-C(＝O)-、-(CR3R4)a-(CR9＝CR10)-、-(CR9＝CR10)-(CR3R4)a-、-C(＝O)-O-、-O-C(＝O)- 、-C(＝O)-NR2-、-(CR3R4)a-C(＝O)-NR2-、-NR2-C(＝O)-、-(CR3R4)a-NR2-C(＝O)-、-S(＝O)2-NR2-、-NR2-S(＝O)2-、-NR2-(CR3R4)a-C(＝O)-、-C(＝O)-(CR3R4)a-NR2-、-NR2-(CR3R4)a-C(＝O)-NR5-、-NR2-C(＝O)-(CR3R4)a-NR5-、-C(＝S)-NR2-、-NR2-C(＝S)-；
L2选自键、-NR6-、-O-、-S-、-NR6-(CR7R8)b-、-(CR7R8)b-NR6-、-O-(CR7R8)b-、-(CR7R8)b-O-、-S-(CR7R8)b-、-(CR7R8)b-S-；
各R2、R5、R6、R9和R10各自独立地选自：氢、氘、C1-6烷基；
各R3、R4、R7和R8各自独立地选自：氢、氘、卤素、氧代、羟基、氨基、C1-6烷基；
R1选自：3-6元环烷基、3-6元单环杂环基或6-11元双环杂环基，所述3-6元环烷基、3-6元单环杂环基或6-11元双环杂环基被1或2个选自-C(＝O)-Rc3、-S(＝O)-Rc3、-S(＝O)2-Rc3、-C(＝O)-NRc5Rc6、-P(＝O)Rc5Rc6的取代基所取代，并且所述3-6元环烷基、3-6元单环杂环基或6-11元双环杂环基还任选被1、2、3个选自氢、氘、卤素、羟基、氧代、氰基、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C1-6烷氧基-C1-6烷基、-(CH2)s-N(Rc1)(Rc2)、C3-6环烷基、3-6元单环杂环基的取代基所取代；
各Rc1和Rc2独立地选自：氢、C1-6烷基、C1-6卤代烷氧基、C3-6环烷基或4-7元杂环基；
Rc3选自C1-6烷基、C3-6环烷基，所述C1-6烷基和C3-6环烷基进一步任选被1、2、3个选自氘、卤素、羟基、氨基、氰基、氧代、C1-6烷基、C1-6烷氧基、C1-6卤代烷基、C1-6卤代烷氧基、C1-6烷氧基-C1-6烷基、-NH(C1-6烷基)、-N(C1-6烷基)(C1-6烷基)的取代基所取代；
Rc5和Rc6选自H、氘、C1-6烷基、C3-6环烷基，或者Rc5和Rc6与其所连接的N原子一起形成4-6元杂环基，所述C1-6烷基、C3-6环烷基和4-6元杂环基进一步任选被1、2、3个选自氘、卤素、羟基、氨基、氰基、氧代、C1-6烷基、C1-6烷氧基、C1-6卤代烷基、C1-6卤代烷氧基、C1-6烷氧基-C1-6烷基、-NH(C1-6烷基)、-N(C1-6烷基)(C1-6烷基)的取代基所取代；
R11选自：氢、氘、C1-6烷基、3-6元单环杂环基；
各a和b各自独立地为1、2、3或4；
各m为0或1；
各p为0、1或2；
各s、n各自独立地选自0、1、2、3或4。
在一些实施例中，其中所述化合物具有式VIII-3所示的结构：
在一些实施例中，其中L2为键。
在一些实施例中，其中Ra和Rb各自独立地选自氢、氘、F、Cl、Br、氰基、甲基、乙基、三氟甲基、甲氧基、1-羟基乙基-1-基、甲胺基、二甲胺基、乙酰基、3-羟基氮杂环丁烷基；优选地，Ra和Rb各自独立地选自氢、氘、F、Cl、Br、甲基、乙基；更优选地，Ra和Rb各自独立地选自氢、氘、甲基。
在一些实施例中，其中各Rcn独立地选自：氢、氘、氟、氯、溴、羟基、氨基、氰基、C1-4烷氧基、C1-4卤代烷氧基、C1-4烷基、C1-4卤代烷基、羟基C1-4烷基、C1-4烷氧基-C1-2烷基、Rc1-S(O)2-、-(CH2)s-N(Rc1)(Rc2)、3-6元环烷基、3-6元杂环基、苯基、5-6元杂芳基，所述3-6元环烷基、3-6元杂环基、苯基、5-6元杂芳基任选地被1、2、3个选自氘、卤素、羟基、氨基、氰基、C1-6烷基、C1-6卤代烷基、C1-6烷氧基的取代基所取代；或者，两个Rcn可与其所连接的C原子一起形成3-6元环烷基、4-7元杂环基、6元芳基或5-6元杂芳基，所述 3-6元环烷基、4-7元杂环基、6元芳基或5-6元杂芳基可任选地被1-3个选自氘、卤素、羟基、氨基、氰基、C1-6烷氧基、C1-6烷基、C1-6卤代烷基的取代基所取代；
在一些实施例中，其中各Rcn独立地选自：氢、氘、氟、氯、溴、羟基、氨基、氰基、C1-4烷氧基、C1-4卤代烷氧基、C1-4烷基、C1-4卤代烷基、羟基C1-4烷基、C1-4烷氧基-C1-2烷基、Rc1-S(O)2-、-(CH2)s-N(Rc1)(Rc2)、3-6元环烷基、3-6元杂环基、苯基、一个或多个卤素取代的苯基或一个或多个羟基取代苯基，或者，两个Rcn可与其所连接的C原子一起形成3-6元环烷基、4-7元杂环基、6元芳基或5-6元杂芳基，所述3-6元环烷基、4-7元杂环基、6元芳基或5-6元杂芳基可任选地被1-3个选自氘、卤素、羟基、氨基、氰基、C1-6烷氧基、C1-6烷基、C1-6卤代烷基的取代基所取代。
在一些实施例中，其中各Rcn独立地选自：氟、氯、溴、羟基、氨基、氰基、甲氧基、乙氧基、异丙氧基、甲氨基、乙氨基、异丙氨基、甲基、乙基、正丙基、异丙基、正丁基、异丁基、三氟甲基、二氟甲基、2,2,2-三氟乙基、五氟乙基、三氟甲氧基、二氟甲氧基、羟甲基、氨基乙基、甲氧基甲基、甲氧基乙基、乙氧基甲基、环丙基、环丁基、环戊基、环己基、环戊烯基、环丁烯基、环己烯基、氧杂环丁基、苯基、4-氯-苯基、2-氯-4-氟-苯基、4-羟基苯基、4-甲基-苯基、4-氟-苯基、吡啶基、环丁基氨基、或者，两个Rcn与其所连接的C原子一起形成环戊烯基、2,3-二氢呋喃基、环丁烯基、噻吩基、1,4-二氧六环基、吡啶基、环戊-1,3-二烯基、苯基、1,4-二氧杂-2-己烯基。
在一些实施例中，其中各Rcn独立地选自：氟、氯、溴、羟基、氰基、甲氧基、乙氧基、甲基、乙基、三氟甲基、二氟甲基、三氟甲氧基、二氟甲氧基。
在一些实施例中，其中选自
在一些实施例中，其中选自
在一些实施例中，其中L2选自键、-NR6-、-O-、-S-、-NR6-(CR7R8)b1-、-(CR7R8)b1-NR6-、-O-(CR7R8)b1-、-(CR7R8)b1-O-、-S-(CR7R8)b1-、-(CR7R8)b1-S-，其中b1为1或2。
在一些实施例中，其中L2选自键、-NR6-、-NR6-(CR7R8)b1-、-(CR7R8)b1-NR6-，其中b1为1或2。
在一些实施例中，其中L2选自-NR6-、-NR6-(CR7R8)b1-、-(CR7R8)b1-NR6-，其中b1为1。
在一些实施例中，其中L2选自-NH-、-NH-(CR7R8)-。
在一些实施例中，其中L2选自-NH-、-NH-CH2-。
在一些实施例中，其中R1选自：环戊烷、环己烷、氮杂环丁烷、四氢吡咯、哌啶、吗啉、哌嗪、 所述环戊烷、环己烷、氮杂环丁烷、四氢吡咯、哌啶、吗啉、哌嗪、 被1或2个选自-C(＝O)-Rc3、-S(＝O)-Rc3、-S(＝O)2-Rc3、-C(＝O)-NRc5Rc6、-P(＝O)Rc5Rc6的取代基所取代，并且所述环戊烷、环己烷、氮杂环丁烷、四氢吡咯、哌啶、吗啉、哌嗪、 还任选被1、2、3个选自氢、氘、卤素、羟基、氧代、C1-6烷基、C1-6烷氧基、C1-6烷氧基-C1-6烷基、-(CH2)s-N(Rc1)(Rc2)、C3-6环烷基、3-6元单环杂环基的取代基所取代。
在一些实施例中，R1选自：四氢吡咯、哌啶、吗啉、哌嗪、 所述四氢吡咯、哌啶、吗啉、哌嗪、 被1或2个选自-C(＝O)-Rc3、-S(＝O)-Rc3、-S(＝O)2-Rc3、-C(＝O)-NRc5Rc6、-P(＝O)Rc5Rc6的取代基所取代，并且所述四氢吡咯、哌啶、吗啉、哌嗪、 还任选被1、2、3个选自氢、氘、卤素、羟基、氧代、C1-6烷基、C1-6烷氧基、-(CH2)s-N(Rc1)(Rc2)、C3-6环烷基、C1-6烷氧基-C1-6烷基、3-6元单环杂环基的取代基所取代。
在一些实施例中，R1选自：四氢吡咯、哌啶、吗啉、哌嗪、 所述四氢吡咯、哌啶、吗啉、哌嗪、被1个选自-C(＝O)-Rc3、-S(＝O)2-Rc3、-P(＝O)Rc5Rc6的取代基所取代，并且所述四氢吡咯、哌啶、吗啉、哌嗪、还任选被1或2个选自氘、卤素、羟基、C1-6烷基、C1-6烷氧基、C1-6烷氧基-C1-6烷基的取代基所取代。
在一些实施例中，R1选自：
在一些实施例中，R1选自：
在一些实施例中，其中所述化合物具有式VIII-8或VIII-12所示的结构：
其中R1、L1、Ra、Rb、Rc、L2、m、n、p的定义如上文所述。
在一些实施例中，各Rc独立地选自：氢、氘、卤素、羟基、氰基、C1-6烷氧基、C1-6烷基、C1-6卤代烷基、C1-6卤代烷氧基、C1-6烷氧基-C1-6烷基、Rc1S(O)2-、3-6元环烷基、3-6元杂环基、苯基、5-6元杂芳基，所述3-6元环烷基、3-6元杂环基、苯基、5-6元杂芳基任选地被1、2、3个选自氘、卤素、羟基、氨基、氰基、C1-6烷基、C1-6卤代烷基、C1-6烷氧基的取代基所取代；
或者，两个Rc可与其所连接的C原子一起形成3-6元环烷基、4-7元杂环基、6元芳基或5-6元杂芳基，所述3-6元环烷基、4-7元杂环基、6元芳基或5-6元杂芳基可任选地被1、2、3个选自氘、卤素、羟基、氨基、氰基、C1-6烷氧基、C1-6烷基、C1-6卤代烷基的取代基所取代；
L2选自键、-NR6-、-O-、-S-；
Ra、Rb、Rc、Rc1、R6、R1、L1、n、m、p如上文所定义。
在一些实施例中，其中所述化合物具有式VIII-8所示的结构：
其中R1、L1、Ra、Rb、Rc、L2、m、n、p的定义如上文所述。
在一些实施例中，其中，R1为3-6元单环杂环基，所述3-6元单环杂环基任选地被1、2、3个选自氘、卤素、羟基、氧代、氰基、C1-6烷基、C1-6卤代烷基、羟基C1-6烷基、C1-6烷氧基、-(CH2)S-O(Rc1)、-(CH2)S-N(Rc1)(Rc2)、C3-6环烷基、3-6元单环杂环基、5-6元杂芳基、-C(＝O)-Rc3、-S(O)-Rc3、-S(O)2-Rc3、-C(＝O)O-Rc3、-N(Rc4)-C(＝O)-Rc3、-CH2-N(Rc4)-C(＝O)-Rc4、-C(＝O)-N(Rc6)(Rc5)、-N(Rc4)-C(＝O)-N(Rc6)(Rc5)、-P(＝O)Rc5Rc6的取代基进一步取代；
在一些实施例中，所述R1选自四氢吡咯、哌啶、吗啉、哌嗪、1,4-氧硫杂环己烷，所述四氢吡咯、哌啶、吗啉、哌嗪、1,4-氧硫杂环己烷各自独立地任意地被1、2、3个选自氘、卤素、羟基、氨基、氧代、C1-4烷基、C1-4卤代烷基、羟基C1-4烷基、C1-4烷氧基、C3-6环烷基、3-6元单环杂环基、-C(＝O)-Rc3、-S(O)-Rc3、-S(O)2-Rc3、-C(＝O)O-Rc3、-N(Rc4)-C(＝O)-Rc3、-CH2-N(Rc4)-C(＝O)-Rc4、-C(＝O)-N(Rc6)(Rc5)、-N(Rc4)-C(＝O)-N(Rc6)(Rc5)、-P(＝O)Rc5Rc6的取代基进一步取代；优选地，所述R1选自吗啉，所述吗啉任意地被1、2、3个选自氘、卤素、羟基、氨基、氧代、C1-4烷基、C1-4烷氧基、C3-6环烷基、3-6元单环杂环基、-C(＝O)-Rc3、-S(O)-Rc3、-S(O)2-Rc3、-C(＝O)O-Rc3、-N(Rc4)-C(＝O)-Rc3、-CH2-N(Rc4)-C(＝O)-Rc4、-C(＝O)-N(Rc6)(Rc5)、-N(Rc4)-C(＝O)-N(Rc6)(Rc5)、-P(＝O)Rc5Rc6的取代基进一步取代。
在一些实施例中，其中R1选自：
在一些实施例中，本发明化合物具有式VIII-9所示的结构：
其中R1、L1、Ra、Rb、Rc、L2、m、n、p的定义如上文所述；条件是：不是
在一些实施例中，所述R1为3-6元单环杂环基，所述3-6元单环杂环基任选地被1、2、3个选自氘、卤素、羟基、氰基、C1-6烷基、C1-6卤代烷基、羟基C1-6烷基、C1-6烷氧基、-(CH2)s-N(Rc1)(Rc2)-、C3-6环烷基、3-6元单环杂环基、-C(＝O)-Rc3、-S(O)-Rc3、-S(O)2-Rc3、-C(＝O)O-Rc3、-N(Rc4)-C(＝O)-Rc3、-CH2-N(Rc4)-C(＝O)-Rc4、-C(＝O)-N(Rc6)(Rc5)、-N(Rc4)-C(＝O)-N(Rc6)(Rc5)、-P(＝O)Rc5Rc6的取代基进一步取代。
在一些实施例中，所述R1选自吗啉、哌啶，所述吗啉、哌啶各自独立地任意地被1、2、3个选自氘、卤素、羟基、氨基、C1-4烷基、C1-4烷氧基、C3-6环烷基、3-6元单环杂环基、-C(＝O)-Rc3、-S(O)-Rc3、-S(O)2-Rc3、-C(＝O)O-Rc3、-N(Rc4)-C(＝O)-Rc3、-CH2-N(Rc4)-C(＝O)-Rc4、-C(＝O)-N(Rc6)(Rc5)、-N(Rc4)-C(＝O)-N(Rc6)(Rc5)、-P(＝O)Rc5Rc6的取代基进一步取代。
在一些实施例中，所述R1选自：
在一些实施例中，本发明化合物具有如下结构：








在一些实施例中，本发明化合物具有如下结构：







在一些实施例中，本发明化合物具有如下结构：











在一些实施例中，本发明化合物具有如下结构：







在一些实施例中，本发明化合物具有如下结构：







另一方面，本发明提供了一种药物组合物，所述药物组合物包含治疗有效量的本发明所述的化合物、或其对映异构体、非对映异构体、消旋体、互变异构体、立体异构体、几何异构体、氮氧化物、代谢产物或其药学上可接受的盐、酯、溶剂化物、水合物、同位素标记化合物(优选氘代物)或前药。
另一方面，本发明提供了一种组合，所述组合包含治疗有效量的本发明所述的化合物或其对映异构体、非对映异构体、消旋体、互变异构体、立体异构体、几何异构体、氮氧化物、代谢产物或其药学上可接受的盐、酯、溶剂化物、水合物、同位素标记化合物(优选氘代物)或前药，和一种或多种治疗剂。
在本发明的一些组合的实施例中，其中一种或多种治疗剂独立地选自类法尼醇X受体(FXR)激动剂；抗脂肪变性剂；抗纤维化剂；JAK抑制剂；检查点抑制剂；化学疗法、放射疗法和外科手术；降尿酸疗法；合成代谢剂和软骨再生疗法；IL-17的阻断剂；补体抑制剂； 布鲁顿酪氨酸激酶抑制剂(BTK抑制剂)；Toll样受体抑制剂(TLR7/8抑制剂)；CAR-T疗法；抗高血压剂；降胆固醇剂；白三烯A4水解酶(LTAH4)抑制剂；SGLT2抑制剂；β2-激动剂；抗炎剂；非类固醇抗炎药(“NSAID”)；乙酰水杨酸药(ASA)；再生疗法治疗；囊性纤维化治疗；和动脉粥样硬化治疗。
另一方面，本发明提供了本发明所述的化合物、或其对映异构体、非对映异构体、消旋体、互变异构体、立体异构体、几何异构体、氮氧化物、代谢产物或其药学上可接受的盐、酯、溶剂化物、水合物、同位素标记化合物(优选氘代物)或前药，或本发明所述的组合，用于作为药物使用。
另一方面，本发明提供了本发明所述的化合物、或其对映异构体、非对映异构体、消旋体、互变异构体、立体异构体、几何异构体、氮氧化物、代谢产物或其药学上可接受的盐、酯、溶剂化物、水合物、同位素标记化合物(优选氘代物)或前药，用于在下述疾病或障碍的治疗中使用，在所述疾病或障碍中，NLRP3信号传导促成所述疾病或障碍的病理学、和/或症状、和/或进展。另一方面，本发明提供了一种治疗下述疾病或障碍的方法，在所述疾病或障碍中，NLRP3信号传导促成所述疾病或障碍的病理学、和/或症状、和/或进展，所述方法包括施用治疗有效量的本发明化合物、或其对映异构体、非对映异构体、消旋体、互变异构体、立体异构体、几何异构体、氮氧化物、代谢产物或其药学上可接受的盐、酯、溶剂化物、水合物、同位素或前药。
另一方面，本发明提供了本发明所述的化合物、或其对映异构体、非对映异构体、消旋体、互变异构体、立体异构体、几何异构体、氮氧化物、代谢产物或其药学上可接受的盐、酯、溶剂化物、水合物、同位素标记化合物(优选氘代物)或前药，在制备下述疾病或障碍的治疗中使用药物的用途，在所述疾病或障碍中，NLRP3信号传导促成所述疾病或障碍的病理学、和/或症状、和/或进展。
另一方面，本发明用于本发明所述使用的化合物或本发明所述的治疗方法，其中所述疾病或障碍选自：炎性小体相关疾病/障碍、免疫性疾病、炎症性疾病、自身免疫性疾病、或自身炎症性疾病，例如，自身炎症性发热综合征(例如隐热蛋白相关周期性综合征)、肝相关疾病/障碍(例如慢性肝疾病、病毒性肝炎、非酒精性脂肪性肝炎(NASH)、酒精性脂肪性肝炎、和酒精性肝疾病)、炎症性关节炎相关障碍(例如痛风、假性痛风(软骨钙质沉着病)、骨关节炎、类风湿性关节炎、关节病例如急性、慢性关节病)、肾脏相关疾病(例如高草酸尿症、狼疮性肾炎、I型/II型糖尿病及相关并发症(例如肾病、视网膜病)、高血压性肾病、血液透析相关炎症)、神经炎症相关疾病(例如多发性硬化症、脑部感染、急性损伤、神经退行性疾病、阿尔茨海默氏病)、心血管/代谢疾病/障碍(例如心血管风险降低(CvRR)、高血压、动脉粥样硬化、I型和II型糖尿病及相关并发症、外周动脉疾病(PAD)、急性心力衰竭)、炎症性皮肤疾病(例如化脓性汗腺炎、痤疮)、创伤愈合和瘢痕形成、哮喘、结节病、年龄相关黄斑变性、和癌症相关疾病/障碍(例如结肠癌、肺癌、骨髓增生性肿瘤、白血病、骨髓增生异常综合征(MDS)、骨髓纤维化)。
另一方面，本发明提供了一种在有需要的受试者中抑制NLRP3炎性小体活性的方法，所述方法包括向有需要的受试者施用治疗有效量的本发明化合物、或其对映异构体、非对映异构体、消旋体、互变异构体、立体异构体、几何异构体、氮氧化物、代谢产物或其药学上可接受的盐、酯、溶剂化物、水合物、同位素或前药。
本发明另一方面涉及式I、II、III、IV-1、IV-2、IV-3、IV-4、IV-5、IV-6、IV-7、IV-8、V-1、V-2、V-3、V-4、V-5、V-6、V-7、V-8、VI-1、VI-2、VI-3、VI-4、VI-5、VI-6、VI-7、VI-8、VII-1、VII-2、VII-3、VII-4、VII-5、VII-6、VII-7、VII-8、VIII-1、VIII-2、VIII-3、VIII-4、VIII-5、VIII-6、VIII-7、VIII-8、IX-1、IX-2、IX-3、IX-4、IX-5、IX-6所示的化合物的制备、分离和纯化的方法。
本发明的任一方面的任一实施方案，可以与其它实施方案进行组合，只要它们不会出现 矛盾。此外，在本发明任一方面的任一实施方案中，任一技术特征可以适用于其它实施方案中的该技术特征，只要它们不会出现矛盾。
前面所述内容只概述了本发明的某些方面，但并不限于这些方面。这些方面及其他方面的内容将在下面作更加具体完整的描述。本说明书中的所有参考文献通过整体引用于此。
具体实施方式
为使本发明的目的、技术方案及优点更加清楚明白，以下结合实施例，对本发明进行进一步的详细说明。此处所描述的具体实施例仅用于解释本发明，并不用于构成对本发明的任何限制。此外，在以下说明中，省略了对公知结构和技术的描述，以避免不必要地混淆本公开的概念。这样的结构和技术在许多出版物中也进行了描述。
定义
现在详细描述本发明的某些实施方案，其实例由随附的结构式和化学式说明。本发明意图涵盖所有的替代、修改和等同技术方案，它们均包括在如权利要求定义的本发明范围内。本领域技术人员应认识到，许多与本文所述类似或等同的方法和材料能够用于实践本发明。本发明绝不限于本文所述的方法和材料。在所结合的文献、专利和类似材料的一篇或多篇与本申请不同或相矛盾的情况下(包括但不限于所定义的术语、术语应用、所描述的技术，等等)，以本申请为准。
应进一步认识到，本发明的某些特征，为清楚可见，在多个独立的实施方案中进行了描述，但也可以在单个实施例中以组合形式提供。反之，本发明的各种特征，为简洁起见，在单个实施方案中进行了描述，但也可以单独或以任意适合的子组合提供。
除非另外说明，本发明所使用的所有科技术语具有与本发明所属领域技术人员的通常理解相同的含义。本发明涉及的所有专利和公开出版物通过引用方式整体并入本发明。
除非另外说明，应当应用本文所使用的下列定义。出于本发明的目的，化学元素与元素周期表CAS版，和《化学和物理手册》，第75版，1994一致。此外，有机化学一般原理可参考“Organic Chemistry”,Thomas Sorrell,University Science Books,Sausalito:1999,和“March's Advanced Organic Chemistry”by Michael B.Smith and Jerry March,JohnWiley&Sons,New York:2007中的描述，其全部内容通过引用并入本文。
除非另有说明或者上下文中有明显的冲突，本文所使用的冠词“一”、“一个(种)”和“所述”旨在包括“至少一个”或“一个或多个”。因此，本文所使用的这些冠词是指一个或多于一个(即至少一个)宾语的冠词。例如，“一组分”指一个或多个组分，即可能有多于一个的组分被考虑在所述实施方案的实施方式中采用或使用。
术语“受试对象”是指动物。典型地所述动物是哺乳动物。受试对象，例如也指灵长类动物(例如人类，男性或女性)、牛、绵羊、山羊、马、犬、猫、兔、大鼠、小鼠、鱼、鸟等。在某些实施方案中，所述受试对象是灵长类动物。在其他实施方案中，所述受试对象是人。
术语“患者”是指人(包括成人和儿童)或者其他动物。在一些实施方案中，“患者”是指人。
术语“包含”为开放式表达，即包括本发明所指明的内容，但并不排除其他方面的内容。
当通过从左向右书写的常规化学式描述取代基时，该取代基也同样包括从右向左书写结构式时所得到的在化学上等同的取代基。举例而言，-CH2O-等同于-OCH2-。
术语“对映异构体”是指一个化合物的两个不能重叠但互成镜像关系的异构体。
术语“非对映异构体”是指有两个或多个手性中性并且其分子不互为镜像的立体异构体。非对映异构体具有不同的物理性质，如熔点、沸点、光谱性质和反应性。非对映异构体混合物可通过高分辨分析操作如电泳和色谱，例如HPLC来分离。
术语“消旋体”、“外消旋物”或“外消旋混合物”是指缺少光学活性的两个对映异构体的等摩尔混合物。
术语“互变异构体”或“互变异构形式”是指具有不同能量的可通过低能垒(lowenergy barrier)互相转化的结构异构体。若互变异构是可能的(如在溶液中)，则可以达到互变异构体 的化学平衡。例如，质子互变异构体(protontautomer)(也称为质子转移互变异构体(prototropic tautomer))包括通过质子迁移来进行的互相转化，如酮-烯醇异构化和亚胺-烯胺异构化。价键互变异构体(valence tautomer)包括通过一些成键电子的重组来进行的互相转化。酮-烯醇互变异构的具体实例是戊烷-2,4-二酮和4-羟基戊-3-烯-2-酮互变异构体的互变。互变异构的另一个实例是酚-酮互变异构。酚-酮互变异构的一个具体实例是吡啶-4-醇和吡啶-4(1H)-酮互变异构体的互变。还例如，咪唑环上1-位氮原子上的氢能够转移到3-位氮原子上，咪唑环的两种形式为互变异构体，即本文中包含咪唑环的基团存在互变异构体情况，如与为互变异构体；以及与为互变异构体。除非另外指出，本发明化合物的所有互变异构体形式都在本发明的范围之内。
术语“立体异构体”是指具有相同化学构造，但原子或基团在空间上排列方式不同的化合物。立体异构体包括对映异构体、非对映异构体、构象异构体(旋转异构体)、几何异构体(顺/反异构体)、阻转异构体，等等。
术语“几何异构体”也称“顺反异构体”，因双键(包括烯烃的双键、C＝N双键和N＝N双键)或环碳原子的单健不能自由旋转而引起的异构体。
本发明所使用的立体化学定义和规则一般遵循S.P.Parker，Ed.,McGraw-HillDictionary of Chemical Terms(1984)McGraw-Hill Book Company,New York；andEliel,E.and Wilen,S,“Stereochemistry of Organic Compounds”,John Wiley&Sons,Inc,New York,1994。许多有机化合物以光学活性形式存在，即它们具有使平面偏振光的平面发生旋转的能力。在描述光学活性化合物时，使用前缀D和L或R和S来表示分子关于其一个或多个手性中心的绝对构型。前缀d和l或(+)和(-)是用于指定化合物所致平面偏振光旋转的符号，其中(-)或l表示化合物是左旋的。前缀为(+)或d的化合物是右旋的。一种具体的立体异构体是对映异构体，这种异构体的混合物称作对映异构体混合物。对映异构体的50:50混合物称为外消旋混合物或外消旋体，当在化学反应或过程中没有立体选择性或立体特异性时，可出现这种情况。
本发明公开化合物的任何不对称原子(例如，碳等)都可以以外消旋或对映体富集的形式存在，例如(R)-、(S)-或(R,S)-构型形式存在。在某些实施方案中，各不对称原子在(R)-或(S)-构型方面具有至少50％对映体过量，至少60％对映体过量，至少70％对映体过量，至少80％对映体过量，至少90％对映体过量，至少95％对映体过量，或至少99％对映体过量。
依据起始物料和方法的选择，本发明化合物可以以可能的异构体中的一个或它们的混合物，例如外消旋体和非对映异构体混合物(这取决于不对称碳原子的数量)的形式存在。光学活性的(R)-或(S)-异构体可使用手性合成子或手性试剂制备，或使用常规技术拆分。如果化合物含有一个双键，取代基可能为E或Z构型；如果化合物中含有二取代的环烷基，环烷基的取代基可能有顺式或反式构型。
所得的任何立体异构体的混合物可以依据组分物理化学性质上的差异被分离成纯的或基本纯的几何异构体，对映异构体，非对映异构体，例如，通过色谱法和/或分步结晶法。
可以用已知的方法将任何所得终产物或中间体的外消旋体通过本领域技术人员熟悉的方法拆分成光学对映体，如，通过对获得的其非对映异构的盐进行分离。外消旋的产物也可以通过手性色谱来分离，如，使用手性吸附剂的高效液相色谱(HPLC)。特别地，对映异构体可以通过不对称合成制备，例如，可参考Jacques,et al.,Enantiomers,Racematesand Resolutions(Wiley Interscience,New York,1981)；Principles of AsymmetricSynthesis(2nd Ed.Robert E.Gawley,JeffreyAube,Elsevier,Oxford,UK,2012)；Eliel,E.L.Stereochemistry ofCarbon Compounds(McGraw-Hill,NY,1962)；Wilen,S.H.Tablesof Resolving Agents and Optical Resolutions p.268(E.L.Eliel,Ed.,Univ.of NotreDame Press,Notre Dame,IN 1972)；Chiral  Separation Techniques:A PracticalApproach(Subramanian,G.Ed.,Wiley-VCH Verlag GmbH&Co.KGaA,Weinheim,Germany,2007)。
术语“氮氧化物”是指当化合物含几个胺官能团时，可将1个或大于1个的氮原子氧化形成N-氧化物。N-氧化物的特殊实例是叔胺的N-氧化物或含氮杂环氮原子的N-氧化物。可用氧化剂例如过氧化氢或过酸(例如过氧羧酸)处理相应的胺形成N-氧化物(参见Advanced Organic Chemistry,Wiley Interscience,第4版,Jerry March,pages)。尤其是，N-氧化物可用L.W.Deady的方法制备(Syn.Comm.1977,7,509-514)，其中例如在惰性溶剂，例如二氯甲烷中，使胺化合物与间-氯过苯甲酸(MCPBA)反应。
术语“代谢产物”是指具体的化合物或其盐在体内通过代谢作用所得到的产物。一个化合物的代谢产物可以通过所属领域公知的技术来进行鉴定，其活性可以通过如本发明所描述的那样采用试验的方法进行表征。这样的产物可以是通过给药化合物经过氧化，还原，水解，酰氨化，脱酰氨作用，酯化，脱脂作用，酶裂解等等方法得到。相应地，本发明包括化合物的代谢产物，包括将本发明的化合物与哺乳动物充分接触一段时间所产生的代谢产物。
术语“药学上可接受的”是指物质或组合物必须与包含制剂的其它成分和/或用其治疗的哺乳动物化学上和/或毒理学上相容。优选地，本发明所述的“药学上可接受的”是指联邦监管机构或国家政府批准的或美国药典或其他一般认可药典上列举的在动物中、特别是人体中使用的。
术语“药学上可接受的盐”是指本发明的化合物的有机盐和无机盐。药学上可接受的盐在所属领域是为我们所熟知的，如文献：S.M.Berge et al.,J.Pharmaceutical Sciences,66：1-19,1977所记载的。药学上可接受的盐包括化合物与酸形成的盐，包括但并不限于，无机酸盐(如盐酸盐，氢溴酸盐，磷酸盐，硫酸盐，硝酸盐，高氯酸盐)和有机酸盐(如乙酸盐，羟基乙酸盐，草酸盐，马来酸盐，酒石酸盐，柠檬酸盐，琥珀酸盐，富马酸盐，扁桃酸盐，磺基水杨酸盐)，或通过书籍文献上所记载的其他方法如离子交换法来得到这些盐。更多的药学上可接受的盐包括己二酸盐，藻酸盐，抗坏血酸盐，天冬氨酸盐，苯磺酸盐，苯甲酸盐，重硫酸盐，硼酸盐，丁酸盐，樟脑酸盐，樟脑磺酸盐，环戊基丙酸盐，二葡萄糖酸盐，十二烷基硫酸盐，乙磺酸盐，甲酸盐，反丁烯二酸盐，葡庚糖酸盐，甘油磷酸盐，葡萄糖酸盐，半硫酸盐，庚酸盐，己酸盐，氢碘酸盐，2-羟基-乙磺酸盐，乳糖醛酸盐，乳酸盐，月桂酸盐，月桂基硫酸盐，苹果酸盐，丙二酸盐，甲磺酸盐，2-萘磺酸盐，烟酸盐，油酸盐，棕榈酸盐，扑酸盐，果胶酸盐，过硫酸盐，3-苯基丙酸盐，苦味酸盐，特戊酸盐，丙酸盐，硬脂酸盐，硫氰酸盐，对甲苯磺酸盐，十一酸盐，戊酸盐，等等。药学上可接受的盐还包括化合物与碱形成的盐，包括但不限于，无机碱盐(如碱金属盐，碱土金属盐，铵盐和N+(C1-4烷基)4盐)，碱金属或碱土金属盐包括钠，锂，钾，钙，镁，等等。本发明也拟构思了任何所包含N的基团的化合物所形成的季铵盐。水溶性或油溶性或分散产物可以通过季铵化作用得到。药学上可接受的盐进一步包括适当的、无毒的铵，季铵盐和抗平衡离子形成的胺阳离子，如卤化物，氢氧化物，羧化物，硫酸化物，磷酸化物，硝酸化物，C1-8磺酸化物和芳香磺酸化物。有机碱盐(如伯胺盐、仲胺盐和叔胺盐，取代的胺(包括天然存在的取代的胺、环状胺、碱性离子交换树脂)盐)，某些有机胺盐包括，例如，异丙胺盐、苄星青霉素(benzathine)盐、胆碱盐(cholinate)、二乙醇胺盐、二乙胺盐、赖氨酸盐、葡甲胺(meglumine)盐、哌嗪盐和氨丁三醇盐。
可药用的酸加成盐可由本发明化合物与无机酸或有机酸作用形成，可药用碱加成盐可由本发明化合物与无机碱或有机碱作用形成。本发明的可药用盐可以用常规化学方法由母体化合物、碱性或酸性部分来合成。一般而言，该类盐可以通过使这些化合物的游离酸形式与化学计量量的适宜碱(如Na、Ca、Mg或K的氢氧化物、碳酸盐、碳酸氢盐等)反应，或者通过使这些化合物的游离碱形式与化学计量量的适宜酸反应来进行制备。该类反应通常在水或有机溶剂或二者的混合物中进行。一般地，在适当的情况中，需要使用非水性介质如乙醚、乙酸乙酯、乙醇、异丙醇或乙腈。在例如“Remington’s Pharmaceutical Sciences”，第20版， Mack Publishing Company,Easton,Pa.,(1985)；和“药用盐手册：性质、选择和应用(Handbook ofPharmaceutical Salts:Properties,Selection,and Use)”，Stahl andWermuth(Wiley-VCH,Weinheim,Germany,2002)中可找到另外一些适宜盐的列表。
术语“溶剂化物”是指一个或多个溶剂分子与本发明的化合物所形成的缔合物。所述溶剂可以是水、乙酸、乙醚、异丙醚、石油醚、甲酸乙酯、乙酸乙酯、乙酸异丙酯、乙酸正丙酯、乙酸异丁酯、乙酸正丁酯、甲基叔丁基醚(MTBE)、正庚烷、体积比为10:90～90:10的乙醇和水的混合溶剂、丙酮、甲基异丁基甲酮、乙腈、苯、氯仿、四氯化碳、二氯甲烷、二甲基亚砜、1,4-二氧六环、乙醇、乙酸乙酯、乙二醇、正丁醇、叔丁醇、仲丁醇、N,N-二甲基乙酰胺、N,N-二甲基甲酰胺、甲酰胺、蚁酸、正己烷、环己烷、正庚烷、体积比为1:5～5:1的正庚烷和乙酸乙酯的混合溶剂、异丙醇、甲醇、丁酮、l-甲基-2-吡咯烷酮、均三甲苯、硝基甲烷、聚乙二醇、正丙醇、异丙醇、2-丙酮、4-甲基-2戊酮、吡啶、四氢呋喃、甲乙酮、甲苯、二甲苯、异丙苯或它们的混合物等等。
术语“水合物”是指一个或多个水分子与本发明的化合物所形成的缔合物。
另外，本发明公开的化合物、包括它们的盐，也可以以它们的水合物形式或包含其溶剂(例如乙醇、DMSO，等等)的形式得到，用于它们的结晶。本发明公开化合物可以与药学上可接受的溶剂(包括水)固有地或通过设计形成溶剂化物；因此，本发明旨在包括溶剂化的和未溶剂化的形式。
术语“酯”通过式-OC(O)R或者-C(O)OR表示，其中R可为本发明所述的烷基、环烷基、烯基、环烯基、炔基、环炔基、芳基或者杂芳基。
术语“同位素标记化合物”是指本发明化合物用同位素标记。其除以下事实外与本发明所述的那些化合物相同：一个或多个原子被原子质量或质量数不同于天然常见原子质量或质量数的原子代替。还可引入本发明化合物中的示例性同位素包括氢、碳、氮、氧、磷、硫、氟和氯的同位素，如2H，3H，13C，14C，15N，16O，17O，31P，32P，36S，18F和37Cl。
包含前述同位素和/或其他原子的其他同位素的本发明化合物以及所述化合物的药学上可接受的盐都包括在本发明范围内。同位素标记的本发明化合物，例如放射性同位素，如3H和14C掺入到本发明化合物中可用于药物和/或底物组织分布分析。由于易于制备以及检测，氚代的，即，3H，以及碳-14，即14C，同位素特别优选。此外，用质量数较大的同位素，如氘，即2H取代，可提供一些更大的代谢稳定性的治疗上的优势，例如增加的体内半衰期或减少的剂量需求。因此，在一些情形下可能是优选的。
此外，较重同位素特别是氘(即，2H或D)的取代可提供某些治疗优点，这些优点是由代谢稳定性更高带来的。例如，体内半衰期增加或剂量需求降低或治疗指数得到改善带来的。应当理解，本发明中的氘被看做式(I)至(IV)化合物的取代基。可以用同位素富集因子来定义该类较重同位素特别是氘的浓度。本发明所使用的术语“同位素富集因子”是指所指定同位素的同位素丰度和天然丰度之间的比例。如果本发明化合物的取代基被指定为氘，该化合物对各指定的氘原子而言具有至少3500(各指定氘原子处52.5％的氘掺入)、至少4000(60％的氘掺入)、至少4500(67.5％的氘掺入)，至少5000(75％的氘掺入)，至少5500(82.5％的氘掺入)、至少6000(90％的氘掺入)、至少6333.3(95％的氘掺入)、至少6466.7(97％的氘掺入)、至少6600(99％的氘掺入)或至少6633.3(99.5％的氘掺入)的同位素富集因子。本发明可药用的溶剂化物包括其中结晶溶剂可以是同位素取代的例如D2O、丙酮-d6、DMSO-d6的那些溶剂化物。
本发明所使用的术语“前药”，代表一个化合物在体内转化为式(I)所示的化合物。这样的转化受前体药物在血液中水解或在血液或组织中经酶转化为母体结构的影响。本发明前体药物类化合物可以是酯，在现有的发明中酯可以作为前体药物的有苯酯类，脂肪族(C1-24)酯类，酰氧基甲基酯类，碳酸酯，氨基甲酸酯类和氨基酸酯类。例如本发明里的一个化合物包含羟基，即可以将其酰化得到前体药物形式的化合物。其他的前体药物形式包括磷酸酯，如这些磷酸酯类化合物是经母体上的羟基磷酸化得到的。关于前体药物完整的讨论可以参考以 下文献：Higuchi et al.,Pro-drugs as Novel Delivery Systems,Vol.14,A.C.S.Symposium Series；Roche et al.,Bioreversible Carriers in Drug Design,American Pharmaceutical Association and Pergamon Press,1987；Rautio et al.,Prodrugs:Design and Clinical Applications,Nature Reviews Drug Discovery,2008,7,255-270,and Hecker et al.,Prodrugs of Phosphates and Phosphonates,J.Med.Chem.,2008,51,2328-2345。
除非以其他方式明确指出，在本发明中所采用的描述方式“各…独立地为”与“…各自独立地为”和“…独立地为”可以互换，均应做广义理解，其既可以是指在不同基团中，相同符号之间所表达的具体选项之间互相不影响，也可以表示在相同的基团中，相同符号之间所表达的具体选项之间互相不影响。
术语“任选”、“任选地”或“任意、“任意地”是指随后描述的事件或情形可以但不一定出现，并且该描述包括其中所述事件或情形出现的情况以及其中它不出现的情况。例如，“任选地被……取代”是指该取代可以存在或可以不存在。
术语“不饱和”或“不饱和的”表示部分含有一个或多个不饱和度。
在本说明书的各部分，本发明公开化合物的取代基按照基团种类或范围公开。特别指出，本发明包括这些基团种类和范围的各个成员的每一个独立的次级组合。例如，术语“C1-6烷基”特别指独立公开的甲基、乙基、C3烷基、C4烷基、C5烷基和C6烷基。
在本发明的各部分，描述了连接取代基。当该结构清楚地需要连接基团时，针对该基团所列举的马库什变量应理解为连接基团。例如，如果该结构需要连接基团并且针对该变量的马库什基团定义列举了“烷基”或“芳基”，则应该理解，该“烷基”或“芳基”分别代表连接的亚烷基基团或亚芳基基团。
术语“杂原子”是指O、S、N、P和Si，包括S，N和P任何氧化态的形式；伯、仲、叔胺和季铵盐的形式；或者杂环中氮原子上的氢被取代的形式，例如，N(像3,4-二氢-2H-吡咯基中的N)，NH(像吡咯烷基中的NH)或NRT(像N-取代的吡咯烷基中的NRT，RT为N上的取代基)。在本发明涉及的化合物中，当含有多个杂原子时，其组成的化合物是符合有机化合物的共价规则和组成规则，即含多个杂原子的化合物应当是排除了不符合有机化合物共价规则和组成规则的化合物。
术语“杂环基”或“杂环”表示含有碳原子和杂原子的单价或多价的单环，双环或三环体系。所述杂原子具有如本发明所述的含义。所述双环或三环体系可以是螺环、桥环、稠环，例如双环体系包括环螺双环、桥双环、稠双环。饱和或部分不饱和杂环基可以是完全饱和的或包含一个或多个不饱和度，但一个芳香环都不能有。在一实施方案中，杂环基基团是3-6元环，如3-6元饱和或部分不饱和杂环基(2-6个碳原子和选自N，O，P，S的1-3个杂原子，在此S或P任选地被一个或多个氧原子所取代得到像SO，SO2，PO，PO2的基团)。在一实施方案中，所述饱和或部分不饱和杂环基选自：饱和单环杂环基、饱和双环杂环基、饱和三环杂环基、部分不饱和单环杂环基、部分不饱和双环杂环基、部分不饱和三环杂环基。双环杂环基表示双环体系的杂环基，例如双环杂环体系包括环螺双环杂环、桥双环杂环、稠双环杂环。单环杂环基表示单环体系的杂环基。5-6元杂环基表示环原子为5-6个的杂环基。4-7元杂环基表示环原子为4-7个的杂环基。3-6元杂环基表示为环原子为3-6个的杂环基。
术语“环烷基”表示含有碳原子的，单价或多价的单环，双环或三环体系。饱和或部分不饱和环烷基可以是完全饱和的或包含一个或多个不饱和度，但一个芳香环都不能有。在一实施方案中，环烷基包含3-6个碳原子，如C3-C6饱和或部分不饱和环烷基。环烷基基团的实例包含，但并不限于，环丙基，环丁基，环戊基，环己基、环戊烯基、环己烯基等等。在一实施方案中，所述饱和或部分不饱和环烷基选自：饱和单环环烷基、饱和双环环烷基、饱和三环环烷基、部分不饱和单环环烷基、部分不饱和双环环烷基、部分不饱和三环环烷基。双环环烷基表示双环体系的环烷基，例如双环环烷基体系包括环螺双环环烷基、桥双环环烷基、稠双环环烷基。单环环烷基表示单环体系的环烷基。4-7元环烷基表示环原子为4-7个的环烷基。3-6元环烷基表示环原子为3-6个的环烷基。
术语“杂芳基”表示含有5-10环原子的单环、双环和三环的芳香性体系，术语“杂芳基”可以与术语“杂芳环”或“杂芳族化合物”交换使用。在一些实施方案中，杂芳基为包含1，2，3或4个独立选自O，S和N的杂原子的5-10个原子组成的杂芳基，即5-10元杂芳基；杂芳基为包含1，2，3或4个独立选自O，S和N的杂原子的5-8个原子组成的杂芳基，即5-8元杂芳基；在一些实施方案中，杂芳基为包含1，2，3或4个独立选自O，S和N的杂原子的5-7个原子组成的杂芳基，即5-7元杂芳基；在一些实施方案中，杂芳基为包含1，2，3或4个独立选自O，S和N的杂原子的5-6个原子组成的杂芳基，即5-6元杂芳基；在一些实施方案中，杂芳基为包含1，2，3或4个独立选自O，S和N的杂原子的5个原子组成的杂芳基，即5元杂芳基；在一些实施方案中，杂芳基为包含1，2，3或4个独立选自O，S和N的杂原子的6个原子组成的杂芳基，即6元杂芳基。
术语“芳基”表示单环、双环、三环的芳香性碳环体系。术语“芳基”可以和术语“芳环”或“芳香环”交换使用。6-10元芳基表示含有6-10个环原子的芳基基团。其实例包括但不限于：苯基，萘基等。
术语“氢”是指1H；“氘”是指2H。
术语“卤素”和“卤代”是指氟(F)、氯(Cl)、溴(Br)或碘(I)。
术语“氨基”是指-NH2。
术语“羟基”是指-OH。
术语“氰基”是指-CN。
术语“硝基”是指-NO2。
术语“羧基”是指HO(C＝O)-。
术语“O＝”是指氧代，即当取代基为O＝时，O通过双键与被取代基团相连。
术语“烷基”或“烷基基团”，表示含碳原子、饱和的直链或支链一价烃基基团。在一实施方案中，烷基基团含有1-6个碳原子，即C1-C6烷基；在又一实施方案中，烷基基团含有1-4个碳原子，即C1-C4烷基；还在一实施方案中，烷基基团含有1-3个碳原子，即C1-C3烷基。烷基的实例包括但不限于甲基、乙基、正丙基、异丙基、正丁基、叔丁基、异丁基、仲丁基、正戊基、正己基及其类似烷基。
术语“烷氧基”表示烷基基团通过氧原子与分子其余部分相连，其中烷基基团具有如本发明所述的含义。在一实施方案中，烷氧基基团含有1-6个碳原子，即C1-C6烷氧基；在另一实施方案中，烷氧基基团含有1-4个碳原子，即C1-C4烷氧基；在又一实施方案中，烷氧基基团含有1-3个碳原子，即C1-C3烷氧基。
术语“烷氨基”表示烷基基团通过氮原子与分子其余部分相连，其中烷基基团具有如本发明所述的含义。在一实施方案中，烷氨基是一烷基氨基，表示为“烷基-NH-“。在一实施方案中，烷氨基是二烷基氨基，表示为“(烷基)2N-”。在一实施方案中，烷氨基基团含有1-6个碳原子，即C1-C6烷氨基；在另一实施方案中，烷氨基基团含有1-4个碳原子，即C1-C4烷氨基；在又一实施方案中，烷氨基基团含有1-3个碳原子，即C1-C3烷氨基。术语“卤代烷基”表示烷基上的氢被1个或多个卤素(F、Cl、Br)取代；术语“羟基烷基”表示烷基上的氢被1个或多个羟基(OH)取代；术语“氨基烷基”表示烷基上的氢被1个或多个氨基(NH2)取代。
一个或多个卤代苯基表示苯基上有1、2、3、4或5个卤素取代。所述卤素具有本文所述的定义。一个或多个卤代苯基，也表示为一个或多个卤素取代的苯基。
一个或多个羟基取代苯基表示苯基上有1、2、3、4或5个羟基取代。所述羟基具有本文所述的定义。
当采用“并”将两个环体系基团连接时，表示两个环体系为稠和关系，两个相应的环各自具有其在本文所述的定义。如苯基并4-7元环烷基表示苯基稠和本发明所述的环原子为4-7个的环烷基；5-6元杂芳基并4-7元环烷基表示本发明所述的环原子为5-6个的杂芳基稠和本发明所述的环原子为4-7个的环烷基。
当两个基团联合使用时，表示其中写在前的基团通过写在后的基团与分子其余部分相连，例如C1-6烷氧基-C1-6烷基表示C1-6烷氧基通过C1-6亚烷基与分子其余部分相连，羟基C1-6烷基表示羟基通过C1-6亚烷基与分子其余部分相连。
像本发明所描述的，取代基R由一个键连接到中心的环上形成的环体系(如下图所示)代表取代基R只限在A环上任何可取代或任何合理的位置进行取代。例如，式f代表A环上任何可能被取代的位置，如式f1-f4所示：
像本发明所描述的，取代基R由一个键贯穿连接多环形成的环体系(如下图所示)代表取代基R可在A环和B环上任何可取代或任何合理的位置进行取代。例如，式e代表A环上任何可能被取代的位置，如式e1-e7所示：
如本发明所描述，取代基由一个键连接到中心的环上形成的环体系，如(Rx)n，代表n个取代基Rx可以在所在的环上任何可取代的位置进行取代。例如，式a代表苯环可被n个Rx取代。
术语“取代”指特定的基团上的一个或多个氢原子被特定的取代基所取代。特定的取代基为在前文中相应描述的取代基，或各实施例中所出现的取代基。除非特别说明，某个取代的基团可以在该基团的任何可取代的位点上具有一个选自特定组的取代基，所述的取代基在各个位置上可以是相同或不同的，即各个取代之间是相互独立地。本领域技术人员应理解，本发明所预期的取代基的组合是那些稳定的或化学上可实现的组合。
本发明中，环A和环B涉及的基团是指环A和环B以共有环边而形成的稠合结构(即环A和环B形成稠合双环)，例如
本发明中，取代基的定义意为从左至右连接至相应的基团上，例如式I结构中，Rc选自C1-6烷氧基-C1-6烷基时，意为C1-6烷氧基连接至C1-6烷基，C1-6烷基再连接至环C上。
本发明化合物的描述
本发明提供了一种化合物，具有式I所示的结构或其对映异构体、非对映异构体、消旋体、互变异构体、立体异构体、几何异构体、氮氧化物、代谢产物或其药学上可接受的盐、酯、溶剂化物、水合物、同位素标记化合物(优选氘代物)或前药；
其中与环A相连接，与环B相连接；
其中，环A、环B、环C、L1、L2、Ra、Rb、Rc、n、m、p、R1具有如本发明所述的定义。
在一些实施例中，本发明提供了一种化合物，具有式II所示的结构，
其中，环B、环C、L1、L2、Ra、Rb、Rc、n、m、p、R1、M1、M2、M3、M4具有如本发明所述的定义。
在一些实施例中，本发明提供了一种化合物，具有式III所示的结构，
其中，环B、L1、L2、Ra、Rb、Rc、n、m、p、R1、M1、M2、M3、M4具有如本发明所述的定义。
在一些实施例中，本发明提供了一种化合物，具有式IV-1、IV-2、IV-3、IV-4、IV-5、IV-6、IV-7或IV-8所示的结构；
其中，环C、L1、L2、Ra、Rb、Rc、n、m、p、R1、、M1、M2、M3、M4、M5、M6、U1、U3、U4、U5具有如本发明所述的定义。
在一些实施例中，本发明提供了一种化合物，具有式V-1、V-2、V-3、V-4、V-5、V-6、V-7或V-8所示的结构；

其中，L1、L2、Ra、Rb、Rc、n、m、p、R1、M1、M2、M3、M4、M5、M6、U1、U3、U4、U5具有如本发明所述的定义。
在一些实施例中，本发明提供了一种化合物，具有式VI-1、VI-2、VI-3、VI-4、VI-5、VI-6、VI-7或VI-8所示的结构；
其中，n1为0、1、2或3，L1、L2、Ra、Rb、Rc、n、m、p、R1、M1、M2、M3、M4、M5、M6、U1、U3、U4、U5具有如本发明所述的定义。
在一些实施例中，本发明化合物具有式VII-1、VII-2、VII-3、VII-4、VII-5或VII-6所示的结构；
其中，L1、L2、Ra、Rb、m、p、R1、M1、M2、M3、M4、M5、U1具有如本发明所述的定义。
在一些实施例中，本发明化合物具有式VIII-1、VIII-2、VIII-3、VIII-4、VIII-5、VIII-6、VIII-7或VIII-8所示的结构：

其中，Rc、n、L1、L2、R1、Ra、Rb、m、n具有如本发明所述的定义。
在一些实施例中，本发明化合物具有式IX-1、IX-2、IX-3、IX-4、IX-5或IX-6所示的结构：
其中，L1、L2、R1具有如本发明所述的定义；
Rab各自独立地选自：氢、氘、卤素、羟基、氨基、氰基、氧代、甲基、乙基、丙基、异丙基、丁基；
k各自独立地选自：0、1、2或3。
药物组合物和施用方法
本发明涉及一种药物组合物，其包含本发明所述的化合物或其对映异构体、非对映异构体、消旋体、互变异构体、立体异构体、几何异构体、氮氧化物、代谢产物或其药学上可接受的盐、酯、溶剂化物、水合物、同位素标记化合物或前药；和药学上可接受的载体或稀释剂。
术语“药物组合物”表示一种或多种本文所述化合物或者其生理学上/药学上可以接受的盐或前体药物与其他化学组分的混合物，其他组分例如生理学上/药学上可以接受的载体、稀释剂，更进一步的还可包含赋形剂、粘合剂、填充剂等辅料，以及抗糖尿病试剂、抗高血糖试剂、抗肥胖症试剂、抗高血压试剂、抗血小板试剂、抗动脉粥样硬化试剂或者降脂试剂等附加治疗剂。药物组合物的目的是促进化合物对生物体的给药。
术语“载体”包括任何溶剂，分散介质，包衣衣料，表面活性剂，抗氧化剂，防腐剂(例如抗细菌剂、抗真菌剂)，等渗剂，盐，药物稳定剂，粘合剂，赋形剂，分散剂，润滑剂，甜味剂，调味剂，着色剂，或其组合物，这些载体都是所属技术领域技术人员已知的(如Remington's Pharmaceutical Sciences,18th Ed.Mack Printing Company,1990,pp.1289-1329所述)。 除了任意常规载体与活性成分不相容的情况外，涵盖其在治疗或药物组合物中的用途。
本发明还涉及包含作为活性成分的具有式I、II、III、IV-1、IV-2、IV-3、IV-4、IV-5、IV-6、IV-7、IV-8、V-1、V-2、V-3、V-4、V-5、V-6、V-7、V-8、VI-1、VI-2、VI-3、VI-4、VI-5、VI-6、VI-7、VI-8、VII-1、VII-2、VII-3、VII-4、VII-5、VII-6、VII-7、VII-8、VIII-1、VIII-2、VIII-3、VIII-4、VIII-5、VIII-6、VIII-7、VIII-8、IX-1、IX-2、IX-3、IX-4、IX-5、IX-6的化合物或其药学上可接受的盐的药物组合物，其可尤其用于治疗肿瘤性疾病，特别是癌症，如本文所述。可以将组合物配制用于非肠胃外施用，例如鼻、口腔、直肠、肺、阴道、舌下、局部、透皮、眼，或尤其用于口服施用，例如以口服固体剂型的形式，例如颗粒剂、丸剂、粉剂、片剂、薄膜衣片剂或糖衣片剂、泡腾片剂、硬胶囊剂和软胶囊剂或羟丙基甲基纤维素(HPMC)胶囊剂(适用地进行包衣)、口腔崩解片剂、口服溶液、脂质乳剂或悬浮液，或用于肠胃外施用，比如静脉内、肌内或皮下、鞘内、皮内或硬膜外施用至哺乳动物，特别是人，例如以溶液、脂质乳剂或含有微粒或纳米颗粒的悬浮液的形式。这些组合物可以包含单独的活性成分，或优选地，连同药学上可接受的载体。
具有式I、II、III、IV-1、IV-2、IV-3、IV-4、IV-5、IV-6、IV-7、IV-8、V-1、V-2、V-3、V-4、V-5、V-6、V-7、V-8、VI-1、VI-2、VI-3、VI-4、VI-5、VI-6、VI-7、VI-8、VII-1、VII-2、VII-3、VII-4、VII-5、VII-6、VII-7、VII-8、VIII-1、VIII-2、VIII-3、VIII-4、VIII-5、VIII-6、VIII-7、VIII-8、IX-1、IX-2、IX-3、IX-4、IX-5、IX-6的化合物或其药学上可接受的盐可以用药学惰性的无机或有机赋形剂加工，以用于生产口服固体剂型，例如颗粒剂、丸剂、粉剂、片剂、薄膜衣片剂或糖衣片剂、泡腾片剂、硬胶囊剂或HPMC胶囊剂或口腔崩解片剂。填充剂例如乳糖、纤维素、甘露糖醇、山梨醇、磷酸钙、淀粉或其衍生物，粘合剂例如纤维素、淀粉、聚乙烯吡咯烷酮或其衍生物，助流剂例如滑石、硬脂酸或其盐，流动剂例如煅制二氧化硅，可以用作这类赋形剂，用于配制和制造口服固体剂型，例如颗粒剂、丸剂、粉剂、片剂、薄膜衣片剂或糖衣片剂、泡腾片剂、硬胶囊剂或HPMC胶囊剂或口腔崩解片剂。软胶囊剂的合适赋形剂是例如植物油、蜡、脂肪、半固体和液体多元醇等。
用于制造口服溶液、脂质乳剂或悬浮液的合适的赋形剂例如是水、醇、多元醇、蔗糖、转化糖、葡萄糖等。
用于肠胃外配制品的合适的赋形剂例如是水、醇、多元醇、甘油、植物油、卵磷脂、表面活性剂等。
此外，药物制剂可以含有防腐剂、增溶剂、稳定剂、润湿剂、乳化剂、甜味剂、着色剂、调味剂、用于改变渗透压的盐、缓冲剂、掩蔽剂或抗氧化剂。药物制剂还可以含有其他治疗上有价值的物质。
剂量可以在宽范围内变化，并且当然，在每种特定情况下都符合个体要求。通常，在口服施用的情况下，每日约1至1000mg具有通式(I)的化合物/人的剂量应该是适当的，尽管也可以在必要时超出上述下限或上限。
具有式I、II、III、IV-1、IV-2、IV-3、IV-4、IV-5、IV-6、IV-7、IV-8、V-1、V-2、V-3、V-4、V-5、V-6、V-7、V-8、VI-1、VI-2、VI-3、VI-4、VI-5、VI-6、VI-7、VI-8、VII-1、VII-2、VII-3、VII-4、VII-5、VII-6、VII-7、VII-8、VIII-1、VIII-2、VIII-3、VIII-4、VIII-5、VIII-6、VIII-7、VIII-8、IX-1、IX-2、IX-3、IX-4、IX-5、IX-6的化合物还可以与一种或多种其他具有药理学活性的化合物组合使用，这些其他化合物也有效对抗同一疾病，优选使用不同作用方式，或者减少或预防具有式I、II、III、IV-1、IV-2、IV-3、IV-4、IV-5、IV-6、IV-7、IV-8、V-1、V-2、V-3、V-4、V-5、V-6、V-7、V-8、VI-1、VI-2、VI-3、VI-4、VI-5、VI-6、VI-7、VI-8、VII-1、VII-2、VII-3、VII-4、VII-5、VII-6、VII-7、VII-8、VIII-1、VIII-2、VIII-3、VIII-4、VIII-5、VIII-6、VIII-7、VIII-8、IX-1、IX-2、IX-3、IX-4、IX-5、IX-6的化合物的可能的不希望的副作用。组合伴侣可以在这种治疗中例如通过将它们掺入单一药物配制品中而同时施用，或通过施用两种或更多种不同的剂型(每种剂型含有一种或多于一种组合伴侣)而连续施用。
如本文所用，术语“药学上可接受的载体”是指可用于制备或使用药物组合物的物质，并且包括例如合适的稀释剂、溶剂、分散介质、表面活性剂、抗氧化剂、防腐剂、等渗剂、缓冲剂、乳化剂、吸收延迟剂、盐、药物稳定剂、粘合剂、赋形剂、崩解剂、润滑剂、润湿剂、甜味剂、矫味剂、染料，以及它们的组合，如本领域技术人员已知的(参见例如Remington TheScience and Practice of Pharmacy[雷明顿：药物科学与实践]，第22版，PharmaceuticalPress[药物出版社]，2013年，第1049至1070页)。
术语“治疗有效量”的本发明化合物是指将引起受试者的生物或医学应答(例如，酶或蛋白活性的减小或抑制，或改善症状、缓解病症、减缓或延迟疾病进展或预防疾病等)的本发明化合物的量。在一个非限制性实施例中，术语“治疗有效量”是指本发明化合物的如下量，所述量当被施用至受试者时有效地(1)至少部分缓解、抑制、预防和/或改善(i)由NLRP3介导的、或(ii)与NLRP3活性相关联的、或(iii)特征为NLRP3的活性(正常或异常)的病症、或障碍或疾病；或(2)减少或抑制NLRP3的活性；或(3)减少或抑制NLRP3的表达。在另一个非限制性实施例中，术语“治疗有效量”的本发明化合物是指如下量，当施用至细胞、或组织、或非细胞生物材料或介质时，所述量有效地至少部分减少或抑制NLRP3的活性；或至少部分地减少或抑制NLRP3的表达。
如本文在治疗疾病或障碍的上下文中所使用的术语“治疗(treatment或treating)”总体上涉及人或动物(例如在兽医应用)的治疗和疗法，其中获得一些希望的治疗效果，例如，抑制疾病或障碍的进展，并且包括降低进展的速率、停止进展的速率、缓解疾病或障碍的症状、改善疾病或障碍、以及治愈疾病或障碍。也包括作为预防措施的治疗(即，预防)。例如，用于尚未发展出该疾病或障碍、但处于发展该疾病或障碍风险的患者被术语“治疗”涵盖。例如，治疗包括癌症的预防、降低癌症发病率、缓解癌症症状等。
如本文所用，术语“抑制(inhibit、inhibition或inhibiting)”是指减轻或抑制给定的病症、症状、或障碍、或疾病，或显著降低生物活性或过程的基线活性。具体地，抑制NLRP3或抑制NLRP3炎性小体通路包含降低NLRP3或NLRP3炎性小体通路诱导IL‐1β和/或IL‐18的产生的能力。这可以通过，包括但不限于灭活、去稳定化NLRP3、和/或改变NLRP3分布的机制来实现。
如本文所用，术语任何疾病或障碍的“预防(prevent、preventing或prevention)”是指疾病或障碍的预防性治疗；或延迟疾病或障碍的发作或进展。
如本文所用，术语“NLRP3”意指包括但不限于核酸、多核苷酸、寡核苷酸、有义和反义多核苷酸链、互补序列、肽、多肽、蛋白质、同源和/或直系同源NLRP分子、同种型、前体、突变体、变体、衍生物、剪接变体、等位基因、不同物种、及其活性片段。
合成方法
具有式I、II、III、IV-1、IV-2、IV-3、IV-4、IV-5、IV-6、IV-7、IV-8、V-1、V-2、V-3、V-4、V-5、V-6、V-7、V-8、VI-1、VI-2、VI-3、VI-4、VI-5、VI-6、VI-7、VI-8、VII-1、VII-2、VII-3、VII-4、VII-5、VII-6、VII-7、VII-8、VIII-1、VIII-2、VIII-3、VIII-4、VIII-5、VIII-6、VIII-7、VIII-8、IX-1、IX-2、IX-3、IX-4、IX-5、IX-6的化合物可以通过下面给出的方法、通过下面实验部分给出的方法或通过类似方法合成。本文所述的方案不旨在呈现用于制备具有式I、II、III、IV-1、IV-2、IV-3、IV-4、IV-5、IV-6、IV-7、IV-8、V-1、V-2、V-3、V-4、V-5、V-6、V-7、V-8、VI-1、VI-2、VI-3、VI-4、VI-5、VI-6、VI-7、VI-8、VII-1、VII-2、VII-3、VII-4、VII-5、VII-6、VII-7、VII-8、VIII-1、VIII-2、VIII-3、VIII-4、VIII-5、VIII-6、VIII-7、VIII-8、IX-1、IX-2、IX-3、IX-4、IX-5、IX-6化合物的方法的详尽列表；相反，熟练的化学家知道的其他技术也可以用于化合物合成。
化合物的结构是通过核磁共振(1H-NMR、13C-NMR或/和19F-NMR)来确定的。1H-NMR、13C-NMR、19F-NMR化学位移(δ)以百万分之一(ppm)的单位给出。1H-NMR、13C-NMR、19F-NMR的测定是用Bruker Ultrashield-400核磁共振谱仪和BrukerAvance III HD 600核磁共振 谱仪，测定溶剂为氘代氯仿(CDCl3)、氘代甲醇(CD3OD或MeOH-d4)或者氘代二甲基亚砜(DMSO-d6)。用TMS(0ppm)或氯仿(7.25ppm)作为参照标准。当出现多重峰的时候，将使用下面的缩写：s(singlet,单峰)，d(doublet,双峰)，t(triplet,三重峰)，m(multiplet,多重峰)，br(broadened,宽峰)，dd(doublet of doublets,双二重峰)，dt(doublet of triplets,双三重峰)，td(triplet of doublets,三双重峰)，brs(broadened singlet,宽单峰)。偶合常数J，单位用赫兹(Hz)表示。
液质联用色谱(LC-MS)是使用Agilent 1260质谱仪检测的。HPLC的测定使用Agilent1100高压色谱仪(Microsorb 5micron C18 100x 3.0mm色谱柱)。
薄层层析硅胶板使用青岛GF254硅胶板，TLC采用的是0.15-0.20mm，制备薄层色谱采用的是0.4mm-0.5mm。柱层析一般使用青岛硅胶200-300目硅胶作为载体。
本发明实施例中的起始原料都是已知并有市售的，或者可以采用或按照本领域已报道的文献资料合成的。
除特殊说明外，本发明所有反应均在干燥的惰性气体(如氮气或氩气)保护下通过连续磁力搅拌进行，反应温度均为摄氏度。
有机合成领域的技术人员应理解，最佳反应条件可随所用的特定反应物或溶剂而变化，但这些条件可通过常规优化程序确定。在一些情况下，可以改变进行以下反应方案和/或反应步骤的顺序以促进反应或避免形成不需要的副产物。此外，存在于分子各个位置的官能团必须与所提出的试剂和反应相容。对与反应条件相容的取代基的这种限制对于本领域技术人员来说是显而易见的，并且然后必须使用替代方法。此外，在本文提到的一些反应中，可能需要或希望保护化合物中的任何敏感基团，并且假定必要时这样的保护基团(PG)在适当的位置。常规保护基团可根据本领域熟知的标准实践使用(关于说明，参见Greene T.W,Wuts P.G.M,Protective Groups in Organic Synthesis[有机合成中的保护基团],第5版,出版商:约翰·威利父子出版公司(JohnWiley&Sons),2014)。可以使用本领域熟知的常规技术在合成中的任何方便的阶段除去保护基团，或者可以在后续反应步骤或后处理中除去保护基团。
下列简写词的使用贯穿本发明
℃：摄氏度
h,hr：小时
MW：微波
TEA：三乙胺
TFA：三氟乙酸
DCM：二氯甲烷
MeOH：甲醇
EtOH：乙醇
DMF：N,N-二甲基甲酰胺
DMSO：二甲基亚砜
DIPEA：N,N-二异丙基乙胺
THF：四氢呋喃
ACN：乙腈
BrCN：溴化氰
DCM/TFA＝1:1：以1：1的体积比例混合的二氯甲烷与三氟乙酸的混合溶液
K3PO4：磷酸钾
NaIO4：高碘酸钠
NH4OAc：醋酸胺
TsCl：4-甲苯磺酰氯
Cs2CO3：碳酸铯
K2CO3：碳酸钾
NH3H2O：氨水
Pd(dppf)Cl2：1,1'-双二苯基膦二茂铁二氯化钯
XPhos Pd G3：甲烷磺酸(2-二环己基膦基-2',4',6'-三-异丙基-1,1'-联苯基)(2'-氨基-1,1'-联苯-2-基)钯(II)
SPhos Pd G3：甲烷磺酸(2-二环己基膦基-2',6'-二甲氧基-1,1'-联苯基)(2'-氨基-1,1'-联苯-2-基)钯(II)
NaBH3CN：氰基硼氢化钠
-OMOM：甲氧基甲氧基
Boc-：叔丁氧羰基
Boc2O：二碳酸二叔丁酯
LHMDS：双三甲基硅基氨基锂
CDI：N,N'-羰基二咪唑
POCl3：三氯氧磷
NMP：N-甲基吡咯烷酮
DMAP：4-二甲氨基吡啶
一般合成方法
制备本发明公开化合物的典型合成步骤如下面的合成方案所示。
方案一
采用以下方法合成以下的式I-1化合物
式I-1-1经过环合反应获得化合物式I-1-2，式I-1-2经过偶联反应获得化合物I-1。其中X为卤素，M1、M2、M3、Ra、Rc、L1、R1、m、n的定义如上文各实施例所述。
附图说明
图1和图2为本申请化合物111与阳参化合物在碘乙酸诱导的SD大鼠膝骨关节炎模型上的药效。
下面提供实施例和附图以帮助理解本发明。但应理解，这些实施例和附图仅用于说明本发明，但不构成任何限制。本发明的实际保护范围在权利要求书中进行阐述。应理解，在不脱离本发明精神的情况下，可以进行任何修改和改变。
中间体M-1的制备
向化合物M-0(700mg,2.02mmol)的丙酮(10mL)和水(10mL)的混合溶液中加入乙酸铵(935mg,12.1mmol)、高碘酸钠(2.59g,12.1mmol)反应在50℃下搅拌18小时。反应液过滤，丙酮(2mL)洗涤滤饼3次，滤液旋干，加水(10mL)稀释，二氯甲烷(5mL)萃取3次，合并有机相，无水硫酸钠干燥，过滤旋干粗产物直接用于下一步反应不需进一步纯化，得到化合物M-1。
实施例1：化合物12的制备
步骤1)：室温下，向100mL三口瓶中依次加入化合物12-1(3.0g,18.29mmol，毕得)，三乙胺(5.07mL,36.59mmol)，无水二氯甲烷(15mL)，充分混合均匀后，冰水浴冷却到0℃，缓慢滴加氯乙酰氯(1.60mL,20.12mmol)的二氯甲烷溶液(15mL)。反应液在20℃下搅拌16个小时。LCMS监测原料反应完。反应液倒入水中，二氯甲烷萃取，饱和氯化钠溶液洗，无水硫酸钠干燥，减压浓缩得到固体。柱层析纯化(石油醚/乙酸乙酯/氨水＝1:1：0.1)得到化合物12-2。LC-MS:m/z:240.2[M+H]+。
步骤2)：室温下，向40mL IKA瓶中依次加入化合物12-2(600mg,2.50mmol)，N,N-二甲基甲酰胺(6mL)，然后向反应瓶中加入三乙胺(1.04mL,7.49mmol),1-乙基哌啶-3-胺盐酸盐(534.16mg,3.24mmol，乐研)。反应液60℃下搅拌5个小时。LCMS监测原料反应完。向反应液加入10mL饱和氯化钠溶液，然后用10mL的四氢呋喃萃取2次，有机相减压浓缩，柱层析纯化(石油醚/乙酸乙酯/氨水＝1:1：0.1)得到12-3。LC-MS:m/z:332.1[M+H]+。
步骤3)：室温下，向40mL IKA瓶中依次加入化合物12-3(400mg,2.50mmol)，二甲基亚砜(4mL)，然后向反应瓶中加入DIPEA(0.60mL,3.61mmol)，反应液130℃下搅拌3个小时。LCMS监测原料反应完。冷却至室温，向反应液加入10mL饱和氯化钠溶液，然后用10mL的四氢呋喃萃取2次，有机相减压浓缩，柱层析纯化(石油醚/乙酸乙酯/氨水＝1:1:0.1)得到化合物12-4。LC-MS:m/z:296.1(M+H)+。
1H NMR(400MHz,CDCl3)δ6.70(s,1H),4.86-4.78(m,1H),4.33-4.16(m,2H),3.06-3.04(m,1H),2.92-2.89(m,1H),2.51-2.46(m,2H),2.30-2.24(m,1H),2.02-1.92(m,1H),1.90-1.89(m,1H),1.82-1.71(m,4H),1.11(t,J＝7.2Hz,3H).
步骤4)：室温下，向8mL单口瓶中加入，化合物12-4(90.0mg,0.300mmol)，中间体M-1(137mg,0.520mmol)，Xphos PdG3(25.8mg,0.030mmol)，磷酸钾(258mg,1.22mmol)，二氧六环(2mL)，水(0.2mL)。反应在80℃下反应1小时。反应液加水(3mL)稀释，二氯甲烷(6mL)萃取3次，合并有机相，无水硫酸钠干燥，过滤，旋干，残余物经制备薄层层析硅胶板(二氯甲烷/胺甲醇(7M)＝20/1),，得到化合物12-5。LC-MS:m/z:480.2(M+H)+。
步骤5)：室温下,向8mL单口瓶中加入，化合物12-5,二氯甲烷(1mL)，三氟乙酸(1mL)。反应在25℃下反应3小时。反应液旋干。残余物用高效液相色谱法(Waters-SunFire-C18-10μm-19*250mm；流动相：水(含有10mmol/L甲酸)和乙腈，梯度配比：乙腈23％-48％，流速：30mL/min)纯化，得到化合物12。LC-MS:m/z:436.1(M+H)+。
1H NMR(400MHz,DMSO-d6)δ11.01(s,1H),10.22(s,1H),7.11(s,1H),7.05(s,1H),6.68(s,1H),4.81-4.77(m,1H),4.21-4.22(m,2H),2.98(d,J＝8.8Hz,1H),2.88(d,J＝11.2Hz,1H),2.48-2.44(m,1H),2.30-2.20(m,1H),2.14(s,3H),2.02-1.92(m,2H),1.78-1.70(m,2H),1.71-1.56(m,2H),1.03(t,J＝7.1Hz,3H).
实施例2：化合物11的制备
步骤1)：室温下，向40mL的IKA瓶中依次加入化合物2-2(200.0mg,1.30mmol)，N,N-二甲基甲酰胺(5mL)，然后向反应瓶中加入碳酸铯(636.0mg,1.95mmol)以及化合物3-氯-7H-吡咯并[2,3-c]哒嗪(442.88mg,1.56mmol，毕得)。反应液100℃下搅拌2个小时。LCMS监测原料反应完。向反应液加入20mL的水，然后用50mL的乙酸乙酯萃取2次，有机相减压浓缩，剩余物经硅胶柱纯化(四氢呋喃/二氯甲烷＝0～10％)得到化合物11-1。LC-MS:m/z:265.3[M+H]+。
1H NMR(400MHz,CDCl3)δ7.69(d,J＝3.4Hz,1H),7.66(s,1H),6.39(d,J＝3.4Hz,1H),4.60(dd,J＝4.8,13.9Hz,1H),4.25(dd,J＝5.8,14.0Hz,1H),3.18-3.16(m,1H),3.03-3.02(m,1H),2.74-2.69(m,1H),2.35-2.31(m,1H),2.23-2.21(m,1H),1.82-1.80(m,1H),1.69-1.62(m,1H),1.56-1.52(m,2H),1.10(t,J＝7.3Hz,3H).
步骤2)：25℃下，向25mL单口瓶中加入化合物11-1(100mg,0.380mmol)，中间体M-1(169mg,0.640mmol)，XPhos Pd G3(31.9mg,0.040mmol)，磷酸钾(320mg,1.51mmol)，水(0.2mL)和二氧六环(2.0mL)，混合物置换氮气3次，反应在80℃下搅拌1小时。向反应液中加入饱和氯化钠溶液(3mL)稀释，二氯甲烷(5mL)萃取3次，合并有机相，无水硫酸钠干燥，旋干。残余物通过柱层析硅胶柱(二氯甲烷/甲醇＝15/1)纯化，得到化合物11-2。LC-MS:m/z449.2[M+H]+。
步骤3)：25℃下，向25mL单口瓶中加入化合物11-2(45.0mg,0.100mmol)，盐酸/二氧六环溶液(2.0mL,4.0M)，反应在25℃下搅拌1小时。将反应液旋干。粗产品通过制备(Waters-SunFire-C18-10μm-19*250mm；流动相：水(含有10mmol/L甲酸)和乙腈，梯度配比：乙腈23％-48％，流速：30mL/min)纯化，得到化合物11。LC-MS:m/z 405.1[M+H]+。
1HNMR(400MHz,DMSO-d6)δ10.05(s,1H),8.15(s,1H),7.80(s,1H),7.15(s,1H),7.10(s,1H),6.60(d,J＝3.4Hz,1H),5.14-5.05(m,1H),3.15-3.11(m,1H),2.88(d,J＝11.1Hz,1H),2.63-2.52(m,2H),2.24-2.16(m,1H),2.15-1.95(m,6H),1.90-1.80(m,1H),1.77-1.67(m,1H),1.05(t,J＝7.2Hz,3H).
实施例3：化合物5的制备
步骤1)：室温下，将化合物5-1(1.00g,6.28mmol)，化合物5-1a(1.14g,5.85mmol)加入到EtOH(10mL)中，回流搅拌过夜。直接将反应体系浓缩，残余物经柱层析纯化(0-3％甲醇/二氯甲烷)得到化合物5-2。LC-MS:m/z:283.8(M+H)+。
步骤2)：将化合物5-2(250mg,1.04mmol)的氨水(10mL,28％)的溶液在50℃下搅拌5个小时。反应液减压蒸干，剩余物中加入乙酸乙酯(3mL)和石油醚(6mL)，搅拌2个小时，然后过滤混合物，得到化合物5-3(150mg)。LC-MS:m/z:254.9(M+H)+。
步骤3)：向化合物5-3(100mg,0.39mmol)和化合物5-3a(207mg,0.78mmol)在二氧六环(3mL)和水(0.5mL)的混合物中加入碳酸钾(162mg,1.18mmol)和[1,1'-双(二苯基膦)二茂铁]二氯化钯(28.69mg，0.04mmol)。将反应在氮气保护下在80℃下搅拌2小时。反应液过滤减压浓缩，通过硅胶色谱(洗脱液：二氯甲烷/甲醇＝20/1)纯化粗产品得到化合物5-4。LC-MS:m/z:395.0(M+H)+。
步骤4)：室温下，向化合物5-4(120mg，0.30mmol)的二氯甲烷(1mL)中的溶液中加入三氟乙酸(1mL，13.42mmol)。将反应在25℃下搅拌2小时。反应液减压浓缩，残余物用高效液相色谱法(Waters-SunFire-C18-10μm-19*250mm；流动相：水(含有10mmol/L甲酸)和乙腈，梯度配比：乙腈23％-48％，流速：30mL/min)纯化得到化合物5。LC-MS:m/z:351.1(M+H)+。
实施例4：化合物9的制备
步骤1)：向化合物4-1(2.00g,13.9mmol)的乙醇(15mL)的溶液中加入化合物9-1(3.86g,18.1mmol，毕得)和乙酸铵(1.61g,20.90mmol)。将反应混合物在70℃下搅拌18小时。反应液除去溶剂。剩余物用C18反相柱(甲醇/水＝62％)，得到化合物9-2。LC-MS:m/z:337.5[M+H]+。
步骤2)：25℃下，向单口瓶中加入化合物9-2(100mg,0.300mmol)，中间体M-1(195mg,0.740mmol)，二氧六环(2mL)，水(0.3mL)，磷酸钾(126mg,0.590mmol)，XPhos Pd G3(25.1mg,0.03mmol)，反应在80℃下，搅拌2小时。向反应液加入水(3mL)稀释，乙酸乙酯(3mL)萃取3次，合并有机相，无水硫酸钠干燥，过滤，旋干。残余物通过柱层析硅胶柱(MeOH/DCM＝1/10)纯化得到化合物9-3。LC-MS:m/z 521.1[M+H]+。
步骤3)：25℃下，向25mL单口瓶中加入化合物9-3(70mg,0.13mmol)，二氯甲烷(1mL)，三氟乙酸(1mL,0.670mmol)反应在室温下搅拌1小时。将反应液旋干，通过制备 (Waters-SunFire-C18-10μm-19*250mm；流动相：水(含有10mmol/L甲酸)和乙腈，梯度配比：乙腈23％-48％，流速：30mL/min)纯化，得到化合物9。LC-MS:m/z 377.1[M+H]+。
实施例5：化合物10的制备
步骤1)：向化合物9-2(360mg,1.07mmol)的二氯甲烷(5mL)的溶液中添加三氟乙酸(1mL,13.42mmol)。将反应在25℃下搅拌3小时，反应液浓缩得到化合物10-1。LC-MS:m/z:237.1[M+H]+。
步骤2)：将化合物10-1(360mg,1.44mmol)和乙醛(0.54mL,3.06mmol)的甲醇(1mL)的溶液在25℃下搅拌1小时。然后加入氰基硼氢化钠(191.2mg,3.06mmol)，反应在25℃下搅拌18小时。反应液加入乙酸乙酯(50ml)和水(50ml)萃取。有机相用饱和食盐水(50mL)洗涤，用无水硫酸钠干燥，过滤并浓缩，通过硅胶色谱(洗脱液：石油醚/乙酸乙酯＝1/1)纯化粗产品得到化合物10-2。LC-MS:m/z:265.1[M+H]+。
步骤3)：室温下，向三口瓶中加入化合物10-2(150mg,0.57mmol)，中间体M-1(226mg,0.86mmol)，磷酸钾(481mg,2.27mmol),二氧六环(2mL)和水(0.2mL)，氮气置换三次，加入XPhos PdG3(48mg,0.06mmol)，氮气置换三次。反应液升温至80℃，搅拌1小时，缓慢恢复至室温。向反应液中加入水(15mL)，用二氯甲烷萃取(6mL×3)，有机层分离合并，无水硫酸钠干燥，减压浓缩，剩余物经柱层析纯化(甲醇/二氯甲烷＝0-10％)得到化合物10-6。LC-MS:m/z:449.1[M+H]+。
步骤4)：25℃下，向化合物10-3(60.0mg,0.130mmol)的二氯甲烷(1.0mL)溶液中加入三氟乙酸(1.0mL)，反应在室温下搅拌2小时。反应液旋干，粗产品通过制备(Waters-SunFire-C18-10μm-19*250mm；流动相：水(含有10mmol/L甲酸)和乙腈，梯度配比：乙腈23％-48％，流速：30mL/min)纯化，得到化合物10。LC-MS:m/z 405.1[M+H]+。
1H NMR(400MHz,CDCl3)δ7.69(d,J＝3.4Hz,1H),7.66(s,1H),6.39(d,J＝3.4Hz,1H),4.60(dd,J＝4.8,13.9Hz,1H),4.25(dd,J＝5.8,14.0Hz,1H),3.18-3.16(m,1H),3.03-3.02(m,1H),2.74-2.69(m,1H),2.35-2.31(m,1H),2.23-2.21(m,1H),1.82-1.80(m,1H),1.69-1.62(m,1H),1.56-1.52(m,2H),1.10(t,J＝7.3Hz,3H).
实施例6：化合物14的制备
步骤1)：室温下，向250mL单口瓶中加入化合物14-1(2.00g,10.6mmol)，甲醇(10mL)和水(10mL)搅拌，加入溴化氰(2.33mL,31.74mmol)，反应液在氮气气氛下70℃搅拌3小时，向反应液中加入水，用乙酸乙酯萃取(50mL×3)，饱和食盐水洗涤(20mL×1)，无水硫酸钠干燥，减压浓缩。剩余物经柱层析纯化(0-5％甲醇/二氯甲烷)得到化合物14-2。LC-MS:m/z:213.9(M+H)+。
步骤2)：室温下，向50mL单口瓶中加入化合物14-2(100mg,0.47mmol)，1,4二氧六环(5mL)和水(1mL)搅拌，加入中间体M-1(123mg,0.470mmol)，加入碳酸钾(193mg,1.40mmol)和[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(38.2mg,0.05mmol)，反应液在氮气气氛下80℃搅拌2小时，向反应液中加入水，用乙酸乙酯萃取(50mL×3)，饱和食盐水洗涤(20mL×1)，无水硫酸钠干燥，减压浓缩。剩余物经柱层析纯化(0-5％甲醇/二氯甲烷)得到化合物14-3。LC-MS:m/z:354.0(M+H)+
步骤3)：室温下，向50mL单口瓶中加入化合物12-3(100mg,0.28mmol)，加入二氯甲烷(2mL)和TFA(2mL)搅拌，反应液室温搅拌2小时。粗品经高效液相(Waters-SunFire-C18-10μm-19*250mm；流动相：水(含有10mmol/L甲酸)和乙腈，梯度配比：乙腈23％-48％，流速：30mL/min)，制备得到化合物14。LC-MS:m/z:310.0(M+H)+。
1H NMR(400MHz,DMSO-d6)δ7.90(s,1H),7.71(d,J＝8.0Hz,1H),7.06(d,J＝12.7Hz,2H),6.90(d,J＝8.0Hz,1H),3.36(s,2H),2.07(s,3H).
实施例7：化合物3的制备
步骤1)：0℃下，向化合物3-1(50.0mg,0.320mmol，合成方法参考：WO2021018858A1)的THF(1mL)溶液中缓慢加入双三甲基硅基氨基锂(0.64mL,0.64mmol,1M)，反应在0℃下搅拌1小时，向反应液中加入化合物3-1a(40.8mg,0.320mmol，毕得)，反应在室温下搅拌3小时。LCMS检测反应完成，向反应液中加入饱和氯化铵溶液(2mL)淬灭反应，乙酸乙酯(2mL)萃取3次，合并有机相，无水硫酸钠干燥，过滤，旋干。粗产品通过柱层析纯化(氨水/甲醇/二氯甲烷＝1/10/100)得到化合物3-2。LC-MS:,m/z 247.1[M+H]+。
步骤2)：室温下，向化合物3-2(30.0mg,0.120mmol)的丙酮(0.5mL)水(0.5mL)溶液中加入化合物3-2a(26.7mg,0.120mmol，合成方法参考：US20200361898A1，第39页中间体B005的合成)，碳酸钾(33.6mg,0.240mmol)，Pd(dtbpf)Cl2(7.85mg,0.01mmol)，反应在微波反应器中120℃下反应30分钟。将反应液减压蒸干，残余物用二氯甲烷(1mL)萃取3次，合并有机相，无水硫酸钠干燥，过滤，旋干。粗产品通过制备(Waters-SunFire-C18-10μm-19*250mm；流动相：水(含有10mmol/L甲酸)和乙腈，梯度配比：乙腈23％-48％，流速：30mL/min)得到化合物3。LC-MS:m/z 387.3[M+H]+。
实施例8：化合物2的制备
步骤1)：室温下，向40mLIKA瓶中依次加入化合物2-1(1.03mL,7.74mmol，毕得)，吡啶(10mL)，充分混合均匀后继续加入对甲苯磺酰氯(1.62g,8.51mmol)。反应液在25℃下搅拌16个小时。LCMS监测原料反应完。利用减压旋蒸将反应液浓缩成暗红色泥状物，后加入10mL乙醇，震荡均匀得到暗红色悬浊液，再次利用减压旋蒸将其浓缩。加乙醇、浓缩，反复三次之后得到略带红色的白色固体。加入尽可能少量的乙醇，震荡均匀得到有大量白色固体的悬浊液。减压过滤，滤渣用少量乙醇洗涤2遍，得到固体。将固体在减压旋蒸下干燥，得到化合物2-2。LC-MS:m/z:284.3[M+H]+。
1H NMR(400MHz,CDCl3)δ7.87(d,J＝8.3Hz,2H),7.40(d,J＝8.3Hz,2H),5.08-5.00(m,1H),3.60-3.56(m,1H),3.43-3.40(m,1H),3.12-3.09(m,2H),2.69-2.60(m,2H),2.47(s,3H),2.30-2.20(m,1H),2.13-2.05(m,1H),1.96-1.90(m,1H),1.66-1.57(m,1H),1.44(t,J＝7.4Hz,3H)。
步骤2)：室温下，向100mL单口瓶中加入化合物3-氯-5H-吡咯并[3,2-c]哒嗪(1.30g,8.47mmol，制备方法参考：WO2022121914A1，第73页化合物25c的合成)，溶解于二甲基甲酰胺(20mL)，然后向反应瓶中加入碳酸铯(11.0g,33.9mmol)和化合物2-2(5.28g,18.62mmol)。反应液在100℃下搅拌6个小时。将反应液倒入50毫升的水中，用乙酸乙酯(50ml)萃取，有机相减压浓缩，剩余物经柱层析(乙酸乙酯/石油醚＝0-50％)得到化合物2-3。LC-MS:m/z:265.2[M+H]+。
1HNMR(400MHz,DMSO-d6)δ8.09(d,J＝0.7Hz,1H),7.96-7.94(m,2H),6.93-6.92(m,1H),4.20(d,J＝5.3Hz,2H),3.00-2.97(m,1H),2.82-2.78(m,1H),2.20-2.09(m,2H),1.74-1.73(m,1H),1.58-1.57(m,1H),1.41-1.37(m,2H),0.90(t,J＝7.2Hz,3H).
步骤3)：室温下，向25mL三口瓶中加入化合物2-3(90.0mg,0.340mmol)，化合物M-1(90.0mg,0.340mmol)，磷酸钾(289mg,1.36mmol)和二氧六环(2mL)，水(0.2mL)搅拌均匀，加入XPhos PdG3(29mg,0.03mmol)，再氮气置换体系3次。反应液在80℃搅拌1小时。反应液冷却至室温，加入水(10mL)，乙酸乙酯(5mL×3)萃取，有机相使用饱和食盐水(5mL)洗涤，无水硫酸钠干燥，减压浓缩除去溶剂。剩余物经柱层析纯化(0％-10％甲醇/二氯甲烷)得到化合物2-4。LC-MS:m/z:449.2[M+H]+。
步骤4)：室温下，向25mL单口瓶中加入2-5(60mg,0.13mmol)和二氯甲烷(1mL)搅拌均匀，加入三氟乙酸(1mL)，反应液室温搅拌2小时。向反应液中加入饱和碳酸氢钠水溶液，调节pH至7-8。混合物用二氯甲烷(5mL)萃取三次，有机相合并，饱和食盐水(8mL)洗涤，无水硫酸钠干燥，过滤后减压浓缩。残余物经高效液相(A相为0.01摩尔每升碳酸氢铵水溶液，B相为乙腈)，制备得到化合物2。LC-MS:m/z:405.1[M+H]+。
1H NMR(400MHz,DMSO-d6)δ10.08(s,1H),7.90(d,J＝3.6Hz,1H),7.81(s,1H),7.16(s,1H),7.11(s,1H),6.91(d,J＝3.2Hz,1H),4.21-4.17(m,2H),2.99-2.97(m,1H),2.81-2.79(m,1H),2.59-2.56(m,1H),2.19-2.08(m,2H),2.06(s,3H),1.72-1.68(m,1H),1.60-1.56(m,1H),1.47-1.42(m,2H),0.91-0.85(m,3H).
实施例9：化合物4的制备
步骤1)：室温下，将化合物4-1(1.00g,6.97mmol，毕得)，化合物4-1a(1.50g,7.66mmol，毕得)加入到乙醇(10mL)中，回流搅拌过夜。直接将反应体系浓缩，残余物经柱层析纯化(0-3％甲醇/二氯甲烷)得到化合物4-2。LC-MS:m/z:240.1[M+H]+。
步骤2)：室温下，向化合物4-2的乙腈(0.5mL)和水(0.5mL)溶液中加入化合物3-2a(97.4mg,0.440mmol，合成方法参考：US20200361898A1，第39页中间体B005的合成)，Pd(dtbpf)Cl2(28.6mg,0.040mmol)和碳酸钾(122mg,0.890mmol)，反应在微波反应器中120℃反应40分钟。反应液浓缩，残余物与水(5mL)混合，用二氯甲烷(5mL)萃取3次，合并有机相，无水硫酸钠干燥，过滤，旋干。残余物通过制备纯化(Waters-SunFire-C18-10μm-19*250mm；流动相：水(含有10mmol/L甲酸)和乙腈，梯度配比：乙腈23％-48％，流速：30mL/min)得到化合物4。LC-MS:m/z 352.3[M+H]+。
实施例10：化合物6的制备
步骤1)：在室温下，向化合物1-1(1000mg,5.32mmol，毕得)的四氢呋喃(10mL)的溶液中加入N,N'-羰基二咪唑(1.29g,7.98mmol)。将反应在70℃下搅拌3小时。然后过滤混合物得到化合物6-1。LC-MS:m/z:214.0[M+H]+。
步骤2)：向化合物6-1(400mg，1.87mmol)的三氯氧磷(20mL)的溶液中加入四甲基氯化铵(410mg，3.74mmol)。将反应在110℃下搅拌3小时。反应完毕，冷却到室温，减压蒸馏除去三氯氧磷，再加入饱和碳酸氢钠溶液(200mL)中和，乙酸乙酯(200*3)萃取。有机相使用无水硫酸钠干燥，浓缩得到化合物6-2。LC-MS:m/z:233.9[M+H]+。
步骤3)：向化合物6-2(250mg,1.08mmol)的N-甲基吡咯烷酮(4mL)的溶液中加入化合物6-3(481mg,5.38mmol)和N-甲基吗啉(0.35mL,3.23mmol)。将反应在100℃下搅拌18小时。反应液通过C18液相色谱(洗脱液：17％的乙腈水溶液)纯化得到化合物6-4。LC-MS:m/z:284.9[M+H]+。
步骤4)：室温下，向化合物6-4(100mg,0.35mmol)和化合物M-1(93mg,0.35mmol)的二氧六环(5mL)和水(1mL)的溶液中加入碳酸钾(145mg,1.05mmol)和[1,1'-双(二苯基膦)二茂铁]二氯化钯(26mg，0.04mmol)。将反应在氮气保护下在80℃下搅拌2小时。反应液过滤减压浓缩，通过层析硅胶板(洗脱液：二氯甲烷/甲醇＝10/1)纯化残留物得到化合物6-5。LC-MS:m/z:425.5[M+H]+。
步骤5)：室温下，向化合物6-5(60mg，0.14mmol)的二氯甲烷(2mL)中的溶液中加入三氟乙酸(1mL)。将反应在25℃下搅拌1小时。反应液减压浓缩，残留物经高效液相(Waters- SunFire-C18-10μm-19*250mm；流动相：水(含有10mmol/L甲酸)和乙腈，梯度配比：乙腈23％-48％，流速：30mL/min)制备得到化合物6。LC-MS:m/z:381.1[M+H]+。
1H NMR(400MHz,DMSO-d6)δ7.67(s,1H),7.12(s,1H),7.06-7.02(m,2H),3.32(s,2H),2.13(s,3H),1.17(s,6H).
实施例11：化合物13的制备
步骤1)：室温下，向8mL单口瓶中加入化合物13-1(50.0mg,0.290mmol)，化合物M-1(132mg,0.500mmol)，Xphos Pd G3(49.92mg，0.06mmol)，磷酸钾(250mg，1.18mmol),二氧六环(2mL)，水(0.2mL)。反应在氮气保护下，80℃反应1小时。反应液加入二氯甲烷(10mL)，饱和氯化钠水溶液(3mL)稀释，用二氯甲烷(5mL)萃取3次，合并有机相，无水硫酸钠干燥，过滤，旋干，残余物经制备薄层层析硅胶板(二氯甲烷/甲醇＝20/1),得到化合物13-2。LC-MS:m/z:354.0[M+H]+。
步骤2)：室温下，在8mL单口瓶中将化合物13-2溶于二氯甲烷(1mL)，加入三氟乙酸(1mL)。反应在25℃下反应0.5小时。反应液旋干。残余物用高效液相色谱法(Waters-SunFire-C18-10μm-19*250mm；流动相：水(含有10mmol/L甲酸)和乙腈，梯度配比：乙腈23％-48％，流速：30mL/min)纯化得到标题化合物)13。LC-MS:m/z:310.1[M+H]+。
1H NMR(400MHz,DMSO-d6)δ10.32(s,1H),7.96(d,J＝9.1Hz,1H),7.39(d,J＝9.1Hz,1H),7.17(s,1H),7.09(s,1H),6.35(s,2H),2.15(s,3H).
实施例12：化合物7的制备
步骤1)：室温下，向化合物7-1(50.0mg,0.280mmol)的二氧六环/水(1.0mL/0.2mL)溶液中加入化合物M-1(73.9mg,0.280mmol)，碳酸钾(0.56mL,0.56mmol,1M水溶液)，SPhos Pd G3(24.1mg,0.03mmol)，体系置换氮气3次，反应在90℃下搅拌3小时。反应液加水(5mL)稀释，乙酸乙酯(5mL)萃取3次，合并有机相，无水硫酸钠干燥，过滤，旋干，得到化合物7-2粗品，直接用于下一步反应，不需进一步纯化。
步骤2)：室温下，向化合物7-2(45.0mg,0.120mmol)的二氯甲烷(3mL)溶液中加入三氟乙酸(1mL)，反应在室温下搅拌2小时，反应液减压蒸干，残余物通过制备纯化(Waters-SunFire-C18-10μm-19*250mm；流动相：水(含有10mmol/L甲酸)和乙腈，梯度配比：乙腈23％-48％，流速：30mL/min)，得到化合物7。LC-MS:m/z:320.1[M+H]+。
实施例13：化合物8的制备
步骤1)：室温下，向单口瓶中加入化合物8-1(3.58g,18.9mmol，毕得)，再加入甲醇(35mL)，向快速搅拌的反应液中加入溴化氰(2.01g,18.9mmol)，加完后50℃条件下反应2小时。反应体系恢复至室温后，向反应体系中加入饱和碳酸氢钠溶液(200mL)，固体析出后抽滤。滤饼用水(20mL×3)洗涤，干燥后得到化合物8-2。LC-MS:m/z:214.0[M+H]+。
1H NMR(400MHz,DMSO-d6)δ7.92(s,2H),7.51(d,J＝8.0Hz,1H),7.36(d,J＝8.0Hz,1H).
步骤2)：室温下，向单口瓶中加入化合物8-2(100mg,0.470mmol)，化合物M-1(248mg,0.940mmol)，Pd(dppf)Cl2(34.4mg,0.050mmol)，碳酸钾(260mg,1.88mmol),二氧六环(2mL)，水(0.2mL)。反应在氮气保护下，80℃反应1小时。反应液加入二氯甲烷(10mL)，水(5mL)稀释，分液，用二氯甲烷(5mL)萃取3次，合并有机相，无水硫酸钠干燥，过滤，旋干得到粗品化合物8-3。
步骤3)：室温下，向单口瓶中加入化合物8-3(145mg,0.410mmol)，二氯甲烷(3mL)，三氟乙酸(1.5mL)。反应在25℃下反应1小时。反应液减压蒸干。残余物制备纯化(Waters-SunFire-C18-10μm-19*250mm；流动相：水(含有10mmol/L甲酸)和乙腈，梯度配比：乙腈23％-48％，流速：30mL/min)，得到化合物8。LC-MS:m/z:310.0[M+H]+。
实施例14：化合物1的制备
步骤1)：室温下，将化合物1-1(500mg,2.66mmol)，溴化氰(282mg,2.66mmol)，甲醇(5mL)和水(5mL)的混合物在50℃下搅拌3小时。所得混合物减压蒸馏，剩余物中加入乙酸乙酯(10mL)和石油醚(10mL)，搅拌2个小时，然后过滤混合物，得到化合物1-2。LC-MS:m/z:212.9[M+H]+。
步骤2)：室温下，向化合物1-2(600mg,2.82mmol)的四氢呋喃(3mL)的溶液中加入二碳酸二叔丁酯(799mg,3.66mmol),三乙胺(0.78mL,5.63mmol)和4-二甲氨基吡啶(1.03g,8.45mmol)。将反应在25℃下搅拌18小时。反应液加入乙酸乙酯(50ml)和水(50ml)萃取。有机相用饱和食盐水(50mL)洗涤，用无水硫酸钠干燥，过滤并浓缩，通过硅胶色谱(洗脱液：石油醚/乙酸乙酯＝1/1)纯化粗产品得到化合物1-3。LC-MS:m/z:312.9[M+H]+。
步骤3)：室温下，向化合物1-3(160mg,0.51mmol)，化合物M-1(270mg,1.02mmol)，二氧六环(3mL)和水(0.5mL)的混合物中加入碳酸钾(212mg,1.53mmol)和[1,1'-双(二苯基膦)二茂铁]二氯化钯(37.4mg，0.050mmol)。混合物氮气置换三次，在80℃下搅拌18小时。反应液过滤减压浓缩，残留物通过硅胶色谱(洗脱液：二氯甲烷/甲醇＝20/1)纯化，得到化合物1-5。LC-MS:m/z:353.1[M+H]+。
步骤4)：室温下，向化合物1-5(80mg，0.23mmol)的二氯甲烷(1mL)中的溶液中加入三氟乙酸(1mL)。将反应在25℃下搅拌2小时。反应液减压浓缩，残留物经高效液相(Waters-SunFire-C18-10μm-19*250mm；流动相：水(含有10mmol/L甲酸)和乙腈，梯度配比：乙腈23％-48％，流速：30mL/min)制备得到化合物1。LC-MS:m/z:309.1[M+H]+。
1H NMR(400MHz,DMSO-d6)δ8.16(s,1H),7.43(d,J＝7.9Hz,1H),7.07(s,1H),7.02(s,1H),6.86(d,J＝7.9Hz,1H),6.60(s,2H),2.14(s,3H).
实施例15：化合物111的制备
步骤1)：室温下，向500mL单口瓶中加入化合物111-1(10.0g,43.3mmol，采用专利申请“WO2022078971A1”中说明书第102页的中间体步骤A化合物公开的方法制备而得)，氯化亚砜(100mL)搅拌，缓慢滴加N,N-二甲基甲酰胺(1mL)，反应液70℃下搅拌3小时，浓缩反应液，向残余物中加入水，用乙酸乙酯萃取(100mL×3)，饱和食盐水洗涤(50mL×1)，无水硫酸钠干燥，减压浓缩。残余物用硅胶柱色谱法以洗脱剂体系(石油醚/乙酸乙酯＝50/1至10/1)纯化得到化合物111-2。
1HNMR(400MHz,DMSO-d6)δ8.25(d,J＝8.5Hz,1H),7.75(d,J＝8.5Hz,1H).
步骤2)：将化合物111-3(1.00g，4.28mmol，乐研)，化合物111-2(923mg，4.28mmol)溶于乙腈(20mL)中，加入碳酸钾(1.78g，12.8mmol)，80℃搅拌反应2小时后，反应液中加入水(50mL)，二氯甲烷(50mL×3)萃取，有机相合并，用饱和食盐水洗涤，有机相用无水硫酸钠干燥，过滤除去干燥剂后滤液减压浓缩，残余物用硅胶柱色谱法以洗脱剂体系(二氯甲烷/甲醇＝40/1至15/1)纯化得到化合物111-4。MS m/z(ESI):415.1[M+1]+。
步骤3)：将化合物111-4(1.70g，4.11mmol)溶于二氯甲烷(10mL)中，加入三氟乙酸(10mL)，反应液在25℃下，搅拌反应3小时，反应液减压浓缩后得到化合物111-5。MS m/z(ESI):314.9[M+1]+。
步骤4)：将化合物111-5(1.50g，4.79mmol)溶于二氯甲烷(20mL)中，加入三乙胺(3.32mL，23.4mmol)，0℃搅拌反应10分钟。乙酸酐(0.47mL，5.03mmol)加入反应液，25℃继续反应15分钟后。反应液中加入水(50mL)，二氯甲烷(50mL×3)萃取，有机相合并，用饱和食盐水洗涤，有机相用无水硫酸钠干燥，过滤除去干燥剂后滤液减压浓缩，残余物用硅胶柱色谱法以洗脱剂体系(二氯甲烷/甲醇＝40/1至15/1)纯化得到化合物111-6。MS m/z(ESI):355.0[M+1]+。
步骤5)：将化合物111-6(1.15g，3.24mmol)，化合物M-1(1.71g，6.48mmol)溶于二氧六环(30mL)和水(6mL)，加入1,1-双(二苯基膦)二荗铁二氯化钯(236mg，0.320mmol，adamas)和碳酸钾(1.78g，12.6mmol)。反应置换氮气三次，并在氮气气氛中，80℃下，搅拌18小时。反应结束后向反应液中加入水(50mL)，并用二氯甲烷(50mL×2)萃取。合并的有机相用无水硫酸钠干燥，过滤除去干燥剂后滤液减压浓缩，残余物用硅胶柱色谱法以(二氯甲烷/甲醇＝100/1至5/10)得到化合物111-7。MS m/z(ESI):495.3[M+1]+。
步骤6)：将化合物111-7(1.26g，2.29mmol)溶于盐酸/二氧六环溶液(12mL,4M)中，反 应液在25℃下，搅拌反应2小时。反应液过滤得到滤饼，滤饼用甲醇(3mL)和二氯甲烷(20mL)溶解，加入饱和碳酸氢钠溶液(20mL)萃取。有机相用无水硫酸钠干燥，过滤除去干燥剂后滤液减压浓缩，残余物用硅胶柱色谱法以(二氯甲烷/甲醇＝100/1至5/10)得到化合物111。MS m/z(ESI):451.2[M+1]+。
1H NMR(400MHz,DMSO-d6)δ9.93(d,J＝3.8Hz,1H),8.79-8.43(m,1H),7.82-7.65(m,1H),7.07(d,J＝14.2Hz,2H),6.98-6.87(m,1H),4.68-4.00(m,2H),3.94-3.80(m,2H),3.74-3.61(m,2H),3.56-3.41(m,2H),3.29-2.95(m,1H),2.12-1.91(m,6H).
实施例16：化合物247的合成
步骤1)：将化合物111-5(80.0mg，0.26mmol)溶于二氯甲烷(5mL)中，加入三氟乙酸酐(82.0mg，0.39mmol，毕得)，三乙胺(78.0mg，0.77mmol)，室温搅拌反应2小时后，反应液加入到饱和的碳酸氢钠溶液(10ml)中，二氯甲烷萃取(10mL×3)，有机相合并，有机相用无水硫酸钠干燥，过滤除去干燥剂后滤液减压浓缩，残余物用薄层色谱法以洗脱剂体系(二氯甲烷/甲醇＝20/1)纯化得到化合物247-1。MS m/z(ESI):408.0[M+1]+。
步骤2)：将化合物247-1(50.0mg，0.12mmol)溶于1,4-二氧六环(3mL)和水(0.6mL)的混合溶液中，加入M-1(65.0mg，0.24mmol)，碳酸钾(51.0mg，0.37mmol)和1,1'-双二苯基膦二茂铁二氯化钯(8.94mg，0.01mmol)，置换氮气三次，80度搅拌反应2小时后，反应液加入水(15ml)，乙酸乙酯萃取(10mL×3)，有机相合并，有机相用无水硫酸钠干燥，过滤除去干燥剂后滤液减压浓缩，残余物用薄层色谱法以洗脱剂体系(二氯甲烷/甲醇＝20/1)纯化得到化合物247-2MS m/z(ESI):547.3[M+1]+。
步骤3)：将化合物247-2(50.0mg，0.09mmoL)溶于二氯甲烷(3mL)中，加入三氟乙酸(3mL)，室温搅拌反应2小时后，直接将反应液减压浓缩，残余物用高效液相色谱法(Waters-2545，色谱柱:SharpSil-TC18，30*150mm，5μm；流动相:水(含有10mmol/L甲酸)和乙腈，梯度配比:乙腈38％-45％，流速:30mL/min)纯化，得到化合物247。MS m/z(ESI):505.3[M+1]+。
1H NMR(400MHz,DMSO-d6)δ9.92(s,1H),8.71-8.63(m,1H),7.77-7.73(m,1H),7.08(s,1H),7.05(s,1H),6.96-6.92(m,1H),4.63(s,1H),4.10-4.07(m,1H),4.00-3.93(m,2H),3.87-3.82(m,2H),3.67-3.56(m,2H),3.49-3.44(m,1H),2.07(s,3H).
实施例17：化合物248的制备
步骤1)：将化合物248-1(70.0mg，0.32mmol)溶于二氯甲烷(3mL)中，0℃下加入三乙胺(98.3mg，0.97mmol)，异丁酰氯(44.8mg，0.42mmol，毕得)，室温搅拌反应2小时后，反应液加入到饱和的碳酸氢钠溶液(15ml)中，二氯甲烷萃取(10mL×3)，有机相合并，有机相用无水硫酸钠干燥，过滤除去干燥剂后滤液减压浓缩，残余物直接作为下一步原料，无需纯化，得到化合物248-2。MS m/z(ESI):231.2[M-55]+。
步骤2)：将化合物248-2(140mg，0.49mmoL)溶于二氯甲烷(3mL)中，加入三氟乙酸(3mL)，室温搅拌反应1.5小时后，直接将反应液减压浓缩，得到化合物248-3，残余物直接作为下一步原料，无需纯化。MS m/z(ESI):187.2[M+1]+。
步骤3)：将化合物111-2(110mg，0.47mmol)溶于乙腈(8mL)中，加入248-3(87.8mg，0.47mmol)，碳酸钾(195mg，1.41mmol)，80℃搅拌反应2小时后，反应液加入水(20ml)，乙酸乙酯萃取(15mL×3)，有机相合并，有机相用无水硫酸钠干燥，过滤除去干燥剂后滤液减压浓缩，残余物用硅胶柱色谱法以洗脱剂体系(二氯甲烷/甲醇＝100/1至20/1)纯化得到化合物248-4。MS m/z(ESI):383.1[M+1]+。
步骤4)：将化合物248-4(50.0mg，0.13mmol)溶于1,4-二氧六环(3mL)和水(0.6mL)的混合溶液中，加入M-1(68.9mg，0.24mmol)，碳酸钾(54.1mg，0.39mmol)和1,1'-双二苯基膦二茂铁二氯化钯(9.55mg，0.01mmol)，置换氮气三次，80度搅拌反应12小时后，反应液加入水(10ml)，乙酸乙酯萃取(10mL×3)，有机相合并，有机相用无水硫酸钠干燥，过滤除去干燥剂后滤液减压浓缩，残余物用薄层色谱法以洗脱剂体系(二氯甲烷/甲醇＝20/1)纯化得到化合物248-5。MS m/z(ESI):523.3[M+1]+。
步骤5)：将化合物248-5(50.0mg，0.10mmoL)溶于二氯甲烷(2mL)中，加入三氟乙酸(2mL)，室温搅拌反应2小时后，直接将反应液减压浓缩，残余物用高效液相色谱法(Waters-2545，色谱柱:SharpSil-TC18，30*150mm，5μm；流动相:水(含有10mmol/L甲酸)和乙腈，梯度配比:乙腈38％-45％，流速:30mL/min)纯化，得到化合物248。MS m/z(ESI):479.3[M+1]+。
1H NMR(400MHz,DMSO-d6)δ9.95(s,1H),8.63(d,J＝81.9Hz,1H),7.78-7.71(m,1H),7.08(s,1H),7.05(s,1H),6.93(dd,J＝11.9,8.0Hz,1H),4.68-4.63(m,1H),4.14-4.11(m,1H),3.89-3.78(m,1H),3.70-3.63(m,2H),3.55-3.50(m,2H),3.32-3.25(m,2H),3.04-2.93(m,1H),2.07(s,3H),1.00-0.96(m,3H),0.90-0.75(m,3H).
实施例18：化合物249的制备
步骤1)：将化合物111-5(80.0mg，0.26mmol)溶于二氯甲烷(5mL)中，0℃下加入三乙胺(77.6mg，0.77mmol)，二氟乙酸酐(67.9mg，0.39mmol，毕得)，室温搅拌反应2小时后，反应液加入到饱和的碳酸氢钠溶液(15mL)中，二氯甲烷萃取(10mL×3)，有机相合并，有机相用无水硫酸钠干燥，过滤除去干燥剂后滤液减压浓缩，残余物用薄层色谱法以洗脱剂体系(二氯甲烷/甲醇＝20/1)纯化得到化合物249-1。MS m/z(ESI):390.1[M+1]+。
步骤2)：将化合物249-1(50.0mg，0.13mmol)溶于1,4-二氧六环(3mL)和水(0.6mL)的混合溶液中，加入M-1(67.5mg，0.26mmol)，碳酸钾(53.0mg，0.38mmol)和1,1'-双二苯基膦二茂铁二氯化钯(9.35mg，0.01mmol)，置换氮气三次，80℃搅拌反应2小时后，反应液加入水(15mL)，乙酸乙酯萃取(10mL×3)，有机相合并，有机相用无水硫酸钠干燥，过滤除去干燥剂后滤液减压浓缩，残余物用薄层色谱法以洗脱剂体系(二氯甲烷/甲醇＝20/1)纯化得到化合物249-2。MS m/z(ESI):531.7[M+1]+
步骤3)：将化合物249-2(50.0mg，0.09mmoL)溶于二氯甲烷(2mL)中，加入三氟乙酸(2mL)，室温搅拌反应2小时后，直接将反应液减压浓缩，残余物用高效液相色谱法(Waters-2545，色谱柱:SharpSil-TC18，30*150mm，5μm；流动相:水(含有10mmol/L甲酸)和乙腈，梯度配比:乙腈38％-45％，流速:30mL/min)纯化，得到化合物249。MS m/z(ESI):487.4[M+1]+。
1H NMR(400MHz,DMSO-d6)δ9.91(s,1H),8.67-8.52(m,1H),7.77-7.10(m,1H),7.07(d,J＝12.2Hz,2H),6.96-6.91(m,1H),6.81-6.53(m,1H),4.60-4.15(m,1H),4.06(d,J＝13.8Hz,1H),4.00-3.90(m,2H),3.85-3.70(m,2H),3.64-3.54(m,2H),3.45-3.40(m,1H),2.07(d,J＝2.8Hz,3H).
实施例19：化合物250的制备
步骤1)：将化合物111-5(50.0mg，0.16mmol)溶于二氯甲烷(3mL)中，0℃下加入三乙胺(48.5mg，0.48mmol)，丙酰氯(14.8mg，0.16mmol，毕得)，0度下搅拌反应3分钟后，反应液加入到饱和的碳酸氢钠溶液(15ml)中，二氯甲烷萃取(10mL×3)，有机相合并，有机相用无水硫酸钠干燥，过滤除去干燥剂后滤液减压浓缩，残余物用薄层色谱法以洗脱剂体系(二氯甲烷/甲醇＝20/1)纯化得到化合物250-1。MS m/z(ESI):371.1[M+1]+
步骤2)：将化合物250-1(50.0mg，0.14mmol)溶于1,4-二氧六环(3mL)和水(0.6mL)的混合溶液中，加入M-1(71.5mg，0.27mmol)，碳酸钾(56.2mg，0.41mmol)和1,1'-双二苯基膦二茂铁二氯化钯(9.91mg，0.01mmol)，置换氮气三次，80℃搅拌反应12小时后，反应液加入水(10mL)，乙酸乙酯萃取(10mL×3)，有机相合并，有机相用无水硫酸钠干燥，过滤除去干燥剂后滤液减压浓缩，残余物用薄层色谱法以洗脱剂体系(二氯甲烷/甲醇＝20/1)纯化得到化合物250-2。MS m/z(ESI):509.4[M+1]+。
步骤3)：将化合物250-2(50.0mg，0.10mmoL)溶于二氯甲烷(2mL)中，加入三氟乙酸(2mL)，室温搅拌反应2小时后，直接将反应液减压浓缩，残余物用高效液相色谱法(Waters-2545，色谱柱:SharpSil-TC18，30*150mm，5μm；流动相:水(含有10mmol/L甲酸)和乙腈， 梯度配比:乙腈38％-45％，流速:30mL/min)纯化，得到化合物250。MS m/z(ESI):465.7[M+1]+。
1H NMR(400MHz,DMSO-d6)δ10.07(s,1H),9.02-8.80(m,1H),7.89-7.82(m,1H),7.12-7.10(m,1H),7.07(s,1H),7.03-6.99(m,1H),4.70-4.60(m,1H),4.16-4.07(m,1H),3.90-3.83(m,2H),3.70-3.62(m,2H),3.58-3.43(m,2H),3.38-3.26(m,1H),2.43-2.29(m,2H),2.10-2.07(m,3H),0.97-0.84(m,3H).
实施例20：化合物253的制备
步骤1)：将化合物253-1(209mg,1.13mmol,毕得)溶于二氧六环-水溶液(5/1,5mL)中，加入化合物111-6(200mg,0.56mmol)，[1,1'-双(二苯基膦)二茂铁]二氯化钯(41.2mg,0.06mmol)，碳酸钾(312mg,2.25mmol)，体系置换氮气3次，反应在80℃下搅拌2小时，反应液加水(5mL)稀释，乙酸乙酯(5mL)萃取3次，合并有机相，无水硫酸钠干燥，过滤，旋干。残余物用高效液相色谱法(Waters-2545，色谱柱:SharpSil-T C18,30*150mm,5μm；流动相:水(含有10mmol/L甲酸)和乙腈，梯度配比:乙腈38％-45％，流速:30mL/min)纯化得到化合物253。MS m/z(ESI):417.5[M+1]+。
1H NMR(400MHz,DMSO-d6)δ9.81–9.71(m,1H),8.77–8.43(m,1H),7.76–7.66(m,1H),6.94–6.84(m,1H),6.83–6.76(m,2H),4.68–4.07(m,1H),3.90–3.81(m,2H),3.73–3.58(m,2H),3.56–3.39(m,3H),3.28–2.94(m,1H),2.09–1.91(m,6H).
实施例21：化合物254的制备
步骤1)：将化合物254-1(120mg，0.72mmol，毕得)，化合物111-6(154mg，0.43mmol)溶于二氧六环(5mL)和水(1mL)，加入1,1-双(二苯基膦)二荗铁二氯化钯(52.9mg，0.07mmol，adamas)和碳酸钾(199mg，1.45mmol)。反应置换氮气三次，并在氮气气氛中，80℃下，搅拌18小时。反应结束后向反应液中加入水(20mL)，并用二氯甲烷(20mL×2)萃取。合并的有机相用无水硫酸钠干燥，过滤除去干燥剂后滤液减压浓缩，残余物用高效液相色谱法(Gilson_306_1741，色谱柱：Waters-SunFire-C18-10μm-19*250mm；流动相：水(含有10mmol/L甲酸)和乙腈，梯度配比：乙腈46％-95％，流速：25mL/min)纯化得到化合物254。MS m/z(ESI):397.3[M+1]+。
1H NMR(400MHz,DMSO-d6)δ9.09(s,1H),8.52–8.13(m,1H),7.67(d,J＝7.9Hz,1H),6.93(d,J＝9.0Hz,1H),6.56(d,J＝6.6Hz,2H),4.87–4.38(m,1H),4.24–4.05(m,1H),3.94–3.81(m,2H),3.75–3.60(m,2H),3.58–3.26(m,3H),2.23(s,3H),2.12–1.84(m,6H).
实施例22：化合物252的制备
步骤1)：将化合物252-1(500mg，2.16mmol，采用专利申请“WO 2022/166890Al”中说明书第66页的中间体20-3公开的方法制备而得)和氯甲基甲醚(0.25mL，3.27mmol)溶于二氯甲烷(10mL)中，加入N,N-二异丙基乙胺(0.72mL，4.3mmol)，反应液在25℃下，搅拌反应18小时后，反应液中加入水(50mL)，乙酸乙酯萃取(50mL×3)，有机相合并，用饱和食盐水洗涤，有机相用无水硫酸钠干燥，过滤除去干燥剂后滤液减压浓缩，残余物用硅胶柱色谱法以洗脱剂体系(石油醚/乙酸乙酯＝50/1至10/1)纯化得到化合物252-2。
步骤2)：将化合物252-2(300mg，1.10mmol)溶于无水四氢呋喃中，在-40℃加入正丁基锂(0.57mL,2.33mmol,2.5M)，反应液在-40℃下，搅拌反应半小时后，再加入异丙醇频哪醇硼酸酯(0.45mL,2.20mmol)，继续在25℃反应2小时。反应液加入冰水(20mL)，乙酸乙酯萃取(20mL×3)，有机相合并，用饱和食盐水洗涤，有机相用无水硫酸钠干燥，过滤除去干燥剂后滤液减压浓缩，残余物用硅胶柱色谱法以洗脱剂体系(石油醚/乙酸乙酯＝50/1至10/1)纯化得到化合物252-3。
1H NMR(400MHz,CDCl3)δ8.09(s,1H),7.53(d,J＝8.3Hz,1H),7.29(t,J＝8.0Hz,1H),6.96(d,J＝7.8Hz,1H),5.31(s,2H),3.51(s,3H),1.38(s,12H).
步骤3)：将化合物252-3(200mg，0.62mmol)，化合物111-6(155mg，0.44mmol)溶于二氧六环(5mL)和水(1mL)，加入1,1-双(二苯基膦)二荗铁二氯化钯(45.7mg，0.06mmol，adamas)和碳酸钾(172mg，1.25mmol)。反应置换氮气三次，并在氮气气氛中，80℃下，搅拌18小时。反应结束后向反应液中加入水(50mL)，并用乙酸乙酯(50mL×2)萃取。合并的有机相用无水硫酸钠干燥，过滤除去干燥剂后滤液减压浓缩，残余物残余物用硅胶柱色谱法(二氯甲烷/甲醇＝100/1至20/1)纯化得到化合物122-4。MS m/z(ESI):469.2[M+1]+。
步骤4)：将化合物252-4(80mg，0.17mmol)溶于二氯甲烷(4mL)，加入三氟乙酸(1mL)。反应液在25℃下搅拌2小时。反应结束后减压浓缩，残余物用高效液相色谱法(Gilson_306_1741，色谱柱：Waters-SunFire-C18-10μm-19*250mm；流动相：水(含有10mmol/L甲酸)和乙腈，梯度配比：乙腈46％-95％，流速：25mL/min)纯化得到化合物252。MS m/z(ESI):425.2[M+1]+。
1H NMR(400MHz,DMSO-d6)δ9.80(s,1H),8.70–8.40(m,1H),8.00(s,1H),7.76–7.69(m,1H),7.65–7.57(m,1H),7.35(d,J＝8.0Hz,1H),7.16(t,J＝7.9Hz,1H),6.74(d,J＝7.7Hz,1H),4.79–4.53(m,1H),4.19–4.05(m,1H),3.93–3.84(m,2H),3.76–3.63(m,2H),3.62–3.46(m,2H),3.42–3.30(m,1H),2.01(s,3H).
实施例23：化合物251的制备
步骤1)：将化合物251-1(500mg，2.35mmol，毕得)和氯甲基甲醚(0.23mL，3.05mmol)溶于二氯甲烷(10mL)中，加入N,N-二异丙基乙胺(0.78mL，4.69mmol)，反应液在25℃下，搅拌反应18小时后，反应液中加入水(50mL)，乙酸乙酯萃取(50mL×3)，有机相合并，用饱和食盐水洗涤，有机相用无水硫酸钠干燥，过滤除去干燥剂后滤液减压浓缩，残余物用硅胶柱色谱法以洗脱剂体系(石油醚/乙酸乙酯＝50/1至10/1)纯化得到化合物251-2。
步骤2)：将化合物251-2(300mg，1.17mmol)溶于无水四氢呋喃中，在-78℃加入正丁基锂(0.93mL,2.33mmol,2.5M己烷溶液)，反应液在-78℃下，搅拌反应1小时后，再加入异丙醇频哪醇硼酸酯(0.38mL,1.87mmol)，继续在-78℃反应1小时。反应液加入冰水(20mL)，乙酸乙酯萃取(20mL×3)，有机相合并，用饱和食盐水洗涤，有机相用无水硫酸钠干燥，过滤除去干燥剂后滤液减压浓缩，残余物用硅胶柱色谱法以洗脱剂体系(石油醚/乙酸乙酯＝50/1至10/1)纯化得到化合物251-3。
1H NMR(400MHz,CDCl3)δ7.57(d,J＝7.4Hz,1H),7.01(d,J＝7.4Hz,1H),5.09(s,2H),3.56(s,3H),2.99(t,J＝7.4Hz,2H),2.93(t,J＝7.5Hz,2H),2.10–2.00(m,2H),1.33(s,12H).
步骤3)：将化合物251-3(230mg，0.76mmol)，化合物111-6(188mg，0.53mmol)溶于二氧六环(5mL)和水(1mL)，加入1,1-双(二苯基膦)二荗铁二氯化钯(55.3mg，0.08mmol，adamas)和碳酸钾(209mg，1.51mmol)。反应置换氮气三次，并在氮气气氛中，80℃下，搅拌18小时。反应结束后向反应液中加入水(50mL)，并用乙酸乙酯(50mL×2)萃取。合并的有机相用无水硫酸钠干燥，过滤除去干燥剂后滤液减压浓缩，残余物残余物用硅胶柱色谱法(二氯甲烷/甲醇＝100/1至20/1)纯化得到化合物251-4。MS m/z(ESI):453.6[M+1]+。
步骤4)：将化合物251-4(130mg，0.29mmol)溶于二氯甲烷(2mL)，加入三氟乙酸(2mL)。反应液在25℃下搅拌2小时。反应结束后减压浓缩，残余物用高效液相色谱法(Gilson_306_1741，色谱柱：Waters-SunFire-C18-10μm-19*250mm；流动相：水(含有10mmol/L甲酸)和乙腈，梯度配比：乙腈46％-95％，流速：25mL/min)纯化得到化合物251。MS m/z(ESI):409.2[M+1]+。
1H NMR(400MHz,DMSO-d6)δ13.56(s,1H),8.84–8.41(m,1H),7.88–7.78(m,1H),7.70–7.64(m,2H),6.78(d,J＝8.0Hz,1H),4.79–4.01(m,2H),3.93–3.83(m,2H),3.77–3.63(m,2H),3.55–3.37(m,3H),2.90–2.85(m,4H),2.12–1.88(m,5H).
实施例24：化合物255的制备
步骤1)：将化合物255-1(1.00g，3.26mmol，采用文献Journal ofAgricultural and Food Chemistry(1995),43(3),804-8中公开的方法制备而得)加入四氢呋喃(15mL)中，搅拌均匀，氮气置换三次，反应液降温至-70℃，缓慢加入正丁基锂(1.60mL,3.91mmol，2.5M四氢呋喃溶液)，控制温度低于-65℃。反应液搅拌30分钟，缓慢加入硼酸三异丙酯(0.92g,4.88mmol)，加入结束后反应液缓慢升温至室温，室温下搅拌18小时。反应液缓慢加入冰水(20mL)中，用乙酸乙酯(8mL×3)萃取，有机相用饱和食盐水和无水硫酸钠干燥，减压除去溶剂。无需纯化，直接用于下一步反应。得到化合物255-2。MS m/z(ESI):273.1[M+1]+。
步骤2)：将化合物255-2(500mg，0.92mmol)，化合物111-6(100mg，0.28mmol)溶于二氧六环(5mL)和水(1mL)，加入1,1-双(二苯基膦)二荗铁二氯化钯(67.2mg，0.09mmol，adamas)和碳酸钾(254mg，1.84mmol)。反应置换氮气三次，并在氮气气氛中，80℃下，搅拌18小时。反应结束后向反应液中加入水(50mL)，并用乙酸乙酯(50mL×2)萃取。合并的有机相用无水硫酸钠干燥，过滤除去干燥剂后滤液减压浓缩，残余物残余物用硅胶柱色谱法(二氯甲烷/甲醇＝100/1至20/1)纯化得到化合物255-3。MS m/z(ESI):503.8[M+1]+。
步骤3)：将化合物255-3(160mg，0.22mmol)溶于甲醇(15mL)，加入10％湿钯碳(20mg，adamas)。反应液在氢气气氛下搅拌18小时。反应结束后过滤除去钯碳，滤液减压浓缩，残余物用高效液相色谱法(Gilson_306_1741，色谱柱：Waters-SunFire-C18-10μm-19*250mm；流动相：水(含有10mmol/L甲酸)和乙腈，梯度配比：乙腈46％-95％，流速：25mL/min)纯化得到化合物255。MS m/z(ESI):413.3[M+1]+。
1H NMR(400MHz,DMSO-d6)δ9.59–9.40(m,1H),8.72–8.36(m,1H),7.77–7.59(m,1H),6.97–6.83(m,1H),6.32(s,2H),4.67–4.08(m,1H),4.07–3.80(m,3H),3.72(s,3H),3.69–3.57(m,2H),3.56–3.43(m,2H),3.20–2.87(m,1H),2.07–1.92(m,6H).
实施例25：化合物257的制备
步骤1)：在0℃将环丙基甲酰氯(126μL,1.39mmol)加入包含化合物248-1(150mg,0.69mmol，毕得)，三乙胺(192μL,1.39mmol)和二氯甲烷(1mL)的溶液中。反应液在25℃下，搅拌反应0.5小时，之后加入水(20mL)，乙酸乙酯(20mL×2)萃取，有机相合并，用饱和食盐水洗涤，有机相用无水硫酸钠干燥，过滤除去干燥剂后滤液减压浓缩，得到化合物257-1。MS m/z(ESI):307.2[M+23]+。
步骤2)：将化合物257-1(190mg,0.67mmol)溶于二氯甲烷(2mL)中，加入三氟乙酸(1mL)，反应液在25℃下，搅拌反应1小时，反应液减压浓缩后得到化合物257-2。MS m/z(ESI):185.0[M+1]+。
步骤3)：将碳酸钾(277mg,2.00mmol)加入到111-2(156mg,0.67mmol),257-2(123mg,0.67mmol),和乙腈(3mL)的溶液中。反应液在25℃下搅拌18小时。之后加入水(20mL)，乙酸乙酯(20mL×3)萃取，有机相合并，用饱和食盐水洗涤，有机相用无水硫酸钠干燥，过滤除去干燥剂后滤液减压浓缩，残余物用硅胶柱色谱法以洗脱剂体系(二氯甲烷/甲醇＝40/1至15/1)纯化得到化合物257-3。MS m/z(ESI):383.0[M+1]+。
步骤4)：将1,1'-双二苯基膦基二茂铁二氯化钯(28.8mg,0.04mmol)加入到257-3(150mg,0.39mmol),M-1(156mg,0.59mmol),碳酸钾(109mg,0.79mmol)，水(0.5mL)和二氧六环(2.5mL)的溶液中。氮气置换三次后在80℃下搅拌2小时。反应液中加入水(20mL)，乙酸乙酯(20mL×3)萃取，有机相合并，用饱和食盐水洗涤，有机相用无水硫酸钠干燥，过滤除去干燥剂后滤液减压浓缩，残余物用硅胶柱色谱法以洗脱剂体系(二氯甲烷/甲醇＝40/1至15/1)纯化得到化合物257-4。MS m/z(ESI):521.6[M+1]+。
步骤5)：将三氟乙酸(1mL)加入到257-4(100mg,0.19mmol)和二氯甲烷(3mL)的溶液中。在25℃下搅拌18小时。反应液减压浓缩后用高效液相色谱法(Waters-2545，色谱柱:Waters-SunFire-C18-10μm-19*250mm；流动相:水(含有10mmol/L甲酸)和乙腈，梯度配比:乙腈42％-52％，流速:25mL/min)纯化得到化合物257。MS m/z(ESI):477.0[M+1]+。1H NMR(400MHz,DMSO-d6)δ10.12–9.87(m,1H),8.89–8.54(m,1H),7.84–7.70(m,1H),7.16–7.01(m,2H),6.99–6.89(m,1H),4.70–4.46(m,1H),4.13–3.85(m,3H),3.67–3.59(m,2H),3.47–3.30(m,2H),3.18–2.94(m,1H),2.15–2.01(m,3H),2.00–1.81(m,1H),0.77–0.29(m,4H).
实施例26：化合物258的制备
步骤1)：室温下，将化合物248-1(80.0mg，0.37mmol，乐研)，三乙胺(110mg，1.09mmol)加入二氯甲烷(2mL)中，搅拌均匀。冰浴降温至0℃，缓慢加入甲基磺酰氯(64.0mg，0.56mmol)，缓慢升温至室温，反应2小时。反应液加入水(10mL)，用二氯甲烷(5mL×3)萃取，有机相用饱和食盐水和无水硫酸钠干燥，减压除去溶剂。无需纯化，直接用于下一步反应。得到化合物258-1。MS m/z(ESI):195.0[M-100]+。
步骤2)：室温下，将化合物258-1(120mg，0.41mmol)加入到二氯甲烷(1mL)搅拌均匀，缓慢加入三氟乙酸(1mL)，室温反应1小时。反应液减压除去溶剂，无需纯化，可直接用于下一步，得到化合物258-2。MS m/z(ESI):194.9[M+1]+。
步骤3)：室温下，将化合物258-2(119mg，0.52mmol)，111-2(100mg，0.43mmol)和碳酸钾(178mg，1.29mmol)加入乙腈(3mL)中，搅拌均匀，反应液升温至70℃，反应2小时。反应液降温至室温，过滤，滤饼用二氯甲烷(5mL×3)洗涤，减压除去溶剂。剩余物用硅 胶柱色谱法(石油醚/乙酸乙酯＝100/1至1/1)纯化，得到化合物258-3。MS m/z(ESI):392.6[M+1]+。
步骤4)：室温下，将化合物258-3(110mg，0.28mmol)，M-1(124mg，0.47mmol)，碳酸钾(118mg，0.85mmol)和[1，1'-双(二苯基膦)二茂铁]二氯化钯(41.0mg，0.06mmol)加入到二氧六环(3mL)和水(0.3mL)中搅拌均匀，氮气置换三次，升温至80℃反应2小时。反应液降温至室温，加入到水(20mL)中，乙酸乙酯(6mL×3)萃取，有机相用饱和食盐水和无水硫酸钠干燥，减压除去溶剂。剩余物用硅胶柱色谱法(石油醚/乙酸乙酯＝100/1至1/1)纯化得到化合物258-4。MS m/z(ESI):531.2[M+1]+。
步骤5)：室温下，将化合物258-4(50.0mg，0.09mmol)加入到二氯甲烷(1mL)搅拌均匀，缓慢加入三氟乙酸(1mL)，室温反应1小时。反应液减压除去溶剂。剩余物高效液相色谱法(Gilson_306_1741，色谱柱：Waters-SunFire-C18-10μm-19*250mm；流动相：水(含有0.1％甲酸)和乙腈，梯度配比：乙腈33％-67％，流速：25mL/min)纯化得到化合物258。MS m/z(ESI):487.2[M+1]+。
1H NMR(400MHz,DMSO-d6)δ9.98(s,1H),8.71(s,1H),7.77(d,J＝8.0Hz,1H),7.09(s,1H),7.05(s,1H),6.94(d,J＝8.1Hz,1H),3.99–3.97(m,1H),3.86–3.78(m,2H),3.71–3.65(m,2H),3.60–3.57(m,1H),3.45–3.40(m,3H),3.04(s,3H),2.08(s,3H).
实施例27：化合物260的制备
步骤1)：室温下，将化合物248-1(100mg，0.46mmol，毕得)和三乙胺(0.200mL，1.39mmol)加入二氯甲烷(2mL)中，搅拌均匀。冰浴降温至0℃，缓慢加入环丙磺酰氯(0.10mL，0.92mmol，毕得)，加入结束后缓慢升温至室温，反应18小时。反应液加入水(10mL)，用二氯甲烷(5mL×3)萃取，有机相用饱和食盐水和无水硫酸钠干燥，减压除去溶剂。无需纯化，直接用于下一步反应。得到化合物260-1。MS m/z(ESI):221.0[M-100]+。
步骤2)：室温下，将260-1(130mg,0.41mmol)加入到二氯甲烷(1mL)搅拌均匀，缓慢加入三氟乙酸(1mL)，室温反应1小时。反应液减压除去溶剂。无需纯化，可直接用于下一步，得到化合物260-2。MS m/z(ESI):221.0[M+1]+。
步骤3)：室温下，将化合物111-2(75mg,0.32mmol)，化合物260-2(85.0mg，0.39mmol)和碳酸钾(133mg，0.96mmol)加入乙腈(3mL)，搅拌均匀，反应液升温至70℃，反应2小时。反应液降温过滤，滤饼用二氯甲烷(5mL×3)洗涤，减压除去溶剂。无需纯化，可直接用于下一步反应。得到化合物260-3。MS m/z(ESI):419.0[M+1]+。
步骤4)：室温下，将化合物260-3(60.0mg，0.14mmol)，M-1(62mg，0.23mmol)，碳酸钾(60mg，0.43mmol)和[1，1'-双(二苯基膦)二茂铁]二氯化钯(21mg，0.03mmol)加入到二氧六环(2mL)和水(0.2mL)搅拌均匀，氮气置换三次，升温至80℃反应2小时。反应液降至室温，加入到水(20mL)中，乙酸乙酯(6mL×3)萃取，有机相用饱和食盐水和无水硫酸钠干 燥，减压除去溶剂。剩余物用硅胶柱色谱法(石油醚/乙酸乙酯＝100/1至1/1)纯化得到化合物260-4。MS m/z(ESI):555.2[M-1]-。
步骤5)：室温下，将化合物260-4(50mg，0.09mmol)加入到二氯甲烷(1mL)搅拌均匀，缓慢加入三氟乙酸(1mL)，室温反应1小时。反应液减压除去溶剂剩余物高效液相色谱法(Gilson_306_1741，色谱柱：Waters-SunFire-C18-10μm-19*250mm；流动相：水(含有0.1％甲酸)和乙腈，梯度配比：乙腈35％-65％，流速：25mL/min)得到化合物260。MS m/z(ESI):513.0[M+1]+。
1H NMR(400MHz,DMSO-d6)δ9.96(s,1H),8.68(s,1H),7.75(d,J＝8.0Hz,1H),7.09(s,1H),7.05(s,1H),6.93(d,J＝8.0Hz,1H),4.02–3.95(m,1H),3.88–3.81(m,2H),3.74–3.66(m,2H),3.64–3.60(m,1H),3.49–3.47(m,3H),2.76–2.73(m,1H),2.07(s,3H),1.00–0.90(m,4H).
实施例28：化合物259的制备
步骤1)：在0℃将乙基磺酰氯(44.0μL,0.46mmol，乐研)加入包含化合物248-1(50.0mg,0.23mmol，毕得)，三乙胺(64.0μL,0.46mmol)和二氯甲烷(1mL)的溶液中。反应液在25℃下，搅拌反应0.5小时，之后加入水(20mL)，乙酸乙酯(20mL×2)萃取，有机相合并，用饱和食盐水洗涤，有机相用无水硫酸钠干燥，过滤除去干燥剂后滤液减压浓缩，得到化合物259-1。MS m/z(ESI):331.0[M+23]+。
步骤2)：将化合物128-1(70mg,0.23mmol)溶于二氯甲烷(2mL)中，加入三氟乙酸(0.5mL)，反应液在25℃下，搅拌反应1小时，反应液减压浓缩后得到化合物259-2。MS m/z(ESI):209.0[M+1]+。
步骤3)：将碳酸钾(145mg,1.05mmol)加入到111-2(82.0mg,0.35mmol),259-2(73.0mg,0.35mmol),和乙腈(5mL)的溶液中。反应液在25℃下搅拌18小时。之后加入水(20mL)，乙酸乙酯(20mL×3)萃取，有机相合并，用饱和食盐水洗涤，有机相用无水硫酸钠干燥，过滤除去干燥剂后滤液减压浓缩，残余物用硅胶柱色谱法以洗脱剂体系(二氯甲烷/甲醇＝40/1至15/1)纯化得到化合物259-3。MS m/z(ESI):407.0[M+1]+。
步骤4)：将1,1'-双二苯基膦基二茂铁二氯化钯(18.0mg,0.02mmol)加入到259-3(100mg,0.25mmol),M-1(130mg,0.49mmol),碳酸钾(68.0mg,0.49mmol)，水(0.5mL)和二氧六环(2.5mL)的溶液中。氮气置换三次后在80℃下搅拌2小时。反应液中加入水(20mL)，乙酸乙酯(20mL×3)萃取，有机相合并，用饱和食盐水洗涤，有机相用无水硫酸钠干燥，过滤除去干燥剂后滤液减压浓缩，残余物用硅胶柱色谱法以洗脱剂体系(二氯甲烷/甲醇＝40/1至15/1)纯化得到化合物259-4。MS m/z(ESI):545.7[M+1]+。
步骤5)：将三氟乙酸(1mL)加入到259-4(80.0mg,0.15mmol)和二氯甲烷(3mL)的溶液中。在25℃下搅拌18小时。反应液减压浓缩后用高效液相色谱法(Waters-2545，色谱柱:Waters-SunFire-C18-10μm-19*250mm；流动相:水(含有10mmol/L甲酸)和乙腈，梯度配比:乙 腈45％-55％，流速:25mL/min)纯化得到化合物259。MS m/z(ESI):501.0[M+1]+。
1H NMR(400MHz,DMSO-d6)δ9.99(s,1H),8.72(s,1H),7.78(d,J＝8.0Hz,1H),7.09(s,1H),7.05(s,1H),6.95(d,J＝8.0Hz,1H),3.98–3.91(m,1H),3.89–3.80(m,2H),3.77–3.64(m,3H),3.58–3.53(m,3H),3.19–3.10(m,2H),2.08(s,3H),1.16(t,J＝7.2Hz,3H).
实施例29：化合物420的制备
步骤1)：将化合物420-1(1.00g，4.67mmol，采用专利申请“WO2014198594A1”中说明书第84页的中间体33公开的方法制备而得)和氯化亚铜(0.320g，3.27mmol，毕得)溶于浓盐酸(12mL)，在5℃下加入亚硝酸钠(0.520g，7.48mmol，毕得)的水(1mL)溶液。反应液在5℃下，搅拌1小时后，反应液缓慢倒入饱和碳酸氢钠水溶液中(50mL)，混合物用二氯甲烷(20mL)稀释。水相分液后，用二氯甲烷萃取(30mL×3)。合并的有机相用无水硫酸钠干燥。过滤除去干燥剂后，滤液减压浓缩。残余物用硅胶柱色谱法以洗脱剂体系(二氯甲烷/甲醇＝100/1至40/1)纯化得到化合物420-2。MS m/z(ESI):232.9，234.9[M+H]+。
1H NMR(400MHz,DMSO-d6):δ8.41(d,J＝9.5Hz,1H),8.01(d,J＝9.5Hz,1H).
步骤2)：将化合物420-2(100mg，0.430mmol)，化合物A(104mg，0.560mmol)，碳酸钾(178mg，1.29mmol)和1,1-双(二苯基膦)二荗铁二氯化钯(II)(31.5mg，40μmol，毕得)溶于二氧六环(2.5mL)和水(0.5mL)。反应液在氮气氛围下加热至80℃，反应2小时。反应液用二氯甲烷(5mL)和水(5mL)稀释，水相分液后，用二氯甲烷萃取(5mL×3)。合并的有机相用无水硫酸钠干燥。过滤除去干燥剂后，滤液减压浓缩。残余物用硅胶柱色谱法以洗脱剂体系(二氯甲烷/甲醇＝100/1至40/1)纯化得到化合物420-3。MS m/z(ESI):294.9[M+H]+。
步骤3)：将化合物420-3(100mg，0.430mmol)溶于吗啉(1mL)。混合物使用微波加热至200℃，并在该温度下，反应30分钟。将反应液倒入水(5mL)中。水相用二氯甲烷萃取(5mL×3)。合并的有机相用饱和食盐水(5mL)洗涤，无水硫酸钠干燥。过滤除去干燥剂后，滤液减压浓缩。残余物用高效液相色谱法(色谱柱：Waters-SunFire-C18-10μm-19*250mm；流动相：水(含有0.1％甲酸)和乙腈，梯度配比：乙腈32％-48％，流速：25mL/min)纯化得到化合物420。MS m/z(ESI):346.1[M+H]+。
1H NMR(400MHz,DMSO-d6):δ10.22(s,1H),8.07(d,J＝9.2Hz,1H),7.46(d,J＝9.2Hz,1H),6.87(d,J＝13.3Hz,2H),3.77–3.67(m,4H),3.55–3.48(m,4H),2.07(s,3H).
实施例30：化合物419的制备
步骤1)：将化合物439-2(150mg，360μmol)溶于二氧六环(6mL)中，加入(R)-4-Boc-3-吗啉甲胺(156mg，720μmol，乐研)，4,5-双二苯基膦-9,9-二甲基氧杂蒽(41.6mg，72.0μmol)，叔 丁醇钠(69.1mg，720μmol)和三(二亚苄基丙酮)二钯(65.9mg，72.0μmol)，置换氮气三次，100℃搅拌2小时后，反应液倒入水(20mL)中，乙酸乙酯萃取(20mL×3)，有机相合并，有机相用无水硫酸钠干燥，过滤，滤液减压浓缩，残余物用硅胶柱色谱法以洗脱剂体系(二氯甲烷/甲醇＝100/1至20/1)纯化得到化合物419-1。MS m/z(ESI):453.6[M-Boc+1]+；
步骤2)：将化合物419-1(100mg，181μmol)溶于二氯甲烷(2mL)中，加入氯化氢/二氧六环(4mL，4M)，室温搅拌反应1小时后，直接将反应液减压浓缩，残余物直接作为下一步原料，无需纯化，得到化合物419-2。MS m/z(ESI):409.3[M+1]+；
步骤3)：将化合物419-2(60mg，147μmol)溶于二氯甲烷(5mL)中，0℃下加入三乙胺(44.6mg，441μmol)和乙酸酐(15.0mg，147μmol)，0℃下搅拌30分钟后，反应液与碳酸氢钠水溶液(10mL)混和，二氯甲烷萃取(20mL×3)，有机相合并，无水硫酸钠干燥，过滤，滤液减压浓缩，残余物用高效液相色谱法(Waters-2545，色谱柱:SharpSil-TC18，30*150mm，5μm；流动相:水(含有10mmol/L甲酸)和乙腈，梯度配比:乙腈38％-45％，流速:30mL/min)纯化，得到化合物419。MS m/z(ESI):451.2[M+1]+；
1H NMR(400MHz,DMSO-d6):δ10.38(s,1H),8.08–7.90(m,1H),7.52–7.38(m,1H),7.33–6.86(m,3H),4.75–3.75(m,4H),3.70–3.35(m,4H),3.30–2.93(m,1H),2.20–2.09(m,3H),2.05–1.89(m,3H).
实施例31：化合物425的制备
步骤1)：室温下，将化合物424-5(50mg,120μmol)，(R)-4-Boc-3-吗啉甲胺(26mg,120μmol，乐研)，三(二亚苄基丙酮)二钯(11mg,12.0μmol)，叔丁醇钠(34mg,360μmol)和4,5-双二苯基膦-9,9-二甲基氧杂蒽(7.0mg,12.0μmol)加入到二氧六环(2mL)搅拌均匀，氮气置换三次，升温至80℃反应3小时，反应液加入到水(20mL)稀释，乙酸乙酯(6mL×3)萃取，有机相合并，用食盐水(20mL)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，残余物用硅胶柱色谱法(石油醚/乙酸乙酯＝100/1至1/1)纯化，得到化合物425-1。MS m/z(ESI):467.3[M-Boc+1]+；
步骤2)：将三氟乙酸(1mL)加入到含有425-1(50mg,180μmol)和二氯甲烷(2mL)的溶液中。反应在25℃下搅拌1小时。将反应液减压浓缩后即得化合物425-2，无需纯化直接用于下一步。MS m/z(ESI):423.4[M+1]+；
步骤3)：将化合物425-2(30mg,71μmol)，三乙胺(8.0mg,79μmol)和醋酸酐(7.0mg,69μmol)溶于二氯甲烷(2mL)。反应液在25℃下搅拌2小时，反应液与二氯甲烷(10mL)和水(5mL)混和，水相分液后，用二氯甲烷萃取(5mL×3)。合并的有机相用无水硫酸钠干燥，过滤，滤液减压浓缩。残余物用硅胶柱色谱法以洗脱剂体系(二氯甲烷/甲醇＝100/1至30/1)纯化得到425-3。MS m/z(ESI):507.3[M+1]+；
步骤4)：将化合物425-3(40mg,79μmol)和碳酸钾(17mg,180μmol)溶于甲醇(2mL)， 所得混合物加热至60℃，搅拌2小时，反应液与二氯甲烷(10mL)和水(5mL)混和，水相分液后，用二氯甲烷萃取(5mL×3)，合并的有机相用无水硫酸钠干燥，过滤，滤液减压浓缩。残留物经高效液相(A:0.1％甲酸/水，B:乙腈，色谱柱：Waters-SunFire-C18-10μm-19*250mm；流动相：水(含有0.1％甲酸)和乙腈，梯度配比：乙腈32％-48％，流速：25mL/min)制备得到化合物425。MS m/z(ESI):465.3[M+1]+。
1H NMR(400MHz,DMSO-d6)δ10.44(s,1H),7.30–7.22(m,2H),7.15–7.11(m,1H),6.89–6.56(m,1H),5.37–5.30(m,1H),4.60–4.00(m,2H),3.89–3.81(m,2H),3.58–3.51(m,2H),3.18–2.87(m,1H),2.82–2.59(m,1H),2.13–1.97(m,8H),1.48–1.44(m,1H).
实施例32：化合物451的制备
步骤1)：向化合物451-1(10.0g，64.8mmol，安耐吉)的甲醇(220mL)溶液中加入甲醇钠甲醇溶液(12mL，30％甲醇溶液)，混合物在25℃氮气氛围下搅拌反应30分钟。然后将混合物冷却至0℃，并加入液溴(3.33mL，64.8mmol)。反应液在0℃氮气氛围下搅拌2小时。将反应液减压浓缩，残留物与水(100mL)混合搅拌，过滤，滤饼收集真空干燥，得到化合物451-2。MS m/z(ESI):233.0[M+1]+；
步骤2)：向化合物451-2(6.00g，25.7mmol)的甲醇(60mL)溶液中加入雷尼镍(3.00g)，混合物在25℃，氢气(1大气压)氛围下搅拌3小时，过滤，滤液浓缩，得到化合物451-3。MS m/z(ESI):204.9[M+1]+；
步骤3)：向化合物451-3(1.00g，4.93mmol)的乙醇(10mL)溶液中加入氢氧化钾(330mg，5.91mmol)和二硫化碳(7mL)，混合物在80℃氮气氛围下搅拌反应24小时。将混合物减压浓缩，残留物通过硅胶色谱法(二氯甲烷/甲醇＝100/1至10/1)纯化得到化合物451-4。MS m/z(ESI):245.0[M+1]+；
步骤4)：在0℃氮气氛围下，向451-4(1.00g，4.08mmol)的二氯甲烷(15mL)溶液中加入氯化亚砜(0.90mL，12.4mmol)和N,N-二甲基甲酰胺(0.80mL，10.3mmol)，混合物在25℃氮气氛围下搅拌反应1小时。反应液用乙酸乙酯(50mL)稀释并倒入水(20mL)，有机相用食盐水(20mL×2)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，得到化合物451-5。MS m/z(ESI):247.0[M+1]+；
步骤5)：将化合物(R)-4-Boc-3-吗啉甲胺(577mg，2.67mmol，乐研)，化合物451-5(440mg，1.78mmol)溶于乙腈(5mL)中，加入碳酸钾(246mg，1.78mmol)，80℃搅拌反应2小时后，反应液中加入水(30mL)，二氯甲烷(30mL×3)萃取，有机相合并，用饱和食盐水(30mL)洗涤，有机相用无水硫酸钠干燥，过滤除去干燥剂后滤液减压浓缩，残余物用硅胶柱色谱法 (二氯甲烷/甲醇＝40/1至15/1)纯化得到化合物451-6。MS m/z(ESI):429.2[M+1]+；
步骤6)：将化合物451-6(430mg，1.01mmol)溶于二氧六环(4mL)中，加入氯化氢/二氧六环(4mL，4M)，反应液在25℃下，搅拌反应3小时，反应液减压浓缩后得到化合物451-7。MS m/z(ESI):328.8[M+1]+；
步骤7)：将化合物451-7(430mg，1.31mmol)溶于二氯甲烷(10mL)中，加入三乙胺(0.55mL，3.94mmol)，0℃搅拌反应10分钟。乙酸酐(0.13mL，1.38mmol)加入反应液，25℃继续反应15分钟后。反应液中加入水(50mL)，二氯甲烷(50mL×3)萃取，有机相合并，用饱和食盐水(50mL)洗涤，有机相用无水硫酸钠干燥，过滤除去干燥剂后滤液减压浓缩，残余物用硅胶柱色谱法以洗脱剂体系(二氯甲烷/甲醇＝40/1至15/1)纯化得到化合物451-8。MS m/z(ESI):371.1[M+1]+；
步骤8)：将化合物451-8(130mg，0.35mmol)，化合物M-1(167mg，0.63mmol)溶于二氧六环(5mL)和水(0.5mL)，加入1,1-双(二苯基膦)二茂铁二氯化钯(25.7mg，0.035mmol，adamas)和碳酸钾(146mg，1.06mmol)。反应置换氮气三次，并在氮气气氛中，80℃下，搅拌18小时。反应结束后向反应液中加入水(20mL)，并用二氯甲烷(20mL×2)萃取。合并的有机相用无水硫酸钠干燥，过滤除去干燥剂后滤液减压浓缩，残余物用硅胶柱色谱法以(二氯甲烷/甲醇＝100/1至20/1)得到化合物451-9。MS m/z(ESI):509.4[M+1]+；
步骤9)：将化合物451-9(150mg，0.29mmol)溶于氯化氢/二氧六环溶液(4mL,4M)中，反应液在25℃下，搅拌反应2小时。反应液减压浓缩，残余物用高效液相色谱法(A:0.1％甲酸/水，B:乙腈，色谱柱：Waters-SunFire-C18-10μm-19*250mm；流动相：水(含有0.1％甲酸)和乙腈，梯度配比：乙腈32％-48％，流速：25mL/min)纯化得到化合物451。MS m/z(ESI):465.7[M+1]+；
1H NMR(400MHz,DMSO-d6)δ9.94(s,1H),8.75–8.41(m,1H),7.06(d,J＝11.5Hz,2H),6.84–6.76(m,1H),4.67–4.08(m,1H),4.07–3.69(m,3H),3.68–3.42(m,4H),3.29–2.93(m,1H),2.44–2.36(m,3H),2.11–1.93(m,6H).
实施例33：化合物452的制备
步骤1)：将化合物451-8(130mg，0.352mmol)，化合物253-1(164mg，0.882mmol，毕得)溶于二氧六环(5mL)和水(1mL)，加入1,1-双(二苯基膦)二茂铁二氯化钯(25.7mg，0.04mmol，adamas)和碳酸钾(195mg，1.41mmol)。反应置换氮气三次，并在氮气气氛中，80℃下，搅拌18小时。反应结束后向反应液中加入水(20mL)，并用二氯甲烷(20mL×2)萃取。合并的有机相用无水硫酸钠干燥，过滤除去干燥剂后滤液减压浓缩，残余物用高效液相色谱法(Gilson_306_1741，色谱柱：Waters-SunFire-C18-10μm-19*250mm；流动相：水(含有10mmol/L甲酸)和乙腈，梯度配比：乙腈46％-95％，流速：25mL/min)纯化得到化合物452。MS m/z(ESI):431.3[M+1]+；
1H NMR(400MHz,DMSO-d6)δ9.79–9.70(m,1H),8.72–8.36(m,1H),6.83–6.72(m,3H),4.67–4.08(m,1H),4.07–3.68(m,3H),3.67–3.50(m,3H),3.47–3.35(m,1H),3.30–2.94(m,1H),2.43–2.36(m,3H),2.08–1.93(m,6H).
实施例34：化合物453的制备
步骤1)：室温下，将化合物444-1和化合物444-1A的混合物(200mg,479μmol)加入到(R)-4-Boc-3-吗啉甲胺(1.08g，5.0mmol，乐研)中，微波加热至190℃，反应30分钟。冷却至室温，加入水(15mL)，用二氯甲烷/甲醇(10/1，5mL×3)萃取，有机相用饱和食盐水(10mL)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，得到化合物453-1和化合物453-1A的混合物。MS m/z(ESI):509.8[M+1]+；
步骤2)：室温下，将453-1和453-1A的混合物(240mg,434μmol)加入氯化氢/二氧六环(4mL,4M)，室温反应1小时。减压除去溶剂，加入二氯甲烷(15mL)，水(5mL)，加入碳酸氢钠饱和溶液(5mL)搅拌，静置分液，水层用二氯甲烷(5mL×3)萃取，有机相合并，无水硫酸钠干燥，过滤，滤液减压浓缩，残留物用硅胶柱色谱法(甲醇/二氯甲烷＝1/100到1/10)纯化，得到化合物453-2和化合物453-2A的混合物。MS m/z(ESI):409.7[M+1]+；
步骤3)：室温下，将化合物453-2和化合物453-2A的混合物(150mg,367μmol)加入二氯甲烷(3mL)中，加入三乙胺(148mg,1.47mmol)，搅拌均匀，缓慢加入醋酸酐(45.0mg,440μmol)，室温反应3小时。减压除去溶剂，加入二氯甲烷(15mL)，水(5mL)，加入碳酸氢钠水溶液(5mL)搅拌5分钟，静置，分液，水相二氯甲烷(5mL×3)萃取，有机相合并，无水硫酸钠干燥，过滤，滤液减压浓缩，残余物用高效液相色谱法(Gilson_306_1741，色谱柱：Waters-SunFire-C18-10μm-19*250mm；流动相：水(含有10mmol/L甲酸)和乙腈，梯度配比：乙腈30％-70％，流速：25mL/min)纯化，得到化合物453。MS m/z(ESI):451.6[M+1]+；
1H NMR(400MHz,DMSO-d6)δ10.39(s,1H),9.06–9.03(m,1H),7.35–6.98(m,4H),4.60–4.08(m,1H),3.99–3.82(m,3H),3.61–3.38(m,4H),3.27–2.95(m,1H),2.16(s,3H),2.02–1.98(m,3H).
实施例35：化合物454的制备
步骤1)：将化合物454-1(16.0g，40.7mmol，采用专利申请“WO2023159148A2”中说明书第94页的第三步中间体公开的方法制备而得)溶于甲醇(60mL)，加入10％湿钯碳(500 mg)所得混和物在氢气(1大气压)气氛下搅拌18小时，过滤，滤液浓缩后得到化合物454-2。MS m/z(ESI):259.6[M+1]+；
步骤2)：将化合物439-2(100mg，0.241mmol)，454-2(93mg，0.361mmol)，三(二亚苄基丙酮)二钯(21.9mg，0.025mmol)，4,5-双二苯基膦-9,9-二甲基氧杂蒽(27.7mg，0.051mmol)和叔丁醇钠(46.7mg，0.481mmol，毕得)与二氧六环(3mL)混和，所得混合物在氮气氛围下加热至100℃，反应2小时，冷却，反应混合物与二氯甲烷(5mL)和水(5mL)混合，静置分液后，水相用二氯甲烷萃取(5mL×3)，合并的有机相用无水硫酸钠干燥。过滤，滤液减压浓缩，残余物用硅胶柱色谱法(二氯甲烷/甲醇＝100/1至30/1)纯化得到化合物454-3。MS m/z(ESI):481.3[M+1]+；
步骤3)：将化合物454-3(100mg，0.21mmol)溶于氯化氢/二氧六环溶液(4mL,4M)中，反应液在25℃下，搅拌反应2小时。反应液减压浓缩，残余物用高效液相色谱法(A:0.1％甲酸/水，B:乙腈，色谱柱：Waters-SunFire-C18-10μm-19*250mm；流动相：水(含有0.1％甲酸)和乙腈，梯度配比：乙腈32％-48％，流速：25mL/min)纯化得到化合物454。MS m/z(ESI):437.7[M+1]+；
1H NMR(400MHz,DMSO-d6)δ8.18(s,1H),8.00(d,J＝9.1Hz,1H),7.42(d,J＝9.1Hz,1H),7.17(s,1H),7.11(s,1H),6.87(d,J＝8.3Hz,1H),4.52–4.12(m,1H),3.81–3.72(m,1H),3.50(t,J＝6.1Hz,2H),3.03–2.95(m,1H),2.76–2.65(m,1H),2.44(t,J＝6.1Hz,2H),2.16(s,3H),2.14–2.01(m,2H),1.92–1.82(m,1H),1.75–1.66(m,1H),1.57–1.46(m,1H),1.41–1.30(m,1H).
实施例36：化合物455的制备
步骤1)：室温下，将化合物444-1和化合物444-1A的混合物(100mg,240μmol)加入到化合物454-2(1.5mL)中，微波加热至190℃，反应1小时。冷却至室温，加入水(15mL)，用二氯甲烷/甲醇(10/1，5mL×3)萃取，有机相用饱和食盐水(15mL)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，剩余物用硅胶柱色谱法(二氯甲烷/甲醇＝100/1到10/1)纯化，得到化合物455-1和化合物455-1A的混合物。MS m/z(ESI):481.4[M+1]+。
步骤2)：室温下，将化合物455-1和化合物455-1A的混合物(100mg,208μmol)加入氯化氢/二氧六环(2mL,4M)中，室温反应1小时。减压浓缩，除去溶剂。剩余物用高效液相色谱法(Gilson_306_1741，色谱柱：Waters-SunFire-C18-10μm-19*250mm；流动相：水(含有10mmol/L甲酸)和乙腈，梯度配比：乙腈20％-80％，流速：25mL/min)纯化，得到化合物455。MS m/z(ESI):437.4[M+1]+.1H NMR(400MHz,DMSO-d6):δ10.29(s,1H),9.05(d,J＝6.7Hz,1H),7.14(s,1H),7.09(s,1H),7.02(d,J＝6.7Hz,1H),6.94(d,J＝8.4Hz,1H),4.50–4.35(m,1H),3.75–3.73(m,1H),3.52–3.49(m,2H),3.00–2.98(m,1H),2.74–2.68(m,1H),2.47–2.44(m,2H),2.16(s,3H),2.11–2.07(m,2H),1.88–1.85(m,1H),1.72–1.68(m,1H),1.56–1.47(m,1H),1.39–1.34(m,1H).
实施例37：化合物456的制备
步骤1)：室温下，将化合物424-5(150mg,350μmol)，化合物454-2(90mg,350μmol)，三(二亚苄基丙酮)二钯(32mg,30.0μmol)，叔丁醇钠(100mg,1.04mmol)和4,5-双二苯基膦-9,9-二甲基氧杂蒽(21mg,30.0μmol)加入到二氧六环(2mL)搅拌均匀，氮气置换三次，所得混合物升温至80℃反应3小时，然后反应混合物与水(20mL)混和，乙酸乙酯(6mL×3)萃取，有机相合并，饱和食盐水(10mL)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，残余物用硅胶柱色谱法(石油醚/乙酸乙酯＝100/1至1/1)纯化，得到化合物456-1。MS m/z(ESI):495.3[M+H]+；
步骤2)：室温下，向50mL单口瓶中加入化合物456-1(20mg,30.0μmol)，加入氯化氢/二氧六环溶液(2mL，4M)搅拌，反应液室温搅拌1.5小时，减压浓缩，残余物经高效液相(A:0.1％甲酸/水，B:乙腈，色谱柱：Waters-SunFire-C18-10μm-19*250mm；流动相：水(含有0.1％甲酸)和乙腈，梯度配比：乙腈32％-48％，流速：25mL/min)，制备得到化合物456。MS m/z(ESI):451.2[M+1]+；
1H NMR(400MHz,DMSO-d6)δ10.29(s,1H),7.28(s,1H),7.17(s,1H),7.10(s,1H),6.86–6.65(m,1H),5.38–5.28(m,1H),4.53–3.34(m,2H),3.24–2.55(m,2H),2.33(s,1H),2.15(s,3H),2.09–1.95(m,3H),1.91–1.82(m,1H),1.76–1.67(m,1H),1.61–1.42(m,2H),1.30–1.25(m,4H).
实施例38：化合物457的制备
步骤1)：将443-4和443-4A的混合物(200mg，0.460mmol)和(R)-4-Boc-3-吗啉甲胺(1.00g，4.64mmol，毕得)混合后，反应液在微波170℃下，搅拌反应1小时。反应液与二氯甲烷(10mL)和水(2mL)混合，水相分液后，用二氯甲烷(2mL×3)萃取。合并的有机相用无水硫酸钠干燥，过滤，滤液减压浓缩。残余物用硅胶柱色谱法(二氯甲烷/甲醇＝100/1至15/1)纯化得到化合物457-1和457-1A的混合物。MS m/z(ESI):423.3[M+H]+；
步骤2)：将457-1和457-1A的混合物(164mg，0.390mmol)和三乙胺(0.161mL，1.16mmol)溶于二氯甲烷(2mL)中。反应液在0℃下，缓慢滴加乙酰氯(79.3mg，0.780mmol)。反 应液在该温度下，反应1小时。反应液减压浓缩得到化合物457-2和457-2A的混合物。MS m/z(ESI):507.5[M+H]+；
步骤3)：将混合物457-2和457-2A(197mg，0.390mmol)溶于甲醇(3mL)和水(0.3mL)中，加入碳酸钾(107mg，0.780mmol)。反应液在25℃下，反应1小时。反应液减压浓缩除去溶剂。残余物用稀盐酸(1.0M)调节pH至7-8，然后二氯甲烷(5mL×3)萃取，合并的有机相用无水硫酸钠干燥，过滤，滤液减压浓缩。残余物用高效液相色谱法(A:0.1％甲酸/水，B:乙腈，色谱柱：Waters-SunFire-C18-10μm-19*250mm；流动相：水(含有0.1％甲酸)和乙腈，梯度配比：乙腈32％-48％，流速：25mL/min)纯化得到粗品，粗品使用手性分离(色谱柱：ChiralCel OX,250×30mm I.D.,5μm；流动相：A：二氧化碳B：乙醇；梯度：35％B；流速：150mL/min)纯化得到457。MS m/z(ESI):465.3[M+H]+；
1H NMR(400MHz,DMSO-d6):δ10.34–10.14(m,1H),7.37–7.33(s,1H),7.12(s,1H),7.07(s,1H),6.99(s,1H),4.14–3.97(m,2H),3.91–3.84(m,2H),3.61–3.46(m,4H),3.10–2.83(m,1H),2.66(s,3H),2.13(s,3H),2.09(s,3H).
生物测试
1.NLPR3结合试验
本实验通过荧光偏振技术检测开展结合实验评估。
本测试中所用荧光探针为Journal of Molecular Biology(2021)433,167309文献中的化合物NP3-301，参考文献自行合成获得。
His6-Flag-TEV-NLRP3(134-1036)蛋白(SEQ NO.1)来自凯惠睿智生物科技(上海)有限公司(ChemPartner)定制表达。
准备1X实验检测缓冲液成分：50mM Hepes,pH 7.4,150mM NaCl,2.5mM MgCl2,0.005％Tween-20,1mM TCEP,100μM ATP。
首先在黑色浅384孔板(Greiner；784076)中加入2.5μL 4X的化合物溶液，密封浅孔板，1000rpm离心1min；然后加入2X NLPR3蛋白溶液(终浓度30nM)，密封浅孔板，1000rpm离心1min，室温孵育60min,最后加入2.5μL4X的NP3-301(终浓度0.5nM)，密封浅孔板，1000rpm离心1min，室温孵育30min，使用Envision读取λex＝485±20nm，λem＝535±25nm的荧光偏振值。使用GraphPad Prism 9.5.0对数据进行分析，四参数Logistic拟合化合物与NP3-301竞争结合His6-Flag-TEV-NLRP3(134-1036)的IC50值。本发明的化合物具有较好的NLRP3结合活性，部分代表性化合物的测试结果如表1所示。
表1

表1中，A表示IC50≤100nM，B表示100nM<IC50≤500nM，C表示500nM<IC50≤
1000nM，D表示IC50>1000nM。
2.检测NLRP3抑制剂对THP-1细胞分泌IL-1β的影响实验
本实验使用PerkinElmer AlphaLISA_human_IL1β试剂盒(AL220C/F)，检测缓冲液为RPMI-1640+10FBS，AlphaLISA Immunoassay Buffer、AlphaLISAAnti-IL1βAcceptor beads、Streptavidin(SA)-coated Donor beads、Biotinylated Antibody Anti-IL1β均包含在试剂盒中。
将THP1细胞密度调整为4*105个/ml，加入PMA(终浓度50nM)，200μL/孔接种到96孔平底板，37℃，5％CO2刺激过夜(尽量＜16h)。次日，弃上清，用DPBS洗两遍(200μL/次)。加入198μL/孔LPS溶液(终浓度100ng/ml)，37℃，5％CO2孵育3h。每孔根据实验MAP加入1μL对应浓度的化合物，37℃，5％CO2孵育1h。每孔再加入1μL Nigericin(终浓度10μM),5％CO2孵育过夜(＞18h)。第三天，取上清5μL，稀释20倍，通过Human Interleukin 1beta(IL1β)Kit检测上清中的IL-Iβ的含量。使用Envision读取Ex＝680/Em＝570的AlphaLISA测试值。使用GraphPad Prism 9.5.0对数据进行分析，四参数Logistic拟合化合物对IL-Iβ拮抗的IC50值。经检测，本发明化合物对THP-1细胞IL-1β的成熟和分泌具有较好的抑制活性，本发明部分代表性化合物的测试结果如表2所示。
表2：利用THP-1细胞检测NLRP3抑制剂的IC50实验的测试结果

表2中A表示IC50<50nM，B表示50nM≤IC50<100nM，C表示100nM≤IC50<500nM，D表示IC50≥500nM。
3.肝微粒体代谢稳定性实验
测试目的：本实验考察化合物在人、大小鼠等不同种属肝微粒体中代谢稳定性，测试化合物与人、大小鼠等不同种属肝微粒体孵育后的剩余含量。
实验方法
(1)溶液配制
目标化合物及阳性对照500μM溶液配制：取各10mM储备液5μL，加入至95μL乙腈，混匀30s即得；
6mM NADPH溶液配制：用Mg-Mg-K-Buffer稀释100mM Stock分装液。
(2)样品准备
2.1反应液配置
2.1.1肝微粒体溶液：分别取18.75μL的20mg/mL HLM、RLM、MLM、DLM、MOLM(终浓度：0.5mg/ml)于在96孔板中；
2.1.2分别加入各化合物500μM溶液1.5μL；
2.1.3取分别磷酸盐缓冲液479.8μL，加入至各化合物孔中，于振荡混匀器中1000rpm混匀10s。
2.2.样品分板
将以上样品分别取30μL分装至新的96深孔板中(含NADPH组n＝2，0和45min另有无NADPH组(n＝1,))，分别标记为0、5、15、30和45min；
2.3.孵育
将以上分装样品37℃预孵育5min后，按45、30、15和5min样品顺序依次加入15μL37℃预热的6mM NADPH启动反应，无NADPH组加入15μL的Mg-K-Buffer溶液，于振荡混匀器中1000rpm混匀10s后继续孵育(盖好盖子不用封板)；
3.样品后处理
0min时间点样品，加入200μL乙腈内标，再加NADPH，封板振荡混匀1min，4℃保存待离心；
待其余时间点样品完成孵育，分别加入200μL乙腈内标，封板振荡混匀1min，4℃保存待离心；
孵育结束，涡旋混匀1min后，4000rpm离心50min，取上清80μL于含有160μL的纯水的96孔板中，混匀30s，4000rpm离心5min待测。
(3)数据分析
根据化合物浓度百分比的LN值和时间为坐标轴计算斜率，依据斜率和公式算得化合物与肝微粒体孵育后的剩余含量。本发明的化合物在不同种属的肝微粒体中表现出较好的稳定性，代表性化合物的测试结果(测试化合物与肝微粒体孵育45min后的剩余含量)如表3所示。
表3
4.人肝微粒CYP450酶抑制作用体外评价
(1)测试目的
本实验通过将化合物，肝微粒体以及不同CYP亚型酶底物放置37℃水浴孵育，测定底物代谢产物的生成量，根据IC50大小评价本公开化合物对CYP酶抑制作用。
(2)实验方法
i.用DMSO(阿拉丁，货号：D103273-500ml)将化合物稀释至0,0.02,0.06,0.2,0.6,2和6mM浓度，各CYP亚型阳参抑制剂以及浓度见表4
表4 CYP亚型酶的阳参抑制剂及其浓度
ii.用磷酸盐缓冲液(sigma：V900050-500G)配置各CYP亚型酶底物溶液。各CYP亚型酶底物及浓度见表5。
表5 CYP亚型酶底物及其浓度
iii.样品孵育。取1μL各浓度化合物以及CYP亚型酶阳参抑制剂于96深孔板(A-gen：P-1.0-RD-96-S)中，加入169μL 0.05mg/mL肝微粒(BioIVT，IHG)体磷酸盐缓冲溶液(CYP2C19使用0.2mg/mL肝微粒体)，混匀后放置37℃振荡水浴(上海精宏实验设备有限公司，DK-500)预孵育15min。加入10μL底物(CYP3A4-Testosterone加入1μL底物)和20μL 10mM NADPH磷酸盐缓冲溶液(MCE，HYF003/CS-4998)，混匀后振荡水浴孵育至以下时间：CYP1A2:20min,CYP2C9:10min,CYP2C19:10min,CYP2D6:10min,CYP3A4-Testosterone:10min,CYP3A4-Midazolam:5min。加入400μL含内标(500nM甲苯磺丁脲，5nM特非那定)的冰乙腈/甲醇(v/v，1:1)终止反应。4000rpm 4℃离心40min后，取上清用纯水根据底物代谢产物的响应进行稀释后用UPLC-MS/MS(Sciex，Q-Trap 4500)检测其浓度。C18色谱柱为Kinetex 2.6u C18 100A(50mm*3mm)
(3)数据分析
化合物对人肝微粒体中每种P450酶的抑制作用以与非抑制对照(即空白DMSO)相比，代谢物形成降低的百分比计算。用Graphpad Prism软件以剩余活性(RemainingActivity)和抑制剂浓度的对数来计算其对人肝微粒体中每种P450酶的IC50值，计算公式如下：
Area Ratio＝Peak Area Analyte/Peak Area Internal Standard
Remaining Activity(％)＝Area Ratio test compound/Area Ratio vehicle×100％
本公开化合物对CYP1A2,CYP2C9,CYP2C19,CYP2D6,CYP3A4酶活性的抑制作用弱。代表性化合物的测试结果如表6所示。
表6抑制活性数据
5.hERG离子通道的抑制作用评价
(1)测试目的
本实验通过手动膜片钳电生理方法检测化合物对hERG离子通道的抑制作用，根据化合物的单一浓度抑制率或者IC50大小进行心脏安全性评价。
(2)实验方法
本试验所用的细胞为转染有hERG cDNA与稳定表达hERG通道HEK293细胞系(#60187，由BPS公司提供，P3-P23代用于试验研究)。细胞培养在含有下列成分的培养基中培养：MEM培养基，10％(v/v)灭活的胎牛血清，1mM丙酮酸钠，500μg遗传霉素,0.1mM非必须氨基酸，100U青链霉素。HEK293 hERG细胞生长于含上述培养液的培养瓶中，并在37℃、含5％CO2的培养箱中进行培养，每周传代约三次，并维持细胞融合率在40％至80％之间。电生理实验之前24到48小时，HEK293 hERG细胞被转移到0.05mg/ml多聚赖氨酸(PDL)预处理的玻璃细胞爬片上，以1×104个细胞数量置于48孔板中，并在相同的培养液及培养条件下生长。每个细胞爬片上HEK293hERG细胞的密度需要达到绝大多数细胞是独立、单个的要求。
hERG试验所用细胞外液成分如下所述(mM)：145NaCl,4KCl,2CaCl2,1MgCl2,10glucose,and 10HEPES(使用NaOH将PH调节至7.40)。细胞内液成分如下所述(mM)：130KCl,2MgCl2,5EGTA,10HEPES and 5Na2ATP(使用KOH将PH调节至7.25)。
为了取得化合物的IC50，以下列浓度(30，10，3，1，0.3和0.1μM)来进行测试。在试验之前，首先用DMSO以梯度稀释的方式稀释成10,3,1,0.3和0.1mM的贮备液，再用细胞外液稀释成最终的μM测试浓度。各浓度化合物溶液中DMSO的最终浓度为0.1％至0.3％之间。所有的化合物溶液都将经过常规的5到10min超声和充分震荡以保证化合物完全溶解，所有测试溶液经旋转混匀至少10min。
电生理试验采用手动膜片钳系统(HEKA EPC-10信号放大器及数字转换系统,购自德国HEKA Electronics)作全细胞电流的记录。具体测试方法如下描述：表面生长有稳定表达hERG通道HEK293细胞的圆形玻璃爬片被放置于倒置显微镜下的电生理记录槽中。记录槽内以细胞外液作持续灌流(大约每分钟1毫升)。实验过程采用常规全细胞膜片钳电流记录技术。如无特殊说明，实验都是在常规室温下进行(～25℃)。细胞钳制在-80mV的电压下。细胞钳制电压去极化到+30mV以激活hERG钾通道，5秒后再钳制到-50mV以消除失活并产生尾电流。尾电流峰值用作hERG电流大小的数值。上述步骤记录的hERG电流在记录槽内持续的细胞外液灌流下达到稳定后则可以灌流不同浓度的待测试化合物，直到药物对hERG电流的抑制作用达到稳定状态。
(3)数据分析
使用Excel软件来计算每个浓度下化合物对于hERG离子通道抑制率，用Graphpad Prism 9.0软件根据测试化合物的剂量反应曲线以％hERG抑制率为纵轴，测试化合物的浓度为横轴作图，使用log(inhibitor)vs.response--Variable slope(four parameters)参数进行曲线拟合计算IC50，具体方程参数如下所示：Y＝Bottom+(Top-Bottom)/(1+10^((LogIC50-X)*HillSlope))。本公开的化合物对hERG离子通道的抑制作用较小，部分代表性化合物的测 试结果参见下表7。
表7
6.化合物的小鼠药代动力学评价
实验目的：
受试动物选用ICR雄性小鼠，应用LC-MS/MS法定量测定小鼠静脉注射或灌胃给予测试化合物不同时间点的血浆中的药物浓度，以评价受试药物在小鼠体内的药代动力学特征。
实验材料：
ICR小鼠(雄性，15-35g,5～10周龄，上海西普尔-必凯实验动物有限公司)
实验操作A:
将测试化合物的澄清溶液经尾静脉注射到ICR小鼠体内(不禁食，溶媒：5％DMSO/10％Solutol/85％Saline)，灌胃给予到ICR小鼠体内(禁食10-14h)。静脉注射给药于给药后0.033，0.083，0.25，0.5，1，2，4，8，24h，于颌下静脉丛采血，置于EDTA-K2抗凝管(江苏康健医疗用品有限公司)中，混匀，并于2-8℃，6800g离心6分钟得血浆；口服灌胃给药于给药后0.083，0.25，0.5，1，2，4，6，8，24h于颌下静脉丛采血，置于添加了EDTA-K2的抗凝管(江苏康健医疗用品有限公司)中，混匀，并于2-8℃，6800g离心6分钟得血浆。采用LC-MS/MS法测定血药浓度，使用Phoenix WinNonlinTM Version 7.0(Pharsight,USA)药动学软件，以非房室模型线性对数梯形法计算相关药代动力学参数。本公开的化合物在小鼠体内具有较好的药代动力学特征，代表性化合物的测试结果参见表8。
表8
7.化合物的大鼠药代动力学评价
实验目的：
受试动物选用SD雄性大鼠，应用LC-MS/MS法定量测定大鼠静脉注射或灌胃给予测试化合物不同时间点的血浆中的药物浓度，以评价受试药物在大鼠体内的药代动力学特征。
实验材料：
SD大鼠(雄性，160-300g,5～10周龄，上海西普尔-必凯实验动物有限公司)
实验操作A:
将测试化合物的澄清溶液经尾静脉注射到SD大鼠体内(不禁食)(溶媒：5％DMSO/10％Solutol/85％Saline)，灌胃给予到SD大鼠体内(禁食10-14h，自由饮水)(溶媒：5％DMSO/10％Solutol/85％Saline)。静脉注射给药于给药后0.033，0.083，0.25，0.5，1，2， 4，8，24h颈静脉处采血，置于EDTA-K2抗凝管(江苏康健医疗用品有限公司)中，混匀，并于2-8℃，6800g离心6分钟得血浆；口服灌胃给药于给药后0.083，0.25，0.5，1，2，4，6，8，24h颈静脉处采血，置于添加了EDTA-K2的抗凝管(江苏康健医疗用品有限公司)中，混匀，并于2-8℃，6800g离心6分钟得血浆。采用LC-MS/MS法测定血药浓度，使用Phoenix WinNonlinTM Version 7.0(Pharsight,USA)药动学软件，以非房室模型线性对数梯形法计算相关药代动力学参数。本公开的化合物在大鼠体内具有较好的药代动力学特征，代表性化合物的测试结果参见表9。
表9
8.化合物对碘乙酸诱导的SD大鼠膝骨关节炎模型的药效研究
实验目的：
评价MCC950(阳参化合物)和本发明化合物111在碘乙酸(MIA)诱导的SD大鼠膝骨关节炎模型上的药效。
实验材料：
实验用SD大鼠，雄性，4周龄。
实验方法：
实验动物适应动物环境7天后开始模型诱导。Day 0将大鼠麻醉，剔除左膝关节周围毛发，皮肤消毒。将左腿屈曲90°，暴露髌骨平台，用手触摸平台中间凹陷处，找出股骨髁、髌骨及韧带。注射器针头从髌韧带两侧髌骨下方对准股骨髁方向进针，感觉到明显落空感时推注碘乙酸溶液50μL。Day 7根据诱导侧膝关节宽度分组。组别为：正常对照组(不造模的健康对照，5％DMSO+10％Solutol+85％Saline)、模型空白对照组(5％DMSO+10％Solutol+85％Saline)、MCC95030mg/kg、本发明化合物11130mg/kg。Day 7开始，正常对照组和模型空白对照组每日口服一次给予溶媒(5％DMSO+10％Solutol+85％Saline)，其他组每日口服一次给予相应化合物，直到Day 42结束给药。Day 7、14、21、28、35、42各测量一次大鼠膝关节宽度和体重。
实验结论：
本实验测试MCC950(阳参化合物)和本发明化合物111在碘乙酸(MIA)诱导的SD大鼠膝骨关节炎模型上的药效见图1和图2。每日口服一次给予化合物结果显示，与模型空白对照组相比，MCC950(阳参化合物)和本发明化合物111在造模后21天到42天均能显著抑制膝骨关节炎模型大鼠的膝关节变宽，而不影响大鼠的体重。
本发明的技术方案不限于上述具体实施例的限制，凡是根据本发明的技术方案做出的技术变形，均落入本发明的保护范围之内。

Claims (66)

  1. 一种式I所示的化合物或其对映异构体、非对映异构体、消旋体、互变异构体、立体异构体、几何异构体、氮氧化物、代谢产物或其药学上可接受的盐、酯、溶剂化物、水合物、同位素标记化合物(优选氘代物)或前药；
    其中与环A相连接，与环B相连接；
    环A和环B各自独立地选自：5-6元杂芳基、5-6元杂环基、苯基；
    环C选自：6-10元芳基、5-10元杂芳基、苯基并4-7元环烷基、苯基并4-7元杂环基、5-6元杂芳基并4-7元环烷基、5-6元杂芳基并4-7元杂环基、4-7元环烷基、4-7元杂环基；
    各Rc独立地选自：氢、氘、卤素、羟基、氨基、氰基、C1-6烷氧基、C1-6烷基、C1-6卤代烷基、C1-6卤代烷氧基、羟基C1-6烷基、C1-6烷氧基-C1-6烷基、Rc1S(O)2-、-(CH2)s-N(Rc1)(Rc2)、3-6元环烷基、3-6元杂环基、苯基、5-6元杂芳基，所述3-6元环烷基、3-6元杂环基、苯基、5-6元杂芳基任选地被1、2、3个选自氘、卤素、羟基、氨基、氰基、C1-6烷基、C1-6卤代烷基、C1-6烷氧基的取代基所取代；
    或者，两个Rc可与其所连接的C原子一起形成3-6元环烷基、4-7元杂环基、6元芳基或5-6元杂芳基，所述3-6元环烷基、4-7元杂环基、6元芳基或5-6元杂芳基可任选地被1、2、3个选自氘、卤素、羟基、氨基、氰基、C1-6烷氧基、C1-6烷基、C1-6卤代烷基的取代基所取代；
    各Ra和Rb独立地选自：氢、氘、卤素、羟基、氨基、氰基、氧代、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C1-6烷氧基-C1-6烷基、C1-6卤代烷氧基、羟基-C1-6烷基、-NH(C1-6烷基)、-N(C1-6烷基)(C1-6烷基)、-C(＝O)-(C1-6烷基)、任选地被羟基取代的3-6元杂环基；
    L1选自：键、C3-6亚环烷基、-NR2-、-O-、-S-、-C(＝O)-、-(CR3R4)a-、-NR2-(CR3R4)a-、-(CR3R4)a-NR2-、-O-(CR3R4)a-、-(CR3R4)a-O-、-S-(CR3R4)a-、-(CR3R4)a-S-、-C(＝O)-(CR3R4)a-、-(CR3R4)a-C(＝O)-、-(CR3R4)a-(CR9＝CR10)-、-(CR9＝CR10)-(CR3R4)a-、-C(＝O)-O-、-O-C(＝O)-、-C(＝O)-NR2-、-(CR3R4)a-C(＝O)-NR2-、-NR2-C(＝O)-、-(CR3R4)a-NR2-C(＝O)-、-S(＝O)2-NR2-、-NR2-S(＝O)2-、-NR2-(CR3R4)a-C(＝O)-、-C(＝O)-(CR3R4)a-NR2-、-NR2-(CR3R4)a-C(＝O)-NR5-、-NR2-C(＝O)-(CR3R4)a-NR5-、-C(＝S)-NR2-、-NR2-C(＝S)-；
    L2选自键、-NR6-、-O-、-S-、-NR6-(CR7R8)b-、-(CR7R8)b-NR6-、-O-(CR7R8)b-、-(CR7R8)b-O-、-S-(CR7R8)b-、-(CR7R8)b-S-；
    各R2、R5、R6、R9和R10各自独立地选自：氢、氘、C1-6烷基；
    各R3、R4、R7和R8各自独立地选自：氢、氘、卤素、氧代、羟基、氨基、C1-6烷基；
    R1选自：氢、羟基、氨基、羧基、C1-6烷基、C1-6烷氧基、NHR11-C(＝O)-、C1-6烷基-C(＝O)-O-、C1-6烷基-O-C(＝O)-、3-10元环烷基、3-6元单环杂环基、6-11元双环杂环基、6-10元芳基、5-10元杂芳基；其中所述氨基、C1-6烷基、C1-6烷氧基、NHR11-C(＝O)-、C1-6烷基-C(＝O)-O-、C1-6烷基-O-C(＝O)-、3-10元环烷基、3-6元单环杂环基、6-11元双环杂环基、6-10元芳基、5-10元杂芳基各自独立地任意地被1、2、3个选自氢、氘、卤素、羟基、氧代、氰基、C1-6烷基、羟基C1-6烷基、C1-6卤代烷基、C1-6烷氧基、-(CH2)s-O(Rc1)、-(CH2)s-N(Rc1)(Rc2)、C3-6环烷基、3-6元单环杂环基、5-6元杂芳基、-C(＝O)-Rc3、-S(O)-Rc3、-S(O)2- Rc3、-C(＝O)O-Rc3、-CH2-C(＝O)O-Rc4、-N(Rc4)-C(＝O)-Rc3、-CH2-N(Rc4)-C(＝O)-Rc4、-C(＝O)-N(Rc6)(Rc5)、-CH2-C(＝O)-N(Rc4)(Rc4)、-N(Rc4)-C(＝O)-N(Rc6)(Rc5)、-P(＝O)Rc5Rc6、-CRc7Rc8-CN、-(CH2)s-Rc9的取代基进一步取代；
    各Rc1和Rc2独立地选自：氢、C1-6烷基、C1-6卤代烷氧基、C3-6环烷基或4-7元杂环基；
    Rc3选自氢、氘、C1-6烷基、C1-6卤代烷基、C3-6环烷基，所述C1-6烷基和C3-6环烷基任意地被1、2、3个选自氘、卤素、羟基、氨基、氰基、氧代、C1-6烷基、C1-6烷氧基、C1-6卤代烷基、C1-6卤代烷氧基、C1-6烷氧基-C1-6烷基、-NH(C1-6烷基)、-N(C1-6烷基)(C1-6烷基)的取代基所取代；
    Rc4选自氢、氘、C1-6烷基；
    Rc5和Rc6选自氢、氘、C1-6烷基、C3-6环烷基，或者Rc5和Rc6与其所连接的N原子一起形成4-6元杂环基，所述C1-6烷基、C3-6环烷基和4-6元杂环基任意地被1-3个选自氘、卤素、羟基、氨基、氰基、氧代、C1-6烷基、C1-6烷氧基、C1-6卤代烷基、C1-6卤代烷氧基、C1-6烷氧基-C1-6烷基、-NH(C1-6烷基)、-N(C1-6烷基)(C1-6烷基)的取代基所取代；
    Rc7和Rc8选自氢、氘、C1-6烷基，或者Rc7和Rc8与其所连接的C原子一起形成3-6元环烷基；
    Rc9选自3-6元杂环基，所述杂环基任选地被1、2、3个选自氢、氘、C1-6烷基取代；
    R11选自：氢、氘、C1-6烷基、3-6元单环杂环基；
    各a和b各自独立地为1、2、3或4；
    各s、n、m和p各自独立地选自：0、1、2、3或4；
    条件是不是氢、C1-6烷基。
  2. 如权利要求1所述的化合物，其中，
    环A和环B涉及的基团选自如下基团：

    各M1、M2、M3、M4、U1、U2各自独立地选自：CH、N；
    各U3、U4、U5、U6各自独立地选自：CH2、NH、O、S。
  3. 如权利要求1所述的化合物，其中，
    环A和环B涉及的基团选自如下基团：

    各M1、M2、M3、M4、U1、U2各自独立地选自：CH、N；各U3、U4、U5、U6各自独立地选自：CH2、NH、O、S。
  4. 如权利要求1所述的化合物，其中，
    环A和环B涉及的基团选自如下基团：


    各M1、M2、M3、M4、M5、M6、U1、U2各自独立地选自：CH、N；
    各U3、U4、U5、U6各自独立地选自：CH2、NH、O、S。
  5. 如权利要求1-4任一项所述的化合物，其中所述化合物具有式VIII-3或VIII-4所示的结构：
    其中，R1选自：羟基、氨基、羧基、C1-6烷基、C1-6烷氧基、NHR11-C(＝O)-、C1-6烷基-C(＝O)-O-、C1-6烷基-O-C(＝O)-、3-10元环烷基、3-6元单环杂环基、6-11元双环杂环基、6-10元芳基、5-10元杂芳基；其中所述氨基、C1-6烷基、C1-6烷氧基、NHR11-C(＝O)-、C1-6烷基-C(＝O)-O-、C1-6烷基-O-C(＝O)-、3-10元环烷基、3-6元单环杂环基、6-11元双环杂环基、6-10元芳基、5-10元杂芳基各自独立地任意地被1、2、3个选自氢、氘、卤素、羟基、氧代、氰基、C1-6烷基、羟基C1-6烷基、C1-6卤代烷基、C1-6烷氧基、-(CH2)s-O(Rc1)、-(CH2)s-N(Rc1)(Rc2)、C3-6环烷基、3-6元单环杂环基、5-6元杂芳基、-CRc7Rc8-CN、-(CH2)s-Rc9的取代基进一步取代；Rcn如权利要求1中Rc所定义；
    条件是同时满足下列1)～45)：
    1)当为L2为键，m＝p＝0或Ra＝Rb＝H，以及L1为-NH-的同时，R1不为如下基团：
    2)当为L2为键，m＝p＝0或Ra＝Rb＝H，以及L1为-NH-CH2-的同时，R1不为如下基团：
    3)当为L2为键，m＝p＝0或Ra＝Rb＝H，以及L1为键的同时，R1不为如下基团：
    4)当为L2为键，m＝p＝0或Ra＝Rb＝H，以及L1为-NH-的同时，R1不为如下基团：
    5)当为L2为键，m＝p＝0或Ra＝Rb＝H，以及L1为键的同时，R1不为如下基团：
    6)当为L2为键，m＝p＝0或Ra＝Rb＝H，以及L1为-NH-CH2-的同时，R1不为如下基团：
    7)当为L2为键，m＝p＝0或Ra＝Rb＝H，以及L1为-CH2-的同时，R1不为如下基团：
    8)当为L2为键，为以及L1为-NH-的同时，R1不为如下基团：
    9)当为L2为键，m＝p＝0或Ra＝Rb＝H，以及L1为-NH-的同时，R1不为如下基团：
    10)当为L2为键，m＝p＝0或Ra＝Rb＝H，以及L1为-NH-的同 时，R1不为如下基团：
    11)当为L2为键，m＝p＝0或Ra＝Rb＝H，以及L1为-NH-的同时，R1不为如下基团：
    12)当为L2为键，m＝p＝0或Ra＝Rb＝H，以及L1为-NH-的同时，R1不为如下基团：
    13)当为L2为键，m＝p＝0或Ra＝Rb＝H，以及L1为-NH-的同时，R1不为如下基团：
    14)当为L2为键，m＝p＝0或Ra＝Rb＝H，以及L1为-NH-的同时，R1不为如下基团：
    15)当为L2为键，m＝p＝0或Ra＝Rb＝H，以及L1为-NH-的同时，R1不为如下基团：
    16)当为L2为键，m＝p＝0或Ra＝Rb＝H，以及L1为-NH-的同时， R1不为如下基团：
    17)当为L2为键，m＝p＝0或Ra＝Rb＝H，以及L1为-NH-的同时，R1不为如下基团：
    18)当为L2为键，m＝p＝0或Ra＝Rb＝H，以及L1为-NH-的同时，R1不为如下基团：
    19)当为L2为键，m＝p＝0或Ra＝Rb＝H，以及L1为-NH-的同时，R1不为如下基团：
    20)当为L2为键，m＝p＝0或Ra＝Rb＝H，以及L1为-NH-的同时，R1不为如下基团：
    21)当为L2为键，m＝p＝0或Ra＝Rb＝H，以及L1为-NH-的同时，R1不为如下基团：
    22)当为L2为键，m＝p＝0或Ra＝Rb＝H，以及L1为-NH-的同时， R1不为如下基团：
    23)当为L2为键，m＝p＝0或Ra＝Rb＝H，以及L1为-NH-的同时，R1不为如下基团：
    24)当为L2为键，m＝p＝0或Ra＝Rb＝H，以及L1为-NH-的同时，R1不为如下基团：
    25)当为L2为键，m＝p＝0或Ra＝Rb＝H，以及L1为-NH-的同时，R1不为如下基团：
    26)当为L2为键，m＝p＝0或Ra＝Rb＝H，以及L1为-NH-的同时，R1不为如下基团：
    27)当为L2为键，m＝p＝0或Ra＝Rb＝H，以及L1为-NH-的同时，R1不为如下基团：
    28)当为L2为键，为以及L1 为-NH-的同时，R1不为如下基团：
    29)当为L2为键，m＝p＝0或Ra＝Rb＝H，以及L1为-NH-的同时，R1不为如下基团：
    30)当为L2为键，m＝p＝0或Ra＝Rb＝H，以及L1为-NH-的同时，R1不为如下基团：
    31)当为L2为键，m＝p＝0或Ra＝Rb＝H，以及L1为-NH-的同时，R1不为如下基团：
    32)当为为以及L1为-NH-的同时，R1不为如下基团：
    33)当为L2为键，m＝p＝0或Ra＝Rb＝H，以及L1为-NH-的同时，R1不为如下基团：
    34)当为L2为键，m＝p＝0或Ra＝Rb＝H，以及L1为-NH-的同 时，R1不为如下基团：
    35)当为L2为键，m＝p＝0或Ra＝Rb＝H，以及L1为-NH-的同时，R1不为如下基团：
    36)当为L2为键，m＝p＝0或Ra＝Rb＝H，以及L1为-NH-的同时，R1不为如下基团：
    37)当为L2为键，m＝p＝0或Ra＝Rb＝H，以及L1为-NH-的同时，R1不为如下基团：
    38)当为L2为键，m＝p＝0或Ra＝Rb＝H，以及L1为-NH-的同时，R1不为如下基团：
    39)当为L2为键，m＝p＝0或Ra＝Rb＝H，以及L1为-NH-的同时，R1不为如下基团：
    40)当为L2为键，m＝p＝0或Ra＝Rb＝H，以及L1为键的同时，R1不为如下基团：
    41)当为L2为键，为以及L1为键的同时，R1不为如下基团：
    42)当为L2为键，L1为-NH-，以及R1为的同时，不为如下基团：
    43)当为L2为键，L1为-NH-，以及R1为的同时， 不为如下基团：
    44)当为L2为键，m＝p＝0或Ra＝Rb＝H，以及L1为键的同时，R1不为如下基团：
    45)不是
  6. 如权利要求1所述的化合物，其中，
    环A和环B涉及的基团选自如下基团，其中，以下双环基团从左向右表示环A和环B或从右向左表示环A和环B：

    其中，Rab各自独立地选自：氢、氘、卤素、羟基、氨基、氰基、氧代、甲基、乙基、丙基、异丙基、丁基；
    k各自独立地选自：0、1、2、3或4。
  7. 如权利要求1所述的化合物，其中，
    环A和环B涉及的基团选自如下基团，其中，以下双环基团从左向右表示环A和环B或从右向左表示环A和环B：

    其中，Rab各自独立地选自：氢、氘、卤素、羟基、氨基、氰基、氧代、甲基、乙基、丙基、异丙基、丁基；
    k各自独立地选自：0、1、2、3或4。
  8. 如权利要求1所述的化合物，其中，
    环A和环B涉及的基团选自如下基团，其中，以下双环基团从左向右表示环A和环B或从右向左表示环A和环B：

  9. 如权利要求1所述的化合物，其中，
    环A和环B涉及的基团选自如下基团，其中，以下双环基团从左向右表示环A和环B或从右向左表示环A和环B：

  10. 如权利要求1-9任一项所述的化合物，其中，
    环C选自：6-10元芳基、5-6元杂芳基、苯基并5-6元杂芳基、苯基并4-6元环烷基、苯基并4-6元杂环基、5-6元杂芳基并5-6元杂芳基、5-6元杂芳基并4-6元环烷基、5-6元杂芳基并4-6元杂环基、5-6元环烷基、5-6元杂环基。
  11. 如权利要求1-10任一项所述的化合物，其中，
    环C选自：6-10元芳基、5-6元杂芳基、苯基并5-6元杂芳基、苯基并4-6元环烷基、苯基并4-6元杂环基、含氮6元杂芳基并5-6元杂芳基、含氮6元杂芳基并4-6元环烷基、含氮6元杂芳基并4-6元杂环基、5-6元环烷基、5-6元杂环基。
  12. 如权利要求1-11任一项所述的化合物，其中，
    环C涉及的基团选自以下基团：

    其中，环C1和C2各自独立地选自：苯基、5元杂芳基、6元杂芳基、4元杂环基、5元杂环基、6元杂环基、4元环烷基、5元环烷基、6元环烷基；优选地，环C1和C2各自独立地选自：苯基、吡啶基、嘧啶基、吡嗪基、吡咯基、呋喃基、噻吩基、咪唑基、噁唑基、噻唑基、三氮唑基、2,3-二氢呋喃基、2,3-二氢噻吩基、2,3-二氢吡咯基、2,3-二氢二噁英基、环丁基、环戊基、环己基；
    E1、E2、E3、E4和E5各自独立地选自：CH2、O、S、NH，条件是，E1、E2、E3、E4和E5中至少一个为NH，且一起组成稳定的环。
  13. 如权利要求1-12任一项所述的化合物，其中，
    环C涉及的基团选自以下基团：

  14. 如权利要求1-13任一项所述的化合物，其中，环C涉及的基团选自以下基团：

  15. 如权利要求1-5和权利要求10-14任一项所述的化合物，其中，各Ra和Rb独立地选自：氢、氘、氟、氯、溴、羟基、氨基、氰基、氧代、甲基、乙基、三氟甲基、甲氧基、正 丙基、异丙基、二甲胺基、乙酰基。
  16. 如权利要求1-13和权利要求15任一项所述的化合物，其中，
    各Rc独立地选自：氢、氘、氟、氯、溴、羟基、氨基、氰基、C1-4烷氧基、C1-4卤代烷氧基、C1-4烷基、C1-4卤代烷基、羟基C1-4烷基、C1-4烷氧基-C1-2烷基、Rc1S(O)2-、-(CH2)s-N(Rc1)(Rc2)、3-6元环烷基、3-6元杂环基、苯基，所述苯基任选地被1、2、3个选自氘、卤素、羟基、氨基、氰基、C1-6烷基、C1-6卤代烷基、C1-6烷氧基的取代基所取代；
    或者，两个Rc可与其所连接的C原子一起形成3-6元环烷基、4-7元杂环基、6元芳基或5-6元杂芳基，所述3-6元环烷基、4-7元杂环基、6元芳基或5-6元杂芳基可任选地被1、2、3个选自氘、卤素、羟基、氨基、氰基、C1-6烷氧基、C1-6烷基、C1-6卤代烷基的取代基所取代；
    任选地，各Rc独立地选自：氟、氯、溴、羟基、氨基、氰基、甲氧基、乙氧基、异丙氧基、甲氨基、乙氨基、异丙氨基、甲基、乙基、正丙基、异丙基、正丁基、异丁基、三氟甲基、二氟甲基、2,2,2-三氟乙基、五氟乙基、三氟甲氧基、二氟甲氧基、羟甲基、氨基乙基、甲氧基甲基、甲氧基乙基、乙氧基甲基、环丙基、环丁基、环戊基、环己基、环戊烯基、环丁烯基、环己烯基、氧杂环丁基、苯基、4-氯-苯基、2-氯-4-氟-苯基、4-羟基苯基、4-甲基-苯基、4-氟-苯基、吡啶基、环丁基氨基、甲磺酰基；或者，两个Rc与其所连接的C原子一起形成环戊烯基、2,3-二氢呋喃基、环丁烯基、噻吩基、1,4-二氧六环基、吡啶基、环戊-1,3-二烯基、苯基、二噁烯基。
  17. 如权利要求1-16任一项所述的化合物，其中，
    各R2、R5和R6各自独立地选自：氢、氘、甲基、乙基、丙基、异丙基；
    各R3、R4、R7和R8各自独立地选自：氢、氘、氧代、羟基、氨基、甲基、乙基、丙基、异丙基；
    各a和b各自独立地为1或2。
  18. 如权利要求1-17任一项所述的化合物，其中，
    L1选自：键、-NR2-、-O-、-S-、-C(＝O)-、-NR2-(CR3R4)a-、-(CR3R4)a-NR2-、-O-(CR3R4)a-、-(CR3R4)a-O-、-S-(CR3R4)a-、-(CR3R4)a-S-，，其中a为1或2；
    L2选自：键、-NR6-、-NR6-(CR7R8)b-、-O-、-S-。
  19. 如权利要求1-18任一项所述的化合物，其中，
    各s、n、m和p各自独立地选自：0、1、2或3。
  20. 如权利要求1-4、6-19任一项所述的化合物，其中，
    R1选自：氢、羟基、氨基、羧基、C1-4烷基、C1-4烷氧基、NHR11-C(＝O)-、C1-4烷基-C(＝O)-O-、C1-4烷基-O-C(＝O)-、3-6元环烷基、3-6元单环杂环基、6-11元螺双环杂环基、6-11元桥双环杂环基、6-11元稠双环杂环基、苯基、萘基、5-10元杂芳基；其中所述氨基、C1-4烷基、C1-4烷氧基、NHR11-C(＝O)-、C1-4烷基-C(＝O)-O-、C1-4烷基-O-C(＝O)-、3-6元环烷基、3-6元单环杂环基、6-11元螺双环杂环基、6-11元桥双环杂环基、6-11元稠双环杂环基、苯基、萘基、5-10元杂芳基各自独立地任意地被1、2、3个选自氢、氘、卤素、羟基、氨基、氧代、C1-4烷基、羟基C1-4烷基、C1-4卤代烷基、C1-4烷氧基、C3-6环烷基、3-6元单环杂环基、-C(＝O)-Rc3、-S(O)-Rc3、-S(O)2-Rc3、-C(＝O)O-Rc3、-CH2-C(＝O)O-Rc4、-N(Rc4)-C(＝O)-Rc3、-CH2-N(Rc4)-C(＝O)-Rc4、-C(＝O)-N(Rc6)(Rc5)、-CH2-C(＝O)-N(Rc4)(Rc4)、-N(Rc4)-C(＝O)-N(Rc6)(Rc5)、-P(＝O)Rc5Rc6、-CRc7Rc8-CN、-(CH2)s-Rc9的取代基进一步取代；
    R11选自：氢、氘、C1-4烷基、3-6元单环杂环基。
  21. 如权利要求1-4、6-20任一项所述的化合物，其中，
    R1选自：氢、羟基、氨基、羧基、甲基、乙基、正丙基、异丙基、甲氧基、乙氧基、正丙氧基、异丙氧基、NH2-C(＝O)-、CH3NH-C(＝O)-、CH3CH2NH-C(＝O)-、CH3-C(＝O)-O-、CH3CH2-C(＝O)-O-、CH3-O-C(＝O)-、CH3CH2-O-C(＝O)-、环丙基、环丁基、环戊基、环己基、氮杂环丁基、氧杂环丁基、四氢呋喃基、吡咯烷基、哌啶基、哌嗪基、吗啉基、1,4-二氧六环基、四氢-2H-吡喃基、苯基、萘基、吡啶基、嘧啶基、吡嗪基、吡咯基、呋喃基、噻吩基、咪唑基、吡唑基、噁唑基、异噁唑基、噻唑基、异噻唑基、噻二唑基、三氮唑基、喹啉基、异喹啉基，或选自下列基团：
    其中所述甲基、乙基、正丙基、异丙基、甲氧基、乙氧基、正丙氧基、异丙氧基、NH2-C(＝O)-、CH3NH-C(＝O)-、CH3CH2NH-C(＝O)-、CH3-C(＝O)-O-、CH3CH2-C(＝O)-O-、CH3-O-C(＝O)-、CH3CH2-O-C(＝O)-、环丙基、环丁基、环戊基、环己基、氮杂环丁基、氧杂环丁基、四氢呋喃基、吡咯烷基、哌啶基、哌嗪基、吗啉基、1,4-二氧六环基、四氢-2H-吡喃基、苯基、萘基、吡啶基、嘧啶基、吡嗪基、吡咯基、呋喃基、噻吩基、咪唑基、吡唑基、噁唑基、异噁唑基、噻唑基、异噻唑基、噻二唑基、三氮唑基、喹啉基、异喹啉基、 各自独立地任意地被1、2、3个选自氢、氘、卤素、羟基、氨基、氧代、甲基、乙基、正丙基、异丙基、3-6元单环杂环基、-C(＝O)-Rc3、-S(O)-Rc3、-S(O)2-Rc3、-C(＝O)O-Rc3、-N(Rc4)-C(＝O)-Rc3、-CH2-N(Rc4)-C(＝O)-Rc4、-C(＝O)-N(Rc6)(Rc5)、-N(Rc4)-C(＝O)-N(Rc6)(Rc5)、-P(＝O)Rc5Rc6、-CRc7Rc8-CN的取代基进一步取代。
  22. 如权利要求1-19任一项所述的化合物，其中R1选自：3-6元环烷基、3-6元单环杂环基或6-11元双环杂环基，所述3-6元环烷基、3-6元单环杂环基或6-11元双环杂环基被1或2个选自-C(＝O)-Rc3、-S(＝O)-Rc3、-S(＝O)2-Rc3、-C(＝O)-NRc6Rc5、-P(＝O)Rc5Rc6的取代基所取代，并且所述3-6元环烷基、3-6元单环杂环基或6-11元双环杂环基还任选被1、2、3个选自氢、氘、卤素、羟基、氧代、C1-6烷基、C1-6烷氧基、C1-6烷氧基-C1-4烷基、-(CH2)s-N(Rc1)(Rc2)、C3-6环烷基、3-6元单环杂环基的取代基所取代；
    Rc3选自C1-6烷基、C3-6环烷基，所述C1-6烷基和C3-6环烷基进一步任选被1-3个选自氘、卤素、羟基、氨基、氰基、氧代、C1-6烷基、C1-6烷氧基、C1-6卤代烷基、C1-6卤代烷氧基、C1-6烷氧基-C1-6烷基、-NH(C1-6烷基)、-N(C1-6烷基)(C1-6烷基)的取代基所取代；
    Rc5和Rc6选自H、氘、C1-6烷基、C3-6环烷基，所述C1-6烷基和C3-6环烷基进一步任选被1-3个选自氘、卤素、羟基、氨基、氰基、氧代、C1-6烷基、C1-6烷氧基、C1-6卤代烷基、C1-6卤代烷氧基、C1-6烷氧基-C1-6烷基、-NH(C1-6烷基)、-N(C1-6烷基)(C1-6烷基)的取代基所取代。
  23. 如权利要求1-19任一项所述的化合物，其中R1选自：环戊烷、环己烷、氮杂环丁烷、四氢吡咯、哌啶、吗啉、哌嗪、 所述环戊烷、环己烷、氮杂环丁烷、四 氢吡咯、哌啶、吗啉、哌嗪、 被1或2个选自-C(＝O)-Rc3、-S(＝O)-Rc3、-S(＝O)2-Rc3、-C(＝O)-NRc5Rc6、-P(＝O)Rc5Rc6的取代基所取代，并且所述环戊烷、环己烷、氮杂环丁烷、四氢吡咯、哌啶、吗啉、哌嗪、 还任选被1、2、3个选自氢、氘、卤素、羟基、氧代、C1-6烷基、C1-6烷氧基、C1-6烷氧基-C1-4烷基、-(CH2)s-N(Rc1)(Rc2)、C3-6环烷基、3-6元单环杂环基的取代基所取代；
    优选地，R1选自：四氢吡咯、哌啶、吗啉、哌嗪、所述四氢吡咯、哌啶、吗啉、哌嗪、被1或2个选自-C(＝O)-Rc3、-S(＝O)-Rc3、-S(＝O)2-Rc3、-C(＝O)-NRc5Rc6、-P(＝O)Rc5Rc6的取代基所取代，并且所述四氢吡咯、哌啶、吗啉、哌嗪、还任选被1、2、3个选自氢、氘、卤素、羟基、氧代、C1-6烷基、C1-6烷氧基、-(CH2)s-N(Rc1)(Rc2)、C3-6环烷基、C1-6烷氧基-C1-4烷基、3-6元单环杂环基的取代基所取代；
    更优选地，R1选自：四氢吡咯、哌啶、吗啉或哌嗪，所述四氢吡咯、哌啶、吗啉或哌嗪 被1个选自-C(＝O)-Rc3、-S(＝O)2-Rc3、-P(＝O)Rc5Rc6的取代基所取代，并且所述四氢吡咯、哌啶、吗啉或哌嗪还任选被1或2个选自氘、卤素、羟基、C1-6烷基、C1-6烷氧基、C1-6烷氧基-C1-4烷基的取代基所取代。
  24. 如权利要求1-19任一项所述的化合物，其中R1选自：
  25. 如权利要求1-4、6-24任一项所述的化合物，其中，所述化合物具有式II所示的结构；
  26. 如权利要求1-4、6-25任一项所述的化合物，其中，所述化合物具有式III所示的结构；
  27. 如权利要求1-4、6-26任一项所述的化合物，其中，所述化合物具有式IV-1、IV-2、IV-3、IV-4、IV-5、IV-6、IV-7、IV-8、IV-9或IV-10所示的结构；

  28. 如权利要求1-4、6-27任一项所述的化合物，其中所述化合物具有式V-1、V-2、V-3、V-4、V-5、V-6、V-7、V-8、V-9或V-10所示的结构；
  29. 如权利要求1-4、6-28任一项所述的化合物，其中所述化合物具有式VI-1、VI-2、VI-3、VI-4、VI-5、VI-6、VI-7 VI-8、VI-9或VI-10所示的结构；
    其中n1为0、1、2或3。
  30. 如权利要求1-4、6-29任一项所述的化合物，其中所述化合物具有式VII-1、VII-2、VII-3、VII-4、VII-5、VII-6、VII-7、VII-8、VII-9或VII-10所示的结构；


    其中n2为0、1或2。
  31. 如权利要求1-4、6-30任一项所述的化合物，其中所述化合物具有式VIII-1、VIII-2、VIII-3、VIII-4、VIII-5、VIII-6、VIII-7、VIII-8、VIII-9、VIII-10、VIII-11或VIII-12所示的结构：

  32. 如权利要求1-4、6-31任一项所述的化合物，其中所述化合物具有式IX-1、IX-2、IX-3、IX-4、IX-5或IX-6所示的结构：

  33. 一种VIII-1或VIII-2所示的化合物或其对映异构体、非对映异构体、消旋体、互变异构体、立体异构体、几何异构体、氮氧化物、代谢产物或其药学上可接受的盐、酯、溶剂化物、水合物、同位素标记化合物(优选氘代物)或前药；
    各Rcn独立地选自：氢、氘、卤素、羟基、氨基、氰基、C1-6烷氧基、C1-6烷基、C1-6卤代烷基、C1-6卤代烷氧基、羟基C1-6烷基、C1-6烷氧基-C1-6烷基、-(CH2)s-N(Rc1)(Rc2)、3-6元环烷基、3-6元杂环基、苯基、5-6元杂芳基，所述3-6元环烷基、3-6元杂环基、苯基、5-6元杂芳基任选地被1、2、3个选自氘、卤素、羟基、氨基、氰基、C1-6烷基、C1-6卤代烷基、C1-6烷氧基的取代基所取代；或者，两个Rcn可与其所连接的C原子一起形成3-6元环烷基、4-7元杂环基、6元芳基或5-6元杂芳基，所述3-6元环烷基、4-7元杂环基、6元芳基或5-6元杂芳基可任选地被1、2、3个选自氘、卤素、羟基、氨基、氰基、C1-6烷氧基、C1-6烷基、C1-6卤代烷基的取代基所取代；
    各Ra和Rb独立地选自：氢、氘、卤素、羟基、氨基、氰基、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C1-6烷氧基-C1-6烷基、C1-6卤代烷氧基、羟基-C1-6烷基、-NH(C1-6烷基)、-N(C1-6烷基)(C1-6烷基)、-C(＝O)-(C1-6烷基)、任选地被羟基取代的3-6元杂环基；
    L1选自：键、C3-6亚环烷基、-NR2-、-O-、-S-、-C(＝O)-、-(CR3R4)a-、-NR2-(CR3R4)a-、-(CR3R4)a-NR2-、-O-(CR3R4)a-、-(CR3R4)a-O-、-S-(CR3R4)a-、-(CR3R4)a-S-、-C(＝O)-(CR3R4)a-、-(CR3R4)a-C(＝O)-、-(CR3R4)a-(CR9＝CR10)-、-(CR9＝CR10)-(CR3R4)a-、-C(＝O)-O-、-O-C(＝O)-、-C(＝O)-NR2-、-(CR3R4)a-C(＝O)-NR2-、-NR2-C(＝O)-、-(CR3R4)a-NR2-C(＝O)-、-S(＝O)2-NR2-、-NR2-S(＝O)2-、-NR2-(CR3R4)a-C(＝O)-、-C(＝O)-(CR3R4)a-NR2-、-NR2-(CR3R4)a-C(＝O)-NR5-、-NR2-C(＝O)-(CR3R4)a-NR5-、-C(＝S)-NR2-、-NR2-C(＝S)-；
    L2选自键、-NR6-、-O-、-S-、-NR6-(CR7R8)b-、-(CR7R8)b-NR6-、-O-(CR7R8)b-、-(CR7R8)b-O-、-S-(CR7R8)b-、-(CR7R8)b-S-；
    各R2、R5、R6、R9和R10各自独立地选自：氢、氘、C1-6烷基；
    各R3、R4、R7和R8各自独立地选自：氢、氘、卤素、氧代、羟基、氨基、C1-6烷基；
    R1选自：氢、羟基、氨基、羧基、C1-6烷基、C1-6烷氧基、NHR11-C(＝O)-、C1-6烷基-C(＝O)-O-、C1-6烷基-O-C(＝O)-、3-10元环烷基、3-6元单环杂环基、6-11元双环杂环基、6-10元芳基、5-10元杂芳基；其中所述氨基、C1-6烷基、C1-6烷氧基、NHR11-C(＝O)-、C1-6烷基-C(＝O)-O-、C1-6烷基-O-C(＝O)-、3-10元环烷基、3-6元单环杂环基、6-11元双环杂环基、6-10元芳基、5-10元杂芳基各自独立地任意地被1、2、3个选自氢、氘、卤素、羟基、氧代、氰基、C1-6烷基、羟基C1-6烷基、C1-6卤代烷基、C1-6烷氧基、-(CH2)s-O(Rc1)、-(CH2)s- N(Rc1)(Rc2)、C3-6环烷基、3-6元单环杂环基、5-6元杂芳基、-C(＝O)-Rc3、-S(O)-Rc3、-S(O)2-Rc3、-C(＝O)O-Rc3、-N(Rc4)-C(＝O)-Rc3、-C(O)-N(Rc6)(Rc5)、-CH2-C(＝O)-N(Rc4)(Rc4)、-N(Rc4)-C(＝O)-N(Rc6)(Rc5)的取代基进一步取代；
    各Rc1和Rc2独立地选自：氢、C1-6烷基、C1-6卤代烷氧基、C3-6环烷基或4-7元杂环基；
    Rc3选自氢、氘、C1-6烷基、C1-6卤代烷基、C3-6环烷基，所述C3-6环烷基任意地被1-3个选自氘、羟基、卤素、C1-6烷基的取代基进一步取代；
    Rc4选自氢、氘、C1-6烷基；
    Rc5和Rc6选自氢、氘、C1-6烷基、C1-6卤代烷基、C3-6环烷基，或者Rc5和Rc6与其所连接的N原子一起形成4-6元杂环基，所述C3-6环烷基和4-6元杂环基任意地被1-3个选自氘、羟基、卤素、C1-6烷基的取代基进一步取代；
    R11选自：氢、氘、C1-6烷基、3-6元单环杂环基；
    各a和b各自独立地为1、2、3或4；
    各m为0或1；
    各p为0、1或2；
    各s、n各自独立地选自0、1、2、3或4；
    条件是同时满足下列1)和2)：
    1)不是H、甲基、乙基、CHF2、Boc；
    2)不是
  34. 如权利要求33所述的化合物，其中所述化合物具有式VIII-1所示的结构：
  35. 如权利要求33或34所述的化合物，其中L2为键。
  36. 如权利要求33-35任一项所述的化合物，其中Ra和Rb各自独立地选自氢、氘、F、Cl、Br、氰基、甲基、乙基、三氟甲基、甲氧基、二甲胺基、乙酰基；优选地，Ra和Rb各自独立地选自氢、氘、F、Cl、Br、甲基、乙基；更优选地，Ra和Rb各自独立地选自氢、氘、甲基。
  37. 如权利要求33-36任一项所述的化合物，其中各Rcn独立地选自：氢、氘、氟、氯、溴、羟基、氨基、氰基、C1-4烷氧基、C1-4卤代烷氧基、C1-4烷基、C1-4卤代烷基、羟基C1-4烷基、C1-4烷氧基-C1-2烷基、-(CH2)s-N(Rc1)(Rc2)、3-6元环烷基、3-6元杂环基、苯基，所述3-6元环烷基、3-6元杂环基、苯基任选地被1、2、3个选自氘、卤素、羟基、氨基、氰基、C1-6烷基、C1-6卤代烷基、C1-6烷氧基的取代基所取代；，或者，两个Rcn可与其所连接的C原子一起形成3-6元环烷基、4-7元杂环基或5-6元杂芳基；
    优选地，各Rcn独立地选自：氟、氯、溴、羟基、氨基、氰基、甲氧基、乙氧基、异丙氧基、甲氨基、乙氨基、异丙氨基、甲基、乙基、正丙基、异丙基、三氟甲基、二氟甲基、2,2,2-三氟乙基、五氟乙基、三氟甲氧基、二氟甲氧基、羟甲基、氨基乙基、甲氧基甲基、甲氧基乙基、乙氧基甲基、环丙基、环丁基、环戊基、氧杂环丁基、苯基、4-氯-苯基、2-氯-4-氟-苯基、4-羟基苯基、环丁基氨基、或者，两个Rcn与其所连接的C原子一起形成环戊基或四氢呋喃基；
    更优选地，各Rcn独立地选自：氟、氯、溴、羟基、甲氧基、乙氧基、甲基、乙基、三氟甲基、二氟甲基、三氟甲氧基、二氟甲氧基。
  38. 如权利要求33-37任一项所述的化合物，其中选自
    优选地，其中选自
  39. 如权利要求33-38任一项所述的化合物，其中L1选自：键、C3-6亚环烷基、-NR2-、-O-、-S-、-C(＝O)-、-(CR3R4)a-、-NR2-(CR3R4)a-、-(CR3R4)a-NR2-、-O-(CR3R4)a-、-(CR3R4)a-O-、-S-(CR3R4)a-、-(CR3R4)a-S-、-C(＝O)-(CR3R4)a-、-(CR3R4)a-C(＝O)-、-(CR3R4)a-(CR9＝CR10)-、-(CR9＝CR10)-(CR3R4)a-、-C(＝O)-O-、-O-C(＝O)-、-C(＝O)-NR2-、-(CR3R4)a-C(＝O)-NR2-、-NR2-C(＝O)-、-(CR3R4)a-NR2-C(＝O)-、-S(＝O)2-NR2-、-NR2-S(＝O)2-、-NR2-(CR3R4)a-C(＝O)-、-C(＝O)-(CR3R4)a-NR2-；
    优选地，L1选自：键、C3-6亚环烷基、-C(＝O)-、-(CR3R4)a-、-(CR3R4)a-(CR9＝CR10)-、-(CR3R4)a-C(＝O)-NR2-、-(CR3R4)a-NR2-C(＝O)-。
  40. 如权利要求39所述的化合物，其中，
    各R2各自独立地选自：氢、氘、C1-4烷基；
    各R3、R4各自独立地选自：氢、氘、卤素、羟基、C1-4烷基。
  41. 如权利要求33-40任一项所述的化合物，其中，L1选自：键、亚甲基、-C(＝O)-、亚环丙基、亚正丙基、亚正丁基、亚乙基、 优选地，L1选自：键、亚甲基、-C(＝O)-、亚环丙基。
  42. 如权利要求33-41任一项所述的化合物，其中，R1选自：C1-6烷基、C1-6烷氧基、NHR11-C(＝O)-、C1-6烷基-C(＝O)-O-、C1-6烷基-O-C(＝O)-、3-10元环烷基、3-6元单环杂环基、6-11元双环杂环基、6-10元芳基、5-10元杂芳基；其中所述C1-6烷基、C1-6烷氧基、C1-6烷基-C(＝O)-O-、C1-6烷基-O-C(＝O)-、3-10元环烷基、3-6元单环杂环基、6-11元双环杂环基、6-10元芳基、5-10元杂芳基各自独立地任意地被1、2、3个选自氢、氘、卤素、羟基、氧代、氰基、C1-6烷基、C1-6烷氧基、-(CH2)s-O(Rc1)、-(CH2)s-N(Rc1)(Rc2)、C3-6环烷基、3-6元单环杂环基、-C(＝O)-Rc3、-S(O)-Rc3、-S(O)2-Rc3、-C(＝O)O-Rc3、-N(Rc4)-C(＝O)-Rc3、-C(O)-N(Rc6)(Rc5)、-N(Rc4)-C(＝O)-N(Rc6)(Rc5)的取代基进一步取代；
    优选地，R1选自：C1-3烷基、NHR11-C(＝O)-、3-10元环烷基、3-6元单环杂环基、6-11元双环杂环基、6-10元芳基、5-10元杂芳基；其中所述C1-3烷基、3-10元环烷基、3-6元单 环杂环基、6-11元双环杂环基、6-10元芳基、5-10元杂芳基各自独立地任意地被1、2、3个选自氘、卤素、羟基、氧代、氰基、C1-6烷基、C1-6烷氧基、-(CH2)s-O(Rc1)、-(CH2)s-N(Rc1)(Rc2)、C3-6环烷基、3-6元单环杂环基、-C(＝O)-Rc3、-S(O)2-Rc3、-C(＝O)O-Rc3、-N(Rc4)-C(＝O)-Rc3、-C(O)-N(Rc6)(Rc5)、-N(Rc4)-C(＝O)-N(Rc6)(Rc5)的取代基进一步取代；
    更优选地，R1选自：甲基、乙基、异丙基、吡咯烷、四氢呋喃、四氢噻吩、四氢噻喃、四氢吡喃、硫杂环丁烷、氧杂环丁烷、氮杂环丁烷、哌啶、吗啉、哌嗪、环丁烷、环戊烷、环己烷、正庚烷、苯基、吡啶、嘧啶、吡咯、咪唑、噁唑、异噁唑、噻唑、吡唑、呋喃、三唑、-C(＝O)-NH2、 其中所述甲基、乙基、异丙基、吡咯烷、四氢呋喃、四氢噻吩、四氢噻喃、四氢吡喃、硫杂环丁烷、氧杂环丁烷、氮杂环丁烷、哌啶、吗啉、哌嗪、环丁烷、环戊烷、环己烷、正庚烷、苯基、吡啶、嘧啶、吡咯、咪唑、噁唑、异噁唑、噻唑、吡唑、呋喃、三唑、 各自独立地任意地被1、2、3个选自氘、卤素、羟基、氧代、氰基、C1-6烷基、C1- 6烷氧基、-(CH2)s-O(Rc1)、-(CH2)s-N(Rc1)(Rc2)、C3-6环烷基、3-6元单环杂环基、-C(＝O)-Rc3、-S(O)2-Rc3、-C(＝O)O-Rc3、-N(Rc4)-C(＝O)-Rc3、-C(O)-N(Rc6)(Rc5)、-N(Rc4)-C(＝O)-N(Rc6)(Rc5)的取代基进一步取代；
    进一步更优选地，R1选自：甲基、异丙基、吡咯烷、四氢呋喃、四氢噻吩、四氢噻喃、四氢吡喃、硫杂环丁烷、氧杂环丁烷、氮杂环丁烷、哌啶、吗啉、哌嗪、环丁烷、环戊烷、环己烷、正庚烷、苯基、吡啶、嘧啶、吡咯、咪唑、噁唑、异噁唑、噻唑、吡唑、呋喃、三唑，其中所述甲基、异丙基、吡咯烷、四氢呋喃、四氢噻吩、四氢噻喃、四氢吡喃、硫杂环丁烷、氧杂环丁烷、氮杂环丁烷、哌啶、吗啉、哌嗪、环丁烷、环戊烷、环己烷、正庚烷、苯基、吡啶、嘧啶、吡咯、咪唑、噁唑、异噁唑、噻唑、吡唑、呋喃、三唑各自独立地任意地被1、2、3个选自氘、卤素、羟基、氧代、氰基、C1-6烷基、C1-6烷氧基、-(CH2)s-O(Rc1)、-(CH2)s-N(Rc1)(Rc2)、C3-6环烷基、3-6元单环杂环基、-C(＝O)-Rc3、-S(O)2-Rc3、-C(＝O)O-Rc3、-N(Rc4)-C(＝O)-Rc3、-C(O)-N(Rc6)(Rc5)、-N(Rc4)-C(＝O)-N(Rc6)(Rc5)的取代基进一步取代。
  43. 如权利要求33-42任一项所述的化合物，其中，-L1-R1选自
    优选地，-L1-R1选自
    更优选地，-L1-R1选自
  44. 一种式(X-1)或(X-2)所示的化合物或其对映异构体、非对映异构体、消旋体、互变异构体、立体异构体、几何异构体、氮氧化物、代谢产物或其药学上可接受的盐、酯、溶剂化物、水合物、同位素标记化合物(优选氘代物)或前药；
    其中，
    环C选自：6-10元芳基、5-10元杂芳基、苯基并4-7元环烷基、苯基并4-7元杂环基、5-6元杂芳基并4-7元环烷基、5-6元杂芳基并4-7元杂环基、4-7元环烷基、4-7元杂环基；
    各Rcn独立地选自：氢、氘、卤素、羟基、氨基、氰基、C1-6烷氧基、C1-6烷基、C1-6卤代烷基、C1-6卤代烷氧基、羟基C1-6烷基、C1-6烷氧基-C1-6烷基、Rc1S(O)2-、-(CH2)s-N(Rc1)(Rc2)、3-6元环烷基、3-6元杂环基、苯基、5-6元杂芳基，所述3-6元环烷基、3-6元杂环基、苯基、5-6元杂芳基任选地被1、2、3个选自氘、卤素、羟基、氨基、氰基、C1-6烷基、C1-6卤代烷基、C1-6烷氧基的取代基所取代；
    或者，两个Rcn可与其所连接的C原子一起形成3-6元环烷基、4-7元杂环基、6元芳基或5-6元杂芳基，所述3-6元环烷基、4-7元杂环基、6元芳基或5-6元杂芳基可任选地被1、2、3个选自氘、卤素、羟基、氨基、氰基、C1-6烷氧基、C1-6烷基、C1-6卤代烷基的取代基所取代；
    各Ra和Rb独立地选自：氢、氘、卤素、羟基、氨基、氰基、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C1-6烷氧基-C1-6烷基、C1-6卤代烷氧基、羟基-C1-6烷基、-NH(C1-6烷基)、-N(C1-6烷基)(C1-6烷基)、-C(＝O)-(C1-6烷基)、任选地被羟基取代的3-6元杂环烷基；
    L1选自：键、C3-6亚环烷基、-NR2-、-O-、-S-、-C(＝O)-、-(CR3R4)a-、-NR2-(CR3R4)a-、-(CR3R4)a-NR2-、-O-(CR3R4)a-、-(CR3R4)a-O-、-S-(CR3R4)a-、-(CR3R4)a-S-、-C(＝O)-(CR3R4)a-、-(CR3R4)a-C(＝O)-、-(CR3R4)a-(CR9＝CR10)-、-(CR9＝CR10)-(CR3R4)a-、-C(＝O)-O-、-O-C(＝O)-、-C(＝O)-NR2-、-(CR3R4)a-C(＝O)-NR2-、-NR2-C(＝O)-、-(CR3R4)a-NR2-C(＝O)-、-S(＝O)2-NR2-、-NR2-S(＝O)2-、-NR2-(CR3R4)a-C(＝O)-、-C(＝O)-(CR3R4)a-NR2-、-NR2-(CR3R4)a-C(＝O)-NR5-、-NR2-C(＝O)-(CR3R4)a-NR5-、-C(＝S)-NR2-、-NR2-C(＝S)-；
    L2选自键、-NR6-、-O-、-S-、-NR6-(CR7R8)b-、-(CR7R8)b-NR6-、-O-(CR7R8)b-、-(CR7R8)b-O-、-S-(CR7R8)b-、-(CR7R8)b-S-；
    各R2、R5、R6、R9和R10各自独立地选自：氢、氘、C1-6烷基；
    各R3、R4、R7和R8各自独立地选自：氢、氘、卤素、氧代、羟基、氨基、C1-6烷基；
    R1选自：3-10元环烷基、3-6元单环杂环基、6-11元双环杂环基、6-10元芳基、5-10元杂芳基，所述3-10元环烷基、3-6元单环杂环基、6-11元双环杂环基、6-10元芳基、5-10元杂芳基被1或2个选自-C(＝O)-Rc3、-S(＝O)-Rc3、-S(＝O)2-Rc3、-C(＝O)-NRc5Rc6、-P(＝O)Rc5Rc6 的取代基所取代，并且所述3-10元环烷基、3-6元单环杂环基、6-11元双环杂环基、6-10元芳基、5-10元杂芳基还任选被1、2、3个选自氢、氘、卤素、羟基、氧代、氰基、C1-6烷基、羟基C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C1-6烷氧基-C1-6烷基、-(CH2)s-N(Rc1)(Rc2)、C3-6环烷基、3-6元单环杂环基的取代基所取代；
    各Rc1和Rc2独立地选自：氢、C1-6烷基、C1-6卤代烷氧基、C3-6环烷基或4-7元杂环基；
    Rc3选自C1-6烷基、C3-6环烷基，所述C1-6烷基和C3-6环烷基进一步任选被1、2、3个选自氘、卤素、羟基、氨基、氰基、氧代、C1-6烷基、C1-6烷氧基、C1-6卤代烷基、C1-6卤代烷氧基、C1-6烷氧基-C1-6烷基、-NH(C1-6烷基)、-N(C1-6烷基)(C1-6烷基)的取代基所取代；
    Rc5和Rc6选自H、氘、C1-6烷基、C3-6环烷基，或者Rc5和Rc6与其所连接的N原子一起形成4-6元杂环基，所述C1-6烷基、C3-6环烷基和4-6元杂环基进一步任选被1、2、3个选自氘、卤素、羟基、氨基、氰基、氧代、C1-6烷基、C1-6烷氧基、C1-6卤代烷基、C1-6卤代烷氧基、C1-6烷氧基-C1-6烷基、-NH(C1-6烷基)、-N(C1-6烷基)(C1-6烷基)的取代基所取代；
    各a和b各自独立地为1、2、3或4；
    各m为0或1；
    各p为0、1或2；
    各s、n各自独立地选自0、1、2、3或4；
    条件是：不是
  45. 根据权利要求44所述的化合物，其中所述化合物具有式VIII-3或VIII-4所示结构；
  46. 根据权利要求44或45所述的化合物，其中所述化合物具有式VIII-3所示的结构：
  47. 根据权利要求44-46任一项所述的化合物，其中R1选自：3-6元环烷基、3-6元单环杂环基或6-11元双环杂环基，所述3-6元环烷基、3-6元单环杂环基或6-11元双环杂环基被1或2个选自-C(＝O)-Rc3、-S(＝O)-Rc3、-S(＝O)2-Rc3、-C(＝O)-NRc5Rc6、-P(＝O)Rc5Rc6的取代基所取代，并且所述3-6元环烷基、3-6元单环杂环基或6-11元双环杂环基还任选被1、2、3个选自氢、氘、卤素、羟基、氧代、氰基、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C1-6烷氧基-C1-6烷基、-(CH2)s-N(Rc1)(Rc2)、C3-6环烷基、3-6元单环杂环基的取代基所取代；
    各Rc1和Rc2独立地选自：氢、C1-6烷基、C1-6卤代烷氧基、C3-6环烷基或4-7元杂环基；
    Rc3选自C1-6烷基、C3-6环烷基，所述C1-6烷基和C3-6环烷基进一步任选被1-3个选自氘、卤素、羟基、氨基、氰基、氧代、C1-6烷基、C1-6烷氧基、C1-6卤代烷基、C1-6卤代烷氧 基、C1-6烷氧基-C1-6烷基、-NH(C1-6烷基)、-N(C1-6烷基)(C1-6烷基)的取代基所取代；Rc5和Rc6选自H、氘、C1-6烷基、C3-6环烷基，或者Rc5和Rc6与其所连接的N原子一起形成4-6元杂环基，所述C1-6烷基、C3-6环烷基和4-6元杂环基进一步任选被1-3个选自氘、卤素、羟基、氨基、氰基、氧代、C1-6烷基、C1-6烷氧基、C1-6卤代烷基、C1-6卤代烷氧基、C1-6烷氧基-C1-6烷基、-NH(C1-6烷基)、-N(C1-6烷基)(C1-6烷基)的取代基所取代；
    各a和b各自独立地为1、2、3或4；
    各m为0或1；
    各p为0、1或2；
    各s、n各自独立地选自0、1、2、3或4。48.如权利要求44-47任一项所述的化合物，其中L2为键。
  48. 如权利要求44-48任一项所述的化合物，其中Ra和Rb各自独立地选自氢、氘、F、Cl、Br、氰基、甲基、乙基、三氟甲基、甲氧基、1-羟基乙基-1-基、甲胺基、二甲胺基、乙酰基、3-羟基氮杂环丁烷基；优选地，Ra和Rb各自独立地选自氢、氘、F、Cl、Br、甲基、乙基；更优选地，Ra和Rb各自独立地选自氢、氘、甲基。
  49. 如权利要求44-49任一项所述的化合物，各Rcn独立地选自：氢、氘、氟、氯、溴、羟基、氨基、氰基、C1-4烷氧基、C1-4卤代烷氧基、C1-4烷基、C1-4卤代烷基、羟基C1-4烷基、C1-4烷氧基-C1-2烷基、Rc1-S(O)2-、-(CH2)s-N(Rc1)(Rc2)、3-6元环烷基、3-6元杂环基、苯基、5-6元杂芳基，所述3-6元环烷基、3-6元杂环基、苯基、5-6元杂芳基任选地被1-3个选自氘、卤素、羟基、氨基、氰基、C1-6烷基、C1-6卤代烷基、C1-6烷氧基的取代基所取代；
    或者，两个Rcn可与其所连接的C原子一起形成3-6元环烷基、4-7元杂环基、6元芳基或5-6元杂芳基，所述3-6元环烷基、4-7元杂环基、6元芳基或5-6元杂芳基可任选地被1-3个选自氘、卤素、羟基、氨基、氰基、C1-6烷氧基、C1-6烷基、C1-6卤代烷基的取代基所取代；
    优选地，各Rcn独立地选自：氟、氯、溴、羟基、氨基、氰基、甲氧基、乙氧基、异丙氧基、甲氨基、乙氨基、异丙氨基、甲基、乙基、正丙基、异丙基、正丁基、异丁基、三氟甲基、二氟甲基、2,2,2-三氟乙基、五氟乙基、三氟甲氧基、二氟甲氧基、羟甲基、氨基乙基、甲氧基甲基、甲氧基乙基、乙氧基甲基、环丙基、环丁基、环戊基、环己基、环戊烯基、环丁烯基、环己烯基、氧杂环丁基、苯基、4-氯-苯基、2-氯-4-氟-苯基、4-羟基苯基、4-甲基-苯基、4-氟-苯基、吡啶基、环丁基氨基、或者，两个Rcn与其所连接的C原子一起形成环戊烯基、2,3-二氢呋喃基、环丁烯基、噻吩基、1,4-二氧六环基、吡啶基、环戊-1,3-二烯基、苯基、1,4-二氧杂-2-己烯基；
    更优选地，各Rcn独立地选自：氟、氯、溴、羟基、氰基、甲氧基、乙氧基、甲基、乙基、三氟甲基、二氟甲基、三氟甲氧基、二氟甲氧基。
  50. 如权利要求44-50任一项所述的化合物，其中选自
    优选地，其中选自
  51. 如权利要求44-51任一项所述的化合物，其中，L2选自键、-NR6-、-O-、-S-、-NR6-(CR7R8)b1-、-(CR7R8)b1-NR6-、-O-(CR7R8)b1-、-(CR7R8)b1-O-、-S-(CR7R8)b1-、-(CR7R8)b1-S-，其中b1为1或2；
    优选地，L2选自键、-NR6-、-NR6-(CR7R8)b1-、-(CR7R8)b1-NR6-，其中b1为1或2；
    更优选地，L2选自-NR6-、-NR6-(CR7R8)b1-、-(CR7R8)b1-NR6-，其中b1为1；
    进一步更优选地，L2选自-NH-、-NH-(CR7R8)-；
    进一步更优选地，L2选自-NH-、-NH-CH2-。
  52. 如权利要求44-52任一项所述的化合物，其中，其中R1选自：环戊烷、环己烷、氮杂环丁烷、四氢吡咯、哌啶、吗啉、哌嗪、 所述环戊烷、环己烷、氮杂环丁烷、四氢吡咯、哌啶、 吗啉、哌嗪、 被1或2个选自-C(＝O)-Rc3、-S(＝O)-Rc3、-S(＝O)2-Rc3、-C(＝O)-NRc5Rc6、-P(＝O)Rc5Rc6的取代基所取代，并且所述环戊烷、环己烷、氮杂环丁烷、四氢吡咯、哌啶、吗啉、哌嗪、 还任选被1、2、3个选自氢、氘、卤素、羟基、氧代、C1-6烷基、C1-6烷氧基、C1-6烷氧基-C1-6烷基、-(CH2)s-N(Rc1)(Rc2)、C3-6环烷基、3-6元单环杂环基的取代基所取代；
    优选地，R1选自：四氢吡咯、哌啶、吗啉、哌嗪、 所述四氢吡咯、哌啶、吗啉、哌嗪、 被1或2个选自-C(＝O)-Rc3、-S(＝O)-Rc3、-S(＝O)2-Rc3、-C(＝O)-NRc5Rc6、-P(＝O)Rc5Rc6的取代基所取代，并且所述四氢吡咯、哌啶、吗啉、哌嗪、 还任选被1、2、3个选自氢、氘、卤素、羟基、氧代、C1-6烷基、C1-6烷氧基、-(CH2)s-N(Rc1)(Rc2)、C3-6环烷基、C1-6烷氧基-C1-6烷基、3-6元单环杂环基的取代基所取代；
    更优选地，R1选自：四氢吡咯、哌啶、吗啉、哌嗪、 所述四氢吡咯、哌啶、吗啉、哌嗪、被1个选自-C(＝O)-Rc3、-S(＝O)2-Rc3、-P(＝O)Rc5Rc6的取代基所取代，并且所述四氢吡咯、哌啶、吗啉、哌嗪、还任选被1或2个选自氘、卤素、羟基、C1-6烷基、C1-6烷氧基、C1-6烷氧基-C1-6烷基的取代基所取代。
    进一步优选地，其中R1选自：
    进一步更优选地，其中R1选自：
  53. 权利要求1-4、6-27任一项所示的化合物或其对映异构体、非对映异构体、消旋体、互变异构体、立体异构体、几何异构体、氮氧化物、代谢产物或其药学上可接受的盐、酯、溶剂化物、水合物、同位素标记化合物(优选氘代物)或前药，其中，所述化合物具有式VIII-8或VIII-12所示的结构：
    其中，各Rc独立地选自：氢、氘、卤素、羟基、氰基、C1-6烷氧基、C1-6烷基、C1-6卤代烷基、C1-6卤代烷氧基、C1-6烷氧基-C1-6烷基、Rc1S(O)2-、3-6元环烷基、3-6元杂环基、苯基、5-6元杂芳基，所述3-6元环烷基、3-6元杂环基、苯基、5-6元杂芳基任选地被1、2、3个选自氘、卤素、羟基、氨基、氰基、C1-6烷基、C1-6卤代烷基、C1-6烷氧基的取代基所取代；
    或者，两个Rc可与其所连接的C原子一起形成3-6元环烷基、4-7元杂环基、6元芳基或5-6元杂芳基，所述3-6元环烷基、4-7元杂环基、6元芳基或5-6元杂芳基可任选地被1、2、3个选自氘、卤素、羟基、氨基、氰基、C1-6烷氧基、C1-6烷基、C1-6卤代烷基的取代基所取代；
    L2选自键、-NR6-、-O-、-S-；
    Ra、Rb、Rc、Rc1、R6、R1、L1、n、m、p如权利要求1所定义。
  54. 根据权利要求54所述的化合物，其中，所述化合物具有式VIII-8所示的结构：
  55. 权利要求54或55所述的化合物或其对映异构体、非对映异构体、消旋体、互变异构体、立体异构体、几何异构体、氮氧化物、代谢产物或其药学上可接受的盐、酯、溶剂化物、水合物、同位素标记化合物(优选氘代物)或前药，其中，R1为3-6元单环杂环基，所述3-6元单环杂环基任选地被1、2、3个选自氘、卤素、羟基、氧代、氰基、C1-6烷基、C1-6卤代烷基、羟基C1-6烷基、C1-6烷氧基、-(CH2)S-O(Rc1)、-(CH2)S-N(Rc1)(Rc2)、C3-6环烷基、3-6元单环杂环基、5-6元杂芳基、-C(＝O)-Rc3、-S(O)-Rc3、-S(O)2-Rc3、-C(＝O)O-Rc3、-N(Rc4)-C(＝O)-Rc3、-CH2-N(Rc4)-C(＝O)-Rc4、-C(＝O)-N(Rc6)(Rc5)、-N(Rc4)-C(＝O)-N(Rc6)(Rc5)、-P(＝O)Rc5Rc6的取代基进一步取代；优选地，所述R1选自四氢吡咯、哌啶、吗啉、哌嗪、1,4-氧硫杂环己烷，所述四氢吡咯、哌啶、吗啉、哌嗪、1,4-氧硫杂环己烷各自独立地任意地被1、2、3个选自氘、卤素、羟基、氨基、氧代、C1-4烷基、C1-4卤代烷基、羟基C1-4烷基、C1-4烷氧基、C3-6环烷基、3-6元单环杂环基、-C(＝O)-Rc3、-S(O)-Rc3、-S(O)2-Rc3、-C(＝O)O-Rc3、-N(Rc4)-C(＝O)-Rc3、-CH2-N(Rc4)-C(＝O)-Rc4、-C(＝O)-N(Rc6)(Rc5)、-N(Rc4)-C(＝O)-N(Rc6)(Rc5)、-P(＝O)Rc5Rc6的取代基进一步取代；优选地，所述R1选自吗啉，所述吗啉任意地被1、2、3个选自氘、卤素、羟基、氨基、氧代、C1-4烷基、C1-4烷氧基、C3-6环烷 基、3-6元单环杂环基、-C(＝O)-Rc3、-S(O)-Rc3、-S(O)2-Rc3、-C(＝O)O-Rc3、-N(Rc4)-C(＝O)-Rc3、-CH2-N(Rc4)-C(＝O)-Rc4、-C(＝O)-N(Rc6)(Rc5)、-N(Rc4)-C(＝O)-N(Rc6)(Rc5)、-P(＝O)Rc5Rc6的取代基进一步取代；进一步优选地，其中R1选自：
  56. 权利要求1-4、6-27任一项所示的化合物或其对映异构体、非对映异构体、消旋体、互变异构体、立体异构体、几何异构体、氮氧化物、代谢产物或其药学上可接受的盐、酯、溶剂化物、水合物、同位素标记化合物(优选氘代物)或前药，其中，所述化合物具有式VIII-9所示的结构：
    其中，R1为3-6元单环杂环基，所述3-6元单环杂环基任选地被1、2、3个选自氘、卤素、羟基、氰基、C1-6烷基、C1-6卤代烷基、羟基C1-6烷基、C1-6烷氧基、-(CH2)s-N(Rc1)(Rc2)-、C3-6环烷基、3-6元单环杂环基、-C(＝O)-Rc3、-S(O)-Rc3、-S(O)2-Rc3、-C(＝O)O-Rc3、-N(Rc4)-C(＝O)-Rc3、-CH2-N(Rc4)-C(＝O)-Rc4、-C(＝O)-N(Rc6)(Rc5)、-N(Rc4)-C(＝O)-N(Rc6)(Rc5)、-P(＝O)Rc5Rc6的取代基进一步取代；优选地，所述R1选自吗啉、哌啶，所述吗啉、哌啶各自独立地任意地被1、2、3个选自氘、卤素、羟基、氨基、C1-4烷基、C1-4烷氧基、C3-6环烷基、3-6元单环杂环基、-C(＝O)-Rc3、-S(O)-Rc3、-S(O)2-Rc3、-C(＝O)O-Rc3、-N(Rc4)-C(＝O)-Rc3、-CH2-N(Rc4)-C(＝O)-Rc4、-C(＝O)-N(Rc6)(Rc5)、-N(Rc4)-C(＝O)-N(Rc6)(Rc5)、-P(＝O)Rc5Rc6的取代基进一步取代；进一步优选地，所述R1选自：
    Ra、Rb、Rc、Rc1、Rc2、Rc3、Rc4、Rc5、Rc6、R、L2、L1、s、n、m、p如权利要求1所定义；
    条件是：不是
  57. 如权利要求1-57任一项所述的化合物，其中，所述化合物选自：


































  58. 一种药物组合物，所述药物组合物包含治疗有效量的如权利要求1至58中任一项所述的化合物、或其对映异构体、非对映异构体、消旋体、互变异构体、立体异构体、几何异构体、氮氧化物、代谢产物或其药学上可接受的盐、酯、溶剂化物、水合物、同位素标记化合物(优选氘代物)或前药。
  59. 一种组合，所述组合包含治疗有效量的如权利要求1至58中任一项所述的化合物或其对映异构体、非对映异构体、消旋体、互变异构体、立体异构体、几何异构体、氮氧化物、代谢产物或其药学上可接受的盐、酯、溶剂化物、水合物、同位素标记化合物(优选氘代物)或前药，和一种或多种治疗剂。
  60. 如权利要求60所述的组合，其中一种或多种治疗剂独立地选自类法尼醇X受体(FXR)激动剂；抗脂肪变性剂；抗纤维化剂；JAK抑制剂；检查点抑制剂；化学疗法、放射疗法和外科手术；降尿酸疗法；合成代谢剂和软骨再生疗法；IL-17的阻断剂；补体抑制剂；布鲁顿酪氨酸激酶抑制剂(BTK抑制剂)；Toll样受体抑制剂(TLR7/8抑制剂)；CAR-T疗法；抗高血压剂；降胆固醇剂；白三烯A4水解酶(LTAH4)抑制剂；SGLT2抑制剂；β2-激动剂；抗炎剂；非类固醇抗炎药(“NSAID”)；乙酰水杨酸药(ASA)；再生疗法治疗；囊性纤维化治疗；和动脉粥样硬化治疗。
  61. 如权利要求1至58中任一项所述的化合物、或其对映异构体、非对映异构体、消旋体、互变异构体、立体异构体、几何异构体、氮氧化物、代谢产物或其药学上可接受的盐、酯、溶剂化物、水合物、同位素标记化合物(优选氘代物)或前药，或如权利要求60至61中任一项所述的组合，用于作为药物使用。
  62. 如权利要求1至58中任一项所述的化合物、或其对映异构体、非对映异构体、消旋体、互变异构体、立体异构体、几何异构体、氮氧化物、代谢产物或其药学上可接受的盐、酯、溶剂化物、水合物、同位素标记化合物(优选氘代物)或前药，用于在下述疾病或障碍的治疗中使用，在所述疾病或障碍中，NLRP3信号传导促成所述疾病或障碍的病理学、和/或症状、和/或进展。
  63. 一种治疗下述疾病或障碍的方法，在所述疾病或障碍中，NLRP3信号传导促成所述疾病或障碍的病理学、和/或症状、和/或进展，所述方法包括施用治疗有效量的如权利要求1至58中任一项所述的化合物、或其对映异构体、非对映异构体、消旋体、互变异构体、立体异构体、几何异构体、氮氧化物、代谢产物或其药学上可接受的盐、酯、溶剂化物、水合物、同位素标记化合物(优选氘代物)或前药。
  64. 如权利要求1至58中任一项所述的化合物、或其对映异构体、非对映异构体、消旋体、互变异构体、立体异构体、几何异构体、氮氧化物、代谢产物或其药学上可接受的盐、酯、溶剂化物、水合物、同位素标记化合物(优选氘代物)或前药，在制备下述疾病或障碍的治疗中使用药物的用途，在所述疾病或障碍中，NLRP3信号传导促成所述疾病或障碍的病理学、和/或症状、和/或进展。
  65. 用于如权利要求62-63所述使用的化合物或如权利要求64所述的治疗方法或权利要求65所述的用途，其中所述疾病或障碍选自：炎性小体相关疾病/障碍、免疫性疾病、炎症性疾病、自身免疫性疾病、或自身炎症性疾病，例如，自身炎症性发热综合征(例如隐热蛋白相关周期性综合征)、肝相关疾病/障碍(例如慢性肝疾病、病毒性肝炎、非酒精性脂肪性肝 炎(NASH)、酒精性脂肪性肝炎、和酒精性肝疾病)、炎症性关节炎相关障碍(例如痛风、假性痛风(软骨钙质沉着病)、骨关节炎、类风湿性关节炎、关节病例如急性、慢性关节病)、肾脏相关疾病(例如高草酸尿症、狼疮性肾炎、I型/II型糖尿病及相关并发症(例如肾病、视网膜病)、高血压性肾病、血液透析相关炎症)、神经炎症相关疾病(例如多发性硬化症、脑部感染、急性损伤、神经退行性疾病、阿尔茨海默氏病)、心血管/代谢疾病/障碍(例如心血管风险降低(CvRR)、高血压、动脉粥样硬化、I型和II型糖尿病及相关并发症、外周动脉疾病(PAD)、急性心力衰竭)、炎症性皮肤疾病(例如化脓性汗腺炎、痤疮)、创伤愈合和瘢痕形成、哮喘、结节病、年龄相关黄斑变性、和癌症相关疾病/障碍(例如结肠癌、肺癌、骨髓增生性肿瘤、白血病、骨髓增生异常综合征(MDS)、骨髓纤维化)。
  66. 一种在有需要的受试者中抑制NLRP3炎性小体活性的方法，所述方法包括向有需要的受试者施用治疗有效量的如权利要求1至58中任一项所述的化合物、或其对映异构体、非对映异构体、消旋体、互变异构体、立体异构体、几何异构体、氮氧化物、代谢产物或其药学上可接受的盐、酯、溶剂化物、水合物、同位素标记化合物(优选氘代物)或前药。
PCT/CN2024/076764 2023-02-14 2024-02-07 一种抑制nlrp3的化合物及制备方法和应用 Ceased WO2024169895A1 (zh)

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WO2025128781A1 (en) * 2023-12-14 2025-06-19 Merck Sharp & Dohme Llc Azaindazole derivatives useful as inhibitors of nod-like receptor protein 3
WO2025153532A1 (en) 2024-01-16 2025-07-24 NodThera Limited Nlrp3 inhibitors and glp-1 agonists combination therapies
US12390462B2 (en) 2019-12-02 2025-08-19 Contineum Therapeutics, Inc. Muscarinic acetylcholine M1 receptor antagonists
WO2025180453A1 (zh) * 2024-02-28 2025-09-04 纽欧申医药(上海)有限公司 哒嗪环衍生物及其应用
WO2026041127A1 (zh) * 2024-08-23 2026-02-26 浙江众神创新医药科技有限公司 Nlrp3抑制剂及其制备方法和用途
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Cited By (7)

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Publication number Priority date Publication date Assignee Title
US12565501B2 (en) 2019-10-07 2026-03-03 Contineum Therapeutics, Inc. Muscarinic acetylcholine M1 receptor antagonists
US12390462B2 (en) 2019-12-02 2025-08-19 Contineum Therapeutics, Inc. Muscarinic acetylcholine M1 receptor antagonists
WO2025067343A1 (zh) * 2023-09-27 2025-04-03 纽欧申医药(上海)有限公司 并环化合物及其应用
WO2025128781A1 (en) * 2023-12-14 2025-06-19 Merck Sharp & Dohme Llc Azaindazole derivatives useful as inhibitors of nod-like receptor protein 3
WO2025153532A1 (en) 2024-01-16 2025-07-24 NodThera Limited Nlrp3 inhibitors and glp-1 agonists combination therapies
WO2025180453A1 (zh) * 2024-02-28 2025-09-04 纽欧申医药(上海)有限公司 哒嗪环衍生物及其应用
WO2026041127A1 (zh) * 2024-08-23 2026-02-26 浙江众神创新医药科技有限公司 Nlrp3抑制剂及其制备方法和用途

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