WO2020093905A1 - 并环化合物、其制备方法及用途 - Google Patents

并环化合物、其制备方法及用途 Download PDF

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WO2020093905A1
WO2020093905A1 PCT/CN2019/113877 CN2019113877W WO2020093905A1 WO 2020093905 A1 WO2020093905 A1 WO 2020093905A1 CN 2019113877 W CN2019113877 W CN 2019113877W WO 2020093905 A1 WO2020093905 A1 WO 2020093905A1
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membered
group
alkyl
compound
aryl
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PCT/CN2019/113877
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English (en)
French (fr)
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李桂英
何云
游泽金
陈忠辉
田强
宋宏梅
薛彤彤
王利春
王晶翼
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四川科伦博泰生物医药股份有限公司
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Priority to CN202311141511.0A priority Critical patent/CN117186092A/zh
Priority to CN201980058276.6A priority patent/CN112654622B/zh
Publication of WO2020093905A1 publication Critical patent/WO2020093905A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • the present invention belongs to the field of medicine and relates to a class of nitrogen-containing cyclic compounds, stereoisomers, tautomers or mixtures of the compounds, pharmaceutically acceptable salts, co-crystals, and polymorphs of the compounds Substances or solvates, or stable isotope derivatives, metabolites or prodrugs of the compounds.
  • the compounds of the invention can be used as NLRP3 modulators (eg agonists) for the treatment of diseases (eg tumor diseases) associated with NLRP3 inflammatory body activity.
  • NLRP3 (NLR family pyrin domain containing 3) belongs to the NOD-like receptor family and is the most studied intracellular pattern recognition receptor in recent years. It is mainly expressed in macrophages and neutrophils and participates in the body's innate immunity. Resist pathogen infection and stress damage. The role of NLRP3 inflammasome in inflammatory and metabolic diseases is very clear, and its excessive activation will lead to immune diseases such as type 2 diabetes, rheumatoid arthritis and atherosclerosis. However, recent studies have shown that NLRP3 has an anti-tumor effect that inhibits tumor growth and metastasis.
  • NLRP3 protein recognizes pathogen-associated molecular pattern (PAMP) or endogenous damage-related molecular pattern (DAMP), its NOD domain oligomerizes and recruits proteins such as ASC and pro-caspase-1 to form functional NLRP3 Inflammatory bodies.
  • pro-caspase-1 is activated by cleavage to caspase-1, caspase-1 shears pro-IL-1 ⁇ and pro-IL-18 in large amounts to convert them into active forms IL-1 ⁇ and IL-18 and release them into the cell In addition, amplify the inflammatory response.
  • Excited NLRP3 inflammasome can significantly increase the levels of immune factors IL-1 ⁇ and IL-18 in the tumor microenvironment, initiate natural immune killing and subsequent acquired immune responses to exert its anti-tumor effect.
  • IL-1 ⁇ can induce CD8 + T cells to secrete interferon ⁇ (IFN- ⁇ ) and CD4 + cells to secrete IL-17, causing an effective anti-tumor immune response; while IL-18 can promote NK cell maturation , Activate the downstream signaling pathway of STAT1 in immune cells and enhance the killing function of immune cells.
  • IFN- ⁇ interferon ⁇
  • IL-18 can promote NK cell maturation , Activate the downstream signaling pathway of STAT1 in immune cells and enhance the killing function of immune cells.
  • Clinical studies have shown that the down-regulation of NLRP3 is significantly negatively correlated with the prognosis of liver cancer patients.
  • NLRP3 deficient mice have a higher rate of colorectal tumor formation and worse liver metastases from colorectal cancer. It can be seen that NLRP3 plays an important role in the tumor microenvironment, and can be used as a key target for tumor immunotherapy and as a tumor prognostic marker.
  • VentiRx Pharmaceutical's VTX2337 which is a TLR8 / NLRP3 inflammatory corpuscle dual agonist, has entered clinical phase II, and its indications are ovarian cancer and head and neck cancer (PLOS
  • the inventors of the present invention have obtained a new class of cyclic compounds through creative work, which can be used as NLRP3 modulators (such as agonists), directly bind or modify NLRP3 at the protein level, and activate, stabilize, or change the distribution of NLRP3 or Other ways to enhance the function of the NLRP3 inflammatory body provide the following invention.
  • the present invention relates to compounds represented by formula I, stereoisomers, tautomers or mixtures thereof, pharmaceutically acceptable salts, co-crystals, and polymorphs of the compounds Or a solvate, or a stable isotope derivative, metabolite, or prodrug of the compound:
  • X 1 is C (R 7 ) 2 , NR 7 , O or S,
  • X 2 is CR 7 or N
  • X 3 is C, N, O or S, and meets the following conditions:
  • R 6 is selected from H, C 1-6 alkyl, and C 3-8 cycloalkyl, and each of the C 1-6 alkyl and C 3-8 cycloalkyl is optional Is substituted by one or more of the following groups: halogen, OH, CN, NO 2 , C 1-4 alkoxy and C 1-4 hydroxyalkyl,
  • R 1 is selected from C 1-8 alkyl, C 1-8 alkoxy, C 3-8 cycloalkyl, 4-10 membered heterocyclyl, C 6-12 aryl, 5-10 membered heteroaryl and 9-12 membered arylheterocyclic group, the C 1-8 alkyl group, C 1-8 alkoxy group, C 3-8 cycloalkyl group, 4-10 membered heterocyclic group, C 6-12 aryl group , 5-10 membered heteroaryl and 9-12 membered arylheterocyclyl are each optionally substituted with one or more of the following substituents: halogen, CN, NO 2 , C 1-4 alkyl, C 3-8 cycloalkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy, C 1-4 hydroxyalkyl, 4-10 membered heterocyclic group, C 6-12 Aryl, 5-10 membered heteroaryl, 9-12 membered aryl
  • R 2 is selected from H, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 6-12 aryl, C 3-8 cycloalkyl, 5-10 membered heteroaryl and 4-10 membered heterocyclic group, said C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 6-12 aryl, C 3-8 cycloalkyl, 5-10 member Heteroaryl and 4-10 membered heterocyclic groups are each optionally substituted with one or more of the following substituents: halogen, C 1-4 haloalkyl, C 1-4 hydroxyalkyl, C 1-4 alkoxy Group, C 1-4 haloalkoxy, 4-7 membered heterocyclic group, CN, NO 2 , OR 37 , SR 37 , C (O) R 30 , C (O) NR 31 R 32 , NR 31 R 32 C (O), C (O) OR 30 , OC (O) R 30
  • R 4 and R 5 are each independently selected from H, C 1-8 alkyl, C 3-8 cycloalkyl and C 1-8 alkoxy, the C 1-8 alkyl, C 3-8 cycloalkane
  • the group and C 1-8 alkoxy are each optionally substituted with one or more of the following substituents: halogen, OH, CN, NO 2 , C 1-6 alkyl, C 1-4 haloalkyl, and C 1 -4 hydroxyalkyl; or R 4 and R 5 together with the nitrogen atom to which they are attached form a 4-7 membered heterocyclic ring;
  • R 7 is selected from H, C 1-6 alkyl and C 3-8 cycloalkyl group, the C 1-6 alkyl and C 3-8 cycloalkyl each optionally substituted with a group of the following or Substitutions: halogen, OH, CN, C 1-4 alkoxy and C 1-4 hydroxyalkyl; or two R 7 together with the carbon atom to which they are attached to form a 3-5 membered cycloalkyl; when two R When 7 exists at the same time, each R 7 may be the same or different;
  • V is absent or selected from C 1-8 alkylene, C (R 36a R 36b ), O, S, NR 33 , SO, SO 2 and CO, the C 1-8 alkylene is optionally substituted Substitution of one or more of the following substituents: halogen, OH, CN, NO 2 , C 1-6 alkyl, C 1-4 haloalkyl, C 1-4 hydroxyalkyl, and C 1-4 alkoxy;
  • V and X 1 are not heteroatoms N, O or S;
  • L is-(L 1 ) n- (L 2 ) p- (L 3 ) q- , where L 1 , L 2 and L 3 are the same or different, and are each independently selected from C 1-8 alkylene, C 2-8 alkenylene, C 2-8 alkynylene, C 1-8 haloalkylene, C 1-8 alkyleneoxy, C 1-8 haloalkyleneoxy, C 1-8 hydroxy Alkylene, C 3-8 cycloalkylene, 4-10 membered heterocyclylene, C 6-12 arylene, 5-10 membered heteroarylene, O, S, NR 33 , SO, SO 2 , CO and C (R 36a R 36b ), the C 1-8 alkylene, C 2-8 alkenylene, C 2-8 alkynylene, C 1-8 haloalkylene, C 1- 8 alkyleneoxy, C 1-8 haloalkyleneoxy, C 1-8 hydroxyalkylene, C 3-8 cycloalkylene, 4-10 membered
  • n, p and q are independently 0 or 1;
  • R 30 , R 37 , R 39 and R 40 are each independently selected from hydrogen, C 1-8 alkyl, C 1-8 hydroxyalkyl, C 1-8 haloalkyl, C 1-8 alkoxy, C 1 -8 haloalkoxy, C 3-8 cycloalkyl, 4-10 membered heterocyclyl, C 6-12 aryl, 5-10 membered heteroaryl, C 1-8 alkyl-C 6-12 aryl And C 1-8 alkyl- (5-10 membered heteroaryl), the C 1-8 alkyl, C 1-8 hydroxyalkyl, C 1-8 haloalkyl, C 1-8 alkoxy, C 1-8 haloalkoxy, C 3-8 cycloalkyl, 4-10 membered heterocyclic group, C 6-12 aryl group and 5-10 membered heteroaryl group are each optionally substituted by one of the following Multiple substitutions: OH, CN, NO 2 , C 1-4 alkyl, C 1-4 alkoxy, C 1-4
  • each R 30 may be the same or different;
  • each R 37 may be the same or different;
  • each R 39 may be the same or different;
  • each R 40 may be the same or different;
  • R 31 , R 32 , R 33 and R 34 are each independently selected from H, C 1-8 alkyl, C 1-8 hydroxyalkyl, C 1-8 alkoxy, 4-10 membered heterocyclyl, C 6-12 aryl, C 3-8 cycloalkyl and 5-10 membered heteroaryl, the C 1-8 alkyl, C 1-8 hydroxyalkyl, C 1-8 alkoxy, 4-10
  • the membered heterocyclic group, C 6-12 aryl group, C 3-8 cycloalkyl group, and 5-10 membered heteroaryl group are each optionally substituted with one or more of the following substituents: OH, CN, halogen, NO 2 , C 1-4 alkyl, C 1-4 alkoxy, C 1-4 hydroxyalkyl, C 1-4 haloalkyl, C 1-4 haloalkoxy, 4-10 membered heterocyclic group, C 6 -12 aryl and 5-10 membered heteroaryl; or R 31 and R 32 together with
  • R 35 is selected from C 1-8 alkyl, C 1-8 hydroxyalkyl, C 1-8 haloalkyl, C 1-8 alkoxy, C 1-8 haloalkoxy, C 3-8 cycloalkyl, 4-10 membered heterocyclyl, C 6-12 aryl, 5-10 membered heteroaryl, C 1-8 alkyl-C 6-12 aryl and C 1-8 alkyl- (5-10 membered hetero Aryl), the C 1-8 alkyl, C 1-8 hydroxyalkyl, C 1-8 haloalkyl, C 1-8 alkoxy, C 1-8 haloalkoxy, C 3-8 cycloalkane Group, 4-10 membered heterocyclic group, C 6-12 aryl group and 5-10 membered heteroaryl group are each optionally substituted with one or more of the following substituents: OH, CN, NO 2 , C 1- 4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl, halogen, C 1-4
  • each R 31 may be the same or different;
  • each R 32 may be the same or different;
  • each R 33 may be the same or different;
  • each R 34 may be the same or different;
  • each R 35 may be the same or different;
  • R 36a and R 36b are the same or different, and are each independently selected from H, C 1-6 alkyl, C 1-6 alkoxy, C 1-8 hydroxyalkyl, and C 1-8 haloalkyl, the C 1 -6 alkyl, C 1-6 alkoxy, C 1-8 hydroxyalkyl, and C 1-8 haloalkyl are each optionally substituted with one or more of the following groups: OH, CN, NH 2 , NHCH 3 and N (CH 3 ) 2 ; or R 36a and R 36b together with the carbon atom to which they are attached form a 3-7 membered cycloalkyl group or a 3-7 membered heterocyclic group;
  • each R 38 is the same or different and is independently selected from H, OH, CN, NO 2 , S (O) R 35 and S (O) 2 R 35 .
  • R 1 is selected from C 1-4 alkyl, C 1-4 alkoxy, C 3-6 cycloalkyl, 4-7 membered heterocyclyl, C 6-12 aryl, 5 -10 membered heteroaryl group and 9-12 membered arylheterocyclic group, the C 1-4 alkyl group, C 1-4 alkoxy group, C 3-6 cycloalkyl group, 4-7 membered heterocyclic group , C 6-12 aryl, 5-10 membered heteroaryl and 9-12 membered arylheterocyclyl are each optionally substituted with one or more of the following substituents: halogen, CN, NO 2 , C 1-4 alkyl, C 3-8 cycloalkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy, C 1-4 hydroxyalkyl, 4-10 membered hetero Cyclic group, C 6-12 aryl group, 5-10 membered heteroaryl
  • R 1 is selected from C 1-4 alkyl, C 6-12 aryl, and 5-10 membered heteroaryl, said C 1-4 alkyl, C 6-12 aryl, and 5
  • the -10 membered heteroaryl groups are each optionally substituted with one or more of the following substituents: halogen, CN, NO 2 , C 1-4 alkyl, C 3-8 cycloalkyl, C 1-4 haloalkyl , C 1-4 alkoxy, C 1-4 haloalkoxy, C 1-4 hydroxyalkyl, 4-10 membered heterocyclic group, C 6-12 aryl group, 5-10 membered heteroaryl group, 9- 12-membered arylheterocyclic group, CO 2 R 30 , C (O) R 30 , C (O) NR 31 R 32 , NR 33 C (O) R 34 , NR 31 R 32 , OC (O) R 30 ⁇ OC (O) NR 31 R 32 ⁇ NR 33
  • R 1 is selected from isobutyl
  • V and X 1 are not heteroatoms N, O or S, which means that when X 1 is NR 7 , O or S, V is not O, S, NR 33 , SO or SO 2 .
  • V is absent or selected from CO and C 1-8 alkylene (eg methylene).
  • X 1 is selected from O and NR 7 , preferably, X 1 is selected from O, NH and N (CH 3 ).
  • X 1 is selected from NR 7 , preferably, X 1 is selected from NH and N (CH 3 ).
  • X 1 is O.
  • X 1 is S.
  • X 2 is CR 7 , preferably, X 2 is CH.
  • X 2 is N.
  • X 3 is N, which is substituted by R 2 , and R 6 is not present; preferably, R 2 is selected from H, C 1-4 alkyl, C 3-8 cycloalkyl, and C 6 -12 aryl; more preferably, R 2 is selected from H, methyl, ethyl and propyl, especially H and methyl.
  • R 3 is selected from OH, C 1-8 alkyl, 4-10 membered heterocyclyl, C 6-12 aryl, NR 31 R 32 , NR 33 C (O) R 34 , NR 33 S (O) 2 R 34 , C (O) NR 31 R 32 , 9-12 membered arylheterocyclic group, 5-10 membered heteroaryl and NR 33 C (O) NR 31 R 32 , said C 1-8 alkyl, 4-10 membered heterocyclyl, C 6-12 aryl, 5-10 membered heteroaryl and 9-12 membered arylheterocyclyl are each optionally substituted by One or more substitutions: C 1-4 alkyl, C 1-4 alkoxy, C 6-12 aryl, C (O) R 30 , C (O) NR 31 R 32 , NR 33 C (O) R 34 , NR 31 R 32 , S (O) 2 R 35 and OR 37 .
  • R 3 is selected from OH, C 1-8 alkyl, 4-10 membered heterocyclyl, C 6-12 aryl, NR 31 R 32 , NR 33 C (O) R 34 , NR 33 S (O) 2 R 34 , C (O) NR 31 R 32 , 9-12 membered arylheterocyclic group, 5-10 membered heteroaryl and NR 33 C (O) NR 31 R 32 , said C 1-8 alkyl, 4-10 membered heterocyclyl, C 6-12 aryl, 5-10 membered heteroaryl and 9-12 membered arylheterocyclyl are each optionally substituted by One or more substitutions: methyl, methoxy, phenyl, C (O) CH 3 , C (O) NH 2 , NHC (O) CH 3 , NHC (O) H, NH 2 , NH (CH 3 ), S (O) 2 CH 3 and OH.
  • R 3 is selected from OH, -NHC (O) CH 3 , -C (O) NH 2 , -N (CH 2 CH 3 ) C (O) N (CH 3 ) 2 ,
  • R 4 and R 5 are each independently selected from H, C 1-3 alkyl, C 3-6 cycloalkyl and C 1-3 alkoxy, said C 1-3 alkyl , C 1-3 alkoxy and C 3-6 cycloalkyl are each optionally substituted with one or more of the following substituents: halogen, OH, CN, NO 2 , C 1-6 alkyl, C 1 -4 haloalkyl and C 1-4 hydroxyalkyl; or R 4 and R 5 together with the nitrogen atom to which they are attached form a 4-7 membered heterocyclic ring; preferably, R 4 and R 5 are both H.
  • L is absent or selected from propylene, methylene, ethylene, O, S, NR 33 , -C 1-3 alkylene -O-, -C 1-3 Alkylene-S- and -C 1-3 alkylene-NR 33- ; preferably, R 33 is selected from H and methyl.
  • L is absent or is selected from propylene, ethylene, O, S, NR 33, -C 1-3 alkylene -O -, - C 1-3 alkylene group -S- and - C 1-3 alkylene-NR 33- ; preferably, R 33 is selected from H and methyl.
  • L is absent or selected from propylene, ethylene, -C 1-3 alkylene-O- (eg -ethylene-O- or -propylene-O-) and- C 1-3 alkylene-NH- (for example, ethylene-NH-).
  • the compound has the structure of Formula II:
  • R 1 , R 2 , R 3 , R 4 , R 5 , X 1 , V and L are as defined in the above formula I; preferably, wherein R 1 , R 2 , R 3 , R 4 , R 5 and L are as As defined in claim 1, V is absent or selected from CO, methylene, ethylene and propylene, X 1 is NR 7 , R 7 is selected from H, C 1-4 alkyl and C 3-6 Cycloalkyl, the C 1-4 alkyl and C 3-6 cycloalkyl are each optionally substituted with one or more of the following groups: halogen, OH, CN, C 1-4 alkoxy and C 1-4 hydroxyalkyl, for example X 1 is selected from NH and N (CH 3 ).
  • the compound has the structure of formula II, wherein R 1 is selected from C 1-4 alkyl, C 6-12 aryl (eg phenyl) and 5-10 membered heteroaryl ( (Eg pyridyl or pyrazinyl), the C 1-4 alkyl, C 6-12 aryl and 5-10 membered heteroaryl groups are each optionally substituted with one or more of the following substituents: halogen, CN, NO 2 , C 1-4 alkyl, C 3-8 cycloalkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy, C 1-4 hydroxyalkyl , 4-10 membered heterocyclic group, C 6-12 aryl group, 5-10 membered heteroaryl group, 9-12 membered arylheterocyclic group, CO 2 R 30 , C (O) R 30 , C (O ) NR 31 R 32 , NR 33 C (O)
  • the compound has the structure of formula II, wherein R 2 is selected from H and methyl.
  • the compound has the structure of formula II, wherein R 3 is selected from OH, C 1-8 alkyl, 4-10 membered heterocyclyl, C 6-12 aryl, NR 31 R 32 , NR 33 C (O) R 34 , NR 33 S (O) 2 R 34 , C (O) NR 31 R 32 , 9-12 membered arylheterocyclic group, 5-10 membered heteroaryl and NR 33 C (O) NR 31 R 32 , the C 1-8 alkyl group, 4-10 membered heterocyclic group, C 6-12 aryl group, 5-10 membered heteroaryl group and 9-12 membered aryl group are hetero
  • the cyclic groups are each optionally substituted with one or more of the following substituents: C 1-4 alkyl, C 1-4 alkoxy, C 6-12 aryl, C (O) R 30 , C (O ) NR 31 R 32 , NR 33 C (O) R 34 ,
  • the compound has the structure of formula II, wherein R 4 and R 5 are each independently selected from H, C 1-3 alkyl, C 1-3 alkoxy, and C 3-6 Cycloalkyl, the C 1-3 alkyl, C 1-3 alkoxy, and C 3-6 cycloalkyl are each optionally substituted with one or more of the following substituents: halogen, OH, CN, NO 2 , C 1-6 alkyl, C 1-4 haloalkyl and C 1-4 hydroxyalkyl; or R 4 and R 5 together with the nitrogen atom to which they are attached form a 4-7 membered heterocyclic ring; preferably, R 4 and R 5 are both H.
  • the compound has the structure of formula II, wherein X 1 is selected from C (R 7 ) 2 , NR 7 , O and S; preferably, X 1 is selected from O and NR 7 , more Preferably, X 1 is selected from O, NH and N (CH 3 ).
  • the compound has the structure of formula II, wherein V is absent or selected from C 1-8 alkylene, C (R 36a R 36b ), O, S, NR 33 , SO , SO 2 and CO, the C 1-8 alkylene is optionally substituted with one or more of the following substituents: halogen, OH, CN, NO 2 , C 1-6 alkyl, C 1-4 Haloalkyl, C 1-4 hydroxyalkyl, and C 1-4 alkoxy; preferably, V is absent or selected from CO and C 1-8 alkylene (eg, methylene).
  • V is absent or selected from C 1-8 alkylene, C (R 36a R 36b ), O, S, NR 33 , SO , SO 2 and CO
  • the C 1-8 alkylene is optionally substituted with one or more of the following substituents: halogen, OH, CN, NO 2 , C 1-6 alkyl, C 1-4 Haloalkyl, C 1-4 hydroxyalkyl, and C
  • the compound has the structure of formula II, wherein V and X 1 are not heteroatoms N, O or S, that is, when X 1 is NR 7 , O or S, V is not O , S, NR 33 , SO or SO 2 .
  • the compound has the structure of formula II, wherein L is absent, or is selected from propylene, methylene, ethylene, O, S, NR 33 , -C 1-3 Alkylene-O-, -C 1-3 alkylene-S- and -C 1-3 alkylene-NR 33- , wherein R 33 is selected from H and methyl; preferably, L is not present, or is selected from propylene, ethylene, O, S, NR 33, -C 1-3 alkylene -O -, - C 1-3 alkylene group -S- and -C 1-3 alkylene - NR 33- , wherein R 33 is selected from H and methyl; more preferably, L is absent, or selected from propylene, ethylene, -C 1-3 alkylene-O- (eg -ethylene -O- or -propylene-O-) and -C 1-3 alkylene-NH- (for example -ethylene-NH-).
  • L is absent, or is selected from prop
  • the compound has the structure of formula II, wherein n, p, and q are each independently 0.
  • the compound has the structure of formula II, wherein n, p, and q are each independently 1.
  • the compound has the structure of formula II, wherein:
  • R 1 is selected from C 1-4 alkyl, C 6-12 aryl (eg phenyl) and 5-10 membered heteroaryl (eg pyridyl or pyrazinyl), said C 1-4 alkyl, C 6-12 aryl groups and 5-10 membered heteroaryl groups are each optionally substituted with one or more of the following substituents: halogen, CN, NO 2 , C 1-4 alkyl, C 3-8 cycloalkyl , C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy, C 1-4 hydroxyalkyl, 4-10 membered heterocyclic group, C 6-12 aryl, 5-10 Heteroaryl, 9-12 membered arylheterocyclyl, CO 2 R 30 , C (O) R 30 , C (O) NR 31 R 32 , NR 33 C (O) R 34 , NR 31 R 32 , OC (O) R 30 , OC (
  • R 2 is selected from H and methyl
  • R 3 is selected from OH, C 1-8 alkyl, 4-10 membered heterocyclic group, C 6-12 aryl group, NR 31 R 32 , NR 33 C (O) R 34 , NR 33 S (O) 2 R 34 , C (O) NR 31 R 32 , 9-12 membered arylheterocyclic group, 5-10 membered heteroaryl group and NR 33 C (O) NR 31 R 32 , the C 1-8 alkyl group,
  • the 4-10 membered heterocyclic group, C 6-12 aryl group, 5-10 membered heteroaryl group and 9-12 membered arylheterocyclic group are each optionally substituted with one or more of the following substituents: 1-4 alkyl, C 1-4 alkoxy, C 6-12 aryl, C (O) R 30 , C (O) NR 31 R 32 , NR 33 C (O) R 34 , NR 31 R 32 , S (O) 2 R 35 and OR 37 ;
  • R 4 and R 5 are each independently selected from H, C 1-8 alkyl, C 3-8 cycloalkyl and C 1-8 alkoxy, the C 1-8 alkyl, C 1-8 alkoxy
  • the group and the C 3-8 cycloalkyl are each optionally substituted with one or more of the following substituents: halogen, OH, CN, NO 2 , C 1-6 alkyl, C 1-4 haloalkyl, and C 1 -4 hydroxyalkyl; or R 4 and R 5 together with the nitrogen atom to which they are attached form a 4-7 membered heterocyclic ring;
  • X 1 is selected from C (R 7 ) 2 , NR 7 , O and S;
  • V is absent or selected from C 1-8 alkylene, C (R 36a R 36b ), O, S, NR 33 , SO, SO 2 and CO, the C 1-8 alkylene is optionally substituted Substitution of one or more of the following substituents: halogen, OH, CN, NO 2 , C 1-6 alkyl, C 1-4 haloalkyl, C 1-4 hydroxyalkyl, and C 1-4 alkoxy;
  • V and X 1 are not heteroatoms N, O or S;
  • L is-(L 1 ) n- (L 2 ) p- (L 3 ) q- , where L 1 , L 2 and L 3 are the same or different, and are each independently selected from C 1-8 alkylene (eg C 1-3 alkylene), C 2-8 alkenylene, C 2-8 alkynylene, C 1-8 haloalkylene, C 1-8 alkyleneoxy, C 1-8 halo Alkyleneoxy, C 1-8 hydroxyalkylene, C 3-8 cycloalkylene, 4-10 membered heterocyclylene, C 6-12 arylene, 5-10 membered heteroarylene, O , S, NR 33 , SO, SO 2 , -CO- and -C (R 36a R 36b )-, the C 1-8 alkylene, C 2-8 alkenylene, C 2-8 alkynylene , C 1-8 haloalkylene, C 1-8 alkyleneoxy, C 1-8 haloalkyleneoxy, C 1-8 hydroxyal
  • n, p, and q are each independently 0 or 1.
  • the compound has the structure of formula II, wherein:
  • R 1 is selected from isobutyl
  • R 2 is selected from H and methyl
  • R 3 is selected from OH, -NHC (O) CH 3 , -C (O) NH 2 , -N (CH 2 CH 3 ) C (O) N (CH 3 ) 2 ,
  • R 4 and R 5 are both H
  • X 1 is selected from O, NH and N (CH 3 );
  • V does not exist, or is selected from CO and methylene
  • L is absent, or is selected from propylene, methylene group, ethylene group, O, S, NR 33, -C 1-3 alkylene -O -, - C 1-3 alkylene group and -S- -C 1-3 alkylene-NR 33- , wherein R 33 is selected from H and methyl; preferably, L is absent, or selected from propylene, ethylene, O, S, NR 33 , -C 1-3 alkylene-O-, -C 1-3 alkylene-S- and -C 1-3 alkylene-NR 33- , wherein R 33 is selected from H and methyl; more preferably, L Not present, or selected from propylene, ethylene, -C 1-3 alkylene-O- (eg -ethylene-O- or -propylene-O-) and -C 1-3 propylene Alkyl-NH- (eg -ethylene-NH-).
  • the compound has the structure of Formula II-A:
  • R 1 , R 2 , R 3 and L are as defined above in Formula II.
  • the compound has the structure of Formula II-A, wherein:
  • R 1 is selected from isobutyl
  • R 2 is selected from H and methyl
  • R 3 is selected from OH, -NHC (O) CH 3 , C (O) NH 2 , -N (CH 2 CH 3 ) C (O) N (CH 3 ) 2 ,
  • L is absent, or is selected from propylene, methylene group, ethylene group, O, S, NR 33, -C 1-3 alkylene -O -, - C 1-3 alkylene group and -S- -C 1-3 alkylene-NR 33- , wherein R 33 is selected from H and methyl; preferably, L is absent, or selected from propylene, ethylene, O, S, NR 33 , -C 1-3 alkylene-O-, -C 1-3 alkylene-S- and -C 1-3 alkylene-NR 33- , wherein R 33 is selected from H and methyl; more preferably, L Not present, or selected from propylene, ethylene, -C 1-3 alkylene-O- (eg -ethylene-O- or -propylene-O-) and -C 1-3 propylene Alkyl-NH- (eg -ethylene-NH-).
  • the compound has the structure of Formula III:
  • R 1 , R 2 , R 3 , R 4 , R 5 , X 1 , V and L are as defined in formula I above.
  • the compound has the structure of formula III, wherein:
  • R 1 is selected from isobutyl, C 6-12 aryl (eg phenyl) and 5-10 membered heteroaryl (eg pyridyl or pyrazinyl), said C 6-12 aryl and 5-10 membered
  • the heteroaryl groups are each optionally substituted with one or more of the following substituents: halogen, CN, NO 2 , C 1-4 alkyl, C 3-8 cycloalkyl, C 1-4 haloalkyl, C 1 -4 alkoxy, C 1-4 haloalkoxy, C 1-4 hydroxyalkyl, 4-10 membered heterocyclic group, C 6-12 aryl group, 5-10 membered heteroaryl group, 9-12 membered aryl group Heterocyclyl, CO 2 R 30 , C (O) R 30 , C (O) NR 31 R 32 , NR 33 C (O) R 34 , NR 31 R 32 , OC (O) R 30 , OC ( O)
  • R 2 is selected from H and methyl
  • R 3 is selected from OH, C 1-8 alkyl, 4-10 membered heterocyclic group, C 6-12 aryl group, NR 31 R 32 , NR 33 C (O) R 34 , NR 33 S (O) 2 R 34 , C (O) NR 31 R 32 , 9-12 membered arylheterocyclic group, 5-10 membered heteroaryl group and NR 33 C (O) NR 31 R 32 , the C 1-8 alkyl group,
  • the 4-10 membered heterocyclic group, C 6-12 aryl group, 5-10 membered heteroaryl group and 9-12 membered arylheterocyclic group are each optionally substituted with one or more of the following substituents: C 1-4 alkyl, C 1-4 alkoxy, C 6-12 aryl, C (O) R 30 , C (O) NR 31 R 32 , NR 33 C (O) R 34 , NR 31 R 32 , S (O) 2 R 35 and OR 37 ;
  • R 4 and R 5 are each independently selected from H, C 1-8 alkyl, C 3-8 cycloalkyl and C 1-8 alkoxy, the C 1-8 alkyl, C 3-8 cycloalkane
  • the group and C 1-8 alkoxy are each optionally substituted with one or more of the following substituents: halogen, OH, CN, NO 2 , C 1-6 alkyl, C 1-4 haloalkyl, and C 1 -4 hydroxyalkyl; or R 4 and R 5 together with the nitrogen atom to which they are attached form a 4-7 membered heterocyclic ring;
  • X 1 is selected from C (R 7 ) 2 , NR 7 , O and S;
  • V is absent or selected from C 1-8 alkylene, C (R 36a R 36b ), O, S, NR 33 , SO, SO 2 and CO, the C 1-8 alkylene is optionally substituted Substitution of one or more of the following substituents: halogen, OH, CN, NO 2 , C 1-6 alkyl, C 1-4 haloalkyl, C 1-4 hydroxyalkyl, and C 1-4 alkoxy;
  • V and X 1 are not heteroatoms N, O or S;
  • L is-(L 1 ) n- (L 2 ) p- (L 3 ) q- , where L 1 , L 2 and L 3 are the same or different, and are each independently selected from C 1-8 alkylene (eg C 1-3 alkylene), C 2-8 alkenylene, C 2-8 alkynylene, C 1-8 haloalkylene, C 1-8 alkyleneoxy, C 1-8 halo Alkyleneoxy, C 1-8 hydroxyalkylene, C 3-8 cycloalkylene, 4-10 membered heterocyclylene, C 6-12 arylene, 5-10 membered heteroarylene, O , S, NR 33 , SO, SO 2 , -CO- and -C (R 36a R 36b )-, the C 1-8 alkylene, C 2-8 alkenylene, C 2-8 alkynylene , C 1-8 haloalkylene, C 1-8 alkyleneoxy, C 1-8 haloalkyleneoxy, C 1-8 hydroxyal
  • n, p, and q are each independently 0 or 1.
  • the compound has the structure of formula III, wherein:
  • R 1 is selected from isobutyl
  • R 2 is selected from H and methyl
  • R 3 is selected from OH, -NHC (O) CH 3 , -C (O) NH 2 , -N (CH 2 CH 3 ) C (O) N (CH 3 ) 2 ,
  • R 4 and R 5 are both H
  • X 1 is selected from O, NH and N (CH 3 );
  • V does not exist, or is selected from CO and methylene
  • L is absent, or is selected from propylene, methylene group, ethylene group, O, S, NR 33, -C 1-3 alkylene -O -, - C 1-3 alkylene group and -S- -C 1-3 alkylene-NR 33- , wherein R 33 is selected from H and methyl; preferably, L is absent, or selected from propylene, ethylene, O, S, NR 33 , -C 1-3 alkylene-O-, -C 1-3 alkylene-S- and -C 1-3 alkylene-NR 33- , wherein R 33 is selected from H and methyl; more preferably, L Not present, or selected from propylene, ethylene, -C 1-3 alkylene-O- (eg -ethylene-O- or -propylene-O-) and -C 1-3 propylene Alkyl-NH- (eg -ethylene-NH-).
  • the compound has the structure of Formula IV:
  • R 1 , R 3 , R 4 , R 5 , X 1 , V and L are as defined in formula I above.
  • the compound has the structure of formula IV, wherein:
  • R 1 is selected from C 1-4 alkyl, C 6-12 aryl (eg phenyl) and 5-10 membered heteroaryl (eg pyridyl or pyrazinyl), said C 1-4 alkyl, C 6-12 aryl groups and 5-10 membered heteroaryl groups are each optionally substituted with one or more of the following substituents: halogen, CN, NO 2 , C 1-4 alkyl, C 3-8 cycloalkyl , C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy, C 1-4 hydroxyalkyl, 4-10 membered heterocyclic group, C 6-12 aryl, 5-10 Heteroaryl, 9-12 membered arylheterocyclyl, CO 2 R 30 , C (O) R 30 , C (O) NR 31 R 32 , NR 33 C (O) R 34 , NR 31 R 32 , OC (O) R 30 , OC (
  • R 3 is selected from OH, C 1-8 alkyl, 4-10 membered heterocyclic group, C 6-12 aryl group, NR 31 R 32 , NR 33 C (O) R 34 , NR 33 S (O) 2 R 34 , C (O) NR 31 R 32 , 9-12 membered arylheterocyclic group, 5-10 membered heteroaryl group and NR 33 C (O) NR 31 R 32 , the C 1-8 alkyl group,
  • the 4-10 membered heterocyclic group, C 6-12 aryl group, 5-10 membered heteroaryl group and 9-12 membered arylheterocyclic group are each optionally substituted with one or more of the following substituents: C 1-4 alkyl, C 1-4 alkoxy, C 6-12 aryl, C (O) R 30 , C (O) NR 31 R 32 , NR 33 C (O) R 34 , NR 31 R 32 , S (O) 2 R 35 and OR 37 ;
  • R 4 and R 5 are each independently selected from H, C 1-8 alkyl, C 1-8 alkoxy, and C 3-8 cycloalkyl, the C 1-8 alkyl, C 1-8 alkoxy
  • the group and the C 3-8 cycloalkyl are each optionally substituted with one or more of the following substituents: halogen, OH, CN, NO 2 , C 1-6 alkyl, C 1-4 haloalkyl, and C 1 -4 hydroxyalkyl; or R 4 and R 5 together with the nitrogen atom to which they are attached form a 4-7 membered heterocyclic ring;
  • X 1 is selected from C (R 7 ) 2 , NR 7 , O and S;
  • V is absent or selected from C 1-8 alkylene, C (R 36a R 36b ), O, S, NR 33 , SO, SO 2 and CO, the C 1-8 alkylene is optionally substituted Substitution of one or more of the following substituents: halogen, OH, CN, NO 2 , C 1-6 alkyl, C 1-4 haloalkyl, C 1-4 hydroxyalkyl, and C 1-4 alkoxy;
  • V and X 1 are not heteroatoms N, O or S;
  • L is-(L 1 ) n- (L 2 ) p- (L 3 ) q- , where L 1 , L 2 and L 3 are the same or different, and are each independently selected from C 1-8 alkylene (eg C 1-3 alkylene), C 2-8 alkenylene, C 2-8 alkynylene, C 1-8 haloalkylene, C 1-8 alkyleneoxy, C 1-8 halo Alkyleneoxy, C 1-8 hydroxyalkylene, C 3-8 cycloalkylene, 4-10 membered heterocyclylene, C 6-12 arylene, 5-10 membered heteroarylene, O , S, NR 33 , SO, SO 2 , -CO- and -C (R 36a R 36b )-, the C 1-8 alkylene, C 2-8 alkenylene, C 2-8 alkynylene , C 1-8 haloalkylene, C 1-8 alkyleneoxy, C 1-8 haloalkyleneoxy, C 1-8 hydroxyal
  • n, p, and q are each independently 0 or 1.
  • the compound has the structure of formula IV, wherein:
  • R 1 is selected from isobutyl
  • R 3 is selected from OH, -NHC (O) CH 3 , -C (O) NH 2 , -N (CH 2 CH 3 ) C (O) N (CH 3 ) 2 ,
  • R 4 and R 5 are both H
  • X 1 is selected from O, NH and N (CH 3 );
  • V does not exist, or is selected from CO and methylene
  • L does not exist, or is selected from propylene, ethylene, -C 1-3 alkylene-O- (for example -ethylene-O- or -propylene-O-) and -C 1-3 Alkylene-NH- (eg -ethylene-NH-).
  • the compounds of the invention are selected from, but not limited to:
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound as described above, a stereoisomer, tautomer or mixture of the compound, a pharmaceutically acceptable salt of the compound , Co-crystals, polymorphs or solvates, or stable isotope derivatives, metabolites or prodrugs of the compounds.
  • the pharmaceutical composition further comprises one or more pharmaceutically acceptable carriers.
  • the pharmaceutical composition is used to prevent and / or treat diseases associated with NLRP3 inflammatory body activity (eg, tumor diseases).
  • diseases associated with NLRP3 inflammatory body activity eg, tumor diseases.
  • the pharmaceutical composition of the present invention further comprises one or more second therapeutic agents.
  • the second therapeutic agent includes other drugs for treating tumor diseases and the like.
  • the present invention provides a pharmaceutical formulation comprising a compound as described above, a stereoisomer, tautomer or mixture of the compound, a pharmaceutically acceptable salt of the compound, A eutectic, polymorph or solvate, or a stable isotopic derivative, metabolite or prodrug of the compound, or a pharmaceutical composition as described above.
  • the invention provides compounds as described above, stereoisomers, tautomers or mixtures of the compounds, pharmaceutically acceptable salts, co-crystals, polymorphs of the compounds Or a solvate, or a stable isotope derivative, metabolite, or prodrug of the compound, or the use of a pharmaceutical composition as described above for the preparation of a medicament for the prevention and / or treatment of small inflammation associated with NLRP3 Diseases related to body activity (eg, tumor diseases).
  • NLRP3 Diseases related to body activity eg, tumor diseases.
  • the invention provides compounds as described above, stereoisomers, tautomers or mixtures of the compounds, pharmaceutically acceptable salts, co-crystals, polymorphs of the compounds Or a solvate, or a stable isotope derivative, metabolite, or prodrug of the compound, or the use of a pharmaceutical composition as described above for the preparation of a formulation for regulating (eg, increasing) NLRP3 inflammatory bodies Of activity.
  • the formulation is administered to a subject (e.g., a mammal; for example, bovine, equine, ovine, porcine, canine, feline, rodent, psychic) Long animal; for example, human) in vivo to increase the activity of NLRP3 inflammatory bodies in cells in the subject; or, the formulation is administered to cells in vitro (eg, cell lines or cells from the subject) to increase The activity of NLRP3 inflammatory bodies in cells.
  • a subject e.g., a mammal; for example, bovine, equine, ovine, porcine, canine, feline, rodent, psychic
  • Long animal for example, human
  • the formulation is administered to cells in vitro (eg, cell lines or cells from the subject) to increase The activity of NLRP3 inflammatory bodies in cells.
  • the present invention provides a method of modulating (eg, increasing) the activity of NLRP3 inflammatory bodies in cells, which comprises administering to the cells an effective amount of a compound as described above, a stereoisomer of the compound, Tautomers or mixtures thereof, pharmaceutically acceptable salts, co-crystals, polymorphs or solvates of the compound, or stable isotope derivatives, metabolites or prodrugs of the compound, or as above.
  • a method of modulating eg, increasing) the activity of NLRP3 inflammatory bodies in cells, which comprises administering to the cells an effective amount of a compound as described above, a stereoisomer of the compound, Tautomers or mixtures thereof, pharmaceutically acceptable salts, co-crystals, polymorphs or solvates of the compound, or stable isotope derivatives, metabolites or prodrugs of the compound, or as above
  • a pharmaceutical composition, or the pharmaceutical preparation as described above as described above.
  • the present invention provides a kit for modulating (eg, increasing) the activity of NLRP3 inflammatory bodies, the kit comprising a compound as described above, the stereoisomers, intermutations of the compound Structure or mixtures thereof, pharmaceutically acceptable salts, co-crystals, polymorphs or solvates of the compound, or stable isotope derivatives, metabolites or prodrugs of the compound, or as described above Pharmaceutical composition, or formulation as described above.
  • the present invention provides a method of treating a disease associated with NLRP3 inflammatory body activity (eg, tumor disease), which comprises administering to a subject in need thereof a therapeutically and / or prophylactically effective amount of a compound as described above, Stereoisomers, tautomers or mixtures of the compounds, pharmaceutically acceptable salts, co-crystals, polymorphs or solvates of the compounds, or stable isotope derivatives of the compounds , Metabolites or prodrugs, or a pharmaceutical composition as described above, or a formulation as described above.
  • a disease associated with NLRP3 inflammatory body activity eg, tumor disease
  • the method further includes administering one or more second therapeutic agents to the subject in need.
  • the second therapeutic agent includes other drugs for treating diseases such as tumors.
  • the invention provides compounds as described above, stereoisomers, tautomers or mixtures of the compounds, pharmaceutically acceptable salts, co-crystals, polymorphs of the compounds Or a solvate, or a stable isotope derivative, metabolite, or prodrug of the compound, the pharmaceutical composition, pharmaceutical preparation, or kit for preventing and / or treating diseases related to NLRP3 inflammatory body activity (E.g. tumor disease).
  • diseases related to NLRP3 inflammatory body activity E.g. tumor disease.
  • the tumor diseases include but are not limited to: brain tumor, lung cancer, squamous cell carcinoma, bladder cancer, gastric cancer, ovarian cancer, peritoneal cancer, pancreatic cancer, breast cancer, head and neck cancer, cervical cancer, intrauterine Membrane cancer, rectal cancer, liver cancer, kidney cancer, esophageal adenocarcinoma, esophageal squamous cell carcinoma, prostate cancer, female reproductive tract cancer, carcinoma in situ, lymphoma, neurofibroma, thyroid cancer, bone cancer, skin cancer, brain Cancer, colon cancer, testicular cancer, gastrointestinal stromal tumor, prostate tumor, mast cell tumor, multiple myeloma, melanoma, glioma, or sarcoma.
  • the compounds of the invention are full agonists; in some embodiments, the compounds of the invention are partial agonists.
  • agonist refers to a compound that binds to a receptor and activates it to elicit a downstream biological effect or response, including full agonist and partial agonist.
  • Full agonists can activate the receptor and produce the maximum effect (maximal effect or E max ).
  • Partial agonists can bind to and activate receptors, but compared to full agonists, only partial effects are produced. When full agonists and partial agonists coexist, partial agonists can sometimes become partial antagonists by competing with full agonists for binding sites on receptors or other mechanisms. Potency (concentration of the compound potency, by the EC 50 (producing 50% of the E max) measured) is a partial agonists may be higher or lower than in a full agonist efficacy.
  • the NLRP3 agonists of the present invention include NLRP3 full agonists and NLRP3 partial agonists.
  • NLRP3 NLR family pyrin domain containing 3, which is an inflammatory body.
  • the meanings included include nucleic acid, polynucleotide, oligonucleotide, sense and antisense polynucleotide chains, complementary sequences, short peptides, polypeptides of NLRP3 , Proteins, homologous or heterologous molecules, subtypes, precursors, mutants, variants, derivatives, various spliceosomes, alleles, different species and activated fragments, etc.
  • halo refers to being replaced by a halogen atom, and the "halogen” includes F, Cl, Br or I.
  • alkyl is a linear or branched saturated aliphatic hydrocarbon group.
  • C 1-8 alkyl refers to having 1 to 8 carbon atoms, 1 to 6 carbon atoms and 1 to 4 carbon atoms, respectively Straight or branched chain alkyl groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl or n-hexyl.
  • the alkyl group may be optionally substituted with one or more (such as 1 to 3) the same or different substituents.
  • alkylene refers to a saturated divalent hydrocarbon group obtained by removing two hydrogen atoms from a linear or branched saturated hydrocarbon group, which contains the specified number of carbon atoms.
  • alkylene having 1 to 8 carbon atoms such as methylene (-CH 2- ), ethylene (-CH 2 CH 2- ), propylene (-CH 2 CH 2 CH 2- ), methylene Isopropyl (-CH (CH 3 ) CH 2- ) and so on.
  • the alkylene group may be optionally substituted with one or more (such as 1 to 3) the same or different substituents.
  • haloalkyl refers to an alkyl group substituted with one or more (such as 1 to 3) the same or different halogen atoms
  • C 1-8 haloalkyl refers to haloalkyl groups having 1 to 8 carbon atoms, 1 to 6 carbon atoms, and 1 to 4 carbon atoms, such as -CF 3 , -C 2 F 5 , -CHF 2 ,- CH 2 F, -CH 2 CF 3 , -CH 2 Cl, -CH 2 CH 2 CF 3, etc.
  • hydroxyalkyl refers to a group formed by substitution of a hydrogen atom of an alkyl group with one or more hydroxyl groups, such as C 1-4 hydroxyalkyl or C 1-3 hydroxyalkyl, examples of which include but are not limited to hydroxy Methyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, -CH (OH) CH 3 and so on.
  • the alkenyl group may be optionally substituted with one or more (such as 1 to 3) the same or different substituents.
  • the alkenylene group may be optionally substituted with one or more (such as 1 to 3) the same or different substituents.
  • alkynyl refers to a monovalent linear or branched hydrocarbon group having one or more carbon-carbon triple bonds, including but not limited to ethynyl, 2-propynyl, 2-butynyl, 1,3-butane Diynyl and so on.
  • the alkynyl group may be optionally substituted with one or more (such as 1 to 3) the same or different substituents.
  • alkynylene refers to a divalent linear or branched hydrocarbon group having one or more carbon-carbon triple bonds, which contains the specified number of carbon atoms, such as 2 to 8 carbon atoms, including but not limited to Wait.
  • the alkynylene group may be optionally substituted with one or more (such as 1 to 3) the same or different substituents.
  • alkoxy means a group in which an oxygen atom is inserted at any reasonable position of an alkyl group (as defined above), preferably C 1-8 alkoxy, C 1-6 alkoxy, C 1-4 Alkoxy or C 1-3 alkoxy.
  • Representative examples of C 1-6 alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy Group, tert-butoxy, pentyloxy, hexyloxy, -CH 2 -OCH 3 and the like.
  • the alkoxy group may be optionally substituted with one or more (such as 1 to 3) the same or different substituents.
  • alkyleneoxy refers to a divalent alkoxy group, such as -OCH 2- , -OCH (CH 3 ) CH 2- , -OCH 2 CH 2 O-, -CH 2 CH 2 O-, and the like.
  • the alkyleneoxy group may be optionally substituted with one or more (such as 1 to 3) the same or different substituents.
  • parallel ring or “fused ring” refers to a ring system formed by two or more ring structures sharing two adjacent atoms with each other.
  • spiro ring refers to a ring system formed by two or more ring structures sharing one ring atom with each other.
  • bridge ring refers to a ring system formed by two or more ring structures sharing two atoms that are not directly connected to each other.
  • cycloalkyl refers to saturated or unsaturated non-aromatic monocyclic or polycyclic (such as bicyclic) hydrocarbon ring groups, including but not limited to monocyclic alkyl groups (such as cyclopropyl, cyclobutyl, cyclopentyl, (Cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl) and bicycloalkyl, including spiro ring, paracyclic (fused ring) or bridged ring systems (ie, spirocycloalkyl, paracyclic (fused ring) alkyl And bridged cycloalkyl groups, such as bicyclo [1.1.1] pentyl, bicyclo [2.2.1] heptyl, etc.).
  • monocyclic alkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl, (Cyclohexyl, cycloheptyl
  • the cycloalkyl group may be optionally substituted with one or more (such as 1 to 3) the same or different substituents.
  • cycloalkylene refers to a cycloalkyl group as defined herein having two monovalent group centers obtained by removing two hydrogen atoms from the same carbon atom or two different carbon atoms of the parent cycloalkyl group.
  • Typical cycloalkylene groups include but are not limited to cyclopropylene, cyclobutylene, cyclopentylene, cyclohexylene, cycloheptylene, cyclooctylene, cyclononylene, cyclohexenylene, etc. .
  • 3-7 membered cycloalkyl refers to a cycloalkyl group having 3 to 7 ring-forming carbon atoms, which may be a monocyclic alkyl group, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cyclo Heptyl can also be a bicycloalkyl, such as C 5-7 spirocycloalkyl, C 5-7 bridge cycloalkyl or C 4-7 condensed cycloalkyl.
  • C 3-8 cycloalkyl refers to a cycloalkyl having 3 to 8 ring-forming carbon atoms, such as C 3-6 cycloalkyl, which may be a monocyclic alkyl, such as cyclopropyl, cyclobutyl , Cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl, can also be bicycloalkyl, such as C 3-8 spirocycloalkyl, C 3-8 bridge cycloalkyl, C 3-8 condensed cycloalkyl , C 3-6 spirocycloalkyl, C 3-6 bridge cycloalkyl or C 3-6 condensed cycloalkyl.
  • aryl refers to an all-carbon monocyclic or fused polycyclic aromatic group having a conjugated pi electron system.
  • C 6-12 aryl means an aryl group containing 6 to 12 carbon atoms, preferably C 6-10 aryl, preferably phenyl or naphthyl.
  • the aryl group is optionally substituted with one or more (such as 1 to 3) the same or different substituents (for example, halogen, OH, CN, NO 2 , C 1-6 alkyl, etc.).
  • arylene refers to an aryl group as defined herein having two monovalent group centers obtained by removing two hydrogen atoms from the same carbon atom or two different carbon atoms of the parent aryl group.
  • Typical arylene groups include but are not limited to phenylene and naphthylene.
  • arylcyclocycloalkyl refers to a paracyclic group formed by an aryl group and a cycloalkyl group (such as a monocyclic alkyl group) sharing two adjacent atoms with each other, where the point of attachment to other groups may be Radical or cycloalkyl.
  • arylcyclocycloalkyl refers to an arylcyclocycloalkyl group containing 9-12 ring atoms in total, such as benzocyclopentyl, benzocyclohexyl, for example
  • heterocyclic group refers to a heterocyclic group as defined herein having the same carbon atom or two different carbon atoms from the parent heterocyclic group, removed from one carbon atom and one heteroatom, or removed from two heteroatoms Two monovalent group centers resulting from two hydrogen atoms.
  • 3-14 membered heterocyclic group means a heterocyclic group containing 3-14 ring atoms, including but not limited to 4-10 membered heterocyclic group, 4-8 membered heterocyclic group, 4-7 membered heterocyclic group Group, 5-6 membered heterocyclic group, 3-8 membered heterocyclic group, 3-7 membered heterocyclic group, 4-7 membered nitrogen-containing heterocyclic group, 4-7 membered oxygen-containing heterocyclic group, 4-7 membered Sulfur-containing heterocyclic group, 5-6 membered nitrogen-containing heterocyclic group, 5-6 membered oxygen-containing heterocyclic group, 5-6 membered sulfur-containing heterocyclic group, etc.
  • nitrogen-containing heterocyclic group "oxygen-containing The "heterocyclic group” and “sulfur-containing heterocyclic group” each optionally further contain one or more other heteroatoms selected from oxygen, nitrogen, and sulfur.
  • 3-14 membered heterocyclic groups include, but are not limited to, ethylene oxide, aziridine, azetidinyl, oxetanyl, tetrahydrofuranyl, pyrrolidinyl, pyrrolidinyl, imidazolidinyl, Pyrazolidinyl, tetrahydropyranyl, piperidinyl, morpholinyl, dithianyl, dithianyl, thiomorpholinyl, piperazinyl, trithianyl, Wait.
  • the heterocyclic group further includes a fused ring structure, and the connection point between the fused ring structure and other groups may be on any ring in the fused ring structure. Therefore, the heterocyclic group of the present invention also includes (but is not limited to) heterocyclic heterocycloheterocyclic group, heterocyclic heterocyclocycloalkyl group, monoheterocyclic heterocycloheterocyclic group, monoheterocyclic heteromonomonocycloalkyl group , For example, 3-7 membered (mono) heterocyclic 3-7 membered (mono) heterocyclic, 3-7 membered (mono) heterocyclic (mono) cycloalkyl, 3-7 membered (mono) hetero Cyclo-C 4-6 (mono) cycloalkyl and the like, examples of which include but are not limited to pyrrolidinocyclopropyl, cyclopentylazaazacyclopropyl, pyrrolidinocyclobuty
  • the heterocyclic group also includes a bridged heterocyclic group and a spiro heterocyclic group.
  • bridged heterocyclic group refers to two saturated rings that share two or less directly connected ring atoms and contain one or more (eg 1, 2, 3 or 4) heteroatoms (eg oxygen atoms, Nitrogen atom or sulfur atom) ring structure, including but not limited to 7-10 member bridge heterocyclic group, 8-10 member bridge heterocyclic group, 7-10 member nitrogen bridge heterocyclic group, 7-10 member oxygen containing Bridged heterocyclic groups, 7-10 membered sulfur-containing bridged heterocyclic groups, etc., for example Wait.
  • the "nitrogen-containing bridge heterocycle”, “oxygen-containing bridge heterocycle”, and “sulfur-containing bridge heterocycle” each optionally further contain one or more other heteroatoms selected from oxygen, nitrogen, and sulfur.
  • spiroheterocyclyl refers to one or more (eg 1, 2, 3 or 4) heteroatoms (eg oxygen atoms, formed by two or more saturated rings sharing a ring atom) Nitrogen atom or sulfur atom), including but not limited to 5-10 membered spiro heterocyclic group, 6-10 membered spiro heterocyclic group, 6-10 membered spiro heterocyclic group containing nitrogen, 6-10 member containing oxygen Spiroheterocyclyl, 6-10 membered sulfur-containing spiroheterocycle, etc., for example Wait.
  • heteroatoms eg oxygen atoms, formed by two or more saturated rings sharing a ring atom
  • Nitrogen atom or sulfur atom including but not limited to 5-10 membered spiro heterocyclic group, 6-10 membered spiro heterocyclic group, 6-10 membered spiro heterocyclic group containing nitrogen, 6-10 member containing oxygen Spiroheterocyclyl, 6
  • nitrogen-containing spiro heterocycle each optionally further contain one or more other heteroatoms selected from oxygen, nitrogen, and sulfur.
  • oxygen-containing spiro heterocycle refers to a spiro heterocyclic group containing a total of 6-10 ring atoms and at least one of which is a nitrogen atom.
  • arylheterocyclic group refers to a cyclic group formed by an aryl group and a heterocyclic group sharing two adjacent carbon atoms with each other (where the aryl group and the heterocyclic group are as defined above), which is different from other groups
  • the point of attachment of the group may be on an aryl or heterocyclic group.
  • 9-12 membered arylheterocyclic group means a group containing a total of 9-12 ring atoms of arylheterocyclic groups, including but not limited to 9-10 membered Benzoheterocyclic groups, such as benzo 5-8 membered heterocyclic groups, such as benzo 5-6 membered heterocyclic groups, such as benzo 5-6 membered heterocyclic groups, benzo 5-6 membered nitrogen-containing monoheterocyclic groups Cyclic group, benzo 5-6 membered oxygen-containing monoheterocyclic group, benzo 5-6 membered sulfur-containing heterocyclic group, etc.
  • Benzoheterocyclic groups such as benzo 5-8 membered heterocyclic groups, such as benzo 5-6 membered heterocyclic groups, such as benzo 5-6 membered heterocyclic groups, benzo 5-6 membered nitrogen-containing monoheterocyclic groups Cyclic group, benzo 5-6 membered oxygen-containing monoheterocyclic group,
  • nitrogen-containing heterocyclic group each optionally further contain one or more other heteroatoms selected from oxygen, nitrogen and sulfur.
  • arylheterocyclic groups include, but are not limited to: indazolyl,
  • heteroaryl refers to a monocyclic or polycyclic aromatic group containing one or more heteroatoms which are the same or different, including monocyclic heteroaryl and at least one heteroaromatic ring (aromatic containing at least one heteroatom) Ring system) bicyclic or polycyclic ring systems, which may have 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 ring atoms, for example 5, 6, 7, 8, 9 or 10 Ring atom.
  • the heteroatom may be oxygen, nitrogen or sulfur.
  • heteroarylene refers to a heteroaryl group as described above, which has two hydrogen atoms removed from the same carbon atom or two different carbon atoms of the parent heteroaryl group or one hydrogen atom removed from the carbon atom And the two monovalent group centers obtained by removing one hydrogen atom from the nitrogen atom.
  • 5-10 membered heteroaryl means a heteroaryl group containing 5 to 10 ring atoms, including 5-6 membered heteroaryl, 5-6 membered monoheteroaryl, 5-10 membered nitrogen-containing heteroaryl Group, 5-10 membered oxygen-containing heteroaryl, 5-10 membered sulfur-containing heteroaryl, 5-6 membered nitrogen-containing heteroaryl, 5-6 membered oxygen-containing heteroaryl, 5-6 membered sulfur-containing heteroaryl Group, 5-6 membered nitrogen-containing monoheteroaryl group, 5-6 membered oxygen-containing monoheteroaryl group, 5-6 membered sulfur-containing monoheteroaryl group, etc.
  • Examples of 5-10 membered heteroaryl groups include, but are not limited to, thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, triazolyl, tetrakisyl
  • heteroaryl encompasses a paracyclic structure, that is, a heteroaromatic ring (such as a monoheteroaryl group) can be combined with an aryl group (such as a monocyclic aryl group, such as phenyl), a heterocyclic group (such as a single heterocyclic Group), cycloalkyl group (such as monocyclic alkyl group) or another heteroaromatic ring (such as another monoheteroaryl group) sharing two adjacent atoms with each other to form a ring structure, and its connection point May be on any heteroaryl ring or other rings, including but not limited to (mono) heteroaryl and (mono) heteroaryl, (mono) heteroaryl and (monocyclic) aryl, (mono) heteroaryl (Mono) heterocyclic or (mono) heteroaryl and (mono) cycloalkyl, such as 5-6 membered (mono) heteroaryl and 5
  • heteroaryl is also referred to as "arylheteroaryl", which is an aryl group (such as a monocyclic aryl group, such as phenyl) and a heteroaryl group (such as a monoheteroaryl group)
  • arylheteroaryl is an aryl group (such as a monocyclic aryl group, such as phenyl) and a heteroaryl group (such as a monoheteroaryl group)
  • An aryl group, such as a 5-6 membered monoheteroaryl group) formed a paracyclic group, and its connection point with other groups may be on the aromatic ring or on the heteroaromatic ring.
  • the "arylheteroaryl” includes, but is not limited to, monocyclic aryl and monoheteroaryl.
  • 9-12 membered arylheteroaryl refers to an arylheteroaryl group containing a total of 9-12 ring atoms, such as a benzo 5-6 membered nitrogen-containing monoheteroaryl group.
  • heteroaryl is also called “heteroarylcyclocycloalkyl” and is a heteroaryl group (such as a monoheteroaryl group, such as a 5-6 membered monoheteroaryl group) )
  • a cycloalkyl group formed with a cycloalkyl group may have a point of attachment to another group on a heteroaromatic ring or a cycloalkyl group.
  • the "heteroarylcyclocycloalkyl” includes but is not limited to monoheteroarylmonocycloalkyl.
  • 9-10 membered heteroarylcyclocycloalkyl refers to a heteroarylcycloalkyl group containing a total of 9-10 ring atoms, such as a 4-6 membered nitrogen-containing monoheteroaryl and C 4-6 mono Cycloalkyl.
  • substituted means that one or more (eg 1, 2, 3, or 4) hydrogens on the designated atom are replaced by the choice of the indicated group, provided that the designated atom is not exceeded Normal valence in the current situation and the substitution forms a stable compound. Combinations of substituents and / or variables are only allowed when such combinations form stable compounds.
  • substituent may be (1) unsubstituted or (2) substituted. If the carbon of the substituent is described as being optionally substituted by one or more of the list of substituents, then one or more hydrogens on the carbon (to the extent of any hydrogen present) can each be independently selected Substitution. If the nitrogen of the substituent is described as optionally substituted by one or more of the list of substituents, then one or more hydrogens on the nitrogen (to the extent of any hydrogen present) can each be independently selected Substitution.
  • each substituent is selected independently of the other. Therefore, each substituent may be the same as or different from another (other) substituent.
  • one or more means 1 or more than 1 under reasonable conditions, such as 2, 3, 4, 5, 6, 7, 8, 9, Or 10.
  • the point of attachment of a substituent can be from any suitable position of the substituent.
  • the present invention also includes all pharmaceutically acceptable isotope compounds of the compounds of the present invention, which are the same as the compounds of the present invention, except that one or more atoms have the same atomic number but the atomic mass or mass number is different from that prevailing in nature Atomic substitution of atomic mass or mass number.
  • isotopes suitable for inclusion in the compounds of the present invention include, but are not limited to, isotopes of hydrogen (eg, 2 H, 3 H); isotopes of carbon (eg, 11 C, 13 C, and 14 C); isotopes of chlorine (eg 36 Cl); fluorine isotopes (eg 18 F); iodine isotopes (eg 123 I and 125 I); nitrogen isotopes (eg 13 N and 15 N); oxygen isotopes (eg 15 O, 17 O and 18 O ); Phosphorus isotopes (such as 32 P); and sulfur isotopes (such as 35 S).
  • stable isotope derivative means that one or more atoms in the compound of the present invention are formed by replacing atoms having the same atomic number but atomic mass or mass number different from the atomic mass or mass number prevailing in nature Stable compound.
  • stereoisomer means an isomer formed by a compound because it contains at least one asymmetric center. In compounds with one or more (eg 1, 2, 3 or 4) asymmetric centers, it can produce racemic mixtures, single enantiomers, diastereomer mixtures and Individual diastereomers. Specific individual molecules may also exist as geometric isomers (cis / trans).
  • the compounds of the present invention may exist as a mixture of two or more different structural forms in rapid equilibrium (commonly referred to as tautomers). Representative examples of tautomers include keto-enol tautomers, phenol-ketone tautomers, nitroso-oxime tautomers, imine-enamine tautomers Wait. For example, nitroso-oxime can exist in equilibrium in the following tautomeric forms in solution:
  • the compounds of the present invention are intended to be stereoisomers (which include cis and trans isomers), optical isomers (such as R and S enantiomers), diastereomers , Geometric isomers, rotamers, conformers, atropisomers or their mixtures exist.
  • the compounds of the present invention can exhibit more than one type of isomerism and consist of mixtures thereof (e.g. racemic mixtures and diastereomeric pairs).
  • the present invention encompasses all possible crystalline forms or polymorphs of the compounds of the present invention, which may be a single polymorph or a mixture of more than one polymorph in any ratio. It should also be understood that certain compounds of the invention may exist in free form for therapy, or where appropriate, in the form of pharmaceutically acceptable derivatives.
  • pharmaceutically acceptable derivatives include but are not limited to: pharmaceutically acceptable salts, solvates, metabolites or prodrugs, which can be directly or indirectly after they are administered to patients in need thereof
  • the compound of the present invention or its metabolite or residue is provided. Therefore, when referring to the "compound of the present invention" herein, it is also intended to cover the above-mentioned various derivative forms of the compound.
  • the pharmaceutically acceptable salts of the compounds of the present invention include acid addition salts and base addition salts.
  • acid addition salts for example, hexafluorophosphate, meglumine salt, etc.
  • base addition salts for example, hexafluorophosphate, meglumine salt, etc.
  • “Pharmaceutically acceptable carrier” in the present invention refers to a diluent, adjuvant, excipient or vehicle administered together with a therapeutic agent, and it is suitable for contact with humans and / or within the scope of reasonable medical judgment The tissues of other animals without excessive toxicity, irritation, allergic reactions or other problems or complications corresponding to a reasonable benefit / risk ratio.
  • Pharmaceutically acceptable carriers that can be used in the pharmaceutical compositions of the present invention include, but are not limited to, sterile liquids, such as water and oils, including those of petroleum, animal, plant, or synthetic origin, such as peanut oil, soybean oil, minerals Oil, sesame oil, etc.
  • sterile liquids such as water and oils, including those of petroleum, animal, plant, or synthetic origin, such as peanut oil, soybean oil, minerals Oil, sesame oil, etc.
  • water is an exemplary carrier.
  • Physiological saline and aqueous solutions of glucose and glycerin can also be used as liquid carriers, especially for injections.
  • Suitable pharmaceutical excipients include starch, glucose, lactose, sucrose, gelatin, maltose, chalk, silica gel, sodium stearate, glyceryl monostearate, talc, sodium chloride, skimmed milk powder, glycerin, propylene glycol, water, Ethanol, etc.
  • the composition may also contain small amounts of wetting agents, emulsifying agents or pH buffering agents as needed.
  • Oral preparations may contain standard carriers such as pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharin, cellulose, magnesium carbonate, and the like. Examples of suitable pharmaceutically acceptable carriers are described in Remington's Pharmaceuticals (1990).
  • the pharmaceutical composition of the present invention can act systemically and / or locally.
  • they can be administered by suitable routes, for example by injection, intravenous, intraarterial, subcutaneous, intraperitoneal, intramuscular or transdermal administration; or by oral, buccal, nasal, transmucosal, topical, It is administered in the form of an ophthalmic preparation or by inhalation.
  • the pharmaceutical composition of the present invention can be administered in a suitable dosage form.
  • the dosage form includes but is not limited to tablets, capsules, lozenges, hard candy, powder, spray, cream, ointment, suppository, gel, paste, lotion, ointment, aqueous suspension , Injectable solutions, elixirs, syrups.
  • an effective dose refers to an amount of a compound that, after being administered, will alleviate to some extent one or more symptoms of the condition being treated.
  • the dosage regimen can be adjusted to provide the best desired response. For example, a single bolus injection can be administered, several divided doses can be administered over time, or the dosage can be reduced or increased proportionally as indicated by the urgent need for the treatment. It should be noted that the dose value may vary with the type and severity of the condition to be reduced, and may include single or multiple doses. It is to be further understood that for any particular individual, the specific dosing regimen should be adjusted over time based on the individual's needs and the professional judgment of the person administering the composition or supervising the administration of the composition.
  • the amount of the compound of the present invention administered will depend on the individual, the severity of the condition or condition being treated, the rate of administration, the treatment of the compound, and the judgment of the prescribing physician.
  • the effective dose is about 0.0001 to about 50 mg per kg of body weight per day, for example about 0.01 to about 10 mg / kg / day (single or divided doses). For a 70 kg person, this would add up to about 0.007 mg / day to about 3500 mg / day, such as about 0.7 mg / day to about 700 mg / day.
  • a dose level not higher than the lower limit of the foregoing range may be sufficient, while in other cases, a larger dose may still be used without causing any harmful side effects, provided that the larger The dose is divided into several smaller doses to be administered throughout the day.
  • the content or amount of the compound of the present invention in the pharmaceutical composition may be about 0.01 mg to about 1000 mg.
  • treating means reversing, alleviating, inhibiting a disorder or condition to which such terms apply, or the progression of one or more symptoms of such disorder or condition, Or prevent such a condition or condition, or one or more symptoms of such a condition or condition.
  • “Individual” as used herein includes human or non-human animals.
  • Exemplary human individuals include human individuals (referred to as patients) or normal individuals with a disease (such as the diseases described herein).
  • “Non-human animals” in the present invention include all vertebrates, such as non-mammals (eg birds, amphibians, reptiles) and mammals, such as non-human primates, domestic animals and / or domesticated animals (eg sheep, dogs , Cats, cows, pigs, etc.).
  • the compound of the present invention may exist in the form of a solvate (preferably a hydrate), wherein the compound of the present invention contains a polar solvent as a structural element of the crystal lattice of the compound, particularly, for example, water, methanol, or ethanol.
  • a polar solvent as a structural element of the crystal lattice of the compound, particularly, for example, water, methanol, or ethanol.
  • the amount of polar solvents, especially water can be present in stoichiometric or non-stoichiometric ratios.
  • metabolites of the compounds of the present invention that is, substances formed in the body when the compounds of the present invention are administered. Such products can be produced, for example, by oxidation, reduction, hydrolysis, amidation, deamidation, esterification, defatting, enzymatic hydrolysis, etc. of the administered compound. Therefore, the present invention includes metabolites of the compounds of the present invention, including compounds obtained by contacting the compounds of the present invention with mammals for a time sufficient to produce their metabolites.
  • the present invention further includes within its scope prodrugs of the compounds of the present invention, which are certain derivatives of the compounds of the present invention that may themselves have less or no pharmacological activity when administered into the body or
  • the above can be converted into the compound of the present invention having a desired activity by, for example, hydrolytic cleavage.
  • a prodrug will be a functional group derivative of the compound, which is easily converted into the desired therapeutically active compound in vivo.
  • prodrugs of the present invention can be used, for example, by those skilled in the art known as "pro-moiety” (such as “Design of Prodrugs", described in H. Bundgaard (Elsevier, 1985)) " They are prepared in place of the appropriate functional groups present in the compounds of the invention.
  • the present invention also encompasses compounds of the present invention containing protecting groups.
  • protecting groups In any process for preparing the compounds of the present invention, it may be necessary and / or desirable to protect sensitive or reactive groups on any relevant molecules, thereby forming a chemically protected form of the compounds of the present invention. This can be achieved with conventional protecting groups, such as those described in Protective Groups in Organic Chemistry, ed. JFW McOmie, Plenum Press, 1973; and TW Greene & P. GMWuts, Protective Groups in Organic Synthesis, Synthesis, John Wiley & Sons, 1991 Protective group, these references are incorporated herein by reference. Using methods known in the art, the protecting group can be removed at an appropriate subsequent stage.
  • room temperature refers to 15-30 ° C.
  • R 1 , R 2 , R 3 , R 4 , R 5 and L are as defined in formula I above.
  • Step 1 Compound II-1 is substituted under basic conditions to form intermediate II-2.
  • the solvent used is DMF, DMSO, THF, CH 3 CN, DCM, etc.
  • the base used is triethylamine, N, N-diisopropylethylamine, potassium carbonate, potassium t-butoxide, sodium hydroxide, etc.
  • the temperature is- 20 °C to 180 °C.
  • Step 2 Compound II-2 is substituted under basic conditions to form intermediate II-3.
  • the solvent used is DMF, DMSO, THF, CH 3 CN, DCM, etc.
  • the base used is triethylamine, N, N-diisopropylethylamine, potassium carbonate, potassium t-butoxide, sodium hydroxide, etc.
  • the temperature is 20 °C to 150 °C.
  • Step 3 Compound II-3 is reduced to intermediate II-4.
  • the reducing agent used is Zn powder / ammonium formate, Zn powder / ammonium chloride, safety powder, Fe powder / ammonium formate, and the solvent is methanol, ethanol, THF, etc., and the temperature is 20 ° C to 110 ° C.
  • Step 4 Compound II-4 undergoes condensation reaction to form intermediate II-5.
  • the condensation reagents used are HATU, HBTU, TBTU, EDCI, etc.
  • the solvents are THF, DMF, 1,4-dioxane, etc.
  • the temperature is 20 ° C to 100 ° C.
  • Step 5 Compound II-5 is ring closed under basic conditions to form intermediate II-6.
  • the base used is triethylamine, N, N-diisopropylethylamine, potassium carbonate, potassium tert-butoxide, sodium hydroxide, etc.
  • the solvent is MeOH, EtOH, THF, 1,4-dioxane, etc., temperature It is 20 ° C to 150 ° C.
  • Step 6 Compound II-6 undergoes coupling reaction under basic conditions to generate intermediate II-7.
  • the coupling reagents used are tetrakis (triphenylphosphine) palladium (0), tris (bisbenzylideneacetone) dipalladium (0), etc.
  • the base used is sodium bis (trimethylsilyl) amide, tBuOK, tBuONa, tBuOLi, NaH, NaOH, KOH, Cs 2 CO 3 , K 2 CO 3 , Na 2 CO 3, etc.
  • the solvent is toluene, xylene, THF, DME, 1,4-dioxane, DMF, NMP, DMSO, etc., temperature It is 0 ° C to 160 ° C.
  • Step 7 Intermediate II-7 undergoes deprotection reaction under acidic conditions to produce compound II-A.
  • the acid used is trifluoroacetic acid, trifluoromethanesulfonic acid, acetic acid, hydrochloric acid, sulfuric acid, nitric acid, etc.
  • the solvent is DCM, 1,4-dioxane, methanol, EA, etc., or no solvent, directly dissolved with acid, temperature It is -20 °C to 100 °C.
  • Step 1 Compound II-3 is substituted under basic conditions to form intermediate II-8.
  • the solvent used is DMF, DMSO, THF, CH 3 CN, DCM, etc.
  • the base used is cesium carbonate, triethylamine, N, N-diisopropylethylamine, potassium carbonate, potassium tert-butoxide, sodium hydroxide, butyl Based on lithium, etc.
  • the temperature is 20 °C to 180 °C.
  • Step 2 Compound II-8 is reduced to intermediate II-9.
  • the reducing agent used is Zn powder / ammonium formate, Zn powder / ammonium chloride, safety powder, Fe powder / ammonium formate, and the solvent is methanol, ethanol, THF, etc., and the temperature is 20 ° C to 110 ° C.
  • Step 3 Compound II-9 undergoes condensation reaction to form intermediate II-10.
  • the condensation reagents used are HATU, HBTU, TBTU, EDCI, etc.
  • the solvents are THF, DMF, 1,4-dioxane, etc.
  • the temperature is 20 ° C to 100 ° C.
  • Step 4 Compound II-10 is closed under basic conditions to form intermediate II-11.
  • the base used is triethylamine, N, N-diisopropylethylamine, potassium carbonate, potassium tert-butoxide, sodium hydroxide, etc.
  • the solvent is MeOH, EtOH, THF, 1,4-dioxane, etc., temperature It is 20 ° C to 150 ° C.
  • Step 5 Intermediate II-11 undergoes deprotection reaction under acidic conditions to produce compound II-A.
  • the acid used is trifluoroacetic acid, boron tribromide, boron trichloride, trifluoromethanesulfonic acid, acetic acid, hydrochloric acid, sulfuric acid, nitric acid, etc.
  • the solvent is 1,4-dioxane, methanol, EA, etc., or no need Solvent, dissolved directly with acid, the temperature is -20 °C to 100 °C.
  • the compound of the present invention has obvious agonistic activity on NLRP3 and its signaling pathway without obvious toxic and side effects, and can be used for the treatment of diseases (such as tumors) related to the activity of NLRP3 inflammatory body.
  • the structure of the compound was confirmed by nuclear magnetic resonance spectroscopy ( 1 H NMR) or mass spectrometry (MS).
  • reaction is monitored by silica gel thin layer chromatography (TLC) or LC-MS.
  • the microwave reaction was carried out using BiotageInitiator + microwave reactor.
  • the eluent system includes: A: dichloromethane and methanol; B: PE and EA, and the volume ratio of the solvent is adjusted according to the polarity of the compound.
  • reaction temperature is room temperature (15 ° C to 30 ° C).
  • the reagents used in this application were purchased from companies such as Acros Organics, Aldrich Chemical Company, and Tebo Chemical.
  • Step 7 3- (4-amino-1-methyl-6-((3-methylbenzyl) amino) -1H-imidazo [4,5-c] pyridin-2-yl) propan-1 -Alcohol (Compound 1)
  • Instrument model Agilent 1260; chromatography column: Waters XBridge prep C18 (19mm ⁇ 150mm ⁇ 5.0 ⁇ m); mobile phase: acetonitrile / 0.05% NH 4 HCO 3 aqueous solution; elution gradient: 0-16min acetonitrile 10% -90%; flow rate : 24ml / min; detection wavelength: 214nm, 254nm, 280nm; compound collection time: 6.7-7.1min.
  • Instrument model Agilent 1260; Column: Waters SunFire Prep C18 OBD (19mm ⁇ 150mm ⁇ 5.0 ⁇ m); Column temperature: 40 °C; Flow rate: 28.0mL / min; Detection wavelength: 254nm; Elution gradient: (0min: 10 % A, 90% B; 16 min: 90% A, 10% B); mobile phase A: 100% acetonitrile; mobile phase B: 0.05% aqueous formic acid; compound collection time: 6.1-6.6 min.
  • Step 2 3- (4-Amino-1-methyl-6- (methyl (3-methylbenzyl) amino) -1H-imidazo [4,5-c] pyridin-2-yl) propan -1-ol (Compound 3)
  • Instrument model Waters 2489; Column: Waters SunFire Prep C18 OBD (19mm ⁇ 150mm ⁇ 5.0 ⁇ m); Column temperature: 25 °C; Flow rate: 24.0mL / min; Detection wavelength: 214nm, 254nm, 280nm; Elution gradient: (0min: 30% A, 70% B; 4min: 30% A, 70% B; 16.0min: 90% A, 10% B); mobile phase A: 100% acetonitrile; mobile phase B: 0.05% ammonium bicarbonate Water solution. Compound collection time: 7.6-8.1 min.
  • Zinc powder (67.93 mg, 1.05 mmol) and ammonium chloride (55.91 mg, 1.05 mmol) were added to a solution of compound 4a (100 mg, 209.02 ⁇ mol) in methanol (5 mL) in turn, and then kept at room temperature for 5 min until the color disappeared. The insoluble matter was removed by filtration, and the mother liquor was concentrated to obtain compound 4b (60 mg).
  • Step 6 3- [4-Amino-6-[(4-bromobenzyl) (methyl) amino] -1-methyl-1H-imidazo [4,5-c] pyridin-2-yl] Propan-1-ol (Compound 4)
  • Instrument model Agilent 1260; Column: Waters SunFire Prep C18 OBD (19mm ⁇ 150mm ⁇ 5.0 ⁇ m); mobile phase: acetonitrile / 0.05% NH 4 HCO 3 aqueous solution; elution gradient: 0-7.8min acetonitrile 30% -49.5% ; Flow rate: 24ml / min.
  • Detection wavelength 214nm, 254nm, 280nm; compound collection time: 7.1-7.5min.
  • Instrument model Agilent 1260; Column: Waters, SunFire, Prep, C18, OBD (19mm ⁇ 150mm ⁇ 5.0 ⁇ m); Column temperature: 25 ° C; Flow rate: 20.0mL / min; Detection wavelength: 214nm; Elution gradient: (0min: 10 % A, 90% B; 16.0 min: 90% A, 10% B); mobile phase A: 100% acetonitrile; mobile phase B: 0.05% aqueous ammonium bicarbonate solution. Compound collection time: 6.25-6.90 min.
  • Step 2 2- (3- (benzyloxy) propyl) -N 6 , 1-dimethyl-N 6- (pyridin-3-ylmethyl) -1H-imidazo [4,5-c ] Pyridine-4,6-diamine (compound 6h)
  • Instrument model Agilent 1260; chromatography column: Waters SunFire Prep C18 OBD (19mm ⁇ 150mm ⁇ 5.0 ⁇ m), mobile phase: acetonitrile / 0.05% NH 4 HCO 3 aqueous solution; elution gradient: 0-16min acetonitrile 10% -60%; Flow rate: 24ml / min; detection wavelength: 214nm, 254nm, 280nm; compound collection time: 6.0-6.5min.
  • Instrument model Agilent1260; Column: XBridge, Prep, C18, OBD (19mm ⁇ 150mm ⁇ 5.0 ⁇ m); Column temperature: 25 °C; Flow rate: 24.0mL / min; Detection wavelength: 214nm, 254nm, 280nm; Elution gradient: (0min : 10% A, 90% B; 16.0 min: 90% A, 10% B); mobile phase A: 100% acetonitrile; mobile phase B: 0.05% aqueous ammonium bicarbonate solution. Compound collection time: 6.6-7.5 min.
  • Instrument model Agilent 1260; Column: XBridge Prep C18 OBD (19mm ⁇ 150mm ⁇ 5.0 ⁇ m); Column temperature: 25 °C; Flow rate: 24.0mL / min; Detection wavelength: 214nm, 254nm, 280nm; Elution gradient: ( 0 min: 20% A, 80% B; 7.6 min: 48.5% A, 51.5% B); mobile phase A: 100% acetonitrile; mobile phase B: 0.05% aqueous formic acid. Compound collection time: 6.8-7.5 min.
  • Instrument model Agilent1260; Column: XBridge, Prep, C18, OBD (19mm ⁇ 150mm ⁇ 5.0 ⁇ m); Column temperature: 25 °C; Flow rate: 24.0mL / min; Detection wavelength: 214nm, 254nm, 280nm; Elution gradient: (0min : 10% A, 90% B; 4.6 min: 18.6% A, 81.4% B); mobile phase A: 100% acetonitrile; mobile phase B: 0.05% aqueous ammonium bicarbonate solution. Compound collection time: 3.6-4.3 min.
  • This experiment uses a homogeneous time-resolved fluorescence (HTRF) detection method to test the effect of the compound of the present invention on the level of IL-1 ⁇ downstream NLRP3 cytokine in order to evaluate the activation of hNLRP3 inflammatory body or NLRP3 inflammatory body pathway at the cellular level effect.
  • HTRF time-resolved fluorescence
  • RPMI 1640 Hyclone
  • heat-inactivated FBS Gabco
  • PMA Biyuntian
  • Kit IL-1 ⁇ assay kit (CISBIO)
  • THP-1 cells Inoculate THP-1 cells in the logarithmic growth phase at a density of 5 ⁇ 10 5 cells / well in T75 culture flasks, place them in an incubator at 37 ° C and 5% CO 2 for 24 h to induce THP-1 Suspended cells become adherent macrophages.
  • the complete growth medium was RPMI 1640, containing 10% heat-inactivated FBS, 0.05 mM ⁇ -mercaptoethanol, and 1 ⁇ M PMA.
  • the HTRF detection method was used to test the effect of the compound of the present invention on the level of IL-1 ⁇ in THP1- def NLRP3 cells to evaluate the specificity of the compound on the hNLRP3 inflammatory body or NLRP3 inflammatory body pathway activation.
  • RPMI 1640 Hyclone
  • heat-inactivated FBS Gabco
  • PMA Biyuntian
  • Kit IL-1 ⁇ assay kit (CISBIO)
  • THP1- def NLRP3 cells in the logarithmic growth phase were seeded in T75 flasks at a density of 5 ⁇ 10 5 cells / well, placed in a 37 ° C, 5% CO 2 incubator for 24 h to induce THP1- def NLRP3 suspension cells become adherent macrophages.
  • the complete growth medium was RPMI 1640, containing 10% heat-inactivated FBS, 0.05 mM ⁇ -mercaptoethanol, and 1 ⁇ M PMA.
  • the activating effect of the compound of the present invention on the TLR7 signaling pathway was tested by detecting the luciferase in HEK-hTLR7-NF- ⁇ B-luciferase reporter cells to evaluate the specificity of the compound on the NLRP3 inflammatory body pathway activation .
  • DMEM High Glucose
  • FBS Gabco
  • HEK-hTLR7-NF-kB-Luciferase reporter gene cells human-derived TLR7 NF-kB-luciferase reporter gene cells (Nanjing Kebai)
  • DMEM High Glucose
  • FBS Gabco
  • QUANTI-Blue InvivoGen
  • HEK-Blue TM hTLR8 cells human TLR 8 cells (InvivoGen)
  • the compounds of the present invention for example, compound 1, compound 2, compound 3, compound 4, compound 5, compound 6, compound 7, and compound 8) had significant expression of IL-1 ⁇ in THP-1 cells after PMA-induced differentiation Agonistic effect, while IL-1 ⁇ expression in THP1- def NLRP3 cells had no agonistic effect at the highest compound test concentration (27 ⁇ M); all compounds had no significant activation of hTLR7 and hTLR8.
  • the compounds of the present invention eg Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7 and Compound 8) have specific and selective agonistic activity on hNLRP3 and its signaling pathway.

Abstract

属于医药领域，涉及并环化合物、其制备方法及用途。具体而言，涉及式I所示的化合物，所述化合物的立体异构体、互变异构体或其混合物，所述化合物的药学上可接受的盐、共晶、多晶型物或溶剂合物，或者所述化合物的稳定同位素衍生物、代谢物或前药。

Description

并环化合物、其制备方法及用途 发明领域
本发明属于医药领域，涉及一类含氮并环化合物，所述化合物的立体异构体、互变异构体或其混合物，所述化合物的药学上可接受的盐、共晶、多晶型物或溶剂合物，或者所述化合物的稳定同位素衍生物、代谢物或前药。本发明的化合物可用作NLRP3调节剂(例如激动剂)，用于与NLRP3炎症小体活性相关的疾病(例如肿瘤疾病)的治疗。
发明背景
NLRP3(NLR family pyrin domain containing 3)属于NOD样受体家族，是近几年来研究最多的一种细胞内模式识别受体，主要表达于巨噬细胞和嗜中性粒细胞，参与机体固有免疫，抵抗病原体感染和应激损伤。NLRP3炎症小体在炎性和代谢类疾病中作用十分明确，其过度活化会导致2型糖尿病、类风湿性关节炎和动脉粥样硬化等免疫性疾病。然而，近年来的研究表明NLRP3有抑制肿瘤生长和转移的抗肿瘤作用。
NLRP3蛋白在识别病原相关分子模式(PAMP)或内源性的损伤相关分子模式(DAMP)后，其NOD结构域发生寡聚化并招募ASC和pro-caspase-1等蛋白，形成具有功能的NLRP3炎症小体。在pro-caspase-1被剪切活化成caspase-1之后，caspase-1大量剪切pro-IL-1β和pro-IL-18使之转化成活性形式IL-1β和IL-18并释放到胞外，放大炎性反应。激动的NLRP3炎症小体可以显著提高肿瘤微环境中免疫因子IL-1β和IL-18的水平，启动天然免疫杀伤以及后续的获得性免疫应答以发挥其抗肿瘤作用。具体地，IL-1β可诱导CD8+T细胞分泌干扰素γ(IFN-γ)，也可诱导CD4+细胞分泌IL-17，引起有效的抗肿瘤免疫反应；而IL-18则能够促进NK细胞成熟，激活免疫细胞内STAT1下游信号通路，增强免疫细胞的杀伤功能。临床研究显示，NLRP3的下调与肝癌病人的预后呈显著负相关。临床前研究也显示，NLRP3缺陷小鼠结直肠肿瘤的形成率更高且结直肠癌肝转移更加恶化。由此可见，NLRP3在肿瘤微环境中起着重要作用，可以作为肿瘤免疫治疗的一个关键靶点，也可作为肿瘤预后标志物。
尽管NLRP3激动剂有肿瘤免疫治疗的潜能，但目前仅有两家公司报道了具有NLRP3激动活性的化合物。VentiRx Pharmaceutical的VTX2337，其为TLR8/NLRP3炎性小体双激动剂，已经进入临床II期，适应症为卵巢癌和头颈癌(PLOS|one,2016.02.29)。Bristol-Myers Squibb company and IFM Therapeutis,INC(被Bristol-Myers Squibb company收购)的四篇专利申请(WO2017184746、WO2017040670、WO2017184735、WO2018152396)覆盖同一类母核的化合物，该类化合物对TLR7和TLR8有一定的选择性，目前尚处于临床前研究阶段。因此，需要开发新的、高效低毒的NLRP3激动剂来满足临床治疗需求。
发明概述
本发明的发明人通过创造性的劳动，得到了一类新型并环化合物，其可作为NLRP3调节剂(例如激动剂)，在蛋白水平上直接结合或修饰NLRP3，通过活化、稳定、改变NLRP3分布或其它方式来增强NLRP3炎症小体的功能，从而提供了下述发明。
在一个方面，本发明涉及式I所示的化合物，所述化合物的立体异构体、互变异构体或其混合物，所述化合物的药学上可接受的盐、共晶、多晶型物或溶剂合物，或者所述化合物的稳定同位素衍生物、代谢物或前药：
Figure PCTCN2019113877-appb-000001
其中：
X 1为C(R 7) 2、NR 7、O或S，
X 2为CR 7或N，
X 3为C、N、O或S，且满足下列条件：
(1)当X 3为C时，R 6选自H、C 1-6烷基和C 3-8环烷基，所述C 1-6烷基和C 3-8环烷基各自任选地被下列基团中的一个或多个取代：卤素、OH、CN、NO 2、C 1-4烷氧基和C 1-4羟烷基，
(2)当X 3为N、O或S时，R 6不存在，并且当X 3为O或S时，R 2不存在，
R 1选自C 1-8烷基、C 1-8烷氧基、C 3-8环烷基、4-10元杂环基、C 6-12芳基、5-10元杂芳基和9-12元芳基并杂环基，所述C 1-8烷基、C 1-8烷氧基、C 3-8环烷基、4-10元杂环基、C 6-12芳基、5-10元杂芳基和9-12元芳基并杂环基各自任选地被下列取代基中的一个或多个取代：卤素、CN、NO 2、C 1-4烷基、C 3-8环烷基、C 1-4卤代烷基、C 1-4烷氧基、C 1-4卤代烷氧基、C 1-4羟烷基、4-10元杂环基、C 6-12芳基、5-10元杂芳基、9-12元芳基并杂环基、CO 2R 30、C(O)R 30、C(O)NR 31R 32、NR 33C(O)R 34、NR 31R 32、OC(O)R 30、OC(O)NR 31R 32、NR 33C(O)NR 31R 32、NR 33C(O)OR 30、S(O)NR 31R 32、S(O) 2NR 31R 32、S(O)R 35、S(O) 2R 35、OR 37和SR 37；
R 2选自H、C 1-8烷基、C 2-8烯基、C 2-8炔基、C 6-12芳基、C 3-8环烷基、5-10元杂芳基和4-10元杂环基，所述C 1-8烷基、C 2-8烯基、C 2-8炔基、C 6-12芳基、C 3-8环烷基、5-10元杂芳基和4-10元杂环基各自任选地被下列取代基中的一个或多个取代：卤素、C 1-4卤代烷基、C 1-4羟烷基、C 1-4烷氧基、C 1-4卤代烷氧基、4-7元杂环基、CN、NO 2、OR 37、SR 37、C(O)R 30、C(O)NR 31R 32、NR 31R 32C(O)、C(O)OR 30、OC(O)R 30、OC(O)NR 31R 32、NR 33C(O)NR 31R 32和NR 31R 32；
R 3选自H、OH、卤素、CN、NO 2、C 1-8烷基、C 1-8卤代烷基、C 1-8烷氧基、C 1-8卤代烷氧基、C 3-8环烷基、4-10元杂环基、C 6-12芳基、5-10元杂芳基、9-12元芳基并杂环基、9-12元芳基并杂芳基、9-12元芳基并环烷基、CO 2R 30、C(O)NR 31R 32、NR 33S(O) 2R 34、NR 33C(O)R 34、NR 31R 32、SO 2R 35、OR 37、SR 37、C(O)R 30、OC(O)R 30、OC(O)NR 31R 32、NR 33C(O)NR 31R 32、NR 33C(O)OR 30、C(＝NR 38)NR 31R 32、NR 33C(＝NR 38)NR 31R 32、P(R 39) 2、P(OR 39) 2、P(O)R 39R 40、P(O)OR 39OR 30、S(O)R 35、S(O) 2R 35、S(O)NR 31R 32和S(O) 2NR 31R 32，所述C 1-8烷基、C 1-8卤代烷基、C 1-8烷氧基、C 1-8卤代烷氧基、C 3-8环烷基、4-10元杂环基、C 6-12芳基、5-10元杂芳基、9-12元芳基并杂环基、9-12元芳基并杂芳基和9-12元芳基并环烷基各自任选地被下列取代基中的一个或多个取代：卤素、CN、NO 2、C 1-4烷基、C 3-8环烷基、C 1-4卤代烷基、C 1-4烷氧基、C 1-4卤代烷氧基、C 1-4羟烷基、4-10元杂环基、C 6-12芳基、5-10元杂芳基、9-12元芳基并杂环基、CO 2R 30、C(O)R 30、C(O)NR 31R 32、NR 33C(O)R 34、NR 31R 32、S(O)R 35、S(O) 2R 35、S(O)NR 31R 32、S(O) 2NR 31R 32、OR 37、SR 37、OC(O)R 30、OC(O)NR 31R 32、NR 33C(O)NR 31R 32、NR 33C(O)OR 30、C(＝NR 38)NR 31R 32、NR 33C(＝NR 38)NR 31R 32、＝NNR 31R 32、P(R 39) 2、P(OR 39) 2、P(O)R 39R 40和P(O)OR 39OR 30；或者R 2和R 3连接形成5-8元环；
R 4和R 5各自独立地选自H、C 1-8烷基、C 3-8环烷基和C 1-8烷氧基，所述C 1-8烷基、C 3-8环烷基和C 1-8烷氧基各自任选地被下列取代基中的一个或多个取代：卤素、OH、CN、NO 2、C 1-6烷基、C 1-4卤代烷基和C 1-4羟烷基；或R 4、R 5和与其相连的氮原子一起形成4-7元杂环；
R 7选自H、C 1-6烷基和C 3-8环烷基，所述C 1-6烷基和C 3-8环烷基各自任选地被下列基团中的一个或多个取代：卤素、OH、CN、C 1-4烷氧基和C 1-4羟烷基；或者两个R 7和与其相连的碳原子一起形成3-5元环烷基；当两个R 7同时存在时，各R 7可以相同或不同；
V不存在，或选自C 1-8亚烷基、C(R 36aR 36b)、O、S、NR 33、SO、SO 2和CO，所述C 1-8亚烷基任选地被下列取代基中的一个或多个取代：卤素、OH、CN、NO 2、C 1-6烷基、C 1-4卤代烷基、C 1-4羟烷基和C 1-4烷氧基；
V与X 1不同时为杂原子N、O或S；
L为-(L 1) n-(L 2) p-(L 3) q-，其中L 1、L 2和L 3相同或不同，并且各自独立地选自C 1-8亚烷基、C 2-8亚烯基、C 2-8亚炔基、C 1-8卤代亚烷基、C 1-8亚烷氧基、C 1-8卤代亚烷氧基、C 1-8羟亚烷基、C 3-8亚环烷基、4-10元亚杂环基、C 6-12亚芳基、5-10元亚杂芳基、O、S、NR 33、SO、SO 2、CO和C(R 36aR 36b)，所述C 1-8亚烷基、C 2-8亚烯基、C 2-8亚炔基、C 1-8卤代亚烷基、C 1-8亚烷氧基、C 1-8卤代亚烷氧基、C 1-8羟亚烷基、C 3-8亚环烷基、4-10元亚杂环基、C 6-12亚芳基和5-10元亚杂芳基各自任选地被下列取代基中的一个或多个取代：卤素、OH、CN、NO 2、C 1-6烷基、C 1-4卤代烷基、C 1-4羟烷基和C 1-4烷氧基；
n、p和q各自独立地为0或1；
R 30、R 37、R 39和R 40各自独立地选自氢、C 1-8烷基、C 1-8羟烷基、C 1-8卤代烷基、C 1-8烷氧基、C 1-8卤代烷氧基、C 3-8环烷基、4-10元杂环基、C 6-12芳基、5-10元杂芳基、C 1-8烷基-C 6-12芳基和C 1-8烷基-(5-10元杂芳基)，所述C 1-8烷基、C 1-8羟烷基、C 1-8卤代烷基、C 1-8烷氧基、C 1-8卤代烷氧基、C 3-8环 烷基、4-10元杂环基、C 6-12芳基和5-10元杂芳基各自任选地被下列取代基中的一个或多个取代：OH、CN、NO 2、C 1-4烷基、C 1-4烷氧基、C 1-4卤代烷基、卤素、C 1-4卤代烷氧基、CO 2(C 1-6烷基)、CONR 31R 32、NR 31R 32、NR 33C(O)R 34、S(O)R 35、S(O) 2R 35、S(O)NR 31R 32和S(O) 2NR 31R 32；
当多个R 30同时存在时，各R 30可以相同或不同；
当多个R 37同时存在时，各R 37可以相同或不同；
当多个R 39同时存在时，各R 39可以相同或不同；
当多个R 40同时存在时，各R 40可以相同或不同；
R 31、R 32、R 33和R 34各自独立地选自H、C 1-8烷基、C 1-8羟烷基、C 1-8烷氧基、4-10元杂环基、C 6-12芳基、C 3-8环烷基和5-10元杂芳基，所述C 1-8烷基、C 1-8羟烷基、C 1-8烷氧基、4-10元杂环基、C 6-12芳基、C 3-8环烷基和5-10元杂芳基各自任选地被下列取代基中的一个或多个取代：OH、CN、卤素、NO 2、C 1-4烷基、C 1-4烷氧基、C 1-4羟烷基、C 1-4卤代烷基、C 1-4卤代烷氧基、4-10元杂环基、C 6-12芳基和5-10元杂芳基；或者R 31和R 32和与其相连的N原子一起形成3-8元杂环基；或者R 33和R 34和与其相连的N和C原子或者N和S原子一起形成4-8元杂环基；
R 35选自C 1-8烷基、C 1-8羟烷基、C 1-8卤代烷基、C 1-8烷氧基、C 1-8卤代烷氧基、C 3-8环烷基、4-10元杂环基、C 6-12芳基、5-10元杂芳基、C 1-8烷基-C 6-12芳基和C 1-8烷基-(5-10元杂芳基)，所述C 1-8烷基、C 1-8羟烷基、C 1-8卤代烷基、C 1-8烷氧基、C 1-8卤代烷氧基、C 3-8环烷基、4-10元杂环基、C 6-12芳基和5-10元杂芳基各自任选地被下列取代基中的一个或多个取代：OH、CN、NO 2、C 1-4烷基、C 1-4烷氧基、C 1-4卤代烷基、卤素、C 1-4卤代烷氧基、CO 2(C 1-6烷基)、CONR 31R 32、NR 31R 32、NR 33C(O)R 34、S(O)Me、S(O) 2Me、S(O)NR 31R 32和S(O) 2NR 31R 32，其中R 31、R 32、R 33和R 34如上所定义；
当多个R 31同时存在时，各R 31可以相同或不同；
当多个R 32同时存在时，各R 32可以相同或不同；
当多个R 33同时存在时，各R 33可以相同或不同；
当多个R 34同时存在时，各R 34可以相同或不同；
当多个R 35同时存在时，各R 35可以相同或不同；
R 36a和R 36b相同或不同，各自独立地选自H、C 1-6烷基、C 1-6烷氧基、C 1-8羟烷基和C 1-8卤代烷基，所述C 1-6烷基、C 1-6烷氧基、C 1-8羟烷基和C 1-8卤代烷基各自任选地被下列基团中的一个或多个取代：OH、CN、NH 2、NHCH 3和N(CH 3) 2；或R 36a、R 36b和与其相连的碳原子一起形成3-7元环烷基或3-7元杂环基；
当多个R 38同时存在时，各R 38相同或不同，各自独立地选自H、OH、CN、NO 2、S(O)R 35和S(O) 2R 35。
在优选的实施方案中，R 1选自C 1-4烷基、C 1-4烷氧基、C 3-6环烷基、4-7元杂环基、C 6-12芳基、5-10元杂芳基和9-12元芳基并杂环基，所述C 1-4烷基、C 1-4烷氧基、C 3-6环烷基、4-7元杂环基、C 6-12芳基、5-10元杂芳基和9-12元芳基并杂环基各自任选地被下列取代基中的一个或多个取代：卤素、CN、NO 2、C 1-4烷基、C 3-8环烷基、C 1-4卤代烷基、C 1-4烷氧基、C 1-4卤代烷氧基、C 1-4羟烷基、4-10元杂环基、C 6-12芳基、5-10元杂芳基、9-12元芳基并杂环基、CO 2R 30、C(O)R 30、C(O)NR 31R 32、NR 33C(O)R 34、NR 31R 32、OC(O)R 30、OC(O)NR 31R 32、NR 33C(O)NR 31R 32、NR 33C(O)OR 30、S(O)NR 31R 32、S(O) 2NR 31R 32、S(O)R 35、S(O) 2R 35、OR 37和SR 37。
在优选的实施方案中，R 1选自C 1-4烷基、C 6-12芳基和5-10元杂芳基，所述C 1-4烷基、C 6-12芳基和5-10元杂芳基各自任选地被下列取代基中的一个或多个取代：卤素、CN、NO 2、C 1-4烷基、C 3-8环烷基、C 1-4卤代烷基、C 1-4烷氧基、C 1-4卤代烷氧基、C 1-4羟烷基、4-10元杂环基、C 6-12芳基、5-10元杂芳基、9-12元芳基并杂环基、CO 2R 30、C(O)R 30、C(O)NR 31R 32、NR 33C(O)R 34、NR 31R 32、OC(O)R 30、OC(O)NR 31R 32、NR 33C(O)NR 31R 32、NR 33C(O)OR 30、S(O)NR 31R 32、S(O) 2NR 31R 32、S(O)R 35、S(O) 2R 35、OR 37和SR 37。
在优选的实施方案中，R 1选自异丁基、
Figure PCTCN2019113877-appb-000002
Figure PCTCN2019113877-appb-000003
在上述式I中，V与X 1不同时为杂原子N、O或S，其含义是当X 1为NR 7、O或S时，V不是O、S、NR 33、SO或SO 2。
在优选的实施方案中，V不存在，或者选自CO和C 1-8亚烷基(例如亚甲基)。
在优选的实施方案中，X 1选自O和NR 7，优选地，X 1选自O、NH和N(CH 3)。
在优选的实施方案中，X 1选自NR 7，优选地，X 1选自NH和N(CH 3)。
在优选的实施方案中，X 1为O。
在优选的实施方案中，X 1为S。
在优选的实施方案中，X 2为CR 7，优选地，X 2为CH。
在优选的实施方案中，X 2为N。
在优选的实施方案中，X 3为N，其被R 2取代，且R 6不存在；优选地，R 2选自H、C 1-4烷基、C 3-8环烷基和C 6-12芳基；更优选地，R 2选自选自H、甲基、乙基和丙基，特别是H和甲基。
在优选的实施方案中，R 3选自OH、C 1-8烷基、4-10元杂环基、C 6-12芳基、NR 31R 32、NR 33C(O)R 34、NR 33S(O) 2R 34、C(O)NR 31R 32、9-12元芳基并杂环基、5-10元杂芳基和NR 33C(O)NR 31R 32，所述C 1-8烷基、4-10元杂环基、C 6-12芳基、5-10元杂芳基和9-12元芳基并杂环基各自任选地被下列取代基中的一个或多个取代：C 1-4烷基、C 1-4烷氧基、C 6-12芳基、C(O)R 30、C(O)NR 31R 32、NR 33C(O)R 34、NR 31R 32、S(O) 2R 35和OR 37。
在优选的实施方案中，R 3选自OH、C 1-8烷基、4-10元杂环基、C 6-12芳基、NR 31R 32、NR 33C(O)R 34、NR 33S(O) 2R 34、C(O)NR 31R 32、9-12元芳基并杂环基、5-10元杂芳基和NR 33C(O)NR 31R 32，所述C 1-8烷基、4-10元杂环基、C 6-12芳基、5-10元杂芳基和9-12元芳基并杂环基各自任选地被下列取代基中的一个或多个取代：甲基、甲氧基、苯基、C(O)CH 3、C(O)NH 2、NHC(O)CH 3、NHC(O)H、NH 2、NH(CH 3)、S(O) 2CH 3和OH。
在优选的实施方案中，R 3选自OH、-NHC(O)CH 3、-C(O)NH 2、-N(CH 2CH 3)C(O)N(CH 3) 2、
Figure PCTCN2019113877-appb-000004
Figure PCTCN2019113877-appb-000005
在优选的实施方案中，R 4和R 5各自独立地选自H、C 1-3烷基、C 3-6环烷基和C 1-3烷氧基，所述C 1-3烷基、C 1-3烷氧基和C 3-6环烷基各自任选地被下列取代基中的一个或多个取代：卤素、OH、CN、NO 2、C 1-6烷基、C 1-4卤代烷基和C 1-4羟烷基；或R 4、R 5和与其相连的氮原子一起形成4-7元杂环；优选地，R 4和R 5均为H。
在优选的实施方案中，L不存在，或者选自亚丙基、亚甲基、亚乙基、O、S、NR 33、-C 1-3亚烷 基-O-、-C 1-3亚烷基-S-和-C 1-3亚烷基-NR 33-；优选地，R 33选自H和甲基。
优选地，L不存在，或者选自亚丙基、亚乙基、O、S、NR 33、-C 1-3亚烷基-O-、-C 1-3亚烷基-S-和-C 1-3亚烷基-NR 33-；优选地，R 33选自H和甲基。
更优选地，L不存在，或者选自亚丙基、亚乙基、-C 1-3亚烷基-O-(例如-亚乙基-O-或-亚丙基-O-)和-C 1-3亚烷基-NH-(例如-亚乙基-NH-)。
在本发明的一些实施方案中，所述化合物具有式II的结构：
Figure PCTCN2019113877-appb-000006
其中R 1、R 2、R 3、R 4、R 5、X 1、V和L如上述式I所定义；优选地，其中R 1、R 2、R 3、R 4、R 5和L如权利要求1所定义，V不存在，或选自CO、亚甲基、亚乙基和亚丙基，X 1为NR 7，R 7选自H、C 1-4烷基和C 3-6环烷基，所述C 1-4烷基和C 3-6环烷基各自任选地被下列基团中的一个或多个取代：卤素、OH、CN、C 1-4烷氧基和C 1-4羟烷基，例如X 1选自NH和N(CH 3)。
在本发明的优选实施方案中，所述化合物具有式II的结构，其中R 1选自C 1-4烷基、C 6-12芳基(例如苯基)和5-10元杂芳基(例如吡啶基或吡嗪基)，所述C 1-4烷基、C 6-12芳基和5-10元杂芳基各自任选地被下列取代基中的一个或多个取代：卤素、CN、NO 2、C 1-4烷基、C 3-8环烷基、C 1-4卤代烷基、C 1-4烷氧基、C 1-4卤代烷氧基、C 1-4羟烷基、4-10元杂环基、C 6-12芳基、5-10元杂芳基、9-12元芳基并杂环基、CO 2R 30、C(O)R 30、C(O)NR 31R 32、NR 33C(O)R 34、NR 31R 32、OC(O)R 30、OC(O)NR 31R 32、NR 33C(O)NR 31R 32、NR 33C(O)OR 30、S(O)NR 31R 32、S(O) 2NR 31R 32、S(O)R 35、S(O) 2R 35、OR 37和SR 37；优选地，R 1选自异丁基、
Figure PCTCN2019113877-appb-000007
Figure PCTCN2019113877-appb-000008
在本发明的优选实施方案中，所述化合物具有式II的结构，其中R 2选自H和甲基。
在本发明的优选实施方案中，所述化合物具有式II的结构，其中R 3选自OH、C 1-8烷基、4-10元杂环基、C 6-12芳基、NR 31R 32、NR 33C(O)R 34、NR 33S(O) 2R 34、C(O)NR 31R 32、9-12元芳基并杂环基、5-10元杂芳基和NR 33C(O)NR 31R 32，所述C 1-8烷基、4-10元杂环基、C 6-12芳基、5-10元杂芳基和9-12元芳基并杂环基各自任选地被下列取代基中的一个或多个取代：C 1-4烷基、C 1-4烷氧基、C 6-12芳基、C(O)R 30、C(O)NR 31R 32、NR 33C(O)R 34、NR 31R 32、S(O) 2R 35和OR 37；优选地，R 3选自OH、C 1-8烷基、4-10元杂环基、C 6-12芳基、NR 31R 32、NR 33C(O)R 34、NR 33S(O) 2R 34、C(O)NR 31R 32、9-12元芳基并杂环基、5-10元杂芳基和NR 33C(O)NR 31R 32，所述C 1-8烷基、4-10元杂环基、C 6-12芳基、5-10元杂芳基和9-12元芳基并杂环基各自任选地被下列取代基中的一个或多个取代：甲基、甲氧基、苯基、C(O)CH 3、C(O)NH 2、NHC(O)CH 3、NHC(O)H、NH 2、NH(CH 3)、S(O) 2CH 3和OH。
在本发明的优选实施方案中，所述化合物具有式II的结构，其中R 4和R 5各自独立地选自H、C 1-3烷基、C 1-3烷氧基和C 3-6环烷基，所述C 1-3烷基、C 1-3烷氧基和C 3-6环烷基各自任选地被下列取代基中的一个或多个取代：卤素、OH、CN、NO 2、C 1-6烷基、C 1-4卤代烷基和C 1-4羟烷基；或R 4、R 5和与其相连的氮原子一起形成4-7元杂环；优选地，R 4和R 5均为H。
在本发明的优选实施方案中，所述化合物具有式II的结构，其中X 1选自C(R 7) 2、NR 7、O和S；优选地，X 1选自O和NR 7，更优选地，X 1选自O、NH和N(CH 3)。
在本发明的优选实施方案中，所述化合物具有式II的结构，其中V不存在，或者选自C 1-8亚烷基、C(R 36aR 36b)、O、S、NR 33、SO、SO 2和CO，所述C 1-8亚烷基任选地被下列取代基中的一个或多个取代：卤素、OH、CN、NO 2、C 1-6烷基、C 1-4卤代烷基、C 1-4羟烷基和C 1-4烷氧基；优选地，V不存在，或者选自CO和C 1-8亚烷基(例如亚甲基)。
在本发明的优选实施方案中，所述化合物具有式II的结构，其中V与X 1不同时为杂原子N、O 或S，即当X 1为NR 7、O或S时，V不是O、S、NR 33、SO或SO 2。
在本发明的优选实施方案中，所述化合物具有式II的结构，其中L不存在，或者选自亚丙基、亚甲基、亚乙基、O、S、NR 33、-C 1-3亚烷基-O-、-C 1-3亚烷基-S-和-C 1-3亚烷基-NR 33-，其中R 33选自H和甲基；优选地，L不存在，或者选自亚丙基、亚乙基、O、S、NR 33、-C 1-3亚烷基-O-、-C 1-3亚烷基-S-和-C 1-3亚烷基-NR 33-，其中R 33选自H和甲基；更优选地，L不存在，或者选自亚丙基、亚乙基、-C 1-3亚烷基-O-(例如-亚乙基-O-或-亚丙基-O-)和-C 1-3亚烷基-NH-(例如-亚乙基-NH-)。
在本发明的优选实施方案中，所述化合物具有式II的结构，其中n、p和q各自独立地为0。
在本发明的优选实施方案中，所述化合物具有式II的结构，其中n、p和q各自独立地为1。
在本发明的优选实施方案中，所述化合物具有式II的结构，其中：
R 1选自C 1-4烷基、C 6-12芳基(例如苯基)和5-10元杂芳基(例如吡啶基或吡嗪基)，所述C 1-4烷基、C 6-12芳基和5-10元杂芳基各自任选地被下列取代基中的一个或多个取代：卤素、CN、NO 2、C 1-4烷基、C 3-8环烷基、C 1-4卤代烷基、C 1-4烷氧基、C 1-4卤代烷氧基、C 1-4羟烷基、4-10元杂环基、C 6-12芳基、5-10元杂芳基、9-12元芳基并杂环基、CO 2R 30、C(O)R 30、C(O)NR 31R 32、NR 33C(O)R 34、NR 31R 32、OC(O)R 30、OC(O)NR 31R 32、NR 33C(O)NR 31R 32、NR 33C(O)OR 30、S(O)NR 31R 32、S(O) 2NR 31R 32、S(O)R 35、S(O) 2R 35、OR 37和SR 37；
R 2选自H和甲基；
R 3选自OH、C 1-8烷基、4-10元杂环基、C 6-12芳基、NR 31R 32、NR 33C(O)R 34、NR 33S(O) 2R 34、C(O)NR 31R 32、9-12元芳基并杂环基、5-10元杂芳基和NR 33C(O)NR 31R 32，所述C 1-8烷基、4-10元杂环基、C 6-12芳基、5-10元杂芳基和9-12元芳基并杂环基各自任选地被下列取代基中的一个或多个取代：C 1-4烷基、C 1-4烷氧基、C 6-12芳基、C(O)R 30、C(O)NR 31R 32、NR 33C(O)R 34、NR 31R 32、S(O) 2R 35和OR 37；优选地，R 3选自OH、C 1-8烷基、4-10元杂环基、C 6-12芳基、NR 31R 32、NR 33C(O)R 34、NR 33S(O) 2R 34、C(O)NR 31R 32、9-12元芳基并杂环基、5-10元杂芳基和NR 33C(O)NR 31R 32，所述C 1-8烷基、4-10元杂环基、C 6-12芳基、5-10元杂芳基和9-12元芳基并杂环基各自任选地被下列取代基中的一个或多个取代：甲基、甲氧基、苯基、C(O)CH 3、C(O)NH 2、NHC(O)CH 3、NHC(O)H、NH 2、NH(CH 3)、S(O) 2CH 3和OH；
R 4和R 5各自独立地选自H、C 1-8烷基、C 3-8环烷基和C 1-8烷氧基，所述C 1-8烷基、C 1-8烷氧基和C 3-8环烷基各自任选地被下列取代基中的一个或多个取代：卤素、OH、CN、NO 2、C 1-6烷基、C 1-4卤代烷基和C 1-4羟烷基；或R 4、R 5和与其相连的氮原子一起形成4-7元杂环；
X 1选自C(R 7) 2、NR 7、O和S；
V不存在，或者选自C 1-8亚烷基、C(R 36aR 36b)、O、S、NR 33、SO、SO 2和CO，所述C 1-8亚烷基任选地被下列取代基中的一个或多个取代：卤素、OH、CN、NO 2、C 1-6烷基、C 1-4卤代烷基、C 1-4羟烷基和C 1-4烷氧基；
V与X 1不同时为杂原子N、O或S；
L为-(L 1) n-(L 2) p-(L 3) q-，其中L 1、L 2和L 3相同或不同，并且各自独立地选自C 1-8亚烷基(例如C 1-3亚烷基)、C 2-8亚烯基、C 2-8亚炔基、C 1-8卤代亚烷基、C 1-8亚烷氧基、C 1-8卤代亚烷氧基、C 1-8羟亚烷基、C 3-8亚环烷基、4-10元亚杂环基、C 6-12亚芳基、5-10元亚杂芳基、O、S、NR 33、SO、SO 2、-CO-和-C(R 36aR 36b)-，所述C 1-8亚烷基、C 2-8亚烯基、C 2-8亚炔基、C 1-8卤代亚烷基、C 1-8亚烷氧基、C 1-8卤代亚烷氧基、C 1-8羟亚烷基、C 3-8亚环烷基、4-10元亚杂环基、C 6-12亚芳基和5-10元亚杂芳基各自任选地被下列取代基中的一个或多个取代：卤素、OH、CN、NO 2、C 1-6烷基、C 1-4卤代烷基、C 1-4羟烷基和C 1-4烷氧基；
n、p、q各自独立地为0或1。
在本发明的优选实施方案中，所述化合物具有式II的结构，其中：
R 1选自异丁基、
Figure PCTCN2019113877-appb-000009
Figure PCTCN2019113877-appb-000010
R 2选自H和甲基；
R 3选自OH、-NHC(O)CH 3、-C(O)NH 2、-N(CH 2CH 3)C(O)N(CH 3) 2、
Figure PCTCN2019113877-appb-000011
Figure PCTCN2019113877-appb-000012
R 4和R 5均为H；
X 1选自O、NH和N(CH 3)；
V不存在，或者选自CO和亚甲基；
L不存在，或者选自亚丙基、亚甲基、亚乙基、O、S、NR 33、-C 1-3亚烷基-O-、-C 1-3亚烷基-S-和-C 1-3亚烷基-NR 33-，其中R 33选自H和甲基；优选地，L不存在，或者选自亚丙基、亚乙基、O、S、NR 33、-C 1-3亚烷基-O-、-C 1-3亚烷基-S-和-C 1-3亚烷基-NR 33-，其中R 33选自H和甲基；更优选地，L不存在，或者选自亚丙基、亚乙基、-C 1-3亚烷基-O-(例如-亚乙基-O-或-亚丙基-O-)和-C 1-3亚烷基-NH-(例如-亚乙基-NH-)。
在本发明的一些实施方案中，所述化合物具有式II-A的结构：
Figure PCTCN2019113877-appb-000013
其中R 1、R 2、R 3和L如上述式II所定义。
在本发明的优选实施方案中，所述化合物具有式II-A的结构，其中：
R 1选自异丁基、
Figure PCTCN2019113877-appb-000014
Figure PCTCN2019113877-appb-000015
R 2选自H和甲基；
R 3选自OH、-NHC(O)CH 3、C(O)NH 2、-N(CH 2CH 3)C(O)N(CH 3) 2、
Figure PCTCN2019113877-appb-000016
Figure PCTCN2019113877-appb-000017
L不存在，或者选自亚丙基、亚甲基、亚乙基、O、S、NR 33、-C 1-3亚烷基-O-、-C 1-3亚烷基-S-和-C 1-3亚烷基-NR 33-，其中R 33选自H和甲基；优选地，L不存在，或者选自亚丙基、亚乙基、O、S、NR 33、-C 1-3亚烷基-O-、-C 1-3亚烷基-S-和-C 1-3亚烷基-NR 33-，其中R 33选自H和甲基；更优选地，L不存在，或者选自亚丙基、亚乙基、-C 1-3亚烷基-O-(例如-亚乙基-O-或-亚丙基-O-)和-C 1-3亚烷基-NH-(例如-亚乙基-NH-)。
在本发明的一些实施方案中，所述化合物具有式III的结构：
Figure PCTCN2019113877-appb-000018
其中R 1、R 2、R 3、R 4、R 5、X 1、V和L如上述式I所定义。
在本发明的优选实施方案中，所述化合物具有式III的结构，其中：
R 1选自异丁基、C 6-12芳基(例如苯基)和5-10元杂芳基(例如吡啶基或吡嗪基)，所述C 6-12芳基和5-10元杂芳基各自任选地被下列取代基中的一个或多个取代：卤素、CN、NO 2、C 1-4烷基、C 3-8环烷基、C 1-4卤代烷基、C 1-4烷氧基、C 1-4卤代烷氧基、C 1-4羟烷基、4-10元杂环基、C 6-12芳基、5-10元杂芳基、9-12元芳基并杂环基、CO 2R 30、C(O)R 30、C(O)NR 31R 32、NR 33C(O)R 34、NR 31R 32、OC(O)R 30、OC(O)NR 31R 32、NR 33C(O)NR 31R 32、NR 33C(O)OR 30、S(O)NR 31R 32、S(O) 2NR 31R 32、S(O)R 35、S(O) 2R 35、OR 37和SR 37；
R 2选自H和甲基；
R 3选自OH、C 1-8烷基、4-10元杂环基、C 6-12芳基、NR 31R 32、NR 33C(O)R 34、NR 33S(O) 2R 34、C(O)NR 31R 32、9-12元芳基并杂环基、5-10元杂芳基和NR 33C(O)NR 31R 32，所述C 1-8烷基、4-10元杂环基、C 6-12芳基、5-10元杂芳基和9-12元芳基并杂环基各自任选地被下列取代基中的一个或多个取代：C 1-4烷基、C 1-4烷氧基、C 6-12芳基、C(O)R 30、C(O)NR 31R 32、NR 33C(O)R 34、NR 31R 32、S(O) 2R 35和OR 37；优选地，R 3选自OH、C 1-8烷基、4-10元杂环基、C 6-12芳基、NR 31R 32、NR 33C(O)R 34、NR 33S(O) 2R 34、C(O)NR 31R 32、9-12元芳基并杂环基、5-10元杂芳基和NR 33C(O)NR 31R 32，所述C 1-8烷基、4-10元杂环基、C 6-12芳基、5-10元杂芳基和9-12元芳基并杂环基各自任选地被下列取代基中的一个或多个取代：甲基、甲氧基、苯基、C(O)CH 3、C(O)NH 2、NHC(O)CH 3、NHC(O)H、NH 2、NH(CH 3)、S(O) 2CH 3和OH；
R 4和R 5各自独立地选自H、C 1-8烷基、C 3-8环烷基和C 1-8烷氧基，所述C 1-8烷基、C 3-8环烷基和C 1-8烷氧基各自任选地被下列取代基中的一个或多个取代：卤素、OH、CN、NO 2、C 1-6烷基、C 1-4卤代烷基和C 1-4羟烷基；或R 4、R 5和与其相连的氮原子一起形成4-7元杂环；
X 1选自C(R 7) 2、NR 7、O和S；
V不存在，或者选自C 1-8亚烷基、C(R 36aR 36b)、O、S、NR 33、SO、SO 2和CO，所述C 1-8亚烷基任选地被下列取代基中的一个或多个取代：卤素、OH、CN、NO 2、C 1-6烷基、C 1-4卤代烷基、C 1-4羟烷基和C 1-4烷氧基；
V与X 1不同时为杂原子N、O或S；
L为-(L 1) n-(L 2) p-(L 3) q-，其中L 1、L 2和L 3相同或不同，并且各自独立地选自C 1-8亚烷基(例如C 1-3亚烷基)、C 2-8亚烯基、C 2-8亚炔基、C 1-8卤代亚烷基、C 1-8亚烷氧基、C 1-8卤代亚烷氧基、C 1-8羟亚烷基、C 3-8亚环烷基、4-10元亚杂环基、C 6-12亚芳基、5-10元亚杂芳基、O、S、NR 33、SO、SO 2、-CO-和-C(R 36aR 36b)-，所述C 1-8亚烷基、C 2-8亚烯基、C 2-8亚炔基、C 1-8卤代亚烷基、C 1-8亚烷氧基、C 1-8卤代亚烷氧基、C 1-8羟亚烷基、C 3-8亚环烷基、4-10元亚杂环基、C 6-12亚芳基和5-10元亚杂芳基各自任选地被下列取代基中的一个或多个取代：卤素、OH、CN、NO 2、C 1-6烷基、C 1-4卤代烷基、C 1-4羟烷基和C 1-4烷氧基；
n、p、q各自独立地为0或1。
在本发明的优选实施方案中，所述化合物具有式III的结构，其中：
R 1选自异丁基、
Figure PCTCN2019113877-appb-000019
Figure PCTCN2019113877-appb-000020
R 2选自H和甲基；
R 3选自OH、-NHC(O)CH 3、-C(O)NH 2、-N(CH 2CH 3)C(O)N(CH 3) 2、
Figure PCTCN2019113877-appb-000021
Figure PCTCN2019113877-appb-000022
Figure PCTCN2019113877-appb-000023
R 4和R 5均为H；
X 1选自O、NH和N(CH 3)；
V不存在，或者选自CO和亚甲基；
L不存在，或者选自亚丙基、亚甲基、亚乙基、O、S、NR 33、-C 1-3亚烷基-O-、-C 1-3亚烷基-S-和-C 1-3亚烷基-NR 33-，其中R 33选自H和甲基；优选地，L不存在，或者选自亚丙基、亚乙基、O、S、NR 33、-C 1-3亚烷基-O-、-C 1-3亚烷基-S-和-C 1-3亚烷基-NR 33-，其中R 33选自H和甲基；更优选地，L不存在，或者选自亚丙基、亚乙基、-C 1-3亚烷基-O-(例如-亚乙基-O-或-亚丙基-O-)和-C 1-3亚烷基-NH-(例如-亚乙基-NH-)。
在本发明的一些实施方案中，所述化合物具有式IV的结构：
Figure PCTCN2019113877-appb-000024
其中R 1、R 3、R 4、R 5、X 1、V和L如上述式I所定义。
在本发明的优选实施方案中，所述化合物具有式IV的结构，其中：
R 1选自C 1-4烷基、C 6-12芳基(例如苯基)和5-10元杂芳基(例如吡啶基或吡嗪基)，所述C 1-4烷基、C 6-12芳基和5-10元杂芳基各自任选地被下列取代基中的一个或多个取代：卤素、CN、NO 2、C 1-4烷基、C 3-8环烷基、C 1-4卤代烷基、C 1-4烷氧基、C 1-4卤代烷氧基、C 1-4羟烷基、4-10元杂环基、C 6-12芳基、5-10元杂芳基、9-12元芳基并杂环基、CO 2R 30、C(O)R 30、C(O)NR 31R 32、NR 33C(O)R 34、NR 31R 32、OC(O)R 30、OC(O)NR 31R 32、NR 33C(O)NR 31R 32、NR 33C(O)OR 30、S(O)NR 31R 32、S(O) 2NR 31R 32、S(O)R 35、S(O) 2R 35、OR 37和SR 37；
R 3选自OH、C 1-8烷基、4-10元杂环基、C 6-12芳基、NR 31R 32、NR 33C(O)R 34、NR 33S(O) 2R 34、C(O)NR 31R 32、9-12元芳基并杂环基、5-10元杂芳基和NR 33C(O)NR 31R 32，所述C 1-8烷基、4-10元杂环基、C 6-12芳基、5-10元杂芳基和9-12元芳基并杂环基各自任选地被下列取代基中的一个或多个取代：C 1-4烷基、C 1-4烷氧基、C 6-12芳基、C(O)R 30、C(O)NR 31R 32、NR 33C(O)R 34、NR 31R 32、S(O) 2R 35和OR 37；优选地，R 3选自OH、C 1-8烷基、4-10元杂环基、C 6-12芳基、NR 31R 32、NR 33C(O)R 34、NR 33S(O) 2R 34、C(O)NR 31R 32、9-12元芳基并杂环基、5-10元杂芳基和NR 33C(O)NR 31R 32，所述C 1-8烷基、4-10元杂环基、C 6-12芳基、5-10元杂芳基和9-12元芳基并杂环基各自任选地被下列取代基中的一个或多个取代：甲基、甲氧基、苯基、C(O)CH 3、C(O)NH 2、NHC(O)CH 3、NHC(O)H、NH 2、NH(CH 3)、S(O) 2CH 3和OH；
R 4和R 5各自独立地选自H、C 1-8烷基、C 1-8烷氧基和C 3-8环烷基，所述C 1-8烷基、C 1-8烷氧基和C 3-8环烷基各自任选地被下列取代基中的一个或多个取代：卤素、OH、CN、NO 2、C 1-6烷基、C 1-4卤代烷基和C 1-4羟烷基；或R 4、R 5和与其相连的氮原子一起形成4-7元杂环；
X 1选自C(R 7) 2、NR 7、O和S；
V不存在，或者选自C 1-8亚烷基、C(R 36aR 36b)、O、S、NR 33、SO、SO 2和CO，所述C 1-8亚烷基任选地被下列取代基中的一个或多个取代：卤素、OH、CN、NO 2、C 1-6烷基、C 1-4卤代烷基、C 1-4羟烷基和C 1-4烷氧基；
V与X 1不同时为杂原子N、O或S；
L为-(L 1) n-(L 2) p-(L 3) q-，其中L 1、L 2和L 3相同或不同，并且各自独立地选自C 1-8亚烷基(例如C 1-3亚烷基)、C 2-8亚烯基、C 2-8亚炔基、C 1-8卤代亚烷基、C 1-8亚烷氧基、C 1-8卤代亚烷氧基、C 1-8羟亚烷基、C 3-8亚环烷基、4-10元亚杂环基、C 6-12亚芳基、5-10元亚杂芳基、O、S、NR 33、SO、SO 2、-CO-和-C(R 36aR 36b)-，所述C 1-8亚烷基、C 2-8亚烯基、C 2-8亚炔基、C 1-8卤代亚烷基、C 1-8亚烷氧基、C 1-8卤代亚烷氧基、C 1-8羟亚烷基、C 3-8亚环烷基、4-10元亚杂环基、C 6-12亚芳基和5-10元亚杂芳基各自任选地被下列取代基中的一个或多个取代：卤素、OH、CN、NO 2、C 1-6烷基、C 1-4卤代烷基、C 1-4羟烷基和C 1-4烷氧基；
n、p、q各自独立地为0或1。
在本发明的优选实施方案中，所述化合物具有式IV的结构，其中：
R 1选自异丁基、
Figure PCTCN2019113877-appb-000025
Figure PCTCN2019113877-appb-000026
R 3选自OH、-NHC(O)CH 3、-C(O)NH 2、-N(CH 2CH 3)C(O)N(CH 3) 2、
Figure PCTCN2019113877-appb-000027
Figure PCTCN2019113877-appb-000028
R 4和R 5均为H；
X 1选自O、NH和N(CH 3)；
V不存在，或者选自CO和亚甲基；
L不存在，或者选自亚丙基、亚乙基、-C 1-3亚烷基-O-(例如-亚乙基-O-或-亚丙基-O-)和-C 1-3亚烷基-NH-(例如-亚乙基-NH-)。
在本发明的一些实施方案中，本发明的化合物选自，但不限于：
Figure PCTCN2019113877-appb-000029
Figure PCTCN2019113877-appb-000030
Figure PCTCN2019113877-appb-000031
在另一方面，本发明提供一种药物组合物，其包含如上所述的化合物，所述化合物的立体异构体、互变异构体或其混合物，所述化合物的药学上可接受的盐、共晶、多晶型物或溶剂合物，或者所述化合物的稳定同位素衍生物、代谢物或前药。任选地，所述药物组合物还包含一种或多种药学上可接受的载体。
在一些实施方案中，所述药物组合物用于预防和/或治疗与NLRP3炎症小体活性相关的疾病(例如肿瘤疾病)。
任选地，本发明的药物组合物还包含一种或多种第二治疗剂。在某些实施方案中，所述第二治疗剂包括治疗肿瘤疾病等的其他药物。
在另一方面，本发明提供一种药物制剂，其包含如上所述的化合物，所述化合物的立体异构体、互变异构体或其混合物，所述化合物的药学上可接受的盐、共晶、多晶型物或溶剂合物，或者所述化合物的稳定同位素衍生物、代谢物或前药，或者如上所述的药物组合物。
在另一方面，本发明提供如上所述的化合物，所述化合物的立体异构体、互变异构体或其混合物，所述化合物的药学上可接受的盐、共晶、多晶型物或溶剂合物，或者所述化合物的稳定同位素衍生物、代谢物或前药，或者如上所述的药物组合物用于制备药物的用途，所述药物用于预防和/或治疗与NLRP3炎症小体活性相关的疾病(例如肿瘤疾病)。
在另一方面，本发明提供如上所述的化合物，所述化合物的立体异构体、互变异构体或其混合物，所述化合物的药学上可接受的盐、共晶、多晶型物或溶剂合物，或者所述化合物的稳定同位素衍生物、代谢物或前药，或者如上所述的药物组合物用于制备制剂的用途，所述制剂用于调节(例如增加)NLRP3炎症小体的活性。
在一些实施方案中，所述制剂被施用至受试者(例如哺乳动物；例如牛科动物、马科动物、羊科动物、猪科动物、犬科动物、猫科动物、啮齿类动物、灵长类动物；例如，人)体内，以增加受试者体内细胞中的NLRP3炎症小体活性；或者，所述制剂被施用至体外细胞(例如细胞系或者来自受试者的细胞)，以增加细胞中NLRP3炎症小体的活性。
在另一方面，本发明提供一种调节(例如增加)细胞中NLRP3炎症小体活性的方法，其包括给所述细胞施用有效量的如上所述的化合物，所述化合物的立体异构体、互变异构体或其混合物，所述化合物的药学上可接受的盐、共晶、多晶型物或溶剂合物，或者所述化合物的稳定同位素衍生物、代谢物或前药，或者如上所述的药物组合物，或者如上所述的药物制剂。
在另一方面，本发明提供一种用于调节(例如增加)NLRP3炎症小体的活性的试剂盒，所述试剂盒包括如上所述的化合物，所述化合物的立体异构体、互变异构体或其混合物，所述化合物的药学上可接受的盐、共晶、多晶型物或溶剂合物，或者所述化合物的稳定同位素衍生物、代谢物或前药，或者如上所述的药物组合物，或者如上所述的制剂。
另一方面，本发明提供治疗与NLRP3炎症小体活性相关的疾病(例如肿瘤疾病)的方法，其包括给有此需要的受试者施用治疗和/或预防有效量的如上所述的化合物，所述化合物的立体异构体、互变异构体或其混合物，所述化合物的药学上可接受的盐、共晶、多晶型物或溶剂合物，或者所述化合物的稳定同位素衍生物、代谢物或前药，或如上所述的药物组合物，或如上所述的制剂。
任选地，所述方法还包括给有此需要的受试者施用一种或多种第二治疗剂。在一些实施方案中，所述第二治疗剂包括治疗肿瘤等疾病的其他药物。
在另一方面，本发明提供如上所述的化合物，所述化合物的立体异构体、互变异构体或其混合物，所述化合物的药学上可接受的盐、共晶、多晶型物或溶剂合物，或者所述化合物的稳定同位素衍生物、代谢物或前药，所述的药物组合物、药物制剂或者试剂盒，用于预防和/或治疗与NLRP3炎症小体活性相关的疾病(例如肿瘤疾病)。
本发明中，所述肿瘤疾病包括但不限于：脑瘤、肺癌、鳞状上皮细胞癌、膀胱癌、胃癌、卵巢癌、腹膜癌、胰腺癌、乳腺癌、头颈癌、子宫颈癌、子宫内膜癌、直肠癌、肝癌、肾癌、食管腺癌、食管鳞状细胞癌、前列腺癌、雌性生殖道癌、原位癌、淋巴瘤、神经纤维瘤、甲状腺癌、骨癌、皮肤癌、脑癌、结肠癌、睾丸癌、胃肠道间质瘤、前列腺肿瘤、肥大细胞肿瘤、多发性骨髓瘤、黑色素瘤、胶 质瘤或肉瘤。
在一些实施方案中，本发明的化合物为全激动剂(full agonists)；在一些实施方案中，本发明的化合物为部分激动剂(partial agonists)。
发明详述
术语定义
除非在下文中另有定义，本文中所用的所有技术术语和科学术语的含义意图与本领域技术人员通常所理解的相同。提及本文中使用的技术意图指在本领域中通常所理解的技术，包括那些对本领域技术人员显而易见的技术的变化或等效技术的替换。虽然相信以下术语对于本领域技术人员很好理解，但仍然阐述以下定义以更好地解释本发明。
术语“激动剂(agonist)”指的是一种与受体结合并将其激活而引发下游的生物学效应或应答的化合物，包括全激动剂(full agonist)和部分激动剂(partial agonist)。全激动剂能激活受体并产生最大的效应(maximal effect或E max)。部分激动剂可以和受体结合并将其激活，但相对于完全激动剂而言，只产生部分的效应(partial effect)。当全激动剂和部分激动剂共存时，部分激动剂有时可以通过与全激动剂竞争受体上的结合位点或其他机制而成为部分拮抗剂。一个部分激动剂的效力(potency，可由EC 50(产生50％的E max时的化合物浓度)衡量)有可能高于或低于于一个全激动剂的效力。本发明的NLRP3激动剂包括NLRP3全激动剂和NLRP3部分激动剂。
术语“NLRP3”的全称是NLR family pyrin domain containing 3，是一种炎症小体。本发明中，当提及“NLRP3”时，所指的含义包括NLRP3的核酸、多聚核苷酸、寡核苷酸、正义和反义多聚核苷酸链、互补序列、短肽、多肽、蛋白、同源或异源分子、亚型、前体、突变体、变体、衍生物、各种剪接体、等位基因、不同种属以及活化片段等。
术语“包括”、“包含”、“具有”、“含有”或“涉及”及其在本文中的其它变体形式为包含性的(inclusive)或开放式的，且不排除其它未列举的元素或方法步骤。
术语“卤代”是指被卤素原子所取代，所述“卤素”包括F、Cl、Br或I。
术语“烷基”为直链或支链的饱和脂肪烃基。术语“C 1-8烷基”、“C 1-6烷基”和“C 1-4烷基”分别指具有1至8个碳原子、1至6个碳原子和1至4个碳原子的直链或支链烷基，例如甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基或正己基。所述烷基可以任选地被一个或多个(诸如1至3个)相同或不同的取代基取代。
术语“亚烷基”指从直链或支链的饱和烃基中去掉两个氢原子所得到的饱和的二价烃基，其含有指定的碳原子数目。例如1至8个碳原子的亚烷基，例如亚甲基(-CH 2-)、亚乙基(-CH 2CH 2-)、亚丙基(-CH 2CH 2CH 2-)、亚异丙基(-CH(CH 3)CH 2-)等。所述亚烷基可以任选地被一个或多个(诸如1至3个)相同或不同的取代基取代。
术语“卤代烷基”是指被一个或多个(诸如1至3个)相同或不同的卤素原子取代的烷基，术语“C 1-8卤代烷基”、“C 1-6卤代烷基”和“C 1-4卤代烷基”分别指具有1至8个碳原子、1至6个碳原子和1至4个碳原子的卤代烷基，例如-CF 3、-C 2F 5、-CHF 2、-CH 2F、-CH 2CF 3、-CH 2Cl、-CH 2CH 2CF 3等。
术语“羟烷基”是指烷基的氢原子被一个或多个羟基取代所形成的基团，例如C 1-4羟烷基或C 1-3羟烷基，其实例包括但不限于羟甲基、羟乙基、羟丙基、羟丁基、-CH(OH)CH 3等。
术语“烯基”是指含有一个或多个碳-碳双键的单价直链或支链烃基，例如-CH＝CH 2、-CH 2CH＝CH 2、-C(CH 3)＝CH 2、-CH 2-CH＝CH-CH 3等。所述烯基可以任选地被一个或多个(诸如1至3个)相同或不同的取代基取代。
术语“亚烯基”指含有一个或多个碳-碳双键的的二价直链或支链脂肪烃基团，其含有指定的碳原子数目，例如2至8个碳原子，例如-CH＝CH-、-CH 2CH＝CH-、-C(CH 3)＝CH-等。所述亚烯基可以任选地被一个或多个(诸如1至3个)相同或不同的取代基取代。
术语“炔基”是指具有一个或多个碳-碳三键的单价直链或支链烃基，包括但不限于乙炔基、2-丙炔基、2-丁炔基、1,3-丁二炔基等。所述炔基可以任选地被一个或多个(诸如1至3个)相同或不同的取代基取代。
术语“亚炔基”是指具有一个或多个碳-碳三键的二价直链或支链烃基，其含有指定的碳原子数目，例如2到8个碳原子，包括但不限于
Figure PCTCN2019113877-appb-000032
等。所述亚炔基可以任选地被一个或多个(诸如1至3个)相同或不同的取代基取代。
术语“烷氧基”意指在烷基(如上文所定义)任意合理的位置插入氧原子的基团，优选为C 1-8烷氧基、 C 1-6烷氧基、C 1-4烷氧基或C 1-3烷氧基。C 1-6烷氧基的代表性实例包括但不限于甲氧基、乙氧基、丙氧基、异丙氧基、正丙氧基、异丙氧基、正丁氧基、异丁氧基、叔丁氧基、戊氧基、己氧基、-CH 2-OCH 3等。所述烷氧基可以任选地被一个或多个(诸如1至3个)相同或不同的取代基取代。
术语“亚烷氧基”指二价的烷氧基，例如-OCH 2-、-OCH(CH 3)CH 2-、-OCH 2CH 2O-、-CH 2CH 2O-等。所述亚烷氧基可以任选地被一个或多个(诸如1至3个)相同或不同的取代基取代。
术语“并环”或“稠环”指由两个或两个以上环状结构彼此共用两个相邻的原子所形成的环系。
术语“螺环”指由两个或两个以上环状结构彼此共用一个环原子所形成的环系。
术语“桥环”指由两个或两个以上环状结构彼此共用两个不直接相连的原子所形成的环系。
术语“环烷基”指饱和或不饱和的非芳族单环或多环(诸如双环)烃环基，包括但不限于单环烷基(诸如环丙基、环丁基、环戊基、环己基、环庚基、环辛基、环壬基)和双环烷基，包括螺环、并环(稠环)或桥环系统(即，螺环烷基、并环(稠环)烷基和桥环烷基，诸如双环[1.1.1]戊基、双环[2.2.1]庚基等)。本发明中，环烷基可以任选地被一个或多个(诸如1至3个)相同或不同的取代基取代。环烷基上的碳原子任选地被氧代(oxo)基团取代(即形成C＝O)。
术语“亚环烷基”指如本文定义的环烷基，其具有自母体环烷基的相同碳原子或两个不同碳原子上去除两个氢原子而得到的两个单价基团中心。典型的亚环烷基包括但不限于亚环丙基、亚环丁基、亚环戊基、亚环己基、亚环庚基、亚环辛基、亚环壬基、亚环己烯基等。
术语“3-7元环烷基”指具有3至7个成环碳原子的环烷基，其可以是单环烷基，例如环丙基、环丁基、环戊基、环己基或环庚基，也可以是双环烷基，例如C 5-7螺环烷基、C 5-7桥环烷基或C 4-7稠环烷基。
术语“C 3-8环烷基”指具有3至8个成环碳原子的环烷基，例如C 3-6环烷基，其可以是单环烷基，例如环丙基、环丁基、环戊基、环己基、环庚基或环辛基，也可以是双环烷基，例如C 3-8螺环烷基、C 3-8桥环烷基、C 3-8稠环烷基、C 3-6螺环烷基、C 3-6桥环烷基或C 3-6稠环烷基。
术语“芳基”指具有共轭π电子系统的全碳单环或稠合多环芳族基团。如本文中所使用，术语“C 6-12芳基”意指含有6至12个碳原子的芳基，优选为C 6-10芳基，优选为苯基或萘基。芳基任选地被一个或多个(诸如1至3个)相同或不同的取代基(例如卤素、OH、CN、NO 2、C 1-6烷基等)取代。
术语“亚芳基”指如本文定义的芳基，其具有自母体芳基的相同碳原子或两个不同碳原子上去除两个氢原子而得到的两个单价基团中心。典型的亚芳基包括但不限于亚苯基和亚萘基。
术语“芳基并环烷基”是指芳基与环烷基(例如单环烷基)彼此共用两个相邻的原子形成的并环基团，其中与其他基团的连接点可以在芳基上或在环烷基上。术语“9-12元芳基并环烷基”是指共计包含9-12个环原子的芳基并环烷基，例如苯并环戊基、苯并环己基，例如
Figure PCTCN2019113877-appb-000033
术语“杂环基”指具有2个或2个以上(例如3、4、5、6、7、8、9、10、11、12、13或14个)碳原子，以及一个或多个(例如1个、2个、3个或4个)杂原子的单环或多环(例如并环、螺环或桥环)基团，所述杂原子包括但不限于氧原子、氮原子或硫原子，所述杂环基上的碳原子和杂原子任选地被氧代基团取代(例如形成C＝O、S(＝O)或S(＝O) 2)。
术语“亚杂环基”指如本文定义的杂环基，其具有自母体杂环基的相同碳原子或两个不同碳原子、自一个碳原子和一个杂原子或者自两个杂原子上去除两个氢原子而得到的两个单价基团中心。
术语“3-14元杂环基”意指含有3-14个环原子的杂环基，包括但不限于4-10元杂环基、4-8元杂环基、4-7元杂环基、5-6元杂环基、3-8元杂环基、3-7元杂环基、4-7元含氮杂环基、4-7元含氧杂环基、4-7元含硫杂环基、5-6元含氮杂环基、5-6元含氧杂环基、5-6元含硫杂环基等，所述“含氮杂环基”、“含氧杂环基”和“含硫杂环基”各自任选地还含有一个或多个选自氧、氮和硫的其他杂原子。3-14元杂环基的实例包括但不限于环氧乙烷基、氮丙啶基、氮杂环丁基、氧杂环丁基、四氢呋喃基、吡咯烷基、吡咯烷酮基、咪唑烷基、吡唑烷基、四氢吡喃基、哌啶基、吗啉基、二噻烷基(dithianyl)、硫吗啉基、哌嗪基、三噻烷基(trithianyl)、
Figure PCTCN2019113877-appb-000034
等。
本发明中，杂环基还包括并环结构，所述并环结构与其他基团的连接点可以在并环结构中的任一环上。因此，本发明的杂环基还包括(但不限于)杂环基并杂环基、杂环基并环烷基、单杂环基并单杂环基、单杂环基并单环烷基，例如3-7元(单)杂环基并3-7元(单)杂环基、3-7元(单)杂环基并(单)环烷基、3-7元(单)杂环基并C 4-6(单)环烷基等，其实例包括但不限于吡咯烷基并环丙基、环戊基并氮杂环 丙基、吡咯烷基并环丁基、吡咯烷基并吡咯烷基、吡咯烷基并哌啶基、吡咯烷基并哌嗪基、哌啶基并吗啉基、
Figure PCTCN2019113877-appb-000035
等。
本发明中，杂环基还包括桥杂环基和螺杂环基。
术语“桥杂环基”是指两个饱和环共用两个不直接相连的环原子形成的含有一个或多个(例如1个、2个、3个或4个)杂原子(例如氧原子、氮原子或硫原子)的环状结构，包括但不限于7-10元桥杂环基、8-10元桥杂环基、7-10元含氮桥杂环基、7-10元含氧桥杂环基、7-10元含硫桥杂环基等，例如
Figure PCTCN2019113877-appb-000036
Figure PCTCN2019113877-appb-000037
Figure PCTCN2019113877-appb-000038
等。所述“含氮桥杂环”、“含氧桥杂环”、“含硫桥杂环”各自任选地还含有一个或多个选自氧、氮和硫的其他杂原子。
术语“螺杂环基”是指由两个或两个以上饱和环共用一个环原子形成的含有一个或多个(例如1个、2个、3个或4个)杂原子(例如氧原子、氮原子或硫原子)的环状结构，包括但不限于5-10元螺杂环基、6-10元螺杂环基、6-10元含氮螺杂环基、6-10元含氧螺杂环基、6-10元含硫螺杂环等，例如
Figure PCTCN2019113877-appb-000039
Figure PCTCN2019113877-appb-000040
Figure PCTCN2019113877-appb-000041
等。所述“含氮螺杂环”、“含氧螺杂环”和“含硫螺杂环”各自任选地还含有一个或多个选自氧、氮和硫的其他杂原子。术语“6-10元含氮螺杂环基”是指含有共计6-10个环原子并且其中至少一个环原子为氮原子的螺杂环基。
术语“芳基并杂环基”指芳基与杂环基彼此共用两个相邻的碳原子所形成的环状基团(其中芳基和杂环基如上文所定义)，其与其他基团的连接点在可以在芳基或杂环基上。例如，如本文中所使用，术语“9-12元芳基并杂环基”意指含有共计9-12个环原子的芳基并杂环基的基团，包括但不限于9-10元苯并杂环基，例如苯并5-8元杂环基，例如苯并5-6元杂环基，例如苯并5-6元单杂环基、苯并5-6元含氮单杂环基、苯并5-6元含氧单杂环基、苯并5-6元含硫杂环基等。所述“含氮杂环基”、“含氧杂环基”和“含硫杂环基”各自任选地还含有一个或多个选自氧、氮和硫的其他杂原子。所述杂环基上的碳原子和杂原子任选地被氧代基团取代(例如形成C＝O、S(＝O)或S(＝O) 2)。芳基并杂环基的实例包括但不限于：吲唑基、
Figure PCTCN2019113877-appb-000042
术语“杂芳基”指含有一个或多个相同或不同杂原子的单环或多环芳族基团，包括单环杂芳基和含有至少一个杂芳环(至少含有一个杂原子的芳族环系)的双环或多环环系，其可以具有5、6、7、8、9、10、11、12、13或14个环原子，例如5、6、7、8、9或10个环原子。所述杂原子可以是氧、氮或硫。所述杂芳基上的碳原子和杂原子任选地被氧代基团取代(例如形成C＝O、S(＝O)或S(＝O) 2)。
术语“亚杂芳基”是指如上所述的杂芳基，其具有自母体杂芳基的相同碳原子或两个不同碳原子上去除两个氢原子或是自碳原子上去除一个氢原子且自氮原子上去除一个氢原子而得到的两个单价 基团中心。
术语“5-10元杂芳基”意指含有5至10个环原子的杂芳基，包括5-6元杂芳基，5-6元单杂芳基、5-10元含氮杂芳基、5-10元含氧杂芳基、5-10元含硫杂芳基、5-6元含氮杂芳基、5-6元含氧杂芳基、5-6元含硫杂芳基、5-6元含氮单杂芳基、5-6元含氧单杂芳基、5-6元含硫单杂芳基等。所述“含氮杂芳基”、“含氧杂芳基”、“含硫杂芳基”、“含氮单杂芳基”、“含氧单杂芳基”和“含硫单杂芳基”各自任选地还含有一个或多个选自氧、氮和硫的其他杂原子。5-10元杂芳基的实例包括但不限于噻吩基、呋喃基、吡咯基、噁唑基、噻唑基、咪唑基、吡唑基、异噁唑基、异噻唑基、三唑基、四唑基、噁二唑基、噻二唑基、吡啶基、哒嗪基、嘧啶基、吡嗪基、三嗪基等，以及包含这些基团的5-10元并环基团。
本发明中，术语“杂芳基”涵盖并环结构，即杂芳环(例如单杂芳基)可以与芳基(例如单环芳基，例如苯基)、杂环基(例如单杂环基)、环烷基(例如单环烷基)或另一杂芳环(例如另一单杂芳基)彼此共用两个相邻的原子形成的并环结构，其与其他基团的连接点可以在任一杂芳环上或其它环上，包括但不限于(单)杂芳基并(单)杂芳基、(单)杂芳基并(单环)芳基、(单)杂芳基并(单)杂环基或(单)杂芳基并(单)环烷基，例如5-6元(单)杂芳基并5-6元(单)杂芳基、5-6元(单)杂芳基并苯基、5-6元(单)杂芳基并5-6元(单)杂环基或5-6元(单)杂芳基并C 4-6(单)环烷基(例如5-6元杂芳基并环丁基、5-6元杂芳基并环戊基或5-6元杂芳基并环己基)，其实例包括但不限于吲哚基、异吲哚基、吲唑基、苯并咪唑、喹啉基、异喹啉基、
Figure PCTCN2019113877-appb-000043
Figure PCTCN2019113877-appb-000044
等。
术语“杂芳基”所涵盖的含芳基的并环结构也称为“芳基并杂芳基”，是芳基(例如单环芳基，例如苯基)与杂芳基(例如单杂芳基，例如5-6元单杂芳基)形成的并环基团，其与其他基团的连接点可以在芳环上，也可以在杂芳环上。所述“芳基并杂芳基”包括但不限于单环芳基并单杂芳基。术语“9-12元芳基并杂芳基”是指含有共计9-12个环原子的芳基并杂芳基，例如苯并5-6元含氮单杂芳基。
术语“杂芳基”所涵盖的含环烷基的并环结构也称为“杂芳基并环烷基”，是杂芳基(例如单杂芳基，例如5-6元单杂芳基)与环烷基(例如C 4-6环烷基)形成的并环基团，其与其他基团的连接点可以在杂芳环上，也可以在环烷基上。所述“杂芳基并环烷基”包括但不限于单杂芳基并单环烷基。术语“9-10元杂芳基并环烷基”是指含有共计9-10个环原子的杂芳基并环烷基，例如4-6元含氮单杂芳基并C 4-6单环烷基。
术语“取代”指所指定的原子上的一个或多个(例如1个、2个、3个或4个)氢被从所指出的基团的选择代替，条件是未超过所指定的原子在当前情况下的正常原子价并且所述取代形成稳定的化合物。取代基和/或变量的组合仅仅当这种组合形成稳定的化合物时才是允许的。
如果取代基被描述为“任选地被……取代”，则取代基可(1)未被取代或(2)被取代。如果取代基的碳被描述为任选地被取代基列表中的一个或多个取代，则碳上的一个或多个氢(至存在的任何氢的程度)可各自被独立地选择的任选的取代基替代。如果取代基的氮被描述为任选地被取代基列表中的一个或多个取代，则氮上的一个或多个氢(至存在的任何氢的程度)可各自被独立地选择的任选的取代基替代。
如果取代基被描述为“独立地选自”一组，则各取代基独立于另一者被选择。因此，各取代基可与另一(其他)取代基相同或不同。
如本文中所使用，术语“一个或多个”意指在合理条件下的1个或超过1个，例如2个、3个、4个、5个、6个、7个、8个、9个或10个。
除非指明，否则如本文中所使用，取代基的连接点可来自取代基的任意适宜位置。
本发明还包括本发明化合物的所有药学上可接受的同位素化合物，其与本发明的化合物相同，除了一个或多个原子被具有相同原子序数但原子质量或质量数不同于在自然界中占优势的原子质量或质量数的原子替代。适合包含入本发明的化合物中的同位素的实例包括(但不限于)氢的同位素(例如 2H、 3H)；碳的同位素(例如 11C、 13C及 14C)；氯的同位素(例如 36Cl)；氟的同位素(例如 18F)；碘的同位素(例如 123I及 125I)；氮的同位素(例如 13N及 15N)；氧的同位素(例如 15O、 17O及 18O)；磷的同位素(例如 32P)；及硫的同位素(例如 35S)。术语“稳定的同位素衍生物”是指本发明的化合物中的一个或多个原子被具有相同原子序数但原子质量或质量数不同于在自然界中占优势的原子质量或质量数的原子替代所形成 的稳定的化合物。
术语“立体异构体”表示化合物由于含有至少一个不对称中心而形成的异构体。在具有一个或多个(例如1个、2个、3个或4个)不对称中心的化合物中，其可产生外消旋混合物、单一对映异构体、非对映异构体混合物和单独的非对映异构体。特定个别分子也可以几何异构体(顺式/反式)存在。本发明的化合物可以两种或更多种处于快速平衡的不同结构形式的混合物(通常称作互变异构体)存在。互变异构体的代表性实例包括酮-烯醇互变异构体、苯酚-酮互变异构体、亚硝基-肟互变异构体、亚胺-烯胺互变异构体等。例如，亚硝基-肟在溶液中可以下列互变异构形式平衡存在：
Figure PCTCN2019113877-appb-000045
要理解，本申请的范围涵盖所有这样的以任意比例(例如60％、65％、70％、75％、80％、85％、90％、95％、96％、97％、98％或99％)的异构体或其混合物。
除非另外指明，否则本发明的化合物意欲可以立体异构体(其包括顺式及反式异构体)、光学异构体(例如R及S对映异构体)、非对映异构体、几何异构体、旋转异构体、构象异构体、阻转异构体或其混合物的形式存在。本发明的化合物可表现一种以上类型的异构现象，且由其混合物(例如外消旋混合物及非对映异构体对)组成。
本发明涵盖本发明的化合物的所有可能的结晶形式或多晶型物，其可为单一多晶型物或多于一种多晶型物的任意比例的混合物。还应当理解，本发明的某些化合物可以游离形式存在用于治疗，或适当时，以其药学上可接受的衍生物形式存在。在本发明中，药学上可接受的衍生物包括但不限于：药学上可接受的盐、溶剂合物、代谢物或前药，在将它们向需要其的患者给药后，能够直接或间接提供本发明的化合物或其代谢物或残余物。因此，当在本文中提及“本发明的化合物”时，也意在涵盖化合物的上述各种衍生物形式。
本发明的化合物的药学上可接受的盐包括其酸加成盐及碱加成盐。例如六氟磷酸盐、葡甲胺盐等。适合的盐的综述参见Stahl及Wermuth的“Handbook of Pharmaceutical Salts:Properties,Selection,and Use”(Wiley-VCH,2002)。
本发明中“药学上可接受的载体”是指与治疗剂一同给药的稀释剂、辅剂、赋形剂或媒介物，并且其在合理的医学判断的范围内适于接触人类和/或其它动物的组织而没有过度的毒性、刺激、过敏反应或与合理的益处/风险比相应的其它问题或并发症。
在本发明的药物组合物中可使用的药学上可接受的载体包括但不限于无菌液体，例如水和油，包括那些石油、动物、植物或合成来源的油，例如花生油、大豆油、矿物油、芝麻油等。当所述药物组合物通过静脉内给药时，水是示例性载体。还可以使用生理盐水和葡萄糖及甘油水溶液作为液体载体，特别是用于注射液。适合的药物赋形剂包括淀粉、葡萄糖、乳糖、蔗糖、明胶、麦芽糖、白垩、硅胶、硬脂酸钠、单硬脂酸甘油酯、滑石、氯化钠、脱脂奶粉、甘油、丙二醇、水、乙醇等。所述组合物还可以视需要包含少量的湿润剂、乳化剂或pH缓冲剂。口服制剂可以包含标准载体，如药物级的甘露醇、乳糖、淀粉、硬脂酸镁、糖精钠、纤维素、碳酸镁等。适合的药学上可接受的载体的实例如在Remington’s Pharmaceutical Sciences(1990)中所述。
本发明的药物组合物可以系统地作用和/或局部地作用。为此目的，它们可以适合的途径给药，例如通过注射、静脉内、动脉内、皮下、腹膜内、肌内或经皮给药；或通过口服、含服、经鼻、透粘膜、局部、以眼用制剂的形式或通过吸入给药。
对于这些给药途径，可以适合的剂型给药本发明的药物组合物。
所述剂型包括但不限于片剂、胶囊剂、锭剂、硬糖剂、散剂、喷雾剂、乳膏剂、软膏剂、栓剂、凝胶剂、糊剂、洗剂、软膏剂、水性混悬剂、可注射溶液剂、酏剂、糖浆剂。
如本文中所使用的术语“有效剂量”指被给药后会在一定程度上缓解所治疗病症的一或多种症状的化合物的量。
可调整给药方案以提供最佳所需响应。例如，可给药单次推注，可随时间给药数个分剂量，或可如治疗情况的急需所表明而按比例减少或增加剂量。要注意，剂量值可随要减轻的病况的类型及严重性而变化，且可包括单次或多次剂量。要进一步理解，对于任何特定个体，具体的给药方案应根据个体需要及给药组合物或监督组合物的给药的人员的专业判断来随时间调整。
所给药的本发明的化合物的量会取决于所治疗的个体、病症或病况的严重性、给药的速率、化合物的处置及处方医师的判断。一般而言，有效剂量在每日每kg体重约0.0001至约50mg，例如约0.01至约10mg/kg/日(单次或分次给药)。对70kg的人而言，这会合计为约0.007mg/日至约3500mg/日，例如约0.7mg/日至约700mg/日。在一些情况下，不高于前述范围的下限的剂量水平可以是足够的，而 在其它情况下，仍可在不引起任何有害副作用的情况下采用较大剂量，条件是首先将所述较大剂量分成数个较小剂量以在一整天中给药。
本发明的化合物在药物组合物中的含量或用量可以是约0.01mg至约1000mg。
除非另外说明，否则如本文中所使用，术语“治疗(treating)”意指逆转、减轻、抑制这样的术语所应用的病症或病况、或者这样的病症或病况的一或多种症状的进展，或预防这样的病症或病况、或者这样的病症或病况的一或多种症状。
如本文所使用的“个体”包括人或非人动物。示例性人个体包括患有疾病(例如本文所述的疾病)的人个体(称为患者)或正常个体。本发明中“非人动物”包括所有脊椎动物，例如非哺乳动物(例如鸟类、两栖动物、爬行动物)和哺乳动物，例如非人灵长类、家畜和/或驯化动物(例如绵羊、犬、猫、奶牛、猪等)。
本发明的化合物可以溶剂合物(优选水合物)的形式存在，其中本发明的化合物包含作为所述化合物晶格的结构要素的极性溶剂，特别是例如水、甲醇或乙醇。极性溶剂特别是水的量可以化学计量比或非化学计量比存在。
在本发明的范围内还包括本发明的化合物的代谢物，即在给药本发明的化合物时体内形成的物质。这样的产物可由例如被给药的化合物的氧化、还原、水解、酰胺化、脱酰胺化、酯化、脱脂化、酶解等产生。因此，本发明包括本发明的化合物的代谢物，包括通过使本发明的化合物与哺乳动物接触足以产生其代谢产物的时间的方法得到的化合物。
本发明在其范围内进一步包括本发明的化合物的前药，其为自身可具有较小药理学活性或无药理学活性的本发明的化合物的某些衍生物，当被给药至身体中或其上时可通过例如水解裂解转化成具有期望活性的本发明的化合物。通常这样的前药会是所述化合物的官能团衍生物，其易于在体内转化成期望的治疗活性化合物。关于前药的使用的其他信息可参见“Pro-drugs as Novel Delivery Systems”，第14卷，ACS Symposium Series(T.Higuchi及V.Stella)及“Bioreversible Carriers in Drug Design,”Pergamon Press,1987(E.B.Roche编辑，American Pharmaceutical Association)。本发明的前药可例如通过用本领域技术人员已知作为“前-部分(pro-moiety)(例如“Design of Prodrugs”，H.Bundgaard(Elsevier,1985)中所述)”的某些部分替代本发明的化合物中存在的适当官能团来制备。
本发明还涵盖含有保护基的本发明的化合物。在制备本发明的化合物的任何过程中，保护在任何有关分子上的敏感基团或反应基团可能是必需的和/或期望的，由此形成本发明的化合物的化学保护的形式。这可以通过常规的保护基实现，例如，在Protective Groups in Organic Chemistry,ed.J.F.W.McOmie,Plenum Press,1973；和T.W.Greene&P.G.M.Wuts,Protective Groups in Organic Synthesis,John Wiley&Sons,1991中所述的那些保护基，这些参考文献通过援引加入本文。使用本领域已知的方法，在适当的后续阶段可以移除保护基。
本文用
Figure PCTCN2019113877-appb-000046
表示结构式中的键为单键或双键。
本文用
Figure PCTCN2019113877-appb-000047
表示双键位置不确定，但仍保证其所在的环具有芳香性。
本文用
Figure PCTCN2019113877-appb-000048
表示结构式中的键存在或不存在。
本文中所述“室温”是指15-30℃。
制备方法
化合物II-A的合成方法1
Figure PCTCN2019113877-appb-000049
其中R 1、R 2、R 3、R 4、R 5和L如上述式I所定义。
第一步：化合物II-1在碱性条件下取代生成中间体II-2。
所用溶剂为DMF、DMSO、THF、CH 3CN、DCM等，所用碱为三乙胺、N,N-二异丙基乙胺、碳酸钾、叔丁醇钾、氢氧化钠等，温度为-20℃至180℃。
第二步：化合物II-2在碱性条件下取代生成中间体II-3。
所用溶剂为DMF、DMSO、THF、CH 3CN、DCM等，所用碱为三乙胺、N,N-二异丙基乙胺、碳酸钾、叔丁醇钾、氢氧化钠等，温度为20℃至150℃。
第三步：化合物II-3被还原成中间体II-4。
所用还原剂为Zn粉/甲酸铵、Zn粉/氯化铵、保险粉、Fe粉/甲酸铵等，溶剂为甲醇、乙醇、THF等，温度为20℃至110℃。
第四步：化合物II-4经过缩合反应生成中间体II-5。
所用缩合试剂为HATU、HBTU、TBTU、EDCI等，溶剂为THF、DMF、1,4-二氧六环等，温度为20℃至100℃。
第五步：化合物II-5在碱性条件下关环生成中间体II-6。
所用碱为三乙胺、N,N-二异丙基乙胺、碳酸钾、叔丁醇钾、氢氧化钠等，溶剂为MeOH、EtOH、THF、1,4-二氧六环等，温度为20℃至150℃。
第六步：化合物II-6在碱性条件下进行偶联反应生成中间体II-7。
所用偶联试剂为四(三苯基膦)钯(0)、三(双亚苄基丙酮)二钯(0)等，所用碱为双(三甲硅基)氨基钠、tBuOK、tBuONa、tBuOLi、NaH、NaOH、KOH、Cs 2CO 3、K 2CO 3、Na 2CO 3等，溶剂为甲苯、二甲苯、THF、DME、1,4-二氧六环、DMF、NMP、DMSO等，温度为0℃至160℃。
第七步：中间体II-7在酸性条件下进行脱保护基反应生成化合物II-A。
所用酸为三氟乙酸、三氟甲磺酸、醋酸、盐酸、硫酸、硝酸等，溶剂为DCM、1,4-二氧六环、甲醇、EA等，或者无需溶剂，直接用酸溶解，温度为-20℃至100℃。
化合物II-A的合成方法2
Figure PCTCN2019113877-appb-000050
第一步：化合物II-3在碱性条件下取代生成中间体II-8。
所用溶剂为DMF、DMSO、THF、CH 3CN、DCM等，所用碱为碳酸铯、三乙胺、N,N-二异丙基乙胺、碳酸钾、叔丁醇钾、氢氧化钠、丁基锂等，温度为20℃至180℃。
第二步：化合物II-8被还原成中间体II-9。
所用还原剂为Zn粉/甲酸铵、Zn粉/氯化铵、保险粉、Fe粉/甲酸铵等，溶剂为甲醇、乙醇、THF等，温度为20℃至110℃。
第三步：化合物II-9经过缩合反应生成中间体II-10。
所用缩合试剂为HATU、HBTU、TBTU、EDCI等，溶剂为THF、DMF、1,4-二氧六环等，温度为20℃至100℃。
第四步：化合物II-10在碱性条件下关环生成中间体II-11。
所用碱为三乙胺、N,N-二异丙基乙胺、碳酸钾、叔丁醇钾、氢氧化钠等，溶剂为MeOH、EtOH、THF、1,4-二氧六环等，温度为20℃至150℃。
第五步：中间体II-11在酸性条件下进行脱保护基反应生成化合物II-A。
所用酸为三氟乙酸、三溴化硼、三氯化硼、三氟甲磺酸、醋酸、盐酸、硫酸、硝酸等，溶剂为1,4-二氧六环、甲醇、EA等，或者无需溶剂，直接用酸溶解，温度为-20℃至100℃。
有益效果
本发明化合物对NLRP3及其信号通路有明显的激动活性，无明显毒副作用，可用于与NLRP3炎症小体活性相关的疾病(例如肿瘤)的治疗。
实施例
以下结合实施例进一步描述本发明，但提供这些实施例并非意图限制本发明的范围。
本文中的缩写具有以下含义：
Figure PCTCN2019113877-appb-000051
Figure PCTCN2019113877-appb-000052
化合物的结构通过核磁共振波谱( 1H NMR)或质谱(MS)来确证。
反应的监测采用硅胶薄层色谱法(TLC)或LC-MS进行。
微波反应使用BiotageInitiator+微波反应器进行。
柱色谱法一般使用200～300目硅胶(青岛海洋)为固定相。洗脱剂的体系包括：A：二氯甲烷和甲醇；B：PE和EA，溶剂的体积比根据化合物的极性不同而进行调节。
在以下实施例中，如无特殊说明，反应的温度为室温(15℃～30℃)。
本申请中所使用的试剂购自Acros Organics、Aldrich Chemical Company、特伯化学等公司。
实施例1：3-(4-氨基-1-甲基-6-((3-甲基苄基)氨基)-1H-咪唑并[4,5-c]吡啶-2-基)丙-1-醇(化合物1)
Figure PCTCN2019113877-appb-000053
第一步：2,6-二氯-N-甲基-3-硝基吡啶-4-胺(化合物1b)
将化合物1a(5.0g,24.15mmol)、K 2CO 3(6.66g,48.30mmol)、碘甲烷(8.29g,60.375mmol)加入乙腈(40mL)中，加热至80℃搅拌反应12h。反应结束后，用硅藻土过滤，滤液旋干后经快速柱层析(洗脱剂体系B)得到化合物1b(4.80g)。
MS(ESI,m/z):222.0[M+H] +.
第二步：6-氯-N 4-甲基-3-硝基-N 2-(2,4,4-三甲基戊-2-基)吡啶-2,4-二胺(化合物1c)
将化合物1b(4.80g,21.71mmol)、2,4,4-三甲基戊-2-胺(5.61g,43.42mmol)、三乙胺(6.58mg,65.13mmol)加入二氯甲烷(40mL)中，加热至40℃搅拌反应12h。反应结束后，旋干溶剂再经快速柱层析(洗脱剂体系B)得到化合物1c(5.10g)。
MS(ESI,m/z):315.1[M+H] +.
第三步：6-氯-N 4-甲基-N 2-(2,4,4-三甲基戊-2-基)吡啶-2,3,4-三胺(化合物1d)
将化合物1c(5.0g,15.87mmol)、锌粉(5.17g,79.35mmol)、HCOONH 4(3.0g,47.16mmol)加入MeOH(30mL)中，室温下搅拌反应3h。反应结束后，用硅藻土过滤，滤液旋干后经快速柱层析(洗脱剂体系B)得到化合物1d(3.60g)。
MS(ESI,m/z):270.2[M+H] +.
第四步：4-(苄氧基)-N-(6-氯-4-(甲基氨基)-2-((2,4,4-三甲基戊-2-基)氨基)吡啶-3-基)丁酰胺(化合物1e)
将化合物1d(3.60g,128.04μmol)、4-苄氧基丁酸(5.61g,43.42mmol)、HATU(6.58mg,65.13mmol)、DIPEA(5.17g,79.35mmol)加入DMF(15mL)中，N 2保护下室温搅拌反应12h。反应结束后，将反应液倾倒入冰水中，用EA萃取。浓缩有机相，再经快速柱层析(洗脱剂体系B)得到化合物1e(5.58g)。
MS(ESI,m/z):461.3[M+H] +.
第五步：2-(3-(苄氧基)丙基)-6-氯-1-甲基-N-(2,4,4-三甲基戊-2-基)-1H-咪唑并[4,5-c]吡啶-4-胺(化合物1f)
将化合物1e(5.50g,11.96mmol)、NaOH(1.44g,35.88mmol)加入乙醇(40mL)中，N 2保护下加热至90℃搅拌反应12h。反应结束后，用硅藻土过滤，滤液旋干后经快速柱层析(洗脱剂体系B)得到化合物1f(4.20g)。
MS(ESI,m/z):443.2[M+H] +.
第六步：2-(3-苄氧基丙基)-1-甲基-N 6-(3-甲基苄基)-N 4-(2,4,4-三甲基戊-2-基)-1H-咪唑并[4,5-c]吡啶-4,6-二胺(化合物1g)
将DavePhos(17.74mg,45.14μmol)、Pd 2(dba) 3(20.65mg,22.57μmol)、tBuOK(151.97mg,1.35mmol)加入到3-甲基苄胺(82.06mg,677.17μmol)、化合物1f(200mg,451.44μmol)的1,4-二氧六环(3mL)溶液中，然后氮气鼓泡两分钟除去氧气。将反应体系置于微波反应器中，加热至100℃反应1h。过滤除去不溶物，母液浓缩后通过硅胶薄层色谱制备板分离纯化(洗脱剂体系A)得到化合物1g(120mg)。
第七步：3-(4-氨基-1-甲基-6-((3-甲基苄基)氨基)-1H-咪唑并[4,5-c]吡啶-2-基)丙-1-醇(化合物1)
将三溴化硼(27.07mg,108.30μmol)加入到化合物1g(30.00mg,72.20μmol)的DCM(2mL)溶液中，然后保持室温反应5min。加水淬灭反应，用碳酸钾调节pH＝8。用EA(10mL)萃取，将有机相干燥、浓缩得到粗品，再通过Prep-HPLC纯化得到化合物1(10mg)。
Prep-HPLC条件：
仪器型号：Agilent 1260；色谱柱：Waters XBridge prep C18(19mm×150mm×5.0μm)；流动相：乙腈/0.05％NH 4HCO 3水溶液；洗脱梯度：0-16min乙腈10％-90％；流速：24ml/min；检测波长：214nm、254nm、280nm；化合物收集时间：6.7-7.1min。
MS(ESI,m/z):326.2[M+H] +.
1H NMR(400MHz,MeOD)δ7.18(dd,J＝13.8,6.7Hz,3H),7.04(d,J＝6.6Hz,1H),5.69(s,1H),4.35(s,2H),3.65(t,J＝6.2Hz,2H),3.55(s,3H),2.91–2.86(m,2H),2.31(s,3H),2.00(dd,J＝14.6,6.8Hz,2H).
实施例2：2-(3-(苄氧基)丙基)-1-甲基-N 6-(2-甲基苄基)-1H-咪唑并[4,5-c]吡啶-4,6-二胺(化合物2)
Figure PCTCN2019113877-appb-000054
第一步：2-(3-(苄氧基)丙基)-1-甲基-N 6-(2-甲基苄基)-N 4-(2,4,4-三甲基戊-2-基)-1H-咪唑并[4,5-c]吡啶-4,6-二胺(化合物2a)
将化合物1f(150mg,338.58μmol)、2-甲基苄胺(61.54mg,507.87μmol)、Pd 2(dba) 3(15.49mg,16.93μmol)、DavePhos(13.32mg,33.86μmol)、tBuOK(113.98mg,1.02mmol)加入1,4-二氧六环(5mL)中，氮气鼓泡两分钟除去氧气，并密闭。将反应体系置于微波反应器中，加热至100℃反应1h。用硅藻土过滤，滤液旋干后经快速柱层析(洗脱剂体系B)得到化合物2a(110mg)。
MS(ESI,m/z):528.2[M+H] +.
第二步：2-(3-(苄氧基)丙基)-1-甲基-N 6-(2-甲基苄基)-1H-咪唑并[4,5-c]吡啶-4,6-二胺(化合物2)
25℃下，将TFA(2mL)加入到化合物2a(110mg,473.72μmol)的DCM(3mL)溶液中并搅拌4h，LC-MS监测无明显原料剩余，经Prep-HPLC分离后冻干得到化合物2(9mg)。
Prep-HPLC条件：
仪器型号：Agilent 1260；色谱柱：Waters SunFire Prep C18 OBD(19mm×150mm×5.0μm)；色谱柱温：40℃；流速：28.0mL/min；检测波长：254nm；洗脱梯度：(0min：10％A，90％B；16min：90％A，10％B)；流动相A：100％乙腈；流动相B：0.05％甲酸水溶液；化合物收集时间：6.1-6.6min。
MS(ESI,m/z):416.2[M+H] +.
1H NMR(400MHz,MeOD)δ7.35–7.10(m,9H),4.47(s,2H),4.35(s,2H),3.60(t,J＝5.9Hz,2H),3.52(s,3H),2.90(t,J＝7.5Hz,2H),2.38(s,3H),2.15–2.03(m,2H).
实施例3：3-(4-氨基-1-甲基-6-(甲基(3-甲基苄基)氨基)-1H-咪唑并[4,5-c]吡啶-2-基)丙-1-醇(化合物3)
Figure PCTCN2019113877-appb-000055
第一步：2-(3-(苄氧基)丙基)-N 6,1-二甲基-N 6-(3-甲基苄基)-N 4-(2,4,4-三甲基戊-2-基)-1H-咪唑并[4,5-c]吡啶-4,6-二胺(化合物3a)
将化合物1f(120mg,270.87μmol)、N,3-二甲基苄胺(43.95mg,325.04μmol)、Pd 2(dba) 3(24.80mg,27.09μmol)、DavePhos(21.32mg,54.17μmol)、tBuOK(91.18mg,812.60μmol)加入1,4-二氧六环(3mL)中，N 2保护下加热至100℃反应3.5h。反应结束后，用硅藻土过滤，滤液旋干后经TLC(洗脱剂体系B)得到化合物3a(92mg)。
MS(ESI,m/z):542.4[M+H] +.
第二步：3-(4-氨基-1-甲基-6-(甲基(3-甲基苄基)氨基)-1H-咪唑并[4,5-c]吡啶-2-基)丙-1-醇(化合物3)
将化合物3a(92mg,169.81μmol)溶于二氯甲烷(10mL)中，室温下搅拌均匀后，向体系中加入三溴化硼的DCM混合液(30％,0.2mL)。反应结束后，加入无水甲醇(5mL)淬灭反应，用饱和碳酸氢钠水溶液调节pH＝7。浓缩后加水稀释，用EA萃取三次(20mL×3)。合并有机相后用无水硫酸钠干燥，经Prep-HPLC分离得到化合物3(18mg)。
Prep-HPLC条件：
仪器型号：Waters 2489；色谱柱：Waters SunFire Prep C18 OBD(19mm×150mm×5.0μm)；色谱柱温：25℃；流速：24.0mL/min；检测波长：214nm、254nm、280nm；洗脱梯度：(0min：30％A，70％B；4min：30％A，70％B；16.0min：90％A，10％B)；流动相A：100％乙腈；流动相B：0.05％碳酸氢铵水溶液。化合物收集时间：7.6-8.1min。
MS(ESI,m/z):340.2[M+H] +.
1H NMR(DMSO-d 6,400MHz)δ7.15(t,J＝7.4Hz,1H),6.99(dd,J＝12.5,8.3Hz,3H),5.76(s,1H),5.68(s,2H),4.76(s,2H),4.57(t,J＝5.0Hz,1H),3.54–3.46(m,5H),2.86(s,3H),2.80–2.73(m,2H),2.25(s,3H),1.90–1.79(m,2H).
实施例4：3-(4-氨基-6-[(4-溴苄基)(甲基)氨基]-1-甲基-1H-咪唑并[4,5-c]吡啶-2-基)丙-1-醇(化合物4)
Figure PCTCN2019113877-appb-000056
第一步：N 6-(4-溴苄基)-N 4,N 6-二甲基-3-硝基-N 2-(2,4,4-三甲基戊-2-基)吡啶-2,4,6-三胺(化合物4a)
将碳酸铯(309.71mg,952.96μmol)加入到N-甲基-4-溴苄胺(114.40mg,571.77μmol)、化合物1c(150mg,476.48μmol)的乙腈(5mL)溶液中，加热至80℃搅拌反应16h。加EA(10mL)稀释反应液，加水洗涤(5mL×3)。有机相干燥浓缩后，通过硅胶薄层色谱制备板分离纯化得到化合物4a(100mg)。
第二步：N 6-(4-溴苄基)-N 4,N 6-二甲基-N 2-(2,4,4-三甲基戊-2-基)吡啶-2,3,4,6-四胺(化合物4b)
依次将锌粉(67.93mg,1.05mmol)、氯化铵(55.91mg,1.05mmol)加入到化合物4a(100mg,209.02μmol)的甲醇(5mL)溶液中，然后保持室温反应5min，直到颜色消失。过滤除去不溶物，母液浓缩后得到化合物4b(60mg)。
第三步：4-苄氧基-N-[6-[(4-溴苄基)(甲基)氨基]-4-(甲基氨基)-2-[((2,4,4-三甲基戊-2-基)氨基)吡啶-3-基]丁酰胺(化合物4d)
依次将HATU(42.37mg,111.50μmol)、DIPEA(57.64mg,445.99μmol)加入到4-苄氧基丁酸(25.99mg,133.80μmol)、化合物4b(50mg,111.50μmol)的DMF(2mL)溶液中，然后保持25℃反应4h。加EA(10mL)，然后清水洗涤(5mL×3)。将EA层干燥、浓缩，通过硅胶薄层色谱制备板分离纯化(洗脱剂体系A)得到化合物4d(50mg)。
MS(ESI，m/z):624.2[M+H] +.
第四步：2-(3-(苄氧基)丙基)-N 6-(4-溴苄基)-N 6,1-二甲基-N 4-(2,4,4-三甲基戊-2-基)-1H-咪唑并[4,5-c]吡啶-4,6-二胺(化合物4e)
将氢氧化钠(12.81mg,320.18μmol)加入到化合物4d(50mg,80.04μmol)的乙醇(2mL)溶液中，然后加热至90℃反应4h。直接浓缩反应液至干，然后加水(5mL)。用EA萃取(5mL×3)，将有机相干燥、浓缩得到化合物4e(30mg)。
MS(ESI，m/z):606.3[M+H] +.
第五步：2-(3-(苄氧基)丙基)-N 6-(4-溴苄基)-N 6,1-二甲基-1H-咪唑并[4,5-c]吡啶-4,6-二胺(化合物4f)
将TFA(1.00mL)加入到化合物4e(30mg,49.45μmol)的DCM(1.00mL)溶液中，然后保持室温反应2h。减压浓缩除去溶剂，然后加水(5mL)，用碳酸钠调节pH＝8。用EA萃取，将有机相干燥、浓缩得到化合物4f(20mg)。
MS(ESI，m/z):496.1[M+H] +.
第六步：3-[4-氨基-6-[(4-溴苄基)(甲基)氨基]-1-甲基-1H-咪唑并[4,5-c]吡啶-2-基]丙-1-醇(化合物4)
缓慢地将三溴化硼(25.28mg,101.13μmol)加入到化合物4f(20mg,40.45μmol)的DCM(4mL)溶液中，室温搅拌反应5min。加水淬灭反应，用碳酸钠调节pH＝8。用EA(10mL)萃取，将有机相干燥、浓缩，然后通过Prep-HPLC纯化得到化合物4(3mg)。
Prep-HPLC条件：
仪器型号：Agilent 1260；色谱柱：Waters SunFire Prep C18 OBD(19mm×150mm×5.0μm)；流动相：乙腈/0.05％NH 4HCO 3水溶液；洗脱梯度：0-7.8min乙腈30％-49.5％；流速：24ml/min。检测 波长：214nm、254nm、280nm；化合物收集时间：7.1-7.5min。
MS(ESI，m/z):406.1[M+H] +.
1H NMR(400MHz,DMSO-d 6)δ7.48(d,J＝8.4Hz,2H),7.18(d,J＝8.4Hz,2H),5.78(s,1H),5.73(s,2H),4.79(s,2H),4.60(t,J＝5.1Hz,1H),3.55(s,3H),3.51(dd,J＝11.4,6.1Hz,2H),2.87(s,3H),2.81–2.76(m,2H),1.90–1.82(m,2H).
实施例5：3-(4-氨基-6-((3-甲氧基苄基)(甲基)氨基)-1-甲基-1H-咪唑并[4,5-c]吡啶-2-基)丙-1-醇(化合物5)
Figure PCTCN2019113877-appb-000057
第一步：2-(3-(苄氧基)丙基)-N 6,1-二甲基-N 4-(2,4,4-三甲基戊-2-基)-1H-咪唑并[4,5-c]吡啶-4,6-二胺(化合物5a)
将化合物1f(100mg,225.73μmol)、5b(40.90mg,270.88μmol)、Pd 2(dba) 3(20.65mg,22.57μmol)、DavePhos(17.76mg,45.14μmol)、tBuOK(50.65mg,451.46μmol)加入1,4-二氧六环(5mL)中，N 2保护下加热至100℃反应5h。反应结束后，用硅藻土过滤，滤液旋干后经快速柱层析(洗脱剂体系B)得到化合物5a(70mg)。
MS(ESI,m/z):558.4[M+H] +.
第二步：3-(4-氨基-6-((3-甲氧基苄基)(甲基)氨基)-1-甲基-1H-咪唑并[4,5-c]吡啶-2-基)丙-1-醇(化合物5)
将化合物5a(70mg,12.57μmol)溶于TFA(4mL)中，N 2保护下加热至80℃搅拌反应12h。反应结束后，将反应液减压浓缩至干，复溶于甲醇(2mL)中。用1N NaOH/H 2O溶液调节pH＝9.0，经Prep-HPLC分离得到化合物5(14mg)。
Prep-HPLC条件：
仪器型号：Agilent 1260；色谱柱：Waters SunFire Prep C18 OBD(19mm×150mm×5.0μm)；色谱柱温：25℃；流速：20.0mL/min；检测波长：214nm；洗脱梯度：(0min：10％A，90％B；16.0min：90％A，10％B)；流动相A：100％乙腈；流动相B：0.05％碳酸氢铵水溶液。化合物收集时间：6.25-6.90min。
MS(ESI,m/z):326.3[M+H] +.
1H NMR(DMSO-d 6,400MHz)δ7.27-7.29(m,2H),7.20-7.22(m,3H),5.79(s,1H),5.72(s,2H),4.82(s,2H),4.63(s,1H),3.54(s,3H),3.50-3.52(m,2H),2.88(s,3H),2.78-2.81(m,2H),1.86-1.88(m,2H).
实施例6：3-(4-氨基-1-甲基-6-(甲基(吡啶-3-基甲基)氨基)-1H-咪唑并[4,5-c]吡啶-2-基)丙-1-醇(化合物6)
Figure PCTCN2019113877-appb-000058
第一步：2-(3-(苄氧基)丙基)-N 6,1-二甲基-N 6-(吡啶-3-基甲基)-N 4-(2,4,4-三甲基戊-2-基)-1H-咪唑并[4,5-c]吡啶-4,6-二胺(化合物6g)
将DavePhos(8.87mg,22.57μmol)、Pd 2(dba) 3(10.33mg,11.29μmol)、tBuOK(75.98mg,677.17μmol)加入到N-甲基-1-(吡啶-3-基)甲胺(33.09mg,270.87μmol)、化合物1f(100mg,225.72μmol)的1,4- 二氧六环(3mL)溶液中，然后氮气鼓泡两分钟除去氧气。将反应体系置于微波反应器中，加热至100℃反应1h。过滤除去不溶物，母液浓缩后通过硅胶薄层色谱制备板分离纯化(洗脱剂体系A)得到化合物6g(80mg)。
第二步：2-(3-(苄氧基)丙基)-N 6,1-二甲基-N 6-(吡啶-3-基甲基)-1H-咪唑并[4,5-c]吡啶-4,6-二胺(化合物6h)
将TFA(2mL)加入到化合物6g(80.00mg,151.31μmol)的DCM(2mL)溶液中，然后保持室温反应4h。直接减压浓缩除去溶剂，得到化合物6h(50mg)。
MS(ESI,m/z):417.2[M+H] +.
第三步：3-(4-氨基-1-甲基-6-(甲基(吡啶-3-基甲基)氨基)-1H-咪唑并[4,5-c]吡啶-2-基)丙-1-醇(化合物6)
将三溴化硼(45.02mg,180.06μmol)加入到化合物6h(50.00mg,120.04μmol)的DCM(2mL)溶液中，然后保持室温反应5min。加水淬灭反应，用碳酸钾调节pH＝8。用EA(10mL)萃取，然后将有机相干燥、浓缩得到粗品，再通过Prep-HPLC得到化合物6(25mg)。
Prep-HPLC条件：
仪器型号：Agilent 1260；色谱柱：Waters SunFire Prep C18 OBD(19mm×150mm×5.0μm)，流动相：乙腈/0.05％NH 4HCO 3水溶液；洗脱梯度：0-16min 乙腈10％-60％；流速：24ml/min；检测波长：214nm、254nm、280nm；化合物收集时间：6.0-6.5min。
MS(ESI,m/z):327.2[M+H] +.
1H NMR(400MHz,DMSO-d 6)δ8.48(d,J＝1.7Hz,1H),8.41(dd,J＝4.7,1.6Hz,1H),7.61(dt,J＝7.8,1.8Hz,1H),7.29(dd,J＝7.6,4.9Hz,1H),5.78(s,1H),5.76(s,2H),4.82(s,2H),4.61(s,1H),3.53(s,3H),3.49(t,J＝6.1Hz,2H),2.88(s,3H),2.80–2.74(m,2H),1.89–1.81(m,2H).
实施例7：3-(4-氨基-6-((2,4-二氟苄基)氨基)-1-甲基-1H-咪唑并[4,5-c]吡啶-2-基)丙-1-醇(化合物7)
Figure PCTCN2019113877-appb-000059
第一步：2-(3-(苄氧基)丙基)-N 6-(2,4-二氟苄基)-1-甲基-N 4-(2,4,4-三甲基戊基-2-基)-1H-咪唑并[4,5-c]吡啶-4,6-二胺(化合物7a)
将化合物1f(80mg,180.58μmol)、2,4-二氟苄胺(31.02mg,216.69μmol)、Pd 2(dba) 3(16.54mg,18.06μmol)、DavePhos(14.21mg,36.12μmol)、tBuOK(60.79mg,541.73μmol)加入1,4-二氧六环(3mL)中，N 2保护下加热至100℃反应16h。反应结束后，用硅藻土过滤，滤液旋干后经TLC(洗脱剂体系B)得到化合物7a(70mg)。
MS(ESI,m/z):550.3[M+H] +.
第二步：3-(4-氨基-6-((2,4-二氟苄基)氨基)-1-甲基-1H-咪唑并[4,5-c]吡啶-2-基)丙-1-醇(化合物7)
将化合物7a(70mg,127.34μmol)溶于二氯甲烷(10mL)中，室温下搅拌均匀后，向体系中加入三溴化硼的DCM混合液(体积比为30％,0.2mL)。反应结束后，加入无水甲醇(5mL)淬灭反应，用饱和碳酸氢钠水溶液调节pH＝7。浓缩后加水稀释，用EA萃取三次(20mL×3)。合并有机相，用无水硫酸钠干燥，经Prep-HPLC分离得到化合物7(6mg)。
Prep-HPLC条件：
仪器型号：Agilent1260；色谱柱：XBridge Prep C18 OBD(19mm×150mm×5.0μm)；色谱柱温：25℃；流速：24.0mL/min；检测波长：214nm、254nm、280nm；洗脱梯度：(0min：10％A，90％B；16.0min：90％A，10％B)；流动相A：100％乙腈；流动相B：0.05％碳酸氢铵水溶液。化合物收集时间：6.6-7.5min。
MS(ESI,m/z):348.2[M+H] +.
1H NMR(DMSO-d 6,400MHz)δ7.46(dd,J＝15.6,8.7Hz,1H),7.19(td,J＝10.5,2.5Hz,1H),7.01(td,J＝8.5,1.9Hz,1H),6.17(s,1H),5.95(s,1H),5.71(s,1H),4.57(s,1H),4.40(d,J＝6.1Hz,2H),3.47(d,J＝6.8Hz,5H),2.80–2.71(m,2H),1.91–1.76(m,2H).
实施例8：3-(4-氨基-1-甲基-6-((吡嗪-2-基甲基)氨基)-1H-咪唑并[4,5-c]吡啶-2-基)丙-1-醇(化合物8)
Figure PCTCN2019113877-appb-000060
第一步：2-(3-(苄氧基)丙基)-1-甲基-N 6-(吡嗪-2-基甲基)-N 4-(2,4,4-三甲基戊基-2-基)-1H-咪唑并[4,5-c]吡啶-4,6-二胺(化合物8a)
将化合物1f(150mg,338.58μmol)、吡嗪-2-基甲胺(48.03mg,440.16μmol)、Pd 2(dba) 3(31.00mg,33.86μmol)、DavePhos(26.65mg,67.72μmol)、tBuOK(113.98mg,1.02mmol)加入1,4-二氧六环(3mL)中，加热至100℃微波反应5h。反应结束后，用硅藻土过滤，滤液旋干后经Prep-HPLC分离得到化合物8a(46mg)。
Prep-HPLC条件：
仪器型号：Agilent 1260；色谱柱：XBridge Prep C18 OBD(19mm×150mm×5.0μm)；色谱柱温：25℃；流速：24.0mL/min；检测波长：214nm、254nm、280nm；洗脱梯度：(0min：20％A，80％B；7.6min：48.5％A，51.5％B)；流动相A：100％乙腈；流动相B：0.05％甲酸水溶液。化合物收集时间：6.8-7.5min。
MS(ESI,m/z):516.3[M+H] +.
第二步：3-(4-氨基-1-甲基-6-((吡嗪-2-基甲基)氨基)-1H-咪唑并[4,5-c]吡啶-2-基)丙-1-醇(化合物8)
将化合物8a(46mg,90.39μmol)溶于TFA(20mL)中，加热至75℃下搅拌过夜。反应结束后，体系浓缩至干，加入甲醇(5mL)稀释。用饱和碳酸氢钠水溶液调节pH＝9，室温下搅拌15min。体系再次浓缩，用甲醇洗涤。过滤除去不溶物，滤液浓缩后经Prep-HPLC分离得到化合物138(4mg)。
Prep-HPLC条件：
仪器型号：Agilent1260；色谱柱：XBridge Prep C18 OBD(19mm×150mm×5.0μm)；色谱柱温：25℃；流速：24.0mL/min；检测波长：214nm、254nm、280nm；洗脱梯度：(0min：10％A，90％B；4.6min：18.6％A，81.4％B)；流动相A：100％乙腈；流动相B：0.05％碳酸氢铵水溶液。化合物收集时间：3.6-4.3min。
MS(ESI,m/z):314.2[M+H] +.
1H NMR(DMSO-d 6,400MHz)δ8.63(s,1H),8.57(d,J＝2.3Hz,1H),8.48(d,J＝2.5Hz,1H),6.24(t,J＝6.3Hz,1H),5.67(d,J＝5.7Hz,3H),4.63–4.44(m,3H),3.53–3.42(m,5H),2.75(t,J＝7.6Hz,2H),1.88–1.77(m,2H).
药效筛选方法及数据
实验例1：本发明化合物对PMA诱导分化后的THP-1细胞中的IL-1β表达的激动作用
本实验采用均相时间分辨荧光(HTRF)检测方法，测试本发明化合物对NLRP3下游细胞因子IL-1β水平的影响，以评估化合物在细胞水平上对hNLRP3炎症小体或NLRP3炎症小体通路的激动作用。
试剂：RPMI 1640(Hyclone)；热灭活的FBS(Gibco)；PMA(碧云天)
细胞：THP-1(南京科佰)
试剂盒：IL-1βassay kit(CISBIO)
实验步骤：
1)将处于对数生长期的THP-1细胞以5×10 5个/孔的密度接种于T75培养瓶中，置于37℃，5％CO 2的培养箱中培养24h，诱导THP-1悬浮细胞成为贴壁状态的巨噬细胞。完全生长培养基为RPMI 1640，包含10％热灭活FBS，0.05mMβ-巯基乙醇，1μM PMA。
2)诱导培养24h后，胰酶消化贴壁细胞。在1000rpm的条件下离心5min，然后去上清液。使用包含2％热灭活FBS的检测培养基RPMI 1640重悬细胞，至密度为2×10 6个/mL。铺细胞至96孔板，达到50μL/孔，每孔细胞数目为1×10 5个。
3)取适量的10mM待测化合物的DMSO溶液，用含2％热灭活FBS的RPMI 1640培养基配制成2×测试浓度。取50μL/孔稀释液加至96孔板的细胞中，充分混匀后，将96孔板放置于37℃，5％CO 2的培养箱中培养6h。收集上清液，按照IL-1β检测试剂盒说明书测量上清液中IL-1β的水平。
4)待测化合物对IL-1β的刺激作用EC 50通过GraphPad软件log(agonist)vs.response--Variable slope四参数法拟合。
本发明化合物对PMA诱导分化后的THP-1细胞中的IL-1β表达的激动作用见表1。
实验例2：本发明化合物对PMA诱导分化后的NLRP3缺失的THP1细胞(THP1- defNLRP3细胞)中的IL-1β表达的激动作用
本实验采用HTRF检测方法，测试本发明化合物对THP1- defNLRP3细胞中IL-1β水平的影响，以评估化合物对hNLRP3炎症小体或NLRP3炎症小体通路激动作用的特异性。
试剂：RPMI 1640(Hyclone)；热灭活的FBS(Gibco)；PMA(碧云天)
细胞：THP1- defNLRP3(InvivoGen)
试剂盒：IL-1βassay kit(CISBIO)
实验步骤：
1)将处于对数生长期的THP1- defNLRP3细胞以5×10 5个/孔的密度接种于T75培养瓶中，置于37℃，5％CO 2的培养箱中培养24h，诱导THP1- defNLRP3悬浮细胞成为贴壁状态的巨噬细胞。完全生长培养基为RPMI 1640，包含10％热灭活FBS，0.05mMβ-巯基乙醇，1μM PMA。
2)诱导培养24h后，胰酶消化贴壁细胞。在1000rpm的条件下离心5min，然后去上清液。使用包含2％热灭活FBS的检测培养基RPMI 1640重悬细胞，至密度为2×10 6个/mL。铺细胞至96孔板，达到50μL/孔，每孔细胞数目为1×10 5个。
3)取适量的10mM待测化合物的DMSO溶液，用含2％热灭活FBS的RPMI 1640培养基配制成2×测试浓度。取50μL/孔稀释液加至96孔板的细胞中，充分混匀后，将96孔板置于37℃，5％CO 2的培养箱中培养6h。收集上清液，按照IL-1β检测试剂盒说明书测量上清液中IL-1β的水平。
4)待测化合物对IL-1β的刺激作用EC 50通过GraphPad软件log(agonist)vs.response--Variable slope四参数法拟合。
本发明化合物对PMA诱导分化后的THP1- defNLRP3细胞中的IL-1β表达的激动作用见表1。
实验例3：本发明化合物对hTLR7的激动作用
本实验通过检测HEK-hTLR7-NF-κB-荧光素酶报告基因细胞中的荧光素酶来测试本发明化合物对TLR7信号通路的激活作用，以评估化合物对NLRP3炎症小体通路激动作用的特异性。
试剂：DMEM(High glucose)；FBS(Gibco)；
细胞：HEK-hTLR7-NF-kB-Luciferase报告基因细胞(人源TLR7 NF-kB-荧光素酶报告基因细胞)(南京科佰)
试剂盒：Bright-Glo TM Luciferase检测试剂盒(Promega)
实验步骤：
1)将处于对数生长期的HEK-hTLR7-NF-kB-Luciferase报告基因细胞离心，用培养基重悬至2×10 6个/mL的浓度，以50μL/孔将细胞悬液加入96孔板中。取适量的10mM待测化合物的DMSO溶液，用含10％FBS的DMEM(High glucose)培养基配制成2×测试浓度。取50μL/孔稀释液加至96孔板的细胞中，将96孔板置于细胞培养箱孵育16h。培养基为DMEM(High glucose)，包含10％FBS。
2)细胞孵育结束后，加入100μl Bright-Glo TM Luciferase检测试剂，室温孵育5min，酶标仪读取相对荧光酶活性单位(Relative Luciferase Unit，RLU)。
3)待测化合物对hTLR7的刺激作用EC 50通过GraphPad软件log(agonist)vs.response--Variable slope四参数法拟合。
本发明化合物对hTLR7的激动作用见表1。
实验例4：本发明化合物对hTLR8的激动作用
本实验通过检测HEK-Blue细胞株中碱性磷酸酶的分泌量来测试本发明化合物对TLR8信号通路的激活作用，以评估化合物对NLRP3炎症小体通路激动作用的特异性。
试剂：DMEM(High glucose)；FBS(Gibco)；QUANTI-Blue(InvivoGen)；
细胞：HEK-Blue TMhTLR8细胞(人源TLR 8细胞)(InvivoGen)
实验步骤：
1)将处于对数生长期的HEK-Blue TMhTLR8细胞离心，用培养基重悬至2×10 6个/mL的浓度，以50μL/孔将细胞悬液加入96孔板中。取适量的10mM待测化合物的DMSO溶液，用含10％FBS的DMEM(High glucose)培养基配制成2×测试浓度。取50μL/孔稀释液加至96孔板的细胞中，将96孔板置于细胞培养箱孵育16h。培养基为DMEM(High glucose)，包含10％FBS。
2)细胞孵育结束后，取10μL细胞培养上清转移至96孔板中，加入90μL/孔的QUANTI-Blue检测溶液，37℃孵育3h，酶标仪OD 620读数。
3)待测化合物对hTLR8的刺激作用EC 50通过GraphPad软件log(agonist)vs.response--Variable slope四参数法拟合。
本发明化合物对hTLR8的激动作用见表1。
表1
Figure PCTCN2019113877-appb-000061
结果表明，本发明化合物(例如化合物1、化合物2、化合物3、化合物4、化合物5、化合物6、化合物7以及化合物8)对PMA诱导分化后的THP-1细胞中的IL-1β表达有明显的激动作用，而对THP1- defNLRP3细胞中的IL-1β表达在最高化合物测试浓度(27μM)无激动作用；所有化合物对hTLR7和hTLR8均无明显激活。综上，本发明化合物(例如化合物1、化合物2、化合物3、化合物4、化合物5、化合物6、化合物7以及化合物8)特异性和选择性的对hNLRP3及其信号通路有明显的激动活性。
除本文中描述的那些外，根据前述描述，本发明的多种修改对本领域技术人员而言会是显而易见的。这样的修改也意图落入所附权利要求书的范围内。本申请中所引用的各参考文献(包括所有专利、专利申请、期刊文章、书籍及任何其它公开)均以其整体援引加入本文。

Claims (16)

  1. 式I所示的化合物，所述化合物的立体异构体、互变异构体或其混合物，所述化合物的药学上可接受的盐、共晶、多晶型物或溶剂合物，或者所述化合物的稳定同位素衍生物、代谢物或前药：
    Figure PCTCN2019113877-appb-100001
    其中：
    X 1为C(R 7) 2、NR 7、O或S，
    X 2为CR 7或N，
    X 3为C、N、O或S，且满足下列条件：
    (1)当X 3为C时，R 6选自H、C 1-6烷基和C 3-8环烷基，所述C 1-6烷基和C 3-8环烷基各自任选地被下列基团中的一个或多个取代：卤素、OH、CN、NO 2、C 1-4烷氧基和C 1-4羟烷基，
    (2)当X 3为N、O或S时，R 6不存在，并且当X 3为O或S时，R 2不存在，
    R 1选自C 1-8烷基、C 1-8烷氧基、C 3-8环烷基、4-10元杂环基、C 6-12芳基、5-10元杂芳基和9-12元芳基并杂环基，所述C 1-8烷基、C 1-8烷氧基、C 3-8环烷基、4-10元杂环基、C 6-12芳基、5-10元杂芳基和9-12元芳基并杂环基各自任选地被下列取代基中的一个或多个取代：卤素、CN、NO 2、C 1-4烷基、C 3-8环烷基、C 1-4卤代烷基、C 1-4烷氧基、C 1-4卤代烷氧基、C 1-4羟烷基、4-10元杂环基、C 6-12芳基、5-10元杂芳基、9-12元芳基并杂环基、CO 2R 30、C(O)R 30、C(O)NR 31R 32、NR 33C(O)R 34、NR 31R 32、OC(O)R 30、OC(O)NR 31R 32、NR 33C(O)NR 31R 32、NR 33C(O)OR 30、S(O)NR 31R 32、S(O) 2NR 31R 32、S(O)R 35、S(O) 2R 35、OR 37和SR 37；
    R 2选自H、C 1-8烷基、C 2-8烯基、C 2-8炔基、C 6-12芳基、C 3-8环烷基、5-10元杂芳基和4-10元杂环基，所述C 1-8烷基、C 2-8烯基、C 2-8炔基、C 6-12芳基、C 3-8环烷基、5-10元杂芳基和4-10元杂环基各自任选地被下列取代基中的一个或多个取代：卤素、C 1-4卤代烷基、C 1-4羟烷基、C 1-4烷氧基、C 1-4卤代烷氧基、4-7元杂环基、CN、NO 2、OR 37、SR 37、C(O)R 30、C(O)NR 31R 32、NR 31R 32C(O)、C(O)OR 30、OC(O)R 30、OC(O)NR 31R 32、NR 33C(O)NR 31R 32和NR 31R 32；
    R 3选自H、OH、卤素、CN、NO 2、C 1-8烷基、C 1-8卤代烷基、C 1-8烷氧基、C 1-8卤代烷氧基、C 3-8环烷基、4-10元杂环基、C 6-12芳基、5-10元杂芳基、9-12元芳基并杂环基、9-12元芳基并杂芳基、9-12元芳基并环烷基、CO 2R 30、C(O)NR 31R 32、NR 33S(O) 2R 34、NR 33C(O)R 34、NR 31R 32、SO 2R 35、OR 37、SR 37、C(O)R 30、OC(O)R 30、OC(O)NR 31R 32、NR 33C(O)NR 31R 32、NR 33C(O)OR 30、C(＝NR 38)NR 31R 32、NR 33C(＝NR 38)NR 31R 32、P(R 39) 2、P(OR 39) 2、P(O)R 39R 40、P(O)OR 39OR 30、S(O)R 35、S(O) 2R 35、S(O)NR 31R 32和S(O) 2NR 31R 32，所述C 1-8烷基、C 1-8卤代烷基、C 1-8烷氧基、C 1-8卤代烷氧基、C 3-8环烷基、4-10元杂环基、C 6-12芳基、5-10元杂芳基、9-12元芳基并杂环基、9-12元芳基并杂芳基和9-12元芳基并环烷基各自任选地被下列取代基中的一个或多个取代：卤素、CN、NO 2、C 1-4烷基、C 3-8环烷基、C 1-4卤代烷基、C 1-4烷氧基、C 1-4卤代烷氧基、C 1-4羟烷基、4-10元杂环基、C 6-12芳基、5-10元杂芳基、9-12元芳基并杂环基、CO 2R 30、C(O)R 30、C(O)NR 31R 32、NR 33C(O)R 34、NR 31R 32、S(O)R 35、S(O) 2R 35、S(O)NR 31R 32、S(O) 2NR 31R 32、OR 37、SR 37、OC(O)R 30、OC(O)NR 31R 32、NR 33C(O)NR 31R 32、NR 33C(O)OR 30、C(＝NR 38)NR 31R 32、NR 33C(＝NR 38)NR 31R 32、＝NNR 31R 32、P(R 39) 2、P(OR 39) 2、P(O)R 39R 40和P(O)OR 39OR 30；或者R 2和R 3连接形成5-8元环；
    R 4和R 5各自独立地选自H、C 1-8烷基、C 3-8环烷基和C 1-8烷氧基，所述C 1-8烷基、C 3-8环烷基和C 1-8烷氧基各自任选地被下列取代基中的一个或多个取代：卤素、OH、CN、NO 2、C 1-6烷基、C 1-4卤代烷基和C 1-4羟烷基；或R 4、R 5和与其相连的氮原子一起形成4-7元杂环；优选地，R 4和R 5均为H；
    R 7选自H、C 1-6烷基和C 3-8环烷基，所述C 1-6烷基和C 3-8环烷基各自任选地被下列基团中的一个或多个取代：卤素、OH、CN、C 1-4烷氧基和C 1-4羟烷基；或者两个R 7和与其相连的碳原子一起形成3-5元环烷基；当两个R 7同时存在时，各R 7可以相同或不同；
    V不存在，或选自C 1-8亚烷基、C(R 36aR 36b)、O、S、NR 33、SO、SO 2和CO，所述C 1-8亚烷基任选地被下列取代基中的一个或多个取代：卤素、OH、CN、NO 2、C 1-6烷基、C 1-4卤代烷基、C 1-4羟烷基和C 1-4烷氧基；优选地，V不存在，或者选自CO和C 1-8亚烷基(例如亚甲基)；
    V与X 1不同时为杂原子N、O或S；
    L为-(L 1) n-(L 2) p-(L 3) q-，其中L 1、L 2和L 3相同或不同，并且各自独立地选自C 1-8亚烷基、C 2-8亚烯基、C 2-8亚炔基、C 1-8卤代亚烷基、C 1-8亚烷氧基、C 1-8卤代亚烷氧基、C 1-8羟亚烷基、C 3-8亚环烷基、4-10元亚杂环基、C 6-12亚芳基、5-10元亚杂芳基、O、S、NR 33、SO、SO 2、CO和C(R 36aR 36b)，所述C 1-8亚烷基、C 2-8亚烯基、C 2-8亚炔基、C 1-8卤代亚烷基、C 1-8亚烷氧基、C 1-8卤代亚烷氧基、C 1-8羟亚烷基、C 3-8亚环烷基、4-10元亚杂环基、C 6-12亚芳基和5-10元亚杂芳基各自任选地被下列取代基中的一个或多个取代：卤素、OH、CN、NO 2、C 1-6烷基、C 1-4卤代烷基、C 1-4羟烷基和C 1-4烷氧基；
    n、p和q各自独立地为0或1；
    R 30、R 37、R 39和R 40各自独立地选自氢、C 1-8烷基、C 1-8羟烷基、C 1-8卤代烷基、C 1-8烷氧基、C 1-8卤代烷氧基、C 3-8环烷基、4-10元杂环基、C 6-12芳基、5-10元杂芳基、C 1-8烷基-C 6-12芳基和C 1-8烷基-(5-10元杂芳基)，所述C 1-8烷基、C 1-8羟烷基、C 1-8卤代烷基、C 1-8烷氧基、C 1-8卤代烷氧基、C 3-8环烷基、4-10元杂环基、C 6-12芳基和5-10元杂芳基各自任选地被下列取代基中的一个或多个取代：OH、CN、NO 2、C 1-4烷基、C 1-4烷氧基、C 1-4卤代烷基、卤素、C 1-4卤代烷氧基、CO 2(C 1-6烷基)、CONR 31R 32、NR 31R 32、NR 33C(O)R 34、S(O)R 35、S(O) 2R 35、S(O)NR 31R 32和S(O) 2NR 31R 32；
    当多个R 30同时存在时，各R 30可以相同或不同；
    当多个R 37同时存在时，各R 37可以相同或不同；
    当多个R 39同时存在时，各R 39可以相同或不同；
    当多个R 40同时存在时，各R 40可以相同或不同；
    R 31、R 32、R 33和R 34各自独立地选自H、C 1-8烷基、C 1-8羟烷基、C 1-8烷氧基、4-10元杂环基、C 6-12芳基、C 3-8环烷基和5-10元杂芳基，所述C 1-8烷基、C 1-8羟烷基、C 1-8烷氧基、4-10元杂环基、C 6-12芳基、C 3-8环烷基和5-10元杂芳基各自任选地被下列取代基中的一个或多个取代：OH、CN、卤素、NO 2、C 1-4烷基、C 1-4烷氧基、C 1-4羟烷基、C 1-4卤代烷基、C 1-4卤代烷氧基、4-10元杂环基、C 6-12芳基和5-10元杂芳基；或者R 31和R 32和与其相连的N原子一起形成3-8元杂环基；或者R 33和R 34和与其相连的N和C原子或者N和S原子一起形成4-8元杂环基；
    R 35选自C 1-8烷基、C 1-8羟烷基、C 1-8卤代烷基、C 1-8烷氧基、C 1-8卤代烷氧基、C 3-8环烷基、4-10元杂环基、C 6-12芳基、5-10元杂芳基、C 1-8烷基-C 6-12芳基和C 1-8烷基-(5-10元杂芳基)，所述C 1-8烷基、C 1-8羟烷基、C 1-8卤代烷基、C 1-8烷氧基、C 1-8卤代烷氧基、C 3-8环烷基、4-10元杂环基、C 6-12芳基和5-10元杂芳基各自任选地被下列取代基中的一个或多个取代：OH、CN、NO 2、C 1-4烷基、C 1-4烷氧基、C 1-4卤代烷基、卤素、C 1-4卤代烷氧基、CO 2(C 1-6烷基)、CONR 31R 32、NR 31R 32、NR 33C(O)R 34、S(O)Me、S(O) 2Me、S(O)NR 31R 32和S(O) 2NR 31R 32；
    当多个R 31同时存在时，各R 31可以相同或不同；
    当多个R 32同时存在时，各R 32可以相同或不同；
    当多个R 33同时存在时，各R 33可以相同或不同；
    当多个R 34同时存在时，各R 34可以相同或不同；
    当多个R 35同时存在时，各R 35可以相同或不同；
    R 36a和R 36b相同或不同，各自独立地选自H、C 1-6烷基、C 1-6烷氧基、C 1-8羟烷基和C 1-8卤代烷基，所述C 1-6烷基、C 1-6烷氧基、C 1-8羟烷基和C 1-8卤代烷基各自任选地被下列基团中的一个或多个取代：OH、CN、NH 2、NHCH 3和N(CH 3) 2；或R 36a、R 36b和与其相连的碳原子一起形成3-7元环烷基或3-7元杂环基；
    当多个R 38同时存在时，各R 38相同或不同，并且各自独立地选自H、OH、CN、NO 2、S(O)R 35和S(O) 2R 35。
  2. 权利要求1的化合物，所述化合物的立体异构体、互变异构体或其混合物，所述化合物的药学上可接受的盐、共晶、多晶型物或溶剂合物，或者所述化合物的稳定同位素衍生物、代谢物或前药，所述化合物具有式II的结构：
    Figure PCTCN2019113877-appb-100002
    其中R 1、R 2、R 3、R 4、R 5、X 1、V和L如权利要求1所定义；优选地，其中R 1、R 2、R 3、R 4、R 5和L如权利要求1所定义，V不存在，或选自CO、亚甲基、亚乙基和亚丙基，X 1为NR 7，R 7选自H、C 1-4烷基和C 3-6环烷基，所述C 1-4烷基和C 3-6环烷基各自任选地被下列基团中的一个或多个取代：卤素、OH、CN、C 1-4烷氧基和C 1-4羟烷基，例如X 1选自NH和N(CH 3)。
  3. 权利要求1或2的化合物，所述化合物的立体异构体、互变异构体或其混合物，所述化合物的药学上可接受的盐、共晶、多晶型物或溶剂合物，或者所述化合物的稳定同位素衍生物、代谢物或前药，所述化合物具有式II-A的结构：
    Figure PCTCN2019113877-appb-100003
    其中R 1、R 2、R 3和L如权利要求1或2所定义。
  4. 权利要求1-3任一项的化合物，所述化合物的立体异构体、互变异构体或其混合物，所述化合物的药学上可接受的盐、共晶、多晶型物或溶剂合物，或者所述化合物的稳定同位素衍生物、代谢物或前药，其中：
    R 1选自C 1-4烷基、C 1-4烷氧基、C 3-6环烷基、4-7元杂环基、C 6-12芳基、5-10元杂芳基和9-12元芳基并杂环基，所述C 1-4烷基、C 1-4烷氧基、C 3-6环烷基、4-7元杂环基、C 6-12芳基、5-10元杂芳基和9-12元芳基并杂环基各自任选地被下列取代基中的一个或多个取代：卤素、CN、NO 2、C 1-4烷基、C 3-8环烷基、C 1-4卤代烷基、C 1-4烷氧基、C 1-4卤代烷氧基、C 1-4羟烷基、4-10元杂环基、C 6-12芳基、5-10元杂芳基、9-12元芳基并杂环基、CO 2R 30、C(O)R 30、C(O)NR 31R 32、NR 33C(O)R 34、NR 31R 32、OC(O)R 30、OC(O)NR 31R 32、NR 33C(O)NR 31R 32、NR 33C(O)OR 30、S(O)NR 31R 32、S(O) 2NR 31R 32、S(O)R 35、S(O) 2R 35、OR 37和SR 37；
    优选地，R 1选自C 1-4烷基、C 6-12芳基和5-10元杂芳基，所述C 1-4烷基、C 6-12芳基和5-10元杂芳基各自任选地被下列取代基中的一个或多个取代：卤素、CN、NO 2、C 1-4烷基、C 3-8环烷基、C 1-4卤代烷基、C 1-4烷氧基、C 1-4卤代烷氧基、C 1-4羟烷基、4-10元杂环基、C 6-12芳基、5-10元杂芳基、9-12元芳基并杂环基、CO 2R 30、C(O)R 30、C(O)NR 31R 32、NR 33C(O)R 34、NR 31R 32、OC(O)R 30、OC(O)NR 31R 32、NR 33C(O)NR 31R 32、NR 33C(O)OR 30、S(O)NR 31R 32、S(O) 2NR 31R 32、S(O)R 35、S(O) 2R 35、OR 37和SR 37；
    优选地，R 1选自异丁基、
    Figure PCTCN2019113877-appb-100004
    Figure PCTCN2019113877-appb-100005
  5. 权利要求1-4任一项的化合物，所述化合物的立体异构体、互变异构体或其混合物，所述化合物的药学上可接受的盐、共晶、多晶型物或溶剂合物，或者所述化合物的稳定同位素衍生物、代谢物或前药，其中：
    R 2选自H、C 1-4烷基、C 3-8环烷基和C 6-12芳基；
    优选地，R 2选自H、甲基、乙基和丙基，特别是H和甲基。
  6. 权利要求1-5任一项的化合物，所述化合物的立体异构体、互变异构体或其混合物，所述化合物的药学上可接受的盐、共晶、多晶型物或溶剂合物，或者所述化合物的稳定同位素衍生物、代谢 物或前药，其中：
    R 3选自OH、C 1-8烷基、4-10元杂环基、C 6-12芳基、NR 31R 32、NR 33C(O)R 34、NR 33S(O) 2R 34、C(O)NR 31R 32、9-12元芳基并杂环基、5-10元杂芳基和NR 33C(O)NR 31R 32，所述C 1-8烷基、4-10元杂环基、C 6-12芳基、5-10元杂芳基和9-12元芳基并杂环基各自任选地被下列取代基中的一个或多个取代：C 1-4烷基、C 1-4烷氧基、C 6-12芳基、C(O)R 30、C(O)NR 31R 32、NR 33C(O)R 34、NR 31R 32、S(O) 2R 35和OR 37；
    优选地，R 3选自OH、C 1-8烷基、4-10元杂环基、C 6-12芳基、NR 31R 32、NR 33C(O)R 34、NR 33S(O) 2R 34、C(O)NR 31R 32、9-12元芳基并杂环基、5-10元杂芳基和NR 33C(O)NR 31R 32，所述C 1-8烷基、4-10元杂环基、C 6-12芳基、5-10元杂芳基和9-12元芳基并杂环基各自任选地被下列取代基中的一个或多个取代：甲基、甲氧基、苯基、C(O)CH 3、C(O)NH 2、NHC(O)CH 3、NHC(O)H、NH 2、NH(CH 3)、S(O) 2CH 3和OH；
    优选地，R 3选自OH、-NHC(O)CH 3、-C(O)NH 2、-N(CH 2CH 3)C(O)N(CH 3) 2、
    Figure PCTCN2019113877-appb-100006
    Figure PCTCN2019113877-appb-100007
  7. 权利要求1-6任一项的化合物，所述化合物的立体异构体、互变异构体或其混合物，所述化合物的药学上可接受的盐、共晶、多晶型物或溶剂合物，或者所述化合物的稳定同位素衍生物、代谢物或前药，其中：
    L不存在，或者选自亚丙基、亚甲基、亚乙基、O、S、NR 33、-C 1-3亚烷基-O-、-C 1-3亚烷基-S-和-C 1-3亚烷基-NR 33-；优选地，R 33选自H和甲基；
    优选地，L不存在，或者选自亚丙基、亚乙基、-亚乙基-O-、-亚丙基-O-和-亚乙基-NH-。
  8. 权利要求1-7任一项的化合物，所述化合物的立体异构体、互变异构体或其混合物，所述化合物的药学上可接受的盐、共晶、多晶型物或溶剂合物，或者所述化合物的稳定同位素衍生物、代谢物或前药，所述化合物选自：
    Figure PCTCN2019113877-appb-100008
    Figure PCTCN2019113877-appb-100009
    Figure PCTCN2019113877-appb-100010
  9. 一种药物组合物，其包含权利要求1-8任一项的化合物，所述化合物的立体异构体、互变异构体或其混合物，所述化合物的药学上可接受的盐、共晶、多晶型物或溶剂合物，或者所述化合物的稳定同位素衍生物、代谢物或前药，优选地，所述药物组合物还包含一种或多种药学上可接受的载体。
  10. 权利要求9的药物组合物，其用于预防和/或治疗与NLRP3炎症小体活性相关的疾病(例如肿瘤疾病)。
  11. 权利要求9-10任一项的药物组合物，其还包含一种或多种第二治疗剂。
  12. 权利要求11的药物组合物，所述一种或多种第二治疗剂为一种或多种治疗肿瘤疾病的其他药物。
  13. 一种药物制剂，其包含权利要求1-8任一项的化合物，所述化合物的立体异构体、互变异构体或其混合物，所述化合物的药学上可接受的盐、共晶、多晶型物或溶剂合物，或者所述化合物的稳定同位素衍生物、代谢物或前药，或者包含权利要求9-12任一项的药物组合物。
  14. 权利要求1-8任一项的化合物，所述化合物的立体异构体、互变异构体或其混合物，所述化合物的药学上可接受的盐、共晶、多晶型物或溶剂合物，或者所述化合物的稳定同位素衍生物、代谢物或前药，或者权利要求9-12任一项的药物组合物，或者权利要求13的药物制剂用于制备药物的用途，所述药物用于预防和/或治疗与NLRP3炎症小体活性相关的疾病(例如肿瘤疾病)。
  15. 权利要求14的用途，其中所述药物用于调节(例如增加)NLRP3炎症小体的活性。
  16. 一种调节(例如增加)细胞中NLRP3炎症小体活性的方法，其包括给所述细胞施用有效量的权利要求1-8任一项的化合物，所述化合物的立体异构体、互变异构体或其混合物，所述化合物的药学上可接受的盐、共晶、多晶型物或溶剂合物，或者所述化合物的稳定同位素衍生物、代谢物或前药，或者权利要求9-12任一项的药物组合物，或者权利要求13的药物制剂。
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