WO2022242724A1 - 一种含氮化合物、含其的偶联物及其应用 - Google Patents

一种含氮化合物、含其的偶联物及其应用 Download PDF

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WO2022242724A1
WO2022242724A1 PCT/CN2022/093953 CN2022093953W WO2022242724A1 WO 2022242724 A1 WO2022242724 A1 WO 2022242724A1 CN 2022093953 W CN2022093953 W CN 2022093953W WO 2022242724 A1 WO2022242724 A1 WO 2022242724A1
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alkyl
group
halogen
independently
cyano
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PCT/CN2022/093953
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English (en)
French (fr)
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仝朝龙
张曼
杨和平
刘小缓
王龙生
任继承
高大新
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上海迪诺医药科技有限公司
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Priority to AU2022279185A priority Critical patent/AU2022279185A1/en
Priority to EP22804044.0A priority patent/EP4342884A1/en
Priority to KR1020237043620A priority patent/KR20240009486A/ko
Priority to CA3218829A priority patent/CA3218829A1/en
Publication of WO2022242724A1 publication Critical patent/WO2022242724A1/zh

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Definitions

  • the invention relates to a nitrogen-containing compound, a conjugate containing it and applications thereof.
  • TLRs The Toll-like receptor family
  • mDC myeloid dendritic cells
  • pDC plasma dendritic cells
  • monocytes and B cells monocytes and B cells (Kawai and Akira, 2010) and the lung.
  • TLR1/2/4/5 and 6 are located in the cell membrane, and their main function is to recognize extracellular macromolecule ligands from bacteria and fungi.
  • TLR3/7/8/9 is located in the endosomal membrane in cells, and its main function is to recognize exogenous nucleic acids from pathogen cells. Although most TLRs function through specific signaling pathways (mainly through MyD88-dependent pathways), different TLRs can coordinate different downstream molecules. The addition of specific TLRs leads to the activation of different cell populations (Schreibelt, et al, 2010) and the production of different patterns of cytokines and other inflammatory mediators (Ghosh, et al, 2006), resulting in different immune responses.
  • TLR8 upon ligand binding, TLR8 forms a dimer and undergoes a conformational change leading to the engagement of the adapter protein MyD88, which recruits interleukin-1 receptor-associated kinases, leading to the activation of downstream signaling pathways, including mitogen-associated protein kinase and the transcription factor NF -B.
  • TLRs located in endosomes mainly TLR7/8/9
  • TLR7/8/9 have been considered as attractive new targets for anticancer immunotherapy (Kanzler, et al, 2007; Kreig 2008; Smits, et al, 2008; Hennessy, et al. al, 2010; Kaczanowska, et al, 2013; Beesu, et al, 2016).
  • TLR7 activates pDCs to respond to viral infection, induces high levels of interferon ⁇ , and induces primary cellular adaptive T cell responses to endogenous viral antigens (Liu, et al, 2009).
  • TLR8 is more widely expressed in different subtypes of immune cells.
  • Treg Regulatory T cells
  • TLR8 signaling was shown to be both necessary and sufficient for reversing the suppressive function of Treg cells leading to strong tumor suppression.
  • TLR8 selective agonists effectively activate a variety of immune cells, including mDCs and monocytes (Gorden, et al, 2005), which can promote the generation of adaptive immune responses against cancer cells (Krug, et al, 2003; Schnurr, et al, 2005).
  • mDCs phagocytize apoptotic and dead tumor cells and then cross-present tumor-associated antigens to CD8+ CTLs more efficiently than pDCs (Berard, et al, 2000; Dalgaard, et al, 2005).
  • activation of mDCs resulting in the release of TNF ⁇ and interleukin 12 (IL-12) can stimulate the activation of T cells and NK cells.
  • Activation of NK cells is the main mechanism of antibody-mediated cytotoxicity (ADCC).
  • ADCC antibody-mediated cytotoxicity
  • TLR8 agonists can directly play an anti-tumor effect independent of its immunomodulatory function (Ignatz-Hoover, et al, 2015). Therefore, TLR8 agonists can not only act as monotherapy, but also improve the efficacy of various chemotherapy and targeted anticancer drugs by enhancing the host immune response.
  • TLR7 and TLR8 have high homology, and can recognize some artificially synthesized small molecules with antiviral effects, such as Imidazoquinolines imidazoquinoline small molecule compounds (ligands of TLR7 and TLR8) .
  • Imidazoquinolines were studied in the guinea pig genital herpes model infected by HSV, and it was found that the compound had less effect on virus replication in vitro, but had a stronger effect in vivo, indicating that this type of compound promoted the production of pro-inflammatory factors and regulatory cytokines by immune cells , resulting in an antiviral response (Int Immunopharmacol 2002; 2:443-451).
  • TLR7 and TLR8 can recognize viral ssRNA.
  • ssRNA viruses are natural ligands of TLR7 and TLR8, such as type I human immunodeficiency virus (HIV), influenza virus, Sendai virus, dengue virus, Newcastle disease virus (NDV), vesicular stomatitis virus (VSV), Hepatitis B virus (HBV) and hepatitis C virus (HCV), etc.
  • TLR8 can recognize antiviral compounds, ssRNA viruses, synthetic oligonucleotides, etc., induce Th1 through MyD88-dependent signaling pathways, inhibit Th2 cytokine secretion and Tregs proliferation, mediate antiviral immunity, and exert anti-infection and anti-allergic effects.
  • TLR8 is currently an attractive therapeutic target. Although there have been many studies on TLRs, there are still huge opportunities to further expand their use and advantages. The compounds and applications described in the present invention will contribute to the development of TLR8 agonists and meet the clinical unmet needs.
  • the technical problem to be solved by the present invention is that the structure of the existing TLR8 agonist is relatively simple. Therefore, the present invention provides a nitrogen-containing compound, a conjugate containing it and applications thereof.
  • the nitrogen-containing compound has a good regulating effect on TLR8, and can effectively treat, alleviate and/or prevent various related diseases caused by immunosuppression, such as cancer or virus infection.
  • the present invention provides a compound represented by formula I, its solvate, its pharmaceutically acceptable salt or the solvate of its pharmaceutically acceptable salt;
  • ⁇ and ⁇ are independently a single bond or a double bond; and, at least one of ⁇ and ⁇ is a single bond;
  • n 0 or 1
  • X 1 is N or CR 2
  • X 2 is N or CR 3
  • X 3 is N or CR 1 ;
  • R 1 , R 2 and R 3 are independently hydrogen, deuterium, halogen, hydroxyl, amino, cyano, alkyl, haloalkyl, -L 2 -OR a or -L 2 -NR a R b ;
  • R and R are independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, Arylalkyl or heteroarylalkyl; said R 4 or R 4' is unsubstituted, or optionally replaced by one or more selected from halogen, cyano, -L 2 -OR a , -L 2 - OC(O)R a , -L 2 -NR a R b , -L 2 -NR a C(O)OR b , -L 2 -NR a C(O)NR a R b , -L 2 -NR b
  • the substituents of C(NR b )NR a R b and -L 2 -C(O)OR b are substituted at any position; or, R 4 and R 4' form a 3-8 member
  • R 5' is absent, or R 5' is -R c , -L 2 -OR a , -L 2 -NR a R b , -L 2 -NR a C(O)OR b , -L 2 -NR a C(O)NR a R b , -L 2 -NR b C(NR b )NR a R b or -L 2 -C(O)OR b ;
  • R 7 is phenyl, 5-6 membered heteroaryl, 3-8 membered heterocycloalkyl or 8-12 membered ring group; said R 7 is unsubstituted, or optionally selected from one or more Substituents of -L 3 -W, -R c , halogen, cyano, nitro, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy and alkylamino are substituted at any position;
  • R 8 and R 8' are independently hydrogen, halogen or alkyl, and said R 8 or R 8' is unsubstituted, or optionally replaced by one or more selected from -L 3 -W, halogen, cyano,
  • the substituents of nitro, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy and alkylamino are substituted at any position;
  • R8 and R8 ' are independent substituents respectively, or R8 and R 8' forms oxo group, thio group, C 1-6 alkylene group, C 3-10 cycloalkyl group or 3-10 membered heterocycloalkyl group together with the carbon atom to which it is connected;
  • the C 1-6 Alkylene, C 3-10 cycloalkyl or 3-10 membered heterocycloalkyl are unsubstituted, or optionally replaced by one or more selected from deuterium, halogen, hydroxyl,
  • R 9 is hydrogen, alkyl, haloalkyl, -L 2 -OR a or -L 2 -NR a R b ;
  • Cy 1 is cycloalkyl, heterocycloalkyl, aryl or heteroaryl; said Cy 1 is unsubstituted, or optionally replaced by one or more selected from halogen, alkyl, haloalkyl, haloalkoxy, Alkenyl, alkynyl, cyano, -R c , -L 4 -SR d , -L 4 -OC(O)R e , -L 4 -C(O)OR e , -L 4 -C(O) R e , -L 4 -C(O)NR e R e' , -L 4 -NR d C(O)R e , -L 4 -NR d S(O) 2 R e , -L 4 -S( O) 1-2 R e , -L 4 -S(O) 2 NR e R e' , -L 4 -OR d and -L 4
  • L 1 , L 2 , L 3 and L 4 are each independently a link, a C 1-6 alkylene group, a C 2-6 alkenylene group or a C 2-6 alkynylene group; said L 1 , L 2 , L or L is unsubstituted, or optionally substituted by one or more substituents selected from oxo, hydroxy, amino, halogen, cyano, alkyl, haloalkyl, alkoxy, and haloalkoxy. any position;
  • Each R a , R b , R d , Re and Re ' are independently -R c , amino, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3 -10 cycloalkyl, 3-10 membered heterocycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl, C 3-10 cycloalkyl, C 1-6 alkyl, 3-10 membered heterocyclic Alkyl C 1-6 alkyl, phenyl C 1-6 alkyl or 5-10 membered heteroaryl C 1-6 alkyl; said R a , R b , R d , R e or R e' are Unsubstituted or optionally 1 to 3 selected from -OR f , -OC(O)-L 4 -R f , -NR f R f' , halogen, cyano, nitro, C 1-6 alkyl , halogenated C
  • Each R f and R f' is independently -R c , -NHR c or C 1-6 alkyl;
  • each R c is independently hydrogen
  • At least one of X 1 , X 2 and X 3 is N;
  • At least one of R 4 and R 4' is replaced by one or more selected from halogen, cyano, -L 2 -OR a , -L 2 -OC(O)R a , -L 2 -NR a R b , -L 2 -NR a C(O)OR b , -L 2 -NR a C(O)NR a R b , -L 2 -NR b C(NR b )NR a R b and -L 2 -
  • the substituent of C(O)OR b is substituted at any position.
  • m can be 1.
  • m can be 1, and R 8 and R 8' are independently unsubstituted alkyl groups; or, R 8 and R 8' form an oxo group or an unsubstituted C 3-10 cycloalkyl.
  • R can be -C(S)-NR 9 -L 1 -R 7 or -NR 9 -L 1 -R 7 ;
  • R can be -NR 9 -L 1 -R 7 .
  • At least one of Xi, X2, and X3 can be N.
  • Xi can be N.
  • X 1 can be N, and X 2 and X 3 are CH.
  • At least one of R 4 and R 4' is replaced by one or more selected from halogen, cyano, -L 2 -OR a , -L 2 -OC(O)R a , -L 2 - NR a R b , -L 2 -NR a C(O)OR b , -L 2 -NR a C(O)NR a R b , -L 2 -NR b C(NR b )NR a R b and -
  • the substituent of L 2 -C(O)OR b is substituted at any position.
  • At least one of R 4 and R 4' is substituted at any position with one or more substituents selected from -L 2 -OR a and -L 2 -NR a R b .
  • R 4 and R 4' are each independently an alkyl group; at least one of said R 4 or R 4' is selected from one or more of -L 2 -OR a and -L 2 -NR The substituents of a R b are substituted at any position.
  • R 4 and R 4' are each independently an alkyl group; at least one of R 4 or R 4' is substituted at any position by a substituent selected from hydroxyl and amino.
  • R 4 and R 4' are each independently an alkyl group; at least one of R 4 or R 4' is substituted at any position by a hydroxyl group.
  • R is -C(O)-NR 9 -L 1 -R 7 , -C(S)-NR 9 -L 1 -R 7 or -NR 9 -L 1 -R 7 ;
  • R 9 is hydrogen, L 1 is a connecting bond, R 7 is an unsubstituted 8-12-membered ring group or a 5-6-membered heteroaryl group substituted by a -L 3 -W;
  • L 3 is a C 1-6 alkylene base, W is -NR d Re ; R d and Re are -R c , and R c is hydrogen.
  • m is 0 or 1; R 8 and R 8' are independently unsubstituted alkyl; or, R 8 and R 8' form an oxo group or unsubstituted C 3-10 cycloalkyl.
  • X 1 is N or CR 2
  • X 2 is N or CR 3
  • X 3 is N or CR 1
  • R 1 , R 2 and R 3 are independently hydrogen, deuterium, halogen or cyano .
  • ⁇ is a double bond and R 5′ is absent; ⁇ is a single bond and R 5 is —NR a R b ; Ra and R b are —R c , and R c is hydrogen.
  • R 4 and R 4' are independently alkyl; said R 4 and R 4' are independently unsubstituted, or optionally replaced by one or more selected from -L 2 -OR
  • the substituents of a and -L 2 -NR a R b are substituted at any position; L 2 is a link; R a and R b are -R c , and R c is hydrogen.
  • R is -C(O)-NR 9 -L 1 -R 7 , -C(S)-NR 9 -L 1 -R 7 or -NR 9 -L 1 -R 7 ;
  • R 9 is hydrogen, L 1 is Linkage,
  • R 7 is an unsubstituted 8-12-membered ring group or a 5-6-membered heteroaryl group substituted by one -L 3 -W;
  • L 3 is C 1-6 alkylene, W is -NR d R e ;
  • n 0 or 1;
  • R 8 and R 8' are independently unsubstituted alkyl groups; or, R 8 and R 8' form an oxo group or an unsubstituted C 3-10 ring together with the carbon atoms they are connected to alkyl;
  • X 1 is N or CR 2
  • X 2 is N or CR 3
  • X 3 is N or CR 1
  • R 1 , R 2 and R 3 are independently hydrogen, deuterium, halogen or cyano
  • ⁇ is a double bond, R 5' does not exist; ⁇ is a single bond, R 5 is -NR a R b ;
  • R 4 and R 4' are independently alkyl; said R 4 and R 4' are independently unsubstituted, or optionally replaced by one or more selected from -L 2 -OR a and -L 2 - The substituent of NR a R b is substituted at any position; L 2 is a connecting bond;
  • R a , R b , R d and R e are -R c , R c is hydrogen;
  • R is -C(S)-NR 9 -L 1 -R 7 or -NR 9 -L 1 -R 7 ;
  • At least one of X 1 , X 2 and X 3 is N;
  • At least one of R 4 and R 4' is substituted at any position by one or more substituents selected from -L 2 -OR a and -L 2 -NR a R b .
  • the 8-12-membered ring group can be ring A and ring B, the ring A is a 5-6-membered heteroaryl group, and the ring B is a 5-6-membered heteroaryl group Heteroalkene ring; in the 5- to 6-membered heteroaryl group, the heteroatoms are selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3; the In the 5- to 6-membered heteroalkene ring, the heteroatoms are selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3.
  • the 8-12-membered ring group can be ring A and ring B, the ring A is a 5-6-membered heteroaryl group, and the ring B is a 5-6-membered heteroaryl group Heteroalkene ring, which is connected to said L1 through said ring A ; in said 5-6 membered heteroaryl group, the heteroatom is N, and the number of heteroatoms is 1 or 2; said In the 5- to 6-membered heteroalkene ring, the heteroatom is N, and the number of heteroatoms is 1 or 2.
  • the 8-12 membered ring group can be can also be
  • the heteroatoms in R7 , in the 5-6 membered heteroaryl group, can be selected from one or more of N, O and S, and the number of heteroatoms can be 1, 2 or 3.
  • the heteroatom in R 7 , in the 5-6 membered heteroaryl group, can be N, and the number of heteroatoms can be 1 or 2.
  • the 5-6 membered heteroaryl in R7 , can be pyridyl or pyridin-3-yl.
  • the C 1-6 alkylene group in L 3 , can be a C 1-3 alkylene group, or it can be -CH 2 -, -CH 2 CH 2 - or -CH 2 CH 2 CH 2 - .
  • the 5-6 membered heteroaryl substituted by one -L 3 -W can be can also be can also be can also be can also be can also be
  • the alkyl group in R 8 and R 8' , can be C 1-6 alkyl, and can also be methyl, ethyl, n-propyl, isopropyl, n-butyl, iso Butyl, sec-butyl or tert-butyl.
  • the C 3-10 cycloalkyl formed by R 8 and R 8′ together with the carbon atom to which they are jointly attached may be a saturated monocyclic group.
  • the C 3-10 cycloalkyl formed by R 8 and R 8' together with the carbon atom they are connected to can be C 3-6 cycloalkyl, and can also be cyclopropyl, cyclobutyl, cyclo Pentyl or cyclohexyl.
  • the halogen can be fluorine, chlorine, bromine or iodine, or can be fluorine.
  • the alkyl group in R 4 and R 4' , can be C 1-6 alkyl, and can also be methyl, ethyl, n-propyl, isopropyl, n-butyl, iso Butyl, sec-butyl or tert-butyl.
  • R 4 is -CH 2 CH 2 OH or -CH 2 CH 2 CH 3 .
  • R 4' is -CH 2 CH 2 OH or -CH 2 CH 2 CH 3 .
  • R 4 is -CH 2 CH 2 OH or -CH 2 CH 2 CH 3 ;
  • R 4' is -CH 2 CH 2 OH or -CH 2 CH 2 CH 3 .
  • ⁇ and ⁇ are independently a single bond or a double bond; and, at least one of ⁇ and ⁇ is a single bond;
  • n 0 or 1
  • X 1 is N or CR 2
  • X 2 is N or CR 3
  • X 3 is N or CR 1
  • m is 1;
  • R 1 , R 2 and R 3 are independently hydrogen, deuterium, halogen, hydroxyl, amino, cyano, alkyl, haloalkyl, -L 2 -OR a or -L 2 -NR a R b ;
  • R and R are independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, Arylalkyl or heteroarylalkyl; said R 4 or R 4' is unsubstituted, or optionally replaced by one or more selected from halogen, cyano, -L 2 -OR a , -L 2 - OC(O)R a , -L 2 -NR a R b , -L 2 -NR a C(O)OR b , -L 2 -NR a C(O)NR a R b , -L 2 -NR b
  • the substituents of C(NR b )NR a R b and -L 2 -C(O)OR b are substituted at any position; or, R 4 and R 4' form a 3-8 member
  • R 5' is absent, or R 5' is -R c , -L 2 -OR a , -L 2 -NR a R b , -L 2 -NR a C(O)OR b , -L 2 -NR a C(O)NR a R b , -L 2 -NR b C(NR b )NR a R b or -L 2 -C(O)OR b ;
  • R 7 is phenyl, 5-6 membered heteroaryl, 3-8 membered heterocycloalkyl or 8-12 membered ring group; said R 7 is unsubstituted, or optionally selected from one or more Substituents of -L 3 -W, -R c , halogen, cyano, nitro, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy and alkylamino are substituted at any position;
  • R 8 and R 8' are independently hydrogen, halogen or alkyl, and said R 8 or R 8' is unsubstituted, or optionally replaced by one or more selected from -L 3 -W, halogen, cyano,
  • the substituents of nitro, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy and alkylamino are substituted at any position;
  • R8 and R8 ' are independent substituents respectively, or R8 and R 8' forms oxo group, thio group, C 1-6 alkylene group, C 3-10 cycloalkyl group or 3-10 membered heterocycloalkyl group together with the carbon atom to which it is connected;
  • the C 1-6 Alkylene, C 3-10 cycloalkyl or 3-10 membered heterocycloalkyl are unsubstituted, or optionally replaced by one or more selected from deuterium, halogen, hydroxyl,
  • R 9 is hydrogen, alkyl, haloalkyl, -L 2 -OR a or -L 2 -NR a R b ;
  • Cy 1 is cycloalkyl, heterocycloalkyl, aryl or heteroaryl; said Cy 1 is unsubstituted, or optionally replaced by one or more selected from halogen, alkyl, haloalkyl, haloalkoxy, Alkenyl, alkynyl, cyano, -R c , -L 4 -SR d , -L 4 -OC(O)R e , -L 4 -C(O)OR e , -L 4 -C(O) R e , -L 4 -C(O)NR e R e' , -L 4 -NR d C(O)R e , -L 4 -NR d S(O) 2 R e , -L 4 -S( O) 1-2 R e , -L 4 -S(O) 2 NR e R e' , -L 4 -OR d and -L 4
  • L 1 , L 2 , L 3 and L 4 are each independently a link, a C 1-6 alkylene group, a C 2-6 alkenylene group or a C 2-6 alkynylene group; said L 1 , L 2 , L or L is unsubstituted, or optionally substituted by one or more substituents selected from oxo, hydroxy, amino, halogen, cyano, alkyl, haloalkyl, alkoxy, and haloalkoxy. any position;
  • Each R a , R b , R d , Re and Re ' are independently -R c , amino, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3 -10 cycloalkyl, 3-10 membered heterocycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl, C 3-10 cycloalkyl, C 1-6 alkyl, 3-10 membered heterocyclic Alkyl C 1-6 alkyl, phenyl C 1-6 alkyl or 5-10 membered heteroaryl C 1-6 alkyl; said R a , R b , R d , R e or R e' are Unsubstituted or optionally 1 to 3 selected from -OR f , -OC(O)-L 4 -R f , -NR f R f' , halogen, cyano, nitro, C 1-6 alkyl , halogenated C
  • Each R f and R f' is independently -R c , -NHR c or C 1-6 alkyl;
  • Each R c is independently hydrogen.
  • ⁇ and ⁇ are independently a single bond or a double bond; and, at least one of ⁇ and ⁇ is a single bond;
  • n 0 or 1
  • X 1 is N or CR 2
  • X 2 is N or CR 3
  • X 3 is N or CR 1
  • m is 1;
  • R 1 , R 2 and R 3 are independently hydrogen, deuterium, halogen, hydroxyl, amino, cyano, alkyl, haloalkyl, -L 2 -OR a or -L 2 -NR a R b ;
  • R and R are independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, Arylalkyl or heteroarylalkyl; said R 4 or R 4' is unsubstituted, or optionally replaced by one or more selected from halogen, cyano, -L 2 -OR a , -L 2 - NR a R b , -L 2 -NR a C(O)OR b , -L 2 -NR a C(O)NR a R b , -L 2 -NR b C(NR b )NR a R b and -
  • the substituent of L 2 -C(O)OR b is substituted at any position; or, R 4 and R 4' form a 3-8 membered heterocycloalkyl group together with the N atom they
  • R 5' is absent, or R 5' is -R c , -L 2 -OR a , -L 2 -NR a R b , -L 2 -NR a C(O)OR b , -L 2 -NR a C(O)NR a R b , -L 2 -NR b C(NR b )NR a R b or -L 2 -C(O)OR b ;
  • R 7 is phenyl, 5-6 membered heteroaryl, 3-8 membered heterocycloalkyl or 8-12 membered ring group; said R 7 is unsubstituted, or optionally selected from one or more Substituents of -L 3 -W, -R c , halogen, cyano, nitro, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy and alkylamino are substituted at any position;
  • R 8 and R 8' are independently hydrogen, halogen or alkyl, and said R 8 or R 8' is unsubstituted, or optionally replaced by one or more selected from -L 3 -W, halogen, cyano,
  • the substituents of nitro, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy and alkylamino are substituted at any position;
  • R8 and R8 ' are independent substituents respectively, or R8 and R 8' forms oxo group, thio group, C 1-6 alkylene group, C 3-10 cycloalkyl group or 3-10 membered heterocycloalkyl group together with the carbon atom to which it is connected;
  • the C 1-6 Alkylene, C 3-10 cycloalkyl or 3-10 membered heterocycloalkyl are unsubstituted, or optionally replaced by one or more selected from deuterium, halogen, hydroxyl,
  • R 9 is hydrogen, alkyl, haloalkyl, -L 2 -OR a or -L 2 -NR a R b ;
  • Cy 1 is cycloalkyl, heterocycloalkyl, aryl or heteroaryl; said Cy 1 is unsubstituted, or optionally replaced by one or more selected from halogen, alkyl, haloalkyl, haloalkoxy, Alkenyl, alkynyl, cyano, -R c , -L 4 -SR d , -L 4 -OC(O)R e , -L 4 -C(O)OR e , -L 4 -C(O) R e , -L 4 -C(O)NR e R e' , -L 4 -NR d C(O)R e , -L 4 -NR d S(O) 2 R e , -L 4 -S( O) 1-2 R e , -L 4 -S(O) 2 NR e R e' , -L 4 -OR d and -L 4
  • L 1 , L 2 , L 3 and L 4 are each independently a link, a C 1-6 alkylene group, a C 2-6 alkenylene group or a C 2-6 alkynylene group; said L 1 , L 2 , L3 or L4 is unsubstituted, or optionally substituted by one or more substituents selected from oxo, hydroxy, amino, halogen, cyano, alkyl, haloalkyl, alkoxy and haloalkoxy in any position;
  • Each R a , R b , R d , Re and Re ' are independently -R c , amino, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3 -10 cycloalkyl, 3-10 membered heterocycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl, C 3-10 cycloalkyl, C 1-6 alkyl, 3-10 membered heterocyclic Alkyl C 1-6 alkyl, phenyl C 1-6 alkyl or 5-10 membered heteroaryl C 1-6 alkyl; said R a , R b , R d , R e or R e' are Unsubstituted or optionally 1 to 3 selected from -OR f , -NR f R f' , halogen, cyano, nitro, C 1-6 alkyl, halogenated C 1-6 alkyl and halogenated The substituent of C 1-6 al
  • Each R f and R f' is independently -R c , -NHR c or C 1-6 alkyl;
  • Each R c is independently hydrogen.
  • X 3 is CR 1 .
  • X 1 is N or CR 2 ; X 2 is CR 3 .
  • X 1 is CR 2 ; X 2 is N.
  • each of R a , R b , R d , Re and Re ' is independently -R c , amino, C 1-6 alkyl, C 2-6 alkenyl, C 2- 6 alkynyl, C 3-10 cycloalkyl, 3-10 membered heterocycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl, C 3-10 cycloalkyl, C 1-6 alkyl, 3-10 membered heterocycloalkyl C 1-6 alkyl, phenyl C 1-6 alkyl or 5-10 membered heteroaryl C 1-6 alkyl; said R a , R b , R d , R e or R e' is unsubstituted or optionally replaced by 1 to 3 selected from -OR f , -OC(O)-(CH 2 ) 1-5 -R f , -NR f R f' , halogen, cyanide
  • R is -C(O) -NR9 -L1 - R7 .
  • R 1 , R 2 and R 3 are independently hydrogen, deuterium, halogen, hydroxyl, amino, cyano, C 1-6 alkyl, halogenated C 1-6 alkyl, -L 2 -OR a or -L 2 -NR a R b .
  • R 1 , R 2 and R 3 are independently H, F, Cl, Br, -CH 3 , -OCH 3 , -CF 3 , -CH 2 F, -CHF 2 , -OCF 3 , -CN or -(CH 2 ) 0-5 -NH 2 .
  • R 1 is H; R 2 is H.
  • R 4 and R 4' are independently hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, 3-8 Heterocycloalkyl, C 6-10 aryl, 5-10 heteroaryl, C 3-8 cycloalkyl C 1-6 alkyl, 3-8 heterocycloalkyl C 1-6 alkyl, C 6-10 aryl C 1-6 alkyl or 5-10 membered heteroaryl C 1-6 alkyl; said R 4 or R 4' is unsubstituted, or optionally 1 to 3 selected from Halogen, cyano, -L 2 -OR a , -L 2 -OC(O)R a , -L 2 -NR a R b , -L 2 -NR a C(O)OR b , -L 2 -NR The substituents of a C(O)NR a R b , -L 2 -NR b
  • R 4 and R 4' are independently C 1-6 alkyl; said R 4 or R 4' is unsubstituted, or optionally replaced by 1 to 3 selected from -OR a , -NR a R b , -OC(O)R a , -NR a C(O)OR b , -NR a C(O)NR a R b , -NR b C(NR b )NR a R b and - The substituent of C(O)OR b is substituted at any position.
  • R 4 is C 1-6 alkyl; said R 4 is unsubstituted or optionally replaced by 1 -OR a , -OC(O)R a , -NR a R b , -NR
  • the substituents of a C(O)OR b , -NR a C(O)NR a R b , -NR b C(NR b )NR a R b or -C(O)OR b are substituted at any position;
  • R 4 ' is a C 1-6 alkyl group; the R 4' is unsubstituted or optionally substituted at any position by 1 to 3 substituents selected from halogen, -OR a and -NR a R b .
  • R 4 and R 4' are independently C 1-6 alkyl; said R 4 or R 4' is unsubstituted or optionally replaced by one selected from halogen, -OR a and - The substituent of NR a R b is substituted at any position.
  • R 4 is -CH 2 CH 2 OH or -CH 2 CH 2 CH 3 ;
  • R 4' is -CH 2 CH 2 OH, -CH 2 CH 2 CH 3 , -CH 2 CH 2 CF 3 or -CH2CH2CHF2 .
  • ⁇ is a double bond
  • ⁇ is a single bond
  • R 5′ is absent
  • R 5 is —NR a R b .
  • ⁇ is a double bond
  • ⁇ is a single bond
  • R 5′ is absent
  • R 5 is —NH 2 .
  • ⁇ is a single bond
  • ⁇ is a double bond
  • R 5′ is H
  • R 5 0.
  • R 8 and R 8' are independently hydrogen, halogen or C 1-6 alkyl; said R 8 or R 8' is unsubstituted, or optionally 1 to 3 selected from- L 3 -W, halogen, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, halogenated C 1-6 alkyl
  • the substituents of , halogenated C 1-6 alkoxy and C 1-6 alkylamino are substituted at any position.
  • R 8 and R 8' are independently C 1-6 alkyl, and the C 1-6 alkyl is preferably methyl.
  • R 8 and R 8' form oxo, thio, C 3-6 cycloalkyl or 3-6 membered heterocycloalkyl together with the carbon atom to which they are jointly attached; the C 3- 6 -cycloalkyl or 3-6 membered heterocycloalkyl is unsubstituted, or optionally replaced by 1 to 3 members selected from deuterium, halogen, hydroxyl, amino, cyano, oxo, C 1-6 alkyl, halogen
  • the substituents substituting C 1-6 alkyl, -L 2 -OR a and -L 2 -NR a R b are substituted at any position.
  • R and R together with the carbon atom to which they are attached form oxo, thio, cyclopropyl, cyclobutyl, azetidinyl or oxetanyl; Cyclopropyl, cyclobutyl, azetidinyl or oxetanyl is unsubstituted, or optionally 1 to 3 selected from deuterium, halogen, hydroxyl, amino, cyano, oxo, C 1 Substituents of -6 alkyl, halogenated C 1-6 alkyl, -L 2 -OR a and -L 2 -NR a R b are substituted at any position.
  • R and R together with the carbon atom to which they are attached form oxo, thio, cyclopropyl or cyclobutyl.
  • R 9 is hydrogen, C 1-6 alkyl, haloC 1-6 alkyl, -L 2 -OR a or -L 2 -NR a R b .
  • R9 is hydrogen
  • Cy 1 is C 3-8 cycloalkyl, 3-8 membered heterocycloalkyl, C 6-10 aryl or 5-10 membered heteroaryl; said Cy 1 is unsubstituted or selected is optionally replaced by 1 to 3 members selected from halogen, cyano, C 1-6 alkyl, halogenated C 1-6 alkyl, halogenated C 1-6 alkoxy, C 2-6 alkenyl, C 2- 6 alkynyl, -L 4 -SR d , -L 4 -OC(O)R e , -L 4 -C(O)OR e , -L 4 -C(O)R e , -L 4 -C( O)NR e R e' , -L 4 -NR d C(O)R e , -L 4 -NR d S(O) 2 R e , -L 4 -S(O) 1-2 R e , - The
  • L 1 is a linkage or a C 1-6 alkylene group; said L 1 is unsubstituted, or optionally replaced by 1 to 3 selected from oxo, halogen, hydroxyl, amino, cyano , C 1-6 alkyl, halogenated C 1-6 alkyl, C 1-6 alkoxy or a substituent of halogenated C 1-6 alkoxy is substituted at any position.
  • L 1 is a linker or -CH 2 -.
  • L 2 is a linkage or a C 1-6 alkylene group; said L 2 is unsubstituted, or optionally replaced by 1 to 3 selected from oxo, halogen, hydroxyl, amino, cyano , C 1-6 alkyl, halogenated C 1-6 alkyl, C 1-6 alkoxy or a substituent of halogenated C 1-6 alkoxy is substituted at any position.
  • L 3 is a linkage or C 1-6 alkylene; said L 3 is unsubstituted, or optionally replaced by 1 to 3 selected from oxo, halogen, hydroxyl, amino, cyano , C 1-6 alkyl, halogenated C 1-6 alkyl, C 1-6 alkoxy or a substituent of halogenated C 1-6 alkoxy is substituted at any position.
  • L 3 is a linker, -CH 2 -, -CH 2 CH 2 -, -CH 2 CH 2 CH 2 -, -CH 2 CH 2 C(CH 3 ) 2 -, -CH 2 CH 2CH2CH2- or -CH2CH ( CH3 ) CH2- .
  • L3 is -CH2- .
  • L 4 is a linkage or C 1-6 alkylene; said L 4 is unsubstituted, or optionally replaced by one or more selected from oxo, halogen, hydroxyl, amino, cyano , C 1-6 alkyl, halogenated C 1-6 alkyl, C 1-6 alkoxy or a substituent of halogenated C 1-6 alkoxy is substituted at any position.
  • the group -L 3 -W is
  • the group -L 3 -W is
  • R 7 is phenyl, 5-6 membered heteroaryl, 3-8 membered heterocycloalkyl or 8-12 membered ring group; said R 7 is unsubstituted, or optionally replaced by 1 to 3 selected from -L 3 -W, halogen, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, halogen Substituents of C 1-6 alkyl, halogenated C 1-6 alkoxy and C 1-6 alkylamino are substituted at any position.
  • R 7 is an 8-12 membered ring group; said R 7 is unsubstituted, or optionally replaced by 1 to 3 members selected from -L 3 -W, halogen, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, halogenated C 1-6 alkyl, halogenated C 1-6 alkoxy and C 1
  • the substituent of -6 alkylamino is substituted at any position.
  • R 7 is The R 7 is unsubstituted, or optionally replaced by 1 to 3 selected from -L 3 -W, halogen, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 Substituents of alkynyl, C 1-6 alkoxy, halogenated C 1-6 alkyl, halogenated C 1-6 alkoxy and C 1-6 alkylamino are substituted at any position.
  • R 7 is
  • R 7 is
  • X 1 is N or CR 2
  • X 2 is N or CR 3
  • X 3 is N or CR 1
  • m is 1.
  • m is 0 or 1;
  • X 1 is N or CR 2
  • X 2 is N or CR 3
  • X 3 is N or CR 1
  • m is 1;
  • R is -C(O)-L 1 -R 7 , -C(O)-NR 9 -L 1 -R 7 or -C(S)-NR 9 -L 1 -R 7 .
  • m is 1;
  • X 1 is N or CR 2
  • X 2 is N or CR 3
  • X 3 is N or CR 1 ;
  • R is -C(O)-L 1 -R 7 , -C(O)-NR 9 -L 1 -R 7 or -C(S)-NR 9 -L 1 -R 7 .
  • the compound shown in formula I is a compound shown in formula IA,
  • R is -C(O)-L 1 -R 7 , -C(O)-NR 9 -L 1 -R 7 or -C(S)-NR 9 -L 1 -R 7 ;
  • X 1 , X 2 , X 3 , R, R 4 , R 4' , R 5 , R 8 and R 8' are as defined above.
  • L is a linker
  • R 8 and R 8' form a C 3-6 cycloalkyl or a 3-6 membered heterocycloalkyl together with the carbon atom to which they are jointly attached; the C 3-6 cycloalkyl or The 3-6 membered heterocycloalkyl is unsubstituted, or optionally replaced by 1 to 3 members selected from deuterium, halogen, hydroxyl, amino, cyano, oxo, C 1-6 alkyl, halogenated C 1-6
  • the substituents of the alkyl group, -L 2 -OR a and -L 2 -NR a R b are substituted at any position.
  • R 8 and R 8' together with the carbon atom to which they are jointly attached form the following group:
  • X1 is CH , X2 is CR3, X3 is CH; m is 1 ; R3 is H or halo.
  • R5 is -NH2 .
  • the compound shown in formula I is a compound shown in formula IB,
  • R is -C(O)-L 1 -R 7 , -C(O)-NR 9 -L 1 -R 7 or -C(S)-NR 9 -L 1 -R 7 ;
  • R 4 is C 1-6 alkyl; said R 4 is optionally substituted by one -OR a at any position;
  • X 1 , X 2 , X 3 , R, R 4' , R 5 , R 8 , R 8' , R a and m are as defined above.
  • R a is H in IB.
  • X 1 is N or CR 2
  • X 2 is N or CR 3
  • X 3 is N or CR 1
  • m is 1
  • L 1 is a linker.
  • R 8 and R 8' form a C 3-6 cycloalkyl group or a 3-6 membered heterocycloalkyl group together with the carbon atom to which they are jointly attached; the C 3-6 cycloalkyl group or The 3-6 membered heterocycloalkyl is unsubstituted, or optionally replaced by 1 to 3 members selected from deuterium, halogen, hydroxyl, amino, cyano, oxo, C 1-6 alkyl, halogenated C 1-6
  • the substituents of the alkyl group, -L 2 -OR a and -L 2 -NR a R b are substituted at any position.
  • R 8 and R 8' together with the carbon atom to which they are jointly attached form the following group:
  • R5 is -NH2 .
  • the compound shown in Formula I is any structure in Table 1:
  • the present invention also provides any of the following nitrogen-containing compounds:
  • the present invention also provides a compound represented by formula II', its solvate, its pharmaceutically acceptable salt or its pharmaceutically acceptable salt solvate,
  • D is the group formed by losing a hydrogen atom in the compound shown in formula I above;
  • LinkerX is linker 2.
  • the D can be the group formed by losing a hydrogen atom at the group R 7 of the compound shown in formula I above.
  • the D can be the group formed by losing a hydrogen atom at the secondary or primary amine of the compound shown in formula I above, that is, through the N atom and the LinkerX connection.
  • the D can be obtained by The a end is connected with the LinkerX.
  • the linker 2 is a monovalent group, through One site is linked to said D.
  • the linker 2 is a conventional linker in the field of ISAC son.
  • the LinkerX can be a degradable linker or a non-degradable linker.
  • the LinkerX can be a linker that can be degraded by lysosomal enzymes.
  • the LinkerX can be any linkerX.
  • the LinkerX can be any linkerX.
  • x 1;
  • u is 1, 2, 3, 4, 5 or 6;
  • w 1;
  • L 5 is p is 1; R 10 is hydrogen; the carbonyl end of said L 5 is connected to said D;
  • Each Z is independently
  • Each R 12a is independently hydrogen, methyl, ethyl, n-propyl, isopropyl, said The carbonyl end of is connected to the amino end of said L5;
  • T is v3 is 1, 2, 3, 4, 5 or 6; the carbonyl end of said T is the same as said The amino-terminal connection of;
  • the compound shown in formula II' can be any organic compound shown in formula II'.
  • D is the group formed by losing a hydrogen atom in the compound shown in formula I above;
  • x 0, 1, 2 or 3;
  • u 0, 1, 2, 3, 4, 5 or 6;
  • w 0, 1, 2, 3, 4, 5 or 6;
  • Each Z is independently and -(CH 2 CH 2 O) o7 -; each o1, o2, o3, o4, o5, o6, o7 is independently 0, 1, 2, 3, 4, 5, 6, 7 or 8; each R 12a , R 12b and R 12c are independently hydrogen, methyl, ethyl, n-propyl, isopropyl, -SO 3 H, each R 13a and each R 13b is independently hydrogen or methyl;
  • Each T is independently -(CH 2 ) v1 -, -(CH 2 CH 2 O) v2 -, v1, v2, v3, v4 and v5 are each independently 1, 2, 3, 4, 5 or 6;
  • the D is a group formed by losing a hydrogen atom at the group R 7 of the compound shown in formula I above;
  • x 1;
  • u is 1, 2, 3, 4, 5 or 6;
  • w 1;
  • L 5 is p is 1; R 10 is hydrogen; the carbonyl end of said L 5 is connected to said D;
  • Each Z is independently
  • Each R 12a is independently hydrogen, methyl, ethyl, n-propyl, isopropyl, said The carbonyl end of is connected to the amino end of said L5;
  • T is v3 is 1, 2, 3, 4, 5 or 6; the carbonyl end of said T is the same as said The amino-terminal connection; M' is The amino terminus of said M' is connected to the non-carbonyl terminus of said T.
  • the L 5 can be any organic compound. In some embodiments, the L 5 can be any organic compound.
  • the carbonyl terminus of said L5 can be attached to said D.
  • said Z can be an amino acid.
  • the Can be a peptide chain.
  • the Can be a dipeptide, tripeptide or tetrapeptide linker.
  • the The carbonyl terminus of can be connected to the amino terminus of said L5.
  • the carbonyl end of T can be combined with the the amino-terminal connection.
  • amino terminus of said M' can be linked to the non-carbonyl terminus of said T.
  • the compound shown in formula II' can be any organic compound shown in formula II'.
  • ⁇ and ⁇ are independently a single bond or a double bond; and, at least one of ⁇ and ⁇ is a single bond;
  • n 0 or 1
  • X 1 is N or CR 2
  • X 2 is N or CR 3
  • X 3 is N or CR 1
  • m is 1;
  • R 1 , R 2 and R 3 are independently hydrogen, deuterium, halogen, hydroxyl, amino, cyano, alkyl, haloalkyl, -L 2 -OR a or -L 2 -NR a R b ;
  • R and R are independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, Arylalkyl or heteroarylalkyl; said R 4 or R 4' is unsubstituted or optionally replaced by one or more selected from halogen, cyano, -L 2 -OR a , -L 2 -OC (O)R a , -L 2 -NR a R b , -L 2 -NR a C(O)OR b , -L 2 -NR a C(O)NR a R b , -L 2 -NR b C (NR b )
  • the substituents of NR a R b and -L 2 -C(O)OR b are substituted at any position; or, R 4 and R 4' form a 3-8 membere
  • R 5' is absent, or R 5' is -R c , -L 2 -OR a , -L 2 -NR a R b , -L 2 -NR a C(O)OR b , -L 2 -NR a C(O)NR a R b , -L 2 -NR b C(NR b )NR a R b or -L 2 -C(O)OR b ;
  • R 7 is phenyl, 5-6 membered heteroaryl, 3-8 membered heterocycloalkyl or 8-12 membered ring group; said R 7 is unsubstituted, or optionally selected from one or more Substituents of -L 3 -W, -R c , halogen, cyano, nitro, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy and alkylamino are substituted at any position;
  • R 8 and R 8' are independently hydrogen, halogen or alkyl, and said R 8 or R 8' is unsubstituted, or optionally replaced by one or more selected from -L 3 -W, halogen, cyano,
  • the substituents of nitro, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy and alkylamino are substituted at any position;
  • R8 and R8 ' are independent substituents respectively, or R8 and R 8' forms oxo group, thio group, C 1-6 alkylene group, C 3-10 cycloalkyl group or 3-10 membered heterocycloalkyl group together with the carbon atom to which it is connected;
  • the C 1-6 Alkylene, C 3-10 cycloalkyl or 3-10 membered heterocycloalkyl are unsubstituted, or optionally replaced by one or more selected from deuterium, halogen, hydroxyl,
  • R 9 is hydrogen, alkyl, haloalkyl, -L 2 -OR a or -L 2 -NR a R b ;
  • Cy 1 is cycloalkyl, heterocycloalkyl, aryl or heteroaryl; said Cy 1 is unsubstituted, or optionally replaced by one or more selected from halogen, alkyl, haloalkyl, haloalkoxy, Alkenyl, alkynyl, cyano, -R c , -L 4 -SR d , -L 4 -OC(O)R e , -L 4 -C(O)OR e , -L 4 -C(O) R e , -L 4 -C(O)NR e R e' , -L 4 -NR d C(O)R e , -L 4 -NR d S(O) 2 R e , -L 4 -S( O) 1-2 R e , -L 4 -S(O) 2 NR e R e' , -L 4 -OR d and -L 4
  • L 1 , L 2 , L 3 and L 4 are each independently a link, a C 1-6 alkylene group, a C 2-6 alkenylene group or a C 2-6 alkynylene group; said L 1 , L 2 , L or L is unsubstituted, or optionally substituted by one or more substituents selected from oxo, hydroxy, amino, halogen, cyano, alkyl, haloalkyl, alkoxy, and haloalkoxy. any position;
  • Each R a , R b , R d , Re and Re ' are independently -R c , amino, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3 -10 cycloalkyl, 3-10 membered heterocycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl, C 3-10 cycloalkyl, C 1-6 alkyl, 3-10 membered heterocyclic Alkyl C 1-6 alkyl, phenyl C 1-6 alkyl or 5-10 membered heteroaryl C 1-6 alkyl; said R a , R b , R d , R e or R e' are Unsubstituted, or optionally 1 to 3 selected from -OR f , -OC(O)-L 4 -R f , -NR f R f' , halogen, cyano, nitro, C 1-6 alkane
  • Each R f and R f' is independently -R c , -NHR c or C 1-6 alkyl;
  • Each R c is independently hydrogen or a link; and at least one R c in D is a link;
  • x 0, 1, 2 or 3;
  • u 0, 1, 2, 3, 4, 5 or 6;
  • w 0, 1, 2, 3, 4, 5 or 6;
  • Each Z is independently and -(CH 2 CH 2 O) o7 -; each o1, o2, o3, o4, o5, o6, o7 is independently 0, 1, 2, 3, 4, 5, 6, 7 or 8; each R 12a , R 12b and R 12c are independently hydrogen, methyl, ethyl, n-propyl, isopropyl, -SO 3 H, each R 13a and each R 13b is independently hydrogen or methyl;
  • Each T is independently -(CH 2 ) v1 -, -(CH 2 CH 2 O) v2 -, v1, v2, v3, v4 and v5 are each independently 1, 2, 3, 4, 5 or 6;
  • the compound shown in formula II' can be any organic compound shown in formula II'.
  • ⁇ and ⁇ are independently a single bond or a double bond; and, at least one of ⁇ and ⁇ is a single bond;
  • n 0 or 1
  • X 1 is N or CR 2
  • X 2 is N or CR 3
  • X 3 is N or CR 1
  • m is 1;
  • R 1 , R 2 and R 3 are independently hydrogen, deuterium, halogen, hydroxyl, amino, cyano, alkyl, haloalkyl, -L 2 -OR a or -L 2 -NR a R b ;
  • R and R are independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, Arylalkyl or heteroarylalkyl; said R 4 or R 4' is unsubstituted or optionally replaced by one or more selected from halogen, cyano, -L 2 -OR a , -L 2 -NR a R b , -L 2 -NR a C(O)OR b , -L 2 -NR a C(O)NR a R b , -L 2 -NR b C(NR b )NR a R b and -L
  • the substituent of 2 -C(O)OR b is substituted at any position; or, R 4 and R 4' form a 3-8 membered heterocycloalkyl group together with the N atoms they are
  • R 5' is absent, or R 5' is -R c , -L 2 -OR a , -L 2 -NR a R b , -L 2 -NR a C(O)OR b , -L 2 -NR a C(O)NR a R b , -L 2 -NR b C(NR b )NR a R b or -L 2 -C(O)OR b ;
  • R 7 is phenyl, 5-6 membered heteroaryl, 3-8 membered heterocycloalkyl or 8-12 membered ring group; said R 7 is unsubstituted, or optionally selected from one or more Substituents of -L 3 -W, -R c , halogen, cyano, nitro, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy and alkylamino are substituted at any position;
  • R 8 and R 8' are independently hydrogen, halogen or alkyl, and said R 8 or R 8' is unsubstituted, or optionally replaced by one or more selected from -L 3 -W, halogen, cyano,
  • the substituents of nitro, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy and alkylamino are substituted at any position;
  • R8 and R8 ' are independent substituents respectively, or R8 and R 8' forms oxo group, thio group, C 1-6 alkylene group, C 3-10 cycloalkyl group or 3-10 membered heterocycloalkyl group together with the carbon atom to which it is connected;
  • the C 1-6 Alkylene, C 3-10 cycloalkyl or 3-10 membered heterocycloalkyl are unsubstituted, or optionally replaced by one or more selected from deuterium, halogen, hydroxyl,
  • R 9 is hydrogen, alkyl, haloalkyl, -L 2 -OR a or -L 2 -NR a R b ;
  • Cy 1 is cycloalkyl, heterocycloalkyl, aryl or heteroaryl; said Cy 1 is unsubstituted, or optionally replaced by one or more selected from halogen, alkyl, haloalkyl, haloalkoxy, Alkenyl, alkynyl, cyano, -R c , -L 4 -SR d , -L 4 -OC(O)R e , -L 4 -C(O)OR e , -L 4 -C(O) R e , -L 4 -C(O)NR e R e' , -L 4 -NR d C(O)R e , -L 4 -NR d S(O) 2 R e , -L 4 -S( O) 1-2 R e , -L 4 -S(O) 2 NR e R e' , -L 4 -OR d and -L 4
  • L 1 , L 2 , L 3 and L 4 are each independently a link, a C 1-6 alkylene group, a C 2-6 alkenylene group or a C 2-6 alkynylene group; said L 1 , L 2 , L or L is unsubstituted, or optionally substituted by one or more substituents selected from oxo, hydroxy, amino, halogen, cyano, alkyl, haloalkyl, alkoxy, and haloalkoxy. any position;
  • Each R a , R b , R d , Re and Re ' are independently -R c , amino, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3 -10 cycloalkyl, 3-10 membered heterocycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl, C 3-10 cycloalkyl, C 1-6 alkyl, 3-10 membered heterocyclic Alkyl C 1-6 alkyl, phenyl C 1-6 alkyl or 5-10 membered heteroaryl C 1-6 alkyl; said R a , R b , R d , R e or R e' are Unsubstituted, or optionally 1 to 3 selected from -OR f , -NR f R f' , halogen, cyano, nitro, C 1-6 alkyl, halogenated C 1-6 alkyl and halogen A substituent substituting C 1-6
  • Each R f and R f' is independently -R c , -NHR c or C 1-6 alkyl;
  • Each R c is independently hydrogen or a link; and at least one R c in D is a link;
  • x 0, 1, 2 or 3;
  • u 0, 1, 2, 3, 4, 5 or 6;
  • w 0, 1, 2, 3, 4, 5 or 6;
  • Each Z is independently and -(CH 2 CH 2 O) o7 -; each o1, o2, o3, o4, o5, o6, o7 is independently 0, 1, 2, 3, 4, 5, 6, 7 or 8; each R 12a , R 12b and R 12c are independently hydrogen, methyl, ethyl, n-propyl, isopropyl, -SO 3 H, each R 13a and each R 13b is independently hydrogen or methyl;
  • Each T is independently -(CH 2 ) v1 -, -(CH 2 CH 2 O) v2 -, v1, v2, v3, v4 and v5 are each independently 1, 2, 3, 4, 5 or 6;
  • M' is N
  • x is 0 or 1.
  • x is 0 or 1
  • -L 5 - is
  • x is 1, -L 5 - is
  • -(T) w - is the connecting key, -(CH 2 CH 2 O) v2 -*,
  • the definitions of v1, v2, v5 and R 12c are as described above; the site marked with * is the site connected with Z.
  • -(Z) u - is The definitions of o1, R 12a and R 12b are as described above; the site marked with * is the site connected with L 5 .
  • -(Z) u - is The definition of o1 is as mentioned above ; the site marked with * is the site connected with L5.
  • -(Z) u - is The definition of o1 is as mentioned above ; the site marked with * is the site connected with L5.
  • X 3 is CR 1 ; X 1 is N; X 2 is CR 3 .
  • X 3 is CR 1 ; X 1 is CR 2 ; X 2 is CR 3 .
  • each of R a , R b , R d , Re and Re ' is independently -R c , amino, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, 3-10 membered heterocycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl, C 3-10 cycloalkyl C 1-6 Alkyl, 3-10 membered heterocycloalkyl C 1-6 alkyl, phenyl C 1-6 alkyl or 5-10 membered heteroaryl C 1-6 alkyl; said R a , R b , R d , Re or Re ' is unsubstituted or optionally replaced by 1 to 3 selected from -OR f , -OC(O)-(CH 2 ) 1-5 -R f , -NR f R f' , The substituents of halogen, cyano, C
  • R is -C(O)-NR 9 -L 1 -R 7 .
  • R 1 , R 2 and R 3 are independently hydrogen, deuterium, halogen, hydroxyl, amino, cyano, C 1-6 alkyl, halogenated C 1-6 alkyl, -L 2 -OR a or -L 2 -NR a R b .
  • R 1 , R 2 and R 3 are independently preferably H, F, Cl, Br, -CH 3 , -OCH 3 , -CF 3 , -CH 2 F, -CHF 2 , -OCF 3 , -CN or -(CH 2 ) 0-5 -NH 2 .
  • R 1 is H; R 2 is H.
  • R 4 and R 4' are independently hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, 3-8 membered heterocycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl, cycloalkyl C 1-6 alkyl, 3-8 membered heterocycloalkyl C 1-6 alkyl, C 6-10 aryl C 1-6 alkyl or 5-10 membered heteroaryl C 1-6 alkyl; said R 4 or R 4' is unsubstituted or optionally replaced by 1 to 3 selected from halogen, Cyano, -L 2 -OR a , -L 2 -OC(O)R a , -L 2 -NR a R b , -L 2 -NR a C(O)OR b , -L 2 -NR a C Substituents of (O)NR a R b
  • R 4 and R 4' are independently C 1-6 alkyl; said R 4 or R 4' is unsubstituted or optionally replaced by 1 to 3 selected from -OR a ⁇ -OC(O)R a ⁇ -NR a R b ⁇ -NR a C(O)OR b ⁇ -NR a C(O)NR a R b ⁇ -NR b C(NR b )NR a R b and the substituent of -C(O)OR b is substituted at any position.
  • R 4 is C 1-6 alkyl; said R 4 is unsubstituted or optionally replaced by 1 -OR a , -OC(O)R a , -NR a R b , -NR a C(O)OR b , -NR a C(O)NR a R b , -NR b C(NR b )NR a R b or -C(O)OR b are substituted at any position ; R 4' is C 1-6 alkyl; said R 4' is unsubstituted or optionally substituted at any position by 1 to 3 substituents selected from halogen, -OR a and -NR a R b .
  • R 4 and R 4' are independently C 1-6 alkyl; said R 4 or R 4' is unsubstituted or optionally replaced by one selected from halogen, -OR
  • the substituents of a and -NR a R b are substituted at any position.
  • R 4 is -CH 2 CH 2 OH or -CH 2 CH 2 CH 3 ;
  • R 4' is -CH 2 CH 2 OH, -CH 2 CH 2 CH 3 , -CH 2 CH 2 CF 3 or -CH 2 CH 2 CHF 2 .
  • ⁇ is a double bond
  • ⁇ is a single bond
  • R 5′ is absent
  • R 5 is —NR a R b .
  • ⁇ is a double bond
  • ⁇ is a single bond
  • R 5′ is absent
  • R 5 is —NH 2 .
  • ⁇ is a single bond
  • ⁇ is a double bond
  • R 5′ is H
  • R 5 0.
  • R 8 and R 8' are independently hydrogen, halogen or C 1-6 alkyl; said R 8 or R 8' is unsubstituted, or optionally replaced by 1 to 3 selected from -L 3 -W, halogen, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, halogenated C 1- Substituents of 6 alkyl, halogenated C 1-6 alkoxy and C 1-6 alkylamino are substituted at any position.
  • R 8 and R 8' are independently C 1-6 alkyl, and the C 1-6 alkyl is preferably methyl.
  • R 8 and R 8' form an oxo group, a thio group, a C 3-6 cycloalkyl group or a 3-6 membered heterocycloalkyl group together with the carbon atoms they are connected to;
  • C 3-6 cycloalkyl or 3-6 membered heterocycloalkyl is unsubstituted, or optionally selected from 1 to 3 selected from deuterium, halogen, hydroxyl, amino, cyano, oxo, C 1-6 alkyl
  • the substituents of , halogenated C 1-6 alkyl, -L 2 -OR a and -L 2 -NR a R b are substituted at any position.
  • R and R together with the carbon atom to which they are attached form oxo, thio, cyclopropyl, cyclobutyl, azetidinyl or oxetanyl ;
  • the cyclopropyl, cyclobutyl, azetidinyl or oxetanyl is unsubstituted, or selectively replaced by 1 to 3 selected from deuterium, halogen, hydroxyl, amino, cyano, oxo , C 1-6 alkyl, halogenated C 1-6 alkyl, -L 2 -OR a and -L 2 -NR a R b are substituted at any position.
  • R and R together with the carbon atom to which they are attached form oxo, thio, cyclopropyl or cyclobutyl.
  • R 9 is hydrogen, C 1-6 alkyl, halogenated C 1-6 alkyl, -L 2 -OR a or -L 2 -NR a R b .
  • R9 is hydrogen
  • Cy 1 is C 3-8 cycloalkyl, 3-8 membered heterocycloalkyl, C 6-10 aryl or 5-10 membered heteroaryl; said Cy 1 is not Substituted or optionally 1 to 3 selected from halogen, cyano, C 1-6 alkyl, halogenated C 1-6 alkyl, halogenated C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, -L 4 -SR d , -L 4 -OC(O)R e , -L 4 -C(O)OR e , -L 4 -C(O)R e , -L 4 -C(O)NR e R e' , -L 4 -NR d C(O)R e , -L 4 -NR d S(O) 2 R e , -L 4 -S(O) 1-2 R e , -L 4 -S(O) 1-2
  • L 1 is a linkage or a C 1-6 alkylene group; said L 1 is unsubstituted, or optionally replaced by 1 to 3 members selected from oxo, halogen, hydroxyl, Substituents of amino, cyano, C 1-6 alkyl, halogenated C 1-6 alkyl, C 1-6 alkoxy or halogenated C 1-6 alkoxy are substituted at any position.
  • L 1 is a linker or -CH 2 -.
  • L 2 is a linkage or C 1-6 alkylene; said L 2 is unsubstituted, or optionally replaced by 1 to 3 selected from oxo, halogen, hydroxyl, amino , cyano, C 1-6 alkyl, halogenated C 1-6 alkyl, C 1-6 alkoxy or a substituent of halogenated C 1-6 alkoxy is substituted at any position.
  • L 3 is a linkage or C 1-6 alkylene; said L 3 is unsubstituted, or optionally replaced by 1 to 3 selected from oxo, halogen, hydroxyl, amino , cyano, C 1-6 alkyl, halogenated C 1-6 alkyl, C 1-6 alkoxy or a substituent of halogenated C 1-6 alkoxy is substituted at any position.
  • L 3 is a linker, -CH 2 -, -CH 2 CH 2 -, -CH 2 CH 2 CH 2 -, -CH 2 CH 2 C(CH 3 ) 2 -, - CH2CH2CH2CH2- or -CH2CH ( CH3 ) CH2- .
  • L3 is -CH2- .
  • L 4 is a linkage or C 1-6 alkylene; said L 4 is unsubstituted, or optionally replaced by 1 to 3 selected from oxo, halogen, hydroxyl, amino , cyano, C 1-6 alkyl, halogenated C 1-6 alkyl, C 1-6 alkoxy or a substituent of halogenated C 1-6 alkoxy is substituted at any position.
  • R 7 is phenyl, 5-6 membered heteroaryl, 3-8 membered heterocycloalkyl or 8-12 membered ring group; said R 7 is unsubstituted, or Optionally selected from one or more of -L 3 -W, -R c , halogen, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1 Substituents of -6 alkoxy, halogenated C 1-6 alkyl, halogenated C 1-6 alkoxy and C 1-6 alkylamino are substituted at any position.
  • R 7 is an 8-12 membered ring group; the R 7 is unsubstituted, or optionally replaced by one or more selected from -L 3 -W, -R c , halogen , cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, halogenated C 1-6 alkyl, halogenated C 1-
  • the substituents of 6 alkoxy and C 1-6 alkylamino are substituted at any position.
  • R is The R 7 is unsubstituted, or optionally replaced by 1 to 3 selected from -L 3 -W, -R c , halogen, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, Substituents of C 2-6 alkynyl, C 1-6 alkoxy, halogenated C 1-6 alkyl, halogenated C 1-6 alkoxy and C 1-6 alkylamino are substituted at any position.
  • R is
  • R is
  • X 1 is N or CR 2
  • X 2 is N or CR 3
  • X 3 is N or CR 1
  • X 1 is CR 2
  • X 2 is CR 3
  • X 3 is When CR is 1 , m is 1.
  • m is 0 or 1;
  • X 1 is N or CR 2
  • X 2 is N or CR 3
  • X 3 is N or CR 1
  • m is 1;
  • R is -C(O)-L 1 -R 7 , -C(O)-NR 9 -L 1 -R 7 or -C(S)-NR 9 -L 1 -R 7 .
  • m 1;
  • X 1 is N or CR 2
  • X 2 is N or CR 3
  • X 3 is N or CR 1 ;
  • R is -C(O)-L 1 -R 7 , -C(O)-NR 9 -L 1 -R 7 or -C(S)-NR 9 -L 1 -R 7 .
  • D is a compound as shown in Formula IA:
  • R is -C(O)-L 1 -R 7 , -C(O)-NR 9 -L 1 -R 7 or -C(S)-NR 9 -L 1 -R 7 ;
  • X 1 , X 2 , X 3 , R, R 4 , R 4' , R 5 , R 8 and R 8' are as defined above.
  • D is a compound as shown in Formula IB:
  • R is -C(O)-L 1 -R 7 , -C(O)-NR 9 -L 1 -R 7 or -C(S)-NR 9 -L 1 -R 7 ;
  • R 4 is C 1-6 alkyl; said R 4 is optionally substituted by one -OR a at any position;
  • X 1 , X 2 , X 3 , R, R 4' , R 5 , R 8 , R 8' , R a and m are as defined above.
  • L is a linker
  • R 8 and R 8' form a C 3-6 cycloalkyl group or a 3-6 membered heterocycloalkyl group together with the carbon atom to which they are jointly attached; the C 3-6 ring Alkyl or 3-6 membered heterocycloalkyl is unsubstituted, or optionally replaced by 1 to 3 members selected from deuterium, halogen, hydroxyl, amino, cyano, oxo, C 1-6 alkyl, halogenated C
  • the substituents of 1-6 alkyl, -L 2 -OR a and -L 2 -NR a R b are substituted at any position.
  • R 8 and R 8' together with the carbon atom to which they are jointly attached form the following group:
  • X 1 is CH
  • X 2 is CR 3
  • X 3 is CH
  • m is 1
  • R 3 is H or halo.
  • R5 is -NH2 .
  • Ra is hydrogen
  • X 1 is N or CR 2
  • X 2 is N or CR 3
  • X 3 is N or CR 1
  • m is 1
  • L 1 is a linkage.
  • R 8 and R 8' form a C 3-6 cycloalkyl group or a 3-6 membered heterocycloalkyl group together with the carbon atom to which they are jointly attached; the C 3-6 ring Alkyl or 3-6 membered heterocycloalkyl is unsubstituted, or optionally replaced by 1 to 3 members selected from deuterium, halogen, hydroxyl, amino, cyano, oxo, C 1-6 alkyl, halogenated C
  • the substituents of 1-6 alkyl, -L 2 -OR a and -L 2 -NR a R b are substituted at any position.
  • R 8 and R 8' together with the carbon atom to which they are jointly attached form the following group:
  • R5 is -NH2 .
  • D is a compound shown in Table 1 and is covalently linked to L5.
  • D is a compound shown in Table 1 , and is covalently linked to L5 through a nitrogen atom in the molecule.
  • the compound shown in formula II' is any of the following structures:
  • the present invention also provides an antibody-immunostimulatory conjugate represented by formula III or a pharmaceutically acceptable salt thereof,
  • Ab is an antibody
  • L is the linker (Linker) connecting Ab and D;
  • D is the group formed by losing a hydrogen atom in the compound shown in formula I above;
  • t is any numerical value of 1-8.
  • said antibody in the antibody-immunostimulatory conjugate shown in formula III or a pharmaceutically acceptable salt thereof, the definitions of some groups are as follows, and the definitions of other groups are as in any other scheme Said (hereinafter referred to as "in some embodiments"): said antibody may comprise one or more antigen-binding domains capable of binding to an antigen.
  • the antibody may comprise one or two antigen-binding domains capable of binding an antigen.
  • the antibody may comprise an antigen-binding domain that binds an antigen.
  • the antibody may comprise only one antigen-binding domain capable of binding the antigen.
  • the antibody may comprise an Fc terminus.
  • the antibody may comprise only one Fc terminus.
  • the antibody may only comprise an antigen-binding domain capable of binding to an antigen and an Fc-terminus.
  • the antibody can be a monoclonal antibody.
  • the antibody may be an anti-HER2 antibody.
  • the antibody may be Trastuzumab (trastuzumab).
  • the D may be a group formed by losing a hydrogen atom at the group R 7 of the compound shown in formula I above.
  • the D can be the group formed by losing a hydrogen atom at the secondary or primary amine of the compound shown in formula I above, that is, through the N atom and the Linker connection.
  • the D can be obtained by The a end is connected with the Linker.
  • the linker is a divalent group connected to the D through a site, Linked to the Ab via another site.
  • the linker is a conventional linker (Linker) in the field of ISAC.
  • the L can be a degradable linker or a non-degradable linker.
  • the L can be a linker that can be degraded by lysosomal enzymes.
  • the L can be any organic compound. In some embodiments, the L can be any organic compound.
  • x 1;
  • u is 1, 2, 3, 4, 5 or 6;
  • w 1;
  • L 5 is p is 1; R 10 is hydrogen; the carbonyl end of said L 5 is connected to said D;
  • Each Z is independently
  • Each R 12a is independently hydrogen, methyl, ethyl, n-propyl, isopropyl, said The carbonyl end of is connected to the amino end of said L5;
  • T is v3 is 1, 2, 3, 4, 5 or 6; the carbonyl end of said T is the same as said The amino-terminal connection of;
  • the Ab is an antibody
  • L is the linker (Linker) connecting Ab and D;
  • D is the group formed by losing a hydrogen atom in the compound shown in formula I above;
  • t is any numerical value of 1-8.
  • Ab is an anti-HER2 monoclonal antibody
  • x 1;
  • u is 1, 2, 3, 4, 5 or 6;
  • w 1;
  • L 5 is p is 1; R 10 is hydrogen; the carbonyl end of said L 5 is connected to said D;
  • Each Z is independently
  • Each R 12a is independently hydrogen, methyl, ethyl, n-propyl, isopropyl, said The carbonyl end of is connected to the amino end of said L5;
  • T is v3 is 1, 2, 3, 4, 5 or 6; the carbonyl end of said T is the same as said The amino-terminal connection of;
  • Said D is the group formed by losing a hydrogen atom at the group R7 in the compound shown in formula I above;
  • t is any numerical value of 1-8.
  • the L 5 can be any organic compound. In some embodiments, the L 5 can be any organic compound.
  • the carbonyl terminus of said L5 can be attached to said D.
  • said Z can be an amino acid.
  • the Can be a peptide chain.
  • the Can be a dipeptide, tripeptide or tetrapeptide linker.
  • the The carbonyl terminus of can be connected to the amino terminus of said L5.
  • the carbonyl end of T can be combined with the the amino-terminal connection.
  • amino terminus of said M may be linked to the non-carbonyl terminus of said T.
  • the t is an integer or a non-integer, and when it is a non-integer, it refers to the antibody shown in formula III -
  • the immunostimulatory conjugate is a mixture of antibody-immunostimulatory conjugates with different coupling ratios; when it is an integer, it can mean that the antibody-immunostimulatory conjugate shown in formula III is single and the coupling ratio is fixed
  • the antibody-immunostimulatory conjugate may also refer to the antibody-immunostimulatory conjugate as shown in Formula III, which is a mixture of antibody-immunostimulatory conjugates with different conjugation ratios.
  • the t can be any value from 2 to 5.
  • the t can be any value from 3 to 5.
  • Ab is an antibody
  • L is the linker (Linker) connecting Ab and D;
  • t is any value from 1 to 8;
  • ⁇ and ⁇ are independently a single bond or a double bond; and, at least one of ⁇ and ⁇ is a single bond;
  • n 0 or 1
  • X 1 is N or CR 2
  • X 2 is N or CR 3
  • X 3 is N or CR 1
  • m is 1;
  • R 1 , R 2 and R 3 are independently hydrogen, deuterium, halogen, hydroxyl, amino, cyano, alkyl, haloalkyl, -L 2 -OR a or -L 2 -NR a R b ;
  • R and R are independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, Arylalkyl or heteroarylalkyl; said R 4 or R 4' is unsubstituted, or optionally replaced by one or more selected from halogen, cyano, -L 2 -OR a , -L 2 - OC(O)R a , -L 2 -NR a R b , -L 2 -NR a C(O)OR b , -L 2 -NR a C(O)NR a R b , -L 2 -NR b
  • the substituents of C(NR b )NR a R b and -L 2 -C(O)OR b are substituted at any position; or, R 4 and R 4' form a 3-8 member
  • R 5' is absent, or R 5' is -R c , -L 2 -OR a , -L 2 -NR a R b , -L 2 -NR a C(O)OR b , -L 2 -NR a C(O)NR a R b , -L 2 -NR b C(NR b )NR a R b or -L 2 -C(O)OR b ;
  • R 7 is phenyl, 5-6 membered heteroaryl, 3-8 membered heterocycloalkyl or 8-12 membered ring group; said R 7 is unsubstituted, or optionally selected from one or more Substituents of -L 3 -W, -R c , halogen, cyano, nitro, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy and alkylamino are substituted at any position;
  • R 8 and R 8' are independently hydrogen, halogen or alkyl, and said R 8 or R 8' is unsubstituted, or optionally replaced by one or more selected from -L 3 -W, halogen, cyano,
  • the substituents of nitro, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy and alkylamino are substituted at any position;
  • R8 and R8 ' are independent substituents respectively, or R8 and R 8' forms oxo group, thio group, C 1-6 alkylene group, C 3-10 cycloalkyl group or 3-10 membered heterocycloalkyl group together with the carbon atom to which it is connected;
  • the C 1-6 Alkylene, C 3-10 cycloalkyl or 3-10 membered heterocycloalkyl are unsubstituted, or optionally replaced by one or more selected from deuterium, halogen, hydroxyl,
  • R 9 is hydrogen, alkyl, haloalkyl, -L 2 -OR a or -L 2 -NR a R b ;
  • Cy 1 is cycloalkyl, heterocycloalkyl, aryl or heteroaryl; said Cy 1 is unsubstituted, or optionally replaced by one or more selected from halogen, alkyl, haloalkyl, haloalkoxy, Alkenyl, alkynyl, cyano, -R c , -L 4 -SR d , -L 4 -OC(O)R e , -L 4 -C(O)OR e , -L 4 -C(O) R e , -L 4 -C(O)NR e R e' , -L 4 -NR d C(O)R e , -L 4 -NR d S(O) 2 R e , -L 4 -S( O) 1-2 R e , -L 4 -S(O) 2 NR e R e' , -L 4 -OR d and -L 4
  • L 1 , L 2 , L 3 and L 4 are each independently a link, a C 1-6 alkylene group, a C 2-6 alkenylene group or a C 2-6 alkynylene group; said L 1 , L 2 , L or L is unsubstituted, or optionally substituted by one or more substituents selected from oxo, hydroxy, amino, halogen, cyano, alkyl, haloalkyl, alkoxy, and haloalkoxy. any position
  • Each R a , R b , R d , Re and Re ' are independently -R c , amino, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3 -10 cycloalkyl, 3-10 membered heterocycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl, C 3-10 cycloalkyl, C 1-6 alkyl, 3-10 membered heterocyclic Alkyl C 1-6 alkyl, phenyl C 1-6 alkyl or 5-10 membered heteroaryl C 1-6 alkyl; said R a , R b , R d , R e or R e' are Unsubstituted or optionally 1 to 3 selected from -OR f , -OC(O)-L 4 -R f , -NR f R f' , halogen, cyano, nitro, C 1-6 alkyl , halogenated C
  • Each R f and R f' is independently -R c , -NHR c or C 1-6 alkyl;
  • Each R c is independently hydrogen or a linkage to L; and at least one R c in D is a linkage to L.
  • Ab is an antibody
  • L is the linker (Linker) connecting Ab and D;
  • t is any value from 1 to 8;
  • D is a compound as shown in formula I, its stereoisomer or a pharmaceutically acceptable salt thereof:
  • ⁇ and ⁇ are independently a single bond or a double bond; and, at least one of ⁇ and ⁇ is a single bond;
  • n 0 or 1
  • X 1 is N or CR 2
  • X 2 is N or CR 3
  • X 3 is N or CR 1
  • m is 1;
  • R 1 , R 2 and R 3 are independently hydrogen, deuterium, halogen, hydroxyl, amino, cyano, alkyl, haloalkyl, -L 2 -OR a or -L 2 -NR a R b ;
  • R and R are independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, Arylalkyl or heteroarylalkyl; said R 4 or R 4' is unsubstituted, or optionally replaced by one or more selected from halogen, cyano, -L 2 -OR a , -L 2 - NR a R b , -L 2 -NR a C(O)OR b , -L 2 -NR a C(O)NR a R b , -L 2 -NR b C(NR b )NR a R b and -
  • the substituent of L 2 -C(O)OR b is substituted at any position; or, R 4 and R 4' form a 3-8 membered heterocycloalkyl group together with the N atom they
  • R 5' is absent, or R 5' is -R c , -L 2 -OR a , -L 2 -NR a R b , -L 2 -NR a C(O)OR b , -L 2 -NR a C(O)NR a R b , -L 2 -NR b C(NR b )NR a R b or -L 2 -C(O)OR b ;
  • R 7 is phenyl, 5-6 membered heteroaryl, 3-8 membered heterocycloalkyl or 8-12 membered ring group; said R 7 is unsubstituted, or optionally selected from one or more Substituents of -L 3 -W, -R c , halogen, cyano, nitro, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy and alkylamino are substituted at any position;
  • R 8 and R 8' are independently hydrogen, halogen or alkyl, and said R 8 or R 8' is unsubstituted, or optionally replaced by one or more selected from -L 3 -W, halogen, cyano,
  • the substituents of nitro, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy and alkylamino are substituted at any position;
  • R8 and R8 ' are independent substituents respectively, or R8 and R 8' forms oxo group, thio group, C 1-6 alkylene group, C 3-10 cycloalkyl group or 3-10 membered heterocycloalkyl group together with the carbon atom to which it is connected;
  • the C 1-6 Alkylene, C 3-10 cycloalkyl or 3-10 membered heterocycloalkyl are unsubstituted, or optionally replaced by one or more selected from deuterium, halogen, hydroxyl,
  • R 9 is hydrogen, alkyl, haloalkyl, -L 2 -OR a or -L 2 -NR a R b ;
  • Cy 1 is cycloalkyl, heterocycloalkyl, aryl or heteroaryl; said Cy 1 is unsubstituted, or optionally replaced by one or more selected from halogen, alkyl, haloalkyl, haloalkoxy, Alkenyl, alkynyl, cyano, -R c , -L 4 -SR d , -L 4 -OC(O)R e , -L 4 -C(O)OR e , -L 4 -C(O) R e , -L 4 -C(O)NR e R e' , -L 4 -NR d C(O)R e , -L 4 -NR d S(O) 2 R e , -L 4 -S( O) 1-2 R e , -L 4 -S(O) 2 NR e R e' , -L 4 -OR d and -L 4
  • L 1 , L 2 , L 3 and L 4 are each independently a link, a C 1-6 alkylene group, a C 2-6 alkenylene group or a C 2-6 alkynylene group; said L 1 , L 2 , L or L is unsubstituted, or optionally substituted by one or more substituents selected from oxo, hydroxy, amino, halogen, cyano, alkyl, haloalkyl, alkoxy, and haloalkoxy. any position
  • Each R a , R b , R d , Re and Re ' are independently -R c , amino, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3 -10 cycloalkyl, 3-10 membered heterocycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl, C 3-10 cycloalkyl, C 1-6 alkyl, 3-10 membered heterocyclic Alkyl C 1-6 alkyl, phenyl C 1-6 alkyl or 5-10 membered heteroaryl C 1-6 alkyl; said R a , R b , R d , R e or R e' are Unsubstituted or optionally 1 to 3 selected from -OR f , -NR f R f' , halogen, cyano, nitro, C 1-6 alkyl, halogenated C 1-6 alkyl and halogenated The substituent of C 1-6 al
  • Each R f and R f' is independently -R c , -NHR c or C 1-6 alkyl;
  • Each R c is independently hydrogen or a linkage to L; and at least one R c in D is a linkage to L.
  • the Linker is a degradable linker.
  • the Linker is a non-degradable linker.
  • the Linker is degradable by lysosomal enzymes.
  • the Linker is -[(L 5 ) x -(Z) u -(T) w ] y -M-; x is 0, 1, 2 or 3; u is 0, 1, 2 , 3, 4, 5 or 6; w is 0, 1, 2, 3, 4, 5 or 6; y is 1, 2 or 3;
  • Each Z is independently and -(CH 2 CH 2 O) o7 -; each o1, o2, o3, o4, o5, o6, o7 is independently 0, 1, 2, 3, 4, 5, 6, 7 or 8; each R 12a , R 12b and R 12c are independently hydrogen, methyl, ethyl, n-propyl, isopropyl, -SO 3 H, each R 13a and each R 13b is independently hydrogen or methyl;
  • Each T is independently -(CH 2 ) v1 -, -(CH 2 CH 2 O) v2 -, v1, v2, v3, v4 and v5 are each independently 1, 2, 3, 4, 5 or 6;
  • M is the connection key or connector (for example: *The marked site is the site linked to Ab).
  • the Linker is -(L 5 ) x -(Z) u -(T) w -M-; x is 0, 1 or 2; u is 0, 1, 2, 3, 4 or 5; w is 1, 2 or 3.
  • -L 5 - is
  • -L 5 - is
  • -(T) w - is the connecting key, -(CH 2 CH 2 O) v2 -*,
  • the definitions of v1, v2, v5 and R 12c are as described above; the site marked with * is the site connected with Z.
  • -(Z) u - is The definitions of o1, R 12a and R 12b are as described above; the site marked with * is the site connected with L 5 .
  • -(Z) u - is The definition of o1 is as mentioned above ; the site marked with * is the site connected with L5.
  • -(Z) u - is The definition of o1 is as mentioned above ; the site marked with * is the site connected with L5.
  • the Linker is any of the following structures:
  • the Linker is any of the following structures:
  • the Ab is an antibody comprising an antigen binding domain that binds an antigen.
  • the Ab is an antibody comprising an antigen-binding domain capable of binding an antigen and an Fc-terminus.
  • the Ab is an antibody comprising an antigen binding domain that binds HER2.
  • the Ab is an anti-HER2 monoclonal antibody or antibody fragment thereof.
  • the anti-HER2 monoclonal antibodies include, but are not limited to: Trastuzumab (trastuzumab), Trastuzumab biosimilar (trastuzumab biosimilar), Pertuzumab (pertuzumab), Pertuzumab biosimilar (Pertuzumab biosimilar), Margetuximab, HT-19, etc.
  • the antibody is Trastuzumab, Pertuzumab, Margetuximab, or HT-19.
  • t is any value from 1-6 or 1-5.
  • t is any value from 2-8, 2-6, or 2-5.
  • t is any value between 3-6 or 3-5.
  • X 3 is CR 1 ; X 1 is N; X 2 is CR 3 .
  • X 3 is CR 1 ; X 1 is CR 2 ; X 2 is CR 3 .
  • each of R a , R b , R d , Re and Re ' is independently -R c , amino, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, 3-10 membered heterocycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl, C 3-10 cycloalkyl C 1-6 Alkyl, 3-10 membered heterocycloalkyl C 1-6 alkyl, phenyl C 1-6 alkyl or 5-10 membered heteroaryl C 1-6 alkyl; said R a , R b , R d , Re or Re ' is unsubstituted or optionally replaced by 1 to 3 selected from -OR f , -OC(O)-(CH 2 ) 1-5 -R f , -NR f R f' , The substituents of halogen, cyano, C
  • R is -C(O)-NR 9 -L 1 -R 7 .
  • R 1 , R 2 and R 3 are independently hydrogen, deuterium, halogen, hydroxyl, amino, cyano, C 1-6 alkyl, halogenated C 1-6 alkyl, -L 2 -OR a or -L 2 -NR a R b .
  • R 1 , R 2 and R 3 are independently preferably H, F, Cl, Br, -CH 3 , -OCH 3 , -CF 3 , -CH 2 F, -CHF 2 , -OCF 3 , -CN or -(CH 2 ) 0-5 -NH 2 .
  • R 1 is H; R 2 is H.
  • R 4 and R 4' are independently hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, 3-8 membered heterocycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl, cycloalkyl C 1-6 alkyl, 3-8 membered heterocycloalkyl C 1-6 alkyl, C 6-10 aryl C 1-6 alkyl or 5-10 membered heteroaryl C 1-6 alkyl; said R 4 or R 4' is unsubstituted or optionally replaced by 1 to 3 selected from halogen, Cyano, -L 2 -OR a , -L 2 -OC(O)R a , -L 2 -NR a R b , -L 2 -NR a C(O)OR b , -L 2 -NR a C Substituents of (O)NR a R b
  • R 4 and R 4' are independently C 1-6 alkyl; said R 4 or R 4' is unsubstituted or optionally replaced by 1 to 3 selected from -OR a ⁇ -OC(O)R a ⁇ -NR a R b ⁇ -NR a C(O)OR b ⁇ -NR a C(O)NR a R b ⁇ -NR b C(NR b )NR a R b and the substituent of -C(O)OR b is substituted at any position.
  • R 4 is C 1-6 alkyl; said R 4 is unsubstituted or optionally replaced by 1 -OR a , -OC(O)R a , -NR a R b , -NR a C(O)OR b , -NR a C(O)NR a R b , -NR b C(NR b )NR a R b or -C(O)OR b are substituted at any position ; R 4' is C 1-6 alkyl; said R 4' is unsubstituted or optionally substituted at any position by 1 to 3 substituents selected from halogen, -OR a and -NR a R b .
  • R 4 and R 4' are independently C 1-6 alkyl; said R 4 or R 4' is unsubstituted or optionally replaced by one selected from halogen, -OR
  • the substituents of a and -NR a R b are substituted at any position.
  • R 4 is -CH 2 CH 2 OH or -CH 2 CH 2 CH 3 ;
  • R 4' is -CH 2 CH 2 OH, -CH 2 CH 2 CH 3 , -CH 2 CH 2 CF 3 or -CH 2 CH 2 CHF 2 .
  • ⁇ is a double bond
  • ⁇ is a single bond
  • R 5′ is absent
  • R 5 is —NR a R b .
  • ⁇ is a double bond
  • ⁇ is a single bond
  • R 5′ is absent
  • R 5 is —NH 2 .
  • ⁇ is a single bond
  • ⁇ is a double bond
  • R 5′ is H
  • R 5 0.
  • R 8 and R 8' are independently hydrogen, halogen or C 1-6 alkyl; said R 8 or R 8' is unsubstituted, or optionally replaced by 1 to 3 selected from -L 3 -W, halogen, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, halogenated C 1- Substituents of 6 alkyl, halogenated C 1-6 alkoxy and C 1-6 alkylamino are substituted at any position.
  • R 8 and R 8' are independently C 1-6 alkyl, and the C 1-6 alkyl is preferably methyl.
  • R 8 and R 8' form an oxo group, a thio group, a C 3-6 cycloalkyl group or a 3-6 membered heterocycloalkyl group together with the carbon atoms they are connected to;
  • C 3-6 cycloalkyl or 3-6 membered heterocycloalkyl is unsubstituted, or optionally selected from 1 to 3 selected from deuterium, halogen, hydroxyl, amino, cyano, oxo, C 1-6 alkyl
  • the substituents of , halogenated C 1-6 alkyl, -L 2 -OR a and -L 2 -NR a R b are substituted at any position.
  • R and R together with the carbon atom to which they are attached form oxo, thio, cyclopropyl, cyclobutyl, azetidinyl or oxetanyl ;
  • the cyclopropyl, cyclobutyl, azetidinyl or oxetanyl is unsubstituted, or selectively replaced by 1 to 3 selected from deuterium, halogen, hydroxyl, amino, cyano, oxo , C 1-6 alkyl, halogenated C 1-6 alkyl, -L 2 -OR a and -L 2 -NR a R b are substituted at any position.
  • R and R together with the carbon atom to which they are attached form oxo, thio, cyclopropyl or cyclobutyl.
  • R 9 is hydrogen, C 1-6 alkyl, halogenated C 1-6 alkyl, -L 2 -OR a or -L 2 -NR a R b .
  • R9 is hydrogen
  • Cy 1 is C 3-8 cycloalkyl, 3-8 membered heterocycloalkyl, C 6-10 aryl or 5-10 membered heteroaryl; said Cy 1 is not Substituted or optionally 1 to 3 selected from halogen, cyano, C 1-6 alkyl, halogenated C 1-6 alkyl, halogenated C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, -L 4 -SR d , -L 4 -OC(O)R e , -L 4 -C(O)OR e , -L 4 -C(O)R e , -L 4 -C(O)NR e R e' , -L 4 -NR d C(O)R e , -L 4 -NR d S(O) 2 R e , -L 4 -S(O) 1-2 R e , -L 4 -S(O) 1-2
  • L 1 is a linkage or a C 1-6 alkylene group; said L 1 is unsubstituted, or optionally replaced by 1 to 3 members selected from oxo, halogen, hydroxyl, Substituents of amino, cyano, C 1-6 alkyl, halogenated C 1-6 alkyl, C 1-6 alkoxy or halogenated C 1-6 alkoxy are substituted at any position.
  • L 1 is a linker or -CH 2 -.
  • L 2 is a linkage or C 1-6 alkylene; said L 2 is unsubstituted, or optionally replaced by 1 to 3 selected from oxo, halogen, hydroxyl, amino , cyano, C 1-6 alkyl, halogenated C 1-6 alkyl, C 1-6 alkoxy or a substituent of halogenated C 1-6 alkoxy is substituted at any position.
  • L 3 is a linkage or C 1-6 alkylene; said L 3 is unsubstituted, or optionally replaced by 1 to 3 selected from oxo, halogen, hydroxyl, amino , cyano, C 1-6 alkyl, halogenated C 1-6 alkyl, C 1-6 alkoxy or a substituent of halogenated C 1-6 alkoxy is substituted at any position.
  • L 3 is a linker, -CH 2 -, -CH 2 CH 2 -, -CH 2 CH 2 CH 2 -, -CH 2 CH 2 C(CH 3 ) 2 -, - CH2CH2CH2CH2- or -CH2CH ( CH3 ) CH2- .
  • L3 is -CH2- .
  • L 4 is a linkage or C 1-6 alkylene; said L 4 is unsubstituted, or optionally replaced by 1 to 3 selected from oxo, halogen, hydroxyl, amino , cyano, C 1-6 alkyl, halogenated C 1-6 alkyl, C 1-6 alkoxy or a substituent of halogenated C 1-6 alkoxy is substituted at any position.
  • R 7 is phenyl, 5-6 membered heteroaryl, 3-8 membered heterocycloalkyl or 8-12 membered ring group; said R 7 is unsubstituted, or Optionally selected from one or more of -L 3 -W, -R c , halogen, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1 Substituents of -6 alkoxy, halogenated C 1-6 alkyl, halogenated C 1-6 alkoxy and C 1-6 alkylamino are substituted at any position.
  • R 7 is an 8-12 membered ring group; the R 7 is unsubstituted, or optionally replaced by one or more selected from -L 3 -W, -R c , halogen , cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, halogenated C 1-6 alkyl, halogenated C 1-
  • the substituents of 6 alkoxy and C 1-6 alkylamino are substituted at any position.
  • R is The R 7 is unsubstituted, or optionally replaced by 1 to 3 selected from -L 3 -W, -R c , halogen, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, Substituents of C 2-6 alkynyl, C 1-6 alkoxy, halogenated C 1-6 alkyl, halogenated C 1-6 alkoxy and C 1-6 alkylamino are substituted at any position.
  • R is
  • R is
  • X 1 is N or CR 2
  • X 2 is N or CR 3
  • X 3 is N or CR 1
  • X 1 is CR 2
  • X 2 is CR 3
  • X 3 is When CR is 1 , m is 1.
  • m is 0 or 1;
  • X 1 is N or CR 2
  • X 2 is N or CR 3
  • X 3 is N or CR 1
  • m is 1;
  • R is -C(O)-L 1 -R 7 , -C(O)-NR 9 -L 1 -R 7 or -C(S)-NR 9 -L 1 -R 7 .
  • m 1;
  • X 1 is N or CR 2
  • X 2 is N or CR 3
  • X 3 is N or CR 1 ;
  • R is -C(O)-L 1 -R 7 , -C(O)-NR 9 -L 1 -R 7 or -C(S)-NR 9 -L 1 -R 7 .
  • D is a compound as shown in Formula IA:
  • R is -C(O)-L 1 -R 7 , -C(O)-NR 9 -L 1 -R 7 or -C(S)-NR 9 -L 1 -R 7 ;
  • X 1 , X 2 , X 3 , R, R 4 , R 4' , R 5 , R 8 and R 8' are as defined above.
  • D is a compound as shown in Formula IB:
  • R is -C(O)-L 1 -R 7 , -C(O)-NR 9 -L 1 -R 7 or -C(S)-NR 9 -L 1 -R 7 ;
  • R 4 is C 1-6 alkyl; said R 4 is optionally substituted by one -OR a at any position;
  • X 1 , X 2 , X 3 , R, R 4' , R 5 , R 8 , R 8' , R a and m are as defined above.
  • L is a linker
  • R 8 and R 8' form a C 3-6 cycloalkyl group or a 3-6 membered heterocycloalkyl group together with the carbon atom to which they are jointly attached; the C 3-6 ring Alkyl or 3-6 membered heterocycloalkyl is unsubstituted, or optionally replaced by 1 to 3 members selected from deuterium, halogen, hydroxyl, amino, cyano, oxo, C 1-6 alkyl, halogenated C
  • the substituents of 1-6 alkyl, -L 2 -OR a and -L 2 -NR a R b are substituted at any position.
  • R 8 and R 8' together with the carbon atom to which they are jointly attached form the following group:
  • X 1 is CH
  • X 2 is CR 3
  • X 3 is CH
  • m is 1
  • R 3 is H or halo.
  • R5 is -NH2 .
  • Ra is hydrogen
  • X 1 is N or CR 2
  • X 2 is N or CR 3
  • X 3 is N or CR 1
  • m is 1
  • L 1 is a linkage.
  • R 8 and R 8' form a C 3-6 cycloalkyl group or a 3-6 membered heterocycloalkyl group together with the carbon atom to which they are jointly attached; the C 3-6 ring Alkyl or 3-6 membered heterocycloalkyl is unsubstituted, or optionally replaced by 1 to 3 members selected from deuterium, halogen, hydroxyl, amino, cyano, oxo, C 1-6 alkyl, halogenated C
  • the substituents of 1-6 alkyl, -L 2 -OR a and -L 2 -NR a R b are substituted at any position.
  • R 8 and R 8' together with the carbon atom to which they are jointly attached form the following group:
  • R5 is -NH2 .
  • D is a compound shown in Table 1, and is covalently linked to Linker.
  • D is a compound shown in Table 1, and is covalently linked to the Linker through a nitrogen atom in the molecule.
  • the antibody-immunostimulatory conjugate shown in formula III is any of the following structures:
  • the antibody-immunostimulatory conjugate shown in formula III is any of the following structures:
  • the present invention provides a pharmaceutical composition, which includes substance K and pharmaceutically acceptable auxiliary materials;
  • the substance K is substance K-1, substance K-2 or substance K-3;
  • the substance K-1 is the above-mentioned compound represented by formula I, its solvate, its pharmaceutically acceptable salt or its pharmaceutically acceptable salt solvate;
  • the substance K-2 is the above-mentioned compound represented by formula II', its solvate, its pharmaceutically acceptable salt or its pharmaceutically acceptable salt solvate;
  • the substance K-3 is the above-mentioned antibody-immunostimulatory conjugate represented by formula III or a pharmaceutically acceptable salt thereof.
  • the substance K is the above-mentioned compound shown in formula I or a pharmaceutically acceptable salt, a compound shown in formula II or a pharmaceutically acceptable salt thereof, or an antibody shown in formula III - an immunostimulatory conjugate or a pharmaceutically acceptable salt thereof.
  • the amount of substance K used may be a therapeutically effective amount.
  • the compound shown in formula I or a pharmaceutically acceptable salt, the compound shown in formula II or a pharmaceutically acceptable salt thereof, or the antibody-immunostimulatory conjugate shown in formula III may be in a therapeutically effective amount.
  • the pharmaceutically acceptable adjuvant may include a pharmaceutically acceptable carrier, diluent and/or excipient.
  • the pharmaceutical composition can be administered through conventional routes, including (but not limited to): intramuscular, intraperitoneal, intravenous, subcutaneous, intradermal, local administration (such as intratumoral injection) and the like.
  • the present invention also provides an application of substance K or the above-mentioned pharmaceutical composition in the preparation of drugs for regulating T cells and other immune cells, wherein the substance K is substance K-1, substance K-2 or substance K-3;
  • the substance K-1 is the above-mentioned compound represented by formula I, its solvate, its pharmaceutically acceptable salt or its pharmaceutically acceptable salt solvate;
  • the substance K-2 is the above-mentioned compound represented by formula II', its solvate, its pharmaceutically acceptable salt or its pharmaceutically acceptable salt solvate;
  • the substance K-3 is the above-mentioned antibody-immunostimulatory conjugate represented by formula III or a pharmaceutically acceptable salt thereof.
  • the substance K is the above-mentioned compound shown in formula I or a pharmaceutically acceptable salt, a compound shown in formula II or a pharmaceutically acceptable salt thereof, or an antibody shown in formula III - an immunostimulatory conjugate or a pharmaceutically acceptable salt thereof.
  • the amount of substance K used may be a therapeutically effective amount.
  • the present invention provides an application of substance K or the above-mentioned pharmaceutical composition in the preparation of medicines for treating and/or alleviating tumors or viral infectious diseases, and the substance K is substance K-1, substance K-2 or substance K -3;
  • the substance K-1 is the above-mentioned compound represented by formula I, its solvate, its pharmaceutically acceptable salt or its pharmaceutically acceptable salt solvate;
  • the substance K-2 is the above-mentioned compound represented by formula II', its solvate, its pharmaceutically acceptable salt or its pharmaceutically acceptable salt solvate;
  • the substance K-3 is the above-mentioned antibody-immunostimulatory conjugate represented by formula III or a pharmaceutically acceptable salt thereof.
  • the substance K is the above-mentioned compound shown in formula I or a pharmaceutically acceptable salt, a compound shown in formula II or a pharmaceutically acceptable salt thereof, or an antibody shown in formula III - an immunostimulatory conjugate or a pharmaceutically acceptable salt thereof.
  • the amount of substance K used may be a therapeutically effective amount.
  • the present invention provides an application of substance K or the above-mentioned pharmaceutical composition in the preparation of medicines for treating, alleviating and/or preventing TLR8-mediated related diseases, and the substance K is substance K-1 and substance K-2 or substance K-3;
  • the substance K-1 is the above-mentioned compound represented by formula I, its solvate, its pharmaceutically acceptable salt or its pharmaceutically acceptable salt solvate;
  • the substance K-2 is the above-mentioned compound represented by formula II', its solvate, its pharmaceutically acceptable salt or its pharmaceutically acceptable salt solvate;
  • the substance K-3 is the above-mentioned antibody-immunostimulatory conjugate represented by formula III or a pharmaceutically acceptable salt thereof.
  • the substance K is the above-mentioned compound shown in formula I or a pharmaceutically acceptable salt, a compound shown in formula II or a pharmaceutically acceptable salt thereof, or an antibody shown in formula III - an immunostimulatory conjugate or a pharmaceutically acceptable salt thereof.
  • the TLR8-mediated related diseases refer to tumors or viral infectious diseases.
  • the amount of substance K used may be a therapeutically effective amount.
  • the tumor can be a malignant tumor, including metastatic and non-metastatic cancers, family hereditary and sporadic cancers, solid tumors and non-solid tumors.
  • the tumor is preferably a tumor with HER2 expression (it can be a tumor with high expression of HER2 or a tumor with low expression of HER2).
  • the tumor is more preferably a tumor with high expression of HER2.
  • the term "optionally substituted at any position by one or more groups” means that any one or more hydrogen atoms of one or more atoms designated on the group are replaced by the designated Substitution of the group, provided that the normal valence of the specified atom is not exceeded, at any position is a reasonable substitution common in the art.
  • any combination of variables is permissible only if such combination results in a stable compound.
  • each substituent when any variable occurs more than once in the composition or structure of a compound, its definition is independent in each case.
  • each substituent is an independent substituent, which may be the same or different.
  • antibody refers to any form of antibody that exhibits a desired biological activity, such as inhibiting the binding of a ligand to its receptor or by inhibiting ligand-induced receptor signaling. Accordingly, “antibody” is used in its broadest sense and specifically includes, but is not limited to, monoclonal antibodies (including full-length monoclonal antibodies), polyclonal antibodies, and multispecific antibodies (including bispecific antibodies).
  • Naturally occurring "antibodies” are glycoproteins comprising at least two heavy (H) chains and two light (L) chains inter-connected by disulfide bonds. Each heavy chain is composed of a heavy chain variable region and a heavy chain constant region. The heavy chain constant region consists of three domains (CH1, CH2 and CH3).
  • Each light chain is composed of a light chain variable region and a light chain constant region.
  • the light chain constant region contains a CL domain.
  • the variable regions of the heavy and light chains contain binding domains (antigen-binding domains) that interact with antigens, and the antigen-binding domains can be provided by one or more variable regions on an antibody.
  • the antigen-binding domains that comprise the antibody light chain can Variable domain (VL) and antibody heavy chain variable domain (VH).
  • Antibodies can be monoclonal antibodies, human antibodies, humanized antibodies or chimeric antibodies.
  • antibodies may be of any class (IgG, IgE, IgM, IgD, IgA and IgY) or subtype (IgG1, IgG2, IgG3, IgG4, IgA1 and IgA2).
  • the present invention not only includes intact antibodies, but also fragments of antibodies with immunological activity (including Fab, F(ab')2, scFv or Fv fragments) or fusion proteins formed by antibodies and other sequences. Therefore, the "antibody” of the present invention also includes fragments, derivatives and analogs of the antibody.
  • monoclonal antibody also known as “monoclonal antibody” refers to polypeptides (including antibodies, bispecific antibodies, etc.) that have substantially the same amino acid sequence or are derived from the same genetic source. Monoclonal antibodies are highly specific, targeting a single antigenic site. Furthermore, each monoclonal antibody is directed against only a single determinant on the antigen, in contrast to conventional (polyclonal) antibody preparations which usually comprise a number of different antibodies directed against a number of different determinants (epitopes). In some specific embodiments, the monoclonal antibody binds to an optional antigen including but not limited to: HER2.
  • HER2 refers to a transmembrane tyrosine kinase receptor of the epidermal growth factor (EGF) receptor family.
  • EGF epidermal growth factor
  • HER2 contains an extracellular binding domain, a transmembrane domain and an intracellular tyrosine kinase domain.
  • HER2 does not have its own ligand-binding domain and therefore cannot bind growth factors, however HER2 binds tightly to other ligand-binding EGF receptor family members (such as HER1 or HER3) to form heterodimers, stabilizing the ligands Binds and enhances kinase-mediated activation of downstream signaling pathways.
  • EGF receptor family members such as HER1 or HER3
  • HER2 isoforms: A, B, C, D and E.
  • "HER2" in the present invention includes all HER2 isoforms.
  • anti-HER2 antibody refers to an antibody targeting HER2, and the anti-HER2 antibody can be derived from any species, such as human, rat, mouse and rabbit.
  • the anti-HER2 antibody is preferably a monoclonal anti-HER2 antibody, and the anti-HER2 antibody is more preferably a humanized anti-HER2 antibody.
  • the anti-HER2 antibodies include but are not limited to: pertuzumab, trastuzumab, trastuzumab biosimilar (trastuzumab biosimilar) (for example: inetetamab), pertuzumab biosimilar (pertuzumab biosimilar), margetuximab, HT-19, etc.;
  • Trastuzumab (Trastuzumab, also known as Herceptin or Herclon) is a humanized monoclonal antibody that can bind to the proximal membrane region of the extracellular structure of the HER2 receptor (Hudis CA, N Engl J Med.2007; 357(1):39-51).
  • the amino acid sequences of the variable regions of the heavy and light chains of trastuzumab are disclosed in US Patent No. 5,821,337.
  • Trastuzumab interacts with the kringle region formed by human HER2 residues 557-561, 570-573, and 593-603 (Cho et al., Nature 421:756-760, 2003).
  • Trastuzumab can interfere with HER2 signaling by preventing HER2 receptor dimerization, promoting HER2 receptor endocytosis, and inhibiting the shedding of the extracellular domain.
  • ADCC antibody-dependent cellular cytotoxicity
  • anti-HER2 antibodies bind to tumor cells and then recruit immune cells, such as macrophages, through Fc ⁇ receptor (Fc ⁇ R) interactions.
  • Fc ⁇ R Fc ⁇ receptor
  • Trastuzumab has a conserved human IgG Fc region and is able to recruit immune effector cells responsible for antibody-dependent cellular cytotoxicity (Hudis CA, N Engl J Med. 2007; 357(1):39-51).
  • Trastuzumab The monoclonal antibody was approved by the US FDA in September 1998 for the treatment of patients with tumors overexpressing HER2 and receiving one or more chemotherapy regimens for metastatic breast cancer;
  • Pertuzumab (also known as Perjeta, Omnitarg) is a humanized monoclonal antibody that binds to the extracellular domain of the HER2 receptor and inhibits dimerization of HER2 and together with the HER receptor.
  • the amino acid sequences of the variable regions of the heavy and light chains of Pertuzumab are disclosed in US Patent No. 7,560,111.
  • Pertuzumab primarily interacts with residues within the 245-333 region of human HER2, specifically residues His245, Val286, Ser288, Leu295, His296, or Lys311 (Franklin et al., Cancer Cell 5:317-328 ,2004).
  • Pertuzumab was shown to be more effective than trastuzumab at disrupting HER1-HER2 and HER3-HER2 complex formation in breast and prostate cancer cell lines (Agus et al., J Clin Oncol. 2005 ; 23(11):2534-43.Epub Feb 7,2005), Pertuzumab was approved by the US FDA in June 2012, and it was used in combination with trastuzumab and docetaxel for the treatment of na ⁇ ve Patients with HER2-positive metastatic breast cancer treated with anti-HER2 therapy or chemotherapy;
  • Margetuximab (also known as MGAH22, Margenza) is an Fc engineered monoclonal antibody targeting the HER2 protein, which binds to the extracellular region of HER2. Only a few amino acids differ from the variable region sequence of trastuzumab, and the Fc is mutated at five sites of F243L/R292P/Y300L/L235V/P396L, which improves the affinity for CD16A and enhances ADCC activity.
  • the modified Fc region of Margetuximab increases binding to the activating Fc receptor FCGR3A (CD16A) and reduces binding to the inhibitory Fc receptor FCGR2B (CD32B), resulting in stronger ADCC and NK cell activation (Nordstrom J.
  • Margetuximab was approved by the US FDA in December 2020 for the treatment of adult patients with metastatic HER2-positive breast cancer (MBC) who have received two or more anti-HER2 targeted therapies, at least one of which is For the treatment of metastatic breast cancer;
  • HT-19 is another anti-HER2 monoclonal antibody that binds to a different epitope of human HER2 than that of trastuzumab or pertuzumab and has been shown to inhibit HER2 signaling in the same way as trastuzumab Tocilizumab is comparable, and combination with trastuzumab and pertuzumab can promote HER2 degradation (Bergstrom D.A. et al., Cancer Res. 2015;75:LB-231).
  • the anti-HER2 antibody is not limited to the antibodies listed above as long as it specifically binds to HER2 (for example, an anti-HER2 antibody that binds to HER2 and has an activity of internalizing in HER2-expressing cells).
  • the isotype of "anti-HER2 antibody” in the present invention includes IgG1, IgG2, IgG3, IgG4, etc., preferably IgG1, IgG2 or IgG4.
  • the "anti-HER2 antibody” or antigen-binding fragment thereof in the present invention may comprise an Fc region, and the Fc region may be further modified.
  • one or more mutations in the Fc region result in improvements in the drug comprising such a modified Fc region, for example: reduction of effector function, alteration of drug metabolism half-life regulation, and drug stability Change.
  • the modified Fc region may contain one or more mutations that reduce or eliminate the interaction between the antibody and the immune system. Key interactions may include the interaction of antibody Fc with Fc ⁇ receptors, and with CIq of the complement system.
  • IgG1 is used as the isotype of the antibody of the present invention, effector functions can be adjusted by substituting a part of the amino acid residues in the constant region.
  • IgG1 variants that reduce or weaken effector functions include but are not limited to: IgG1LALA (IgG1-L234A, L235A), IgG1LAGA (IgG1-L235A, G237A), etc., preferably IgG1LALA.
  • the above-mentioned L234A and L235A represent the leucine at the 234th and 235th positions determined by the EU index (Proc.Natl.Acad.Sci.U.S.A., Vol.63, No.1 (May 15, 1969), p.78-85)
  • G237A indicates that glycine at position 237 determined by EUindex is substituted by alanine.
  • low expression of HER2 generally means that the expression level of HER2 in clinical testing is IHC 1+, or IHC 2+/FISH negative (ie IHC 2+ and FISH test is negative at the same time).
  • HER2 high expression and HER2 positive are used interchangeably and generally refer to the expression level of HER2 in clinical testing as IHC 2+/FISH positive (i.e., IHC 2+ and FISH is positive at the same time), or IHC 3+ .
  • IHC staining intensity is reported as a range
  • the term "HER2 low expression” in this context includes IHC 0 to 1+ and IHC 1+ to 2+ ranges in addition to IHC 1+, or IHC 2+/FISH negative .
  • HER2 high expression and "HER2 positive” each include the range of IHC 2+ to 3+ in addition to IHC 2+/FISH positive, or IHC 3+.
  • FISH negative means that the FISH test result shows no amplification of the HER2 gene
  • FISH positive means that the FISH test result shows that the HER2 gene is amplified.
  • fragment refers to a polypeptide that substantially retains the same biological function or activity of the antibody of the present invention.
  • the polypeptide fragments, derivatives or analogs of the present invention may be a) a polypeptide having one or more conservative or non-conservative amino acid residues (preferably conservative amino acid residues) substituted, and such substituted amino acid residues may is or may not be encoded by the genetic code, or b) a polypeptide having a substituent group in one or more amino acid residues, or c) the mature polypeptide is combined with another compound (such as a compound that extends the half-life of the polypeptide, such as polyethylene glycol Alcohol)
  • the polypeptide formed by fusion, or d) The polypeptide formed by fusing an additional amino acid sequence to this polypeptide sequence (such as a leader sequence or secretory sequence or a sequence or protein sequence used to purify this polypeptide, or formed with a 6His tag fusion protein).
  • the biosimilar of the monoclonal antibody refers to a biosimilar of the monoclonal antibody that is highly similar to the monoclonal antibody, and has a high degree of similarity in terms of safety and There were no clinically meaningful differences in terms of effectiveness and/or effectiveness.
  • linker and “Linker” refer to degradable or non-degradable linking fragments used to connect the small molecule drug D and the antibody.
  • One antibody molecule can be connected to multiple Linkers with small molecule drugs D, and usually, each Linker can be connected to one or more small molecule drugs.
  • each Linker is preferably connected to one small molecule drug D.
  • each antibody can be linked with multiple Linkers.
  • each antibody is linked with 1-10 Linkers; more preferably, each antibody is linked with 1-8 Linkers.
  • the non-degradable Linker means that the Linker has enzyme stability and/or chemical stability in vivo and in vitro, and the release of small molecule drug D may not depend on plasma and tumor tissue and intracellular enzyme levels. Differentiated nature.
  • the release of the small molecule drug D can endocytose the antibody-immunostimulatory conjugate through antigen-mediated phagocytosis, then degrade the antibody to the amino acid level, and then release the derivative of the small molecule drug D, the derivative of the small molecule drug D
  • the substance consists of small molecule drug D, linker and amino acid residues or residues covalently linked by small molecule drug D and linker.
  • the degradable Linker can be degraded in vivo or in vitro, and it includes a linker that can be degraded by specific enzymes in vivo or in vitro or a linker that is itself chemically unstable.
  • the degradable Linker can be degraded in the cell to release the small molecule drug D, for example, it can be reduced in the cytoplasm, degraded in the acidic condition of the lysosome, or degraded by specific proteases or other enzymes in the cell.
  • the degradable Linker includes one or more enzymatically degradable linkers, chemically unstable linkers or other degradable linkers, and other parts may be linkers that are not degraded by enzymes or are chemically stable.
  • Such chemically labile linkers include oxime, hydrazone and/or disulfide groups (eg: ).
  • the linker specifically degraded by the enzyme is based on 1) peptide formation. Peptide bonds can have good serum stability because the activity of lysosomal proteolytic enzymes in blood is much lower than that in some tumor tissues. Therefore, Linker can be selectively degraded in some tumor tissues or cells and then Release small molecule drug D.
  • the lysosomal enzyme may be selected from cathepsin B, cathepsin S, plasmin, elastase, ⁇ -glucuronidase or ⁇ -galactosidase and the like.
  • Peptide-based linkers can be tetrapeptides (eg: Gly-Phe-Leu-Gly, Ala-Leu-Ala-Leu, Gly-Gly-Phe-Gly), tripeptides (Val-Leu-Lys, Ala-Pro -Val), dipeptides (e.g.
  • Val-Cit Cit-Val, Val-Ala, Ala-Val, Ala-Cit, Cit-Ala, Asn-Cit, Cit-Asn, Cit-Cit, Val-Glu, Glu- Val, Ser-Cit, Cit-Ser, Lys-Cit, Cit-Lys, Asp-Cit, Cit-Asp, Ala-Val, Val-Ala, Phe-Lys, Lys-Phe, Val-Lys, Lys-Val, Ala-Lys, Lys-Ala, Phe-Cit, Cit-Phe, Leu-Cit, Cit-Leu, Ile-Cit, Cit-Ile, Phe-Arg, Arg-Phe, Cit-Trp, Trp-Cit) or amino acids
  • Monomeric, peptide-based linkers are preferably dipeptide linkers.
  • the other degradable linkers may include ester linkages formed by the reaction of PEG carboxylic acid or activated PEG carboxylic acid with hydroxyl groups on the small molecule drug D, wherein such ester linkages can be hydrolyzed under physiological conditions to further Release small molecule drug D.
  • Hydrolytically degradable linkages include, but are not limited to, carbonate linkages, imine linkages resulting from the reaction of amines and aldehydes, phosphate linkages resulting from the reaction of hydroxyl and phosphate groups, acetal linkages resulting from the reaction of hydroxyl and aldehydes , orthoester linkages obtained by reacting formate esters with hydroxyl groups, etc.
  • a cleavable linker may also include non-cleavable fragments, such as polyethylene glycol (PEG) and related polymers.
  • PEG polyethylene glycol
  • Linkers formed by pyrophosphate or phosphate are enzymes that hydrolyze pyrophosphate and terminal monophosphate, respectively, to their parent alcohols in lysosomes. Targeting these enzymes could effectively release small-molecule drug D terminated with an alkyl alcohol.
  • the "linker” also includes a linker that can be connected to the antibody.
  • the linker can pass through the linker and the sulfhydryl group (such as cysteine group) in the antibody.
  • the linker is preferably a maleimide group and a ring-opened maleimide group (for example: *
  • the labeling site is the site linked to the antibody), the maleimide group and the sulfhydryl group (for example: cysteine group) of the antibody are specifically linked (for example, as shown in formula 1 or formula 2 Show).
  • the "linker” can further include an extension group (Spacer), and the linker can be directly connected to the linker in the linker, or connected to the linker in the linker through an extension group (Spacer).
  • Linkers connect to each other.
  • the extended group may be polyethylene glycol and its related polymers, an alkylene group containing 1 to 10 carbon atoms, a cyclohexyl group, an amide group, an ester group, an oxo group, And any one or more combinations of the above extension groups.
  • the "linker” can also form an amide bond (such as shown in formula 3) by reacting the carboxyl or ester group in the linker or the extension group with the amino group (such as lysine group) in the antibody.
  • the "linker” may further include a self-immolative group, which spatially separates the small molecule drug D from the enzyme degradation site.
  • a self-immolative group which spatially separates the small molecule drug D from the enzyme degradation site.
  • Common self-extracting groups usually contain the following basic structures:
  • the self-shedding group can also be connected with the hydroxyl group on the small molecule D through an aminomethylene group, an amino C 3-5 alkanoyl group, a phosphoric acid ester group or a pyrophosphate ester group;
  • the site marked with * is the site connected to the small molecule drug D, preferably connected to the amino group on the small molecule drug D; 2) The site marked with * is the site connected to the small molecule drug D, preferably It is connected with the hydroxyl group on the small molecule drug D.
  • Linker 2 and “LinkerX” refer to degradable or non-degradable linking fragments used to link small molecule drugs D, which are not linked to antibody molecules; but can continue to be linked to antibody molecules through reactions to form the above-mentioned " Connector”.
  • each LinkerX can be connected with one or more small molecule drugs.
  • each LinkerX is connected with one small molecule drug D. Except that it is not connected with the antibody molecule, the other definitions of the linker 2 are the same as the above-mentioned "linker”.
  • the "linker 2" also includes a linker that has not been connected to the antibody.
  • the linker can pass through the linker and the sulfhydryl group (such as cysteine group) in the antibody.
  • the linker is preferably a maleimide group and a ring-opened maleimide group (for example, a linker that is not connected to an antibody includes but is not limited to: ), the connection between the maleimide group and the sulfhydryl group (for example: cysteine group) of the antibody is specific (for example as shown in formula 1 or formula 2).
  • C AB refers to the range from the start point to the end point, where A and B and each point in the range are integers, indicating the number of carbon atoms, for example, C 1-4 means that the number of carbon atoms is 1, 2, or 3 Or 4; C 1-6 means that the number of carbon atoms is 1, 2, 3, 4, 5 or 6; C 3-8 means that the number of carbon atoms is 3, 4, 5, 6, 7 or 8; C AB can follow any Groups containing carbon atoms are used in combination to limit the number of carbon atoms, such as C 1-6 alkyl, C 3-8 cycloalkyl, C 6-10 aryl, C 1-4 alkoxy, C 3 -8 cycloalkyl C 1-4 alkyl etc.
  • alkyl refers to a saturated straight or branched chain hydrocarbon group containing 1-20 carbon atoms, preferably 1-10 carbon atoms, more preferably 1-8, 1-6, 1-4 or 1-3 carbons atom
  • representative examples of alkyl include, but are not limited to: methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, isobutyl, n-pentyl, n-hexyl, n-heptyl, octyl, nonyl, decyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1, 2-Dimethylbutyl, 2,2-Dimethylbut
  • alkenyl refers to a straight-chain, branched-chain or cyclic non-aromatic hydrocarbon group containing at least one carbon-carbon double bond. There may be 1-3 carbon-carbon double bonds, preferably 1 carbon-carbon double bond.
  • C 2-4 alkenyl refers to an alkenyl group with 2-4 carbon atoms
  • C 2-6 alkenyl refers to an alkenyl group with 2-6 carbon atoms, including ethenyl, propenyl , butenyl, 2-methylbutenyl and cyclohexenyl. Said alkenyl groups may be substituted.
  • alkynyl refers to a straight-chain, branched-chain or cyclic hydrocarbon group containing at least one carbon-carbon triple bond. There may be 1-3 carbon-carbon triple bonds, preferably 1 carbon-carbon triple bond.
  • C 2-6 alkynyl refers to an alkynyl group having 2-6 carbon atoms, including ethynyl, propynyl, butynyl and 3-methylbutynyl.
  • alkenylene refers to a straight-chain, branched or cyclic non-aromatic divalent hydrocarbon group containing at least 1 carbon-carbon double bond, wherein there may be 1-3 carbon-carbon double bonds, preferably 1 carbon-carbon double bond. key.
  • the alkenylene group preferably contains 2-8 carbon atoms, more preferably 2-6 or 2-4 carbon atoms.
  • alkynylene refers to a straight-chain, branched-chain or cyclic non-aromatic divalent hydrocarbon group containing at least one carbon-carbon triple bond. There may be 1-3 carbon-carbon triple bonds, preferably 1 carbon-carbon triple bond.
  • the alkynylene group preferably contains 2-8 carbon atoms, more preferably 2-6 or 2-4 carbon atoms.
  • cycloalkyl refers to a saturated or partially unsaturated (containing 1 or 2 double bonds) monocyclic or polycyclic group containing 3-20 carbon atoms.
  • “Monocyclic cycloalkyl” is preferably 3-10 membered monocycloalkyl, more preferably 3-8 membered monocycloalkyl, for example: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclo Octyl, cyclodecyl, cyclododecyl, cyclohexenyl.
  • Polycyclic cycloalkyl includes “bridged cycloalkyl”, “fused cycloalkyl” and “spirocycloalkyl”.
  • Representative examples of “bridged cycloalkyl” include, but are not limited to: bornyl, bicyclo[2.2. 1] Heptenyl, bicyclo[3.1.1]heptyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, bicyclo[3.2.2]nonyl, bicyclo[3.3. 1] Nonyl, Bicyclo[4.2.1] Nonyl and Adamantyl etc.
  • fused cycloalkyl includes a cycloalkyl ring fused to a phenyl, cycloalkyl or heteroaryl group, fused cycloalkyl groups include but are not limited to: benzocyclobutenyl, 2,3-di Hydrogenated indenyl, decahydronaphthyl, etc.
  • a monocyclic or multicyclic cycloalkyl may be linked to the parent molecule through any carbon atom in the ring.
  • heterocycloalkyl refers to a saturated or partially unsaturated (containing 1 or 2 double bonds) compound composed of carbon atoms and heteroatoms selected from nitrogen, oxygen, sulfur, boron and/or sulfur-containing heteroatom groups.
  • Non-aromatic cyclic group this cyclic group can be monocyclic or polycyclic group, wherein, described sulfur-containing heteroatom group is selected from but not limited to S(O), S(O) 2 and S( O)(NH).
  • the number of heteroatoms and/or heteroatom groups in the heterocycloalkyl group is preferably 1, 2, 3 or 4, and the boron, nitrogen or carbon atoms in the heterocycloalkyl group can be optionally oxidized.
  • the nitrogen atom can optionally be further substituted with other groups to form tertiary amines or quaternary ammonium salts.
  • "Monocyclic heterocycloalkyl” is preferably 3-10 membered monocyclic heterocycloalkyl, more preferably 3-8 membered monocyclic heterocycloalkyl.
  • Polycyclic heterocycloalkyl includes “fused heterocycloalkyl”, “spiroheterocyclyl” and “bridged heterocycloalkyl”.
  • “Fused heterocycloalkyl” comprises a monocyclic heterocycloalkyl ring fused to a phenyl, cycloalkyl, heterocycloalkyl, or heteroaryl, fused heterocycloalkyl includes, but is not limited to:2,3 -Dihydrobenzofuryl, 1,3-dihydroisobenzofuryl, dihydroindolyl, 2,3-dihydrobenzo[b]thienyl, dihydrobenzopyranyl, 1, 2,3,4-tetrahydroquinolinyl, 1,2,3,4-tetrahydroisoquinolinyl, 1,2,3,4-tetrahydronaphthyridinyl, 5,6,7,8-tetrahydro Hydronaphthyridinyl, 1-hydroxy
  • Monocyclic heterocycloalkyl and polycyclic heterocycloalkyl groups can be linked to the parent molecule through any ring atom in the ring.
  • the aforementioned ring atoms specifically refer to carbon atoms and/or nitrogen atoms constituting the ring skeleton.
  • cycloalkylalkyl refers to the connection between a cycloalkyl group and a core structure through an alkyl group.
  • cycloalkylalkyl includes the above definitions of alkyl and cycloalkyl.
  • heterocycloalkylalkyl refers to the connection between the heterocycloalkyl group and the core structure through an alkyl group.
  • heterocycloalkylalkyl includes the above definitions of alkyl and heterocycloalkyl.
  • alkoxy refers to a cyclic or acyclic alkyl group having the stated number of carbon atoms attached through an oxygen bridge, including alkyloxy, cycloalkyloxy and heterocycloalkyloxy. "Alkoxy” thus includes the above definitions for alkyl, heterocycloalkyl and cycloalkyl.
  • hydroxyalkyl means that any hydrogen atom on the alkyl group is replaced by a hydroxyl group, including but not limited to: -CH 2 OH, -CH 2 CH 2 OH, -CH 2 CH 2 C(CH 3 ) 2 OH.
  • heterocycloalkenyl refers to a specified number of ring atoms (for example, 5-10 members), a specified number of heteroatoms (for example, 1, 2 or 3), a specified heteroatom type (N, O and one or more of S), cyclic, unsaturated monovalent hydrocarbon groups, which have one or more (for example, 1, 2 or 3) carbon-carbon sp 2 double bonds, which It is monocyclic and not aromatic.
  • a heterocycloalkenyl group is attached to the rest of the molecule through a carbon atom or a heteroatom.
  • Heterocyclenyl groups include, but are not limited to: Wait.
  • heteroalkenyl ring satisfies any of the following conditions, and the rest of the definitions are the same as the term “heterocycloalkenyl”: it shares two atoms and a bond with the rest of the molecule.
  • aryl refers to any stable 6-20 membered monocyclic or polycyclic aromatic group, such as: phenyl, naphthyl, tetrahydronaphthyl, 2,3-indanyl or biphenyl, etc. .
  • heteroaryl refers to an aromatic ring group formed by replacing at least one carbon atom on the ring with a heteroatom selected from nitrogen, oxygen or sulfur, which can be a 5-7 membered single ring structure or a 7-20 Fused ring structure, preferably 5-6 membered heteroaryl.
  • the number of heteroatoms is preferably 1, 2 or 3, including: pyridyl, pyridonyl, pyrimidyl, pyrimidine-2,4(1H,3H)-diketone, pyrimidinyl, piperazinyl , pyridazinone, furyl, thienyl, thiazolyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, 1,2,5-oxadiazolyl, 1,2,4 -Oxadiazolyl, 1,3,4-oxadiazolyl, 1,3,4-thiadiazole, 1,2,4-triazolyl, 1,2,3-triazolyl, tetra Azazolyl, indazolyl, isoindazolyl, indolyl, isoindolyl, benzofuryl, benzothienyl, benzo[d][1,3]dioxolan
  • joint ring group refers to a double ring structure formed by two, three or four ring structures sharing two adjacent atoms with each other, and the described ring structure may further include a spiro ring or a bridge ring group.
  • the cyclic group referred to in the present invention is a saturated, unsaturated or partially saturated cyclic structure, preferably at least one ring is an aromatic ring. More preferred are bicyclic or tricyclic ring groups, and at least one ring is an aromatic ring.
  • the ring-joining group is 8-20 membered, preferably 8-12 membered, more preferably 8-10 membered.
  • acyclic groups include, but are not limited to: benzocyclobutenyl, 2,3-dihydro-1H-indenyl, 1,2,3,4-tetrahydronaphthyl, 6,7,8 ,9-tetrahydro-5H-benzo[7]annulenyl, 6,9-dihydro-5H-benzo[7]annulenyl, 5,6,7,8,9,10-hexahydrobenzene And[8]annyl, 2,3-cyclopentenylpyridyl, 5,6-dihydro-4H-cyclopentyl[b]thienyl, 5,6-dihydro-4H-cyclopentyl[ b]furyl, 2,3-dihydrobenzofuryl, 1,3-dihydroisobenzofuryl, dihydroindolyl, 2,3-dihydrobenzo[b]thienyl, dihydro Benzopyranyl, 1,2,
  • arylalkyl means that the aryl group is connected to the core structure through an alkyl group.
  • arylalkyl includes the above definitions for alkyl and aryl.
  • heteroarylalkyl refers to the connection between the heterocycloalkyl group and the core structure through an alkyl group.
  • heteroarylalkyl includes the above definitions for alkyl and heteroaryl.
  • halogen means fluorine, chlorine, bromine or iodine.
  • haloalkyl refers to an alkyl group optionally substituted with halogen.
  • haloalkyl includes the definitions of halo and alkyl above.
  • haloalkoxy refers to an alkoxy group optionally substituted with halogen.
  • haloalkoxy includes the above definitions for halo and alkoxy.
  • amino refers to -NH 2
  • alkylamino refers to at least one hydrogen atom on the amino group being replaced by an alkyl group, including but not limited to: -NHCH 3 , -N(CH 3 ) 2 , -NHCH 2 CH 3. -N(CH 2 CH 3 ) 2 .
  • Alkylamino thus includes the above definitions of alkyl and amino.
  • nitro refers to -NO2 .
  • cyano refers to -CN.
  • amino acid is conventional abbreviation, for example: alanine (Ala), arginine (Arg), aspartic acid (Asp), cysteine (Cys), asparagine (Asn), Glutamic acid (Glu), glycine (Gly), histidine (His), isoleucine (Ile), leucine (Leu), lysine (Lys), phenylalanine (Phe), serine (Ser), tryptophan (Trp), citrulline (Cit), valine (Val), proline (Pro).
  • room temperature refers to 15-30°C.
  • the “pharmaceutically acceptable salts” of the present invention are discussed in Berge, et al., "Pharmaceutically acceptable salts", J.Pharm.Sci., 66, 1-19 (1977), and to medicinal chemists As will be apparent, such salts are substantially non-toxic and provide the desired pharmacokinetic properties, palatability, absorption, distribution, metabolism or excretion, and the like.
  • the compound of the present invention may have an acidic group, a basic group or an amphoteric group, and typical pharmaceutically acceptable salts include salts prepared by reacting the compound of the present invention with an acid.
  • solvate refers to a substance formed by combining a compound with a solvent (including but not limited to: water, methanol, ethanol, etc.). Solvates are divided into stoichiometric solvates and non-stoichiometric solvates. Solvates include, but are not limited to, monohydrates.
  • solvate of a pharmaceutically acceptable salt refers to a substance formed by combining a compound with a pharmaceutically acceptable acid, base, or solvent (including but not limited to: water, methanol, ethanol, etc.). Wherein, the amount of the solvent may be stoichiometric or non-stoichiometric. Solvates of pharmaceutically acceptable salts include, but are not limited to, monohydrochloride monohydrate.
  • the reagents and raw materials used in the present invention are all commercially available.
  • the positive progress effect of the present invention is: the nitrogen-containing compound has a good regulating effect on TLR8, and can effectively treat, alleviate and/or prevent various related diseases caused by immunosuppression, such as cancer or viral infection.
  • Fig. 1 is the anti-tumor effect diagram of the carrier, the antibody-immunostimulatory conjugate of the present invention and the positive control in the subcutaneous transplanted tumor model of MC38-HER2 mouse colon cancer cells, it can be seen that the antibody-immunostimulatory conjugate of the present invention The antitumor effect of the compound was significantly better than that of the positive control.
  • the structures of all compounds of the present invention can be identified by nuclear magnetic resonance ( 1 H NMR) and/or mass spectrometry (MS).
  • Liquid mass spectrometry is determined by Agilent 1200HPLC/6120 mass spectrometer, using chromatographic column: Xtimate C18, 3.0 ⁇ 50mm, 3 ⁇ m, column temperature 40°C; or determined by Thermo UltiMate 3000HPLC/MSQ PLUS mass spectrometer, using chromatographic column Xbridge C18, 3.0 ⁇ 50mm, 3.5 ⁇ m, column temperature 30°C.
  • Agilent gradient elution condition one: 95-5% solvent A 1 and 5-95% solvent B 1 (0-2.0 minutes), then 95% solvent B 1 and 5% solvent A 1 (hold for 1.1 minutes), the percentage is a certain The volume percentage of a solvent to the total solvent volume.
  • Solvent A 1 0.01% trifluoroacetic acid (TFA) in water
  • Solvent B 1 0.01% trifluoroacetic acid in acetonitrile
  • Thermo gradient elution condition two 95-5% solvent A 2 and 5-95% solvent B 2 (0-2 minutes), then 95% solvent B 2 and 5% solvent A 2 (hold for 1.8 minutes), the percentage is a certain The volume percentage of a solvent to the total solvent volume.
  • Solvent A 2 10 mM ammonium bicarbonate in water
  • Solvent B 2 acetonitrile.
  • Preparative high-performance liquid chromatography uses Gilson GX-281 preparative liquid chromatography or Agela FLEXA-HP preparative liquid chromatography.
  • the column is: Xtimate 21.2*250mm, 10um.
  • Separation condition 1 mobile phase A: 0.05% hydrochloric acid aqueous solution, mobile phase B: acetonitrile;
  • separation condition 2 mobile phase A: 10mmol/L ammonium bicarbonate aqueous solution, mobile phase B: acetonitrile; separation condition 3: mobile phase A: 0.1 % trifluoroacetic acid in water, mobile phase B: acetonitrile.
  • Detection wavelength 214nm&254nm; flow rate: 15.0mL/min.
  • Flash column chromatography Flash column chromatography
  • flash system/CheetahTM Flash system/CheetahTM
  • the supporting normal phase separation column is Flash column Silica-CS (25g, 40g, 80g, 120g or 330g), Tianjin Bo Naygel
  • the elution system is ethyl acetate/petroleum ether, or dichloromethane/methanol
  • the reversed-phase separation column is a C18 reversed-phase column (Spherical C18, 40-75um, Model: SW-040)
  • the elution system is 10mM ammonium bicarbonate aqueous solution/acetonitrile or 0.05% trifluoroacetic acid aqueous solution/acetonitrile.
  • (Boc) 2 O Di-tert-butyl dicarbonate; BINAP: 1,1'-binaphthyl-2,2'-bisdiphenylphosphine; DMF: N,N-dimethylformamide; DMSO: Dimethylmethylene Sulfone; DIPEA: N,N-diisopropylethylamine; EDCI: 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride; HATU: O-(7-aza Benzotriazol-1-yl)-N,N,N',N'-tetramethylurea; LiHMDS: lithium bistrimethylsilylamide; PdCl 2 dppf .
  • CH 2 Cl 2 [1,1 '-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex
  • Pd 2 (dba) 3 tris(dibenzylideneacetone)dipalladium
  • Pd(PPh 3 ) 4 tetra (Triphenylphosphine) palladium
  • TBSCl tert-butyldimethylsilyl chloride
  • Xantphos 4,5-bisdiphenylphosphine-9,9-dimethylxanthene
  • Xphos 2-dicyclohexylphosphine -2,4,6-Triisopropylbiphenyl.
  • Step 1 In an ice bath, (Boc) 2 O (74.7g , 342mmol). The reaction system was stirred overnight at room temperature and then concentrated, diluted with ethyl acetate (400 mL), the organic phase was washed with hydrochloric acid (1M), saturated aqueous sodium bicarbonate solution and saturated brine, and the organic phase was separated and washed with anhydrous sodium sulfate Dry, filter, and concentrate the filtrate under reduced pressure. The residue is recrystallized from ethanol, filtered, and the filter cake is vacuum-dried to obtain Intermediate 1.1 (39.5 g, yield: 56%) as a yellow solid.
  • Step 2 Intermediate 1.1 (39.5g, 173mmol) and N,N,N',N'-tetramethylethylenediamine (74.4g, 432mmol) in tetrahydrofuran (400mL) were prepared at -78°C under nitrogen n-Butyl lithium (173 mL, 432 mmol, 2.5M n-hexane solution) was added dropwise to the solution. After the addition was complete, the reaction system was slowly raised to -10°C and stirred at this temperature for 2 hours. The reaction system was cooled to -78°C again, and DMF (25.3 g, 347 mmol) was added. After the addition was complete, the reaction system was slowly raised to room temperature and stirred overnight.
  • Step 3 Intermediate 1.2 (32.9 g, 128 mmol) was added to a solution of hydrogen chloride in 1,4-dioxane (300 mL, 4M), and the reaction solution was stirred overnight at room temperature. Concentrate under reduced pressure, adjust the pH of the residue to 7-8 with saturated aqueous sodium bicarbonate solution, extract the aqueous phase with ethyl acetate, combine the organic phases, and wash with water and saturated brine respectively, separate the organic phase and dry over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to obtain Intermediate 1.3 (18.9 g, yield: 94%) as a yellow solid. m/z: [M+H] + 157.0.
  • Step 4 A solution of intermediate 1.3 (18.9 g, 121 mmol) and compound 1.4A (46.8 g, 121 mmol) in toluene (400 mL) was stirred at reflux overnight. The solvent was removed by concentration under reduced pressure, the residue was recrystallized with ethanol (150 mL), filtered, and the filter cake was vacuum-dried to obtain intermediate 1.4 (13.1 g, yield: 41%) as a yellow solid. m/z: [M+H] + 266.0.
  • intermediate 1.5 was reacted to obtain intermediate 1.8.
  • Step 1 A solution of Intermediate 2.1 (20 g, 57.4 mmol) and bromoacetonitrile (6.9 g, 57.4 mmol) in ethyl acetate (200 mL) was stirred at reflux for 3 hours, the solid was removed by filtration, and the filter cake was washed with ethyl acetate. The filtrate was concentrated under reduced pressure to obtain intermediate 2.2 (17 g, yield: 76%) as a pale yellow oil.
  • Step 2 A solution of 4-bromo-2-nitrobenzaldehyde (10g, 43.9mmol) and intermediate 2.2 (17g, 43.9mmol) in toluene (170mL) was stirred under reflux for 2 hours. After the mixture was cooled to room temperature, it was washed with a short silica gel Filter the column, elute with 25% ethyl acetate petroleum ether solution, concentrate under reduced pressure to remove most of the eluent, and place the remaining solution at -18°C for 16 hours. A solid was precipitated, and after filtration and vacuum drying of the filter cake, intermediate 2.3 (8.2 g, yield: 55%) was obtained as an off-white solid.
  • Step 3 After heating the acetic acid (80mL) solution of intermediate 2.3 (4.2g, 12.4mmol) to 80°C, add iron powder (4.1g, 74.3mmol) in batches to the above solution within 15 minutes, keeping the internal temperature not exceeding 90°C, after the addition was complete, the stirring was continued for 3 hours.
  • the reaction system was cooled to room temperature, filtered through celite, and rinsed with ethyl acetate.
  • the filtrate was concentrated under reduced pressure, the residue was diluted with cold water and adjusted to pH>8 with saturated aqueous sodium bicarbonate solution, the aqueous phase was extracted with ethyl acetate, the organic phases were combined and washed with saturated brine, the organic phase was separated and dried over anhydrous sodium sulfate, After filtration, the filtrate was concentrated under reduced pressure. The residue was slurried with 10% ethyl acetate petroleum ether solution, filtered, and the filter cake was vacuum-dried to obtain Intermediate 2.4 (3 g, yield: 78%) as an off-white solid.
  • Step 4 To a solution of Intermediate 2.4 (3 g, 9.7 mmol) and triethylamine (1.47 g, 14.6 mmol) in dichloromethane (50 mL) was added (BOC) 2 O (3.2 g, 14.6 mmol). The reaction system was stirred at room temperature for 2 days and then diluted with dichloromethane. The organic phase was washed with hydrochloric acid (3M), saturated aqueous sodium bicarbonate solution and saturated brine respectively.
  • BOC hydrochloric acid
  • aqueous sodium hydroxide 1.0 M, 5.9 mL
  • step 5 of intermediate 2.6 react with ethyl 2-amino-8-bromo-6-fluoro-3H-benzo[b]azepine-4-carboxylate to obtain intermediate 3.2.
  • intermediate 2.4 was reacted to obtain intermediate 4.1.
  • Step 1 At -70°C, compound 1.7 (2.97g, 8.8mmol), DIPEA (2.84g, 22mmol), di-n-propylamine (2.22g, 22mmol) and HATU (7.13g) were sequentially added to DMF (30mL) , 22mmol).
  • Step 2 A mixed solution of compound 1.8 (1 g, 2.38 mmol), Xantphos (69 mg, 0.12 mmol), palladium acetate (53 mg, 0.24 mmol) and tripotassium phosphate (1.51 g) in tetrahydrofuran (10 mL) and water (10 mL) After replacing each with nitrogen and carbon monoxide three times, the mixture was stirred at 70° C. for 6 hours under a carbon monoxide atmosphere. The reaction system was cooled to room temperature, filtered, and the filter cake was washed with methanol. The filtrate was concentrated under reduced pressure and purified directly by prep-HPLC (separation condition 2) to obtain compound 1.9 (220 mg, yield: 22%) as a brown solid. m/z: [M+H] + 431.2.
  • Step 3 Add isobutyl chloroformate (38 mg, 0.28 mmol) to a solution of compound 1.9 (100 mg, 0.23 mmol) and N-methylmorpholine (28 mg, 0.28 mmol) in THF (10 mL) at -78 °C , the reaction solution was stirred at -78°C for 1 hour, then 3-amino-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylic acid tert-butyl ester (69mg, 0.28mmol) was added to In the above reaction solution, the reaction system continued to stir at this temperature for 1 hour, then rose to room temperature and continued to stir for 1 hour.
  • Step 4 A solution of compound 1.10 (100 mg, 0.15 mmol) and trifluoroacetic acid (1 mL) in dichloromethane (3 mL) was stirred at room temperature for 2 hours, concentrated under reduced pressure directly, and the residue was analyzed by prep-HPLC (separation condition 2) Purification gave Compound 1 (24.7 mg, yield: 35%) as a white solid.
  • Step 1 A solution of compound 2.6 (1.1 g, 2.8 mmol), HATU (1.6 g, 4.33 mmol), di-n-propylamine (580 mg, 22 mmol) and DIPEA (560 mg, 4.37 mmol) in DMF (10 mL) was prepared at room temperature Stir for 3 hours.
  • Step 3 Lithium hydroxide monohydrate (130 mg, 3.1 mmol) was added to a mixed solution of compound 2.8 (500 mg, 1.03 mmol) in tetrahydrofuran (5 mL), methanol (0.5 mL) and water (0.5 mL), and the reaction system was heated at room temperature The mixture was stirred for 16 hours, then the reaction solution was neutralized with hydrochloric acid (1M), the aqueous phase was extracted with ethyl acetate, the organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound 2.9 ( 400 mg, yield: 82%) as an off-white solid. m/z: [M+H] + 470.2.
  • Step 1 Using the synthesis method of compound 2.7, react with compound 4.1 to obtain compound 4.2.
  • Step 4 Add Pd 2 (dba) 3 to a solution of compound 4.4 (400 mg, 0.62 mmol), DIPEA (120 mg, 0.92 mmol) and potassium carbonate (17 mg, 0.12 mmol) in anhydrous THF (6 mL) in an ice bath (33 mg, 0.06 mmol), the reaction system was replaced with nitrogen three times, and then a solution of monomethyl oxalyl chloride (113 mg, 0.92 mmol) in tetrahydrofuran (1 mL) was added dropwise to the system.
  • Step 6 To a solution of compound 4.6 (80 mg, 0.14 mmol) in DMF (4 mL) was sequentially added tert-butyl 3-amino-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate ( 43mg, 0.17mmol), HATU (65mg, 0.17mmol) and DIPEA (22mg, 0.17mmol), the reaction solution was microwaved at 50°C for 1 hour. Water was then added to quench the reaction, and the aqueous phase was extracted with ethyl acetate.
  • Example 8 8-amino-N-(2-hydroxyethyl)-N-n-propyl-2-((5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl) Synthesis of Amino)-7H-pyrido[2,3-b]azepine-6-carboxamide (Compound 8)
  • Step 1 Compound 5.1 (obtained by reacting intermediate 1.7 with 2-(propylamino)ethanol) (200 mg, 0.47 mmol) using the synthesis method of compound 2.7, 3-amino-7,8-dihydro-1,6 1,4 of -naphthyridine-6(5H)-tert-butylcarboxylate (142mg, 0.57mmol), cesium carbonate (170mg, 0.52mmol), palladium acetate (32mg, 0.14mmol) and Xantphos (82mg, 0.14mmol) - The mixture of dioxane (6 mL) was replaced with nitrogen three times, and the reaction system was stirred at 90° C. for 4 hours under the protection of nitrogen.
  • Step 2 To a solution of compound 5.2 (200 mg, 0.31 mmol) in dichloromethane (10 mL) was added trifluoroacetic acid (2 mL). The reaction system was stirred at room temperature for 2 hours. It was concentrated under reduced pressure, and the residue was purified by prep-HPLC (separation condition 3) to obtain compound 8 (31 mg, yield: 23%) as a light yellow solid.
  • Example 10 8-amino-N-(2-hydroxyethyl)-N-n-propyl-2-(1-((5,6,7,8-tetrahydro-1,6-naphthyridine-3 Synthesis of -yl)carbamoyl)cyclopropyl)-7H-pyrido[2,3-b]azepine-6-carboxamide (compound 10)
  • compound 10 was synthesized as a white solid using 1.7 and 2-(propylamino)ethanol as starting materials. m/z: [M+H] + 504.2.
  • Step 3 Add triethylamine (220mg, 2.18mmol) and (Boc) 2 O (285mg, 1.31mmol) to a solution of compound 6.3 (500mg, 0.97mmol) in dichloromethane (15mL) successively, and the reaction system is at room temperature Stir for 12 hours.
  • Step 5 Add HATU (46mg, 0.12mmol) and DIPEA (31mg, 0.24mmol) successively to compound 6.5 (50mg, 0.08mmol) in DMF (5mL) solution, the reaction solution was stirred at room temperature for 30 minutes, then added 3- Amino-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylic acid tert-butyl ester (25 mg, 0.1 mmol).
  • Step 2 Mix compound 7.7 (600mg, 1.29mmol), potassium phosphate (820mg, 3.86mmol), palladium acetate (29mg, 0.13mmol) and Xantphos (37mg, 0.06mmol) in THF (10mL) and water (5mL) The solution was replaced with nitrogen and carbon monoxide three times, respectively, and then stirred at 70° C. for 4 hours under a carbon monoxide atmosphere. The reaction system was cooled to room temperature and then concentrated under reduced pressure.
  • Step 3 To a solution of compound 7.8 (50 mg, 0.11 mmol), HATU (49 mg, 0.13 mmol) and DIPEA (17 mg, 0.13 mmol) in DMF (3 mL) was added 3-amino-7,8-dihydro-1,6 -Naphthyridine-6(5H)-tert-butyl carboxylate (32mg, 0.13mmol), the reaction solution was stirred overnight at room temperature. The reaction solution was poured into water to quench the reaction, the aqueous phase was extracted with ethyl acetate, and the organic phases were combined and concentrated under reduced pressure.
  • Step 4 A solution of compound 7.9 (25mg, 0.04mmol) and trifluoroacetic acid (2mL) in dichloromethane (5mL) was stirred at room temperature for 2 hours, concentrated under reduced pressure directly, and the residue was analyzed by prep-HPLC (separation condition 2) Compound 13 (16 mg, yield: 94%) was prepared as a white solid.
  • Step 1 Compound 4.1 (3g, 10.7mmol), HATU (5.36g, 14.1mmol), bis(2-((tert-butyldimethylsilyl)oxy)ethyl)amine (3.76g, 11.3mmol ) and DIPEA (3.64 g, 28.2 mmol) in DMF (30 mL) was stirred overnight at room temperature.
  • Step 2 Compound 8.1 (6.5g, 10.9mmol), Xphos (0.5g, 1mmol), Pd2(dba )3 ( 0.5g, 0.54mmol) were dissolved in fresh (1-(methoxycarbonyl)cyclopropyl) Zinc bromide in tetrahydrofuran (1eq, 160mL), the reaction system was replaced with nitrogen three times, then stirred at 75°C for 5 hours under nitrogen protection, after cooling to room temperature, ice water was added to quench the reaction, and the aqueous phase was extracted with ethyl acetate , the organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure.
  • Step 5 To a solution of compound 8.4 (200 mg, 0.28 mmol) in DMF (5 mL) was sequentially added tert-butyl 3-amino-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate ( 84mg, 0.34mmol), HATU (160mg, 0.42mmol) and DIPEA (109mg, 0.84mmol), the reaction solution was stirred overnight at room temperature.
  • Step 6 Trifluoroacetic acid (1 mL) was added to a solution of compound 8.5 (200 mg, 0.21 mmol) in dichloromethane (4 mL), the reaction solution was stirred at room temperature for 1 hour, concentrated under reduced pressure and directly purified by prep-HPLC to obtain Compound 14 (23 mg, yield: 21%) was a white solid.
  • tert-butyl 3-amino-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate in step 5 was replaced by ((5-aminopyridine-3 -yl)methyl)carbamate tert-butyl ester afforded compound 16 as a white solid.
  • Step 1 Using the synthesis method of compound 14 step 1, react with 2-amino-8-(methoxycarbonyl)-3H-benzo[b]azepine-4-carboxylate hydrochloride to obtain compound 9.1 as yellow solid. m/z: [M+H] + 640.1.
  • Steps 2-5 Using the synthesis method of compound 14 in steps 3-6, react with compound 9.1 to obtain compound 18 as a white solid. m/z: [M+H] + 465.2.
  • Embodiment 19 Synthesis of compound II-1
  • Embodiment 20 ⁇ 42 the synthesis of compound II-2 ⁇ II-24
  • Antibody reduction Put 2mL (10.4mg/mL) of antibody solution into the container of Amicon Ultra-15 (30,000MWCO, Millipore Corporation), and use a centrifuge to perform centrifugation (centrifuge at 3800G for 5 minutes), and the antibody solution concentrate. Use the antibody concentration determination method to measure the concentration of the antibody solution at 25 mg/mL.
  • the Sephadex G-25 carrier NAP-25 column (5mL/12mL) was equilibrated with phosphate buffer (50mM, pH6.5; called PBS6.5/EDTA) containing sodium chloride (50mM) and EDTA (2mM).
  • the concentration of the linked drug in the antibody-drug conjugate can be calculated by measuring the UV absorbance of an aqueous solution of the antibody-drug conjugate at a wavelength of 280 nm, and then performing the following calculation.
  • the total absorbance at a certain wavelength is equal to the sum of the absorbances of all types of absorbing chemical substances present in the system (the additivity of absorbance), it is assumed that the molar absorptivity of the antibody and the drug is different before and after the coupling of the antibody and the drug.
  • the antibody concentration and drug concentration in the antibody-drug conjugate are expressed by the following relational formula.
  • the average number of drug linkages per molecule of antibody in the antibody-drug conjugate can be determined by high-performance liquid chromatography (HPLC) analysis using the following method.
  • Mobile phase B 50mM sodium phosphate (pH 7.0)/isopropanol (75:25V/V)
  • Hydrophobic interaction chromatography can be used to determine the drug-antibody coupling ratio (DAR) of antibody-conjugated drugs.
  • the unconjugated antibody drug has the weakest hydrophobicity and is eluted first; the antibody linked to 8 drugs has the strongest hydrophobicity and is finally eluted. elute.
  • the sample was diluted to about 2.0 mg/ml with mobile phase A, and an appropriate amount of the diluted solution was centrifuged at 12000 rpm for 5 min, and the supernatant was taken for analysis.
  • the chromatograms were integrated, and the peak area percentages of monomers, polymers, and low molecular weight impurities were calculated using the peak area normalization method.
  • Embodiment 44 ⁇ 66 Preparation of III-1 ⁇ III-23
  • Example 43 Using the general preparation method of Example 43, antibody (Trastuzumab-LALA, B801901, Shanghai Baiying Biotechnology Co., Ltd.) and compound II-4 were used to prepare III-24, with a DAR value of 4.53.
  • Ref.A was prepared with antibody (Trastuzumab, Shanghai Roche Pharmaceutical Co., Ltd.) and compound A (CN110612104A compound 2.14), with a DAR value of 3.21.
  • TLR7 and TLR8 biological activities of compounds represented by formula I were measured using cell assays.
  • the method is carried out in human embryonic kidney cells (HEK293) expressing TLR family members such as TLR4, TLR7, TLR8 or TLR9.
  • TLR agonists activate TLRs, causing downstream NF-kB activation, which in turn activates secreted embryonic alkaline phosphatase (secreted embryonic alkaline phosphatase, SEAP) reporter gene, using Quanti-Blue (InvivoGen) reagent to detect SEAP activity, thus reflecting the activity of TLR7 and TLR8 agonists.
  • HEK-BLUE-hTLR7 and HEK-BLUE-hTLR8 cell lines were purchased from Invivogen, and cultured in DMEM medium containing 4.5 g/L glucose (Sigma-Aldrich) and 10% fetal bovine serum at a temperature of 37°C, Humidity 95% and 5% CO 2 .
  • the compound test concentration was 10 concentration gradients from 0.5 nM to 15 ⁇ M.
  • the cells were treated as follows: remove the cells from the culture dish and centrifuge to remove the medium, resuspend them in a T-150 bottle with 10 mL of preheated PBS, add 12 mL of preheated medium, gently blow up and down, and count under a microscope. Immediately prepare 200,000 cells/mL single-cell suspension with culture medium, and add 200 ⁇ L/well (40,000 cells/well) to a 96-well plate. The final concentration of DMSO was 0.5%.
  • Effect% (OD average value of drug administration group-OD average value of DMSO group)/(OD average value of positive drug group-OD average value of DMSO group) ⁇ 100
  • the concentration-effect curve was fitted by Graphpad software, and the EC 50 was calculated.
  • the test results are as shown in Table 4 (A represents ⁇ 100nM, B represents 100nM-250nM, C represents 250nM-1 ⁇ M, D represents> 2 ⁇ M, / represents not tested), except for the compounds in Table 4, the rest are as shown in Formula I Shown compound also all has preferred activity:
  • Human breast cancer epithelial cells BT474 in normal growth state (Nanjing Kebai Biotechnology Co., Ltd.) were collected, resuspended in RPMI 1640 complete medium, and adjusted to a density of 4 ⁇ 10 5 /mL. Add it to a 96-well plate, 50 ⁇ L per well, and mix with hPBMC.
  • the final concentration of the compound of formula III is 100 nM-0.032 nM (6 gradients), such as the final concentration of the compound of formula I is 400 nM-0.128 nM (6 gradients).
  • concentrations of TNF- ⁇ and IFN- ⁇ were detected and analyzed by HTRF (Cisbio) and Infinite M1000PRO (TECAN). The test results of TNF- ⁇ are shown in Table 5 (D means >400nM).
  • Human breast cancer epithelial cells BT474 in normal growth state (Nanjing Kebai Biotechnology Co., Ltd.) were collected, resuspended in RPMI 1640 complete medium, and adjusted to a density of 4 ⁇ 10 5 /mL. Add it to a 96-well plate, 50 ⁇ L per well, and mix with hPBMC.
  • TNF- ⁇ test results are shown in Table 5 (A means ⁇ 1nM, B means 1-10nM, C means>10nM):
  • TNF- ⁇ (BT474/hPBMC) EC 50 TNF- ⁇ (hPBMC) EC 50 III-2 B D. III-3 B D. III-4 A D. III-11 A D. III-12 A D. III-13 A D.
  • Steps Coat a 96-well plate with goat anti-human IgG antibody, freeze overnight at 4°C, wash three times with PBS/0.05% Tween20 the next day, block the plate with PBS/0.05% Tween20/1% BSA, and incubate at 37°C for 1-2 hours , wash three times, and add diluted standard and test samples to the wells, incubate at room temperature for 2 hours, wash three times, then add HRP-labeled anti-human IgG antibody diluted in buffer, and incubate at room temperature for 1 hour. Finally, add the chromogenic solution and incubate at room temperature for 10 minutes to terminate the reaction. Read the OD value at 450nm absorbance. The experimental results are shown in Table 6:
  • Mouse colon cancer MC38-HER2 cells were maintained in monolayer culture in a DMEM medium containing 10% fetal bovine serum and 4ug/ml puromycin at 37°C in a constant temperature incubator containing 5% CO2. Tumor cells were subcultured twice a week. Cells in exponential growth phase were harvested and counted for inoculation.
  • mice B6-hTLR8-HO mice, 6-8 weeks, 18-22g.
  • mice were randomly divided into groups according to the tumor size and body weight, and administered according to the dosing plan shown in Table 7. During the whole experiment, the mouse body weight and tumor size were measured twice a week.

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Abstract

涉及一种含氮化合物、含其的偶联物及其应用。具体提供了一种如式（I）所示化合物、其溶剂合物、其药学上可接受的盐或其药学上可接受的盐的溶剂合物。该含氮化合物对TLR8具有良好调节作用，可以有效治疗、缓解和/或预防由于免疫抑制所引起的各种相关疾病，例如癌症或病毒感染。

Description

一种含氮化合物、含其的偶联物及其应用
本申请要求申请日为2021/5/19的中国专利申请202110547613.7的优先权，本申请要求申请日为2021/7/21的中国专利申请202110825530.X的优先权，本申请要求申请日为2022/5/11的中国专利申请202210515784.6的优先权。本申请引用上述中国专利申请的全文。
技术领域
本发明涉及了一种含氮化合物、含其的偶联物及其应用。
背景技术
Toll样受体家族(TLRs)是识别病原相关分子模式重要蛋白家族，可以感应并启动固有免疫应答并促进适应性免疫应答的发展。TLRs主要表达于免疫细胞，如髓样树突状细胞(mDC)、浆样树突状细胞(pDC)、单核细胞及B细胞(Kawai and Akira,2010)及肺。在人体中，超过10个TLRs被认为具有显著的功能。TLR1/2/4/5及6位于细胞膜中，主要功能是识别来自于细菌及真菌的细胞外大分子配体。相反，TLR3/7/8/9位于细胞内的内涵体膜中，主要功能是识别来自病原体细胞内的外源性核酸类。尽管多数TLRs通过特定的信号通路(主要是通过MyD88依赖型通路)来发挥作用，不同的TLRs可以协调不同的下游分子。特定TLRs的加入导致不同细胞群体的激活(Schreibelt,et al,2010)及不同模式细胞因子与其它炎性介质的产生(Ghosh,et al,2006)，从而引起不同的免疫应答。例如，与配体结合后，TLR8形成二聚体并发生构象变化导致衔接蛋白MyD88的参与，MyD88招募白介素1受体相关激酶，导致下游信号通路的激活，包括分裂素相关蛋白激酶及转录因子NF-B。
位于内涵体的TLRs，主要是TLR7/8/9已被认为是抗癌免疫疗法极具吸引力的新靶点(Kanzler,et al,2007；Kreig 2008；Smits,et al,2008；Hennessy,et al,2010；Kaczanowska,et al,2013；Beesu,et al,2016)。如TLR7活化pDCs对病毒性感染产生应答，诱导高水平的干扰素α，并诱导主要细胞对内源性病毒抗原的适应性T细胞应答(Liu,et al,2009)。与TLR7/9相比，TLR8在不同亚型的免疫细胞中的表达更广泛。调节性T细胞(Treg)具有强有力的免疫应答抑制能力，是有效的癌症免疫治疗的主要障碍。TLR8信号通路被证明是逆转Treg细胞抑制功能导致强烈肿瘤抑制所必要且充分的条件。TLR8选择性激动剂有效的激活多种免疫细胞，包括mDCs及单核细胞(Gorden,et al,2005)，可促进针对癌症细胞的适应性免疫应答的产生(Krug,et al,2003；Schnurr,et al,2005)。激活的mDCs吞噬凋亡及死亡的肿瘤细胞，接着，与pDCs相比，更有效的向CD8+CTLs交叉呈递肿瘤相关抗原(Berard,et al,2000；Dalgaard,et al,2005)。此外，mDCs激活，导致TNFα及白介素12(IL-12)的释放可刺激T细胞及NK细胞的活化。NK细胞的激活是抗体介导的细胞毒性(ADCC)的主要机制。因而，通过ADCC加强对肿瘤细胞的杀伤可能为TLR8选择性抑制剂呈现出重要的治疗机遇(Lu,et al,2011)。一些单克隆抗体疗法被广泛用于癌症患者的治疗，如利妥昔单抗及曲妥单抗，它们可通过ADCC起 到治疗作用(Ferris,et al,2010)。事实上，在mAb治疗方法中加入TLR8激动剂可增强ADCC从而增加mAb治疗的疗效(Ferris,et al,2015)。此外，最近的研究还表明TLR8激动剂可直接起到抗肿瘤的作用，而不依赖于它的免疫调节功能(Ignatz-Hoover,et al,2015)。因此，TLR8激动剂不仅可作为单药治疗而起作用，还可通过增强宿主免疫应答提高多种化疗及靶向抗癌药物的疗效。
在识别病原微生物核酸的TLRs家族成员中，TLR7和TLR8具有很高同源性，可以识别一些人工合成的具有抗病毒作用的小分子，例如Imidazoquinolines咪唑喹啉类小分子化合物(TLR7和TLR8的配体)。在由HSV感染的天竺鼠生殖器疱疹模型中对Imidazoquinolines进行研究，发现该化合物对体外病毒复制效果较小，但在体内有较强的效果，表明该类化合物促进免疫细胞生成前炎因子及调节细胞因子，导致抗病毒反应(Int Immunopharmacol 2002；2:443-451)。更重要的是TLR7和TLR8可以识别病毒ssRNA。研究证明，ssRNA病毒是TLR7和TLR8的天然配体，例如I型人类免疫缺陷病毒(HIV)、流感病毒、仙台病毒、登革热病毒、新城疫病毒(NDV)、水泡性口炎病毒(VSV)、乙型肝炎病毒(HBV)及丙型肝炎病毒(HCV)等。TLR8能识别抗病毒化合物、ssRNA病毒、人工合成的寡核苷酸等，通过MyD88依赖信号通路诱导Th1、抑制Th2细胞因子分泌和Tregs增殖，介导抗病毒免疫，发挥抗感染、抗过敏效应。
因此，目前TLR8是一个极具吸引力的治疗靶点。尽管已经有了较多关于TLRs的研究，但对于进一步扩展其运用及优势仍具有巨大的机遇。本发明所描述的化合物及应用将有助于TLR8激动剂的发展，满足临床上未满足的需求。
发明内容
本发明所要解决的技术问题为现有的TLR8激动剂的结构较为单一，为此，本发明提供了一种含氮化合物、含其的偶联物及其应用。该含氮化合物对TLR8具有良好调节作用，可以有效治疗、缓解和/或预防由于免疫抑制所引起的各种相关疾病，例如癌症或病毒感染。
本发明提供了一种如式I所示化合物、其溶剂合物、其药学上可接受的盐或其药学上可接受的盐的溶剂合物；
Figure PCTCN2022093953-appb-000001
其中，
α和β独立地为单键或双键；并且，α和β至少有一个为单键；
m为0或1；
X 1为N或CR 2，X 2为N或CR 3，X 3为N或CR 1；
R为-C(O)-L 1-R 7、-C(O)-NR 9-L 1-R 7、-C(S)-NR 9-L 1-R 7、-NR 9-L 1-R 7、-NR 9-C(O)-L 1-R 7、-NR 9-C(O)-NR 9-L 1-R 7、-O-L 1-R 7、-S(O) 2-NR 9-L 1-R 7、-CH＝CH-L 1-R 7或-S(O) 2-L 1-R 7；
R 1、R 2和R 3分别独立地为氢、氘、卤素、羟基、氨基、氰基、烷基、卤代烷基、-L 2-OR a或-L 2-NR aR b；
R 4和R 4’分别独立地为氢、烷基、烯基、炔基、环烷基、杂环烷基、芳基、杂芳基、环烷基烷基、杂环烷基烷基、芳基烷基或杂芳基烷基；所述R 4或R 4’为未取代，或者选择性地被一个或多个选自卤素、氰基、-L 2-OR a、-L 2-OC(O)R a、-L 2-NR aR b、-L 2-NR aC(O)OR b、-L 2-NR aC(O)NR aR b、-L 2-NR bC(NR b)NR aR b和-L 2-C(O)OR b的取代基取代在任意位置；或者，R 4和R 4’与它们共同连接的N原子一起形成3-8元杂环烷基；所述3-8元杂环烷基为未取代或者进一步被1～3个选自卤素、氰基、-L 2-OR a、-L 2-OC(O)R a、-L 2-NR aR b、-L 2-NR aC(O)OR b、-L 2-NR aC(O)NR aR b、-L 2-NR bC(NR b)NR aR b和-L 2-C(O)OR b的取代基取代在任意位置；
R 5为＝O、＝NR a、-OR a或-NR aR b；
R 5’不存在，或者R 5’为-R c、-L 2-OR a、-L 2-NR aR b、-L 2-NR aC(O)OR b、-L 2-NR aC(O)NR aR b、-L 2-NR bC(NR b)NR aR b或-L 2-C(O)OR b；
R 7为苯基、5-6元杂芳基、3-8元杂环烷基或8-12元并环基团；所述R 7为未取代，或者选择性被一个或多个选自-L 3-W、-R c、卤素、氰基、硝基、烷基、烯基、炔基、烷氧基、卤代烷基、卤代烷氧基和烷氨基的取代基取代在任意位置；
R 8和R 8’分别独立地为氢、卤素或烷基，所述R 8或R 8’为未取代，或者选择性被一个或多个选自-L 3-W、卤素、氰基、硝基、烷基、烯基、炔基、烷氧基、卤代烷基、卤代烷氧基和烷氨基的取代基取代在任意位置；R 8和R 8’分别为独立取代基，或者，R 8和R 8’与其共同连接的碳原子一起形成氧代基、硫代基、C 1-6亚烷基、C 3-10环烷基或3-10元杂环烷基；所述C 1-6亚烷基、C 3-10环烷基或3-10元杂环烷基为未取代，或者选择性被一个或多个选自氘、卤素、羟基、氨基、氰基、氧代基、烷基、卤代烷基、-L 2-OR a和-L 2-NR aR b的取代基取代在任意位置；
R 9为氢、烷基、卤代烷基、-L 2-OR a或-L 2-NR aR b；
W为Cy 1、-SR d、-OR d、-OC(O)R e、-OC(O)NR eR e’、-C(O)OR e、-C(O)R e、-C(O)NR eR e’、-C(O)NR eS(O) 2R e、-NR dR e、-NR dC(O)R e、-N(R d)C(O)OR e、-N(R d)C(O)NR eR e’、-NR dS(O) 2R e、-NR dS(O) 2NR eR e’、-S(O) 1-2R e、-S(O) 2NR eR e’、-S(O)(＝NR d)R e、-S(O) 2N(R e)C(O)R e’、-P(O)(OR e) 2、-P(O)(OR e)R e’、-OP(O)(OR e) 2或-B(OR e) 2；
Cy 1为环烷基、杂环烷基、芳基或杂芳基；所述Cy 1为未取代，或者选择性地被一个或多个选自卤素、烷基、卤代烷基、卤代烷氧基、烯基、炔基、氰基、-R c、-L 4-SR d、-L 4-OC(O)R e、-L 4-C(O)OR e、-L 4-C(O)R e、-L 4-C(O)NR eR e’、-L 4-NR dC(O)R e、-L 4-NR dS(O) 2R e、-L 4-S(O) 1-2R e、-L 4-S(O) 2NR eR e’、-L 4-OR d和-L 4-NR eR e’的取代基取代在任意位置；
L 1、L 2、L 3和L 4分别独立地为连接键、C 1-6亚烷基、C 2-6亚烯基或C 2-6亚炔基；所述L 1、L 2、L 3或L 4为未取代，或者选择性被一个或多个选自氧代基、羟基、氨基、卤素、氰基、烷基、卤代烷基、烷氧基和卤代烷氧基的取代基取代在任意位置；
每个R a、R b、R d、R e和R e’分别独立地为-R c、氨基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-10环烷 基、3-10元杂环烷基、C 6-10芳基、5-10元杂芳基、C 3-10环烷基C 1-6烷基、3-10元杂环烷基C 1-6烷基、苯基C 1-6烷基或5-10元杂芳基C 1-6烷基；所述R a、R b、R d、R e或R e’为未取代或者选择性地被1～3个选自-OR f、-OC(O)-L 4-R f、-NR fR f’、卤素、氰基、硝基、C 1-6烷基、卤代C 1-6烷基和卤代C 1-6烷氧基的取代基取代在任意位置；
每个R f和R f’分别独立地为-R c、-NHR c或C 1-6烷基；
每个R c分别独立地为氢；
且如式I所示化合物满足下列条件中的1个、2个、3个或4个：
(1)m为1；
(2)R为-C(S)-NR 9-L 1-R 7、-NR 9-L 1-R 7、-NR 9-C(O)-L 1-R 7、-NR 9-C(O)-NR 9-L 1-R 7、-O-L 1-R 7、-S(O) 2-NR 9-L 1-R 7、-CH＝CH-L 1-R 7或-S(O) 2-L 1-R 7；
(3)X 1、X 2和X 3中至少一个为N；
(4)R 4和R 4’中的至少一个被一个或多个选自卤素、氰基、-L 2-OR a、-L 2-OC(O)R a、-L 2-NR aR b、-L 2-NR aC(O)OR b、-L 2-NR aC(O)NR aR b、-L 2-NR bC(NR b)NR aR b和-L 2-C(O)OR b的取代基取代在任意位置。
在一些实施方案中，所述的如式I所示化合物、其溶剂合物、其药学上可接受的盐或其药学上可接受的盐的溶剂合物里，部分基团的定义如下所述，其余基团的定义如其他任一方案所述(以下简称“在一些实施方案中”)：m可为1。
在一些实施方案中，m可为1，R 8和R 8’分别独立地为未取代的烷基；或者，R 8和R 8’与其共同连接的碳原子一起形成氧代基或未取代的C 3-10环烷基。
在一些实施方案中，R可为-C(S)-NR 9-L 1-R 7、-NR 9-L 1-R 7、-NR 9-C(O)-L 1-R 7、-NR 9-C(O)-NR 9-L 1-R 7、-O-L 1-R 7、-S(O) 2-NR 9-L 1-R 7、-CH＝CH-L 1-R 7或-S(O) 2-L 1-R 7。
在一些实施方案中，R可为-C(S)-NR 9-L 1-R 7或-NR 9-L 1-R 7；
在一些实施方案中，R可为-NR 9-L 1-R 7。
在一些实施方案中，X 1、X 2和X 3中至少一个可为N。
在一些实施方案中，X 1可为N。
在一些实施方案中，X 1可为N，X 2和X 3为CH。
在一些实施方案中，R 4和R 4’中的至少一个被一个或多个选自卤素、氰基、-L 2-OR a、-L 2-OC(O)R a、-L 2-NR aR b、-L 2-NR aC(O)OR b、-L 2-NR aC(O)NR aR b、-L 2-NR bC(NR b)NR aR b和-L 2-C(O)OR b的取代基取代在任意位置。
在一些实施方案中，R 4和R 4’中的至少一个被一个或多个选自-L 2-OR a和-L 2-NR aR b的取代基取代在任意位置。
在一些实施方案中，R 4和R 4’分别独立地为烷基；所述R 4或R 4’中的至少一个被一个或多个选自-L 2-OR a和-L 2-NR aR b的取代基取代在任意位置。
在一些实施方案中，R 4和R 4’分别独立地为烷基；所述R 4或R 4’中的至少一个被一个选自羟基和氨基的取代基取代在任意位置。
在一些实施方案中，R 4和R 4’分别独立地为烷基；所述R 4或R 4’中的至少一个被一个羟基取代在任意位置。
在一些实施方案中，R为-C(O)-NR 9-L 1-R 7、-C(S)-NR 9-L 1-R 7或-NR 9-L 1-R 7；R 9为氢，L 1为连接键，R 7为未取代的8-12元并环基团或者被一个-L 3-W取代的5-6元杂芳基；L 3为C 1-6亚烷基，W为-NR dR e；R d和R e为-R c，R c为氢。
在一些实施方案中，m为0或1；R 8和R 8’分别独立地为未取代的烷基；或者，R 8和R 8’与其共同连接的碳原子一起形成氧代基或未取代的C 3-10环烷基。
在一些实施方案中，X 1为N或CR 2，X 2为N或CR 3，X 3为N或CR 1；R 1、R 2和R 3分别独立地为氢、氘、卤素或氰基。
在一些实施方案中，α为双键，R 5’不存在；β为单键，R 5为-NR aR b；R a和R b为-R c，R c为氢。
在一些实施方案中，R 4和R 4’分别独立地为烷基；所述R 4和R 4’分别独立地为未取代，或者选择性地被一个或多个选自-L 2-OR a和-L 2-NR aR b的取代基取代在任意位置；L 2为连接键；R a和R b为-R c，R c为氢。
在一些实施方案中，
Figure PCTCN2022093953-appb-000002
R为-C(O)-NR 9-L 1-R 7、-C(S)-NR 9-L 1-R 7或-NR 9-L 1-R 7；R 9为氢，L 1为连接键，R 7为未取代的8-12元并环基团或者被一个-L 3-W取代的5-6元杂芳基；L 3为C 1-6亚烷基，W为-NR dR e；
m为0或1；R 8和R 8’分别独立地为未取代的烷基；或者，R 8和R 8’与其共同连接的碳原子一起形成氧代基或未取代的C 3-10环烷基；
X 1为N或CR 2，X 2为N或CR 3，X 3为N或CR 1；R 1、R 2和R 3分别独立地为氢、氘、卤素或氰基；
α为双键，R 5’不存在；β为单键，R 5为-NR aR b；
R 4和R 4’分别独立地为烷基；所述R 4和R 4’分别独立地为未取代，或者选择性地被一个或多个选自-L 2-OR a和-L 2-NR aR b的取代基取代在任意位置；L 2为连接键；
R a、R b、R d和R e为-R c，R c为氢；
且如式I所示化合物满足下列条件中的1个、2个、3个或4个：
(1)m为1；
(2)R为-C(S)-NR 9-L 1-R 7或-NR 9-L 1-R 7；
(3)X 1、X 2和X 3中至少一个为N；
(4)R 4和R 4’中的至少一个被一个或多个选自-L 2-OR a和-L 2-NR aR b的取代基取代在任意位置。
在一些实施方案中，R 7中，所述的8-12元并环基团可为环A并环B，所述的环A为5～6元杂芳基，环B为5～6元杂烯环；所述的5～6元杂芳基中，杂原子选自N、O和S中的一种或多种，杂原子的数量为1个、2个或3个；所述的5～6元杂烯环中，杂原子选自N、O和S中的一种或多种，杂原子的数量为1个、2个或3个。
在一些实施方案中，R 7中，所述的8-12元并环基团可为环A并环B，所述的环A为5～6元杂芳基，环B为5～6元杂烯环，其通过所述的环A与所述的L 1连接；所述的5～6元杂芳基中，杂原子为N，杂原子的数量为1个或2个；所述的5～6元杂烯环中，杂原子为N，杂原子的数量为1个或2个。
在一些实施方案中，R 7中，所述的8-12元并环基团可为
Figure PCTCN2022093953-appb-000003
又可为
Figure PCTCN2022093953-appb-000004
在一些实施方案中，R 7中，所述的5-6元杂芳基里，杂原子可选自N、O和S中的一种或多种，杂原子的数量可为1个、2个或3个。
在一些实施方案中，R 7中，所述的5-6元杂芳基里，杂原子可为N，杂原子的数量可为1个或2个。
在一些实施方案中，R 7中，所述的5-6元杂芳基可为吡啶基，又可为吡啶-3-基。
在一些实施方案中，L 3中，C 1-6亚烷基可为C 1-3亚烷基，又可为-CH 2-、-CH 2CH 2-或-CH 2CH 2CH 2-。
在一些实施方案中，R 7中，所述的被一个-L 3-W取代的5-6元杂芳基可为
Figure PCTCN2022093953-appb-000005
又可为
Figure PCTCN2022093953-appb-000006
还可为
Figure PCTCN2022093953-appb-000007
在一些实施方案中，R 8和R 8’中，所述的烷基可为C 1-6烷基，又可为甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基。
在一些实施方案中，R 8和R 8’与其共同连接的碳原子一起形成的C 3-10环烷基可为饱和单环基团。
在一些实施方案中，R 8和R 8’与其共同连接的碳原子一起形成的C 3-10环烷基可为C 3-6环烷基，又可为环丙基、环丁基、环戊基或环己基。
在一些实施方案中，R 1、R 2和R 3中，所述的卤素可为氟、氯、溴或碘，又可为氟。
在一些实施方案中，R 4和R 4’中，所述的烷基可为C 1-6烷基，又可为甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基。
在一些实施方案中，R 4为-CH 2CH 2OH或-CH 2CH 2CH 3。
在一些实施方案中，R 4’为-CH 2CH 2OH或-CH 2CH 2CH 3。
在一些实施方案中，R 4为-CH 2CH 2OH或-CH 2CH 2CH 3；R 4’为-CH 2CH 2OH或-CH 2CH 2CH 3。
在一些实施方案中，
Figure PCTCN2022093953-appb-000008
其中，
α和β独立地为单键或双键；并且，α和β至少有一个为单键；
m为0或1；
X 1为N或CR 2，X 2为N或CR 3，X 3为N或CR 1；并且，X 1为CR 2，X 2为CR 3和X 3为CR 1时，m为1；
R为-C(O)-L 1-R 7、-C(O)-NR 9-L 1-R 7、-C(S)-NR 9-L 1-R 7、-NR 9-L 1-R 7、-NR 9-C(O)-L 1-R 7、-NR 9-C(O)-NR 9-L 1-R 7、-O-L 1-R 7、-S(O) 2-NR 9-L 1-R 7、-CH＝CH-L 1-R 7或-S(O) 2-L 1-R 7；
R 1、R 2和R 3分别独立地为氢、氘、卤素、羟基、氨基、氰基、烷基、卤代烷基、-L 2-OR a或-L 2-NR aR b；
R 4和R 4’分别独立地为氢、烷基、烯基、炔基、环烷基、杂环烷基、芳基、杂芳基、环烷基烷基、杂环烷基烷基、芳基烷基或杂芳基烷基；所述R 4或R 4’为未取代，或者选择性地被一个或多个选自卤素、氰基、-L 2-OR a、-L 2-OC(O)R a、-L 2-NR aR b、-L 2-NR aC(O)OR b、-L 2-NR aC(O)NR aR b、-L 2-NR bC(NR b)NR aR b和-L 2-C(O)OR b的取代基取代在任意位置；或者，R 4和R 4’与它们共同连接的N原子一起形成3-8元杂环烷基；所述3-8元杂环烷基为未取代或者进一步被1～3个选自卤素、氰基、-L 2-OR a、-L 2-OC(O)R a、-L 2-NR aR b、-L 2-NR aC(O)OR b、-L 2-NR aC(O)NR aR b、-L 2-NR bC(NR b)NR aR b和-L 2-C(O)OR b的取代基取代在任意位置；
R 5为＝O、＝NR a、-OR a或-NR aR b；
R 5’不存在，或者R 5’为-R c、-L 2-OR a、-L 2-NR aR b、-L 2-NR aC(O)OR b、-L 2-NR aC(O)NR aR b、-L 2-NR bC(NR b)NR aR b或-L 2-C(O)OR b；
R 7为苯基、5-6元杂芳基、3-8元杂环烷基或8-12元并环基团；所述R 7为未取代，或者选择性被一个或多个选自-L 3-W、-R c、卤素、氰基、硝基、烷基、烯基、炔基、烷氧基、卤代烷基、卤代烷氧基和烷氨基的取代基取代在任意位置；
R 8和R 8’分别独立地为氢、卤素或烷基，所述R 8或R 8’为未取代，或者选择性被一个或多个选自-L 3-W、卤素、氰基、硝基、烷基、烯基、炔基、烷氧基、卤代烷基、卤代烷氧基和烷氨基的取代基取代在任意位置；R 8和R 8’分别为独立取代基，或者，R 8和R 8’与其共同连接的碳原子一起形成氧代 基、硫代基、C 1-6亚烷基、C 3-10环烷基或3-10元杂环烷基；所述C 1-6亚烷基、C 3-10环烷基或3-10元杂环烷基为未取代，或者选择性被一个或多个选自氘、卤素、羟基、氨基、氰基、氧代基、烷基、卤代烷基、-L 2-OR a和-L 2-NR aR b的取代基取代在任意位置；
R 9为氢、烷基、卤代烷基、-L 2-OR a或-L 2-NR aR b；
W为Cy 1、-SR d、-OR d、-OC(O)R e、-OC(O)NR eR e’、-C(O)OR e、-C(O)R e、-C(O)NR eR e’、-C(O)NR eS(O) 2R e-NR dR e、-NR dC(O)R e、-N(R d)C(O)OR e、-N(R d)C(O)NR eR e’、-NR dS(O) 2R e、-NR dS(O) 2NR eR e’、-S(O) 1-2R e、-S(O) 2NR eR e’、-S(O)(＝NR d)R e、-S(O) 2N(R e)C(O)R e’、-P(O)(OR e) 2、-P(O)(OR e)R e’、-OP(O)(OR e) 2或-B(OR e) 2；
Cy 1为环烷基、杂环烷基、芳基或杂芳基；所述Cy 1为未取代，或者选择性地被一个或多个选自卤素、烷基、卤代烷基、卤代烷氧基、烯基、炔基、氰基、-R c、-L 4-SR d、-L 4-OC(O)R e、-L 4-C(O)OR e、-L 4-C(O)R e、-L 4-C(O)NR eR e’、-L 4-NR dC(O)R e、-L 4-NR dS(O) 2R e、-L 4-S(O) 1-2R e、-L 4-S(O) 2NR eR e’、-L 4-OR d和-L 4-NR eR e’的取代基取代在任意位置；
L 1、L 2、L 3和L 4分别独立地为连接键、C 1-6亚烷基、C 2-6亚烯基或C 2-6亚炔基；所述L 1、L 2、L 3或L 4为未取代，或者选择性被一个或多个选自氧代基、羟基、氨基、卤素、氰基、烷基、卤代烷基、烷氧基和卤代烷氧基的取代基取代在任意位置；
每个R a、R b、R d、R e和R e’分别独立地为-R c、氨基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-10环烷基、3-10元杂环烷基、C 6-10芳基、5-10元杂芳基、C 3-10环烷基C 1-6烷基、3-10元杂环烷基C 1-6烷基、苯基C 1-6烷基或5-10元杂芳基C 1-6烷基；所述R a、R b、R d、R e或R e’为未取代或者选择性地被1～3个选自-OR f、-OC(O)-L 4-R f、-NR fR f’、卤素、氰基、硝基、C 1-6烷基、卤代C 1-6烷基和卤代C 1-6烷氧基的取代基取代在任意位置；
每个R f和R f’分别独立地为-R c、-NHR c或C 1-6烷基；
每个R c分别独立地为氢。
在一些实施方案中，
Figure PCTCN2022093953-appb-000009
其中，
α和β独立地为单键或双键；并且，α和β至少有一个为单键；
m为0或1；
X 1为N或CR 2，X 2为N或CR 3，X 3为N或CR 1；并且，X 1为CR 2，X 2为CR 3和X 3为CR 1时，m为1；
R为-C(O)-L 1-R 7、-C(O)-NR 9-L 1-R 7、-C(S)-NR 9-L 1-R 7、-NR 9-L 1-R 7、-NR 9-C(O)-L 1-R 7、-NR 9-C(O)-NR 9-L 1-R 7、-O-L 1-R 7、-S(O) 2-NR 9-L 1-R 7、-CH＝CH-L 1-R 7或-S(O) 2-L 1-R 7；
R 1、R 2和R 3分别独立地为氢、氘、卤素、羟基、氨基、氰基、烷基、卤代烷基、-L 2-OR a或-L 2-NR aR b；
R 4和R 4’分别独立地为氢、烷基、烯基、炔基、环烷基、杂环烷基、芳基、杂芳基、环烷基烷基、杂环烷基烷基、芳基烷基或杂芳基烷基；所述R 4或R 4’为未取代，或者选择性地被一个或多个选自卤素、氰基、-L 2-OR a、-L 2-NR aR b、-L 2-NR aC(O)OR b、-L 2-NR aC(O)NR aR b、-L 2-NR bC(NR b)NR aR b和-L 2-C(O)OR b的取代基取代在任意位置；或者，R 4和R 4’与它们共同连接的N原子一起形成3-8元杂环烷基；所述3-8元杂环烷基为未取代或者进一步被1～3个选自卤素、氰基、-L 2-OR a、-L 2-NR aR b、-L 2-NR aC(O)OR b、-L 2-NR aC(O)NR aR b、-L 2-NR bC(NR b)NR aR b和-L 2-C(O)OR b的取代基取代在任意位置；
R 5为＝O、＝NR a、-OR a或-NR aR b；
R 5’不存在，或者R 5’为-R c、-L 2-OR a、-L 2-NR aR b、-L 2-NR aC(O)OR b、-L 2-NR aC(O)NR aR b、-L 2-NR bC(NR b)NR aR b或-L 2-C(O)OR b；
R 7为苯基、5-6元杂芳基、3-8元杂环烷基或8-12元并环基团；所述R 7为未取代，或者选择性被一个或多个选自-L 3-W、-R c、卤素、氰基、硝基、烷基、烯基、炔基、烷氧基、卤代烷基、卤代烷氧基和烷氨基的取代基取代在任意位置；
R 8和R 8’分别独立地为氢、卤素或烷基，所述R 8或R 8’为未取代，或者选择性被一个或多个选自-L 3-W、卤素、氰基、硝基、烷基、烯基、炔基、烷氧基、卤代烷基、卤代烷氧基和烷氨基的取代基取代在任意位置；R 8和R 8’分别为独立取代基，或者，R 8和R 8’与其共同连接的碳原子一起形成氧代基、硫代基、C 1-6亚烷基、C 3-10环烷基或3-10元杂环烷基；所述C 1-6亚烷基、C 3-10环烷基或3-10元杂环烷基为未取代，或者选择性被一个或多个选自氘、卤素、羟基、氨基、氰基、氧代基、烷基、卤代烷基、-L 2-OR a和-L 2-NR aR b的取代基取代在任意位置；
R 9为氢、烷基、卤代烷基、-L 2-OR a或-L 2-NR aR b；
W为Cy 1、-SR d、-OR d、-OC(O)R e、-OC(O)NR eR e’、-C(O)OR e、-C(O)R e、-C(O)NR eR e’、-C(O)NR eS(O) 2R e-NR dR e、-NR dC(O)R e、-N(R d)C(O)OR e、-N(R d)C(O)NR eR e’、-NR dS(O) 2R e、-NR dS(O) 2NR eR e’、-S(O) 1-2R e、-S(O) 2NR eR e’、-S(O)(＝NR d)R e、-S(O) 2N(R e)C(O)R e’、-P(O)(OR e) 2、-P(O)(OR e)R e’、-OP(O)(OR e) 2或-B(OR e) 2；
Cy 1为环烷基、杂环烷基、芳基或杂芳基；所述Cy 1为未取代，或者选择性地被一个或多个选自卤素、烷基、卤代烷基、卤代烷氧基、烯基、炔基、氰基、-R c、-L 4-SR d、-L 4-OC(O)R e、-L 4-C(O)OR e、-L 4-C(O)R e、-L 4-C(O)NR eR e’、-L 4-NR dC(O)R e、-L 4-NR dS(O) 2R e、-L 4-S(O) 1-2R e、-L 4-S(O) 2NR eR e’、-L 4-OR d和-L 4-NR eR e’的取代基取代在任意位置；
L 1、L 2、L 3和L 4分别独立地为连接键、C 1-6亚烷基、C 2-6亚烯基或C 2-6亚炔基；所述L 1、L 2、L 3或L 4为未取代，或者选择性被一个或多个选自氧代基、羟基、氨基、卤素、氰基、烷基、卤代烷基、 烷氧基和卤代烷氧基的取代基取代在任意位置；
每个R a、R b、R d、R e和R e’分别独立地为-R c、氨基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-10环烷基、3-10元杂环烷基、C 6-10芳基、5-10元杂芳基、C 3-10环烷基C 1-6烷基、3-10元杂环烷基C 1-6烷基、苯基C 1-6烷基或5-10元杂芳基C 1-6烷基；所述R a、R b、R d、R e或R e’为未取代或者选择性地被1～3个选自-OR f、-NR fR f’、卤素、氰基、硝基、C 1-6烷基、卤代C 1-6烷基和卤代C 1-6烷氧基的取代基取代在任意位置；
每个R f和R f’分别独立地为-R c、-NHR c或C 1-6烷基；
每个R c分别独立地为氢。
在一些实施方案中，X 3为CR 1。
在一些实施方案中，X 1为N或CR 2；X 2为CR 3。
在一些实施方案中，X 1为CR 2；X 2为N。
在一些实施方案中，每个R a、R b、R d、R e和R e’分别独立地为-R c、氨基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-10环烷基、3-10元杂环烷基、C 6-10芳基、5-10元杂芳基、C 3-10环烷基C 1-6烷基、3-10元杂环烷基C 1-6烷基、苯基C 1-6烷基或5-10元杂芳基C 1-6烷基；所述R a、R b、R d、R e或R e’为未取代或者选择性地被1～3个选自-OR f、-OC(O)-(CH 2) 1-5-R f、-NR fR f’、卤素、氰基、C 1-6烷基、卤代C 1-6烷基和卤代C 1-6烷氧基的取代基取代在任意位置。
在一些实施方案中，R为-C(O)-NR 9-L 1-R 7。
在一些实施方案中，R 1、R 2和R 3分别独立地为氢、氘、卤素、羟基、氨基、氰基、C 1-6烷基、卤代C 1-6烷基、-L 2-OR a或-L 2-NR aR b。
在一些实施方案中，R 1、R 2和R 3分别独立地为H、F、Cl、Br、-CH 3、-OCH 3、-CF 3、-CH 2F、-CHF 2、-OCF 3、-CN或-(CH 2) 0-5-NH 2。
在一些实施方案中，R 1为H；R 2为H。
在一些实施方案中，R 4和R 4’分别独立地为氢、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-8环烷基、3-8元杂环烷基、C 6-10芳基、5-10元杂芳基、C 3-8环烷基C 1-6烷基、3-8元杂环烷基C 1-6烷基、C 6-10芳基C 1-6烷基或5-10元杂芳基C 1-6烷基；所述R 4或R 4’为未取代，或者选择性地被1～3个选自卤素、氰基、-L 2-OR a、-L 2-OC(O)R a、-L 2-NR aR b、-L 2-NR aC(O)OR b、-L 2-NR aC(O)NR aR b、-L 2-NR bC(NR b)NR aR b和-L 2-C(O)OR b的取代基取代在任意位置；或者，R 4和R 4’与它们共同连接的N原子一起形成3-8元杂环烷基；所述3-8元杂环烷基为未取代，或者选择性地被1～3个选自卤素、氰基、-L 2-OR a、-L 2-NR aR b、-L 2-NR aC(O)OR b、-L 2-NR aC(O)NR aR b、-L 2-NR bC(NR b)NR aR b和-L 2-C(O)OR b的取代基取代在任意位置。
在一些实施方案中，R 4和R 4’分别独立地为C 1-6烷基；所述R 4或R 4’为未取代，或者选择性地被1～3个选自-OR a、-NR aR b、-OC(O)R a、-NR aC(O)OR b、-NR aC(O)NR aR b、-NR bC(NR b)NR aR b和-C(O)OR b的取代基取代在任意位置。
在一些实施方案中，R 4为C 1-6烷基；所述R 4为未取代或者选择性地被1个-OR a、-OC(O)R a、-NR aR b、-NR aC(O)OR b、-NR aC(O)NR aR b、-NR bC(NR b)NR aR b或-C(O)OR b的取代基取代在任意位置；R 4’为C 1-6 烷基；所述R 4’为未取代或者选择性地被1～3个选自卤素、-OR a和-NR aR b的取代基取代在任意位置。
在一些实施方案中，R 4和R 4’分别独立地为C 1-6烷基；所述R 4或R 4’为未取代或者选择性地被1个选自卤素、-OR a和-NR aR b的取代基取代在任意位置。
在一些实施方案中，R 4为-CH 2CH 2OH或-CH 2CH 2CH 3；R 4’为-CH 2CH 2OH、-CH 2CH 2CH 3、-CH 2CH 2CF 3或-CH 2CH 2CHF 2。
在一些实施方案中，α为双键、β为单键、R 5’为不存在、R 5为-NR aR b。
在一些实施方案中，α为双键、β为单键、R 5’为不存在，R 5为-NH 2。
在一些实施方案中，α为单键、β为双键、R 5’为H，R 5为＝O。
在一些实施方案中，R 8和R 8’分别独立地为氢、卤素或C 1-6烷基；所述R 8或R 8’为未取代，或者选择性被1～3个选自-L 3-W、卤素、氰基、硝基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6烷氧基、卤代C 1-6烷基、卤代C 1-6烷氧基和C 1-6烷氨基的取代基取代在任意位置。
在一些实施方案中，R 8和R 8’分别独立地为C 1-6烷基，所述C 1-6烷基优选为甲基。
在一些实施方案中，R 8和R 8’与其共同连接的碳原子一起形成氧代基、硫代基、C 3-6环烷基或3-6元杂环烷基；所述C 3-6环烷基或3-6元杂环烷基为未取代，或者选择性被1～3个选自氘、卤素、羟基、氨基、氰基、氧代基、C 1-6烷基、卤代C 1-6烷基、-L 2-OR a和-L 2-NR aR b的取代基取代在任意位置。
在一些实施方案中，R 8和R 8’与其共同连接的碳原子一起形成氧代基、硫代基、环丙基、环丁基、氮杂环丁基或氧杂环丁基；所述环丙基、环丁基、氮杂环丁基或氧杂环丁基为未取代，或者选择性被1～3个选自氘、卤素、羟基、氨基、氰基、氧代基、C 1-6烷基、卤代C 1-6烷基、-L 2-OR a和-L 2-NR aR b的取代基取代在任意位置。
在一些实施方案中，R 8和R 8’与其共同连接的碳原子一起形成氧代基、硫代基、环丙基或环丁基。
在一些实施方案中，R 9为氢、C 1-6烷基、卤代C 1-6烷基、-L 2-OR a或-L 2-NR aR b。
在一些实施方案中，R 9为氢。
在一些实施方案中，Cy 1为C 3-8环烷基、3-8元杂环烷基、C 6-10芳基或者5-10元杂芳基；所述Cy 1为未取代或者选择性地被1～3个选自卤素、氰基、C 1-6烷基、卤代C 1-6烷基、卤代C 1-6烷氧基、C 2-6烯基、C 2-6炔基、-L 4-SR d、-L 4-OC(O)R e、-L 4-C(O)OR e、-L 4-C(O)R e、-L 4-C(O)NR eR e’、-L 4-NR dC(O)R e、-L 4-NR dS(O) 2R e、-L 4-S(O) 1-2R e、-L 4-S(O) 2NR eR e’、-L 4-OR d或-L 4-NR eR e’的取代基取代在任意位置。
在一些实施方案中，L 1为连接键或C 1-6亚烷基；所述L 1为未取代，或者选择性被1～3个选自氧代基、卤素、羟基、氨基、氰基、C 1-6烷基、卤代C 1-6烷基、C 1-6烷氧基或卤代C 1-6烷氧基的取代基取代在任意位置。
在一些实施方案中，L 1为连接键或-CH 2-。
在一些实施方案中，L 2为连接键或C 1-6亚烷基；所述L 2为未取代，或者选择性被1～3个选自氧代基、卤素、羟基、氨基、氰基、C 1-6烷基、卤代C 1-6烷基、C 1-6烷氧基或卤代C 1-6烷氧基的取代基取代在任意位置。
在一些实施方案中，L 3为连接键或C 1-6亚烷基；所述L 3为未取代，或者选择性被1～3个选自氧 代基、卤素、羟基、氨基、氰基、C 1-6烷基、卤代C 1-6烷基、C 1-6烷氧基或卤代C 1-6烷氧基的取代基取代在任意位置。
在一些实施方案中，L 3为连接键、-CH 2-、-CH 2CH 2-、-CH 2CH 2CH 2-、-CH 2CH 2C(CH 3) 2-、-CH 2CH 2CH 2CH 2-或-CH 2CH(CH 3)CH 2-。
在一些实施方案中，L 3为-CH 2-。
在一些实施方案中，L 4为连接键或C 1-6亚烷基；所述L 4为未取代，或者选择性被一个或多个选自氧代基、卤素、羟基、氨基、氰基、C 1-6烷基、卤代C 1-6烷基、C 1-6烷氧基或卤代C 1-6烷氧基的取代基取代在任意位置。
在一些实施方案中，基团-L 3-W为
Figure PCTCN2022093953-appb-000010
Figure PCTCN2022093953-appb-000011
在一些实施方案中，基团-L 3-W为
Figure PCTCN2022093953-appb-000012
在一些实施方案中，R 7为苯基、5-6元杂芳基、3-8元杂环烷基或8-12元并环基团；所述R 7为未取代，或者选择性被1～3个选自-L 3-W、卤素、氰基、硝基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6烷氧基、卤代C 1-6烷基、卤代C 1-6烷氧基和C 1-6烷氨基的取代基取代在任意位置。
在一些实施方案中，R 7为8-12元并环基团；所述R 7为未取代，或者选择性被1～3个选自-L 3-W、卤素、氰基、硝基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6烷氧基、卤代C 1-6烷基、卤代C 1-6烷氧基和C 1-6烷氨基的取代基取代在任意位置。
在一些实施方案中，R 7为
Figure PCTCN2022093953-appb-000013
Figure PCTCN2022093953-appb-000014
Figure PCTCN2022093953-appb-000015
所述R 7为未取代，或者选择性被1～3个选自-L 3-W、卤素、氰基、硝基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6烷氧基、卤代C 1-6烷基、卤代C 1-6烷氧基和C 1-6烷氨基的取代基取代在任意位置。
在一些实施方案中，R 7为
Figure PCTCN2022093953-appb-000016
Figure PCTCN2022093953-appb-000017
在一些实施方案中，R 7为
Figure PCTCN2022093953-appb-000018
在一些实施方案中，X 1为N或CR 2，X 2为N或CR 3，X 3为N或CR 1；并且，X 1为CR 2，X 2为CR 3和X 3为CR 1时，m为1。
在一些实施方案中，m为0或1；
X 1为N或CR 2，X 2为N或CR 3，X 3为N或CR 1；并且，X 1为CR 2，X 2为CR 3和X 3为CR 1时，m为1；
R为-C(O)-L 1-R 7、-C(O)-NR 9-L 1-R 7或-C(S)-NR 9-L 1-R 7。
在一些实施方案中，m为1；
X 1为N或CR 2，X 2为N或CR 3，X 3为N或CR 1；
R为-C(O)-L 1-R 7、-C(O)-NR 9-L 1-R 7或-C(S)-NR 9-L 1-R 7。
在一些实施方案中，所述如式I所示化合物为如式IA所示化合物，
Figure PCTCN2022093953-appb-000019
其中，R为-C(O)-L 1-R 7、-C(O)-NR 9-L 1-R 7或-C(S)-NR 9-L 1-R 7；
X 1、X 2、X 3、R、R 4、R 4’、R 5、R 8和R 8’的定义如前所述。
在一些实施方案中，IA中，L 1为连接键。
在一些实施方案中，IA中，R 8和R 8’与其共同连接的碳原子一起形成C 3-6环烷基或3-6元杂环烷基；所述C 3-6环烷基或3-6元杂环烷基为未取代，或者选择性被1～3个选自氘、卤素、羟基、氨基、氰基、氧代基、C 1-6烷基、卤代C 1-6烷基、-L 2-OR a和-L 2-NR aR b的取代基取代在任意位置。
在一些实施方案中，IA中，R 8和R 8’与其共同连接的碳原子一起形成如下基团：
Figure PCTCN2022093953-appb-000020
Figure PCTCN2022093953-appb-000021
在一些实施方案中，IA中，X 1为CH，X 2为CR 3，X 3为CH；m为1；R 3为H或卤素。
在一些实施方案中，R 5为-NH 2。
在一些实施方案中，所述如式I所示化合物为如式IB所示化合物，
Figure PCTCN2022093953-appb-000022
其中，R为-C(O)-L 1-R 7、-C(O)-NR 9-L 1-R 7或-C(S)-NR 9-L 1-R 7；
R 4为C 1-6烷基；所述R 4选择性被1个-OR a取代在任意位置；
X 1、X 2、X 3、R、R 4’、R 5、R 8、R 8’、R a和m的定义如前所述。
在一些实施方案中，IB中，R a为H。
在一些实施方案中，IB中，X 1为N或CR 2，X 2为N或CR 3，X 3为N或CR 1；m为1；L 1为连接键。
在一些实施方案中，IB中，R 8和R 8’与其共同连接的碳原子一起形成C 3-6环烷基或3-6元杂环烷基；所述C 3-6环烷基或3-6元杂环烷基为未取代，或者选择性被1～3个选自氘、卤素、羟基、氨基、氰基、氧代基、C 1-6烷基、卤代C 1-6烷基、-L 2-OR a和-L 2-NR aR b的取代基取代在任意位置。
在一些实施方案中，IB中，R 8和R 8’与其共同连接的碳原子一起形成如下基团：
Figure PCTCN2022093953-appb-000023
Figure PCTCN2022093953-appb-000024
在一些实施方案中，R 5为-NH 2。
在一些实施方案中，所述如式I所示化合物为表1中任一结构：
表1：
Figure PCTCN2022093953-appb-000025
Figure PCTCN2022093953-appb-000026
Figure PCTCN2022093953-appb-000027
Figure PCTCN2022093953-appb-000028
，及其药学上可接受的盐。
本发明还提供了如下任一含氮化合物：
Figure PCTCN2022093953-appb-000029
Figure PCTCN2022093953-appb-000030
Figure PCTCN2022093953-appb-000031
本发明还提供了一种如式II’所示化合物、其溶剂合物、其药学上可接受的盐或其药学上可接受的盐的溶剂合物，
D-LinkerX
(II′)；
D为上述的如式I所示化合物失去一个氢原子所形成的基团；
LinkerX为连接体2。
在一些实施方案中，所述的如式II’所示化合物、其溶剂合物、其药学上可接受的盐或其药学上可接受的盐的溶剂合物里，部分基团的定义如下所述，其余基团的定义如其他任一方案所述(以下简称“在一些实施方案中”)：
所述的D可为上述的如式I所示化合物在基团R 7处失去一个氢原子所形成的基团。
在一些实施方案中，所述的D可为上述的如式I所示化合物在基团R 7的仲胺或伯胺处失去一个氢原子所形成的基团，也即通过N原子与所述的LinkerX连接。
在一些实施方案中，所述的D可通过
Figure PCTCN2022093953-appb-000032
的a端与所述的LinkerX连接。
所述的如式II’所示化合物、其溶剂合物、其药学上可接受的盐或其药学上可接受的盐的溶剂合物里，所述的连接体2为一价基团，通过一个位点与所述的D连接。
所述的如式II’所示化合物、其溶剂合物、其药学上可接受的盐或其药学上可接受的盐的溶剂合 物里，所述的连接体2为ISAC领域中常规的连接子。
在一些实施方案中，所述的LinkerX可为可降解连接体或不可降解连接体。
在一些实施方案中，所述的LinkerX可为可被溶酶体酶降解的连接体。
在一些实施方案中，所述的LinkerX可为
Figure PCTCN2022093953-appb-000033
x为1；
u为1、2、3、4、5或6；
w为1；
L 5为
Figure PCTCN2022093953-appb-000034
p为1；R 10为氢；所述的L 5的羰基端与所述的D连接；
每个Z分别独立地为
Figure PCTCN2022093953-appb-000035
每个R 12a分别独立地为氢、甲基、乙基、正丙基、异丙基、
Figure PCTCN2022093953-appb-000036
所述的
Figure PCTCN2022093953-appb-000037
的羰基端与所述的L 5的氨基端连接；
T为
Figure PCTCN2022093953-appb-000038
v3为1、2、3、4、5或6；所述的T的羰基端与所述的
Figure PCTCN2022093953-appb-000039
的氨基端连接；
M’为
Figure PCTCN2022093953-appb-000040
所述的M’的氨基端与所述的T的非羰基端连接。
在一些实施方案中，所述的如式II’所示化合物可为
Figure PCTCN2022093953-appb-000041
D为上述的如式I所示化合物失去一个氢原子所形成的基团；
x为0、1、2或3；
u为0、1、2、3、4、5或6；
w为0、1、2、3、4、5或6；
每个L 5分别独立地为
Figure PCTCN2022093953-appb-000042
Figure PCTCN2022093953-appb-000043
p为1、2或3；每个R 10分别独立地为氢、卤素、C 1-6烷基、卤代C 1-6烷基、硝基、氰基、C 1-6烷氧基、C 1-6烷氨基、-OC(O)R 11或-C(O)N(R 11) 2；R 11为氢、C 1-6烷基或C 1-6烷氨基C 1-6烷基；
每个Z分别独立地为
Figure PCTCN2022093953-appb-000044
Figure PCTCN2022093953-appb-000045
和-(CH 2CH 2O) o7-；每个o1、o2、o3、o4、o5、o6、o7分别独立地为0、1、2、3、4、5、6、7或8；每个R 12a、R 12b和R 12c分别独立地为氢、甲基、乙基、正丙基、异丙基、-SO 3H、
Figure PCTCN2022093953-appb-000046
Figure PCTCN2022093953-appb-000047
每个R 13a和每个R 13b分别独立地为氢或甲基；
每个T分别独立地为-(CH 2) v1-、-(CH 2CH 2O) v2-、
Figure PCTCN2022093953-appb-000048
Figure PCTCN2022093953-appb-000049
v1、v2、v3、v4和v5分别独立地为1、2、3、4、5或6；
M’为
Figure PCTCN2022093953-appb-000050
在一些实施方案中，所述的D为上述的如式I所示化合物在基团R 7处失去一个氢原子所形成的基团；
LinkerX为
Figure PCTCN2022093953-appb-000051
x为1；
u为1、2、3、4、5或6；
w为1；
L 5为
Figure PCTCN2022093953-appb-000052
p为1；R 10为氢；所述的L 5的羰基端与所述的D连接；
每个Z分别独立地为
Figure PCTCN2022093953-appb-000053
每个R 12a分别独立地为氢、甲基、乙基、正丙基、异丙基、
Figure PCTCN2022093953-appb-000054
所述的
Figure PCTCN2022093953-appb-000055
的羰基端与所述的L 5的氨基端连接；
T为
Figure PCTCN2022093953-appb-000056
v3为1、2、3、4、5或6；所述的T的羰基端与所述的
Figure PCTCN2022093953-appb-000057
的氨基端连接；M’为
Figure PCTCN2022093953-appb-000058
所述的M’的氨基端与所述的T的非羰基端连接。
在一些实施方案中，所述的L 5可为
Figure PCTCN2022093953-appb-000059
在一些实施方案中，所述的L 5的羰基端可与所述的D连接。
在一些实施方案中，所述的Z可为氨基酸。
在一些实施方案中，所述的
Figure PCTCN2022093953-appb-000060
可为肽链。
在一些实施方案中，所述
Figure PCTCN2022093953-appb-000061
可为二肽、三肽或四肽连接子。
在一些实施方案中，所述的
Figure PCTCN2022093953-appb-000062
的羰基端可与所述的L 5的氨基端连接。
在一些实施方案中，所述的
Figure PCTCN2022093953-appb-000063
可为
Figure PCTCN2022093953-appb-000064
又可为
Figure PCTCN2022093953-appb-000065
在一些实施方案中，所述的T的羰基端可与所述的
Figure PCTCN2022093953-appb-000066
的氨基端连接。
在一些实施方案中，所述的M’的氨基端可与所述的T的非羰基端连接。
在一些实施方案中，所述的如式II’所示化合物可为
Figure PCTCN2022093953-appb-000067
其中，D为如式I所示化合物，
Figure PCTCN2022093953-appb-000068
α和β独立地为单键或双键；并且，α和β至少有一个为单键；
m为0或1；
X 1为N或CR 2，X 2为N或CR 3，X 3为N或CR 1；并且，X 1为CR 2，X 2为CR 3和X 3为CR 1时，m为1；
R为-C(O)-L 1-R 7、-C(O)-NR 9-L 1-R 7、-C(S)-NR 9-L 1-R 7、-NR 9-L 1-R 7、-NR 9-C(O)-L 1-R 7、-NR 9-C(O)-NR 9-L 1-R 7、-O-L 1-R 7、-S(O) 2-NR 9-L 1-R 7、-CH＝CH-L 1-R 7或-S(O) 2-L 1-R 7；
R 1、R 2和R 3分别独立地为氢、氘、卤素、羟基、氨基、氰基、烷基、卤代烷基、-L 2-OR a或-L 2-NR aR b；
R 4和R 4’分别独立地为氢、烷基、烯基、炔基、环烷基、杂环烷基、芳基、杂芳基、环烷基烷基、杂环烷基烷基、芳基烷基或杂芳基烷基；所述R 4或R 4’为未取代或者选择性地被一个或多个选自卤素、氰基、-L 2-OR a、-L 2-OC(O)R a、-L 2-NR aR b、-L 2-NR aC(O)OR b、-L 2-NR aC(O)NR aR b、-L 2-NR bC(NR b)NR aR b和-L 2-C(O)OR b的取代基取代在任意位置；或者，R 4和R 4’与它们共同连接的N原子一起形成3-8元杂环烷基；所述3-8元杂环烷基为未取代或者进一步被1～3个选自卤素、氰基、-L 2-OR a、-L 2-OC(O)R a、-L 2-NR aR b、-L 2-NR aC(O)OR b、-L 2-NR aC(O)NR aR b、-L 2-NR bC(NR b)NR aR b和-L 2-C(O)OR b的取代基取代在任意位置；
R 5为＝O、＝NR a、-OR a或-NR aR b；
R 5’不存在，或者R 5’为-R c、-L 2-OR a、-L 2-NR aR b、-L 2-NR aC(O)OR b、-L 2-NR aC(O)NR aR b、-L 2-NR bC(NR b)NR aR b或-L 2-C(O)OR b；
R 7为苯基、5-6元杂芳基、3-8元杂环烷基或8-12元并环基团；所述R 7为未取代，或者选择性被一个或多个选自-L 3-W、-R c、卤素、氰基、硝基、烷基、烯基、炔基、烷氧基、卤代烷基、卤代烷氧基和烷氨基的取代基取代在任意位置；
R 8和R 8’分别独立地为氢、卤素或烷基，所述R 8或R 8’为未取代，或者选择性被一个或多个选自-L 3-W、卤素、氰基、硝基、烷基、烯基、炔基、烷氧基、卤代烷基、卤代烷氧基和烷氨基的取代基取代在任意位置；R 8和R 8’分别为独立取代基，或者，R 8和R 8’与其共同连接的碳原子一起形成氧代基、硫代基、C 1-6亚烷基、C 3-10环烷基或3-10元杂环烷基；所述C 1-6亚烷基、C 3-10环烷基或3-10元杂环烷基为未取代，或者选择性被一个或多个选自氘、卤素、羟基、氨基、氰基、氧代基、烷基、卤代烷基、-L 2-OR a和-L 2-NR aR b的取代基取代在任意位置；
R 9为氢、烷基、卤代烷基、-L 2-OR a或-L 2-NR aR b；
W为Cy 1、-SR d、-OR d、-OC(O)R e、-OC(O)NR eR e’、-C(O)OR e、-C(O)R e、-C(O)NR eR e’、-C(O)NR eS(O) 2R e–NR dR e、-NR dC(O)R e、-N(R d)C(O)OR e、-N(R d)C(O)NR eR e’、-NR dS(O) 2R e、-NR dS(O) 2NR eR e’、-S(O) 1-2R e、-S(O) 2NR eR e’、-S(O)(＝NR d)R e、-S(O) 2N(R e)C(O)R e’、-P(O)(OR e) 2、-P(O)(OR e)R e’、-OP(O)(OR e) 2或-B(OR e) 2；
Cy 1为环烷基、杂环烷基、芳基或者杂芳基；所述Cy 1为未取代，或者选择性地被一个或多个选自卤素、烷基、卤代烷基、卤代烷氧基、烯基、炔基、氰基、-R c、-L 4-SR d、-L 4-OC(O)R e、-L 4-C(O)OR e、-L 4-C(O)R e、-L 4-C(O)NR eR e’、-L 4-NR dC(O)R e、-L 4-NR dS(O) 2R e、-L 4-S(O) 1-2R e、-L 4-S(O) 2NR eR e’、-L 4-OR d和-L 4-NR eR e’的取代基取代在任意位置；
L 1、L 2、L 3和L 4分别独立地为连接键、C 1-6亚烷基、C 2-6亚烯基或C 2-6亚炔基；所述L 1、L 2、L 3或L 4为未取代，或者选择性被一个或多个选自氧代基、羟基、氨基、卤素、氰基、烷基、卤代烷基、烷氧基和卤代烷氧基的取代基取代在任意位置；
每个R a、R b、R d、R e和R e’分别独立地为-R c、氨基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-10环烷基、3-10元杂环烷基、C 6-10芳基、5-10元杂芳基、C 3-10环烷基C 1-6烷基、3-10元杂环烷基C 1-6烷基、苯基C 1-6烷基或5-10元杂芳基C 1-6烷基；所述R a、R b、R d、R e或R e’为未取代，或者选择性地被1～3个选自-OR f、-OC(O)-L 4-R f、-NR fR f’、卤素、氰基、硝基、C 1-6烷基、卤代C 1-6烷基和卤代C 1-6烷氧基的取代基取代在任意位置；
每个R f和R f’分别独立地为-R c、-NHR c或C 1-6烷基；
每个R c分别独立地为氢或连接键；并且D中至少有一个R c为连接键；
x为0、1、2或3；
u为0、1、2、3、4、5或6；
w为0、1、2、3、4、5或6；
每个L 5分别独立地为
Figure PCTCN2022093953-appb-000069
Figure PCTCN2022093953-appb-000070
p为1、2或3；每个R 10分别独立地为氢、卤素、C 1-6烷基、卤代C 1-6烷基、硝基、氰基、C 1-6烷氧基、C 1-6烷氨基、-OC(O)R 11或-C(O)N(R 11) 2；R 11为氢、C 1-6烷基或C 1-6烷氨基C 1-6烷基；
每个Z分别独立地为
Figure PCTCN2022093953-appb-000071
Figure PCTCN2022093953-appb-000072
和-(CH 2CH 2O) o7-；每个o1、o2、o3、o4、o5、o6、o7分别独立地为0、1、2、3、4、5、6、7或8；每个R 12a、R 12b和R 12c分别独立地为氢、甲基、乙基、正丙基、异丙基、-SO 3H、
Figure PCTCN2022093953-appb-000073
Figure PCTCN2022093953-appb-000074
每个R 13a和每个R 13b分别独立地为氢或甲基；
每个T分别独立地为-(CH 2) v1-、-(CH 2CH 2O) v2-、
Figure PCTCN2022093953-appb-000075
Figure PCTCN2022093953-appb-000076
v1、v2、v3、v4和v5分别独立地为1、2、3、4、5或6；
M’为
Figure PCTCN2022093953-appb-000077
在一些实施方案中，所述的如式II’所示化合物可为
Figure PCTCN2022093953-appb-000078
其中，D为如式I所示化合物，
Figure PCTCN2022093953-appb-000079
α和β独立地为单键或双键；并且，α和β至少有一个为单键；
m为0或1；
X 1为N或CR 2，X 2为N或CR 3，X 3为N或CR 1；并且，X 1为CR 2，X 2为CR 3和X 3为CR 1时，m为1；
R为-C(O)-L 1-R 7、-C(O)-NR 9-L 1-R 7、-C(S)-NR 9-L 1-R 7、-NR 9-L 1-R 7、-NR 9-C(O)-L 1-R 7、-NR 9-C(O)-NR 9-L 1-R 7、-O-L 1-R 7、-S(O) 2-NR 9-L 1-R 7、-CH＝CH-L 1-R 7或-S(O) 2-L 1-R 7；
R 1、R 2和R 3分别独立地为氢、氘、卤素、羟基、氨基、氰基、烷基、卤代烷基、-L 2-OR a或-L 2-NR aR b；
R 4和R 4’分别独立地为氢、烷基、烯基、炔基、环烷基、杂环烷基、芳基、杂芳基、环烷基烷基、杂环烷基烷基、芳基烷基或杂芳基烷基；所述R 4或R 4’为未取代或者选择性地被一个或多个选自卤素、氰基、-L 2-OR a、-L 2-NR aR b、-L 2-NR aC(O)OR b、-L 2-NR aC(O)NR aR b、-L 2-NR bC(NR b)NR aR b和-L 2-C(O)OR b的取代基取代在任意位置；或者，R 4和R 4’与它们共同连接的N原子一起形成3-8元杂环烷基；所述3-8元杂环烷基为未取代或者进一步被1～3个选自卤素、氰基、-L 2-OR a、-L 2-NR aR b、-L 2-NR aC(O)OR b、-L 2-NR aC(O)NR aR b、-L 2-NR bC(NR b)NR aR b和-L 2-C(O)OR b的取代基取代在任意位置；
R 5为＝O、＝NR a、-OR a或-NR aR b；
R 5’不存在，或者R 5’为-R c、-L 2-OR a、-L 2-NR aR b、-L 2-NR aC(O)OR b、-L 2-NR aC(O)NR aR b、-L 2-NR bC(NR b)NR aR b或-L 2-C(O)OR b；
R 7为苯基、5-6元杂芳基、3-8元杂环烷基或8-12元并环基团；所述R 7为未取代，或者选择性被一个或多个选自-L 3-W、-R c、卤素、氰基、硝基、烷基、烯基、炔基、烷氧基、卤代烷基、卤代烷氧基和烷氨基的取代基取代在任意位置；
R 8和R 8’分别独立地为氢、卤素或烷基，所述R 8或R 8’为未取代，或者选择性被一个或多个选自-L 3-W、卤素、氰基、硝基、烷基、烯基、炔基、烷氧基、卤代烷基、卤代烷氧基和烷氨基的取代基取代在任意位置；R 8和R 8’分别为独立取代基，或者，R 8和R 8’与其共同连接的碳原子一起形成氧代基、硫代基、C 1-6亚烷基、C 3-10环烷基或3-10元杂环烷基；所述C 1-6亚烷基、C 3-10环烷基或3-10元杂环烷基为未取代，或者选择性被一个或多个选自氘、卤素、羟基、氨基、氰基、氧代基、烷基、卤代烷基、-L 2-OR a和-L 2-NR aR b的取代基取代在任意位置；
R 9为氢、烷基、卤代烷基、-L 2-OR a或-L 2-NR aR b；
W为Cy 1、-SR d、-OR d、-OC(O)R e、-OC(O)NR eR e’、-C(O)OR e、-C(O)R e、-C(O)NR eR e’、-C(O)NR eS(O) 2R e–NR dR e、-NR dC(O)R e、-N(R d)C(O)OR e、-N(R d)C(O)NR eR e’、-NR dS(O) 2R e、-NR dS(O) 2NR eR e’、-S(O) 1-2R e、-S(O) 2NR eR e’、-S(O)(＝NR d)R e、-S(O) 2N(R e)C(O)R e’、-P(O)(OR e) 2、-P(O)(OR e)R e’、-OP(O)(OR e) 2或-B(OR e) 2；
Cy 1为环烷基、杂环烷基、芳基或者杂芳基；所述Cy 1为未取代，或者选择性地被一个或多个选自卤素、烷基、卤代烷基、卤代烷氧基、烯基、炔基、氰基、-R c、-L 4-SR d、-L 4-OC(O)R e、-L 4-C(O)OR e、-L 4-C(O)R e、-L 4-C(O)NR eR e’、-L 4-NR dC(O)R e、-L 4-NR dS(O) 2R e、-L 4-S(O) 1-2R e、-L 4-S(O) 2NR eR e’、-L 4-OR d和-L 4-NR eR e’的取代基取代在任意位置；
L 1、L 2、L 3和L 4分别独立地为连接键、C 1-6亚烷基、C 2-6亚烯基或C 2-6亚炔基；所述L 1、L 2、L 3或L 4为未取代，或者选择性被一个或多个选自氧代基、羟基、氨基、卤素、氰基、烷基、卤代烷基、烷氧基和卤代烷氧基的取代基取代在任意位置；
每个R a、R b、R d、R e和R e’分别独立地为-R c、氨基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-10环烷基、3-10元杂环烷基、C 6-10芳基、5-10元杂芳基、C 3-10环烷基C 1-6烷基、3-10元杂环烷基C 1-6烷基、 苯基C 1-6烷基或5-10元杂芳基C 1-6烷基；所述R a、R b、R d、R e或R e’为未取代，或者选择性地被1～3个选自-OR f、-NR fR f’、卤素、氰基、硝基、C 1-6烷基、卤代C 1-6烷基和卤代C 1-6烷氧基的取代基取代在任意位置；
每个R f和R f’分别独立地为-R c、-NHR c或C 1-6烷基；
每个R c分别独立地为氢或连接键；并且D中至少有一个R c为连接键；
x为0、1、2或3；
u为0、1、2、3、4、5或6；
w为0、1、2、3、4、5或6；
每个L 5分别独立地为
Figure PCTCN2022093953-appb-000080
Figure PCTCN2022093953-appb-000081
p为1、2或3；每个R 10分别独立地为氢、卤素、C 1-6烷基、卤代C 1-6烷基、硝基、氰基、C 1-6烷氧基、C 1-6烷氨基、-OC(O)R 11或-C(O)N(R 11) 2；R 11为氢、C 1-6烷基或C 1-6烷氨基C 1-6烷基；
每个Z分别独立地为
Figure PCTCN2022093953-appb-000082
Figure PCTCN2022093953-appb-000083
和-(CH 2CH 2O) o7-；每个o1、o2、o3、o4、o5、o6、o7分别独立地为0、1、2、3、4、5、6、7或8；每个R 12a、R 12b和R 12c分别独立地为氢、甲基、乙基、正丙基、异丙基、-SO 3H、
Figure PCTCN2022093953-appb-000084
Figure PCTCN2022093953-appb-000085
每个R 13a和每个R 13b分别独立地为氢或甲基；
每个T分别独立地为-(CH 2) v1-、-(CH 2CH 2O) v2-、
Figure PCTCN2022093953-appb-000086
Figure PCTCN2022093953-appb-000087
v1、v2、v3、v4和v5分别独立地为1、2、3、4、5或6；
M’为
Figure PCTCN2022093953-appb-000088
以下所述的如式II所述的所有实施方案及各变量的组合均包含在本发明如式II所示的结构式的范围中。
在一些实施方案中，M’为
Figure PCTCN2022093953-appb-000089
在一些实施方案中，x为0或1。
在一些实施方案中，x为0或1，-L 5-为
Figure PCTCN2022093953-appb-000090
-(Z) u-为
Figure PCTCN2022093953-appb-000091
o1、o2、o6、o7、R 12a、R 12b、R 12c、R 13a和R 13b的定义如前所述；*标记位点是和L 5连接的位点；
-(T) w-为-(CH 2CH 2O) v2-*、
Figure PCTCN2022093953-appb-000092
v1、v2、v5和R 12c的定义如前所述；*标记位点是和Z连接的位点。
在一些实施方案中，x为1，-L 5-为
Figure PCTCN2022093953-appb-000093
-(Z) u-为
Figure PCTCN2022093953-appb-000094
o1、R 12a和R 12b的定义如前所述；*标记位点是和L 5连接的位点；
-(T) w-为连接键、-(CH 2CH 2O) v2-*、
Figure PCTCN2022093953-appb-000095
v1、v2、v5和R 12c的定义如前所述；*标记位点是和Z连接的位点。
在一些实施方案中，-(Z) u-为
Figure PCTCN2022093953-appb-000096
o1、R 12a和R 12b的定义如前所述；*标记位点是和L 5连接的位点。
在一些实施方案中，-(Z) u-为
Figure PCTCN2022093953-appb-000097
Figure PCTCN2022093953-appb-000098
o1的定义如前所述；*标记位点是和L 5连接的位点。
在一些实施方案中，-(Z) u-为
Figure PCTCN2022093953-appb-000099
o1的定义如前所述；*标记位点是和L 5连接的位点。
在一些实施方案中，D中，X 3为CR 1；X 1为N；X 2为CR 3。
在一些实施方案中，D中，X 3为CR 1；X 1为CR 2；X 2为CR 3。
在一些实施方案中，D中，每个R a、R b、R d、R e和R e’分别独立地为-R c、氨基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-10环烷基、3-10元杂环烷基、C 6-10芳基、5-10元杂芳基、C 3-10环烷基C 1-6烷基、3-10元杂环烷基C 1-6烷基、苯基C 1-6烷基或5-10元杂芳基C 1-6烷基；所述R a、R b、R d、R e或R e’为未取代或者选择性地被1～3个选自-OR f、-OC(O)-(CH 2) 1-5-R f、-NR fR f’、卤素、氰基、C 1-6烷基、卤代C 1-6烷基和卤代C 1-6烷氧基的取代基取代在任意位置。
在一些实施方案中，D中，R为-C(O)-NR 9-L 1-R 7。
在一些实施方案中，D中，R 1、R 2和R 3分别独立地为氢、氘、卤素、羟基、氨基、氰基、C 1-6烷基、卤代C 1-6烷基、-L 2-OR a或-L 2-NR aR b。
在一些实施方案中，D中，R 1、R 2和R 3分别独立地优选为H、F、Cl、Br、-CH 3、-OCH 3、-CF 3、 -CH 2F、-CHF 2、-OCF 3、-CN或-(CH 2) 0-5-NH 2。
在一些实施方案中，D中，R 1为H；R 2为H。
在一些实施方案中，D中，R 4和R 4’分别独立地为氢、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-8环烷基、3-8元杂环烷基、C 6-10芳基、5-10元杂芳基、环烷基C 1-6烷基、3-8元杂环烷基C 1-6烷基、C 6-10芳基C 1-6烷基或5-10元杂芳基C 1-6烷基；所述R 4或R 4’为未取代或者选择性地被1～3个选自卤素、氰基、-L 2-OR a、-L 2-OC(O)R a、-L 2-NR aR b、-L 2-NR aC(O)OR b、-L 2-NR aC(O)NR aR b、-L 2-NR bC(NR b)NR aR b和-L 2-C(O)OR b的取代基取代在任意位置；或者，R 4和R 4’与它们共同连接的N原子一起形成3-8元杂环烷基；所述3-8元杂环烷基为未取代或者选择性地被1～3个选自卤素、氰基、-L 2-OR a、-L 2-NR aR b、-L 2-NR aC(O)OR b、-L 2-NR aC(O)NR aR b、-L 2-NR bC(NR b)NR aR b和-L 2-C(O)OR b的取代基取代在任意位置。
在一些实施方案中，D中，R 4和R 4’分别独立地为C 1-6烷基；所述R 4或R 4’为未取代或者选择性地被1～3个选自-OR a、-OC(O)R a、-NR aR b、-NR aC(O)OR b、-NR aC(O)NR aR b、-NR bC(NR b)NR aR b和-C(O)OR b的取代基取代在任意位置。
在一些实施方案中，D中，R 4为C 1-6烷基；所述R 4为未取代或者选择性地被1个-OR a、-OC(O)R a、-NR aR b、-NR aC(O)OR b、-NR aC(O)NR aR b、-NR bC(NR b)NR aR b或-C(O)OR b的取代基取代在任意位置；R 4’为C 1-6烷基；所述R 4’为未取代或者选择性地被1～3个选自卤素、-OR a和-NR aR b的取代基取代在任意位置。
在一些实施方案中，D中，R 4和R 4’分别独立地为C 1-6烷基；所述R 4或R 4’为未取代或者选择性地被1个选自卤素、-OR a和-NR aR b的取代基取代在任意位置。
在一些实施方案中，D中，R 4为-CH 2CH 2OH或-CH 2CH 2CH 3；R 4’为-CH 2CH 2OH、-CH 2CH 2CH 3、-CH 2CH 2CF 3或-CH 2CH 2CHF 2。
在一些实施方案中，D中，α为双键、β为单键、R 5’为不存在、R 5为-NR aR b。
在一些实施方案中，D中，α为双键、β为单键、R 5’为不存在，R 5为-NH 2。
在一些实施方案中，D中，α为单键、β为双键、R 5’为H，R 5为＝O。
在一些实施方案中，D中，R 8和R 8’分别独立地为氢、卤素或C 1-6烷基；所述R 8或R 8’为未取代，或者选择性被1～3个选自-L 3-W、卤素、氰基、硝基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6烷氧基、卤代C 1-6烷基、卤代C 1-6烷氧基和C 1-6烷氨基的取代基取代在任意位置。
在一些实施方案中，D中，R 8和R 8’分别独立地为C 1-6烷基，所述C 1-6烷基优选为甲基。
在一些实施方案中，D中，R 8和R 8’与其共同连接的碳原子一起形成氧代基、硫代基、C 3-6环烷基或3-6元杂环烷基；所述C 3-6环烷基或3-6元杂环烷基为未取代，或者选择性被1～3选自氘、卤素、羟基、氨基、氰基、氧代基、C 1-6烷基、卤代C 1-6烷基、-L 2-OR a和-L 2-NR aR b的取代基取代在任意位置。
在一些实施方案中，D中，R 8和R 8’与其共同连接的碳原子一起形成氧代基、硫代基、环丙基、环丁基、氮杂环丁基或氧杂环丁基；所述环丙基、环丁基、氮杂环丁基或氧杂环丁基为未取代，或者选择性被1～3个选自氘、卤素、羟基、氨基、氰基、氧代基、C 1-6烷基、卤代C 1-6烷基、-L 2-OR a和-L 2-NR aR b 的取代基取代在任意位置。
在一些实施方案中，D中，R 8和R 8’与其共同连接的碳原子一起形成氧代基、硫代基、环丙基或环丁基。
在一些实施方案中，D中，R 9为氢、C 1-6烷基、卤代C 1-6烷基、-L 2-OR a或-L 2-NR aR b。
在一些实施方案中，D中，R 9为氢。
在一些实施方案中，D中，Cy 1为C 3-8环烷基、3-8元杂环烷基、C 6-10芳基或者5-10元杂芳基；所述Cy 1为未取代或者选择性地被1～3个选自卤素、氰基、C 1-6烷基、卤代C 1-6烷基、卤代C 1-6烷氧基、C 2-6烯基、C 2-6炔基、-L 4-SR d、-L 4-OC(O)R e、-L 4-C(O)OR e、-L 4-C(O)R e、-L 4-C(O)NR eR e’、-L 4-NR dC(O)R e、-L 4-NR dS(O) 2R e、-L 4-S(O) 1-2R e、-L 4-S(O) 2NR eR e’、-L 4-OR d或-L 4-NR eR e’的取代基取代在任意位置；
在一些实施方案中，D中，L 1为连接键或C 1-6亚烷基；所述L 1为未取代，或者选择性被1～3个个选自氧代基、卤素、羟基、氨基、氰基、C 1-6烷基、卤代C 1-6烷基、C 1-6烷氧基或卤代C 1-6烷氧基的取代基取代在任意位置。
在一些实施方案中，D中，L 1为连接键或-CH 2-。
在一些实施方案中，D中，L 2为连接键或C 1-6亚烷基；所述L 2为未取代，或者选择性被1～3个选自氧代基、卤素、羟基、氨基、氰基、C 1-6烷基、卤代C 1-6烷基、C 1-6烷氧基或卤代C 1-6烷氧基的取代基取代在任意位置。
在一些实施方案中，D中，L 3为连接键或C 1-6亚烷基；所述L 3为未取代，或者选择性被1～3个选自氧代基、卤素、羟基、氨基、氰基、C 1-6烷基、卤代C 1-6烷基、C 1-6烷氧基或卤代C 1-6烷氧基的取代基取代在任意位置。
在一些实施方案中，D中，L 3为连接键、-CH 2-、-CH 2CH 2-、-CH 2CH 2CH 2-、-CH 2CH 2C(CH 3) 2-、-CH 2CH 2CH 2CH 2-或-CH 2CH(CH 3)CH 2-。
在一些实施方案中，D中，L 3为-CH 2-。
在一些实施方案中，D中，L 4为连接键或C 1-6亚烷基；所述L 4为未取代，或者选择性被1～3个选自氧代基、卤素、羟基、氨基、氰基、C 1-6烷基、卤代C 1-6烷基、C 1-6烷氧基或卤代C 1-6烷氧基的取代基取代在任意位置。
在一些实施方案中，D中，R 7为苯基、5-6元杂芳基、3-8元杂环烷基或8-12元并环基团；所述R 7为未取代，或者选择性被一个或多个选自-L 3-W、-R c、卤素、氰基、硝基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6烷氧基、卤代C 1-6烷基、卤代C 1-6烷氧基和C 1-6烷氨基的取代基取代在任意位置。
在一些实施方案中，D中，R 7为8-12元并环基团；所述R 7为未取代，或者选择性被一个或多个选自-L 3-W、-R c、卤素、氰基、硝基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6烷氧基、卤代C 1-6烷基、卤代C 1-6烷氧基和C 1-6烷氨基的取代基取代在任意位置。
在一些实施方案中，D中，R 7为
Figure PCTCN2022093953-appb-000100
Figure PCTCN2022093953-appb-000101
Figure PCTCN2022093953-appb-000102
所述R 7为未取代，或者选择性被1～3个选自-L 3-W、-R c、卤素、氰基、硝基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6烷氧基、卤代C 1-6烷基、卤代C 1-6烷氧基和C 1-6烷氨基的取代基取代在任意位置。
在一些实施方案中，D中，R 7为
Figure PCTCN2022093953-appb-000103
Figure PCTCN2022093953-appb-000104
在一些实施方案中，D中，R 7为
Figure PCTCN2022093953-appb-000105
在一些实施方案中，D中，X 1为N或CR 2，X 2为N或CR 3，X 3为N或CR 1；并且，X 1为CR 2， X 2为CR 3和X 3为CR 1时，m为1。
在一些实施方案中，D中，m为0或1；
X 1为N或CR 2，X 2为N或CR 3，X 3为N或CR 1；并且，X 1为CR 2，X 2为CR 3和X 3为CR 1时，m为1；
R为-C(O)-L 1-R 7、-C(O)-NR 9-L 1-R 7或-C(S)-NR 9-L 1-R 7。
在一些实施方案中，D中，m为1；
X 1为N或CR 2，X 2为N或CR 3，X 3为N或CR 1；
R为-C(O)-L 1-R 7、-C(O)-NR 9-L 1-R 7或-C(S)-NR 9-L 1-R 7。
在一些实施方案中，D为如式IA所示化合物：
Figure PCTCN2022093953-appb-000106
R为-C(O)-L 1-R 7、-C(O)-NR 9-L 1-R 7或-C(S)-NR 9-L 1-R 7；
X 1、X 2、X 3、R、R 4、R 4’、R 5、R 8和R 8’的定义如前所述。
在一些实施方案中，D为如式IB所示化合物：
Figure PCTCN2022093953-appb-000107
R为-C(O)-L 1-R 7、-C(O)-NR 9-L 1-R 7或-C(S)-NR 9-L 1-R 7；
R 4为C 1-6烷基；所述R 4选择性被1个-OR a取代在任意位置；
X 1、X 2、X 3、R、R 4’、R 5、R 8、R 8’、R a和m的定义如前所述。
在一些实施方案中，D中，IA中，L 1为连接键。
在一些实施方案中，D中，IA中，R 8和R 8’与其共同连接的碳原子一起形成C 3-6环烷基或3-6元杂环烷基；所述C 3-6环烷基或3-6元杂环烷基为未取代，或者选择性被1～3个选自氘、卤素、羟基、氨基、氰基、氧代基、C 1-6烷基、卤代C 1-6烷基、-L 2-OR a和-L 2-NR aR b的取代基取代在任意位置。
在一些实施方案中，D中，IA中，R 8和R 8’与其共同连接的碳原子一起形成如下基团：
Figure PCTCN2022093953-appb-000108
Figure PCTCN2022093953-appb-000109
在一些实施方案中，D中，IA中，X 1为CH，X 2为CR 3，X 3为CH；m为1；R 3为H或卤素。
在一些实施方案中，D中，IA中，R 5为-NH 2。
在一些实施方案中，D中，IB中，R a为氢。
在一些实施方案中，D中，IB中，X 1为N或CR 2，X 2为N或CR 3，X 3为N或CR 1；m为1；L 1为连接键。
在一些实施方案中，D中，IB中，R 8和R 8’与其共同连接的碳原子一起形成C 3-6环烷基或3-6元杂环烷基；所述C 3-6环烷基或3-6元杂环烷基为未取代，或者选择性被1～3个选自氘、卤素、羟基、氨基、氰基、氧代基、C 1-6烷基、卤代C 1-6烷基、-L 2-OR a和-L 2-NR aR b的取代基取代在任意位置。
在一些实施方案中，D中，IB中，R 8和R 8’与其共同连接的碳原子一起形成如下基团：
Figure PCTCN2022093953-appb-000110
Figure PCTCN2022093953-appb-000111
在一些实施方案中，D中，IB中，R 5为-NH 2。
在一些实施方案中，D为表1所示化合物，并与L 5共价连接。
在一些实施方案中，D为表1所示化合物，并通过分子中的氮原子与L 5共价连接。
在一些实施方案中，所述如式II’所示化合物为如下任一结构：
Figure PCTCN2022093953-appb-000112
Figure PCTCN2022093953-appb-000113
Figure PCTCN2022093953-appb-000114
Figure PCTCN2022093953-appb-000115
Figure PCTCN2022093953-appb-000116
本发明还提供了一种如式III所示抗体-免疫刺激偶联物或其药学上可接受的盐，
Figure PCTCN2022093953-appb-000117
其中，Ab为抗体；
L为连接Ab和D的连接体(Linker)；
D为上述的如式I所示化合物失去一个氢原子所形成的基团；
t为1～8的任意数值。
在一些实施方案中，所述的如式III所示抗体-免疫刺激偶联物或其药学上可接受的盐里，部分基团的定义如下所述，其余基团的定义如其他任一方案所述(以下简称“在一些实施方案中”)：所述的抗体可包含一个或多个可以跟抗原结合的抗原结合域。
在一些实施方案中，所述的抗体可包含一个或两个可以跟抗原结合的抗原结合域。
在一些实施方案中，所述的抗体可包含一个可以跟抗原结合的抗原结合域。
在一些实施方案中，所述的抗体可仅包含一个可以跟抗原结合的抗原结合域。
在一些实施方案中，所述的抗体可包含一个Fc端。
在一些实施方案中，所述的抗体可仅包含一个Fc端。
在一些实施方案中，所述的抗体可仅包含一个可以跟抗原结合的抗原结合域和一个Fc端。
在一些实施方案中，所述的抗体可为单克隆抗体。
在一些实施方案中，所述的抗体可为抗HER2抗体。
在一些实施方案中，所述的抗体可为Trastuzumab(曲妥珠单抗)。
在一些实施方案中，所述的D可为上述的如式I所示化合物在基团R 7处失去一个氢原子所形成的基团。
在一些实施方案中，所述的D可为上述的如式I所示化合物在基团R 7的仲胺或伯胺处失去一个 氢原子所形成的基团，也即通过N原子与所述的Linker连接。
在一些实施方案中，所述的D可通过
Figure PCTCN2022093953-appb-000118
的a端与所述的Linker连接。
所述的如式III所示抗体-免疫刺激偶联物或其药学上可接受的盐里，所述的连接体(Linker)为二价基团，通过一个位点与所述的D连接，通过另一个位点与所述的Ab连接。
所述的如式III所示抗体-免疫刺激偶联物或其药学上可接受的盐里，所述的连接体(Linker)为ISAC领域中常规的连接体(Linker)。
在一些实施方案中，所述的L可为可降解连接体或不可降解连接体。
在一些实施方案中，所述的L可为可被溶酶体酶降解的连接体。
在一些实施方案中，所述的L可为
Figure PCTCN2022093953-appb-000119
x为1；
u为1、2、3、4、5或6；
w为1；
L 5为
Figure PCTCN2022093953-appb-000120
p为1；R 10为氢；所述的L 5的羰基端与所述的D连接；
每个Z分别独立地为
Figure PCTCN2022093953-appb-000121
每个R 12a分别独立地为氢、甲基、乙基、正丙基、异丙基、
Figure PCTCN2022093953-appb-000122
所述的
Figure PCTCN2022093953-appb-000123
的羰基端与所述的L 5的氨基端连接；
T为
Figure PCTCN2022093953-appb-000124
v3为1、2、3、4、5或6；所述的T的羰基端与所述的
Figure PCTCN2022093953-appb-000125
的氨基端连接；
M为
Figure PCTCN2022093953-appb-000126
所述的M的氨基端与所述的T的非羰基端连接。
在一些实施方案中，Ab为抗体；
L为连接Ab和D的连接体(Linker)；
D为上述的如式I所示化合物失去一个氢原子所形成的基团；
t为1～8的任意数值。
在一些实施方案中，
Ab为抗HER2单克隆抗体；
L为
Figure PCTCN2022093953-appb-000127
x为1；
u为1、2、3、4、5或6；
w为1；
L 5为
Figure PCTCN2022093953-appb-000128
p为1；R 10为氢；所述的L 5的羰基端与所述的D连接；
每个Z分别独立地为
Figure PCTCN2022093953-appb-000129
每个R 12a分别独立地为氢、甲基、乙基、正丙基、异丙基、
Figure PCTCN2022093953-appb-000130
所述的
Figure PCTCN2022093953-appb-000131
的羰基端与所述的L 5的氨基端连接；
T为
Figure PCTCN2022093953-appb-000132
v3为1、2、3、4、5或6；所述的T的羰基端与所述的
Figure PCTCN2022093953-appb-000133
的氨基端连接；
M为
Figure PCTCN2022093953-appb-000134
所述的M的氨基端与所述的T的非羰基端连接；
所述的D为上述的如式I所示化合物在基团R 7处失去一个氢原子所形成的基团；
t为1～8的任意数值。
在一些实施方案中，所述的L 5可为
Figure PCTCN2022093953-appb-000135
在一些实施方案中，所述的L 5的羰基端可与所述的D连接。
在一些实施方案中，所述的Z可为氨基酸。
在一些实施方案中，所述的
Figure PCTCN2022093953-appb-000136
可为肽链。
在一些实施方案中，所述
Figure PCTCN2022093953-appb-000137
可为二肽、三肽或四肽连接子。
在一些实施方案中，所述的
Figure PCTCN2022093953-appb-000138
的羰基端可与所述的L 5的氨基端连接。
在一些实施方案中，所述的
Figure PCTCN2022093953-appb-000139
可为
Figure PCTCN2022093953-appb-000140
又可为
Figure PCTCN2022093953-appb-000141
在一些实施方案中，所述的T的羰基端可与所述的
Figure PCTCN2022093953-appb-000142
的氨基端连接。
在一些实施方案中，所述的M的氨基端可与所述的T的非羰基端连接。
所述的如式III所示抗体-免疫刺激偶联物或其药学上可接受的盐里，所述的t为整数或非整数，当其为非整数时，是指如式III所示抗体-免疫刺激偶联物为不同偶联比抗体-免疫刺激偶联物的混合物；当其为整数时，可以指如式III所示抗体-免疫刺激偶联物为单一的、偶联比固定的抗体-免疫刺激偶联物，也可以指如式III所示抗体-免疫刺激偶联物为不同偶联比抗体-免疫刺激偶联物的混合物。
在一些实施方案中，所述的t可为2～5的任意数值。
在一些实施方案中，所述的t可为3～5的任意数值。
在一些实施方案中，
Figure PCTCN2022093953-appb-000143
其中，Ab为抗体；
L为连接Ab和D的连接体(Linker)；
t为1～8的任意数值；
D为如式I所示化合物；
Figure PCTCN2022093953-appb-000144
α和β独立地为单键或双键；并且，α和β至少有一个为单键；
m为0或1；
X 1为N或CR 2，X 2为N或CR 3，X 3为N或CR 1；并且，X 1为CR 2，X 2为CR 3和X 3为CR 1时，m为1；
R为-C(O)-L 1-R 7、-C(O)-NR 9-L 1-R 7、-C(S)-NR 9-L 1-R 7、-NR 9-L 1-R 7、-NR 9-C(O)-L 1-R 7、-NR 9-C(O)-NR 9-L 1-R 7、-O-L 1-R 7、-S(O) 2-NR 9-L 1-R 7、-CH＝CH-L 1-R 7或-S(O) 2-L 1-R 7；
R 1、R 2和R 3分别独立地为氢、氘、卤素、羟基、氨基、氰基、烷基、卤代烷基、-L 2-OR a或-L 2-NR aR b；
R 4和R 4’分别独立地为氢、烷基、烯基、炔基、环烷基、杂环烷基、芳基、杂芳基、环烷基烷基、 杂环烷基烷基、芳基烷基或杂芳基烷基；所述R 4或R 4’为未取代，或者选择性地被一个或多个选自卤素、氰基、-L 2-OR a、-L 2-OC(O)R a、-L 2-NR aR b、-L 2-NR aC(O)OR b、-L 2-NR aC(O)NR aR b、-L 2-NR bC(NR b)NR aR b和-L 2-C(O)OR b的取代基取代在任意位置；或者，R 4和R 4’与它们共同连接的N原子一起形成3-8元杂环烷基；所述3-8元杂环烷基为未取代或者进一步被1～3个选自卤素、氰基、-L 2-OR a、-L 2-OC(O)R a、-L 2-NR aR b、-L 2-NR aC(O)OR b、-L 2-NR aC(O)NR aR b、-L 2-NR bC(NR b)NR aR b和-L 2-C(O)OR b的取代基取代在任意位置；
R 5为＝O、＝NR a、-OR a或-NR aR b；
R 5’不存在，或者R 5’为-R c、-L 2-OR a、-L 2-NR aR b、-L 2-NR aC(O)OR b、-L 2-NR aC(O)NR aR b、-L 2-NR bC(NR b)NR aR b或-L 2-C(O)OR b；
R 7为苯基、5-6元杂芳基、3-8元杂环烷基或8-12元并环基团；所述R 7为未取代，或者选择性被一个或多个选自-L 3-W、-R c、卤素、氰基、硝基、烷基、烯基、炔基、烷氧基、卤代烷基、卤代烷氧基和烷氨基的取代基取代在任意位置；
R 8和R 8’分别独立地为氢、卤素或烷基，所述R 8或R 8’为未取代，或者选择性被一个或多个选自-L 3-W、卤素、氰基、硝基、烷基、烯基、炔基、烷氧基、卤代烷基、卤代烷氧基和烷氨基的取代基取代在任意位置；R 8和R 8’分别为独立取代基，或者，R 8和R 8’与其共同连接的碳原子一起形成氧代基、硫代基、C 1-6亚烷基、C 3-10环烷基或3-10元杂环烷基；所述C 1-6亚烷基、C 3-10环烷基或3-10元杂环烷基为未取代，或者选择性被一个或多个选自氘、卤素、羟基、氨基、氰基、氧代基、烷基、卤代烷基、-L 2-OR a和-L 2-NR aR b的取代基取代在任意位置；
R 9为氢、烷基、卤代烷基、-L 2-OR a或-L 2-NR aR b；
W为Cy 1、-SR d、-OR d、-OC(O)R e、-OC(O)NR eR e’、-C(O)OR e、-C(O)R e、-C(O)NR eR e’、-C(O)NR eS(O) 2R e–NR dR e、-NR dC(O)R e、-N(R d)C(O)OR e、-N(R d)C(O)NR eR e’、-NR dS(O) 2R e、-NR dS(O) 2NR eR e’、-S(O) 1-2R e、-S(O) 2NR eR e’、-S(O)(＝NR d)R e、-S(O) 2N(R e)C(O)R e’、-P(O)(OR e) 2、-P(O)(OR e)R e’、-OP(O)(OR e) 2或-B(OR e) 2；
Cy 1为环烷基、杂环烷基、芳基或者杂芳基；所述Cy 1为未取代，或者选择性地被一个或多个选自卤素、烷基、卤代烷基、卤代烷氧基、烯基、炔基、氰基、-R c、-L 4-SR d、-L 4-OC(O)R e、-L 4-C(O)OR e、-L 4-C(O)R e、-L 4-C(O)NR eR e’、-L 4-NR dC(O)R e、-L 4-NR dS(O) 2R e、-L 4-S(O) 1-2R e、-L 4-S(O) 2NR eR e’、-L 4-OR d和-L 4-NR eR e’的取代基取代在任意位置；
L 1、L 2、L 3和L 4分别独立地为连接键、C 1-6亚烷基、C 2-6亚烯基或C 2-6亚炔基；所述L 1、L 2、L 3或L 4为未取代，或者选择性被一个或多个选自氧代基、羟基、氨基、卤素、氰基、烷基、卤代烷基、烷氧基和卤代烷氧基的取代基取代在任意位置
每个R a、R b、R d、R e和R e’分别独立地为-R c、氨基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-10环烷基、3-10元杂环烷基、C 6-10芳基、5-10元杂芳基、C 3-10环烷基C 1-6烷基、3-10元杂环烷基C 1-6烷基、苯基C 1-6烷基或5-10元杂芳基C 1-6烷基；所述R a、R b、R d、R e或R e’为未取代或者选择性地被1～3个选自-OR f、-OC(O)-L 4-R f、-NR fR f’、卤素、氰基、硝基、C 1-6烷基、卤代C 1-6烷基和卤代C 1-6烷氧基的取代基取代在任意位置；
每个R f和R f’分别独立地为-R c、-NHR c或C 1-6烷基；
每个R c分别独立地为氢或与L连接的连接键；并且D中至少有一个R c为与L连接的连接键。
在一些实施方案中，
Figure PCTCN2022093953-appb-000145
其中，Ab为抗体；
L为连接Ab和D的连接体(Linker)；
t为1～8的任意数值；
D为如式I所示化合物、其立体异构体或其药学上可接受的盐：
Figure PCTCN2022093953-appb-000146
α和β独立地为单键或双键；并且，α和β至少有一个为单键；
m为0或1；
X 1为N或CR 2，X 2为N或CR 3，X 3为N或CR 1；并且，X 1为CR 2，X 2为CR 3和X 3为CR 1时，m为1；
R为-C(O)-L 1-R 7、-C(O)-NR 9-L 1-R 7、-C(S)-NR 9-L 1-R 7、-NR 9-L 1-R 7、-NR 9-C(O)-L 1-R 7、-NR 9-C(O)-NR 9-L 1-R 7、-O-L 1-R 7、-S(O) 2-NR 9-L 1-R 7、-CH＝CH-L 1-R 7或-S(O) 2-L 1-R 7；
R 1、R 2和R 3分别独立地为氢、氘、卤素、羟基、氨基、氰基、烷基、卤代烷基、-L 2-OR a或-L 2-NR aR b；
R 4和R 4’分别独立地为氢、烷基、烯基、炔基、环烷基、杂环烷基、芳基、杂芳基、环烷基烷基、杂环烷基烷基、芳基烷基或杂芳基烷基；所述R 4或R 4’为未取代，或者选择性地被一个或多个选自卤素、氰基、-L 2-OR a、-L 2-NR aR b、-L 2-NR aC(O)OR b、-L 2-NR aC(O)NR aR b、-L 2-NR bC(NR b)NR aR b和-L 2-C(O)OR b的取代基取代在任意位置；或者，R 4和R 4’与它们共同连接的N原子一起形成3-8元杂环烷基；所述3-8元杂环烷基为未取代或者进一步被1～3个选自卤素、氰基、-L 2-OR a、-L 2-NR aR b、-L 2-NR aC(O)OR b、-L 2-NR aC(O)NR aR b、-L 2-NR bC(NR b)NR aR b和-L 2-C(O)OR b的取代基取代在任意位置；
R 5为＝O、＝NR a、-OR a或-NR aR b；
R 5’不存在，或者R 5’为-R c、-L 2-OR a、-L 2-NR aR b、-L 2-NR aC(O)OR b、-L 2-NR aC(O)NR aR b、-L 2-NR bC(NR b)NR aR b或-L 2-C(O)OR b；
R 7为苯基、5-6元杂芳基、3-8元杂环烷基或8-12元并环基团；所述R 7为未取代，或者选择性被一个或多个选自-L 3-W、-R c、卤素、氰基、硝基、烷基、烯基、炔基、烷氧基、卤代烷基、卤代烷氧基和烷氨基的取代基取代在任意位置；
R 8和R 8’分别独立地为氢、卤素或烷基，所述R 8或R 8’为未取代，或者选择性被一个或多个选自 -L 3-W、卤素、氰基、硝基、烷基、烯基、炔基、烷氧基、卤代烷基、卤代烷氧基和烷氨基的取代基取代在任意位置；R 8和R 8’分别为独立取代基，或者，R 8和R 8’与其共同连接的碳原子一起形成氧代基、硫代基、C 1-6亚烷基、C 3-10环烷基或3-10元杂环烷基；所述C 1-6亚烷基、C 3-10环烷基或3-10元杂环烷基为未取代，或者选择性被一个或多个选自氘、卤素、羟基、氨基、氰基、氧代基、烷基、卤代烷基、-L 2-OR a和-L 2-NR aR b的取代基取代在任意位置；
R 9为氢、烷基、卤代烷基、-L 2-OR a或-L 2-NR aR b；
W为Cy 1、-SR d、-OR d、-OC(O)R e、-OC(O)NR eR e’、-C(O)OR e、-C(O)R e、-C(O)NR eR e’、-C(O)NR eS(O) 2R e–NR dR e、-NR dC(O)R e、-N(R d)C(O)OR e、-N(R d)C(O)NR eR e’、-NR dS(O) 2R e、-NR dS(O) 2NR eR e’、-S(O) 1-2R e、-S(O) 2NR eR e’、-S(O)(＝NR d)R e、-S(O) 2N(R e)C(O)R e’、-P(O)(OR e) 2、-P(O)(OR e)R e’、-OP(O)(OR e) 2或-B(OR e) 2；
Cy 1为环烷基、杂环烷基、芳基或者杂芳基；所述Cy 1为未取代，或者选择性地被一个或多个选自卤素、烷基、卤代烷基、卤代烷氧基、烯基、炔基、氰基、-R c、-L 4-SR d、-L 4-OC(O)R e、-L 4-C(O)OR e、-L 4-C(O)R e、-L 4-C(O)NR eR e’、-L 4-NR dC(O)R e、-L 4-NR dS(O) 2R e、-L 4-S(O) 1-2R e、-L 4-S(O) 2NR eR e’、-L 4-OR d和-L 4-NR eR e’的取代基取代在任意位置；
L 1、L 2、L 3和L 4分别独立地为连接键、C 1-6亚烷基、C 2-6亚烯基或C 2-6亚炔基；所述L 1、L 2、L 3或L 4为未取代，或者选择性被一个或多个选自氧代基、羟基、氨基、卤素、氰基、烷基、卤代烷基、烷氧基和卤代烷氧基的取代基取代在任意位置
每个R a、R b、R d、R e和R e’分别独立地为-R c、氨基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-10环烷基、3-10元杂环烷基、C 6-10芳基、5-10元杂芳基、C 3-10环烷基C 1-6烷基、3-10元杂环烷基C 1-6烷基、苯基C 1-6烷基或5-10元杂芳基C 1-6烷基；所述R a、R b、R d、R e或R e’为未取代或者选择性地被1～3个选自-OR f、-NR fR f’、卤素、氰基、硝基、C 1-6烷基、卤代C 1-6烷基和卤代C 1-6烷氧基的取代基取代在任意位置；
每个R f和R f’分别独立地为-R c、-NHR c或C 1-6烷基；
每个R c分别独立地为氢或与L连接的连接键；并且D中至少有一个R c为与L连接的连接键。
以下所述的如式III所述的所有实施方案及各变量的组合均包含在本发明如式III所示的结构式的范围中。
在一些实施方案中，所述Linker为可降解连接体。
在一些实施方案中，所述Linker为不可降解连接体。
在一些实施方案中，所述Linker可被溶酶体酶降解。
在一些实施方案中，所述Linker为-[(L 5) x-(Z) u-(T) w] y-M-；x为0、1、2或3；u为0、1、2、3、4、5或6；w为0、1、2、3、4、5或6；y为1、2或3；
每个L 5分别独立地为
Figure PCTCN2022093953-appb-000147
Figure PCTCN2022093953-appb-000148
p为1、2或3；每个R 10分别独立地为氢、卤素、C 1-6烷基、卤代C 1-6烷基、硝基、氰基、C 1-6烷氧基、C 1-6烷氨基、-OC(O)R 11或-C(O)N(R 11) 2；R 11为氢、C 1-6烷基或C 1-6烷氨基C 1-6烷基；
每个Z分别独立地为
Figure PCTCN2022093953-appb-000149
Figure PCTCN2022093953-appb-000150
和-(CH 2CH 2O) o7-；每个o1、o2、o3、o4、o5、o6、o7分别独立地为0、1、2、3、4、5、6、7或8；每个R 12a、R 12b和R 12c分别独立地为氢、甲基、乙基、正丙基、异丙基、-SO 3H、
Figure PCTCN2022093953-appb-000151
Figure PCTCN2022093953-appb-000152
每个R 13a和每个R 13b分别独立地为氢或甲基；
每个T分别独立地为-(CH 2) v1-、-(CH 2CH 2O) v2-、
Figure PCTCN2022093953-appb-000153
Figure PCTCN2022093953-appb-000154
v1、v2、v3、v4和v5分别独立地为1、2、3、4、5或6；
M为连接键或连接头(例如：
Figure PCTCN2022093953-appb-000155
*标记位点是和Ab相连接的位点)。
在一些实施方案中，所述Linker为-(L 5) x-(Z) u-(T) w-M-；x为0、1或2；u为0、1、2、3、4或5；w为1、2或3。
在一些实施方案中，-L 5-为
Figure PCTCN2022093953-appb-000156
-(Z) u-为
Figure PCTCN2022093953-appb-000157
o1、o2、o7、R 12a、R 12b、R 12c、R 13a和R 13b的定义如前所述；*标记位点是和L 5连接的位点；
-(T) w-为-(CH 2CH 2O) v2-*、
Figure PCTCN2022093953-appb-000158
v1、v2、v5和R 12c的定义如前所述；*标记位点是和Z连接的位点。
在一些实施方案中，-L 5-为
Figure PCTCN2022093953-appb-000159
-(Z) u-为
Figure PCTCN2022093953-appb-000160
o1、R 12a和R 12b的定义如前所述；*标记位点是和L 5连接的位点；
-(T) w-为连接键、-(CH 2CH 2O) v2-*、
Figure PCTCN2022093953-appb-000161
v1、v2、v5和R 12c的定义如前所述；*标记位点是和Z连接的位点。
在一些实施方案中，-(Z) u-为
Figure PCTCN2022093953-appb-000162
o1、R 12a和R 12b的定义如前所述；*标记位点是和L 5连接的位点。
在一些实施方案中，-(Z) u-为
Figure PCTCN2022093953-appb-000163
Figure PCTCN2022093953-appb-000164
o1的定义如前所述；*标记位点是和L 5连接的位点。
在一些实施方案中，-(Z) u-为
Figure PCTCN2022093953-appb-000165
o1的定义如前所述；*标记位点是和L 5连接的位点。
在一些实施方案中，所述Linker为以下任一结构：
Figure PCTCN2022093953-appb-000166
Figure PCTCN2022093953-appb-000167
在一些实施方案中，所述Linker为以下任一结构：
Figure PCTCN2022093953-appb-000168
Figure PCTCN2022093953-appb-000169
Figure PCTCN2022093953-appb-000170
Figure PCTCN2022093953-appb-000171
其羰基端与所述的D连接。
在一些实施方案中，所述Ab为抗体，所述抗体包含一个可以跟抗原结合的抗原结合域。
在一些实施方案中，所述Ab为抗体，所述抗体包含一个可以跟抗原结合的抗原结合域和一个Fc端。
在一些实施方案中，所述Ab为抗体，所述抗体包含一个可以跟HER2结合的抗原结合域。
在一些实施方案中，所述Ab为抗HER2单克隆抗体或其抗体片段。
在一些实施方案中，所述抗HER2单抗包括但不限于：Trastuzumab(曲妥珠单抗)、Trastuzumab biosimilar(曲妥珠单抗生物类似物)、Pertuzumab(帕妥珠单抗)、Pertuzumab biosimilar(帕妥珠单抗生物类似物)、Margetuximab、HT-19等。
在一些实施方案中，所述抗体为Trastuzumab、Pertuzumab、Margetuximab或HT-19。
在一些实施方案中，t为1～6或1～5的任意数值。
在一些实施方案中，t为2～8、2～6或2～5的任意数值。
在一些实施方案中，t为3～6或3～5的任意数值。
在一些实施方案中，D中，X 3为CR 1；X 1为N；X 2为CR 3。
在一些实施方案中，D中，X 3为CR 1；X 1为CR 2；X 2为CR 3。
在一些实施方案中，D中，每个R a、R b、R d、R e和R e’分别独立地为-R c、氨基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-10环烷基、3-10元杂环烷基、C 6-10芳基、5-10元杂芳基、C 3-10环烷基C 1-6烷基、3-10元杂环烷基C 1-6烷基、苯基C 1-6烷基或5-10元杂芳基C 1-6烷基；所述R a、R b、R d、R e或R e’为未取代或者选择性地被1～3个选自-OR f、-OC(O)-(CH 2) 1-5-R f、-NR fR f’、卤素、氰基、C 1-6烷基、卤代C 1-6烷基和卤代C 1-6烷氧基的取代基取代在任意位置。
在一些实施方案中，D中，R为-C(O)-NR 9-L 1-R 7。
在一些实施方案中，D中，R 1、R 2和R 3分别独立地为氢、氘、卤素、羟基、氨基、氰基、C 1-6烷基、卤代C 1-6烷基、-L 2-OR a或-L 2-NR aR b。
在一些实施方案中，D中，R 1、R 2和R 3分别独立地优选为H、F、Cl、Br、-CH 3、-OCH 3、-CF 3、-CH 2F、-CHF 2、-OCF 3、-CN或-(CH 2) 0-5-NH 2。
在一些实施方案中，D中，R 1为H；R 2为H。
在一些实施方案中，D中，R 4和R 4’分别独立地为氢、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-8环烷基、3-8元杂环烷基、C 6-10芳基、5-10元杂芳基、环烷基C 1-6烷基、3-8元杂环烷基C 1-6烷基、C 6-10芳基C 1-6烷基或5-10元杂芳基C 1-6烷基；所述R 4或R 4’为未取代或者选择性地被1～3个选自卤素、氰基、-L 2-OR a、-L 2-OC(O)R a、-L 2-NR aR b、-L 2-NR aC(O)OR b、-L 2-NR aC(O)NR aR b、-L 2-NR bC(NR b)NR aR b和-L 2-C(O)OR b的取代基取代在任意位置；或者，R 4和R 4’与它们共同连接的N原子一起形成3-8元杂环烷基；所述3-8元杂环烷基为未取代或者选择性地被1～3个选自卤素、氰基、-L 2-OR a、-L 2-NR aR b、-L 2-NR aC(O)OR b、-L 2-NR aC(O)NR aR b、-L 2-NR bC(NR b)NR aR b和-L 2-C(O)OR b的取代基取代在任意位置。
在一些实施方案中，D中，R 4和R 4’分别独立地为C 1-6烷基；所述R 4或R 4’为未取代或者选择性地被1～3个选自-OR a、-OC(O)R a、-NR aR b、-NR aC(O)OR b、-NR aC(O)NR aR b、-NR bC(NR b)NR aR b和-C(O)OR b的取代基取代在任意位置。
在一些实施方案中，D中，R 4为C 1-6烷基；所述R 4为未取代或者选择性地被1个-OR a、-OC(O)R a、-NR aR b、-NR aC(O)OR b、-NR aC(O)NR aR b、-NR bC(NR b)NR aR b或-C(O)OR b的取代基取代在任意位置；R 4’为C 1-6烷基；所述R 4’为未取代或者选择性地被1～3个选自卤素、-OR a和-NR aR b的取代基取代在任意位置。
在一些实施方案中，D中，R 4和R 4’分别独立地为C 1-6烷基；所述R 4或R 4’为未取代或者选择性地被1个选自卤素、-OR a和-NR aR b的取代基取代在任意位置。
在一些实施方案中，D中，R 4为-CH 2CH 2OH或-CH 2CH 2CH 3；R 4’为-CH 2CH 2OH、-CH 2CH 2CH 3、-CH 2CH 2CF 3或-CH 2CH 2CHF 2。
在一些实施方案中，D中，α为双键、β为单键、R 5’为不存在、R 5为-NR aR b。
在一些实施方案中，D中，α为双键、β为单键、R 5’为不存在，R 5为-NH 2。
在一些实施方案中，D中，α为单键、β为双键、R 5’为H，R 5为＝O。
在一些实施方案中，D中，R 8和R 8’分别独立地为氢、卤素或C 1-6烷基；所述R 8或R 8’为未取代，或者选择性被1～3个选自-L 3-W、卤素、氰基、硝基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6烷氧基、卤代C 1-6烷基、卤代C 1-6烷氧基和C 1-6烷氨基的取代基取代在任意位置。
在一些实施方案中，D中，R 8和R 8’分别独立地为C 1-6烷基，所述C 1-6烷基优选为甲基。
在一些实施方案中，D中，R 8和R 8’与其共同连接的碳原子一起形成氧代基、硫代基、C 3-6环烷基或3-6元杂环烷基；所述C 3-6环烷基或3-6元杂环烷基为未取代，或者选择性被1～3选自氘、卤素、羟基、氨基、氰基、氧代基、C 1-6烷基、卤代C 1-6烷基、-L 2-OR a和-L 2-NR aR b的取代基取代在任意位置。
在一些实施方案中，D中，R 8和R 8’与其共同连接的碳原子一起形成氧代基、硫代基、环丙基、环丁基、氮杂环丁基或氧杂环丁基；所述环丙基、环丁基、氮杂环丁基或氧杂环丁基为未取代，或者选择性被1～3个选自氘、卤素、羟基、氨基、氰基、氧代基、C 1-6烷基、卤代C 1-6烷基、-L 2-OR a和-L 2-NR aR b的取代基取代在任意位置。
在一些实施方案中，D中，R 8和R 8’与其共同连接的碳原子一起形成氧代基、硫代基、环丙基或环丁基。
在一些实施方案中，D中，R 9为氢、C 1-6烷基、卤代C 1-6烷基、-L 2-OR a或-L 2-NR aR b。
在一些实施方案中，D中，R 9为氢。
在一些实施方案中，D中，Cy 1为C 3-8环烷基、3-8元杂环烷基、C 6-10芳基或者5-10元杂芳基；所述Cy 1为未取代或者选择性地被1～3个选自卤素、氰基、C 1-6烷基、卤代C 1-6烷基、卤代C 1-6烷氧基、C 2-6烯基、C 2-6炔基、-L 4-SR d、-L 4-OC(O)R e、-L 4-C(O)OR e、-L 4-C(O)R e、-L 4-C(O)NR eR e’、-L 4-NR dC(O)R e、-L 4-NR dS(O) 2R e、-L 4-S(O) 1-2R e、-L 4-S(O) 2NR eR e’、-L 4-OR d或-L 4-NR eR e’的取代基取代在任意位置；
在一些实施方案中，D中，L 1为连接键或C 1-6亚烷基；所述L 1为未取代，或者选择性被1～3个个选自氧代基、卤素、羟基、氨基、氰基、C 1-6烷基、卤代C 1-6烷基、C 1-6烷氧基或卤代C 1-6烷氧基的取代基取代在任意位置。
在一些实施方案中，D中，L 1为连接键或-CH 2-。
在一些实施方案中，D中，L 2为连接键或C 1-6亚烷基；所述L 2为未取代，或者选择性被1～3个选自氧代基、卤素、羟基、氨基、氰基、C 1-6烷基、卤代C 1-6烷基、C 1-6烷氧基或卤代C 1-6烷氧基的取代基取代在任意位置。
在一些实施方案中，D中，L 3为连接键或C 1-6亚烷基；所述L 3为未取代，或者选择性被1～3个选自氧代基、卤素、羟基、氨基、氰基、C 1-6烷基、卤代C 1-6烷基、C 1-6烷氧基或卤代C 1-6烷氧基的取代基取代在任意位置。
在一些实施方案中，D中，L 3为连接键、-CH 2-、-CH 2CH 2-、-CH 2CH 2CH 2-、-CH 2CH 2C(CH 3) 2-、-CH 2CH 2CH 2CH 2-或-CH 2CH(CH 3)CH 2-。
在一些实施方案中，D中，L 3为-CH 2-。
在一些实施方案中，D中，L 4为连接键或C 1-6亚烷基；所述L 4为未取代，或者选择性被1～3个选自氧代基、卤素、羟基、氨基、氰基、C 1-6烷基、卤代C 1-6烷基、C 1-6烷氧基或卤代C 1-6烷氧基的取代基取代在任意位置。
在一些实施方案中，D中，R 7为苯基、5-6元杂芳基、3-8元杂环烷基或8-12元并环基团；所述R 7为未取代，或者选择性被一个或多个选自-L 3-W、-R c、卤素、氰基、硝基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6烷氧基、卤代C 1-6烷基、卤代C 1-6烷氧基和C 1-6烷氨基的取代基取代在任意位置。
在一些实施方案中，D中，R 7为8-12元并环基团；所述R 7为未取代，或者选择性被一个或多个选自-L 3-W、-R c、卤素、氰基、硝基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6烷氧基、卤代C 1-6烷基、卤代C 1-6烷氧基和C 1-6烷氨基的取代基取代在任意位置。
在一些实施方案中，D中，R 7为
Figure PCTCN2022093953-appb-000172
Figure PCTCN2022093953-appb-000173
Figure PCTCN2022093953-appb-000174
所述R 7为未取代，或者选择性被1～3个选自-L 3-W、-R c、卤素、氰基、硝基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6烷氧基、卤代C 1-6烷基、卤代C 1-6烷氧基和C 1-6烷氨基的取代基取代在任意位置。
在一些实施方案中，D中，R 7为
Figure PCTCN2022093953-appb-000175
Figure PCTCN2022093953-appb-000176
在一些实施方案中，D中，R 7为
Figure PCTCN2022093953-appb-000177
在一些实施方案中，D中，X 1为N或CR 2，X 2为N或CR 3，X 3为N或CR 1；并且，X 1为CR 2，X 2为CR 3和X 3为CR 1时，m为1。
在一些实施方案中，D中，m为0或1；
X 1为N或CR 2，X 2为N或CR 3，X 3为N或CR 1；并且，X 1为CR 2，X 2为CR 3和X 3为CR 1时，m为1；
R为-C(O)-L 1-R 7、-C(O)-NR 9-L 1-R 7或-C(S)-NR 9-L 1-R 7。
在一些实施方案中，D中，m为1；
X 1为N或CR 2，X 2为N或CR 3，X 3为N或CR 1；
R为-C(O)-L 1-R 7、-C(O)-NR 9-L 1-R 7或-C(S)-NR 9-L 1-R 7。
在一些实施方案中，D为如式IA所示化合物：
Figure PCTCN2022093953-appb-000178
R为-C(O)-L 1-R 7、-C(O)-NR 9-L 1-R 7或-C(S)-NR 9-L 1-R 7；
X 1、X 2、X 3、R、R 4、R 4’、R 5、R 8和R 8’的定义如前所述。
在一些实施方案中，D为如式IB所示化合物：
Figure PCTCN2022093953-appb-000179
R为-C(O)-L 1-R 7、-C(O)-NR 9-L 1-R 7或-C(S)-NR 9-L 1-R 7；
R 4为C 1-6烷基；所述R 4选择性被1个-OR a取代在任意位置；
X 1、X 2、X 3、R、R 4’、R 5、R 8、R 8’、R a和m的定义如前所述。
在一些实施方案中，D中，IA中，L 1为连接键。
在一些实施方案中，D中，IA中，R 8和R 8’与其共同连接的碳原子一起形成C 3-6环烷基或3-6元杂环烷基；所述C 3-6环烷基或3-6元杂环烷基为未取代，或者选择性被1～3个选自氘、卤素、羟基、氨基、氰基、氧代基、C 1-6烷基、卤代C 1-6烷基、-L 2-OR a和-L 2-NR aR b的取代基取代在任意位置。
在一些实施方案中，D中，IA中，R 8和R 8’与其共同连接的碳原子一起形成如下基团：
Figure PCTCN2022093953-appb-000180
Figure PCTCN2022093953-appb-000181
在一些实施方案中，D中，IA中，X 1为CH，X 2为CR 3，X 3为CH；m为1；R 3为H或卤素。
在一些实施方案中，D中，IA中，R 5为-NH 2。
在一些实施方案中，D中，IB中，R a为氢。
在一些实施方案中，D中，IB中，X 1为N或CR 2，X 2为N或CR 3，X 3为N或CR 1；m为1；L 1为连接键。
在一些实施方案中，D中，IB中，R 8和R 8’与其共同连接的碳原子一起形成C 3-6环烷基或3-6元杂环烷基；所述C 3-6环烷基或3-6元杂环烷基为未取代，或者选择性被1～3个选自氘、卤素、羟基、氨基、氰基、氧代基、C 1-6烷基、卤代C 1-6烷基、-L 2-OR a和-L 2-NR aR b的取代基取代在任意位置。
在一些实施方案中，D中，IB中，R 8和R 8’与其共同连接的碳原子一起形成如下基团：
Figure PCTCN2022093953-appb-000182
Figure PCTCN2022093953-appb-000183
在一些实施方案中，D中，IB中，R 5为-NH 2。
在一些实施方案中，D为表1所示化合物，并与Linker共价连接。
在一些实施方案中，D为表1所示化合物，并通过分子中的氮原子与Linker共价连接。
在一些实施方案中，所述如式III所示抗体-免疫刺激偶联物为如下任一结构：
Figure PCTCN2022093953-appb-000184
Figure PCTCN2022093953-appb-000185
Figure PCTCN2022093953-appb-000186
Figure PCTCN2022093953-appb-000187
Figure PCTCN2022093953-appb-000188
在一些实施方案中，所述如式III所示抗体-免疫刺激偶联物为如下任一结构：
Figure PCTCN2022093953-appb-000189
Figure PCTCN2022093953-appb-000190
Figure PCTCN2022093953-appb-000191
Figure PCTCN2022093953-appb-000192
本发明提供了一种药物组合物，其包括物质K和药学上可接受的辅料；
所述的物质K为物质K-1、物质K-2或物质K-3；
所述的物质K-1为上述的如式I所示化合物、其溶剂合物、其药学上可接受的盐或其药学上可接受的盐的溶剂合物；
所述的物质K-2为上述的如式II’所示化合物、其溶剂合物、其药学上可接受的盐或其药学上可接受的盐的溶剂合物；
所述的物质K-3为上述的如式III所示抗体-免疫刺激偶联物或其药学上可接受的盐。
在一些实施方案中，所述的物质K为上述的如式I所示化合物或药学上可接受的盐、如式II所示化合物或其药学上可接受的盐或如式III所示的抗体-免疫刺激偶联物或其药学上可接受的盐。
在一些实施方案中，所述的物质K的用量可为治疗有效量。
在一些实施方案中，所述的如式I所示化合物或药学上可接受的盐、如式II所示化合物或其药学上可接受的盐或如式III所示的抗体-免疫刺激偶联物或其药学上可接受的盐可为治疗有效量。
所述药物组合物中，所述药学上可接受的辅料可包括药学上可接受的载体、稀释剂和/或赋形剂。
所述的药物组合物可以通过常规途径进行给药，包括(但并不限于)：肌内、腹膜内、静脉内、皮下、皮内、局部给药(例如瘤内注射)等。
本发明还提供了一种物质K或上述的药物组合物在制备调节T细胞及其它免疫细胞药物中的应用，所述的物质K为物质K-1、物质K-2或物质K-3；
所述的物质K-1为上述的如式I所示化合物、其溶剂合物、其药学上可接受的盐或其药学上可接受的盐的溶剂合物；
所述的物质K-2为上述的如式II’所示化合物、其溶剂合物、其药学上可接受的盐或其药学上可接受的盐的溶剂合物；
所述的物质K-3为上述的如式III所示抗体-免疫刺激偶联物或其药学上可接受的盐。
在一些实施方案中，所述的物质K为上述的如式I所示化合物或药学上可接受的盐、如式II所示化合物或其药学上可接受的盐或如式III所示的抗体-免疫刺激偶联物或其药学上可接受的盐。
在一些实施方案中，所述的物质K的用量可为治疗有效量。
本发明提供了一种物质K或上述的药物组合物在制备治疗和/或缓解肿瘤或病毒感染性疾病药物中的应用，所述的物质K为物质K-1、物质K-2或物质K-3；
所述的物质K-1为上述的如式I所示化合物、其溶剂合物、其药学上可接受的盐或其药学上可接受的盐的溶剂合物；
所述的物质K-2为上述的如式II’所示化合物、其溶剂合物、其药学上可接受的盐或其药学上可接受的盐的溶剂合物；
所述的物质K-3为上述的如式III所示抗体-免疫刺激偶联物或其药学上可接受的盐。
在一些实施方案中，所述的物质K为上述的如式I所示化合物或药学上可接受的盐、如式II所示化合物或其药学上可接受的盐或如式III所示的抗体-免疫刺激偶联物或其药学上可接受的盐。
在一些实施方案中，所述的物质K的用量可为治疗有效量。
本发明提供了一种物质K或上述的药物组合物在制备治疗、缓解和/或预防TLR8介导的相关疾病的药物中的应用，所述的物质K为物质K-1、物质K-2或物质K-3；
所述的物质K-1为上述的如式I所示化合物、其溶剂合物、其药学上可接受的盐或其药学上可接受的盐的溶剂合物；
所述的物质K-2为上述的如式II’所示化合物、其溶剂合物、其药学上可接受的盐或其药学上可接受的盐的溶剂合物；
所述的物质K-3为上述的如式III所示抗体-免疫刺激偶联物或其药学上可接受的盐。
在一些实施方案中，所述的物质K为上述的如式I所示化合物或药学上可接受的盐、如式II所示化合物或其药学上可接受的盐或如式III所示的抗体-免疫刺激偶联物或其药学上可接受的盐。
在一些实施方案中，所述的TLR8介导的相关疾病是指肿瘤或病毒感染性疾病。
在一些实施方案中，所述的物质K的用量可为治疗有效量。
所述的肿瘤可为恶性肿瘤，包括转移性的和非转移性的癌症，也包括家族遗传性的和偶发性的癌症，还可包括固体肿瘤和非固体肿瘤。本发明中，所述肿瘤优选为有HER2表达的肿瘤(可以为HER2高表达肿瘤也可以为HER2低表达肿瘤)。本发明中，所述肿瘤更优选为HER2高表达肿瘤。
本发明中，所述“肿瘤”和“癌症”具有相同含义。
本发明中，除非另有说明，术语“选择性地被一个或多个基团取代在任意位置”是指基团上所指定的一个或多个原子的任何一个或者多个氢原子用所指定的基团取代，条件是不超过指定原子的正常化合价，所述取代在任意位置均为本领域常见的合理取代。
本发明中，当与取代基的键合显示与连接环中两个原子的键合相交时，那么这样的取代基可键合在环上的任何可键合的环原子。
本发明中，任何变量的组合只有在这种组合会产生稳定的化合物的情况下才被允许。
本发明中，任何变量在化合物的组成或结构中出现一次以上时，其在每一种情况下的定义都是独立的。例如，R被一个或多个基团取代时，每个取代基均是独立取代基，可以相同也可以不同。
除非另有说明，在本发明说明书和权利要求书中出现的以下术语具有下述含义：
术语“抗体”是指表现所需生物学活性(例如抑制配体与其受体的结合或通过抑制配体诱导的受体信号转导)的抗体的任何形式。因此，“抗体”以其最广泛的意义来施用，并明确包括但不限于单克隆抗体(包括全长单克隆抗体)、多克隆抗体和多特异性抗体(包括双特异性抗体)。天然存在的“抗体”是包含通过二硫键相互连接的至少两条重(H)链和两条轻(L)链的糖蛋白。每条重链由重链 可变区和重链恒定区组成。重链恒定区由三个结构域(CH1、CH2和CH3)组成。每条轻链由轻链可变区和轻链恒定区组成。轻链恒定区包含一个CL结构域。重链和轻链的可变区含有与抗原相互作用的结合结构域(抗原结合域)，抗原结合域可由抗体上一个或多个可变区提供，具体地，抗原结合域包含抗体轻链可变域(VL)和抗体重链可变域(VH)。抗体可以是单克隆抗体、人抗体、人源化抗体或嵌合抗体。这些抗体可以具有任何类别(IgG、IgE、IgM、IgD、IgA和IgY)或亚型(IgG1、IgG2、IgG3、IgG4、IgA1和IgA2)。本发明不仅包括完整的抗体，还包括具有免疫活性的抗体的片段(包括Fab、F(ab’)2、scFv或Fv片段)或抗体与其他序列形成的融合蛋白。因此，本发明所述“抗体”还包括所述抗体的片段、衍生物和类似物。
术语“单抗”也称“单克隆抗体”，是指具有基本上相同的氨基酸序列或源自相同的遗传来源的多肽(包括抗体、双特异性抗体等)。单克隆抗体具有高度特异性，可针对单个的抗原位点。此外，与通常包括针对多个不同决定簇(表位)的多种不同抗体的常规(多克隆)抗体制备物相反，每种单克隆抗体仅针对抗原上的单个决定簇。在一些特定实施例中，所述的单抗结合于包括但不限于以下任选抗原：HER2。
术语“HER2”(也称为ERBB2、NEU、NGL、TKR1、CD340、p185、MLN19、HER-2/neu)是指表皮生长因子(EGF)受体家族的跨膜酪氨酸激酶受体。HER2包含胞外结合结构域、跨膜结构域和细胞内酪氨酸激酶结构域。HER2不具有其自身的配体结合结构域，因此不能结合生长因子，然而HER2与其它结合配体的EGF受体家族成员(例如HER1或HER3)紧密结合，以形成异二聚体，稳定配体结合并增强激酶介导的下游信号传导途径的激活。在人中，存在物种HER2同种型：A、B、C、D和E。本发明所述“HER2”包括所有HER2同种型。
术语“抗HER2抗体”(Anti-HER2antibody)是指以HER2为靶标蛋白的抗体，并且所述抗HER2抗体可来源于任何物种，例如人、大鼠、小鼠及兔。所述抗HER2抗体优选为单克隆抗HER2抗体，所述抗HER2抗体更优选为人源化抗HER2抗体。所述抗HER2抗体包括但不限于：帕妥珠单抗、曲妥珠单抗、曲妥珠单抗生物类似物(trastuzumab biosimilar)(例如：inetetamab)、帕妥珠单抗生物类似物(pertuzumab biosimilar)、margetuximab、HT-19等；
其中，曲妥珠单抗(Trastuzumab，又被称为Herceptin或Herclon)是人源化单克隆抗体，可以与HER2受体胞外结构的近膜区结合(Hudis CA,N Engl J Med.2007；357(1):39-51)。曲妥珠单抗重链和轻链可变区的氨基酸序列在美国专利5,821,337中公开。曲妥珠单抗与人HER2残基557-561、570-573和593-603形成的三环区相互作用(Cho et al.,Nature 421:756-760,2003)。曲妥珠单抗可以通过预防HER2受体二聚化、促进HER2受体内吞、抑制胞外结构域的脱落而干扰HER2信号传导。另外，抗HER2抗体的另一个重要作用机制是介导抗体依赖性细胞毒性(ADCC)。在ADCC中，抗HER2抗体与肿瘤细胞结合，然后通过Fcγ受体(FcγR)相互作用招募免疫细胞，如巨噬细胞。曲妥珠单抗具有保守的人IgG Fc区域，并且能够招募负责抗体依赖性细胞毒性的免疫效应细胞(Hudis CA,N Engl J Med.2007；357(1):39-51).曲妥珠单抗于1998年9月获得美国FDA批准，用于治疗肿瘤过度表达HER2并接受一种或多种化疗方案治疗转移性乳腺癌的患者；
帕妥珠单抗(Pertuzumab，又被称为Perjeta、Omnitarg)是人源化单克隆抗体，其结合HER2受体的胞外结构域，并且抑制HER2和一起HER受体的二聚化。帕妥珠单抗重链和轻链可变区的氨基酸序列在美国专利7,560,111中公开。帕妥珠单抗主要与人HER2的245-333区内的残基发生相互作用，特别是残基His245、Val286、Ser288、Leu295、His296或Lys311(Franklin et al.,Cancer Cell 5:317-328,2004)。研究表明，帕妥珠单抗在破坏乳腺癌和前列腺癌细胞系中HER1-HER2和HER3-HER2复合物形成方面的有效性强于曲妥珠单抗(Agus et al.,J Clin Oncol.2005；23(11):2534-43.Epub Feb 7,2005)，帕妥珠单抗在2012年6月获得美国FDA批准，和曲妥珠单抗及多西他赛联合用于治疗未接受过抗HER2治疗或化疗的HER2阳性转移性乳腺癌患者；
Margetuximab(又被称为MGAH22、Margenza)是一种靶向HER2蛋白的Fc工程单克隆抗体，与HER2的胞外区结合。与曲妥珠单抗的可变区序列仅相差几个氨基酸，Fc经过F243L/R292P/Y300L/L235V/P396L五个位点突变，提高对CD16A亲和力，增强了ADCC活性。修饰后Margetuximab的Fc区增加与激活性Fc受体FCGR3A(CD16A)的结合，并减少与抑制性Fc受体FCGR2B(CD32B)的结合，从而导致更强的ADCC作用和NK细胞活化(Nordstrom J.et al.,Breast Cancer Research,2011；13:R123)。Margetuximab在2020年12获美国FDA批准，用于治疗已接受过2种或2种以上抗HER2靶向治疗的成年转移性HER2阳性乳腺癌(MBC)患者，其中至少1种抗HER2靶向疗法是用于治疗转移性乳腺癌；
HT-19是另一种抗HER2单克隆抗体，它结合人HER2的表位不同于曲妥珠单抗或帕妥珠单抗的结合表位，并经证实其抑制HER2信号传导的能力与曲妥珠单抗相当，与曲妥珠单抗和帕妥珠单抗组合可促进HER2降解(Bergstrom D.A.et al.,Cancer Res.2015；75:LB-231)。
本发明中，所述抗HER2抗体只要是特异性地与HER2结合(例如通过HER2结合而具有在HER2表达细胞中内化的活性的抗HER2抗体)即可，不限于上述列举的抗体。
本发明中“抗HER2抗体”的同种型(isotype)包括IgG1、IgG2、IgG3、IgG4等，优选IgG1、IgG2或IgG4。
本发明中所述“抗HER2抗体”或其抗原结合片段可包含Fc区，所述Fc区可进一步被修饰。在一些情况下，所述Fc区中的一个或多个突变导致包含这样的修饰的Fc区的药物在以下方面的改善，例如：效应功能的降低、药物代谢半衰期调节的改变及药物稳定性的改变。在一些情况下，修饰的Fc区可包含一个或多个突变，这些突变将降低或消除抗体与免疫系统之间的相互作用。关键的相互作用可包括抗体Fc与Fcγ受体的相互作用，以及与补体系统的C1q的相互作用。在使用IgG1作为本发明的抗体的同种型的情况下，能够通过取代恒定区的氨基酸残基的一部分来调整效应功能。作为减少或减弱效应功能的IgG1的变异体，包括但不限于：IgG1LALA(IgG1-L234A、L235A)、IgG1LAGA(IgG1-L235A、G237A)等，优选为IgG1LALA。上述L234A、L235A表示由EU index(Proc.Natl.Acad.Sci.U.S.A.,Vol.63，No.1(May 15，1969)，p.78-85)确定的234位、235位的亮氨酸被丙氨酸取代，G237A表示由EUindex确定的237位的甘氨酸被丙氨酸取代。
术语“HER2低表达”一般是指在临床检测中HER2表达水平为IHC 1+，或IHC 2+/FISH阴性(即 IHC 2+且同时FISH检测为阴性)。术语“HER2高表达”和“HER2阳性”可互换使用，一般是指在临床检测中HER2表达水平为IHC 2+/FISH阳性(即IHC 2+且同时FISH检测为阳性)，或IHC 3+。当IHC染色强度报告为一个范围时，本文中的术语“HER2低表达”除包括IHC 1+，或IHC 2+/FISH阴性外，还包括IHC 0至1+及IHC 1+至2+的范围。术语“HER2高表达”和“HER2阳性”各自除包括IHC 2+/FISH阳性，或IHC 3+外，还包括IHC 2+至3+的范围。在本发明中，FISH阴性是指FISH检测结果显示HER2基因无扩增，FISH阳性是指FISH检测结果显示HER2基因扩增。
术语“片段”、“衍生物”和“类似物”是指基本上保持本发明抗体相同的生物学功能或活性的多肽。本发明的多肽片段、衍生物或类似物可以是a)有一个或多个保守或非保守性氨基酸残基(优选保守性氨基酸残基)被取代的多肽，而这样的取代的氨基酸残基可以是也可以不是由遗传密码编码的，或b)在一个或多个氨基酸残基中具有取代基团的多肽，或c)成熟多肽与另一个化合物(比如延长多肽半衰期的化合物，例如聚乙二醇)融合所形成的多肽，或d)附加的氨基酸序列融合到此多肽序列而形成的多肽(如前导序列或分泌序列或用来纯化此多肽的序列或蛋白原序列，或与6His标签形成的融合蛋白)。
本发明中，所述单抗的生物类似物(biosimilar)是指尽管在临床上其非活性成分存在微小差异，但该单抗的生物类似物和所述单抗高度相似，并且在安全性和/或有效性等方面没有临床意义上的差异。
术语“连接体”和“Linker”是指用于连接小分子药物D和抗体的可降解或不可降解的连接片段。一个抗体分子可以连接多个带有小分子药物D的Linker，通常情况下，每个Linker可以连接一个或多个小分子药物，本发明中，优选每个Linker连接一个小分子药物D。通常情况下，每个抗体可以和多个Linker连接，本发明中，优选每个抗体和1～10个Linker连接；更优选每个抗体和1～8个Linker连接。
本发明中，所述不可降解的Linker是指所述Linker在体内和体外具有酶稳定性和/或化学稳定性，小分子药物D的释放可能不依赖于血浆和肿瘤组织及细胞内酶水平的差异化性质。小分子药物D的释放可以通过抗原介导的吞噬作用将抗体-免疫刺激偶联物内吞后将抗体降解至氨基酸水平，进而释放小分子药物D的衍生物，所述小分子药物D的衍生物由小分子药物D、连接子和氨基酸残基或小分子药物D和连接子所共价连接的残基所组成。
本发明中，所述可降解的Linker可以在体内或体外被降解，其包含可被体内或体外特定酶降解的连接子或包含自身化学不稳定的连接子。可降解的Linker可以在细胞内被降解从而释放小分子药物D，例如可以在细胞质中被还原，在溶酶体酸性条件下降解或被细胞内特定的蛋白酶或其它酶降解。所述可降解Linker包含一个或多个酶促降解连接子、化学不稳定连接子或其它可降解的连接子，其它部分可以是不被酶降解或化学稳定的连接子。所述化学不稳定连接子包括肟、腙和/或二硫化物基团(例如：
Figure PCTCN2022093953-appb-000193
)。所述被 酶特异性降解的连接子是基于1)肽形成的连接子。肽键可具有良好的血清稳定性，是由于溶酶体蛋白水解酶在血液中活性较在某些肿瘤组织内活性低很多，因此，Linker可以选择性在某些肿瘤组织或细胞内被降解进而释放小分子药物D。所述溶酶体酶可以选自组织蛋白酶B、组织蛋白酶S、纤溶酶、弹性蛋白酶、β-葡萄糖醛酸酶或β-半乳糖苷酶等。基于肽形成的连接子可以是四肽(例如：Gly-Phe-Leu-Gly、Ala-Leu-Ala-Leu、Gly-Gly-Phe-Gly)、三肽(Val-Leu-Lys、Ala-Pro-Val)、二肽(例如Val-Cit、Cit-Val、Val-Ala、Ala-Val、Ala-Cit、Cit-Ala、Asn-Cit、Cit-Asn、Cit-Cit、Val-Glu、Glu-Val、Ser-Cit、Cit-Ser、Lys-Cit、Cit-Lys、Asp-Cit、Cit-Asp、Ala-Val、Val-Ala、Phe-Lys、Lys-Phe、Val-Lys、Lys-Val、Ala-Lys、Lys-Ala、Phe-Cit、Cit-Phe、Leu-Cit、Cit-Leu、Ile-Cit、Cit-Ile、Phe-Arg、Arg-Phe、Cit-Trp、Trp-Cit)或氨基酸单体，基于肽形成的连接子优选为二肽连接子。所述其它可被降解的连接子可包括通过PEG羧酸或活化的PEG羧酸与小分子药物D上的羟基反应所形成的酯连接键，其中此类酯连接键可以在生理条件下水解进而释放小分子药物D。可水解降解的连接键包括但不限于碳酸酯键、由胺和醛反应产生的亚胺连接键、通过羟基和磷酸基团反应得到的磷酸酯键、通过羟基和醛反应得到的缩醛连接键、通过甲酸酯和羟基反应得到的原酸酯连接键等。可裂解的Linker中还可以包括不可裂解的片段，例如包括聚乙二醇(PEG)及其相关聚合物。2)通过焦磷酸酯或磷酸酯形成的连接子。溶酶体酸性焦磷酸酯酶和酸性磷酸酯酶是在溶酶体中将焦磷酸酯和末端单磷酸酯分别水解为其母体醇的酶。靶向这些酶可以有效释放末端为烷基醇的小分子药物D。
本发明中，所述“连接体”还包括可与抗体连接的连接头，本发明中，连接体可通过连接头和抗体中的巯基(例如半胱氨酸基团)。所述连接头优选为马来酰亚胺基团及开环后的马来酰亚胺基团(例如：
Figure PCTCN2022093953-appb-000194
*标记位点是和抗体相连接的位点)，所述马来酰亚胺基团和抗体的巯基(例如：半胱氨酸基团)的连接具有特异性(例如式1或式2所示)。
Figure PCTCN2022093953-appb-000195
Figure PCTCN2022093953-appb-000196
本发明中，所述“连接体”进一步还可以包括延伸基团(Spacer)，所述连接头可以直接与连接体中的连接子相互连接，或者通过延伸基团(Spacer)与连接体中的连接子相互连接。所述延伸基团可以是聚乙二醇及其相关聚合物、包含1～10个碳原子的亚烷基、环己基、酰胺基、酯基、氧代基、
Figure PCTCN2022093953-appb-000197
及上述延伸基团的任意一个或多个的组合。
所述“连接体”还可以通过连接子或延伸基团中的羧基或酯基和抗体中的氨基(例如赖氨酸基团)反应形成酰胺键(例如式3所示)。
Figure PCTCN2022093953-appb-000198
本发明中，所述“连接体”还可以进一步包括自脱落基团(self-immolative)，所述自脱落基团将小分子药物D和酶降解位点从空间上分开。常见的自脱落基团通常包含以下基本结构：
1)
Figure PCTCN2022093953-appb-000199
自脱落基团还可以通过氨基亚甲基基团、氨基C 3-5烷酰基基团、磷酸酯基或焦磷酸酯基和小分子D上的羟基连接；
2)
Figure PCTCN2022093953-appb-000200
Figure PCTCN2022093953-appb-000201
1)中 *标记位点是和小分子药物D相连接的位点，优选和小分子药物D上的氨基连接；2)中 * 标记位点是和小分子药物D相连接的位点，优选和小分子药物D上的羟基连接。
术语“连接体2”和“LinkerX”是指用于连接小分子药物D的可降解或不可降解的连接片段，其未和抗体分子连接；但可继续通过反应与抗体分子连接，形成上述的“连接体”。通常情况下，每个LinkerX可以连接一个或多个小分子药物，本发明中，优选每个LinkerX连接一个小分子药物D。除未和抗体分子连接外，所述的连接体2的其余定义与上述的“连接体”相同。
本发明中，所述“连接体2”还包括尚未和抗体连接的连接头，本发明中，连接子可通过连接头和抗体中的巯基(例如半胱氨酸基团)。所述连接头优选为马来酰亚胺基团及开环后的马来酰亚胺基团(例如未和抗体连接的连接头包括但不限于：
Figure PCTCN2022093953-appb-000202
Figure PCTCN2022093953-appb-000203
)，所述马来酰亚胺基团和抗体的巯基(例如：半胱氨酸基团)的连接具有特异性(例如式1或式2所示)。
Figure PCTCN2022093953-appb-000204
术语“和/或”包括一个或多个相关的所列项目的任意的和所有的组合。
术语“C A-B”是指包括起点到终点的范围，其中A和B及其范围中的各点均为整数，表示碳原子 的数目，例如C 1-4表示碳原子数目为1、2、3或4；C 1-6表示碳原子数目为1、2、3、4、5或6；C 3-8表示碳原子数目为3、4、5、6、7或8；C A-B可以跟任何包含碳原子的基团联合使用用于限定碳原子的个数，例如C 1-6烷基、C 3-8环烷基、C 6-10芳基、C 1-4烷氧基、C 3-8环烷基C 1-4烷基等。
术语“烷基”是指包含1-20个碳原子的饱和直链或支链烃基，优选1-10个碳原子，更优选1-8，1-6，1-4或1-3个碳原子，烷基的代表性例子包括但不限于：甲基、乙基、正丙基、异丙基、正丁基、仲丁基、叔丁基、异丁基、正戊基、正己基、正庚基、辛基、壬基、癸基、1,1-二甲基丙基、1,2-二甲基丙基、2,2-二甲基丙基、1-乙基丙基、2-甲基丁基、3-甲基丁基、1-乙基-2-甲基丙基、1,1,2-三甲基丙基、1,1-二甲基丁基、1,2-二甲基丁基、2,2-二甲基丁基、1,3-二甲基丁基、2,3-二甲基丁基、2-乙基丁基、2-甲基戊基、3-甲基戊基、4-甲基戊基、4,4-二甲基戊基、2-甲基己基、3-甲基己基、4-甲基己基、5-甲基己基、2,3-二甲基戊基、2,4-二甲基戊基、2,2-二甲基戊基、3,3-二甲基戊基、2-乙基戊基、3-乙基戊基、2,2,4-三甲基戊基、十一烷基、十二烷基，及它们的各种异构体等。
术语“烯基”指含有至少1个碳碳双键的直链、支链或者环状非芳香烃基。其中可以存在1-3个碳碳双键，优选存在1个碳碳双键。术语“C 2-4烯基”是指具有2-4个碳原子的烯基，术语“C 2-6烯基”是指具有2-6个碳原子的烯基，包括乙烯基、丙烯基、丁烯基、2-甲基丁烯基和环己烯基。所述的烯基可以被取代。
术语“炔基”是指含有至少1个碳碳三键的直链、支链或者环状烃基。其中可以存在1-3个碳碳三键，优选存在1个碳碳三键。术语“C 2-6炔基”是指具有2-6个碳原子的炔基，包括乙炔基、丙炔基、丁炔基和3-甲基丁炔基。
术语“亚烷基”是指包含1-20个碳原子的饱和直链或支链非桥连性的二价烷基，优选1-8个碳原子，更优选1-6或1-4个碳原子，例子包括但不限于-CH 2-、-CH 2CH 2-、-CH 2CH 2CH 2-、-CH 2CH 2CH 2CH 2-、-CH 2CH(CH 3)-、-CH 2C(CH 3) 2CH 2-、-CH 2C(CH 3) 2CH 2CH 2-、＝CH 2、＝CHCH 3、＝C(CH 3) 2。
术语“亚烯基”是指包含至少1个碳碳双键的直链、支链或者环状非芳香二价烃基，其中可以存在1-3个碳碳双键，优选存在1个碳碳双键。所述亚烯基优选包含2-8个碳原子，更优选2-6或2-4个碳原子。
术语“亚炔基”是指包含至少1个碳碳三键的直链、支链或者环状非芳香二价烃基。其中可以存在1-3个碳碳三键，优选存在1个碳碳三键。所述亚炔基优选包含2-8个碳原子，更优选2-6或2-4个碳原子。
术语“环烷基”是指包含3-20个碳原子的饱和或部分不饱和(包含1或2个双键)的单环或多环基团。“单环环烷基”优选3-10元单环烷基，更优选3-8元单环烷基，例如：环丙基、环丁基、环戊基、环己基、环庚基、环辛基、环癸基、环十二烷基、环己烯基。“多环环烷基”包括“桥环基”、“稠合环烷基”和“螺环烷基”，“桥环基”的代表性例子包括但不限于：冰片基、双环[2.2.1]庚烯基、双环[3.1.1]庚烷基、双环[2.2.1]庚烷基、双环[2.2.2]辛烷基、双环[3.2.2]壬烷基、双环[3.3.1]壬烷基、双环[4.2.1]壬烷基和金刚烷基等。“稠合环烷基”包含稠合到苯基、环烷基或杂芳基上的环烷基环，稠合环烷基包括但不限于：苯并环丁烯基、2,3-二氢化茚基、十氢萘基等。单环环烷基或多环环烷基可 以通过环上任意的碳原子链接到母体分子上。
术语“杂环烷基”指由碳原子以及选自氮、氧、硫、硼等杂原子和/或含硫杂原子基团组成的饱和或部分不饱和(包含1或2个双键)的非芳香环状基团，此环状基团可为单环或多环基团，其中，所述含硫杂原子基团选自但不限于S(O)、S(O) 2和S(O)(NH)。在本发明中，杂环烷基中杂原子和/或杂原子基团个数优选1、2、3或4，杂环烷基中的硼、氮或碳原子可任选地被氧化。氮原子可任选进一步被其他基团取代而形成叔胺或季铵盐。“单环杂环烷基”优选3-10元单环杂环烷基，更优选3-8元单环杂环烷基。例如：吡咯烷基、二氢吡咯烷基、二氢咪唑基、二氢吡唑基、四氢呋喃基、四氢吡嗪基、二氢呋喃基、四氢噻吩基、四氢吡喃基、二氢吡喃基、四氢硫代吡喃基、四氢吡啶基、四氢嘧啶基、哌啶基、氮丙啶基、吗啉基、硫代吗啉基、硫代吗啉-S-氧化物-4-基、哌啶基、哌嗪基、1,4-二氧六环基、高哌嗪基、1-亚氨基-1-氧化四氢-2H-噻喃基、1,1-二氧化四氢噻吩基、1-亚氨基-1-氧化四氢噻吩基、1,1-二氧化-3,4-二氢-2H-噻喃基、1-亚氨基-1-氧化-3,4-二氢-2H-噻喃基、1,1-二氧化-2,3-二氢噻吩基、1-亚氨基-1-氧化-2,3-二氢噻吩基等。“多环杂环烷基”包括“稠合杂环烷基”、“螺杂环基”和“桥杂环烷基”。“稠合杂环烷基”包含稠合到苯基、环烷基、杂环烷基或杂芳基的单环杂环烷基环，稠合杂环烷基包括但不限于：2,3-二氢苯并呋喃基、1,3-二氢异苯并呋喃基、二氢吲哚基、2,3-二氢苯并[b]噻吩基、二氢苯并哌喃基、1,2,3,4-四氢喹啉基、1,2,3,4-四氢异喹啉基、1,2,3,4-四氢萘啶基、5,6,7,8-四氢萘啶基、1-羟基-1,3-二氢苯并[c][1,2]氧杂硼戊环基等。单环杂环烷基和多环杂环烷基可以通过环上任意的环原子链接到母体分子上。上述环原子特指组成环骨架的碳原子和/或氮原子。
术语“环烷基烷基”是指环烷基与母核结构之间通过烷基连接。由此，“环烷基烷基”包含上述烷基和环烷基的定义。
术语“杂环烷基烷基”是指杂环烷基与母核结构之间通过烷基连接。由此，“杂环烷基烷基”包含上述烷基和杂环烷基的定义。
术语“烷氧基”指通过氧桥连接的具有所述碳原子数目的环状或者非环状烷基，包含烷基氧基、环烷基氧基和杂环烷基氧基。由此，“烷氧基”包含上述烷基、杂环烷基和环烷基的定义。
术语“羟基烷基”是指烷基上任意一个氢原子被羟基所取代，包括但不限于：-CH 2OH、-CH 2CH 2OH、-CH 2CH 2C(CH 3) 2OH。
术语“杂环烯基”是指具有指定环原子数(例如，5～10元)的、指定杂原子数(例如，1个、2个或3个)的、指定杂原子种类(N、O和S中的一种或多种)的、环状的、不饱和的一价烃基，其具有一个或多个(例如，1个、2个或3个)碳-碳sp 2双键，其为单环，不具有芳香性。杂环烯基通过碳原子或杂原子与分子其余部分相连。杂环烯基包括但不限于：
Figure PCTCN2022093953-appb-000205
Figure PCTCN2022093953-appb-000206
等。
术语“杂烯环”满足下述任一条件，其余定义同术语“杂环烯基”：与分子其余部分共用两个原 子和一根键。
术语“芳基”是指任何稳定的6-20元单环或多环芳香族基团，例如：苯基、萘基、四氢萘基、2,3-二氢化茚基或联苯基等。
术语“杂芳基”是指至少1个环上的碳原子被选自氮、氧或硫的杂原子置换所形成的芳香环基团，其可为5-7元单环结构或7-20稠合环结构，优选5-6元杂芳基。在本发明中，杂原子个数优选1、2或3，包括:吡啶基、吡啶酮基、嘧啶基、嘧啶-2,4(1H,3H)-二酮基、嘧啶酮基、哌嗪基、哒嗪酮基、呋喃基、噻吩基、噻唑基、吡咯基、咪唑基、吡唑基、噁唑基、异噁唑基、1,2,5-噁二唑基、1,2,4-噁二唑基、1,3,4-噁二唑基、1,3,4-噻二唑、1,2,4-三氮唑基、1,2,3-三氮唑基、四氮唑基、吲唑基、异吲唑基、吲哚基、异吲哚基、苯并呋喃基、苯并噻吩基、苯并[d][1,3]二氧戊环基、苯并噻唑基、苯并噁唑基、喹啉基、异喹啉基、异喹啉酮基、喹唑啉基、4-羟基噻吩并[3,2-c]吡啶基、4,5-二氢-4-氧代呋喃[3,2]吡啶基、4-羟基-5-氮杂吲哚基、呋喃[2,3-c]并吡啶-7(6H)-酮基、噻吩[2,3-c]并吡啶-7(6H)-酮基等。
术语“并环基团”是指有两个、三个或四个环状结构彼此共用两个相邻原子形成的并环结构，所述并环基团中还可进一步包括一个螺环或桥环基团。本发明所指并环基团为饱和、不饱和或者部分饱和的并环结构，优选至少一个环为芳香环。更优选二环或三环并环基团，并且至少有一个环为芳香环。本发明中，所述并环基团为8-20元，优选8-12元并环基团，更优选为8-10元并环基团。并环基团的具体实施例包括但不限于：苯并环丁烯基、2,3-二氢-1H-茚基、1,2,3,4-四氢萘基、6,7,8,9-四氢-5H-苯并[7]轮烯基、6,9-二氢-5H-苯并[7]轮烯基、5,6,7,8,9,10-六氢苯并[8]轮烯基、2,3-环戊烯并吡啶基、5,6-二氢-4H-环戊基[b]噻吩基、5,6-二氢-4H-环戊基[b]呋喃基、2,3-二氢苯并呋喃基、1,3-二氢异苯并呋喃基、二氢吲哚基、2,3-二氢苯并[b]噻吩基、二氢苯并哌喃基、1,2,3,4-四氢喹啉基、2,3-二氢-1,4-苯并二噁烷基、3,4-二氢-2H-1,4-苯并噁嗪基、萘啶基、萘基、苯并呋喃基、苯并噻吩基、苯并吡咯基、苯并噻唑基、苯并噁唑基、吲唑基、苯并哒嗪基、苯并咪唑基、吲哚基、喹啉基、异喹啉基、嘌呤基、喋啶基、
Figure PCTCN2022093953-appb-000207
Figure PCTCN2022093953-appb-000208
Figure PCTCN2022093953-appb-000209
Figure PCTCN2022093953-appb-000210
所述并环基团可通过环碳原子与母体分子连接，优选通过芳香环碳原子与母体分子链接。所述并环基团可以为未取代或者选择性地被一个或多个取代基取代在任意位置。
术语“芳基烷基”是指芳基与母核结构之间通过烷基连接。由此，“芳基烷基”包含上述烷基和芳基的定义。
术语“杂芳基烷基”是指杂环烷基与母核结构之间通过烷基连接。由此，“杂芳基烷基”包含上述烷基和杂芳基的定义。
术语“卤素”表示氟、氯、溴或碘。
术语“卤代烷基”是指被卤素任意取代的烷基。由此，“卤代烷基”包含以上卤素和烷基的定义。
术语“卤代烷氧基”是指被卤素任意取代的烷氧基。由此，“卤代烷氧基”包含以上卤素和烷氧基的定义。
术语“氨基”是指-NH 2，术语“烷氨基”是指氨基上至少一个氢原子被烷基所取代，包括但不限于：-NHCH 3、-N(CH 3) 2、-NHCH 2CH 3、-N(CH 2CH 3) 2。由此，“烷氨基”包含上述烷基和氨基的定义。
术语“硝基”是指-NO 2。
术语“氰基”是指-CN。
术语“氧代基”是指＝O。
本发明中，氨基酸的缩写为常规缩写，例如：丙氨酸(Ala)、精氨酸(Arg)、天冬氨酸(Asp)、 半胱氨酸(Cys)、天冬酰胺(Asn)、谷氨酸(Glu)、甘氨酸(Gly)、组氨酸(His)、异亮氨酸(Ile)、亮氨酸(Leu)、赖氨酸(Lys)、苯丙氨酸(Phe)、丝氨酸(Ser)、色氨酸(Trp)、瓜氨酸(Cit)、缬氨酸(Val)、脯氨酸(Pro)。
本发明所述“室温”是指15-30℃。
本发明“抗体-免疫刺激偶联物”、“化合物”和“药学上可接受的盐”中的取代基R、R 1、R 2、R 3、R 4、R 4’、R 5、R 6、R 7、R 8、R 8’、R 9、R 10、R 11、R 12a、R 12b、R 12c、R 13a、R 13b、R a、R b、R d、R e、R e’、R f、R f’和L 1～5中如存在互变异构体，则可以以单一的互变异构体或它们的混合物的形式存在，较佳地以较稳定的互变异构体为主的形式存在。
本发明所述的“药学上可接受的盐”在Berge，et al.，“Pharmaceutically acceptable salts”，J.Pharm.Sci.,66,1-19(1977)中有讨论，并对药物化学家来说是显而易见，所述的盐是基本上无毒性的，并能提供所需的药代动力学性质、适口性、吸收、分布、代谢或排泄等。本发明所述化合物可以具有酸性基团、碱性基团或两性基团，典型的药学上可接受的盐包括通过本发明化合物和酸反应制备得到的盐。
术语“溶剂合物”是指化合物与溶剂(包括但不限于：水、甲醇、乙醇等)结合形成的物质。溶剂合物分为化学计量类溶剂合物和非化学计量类溶剂合物。溶剂合物包括但不限于：一水合物。
术语“药学上可接受的盐的溶剂合物”是指化合物与药学上可接受的酸或碱、溶剂(包括但不限于：水、甲醇、乙醇等)结合形成的物质。其中，溶剂的数量可以是化学计量的，也可以是非化学计量的。药学上可接受的盐的溶剂合物包括但不限于：单盐酸盐一水合物。
在不违背本领域常识的基础上，上述各优选条件，可任意组合，即得本发明各较佳实例。
本发明所用试剂和原料均市售可得。
本发明的积极进步效果在于：该含氮化合物对TLR8具有良好调节作用，可以有效治疗、缓解和/或预防由于免疫抑制所引起的各种相关疾病，例如癌症或病毒感染。
附图说明
图1为载体、本发明抗体-免疫刺激偶联物和阳性对照在MC38-HER2小鼠结肠癌细胞小鼠皮下移植瘤模型中的抗肿瘤效果图，可以看出本发明抗体-免疫刺激偶联物的抗肿瘤效果明显优于阳性对照。
具体实施方式
下面通过实施例的方式进一步说明本发明，但并不因此将本发明限制在所述的实施例范围之中。下列实施例中未注明具体条件的实验方法，按照常规方法和条件，或按照商品说明书选择。
本发明所有化合物的结构可通过核磁共振( 1H NMR)和/或质谱检测(MS)鉴定。
1H NMR化学位移(δ)以PPM记录(10 -6)。NMR通过Bruker AVANCE-400光谱仪进行。合适的溶剂是氘代氯仿(CDCl 3)，氘代甲醇(CD 3OD)，氘代二甲亚砜(DMSO-d 6)，重水(D 2O)，四甲基硅烷作为内标(TMS)。
液质联用(LCMS)由Agilent 1200HPLC/6120质谱仪测定，使用色谱柱：Xtimate C18,3.0×50mm，3μm，柱温40℃；或由Thermo UltiMate 3000HPLC/MSQ PLUS质谱仪测定，使用色谱柱Xbridge C18，3.0×50mm，3.5μm，柱温30℃。Agilent梯度洗脱条件一：95-5％溶剂A 1和5-95％溶剂B 1(0-2.0分钟)，然后95％溶剂B 1和5％溶剂A 1(保持1.1分钟)，百分数为某一溶剂占总溶剂体积的体积百分数。溶剂A 1：0.01％三氟乙酸(TFA)的水溶液；溶剂B 1：0.01％三氟乙酸的乙腈溶液；百分数为溶质占溶液的体积百分数。Thermo梯度洗脱条件二：95-5％溶剂A 2和5-95％溶剂B 2(0-2分钟)，然后95％溶剂B 2和5％溶剂A 2(保持1.8分钟)，百分数为某一溶剂占总溶剂体积的体积百分数。溶剂A 2：10mM的碳酸氢铵的水溶液；溶剂B 2：乙腈。
制备高效液相色谱仪(prep-HPLC)使用Gilson GX-281制备液相色谱或Agela FLEXA-HP制备液相色谱。色谱柱为：Xtimate 21.2*250mm，10um。分离条件1：流动相A：0.05％盐酸水溶液，流动相B：乙腈；分离条件2：流动相A：10mmol/L碳酸氢铵水溶液，流动相B：乙腈；分离条件3：流动相A：0.1％三氟乙酸水溶液，流动相B：乙腈。检测波长：214nm&254nm；流速：15.0mL/分钟。
快速柱层析(Flash柱层析)(flash system/CheetahTM)使用的是Agela Technologies MP200，配套使用的正相分离柱为Flash columm Silica-CS(25g、40g、80g、120g或330g)，天津博纳艾杰尔，洗脱体系为乙酸乙酯/石油醚，或二氯甲烷/甲醇；反相分离柱为C18反相柱(Spherical C18,40-75um,
Figure PCTCN2022093953-appb-000211
型号：SW-040)，洗脱体系为10mM碳酸氢铵水溶液/乙腈或0.05％三氟乙酸水溶液/乙腈。
本发明实施例中使用的缩写含义如下：
(Boc) 2O：二碳酸二叔丁酯；BINAP：1,1’-联萘-2,2’-双二苯膦；DMF：N,N-二甲基甲酰胺；DMSO：二甲亚砜；DIPEA：N,N-二异丙基乙胺；EDCI：1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐；HATU：O-(7-氮杂苯并三唑-1-基)-N,N,N’,N’-四甲基脲；LiHMDS：双三甲基硅基胺基锂；PdCl 2dppf .CH 2Cl 2：[1,1’-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物；Pd 2(dba) 3：三(二亚苄基丙酮)二钯；Pd(PPh 3) 4：四(三苯基膦)钯；TBSCl：叔丁基二甲基氯硅烷；Xantphos：4,5-双二苯基膦-9,9-二甲基氧杂蒽；Xphos：2-二环己基磷-2,4,6-三异丙基联苯。
中间体的合成：
Linker-1的合成
Figure PCTCN2022093953-appb-000212
向化合物1A(150mg，0.26mmol)的DMF(4mL)溶液中依次加入二(对硝基苯)碳酸酯(158mg，0.52mmol)和DIPEA(101mg，0.78mmol)，反应液在室温下搅拌过夜。反应液过滤后减压浓缩，残留物经Flash柱层析(10mM碳酸氢铵水溶液/乙腈＝0-65％)纯化得到Linker-1(125mg)为淡黄色 固体。m/z:[M+H] +738.1。
Linker-2的合成
Figure PCTCN2022093953-appb-000213
向化合物2A(120mg，0.25mmol)的DMF(3mL)溶液中依次加入二(对硝基苯)碳酸酯(152mg，0.50mmol)和DIPEA(97mg，0.75mmol)，反应液在室温下搅拌过夜。反应液过滤后减压浓缩，残留物经Flash柱层析(10mM碳酸氢铵水溶液/乙腈＝0-85％)纯化得到Linker-2(115mg)为淡黄色固体。m/z:[M+H] +652.1。
Linker-3的合成
Figure PCTCN2022093953-appb-000214
步骤1：向化合物3A(436mg，1.0mmol)的DMF(5mL)溶液中依次加入2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(456mg，1.2mmol)和DIPEA(258mg，2.0mmol)，反应体系在室温下搅拌5分钟，然后加入(4-氨基苯基)甲醇(135mg，1.1mmol)。该反应体系于室温下搅拌16小时后直接通过Flash柱层析(10mM碳酸氢铵水溶液/乙腈＝5％-75％)纯化得化合物3B(350mg)为白色固体。m/z:[M+H] +542.1。
步骤2：冰浴条件下，向化合物3B(350mg，0.65mmol)的二氯甲烷(3mL)溶液中滴加三氟醋酸(2mL)，反应液缓慢升到室温并继续搅拌2小时，减压浓缩除去大部分溶剂后直接通过Flash柱层析(10mM碳酸氢铵水溶液/乙腈＝5％-85％)纯化得化合物3C(270mg)为白色固体。m/z:[M+H] +442.0。
步骤3：向化合物3C(260mg，0.59mmol)的DMF(2mL)溶液中滴加DIPEA(152mg，1.18mmol)和6-(马来酰亚胺基)己酸琥珀酰亚胺酯(200mg，0.65mmol)，反应液在室温下搅拌2小时后 直接通过Flash柱层析(10mM碳酸氢铵水溶液/乙腈＝5％-50％)纯化得化合物3D(300mg)为白色固体。m/z:[M+H] +635.3。
步骤4：向化合物3D(280mg，0.44mmol)的DMF(3mL)溶液中依次滴加DIPEA(170mg，1.32mmol)和二(对硝基苯)碳酸酯(240mg，0.79mmol)，反应液在室温下搅拌2小时后直接通过Flash柱层析(10mM碳酸氢铵水溶液/乙腈＝0％-60％)纯化得Linker-3(290mg)为白色固体。m/z:[M+H] +800.1。
8-((叔丁氧羰基)氨基)-2-氯-7H-吡啶并[2,3-b]氮杂卓-6-甲酸(中间体1.7)的合成
Figure PCTCN2022093953-appb-000215
步骤1：冰浴条件下，向2-氨基-6-氯吡啶(40g，311mmol)和LiHMDS(685mL，685mmol，1M四氢呋喃溶液)的四氢呋喃(400mL)溶液中滴加(Boc) 2O(74.7g，342mmol)。将该反应体系在室温下搅拌过夜后浓缩，用乙酸乙酯(400mL)稀释，有机相分别用盐酸(1M)、饱和的碳酸氢钠水溶液和饱和食盐水洗涤，分离有机相用无水硫酸钠干燥，过滤、滤液减压浓缩，残留物用乙醇重结晶，过滤，滤饼真空干燥后得到中间体1.1(39.5g，产率：56％)为黄色固体。
步骤2：氮气保护下，于-78℃下向中间体1.1(39.5g，173mmol)和N,N,N’,N’-四甲基乙二胺(74.4g，432mmol)的四氢呋喃(400mL)溶液中滴加正丁基锂(173mL，432mmol，2.5M正己烷溶液)。加毕，将反应体系缓慢升至-10℃并在该温度下搅拌2小时。将反应体系再次冷却至-78℃，加入DMF(25.3g，347mmol)。加毕，将反应体系缓慢升至室温并搅拌过夜。-10℃下用盐酸(1M)淬灭反应并调节pH＝2～3，水相用乙酸乙酯萃取，有机相分别用水和饱和食盐水洗涤，分离有机相用无水硫酸钠干燥，过滤、滤液减压浓缩得中间体1.2(32.9g，产率：74％)为黄色固体。
步骤3：将中间体1.2(32.9g，128mmol)加入到氯化氢的1,4-二氧六环溶液中(300mL，4M)，反应液在室温下搅拌过夜。减压浓缩，残留物用饱和碳酸氢钠水溶液调pH＝7～8，水相用乙酸乙酯萃取，合并有机相，并分别用水和饱和食盐水洗涤，分离有机相用无水硫酸钠干燥，过滤、滤液减压浓缩得中间体1.3(18.9g，产率：94％)为黄色固体。m/z:[M+H] +157.0。
步骤4：将中间体1.3(18.9g，121mmol)和化合物1.4A(46.8g，121mmol)的甲苯(400mL) 溶液回流搅拌过夜。减压浓缩除去溶剂，残留物用乙醇(150mL)重结晶，过滤，滤饼真空干燥后得中间体1.4(13.1g，产率：41％)为黄色固体。m/z:[M+H] +266.0。
步骤5：将中间体1.4(6.6g，24.9mmol)的氯化氢的乙醇溶液(80mL，2M)在30℃下搅拌两天。减压浓缩除掉溶剂，残留物用饱和碳酸氢钠水溶液调pH＝7～8，用二氯甲烷甲醇的混合溶剂(10/1)萃取水相，有机相分别用水和饱和食盐水洗涤，分离有机相用无水硫酸钠干燥，过滤、滤液减压浓缩得中间体1.5(6.5g，产率：98％)为黄色固体。m/z:[M+H] +266.0； 1H NMR(400MHz,DMSO-d 6):δ7.90(d,J＝8.0Hz,1H),7.75(s,1H),7.39(br.s,2H),7.02(d,J＝8.0Hz,1H),4.24(q,J＝7.6Hz,2H),2.98(s,2H),1.29(t,J＝7.0Hz,3H)。
步骤6：向中间体1.5(6.5g，24.5mmol)的二氯甲烷(130mL)溶液中加入(Boc) 2O(13.4g，61.2mmol)。将反应体系在室温下搅拌5天后再加二氯甲烷(100mL)稀释，有机相分别用柠檬酸水溶液(2M)、饱和的碳酸氢钠水溶液和饱和食盐水洗涤。分离有机相用无水硫酸钠干燥，过滤、滤液减压浓缩，残留物用Flash柱层析(石油醚/乙酸乙酯＝100～1/1)纯化得到中间体1.6(8.6g，产率：78％)为黄色固体。
步骤7：向中间体1.6(4g，10.9mmol)的四氢呋喃(21mL)、乙醇(14mL)和水(7mL)的混合溶液中加入一水合氢氧化锂(1.38g，32.8mmol)。反应体系在室温下搅拌过夜后倒入水中，然后用柠檬酸水溶液(2M)调节pH＝4，过滤，滤饼分别用水和甲基叔丁基醚洗涤，有机相减压浓缩得到中间体1.7(2.97g，产率：80％)为土黄色固体。
8-氨基-2-氯-7H-吡啶并[2,3-b]氮杂卓-6-甲酸(中间体1.8)的合成
Figure PCTCN2022093953-appb-000216
利用中间体1.7步骤7的合成方法，用中间体1.5反应得到中间体1.8。
8-溴-2-((叔丁氧羰基)氨基)-3H-苯并[b]氮杂卓-4-甲酸(中间体2.6)的合成
Figure PCTCN2022093953-appb-000217
步骤1：将中间体2.1(20g，57.4mmol)和溴乙腈(6.9g，57.4mmol)的乙酸乙酯(200mL)溶液回流搅拌3小时，过滤除去固体，滤饼用乙酸乙酯洗涤。滤液减压浓缩得中间体2.2(17g，产 率：76％)为淡黄色油状物。
步骤2：将4-溴-2-硝基苯甲醛(10g，43.9mmol)和中间体2.2(17g，43.9mmol)的甲苯(170mL)溶液回流搅拌2小时，混合物冷却至室温后用短的硅胶柱过滤，用25％的乙酸乙酯石油醚溶液洗脱，减压浓缩除去大部分洗脱液，将剩余溶液置于-18℃，放置16小时。有固体析出，过滤、滤饼真空干燥后得中间体2.3(8.2g，产率：55％)为类白色固体。
步骤3：将中间体2.3(4.2g，12.4mmol)的乙酸(80mL)溶液加热到80℃后，15分钟内向上述溶液中分批加入铁粉(4.1g，74.3mmol)，保持内温不超过90℃，加毕，继续搅拌3小时。将反应体系冷却至室温，用硅藻土过滤，用乙酸乙酯淋洗。滤液减压浓缩，残留物用冷水稀释后用饱和的碳酸氢钠水溶液调节pH>8，水相用乙酸乙酯萃取，合并有机相并用饱和食盐水洗涤，分离有机相并用无水硫酸钠干燥，过滤、滤液减压浓缩，残留物用10％的乙酸乙酯石油醚溶液打浆，过滤，滤饼真空干燥后得中间体2.4(3g，产率：78％)为类白色固体。
步骤4：向中间体2.4(3g，9.7mmol)和三乙胺(1.47g，14.6mmol)的二氯甲烷(50mL)溶液中加入(BOC) 2O(3.2g，14.6mmol)。将反应体系在室温下搅拌2天后用二氯甲烷稀释，有机相分别用盐酸(3M)、饱和的碳酸氢钠水溶液和饱和食盐水洗涤，分离有机相用无水硫酸钠干燥，过滤、滤液减压浓缩，残留物用10％的乙酸乙酯石油醚溶液打浆，过滤，滤饼干燥后得中间体2.5(1.6g，产率：40％)为类白色固体。
步骤5：冰浴条件下，向中间体2.5(1.6g，3.91mmol)的四氢呋喃(50mL)溶液中加入氢氧化钠水溶液(1.0M，5.9mL)。反应体系在室温下搅拌16小时，然后用盐酸(0.5M)调节pH＝6，水相用乙酸乙酯萃取，合并有机相用饱和食盐水洗涤，分离有机相并用无水硫酸钠干燥，过滤、滤液减压浓缩得中间体2.6(1.1g，产率：74％)为淡黄色泡沫状固体。
8-溴-2-((叔丁氧羰基)氨基)-6-氟-3H-苯并[b]氮杂卓-4-甲酸(中间体3.1)的合成
Figure PCTCN2022093953-appb-000218
利用中间体2.6的合成方法，将步骤2中的4-溴-2-硝基苯甲醛替换为4-溴-2-氟-6-硝基苯甲醛得到中间体3.1。
2-氨基-8-溴-6-氟-3H-苯并[b]氮杂卓-4-甲酸(中间体3.2)的合成
Figure PCTCN2022093953-appb-000219
利用中间体2.6步骤5的合成方法，用2-氨基-8-溴-6-氟-3H-苯并[b]氮杂卓-4-甲酸乙酯反应得到中间体3.2。
2-氨基-8-溴-3H-苯并[b]氮杂卓-4-甲酸(中间体4.1)的合成
Figure PCTCN2022093953-appb-000220
利用中间体2.6步骤5的合成方法，用中间体2.4反应得到中间体4.1。
(2-(丙基氨基)乙基)氨基甲酸叔丁酯(中间体7.1)的合成
Figure PCTCN2022093953-appb-000221
冰浴条件下，向N-丙基亚乙基二胺(3.40g，33.3mmol)的四氢呋喃(40mL)溶液中滴加二碳酸二叔丁酯(2.2g，10.1mmol)的四氢呋喃(30mL)溶液，30分钟滴加完后，反应体系在室温下搅拌过夜。然后减压浓缩，加入饱和食盐水(50mL)，用乙酸乙酯(3×30mL)萃取，合并有机相后用饱和食盐水洗涤、无水硫酸钠干燥，过滤、减压浓缩，将残留物用正戊烷(30mL)溶解置于冰箱中静置过夜，过滤收集析出的固体得到中间体7.1(1.26g，产率：61％)，室温放置下为无色油状物。m/z:[M+H] +203.2。
化合物的合成
实施例1：8-氨基-N 6,N 6-二正丙基-N 2-(5,6,7,8-四氢-1,6-萘啶-3-基)-7H-吡啶并[2,3-b]氮杂卓-2,6-二甲酰胺(化合物1)的合成
Figure PCTCN2022093953-appb-000222
步骤1：-70℃下，往DMF(30mL)中依次加入化合物1.7(2.97g，8.8mmol)、DIPEA(2.84g，22mmol)、二正丙基胺(2.22g，22mmol)和HATU(7.13g，22mmol)。加毕，反应体系在0℃下搅拌20分钟，将反应液倒入水中，水相用乙酸乙酯萃取，合并有机相并用饱和食盐水洗涤，分离有机相用无水硫酸钠干燥，过滤、滤液减压浓缩，残留物用Flash柱层析(石油醚/乙酸乙酯＝1/1)纯化得到化合物1.8(1.2g，产率：32％)为黄色油状物。m/z:[M+H] +421.0。
步骤2：将化合物1.8(1g，2.38mmol)、Xantphos(69mg，0.12mmol)、醋酸钯(53mg，0.24mmol)和磷酸三钾(1.51g)的四氢呋喃(10mL)和水(10mL)的混合溶液分别用氮气和一氧化碳置换三次后，在一氧化碳气氛下70℃搅拌6小时。反应体系冷却至室温，过滤，滤饼用甲醇洗涤， 滤液减压浓缩后直接用prep-HPLC(分离条件2)纯化得到化合物1.9(220mg，产率：22％)为棕色固体。m/z:[M+H] +431.2。
步骤3：-78℃条件下，向化合物1.9(100mg，0.23mmol)和N-甲基吗啉(28mg，0.28mmol)的四氢呋喃(10mL)溶液中加入氯甲酸异丁酯(38mg，0.28mmol)，反应液在-78℃下搅拌1小时，然后将3-氨基-7,8-二氢-1,6-萘啶-6(5H)-羧酸叔丁酯(69mg，0.28mmol)加入到上述反应液中，反应体系继续在此温度下搅拌1小时，然后升至室温继续搅拌1小时。加水淬灭反应，水相用乙酸乙酯萃取，合并有机相并减压浓缩。残留物用prep-TLC(二氯甲烷/甲醇＝10/1)纯化得到化合物1.10(100mg，产率：65％)为棕色油状物。m/z:[M+H] +662.4。
步骤4：将化合物1.10(100mg，0.15mmol)和三氟乙酸(1mL)的二氯甲烷(3mL)溶液在室温下搅拌2小时，直接减压浓缩，残留物用prep-HPLC(分离条件2)纯化得到化合物1(24.7mg，产率：35％)为白色固体。m/z:[M+H] +462.3； 1H NMR(400MHz,DMSO-d 6):δ10.49(s,1H),8.73(d,J＝2.4Hz,1H),8.07-7.89(m,2H),7.69(d,J＝7.6Hz,1H),7.25(d,J＝21.2Hz,2H),6.86(s,1H),3.87(s,2H),3.34-3.25(m,5H),3.03(t,J＝6.0Hz,2H),2.86(s,2H),2.75(t,J＝6.0Hz,2H),1.68-1.46(m,4H),1.02-0.59(m,6H)。
实施例2：8-氨基-N 6-(2-羟基乙基)-N 6-正丙基-N 2-(5,6,7,8-四氢-1,6-萘啶-3-基)-7H-吡啶并[2,3-b]氮杂卓-2,6-二甲酰胺(化合物2)的合成
Figure PCTCN2022093953-appb-000223
利用化合物1的合成方法，将步骤1中的二正丙基胺替换为2-(丙氨基)乙醇得到化合物2为白色固体。m/z:[M+H] +464.2； 1H NMR(400MHz,DMSO-d 6):δ10.48(s,1H),8.73(d,J＝2.4Hz,1H),8.02-7.89(m,2H),7.69(d,J＝8.0Hz,1H),7.24(s,2H),6.90(s,1H),4.82(s,1H),3.86(s,2H),3.63-3.50(m,3H),3.44(t,J＝6.0Hz,3H),3.02(t,J＝6.0Hz,3H),2.85(s,2H),2.74(t,J＝6.0Hz,2H),1.64-1.51(m,2H),0.93-0.77(m,3H)。
实施例3：2-氨基-N,N-二正丙基-8-(1-((5,6,7,8-四氢-1,6-萘啶-3-基)氨基甲酰基)环丙基)-3H-苯并[b]氮杂卓-4-甲酰胺(化合物3)的合成
Figure PCTCN2022093953-appb-000224
Figure PCTCN2022093953-appb-000225
步骤1：将化合物2.6(1.1g，2.8mmol)、HATU(1.6g，4.33mmol)、二正丙基胺(580mg，22mmol)和DIPEA(560mg，4.37mmol)的DMF(10mL)溶液在室温下搅拌3小时。将反应体系用乙酸乙酯(100mL)稀释后分别用水和饱和食盐水洗涤，分离有机相，用无水硫酸钠干燥，过滤、滤液减压浓缩，残留物用Flash柱层析(甲醇/二氯甲烷＝1/20)纯化得化合物2.7(500mg，产率：39％)为淡黄色固体。
步骤2：化合物2.7(2g，4.31mmol)、Xphos(0.2g)、Pd 2(dba) 3(0.2g)溶于新制的(1-(甲氧羰基)环丙基)溴化锌的四氢呋喃溶液(1eq，30mL)(参考WO2018/138356A1)，反应系统用氮气置换三次，然后在75℃，氮气保护下搅拌2小时，冷却至室温后，加入冰水淬灭反应，水相用乙酸乙酯萃取，合并有机相并用饱和食盐水洗涤，无水硫酸钠干燥、过滤、滤液减压浓缩，残留物用Flash柱层析(石油醚/乙酸乙酯＝3/1)纯化得化合物2.8(500mg，产率：24％)为淡黄色固体。m/z:[M+H] +484.2。
步骤3：向化合物2.8(500mg，1.03mmol)的四氢呋喃(5mL)、甲醇(0.5mL)和水(0.5mL)的混合溶液中加入一水合氢氧化锂(130mg，3.1mmol)，反应体系在室温下搅拌16小时，然后将反应液用盐酸(1M)中和，水相用乙酸乙酯萃取，合并有机相并用饱和食盐水洗涤，无水硫酸钠干燥、过滤、滤液减压浓缩得到化合物2.9(400mg，产率：82％)为类白色固体。m/z:[M+H] +470.2。
步骤4：向化合物2.9(100mg，0.21mmol)的DMF(1mL)溶液中依次加入3-氨基-7,8-二氢-1,6-萘啶-6(5H)-羧酸叔丁酯(64mg，0.25mmol)、HATU(97mg，0.25mmol)和DIPEA(55mg，0.42mmol)，反应液在室温下搅拌4小时。然后直接用Flash柱层析(10mM碳酸氢铵水溶液/乙腈＝15/85)纯化得到化合物2.10(28mg，产率：19％)为白色固体。m/z:[M+H] +701.3。
步骤5：向化合物2.10(28mg，0.04mmol)的二氯甲烷(2mL)溶液中加入三氟乙酸(1mL)，反应液在室温下搅拌2小时后直接减压浓缩，残留物用氨甲醇溶液(7M)中和后用Flash柱层析(10mM碳酸氢铵水溶液/乙腈＝40/60)纯化得到化合物3(17mg，产率：85％)为白色固体。m/z:[M+H] +501.3； 1H NMR(400MHz,DMSO-d 6):δ9.19(s,1H),8.42(s,1H),7.63(s,1H),7.25(d,J＝7.6Hz,1H),7.00(s,1H),6.91(d,J＝8.4Hz,1H),6.74(s,2H),6.69(s,1H),3.78(s,2H),2.97(br.s,2H),2.63(s,6H),1.55-0.74(m,17H)。
实施例4：2-氨基-N-(2-羟基乙基)-N-正丙基-8-(1-((5,6,7,8-四氢-1,6-萘啶-3-基)氨基甲酰基)环丙基)-3H-苯并[b]氮杂卓-4-甲酰胺(化合物4)的合成
Figure PCTCN2022093953-appb-000226
利用化合物3的合成方法，将步骤1中的二正丙基胺替换为2-(丙氨基)乙醇得到化合物4为白色固体。m/z:[M+H] +503.3。
实施例5：2-氨基-6-氟-N,N-二正丙基-8-(1-((5,6,7,8-四氢-1,6-萘啶-3-基)氨基甲酰基)环丙基)-3H-苯并[b]氮杂卓-4-甲酰胺(化合物5)的合成
Figure PCTCN2022093953-appb-000227
利用化合物3的合成方法，将步骤1中的中间体2.6替换为中间体3.1得到化合物5为白色固体。m/z:[M+H] +519.1。
实施例6：2-氨基-8-(2-氧代-2-((5,6,7,8-四氢-1,6-萘啶-3-基)氨基)乙酰基)-N,N-二正丙基-3H-苯并[b]氮杂卓-4-甲酰胺(化合物6)的合成
Figure PCTCN2022093953-appb-000228
步骤1：利用化合物2.7的合成方法，用化合物4.1反应得到化合物4.2。
步骤2：将化合物4.2(2g，5.49mmol)、六甲基二锡(1.89g，5.76mmol)和Pd(PPh 3) 4(127mg，0.11mmol)的甲苯(25mL)混合物用氮气置换三次，反应体系在氮气保护下，100℃下搅拌6小时。然后，将反应体系冷却至室温，过滤，滤液减压浓缩，残留物用Flash柱层析(石油醚/乙酸乙酯＝1/1)纯化得到化合物4.3(1.45g，产率：59％)为浅褐色固体。m/z:[M+H] +450.2。
步骤3：向化合物4.3(1.45g，3.24mmol)的二氯甲烷(30mL)溶液中分别加入三乙胺(0.98g，9.71mmol)、4-二甲氨基吡啶(79mg，0.65mmol)和(Boc) 2O(2.12g，9.71mmol)。反应液在室温下搅拌过夜，然后直接减压浓缩，残留物用Flash柱层析(石油醚/乙酸乙酯＝10/1)纯化得到化合物4.4(1.2g，产率：57％)为浅黄色固体。m/z:[M+H] +650.0。
步骤4：冰浴条件下，向化合物4.4(400mg，0.62mmol)、DIPEA(120mg，0.92mmol)和碳 酸钾(17mg，0.12mmol)的无水四氢呋喃(6mL)溶液中加入Pd 2(dba) 3(33mg，0.06mmol)，反应体系用氮气置换三次，然后向体系中滴加草酰氯单甲酯(113mg，0.92mmol)的四氢呋喃(1mL)溶液。加毕，将反应体系升至室温并搅拌过夜，加水淬灭反应，水相用乙酸乙酯萃取，合并有机相并减压浓缩，残留物用Flash柱层析(石油醚/乙酸乙酯＝2/1)纯化得到化合物4.5(145mg，产率：41％)为浅黄色固体。m/z:[M+Na] +594.3。
步骤5：冰浴条件下，向化合物4.5(145mg，0.25mmol)的四氢呋喃(5mL)溶液中加入一水合氢氧化锂(289mg，0.88mmol)的水溶液(2mL)。反应体系在0℃下搅拌1小时。然后，用盐酸(1M)调节pH＝7，混合物直接用Flash柱层析(MeCN/NH 4HCO 3(10mM)＝85/15)纯化得到化合物4.6(90mg，产率：65％)为浅褐色固体。m/z:[M+H] +558.3。
步骤6：向化合物4.6(80mg，0.14mmol)的DMF(4mL)溶液中依次加入3-氨基-7,8-二氢-1,6-萘啶-6(5H)-羧酸叔丁酯(43mg，0.17mmol)、HATU(65mg，0.17mmol)和DIPEA(22mg，0.17mmol)，反应液在50℃下微波反应1小时。然后加水淬灭反应，水相用乙酸乙酯萃取。合并有机相并减压浓缩，残留物用prep-TLC(石油醚/乙酸乙酯＝1/2)纯化得到化合物4.7(39mg，产率：34％)为浅黄色固体。m/z:[M+H] +789.5。
步骤7：向化合物4.7(39mg，0.05mmol)的二氯甲烷(4mL)溶液中加入三氟乙酸(2mL)，反应液在室温下搅拌2小时后直接减压浓缩，残留物用氨甲醇溶液(7M)中和后用Flash柱层析(10mM碳酸氢铵水溶液/乙腈＝40/60)纯化得到化合物6(15mg，产率：62％)为黄色固体。m/z:[M+H] +489.3。
实施例7：2-氨基-8-(2-甲基-1-氧代-1-((5,6,7,8-四氢-1,6-萘啶-3-基)氨基)丙-2-基)-N,N-二正丙基-3H-苯并[b]氮杂卓-4-甲酰胺(化合物7)的合成
Figure PCTCN2022093953-appb-000229
利用化合物3的合成方法，将步骤2中的(1-(甲氧羰基)环丙基)溴化锌替换为(1-甲氧基-2-甲基-1-氧代丙-2-基)溴化锌得到化合物7为白色固体。m/z:[M+H] +503.3； 1H NMR(400MHz,CD 3OD):δ8.45(d,J＝2.0Hz,1H),7.77(d,J＝2.0Hz,1H),7.31(d,J＝8.4Hz,1H),7.20(d,J＝1.6Hz,1H),7.09-7.05(m,1H),6.82(s,1H),3.96(s,2H),3.44-3.37(m,4H),3.19-3.14(m,2H),2.94-2.73(m,4H),1.75-1.56(m,10H),1.05-0.78(m,6H)。
实施例8：8-氨基-N-(2-羟基乙基)-N-正丙基-2-((5,6,7,8-四氢-1,6-萘啶-3-基)氨基)-7H-吡啶并[2,3-b]氮杂卓-6-甲酰胺(化合物8)的合成
Figure PCTCN2022093953-appb-000230
Figure PCTCN2022093953-appb-000231
步骤1：将化合物5.1(利用化合物2.7的合成方法，用中间体1.7和2-(丙氨基)乙醇反应得到)(200mg，0.47mmol)，3-氨基-7,8-二氢-1,6-萘啶-6(5H)-羧酸叔丁酯(142mg，0.57mmol)，碳酸铯(170mg，0.52mmol)，醋酸钯(32mg，0.14mmol)和Xantphos(82mg，0.14mmol)的1,4-二氧六环(6mL)混合物用氮气置换三次，反应体系在氮气保护下，90℃下搅拌4小时。加水淬灭反应，水相用乙酸乙酯萃取。合并有机相后减压浓缩，残留物经prep-TLC(二氯甲烷/甲醇＝10/1)纯化得化合物5.2(200mg，产率：67％)为浅褐色固体。
步骤2：向化合物5.2(200mg，0.31mmol)的二氯甲烷(10mL)溶液中加入三氟乙酸(2mL)。反应体系在室温下搅拌2小时。减压浓缩，残留物经prep-HPLC(分离条件3)纯化得化合物8(31mg，产率：23％)为浅黄色固体。m/z:[M+H] +436.2； 1H NMR(400MHz,DMSO-d 6):δ9.08(s,1H),8.63(d,J＝2.4Hz,1H),8.00(d,J＝2.0Hz,1H),7.48(d,J＝8.8Hz,1H),7.09(br.s,1H),6.87(br.s,1H),6.66(s,1H),6.44(d,J＝8.4Hz,1H),4.79(s,1H),3.82(s,2H),3.30-3.61(m,2H),3.10-3.20(m,5H),3.00(t,J＝6.0Hz,2H),2.82-2.62(m,4H),1.65-1.47(m,2H),0.81(br.s,3H)。
实施例9：8-氨基-N,N-二正丙基-2-(1-((5,6,7,8-四氢-1,6-萘啶-3-基)氨基甲酰基)环丙基)-7H-吡啶并[2,3-b]氮杂卓-6-甲酰胺(化合物9)的合成
Figure PCTCN2022093953-appb-000232
利用化合物3的合成方法，将步骤1中的中间体2.6替换为中间体1.8得到化合物9为白色固体。m/z:[M+H] +502.4； 1H NMR(400MHz,DMSO-d 6):δ12.43(s,1H),8.51(d,J＝2.4Hz,1H),7.81(d,J＝2.4Hz,1H),7.70(d,J＝8.0Hz,1H),7.26(s,1H),7.15(s,1H),6.80(d,J＝8.4Hz,1H),6.73(s,1H),3.84(s,2H),3.29-3.19(m,5H),3.01(t,J＝6.0Hz,2H),2.85-2.66(m,4H),1.67-1.48(m,6H),1.40(q,J＝3.6Hz,2H),0.82(s,6H)。
实施例10：8-氨基-N-(2-羟基乙基)-N-正丙基-2-(1-((5,6,7,8-四氢-1,6-萘啶-3-基)氨基甲酰基)环丙基)-7H-吡啶并[2,3-b]氮杂卓-6-甲酰胺(化合物10)的合成
Figure PCTCN2022093953-appb-000233
利用化合物3的合成方法，用1.7和2-(丙氨基)乙醇为起始原料合成化合物10为白色固体。m/z:[M+H] +504.2。
实施例11：2-氨基-6-氟-N-(2-羟基乙基)-N-正丙基-8-(1-((5,6,7,8-四氢-1,6-萘啶-3-基)氨基甲酰基)环丙基)-3H-苯并[b]氮杂卓-4-甲酰胺(化合物11)的合成
Figure PCTCN2022093953-appb-000234
步骤1：化合物6.1(利用化合物2.7的合成方法，用中间体3.1和2-(丙氨基)乙醇反应得到)(1g，2.06mmol)、Xphos(0.1g)、Pd 2(dba) 3(0.2g)溶于新制的(1-(甲氧羰基)环丙基)溴化锌的四氢呋喃溶液(35mL)，反应系统用氮气置换三次，然后在75℃，氮气保护下搅拌2小时，冷却至室温后，加入氯化氢甲醇溶液(1mL，4M)淬灭反应后直接用Flash柱层析纯化(10mM碳酸氢铵水溶液/乙腈＝0～7/3)纯化得化合物6.2(600mg，产率：72％)为类白色固体。m/z:[M+H] +404.2。
步骤2：向化合物6.2(500mg，1.24mmol)的DMF(5mL)溶液中依次加入咪唑(422mg，6.2mmol)和TBSCl(561mg，3.72mmol)，反应体系在室温下搅拌3小时后直接用Flash柱层析(10mM碳酸氢铵水溶液/乙腈＝0～4/1)纯化得化合物6.3(510mg，产率：79％)为白色固体。m/z:[M+H] +518.2。
步骤3：向化合物6.3(500mg，0.97mmol)的二氯甲烷(15mL)溶液中依次加入三乙胺(220mg，2.18mmol)和(Boc) 2O(285mg，1.31mmol)，反应体系在室温下搅拌12小时。加水淬灭反应，水相用二氯甲烷萃取，合并有机相并用饱和食盐水洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，残留物经Flash柱层析(石油醚/乙酸乙酯＝10/1)纯化得化合物6.4(510mg，产率：85％)为类白色固体。m/z:[M+H] +618.3。
步骤4：向化合物6.4(500mg，0.81mmol)的四氢呋喃(2mL)、甲醇(1mL)和水(1mL)的混合溶液中加入一水合氢氧化锂合(102mg，2.43mmol)，反应体系在室温下搅拌3小时，然后将反应液用盐酸(1M)调节pH＝6后直接用Flash柱层析(10mM碳酸氢铵水溶液/乙腈＝0～1/1)纯化得到化合物6.5(330mg，产率：68％)为白色固体。m/z:[M+H] +604.3。
步骤5：向化合物6.5(50mg，0.08mmol)的DMF(5mL)溶液中依次加入HATU(46mg，0.12 mmol)和DIPEA(31mg，0.24mmol)，反应液在室温下搅拌30分钟，然后加入3-氨基-7,8-二氢-1,6-萘啶-6(5H)-羧酸叔丁酯(25mg，0.1mmol)。得到的反应液在室温下继续搅拌16小时后直接用Flash柱层析(10mM碳酸氢铵水溶液/乙腈＝1/20～3/1)纯化得到化合物6.6(35mg，产率：52％)为白色固体。m/z:[M+H] +835.4。
步骤6：向化合物6.6(30mg，0.04mmol)的二氯甲烷(2mL)溶液中加入三氟乙酸(1mL)。反应体系在室温下搅拌1小时，将反应液减压浓缩后加入氨甲醇(1mL，7M)溶液，然后直接用Flash柱层析(10mM碳酸氢铵水溶液/乙腈＝0～2/1)纯化得化合物11(12mg，产率：58％)为白色固体。m/z:[M+H] +521.3。
实施例12：2-氨基-8-(1-((5-(氨基甲基)吡啶-3-基)氨基甲酰基)环丙基)-N-(2-羟基乙基)-N-正丙基-3H-苯并[b]氮杂卓-4-甲酰胺(化合物12)的合成
Figure PCTCN2022093953-appb-000235
利用化合物3的合成方法，将步骤1中的二正丙基胺替换为2-(丙氨基)乙醇，步骤3中的3-氨基-7,8-二氢-1,6-萘啶-6(5H)-羧酸叔丁酯替换为((5-氨基吡啶-3-基)甲基)氨基甲酸叔丁酯得到化合物12为白色固体。m/z:[M+H] +477.3。
实施例13：2-氨基-N 4-(2-羟基乙基)-N 4-正丙基-N 8-(5,6,7,8-四氢-1,6-萘啶-3-基)-3H-苯并[b]氮杂卓-4,8-二甲酰胺(化合物13)的合成
Figure PCTCN2022093953-appb-000236
步骤1：向化合物2.6(8.8g，23.1mmol)的DMF(100mL)溶液中依次按顺序加入DIPEA(8.9g，69.2mmol)、2-(丙氨基)乙醇(2.9g，27.7mmol)和HATU(13.2g，34.63mmol)。加毕，该反应体系在室温下搅拌2小时，然后加水淬灭反应，水相用乙酸乙酯(100mL×2)萃取，合并有机相并用饱和食盐水洗涤，分离有机相，用无水硫酸钠干燥，过滤、浓缩，残留物用硅胶柱层析(石油醚/乙酸乙酯＝1/1)纯化得到化合物7.7(10g，产率：93％)为类白色固体。m/z:[M+H] +466.2。
步骤2：将化合物7.7(600mg,1.29mmol)，磷酸钾(820mg，3.86mmol)，醋酸钯(29mg，0.13mmol)和Xantphos(37mg，0.06mmol)的四氢呋喃(10mL)和水(5mL)的混合溶液分别用氮气 和一氧化碳置换三次后，在一氧化碳气氛下70℃搅拌4小时。反应体系冷却至室温后减压浓缩，粗品分散到甲醇中，过滤，滤饼用甲醇洗涤，滤液减压浓缩后直接用Flash柱层析(10mM碳酸氢铵水溶液/乙腈＝30/70)纯化得到化合物7.8(100mg，产率：18％)为浅褐色固体。m/z:[M+H] +432.2。
步骤3：向化合物7.8(50mg，0.11mmol)、HATU(49mg，0.13mmol)和DIPEA(17mg，0.13mmol)的DMF(3mL)溶液中加入3-氨基-7,8-二氢-1,6-萘啶-6(5H)-羧酸叔丁酯(32mg，0.13mmol)，反应液在室温下搅拌过夜。将反应液倒入水中淬灭反应，水相用乙酸乙酯萃取，合并有机相并减压浓缩。残留物用Flash柱层析(10mM碳酸氢铵水溶液/乙腈＝30/70)纯化得到化合物7.9(25mg，产率：32％)为浅褐色固体。m/z:[M+H] +663.2。
步骤4：将化合物7.9(25mg，0.04mmol)和三氟乙酸(2mL)的二氯甲烷(5mL)溶液在室温下搅拌2小时，直接减压浓缩，残留物用prep-HPLC(分离条件2)制备得到化合物13(16mg，产率：94％)为白色固体。m/z:[M+H] +463.2； 1H NMR(400MHz,DMSO-d 6):δ10.36(s,1H),8.69(d,J＝2.0Hz,1H),8.00(s,1H),7.69(s,1H),7.53-7.45(m,1H),7.42(d,J＝8.4Hz,1H),6.99-6.76(m,2H),4.81(s,1H),4.01(s,2H),3.55(br.s,4H),3.38(m,5H),3.17(t,J＝6.0Hz,3H),2.83(t,J＝6.0Hz,2H),2.73(s,2H),1.67-1.43(m,2H),0.86(s,3H)。
实施例14：2-氨基-N,N-二(2-羟基乙基)-8-(1-((5,6,7,8-四氢-1,6-萘啶-3-基)氨基甲酰基)环丙基)-3H-苯并[b]氮杂卓-4-甲酰胺(化合物14)的合成
Figure PCTCN2022093953-appb-000237
步骤1：将化合物4.1(3g，10.7mmol)、HATU(5.36g，14.1mmol)、二(2-((叔丁基二甲基硅基)氧基)乙基)胺(3.76g，11.3mmol)和DIPEA(3.64g，28.2mmol)的DMF(30mL)溶液在室温下搅拌过夜。将反应体系用乙酸乙酯(100mL)稀释后分别用饱和碳酸氢钠水溶液和饱和食盐水洗涤，分离有机相，用无水硫酸钠干燥，过滤、滤液减压浓缩，残留物用Flash柱层析(甲醇/二氯甲烷＝1/20)纯化得化合物8.1(6.6g，产率：100％)为黄色固体。m/z:[M+H] +596.2。
步骤2：化合物8.1(6.5g，10.9mmol)、Xphos(0.5g，1mmol)、Pd 2(dba) 3(0.5g，0.54mmol)溶于新制的(1-(甲氧羰基)环丙基)溴化锌的四氢呋喃溶液(1eq，160mL)，反应系统用氮气置换三次， 然后在75℃，氮气保护下搅拌5小时，冷却至室温后，加入冰水淬灭反应，水相用乙酸乙酯萃取，合并有机相并用饱和食盐水洗涤，无水硫酸钠干燥、过滤、滤液减压浓缩，残留物用Flash柱层析(石油醚/乙酸乙酯＝3/1)纯化得化合物8.2(4.23g，产率：63％)为黄色固体。m/z:[M+H] +616.4。
步骤3：向化合物8.2(4.23g，6.87mmol)和三乙胺(1.74g，17.2mmol)的二氯甲烷(50mL)溶液中加入(BOC) 2O(2.25g，10.3mmol)。将反应体系在室温下搅拌过夜，有机相分别用饱和的碳酸氢钠水溶液和饱和食盐水洗涤，分离有机相用无水硫酸钠干燥，过滤、滤液减压浓缩，残留物用Flash柱层析(石油醚/乙酸乙酯＝2/1)纯化得化合物8.3(1.24g，产率：25％)为黄色固体。m/z:[M+H] +716.4。
步骤4：向化合物8.3(1.23g，1.72mmol)的四氢呋喃(2.55mL)、甲醇(0.5mL)和水(0.5mL)的混合溶液中加入三甲基硅醇钾(0.88g，6.88mmol)，反应体系在室温下搅拌1小时，然后冰浴条件下，向反应液中加入饱和的氯化铵水溶液，水相用乙酸乙酯萃取，合并有机相并用饱和食盐水洗涤，无水硫酸钠干燥、过滤、滤液减压浓缩，残留物用Flash柱层析(二氯甲烷/甲醇＝10/1)纯化得到化合物8.4(400mg，产率：83％)为黄色固体。m/z:[M+H] +702.4。
步骤5：向化合物8.4(200mg，0.28mmol)的DMF(5mL)溶液中依次加入3-氨基-7,8-二氢-1,6-萘啶-6(5H)-羧酸叔丁酯(84mg，0.34mmol)、HATU(160mg，0.42mmol)和DIPEA(109mg，0.84mmol)，反应液在室温下搅拌过夜。向反应液中加入饱和的碳酸氢钠水溶液，水相用乙酸乙酯萃取，有机相减压浓缩，残留物用prep-TLC(二氯甲烷/甲醇＝10/1)纯化得到化合物8.5(229mg，产率：88％)为黄色固体。m/z:[M+H] +993.4。
步骤6：向化合物8.5(200mg，0.21mmol)的二氯甲烷(4mL)溶液中加入三氟乙酸(1mL)，反应液在室温下搅拌1小时后直接减压浓缩后直接用prep-HPLC纯化得到化合物14(23mg，产率：21％)为白色固体。m/z:[M+H] +505.2； 1H NMR(400MHz,CD 3OD):δ8.38(d,J＝2.4Hz,1H),7.68(d,J＝2.0Hz,1H),7.37(d,J＝8.0Hz,1H),7.24(d,J＝1.6Hz,1H),7.17-7.11(m,1H),7.00(s,1H),3.94(s,2H),3.86-3.69(m,4H),3.69-3.57(m,4H),3.18-3.11(m,2H),3.07-2.95(m,1H),2.90-2.79(m,3H),1.63-1.56(m,2H),1.26-1.19(m,2H)。
实施例15：2-氨基-6-氟-N,N-二(2-羟基乙基)-8-(1-((5,6,7,8-四氢-1,6-萘啶-3-基)氨基甲酰基)环丙基)-3H-苯并[b]氮杂卓-4-甲酰胺(化合物15)的合成
Figure PCTCN2022093953-appb-000238
利用化合物14的合成方法，用中间体3.2为起始原料得到化合物15为白色固体。m/z:[M+H] +523.1； 1H NMR(400MHz,CD 3OD):δ8.42(d,J＝2.4Hz,1H),7.72(d,J＝2.4Hz,1H),7.12(d,J＝1.6Hz,1H),7.08(s,1H),6.92(dd,J＝1.2,10.8Hz,1H),3.97(s,2H),3.68-3.81(m,8H),3.32-3.34(m,2H),3.17-3.20(m,2H),2.88-2.91(m,2H),1.60-1.62(m,2H),1.23-1.26(m,2H)。
实施例16：2-氨基-8-(1-((5-(氨基甲基)吡啶-3-基)氨基甲酰基)环丙基)-N,N-二(2-羟基乙基)-3H-苯 并[b]氮杂卓-4-甲酰胺(化合物16)的合成
Figure PCTCN2022093953-appb-000239
利用化合物14的合成方法，将步骤5中的3-氨基-7,8-二氢-1,6-萘啶-6(5H)-羧酸叔丁酯替换为((5-氨基吡啶-3-基)甲基)氨基甲酸叔丁酯得到化合物16为白色固体。m/z:[M+H] +479.2； 1H NMR(400MHz,CD 3OD):δ8.53(d,J＝2.4Hz,1H),8.24(d,J＝2.0Hz,1H),7.93(t,J＝2.4Hz,1H),7.37(d,J＝8.0Hz,1H),7.24(d,J＝2.0Hz,1H),7.14(dd,J＝1.8,8.0Hz,1H),7.00(s,1H),4.62(s,2H),3.81(s,2H),3.79-3.61(m,8H),1.65-1.58(m,2H),1.27-1.19(m,2H)。
实施例17：2-氨基-N 4-(2-氨基乙基)-N 4-正丙基-N 8-(5,6,7,8-四氢-1,6-萘啶-3-基)-3H-苯并[b]氮杂卓-4,8-二甲酰胺(化合物17)的合成
Figure PCTCN2022093953-appb-000240
利用化合物13的合成方法，用中间体2.6和7.1为起始原料得到化合物17为白色固体。m/z:[M+H] +462.2； 1H NMR(400MHz,CD 3OD):δ8.81(s,1H),8.26(s,1H),7.92(d,J＝7.6Hz,1H),7.82(s,1H),7.52(d,J＝8.0Hz,1H),4.48(s,2H),3.69-3.60(m,2H),3.59-3.44(m,4H),3.41-3.34(m,1H),3.26-3.19(m,3H),3.17-3.05(m,2H),2.65-2.55(m,1H),1.73-1.57(m,2H),0.96(t,J＝7.2Hz,3H)。
实施例18：2-氨基-N 4,N 4-二(2-羟基乙基)-N 8-(5,6,7,8-四氢-1,6-萘啶-3-基)-3H-苯并[b]氮杂卓-4,8-二甲酰胺(化合物18)的合成
Figure PCTCN2022093953-appb-000241
步骤1：利用化合物14步骤1的合成方法，用2-氨基-8-(甲氧基羰基)-3H-苯并[b]氮杂卓-4-甲酸盐酸盐反应得到化合物9.1为淡黄色固体。m/z:[M+H] +640.1。
步骤2～5：利用化合物14步骤3～6的合成方法，用化合物9.1反应得到得到化合物18为白色固体。m/z:[M+H] +465.2。
实施例1～18的中间体结构和鉴定数据如下所示：
Figure PCTCN2022093953-appb-000242
Figure PCTCN2022093953-appb-000243
Figure PCTCN2022093953-appb-000244
实施例19：化合物II-1的合成
Figure PCTCN2022093953-appb-000245
将化合物1(20mg，0.04mmol)、Linker-1(32mg，0.04mmol)和DIPEA(11mg，0.09mmol)的DMF(3mL)溶液在室温下搅拌2小时，然后将反应液直接用prep-HPLC(分离条件2)纯化得到化合物II-1(24.4mg，产率：53％)为白色固体。m/z:[M+H] +1060.6。
实施例20～42：化合物II-2～II-24的合成
利用化合物II-1的合成方法，分别用化合物2～18反应得到化合物II-2～II-24：
表2：
Figure PCTCN2022093953-appb-000246
Figure PCTCN2022093953-appb-000247
Figure PCTCN2022093953-appb-000248
实施例43：抗体药物偶联反应
一、抗体药物偶联反应通用方法：
1)抗体浓度测定：使用紫外/可见光分光光度计(Nanodrop ONE)，利用朗伯比尔定律(A＝εcl)测定抗体的浓度。
2)抗体还原：在Amicon Ultra-15(30,000MWCO，Millipore Corporation)的容器内，放入抗体溶液2mL(10.4mg/mL)，使用离心机进行离心操作(以3800G离心5分钟)，将抗体溶液浓缩。利用抗体的浓度测定方法测定抗体溶液浓度25mg/mL。用含有氯化钠(50mM)及EDTA(2mM)的磷酸缓冲液(50mM，pH6.5；称为PBS6.5/EDTA)平衡Sephadex G-25载体的NAP-25色谱柱(5mL/12mL)。针对一根该NAP-25柱，装填1.27mL的抗体水溶液，然后分离获取用PBS6.5/EDTA洗脱的组分。利用抗体的浓度测定方法测定抗体溶液浓度为13mg/mL，然后使用PBS6.5/EDTA，将抗体浓度调整为10mg/mL。取本溶液至15mL试管中，添加TCEP(74μL，2mg/mL，sigma-aldrich)水溶液后(相对于一分子抗体，5当量)，于25℃孵育2小时。
3)抗体偶联：还原反应结束后，使用PBS6.5/EDTA溶液3mL，将还原后抗体浓度调整为5mg/mL。添加N,N-二甲基乙酰胺(DMA)179μL，然后添加如式II所示化合物(Linker-payload)的二甲基亚砜溶液121μL(10mg/mL；相对于一分子抗体,10当量)，最终DMA的比例控制在10％左右。该溶液在室温条件下继续搅拌60分钟，使药物接头与抗体偶联。
4)抗体偶联样品纯化：用磷酸缓冲液(PB 7.4)平衡NAP-25色谱柱，针对一根该NAP-25柱，装填6.6mL的抗体-药物偶联物水溶液，然后分离获取用PB7.4洗脱的组分。反复重复2-3次此操作后，收集洗脱组分，使用Amicon Ultra-15(30000MWCO，Millipore Corporation)对偶联溶液进行换液浓缩后，除菌过滤。使用抗体-药物偶联物浓度测定方法测定样品浓度。
二：抗体-药物偶联物中抗体浓度的测定
抗体-药物偶联物中的连接药物浓度可通过以下方式算出：测定抗体-药物偶联物水溶液在280nm波长下的UV吸光度，然后进行下述计算，由此算出。
由于某一波长下的总吸光度等于存在于体系内的所有吸收化学物质种类的吸光度的和(吸光度的加成性)，所以，假设在抗体与药物偶联前后，抗体及药物的摩尔吸光系数不发生变化时，抗体-药物偶联物中的抗体浓度及药物浓度如下述的关系式所示。
Figure PCTCN2022093953-appb-000249
因此，抗体-免疫刺激偶联物浓度
Figure PCTCN2022093953-appb-000250
其中，
Figure PCTCN2022093953-appb-000251
DAR(抗体-免疫刺激偶联物中的每一分子抗体的药物平均连接数)的测定见共通操作三。
三：抗体-药物偶联物中的每一分子抗体的药物平均连接数(DAR)的测定
对于抗体-药物偶联物中的每一分子抗体的药物平均连接数而言，可通过使用了以下的方法的高效液相色谱法(HPLC)分析求出。
1)：分析用样品的前处理
将样品稀释到5mg/mL，加入到进样瓶中。
2)：HPLC分析
HPLC仪器：Waters/Waters e2695
流动相A：1.5M(NH4)2SO4+50mM磷酸钾盐(pH 7.0)
流动相B：50mM磷酸钠盐(pH 7.0)/异丙醇(75:25V/V)
分析柱：Thermo MabPac TMHIC-Butyl 5μm 4.6×100mm，PN.088558
进样体积：5μL
流速：1mL/min
柱温：30℃
检测器：PDA检测器
检测波长：280nm
洗脱梯度：
时间 流动相A/％ 流动相B/％
0.00 100 0
2.00 80 20
22.00 20 80
24.00 0 100
26.00 100 0
30.00 100 0
3)：数据分析
疏水作用色谱可用于测定抗体偶联药物中药物抗体偶联比率(DAR)，未偶联的抗体药物疏水性最弱，最先被洗脱；连接8个药物的抗体疏水性最强，最后被洗脱。峰面积百分比代表特定药物数量连接的ADC的相对分布，通过峰面积百分比和偶联药物个数计算加权平均DAR＝∑(相对峰面积*药物连接数)/总的峰面积。
四：抗体-免疫刺激偶联物分子大小异质性(SEC)的分析
1)：分析用样品的前处理
样品用流动相A稀释至约2.0mg/ml，取适量稀释液12000rpm离心5min，取上清进样分析。
2)：HPLC分析
HPLC仪器：Waters Acquity Arc
流动相：100mM PB+200mM Arg·HCl+5％IPA，pH 6.8
分析柱：TOSOH TSKgel G3000SWxl,7.8*300mm,5μM,
Figure PCTCN2022093953-appb-000252
PN0008541
进样体积：10μL
流速：0.6mL/min
柱温：30℃
检测器：PDA检测器
检测波长：280nm
梯度：等度洗脱
3)：数据分析
通过与空白缓冲液的谱图比对，对色谱图进行积分，采用峰面积归一法分别计算单体、聚体和低分子量杂质的峰面积百分比。
实施例44～66：III-1～III-23的制备
利用实施例43通用制备方法，用抗体(Trastuzumab，上海罗氏制药有限公司)和化合物II-1～II-23制备得到III-1～III-23。
表3：
Figure PCTCN2022093953-appb-000253
Figure PCTCN2022093953-appb-000254
Figure PCTCN2022093953-appb-000255
Figure PCTCN2022093953-appb-000256
实施例67：III-24的合成
利用实施例43通用制备方法，用抗体(Trastuzumab-LALA，B801901，上海百英生物科技有限公司)和化合物II-4制备得到III-24，DAR值为4.53。
实施例68：Ref.A的合成
利用实施例43通用制备方法，用抗体(Trastuzumab，上海罗氏制药有限公司)和化合物A(CN110612104A化合物2.14)制备得到Ref.A，DAR值为3.21。
效果实施例1：TLR7和TLR8的细胞活性检测
在此项实验中，如式I所示化合物的TLR7和TLR8生物活性测定采用细胞测试进行检测。该法在表达有TLR家族成员如TLR4、TLR7、TLR8或TLR9的人胚胎肾细胞(HEK293)中进行，TLR激动剂激活TLR后，引起下游NF-kB活化，进而激活分泌型胚胎碱性磷酸酶(secreted embryonic alkaline phosphatase,SEAP)报告基因，采用Quanti-Blue(InvivoGen)试剂检测SEAP活性，从而反映TLR7和TLR8激动剂的活性。
详细的实验方法如下：
HEK-BLUE-hTLR7和HEK-BLUE-hTLR8细胞株购自Invivogen公司，在含4.5g/L葡萄糖(Sigma-Aldrich)和10％胎牛血清的DMEM培养基中培养，培养条件为温度37℃、湿度95％和5％CO 2。
化合物试验浓度为0.5nM至15μM共10个浓度梯度。加入已知活性的TLR7或TLR8激动剂作为阳性对照，及1μL DMSO作为阴性对照。
细胞处理如下：将细胞从培养皿中移出并离心去除培养基，用10mL预热的PBS重悬于T-150瓶，加入12mL预热的培养基，上下轻轻吹打，显微镜下计数。立即用培养基配成200,000个/mL单细胞悬液，200μL/孔(40,000个/孔)加到96孔板。DMSO终浓度为0.5％。
加入化合物，并在37℃、5％CO2培养箱中培养24小时。
吸取20μL/孔上清至180μL 37℃预热的Quanti-Blue中，在37℃孵育1.5小时，用分光光度计在650nm检测吸光度(OD值)。激动效应计算公式如下：
效应％＝(给药组OD平均值-DMSO组OD平均值)/(阳性药组OD平均值-DMSO组OD平均值)×100
用Graphpad软件拟合浓度-效应曲线，并计算出EC 50。测试结果如表4所示(A表示＜100nM、B表示100nM-250nM、C表示250nM-1μM、D表示＞2μM、/表示未测试)，除表4中的化合物外，其余的如式I所示化合物也均具有较佳的活性：
表4：
化合物编号 TLR8EC 50 TLR7EC 50
1 C /
3 B D
4 C D
5 A D
11 C D
12 B /
13 C D
效果实施例2：hPBMC体系中的活性筛选
冻存的人外周血单核细胞(Allcells)于37℃水浴锅中快速解冻后，加入9mL含有10％胎牛血清(Fetal bovine serum)，100U/mL青霉素(Penicillin)，100μg/mL链霉素(Streptomycin)，1mM丙酮酸钠(Sodium Pyruvate)的RPMI 1640培养基中(均来自Gibco)。室温400×g离心5分钟，弃掉上清，用培养基重悬，调整细胞密度到4×10 6/mL。加入到96孔平底板(Corning)中，每孔50μL。向培养体系中，加入50μL培养基。
用培养基配制3倍工作浓度的待测样品稀释液，加入到细胞悬液中，每孔50μL。总体系150μL，如式I化合物终浓度为400nM。向空白对照中补充50μL培养基，在37℃，5％CO 2培养箱中孵育20小时。室温500×g离心5分钟，收集上清。TNF-α的浓度均用HTRF(Cisbio)和Infinite M1000 PRO(TECAN)检测分析。结果显示：化合物6、7、9和10在人外周血单核细胞体系中，400nM浓度下TNF-α分泌值在500-2500pg/mL之间；其余如式I所示化合物也均具有较佳的安全性，如TNF-α分泌值在0-10000pg/mL之间。
效果实施例3：hPBMC和BT474共培养体系中的活性筛选
冻存的人外周血单核细胞(Allcells)于37℃水浴锅中快速解冻后，加入9mL含有10％胎牛血清(Fetal bovine serum)，100U/mL青霉素(Penicillin)，100μg/mL链霉素(Streptomycin)，1mM丙酮酸钠(Sodium Pyruvate)的RPMI 1640培养基中(均来自Gibco)。室温400×g离心5分钟，弃掉上清，用培养基重悬，调整细胞密度到4×10 6/mL。加入到96孔平底板(Corning)中，每孔50μL。收集正常生长状态的人乳腺癌上皮细胞BT474(南京科佰生物科技有限公司)，重悬于RPMI 1640完全培养基中，调整密度到4×10 5/mL。加入到96孔板中，每孔50μL，和hPBMC混匀。
用培养基配制3倍工作浓度的待测样品稀释液，加入到细胞悬液中，每孔50μL。总体系150μL，如式III化合物终浓度为500nM。向空白对照中补充50μL培养基，在37℃，5％CO 2培养箱中孵育20小时。室温500x g离心5分钟，收集上清。TNF-α和IFN-γ的浓度均用HTRF(Cisbio)和Infinite M1000PRO(TECAN)检测分析。结果显示：化合物III-6、III-7、III-9和III-10在人外周血单核细胞和BT474共培养体系体系中，500nM浓度下TNF-α分泌值在5000-6000pg/mL之间；其余如式III所示化合物也均具有较佳的活性，如TNF-α分泌值在0-10000pg/mL(但不包括0pg/mL)之间。
效果实施例4：hPBMC体系中的活性检测
冻存的人外周血单核细胞(Allcells)于37℃水浴锅中快速解冻后，加入9mL含有10％胎牛血清(Fetal bovine serum)，100U/mL青霉素(Penicillin)，100μg/mL链霉素(Streptomycin)，1mM丙酮酸钠(Sodium Pyruvate)的RPMI 1640培养基中(均来自Gibco)。室温400×g离心5分钟，弃掉上清，用培养基重悬，调整细胞密度到4×10 6/mL。加入到96孔平底板(Corning)中，每孔50μL。向培养体系中，加入50μL培养基。
用培养基配制3倍工作浓度的待测样品稀释液，加入到细胞悬液中，每孔50μL。总体系150μL，如式III化合物终浓度为100nM～0.032nM(6个梯度)，如式I化合物终浓度为400nM～0.128nM(6个梯度)。向空白对照中补充50μL培养基，在37℃，5％CO 2培养箱中孵育20小时。室温500×g离心5分钟，收集上清。TNF-α和IFN-γ的浓度均用HTRF(Cisbio)和Infinite M1000PRO(TECAN)检测分析。TNF-α的测试结果如表5所示(D表示＞400nM)。
效果实施例5：hPBMC和BT474共培养体系中的活性检测
冻存的人外周血单核细胞(Allcells)于37℃水浴锅中快速解冻后，加入9mL含有10％胎牛血清(Fetal bovine serum)，100U/mL青霉素(Penicillin)，100μg/mL链霉素(Streptomycin)，1mM丙酮酸钠(Sodium Pyruvate)的RPMI 1640培养基中(均来自Gibco)。室温400×g离心5分钟，弃掉上清，用培养基重悬，调整细胞密度到4×10 6/mL。加入到96孔平底板(Corning)中，每孔50μL。收集正常生长状态的人乳腺癌上皮细胞BT474(南京科佰生物科技有限公司)，重悬于RPMI 1640完全培养基中，调整密度到4×10 5/mL。加入到96孔板中，每孔50μL，和hPBMC混匀。
用培养基配制3倍工作浓度的待测样品稀释液，加入到细胞悬液中，每孔50μL。总体系150μL，如式III化合物终浓度为100nM～0.032nM(6个梯度)。向空白对照中补充50μL培养基，在37℃，5％CO 2培养箱中孵育20小时。室温500x g离心5分钟，收集上清。TNF-α和IFN-γ的浓度均用HTRF(Cisbio)和Infinite M1000PRO(TECAN)检测分析。TNF-α测试结果如表5所示(A表示＜1nM、B表示1-10nM、C表示＞10nM)：
表5：
编号 TNF-α(BT474/hPBMC)EC 50 TNF-α(hPBMC)EC 50
III-2 B D
III-3 B D
III-4 A D
III-11 A D
III-12 A D
III-13 A D
效果实施例6：PK总抗体浓度检测
目的：PK检测两种ISAC化合物和曲妥珠单抗的总抗体浓度(小鼠腹腔注射20mg/kg)。
步骤：用山羊抗人IgG抗体包被96孔板，冰箱4℃过夜，次日PBS/0.05％Tween20清洗三次后，使用PBS/0.05％Tween20/1％BSA封闭平板，37℃孵育1-2小时，清洗三次，并向孔中加入稀释后的标 准品和待测样品，室温孵育2小时，清洗三次，随后加入缓冲液稀释的HRP标记的抗人IgG抗体，室温孵育1小时。最后加入显色液，室温孵育10分钟后终止反应，在450nm吸光度下读取OD值，实验结果见表6：
表6：
Figure PCTCN2022093953-appb-000257
结论：小鼠腹腔给药20mg/kg后，III-4的AUC(总抗)和C max比Ref.A高。III-4的t 1/2比Ref.A的长。曲妥珠单抗的AUC、Cmax和AUC，均高于III-4和Ref.A。
效果实施例7：MC38-HER2小鼠结肠癌细胞小鼠皮下移植瘤模型体内药效实验
细胞培养：小鼠结肠癌MC38-HER2细胞在含有10％胎牛血清和4ug/ml嘌呤霉素的DMEM培养基中于37℃含有5％CO2的恒温培养箱中维持单层培养。肿瘤细胞每周传代培养2次。收取指数生长期的细胞并计数，以供接种。
实验动物：B6-hTLR8-HO小鼠，6-8周，18-22g。
对于Vehicle、III-11、III-12、III-24和Ref.A共设置5个实验组，如下表7：
表7：
组别 小鼠数量 受试化合物 剂量 给药方式 给药计划
1 6 Vehicle -- i.p. 单次给药
2 6 III-11 20mg/kg i.p. 单次给药
3 6 III-12 20mg/kg i.p. 单次给药
4 6 III-24 20mg/kg i.p. 单次给药
5 6 Ref.A 20mg/kg i.p. 单次给药
注：i.p.：腹腔给药
实验方法：将MC38-HER2细胞株(5.0×10 6个/只)接种于实验小鼠右侧背部皮下，每只小鼠接种量是0.1mL，定期观察肿瘤的生长情况，待肿瘤生长至约100mm 3左右时根据肿瘤大小和小鼠体重随机分组，按照表7所示给药计划给药，整个实验过程中，每周测量2次小鼠体重和肿瘤大小。
肿瘤大小计算公式：肿瘤体积(mm 3)＝0.5×(肿瘤长径×肿瘤短径 2)。
实验结果见表8和图1：
表8：
Figure PCTCN2022093953-appb-000258
Figure PCTCN2022093953-appb-000259

Claims (33)

  1. 一种如式I所示化合物、其溶剂合物、其药学上可接受的盐或其药学上可接受的盐的溶剂合物；
    Figure PCTCN2022093953-appb-100001
    其中，
    α和β独立地为单键或双键；并且，α和β至少有一个为单键；
    m为0或1；
    X 1为N或CR 2，X 2为N或CR 3，X 3为N或CR 1；
    R为-C(O)-L 1-R 7、-C(O)-NR 9-L 1-R 7、-C(S)-NR 9-L 1-R 7、-NR 9-L 1-R 7、-NR 9-C(O)-L 1-R 7、-NR 9-C(O)-NR 9-L 1-R 7、-O-L 1-R 7、-S(O) 2-NR 9-L 1-R 7、-CH＝CH-L 1-R 7或-S(O) 2-L 1-R 7；
    R 1、R 2和R 3分别独立地为氢、氘、卤素、羟基、氨基、氰基、烷基、卤代烷基、-L 2-OR a或-L 2-NR aR b；
    R 4和R 4’分别独立地为氢、烷基、烯基、炔基、环烷基、杂环烷基、芳基、杂芳基、环烷基烷基、杂环烷基烷基、芳基烷基或杂芳基烷基；所述R 4或R 4’为未取代，或者选择性地被一个或多个选自卤素、氰基、-L 2-OR a、-L 2-OC(O)R a、-L 2-NR aR b、-L 2-NR aC(O)OR b、-L 2-NR aC(O)NR aR b、-L 2-NR bC(NR b)NR aR b和-L 2-C(O)OR b的取代基取代在任意位置；或者，R 4和R 4’与它们共同连接的N原子一起形成3-8元杂环烷基；所述3-8元杂环烷基为未取代或者进一步被1～3个选自卤素、氰基、-L 2-OR a、-L 2-OC(O)R a、-L 2-NR aR b、-L 2-NR aC(O)OR b、-L 2-NR aC(O)NR aR b、-L 2-NR bC(NR b)NR aR b和-L 2-C(O)OR b的取代基取代在任意位置；
    R 5为＝O、＝NR a、-OR a或-NR aR b；
    R 5’不存在，或者R 5’为-R c、-L 2-OR a、-L 2-NR aR b、-L 2-NR aC(O)OR b、-L 2-NR aC(O)NR aR b、-L 2-NR bC(NR b)NR aR b或-L 2-C(O)OR b；
    R 7为苯基、5-6元杂芳基、3-8元杂环烷基或8-12元并环基团；所述R 7为未取代，或者选择性被一个或多个选自-L 3-W、-R c、卤素、氰基、硝基、烷基、烯基、炔基、烷氧基、卤代烷基、卤代烷氧基和烷氨基的取代基取代在任意位置；
    R 8和R 8’分别独立地为氢、卤素或烷基，所述R 8或R 8’为未取代，或者选择性被一个或多个选自-L 3-W、卤素、氰基、硝基、烷基、烯基、炔基、烷氧基、卤代烷基、卤代烷氧基和烷氨基的取代基取代在任意位置；R 8和R 8’分别为独立取代基，或者，R 8和R 8’与其共同连接的碳原子一起形成氧代基、硫代基、C 1-6亚烷基、C 3-10环烷基或3-10元杂环烷基；所述C 1-6亚烷基、C 3-10环烷基或3-10元杂环烷基为未取代，或者选择性被一个或多个选自氘、卤素、羟基、氨基、氰基、氧代基、烷基、卤 代烷基、-L 2-OR a和-L 2-NR aR b的取代基取代在任意位置；
    R 9为氢、烷基、卤代烷基、-L 2-OR a或-L 2-NR aR b；
    W为Cy 1、-SR d、-OR d、-OC(O)R e、-OC(O)NR eR e’、-C(O)OR e、-C(O)R e、-C(O)NR eR e’、-C(O)NR eS(O) 2R e、-NR dR e、-NR dC(O)R e、-N(R d)C(O)OR e、-N(R d)C(O)NR eR e’、-NR dS(O) 2R e、-NR dS(O) 2NR eR e’、-S(O) 1-2R e、-S(O) 2NR eR e’、-S(O)(＝NR d)R e、-S(O) 2N(R e)C(O)R e’、-P(O)(OR e) 2、-P(O)(OR e)R e’、-OP(O)(OR e) 2或-B(OR e) 2；
    Cy 1为环烷基、杂环烷基、芳基或杂芳基；所述Cy 1为未取代，或者选择性地被一个或多个选自卤素、烷基、卤代烷基、卤代烷氧基、烯基、炔基、氰基、-R c、-L 4-SR d、-L 4-OC(O)R e、-L 4-C(O)OR e、-L 4-C(O)R e、-L 4-C(O)NR eR e’、-L 4-NR dC(O)R e、-L 4-NR dS(O) 2R e、-L 4-S(O) 1-2R e、-L 4-S(O) 2NR eR e’、-L 4-OR d和-L 4-NR eR e’的取代基取代在任意位置；
    L 1、L 2、L 3和L 4分别独立地为连接键、C 1-6亚烷基、C 2-6亚烯基或C 2-6亚炔基；所述L 1、L 2、L 3或L 4为未取代，或者选择性被一个或多个选自氧代基、羟基、氨基、卤素、氰基、烷基、卤代烷基、烷氧基和卤代烷氧基的取代基取代在任意位置；
    每个R a、R b、R d、R e和R e’分别独立地为-R c、氨基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-10环烷基、3-10元杂环烷基、C 6-10芳基、5-10元杂芳基、C 3-10环烷基C 1-6烷基、3-10元杂环烷基C 1-6烷基、苯基C 1-6烷基或5-10元杂芳基C 1-6烷基；所述R a、R b、R d、R e或R e’为未取代或者选择性地被1～3个选自-OR f、-OC(O)-L 4-R f、-NR fR f’、卤素、氰基、硝基、C 1-6烷基、卤代C 1-6烷基和卤代C 1-6烷氧基的取代基取代在任意位置；
    每个R f和R f’分别独立地为-R c、-NHR c或C 1-6烷基；
    每个R c分别独立地为氢；
    且如式I所示化合物满足下列条件中的1个、2个、3个或4个：
    (1)m为1；
    (2)R为-C(S)-NR 9-L 1-R 7、-NR 9-L 1-R 7、-NR 9-C(O)-L 1-R 7、-NR 9-C(O)-NR 9-L 1-R 7、-O-L 1-R 7、-S(O) 2-NR 9-L 1-R 7、-CH＝CH-L 1-R 7或-S(O) 2-L 1-R 7；
    (3)X 1、X 2和X 3中至少一个为N；
    (4)R 4和R 4’中的至少一个被一个或多个选自卤素、氰基、-L 2-OR a、-L 2-OC(O)R a、-L 2-NR aR b、-L 2-NR aC(O)OR b、-L 2-NR aC(O)NR aR b、-L 2-NR bC(NR b)NR aR b和-L 2-C(O)OR b的取代基取代在任意位置。
  2. 如权利要求1所述的如式I所示化合物、其溶剂合物、其药学上可接受的盐或其药学上可接受的盐的溶剂合物，其特征在于，所述的如式I所示化合物满足以下条件中的一个或多个：
    a)R 7中，所述的8-12元并环基团为环A并环B，所述的环A为5～6元杂芳基，环B为5～6元杂烯环；所述的5～6元杂芳基中，杂原子选自N、O和S中的一种或多种，杂原子的数量为1个、2个或3个；所述的5～6元杂烯环中，杂原子选自N、O和S中的一种或多种，杂原子的数量为1个、2个或3个；
    b)R 7中，所述的5-6元杂芳基里，杂原子选自N、O和S中的一种或多种，杂原子的数量为1个、2个或3个；
    c)L 3中，C 1-6亚烷基为C 1-3亚烷基；
    d)R 8和R 8’中，所述的烷基为C 1-6烷基；
    e)R 8和R 8’与其共同连接的碳原子一起形成的C 3-10环烷基为饱和单环基团；
    f)R 8和R 8’与其共同连接的碳原子一起形成的C 3-10环烷基为C 3-6环烷基；
    g)R 1、R 2和R 3中，所述的卤素为氟、氯、溴或碘；
    h)R 4和R 4’中，所述的烷基为C 1-6烷基。
  3. 如权利要求2所述的如式I所示化合物、其溶剂合物、其药学上可接受的盐或其药学上可接受的盐的溶剂合物，其特征在于，所述的如式I所示化合物满足以下条件中的一个或多个：
    i)R 7中，所述的8-12元并环基团为环A并环B，所述的环A为5～6元杂芳基，环B为5～6元杂烯环，其通过所述的环A与所述的L 1连接；所述的5～6元杂芳基中，杂原子为N，杂原子的数量为1个或2个；所述的5～6元杂烯环中，杂原子为N，杂原子的数量为1个或2个；
    j)R 7中，所述的5-6元杂芳基里，杂原子为N，杂原子的数量为1个或2个；
    k)L 3中，C 1-6亚烷基为-CH 2-、-CH 2CH 2-或-CH 2CH 2CH 2-；
    l)R 8和R 8’中，所述的烷基为甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基；
    m)R 8和R 8’与其共同连接的碳原子一起形成的C 3-10环烷基为环丙基、环丁基、环戊基或环己基；
    n)R 1、R 2和R 3中，所述的卤素为氟；
    o)R 4和R 4’中，所述的烷基为甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基。
  4. 如权利要求3所述的如式I所示化合物、其溶剂合物、其药学上可接受的盐或其药学上可接受的盐的溶剂合物，其特征在于，所述的如式I所示化合物满足以下条件中的一个或多个：
    p)R 7中，所述的8-12元并环基团为
    Figure PCTCN2022093953-appb-100002
    q)R 7中，所述的5-6元杂芳基为吡啶基；
    r)R 4为-CH 2CH 2OH或-CH 2CH 2CH 3；
    s)R 4’为-CH 2CH 2OH或-CH 2CH 2CH 3。
  5. 如权利要求4所述的如式I所示化合物、其溶剂合物、其药学上可接受的盐或其药学上可接受的盐的溶剂合物，其特征在于，所述的如式I所示化合物满足以下条件中的一个或多个：
    t)R 7中，所述的8-12元并环基团为
    Figure PCTCN2022093953-appb-100003
    u)R 7中，所述的被一个-L 3-W取代的5-6元杂芳基为
    Figure PCTCN2022093953-appb-100004
    v)R 4为-CH 2CH 2OH或-CH 2CH 2CH 3；R 4’为-CH 2CH 2OH或-CH 2CH 2CH 3。
  6. 如权利要求1～5中至少一项所述的如式I所示化合物、其溶剂合物、其药学上可接受的盐或其药学上可接受的盐的溶剂合物，其特征在于，所述的如式I所示化合物满足以下条件中的一个或多个：
    w)m为1，R 8和R 8’分别独立地为未取代的烷基；或者，R 8和R 8’与其共同连接的碳原子一起形成氧代基或未取代的C 3-10环烷基；
    x)R为-C(S)-NR 9-L 1-R 7、-NR 9-L 1-R 7、-NR 9-C(O)-L 1-R 7、-NR 9-C(O)-NR 9-L 1-R 7、-O-L 1-R 7、-S(O) 2-NR 9-L 1-R 7、-CH＝CH-L 1-R 7或-S(O) 2-L 1-R 7；
    y)X 1、X 2和X 3中至少一个为N；
    z)R 4和R 4’中的至少一个被一个或多个选自卤素、氰基、-L 2-OR a、-L 2-OC(O)R a、-L 2-NR aR b、-L 2-NR aC(O)OR b、-L 2-NR aC(O)NR aR b、-L 2-NR bC(NR b)NR aR b和-L 2-C(O)OR b的取代基取代在任意位置。
  7. 如权利要求6所述的如式I所示化合物、其溶剂合物、其药学上可接受的盐或其药学上可接受的盐的溶剂合物，其特征在于，所述的如式I所示化合物满足以下条件中的一个或多个：
    aa)R为-C(S)-NR 9-L 1-R 7或-NR 9-L 1-R 7；
    bb)X 1为N；
    cc)R 4和R 4’中的至少一个被一个或多个选自-L 2-OR a和-L 2-NR aR b的取代基取代在任意位置。
  8. 如权利要求7所述的如式I所示化合物、其溶剂合物、其药学上可接受的盐或其药学上可接受的盐的溶剂合物，其特征在于，所述的如式I所示化合物满足以下条件中的一个或多个：
    dd)R为-NR 9-L 1-R 7；
    ee)X 1为N，X 2和X 3为CH；
    ff)R 4和R 4’分别独立地为烷基；所述R 4或R 4’中的至少一个被一个或多个选自-L 2-OR a和-L 2-NR aR b的取代基取代在任意位置。
  9. 如权利要求1～5中至少一项所述的如式I所示化合物、其溶剂合物、其药学上可接受的盐或其药学上可接受的盐的溶剂合物，其特征在于，所述的如式I所示化合物满足以下条件中的一个或多个：
    gg)R为-C(O)-NR 9-L 1-R 7、-C(S)-NR 9-L 1-R 7或-NR 9-L 1-R 7；R 9为氢，L 1为连接键，R 7为未取代的8-12元并环基团或者被一个-L 3-W取代的5-6元杂芳基；L 3为C 1-6亚烷基，W为-NR dR e；R d和R e为-R c，R c为氢；
    hh)m为0或1；R 8和R 8’分别独立地为未取代的烷基；或者，R 8和R 8’与其共同连接的碳原子一起形成氧代基或未取代的C 3-10环烷基；
    ii)X 1为N或CR 2，X 2为N或CR 3，X 3为N或CR 1；R 1、R 2和R 3分别独立地为氢、氘、卤素或氰基；
    jj)α为双键，R 5’不存在；β为单键，R 5为-NR aR b；R a和R b为-R c，R c为氢；
    kk)R 4和R 4’分别独立地为烷基；所述R 4和R 4’分别独立地为未取代，或者选择性地被一个或多个选自-L 2-OR a和-L 2-NR aR b的取代基取代在任意位置；L 2为连接键；R a和R b为-R c，R c为氢。
  10. 如权利要求1～5中至少一项所述的如式I所示化合物、其溶剂合物、其药学上可接受的盐或其药学上可接受的盐的溶剂合物，其特征在于，所述的如式I所示化合物的定义如下述任一方案所述：
    方案10-1：
    R为-C(O)-NR 9-L 1-R 7、-C(S)-NR 9-L 1-R 7或-NR 9-L 1-R 7；R 9为氢，L 1为连接键，R 7为未取代的8-12元并环基团或者被一个-L 3-W取代的5-6元杂芳基；L 3为C 1-6亚烷基，W为-NR dR e；
    m为0或1；R 8和R 8’分别独立地为未取代的烷基；或者，R 8和R 8’与其共同连接的碳原子一起形成氧代基或未取代的C 3-10环烷基；
    X 1为N或CR 2，X 2为N或CR 3，X 3为N或CR 1；R 1、R 2和R 3分别独立地为氢、氘、卤素或氰基；
    α为双键，R 5’不存在；β为单键，R 5为-NR aR b；
    R 4和R 4’分别独立地为烷基；所述R 4和R 4’分别独立地为未取代，或者选择性地被一个或多个选自-L 2-OR a和-L 2-NR aR b的取代基取代在任意位置；L 2为连接键；
    R a、R b、R d和R e为-R c，R c为氢；
    且如式I所示化合物满足下列条件中的1个、2个、3个或4个：
    (1)m为1；
    (2)R为-C(S)-NR 9-L 1-R 7或-NR 9-L 1-R 7；
    (3)X 1、X 2和X 3中至少一个为N；
    (4)R 4和R 4’中的至少一个被一个或多个选自-L 2-OR a和-L 2-NR aR b的取代基取代在任意位置；
    方案10-2：
    α和β独立地为单键或双键；并且，α和β至少有一个为单键；
    m为0或1；
    X 1为N或CR 2，X 2为N或CR 3，X 3为N或CR 1；并且，X 1为CR 2，X 2为CR 3和X 3为CR 1时，m为1；
    R为-C(O)-L 1-R 7、-C(O)-NR 9-L 1-R 7、-C(S)-NR 9-L 1-R 7、-NR 9-L 1-R 7、-NR 9-C(O)-L 1-R 7、-NR 9-C(O)-NR 9-L 1-R 7、-O-L 1-R 7、-S(O) 2-NR 9-L 1-R 7、-CH＝CH-L 1-R 7或-S(O) 2-L 1-R 7；
    R 1、R 2和R 3分别独立地为氢、氘、卤素、羟基、氨基、氰基、烷基、卤代烷基、-L 2-OR a或-L 2-NR aR b；
    R 4和R 4’分别独立地为氢、烷基、烯基、炔基、环烷基、杂环烷基、芳基、杂芳基、环烷基烷基、杂环烷基烷基、芳基烷基或杂芳基烷基；所述R 4或R 4’为未取代，或者选择性地被一个或多个选自卤素、氰基、-L 2-OR a、-L 2-OC(O)R a、-L 2-NR aR b、-L 2-NR aC(O)OR b、-L 2-NR aC(O)NR aR b、-L 2-NR bC(NR b)NR aR b和-L 2-C(O)OR b的取代基取代在任意位置；或者，R 4和R 4’与它们共同连接的N原子一起形成3-8元 杂环烷基；所述3-8元杂环烷基为未取代或者进一步被1～3个选自卤素、氰基、-L 2-OR a、-L 2-OC(O)R a、-L 2-NR aR b、-L 2-NR aC(O)OR b、-L 2-NR aC(O)NR aR b、-L 2-NR bC(NR b)NR aR b和-L 2-C(O)OR b的取代基取代在任意位置；
    R 5为＝O、＝NR a、-OR a或-NR aR b；
    R 5’不存在，或者R 5’为-R c、-L 2-OR a、-L 2-NR aR b、-L 2-NR aC(O)OR b、-L 2-NR aC(O)NR aR b、-L 2-NR bC(NR b)NR aR b或-L 2-C(O)OR b；
    R 7为苯基、5-6元杂芳基、3-8元杂环烷基或8-12元并环基团；所述R 7为未取代，或者选择性被一个或多个选自-L 3-W、-R c、卤素、氰基、硝基、烷基、烯基、炔基、烷氧基、卤代烷基、卤代烷氧基和烷氨基的取代基取代在任意位置；
    R 8和R 8’分别独立地为氢、卤素或烷基，所述R 8或R 8’为未取代，或者选择性被一个或多个选自-L 3-W、卤素、氰基、硝基、烷基、烯基、炔基、烷氧基、卤代烷基、卤代烷氧基和烷氨基的取代基取代在任意位置；R 8和R 8’分别为独立取代基，或者，R 8和R 8’与其共同连接的碳原子一起形成氧代基、硫代基、C 1-6亚烷基、C 3-10环烷基或3-10元杂环烷基；所述C 1-6亚烷基、C 3-10环烷基或3-10元杂环烷基为未取代，或者选择性被一个或多个选自氘、卤素、羟基、氨基、氰基、氧代基、烷基、卤代烷基、-L 2-OR a和-L 2-NR aR b的取代基取代在任意位置；
    R 9为氢、烷基、卤代烷基、-L 2-OR a或-L 2-NR aR b；
    W为Cy 1、-SR d、-OR d、-OC(O)R e、-OC(O)NR eR e’、-C(O)OR e、-C(O)R e、-C(O)NR eR e’、-C(O)NR eS(O) 2R e-NR dR e、-NR dC(O)R e、-N(R d)C(O)OR e、-N(R d)C(O)NR eR e’、-NR dS(O) 2R e、-NR dS(O) 2NR eR e’、-S(O) 1-2R e、-S(O) 2NR eR e’、-S(O)(＝NR d)R e、-S(O) 2N(R e)C(O)R e’、-P(O)(OR e) 2、-P(O)(OR e)R e’、-OP(O)(OR e) 2或-B(OR e) 2；
    Cy 1为环烷基、杂环烷基、芳基或杂芳基；所述Cy 1为未取代，或者选择性地被一个或多个选自卤素、烷基、卤代烷基、卤代烷氧基、烯基、炔基、氰基、-R c、-L 4-SR d、-L 4-OC(O)R e、-L 4-C(O)OR e、-L 4-C(O)R e、-L 4-C(O)NR eR e’、-L 4-NR dC(O)R e、-L 4-NR dS(O) 2R e、-L 4-S(O) 1-2R e、-L 4-S(O) 2NR eR e’、-L 4-OR d和-L 4-NR eR e’的取代基取代在任意位置；
    L 1、L 2、L 3和L 4分别独立地为连接键、C 1-6亚烷基、C 2-6亚烯基或C 2-6亚炔基；所述L 1、L 2、L 3或L 4为未取代，或者选择性被一个或多个选自氧代基、羟基、氨基、卤素、氰基、烷基、卤代烷基、烷氧基和卤代烷氧基的取代基取代在任意位置；
    每个R a、R b、R d、R e和R e’分别独立地为-R c、氨基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-10环烷基、3-10元杂环烷基、C 6-10芳基、5-10元杂芳基、C 3-10环烷基C 1-6烷基、3-10元杂环烷基C 1-6烷基、苯基C 1-6烷基或5-10元杂芳基C 1-6烷基；所述R a、R b、R d、R e或R e’为未取代或者选择性地被1～3个选自-OR f、-OC(O)-L 4-R f、-NR fR f’、卤素、氰基、硝基、C 1-6烷基、卤代C 1-6烷基和卤代C 1-6烷氧基的取代基取代在任意位置；
    每个R f和R f’分别独立地为-R c、-NHR c或C 1-6烷基；
    每个R c分别独立地为氢；
    方案10-3：
    α和β独立地为单键或双键；并且，α和β至少有一个为单键；
    m为0或1；
    X 1为N或CR 2，X 2为N或CR 3，X 3为N或CR 1；并且，X 1为CR 2，X 2为CR 3和X 3为CR 1时，m为1；
    R为-C(O)-L 1-R 7、-C(O)-NR 9-L 1-R 7、-C(S)-NR 9-L 1-R 7、-NR 9-L 1-R 7、-NR 9-C(O)-L 1-R 7、-NR 9-C(O)-NR 9-L 1-R 7、-O-L 1-R 7、-S(O) 2-NR 9-L 1-R 7、-CH＝CH-L 1-R 7或-S(O) 2-L 1-R 7；
    R 1、R 2和R 3分别独立地为氢、氘、卤素、羟基、氨基、氰基、烷基、卤代烷基、-L 2-OR a或-L 2-NR aR b；
    R 4和R 4’分别独立地为氢、烷基、烯基、炔基、环烷基、杂环烷基、芳基、杂芳基、环烷基烷基、杂环烷基烷基、芳基烷基或杂芳基烷基；所述R 4或R 4’为未取代，或者选择性地被一个或多个选自卤素、氰基、-L 2-OR a、-L 2-NR aR b、-L 2-NR aC(O)OR b、-L 2-NR aC(O)NR aR b、-L 2-NR bC(NR b)NR aR b和-L 2-C(O)OR b的取代基取代在任意位置；或者，R 4和R 4’与它们共同连接的N原子一起形成3-8元杂环烷基；所述3-8元杂环烷基为未取代或者进一步被1～3个选自卤素、氰基、-L 2-OR a、-L 2-NR aR b、-L 2-NR aC(O)OR b、-L 2-NR aC(O)NR aR b、-L 2-NR bC(NR b)NR aR b和-L 2-C(O)OR b的取代基取代在任意位置；
    R 5为＝O、＝NR a、-OR a或-NR aR b；
    R 5’不存在，或者R 5’为-R c、-L 2-OR a、-L 2-NR aR b、-L 2-NR aC(O)OR b、-L 2-NR aC(O)NR aR b、-L 2-NR bC(NR b)NR aR b或-L 2-C(O)OR b；
    R 7为苯基、5-6元杂芳基、3-8元杂环烷基或8-12元并环基团；所述R 7为未取代，或者选择性被一个或多个选自-L 3-W、-R c、卤素、氰基、硝基、烷基、烯基、炔基、烷氧基、卤代烷基、卤代烷氧基和烷氨基的取代基取代在任意位置；
    R 8和R 8’分别独立地为氢、卤素或烷基，所述R 8或R 8’为未取代，或者选择性被一个或多个选自-L 3-W、卤素、氰基、硝基、烷基、烯基、炔基、烷氧基、卤代烷基、卤代烷氧基和烷氨基的取代基取代在任意位置；R 8和R 8’分别为独立取代基，或者，R 8和R 8’与其共同连接的碳原子一起形成氧代基、硫代基、C 1-6亚烷基、C 3-10环烷基或3-10元杂环烷基；所述C 1-6亚烷基、C 3-10环烷基或3-10元杂环烷基为未取代，或者选择性被一个或多个选自氘、卤素、羟基、氨基、氰基、氧代基、烷基、卤代烷基、-L 2-OR a和-L 2-NR aR b的取代基取代在任意位置；
    R 9为氢、烷基、卤代烷基、-L 2-OR a或-L 2-NR aR b；
    W为Cy 1、-SR d、-OR d、-OC(O)R e、-OC(O)NR eR e’、-C(O)OR e、-C(O)R e、-C(O)NR eR e’、-C(O)NR eS(O) 2R e-NR dR e、-NR dC(O)R e、-N(R d)C(O)OR e、-N(R d)C(O)NR eR e’、-NR dS(O) 2R e、-NR dS(O) 2NR eR e’、-S(O) 1-2R e、-S(O) 2NR eR e’、-S(O)(＝NR d)R e、-S(O) 2N(R e)C(O)R e’、-P(O)(OR e) 2、-P(O)(OR e)R e’、-OP(O)(OR e) 2或-B(OR e) 2；
    Cy 1为环烷基、杂环烷基、芳基或杂芳基；所述Cy 1为未取代，或者选择性地被一个或多个选自卤素、烷基、卤代烷基、卤代烷氧基、烯基、炔基、氰基、-R c、-L 4-SR d、-L 4-OC(O)R e、-L 4-C(O)OR e、-L 4-C(O)R e、-L 4-C(O)NR eR e’、-L 4-NR dC(O)R e、-L 4-NR dS(O) 2R e、-L 4-S(O) 1-2R e、-L 4-S(O) 2NR eR e’、-L 4-OR d 和-L 4-NR eR e’的取代基取代在任意位置；
    L 1、L 2、L 3和L 4分别独立地为连接键、C 1-6亚烷基、C 2-6亚烯基或C 2-6亚炔基；所述L 1、L 2、L 3或L 4为未取代，或者选择性被一个或多个选自氧代基、羟基、氨基、卤素、氰基、烷基、卤代烷基、烷氧基和卤代烷氧基的取代基取代在任意位置；
    每个R a、R b、R d、R e和R e’分别独立地为-R c、氨基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-10环烷基、3-10元杂环烷基、C 6-10芳基、5-10元杂芳基、C 3-10环烷基C 1-6烷基、3-10元杂环烷基C 1-6烷基、苯基C 1-6烷基或5-10元杂芳基C 1-6烷基；所述R a、R b、R d、R e或R e’为未取代或者选择性地被1～3个选自-OR f、-NR fR f’、卤素、氰基、硝基、C 1-6烷基、卤代C 1-6烷基和卤代C 1-6烷氧基的取代基取代在任意位置；
    每个R f和R f’分别独立地为-R c、-NHR c或C 1-6烷基；
    每个R c分别独立地为氢。
  11. 如权利要求1～5中至少一项所述的如式I所示化合物、其溶剂合物、其药学上可接受的盐或其药学上可接受的盐的溶剂合物，其特征在于，所述的如式I所示化合物为下述任一化合物：
    Figure PCTCN2022093953-appb-100005
    Figure PCTCN2022093953-appb-100006
    Figure PCTCN2022093953-appb-100007
  12. 一种含氮化合物，其特征在于，其为下述任一化合物：
    Figure PCTCN2022093953-appb-100008
    Figure PCTCN2022093953-appb-100009
    Figure PCTCN2022093953-appb-100010
    Figure PCTCN2022093953-appb-100011
  13. 一种如式II’所示化合物、其溶剂合物、其药学上可接受的盐或其药学上可接受的盐的溶剂合物，
    D-LinkerX
    (II′)；
    D为如权利要求1～11中至少一项所述的如式I所示化合物失去一个氢原子所形成的基团；
    LinkerX为连接体2。
  14. 如权利要求13所述的如式II’所示化合物、其溶剂合物、其药学上可接受的盐或其药学上可接受的盐的溶剂合物，其特征在于，所述的如式II’所示化合物满足以下条件中的一个或多个：
    ll)所述的D为所述的如式I所示化合物在基团R 7处失去一个氢原子所形成的基团；
    mm)所述的LinkerX为可降解连接体或不可降解连接体。
  15. 如权利要求14所述的如式II’所示化合物、其溶剂合物、其药学上可接受的盐或其药学上可接受的盐的溶剂合物，其特征在于，所述的如式II’所示化合物满足以下条件中的一个或多个：
    nn)所述的D为所述的如式I所示化合物在基团R 7的仲胺或伯胺处失去一个氢原子所形成的基团；
    oo)所述的LinkerX为可被溶酶体酶降解的连接体。
  16. 如权利要求15所述的如式II’所示化合物、其溶剂合物、其药学上可接受的盐或其药学上可接受的盐的溶剂合物，其特征在于，所述的如式II’所示化合物满足以下条件中的一个或多个：
    pp)所述的D通过
    Figure PCTCN2022093953-appb-100012
    的a端与所述的LinkerX连接；
    qq)所述的LinkerX为
    Figure PCTCN2022093953-appb-100013
    x为0、1、2或3；
    u为0、1、2、3、4、5或6；
    w为0、1、2、3、4、5或6；
    每个L 5分别独立地为
    Figure PCTCN2022093953-appb-100014
    Figure PCTCN2022093953-appb-100015
    p为1、2或3；每个R 10分别独立地为氢、卤素、C 1-6烷基、卤代C 1-6烷基、硝基、氰基、C 1-6烷氧基、C 1-6烷氨基、-OC(O)R 11或-C(O)N(R 11) 2；R 11为氢、C 1-6烷基或C 1-6烷氨基C 1-6烷基；
    每个Z分别独立地为
    Figure PCTCN2022093953-appb-100016
    Figure PCTCN2022093953-appb-100017
    和-(CH 2CH 2O) o7-；每个o1、o2、o3、o4、o5、o6、o7分别独立地为0、1、2、3、4、5、6、7或8；每个R 12a、R 12b和R 12c分别独立地为氢、甲基、乙基、正丙基、异丙基、-SO 3H、
    Figure PCTCN2022093953-appb-100018
    Figure PCTCN2022093953-appb-100019
    每个R 13a和每个R 13b分别独立地为氢或甲基；
    每个T分别独立地为-(CH 2) v1-、-(CH 2CH 2O) v2-、
    Figure PCTCN2022093953-appb-100020
    Figure PCTCN2022093953-appb-100021
    v1、v2、v3、v4和v5分别独立地为1、2、3、4、5或6；
    M’为
    Figure PCTCN2022093953-appb-100022
  17. 如权利要求16所述的如式II’所示化合物、其溶剂合物、其药学上可接受的盐或其药学上可接受的盐的溶剂合物，其特征在于，所述的如式II’所示化合物满足以下条件中的一个或多个：
    rr)所述的L 5为
    Figure PCTCN2022093953-appb-100023
    ss)所述的L 5的羰基端与所述的D连接；
    tt)所述的Z为氨基酸；
    uu)所述的
    Figure PCTCN2022093953-appb-100024
    为肽链；
    vv)所述的
    Figure PCTCN2022093953-appb-100025
    的羰基端与所述的L 5的氨基端连接；
    ww)所述的
    Figure PCTCN2022093953-appb-100026
    为
    Figure PCTCN2022093953-appb-100027
    xx)所述的T的羰基端与所述的
    Figure PCTCN2022093953-appb-100028
    的氨基端连接；
    yy)所述的M’的氨基端与所述的T的非羰基端连接。
  18. 如权利要求17所述的如式II’所示化合物、其溶剂合物、其药学上可接受的盐或其药学上可接受的盐的溶剂合物，其特征在于，所述的LinkerX为
    Figure PCTCN2022093953-appb-100029
    x为1；
    u为1、2、3、4、5或6；
    w为1；
    L 5为
    Figure PCTCN2022093953-appb-100030
    p为1；R 10为氢；所述的L 5的羰基端与所述的D连接；
    每个Z分别独立地为
    Figure PCTCN2022093953-appb-100031
    每个R 12a分别独立地为氢、甲基、乙基、正丙基、异丙基、
    Figure PCTCN2022093953-appb-100032
    所述的
    Figure PCTCN2022093953-appb-100033
    的羰基端与所述的L 5的氨基端连接；
    T为
    Figure PCTCN2022093953-appb-100034
    v3为1、2、3、4、5或6；所述的T的羰基端与所述的
    Figure PCTCN2022093953-appb-100035
    的氨基端连接；
    M’为
    Figure PCTCN2022093953-appb-100036
    所述的M’的氨基端与所述的T的非羰基端连接。
  19. 如权利要求13～18中至少一项所述的如式II’所示化合物、其溶剂合物、其药学上可接受的盐或其药学上可接受的盐的溶剂合物，其特征在于，所述的如式II’所示化合物的定义如下述任一方案所述：
    方案19-1：
    所述的如式II’所示化合物为
    Figure PCTCN2022093953-appb-100037
    D为所述的的如式I所示化合物失去一个氢原子所形成的基团；
    x为0、1、2或3；
    u为0、1、2、3、4、5或6；
    w为0、1、2、3、4、5或6；
    每个L 5分别独立地为
    Figure PCTCN2022093953-appb-100038
    Figure PCTCN2022093953-appb-100039
    p为1、2或3；每个R 10分别独立地为氢、卤素、C 1-6烷基、卤代C 1-6烷基、硝基、氰基、C 1-6烷氧基、C 1-6烷氨基、-OC(O)R 11或-C(O)N(R 11) 2；R 11为氢、C 1-6烷基或C 1-6烷氨基C 1-6烷基；
    每个Z分别独立地为
    Figure PCTCN2022093953-appb-100040
    Figure PCTCN2022093953-appb-100041
    和-(CH 2CH 2O) o7-；每个o1、o2、o3、o4、o5、o6、o7分别独立地为0、1、2、3、4、5、6、7或8；每个R 12a、R 12b和R 12c分别独立地为氢、甲基、乙基、正丙基、异丙基、-SO 3H、
    Figure PCTCN2022093953-appb-100042
    Figure PCTCN2022093953-appb-100043
    每个R 13a和每个R 13b分别独立地为氢或甲基；
    每个T分别独立地为-(CH 2) v1-、-(CH 2CH 2O) v2-、
    Figure PCTCN2022093953-appb-100044
    Figure PCTCN2022093953-appb-100045
    v1、v2、v3、v4和v5分别独立地为1、2、3、4、5或6；
    M’为
    Figure PCTCN2022093953-appb-100046
    方案19-2：
    所述的D为所述的如式I所示化合物在基团R 7处失去一个氢原子所形成的基团；
    LinkerX为
    Figure PCTCN2022093953-appb-100047
    x为1；
    u为1、2、3、4、5或6；
    w为1；
    L 5为
    Figure PCTCN2022093953-appb-100048
    p为1；R 10为氢；所述的L 5的羰基端与所述的D连接；
    每个Z分别独立地为
    Figure PCTCN2022093953-appb-100049
    每个R 12a分别独立地为氢、甲基、乙基、正丙基、异丙基、
    Figure PCTCN2022093953-appb-100050
    所述的
    Figure PCTCN2022093953-appb-100051
    的羰基端与所述的L 5的氨基端连接；
    T为
    Figure PCTCN2022093953-appb-100052
    v3为1、2、3、4、5或6；所述的T的羰基端与所述的
    Figure PCTCN2022093953-appb-100053
    的氨基端连接；
    M’为
    Figure PCTCN2022093953-appb-100054
    所述的M’的氨基端与所述的T的非羰基端连接；
    方案19-3：
    所述的如式II’所示化合物为
    Figure PCTCN2022093953-appb-100055
    其中，D为所述的如式I所示化合物，
    Figure PCTCN2022093953-appb-100056
    α和β独立地为单键或双键；并且，α和β至少有一个为单键；
    m为0或1；
    X 1为N或CR 2，X 2为N或CR 3，X 3为N或CR 1；并且，X 1为CR 2，X 2为CR 3和X 3为CR 1时，m为1；
    R为-C(O)-L 1-R 7、-C(O)-NR 9-L 1-R 7、-C(S)-NR 9-L 1-R 7、-NR 9-L 1-R 7、-NR 9-C(O)-L 1-R 7、-NR 9-C(O)-NR 9-L 1-R 7、-O-L 1-R 7、-S(O) 2-NR 9-L 1-R 7、-CH＝CH-L 1-R 7或-S(O) 2-L 1-R 7；
    R 1、R 2和R 3分别独立地为氢、氘、卤素、羟基、氨基、氰基、烷基、卤代烷基、-L 2-OR a或-L 2-NR aR b；
    R 4和R 4’分别独立地为氢、烷基、烯基、炔基、环烷基、杂环烷基、芳基、杂芳基、环烷基烷基、杂环烷基烷基、芳基烷基或杂芳基烷基；所述R 4或R 4’为未取代或者选择性地被一个或多个选自卤素、氰基、-L 2-OR a、-L 2-OC(O)R a、-L 2-NR aR b、-L 2-NR aC(O)OR b、-L 2-NR aC(O)NR aR b、-L 2-NR bC(NR b)NR aR b和-L 2-C(O)OR b的取代基取代在任意位置；或者，R 4和R 4’与它们共同连接的N原子一起形成3-8元杂环烷基；所述3-8元杂环烷基为未取代或者进一步被1～3个选自卤素、氰基、-L 2-OR a、-L 2-OC(O)R a、-L 2-NR aR b、-L 2-NR aC(O)OR b、-L 2-NR aC(O)NR aR b、-L 2-NR bC(NR b)NR aR b和-L 2-C(O)OR b的取代基取代在任意位置；
    R 5为＝O、＝NR a、-OR a或-NR aR b；
    R 5’不存在，或者R 5’为-R c、-L 2-OR a、-L 2-NR aR b、-L 2-NR aC(O)OR b、-L 2-NR aC(O)NR aR b、-L 2-NR bC(NR b)NR aR b或-L 2-C(O)OR b；
    R 7为苯基、5-6元杂芳基、3-8元杂环烷基或8-12元并环基团；所述R 7为未取代，或者选择性被 一个或多个选自-L 3-W、-R c、卤素、氰基、硝基、烷基、烯基、炔基、烷氧基、卤代烷基、卤代烷氧基和烷氨基的取代基取代在任意位置；
    R 8和R 8’分别独立地为氢、卤素或烷基，所述R 8或R 8’为未取代，或者选择性被一个或多个选自-L 3-W、卤素、氰基、硝基、烷基、烯基、炔基、烷氧基、卤代烷基、卤代烷氧基和烷氨基的取代基取代在任意位置；R 8和R 8’分别为独立取代基，或者，R 8和R 8’与其共同连接的碳原子一起形成氧代基、硫代基、C 1-6亚烷基、C 3-10环烷基或3-10元杂环烷基；所述C 1-6亚烷基、C 3-10环烷基或3-10元杂环烷基为未取代，或者选择性被一个或多个选自氘、卤素、羟基、氨基、氰基、氧代基、烷基、卤代烷基、-L 2-OR a和-L 2-NR aR b的取代基取代在任意位置；
    R 9为氢、烷基、卤代烷基、-L 2-OR a或-L 2-NR aR b；
    W为Cy 1、-SR d、-OR d、-OC(O)R e、-OC(O)NR eR e’、-C(O)OR e、-C(O)R e、-C(O)NR eR e’、-C(O)NR eS(O) 2R e–NR dR e、-NR dC(O)R e、-N(R d)C(O)OR e、-N(R d)C(O)NR eR e’、-NR dS(O) 2R e、-NR dS(O) 2NR eR e’、-S(O) 1-2R e、-S(O) 2NR eR e’、-S(O)(＝NR d)R e、-S(O) 2N(R e)C(O)R e’、-P(O)(OR e) 2、-P(O)(OR e)R e’、-OP(O)(OR e) 2或-B(OR e) 2；
    Cy 1为环烷基、杂环烷基、芳基或者杂芳基；所述Cy 1为未取代，或者选择性地被一个或多个选自卤素、烷基、卤代烷基、卤代烷氧基、烯基、炔基、氰基、-R c、-L 4-SR d、-L 4-OC(O)R e、-L 4-C(O)OR e、-L 4-C(O)R e、-L 4-C(O)NR eR e’、-L 4-NR dC(O)R e、-L 4-NR dS(O) 2R e、-L 4-S(O) 1-2R e、-L 4-S(O) 2NR eR e’、-L 4-OR d和-L 4-NR eR e’的取代基取代在任意位置；
    L 1、L 2、L 3和L 4分别独立地为连接键、C 1-6亚烷基、C 2-6亚烯基或C 2-6亚炔基；所述L 1、L 2、L 3或L 4为未取代，或者选择性被一个或多个选自氧代基、羟基、氨基、卤素、氰基、烷基、卤代烷基、烷氧基和卤代烷氧基的取代基取代在任意位置；
    每个R a、R b、R d、R e和R e’分别独立地为-R c、氨基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-10环烷基、3-10元杂环烷基、C 6-10芳基、5-10元杂芳基、C 3-10环烷基C 1-6烷基、3-10元杂环烷基C 1-6烷基、苯基C 1-6烷基或5-10元杂芳基C 1-6烷基；所述R a、R b、R d、R e或R e’为未取代，或者选择性地被1～3个选自-OR f、-OC(O)-L 4-R f、-NR fR f’、卤素、氰基、硝基、C 1-6烷基、卤代C 1-6烷基和卤代C 1-6烷氧基的取代基取代在任意位置；
    每个R f和R f’分别独立地为-R c、-NHR c或C 1-6烷基；
    每个R c分别独立地为氢或连接键；并且D中至少有一个R c为连接键；
    x为0、1、2或3；
    u为0、1、2、3、4、5或6；
    w为0、1、2、3、4、5或6；
    每个L 5分别独立地为
    Figure PCTCN2022093953-appb-100057
    Figure PCTCN2022093953-appb-100058
    p为1、2或3；每个R 10分别独立地为氢、卤素、C 1-6烷基、卤代C 1-6烷基、硝基、氰基、C 1-6烷氧基、C 1-6烷氨基、-OC(O)R 11或-C(O)N(R 11) 2；R 11为氢、C 1-6烷基或C 1-6烷氨基C 1-6烷基；
    每个Z分别独立地为
    Figure PCTCN2022093953-appb-100059
    Figure PCTCN2022093953-appb-100060
    和-(CH 2CH 2O) o7-；每个o1、o2、o3、o4、o5、o6、o7分别独立地为0、1、2、3、4、5、6、7或8；每个R 12a、R 12b和R 12c分别独立地为氢、甲基、乙基、正丙基、异丙基、-SO 3H、
    Figure PCTCN2022093953-appb-100061
    Figure PCTCN2022093953-appb-100062
    每个R 13a和每个R 13b分别独立地为氢或甲基；
    每个T分别独立地为-(CH 2) v1-、-(CH 2CH 2O) v2-、
    Figure PCTCN2022093953-appb-100063
    Figure PCTCN2022093953-appb-100064
    v1、v2、v3、v4和v5分别独立地为1、2、3、4、5或6；
    M’为
    Figure PCTCN2022093953-appb-100065
    方案19-4：
    所述的如式II’所示化合物为
    Figure PCTCN2022093953-appb-100066
    其中，D为所述的如式I所示化合物，
    Figure PCTCN2022093953-appb-100067
    α和β独立地为单键或双键；并且，α和β至少有一个为单键；
    m为0或1；
    X 1为N或CR 2，X 2为N或CR 3，X 3为N或CR 1；并且，X 1为CR 2，X 2为CR 3和X 3为CR 1时，m为1；
    R为-C(O)-L 1-R 7、-C(O)-NR 9-L 1-R 7、-C(S)-NR 9-L 1-R 7、-NR 9-L 1-R 7、-NR 9-C(O)-L 1-R 7、-NR 9-C(O)-NR 9-L 1-R 7、-O-L 1-R 7、-S(O) 2-NR 9-L 1-R 7、-CH＝CH-L 1-R 7或-S(O) 2-L 1-R 7；
    R 1、R 2和R 3分别独立地为氢、氘、卤素、羟基、氨基、氰基、烷基、卤代烷基、-L 2-OR a或-L 2-NR aR b；
    R 4和R 4’分别独立地为氢、烷基、烯基、炔基、环烷基、杂环烷基、芳基、杂芳基、环烷基烷基、杂环烷基烷基、芳基烷基或杂芳基烷基；所述R 4或R 4’为未取代或者选择性地被一个或多个选自卤素、氰基、-L 2-OR a、-L 2-NR aR b、-L 2-NR aC(O)OR b、-L 2-NR aC(O)NR aR b、-L 2-NR bC(NR b)NR aR b和-L 2-C(O)OR b的取代基取代在任意位置；或者，R 4和R 4’与它们共同连接的N原子一起形成3-8元杂环烷基；所述3-8元杂环烷基为未取代或者进一步被1～3个选自卤素、氰基、-L 2-OR a、-L 2-NR aR b、-L 2-NR aC(O)OR b、-L 2-NR aC(O)NR aR b、-L 2-NR bC(NR b)NR aR b和-L 2-C(O)OR b的取代基取代在任意位置；
    R 5为＝O、＝NR a、-OR a或-NR aR b；
    R 5’不存在，或者R 5’为-R c、-L 2-OR a、-L 2-NR aR b、-L 2-NR aC(O)OR b、-L 2-NR aC(O)NR aR b、-L 2-NR bC(NR b)NR aR b或-L 2-C(O)OR b；
    R 7为苯基、5-6元杂芳基、3-8元杂环烷基或8-12元并环基团；所述R 7为未取代，或者选择性被一个或多个选自-L 3-W、-R c、卤素、氰基、硝基、烷基、烯基、炔基、烷氧基、卤代烷基、卤代烷氧基和烷氨基的取代基取代在任意位置；
    R 8和R 8’分别独立地为氢、卤素或烷基，所述R 8或R 8’为未取代，或者选择性被一个或多个选自-L 3-W、卤素、氰基、硝基、烷基、烯基、炔基、烷氧基、卤代烷基、卤代烷氧基和烷氨基的取代基取代在任意位置；R 8和R 8’分别为独立取代基，或者，R 8和R 8’与其共同连接的碳原子一起形成氧代基、硫代基、C 1-6亚烷基、C 3-10环烷基或3-10元杂环烷基；所述C 1-6亚烷基、C 3-10环烷基或3-10元杂环烷基为未取代，或者选择性被一个或多个选自氘、卤素、羟基、氨基、氰基、氧代基、烷基、卤代烷基、-L 2-OR a和-L 2-NR aR b的取代基取代在任意位置；
    R 9为氢、烷基、卤代烷基、-L 2-OR a或-L 2-NR aR b；
    W为Cy 1、-SR d、-OR d、-OC(O)R e、-OC(O)NR eR e’、-C(O)OR e、-C(O)R e、-C(O)NR eR e’、-C(O)NR eS(O) 2R e–NR dR e、-NR dC(O)R e、-N(R d)C(O)OR e、-N(R d)C(O)NR eR e’、-NR dS(O) 2R e、-NR dS(O) 2NR eR e’、-S(O) 1-2R e、 -S(O) 2NR eR e’、-S(O)(＝NR d)R e、-S(O) 2N(R e)C(O)R e’、-P(O)(OR e) 2、-P(O)(OR e)R e’、-OP(O)(OR e) 2或-B(OR e) 2；
    Cy 1为环烷基、杂环烷基、芳基或者杂芳基；所述Cy 1为未取代，或者选择性地被一个或多个选自卤素、烷基、卤代烷基、卤代烷氧基、烯基、炔基、氰基、-R c、-L 4-SR d、-L 4-OC(O)R e、-L 4-C(O)OR e、-L 4-C(O)R e、-L 4-C(O)NR eR e’、-L 4-NR dC(O)R e、-L 4-NR dS(O) 2R e、-L 4-S(O) 1-2R e、-L 4-S(O) 2NR eR e’、-L 4-OR d和-L 4-NR eR e’的取代基取代在任意位置；
    L 1、L 2、L 3和L 4分别独立地为连接键、C 1-6亚烷基、C 2-6亚烯基或C 2-6亚炔基；所述L 1、L 2、L 3或L 4为未取代，或者选择性被一个或多个选自氧代基、羟基、氨基、卤素、氰基、烷基、卤代烷基、烷氧基和卤代烷氧基的取代基取代在任意位置；
    每个R a、R b、R d、R e和R e’分别独立地为-R c、氨基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-10环烷基、3-10元杂环烷基、C 6-10芳基、5-10元杂芳基、C 3-10环烷基C 1-6烷基、3-10元杂环烷基C 1-6烷基、苯基C 1-6烷基或5-10元杂芳基C 1-6烷基；所述R a、R b、R d、R e或R e’为未取代，或者选择性地被1～3个选自-OR f、-NR fR f’、卤素、氰基、硝基、C 1-6烷基、卤代C 1-6烷基和卤代C 1-6烷氧基的取代基取代在任意位置；
    每个R f和R f’分别独立地为-R c、-NHR c或C 1-6烷基；
    每个R c分别独立地为氢或连接键；并且D中至少有一个R c为连接键；
    x为0、1、2或3；
    u为0、1、2、3、4、5或6；
    w为0、1、2、3、4、5或6；
    每个L 5分别独立地为
    Figure PCTCN2022093953-appb-100068
    Figure PCTCN2022093953-appb-100069
    p为1、2或3；每个R 10分别独立地为氢、卤素、C 1-6烷基、卤代C 1-6烷基、硝基、氰基、C 1-6烷氧基、C 1-6烷氨基、-OC(O)R 11或-C(O)N(R 11) 2；R 11为氢、C 1-6烷基或C 1-6烷氨基C 1-6烷基；
    每个Z分别独立地为
    Figure PCTCN2022093953-appb-100070
    Figure PCTCN2022093953-appb-100071
    和-(CH 2CH 2O) o7-；每个o1、o2、o3、o4、o5、o6、o7分别独立地为0、1、2、3、4、5、6、7或8；每个R 12a、R 12b和R 12c分别独立地为氢、甲基、乙基、正丙基、 异丙基、-SO 3H、
    Figure PCTCN2022093953-appb-100072
    Figure PCTCN2022093953-appb-100073
    每个R 13a和每个R 13b分别独立地为氢或甲基；
    每个T分别独立地为-(CH 2) v1-、-(CH 2CH 2O) v2-、
    Figure PCTCN2022093953-appb-100074
    Figure PCTCN2022093953-appb-100075
    v1、v2、v3、v4和v5分别独立地为1、2、3、4、5或6；
    M’为
    Figure PCTCN2022093953-appb-100076
  20. 如权利要求13～18中至少一项所述的如式II’所示化合物、其溶剂合物、其药学上可接受的盐或其药学上可接受的盐的溶剂合物，其特征在于，所述的如式II’所示化合物为如下任一化合物：
    Figure PCTCN2022093953-appb-100077
    Figure PCTCN2022093953-appb-100078
    Figure PCTCN2022093953-appb-100079
    Figure PCTCN2022093953-appb-100080
    Figure PCTCN2022093953-appb-100081
  21. 一种如式III所示抗体-免疫刺激偶联物或其药学上可接受的盐，
    Figure PCTCN2022093953-appb-100082
    其中，Ab为抗体；
    L为连接Ab和D的连接体；
    D为如权利要求1～11中至少一项所述的如式I所示化合物失去一个氢原子所形成的基团；
    t为1～8的任意数值。
  22. 如权利要求21所述的如式III所示抗体-免疫刺激偶联物或其药学上可接受的盐，其特征在于，如式III所示抗体-免疫刺激偶联物满足以下条件中的一个或多个：
    zz)所述的抗体包含一个或多个可以跟抗原结合的抗原结合域；
    aaa)所述的抗体包含一个Fc端；
    bbb)所述的抗体为单克隆抗体；
    ccc)所述的D为所述的如式I所示化合物在基团R 7处失去一个氢原子所形成的基团；
    ddd)所述的L为可降解连接体或不可降解连接体；
    eee)所述的t为2～5的任意数值。
  23. 如权利要求22所述的如式III所示抗体-免疫刺激偶联物或其药学上可接受的盐，其特征在于，如式III所示抗体-免疫刺激偶联物满足以下条件中的一个或多个：
    fff)所述的抗体包含一个或两个可以跟抗原结合的抗原结合域；
    ggg)所述的D为所述的如式I所示化合物在基团R 7的仲胺或伯胺处失去一个氢原子所形成的基团；
    hhh)所述的L为可被溶酶体酶降解的连接体。
  24. 如权利要求23所述的如式III所示抗体-免疫刺激偶联物或其药学上可接受的盐，其特征在于，如式III所示抗体-免疫刺激偶联物满足以下条件中的一个或多个：
    iii)所述的抗体为抗HER2抗体；
    jjj)所述的D通过
    Figure PCTCN2022093953-appb-100083
    的a端与所述的Linker连接；
    kkk)所述的L为
    Figure PCTCN2022093953-appb-100084
    x为0、1、2或3；
    u为0、1、2、3、4、5或6；
    w为0、1、2、3、4、5或6；
    每个L 5分别独立地为
    Figure PCTCN2022093953-appb-100085
    Figure PCTCN2022093953-appb-100086
    p为1、2或3；每个R 10分别独立地为氢、卤素、C 1-6烷基、卤代C 1-6烷基、硝基、氰基、C 1-6烷氧基、C 1-6烷氨基、-OC(O)R 11或-C(O)N(R 11) 2；R 11为氢、C 1-6烷基或C 1-6烷氨基C 1-6烷基；
    每个Z分别独立地为
    Figure PCTCN2022093953-appb-100087
    Figure PCTCN2022093953-appb-100088
    和-(CH 2CH 2O) o7-；每个o1、o2、o3、o4、o5、o6、o7分别独立地为0、1、2、3、4、5、6、7或8；每个R 12a、R 12b和R 12c分别独立地为氢、甲基、乙基、正丙基、异丙基、-SO 3H、
    Figure PCTCN2022093953-appb-100089
    Figure PCTCN2022093953-appb-100090
    每个R 13a和每个R 13b分别独立地为氢或甲基；
    每个T分别独立地为-(CH 2) v1-、-(CH 2CH 2O) v2-、
    Figure PCTCN2022093953-appb-100091
    Figure PCTCN2022093953-appb-100092
    v1、v2、v3、v4和v5分别独立地为1、2、3、4、5或6；
    M为连接键或连接头。
  25. 如权利要求24所述的如式III所示抗体-免疫刺激偶联物或其药学上可接受的盐，其特征在于，如式III所示抗体-免疫刺激偶联物满足以下条件中的一个或多个：
    lll)所述的抗体为Trastuzumab；
    mmm)所述的L 5为
    Figure PCTCN2022093953-appb-100093
    nnn)所述的L 5的羰基端与所述的D连接；
    ooo)所述的Z为氨基酸；
    ppp)所述的
    Figure PCTCN2022093953-appb-100094
    为肽链；
    qqq)所述的
    Figure PCTCN2022093953-appb-100095
    的羰基端与所述的L 5的氨基端连接；
    rrr)所述的
    Figure PCTCN2022093953-appb-100096
    为
    Figure PCTCN2022093953-appb-100097
    sss)所述的T的羰基端与所述的
    Figure PCTCN2022093953-appb-100098
    的氨基端连接；
    ttt)所述的M的氨基端与所述的T的非羰基端连接。
  26. 如权利要求25所述的如式III所示抗体-免疫刺激偶联物或其药学上可接受的盐，其特征在于，所述的L为
    Figure PCTCN2022093953-appb-100099
    x为1；
    u为1、2、3、4、5或6；
    w为1；
    L 5为
    Figure PCTCN2022093953-appb-100100
    p为1；R 10为氢；所述的L 5的羰基端与所述的D连接；
    每个Z分别独立地为
    Figure PCTCN2022093953-appb-100101
    每个R 12a分别独立地为氢、甲基、乙基、正丙基、异丙基、
    Figure PCTCN2022093953-appb-100102
    所述的
    Figure PCTCN2022093953-appb-100103
    的羰基端与所述的L 5的氨基端连接；
    T为
    Figure PCTCN2022093953-appb-100104
    v3为1、2、3、4、5或6；所述的T的羰基端与所述的
    Figure PCTCN2022093953-appb-100105
    的氨基端连接；
    M为
    Figure PCTCN2022093953-appb-100106
    所述的M的氨基端与所述的T的非羰基端连接。
  27. 如权利要求21～26中至少一项所述的如式III所示抗体-免疫刺激偶联物或其药学上可接受的盐，其特征在于，如式III所示抗体-免疫刺激偶联物的定义如下述任一方案所述：
    方案27-1：
    Ab为抗体；
    L为连接Ab和D的连接体；
    D为所述的如式I所示化合物失去一个氢原子所形成的基团；
    t为1～8的任意数值；
    方案27-2：
    Ab为抗HER2单克隆抗体；
    L为
    Figure PCTCN2022093953-appb-100107
    x为1；
    u为1、2、3、4、5或6；
    w为1；
    L 5为
    Figure PCTCN2022093953-appb-100108
    p为1；R 10为氢；所述的L 5的羰基端与所述的D连接；
    每个Z分别独立地为
    Figure PCTCN2022093953-appb-100109
    每个R 12a分别独立地为氢、甲基、乙基、正丙基、异丙基、
    Figure PCTCN2022093953-appb-100110
    所述的
    Figure PCTCN2022093953-appb-100111
    的羰基端与所述的L 5的氨基端连接；
    T为
    Figure PCTCN2022093953-appb-100112
    v3为1、2、3、4、5或6；所述的T的羰基端与所述的
    Figure PCTCN2022093953-appb-100113
    的氨基端连接；
    M为
    Figure PCTCN2022093953-appb-100114
    所述的M的氨基端与所述的T的非羰基端连接；
    所述的D为所述的如式I所示化合物在基团R 7处失去一个氢原子所形成的基团；
    t为1～8的任意数值；
    方案27-3：
    Ab为抗体；
    L为连接Ab和D的连接体；
    t为1～8的任意数值；
    D为所述的如式I所示化合物；
    Figure PCTCN2022093953-appb-100115
    α和β独立地为单键或双键；并且，α和β至少有一个为单键；
    m为0或1；
    X 1为N或CR 2，X 2为N或CR 3，X 3为N或CR 1；并且，X 1为CR 2，X 2为CR 3和X 3为CR 1时，m为1；
    R为-C(O)-L 1-R 7、-C(O)-NR 9-L 1-R 7、-C(S)-NR 9-L 1-R 7、-NR 9-L 1-R 7、-NR 9-C(O)-L 1-R 7、-NR 9-C(O)-NR 9-L 1-R 7、-O-L 1-R 7、-S(O) 2-NR 9-L 1-R 7、-CH＝CH-L 1-R 7或-S(O) 2-L 1-R 7；
    R 1、R 2和R 3分别独立地为氢、氘、卤素、羟基、氨基、氰基、烷基、卤代烷基、-L 2-OR a或-L 2-NR aR b；
    R 4和R 4’分别独立地为氢、烷基、烯基、炔基、环烷基、杂环烷基、芳基、杂芳基、环烷基烷基、杂环烷基烷基、芳基烷基或杂芳基烷基；所述R 4或R 4’为未取代，或者选择性地被一个或多个选自卤素、氰基、-L 2-OR a、-L 2-OC(O)R a、-L 2-NR aR b、-L 2-NR aC(O)OR b、-L 2-NR aC(O)NR aR b、-L 2-NR bC(NR b)NR aR b 和-L 2-C(O)OR b的取代基取代在任意位置；或者，R 4和R 4’与它们共同连接的N原子一起形成3-8元杂环烷基；所述3-8元杂环烷基为未取代或者进一步被1～3个选自卤素、氰基、-L 2-OR a、-L 2-OC(O)R a、-L 2-NR aR b、-L 2-NR aC(O)OR b、-L 2-NR aC(O)NR aR b、-L 2-NR bC(NR b)NR aR b和-L 2-C(O)OR b的取代基取代在任意位置；
    R 5为＝O、＝NR a、-OR a或-NR aR b；
    R 5’不存在，或者R 5’为-R c、-L 2-OR a、-L 2-NR aR b、-L 2-NR aC(O)OR b、-L 2-NR aC(O)NR aR b、-L 2-NR bC(NR b)NR aR b或-L 2-C(O)OR b；
    R 7为苯基、5-6元杂芳基、3-8元杂环烷基或8-12元并环基团；所述R 7为未取代，或者选择性被一个或多个选自-L 3-W、-R c、卤素、氰基、硝基、烷基、烯基、炔基、烷氧基、卤代烷基、卤代烷氧基和烷氨基的取代基取代在任意位置；
    R 8和R 8’分别独立地为氢、卤素或烷基，所述R 8或R 8’为未取代，或者选择性被一个或多个选自-L 3-W、卤素、氰基、硝基、烷基、烯基、炔基、烷氧基、卤代烷基、卤代烷氧基和烷氨基的取代基取代在任意位置；R 8和R 8’分别为独立取代基，或者，R 8和R 8’与其共同连接的碳原子一起形成氧代基、硫代基、C 1-6亚烷基、C 3-10环烷基或3-10元杂环烷基；所述C 1-6亚烷基、C 3-10环烷基或3-10元杂环烷基为未取代，或者选择性被一个或多个选自氘、卤素、羟基、氨基、氰基、氧代基、烷基、卤代烷基、-L 2-OR a和-L 2-NR aR b的取代基取代在任意位置；
    R 9为氢、烷基、卤代烷基、-L 2-OR a或-L 2-NR aR b；
    W为Cy 1、-SR d、-OR d、-OC(O)R e、-OC(O)NR eR e’、-C(O)OR e、-C(O)R e、-C(O)NR eR e’、-C(O)NR eS(O) 2R e–NR dR e、-NR dC(O)R e、-N(R d)C(O)OR e、-N(R d)C(O)NR eR e’、-NR dS(O) 2R e、-NR dS(O) 2NR eR e’、-S(O) 1-2R e、-S(O) 2NR eR e’、-S(O)(＝NR d)R e、-S(O) 2N(R e)C(O)R e’、-P(O)(OR e) 2、-P(O)(OR e)R e’、-OP(O)(OR e) 2或-B(OR e) 2；
    Cy 1为环烷基、杂环烷基、芳基或者杂芳基；所述Cy 1为未取代，或者选择性地被一个或多个选自卤素、烷基、卤代烷基、卤代烷氧基、烯基、炔基、氰基、-R c、-L 4-SR d、-L 4-OC(O)R e、-L 4-C(O)OR e、-L 4-C(O)R e、-L 4-C(O)NR eR e’、-L 4-NR dC(O)R e、-L 4-NR dS(O) 2R e、-L 4-S(O) 1-2R e、-L 4-S(O) 2NR eR e’、-L 4-OR d和-L 4-NR eR e’的取代基取代在任意位置；
    L 1、L 2、L 3和L 4分别独立地为连接键、C 1-6亚烷基、C 2-6亚烯基或C 2-6亚炔基；所述L 1、L 2、L 3或L 4为未取代，或者选择性被一个或多个选自氧代基、羟基、氨基、卤素、氰基、烷基、卤代烷基、烷氧基和卤代烷氧基的取代基取代在任意位置
    每个R a、R b、R d、R e和R e’分别独立地为-R c、氨基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-10环烷基、3-10元杂环烷基、C 6-10芳基、5-10元杂芳基、C 3-10环烷基C 1-6烷基、3-10元杂环烷基C 1-6烷基、苯基C 1-6烷基或5-10元杂芳基C 1-6烷基；所述R a、R b、R d、R e或R e’为未取代或者选择性地被1～3个选自-OR f、-OC(O)-L 4-R f、-NR fR f’、卤素、氰基、硝基、C 1-6烷基、卤代C 1-6烷基和卤代C 1-6烷氧基的取代基取代在任意位置；
    每个R f和R f’分别独立地为-R c、-NHR c或C 1-6烷基；
    每个R c分别独立地为氢或与L连接的连接键；并且D中至少有一个R c为与L连接的连接键；
    方案27-4：
    Ab为抗体；
    L为连接Ab和D的连接体；
    t为1～8的任意数值；
    D为所述的如式I所示化合物、其立体异构体或其药学上可接受的盐：
    Figure PCTCN2022093953-appb-100116
    α和β独立地为单键或双键；并且，α和β至少有一个为单键；
    m为0或1；
    X 1为N或CR 2，X 2为N或CR 3，X 3为N或CR 1；并且，X 1为CR 2，X 2为CR 3和X 3为CR 1时，m为1；
    R为-C(O)-L 1-R 7、-C(O)-NR 9-L 1-R 7、-C(S)-NR 9-L 1-R 7、-NR 9-L 1-R 7、-NR 9-C(O)-L 1-R 7、-NR 9-C(O)-NR 9-L 1-R 7、-O-L 1-R 7、-S(O) 2-NR 9-L 1-R 7、-CH＝CH-L 1-R 7或-S(O) 2-L 1-R 7；
    R 1、R 2和R 3分别独立地为氢、氘、卤素、羟基、氨基、氰基、烷基、卤代烷基、-L 2-OR a或-L 2-NR aR b；
    R 4和R 4’分别独立地为氢、烷基、烯基、炔基、环烷基、杂环烷基、芳基、杂芳基、环烷基烷基、杂环烷基烷基、芳基烷基或杂芳基烷基；所述R 4或R 4’为未取代，或者选择性地被一个或多个选自卤素、氰基、-L 2-OR a、-L 2-NR aR b、-L 2-NR aC(O)OR b、-L 2-NR aC(O)NR aR b、-L 2-NR bC(NR b)NR aR b和-L 2-C(O)OR b的取代基取代在任意位置；或者，R 4和R 4’与它们共同连接的N原子一起形成3-8元杂环烷基；所述3-8元杂环烷基为未取代或者进一步被1～3个选自卤素、氰基、-L 2-OR a、-L 2-NR aR b、-L 2-NR aC(O)OR b、-L 2-NR aC(O)NR aR b、-L 2-NR bC(NR b)NR aR b和-L 2-C(O)OR b的取代基取代在任意位置；
    R 5为＝O、＝NR a、-OR a或-NR aR b；
    R 5’不存在，或者R 5’为-R c、-L 2-OR a、-L 2-NR aR b、-L 2-NR aC(O)OR b、-L 2-NR aC(O)NR aR b、-L 2-NR bC(NR b)NR aR b或-L 2-C(O)OR b；
    R 7为苯基、5-6元杂芳基、3-8元杂环烷基或8-12元并环基团；所述R 7为未取代，或者选择性被一个或多个选自-L 3-W、-R c、卤素、氰基、硝基、烷基、烯基、炔基、烷氧基、卤代烷基、卤代烷氧基和烷氨基的取代基取代在任意位置；
    R 8和R 8’分别独立地为氢、卤素或烷基，所述R 8或R 8’为未取代，或者选择性被一个或多个选自-L 3-W、卤素、氰基、硝基、烷基、烯基、炔基、烷氧基、卤代烷基、卤代烷氧基和烷氨基的取代基取代在任意位置；R 8和R 8’分别为独立取代基，或者，R 8和R 8’与其共同连接的碳原子一起形成氧代基、硫代基、C 1-6亚烷基、C 3-10环烷基或3-10元杂环烷基；所述C 1-6亚烷基、C 3-10环烷基或3-10元杂环烷基为未取代，或者选择性被一个或多个选自氘、卤素、羟基、氨基、氰基、氧代基、烷基、卤 代烷基、-L 2-OR a和-L 2-NR aR b的取代基取代在任意位置；
    R 9为氢、烷基、卤代烷基、-L 2-OR a或-L 2-NR aR b；
    W为Cy 1、-SR d、-OR d、-OC(O)R e、-OC(O)NR eR e’、-C(O)OR e、-C(O)R e、-C(O)NR eR e’、-C(O)NR eS(O) 2R e–NR dR e、-NR dC(O)R e、-N(R d)C(O)OR e、-N(R d)C(O)NR eR e’、-NR dS(O) 2R e、-NR dS(O) 2NR eR e’、-S(O) 1-2R e、-S(O) 2NR eR e’、-S(O)(＝NR d)R e、-S(O) 2N(R e)C(O)R e’、-P(O)(OR e) 2、-P(O)(OR e)R e’、-OP(O)(OR e) 2或-B(OR e) 2；
    Cy 1为环烷基、杂环烷基、芳基或者杂芳基；所述Cy 1为未取代，或者选择性地被一个或多个选自卤素、烷基、卤代烷基、卤代烷氧基、烯基、炔基、氰基、-R c、-L 4-SR d、-L 4-OC(O)R e、-L 4-C(O)OR e、-L 4-C(O)R e、-L 4-C(O)NR eR e’、-L 4-NR dC(O)R e、-L 4-NR dS(O) 2R e、-L 4-S(O) 1-2R e、-L 4-S(O) 2NR eR e’、-L 4-OR d和-L 4-NR eR e’的取代基取代在任意位置；
    L 1、L 2、L 3和L 4分别独立地为连接键、C 1-6亚烷基、C 2-6亚烯基或C 2-6亚炔基；所述L 1、L 2、L 3或L 4为未取代，或者选择性被一个或多个选自氧代基、羟基、氨基、卤素、氰基、烷基、卤代烷基、烷氧基和卤代烷氧基的取代基取代在任意位置
    每个R a、R b、R d、R e和R e’分别独立地为-R c、氨基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-10环烷基、3-10元杂环烷基、C 6-10芳基、5-10元杂芳基、C 3-10环烷基C 1-6烷基、3-10元杂环烷基C 1-6烷基、苯基C 1-6烷基或5-10元杂芳基C 1-6烷基；所述R a、R b、R d、R e或R e’为未取代或者选择性地被1～3个选自-OR f、-NR fR f’、卤素、氰基、硝基、C 1-6烷基、卤代C 1-6烷基和卤代C 1-6烷氧基的取代基取代在任意位置；
    每个R f和R f’分别独立地为-R c、-NHR c或C 1-6烷基；
    每个R c分别独立地为氢或与L连接的连接键；并且D中至少有一个R c为与L连接的连接键。
  28. 如权利要求21～26中至少一项所述的如式III所示抗体-免疫刺激偶联物或其药学上可接受的盐，其特征在于，所述Linker为以下任一结构：
    Figure PCTCN2022093953-appb-100117
    Figure PCTCN2022093953-appb-100118
    Figure PCTCN2022093953-appb-100119
    其羰基端与所述的D连接。
  29. 如权利要求21～26中至少一项所述的如式III所示抗体-免疫刺激偶联物或其药学上可接受的盐，其特征在于，所述如式III所示抗体-免疫刺激偶联物为如下任一结构：
    Figure PCTCN2022093953-appb-100120
    Figure PCTCN2022093953-appb-100121
    Figure PCTCN2022093953-appb-100122
    Figure PCTCN2022093953-appb-100123
    例如
    Figure PCTCN2022093953-appb-100124
    Figure PCTCN2022093953-appb-100125
    Figure PCTCN2022093953-appb-100126
    Figure PCTCN2022093953-appb-100127
  30. 一种药物组合物，其包括物质K和药学上可接受的辅料；
    所述的物质K为物质K-1、物质K-2或物质K-3；
    所述的物质K-1为如权利要求1～11所述的如式I所示化合物、其溶剂合物、其药学上可接受的盐或其药学上可接受的盐的溶剂合物；
    所述的物质K-2为如权利要求13～20所述的如式II’所示化合物、其溶剂合物、其药学上可接受的盐或其药学上可接受的盐的溶剂合物；
    所述的物质K-3为如权利要求21～29所述的如式III所示抗体-免疫刺激偶联物或其药学上可接受的盐。
  31. 如权利要求30所述的药物组合物，其特征在于，其满足以下条件中的一个或多个：
    uuu)所述的物质K为所述的如式I所示化合物或药学上可接受的盐、如式II所示化合物或其药学上可接受的盐或如式III所示的抗体-免疫刺激偶联物或其药学上可接受的盐；
    vvv)所述的物质K的用量为治疗有效量；
    www)所述药学上可接受的辅料包括药学上可接受的载体、稀释剂和/或赋形剂；
    xxx)所述的药物组合物通过以下途径进行：肌内、腹膜内、静脉内、皮下、皮内或局部给药。
  32. 一种物质K或如权利要求30或31所述的药物组合物在制备药物中的应用；
    所述的物质K为物质K-1、物质K-2或物质K-3；
    所述的物质K-1为如权利要求1～11所述的如式I所示化合物、其溶剂合物、其药学上可接受的盐或其药学上可接受的盐的溶剂合物；
    所述的物质K-2为如权利要求13～20所述的如式II’所示化合物、其溶剂合物、其药学上可接受的盐或其药学上可接受的盐的溶剂合物；
    所述的物质K-3为如权利要求21～29所述的如式III所示抗体-免疫刺激偶联物或其药学上可接受的盐；
    所述的药物为1)调节T细胞及其它免疫细胞药物、2)治疗和/或缓解肿瘤或病毒感染性疾病药物或3)治疗、缓解和/或预防TLR8介导的相关疾病的药物。
  33. 如权利要求32所述的应用，其特征在于，其满足以下条件中的一个或多个：
    yyy)所述的物质K为所述的如式I所示化合物或药学上可接受的盐、如式II所示化合物或其药学上可接受的盐或如式III所示的抗体-免疫刺激偶联物或其药学上可接受的盐；
    zzz)所述的物质K的用量为治疗有效量；
    aaaa)所述的TLR8介导的相关疾病是指肿瘤或病毒感染性疾病；
    bbbb)所述的肿瘤为恶性肿瘤。
PCT/CN2022/093953 2021-05-19 2022-05-19 一种含氮化合物、含其的偶联物及其应用 WO2022242724A1 (zh)

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