WO2019214546A1 - Fused ring compound, preparation method therefor and use thereof - Google Patents

Fused ring compound, preparation method therefor and use thereof Download PDF

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WO2019214546A1
WO2019214546A1 PCT/CN2019/085535 CN2019085535W WO2019214546A1 WO 2019214546 A1 WO2019214546 A1 WO 2019214546A1 CN 2019085535 W CN2019085535 W CN 2019085535W WO 2019214546 A1 WO2019214546 A1 WO 2019214546A1
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group
membered
compound
alkyl
aryl
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PCT/CN2019/085535
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French (fr)
Chinese (zh)
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李桂英
游泽金
何云
冉茂盛
孙晓阳
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 CN202311228762.2A priority Critical patent/CN117263952A/en
Priority to CN201980018863.2A priority patent/CN111836814B/en
Publication of WO2019214546A1 publication Critical patent/WO2019214546A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—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
    • 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
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
    • C07D495/14—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
    • C07D498/14—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Definitions

  • the present invention relates to novel fused ring compounds, stereoisomers, tautomers or mixtures thereof, pharmaceutically acceptable salts, eutectic, polymorphs or solvates of said compounds, or A stable isotope derivative, metabolite or prodrug of the compound.
  • the compounds of the present invention are useful as NLRP3 modulators (e.g., agonists) for the treatment of cell proliferative disorders such as cancer.
  • NLRP3 (NLR family pyrin domain containing 3) belongs to the NOD-like receptor family and is one of the most studied intracellular pattern recognition receptors 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. NLRP3 inflammatory bodies play a clear role in inflammatory and metabolic diseases, and their over-activation leads to immune diseases such as type 2 diabetes, rheumatoid arthritis and atherosclerosis. However, recent studies have shown that NLRP3 has an anti-tumor effect of inhibiting tumor growth and metastasis.
  • the NLRP3 protein After identifying the pathogen-associated molecular pattern (PAMP) or the endogenous damage-associated molecular pattern (DAMP), the NLRP3 protein oligomerizes its NOD domain and recruits proteins such as ASC and pro-caspase-1 to form a functional NLRP3. Inflammatory bodies. After pro-caspase-1 is cleaved and activated into caspase-1, caspase-1 cleaves pro-IL-1 ⁇ and pro-IL-18 to convert it into active forms of IL-1 ⁇ and IL-18 and release them into cells. In addition, the inflammatory response is amplified.
  • PAMP pathogen-associated molecular pattern
  • DAMP endogenous damage-associated molecular pattern
  • the inflammatory NLRP3 inflammatory vesicles can significantly increase the levels of the immune factors IL-1 ⁇ and IL-18 in the tumor microenvironment, initiate natural immune killing and subsequent acquired immune responses to exert their anti-tumor effects.
  • IL-1 ⁇ induces secretion of interferon-gamma (IFN- ⁇ ) by CD8+ T cells, and also induces secretion of IL-17 by CD4+ cells, resulting in an effective anti-tumor immune response;
  • IL-18 can promote NK cell maturation. It activates the downstream signaling pathway of STAT1 in immune cells and enhances the killing function of immune cells.
  • Clinical studies have shown that the down-regulation of NLRP3 is significantly negatively correlated with the prognosis of patients with liver cancer.
  • NLRP3-deficient mice have a higher rate of colorectal tumor formation and liver metastasis of colorectal cancer is worse. 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 prognostic marker for tumors.
  • NLRP3 agonists have the potential for tumor immunotherapy, only one compound is currently in clinical phase I studies, and compounds having NLRP3 agonistic activity are disclosed in the patent applications (WO2017184746, WO2017184735, WO2018152396, WO2019014402). Therefore, there is a need to develop new, highly effective and low toxicity NLRP3 agonists to meet clinical treatment needs.
  • NLRP3 modulators eg, agonists
  • directly bind or modify NLRP3 at the protein level by activating, stabilizing, and altering NLRP3 distribution.
  • other means to enhance the function of the NLRP3 inflammatory body thereby providing the following invention:
  • the invention relates to compounds of Formula I, stereoisomers, tautomers or mixtures thereof, pharmaceutically acceptable salts, eutectic, polymorphs or a solvate, or a stable isotope derivative, metabolite or prodrug of the compound:
  • X 1 and X 2 are each independently selected from CH, CR 8 , NR 7 , N, O or S, and at least one of X 1 and X 2 is NR 7 , N, O or S, and X 1 , X 2 and The carbon atom to which it is bonded (X 1 and/or X 2 ) together form a five-membered heteroaryl ring;
  • R 7 is selected from H, C 1-6 alkyl, C 3-8 cycloalkyl, said C 1-6 alkane
  • the group and the C 3-8 cycloalkyl group may be optionally substituted by one or more of the following groups: halogen, OH, CN, C 1-4 alkoxy, C 1-4 hydroxyalkyl,
  • X 3 is C, N, O or S and the following conditions are met:
  • R 1 is selected from the group consisting of H, halogen, CN, NO 2 , C 1-8 alkyl, 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, 5-10 membered heteroaryl group, 9-12 membered arylheterocyclyl group, C(O)OR 30 , C(O)NR 31 R 32 , NR 33 C(O)R 34 , NR 31 R 32 , S(O) 2 R 35 ; said C 1-8 alkyl group, C 1-8 haloalkyl group, C 1-8 alkoxy group, C 1- 8 haloalkoxy, C 3-8 cycloalkyl, 4-10 membered heterocyclyl, C 6-12 aryl, 5-10 membered heteroaryl, 9-12 membered arylheterocyclyl optionally Substituted by one or more
  • R 2 is selected from the group consisting of H, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 6-12 aryl, -C 1-3 alkyl-C 6-12 aryl, C 3-8 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocyclyl, said C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 6-12 An aryl group, a -C 1-3 alkyl-C 6-12 aryl group, a C 3-8 cycloalkyl group, a 5-10 membered heteroaryl group, a 4-10 membered heterocyclic group may be optionally substituted by the following substituents One or more substitutions: halogen, C 1-4 haloalkyl, C 1-4 hydroxyalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy, 4-7 membered heterocyclyl, CN, NO 2 , OR 37
  • R 4 and R 5 are each independently selected from H, C 1-8 alkyl, C 1-8 alkoxy, or R 4 , R 5 and a nitrogen atom bonded to R 4 and R 5 together form 4-7. Heterocyclic; the C 1-8 alkyl, C 1-8 alkoxy group may be optionally substituted by one or more of the following substituents: halogen, OH, CN, NO 2 , C 1-6 alkyl , C 1-4 haloalkyl, C 1-4 hydroxyalkyl;
  • R 6 is selected from H, C 1-6 alkyl, C 3-8 cycloalkyl, and the C 1-6 alkyl and C 3-8 cycloalkyl may be optionally one or more of the following groups Substitutions: halogen, OH, CN, NO 2 , C 1-4 alkoxy, C 1-4 hydroxyalkyl;
  • R 8 is selected from the group consisting of halogen, C 1-8 alkyl, C 1-8 alkoxy, C 3-8 cycloalkyl, C 2-8 heteroalkyl, 4-7 membered heterocyclic, said C 1- 8- alkyl, C 1-8 alkoxy, C 3-8 cycloalkyl, C 2-8 heteroalkyl, 4-7 membered heterocyclyl can be optionally substituted by one or more of the following substituents :OR 37 , NR 31 R 32 , halogen, CN;
  • V is -(V 1 ) r -(V 2 ) s -(V 3 ) t -, wherein V 1 , V 2 and V 3 are the same or different and are each independently selected from a C 1-8 alkylene group, C 2-8 alkenylene group, C 2-8 alkynylene group, C 1-8 alkyleneoxy group, C 3-8 cycloalkylene group, 4-10 membered heterocyclylene group, C 6-12 arylene group 5-10 membered heteroarylene, -O-, -S-, -N(R 33 )-, -S(O)-, -S(O) 2 -, -C(O)-, -C (R 36a R 36b )-; said C 1-8 alkylene, C 2-8 alkenylene, C 2-8 alkynylene, C 1-8 alkyleneoxy, C 3-8 hypocycloalkane
  • r, s, t are each independently selected from 0 and 1;
  • L is -(L 1 ) n -(L 2 ) p -(L 3 ) q -, wherein L 1 , L 2 and L 3 are the same or different and are each independently selected from a C 1-8 alkylene group, C 2-8 alkenylene group, C 2-8 alkynylene group, C 1-8 haloalkylene group, C 1-8 alkyleneoxy group, C 1-8 haloalkyleneoxy group, C 1-8 Hydroxyalkylene, C 3-8 cycloalkylene, 4-10 membered heterocyclylene, C 6-12 arylene, 5-10 membered heteroarylene, -O-, -S-, -N (R 33 )-, -S(O)-, -S(O) 2 -, -C(O)-, -C(R 36a R 36b )-; the C 1-8 alkylene group, C 2 -8 alkenylene, C 2-8 alkynylene, C 1-8 haloal
  • n, p, q are each independently selected from 0 or 1;
  • R 30 , R 37 , R 39 , R 40 are each independently selected from the group consisting of 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 heterocyclic, C 6-12 aryl, 5-10 membered heteroaryl, -C 1-8 alkyl-C 6-12 Base, -C 1-8 alkyl-(5-10 membered heteroaryl); said C 1-8 alkyl, C 1-8 hydroxyalkyl, C 1-8 haloalkyl, C 1-8 alkoxy a group, a C 1-8 haloalkoxy group, a C 3-8 cycloalkyl group, a 4-10 membered heterocyclic group, a C 6-12 aryl group, a 5-10 membered heteroaryl group, optionally in the following substituents One or more substitutions: OH, CN
  • 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 heterocyclic, C. 6-12 aryl, 5-10 membered heteroaryl; or R 31 and R 32 together with the respective attached N atom form a 3-8 membered heterocyclic group; or R 33 and R 34 are bonded to each C or N The atoms together form a 4-8 membered heterocyclic group; said C 1-8 alkyl group, C 1-8 hydroxyalkyl group, C 1-8 alkoxy group, C 3-8 cycloalkyl group, 4-10 membered heterocyclic ring
  • the base, C 6-12 aryl, 5-10 membered heteroaryl may be optionally substituted by 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
  • R 35 is selected from the group consisting of 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, 5-10 membered heteroaryl group, -C 1-8 alkyl-C 6-12 aryl group, -C 1-8 alkyl group (5-10 a heteroaryl group; the C 1-8 alkyl group, a C 1-8 hydroxyalkyl group, a C 1-8 haloalkyl group, a C 1-8 alkoxy group, a C 1-8 haloalkoxy group, a C 3-8 A cycloalkyl, 4-10 membered heterocyclyl, C 6-12 aryl, 5-10 membered heteroaryl can be optionally substituted with one or more of the following substituents: OH, CN, NO 2 , C 1-4 alkyl
  • 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, are each independently selected from H, C 1-6 alkyl, C 1-6 alkoxy, C 1-8 hydroxyalkyl, C 1-8 haloalkyl group; a C 1 -6 alkyl, C 1-6 alkoxy, C 1-8 hydroxyalkyl, C 1-8 haloalkyl can be optionally substituted by one or more of the following groups: OH, CN, NH 2 , NHCH 3 , N(CH 3 ) 2 ; or R 36a , R 36b and a carbon atom bonded to R 36a , R 36b together form a 3-7 membered cycloalkyl group or a 4-7 membered heterocyclic group;
  • each R 38 is the same or different and is each independently selected from the group consisting of H, OH, CN, NO 2 , S(O)R 35 , S(O) 2 R 35 .
  • R 1 is selected from the group consisting of C 1-8 alkyl, C 1-8 haloalkyl, C 1-8 alkoxy, C 1-8 haloalkoxy, C 3-8 cycloalkyl, 4- a 10-membered heterocyclic group, a C 6-12 aryl group, a 5-10 membered heteroaryl group, a 9-12 membered arylheterocyclyl group; said C 1-8 alkyl group, C 1-8 haloalkyl group, C 1 -8 alkoxy, C 1-8 haloalkoxy, C 3-8 cycloalkyl, 4-10 membered heterocyclic, C 6-12 aryl, 5-10 membered heteroaryl, 9-12 membered aromatic
  • R 1 is selected from C 6-12 aryl (eg, phenyl), 5-10 membered heteroaryl, 9-12 membered arylheterocyclyl; said C 6-12 aryl ( For example, phenyl), 5-10 membered heteroaryl, 9-12 membered arylheterocyclyl can be 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, C 6 -12 aryl, 5-10 membered heteroaryl, 9-12 membered arylheterocyclyl, -C(O)OR 30 , C(O)R 30 , C(O)NR 31 R 32 , -NR 33 C(O)R 34 , -NR 31
  • R 1 is selected from halo, 5-6 membered heteroaryl, and C 6-12 aryl, optionally, the 5-10 membered heteroaryl and C 6-12 aryl are optionally Substituted by one or more C 1-4 alkyl groups.
  • R 1 is selected from the group consisting of fluorine, chlorine, bromine, iodine, 5-6 membered heteroaryl, and phenyl, optionally, said 5-6 membered heteroaryl and phenyl are optionally One or more methyl or ethyl groups are substituted.
  • R 1 is selected from the group consisting of fluorine, chlorine, bromine, iodine, 5-6 membered nitrogen-containing heteroaryl, 5-6 membered sulfur-containing heteroaryl, and phenyl, optionally, 5-.
  • the 6-membered nitrogen-containing heteroaryl group, the 5-6 membered sulfur-containing heteroaryl group, and the phenyl group are optionally substituted with one or more methyl groups and ethyl groups.
  • the 5-6 membered nitrogen-containing monocyclic heteroaryl contains 1, 2, or 3 nitrogen atoms, and optionally, 1 sulfur atom or oxygen atom.
  • the 5-6 membered sulfur-containing monocyclic heteroaryl contains 1, 2, or 3 sulfur atoms.
  • R 1 is selected from halogen (e.g. fluorine, chlorine, bromine, iodine), phenyl, imidazolyl, pyridinyl, thiazolyl, pyrazinyl, thienyl, pyrazolyl, pyridazinyl, pyrimidinyl,
  • halogen e.g. fluorine, chlorine, bromine, iodine
  • phenyl, imidazolyl, pyridinyl, thiazolyl, pyrazinyl, thienyl, pyrazolyl, pyridazinyl, pyrimidinyl is 1, 2, 3 or 4 C 1-4 alkyl (eg methyl, ethyl) substituted.
  • R 1 is selected from bromo
  • R 2 is selected from the group consisting of H, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 6-12 aryl, -CH 2 -C 6-12 aryl a C 3-8 cycloalkyl group, a 5-10 membered heteroaryl group, a 4-10 membered heterocyclic group, said C 1-8 alkyl group, C 2-8 alkenyl group, C 2-8 alkynyl group, C 6 -12 aryl, -CH 2 -C 6-12 aryl, C 3-8 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocyclyl can be optionally substituted by one of the following substituents Or a plurality of substitutions: halogen, C 1-4 haloalkyl, C 1-4 hydroxyalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy, 4-7 membered heterocyclic, CN, NO 2 , OR 37
  • R 2 is selected from the group consisting of H, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-8 cycloalkyl, said C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-8 cycloalkyl may be optionally substituted by one or more of the following substituents: halo, C 1-4 haloalkyl, C 1-4 Hydroxyalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy, 4-7 membered heterocyclic, CN, NO 2 , OR 37 , SR 37 , C(O)R 30 , C(O) NR 31 R 32 , C(O)OR 30 , OC(O)R 30 , OC(O)NR 31 R 32 , NR 33 C(O)NR 31 R 32 , NR 31 R 32 .
  • R 2 is selected from the group consisting of H, C 1-8 alkyl, C 3-8 cycloalkyl, and —CH 2 -C 6-12 aryl, said C 1-8 alkyl, C 3 -
  • the 8 -cycloalkyl, -CH 2 -C 6-12 aryl group may be optionally substituted by 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 group, 4-7 membered heterocyclic group, CN, NO 2 , OR 37 , SR 37 , C(O)R 30 , C(O)NR 31 R 32 , C (O)OR 30 , OC(O)R 30 , OC(O)NR 31 R 32 , NR 33 C(O)NR 31 R 32 , NR 31 R 32 .
  • R 2 is selected from the group consisting of H, C 1-8 alkyl, and C 3-8 cycloalkyl, and the C 1-8 alkyl, C 3-8 cycloalkyl can be optionally substituted with One or more substitutions in the group: halogen, C 1-4 haloalkyl, C 1-4 hydroxyalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy, 4-7 membered heterocyclyl, CN, NO 2 , OR 37 , SR 37 , C(O)R 30 , C(O)NR 31 R 32 , C(O)OR 30 , OC(O)R 30 , OC(O)NR 31 R 32 , NR 33 C(O)NR 31 R 32 , NR 31 R 32 .
  • R 2 is selected from the group consisting of H, C 1-8 alkyl, and p-methoxybenzyl.
  • R 2 is selected from H, C 1-8 alkyl (eg, C 1-4 alkyl), preferably, R 2 is selected from H, methyl, and ethyl.
  • R 2 is selected from the group consisting of H and methyl.
  • R 3 is selected from the group consisting of C 1-8 alkyl, C 1-8 haloalkyl, C 1-8 alkoxy, C 1-8 haloalkoxy, C 2-8 heteroalkyl, C 3 -8 cycloalkyl, 4-10 membered heterocyclyl, C 6-12 aryl, 5-10 membered heteroaryl (eg 5-6 membered heteroaryl, 9-10 membered heteroarylcycloalkyl) , 9-12 membered arylheterocyclyl, 9-12 membered arylheteroaryl, 9-12 membered arylcycloalkyl, C(O)OR 30 , C(O)NR 31 R 32 , NR 33 C(O)R 34 , NR 31 R 32 , OR 37 , SR 37 , C(O)R 30 , OC(O)R 30 , OC(O)NR 31 R 32 , NR 33 C(O)NR 31 R 32 , NR 33 C(O)NR 31
  • R 3 is selected from the group consisting of C 1-8 alkyl, C 1-8 haloalkyl, C 1-8 alkoxy, C 1-8 haloalkoxy, C 3-8 cycloalkyl, 4- a 10-membered heterocyclic group, a C 6-12 aryl group, a 5-10 membered heteroaryl group (for example, a 5-6 membered heteroaryl group, a 9-10 membered heteroarylcycloalkyl group), and a 9-12 membered aryl group.
  • R 3 is selected from the group consisting of C 1-8 alkyl, C 1-8 haloalkyl, C 1-8 alkoxy, C 1-8 haloalkoxy, C 2-8 heteroalkyl, C 3 -8 cycloalkyl, 4-10 membered heterocyclyl, C 6-12 aryl, 5-10 membered heteroaryl (eg 5-6 membered heteroaryl, 9-10 membered heteroarylcycloalkyl) , 9-12 membered arylheterocyclyl, 9-12 membered arylheteroaryl, 9-12 membered arylcycloalkyl, OR 37 , SR 37 , C(O)R 30 ; 1-8 alkyl, C 1-8 haloalkyl, C 1-8 alkoxy, C 1-8 haloalkoxy, C 2-8 heteroalkyl, C 3-8 cycloalkyl, 4-10 membered Cyclo, C 6-12 aryl, 5-10 membered heteroaryl,
  • R 3 is selected from the group consisting of C 1-8 alkyl, C 1-8 haloalkyl, C 1-8 alkoxy, C 1-8 haloalkoxy, C 3-8 cycloalkyl, 4- a 10-membered heterocyclic group, a C 6-12 aryl group, a 5-10 membered heteroaryl group (for example, a 5-6 membered heteroaryl group, a 9-10 membered heteroarylcycloalkyl group), and a 9-12 membered aryl group.
  • the homoheterocyclyl, 9-12 membered arylheteroaryl, 9-12 membered arylcycloalkyl can be optionally substituted by 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 Heterocyclyl, C 6-12 aryl
  • R 3 is selected from the group consisting of C 1-8 alkyl, C 1-8 haloalkyl, C 1-8 alkoxy, C 1-8 haloalkoxy, C 3-8 cycloalkyl, 4- a 10-membered heterocyclic group, a C 6-12 aryl group, a 5-10 membered heteroaryl group (for example, a 5-6 membered heteroaryl group, a 9-10 membered heteroarylcycloalkyl group), and a 9-12 membered aryl group.
  • the 9-12 membered arylheterocyclyl, 9-12 membered arylheteroaryl, 9-12 membered arylcycloalkyl group can be 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 hydroxy Alkyl, 4-7 membered heterocycl
  • R 3 is selected from the group consisting of C 1-8 alkyl, C 1-8 haloalkyl, C 1-8 alkoxy, C 1-8 haloalkoxy, C 3-8 cycloalkyl, 4- a 10-membered heterocyclic group, a C 6-12 aryl group, a 5-10 membered heteroaryl group (for example, a 5-6 membered heteroaryl group, a 9-10 membered heteroarylcycloalkyl group), and a 9-12 membered aryl group.
  • the homoheterocyclyl, 9-12 membered arylheteroaryl, 9-12 membered arylcycloalkyl can be optionally substituted by 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, 4-7 Heterocyclyl, C 6-10 aryl
  • R 3 is selected from the group consisting of C(O)R 30 , C 1-4 alkyl, C 1-4 alkoxy, benzyl, C 3-6 cycloalkyl, C 6-12 aryl ( For example, phenyl), OH, 4-10 membered heterocyclic group (for example, 4-6 membered nitrogen-containing monoheterocyclic group, 8-10 membered nitrogen-containing heterocyclic group, 6-10 membered nitrogen-containing spiroheterocyclic group), 9-12 membered arylheterocyclyl (eg, benzo 5-6 membered nitrogen-containing monoheterocyclic group), 9-12 membered arylheteroaryl (eg, benzo 5-6 membered nitrogen-containing monoheteroaryl) , 9-12 membered arylcycloalkyl (for example, benzo C 5-6 monocycloalkyl), 5-6 membered monoheteroaryl (for example, 5-6 membered nitrogen-containing nitrogen-containing
  • R 3 is selected from C 6-12 aryl (eg, phenyl), OH, 4-10 membered heterocyclyl (eg, 5-6 membered nitrogen-containing monoheterocyclyl, 8-10 membered nitrogen) And a heterocyclic group, a 6-10 membered nitrogen-containing spiroheterocyclyl group, a 9-12 membered arylheterocyclyl group (for example, a benzo 5-6 membered nitrogen-containing monoheterocyclic group), and a 9-12 membered aryl group.
  • C 6-12 aryl eg, phenyl
  • 4-10 membered heterocyclyl eg, 5-6 membered nitrogen-containing monoheterocyclyl, 8-10 membered nitrogen
  • a heterocyclic group eg, a 6-10 membered nitrogen-containing spiroheterocyclyl group, a 9-12 membered arylheterocyclyl group (for example, a be
  • Heteroaryl eg, benzo 5-6 membered nitrogen-containing monoheteroaryl
  • 9-12 membered arylcycloalkyl eg, benzo C 5-6 cycloalkyl
  • 5-6 membered monoheteroaryl for example, a 5-6 membered nitrogen-containing monoheteroaryl group
  • a 9-10 membered monoheteroarylcycloalkyl group for example, a 4-6 membered nitrogen-containing monoheteroaryl group and a C4-6 monocycloalkyl group
  • C 6-12 aryl eg phenyl
  • 4-10 membered heterocyclic group eg 4-6 membered nitrogen-containing monoheterocyclyl, 8-10 membered nitrogen-containing heterocyclic group, 6-10 membered nitrogen-containing snail a heterocyclic group
  • a 9-12 membered arylheterocyclyl group for example, a benzo 5-6 membered nitrogen-containing monoheterocyclic
  • the groups each independently contain one, two or three nitrogen atoms, and optionally each independently contain one sulfur atom and/or one oxygen atom.
  • the 5-6 membered nitrogen-containing monoheterocyclyl group, the 8-10 membered nitrogen-containing heterocyclic group, the 6-10 membered nitrogen-containing spiroheterocyclyl group, and the 5-6 membered nitrogen-containing monoheteroaryl group each independently contain one, two or three nitrogen atoms, and optionally each independently contain one sulfur atom and/or one oxygen atom.
  • R 3 is selected from phenyl, OH, and 4-10 membered heterocyclyl, and the 4-10 membered heterocyclyl can be optionally substituted with one or more of the following substituents: C1- 4 alkyl, OH, S(O) 2 R 35 .
  • R 3 is selected from phenyl, OH, and 4-10 membered heterocyclyl, and the 4-10 membered heterocyclyl can be optionally substituted with one or more of the following substituents: C 1 -4 alkyl, OH.
  • R 3 is selected from phenyl, OH, 4-6 membered nitrogen-containing monoheterocyclyl, 8-10 membered nitrogen-containing heterocyclyl or 6-10 membered nitrogen-containing spiroheterocyclyl,
  • the 4-6 membered nitrogen-containing monoheterocyclyl group, the 8-10 membered nitrogen-containing heterocyclic group or the 6-10 membered nitrogen-containing spiroheterocyclyl group may be optionally substituted with one or more of the following substituents: C 1 -4 alkyl, OH or S(O) 2 R 35 .
  • R 3 is selected from benzo C 5-6 cycloalkyl, benzo 5-6 membered nitrogen-containing monoheterocyclyl, benzo 5-6 membered nitrogen-containing monoheteroaryl, 5-6. a nitrogen-containing monoheteroaryl-C 5-6 monocycloalkyl group, the benzo C 5-6 cycloalkyl group, a benzo 5-6 membered nitrogen-containing monoheterocyclic group, a benzo 5-6 membered nitrogen-containing single
  • the heteroaryl, 5-6 membered nitrogen-containing monoheteroaryl and C5-6 monocyclic alkyl group can be optionally substituted with one or more of the following substituents: C1-4 alkyl or OH.
  • R 3 is selected from
  • R 3 has a cyclic structure, and the carbon atom on the cyclic structure is optionally oxo.
  • R 3 is selected from the group consisting of H, C 1-4 alkyl, C 1-4 alkoxy, benzyl, methyl substituted benzyl, 5-6 membered nitrogen containing monoheteroaryl, C 3-8 cycloalkyl.
  • R 3 is selected from the group consisting of H, OH, methyl, ethyl, methoxy, t-butoxy, tert-butoxycarbonyl, and optionally by one or more (eg, 2, 3, or 4) C 1-4 alkyl, oxo (oxo), OH or S(O) 2 R 35 substituted phenyl, benzyl, pyrrolidinyl, morpholinyl, piperazinyl, hexahydro-furan [3,4-c]pyrrolyl, 5,6,7,8-tetrahydro-quinolinyl, 1,2,3,4-tetrahydro-naphthyl, 3,4-dihydro-2H-benzo [1,4]oxazinyl, 1H-carbazolyl, 1,2,3,4-tetrahydro-isoquinolinyl, pyridyl, indanyl, 2-oxa-6-aza-spiro [
  • R 3 is selected from the group consisting of H, methyl, ethyl, methoxy, tert-butoxy, tert-butoxycarbonyl, benzyl, cyclopropyl, phenyl, OH,
  • R 3 is selected from the group consisting of phenyl, OH,
  • R 4 is hydrogen
  • R 5 is hydrogen
  • both R 4 and R 5 are hydrogen.
  • r, s, t are both zero.
  • L is -(L 1 ) n -(L 2 ) p -(L 3 ) q -, wherein 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 haloalkylene oxide , C 1-8 hydroxyalkylene, C 3-8 cycloalkylene, 4-10 membered heterocyclylene, C 6-12 arylene, 5-10 membered heteroarylene-C (R 36a R 36b )-, O, -N(R 33 )-, -C(O)-; the C 1-8 alkylene group, C 2-8 alkenylene group, C 2-8 alkynylene group, C 1 -8 haloalkylene, C 1-8 alkyleneoxy, C 1-8 haloalkyleneoxy, C 1-8 hydroxyal
  • L is -(L 1 ) n -(L 2 ) p -(L 3 ) q -, wherein L 1 , L 2 and L 3 are the same or different and are each independently selected from C 1 -4 alkylene, C 1-4 alkyleneoxy, O, NR 33 , -CO-, 4-10 membered heterocyclic group (for example, 6-membered nitrogen-containing monoheterocyclic group) and aryl; n, p, q are each independently selected from 0 or 1.
  • L is selected from the group consisting of -(CH 2 ) 3 -O-CH 2 -, -(CH 2 ) 3 -, -CH 2 -, -(CH 2 ) 2 C(CH 3 ) 2 -, -(CH 2 ) 2 -, -(CH 2 ) 3 -O-, 4-10 membered heterocyclic group (for example, 6-membered nitrogen-containing monoheterocyclic group), -O-(CH 2 ) 3 -O -, -(CH 2 ) 3 -(4-10 membered heterocyclyl)-C(O)- or -(CH 2 ) 3 -OC 6-12 aryl-.
  • L is selected from -CH 2 -NR 33 -CO -, - CH 2 -NR 33 -.
  • R 33 is hydrogen or C 1-4 alkyl (eg, methyl, ethyl).
  • L is selected from the group consisting of -(CH 2 ) 3 -O-CH 2 -, -(CH 2 ) 3 -, -CH 2 -, -(CH 2 ) 2 C(CH 3 ) 2 -, -(CH 2 ) 2 -, -(CH 2 ) 3 -O-, -O-(CH 2 ) 3 O-, -CH 2 -N(CH 2 CH 3 )-CO-, -CH 2 -N(CH 2 CH 3 )-CH 2 -, -CH 2 -NH-, -NH-(CH 2 ) 3 -,
  • -LR 3 is selected from the group consisting of -C 1-4 alkylene-OC 1-4 alkylene-C 6-12 aryl, -C 1-4 alkylene-OH, -C 1-4 alkylene-(6-10 membered nitrogen-containing spiroheterocyclyl), -C 1-4 alkylene-(4-6 membered nitrogen-containing monoheterocyclic group), -C 1-4 Alkyl-(4-6 membered nitrogen-containing monoheterocyclic group and 4-6 membered alkoxymonoheterocyclic group), -C 1-4 alkylene-C(CH 3 ) 2 -OH, -C 1-4 Alkylene O-(5-6 membered nitrogen-containing monoheteroaryl and C5-6 monocycloalkyl), -C 1-4 alkylene-O-(benzo C5-6 monocycloalkyl), - C 1-4 alkylene-O-(benzo 5-6 membered nitrogen-containing monoheterocyclic
  • -LR 3 is selected from the group consisting of -(CH 2 ) 3 -O-CH 2 -C 6-12 aryl, -(CH 2 ) 3 -OH, -CH 2 -(4- 6-membered nitrogen-containing monoheterocyclic group and 4-6 membered oxygen-containing monoheterocyclic group), -CH 2 -(4-6 membered nitrogen-containing monoheterocyclic group), -(CH 2 ) 2 C(CH 3 ) 2 -OH, -(CH 2 ) 2 -(4-6 membered nitrogen-containing monoheterocyclic group), -(CH 2 ) 3 -O- (5-6 membered nitrogen-containing monoheteroaryl group and C 5-6 monocyclic ring) Alkyl), -(CH 2 ) 3 -O-(benzo C 5-6 monocycloalkyl), -(CH 2 ) 3 -O-(benzo 5-6 membered nitrogen-containing monoheterocyclic group
  • -LR 3 is selected from the group consisting of:
  • X 1 is CH or NR 7 ; preferably, X 1 is CH.
  • X 2 is S or NR 7 ; preferably, X 2 is S.
  • X 1 is CH and X 2 is S.
  • X 1 and X 2 are each independently selected from CH, NR 7 , N, O, or S, and at least one of X 1 and X 2 is NR 7 , N, O, or S, and X 1 , X 2 and a carbon atom attached thereto (X 1 and/or X 2 ) together form a five-membered heteroaryl ring;
  • R 2 is selected from the group consisting of 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, 4-10 membered heterocyclic group, said C 1-8 alkyl group, C 2-8 alkenyl group, C 2-8 alkynyl group, C 6-12 aryl group, C 3-8 cycloalkyl group, 5-10 yuan
  • the heteroaryl, 4-10 membered heterocyclyl can be optionally substituted by one or more of the following substituents: halo, C 1-4 haloalkyl, C 1-4 hydroxyalkyl, C 1-4 alkoxy , C 1-4 haloalkoxy, 4-7 membered heterocyclic, CN, NO 2 , OR 37 , SR 37 , C(O)R 30 , C(O)NR 31 R 32 , C(O)OR 30 , OC(O
  • the compound has the structure of Formula II-1:
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , X 1 , X 3 , V and L are as defined in the above formula I.
  • the compound has the structure of Formula II-2:
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , X 1 , X 3 , V and L are as defined in the above formula I.
  • the compound has the structure of Formula II-3:
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , X 1 , X 3 , V and L are as defined in the above formula I.
  • the compound has the structure of Formula II-4:
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , X 1 , X 3 , V and L are as defined in the above formula I.
  • the compound has the structure of Formula II-5:
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , X 1 , X 3 , V and L are as defined in the above formula I.
  • the compound has the structure of Formula III-1:
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , X 1 , X 2 , V and L are as defined in the above formula I.
  • the compound has the structure of Formula III-2:
  • R 1 , R 2 , R 3 , R 4 , R 5 , X 1 , X 2 , V and L are as defined in the above formula I.
  • the compound has the structure of Formula III-3:
  • R 1 , R 3 , R 4 , R 5 , X 1 , X 2 , V and L are as defined in the above formula I.
  • the compound has the structure of Formula IV:
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , X 3 , V and L are as defined in the above formula II-1.
  • the compound has the structure of Formula V:
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and L are as defined in the above formula II-1.
  • R 1 is selected from the group consisting of halogen, C 1-8 alkyl, C 1-8 haloalkyl, C 1-8 alkoxy, C 1-8 haloalkoxy, C 3-8 cycloalkyl a 4-10 membered heterocyclic group, a C 6-10 aryl group and a 5-10 membered heteroaryl group; preferably, R 1 is selected from the group consisting of Br, C 1-6 alkyl, C 1-8 alkoxy, C 3 -8 cycloalkyl, 4-10 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl; preferably, R 1 is selected from C 2-6 alkyl, C 3-8 cycloalkyl a 4-7 membered heterocyclic group, a phenyl group and a 5-6 membered heteroaryl group; preferably, R 1 is a 5-6 membered heteroaryl group; said alkyl group, haloalkyl group, alkoxy group
  • R 1 is selected from the group consisting of halogen, C 1-8 alkyl, C 1-8 haloalkyl, C 1-8 alkoxy, C 1-8 haloalkoxy, C 3-8 cycloalkyl a 4-10 membered heterocyclic group, a C 6-10 aryl group and a 5-10 membered heteroaryl group; preferably, R 1 is selected from the group consisting of Br, C 1-6 alkyl, C 1-8 alkoxy, C 3 -8 cycloalkyl, 4-10 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl; preferably, R 1 is selected from C 2-6 alkyl, C 3-8 cycloalkyl a 4-7 membered heterocyclic group, a phenyl group and a 5-6 membered heteroaryl group; preferably, R 1 is a 5-6 membered heteroaryl group and a C 6-10 aryl group; preferably, R 1 is 5-6
  • R 1 is selected from bromine
  • R 1 is an unsubstituted pyrazolyl group.
  • R 2 is methyl
  • R 3 is OH.
  • R 6 is H.
  • L is -(CH 2 ) 3 -.
  • R 1 is selected from the group consisting of halogen, C 1-8 alkyl, C 1-8 haloalkyl, C 1-8 alkoxy, C 1-8 haloalkoxy, C 3-8 cycloalkyl a 4-10 membered heterocyclic group, a C 6-10 aryl group and a 5-10 membered heteroaryl group; preferably, R 1 is selected from the group consisting of Br, C 1-6 alkyl, C 1-8 alkoxy, C 3 -8 cycloalkyl, 4-10 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl; preferably, R 1 is selected from C 2-6 alkyl, C 3-8 cycloalkyl a 4-7 membered heterocyclic group, a phenyl group and a 5-6 membered heteroaryl group; preferably, R 1 is a 5-6 membered heteroaryl group and a C 6-10 aryl group; preferably, R 1 is 5-6
  • R 2 is a methyl group
  • R 3 is OH
  • R 6 is H
  • -LR 3 is -(CH 2 ) 3 -OH.
  • the compound has the structure of Formula V-1:
  • R 1 , R 2 , R 3 , R 4 , R 5 and R 6 are as defined in the above formula V.
  • the compound has the structure of Formula VI:
  • R 1 , R 2 , R 3 , R 4 , R 5 and L are as defined in the above formula III-2.
  • R 1 is selected from the group consisting of halogen, C 1-8 alkyl, C 1-8 haloalkyl, C 1-8 alkoxy, C 1-8 haloalkoxy, C 3-8 cycloalkyl a 4-10 membered heterocyclic group, a C 6-10 aryl group and a 5-10 membered heteroaryl group; preferably, R 1 is selected from the group consisting of Br, C 1-6 alkyl, C 1-8 alkoxy, C 3 -8 cycloalkyl, 4-10 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl; preferably, R 1 is selected from C 2-6 alkyl, C 3-8 cycloalkyl a 4-7 membered heterocyclic group, a phenyl group and a 5-6 membered heteroaryl group; preferably, R 1 is a 5-6 membered heteroaryl group; the above alkyl group, haloalkyl group, alkoxy
  • R 1 is selected from the group consisting of halogen, C 1-8 alkyl, C 1-8 haloalkyl, C 1-8 alkoxy, C 1-8 haloalkoxy, C 3-8 cycloalkyl a 4-10 membered heterocyclic group, a C 6-10 aryl group and a 5-10 membered heteroaryl group; preferably, R 1 is selected from the group consisting of Br, C 1-6 alkyl, C 1-8 alkoxy, C 3 -8 cycloalkyl, 4-10 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl; preferably, R 1 is selected from C 2-6 alkyl, C 3-8 cycloalkyl a 4-7 membered heterocyclic group, a phenyl group and a 5-6 membered heteroaryl group; preferably, R 1 is a 5-6 membered heteroaryl group; the above alkyl group, haloalkyl group, alkoxy
  • R 1 is selected from bromine
  • R 1 is an unsubstituted pyrazolyl group.
  • R 2 is selected from the group consisting of H, C 1-4 alkyl and p-methoxybenzyl.
  • R 3 is selected from the group consisting of H, methyl, ethyl, methoxy, tert-butoxy, benzyl, cyclopropyl, phenyl, OH,
  • R 1 is selected from the group consisting of halogen, C 1-8 alkyl, C 1-8 haloalkyl, C 1-8 alkoxy, C 1-8 haloalkoxy, C 3-8 cycloalkyl a 4-10 membered heterocyclic group, a C 6-10 aryl group and a 5-10 membered heteroaryl group; preferably, R 1 is selected from the group consisting of Br, C 1-6 alkyl, C 1-8 alkoxy, C 3 -8 cycloalkyl, 4-10 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl; preferably, R 1 is selected from C 2-6 alkyl, C 3-8 cycloalkyl a 4-7 membered heterocyclic group, a phenyl group and a 5-6 membered heteroaryl group; preferably, R 1 is a 5-6 membered heteroaryl group; the above alkyl group, haloalkyl group, alkoxy
  • R 2 is selected from the group consisting of H, C 1-4 alkyl and p-methoxybenzyl;
  • -LR 3 is selected from the following groups:
  • the compound has the structure of Formula VI-1:
  • R 1 , R 2 , R 3 , R 4 and R 5 are as defined in the above formula VI.
  • the compound has the structure of Formula VII:
  • R 1 , R 3 , R 4 , R 5 and L are as defined in the above formula III-3.
  • R 1 is selected from the group consisting of halogen, C 1-8 alkyl, C 1-8 haloalkyl, C 1-8 alkoxy, C 1-8 haloalkoxy, C 3-8 cycloalkyl a 4-10 membered heterocyclic group, a C 6-10 aryl group and a 5-10 membered heteroaryl group; preferably, R 1 is selected from the group consisting of Br, C 1-6 alkyl, C 1-8 alkoxy, C 3 -8 cycloalkyl, 4-10 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl; preferably, R 1 is selected from C 2-6 alkyl, C 3-8 cycloalkyl a 4-7 membered heterocyclic group, a phenyl group and a 5-6 membered heteroaryl group; preferably, R 1 is a 5-6 membered heteroaryl group; the above alkyl group, haloalkyl group, alkoxy
  • R 1 is selected from the group consisting of halogen, C 1-8 alkyl, C 1-8 haloalkyl, C 1-8 alkoxy, C 1-8 haloalkoxy, C 3-8 cycloalkyl a 4-10 membered heterocyclic group, a C 6-10 aryl group and a 5-10 membered heteroaryl group; preferably, R 1 is selected from the group consisting of Br, C 1-6 alkyl, C 1-8 alkoxy, C 3 -8 cycloalkyl, 4-10 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl; preferably, R 1 is selected from C 2-6 alkyl, C 3-8 cycloalkyl a 4-7 membered heterocyclic group, a phenyl group and a 5-6 membered heteroaryl group; preferably, R 1 is selected from a 5-6 membered heteroaryl group, a C 6-10 aryl group; preferably, R 1 is selected from a 5
  • R 1 is selected from bromine
  • R 1 is an unsubstituted pyrazolyl group.
  • -LR 3 is -(CH 2 ) 3 -OH.
  • R 1 is selected from bromine
  • -LR 3 is -(CH 2 ) 3 -OH.
  • the compound has the structure of Formula VII-1:
  • R 1 , R 3 , R 4 and R 5 are as defined in the above formula VII.
  • the compound of the invention is selected from, but not limited to:
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound as described above, a stereoisomer, a tautomer or a mixture thereof, a pharmaceutically acceptable salt of the compound a eutectic, polymorph or solvate, or a stable isotope derivative, metabolite or prodrug of said compound.
  • the pharmaceutical composition further comprises one or more pharmaceutically acceptable carriers.
  • the pharmaceutical composition is for preventing, ameliorating, and/or treating a disease associated with NLRP3 inflammatory body activity (eg, a neoplastic disease).
  • a disease associated with NLRP3 inflammatory body activity eg, a neoplastic disease
  • the pharmaceutical composition is for preventing, ameliorating, and/or treating a cell proliferative disorder (eg, cancer).
  • a cell proliferative disorder eg, cancer
  • compositions of the invention further comprise one or more second therapeutic agents.
  • the second therapeutic agent includes other drugs that treat tumor diseases and the like.
  • the present invention provides a pharmaceutical preparation comprising a compound as described above, a stereoisomer, a tautomer or a mixture thereof, a pharmaceutically acceptable salt of the compound, Eutectic, polymorph or solvate, or a stable isotope derivative, metabolite or prodrug of the compound, or a pharmaceutical composition as described above.
  • the invention provides a compound as described above, a stereoisomer, a tautomer or a mixture thereof, a pharmaceutically acceptable salt, eutectic, polymorph of the compound Or a solvate, or a stable isotope derivative, metabolite or prodrug of said compound, or a pharmaceutical composition as described above for use in the manufacture of a medicament for the prevention, alleviation and/or treatment of NLRP3 A disease associated with inflammatory body activity (eg, a neoplastic disease).
  • a disease associated with inflammatory body activity eg, a neoplastic disease.
  • the invention provides a compound as described above, a stereoisomer, a tautomer or a mixture thereof, a pharmaceutically acceptable salt, eutectic, polymorph of the compound Or a solvate, or a stable isotope derivative, metabolite or prodrug of said compound, or a pharmaceutical composition as described above, for use in the preparation of a formulation for modulating (e.g., increasing) NLRP3 inflammatory bodies Activity.
  • the formulation is administered to a subject (eg, a mammal; eg, a bovine, an equine, a sheep, a porcine, a canine, a feline, a rodent, a spirit) a long-lived animal; for example, a human) to increase NLRP3 inflammatory corpuscle activity in cells in a subject; or, the preparation is administered to an in vitro cell (eg, a cell line or a cell from a subject) to increase Activity of NLRP3 inflammatory bodies in cells.
  • a subject eg, a mammal; eg, a bovine, an equine, a sheep, a porcine, a canine, a feline, a rodent, a spirit
  • a long-lived animal for example, a human
  • the preparation is administered to an in vitro cell (eg, a cell line or a cell from a subject) to increase Activity of NLRP3 inflammatory bodies in cells.
  • the invention provides a method of modulating (e.g., increasing) NLRP3 inflammatory body activity in a cell, comprising administering to said cell an effective amount of a compound as described above, a stereoisomer of said compound a tautomer or a mixture thereof, a pharmaceutically acceptable salt, eutectic, polymorph or solvate of said compound, or a stable isotope derivative, metabolite or prodrug of said compound, or Said pharmaceutical composition, or a pharmaceutical preparation as described above.
  • the invention provides a kit for modulating (e.g., increasing) the activity of an NLRP3 inflammatory steroid comprising a compound, a stereoisomer, a tautomer of the compound Or a mixture thereof, a pharmaceutically acceptable salt, eutectic, polymorph or solvate of the compound, or a stable isotope derivative, metabolite or prodrug of the compound, or a pharmaceutical composition as described above Or a formulation as described above.
  • a kit for modulating e.g., increasing) the activity of an NLRP3 inflammatory steroid comprising a compound, a stereoisomer, a tautomer of the compound Or a mixture thereof, a pharmaceutically acceptable salt, eutectic, polymorph or solvate of the compound, or a stable isotope derivative, metabolite or prodrug of the compound, or a pharmaceutical composition as described above Or a formulation as described above.
  • the invention provides a method of treating a disease (eg, a neoplastic disease) associated with NLRP3 inflammatory steroid activity comprising administering to a subject in need thereof a therapeutic, ameliorating and/or prophylactically effective amount of the invention a compound, a stereoisomer, a tautomer or a mixture thereof, a pharmaceutically acceptable salt, eutectic, polymorph or solvate of the compound, or a stable isotope derivative of the compound A substance, metabolite or prodrug, or a pharmaceutical composition as described above, or a formulation as described above.
  • a disease eg, a neoplastic disease
  • a pharmaceutically acceptable salt eutectic, polymorph or solvate of the compound
  • a stable isotope derivative of the compound A substance, metabolite or prodrug, or a pharmaceutical composition as described above, or a formulation as described above.
  • the method further comprises administering to the subject in need thereof one or more second therapeutic agents.
  • the second therapeutic agent comprises other drugs that treat diseases such as tumors.
  • the tumor diseases include, but are not limited to, lung cancer, pancreatic cancer, breast cancer, head and neck cancer, liver cancer, 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 and activates a receptor to initiate a biological effect or response, including full agonists and partial agonists ( Partial agonist).
  • a full agonist activates the receptor and produces the greatest effect (maximal effect or Emax ).
  • Partial agonists can bind to and activate the receptor, but only produce a partial effect relative to the full agonist.
  • a full agonist and a partial agonist coexist, a partial agonist can sometimes become a partial antagonist by competing with a full agonist for a binding site on the receptor or other mechanism.
  • Potency concentration of the compound potency, by the EC 50 (producing 50% of the Emax of) measure
  • a partial agonist may be higher or lower than in a full agonist efficacy.
  • the NLRP3 agonists of the invention include NLRP3 full agonists and NLRP3 partial agonists.
  • NLRP3 NLR family pyrin domain containing 3, which is an inflammatory body.
  • the meanings indicated include nucleic acids, polynucleotides, oligonucleotides, sense and antisense polynucleotide chains, complementary sequences, short peptides, polypeptides of NLRP3. , proteins, homologous or heterologous molecules, subtypes, precursors, mutants, variants, derivatives, various splices, alleles, different species, and activated fragments, and the like.
  • halo means substituted by a halogen atom, and the “halogen” includes F, Cl, Br or I.
  • alkyl is a straight or branched saturated aliphatic hydrocarbon group.
  • C 1-8 alkyl C 1-6 alkyl
  • C 1-4 alkyl respectively have from 1 to 8 carbon atoms, from 1 to 6 carbon atoms and from 1 to 4 carbon atoms.
  • a linear or branched alkyl group 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) identical or different substituents.
  • alkylene refers to a saturated divalent hydrocarbon radical derived from the removal of two hydrogen atoms from a straight or branched saturated hydrocarbon radical, which contains the specified number of carbon atoms.
  • an alkylene group of 1 to 8 carbon atoms such as methylene (-CH 2 -), ethylene (-CH 2 CH 2 -), isopropylidene (-CH(CH 3 )CH 2 -) And the like; the alkylene group may be optionally substituted by one or more (such as 1 to 3) identical or different substituents.
  • haloalkyl refers to an alkyl group substituted by one or more (such as 1 to 3) identical or different halogen atoms
  • C 1-8 haloalkyl means a haloalkyl group having 1 to 8 carbon atoms, 1 to 6 carbon atoms and 1 to 4 carbon atoms, respectively, such as -CF 3 , -C 2 F 5 , -CHF 2 , CH 2 F, -CH 2 CF 3 , -CH 2 Cl or -CH 2 CH 2 CF 3 or the like.
  • hydroxyalkyl refers to a group formed by the substitution of a hydrogen atom of an alkyl group with one or more hydroxy groups, such as a C 1-4 hydroxyalkyl group or a C 1-3 hydroxyalkyl group, examples of which include, but are not limited to, hydroxy methyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, -CH (OH) CH 3 and the like.
  • alkynyl refers to a monovalent straight or branched chain hydrocarbon radical having one or more carbon-carbon triple bonds including, but not limited to, ethynyl, 2-propynyl, 2-butynyl, and 1,3-butyl Diacetylene or the like, which may be optionally substituted by one or more (such as 1 to 3) identical or different substituents.
  • alkynylene refers to a divalent straight or branched chain hydrocarbon radical having one or more carbon-carbon triple bonds containing a specified number of carbon atoms, for example 2 to 8 carbon atoms, including but not limited to And the alkynylene group may be optionally substituted by one or more (such as 1 to 3) identical or different substituents.
  • alkoxy means a group which is inserted into the oxygen atom at any reasonable position of the alkyl group (as defined above), preferably a C 1 -C 6 alkoxy group or a C 1 -C 3 alkoxy group.
  • Representative examples of C 1 -C 6 alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, n-propoxy, isopropoxy, n-butoxy, isobutyl Oxyl, tert-butoxy, pentyloxy, hexyloxy, -CH 2 -OCH 3 and the like, which may optionally be substituted by one or more (such as 1 to 3) identical or different Substituted.
  • alkoxy 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 by one or more (such as 1 to 3) identical or different substituents.
  • heteroalkyl refers to an alkyl group containing two or more carbon atoms, optionally having one or more backbone chain atoms selected from atoms other than carbon, such as oxygen, nitrogen, which may be optionally substituted. , sulfur, phosphorus or a combination thereof, the numerical range given refers to the number of carbons in the chain, for example C 2 -8 heteroalkyl contains 2-8 carbon atoms.
  • -CH 2 OCH 2 CH 3 , -CH 2 NHCH 2 CH 3 or -CH 2 N(Me)CH 2 CH 3 is referred to as a C 3 heteroalkyl group.
  • heteroalkylene denotes the corresponding divalent group, for example, -CH 2 OCH 2 CH 2 -.
  • paracyclic or “fused ring” refers to a ring system formed by two or more cyclic structures sharing two adjacent atoms with each other.
  • spiro refers to a ring system formed by two or more ring structures sharing one ring atom with each other.
  • bridged ring refers to a ring system formed by two or more cyclic structures sharing two atoms that are not directly connected to each other.
  • cycloalkyl refers to a saturated or unsaturated, non-aromatic monocyclic or polycyclic (such as bicyclic) hydrocarbon ring group including, but not limited to, monocycloalkyl (such as cyclopropyl, cyclobutyl, cyclopentyl, Cyclohexyl, cycloheptyl, cyclooctyl, cyclodecyl) and bicycloalkyl, including spiro, cyclo (fused ring) or bridged ring systems (ie, spirocycloalkyl, cyclo (fused) alkyl) And bridged cycloalkyl, such as bicyclo [1.1.1] pentyl, bicyclo [2.2.1] heptyl, etc.).
  • monocycloalkyl such as cyclopropyl, cyclobutyl, cyclopentyl, Cyclohexyl, cycloheptyl, cycloo
  • the cycloalkyl group may be optionally substituted by one or more (such as 1 to 3) identical or different substituents.
  • C 3-8 cycloalkyl refers to a cycloalkyl group having from 3 to 8 ring-forming carbon atoms which may be a monocyclic alkyl group such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, ring. Heptyl, cyclooctyl) may also be a bicycloalkyl group such as a C 3-8 spirocycloalkyl group, a C 3-8 bridged cycloalkyl group, a C 3-8 fused ring alkyl group.
  • aryl refers to an all-carbon monocyclic or fused polycyclic aromatic group having a conjugated pi-electron system.
  • C 6 - 12 aryl as used herein means an aryl group having 6 to 12 carbon atoms, such as a C 6 -C 10 aryl group, for example, a phenyl group or a naphthyl group.
  • the aryl group is optionally substituted by one or more (such as 1 to 3) identical or different substituents (e.g., halogen, OH, CN, NO 2 , C 1 -C 6 alkyl, etc.).
  • arylcycloalkyl refers to a cis-group in which an aryl group and a cycloalkyl group (eg, a monocycloalkyl group) share two adjacent atoms with each other, wherein the point of attachment to other groups may be On the aryl group or on the cycloalkyl group.
  • arylcycloalkyl refers to an arylcycloalkyl group having a total of 9 to 12 ring atoms, such as phenylcyclopentyl, phenylcyclohexyl, for example,
  • heterocyclyl refers to having two or more (eg, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14) carbon atoms, and one or more (for example, one, two, three or four) heterocyclic monocyclic or polycyclic (eg, cyclo, spiro or bridged) groups including, but not limited to, oxygen, nitrogen, sulfur
  • 3-14 membered heterocyclic group means a heterocyclic group having 3 to 14 ring atoms, including but not limited to a 4-10 membered heterocyclic group, a 4-7 membered heterocyclic group, and a 5-6 membered heterocyclic ring.
  • Base 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 nitrogen-containing heterocyclic ring a 5- to 6-membered oxygen-containing heterocyclic group, a 5-6 membered sulfur-containing heterocyclic group, said "nitrogen-containing heterocyclic group", “oxygen-containing heterocyclic group”, or "sulfur-containing heterocyclic group”, optionally It also contains one or more other heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur.
  • 3-14 membered heterocyclic groups include, but are not limited to, oxiranyl, aziridine, azetidinyl, oxetanyl, tetrahydrofuranyl, pyrrolidinyl, pyrrolidinyl, imidazolidinyl, Pyrazolidinyl, tetrahydropyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl, trithianyl, and the like.
  • heterocyclic group may form a cyclic structure with a heterocyclic group or a cycloalkyl group, and the point of attachment of the cyclo-ring structure to other groups may be on either a heterocyclic group or a cycloalkyl group, and thus, the present invention
  • Heterocyclyl also includes, but is not limited to, heterocyclylheterocyclyl, heterocyclylcycloalkyl, monoheterocyclylmonoheterocyclyl, monoheterocyclylmonocycloalkyl, such as 3- 7-membered (mono)heterocyclic and 3-7 membered (mono)heterocyclyl, 3-7 membered (mono)heterocyclyl(mono)cycloalkyl, 3-7 membered (mono)heterocyclyl and C 4-6 (mono)cycloalkyl, examples of which include, but are not limited to, pyrrolidinylcycloprop
  • the heterocyclic group further includes a bridged heterocyclic group and a spiroheterocyclic group.
  • bridge heterocycle means that two saturated rings share two or more (eg, 1, 2, 3 or 4) heteroatoms (eg, oxygen, nitrogen) formed by ring atoms that are not directly joined.
  • a cyclic structure of a sulfur atom including but not limited to a 7-10 membered bridged heterocyclic ring, an 8-10 membered bridged heterocyclic ring, a 7-10 membered nitrogen-containing bridged heterocyclic ring, and a 7-10 membered oxygenated bridged heterocyclic ring, 7 -10 yuan sulfur-containing bridge heterocycle, etc., for example Wait.
  • the "nitrogen-containing bridged heterocycle", “oxygen-containing bridged heterocycle”, and “sulfur-containing bridged heterocycle” optionally further contain one or more other heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur.
  • spiroheterocycle refers to a heteroatom containing one or more (eg, 1, 2, 3 or 4) heteroatoms (eg, an oxygen atom, nitrogen) formed by the sharing of one ring atom by two or more saturated rings.
  • a cyclic structure of an atom, a sulfur atom including but not limited to a 5-10 membered spiro heterocyclic ring, a 6-10 membered spiro heterocyclic ring, a 6-10 membered nitrogen-containing spiro heterocyclic ring, and a 6-10 membered oxygenated spiro heterocyclic ring.
  • nitrogen-containing spiroheterocycle 6-10 yuan sulfur-containing spiro heterocycle, etc.
  • the "nitrogen-containing spiroheterocycle”, “oxygen-containing spiroheterocycle”, and “sulfur-containing spiroheterocycle” optionally further contain one or more other heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur.
  • the term "6-10 membered nitrogen-containing spiroheterocyclyl” means a spiroheterocyclyl group containing a total of 6 to 10 ring atoms and at least one of which is a nitrogen atom.
  • arylheterocyclyl refers to a cyclic group formed by the aryl group and the heterocyclic group sharing two adjacent carbon atoms with each other, and the point of attachment to other groups may be at an aryl or heterocyclic group. on. Wherein the aryl group and the heterocyclic group are as defined above.
  • the term “9-12 membered arylheterocyclyl” means a group containing an arylheterocyclyl group of a total of 9 to 12 ring atoms, including but not limited to 9-10 members.
  • a benzoheterocyclyl group such as a phenyl- and 5- to 8-membered heterocyclic group, such as a phenyl- and 5- to 6-membered heterocyclic group, such as a benzo 5-6 membered monoheterocyclic group, a benzo 5-6 membered nitrogen group.
  • a monoheterocyclic group, a benzo 5-6 membered oxygen monoheterocyclic group, a benzo 5-6 membered sulfur-containing heterocyclic group, said "nitrogen-containing heterocyclic group", “oxygen-containing heterocyclic group", "including The thiaheterocyclyl” optionally further contains one or more other heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur.
  • Examples include, but are not limited to, carbazolyl,
  • heteroaryl refers to a monocyclic or polycyclic aromatic group containing one or more (eg, 1, 2, 3 or 4) identical or different heteroatoms, including monocyclic heteroaryls and a bicyclic or polycyclic ring system containing at least one heteroaromatic ring (an aromatic ring system containing at least one hetero atom) which may have 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 rings An atom such as 5, 6, 7, 8, 9 or 10 ring atoms.
  • the hetero atom can be oxygen, nitrogen or sulfur.
  • 5-10 membered heteroaryl means a heteroaryl group containing 5 to 10 ring atoms, including a 5-6 membered heteroaryl group, a 5-6 membered monoheteroaryl group, and a 5-10 membered nitrogen-containing heteroaryl group.
  • the base optionally also contains one or more other heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur.
  • Examples thereof include, but are not limited to, thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, triazolyl, tetrazolyl, oxadiazolyl A thiadiazolyl group or the like, or a pyridyl group, a pyridazinyl group, a pyrimidinyl group, a pyrazinyl group, a triazinyl group or the like, and a 5- to 10-membered cyclized group containing these groups.
  • a heteroaryl group (for example, a monoheteroaryl group) may be bonded to an aryl group (for example, a monocyclic aryl group such as a phenyl group), a heterocyclic group (for example, a monoheterocyclic group), or a cycloalkyl group (for example, a monocycloalkyl group).
  • aryl group for example, a monocyclic aryl group such as a phenyl group
  • a heterocyclic group for example, a monoheterocyclic group
  • a cycloalkyl group for example, a monocycloalkyl group
  • heteroaryl group e.g., another monoheteroaryl group
  • shares a concatenation structure formed by two adjacent atoms, and the point of attachment may be on any heteroaromatic ring or other ring, including but not limited to Mono)heteroaryl(mono)heteroaryl, (mono)heteroaryl(monocyclic)aryl, (mono)heteroaryl(mono)heterocyclyl, and (mono)heteroaryl Mono)cycloalkyl, for example 5-6 membered (mono)heteroaryl and 5-6 membered (mono)heteroaryl, 5-6 membered (mono)heteroarylphenyl, 5-6 (single) Heteroaryl and 5-6 membered (mono)heterocyclyl, or 5-6 membered (mono)heteroaryl and C 4-6 (mono)cycloalkyl (eg 5-6 membered heteroarylcyclo
  • arylheteroaryl refers to a cis-based group formed from an aryl group (eg, a monocyclic aryl group such as phenyl) and a heteroaryl group (eg, a monoheteroaryl group such as a 5-6 membered monoheteroaryl group).
  • the group, its point of attachment to other groups may be on the aromatic ring or on the heteroaryl ring.
  • the "arylheteroaryl” includes, but is not limited to, a monocyclic aryl-heteroaryl group.
  • 9-12 membered arylheteroaryl refers to an arylheteroaryl group containing a total of 9 to 12 ring atoms, such as a benzo 5-6 membered nitrogen-containing monoheteroaryl group.
  • heteroarylcycloalkyl refers to a heterocyclic ring formed by a heteroaryl group (eg, a monoheteroaryl group, eg, a 5-6 membered monoheteroaryl group) and a cycloalkyl group (eg, a C4-6 cycloalkyl group).
  • a heteroaryl group eg, a monoheteroaryl group, eg, a 5-6 membered monoheteroaryl group
  • a cycloalkyl group eg, a C4-6 cycloalkyl group.
  • the group, its point of attachment to other groups may be on the heteroaryl ring or on the cycloalkyl group.
  • the "heteroaryl-cycloalkyl” includes, but is not limited to, a monoheteroaryl-monocycloalkyl group.
  • 9-10 membered heteroarylcycloalkyl refers to a heteroarylcycloalkyl group containing a total of 9 to 10 ring atoms, for example, a 4-6 membered nitrogen-containing monoheteroaryl group and a C 4-6 single Cycloalkyl.
  • substituted means that one or more (eg, 1, 2, 3 or 4) hydrogens on the designated atom are replaced by the selection of the indicated group, provided that the specified atom is not exceeded.
  • the normal valence of the current case and the substitution form a stable compound. Combinations of substituents and/or variables are permissible only if such combinations form stable compounds.
  • substituent may be 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) may be independently and/or together independently The selected substituents are optionally substituted. If the nitrogen 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 nitrogen (to the extent of any hydrogen present) may each independently be independently selected substituent Optionally substituted.
  • each substituent is selected independently of the other.
  • each substituent may be the same or different from another (other) substituent.
  • one or more means one or more than one, such as two, three, four, five, six, seven, eight, nine, under reasonable conditions. Or 10 or so.
  • a point of attachment of a substituent may come from any suitable position of the substituent.
  • the invention also includes all pharmaceutically acceptable isotopic compounds of the compounds of the invention which are identical to the compounds of the invention, except that one or more atoms are of the same atomic number but differ in atomic mass or mass number in nature. Atomic mass or mass atom substitution.
  • isotopes suitable for inclusion in the compounds of the invention include, but are not limited to, isotopes of hydrogen (e.g., 2 H, 3 H); isotopes of carbon (e.g., 11 C, 13 C, and 14 C); isotopes of chlorine (e.g.
  • stable isotopic derivative means that one or more atoms in a compound of the invention are formed by atomic substitutions having the same atomic number but differing in atomic mass or mass number from the atomic mass or mass number prevailing in nature. Stable compound.
  • stereoisomer refers to an isomer of a compound formed by the inclusion of at least one asymmetric center.
  • a compound having one or more (eg, 1, 2, 3, or 4) asymmetric centers which can produce a racemic mixture, a single enantiomer, a mixture of diastereomers, and Separate diastereomers.
  • Specific individual molecules can also exist as geometric isomers (cis/trans).
  • the compounds of the invention may exist as mixtures (often referred to as tautomers) of two or more different structural forms in rapid equilibrium.
  • tautomers include keto-enol tautomers, phenol-keto tautomers, nitroso-oxime tautomers, imine-enamine tautomers Wait.
  • nitroso-oxime can be present in solution in the following tautomeric forms:
  • the compounds of the invention are intended to be stereoisomers (including cis and trans isomers), optical isomers (such as R and S enantiomers), diastereomers. , geometric isomers, rotamers, conformers, atropisomers or mixtures thereof are present.
  • the compounds of the invention may exhibit more than one type of isomerism and consist of a mixture thereof (e.g., a racemic mixture and a diastereomeric pair).
  • the invention encompasses all possible crystalline forms or polymorphs of the compounds of the invention, which may be a single polymorph or a mixture of more than one polymorph in any ratio. It will also be understood that certain compounds of the invention may exist in free form for treatment or, where appropriate, in the form of their pharmaceutically acceptable derivatives.
  • pharmaceutically acceptable derivatives include, but are not limited to, pharmaceutically acceptable salts, solvates, metabolites or prodrugs which, after administration to a patient in need thereof, can be directly or indirectly A compound of the invention or a metabolite or residue thereof is provided.
  • a compound of the invention it is also intended to encompass the various derivative forms described above for the compound.
  • the pharmaceutically acceptable salts of the compounds of the present invention include the acid addition salts and base addition salts thereof.
  • suitable salts see “Handbook of Pharmaceutical Salts: Properties, Selection, and Use” by Stahl and Wermuth (Wiley-VCH, 2002).
  • “Pharmaceutically acceptable carrier” in the context of the present invention means a diluent, adjuvant, excipient or vehicle with which the therapeutic agent is administered, and which is suitable for contacting humans and/or within the scope of sound medical judgment. 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, vegetable or synthetic origin, such as peanut oil, soybean oil, minerals. Oil, sesame oil, etc.
  • compositions of the invention may be administered in a suitable dosage form.
  • an effective amount refers to an amount of a compound that, to a certain extent, relieves one or more symptoms of the condition being treated after administration.
  • the dosing regimen can be adjusted to provide the optimal desired response. For example, a single bolus may be administered, several divided doses may be administered over time, or the dose may be proportionally reduced or increased as indicated by the urgent need for treatment. It is noted that the dose value can vary with the type and severity of the condition to be alleviated and can include single or multiple doses. It is to be further understood that for any particular individual, the particular dosage regimen will be adjusted over time according to the individual needs and the professional judgment of the person administering the composition or the composition of the supervised composition.
  • an effective dose will be from about 0.0001 to about 50 mg per kg body weight per day, for example from 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 from about 0.7 mg/day to about 700 mg/day.
  • a dose level that is not higher than the lower limit of the aforementioned range may be sufficient, while in other cases, a larger dose may still be employed 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 amount of the compound of the present invention in the pharmaceutical composition may be from about 0.01 mg to about 1000 mg.
  • treating means reversing, alleviating, inhibiting the progression of a condition or condition to which such a term applies, or the progression of one or more symptoms of such a condition or condition, Or preventing such a condition or condition, or one or more symptoms of such condition or condition.
  • “Individual” as used herein includes human or non-human animals.
  • Exemplary human individuals include a human individual (referred to as a patient) or a normal individual having a disease, such as the disease 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 such as water, methanol or ethanol.
  • a polar solvent as a structural element of the crystal lattice of the compound, particularly such as water, methanol or ethanol.
  • the amount of polar solvent, particularly water, may be present in stoichiometric or non-stoichiometric ratios.
  • metabolites of the compounds of the invention i.e., substances formed in vivo upon administration of a compound of the invention. Such products may be produced, for example, by oxidation, reduction, hydrolysis, amidation, deamidation, esterification, delipidization, enzymatic hydrolysis, and the like of the administered compound. Accordingly, the invention includes metabolites of the compounds of the invention, including compounds obtained by contacting a compound of the invention with a mammal for a time sufficient to produce a metabolic product thereof.
  • the invention further includes within its scope prodrugs of the compounds of the invention, which are certain derivatives of the compounds of the invention which may themselves have less or no pharmacological activity, when administered to the body or
  • the above compounds can be converted to the compounds of the invention having the desired activity by, for example, hydrolytic cleavage.
  • prodrugs will be functional group derivatives of the compounds which are readily converted in vivo to the desired therapeutically active compound. Additional information on the use of prodrugs can be found in "Pro-drugs as Novel Delivery Systems", Volume 14, ACS Symposium Series (T. Higuchi and V. Stella) and "Bioreversible Carriers in Drug Design," Pergamon Press, 1987 ( Edited by EBRoche, American Pharmaceutical Association).
  • Prodrugs of the invention may, for example, be known by those skilled in the art as “pro-moiety” (e.g., “Design of Prodrugs", H. Bundgaard (Elsevier, 1985))" It is prepared in place of the appropriate functional groups present in the compounds of the invention.
  • the invention also encompasses compounds of the invention containing a protecting group.
  • a protecting group In any process for preparing a compound of the invention, it may be necessary and/or desirable to protect sensitive groups or reactive groups on any of the molecules of interest, thereby forming a chemically protected form of the compounds of the invention. This can be achieved by conventional protecting groups such as those described in Protective Groups in Organic Chemistry, ed. JFW McOmie, Plenum Press, 1973; and TW Greene & P. GM Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991. Protecting groups, which are incorporated herein by reference. The protecting group can be removed at a suitable subsequent stage using methods known in the art.
  • the bond in the structural formula represented by the wavy line " ⁇ " is intended to mean a cis or trans isomer, or a mixture of cis and trans isomers in any ratio.
  • This article uses Indicates that the key in the formula is a single bond or a double bond.
  • This article uses Indicates that the position of the double bond is uncertain, but still guarantees that the ring in which it is located is aromatic.
  • room temperature means 15-30 °C.
  • R 2 is hydrogen, R 4 , R 5 , R 6 are as defined in the above formula V, and R 1 is as defined in the above formula V, but does not contain NO 2 ;
  • the bromination reaction can be carried out using a brominating reagent such as Br 2 or NBS.
  • a brominating reagent such as Br 2 or NBS.
  • the reaction is carried out in a solvent, and the solvent that can be used is DMF, CH 3 COOH, THF, CH 3 CN or DCM, and the like.
  • the reaction temperature is from -20 °C to 180 °C.
  • the second step the compound V-1-2 is subjected to nitration to form a compound V-1-3.
  • the nitration reaction can be carried out using a nitrating agent such as concentrated nitric acid, fuming nitric acid, tetrabutylammonium nitrate or the like.
  • a nitrating agent such as concentrated nitric acid, fuming nitric acid, tetrabutylammonium nitrate or the like.
  • the reaction is carried out in a solvent, and the solvent that can be used is acetic acid, propionic acid or butyric acid, and the like.
  • the reaction temperature is from 100 °C to 150 °C.
  • the chlorination reaction can be carried out using a chlorinating agent such as POCl 3 , PCl 3 or PCl 5 .
  • the reaction is carried out in a solvent, and the solvent that can be used is DCM or DCE or the like.
  • the reaction is carried out in the absence of solvent.
  • the reaction temperature is from rt to 110 °C.
  • the fourth step Compound V-1-4 is subjected to iodine substitution reaction to give compound V-1-5.
  • an iodine substitution reaction can be carried out using an iodine reagent such as KI or NaI.
  • the reaction is carried out in a solvent, and the solvent that can be used is THF, CH 3 CN or 1,4-dioxane, and the like.
  • the reaction temperature is from rt to 100 °C.
  • the reduction reaction can be carried out using a reducing agent such as sodium dithionite, SnCl 2 , Fe or Zn.
  • a reducing agent such as sodium dithionite, SnCl 2 , Fe or Zn.
  • the reaction is carried out in a solvent, and the solvent that can be used is MeOH, EtOH, THF or 1,4-dioxane, and the like.
  • the reaction temperature is from 0 °C to 110 °C.
  • the sixth step the compound V-1-6 is subjected to an amino-protective reaction under basic conditions to give a compound V-1-7.
  • the reaction can be carried out using an amino protecting reagent such as (Boc) 2 O.
  • the reaction can be carried out using a base such as t BuOK, t BuONa, t BuOLi, NaH, NaOH, KOH, Cs 2 CO 3 , K 2 CO 3 or Na 2 CO 3 .
  • the reaction is carried out in a solvent, the solvent may be used are THF, DCM, DCE, CH 3 CN, 1,4-dioxane and the like or DMF.
  • the reaction temperature is from 0 °C to 160 °C.
  • the seventh step the compound V-1-7 and the R 3 -alkyne are subjected to a coupling reaction (for example, Sonogashira reaction) under the action of a catalyst, a cuprous salt and a base to form a compound V-1-8.
  • a coupling reaction for example, Sonogashira reaction
  • the catalyst that can be used is Pd(PPh 3 ) 4 or Pd(PPh 3 )Cl 2 , etc.
  • the base that can be used is Et 2 NH, TEA or DIPEA, and the like.
  • the reaction is carried out in a solvent, and the solvent that can be used is 1,4-dioxane, CH 3 CN or EA, and the like.
  • the cuprous salt that can be used is CuI, CuBr, CuCl, and the like.
  • the reaction temperature is from -20 °C to 100 °C.
  • Step 8 Compound V-1-8 is cleaved under basic conditions to give the product V-1-9.
  • the reaction can be carried out with a base such as DBU, TEA, DIPEA, t BuOK, t BuONa, t BuOLi, NaOH, Cs 2 CO 3 , K 3 PO 4 or Na 2 CO 3 .
  • the reaction is carried out in a solvent, and the solvent that can be used is THF/H 2 O, MeOH/H 2 O, EtOH/H 2 O, DMF/H 2 O, DMSO/H 2 O, CH 3 CN /H 2 O or 1,4-dioxane/H 2 O, and the like.
  • the reaction temperature is from rt to 120 °C.
  • Step 9 Compound V-1-9 is reacted with R 6 -Cl (or R 6 -Br) under basic conditions to give compound V-1-10.
  • the reaction can be carried out using a base such as t BuOK, t BuONa, t BuOLi, NaH, NaOH, KOH, Cs 2 CO 3 , K 2 CO 3 or Na 2 CO 3 .
  • the reaction is carried out in a solvent, and the solvent that can be used is THF, DCM, CH 3 CN, 1,4-dioxane or DMF, and the like.
  • the reaction temperature is from 0 °C to 160 °C.
  • Step 10 Compound V-1-10 is oxidized to give compound V-1-11.
  • the reaction can be carried out using an oxidizing agent such as m-CPBA, H 2 O 2 or CH 3 COOOH.
  • the reaction is carried out in a solvent, and the solvent that can be used is DCM, DCE, CHCl 3 or DMF, and the like.
  • the reaction temperature is from 0 °C to 100 °C.
  • the catalyst that can be used is TsCl or the like.
  • the base that can be used is TEA or DIPEA, and the like.
  • the reaction is carried out in a solvent such as DCM, CHCl 3 or DCE, and the like.
  • the reaction temperature is from 0 °C to 100 °C.
  • Step 12 Compound V-1-12 is reacted with R 1 -Y by a coupling reaction, a substitution reaction, or V-1-12 is reduced to form compound V-1.
  • V-1-12 and R 1 -Y are subjected to a Suzuki coupling reaction to form a compound V-1.
  • the reaction can be carried out using a catalyst such as Pd(PPh 3 ) 4 or Pd(dppf)Cl 2 .
  • the reaction can be carried out using a base such as Cs 2 CO 3 , K 3 PO 4 , Na 2 CO 3 , AcOK, NaHCO 3 or K 2 CO 3 .
  • the reaction is carried out in a solvent such as 1,4-dioxane/H 2 O, DMF/H 2 O, DMSO/H 2 O, CH 3 CN/H 2 O or toluene/H. 2 O and so on.
  • the reaction temperature is from 60 °C to 160 °C.
  • V-1-12 is reacted with R 1 -Y by a coupling reaction (such as Ullmann reaction, Heck reaction, Buchwald-Hartwig reaction or Sonogashira reaction) to form compound V. -1.
  • a coupling reaction such as Ullmann reaction, Heck reaction, Buchwald-Hartwig reaction or Sonogashira reaction
  • the reaction can be carried out using a catalyst such as Cu, Cu 2 O, CuI, CuBr, CuCl, PdCl 2 , Pd(OAc) 2 , Pd(PPh 3 ) 4 or Pd(PPh 3 ) 2 Cl 2 .
  • the reaction can be carried out using a base such as Cs 2 CO 3 , K 3 PO 4 , Na 2 CO 3 , AcOK, TEA, NaHCO 3 or K 2 CO 3 .
  • a base such as Cs 2 CO 3 , K 3 PO 4 , Na 2 CO 3 , AcOK, TEA, NaHCO 3 or K 2 CO 3 .
  • Reaction is carried out in a solvent in some embodiments, the solvent is 1,4-dioxane, EA, DMF, DMSO, CH 3 CN or toluene.
  • the reaction temperature is from 60 °C to 160 °C.
  • V-1-12 and R 1 -Y are reacted by Negishi to form compound V-1.
  • the reaction can be carried out using a catalyst such as Pd(OAc) 2 or Pd(PPh 3 ) 4 .
  • a ligand such as PPh 3 reaction.
  • the reaction is carried out in a solvent, and the solvent that can be used is DMF or NMP or the like.
  • the reaction temperature is from 0 °C to 160 °C.
  • V-1-12 and R 1 -Y are reacted by Stille to form compound V-1.
  • the reaction can be carried out using a catalyst such as PdCl 2 , Pd(OAc) 2 or Pd(PPh 3 ) 2 Cl 2 .
  • a ligand such as PPh 3 reaction.
  • the reaction is carried out in a solvent, and the solvent that can be used is 1,4-dioxane, THF or CH 3 CN, and the like.
  • the reaction temperature is from 0 °C to 160 °C.
  • V-1-12 and R 1 -Y are substituted to form compound V-1.
  • the reaction is carried out in a solvent, and the solvent that can be used is 1,4-dioxane, THF or CH 3 CN, and the like.
  • the reaction temperature is from 0 °C to 110 °C.
  • V-1-12 is reduced to give compound V-1 (R 1 is H).
  • the reaction can be carried out using a reducing agent such as Pd or Pd(OH) 2 .
  • the reaction is carried out in a solvent, and the solvent that can be used is 1,4-dioxane, THF, methanol, ethanol or toluene, and the like.
  • the reaction temperature is from 0 °C to 100 °C.
  • R 1 , R 2 , R 3 , R 4 and R 5 are as defined in the above formula VI, but R 1 does not contain NO 2 , and R 3 does not contain halogen, OH, CN and NO 2 .
  • the first step the compound VI-1-1 is nitrated to form compound VI-1-2.
  • the reaction can be carried out using a nitrating agent such as concentrated nitric acid, fuming nitric acid, tetrabutylammonium nitrate or the like.
  • a nitrating agent such as concentrated nitric acid, fuming nitric acid, tetrabutylammonium nitrate or the like.
  • the reaction is carried out in a solvent, and the solvent that can be used is acetic acid, propionic acid or butyric acid, and the like.
  • the reaction temperature is from 100 °C to 150 °C.
  • the reaction can be carried out using a chlorinating agent such as POCl 3 , PCl 3 or PCl 5 .
  • the reaction is carried out in a solvent, and the solvent that can be used is DCM or DCE or the like.
  • the reaction is carried out in the absence of solvent.
  • the reaction temperature is from rt to 110 °C.
  • the third step the compound VI-1-3 and R 2 -NH 2 are subjected to a substitution reaction under a base to form a compound VI-1-4.
  • the base that can be used is TEA or DIPEA, and the like.
  • the reaction is carried out in a solvent, and the solvent that can be used is NMP or DMF or the like.
  • the reaction temperature is from 0 °C to 180 °C.
  • the reaction can be carried out using a reducing agent such as sodium dithionite, SnCl 2 , Fe, Zn, or Pd/C.
  • a reducing agent such as sodium dithionite, SnCl 2 , Fe, Zn, or Pd/C.
  • the reaction is carried out in a solvent, and the solvent that can be used is MeOH, EtOH, THF or 1,4-dioxane, and the like.
  • the reaction temperature is from rt to 110 °C.
  • Step 5 Compound VI-1-5 is reacted with R 3 -COOH under basic conditions to form compound VI-1-6, or VI-1-5 is directly reacted with R 3 -COCl under alkali to form VI -1-6.
  • the reaction can be carried out using a condensing agent such as HATU, DCC/NHS, EDCI/HOBt or HBTU.
  • the base that can be used is TEA or DIPEA, and the like.
  • the reaction is carried out in a solvent, the solvent may be used are THF, DCM, DCE, CH 3 CN, 1,4-dioxane and the like or DMF.
  • the reaction temperature is from 0 °C to 160 °C.
  • Step 6 Compound VI-1-6 is subjected to ring closure under basic conditions and then brominated to give compound VI-1-7.
  • a ring closure reaction can be carried out with a base such as TEA or DIPEA.
  • the ring closure reaction is carried out in a solvent, and the solvent that can be used is MeOH, EtOH, THF, CH 3 CN or 1,4-dioxane, and the like.
  • the reaction temperature is from 60 °C to 100 °C.
  • the bromination reaction can be carried out using a brominating agent such as bromine, NBS, dibromohydantoin or the like.
  • the bromination reaction is carried out in a solvent, and the solvents that can be used are acetic acid, 1,4-dioxane, DMF, EA, and the like.
  • the reaction temperature is from -20 °C to 100 °C.
  • Step 7 Compound VI-1-7 is oxidized to compound VI-1-8.
  • the reaction can be carried out using an oxidizing agent such as m-CPBA, H 2 O 2 or CH 3 COOOH.
  • the reaction is carried out in a solvent, and the solvent that can be used is DCM, DCE, CHCl 3 or DMF, and the like.
  • the reaction temperature is from 0 °C to 160 °C.
  • Step 8 Compound VI-1-8 is reacted with NHR 4 R 5 under the action of a base and an activator to give compound VI-1-9.
  • the activator that can be used is TsCl, Ts 2 O, and the like, and in some embodiments, the base that can be used is TEA or DIPEA, and the like.
  • the reaction is carried out in a solvent, and the solvent that can be used is DCM, CHCl 3 or DCE, and the like.
  • the reaction temperature is from 0 °C to 80 °C.
  • the ninth step the compound VI-1-9 and R 1 -Y can be subjected to a coupling reaction, a substitution reaction or a reduction reaction of VI-1-9 to form a compound VI-1.
  • the reaction conditions are the same as those of the twelfth step of V-1.
  • R 1 , R 2 , R 3 , R 4 , R 5 are as defined in the above formula VI, but R 1 does not contain NO 2 ;
  • L is as defined in the above formula VI, but n+p+q is not 0, and -LR 3 is bonded to -COOH or -COCl as a carbon atom.
  • the first step: compound VI-1-5 and R 3 -L-COOH can be subjected to condensation reaction under basic conditions to form compound VI-2-1, or VI-1-5 can directly react with R 3 -L under the action of a base.
  • the -COCl reaction produces VI-2-1, and in some embodiments, the reaction conditions are as described in the fifth step of the synthesis of VI-1.
  • the reaction can be carried out using a base such as NaOH, KOH, TEA or DIPEA.
  • a base such as NaOH, KOH, TEA or DIPEA.
  • the reaction is carried out in a solvent, and the solvent that can be used is MeOH, EtOH, THF, CH 3 CN or 1,4-dioxane, and the like.
  • the reaction temperature is from 60 °C to 100 °C.
  • the third step the compound VI-2-2 is brominated to form the compound VI-2-3.
  • the reaction can be carried out using a brominating agent such as bromine, NBS, and dibromohydantoin.
  • a brominating agent such as bromine, NBS, and dibromohydantoin.
  • the reaction is carried out in a solvent, and the solvents that can be used are acetic acid, 1,4-dioxane, DMF, EA, and the like.
  • the reaction temperature is from -20 °C to 100 °C.
  • Step 7 of VI-1 Compound VI-2-3 is oxidized to form compound VI-2-4.
  • the reaction conditions are as described in step 7 of VI-1.
  • Step 5 Compound VI-2-4 is reacted with NHR 4 R 5 under the action of a base and an activator to form compound VI-2-5.
  • the reaction conditions are as described in the eighth step of the synthesis of VI-1. .
  • Step 6 Compound VI-2-5 and R 1 -Y are subjected to a coupling reaction, a substitution reaction or a reduction reaction of VI-2-5 to form compound VI.
  • the reaction conditions are as described in the synthesis of V-1. The twelve steps are described.
  • R 1 , R 2 , R 4 , R 5 are as defined in the above formula VI, but R 1 does not contain NO 2 ;
  • R 3a is NR 31 R 32 , OR 37 or SR 37 ;
  • L is as defined in the above formula VI, but n+p+q is not 0, and -LR 3a is bonded to the imidazole group of VI-2 by a carbon atom;
  • R 31 , R 32 and R 37 are as defined in the above formula I;
  • R 41 is OPG, PG is Bn, DMB, PMB, Me, Et, Pr, etc.; and W is selected from chlorine, bromine and iodine.
  • the reaction can be carried out using an acid such as BBr 3 , AlCl 3 , FeCl 3 , or CF 3 COOH.
  • the reaction is carried out in a solvent, and the solvent that can be used is THF, DCM, DCE, CH 3 CN or 1,4-dioxane, and the like.
  • the reaction temperature is from 20 °C to 160 °C.
  • the reaction can be carried out using a halogenating agent such as thionyl chloride, PCl 3 , PCl 5 , PBr 3 or HI.
  • the reaction is carried out in a solvent, and the solvent that can be used is THF, DCM, DCE or 1,4-dioxane, and the like.
  • the reaction temperature is from 20 °C to 120 °C.
  • phase transfer catalysts that can be used are 18-crown-6-ether, benzyltriethylammonium chloride (TEBA), tetrabutylammonium iodide, tetrabutylammonium bromide (TBAB), Tetrabutylammonium chloride, tetrabutylammonium hydrogen sulfate, trioctylmethylammonium chloride, dodecyltrimethylammonium chloride or tetradecyltrimethylammonium chloride, etc., in some embodiments Among them, the base which can be used is NaOH, KOH, TEA or DIPEA.
  • the reaction is carried out in a solvent, and the solvent that can be used is toluene, DCM, CHCl 3 or DCE, and the like.
  • the reaction temperature is from 20 °C to 160 °C.
  • the fourth step: the compound VI-2 is formed by a coupling reaction of a compound VI-2-8 with R 1 -Y, a substitution reaction, or a reduction reaction of the compound VI-2-8.
  • the reaction conditions are as described in the twelfth step of the synthesis of V-1.
  • R 1 , R 2 , R 4 , R 5 are as defined in the above formula VI, but R 1 does not contain NO 2 ;
  • L is as defined in the above formula VI, but n+p+q is not 0, and both ends of L are bonded to the imidazolyl group and R 42 in VI-3-1 by a carbon atom;
  • R 33 and R 34 are as defined in the above formula I;
  • the reaction is carried out in a solvent, and the solvent that can be used is methanol, ethanol, THF, DCM, DCE, CH 3 CN or 1,4-dioxane, and the like.
  • the reaction temperature is from 0 °C to 100 °C.
  • the second step: compound VI-3-2 and R 34 COOH can be reacted under basic conditions to form compound VI-3, or VI-3-2 can directly react with R 34 COCl to form VI-3 under the action of a base.
  • the reaction conditions are as described in the fifth step of the synthesis of VI-1.
  • R 1 , R 2 , R 3 , R 4 , R 5 are as defined in the above formula VI, but R 1 does not contain NO 2 ;
  • L 1a is -NR 33b -, -O- or -S-;
  • L 2a is 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 hydroxyalkylene, C 3-8 cycloalkylene, 4-10 membered heterocyclylene, C 6-12 arylene, 5-10 membered heteroarylene -O-, -S-, -NR 33 -, -S(O)-, -S(O) 2 -, -C(O)-, -C(R 36a R 36b )-; said C 1 -8 alkylene, C 2-8 alkenylene, C 2-8 alkynylene, C 1-8 haloalkylene, C 1-8 alkyleneoxy, C 1-8 haloalkylene oxide a group, a C 1-8 hydroxyalkylene group, a C 3-8 cycloalkylene group, a 4-10 membered heterocyclylene
  • p is 0 or 1; and when p is 0, R 3 is bonded to L 1a by a C atom; when p is 1, L 2a is bonded to L 1a by a C atom;
  • R 33b is selected from the group consisting of H, C 1-8 alkyl, C 1-8 hydroxyalkyl, C 1-8 alkoxy, 4-10 membered heterocyclic, C 6-12 aryl, 5-10 membered heteroaryl a C 1-8 alkyl group, a C 1-8 hydroxyalkyl group, a C 1-8 alkoxy group, a C 3-8 cycloalkyl group, a 4-10 membered heterocyclic group, a C 6-12 aryl group,
  • the 5-10 membered heteroaryl group can be 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 heterocyclyl, C 6-12 aryl, 5-10 membered heteroaryl; said C 6-12 The group may be optionally substituted by one
  • the ring-closing reagent that can be used is carbon disulfide, thiophosgene, etc.
  • the reaction is carried out in the presence of a base, and the base that can be used is TEA or DIPEA, and the like.
  • the reaction is carried out in a solvent, the solvent may be used are THF, DCM, DCE, CH 3 CN, 1,4-dioxane and the like or DMF.
  • the reaction temperature is from 0 °C to 160 °C.
  • WR 43 is an alkylating agent wherein W is chlorine, bromine, iodine, and R 43 is selected from C 1-8 alkyl, C 1-8 hydroxyalkyl, C 1-8 alkoxy, C 3-8 naphthenic a 4-10 membered heterocyclic group, a C 6-12 aryl group, a 5-10 membered heteroaryl group; said C 1-8 alkyl group, C 1-8 hydroxyalkyl group, C 1-8 alkoxy group, C 3-8 cycloalkyl, 4-10 membered heterocyclyl, C 6-12 aryl, 5-10 membered heteroaryl may be optionally substituted by 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, 5-10 membered hetero
  • the reaction can be carried out using a base such as NaOH, KOH, potassium carbonate, cesium carbonate, TEA or DIPEA.
  • a base such as NaOH, KOH, potassium carbonate, cesium carbonate, TEA or DIPEA.
  • the solvent in which the reaction is carried out in a solvent is acetone, MeOH, EtOH, THF, CH 3 CN or 1,4-dioxane, and the like.
  • the reaction temperature is from 0 °C to 100 °C.
  • the third step the compound VI-4-2 is oxidized to form the compound VI-4-3.
  • the reaction can be carried out using an oxidizing agent such as potassium permanganate, m-CPBA, H 2 O 2 or CH 3 COOOH.
  • the reaction is carried out in a solvent such as acetic acid, water, DCM, DCE, CHCl 3 or DMF, and the like.
  • the reaction temperature is from 0 °C to 160 °C.
  • the fourth step the compound VI-4-3 is reacted with HL 1a -(L 2a ) p -R 3 under the action of a base to form a compound VI-4-4.
  • the base that can be used is TEA or DIPEA, and the like.
  • the reaction is carried out in a solvent, and the solvent that can be used is DMSO, NMP, CHCl 3 or DMF, and the like.
  • the reaction temperature is from 20 °C to 160 °C.
  • Step 5 Compound VI-4-4 is brominated to give compound VI-4-5.
  • the reaction conditions are as described in the third step of the VI-2 synthesis.
  • Step 6 Compound VI-4-5 is oxidized to give compound VI-4-6.
  • the reaction conditions are as described in step 7 of VI-1.
  • Step 7 Compound VI-4-6 is reacted with NHR 4 R 5 under the action of a base and an activator to give compound VI-4-7.
  • the reaction conditions are as described in the eighth step of the synthesis of VI-1.
  • the eighth step: the compound VI-4 is formed by a coupling reaction or a substitution reaction of the compound VI-4-7 with R 1 -Y or a reduction reaction of the compound VI-4-7.
  • the reaction conditions are as described in the twelfth step of the V-1 synthesis.
  • R 3 , R 4 and R 5 are as defined in the above formula VII;
  • R 1 is as defined in the above formula V, but does not contain NO 2 , and
  • R 3 does not contain halogen, OH, CN and NO 2 .
  • First step Compound VII-1-1 is subjected to nitration to give compound VII-1-2.
  • the reaction conditions are as described in the first step of the synthesis of VI-1.
  • Second step Compound VII-1-2 is reduced to give compound VII-1-3.
  • the reaction conditions are as described in the fourth step of the synthesis of VI-1.
  • the third step compound VII-1-3 and R 3 -COOH are subjected to condensation reaction under basic conditions to form compound VII-1-4, or VII-1-3 is directly reacted with R 3 -COCl under the action of a base to form VII. -1-4.
  • the reaction conditions are as described in the fifth step of the synthesis of VI-1.
  • the reaction is carried out in a solvent, and the solvent that can be used is MeOH, EtOH, THF, CH 3 CN, 1,4-dioxane, DCM, DCE or CHCl 3 and the like.
  • the reaction temperature is from rt to 100 °C.
  • an oxidizing agent and a solvent that can be used are as described in the seventh step of the synthesis of VI-1.
  • the reaction temperature is from 0 °C to 100 °C.
  • Step 6 Compound VII-1-6 is reacted with NHR 4 R 5 under the action of a base and an activator to give compound VII-1-7.
  • the reaction conditions are as described in the eighth step of the synthesis of VI-1.
  • Step 7 Compound VII-1-7 and R 1 -Y are subjected to a coupling reaction, a substitution reaction or a reduction reaction of VII-1-7 to give compound VII-1.
  • the reaction conditions are the same as those of the twelfth step of the V-1 synthesis.
  • the compound of the present invention has obvious agonistic activity against NLRP3 and its signaling pathway, has no obvious toxic and side effects, and can be used for the treatment of abnormal cell proliferation diseases (such as cancer).
  • the structure of the compound was confirmed by nuclear magnetic resonance spectroscopy ( 1 H NMR) and/or mass spectrometry (MS).
  • reaction was monitored by silica gel thin layer chromatography (TLC) or LC-MS.
  • Thin layer chromatography was performed using silica gel GF 254 as the stationary phase.
  • the compound of the present invention can be isolated and purified by chromatography on silica gel, silica gel column chromatography, preparative high performance liquid chromatography (Prep-HPLC), and flash column chromatography (Flash column chromatography).
  • Prep-HPLC was prepared using Agilent 1260 preparative liquid chromatography, detection wavelength: 214 nm, 254 nm; column: Waters SunFire Prep C18 OBD (19 mm x 150 mm x 5.0 ⁇ m); column temperature: 25 °C.
  • Condition 1 10%-90% acetonitrile, 90%-10% ammonium formate aqueous solution (0.05%), 0-16 min; flow rate: 24 mL/min;
  • Condition 3 10%-90% acetonitrile, 90%-10% aqueous formic acid (0.05%), 0-16 min; flow rate: 28 mL/min;
  • Condition 4 10%-90% acetonitrile, 90%-10% aqueous ammonium hydrogencarbonate solution (0.05%), 0-16 min; flow rate: 24 mL/min;
  • the microwave reaction was carried out using a Biotage Initiator + microwave reactor.
  • the temperature of the reaction was room temperature (15 ° C to 30 ° C) unless otherwise specified.
  • the reagents used in the present application were purchased from companies such as Acros Organics, Aldrich Chemical Company or Tiber Chemical.
  • Step 7 2-(3-(Benzyloxy)propyl)-7-bromo-1-methyl-1H-imidazo[4,5-d]thieno[3,2-b]pyridine (1h )
  • Step 8 2-(3-(Benzyloxy)propyl)-7-bromo-1-methyl-1H-imidazo[4,5-d]thieno[3,2-b]pyridine-5 - oxygen (1i)
  • Step 9 2-(3-(Benzyloxy)propyl)-7-bromo-1-methyl-1H-imidazo[4,5-d-thieno[3,2-b]pyridine-4- Amine (1)
  • Step 10 3-(4-Amino-7-bromo-1-methyl-1H-imidazo[4,5-d]thieno[3,2-b]pyridin-2-yl)propyl-1 -alcohol (1j)
  • Step 7 2-(3-(Benzyloxy)propyl)-7-bromo-1-(4-methoxybenzyl)-1H-imidazo[4,5-d]thieno[3, 2-b]pyridin-4-amine (9g)
  • Step 8 3-(4-Amine-7-bromo-1-(4-methoxybenzyl)-1H-imidazo[4,5-d]thieno[3,2-b]pyridine-2 -yl)propyl-1-ol (9h)
  • Step 9 7-Bromo-2-(3-chloropropyl)-1-(4-methoxybenzyl)-1H-imidazo[4,5-d]thieno[3,2-b] Pyridine-4-amine (9i)
  • Step 7 2-(3-(Benzyloxy)propyl)-7-bromo-1-methyl-1H-imidazo[4,5-d]thieno[3,2-b]pyridine (1h )
  • Step 8 2-(3-(Benzyloxy)propyl)-1-methyl-1H-imidazo[4,5-d]thieno[3,2-b]pyridine 5-oxide (1i )
  • Step 9 2-(3-(Benzyloxy)propyl)-7-bromo-1-methyl-1H-imidazo[4,5-d]thieno[3,2-b]pyridine-4 -amine (1)
  • Detection wavelength 214nm, 254nm, 280nm
  • Mobile phase A 100% acetonitrile
  • mobile phase B 100% water, 0.05% formate
  • Prep-HPLC The remaining conditions were the same as in Example 2 except for the following two items.
  • Prep-HPLC The remaining conditions were the same as in Example 2 except for the following two items.
  • Prep-HPLC The remaining conditions were the same as in Example 2 except for the following two items.
  • Prep-HPLC The remaining conditions were the same as in Example 2 except for the following two items.
  • Prep-HPLC The remaining conditions were the same as in Example 2 except for the following two items.
  • Prep-HPLC The remaining conditions were the same as in Example 2 except for the following two items.
  • Step 7 7-Bromo-2-(chloromethyl)-1-methyl-1H-imidazo[4,5-d]thieno[3,2-b]pyridin-4-amine (11 g)
  • Step 8 7-Bromo-1-methyl-2-((4-methylpiperazin-1-yl)methyl)-1H-imidazo[4,5-d]thieno[3,2- b] Pyridin-4-amine (11h)
  • Step 9 1-Methyl-2-((4-methylpiperazin-1-yl)methyl)-7-(1H-pyrazol-3-yl)-1H-imidazo[4,5- d] thieno[3,2-b]pyridin-4-amine (37)
  • Step 4 3-((1-Methyl-1H-imidazo[4,5-d]thieno[3,2-b]pyridin-2-yl)amino)propan-1-ol (12d)
  • Step 5 N-(3-(Benzyloxy)propyl)-N-(4-methoxybenzyl)-1-methyl-1H-imidazo[4,5-d]thieno[3 ,2-b]pyridin-2-amine (12e)
  • Step 7 2-((3-Benzyloxy)propyl)(4-methoxybenzyl)amino)-7-bromo-1-methyl-1H-imidazole [4,5-d]thiophene [3,2-b]pyridine-5-oxide (12g)
  • Step 8 N 2 -(3-(Benzyloxy)propyl)-7-bromo-N2-(4-methoxybenzyl)-1-methyl-1H-imidazole [4,5-d] Thieno[3,2-b]pyridine-2,4-diamine (12h)
  • Step 10 3-((4-Amino-1-methyl-7-(1H-pyrazol-3-yl)-1H-imidazole[4,5-d]thieno[3,2-b]pyridine -2-yl)amino)propan-1-ol (67)
  • Step 2 1-(3-(4-Amino-1-methyl-7-(1H-pyrazol-3-yl)-1H-imidazo[4,5-d]thieno[3,2- b]pyridin-2-yl)propyl)pyrrolidin-3-ol (70)
  • the compound 26a (1.00 g, 5.77 mmol) was added to 16 mL of anhydrous THF. The mixture was placed in an ice bath and then warmed to 5 ° C. Then, 60% NaH (53 mg, 1.39 mmol) was added to the system, and the mixture was allowed to react at room temperature for 2 h. The reaction mixture was concentrated to give compound 26b (1.
  • Step 4 tert-Butyl ((4-amino-1-(4-methoxybenzyl)-1H imidazo[4,5-d]thieno[3,2-b]pyridin-2-yl)) (ethyl)carbamate (28d)
  • Step 5 tert-Butyl ((4-amino-7-bromo-1-(4-methoxybenzyl)-1H imidazo[4,5-d]thieno[3,2-b]pyridine-2 -yl)methyl)(ethyl)carbamate (28e)
  • Step 6 tert-Butyl ((4-amino-1-(4-methoxybenzyl)-7-(1H-pyrazol-3-yl)-1H-imidazole[4,5-d]thiophene [3,2-b]pyridin-2-yl)methyl)(ethyl)carbamate (84)
  • Step 2 Synthesis of compound N7 ethylthieno[3,2-b]pyridine-6,7-diamine (91b)
  • the third step synthesis of the compound 2-(2-oxopyrrolidin-1-yl)ethyl acetate (91d)
  • Step 5 Synthesis of the compound N-(7-ethylamino)thieno[3,2-b]pyridin-6-yl)-2-(2-oxopyrrolidin-1-yl)acetamide (91f )
  • Step 6 Synthesis of the compound 1-((1-methyl-1H-imidazo[4,5-d]thieno[3,2-b]pyridin-2-yl)methyl)pyrrolidin-2-one (91g)
  • Step 7 Compound 1-((7-bromo-1-methyl-1H-imidazo[4,5-d]thieno[3,2-b]pyridin-2-yl)methyl)pyrrolidine-2 -ketone synthesis (91h)
  • Step 8 Compound 7-bromo-1-methyl-2-((2-oxopyrrolidin-1-yl)methyl)-1H imidazole [4,5-d]thieno[3,2-b Pyridine 5-oxide (91i)
  • Step 9 Compound 1-((4-amino-7-bromo-1-methyl-1H-imidazo[4,5-d]thieno[3,2-b]pyridin-2-yl)methyl) Pyrrolidin-2-one (91j)
  • Step 10 Compound 1-((4-amino-1-ethyl-7-(thiophen-2-yl)-1H imidazo[4,5-d]thieno[3,2-b]pyridine-2- Synthesis of methyl)pyrrolidin-2-one (91)
  • Step 5 tert-Butyl ((4-amino-7-bromo-1-methyl-1H-imidazole[4,5-d]thieno[3,2-b]pyridin-2-yl)methyl) (ethyl)carbamate (93e)
  • Step 6 tert-Butyl ((4-amino-1-methyl-7-(1H-pyrazol-3-yl)-1H-imidazole[4,5-d]thieno[3,2-b] Pyridin-2-yl)methyl)(ethyl)carbamate (93f)
  • Step 7 2-((Ethylamino)methyl)-1-methyl-7-(1H-pyrazol-3-yl)-1H-imidazole [4,5-d]thieno[3,2 -b]pyridin-4-amine hydrochloride (93g)
  • Step 8 N-((4-Amino-1-methyl-7-(1H-pyrazol-3-yl)-1H-imidazole[4,5-d]thieno[3,2-b]pyridine -2-yl)methyl)-N-ethylcyclopropanecarboxamide (93)
  • Step 2 1-(4-(3-(4-Amino-1-(4-methoxybenzyl)-7-(1H-pyrazol-3-yl)-1H imidazole [4,5-d Thieno[3,2-b]pyridin-2-yl)propyl)piperazin-1-yl)ethanone (107b)
  • Step 3 2-(3-(4-(methylsulfonyl)piperazin-1-yl)propyl)-7-(1H-pyrazol-3-yl)-1H imidazole [4,5-d Thio[3,2-b]pyridin-4-amine (107)
  • This experiment used HTRF (Homogeneous Time-Resolved Fluorescence) assay to test the effect of the compounds of the present invention on the level of IL-1 ⁇ downstream of NLRP3 to assess the potency of compounds at the cellular level for hNLRP3 inflammatory bodies or hNLRP3 inflammatory bodies. effect.
  • HTRF Homogeneous Time-Resolved Fluorescence
  • RPMI 1640 Hyclone
  • FBS fetal calf serum
  • PMA tetradecanoyl phorbol acetate
  • Kit IL-1 ⁇ assay kit (CISBIO)
  • THP-1 cells in logarithmic growth phase were inoculated into T75 flasks at a density of 5 ⁇ 10 5 /well, and cultured in a 37 ° C, 5% CO 2 incubator for 24 h, induced with 1 ⁇ M PMA.
  • the THP-1 suspension cells become adherent macrophages.
  • the medium was RPMI 1640 containing 10% heat inactivated FBS and 0.05 mM ⁇ -mercaptoethanol.
  • test compound 3 Take an appropriate amount of 10 mM test compound in DMSO solution, prepare 2 ⁇ test concentration with RPMI 1640 medium containing 2% heat-inactivated FBS, add 50 ⁇ L/well dilution to cells of 96-well plate, and mix thoroughly. After homogenization, the plate was placed in a 37 ° C, 5% CO 2 incubator for 6 h, and the supernatant was collected, and the IL-1 ⁇ level was measured according to the IL-1 ⁇ test kit instructions.
  • This experiment used the HTRF assay to test the effect of the compounds of the invention on IL-1 ⁇ levels in THP-1 def NLRP3 cells to assess the specificity of compounds in agonizing effects on NLRP3 inflammatory bodies or hNLRP3 inflammatory body pathways.
  • Kit IL-1 ⁇ assay kit (CISBIO)
  • THP-1 def NLRP3 cells in logarithmic growth phase were seeded in T75 flasks at a density of 5 ⁇ 10 5 /well, and cultured in a 37 ° C, 5% CO 2 incubator for 24 h with 1 ⁇ M PMA.
  • the THP-1 def NLRP3 suspension cells were induced to become adherent macrophages.
  • the medium was RPMI 1640 containing 10% heat inactivated FBS and 0.05 mM ⁇ -mercaptoethanol.
  • test compound 3 Take an appropriate amount of 10 mM test compound in DMSO solution, prepare 2 ⁇ test concentration with RPMI 1640 medium containing 2% heat-inactivated FBS, add 50 ⁇ L/well dilution to cells of 96-well plate, and mix thoroughly. After homogenization, the plate was placed in a 37 ° C, 5% CO 2 incubator for 6 h, and the supernatant was collected, and the IL-1 ⁇ level was measured according to the IL-1 ⁇ test kit instructions.
  • the activation of the TLR 7 signaling pathway by the compounds of the present invention was tested by detecting luciferase in HEK-hTLR 7 -NF- ⁇ B-reporter cells to assess the specificity of the compounds for agonism of the NLRP3 pathway.
  • DMEM High glucose
  • FBS fetal calf serum
  • Bright-Glo TM Luciferase test kit Promega

Abstract

Disclosed are a compound represented by formula (I) as well as stereoisomers, tautomer or mixtures of the compound, pharmaceutically acceptable salts, eutectics, polymorphs or solvates of the compound, or stable isotope derivatives, metabolites or prodrugs of the compound. According to the present invention, the compound can be used as an NLRP3 regulator (e.g. an agonist) and for treatment of diseases (such as tumor diseases) relevant to the NLRP3 inflammasome activity. (Formula I)

Description

稠环化合物、其制备方法及用途Fused ring compound, preparation method and use thereof 技术领域Technical field
本发明涉及新的稠环化合物，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。本发明的化合物作为NLRP3调节剂(例如激动剂)，可用于细胞增殖异常性疾病(例如癌症)的治疗。The present invention relates to novel fused ring compounds, stereoisomers, tautomers or mixtures thereof, pharmaceutically acceptable salts, eutectic, polymorphs or solvates of said compounds, or A stable isotope derivative, metabolite or prodrug of the compound. The compounds of the present invention are useful as NLRP3 modulators (e.g., agonists) for the treatment of cell proliferative disorders such as cancer.
背景技术Background technique
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 (NLR family pyrin domain containing 3) belongs to the NOD-like receptor family and is one of the most studied intracellular pattern recognition receptors 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. NLRP3 inflammatory bodies play a clear role in inflammatory and metabolic diseases, and their over-activation leads to immune diseases such as type 2 diabetes, rheumatoid arthritis and atherosclerosis. However, recent studies have shown that NLRP3 has an anti-tumor effect of inhibiting tumor growth and metastasis.
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。具体的，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。After identifying the pathogen-associated molecular pattern (PAMP) or the endogenous damage-associated molecular pattern (DAMP), the NLRP3 protein oligomerizes its NOD domain and recruits proteins such as ASC and pro-caspase-1 to form a functional NLRP3. Inflammatory bodies. After pro-caspase-1 is cleaved and activated into caspase-1, caspase-1 cleaves pro-IL-1β and pro-IL-18 to convert it into active forms of IL-1β and IL-18 and release them into cells. In addition, the inflammatory response is amplified. The inflammatory NLRP3 inflammatory vesicles can significantly increase the levels of the immune factors IL-1β and IL-18 in the tumor microenvironment, initiate natural immune killing and subsequent acquired immune responses to exert their anti-tumor effects. Specifically, IL-1β induces secretion of interferon-gamma (IFN-γ) by CD8+ T cells, and also induces secretion of IL-17 by CD4+ cells, resulting in an effective anti-tumor immune response; IL-18 can promote NK cell maturation. It activates the downstream signaling pathway of STAT1 in immune cells and enhances the killing function of immune cells. Clinical studies have shown that the down-regulation of NLRP3 is significantly negatively correlated with the prognosis of patients with liver cancer. Preclinical studies have also shown that NLRP3-deficient mice have a higher rate of colorectal tumor formation and liver metastasis of colorectal cancer is worse. 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 prognostic marker for tumors.
尽管NLRP3激动剂有肿瘤免疫治疗的潜能，但目前仅有一个化合物处于临床I期研究，专利申请(WO2017184746、WO2017184735、WO2018152396，WO2019014402)中公开了具有NLRP3激动活性的化合物。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。Although NLRP3 agonists have the potential for tumor immunotherapy, only one compound is currently in clinical phase I studies, and compounds having NLRP3 agonistic activity are disclosed in the patent applications (WO2017184746, WO2017184735, WO2018152396, WO2019014402). Therefore, there is a need to develop new, highly effective and low toxicity NLRP3 agonists to meet clinical treatment needs.
发明内容Summary of the invention
本发明的发明人通过创造性的劳动，得到了一类新的稠环化合物，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：The inventors of the present invention have worked through creative labor to obtain a new class of fused ring compounds which act as NLRP3 modulators (eg, agonists), directly bind or modify NLRP3 at the protein level, by activating, stabilizing, and altering NLRP3 distribution. Or other means to enhance the function of the NLRP3 inflammatory body, thereby providing the following invention:
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：In one aspect, the invention relates to compounds of Formula I, stereoisomers, tautomers or mixtures thereof, pharmaceutically acceptable salts, eutectic, polymorphs or a solvate, or a stable isotope derivative, metabolite or prodrug of the compound:
Figure PCTCN2019085535-appb-000001
Figure PCTCN2019085535-appb-000001
其中:among them:
X 1和X 2各自独立地选自CH、CR 8、NR 7、N、O或S，X 1和X 2中的至少一个为NR 7、N、O或S，且X 1、X 2和与其(X 1和/或X 2)相连的碳原子一起形成五元杂芳环；R 7选自H、C 1-6烷基、C 3-8环烷基，所述C 1-6烷基和C 3-8环烷基可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、C 1-4羟烷基， X 1 and X 2 are each independently selected from CH, CR 8 , NR 7 , N, O or S, and at least one of X 1 and X 2 is NR 7 , N, O or S, and X 1 , X 2 and The carbon atom to which it is bonded (X 1 and/or X 2 ) together form a five-membered heteroaryl ring; R 7 is selected from H, C 1-6 alkyl, C 3-8 cycloalkyl, said C 1-6 alkane The group and the C 3-8 cycloalkyl group may be optionally substituted by one or more of the following groups: halogen, OH, CN, C 1-4 alkoxy, C 1-4 hydroxyalkyl,
X 3为C、N、O或S，且满足下列条件： X 3 is C, N, O or S and the following conditions are met:
(1)当X 3为O或S时，R 2和R 6不存在； (1) When X 3 is O or S, R 2 and R 6 are absent;
(2)当X 3为N时，R 2和R 6不同时存在； (2) When X 3 is N, R 2 and R 6 are not present at the same time;
R 1选自H、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、C(O)OR 30、C(O)NR 31R 32、NR 33C(O)R 34、NR 31R 32、S(O) 2R 35；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元芳基并杂环基可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、C(O)OR 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、SR 37； R 1 is selected from the group consisting of H, halogen, CN, NO 2 , C 1-8 alkyl, 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, 5-10 membered heteroaryl group, 9-12 membered arylheterocyclyl group, C(O)OR 30 , C(O)NR 31 R 32 , NR 33 C(O)R 34 , NR 31 R 32 , S(O) 2 R 35 ; said C 1-8 alkyl group, C 1-8 haloalkyl group, C 1-8 alkoxy group, C 1- 8 haloalkoxy, C 3-8 cycloalkyl, 4-10 membered heterocyclyl, C 6-12 aryl, 5-10 membered heteroaryl, 9-12 membered arylheterocyclyl optionally Substituted by 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, C 6-12 aryl, 5-10 membered heteroaryl, 9-12 membered arylheterocyclyl, C (O)OR 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 C(O)NR 31 R 32 , NR 33 C(O)OR 30 , S(O)NR 31 R 32 , S(O) 2 NR 31 R 32 , S(O)R 35 , S( O) 2 R 35 , OR 37 , 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 1-3烷基-C 6-12芳基、C 3-8环烷基、5-10元杂芳基、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 1-3烷基-C 6-12芳基、C 3-8环烷基、5-10元杂芳基、4-10元杂环基可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、C(O)OR 30、OC(O)R 30、OC(O)NR 31R 32、NR 33C(O)NR 31R 32、NR 31R 32； R 2 is selected from the group consisting of H, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 6-12 aryl, -C 1-3 alkyl-C 6-12 aryl, C 3-8 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocyclyl, said C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 6-12 An aryl group, a -C 1-3 alkyl-C 6-12 aryl group, a C 3-8 cycloalkyl group, a 5-10 membered heteroaryl group, a 4-10 membered heterocyclic group may be optionally substituted by the following substituents One or more substitutions: halogen, C 1-4 haloalkyl, C 1-4 hydroxyalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy, 4-7 membered heterocyclyl, CN, NO 2 , OR 37 , SR 37 , C(O)R 30 , C(O)NR 31 R 32 , C(O)OR 30 , OC(O)R 30 , OC(O)NR 31 R 32 , NR 33 C(O)NR 31 R 32 , NR 31 R 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 2-8杂烷基、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、C(O)OR 30、C(O)NR 31R 32、NR 33C(O)R 34、NR 31R 32、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、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 2-8杂烷基、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元芳基并环烷基可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、-C 6-12芳基-C 1-4烷基、5-10元杂芳基、9-12元芳基并杂环基、C(O)OR 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、P(O)OR 39OR 30； R 3 is selected from the group consisting of H, OH, halogen, CN, NO 2 , C 1-8 alkyl, C 1-8 haloalkyl, C 1-8 alkoxy, C 1-8 haloalkoxy, C 2-8 Alkyl, C 3-8 cycloalkyl, 4-10 membered heterocyclic, C 6-12 aryl, 5-10 membered heteroaryl, 9-12 membered arylheterocyclyl, 9-12 membered aromatic Alkylheteroaryl, 9-12 membered arylcycloalkyl, C(O)OR 30 , C(O)NR 31 R 32 , NR 33 C(O)R 34 , NR 31 R 32 , OR 37 , SR 37 , C(O)R 30 , OC(O)R 30 , OC(O)NR 31 R 32 , NR 33 C(O)NR 31 R 32 , NR 33 C(O)OR 30 , C(=NR 38 ) NR 31 R 32 , NR 33 C(=NR 38 )NR 31 R 32 , P(R 39 ) 2 , P(OR 39 ) 2 , P(O)R 39 R 40 , P(O)OR 39 OR 30 , S(O)R 35 , S(O) 2 R 35 , S(O)NR 31 R 32 , S(O) 2 NR 31 R 32 ; the C 1-8 alkyl group, C 1-8 halogenated alkane , C 1-8 alkoxy, C 1-8 haloalkoxy, C 2-8 heteroalkyl, C 3-8 cycloalkyl, 4-10 membered heterocyclyl, C 6-12 aryl, 5 a -10 membered heteroaryl group, a 9-12 membered arylheterocyclyl group, a 9-12 membered arylheteroaryl group, a 9-12 membered arylcycloalkyl group, optionally may be one of the following substituents Or multiple substitutions: 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, C 6-12 aryl, -C 6 -12 aryl-C 1-4 alkyl, 5-10 membered heteroaryl, 9-12 membered arylheterocyclyl, C(O)OR 30 , C(O)R 30 , C(O)NR 31 R 32 , NR 33 C(O)R 34 , NR 31 R 32 , S(O)R 35 , S(O) 2 R 35 , S(O)NR 31 R 32 , S(O) 2 NR 31 R 32 , OR 37 , SR 37 , OC(O)R 30 , OC(O)NR 31 R 32 , NR 33 C(O)NR 31 R 32 , NR 33 C(O)OR 30 , C(=NR 38 ) NR 31 R 32 , NR 33 C(=NR 38 )NR 31 R 32 , =NNR 31 R 32 , P(R 39 ) 2 , P(OR 39 ) 2 , P(O)R 39 R 40 , P(O ) OR 39 OR 30 ;
R 4和R 5各自独立地选自H、C 1-8烷基、C 1-8烷氧基，或R 4、R 5和与R 4和R 5相连的氮原子一起形成4-7元杂环；所述C 1-8烷基、C 1-8烷氧基可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； R 4 and R 5 are each independently selected from H, C 1-8 alkyl, C 1-8 alkoxy, or R 4 , R 5 and a nitrogen atom bonded to R 4 and R 5 together form 4-7. Heterocyclic; the C 1-8 alkyl, C 1-8 alkoxy group may be optionally substituted by one or more of the following substituents: halogen, OH, CN, NO 2 , C 1-6 alkyl , C 1-4 haloalkyl, C 1-4 hydroxyalkyl;
R 6选自H、C 1-6烷基、C 3-8环烷基，所述C 1-6烷基和C 3-8环烷基可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、C 1-4羟烷基； R 6 is selected from H, C 1-6 alkyl, C 3-8 cycloalkyl, and the C 1-6 alkyl and C 3-8 cycloalkyl may be optionally one or more of the following groups Substitutions: halogen, OH, CN, NO 2 , C 1-4 alkoxy, C 1-4 hydroxyalkyl;
R 8选自卤素、C 1-8烷基、C 1-8烷氧基、C 3-8环烷基、C 2-8杂烷基、4-7元杂环基，所述C 1-8烷基、C 1-8烷氧基、C 3-8环烷基、C 2-8杂烷基、4-7元杂环基可任选地被下列取代基中的一个或多个取代：OR 37、NR 31R 32、卤素、CN； R 8 is selected from the group consisting of halogen, C 1-8 alkyl, C 1-8 alkoxy, C 3-8 cycloalkyl, C 2-8 heteroalkyl, 4-7 membered heterocyclic, said C 1- 8- alkyl, C 1-8 alkoxy, C 3-8 cycloalkyl, C 2-8 heteroalkyl, 4-7 membered heterocyclyl can be optionally substituted by one or more of the following substituents :OR 37 , NR 31 R 32 , halogen, CN;
V为-(V 1) r–(V 2) s–(V 3) t-，其中，V 1、V 2和V 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亚烷氧基、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-、-N(R 33)-、-S(O)-、-S(O) 2-、-C(O)-、-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亚烷氧基、C 3-8亚环烷基、4-10元亚杂环基、C 6-12亚芳基、5-10元亚杂芳基可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、C 1-4烷氧基； V is -(V 1 ) r -(V 2 ) s -(V 3 ) t -, wherein V 1 , V 2 and V 3 are the same or different and are each independently selected from a C 1-8 alkylene group, C 2-8 alkenylene group, C 2-8 alkynylene group, C 1-8 alkyleneoxy group, C 3-8 cycloalkylene group, 4-10 membered heterocyclylene group, C 6-12 arylene group 5-10 membered heteroarylene, -O-, -S-, -N(R 33 )-, -S(O)-, -S(O) 2 -, -C(O)-, -C (R 36a R 36b )-; said C 1-8 alkylene, C 2-8 alkenylene, C 2-8 alkynylene, C 1-8 alkyleneoxy, C 3-8 hypocycloalkane The base, 4-10 membered heterocyclylene, C 6-12 arylene, 5-10 membered heteroarylene can be optionally substituted by one or more of the following substituents: halogen, OH, CN, NO 2 , C 1-6 alkyl, C 1-4 haloalkyl, C 1-4 hydroxyalkyl, C 1-4 alkoxy;
r、s、t各自独立地选自0和1；r, s, t are each independently selected from 0 and 1;
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-、-N(R 33)-、-S(O)-、-S(O) 2-、-C(O)-、-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、5-10元亚杂芳基可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、C 1-4烷氧基； L is -(L 1 ) n -(L 2 ) p -(L 3 ) q -, wherein L 1 , L 2 and L 3 are the same or different and are each independently selected from a C 1-8 alkylene group, C 2-8 alkenylene group, C 2-8 alkynylene group, C 1-8 haloalkylene group, C 1-8 alkyleneoxy group, C 1-8 haloalkyleneoxy group, C 1-8 Hydroxyalkylene, C 3-8 cycloalkylene, 4-10 membered heterocyclylene, C 6-12 arylene, 5-10 membered heteroarylene, -O-, -S-, -N (R 33 )-, -S(O)-, -S(O) 2 -, -C(O)-, -C(R 36a R 36b )-; the C 1-8 alkylene group, C 2 -8 alkenylene, C 2-8 alkynylene, C 1-8 haloalkylene, C 1-8 alkyleneoxy, C 1-8 haloalkyleneoxy, C 1-8 hydroxyl Alkyl, C 3-8 cycloalkylene, 4-10 membered heterocyclylene, C 6-12 arylene, 5-10 membered heteroarylene may be optionally substituted by one or more of the following substituents Substituents: halogen, OH, CN, NO 2 , C 1-6 alkyl, C 1-4 haloalkyl, C 1-4 hydroxyalkyl, C 1-4 alkoxy;
n、p、q各自独立地选自0或1；n, p, q are each independently selected from 0 or 1;
R 30、R 37、R 39、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、-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、5-10元杂芳基可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、C(O)O(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、S(O) 2NR 31R 32； R 30 , R 37 , R 39 , R 40 are each independently selected from the group consisting of 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 heterocyclic, C 6-12 aryl, 5-10 membered heteroaryl, -C 1-8 alkyl-C 6-12 Base, -C 1-8 alkyl-(5-10 membered heteroaryl); said C 1-8 alkyl, C 1-8 hydroxyalkyl, C 1-8 haloalkyl, C 1-8 alkoxy a group, a C 1-8 haloalkoxy group, a C 3-8 cycloalkyl group, a 4-10 membered heterocyclic group, a C 6-12 aryl group, a 5-10 membered heteroaryl group, optionally in the following substituents One or more substitutions: OH, CN, NO 2 , C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl, halogen, C 1-4 haloalkoxy, C(O)O (C 1-6 alkyl), CONR 31 R 32 , NR 31 R 32 , NR 33 C(O)R 34 , S(O)R 35 , S(O) 2 R 35 , S(O)NR 31 R 32 , S(O) 2 NR 31 R 32 ;
当多个R 30同时存在时，各R 30可以相同或不同； When a plurality of R 30 are simultaneously present, each R 30 may be the same or different;
当多个R 37同时存在时，各R 37可以相同或不同； When a plurality of R 37 are simultaneously present, each R 37 may be the same or different;
当多个R 39同时存在时，各R 39可以相同或不同； When a plurality of R 39 are simultaneously present, each R 39 may be the same or different;
当多个R 40同时存在时，各R 40可以相同或不同； When a plurality of R 40 are simultaneously present, each R 40 may be the same or different;
R 31、R 32、R 33、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、5-10元杂芳基；或者R 31和R 32与各自连接的N原子一起形成含有3-8元杂环基；或者R 33和R 34与各自连接的C或N原子一起形成4-8元杂环基；所述C 1-8烷基、C 1-8羟烷基、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元杂芳基可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、5-10元杂芳基； 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 heterocyclic, C. 6-12 aryl, 5-10 membered heteroaryl; or R 31 and R 32 together with the respective attached N atom form a 3-8 membered heterocyclic group; or R 33 and R 34 are bonded to each C or N The atoms together form a 4-8 membered heterocyclic group; said C 1-8 alkyl group, C 1-8 hydroxyalkyl group, C 1-8 alkoxy group, C 3-8 cycloalkyl group, 4-10 membered heterocyclic ring The base, C 6-12 aryl, 5-10 membered heteroaryl may be optionally substituted by 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, C 6-12 aryl, 5-10 membered heteroaryl base;
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、-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、5-10元杂芳基可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、C(O)O(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、S(O) 2NR 31R 32；其中，R 31、R 32、R 33、R 34如上所定义； R 35 is selected from the group consisting of 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, 5-10 membered heteroaryl group, -C 1-8 alkyl-C 6-12 aryl group, -C 1-8 alkyl group (5-10 a heteroaryl group; the C 1-8 alkyl group, a C 1-8 hydroxyalkyl group, a C 1-8 haloalkyl group, a C 1-8 alkoxy group, a C 1-8 haloalkoxy group, a C 3-8 A cycloalkyl, 4-10 membered heterocyclyl, C 6-12 aryl, 5-10 membered heteroaryl can be 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 haloalkoxy, C(O)O(C 1-6 alkyl), CONR 31 R 32 , NR 31 R 32 , NR 33 C(O)R 34 , S(O)Me, S(O) 2 Me, S(O)NR 31 R 32 , S(O) 2 NR 31 R 32 , wherein R 31 , R 32 , R 33 , R 34 are as defined above;
当多个R 31同时存在时，各R 31可以相同或不同； When a plurality of R 31 are simultaneously present, each R 31 may be the same or different;
当多个R 32同时存在时，各R 32可以相同或不同； When a plurality of R 32 are present at the same time, each R 32 may be the same or different;
当多个R 33同时存在时，各R 33可以相同或不同； When a plurality of R 33 are simultaneously present, each R 33 may be the same or different;
当多个R 34同时存在时，各R 34可以相同或不同； When a plurality of R 34 are simultaneously present, each R 34 may be the same or different;
当多个R 35同时存在时，各R 35可以相同或不同； When a plurality of R 35 are simultaneously present, each R 35 may be the same or different;
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、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、C 1-8卤代烷基可任选地被下列基团中的一个或多个取代：OH、CN、NH 2、NHCH 3、N(CH 3) 2；或R 36a、R 36b和与R 36a、R 36b连接的碳原子一起形成3-7元环烷基或4-7元杂环基； R 36a and R 36b are the same or different, are each independently selected from H, C 1-6 alkyl, C 1-6 alkoxy, C 1-8 hydroxyalkyl, C 1-8 haloalkyl group; a C 1 -6 alkyl, C 1-6 alkoxy, C 1-8 hydroxyalkyl, C 1-8 haloalkyl can be optionally substituted by one or more of the following groups: OH, CN, NH 2 , NHCH 3 , N(CH 3 ) 2 ; or R 36a , R 36b and a carbon atom bonded to R 36a , R 36b together form a 3-7 membered cycloalkyl group or a 4-7 membered heterocyclic group;
当多于一个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、S(O) 2R 35。在一些实施方案中，R 1选自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；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元芳基并杂环基可任选地被一个或多个下列取代基取代：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、C(O)OR 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、SR 37。在一些实施方案中，R 1选自C 6-12芳基(例如苯基)、5-10元杂芳基、9-12元芳基并杂环基；所述C 6-12芳基(例如苯基)、5-10元杂芳基、9-12元芳基并杂环基可任选地被一个或多个下列取代基取代：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、-C(O)OR 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、SR 37。 When more than one R 38 are present simultaneously, each R 38 is the same or different and is each independently selected from the group consisting of H, OH, CN, NO 2 , S(O)R 35 , S(O) 2 R 35 . In some embodiments, R 1 is selected from the group consisting of C 1-8 alkyl, C 1-8 haloalkyl, C 1-8 alkoxy, C 1-8 haloalkoxy, C 3-8 cycloalkyl, 4- a 10-membered heterocyclic group, a C 6-12 aryl group, a 5-10 membered heteroaryl group, a 9-12 membered arylheterocyclyl group; said C 1-8 alkyl group, C 1-8 haloalkyl group, C 1 -8 alkoxy, C 1-8 haloalkoxy, C 3-8 cycloalkyl, 4-10 membered heterocyclic, C 6-12 aryl, 5-10 membered heteroaryl, 9-12 membered aromatic The arylheterocyclyl can be optionally substituted by 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, C 6-12 aryl, 5-10 membered heteroaryl, 9-12 membered aromatic Alkylheterocyclyl, C(O)OR 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 C(O)NR 31 R 32 , NR 33 C(O)OR 30 , S(O)NR 31 R 32 , S(O) 2 NR 31 R 32 , S( O) R 35 , S(O) 2 R 35 , OR 37 , SR 37 . In some embodiments, R 1 is selected from C 6-12 aryl (eg, phenyl), 5-10 membered heteroaryl, 9-12 membered arylheterocyclyl; said C 6-12 aryl ( For example, phenyl), 5-10 membered heteroaryl, 9-12 membered arylheterocyclyl can be 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, C 6 -12 aryl, 5-10 membered heteroaryl, 9-12 membered arylheterocyclyl, -C(O)OR 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 C(O)NR 31 R 32 , NR 33 C(O)OR 30 , S(O)NR 31 R 32 , S(O) 2 NR 31 R 32 , S(O)R 35 , S(O) 2 R 35 , OR 37 , SR 37 .
在一些实施方案中，R 1选自卤素、5-6元杂芳基和C 6-12芳基，任选地，所述5-10元杂芳基和C 6-12芳基任选地被一个或多个C 1-4烷基取代。 In some embodiments, R 1 is selected from halo, 5-6 membered heteroaryl, and C 6-12 aryl, optionally, the 5-10 membered heteroaryl and C 6-12 aryl are optionally Substituted by one or more C 1-4 alkyl groups.
在一些实施方案中，R 1选自氟、氯、溴、碘、5-6元杂芳基和苯基，任选地，所述的5-6元杂芳基和苯基任选地被一个或多个甲基、乙基取代。 In some embodiments, R 1 is selected from the group consisting of fluorine, chlorine, bromine, iodine, 5-6 membered heteroaryl, and phenyl, optionally, said 5-6 membered heteroaryl and phenyl are optionally One or more methyl or ethyl groups are substituted.
在一些实施方案中，R 1选自氟、氯、溴、碘、5-6元含氮杂芳基、5-6元含硫杂芳基和苯基，任选地，所述的5-6元含氮杂芳基、5-6元含硫杂芳基和苯基任选地被一个或多个甲基、乙基取代。 In some embodiments, R 1 is selected from the group consisting of fluorine, chlorine, bromine, iodine, 5-6 membered nitrogen-containing heteroaryl, 5-6 membered sulfur-containing heteroaryl, and phenyl, optionally, 5-. The 6-membered nitrogen-containing heteroaryl group, the 5-6 membered sulfur-containing heteroaryl group, and the phenyl group are optionally substituted with one or more methyl groups and ethyl groups.
在一些实施方案中，所述5-6元含氮单环杂芳基含有1个、2个或3个氮原子，任选地，还含有1个硫原子或氧原子。In some embodiments, the 5-6 membered nitrogen-containing monocyclic heteroaryl contains 1, 2, or 3 nitrogen atoms, and optionally, 1 sulfur atom or oxygen atom.
在一些实施方案中，所述5-6元含硫单环杂芳基含有1个、2个或3个硫原子。In some embodiments, the 5-6 membered sulfur-containing monocyclic heteroaryl contains 1, 2, or 3 sulfur atoms.
在一些实施方案中，R 1选自卤素(例如氟、氯、溴、碘)、苯基、咪唑基、吡啶基、噻唑基、吡嗪基、噻吩基、吡唑基、哒嗪基、嘧啶基；任选地，所述苯基、咪唑基、吡啶基、噻唑基、吡嗪基、噻吩基、吡唑基、哒嗪基、嘧啶基被1个、2个、3个或4个C 1-4 烷基(例如甲基、乙基)取代。 In some embodiments, R 1 is selected from halogen (e.g. fluorine, chlorine, bromine, iodine), phenyl, imidazolyl, pyridinyl, thiazolyl, pyrazinyl, thienyl, pyrazolyl, pyridazinyl, pyrimidinyl, Optionally, the phenyl, imidazolyl, pyridyl, thiazolyl, pyrazinyl, thienyl, pyrazolyl, pyridazinyl, pyrimidinyl is 1, 2, 3 or 4 C 1-4 alkyl (eg methyl, ethyl) substituted.
在一些实施方案中，R 1选自溴、
Figure PCTCN2019085535-appb-000002
Figure PCTCN2019085535-appb-000003
In some embodiments, R 1 is selected from bromo,
Figure PCTCN2019085535-appb-000002
Figure PCTCN2019085535-appb-000003
在一些实施方案中，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、-CH 2-C 6-12芳基、C 3-8环烷基、5-10元杂芳基、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、-CH 2-C 6-12芳基、C 3-8环烷基、5-10元杂芳基、4-10元杂环基可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、C(O)OR 30、-OC(O)R 30、-OC(O)NR 31R 32、NR 33C(O)NR 31R 32、NR 31R 32。 In some embodiments, R 2 is selected from the group consisting of H, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 6-12 aryl, -CH 2 -C 6-12 aryl a C 3-8 cycloalkyl group, a 5-10 membered heteroaryl group, a 4-10 membered heterocyclic group, said C 1-8 alkyl group, C 2-8 alkenyl group, C 2-8 alkynyl group, C 6 -12 aryl, -CH 2 -C 6-12 aryl, C 3-8 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocyclyl can be optionally substituted by one of the following substituents Or a plurality of substitutions: halogen, C 1-4 haloalkyl, C 1-4 hydroxyalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy, 4-7 membered heterocyclic, CN, NO 2 , OR 37 , SR 37 , C(O)R 30 , C(O)NR 31 R 32 , C(O)OR 30 , -OC(O)R 30 , -OC(O)NR 31 R 32 , NR 33 C(O)NR 31 R 32 , NR 31 R 32 .
在一些实施方案中，R 2选自H、C 1-8烷基、C 2-8烯基、C 2-8炔基、C 3-8环烷基，所述C 1-8烷基、C 2-8烯基、C 2-8炔基、C 3-8环烷基可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、C(O)OR 30、OC(O)R 30、OC(O)NR 31R 32、NR 33C(O)NR 31R 32、NR 31R 32。 In some embodiments, R 2 is selected from the group consisting of H, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-8 cycloalkyl, said C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-8 cycloalkyl may be optionally substituted by one or more of the following substituents: halo, C 1-4 haloalkyl, C 1-4 Hydroxyalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy, 4-7 membered heterocyclic, CN, NO 2 , OR 37 , SR 37 , C(O)R 30 , C(O) NR 31 R 32 , C(O)OR 30 , OC(O)R 30 , OC(O)NR 31 R 32 , NR 33 C(O)NR 31 R 32 , NR 31 R 32 .
在一些实施方案中，R 2选自H、C 1-8烷基、C 3-8环烷基和-CH 2-C 6-12芳基，所述C 1-8烷基、C 3-8环烷基、-CH 2-C 6-12芳基可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、C(O)OR 30、OC(O)R 30、OC(O)NR 31R 32、NR 33C(O)NR 31R 32、NR 31R 32。 In some embodiments, R 2 is selected from the group consisting of H, C 1-8 alkyl, C 3-8 cycloalkyl, and —CH 2 -C 6-12 aryl, said C 1-8 alkyl, C 3 - The 8 -cycloalkyl, -CH 2 -C 6-12 aryl group may be optionally substituted by 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 group, 4-7 membered heterocyclic group, CN, NO 2 , OR 37 , SR 37 , C(O)R 30 , C(O)NR 31 R 32 , C (O)OR 30 , OC(O)R 30 , OC(O)NR 31 R 32 , NR 33 C(O)NR 31 R 32 , NR 31 R 32 .
在一些实施方案中，R 2选自H、C 1-8烷基和C 3-8环烷基，所述C 1-8烷基、C 3-8环烷基可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、C(O)OR 30、OC(O)R 30、OC(O)NR 31R 32、NR 33C(O)NR 31R 32、NR 31R 32。 In some embodiments, R 2 is selected from the group consisting of H, C 1-8 alkyl, and C 3-8 cycloalkyl, and the C 1-8 alkyl, C 3-8 cycloalkyl can be optionally substituted with One or more substitutions in the group: halogen, C 1-4 haloalkyl, C 1-4 hydroxyalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy, 4-7 membered heterocyclyl, CN, NO 2 , OR 37 , SR 37 , C(O)R 30 , C(O)NR 31 R 32 , C(O)OR 30 , OC(O)R 30 , OC(O)NR 31 R 32 , NR 33 C(O)NR 31 R 32 , NR 31 R 32 .
在一些实施方案中，R 2选自H、C 1-8烷基和对甲氧基苄基。 In some embodiments, R 2 is selected from the group consisting of H, C 1-8 alkyl, and p-methoxybenzyl.
在一些实施方案中，R 2选自H、C 1-8烷基(例如C 1-4烷基)，优选地，R 2选自H、甲基和乙基。 In some embodiments, R 2 is selected from H, C 1-8 alkyl (eg, C 1-4 alkyl), preferably, R 2 is selected from H, methyl, and ethyl.
在一些实施方案中，R 2选自H和甲基。 In some embodiments, R 2 is selected from the group consisting of H and methyl.
在一些实施方案中，R 3选自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 2-8杂烷基、C 3-8环烷基、4-10元杂环基、C 6-12芳基、5-10元杂芳基(例如5-6元杂芳基、9-10元杂芳基并环烷基)、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、C(O)OR 30、C(O)NR 31R 32、NR 33C(O)R 34、NR 31R 32、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、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 2-8杂烷基、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元芳基并环烷基可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、-C 6-12芳基-C 1-4烷基、5-10元杂芳基、9-12元芳基并杂环基、-C(O)OR 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、P(R 39) 2、P(OR 39) 2、P(O)R 39R 40、P(O)OR 39OR 30、＝NNR 31R 32。 In some embodiments, R 3 is selected from the group consisting of C 1-8 alkyl, C 1-8 haloalkyl, C 1-8 alkoxy, C 1-8 haloalkoxy, C 2-8 heteroalkyl, C 3 -8 cycloalkyl, 4-10 membered heterocyclyl, C 6-12 aryl, 5-10 membered heteroaryl (eg 5-6 membered heteroaryl, 9-10 membered heteroarylcycloalkyl) , 9-12 membered arylheterocyclyl, 9-12 membered arylheteroaryl, 9-12 membered arylcycloalkyl, C(O)OR 30 , C(O)NR 31 R 32 , NR 33 C(O)R 34 , NR 31 R 32 , OR 37 , SR 37 , C(O)R 30 , OC(O)R 30 , OC(O)NR 31 R 32 , NR 33 C(O)NR 31 R 32 , NR 33 C(O)OR 30 , C(=NR 38 )NR 31 R 32 , NR 33 C(=NR 38 )NR 31 R 32 , P(R 39 ) 2 , P(OR 39 ) 2 , P(O)R 39 R 40 , P(O)OR 39 OR 30 , S(O)R 35 , S(O) 2 R 35 , S(O)NR 31 R 32 , S(O) 2 NR 31 R 32 ; the C 1-8 alkyl group, the C 1-8 haloalkyl group, the C 1-8 alkoxy group, the C 1-8 haloalkoxy group, the C 2-8 heteroalkyl group, the C 3-8 cycloalkyl group 4-10 membered heterocyclic group, C 6-12 aryl group, 5-10 membered heteroaryl group, 9-12 membered arylheterocyclyl group, 9-12 membered arylheteroaryl group, 9-12 member The arylcycloalkyl group can be 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 hydroxy Alkyl, 4-10 membered heterocyclyl, C 6-12 aryl, -C 6-12 aryl-C 1-4 alkyl, 5-10 membered heteroaryl, 9-12 membered arylheterocyclic Base, -C(O)OR 30 , C(O)R 30 , C(O)NR 31 R 32 , -NR 33 C(O)R 34 , -NR 31 R 32 , S(O)R 35 , S (O) 2 R 35 , S(O)NR 31 R 32 , S(O) 2 NR 31 R 32 , OR 37 , SR 37 , OC(O)R 30 , OC(O)NR 31 R 32 , NR 33 C(O)NR 31 R 32 , NR 33 C(O)OR 30 , C(=NR 38 )NR 31 R 32 , NR 33 C(=NR 38 )NR 31 R 32 , P(R 39 ) 2 , P (OR 39 ) 2 , P(O)R 39 R 40 , P(O)OR 39 OR 30 , =NNR 31 R 32 .
在一些实施方案中，R 3选自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(例如5-6元杂芳基、9-10元杂芳基并环烷基)、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、C(O)OR 30、C(O)NR 31R 32、NR 33C(O)R 34、NR 31R 32、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、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、9-12元芳基并环烷基可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、-C(O)OR 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、P(R 39) 2、P(OR 39) 2、P(O)R 39R 40、P(O)OR 39OR 30、＝NNR 31R 32。 In some embodiments, R 3 is selected from the group consisting of C 1-8 alkyl, C 1-8 haloalkyl, C 1-8 alkoxy, C 1-8 haloalkoxy, C 3-8 cycloalkyl, 4- a 10-membered heterocyclic group, a C 6-12 aryl group, a 5-10 membered heteroaryl group (for example, a 5-6 membered heteroaryl group, a 9-10 membered heteroarylcycloalkyl group), and a 9-12 membered aryl group. Heterocyclyl, 9-12 membered arylheteroaryl, 9-12 membered arylcycloalkyl, C(O)OR 30 , C(O)NR 31 R 32 , NR 33 C(O)R 34 , NR 31 R 32 , OR 37 , SR 37 , C(O)R 30 , OC(O)R 30 , OC(O)NR 31 R 32 , NR 33 C(O)NR 31 R 32 , NR 33 C( O) OR 30 , C(=NR 38 )NR 31 R 32 , NR 33 C(=NR 38 )NR 31 R 32 , P(R 39 ) 2 , P(OR 39 ) 2 , P(O)R 39 R 40, P (O) OR 39 OR 30, S (O) R 35, S (O) 2 R 35, S (O) NR 31 R 32, S (O) 2 NR 31 R 32; said C 1- 8- alkyl, C 1-8 haloalkyl, C 1-8 alkoxy, C 1-8 haloalkoxy, C 3-8 cycloalkyl, 4-10 membered heterocyclic, C 6-12 aryl, 5-10 membered heteroaryl, 9-12 membered arylheterocyclyl, 9-12 membered arylheteroaryl, 9-12 membered arylcycloalkyl can be optionally included in the following substituents substituted with one or more of: halo, 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 heterocyclyl, C 6- 12 aryl, 5-10 membered heteroaryl, 9-12 membered arylheterocyclyl, -C(O)OR 30 , C(O)R 30 , C(O)NR 31 R 32 , -NR 33 C(O)R 34 , -NR 31 R 32 , S(O)R 35 , S(O) 2 R 35 , S(O)NR 31 R 32 , S(O) 2 NR 31 R 32 , OR 37 , SR 37 , OC(O)R 30 , OC(O)NR 31 R 32 , NR 33 C(O)NR 31 R 32 , NR 33 C(O)OR 30 , C(=NR 38 )NR 31 R 32 , NR 33 C(=NR 38 )NR 31 R 32 , P(R 39 ) 2 , P(OR 39 ) 2 , P(O)R 39 R 40 , P(O)OR 39 OR 30 , =NNR 31 R 32 .
在一些实施方案中，R 3选自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 2-8杂烷基、C 3-8环烷基、4-10元杂环基、C 6-12芳基、5-10元杂芳基(例如5-6元杂芳基、9-10元杂芳基并环烷基)、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、OR 37、SR 37、C(O)R 30；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 2-8杂烷基、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元芳基并环烷基可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、-C 6-12芳基-C 1-4烷基、5-10元杂芳基、9-12元芳基并杂环基、-C(O)OR 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、P(R 39) 2、P(OR 39) 2、P(O)R 39R 40、P(O)OR 39OR 30、＝NNR 31R 32。 In some embodiments, R 3 is selected from the group consisting of C 1-8 alkyl, C 1-8 haloalkyl, C 1-8 alkoxy, C 1-8 haloalkoxy, C 2-8 heteroalkyl, C 3 -8 cycloalkyl, 4-10 membered heterocyclyl, C 6-12 aryl, 5-10 membered heteroaryl (eg 5-6 membered heteroaryl, 9-10 membered heteroarylcycloalkyl) , 9-12 membered arylheterocyclyl, 9-12 membered arylheteroaryl, 9-12 membered arylcycloalkyl, OR 37 , SR 37 , C(O)R 30 ; 1-8 alkyl, C 1-8 haloalkyl, C 1-8 alkoxy, C 1-8 haloalkoxy, C 2-8 heteroalkyl, C 3-8 cycloalkyl, 4-10 membered Cyclo, C 6-12 aryl, 5-10 membered heteroaryl, 9-12 membered arylheterocyclyl, 9-12 membered arylheteroaryl, 9-12 membered arylcycloalkyl It may be optionally substituted by 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 alkane Oxy, C 1-4 haloalkoxy, C 1-4 hydroxyalkyl, 4-10 membered heterocyclyl, C 6-12 aryl, -C 6-12 aryl-C 1-4 alkyl, 5 -10 membered heteroaryl, 9-12 membered arylheterocyclyl, -C(O)OR 30 , C(O)R 30 , C(O)NR 31 R 32 , -NR 33 C(O)R 34 , -NR 31 R 32 , S(O)R 35 , S(O) 2 R 35 , S(O)NR 31 R 32 , S(O) 2 NR 31 R 32 , OR 37 , SR 37 , OC(O)R 30 , OC(O)NR 31 R 32 , NR 33 C(O)NR 31 R 32 , NR 33 C(O)OR 30 , C(=NR 38 )NR 31 R 32 , NR 33 C(=NR 38 )NR 31 R 32 , P(R 39 ) 2 , P(OR 39 ) 2 , P(O)R 39 R 40 , P(O)OR 39 OR 30 , =NNR 31 R 32 .
在一些实施方案中，R 3选自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(例如5-6元杂芳基、9-10元杂芳基并环烷基)、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、OR 37、SR 37；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、9-12元芳基并环烷基可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、-C(O)OR 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、P(R 39) 2、P(OR 39) 2、P(O)R 39R 40、P(O)OR 39OR 30、＝NNR 31R 32。 In some embodiments, R 3 is selected from the group consisting of C 1-8 alkyl, C 1-8 haloalkyl, C 1-8 alkoxy, C 1-8 haloalkoxy, C 3-8 cycloalkyl, 4- a 10-membered heterocyclic group, a C 6-12 aryl group, a 5-10 membered heteroaryl group (for example, a 5-6 membered heteroaryl group, a 9-10 membered heteroarylcycloalkyl group), and a 9-12 membered aryl group. Heterocyclyl, 9-12 membered arylheteroaryl, 9-12 membered arylcycloalkyl, OR 37 , SR 37 ; said C 1-8 alkyl, C 1-8 haloalkyl, C 1 -8 alkoxy, C 1-8 haloalkoxy, C 3-8 cycloalkyl, 4-10 membered heterocyclic, C 6-12 aryl, 5-10 membered heteroaryl, 9-12 membered aromatic The homoheterocyclyl, 9-12 membered arylheteroaryl, 9-12 membered arylcycloalkyl can be optionally substituted by 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 Heterocyclyl, C 6-12 aryl, 5-10 membered heteroaryl, 9-12 membered arylheterocyclyl, -C(O)OR 30 , C(O)R 30 , C(O)NR 31 R 32 , -NR 33 C(O)R 34 , -NR 31 R 32 , S(O)R 35 , S(O) 2 R 35 , S(O)NR 31 R 32 , S(O) 2 NR 31 R 32 , OR 37 , SR 37 , OC(O)R 30 , OC(O)NR 31 R 32 , NR 33 C(O)NR 31 R 32 , NR 33 C(O)OR 30 , C(=NR 38 )NR 31 R 32 , NR 33 C (=NR 38 )NR 31 R 32 , P(R 39 ) 2 , P(OR 39 ) 2 , P(O)R 39 R 40 , P(O)OR 39 OR 30 , =NNR 31 R 32 .
在一些实施方案中，R 3选自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(例如5-6元杂芳基、9-10元杂芳基并环烷基)、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、OR 37、SR 37、C(O)R 30；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、9-12元芳基并环烷基可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、4-7元杂环基、C 6-10芳基、-C 6-10芳基-C 1-4烷基、5-10元杂芳基、9-10元芳基并杂环基、C(O)OR 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。 In some embodiments, R 3 is selected from the group consisting of C 1-8 alkyl, C 1-8 haloalkyl, C 1-8 alkoxy, C 1-8 haloalkoxy, C 3-8 cycloalkyl, 4- a 10-membered heterocyclic group, a C 6-12 aryl group, a 5-10 membered heteroaryl group (for example, a 5-6 membered heteroaryl group, a 9-10 membered heteroarylcycloalkyl group), and a 9-12 membered aryl group. Heterocyclyl, 9-12 membered arylheteroaryl, 9-12 membered arylcycloalkyl, OR 37 , SR 37 , C(O)R 30 ; said C 1-8 alkyl, C 1 -8 haloalkyl, C 1-8 alkoxy, C 1-8 haloalkoxy, C 3-8 cycloalkyl, 4-10 membered heterocyclic, C 6-12 aryl, 5-10 membered heteroaryl The 9-12 membered arylheterocyclyl, 9-12 membered arylheteroaryl, 9-12 membered arylcycloalkyl group can be 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 hydroxy Alkyl, 4-7 membered heterocyclyl, C 6-10 aryl, -C 6-10 aryl-C 1-4 alkyl, 5-10 membered heteroaryl, 9-10 membered arylheterocyclic Base, C(O)OR 30 , C(O)R 30 , C(O)NR 31 R 32 , NR 33 C(O)R 34 , NR 31 R 32 , S(O)R 35 , S(O) 2 R 35 , S(O)NR 31 R 32 , S(O 2 NR 31 R 32 , OR 37 , SR 37 , OC(O)R 30 , OC(O)NR 31 R 32 , NR 33 C(O)NR 31 R 32 , NR 33 C(O)OR 30 , C (=NR 38 )NR 31 R 32 , NR 33 C(=NR 38 )NR 31 R 32 , =NNR 31 R 32 .
在一些实施方案中，R 3选自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(例如5-6元杂芳基、9-10元杂芳基并环烷基)、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、OR 37、SR 37；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、9-12元芳基并环烷基可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、4-7元杂环基、C 6-10芳基、5-10元杂芳基、9-10元芳基并杂环基、C(O)OR 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。 In some embodiments, R 3 is selected from the group consisting of C 1-8 alkyl, C 1-8 haloalkyl, C 1-8 alkoxy, C 1-8 haloalkoxy, C 3-8 cycloalkyl, 4- a 10-membered heterocyclic group, a C 6-12 aryl group, a 5-10 membered heteroaryl group (for example, a 5-6 membered heteroaryl group, a 9-10 membered heteroarylcycloalkyl group), and a 9-12 membered aryl group. Heterocyclyl, 9-12 membered arylheteroaryl, 9-12 membered arylcycloalkyl, OR 37 , SR 37 ; said C 1-8 alkyl, C 1-8 haloalkyl, C 1 -8 alkoxy, C 1-8 haloalkoxy, C 3-8 cycloalkyl, 4-10 membered heterocyclic, C 6-12 aryl, 5-10 membered heteroaryl, 9-12 membered aromatic The homoheterocyclyl, 9-12 membered arylheteroaryl, 9-12 membered arylcycloalkyl can be optionally substituted by 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, 4-7 Heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, 9-10 membered arylheterocyclyl, C(O)OR 30 , C(O)R 30 , C(O)NR 31 R 32 , NR 33 C(O)R 34 , NR 31 R 32 , S(O)R 35 , S(O) 2 R 35 , S(O)NR 31 R 32 , S(O) 2 NR 31 R 32 , OR 37 , SR 37 , OC(O) R 30 , OC(O)NR 31 R 32 , NR 33 C(O)NR 31 R 32 , NR 33 C(O)OR 30 , C(=NR 38 )NR 31 R 32 , NR 33 C(=NR 38 ) NR 31 R 32 , =NNR 31 R 32 .
在一些实施方案中，R 3选自C(O)R 30、C 1-4烷基、C 1-4烷氧基、苄基、C 3-6环烷基、C 6-12芳基(例如苯基)、OH、4-10元杂环基(例如4-6元含氮单杂环基、8-10元含氮并杂环基、6-10元含氮螺杂环基)、9-12元芳基并杂环基(例如苯并5-6元含氮单杂环基)、9-12元芳基并杂芳基(例如苯并5-6元含氮单杂芳基)、9-12元芳基并环烷基(例如苯并C 5-6单环烷基)、5-6元单杂芳基(例如5-6元含氮单杂芳基)、9-10元单杂芳基并环烷基(例如4-6元含氮单杂芳基并C 4-6单环烷基)，所述C 1-4烷基、C 6-12芳基(例如苯基)、4-10元杂环基(例如4-6元含氮单杂环基、8-10元含氮并杂环基、6-10元含氮螺杂环基)、9-12元芳基并杂环基(例如苯并5-6元含氮单杂环基)、9-12元芳基并杂芳基(例如苯并5-6元含氮单杂芳基)、9-12元芳基并环烷基(例如苯并C 5-6单环烷基)、5-6元单杂芳基(例如5-6元含氮单杂芳基)、9-10元单杂芳基并环烷基(例如4-6元含氮单杂芳基并C 4-6单环烷基可任选地被以下取代基中的一个或多个取代：C 1-4烷基、OH、甲苯基、S(O) 2R 35。在一些实施方案中，R 35为C 1-4烷基(例如甲基)。 In some embodiments, R 3 is selected from the group consisting of C(O)R 30 , C 1-4 alkyl, C 1-4 alkoxy, benzyl, C 3-6 cycloalkyl, C 6-12 aryl ( For example, phenyl), OH, 4-10 membered heterocyclic group (for example, 4-6 membered nitrogen-containing monoheterocyclic group, 8-10 membered nitrogen-containing heterocyclic group, 6-10 membered nitrogen-containing spiroheterocyclic group), 9-12 membered arylheterocyclyl (eg, benzo 5-6 membered nitrogen-containing monoheterocyclic group), 9-12 membered arylheteroaryl (eg, benzo 5-6 membered nitrogen-containing monoheteroaryl) , 9-12 membered arylcycloalkyl (for example, benzo C 5-6 monocycloalkyl), 5-6 membered monoheteroaryl (for example, 5-6 membered nitrogen-containing monoheteroaryl), 9- 10-membered monoheteroarylcycloalkyl (eg, 4-6 membered nitrogen-containing monoheteroaryl and C 4-6 monocycloalkyl), said C 1-4 alkyl, C 6-12 aryl (eg, Phenyl), 4-10 membered heterocyclic group (for example, 4-6 membered nitrogen-containing monoheterocyclic group, 8-10 membered nitrogen-containing heterocyclic group, 6-10 membered nitrogen-containing spiroheterocyclic group), 9-12 a arylheterocyclic heterocyclic group (for example, a benzo 5-6 membered nitrogen-containing monoheterocyclic group), a 9-12 membered arylheteroaryl group (for example, a benzo 5-6 membered nitrogen-containing monoheteroaryl group), 9 -12-membered arylcycloalkyl (for example, benzo C 5-6 monocycloalkyl), 5-6 membered monoheteroaryl (for example, 5-6 membered nitrogen-containing monoheteroaryl), 9-10 member Heteroaryl Alkyl (e.g., 4-6 membered nitrogen-containing monocyclic heteroaryl and monocyclic C 4-6 alkyl may be optionally substituted with one or more substituents: C 1-4 alkyl, OH, tolyl And S(O) 2 R 35. In some embodiments, R 35 is C 1-4 alkyl (eg, methyl).
在一些实施方案中，R 3选自C 6-12芳基(例如苯基)、OH、4-10元杂环基(例如5-6元含氮单杂环基、8-10元含氮并杂环基、6-10元含氮螺杂环基)、9-12元芳基并杂环基(例如苯并5-6元含氮单杂环基)、9-12元芳基并杂芳基(例如苯并5-6元含氮单杂芳基)、9-12元芳基并环烷基(例如苯并C 5-6环烷基)、5-6元单杂芳基(例如5-6元含氮单杂芳基)、9-10元单杂芳基并环烷基(例如4-6元含氮单杂芳基并C4-6单环烷基)，所述C 6-12芳基(例如苯基)、4-10元杂环基(例如4-6元含氮单杂环基、8-10元含氮并杂环基、6-10元含氮螺杂环基)、9-12元芳基并杂环基(例如苯并5-6元含氮单杂环基)、9-12元芳基并杂芳基(例如苯并5-6元含氮单杂芳基)、9-12元芳基并环烷基(例如苯并C 5-6环烷基)、5-6元单杂芳基(例如5-6元含氮单杂芳基)、9-10元单杂芳基并环烷基(例如4-6元含氮单杂芳基并C 4-6单环烷基可任选地被以下取代基中的一个或多个取代：C 1-4烷基、OH。 In some embodiments, R 3 is selected from C 6-12 aryl (eg, phenyl), OH, 4-10 membered heterocyclyl (eg, 5-6 membered nitrogen-containing monoheterocyclyl, 8-10 membered nitrogen) And a heterocyclic group, a 6-10 membered nitrogen-containing spiroheterocyclyl group, a 9-12 membered arylheterocyclyl group (for example, a benzo 5-6 membered nitrogen-containing monoheterocyclic group), and a 9-12 membered aryl group. Heteroaryl (eg, benzo 5-6 membered nitrogen-containing monoheteroaryl), 9-12 membered arylcycloalkyl (eg, benzo C 5-6 cycloalkyl), 5-6 membered monoheteroaryl (for example, a 5-6 membered nitrogen-containing monoheteroaryl group), a 9-10 membered monoheteroarylcycloalkyl group (for example, a 4-6 membered nitrogen-containing monoheteroaryl group and a C4-6 monocycloalkyl group), C 6-12 aryl (eg phenyl), 4-10 membered heterocyclic group (eg 4-6 membered nitrogen-containing monoheterocyclyl, 8-10 membered nitrogen-containing heterocyclic group, 6-10 membered nitrogen-containing snail a heterocyclic group), a 9-12 membered arylheterocyclyl group (for example, a benzo 5-6 membered nitrogen-containing monoheterocyclic group), a 9-12 membered arylheteroaryl group (for example, a benzo-5-6 member) a nitrogen monoheteroaryl), a 9-12 membered arylcycloalkyl group (eg, benzo C 5-6 cycloalkyl), a 5-6 membered monoheteroaryl group (eg, a 5-6 membered nitrogen-containing monoheteroaryl group) ), 9-10 membered monocyclic heteroaryl group and a cycloalkyl group (e.g., 4-6 membered nitrogen-containing monocyclic heteroaryl and monocyclic C 4-6 alkyl may be optionally substituted Substituted with one or more of: C 1-4 alkyl, OH.
在一些实施方案中，所述4-6元含氮单杂环基、8-10元含氮并杂环基、6-10元含氮螺杂环基、5-6元含氮单杂芳基各自独立地含有1个、2个或3个氮原子，任选地，还各自独立地含有1个硫原子和/或1个氧原子。In some embodiments, the 4-6 membered nitrogen-containing monoheterocyclyl, 8-10 membered nitrogen-containing heterocyclic group, 6-10 membered nitrogen-containing spiroheterocyclyl, 5-6 membered nitrogen-containing monoheteroaryl The groups each independently contain one, two or three nitrogen atoms, and optionally each independently contain one sulfur atom and/or one oxygen atom.
在一些实施方案中，所述5-6元含氮单杂环基、8-10元含氮并杂环基、6-10元含氮螺杂环基、5-6元含氮单杂芳基各自独立地含有1个、2个或3个氮原子，任选地，还各自独立地含有1个硫原子和/或1个氧原子。In some embodiments, the 5-6 membered nitrogen-containing monoheterocyclyl group, the 8-10 membered nitrogen-containing heterocyclic group, the 6-10 membered nitrogen-containing spiroheterocyclyl group, and the 5-6 membered nitrogen-containing monoheteroaryl group. The groups each independently contain one, two or three nitrogen atoms, and optionally each independently contain one sulfur atom and/or one oxygen atom.
在一些实施方案中，R 3选自苯基、OH和4-10元杂环基，所述4-10元杂环基可任选地被以下取代基中的一个或多个取代：C1-4烷基、OH、S(O) 2R 35。 In some embodiments, R 3 is selected from phenyl, OH, and 4-10 membered heterocyclyl, and the 4-10 membered heterocyclyl can be optionally substituted with one or more of the following substituents: C1- 4 alkyl, OH, S(O) 2 R 35 .
在一些实施方案中，R 3选自苯基、OH和4-10元杂环基，所述4-10元杂环基可任选地被以下取代基中的一个或多个取代：C 1-4烷基、OH。 In some embodiments, R 3 is selected from phenyl, OH, and 4-10 membered heterocyclyl, and the 4-10 membered heterocyclyl can be optionally substituted with one or more of the following substituents: C 1 -4 alkyl, OH.
在一些实施方案中，R 3选自苯基、OH、4-6元含氮单杂环基、8-10元含氮并杂环基或6-10元含氮螺杂环基，所述4-6元含氮单杂环基、8-10元含氮并杂环基或6-10元含氮螺杂环基可任选地被以下取代基中的一个或多个取代：C 1-4烷基、OH或S(O) 2R 35。 In some embodiments, R 3 is selected from phenyl, OH, 4-6 membered nitrogen-containing monoheterocyclyl, 8-10 membered nitrogen-containing heterocyclyl or 6-10 membered nitrogen-containing spiroheterocyclyl, The 4-6 membered nitrogen-containing monoheterocyclyl group, the 8-10 membered nitrogen-containing heterocyclic group or the 6-10 membered nitrogen-containing spiroheterocyclyl group may be optionally substituted with one or more of the following substituents: C 1 -4 alkyl, OH or S(O) 2 R 35 .
在一些实施方案中，R 3选自苯并C 5-6环烷基、苯并5-6元含氮单杂环基、苯并5-6元含氮单杂芳基、5-6元含氮单杂芳基并C 5-6单环烷基，所述苯并C 5-6环烷基、苯并5-6元含氮单杂环基、苯并5-6元含氮单杂芳基、5-6元含氮单杂芳基并C 5-6单环烷基可任选地被以下取代基中的一个或多个取代：C 1-4烷基或OH。 In some embodiments, R 3 is selected from benzo C 5-6 cycloalkyl, benzo 5-6 membered nitrogen-containing monoheterocyclyl, benzo 5-6 membered nitrogen-containing monoheteroaryl, 5-6. a nitrogen-containing monoheteroaryl-C 5-6 monocycloalkyl group, the benzo C 5-6 cycloalkyl group, a benzo 5-6 membered nitrogen-containing monoheterocyclic group, a benzo 5-6 membered nitrogen-containing single The heteroaryl, 5-6 membered nitrogen-containing monoheteroaryl and C5-6 monocyclic alkyl group can be optionally substituted with one or more of the following substituents: C1-4 alkyl or OH.
在一些实施方案中，R 3选自
Figure PCTCN2019085535-appb-000004
Figure PCTCN2019085535-appb-000005
In some embodiments, R 3 is selected from
Figure PCTCN2019085535-appb-000004
Figure PCTCN2019085535-appb-000005
在某些实施方案中，R 3具有环状结构，所述环状结构上的碳原子任选地被氧代(oxo)。 In certain embodiments, R 3 has a cyclic structure, and the carbon atom on the cyclic structure is optionally oxo.
在一些实施方案中，R 3选自H、C 1-4烷基、C 1-4烷氧基、苄基、被甲基取代的苄基、5-6元含氮单杂芳基、C 3-8环烷基。 In some embodiments, R 3 is selected from the group consisting of H, C 1-4 alkyl, C 1-4 alkoxy, benzyl, methyl substituted benzyl, 5-6 membered nitrogen containing monoheteroaryl, C 3-8 cycloalkyl.
在一些实施方案中，R 3选自H、OH、甲基、乙基、甲氧基、叔丁氧基、叔丁氧羰基，以及任选被一个或多个(例如2个、3个或4个)C 1-4烷基、氧代(oxo)、OH或S(O) 2R 35取代的苯基、苄基、吡咯烷基、吗啉基、哌嗪基、六氢-呋喃并[3,4-c]吡咯基、5,6,7,8-四氢-喹啉基、1,2,3,4-四氢-萘基、3,4-二氢-2H-苯并[1,4]恶嗪基、1H-吲唑基、1,2,3,4-四氢-异喹啉基、吡啶基、茚满基、2-氧杂-6-氮杂-螺[3.3]己烷基、氮杂环丁二烯基、1H-吡咯基、哌啶基。 In some embodiments, R 3 is selected from the group consisting of H, OH, methyl, ethyl, methoxy, t-butoxy, tert-butoxycarbonyl, and optionally by one or more (eg, 2, 3, or 4) C 1-4 alkyl, oxo (oxo), OH or S(O) 2 R 35 substituted phenyl, benzyl, pyrrolidinyl, morpholinyl, piperazinyl, hexahydro-furan [3,4-c]pyrrolyl, 5,6,7,8-tetrahydro-quinolinyl, 1,2,3,4-tetrahydro-naphthyl, 3,4-dihydro-2H-benzo [1,4]oxazinyl, 1H-carbazolyl, 1,2,3,4-tetrahydro-isoquinolinyl, pyridyl, indanyl, 2-oxa-6-aza-spiro [ 3.3] Hexyl group, azetidinyl group, 1H-pyrrolyl group, piperidinyl group.
在一些实施方案中，R 3选自H、甲基、乙基、甲氧基、叔丁氧基、叔丁氧羰基、苄基、环丙基、苯基、OH、
Figure PCTCN2019085535-appb-000006
Figure PCTCN2019085535-appb-000007
In some embodiments, R 3 is selected from the group consisting of H, methyl, ethyl, methoxy, tert-butoxy, tert-butoxycarbonyl, benzyl, cyclopropyl, phenyl, OH,
Figure PCTCN2019085535-appb-000006
Figure PCTCN2019085535-appb-000007
在一些实施方案中，R 3选自苯基、OH、
Figure PCTCN2019085535-appb-000008
Figure PCTCN2019085535-appb-000009
In some embodiments, R 3 is selected from the group consisting of phenyl, OH,
Figure PCTCN2019085535-appb-000008
Figure PCTCN2019085535-appb-000009
在一些实施方案中，R 4为氢。 In some embodiments, R 4 is hydrogen.
在一些实施方案中，R 5为氢。 In some embodiments, R 5 is hydrogen.
在一些实施方案中，R 4和R 5均为氢。 In some embodiments, both R 4 and R 5 are hydrogen.
在一些实施方案中，r、s、t均为0。In some embodiments, r, s, t are both zero.
在一些实施方案中，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-C(R 36aR 36b)-、O、-N(R 33)-、-C(O)-；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、5-10元亚杂芳基可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、C 1-4烷氧基；n、p、q各自独立地选自0或1。 In some embodiments, L is -(L 1 ) n -(L 2 ) p -(L 3 ) q -, wherein 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 haloalkylene oxide , C 1-8 hydroxyalkylene, C 3-8 cycloalkylene, 4-10 membered heterocyclylene, C 6-12 arylene, 5-10 membered heteroarylene-C (R 36a R 36b )-, O, -N(R 33 )-, -C(O)-; the C 1-8 alkylene group, C 2-8 alkenylene group, C 2-8 alkynylene group, C 1 -8 haloalkylene, C 1-8 alkyleneoxy, C 1-8 haloalkyleneoxy, C 1-8 hydroxyalkylene C 3-8 cycloalkylene, 4-10 member Heterocyclyl, C 6-12 arylene, 5-10 membered heteroarylene may be optionally substituted by one or more of the following substituents: halogen, OH, CN, NO 2 , C 1-6 alkane a group, C 1-4 haloalkyl, C 1-4 hydroxyalkyl, C 1-4 alkoxy; n, p, q are each independently selected from 0 or 1.
在一些实施方案中，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 1-4亚烷基、C 1-4亚烷氧基、O、NR 33、-CO-、4-10元杂环基(例如6元含氮单杂环基)和芳基；n、p、q各自独立地选自0或1。 In some embodiments, L is -(L 1 ) n -(L 2 ) p -(L 3 ) q -, wherein L 1 , L 2 and L 3 are the same or different and are each independently selected from C 1 -4 alkylene, C 1-4 alkyleneoxy, O, NR 33 , -CO-, 4-10 membered heterocyclic group (for example, 6-membered nitrogen-containing monoheterocyclic group) and aryl; n, p, q are each independently selected from 0 or 1.
在一些实施方案中，L选自以下基团：-(CH 2) 3-O-CH 2-、-(CH 2) 3-、-CH 2-、-(CH 2) 2C(CH 3) 2-、-(CH 2) 2-、-(CH 2) 3-O-、4-10元杂环基(例如6元含氮单杂环基)、-O-(CH 2) 3-O-、-(CH 2) 3-(4-10元杂环基)-C(O)-或-(CH 2) 3-O-C 6-12芳基-。 In some embodiments, L is selected from the group consisting of -(CH 2 ) 3 -O-CH 2 -, -(CH 2 ) 3 -, -CH 2 -, -(CH 2 ) 2 C(CH 3 ) 2 -, -(CH 2 ) 2 -, -(CH 2 ) 3 -O-, 4-10 membered heterocyclic group (for example, 6-membered nitrogen-containing monoheterocyclic group), -O-(CH 2 ) 3 -O -, -(CH 2 ) 3 -(4-10 membered heterocyclyl)-C(O)- or -(CH 2 ) 3 -OC 6-12 aryl-.
在一些实施方案中，L选自-CH 2-NR 33-CO-、-CH 2-NR 33-。在一些实施方案中，R 33 为氢或C 1-4烷基(例如甲基、乙基)。 In some embodiments, L is selected from -CH 2 -NR 33 -CO -, - CH 2 -NR 33 -. In some embodiments, R 33 is hydrogen or C 1-4 alkyl (eg, methyl, ethyl).
在一些实施方案中，L选自以下基团：-(CH 2) 3-O-CH 2-、-(CH 2) 3-、-CH 2-、-(CH 2) 2C(CH 3) 2-、-(CH 2) 2-、-(CH 2) 3-O-、-O-(CH 2) 3O-、-CH 2-N(CH 2CH 3)-CO-、-CH 2-N(CH 2CH 3)-CH 2-、-CH 2-NH-、-NH-(CH 2) 3-、
Figure PCTCN2019085535-appb-000010
Figure PCTCN2019085535-appb-000011
In some embodiments, L is selected from the group consisting of -(CH 2 ) 3 -O-CH 2 -, -(CH 2 ) 3 -, -CH 2 -, -(CH 2 ) 2 C(CH 3 ) 2 -, -(CH 2 ) 2 -, -(CH 2 ) 3 -O-, -O-(CH 2 ) 3 O-, -CH 2 -N(CH 2 CH 3 )-CO-, -CH 2 -N(CH 2 CH 3 )-CH 2 -, -CH 2 -NH-, -NH-(CH 2 ) 3 -,
Figure PCTCN2019085535-appb-000010
Figure PCTCN2019085535-appb-000011
在一些实施方案中，-L-R 3选自以下基团：-C 1-4亚烷基-O-C 1-4亚烷基-C 6-12芳基、-C 1-4亚烷基-OH、-C 1-4亚烷基-(6-10元含氮螺杂环基)、-C 1-4亚烷基-(4-6元含氮单杂环基)、-C 1-4亚烷基-(4-6元含氮单杂环基并4-6元含氧单杂环基)、-C 1-4亚烷基-C(CH 3) 2-OH、-C 1-4亚烷基O-(5-6元含氮单杂芳基并C5-6单环烷基)、-C 1-4亚烷基-O-(苯并C5-6单环烷基)、-C 1-4亚烷基-O-(苯并5-6元含氮单杂环基)、-C 1-4亚烷基-O-(苯并5-6元含氮单杂芳基)、-C 1-4亚烷基-O-苯基-(4-6元含氮单杂环基)、-C 1-4亚烷基-O-苯基-(苯并5-6元含氮单杂环基)、-(6元含氮单杂环基)-C 6-12芳基、-C 1-4亚烷基-(苯并5-6元含氮单杂环基)、-C 1-4亚烷基-O-(5-6元含氮单杂芳基)、-NH-C 1-4亚烷基-OH、-O-C 1-4亚烷基-O-苄基、-(4-6元含氮单杂环基)-C 1-4烷氧基、-(4-6元含氮单杂环基)-OH、-C 1-3烷基-(4-6元含氮单杂环基)-OH、-C 1-4亚烷基-O-(4-6元含氮单杂环基)、-CH 2-N(CH 2CH 3)-C(O)-O-C 1-4烷基、-CH 2-N(CH 2CH 3)-CH 2-C(O)-O-C 1-4烷基、-CH 2-N(CH 2CH 3)-C(O)-C 1-4亚烷基-C 6-12芳基、-CH 2-N(CH 2CH 3)-C(O)-(4-6元含氮单杂环基)、-CH 2-N(CH 2CH 3)-C(O)-(5-6元含氮单杂芳基)、-CH 2-NH-C 1-4烷基、-CH 2-N(CH 2CH 3)-C(O)H、-CH 2-N(CH 2CH 3)-C(O)-C 3-8环烷基、-CH 2-N(CH 2CH 3)-C(O)-C 1-4烷基，其中，4-6元含氮单杂环基、C 6-12芳基、5-6元含氮单杂芳基、5-6元含氮单杂环基可任选地被一个或多个以下的取代基所取代：C 1-3烷基、氧代、-C(O)H、-S(O) 2-C 1-3烷基。 In some embodiments, -LR 3 is selected from the group consisting of -C 1-4 alkylene-OC 1-4 alkylene-C 6-12 aryl, -C 1-4 alkylene-OH, -C 1-4 alkylene-(6-10 membered nitrogen-containing spiroheterocyclyl), -C 1-4 alkylene-(4-6 membered nitrogen-containing monoheterocyclic group), -C 1-4 Alkyl-(4-6 membered nitrogen-containing monoheterocyclic group and 4-6 membered alkoxymonoheterocyclic group), -C 1-4 alkylene-C(CH 3 ) 2 -OH, -C 1-4 Alkylene O-(5-6 membered nitrogen-containing monoheteroaryl and C5-6 monocycloalkyl), -C 1-4 alkylene-O-(benzo C5-6 monocycloalkyl), - C 1-4 alkylene-O-(benzo 5-6 membered nitrogen-containing monoheterocyclic group), -C 1-4 alkylene group-O-(benzo 5-6 membered nitrogen-containing monoheteroaryl group) , -C 1-4 alkylene-O-phenyl-(4-6 membered nitrogen-containing monoheterocyclic group), -C 1-4 alkylene-O-phenyl-(benzo 5-6 member a nitrogen monoheterocyclic group), a (6-membered nitrogen-containing monoheterocyclic group)-C 6-12 aryl group, a -C 1-4 alkylene group-(benzo 5-6 membered nitrogen-containing monoheterocyclic group), -C 1-4 alkylene-O-(5-6 membered nitrogen-containing monoheteroaryl), -NH-C 1-4 alkylene-OH, -OC 1-4 alkylene-O-benzyl , -(4-6 membered nitrogen-containing monoheterocyclic group)-C 1-4 alkoxy group, -(4-6 membered nitrogen-containing monoheterocyclic group)-OH, -C 1-3 alkyl-(4- 6 yuan nitrogen-containing monocyclic heterocyclic group) -OH, -C 1-4 alkylene -O- (4-6-membered nitrogen-containing monocyclic heteroaryl Yl), - CH 2 -N (CH 2 CH 3) -C (O) -OC 1-4 alkyl, -CH 2 -N (CH 2 CH 3) -CH 2 -C (O) -OC 1- 4- alkyl, -CH 2 -N(CH 2 CH 3 )-C(O)-C 1-4 alkylene-C 6-12 aryl, -CH 2 -N(CH 2 CH 3 )-C ( O)-(4-6 membered nitrogen-containing monoheterocyclic group), -CH 2 -N(CH 2 CH 3 )-C(O)-(5-6 membered nitrogen-containing monoheteroaryl group), -CH 2 - NH-C 1-4 alkyl, -CH 2 -N(CH 2 CH 3 )-C(O)H, -CH 2 -N(CH 2 CH 3 )-C(O)-C 3-8 naphthenic , -CH 2 -N(CH 2 CH 3 )-C(O)-C 1-4 alkyl, wherein 4-6 membered nitrogen-containing monoheterocyclic group, C 6-12 aryl group, 5-6 member The nitrogen-containing monoheteroaryl, 5-6 membered nitrogen-containing monoheterocyclyl group may be optionally substituted with one or more substituents: C 1-3 alkyl, oxo, -C(O)H, -S(O) 2 -C 1-3 alkyl.
在一些实施方案中，-L-R 3选自以下基团：-(CH 2) 3-O-CH 2-C 6-12芳基、-(CH 2) 3-OH、-CH 2-(4-6元含氮单杂环基并4-6元含氧单杂环基)、-CH 2-(4-6元含氮单杂环基)、-(CH 2) 2C(CH 3) 2-OH、-(CH 2) 2-(4-6元含氮单杂环基)、-(CH 2) 3-O-(5-6元含氮单杂芳基并C 5-6单环烷基)、-(CH 2) 3-O-(苯并C 5-6单环烷基)、-(CH 2) 3-O-(苯并5-6元含氮单杂环基)、-(CH 2) 3-O-(苯并5-6元含氮单杂芳基)、-(CH 2) 3-O-苯基-(4-6元含氮单杂环基)、-(6元含氮单杂环基)-苯基、-(CH 2) 3-(苯并5-6元含氮单杂环基)、-(CH 2) 3-O-(5-6元含氮单杂芳基)、-(CH 2) 3-(6-10元含氮螺杂环基)、-NH-(CH 2) 3-OH、-(CH 2) 3-(4-6元含氮单杂环基)、-O-(CH 2) 3-O-苄基、-(CH 2) 3-(4-6元含氮单杂环基)-OH、-(CH 2) 2-OH、-6元含氮单杂环基-甲氧基、-6元含氮单杂环基-OH、-(CH 2) 3-O-(4-6元含氮单杂环基)、 -CH 2-N(CH 2CH 3)-C(O)-O-C 1-4烷基、-CH 2-N(CH 2CH 3)-CH 2-C(O)-O-C 1-4烷基、-CH 2-N(CH 2CH 3)-C(O)-(CH 3) 2-C 6-12芳基、-CH 2-N(CH 2CH 3)-C(O)-(4-6元含氮单杂环基)、-CH 2-N(CH 2CH 3)-C(O)-(5-6元含氮单杂芳基)、-CH 2-NH-CH 2CH 3、-CH 2-N(CH 2CH 3)-C(O)H、-CH 2-N(CH 2CH 3)-C(O)-C 3-8环烷基、-CH 2-N(CH 2CH 3)-C(O)-C 1-4烷基、-CH 2-N(CH 2CH 3)-C(O)-CH 3-C 6-12芳基、-CH 2-N(CH 2CH 3)-CH 2-C(O)-O-C 1-4烷基、-CH 2-(4-6元含氮单杂环基)、-(CH 2) 3-(4-6元含氮单杂环基),其中，4-6元含氮单杂环基、C 6-12芳基、5-6元含氮单杂芳基、5-6元含氮单杂环基可任选地被一个或多个以下的取代基所取代：甲基、乙基、氧代、-C(O)H、-S(O) 2-CH 3。 In some embodiments, -LR 3 is selected from the group consisting of -(CH 2 ) 3 -O-CH 2 -C 6-12 aryl, -(CH 2 ) 3 -OH, -CH 2 -(4- 6-membered nitrogen-containing monoheterocyclic group and 4-6 membered oxygen-containing monoheterocyclic group), -CH 2 -(4-6 membered nitrogen-containing monoheterocyclic group), -(CH 2 ) 2 C(CH 3 ) 2 -OH, -(CH 2 ) 2 -(4-6 membered nitrogen-containing monoheterocyclic group), -(CH 2 ) 3 -O- (5-6 membered nitrogen-containing monoheteroaryl group and C 5-6 monocyclic ring) Alkyl), -(CH 2 ) 3 -O-(benzo C 5-6 monocycloalkyl), -(CH 2 ) 3 -O-(benzo 5-6 membered nitrogen-containing monoheterocyclic group), -(CH 2 ) 3 -O-(benzo 5-6 membered nitrogen-containing monoheteroaryl), -(CH 2 ) 3 -O-phenyl-(4-6 membered nitrogen-containing monoheterocyclic group), - (6-membered nitrogen-containing monoheterocyclic group)-phenyl, -(CH 2 ) 3 -(benzo 5-6 membered nitrogen-containing monoheterocyclic group), -(CH 2 ) 3 -O- (5-6 member) Nitrogen-containing monoheteroaryl), -(CH 2 ) 3 -(6-10 membered nitrogen-containing spiroheterocyclyl), -NH-(CH 2 ) 3 -OH, -(CH 2 ) 3 -(4-6 a nitrogen-containing monoheterocyclic group), -O-(CH 2 ) 3 -O-benzyl, -(CH 2 ) 3 -(4-6 membered nitrogen-containing monoheterocyclic group)-OH, -(CH 2 ) 2- OH, -6 membered nitrogen-containing monoheterocyclyl-methoxy group, -6 membered nitrogen-containing monoheterocyclic group-OH, -(CH 2 ) 3 -O- (4-6 membered nitrogen-containing monoheterocyclic group) ), -CH 2 -N(CH 2 CH 3 )-C(O)-OC 1-4 alkyl, -CH 2 -N (C H 2 CH 3 )-CH 2 -C(O)-OC 1-4 alkyl, -CH 2 -N(CH 2 CH 3 )-C(O)-(CH 3 ) 2 -C 6-12 aryl , -CH 2 -N(CH 2 CH 3 )-C(O)-(4-6 membered nitrogen-containing monoheterocyclic group), -CH 2 -N(CH 2 CH 3 )-C(O)-(5 -6-membered nitrogen-containing monoheteroaryl), -CH 2 -NH-CH 2 CH 3 , -CH 2 -N(CH 2 CH 3 )-C(O)H, -CH 2 -N (CH 2 CH 3 )-C(O)-C 3-8 cycloalkyl, -CH 2 -N(CH 2 CH 3 )-C(O)-C 1-4 alkyl, -CH 2 -N(CH 2 CH 3 ) -C(O)-CH 3 -C 6-12 aryl, -CH 2 -N(CH 2 CH 3 )-CH 2 -C(O)-OC 1-4 alkyl, -CH 2 -(4- 6-membered nitrogen-containing monoheterocyclic group), -(CH 2 ) 3 -(4-6 membered nitrogen-containing monoheterocyclic group), wherein 4-6 membered nitrogen-containing monoheterocyclic group, C 6-12 aryl group, A 5-6 membered nitrogen-containing monoheteroaryl group, a 5-6 membered nitrogen-containing monoheterocyclyl group, may be optionally substituted with one or more substituents: methyl, ethyl, oxo, -C(O H, -S(O) 2 -CH 3 .
在一些实施方案中，-L-R 3选自以下基团： In some embodiments, -LR 3 is selected from the group consisting of:
Figure PCTCN2019085535-appb-000012
Figure PCTCN2019085535-appb-000012
在一些实施方案中，X 1为CH或NR 7；优选地，X 1为CH。 In some embodiments, X 1 is CH or NR 7 ; preferably, X 1 is CH.
在一些实施方案中，X 2为S或NR 7；优选地，X 2为S。 In some embodiments, X 2 is S or NR 7 ; preferably, X 2 is S.
在一些实施方案中，X 1为CH，X 2为S。 In some embodiments, X 1 is CH and X 2 is S.
在一些实施方案中，X 1和X 2各自独立地选自CH、NR 7、N、O或S，X 1和X 2中的至少一个为NR 7、N、O或S，且X 1、X 2和与其(X 1和/或X 2)相连的碳原子一起形成五元杂芳环； In some embodiments, X 1 and X 2 are each independently selected from CH, NR 7 , N, O, or S, and at least one of X 1 and X 2 is NR 7 , N, O, or S, and X 1 , X 2 and a carbon atom attached thereto (X 1 and/or X 2 ) together form a five-membered heteroaryl ring;
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、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、4-10元杂环基可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、C(O)OR 30、OC(O)R 30、OC(O)NR 31R 32、NR 33C(O)NR 31R 32、NR 31R 32；并且 R 2 is selected from the group consisting of 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, 4-10 membered heterocyclic group, said C 1-8 alkyl group, C 2-8 alkenyl group, C 2-8 alkynyl group, C 6-12 aryl group, C 3-8 cycloalkyl group, 5-10 yuan The heteroaryl, 4-10 membered heterocyclyl can be optionally substituted by one or more of the following substituents: halo, C 1-4 haloalkyl, C 1-4 hydroxyalkyl, C 1-4 alkoxy , C 1-4 haloalkoxy, 4-7 membered heterocyclic, CN, NO 2 , OR 37 , SR 37 , C(O)R 30 , C(O)NR 31 R 32 , C(O)OR 30 , OC(O)R 30 , OC(O)NR 31 R 32 , NR 33 C(O)NR 31 R 32 , NR 31 R 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、C(O)OR 30、C(O)NR 31R 32、NR 33C(O)R 34、NR 31R 32、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、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、9-12元芳基并环烷基可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、C(O)OR 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、P(O)OR 39OR 30。 R 3 is selected from the group consisting of H, OH, halogen, CN, NO 2 , C 1-8 alkyl, C 1-8 haloalkyl, C 1-8 alkoxy, C 1-8 haloalkoxy, C 3-8 ring Alkyl, 4-10 membered heterocyclyl, C 6-12 aryl, 5-10 membered heteroaryl, 9-12 membered arylheterocyclyl, 9-12 membered arylheteroaryl, 9- 12-membered arylcycloalkyl, C(O)OR 30 , C(O)NR 31 R 32 , NR 33 C(O)R 34 , NR 31 R 32 , OR 37 , SR 37 , C(O)R 30 , OC(O)R 30 , OC(O)NR 31 R 32 , NR 33 C(O)NR 31 R 32 , NR 33 C(O)OR 30 , C(=NR 38 )NR 31 R 32 , NR 33 C(=NR 38 )NR 31 R 32 , P(R 39 ) 2 , P(OR 39 ) 2 , P(O)R 39 R 40 , P(O)OR 39 OR 30 , S(O)R 35 , S(O) 2 R 35 , S(O)NR 31 R 32 , S(O) 2 NR 31 R 32 ; the C 1-8 alkyl group, the C 1-8 haloalkyl group, the C 1-8 alkoxy group , C 1-8 haloalkoxy, C 3-8 cycloalkyl, 4-10 membered heterocyclyl, C 6-12 aryl, 5-10 membered heteroaryl, 9-12 membered arylheterocyclic The 9-12 membered arylheteroaryl, 9-12 membered arylcycloalkyl group can be 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, C 6-12 aryl, 5-10 membered heteroaryl, 9-12 membered aryl heterocycle Base, C(O)OR 30 , C(O)R 30 , C(O)NR 31 R 32 , -NR 33 C(O)R 34 , -NR 31 R 32 , -S(O)R 35 , S (O) 2 R 35 , S(O)NR 31 R 32 , S(O) 2 NR 31 R 32 , OR 37 , SR 37 , OC(O)R 30 , OC(O)NR 31 R 32 , NR 33 C(O)NR 31 R 32 , NR 33 C(O)OR 30 , C(=NR 38 )NR 31 R 32 , NR 33 C(=NR 38 )NR 31 R 32 , =NNR 31 R 32 , P( R 39 ) 2 , P(OR 39 ) 2 , P(O)R 39 R 40 , P(O)OR 39 OR 30 .
在本发明的一些实施方案中，所述的化合物具有式II-1的结构：In some embodiments of the invention, the compound has the structure of Formula II-1:
Figure PCTCN2019085535-appb-000013
Figure PCTCN2019085535-appb-000013
其中，R 1、R 2、R 3、R 4、R 5、R 6、X 1、X 3、V和L如上述式I所定义。 Wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , X 1 , X 3 , V and L are as defined in the above formula I.
在本发明的一些实施方案中，所述的化合物具有式II-2的结构：In some embodiments of the invention, the compound has the structure of Formula II-2:
Figure PCTCN2019085535-appb-000014
Figure PCTCN2019085535-appb-000014
其中，R 1、R 2、R 3、R 4、R 5、R 6、X 1、X 3、V和L如上述式I所定义。 Wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , X 1 , X 3 , V and L are as defined in the above formula I.
在本发明的一些实施方案中，所述的化合物具有式II-3的结构：In some embodiments of the invention, the compound has the structure of Formula II-3:
Figure PCTCN2019085535-appb-000015
Figure PCTCN2019085535-appb-000015
其中，R 1、R 2、R 3、R 4、R 5、R 6、R 7、X 1、X 3、V和L如上述式I所定义。在本发明的一些实施方案中，所述的化合物具有式II-4的结构： Wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , X 1 , X 3 , V and L are as defined in the above formula I. In some embodiments of the invention, the compound has the structure of Formula II-4:
Figure PCTCN2019085535-appb-000016
Figure PCTCN2019085535-appb-000016
其中，R 1、R 2、R 3、R 4、R 5、R 6、X 1、X 3、V和L如上述式I所定义。 Wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , X 1 , X 3 , V and L are as defined in the above formula I.
在本发明的一些实施方案中，所述的化合物具有式II-5的结构：In some embodiments of the invention, the compound has the structure of Formula II-5:
Figure PCTCN2019085535-appb-000017
Figure PCTCN2019085535-appb-000017
其中，R 1、R 2、R 3、R 4、R 5、R 6、X 1、X 3、V和L如上述式I所定义。 Wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , X 1 , X 3 , V and L are as defined in the above formula I.
在本发明的一些实施方案中，所述的化合物具有式III-1的结构：In some embodiments of the invention, the compound has the structure of Formula III-1:
Figure PCTCN2019085535-appb-000018
Figure PCTCN2019085535-appb-000018
其中，R 1、R 2、R 3、R 4、R 5、R 6、X 1、X 2、V和L如上述式I所定义。 Wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , X 1 , X 2 , V and L are as defined in the above formula I.
在本发明的一些实施方案中，所述的化合物具有式III-2的结构：In some embodiments of the invention, the compound has the structure of Formula III-2:
Figure PCTCN2019085535-appb-000019
Figure PCTCN2019085535-appb-000019
其中，R 1、R 2、R 3、R 4、R 5、X 1、X 2、V和L如上述式I所定义。 Wherein R 1 , R 2 , R 3 , R 4 , R 5 , X 1 , X 2 , V and L are as defined in the above formula I.
在本发明的一些实施方案中，所述的化合物具有式III-3的结构：In some embodiments of the invention, the compound has the structure of Formula III-3:
Figure PCTCN2019085535-appb-000020
Figure PCTCN2019085535-appb-000020
其中，R 1、R 3、R 4、R 5、X 1、X 2、V和L如上述式I所定义。 Wherein R 1 , R 3 , R 4 , R 5 , X 1 , X 2 , V and L are as defined in the above formula I.
在本发明的一些实施方案中，所述的化合物具有式IV的结构：In some embodiments of the invention, the compound has the structure of Formula IV:
Figure PCTCN2019085535-appb-000021
Figure PCTCN2019085535-appb-000021
其中，R 1、R 2、R 3、R 4、R 5、R 6、X 3、V和L如上述式II-1所定义。 Wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , X 3 , V and L are as defined in the above formula II-1.
在本发明的一些实施方案中，所述的化合物具有式V的结构：In some embodiments of the invention, the compound has the structure of Formula V:
Figure PCTCN2019085535-appb-000022
Figure PCTCN2019085535-appb-000022
其中，R 1、R 2、R 3、R 4、R 5、R 6、L如上述式II-1所定义。 Wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and L are as defined in the above formula II-1.
在优选的实施方案中，R 1选自卤素、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 6-10芳基和5-10元杂芳基；优选地，R 1选自Br、C 1-6烷基、C 1-8烷氧基、C 3-8环烷基、4-10元杂环基、C 6-10芳基和5-10元杂芳基；优选地，R 1选自C 2-6烷基、C 3-8环烷基、4-7元杂环基、苯基和5-6元杂芳基；优选地，R 1为5-6元杂芳基；所述的烷基、卤代烷基、烷氧基、卤代烷氧基、环烷基、杂环基、苯基、芳基、杂芳基可任选地被下列取代基中的一个或多个取代:卤素、NO 2、CN、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、4-7元杂环基、C 6-10芳基、5-6元杂芳基、C(O)OR 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、SR 37。 In a preferred embodiment, R 1 is selected from the group consisting of halogen, C 1-8 alkyl, C 1-8 haloalkyl, C 1-8 alkoxy, C 1-8 haloalkoxy, C 3-8 cycloalkyl a 4-10 membered heterocyclic group, a C 6-10 aryl group and a 5-10 membered heteroaryl group; preferably, R 1 is selected from the group consisting of Br, C 1-6 alkyl, C 1-8 alkoxy, C 3 -8 cycloalkyl, 4-10 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl; preferably, R 1 is selected from C 2-6 alkyl, C 3-8 cycloalkyl a 4-7 membered heterocyclic group, a phenyl group and a 5-6 membered heteroaryl group; preferably, R 1 is a 5-6 membered heteroaryl group; said alkyl group, haloalkyl group, alkoxy group, haloalkoxy group A cycloalkyl, heterocyclyl, phenyl, aryl, heteroaryl group can be optionally substituted by one or more of the following substituents: halogen, NO 2 , CN, C 1-4 alkyl, C 3 -8 cycloalkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy, C 1-4 hydroxyalkyl, 4-7 membered heterocyclic, C 6-10 aryl , 5-6 membered heteroaryl, C(O)OR 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 C(O)NR 31 R 32 , NR 33 C(O)OR 30 , S(O)NR 31 R 32 , S(O) 2 NR 31 R 32 , S(O)R 35 , S(O) 2 R 35 , OR 37 , SR 37 .
在优选的实施方案中，R 1选自卤素、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 6-10芳基和5-10元杂芳基；优选地，R 1选自Br、C 1-6烷基、C 1-8烷氧基、C 3-8环烷基、4-10元杂环基、C 6-10芳基和5-10元杂芳基；优选地，R 1选自C 2-6烷基、C 3-8环烷基、4-7元杂环基、苯基和5-6元杂芳基；优选地，R 1为5-6元杂芳基和C 6-10芳基；优选地，R 1为5-6元杂芳基；所述的烷基、卤代烷基、烷氧基、卤代烷氧基、环烷基、杂环基、苯基、芳基、杂芳基可任选地被下列取代基中的一个或多个取代:F、Cl、CN、OH、C 1-3烷基、环丙基、C 1-3烷氧基、4-7元杂环基。 In a preferred embodiment, R 1 is selected from the group consisting of halogen, C 1-8 alkyl, C 1-8 haloalkyl, C 1-8 alkoxy, C 1-8 haloalkoxy, C 3-8 cycloalkyl a 4-10 membered heterocyclic group, a C 6-10 aryl group and a 5-10 membered heteroaryl group; preferably, R 1 is selected from the group consisting of Br, C 1-6 alkyl, C 1-8 alkoxy, C 3 -8 cycloalkyl, 4-10 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl; preferably, R 1 is selected from C 2-6 alkyl, C 3-8 cycloalkyl a 4-7 membered heterocyclic group, a phenyl group and a 5-6 membered heteroaryl group; preferably, R 1 is a 5-6 membered heteroaryl group and a C 6-10 aryl group; preferably, R 1 is 5-6 a heteroaryl group; the alkyl group, haloalkyl group, alkoxy group, haloalkoxy group, cycloalkyl group, heterocyclic group, phenyl group, aryl group, heteroaryl group may be optionally one of the following substituents Or a plurality of substitutions: F, Cl, CN, OH, C 1-3 alkyl, cyclopropyl, C 1-3 alkoxy, 4-7 membered heterocyclic.
在优选的实施方案中，R 1选自溴、
Figure PCTCN2019085535-appb-000023
In a preferred embodiment, R 1 is selected from bromine,
Figure PCTCN2019085535-appb-000023
在优选的实施方案中，R 1为未被取代的吡唑基。 In a preferred embodiment, R 1 is an unsubstituted pyrazolyl group.
在优选的实施方案中，R 2为甲基。 In a preferred embodiment, R 2 is methyl.
在优选的实施方案中，R 3为OH。 In a preferred embodiment, R 3 is OH.
在优选的实施方案中，R 6为H。 In a preferred embodiment, R 6 is H.
在优选的实施方案中，L为-(CH 2) 3-。 In a preferred embodiment, L is -(CH 2 ) 3 -.
在优选的实施方案中，R 1选自卤素、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 6-10芳基和5-10元杂芳基；优选地，R 1选自Br、C 1-6烷基、C 1-8烷氧基、C 3-8环烷基、4-10元杂环基、C 6-10芳基和5-10元杂芳基；优选地，R 1选自C 2-6烷基、C 3-8环烷基、4-7元杂环基、苯基和5-6元杂芳基；优选地，R 1为5-6元杂芳基和C 6-10芳基；优选地，R 1为5-6元杂芳基；所述的烷基、卤代烷基、烷氧基、卤代烷氧基、环烷基、杂环基、苯基、芳基、杂芳基可任选地被下列取代基中的一个或多个取代:F、Cl、CN、OH、C 1-3烷基、环丙基、C 1-3烷氧基、4-7元杂环基； In a preferred embodiment, R 1 is selected from the group consisting of halogen, C 1-8 alkyl, C 1-8 haloalkyl, C 1-8 alkoxy, C 1-8 haloalkoxy, C 3-8 cycloalkyl a 4-10 membered heterocyclic group, a C 6-10 aryl group and a 5-10 membered heteroaryl group; preferably, R 1 is selected from the group consisting of Br, C 1-6 alkyl, C 1-8 alkoxy, C 3 -8 cycloalkyl, 4-10 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl; preferably, R 1 is selected from C 2-6 alkyl, C 3-8 cycloalkyl a 4-7 membered heterocyclic group, a phenyl group and a 5-6 membered heteroaryl group; preferably, R 1 is a 5-6 membered heteroaryl group and a C 6-10 aryl group; preferably, R 1 is 5-6 a heteroaryl group; the alkyl group, haloalkyl group, alkoxy group, haloalkoxy group, cycloalkyl group, heterocyclic group, phenyl group, aryl group, heteroaryl group may be optionally one of the following substituents Or a plurality of substitutions: F, Cl, CN, OH, C 1-3 alkyl, cyclopropyl, C 1-3 alkoxy, 4-7 membered heterocyclic;
R 2为甲基，R 3为OH，R 6为H，-L-R 3为-(CH 2) 3-OH。 R 2 is a methyl group, R 3 is OH, R 6 is H, and -LR 3 is -(CH 2 ) 3 -OH.
在本发明的一些实施方案中，所述的化合物具有式V-1的结构：In some embodiments of the invention, the compound has the structure of Formula V-1:
Figure PCTCN2019085535-appb-000024
Figure PCTCN2019085535-appb-000024
其中，R 1、R 2、R 3、R 4、R 5、R 6如上述式V所定义。 Wherein R 1 , R 2 , R 3 , R 4 , R 5 and R 6 are as defined in the above formula V.
在本发明的一些实施方案中，所述的化合物具有式VI的结构：In some embodiments of the invention, the compound has the structure of Formula VI:
Figure PCTCN2019085535-appb-000025
Figure PCTCN2019085535-appb-000025
其中，R 1、R 2、R 3、R 4、R 5、L如上述式III-2所定义。 Wherein R 1 , R 2 , R 3 , R 4 , R 5 and L are as defined in the above formula III-2.
在优选的实施方案中，R 1选自卤素、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 6-10芳基和5-10元杂芳基；优选地，R 1选自Br、C 1-6烷基、C 1-8烷氧基、C 3-8环烷基、4-10元杂环基、C 6-10芳基和5-10元杂芳基；优选地，R 1选自C 2-6烷基、C 3-8环烷基、4-7元杂环基、苯基和5-6元杂芳基；优选地，R 1为5-6元杂芳基；上述烷基、卤代烷基、烷氧基、卤代烷氧基、环烷基、杂环基、苯基、芳基、杂芳基可任选地被下列取代基中的一个或多个取代:卤素、NO 2、CN、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、4-7元杂环基、C 6-10芳基、5-6元杂芳基、C(O)OR 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、SR 37。 In a preferred embodiment, R 1 is selected from the group consisting of halogen, C 1-8 alkyl, C 1-8 haloalkyl, C 1-8 alkoxy, C 1-8 haloalkoxy, C 3-8 cycloalkyl a 4-10 membered heterocyclic group, a C 6-10 aryl group and a 5-10 membered heteroaryl group; preferably, R 1 is selected from the group consisting of Br, C 1-6 alkyl, C 1-8 alkoxy, C 3 -8 cycloalkyl, 4-10 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl; preferably, R 1 is selected from C 2-6 alkyl, C 3-8 cycloalkyl a 4-7 membered heterocyclic group, a phenyl group and a 5-6 membered heteroaryl group; preferably, R 1 is a 5-6 membered heteroaryl group; the above alkyl group, haloalkyl group, alkoxy group, haloalkoxy group, ring Alkyl, heterocyclyl, phenyl, aryl, heteroaryl may be optionally substituted by one or more of the following substituents: halogen, NO 2 , CN, C 1-4 alkyl, C 3-8 Cycloalkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy, C 1-4 hydroxyalkyl, 4-7 membered heterocyclyl, C 6-10 aryl, 5-6 membered heteroaryl, C(O)OR 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 C(O)NR 31 R 32 , NR 33 C(O)OR 30 , S(O)NR 31 R 32 , S(O) 2 NR 31 R 32 , S(O)R 35 , S(O) 2 R 35 , OR 37 , SR 37 .
在优选的实施方案中，R 1选自卤素、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 6-10芳基和5-10元杂芳基；优选地，R 1选自Br、C 1-6烷基、C 1-8烷氧基、C 3-8环烷基、4-10元杂环基、C 6-10芳基和5-10元杂芳基；优选地，R 1选自C 2-6烷基、C 3-8环烷基、4-7元杂环基、苯基和5-6元杂芳基；优选地，R 1为5-6元杂芳基；上述烷基、卤代烷基、烷氧基、卤代烷氧基、环烷基、杂环基、苯基、芳基、杂芳基可任选地被下列取代基中的一个或多个取代:F、Cl、CN、OH、C 1-3烷基、环丙基、C 1-3烷氧基、4-7元杂环基。 In a preferred embodiment, R 1 is selected from the group consisting of halogen, C 1-8 alkyl, C 1-8 haloalkyl, C 1-8 alkoxy, C 1-8 haloalkoxy, C 3-8 cycloalkyl a 4-10 membered heterocyclic group, a C 6-10 aryl group and a 5-10 membered heteroaryl group; preferably, R 1 is selected from the group consisting of Br, C 1-6 alkyl, C 1-8 alkoxy, C 3 -8 cycloalkyl, 4-10 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl; preferably, R 1 is selected from C 2-6 alkyl, C 3-8 cycloalkyl a 4-7 membered heterocyclic group, a phenyl group and a 5-6 membered heteroaryl group; preferably, R 1 is a 5-6 membered heteroaryl group; the above alkyl group, haloalkyl group, alkoxy group, haloalkoxy group, ring Alkyl, heterocyclyl, phenyl, aryl, heteroaryl may be optionally substituted by one or more of the following substituents: F, Cl, CN, OH, C 1-3 alkyl, cyclopropyl , C 1-3 alkoxy, 4-7 membered heterocyclic group.
在优选的实施方案中，R 1选自溴、
Figure PCTCN2019085535-appb-000026
Figure PCTCN2019085535-appb-000027
In a preferred embodiment, R 1 is selected from bromine,
Figure PCTCN2019085535-appb-000026
Figure PCTCN2019085535-appb-000027
在优选的实施方案中，R 1为未被取代的吡唑基。 In a preferred embodiment, R 1 is an unsubstituted pyrazolyl group.
在优选的实施方案中，R 2选自H、C 1-4烷基和对甲氧基苄基。 In a preferred embodiment, R 2 is selected from the group consisting of H, C 1-4 alkyl and p-methoxybenzyl.
在优选的实施方案中，R 3选自H、甲基、乙基、甲氧基、叔丁氧基、苄基、环丙基、苯基、OH、
Figure PCTCN2019085535-appb-000028
Figure PCTCN2019085535-appb-000029
In a preferred embodiment, R 3 is selected from the group consisting of H, methyl, ethyl, methoxy, tert-butoxy, benzyl, cyclopropyl, phenyl, OH,
Figure PCTCN2019085535-appb-000028
Figure PCTCN2019085535-appb-000029
在优选的实施方案中，R 1选自卤素、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 6-10芳基和5-10元杂芳基；优选地，R 1选自Br、C 1-6烷基、C 1-8烷氧基、C 3-8环烷基、4-10元杂环基、C 6-10芳基和5-10元杂芳基；优选地，R 1选自C 2-6烷基、C 3-8环烷基、4-7元杂环基、苯基和5-6元杂芳基；优选地，R 1为5-6元杂芳基；上述烷基、卤代烷基、烷氧基、卤代烷氧基、环烷基、杂环基、苯基、芳基、杂芳基可任选地被下列取代基中的一个或多个取代:F、Cl、CN、OH、C 1-3烷基、环丙基、C 1-3烷氧基、4-7元杂环基； In a preferred embodiment, R 1 is selected from the group consisting of halogen, C 1-8 alkyl, C 1-8 haloalkyl, C 1-8 alkoxy, C 1-8 haloalkoxy, C 3-8 cycloalkyl a 4-10 membered heterocyclic group, a C 6-10 aryl group and a 5-10 membered heteroaryl group; preferably, R 1 is selected from the group consisting of Br, C 1-6 alkyl, C 1-8 alkoxy, C 3 -8 cycloalkyl, 4-10 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl; preferably, R 1 is selected from C 2-6 alkyl, C 3-8 cycloalkyl a 4-7 membered heterocyclic group, a phenyl group and a 5-6 membered heteroaryl group; preferably, R 1 is a 5-6 membered heteroaryl group; the above alkyl group, haloalkyl group, alkoxy group, haloalkoxy group, ring Alkyl, heterocyclyl, phenyl, aryl, heteroaryl may be optionally substituted by one or more of the following substituents: F, Cl, CN, OH, C 1-3 alkyl, cyclopropyl , C 1-3 alkoxy, 4-7 membered heterocyclic group;
R 2选自H、C 1-4烷基和对甲氧基苄基；并且 R 2 is selected from the group consisting of H, C 1-4 alkyl and p-methoxybenzyl;
-L-R 3选自以下基团： -LR 3 is selected from the following groups:
Figure PCTCN2019085535-appb-000030
Figure PCTCN2019085535-appb-000031
Figure PCTCN2019085535-appb-000030
Figure PCTCN2019085535-appb-000031
在本发明的一些实施方案中，所述的化合物具有式VI-1的结构：In some embodiments of the invention, the compound has the structure of Formula VI-1:
Figure PCTCN2019085535-appb-000032
Figure PCTCN2019085535-appb-000032
其中，R 1、R 2、R 3、R 4、R 5如上述式VI所定义。 Wherein R 1 , R 2 , R 3 , R 4 and R 5 are as defined in the above formula VI.
在本发明的一些实施方案中，所述的化合物具有式VII的结构：In some embodiments of the invention, the compound has the structure of Formula VII:
Figure PCTCN2019085535-appb-000033
Figure PCTCN2019085535-appb-000033
其中，R 1、R 3、R 4、R 5、L如上述式III-3所定义。 Wherein R 1 , R 3 , R 4 , R 5 and L are as defined in the above formula III-3.
在优选的实施方案中，R 1选自卤素、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 6-10芳基和5-10元杂芳基；优选地，R 1选自Br、C 1-6烷基、C 1-8烷氧基、C 3-8环烷基、4-10元杂环基、C 6-10芳基和5-10元杂芳基；优选地，R 1选自C 2-6烷基、C 3-8环烷基、4-7元杂环基、苯基和5-6元杂芳基；优选地，R 1为5-6 元杂芳基；上述烷基、卤代烷基、烷氧基、卤代烷氧基、环烷基、杂环基、苯基、芳基、杂芳基可任选地被下列取代基中的一个或多个取代:卤素、NO 2、CN、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、4-7元杂环基、C 6-10芳基、5-6元杂芳基、C(O)OR 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、SR 37。 In a preferred embodiment, R 1 is selected from the group consisting of halogen, C 1-8 alkyl, C 1-8 haloalkyl, C 1-8 alkoxy, C 1-8 haloalkoxy, C 3-8 cycloalkyl a 4-10 membered heterocyclic group, a C 6-10 aryl group and a 5-10 membered heteroaryl group; preferably, R 1 is selected from the group consisting of Br, C 1-6 alkyl, C 1-8 alkoxy, C 3 -8 cycloalkyl, 4-10 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl; preferably, R 1 is selected from C 2-6 alkyl, C 3-8 cycloalkyl a 4-7 membered heterocyclic group, a phenyl group and a 5-6 membered heteroaryl group; preferably, R 1 is a 5-6 membered heteroaryl group; the above alkyl group, haloalkyl group, alkoxy group, haloalkoxy group, ring Alkyl, heterocyclyl, phenyl, aryl, heteroaryl may be optionally substituted by one or more of the following substituents: halogen, NO 2 , CN, C 1-4 alkyl, C 3-8 Cycloalkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy, C 1-4 hydroxyalkyl, 4-7 membered heterocyclyl, C 6-10 aryl, 5-6 membered heteroaryl, C(O)OR 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 C(O)NR 31 R 32 , NR 33 C(O)OR 30 , S(O)NR 31 R 32 , S(O) 2 NR 31 R 32 , S(O)R 35 , S(O) 2 R 35 , OR 37 , SR 37 .
在优选的实施方案中，R 1选自卤素、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 6-10芳基和5-10元杂芳基；优选地，R 1选自Br、C 1-6烷基、C 1-8烷氧基、C 3-8环烷基、4-10元杂环基、C 6-10芳基和5-10元杂芳基；优选地，R 1选自C 2-6烷基、C 3-8环烷基、4-7元杂环基、苯基和5-6元杂芳基；优选地，R 1选自5-6元杂芳基、C 6-10芳基；优选地，R 1为5-6元杂芳基；上述烷基、卤代烷基、烷氧基、卤代烷氧基、环烷基、杂环基、苯基、芳基、杂芳基可任选地被下列取代基中的一个或多个取代:F、Cl、CN、OH、C 1-3烷基、环丙基、C 1-3烷氧基、4-7元杂环基。 In a preferred embodiment, R 1 is selected from the group consisting of halogen, C 1-8 alkyl, C 1-8 haloalkyl, C 1-8 alkoxy, C 1-8 haloalkoxy, C 3-8 cycloalkyl a 4-10 membered heterocyclic group, a C 6-10 aryl group and a 5-10 membered heteroaryl group; preferably, R 1 is selected from the group consisting of Br, C 1-6 alkyl, C 1-8 alkoxy, C 3 -8 cycloalkyl, 4-10 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl; preferably, R 1 is selected from C 2-6 alkyl, C 3-8 cycloalkyl a 4-7 membered heterocyclic group, a phenyl group and a 5-6 membered heteroaryl group; preferably, R 1 is selected from a 5-6 membered heteroaryl group, a C 6-10 aryl group; preferably, R 1 is 5- a 6-membered heteroaryl group; the above alkyl group, haloalkyl group, alkoxy group, haloalkoxy group, cycloalkyl group, heterocyclic group, phenyl group, aryl group, heteroaryl group may be optionally one of the following substituents or Multiple substitutions: F, Cl, CN, OH, C 1-3 alkyl, cyclopropyl, C 1-3 alkoxy, 4-7 membered heterocyclic.
在优选的实施方案中，R 1选自溴、
Figure PCTCN2019085535-appb-000034
In a preferred embodiment, R 1 is selected from bromine,
Figure PCTCN2019085535-appb-000034
在优选的实施方案中，R 1为未被取代的吡唑基。 In a preferred embodiment, R 1 is an unsubstituted pyrazolyl group.
在优选的实施方案中，-L-R 3为-(CH 2) 3-OH。 In a preferred embodiment, -LR 3 is -(CH 2 ) 3 -OH.
在优选的实施方案中，R 1选自溴、
Figure PCTCN2019085535-appb-000035
-L-R 3为-(CH 2) 3-OH。 In a preferred embodiment, R 1 is selected from bromine,
Figure PCTCN2019085535-appb-000035
-LR 3 is -(CH 2 ) 3 -OH.
在本发明的一些实施方案中，所述的化合物具有式VII-1的结构：In some embodiments of the invention, the compound has the structure of Formula VII-1:
Figure PCTCN2019085535-appb-000036
Figure PCTCN2019085535-appb-000036
其中，R 1、R 3、R 4、R 5如上述式VII所定义。 Wherein R 1 , R 3 , R 4 and R 5 are as defined in the above formula VII.
本发明的实施方案中，本发明的化合物选自，但不限于：In an embodiment of the invention, the compound of the invention is selected from, but not limited to:
Figure PCTCN2019085535-appb-000037
Figure PCTCN2019085535-appb-000037
Figure PCTCN2019085535-appb-000038
Figure PCTCN2019085535-appb-000038
Figure PCTCN2019085535-appb-000039
Figure PCTCN2019085535-appb-000039
Figure PCTCN2019085535-appb-000040
Figure PCTCN2019085535-appb-000040
在另一方面，本发明提供了一种药物组合物，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。In another aspect, the present invention provides a pharmaceutical composition comprising a compound as described above, a stereoisomer, a tautomer or a mixture thereof, a pharmaceutically acceptable salt of the compound a eutectic, polymorph or solvate, or a stable isotope derivative, metabolite or prodrug of said compound. Optionally, the pharmaceutical composition further comprises one or more pharmaceutically acceptable carriers.
在一些实施方案中，所述药物组合物用于预防、缓解和/或治疗与NLRP3炎症小体活性相关的疾病(例如肿瘤疾病)。In some embodiments, the pharmaceutical composition is for preventing, ameliorating, and/or treating a disease associated with NLRP3 inflammatory body activity (eg, a neoplastic disease).
在一些实施方案中，所述药物组合物用于预防、缓解和/或治疗细胞增殖异常性疾病(例如癌症)。In some embodiments, the pharmaceutical composition is for preventing, ameliorating, and/or treating a cell proliferative disorder (eg, cancer).
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。Optionally, the pharmaceutical compositions of the invention further comprise one or more second therapeutic agents. In certain embodiments, the second therapeutic agent includes other drugs that treat tumor diseases and the like.
在另一方面，本发明提供了一种药物制剂，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。In another aspect, the present invention provides a pharmaceutical preparation comprising a compound as described above, a stereoisomer, a tautomer or a mixture thereof, a pharmaceutically acceptable salt of the compound, Eutectic, polymorph or solvate, or a stable isotope derivative, metabolite or prodrug of the compound, or a pharmaceutical composition as described above.
在另一方面，本发明提供了如上所述的化合物，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、缓解和/或治疗与NLRP3炎症小体活性相关的疾病(例如肿瘤疾病)。In another aspect, the invention provides a compound as described above, a stereoisomer, a tautomer or a mixture thereof, a pharmaceutically acceptable salt, eutectic, polymorph of the compound Or a solvate, or a stable isotope derivative, metabolite or prodrug of said compound, or a pharmaceutical composition as described above for use in the manufacture of a medicament for the prevention, alleviation and/or treatment of NLRP3 A disease associated with inflammatory body activity (eg, a neoplastic disease).
在另一方面，本发明提供了如上所述的化合物，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。In another aspect, the invention provides a compound as described above, a stereoisomer, a tautomer or a mixture thereof, a pharmaceutically acceptable salt, eutectic, polymorph of the compound Or a solvate, or a stable isotope derivative, metabolite or prodrug of said compound, or a pharmaceutical composition as described above, for use in the preparation of a formulation for modulating (e.g., increasing) NLRP3 inflammatory bodies Activity.
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。In some embodiments, the formulation is administered to a subject (eg, a mammal; eg, a bovine, an equine, a sheep, a porcine, a canine, a feline, a rodent, a spirit) a long-lived animal; for example, a human) to increase NLRP3 inflammatory corpuscle activity in cells in a subject; or, the preparation is administered to an in vitro cell (eg, a cell line or a cell from a subject) to increase Activity of NLRP3 inflammatory bodies in cells.
在另一方面，本发明提供了一种调节(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。In another aspect, the invention provides a method of modulating (e.g., increasing) NLRP3 inflammatory body activity in a cell, comprising administering to said cell an effective amount of a compound as described above, a stereoisomer of said compound a tautomer or a mixture thereof, a pharmaceutically acceptable salt, eutectic, polymorph or solvate of said compound, or a stable isotope derivative, metabolite or prodrug of said compound, or Said pharmaceutical composition, or a pharmaceutical preparation as described above.
在另一方面，本发明提供了一种用于调节(例如增加)NLRP3炎症小体的活性的试剂盒，所述的试剂盒包括化合物，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。In another aspect, the invention provides a kit for modulating (e.g., increasing) the activity of an NLRP3 inflammatory steroid comprising a compound, a stereoisomer, a tautomer of the compound Or a mixture thereof, a pharmaceutically acceptable salt, eutectic, polymorph or solvate of the compound, or a stable isotope derivative, metabolite or prodrug of the compound, or a pharmaceutical composition as described above Or a formulation as described above.
另一方面，本发明提供了治疗与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、缓解和/或预防有效量的本发明的化合物，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。In another aspect, the invention provides a method of treating a disease (eg, a neoplastic disease) associated with NLRP3 inflammatory steroid activity comprising administering to a subject in need thereof a therapeutic, ameliorating and/or prophylactically effective amount of the invention a compound, a stereoisomer, a tautomer or a mixture thereof, a pharmaceutically acceptable salt, eutectic, polymorph or solvate of the compound, or a stable isotope derivative of the compound A substance, metabolite or prodrug, or a pharmaceutical composition as described above, or a formulation as described above.
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。Optionally, the method further comprises administering to the subject in need thereof one or more second therapeutic agents. In some embodiments, the second therapeutic agent comprises other drugs that treat diseases such as tumors.
本发明中，所述肿瘤疾病包括但不限于：肺癌、胰腺癌、乳腺癌、头颈癌、肝癌、黑色素瘤、胶质瘤或肉瘤。In the present invention, the tumor diseases include, but are not limited to, lung cancer, pancreatic cancer, breast cancer, head and neck cancer, liver cancer, melanoma, glioma or sarcoma.
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)。In some embodiments, the compounds of the invention are full agonists; in some embodiments, the compounds of the invention are partial agonists.
术语定义Definition of Terms
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。Unless otherwise defined below, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. References to techniques used herein are intended to refer to techniques that are generally understood in the art, including those that are obvious to those skilled in the art. While the following terms are believed to be well understood by those skilled in the art, the following definitions are set forth to better explain the invention.
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(biological effect或response)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Emax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。 The term "agonist" refers to a compound that binds to and activates a receptor to initiate a biological effect or response, including full agonists and partial agonists ( Partial agonist). A full agonist activates the receptor and produces the greatest effect (maximal effect or Emax ). Partial agonists can bind to and activate the receptor, but only produce a partial effect relative to the full agonist. When a full agonist and a partial agonist coexist, a partial agonist can sometimes become a partial antagonist by competing with a full agonist for a binding site on the receptor or other mechanism. Potency (concentration of the compound potency, by the EC 50 (producing 50% of the Emax of) measure) a partial agonist may be higher or lower than in a full agonist efficacy. The NLRP3 agonists of the invention include NLRP3 full agonists and NLRP3 partial agonists.
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。The full name of the term "NLRP3" is NLR family pyrin domain containing 3, which is an inflammatory body. In the present invention, when referring to "NLRP3", the meanings indicated include nucleic acids, polynucleotides, oligonucleotides, sense and antisense polynucleotide chains, complementary sequences, short peptides, polypeptides of NLRP3. , proteins, homologous or heterologous molecules, subtypes, precursors, mutants, variants, derivatives, various splices, alleles, different species, and activated fragments, and the like.
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。The terms "comprising," "comprising," "having," "containing," Or method steps.
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。The term "halo" means substituted by a halogen atom, and the "halogen" includes F, Cl, Br or 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1-4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。 The term "alkyl" is a straight or branched saturated aliphatic hydrocarbon group. The terms "C 1-8 alkyl", "C 1-6 alkyl" and "C 1-4 alkyl" respectively have from 1 to 8 carbon atoms, from 1 to 6 carbon atoms and from 1 to 4 carbon atoms. A linear or branched alkyl group 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) identical or different substituents.
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。 The term "alkylene" refers to a saturated divalent hydrocarbon radical derived from the removal of two hydrogen atoms from a straight or branched saturated hydrocarbon radical, which contains the specified number of carbon atoms. For example, an alkylene group of 1 to 8 carbon atoms, such as methylene (-CH 2 -), ethylene (-CH 2 CH 2 -), isopropylidene (-CH(CH 3 )CH 2 -) And the like; the alkylene group may be optionally substituted by one or more (such as 1 to 3) identical or different substituents.
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1-4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或-CH 2CH 2CF 3等。 The term "haloalkyl" refers to an alkyl group substituted by one or more (such as 1 to 3) identical or different halogen atoms, the terms "C 1-8 haloalkyl", "C 1-6 haloalkyl" and " C 1-4 haloalkyl" means a haloalkyl group having 1 to 8 carbon atoms, 1 to 6 carbon atoms and 1 to 4 carbon atoms, respectively, such as -CF 3 , -C 2 F 5 , -CHF 2 , CH 2 F, -CH 2 CF 3 , -CH 2 Cl or -CH 2 CH 2 CF 3 or the like.
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。 The term "hydroxyalkyl" refers to a group formed by the substitution of a hydrogen atom of an alkyl group with one or more hydroxy groups, such as a C 1-4 hydroxyalkyl group or a C 1-3 hydroxyalkyl group, examples of which include, but are not limited to, hydroxy methyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, -CH (OH) CH 3 and the like.
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。 The term "alkenyl" refers to a monovalent straight or branched chain hydrocarbon radical containing one or more carbon-carbon double bonds, for example -CH=CH 2 , -CH 2 CH=CH 2 , -C(CH 3 )=CH 2 And -CH 2 -CH=CH-CH 3 and the like, which may be optionally substituted by one or more (such as 1 to 3) identical or different substituents.
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到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。 The term "alkenylene" refers to a divalent straight or branched aliphatic hydrocarbon group containing one or more carbon-carbon double bonds containing the specified number of carbon atoms, for example 2 to 8 carbon atoms, for example -CH= CH-, -CH 2 CH=CH-, -C(CH 3 )=CH-, etc., the alkenylene group may be optionally substituted by one or more (such as 1 to 3) identical or different substituents .
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-丁炔基和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。The term "alkynyl" refers to a monovalent straight or branched chain hydrocarbon radical having one or more carbon-carbon triple bonds including, but not limited to, ethynyl, 2-propynyl, 2-butynyl, and 1,3-butyl Diacetylene or the like, which may be optionally substituted by one or more (such as 1 to 3) identical or different substituents.
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 PCTCN2019085535-appb-000041
Figure PCTCN2019085535-appb-000042
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。 The term "alkynylene" refers to a divalent straight or branched chain hydrocarbon radical having one or more carbon-carbon triple bonds containing a specified number of carbon atoms, for example 2 to 8 carbon atoms, including but not limited to
Figure PCTCN2019085535-appb-000041
Figure PCTCN2019085535-appb-000042
And the alkynylene group may be optionally substituted by one or more (such as 1 to 3) identical or different substituents.
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-C 6烷氧基或C 1-C 3烷氧基。C 1-C 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。 The term "alkoxy" means a group which is inserted into the oxygen atom at any reasonable position of the alkyl group (as defined above), preferably a C 1 -C 6 alkoxy group or a C 1 -C 3 alkoxy group. Representative examples of C 1 -C 6 alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, n-propoxy, isopropoxy, n-butoxy, isobutyl Oxyl, tert-butoxy, pentyloxy, hexyloxy, -CH 2 -OCH 3 and the like, which may optionally be substituted by one or more (such as 1 to 3) identical or different Substituted.
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。 The term "alkoxy" 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 by one or more (such as 1 to 3) identical or different substituents.
术语“杂烷基”指可任选地被取代的含两个碳或两个碳原子以上的烷基，其具有一个或多个选自除碳以外的原子的骨架链原子，例如氧、氮、硫、磷或其组合，所给出数值范围是指链中的碳数目，例如C 2- 8杂烷基含有2-8个碳原子。例如，-CH 2OCH 2CH 3、-CH 2NHCH 2CH 3或-CH 2N(Me)CH 2CH 3被称为C 3杂烷基。其中，杂烷基与其他基团的连接点在杂烷基骨架链中的碳上。术语“亚杂烷基”表示相应的二价基团,例如，-CH 2OCH 2CH 2-。 The term "heteroalkyl" refers to an alkyl group containing two or more carbon atoms, optionally having one or more backbone chain atoms selected from atoms other than carbon, such as oxygen, nitrogen, which may be optionally substituted. , sulfur, phosphorus or a combination thereof, the numerical range given refers to the number of carbons in the chain, for example C 2 -8 heteroalkyl contains 2-8 carbon atoms. For example, -CH 2 OCH 2 CH 3 , -CH 2 NHCH 2 CH 3 or -CH 2 N(Me)CH 2 CH 3 is referred to as a C 3 heteroalkyl group. Wherein, the point of attachment of the heteroalkyl group to the other group is on the carbon in the heteroalkyl skeleton chain. The term "heteroalkylene" denotes the corresponding divalent group, for example, -CH 2 OCH 2 CH 2 -.
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。The term "paracyclic" or "fused ring" refers to a ring system formed by two or more cyclic structures sharing two adjacent atoms with each other.
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。The term "spiro" refers to a ring system formed by two or more ring structures sharing one ring atom with each other.
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。The term "bridged ring" refers to a ring system formed by two or more cyclic structures sharing two atoms that are not directly connected to each other.
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(即形成C＝O)。The term "cycloalkyl" refers to a saturated or unsaturated, non-aromatic monocyclic or polycyclic (such as bicyclic) hydrocarbon ring group including, but not limited to, monocycloalkyl (such as cyclopropyl, cyclobutyl, cyclopentyl, Cyclohexyl, cycloheptyl, cyclooctyl, cyclodecyl) and bicycloalkyl, including spiro, cyclo (fused ring) or bridged ring systems (ie, spirocycloalkyl, cyclo (fused) alkyl) And bridged cycloalkyl, such as bicyclo [1.1.1] pentyl, bicyclo [2.2.1] heptyl, etc.). In the present invention, the cycloalkyl group may be optionally substituted by one or more (such as 1 to 3) identical or different substituents. The carbon atom on the cycloalkyl group is optionally oxo (ie, forms C=O).
术语“C 3-8环烷基”指具有3至8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、环庚基、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。 The term "C 3-8 cycloalkyl" refers to a cycloalkyl group having from 3 to 8 ring-forming carbon atoms which may be a monocyclic alkyl group such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, ring. Heptyl, cyclooctyl) may also be a bicycloalkyl group such as a C 3-8 spirocycloalkyl group, a C 3-8 bridged cycloalkyl group, a C 3-8 fused ring alkyl group.
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，例如为C 6-C 10芳基，例如为，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-C 6烷基等)取代。 The term "aryl" refers to an all-carbon monocyclic or fused polycyclic aromatic group having a conjugated pi-electron system. The term "C 6 - 12 aryl" as used herein means an aryl group having 6 to 12 carbon atoms, such as a C 6 -C 10 aryl group, for example, a phenyl group or a naphthyl group. The aryl group is optionally substituted by one or more (such as 1 to 3) identical or different substituents (e.g., halogen, OH, CN, NO 2 , C 1 -C 6 alkyl, etc.).
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，例如苯基并环戊基、苯基并环己基，例如，
Figure PCTCN2019085535-appb-000043
The term "arylcycloalkyl" refers to a cis-group in which an aryl group and a cycloalkyl group (eg, a monocycloalkyl group) share two adjacent atoms with each other, wherein the point of attachment to other groups may be On the aryl group or on the cycloalkyl group. The term "9-12 membered arylcycloalkyl" refers to an arylcycloalkyl group having a total of 9 to 12 ring atoms, such as phenylcyclopentyl, phenylcyclohexyl, for example,
Figure PCTCN2019085535-appb-000043
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、硫原子，所述杂环基上的碳原子和杂原子任选地被氧代(oxo)(例如形成C＝O、S(＝O)或S(＝O) 2)。 The term "heterocyclyl" refers to having two or more (eg, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14) carbon atoms, and one or more ( For example, one, two, three or four) heterocyclic monocyclic or polycyclic (eg, cyclo, spiro or bridged) groups including, but not limited to, oxygen, nitrogen, sulfur The atom, the carbon atom and the hetero atom on the heterocyclic group are optionally oxo (for example, forming C=O, S(=O) or S(=O) 2 ).
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、4-7元杂环基、5-6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元含氮杂环基、5-6元含氧杂环基、5-6元含硫杂环基，所述“含氮杂环基”、“含氧杂环基”、“含硫杂环基”任选地还含有一个或多个选自氧、氮、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)等。The term "3-14 membered heterocyclic group" means a heterocyclic group having 3 to 14 ring atoms, including but not limited to a 4-10 membered heterocyclic group, a 4-7 membered heterocyclic group, and a 5-6 membered heterocyclic ring. Base, 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 nitrogen-containing heterocyclic ring a 5- to 6-membered oxygen-containing heterocyclic group, a 5-6 membered sulfur-containing heterocyclic group, said "nitrogen-containing heterocyclic group", "oxygen-containing heterocyclic group", or "sulfur-containing heterocyclic group", optionally It also contains one or more other heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur. Examples of 3-14 membered heterocyclic groups include, but are not limited to, oxiranyl, aziridine, azetidinyl, oxetanyl, tetrahydrofuranyl, pyrrolidinyl, pyrrolidinyl, imidazolidinyl, Pyrazolidinyl, tetrahydropyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl, trithianyl, and the like.
本发明中，杂环基可以与杂环基或环烷基形成并环结构，所述并环结构与其他基团的连接点可以在任一杂环基上或环烷基上，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，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 PCTCN2019085535-appb-000044
In the present invention, the heterocyclic group may form a cyclic structure with a heterocyclic group or a cycloalkyl group, and the point of attachment of the cyclo-ring structure to other groups may be on either a heterocyclic group or a cycloalkyl group, and thus, the present invention Heterocyclyl also includes, but is not limited to, heterocyclylheterocyclyl, heterocyclylcycloalkyl, monoheterocyclylmonoheterocyclyl, monoheterocyclylmonocycloalkyl, such as 3- 7-membered (mono)heterocyclic and 3-7 membered (mono)heterocyclyl, 3-7 membered (mono)heterocyclyl(mono)cycloalkyl, 3-7 membered (mono)heterocyclyl and C 4-6 (mono)cycloalkyl, examples of which include, but are not limited to, pyrrolidinylcyclopropyl, cyclopentyloxaziridine, pyrrolidinocyclobutyl, pyrrolidinopyrrolidinyl, Pyrrolidinopiperidinyl, pyrrolidinopiperazinyl, piperidinylmorpholinyl,
Figure PCTCN2019085535-appb-000044
本发明中，杂环基还包括桥杂环基和螺杂环基。In the present invention, the heterocyclic group further includes a bridged heterocyclic group and a spiroheterocyclic group.
术语“桥杂环”是指两个饱和环共用两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、硫原子)的环状结构，包括但 不限于7-10元桥杂环、8-10元桥杂环、7-10元含氮桥杂环、7-10元含氧桥杂环、7-10元含硫桥杂环等，例如
Figure PCTCN2019085535-appb-000045
Figure PCTCN2019085535-appb-000046
等。所述“含氮桥杂环”、“含氧桥杂环”、“含硫桥杂环”任选地还含有一个或多个选自氧、氮、硫的其他杂原子。 The term "bridge heterocycle" means that two saturated rings share two or more (eg, 1, 2, 3 or 4) heteroatoms (eg, oxygen, nitrogen) formed by ring atoms that are not directly joined. a cyclic structure of a sulfur atom, including but not limited to a 7-10 membered bridged heterocyclic ring, an 8-10 membered bridged heterocyclic ring, a 7-10 membered nitrogen-containing bridged heterocyclic ring, and a 7-10 membered oxygenated bridged heterocyclic ring, 7 -10 yuan sulfur-containing bridge heterocycle, etc., for example
Figure PCTCN2019085535-appb-000045
Figure PCTCN2019085535-appb-000046
Wait. The "nitrogen-containing bridged heterocycle", "oxygen-containing bridged heterocycle", and "sulfur-containing bridged heterocycle" optionally further contain one or more other heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur.
术语“螺杂环”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、硫原子)的环状结构，包括但不限于5-10元螺杂环、6-10元螺杂环、6-10元含氮螺杂环、6-10元含氧螺杂环、6-10元含硫螺杂环等，例如
Figure PCTCN2019085535-appb-000047
Figure PCTCN2019085535-appb-000048
Figure PCTCN2019085535-appb-000049
所述“含氮螺杂环”、“含氧螺杂环”、“含硫螺杂环”任选地还含有一个或多个选自氧、氮、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。 The term "spiroheterocycle" refers to a heteroatom containing one or more (eg, 1, 2, 3 or 4) heteroatoms (eg, an oxygen atom, nitrogen) formed by the sharing of one ring atom by two or more saturated rings. a cyclic structure of an atom, a sulfur atom, including but not limited to a 5-10 membered spiro heterocyclic ring, a 6-10 membered spiro heterocyclic ring, a 6-10 membered nitrogen-containing spiro heterocyclic ring, and a 6-10 membered oxygenated spiro heterocyclic ring. 6-10 yuan sulfur-containing spiro heterocycle, etc., for example
Figure PCTCN2019085535-appb-000047
Figure PCTCN2019085535-appb-000048
Figure PCTCN2019085535-appb-000049
The "nitrogen-containing spiroheterocycle", "oxygen-containing spiroheterocycle", and "sulfur-containing spiroheterocycle" optionally further contain one or more other heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur. The term "6-10 membered nitrogen-containing spiroheterocyclyl" means a spiroheterocyclyl group containing a total of 6 to 10 ring atoms and at least one of which is a nitrogen atom.
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，其与其他基团的连接点在可以在芳基或杂环基上。其中，芳基和杂环基如上文所定义。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，例如苯基并5-8元杂环基，例如苯基并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，所述“含氮杂环基”、“含氧杂环基”、“含硫杂环基”任选地还含有一个或多个选自氧、氮、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(oxo)(例如形成C＝O、S(＝O)或S(＝O) 2)。 The term "arylheterocyclyl" refers to a cyclic group formed by the aryl group and the heterocyclic group sharing two adjacent carbon atoms with each other, and the point of attachment to other groups may be at an aryl or heterocyclic group. on. Wherein the aryl group and the heterocyclic group are as defined above. For example, as used herein, the term "9-12 membered arylheterocyclyl" means a group containing an arylheterocyclyl group of a total of 9 to 12 ring atoms, including but not limited to 9-10 members. a benzoheterocyclyl group, such as a phenyl- and 5- to 8-membered heterocyclic group, such as a phenyl- and 5- to 6-membered heterocyclic group, such as a benzo 5-6 membered monoheterocyclic group, a benzo 5-6 membered nitrogen group. a monoheterocyclic group, a benzo 5-6 membered oxygen monoheterocyclic group, a benzo 5-6 membered sulfur-containing heterocyclic group, said "nitrogen-containing heterocyclic group", "oxygen-containing heterocyclic group", "including The thiaheterocyclyl" optionally further contains one or more other heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur. The carbon atom and hetero atom on the heterocyclic group are optionally oxo (e.g., form C=O, S(=O) or S(=O) 2 ).
其实例包括但不限于：吲唑基、
Figure PCTCN2019085535-appb-000050
Figure PCTCN2019085535-appb-000051
Examples include, but are not limited to, carbazolyl,
Figure PCTCN2019085535-appb-000050
Figure PCTCN2019085535-appb-000051
术语“杂芳基”指含有一个或多个(例如1个、2个、3个或4个)相同或不同杂原子的单环或多环芳族基团，包括单环的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。所述杂原子可以使氧、氮或硫。所述杂芳基上的碳原子和杂原子任选地被氧代(oxo)(例如形成C＝O、S(＝O)或S(＝O) 2)。 The term "heteroaryl" refers to a monocyclic or polycyclic aromatic group containing one or more (eg, 1, 2, 3 or 4) identical or different heteroatoms, including monocyclic heteroaryls and a bicyclic or polycyclic ring system containing at least one heteroaromatic ring (an aromatic ring system containing at least one hetero atom) which may have 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 rings An atom such as 5, 6, 7, 8, 9 or 10 ring atoms. The hetero atom can be oxygen, nitrogen or sulfur. The carbon and heteroatoms on the heteroaryl group are optionally oxo (e.g., form C=O, S(=O) or S(=O) 2 ).
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。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”、“含硫单杂芳基”任选地还含有一个或多个选自氧、氮、硫的其他杂原子。其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、噻二唑基等，或吡啶基、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。The term "5-10 membered heteroaryl" means a heteroaryl group containing 5 to 10 ring atoms, including a 5-6 membered heteroaryl group, a 5-6 membered monoheteroaryl group, and a 5-10 membered nitrogen-containing heteroaryl group. Base, 5-10 membered oxygen-containing heteroaryl group, 5-10 membered sulfur-containing heteroaryl group, 5-6 membered nitrogen-containing heteroaryl group, 5-6 membered oxygen-containing heteroaryl group, 5-6 membered sulfur-containing heteroaryl group A 5- to 6-membered nitrogen-containing monoheteroaryl group, a 5-6 membered oxygen-containing monoheteroaryl group, and a 5-6 membered sulfur-containing monoheteroaryl group. The "nitrogen-containing heteroaryl group", "oxygen-containing heteroaryl group", "sulfur-containing heteroaryl group", "nitrogen-containing monoheteroaryl group", "oxygen-containing monoheteroaryl group", "sulfur-containing monoheteroaryl group" The base "optionally also contains one or more other heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur. Examples thereof include, but are not limited to, thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, triazolyl, tetrazolyl, oxadiazolyl A thiadiazolyl group or the like, or a pyridyl group, a pyridazinyl group, a pyrimidinyl group, a pyrazinyl group, a triazinyl group or the like, and a 5- to 10-membered cyclized group containing these groups.
本发明中，杂芳基(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)或另一杂芳基(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，和(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、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 PCTCN2019085535-appb-000052
Figure PCTCN2019085535-appb-000053
等。 In the present invention, a heteroaryl group (for example, a monoheteroaryl group) may be bonded to an aryl group (for example, a monocyclic aryl group such as a phenyl group), a heterocyclic group (for example, a monoheterocyclic group), or a cycloalkyl group (for example, a monocycloalkyl group). Or another heteroaryl group (e.g., another monoheteroaryl group) shares a concatenation structure formed by two adjacent atoms, and the point of attachment may be on any heteroaromatic ring or other ring, including but not limited to Mono)heteroaryl(mono)heteroaryl, (mono)heteroaryl(monocyclic)aryl, (mono)heteroaryl(mono)heterocyclyl, and (mono)heteroaryl Mono)cycloalkyl, for example 5-6 membered (mono)heteroaryl and 5-6 membered (mono)heteroaryl, 5-6 membered (mono)heteroarylphenyl, 5-6 (single) Heteroaryl and 5-6 membered (mono)heterocyclyl, or 5-6 membered (mono)heteroaryl and C 4-6 (mono)cycloalkyl (eg 5-6 membered heteroarylcyclobutyl) , 5-6 membered heteroaryl and cyclopentyl, 5-6 membered heteroarylcyclohexyl), examples of which include, but are not limited to, fluorenyl, isodecyl, oxazolyl, benzimidazole, quinoline Base, isoquinolyl,
Figure PCTCN2019085535-appb-000052
Figure PCTCN2019085535-appb-000053
Wait.
术语“芳基并杂芳基”是指芳基(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。The term "arylheteroaryl" refers to a cis-based group formed from an aryl group (eg, a monocyclic aryl group such as phenyl) and a heteroaryl group (eg, a monoheteroaryl group such as a 5-6 membered monoheteroaryl group). The group, its point of attachment to other groups may be on the aromatic ring or on the heteroaryl ring. The "arylheteroaryl" includes, but is not limited to, a monocyclic aryl-heteroaryl group. The term "9-12 membered arylheteroaryl" refers to an arylheteroaryl group containing a total of 9 to 12 ring atoms, such as a benzo 5-6 membered nitrogen-containing monoheteroaryl group.
术语“杂芳基并环烷基”是指杂芳基(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。 The term "heteroarylcycloalkyl" refers to a heterocyclic ring formed by a heteroaryl group (eg, a monoheteroaryl group, eg, a 5-6 membered monoheteroaryl group) and a cycloalkyl group (eg, a C4-6 cycloalkyl group). The group, its point of attachment to other groups may be on the heteroaryl ring or on the cycloalkyl group. The "heteroaryl-cycloalkyl" includes, but is not limited to, a monoheteroaryl-monocycloalkyl group. The term "9-10 membered heteroarylcycloalkyl" refers to a heteroarylcycloalkyl group containing a total of 9 to 10 ring atoms, for example, a 4-6 membered nitrogen-containing monoheteroaryl group and a C 4-6 single Cycloalkyl.
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。The term "substituted" means that one or more (eg, 1, 2, 3 or 4) hydrogens on the designated atom are replaced by the selection of the indicated group, provided that the specified atom is not exceeded. The normal valence of the current case and the substitution form a stable compound. Combinations of substituents and/or variables are permissible only if such combinations form stable compounds.
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)可单独和/或一起被独立地选择的取代基任选地替代。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取代基任选地替代。If a substituent is described as "optionally substituted with", the substituent may be 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) may be independently and/or together independently The selected substituents are optionally substituted. If the nitrogen 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 nitrogen (to the extent of any hydrogen present) may each independently be independently selected substituent Optionally substituted.
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。If a substituent is described as being "independently selected from" a group, each substituent is selected independently of the other. Thus, each substituent may be the same or different from another (other) substituent.
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。As used herein, the term "one or more" means one or more than one, such as two, three, four, five, six, seven, eight, nine, under reasonable conditions. Or 10 or so.
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。Unless otherwise indicated, a point of attachment of a substituent, as used herein, may come from any suitable position of the substituent.
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。 The invention also includes all pharmaceutically acceptable isotopic compounds of the compounds of the invention which are identical to the compounds of the invention, except that one or more atoms are of the same atomic number but differ in atomic mass or mass number in nature. Atomic mass or mass atom substitution. Examples of isotopes suitable for inclusion in the compounds of the invention include, but are not limited to, isotopes of hydrogen (e.g., 2 H, 3 H); isotopes of carbon (e.g., 11 C, 13 C, and 14 C); isotopes of chlorine (e.g. 36 Cl); isotope of fluorine (eg 18 F); isotopes of iodine (eg 123 I and 125 I); isotopes of nitrogen (eg 13 N and 15 N); isotopes of oxygen (eg 15 O, 17 O and 18 O) ); an isotope of phosphorus (eg, 32 P); and an isotope of sulfur (eg, 35 S). The term "stable isotopic derivative" means that one or more atoms in a compound of the invention are formed by atomic substitutions having the same atomic number but differing in atomic mass or mass number from the atomic mass or mass number prevailing in nature. Stable compound.
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：The term "stereoisomer" refers to an isomer of a compound formed by the inclusion of at least one asymmetric center. In a compound having one or more (eg, 1, 2, 3, or 4) asymmetric centers, which can produce a racemic mixture, a single enantiomer, a mixture of diastereomers, and Separate diastereomers. Specific individual molecules can also exist as geometric isomers (cis/trans). The compounds of the invention may exist as mixtures (often referred to as tautomers) of two or more different structural forms in rapid equilibrium. Representative examples of tautomers include keto-enol tautomers, phenol-keto tautomers, nitroso-oxime tautomers, imine-enamine tautomers Wait. For example, nitroso-oxime can be present in solution in the following tautomeric forms:
Figure PCTCN2019085535-appb-000054
Figure PCTCN2019085535-appb-000054
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。It is to be understood that the scope of the present application covers all such ratios in any ratio (eg, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99). %) isomer or a mixture thereof.
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。Unless otherwise indicated, the compounds of the invention are intended to be stereoisomers (including cis and trans isomers), optical isomers (such as R and S enantiomers), diastereomers. , geometric isomers, rotamers, conformers, atropisomers or mixtures thereof are present. The compounds of the invention may exhibit more than one type of isomerism and consist of a mixture thereof (e.g., a racemic mixture and a diastereomeric pair).
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。The invention encompasses all possible crystalline forms or polymorphs of the compounds of the invention, which may be a single polymorph or a mixture of more than one polymorph in any ratio. It will also be understood that certain compounds of the invention may exist in free form for treatment or, where appropriate, in the form of their pharmaceutically acceptable derivatives. In the present invention, pharmaceutically acceptable derivatives include, but are not limited to, pharmaceutically acceptable salts, solvates, metabolites or prodrugs which, after administration to a patient in need thereof, can be directly or indirectly A compound of the invention or a metabolite or residue thereof is provided. Thus, when reference is made herein to a "compound of the invention," it is also intended to encompass the various derivative forms described above for the compound.
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。适合的盐的综述参见Stahl及Wermuth的“Handbook of Pharmaceutical Salts:Properties,Selection,and Use”(Wiley-VCH,2002)。The pharmaceutically acceptable salts of the compounds of the present invention include the acid addition salts and base addition salts thereof. For a review of suitable salts, see "Handbook of Pharmaceutical Salts: Properties, Selection, and Use" by Stahl and Wermuth (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。"Pharmaceutically acceptable carrier" in the context of the present invention means a diluent, adjuvant, excipient or vehicle with which the therapeutic agent is administered, and which is suitable for contacting humans and/or within the scope of sound medical judgment. Tissues of other animals without excessive toxicity, irritation, allergic reactions, or other problems or complications corresponding to a reasonable benefit/risk ratio.
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。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, vegetable or synthetic origin, such as peanut oil, soybean oil, minerals. Oil, sesame oil, etc.
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。For these routes of administration, the pharmaceutical compositions of the invention may be administered in a suitable dosage form.
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。The term "effective amount" as used herein refers to an amount of a compound that, to a certain extent, relieves one or more symptoms of the condition being treated after administration.
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。The dosing regimen can be adjusted to provide the optimal desired response. For example, a single bolus may be administered, several divided doses may be administered over time, or the dose may be proportionally reduced or increased as indicated by the urgent need for treatment. It is noted that the dose value can vary with the type and severity of the condition to be alleviated and can include single or multiple doses. It is to be further understood that for any particular individual, the particular dosage regimen will be adjusted over time according to the individual needs and the professional judgment of the person administering the composition or the composition of the supervised composition.
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。The amount of the compound of the invention administered will depend on the severity of the individual, condition or condition being treated, the rate of administration, the handling of the compound, and the judgment of the prescribing physician. Generally, an effective dose will be from about 0.0001 to about 50 mg per kg body weight per day, for example from 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 from about 0.7 mg/day to about 700 mg/day. In some cases, a dose level that is not higher than the lower limit of the aforementioned range may be sufficient, while in other cases, a larger dose may still be employed without causing any harmful side effects, provided that the larger The dose is divided into several smaller doses to be administered throughout the day.
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。The amount of the compound of the present invention in the pharmaceutical composition may be from about 0.01 mg to about 1000 mg.
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。The term "treating" as used herein, unless otherwise indicated, means reversing, alleviating, inhibiting the progression of a condition or condition to which such a term applies, or the progression of one or more symptoms of such a condition or condition, Or preventing such a condition or condition, or one or more symptoms of such condition or condition.
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)。"Individual" as used herein includes human or non-human animals. Exemplary human individuals include a human individual (referred to as a patient) or a normal individual having a disease, such as the disease 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.).
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。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 such as water, methanol or ethanol. The amount of polar solvent, particularly water, may be present in stoichiometric or non-stoichiometric ratios.
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。Also included within the scope of the invention are metabolites of the compounds of the invention, i.e., substances formed in vivo upon administration of a compound of the invention. Such products may be produced, for example, by oxidation, reduction, hydrolysis, amidation, deamidation, esterification, delipidization, enzymatic hydrolysis, and the like of the administered compound. Accordingly, the invention includes metabolites of the compounds of the invention, including compounds obtained by contacting a compound of the invention with a mammal for a time sufficient to produce a metabolic product thereof.
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。The invention further includes within its scope prodrugs of the compounds of the invention, which are certain derivatives of the compounds of the invention which may themselves have less or no pharmacological activity, when administered to the body or The above compounds can be converted to the compounds of the invention having the desired activity by, for example, hydrolytic cleavage. Typically such prodrugs will be functional group derivatives of the compounds which are readily converted in vivo to the desired therapeutically active compound. Additional information on the use of prodrugs can be found in "Pro-drugs as Novel Delivery Systems", Volume 14, ACS Symposium Series (T. Higuchi and V. Stella) and "Bioreversible Carriers in Drug Design," Pergamon Press, 1987 ( Edited by EBRoche, American Pharmaceutical Association). Prodrugs of the invention may, for example, be known by those skilled in the art as "pro-moiety" (e.g., "Design of Prodrugs", H. Bundgaard (Elsevier, 1985))" It is prepared in place of the appropriate functional groups present in the compounds of the invention.
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。The invention also encompasses compounds of the invention containing a protecting group. In any process for preparing a compound of the invention, it may be necessary and/or desirable to protect sensitive groups or reactive groups on any of the molecules of interest, thereby forming a chemically protected form of the compounds of the invention. This can be achieved by conventional protecting groups such as those described in Protective Groups in Organic Chemistry, ed. JFW McOmie, Plenum Press, 1973; and TW Greene & P. GM Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991. Protecting groups, which are incorporated herein by reference. The protecting group can be removed at a suitable subsequent stage using methods known in the art.
本文用波浪线“～～”表示的结构式中的键意在表示，该结构表示顺式或反式异构体，或任意比例的顺式和反式异构体的混合物。Herein, the bond in the structural formula represented by the wavy line "~~" is intended to mean a cis or trans isomer, or a mixture of cis and trans isomers in any ratio.
本文用
Figure PCTCN2019085535-appb-000055
表示结构式中的键为单键或双键。 This article uses
Figure PCTCN2019085535-appb-000055
Indicates that the key in the formula is a single bond or a double bond.
本文用
Figure PCTCN2019085535-appb-000056
表示双键位置不确定，但仍保证其所在的环具有芳香性。 This article uses
Figure PCTCN2019085535-appb-000056
Indicates that the position of the double bond is uncertain, but still guarantees that the ring in which it is located is aromatic.
本文用“------”表示结构式中的键存在或不存在。This article uses "------" to indicate the presence or absence of a bond in the structural formula.
本文中所述“室温”是指15-30℃。As used herein, "room temperature" means 15-30 °C.
制备方法Preparation
化合物V-1的合成Synthesis of Compound V-1
Figure PCTCN2019085535-appb-000057
Figure PCTCN2019085535-appb-000057
R 2为氢，R 4、R 5、R 6如上述式V所定义，R 1如上述式V所定义，但不包含NO 2； R 2 is hydrogen, R 4 , R 5 , R 6 are as defined in the above formula V, and R 1 is as defined in the above formula V, but does not contain NO 2 ;
R 3选自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 2-8杂烷基、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、C(O)OR 30、C(O)NR 31R 32、NR 33C(O)R 34、NR 31R 32、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、S(O)R 35、S(O) 2R 35、S(O)NR 31R 32、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 2-8杂烷基、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元芳基并环烷基可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、C(O)OR 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； R 3 is selected from the group consisting of C 1-8 alkyl, C 1-8 haloalkyl, C 1-8 alkoxy, C 1-8 haloalkoxy, C 2-8 heteroalkyl, C 3-8 cycloalkyl, 4-10 membered heterocyclic group, C 6-12 aryl group, 5-10 membered heteroaryl group, 9-12 membered arylheterocyclyl group, 9-12 membered arylheteroaryl group, 9-12 membered aromatic Cycloalkylene, C(O)OR 30 , C(O)NR 31 R 32 , NR 33 C(O)R 34 , NR 31 R 32 , C(O)R 30 , OC(O)R 30 , OC(O)NR 31 R 32 , NR 33 C(O)NR 31 R 32 , NR 33 C(O)OR 30 , C(=NR 38 )NR 31 R 32 , NR 33 C(=NR 38 )NR 31 R 32 , S(O)R 35 , S(O) 2 R 35 , S(O)NR 31 R 32 , S(O) 2 NR 31 R 32 ; the C 1-8 alkyl group, C 1-8 Haloalkyl, C 1-8 alkoxy, C 1-8 haloalkoxy, C 2-8 heteroalkyl, C 3-8 cycloalkyl, 4-10 membered heterocyclyl, C 6-12 aryl, 5-10 membered heteroaryl, 9-12 membered arylheterocyclyl, 9-12 membered arylheteroaryl, 9-12 membered arylcycloalkyl can be optionally included in the following substituents One or more substitutions: 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 heterocyclyl, C 6-12 aryl 5-10 membered heteroaryl, 9-12 membered heterocyclyl, and aryl, C (O) OR 30, C (O) R 30, C (O) NR 31 R 32, NR 33 C (O) R 34 , NR 31 R 32 , S(O)R 35 , S(O) 2 R 35 , S(O)NR 31 R 32 , S(O) 2 NR 31 R 32 , OR 37 , SR 37 , OC(O) R 30 , OC(O)NR 31 R 32 , NR 33 C(O)NR 31 R 32 , NR 33 C(O)OR 30 , C(=NR 38 )NR 31 R 32 , NR 33 C(=NR 38 NR 31 R 32 , =NNR 31 R 32 ;
第一步：化合物V-1-1经溴化生成化合物V-1-2。First step: Compound V-1-1 is brominated to give compound V-1-2.
在一些实施方案中，可使用Br 2或者NBS等溴化试剂进行溴化反应。在一些实施方案中，反应在溶剂中进行，可使用的溶剂为DMF、CH 3COOH、THF、CH 3CN或DCM等。在一些实施方案中，反应温度为-20℃至180℃。 In some embodiments, the bromination reaction can be carried out using a brominating reagent such as Br 2 or NBS. In some embodiments, the reaction is carried out in a solvent, and the solvent that can be used is DMF, CH 3 COOH, THF, CH 3 CN or DCM, and the like. In some embodiments, the reaction temperature is from -20 °C to 180 °C.
第二步：化合物V-1-2经硝化反应生成化合物V-1-3。The second step: the compound V-1-2 is subjected to nitration to form a compound V-1-3.
在一些实施方案中，可使用浓硝酸、发烟硝酸、四丁基硝酸铵等硝化剂进行硝化反应。在一些实施方案中，反应在溶剂中进行，可使用的溶剂为乙酸、丙酸或丁酸等。在一些实施方案中，反应温度为100℃至150℃。In some embodiments, the nitration reaction can be carried out using a nitrating agent such as concentrated nitric acid, fuming nitric acid, tetrabutylammonium nitrate or the like. In some embodiments, the reaction is carried out in a solvent, and the solvent that can be used is acetic acid, propionic acid or butyric acid, and the like. In some embodiments, the reaction temperature is from 100 °C to 150 °C.
第三步：化合物V-1-3被氯代成化合物V-1-4。The third step: Compound V-1-3 is chlorinated to compound V-1-4.
在一些实施方案中，可使用POCl 3、PCl 3或PCl 5等氯化剂进行氯代反应。在一些实施方案中，反应在溶剂中进行，可使用的溶剂为DCM或DCE等。在一些实施方案中，反应在无溶剂条件下进行。在一些实施方案中，反应温度为rt至110℃。 In some embodiments, the chlorination reaction can be carried out using a chlorinating agent such as POCl 3 , PCl 3 or PCl 5 . In some embodiments, the reaction is carried out in a solvent, and the solvent that can be used is DCM or DCE or the like. In some embodiments, the reaction is carried out in the absence of solvent. In some embodiments, the reaction temperature is from rt to 110 °C.
第四步：化合物V-1-4经过碘取代反应生成化合物V-1-5。The fourth step: Compound V-1-4 is subjected to iodine substitution reaction to give compound V-1-5.
在一些实施方案中，可使用KI或NaI等碘试剂进行碘取代反应。在一些实施方案中，反应在溶剂中进行，可使用的溶剂为THF、CH 3CN或1,4-二氧六环等。在一些实施方案中，反应温度为rt至100℃。 In some embodiments, an iodine substitution reaction can be carried out using an iodine reagent such as KI or NaI. In some embodiments, the reaction is carried out in a solvent, and the solvent that can be used is THF, CH 3 CN or 1,4-dioxane, and the like. In some embodiments, the reaction temperature is from rt to 100 °C.
第五步：化合物V-1-5被还原为化合物V-1-6。Fifth step: Compound V-1-5 was reduced to compound V-1-6.
在一些实施方案中，可使用连二亚硫酸钠、SnCl 2、Fe或Zn等还原剂进行还原反应。在一些实施方案中，反应在溶剂中进行，可使用的溶剂为MeOH、EtOH、THF或1,4-二氧六环等。在一些实施方案中，反应温度为0℃至110℃。 In some embodiments, the reduction reaction can be carried out using a reducing agent such as sodium dithionite, SnCl 2 , Fe or Zn. In some embodiments, the reaction is carried out in a solvent, and the solvent that can be used is MeOH, EtOH, THF or 1,4-dioxane, and the like. In some embodiments, the reaction temperature is from 0 °C to 110 °C.
第六步：化合物V-1-6在碱性条件下经氨基保护反应生成化合物V-1-7。The sixth step: the compound V-1-6 is subjected to an amino-protective reaction under basic conditions to give a compound V-1-7.
在一些实施方案中，可使用(Boc) 2O等氨基保护试剂进行反应。在一些实施方案中，可使用 tBuOK、 tBuONa、 tBuOLi、NaH、NaOH、KOH、Cs 2CO 3、K 2CO 3或Na 2CO 3等碱进行反应。在一些实施方案中，反应在溶剂中进行，可使用的溶剂为THF、DCM、DCE、 CH 3CN、1,4-二氧六环或DMF等。在一些实施方案中，反应温度为0℃至160℃。 In some embodiments, the reaction can be carried out using an amino protecting reagent such as (Boc) 2 O. In some embodiments, the reaction can be carried out using a base such as t BuOK, t BuONa, t BuOLi, NaH, NaOH, KOH, Cs 2 CO 3 , K 2 CO 3 or Na 2 CO 3 . , In some embodiments, the reaction is carried out in a solvent, the solvent may be used are THF, DCM, DCE, CH 3 CN, 1,4-dioxane and the like or DMF. In some embodiments, the reaction temperature is from 0 °C to 160 °C.
第七步：化合物V-1-7与R 3-炔烃在催化剂、亚铜盐和碱作用下经偶联反应(例如Sonogashira反应)生成化合物V-1-8。 The seventh step: the compound V-1-7 and the R 3 -alkyne are subjected to a coupling reaction (for example, Sonogashira reaction) under the action of a catalyst, a cuprous salt and a base to form a compound V-1-8.
在一些实施方案中，可使用的催化剂为Pd(PPh 3) 4或Pd(PPh 3)Cl 2等在一些实施方案中，可使用的碱为Et 2NH、TEA或DIPEA等。在一些实施方案中，反应在溶剂中进行，可使用的溶剂为1,4-二氧六环、CH 3CN或EA等。在一些实施方案中，可使用的亚铜盐为CuI、CuBr或CuCl等。在一些实施方案中，反应温度为-20℃至100℃。 In some embodiments, the catalyst that can be used is Pd(PPh 3 ) 4 or Pd(PPh 3 )Cl 2 , etc. In some embodiments, the base that can be used is Et 2 NH, TEA or DIPEA, and the like. In some embodiments, the reaction is carried out in a solvent, and the solvent that can be used is 1,4-dioxane, CH 3 CN or EA, and the like. In some embodiments, the cuprous salt that can be used is CuI, CuBr, CuCl, and the like. In some embodiments, the reaction temperature is from -20 °C to 100 °C.
第八步：化合物V-1-8在碱性条件下关环生成产物V-1-9。Step 8: Compound V-1-8 is cleaved under basic conditions to give the product V-1-9.
在一些实施方案中，可DBU、TEA、DIPEA、 tBuOK、 tBuONa、 tBuOLi、NaOH、Cs 2CO 3、K 3PO 4或Na 2CO 3等碱进行反应。在一些实施方案中，反应在溶剂中进行，可使用的溶剂为THF/H 2O、MeOH/H 2O、EtOH/H 2O、DMF/H 2O、DMSO/H 2O、CH 3CN/H 2O或1,4-二氧六环/H 2O等。在一些实施方案中，反应温度为rt至120℃。 In some embodiments, the reaction can be carried out with a base such as DBU, TEA, DIPEA, t BuOK, t BuONa, t BuOLi, NaOH, Cs 2 CO 3 , K 3 PO 4 or Na 2 CO 3 . In some embodiments, the reaction is carried out in a solvent, and the solvent that can be used is THF/H 2 O, MeOH/H 2 O, EtOH/H 2 O, DMF/H 2 O, DMSO/H 2 O, CH 3 CN /H 2 O or 1,4-dioxane/H 2 O, and the like. In some embodiments, the reaction temperature is from rt to 120 °C.
第九步：化合物V-1-9在碱性条件下与R 6-Cl(或R 6-Br)反应生成化合物V-1-10。 Step 9: Compound V-1-9 is reacted with R 6 -Cl (or R 6 -Br) under basic conditions to give compound V-1-10.
在一些实施方案中，可使用 tBuOK、 tBuONa、 tBuOLi、NaH、NaOH、KOH、Cs 2CO 3、K 2CO 3或Na 2CO 3等碱进行反应。在一些实施方案中，反应在溶剂中进行，可使用的溶剂为THF、DCM、CH 3CN、1,4-二氧六环或DMF等。在一些实施方案中，反应温度为0℃至160℃。 In some embodiments, the reaction can be carried out using a base such as t BuOK, t BuONa, t BuOLi, NaH, NaOH, KOH, Cs 2 CO 3 , K 2 CO 3 or Na 2 CO 3 . In some embodiments, the reaction is carried out in a solvent, and the solvent that can be used is THF, DCM, CH 3 CN, 1,4-dioxane or DMF, and the like. In some embodiments, the reaction temperature is from 0 °C to 160 °C.
第十步：化合物V-1-10被氧化生成化合物V-1-11。Step 10: Compound V-1-10 is oxidized to give compound V-1-11.
在一些实施方案中，可使用m-CPBA、H 2O 2或CH 3COOOH等氧化剂进行反应。在一些实施方案中，反应在溶剂中进行，可使用的溶剂为DCM、DCE、CHCl 3或DMF等。在一些实施方案中，反应温度为0℃至100℃。 In some embodiments, the reaction can be carried out using an oxidizing agent such as m-CPBA, H 2 O 2 or CH 3 COOOH. In some embodiments, the reaction is carried out in a solvent, and the solvent that can be used is DCM, DCE, CHCl 3 or DMF, and the like. In some embodiments, the reaction temperature is from 0 °C to 100 °C.
第十一步：化合物V-1-11在碱和催化剂作用下与NHR 4R 5反应生成化合物V-1-12。 Eleventh step: Compound V-1-11 is reacted with NHR 4 R 5 under the action of a base and a catalyst to form compound V-1-12.
在一些实施方案中，可使用的催化剂为TsCl等。在一些实施方案中，可使用的碱为TEA或DIPEA等。在一些实施方案中，反应在溶剂中进行，溶剂为DCM、CHCl 3或DCE等。在一些实施方案中，反应温度为0℃至100℃。 In some embodiments, the catalyst that can be used is TsCl or the like. In some embodiments, the base that can be used is TEA or DIPEA, and the like. In some embodiments, the reaction is carried out in a solvent such as DCM, CHCl 3 or DCE, and the like. In some embodiments, the reaction temperature is from 0 °C to 100 °C.
第十二步：化合物V-1-12与R 1-Y经偶联反应、取代反应，或V-1-12经还原反应生成化合物V-1。 Step 12: Compound V-1-12 is reacted with R 1 -Y by a coupling reaction, a substitution reaction, or V-1-12 is reduced to form compound V-1.
当Y为硼酸或硼酸酯，R 1不为H、CN或卤素时，V-1-12与R 1-Y经Suzuki偶联反应生成化合物V-1。在一些实施方案中，可使用Pd(PPh 3) 4或Pd(dppf)Cl 2等催化剂进行反应。在一些实施方案中，可使用Cs 2CO 3、K 3PO 4、Na 2CO 3、AcOK、NaHCO 3或K 2CO 3等碱进行反应。在一些实施方案中，反应在溶剂中进行，溶剂为1,4-二氧六环/H 2O、DMF/H 2O、DMSO/H 2O、CH 3CN/H 2O或甲苯/H 2O等。在一些实施方案中，反应温度为60℃至160℃。 When Y is a boric acid or a boric acid ester and R 1 is not H, CN or a halogen, V-1-12 and R 1 -Y are subjected to a Suzuki coupling reaction to form a compound V-1. In some embodiments, the reaction can be carried out using a catalyst such as Pd(PPh 3 ) 4 or Pd(dppf)Cl 2 . In some embodiments, the reaction can be carried out using a base such as Cs 2 CO 3 , K 3 PO 4 , Na 2 CO 3 , AcOK, NaHCO 3 or K 2 CO 3 . In some embodiments, the reaction is carried out in a solvent such as 1,4-dioxane/H 2 O, DMF/H 2 O, DMSO/H 2 O, CH 3 CN/H 2 O or toluene/H. 2 O and so on. In some embodiments, the reaction temperature is from 60 °C to 160 °C.
当Y为H，R 1不为H、CN或卤素时，V-1-12与R 1-Y经偶联反应(如Ullmann反应、 Heck反应、Buchwald-Hartwig反应或Sonogashira反应等)生成化合物V-1。在一些实施方案中，可使用Cu、Cu 2O、CuI、CuBr、CuCl、PdCl 2、Pd(OAc) 2、Pd(PPh 3) 4或Pd(PPh 3) 2Cl 2等催化剂进行反应。在一些实施方案中，可使用Cs 2CO 3、K 3PO 4、Na 2CO 3、AcOK、TEA、NaHCO 3或K 2CO 3等碱进行反应。在一些实施方案中，可使用N,N'-二甲基乙二胺、N,N'-二甲基-1,2-环己二胺、PPh 3或XPhos等配体进行反应。在一些实施方案中，反应在溶剂中进行，溶剂为1,4-二氧六环、EA、DMF、DMSO、CH 3CN或甲苯等。在一些实施方案中，反应温度为60℃至160℃。 When Y is H and R 1 is not H, CN or halogen, V-1-12 is reacted with R 1 -Y by a coupling reaction (such as Ullmann reaction, Heck reaction, Buchwald-Hartwig reaction or Sonogashira reaction) to form compound V. -1. In some embodiments, the reaction can be carried out using a catalyst such as Cu, Cu 2 O, CuI, CuBr, CuCl, PdCl 2 , Pd(OAc) 2 , Pd(PPh 3 ) 4 or Pd(PPh 3 ) 2 Cl 2 . In some embodiments, the reaction can be carried out using a base such as Cs 2 CO 3 , K 3 PO 4 , Na 2 CO 3 , AcOK, TEA, NaHCO 3 or K 2 CO 3 . In some embodiments, may be used N, N'- dimethylethylenediamine, N, N'- dimethyl-1,2-cyclohexanediamine, PPh 3 or other ligands XPhos reaction. , Reaction is carried out in a solvent in some embodiments, the solvent is 1,4-dioxane, EA, DMF, DMSO, CH 3 CN or toluene. In some embodiments, the reaction temperature is from 60 °C to 160 °C.
当Y为ZnCl 2、ZnBr 2或ZnI 2，R 1不为H、CN或卤素时，V-1-12与R 1-Y经Negishi反应生成化合物V-1。在一些实施方案中，可使用Pd(OAc) 2或Pd(PPh 3) 4等催化剂进行反应。在一些实施方案中，可使用PPh 3等配体进行反应。在一些实施方案中，反应在溶剂中进行，可使用的溶剂为DMF或NMP等。在一些实施方案中，反应温度为0℃至160℃。 When Y is ZnCl 2 , ZnBr 2 or ZnI 2 and R 1 is not H, CN or halogen, V-1-12 and R 1 -Y are reacted by Negishi to form compound V-1. In some embodiments, the reaction can be carried out using a catalyst such as Pd(OAc) 2 or Pd(PPh 3 ) 4 . In some embodiments, using a ligand such as PPh 3 reaction. In some embodiments, the reaction is carried out in a solvent, and the solvent that can be used is DMF or NMP or the like. In some embodiments, the reaction temperature is from 0 °C to 160 °C.
当Y为有机锡化合物(例如Sn(n-Bu) 3)，R 1不为H、CN或卤素时，V-1-12与R 1-Y经Stille反应生成化合物V-1。在一些实施方案中，可使用PdCl 2、Pd(OAc) 2或Pd(PPh 3) 2Cl 2等催化剂进行反应。在一些实施方案中，可使用PPh 3等配体进行反应。在一些实施方案中，反应在溶剂中进行，可使用的溶剂为1,4-二氧六环、THF或CH 3CN等。在一些实施方案中，反应温度为0℃至160℃。 When Y is an organotin compound (for example, Sn(n-Bu) 3 ), and R 1 is not H, CN or halogen, V-1-12 and R 1 -Y are reacted by Stille to form compound V-1. In some embodiments, the reaction can be carried out using a catalyst such as PdCl 2 , Pd(OAc) 2 or Pd(PPh 3 ) 2 Cl 2 . In some embodiments, using a ligand such as PPh 3 reaction. In some embodiments, the reaction is carried out in a solvent, and the solvent that can be used is 1,4-dioxane, THF or CH 3 CN, and the like. In some embodiments, the reaction temperature is from 0 °C to 160 °C.
当Y为Na或K，R 1为CN时，V-1-12与R 1-Y经取代反应生成化合物V-1。在一些实施方案中，反应在溶剂中进行，可使用的溶剂为1,4-二氧六环、THF或CH 3CN等。在一些实施方案中，反应温度为0℃至110℃。 When Y is Na or K and R 1 is CN, V-1-12 and R 1 -Y are substituted to form compound V-1. In some embodiments, the reaction is carried out in a solvent, and the solvent that can be used is 1,4-dioxane, THF or CH 3 CN, and the like. In some embodiments, the reaction temperature is from 0 °C to 110 °C.
V-1-12经还原反应生成化合物V-1(R 1为H)。 V-1-12 is reduced to give compound V-1 (R 1 is H).
在一些实施方案中，可使用Pd或Pd(OH) 2等还原剂进行反应。在一些实施方案中，反应在溶剂中进行，可使用的溶剂为1,4-二氧六环、THF、甲醇、乙醇或甲苯等。在一些实施方案中，反应温度为0℃至100℃。 In some embodiments, the reaction can be carried out using a reducing agent such as Pd or Pd(OH) 2 . In some embodiments, the reaction is carried out in a solvent, and the solvent that can be used is 1,4-dioxane, THF, methanol, ethanol or toluene, and the like. In some embodiments, the reaction temperature is from 0 °C to 100 °C.
化合物VI-1的合成Synthesis of Compound VI-1
Figure PCTCN2019085535-appb-000058
Figure PCTCN2019085535-appb-000058
Figure PCTCN2019085535-appb-000059
Figure PCTCN2019085535-appb-000059
R 1、R 2、R 3、R 4、R 5如上述式VI所定义，但R 1不包含NO 2，R 3不包含卤素、OH、CN和NO 2。 R 1 , R 2 , R 3 , R 4 and R 5 are as defined in the above formula VI, but R 1 does not contain NO 2 , and R 3 does not contain halogen, OH, CN and NO 2 .
第一步：化合物VI-1-1发生硝化反应生成化合物VI-1-2。The first step: the compound VI-1-1 is nitrated to form compound VI-1-2.
在一些实施方案中，可使用浓硝酸、发烟硝酸、四丁基硝酸铵等硝化剂进行反应。在一些实施方案中，反应在溶剂中进行，可使用的溶剂为乙酸、丙酸或丁酸等。在一些实施方案中，反应温度为100℃至150℃。In some embodiments, the reaction can be carried out using a nitrating agent such as concentrated nitric acid, fuming nitric acid, tetrabutylammonium nitrate or the like. In some embodiments, the reaction is carried out in a solvent, and the solvent that can be used is acetic acid, propionic acid or butyric acid, and the like. In some embodiments, the reaction temperature is from 100 °C to 150 °C.
第二步：化合物VI-1-2被氯代成化合物VI-1-3。The second step: Compound VI-1-2 is chlorinated to compound VI-1-3.
在一些实施方案中，可使用POCl 3、PCl 3或PCl 5等氯化剂进行反应。在一些实施方案中，反应在溶剂中进行，可使用的溶剂为DCM或DCE等。在一些实施方案中，反应在无溶剂条件下进行。在一些实施方案中，反应温度为rt至110℃。 In some embodiments, the reaction can be carried out using a chlorinating agent such as POCl 3 , PCl 3 or PCl 5 . In some embodiments, the reaction is carried out in a solvent, and the solvent that can be used is DCM or DCE or the like. In some embodiments, the reaction is carried out in the absence of solvent. In some embodiments, the reaction temperature is from rt to 110 °C.
第三步：化合物VI-1-3与R 2-NH 2在碱作用下经取代反应生成化合物VI-1-4。 The third step: the compound VI-1-3 and R 2 -NH 2 are subjected to a substitution reaction under a base to form a compound VI-1-4.
在一些实施方案中，可使用的碱为TEA或DIPEA等。在一些实施方案中，反应在溶剂中进行，可使用的溶剂为NMP或DMF等。在一些实施方案中，反应温度为0℃至180℃。In some embodiments, the base that can be used is TEA or DIPEA, and the like. In some embodiments, the reaction is carried out in a solvent, and the solvent that can be used is NMP or DMF or the like. In some embodiments, the reaction temperature is from 0 °C to 180 °C.
第四步：化合物VI-1-4被还原为化合物VI-1-5。Fourth step: Compound VI-1-4 was reduced to compound VI-1-5.
在一些实施方案中，可使用连二亚硫酸钠、SnCl 2、Fe、Zn或Pd/C等还原剂进行反应。在一些实施方案中，反应在溶剂中进行，可使用的溶剂为MeOH、EtOH、THF或1,4-二氧六环等。在一些实施方案中，反应温度为rt至110℃。 In some embodiments, the reaction can be carried out using a reducing agent such as sodium dithionite, SnCl 2 , Fe, Zn, or Pd/C. In some embodiments, the reaction is carried out in a solvent, and the solvent that can be used is MeOH, EtOH, THF or 1,4-dioxane, and the like. In some embodiments, the reaction temperature is from rt to 110 °C.
第五步：化合物VI-1-5与R 3-COOH在碱性条件下经缩合反应生成化合物VI-1-6，或者VI-1-5在碱作用下直接与R 3-COCl反应生成VI-1-6。 Step 5: Compound VI-1-5 is reacted with R 3 -COOH under basic conditions to form compound VI-1-6, or VI-1-5 is directly reacted with R 3 -COCl under alkali to form VI -1-6.
在一些实施方案中，可使用HATU、DCC/NHS、EDCI/HOBt或HBTU等缩合剂进行反应。在一些实施方案中，可使用的碱为TEA或DIPEA等。在一些实施方案中，反应在溶剂中进行，可使用的溶剂为THF、DCM、DCE、CH 3CN、1,4-二氧六环或DMF等。 在一些实施方案中，反应温度为0℃至160℃。 In some embodiments, the reaction can be carried out using a condensing agent such as HATU, DCC/NHS, EDCI/HOBt or HBTU. In some embodiments, the base that can be used is TEA or DIPEA, and the like. , In some embodiments, the reaction is carried out in a solvent, the solvent may be used are THF, DCM, DCE, CH 3 CN, 1,4-dioxane and the like or DMF. In some embodiments, the reaction temperature is from 0 °C to 160 °C.
第六步：化合物VI-1-6在碱性条件下关环，然后溴化生成化合物VI-1-7。Step 6: Compound VI-1-6 is subjected to ring closure under basic conditions and then brominated to give compound VI-1-7.
在一些实施方案中，可TEA或DIPEA等碱进行关环反应。在一些实施方案中，关环反应在溶剂中进行，可使用的溶剂为MeOH、EtOH、THF、CH 3CN或1,4-二氧六环等。在一些实施方案中，反应温度为60℃至100℃。在一些实施方案中，可使用溴素、NBS、二溴海因等溴化剂进行溴化反应。在一些实施方案中，溴化反应在溶剂中进行，可使用的溶剂为乙酸、1,4-二氧六环、DMF和EA等。在一些实施方案中，反应温度为-20℃至100℃。 In some embodiments, a ring closure reaction can be carried out with a base such as TEA or DIPEA. In some embodiments, the ring closure reaction is carried out in a solvent, and the solvent that can be used is MeOH, EtOH, THF, CH 3 CN or 1,4-dioxane, and the like. In some embodiments, the reaction temperature is from 60 °C to 100 °C. In some embodiments, the bromination reaction can be carried out using a brominating agent such as bromine, NBS, dibromohydantoin or the like. In some embodiments, the bromination reaction is carried out in a solvent, and the solvents that can be used are acetic acid, 1,4-dioxane, DMF, EA, and the like. In some embodiments, the reaction temperature is from -20 °C to 100 °C.
第七步：化合物VI-1-7被氧化为化合物VI-1-8。Step 7: Compound VI-1-7 is oxidized to compound VI-1-8.
在一些实施方案中，可使用m-CPBA、H 2O 2或CH 3COOOH等氧化剂进行反应。在一些实施方案中，反应在溶剂中进行，可使用的溶剂为DCM、DCE、CHCl 3或DMF等。在一些实施方案中，反应温度为0℃至160℃。 In some embodiments, the reaction can be carried out using an oxidizing agent such as m-CPBA, H 2 O 2 or CH 3 COOOH. In some embodiments, the reaction is carried out in a solvent, and the solvent that can be used is DCM, DCE, CHCl 3 or DMF, and the like. In some embodiments, the reaction temperature is from 0 °C to 160 °C.
第八步：化合物VI-1-8在碱和活化剂作用下与NHR 4R 5反应生成化合物VI-1-9。 Step 8: Compound VI-1-8 is reacted with NHR 4 R 5 under the action of a base and an activator to give compound VI-1-9.
在一些实施方案中，可使用的活化剂为TsCl、Ts 2O等，在一些实施方案中，可使用的碱为TEA或DIPEA等。在一些实施方案中，反应在溶剂中进行，可使用的溶剂为DCM、CHCl 3或DCE等。在一些实施方案中，反应温度为0℃至80℃。 In some embodiments, the activator that can be used is TsCl, Ts 2 O, and the like, and in some embodiments, the base that can be used is TEA or DIPEA, and the like. In some embodiments, the reaction is carried out in a solvent, and the solvent that can be used is DCM, CHCl 3 or DCE, and the like. In some embodiments, the reaction temperature is from 0 °C to 80 °C.
第九步：化合物VI-1-9与R 1-Y可经偶联反应、取代反应或VI-1-9经还原反应生成化合物VI-1。在一些实施方案中，反应条件与V-1第十二步的反应条件相同。 The ninth step: the compound VI-1-9 and R 1 -Y can be subjected to a coupling reaction, a substitution reaction or a reduction reaction of VI-1-9 to form a compound VI-1. In some embodiments, the reaction conditions are the same as those of the twelfth step of V-1.
化合物VI的合成Synthesis of Compound VI
Figure PCTCN2019085535-appb-000060
Figure PCTCN2019085535-appb-000060
R 1、R 2、R 3、R 4、R 5如前述通式VI所定义，但R 1不包含NO 2； R 1 , R 2 , R 3 , R 4 , R 5 are as defined in the above formula VI, but R 1 does not contain NO 2 ;
L如前述式VI所定义，但n+p+q不为0，且-LR 3以碳原子和-COOH或-COCl相连。 L is as defined in the above formula VI, but n+p+q is not 0, and -LR 3 is bonded to -COOH or -COCl as a carbon atom.
第一步：化合物VI-1-5与R 3-L-COOH可在碱性条件下经缩合反应生成化合物VI-2-1， 或者VI-1-5在碱作用下直接与R 3-L-COCl反应生成VI-2-1，在一些实施方案中，反应条件如VI-1的合成第五步所述。 The first step: compound VI-1-5 and R 3 -L-COOH can be subjected to condensation reaction under basic conditions to form compound VI-2-1, or VI-1-5 can directly react with R 3 -L under the action of a base. The -COCl reaction produces VI-2-1, and in some embodiments, the reaction conditions are as described in the fifth step of the synthesis of VI-1.
第二步：化合物VI-2-1在碱性条件下关环生成化合物VI-2-2。The second step: Compound VI-2-1 is subjected to ring closure under basic conditions to give compound VI-2-2.
在一些实施方案中，可使用NaOH、KOH、TEA或DIPEA等碱进行反应。在一些实施方案中，反应在溶剂中进行，可使用的溶剂为MeOH、EtOH、THF、CH 3CN或1,4-二氧六环等。在一些实施方案中，反应温度为60℃至100℃。 In some embodiments, the reaction can be carried out using a base such as NaOH, KOH, TEA or DIPEA. In some embodiments, the reaction is carried out in a solvent, and the solvent that can be used is MeOH, EtOH, THF, CH 3 CN or 1,4-dioxane, and the like. In some embodiments, the reaction temperature is from 60 °C to 100 °C.
第三步：化合物VI-2-2经溴化反应生成化合物VI-2-3。The third step: the compound VI-2-2 is brominated to form the compound VI-2-3.
在一些实施方案中，可使用溴素、NBS和二溴海因等溴化剂进行反应。在一些实施方案中，反应在溶剂中进行，可使用的溶剂为乙酸、1,4-二氧六环、DMF和EA等。在一些实施方案中，反应温度为-20℃至100℃。In some embodiments, the reaction can be carried out using a brominating agent such as bromine, NBS, and dibromohydantoin. In some embodiments, the reaction is carried out in a solvent, and the solvents that can be used are acetic acid, 1,4-dioxane, DMF, EA, and the like. In some embodiments, the reaction temperature is from -20 °C to 100 °C.
第四步：化合物VI-2-3被氧化生成化合物VI-2-4，在一些实施方案中，反应条件如VI-1第七步所述。Fourth step: Compound VI-2-3 is oxidized to form compound VI-2-4. In some embodiments, the reaction conditions are as described in step 7 of VI-1.
第五步：化合物VI-2-4在碱和活化剂作用下与NHR 4R 5反应生成化合物VI-2-5，在一些实施方案中，反应条件如VI-1的合成第八步所述。 Step 5: Compound VI-2-4 is reacted with NHR 4 R 5 under the action of a base and an activator to form compound VI-2-5. In some embodiments, the reaction conditions are as described in the eighth step of the synthesis of VI-1. .
第六步：化合物VI-2-5与R 1-Y经偶联反应、取代反应或VI-2-5经还原反应生成化合物VI，在一些实施方案中，反应条件如V-1的合成第十二步所述。 Step 6: Compound VI-2-5 and R 1 -Y are subjected to a coupling reaction, a substitution reaction or a reduction reaction of VI-2-5 to form compound VI. In some embodiments, the reaction conditions are as described in the synthesis of V-1. The twelve steps are described.
化合物VI-2的合成Synthesis of Compound VI-2
Figure PCTCN2019085535-appb-000061
Figure PCTCN2019085535-appb-000061
R 1、R 2、R 4、R 5如前述通式VI所定义，但R 1不包含NO 2； R 1 , R 2 , R 4 , R 5 are as defined in the above formula VI, but R 1 does not contain NO 2 ;
R 3a为NR 31R 32、OR 37或SR 37； R 3a is NR 31 R 32 , OR 37 or SR 37 ;
L如前述式VI所定义，但n+p+q不为0，且-LR 3a以碳原子和VI-2的咪唑基相连； L is as defined in the above formula VI, but n+p+q is not 0, and -LR 3a is bonded to the imidazole group of VI-2 by a carbon atom;
R 31、R 32、R 37如前述通式I所定义； R 31 , R 32 and R 37 are as defined in the above formula I;
R 41为OPG，PG为Bn、DMB、PMB、Me、Et、Pr等；W选自氯、溴和碘。 R 41 is OPG, PG is Bn, DMB, PMB, Me, Et, Pr, etc.; and W is selected from chlorine, bromine and iodine.
第一步：化合物VI-2-5a在酸性条件下脱保护基生成化合物VI-2-6。First step: Compound VI-2-5a deprotects under acidic conditions to give compound VI-2-6.
在一些实施方案中，可使用BBr 3、AlCl 3、FeCl 3、或CF 3COOH等酸进行反应。在一些实施方案中，反应在溶剂中进行，可使用的溶剂为THF、DCM、DCE、CH 3CN或1,4-二氧六环等。在一些实施方案中，反应温度为20℃至160℃。 In some embodiments, the reaction can be carried out using an acid such as BBr 3 , AlCl 3 , FeCl 3 , or CF 3 COOH. In some embodiments, the reaction is carried out in a solvent, and the solvent that can be used is THF, DCM, DCE, CH 3 CN or 1,4-dioxane, and the like. In some embodiments, the reaction temperature is from 20 °C to 160 °C.
第二步：化合物VI-2-6经卤代反应生成化合物VI-2-7。在一些实施方案中，可使用二氯亚砜、PCl 3、PCl 5、PBr 3或HI等卤代剂进行反应。在一些实施方案中，反应在溶剂中进行，可使用的溶剂为THF、DCM、DCE或1,4-二氧六环等。在一些实施方案中，反应温度为20℃至120℃。 The second step: the compound VI-2-6 is halogenated to give the compound VI-2-7. In some embodiments, the reaction can be carried out using a halogenating agent such as thionyl chloride, PCl 3 , PCl 5 , PBr 3 or HI. In some embodiments, the reaction is carried out in a solvent, and the solvent that can be used is THF, DCM, DCE or 1,4-dioxane, and the like. In some embodiments, the reaction temperature is from 20 °C to 120 °C.
第三步：化合物VI-2-7在碱和相转移催化剂存在下和HR 3a反应生成化合物VI-2-8。 Third step: Compound VI-2-7 is reacted with HR 3a in the presence of a base and a phase transfer catalyst to form compound VI-2-8.
在一些实施方案中，可使用的相转移催化剂为18-冠-6-醚、苄基三乙基氯化铵(TEBA)、四丁基碘化铵、四丁基溴化铵(TBAB)、四丁基氯化铵、四丁基硫酸氢铵、三辛基甲基氯化铵、十二烷基三甲基氯化铵或十四烷基三甲基氯化铵等，在一些实施方案中，可使用的碱为NaOH、KOH、TEA或DIPEA等。在一些实施方案中，反应在溶剂中进行，可使用的溶剂为甲苯、DCM、CHCl 3或DCE等。在一些实施方案中，反应温度为20℃至160℃。 In some embodiments, phase transfer catalysts that can be used are 18-crown-6-ether, benzyltriethylammonium chloride (TEBA), tetrabutylammonium iodide, tetrabutylammonium bromide (TBAB), Tetrabutylammonium chloride, tetrabutylammonium hydrogen sulfate, trioctylmethylammonium chloride, dodecyltrimethylammonium chloride or tetradecyltrimethylammonium chloride, etc., in some embodiments Among them, the base which can be used is NaOH, KOH, TEA or DIPEA. In some embodiments, the reaction is carried out in a solvent, and the solvent that can be used is toluene, DCM, CHCl 3 or DCE, and the like. In some embodiments, the reaction temperature is from 20 °C to 160 °C.
第四步：化合物VI-2由化合物VI-2-8与R 1-Y经偶联反应、取代反应生成，或者由化合物VI-2-8经还原反应生成。在一些实施方案中，反应条件如V-1的合成第十二步所述。 The fourth step: the compound VI-2 is formed by a coupling reaction of a compound VI-2-8 with R 1 -Y, a substitution reaction, or a reduction reaction of the compound VI-2-8. In some embodiments, the reaction conditions are as described in the twelfth step of the synthesis of V-1.
化合物VI-3的合成Synthesis of Compound VI-3
Figure PCTCN2019085535-appb-000062
Figure PCTCN2019085535-appb-000062
R 1、R 2、R 4、R 5如上述式VI所定义，但R 1不包含NO 2； R 1 , R 2 , R 4 , R 5 are as defined in the above formula VI, but R 1 does not contain NO 2 ;
L如前述式VI所定义，但n+p+q不为0，且L的两端以碳原子分别与VI-3-1中的咪唑基和R 42相连； L is as defined in the above formula VI, but n+p+q is not 0, and both ends of L are bonded to the imidazolyl group and R 42 in VI-3-1 by a carbon atom;
R 33和R 34如前述通式I所定义； R 33 and R 34 are as defined in the above formula I;
R 42为
Figure PCTCN2019085535-appb-000063
R 42 is
Figure PCTCN2019085535-appb-000063
第一步：化合物VI-3-1在酸性条件下脱Boc生成化合物VI-3-2。First step: Compound VI-3-1 de Boc under acidic conditions to give compound VI-3-2.
在一些实施方案中，可使用HCl、硫酸或CF 3COOH等酸进行反应。在一些实施方案中，反应在溶剂中进行，可使用的溶剂为甲醇、乙醇、THF、DCM、DCE、CH 3CN或1,4-二氧六环等。在一些实施方案中，反应温度为0℃至100℃。 In some embodiments, using HCl, CF 3 COOH, or sulfuric acid and the like reactions. In some embodiments, the reaction is carried out in a solvent, and the solvent that can be used is methanol, ethanol, THF, DCM, DCE, CH 3 CN or 1,4-dioxane, and the like. In some embodiments, the reaction temperature is from 0 °C to 100 °C.
第二步：化合物VI-3-2与R 34COOH可在碱性条件下经缩合反应生成化合物VI-3，或者VI-3-2在碱作用下直接与R 34COCl反应生成VI-3,在一些实施方案中，反应条件如VI-1的合成第五步所述。 The second step: compound VI-3-2 and R 34 COOH can be reacted under basic conditions to form compound VI-3, or VI-3-2 can directly react with R 34 COCl to form VI-3 under the action of a base. In some embodiments, the reaction conditions are as described in the fifth step of the synthesis of VI-1.
化合物VI-4的合成Synthesis of Compound VI-4
Figure PCTCN2019085535-appb-000064
Figure PCTCN2019085535-appb-000064
R 1、R 2、R 3、R 4、R 5如上述式VI所定义，但R 1不包含NO 2； R 1 , R 2 , R 3 , R 4 , R 5 are as defined in the above formula VI, but R 1 does not contain NO 2 ;
L 1a为-NR 33b-、-O-或-S-； L 1a is -NR 33b -, -O- or -S-;
L 2a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-、-S(O)-、-S(O) 2-、-C(O)-、-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、5-10元亚杂芳基可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、C 1-4烷氧基； L 2a is 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 hydroxyalkylene, C 3-8 cycloalkylene, 4-10 membered heterocyclylene, C 6-12 arylene, 5-10 membered heteroarylene -O-, -S-, -NR 33 -, -S(O)-, -S(O) 2 -, -C(O)-, -C(R 36a R 36b )-; said C 1 -8 alkylene, C 2-8 alkenylene, C 2-8 alkynylene, C 1-8 haloalkylene, C 1-8 alkyleneoxy, C 1-8 haloalkylene oxide a group, a C 1-8 hydroxyalkylene group, a C 3-8 cycloalkylene group, a 4-10 membered heterocyclylene group, a C 6-12 arylene group, a 5-10 membered heteroarylene group, optionally Substituting one or more of the following substituents: halogen, OH, CN, NO 2 , C 1-6 alkyl, C 1-4 haloalkyl, C 1-4 hydroxyalkyl, C 1-4 alkoxy;
p为0或1；且当p为0时，R 3以C原子与L 1a相连；当p为1时，L 2a以C原子与L 1a相连； p is 0 or 1; and when p is 0, R 3 is bonded to L 1a by a C atom; when p is 1, L 2a is bonded to L 1a by a C atom;
R 33b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、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、C 3-8环烷基、4-10元杂环基、C 6-12芳基、5-10元杂芳基可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、5-10元杂芳基；所述C 6-12芳基可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。 R 33b is selected from the group consisting of H, C 1-8 alkyl, C 1-8 hydroxyalkyl, C 1-8 alkoxy, 4-10 membered heterocyclic, C 6-12 aryl, 5-10 membered heteroaryl a C 1-8 alkyl group, a C 1-8 hydroxyalkyl group, a C 1-8 alkoxy group, a C 3-8 cycloalkyl group, a 4-10 membered heterocyclic group, a C 6-12 aryl group, The 5-10 membered heteroaryl group can be 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 heterocyclyl, C 6-12 aryl, 5-10 membered heteroaryl; said C 6-12 The group may be optionally substituted by 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.
第一步：化合物VI-1-5与关环试剂反应生成化合物VI-4-1。First step: Compound VI-1-5 is reacted with a ring closure reagent to form compound VI-4-1.
在一些实施方案中，可使用的关环试剂为二硫化碳、硫代光气等，在一些实施方案中，反应在碱存在下进行，可使用的碱为TEA或DIPEA等。在一些实施方案中，反应在溶剂中进行，可使用的溶剂为THF、DCM、DCE、CH 3CN、1,4-二氧六环或DMF等。在一些实施方案中，反应温度为0℃至160℃。 In some embodiments, the ring-closing reagent that can be used is carbon disulfide, thiophosgene, etc., in some embodiments, the reaction is carried out in the presence of a base, and the base that can be used is TEA or DIPEA, and the like. , In some embodiments, the reaction is carried out in a solvent, the solvent may be used are THF, DCM, DCE, CH 3 CN, 1,4-dioxane and the like or DMF. In some embodiments, the reaction temperature is from 0 °C to 160 °C.
第二步：化合物VI-4-1在碱性条件下与W-R 43反应生成化合物VI-4-2。 The second step: Compound VI-4-1 is reacted with WR 43 under basic conditions to form compound VI-4-2.
W-R 43为烷基化试剂，其中W为氯、溴、碘，R 43选自C 1-8烷基、C 1-8羟烷基、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；所述C 1-8烷基、C 1-8羟烷基、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元杂芳基可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、5-10元杂芳基。 WR 43 is an alkylating agent wherein W is chlorine, bromine, iodine, and R 43 is selected from C 1-8 alkyl, C 1-8 hydroxyalkyl, C 1-8 alkoxy, C 3-8 naphthenic a 4-10 membered heterocyclic group, a C 6-12 aryl group, a 5-10 membered heteroaryl group; said C 1-8 alkyl group, C 1-8 hydroxyalkyl group, C 1-8 alkoxy group, C 3-8 cycloalkyl, 4-10 membered heterocyclyl, C 6-12 aryl, 5-10 membered heteroaryl may be optionally substituted by 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, 5-10 membered heteroaryl.
在一些实施方案中，可使用NaOH、KOH、碳酸钾、碳酸铯、TEA或DIPEA等碱进行反应。在一些实施方案中，反应在溶剂中进行可使用的溶剂为丙酮、MeOH、EtOH、THF、CH 3CN或1,4-二氧六环等。在一些实施方案中，反应温度为0℃至100℃。 In some embodiments, the reaction can be carried out using a base such as NaOH, KOH, potassium carbonate, cesium carbonate, TEA or DIPEA. In some embodiments, the solvent in which the reaction is carried out in a solvent is acetone, MeOH, EtOH, THF, CH 3 CN or 1,4-dioxane, and the like. In some embodiments, the reaction temperature is from 0 °C to 100 °C.
第三步：化合物VI-4-2被氧化生成化合物VI-4-3。The third step: the compound VI-4-2 is oxidized to form the compound VI-4-3.
在一些实施方案中，可使用高锰酸钾、m-CPBA、H 2O 2或CH 3COOOH等氧化剂进行反应。在一些实施方案中，反应在溶剂中进行，所用溶剂为醋酸、水、DCM、DCE、CHCl 3或DMF等。在一些实施方案中，反应温度为0℃至160℃。 In some embodiments, the reaction can be carried out using an oxidizing agent such as potassium permanganate, m-CPBA, H 2 O 2 or CH 3 COOOH. In some embodiments, the reaction is carried out in a solvent such as acetic acid, water, DCM, DCE, CHCl 3 or DMF, and the like. In some embodiments, the reaction temperature is from 0 °C to 160 °C.
第四步：化合物VI-4-3在碱作用下与H-L 1a-(L 2a) p-R 3反应生成化合物VI-4-4。 The fourth step: the compound VI-4-3 is reacted with HL 1a -(L 2a ) p -R 3 under the action of a base to form a compound VI-4-4.
在一些实施方案中，可使用的碱为TEA或DIPEA等。在一些实施方案中，反应在溶剂中进行，可使用的溶剂为DMSO、NMP、CHCl 3或DMF等。在一些实施方案中，反应温度为20℃至160℃。 In some embodiments, the base that can be used is TEA or DIPEA, and the like. In some embodiments, the reaction is carried out in a solvent, and the solvent that can be used is DMSO, NMP, CHCl 3 or DMF, and the like. In some embodiments, the reaction temperature is from 20 °C to 160 °C.
第五步：化合物VI-4-4经溴化反应生成化合物VI-4-5。在一些实施方案中，反应条件 如VI-2合成的第三步所描述。Step 5: Compound VI-4-4 is brominated to give compound VI-4-5. In some embodiments, the reaction conditions are as described in the third step of the VI-2 synthesis.
第六步：化合物VI-4-5被氧化生成化合物VI-4-6。在一些实施方案中，反应条件如VI-1第七步所述。Step 6: Compound VI-4-5 is oxidized to give compound VI-4-6. In some embodiments, the reaction conditions are as described in step 7 of VI-1.
第七步：化合物VI-4-6在碱和活化剂作用下与NHR 4R 5反应生成化合物VI-4-7。在一些实施方案中，反应条件如VI-1合成的第八步所述。 Step 7: Compound VI-4-6 is reacted with NHR 4 R 5 under the action of a base and an activator to give compound VI-4-7. In some embodiments, the reaction conditions are as described in the eighth step of the synthesis of VI-1.
第八步：化合物VI-4由化合物VI-4-7与R 1-Y经偶联反应、取代反应生成，或者由化合物VI-4-7经还原反应生成。在一些实施方案中，反应条件如V-1合成的第十二步所述。 The eighth step: the compound VI-4 is formed by a coupling reaction or a substitution reaction of the compound VI-4-7 with R 1 -Y or a reduction reaction of the compound VI-4-7. In some embodiments, the reaction conditions are as described in the twelfth step of the V-1 synthesis.
化合物Ⅶ-1的合成Synthesis of Compound VII-1
Figure PCTCN2019085535-appb-000065
Figure PCTCN2019085535-appb-000065
R 3、R 4、R 5如上述式VII所定义；R 1如上述式V所定义，但不包含NO 2，R 3不包含卤素、OH、CN和NO 2。 R 3 , R 4 and R 5 are as defined in the above formula VII; R 1 is as defined in the above formula V, but does not contain NO 2 , and R 3 does not contain halogen, OH, CN and NO 2 .
第一步：化合物VII-1-1经硝化反应生成化合物VII-1-2。在一些实施方案中，反应条件如VI-1合成的第一步所述。First step: Compound VII-1-1 is subjected to nitration to give compound VII-1-2. In some embodiments, the reaction conditions are as described in the first step of the synthesis of VI-1.
第二步：化合物VII-1-2被还原生成化合物VII-1-3。在一些实施方案中，反应条件如VI-1合成的第四步所述。Second step: Compound VII-1-2 is reduced to give compound VII-1-3. In some embodiments, the reaction conditions are as described in the fourth step of the synthesis of VI-1.
第三步：化合物VII-1-3与R 3-COOH在碱性条件下经缩合反应生成化合物VII-1-4，或者VII-1-3在碱作用下直接与R 3-COCl反应生成VII-1-4。在一些实施方案中，反应条件如VI-1合成的第五步所述。 The third step: compound VII-1-3 and R 3 -COOH are subjected to condensation reaction under basic conditions to form compound VII-1-4, or VII-1-3 is directly reacted with R 3 -COCl under the action of a base to form VII. -1-4. In some embodiments, the reaction conditions are as described in the fifth step of the synthesis of VI-1.
第四步：化合物VII-1-4关环生成化合物VII-1-5。The fourth step: Compound VII-1-4 is closed to give compound VII-1-5.
在一些实施方案中，可使用POCl 3、PCl 5、PCl 3、TEA或DIPEA等试剂进行反应。在一些实施方案中，反应在溶剂中进行，可使用的溶剂为MeOH、EtOH、THF、CH 3CN、 1,4-二氧六环、DCM、DCE或CHCl 3等。在一些实施方案中，反应温度为rt至100℃。 In some embodiments, using POCl 3, PCl 5, PCl 3 , TEA or the like reagent of DIPEA. In some embodiments, the reaction is carried out in a solvent, and the solvent that can be used is MeOH, EtOH, THF, CH 3 CN, 1,4-dioxane, DCM, DCE or CHCl 3 and the like. In some embodiments, the reaction temperature is from rt to 100 °C.
第五步：化合物VII-1-5被氧化生成化合物VII-1-6。Fifth step: Compound VII-1-5 is oxidized to give compound VII-1-6.
在一些实施方案中，可使用的氧化剂和溶剂如VI-1合成的第七步所述。在一些实施方案中，反应温度为0℃至100℃。In some embodiments, an oxidizing agent and a solvent that can be used are as described in the seventh step of the synthesis of VI-1. In some embodiments, the reaction temperature is from 0 °C to 100 °C.
第六步：化合物VII-1-6在碱和活化剂作用下与NHR 4R 5反应生成化合物VII-1-7。在一些实施方案中，反应条件如VI-1合成的第八步所述。 Step 6: Compound VII-1-6 is reacted with NHR 4 R 5 under the action of a base and an activator to give compound VII-1-7. In some embodiments, the reaction conditions are as described in the eighth step of the synthesis of VI-1.
第七步：化合物VII-1-7与R 1-Y经偶联反应、取代反应或VII-1-7经还原反应生成化合物VII-1。在一些实施方案中，反应条件与V-1合成的第十二步反应条件相同。 Step 7: Compound VII-1-7 and R 1 -Y are subjected to a coupling reaction, a substitution reaction or a reduction reaction of VII-1-7 to give compound VII-1. In some embodiments, the reaction conditions are the same as those of the twelfth step of the V-1 synthesis.
有益效果Beneficial effect
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，可用于细胞增殖异常性疾病(例如癌症)的治疗。The compound of the present invention has obvious agonistic activity against NLRP3 and its signaling pathway, has no obvious toxic and side effects, and can be used for the treatment of abnormal cell proliferation diseases (such as cancer).
实施例Example
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。The invention is further described in the following examples, but the examples are not intended to limit the scope of the invention.
本发明中的缩写具有以下含义：The abbreviations in the present invention have the following meanings:
Figure PCTCN2019085535-appb-000066
Figure PCTCN2019085535-appb-000066
Figure PCTCN2019085535-appb-000067
Figure PCTCN2019085535-appb-000067
化合物的结构通过核磁共振波谱( 1H NMR)和/或质谱(MS)来确证。 The structure of the compound was confirmed by nuclear magnetic resonance spectroscopy ( 1 H NMR) and/or mass spectrometry (MS).
反应的监测采用硅胶薄层色谱法(TLC)或LC-MS。The reaction was monitored by silica gel thin layer chromatography (TLC) or LC-MS.
薄层色谱法采用为硅胶GF 254为固定相。Thin layer chromatography was performed using silica gel GF 254 as the stationary phase.
1H NMR波谱：Bruker超导核磁共振波谱仪(型号AVACE III HD 400MHz)。 1 H NMR spectrum: Bruker superconducting nuclear magnetic resonance spectrometer (model AVACE III HD 400 MHz).
LC/MS质谱仪：Aglient 1260 Infinity/Aglient 6120 Quadrupole。LC/MS mass spectrometer: Aglient 1260 Infinity/Aglient 6120 Quadrupole.
本发明化合物可通过层析硅胶板、硅胶柱层析、制备高效液相色谱仪(Prep-HPLC)、快速柱层析(Flash柱层析)分离纯化。The compound of the present invention can be isolated and purified by chromatography on silica gel, silica gel column chromatography, preparative high performance liquid chromatography (Prep-HPLC), and flash column chromatography (Flash column chromatography).
Prep-HPLC使用Agilent 1260制备液相色谱，检测波长：214nm、254nm；色谱柱：Waters SunFire Prep C18 OBD(19mm×150mm×5.0μm)；柱温：25℃。Prep-HPLC was prepared using Agilent 1260 preparative liquid chromatography, detection wavelength: 214 nm, 254 nm; column: Waters SunFire Prep C18 OBD (19 mm x 150 mm x 5.0 μm); column temperature: 25 °C.
洗脱条件：Elution conditions:
条件1：10％-90％乙腈、90％-10％甲酸铵水溶液(0.05％)，0-16min；流速：24mL/min；Condition 1: 10%-90% acetonitrile, 90%-10% ammonium formate aqueous solution (0.05%), 0-16 min; flow rate: 24 mL/min;
条件2：10％-46％乙腈、90％-54％碳酸氢铵水溶液(0.05％)，0-7.2min；流速：24mL/min；Condition 2: 10%-46% acetonitrile, 90%-54% aqueous ammonium hydrogencarbonate solution (0.05%), 0-7.2 min; flow rate: 24 mL/min;
条件3：10％-90％乙腈、90％-10％甲酸水溶液(0.05％)，0-16min；流速：28mL/min；Condition 3: 10%-90% acetonitrile, 90%-10% aqueous formic acid (0.05%), 0-16 min; flow rate: 28 mL/min;
条件4：10％-90％乙腈、90％-10％碳酸氢铵水溶液(0.05％)，0-16min；流速：24mL/min；Condition 4: 10%-90% acetonitrile, 90%-10% aqueous ammonium hydrogencarbonate solution (0.05%), 0-16 min; flow rate: 24 mL/min;
条件5：30％-90％乙腈、70％-10％碳酸氢铵水溶液(0.05％)，0-16min；流速：24mL/min；Condition 5: 30%-90% acetonitrile, 70%-10% aqueous ammonium hydrogencarbonate solution (0.05%), 0-16 min; flow rate: 24 mL/min;
条件6：10％-90％乙腈、90％-10％三氟乙酸水溶液(0.05％)，0-16min；流速：28mL/min。Condition 6: 10%-90% acetonitrile, 90%-10% aqueous trifluoroacetic acid (0.05%), 0-16 min; flow rate: 28 mL/min.
柱色谱法一般使用200～300目硅胶(青岛海洋)为固定相。洗脱剂体系A：二氯甲烷和甲醇；洗脱剂体系B：石油醚和乙酸乙酯；溶剂的体积比根据化合物的极性不同而进行调节。Column chromatography generally uses 200 to 300 mesh silica gel (Qingdao Ocean) as the stationary phase. Eluent system A: dichloromethane and methanol; eluent system B: petroleum ether and ethyl acetate; the volume ratio of the solvent was adjusted depending on the polarity of the compound.
快速柱层析使用Biotage快速柱色谱仪。Fast column chromatography was performed using a Biotage flash column chromatograph.
微波反应使用BiotageInitiator+微波反应器进行。The microwave reaction was carried out using a Biotage Initiator + microwave reactor.
在以下实施例中，如无特殊说明，反应的温度为室温(15℃～30℃)。In the following examples, the temperature of the reaction was room temperature (15 ° C to 30 ° C) unless otherwise specified.
本申请中所使用的试剂购自Acros Organics、Aldrich Chemical Company或特伯化学等公司。The reagents used in the present application were purchased from companies such as Acros Organics, Aldrich Chemical Company or Tiber Chemical.
中间体制备：7-溴-2-(3-氯丙基)-1-甲基-1H-咪唑并[4,5-d]噻吩并[3,2-b]吡啶-4-胺(1k)Preparation of intermediate: 7-bromo-2-(3-chloropropyl)-1-methyl-1H-imidazo[4,5-d]thieno[3,2-b]pyridin-4-amine (1k )
Figure PCTCN2019085535-appb-000068
Figure PCTCN2019085535-appb-000068
第一步：6-硝基噻吩并[3,2-b]吡啶-7-醇(1b)First step: 6-nitrothieno[3,2-b]pyridine-7-ol (1b)
将化合物1a(200g,1.33mol)加入2L丙酸中、升温至100℃，然后将100mL发烟硝酸缓慢滴入上述溶液中。滴毕后升温至130℃继续搅拌反应6h。冷至室温，在反应混合物中加入2L石油醚，过滤，用1.5L石油醚淋洗滤饼，烘干滤饼得化合物1b(210g)。MS(ESI,m/z):197.1[M+H] +. Compound 1a (200 g, 1.33 mol) was added to 2 L of propionic acid, and the temperature was raised to 100 ° C, and then 100 mL of fuming nitric acid was slowly dropped into the above solution. After the completion of the dropwise addition, the temperature was raised to 130 ° C and the reaction was stirred for 6 hours. After cooling to room temperature, 2 L of petroleum ether was added to the reaction mixture, filtered, and the filter cake was rinsed with 1.5 L of petroleum ether, and the cake was dried to give compound 1b (210 g). MS (ESI, m/z): 197.1 [M+H] + .
第二步：7-氯-6-硝基噻吩并[3,2-b]吡啶(1c)Second step: 7-chloro-6-nitrothieno[3,2-b]pyridine (1c)
将化合物1b(210g,1.06mol)、N,N-二甲基甲酰胺(78g,1.06mol)、三氯氧磷((210g,2.12mol)加入1.5L二氯甲烷中，升温至40℃搅拌反应2h。将反应液减压浓缩至干，加入少量乙酸乙酯使溶解，倒入冰水淬灭反应，经乙酸乙酯萃取后浓缩有机相，得化合物1c(200g)。MS(ESI,m/z):215.1[M+H] +. Compound 1b (210 g, 1.06 mol), N,N-dimethylformamide (78 g, 1.06 mol), phosphorus oxychloride ((210 g, 2.12 mol) was added to 1.5 L of dichloromethane, and the mixture was heated to 40 ° C and stirred. The reaction mixture was concentrated to dryness. EtOAc m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m /z): 215.1 [M + H] + .
第三步：N-甲基-6-硝基噻吩并[3,2-b]吡啶-7-胺(1d)The third step: N-methyl-6-nitrothieno[3,2-b]pyridine-7-amine (1d)
将化合物1c(70g,325.6mmol)、甲胺盐酸盐(43.9g,651.2mmol)、N,N-二异丙基乙胺(84.2g,651.2mmol)依次加入350mL N-甲基吡咯烷酮中，20℃下搅拌反应16h。将反应混合物倒入1.5L冰水中，过滤收集析出的固体，烘干得化合物1d(60g)。MS(ESI,m/z):210.1[M+H] +. Compound 1c (70 g, 325.6 mmol), methylamine hydrochloride (43.9 g, 651.2 mmol), N,N-diisopropylethylamine (84.2 g, 651.2 mmol) were sequentially added to 350 mL of N-methylpyrrolidone. The reaction was stirred at 20 ° C for 16 h. The reaction mixture was poured into 1.5 L of ice water, and the precipitated solid was collected by filtration and dried to give compound 1d (60 g). MS (ESI, m / z) : 210.1 [M + H] +.
第四步：N-甲基噻吩并[3,2-b]吡啶-6,7-二胺(1e)Fourth step: N-methylthieno[3,2-b]pyridine-6,7-diamine (1e)
将化合物1d(45g,0.21mol)、10％Pd/C(4.5g,10％m/m)加入700mL甲醇中，氢气置换三次后，25℃下搅拌反应16h。将反应混合物过滤除去钯碳，滤液减压浓缩至干得化 合物1e(36g)。MS(ESI,m/z):180.0[M+H] +. Compound 1d (45 g, 0.21 mol), 10% Pd/C (4.5 g, 10% m/m) was added to 700 mL of methanol, and after three times of hydrogen, the reaction was stirred at 25 ° C for 16 h. The reaction mixture was filtered to remove palladium carbon, and the filtrate was concentrated to dryness to give compound 1e (36 g). MS (ESI, m/z): 180.0 [M+H] + .
第五步：4-(苄氧基)-N-(7-(甲胺基)噻吩并[3,2-b]吡啶-6-基)丁酰胺(1f)Step 5: 4-(Benzyloxy)-N-(7-(methylamino)thieno[3,2-b]pyridin-6-yl)butanamide (1f)
将化合物1e(36g,0.2mol)、4-苄氧基丁酸(40.7g,0.21mol)、HATU(79.8g,0.21mmol)、N,N-二异丙基乙胺(54.3g,0.42mol)加入75mL N,N-二甲基甲酰胺中，25℃下搅拌反应2h。将反应混合物倒入冰水中，经乙酸乙酯萃取后浓缩有机相，得化合物1f(60g)。MS(ESI,m/z):356.1[M+H] +. Compound 1e (36 g, 0.2 mol), 4-benzyloxybutyric acid (40.7 g, 0.21 mol), HATU (79.8 g, 0.21 mmol), N,N-diisopropylethylamine (54.3 g, 0.42 mol) It was added to 75 mL of N,N-dimethylformamide, and the reaction was stirred at 25 ° C for 2 h. The reaction mixture was poured into ice water and extracted with ethyl acetate. MS (ESI, m/z): 356.1 [M+H] + .
第六步：2-(3-(苄氧基)丙基)-7-溴-1,4-二甲基-1H-咪唑并[4,5-d]噻吩并[3,2-b]吡啶(1g)Step 6: 2-(3-(Benzyloxy)propyl)-7-bromo-1,4-dimethyl-1H-imidazo[4,5-d]thieno[3,2-b] Pyridine (1g)
将化合物1f(60g,168.5mmol)、氢氧化钠(13.5g,337mmol)加入300mL乙醇中，升温至80℃搅拌反应3h。用6.0N盐酸将反应混合物调至pH＝7，浓缩至干后复溶于乙酸乙酯中，滤除不溶物，减压浓缩滤液得化合物1g(50g)。MS(ESI,m/z):338.2[M+H] +. Compound 1f (60 g, 168.5 mmol) and sodium hydroxide (13.5 g, 337 mmol) were added to 300 mL of ethanol, and the mixture was heated to 80 ° C and stirred for 3 h. The reaction mixture was adjusted to pH = 7 with EtOAc (EtOAc)EtOAc. MS (ESI, m/z): 338.2 [M+H] + .
第七步：2-(3-(苄氧基)丙基)-7-溴-1-甲基-1H-咪唑并[4,5-d]噻吩并[3,2-b]吡啶(1h)Step 7: 2-(3-(Benzyloxy)propyl)-7-bromo-1-methyl-1H-imidazo[4,5-d]thieno[3,2-b]pyridine (1h )
将化合物1g(50g,0.15mol)、N-溴代丁二酰亚胺(53.1g,0.30mol)加入400mL DMF/冰醋酸＝1:1的混合溶剂中，升温至40℃下搅拌反应4h。将反应混合物倒入冰水中，经乙酸乙酯萃取后用碳酸钾水溶液洗涤至中性，浓缩有机相，再经少量乙酸乙酯打浆后过滤得化合物1h(40g)。MS(ESI,m/z):416.0[M+H] +. The compound 1 g (50 g, 0.15 mol) and N-bromosuccinimide (53.1 g, 0.30 mol) were added to a mixed solvent of 400 mL of DMF / glacial acetic acid = 1:1, and the mixture was heated to 40 ° C and stirred for 4 h. The reaction mixture was poured into ice water, extracted with EtOAc EtOAc (EtOAc) MS (ESI, m/z): 416.0 [M+H] +
第八步：2-(3-(苄氧基)丙基)-7-溴-1-甲基-1H-咪唑并[4,5-d]噻吩并[3,2-b]吡啶-5-氧(1i)Step 8: 2-(3-(Benzyloxy)propyl)-7-bromo-1-methyl-1H-imidazo[4,5-d]thieno[3,2-b]pyridine-5 - oxygen (1i)
将化合物1h(40g,96.2mmol)、mCPBA(28.1g,163.5mmol)加入400mL二氯甲烷中，室温下搅拌反应4h。将反应混合物倒入200mL饱和碳酸氢钠水溶液中，有机相经水洗涤至碘化钾淀粉试纸检测无过氧化物残留时，减压浓缩至干，得化合物1i(32g)。MS(ESI,m/z):432.2[M+H] +. Compound 1h (40g, 96.2mmol), mCPBA (28.1g, 163.5mmol) was added to 400 mL of dichloromethane, and the reaction was stirred at room temperature for 4 h. The reaction mixture was poured into 200 mL of a saturated aqueous solution of sodium hydrogencarbonate, and the organic phase was washed with water to a potassium iodide starch paper to detect the residue without peroxide, and concentrated under reduced pressure to dryness to give Compound 1i (32 g). MS (ESI, m/z): 432.2 [M+H] +
第九步：2-(3-(苄氧基)丙基)-7-溴-1-甲基-1H-咪唑并[4,5-d噻吩并[3,2-b]吡啶-4-胺(1)Step 9: 2-(3-(Benzyloxy)propyl)-7-bromo-1-methyl-1H-imidazo[4,5-d-thieno[3,2-b]pyridine-4- Amine (1)
将化合物1i(32g,74.2mmol)加入700mL二氯甲烷和180mL氨水中，再将对甲苯磺酰氯(21.1g,111.3mmol)的二氯甲烷溶液滴入上述反应混合物中，加毕后25℃搅拌反应3h。将反应混合物倒入冰水中，二氯甲烷萃取后用3N盐酸洗涤至中性，浓缩有机相，再经快速柱层析(洗脱剂体系A)得到化合物1(22g)。MS(ESI,m/z):431.2[M+H] +. Compound 1i (32 g, 74.2 mmol) was added to 700 mL of dichloromethane and 180 mL of aqueous ammonia, and a solution of p-toluenesulfonyl chloride (21.1 g, 111.3 mmol) in dichloromethane was added dropwise to the above reaction mixture, followed by stirring at 25 ° C. Reaction for 3 h. The reaction mixture was poured into ice water, extracted with methylene chloride and washed with 3N hydrochloric acid to neutral. The organic phase was concentrated and then purified by flash column chromatography (eluent system A) to give compound 1 (22 g). MS (ESI, m/z): 4321. [M+H] + .
第十步：3-(4-氨基-7-溴-1-甲基-1H-咪唑并[4,5-d]噻吩并[3,2-b]吡啶-2-基)丙基-1-醇(1j)Step 10: 3-(4-Amino-7-bromo-1-methyl-1H-imidazo[4,5-d]thieno[3,2-b]pyridin-2-yl)propyl-1 -alcohol (1j)
将化合物1(22g,51.0mmol)、三溴化硼(19.1g,76.5mmol)加入220mL二氯甲烷中，25℃搅拌下搅拌反应1h。向反应混合物中加入60mL甲醇淬灭反应，用饱和碳酸氢钠洗涤，有机相浓缩至干，用少量二氯甲烷打浆后过滤得化合物1j(12g)。MS(ESI,m/z):341.0[M+H] +. Compound 1 (22 g, 51.0 mmol) and boron tribromide (19.1 g, 76.5 mmol) were added to 220 mL of dichloromethane, and stirred at 25 ° C for 1 h. The reaction mixture was quenched with EtOAc (EtOAc)EtOAc. MS (ESI, m/z): 341.0 [M+H] + .
第十一步：7-溴-2-(3-氯丙基)-1-甲基-1H-咪唑并[4,5-d]噻吩并[3,2-b]吡啶-4-胺(1k)Eleventh step: 7-bromo-2-(3-chloropropyl)-1-methyl-1H-imidazo[4,5-d]thieno[3,2-b]pyridin-4-amine ( 1k)
将化合物1j(12g,35.2mmol)、二氯亚砜(25mL,352mmol)加入120mL二氯甲烷中，升温至40℃下搅拌反应16h。将反应混合物浓缩，倒入200mL饱和碳酸氢钠中，过滤， 将所得固体溶于DCM/MeOH＝1:1的混合溶剂中，无水硫酸钠干燥后过滤，浓缩滤液至干得化合物1k(9g)。MS(ESI,m/z):359.0[M+H] +. Compound 1j (12 g, 35.2 mmol) and dichlorosulfoxide (25 mL, 352 mmol) were added to 120 mL of dichloromethane, and the mixture was warmed to 40 ° C and stirred for 16 h. The reaction mixture was concentrated, poured into EtOAc EtOAc (EtOAc) ). MS (ESI, m/z): 359.0 [M+H] + .
中间体制备：7-溴-2-(3-氯丙基)-1-甲基-1H-咪唑并[4,5-d]噻吩并[3,2-b]吡啶-4-胺(9i)Preparation of intermediate: 7-bromo-2-(3-chloropropyl)-1-methyl-1H-imidazo[4,5-d]thieno[3,2-b]pyridin-4-amine (9i )
Figure PCTCN2019085535-appb-000069
Figure PCTCN2019085535-appb-000069
第一步：N-(4-甲氧基苄基)-6-硝基噻吩并[3,2-b]吡啶-7-胺(9a)First step: N-(4-methoxybenzyl)-6-nitrothieno[3,2-b]pyridine-7-amine (9a)
将化合物1c(50g,232.5mmol)、4-甲氧基苄胺(38.2g,279.0mmol)、N,N-二异丙基乙胺(39.1g,302.2mmol)依次加入250mL N-甲基吡咯烷酮中，20℃下搅拌反应16h。将反应混合物倒入1.5L冰水中，过滤收集析出的固体，烘干得化合物9a(62g)。MS(ESI,m/z):315.1[M+H] +. Compound 1c (50 g, 232.5 mmol), 4-methoxybenzylamine (38.2 g, 279.0 mmol), N,N-diisopropylethylamine (39.1 g, 302.2 mmol) were sequentially added to 250 mL of N-methylpyrrolidone The reaction was stirred at 20 ° C for 16 h. The reaction mixture was poured into 1.5 L of ice water, and the precipitated solid was collected by filtration and dried to give compound 9a (62 g). MS (ESI, m/z): 315.1 [M+H] + .
第二步：7-(4-甲氧基苄基)噻吩并[3,2-b]吡啶-6,7-二胺(9b)Second step: 7-(4-methoxybenzyl)thieno[3,2-b]pyridine-6,7-diamine (9b)
将化合物9a(20g,63.5mmol)、氯化铵(13.5g,254mmol)、锌粉(16.5g,254mmol)加入200mL甲醇中，25℃下搅拌反应16h。向反应混合物中加入100mL二氯甲烷，过滤，所得固体用200mL四氢呋喃回流，热滤，合并两次滤液减压浓缩至干得化合物9b(14g)。MS(ESI,m/z):286.1[M+H] +. Compound 9a (20 g, 63.5 mmol), ammonium chloride (13.5 g, 254 mmol), zinc powder (16.5 g, 254 mmol) was added to 200 mL of methanol, and the reaction was stirred at 25 ° C for 16 h. 100 mL of methylene chloride was added to the reaction mixture, and the mixture was filtered. MS (ESI, m/z): 286.1 [M+H] + .
第三步：4-(苄氧基)-N-(7-((4-甲氧基苄基)胺)噻吩并[3,2-b]吡啶-6-基)丁酰胺(9c)Third step: 4-(benzyloxy)-N-(7-((4-methoxybenzyl)amine)thieno[3,2-b]pyridin-6-yl)butanamide (9c)
将化合物9b(14g,48.9mmol)、4-苄氧基丁酸(40.7g,53.8mmol)、HATU(79.8g,51.3mmol)、N,N-二异丙基乙胺(54.3g,102.7mmol)加入70mL N,N-二甲基甲酰胺中，25℃下搅拌反应2h。将反应混合物倒入冰水中，经乙酸乙酯萃取后浓缩有机相，得化合物9c(16g)。MS(ESI,m/z):462.2[M+H] +. Compound 9b (14 g, 48.9 mmol), 4-benzyloxybutyric acid (40.7 g, 53.8 mmol), HATU (79.8 g, 51.3 mmol), N,N-diisopropylethylamine (54.3 g, 102.7 mmol) It was added to 70 mL of N,N-dimethylformamide, and the reaction was stirred at 25 ° C for 2 h. The reaction mixture was poured into ice water and extracted with ethyl acetate. MS (ESI, m / z) : 462.2 [M + H] +.
第四步：2-(3-(苄氧基)丙基)-1-(4-甲氧基苄基)-1H-咪唑并[4,5-d]噻吩并[3,2-b]吡啶(9d)Fourth step: 2-(3-(benzyloxy)propyl)-1-(4-methoxybenzyl)-1H-imidazo[4,5-d]thieno[3,2-b] Pyridine (9d)
将化合物9c(15g,32.5mmol)、氢氧化钠(13.5g,81.3mmol)加入150mL乙醇中，升温至80℃搅拌反应3h。将反应混合物用6.0N盐酸调pH＝7.0，浓缩至干后复溶于乙酸乙酯中，滤除不溶物，减压浓缩滤液得化合物9d(12g)。MS(ESI,m/z):444.2[M+H] +. Compound 9c (15 g, 32.5 mmol) and sodium hydroxide (13.5 g, 81.3 mmol) were added to 150 mL of ethanol, and the mixture was heated to 80 ° C and stirred for 3 h. The reaction mixture was adjusted to pH 7.0 with 6.0N hydrochloric acid, and evaporated to dryness. MS (ESI, m / z) : 444.2 [M + H] +.
第五步：2-(3-(苄氧基)丙基)-7-溴-1-(4-甲氧基苄基)-1H-咪唑并[4,5-d]噻吩并[3,2-b]吡啶(9e)Step 5: 2-(3-(Benzyloxy)propyl)-7-bromo-1-(4-methoxybenzyl)-1H-imidazo[4,5-d]thieno[3, 2-b]pyridine (9e)
将化合物9d(12g,27.1mmol)、N-溴代丁二酰亚胺(53.1g,54.2mmol)加入120mL DMF/冰醋酸＝1:1的混合溶剂中，升温至40℃下搅拌反应4h。将反应混合物倒入冰水中，经乙酸乙酯萃取后用碳酸钾水溶液洗涤至中性，浓缩有机相，再经少量乙酸乙酯打浆后过滤得化合物9e(10g)。MS(ESI,m/z):522.1[M+H] +. Compound 9d (12 g, 27.1 mmol) and N-bromosuccinimide (53.1 g, 54.2 mmol) were added to a mixed solvent of 120 mL of DMF / glacial acetic acid = 1:1, and the mixture was heated to 40 ° C and stirred for 4 h. The reaction mixture was poured into ice water, extracted with EtOAc EtOAc (EtOAc)EtOAc. MS (ESI, m/z): 5221. [M+H] + .
第六步：2-(3-(苄氧基)丙基)-7-溴-1-(4-甲氧基苄基)-1H-咪唑并[4,5-d]噻吩并[3,2-b]吡啶-5-氧(9f)Step 6: 2-(3-(Benzyloxy)propyl)-7-bromo-1-(4-methoxybenzyl)-1H-imidazo[4,5-d]thieno[3, 2-b]pyridine-5-oxy (9f)
将化合物9e(10g,19.2mmol)、mCPBA(5.64g,32.6mmol)加入200mL二氯甲烷中，室温下搅拌反应4h。将反应混合物倒入200mL饱和碳酸氢钠水溶液中，有机相经水洗涤至碘化钾淀粉试纸检测无过氧化物残留时，减压浓缩得化合物9f(10g)。MS(ESI,m/z):538.1[M+H] +. Compound 9e (10 g, 19.2 mmol) and mCPBA (5.64 g, 32.6 mmol) were added to 200 mL of dichloromethane, and the mixture was stirred at room temperature for 4 h. The reaction mixture was poured into 200 mL of a saturated aqueous solution of sodium hydrogencarbonate, and the organic phase was washed with water to a potassium iodide starch paper to detect the residue without peroxide, and concentrated under reduced pressure to give compound 9f (10 g). MS (ESI, m/z): 538.1 [M+H] + .
第七步：2-(3-(苄氧基)丙基)-7-溴-1-(4-甲氧基苄基)-1H-咪唑并[4,5-d]噻吩并[3,2-b]吡啶-4-胺(9g)Step 7: 2-(3-(Benzyloxy)propyl)-7-bromo-1-(4-methoxybenzyl)-1H-imidazo[4,5-d]thieno[3, 2-b]pyridin-4-amine (9g)
将化合物9f(10g,18.6mmol)加入200mL二氯甲烷和50mL氨水中，再将对甲苯磺酰氯(5.3g,27.9mmol)的二氯甲烷溶液滴入上述反应混合物中，加毕，25℃搅拌反应3h。将反应混合物倒入冰水中，二氯甲烷萃取并用3N盐酸洗涤至中性，浓缩有机相，再经快速柱层析(洗脱剂体系A)得到化合物9g(5g)。MS(ESI,m/z):537.2[M+H] +. Compound 9f (10 g, 18.6 mmol) was added to 200 mL of dichloromethane and 50 mL of aqueous ammonia, and a solution of p-toluenesulfonyl chloride (5.3 g, 27.9 mmol) in dichloromethane was added dropwise to the above reaction mixture, and the mixture was stirred at 25 ° C. Reaction for 3 h. The reaction mixture was poured into ice water, extracted with dichloromethane and washed with <3>3N hydrochloric acid to neutral. The organic phase was concentrated and purified by flash column chromatography (eluent system A) to give compound 9 g (5 g). MS (ESI, m/z): 537.2 [M+H] + .
第八步：3-(4-胺-7-溴-1-(4-甲氧基苄基)-1H-咪唑并[4,5-d]噻吩并[3,2-b]吡啶-2-基)丙基-1-醇(9h)Step 8: 3-(4-Amine-7-bromo-1-(4-methoxybenzyl)-1H-imidazo[4,5-d]thieno[3,2-b]pyridine-2 -yl)propyl-1-ol (9h)
将化合物9g(5g,9.3mmol)、三溴化硼(3.5g,14.0mmol)加入50mL二氯甲烷中，25℃搅拌下搅拌反应1h。向反应混合物中加入20mL甲醇淬灭反应，用饱和碳酸氢钠洗涤后，有机相浓缩至干，并用少量二氯甲烷打浆后过滤得化合物9h(3.4g)。MS(ESI,m/z):447.1[M+H] +. The compound 9 g (5 g, 9.3 mmol) and boron tribromide (3.5 g, 14.0 mmol) were added to 50 mL of dichloromethane, and the mixture was stirred and stirred at 25 ° C for 1 h. The reaction mixture was quenched with EtOAc (EtOAc)EtOAc. MS (ESI, m/z): 447.1 [M+H] + .
第九步：7-溴-2-(3-氯丙基)-1-(4-甲氧基苄基)-1H-咪唑并[4,5-d]噻吩并[3,2-b]吡啶-4-胺(9i)Step 9: 7-Bromo-2-(3-chloropropyl)-1-(4-methoxybenzyl)-1H-imidazo[4,5-d]thieno[3,2-b] Pyridine-4-amine (9i)
将化合物9h(3.4g,7.6mmol)、二氯亚砜(5.5mL,76mmol)加入40mL二氯甲烷中，升温至40℃下搅拌反应16h。将反应混合物浓缩至干，倒入100mL饱和碳酸氢钠中，过滤，所得固体复溶于DCM/MeOH＝1:1的混合溶剂中，无水硫酸钠干燥后过滤，浓缩有机相至干得化合物9i(2.5g)。MS(ESI,m/z):465.0[M+H] +. Compound 9h (3.4 g, 7.6 mmol) and dichloromethane (5.5 mL, 76 mmol) were added to 40 mL of dichloromethane, and the mixture was warmed to 40 ° C and stirred for 16 h. The reaction mixture was concentrated to dryness. EtOAcjjjjjjjjjjjjjj 9i (2.5g). MS (ESI, m/z): 465.0 [M+H] + .
实施例1：2-(3-(苄氧基)丙基)-7-溴-1-甲基-1H-咪唑并[4,5-d]噻吩并[3,2-b]吡啶-4-胺(1)Example 1: 2-(3-(Benzyloxy)propyl)-7-bromo-1-methyl-1H-imidazo[4,5-d]thieno[3,2-b]pyridine-4 -amine (1)
Figure PCTCN2019085535-appb-000070
Figure PCTCN2019085535-appb-000070
第一步：6-硝基噻吩并[3,2-b]吡啶-7-醇(1b)First step: 6-nitrothieno[3,2-b]pyridine-7-ol (1b)
将化合物1a(噻吩并[3,2-b]吡啶-7-醇)(6.0g，39.685mmol)溶于200mL丙酸中，加热至110℃，滴加浓硝酸(5.5g，59.360mmol)至该反应混合物中，10分钟滴加完毕，升温至130℃反应1.5小时。将反应混合物冷却至室温，减压抽滤，滤饼依次用50mL甲醇洗涤和50mL水洗涤，真空干燥得到化合物1b(4.6g)。粗产品直接用于下步反应。Compound 1a (thieno[3,2-b]pyridine-7-ol) (6.0 g, 39.685 mmol) was dissolved in 200 mL of propionic acid, heated to 110 ° C, and concentrated nitric acid (5.5 g, 59.360 mmol) was added dropwise. The reaction mixture was added dropwise over 10 minutes, and the temperature was raised to 130 ° C for 1.5 hours. The reaction mixture was cooled to room temperature and filtered with suction~~~~~~~~~~~~~~~~~~~~~~ The crude product was used directly in the next step.
1H NMR(DMSO-d 6,400MHz)δ13.42(s,1H),9.12(s,1H),8.17(d,J＝5.2,1H),7.36(d,J＝5.2,1H). 1 H NMR (DMSO-d 6 , 400 MHz) δ 13.42 (s, 1H), 9.12 (s, 1H), 8.17 (d, J = 5.2, 1H), 7.36 (d, J = 5.2, 1H).
第二步：7-氯-6-硝基噻吩并[3,2-b]吡啶(1c)Second step: 7-chloro-6-nitrothieno[3,2-b]pyridine (1c)
将化合物1b(6-硝基噻吩并[3,2-b]吡啶-7-醇)(2.1g，10.700mmol)加入60mL 1,2-二氯乙烷中，滴加三氯氧磷(10.5g，68.480mmol)，氮气保护下升温至85℃反应，待反应结束后，浓缩除溶剂和三氯氧磷。残留物用二氯甲烷溶解，饱和碳酸氢钠溶液洗涤，再用二氯甲烷萃取，有机相合并，用无水Na 2SO 4干燥，过滤后减压浓缩得到化合物1c(2.1g)。粗产品直接用于下步反应。 Compound 1b (6-nitrothieno[3,2-b]pyridine-7-ol) (2.1 g, 10.700 mmol) was added to 60 mL of 1,2-dichloroethane, and phosphorus oxychloride was added dropwise (10.5). g, 68.480 mmol), the temperature was raised to 85 ° C under nitrogen protection, and after the reaction was completed, the solvent and phosphorus oxychloride were concentrated. The residue was dissolved in methylene chloride, washed with saturated sodium bicarbonate solution, extracted with dichloromethane, the organic phases are combined, dried over anhydrous Na 2 SO 4, to obtain compound 1c (2.1g) filtered and concentrated under reduced pressure. The crude product was used directly in the next step.
1H NMR(CDCl 3,400MHz)δ9.21(s,1H),8.05(d,J＝5.6,1H),7.63(d,J＝5.6,1H). 1 H NMR (CDCl 3 , 400 MHz) δ 9.21 (s, 1H), 8.05 (d, J = 5.6, 1H), 7.63 (d, J = 5.6, 1H).
第三步：N-甲基-6-硝基噻吩并[3,2-b]吡啶-7-胺(1d)The third step: N-methyl-6-nitrothieno[3,2-b]pyridine-7-amine (1d)
将化合物1c(7-氯-6-硝基噻吩并[3,2-b]吡啶)(1.5g，6.990mmol)溶解于60mL NMP中，室温下滴加MeNH 2的甲醇溶液(0.7g，7.451mmol)，然后加入DIPEA(2.0g，15.480mmol)，室温下搅拌4h后，向反应混合物中滴加水120mL，继续室温下搅拌1h，减压抽滤得到化合物1d(1.3g)。粗产品直接用于下步反应。 Compound 1c (7-chloro-6-nitrothieno[3,2-b]pyridine) (1.5 g, 6.990 mmol) was dissolved in 60 mL of NMP, and a solution of MeNH 2 in methanol (0.7 g, 7.451) was added dropwise at room temperature. After adding 4 ml of DIPEA (2.0 g, 15.480 mmol), and stirring at room temperature, 120 mL of water was added dropwise to the reaction mixture, and the mixture was stirred at room temperature for 1 hour, and filtered under reduced pressure to give Compound 1d (1.3 g). The crude product was used directly in the next step.
1H NMR(CDCl 3,400MHz)δ9.20(s,1H),7.82(d,J＝5.2,1H),7.45(d,J＝5.2,1H), 3.54(d,J＝5.2,3H). 1 H NMR (CDCl 3 , 400 MHz) δ 9.20 (s, 1H), 7.82 (d, J = 5.2, 1H), 7.45 (d, J = 5.2, 1H), 3.54 (d, J = 5.2, 3H) .
第四步：N 7-甲基噻吩并[3,2-b]吡啶-6,7-二胺(1e) Fourth step: N 7 -methylthieno[3,2-b]pyridine-6,7-diamine (1e)
将化合物1d(N-甲基-6-硝基噻吩并[3,2-b]吡啶-7-胺)(1.5g，7.170mmol)加入50mL甲醇中，氮气置换空气，加入10％Pd/C(1.08g，8.890mmol)，使用装有氢气的气球置换氮气，25℃反应过夜。滤去不溶物，减压浓缩滤液得到化合物1e(1.2g)。Compound 1d (N-methyl-6-nitrothieno[3,2-b]pyridine-7-amine) (1.5 g, 7.170 mmol) was added to 50 mL of methanol, and air was replaced with nitrogen, and 10% Pd/C was added. (1.08 g, 8.890 mmol), the nitrogen was replaced with a balloon containing hydrogen, and reacted at 25 ° C overnight. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure to give Compound 1e (1.2 g).
1H NMR(DMSO-d 6,400MHz)δ7.87(s,1H),7.55(d,J＝5.2,1H),7.17(d,J＝5.2,1H),5.45(q,J＝5.2,1H),4.56(s,2H),3.23(d,J＝5.6,3H). 1 H NMR (DMSO-d 6 , 400 MHz) δ 7.87 (s, 1H), 7.55 (d, J = 5.2, 1H), 7.17 (d, J = 5.2, 1H), 5.45 (q, J = 5.2, 1H), 4.56 (s, 2H), 3.23 (d, J = 5.6, 3H).
第五步：4-(苄氧基)-N-(7-(甲基氨基)噻吩并[3,2-b]吡啶-6-基)丁酰胺(1f)Step 5: 4-(Benzyloxy)-N-(7-(methylamino)thieno[3,2-b]pyridin-6-yl)butanamide (1f)
将化合物1e(N 7-甲基噻吩并[3,2-b]吡啶-6,7-二胺)(3.9g，26.260mmol)，4-苯氧基丁酸(5.1g，21.760mmol)溶于60mL DMF中，室温下加入HATU(11.0g，28.930mmol)，DIPEA(6.0g，46.430mmol)，在氮气保护下于25℃反应5h。加入EA 200mL，依次用饱和氯化钠溶液和水洗涤，萃取，有机相用无水Na 2SO 4干燥，减压浓缩溶剂得到化合物1f(6.9g)。粗产品直接用于下步反应。MS(ESI,m/z):356.2[M+H] +. Compound 1e (N 7 -methylthieno[3,2-b]pyridine-6,7-diamine) (3.9 g, 26.260 mmol), 4-phenoxybutyric acid (5.1 g, 21.760 mmol) In 60 mL of DMF, HATU (11.0 g, 28.930 mmol), DIPEA (6.0 g, 46.430 mmol) was added at room temperature and reacted at 25 ° C for 5 h under nitrogen. Add EA 200mL, washed successively with water and saturated sodium chloride solution, and extracted, the organic phase was dried over anhydrous Na 2 SO 4, solvent was concentrated under reduced pressure to give compound 1f (6.9g). The crude product was used directly in the next step. MS (ESI, m/z): 356.2 [M+H] + .
第六步：2-(3-(苄氧基)丙基)-1-甲基-1H-咪唑并[4,5-d]噻吩并[3,2-b]吡啶(1g)Step 6: 2-(3-(Benzyloxy)propyl)-1-methyl-1H-imidazo[4,5-d]thieno[3,2-b]pyridine (1 g)
将化合物1f(4-(苄氧基)-N-(7-(甲基氨基)噻吩并[3,2-b]吡啶-6-基)丁酰胺(2.5g，7.030mmol))溶于50mL MeOH中，室温下加入DIPEA(3.7g，28.630mmol)，加热回流反应16h。减压浓缩，残留物用EA溶解，0.1N盐酸洗涤，萃取，合并有机相用无水Na 2SO 4干燥，减压浓缩溶剂后通过硅胶柱层析(DCM:MeOH＝20:1)纯化得到化合物1g(1.9g)。MS(ESI,m/z):338.2[M+H] +. Compound 1f (4-(benzyloxy)-N-(7-(methylamino)thieno[3,2-b]pyridin-6-yl)butanamide (2.5 g, 7.030 mmol) was dissolved in 50 mL DIPEA (3.7 g, 28.630 mmol) was added to MeOH and EtOAc was evaporated. Concentrated under reduced pressure, the residue was dissolved in EA, washed with 0.1N hydrochloric acid, dried Na 2 SO 4 The combined organic phases were dried over anhydrous, the solvent was concentrated under reduced pressure and purified by silica gel column chromatography (DCM: MeOH = 20: 1 ) to give Compound 1 g (1.9 g). MS (ESI, m/z): 338.2 [M+H] + .
第七步：2-(3-(苄氧基)丙基)-7-溴-1-甲基-1H-咪唑并[4,5-d]噻吩并[3,2-b]吡啶(1h)Step 7: 2-(3-(Benzyloxy)propyl)-7-bromo-1-methyl-1H-imidazo[4,5-d]thieno[3,2-b]pyridine (1h )
将化合物1g(2-(3-(苄氧基)丙基)-1-甲基-1H-咪唑并[4,5-d]噻吩并[3,2-b]吡啶)(3.4g，10.080mmol)溶于30mL DMF和30mL冰乙酸混合溶剂中，室温下滴加NBS(3.6g，21.150mmol)的30mL DMF溶液，滴加完毕后升温至60℃反应4h。加入水、EA萃取，有机层用无水Na 2SO 4干燥，减压浓缩溶剂后通过硅胶柱层析(DCM:MeOH＝20:1)纯化得到化合物1h(3.1g)。MS(ESI,m/z):416.1[M+H] +. Compound 1g (2-(3-(benzyloxy)propyl)-1-methyl-1H-imidazo[4,5-d]thieno[3,2-b]pyridine) (3.4g, 10.080 Methyl) was dissolved in 30 mL of DMF and 30 mL of glacial acetic acid in a mixed solvent. NBS (3.6 g, 21.150 mmol) in 30 mL of DMF was added dropwise at room temperature. After the addition was completed, the mixture was heated to 60 ° C for 4 h. Water was added, extracted with EA, the organic layer was dried over anhydrous Na 2 SO 4, the solvent was concentrated by silica gel column chromatography (DCM 1:: MeOH = 20 ) under reduced pressure to give compound 1h (3.1g) was purified. MS (ESI, m/z): 416.1 [M+H] + .
1H NMR(DMSO-d 6,400MHz)δ8.87(s,1H),7.85(s,1H),7.32-7.22(m,5H),4.47(s,2H),3.91(s,3H),3.58(t,J＝6.0,2H),3.01(t,J＝7.2,2H),2.14-2.07(m,2H). 1 H NMR (DMSO-d 6 , 400 MHz) δ 8.87 (s, 1H), 7.85 (s, 1H), 7.32-7.22 (m, 5H), 4.47 (s, 2H), 3.91 (s, 3H), 3.58 (t, J = 6.0, 2H), 3.01 (t, J = 7.2, 2H), 2.14 - 2.07 (m, 2H).
第八步：2-(3-(苄氧基)丙基)-1-甲基-1H-咪唑并[4,5-d]噻吩并[3,2-b]吡啶5-氧化物(1i)Step 8: 2-(3-(Benzyloxy)propyl)-1-methyl-1H-imidazo[4,5-d]thieno[3,2-b]pyridine 5-oxide (1i )
将化合物1h(2-(3-(苄氧基)丙基)-7-溴-1-甲基-1H-咪唑并[4,5-d]噻吩并[3,2-b]吡啶)(1.3g，3.850mmol)溶于50mL三氯甲烷中，室温下加入m-CBPA(1.4g，6.250mmol)，25℃反应6h。加入饱和Na 2SO 3溶液，室温下搅拌0.5h，萃取，合并有机层用无水Na 2SO 4干燥，减压浓缩溶剂后通过重结晶(PE:EA＝3:1)纯化得到化合物1i(1.0g)。MS(ESI,m/z):432.1[M+H] +. Compound 1h (2-(3-(benzyloxy)propyl)-7-bromo-1-methyl-1H-imidazo[4,5-d]thieno[3,2-b]pyridine) 1.3 g, 3.850 mmol) was dissolved in 50 mL of chloroform, and m-CBPA (1.4 g, 6.250 mmol) was added at room temperature, and reacted at 25 ° C for 6 h. After adding a saturated Na 2 SO 3 solution, the mixture was stirred at room temperature for 0.5 hr, and then extracted, and the combined organic layer was dried over anhydrous Na 2 SO 4 1.0g). MS (ESI, m/z): 4321. [M+H] + .
第九步：2-(3-(苄氧基)丙基)-7-溴-1-甲基-1H-咪唑并[4,5-d]噻吩并[3,2-b]吡啶-4-胺(1)Step 9: 2-(3-(Benzyloxy)propyl)-7-bromo-1-methyl-1H-imidazo[4,5-d]thieno[3,2-b]pyridine-4 -amine (1)
将化合物1i(2-(3-(苄氧基)丙基)-1-甲基-1H-咪唑并[4,5-d]噻吩并[3,2-b]吡啶5-氧化物)(1.4g，3.239mmol)溶于30mL二氯甲烷中，加入NH 4OH 25mL，冰浴下滴加TsCl(1.29g，6.790mmol)的10mL二氯甲烷溶液，滴加完毕后升温至25℃反应2h。EA萃取，合并有机层用无水Na 2SO 4干燥，减压浓缩溶剂后通过硅胶柱层析(DCM:MeOH＝20:1)纯化得到化合物1(1.1g)。 Compound 1i (2-(3-(benzyloxy)propyl)-1-methyl-1H-imidazo[4,5-d]thieno[3,2-b]pyridine 5-oxide) ( 1.4g, 3.239mmol) was dissolved in 30mL of dichloromethane, 25mL of NH 4 OH was added, and TsCl (1.29g, 6.790mmol) of 10mL dichloromethane solution was added dropwise in ice bath. After the addition was completed, the temperature was raised to 25 ° C for 2h. . Extracted with EA The combined organic layers were dried over anhydrous Na 2 SO 4, the solvent was concentrated by silica gel column chromatography (DCM 1:: MeOH = 20 ) under reduced pressure to give Compound 1 (1.1g) was purified.
MS(ESI,m/z):431.0[M+H] +. MS (ESI, m/z): 431.0 [M+H] + .
1H NMR(DMSO-d 6,400MHz)δ7.40(s,1H),7.31-7.27(m,5H),6.26(s,2H),4.48(s,2H),3.83(s,3H),3.54(t,J＝7.2,2H),2.95(t,J＝7.2,2H),2.07-2.03(m,2H). 1 H NMR (DMSO-d 6 , 400MHz) δ7.40 (s, 1H), 7.31-7.27 (m, 5H), 6.26 (s, 2H), 4.48 (s, 2H), 3.83 (s, 3H), 3.54 (t, J = 7.2, 2H), 2.95 (t, J = 7.2, 2H), 2.07-2.03 (m, 2H).
实施例2：2-(3-(苄氧基)丙基)-1-甲基-7-(1H-吡唑-3-基)-1H-咪唑并[4,5-d]噻吩并[3,2-b]吡啶-4-胺(2)Example 2: 2-(3-(Benzyloxy)propyl)-1-methyl-7-(1H-pyrazol-3-yl)-1H-imidazo[4,5-d]thieno[ 3,2-b]pyridin-4-amine (2)
Figure PCTCN2019085535-appb-000071
Figure PCTCN2019085535-appb-000071
氮气保护下将化合物1(100.0mg,0.231mmol)、化合物2a(3-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)-1H-吡唑)(89.970mg,0.463mmol)、Na 2CO 3(61.440mg，0.579mmol)和Pd(dppf)Cl 2·CH 2Cl 2(18.930mg，0.023mmol)置于25mL单口瓶中，加入DMF(2mL)、水(0.5mL)和EtOH(0.2mL)，氮气保护下加热至105℃反应过夜。冷却至室温，加入EA和水，萃取，减压浓缩有机相，残留物经Prep-HPLC分离纯化得到化合物2(7mg)。 Compound 1 (100.0 mg, 0.231 mmol), compound 2a (3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) under nitrogen atmosphere -1H-pyrazole) (89.970 mg, 0.463 mmol), Na 2 CO 3 (61.440 mg, 0.579 mmol) and Pd(dppf)Cl 2 ·CH 2 Cl 2 (18.930 mg, 0.023 mmol) in a 25 mL single-mouth bottle DMF (2 mL), water (0.5 mL) and EtOH (0.2 mL) were added and the mixture was heated to 105 ° C under nitrogen atmosphere overnight. After cooling to room temperature, EA and water were added, extracted, and the organic layer was evaporated.
MS(ESI,m/z):419.2[M+H]+。MS (ESI, m/z): 4121.
1H NMR(DMSO-d 6,400MHz)δ12.97(s,1H),7.83(s,1H),7.53(s,1H),7.33-7.25(m,5H),6.77(s,1H),6.12(s,2H),4.49(s,2H),3.90(s,3H),3.57(t,J＝6.4,2H),2.96(t,J＝7.6,2H),2.10-2.03(m,2H). 1 H NMR (DMSO-d 6 , 400MHz) δ12.97 (s, 1H), 7.83 (s, 1H), 7.53 (s, 1H), 7.33-7.25 (m, 5H), 6.77 (s, 1H), 6.12 (s, 2H), 4.49 (s, 2H), 3.90 (s, 3H), 3.57 (t, J = 6.4, 2H), 2.96 (t, J = 7.6, 2H), 2.10-2.03 (m, 2H) ).
Prep-HPLC分离条件：Prep-HPLC separation conditions:
仪器型号：Agilent 1260Instrument model: Agilent 1260
色谱柱：Waters XBridge Prep C 18OBD(19mm×150mm×5.0μm) Column: Waters XBridge Prep C 18 OBD (19mm × 150mm × 5.0μm)
色谱柱温：25℃Column temperature: 25 ° C
流速：20.0mL/minFlow rate: 20.0 mL/min
检测波长：214nm、254nm、280nmDetection wavelength: 214nm, 254nm, 280nm
流动相A：100％乙腈；流动相B：100％水，0.05％甲酸胺Mobile phase A: 100% acetonitrile; mobile phase B: 100% water, 0.05% formate
洗脱梯度：0min：30％A，70％B；20.0min：60％A，40％B。Elution gradient: 0 min: 30% A, 70% B; 20.0 min: 60% A, 40% B.
实施例3：3-(4-氨基-1-甲基-7-(1H-吡唑-3-基)-1H-咪唑并[4,5-d]噻吩并[3,2-b]吡啶-2-基)丙-1-醇(3)Example 3: 3-(4-Amino-1-methyl-7-(1H-pyrazol-3-yl)-1H-imidazo[4,5-d]thieno[3,2-b]pyridine -2-yl)propan-1-ol (3)
Figure PCTCN2019085535-appb-000072
Figure PCTCN2019085535-appb-000072
将化合物2(70.0mg,0.167mmol)置于25mL单口瓶中，加入TFA(3mL)，加热至76℃回流反应过夜。冷却至室温，加入MeOH，过滤除去不溶物，减压浓缩有机相，残留物经Prep-HPLC分离纯化得到化合物3(1mg)。Compound 2 (70.0 mg, 0.167 mmol) was placed in a 25 mL single-necked flask, TFA (3 mL) was added and the mixture was heated to reflux at 76 ° C overnight. After cooling to room temperature, MeOH was added, and the insoluble material was filtered, and the organic layer was evaporated.
MS(ESI,m/z):329.1[M+H]+。MS (ESI, m/z): 329.1 [M+H]+.
1H NMR(DMSO-d 6,400MHz)δ12.98(s,1H),7.84(s,1H),7.54(s,1H),6.78(s,1H),6.14(s,2H),4.63(t,J＝5.2,1H),3.93(s,3H),3.53(t,J＝5.6,2H),2.93(t,J＝7.6,2H),1.97-1.90(m,2H). 1 H NMR (DMSO-d 6 , 400 MHz) δ 12.98 (s, 1H), 7.84 (s, 1H), 7.54 (s, 1H), 6.78 (s, 1H), 6.14 (s, 2H), 4.63 ( t, J = 5.2, 1H), 3.93 (s, 3H), 3.53 (t, J = 5.6, 2H), 2.93 (t, J = 7.6, 2H), 1.97-1.90 (m, 2H).
Prep-HPLC：除以下两项，其余的条件与实施例2相同。Prep-HPLC: The remaining conditions were the same as in Example 2 except for the following two items.
洗脱梯度：0min：10％A，90％B；6.5min：26％A，74％B。Elution gradient: 0 min: 10% A, 90% B; 6.5 min: 26% A, 74% B.
实施例4：2-(3-(苄氧基)丙基)-1-甲基-7-苯基-1H-咪唑并[4,5-d]噻吩并[3,2-b]吡啶-4-胺(4)Example 4: 2-(3-(Benzyloxy)propyl)-1-methyl-7-phenyl-1H-imidazo[4,5-d]thieno[3,2-b]pyridine- 4-amine (4)
Figure PCTCN2019085535-appb-000073
Figure PCTCN2019085535-appb-000073
氮气保护下将化合物1(100.000mg,0.231mmol)、化合物4a(苯硼酸)(56.530mg,0.463mmol)、Na 2CO 3(61.440mg，0.579mmol)和Pd(dppf)Cl 2·CH 2Cl 2(9.470mg，0.012mmol)置于25mL单口瓶中，加入甲苯(2mL)、水(0.5mL)和EtOH(1mL)，氮气保护下加热至90℃反应2h。冷却至室温，加入EA和水，萃取，减压浓缩有机相，残留物经Prep-HPLC分离纯化得到化合物4(1mg)。 Compound 1 (100.000 mg, 0.231 mmol), compound 4a (phenylboronic acid) (56.530 mg, 0.463 mmol), Na 2 CO 3 (61.440 mg, 0.579 mmol) and Pd(dppf)Cl 2 ·CH 2 Cl under N2 2 (9.470 mg, 0.012 mmol) was placed in a 25 mL single-necked flask, and toluene (2 mL), water (0.5 mL) and EtOH (1 mL) were added, and the mixture was heated to 90 ° C for 2 h under nitrogen atmosphere. After cooling to room temperature, EA and water were added, extracted, and the organic layer was evaporated.
MS(ESI,m/z):429.2[M+H]+。MS (ESI, m/z): 429.2 [M+H]+.
1H NMR(DMSO-d 6,400MHz)δ7.81(d,J＝7.7Hz,2H),7.71(s,1H),7.48(t,J＝7.5Hz,2H),7.42–7.24(m,6H),6.21(s,2H),4.50(s,2H),3.93(s,3H),3.58(t,J＝6.4,2H),2.98(t,J＝7.6,2H),2.12-2.07(m,2H). 1 H NMR (DMSO-d 6 , 400 MHz) δ 7.81 (d, J = 7.7 Hz, 2H), 7.71 (s, 1H), 7.48 (t, J = 7.5 Hz, 2H), 7.42 - 7.24 (m, 6H), 6.21 (s, 2H), 4.50 (s, 2H), 3.93 (s, 3H), 3.58 (t, J = 6.4, 2H), 2.98 (t, J = 7.6, 2H), 2.12 - 2.07 ( m, 2H).
Prep-HPLC：除以下两项，其余的条件与实施例2相同。Prep-HPLC: The remaining conditions were the same as in Example 2 except for the following two items.
洗脱梯度：0min：40％A，60％B；20min：90％A，10％B。Elution gradient: 0 min: 40% A, 60% B; 20 min: 90% A, 10% B.
实施例5：3-(4-氨基-1-甲基-7-苯基-1H-咪唑并[4,5-d]噻吩并[3,2-b]吡啶-2-基)丙-1-醇(5)Example 5: 3-(4-Amino-1-methyl-7-phenyl-1H-imidazo[4,5-d]thieno[3,2-b]pyridin-2-yl)propan-1 -alcohol (5)
Figure PCTCN2019085535-appb-000074
Figure PCTCN2019085535-appb-000074
将化合物4(80.0mg,0.186mmol)置于25mL单口瓶中，加入TFA(3mL)，加热至76℃回流反应过夜。冷却至室温，加入MeOH，过滤除去不溶物，减压浓缩有机相，残留物经Prep-HPLC分离纯化得到化合物5(2mg)。Compound 4 (80.0 mg, 0.186 mmol) was placed in a 25 mL single-necked flask, TFA (3 mL) was added, and the mixture was heated to reflux at 76 ° C overnight. After cooling to room temperature, MeOH was added, and the residue was evaporated to dryness.
MS(ESI,m/z):339.1[M+H]+。MS (ESI, m/z): 339.1 [M+H]+.
1H NMR(DMSO-d 6,400MHz)δ7.79(d,J＝7.5Hz,2H),7.70(s,1H),7.47(t,J＝7.6Hz,2H),7.36(t,J＝7.3Hz,1H)，6.19(s,2H),4.62(t,J＝5.2,1H),3.94(s,3H),3.52(t,J＝5.6,2H),2.93(t,J＝7.6,2H),1.96-1.89(m,2H). 1 H NMR (DMSO-d 6 , 400 MHz) δ 7.79 (d, J = 7.5 Hz, 2H), 7.70 (s, 1H), 7.47 (t, J = 7.6 Hz, 2H), 7.36 (t, J = 7.3 Hz, 1H), 6.19 (s, 2H), 4.62 (t, J = 5.2, 1H), 3.94 (s, 3H), 3.52 (t, J = 5.6, 2H), 2.93 (t, J = 7.6, 2H), 1.96-1.89 (m, 2H).
Prep-HPLC：除以下两项，其余的条件与实施例2相同。Prep-HPLC: The remaining conditions were the same as in Example 2 except for the following two items.
洗脱梯度：0min：20％A，80％B；8.4min：45％A，55％B。Elution gradient: 0 min: 20% A, 80% B; 8.4 min: 45% A, 55% B.
实施例6：2-(3-(苄氧基)丙基)-1-甲基-7-(1H-吡唑-1-基)-1H-咪唑并[4,5-d]噻吩并[3,2-b]吡啶-4-胺(6)Example 6: 2-(3-(Benzyloxy)propyl)-1-methyl-7-(1H-pyrazol-1-yl)-1H-imidazo[4,5-d]thieno[ 3,2-b]pyridin-4-amine (6)
Figure PCTCN2019085535-appb-000075
Figure PCTCN2019085535-appb-000075
氮气保护下将1(200.0mg,0.464mmol)、化合物6a(1H-吡唑)(63.270mg,0.929mmol)、CH 3NHCH 2CH 2NHCH 3(16.390mg,0.186mmol)，Cs 2CO 3(302.820mg，0.929mmol)和CuI(17.700mg，0.092mmol)置于25mL干燥三口瓶中，加入干燥DMF(2mL)，氮气保护下加热至110℃反应过夜。冷却至室温，加入EA和水，萃取，减压浓缩有机相，残留物经Prep-HPLC分离纯化得到化合物6(1mg)。 1 (200.0 mg, 0.464 mmol), compound 6a (1H-pyrazole) (63.270 mg, 0.929 mmol), CH 3 NHCH 2 CH 2 NHCH 3 (16.390 mg, 0.186 mmol), Cs 2 CO 3 302.820 mg, 0.929 mmol) and CuI (17.700 mg, 0.092 mmol) were placed in a 25 mL dry three-necked flask, and dry DMF (2 mL) was added, and the mixture was heated to 110 ° C under nitrogen atmosphere overnight. After cooling to room temperature, EA and water were added, extracted, and the organic layer was evaporated.
MS(ESI,m/z):419.2[M+H]+。MS (ESI, m/z): 4121.
1H NMR(DMSO-d 6,400MHz)δ8.62(s,1H),7.75(s,1H),7.54(s,1H),7.33-7.27(m,5H),6.61(s,1H),6.20(s,2H),4.49(s,2H),3.88(s,3H),3.56(t,J＝5.6,2H),2.96(t,J＝7.6,2H),2.08-2.04(m,2H). 1 H NMR (DMSO-d 6 , 400 MHz) δ 8.62 (s, 1H), 7.75 (s, 1H), 7.54 (s, 1H), 7.33 - 7.27 (m, 5H), 6.61 (s, 1H), 6.20(s,2H),4.49(s,2H),3.88(s,3H),3.56(t,J=5.6,2H),2.96(t,J=7.6,2H),2.08-2.04(m,2H) ).
Prep-HPLC：除以下两项，其余的条件与实施例2相同。Prep-HPLC: The remaining conditions were the same as in Example 2 except for the following two items.
洗脱梯度：0min：30％A，70％B；8.0min：54％A，46％B。Elution gradient: 0 min: 30% A, 70% B; 8.0 min: 54% A, 46% B.
实施例7：3-(4-氨基-1-甲基-7-(1H-吡唑-1-基)-1H-咪唑并[4,5-d]噻吩并[3,2-b]吡啶-2- 基)丙-1-醇(7)Example 7: 3-(4-Amino-1-methyl-7-(1H-pyrazol-1-yl)-1H-imidazo[4,5-d]thieno[3,2-b]pyridine -2-yl)propan-1-ol (7)
Figure PCTCN2019085535-appb-000076
Figure PCTCN2019085535-appb-000076
将化合物6(130.0mg,0.310mmol)置于25mL单口瓶中，加入TFA(3mL)，加热至76℃回流反应过夜。冷却至室温，加入MeOH，过滤除去不溶物，减压浓缩有机相，残留物经Prep-HPLC分离纯化得到化合物7(1mg)。Compound 6 (130.0 mg, 0.310 mmol) was placed in a 25 mL single-necked flask, TFA (3 mL) was added, and the mixture was heated to reflux at 76 ° C overnight. After cooling to room temperature, MeOH was added, and the insoluble material was removed by filtration. The organic layer was concentrated under reduced pressure, and the residue was purified by Prep-HPLC to afford Compound 7 (1 mg).
MS(ESI,m/z):329.1[M+H]+。MS (ESI, m/z): 329.1 [M+H]+.
1H NMR(DMSO-d 6,400MHz)δ8.62(d,J＝2.4,1H),7.76(d,J＝1.6,1H),7.54(s,1H),6.62(t,J＝2.4,1H),6.20(s,2H),4.64(t,J＝5.2,1H),3.90(s,3H),3.53(t,J＝6.0,2H),2.93(t,J＝7.6,2H),1.96-1.89(m,2H). 1 H NMR (DMSO-d 6 , 400 MHz) δ 8.62 (d, J = 2.4, 1H), 7.76 (d, J = 1.6, 1H), 7.54 (s, 1H), 6.62 (t, J = 2.4, 1H), 6.20 (s, 2H), 4.64 (t, J = 5.2, 1H), 3.90 (s, 3H), 3.53 (t, J = 6.0, 2H), 2.93 (t, J = 7.6, 2H), 1.96-1.89 (m, 2H).
Prep-HPLC：除以下两项，其余的条件与实施例2相同。Prep-HPLC: The remaining conditions were the same as in Example 2 except for the following two items.
洗脱梯度：0min：10％A，90％B；8.4min：31％A，69％B。Elution gradient: 0 min: 10% A, 90% B; 8.4 min: 31% A, 69% B.
实施例8：2-(3-(苄氧基)丙基)-1-甲基-7-(6-甲基吡啶-2-基)-1H-咪唑并[4,5-d]噻吩并[3,2-b]吡啶-4-胺(66)Example 8: 2-(3-(Benzyloxy)propyl)-1-methyl-7-(6-methylpyridin-2-yl)-1H-imidazo[4,5-d]thiophene [3,2-b]pyridin-4-amine (66)
Figure PCTCN2019085535-appb-000077
Figure PCTCN2019085535-appb-000077
氮气保护下将化合物1(50.00mg,0.116mmol)、66a(6-甲基吡啶-2-基)硼酸(31.75mg,0.231mmol)、K 2CO 3(40.00mg，0.289mmol)和Pd(dppf)Cl 2·CH 2Cl 2(9.47mg，0.011mmol)置于25mL单口瓶中，加入DMF(2mL)和水(0.5mL)，氮气保护下加热至125℃反应过夜。冷却至室温，加入EA和水，萃取，减压浓缩有机相，残留物经Prep-HPLC分离纯化得到化合物66(2mg)。 Compound 1 (50.00 mg, 0.116 mmol), 66a (6-methylpyridin-2-yl)boronic acid (31.75 mg, 0.231 mmol), K 2 CO 3 (40.00 mg, 0.289 mmol) and Pd (dppf) Cl 2 ·CH 2 Cl 2 (9.47 mg, 0.011 mmol) was placed in a 25 mL single-necked flask, and DMF (2 mL) and water (0.5 mL) were added, and the mixture was heated to 125 ° C under nitrogen atmosphere overnight. After cooling to room temperature, EA and water were added, and the organic layer was evaporated.
MS(ESI,m/z):444.1[M+H] +。 MS (ESI, m / z) : 444.1 [M + H] +.
1H NMR(DMSO-d 6,400MHz)δ7.95-7.90(m,2H),7.76(t,J＝7.6,1H),7.34-7.18(m,6H),6.23(s,2H),4.51(s,2H),3.96(s,3H),3.58(t,J＝6.4,2H),2.99(t,J＝7.6,2H),2.55(s,3H),2.06-2.12(m,2H). 1 H NMR (DMSO-d 6 , 400 MHz) δ 7.95-7.90 (m, 2H), 7.76 (t, J = 7.6, 1H), 7.34 - 7.18 (m, 6H), 6.23 (s, 2H), 4.51 (s, 2H), 3.96 (s, 3H), 3.58 (t, J = 6.4, 2H), 2.99 (t, J = 7.6, 2H), 2.55 (s, 3H), 2.06-2.12 (m, 2H) .
Prep-HPLC：除以下两项，其余的条件与实施例2相同。Prep-HPLC: The remaining conditions were the same as in Example 2 except for the following two items.
洗脱梯度：0min：30％A，70％B；12.0min：90％A，10％B。Elution gradient: 0 min: 30% A, 70% B; 12.0 min: 90% A, 10% B.
实施例9：3-(4-氨基-7-(1H-吡唑-3-基)-1H-咪唑并[4,5-d]噻吩并[3,2-b]吡啶-2-基)丙-1-醇(9)Example 9: 3-(4-Amino-7-(1H-pyrazol-3-yl)-1H-imidazo[4,5-d]thieno[3,2-b]pyridin-2-yl) Propan-1-ol (9)
Figure PCTCN2019085535-appb-000078
Figure PCTCN2019085535-appb-000078
第一步：2-(3-(苄氧基)丙基)-1-(4-甲氧基苄基)-7-(1H-吡唑-3-基)-1H-咪唑并[4,5-d]噻吩并[3,2-b]吡啶-4-胺(9j)First step: 2-(3-(benzyloxy)propyl)-1-(4-methoxybenzyl)-7-(1H-pyrazol-3-yl)-1H-imidazo[4, 5-d]thieno[3,2-b]pyridin-4-amine (9j)
将化合物9g(50mg,93.03μmol)、3-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-1H-吡唑(36mg,186.06μmol)、Pd(dppf)Cl 2(8mg,9.76μmol)、碳酸钠(25mg,232.57μmol)加入3mL DMF和0.3mL水的混合溶剂中，N 2保护下加热至110℃搅拌反应反应3h，减压浓缩反应溶剂至干，得到化合物9j(40mg)。MS(ESI,m/z):525.2[M+H] +. Compound 9g (50mg, 93.03μmol), 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (36mg , 186.06 μmol), Pd(dppf)Cl 2 (8 mg, 9.76 μmol), sodium carbonate (25 mg, 232.57 μmol), added to a mixed solvent of 3 mL of DMF and 0.3 mL of water, heated to 110 ° C under N 2 protection and stirred for 3 h. The reaction solvent was concentrated to dryness under reduced pressure to give Compound 9j (40mg). MS (ESI, m/z): 525.2 [M+H] + .
第二步：3-(4-氨基-7-(1H-吡唑-3-基)-1H-咪唑并[4,5-d]噻吩并[3,2-b]吡啶-2-基)丙-1-醇(9)Second step: 3-(4-Amino-7-(1H-pyrazol-3-yl)-1H-imidazo[4,5-d]thieno[3,2-b]pyridin-2-yl) Propan-1-ol (9)
将化合物9j(150mg,285.91μmol)加入5mL三氟乙酸中，80℃搅拌反应20h，抽滤除去不溶物，浓缩滤液，通过Prep-HPLC分离纯化(洗脱条件1)，冻干得到化合物9的甲酸盐9s(12mg)。Compound 9j (150 mg, 285.91 μmol) was added to 5 mL of trifluoroacetic acid, and the reaction was stirred at 80 ° C for 20 hours. The insoluble material was removed by suction filtration, and the filtrate was concentrated and purified by Prep-HPLC (elution condition 1), and lyophilized to give compound 9 Formate 9s (12mg).
MS(ESI,m/z):315.1[M+H] +. MS (ESI, m/z): 315.1 [M+H] + .
1H NMR(DMSO-d 6,400MHz)δ13.22-12.10(br,2H),8.19(s,1H),7.79(s,1H),7.48(s,1H),6.72(s,1H),6.06(s,2H),4.63(s,1H),3.49(t,J＝6.4Hz,2H),2.89(t,J＝7.6Hz,2H),2.02–1.90(m,2H). 1 H NMR (DMSO-d 6 , 400MHz) δ13.22-12.10 (br, 2H), 8.19 (s, 1H), 7.79 (s, 1H), 7.48 (s, 1H), 6.72 (s, 1H), 6.06 (s, 2H), 4.63 (s, 1H), 3.49 (t, J = 6.4 Hz, 2H), 2.89 (t, J = 7.6 Hz, 2H), 2.02 - 1.90 (m, 2H).
实施例10：3-(4-氨基-7-(1H-吡唑-1-基)-1H-咪唑并[4,5-d]噻吩并[3,2-b]吡啶-2-基)丙-1-醇(10)Example 10: 3-(4-Amino-7-(1H-pyrazol-1-yl)-1H-imidazo[4,5-d]thieno[3,2-b]pyridin-2-yl) Prop-1-ol (10)
Figure PCTCN2019085535-appb-000079
Figure PCTCN2019085535-appb-000079
第一步：2-(3-(苄氧基)丙基)-1-(4-甲氧基苄基)-7-(1H-吡唑-1-基)-1H-咪唑并[4,5-d]噻吩并[3,2-b]吡啶-4-胺(10a)First step: 2-(3-(benzyloxy)propyl)-1-(4-methoxybenzyl)-7-(1H-pyrazol-1-yl)-1H-imidazo[4, 5-d]thieno[3,2-b]pyridin-4-amine (10a)
将化合物9g(200mg,372.80μmol)、1H-吡唑(51mg,745.60μmol)、CuI(28mg,149.12μmol)、碳酸铯(243mg,745.60μmol)、N,N’-二甲基乙二胺(29mg,298.24μmol)加入2mL DMF中，N 2保护下加热至120℃搅拌反应反应20h。水洗，EA萃取，减压浓缩反应溶 剂至干，得到化合物10a(150mg)。MS(ESI,m/z):525.2[M+H] +. Compound 9g (200mg, 372.80μmol), 1H-pyrazole (51mg, 745.60μmol), CuI (28mg, 149.12μmol), cesium carbonate (243mg, 745.60μmol), N,N'-dimethylethylenediamine ( 29 mg, 298.24 μmol) was added to 2 mL of DMF, and heated to 120 ° C under N 2 protection to stir the reaction for 20 h. It was washed with water, extracted with EA, and the solvent was evaporated. MS (ESI, m/z): 525.2 [M+H] + .
第二步：3-(4-氨基-7-(1H-吡唑-3-基)-1H-咪唑并[4,5-d]噻吩并[3,2-b]吡啶-2-基)-1-丙醇(10)Second step: 3-(4-Amino-7-(1H-pyrazol-3-yl)-1H-imidazo[4,5-d]thieno[3,2-b]pyridin-2-yl) -1-propanol (10)
将化合物10a(150mg,285.91μmol)加入3mL三氟乙酸中，80℃搅拌反应26h。抽滤除去不溶物，浓缩滤液，通过Prep-HPLC分离纯化(洗脱条件1)，冻干得到化合物10(11mg)。Compound 10a (150 mg, 285.91 μmol) was added to 3 mL of trifluoroacetic acid, and the reaction was stirred at 80 ° C for 26 h. The insoluble material was removed by suction filtration, and the filtrate was concentrated, purified and purified by Prep-HPLC (elution condition 1), and lyophilized to give compound 10 (11 mg).
MS(ESI,m/z):315.1[M+H] +. MS (ESI, m/z): 315.1 [M+H] + .
1H NMR(DMSO-d 6,400MHz)δ12.80(s,1H),8.57(s,1H),7.74(s,1H),7.47(s,1H),6.58(s,1H),6.12(s,2H),4.63(s,1H),3.49(t,J＝5.2Hz,2H),2.89(d,J＝7.2Hz,2H),2.01–1.90(m,2H). 1 H NMR (DMSO-d 6 , 400MHz) δ12.80 (s, 1H), 8.57 (s, 1H), 7.74 (s, 1H), 7.47 (s, 1H), 6.58 (s, 1H), 6.12 ( s, 2H), 4.63 (s, 1H), 3.49 (t, J = 5.2 Hz, 2H), 2.89 (d, J = 7.2 Hz, 2H), 2.01 - 1.90 (m, 2H).
实施例11：1-甲基-2-((4-甲基哌嗪-1-基)甲基)-7-(1H-吡唑-3-基)-1H-咪唑并[4,5-d]噻吩并[3,2-b]吡啶-4-胺(37)Example 11:1-Methyl-2-((4-methylpiperazin-1-yl)methyl)-7-(1H-pyrazol-3-yl)-1H-imidazo[4,5- d] thieno[3,2-b]pyridin-4-amine (37)
Figure PCTCN2019085535-appb-000080
Figure PCTCN2019085535-appb-000080
第一步：2-(苄氧基)-N-(7-(甲胺基)噻吩并[3,2-b]吡啶-6-基)乙酰胺(11a)First step: 2-(benzyloxy)-N-(7-(methylamino)thieno[3,2-b]pyridin-6-yl)acetamide (11a)
将化合物1e(3.0g,16.7mmol)、苄氧基乙酸(4.17g,25.1mmol)、HATU(7.63g,20mmol)、N,N-二异丙基乙胺(4.33g,33.4mmol)加入30mL N,N-二甲基甲酰胺中，25℃下搅拌反应4h。将反应混合物倒入冰水中，经乙酸乙酯萃取后浓缩有机相，再经快速柱层析(洗脱剂体系A)得化合物11a(4.8g)。MS(ESI,m/z):328.1[M+H] +. Compound 1e (3.0 g, 16.7 mmol), benzyloxyacetic acid (4.17 g, 25.1 mmol), HATU (7.63 g, 20 mmol), N,N-diisopropylethylamine (4.33 g, 33.4 mmol) were added to 30 mL The reaction was stirred at 25 ° C for 4 h in N,N-dimethylformamide. The reaction mixture was poured into ice water, extracted with ethyl acetate, and then evaporated. MS (ESI, m/z): 328.1 [M+H] + .
第二步：2-((苄氧基)甲基)-1-甲基-1H-咪唑并[4,5-d]噻吩并[3,2-b]吡啶(11b)Second step: 2-((benzyloxy)methyl)-1-methyl-1H-imidazo[4,5-d]thieno[3,2-b]pyridine (11b)
将化合物11a(2.0g,6.11mmol)、氢氧化钠(0.73g,18.33mmol)、加入20mL乙醇中，升温至90℃搅拌反应2h。将反应混合物用6.0N盐酸调PH＝7.0，浓缩至干，再经快速柱层析(洗脱剂体系A)得化合物11b(1.2g)。MS(ESI,m/z):310.2[M+H] +. The compound 11a (2.0 g, 6.11 mmol) and sodium hydroxide (0.73 g, 18.33 mmol) were added to 20 mL of ethanol, and the mixture was heated to 90 ° C and stirred for 2 h. The reaction mixture was adjusted to pH 7.0 with 6.0N hydrochloric acid and evaporated to dryness. MS (ESI, m/z): 310.2 [M+H] + .
第三步：2-((苄氧基)甲基)-1-甲基-1H-咪唑并[4,5-d]噻吩并[3,2-b]吡啶-5-氧(11c)Third step: 2-((benzyloxy)methyl)-1-methyl-1H-imidazo[4,5-d]thieno[3,2-b]pyridine-5-oxo (11c)
将化合物11b(1.2g,3.88mmol)、mCPBA(1.0g,5.82mmol)加入20mL二氯甲烷中， 室温下搅拌反应16h。将反应混合物倒入饱和碳酸氢钠水溶液中，有机相经水洗涤两次，碘化钾淀粉试纸检测无过氧化物残留时，减压浓缩有机相至干，再经快速柱层析(洗脱剂体系A)得化合物11c(1.0g)。MS(ESI,m/z):326.1[M+H] +. Compound 11b (1.2 g, 3.88 mmol) and mCPBA (1.0 g, 5.82 mmol) were added to 20 mL of dichloromethane, and the mixture was stirred at room temperature for 16 h. The reaction mixture was poured into a saturated aqueous solution of sodium hydrogencarbonate, and the organic phase was washed twice with water. The potassium iodide starch paper was used to detect the residue without peroxide. The organic phase was concentrated to dryness under reduced pressure and then subjected to flash column chromatography (eluent system) A) Compound 11c (1.0 g) was obtained. MS (ESI, m/z): 326.1 [M+H] + .
第四步：2-((苄氧基)甲基)-1-甲基-1H-咪唑并[4,5-d]噻吩并[3,2-b]吡啶-4-胺(11d)Fourth step: 2-((benzyloxy)methyl)-1-methyl-1H-imidazo[4,5-d]thieno[3,2-b]pyridin-4-amine (11d)
将化合物11c(1.0g,3.07mmol)、对甲苯磺酰氯(0.48g,6.76mmol)、加入20mL二氯甲烷和5mL氨水中，25℃搅拌反应16h。将反应混合物倒入冰水中，二氯甲烷萃取后浓缩有机相，再经快速柱层析(洗脱剂体系A)得到化合物11d(0.86g)。MS(ESI,m/z):325.1[M+H] +. Compound 11c (1.0 g, 3.07 mmol) and p-toluenesulfonyl chloride (0.48 g, 6.76 mmol) were added to 20 mL of dichloromethane and 5 mL of aqueous ammonia, and the reaction was stirred at 25 ° C for 16 h. The reaction mixture was poured into ice water, extracted with dichloromethane, and then evaporated. MS (ESI, m/z): 325.1 [M+H] + .
第五步：2-((苄氧基)甲基)-7-溴-1-甲基-1H-咪唑并[4,5-d]噻吩并[3,2-b]吡啶-4-胺(11e)Step 5: 2-((Benzyloxy)methyl)-7-bromo-1-methyl-1H-imidazo[4,5-d]thieno[3,2-b]pyridin-4-amine (11e)
将化合物11d(0.8g,2.47mmol)、N-溴代丁二酰亚胺(0.88g,4.93mmol)、加入10mL氯仿/冰醋酸＝1:1的混合溶剂中，25℃下搅拌反应2h。将反应混合物倒入冰水中，经二氯甲烷萃取后，浓缩有机相，再经快速柱层析(洗脱剂体系A)得化合物11e(0.75g)。MS(ESI,m/z):403.0[M+H] +. The compound 11d (0.8 g, 2.47 mmol) and N-bromosuccinimide (0.88 g, 4.93 mmol) were added to a mixed solvent of 10 mL of chloroform / glacial acetic acid = 1:1, and the reaction was stirred at 25 ° C for 2 h. The reaction mixture was poured into ice water and extracted with dichloromethane. MS (ESI, m/z): 403.0 [M+H] +
第六步：(4-胺-7-溴-1-甲基-1H-咪唑并[4,5-d]噻吩并[3,2-b]吡啶-2-基)甲醇(11f)Step 6: (4-Amine-7-bromo-1-methyl-1H-imidazo[4,5-d]thieno[3,2-b]pyridin-2-yl)methanol (11f)
将化合物11e(0.75g,1.86mmol)加入10mL三氟乙酸中，80℃搅拌下搅拌反应16h。反应混合物浓缩至干，复溶于甲醇中，用6N氢氧化钠溶液调PH＝9.0，经乙酸乙酯萃取后浓缩有机相，得到化合物粗品11f(0.60g)。MS(ESI,m/z):313.0[M+H] +. Compound 11e (0.75 g, 1.86 mmol) was added to 10 mL of trifluoroacetic acid, and stirred at 80 ° C for 16 h. The reaction mixture was concentrated to dryness. EtOAc mjjjjjjjjjjjjj MS (ESI, m/z): 313.0 [M+H] +
第七步：7-溴-2-(氯甲基)-1-甲基-1H-咪唑并[4,5-d]噻吩并[3,2-b]吡啶-4-胺(11g)Step 7: 7-Bromo-2-(chloromethyl)-1-methyl-1H-imidazo[4,5-d]thieno[3,2-b]pyridin-4-amine (11 g)
将化合物11f(0.6g,1.92mmol)加入4mL二氯亚砜与2mL二氯甲烷的混合溶液中，25℃下搅拌反应16h。将反应混合物浓缩至干，复溶于二氯甲烷中，滴加甲醇淬灭残余的二氯亚砜，溶剂浓缩至干，再经快速柱层析(洗脱剂体系A)得到化合物11g(0.48g)。MS(ESI,m/z):333.0[M+H] +. Compound 11f (0.6 g, 1.92 mmol) was added to a mixed solution of 4 mL of dichloromethane and 2 mL of dichloromethane, and the reaction was stirred at 25 ° C for 16 h. The reaction mixture was concentrated to dryness, taken-up methylene chloride, and then evaporated toluene toluene toluene, and the solvent was concentrated to dryness and then purified by flash column chromatography (eluent system A) to give compound 11 g (0.48) g). MS (ESI, m/z): 333.0 [M+H] + .
第八步：7-溴-1-甲基-2-((4-甲基哌嗪-1-基)甲基)-1H-咪唑并[4,5-d]噻吩并[3,2-b]吡啶-4-胺(11h)Step 8: 7-Bromo-1-methyl-2-((4-methylpiperazin-1-yl)methyl)-1H-imidazo[4,5-d]thieno[3,2- b] Pyridin-4-amine (11h)
将化合物11g(120mg,0.36mmol)、N-甲基哌嗪(217mg,2.17mmol)、四丁基碘化铵(26.7mg,0.072mmol)、TEA(219mg,2.17mmol)加入5mL甲苯中，N 2保护下加热至100℃反应16h。旋干反应溶剂再经快速柱层析(洗脱剂体系A)得到化合物11h(110mg)。MS(ESI,m/z):395.0[M+H] +. Compound 11g (120mg, 0.36mmol), N-methylpiperazine (217mg, 2.17mmol), tetrabutylammonium iodide (26.7mg, 0.072mmol), TEA (219mg, 2.17mmol) were added to 5mL of toluene, N 2 Heated to 100 ° C under the protection for 16 h. The reaction solvent was dried to dryness and purified by flash column chromatography (eluent system A) to afford compound 11h (110mg). MS (ESI, m/z): 395.0 [M+H] + .
第九步：1-甲基-2-((4-甲基哌嗪-1-基)甲基)-7-(1H-吡唑-3-基)-1H-咪唑并[4,5-d]噻吩并[3,2-b]吡啶-4-胺(37)Step 9: 1-Methyl-2-((4-methylpiperazin-1-yl)methyl)-7-(1H-pyrazol-3-yl)-1H-imidazo[4,5- d] thieno[3,2-b]pyridin-4-amine (37)
将化合物11h(110mg,0.28mmol)、3-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-1H-吡唑(108mg,0.56mmol)、Pd(dppf)Cl 2(90mg,0.11mmol)、碳酸钠(88mg,0.83mmol)加入2.0mL DMF和0.5mL水的混合溶剂中，N 2保护下加热至110℃搅拌反应反应16h。减压 浓缩反应溶剂至干，通过Prep-HPLC分离纯化(洗脱条件2)得到化合物37(6mg)。 Compound 11h (110 mg, 0.28 mmol), 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (108 mg , 0.56 mmol), Pd(dppf)Cl 2 (90 mg, 0.11 mmol), sodium carbonate (88 mg, 0.83 mmol), added to a mixed solvent of 2.0 mL of DMF and 0.5 mL of water, and heated to 110 ° C under N 2 to agitate the reaction. 16h. The reaction solvent was concentrated to dryness under reduced pressure and purified by purified-------
MS(ESI,m/z):383.2[M+H] +. MS (ESI, m/z): 383.2 [M+H] + .
1H NMR(DMSO-d 6,400MHz)δ12.99(s,1H),7.83(s,1H),7.53(s,1H),6.78(s,1H),6.24(s,2H),4.00(s,3H),3.82–3.71(m,2H),2.45–2.31(m,8H),2.14(s,3H). 1 H NMR (DMSO-d 6 , 400 MHz) δ 12.99 (s, 1H), 7.83 (s, 1H), 7.53 (s, 1H), 6.78 (s, 1H), 6.24 (s, 2H), 4.00 ( s, 3H), 3.82–3.71 (m, 2H), 2.45–2.31 (m, 8H), 2.14 (s, 3H).
实施例12：Example 12
3-((4-氨基-1-甲基-7-(1H-吡唑-3-基)-1H-咪唑[4,5-d]噻吩并[3,2-b]吡啶-2-基)氨基)丙-1-醇(67)3-((4-Amino-1-methyl-7-(1H-pyrazol-3-yl)-1H-imidazole[4,5-d]thieno[3,2-b]pyridin-2-yl )amino)propan-1-ol (67)
Figure PCTCN2019085535-appb-000081
Figure PCTCN2019085535-appb-000081
第一步：1-甲基-1H-咪唑[4,5-d]噻吩并[3,2-b]吡啶-2(3H)-硫酮(12a)First step: 1-methyl-1H-imidazo[4,5-d]thieno[3,2-b]pyridine-2(3H)-thione (12a)
将化合物1e(1.00g,5.58mmol)、二硫化碳(2.54g,33.36mmol)加入30mL无水乙醇中，加热至85℃反应2.5h。反应混合物浓缩得到化合物12a(1.23g)。MS(ESI,m/z):222.0[M+H] +. Compound 1e (1.00 g, 5.58 mmol), carbon disulfide (2.54 g, 33.36 mmol) was added to 30 mL of absolute ethanol and heated to 85 ° C for 2.5 h. The reaction mixture was concentrated to give Compound 12a (1.23 g). MS (ESI, m/z): 222.0 [M+H] + .
第二步：1-甲基-2-甲硫基-1H-咪唑[4,5-d]噻吩并[3,2-b]吡啶(12b)Second step: 1-methyl-2-methylthio-1H-imidazole [4,5-d]thieno[3,2-b]pyridine (12b)
将化合物12a(1.23g,5.56mmol)、碘甲烷(0.95g,6.67mmol)、K 2CO 3(2.30g,16.67mmol)加入50mL丙酮中，室温下反应16h。反应混合物浓缩并加水稀释，EA提取三次(100mL×3)，合并后无水硫酸钠干燥，浓缩得到化合物12b(1.1g)。MS(ESI,m/z):236.0[M+H] +. Compound 12a (1.23 g, 5.56 mmol), methyl iodide (0.95 g, 6.67 mmol), K 2 CO 3 (2.30 g, 16.67 mmol) was added to 50 mL of acetone and allowed to react at room temperature for 16 h. The reaction mixture was concentrated and diluted with water and EtOAc EtOAc EtOAcjjjjj MS (ESI, m / z) : 236.0 [M + H] +.
第三步：1-甲基-2-甲磺酰-1H-咪唑[4,5-d]噻吩并[3,2-b]吡啶(12c)Third step: 1-methyl-2-methanesulfonyl-1H-imidazole [4,5-d]thieno[3,2-b]pyridine (12c)
将化合物12b(1.10g,4.67mmol)、高锰酸钾(1.33g,8.41mmol)加入到50mL水和5mL冰乙酸的混合溶剂中，室温下反应3h。将体系置于冰浴下降温至5℃，向体系中滴加饱和亚硫酸氢钠水溶液至紫色褪去，抽滤，滤饼烘干得到化合物12c(1.1g)。MS(ESI, m/z):268.0[M+H] +. Compound 12b (1.10 g, 4.67 mmol) and potassium permanganate (1.33 g, 8.41 mmol) were added to a mixed solvent of 50 mL of water and 5 mL of glacial acetic acid, and reacted at room temperature for 3 h. The system was placed in an ice bath and the temperature was lowered to 5 ° C, and a saturated aqueous solution of sodium hydrogensulfite was added dropwise to the mixture to remove purple, suction filtered, and the cake was dried to give compound 12c (1.1 g). MS (ESI, m/z): 268.0 [M+H] + .
第四步：3-((1-甲基-1H-咪唑[4,5-d]噻吩并[3,2-b]吡啶-2-基)氨基)丙-1-醇(12d)Step 4: 3-((1-Methyl-1H-imidazo[4,5-d]thieno[3,2-b]pyridin-2-yl)amino)propan-1-ol (12d)
将化合物12c(0.80g,2.99mmol)、3-氨基-1-丙醇(2.95g,39.22mmol)加入10mL DMF中，加热至120℃反应3h。加水稀释，EA提取三次(100mL×3)，合并后无水硫酸钠干燥，经薄层层析(洗脱剂体系A)得到化合物12d(450mg)。MS(ESI,m/z):263.1[M+H] +. Compound 12c (0.80 g, 2.99 mmol) and 3-amino-1-propanol (2.95 g, 39.22 mmol) were added to 10 mL of DMF and heated to 120 ° C for 3 h. It was diluted with water, and extracted with EA three times (100 mL×3), and dried over anhydrous sodium sulfate. MS (ESI, m/z): 263.1 [M+H] + .
第五步：N-(3-(苄氧基)丙基)-N-(4-甲氧基苄基)-1-甲基-1H-咪唑并[4,5-d]噻吩并[3,2-b]吡啶-2-胺(12e)Step 5: N-(3-(Benzyloxy)propyl)-N-(4-methoxybenzyl)-1-methyl-1H-imidazo[4,5-d]thieno[3 ,2-b]pyridin-2-amine (12e)
将化合物12d(200mg,0.76mmol)加入15mL DMF中，将体系置于冰盐浴下降温至0℃，继续依次向体系中加入60％NaH(29.80mg,0.78mmol)和对甲氧基苄氯(119.40mg,0.76mmol)，移至室温下反应1h，再依次向体系中加入60％NaH(29.80mg,0.78mmol)和溴化苄(130.40mg,0.76mmol)，继续于室温下反应1h。加水稀释，EA提取三次(100mL×3)，合并后无水硫酸钠干燥，经薄层层析(洗脱剂体系B)得到化合物12e(210mg)。MS(ESI,m/z):473.2[M+H] +. Compound 12d (200 mg, 0.76 mmol) was added to 15 mL of DMF, and the system was placed in an ice-salt bath to warm to 0 ° C. Then, 60% NaH (29.80 mg, 0.78 mmol) and p-methoxybenzyl chloride were added to the system. (119.40 mg, 0.76 mmol), and allowed to react at room temperature for 1 h. Then, 60% NaH (29.80 mg, 0.78 mmol) and benzyl bromide (130.40 mg, 0.76 mmol) were added to the system, and the reaction was continued at room temperature for 1 h. It was diluted with water, and extracted with EA three times (100 mL×3), dried over anhydrous sodium sulfate and evaporated. MS (ESI, m/z): 473.2 [M+H] + .
第六步：N-(3-(苄氧基)丙基)-7-溴-N-(4-甲氧基苄基)-1-甲基-1H-咪唑并[4,5-d]噻吩并[3,2-b]吡啶-2-胺(12f)Step 6: N-(3-(Benzyloxy)propyl)-7-bromo-N-(4-methoxybenzyl)-1-methyl-1H-imidazo[4,5-d] Thieno[3,2-b]pyridin-2-amine (12f)
将化合物12e(210mg,0.44mmol)加入到3mL DMF和0.5mL冰乙酸的混合溶剂中，继续向体系中加入NBS(158mg,0.89mmol)，加热至65℃反应0.5h。反应混合物加水稀释，EA提取三次(50mL×3)，合并后无水硫酸钠干燥。经柱层析(洗脱剂体系B)得到化合物12f(100mg)。MS(ESI,m/z):551.1[M+H] +. Compound 12e (210 mg, 0.44 mmol) was added to a mixed solvent of 3 mL of DMF and 0.5 mL of glacial acetic acid, and NBS (158 mg, 0.89 mmol) was further added to the system and heated to 65 ° C for 0.5 h. The reaction mixture was diluted with water and extracted with EA (3 mL) (3 mL). Column chromatography (eluent system B) gave compound 12f (100 mg). MS (ESI, m/z): 551.1 [M+H] + .
第七步：2-((3-苄氧基)丙基)(4-甲氧基苄基)氨基)-7-溴-1-甲基-1H-咪唑[4,5-d]噻吩并[3,2-b]吡啶-5-氧化物(12g)Step 7: 2-((3-Benzyloxy)propyl)(4-methoxybenzyl)amino)-7-bromo-1-methyl-1H-imidazole [4,5-d]thiophene [3,2-b]pyridine-5-oxide (12g)
将化合物12f(100mg,0.18mmol)加入10mL DCM中，继续向体系中加入mCPBA(38mg,0.22mmol)，室温下反应3h。反应混合物用饱和碳酸氢钠洗涤两次(50mL×2)，有机层无水硫酸钠干燥，浓缩后得到化合物12g(103mg)。MS(ESI,m/z):567.1[M+H] +. Compound 12f (100 mg, 0.18 mmol) was added to 10 mL DCM and mCPBA (38 mg, 0.22 mmol) was then added to the system and allowed to react at room temperature for 3 h. The reaction mixture was washed twice with saturated aqueous sodium hydrogen sulfate (50 mL×2). MS (ESI, m/z): 567.1 [M+H] + .
第八步：N 2-(3-(苄氧基)丙基)-7-溴-N2-(4-甲氧基苄基)-1-甲基-1H-咪唑[4,5-d]噻吩并[3,2-b]吡啶-2,4-二胺(12h) Step 8: N 2 -(3-(Benzyloxy)propyl)-7-bromo-N2-(4-methoxybenzyl)-1-methyl-1H-imidazole [4,5-d] Thieno[3,2-b]pyridine-2,4-diamine (12h)
将化合物12g(103mg,0.18mmol)加入15mL DCM中，继续依次向体系中加入2mL氨水和对甲苯磺酰氯(100mg,1.42mmol)，室温下反应3h。反应混合物用DCM稀释，水洗涤三次(50mL×3)，有机层无水硫酸钠干燥。经柱层析(洗脱剂体系B)得到化合物12h(15mg)。MS(ESI,m/z):566.1[M+H] +. The compound 12 g (103 mg, 0.18 mmol) was added to 15 mL of DCM, and then 2 mL aqueous ammonia and p-toluenesulfonyl chloride (100 mg, 1.42 mmol) were added to the system, and the mixture was reacted at room temperature for 3 h. The reaction mixture was diluted with EtOAc (EtOAc)EtOAc. Column chromatography (eluent system B) gave compound 12h (15 mg). MS (ESI, m/z): 566.1 [M+H] + .
第九步：N 2-(3-(苄氧基)丙基)-N 2-(4-甲氧基苄基)-1-甲基-7-(1H-吡唑-3-基)-1H-咪唑[4,5-d]噻吩并[3,2-b]吡啶-2,4-二胺(12i) Ninth step: N 2 -(3-(benzyloxy)propyl)-N 2 -(4-methoxybenzyl)-1-methyl-7-(1H-pyrazol-3-yl)- 1H-imidazole [4,5-d]thieno[3,2-b]pyridine-2,4-diamine (12i)
将化合物12h(55mg,97.09μmol)、1H-吡唑-3-硼酸频哪酯(35mg,194.17μmol)、[1,1'- 双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(8mg,9.71μmol)、K 2CO 3(34mg,242.72μmol)加入到2mL DMF和0.5mL水的混合溶剂中，N 2保护下加热至120℃反应2h。体系硅藻土过滤，滤液加水稀释，EA提取三次(50mL×3)，合并后无水硫酸钠干燥，浓缩得到化合物12i(54mg)。MS(ESI,m/z):554.2[M+H]+. Compound 12h (55mg, 97.09μmol), 1H-pyrazole-3-boronic acid pinacol ester (35mg, 194.17μmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride A methyl chloride complex (8 mg, 9.71 μmol), K 2 CO 3 (34 mg, 242.72 μmol) was added to a mixed solvent of 2 mL of DMF and 0.5 mL of water, and heated to 120 ° C for 2 h under N 2 protection. The system was filtered through celite, and the filtrate was diluted with water, and then extracted with EA three times (50mL×3), and then dried over anhydrous sodium sulfate and concentrated to give compound 12i (54mg). MS (ESI, m/z): 554.2 [M+H]+.
第十步：3-((4-氨基-1-甲基-7-(1H-吡唑-3-基)-1H-咪唑[4,5-d]噻吩并[3,2-b]吡啶-2-基)氨基)丙-1-醇(67)Step 10: 3-((4-Amino-1-methyl-7-(1H-pyrazol-3-yl)-1H-imidazole[4,5-d]thieno[3,2-b]pyridine -2-yl)amino)propan-1-ol (67)
将化合物12i(54mg,97.09μmol)加入10mL三氟乙酸中，加热至75℃反应16h，体系浓缩并用甲醇稀释，饱和碳酸钾调节体系pH＝9，室温下搅拌0.5h，抽滤，滤液通过Prep-HPLC分离纯化(洗脱条件3)，冻干得到化合物67的甲酸盐67s(7mg)。The compound 12i (54 mg, 97.09 μmol) was added to 10 mL of trifluoroacetic acid, and heated to 75 ° C for 16 h. The system was concentrated and diluted with methanol. The saturated potassium carbonate was adjusted to pH=9, stirred at room temperature for 0.5 h, filtered and filtered. -HPLC separation and purification (elution condition 3), lyophilized to give the title compound 67s (7 mg).
MS(ESI,m/z):344.1[M+H] +. MS (ESI, m/z): 344.1 [M+H] + .
1H NMR(DMSO-d 6,400MHz)δ13.57(s,1H),13.21(s,1H),7.98–7.76(m,3H),7.63(s,1H),7.20(s,1H),6.86(s,1H),4.54(s,1H),3.78(s,3H),3.55–3.46(m,4H),1.85–1.77(m,2H). 1 H NMR (DMSO-d 6 , 400 MHz) δ 13.57 (s, 1H), 13.21 (s, 1H), 7.78 - 7.76 (m, 3H), 7.63 (s, 1H), 7.20 (s, 1H), 6.86(s,1H), 4.54(s,1H), 3.78(s,3H), 3.55–3.46(m,4H),1.85–1.77(m,2H).
实施例13：Example 13
1-甲基-2-(3-吗啉丙基)-7-(1H-吡唑-3-基)-1H-咪唑并[4,5-d]噻吩并[3,2-b]吡啶-4-胺(68)1-methyl-2-(3-morpholinyl)-7-(1H-pyrazol-3-yl)-1H-imidazo[4,5-d]thieno[3,2-b]pyridine -4-amine (68)
Figure PCTCN2019085535-appb-000082
Figure PCTCN2019085535-appb-000082
第一步：7-溴-1-甲基-2-(3-吗啉丙基)-1H-咪唑[4,5-d]噻吩并[3,2-b]吡啶-4-胺(13a)First step: 7-bromo-1-methyl-2-(3-morpholinylpropyl)-1H-imidazo[4,5-d]thieno[3,2-b]pyridin-4-amine (13a )
将化合物1k(30mg,0.08mmol)、吗啉(22mg,0.25mmol)、TEA(26mg,0.25mmol)、四丁基碘化铵(3mg,8.42μmol)加入3mL甲苯中，氮气置换后加热至100℃反应16h。反应混合物浓缩得到化合物13a(35mg)。MS(ESI,m/z):410.1[M+H] +. Compound 1k (30 mg, 0.08 mmol), morpholine (22 mg, 0.25 mmol), TEA (26 mg, 0.25 mmol), tetrabutylammonium iodide (3 mg, 8.42 μmol) were added to 3 mL of toluene, heated to 100 after nitrogen replacement. °C reaction for 16h. The reaction mixture was concentrated to give compound 13a (35 mg). MS (ESI, m/z): 410.1 [M+H] +
第二步：1-甲基-2-(3-吗啉丙基)-7-(1H-吡唑-3-基)-1H-咪唑并[4,5-d]噻吩并[3,2-b]吡啶-4-胺(68)Second step: 1-methyl-2-(3-morpholinyl)-7-(1H-pyrazol-3-yl)-1H-imidazo[4,5-d]thieno[3,2 -b]pyridin-4-amine (68)
将化合物13a(35mg,0.09mmol)、1H-吡唑-3-硼酸频哪酯(33mg,0.17mmol)、[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(7mg,8.50μmol)、K 2CO 3(30mg,0.21mmol)加入到3mL DMF和0.8mL水的混合溶剂中，N 2保护下加热至120℃反应3h。体系硅藻土过滤，滤液通过Prep-HPLC分离纯化(洗脱条件4)，冻干得到化合物68(2mg)。 Compound 13a (35 mg, 0.09 mmol), 1H-pyrazole-3-boronic acid pinacol ester (33 mg, 0.17 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride A methyl chloride complex (7 mg, 8.50 μmol), K 2 CO 3 (30 mg, 0.21 mmol) was added to a mixed solvent of 3 mL of DMF and 0.8 mL of water, and heated to 120 ° C for 3 h under N 2 protection. The system was filtered through celite, and the filtrate was separated and purified by Prep-HPLC (elution condition 4), and lyophilized to give compound 68 (2 mg).
MS(ESI,m/z):398.2[M+H] +. MS (ESI, m/z): 398.2 [M+H] + .
1H NMR(DMSO-d 6,400MHz)δ12.98(s,1H),7.83(s,1H),7.53(s,1H),6.77(s,1H), 6.11(s,2H),3.93(s,3H),3.54–3.51(m,2H),2.91(t,J＝7.5Hz,2H),2.43–2.30(m,7H),2.03–1.90(m,3H). 1 H NMR (DMSO-d 6 , 400MHz) δ12.98 (s, 1H), 7.83 (s, 1H), 7.53 (s, 1H), 6.77 (s, 1H), 6.11 (s, 2H), 3.93 ( s, 3H), 3.54–3.51 (m, 2H), 2.91 (t, J = 7.5 Hz, 2H), 2.43–2.30 (m, 7H), 2.03–1.90 (m, 3H).
实施例14：Example 14
2-(3-(苄氧基)丙氧基)-1-甲基-7-(1H-吡唑-3-基)-1H-咪唑[4,5-d]噻吩并[3,2-b]吡啶-4-胺(69)2-(3-(Benzyloxy)propoxy)-1-methyl-7-(1H-pyrazol-3-yl)-1H-imidazole [4,5-d]thieno[3,2- b] Pyridin-4-amine (69)
Figure PCTCN2019085535-appb-000083
Figure PCTCN2019085535-appb-000083
第一步：2-(3-(苄氧基)丙氧基)-1-甲基-1H-咪唑[4,5-d]噻吩并[3,2-b]吡啶(14a)First step: 2-(3-(benzyloxy)propoxy)-1-methyl-1H-imidazole [4,5-d]thieno[3,2-b]pyridine (14a)
将化合物12c(500mg,1.87mmol)、3-苄氧基-1-丙醇(3.11g,18.70mmol)加入50mL乙腈中，继续向体系中加入60％NaH(717mg,18.70mmol)，加热至50℃反应16h。体系浓缩并加水稀释，EA提取三次(100mL×3)，合并后无水硫酸钠干燥，经柱层析(洗脱剂体系B)得到化合物14a(590mg)。MS(ESI,m/z):354.1[M+H] +. Add compound 12c (500 mg, 1.87 mmol), 3-benzyloxy-1-propanol (3.11 g, 18.70 mmol) to 50 mL of acetonitrile and continue to add 60% NaH (717 mg, 18.70 mmol) to the system and heat to 50 °C reaction for 16h. The system was concentrated and diluted with water, and EA was extracted three times (100 mL×3), and dried over anhydrous sodium sulfate, and then purified by column chromatography (eluent system B) to give compound 14a (590 mg). MS (ESI, m/z): 354.1 [M+H] + .
第二步：N-(3-(苄氧基)丙基)-7-溴-N-(4-甲氧基苄基)-1-甲基-1H-咪唑并[4,5-d]噻吩并[3,2-b]吡啶-2-胺(14b)Second step: N-(3-(benzyloxy)propyl)-7-bromo-N-(4-methoxybenzyl)-1-methyl-1H-imidazo[4,5-d] Thieno[3,2-b]pyridin-2-amine (14b)
将化合物14a(485mg,1.37mmol)加入到10mL DMF和2.5mL冰乙酸的混合溶剂中，继续向体系中加入NBS(488mg,2.74mmol)，加热至65℃反应2h。反应混合物加水稀释，EA提取三次(50mL×3)，合并后无水硫酸钠干燥。经柱层析(洗脱剂体系B)得到化合物14b(466mg)。MS(ESI,m/z):432.0[M+H] +. Compound 14a (485 mg, 1.37 mmol) was added to a mixed solvent of 10 mL of DMF and 2.5 mL of glacial acetic acid, and NBS (488 mg, 2.74 mmol) was further added to the system and heated to 65 ° C for 2 h. The reaction mixture was diluted with water and extracted with EA (3 mL) (3 mL). Column chromatography (eluent system B) gave compound 14b (466 mg). MS (ESI, m/z): 432.0 [M+H] +
第三步：2-(3-(苄氧基)丙氧基)-7-溴-1-甲基-1H-咪唑并[4,5-d]噻吩并[3,2-b]吡啶5-氧化物(14c)Third step: 2-(3-(benzyloxy)propoxy)-7-bromo-1-methyl-1H-imidazo[4,5-d]thieno[3,2-b]pyridine 5 -Oxide (14c)
将化合物14b(466mg,0.18mmol)加入30mL DCM中，继续向体系中加入mCPBA(223mg,1.29mmol)，室温下反应3h。反应混合物用饱和碳酸氢钠洗涤两次(50mL×2)，有机层无水硫酸钠干燥，浓缩后得到化合物14c(483mg)。MS(ESI,m/z):448.0[M+H] +. Compound 14b (466 mg, 0.18 mmol) was added to 30 mL DCM and mCPBA (223 mg, 1.29 mmol) was then added to the system and allowed to react at room temperature for 3 h. The reaction mixture was washed twice with saturated aqueous MS (ESI, m/z): 448.0 [M+H] +
第四步：2-(3-(苄氧基)丙氧基)-7-溴-1-甲基-1H-咪唑并[4,5-d]噻吩并[3,2-b]吡啶-4-胺(14d)Fourth step: 2-(3-(benzyloxy)propoxy)-7-bromo-1-methyl-1H-imidazo[4,5-d]thieno[3,2-b]pyridine- 4-amine (14d)
将化合物14c(448mg,1.08mmol)加入30mL DCM中，继续依次向体系中加入5mL 氨水和对甲苯磺酰氯(190mg,2.70mmol)，室温下反应3h。反应混合物用DCM稀释，水洗涤三次(50mL×3)，有机层无水硫酸钠干燥。经柱层析(洗脱剂体系A)得到化合物14d(100mg)。MS(ESI,m/z):447.0[M+H] +. Compound 14c (448 mg, 1.08 mmol) was added to 30 mL of DCM, and then 5 mL aqueous ammonia and p-toluenesulfonyl chloride (190 mg, 2.70 mmol) were added to the system and reacted at room temperature for 3 h. The reaction mixture was diluted with EtOAc (EtOAc)EtOAc. Column chromatography (eluent system A) gave compound 14d (100 mg). MS (ESI, m/z): 447.0 [M+H] +
第五步：2-(3-(苄氧基)丙氧基)-1-甲基-7-(1H-吡唑-3-基)-1H-咪唑[4,5-d]噻吩并[3,2-b]吡啶-4-胺(69)Step 5: 2-(3-(Benzyloxy)propoxy)-1-methyl-7-(1H-pyrazol-3-yl)-1H-imidazole [4,5-d]thieno[ 3,2-b]pyridin-4-amine (69)
将化合物14d(75mg,166.66μmol)、1H-吡唑-3-硼酸频哪酯(65mg,333.31μmol)、[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(14mg,16.67μmol)、K 2CO 3(58mg,416.64μmol)加入到3mL DMF和0.8mL水的混合溶剂中，N 2保护下加热至120℃反应1h。体系硅藻土过滤，滤液通过Prep-HPLC分离纯化(洗脱条件5)，冻干得到化合物69(20mg)。 Compound 14d (75 mg, 166.66 μmol), 1H-pyrazole-3-boronic acid pinacol ester (65 mg, 333.31 μmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride A methyl chloride complex (14 mg, 16.67 μmol), K 2 CO 3 (58 mg, 416.64 μmol) was added to a mixed solvent of 3 mL of DMF and 0.8 mL of water, and heated to 120 ° C for 1 h under N 2 protection. The system was filtered through celite, and the filtrate was separated and purified by Prep-HPLC (elution condition 5), and lyophilized to give compound 69 (20 mg).
MS(ESI,m/z):435.2[M+H] +. MS (ESI, m/z): 435.2 [M+H] +
1H NMR(DMSO-d 6,400MHz)δ12.96(s,1H),7.82(s,1H),7.51(s,1H),7.36–7.20(m,5H),6.77(s,1H),5.90(s,2H),4.59(t,J＝6.3Hz,2H),4.50(s,2H),3.69–3.60(m,5H),2.15–2.06(m,2H). 1 H NMR (DMSO-d 6 , 400 MHz) δ 12.96 (s, 1H), 7.82 (s, 1H), 7.51 (s, 1H), 7.36 - 7.20 (m, 5H), 6.77 (s, 1H), 5.90(s, 2H), 4.59 (t, J = 6.3 Hz, 2H), 4.50 (s, 2H), 3.69 - 3.60 (m, 5H), 2.15 - 2.06 (m, 2H).
实施例15：1-(3-(4-氨基-1-甲基-7-(1H-吡唑-3-基)-1H-咪唑并[4,5-d]噻吩并[3,2-b]吡啶-2-基)丙基)吡咯烷-3-醇(70)Example 15: 1-(3-(4-Amino-1-methyl-7-(1H-pyrazol-3-yl)-1H-imidazo[4,5-d]thieno[3,2- b]pyridin-2-yl)propyl)pyrrolidin-3-ol (70)
Figure PCTCN2019085535-appb-000084
Figure PCTCN2019085535-appb-000084
第一步：1-(3-(4-氨基-7-溴-1-甲基-1H-咪唑并[4,5-d]噻吩并[3,2-b]吡啶-2-基)丙基)吡咯烷-3-醇(15a)First step: 1-(3-(4-Amino-7-bromo-1-methyl-1H-imidazo[4,5-d]thieno[3,2-b]pyridin-2-yl)-propyl Pyrrolidin-3-ol (15a)
将化合物1k(30mg,83.41μmol)、35b(20mg,225.22μmol)、四丁基碘化钠(3mg,8.34μmol)和TEA(25mg,250.23μmol)加入5mL甲苯中，100℃搅拌反应22h。抽滤除去不溶物，浓缩滤液，得到粗品15a(30mg)。MS(ESI,m/z):410.0[M+H] +. Compound 1k (30 mg, 83.41 μmol), 35b (20 mg, 225.22 μmol), tetrabutylsodium iodide (3 mg, 8.34 μmol) and TEA (25 mg, 250.23 μmol) were added to 5 mL of toluene, and the reaction was stirred at 100 ° C for 22 h. The insoluble material was removed by suction filtration, and the filtrate was concentrated to give crude 15a (30mg). MS (ESI, m/z): 410.0 [M+H] +
第二步：1-(3-(4-氨基-1-甲基-7-(1H-吡唑-3-基)-1H-咪唑并[4,5-d]噻吩并[3,2-b]吡啶-2-基)丙基)吡咯烷-3-醇(70)Step 2: 1-(3-(4-Amino-1-methyl-7-(1H-pyrazol-3-yl)-1H-imidazo[4,5-d]thieno[3,2- b]pyridin-2-yl)propyl)pyrrolidin-3-ol (70)
将化合物15a(40mg,97.48μmol)、3-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-1H-吡唑(38mg,194.96μmol)、Pd(dppf)Cl 2(8mg,9.76μmol)、碳酸钠(26mg,243.71μmol)加入3mL DMF和0.3mL水的混合溶剂中，N 2保护下加热至110℃搅拌反应反应3h。减压浓缩反应溶剂至干，经通过Prep-HPLC分离纯化(洗脱条件4)冻干得到化合物70(5mg)。 Compound 15a (40 mg, 97.48 μmol), 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (38 mg) , 194.96 μmol), Pd(dppf)Cl 2 (8 mg, 9.76 μmol), sodium carbonate (26 mg, 243.71 μmol), added to a mixed solvent of 3 mL of DMF and 0.3 mL of water, heated to 110 ° C under N 2 protection and stirred for 3 h. . The reaction solvent was concentrated to dryness under reduced pressure, and purified by purified--------
MS(ESI,m/z):398.2[M+H] +. MS (ESI, m/z): 398.2 [M+H] + .
1H NMR(DMSO-d 6,400MHz)δ13.01(s,1H),7.82(s,1H),7.55(s,1H),6.77(d,J＝1.6Hz,1H),6.15(s,2H),4.73(d,J＝4.4Hz,1H),4.20–4.16(m,1H),3.93(s,3H),2.92(t,J＝7.4Hz,2H),2.70(dd,J＝9.5,6.2Hz,1H),2.61–2.38(m,8H),2.32(dd,J＝9.6,3.7Hz,1H),2.02–1.88(m,3H),1.54(ddd,J＝13.0,8.2,5.5Hz,1H). 1 H NMR (DMSO-d 6 , 400MHz) δ13.01 (s, 1H), 7.82 (s, 1H), 7.55 (s, 1H), 6.77 (d, J = 1.6Hz, 1H), 6.15 (s, 2H), 4.73 (d, J = 4.4 Hz, 1H), 4.20 - 4.16 (m, 1H), 3.93 (s, 3H), 2.92 (t, J = 7.4 Hz, 2H), 2.70 (dd, J = 9.5) , 6.2 Hz, 1H), 2.61 - 2.38 (m, 8H), 2.32 (dd, J = 9.6, 3.7 Hz, 1H), 2.02 - 1.88 (m, 3H), 1.54 (ddd, J = 13.0, 8.2, 5.5 Hz, 1H).
实施例16：1-甲基-7-(1H-吡唑-3-基)-2-(3-(吡咯烷-1-基)丙基)-1H-咪唑[4,5-d]噻吩并[3,2-b]吡啶-4-胺(71)Example 16: 1-Methyl-7-(1H-pyrazol-3-yl)-2-(3-(pyrrolidin-1-yl)propyl)-1H-imidazole [4,5-d]thiophene And [3,2-b]pyridin-4-amine (71)
Figure PCTCN2019085535-appb-000085
Figure PCTCN2019085535-appb-000085
第一步：7-溴-1-甲基-2-(3-(吡咯烷-1-基)丙基)-1H咪唑[4,5-d]噻吩并[3,2-b]吡啶-4-胺(16a)First step: 7-bromo-1-methyl-2-(3-(pyrrolidin-1-yl)propyl)-1H imidazo[4,5-d]thieno[3,2-b]pyridine- 4-amine (16a)
将化合物1k(151mg,0.42mmol)、四氢吡咯(60mg,0.84mmol)、四丁基碘化铵(29mg,0.08mmol)、DIPEA(109mg,0.84mmol)加入5mL DMF中，N 2保护下加热至100℃反应12h。旋干反应溶剂再经快速柱层析(洗脱剂体系A)得到化合物16a(126mg)。MS(ESI,m/z):394.1[M+H] +. Compound 1k (151 mg, 0.42 mmol), tetrahydropyrrole (60 mg, 0.84 mmol), tetrabutylammonium iodide (29 mg, 0.08 mmol), DIPEA (109 mg, 0.84 mmol) were added to 5 mL DMF and heated under N 2 The reaction was carried out at 100 ° C for 12 h. The reaction solvent was evaporated to dryness and then purified by flash column chromatography (eluent system A) to afford compound 16a (126mg). MS (ESI, m/z): 394.1 [M+H] + .
第二步：1-甲基-7-(1H-吡唑-3-基)-2-(3-(吡咯烷-1-基)丙基)-1H-咪唑[4,5-d]噻吩并[3,2-b]吡啶-4-胺(71)Second step: 1-methyl-7-(1H-pyrazol-3-yl)-2-(3-(pyrrolidin-1-yl)propyl)-1H-imidazole [4,5-d]thiophene And [3,2-b]pyridin-4-amine (71)
将化合物16a(126mg,0.33mmol)、3-(4,4,5,5-四甲基-1,3,2-二氧杂环戊环-2-基)-1H吡唑(128mg,0.66mmol)、Pd(dppf)Cl 2(57mg,0.07mmol)、碳酸钠(56mg,0.66mmol)加入5mL DMF和1mL水的混合溶剂中，N 2保护下加热至110℃搅拌反应反应6h。硅藻土过滤，滤液减压浓缩反应溶剂至干，通过Prep-HPLC分离纯化(洗脱条件4)得到化合物71(15mg)。 Compound 16a (126 mg, 0.33 mmol), 3-(4,4,5,5-tetramethyl-1,3,2-dioxalan-2-yl)-1H pyrazole (128 mg, 0.66) Methyl), Pd(dppf)Cl 2 (57 mg, 0.07 mmol), sodium carbonate (56 mg, 0.66 mmol) were added to a mixed solvent of 5 mL of DMF and 1 mL of water, and the mixture was heated to 110 ° C under N 2 and stirred for 6 h. The mixture was filtered through Celite, and the filtrate was evaporated to dryness.
MS(ESI,m/z):382.2[M+H] +. MS (ESI, m/z): 382.2 [M+H] + .
1HNMR(DMSO-d 6,400MHz)δ12.98(s,1H),7.81-7.82(m,1H),7.53(s,1H),6.76-6.77(m,1H),6.12(s,2H),3.92(s,3H),2.89-2.91(m,2H),2.48-2.50(m,2H),2.42-2.44(m,4H),1.92-1.93(m,2H),1.66-1.68(m,4H). 1 H NMR (DMSO-d 6 , 400 MHz) δ 12.98 (s, 1H), 7.81-7.82 (m, 1H), 7.53 (s, 1H), 6.76-6.77 (m, 1H), 6.12 (s, 2H) , 3.92 (s, 3H), 2.89-2.91 (m, 2H), 2.48-2.50 (m, 2H), 2.42 - 2.44 (m, 4H), 1.92-1.93 (m, 2H), 1.66-1.68 (m, 4H).
实施例17：2-(3-(氮杂环丁烷-1-基)丙基)-1-甲基-7-(1H-吡唑-3-基)-1H咪唑[4,5-d]噻吩并[3,2-b]吡啶-4-胺(72)Example 17: 2-(3-(Azetidin-1-yl)propyl)-1-methyl-7-(1H-pyrazol-3-yl)-1H imidazole [4,5-d Thio[3,2-b]pyridin-4-amine (72)
Figure PCTCN2019085535-appb-000086
Figure PCTCN2019085535-appb-000086
第一步：2-(3-(氮杂环丁烷-1-基)丙基)-7-溴-1-甲基-1H-咪唑并[4,5-d]噻吩并[3,2-b]吡啶-4-胺(17a)First step: 2-(3-(azetidin-1-yl)propyl)-7-bromo-1-methyl-1H-imidazo[4,5-d]thieno[3,2 -b]pyridin-4-amine (17a)
将化合物1k(151mg,0.42mmol)、氮杂环丁烷(48mg,0.84mmol)、四丁基碘化铵(29mg,0.08mmol)、DIPEA(109mg,0.84mmol)加入5mL DMF中，N 2保护下加热至100℃反应12h。旋干反应溶剂再经快速柱层析(洗脱剂体系A)得到化合物17a(126mg)。MS(ESI,m/z):380.0[M+H] +. Compound 1k (151mg, 0.42mmol), azetidine (48mg, 0.84mmol), tetrabutylammonium iodide (29mg, 0.08mmol), DIPEA ( 109mg, 0.84mmol) in 5mL DMF was added, N 2 protection The reaction was heated to 100 ° C for 12 h. The reaction solvent was dried by rotary column chromatography (yield: eluent) to afford compound 17a (126 mg). MS (ESI, m/z): 380.0 [M+H] + .
第二步：2-(3-(氮杂环丁烷-1-基)丙基)-1-甲基-7-(1H-吡唑-3-基)-1H咪唑[4,5-d]噻吩并[3,2-b]吡啶-4-胺(72)Second step: 2-(3-(azetidin-1-yl)propyl)-1-methyl-7-(1H-pyrazol-3-yl)-1H imidazole [4,5-d Thio[3,2-b]pyridin-4-amine (72)
将化合物17a(125mg,0.33mmol)、3-(4,4,5,5-四甲基-1,3,2-二氧杂环戊环-2-基)-1H吡唑(128mg,0.66mmol)、Pd(dppf)Cl 2(57mg,0.07mmol)、碳酸钠(56mg,0.66mmol)加入5mL DMF和1mL水的混合溶剂中，N 2保护下加热至110℃搅拌反应反应6h。硅藻土过滤，滤液减压浓缩反应溶剂至干，通过Prep-HPLC分离纯化(洗脱条件4)得到化合物72(15mg)。 Compound 17a (125 mg, 0.33 mmol), 3-(4,4,5,5-tetramethyl-1,3,2-dioxalan-2-yl)-1H pyrazole (128 mg, 0.66) Methyl), Pd(dppf)Cl 2 (57 mg, 0.07 mmol), sodium carbonate (56 mg, 0.66 mmol) were added to a mixed solvent of 5 mL of DMF and 1 mL of water, and the mixture was heated to 110 ° C under N 2 and stirred for 6 h. The mixture was filtered through Celite, and the filtrate was evaporated to dryness.
MS(ESI,m/z):368.2[M+H] +. MS (ESI, m/z): 368.2 [M+H] + .
1HNMR(CD3OD-d 4,400MHz)δ7.72(d,J＝2.4Hz,1H),7.51(s,1H),6.71(d,J＝2.4Hz,1H),3.95(s,3H),3.31-3.34(m,4H),2.90-2.92(m,2H),2.62-2.64(m,2H),2.12-2.13(m,2H),1.89-1.92(m,2H). 1 H NMR (CD3OD-d 4 , 400 MHz) δ 7.72 (d, J = 2.4 Hz, 1H), 7.51 (s, 1H), 6.71 (d, J = 2.4 Hz, 1H), 3.95 (s, 3H), 3.31-3.34 (m, 4H), 2.90-2.92 (m, 2H), 2.62-2.64 (m, 2H), 2.12-2.13 (m, 2H), 1.89-1.92 (m, 2H).
实施例18：Example 18
1-甲基-2-(3-(4-甲基哌嗪-1-基)丙基)-7-(1H-吡唑-3-基)-1H咪唑[4,5-d]噻吩并[3,2-b]吡啶-4-胺盐酸盐(73s)1-methyl-2-(3-(4-methylpiperazin-1-yl)propyl)-7-(1H-pyrazol-3-yl)-1H imidazo[4,5-d]thiophene [3,2-b]pyridin-4-amine hydrochloride (73s)
Figure PCTCN2019085535-appb-000087
Figure PCTCN2019085535-appb-000087
第一步：7-溴-1-甲基-2-(3-(4-甲基哌嗪-1-基)丙基)-1H咪唑[4,5-d]噻吩并[3,2-b]吡啶-4-胺(18a)First step: 7-bromo-1-methyl-2-(3-(4-methylpiperazin-1-yl)propyl)-1H imidazole [4,5-d]thieno[3,2- b] Pyridin-4-amine (18a)
将化合物1k(100mg,0.27mmol)、N-甲基哌嗪(162mg,1.62mmol)、四丁基碘化铵 (20.54mg,0.05mmol)、TEA(168.80mg,1.62mmol)加入5mL甲苯中，N 2保护下加热至100℃反应12h。旋干反应溶剂再经快速柱层析(洗脱剂体系A)得到化合物18a(80mg)。MS(ESI,m/z):423.1[M+H] +. Compound 1k (100 mg, 0.27 mmol), N-methylpiperazine (162 mg, 1.62 mmol), tetrabutylammonium iodide (20.54 mg, 0.05 mmol), TEA (168.80 mg, 1.62 mmol) was added to 5 mL of toluene. The reaction was heated to 100 ° C under N 2 protection for 12 h. The reaction solvent was evaporated to dryness and then purified by flash column chromatography (eluent system A) to afford compound 18a (80 mg). MS (ESI, m/z): 423.1 [M+H] + .
第二步：1-甲基-2-(3-(4-甲基哌嗪-1-基)丙基)-7-(1H-吡唑-3-基)-1H咪唑[4,5-d]噻吩并[3,2-b]吡啶-4-胺(73)The second step: 1-methyl-2-(3-(4-methylpiperazin-1-yl)propyl)-7-(1H-pyrazol-3-yl)-1H imidazole [4,5- d] thieno[3,2-b]pyridin-4-amine (73)
将化合物18a(50mg,0.12mmol)、3-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-1H-吡唑(45.83mg,0.24mmol)、Pd(dppf)Cl 2(9mg,0.01mmol)、碳酸钠(31.30mg,0.29mmol)加入5mL DMF和1mL水的混合溶剂中，N 2保护下加热至110℃搅拌反应3h。减压浓缩反应溶剂至干，通过Prep-HPLC分离纯化(洗脱条件4)得化合物73。 Compound 18a (50 mg, 0.12 mmol), 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (45.83 Mg, 0.24 mmol), Pd(dppf)Cl 2 (9 mg, 0.01 mmol), sodium carbonate (31.30 mg, 0.29 mmol), added to a mixed solvent of 5 mL of DMF and 1 mL of water, heated to 110 ° C under N 2 and stirred for 3 h. . The reaction solvent was concentrated to dryness under reduced pressure, and purified and purified by <RTIgt;
MS(ESI,m/z):411.2[M+H] +. MS (ESI, m/z): 4121. [M+H] + .
1H NMR(DMSO-d 6,400MHz)δ12.97(s,1H),7.83(s,1H),7.53(s,1H),6.77(s,1H),6.12(s,2H),3.92(s,3H),2.88(t,J＝7.2Hz,7.6Hz,2H),2.42–2.26(m,10H),2.10(s,3H),1.95–1.88(m,2H). 1 H NMR (DMSO-d 6 , 400 MHz) δ 12.97 (s, 1H), 7.83 (s, 1H), 7.53 (s, 1H), 6.77 (s, 1H), 6.12 (s, 2H), 3.92 ( s, 3H), 2.88 (t, J = 7.2 Hz, 7.6 Hz, 2H), 2.42 - 2.26 (m, 10H), 2.10 (s, 3H), 1.95 - 1.88 (m, 2H).
第三步：1-甲基-2-(3-(4-甲基哌嗪-1-基)丙基)-7-(1H-吡唑-3-基)-1H咪唑[4,5-d]噻吩并[3,2-b]吡啶-4-胺盐酸盐(73s)The third step: 1-methyl-2-(3-(4-methylpiperazin-1-yl)propyl)-7-(1H-pyrazol-3-yl)-1H imidazole [4,5- d] thieno[3,2-b]pyridin-4-amine hydrochloride (73s)
再向所得化合物73的制备液中加入0.5mL 1N盐酸，冻干得到化合物73s(10mg)。Further, 0.5 mL of 1N hydrochloric acid was added to the preparation liquid of the obtained Compound 73, and lyophilized to obtain Compound 73s (10 mg).
MS(ESI,m/z):411.2[M+H] +. MS (ESI, m/z): 4121. [M+H] + .
1H NMR(DMSO-d 6,400MHz)δ14.44(s,1H),12.22(s,2H),8.63(s,2H),7.90(s,1H),7.75(s,1H),6.92(d,J＝8.6Hz,1H),4.00(s,3H),3.85–3.34(m,10H),3.12–3.08(m,2H),2.83(s,3H),2.33–2.29(m,2H). 1 H NMR (DMSO-d 6 , 400MHz) δ14.44 (s, 1H), 12.22 (s, 2H), 8.63 (s, 2H), 7.90 (s, 1H), 7.75 (s, 1H), 6.92 ( d, J=8.6 Hz, 1H), 4.00 (s, 3H), 3.85–3.34 (m, 10H), 3.12–3.08 (m, 2H), 2.83 (s, 3H), 2.33–2.29 (m, 2H) .
实施例19：Example 19
2-(3-(2,2-二甲基吗啉)丙基)-1-甲基-7-(1H-吡唑-3-基)-1H-咪唑[4,5-d]噻吩并[3,2-b]吡啶-4-胺(74)2-(3-(2,2-Dimethylmorpholine)propyl)-1-methyl-7-(1H-pyrazol-3-yl)-1H-imidazole[4,5-d]thiophene [3,2-b]pyridin-4-amine (74)
Figure PCTCN2019085535-appb-000088
Figure PCTCN2019085535-appb-000088
第一步：7-溴-2-(3-(2,2-二甲基吗啉)丙基)-1-甲基-1H-咪唑并[4,5-d]噻吩并[3,2-b]吡啶-4-胺(19a)First step: 7-bromo-2-(3-(2,2-dimethylmorpholine)propyl)-1-methyl-1H-imidazo[4,5-d]thieno[3,2 -b]pyridin-4-amine (19a)
将化合物1k(30mg,0.08mmol)、2,2-二甲基吗啉(29mg,0.25mmol)、TEA(26mg, 0.25mmol)、四丁基碘化铵(3mg,8.42μmol)加入4mL甲苯中，氮气置换后加热至100℃反应16h。反应混合物浓缩得到化合物19a(37mg)。MS(ESI,m/z):438.1[M+H] +. Compound 1k (30 mg, 0.08 mmol), 2,2-dimethylmorpholine (29 mg, 0.25 mmol), TEA (26 mg, 0.25 mmol), tetrabutylammonium iodide (3 mg, 8.42 μmol) was added to 4 mL of toluene. After nitrogen substitution, the mixture was heated to 100 ° C for 16 h. The reaction mixture was concentrated to give compound 19a (37 mg). MS (ESI, m/z): 438.1 [M+H] + .
第二步：2-(3-(2,2-二甲基吗啉)丙基)-1-甲基-7-(1H-吡唑-3-基)-1H-咪唑[4,5-d]噻吩并[3,2-b]吡啶-4-胺(74)Second step: 2-(3-(2,2-dimethylmorpholine)propyl)-1-methyl-7-(1H-pyrazol-3-yl)-1H-imidazole [4,5- d] thieno[3,2-b]pyridin-4-amine (74)
将化合物19a(37mg,0.09mmol)、1H-吡唑-3-硼酸频哪酯(33mg,0.17mmol)、[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(7mg,8.50μmol)、Na 2CO 3(27mg,0.26mmol)加入到3mL DMF和0.8mL水的混合溶剂中，N 2保护下加热至110℃反应4h。体系硅藻土过滤，滤液通过Prep-HPLC分离纯化(洗脱条件4)，冻干得到化合物74(8mg)。 Compound 19a (37 mg, 0.09 mmol), 1H-pyrazole-3-boronic acid pinacol ester (33 mg, 0.17 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride A methyl chloride complex (7 mg, 8.50 μmol) and Na 2 CO 3 (27 mg, 0.26 mmol) were added to a mixed solvent of 3 mL of DMF and 0.8 mL of water, and heated to 110 ° C for 4 h under N 2 protection. The system was filtered through celite, and the filtrate was separated and purified by Prep-HPLC (elution condition 4), and lyophilized to give compound 74 (8 mg).
MS(ESI,m/z):426.2[M+H] +. MS (ESI, m/z): 426.2 [M+H] +
1H NMR(DMSO-d 6,400MHz)δ12.98(s,1H),7.82(s,1H),7.53(s,1H),6.77(s,1H),6.12(s,2H),3.93(s,3H),3.57(t,J＝4.8Hz,2H),2.91(t,J＝7.5Hz,2H),2.34(t,J＝6.8Hz,2H),2.31–2.25(m,2H),2.16(s,2H),1.98–1.88(m,2H),1.14(s,6H). 1 H NMR (DMSO-d 6 , 400 MHz) δ 12.98 (s, 1H), 7.82 (s, 1H), 7.53 (s, 1H), 6.77 (s, 1H), 6.12 (s, 2H), 3.93 ( s, 3H), 3.57 (t, J = 4.8 Hz, 2H), 2.91 (t, J = 7.5 Hz, 2H), 2.34 (t, J = 6.8 Hz, 2H), 2.31 - 2.25 (m, 2H), 2.16(s, 2H), 1.98–1.88 (m, 2H), 1.14 (s, 6H).
实施例20：Example 20
1-甲基-2-(3-(4-甲基哌嗪-1-基)丙基)-7-(1H-吡唑-1-基)-1H-咪唑[4,5-d]噻吩并[3，2-b]吡啶-4-胺(75)1-methyl-2-(3-(4-methylpiperazin-1-yl)propyl)-7-(1H-pyrazol-1-yl)-1H-imidazole[4,5-d]thiophene And [3,2-b]pyridin-4-amine (75)
Figure PCTCN2019085535-appb-000089
Figure PCTCN2019085535-appb-000089
将化合物18a(36mg,0.09mmol)、1H-吡唑(19mg,0.28mmol)、CuI(35mg,0.18mmol)、碳酸铯(86mg,0.26mmol)加入5mL DMSO中，N 2保护下加热至120℃搅拌反应反应10h。硅藻土过滤，滤液加水稀释后用EA萃取，无水硫酸钠干燥，过滤减压浓缩至干得粗品，粗品通过Prep-HPLC分离纯化(洗脱条件4)得到化合物75(5mg)。 Compound 18a (36 mg, 0.09 mmol), 1H-pyrazole (19 mg, 0.28 mmol), CuI (35 mg, 0.18 mmol), cesium carbonate (86 mg, 0.26 mmol) were added to 5 mL DMSO and heated to 120 ° C under N 2 The reaction was stirred for 10 h. The mixture was filtered over Celite, and the filtrate was diluted with water and evaporated, evaporated, evaporated, evaporated, evaporated, evaporated
MS(ESI,m/z):411.2[M+H] +. MS (ESI, m/z): 4121. [M+H] + .
1H NMR(DMSO-d 6,400MHz)δ8.62(s,1H),7.75(s,1H),7.54(s,1H),6.61(s,1H),6.21(s,2H),3.90(s,3H),2.89(t,J＝4.8Hz,2H),2.41(t,J＝7.5Hz,7H),2.34(t,J＝6.8Hz,2H),2.31–2.25(m,2H),2.18(s,3H),1.95–1.91(m,3H). 1 H NMR (DMSO-d 6 , 400 MHz) δ 8.62 (s, 1H), 7.75 (s, 1H), 7.54 (s, 1H), 6.61 (s, 1H), 6.21 (s, 2H), 3.90 ( s, 3H), 2.89 (t, J = 4.8 Hz, 2H), 2.41 (t, J = 7.5 Hz, 7H), 2.34 (t, J = 6.8 Hz, 2H), 2.31 - 2.25 (m, 2H), 2.18(s,3H), 1.95–1.91 (m, 3H).
实施例21：Example 21:
2-(4-氨基-7-(1H-吡唑-3-基)-1H-咪唑[4,5-d]噻吩并[3,2-b]吡啶-2-基)乙醇(76)2-(4-Amino-7-(1H-pyrazol-3-yl)-1H-imidazole[4,5-d]thieno[3,2-b]pyridin-2-yl)ethanol (76)
Figure PCTCN2019085535-appb-000090
Figure PCTCN2019085535-appb-000090
第一步：3-(苄氧基)-N-(7-((4-甲氧基苄基)氨基)噻吩并[3,2-b]吡啶-6-基)丙酰胺(21a)First step: 3-(benzyloxy)-N-(7-((4-methoxybenzyl)amino)thieno[3,2-b]pyridin-6-yl)propanamide (21a)
将化合物9b(5.00g,17.52mmol)、4-苄氧基丙酸(4.08g,21.03mmol)、HATU(9.99g,26.28mmol)加入100mL DMF中，继续向体系中加入DIPEA(6.79g,53.56mmol)，室温下反应16h。反应混合物加水稀释，EA提取三次(100mL×3)，合并后无水硫酸钠干燥，浓缩后得到化合物21a(8.09g)。MS(ESI,m/z):448.2[M+H] +. Compound 9b (5.00 g, 17.52 mmol), 4-benzyloxypropionic acid (4.08 g, 21.03 mmol), HATU (9.99 g, 26.28 mmol) was added to 100 mL DMF and DIPEA (6.79 g, 53.56) was added to the system. Methyl), reacted at room temperature for 16 h. The reaction mixture was diluted with water and extracted with EtOAc (3 mL). MS (ESI, m/z): 448.2 [M+H] + .
第二步：2-(2-(苄氧基)乙基)-1-(4-甲氧基苄基)-1H-咪唑[4,5-d]噻吩并[3,2-b]吡啶(21b)Second step: 2-(2-(benzyloxy)ethyl)-1-(4-methoxybenzyl)-1H-imidazole [4,5-d]thieno[3,2-b]pyridine (21b)
将化合物21a(8.09g,17.53mmol)、NaOH(3.2g,0.08mol)加入120mL无水乙醇中，加热至80℃反应4h。体系浓缩并用DCM稀释，经柱层析(洗脱剂体系A)得到化合物21b(5.00g)。MS(ESI,m/z):430.2[M+H] +. Compound 21a (8.09 g, 17.53 mmol), NaOH (3.2 g, 0.08 mol) was added to 120 mL of absolute ethanol and heated to 80 ° C for 4 h. The system was concentrated and diluted with DCM to afford compound 21b (5.00 g). MS (ESI, m/z): 430.2 [M+H] +
第三步：2-(2-(苄氧基)乙基)-7-溴-1-(4-甲氧基苄基)-1H-咪唑[4,5-d]噻吩并[3,2-b]吡啶(21c)Third step: 2-(2-(benzyloxy)ethyl)-7-bromo-1-(4-methoxybenzyl)-1H-imidazole [4,5-d]thieno[3,2 -b]pyridine (21c)
将化合物21b(4.17g,9.40mmol)加入到140mL DMF中，继续向体系中加入NBS(1.76g,9.87mmol)，加热至65℃反应22h。反应混合物加水稀释，EA提取三次(100mL×3)，合并后无水硫酸钠干燥。经柱层析(洗脱剂体系B)得到化合物21c(2.36g)。MS(ESI,m/z):508.1[M+H] +. Compound 21b (4.17 g, 9.40 mmol) was added to 140 mL of DMF and then NBS (1. The reaction mixture was diluted with water and extracted with EA (3 mL). Column chromatography (eluent system B) gave compound 21c (2.36 g). MS (ESI, m/z): 508.1 [M+H] + .
第四步：2-(2-(苄氧基)乙基)-7-溴-1-(4-甲氧基苄基)-1H-咪唑[4,5-d]噻吩并[3,2-b]吡啶-5-氧化物(21d)Fourth step: 2-(2-(benzyloxy)ethyl)-7-bromo-1-(4-methoxybenzyl)-1H-imidazole [4,5-d]thieno[3,2 -b]pyridine-5-oxide (21d)
将化合物21c(2.31g,4.42mmol)加入85mL DCM中，继续向体系中加入m-CPBA(1.53g,8.84mmol)，室温下反应4h。反应混合物用饱和碳酸氢钠洗涤两次(100mL×2)， 有机层无水硫酸钠干燥，浓缩后得到化合物21d(2.38g)。MS(ESI,m/z):524.1[M+H] +. Compound 21c (2.31 g, 4.42 mmol) was added to <RTI ID=0.0></RTI></RTI><RTIID=0.0> The reaction mixture was washed twice with saturated aqueous sodium hydrogen sulfate (100 mL×2). MS (ESI, m/z): 524.1 [M+H] + .
第五步：2-(2-(苄氧基)乙基)-7-溴-1-(4-甲氧基苄基)-1H-咪唑[4,5-d]噻吩并[3,2-b]吡啶-4-胺(21e)Step 5: 2-(2-(Benzyloxy)ethyl)-7-bromo-1-(4-methoxybenzyl)-1H-imidazole [4,5-d]thieno[3,2 -b]pyridin-4-amine (21e)
将化合物21d(2.38g,16.88mmol)加入100mL DCM中，继续依次向体系中加入46mL氨水和对甲苯磺酰氯(1.02g,14.41mmol)，室温下反应3h。反应混合物用DCM稀释，水洗涤三次(200mL×3)，有机层无水硫酸钠干燥。经柱层析(洗脱剂体系A)得到化合物21e(1.00g)。MS(ESI,m/z):523.1[M+H] +. Compound 21d (2.38 g, 16.88 mmol) was added to 100 mL DCM, and then 46 mL aqueous ammonia and p-toluenesulfonyl chloride (1.02 g, 14.41 mmol) were added to the system, and the mixture was reacted at room temperature for 3 h. The reaction mixture was diluted with EtOAc (EtOAc m. Column chromatography (eluent system A) gave compound 21e (1.00 g). MS (ESI, m/z): 523.1 [M+H] + .
第六步：2-(2-(苄氧基)乙基)-1-(4-甲氧基苄基)-7-(1H-吡唑-3-基)-1H-咪唑[4,5-d]噻吩并[3,2-b]吡啶-4-胺(21f)Step 6: 2-(2-(Benzyloxy)ethyl)-1-(4-methoxybenzyl)-7-(1H-pyrazol-3-yl)-1H-imidazole [4,5 -d]thieno[3,2-b]pyridin-4-amine (21f)
将化合物21e(500mg,0.95mmol)、1H-吡唑-3-硼酸频哪酯(350mg,1.9mmol)、[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(80mg,97.1μmol)、Na 2CO 3(254.4mg,2.4mmol)加入到20mL DMF和5mL水的混合溶剂中，N 2保护下加热至110℃反应2h。体系硅藻土过滤，滤液加水稀释，EA提取三次(50mL×3)，合并后无水硫酸钠干燥，浓缩得到化合物21f(300mg)。MS(ESI,m/z):511.2[M+H] +. Compound 21e (500 mg, 0.95 mmol), 1H-pyrazole-3-boronic acid pinacol ester (350 mg, 1.9 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride A methyl chloride complex (80 mg, 97.1 μmol), Na 2 CO 3 (254.4 mg, 2.4 mmol) was added to a mixed solvent of 20 mL of DMF and 5 mL of water, and heated to 110 ° C for 2 h under N 2 protection. The system was filtered through celite, and the filtrate was diluted with water, and then extracted three times with EA (50mL×3), and then dried over anhydrous sodium sulfate and concentrated to give compound 21f (300mg). MS (ESI, m/z): 5121. [M+H] + .
第七步：2-(4-氨基-7-溴-1H-咪唑[4,5-d]噻吩并[3,2-b]吡啶-2-基)乙醇(76)Step 7: 2-(4-Amino-7-bromo-1H-imidazo[4,5-d]thieno[3,2-b]pyridin-2-yl)ethanol (76)
将化合物21f(50mg,98μmol)加入20mL三氟乙酸中，加热至75℃反应16h，体系浓缩并用EA稀释，饱和碳酸氢钠溶液调节体系pH＝8，室温下搅拌0.5h后分层，有机层无水硫酸钠干燥，体系硅藻土过滤，滤液通过Prep-HPLC分离纯化(洗脱条件4)，冻干得到化合物76(10mg)。Compound 21f (50mg, 98μmol) was added to 20mL of trifluoroacetic acid, heated to 75 ° C for 16h, the system was concentrated and diluted with EA, saturated sodium bicarbonate solution to adjust the system pH = 8, stirred at room temperature for 0.5h, layered, organic layer The residue was dried over anhydrous sodium sulfate, filtered over Celite, and then filtered and purified by EtOAc (EtOAc)
MS(ESI,m/z):301.0[M+H] +. MS (ESI, m/z): 301.0 [M+H] + .
1H NMR(DMSO-d 6,400MHz)δ13.06(s,2H),7.90(s,1H),7.60(s,1H),6.84(s,1H),6.23(s,2H),5.08(s,1H),3.96(t,J＝6.5Hz,2H),3.11(t,J＝6.5Hz,2H). 1 H NMR (DMSO-d 6 , 400MHz) δ13.06 (s, 2H), 7.90 (s, 1H), 7.60 (s, 1H), 6.84 (s, 1H), 6.23 (s, 2H), 5.08 ( s, 1H), 3.96 (t, J = 6.5 Hz, 2H), 3.11 (t, J = 6.5 Hz, 2H).
实施例22：Example 22
2-(4-甲氧基哌啶-1-基)-1-甲基-7-(1H-吡唑-3-基)-1H-咪唑[4,5-d]噻吩并[3,2-b]吡啶-4-胺(77)2-(4-methoxypiperidin-1-yl)-1-methyl-7-(1H-pyrazol-3-yl)-1H-imidazole [4,5-d]thieno[3,2 -b]pyridin-4-amine (77)
Figure PCTCN2019085535-appb-000091
Figure PCTCN2019085535-appb-000091
第一步：2-(4-甲氧基哌啶-1-基)-1-甲基-1H-咪唑[4,5-d]噻吩并[3,2-b]吡啶(22a)First step: 2-(4-methoxypiperidin-1-yl)-1-methyl-1H-imidazole [4,5-d]thieno[3,2-b]pyridine (22a)
将化合物12c(1.00g,3.74mmol)、4-甲氧基哌啶(2.79g,24.22mmol)加入25mL DMSO中，加热至120℃反应14h。体系过滤，滤液加水稀释，EA提取三次(100mL×3)，合并后无水硫酸钠干燥，经薄层层析(洗脱剂体系A)得到化合物22a(350mg)。MS(ESI,m/z):303.1[M+H] +. Compound 12c (1.00 g, 3.74 mmol), 4-methoxypiperidine (2.79 g, 24.22 mmol) was added to 25 mL DMSO and heated to 120 ° C for 14 h. The system was filtered, and the filtrate was diluted with water, and EA was applied three times (100 mL×3), and then dried over anhydrous sodium sulfate, and then purified by thin layer chromatography (eluent system A) to give compound 22a (350 mg). MS (ESI, m / z) : 303.1 [M + H] +.
第二步：7-溴-2-(4-甲氧基哌啶-1-基)-1-甲基-1H-咪唑并[4,5-d]噻吩并[3,2-b]吡啶(22b)Second step: 7-bromo-2-(4-methoxypiperidin-1-yl)-1-methyl-1H-imidazo[4,5-d]thieno[3,2-b]pyridine (22b)
将化合物22a(250mg,0.83mmol)加入到15mL DMF和3.8mL冰乙酸的混合溶剂中，继续向体系中加入NBS(309mg,1.74mmol)，加热至65℃反应2h。反应混合物加水稀释，EA提取三次(50mL×3)，合并后无水硫酸钠干燥。经柱层析(洗脱剂体系A)得到化合物22b(80mg)。MS(ESI,m/z):381.0[M+H] +. Compound 22a (250 mg, 0.83 mmol) was added to a mixed solvent of 15 mL of DMF and 3.8 mL of glacial acetic acid, and NBS (309 mg, 1.74 mmol) was further added to the system and heated to 65 ° C for 2 h. The reaction mixture was diluted with water and extracted with EA (3 mL) (3 mL). Column chromatography (eluent system A) gave compound 22b (80 mg). MS (ESI, m/z): 381.0 [M+H] + .
第三步：7-溴-2-(4-甲氧基哌啶-1-基)-1-甲基-1H-咪唑并[4,5-d]噻吩并[3,2-b]吡啶-5-氧化物(22c)Third step: 7-bromo-2-(4-methoxypiperidin-1-yl)-1-methyl-1H-imidazo[4,5-d]thieno[3,2-b]pyridine -5-oxide (22c)
将化合物22b(80mg,0.21mmol)加入20mL DCM中，继续向体系中加入mCPBA(72mg,0.42mmol)，室温下反应2h。反应混合物用饱和碳酸氢钠洗涤两次(50mL×2)，有机层无水硫酸钠干燥，浓缩后得到化合物22c(83mg)。MS(ESI,m/z):397.0[M+H] +. Compound 22b (80 mg, 0.21 mmol) was added to 20 mL DCM and m.sub.c. The reaction mixture was washed twice with aq. EtOAc (EtOAc) MS (ESI, m/z): 397.0 [M+H] +
第四步：7-溴-2-(4-甲氧基哌啶-1-基)-1-甲基-1H-咪唑并[4,5-d]噻吩并[3,2-b]吡啶-4-胺(22d)Fourth step: 7-bromo-2-(4-methoxypiperidin-1-yl)-1-methyl-1H-imidazo[4,5-d]thieno[3,2-b]pyridine 4-amine (22d)
将化合物22c(83mg,0.21mmol)加入15mL DCM中，继续依次向体系中加入3mL氨水和对甲苯磺酰氯(37mg,0.52mmol)，室温下反应4.5h。反应混合物用DCM稀释，水洗涤三次(50mL×3)，有机层无水硫酸钠干燥。经薄层层析(洗脱剂体系A)得到化合物22d(40mg)。MS(ESI,m/z):396.0[M+H] +. Compound 22c (83 mg, 0.21 mmol) was added to 15 mL DCM, and then 3 mL aqueous ammonia and p-toluenesulfonyl chloride (37 mg, 0.52 mmol) were added to the system, and the mixture was reacted at room temperature for 4.5 h. The reaction mixture was diluted with EtOAc (EtOAc)EtOAc. Thin layer chromatography (eluent system A) gave compound 22d (40 mg). MS (ESI, m/z): 396.0 [M+H] +
第五步：2-(4-甲氧基哌啶-1-基)-1-甲基-7-(1H-吡唑-3-基)-1H-咪唑[4,5-d]噻吩并[3,2-b]吡啶-4-胺(77)Step 5: 2-(4-Methoxypiperidin-1-yl)-1-methyl-7-(1H-pyrazol-3-yl)-1H-imidazole [4,5-d]thiophene [3,2-b]pyridin-4-amine (77)
将化合物22d(40mg,100.93μmol)、1H-吡唑-3-硼酸频哪酯(39mg,201.86μmol)、 [1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(8mg,10.09μmol)、Na 2CO 3(32mg,302.80μmol)加入到2mL DMF和0.5mL水的混合溶剂中，N 2保护下加热至110℃反应2.5h。体系硅藻土过滤，滤液通过Prep-HPLC分离纯化(洗脱条件6)，冻干得到化合物77的三氟乙酸盐77s(20mg)。 Compound 22d (40 mg, 100.93 μmol), 1H-pyrazole-3-boronic acid pinacol ester (39 mg, 201.86 μmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride A methyl chloride complex (8 mg, 10.09 μmol), Na 2 CO 3 (32 mg, 302.80 μmol) was added to a mixed solvent of 2 mL of DMF and 0.5 mL of water, and heated to 110 ° C for 2.5 h under N 2 protection. The system was filtered through celite, and the filtrate was separated and purified by Prep-HPLC (elution condition 6), and lyophilized to give compound 77 trifluoroacetate 77s (20 mg).
MS(ESI,m/z):384.2[M+H] +. MS (ESI, m/z): 384.2 [M+H] + .
1H NMR(DMSO-d 6,400MHz)δ13.62(s,1H),13.22(s,1H),8.07(s,2H),7.91(s,1H),7.66(s,1H),6.88(s,1H),3.86(s,3H),3.51–3.44(m,3H),3.31(s,3H),3.14–3.06(m,2H),2.01(s,2H),1.73–1.63(m,2H). 1 H NMR (DMSO-d 6 , 400MHz) δ13.62 (s, 1H), 13.22 (s, 1H), 8.07 (s, 2H), 7.91 (s, 1H), 7.66 (s, 1H), 6.88 ( s, 1H), 3.86 (s, 3H), 3.51–3.44 (m, 3H), 3.31 (s, 3H), 3.14–3.06 (m, 2H), 2.01 (s, 2H), 1.73–1.63 (m, 2H).
实施例23：Example 23
1-(4-氨基-1-甲基-7-(1H-吡唑-3-基)-1H-咪唑并[4,5-d]噻吩并[3,2-b]吡啶-2-基)哌啶-4-醇(79)1-(4-Amino-1-methyl-7-(1H-pyrazol-3-yl)-1H-imidazo[4,5-d]thieno[3,2-b]pyridin-2-yl Piperidin-4-ol (79)
Figure PCTCN2019085535-appb-000092
Figure PCTCN2019085535-appb-000092
第一步：1-(1-甲基-1H-咪唑并[4,5-d]噻吩并[3,2-b]吡啶-2-基)哌啶-4-醇(23a)First step: 1-(1-methyl-1H-imidazo[4,5-d]thieno[3,2-b]pyridin-2-yl)piperidin-4-ol (23a)
将化合物12c(3.00g,11.22mmol)、4-羟基哌啶(15.00g,148.30mmol)加入100mL DMF中，加热至130℃反应20h。向体系中加入100mL水，室温下搅拌0.5h，抽滤，滤饼烘干得到化合物23a(2.2g)。MS(ESI,m/z):289.1[M+H] +. Compound 12c (3.00 g, 11.22 mmol), 4-hydroxypiperidine (15.00 g, 148.30 mmol) was added to 100 mL DMF and heated to 130 ° C for 20 h. 100 mL of water was added to the system, stirred at room temperature for 0.5 h, suction filtered, and the cake was dried to give compound 23a (2.2 g). MS (ESI, m/z): 289.1 [M+H] + .
第二步：1-(7-溴-1-甲基-1H-咪唑并[4,5-d]噻吩并[3,2-b]吡啶-2-基)哌啶-4-醇(23b)Second step: 1-(7-bromo-1-methyl-1H-imidazo[4,5-d]thieno[3,2-b]pyridin-2-yl)piperidin-4-ol (23b )
将化合物23a(333mg,1.15mmol)加入到12mL DMF和3mL冰乙酸的混合溶剂中，继续向体系中加入NBS(400mg,2.25mmol)，加热至65℃反应1h。反应混合物加水稀释，EA提取三次(50mL×3)，合并后无水硫酸钠干燥。经薄层层析(洗脱剂体系A)得到化合物23b(210mg)。MS(ESI,m/z):367.0[M+H] +. Compound 23a (333 mg, 1.15 mmol) was added to a mixed solvent of 12 mL of DMF and 3 mL of glacial acetic acid, and NBS (400 mg, 2.25 mmol) was further added to the system, and the mixture was heated to 65 ° C for 1 h. The reaction mixture was diluted with water and extracted with EA (3 mL) (3 mL). Thin layer chromatography (eluent system A) gave compound 23b (210 mg). MS (ESI, m/z): 367.0 [M+H] + .
第三步：2-(4-苄氧基)哌啶-1-基)-7-溴-1-甲基-1H-咪唑并[4,5-d]噻吩并[3,2-b]吡啶(23c)Third step: 2-(4-benzyloxy)piperidin-1-yl)-7-bromo-1-methyl-1H-imidazo[4,5-d]thieno[3,2-b] Pyridine (23c)
将化合物23b(200mg,0.54mmol)加入25mL DMF中，继续向体系中加入60％NaH(63mg,1.63mmol)，室温下反应0.5h，再继续向体系中依次加入溴化苄(186mg,1.09 mmol)和四丁基碘化铵(101mg,0.27mmol)，加热至30℃反应8h。体系加水稀释，EA提取三次(100mL×3)，合并后无水硫酸钠干燥，经薄层层析(洗脱剂体系B)得到化合物23c(90mg)。MS(ESI,m/z):457.1[M+H] +. Compound 23b (200 mg, 0.54 mmol) was added to 25 mL of DMF, and 60% NaH (63 mg, 1.63 mmol) was added to the system. The reaction was carried out at room temperature for 0.5 h, and then benzyl bromide (186 mg, 1.09 mmol) was added to the system. And tetrabutylammonium iodide (101 mg, 0.27 mmol), heated to 30 ° C for 8 h. The system was diluted with water, extracted with EA three times (100 mL×3), dried over anhydrous sodium sulfate, and then evaporated. MS (ESI, m/z): 457.1 [M+H] + .
第四步：2-(4-苄氧基)哌啶-1-基)-7-溴-1-甲基-1H-咪唑并[4,5-d]噻吩并[3,2-b]吡啶-5-氧化物(23d)Fourth step: 2-(4-benzyloxy)piperidin-1-yl)-7-bromo-1-methyl-1H-imidazo[4,5-d]thieno[3,2-b] Pyridine-5-oxide (23d)
将化合物23c(90mg,0.20mmol)加入20mL DCM中，继续向体系中加入mCPBA(68mg,0.39mmol)，室温下反应4h。反应混合物用饱和碳酸氢钠洗涤两次(50mL×2)，有机层无水硫酸钠干燥，浓缩后得到化合物23d(93mg)。MS(ESI,m/z):473.1[M+H] +. Compound 23c (90 mg, 0.20 mmol) was added to 20 mL DCM and m.sub.c. The reaction mixture was washed twice with aq. MS (ESI, m/z): 473.1 [M+H] + .
第五步：2-(4-苄氧基)哌啶-1-基)-7-溴-1-甲基-1H-咪唑并[4,5-d]噻吩并[3,2-b]吡啶-4-胺(23e)Step 5: 2-(4-Benzyloxy)piperidin-1-yl)-7-bromo-1-methyl-1H-imidazo[4,5-d]thieno[3,2-b] Pyridin-4-amine (23e)
将化合物23d(93mg,0.20mmol)加入15mL DCM中，继续依次向体系中加入3mL氨水和对甲苯磺酰氯(69mg,0.98mmol)，室温下反应3h。反应混合物用DCM稀释，水洗涤三次(50mL×3)，有机层无水硫酸钠干燥。经薄层层析(洗脱剂体系A)得到化合物23e(25mg)。MS(ESI,m/z):472.1[M+H] +. Compound 23d (93 mg, 0.20 mmol) was added to 15 mL DCM, and then 3 mL aqueous ammonia and p-toluenesulfonyl chloride (69 mg, 0.98 mmol) were added to the system, and the mixture was reacted at room temperature for 3 h. The reaction mixture was diluted with EtOAc (EtOAc)EtOAc. Thin layer chromatography (eluent system A) gave compound 23e (25 mg). MS (ESI, m/z): 4721. [M+H] + .
第六步：2-(4-苄氧基)哌啶-1-基)-1-甲基-7-(1H-吡唑-3-基)-1H-咪唑并[4,5-d]噻吩并[3,2-b]吡啶-4-胺(23f)Step 6: 2-(4-Benzyloxy)piperidin-1-yl)-1-methyl-7-(1H-pyrazol-3-yl)-1H-imidazo[4,5-d] Thieno[3,2-b]pyridin-4-amine (23f)
将化合物23e(25mg,52.92μmol)、1H-吡唑-3-硼酸频哪酯(21mg,105.84μmol)、[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(4mg,5.29μmol)、Na 2CO 3(17mg,158.76μmol)加入到2mL DMF和0.5mL水的混合溶剂中，N 2保护下加热至110℃反应3h。体系加水稀释，EA提取三次(50mL×3)，合并后无水硫酸钠干燥，浓缩得到化合物23f(24mg)。MS(ESI,m/z):460.2[M+H] +. Compound 23e (25 mg, 52.92 μmol), 1H-pyrazole-3-boronic acid pinacol ester (21 mg, 105.84 μmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride A methyl chloride complex (4 mg, 5.29 μmol), Na 2 CO 3 (17 mg, 158.76 μmol) was added to a mixed solvent of 2 mL of DMF and 0.5 mL of water, and heated to 110 ° C for 3 h under N 2 protection. The system was diluted with water, and EA was extracted three times (50 mL×3), dried over anhydrous sodium sulfate and concentrated to afford compound 23f (24mg). MS (ESI, m/z): 460.2 [M+H] + .
第七步：1-(4-氨基-1-甲基-7-(1H-吡唑-3-基)-1H-咪唑并[4,5-d]噻吩并[3,2-b]吡啶-2-基)哌啶-4-醇(79)Step 7: 1-(4-Amino-1-methyl-7-(1H-pyrazol-3-yl)-1H-imidazo[4,5-d]thieno[3,2-b]pyridine -2-yl)piperidin-4-ol (79)
将化合物23f(24mg,52.92μmol)加入10mL三氟乙酸中，加热至75℃反应16h，体系浓缩并用甲醇稀释，饱和碳酸钾调节体系pH＝9，室温下搅拌0.5h，过滤后通过Prep-HPLC分离纯化(洗脱条件3)，冻干得到化合物79的甲酸盐79s(1mg)。Compound 23f (24 mg, 52.92 μmol) was added to 10 mL of trifluoroacetic acid, and heated to 75 ° C for 16 h. The system was concentrated and diluted with methanol. The saturated potassium carbonate was adjusted to pH = 9 and stirred at room temperature for 0.5 h. Separation and purification (elution condition 3), lyophilized to give the title compound 79s (1 mg).
MS(ESI,m/z):370.1[M+H] +. MS (ESI, m/z): 370.1 [M+H] + .
1H NMR(DMSO-d 6,400MHz)δ12.95(s,1H),8.25(s,1H),7.81(s,1H),7.51(s,1H),6.76(s,1H),5.92(s,2H),4.78(d,J＝3.8Hz,1H),3.78(s,3H),3.74–3.67(m,1H),3.46–3.41(m,2H),3.03–2.95(m,2H),1.95–1.85(m,2H),1.67–1.55(m,2H). 1 H NMR (DMSO-d 6 , 400 MHz) δ 12.95 (s, 1H), 8.25 (s, 1H), 7.81 (s, 1H), 7.51 (s, 1H), 6.76 (s, 1H), 5.92 ( s, 2H), 4.78 (d, J = 3.8 Hz, 1H), 3.78 (s, 3H), 3.74 - 3.67 (m, 1H), 3.46 - 3.41 (m, 2H), 3.03 - 2.95 (m, 2H) , 1.95–1.85 (m, 2H), 1.67–1.55 (m, 2H).
实施例24：1-甲基-7-(1H-吡唑-1-基)-2-(3-(吡咯烷-1-基)丙基)-1H咪唑[4,5-d]噻吩并[3,2-b]吡啶-4-胺(80)Example 24: 1-Methyl-7-(1H-pyrazol-1-yl)-2-(3-(pyrrolidin-1-yl)propyl)-1Himidazo[4,5-d]thiophene [3,2-b]pyridin-4-amine (80)
Figure PCTCN2019085535-appb-000093
Figure PCTCN2019085535-appb-000093
将化合物16a(36mg,0.09mmol)、1H-吡唑(19mg,0.28mmol)、CuI(35mg,0.18mmol)、碳酸铯(86mg,0.26mmol)加入5mL DMSO中，N 2保护下加热至120℃搅拌反应反应10h。硅藻土过滤，滤液加水稀释后用EA萃取，无水硫酸钠干燥，过滤减压浓缩至干得粗品，粗品通过Prep-HPLC分离纯化(洗脱条件4)得到化合物80(5mg)。 Compound 16a (36 mg, 0.09 mmol), 1H-pyrazole (19 mg, 0.28 mmol), CuI (35 mg, 0.18 mmol), cesium carbonate (86 mg, 0.26 mmol) were added to 5 mL DMSO and heated to 120 ° C under N 2 The reaction was stirred for 10 h. The mixture was filtered over celite, and the filtrate was diluted with water and evaporated, evaporated, evaporated, evaporated, evaporated, evaporated.
MS(ESI,m/z):382.2[M+H] +. MS (ESI, m/z): 382.2 [M+H] + .
1HNMR(CD 3OD-d 4,400MHz)δ8.25-8.26(m,1H),7.70(s,1H),7.28(s,1H),6.55(s,1H),3.88(s,3H),2.92-2.94(m,2H),2.74-2.77(m,6H),2.09-2.13(m,2H),1.84-1.86(m,4H). 1 H NMR (CD 3 OD-d 4 , 400 MHz) δ 8.25-8.26 (m, 1H), 7.70 (s, 1H), 7.28 (s, 1H), 6.55 (s, 1H), 3.88 (s, 3H) , 2.92-2.94 (m, 2H), 2.74-2.77 (m, 6H), 2.09-2.13 (m, 2H), 1.84-1.86 (m, 4H).
实施例25：2-(3-(氮杂环丁烷-1-基)丙基)-1-甲基-7-(1H-吡唑-1-基)-1H咪唑[4,5-d]噻吩并[3,2-b]吡啶-4-胺(81)Example 25: 2-(3-(Azetidin-1-yl)propyl)-1-methyl-7-(1H-pyrazol-1-yl)-1H imidazole [4,5-d Thio[3,2-b]pyridin-4-amine (81)
Figure PCTCN2019085535-appb-000094
Figure PCTCN2019085535-appb-000094
第一步：2-(3-(氮杂环丁烷-1-基)丙基)-1-甲基-7-(1H-吡唑-1-基)-1H咪唑[4,5-d]噻吩并[3,2-b]吡啶-4-胺(81)First step: 2-(3-(azetidin-1-yl)propyl)-1-methyl-7-(1H-pyrazol-1-yl)-1H imidazole [4,5-d Thio[3,2-b]pyridin-4-amine (81)
将化合物17a(35mg,0.09mmol)、1H-吡唑(19mg,0.28mmol)、CuI(35mg,0.18mmol)、碳酸铯(86mg,0.26mmol)加入5mL DMSO中，N 2保护下加热至120℃搅拌反应反应10h。硅藻土过滤，滤液加水稀释后用EA萃取，无水硫酸钠干燥，过滤减压浓缩至干得粗品，粗品通过Prep-HPLC分离纯化(洗脱条件4)得到化合物81(5mg)。 Compound 17a (35 mg, 0.09 mmol), 1H-pyrazole (19 mg, 0.28 mmol), CuI (35 mg, 0.18 mmol), cesium carbonate (86 mg, 0.26 mmol) were added to 5 mL DMSO and heated to 120 ° C under N 2 The reaction was stirred for 10 h. The mixture was filtered over Celite, and the filtrate was diluted with water, and then evaporated, evaporated, evaporated, evaporated, evaporated.
MS(ESI,m/z):368.1[M+H] +. MS (ESI, m/z): 368.1 [M+H] + .
1HNMR(CD 3OD-d 4,400MHz)δ8.29(s,1H),7.71(s,1H),7.31(s,1H),6.56(s,1H),3.92(s,3H),3.30-3.32(m,4H),2.91-2.94(m,2H),2.61-2.63(m,2H),2.12-2.15(m,2H),1.88-1.92(m,2H). 1 H NMR (CD 3 OD-d 4 , 400 MHz) δ 8.29 (s, 1H), 7.71 (s, 1H), 7.31 (s, 1H), 6.56 (s, 1H), 3.92 (s, 3H), 3.30 -3.32 (m, 4H), 2.91-2.94 (m, 2H), 2.61-2.63 (m, 2H), 2.12-2.15 (m, 2H), 1.88-1.92 (m, 2H).
实施例26：Example 26:
2-(3-(氮杂环丁烷-3-基氧)丙基)-1-甲基-7-(1H-吡唑-3-基)-1H-咪唑[4,5-d]噻吩并[3,2-b]吡啶-4-胺(82)2-(3-(azetidin-3-yloxy)propyl)-1-methyl-7-(1H-pyrazol-3-yl)-1H-imidazole[4,5-d]thiophene And [3,2-b]pyridin-4-amine (82)
Figure PCTCN2019085535-appb-000095
Figure PCTCN2019085535-appb-000095
第一步：1-叔丁氧基羰基氮杂环丁酸钠(26b)First step: 1-tert-butoxycarbonylazetidine sodium (26b)
将化合物26a(1.00g,5.77mmol)加入16mL无水THF中，体系置于冰浴下降温至5℃，继续向体系中加入60％NaH(53mg,1.39mmol)，移至室温下反应2h。反应混合物浓缩得到化合物26b(1.13g)。The compound 26a (1.00 g, 5.77 mmol) was added to 16 mL of anhydrous THF. The mixture was placed in an ice bath and then warmed to 5 ° C. Then, 60% NaH (53 mg, 1.39 mmol) was added to the system, and the mixture was allowed to react at room temperature for 2 h. The reaction mixture was concentrated to give compound 26b (1.
第二步：叔丁基3-(3-(4-氨基-7-溴-1-甲基-1H-咪唑并[4,5-d]噻吩并[3,2-b]吡啶-2-基)丙氧基)氮杂环丁烷-1-羧酸酯(61d)Second step: tert-butyl 3-(3-(4-amino-7-bromo-1-methyl-1H-imidazo[4,5-d]thieno[3,2-b]pyridine-2- Propyloxy)azetidin-1-carboxylate (61d)
将化合物26b(1.13g,5.77mmol)、1k(104mg,0.29mmol)、四丁基碘化铵(53mg,0.14mmol)加入20mL甲苯中，氮气置换后加热至100℃反应16h。反应混合物浓缩并加水稀释，EA提取三次(50mL×3)，合并后无水硫酸钠干燥，得到化合物26c(40mg)。MS(ESI,m/z):496.1[M+H] +. Compound 26b (1.13 g, 5.77 mmol), 1 k (104 mg, 0.29 mmol), tetrabutylammonium iodide (53 mg, 0.14 mmol) was added to 20 mL of toluene, and the mixture was replaced with nitrogen and then heated to 100 ° C for 16 h. The reaction mixture was concentrated and diluted with water. EtOAc (EtOAc m. MS (ESI, m/z): 496.1 [M+H] + .
第三步：2-(3-(氮杂环丁烷-3-基氧)丙基)-1-甲基-7-(1H-吡唑-3-基)-1H-咪唑[4,5-d]噻吩并[3,2-b]吡啶-4-胺(82)The third step: 2-(3-(azetidin-3-yloxy)propyl)-1-methyl-7-(1H-pyrazol-3-yl)-1H-imidazole [4,5 -d]thieno[3,2-b]pyridin-4-amine (82)
将化合物26c(40mg,80.59μmol)加入到5mL TFA中，室温下反应16h。体系浓缩并用甲醇稀释，饱和碳酸钾调节体系pH＝10，过滤后通过Prep-HPLC分离纯化(洗脱条件1)，冻干得到化合物82的甲酸盐82s(6mg)。Compound 26c (40 mg, 80.59 μmol) was added to 5 mL of TFA and allowed to react at room temperature for 16 h. The system was concentrated and diluted with methanol, saturated potassium carbonate to adjust the system pH = 10, filtered and purified by Prep-HPLC (elution condition 1), and lyophilized to give the title compound 82s (6 mg).
MS(ESI,m/z):384.2[M+H] +. MS (ESI, m/z): 384.2 [M+H] + .
1H NMR(DMSO-d 6,400MHz)δ13.05(s,1H),8.31(s,1H),7.81(s,1H),7.54(s,1H),6.76(d,J＝2.1Hz,1H),6.14(s,2H),4.37–4.30(m,1H),3.98–3.89(m,6H),3.73–3.67(m,2H),3.47(t,J＝6.2Hz,2H),2.95(t,J＝7.5Hz,2H),2.07–1.96(m,2H). 1 H NMR (DMSO-d 6 , 400MHz) δ13.05 (s, 1H), 8.31 (s, 1H), 7.81 (s, 1H), 7.54 (s, 1H), 6.76 (d, J = 2.1Hz, 1H), 6.14 (s, 2H), 4.37 - 4.30 (m, 1H), 3.98 - 3.89 (m, 6H), 3.73 - 3.67 (m, 2H), 3.47 (t, J = 6.2 Hz, 2H), 2.95 (t, J = 7.5 Hz, 2H), 2.07 - 1.96 (m, 2H).
实施例27：Example 27:
2-(3-吗啉丙基)-7-(1H-吡唑-3-基)-1H-咪唑并[4,5-d]噻吩并[3,2-b]吡啶-4-胺(83)2-(3-morpholinyl)-7-(1H-pyrazol-3-yl)-1H-imidazo[4,5-d]thieno[3,2-b]pyridin-4-amine ( 83)
Figure PCTCN2019085535-appb-000096
Figure PCTCN2019085535-appb-000096
第一步：3-(4-氨基-7-溴-1H-咪唑[4,5-d]噻吩并[3,2-b]吡啶-2-基)丙-1-醇(27a)First step: 3-(4-amino-7-bromo-1H-imidazo[4,5-d]thieno[3,2-b]pyridin-2-yl)propan-1-ol (27a)
将化合物9g(500mg,0.93mmol)加入20mL三氟乙酸中，加热至75℃反应24h，体系浓缩并用EA稀释，饱和碳酸氢钠溶液调节体系pH＝8，室温下搅拌0.5h后分层，有机层无水硫酸钠干燥。经柱层析(洗脱剂体系A)得到化合物27a(280mg)。MS(ESI,m/z):327.0[M+H] +. The compound 9g (500mg, 0.93mmol) was added to 20mL of trifluoroacetic acid, heated to 75 ° C for 24h, the system was concentrated and diluted with EA, saturated sodium bicarbonate solution to adjust the system pH = 8, and stirred at room temperature for 0.5h, layered, organic The layer was dried over anhydrous sodium sulfate. Column chromatography (eluent system A) gave compound 27a (280 mg). MS (ESI, m/z): 327.0 [M+H] + .
第二步：7-溴-2-(3-氯丙基)-1H-咪唑[4,5-d]噻吩并[3,2-b]吡啶-4-胺(27b)Second step: 7-bromo-2-(3-chloropropyl)-1H-imidazole [4,5-d]thieno[3,2-b]pyridin-4-amine (27b)
将化合物27a(130mg,0.40mmol)加入9mL氯化亚砜中，室温下反应24h，体系浓缩得到化合物27b(137mg)。MS(ESI,m/z):344.9[M+H] +. Compound 27a (130 mg, 0.40 mmol) was added to 9 mL of chlorosulfoxide and allowed to react at room temperature for 24 h and then concentrated to give compound 27b (137 mg). MS (ESI, m/z): 344.9 [M+H] + .
第三步：7-溴-2-(3-吗啉丙基)-1H-咪唑[4,5-d]噻吩并[3,2-b]吡啶-4-胺(27c)Third step: 7-bromo-2-(3-morpholinylpropyl)-1H-imidazole [4,5-d]thieno[3,2-b]pyridin-4-amine (27c)
将化合物27b(200mg,0.58mmol)、吗啉(151mg,1.74mmol)、TEA(234mg,2.31mmol)、四丁基碘化铵(21mg,57.86μmol)加入15mL甲苯中，氮气置换后加热至100℃反应4h。反应混合物浓缩并加水稀释，EA提取三次(50mL×3)，合并后无水硫酸钠干燥，得到化合物27c(55mg)。MS(ESI,m/z):396.0[M+H] +. Compound 27b (200 mg, 0.58 mmol), morpholine (151 mg, 1.74 mmol), TEA (234 mg, 2.31 mmol), tetrabutylammonium iodide (21 mg, 57.86 μmol) were added to 15 mL of toluene, replaced with nitrogen and heated to 100. °C reaction for 4h. The reaction mixture was concentrated and diluted with water. EtOAc (EtOAc m. MS (ESI, m/z): 396.0 [M+H] +
第四步：2-(3-吗啉丙基)-7-(1H-吡唑-3-基)-1H-咪唑并[4,5-d]噻吩并[3,2-b]吡啶-4-胺(83)Fourth step: 2-(3-morpholinyl)-7-(1H-pyrazol-3-yl)-1H-imidazo[4,5-d]thieno[3,2-b]pyridine- 4-amine (83)
将化合物27c(55mg,0.14mmol)、1H-吡唑-3-硼酸频哪酯(54mg,0.28mmol)、[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(11mg,13.88μmol)、Na 2CO 3(44mg,0.42mmol)加入到6mL DMF和1.5mL水的混合溶剂中，N 2保护下加热至100℃反应4h。体系硅藻土过滤，滤液通过Prep-HPLC分离纯化(洗脱条件4)，冻干得到化合物83(8mg)。 Compound 27c (55 mg, 0.14 mmol), 1H-pyrazole-3-boronic acid pinacol ester (54 mg, 0.28 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride A methyl chloride complex (11 mg, 13.88 μmol) and Na 2 CO 3 (44 mg, 0.42 mmol) were added to a mixed solvent of 6 mL of DMF and 1.5 mL of water, and heated to 100 ° C for 4 h under N 2 protection. The system was filtered through celite, and the filtrate was separated and purified by Prep-HPLC (elution condition 4), and lyophilized to give compound 83 (8 mg).
MS(ESI,m/z):384.2[M+H] +. MS (ESI, m/z): 384.2 [M+H] + .
1H NMR(DMSO-d 6,400MHz)δ12.91(s,1H),12.78(s,1H),7.82(s,1H),7.48(s,1H),6.74(s,1H),6.04(s,2H),3.59–3.53(m,4H),2.94–2.82(m,2H),2.41–2.31(m,6H),2.01–1.89(m,2H). 1 H NMR (DMSO-d 6 , 400 MHz) δ 12.91 (s, 1H), 12.78 (s, 1H), 7.82 (s, 1H), 7.48 (s, 1H), 6.74 (s, 1H), 6.04 ( s, 2H), 3.59–3.53 (m, 4H), 2.94–2.82 (m, 2H), 2.41–2.31 (m, 6H), 2.01–1.89 (m, 2H).
实施例28：Example 28
叔丁基((4-氨基-1-(4-甲氧基苄基)-7-(1H-吡唑-3-基)-1H-咪唑[4,5-d]噻吩并[3,2-b]吡啶 -2-基)甲基)(乙基)氨基甲酸酯(84)tert-Butyl ((4-amino-1-(4-methoxybenzyl)-7-(1H-pyrazol-3-yl)-1H-imidazole[4,5-d]thieno[3,2 -b]pyridin-2-yl)methyl)(ethyl)carbamate (84)
2-((乙胺基)甲基)-7-(1H-吡唑-3-基)-1H-咪唑并[4,5-d]噻吩并[3,2-b]吡啶-4-胺(88)2-((ethylamino)methyl)-7-(1H-pyrazol-3-yl)-1H-imidazo[4,5-d]thieno[3,2-b]pyridin-4-amine (88)
Figure PCTCN2019085535-appb-000097
Figure PCTCN2019085535-appb-000097
第一步：叔丁基乙基(2-((7-((4-甲氧基苄基)氨基)噻吩并[3,2-b]吡啶-6-基)氨基)-2-氧代乙基)氨基甲酸酯(28a)First step: tert-butylethyl (2-((7-((4-methoxybenzyl))amino)thieno[3,2-b]pyridin-6-yl)amino)-2-oxo Ethyl)carbamate (28a)
将化合物9b(28g,98.24mmol)、BOC-N-乙基甘氨酸(23.93g,117.89mmol)、HATU(63.85g,196.48mmol)加入500mL DMF中，继续向体系中加入DIPEA(25.54g,196.48mmol)，室温下反应16h。反应混合物加水稀释，EA提取三次(300mL×3)，合并后无水硫酸钠干燥，浓缩后得到化合物28a(30g)。MS(ESI,m/z):471.2[M+H] +. Compound 9b (28g, 98.24mmol), BOC-N-ethylglycine (23.93g, 117.89mmol), HATU (63.85g, 196.48mmol) was added to 500mL DMF and DIPEA (25.54g, 196.48mmol) was added to the system. ), react at room temperature for 16 h. The reaction mixture was diluted with water and extracted with EtOAc (3 mL) (3 mL). MS (ESI, m/z): 4721. [M+H] + .
第二步：叔丁基乙基((1-(4-甲氧基苄基)-1H咪唑[4,5-d]噻吩并[3,2-b]吡啶-2-基)甲基)氨基甲酸酯(28b)Second step: tert-butylethyl ((1-(4-methoxybenzyl)-1H imidazo[4,5-d]thieno[3,2-b]pyridin-2-yl)methyl) Carbamate (28b)
将化合物28a(30g,63.83mmol)、NaOH(12.76g,0.32mol)加入600mL无水乙醇中，加热至80℃反应4h。体系浓缩并用DCM稀释，经柱层析(洗脱剂体系A)得到化合物28b(25g)。MS(ESI,m/z):453.1[M+H] +. Compound 28a (30 g, 63.83 mmol), NaOH (12.76 g, 0.32 mol) was added to 600 mL of absolute ethanol and heated to 80 ° C for 4 h. The system was concentrated and diluted with DCM to afford compound 28b (25 g). MS (ESI, m/z): 453.1 [M+H] + .
第三步：2-((叔丁氧羰基)(乙基)氨基)甲基)-1-(4-甲氧基苄基)-1H咪唑[4,5-d]噻吩并[3,2-b]吡啶5-氧化物(28c)Third step: 2-((tert-butoxycarbonyl)(ethyl)amino)methyl)-1-(4-methoxybenzyl)-1H imidazole [4,5-d]thieno[3,2 -b]pyridine 5-oxide (28c)
将化合物28b(25g,55.3mmol)加入500mL氯仿中，继续向体系中加入m-CPBA(19.08g,110.6mmol)，室温下反应4h。反应混合物用饱和碳酸氢钠洗涤两次(300mL×2)，有机层无水硫酸钠干燥，浓缩后得到化合物28c(23g)。MS(ESI,m/z):469.1[M+H] +. Compound 28b (25 g, 55.3 mmol) was added to 500 mL of chloroform, and m-CPBA (19.08 g, 110.6 mmol) was then added to the system and allowed to react at room temperature for 4 h. The reaction mixture was washed twice with saturated aqueous sodium hydrogen sulfate (300 mL, 2). MS (ESI, m/z): 469.1 [M+H] + .
第四步：叔丁基((4-氨基-1-(4-甲氧基苄基)-1H咪唑[4,5-d]噻吩并[3,2-b]吡啶-2-基)甲基)(乙基)氨基甲酸酯(28d)Step 4: tert-Butyl ((4-amino-1-(4-methoxybenzyl)-1H imidazo[4,5-d]thieno[3,2-b]pyridin-2-yl)) (ethyl)carbamate (28d)
将化合物28c(23g,49.14mmol)加入500mL DCM中，继续依次向体系中加入200mL 氨水和对甲苯磺酰氯(18.74g,98.28mmol)，室温下反应3h。反应混合物用DCM稀释，水洗涤三次(400mL×3)，有机层无水硫酸钠干燥。经柱层析(洗脱剂体系A)得到化合物28d(18g)。MS(ESI,m/z):468.1[M+H]+.Compound 28c (23 g, 49.14 mmol) was added to 500 mL DCM, and then 200 mL aqueous ammonia and p-toluenesulfonyl chloride (18.74 g, 98.28 mmol) were added to the system, and the mixture was reacted at room temperature for 3 h. The reaction mixture was diluted with EtOAc (EtOAc m. Column chromatography (eluent system A) gave compound 28d (18 g). MS (ESI, m/z): 468.1 [M+H]+.
第五步：叔丁基((4-氨基-7-溴-1-(4-甲氧基苄基)-1H咪唑[4,5-d]噻吩并[3,2-b]吡啶-2-基)甲基)(乙基)氨基甲酸酯(28e)Step 5: tert-Butyl ((4-amino-7-bromo-1-(4-methoxybenzyl)-1H imidazo[4,5-d]thieno[3,2-b]pyridine-2 -yl)methyl)(ethyl)carbamate (28e)
将化合物28d(18g,38.54mmol)加入到360mL DMF中，继续向体系中加入NBS(13.72g,77.08mmol)，加热至65℃反应5h。反应混合物加水稀释，EA提取三次(200mL×3)，合并后无水硫酸钠干燥，经柱层析(洗脱剂体系A)得到化合物28e(10g)。MS(ESI,m/z):546.1[M+H]+.Compound 28d (18 g, 38.54 mmol) was added to 360 mL DMF and NBS (13.72 g, 77.08 mmol) was then added to the system and heated to 65 ° C for 5 h. The reaction mixture was diluted with water and extracted with EA (3 mL) (3 mL). MS (ESI, m/z): 546.1 [M+H]+.
第六步：叔丁基((4-氨基-1-(4-甲氧基苄基)-7-(1H-吡唑-3-基)-1H-咪唑[4,5-d]噻吩并[3,2-b]吡啶-2-基)甲基)(乙基)氨基甲酸酯(84)Step 6: tert-Butyl ((4-amino-1-(4-methoxybenzyl)-7-(1H-pyrazol-3-yl)-1H-imidazole[4,5-d]thiophene [3,2-b]pyridin-2-yl)methyl)(ethyl)carbamate (84)
将化合物28e(10g,18.35mmol)、1H-吡唑-3-硼酸频哪酯(5.34g,27.53mmol)、[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(1.6g,1.8mmol)、Na 2CO 3(3.89g,36.7mmol)加入到200mL DMF和50mL水的混合溶剂中，N 2保护下加热至120℃反应2h。体系硅藻土过滤，滤液加水稀释，EA提取三次(100mL×3)，合并后无水硫酸钠干燥，经柱层析(洗脱剂体系A)得到粗品化合物84(5g)。取50mg通过Prep-HPLC分离纯化(洗脱条件4)，冻干得到化合物84(10mg)。 Compound 28e (10 g, 18.35 mmol), 1H-pyrazole-3-boronic acid pinacol ester (5.34 g, 27.53 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride A dichloromethane complex (1.6 g, 1.8 mmol) and Na 2 CO 3 (3.89 g, 36.7 mmol) were added to a mixed solvent of 200 mL of DMF and 50 mL of water, and heated to 120 ° C for 2 h under N 2 protection. The system was filtered through celite, and the filtrate was diluted with water, and then EA was applied to three times (100 mL×3), and then dried over anhydrous sodium sulfate and then purified by column chromatography (eluent system A) to give crude compound 84 (5 g). 50 mg was purified by Prep-HPLC (elution condition 4), and lyophilized to give compound 84 (10 mg).
MS(ESI,m/z):534.1[M+H] +. MS (ESI, m/z): 534.1 [M+H] + .
1H NMR(DMSO-d 6,400MHz)δ12.92(s,1H),7.79(t,J＝1.7Hz,1H),7.48(s,1H),6.94–6.86(m,4H),6.72(t,J＝2.1Hz,1H),6.23(s,2H),5.58(s,2H),4.72(s,2H),3.68(s,3H),3.13(s,2H),1.25(s,9H),1.02(t,J＝6.9Hz,3H). 1 H NMR (DMSO-d 6 , 400 MHz) δ 12.92 (s, 1H), 7.79 (t, J = 1.7 Hz, 1H), 7.48 (s, 1H), 6.94 - 6.86 (m, 4H), 6.72 ( t, J = 2.1 Hz, 1H), 6.23 (s, 2H), 5.58 (s, 2H), 4.72 (s, 2H), 3.68 (s, 3H), 3.13 (s, 2H), 1.25 (s, 9H) ), 1.02 (t, J = 6.9 Hz, 3H).
第七步：2-((乙胺基)甲基)-7-(1H-吡唑-3-基)-1H-咪唑并[4,5-d]噻吩并[3,2-b]吡啶-4-胺(88)Step 7: 2-((Ethylamino)methyl)-7-(1H-pyrazol-3-yl)-1H-imidazo[4,5-d]thieno[3,2-b]pyridine -4-amine (88)
将化合物84(100mg,196μmol)加入5mL三氟乙酸中，加热至75℃反应16h，体系浓缩并用EA稀释，饱和碳酸氢钠溶液调节体系pH＝8，室温下搅拌0.5h后分层，有机层无水硫酸钠干燥，体系硅藻土过滤，滤液通过Prep-HPLC分离纯化(洗脱条件4)，冻干得到化合物88(10mg)。Compound 84 (100 mg, 196 μmol) was added to 5 mL of trifluoroacetic acid, heated to 75 ° C for 16 h, the system was concentrated and diluted with EA, saturated sodium bicarbonate solution was adjusted to pH=8, stirred at room temperature for 0.5 h, then layered, organic layer The organic layer was dried over anhydrous sodium sulfate, filtered over Celite, and then filtered and purified by EtOAc (EtOAc)
MS(ESI,m/z):314.1[M+H] +. MS (ESI, m/z): 314.1 [M+H] + .
1H NMR(DMSO-d 6,400MHz)δ12.92(s,2H),7.79(d,J＝2.3Hz,1H),7.49(s,1H),6.72(d,J＝2.3Hz,1H),6.21(s,2H),3.98(s,2H),2.67–2.62(m,2H),1.09(t,J＝7.1Hz,3H). 1 H NMR (DMSO-d 6 , 400 MHz) δ 12.92 (s, 2H), 7.79 (d, J = 2.3 Hz, 1H), 7.49 (s, 1H), 6.72 (d, J = 2.3 Hz, 1H) , 6.21 (s, 2H), 3.98 (s, 2H), 2.67 - 2.62 (m, 2H), 1.09 (t, J = 7.1 Hz, 3H).
实施例29：Example 29
N-((4-氨基-7-(1H-吡唑-3-基)-1H-咪唑[4,5-d]噻吩并[3,2-b]吡啶-2-基)甲基)-N-乙基 -2-(间甲苯基)乙酰胺(85)N-((4-Amino-7-(1H-pyrazol-3-yl)-1H-imidazole[4,5-d]thieno[3,2-b]pyridin-2-yl)methyl)- N-ethyl-2-(m-tolyl)acetamide (85)
Figure PCTCN2019085535-appb-000098
Figure PCTCN2019085535-appb-000098
将化合物88(70mg,0.17mmol)、间甲基苯乙酸(37mg,0.25mmol)、HATU(127.40mg,0.34mmol)加入3mL DMF中，继续向体系中加入DIPEA(144mg,1.12mmol)，室温下反应2h。通过Prep-HPLC分离纯化(洗脱条件5)，冻干得到化合物85(4mg)。Compound 88 (70 mg, 0.17 mmol), m-methylphenylacetic acid (37 mg, 0.25 mmol), HATU (127.40 mg, 0.34 mmol) was added to 3 mL DMF and DIPEA (144 mg, 1.12 mmol) was added to the system at room temperature Reaction 2h. Purification by Prep-HPLC (elution condition 5), lyophilized to give compound 85 (4 mg).
MS(ESI,m/z):446.2[M+H] +. MS (ESI, m/z): 446.2 [M+H] + .
1H NMR(DMSO-d 6,400MHz)δ12.92(s,1H),8.19(s,1H),7.81(s,1H),7.50(d,J＝8.6Hz,1H),7.18(dd,J＝14.9,7.3Hz,1H),7.12–6.97(m,3H),6.73(s,1H),6.22(s,2H),4.88–4.69(m,2H),3.82–3.75(m,2H),3.56–3.48(m,2H),2.28–2.21(m,3H),1.12–1.00(m,3H). 1 H NMR (DMSO-d 6 , 400MHz) δ12.92 (s, 1H), 8.19 (s, 1H), 7.81 (s, 1H), 7.50 (d, J = 8.6Hz, 1H), 7.18 (dd, J=14.9, 7.3 Hz, 1H), 7.12–6.97 (m, 3H), 6.73 (s, 1H), 6.22 (s, 2H), 4.88–4.69 (m, 2H), 3.82–3.75 (m, 2H) , 3.56–3.48 (m, 2H), 2.28–2.21 (m, 3H), 1.12–1.00 (m, 3H).
实施例30：Example 30:
N-((4-氨基-7-(1H-吡唑-3-基)-1H-咪唑[4,5-d]噻吩并[3,2-b]吡啶-2-基)甲基)-N-乙基吗啉-4-甲酰胺(86)N-((4-Amino-7-(1H-pyrazol-3-yl)-1H-imidazole[4,5-d]thieno[3,2-b]pyridin-2-yl)methyl)- N-ethylmorpholine-4-carboxamide (86)
Figure PCTCN2019085535-appb-000099
Figure PCTCN2019085535-appb-000099
将化合物88(70mg,0.17mmol)、DIPEA(115mg,0.89mmol)加入2mL DMF中，继续向体系中加入4-吗啉碳酰氯(50mg,0.34mmol)，室温下反应2h。通过Prep-HPLC分离纯化(洗脱条件3)，冻干得到化合物86(10mg)。Compound 88 (70 mg, 0.17 mmol), DIPEA (115 mg, 0.89 mmol) was added to 2 mL DMF. Purification by Prep-HPLC (elution condition 3) and lyophilization afforded compound 86 (10 mg).
MS(ESI,m/z):427.2[M+H] +. MS (ESI, m/z): 427.2 [M+H] + .
1H NMR(DMSO-d6,400MHz)δ12.93(s,1H),7.81(s,1H),7.49(s,1H),6.74(s,1H),6.45–6.10(m,2H),4.55(s,2H),3.75–3.55(m,5H),3.22–3.08(m,5H),1.11(s,3H). 1 H NMR (DMSO-d6, 400 MHz) δ 12.93 (s, 1H), 7.81 (s, 1H), 7.49 (s, 1H), 6.74 (s, 1H), 6.45 - 6.10 (m, 2H), 4.55 (s, 2H), 3.75–3.55 (m, 5H), 3.22–3.08 (m, 5H), 1.11 (s, 3H).
实施例31：Example 31:
N-((4-氨基-7-(1H-吡唑-3-基)-1H-咪唑并[4,5-d]噻吩并[3,2-b]吡啶-2-基)甲基)-N-乙基-1-甲基-1H-吡咯-2-甲酰胺(87)N-((4-Amino-7-(1H-pyrazol-3-yl)-1H-imidazo[4,5-d]thieno[3,2-b]pyridin-2-yl)methyl) -N-ethyl-1-methyl-1H-pyrrole-2-carboxamide (87)
Figure PCTCN2019085535-appb-000100
Figure PCTCN2019085535-appb-000100
将化合物88(70mg,0.17mmol)、N-甲基-2-吡咯羧酸(31mg,0.25mmol)、HATU(127.40mg,0.34mmol)加入3mL DMF中，继续向体系中加入DIPEA(144mg,1.12mmol)，室温下反应2h。通过Prep-HPLC分离纯化(洗脱条件4)，冻干得到化合物87(3mg)。Compound 88 (70 mg, 0.17 mmol), N-methyl-2-pyrrolecarboxylic acid (31 mg, 0.25 mmol), HATU (127.40 mg, 0.34 mmol) was added to 3 mL DMF and DIPEA (144 mg, 1.12) was added to the system. Methyl), reacted for 2 h at room temperature. Purification by Prep-HPLC (elution condition 4), lyophilized to give compound 87 (3 mg).
MS(ESI,m/z):421.2[M+H] +. MS (ESI, m/z): 421.2 [M+H] + .
1H NMR(DMSO-d 6,400MHz)δ12.94(s,1H),8.18(s,1H),7.80(s,1H),7.50(s,1H),6.93(s,1H),6.74(s,1H),6.45(s,1H),6.22(s,2H),6.08–5.98(m,1H),4.94–4.85(m,2H),3.72(s,3H),3.60(s,2H),1.19(t,J＝6.9Hz,3H). 1 H NMR (DMSO-d 6 , 400MHz) δ12.94 (s, 1H), 8.18 (s, 1H), 7.80 (s, 1H), 7.50 (s, 1H), 6.93 (s, 1H), 6.74 ( s,1H), 6.45(s,1H), 6.22(s,2H),6.08–5.98(m,1H),4.94–4.85(m,2H),3.72(s,3H),3.60(s,2H) , 1.19 (t, J = 6.9 Hz, 3H).
实施例32：Example 32:
N-((4-氨基-7-(1H-吡唑-3-基)-1H-咪唑[4,5-d]噻吩并[3,2-b]吡啶-2-基)甲基)-N-乙基乙酰胺(89)N-((4-Amino-7-(1H-pyrazol-3-yl)-1H-imidazole[4,5-d]thieno[3,2-b]pyridin-2-yl)methyl)- N-ethylacetamide (89)
Figure PCTCN2019085535-appb-000101
Figure PCTCN2019085535-appb-000101
将化合物88(100mg,0.32mmol)、醋酸酐(65.15mg,0.64mmol)、三乙胺(161.15mg,1.6mmol)加入3mL DCM中，室温下反应2h。通过Prep-HPLC分离纯化(洗脱条件3)，冻干得到化合物89(5mg)。Compound 88 (100 mg, 0.32 mmol), acetic anhydride (65.15 mg, 0.64 mmol), triethylamine (161.15 mg, 1.6 mmol) was added to 3 mL DCM and allowed to react at room temperature for 2 h. Purification by Prep-HPLC (elution condition 3), lyophilized to give compound 89 (5 mg).
MS(ESI,m/z):356.1[M+H] +. MS (ESI, m/z): 356.1 [M+H] + .
1H NMR(DMSO-d 6,400MHz)δ12.92(s,2H),7.80(s,1H),7.50(d,J＝8.6Hz,1H),6.75(m,1H),6.28(s,2H),4.80–4.73(m,2H),3.48–3.35(m,2H),2.16–2.14(m,3H),1.16–0.99(m,3H). 1 H NMR (DMSO-d 6 , 400MHz) δ12.92 (s, 2H), 7.80 (s, 1H), 7.50 (d, J = 8.6Hz, 1H), 6.75 (m, 1H), 6.28 (s, 2H), 4.80–4.73 (m, 2H), 3.48–3.35 (m, 2H), 2.16–2.14 (m, 3H), 1.16–0.99 (m, 3H).
实施例33：Example 33:
N-((4-氨基-7-(1H-吡唑-3-基)-1H-咪唑[4,5-d]噻吩并[3,2-b]吡啶-2-基)甲基)-N-乙基环丙烷甲酰胺(90)N-((4-Amino-7-(1H-pyrazol-3-yl)-1H-imidazole[4,5-d]thieno[3,2-b]pyridin-2-yl)methyl)- N-ethylcyclopropanecarboxamide (90)
Figure PCTCN2019085535-appb-000102
Figure PCTCN2019085535-appb-000102
将化合物88(100mg,0.32mmol)、环丙甲酸(32.97mg,0.38mmol)、HATU(242.52mg,0.64mmol)加入2mL DMF中，继续向体系中加入DIPEA(206.20mg,1.6mmol)，室温下反应2h。通过Prep-HPLC分离纯化(洗脱条件3)，冻干得到化合物90的甲酸盐90s(5mg)。Compound 88 (100 mg, 0.32 mmol), cyclopropanoic acid (32.97 mg, 0.38 mmol), HATU (242.52 mg, 0.64 mmol) was added to 2 mL DMF and DIPEA (206.20 mg, 1.6 mmol) was added to the system at room temperature Reaction 2h. Purification by Prep-HPLC (elution condition 3), lyophilized to give the formate 90s (5 mg).
MS(ESI,m/z):382.1[M+H] +. MS (ESI, m/z): 3821. [M+H] + .
1H NMR(DMSO-d 6,400MHz)δ12.93(s,2H),8.28(s,1H),7.80(s,1H),7.49(m,1H),6.73(s,1H),6.27(s,2H),5.00–4.74(m,2H),3.68–3.43(m,2H),2.03–1.97(m,1H),1.21–1.03(m,3H),0.84–0.70(m,4H). 1 H NMR (DMSO-d 6 , 400MHz) δ12.93 (s, 2H), 8.28 (s, 1H), 7.80 (s, 1H), 7.49 (m, 1H), 6.73 (s, 1H), 6.27 ( s, 2H), 5.00–4.74 (m, 2H), 3.68–3.43 (m, 2H), 2.03–1.97 (m, 1H), 1.21–1.03 (m, 3H), 0.84–0.70 (m, 4H).
实施例34：Example 34:
1-((4-氨基-1-乙基-7-(噻吩-2-基)-1H咪唑[4,5-d]噻吩并[3,2-b]吡啶-2-基)甲基)吡咯烷-2-酮(91)1-((4-Amino-1-ethyl-7-(thiophen-2-yl)-1H imidazo[4,5-d]thieno[3,2-b]pyridin-2-yl)methyl) Pyrrolidin-2-one (91)
Figure PCTCN2019085535-appb-000103
Figure PCTCN2019085535-appb-000103
第一步：化合物N-乙基-6-硝基噻吩并[3,2-b]吡啶-7-胺的合成(91a)First step: Synthesis of the compound N-ethyl-6-nitrothieno[3,2-b]pyridine-7-amine (91a)
室温下，将依次将TEA(2.07g，20.50mmol)，乙胺水溶液(68％，5mL)加入到化合物1c(1.1g，5.13mmol)的NMP(5mL)溶液中。室温下反应1h。将反应混合物倒入水(20mL)水中，析出固体。过滤即得到化合物91a(900mg)。MS(ESI，m/z):224.1[M+H] + To a solution of compound 1c (1.1 g, 5.13 mmol) in NMP (5 mL), EtOAc (EtOAc, EtOAc) The reaction was carried out for 1 h at room temperature. The reaction mixture was poured into water (20 mL) and water was evaporated. Filtration gave Compound 91a (900 mg). MS (ESI, m/z): 224.1 [M+H] +
第二步：化合物N7乙基噻吩并[3,2-b]吡啶-6,7-二胺的合成(91b)Step 2: Synthesis of compound N7 ethylthieno[3,2-b]pyridine-6,7-diamine (91b)
室温下，将钯碳(447.93μmol)加入到化合物91a(1g，4.48mmol)的甲醇(10mL)溶液中。然后在氢气氛围下搅拌反应5h。过滤除掉钯碳，母液直接浓缩干，得到化合物91b(720mg)。MS(ESI，m/z):194.1[M+H] + Palladium on carbon (447.93 μmol) was added to a solution of compound 91a (1 g, 4.48 mmol) in methanol (10 mL). The reaction was then stirred under a hydrogen atmosphere for 5 h. The palladium carbon was removed by filtration, and the mother liquid was directly concentrated to dryness to give compound 91b (720 mg). MS (ESI, m/z): 194.1 [M+H] +
第三步：化合物乙酸2-(2-氧代吡咯烷-1-基)乙酯的合成(91d)The third step: synthesis of the compound 2-(2-oxopyrrolidin-1-yl)ethyl acetate (91d)
室温下，将碳酸铯(22.91g，70.50mmol)加入到溴乙酸乙酯(3.92g，23.50mmol)、91c(2g，23.50mmol)的DMF(5mL)溶液中，然后保持室温搅拌反应16h。然后加乙酸乙酯，清水洗涤。萃取、浓缩得到化合物91d(3g)。MS(ESI,mz)：172.2[M+1] +。 Cesium carbonate (22.91 g, 70.50 mmol) was added to a solution of ethyl bromoacetate (3.92 g, 23.50 mmol), 91c (2 g, 23.50 mmol) in DMF (5 mL). Then ethyl acetate was added and the water was washed. Extraction and concentration gave the compound 91d (3 g). MS (ESI, mz): 172.2 [M + 1] +.
第四步：化合物2-(2-氧代吡咯烷-1-基)乙酸的合成(91e)Step 4: Synthesis of the compound 2-(2-oxopyrrolidin-1-yl)acetic acid (91e)
室温下，将氢氧化钠(1.40g，35.05mmol)加入到化合物91d(3g，17.52mmol)的水(2mL)乙醇(5mL)溶液中。然后在室温下反应4h。稀盐酸调节pH＝3后，通过柱层析纯化(洗脱体系A)得到化合物91e(700mg)。Sodium hydroxide (1.40 g, 35.05 mmol) was added to a solution of compound 91d (3 g, 17.52 mmol) in water (2 mL) It was then reacted at room temperature for 4 h. After adjusting pH = 3 with dilute hydrochloric acid, purification by column chromatography (elution of system A) gave compound 91e (700 mg).
1H NMR(400MHz,DMSO-d 6)δ3.49(s,2H),3.39(t,J＝7.0Hz,2H),2.17(t,J＝8.1Hz,2H),1.93-1.83(m,2H). 1 H NMR (400 MHz, DMSO-d 6 ) δ 3.49 (s, 2H), 3.39 (t, J = 7.0 Hz, 2H), 2.17 (t, J = 8.1 Hz, 2H), 1.93-1.83 (m, 2H).
第五步：化合物N-(7-乙基氨基)噻吩并[3,2-b]吡啶-6-基)-2-(2-氧代吡咯烷-1-基)乙酰胺的合成(91f)Step 5: Synthesis of the compound N-(7-ethylamino)thieno[3,2-b]pyridin-6-yl)-2-(2-oxopyrrolidin-1-yl)acetamide (91f )
室温下，依次将HATU(983.09mg，2.59mmol)、DIPEA(668.71mg，5.17mmol)加入到化合物91e(370.31mg，2.59mmol)、化合物91b(500mg，2.59mmol)的DMF(3mL)溶液中。然后保持室温反应16h。然后水洗涤后，乙酸乙酯层干燥浓缩,然后通过柱层析分离纯化(洗脱体系A)得到化合物91f(500mg)。MS(ESI,mz)：318.2[M+1] + HATU (983.09 mg, 2.59 mmol), DIPEA (668.71 mg, 5.17 mmol) was added to a solution of compound 91e (370.31 mg, 2.59 mmol) and compound 91b (500 mg, 2.59 mmol) in DMF (3 mL). Then, the reaction was kept at room temperature for 16 h. After washing with water, the ethyl acetate layer was dried and concentrated, and then purified by column chromatography (elution system A) to give compound 91f (500 mg). MS (ESI, mz): 318.2 [M+1] +
第六步：化合物1-((1-甲基-1H-咪唑[4,5-d]噻吩并[3,2-b]吡啶-2-基)甲基)吡咯烷-2-酮的合成(91g)Step 6: Synthesis of the compound 1-((1-methyl-1H-imidazo[4,5-d]thieno[3,2-b]pyridin-2-yl)methyl)pyrrolidin-2-one (91g)
室温下，将氢氧化钠(125.63mg，3.14mmol)加入到化合物91f(500mg，1.57mmol)的乙醇(4mL)溶液中。然后升温到90℃反应4h。加稀盐酸调节pH＝7淬灭反应，通过柱层析分离纯化(洗脱体系A)得到化合物91g(300mg)。MS(ESI，m/z):301.1[M+H] +。 Sodium hydroxide (125.63 mg, 3.14 mmol) was added to a solution of compound 91f (500 mg, 1.57 mmol) in ethanol (4 mL). The temperature was then raised to 90 ° C for 4 h. The reaction was quenched by the addition of dilute hydrochloric acid to pH = 7 and purified by column chromatography (elution system A) to afford compound 91 g (300 mg). MS (ESI, m / z) : 301.1 [M + H] +.
第七步：化合物1-((7-溴-1-甲基-1H-咪唑[4,5-d]噻吩并[3,2-b]吡啶-2-基)甲基)吡咯烷-2-酮的合成(91h)Step 7: Compound 1-((7-bromo-1-methyl-1H-imidazo[4,5-d]thieno[3,2-b]pyridin-2-yl)methyl)pyrrolidine-2 -ketone synthesis (91h)
室温下，将NBS(177.76mg，998.74μmol)加入到化合物91g(300mg，998.74μmol)的氯仿(2mL)醋酸(2mL)混合溶液中，然后保持室温搅拌反应16h。加水淬灭反应，DCM 萃取。浓缩后，通过制备板分离纯化(洗脱体系A)得到化合物91h(150mg)。MS(ESI，m/z):379.0[M+H] +。 NBS (177.76 mg, 998.74 μmol) was added to a mixed solution of 91 g (300 mg, 998.74 μmol) of chloroform (2 mL) acetic acid (2 mL), and the mixture was stirred at room temperature for 16 h. The reaction was quenched with water and extracted with DCM. After concentration, it was purified by preparative EtOAc (EtOAc (EtOAc) MS (ESI, m / z) : 379.0 [M + H] +.
第八步：化合物7-溴-1-甲基-2-((2-氧代吡咯烷-1-基)甲基)-1H咪唑[4,5-d]噻吩并[3,2-b]吡啶5-氧化物(91i)Step 8: Compound 7-bromo-1-methyl-2-((2-oxopyrrolidin-1-yl)methyl)-1H imidazole [4,5-d]thieno[3,2-b Pyridine 5-oxide (91i)
室温下，将间氯过氧苯甲酸(102.04mg，593.24μmol)加入到化合物91h(150mg，395.49μmol)的DCM(4mL)溶液中，然后保持室温反应4h。加饱和碳酸氢钠溶液淬灭反应，然后DCM萃取。有机层干燥、浓缩后，得到化合物91i(120mg)。MS(ESI，m/z):397.0[M+H] +。 m-Chloroperoxybenzoic acid (102.04 mg, 593.24 μmol) was added to a solution of compound 91h (150 mg, 395.49 μmol) in DCM (4 mL). The reaction was quenched with saturated sodium bicarbonate solution and then extracted with DCM. The organic layer was dried and concentrated to give compound 91i (l. MS (ESI, m / z) : 397.0 [M + H] +.
第九步：化合物1-((4-氨基-7-溴-1-甲基-1H-咪唑[4,5-d]噻吩并[3,2-b]吡啶-2-基)甲基)吡咯烷-2-酮(91j)Step 9: Compound 1-((4-amino-7-bromo-1-methyl-1H-imidazo[4,5-d]thieno[3,2-b]pyridin-2-yl)methyl) Pyrrolidin-2-one (91j)
室温下，依次将氨水(5mL)、对甲苯磺酰氯(57.88mg，303.59μmol)加入到化合物91i(120mg，303.59μmol)的DCM(5mL)溶液中，然后保持室温下搅拌反应2h。然后直接浓缩干溶剂，通过制备板分离纯化(洗脱体系A)得到化合物91j(30mg)。MS(ESI，m/z):395.0[M+H] +。 Aqueous ammonia (5 mL) and p-toluenesulfonyl chloride (57.88 mg, 303.59 μmol) were added to a solution of compound 91i (120 mg, 303.59 μmol) in DCM (5 mL), and then the mixture was stirred at room temperature for 2 h. Then, the dry solvent was directly concentrated, and purified by preparative chromatography (elution system A) to give compound 91j (30 mg). MS (ESI, m / z) : 395.0 [M + H] +.
第十步：化合物1-((4-氨基-1-乙基-7-(噻吩-2-基)-1H咪唑[4,5-d]噻吩并[3,2-b]吡啶-2-基)甲基)吡咯烷-2-酮的合成(91)Step 10: Compound 1-((4-amino-1-ethyl-7-(thiophen-2-yl)-1H imidazo[4,5-d]thieno[3,2-b]pyridine-2- Synthesis of methyl)pyrrolidin-2-one (91)
室温下，依次将Pd(dppf)Cl 2(2.78mg，3.80μmol)、碳酸钾(21.00mg，152.17μmol)加入到2-噻吩硼酸(9.74mg，76.09μmol)、化合物91j(30mg，76.09μmol)的水(0.5mL)、二氧六环(2mL)溶液中。然后在氮气保护下，升温到90℃反应5h。加乙酸乙酯5mL，稀释反应混合物。然后清水洗涤，乙酸乙酯层干燥浓缩，通过Prep-HPLC分离纯化(洗脱条件5)得到化合物91(15mg)。MS(ESI，m/z):398.1[M+H] +。 Pd(dppf)Cl 2 (2.78 mg, 3.80 μmol) and potassium carbonate (21.00 mg, 152.17 μmol) were sequentially added to 2-thiopheneboronic acid (9.74 mg, 76.09 μmol), and compound 91j (30 mg, 76.09 μmol) at room temperature. Water (0.5 mL), dioxane (2 mL) solution. Then, under nitrogen protection, the temperature was raised to 90 ° C for 5 h. Ethyl acetate 5 mL was added and the reaction mixture was diluted. Then, it was washed with water, and the ethyl acetate layer was dried and concentrated, and then purified and purified by Prep-HPLC ( eluting condition 5) to give Compound 91 (15 mg). MS (ESI, m/z): 398.1 [M+H] + .
1H NMR(400MHz，DMSO-d 6)δ7.60(dd，J＝5.1，1.0Hz，1H)，7.48(dd，J＝3.6，1.0Hz，1H)，7.46(s，1H)，7.15(dd，J＝5.1，3.6Hz，1H)，6.40(s，2H)，4.71(s，2H)，4.32(q，J＝7.1Hz，2H)，3.36(m，2H)，2.33(t，J＝8.1Hz，2H)，1.95(dd，J＝15.0，7.5Hz，2H)，1.37(t，J＝7.2Hz，3H). 1 H NMR (400 MHz, DMSO-d 6 ) δ 7.60 (dd, J = 5.1, 1.0 Hz, 1H), 7.48 (dd, J = 3.6, 1.0 Hz, 1H), 7.46 (s, 1H), 7.15 ( Dd, J = 5.1, 3.6 Hz, 1H), 6.40 (s, 2H), 4.71 (s, 2H), 4.32 (q, J = 7.1 Hz, 2H), 3.36 (m, 2H), 2.33 (t, J) = 8.1 Hz, 2H), 1.95 (dd, J = 15.0, 7.5 Hz, 2H), 1.37 (t, J = 7.2 Hz, 3H).
实施例35：Example 35:
N-((4-氨基-7-(1H-吡唑-3-基)-1H-咪唑[4,5-d]噻吩并[3,2-b]吡啶-2-基)甲基)-N-乙基-1-甲基哌啶-4-甲酰胺(92)N-((4-Amino-7-(1H-pyrazol-3-yl)-1H-imidazole[4,5-d]thieno[3,2-b]pyridin-2-yl)methyl)- N-Ethyl-1-methylpiperidine-4-carboxamide (92)
Figure PCTCN2019085535-appb-000104
Figure PCTCN2019085535-appb-000104
将化合物88(100mg,0.32mmol)、1-甲基哌啶-4-甲酸(54.34mg,0.38mmol)、HATU(242.52mg,0.64mmol)加入2mL DMF中，继续向体系中加入DIPEA(206.20mg,1.6mmol)，室温下反应2h。通过Prep-HPLC分离纯化(洗脱条件4)，冻干得到化合物92(2mg)。Compound 88 (100 mg, 0.32 mmol), 1-methylpiperidine-4-carboxylic acid (54.34 mg, 0.38 mmol), HATU (242.52 mg, 0.64 mmol) was added to 2 mL DMF and DIPEA (206.20 mg) was added to the system. , 1.6 mmol), reacted at room temperature for 2 h. Purification by Prep-HPLC (elution condition 4) and lyophilization afforded compound 92 (2 mg).
MS(ESI,m/z):439.1[M+H] +. MS (ESI, m/z): 439.1 [M+H] + .
1HNMR(DMSO-d 6,400MHz)δ12.93(s,2H),7.81(s,1H),7.50(s,1H),6.74(s,1H),6.12(s,2H),4.83–4.71(m,2H),3.51(s,2H),2.80–2.67(m,2H),2.15–2.11(m,3H),1.92–1.84(m,2H),1.68–1.58(m,4H),1.24–0.99(m,3H). 1 H NMR (DMSO-d 6 , 400 MHz) δ 12.93 (s, 2H), 7.81 (s, 1H), 7.50 (s, 1H), 6.74 (s, 1H), 6.12 (s, 2H), 4.83 - 4.71 (m, 2H), 3.51 (s, 2H), 2.80 - 2.67 (m, 2H), 2.15 - 2.11 (m, 3H), 1.92 - 1.84 (m, 2H), 1.68 - 1.58 (m, 4H), 1.24 –0.99(m,3H).
实施例36：Example 36:
N-((4-氨基-1-甲基-7-(1H-吡唑-3-基)-1H-咪唑[4,5-d]噻吩并[3,2-b]吡啶-2-基)甲基)-N-乙基环丙烷甲酰胺(93)N-((4-Amino-1-methyl-7-(1H-pyrazol-3-yl)-1H-imidazole[4,5-d]thieno[3,2-b]pyridin-2-yl )methyl)-N-ethylcyclopropanecarboxamide (93)
Figure PCTCN2019085535-appb-000105
Figure PCTCN2019085535-appb-000105
第一步：叔丁基乙基(2-((7-甲氨基)噻吩并[3,2-b]吡啶-6-基)氨基)-2-氧代乙基)氨基甲酸酯(93a)First step: tert-butylethyl (2-((7-methylamino)thieno[3,2-b]pyridin-6-yl)amino)-2-oxoethyl)carbamate (93a )
将化合物1e(5.65g,31.52mmol)、Boc-N-乙基甘氨酸(7.69g,37.83mmol)、HATU(23.11g,60.78mmol)加入30mL DMF中，继续向体系中加入DIPEA(20.37g,0.16mol)，室温下反应16h。反应混合物加水稀释，EA提取三次，合并后无水硫酸钠干燥，浓缩后得到化合物93a(11.49g)。MS(ESI,m/z):365.2[M+H] +. Compound 1e (5.65 g, 31.52 mmol), Boc-N-ethylglycine (7.69 g, 37.83 mmol), HATU (23.11 g, 60.78 mmol) was added to 30 mL DMF and DIPEA (20.37 g, 0.16) was added to the system. Mol), reacted at room temperature for 16 h. The reaction mixture was diluted with water and extracted with EtOAc EtOAc EtOAc. MS (ESI, m/z): 365.2 [M+H] + .
第二步：叔丁基乙基((1-甲基-1H-咪唑[4,5-d]噻吩并[3,2-b]吡啶-2-基)甲基)氨基甲酸酯(93b)Second step: tert-butylethyl ((1-methyl-1H-imidazo[4,5-d]thieno[3,2-b]pyridin-2-yl)methyl)carbamate (93b )
将化合物93a(11.49g,31.52mmol)、氢氧化钠(6.31g,0.16mol)加入100mL无水乙醇中，加热至90℃反应4h。浓缩后加水稀释，EA提取三次(100mL×3)，合并后无水硫 酸钠干燥。经柱层析(洗脱剂体系B)得到化合物93b(9.66g)。MS(ESI,m/z):347.2[M+H] +. Compound 93a (11.49 g, 31.52 mmol) and sodium hydroxide (6.31 g, 0.16 mol) were added to 100 mL of absolute ethanol and heated to 90 ° C for 4 h. After concentration, it was diluted with water, and EA was extracted three times (100 mL×3), and dried over anhydrous sodium sulfate. Column chromatography (eluent system B) gave compound 93b (9.66 g). MS (ESI, m/z): 347.2 [M+H] + .
第三步：叔丁基(7-溴-1-甲基-1H-咪唑[4,5-d]噻吩并[3,2-b]吡啶-2-基)甲基)(乙基)氨基甲酸酯(93c)Third step: tert-butyl (7-bromo-1-methyl-1H-imidazo[4,5-d]thieno[3,2-b]pyridin-2-yl)methyl)(ethyl)amino Formate (93c)
将化合物93b(9.56g,27.59mmol)加入到200mL DMF和50mL冰乙酸的混合溶剂中，继续向体系中加入NBS(9.56g,53.71mol)，加热至65℃反应1h。反应混合物加水稀释，EA提取三次，合并后无水硫酸钠干燥。经柱层析(洗脱剂体系B)得到化合物93c(7.23g)。MS(ESI,m/z):425.1[M+H] +. Compound 93b (9.56 g, 27.59 mmol) was added to a mixed solvent of 200 mL of DMF and 50 mL of glacial acetic acid, and NBS (9.56 g, 53.71 mol) was further added to the system, and the mixture was heated to 65 ° C for 1 h. The reaction mixture was diluted with water and extracted with EA EtOAc. Column chromatography (eluent system B) gave compound 93c (7.23 g). MS (ESI, m/z): 425.1 [M+H] + .
第四步：7-溴-2-((叔丁氧羰基)(乙基)氨基)甲基)-1-甲基-1H-咪唑并[4,5-d]噻吩并[3,2-b]吡啶-5-氧化物(93d)Fourth step: 7-bromo-2-((tert-butoxycarbonyl)(ethyl)amino)methyl)-1-methyl-1H-imidazo[4,5-d]thieno[3,2- b] Pyridine-5-oxide (93d)
将化合物93c(7.18g,16.88mmol)加入280mL DCM中，继续向体系中加入mCPBA(5.83g,33.76mol)，室温下反应16h。反应混合物用饱和碳酸氢钠洗涤三次(100mL×3)，有机层无水硫酸钠干燥，浓缩后得到化合物93d(7.45g)。MS(ESI,m/z):441.1[M+H] +. Compound 93c (7.18 g, 16.88 mmol) was added to 280 mL DCM and mCPBA (5.83 g, 33.76 mol) was then added to the system and allowed to react at room temperature for 16 h. The reaction mixture was washed three times with saturated sodium hydrogen sulfate (100 mL×3). MS (ESI, m/z): 441.1 [M+H] + .
第五步：叔丁基((4-氨基-7-溴-1-甲基-1H-咪唑[4,5-d]噻吩并[3,2-b]吡啶-2-基)甲基)(乙基)氨基甲酸酯(93e)Step 5: tert-Butyl ((4-amino-7-bromo-1-methyl-1H-imidazole[4,5-d]thieno[3,2-b]pyridin-2-yl)methyl) (ethyl)carbamate (93e)
将化合物93d(7.45g,16.88mmol)加入180mL DCM中，继续依次向体系中加入60mL氨水和对甲苯磺酰氯(3.30g,46.79mmol)，室温下反应5h。反应混合物用DCM稀释，水洗涤三次(200mL×3)，有机层无水硫酸钠干燥。经柱层析(洗脱剂体系A)得到化合物93e(4.18g)。MS(ESI,m/z):440.1[M+H] +. Compound 93d (7.45 g, 16.88 mmol) was added to 180 mL of DCM, and then, 60 mL of aqueous ammonia and p-toluenesulfonyl chloride (3.30 g, 46.79 mmol) were successively added to the system, and reacted at room temperature for 5 h. The reaction mixture was diluted with EtOAc (EtOAc m. Column chromatography (eluent system A) gave compound 93e (4.18 g). MS (ESI, m/z): 440.1 [M+H] + .
第六步：叔丁基((4-氨基-1-甲基-7-(1H-吡唑-3-基)-1H-咪唑[4,5-d]噻吩并[3,2-b]吡啶-2-基)甲基)(乙基)氨基甲酸酯(93f)Step 6: tert-Butyl ((4-amino-1-methyl-7-(1H-pyrazol-3-yl)-1H-imidazole[4,5-d]thieno[3,2-b] Pyridin-2-yl)methyl)(ethyl)carbamate (93f)
将化合物93e(4.08g,8.34mmol)、1H-吡唑-3-硼酸频哪酯(4.08g,21.03mmol)、[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(1.02g,1.2mmol)、Na 2CO 3(2.65g,25.02mmol)加入到80mL DMF和20mL水的混合溶剂中，N 2保护下加热至100℃反应4h。体系硅藻土过滤，滤液加水稀释，EA提取三次，合并后无水硫酸钠干燥。经柱层析(洗脱剂体系A)得到化合物93f(4.1g)。MS(ESI,m/z):428.2[M+H] +. Compound 93e (4.08 g, 8.34 mmol), 1H-pyrazole-3-boronic acid pinacol ester (4.08 g, 21.03 mmol), [1,1'-bis(diphenylphosphino)ferrocene] dichlorinated Palladium-dichloromethane complex (1.02 g, 1.2 mmol), Na 2 CO 3 (2.65 g, 25.02 mmol) was added to a mixed solvent of 80 mL of DMF and 20 mL of water, and heated to 100 ° C under N 2 for 4 h. The system was filtered through celite, and the filtrate was diluted with water and extracted three times with EA. Column chromatography (eluent system A) gave compound 93f (4.1 g). MS (ESI, m/z): 428.2 [M+H] + .
第七步：2-((乙胺基)甲基)-1-甲基-7-(1H-吡唑-3-基)-1H-咪唑[4,5-d]噻吩并[3,2-b]吡啶-4-胺盐酸盐(93g)Step 7: 2-((Ethylamino)methyl)-1-methyl-7-(1H-pyrazol-3-yl)-1H-imidazole [4,5-d]thieno[3,2 -b]pyridin-4-amine hydrochloride (93g)
将化合物93f(3.56g,8.33mmol)加入到30mL 4N盐酸二氧六环中，室温下反应16h。反应混合物浓缩得到化合物93g(3.46g)。MS(ESI,m/z):328.2[M+H] +. Compound 93f (3.56 g, 8.33 mmol) was added to 30 mL of 4N hydrochloric acid dioxane and allowed to react at room temperature for 16 h. The reaction mixture was concentrated to give the title compound (yield: 372 g). MS (ESI, m/z): 328.2 [M+H] + .
第八步：N-((4-氨基-1-甲基-7-(1H-吡唑-3-基)-1H-咪唑[4,5-d]噻吩并[3,2-b]吡啶-2-基)甲基)-N-乙基环丙烷甲酰胺(93)Step 8: N-((4-Amino-1-methyl-7-(1H-pyrazol-3-yl)-1H-imidazole[4,5-d]thieno[3,2-b]pyridine -2-yl)methyl)-N-ethylcyclopropanecarboxamide (93)
将化合物93g(70mg,0.20mmol)、环丙甲酸(18mg,0.21mmol)、HATU(109.72mg,0.29mmol)加入3mL DMF中，继续向体系中加入DIPEA(124mg,0.96mmol)，室温下反 应2h。通过Prep-HPLC分离纯化(洗脱条件4)，冻干得到化合物93(16mg)。The compound 93g (70mg, 0.20mmol), cyclopropanoic acid (18mg, 0.21mmol), HATU (109.72mg, 0.29mmol) was added to 3mL DMF, and DIPEA (124mg, 0.96mmol) was added to the system and reacted for 2h at room temperature. . Purification by Prep-HPLC (elution condition 4), lyophilized to give compound 93 (16 mg).
MS(ESI,m/z):396.2[M+H] +. MS (ESI, m/z): 396.2 [M+H] + .
1H NMR(DMSO-d 6,400MHz)δ12.98(s,1H),7.83(s,1H),7.54(s,1H),6.78(s,1H),6.35–6.13(m,2H),5.14–4.78(m,2H),4.00–3.86(m,3H),3.65–3.37(m,2H),2.10–1.92(m,1H),1.17–0.96(m,3H),0.86–0.67(m,4H). 1 H NMR (DMSO-d 6 , 400 MHz) δ 12.98 (s, 1H), 7.83 (s, 1H), 7.54 (s, 1H), 6.78 (s, 1H), 6.35 - 6.13 (m, 2H), 5.14–4.78 (m, 2H), 4.00–3.86 (m, 3H), 3.65–3.37 (m, 2H), 2.10–1.92 (m, 1H), 1.17–0.96 (m, 3H), 0.86–0.67 (m) , 4H).
实施例37：Example 37:
N-((4-氨基-1-甲基-7-(1H-吡唑-3-基)-1H-咪唑[4,5-d]噻吩并[3,2-b]吡啶-2-基)甲基)-N-乙基乙酰胺(94)N-((4-Amino-1-methyl-7-(1H-pyrazol-3-yl)-1H-imidazole[4,5-d]thieno[3,2-b]pyridin-2-yl )methyl)-N-ethylacetamide (94)
Figure PCTCN2019085535-appb-000106
Figure PCTCN2019085535-appb-000106
将化合物93g(70mg,0.20mmol)、乙酸(13mg,0.21mmol)、HATU(109.72mg,0.29mmol)加入3mL DMF中，继续向体系中加入DIPEA(124mg,0.96mmol)，室温下反应2h。通过Prep-HPLC分离纯化(洗脱条件4)，冻干得到化合物94(9mg)。Compound 93g (70mg, 0.20mmol), acetic acid (13mg, 0.21mmol), HATU (109.72mg, 0.29mmol) was added to 3mL of DMF, and DIPEA (124mg, 0.96mmol) was added to the system and reacted for 2h at room temperature. Purification by Prep-HPLC (elution condition 4), lyophilized to give compound 94 (9 mg).
MS(ESI,m/z):370.2[M+H] +. MS (ESI, m/z): 370.2 [M+H] + .
1H NMR(DMSO-d 6,400MHz)δ12.99(s,1H),7.83(s,1H),7.54(d,J＝3.5Hz,1H),6.79(t,J＝2.0Hz,1H),6.38–6.13(m,2H),4.92–4.78(m,2H),4.02–3.87(m,3H),3.42–3.35(m,2H),2.11(s,3H),1.11–0.95(m,3H). 1 H NMR (DMSO-d 6 , 400MHz) δ12.99 (s, 1H), 7.83 (s, 1H), 7.54 (d, J = 3.5Hz, 1H), 6.79 (t, J = 2.0Hz, 1H) , 6.38–6.13 (m, 2H), 4.92–4.78 (m, 2H), 4.02–3.87 (m, 3H), 3.42–3.35 (m, 2H), 2.11 (s, 3H), 1.11–0.95 (m, 3H).
实施例38：Example 38:
2-(3-(2,6-二甲基吗啉)丙基)-7-(1H-吡唑-3-基)-1H-咪唑并[4,5-d]噻吩并[3,2-b]吡啶-4-胺(95)2-(3-(2,6-dimethylmorpholine)propyl)-7-(1H-pyrazol-3-yl)-1H-imidazo[4,5-d]thieno[3,2 -b]pyridin-4-amine (95)
Figure PCTCN2019085535-appb-000107
Figure PCTCN2019085535-appb-000107
第一步：7-溴-2-(3-(2,6-二甲基吗啉)丙基)-1-(4-甲氧基苄基)-1H-咪唑[4,5-d]噻吩并[3,2-b]吡啶-4-胺(95a)First step: 7-bromo-2-(3-(2,6-dimethylmorpholine)propyl)-1-(4-methoxybenzyl)-1H-imidazole [4,5-d] Thieno[3,2-b]pyridin-4-amine (95a)
将化合物9i(80mg,0.17mmol)、2,6-二甲基吗啉(99mg,0.86mmol)、TEA(70mg,0.69mmol)、四丁基碘化铵(6mg,0.02mmol)加入8mL甲苯中，氮气置换后加热至100℃ 反应16h。反应混合物浓缩并加水稀释，EA提取三次(20mL×3)，合并后无水硫酸钠干燥，经薄层层析(洗脱剂体系A)得到化合物95a(48mg)。Compound 9i (80 mg, 0.17 mmol), 2,6-dimethylmorpholine (99 mg, 0.86 mmol), TEA (70 mg, 0.69 mmol), tetrabutylammonium iodide (6 mg, 0.02 mmol) was added to 8 mL of toluene. After nitrogen substitution, the mixture was heated to 100 ° C for 16 h. The reaction mixture was concentrated and diluted with water. EtOAc (EtOAc m.
MS(ESI,m/z):544.1[M+H] +. MS (ESI, m/z): 544.1 [M+H] + .
第二步：2-(3-(2,6-二甲基吗啉)丙基)-1-(4-甲氧基苄基)-7-(1H-吡唑-3-基)-1H-咪唑[4,5-d]噻吩并[3,2-b]吡啶-4-胺(95b)Second step: 2-(3-(2,6-dimethylmorpholine)propyl)-1-(4-methoxybenzyl)-7-(1H-pyrazol-3-yl)-1H -imidazole [4,5-d]thieno[3,2-b]pyridin-4-amine (95b)
将化合物95a(48mg,0.09mmol)、1H-吡唑-3-硼酸频哪酯(34mg,0.18mmol)、[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(7.2mg,8.82μmol)、Na 2CO 3(28mg,0.26mmol)加入到4mL DMF和1mL水的混合溶剂中，N 2保护下加热至100℃反应4h。体系直接浓缩得到化合物95b(47mg)。MS(ESI,m/z):532.2[M+H] +. Compound 95a (48 mg, 0.09 mmol), 1H-pyrazole-3-boronic acid pina ester (34 mg, 0.18 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride A methyl chloride complex (7.2 mg, 8.82 μmol) and Na 2 CO 3 (28 mg, 0.26 mmol) were added to a mixed solvent of 4 mL of DMF and 1 mL of water, and heated to 100 ° C under N 2 for 4 h. The system was directly concentrated to give compound 95b (47 mg). MS (ESI, m / z) : 532.2 [M + H] +.
第三步：2-(3-(2,6-二甲基吗啉)丙基)-7-(1H-吡唑-3-基)-1H-咪唑并[4,5-d]噻吩并[3,2-b]吡啶-4-胺(95)Step 3: 2-(3-(2,6-Dimethylmorpholine)propyl)-7-(1H-pyrazol-3-yl)-1H-imidazo[4,5-d]thiophene [3,2-b]pyridin-4-amine (95)
将化合物95b(80mg,0.09mmol)加入5mL三氟乙酸中，加热至75℃反应16h，体系浓缩并用甲醇稀释，饱和碳酸钾调节体系pH＝8，过滤后通过Prep-HPLC分离纯化(洗脱条件3)，冻干得到化合物95的甲酸盐95s(4mg)。Compound 95b (80 mg, 0.09 mmol) was added to 5 mL of trifluoroacetic acid, heated to 75 ° C for 16 h, the system was concentrated and diluted with methanol, saturated potassium carbonate was adjusted to pH=8, filtered and purified by Prep-HPLC. 3), lyophilized to give the formate 95s (4 mg) of Compound 95.
MS(ESI,m/z):412.2[M+H] +. MS (ESI, m / z) : 412.2 [M + H] +.
1H NMR(DMSO-d 6,400MHz)δ12.93(s,1H),8.21(s,2H),7.79(s,1H),7.49(s,1H),6.73(s,1H),6.09(s,2H),3.53–3.49(m,2H),2.87(t,J＝7.6Hz,2H),2.75(d,J＝10.2Hz,2H),2.35(t,J＝7.0Hz,2H),2.02–1.89(m,2H),1.57(t,J＝10.7Hz,2H),1.03(d,J＝6.3Hz,6H). 1 H NMR (DMSO-d 6 , 400 MHz) δ 12.93 (s, 1H), 8.21 (s, 2H), 7.79 (s, 1H), 7.49 (s, 1H), 6.73 (s, 1H), 6.09 ( s, 2H), 3.53–3.49 (m, 2H), 2.87 (t, J = 7.6 Hz, 2H), 2.75 (d, J = 10.2 Hz, 2H), 2.35 (t, J = 7.0 Hz, 2H), 2.02–1.89 (m, 2H), 1.57 (t, J = 10.7 Hz, 2H), 1.03 (d, J = 6.3 Hz, 6H).
实施例39：Example 39:
N-((4-氨基-7-(1H-吡唑-3-基)-1H-咪唑[4,5-d]噻吩并[3,2-b]吡啶-2-基)甲基)-N-乙基甲酰胺(96)N-((4-Amino-7-(1H-pyrazol-3-yl)-1H-imidazole[4,5-d]thieno[3,2-b]pyridin-2-yl)methyl)- N-ethylformamide (96)
Figure PCTCN2019085535-appb-000108
Figure PCTCN2019085535-appb-000108
将化合物88(80mg,0.26mmol)、甲酸乙酯(95mg,1.28mmol)、TEA(78mg,0.77mmol)加入5mL无水乙醇中，加热至52℃反应4h，继续加入甲酸乙酯(95mg,1.28mmol)，52℃反应6h，体系浓缩，通过Prep-HPLC分离纯化(洗脱条件5)，冻干得到化合物96(7mg)。Compound 88 (80 mg, 0.26 mmol), ethyl formate (95 mg, 1.28 mmol), TEA (78 mg, 0.77 mmol) was added to 5 mL of absolute ethanol and heated to 52 ° C for 4 h, then ethyl formate (95 mg, 1.28) was added. Methyl), reacted at 52 ° C for 6 h, the system was concentrated, purified by Prep-HPLC (elution condition 5), and lyophilized to give compound 96 (7 mg).
MS(ESI,m/z):342.1[M+H] +. MS (ESI, m/z): 3421. [M+H] + .
1H NMR(DMSO-d 6,400MHz)δ13.40–12.70(m,2H),8.27(d,J＝16.9Hz,1H),7.82(s,1H),7.50(s,1H),6.75(s,1H),6.35–6.05(m,2H),4.71(s,2H),3.46–3.38(m,1H),3.30–3.22(m,1H),1.17–0.92(m,3H). 1 H NMR (DMSO-d 6 , 400 MHz) δ 13.40 - 12.70 (m, 2H), 8.27 (d, J = 16.9 Hz, 1H), 7.82 (s, 1H), 7.50 (s, 1H), 6.75 ( s, 1H), 6.35–6.05 (m, 2H), 4.71 (s, 2H), 3.46–3.38 (m, 1H), 3.30–3.22 (m, 1H), 1.17–0.92 (m, 3H).
实施例40：Example 40:
N-((4-氨基-1-甲基-7-(1H-吡唑-3-基)-1H-咪唑[4,5-d]噻吩并[3,2-b]吡啶-2-基)甲基)-N-乙基丙酰胺(97)N-((4-Amino-1-methyl-7-(1H-pyrazol-3-yl)-1H-imidazole[4,5-d]thieno[3,2-b]pyridin-2-yl )methyl)-N-ethylpropionamide (97)
Figure PCTCN2019085535-appb-000109
Figure PCTCN2019085535-appb-000109
将化合物93g(70mg,0.20mmol)、丙酸(16mg,0.21mmol)、HATU(109.72mg,0.29mmol)加入3mL DMF中，继续向体系中加入DIPEA(124mg,0.96mmol)，室温下反应2h。通过Prep-HPLC分离纯化(洗脱条件3)，冻干得到化合物97的甲酸盐97s(7mg)。Compound 93g (70mg, 0.20mmol), propionic acid (16mg, 0.21mmol), HATU (109.72mg, 0.29mmol) was added to 3mL DMF, and DIPEA (124mg, 0.96mmol) was added to the system and reacted for 2h at room temperature. Purification by Prep-HPLC (elution condition 3), lyophilized to give the title compound 97s (7 mg).
MS(ESI,m/z):384.2[M+H] +. MS (ESI, m/z): 384.2 [M+H] + .
1H NMR(DMSO-d 6,400MHz)δ12.98(s,1H),8.15(s,1H),7.83(s,1H),7.54(s,1H),6.78(s,1H),6.30–6.10(m,2H),4.91–4.78(m,2H),3.99–3.87(m,3H),3.42–3.37(m,2H),2.45–2.38(m,2H),1.09–0.96(m,6H). 1 H NMR (DMSO-d 6 , 400MHz) δ12.98 (s, 1H), 8.15 (s, 1H), 7.83 (s, 1H), 7.54 (s, 1H), 6.78 (s, 1H), 6.30- 6.10 (m, 2H), 4.91 - 4.78 (m, 2H), 3.99 - 3.87 (m, 3H), 3.42 - 3.37 (m, 2H), 2.45 - 2.38 (m, 2H), 1.09 - 0.96 (m, 6H) ).
实施例41：Example 41:
N-(4-氨基-1-甲基-7-(1H-吡唑-3-基)-1H-咪唑[4,5-d]噻吩并[3,2-b]吡啶-2-基)甲基)-N-乙基-2-(3-甲基苯基)乙酰胺(98)N-(4-Amino-1-methyl-7-(1H-pyrazol-3-yl)-1H-imidazole[4,5-d]thieno[3,2-b]pyridin-2-yl) Methyl)-N-ethyl-2-(3-methylphenyl)acetamide (98)
Figure PCTCN2019085535-appb-000110
Figure PCTCN2019085535-appb-000110
将化合物93g(30mg,82.45μmol)、间甲基苯乙酸(12mg,82.45μmol)、HBTU(32mg,123.99μmol)加入2mL DMF中，继续向体系中加入DIPEA(32mg,247.34μmol)，室温下反应1h。通过Prep-HPLC分离纯化(洗脱条件4)，冻干得到化合物98(13mg)。Compound 93g (30mg, 82.45μmol), m-methylphenylacetic acid (12mg, 82.45μmol), HBTU (32mg, 123.99μmol) were added to 2mL DMF, and DIPEA (32mg, 247.34μmol) was added to the system and reacted at room temperature. 1h. Purification by Prep-HPLC (elution condition 4), lyophilized to give compound 98 (13 mg).
MS(ESI,m/z):460.2[M+H] +. MS (ESI, m/z): 460.2 [M+H] + .
1H NMR(DMSO-d 6,400MHz)δ13.00(s,1H),7.84(s,1H),7.55(d,J＝5.5Hz,1H),7.23–6.97(m,4H),6.79(s,1H),6.34–6.11(m,2H),4.98–4.78(m,2H),3.95–3.86(m,3H),3.75(s,2H),3.49–3.41(m,2H),2.30–2.20(m,3H),1.08–0.98(m,3H). 1 H NMR (DMSO-d 6 , 400 MHz) δ 13.00 (s, 1H), 7.84 (s, 1H), 7.55 (d, J = 5.5 Hz, 1H), 7.23 - 6.97 (m, 4H), 6.79 ( s, 1H), 6.34–6.11 (m, 2H), 4.98–4.78 (m, 2H), 3.95–3.86 (m, 3H), 3.75 (s, 2H), 3.49–3.41 (m, 2H), 2.30– 2.20 (m, 3H), 1.08–0.98 (m, 3H).
实施例42：Example 42
N-(4-氨基-1-甲基-7-(1H-吡唑-3-基)-1H-咪唑[4,5-d]噻吩并[3,2-b]吡啶-2-基)甲基)-N-乙基-1-甲基-1H-吡咯-2-甲酰胺(99)N-(4-Amino-1-methyl-7-(1H-pyrazol-3-yl)-1H-imidazole[4,5-d]thieno[3,2-b]pyridin-2-yl) Methyl)-N-ethyl-1-methyl-1H-pyrrole-2-carboxamide (99)
Figure PCTCN2019085535-appb-000111
Figure PCTCN2019085535-appb-000111
将化合物93g(30mg,82.45μmol)、N-甲基-2-吡咯羧酸(10mg,82.45μmol)、HBTU(32mg,123.99μmol)加入2mL DMF中，继续向体系中加入DIPEA(32mg,247.34μmol)，室温下反应4h。通过Prep-HPLC分离纯化(洗脱条件4)，冻干得到化合物99(6mg)。Compound 93g (30mg, 82.45μmol), N-methyl-2-pyrrolecarboxylic acid (10mg, 82.45μmol), HBTU (32mg, 123.99μmol) were added to 2mL DMF, and DIPEA (32mg, 247.34μmol) was added to the system. ), react at room temperature for 4 h. Purification by Prep-HPLC (elution condition 4), lyophilized to give compound 99 (6 mg).
MS(ESI,m/z):435.2[M+H] +. MS (ESI, m/z): 435.2 [M+H] +
1H NMR(DMSO-d 6,400MHz)δ12.99(s,1H),7.83(s,1H),7.55(s,1H),6.92(t,J＝2.0Hz,1H),6.79(s,1H),6.44(dd,J＝3.8,1.6Hz,1H),6.20(s,2H),6.02(dd,J＝3.7,2.6Hz,1H),5.01(s,2H),3.92(s,3H),3.70(s,3H),3.60–3.50(m,2H),1.13(t,J＝7.1Hz,3H). 1 H NMR (DMSO-d 6 , 400MHz) δ12.99 (s, 1H), 7.83 (s, 1H), 7.55 (s, 1H), 6.92 (t, J = 2.0Hz, 1H), 6.79 (s, 1H), 6.44 (dd, J = 3.8, 1.6 Hz, 1H), 6.20 (s, 2H), 6.02 (dd, J = 3.7, 2.6 Hz, 1H), 5.01 (s, 2H), 3.92 (s, 3H) ), 3.70 (s, 3H), 3.60–3.50 (m, 2H), 1.13 (t, J = 7.1 Hz, 3H).
实施例43：Example 43
N-((4-氨基-7-(1H-吡唑-3-基)-1H-咪唑[4,5-d]噻吩并[3,2-b]吡啶-2-基)甲基)-N-乙基丙酰胺(100)N-((4-Amino-7-(1H-pyrazol-3-yl)-1H-imidazole[4,5-d]thieno[3,2-b]pyridin-2-yl)methyl)- N-ethylpropionamide (100)
Figure PCTCN2019085535-appb-000112
Figure PCTCN2019085535-appb-000112
将化合物88(100mg,0.32mmol)、丙酸酐(83.20mg,0.64mmol)、三乙胺(161.15mg,1.6mmol)加入3mL DCM中，室温下反应2h。直接将体系浓缩干，通过Prep-HPLC分离纯化(洗脱条件4)，冻干得到化合物100(7mg)。Compound 88 (100 mg, 0.32 mmol), propionic anhydride (83.20 mg, 0.64 mmol), triethylamine (161.15 mg, 1.6 mmol) was added to 3 mL DCM and allowed to react at room temperature for 2 h. The system was directly concentrated to dryness, purified by Prep-HPLC (elution condition 4), and lyophilized to give compound 100 (7 mg).
MS(ESI,m/z):370.1[M+H] +. MS (ESI, m/z): 370.1 [M+H] + .
1H NMR(DMSO-d 6,400MHz)δ12.94(s,2H),7.81(s,1H),7.51(s,1H),6.74(s,1H),6.23(s,2H),4.80–4.73(m,2H),3.50–3.38(m,2H),2.53–2.42(m,2H),1.15–0.97(m,6H). 1 H NMR (DMSO-d 6 , 400MHz) δ12.94 (s, 2H), 7.81 (s, 1H), 7.51 (s, 1H), 6.74 (s, 1H), 6.23 (s, 2H), 4.80- 4.73 (m, 2H), 3.50–3.38 (m, 2H), 2.53–2.42 (m, 2H), 1.15–0.97 (m, 6H).
实施例44：Example 44:
N-((4-氨基-1-甲基-7-(1H-吡唑-3-基)-1H-咪唑[4,5-d]噻吩并[3,2-b]吡啶-2-基)甲基)-N-乙基甲酰胺(101)N-((4-Amino-1-methyl-7-(1H-pyrazol-3-yl)-1H-imidazole[4,5-d]thieno[3,2-b]pyridin-2-yl )methyl)-N-ethylformamide (101)
Figure PCTCN2019085535-appb-000113
Figure PCTCN2019085535-appb-000113
将化合物93g(70mg,0.19mmol)、甲酸(18mg,0.38mmol)、HATU(109.72mg,0.29mmol)加入3mL DMF中，继续向体系中加入DIPEA(124mg,0.96mmol)，室温下反应2h。通过Prep-HPLC分离纯化(洗脱条件4)，冻干得到化合物101(20mg)。Compound 93g (70mg, 0.19mmol), formic acid (18mg, 0.38mmol), HATU (109.72mg, 0.29mmol) was added to 3mL DMF, and DIPEA (124mg, 0.96mmol) was added to the system and reacted for 2h at room temperature. Purification by Prep-HPLC (elution condition 4), lyophilized to give compound 101 (20 mg).
MS(ESI,m/z):356.2[M+H] +. MS (ESI, m/z): 356.2 [M+H] + .
1H NMR(DMSO-d 6,400MHz)δ12.94(s,1H),8.27-8.14(m,1H),7.77(s,1H),7.49(s,1H),6.72(s,1H),6.24(s,2H),4.81–4.70(m,2H),3.90–3.83(m,3H),3.27–3.19(m,2H),1.02(t,J＝7.1Hz,2H),0.88(t,J＝7.1Hz,1H). 1 H NMR (DMSO-d 6 , 400MHz) δ12.94 (s, 1H), 8.27-8.14 (m, 1H), 7.77 (s, 1H), 7.49 (s, 1H), 6.72 (s, 1H), 6.24 (s, 2H), 4.81 - 4.70 (m, 2H), 3.90 - 3.83 (m, 3H), 3.27 - 3.19 (m, 2H), 1.02 (t, J = 7.1 Hz, 2H), 0.88 (t, J=7.1Hz, 1H).
实施例45：Example 45:
2-((4-氨基-1-甲基-7-(1H-吡唑-3-基)-1H咪唑[4,5-d]噻吩并[3,2-b]吡啶-2-))甲基)(乙基)氨基)乙酸叔丁酯(102)2-((4-Amino-1-methyl-7-(1H-pyrazol-3-yl)-1H imidazo[4,5-d]thieno[3,2-b]pyridine-2-)) Methyl)(ethyl)amino)acetic acid tert-butyl ester (102)
Figure PCTCN2019085535-appb-000114
Figure PCTCN2019085535-appb-000114
将化合物93g(100mg,0.27mmol)、溴乙酸叔丁酯(80mg,0.42mmol)、碳酸钾(114mg,0.83mmol)加入5mL DMF中，25℃反应4h，加入水，用EA萃取三次，饱和氯化钠溶液洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩。通过Prep-HPLC分离纯化(洗脱条件5)，冻干得到化合物102(70mg)。Compound 93g (100mg, 0.27mmol), tert-butyl bromoacetate (80mg, 0.42mmol), potassium carbonate (114mg, 0.83mmol) was added to 5mL DMF, reacted at 25 ° C for 4h, added water, extracted with EA three times, saturated chlorine The solution was washed with sodium chloride, dried over anhydrous sodium sulfate and filtered and evaporated. Purification by Prep-HPLC (elution condition 5) and lyophilization afforded Compound 102 (70 mg).
MS(ESI,m/z):442.2[M+H] +. MS (ESI, m/z): 442.2 [M+H] +
1H NMR(DMSO-d 6,400MHz)δ13.01(s,1H),7.84(s,1H),7.54(s,1H),6.79(s,1H),6.38(s,2H),4.05(s,3H),4.02(s,2H),3.30(s,2H),2.65(d,J＝7.2Hz,2H),1.36(s,9H),0.99(t,J＝7.1Hz,3H). 1 H NMR (DMSO-d 6 , 400 MHz) δ 13.01 (s, 1H), 7.84 (s, 1H), 7.54 (s, 1H), 6.79 (s, 1H), 6.38 (s, 2H), 4.05 ( s, 3H), 4.02 (s, 2H), 3.30 (s, 2H), 2.65 (d, J = 7.2 Hz, 2H), 1.36 (s, 9H), 0.99 (t, J = 7.1 Hz, 3H).
实施例46：Example 46:
N-((4-氨基-1-甲基-7-(1H-吡唑-3-基)-1H-咪唑[4,5-d]噻吩并[3,2-b]吡啶-2-基)甲基)-N-乙基-1-甲基哌啶-4-甲酰胺(103)N-((4-Amino-1-methyl-7-(1H-pyrazol-3-yl)-1H-imidazole[4,5-d]thieno[3,2-b]pyridin-2-yl )methyl)-N-ethyl-1-methylpiperidine-4-carboxamide (103)
Figure PCTCN2019085535-appb-000115
Figure PCTCN2019085535-appb-000115
将化合物93g(70mg,0.19mmol)、1-甲基哌啶-4-甲酸(55mg,0.38mmol)、HATU(109.72mg,0.29mmol)加入3mL DMF中，继续向体系中加入DIPEA(124mg,0.96mmol)，室温下反应2h。通过Prep-HPLC分离纯化(洗脱条件3)，冻干得到化合物103的甲酸盐103s(7mg)。Compound 93g (70mg, 0.19mmol), 1-methylpiperidine-4-carboxylic acid (55mg, 0.38mmol), HATU (109.72mg, 0.29mmol) was added to 3mL DMF and DIPEA (124mg, 0.96) was added to the system. Methyl), reacted for 2 h at room temperature. Purification by Prep-HPLC (elution condition 3), lyophilized to give the title compound 103s (7 mg).
MS(ESI,m/z):453.2[M+H] +. MS (ESI, m/z): 453.2 [M+H] + .
1H NMR(DMSO-d 6,400MHz)δ13.01(s,1H),8.21(s,1H),7.82(s,1H),7.55(m,1H),6.79-6.72(m,1H),6.26-6.14(m,2H),4.93-4.85(m,2H),3.97–3.85(m,3H),3.44–3.35(m,2H),3.0-2.97(m,2H),2.77–2.58(m,1H),2.33(s,3H),2.31-2.25(m,2H),1.77–1.67(m,4H),1.10-0.98(m,3H) 1 H NMR (DMSO-d 6 , 400 MHz) δ 13.01 (s, 1H), 8.21 (s, 1H), 7.82 (s, 1H), 7.55 (m, 1H), 6.79-6.72 (m, 1H), 6.26-6.14 (m, 2H), 4.93-4.85 (m, 2H), 3.97–3.85 (m, 3H), 3.44–3.35 (m, 2H), 3.0-2.97 (m, 2H), 2.77–2.58 (m) , 1H), 2.33 (s, 3H), 2.31-2.25 (m, 2H), 1.77–1.67 (m, 4H), 1.10-0.98 (m, 3H)
实施例47：Example 47:
N-(4-氨基-1-甲基-7-(1H-吡唑-3-基)-1H-咪唑[4,5-d]噻吩并[3,2-b]吡啶-2-基)甲基)-N-乙基吗啉-4-甲酰胺(104)N-(4-Amino-1-methyl-7-(1H-pyrazol-3-yl)-1H-imidazole[4,5-d]thieno[3,2-b]pyridin-2-yl) Methyl)-N-ethylmorpholine-4-carboxamide (104)
Figure PCTCN2019085535-appb-000116
Figure PCTCN2019085535-appb-000116
将化合物93g(50mg,0.14mmol)、DIPEA(53mg,0.41mmol)加入3mL DMF中，将体系温度降至0℃，继续向体系中加入4-吗啉碳酰氯(21mg,0.14mmol)，0℃下反应7h。通过Prep-HPLC分离纯化(洗脱条件4)，冻干得到化合物104(37mg)。The compound 93g (50mg, 0.14mmol), DIPEA (53mg, 0.41mmol) was added to 3mL DMF, the temperature of the system was reduced to 0 ° C, and 4-morpholinecarbonyl chloride (21mg, 0.14mmol) was added to the system, 0°C The reaction was carried out for 7 h. Purification by Prep-HPLC (elution condition 4) and lyophilization gave Compound 104 (37 mg).
MS(ESI,m/z):441.2[M+H] +. MS (ESI, m/z): 441.2 [M+H] + .
1H NMR(DMSO-d 6,400MHz)δ12.98(s,1H),7.88–7.78(m,1H),7.54(s,1H),6.78(t,J＝2.0Hz,1H),6.20(s,2H),4.63(s,2H),3.90(s,3H),3.63–3.55(m,4H),3.23–3.16(m,6H),1.06(t,J＝7.0Hz,3H). 1 H NMR (DMSO-d 6 , 400 MHz) δ 12.98 (s, 1H), 7.88 - 7.78 (m, 1H), 7.54 (s, 1H), 6.78 (t, J = 2.0 Hz, 1H), 6.20 ( s, 2H), 4.63 (s, 2H), 3.90 (s, 3H), 3.63 - 3.55 (m, 4H), 3.23 - 3.16 (m, 6H), 1.06 (t, J = 7.0 Hz, 3H).
实施例48：Example 48:
2-(3-(4-(甲基磺酰)哌嗪-1-基)丙基)-7-(1H-吡唑-3-基)-1H咪唑[4,5-d]噻吩并[3,2-b]吡啶-4-胺(105)2-(3-(4-(methylsulfonyl)piperazin-1-yl)propyl)-7-(1H-pyrazol-3-yl)-1H imidazo[4,5-d]thieno[ 3,2-b]pyridin-4-amine (105)
Figure PCTCN2019085535-appb-000117
Figure PCTCN2019085535-appb-000117
第一步：7-溴-1-(4-甲氧基苄基)-2-(3-(4-(甲基磺酰)哌嗪-1-基)丙基)-1H咪唑[4,5-d]噻吩并[3,2-b]吡啶-4-胺(105a)First step: 7-bromo-1-(4-methoxybenzyl)-2-(3-(4-(methylsulfonyl)piperazin-1-yl)propyl)-1H imidazole [4, 5-d]thieno[3,2-b]pyridin-4-amine (105a)
将化合物9i(100mg,0.21mmol)、1-甲基磺酰哌嗪(51.66mg,0.32mmol)、四丁基碘化铵(14.76mg,0.04mmol)、TEA(42.42mg,0.42mmol)加入5mL甲苯中，N 2保护下加热至100℃反应12h。旋干反应溶剂再经快速柱层析(洗脱剂体系A)得到化合物105a(80mg)。 Compound 9i (100 mg, 0.21 mmol), 1-methylsulfonylpiperazine (51.66 mg, 0.32 mmol), tetrabutylammonium iodide (14.76 mg, 0.04 mmol), TEA (42.42 mg, 0.42 mmol) was added to 5 mL In toluene, the mixture was heated to 100 ° C under N 2 for 12 h. The reaction solvent was dried to dryness and then purified by flash column chromatography (eluent system A) to afford compound 105a (80 mg).
MS(ESI,m/z):594.1[M+H] +. MS (ESI, m/z): 594.1 [M+H] + .
第二步：1-(4-甲氧基苄基)-2-(3-(4-(甲基磺酰)哌嗪-1-基)丙基)-7-(1H-吡唑-3-基)-1H-咪唑并[4,5-d]噻吩并[3,2-b]吡啶-4-胺(105b)Second step: 1-(4-methoxybenzyl)-2-(3-(4-(methylsulfonyl)piperazin-1-yl)propyl)-7-(1H-pyrazole-3 -yl)-1H-imidazo[4,5-d]thieno[3,2-b]pyridin-4-amine (105b)
将化合物105a(80mg,0.13mmol)、3-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-1H-吡唑(50.7mg,0.26mmol)、Pd(dppf)Cl 2(9mg,0.01mmol)、碳酸钠(31.30mg,0.29mmol)加入5mL DMF和1mL水的混合溶剂中，N 2保护下加热至110℃搅拌反应3h。减压浓缩反应溶剂至干再经快速柱层析(洗脱剂体系A)得到化合物105b(70mg)。 Compound 105a (80 mg, 0.13 mmol), 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (50.7 Mg, 0.26 mmol), Pd(dppf)Cl 2 (9 mg, 0.01 mmol), sodium carbonate (31.30 mg, 0.29 mmol), added to a mixed solvent of 5 mL of DMF and 1 mL of water, heated to 110 ° C under N 2 and stirred for 3 h. . The reaction solvent was concentrated to dryness <RTI ID=0.0></RTI> to EtOAc (EtOAc)
第三步：2-(3-(4-(甲基磺酰)哌嗪-1-基)丙基)-7-(1H-吡唑-3-基)-1H咪唑[4,5-d]噻吩并[3,2-b]吡啶-4-胺(105)Step 3: 2-(3-(4-(methylsulfonyl)piperazin-1-yl)propyl)-7-(1H-pyrazol-3-yl)-1H imidazole [4,5-d Thio[3,2-b]pyridin-4-amine (105)
将化合物105b(70mg,0.12mmol)、TFA加到单口瓶中，加热至75℃反应12h。旋干反应溶剂，通过Prep-HPLC分离纯化(洗脱条件3)，冻干得到化合物105的甲酸盐105s(7mg)。Compound 105b (70 mg, 0.12 mmol) and TFA were added to a vial and heated to 75 ° C for 12 h. The reaction solvent was dried, purified by Prep-HPLC (eluting condition 3), and lyophilized to give the title compound 105s (7 mg).
MS(ESI,m/z):461.2[M+H] +. MS (ESI, m/z): 4621. [M+H] + .
1H NMR(DMSO-d 6,400MHz)δ12.94(s,2H),8.19(s,1H),7.80(d,J＝2.4Hz,1H),7.49(s,1H),6.73(d,J＝2.0Hz,1H),6.16(s,2H),3.04–3.03(m,4H),2.90–2.86(t,J＝7.6Hz,9.2Hz,2H),2.79(s,3H),2.47–2.41(m,6H),1.99–1.92(m,2H). 1 H NMR (DMSO-d 6 , 400MHz) δ12.94 (s, 2H), 8.19 (s, 1H), 7.80 (d, J = 2.4Hz, 1H), 7.49 (s, 1H), 6.73 (d, J=2.0 Hz, 1H), 6.16 (s, 2H), 3.04–3.03 (m, 4H), 2.90–2.86 (t, J=7.6 Hz, 9.2 Hz, 2H), 2.79 (s, 3H), 2.47– 2.41 (m, 6H), 1.99–1.92 (m, 2H).
实施例49：Example 49
2-((2,6-二甲基吗啉)甲基)-1-甲基-7-(1H-吡唑-3-基)-1H-咪唑并[4,5-d]噻吩并[3,2-b]吡啶-4-胺(106)2-((2,6-Dimethylmorpholine)methyl)-1-methyl-7-(1H-pyrazol-3-yl)-1H-imidazo[4,5-d]thieno[ 3,2-b]pyridin-4-amine (106)
Figure PCTCN2019085535-appb-000118
Figure PCTCN2019085535-appb-000118
第一步：7-溴-2-((2,6-二甲基吗啉)甲基)-1-甲基-1H-咪唑并[4,5-d]噻吩并[3,2-b]吡啶-4-胺(106a)First step: 7-bromo-2-((2,6-dimethylmorpholine)methyl)-1-methyl-1H-imidazo[4,5-d]thieno[3,2-b Pyridine-4-amine (106a)
将化合物11g(80mg,0.24mmol)、2,-6二甲基吗啉(167mg,1.45mmol)、18-冠-6(13mg,0.048mmol)、TEA(146mg,1.45mmol)加入5mL甲苯中，N 2保护下加热至100℃反应16h。旋干反应溶剂再经快速柱层析(洗脱剂体系A)得到化合物106a(75mg)。MS(ESI,m/z):410.1[M+H] +. Compound 11g (80mg, 0.24mmol), 2,-6-dimethylmorpholine (167mg, 1.45mmol), 18-crown-6 (13mg, 0.048mmol), TEA (146mg, 1.45mmol) were added to 5mL of toluene. The reaction was heated to 100 ° C under N 2 protection for 16 h. The reaction solvent was added to dryness and then purified by flash column chromatography (eluent system A) to give compound 106a (75 mg). MS (ESI, m/z): 410.1 [M+H] +
第二步：2-((2,6-二甲基吗啉)甲基)-1-甲基-7-(1H-吡唑-3-基)-1H-咪唑并[4,5-d]噻吩并[3,2-b]吡啶-4-胺(106)Second step: 2-((2,6-dimethylmorpholine)methyl)-1-methyl-7-(1H-pyrazol-3-yl)-1H-imidazo[4,5-d Thio[3,2-b]pyridin-4-amine (106)
将化合物106a(75mg,0.18mmol)、3-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-1H-吡唑(70mg,0.36mmol)、Pd(dppf)Cl 2(45mg,0.054mmol)、碳酸钠(58mg,0.54mmol)加入2.0mL DMF和0.5mL水的混合溶剂中，N 2保护下加热至110℃搅拌反应反应16h。减压浓缩反应溶剂至干，通过Prep-HPLC分离纯化(洗脱条件5)分离得到化合物106(15mg)。 Compound 106a (75 mg, 0.18 mmol), 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (70 mg , 0.36 mmol), Pd(dppf)Cl 2 (45 mg, 0.054 mmol), sodium carbonate (58 mg, 0.54 mmol), added to a mixed solvent of 2.0 mL of DMF and 0.5 mL of water, heated to 110 ° C under N 2 and stirred to react. 16h. The reaction solvent was concentrated to dryness under reduced vacuo.
MS(ESI,m/z):398.1[M+H] +. MS (ESI, m/z): 398.1 [M+H] + .
1H NMR(DMSO-d 6,400MHz)δ12.99(s,1H),7.83(s,1H),7.54(s,1H),6.78(s,1H),6.26(s,2H),4.09–3.97(m,3H),3.95–3.89(m,0.5H),3.80–3.72(m,1.5H),3.70–3.65(m,0.5H),3.61–3.52(m,1.5H),2.75–2.70(m,1.5H),2.49–2.44(m,0.5H),2.16–2.10(m,0.5H),1.77(t,J＝10.7Hz,1.5H),1.12(d,J＝6.4Hz,1.5H),1.03(d,J＝6.4Hz,4.5H). 1 H NMR (DMSO-d 6 , 400 MHz) δ 12.99 (s, 1H), 7.83 (s, 1H), 7.54 (s, 1H), 6.78 (s, 1H), 6.26 (s, 2H), 4.09– 3.97 (m, 3H), 3.95–3.89 (m, 0.5H), 3.80–3.72 (m, 1.5H), 3.70–3.65 (m, 0.5H), 3.61–3.52 (m, 1.5H), 2.75–2.70 (m, 1.5H), 2.49–2.44 (m, 0.5H), 2.16–2.10 (m, 0.5H), 1.77 (t, J = 10.7 Hz, 1.5H), 1.12 (d, J = 6.4 Hz, 1.5 H), 1.03 (d, J = 6.4 Hz, 4.5H).
实施例50：Example 50
1-(4-(3-(4-氨基-7-(1H-吡唑-3-基)-1H-咪唑并[4,5-d]噻吩并[3,2-b]吡啶-2-基)丙基)哌嗪-1-基)乙酮(107)1-(4-(3-(4-Amino-7-(1H-pyrazol-3-yl)-1H-imidazo[4,5-d]thieno[3,2-b]pyridine-2- Propyl)piperazin-1-yl)ethanone (107)
Figure PCTCN2019085535-appb-000119
Figure PCTCN2019085535-appb-000119
第一步：1-(4-(3-(4-氨基-7-溴-1-(4-甲氧基苄基)-1H咪唑[4,5-d]噻吩并[3,2-b]吡啶-2-基)丙基)哌嗪-1-基)乙酮(107a)First step: 1-(4-(3-(4-amino-7-bromo-1-(4-methoxybenzyl)-1H imidazole [4,5-d]thieno[3,2-b Pyridin-2-yl)propyl)piperazin-1-yl)ethanone (107a)
将化合物9i(100mg,0.21mmol)、1-乙酰哌嗪(40.96mg,0.32mmol)、四丁基碘化铵(14.76mg,0.04mmol)、TEA(42.42mg,0.42mmol)加入5mL甲苯中，N 2保护下加热至100℃反应12h。旋干反应溶剂再经快速柱层析(洗脱剂体系A)得到化合物107a(75mg)。 Compound 9i (100 mg, 0.21 mmol), 1-acetylpiperazine (40.96 mg, 0.32 mmol), tetrabutylammonium iodide (14.76 mg, 0.04 mmol), TEA (42.42 mg, 0.42 mmol) were added to 5 mL of toluene. The reaction was heated to 100 ° C under N 2 protection for 12 h. The reaction solvent was dried to dryness and then purified by flash column chromatography (eluent system A) to afford compound 107a (75 mg).
MS(ESI,m/z):558.1[M+H] +. MS (ESI, m/z): 558.1 [M+H] + .
第二步：1-(4-(3-(4-氨基-1-(4-甲氧基苄基)-7-(1H-吡唑-3-基)-1H咪唑[4,5-d]噻吩并[3,2-b]吡啶-2-基)丙基)哌嗪-1-基)乙酮(107b)Step 2: 1-(4-(3-(4-Amino-1-(4-methoxybenzyl)-7-(1H-pyrazol-3-yl)-1H imidazole [4,5-d Thieno[3,2-b]pyridin-2-yl)propyl)piperazin-1-yl)ethanone (107b)
将化合物107a(75mg,0.13mmol)、3-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-1H-吡唑(50.7mg,0.26mmol)、Pd(dppf)Cl 2(9mg,0.01mmol)、碳酸钠(31.30mg,0.29mmol)加入5mL DMF和1mL水的混合溶剂中，N 2保护下加热至110℃搅拌反应3h。减压浓缩反应溶剂至干再经快速柱层析(洗脱剂体系A)得到化合物107b(60mg)。 Compound 107a (75 mg, 0.13 mmol), 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (50.7 Mg, 0.26 mmol), Pd(dppf)Cl 2 (9 mg, 0.01 mmol), sodium carbonate (31.30 mg, 0.29 mmol), added to a mixed solvent of 5 mL of DMF and 1 mL of water, heated to 110 ° C under N 2 and stirred for 3 h. . The reaction solvent was concentrated to dryness <RTI ID=0.0></RTI> to EtOAc.
第三步：2-(3-(4-(甲基磺酰)哌嗪-1-基)丙基)-7-(1H-吡唑-3-基)-1H咪唑[4,5-d]噻吩并[3,2-b]吡啶-4-胺(107)Step 3: 2-(3-(4-(methylsulfonyl)piperazin-1-yl)propyl)-7-(1H-pyrazol-3-yl)-1H imidazole [4,5-d Thio[3,2-b]pyridin-4-amine (107)
将化合物107b(60mg,0.11mmol)、TFA加到单口瓶中，加热至75℃反应12h。旋干反应溶剂，通过Prep-HPLC分离纯化(洗脱条件3)，冻干得到化合物107的甲酸盐107s(5mg)。Compound 107b (60 mg, 0.11 mmol) and TFA were added to a vial and heated to 75 ° C for 12 h. The reaction solvent was evaporated to dryness, purified by purified-----------
MS(ESI,m/z):425.2[M+H] +. MS (ESI, m/z): 425.2 [M+H] + .
1H NMR(DMSO-d 6,400MHz)δ8.28(s,2H),7.80(d,J＝2.0Hz,1H),7.49(s,1H),6.73(d,J＝2.4Hz,1H),6.20(s,2H),3.43–3.38(m,4H),2.88(t,J＝7.6Hz,7.6Hz,2H),2.41–2.31(m,6H),2.00–1.93(m,5H). 1 H NMR (DMSO-d 6 , 400MHz) δ8.28 (s, 2H), 7.80 (d, J = 2.0Hz, 1H), 7.49 (s, 1H), 6.73 (d, J = 2.4Hz, 1H) , 6.20 (s, 2H), 3.43 - 3.38 (m, 4H), 2.88 (t, J = 7.6 Hz, 7.6 Hz, 2H), 2.41 - 2.31 (m, 6H), 2.00 - 1.93 (m, 5H).
实施例51：Example 51:
1-(4-(3-(4-氨基-1-甲基-7-(1H-吡唑-3-基)-1H咪唑[4,5-d]噻吩并[3,2-b]吡啶-2-基)丙基)哌嗪-1-基)乙酮(108)1-(4-(3-(4-Amino-1-methyl-7-(1H-pyrazol-3-yl)-1H imidazo[4,5-d]thieno[3,2-b]pyridine -2-yl)propyl)piperazin-1-yl)ethanone (108)
Figure PCTCN2019085535-appb-000120
Figure PCTCN2019085535-appb-000120
第一步：1-(4-(3-(4-氨基-7-溴-1-甲基-1H-咪唑[4,5-d]噻吩并[3,2-b]吡啶-2-基)丙基)哌嗪-1-基)乙酮(108b)First step: 1-(4-(3-(4-amino-7-bromo-1-methyl-1H-imidazole[4,5-d]thieno[3,2-b]pyridin-2-yl) )propyl)piperazin-1-yl)ethanone (108b)
室温下，将化合物1k(50mg,139.02μmol)、化合物108a(26.73mg,208.52μmol)、 TEA(56.27mg,556.06μmol)、四丁基碘化铵(51.35mg,139.02μmol)的甲苯(4mL)溶液升温到99℃反应16h。将反应混合物浓缩干，通过制备板分离纯化(洗脱体系A)得到化合物108b(50mg)。MS(ESI,m/z):439.1[M+H] +。 Compound 1k (50 mg, 139.02 μmol), Compound 108a (26.73 mg, 208.52 μmol), TEA (56.27 mg, 556.06 μmol), tetrabutylammonium iodide (51.35 mg, 139.02 μmol) in toluene (4 mL) at room temperature The solution was warmed to 99 ° C for 16 h. The reaction mixture was concentrated to dryness and purified (yield from EtOAc) to afford Compound 108b (50mg). MS (ESI, m / z) : 439.1 [M + H] +.
第二步：1-(4-(3-(4-氨基-1-甲基-7-(1H-吡唑-3-基)-1H咪唑[4,5-d]噻吩并[3,2-b]吡啶-2-基)丙基)哌嗪-1-基)乙酮(108)Second step: 1-(4-(3-(4-amino-1-methyl-7-(1H-pyrazol-3-yl)-1H imidazole [4,5-d] thieno[3,2 -b]pyridin-2-yl)propyl)piperazin-1-yl)ethanone (108)
室温下，将Pd(dppf)Cl 2(4.86mg,6.65μmol)、磷酸钾(112.72mg,531.70μmol)加入到化合物108c(33.53mg,172.80μmol)、108b(60mg,132.92μmol)的二氧六环(2mL)/水(0.5mL)混合溶剂中。吹氮气2分钟后，将体系置于微波中，升温到90℃反应5h。加乙酸乙酯稀释，过滤，浓缩后得到粗品。最后通过Prep-HPLC分离纯化(洗脱条件4)得到化合物108(5mg)。 Pd(dppf)Cl 2 (4.86 mg, 6.65 μmol), potassium phosphate (112.72 mg, 531.70 μmol) was added to compound 108c (33.53 mg, 172.80 μmol), 108b (60 mg, 132.92 μmol) of dioxane at room temperature. Ring (2 mL) / water (0.5 mL) was mixed. After blowing nitrogen for 2 minutes, the system was placed in a microwave and heated to 90 ° C for 5 h. Diluted with ethyl acetate, filtered and concentrated to give a crude material. Finally, it was purified by Prep-HPLC (elution condition 4) to give Compound 108 (5 mg).
MS(ESI,m/z):439.1[M+H] + MS (ESI, m/z): 439.1 [M+H] +
1H NMR(400MHz,MeOD)δ7.73(d,J＝2.3Hz,1H),7.52(s,1H),6.72(d,J＝2.4Hz,1H),3.98(s,3H),3.56-3.51(m,2H),3.51-3.46(m,2H),2.97(t,J＝7.5Hz,2H),2.57-2.43(m,6H),2.07(s,3H),1.98(s,2H). 1 H NMR (400MHz, MeOD) δ7.73 (d, J = 2.3Hz, 1H), 7.52 (s, 1H), 6.72 (d, J = 2.4Hz, 1H), 3.98 (s, 3H), 3.56- 3.51 (m, 2H), 3.51-3.46 (m, 2H), 2.97 (t, J = 7.5 Hz, 2H), 2.57-2.43 (m, 6H), 2.07 (s, 3H), 1.98 (s, 2H) .
生物学评价Biological evaluation
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Experimental Example 1. The agonistic effect of the compound of the present invention on IL-1β expression in THP-1 cells induced by PMA differentiation
本实验采用HTRF(均相时间分辨荧光)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hNLRP3炎症小体通路的激动作用。This experiment used HTRF (Homogeneous Time-Resolved Fluorescence) assay to test the effect of the compounds of the present invention on the level of IL-1β downstream of NLRP3 to assess the potency of compounds at the cellular level for hNLRP3 inflammatory bodies or hNLRP3 inflammatory bodies. effect.
所用试剂：RPMI 1640(Hyclone)；热灭活的FBS(胎牛血清)(Gibco)；PMA(十四烷酰佛波醇乙酸酯)(碧云天)Reagents used: RPMI 1640 (Hyclone); heat-inactivated FBS (fetal calf serum) (Gibco); PMA (tetradecanoyl phorbol acetate) (Biyuntian)
细胞：THP-1(南京科佰)Cell: THP-1 (Nanjing Branch)
试剂盒：IL-1βassay kit(CISBIO)Kit: IL-1βassay kit (CISBIO)
实验步骤：Experimental steps:
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培养箱中培养24h后，用1μM PMA诱导THP-1悬浮细胞成为贴壁状态的巨噬细胞。培养基为包含10％热灭活FBS和0.05mMβ-巯基乙醇的RPMI 1640。 1) THP-1 cells in logarithmic growth phase were inoculated into T75 flasks at a density of 5 × 10 5 /well, and cultured in a 37 ° C, 5% CO 2 incubator for 24 h, induced with 1 μM PMA. The THP-1 suspension cells become adherent macrophages. The medium was RPMI 1640 containing 10% heat inactivated FBS and 0.05 mM β-mercaptoethanol.
2)细胞诱导培养24小时后，胰酶消化贴壁细胞，1000rpm离心5min，去上清液，使用包含2％热灭活FBS的RPMI 1640培养基重悬细胞密度至2×10 6个/mL，取50μL/孔的细胞铺至96孔板，每孔细胞数目为1×10 5个。 2) After induction of cell culture for 24 hours, the adherent cells were trypsinized, centrifuged at 1000 rpm for 5 min, the supernatant was removed, and the cell density was resuspended to 2 × 10 6 /mL using RPMI 1640 medium containing 2% heat-inactivated FBS. 50 μL/well of cells were plated into 96-well plates, and the number of cells per well was 1 × 10 5 .
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，将板 放置于37℃、5％CO 2培养箱中培养6h，收集上清，按照IL-1β检测试剂盒说明书测量IL-1β的水平。 3) Take an appropriate amount of 10 mM test compound in DMSO solution, prepare 2× test concentration with RPMI 1640 medium containing 2% heat-inactivated FBS, add 50 μL/well dilution to cells of 96-well plate, and mix thoroughly. After homogenization, the plate was placed in a 37 ° C, 5% CO 2 incubator for 6 h, and the supernatant was collected, and the IL-1β level was measured according to the IL-1β test kit instructions.
4)EC 50通过GraphPad软件log(agonist)vs.response-Variable slope四参数法拟合，结果见表1。 4) The EC 50 was fitted by the GraphPad software log (agonist) vs. response-Variable slope four-parameter method, and the results are shown in Table 1.
实验例2.本发明化合物对PMA诱导分化后的NLRP3缺失的THP-1细胞(THP-1 defNLRP3细胞)中的IL-1β表达的激动作用 Experimental Example 2. The agonistic effect of the compounds of the present invention on IL-1β expression in NLRP3-deficient THP-1 cells (THP-1 def NLRP3 cells) induced by PMA differentiation
本实验采用HTRF检测方法测试本发明化合物对THP-1 defNLRP3细胞中IL-1β水平的影响，以评估化合物在对NLRP3炎症小体或hNLRP3炎症小体通路激动作用的特异性。 This experiment used the HTRF assay to test the effect of the compounds of the invention on IL-1β levels in THP-1 def NLRP3 cells to assess the specificity of compounds in agonizing effects on NLRP3 inflammatory bodies or hNLRP3 inflammatory body pathways.
所用试剂：如实验例1所述Reagent used: as described in Experimental Example 1
细胞：THP-1 defNLRP3(InvivoGen) Cells: THP-1 def NLRP3 (InvivoGen)
试剂盒：IL-1βassay kit(CISBIO)Kit: IL-1βassay kit (CISBIO)
实验步骤：Experimental steps:
1)将处于对数生长期的THP-1 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培养箱中培养24h，用1μM PMA诱导THP-1 defNLRP3悬浮细胞成为贴壁状态的巨噬细胞。培养基为包含10％热灭活FBS和0.05mMβ-巯基乙醇的RPMI 1640。 1) THP-1 def NLRP3 cells in logarithmic growth phase were seeded in T75 flasks at a density of 5 × 10 5 /well, and cultured in a 37 ° C, 5% CO 2 incubator for 24 h with 1 μM PMA. The THP-1 def NLRP3 suspension cells were induced to become adherent macrophages. The medium was RPMI 1640 containing 10% heat inactivated FBS and 0.05 mM β-mercaptoethanol.
2)细胞诱导培养24小时后，胰酶消化贴壁细胞，1000rpm离心5min，然后去上清，使用包含2％热灭活FBS的RPMI 1640培养基重悬细胞密度至2×10 6个/mL，取50μL/孔的细胞重悬液铺至96孔板，每孔细胞数目为1×10 5个。 2) After induction of cell culture for 24 hours, the adherent cells were trypsinized, centrifuged at 1000 rpm for 5 min, and then the supernatant was removed, and the cell density was resuspended to 2 × 10 6 /mL using RPMI 1640 medium containing 2% heat-inactivated FBS. 50 μL/well of the cell suspension was plated into a 96-well plate, and the number of cells per well was 1 × 10 5 .
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，将板放置于37℃、5％CO 2培养箱中培养6h，收集上清，按照IL-1β检测试剂盒说明书测量IL-1β的水平。 3) Take an appropriate amount of 10 mM test compound in DMSO solution, prepare 2× test concentration with RPMI 1640 medium containing 2% heat-inactivated FBS, add 50 μL/well dilution to cells of 96-well plate, and mix thoroughly. After homogenization, the plate was placed in a 37 ° C, 5% CO 2 incubator for 6 h, and the supernatant was collected, and the IL-1β level was measured according to the IL-1β test kit instructions.
4)EC 50通过GraphPad软件log(agonist)vs.response--Variable slope四参数法拟合，结果见表1。 4) The EC 50 was fitted by the GraphPad software log (agonist) vs. response--Variable slope four-parameter method, and the results are shown in Table 1.
实验例3：本发明化合物对hTLR 7的激动作用 Experimental Example 3: The agonistic effect of the compounds of the present invention on hTLR 7
本实验通过检测HEK-hTLR 7-NF-κB-报告基因细胞中的荧光素酶来测试本发明化合物对TLR 7信号通路的激活作用，以评估化合物对NLRP3通路激动作用的特异性。 In this experiment, the activation of the TLR 7 signaling pathway by the compounds of the present invention was tested by detecting luciferase in HEK-hTLR 7 -NF-κB-reporter cells to assess the specificity of the compounds for agonism of the NLRP3 pathway.
试剂：DMEM(High glucose)；FBS(胎牛血清)(Gibco)；Bright-Glo TM Luciferase检测试剂盒(Promega) Reagents: DMEM (High glucose); FBS (fetal calf serum) (Gibco); Bright-Glo TM Luciferase test kit (Promega)
细胞：人源HEK-TLR 7NF-κB-荧光素酶报告基因细胞(南京科佰) Cells: human HEK-TLR 7 NF-κB-luciferase reporter cell (Nanjing Kezhen)
1)将处于对数生长期的人源HEK-hTLR 7-NF-κB-荧光素酶报告基因细胞胰酶消化，用培养基重悬至2×10 6个/mL的浓度，加入50μL/孔细胞重悬液于96孔板中，每孔细胞 数为1×10 6个。取适量的10mM待测化合物的DMSO溶液，用培养基配制成2×测试浓度，加50μL/孔至96孔板的细胞中，将96孔板置于37℃，5％CO 2的培养箱中培养16h。培养基为包含10％FBS的DMEM。 1) Trypsinize human HEK-hTLR 7 -NF-κB-luciferase reporter cell in logarithmic growth phase, resuspend in medium to a concentration of 2 × 10 6 /mL, and add 50 μL/well. The cell suspension was in a 96-well plate, and the number of cells per well was 1 × 10 6 . Take an appropriate amount of 10 mM test compound in DMSO solution, prepare 2× test concentration with medium, add 50 μL/well to cells of 96-well plate, and place 96-well plate in 37 ° C, 5% CO 2 incubator. Cultured for 16h. The medium was DMEM containing 10% FBS.
2)细胞孵育结束后，加入100μL/孔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)。 2) After the end of the cell incubation, 100 μL/well of Bright-Glo TM Luciferase detection reagent was added, incubated for 5 min at room temperature, and the relative Luciferase Unit (RLU) was read by a microplate reader.
3)EC 50通过GraphPad软件log(agonist)vs.response--Variable slope四参数法拟合，结果见表1。 3) The EC 50 was fitted by the GraphPad software log (agonist) vs. response--Variable slope four-parameter method, and the results are shown in Table 1.
实验例4：本发明化合物对hTLR 8的激动作用 Experimental Example 4: The agonistic effect of the compounds of the present invention on hTLR 8
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TLR 8信号通路的激活作用，以评估化合物对NLRP3通路激动作用的特异性。 In this experiment, the activation of the TLR 8 signaling pathway by the compounds of the present invention was tested by detecting the amount of alkaline phosphatase secreted in the HEK-Blue cell line to evaluate the specificity of the compound for agonism of the NLRP3 pathway.
试剂：DMEM(High glucose)；FBS(胎牛血清)(Gibco)；QUANTI-Blue/InvivoGen/rep-qb2；Reagents: DMEM (High glucose); FBS (fetal calf serum) (Gibco); QUANTI-Blue/InvivoGen/rep-qb2;
细胞：HEK-Blue TMhTLR 8细胞(人源TLR 8细胞)(InvivoGen) Cells: HEK-Blue TM hTLR 8 cells (human TLR 8 cells) (InvivoGen)
实验步骤：Experimental steps:
1)将处于对数生长期的HEK-Blue TMhTLR 8细胞胰酶消化，用培养基重悬至2×10 6个/mL的浓度，加入50μL/孔细胞悬液于96孔板中；取适量的10mM待测化合物的DMSO溶液，用培养基配制成2×测试浓度，加50μL/孔至96孔板的细胞中，将96孔板置于37℃，5％CO 2的培养箱中培养16h。培养基为包含10％FBS的DMEM。 1) in logarithmic growth phase of the HEK-Blue TM hTLR 8 cells were trypsinized, resuspended with medium to a concentration of 2 × 10 6 cells / mL, was added 50μL / well of the cell suspension in 96 well plates; taken Appropriate amount of 10 mM test compound in DMSO solution, prepare 2× test concentration with medium, add 50 μL/well to cells of 96-well plate, and place 96-well plate in 37 ° C, 5% CO 2 incubator 16h. The medium was DMEM containing 10% FBS.
2)细胞孵育结束后，取10μL细胞培养上清液转移至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。 2) After the end of the cell incubation, 10 μL of the cell culture supernatant was transferred to a 96-well plate, and 90 μL/well of the QUANTI-Blue detection solution was added, and the plate was incubated at 37 ° C for 3 hours, and the plate reader OD 620 was read.
3)EC 50通过GraphPad软件log(agonist)vs.response--Variable slope四参数法拟合，结果见表1。 3) The EC 50 was fitted by the GraphPad software log (agonist) vs. response--Variable slope four-parameter method, and the results are shown in Table 1.
表1Table 1
Figure PCTCN2019085535-appb-000121
Figure PCTCN2019085535-appb-000121
Figure PCTCN2019085535-appb-000122
Figure PCTCN2019085535-appb-000122
结果表明，以化合物2、3、5、6、7、9s、10、37、67s-81、83-106为代表的本发明化合物对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THP-1 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；化合物5对hTLR 7有弱激活,其它化合物在100μM对hTLR 7无明显激活；所有上述化合物在100μM对hTLR 8无明显激活。综上，本发明化合物(例如化合物2、3、5、6、7、9s、10、37、67s-81、83-106)对hNLRP3和/或其信号通路有明显的特异性激动活性。 The results show that the compounds of the present invention represented by compounds 2, 3, 5, 6, 7, 9s, 10, 37, 67s-81, 83-106 express IL-1β expression in THP-1 cells after PMA-induced differentiation. There was a significant agonistic effect, and IL-1β expression in THP-1 def NLRP3 cells was not agonistic at the highest compound test concentration (27 μM); Compound 5 had weak activation of hTLR 7 and other compounds were not significantly observed at 100 μM for hTLR 7 Activation; all of the above compounds showed no significant activation of hTLR 8 at 100 μM. In conclusion, the compounds of the invention (e.g., compounds 2, 3, 5, 6, 7, 9s, 10, 37, 67s-81, 83-106) have significant specific agonistic activity against hNLRP3 and/or its signaling pathway.
实验例5：hERG实验Experimental Example 5: hERG experiment
采用Predictor TM hERG Fluorescence Polarization Assay Kit(生产厂家： ThermoFisher)，按照试剂盒说明测试化合物对hERG钾离子通道的抑制作用，测试浓度为1和10μM，试验结果见表2。 Using Predictor TM hERG Fluorescence Polarization Assay Kit (manufacturer: ThermoFisher), according to kit instructions inhibition of the test compound on the hERG potassium ion channel, 1 and 10 M concentration of the test, the test results in Table 2.
表2Table 2
化合物Compound IC 50(μM) IC 50 (μM)
9s9s >10>10
1010 >10>10
3737 >10>10
7676 >10>10
8888 >10>10
9292 >10>10
95s95s >10>10
采用手动膜片钳方法测试了化合物73s对hERG的抑制作用。The inhibitory effect of compound 73s on hERG was tested by manual patch clamp method.
细胞株：过表达hERG钾离子通道HEK-293(人胚肾细胞)Cell line: Overexpression of hERG potassium channel HEK-293 (human embryonic kidney cells)
阴性对照：含0.1％DMSO的细胞外液；阳性对照：Quinidine(奎尼丁)Negative control: extracellular fluid with 0.1% DMSO; positive control: Quinidine
测试化合物浓度：1μM和10μMTest compound concentration: 1 μM and 10 μM
反应温度：22～24℃Reaction temperature: 22 to 24 ° C
数据采集：PATCHMASTER V2X60软件。Data acquisition: PATCHMASTER V2X60 software.
实验步骤：Experimental steps:
将待测化合物溶解于DMSO中，配制成10mM母液，用DMSO稀释母液至1mM(次级母液)；取次级母液30μL稀释至30mL细胞外液中，用于电生理检测。The test compound was dissolved in DMSO to prepare a 10 mM mother liquor, and the mother liquor was diluted to 1 mM (secondary mother liquor) with DMSO; 30 μL of the secondary mother liquor was diluted to 30 mL of extracellular fluid for electrophysiological detection.
将细胞转移到嵌于倒置显微镜平台的细胞浴槽中，灌流细胞外液(2.7ml/分钟)，稳定5分钟后，将膜电压钳制在-80mV，给予细胞持续2s，+20mV电压刺激，激活hERG钾通道，再复极化至-50mV,持续5s，产生外向尾电流，刺激频率15秒/次。The cells were transferred to a cell bath embedded in an inverted microscope platform, and the extracellular fluid (2.7 ml/min) was perfused. After 5 minutes of stabilization, the membrane voltage was clamped at -80 mV, and the cells were given 2 s, +20 mV voltage stimulation to activate hERG. The potassium channel is repolarized to -50 mV for 5 s, producing an outward tail current with a stimulation frequency of 15 sec/time.
灌流细胞外液(2毫升/分钟)并持续记录，电流稳定后灌流含待测化合物的细胞外液并持续记录直到化合物对hERG电流的抑制作用达到稳定状态。The extracellular fluid (2 ml/min) was perfused and recorded continuously. After the current was stabilized, the extracellular fluid containing the test compound was perfused and recorded until the inhibition of the hERG current by the compound reached a steady state.
化合物73s的IC 50>10μM,本实验中阳性对照奎尼丁在30μM时对hERG钾离子通道的抑制率为90.7％，说明试验系统正常。 Compound 73s of the IC 50> 10μM, the positive control in this experiment at 30μM quinidine inhibition rate hERG potassium ion channel 90.7%, indicating that the test system is normal.
结果表明，以化合物9s、10、37、73s、76、88、92、95s为代表的本发明化合物对hERG无明显的抑制作用，对导致心脏QT间期延长的可能性小。The results showed that the compound of the present invention represented by the compounds 9s, 10, 37, 73s, 76, 88, 92, 95s had no significant inhibitory effect on hERG, and was less likely to cause prolongation of the QT interval of the heart.
实验例6：CYP酶抑制试验Experimental Example 6: CYP enzyme inhibition test
CYP450是药物代谢中最重要的酶系统，参与代谢的酶与药物相互作用，其中最主要的为CYP1A2、CYP2D6和CYP3A4。本实验使用P450-Glo TM CYP1A2Screening System、
Figure PCTCN2019085535-appb-000123
CYP2D6Cyan Screening Kit和
Figure PCTCN2019085535-appb-000124
CYP3A4Red Screening Kit，按照试剂盒说明分别测定化合物对CYP1A2、CYP2D6和CYP3A4的抑制活性。测试结果见表3A。 CYP450 is the most important enzyme system in drug metabolism, and enzymes involved in metabolism interact with drugs, the most important of which are CYP1A2, CYP2D6 and CYP3A4. This experiment uses the P450-Glo TM CYP1A2Screening System,
Figure PCTCN2019085535-appb-000123
CYP2D6Cyan Screening Kit and
Figure PCTCN2019085535-appb-000124
For the CYP3A4Red Screening Kit, the inhibitory activities of the compounds against CYP1A2, CYP2D6 and CYP3A4 were determined according to the kit instructions. The test results are shown in Table 3A.
表3ATable 3A
Figure PCTCN2019085535-appb-000125
Figure PCTCN2019085535-appb-000125
Figure PCTCN2019085535-appb-000126
Figure PCTCN2019085535-appb-000126
结果表明，以化合物9s、10、67s、68、70、74、75、78、80、81、83、86、88为代表的本发明化合物对CYP1A2、CYP2D6和CYP3A4酶无明显抑制作用。The results showed that the compounds of the present invention represented by the compounds 9s, 10, 67s, 68, 70, 74, 75, 78, 80, 81, 83, 86, 88 had no significant inhibitory effects on the CYP1A2, CYP2D6 and CYP3A4 enzymes.
此外，用LC-MS方法测定了化合物73s对CYP1A2、CYP2D6、CYP3A4的抑制作用。具体试验如下所述：In addition, the inhibitory effect of compound 73s on CYP1A2, CYP2D6, and CYP3A4 was determined by LC-MS. The specific test is as follows:
试剂及对照品：Reagents and controls:
Figure PCTCN2019085535-appb-000127
Figure PCTCN2019085535-appb-000127
实验步骤：Experimental steps:
将探针底物(50μl)、PBS(49μl)、待测化合物或阳性抑制剂(1μl)和HLM(50μl，孵育浓度为0.1mg/ml)的混合液在37℃预孵5min后，加入NADPH(50μl)并再孵育30min。然后在各反应孵育液中加入800μl含内标的冰乙腈以终止反应，涡旋、离心，取上清进行LC-MS/MS分析。Add a mixture of probe substrate (50 μl), PBS (49 μl), test compound or positive inhibitor (1 μl) and HLM (50 μl, incubation concentration 0.1 mg/ml) for 5 min at 37 ° C, then add NADPH. (50 μl) and incubated for an additional 30 min. Then, 800 μl of internal standard-containing ice acetonitrile was added to each reaction incubation solution to terminate the reaction, vortexed, centrifuged, and the supernatant was taken for LC-MS/MS analysis.
LC-MS/MS：质谱采用Sciex API 5500。液相色谱采用Waters ACQUITY UPLC I-CLASS系统。色谱柱为Hypersil GOLD C 18(2.1mm×50mm,1.9μm)。流动相：A相为水+0.1％甲酸，B相为乙腈；流速为0.4ml/min，柱温为40℃。离子源为ESI源正离子模式，扫描方式为多反应监测(MRM)。 LC-MS/MS: Mass spectrometry using Sciex API 5500. The liquid chromatography was performed using a Waters ACQUITY UPLC I-CLASS system. The column was Hypersil GOLD C 18 (2.1 mm x 50 mm, 1.9 μm). Mobile phase: phase A was water + 0.1% formic acid, phase B was acetonitrile; flow rate was 0.4 ml/min, column temperature was 40 °C. The ion source is the ESI source positive ion mode and the scanning mode is multiple reaction monitoring (MRM).
以溶媒组(DMSO)为阴性对照，测定在不同浓度的化合物下各探针底物产生的主要代谢物的浓度，从而确定化合物对CYP1A2、CYP2D6和CYP3A4的半数抑制浓度(IC 50)。测试结果见表3B。 In the vehicle group (DMSO) as the negative control, measuring the concentration of the major metabolite produced by the respective probe substrates at various concentrations of the compound to determine the compound inhibitory concentration (IC 50) of CYP1A2, CYP2D6 and CYP3A4 half. The test results are shown in Table 3B.
表3BTable 3B
Figure PCTCN2019085535-appb-000128
Figure PCTCN2019085535-appb-000128
结果表明，化合物73s对CYP1A2、CYP2D6和CYP3A4无明显抑制作用。The results showed that compound 73s had no significant inhibitory effect on CYP1A2, CYP2D6 and CYP3A4.
实验例7：CYP3A4酶诱导试验Experimental Example 7: CYP3A4 enzyme induction test
用DMSO将10mM待测化合物按照3倍梯度稀释七个浓度点，作为100×母液。利福平作为阳性对照，1％DMSO作为阴性对照。10 mM of the test compound was diluted with DMSO in seven concentration points as a 100× mother liquor. Rifampicin was used as a positive control and 1% DMSO was used as a negative control.
将处于对数生长期的稳定表达CYP3A4-荧光素酶报告基因系统的Hep G2 C3A肝癌细胞离心收集，重悬至4×10 5个细胞/ml。按照25μl/孔加至384孔白色细胞板，置于37℃5％CO 2培养箱中培养24h。 Hep G2 C3A hepatoma cells stably expressing the CYP3A4-luciferase reporter gene system in the logarithmic growth phase were collected by centrifugation and resuspended to 4 × 10 5 cells/ml. Add 25 μl/well to 384-well white cell plates and incubate in a 37 ° C 5% CO 2 incubator for 24 h.
从上述100×母液中转300nl至细胞板中，置于37℃5％CO 2培养箱中培养72h。加入30μl/孔Brigh-Glo TM(Promega)室温孵育2分钟，酶标仪读取相对化学发光荧光值(RLU)。化合物73s对CYP3A4酶诱导作用的EC50值采用Prism 5软件计算，化合物73s相对诱导活性(10μM)％＝((化合物信号值-阴性对照信号值)/(阳性对照信号值-阴性对照信号值))×100％。测试结果见表4。 300 nl was transferred from the above 100× mother liquor to the cell plate, and cultured in a 37° C. 5% CO 2 incubator for 72 hours. Add 30μl / hole Brigh-Glo TM (Promega) at room temperature for 2 minutes, and relative chemiluminescence microplate reader to read fluorescence values (RLU). The EC50 value of Compound 73s for induction of CYP3A4 enzyme was calculated using Prism 5 software, and the relative inducing activity (10 μM)% of compound 73s = ((compound signal value - negative control signal value) / (positive control signal value - negative control signal value)) ×100%. The test results are shown in Table 4.
表4化合物73s对CYP3A4酶的诱导作用Table 4 Induction of CYP3A4 enzyme by compound 73s
Figure PCTCN2019085535-appb-000129
Figure PCTCN2019085535-appb-000129
结果表明，在10μM时化合物73s对CYP3A4荧光素酶的诱导活性为阳性对照利福平诱导活性的3％，化合物73s对CYP3A4酶EC 50>10μM。综上，本发明化合物73s对CYP3A4酶无明显诱导作用。 The results showed that the induction activity of compound 73s on CYP3A4 luciferase was 3% of the positive control rifampicin-inducing activity at 10 μM, and the compound 73s had an EC 50 of >10 μM against the CYP3A4 enzyme. In summary, the compound 73s of the present invention has no significant induction effect on the CYP3A4 enzyme.
实验例8：对单侧接种CT26小鼠结肠癌皮下移植瘤的体内药效Experimental Example 8: In vivo efficacy of unilateral vaccination of CT26 mouse colon cancer subcutaneous xenografts
CT26小鼠结肠癌细胞体外单层培养，当细胞处于对数生长期时离心收集细胞并计数。CT26 mouse colon cancer cells were cultured in vitro in a single layer, and the cells were collected by centrifugation and counted when the cells were in the logarithmic growth phase.
将0.1ml含3×10 5个CT26细胞的PBS重悬液接种于小鼠一侧肩胛处皮下。待肿瘤长至体积约为100mm 3时，根据肿瘤体积将小鼠随机分为4组，每组8只。 0.1 ml of a PBS resuspension containing 3 x 10 5 CT26 cells was inoculated subcutaneously on one side of the mouse. When the tumor grew to a volume of about 100 mm 3 , the mice were randomly divided into 4 groups according to the tumor volume, 8 in each group.
化合物73s按照5μg，50μg，500μg三个剂量进行瘤内注射给药，每周两次，连续给药两周。每周两次测量肿瘤体积和动物体重。Compound 73s was administered intratumorally at three doses of 5 μg, 50 μg, and 500 μg twice a week for two consecutive weeks. Tumor volume and animal body weight were measured twice a week.
根据肿瘤体积计算抑瘤率TGI(％)来评价化合物对小鼠移植瘤生长的抑制作用，计算公式为：TGI(％)＝100％-(T Vt-T V0)/(C Vt-C V0)×100％；当肿瘤出现消退时，TGI(％)＝100％-(T Vt-T V0)/T V0×100％。T V0为分组给药时测试化合物组的平均瘤体积；T Vt为第t天测量时测试化合物组的平均瘤体积；C V0为分组给药时溶媒组的平均瘤体积；C Vt 为第t天测量时溶媒组的平均瘤体积。如果肿瘤比起始体积缩小，即V t<V 0时，即定义为肿瘤部分消退(PR)；如果肿瘤完全消失，即定义为肿瘤完全消退(CR)。两组间差异统计学分析用t检验计算P值。测试结果见表5。 The inhibitory effect of the compound on the growth of mouse xenografts was evaluated according to the tumor volume TGI (%). The formula is: TGI(%)=100%-(T Vt -T V0 )/(C Vt -C V0 × 100%; when the tumor subsides, TGI (%) = 100% - (T Vt - T V0 ) / T V0 × 100%. T V0 is the average tumor volume of the test compound group at the time of group administration; T Vt is the average tumor volume of the test compound group measured on the t-day; C V0 is the average tumor volume of the vehicle group at the time of group administration; C Vt is the t-th The mean tumor volume of the vehicle group at the time of day measurement. If the tumor is smaller than the initial volume, ie, V t <V 0 , it is defined as tumor partial regression (PR); if the tumor completely disappears, it is defined as complete tumor regression (CR). Difference statistical analysis between the two groups was performed using a t test to calculate the P value. The test results are shown in Table 5.
表5化合物73s对CT26小鼠结肠癌皮下移植瘤的体内药效Table 5 In vivo efficacy of compound 73s on CT26 mouse colon cancer subcutaneous xenografts
Figure PCTCN2019085535-appb-000130
Figure PCTCN2019085535-appb-000130
结果表明，与溶媒组比较本发明化合物73s对CT26皮下移植瘤模型有明显剂量依赖性抑瘤作用，500μg剂量组出现7/8小鼠皮下肿瘤完全消退。The results showed that compared with the vehicle group, the compound 73s of the present invention had a dose-dependent antitumor effect on the CT26 subcutaneous xenograft model, and the subcutaneous tumor of 7/8 mice completely disappeared in the 500 μg dose group.
实验例9：对双侧接种CT26小鼠结肠癌皮下移植瘤的体内药效Experimental Example 9: In vivo efficacy of bilateral inoculation of CT26 mouse colon cancer subcutaneous xenografts
(1)CT26小鼠结肠癌细胞体外单层培养，当细胞处于对数生长期时离心收集细胞并计数。(1) CT26 mouse colon cancer cells were cultured in vitro in a single layer, and the cells were collected by centrifugation and counted when the cells were in the logarithmic growth phase.
(2)分别将0.1ml含3×10 5个CT26细胞的PBS重悬液接种于小鼠双侧肩胛处皮下。待小鼠双侧肩胛肿瘤长至体积约为100mm 3时，根据两侧肿瘤体积将小鼠随机分为4组，每组8只。 (2) 0.1 ml of a PBS resuspension containing 3 × 10 5 CT26 cells was inoculated subcutaneously on the bilateral scapula of the mouse. When the bilateral scapular tumors of the mice grew to a volume of about 100 mm 3 , the mice were randomly divided into 4 groups according to the tumor volume on both sides, 8 in each group.
(3)化合物73s按照50μg，500μg给药剂量分别在小鼠右侧肿瘤采取瘤内注射给药，每周两次，连续给药两周。测量双侧肿瘤体积和动物体重。(3) Compound 73s was administered intratumorally in the right tumor of mice at a dose of 50 μg and 500 μg, twice a week for two weeks. Bilateral tumor volume and animal body weight were measured.
(4)根据肿瘤体积计算抑瘤率TGI(％)来评估化合物73s对小鼠移植瘤生长的抑制作用，计算公式为：TGI(％)＝100％-(T Vt-T V0)/(C Vt-C V0)×100％；当肿瘤出现消退时，TGI(％)＝100％-(T Vt-T V0)/T V0×100％。T V0为分组给药时受试化合物组的平均瘤体积；T Vt为第t天测量时受试化合物组的平均瘤体积；C V0为分组给药时溶媒组的平均瘤体积；C Vt为第t天测量时溶媒组的平均瘤体积。如果肿瘤比起始体积缩小，即V t<V 0时，即定义为肿瘤部分消退(PR)；如果肿瘤完全消失，即定义为肿瘤完全消退(CR)。两组间差异统计学分析用t检验计算P值。结果见表6A和表6B。 (4) Calculate the inhibitory effect of compound 73s on the growth of transplanted tumor in mice according to the tumor volume TGI (%). The formula is: TGI(%)=100%-(T Vt -T V0 )/(C Vt - C V0 ) × 100%; TGI (%) = 100% - (T Vt - T V0 ) / T V0 × 100% when the tumor subsides. T V0 is the average tumor volume of the test compound group at the time of group administration; T Vt is the average tumor volume of the test compound group measured on the t-day; C V0 is the average tumor volume of the vehicle group at the time of group administration; C Vt is The mean tumor volume of the vehicle group at the t-day measurement. If the tumor is smaller than the initial volume, ie, V t <V 0 , it is defined as tumor partial regression (PR); if the tumor completely disappears, it is defined as complete tumor regression (CR). Difference statistical analysis between the two groups was performed using a t test to calculate the P value. The results are shown in Table 6A and Table 6B.
表6A化合物73s对给药侧CT26小鼠皮下结肠肿瘤的抑制作用Table 6A Compound 73s inhibits the subcutaneous colon tumor of CT26 mice on the administration side
Figure PCTCN2019085535-appb-000131
Figure PCTCN2019085535-appb-000131
Figure PCTCN2019085535-appb-000132
Figure PCTCN2019085535-appb-000132
表6B化合物73s对非给药侧CT26小鼠皮下结肠肿瘤的抑制作用Table 6B inhibitory effect of compound 73s on subcutaneous colon tumor of non-administered side CT26 mice
Figure PCTCN2019085535-appb-000133
Figure PCTCN2019085535-appb-000133
表6A和6B结果表明，在双侧接种CT26皮下移植瘤模型中，与溶媒组比较瘤内注射本发明化合物73s对给药侧有明显剂量依赖性抑瘤作用，500μg剂量组给药侧出现6/8小鼠皮下肿瘤完全消退，1/8小鼠皮下肿瘤部分消退；且本发明化合物73s对非给药侧肿瘤也有明显的抑瘤作用。综上，瘤内注射本发明化合物73s对双侧CT26肿瘤均有明显的抑瘤作用。The results of Tables 6A and 6B show that in the bilaterally inoculated CT26 subcutaneous xenograft model, intratumoral injection of the compound of the present invention, 73s, has a dose-dependent antitumor effect on the administration side compared with the vehicle group, and the administration side of the 500 μg dose group appears 6 /8 mouse subcutaneous tumor completely resolved, 1 / 8 mouse subcutaneous tumor partially resolved; and the compound of the present invention 73s also has a significant anti-tumor effect on non-administered side tumors. In conclusion, intratumoral injection of the compound of the present invention 73s has a significant anti-tumor effect on bilateral CT26 tumors.
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。Various modifications of the invention in addition to those described herein will be apparent to those skilled in the art. Such modifications are also intended to fall within the scope of the appended claims. Each of the references (including all patents, patent applications, journal articles, books, and any other publications) cited in this application are hereby incorporated by reference in their entirety.

Claims (31)

  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：a compound of formula I, a stereoisomer, a tautomer or a mixture thereof, a pharmaceutically acceptable salt, eutectic, polymorph or solvate of said compound, or A stable isotope derivative, metabolite or prodrug of a compound:
    Figure PCTCN2019085535-appb-100001
    Figure PCTCN2019085535-appb-100001
    其中:among them:
    X 1和X 2各自独立地选自CH、CR 8、NR 7、N、O或S，X 1和X 2中的至少一个为NR 7、N、O或S，且X 1、X 2和与其(X 1和/或X 2)相连的碳原子一起形成五元杂芳环；R 7选自H、C 1-6烷基、C 3-8环烷基，所述C 1-6烷基和C 3-8环烷基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、C 1-4羟烷基， X 1 and X 2 are each independently selected from CH, CR 8 , NR 7 , N, O or S, and at least one of X 1 and X 2 is NR 7 , N, O or S, and X 1 , X 2 and The carbon atom to which it is bonded (X 1 and/or X 2 ) together form a five-membered heteroaryl ring; R 7 is selected from H, C 1-6 alkyl, C 3-8 cycloalkyl, said C 1-6 alkane And C 3-8 cycloalkyl are optionally substituted by one or more of the following groups: halo, OH, CN, C 1-4 alkoxy, C 1-4 hydroxyalkyl,
    X 3为C、N、O或S，且满足下列条件： X 3 is C, N, O or S and the following conditions are met:
    (1)当X 3为O或S时，R 2和R 6不存在； (1) When X 3 is O or S, R 2 and R 6 are absent;
    (2)当X 3为N时，R 2和R 6不同时存在； (2) When X 3 is N, R 2 and R 6 are not present at the same time;
    R 1选自H、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、C(O)OR 30、C(O)NR 31R 32、NR 33C(O)R 34、NR 31R 32、S(O) 2R 35；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、C(O)OR 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、SR 37； R 1 is selected from the group consisting of H, halogen, CN, NO 2 , C 1-8 alkyl, 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, 5-10 membered heteroaryl group, 9-12 membered arylheterocyclyl group, C(O)OR 30 , C(O)NR 31 R 32 , NR 33 C(O)R 34 , NR 31 R 32 , S(O) 2 R 35 ; said C 1-8 alkyl group, C 1-8 haloalkyl group, C 1-8 alkoxy group, C 1- 8 haloalkoxy, C 3-8 cycloalkyl, 4-10 membered heterocyclyl, C 6-12 aryl, 5-10 membered heteroaryl, 9-12 membered arylheterocyclyl optionally Substituted by 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, C 6-12 aryl, 5-10 membered heteroaryl, 9-12 membered arylheterocyclyl, C ( O) OR 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 C(O)NR 31 R 32 , NR 33 C(O)OR 30 , S(O)NR 31 R 32 , S(O) 2 NR 31 R 32 , S(O)R 35 , S(O 2 R 35 , OR 37 , 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 1-3烷基-C 6-12芳基、C 3-8环烷基、5-10元杂芳基、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 1-3烷基-C 6-12芳基、C 3-8环烷基、5-10元杂芳基、4-10元杂环基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、C(O)OR 30、OC(O)R 30、 OC(O)NR 31R 32、NR 33C(O)NR 31R 32、NR 31R 32； R 2 is selected from the group consisting of H, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 6-12 aryl, -C 1-3 alkyl-C 6-12 aryl, C 3-8 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocyclyl, said C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 6-12 An aryl group, a -C 1-3 alkyl-C 6-12 aryl group, a C 3-8 cycloalkyl group, a 5-10 membered heteroaryl group, a 4-10 membered heterocyclic group, optionally in the following substituents One or more substitutions: halogen, C 1-4 haloalkyl, C 1-4 hydroxyalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy, 4-7 membered heterocyclyl, CN, NO 2 , OR 37 , SR 37 , C(O)R 30 , C(O)NR 31 R 32 , C(O)OR 30 , OC(O)R 30 , OC(O)NR 31 R 32 , NR 33 C (O) NR 31 R 32 , NR 31 R 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 2-8杂烷基、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、C(O)OR 30、C(O)NR 31R 32、NR 33C(O)R 34、NR 31R 32、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、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 2-8杂烷基、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、-C 6-12芳基-C 1-4烷基、5-10元杂芳基、9-12元芳基并杂环基、C(O)OR 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、P(O)OR 39OR 30； R 3 is selected from the group consisting of H, OH, halogen, CN, NO 2 , C 1-8 alkyl, C 1-8 haloalkyl, C 1-8 alkoxy, C 1-8 haloalkoxy, C 2-8 Alkyl, C 3-8 cycloalkyl, 4-10 membered heterocyclic, C 6-12 aryl, 5-10 membered heteroaryl, 9-12 membered arylheterocyclyl, 9-12 membered aromatic Alkylheteroaryl, 9-12 membered arylcycloalkyl, C(O)OR 30 , C(O)NR 31 R 32 , NR 33 C(O)R 34 , NR 31 R 32 , OR 37 , SR 37 , C(O)R 30 , OC(O)R 30 , OC(O)NR 31 R 32 , NR 33 C(O)NR 31 R 32 , NR 33 C(O)OR 30 , C(=NR 38 ) NR 31 R 32 , NR 33 C(=NR 38 )NR 31 R 32 , P(R 39 ) 2 , P(OR 39 ) 2 , P(O)R 39 R 40 , P(O)OR 39 OR 30 , S(O)R 35 , S(O) 2 R 35 , S(O)NR 31 R 32 , S(O) 2 NR 31 R 32 ; the C 1-8 alkyl group, C 1-8 halogenated alkane , C 1-8 alkoxy, C 1-8 haloalkoxy, C 2-8 heteroalkyl, C 3-8 cycloalkyl, 4-10 membered heterocyclyl, C 6-12 aryl, 5 a 10-membered heteroaryl group, a 9-12 membered arylheterocyclyl group, a 9-12 membered arylheteroaryl group, a 9-12 membered arylcycloalkyl group, optionally one of the following substituents or Multiple substitutions: 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, C 6-12 aryl, -C 6- -C 1-4 alkyl-C12 aryl, 5-10 membered heteroaryl, 9-12 membered heterocyclyl, and aryl, C (O) OR 30, C (O) R 30, C (O) NR 31 R 32 , NR 33 C(O)R 34 , NR 31 R 32 , S(O)R 35 , S(O) 2 R 35 , S(O)NR 31 R 32 , S(O) 2 NR 31 R 32 , OR 37 , SR 37 , OC(O)R 30 , OC(O)NR 31 R 32 , NR 33 C(O)NR 31 R 32 , NR 33 C(O)OR 30 , C(=NR 38 )NR 31 R 32 , NR 33 C(=NR 38 )NR 31 R 32 , =NNR 31 R 32 , P(R 39 ) 2 , P(OR 39 ) 2 , P(O)R 39 R 40 , P(O) OR 39 OR 30 ;
    R 4和R 5各自独立地选自H、C 1-8烷基、C 1-8烷氧基，或R 4、R 5和与R 4和R 5相连的氮原子一起形成4-7元杂环；所述C 1-8烷基、C 1-8烷氧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； R 4 and R 5 are each independently selected from H, C 1-8 alkyl, C 1-8 alkoxy, or R 4 , R 5 and a nitrogen atom bonded to R 4 and R 5 together form 4-7. a heterocyclic ring; the C 1-8 alkyl group, C 1-8 alkoxy group is optionally substituted by one or more of the following substituents: halogen, OH, CN, NO 2 , C 1-6 alkyl, C 1-4 haloalkyl, C 1-4 hydroxyalkyl;
    R 6选自H、C 1-6烷基、C 3-8环烷基，所述C 1-6烷基和C 3-8环烷基可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、C 1-4羟烷基； R 6 is selected from H, C 1-6 alkyl, C 3-8 cycloalkyl, and the C 1-6 alkyl and C 3-8 cycloalkyl may be optionally one or more of the following groups Substitutions: halogen, OH, CN, NO 2 , C 1-4 alkoxy, C 1-4 hydroxyalkyl;
    R 8选自卤素、C 1-8烷基、C 1-8烷氧基、C 3-8环烷基、C 2-8杂烷基、4-7元杂环基，所述C 1-8烷基、C 1-8烷氧基、C 3-8环烷基、C 2-8杂烷基、4-7元杂环基可任选地下列取代基中的一个或多个取代:OR 37、NR 31R 32、卤素、CN； R 8 is selected from the group consisting of halogen, C 1-8 alkyl, C 1-8 alkoxy, C 3-8 cycloalkyl, C 2-8 heteroalkyl, 4-7 membered heterocyclic, said C 1- The 8 alkyl, C 1-8 alkoxy, C 3-8 cycloalkyl, C 2-8 heteroalkyl, 4-7 membered heterocyclyl can be optionally substituted with one or more of the following substituents: OR 37 , NR 31 R 32 , halogen, CN;
    V为-(V 1) r–(V 2) s–(V 3) t-，其中，V 1、V 2和V 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亚烷氧基、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、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亚烷氧基、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、C 1-4烷氧基； V is -(V 1 ) r -(V 2 ) s -(V 3 ) t -, wherein V 1 , V 2 and V 3 are the same or different and are each independently selected from a C 1-8 alkylene group, C 2-8 alkenylene group, C 2-8 alkynylene group, C 1-8 alkyleneoxy group, C 3-8 cycloalkylene group, 4-10 membered heterocyclylene group, C 6-12 arylene group 5-10 membered heteroarylene, O, S, NR 33 , SO, SO 2 , CO, C (R 36a R 36b ); the C 1-8 alkylene group, C 2-8 alkenylene group, C 2-8 alkynylene, C 1-8 alkyleneoxy, C 3-8 cycloalkylene, 4-10 membered heterocyclylene, C 6-12 arylene, 5-10 membered heteroarylene The group is optionally substituted by one or more of the following substituents: halogen, OH, CN, NO 2 , C 1-6 alkyl, C 1-4 haloalkyl, C 1-4 hydroxyalkyl, C 1- 4 alkoxy;
    r、s、t各自独立地选自0和1；r, s, t are each independently selected from 0 and 1;
    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-、 -N(R 33)-、-S(O)-、-S(O) 2-、-C(O)-、-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、5-10元亚杂芳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、C 1-4烷氧基； L is -(L 1 ) n -(L 2 ) p -(L 3 ) q -, wherein L 1 , L 2 and L 3 are the same or different and are each independently selected from a C 1-8 alkylene group, C 2-8 alkenylene group, C 2-8 alkynylene group, C 1-8 haloalkylene group, C 1-8 alkyleneoxy group, C 1-8 haloalkyleneoxy group, C 1-8 Hydroxyalkylene, C 3-8 cycloalkylene, 4-10 membered heterocyclylene, C 6-12 arylene, 5-10 membered heteroarylene, -O-, -S-, -N (R 33 )-, -S(O)-, -S(O) 2 -, -C(O)-, -C(R 36a R 36b )-; the C 1-8 alkylene group, C 2 -8 alkenylene, C 2-8 alkynylene, C 1-8 haloalkylene, C 1-8 alkyleneoxy, C 1-8 haloalkyleneoxy, C 1-8 hydroxyl An alkyl group, a C 3-8 cycloalkylene group, a 4-10 membered heterocyclylene group, a C 6-12 arylene group, a 5-10 membered heteroarylene group, optionally one or more of the following substituents Substituted: halogen, OH, CN, NO 2 , C 1-6 alkyl, C 1-4 haloalkyl, C 1-4 hydroxyalkyl, C 1-4 alkoxy;
    n、p、q各自独立地选自0或1；n, p, q are each independently selected from 0 or 1;
    R 30、R 37、R 39、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亚环烷基、4-10元亚杂环基、C 6-12亚芳基、5-10元亚杂芳基、-C 1-8烷基-C 6-12芳基、-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亚环烷基、4-10元亚杂环基、C 6-12亚芳基、5-10元亚杂芳基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、C(O)O(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、S(O) 2NR 31R 32； R 30 , R 37 , R 39 and R 40 are each independently selected from the group consisting of hydrogen, C 1-8 alkyl, C 1-8 hydroxyalkyl, C 1-8 haloalkyl, C 1-8 alkoxy, C 1-8 haloalkoxy, C 3-8 cycloalkylene, 4-10 membered heterocyclylene, C 6-12 arylene, 5-10 membered heteroarylene, -C 1-8 alkyl- C 6-12 aryl, -C 1-8 alkyl-(5-10 membered heteroaryl); said C 1-8 alkyl, C 1-8 hydroxyalkyl, C 1-8 haloalkyl, C 1-8 alkoxy, C 1-8 haloalkoxy, C 3-8 cycloalkylene, 4-10 membered heterocyclylene, C 6-12 arylene, 5-10 membered heteroarylene 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 haloalkane Oxyl, C(O)O(C 1-6 alkyl), CONR 31 R 32 , NR 31 R 32 , NR 33 C(O)R 34 , S(O)R 35 , S(O) 2 R 35 , S(O)NR 31 R 32 , S(O) 2 NR 31 R 32 ;
    当多个R 30同时存在时，各R 30可以相同或不同； When a plurality of R 30 are simultaneously present, each R 30 may be the same or different;
    当多个R 37同时存在时，各R 37可以相同或不同； When a plurality of R 37 are simultaneously present, each R 37 may be the same or different;
    当多个R 39同时存在时，各R 39可以相同或不同； When a plurality of R 39 are simultaneously present, each R 39 may be the same or different;
    当多个R 40同时存在时，各R 40可以相同或不同； When a plurality of R 40 are simultaneously present, each R 40 may be the same or different;
    R 31、R 32、R 33、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、5-10元杂芳基；或者R 31和R 32与各自连接的N原子一起形成含有3-8元杂环基；或者R 33和R 34与各自连接的C或N原子一起形成4-8元杂环基；所述C 1-8烷基、C 1-8羟烷基、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、5-10元杂芳基； R 31 , R 32 , R 33 and R 34 are each independently selected from the group consisting of: H, C 1-8 alkyl, C 1-8 hydroxyalkyl, C 1-8 alkoxy, 4-10 membered heterocyclic, C 6-12 aryl, 5-10 membered heteroaryl; or R 31 and R 32 together with the respective attached N atom form a 3-8 membered heterocyclic group; or R 33 and R 34 are bonded to each C or The N atoms together form a 4-8 membered heterocyclic group; the C 1-8 alkyl group, the C 1-8 hydroxyalkyl group, the C 1-8 alkoxy group, the C 3-8 cycloalkyl group, the 4-10 membered hetero The cyclic group, C 6-12 aryl, 5-10 membered heteroaryl is optionally substituted by 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, C 6-12 aryl, 5-10 membered heteroaryl base;
    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、-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、5-10元杂芳基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、C(O)O(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、S(O) 2NR 31R 32；其中，R 31、R 32、R 33、R 34如上所定义； R 35 is selected from the group consisting of: 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, 5-10 membered heteroaryl group, -C 1-8 alkyl-C 6-12 aryl group, -C 1-8 alkyl group-(5- 10-membered heteroaryl); said C 1-8 alkyl, C 1-8 hydroxyalkyl, C 1-8 haloalkyl, C 1-8 alkoxy, C 1-8 haloalkoxy, C 3 The 8 -cycloalkyl, 4-10 membered heterocyclyl, C 6-12 aryl, 5-10 membered heteroaryl is optionally substituted by 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 haloalkoxy, C(O)O(C 1-6 alkyl), CONR 31 R 32 , NR 31 R 32 , NR 33 C(O)R 34 , S(O)Me, S(O) 2 Me, S(O)NR 31 R 32 , S(O) 2 NR 31 R 32 , wherein R 31 , R 32 , R 33 , R 34 are as defined above;
    当多个R 31同时存在时，各R 31可以相同或不同； When a plurality of R 31 are simultaneously present, each R 31 may be the same or different;
    当多个R 32同时存在时，各R 32可以相同或不同； When a plurality of R 32 are present at the same time, each R 32 may be the same or different;
    当多个R 33同时存在时，各R 33可以相同或不同； When a plurality of R 33 are simultaneously present, each R 33 may be the same or different;
    当多个R 34同时存在时，各R 34可以相同或不同； When a plurality of R 34 are simultaneously present, each R 34 may be the same or different;
    当多个R 35同时存在时，各R 35可以相同或不同； When a plurality of R 35 are simultaneously present, each R 35 may be the same or different;
    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、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、C 1-8卤代烷基任选地被下列基团中的一个或多个取代：OH、CN、NH 2、NHCH 3、N(CH 3) 2；或R 36a、R 36b和与R 36a、R 36b连接的碳原子一起形成3-7元环烷基或4-7元杂环基； R 36a and R 36b are the same or different, are each independently selected from H, C 1-6 alkyl, C 1-6 alkoxy, C 1-8 hydroxyalkyl, C 1-8 haloalkyl group; a C 1 -6 alkyl, C 1-6 alkoxy, C 1-8 hydroxyalkyl, C 1-8 haloalkyl are optionally substituted by one or more of the following groups: OH, CN, NH 2 , NHCH 3 , N(CH 3 ) 2 ; or R 36a , R 36b and a carbon atom bonded to R 36a , R 36b together form a 3-7 membered cycloalkyl group or a 4-7 membered heterocyclic group;
    当多于一个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、S(O) 2R 35。 When more than one R 38 is present simultaneously, each R 38 is the same or different and is each independently selected from the group consisting of: H, OH, CN, NO 2 , S(O)R 35 , S(O) 2 R 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，A compound according to claim 1, a stereoisomer, a tautomer or a mixture thereof, a pharmaceutically acceptable salt, eutectic, polymorph or solvate of said compound, or a compound Stable isotope derivative, metabolite or prodrug, of which
    R 1选自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；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元芳基并杂环基任选地被一个或多个下列取代基取代：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、C(O)OR 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、SR 37； R 1 is selected from the group consisting of C 1-8 alkyl, 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, 9-12 membered arylheterocyclyl; said C 1-8 alkyl, C 1-8 haloalkyl, C 1-8 alkoxy, C 1-8 haloalkoxy, C 3-8 cycloalkyl, 4-10 membered heterocyclic, C 6-12 aryl, 5-10 membered heteroaryl, 9-12 membered arylheterocyclyl 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, C 6-12 aryl, 5-10 membered heteroaryl, 9-12 membered arylheterocyclyl, C (O)OR 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 C(O)NR 31 R 32 , NR 33 C(O)OR 30 , S(O)NR 31 R 32 , S(O) 2 NR 31 R 32 , S(O)R 35 , S( O) 2 R 35 , OR 37 , SR 37 ;
    优选地，R 1选自C 6-12芳基(例如苯基)、5-10元杂芳基(例如5-6元杂芳基)、9-12元芳基并杂环基；所述C 6-12芳基(例如苯基)、5-10元杂芳基(例如5-6元杂芳基)、9-12元芳基并杂环基任选地被一个或多个下列取代基取代：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、-C(O)OR 30、C(O)R 30、C(O)NR 31R 32、-NR 33C(O)R 34、-NR 31R 32、C(O)R 30、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、SR 37； Preferably, R 1 is selected from C 6-12 aryl (eg phenyl), 5-10 membered heteroaryl (eg 5-6 membered heteroaryl), 9-12 membered arylheterocyclyl; C 6-12 aryl (eg phenyl), 5-10 membered heteroaryl (eg 5-6 membered heteroaryl), 9-12 membered arylheterocyclyl optionally substituted by one or more of the following Base substitution: 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 heterocyclyl, C 6-12 aryl, 5-10 membered heteroaryl, 9-12 membered arylheterocyclyl, -C(O)OR 30 , C( O) R 30 , C(O)NR 31 R 32 , -NR 33 C(O)R 34 , -NR 31 R 32 , C(O)R 30 , OC(O)R 30 , OC(O)NR 31 R 32 , NR 33 C(O)NR 31 R 32 , NR 33 C(O)OR 30 , S(O)NR 31 R 32 , S(O) 2 NR 31 R 32 , S(O)R 35 , S (O) 2 R 35 , OR 37 , SR 37 ;
    优选地，R 1选自卤素、5-6元杂芳基和C 6-12芳基，任选地，所述5-6元杂芳基和C 6-12芳基被一个或多个C 1-4烷基取代； Preferably, R 1 is selected from the group consisting of halogen, 5-6 membered heteroaryl and C 6-12 aryl, optionally, said 5-6 membered heteroaryl and C 6-12 aryl are one or more C 1-4 alkyl substitution;
    优选地，R 1选自氟、氯、溴、碘、5-6元杂芳基和苯基，任选地，所述的5-6元杂芳基和苯基任选地被一个或多个甲基、乙基取代； Preferably, R 1 is selected from the group consisting of fluorine, chlorine, bromine, iodine, 5-6 membered heteroaryl, and phenyl, optionally, said 5-6 membered heteroaryl and phenyl are optionally one or more Methyl or ethyl substitution;
    优选地，R 1选自氟、氯、溴、碘、5-6元含氮杂芳基、5-6元含硫杂芳基和苯基，任选地，所述的5-6元含氮杂芳基、5-6元含硫杂芳基和苯基任选地被一个或多个甲基、乙 基取代； Preferably, R 1 is selected from the group consisting of fluorine, chlorine, bromine, iodine, a 5-6 membered nitrogen-containing heteroaryl group, a 5-6 membered sulfur-containing heteroaryl group, and a phenyl group, optionally, said 5-6 member contained Azaheteroaryl, 5-6 membered sulfur-containing heteroaryl and phenyl are optionally substituted by one or more methyl or ethyl groups;
    优选地，所述5-6元含氮单环杂芳基含有1个、2个或3个氮原子，任选地，还含有1个硫原子或氧原子；Preferably, the 5-6 membered nitrogen-containing monocyclic heteroaryl group contains 1, 2 or 3 nitrogen atoms, optionally further containing 1 sulfur atom or oxygen atom;
    优选地，所述5-6元含硫单环杂芳基含有1个、2个或3个硫原子；Preferably, the 5-6 membered sulfur-containing monocyclic heteroaryl group contains 1, 2 or 3 sulfur atoms;
    优选地，R 1选自卤素(例如氟、氯、溴、碘)、苯基、咪唑基、吡啶基、噻唑基、吡嗪基、噻吩基、吡唑基、哒嗪基、嘧啶基；任选地，所述苯基、咪唑基、吡啶基、噻唑基、吡嗪基、噻吩基、吡唑基、哒嗪基、嘧啶基被1个、2个、3个或4个C 1-4烷基(例如甲基、乙基)取代； Preferably, R 1 is selected from halogen (e.g., fluorine, chlorine, bromine, iodine), phenyl, imidazolyl, pyridyl, thiazolyl, pyrazinyl, thienyl, pyrazolyl, pyridazinyl, pyrimidinyl; Optionally, the phenyl, imidazolyl, pyridyl, thiazolyl, pyrazinyl, thienyl, pyrazolyl, pyridazinyl, pyrimidinyl is 1, 2, 3 or 4 C 1-4 Alkylation (eg methyl, ethyl);
    优选地，R 1选自溴、
    Figure PCTCN2019085535-appb-100002
    Figure PCTCN2019085535-appb-100003
    Preferably, R 1 is selected from bromine,
    Figure PCTCN2019085535-appb-100002
    Figure PCTCN2019085535-appb-100003
  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，A compound according to claim 1 or 2, a stereoisomer, a tautomer or a mixture thereof, a pharmaceutically acceptable salt, eutectic, polymorph or solvate thereof, or a stable isotope derivative, metabolite or prodrug of a compound, wherein
    R 2选自H、C 1-8烷基、C 2-8烯基、C 2-8炔基、C 3-8环烷基，所述C 1-8烷基、C 2-8烯基、C 2-8炔基、C 3-8环烷基可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、C(O)OR 30、OC(O)R 30、OC(O)NR 31R 32、NR 33C(O)NR 31R 32、NR 31R 32； R 2 is selected from the group consisting of H, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-8 cycloalkyl, said C 1-8 alkyl, C 2-8 alkenyl The C 2-8 alkynyl group, C 3-8 cycloalkyl group may be optionally substituted by 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 group, 4-7 membered heterocyclic group, CN, NO 2 , OR 37 , SR 37 , C(O)R 30 , C(O)NR 31 R 32 , C (O)OR 30 , OC(O)R 30 , OC(O)NR 31 R 32 , NR 33 C(O)NR 31 R 32 , NR 31 R 32 ;
    优选地，R 2选自H、C 1-8烷基、C 3-8环烷基和-CH 2-C 6-12芳基，所述C 1-8烷基、C 3-8环烷基、-CH 2-C 6-12芳基可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、C(O)OR 30、OC(O)R 30、OC(O)NR 31R 32、NR 33C(O)NR 31R 32、NR 31R 32； Preferably, R 2 is selected from the group consisting of H, C 1-8 alkyl, C 3-8 cycloalkyl and -CH 2 -C 6-12 aryl, said C 1-8 alkyl, C 3-8 naphthenic The group, -CH 2 -C 6-12 aryl, may be optionally substituted by one or more of the following substituents: halogen, C 1-4 haloalkyl, C 1-4 hydroxyalkyl, C 1-4 alkane Oxy group, C 1-4 haloalkoxy group, 4-7 membered heterocyclic group, CN, NO 2 , OR 37 , SR 37 , C(O)R 30 , C(O)NR 31 R 32 , C(O) OR 30 , OC(O)R 30 , OC(O)NR 31 R 32 , NR 33 C(O)NR 31 R 32 , NR 31 R 32 ;
    优选地，R 2选自H、C 1-8烷基和C 3-8环烷基，所述C 1-8烷基、C 3-8环烷基可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、C(O)OR 30、OC(O)R 30、OC(O)NR 31R 32、NR 33C(O)NR 31R 32、NR 31R 32； Preferably, R 2 is selected from the group consisting of H, C 1-8 alkyl and C 3-8 cycloalkyl, and the C 1-8 alkyl, C 3-8 cycloalkyl may be optionally included in the following substituents One or more substitutions: halogen, C 1-4 haloalkyl, C 1-4 hydroxyalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy, 4-7 membered heterocyclyl, CN, NO 2 , OR 37 , SR 37 , C(O)R 30 , C(O)NR 31 R 32 , C(O)OR 30 , OC(O)R 30 , OC(O)NR 31 R 32 , NR 33 C (O) NR 31 R 32 , NR 31 R 32 ;
    优选地，R 2选自H、C 1-8烷基和对甲氧基苄基； Preferably, R 2 is selected from the group consisting of H, C 1-8 alkyl and p-methoxybenzyl;
    优选地，R 2选自H、C 1-8烷基(例如C 1-4烷基)，优选地，R 2选自H、甲基和乙基； Preferably, R 2 is selected from H, C 1-8 alkyl (eg C 1-4 alkyl), preferably R 2 is selected from H, methyl and ethyl;
    优选地，R 2选自H和甲基。 Preferably, R 2 is selected from the group consisting of H and methyl.
  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，A compound according to any one of claims 1 to 3, a stereoisomer, a tautomer or a mixture thereof, a pharmaceutically acceptable salt, eutectic, polymorph or solvate thereof. Or a stable isotope derivative, metabolite or prodrug of the compound, wherein
    R 3选自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 2-8杂烷基、C 3-8环烷基、4-10元杂环基、C 6-12芳基、5-10元杂芳基(例如5-6元杂芳基、9-10元杂芳基并环烷基)、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、C(O)OR 30、C(O)NR 31R 32、NR 33C(O)R 34、NR 31R 32、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、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 2-8杂烷基、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元芳基并环烷基可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、-C 6-12芳基-C 1-4烷基、5-10元杂芳基、9-12元芳基并杂环基、-C(O)OR 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、P(R 39) 2、P(OR 39) 2、P(O)R 39R 40、P(O)OR 39OR 30、＝NNR 31R 32； R 3 is selected from the group consisting of C 1-8 alkyl, C 1-8 haloalkyl, C 1-8 alkoxy, C 1-8 haloalkoxy, C 2-8 heteroalkyl, C 3-8 cycloalkyl, 4-10 membered heterocyclic group, C 6-12 aryl group, 5-10 membered heteroaryl group (for example, 5-6 membered heteroaryl group, 9-10 membered heteroarylcycloalkyl group), 9-12 yuan aromatic Heterocyclyl, 9-12 membered arylheteroaryl, 9-12 membered arylcycloalkyl, C(O)OR 30 , C(O)NR 31 R 32 , NR 33 C(O) R 34 , NR 31 R 32 , OR 37 , SR 37 , C(O)R 30 , OC(O)R 30 , OC(O)NR 31 R 32 , NR 33 C(O)NR 31 R 32 , NR 33 C(O)OR 30 , C(=NR 38 )NR 31 R 32 , NR 33 C(=NR 38 )NR 31 R 32 , P(R 39 ) 2 , P(OR 39 ) 2 , P(O)R 39 R 40 , P(O)OR 39 OR 30 , S(O)R 35 , S(O) 2 R 35 , S(O)NR 31 R 32 , S(O) 2 NR 31 R 32 ; 1-8 alkyl, C 1-8 haloalkyl, C 1-8 alkoxy, C 1-8 haloalkoxy, C 2-8 heteroalkyl, C 3-8 cycloalkyl, 4-10 membered Cyclo, C 6-12 aryl, 5-10 membered heteroaryl, 9-12 membered arylheterocyclyl, 9-12 membered arylheteroaryl, 9-12 membered arylcycloalkyl Optionally substituted with one or more of the following substituents: halogen, CN, NO 2 , C 1-4 An alkyl group, a C 3-8 cycloalkyl group, a C 1-4 haloalkyl group, a C 1-4 alkoxy group, a C 1-4 haloalkoxy group, a C 1-4 hydroxyalkyl group, a 4-10 membered heterocyclic group, C 6-12 aryl, -C 6-12 aryl-C 1-4 alkyl, 5-10 membered heteroaryl, 9-12 membered arylheterocyclyl, -C(O)OR 30 , C (O)R 30 , C(O)NR 31 R 32 , -NR 33 C(O)R 34 , -NR 31 R 32 , S(O)R 35 , S(O)2R 35 , S(O)NR 31 R 32 , S(O) 2NR 31 R 32 , OR 37 , SR 37 , OC(O)R 30 , OC(O)NR 31 R 32 , NR 33 C(O)NR 31 R 32 , NR 33 C( O) OR 30 , C(=NR 38 )NR 31 R 32 , NR 33 C(=NR 38 )NR 31 R 32 , P(R 39 ) 2 , P(OR 39 ) 2 , P(O)R 39 R 40 , P(O)OR 39 OR 30 , =NNR 31 R 32 ;
    优选地，R 3选自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 2-8杂烷基、C 3-8环烷基、4-10元杂环基、C 6-12芳基、5-10元杂芳基(例如5-6元杂芳基、9-10元杂芳基并环烷基)、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、OR 37、SR 37、C(O)R 30；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 2-8杂烷基、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元芳基并环烷基可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、-C(O)OR 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、P(R 39) 2、P(OR 39) 2、P(O)R 39R 40、P(O)OR 39OR 30、＝NNR 31R 32； Preferably, R 3 is selected from the group consisting of C 1-8 alkyl, C 1-8 haloalkyl, C 1-8 alkoxy, C 1-8 haloalkoxy, C 2-8 heteroalkyl, C 3-8 ring Alkyl, 4-10 membered heterocyclyl, C 6-12 aryl, 5-10 membered heteroaryl (eg 5-6 membered heteroaryl, 9-10 membered heteroarylcycloalkyl), 9- 12-membered arylheterocyclyl, 9-12 membered arylheteroaryl, 9-12 membered arylcycloalkyl, OR 37 , SR 37 , C(O)R 30 ; said C 1-8 Alkyl, C 1-8 haloalkyl, C 1-8 alkoxy, C 1-8 haloalkoxy, C 2-8 heteroalkyl, C 3-8 cycloalkyl, 4-10 membered heterocyclyl, C 6-12 aryl, 5-10 membered heteroaryl, 9-12 membered arylheterocyclyl, 9-12 membered arylheteroaryl, 9-12 membered arylcycloalkyl group, optionally The ground is substituted by 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, C 6-12 aryl, 5-10 membered heteroaryl, 9-12 membered arylheterocyclyl, -C(O)OR 30 , C(O)R 30 , C(O)NR 31 R 32 , -NR 33 C(O)R 34 , -NR 31 R 32 , S(O)R 35 , S(O ) 2 R 35 , S(O)NR 31 R 32 , S(O) 2 NR 31 R 32 , OR 37 , SR 37 , OC(O)R 30 , OC(O)NR 31 R 32 , NR 33 C(O)NR 31 R 32 , NR 33 C(O)OR 30 , C(=NR 38 ) NR 31 R 32 , NR 33 C(=NR 38 )NR 31 R 32 , P(R 39 ) 2 , P(OR 39 ) 2 , P(O)R 39 R 40 , P(O)OR 39 OR 30 , =NNR 31 R 32 ;
    优选地，R 3选自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(例如5-6元杂芳基、9-10元杂芳基并环烷基)、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、OR 37、SR 37、 C(O)R 30；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、9-12元芳基并环烷基可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、4-7元杂环基、C 6-10芳基、-C 6-10芳基-C 1-4烷基、5-10元杂芳基、9-10元芳基并杂环基、C(O)OR 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； Preferably, R 3 is selected from the group consisting of C 1-8 alkyl, C 1-8 haloalkyl, C 1-8 alkoxy, C 1-8 haloalkoxy, C 3-8 cycloalkyl, 4-10 membered hetero a cyclic group, a C 6-12 aryl group, a 5-10 membered heteroaryl group (for example, a 5-6 membered heteroaryl group, a 9-10 membered heteroarylcycloalkyl group), a 9-12 membered arylheterocyclyl group. , 9-12 membered arylheteroaryl, 9-12 membered arylcycloalkyl, OR 37 , SR 37 , C(O)R 30 ; said C 1-8 alkyl, C 1-8 alkyl halide , C 1-8 alkoxy, C 1-8 haloalkoxy, C 3-8 cycloalkyl, 4-10 membered heterocyclic, C 6-12 aryl, 5-10 membered heteroaryl, 9 The -12-membered arylheterocyclyl, 9-12 membered arylheteroaryl, 9-12 membered arylcycloalkyl group can be 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, 4-7 membered heterocyclic group, C 6-10 aryl group, -C 6-10 aryl-C 1-4 alkyl group, 5-10 membered heteroaryl group, 9-10 membered arylheterocyclyl group, C (O)OR 30 , C(O)R 30 , C(O)NR 31 R 32 , NR 33 C(O)R 34 , NR 31 R 32 , S(O)R 35 , S(O) 2 R 35 , S (O) NR 31 R 32, S (O) 2 NR 31 R 32 OR 37, SR 37, OC ( O) R 30, OC (O) NR 31 R 32, NR 33 C (O) NR 31 R 32, NR 33 C (O) OR 30, C (= NR 38) NR 31 R 32 , NR 33 C(=NR 38 )NR 31 R 32 , =NNR 31 R 32 ;
    优选地，R 3选自H、甲基、乙基、甲氧基、叔丁氧基、苄基、环丙基、苯基、OH、
    Figure PCTCN2019085535-appb-100004
    Figure PCTCN2019085535-appb-100005
    Preferably, R 3 is selected from the group consisting of H, methyl, ethyl, methoxy, tert-butoxy, benzyl, cyclopropyl, phenyl, OH,
    Figure PCTCN2019085535-appb-100004
    Figure PCTCN2019085535-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，所述的化合物具有以下特征中的一个或多个：A compound according to any one of claims 1 to 4, a stereoisomer, a tautomer or a mixture thereof, a pharmaceutically acceptable salt, eutectic, polymorph or solvate thereof. Or a stable isotope derivative, metabolite or prodrug of said compound, said compound having one or more of the following characteristics:
    (1)R 4为氢； (1) R 4 is hydrogen;
    (2)R 5为氢； (2) R 5 is hydrogen;
    (3)r、s、t均为0。(3) r, s, and t are all 0.
  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，A compound according to any one of claims 1 to 5, a stereoisomer, a tautomer or a mixture thereof, a pharmaceutically acceptable salt, eutectic, polymorph or solvate thereof. Or a stable isotope derivative, metabolite or prodrug of the compound, wherein
    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、-C(R 36aR 36b)-、 O、-N(R 33)-、-C(O)-；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、5-10元亚杂芳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、C 1-4烷氧基；n、p、q各自独立地选自0或1； L is -(L 1 ) n -(L 2 ) p -(L 3 ) q -, wherein L 1 , L 2 and L 3 are the same or different and are each independently selected from a C 1-8 alkylene group, C 2-8 alkenylene group, C 2-8 alkynylene group, C 1-8 haloalkylene group, C 1-8 alkyleneoxy group, C 1-8 haloalkyleneoxy group, C 1-8 Hydroxyalkylene, C 3-8 cycloalkylene, 4-10 membered heterocyclylene, C 6-12 arylene, 5-10 membered heteroarylene, -C(R 36a R 36b )-, O, -N(R 33 )-, -C(O)-; the C 1-8 alkylene group, C 2-8 alkenylene group, C 2-8 alkynylene group, C 1-8 halogenated sub An alkyl group, a C 1-8 alkyleneoxy group, a C 1-8 haloalkyleneoxy group, a C 1-8 hydroxyalkylene group, a C 3-8 cycloalkylene group, a 4-10 membered heterocyclylene group, The C 6-12 arylene, 5-10 membered heteroarylene is optionally substituted by one or more of the following substituents: halogen, OH, CN, NO 2 , C 1-6 alkyl, C 1- a 4- haloalkyl group, a C 1-4 hydroxyalkyl group, a C 1-4 alkoxy group; n, p, q are each independently selected from 0 or 1;
    优选地，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 1-4亚烷基、C 1-4亚烷氧基、O、NR 33、-CO-、4-10元杂环基(例如6元含氮单杂环基)和芳基；n、p、q各自独立地选自0或1； Preferably, L is -(L 1 ) n -(L 2 ) p -(L 3 ) q -, wherein L 1 , L 2 and L 3 are the same or different and are each independently selected from C 1-4 An alkyl group, a C 1-4 alkyleneoxy group, O, NR 33 , -CO-, a 4-10 membered heterocyclic group (for example, a 6-membered nitrogen-containing monoheterocyclic group), and an aryl group; n, p, and q are each independently Selected from 0 or 1;
    优选地，L选自以下基团：-(CH 2) 3-O-CH 2-、-(CH 2) 3-、-CH 2-、-(CH 2) 2C(CH 3) 2、-(CH 2) 2-、-(CH 2) 3-O-、4-10元杂环基(例如6元含氮单杂环基)、-O-(CH 2) 3-O-、-(CH 2) 3-(4-10元杂环基)-C(O)-或-(CH 2) 3-O-C 6-12芳基； Preferably, L is selected from the group consisting of -(CH 2 ) 3 -O-CH 2 -, -(CH 2 ) 3 -, -CH 2 -, -(CH 2 ) 2 C(CH 3 ) 2 , - (CH 2 ) 2 -, -(CH 2 ) 3 -O-, 4-10 membered heterocyclic group (for example, 6-membered nitrogen-containing monoheterocyclic group), -O-(CH 2 ) 3 -O-, -( CH 2 ) 3 -(4-10 membered heterocyclyl)-C(O)- or -(CH 2 ) 3 -OC 6-12 aryl;
    优选地，L选自-CH 2-NR 33-CO-、-CH 2-NR 33-；R 33为氢或C 1-4烷基(例如甲基、乙基)； Preferably, L is selected from -CH 2 -NR 33 -CO-, -CH 2 -NR 33 -; R 33 is hydrogen or C 1-4 alkyl (eg methyl, ethyl);
    优选地，L选自以下基团：-(CH 2) 3-O-CH 2-、-(CH 2) 3-、-CH 2-、-(CH 2) 2C(CH 3) 2-、-(CH 2) 2-、-(CH 2) 3-O-、-O-(CH 2) 3O-、-CH 2-N(CH 2CH 3)-CO-、-CH 2-N(CH 2CH 3)-CH 2-、-CH 2-NH-、-NH-(CH 2) 3-、
    Figure PCTCN2019085535-appb-100006
    Preferably, L is selected from the group consisting of -(CH 2 ) 3 -O-CH 2 -, -(CH 2 ) 3 -, -CH 2 -, -(CH 2 ) 2 C(CH 3 ) 2 -, -(CH 2 ) 2 -, -(CH 2 ) 3 -O-, -O-(CH 2 ) 3 O-, -CH 2 -N(CH 2 CH 3 )-CO-, -CH 2 -N ( CH 2 CH 3 )-CH 2 -, -CH 2 -NH-, -NH-(CH 2 ) 3 -,
    Figure PCTCN2019085535-appb-100006
  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，A compound according to any one of claims 1 to 6, a stereoisomer, a tautomer or a mixture thereof, a pharmaceutically acceptable salt, eutectic, polymorph or solvate thereof. Or a stable isotope derivative, metabolite or prodrug of the compound, wherein
    -L-R 3选自以下基团：-C 1-4亚烷基-O-C 1-4亚烷基-C 6-12芳基、-C 1-4亚烷基-OH、-C 1-4亚烷基-(6-10元含氮螺杂环基)、-C 1-4亚烷基-(4-6元含氮单杂环基)、-C 1-4亚烷基-(4-6元含氮单杂环基并4-6元含氧单杂环基)、-C 1-4亚烷基-C(CH 3) 2-OH、-C 1-4亚烷基O-(5-6元含氮单杂芳基并C5-6单环烷基)、-C1-4亚烷基-O-(苯并C5-6单环烷基)、-C1-4亚烷基-O-(苯并5-6元含氮单杂环基)、-C1-4亚烷基-O-(苯并5-6元含氮单杂芳基)、-C1-4亚烷基-O-苯基-(4-6元含氮单杂环基)、-C 1-4亚烷基-O-苯基-(苯并5-6元含氮单杂环基)、-(6元含氮单杂环基)-C 6-12芳基、-C 1-4亚烷基-(苯并5-6元含氮单杂环基)、-C 1-4亚烷基-O-(5-6元含氮单杂芳基)、-NH-C 1-4亚烷基-OH、-O-C 1-4亚烷基-O-苄基、-(4-6元含氮单杂环基)-C 1-4烷氧基、-(4-6元含氮单杂环基)-OH、-C 1-3烷基-(4-6元含氮单杂环基)-OH、-C 1-4亚烷基-O-(4-6元含氮单杂环基)、-CH 2-N(CH 2CH 3)-C(O)-O-C 1-4烷基、-CH 2-N(CH 2CH 3)-CH 2-C(O)-O-C 1-4烷基、-CH 2-N(CH 2CH 3)-C(O)-C 1-4亚烷基-C 6-12芳基、-CH 2-N(CH 2CH 3)-C(O)-(4-6元含氮单杂环基)、-CH 2-N(CH 2CH 3)-C(O)-(5-6元含氮单杂芳基)、-CH 2-NH-C 1-4烷基、-CH 2-N(CH 2CH 3)-C(O)H、-CH 2-N(CH 2CH 3)-C(O)-C 3-8环烷基、-CH 2-N(CH 2CH 3)-C(O)-C 1-4 烷基，其中，4-6元含氮单杂环基、C 6-12芳基、5-6元含氮单杂芳基、5-6元含氮单杂环基可任选地被一个或多个以下的取代基所取代：C 1-3烷基、氧代、-C(O)H、-S(O) 2-C 1-3烷基； -LR 3 is selected from the group consisting of -C 1-4 alkylene-OC 1-4 alkylene-C 6-12 aryl, -C 1-4 alkylene-OH, -C 1-4 Alkyl-(6-10 membered nitrogen-containing spiroheterocyclyl), -C 1-4 alkylene-(4-6 membered nitrogen-containing monoheterocyclic group), -C 1-4 alkylene group-(4- 6-membered nitrogen-containing monoheterocyclic group and 4-6-membered oxygen-containing monoheterocyclic group), -C 1-4 alkylene-C(CH 3 ) 2 -OH, -C 1-4 alkylene group O-( 5-6 membered nitrogen-containing monoheteroaryl and C5-6 monocycloalkyl), -C1-4 alkylene-O-(benzo C5-6 monocycloalkyl), -C1-4 alkylene- O-(benzo-5-6 membered nitrogen-containing monoheterocyclic group), -C1-4 alkylene-O-(benzo-5-6 membered nitrogen-containing monoheteroaryl group), -C1-4 alkylene group- O-phenyl-(4-6 membered nitrogen-containing monoheterocyclic group), -C 1-4 alkylene-O-phenyl-(benzo-5-6 membered nitrogen-containing monoheterocyclic group), -(6 a nitrogen-containing monoheterocyclic group)-C 6-12 aryl group, -C 1-4 alkylene group-(benzo 5-6 membered nitrogen-containing monoheterocyclic group), -C 1-4 alkylene group-O -(5-6 membered nitrogen-containing monoheteroaryl), -NH-C 1-4 alkylene-OH, -OC 1-4 alkylene-O-benzyl, -(4-6 membered nitrogen-containing single Heterocyclyl)-C 1-4 alkoxy, -(4-6 membered nitrogen-containing monoheterocyclic group)-OH, -C 1-3 alkyl-(4-6 membered nitrogen-containing monoheterocyclic group)- OH, -C 1-4 alkylene-O-(4-6 membered nitrogen-containing monoheterocyclic group), -CH 2 -N(CH 2 CH 3 )-C ( O)-OC 1-4 alkyl, -CH 2 -N(CH 2 CH 3 )-CH 2 -C(O)-OC 1-4 alkyl, -CH 2 -N(CH 2 CH 3 )-C (O)-C 1-4 alkylene-C 6-12 aryl, -CH 2 -N(CH 2 CH 3 )-C(O)-(4-6 membered nitrogen-containing monoheterocyclic group), - CH 2 -N(CH 2 CH 3 )-C(O)-(5-6 membered nitrogen-containing monoheteroaryl), -CH 2 -NH-C 1-4 alkyl, -CH 2 -N (CH 2 CH 3 )-C(O)H, -CH 2 -N(CH 2 CH 3 )-C(O)-C 3-8 cycloalkyl, -CH 2 -N(CH 2 CH 3 )-C(O -C 1-4 alkyl, wherein 4-6 membered nitrogen-containing monoheterocyclic group, C 6-12 aryl group, 5-6 membered nitrogen-containing monoheteroaryl group, 5-6 membered nitrogen-containing monoheterocyclic group Optionally substituted with one or more of the following substituents: C 1-3 alkyl, oxo, -C(O)H, -S(O) 2 -C 1-3 alkyl;
    优选地，-L-R 3选自以下基团：-(CH 2) 3-O-CH 2-C 6-12芳基、-(CH 2) 3-OH、-CH 2-(4-6元含氮单杂环基并4-6元含氧单杂环基)、-CH 2-(4-6元含氮单杂环基)、-(CH 2) 2C(CH 3) 2-OH、-(CH 2) 2-(4-6元含氮单杂环基)、-(CH 2) 3-O-(5-6元含氮单杂芳基并C5-6单环烷基)、-(CH2)3-O-(苯并C5-6单环烷基)、-(CH2)3-O-(苯并5-6元含氮单杂环基)、-(CH2)3-O-(苯并5-6元含氮单杂芳基)、-(CH2)3-O-苯基-(4-6元含氮单杂环基)、-(6元含氮单杂环基)-苯基、-(CH 2) 3-(苯并5-6元含氮单杂环基)、-(CH 2) 3-O-(5-6元含氮单杂芳基)、-(CH 2) 3-(6-10元含氮螺杂环基)、-NH-(CH 2) 3-OH、-(CH 2) 3-(4-6元含氮单杂环基)、-O-(CH 2) 3-O-苄基、-(CH 2) 3-(4-6元含氮单杂环基)-OH、-(CH 2) 2-OH、-6元含氮单杂环基-甲氧基、-6元含氮单杂环基-OH、-(CH 2) 3-O-(4-6元含氮单杂环基)、-CH 2-N(CH 2CH 3)-C(O)-O-C 1-4烷基、-CH 2-N(CH 2CH 3)-CH 2-C(O)-O-C 1-4烷基、-CH 2-N(CH 2CH 3)-C(O)-(CH 3) 2-C 6-12芳基、-CH 2-N(CH 2CH 3)-C(O)-(4-6元含氮单杂环基)、-CH 2-N(CH 2CH 3)-C(O)-(5-6元含氮单杂芳基)、-CH 2-NH-CH 2CH 3、-CH 2-N(CH 2CH 3)-C(O)H、-CH 2-N(CH 2CH 3)-C(O)-C 3-8环烷基、-CH 2-N(CH 2CH 3)-C(O)-C 1-4烷基、-CH 2-N(CH 2CH 3)-C(O)-CH 3-C 6-12芳基、-CH 2-N(CH 2CH 3)-CH 2-C(O)-O-C 1-4烷基、-CH 2-(4-6元含氮单杂环基)、-(CH 2) 3-(4-6元含氮单杂环基),其中，4-6元含氮单杂环基、C 6-12芳基、5-6元含氮单杂芳基、5-6元含氮单杂环基可任选地被一个或多个以下的取代基所取代：甲基、乙基、氧代、-C(O)H、-S(O) 2-CH 3； Preferably, -LR 3 is selected from the group consisting of -(CH 2 ) 3 -O-CH 2 -C 6-12 aryl, -(CH 2 ) 3 -OH, -CH 2 - (4-6 yuan) a nitrogen monoheterocyclic group and a 4-6 membered oxygen monoheterocyclic group), -CH 2 - (4-6 membered nitrogen-containing monoheterocyclic group), -(CH 2 ) 2 C(CH 3 ) 2 -OH, -(CH 2 ) 2 -(4-6 membered nitrogen-containing monoheterocyclic group), -(CH 2 ) 3 -O-(5-6 membered nitrogen-containing monoheteroaryl and C5-6 monocycloalkyl group), -(CH2)3-O-(benzo C5-6 monocycloalkyl), -(CH2)3-O-(benzo 5-6 membered nitrogen-containing monoheterocyclic group), -(CH2)3-O -(Benzo-5-6 membered nitrogen-containing monoheteroaryl), -(CH2)3-O-phenyl-(4-6 membered nitrogen-containing monoheterocyclic group), -(6-membered nitrogen-containing monoheterocyclic group) )-phenyl, -(CH 2 ) 3 -(benzo 5-6 membered nitrogen-containing monoheterocyclic group), -(CH 2 ) 3 -O-(5-6 membered nitrogen-containing monoheteroaryl), - (CH 2 ) 3 -(6-10 membered nitrogen-containing spiroheterocyclyl), -NH-(CH 2 ) 3 -OH, -(CH 2 ) 3 - (4-6 membered nitrogen-containing monoheterocyclic group), -O-(CH 2 ) 3 -O-benzyl, -(CH 2 ) 3 -(4-6 membered nitrogen-containing monoheterocyclic)-OH, -(CH 2 ) 2 -OH, -6-membered nitrogen Monoheterocyclyl-methoxy, -6 membered nitrogen-containing monoheterocyclyl-OH, -(CH 2 ) 3 -O-(4-6 membered nitrogen-containing monoheterocyclic group), -CH 2 -N(CH) 2 CH 3 )-C(O)-OC 1-4 alkyl, -CH 2 -N(CH 2 CH 3 )-CH 2 -C(O)-OC 1-4 alkyl , -CH 2 -N(CH 2 CH 3 )-C(O)-(CH 3 ) 2 -C 6-12 aryl, -CH 2 -N(CH 2 CH 3 )-C(O)-(4 -6 membered nitrogen-containing monoheterocyclic group), -CH 2 -N(CH 2 CH 3 )-C(O)-(5-6 membered nitrogen-containing monoheteroaryl group), -CH 2 -NH-CH 2 CH 3 , -CH 2 -N(CH 2 CH 3 )-C(O)H, -CH 2 -N(CH 2 CH 3 )-C(O)-C 3-8 cycloalkyl, -CH 2 -N (CH 2 CH 3 )-C(O)-C 1-4 alkyl, -CH 2 -N(CH 2 CH 3 )-C(O)-CH 3 -C 6-12 aryl, -CH 2 - N(CH 2 CH 3 )-CH 2 -C(O)-OC 1-4 alkyl, -CH 2 -(4-6 membered nitrogen-containing monoheterocyclic group), -(CH 2 ) 3 -(4- 6-membered nitrogen-containing monoheterocyclic group), wherein 4-6 membered nitrogen-containing monoheterocyclic group, C 6-12 aryl group, 5-6 membered nitrogen-containing monoheteroaryl group, 5-6 membered nitrogen-containing monoheterocyclic ring The base may be optionally substituted with one or more of the following substituents: methyl, ethyl, oxo, -C(O)H, -S(O) 2 -CH 3 ;
    优选地，-L-R 3选自以下基团： Preferably, -LR 3 is selected from the group consisting of:
    Figure PCTCN2019085535-appb-100007
    Figure PCTCN2019085535-appb-100008
    Figure PCTCN2019085535-appb-100007
    Figure PCTCN2019085535-appb-100008
  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，所述的化合物具有以下特征中的一个或多个：A compound according to any one of claims 1 to 7, a stereoisomer, a tautomer or a mixture thereof, a pharmaceutically acceptable salt, eutectic, polymorph or solvate thereof. Or a stable isotope derivative, metabolite or prodrug of said compound, said compound having one or more of the following characteristics:
    (1)X 1为CH或NR 7； (1) X 1 is CH or NR 7 ;
    (2)X 2为S或NR 7； (2) X 2 is S or NR 7 ;
    (3)X 1为CH，X 2为S。 (3) X 1 is CH and X 2 is S.
  9. 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，所述的化合物具有式II-1的结构：A compound according to any one of claims 1-8, a stereoisomer, a tautomer or a mixture thereof, a pharmaceutically acceptable salt, eutectic, polymorph or solvate of said compound Or a stable isotope derivative, metabolite or prodrug of said compound having the structure of formula II-1:
    Figure PCTCN2019085535-appb-100009
    Figure PCTCN2019085535-appb-100009
    其中，R 1、R 2、R 3、R 4、R 5、R 6、X 1、X 3、V和L如上述式I所定义。 Wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , X 1 , X 3 , V and L are as defined in the above formula I.
  10. 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，所述的化合物具有式II-2的结构：A compound according to any one of claims 1-8, a stereoisomer, a tautomer or a mixture thereof, a pharmaceutically acceptable salt, eutectic, polymorph or solvate of said compound Or a stable isotope derivative, metabolite or prodrug of said compound having the structure of formula II-2:
    Figure PCTCN2019085535-appb-100010
    Figure PCTCN2019085535-appb-100010
    其中，R 1、R 2、R 3、R 4、R 5、R 6、X 1、X 3、V和L如上述式I所定义。 Wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , X 1 , X 3 , V and L are as defined in the above formula I.
  11. 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，所述的化合物具有式II-3的结构：A compound according to any one of claims 1-8, a stereoisomer, a tautomer or a mixture thereof, a pharmaceutically acceptable salt, eutectic, polymorph or solvate of said compound Or a stable isotope derivative, metabolite or prodrug of said compound having the structure of formula II-3:
    Figure PCTCN2019085535-appb-100011
    Figure PCTCN2019085535-appb-100011
    其中，R 1、R 2、R 3、R 4、R 5、R 6、R 7、X 1、X 3、V和L如上述式I所定义。 Wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , X 1 , X 3 , V and L are as defined in the above formula I.
  12. 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，所述的化合物具有式II-4的结构：A compound according to any one of claims 1-8, a stereoisomer, a tautomer or a mixture thereof, a pharmaceutically acceptable salt, eutectic, polymorph or solvate of said compound Or a stable isotope derivative, metabolite or prodrug of said compound having the structure of formula II-4:
    Figure PCTCN2019085535-appb-100012
    Figure PCTCN2019085535-appb-100012
    其中，R 1、R 2、R 3、R 4、R 5、R 6、X 1、X 3、V和L如上述式I所定义。 Wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , X 1 , X 3 , V and L are as defined in the above formula I.
  13. 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，所述的化合物具有式II-5的结构：A compound according to any one of claims 1-8, a stereoisomer, a tautomer or a mixture thereof, a pharmaceutically acceptable salt, eutectic, polymorph or solvate of said compound Or a stable isotope derivative, metabolite or prodrug of said compound having the structure of formula II-5:
    Figure PCTCN2019085535-appb-100013
    Figure PCTCN2019085535-appb-100013
    其中，R 1、R 2、R 3、R 4、R 5、R 6、X 1、X 3、V和L如上述式I所定义。 Wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , X 1 , X 3 , V and L are as defined in the above formula I.
  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，所述的化合物具有式III-1的结构：A compound according to any one of claims 1-8, a stereoisomer, a tautomer or a mixture thereof, a pharmaceutically acceptable salt, eutectic, polymorph or solvate of said compound Or a stable isotope derivative, metabolite or prodrug of said compound having the structure of formula III-1:
    Figure PCTCN2019085535-appb-100014
    Figure PCTCN2019085535-appb-100014
    其中，R 1、R 2、R 3、R 4、R 5、R 6、X 1、X 2、V和L如上述式I所定义。 Wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , X 1 , X 2 , V and L are as defined in the above formula I.
  15. 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，所述的化合物具有式III-2的结构：A compound according to any one of claims 1-8, a stereoisomer, a tautomer or a mixture thereof, a pharmaceutically acceptable salt, eutectic, polymorph or solvate of said compound Or a stable isotope derivative, metabolite or prodrug of said compound having the structure of formula III-2:
    Figure PCTCN2019085535-appb-100015
    Figure PCTCN2019085535-appb-100015
    其中，R 1、R 2、R 3、R 4、R 5、X 1、X 2、V和L如上述式I所定义。 Wherein R 1 , R 2 , R 3 , R 4 , R 5 , X 1 , X 2 , V and L are as defined in the above formula I.
  16. 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，所述的化合物具有式III-3的结构：A compound according to any one of claims 1-8, a stereoisomer, a tautomer or a mixture thereof, a pharmaceutically acceptable salt, eutectic, polymorph or solvate of said compound Or a stable isotope derivative, metabolite or prodrug of said compound having the structure of formula III-3:
    Figure PCTCN2019085535-appb-100016
    Figure PCTCN2019085535-appb-100016
    其中，R 1、R 3、R 4、R 5、X 1、X 2、V和L如上述式I所定义。 Wherein R 1 , R 3 , R 4 , R 5 , X 1 , X 2 , V and L are as defined in the above formula I.
  17. 权利要求1-9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，所述的化合物具有式IV的结构：A compound according to any one of claims 1 to 9, a stereoisomer, a tautomer or a mixture thereof, a pharmaceutically acceptable salt, eutectic, polymorph or solvate thereof. Or a stable isotope derivative, metabolite or prodrug of said compound having the structure of formula IV:
    Figure PCTCN2019085535-appb-100017
    Figure PCTCN2019085535-appb-100017
    其中，R 1、R 2、R 3、R 4、R 5、R 6、X 3、V和L如上述式II-1所定义。 Wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , X 3 , V and L are as defined in the above formula II-1.
  18. 权利要求1-9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，所述的化合物具有式V的结构：A compound according to any one of claims 1 to 9, a stereoisomer, a tautomer or a mixture thereof, a pharmaceutically acceptable salt, eutectic, polymorph or solvate thereof. Or a stable isotope derivative, metabolite or prodrug of said compound having the structure of formula V:
    Figure PCTCN2019085535-appb-100018
    Figure PCTCN2019085535-appb-100018
    其中，R 1、R 2、R 3、R 4、R 5、R 6、L如上述式II-1所定义。 Wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and L are as defined in the above formula II-1.
  19. 权利要求18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，所述的化合物具有式V-1的结构：A compound according to claim 18, a stereoisomer, a tautomer or a mixture thereof, a pharmaceutically acceptable salt, eutectic, polymorph or solvate of said compound, or a compound a stable isotope derivative, metabolite or prodrug having the structure of formula V-1:
    Figure PCTCN2019085535-appb-100019
    Figure PCTCN2019085535-appb-100019
    其中，R 1、R 2、R 3、R 4、R 5、R 6如上述式V所定义。 Wherein R 1 , R 2 , R 3 , R 4 , R 5 and R 6 are as defined in the above formula V.
  20. 权利要求15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，所述的化合物具有式VI的结构：A compound according to claim 15, a stereoisomer, a tautomer or a mixture thereof, a pharmaceutically acceptable salt, eutectic, polymorph or solvate of said compound, or a compound a stable isotope derivative, metabolite or prodrug having the structure of formula VI:
    Figure PCTCN2019085535-appb-100020
    Figure PCTCN2019085535-appb-100020
    其中，R 1、R 2、R 3、R 4、R 5、L如上述式III-2所定义。 Wherein R 1 , R 2 , R 3 , R 4 , R 5 and L are as defined in the above formula III-2.
  21. 权利要求20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，所述的化合物具有式VI-1的结构：A compound according to claim 20, a stereoisomer, a tautomer or a mixture thereof, a pharmaceutically acceptable salt, eutectic, polymorph or solvate of said compound, or a compound a stable isotope derivative, metabolite or prodrug having the structure of formula VI-1:
    Figure PCTCN2019085535-appb-100021
    Figure PCTCN2019085535-appb-100021
    其中，R 1、R 2、R 3、R 4、R 5如上述式VI所定义。 Wherein R 1 , R 2 , R 3 , R 4 and R 5 are as defined in the above formula VI.
  22. 权利要求16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，所述的化合物具有式VII的结构：A compound according to claim 16, a stereoisomer, a tautomer or a mixture thereof, a pharmaceutically acceptable salt, eutectic, polymorph or solvate of said compound, or a compound a stable isotope derivative, metabolite or prodrug having the structure of formula VII:
    Figure PCTCN2019085535-appb-100022
    Figure PCTCN2019085535-appb-100022
    其中，R 1、R 3、R 4、R 5、L如上述式III-3所定义。 Wherein R 1 , R 3 , R 4 , R 5 and L are as defined in the above formula III-3.
  23. 权利要求22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，所述的化合物具有式VII-1的结构：A compound according to claim 22, a stereoisomer, a tautomer or a mixture thereof, a pharmaceutically acceptable salt, eutectic, polymorph or solvate of said compound, or a compound a stable isotope derivative, metabolite or prodrug having the structure of formula VII-1:
    Figure PCTCN2019085535-appb-100023
    Figure PCTCN2019085535-appb-100023
    其中，R 1、R 3、R 4、R 5如上述式VII所定义。 Wherein R 1 , R 3 , R 4 and R 5 are as defined in the above formula VII.
  24. 权利要求1-23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，所述的化合物选自：A compound according to any one of claims 1 to 23, a stereoisomer, a tautomer or a mixture thereof, a pharmaceutically acceptable salt, eutectic, polymorph or solvate of said compound Or a stable isotope derivative, metabolite or prodrug of said compound selected from the group consisting of:
    Figure PCTCN2019085535-appb-100024
    Figure PCTCN2019085535-appb-100024
    Figure PCTCN2019085535-appb-100025
    Figure PCTCN2019085535-appb-100025
    Figure PCTCN2019085535-appb-100026
    Figure PCTCN2019085535-appb-100026
    Figure PCTCN2019085535-appb-100027
    Figure PCTCN2019085535-appb-100027
  25. 一种药物组合物，其包含权利要求1-24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；A pharmaceutical composition comprising a compound according to any one of claims 1 to 24, a stereoisomer, a tautomer or a mixture thereof, a pharmaceutically acceptable salt, eutectic, a polymorph or solvate, or a stable isotope derivative, metabolite or prodrug of said compound;
    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；Optionally, the pharmaceutical composition further comprises one or more pharmaceutically acceptable carriers;
    优选地，所述药物组合物用于预防、缓解和/或治疗与NLRP3炎症小体活性相关的疾病(例如肿瘤疾病)；Preferably, the pharmaceutical composition is for preventing, alleviating and/or treating a disease associated with NLRP3 inflammatory body activity (eg, a neoplastic disease);
    优选地，所述药物组合物用于预防、缓解和/或治疗细胞增殖异常性疾病(例如癌症)；Preferably, the pharmaceutical composition is for preventing, alleviating and/or treating a cell proliferative disorder (eg cancer);
    任选地，所述药物组合物还包含一种或多种第二治疗剂；Optionally, the pharmaceutical composition further comprises one or more second therapeutic agents;
    优选地，所述第二治疗剂为包括治疗肿瘤疾病的其他药物；Preferably, the second therapeutic agent is other drugs including treating tumor diseases;
    优选地，所述肿瘤疾病选自：肺癌、胰腺癌、乳腺癌、头颈癌、肝癌、黑色素瘤、胶质瘤或肉瘤。Preferably, the tumor disease is selected from the group consisting of lung cancer, pancreatic cancer, breast cancer, head and neck cancer, liver cancer, melanoma, glioma or sarcoma.
  26. 一种药物制剂，其包含权利要求1-24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25的药物组合物。A pharmaceutical preparation comprising a compound according to any one of claims 1 to 24, a stereoisomer, a tautomer or a mixture thereof, a pharmaceutically acceptable salt, a eutectic, or a plurality of A crystalline form or solvate, or a stable isotope derivative, metabolite or prodrug of said compound, or a pharmaceutical composition of claim 25.
  27. 权利要求1-24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25的药物组合物用于制备药物的用途，所述药物用于预防、缓解、和/或治疗与NLRP3炎症小体活性相关的疾病(例如肿瘤疾病)。A compound according to any one of claims 1 to 24, a stereoisomer, a tautomer or a mixture thereof, a pharmaceutically acceptable salt, eutectic, polymorph or solvate of said compound Or a stable isotope derivative, metabolite or prodrug of the compound, or the use of the pharmaceutical composition of claim 25 for the manufacture of a medicament for the prevention, amelioration, and/or treatment of an NLRP3 inflammatory body Activity-related diseases (eg, neoplastic diseases).
  28. 权利要求1-24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25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。A compound according to any one of claims 1 to 24, a stereoisomer, a tautomer or a mixture thereof, a pharmaceutically acceptable salt, eutectic, polymorph or solvate of said compound Or a stable isotope derivative, metabolite or prodrug of the compound, or the use of the pharmaceutical composition of claim 25 for the preparation of a formulation for modulating (e.g., increasing) the activity of an NLRP3 inflammatory body.
  29. 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1-24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25的药物组合物，或者权利要求26的药物制剂。A method of modulating (e.g., increasing) NLRP3 inflammatory body activity in a cell, comprising administering to the cell an effective amount of a compound of any of claims 1-24, the stereoisomers, tautomers of the compound A pharmaceutically acceptable salt, eutectic, polymorph or solvate of the compound, or a stable isotope derivative, metabolite or prodrug of the compound, or a medicament of claim 25 A composition, or the pharmaceutical preparation of claim 26.
  30. 一种用于调节(例如增加)NLRP3炎症小体的活性的试剂盒，所述的试剂盒包括权利要求1-24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25的药物组合物，或者权利要求26的药物制剂。A kit for modulating (e.g., increasing) the activity of an NLRP3 inflammatory steroid comprising a compound according to any one of claims 1 to 24, a stereoisomer, tautomer of the compound Or a mixture thereof, a pharmaceutically acceptable salt, eutectic, polymorph or solvate of the compound, or a stable isotope derivative, metabolite or prodrug of the compound, or the pharmaceutical composition of claim 25. Or the pharmaceutical preparation of claim 26.
  31. 一种治疗与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、缓解、和/或预防有效量的权利要求1-24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，或权利要求25的药物组合物，或者权利要求26的药物制剂；A method of treating a disease associated with NLRP3 inflammatory steroid activity, such as a neoplastic disease, comprising administering to a subject in need thereof a therapeutic, ameliorating, and/or prophylactically effective amount of any of claims 1-24 a compound, a stereoisomer, a tautomer or a mixture thereof, a pharmaceutically acceptable salt, eutectic, polymorph or solvate of the compound, or a stable isotope of the compound a derivative, metabolite or prodrug, or a pharmaceutical composition according to claim 25, or a pharmaceutical preparation according to claim 26;
    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；Optionally, the method further comprises administering to the subject in need thereof one or more second therapeutic agents;
    优选地，所述第二治疗剂为包括治疗肿瘤疾病的其他药物；Preferably, the second therapeutic agent is other drugs including treating tumor diseases;
    优选地，所述肿瘤疾病选自：肺癌、胰腺癌、乳腺癌、头颈癌、肝癌、黑色素瘤、胶质瘤或肉瘤。Preferably, the tumor disease is selected from the group consisting of lung cancer, pancreatic cancer, breast cancer, head and neck cancer, liver cancer, melanoma, glioma or sarcoma.
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