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WO2017190669A1 - 苯并氮杂卓衍生物、其制备方法、药物组合物及应用 - Google Patents

苯并氮杂卓衍生物、其制备方法、药物组合物及应用 Download PDF

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Publication number
WO2017190669A1
WO2017190669A1 PCT/CN2017/083031 CN2017083031W WO2017190669A1 WO 2017190669 A1 WO2017190669 A1 WO 2017190669A1 CN 2017083031 W CN2017083031 W CN 2017083031W WO 2017190669 A1 WO2017190669 A1 WO 2017190669A1
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alkyl
compound
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formula
alkenyl
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PCT/CN2017/083031
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English (en)
French (fr)
Inventor
高大新
王玉珣
陈寿军
杨和平
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上海迪诺医药科技有限公司
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Priority to DK17792495.8T priority Critical patent/DK3453707T3/da
Priority to SG11201809859VA priority patent/SG11201809859VA/en
Priority to ES17792495T priority patent/ES2907981T3/es
Priority to EP17792495.8A priority patent/EP3453707B1/en
Priority to LTEPPCT/CN2017/083031T priority patent/LT3453707T/lt
Priority to HRP20220577TT priority patent/HRP20220577T1/hr
Priority to CA3023154A priority patent/CA3023154C/en
Priority to RS20220362A priority patent/RS63116B1/sr
Priority to EA201892513A priority patent/EA037488B1/ru
Priority to KR1020187033064A priority patent/KR102274557B1/ko
Priority to MX2018013467A priority patent/MX382727B/es
Priority to US16/098,972 priority patent/US10669252B2/en
Application filed by 上海迪诺医药科技有限公司 filed Critical 上海迪诺医药科技有限公司
Priority to AU2017259654A priority patent/AU2017259654B2/en
Priority to PL17792495T priority patent/PL3453707T3/pl
Priority to SM20220122T priority patent/SMT202200122T1/it
Priority to JP2018558270A priority patent/JP6739548B2/ja
Priority to SI201731103T priority patent/SI3453707T1/sl
Priority to BR112018072591-9A priority patent/BR112018072591B1/pt
Publication of WO2017190669A1 publication Critical patent/WO2017190669A1/zh
Priority to PH12018502336A priority patent/PH12018502336A1/en

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Definitions

  • the present invention relates to a benzazepine derivative, a process for the preparation thereof, a pharmaceutical composition and use thereof.
  • TLRs Toll-like receptor families
  • mDC myeloid dendritic cells
  • pDC plasma-like dendritic cells
  • monocytes and B cells fibroblasts
  • TLR1/2/4/5 and 6 are located in the cell membrane and their primary function is to recognize extracellular macromolecular ligands from bacteria and fungi.
  • TLR3/7/8/9 is located in the endosomal membrane of cells, and its main function is to recognize exogenous nucleic acids from pathogen cells.
  • TLRs work through specific signaling pathways (primarily through the MyD88-dependent pathway)
  • different TLRs can coordinate different downstream molecules.
  • the addition of specific TLRs results in activation of different cell populations (Schreibelt, et al, 2010) and the production of different cytokines and other inflammatory mediators (Ghosh, et al, 2006), resulting in different immune responses.
  • TLR8 when bound to a ligand, TLR8 forms a dimer and conformational changes result in the involvement of the adaptor protein MyD88, which recruits an interleukin-1 receptor-associated kinase, leading to activation of downstream signaling pathways, including mitogen-associated protein kinases and transcription factor NF. - ⁇ B.
  • TLRs located in endosomes mainly TLR7/8/9
  • TLR7/8/9 have been considered to be attractive new targets for anti-cancer immunotherapy (Kanzler, et al, 2007; Kreig 2008; Smiths, et al, 2008; Hennessy, et Al, 2010; Kaczanowska, et al, 2013; Beesu, et al, 2016).
  • TLR7 activates pDCs in response to viral infections, induces high levels of interferon alpha, and induces adaptive T cell responses of major cells to endogenous viral antigens (Liu, et al, 2009).
  • TLR8 is more widely expressed in immune cells of different subtypes.
  • Tregs Regulatory T cells
  • the TLR8 signaling pathway has been shown to be necessary and sufficient for reversing the Treg cell suppressor function leading to strong tumor suppression.
  • TLR8 selective agonists potently activate a variety of immune cells, including mDCs and monocytes (Gorden, et al, 2005), to promote adaptive immune responses against cancer cells (Krug, et al, 2003; Schnurr, Et al, 2005).
  • mDCs phagocytose apoptotic and dead tumor cells, and then more efficiently present tumor-associated antigens to CD8 + CTLs compared to pDCs (Berard, et al, 2000; Dalgaard, et al, 2005).
  • activation of mDCs leads to the release of TNF ⁇ and interleukin 12 (IL-12), which stimulates the activation of T cells and NK cells.
  • IL-12 interleukin 12
  • Activation of NK cells is the primary mechanism of antibody-mediated cytotoxicity (ADCC).
  • ADCC antibody-mediated cytotoxicity
  • TLR8 agonists can directly play an anti-tumor role, independent of its immunomodulatory function (Ignatz-Hoover, et al, 2015). Therefore, TLR8 agonists not only act as monotherapy, but also enhance the efficacy of multiple chemotherapy and targeted anticancer drugs by enhancing the host immune response.
  • TLR7 and TLR8 have high homology and can recognize some synthetic small molecules with antiviral activity, such as Imidazoquinolines imidazoquinoline small molecule compounds (ligands of TLR7 and TLR8) .
  • Imidazoquinolines were studied in the genital herpes model of guinea pigs infected with HSV. The compounds were found to have little effect on viral replication in vitro, but they have strong effects in vivo, indicating that these compounds promote the production of pro-inflammatory factors and cytokines in immune cells. , resulting in an antiviral response (Int Immunopharmacol 2002; 2: 443-451).
  • TLR7 and TLR8 recognize viral ssRNA.
  • ssRNA viruses are natural ligands for 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) and Hepatitis C virus (HCV), etc.
  • TLR8 recognizes antiviral compounds, ssRNA viruses, synthetic oligonucleotides, etc., induces Th1, inhibits Th2 cytokine secretion and Tregs proliferation through MyD88-dependent signaling pathway, mediates antiviral immunity, and exerts anti-infective and anti-allergic effects.
  • TLR8 protein and its associated TLR family members have been extensively studied, which will further facilitate the design and optimization of structure-based drugs.
  • TLR8 is currently an attractive therapeutic target. Although there have been more studies on TLRs, there are still huge opportunities for further expansion of their use and advantages. The compounds and applications described herein will aid in the development of TLR8 agonists to meet clinically unmet needs.
  • the technical problem to be solved by the present invention is to provide a novel benzazepine derivative, a preparation method thereof, a pharmaceutical composition and use thereof.
  • the benzazepine derivative of the present invention has a good regulatory effect on TLRs, and can effectively treat, alleviate and/or prevent various related diseases caused by immunosuppression, such as cancer, autoimmune diseases, infection, inflammation, transplantation. Rejection, graft versus host disease, etc.
  • the present invention provides a compound of the formula (I), an isomer thereof, a prodrug, a stable isotope derivative or a pharmaceutically acceptable salt;
  • L is -C(O)-, -C(S)- or -S(O) 2 -;
  • L 1 is a linkage, C 2-6 alkenylene, C 2-6 alkynylene, -(CR a R b ) m -, -(CR a R b ) u O(CR a R b ) v -, -(CR a R b ) u C(O)(CR a R b ) v -, -(CR a R b ) u C(O)O(CR a R b ) v -, -(CR a R b ) u OC(O)(CR a R b ) v -, -(CR a R b ) u N(R c )C(O)(CR a R b ) v -, -(CR a R b ) u C( O)N(R c )(CR a R b ) v -, -(CR a R b ) u N
  • R is selected from a bicyclic, tricyclic or tetracyclic ring group, which is unsubstituted or optionally substituted at one or more of the following positions: halogen, alkyl, haloalkyl, Haloalkoxy, alkenyl, alkynyl, Cy 1 , -L 2 -Cy 1 , -CN, -NO 2 , -SR d , -OR d , -OC(O)R d , -OC(O)OR d , -OC(O)NR d R e , -C(O)OR d , -C(O)R d , -C(O)NR d R e , -C(O)OR d , -C(O)R d , -C(O)NR d R e , -C(O)N(R d )OR e , -C(O)NR d S(
  • L 2 is a linkage, C 2-6 alkenylene, C 2-6 alkynylene, -(CR a1 R b1 ) m -, -(CR a1 R b1 ) u O(CR a1 R b1 ) v -, -(CR a1 R b1 ) u C(O)(CR a1 R b1 ) v -, -(CR a1 R b1 ) u C(O)O(CR a1 R b1 ) v -, -(CR a1 R b1 ) u OC(O)(CR a1 R b1 ) v -, -(CR a1 R b1 ) u N(R c1 )C(O)(CR a1 R b1 ) v -, -(CR a R b ) u C( O)N(R c1 )(CR a
  • Each Cy 1 is independently cycloalkyl, heterocycloalkyl, aryl or heteroaryl; the Cy 1 is unsubstituted or optionally substituted at one or more of the following positions: halogen, alkane , haloalkyl, haloalkoxy, hydroxyalkyl, aminoalkyl, alkenyl, alkynyl, -CN, -NO 2 , -SR d2 , -OR d2 , -OC(O)R d2 , -OC(O )OR d2 , -OC(O)NR d2 R e2 , -C(O)OR d2 , -C(O)R d2 , -C(O)NR d2 R e2 , -NR d2 R e2 , -NR d2 C(O)OR e2 , -N(R d2 )C(O)OR e2 , -N
  • R 1 , R 2 and R 3 are each independently selected from the group consisting of hydrogen, deuterium, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, said alkyl, alkenyl Or alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is unsubstituted or optionally substituted at any position by the following 1 to 3 groups: halogen, alkyl, haloalkyl, haloalkoxy , hydroxyalkyl, aminoalkyl, alkenyl, alkynyl, -CN, -NO 2 , -SR d2 , -OR d2 , -OC(O)R d2 , -OC(O)OR d2 , -OC(O ) NR d2 R e2 , -C(O)OR d2 , -C(O)
  • R 2 and R 3 together with the C atom to which they are attached form a C 3-8 cycloalkyl group or a 3-8 membered heterocycloalkyl group; said C 3-8 cycloalkyl group or a 3-8 membered hetero
  • the cycloalkyl group is unsubstituted or optionally substituted at any position by the following 1 to 3 groups: halogen, alkyl, haloalkyl, haloalkoxy, hydroxyalkyl, aminoalkyl, alkenyl, alkynyl, - CN, -NO 2 , -SR d2 , -OR d2 , -OC(O)R d2 , -OC(O)OR d2 , -OC(O)NR d2 R e2 , -C(O)OR d2 , -C (O)R d2 , -C(O)NR d2 R e2 , -NR d
  • R 4 , R 5 and R 6 are each independently selected from the group consisting of hydrogen, deuterium, halogen, amino, cyano, nitro, C 1-6 alkyl, halo C 1-6 alkyl, halo C 1-6 alkane Oxyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, hydroxy C 1-6 alkyl C 3-8 cycloalkyl, 3-8 membered heterocycloalkyl, benzene Base or 5-6 membered heteroaryl;
  • R A is selected from -OR d1 or -NR d1 R e1 ;
  • R B is selected from -NR d1 R e1 ;
  • Each R a , each R b , each R a1 and each R b1 are independently selected from the group consisting of hydrogen, deuterium, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 2-6 olefin , C 2-6 alkynyl, C 3-8 cycloalkyl, 3-8 membered heterocycloalkyl, C 6-10 aryl, 5-6 membered heteroaryl, C 3-8 cycloalkyl C 1 -6 alkyl, 3-8 membered heterocycloalkyl C 1-6 alkyl, phenyl C 1-6 alkyl or 5-6 membered heteroaryl C 1-6 alkyl; said C 1-6 alkane , C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, 3-8 membered heterocycloalkyl, C 6-10 aryl or 5- The 6-membered heteroaryl group is unsubstituted or
  • Each R c and each R c1 are each independently selected from hydrogen, C 1-4 alkyl, C 3-8 cycloalkyl or 3-8 membered heterocycloalkyl;
  • Each R d , each R e , each R d1 and each R e1 are independently selected from the group consisting of 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, 5-6 membered heteroaryl, C 3-8 cycloalkyl C 1-6 alkyl, 3-8 membered heterocycloalkane a C 1-6 alkyl group, a phenyl C 1-6 alkyl group or a 5-6 membered heteroaryl C 1-6 alkyl group; said R d , R e , R d1 or R e1 being unsubstituted or selective
  • the ground cover is 1 to 3 selected from the group consisting of halogen, hydroxy, amino, carboxyl, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino, halogenated C 1-6
  • the heterocycloalkyl group may further contain 1 to 3 selected from N a hetero atom of O, S; the heterocycloalkyl group being unsubstituted or further substituted by 1 to 3 selected from the group consisting of halogen, amino, hydroxy, carboxy, cyano, C 1-6 alkyl, halogenated C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-3 alkyl, amino C 1-3 alkyl, -OR d2 , -OC(O)R d2 , -OC(O)OR D2 , -OC(O)NR d2 R e2 , -C(O)OR d2 , -C(O)R d2 , -C(O)NR d2 R
  • Each R d2 and each R e2 are independently selected from the group consisting of hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, 3-8-membered hetero Cycloalkyl, C 6-10 aryl, 5-6 membered heteroaryl, C 3-8 cycloalkyl C 1-6 alkyl, 3-8 membered heterocycloalkyl C 1-6 alkyl, phenyl a C 1-6 alkyl group or a 5-6 membered heteroaryl C 1-6 alkyl group; said R d2 or R e2 being unsubstituted or optionally 1 to 3 selected from the group consisting of halogen, hydroxy, amino, carboxy, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino, halo C 1-6 alkyl, halo C 1-6 alkoxy, C 2-6 alkenyl and C 2 One or more substituents in the
  • the L is preferably -C(O)- or -S(O) 2- ;
  • the R is preferably a -C(O)N( Rd )OR in the definition of R above. a group other than e , wherein the alkyl, alkenyl or alkynyl group in R is unsubstituted or selectively substituted by -P(O)(OR d ) 2 , -OP(O) in the definition of the aforementioned substituent
  • One or more substituents other than (OR d ) 2 and -B(OR d ) 2 are substituted at any position.
  • the L 1 is preferably a linking bond, -CH 2 , -O-, -NH-, -OCH 2 - or -CH 2 O-.
  • said R 1 is preferably H.
  • said R 2 is preferably H.
  • said R 3 is preferably H.
  • R 4 , R 5 and R 6 are each independently preferably H, D, F, Cl, Br, -CH 3 , -OCH 3 , -CF 3 , -CH 2 F , -CHF 2 , -OCF 3 , -CN or -NH 2 ;
  • said R 4 , R 5 and R 6 are each independently preferably H, I, F, Cl, Br, -CH 3 , -OCH 3 , -CF 3 , -CH 2 F, -CHF 2 , -OCF 3 , -CN or -NH 2 ;
  • the R 4 , R 5 and R 6 are each independently preferably H, F, Cl, Br, -CH 3 , -OCH 3 , -CF 3 , -CH 2 F, -CHF 2 , -OCF 3 , -CN or -NH 2 .
  • R d1 and R e1 are each independently preferably hydrogen, C 1-6 alkyl, halogenated C 1-6 alkyl, C 3-8 ring.
  • the heterocycloalkyl group may further contain 1 to 3 heteroatoms selected from N, O, and S.
  • said R B is preferably -NH 2 .
  • the R is preferably a 8-20 membered bicyclic, tricyclic or tetracyclic cyclic group.
  • the R is preferably a 9-15 membered bicyclic or tricyclic acyclic group, and at least one ring is an aromatic ring.
  • the R is a 9-15 membered bicyclic or tricyclic acyclic group, wherein one ring is an aromatic ring, and the other 1 to 2 rings are non-aromatic rings, and the 9
  • the ring atom of the -15 membered bicyclic or tricyclic cyclized group contains 1 to 3 N atoms, and the non-aromatic ring further contains 1 to 2 oxo groups.
  • R is unsubstituted or preferably substituted by 1 to 4 substituents at any position; more preferably substituted by 1, 1, 2 or 1 to 3 substituents position.
  • said halogen is preferably F, Cl or Br in said substituent.
  • the alkyl group is preferably a C 1-6 alkyl group, for example: methyl, ethyl, n-propyl, isopropyl Base, n-butyl, isobutyl, tert-butyl, neopentyl, tepentyl or 2,2-dimethylbutyl.
  • the haloalkyl group is preferably a halogenated C 1-6 alkyl group, for example: -CF 3 , -CHF 2 or -CH 2 F.
  • the haloalkoxy group is preferably a halogenated C 1-6 alkoxy group, for example: -OCF 3 , -OCHF 2 or -OCH 2 F.
  • the alkenyl group is preferably a C 2-6 alkenyl group.
  • said alkynyl group is preferably a C 2-6 alkynyl group in said substituent.
  • the alkyl, alkenyl or alkynyl group is unsubstituted or preferably substituted by 1 to 3 substituents at any position.
  • the L 2 is preferably a linkage or -(CR a1 R b1 ) m -, m, R a1 , R b1 are as defined above; the L 2 is more preferably a linkage, -CH 2 -, -CH 2 CH 2 -, -CH 2 CH 2 CH 2 -, -CH 2 CH 2 C(CH 3 ) 2 -, -CH 2 CH 2 CH 2 CH 2 - or -CH 2 CH(CH 3 )CH 2 -;
  • Cy 1 is preferably C 3-10 cycloalkyl, 3-10 membered heterocycloalkyl, C 6-10 Aryl or 5-10 membered heteroaryl;
  • the 5-10 membered heteroaryl group is more preferably a 5-6 membered heteroaryl group, for example.
  • the C 6-10 aryl group is more preferably a phenyl group
  • Cy 1 is unsubstituted or selectively 1 to 3 is selected from F, Cl, Br, C 1- 4- alkyl (for example: methyl, ethyl, n-propyl, isopropyl or butyl, etc.), halogenated C 1-3 alkyl, halogenated C 1-3 alkoxy, hydroxy C 1-3 alkane Base, amino C 1-3 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, -CN, -NO 2 , -SR d2 , -OR d2 , -OC(O)R d2 , -OC( O) OR d2 , -OC(O)NR d2 R e2 , -C(O)OR d2 , -C(O)R d2 , -C(O)NR d2 R e2 , -NR d2 R
  • the R is more preferably any of the following R-1 to R-19:
  • R is preferably any one of R-1 to R-11 and R-13 to R-16 structures in the R definition structure; and R 7 and R 7a are each independently preferably.
  • 7a is the definition of R 7 and R groups other than -C (O) N (R d ) oR e , wherein R 7 or R 7a in the alkyl, alkenyl or alkynyl group is unsubstituted or optionally
  • R is preferably any one of R-1 to R-16 structures in the above R definition structure; and R 7 and R 7a are each independently preferably defined by the aforementioned R 7 and R 7a a group other than -C(O)N(R d )OR e wherein the alkyl, alkenyl or alkynyl group in R 7 or R 7a is unsubstituted or is optionally defined by the aforementioned substituent One or more substituents other than -P(O)(OR d ) 2 , -OP(O)(OR d ) 2 or -B(OR d ) 2 are substituted at any position; the R 8 is preferably the aforementioned A group other than -C(O)N(R d )OR e in the definition of R 8 .
  • R is preferably any one of R-1 to R-18 structures in the above R definition structure; and R 7 and R 7a are each independently preferably defined by the aforementioned R 7 and R 7a A group other than -C(O)N(R d )OR e .
  • the R 7 is preferably hydrogen, C 1-6 alkyl, halogenated C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkyne.
  • the C 1-6 alkyl group, C 2-6 alkenyl group or C 2-6 alkynyl group is unsubstituted or optionally substituted at any position by the following 1 to 3 substituents: -CN, -NO 2
  • the R 7 is preferably a group other than -C(O)N(R d )OR e in the preferred definition of R 7 in the above R, wherein The C 1-6 alkyl group, C 2-6 alkenyl group or C 2-6 alkynyl group is unsubstituted or selectively substituted by -P(O)(OR d ) 2 , -OP in the definition of the aforementioned substituent One or three substituents other than (O)(OR d ) 2 or -B(OR d ) 2 are substituted at any position.
  • the R 7 is preferably a group other than -C(O)N(R d )OR e in the preferred definition of R 7 in the above R.
  • the R 7 is more preferably: hydrogen, methyl, ethyl, propyl, butyl, isopropyl, isobutyl, n-butyl, neopentyl Base, pentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
  • the R 7 is more preferably:
  • the R 7 is more preferably: benzyl
  • the R 7 is more preferably: phenyl, pyridyl, pyrimidinyl,
  • the R 7 is more preferably:
  • the R 7a is preferably hydrogen, C 1-6 alkyl, halogenated C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkyne a group, Cy 1 or -L 2 -Cy 1 , wherein the C 1-6 alkyl group, C 2-6 alkenyl group or C 2-6 alkynyl group is unsubstituted or optionally 1 to 3 substituents as follows Substitution at any position: -CN, -NO 2 , -CN, -SR d , -OR d , -OC(O)R d , -OC(O)OR d , -OC(O)NR d R e ,- C(O)OR d , -C(O)R d , -C(O)NR d R e , -NR d R e , -NR d C(O)R e , -N(R
  • the R 7a is more preferably hydrogen or a C 1-6 alkyl group (for example, methyl or ethyl).
  • the R 8 is preferably: hydrogen, methyl, ethyl, n-propyl, t-butyl, isopropyl, isobutyl, n-butyl, - CN, -NO 2 , -NH 2 , -CF 3 , -OCF 3 , -CH 3 , -OCH 3 , F, Cl or Br; or R 8 is preferably a group other than -OCH 3 .
  • the n is preferably 1 or 2; the n is more preferably 1.
  • the L 2 is preferably a linkage or -(CR a1 R b1 ) m -.
  • the L 2 is preferably a linkage, -CH 2 -, -CH 2 CH 2 -, -CH 2 -CH 2 CH 2 -, -CH 2 CH 2 CH 2 CH 2 -, -CH 2 CH(CH 2 )CH 2 - or
  • the L 2 is preferably a linkage, -CH 2 -, -CH 2 CH 2 -, -CH 2 CH 2 CH 2 -, -CH 2 CH 2 CH 2 CH 2 - Or -CH 2 CH(CH 2 )CH 2 -.
  • the R d , R e , R d1 , R e1 , R d2 or R e2 are preferably unsubstituted or selectively 1 to 3 selected from the group consisting of halogen, hydroxyl, amino and carboxyl groups. Substituting one or more substituents of a C 1-4 alkyl group, a halogenated C 1-3 alkyl group, a halogenated C 1-3 alkoxy group, a C 2-6 alkenyl group, and a C 2-6 alkynyl group In any position.
  • the R d , R e , R d1 , R e1 , R d2 or R e2 is preferably unsubstituted or selectively 1 to 3 selected from the group consisting of halogen, hydroxyl, amino, a carboxyl group, a C 1-4 alkyl group, a halogenated C 1-3 alkyl group, a halogenated C 1-3 alkoxy group, a C 1-3 alkoxy group, a C 1-3 alkylamino group, a C 2-6 alkenyl group, and One or more substituents in the C 2-6 alkynyl group are substituted at any position.
  • R d and R e , or R d1 and R e1 , or R d2 and R e2 together with the N atom to which they are attached form a 3-8 membered heterocycloalkyl;
  • the cycloalkyl group may further contain 1 to 3 hetero atoms selected from N, O, and S; the heterocycloalkyl group is preferably unsubstituted or further 1 to 3 selected from the group consisting of halogen, amino, carboxyl, cyano, C 1-4 alkyl, halo C 1-3 alkyl, halo C 1-3 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, hydroxyalkyl, aminoalkyl, -OR D2 , -OC(O)R d2 , -OC(O)OR d2 , -OC(O)NR d2 R e2 , -C(O)OR d2 , -C(O)OR d2
  • U is N, C(R 8 ) or C(O)
  • V is N, C(R 8 ) or N(R 7a );
  • U and V are any combination of the following:
  • Y is O or S
  • n 1;
  • L 1 , R d1 , R e1 , R 4 , R 5 , R 6 , R 7 , R 8 and X are as defined above.
  • the compound, an isomer, a prodrug, a stable isotopic derivative or a pharmaceutically acceptable salt thereof, of the formula I is preferably a compound of the formula IB or IC, an isomer thereof, a prodrug, A stable isotope derivative or pharmaceutically acceptable salt:
  • R d1 , R e1 , R 4 , R 5 , R 6 , R 7 , R 8 and Y are as described above.
  • Y is preferably O.
  • the compound, an isomer, a prodrug, a stable isotopic derivative or a pharmaceutically acceptable salt thereof, of the formula I preferably a compound of the formula ID, IE, IF, IG, IH or II, Isomers, prodrugs, stable isotope derivatives or pharmaceutically acceptable salts:
  • R d1 , R e1 , R 4 , R 5 , R 6 , R 7 , R 7a , R 8 and Y are as defined above.
  • Y is preferably O.
  • the compound of the formula I an isomer thereof, a prodrug, a stable isotope derivative or a pharmaceutically acceptable salt, preferably a compound of the formula IJ, an isomer thereof, a prodrug, a stable Isotope derivative or pharmaceutically acceptable salt:
  • Z is N (R 7a ) or S
  • n 1 or 2;
  • L 1 , R d1 , R e1 , R 4 , R 5 , R 6 , R 7 and R 8 are as defined above.
  • the compound, an isomer, a prodrug, a stable isotopic derivative or a pharmaceutically acceptable salt thereof, of the formula I preferably a compound of the formula IK or IL, an isomer thereof, a prodrug, A stable isotope derivative or pharmaceutically acceptable salt:
  • Z is NH, N(CH 3 ) or S
  • R d1 , R e1 , R 4 , R 5 , R 6 , R 7 and R 8 are as described above.
  • the compound of the formula (I), an isomer thereof, a prodrug, a stable isotope derivative or a pharmaceutically acceptable salt is preferably one of the following structures:
  • the present invention also provides a process for the preparation of the compound of the formula (I), an isomer thereof, a prodrug, a stable isotope derivative or a pharmaceutically acceptable salt,
  • the preparation method of the compound represented by the formula (I) is any one of the following methods:
  • Method 1 comprises the steps of: combining a compound as shown in Formula Ia with The suzuki coupling reaction shown below is carried out to obtain the compound of the formula (I);
  • Process 2 comprises the steps of: subjecting a compound of formula I-b to R-M by a suzuki coupling reaction as shown below, to produce the compound of formula (I);
  • M is bromine, chlorine, iodine or -OS(O) 2 CF 3 ; the definitions of R 1 , R 3 , R 4 , R 5 , R 6 , R A , R B , R and L are the same as before Said.
  • the conditions and steps of the suzuki coupling reaction may be the conditions and steps of the conventional reaction in the art, and the present invention particularly preferably has the following reaction conditions: under nitrogen protection, in a mixed solvent (for example, tetrahydrofuran / Water, acetonitrile/water, or N,N-dimethylformamide/water), base (potassium carbonate, cesium carbonate or diethyl isopropylamine) and catalyst (preferably [1,1'-bis(diphenyl) Phosphatidyl)ferrocene]palladium dichloride (Pd(dppf)Cl 2 ) or [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex (Pd (dppf) 2 Cl 2 ), the mixed solvent is preferably used in an amount of 1 to 50 mL/mmol of the compound Ia or Ib, and the reaction time is preferably 0 to 24 hours, and
  • an acidic system such as p-toluenesulfonic acid, hydrochloric acid, hydrogen chloride or trifluoroacetic acid is used, or in the purification process, for example, in the mobile phase of prep-HPLC, the above-mentioned acidic system is present.
  • the compound of formula I-1 will be the corresponding p-toluenesulfonate, hydrochloride or trifluoroacetate salt and the like.
  • a compound as shown in Formula Ia when an amino group, a hydroxyl group or a carboxyl group is present in the RM, the amino group, the hydroxyl group or the carboxyl group can be protected by a protecting group to avoid any side reaction. If the above amino protecting group or hydroxy protecting group is present, it is necessary to undergo a subsequent deprotection step to give a compound of formula I-1. Any suitable amino protecting group, for example, a tert-butoxycarbonyl (Boc) group, can be used to protect the amino group.
  • a tert-butoxycarbonyl (Boc) group can be used to protect the amino group.
  • Boc is used as a protecting group
  • subsequent deprotection reactions can be carried out under standard conditions, for example, p-toluenesulfonic acid/methanol system, dichloromethane/trifluoroacetic acid system, saturated hydrogen chloride ether solution, or trifluoromethanesulfonate
  • the deprotection reaction can be deprotected under standard conditions, for example, sodium hydroxide, potassium hydroxide, lithium hydroxide in tetrahydrofuran, water, and/or
  • the compound of the formula (I), a pharmaceutically acceptable salt thereof, can be synthesized by a general chemical method.
  • the preparation of the salt can be carried out by reacting the free base or acid with an equivalent chemical equivalent or an excess of an acid (inorganic or organic acid) or a base (inorganic or organic base) in a suitable solvent or solvent composition.
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of the compound of the formula (I), an isomer thereof, a prodrug, a stable isotope derivative, and a pharmaceutically acceptable salt.
  • a pharmaceutically acceptable salt comprising a pharmaceutically acceptable salt.
  • compositions may also include other therapeutic agents for the treatment, amelioration and/or prevention of cancer, viral infections or autoimmune diseases.
  • the pharmaceutically acceptable excipient may include a pharmaceutically acceptable carrier, diluent, and/or excipient.
  • the pharmaceutical composition can be formulated into various types of dosage unit dosage forms, such as tablets, pills, powders, liquids, suspensions, emulsions, granules, capsules, suppositories, and injections (solutions and suspensions), etc., depending on the purpose of the treatment.
  • dosage unit dosage forms such as tablets, pills, powders, liquids, suspensions, emulsions, granules, capsules, suppositories, and injections (solutions and suspensions), etc.
  • any excipient known and widely used in the art can be used.
  • carriers such as lactose, white sugar, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose, and silicic acid; binders such as water, ethanol, propanol, ordinary syrup, dextrose solution, starch Solution, gelatin solution, carboxymethyl cellulose, shellac, methyl cellulose and potassium phosphate, polyvinylpyrrolidone, etc.
  • disintegrating agents such as dry starch, sodium alginate, agar powder and kelp powder, sodium bicarbonate, carbonic acid Fatty acid ester of calcium and polyethylene sorbitan, Sodium lauryl sulfate, monoglyceride stearate, starch and lactose; disintegration inhibitors such as white sugar, glyceryl tristearate, coconut oil and hydrogenated oil; adsorption promoters such as qua
  • any excipient known and widely used in the art may be used, for example, a carrier such as lactose, starch, coconut oil, hardened vegetable oil, kaolin and talc, etc.; Such as gum arabic powder, gum tragacanth powder, gelatin and ethanol, etc.; disintegrating agents such as agar and kelp powder.
  • a carrier such as lactose, starch, coconut oil, hardened vegetable oil, kaolin and talc, etc.
  • disintegrating agents such as agar and kelp powder.
  • any excipient known and widely used in the art can be used, for example, polyethylene glycol, coconut oil, higher alcohols, esters of higher alcohols, gelatin and semi-synthetic glycerides, etc. .
  • the solution or suspension may be sterilized (preferably by adding an appropriate amount of sodium chloride, glucose or glycerin, etc.) to prepare an isotonic injection with blood.
  • Any of the commonly used carriers in the art can also be used in the preparation of the injection.
  • water, ethanol, propylene glycol, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol, and fatty acid esters of polyethylene sorbitan can be added.
  • the content of the other therapeutic agent in the pharmaceutical composition is not particularly limited and can be selected within a wide range, and is usually from 5 to 95% by mass, preferably from 30 to 80% by mass.
  • the administration method of the pharmaceutical composition is not particularly limited.
  • Formulations of various dosage forms can be selected depending on the age, sex and other conditions and symptoms of the patient. For example, tablets, pills, solutions, suspensions, emulsions, granules or capsules are administered orally; injections can be administered alone or in combination with injectable solutions (eg, glucose solutions and amino acid solutions); suppositories are given Drug to the rectum.
  • injectable solutions eg, glucose solutions and amino acid solutions
  • suppositories are given Drug to the rectum.
  • the invention also provides the use of a compound of formula (I), an isomer thereof, a prodrug, a stable isotopic derivative or a pharmaceutically acceptable salt for the preparation of a TLRs modulator.
  • the TLRs modulator is preferably a TLRs agonist or a TLRs partial agonist.
  • the TLRs are preferably one or more of TLR7, TLR8 and TLR9.
  • the invention also provides the use of a compound of formula (I), an isomer thereof, a prodrug, a stable isotope derivative or a pharmaceutically acceptable salt for the manufacture of a medicament for modulating T cells and other immune cells.
  • the present invention also provides a compound of the formula (I), an isomer thereof, a prodrug, a stable isotope derivative or a pharmaceutically acceptable salt for the preparation, treatment and alleviation and/or prevention of a disease mediated by TLRs.
  • a medicament the present invention preferably provides a compound, an isomer, a prodrug, a stable isotope derivative or a pharmaceutically acceptable salt thereof as shown in formula (I) in the preparation of a treatment, amelioration and/or prevention
  • TLR8-mediated drugs for related diseases include tumors and non-neoplastic diseases.
  • diseases include, but are not limited to, cancer, viruses, and other infections, diseases caused by immunosuppression, and autoimmune diseases and the like.
  • the present invention preferably employs a compound of the formula (I), an isomer thereof, a prodrug, a stable isotope derivative or Use of a pharmaceutically acceptable salt for the manufacture of a medicament for the treatment and/or alleviation of cancer.
  • the cancer is preferably a cancer associated with an immunological preparation, which refers to tumor-specific immunosuppression.
  • the present invention still further provides the use of the compound of the formula (I), an isomer thereof, a prodrug, a stable isotope derivative or a pharmaceutically acceptable salt thereof for the treatment of cancer, viruses and other infections, autoimmune diseases
  • a method comprising: administering to a mammal a dose of a compound of formula (I), an isomer thereof, a prodrug, a stable isotope derivative or a pharmaceutically acceptable salt, or a pharmaceutical composition.
  • Said mammal preferably a human.
  • the present invention still further provides the compound of the formula (I), an isomer thereof, a prodrug, a stable isotopic derivative or a pharmaceutically acceptable salt, and one or more other kinds of therapeutic agents.
  • And/or therapeutic methods are used in combination to treat, ameliorate, and/or prevent related diseases mediated by TLRs, particularly related diseases mediated by TLR8.
  • the TLR8-mediated related disease refers to a disease caused by TLR8-mediated immunosuppression, which may include cancer, viral infection, inflammation, autoimmune disease, transplant rejection, transplant-versus-host disease, and the like. .
  • the present invention preferably uses the compound of the formula (I), an isomer thereof, a prodrug, a stable isotope derivative or a pharmaceutically acceptable salt thereof, and one or more other kinds of therapeutic agents and/or Or a method of treatment in combination for treating and/or ameliorating a disease mediated by tryptophan TLR8, preferably a cancer.
  • the other kind of therapeutic agent for example, other kinds of therapeutic agents for treating cancer
  • the viral infection may include: from influenza virus, Sendai virus, Coxsackie virus, dengue virus, Newcastle disease virus (NDV), vesicular stomatitis virus (VSV), hepatitis C virus (HCV), human papillary Infections caused by viruses such as neoplastic virus (HPV), cytomegalovirus (CMV), Epstein-Barr virus (EBV), poliovirus, varicella-zoster virus, or human immunodeficiency virus type I (HIV).
  • influenza virus Sendai virus, Coxsackie virus, dengue virus, Newcastle disease virus (NDV), vesicular stomatitis virus (VSV), hepatitis C virus (HCV), human papillary Infections caused by viruses such as neoplastic virus (HPV), cytomegalovirus (CMV), Epstein-Barr virus (EBV), poliovirus, varicella-zoster virus, or human immunodeficiency virus type I (HIV).
  • the cancers include metastatic and non-metastatic cancers, as well as familial hereditary and sporadic cancers, and may also include solid tumors and non-solid tumors.
  • the solid tumor may include, but are not limited to, eye cancer, bone cancer, lung cancer, stomach cancer, pancreatic cancer, breast cancer, prostate cancer, brain cancer (including malignant glioma, medulloblastoma), ovary Cancer, bladder cancer, cervical cancer, testicular cancer, kidney cancer (including adenocarcinoma and nephroblast cancer), oral cancer (including squamous cell carcinoma), tongue cancer, laryngeal cancer, nasopharyngeal cancer, head and neck cancer, colon cancer
  • small bowel cancer rectal cancer, parathyroid cancer, thyroid cancer, esophageal cancer, gallbladder cancer, cholangiocarcinoma, cervical cancer, liver cancer, lung cancer, sarcoma, and skin cancer.
  • non-solid tumors may include, but are not limited to, lymphocytic leukemia (including acute lymphocytic leukemia, lymphoma, myeloma, chronic lymphocytic leukemia, Hodgkin's lymphoma, non-Hodge One or more of gold lymphoma, T cell chronic lymphocytic leukemia, B cell chronic lymphocytic leukemia, myeloid associated leukemia (including acute myelogenous leukemia, chronic myelogenous leukemia), and AIDs-associated leukemia.
  • lymphocytic leukemia including acute lymphocytic leukemia, lymphoma, myeloma, chronic lymphocytic leukemia, Hodgkin's lymphoma, non-Hodge
  • T cell chronic lymphocytic leukemia B cell chronic lymphocytic leukemia
  • myeloid associated leukemia including acute myelogenous leukemia, chronic myelogenous
  • the autoimmune diseases may include, but are not limited to, rheumatoid arthritis, systemic lupus erythematosus, mixed connective tissue disease (MCTD), systemic scleroderma (including: CREST syndrome), dermatomyositis, knot Segmental vasculitis, Nephropathy (including: pulmonary hemorrhagic nephritis syndrome, acute glomerulonephritis, primary proliferative glomerulonephritis, etc.), endocrine-related diseases (including: type I diabetes, gonadal insufficiency, pernicious anemia, hyperthyroidism) Etiology, liver disease (including: primary biliary cirrhosis, autoimmune cholangitis, autoimmune hepatitis, primary sclerosing cholangitis, etc.) and autoimmune reactions due to infection (eg AIDS, malaria, etc.) One or more of them.
  • MCTD mixed connective tissue disease
  • the term "optionally substituted by one or more groups at any position" means that any one or more of the hydrogen atoms of the one or more atoms specified on the group are designated by The group is substituted, provided that it does not exceed the normal valence of the specified atom, which is a reasonable substitution that is common in the art at any position.
  • a chemical bond indicates that the chemical structure indicated by a broken line means that the bond is optionally present or absent.
  • a dashed line drawn next to a solid single button indicates that the key can be a single key or a double key.
  • alkyl refers to a saturated straight or branched chain hydrocarbon group containing from 1 to 20 carbon atoms, preferably from 1 to 10 carbon atoms, more preferably from 1 to 8, 1 to 1, and from 1 to 3 carbons.
  • Representative examples of atoms, alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, isobutyl, pentyl, hexyl, heptyl , octyl, decyl, decyl, 4,4-dimethylpentyl, 2,2,4-trimethylpentyl, undecyl, dodecyl, and various isomers thereof Wait.
  • alkyl When “alkyl” is used as a linking group for other groups, such as -(CH 2 ) m -, it may be a branched or branched chain, and examples include, but are not limited to, -CH 2 -, -CH 2 CH 2 -, -CH 2 CH(CH 3 )-.
  • cycloalkyl refers to a monocyclic or polycyclic group containing from 3 to 20 carbon atoms which is saturated or partially unsaturated (comprising 1 or 2 double bonds).
  • “monocyclic cycloalkyl” is preferably a 3-10 membered monocycloalkyl group, more preferably a 3-8 membered monocycloalkyl group, for example: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, ring Octyl, cyclodecyl, cyclododecyl, cyclohexenyl.
  • Polycyclic cycloalkyl includes “bridged ring”, “fused cycloalkyl” and “spirocycloalkyl”, and representative examples of “bridged ring” include, but are not limited to, borneol, 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] nonylalkyl, bicyclo[4.2.1]nonanyl and adamantyl, and the like.
  • Fused cycloalkyl embraces a cycloalkyl ring fused to a phenyl, cycloalkyl or heteroaryl group, including but not limited to: benzocyclobutene, 2,3-dihydro 1-H-oxime, 2,3-cyclopentenopyridine, 5,6-dihydro-4H-cyclopentyl[B]thiophene, decalin and the like.
  • a monocyclic cycloalkyl or polycyclic cycloalkyl group can be attached to the parent molecule through any carbon atom on the ring.
  • heterocycloalkyl refers to a non-aromatic cyclic group consisting of a carbon atom and a heteroatom consisting of a hetero atom selected from nitrogen, oxygen or sulfur, including one or two double bonds, which is a cyclic group.
  • the group may be a monocyclic or polycyclic group, and in the present invention, the number of hetero atoms in the heterocycloalkyl group is preferably 1, 2, 3 or 4, and the nitrogen, carbon or sulfur atom in the heterocycloalkyl group may optionally be Oxidized.
  • the nitrogen atom can optionally be further substituted with other groups to form a tertiary or quaternary ammonium salt.
  • the "monocyclic heterocycloalkyl group” is preferably a 3-10 membered monocyclic heterocycloalkyl group, more preferably a 3-8 membered monocyclic heterocycloalkyl group.
  • monocyclic heterocycloalkyl group is preferably a 3-10 membered monocyclic heterocycloalkyl group, more preferably a 3-8 membered monocyclic heterocycloalkyl group.
  • aziridine tetrahydrofuran-2-yl, morpholin-4-yl, thiomorpholin-4-yl, thiomorpholine-S-oxide-4-yl, piperidin-1-yl, N-alkylpiperidin-4-yl, pyrrolidin-1-yl, N-alkylpyrrolidin-2-yl, piperazin-1-yl, 4-alkylpiperazin-1-yl and the like.
  • Polycycloheterocycloalkyl includes “Fused heterocycloalkyl”, “spiroheterocyclyl” and “bridge heterocycloalkyl”.
  • “Fused heterocycloalkyl” includes a monocyclic heterocycloalkyl ring fused to a phenyl, cycloalkyl, heterocycloalkyl or heteroaryl group, including but not limited to: 2,3 - dihydrobenzofuranyl, 1,3-dihydroisobenzofuranyl, indanyl, 2,3-dihydrobenzo[b]thienyl, dihydrobenzopyranyl, 1, 2,3,4-tetrahydroquinolyl and the like.
  • Monocyclic heterocycloalkyl and polycyclic heterocycloalkyl groups can be attached to the parent molecule through any ring atom on the ring.
  • the above ring atoms specifically refer to carbon atoms and/or nitrogen atoms constituting the ring skeleton.
  • cycloalkylalkyl refers to a linkage between a cycloalkyl group and a parent core structure through an alkyl group.
  • cycloalkylalkyl embraces the definitions of alkyl and cycloalkyl as described above.
  • heterocycloalkylalkyl refers to an alkyl linkage between a heterocycloalkyl group and a parent core structure.
  • heterocycloalkylalkyl embraces the definitions of alkyl and heterocycloalkyl as described above.
  • alkoxy refers to a cyclic or acyclic alkyl group having the number of carbon atoms attached through an oxygen bridge, and includes an alkyloxy group, a cycloalkyloxy group, and a heterocycloalkyloxy group.
  • alkoxy includes the definitions of alkyl, heterocycloalkyl and cycloalkyl as described above.
  • hydroxyalkyl means an alkyl arbitrary one hydrogen atom is substituted with 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.
  • alkenyl refers to a straight, branched or cyclic non-aromatic hydrocarbon radical containing at least one carbon to carbon double bond. There may be from 1 to 3 carbon-carbon double bonds, preferably one carbon-carbon double bond.
  • C2-4 alkenyl refers to an alkenyl group having 2 to 4 carbon atoms
  • C2-6 alkenyl refers to an alkenyl group having 2 to 6 carbon atoms, including vinyl and propenyl. , butenyl, 2-methylbutenyl and cyclohexenyl.
  • the alkenyl group may be substituted.
  • alkynyl refers to a straight, branched or cyclic hydrocarbon radical containing at least one carbon to carbon triple bond. There may be 1-3 carbon-carbon triple bonds, preferably one carbon-carbon triple bond.
  • C 2-6 alkynyl refers to an alkynyl group having 2 to 6 carbon atoms, and includes ethynyl, propynyl, butynyl and 3-methylbutynyl.
  • aryl refers to any stable 6-20 membered monocyclic or polycyclic aromatic group such as phenyl, naphthyl, tetrahydronaphthyl, indanyl or biphenyl. .
  • heteroaryl refers to an aromatic ring radical formed by the replacement of a carbon atom on at least one ring with a heteroatom selected from nitrogen, oxygen or sulfur, which may be a 5-7 membered monocyclic structure or 7-20.
  • a fused ring structure preferably a 5-6 membered heteroaryl group.
  • the number of hetero atoms is preferably 1, 2 or 3, and includes: pyridyl, pyrimidinyl, piperazinyl, pyridazine-3(2H)-one, 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, tetrazolyl, oxazolyl, isoxazolyl, fluorenyl, Isoindolyl, benzofuranyl, benzothienyl, benzo[d][1,3]dioxolanyl, benzothiazolyl, benzoxazolyl, quinolyl, isoquino
  • heterocyclic group means a concentric ring structure in which two, three or four cyclic structures share two adjacent atoms, and each ring of the ring structure may be a monocyclic aryl group, a single ring. Heteroaryl, monocyclic cycloalkyl or monocyclic heterocycloalkyl.
  • the paracyclic group referred to in the present invention is a saturated, unsaturated or partially saturated concentric ring structure, and preferably at least one ring is an aromatic ring. More preferably, a bicyclic or tricyclic cyclylene group, and at least one ring is an aromatic ring.
  • the non-aromatic ring in the cyclized group may further comprise 1 to 2 oxo or thio groups.
  • the cyclo-group is 8-20 members, preferably 8-15 members, and a cyclic group.
  • Specific examples of the cis-ring group include, but are not limited to, benzocyclobutenyl, 2,3-dihydro-1-H-indenyl, 1,2,3,4-tetrahydronaphthyl, 6,7 , 8,9-tetrahydro-5H-benzo[7]-alkenyl, 6,9-dihydro-5H-benzo[7]-alkenyl, 5,6,7,8,9,10-six Hydrobenzo[8]alkenyl, 2,3-cyclopentenyridyl, 5,6-dihydro-4H-cyclopentyl[B]thienyl, 5,6-dihydro-4H-cyclopentyl a base [B]furanyl, 2,3-dihydro
  • aromatic ring includes “aromatic ring” and “heteroaryl ring”.
  • arylalkyl refers to an alkyl linkage between the aryl group and the parent core structure.
  • arylalkyl embraces the definition of alkyl and aryl as defined above.
  • heteroarylalkyl refers to an alkyl linkage between a heterocycloalkyl group and a parent core structure.
  • heteroarylalkyl Contains the definitions of the above alkyl and heteroaryl groups.
  • halogen means fluoro, chloro, bromo or iodo.
  • haloalkyl refers to an alkyl group optionally substituted by halogen.
  • haloalkyl embraces the definitions of the above halo and alkyl.
  • haloalkoxy refers to an alkoxy group optionally substituted by halogen.
  • haloalkoxy includes the definitions of the above halo and alkoxy.
  • amino means -NH 2
  • alkylamino refers to at least one hydrogen atom is substituted with alkyl amino group, including but not limited to: -NHCH 3, -N (CH 3 ) 2, -NHCH 2 CH 3 , -N(CH 2 CH 3 ) 2 .
  • aminoalkyl means that any one of the hydrogen atoms on the alkyl group is replaced by an amino group, including but not limited to: -CH 2 NH 2 , -CH 2 CH 2 NH 2 .
  • aminoalkyl and alkylamino embrace the definition of alkyl and amino as defined above.
  • nitro refers to -NO 2 .
  • cyano refers to -CN.
  • Root temperature as used herein means 15-30 °C.
  • the isotope-substituted derivative includes an isotope-substituted derivative obtained by substituting any hydrogen atom of the formula I with 1-5 deuterium atoms, and an isotope obtained by substituting any carbon atom of the formula I with 1-3 carbon atoms and 14 atoms.
  • prodrug is meant that the compound is converted to the original active compound after metabolism in the body. Typically, the prodrug is inactive or less active than the active parent compound, but can provide convenient handling, administration or improved metabolic properties.
  • “Pharmaceutically acceptable salts” as described herein are discussed in Berge, et al., “Pharmaceutically acceptable salts", J. Pharm. Sci., 66, 1-19 (1977), and for pharmaceutical chemists It is apparent that the salts are substantially non-toxic and provide the desired pharmacokinetic properties, palatability, absorption, distribution, metabolism or excretion, and the like.
  • the compounds of the present invention may have an acidic group, a basic group or an amphoteric group, and typical pharmaceutically acceptable salts include those prepared by reacting a compound of the present invention with an acid, for example, hydrochloride, hydrobromic acid Salt, sulfate, pyrosulfate, hydrogen sulfate, sulfite, bisulfite, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate, nitrate, acetate, Propionate, citrate, octanoate, formate, acrylate, isobutyrate, hexanoate, heptanoate, oxalate, malonate, succinate, suberate, Benzoate, methyl benzoate, phthalate, maleate, methanesulfonate, p-toluenesulfonate, (D,L)-tartaric acid, citric acid, maleic acid, (D,
  • the pharmaceutically acceptable salt thereof may further include: an alkali metal salt such as a sodium or potassium salt; an alkaline earth metal salt such as a calcium or magnesium salt; an organic base salt such as ammonia and an alkane A salt formed from a base such as a hydroxyalkylamine, an amino acid (lysine, arginine) or N-methylglucamine.
  • an alkali metal salt such as a sodium or potassium salt
  • an alkaline earth metal salt such as a calcium or magnesium salt
  • an organic base salt such as ammonia and an alkane A salt formed from a base such as a hydroxyalkylamine, an amino acid (lysine, arginine) or N-methylglucamine.
  • “isomer” means that the compound of formula (I) of the present invention may have asymmetric centers and racemates, racemic mixtures and individual diastereomers, all of which include Stereoisomers, geometric isomers are all included in the present invention.
  • a compound of the formula I or a salt thereof, in stereoisomeric form is a single stereoisomer (enantiomer and diastereomer). Isomers) and mixtures thereof are included within the scope of the invention.
  • the invention also includes individual isomers of the compound or salt represented by Formula I, as well as mixtures with isomers in which one or more chiral centers are inverted.
  • the scope of the invention includes: mixtures of stereoisomers, as well as purified enantiomers or enantiomerically/diastereomerically enriched mixtures.
  • the invention includes mixtures of stereoisomers of all possible different combinations of all enantiomers and diastereomers.
  • the invention includes all combinations and subsets of stereoisomers of all the specific groups defined above.
  • the invention also includes geometric isomers of a compound of formula I or a salt thereof, including cis-isomers.
  • the reagents and starting materials used in the present invention are commercially available.
  • the structures of all compounds of the invention can be identified by nuclear magnetic resonance ( 1 H NMR) and/or mass spectrometry (MS).
  • All of the compounds of the present invention can be separated by high performance liquid chromatography, silica gel column chromatography or flash column chromatography.
  • High performance liquid chromatography was prepared using Shimadzu LC-20 preparative liquid chromatography column: waters xbridge Pre C18, 10 um, 19 mm * 250 mm.
  • Preparation conditions mobile phase A: 0.05% aqueous solution of trifluoroacetic acid (percentage by volume), mobile phase B: acetonitrile; gradient elution conditions: 25-75% solvent A and 75%-25% solvent B; detection wavelength: 214 nm And/or 254 nm, and/or 262 nm; flow rate: 10.0 mL/min.
  • Flash column chromatography Flash column chromatography (Flash column chromatography) (flash system / Cheetah TM) using Agela Technologies MP200, supporting the use of a separation column for Flash columm Silica-CS (80g) , Cat No.CS140080-0.
  • the thin layer chromatography is Yantai Xinnuo Chemical Co., Ltd.
  • the coating thickness is 0.2 ⁇ 0.03mm and the specification is 20 ⁇ 20cm.
  • Column chromatography generally uses Yantai Yellow Sea 200-300 mesh silica gel as a carrier.
  • Step 8 Synthesis of Compound 1.8
  • Step 4 Synthesis of Compound 2.4
  • compound 2.3 1.0 g, 3.93 mmol
  • sodium periodate 2.5 g, 11.8 mmol
  • the insoluble material was filtered, and the filtrate was evaporated to ethyl acetate. EtOAc was evaporated. 5/1)
  • Compound 2.4 200 mg, 22.0% was obtained as a pale yellow solid.
  • N-bromosuccinimide (960 mg, 5.38 mmol) was added portionwise to a solution of compound 3.1 (1.0 g, 5.12 mmol) in tetrahydrofuran (10 mL).
  • Ethoxyformylmethylenetriphenylphosphine (537 g, 1.54 mmol) was added portionwise to compound 3.3 (145 mg, 0.77 mmol) in THF (10 mL). The reaction was stirred at room temperature for 2 days until the reaction was completed by TLC, and water (30 mL) was added to the reaction mixture to quench the mixture, and the mixture was extracted with ethyl acetate (20 mL ⁇ 2). The organic phase was combined and the organic phase was washed with EtOAc EtOAc (EtOAc m. 3.4 (200 mg, yield: 100%) was an off-white solid.
  • Step 8 Synthesis of Compound 3.8
  • NBS 350 mg, 1.96 mmol
  • azobisisobutyronitrile 100 mg, 0.65 mmol
  • the reaction system was heated to 80 ° C and stirred for 2 hours, then cooled to room temperature, filtered, and the filtrate was washed with brine brine, Filtration and concentration gave Compound 5.2 (300 mg, yield: 75%) as a red oil.
  • Compound 19.2 was synthesized according to the method for synthesizing compound 19.1 of Example 22, which was obtained by replacing compound 16.10 with compound 16.29.
  • Oxalyl chloride (0.81 g, 6.39 mmol) was added to dichloromethane (20 mL), followed by two portions of N,N-dimethylformamide and stirred at room temperature for 15 min.
  • Compound 28.1 (1.15 g, 3.19 mmol) dissolved in dichloromethane (20 mL) was then added dropwise to the system. After stirring at room temperature for 40 minutes, it was concentrated under reduced vacuo.
  • Trifluoroacetic acid (2 mL) was added dropwise to a solution of the compound 1-1-1 (20 mg, 0.04 mmol) in dichloromethane (2 mL), and the mixture was stirred at 0 ° C for 20 min. The solvent was evaporated under reduced pressure. EtOAcqqqqqm
  • Trifluoroacetic acid (1.5 mL) was added dropwise to a solution of Compound 2-1 (100 mg, 0.15 mmol) in dichloromethane (3.0 mL), and the mixture was stirred at room temperature for 1.5 hours. The organic layer was concentrated under reduced pressure.
  • Compound 1-2 was synthesized according to the synthesis of Compound 1-1 of Example 43 using starting materials 1.20 and 16.4.
  • Trifluoroacetic acid (1 mL) was added dropwise to a solution of Compound 2-1 (35 mg, 0.07 mmol) in dichloromethane (1 mL), and the mixture was stirred at 20 ° C for 2 hours. The reaction mixture was quenched with water (10 mL), EtOAc (EtOAc)EtOAc. The residue obtained was purified by prep-HPLC to give Compound 2-1-1 (15 mg, yield: 55%) as white solid.
  • the TLR8 biological activity assay of a compound of formula I was tested using a cellular assay.
  • the method is carried out in human embryonic kidney cells (HEK293) expressing TLR8 or other TLR family members such as TLR4, TLR7 and TLR9.
  • TLR agonist activates TLR, it activates downstream NF-kB activation, thereby activating secretory embryonic alkaline phosphate.
  • SEAP secreted embryonic alkaline phosphatase reporter gene was assayed for activity of TLR8 agonist by detecting the SEAP activity using Quanti-Blue (InvivoGen) reagent.
  • HEK-BLUE-hTLR8 cell line was purchased from Invivogen and cultured in DMEM medium containing 4.5 g/L glucose (Sigma-Aldrich) and 10% fetal bovine serum at 37 ° C, 95% humidity and 5%. CO 2 .
  • the cells were treated as follows: The cells were removed from the culture dish and centrifuged to remove the medium, resuspended in T-150 flasks with 10 mL of pre-warmed PBS, and 12 mL of pre-warmed medium was added, gently pipetted up and down, and counted under a microscope. Immediately, 200,000 cells/mL of single cell suspension was prepared using the medium, and 200 ⁇ L/well (40,000 cells/well) was added to the 96-well plate. The final concentration of DMSO was 0.5%.
  • the compound was added and incubated for 24 hours at 37 ° C in a 5% CO 2 incubator.
  • Effect% (OD value of the administration group - OD value of the DMSO group) / (OD value of the positive drug group - average value of the DMSO group) ⁇ 100
  • the concentration-effect curve was fitted using Graphpad software and the EC50 was calculated.
  • TLR7 biological activity assay of a compound of formula I was tested using a cellular assay.
  • the method is carried out in human embryonic kidney cells (HEK293) expressing TLR7 or other TLR family members such as TLR4, and TLR9.
  • TLR agonist activates TLR, it activates downstream NF-kB activation, thereby activating secreted embryonic alkaline phosphatase. (secreted embryonic alkaline phosphatase, SEAP) reporter gene, which uses SEATI-Blue (InvivoGen) reagent to detect SEAP activity, thereby reflecting the activity of TLR7 agonist.
  • SEAP secreted embryonic alkaline phosphatase reporter gene, which uses SEATI-Blue (InvivoGen) reagent to detect SEAP activity, thereby reflecting the activity of TLR7 agonist.
  • HEK-BLUE-hTLR7 cell line was purchased from Invivogen and cultured in DMEM medium containing 4.5 g/L glucose (Sigma-Aldrich) and 10% fetal bovine serum at 37 ° C, 95% humidity and 5%. CO 2 .
  • Compounds were tested at concentrations ranging from 1.5 nM to 50 [mu]M for a total of 10 concentration gradients.
  • a known active TLR7 agonist was added as a positive control, and 1 ⁇ L of DMSO was used as a negative control.
  • the cells were treated as follows: The cells were removed from the culture dish and centrifuged to remove the medium, resuspended in T-150 flasks with 10 mL of pre-warmed PBS, and 12 mL of pre-warmed medium was added, gently pipetted up and down, and counted under a microscope. Immediately, 200,000 cells/mL of single cell suspension was prepared using the medium, and 200 ⁇ L/well (40,000 cells/well) was added to the 96-well plate. The final concentration of DMSO was 0.5%.
  • the compound was added and incubated for 24 hours at 37 ° C in a 5% CO 2 incubator.
  • Effect% (OD value of the administration group - OD value of the DMSO group) / (OD value of the positive drug group - average value of the DMSO group) ⁇ 100
  • the concentration-effect curve was fitted using Graphpad software and the EC50 was calculated.
  • TLR7 and TLR8EC 50 values reported was: - indicates >50 ⁇ M, -- indicates 10-50 ⁇ M, + indicates 1-10 ⁇ M, ++ indicates 0.1-1 ⁇ M, +++ indicates ⁇ 0.1 ⁇ M, / indicates no determination.
  • VTX-2337 (motolimod)
  • the chemical name is: 2-amino-N,N-dipropyl-8-(4-(pyrrolidin-1-carbonyl)phenyl)-3H-benzo[ b] azepine-4-carboxamide.

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Abstract

本发明公开了一种苯并氮杂卓衍生物、其制备方法、药物组合物及应用。本发明所述的如式(I)所示化合物、其异构体、前药、稳定的同位素衍生物或药学上可接受的盐具有如下结构。本发明的苯并氮杂卓衍生物对TLR家族以及相关的信号通路具有良好的调节作用，尤其对TLR8有很好的调节作用，可以有效治疗、缓解和/或预防与TLR家族以及TLR相关的信号通路介导的各种疾病，特别是可以有效治疗、缓解和/或预防TLR8介导的各种疾病，例如癌症、自身免疫类疾病、感染、炎症、移植排斥、移植物抗宿主病等。

Description

苯并氮杂卓衍生物、其制备方法、药物组合物及应用
本申请要求申请日为2016年5月6日的中国专利申请CN201610296748.X、申请日为2016年7月25日的中国专利申请CN201610589219.9、申请日为2016年11月4日的中国专利申请CN201610965360.4、申请日为2017年1月12日的中国专利申请CN201710020298.6和申请日为2017年1月24日的中国专利申请CN201710054038.0的优先权。本申请引用上述中国专利申请的全文。
技术领域
本发明涉及一种苯并氮杂卓衍生物、其制备方法、药物组合物及应用。
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-κB。
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 Immunopharmacol2002；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)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。
TLR8蛋白的X-射线晶型结构及与其相关的TLR家族成员已被深入研究，这将进一步促进基于结构的药物设计及优化。
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在于，提供了一种新型苯并氮杂卓衍生物、其制备方法、药物组合物及应用。本发明的苯并氮杂卓衍生物对TLRs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、自身免疫类疾病、感染、炎症、移植排斥、移植物抗宿主病等。
本发明提供了一种如式(I)所示化合物、其异构体、前药、稳定的同位素衍生物或药学上可接受的盐；
Figure PCTCN2017083031-appb-000001
其中，
L为-C(O)-、-C(S)-或-S(O)2-；
L1为连接键、C2-6亚烯基、C2-6亚炔基、-(CRaRb)m-、-(CRaRb)uO(CRaRb)v-、-(CRaRb)uC(O)(CRaRb)v-、-(CRaRb)uC(O)O(CRaRb)v-、-(CRaRb)uOC(O)(CRaRb)v-、-(CRaRb)uN(Rc)C(O)(CRaRb)v-、-(CRaRb)uC(O)N(Rc)(CRaRb)v-、-(CRaRb)uN(Rc)C(O)N(Rc)(CRaRb)v-、-(CRaRb)uC(S)(CRaRb)v、-(CRaRb)uS(O)0-2(CRaRb)v、-(CRaRb)uS(O)1-2N(Rc)(CRaRb)v、-(CRaRb)uN(Rc)S(O)2N(Rc)(CRaRb)v或-(CRaRb)uN(Rc)S(O)1-2(CRaRb)v；每个u独立地为0、1、2或3；每个v独立地为0、1、2或3；m为1、2、3、4、5或6；
R选自二环、三环或四环并环基团，所述并环基团为未取代或者选择性地被如下一个或多个基团取代在任意位置：卤素、烷基、卤代烷基、卤代烷氧基、烯基、炔基、Cy1、-L2-Cy1、-CN、-NO2、-SRd、-ORd、-OC(O)Rd、-OC(O)ORd、-OC(O)NRdRe、-C(O)ORd、-C(O)Rd、-C(O)NRdRe、-C(O)N(Rd)ORe、-C(O)NRdS(O)2Re、-C(＝NH)Re、-C(＝NH)NRdRe、-NRdRe、-NRdC(O)Re、-N(Rd)C(O)ORe、-N(Rd)C(O)NRdRe、-NRdS(O)2Re、-NRdC(＝NH)Re、-NRdC(＝NH)NRdRe、-S(O)1-2Re、-S(O)2NRdRe和-NRdS(O)2NRdRe；其中所述烷基、烯基或炔基为未取代或者选择性地被如下一个或多个取代基取代在任意位置：-CN、-NO2、-SRd、-ORd、-OC(O)Rd、-OC(O)ORd、-OC(O)NRdRe、-C(O)ORd、-C(O)Rd、-C(O)NRdRe、-C(O)NRdS(O)2Re、-NRdRe、-NRdC(O)Re、-N(Rd)C(O)ORe、-N(Rd)C(O)NRdRe、-NRdC(＝NH)Re、-NRdC(＝NH)NRdRe、-NRdS(O)2Re、-NRdS(O)2NRdRe、-N(Rd)C(O)N(Rd)S(O)2Re、-S(O)1-2Re、-S(O)2NRdRe、-S(O)(＝NCN)Re、-S(O)(＝NRd)Re、-S(O)(＝NSO2Rd)Re、-S(O)2N(Rd)C(O)Re、-S(O)2N(Rd)C(O)NRdRe、-P(O)(ORd)2、-OP(O)(ORd)2或-B(ORd)2；
L2为连接键、C2-6亚烯基、C2-6亚炔基、-(CRa1Rb1)m-、-(CRa1Rb1)uO(CRa1Rb1)v-、-(CRa1Rb1)uC(O)(CRa1Rb1)v-、-(CRa1Rb1)uC(O)O(CRa1Rb1)v-、-(CRa1Rb1)uOC(O)(CRa1Rb1)v-、-(CRa1Rb1)uN(Rc1)C(O)(CRa1Rb1)v-、-(CRaRb)uC(O)N(Rc1)(CRa1Rb1)v-、-(CRa1Rb1)uN(Rc)C(O)N(Rc1)(CRa1Rb1)v-、-(CRa1Rb1)uC(S)(CRa1Rb1)v、-(CRa1Rb1)uS(O)0-2(CRa1Rb1)v、-(CRa1Rb1)uS(O)1-2N(Rc1)(CRa1Rb1)v、-(CRa1Rb1)uN(Rc1)S(O)2N(Rc1)(CRa1Rb1)v或-(CRa1Rb1)uN(Rc1)S(O)1-2(CRa1Rb1)v；每个u独立地为0、1、2或3；每个v独立地为0、1、2或3；m为1、2、3、4、5或6；
每个Cy1独立地为环烷基、杂环烷基、芳基或者杂芳基；所述Cy1为未取代或者选 择性地被如下一个或多个基团取代在任意位置：卤素、烷基、卤代烷基、卤代烷氧基、羟基烷基、氨基烷基、烯基、炔基、-CN、-NO2、-SRd2、-ORd2、-OC(O)Rd2、-OC(O)ORd2、-OC(O)NRd2Re2、-C(O)ORd2、-C(O)Rd2、-C(O)NRd2Re2、-NRd2Re2、-NRd2C(O)Re2、-N(Rd2)C(O)ORe2、-N(Rd2)C(O)NRd2Re2、-NRd2S(O)2Re2、-NRd2C(＝NH)Re2、-NRd2C(＝NH)NRd2Re2、-S(O)1-2Re2、-S(O)2NRd2Re2和-NRd2S(O)2NRd2Re2；
R1、R2和R3分别独立地选自氢、氘、烷基、烯基、炔基、环烷基、杂环烷基、芳基、和杂芳基，所述烷基、烯基、炔基、环烷基、杂环烷基、芳基或杂芳基为未取代或者选择性地被如下1～3个基团取代在任意位置：卤素、烷基、卤代烷基、卤代烷氧基、羟基烷基、氨基烷基、烯基、炔基、-CN、-NO2、-SRd2、-ORd2、-OC(O)Rd2、-OC(O)ORd2、-OC(O)NRd2Re2、-C(O)ORd2、-C(O)Rd2、-C(O)NRd2Re2、-NRd2Re2、-NRd2C(O)Re2、-N(Rd2)C(O)ORe2、-N(Rd2)C(O)NRd2Re2、-NRd2S(O)2Re2、-NRd2C(＝NH)Re2、-NRd2C(＝NH)NRd2Re2、-S(O)1-2Re2、-S(O)2NRd2Re2和-NRd2S(O)2NRd2Re2；
或者，R2和R3与它们共同连接的C原子一起形成C3-8环烷基或3-8元的杂环烷基；所述C3-8环烷基或3-8元的杂环烷基为未取代或者选择性地被如下1～3个基团取代在任意位置：卤素、烷基、卤代烷基、卤代烷氧基、羟基烷基、氨基烷基、烯基、炔基、-CN、-NO2、-SRd2、-ORd2、-OC(O)Rd2、-OC(O)ORd2、-OC(O)NRd2Re2、-C(O)ORd2、-C(O)Rd2、-C(O)NRd2Re2、-NRd2Re2、-NRd2C(O)Re2、-N(Rd2)C(O)ORe2、-N(Rd2)C(O)NRd2Re2、-NRd2S(O)2Re2、-NRd2C(＝NH)Re2、-NRd2C(＝NH)NRd2Re2、-S(O)1-2Re2、-S(O)2NRd2Re2和-NRd2S(O)2NRd2Re2；
R4、R5和R6分别独立地选自氢、氘、卤素、氨基、氰基、硝基、C1-6烷基、卤代C1-6烷基、卤代C1-6烷氧基、C1-6烷氧基、C2-6烯基、C2-6炔基、羟基C1-6烷基C3-8环烷基、3-8元杂环烷基、苯基或5-6元杂芳基；
RA选自-ORd1或-NRd1Re1；
RB选自-NRd1Re1；
每个Ra、每个Rb、每个Ra1和每个Rb1分别独立地选自氢、氘、卤素、C1-6烷基、C1-6烷氧基、C2-6烯基、C2-6炔基、C3-8环烷基、3-8元杂环烷基、C6-10芳基、5-6元杂芳基、C3-8环烷基C1-6烷基、3-8元杂环烷基C1-6烷基、苯基C1-6烷基或5-6元杂芳基C1-6烷基；所述C1-6烷基、C1-6烷氧基、C2-6烯基、C2-6炔基、C3-8环烷基、3-8元杂环烷基、C6-10芳基或5-6元杂芳基为未取代或者选择性地被1～3个选自卤素、羟基、氨基、羧基、C2-6烯基、C2-6炔基、C1-6烷基、卤代C1-6烷基、C1-6烷氧基和卤代C1-6烷氧基中的一种或多种取代基取代在任意位置；
或者，Ra和Rb、或Ra1和Rb1与它们共同连接的C原子一起形成C3-8环烷基或3-8元杂环烷基；
每个Rc和每个Rc1分别独立地选自氢、C1-4烷基、C3-8环烷基或3-8元杂环烷基；
每个Rd、每个Re、每个Rd1和每个Re1分别独立地选自氢、C1-6烷基、C2-6烯基、C2-6炔基、C3-8环烷基、3-8元杂环烷基、C6-10芳基、5-6元杂芳基、C3-8环烷基C1-6烷基、3-8元杂环烷基C1-6烷基、苯基C1-6烷基或5-6元杂芳基C1-6烷基；所述Rd、Re、Rd1或Re1为未取代或者选择性地被1～3个选自卤素、羟基、氨基、羧基、C1-6烷基、C1-6烷氧基、C1-6烷氨基、卤代C1-6烷基、卤代C1-6烷氧基、C2-6烯基和C2-6炔基中的一种或多种取代基取代在任意位置；
或者，Rd和Re、或Rd1和Re1与它们共同连接的N原子一起形成3-8元的杂环烷基；所述杂环烷基还可以进一步含有1～3个选自N、O、S的杂原子；所述杂环烷基为未取代或者进一步被1～3个选自卤素、氨基、羟基、羧基、氰基、C1-6烷基、卤代C1-6烷基、C2-6烯基、C2-6炔基、C1-3烷基、氨基C1-3烷基、-ORd2、-OC(O)Rd2、-OC(O)ORd2、-OC(O)NRd2Re2、-C(O)ORd2、-C(O)Rd2、-C(O)NRd2Re2、-NRd2Re2、-NRd2C(O)Re2、-N(Rd2)C(O)ORe2、-N(Rd2)C(O)NRd2Re2、-NRd2S(O)2Re2、-NRd2C(＝NH)Re2、-NRd2C(＝NH)NRd2Re2、-NRd2S(O)2NRd2Re2、-S(O)1-2Rd2和-S(O)2NRd2Re2中的一种或多种取代基取代在任意位置；
每个Rd2和每个Re2分别独立地选自氢、C1-6烷基、C2-6烯基、C2-6炔基、C3-8环烷基、3-8元杂环烷基、C6-10芳基、5-6元杂芳基、C3-8环烷基C1-6烷基、3-8元杂环烷基C1-6烷基、苯基C1-6烷基或5-6元杂芳基C1-6烷基；所述Rd2或Re2为未取代或者选择性地被1～3个选自卤素、羟基、氨基、羧基、C1-6烷基、C1-6烷氧基、C1-6烷氨基、卤代C1-6烷基、卤代C1-6烷氧基、C2-6烯基和C2-6炔基中的一种或多种取代基取代在任意位置；或者，Rd2和Re2与它们共同连接的N原子一起形成3-8元杂环烷基。
在本发明一优选实施方案中，所述L优选为-C(O)-或-S(O)2-；所述R优选为前述R定义中除-C(O)N(Rd)ORe以外的基团，其中R中所述烷基、烯基或炔基为未取代或者选择性地被前述取代基定义中的除-P(O)(ORd)2、-OP(O)(ORd)2和-B(ORd)2以外的一个或多个取代基取代在任意位置。
在本发明一优选实施方案中，所述L优选为-C(O)-；所述R优选为前述R定义中除-C(O)N(Rd)ORe以外的基团，其中R中所述烷基、烯基或炔基为未取代或者选择性地被前述取代基定义中的除-S(O)(＝NCN)Re、-S(O)(＝NRd)Re、-S(O)(＝NSO2Rd)Re、-P(O)(ORd)2、-OP(O)(ORd)2和-B(ORd)2以外的一个或多个取代基取代在任意位置。
在本发明一优选实施方案中，所述L1优选为连接键、-CH2、-O-、-NH-、-OCH2-或-CH2O-。
在本发明一优选实施方案中，所述R1优选为H。
在本发明一优选实施方案中，所述R2优选为H。
在本发明一优选实施方案中，所述R3优选为H。
在本发明一优选实施方案中，所述R4、R5和R6分别独立地优选为H、D、F、Cl、 Br、-CH3、-OCH3、-CF3、-CH2F、-CHF2、-OCF3、-CN或-NH2；
在本发明另一优选实施方案中，所述R4、R5和R6分别独立地优选为H、I、F、Cl、Br、-CH3、-OCH3、-CF3、-CH2F、-CHF2、-OCF3、-CN或-NH2；
在本发明再一优选实施方案中，所述R4、R5和R6分别独立地优选为H、F、Cl、Br、-CH3、-OCH3、-CF3、-CH2F、-CHF2、-OCF3、-CN或-NH2。
在本发明一优选实施方案中，所述RA中，所述Rd1和Re1分别独立地优选为氢、C1-6烷基、卤代C1-6烷基、C3-8环烷基或3-8元杂环烷基；所述Rd1或Re1为未取代，或者选择性被1个羟基取代在任意位置。
或者，所述Rd1和Re1与它们共同连接的N原子一起形成C3-8杂环烷基；所述杂环烷基还可以进一步含有1～3个选自N、O、S的杂原子；所述杂环烷基为未取代或者进一步被1个选自C1-4烷基、卤代C1-3烷基、羟基C1-3烷基或氨基C1-3烷基的取代基取代在任意位置。
在本发明一优选实施方案中，所述RB优选为-NH2。
在本发明一优选实施方案中，所述R优选为8-20元的双环、三环或四环并环基团。
在本发明另一优选实施方案中，所述R优选为9-15元双环或三环并环基团，并且至少有一个环为芳香环。
在本发明再一优选实施方案中，所述R为9-15元双环或三环并环基团，其中一个环为芳香环，另外1～2个环为非芳香环，并且，所述9-15元双环或三环并环基团的环原子中包含1～3个N原子，所述非芳香环中进一步包含1～2个氧代基
Figure PCTCN2017083031-appb-000002
和/或硫代基
Figure PCTCN2017083031-appb-000003
在本发明一优选实施方案中，所述R为未取代、或者优选被1～4个取代基取代在任意位置；更优选被1个、1～2个或1～3个取代基取代在任意位置。
在本发明一优选实施方案中，当所述R被取代时，所述取代基中，所述卤素优选为F、Cl或Br。
在本发明一优选实施方案中，当所述R被取代时，所述取代基中，所述烷基优选为C1-6烷基，例如：甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、新戊基、特戊基或2,2-二甲基丁基。
在本发明一优选实施方案中，当所述R被取代时，所述取代基中，所述卤代烷基优选为卤代C1-6烷基，例如：-CF3、-CHF2或-CH2F。
在本发明一优选实施方案中，当所述R被取代时，所述取代基中，所述卤代烷氧基优选为卤代C1-6烷氧基，例如：-OCF3、-OCHF2或-OCH2F。
在本发明一优选实施方案中，当所述R被取代时，所述取代基中，所述烯基优选为C2-6烯基。
在本发明一优选实施方案中，当所述R被取代时，所述取代基中，所述炔基优选为 C2-6炔基。
在本发明一优选实施方案中，当所述R被取代时，所述取代基中，所述烷基、烯基或炔基为未取代或者优选被1～3个取代基取代在任意位置。
在本发明一优选实施方案中，当所述R被取代时，所述取代基中，所述-L2-Cy1中，所述L2优选为连接键或者-(CRa1Rb1)m-，m、Ra1、Rb1的定义同前所述；所述L2更优选为连接键、-CH2-、-CH2CH2-、-CH2CH2CH2-、-CH2CH2C(CH3)2-、-CH2CH2CH2CH2-或-CH2CH(CH3)CH2-；
在本发明一优选实施方案中，当所述R被取代时，所述取代基中，所述Cy1优选为C3-10环烷基、3-10元杂环烷基、C6-10芳基或者5-10元杂芳基；
在本发明一优选实施方案中，当所述R被取代时，所述取代基中，所述Cy1中，所述5-10元杂芳基更优选为5-6元杂芳基，例如：吡啶基、嘧啶基、吡嗪基、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、1,2,3-三氮唑基或四氮唑基；
在本发明一优选实施方案中，当所述R被取代时，所述取代基中，所述Cy1中，所述C6-10芳基更优选为苯基；
在本发明一优选实施方案中，当所述R被取代时，所述取代基中，所述Cy1为未取代或者选择性地被1～3个选自F、Cl、Br、C1-4烷基(例如：甲基、乙基、正丙基、异丙基或丁基等)、卤代C1-3烷基、卤代C1-3烷氧基、羟基C1-3烷基、氨基C1-3烷基、C2-6烯基、C2-6炔基、-CN、-NO2、-SRd2、-ORd2、-OC(O)Rd2、-OC(O)ORd2、-OC(O)NRd2Re2、-C(O)ORd2、-C(O)Rd2、-C(O)NRd2Re2、-NRd2Re2、-NRd2C(O)Re2、-N(Rd2)C(O)ORe2、-N(Rd2)C(O)NRd2Re2、-NRd2S(O)2Re2、-NRd2C(＝NH)Re2、-NRd2C(＝NH)NRd2Re2、-S(O)1-2Re2、-S(O)2NRd2Re2和-NRd2S(O)2NRd2Re2中的一种或多种取代基取代在任意位置；其中Rd2和Re2定义如前所述。
在本发明一优选实施方案中，所述R更优选为如下R-1～R-19任一结构：
Figure PCTCN2017083031-appb-000004
Figure PCTCN2017083031-appb-000005
其中，每个R7和R7a分别独立地选自氢、卤素、烷基、卤代烷基、烯基、炔基、Cy1、-L2-Cy1、-SRd、-ORd、-C(O)ORd、-C(O)Rd、-C(O)NRdRe、-C(O)N(Rd)ORe、-C(O)NRdS(O)2Re、-C(＝NH)Re、-C(＝NH)NRdRe、-S(O)2Re和-S(O)2NRdRe；其中所述烷基、烯基或炔基为未取代或者选择性地被如下一个或多个取代基取代在任意位置：-CN、-NO2、-SRd、-ORd、-OC(O)Rd、-OC(O)ORd、-OC(O)NRdRe、-C(O)ORd、-C(O)Rd、-C(O)NRdRe、-C(O)NRdS(O)2Re、-NRdRe、-NRdC(O)Re、-N(Rd)C(O)ORe、-N(Rd)C(O)NRdRe、-NRdC(＝NH)Re、-NRdC(＝NH)NRdRe、-NRdS(O)2Re、-NRdS(O)2NRdRe、-N(Rd)C(O)N(Rd)S(O)2Re、-S(O)1-2Re、-S(O)2NRdRe、-S(O)(＝NCN)Re、-S(O)(＝NRd)Re、-S(O)(＝NSO2Rd)Re、-S(O)2N(Rd)C(O)Re、-S(O)2N(Rd)C(O)NRdRe、-P(O)(ORd)2、-OP(O)(ORd)2或-B(ORd)2；
每个R8独立地为氢、卤素、烷基、卤代烷基、卤代烷氧基、烯基、炔基、Cy1、-L2-Cy1、-CN、-NO2、-SRd、-ORd、-OC(O)Rd、-OC(O)ORd、-OC(O)NRdRe、-C(O)ORd、-C(O)Rd、-C(O)NRdRe、-C(O)N(Rd)ORe、-C(O)NRdS(O)2Re、-C(＝NH)Re、-C(＝NH)NRdRe、-NRdRe、-NRdC(O)Re、-N(Rd)C(O)ORe、-N(Rd)C(O)NRdRe、-NRdS(O)2Re、-NRdC(＝NH)Re、-NRdC(＝NH)NRdRe、-S(O)1-2Re、-S(O)2NRdRe和-NRdS(O)2NRdRe；其中所述烷基、烯基或炔基为未取代或者选择性地被如下一个或多个取代基取代在任意位置：-CN、-NO2、-SRd、-ORd、-OC(O)Rd、-OC(O)ORd、-OC(O)NRdRe、-C(O)ORd、-C(O)Rd、-C(O)NRdRe、-C(O)NRdS(O)2Re、-NRdRe、-NRdC(O)Re、-N(Rd)C(O)ORe、-N(Rd)C(O)NRdRe、-NRdC(＝NH)Re、-NRdC(＝NH)NRdRe、-NRdS(O)2Re、-NRdS(O)2NRdRe、-N(Rd)C(O)N(Rd)S(O)2Re、-S(O)1-2Re、-S(O)2NRdRe、-S(O)2N(Rd)C(O)Re或-S(O)2N(Rd)C(O)NRdRe；每个n独立地为1、2或3；L2、Cy1、Rd和Re的定义如前所述。
在本发明一优选实施方式中，R优选为前述R定义结构中的R-1～R-11、R-13～R-16结构中任一结构；所述R7和R7a分别独立地优选为前述R7和R7a定义中除-C(O)N(Rd)ORe以外的基团，其中R7或R7a中所述烷基、烯基或炔基为未取代或者选择性地被前述取代 基定义中的除-S(O)(＝NCN)Re、-S(O)(＝NRd)Re、-S(O)(＝NSO2Rd)Re、-P(O)(ORd)2、-OP(O)(ORd)2或-B(ORd)2以外的一个或多个取代基取代在任意位置；所述R8优选为前述R8定义中除-C(O)N(Rd)ORe以外的基团。
在本发明一优选实施方式中，R优选为前述R定义结构中的R-1～R-16结构中任一结构；所述R7和R7a分别独立地优选为前述R7和R7a定义中除-C(O)N(Rd)ORe以外的基团，其中R7或R7a中所述烷基、烯基或炔基为未取代或者选择性地被前述取代基定义中的除-P(O)(ORd)2、-OP(O)(ORd)2或-B(ORd)2以外的一个或多个取代基取代在任意位置；所述R8优选为前述R8定义中除-C(O)N(Rd)ORe以外的基团。
在本发明一优选实施方式中，R优选为前述R定义结构中的R-1～R-18结构中任一结构；所述R7和R7a分别独立地优选为前述R7和R7a定义中除-C(O)N(Rd)ORe以外的基团。
在本发明一优选实施方案中，所述R中，所述R7优选为氢、C1-6烷基、卤代C1-6烷基、C2-6烯基、C2-6炔基、Cy1、-L2-Cy1、-SRd、-ORd、-C(O)ORd、-C(O)Rd、-C(O)NRdRe、-C(O)N(Rd)ORe、-C(＝NH)Re、-C(＝NH)NRdRe、-S(O)2Re或-S(O)2NRdRe；其中所述C1-6烷基、C2-6烯基或C2-6炔基为未取代或者选择性地被如下1～3个取代基取代在任意位置：-CN、-NO2、-SRd、-ORd、-OC(O)Rd、-OC(O)ORd、-OC(O)NRdRe、-C(O)ORd、-C(O)Rd、-C(O)NRdRe、-NRdRe、-NRdC(O)Re、-N(Rd)C(O)ORe、-N(Rd)C(O)NRdRe、-NRdS(O)2Re、-NRdC(＝NH)Re、-NRdC(＝NH)NRdRe、-S(O)1-2Re、-S(O)(＝NCN)Re、-S(O)(＝NRd)Re、-S(O)(＝NSO2Rd)Re、-S(O)2NRdRe、-NRdS(O)2NRdRe、-P(O)(ORd)2、-OP(O)(ORd)2或-B(ORd)2；L2、Cy1、Rd和Re的定义如前所述。
在本发明一优选实施方案中，所述R中，所述R7优选为前述R中所述R7的优选定义中-C(O)N(Rd)ORe以外的基团，其中所述C1-6烷基、C2-6烯基或C2-6炔基为未取代或者选择性地被前述取代基定义中的除-S(O)(＝NCN)Re、-S(O)(＝NRd)Re、-S(O)(＝NSO2Rd)Re、-P(O)(ORd)2、-OP(O)(ORd)2或-B(ORd)2以外的1～3个取代基取代在任意位置。
在本发明另一优选实施方案中，所述R中，所述R7优选为前述R中所述R7的优选定义中-C(O)N(Rd)ORe以外的基团，其中所述C1-6烷基、C2-6烯基或C2-6炔基为未取代或者选择性地被前述取代基定义中的除-P(O)(ORd)2、-OP(O)(ORd)2或-B(ORd)2以外的1～3个取代基取代在任意位置。
在本发明再一优选实施方案中，所述R中，所述R7优选为前述R中所述R7的优选定义中-C(O)N(Rd)ORe以外的基团。
在本发明一优选实施方案中，所述R中，所述R7更优选为：氢、甲基、乙基、丙基、丁基、异丙基、异丁基、正丁基、新戊基、特戊基、环丙基、环丁基、环戊基、环己基、
Figure PCTCN2017083031-appb-000006
Figure PCTCN2017083031-appb-000007
Figure PCTCN2017083031-appb-000008
在本发明一优选实施方案中，所述R中，所述R7更优选为：
Figure PCTCN2017083031-appb-000009
Figure PCTCN2017083031-appb-000010
在本发明一优选实施方案中，所述R中，所述R7更优选为：苄基、
Figure PCTCN2017083031-appb-000011
Figure PCTCN2017083031-appb-000012
在本发明另一优选实施方案中，所述R中，所述R7更优选为：苯基、吡啶基、嘧啶基、
Figure PCTCN2017083031-appb-000013
在本发明一优选实施方案中，所述R中，所述R7更优选为：
Figure PCTCN2017083031-appb-000014
Figure PCTCN2017083031-appb-000015
在本发明一优选实施方案中，所述R中，所述R7a优选为氢、C1-6烷基、卤代C1-6烷基、C2-6烯基、C2-6炔基、Cy1或-L2-Cy1，其中所述C1-6烷基、C2-6烯基或C2-6炔基为未取代或者选择性地被如下1～3个取代基取代在任意位置：-CN、-NO2、-CN、-SRd、-ORd、-OC(O)Rd、-OC(O)ORd、-OC(O)NRdRe、-C(O)ORd、-C(O)Rd、-C(O)NRdRe、-NRdRe、-NRdC(O)Re、-N(Rd)C(O)ORe、-N(Rd)C(O)NRdRe、-NRdS(O)2Re、-NRdC(＝NH)Re、-NRdC(＝NH)NRdRe、-S(O)1-2Re、-S(O)2NRdRe和-NRdS(O)2NRdRe；L2、Cy1、Rd和Re的定义如前所述。
在本发明一优选实施方案中，所述R中，所述R7a更优选为氢或C1-6烷基(例如：甲基或乙基)。
在本发明一优选实施方案中，所述R中，所述R8优选为：氢、甲基、乙基、正丙基、叔丁基、异丙基、异丁基、正丁基、-CN、-NO2、-NH2、-CF3、-OCF3、-CH3、-OCH3、F、Cl或Br；或R8优选为除-OCH3以外的基团。
所述R中，所述n优选为1或2；所述n更优选为1。
在本发明一优选实施方案中，所述L2优选为连接键或-(CRa1Rb1)m-。
在本发明另一优选实施方案中，所述L2优选为连接键、-CH2-、-CH2CH2-、-CH2-CH2CH2-、-CH2CH2CH2CH2-、-CH2CH(CH2)CH2-或
Figure PCTCN2017083031-appb-000016
在本发明再一优选实施方案中，所述L2优选为连接键、-CH2-、-CH2CH2-、-CH2CH2CH2-、-CH2CH2CH2CH2-或-CH2CH(CH2)CH2-。
在本发明一优选实施方案中，所述Rd、Re、Rd1、Re1、Rd2或Re2优选为未取代或者选择性地被1～3个选自卤素、羟基、氨基、羧基、C1-4烷基、卤代C1-3烷基、卤代C1-3烷氧基、C2-6烯基和C2-6炔基中的一种或多种取代基取代在任意位置。
在本发明另一优选实施方案中，所述Rd、Re、Rd1、Re1、Rd2或Re2优选为未取代或者选择性地被1～3个选自卤素、羟基、氨基、羧基、C1-4烷基、卤代C1-3烷基、卤代C1-3烷氧基、C1-3烷氧基、C1-3烷氨基、C2-6烯基和C2-6炔基中的一种或多种取代基取代在任意位置。
在本发明一优选实施方案中，Rd和Re、或Rd1和Re1、或Rd2和Re2与它们共同连接的N原子一起形成3-8元的杂环烷基；所述杂环烷基还可以进一步含有1～3个选自N、O、S的杂原子；所述杂环烷基优选为未取代或者进一步被1～3个选自卤素、氨基、羧基、氰基、C1-4烷基、卤代C1-3烷基、卤代C1-3烷氧基、C2-6烯基、C2-6炔基、羟基烷基、氨基烷基、-ORd2、-OC(O)Rd2、-OC(O)ORd2、-OC(O)NRd2Re2、-C(O)ORd2、-C(O)Rd2、-C(O)NRd2Re2、-NRd2Re2、-NRd2C(O)Re2、-N(Rd2)C(O)ORe2、-N(Rd2)C(O)NRd2Re2、-NRd2S(O)2Re2、-NRd2C(＝NH)Re2、-NRd2C(＝NH)NRd2Re2、-S(O)1-2Rd2和-S(O)2NRd2Re2中的一种或多种取代基取代在任意位置。
所述的如式I所述的化合物、其异构体、前药、稳定的同位素衍生物或药学上可接受的盐，优选为如式IA所示化合物、其异构体、前药、稳定的同位素衍生物或药学上可接受的盐：
Figure PCTCN2017083031-appb-000017
其中，
Figure PCTCN2017083031-appb-000018
为单键或双键，U为N、C(R8)或C(O)，V为N、C(R8)或N(R7a)；并且，
Figure PCTCN2017083031-appb-000019
U和V为如下任一组合：
1)
Figure PCTCN2017083031-appb-000020
为双键，U为N，V为C(R8)；
2)
Figure PCTCN2017083031-appb-000021
为双键，U为C(R8)，V为N；
3)
Figure PCTCN2017083031-appb-000022
为双键，U为C(R8)，V为C(R8)；
4)
Figure PCTCN2017083031-appb-000023
为单键，U为C(R8)，V为C(R8)；
5)
Figure PCTCN2017083031-appb-000024
为单键，U为C(O)，V为N(R7a)；
Y为O或S；
n为1；
L1、Rd1、Re1、R4、R5、R6、R7、R8和X的定义均如前所述。
所述如式I所述的化合物、其异构体、前药、稳定的同位素衍生物或药学上可接受的盐，优选为如式IB或IC所示化合物、其异构体、前药、稳定的同位素衍生物或药学上可接受的盐：
Figure PCTCN2017083031-appb-000025
其中，
Figure PCTCN2017083031-appb-000026
为单键或双键；
Rd1、Re1、R4、R5、R6、R7、R8和Y的定义均如前所述。
在本发明一优选实施方案中，所述如式IB或IC所示化合物、其异构体、前药、稳定的同位素衍生物或药学上可接受的盐中，Y优选为O。
所述如式I所述的化合物、其异构体、前药、稳定的同位素衍生物或药学上可接受的盐，优选为如式ID、IE、IF、IG、IH或II所示化合物、其异构体、前药、稳定的同位素衍生物或药学上可接受的盐：
Figure PCTCN2017083031-appb-000027
其中，Rd1、Re1、R4、R5、R6、R7、R7a、R8和Y的定义均如前所述。
在本发明一优选实施方案中，所述如式ID或IF所示化合物、其异构体、前药、稳定的同位素衍生物或药学上可接受的盐中，Y优选为O。
所述如式I所述的化合物、其异构体、前药、稳定的同位素衍生物或药学上可接受的盐，优选为如式IJ所示化合物、其异构体、前药、稳定的同位素衍生物或药学上可接受的盐：
Figure PCTCN2017083031-appb-000028
其中，
Figure PCTCN2017083031-appb-000029
为单键或双键；Z为N(R7a)或S；
n为1或2；
L1、Rd1、Re1、R4、R5、R6、R7和R8的定义均如前所述。
所述如式I所述的化合物、其异构体、前药、稳定的同位素衍生物或药学上可接受的盐，优选为如式IK或IL所示化合物、其异构体、前药、稳定的同位素衍生物或药学上可接受的盐：
Figure PCTCN2017083031-appb-000030
其中，Z为NH、N(CH3)或S；
Rd1、Re1、R4、R5、R6、R7和R8的定义均如前所述。
所述如式(I)所示化合物、其异构体、前药、稳定的同位素衍生物或药学上可接受的盐最佳地为如下任一结构：
Figure PCTCN2017083031-appb-000031
Figure PCTCN2017083031-appb-000032
Figure PCTCN2017083031-appb-000033
Figure PCTCN2017083031-appb-000034
Figure PCTCN2017083031-appb-000035
Figure PCTCN2017083031-appb-000036
Figure PCTCN2017083031-appb-000037
Figure PCTCN2017083031-appb-000038
Figure PCTCN2017083031-appb-000039
Figure PCTCN2017083031-appb-000040
Figure PCTCN2017083031-appb-000041
Figure PCTCN2017083031-appb-000042
本发明还提供了所述如式(I)所示化合物、其异构体、前药、稳定的同位素衍生物或药学上可接受的盐的制备方法，
其中，所述如式(I)所示化合物的制备方法为如下任一方法：
方法1包括下列步骤：将如式I-a所示的化合物与
Figure PCTCN2017083031-appb-000043
进行如下所示的suzuki偶联反应，制得所述如式(I)所示化合物；
Figure PCTCN2017083031-appb-000044
方法2包括下列步骤：将如式I-b所示的化合物与R-M进行如下所示的suzuki偶联反应，制得所述如式(I)所示化合物；
Figure PCTCN2017083031-appb-000045
其中，M为溴、氯、碘或-OS(O)2CF3；所述R1、R3、R4、R5、R6、RA、RB、R和L的定义均同前所述。
方法1和方法2中，所述的suzuki偶联反应的条件和步骤可为本领域常规的反应的条件和步骤，本发明特别优选以下反应条件：氮气保护下，在混合溶剂(例如：四氢呋喃/水，乙腈/水，或者N,N-二甲基甲酰胺/水)、碱(碳酸钾、碳酸铯或者二乙基异丙基胺)和催化剂(优选[1,1'-双(二苯基膦基)二茂铁]二氯化钯(Pd(dppf)Cl2)或者[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(Pd(dppf)2Cl2)，所述混合溶剂的用量优选1～50mL/mmol化合物I-a或I-b，所述反应时间优选0-24小时，温度优选室温到溶剂回流，更优选为60～90℃，化合物I-a或I-b与催化剂的摩尔比优选1:0.01～1:0.1。
在上述方法最后的合成步骤中使用对甲苯磺酸、盐酸、氯化氢或三氟乙酸等酸性体系，或在纯化过程中，例如：prep-HPLC的流动相中存在上述酸性体系时，则所述的如式I-1所示的化合物将会是相应的对甲苯磺酸盐、盐酸盐或三氟乙酸盐等。
在上述方法中，在如式I-a所示的化合物、如式I-b所示的化合物、
Figure PCTCN2017083031-appb-000046
或者R-M中存在氨基基团、羟基基团或羧基基团时，该氨基基团、羟基基团或羧基基团均可通过保护基保护，避免有任何副反应发生。如果存在上述氨基保护基团或羟基保护基团则需要经过后续的脱保护步骤后，得到如式I-1所示化合物。任何合适的氨基保护基团，例如：叔丁氧羰基(Boc)基团，均可以用于保护氨基基团。如果使用Boc作为保护基，后续的脱保护反应可以在标准条件，例如，对甲苯磺酸/甲醇体系，二氯甲烷/三氟乙酸体系、饱和的氯化氢乙醚溶液、或三氟甲磺酸三甲基硅酯/2,6-二甲基吡啶/二氯甲烷体系中进行；任何合适的羟基保护基团，例如：苄基，均可以用于保护氨基基团，后续的脱保护反应可以在标准条件，例如，钯碳/氢气；任何合适的羧基保护基团，例如：形成羧酸酯基团(例如，羧酸甲酯，羧酸乙酯)，均可以用于保护羧基基团，后续的脱保护反应可以在标准条件，例如，氢氧化钠、氢氧化钾、氢氧化锂在四氢呋喃、水和/或甲醇溶剂中脱保护。上述脱保护反应优选在最后一步进行。
所述如式(I)所示化合物，其药学上可接受的盐可通过一般的化学方法合成。
一般情况下，盐的制备可以通过游离碱或酸与等化学当量或者过量酸(无机酸或有机酸)或碱(无机碱或有机碱)在合适的溶剂或溶剂组合物中反应制得。
本发明还提供了一种药物组合物，其包括治疗有效量的所述的如式(I)所示化合物、其异构体、前药、稳定的同位素衍生物和药学上可接受的盐中的一种或多种以及药学上可接受的辅料。
所述药物组合物还可包括用于治疗、缓解和/或预防癌症、病毒感染或自身免疫疾病的其它治疗剂。
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。
根据治疗目的，可将药物组合物制成各种类型的给药单位剂型，如片剂、丸剂、粉剂、液体、悬浮液、乳液、颗粒剂、胶囊、栓剂和针剂(溶液及悬浮液)等，优选液体、悬浮液、乳液、栓剂和针剂(溶液及悬浮液)等。
为了使片剂形式的药物组合物成形，可使用本领域任何已知并广泛使用的赋形剂。例如，载体，如乳糖、白糖、氯化钠、葡萄糖、尿素、淀粉、碳酸钙、高岭土、结晶纤维素和硅酸等；粘合剂，如水、乙醇、丙醇、普通糖浆、葡萄糖溶液、淀粉溶液、明胶溶液，羧甲基纤维素、紫胶、甲基纤维素和磷酸钾、聚乙烯吡咯烷酮等；崩解剂，如干淀粉、藻酸钠、琼脂粉和海带粉，碳酸氢钠、碳酸钙、聚乙烯脱水山梨醇的脂肪酸酯、 十二烷基硫酸钠、硬脂酸单甘酯、淀粉和乳糖等；崩解抑制剂，如白糖、甘油三硬脂酸酯、椰子油和氢化油；吸附促进剂，如季胺碱和十二烷基硫酸钠等；润湿剂，如甘油、淀粉等；吸附剂，如淀粉、乳糖、高岭土、膨润土和胶体硅酸等；以及润滑剂，如纯净的滑石，硬脂酸盐、硼酸粉和聚乙二醇等。还可以根据需要选用通常的涂渍材料制成糖衣片剂、涂明胶膜片剂、肠衣片剂、涂膜片剂、双层膜片剂及多层片剂。
为了使丸剂形式的药物组合物成形，可使用本领域任何已知的并广泛使用的赋形剂，例如，载体，如乳糖，淀粉，椰子油，硬化植物油，高岭土和滑石粉等；粘合剂，如阿拉伯树胶粉，黄蓍胶粉，明胶和乙醇等；崩解剂，如琼脂和海带粉等。
为了使栓剂形式的药物组合物成形，可使用本领域任何已知并广泛使用的赋性剂，例如，聚乙二醇，椰子油，高级醇，高级醇的酯，明胶和半合成的甘油酯等。
为了制备针剂形式的药物组合物，可将溶液或悬浮液消毒后(最好加入适量的氯化钠，葡萄糖或甘油等)，制成与血液等渗压的针剂。在制备针剂时，也可使用本领域内任何常用的载体。例如，水，乙醇，丙二醇，乙氧基化的异硬脂醇，聚氧基化的异硬脂醇和聚乙烯脱水山梨醇的脂肪酸酯等。此外，还可加入通常的溶解剂、缓冲剂和止痛剂等。
本发明中，所述的所述的如式(I)所示化合物、其异构体、前药、稳定的同位素衍生物和药学上可接受的盐中的一种或多种、和/或其他治疗剂在药物组合物中的含量无特殊限制，可在很宽的范围内进行选择，通常可为质量百分比的5～95％，较佳的为质量百分比30～80％。
本发明中，所述药物组合物的给药方法没有特殊限制。可根据病人年龄、性别和其它条件及症状，选择各种剂型的制剂给药。例如，片剂、丸剂、溶液、悬浮液、乳液、颗粒剂或胶囊口服给药；针剂可以单独给药，或者和注射用输送液(如葡萄糖溶液及氨基酸溶液)混合进行静脉注射；栓剂为给药到直肠。
本发明还提供了如式(I)所示化合物、其异构体、前药、稳定的同位素衍生物或药学上可接受的盐在制备TLRs调节剂中的应用。所述的TLRs调节剂优选为TLRs激动剂或者TLRs部分激动剂。所述TLRs优选TLR7、TLR8和TLR9中的一种或者多种。
本发明还提供了如式(I)所示化合物、其异构体、前药、稳定的同位素衍生物或药学上可接受的盐在制备调节T细胞及其它免疫细胞药物中的应用。
本发明还提供了如式(I)所示化合物、其异构体、前药、稳定的同位素衍生物或药学上可接受的盐在制备治疗、缓解和/或预防由TLRs介导的相关疾病的药物中的应用；本发明优选提供了如式(I)所示化合物、其异构体、前药、稳定的同位素衍生物或药学上可接受的盐在制备治疗、缓解和/或预防由TLR8介导的相关疾病的药物中的应用；所述疾病包括肿瘤和非肿瘤性疾病。所述疾病包括但不限于：癌症、病毒及其它感染、由于免疫抑制导致的疾病，以及自身免疫性疾病等。
本发明优选用所述如式(I)所示化合物、其异构体、前药、稳定的同位素衍生物或 药学上可接受的盐在制备治疗和/或缓解癌症的药物中的应用。所述癌症优选免疫制剂相关的癌症，所述免疫抑制是指肿瘤特异性地免疫抑制。
本发明还进一步提供了用所述如式(I)所示化合物、其异构体、前药、稳定的同位素衍生物或药学上可接受的盐治疗癌症、病毒及其它感染、自身免疫性疾病的方法，包括：给予哺乳动物治疗所需剂量的如式(I)所述化合物、其异构体、前药、稳定的同位素衍生物或药学上可接受的盐，或药物组合物。
所述哺乳动物，优选人。
本发明还进一步提供了所述如式(I)所示化合物、其异构体、前药、稳定的同位素衍生物或药学上可接受的盐还可和一种或多种其它种类的治疗剂和/或治疗方法联合用于治疗、缓解和/或预防由TLRs介导介导的相关疾病，尤其指由TLR8介导的相关疾病。所述的TLR8介导的相关疾病是指由TLR8介导的免疫抑制而引起的疾病，所述的疾病可包括：癌症、病毒感染、炎症、自身免疫性疾病、移植排斥、移植抗宿主病等。
本发明优选用所述如式(I)所示化合物、其异构体、前药、稳定的同位素衍生物或药学上可接受的盐还可和一种或多种其它种类的治疗剂和/或治疗方法联合用于治疗和/或缓解由色氨酸TLR8介导的疾病，所述疾病优选为癌症。
所述其它种类的治疗剂(例如：用于治疗癌症的其它种类的治疗剂)可以和所述的如式(I)所示化合物做成单一给药的治疗剂型，或者分别先后给药的治疗剂型。
所述病毒感染可包括：由流感病毒、仙台病毒、柯萨奇病毒、登革热病毒、新城疫病毒(NDV)、水泡性口炎病毒(VSV)吧、丙型肝炎病毒(HCV)、人类乳头状瘤病毒(HPV)、巨细胞病毒(CMV)、爱泼斯坦-巴尔病毒(EBV)、脊髓灰质炎病毒、水痘-带状疱疹病毒或I型人类免疫缺陷病毒(HIV)等病毒引起的感染。
所述的癌症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。
所述固体肿瘤的具体例子可包括但不限于：眼癌、骨癌、肺癌、胃癌、胰腺癌、乳腺癌、前列腺癌、脑癌(包括噁性胶质瘤、成神经管细胞瘤)、卵巢癌、膀胱癌、子宫颈癌、睾丸癌、肾癌(包括腺癌和肾母细胞癌)、口腔癌(包括鳞状细胞癌)、舌癌、喉癌、鼻咽癌、头颈癌、结肠癌、小肠癌、直肠癌、甲状旁腺癌、甲状腺癌、食管癌、胆囊癌、胆管癌、宫颈癌、肝癌、肺癌、肉瘤、和皮肤癌中的一种或多种。
所述非固体肿瘤(包括血液学肿瘤)的具体例子可包括但不限于：淋巴性白血病(包括急性淋巴细胞白血病、淋巴瘤、骨髓瘤、慢性淋巴细胞白血病、霍奇金淋巴瘤、非霍奇金淋巴瘤、T细胞慢性淋巴性白血病、B细胞慢性淋巴性白血病)、髓性相关的白血病(包括急性髓性白血病、慢性髓性白血病)和AIDs相关的白血病中的一种或多种。
所述的自身免疫性疾病可包括但不限于：类风湿性关节炎、全身性红斑狼疮、混合性结缔组织病(MCTD)、系统硬皮病(包括：CREST综合症)、皮肌炎、结节性脉管炎、 肾病(包括：肺出血肾炎综合症、急性肾小球肾炎、原发性膜增殖性肾小球肾炎等)、内分泌相关疾病(包括：I型糖尿病、性腺机能不全、噁性贫血、甲状腺机能亢进等)、肝病(包括：原发性胆汁性肝硬化、自身免疫性胆管炎、自身免疫性肝炎、原发性硬化性胆管炎等)和由于感染引起的自身免疫反应(例如：艾滋病、疟疾等)中的一种或多种。
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，除非另有说明，化学键显示虚线表示的化学结构指所述键任选地存在或不存在。例如，紧挨实线单键画出的虚线表示键可为单键或者双键。
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。
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“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1-8，1-6，1-4，1-3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、戊基、己基、庚基、辛基、壬基、癸基、4,4-二甲基戊基、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。当“烷基”作为其它基团的链接基团时，如-(CH2)m-，它可以是支链或支链，例子包括但不限于-CH2-、-CH2CH2-、-CH2CH(CH3)-。
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、2,3-二氢-1-H-茚、2,3-环戊烯并吡啶、5,6-二氢-4H-环戊基[B]噻吩、十氢萘等。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、氧或硫等杂原子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，在本发明中，杂环烷基中杂原子个数优选1、2、3或4，杂环烷基中的氮、碳或硫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：氮丙啶基、四氢呋喃-2-基、吗啉-4-基、硫代吗啉-4-基、硫代吗啉-S-氧化物-4-基、哌啶-1-基、N-烷基哌啶-4-基、吡咯烷-1-基、N-烷基吡咯烷-2-基、哌嗪-1-基、4-烷基哌嗪-1-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：-CH2OH、-CH2CH2OH、-CH2CH2C(CH3)2OH。
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“C2-4烯基”是指具有2-4个碳原子的烯基，术语“C2-6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“C2-6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“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、嘧啶基、哌嗪基、哒嗪-3(2H)-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，并环结构每个单环可以为单环芳基、单环杂芳基、单环环烷基或单环杂环烷 基。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。所述并环基团中的非芳香环可进一步包含1～2个氧代或硫代基团。本发明中，所述并环基团为8-20元，优选8-15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-1-H-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 PCTCN2017083031-appb-000047
Figure PCTCN2017083031-appb-000048
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“芳香环”包括“芳环”和“杂芳环”。
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-NH2，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：-NHCH3、-N(CH3)2、-NHCH2CH3、-N(CH2CH3)2。术语“氨基烷基”是指烷基上任意一个氢原子被氨基所取代，包括但不限于：-CH2NH2、-CH2CH2NH2。由此，“氨基烷基”和“烷氨基”包含上述烷基和氨基的定义。
术语“硝基”是指-NO2。
术语“氰基”是指-CN。
符号“＝”表示双键；符号
Figure PCTCN2017083031-appb-000049
表示双键或单键。
本发明所述“室温”是指15-30℃。
所述的同位素取代衍生物包括：式I中任意的氢原子被1-5个氘原子取代得到的同位素取代衍生物、式I中任意的碳原子被1-3个碳14原子取代得到的同位素取代衍生物或式I中任意的氧原子被1-3个氧18原子取代得到的同位素取代衍生物。
所述的“前药”是指化合物在体内代谢后转换成原始活性化合物。代表性地讲，前药为非活性物质，或者比活性母体化合物活性小，但可以提供方便的操作、给药或者改善代谢特性。
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，例如：盐酸盐、氢溴酸盐、硫酸盐、焦硫酸盐、硫酸氢盐、亚硫酸盐、亚硫酸氢盐、磷酸盐、磷酸一氢盐、磷酸二氢盐、偏磷酸盐、焦磷酸盐、硝酸盐、乙酸盐、丙酸盐、癸酸盐、辛酸盐、甲酸盐、丙烯酸盐、异丁酸盐、己酸盐、庚酸盐、草酸盐、丙二酸盐、琥珀酸盐、辛二酸盐、苯甲酸盐、甲基苯甲酸盐、邻苯二甲酸盐、马来酸盐、甲磺酸盐、对甲苯磺酸盐、(D，L)-酒石酸，柠檬酸，马来酸，(D，L)-苹果酸，富马酸，丁二酸、琥珀酸盐、乳酸盐、三氟甲磺酸盐、萘-1-磺酸盐、扁桃酸盐、丙酮酸盐、硬脂酸盐、抗坏血酸盐、水杨酸盐。当本发明化合物含有酸性基团时，其药学上可接受的盐还可以包括：碱金属盐，例如钠或钾盐；碱土金属盐，例如钙或镁盐；有机碱盐，例如和氨、烷基氨类、羟基烷基氨类、氨基酸(赖氨酸、精氨酸)、N-甲基葡糖胺等形成的盐。
本发明所述“异构体”是指本发明的式(I)化合物可以有不对称中心和外消旋体、外消旋混合物和单个非对映异构体，所有这些异构体，包括立体异构体、几何异构体均包含在本发明中。在本发明中，式I化合物或其盐以立体异构的形式(例如，其含有一个或多个不对称碳原子)存在时，单独的立体异构体(对映异构体和非对映异构体)以及它们的混合物包括在本发明的范围内。本发明还包括式I表示的化合物或盐的单独异构体，以及与其中一个或多个手性中心反转的异构体的混合物。本发明的范围包括：立体异构体的混合物，以及纯化的对映异构体或对映异构体/非对映异构体富集的混合物。本发明包括所有对映异构体及非对应异构体所有可能的不同组合的立体异构体的混合物。本发明包括上文定义的所有具体基团的立体异构体的全部组合和子集。本发明还包括式I化合物或其盐的几何异构体，所述几何异构体包括顺反异构体。
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。
具体实施方式
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(CDCl3)，氘代甲醇(CD3OD)，氘代二甲亚砜(DMSO-d6)，四甲基硅烷作为内标(TMS)。
低分辨率质谱(MS)由Agilent 1200HPLC/6120质谱仪测定，使用XBridge C18，4.6×50mm，3.5μm，梯度洗脱条件一：80-5％溶剂A1和20-95％溶剂B1(1.8分钟)，然后95％溶剂B1和5％溶剂A1(3分钟以上)，百分数为某一溶剂占总溶剂体积的体积百分数。溶剂A1：0.01％三氟乙酸(TFA)的水溶液；溶剂B1：0.01％三氟乙酸的乙腈溶液；百分数为溶质占溶液的体积百分数。梯度洗脱条件二：80-5％溶剂A2和20-95％溶剂B2(1.5分钟)，然后95％溶剂B2和5％溶剂A2(2分钟以上)，百分数为某一溶剂占总溶剂体积的体积百分数。溶剂A2：10mM的碳酸氢铵的水溶液；溶剂B2：乙腈。
本发明所有化合物可通过高效液相色谱仪、硅胶柱层析色谱或快速柱层析色谱进行分离。
高效液相色谱仪(prep-HPLC)使用岛津LC-20制备液相色谱，色谱柱为：waters xbridge Pre C18，10um，19mm*250mm。制备条件：流动相A：0.05％三氟乙酸水溶液(百分数为体积百分数)，流动相B：乙腈；梯度洗脱条件：25-75％溶剂A和75％-25％溶剂B；检测波长：214nm、和/或254nm、和/或262nm；流速：10.0mL/分钟。
快速柱层析(Flash柱层析)(flash system/CheetahTM)使用的是Agela Technologies MP200，配套使用的分离柱为Flash columm Silica-CS(80g)，Cat No.CS140080-0。
薄层层析色谱是烟台新诺化工，涂层厚度0.2±0.03mm，规格20×20cm。柱层析一般使用烟台黄海200-300目硅胶作为载体。
实施例1：化合物1.7和1.8的合成
Figure PCTCN2017083031-appb-000050
步骤1：化合物1.2的合成
将化合物1.1(20g，57.4mmol)和溴乙腈(6.9g，57.4mmol)溶于乙酸乙酯(200mL)中，将反应体系加热回流搅拌3小时后过滤除去固体，并将滤饼用乙酸乙酯洗涤两次。滤液减压旋蒸除去溶剂得到化合物1.2(17g，产率：76％)为淡黄色油状物，可直接用于下一步反应。
步骤2：化合物1.3的合成
将4-溴-2-硝基苯甲醛(10g，43.9mmol)、化合物1.2(17g，43.9mmol)和甲苯(170mL)的混合溶液在回流条件下搅拌2小时，得到的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，直到TLC板检测不到产物，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。过滤、滤饼干燥后得到化合物1.3(8.2g，产率：55％)为类白色固体。
步骤3：化合物1.4的合成
将化合物1.3(4.2g，12.4mmol)和乙酸(80mL)的混合物加热到80℃后，15分钟内向上述混合物中分批加入铁粉(4.1g，74.3mmol)，保持反应温度不超过90℃，继续搅拌3小时。将反应体系冷却至室温，用硅藻土过滤，用乙酸乙酯淋洗三次。滤液减压浓缩，得到的残留物用冷水稀释后用饱和的碳酸氢钠水溶液调节pH>8，用乙酸乙酯萃取水相三次，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、浓缩，得到的残留物用10％的乙酸乙酯石油醚溶液打浆，过滤，滤饼干燥后得到化合物1.4(3.0g，产率：78％)为类白色固体。
步骤4：化合物1.5的合成
向化合物1.4(3.0g，9.7mmol)和三乙胺(1.47g，14.6mmol)的二氯甲烷(50mL)溶液中加入二碳酸二叔丁酯((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(100mL)稀释，有机相分别用盐酸溶液(3.0M)、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、浓缩，得到的残留物用 10％的乙酸乙酯石油醚溶液打浆，过滤，滤饼干燥后得到化合物1.5(1.6g，产率：40％)为类白色固体。
m/z:[M+H]+409
步骤5：化合物1.6的合成
冰浴条件下，向化合物1.5(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，5.9mmol)。反应体系在室温下搅拌16小时，然后用盐酸溶液(0.5M)调节pH＝6，混合物用乙酸乙酯萃取两次，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、浓缩得到化合物1.6(1.1g，产率：74％)为淡黄色泡沫状固体。
m/z:[M+H]+381
步骤6：化合物1.7的合成
将化合物1.6(1.1g，2.8mmol)、2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(1.6g，4.33mmol)、二甲胺盐酸盐(470mg，5.77mmol)和N,N-二异丙基乙胺(560mg，4.37mmol)的N,N-二甲基甲酰胺(10mL)混合物在室温下搅拌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、浓缩，得到的残留物用硅胶柱层析(甲醇/二氯甲烷＝1/20)纯化得到化合物1.7(400mg，产率：34％)为淡黄色固体。
m/z:[M+H]+408
步骤8：化合物1.8的合成
氮气保护下，将化合物1.7(380mg，0.93mmol)、醋酸钾(274mg，2.79mmol)、联硼酸频那醇酯(354mg，1.40mmol)和Pd(dppf)2Cl2的1,4-二氧六环(10mL)混合物在80℃下搅拌5小时。反应体系冷却至室温，用硅藻土过滤，并用10％的甲醇二氯甲烷溶液淋洗，滤液浓缩，得到的残留物用硅胶柱层析(甲醇/二氯甲烷＝1/20～1/10)纯化得到化合物1.8(208mg，产率：49％)为红色固体。
m/z:[M+H]+456
实施例2：化合物2.4的合成
Figure PCTCN2017083031-appb-000051
步骤1：化合物2.1的合成
冰浴条件下，向5-溴-2-甲基-3-硝基苯胺(2.0g，8.66mmol)和水(8mL)和6N盐酸(8mL)的混悬液中滴加亚硝酸钠水溶液(627mg，9.09mmol，5mL)，然后滴加氯化亚锡的浓盐酸溶液(5.4g，25.9mmol，5mL)，反应体系在0℃下搅拌30分钟。反应液用浓氨水中和至pH＝8，用乙酸乙酯萃取，合并有机相用饱和食盐水洗涤、无水硫酸 钠干燥，过滤、浓缩。粗品用甲基叔丁基醚打浆，过滤得化合物2.1(700mg，产率：33％)为淡黄色固体。
m/z:[M+H]+246
步骤2：化合物2.2的合成
化合物2.1(700mg，2.84mmol)一次性加入到硝酸铈铵(3.28g，5.97mmol)的氘代甲醇(7mL)溶液中，反应体系室温搅拌10分钟后用硅藻土过滤，滤液浓缩并用硅胶柱层析(100％石油醚)纯化得到化合物2.2(300mg，产率：49％)为淡黄色油状物。
步骤3：化合物2.3的合成
将化合物2.2(0.85g，3.92mmol)和N,N-二甲基甲酰胺二甲基缩醛(5mL)溶于N,N-二甲基甲酰胺(10mL)中，反应体系在105℃下搅拌过夜，减压浓缩得到化合物2.3(1.0g，产率：94％)为红色固体。
m/z:[M+H]+272
步骤4：化合物2.4的合成向化合物2.3(1.0g，3.93mmol)的四氢呋喃和水中(5mL/5mL)的混合溶液中加入高碘酸钠(2.5g，11.8mmol)，反应体系在室温下搅拌16小时，过滤除去不溶物，滤液用乙酸乙酯萃取，合并有机相用饱和食盐水洗涤，无水硫酸钠干燥、浓缩，残留物用硅胶柱层析(石油醚/乙酸乙酯＝10/1～5/1)纯化得化合物2.4(200mg，22.0％)为淡黄色固体。
1H NMR(400MHz,CDCl3):δ10.38(s,1H),8.26(s,1H),7.93(s,1H)。
实施例3：化合物1.9～1.13的合成
化合物1.9～1.13根据实施例1化合物1.7的合成方法，将步骤6中的二甲胺盐酸盐替换为相应的胺得到：
Figure PCTCN2017083031-appb-000052
Figure PCTCN2017083031-appb-000053
实施例4：化合物1.14～1.17的合成
化合物1.14～1.17根据实施例1化合物1.7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-甲氧基-6-硝基苯甲醛、4-溴-2-甲基-6-硝基苯甲醛或4-溴-2-氯-6-硝基苯甲醛或化合物2.4得到：
Figure PCTCN2017083031-appb-000054
编号 R4 R5 MS
1.14 -OCH3 H m/z:[M+H]+494
1.15 -CH3 H m/z:[M+H]+478
1.16 -Cl H m/z:[M+H]+498
1.17 -D H m/z:[M+H]+465
实施例5：化合物1.19的合成
化合物1.19根据实施例1化合物1.8的合成方法，将步骤6中的二甲胺盐酸盐替换为2-(丙基胺)乙醇得到：
Figure PCTCN2017083031-appb-000055
m/z:[M+H]+514
实施例6：化合物1.20～1.22的合成
化合物1.20根据实施例1化合物1.8的合成方法，将步骤7中的化合物1.7替换为化合物1.10得到：
化合物1.21和1.22根据实施例1化合物1.8的合成方法，将步骤2中的4-溴-2-硝基苯甲醛替换为4-溴-5-氟-2-硝基苯甲醛或4-溴-2-氟-6-硝基苯甲醛得到：
Figure PCTCN2017083031-appb-000056
编号 R4 R5 MS
1.20 H H m/z:[M+H]+512
1.21 H F m/z:[M+H]+530
1.22 F H m/z:[M+H]+530
实施例7：化合物3.8的合成
Figure PCTCN2017083031-appb-000057
步骤1：化合物3.1的合成
1，对甲苯磺酸催化剂的制备：将对甲苯磺酸一水合物(100mg)和苯(20mL)在Dean-stark蒸馏器中加热回流2小时，直到溶液变得澄清。
2，将1-甲基-1H-吡咯-2-甲醛(2.0g，18.3mmol)和2,2-二甲基-1,3-丙二醇(4.9g，47.6mmol)的苯(20mL)溶液在Dean-stark蒸馏器中加热回流15分钟，将制备好的对甲苯磺酸催化剂缓慢滴加到上述溶液中，加毕，将反应体系在85℃下搅拌2小时，冷却至室温，过滤，滤液减压浓缩，得到的残留物用硅胶柱层析(乙酸乙酯/石油醚＝1/100)纯化得到化合物3.1(1.0g，产率：28％)为无色油状物。
1HNMR(400MHz,CDCl3):δ6.59-6.58(m,1H),6.25-6.23(m,1H),6.06-6.05(m,1H),5.45(s,1H),3.80(s,3H),3.78(d,J＝11.2Hz,2H),3.63(d,J＝10.8Hz,2H),1.33(s,3H),0.82(s,3H)。
步骤2：化合物3.2的合成
向化合物3.1(1.0g，5.12mmol)的四氢呋喃(10mL)溶液中分批加入N-溴代琥珀酰亚胺(NBS)(960mg，5.38mmol)，反应体系在室温下搅拌1小时后用乙酸乙酯(100mL)稀释，有机相用氢氧化钠水溶液(2.0M)和饱和食盐水洗涤，分离有机相，用无水硫酸钠干燥，过滤、浓缩，得到的残留物用硅胶柱层析(乙酸乙酯/石油醚＝1/100～1/10)纯化得到化合物3.2(800mg，产率：57％)为无色油状物，可直接用于下步反应。
步骤3：化合物3.3的合成
向化合物3.2(800mg，2.92mmol)的丙酮(4mL)中加入浓盐酸(1mL)，反应体系在40℃下搅拌1小时后用水(50mL)稀释，混合物用乙酸乙酯萃取三次，合并有机相，有机相用饱和食盐水洗涤，用无水硫酸钠干燥，过滤、浓缩，得到的残留物用硅胶柱层析(乙酸乙酯/石油醚＝1/9)纯化得到化合物3.3(145mg，产率：26％)为棕色油状物。
1HNMR(400MHz,CDCl3):δ9.45(s,1H),6.90(d,J＝4.0Hz,1H),6.23(d,J＝4.4Hz,1H),3.96(s,3H)。
步骤4：化合物3.4的合成
向化合物3.3(145mg，0.77mmol)的四氢呋喃(10mL)中分批加入乙氧甲酰基亚甲基三苯基膦(537g，1.54mmol)。反应体系在室温下搅拌2天直到TLC监测反应完成，向反应体系中加入水(30mL)淬灭反应，混合物用乙酸乙酯萃取(20mL×2)。合并有机相，有机相用饱和水盐水洗涤，分离有机相，用无水硫酸钠干燥，过滤、浓缩，得到的残留物用硅胶柱层析(25％的乙酸乙酯石油醚溶液)纯化得到化合物3.4(200mg，产率：100％)为类白色固体。
步骤5：化合物3.5的合成
向化合物3.4(200mg，0.77mmol)的甲醇(2mL)、四氢呋喃(0.5mL)和水(0.5mL)的混合溶液中加入氢氧化锂一水合物(162mg，3.87mmol)。反应体系在室温下反 应16小时后用盐酸溶液(3.0M)淬灭反应，并调节pH＝5。将混合物用乙酸乙酯萃取两遍，合并有机相，有机相用饱和食盐水洗涤，并用无水硫酸钠干燥，过滤、浓缩得到化合物3.5(170mg，产率95％)为淡黄色固体，可直接用于下一步反应。
步骤6：化合物3.6的合成
氮气保护下，向化合物3.5(170mg，0.74mmol)的氯仿(2mL)溶液中滴加二氯亚砜(1mL)和1滴N,N-二甲基甲酰胺，加毕，将反应体系升温至回流并搅拌1小时。将反应体系冷却至室温并减压浓缩得到化合物3.6(165mg，产率：90％)为棕色固体，可直接用于下一步反应。
步骤7：化合物3.7的合成
冰浴条件下，向化合物3.6(165mg，0.66mmol)的丙酮(5.0mL)溶液中滴加饱和的叠氮化钠水溶液(1mL)。反应体系在冰浴条件下剧烈搅拌1小时直到TLC检测反应已经完成。反应体系用二氯甲烷稀释，并用水和饱和食盐水洗涤，分离有机相并用无水硫酸钠干燥，过滤、浓缩得到化合物3.7(188mg，产率100％)为淡黄色固体，可直接用于下步反应。
步骤8：化合物3.8的合成
向10mL的装有空气冷凝管的圆底烧瓶中加入二苯乙醚(3mL)，将反应瓶加热至240℃，将化合物3.7(188mg，0.74mmol)的二氯甲烷溶液(3mL)用注射器缓慢加入到上述溶液中，将反应体系在240℃下搅拌20分钟后冷却至50℃，将反应体系倒入石油醚中(50mL)并继续搅拌2小时，将得到的混合物过滤，滤饼用石油醚淋洗，干燥后得到化合物3.8(90mg，产率：54％)为深灰色固体。
m/z:[M+H]+227
实施例8：化合物3.9的合成
化合物3.9根据实施例7化合物3.8的合成方法，将步骤4中的化合物3.3替换为5-溴-噻吩-2-甲醛得到：
Figure PCTCN2017083031-appb-000058
m/z:[M+H]+230
实施例9：化合物4.2的合成
Figure PCTCN2017083031-appb-000059
步骤1：化合物4.1的合成
向2,4-二溴苯甲酸(1.0g，3.57mmol)的N,N-二甲基甲酰胺(10mL)溶液中分别 依次加入1-羟基苯并三唑(530mg，3.93mmol)和1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(820mg，4.29mmol)。将反应体系冷却至0℃后缓慢滴加氨水(20mL，25％)，加毕，反应体系升至室温并搅拌过夜。向反应体系中加入水(50mL)，过滤，滤饼用水淋洗三次，干燥后得到化合物4.1(660mg，产率：66％)为白色固体。
m/z:[M+H]+278
步骤2：化合物4.2的合成
将溴化亚铜(15.4mg，0.11mmol)，碳酸铯(701mg，2.15mmol)，化合物4.1(300mg，1.08mmol)、环戊酮(136mg，1.61mmol)和二甲亚砜(10mL)置于封管(20mL)中，将封管用氮气置换三遍。将反应体系在80℃下搅拌过夜后冷却至室温，分别向反应体系中加入饱和食盐水(50mL)和乙酸乙酯(50mL)，分离有机相，水相用乙酸乙酯(20mL x 2)萃取。合并有机相，用无水硫酸钠干燥，过滤、浓缩，得到的残留物用甲基叔丁基醚(50mL)和二氯甲烷(5mL)的混合溶液打浆，过滤，干燥后得到化合物4.2(150mg，产率：42％)为黄色固体。
m/z:[M+H]+264
实施例10：化合物4.3的合成
化合物4.3根据实施例9化合物4.2的合成方法，将步骤2中的环戊酮替换为丙酮得到：
Figure PCTCN2017083031-appb-000060
m/z:[M+H]+238
实施例11：化合物5.3的合成
Figure PCTCN2017083031-appb-000061
步骤1：化合物5.1的合成
向4-溴-2-甲基苯甲酸(1.0g，4.65mmol)的N,N-二甲基甲酰胺(10mL)溶液中分别加入碳酸钾(670mg，4.89mmol)和碘甲烷(900mg，6.98mmol)。反应体系在室温下搅拌2小时后加入水(60mL)淬灭反应，混合物用乙酸乙酯(40mL×2)萃取，合并有机相，有机相用饱和食盐水洗涤，分离有机相，用无水硫酸钠干燥，过滤、浓缩得到化合物5.1(1.0g，产率93％)为淡红色油状物，可直接用于下一步反应。
步骤2：化合物5.2的合成
向化合物5.1(300mg，1.31mmol)的氯仿(10mL)溶液中一次加入NBS(350mg，1.96mmol)和偶氮二异丁氰(100mg，0.65mmol)。将反应体系加热到80℃并搅拌2小时后冷却至室温，过滤，滤液用饱和食盐水洗涤，分离有机相，用无水硫酸钠干燥， 过滤、浓缩得到化合物5.2(300mg，产率：75％)为红色油状物，可直接用于下一步反应。
步骤3：化合物5.3的合成
向化合物5.2(300mg，0.97mmol)的四氢呋喃(2mL)溶液中加入氨水(2mL)。反应体系在20℃下搅拌12小时。将产生的固体过滤，真空干燥后得到化合物5.3(100mg，产率50％)为类白色固体。
m/z:[M+H]+212
实施例12：化合物5.4的合成
化合物5.4根据实施例11化合物5.3的合成方法，将步骤1中的4-溴-2-甲基苯甲酸替换为5-溴-3-甲基吡啶-2-羧酸得到：
Figure PCTCN2017083031-appb-000062
m/z:[M+H]+213
实施例13：化合物6.2的合成
Figure PCTCN2017083031-appb-000063
步骤1：化合物6.1的合成
冰浴条件下，将甲胺的四氢呋喃溶液(2.0M，11mL，27.8mmol)溶解到四氢呋喃(10mL)中，并向该体系中滴加正丁基锂(8.2mL，20.5mmol)。滴加完毕，反应于0℃下继续搅拌1小时，然后将反应体系冷却至-78℃。向体系中加入4-溴-2-氟-苯甲酸(1.0g，4.57mmol)的四氢呋喃(5mL)溶液，于-78℃搅拌半小时后加入盐酸(1.0M)淬灭，乙酸乙酯(5mLx3)萃取。合并有机相，有机层用饱和食盐水洗涤，无水硫酸钠干燥。过滤，浓缩得化合物6.1(700mg，产率：68％)为淡黄色固体。
m/z:[M+H]+230
步骤2：化合物6.2的合成
将化合物6.1(580mg，2.52mmol)和尿素(3g)加热至熔化，于150℃搅拌7小时。待反应体系冷却至室温后，加水淬灭反应，用乙酸乙酯萃取。合并有机相，有机层用饱和食盐水洗涤，无水硫酸钠干燥。过滤，浓缩得化合物6.2(320mg，产率：35％)为灰色固体。
m/z:[M+H]+255
实施例14：化合物15.1和15.2的合成
Figure PCTCN2017083031-appb-000064
步骤1：化合物15.1的合成
冰浴条件下，向6-溴异喹啉-1(2H)-酮(800mg，3.57mmol)的N,N-二甲基甲酰胺(8mL)溶液中分批加入钠氢(160mg，3.93mmol，60％)，加毕，反应体系升至室温搅拌20分钟，加入碘乙烷(800mg，5.36mmol)。加毕，反应体系在室温下继续搅拌2小时，加入水(20mL)淬灭反应，用乙酸乙酯(20mL×2)萃取，合并有机相，有机相用饱和食盐水洗涤，分离有机相，用无水硫酸钠干燥，过滤、浓缩，得到的残留物用硅胶柱层析(乙酸乙酯：石油醚＝1:4)纯化得到化合物15.1(800mg，产率：91％)为白色固体。
1H NMR(400MHz,CDCl3):δ8.30(d,J＝8.8Hz,1H),7.67(s,1H),7.58(d,J＝8.8Hz,1H),7.12(d,J＝7.2Hz,1H),6.43(d,J＝7.2Hz,1H),4.08-4.02(m,2H),1.40(t,3H)。
步骤2：化合物15.2的合成
氮气保护下，向化合物15.1(500mg，1.98mmol)的1,4-二氧六环(6mL)溶液中分别加入醋酸钾(580mg，5.95mmol)、联硼酸频那醇酯(760mg，2.97mmol)和Pd(dppf)2Cl2(160mg，0.19mmol)。反应体系在80℃下搅拌2小时。反应体系冷却至室温，加入水(60mL)淬灭反应，用乙酸乙酯(40mL×2)萃取，合并有机相，有机相用饱和食盐水洗涤，分离有机相用无水硫酸钠干燥，过滤、浓缩，得到的残留物用硅胶柱层析(乙酸乙酯：石油醚＝1:4)纯化得到化合物15.2(500mg，产率：83％)为黄色固体。
m/z:[M+H]+300
实施例15：化合物15.3～15.10的合成
化合物15.3～15.10根据实施例14化合物15.1的合成方法，用6-溴异喹啉-1(2H)-酮、6-溴-3,4-二氢异喹啉-1(2H)-酮、化合物3.9、4.2、4.3或5.4与相应的碘化物或溴化物反应得到：
Figure PCTCN2017083031-appb-000065
实施例16：化合物16.1的合成
Figure PCTCN2017083031-appb-000066
将6-溴异喹啉-1(2H)-酮(150mg，0.67mmol)、碳酸铯(650mg，2.01mmol)和2-溴乙醇(170mg，1.34mmol)的N,N-二甲基甲酰胺(2mL)溶液在室温下搅拌2天，将反应体系用乙酸乙酯(100mL)稀释，混合物分别用水和饱和食盐水洗涤，分离有机相，有无水硫酸钠干燥，过滤、浓缩，得到的残留物用石油醚打浆，过滤、滤饼干燥后得到化合物16.1(120mg，产率：60％)为类白色固体。
m/z:[M+H]+268
实施例17：化合物16.2～16.75的合成
化合物16.2～16.75根据实施例16化合物16.1的合成方法，用6-溴异喹啉-1(2H)-酮、6-溴-3,4-二氢异喹啉-1(2H)-酮、7-溴喹唑啉-4(3H)-酮、6-溴酞嗪-1(2H)-酮、化合物4.3、5.3、5.4或6.2与相应的溴化物或氯化物反应得到：
Figure PCTCN2017083031-appb-000067
Figure PCTCN2017083031-appb-000068
实施例18：化合物17.1的合成
Figure PCTCN2017083031-appb-000069
将化合物16.5(50.0mg，0.154mmol)溶解在四氢呋喃(5mL)中，用冰水浴冷却至0℃，氮气保护下下滴加甲基溴化镁(0.18mL，3.0M，0.54mmol)。撤掉冰水浴在室温下搅拌1.5小时，加饱和氯化铵水溶液(20mL)，用乙酸乙酯(20mL×2)萃取，合并有机层，并用饱和食盐水洗涤，用无水硫酸钠干燥。过滤，减压蒸馏除去溶剂，到的残留物用薄层层析硅胶板纯化(乙酸乙酯/石油醚＝1/1)得化合物17.1(13mg，产率：27％)为黄色固体。
m/z:[M+H]+310
实施例19：化合物17.2～17.5的合成
化合物17.2～17.5根据实施例18化合物17.1的合成方法，将化合物16.5替换为化合物16.6、16.23、16.26或16.27得到：
编号 名称 MS
17.2 6-溴-2-(2-羟基-2-甲基丙基)异喹啉-1(2H)-酮 m/z:[M+H]+296
17.3 6-溴-2-(2-羟基-2-甲基丙基)-3,4-二氢异喹啉-1(2H)-酮 m/z:[M+H]+298
17.4 6-溴-2-(2-羟基-2-甲基丙基)酞嗪-2(1H)-酮 m/z:[M+H]+297
17.5 7-溴-3-(2-羟基-2-甲基丙基)喹唑啉-4(3H)-酮 m/z:[M+H]+297
实施例20：化合物18.1的合成
Figure PCTCN2017083031-appb-000070
将化合物16.8(0.2g，0.76mmol)，碳酸钾(0.21g，1.52mmol)，双氧水(0.5mL，30％)，二甲基亚砜(2.0mL)加入一个25mL的单口瓶中。将该反应体系在室温下搅拌1h。加水，过滤，洗涤滤饼，得到化合物18.1(160mg，产率：80％)为浅黄色固体。
m/z:[M+H]+281
实施例21：化合物18.2～18.4的合成
化合物18.2～18.4根据实施例20化合物18.1的合成方法，将化合物16.8替换为化合物16.14、16.15或16.19得到：
编号 名称 MS
18.2 2-(6-溴-3-甲基-1-氧代异喹啉基-2(1H)-基)乙酰胺 m/z:[M+H]+295
18.3 2-(7-溴-4-氧代喹唑啉-3(4H)-基)乙酰胺 m/z:[M+H]+282
18.4 2-(6-溴-1-氧代酞嗪-2(1H)-基)乙酰胺 m/z:[M+H]+282
实施例22：化合物19.1的合成
Figure PCTCN2017083031-appb-000071
将化合物16.10(55mg，0.18mmol)，硼氢化锂(0.5mL，2M四氢呋喃溶液)，四氢呋喃(1.0mL)加入一个25mL的单口瓶中。将该反应体系在室温下搅拌2小时。过滤，滤液加入水(10mL)中，用乙酸乙酯(10mL×2)萃取，合并有机层。有机相用饱和食盐水洗涤，用无水硫酸钠干燥。过滤，减压蒸馏除去溶剂，得到的残留物用硅胶柱层析纯化(甲醇/二氯甲烷＝1/10)得化合物19.1(23mg，产率：50％)为白色固体。
m/z:[M+H]+256
实施例23：化合物19.2的合成
化合物19.2根据实施例22化合物19.1的合成方法，将化合物16.10替换为化合物16.29得到：
Figure PCTCN2017083031-appb-000072
m/z:[M+H]+257
实施例24：化合物20.2的合成
Figure PCTCN2017083031-appb-000073
步骤1：化合物20.1的合成
将化合物16.16(2.80g，7.62mmol)溶入二氯甲烷(30mL)中。然后在冰水浴下，滴加三氟乙酸(15mL)，接着撤掉冰浴在室温下搅拌1小时。将反应液直接减压旋干，加碳酸氢钠饱和溶液调pH至7～8，用乙酸乙酯(50mL×2)萃取，合并有机层，并用饱和食盐水洗涤，用无水硫酸钠干燥。过滤，减压蒸馏除去溶剂，得到化合物20.1(2.00g，产率：98％)为黄色固体。
m/z:[M+H]+267
步骤2：化合物20.2的合成
将化合物20.1(150mg，0.56mmol)和三乙胺(284mg，2.81mmol)加入二氯甲烷(3mL)中。然后在冰水浴下，滴加乙酰氯(66mg，0.84mmol)，接着撤掉冰浴在室温下搅拌2小时。往反应体系中加水(5mL)，用二氯甲烷(10mL×2)萃取，合并有机层，并用饱和食盐水洗涤，用无水硫酸钠干燥。过滤，减压蒸馏除去溶剂，得到化合物20.2(90mg，产率：52％)为黄色固体。
m/z:[M+H]+309
实施例25：化合物20.3～20.6的合成
化合物20.3～20.6根据实施例24化合物20.2的合成方法，将化合物步骤2中的乙酰氯替换为甲基磺酰氯和16.16、16.55、16.56或16.57反应得到：
Figure PCTCN2017083031-appb-000074
Figure PCTCN2017083031-appb-000075
实施例26：化合物21.5的合成
Figure PCTCN2017083031-appb-000076
步骤1：化合物21.2的合成
将化合物21.1(10.0g，66.2mmol)，间氯过氧苯甲酸(16.3g，94.5mmol)和二氯甲烷(140mL)加入一个250mL的单口反应瓶中。在室温下搅拌过夜，加碳酸氢钠饱和溶液调pH至7～8，用二氯甲烷(50mL×2)萃取，合并有机层，并用饱和食盐水洗涤，用无水硫酸钠干燥。过滤，减压蒸馏除去溶剂，向残留物中加入三氯氧磷(60mL)，并加热回流搅拌4小时。减压蒸馏除去三氯氧磷，将得到的残留物倒入冰水中并用碳酸钠固体中和至弱碱性，用乙酸乙酯(60mL×3)萃取，合并有机层，并用饱和食盐水洗涤，用无水硫酸钠干燥。过滤，减压蒸馏除去溶剂，得到的残留物用快速柱层析(乙酸乙酯/石油醚＝0％～30％)分离得化合物21.2(1.94g，产率：16％)为橙色油状物。
m/z:[M+H]+186
步骤2：化合物21.3的合成
将化合物21.3(1.94g，10.5mmol)，间氯过氧苯甲酸(2.25g，13.1mmol)和二氯甲烷(25mL)加入一个100mL的单口反应瓶中。在室温下搅拌过夜，加碳酸氢钠饱和溶液调pH至7～8，用二氯甲烷(50mL×2)萃取，合并有机层，并用饱和食盐水洗涤，用无水硫酸钠干燥。过滤，减压蒸馏除去溶剂，得到化合物21.3(1.90g，产率：90％)为白色固体。
m/z:[M+H]+202
步骤3：化合物21.4的合成
将化合物21.3(1.90g，9.42mmol)加入三氯氧磷(20mL)中，并加热回流搅拌4小时。减压蒸馏除去三氯氧磷，将得到的残留物倒入冰水中并用碳酸钠固体中和至弱碱性，用乙酸乙酯(50mL×3)萃取，合并有机层，并用饱和食盐水洗涤，用无水硫酸钠干燥。过滤，减压蒸馏除去溶剂，得到的残留物用快速过柱机纯化(洗脱剂：乙酸乙酯/石油醚＝0％～50％)得化合物21.4(1.40g，产率：68％)为黄色固体。
m/z:[M+H]+220
步骤4：化合物21.5的合成
将化合物21.4(0.40g，1.82mmol)，乙醇胺(1.8mL)和甲醇(40mL)加入一个100mL的单口反应瓶中。在室温下搅拌过夜，减压蒸馏除去溶剂，得到的残留物用快速 柱层析纯化(甲醇/二氯甲烷＝0％～5％)得化合物21.5(0.37g，产率：95％)为黄色油状物。
m/z:[M+H]+213
实施例27：化合物22.1的合成
Figure PCTCN2017083031-appb-000077
将化合物16.17(500mg，1.67mmol)溶解在冰醋酸(2.5mL)中，冰水浴下滴加双氧水(2.5mL)，室温下搅拌过夜。水泵抽真空除掉部分溶剂，将残留物倒入水中(100mL)，降至0℃搅拌15分钟后用布氏漏斗过滤，得到的固体用水(10mL×2)和石油醚(10mL×2)洗涤并干燥得到化合物22.1(460mg，产率：83％)为白色固体。
m/z:[M+H]+331
实施例28：化合物22.2～22.6的合成
化合物22.2～22.6根据实施例27化合物22.1的合成方法，将化合物16.7替换为16.23、16.25、16.28、16.31或16.58得到：
编号 名称 MS
22.2 7-溴-1-甲基-3-(2-(甲磺酰基)乙基)喹唑啉-2,4(1H,3H)-二酮 m/z:[M+H]+361
22.3 6-溴-2-(2-(甲磺酰基)乙基)异喹啉-1(2H)-酮 m/z:[M+H]+330
22.4 6-溴-2-(2-(甲磺酰基)乙基)酞嗪-1(2H)-酮 m/z:[M+H]+331
22.5 6-溴-2-(2-(甲磺酰基)丙基)酞嗪-1(2H)-酮 m/z:[M+H]+345
22.6 6-溴-2-(2-(乙基磺酰基)乙基)酞嗪-1(2H)-酮 m/z:[M+H]+345
实施例29：化合物22.7～22.8的合成
化合物22.7～22.8根据实施例14步骤2化合物15.2的合成方法，用化合物22.4或16.64和联硼酸频那醇酯反应得到：
Figure PCTCN2017083031-appb-000078
m/z:[M+H]+379
Figure PCTCN2017083031-appb-000079
m/z:[M+H]+365
实施例30：化合物22.11的合成
Figure PCTCN2017083031-appb-000080
将化合物16.31(1.22g，4.08mmol)溶解在冰醋酸(10mL)中，冰水浴下滴加双 氧水(10mL)，室温下搅拌1.5小时。将反应液倒入水中(100mL)，降至0℃用饱和碳酸氢钠溶液调至弱碱性，用10％的甲醇二氯甲烷溶液(30mL ×3)萃取，饱和食盐水洗涤分离有机相，用无水硫酸钠干燥，过滤、减压浓缩得到化合物22.11(1.15g，产率：89％)为淡黄色固体。
m/z:[M+H]+315
实施例31：化合物23.1的合成
Figure PCTCN2017083031-appb-000081
将化合物6.2(150mg，0.59mmol)，2-氯-N-甲基乙酰胺(70mg，0.65mmol)和碳酸铯(287mg，0.88mmol)加入到N,N-二甲基甲酰胺(8mL)中，体系于90℃加热搅拌1小时。待冷至室温，加水淬灭，乙酸乙酯萃取。合并有机相，有机层用饱和食盐水洗涤，无水硫酸钠干燥。过滤，浓缩，所得残留物经硅胶柱层析纯化(石油醚/乙酸乙酯＝1/1)得到化合物23.1(70mg，产率：27％)为白色固体。
m/z:[M+H]+299
实施例32：化合物24.1的合成
Figure PCTCN2017083031-appb-000082
将化合物6.2(150mg，0.59mmol)，2-氯-N-甲基乙酰胺(70mg，0.65mmol)和碳酸铯(287mg，0.88mmol)加入到N,N-二甲基甲酰胺(5mL)中，体系于75℃加热搅拌2小时。加水淬灭，有固体析出。过滤，用水洗涤，滤饼干燥得化合物24.1(85mg，产率：44％)为灰色固体。
m/z:[M+H]+326
实施例33：化合物24.2的合成
化合物24.2根据实施例32化合物24.1的合成方法，将2-氯-N-甲基乙酰胺替换为1-氯-2-甲基-2-丙醇得到：
Figure PCTCN2017083031-appb-000083
m/z:[M+H]+327
实施例34：化合物25.1的合成
Figure PCTCN2017083031-appb-000084
将化合物16.30(0.3g，0.8mmol)，甲胺的四氢呋喃溶液(2.0M，10.0mL)加入一个25mL的封管中。室温下搅拌12小时，过滤。滤饼用石油醚洗涤，干燥，得化合物25.1(180mg，产率：66％)为白色固体。
m/z:[M+H]+312
实施例35：化合物26.1的合成
Figure PCTCN2017083031-appb-000085
将氯磺酰异氰酸酯(0.2g，1.41mmol)，叔丁醇(0.19g，2.54mmol)，二氯甲烷(3.0mL)加入一个25mL的单口瓶中。将该反应体系在0℃的条件下搅拌1.5个小时。接着，在0℃的条件下把化合物20.1(0.38g，1.41mmol)和三乙胺(0.71g，7.0mmol)的二氯甲烷溶液(2.0mL)慢慢滴加到上述反应体系中。在室温下搅拌三个小时后，反应用水(20mL)淬灭，用乙酸乙酯(20mL×2)萃取，合并有机层。有机相用饱和食盐水洗涤，用无水硫酸钠干燥。过滤，减压蒸馏除去溶剂，得到的残留物用硅胶柱层析纯化(甲醇/二氯甲烷＝1/10)得化合物26.1(0.26g，产率：42％)为白色固体。
m/z:[M+H]+446
实施例36：化合物27.1的合成
Figure PCTCN2017083031-appb-000086
冰浴条件下，向化合物16.1(100mg，0.373mmol)和中间体氯磷酸二甲酯(108mg，0.746mmol)的二氯甲烷(5mL)中滴加吡啶(148mg，1.86mmol)。反应体系于室温下搅拌1小时。减压浓缩，所得残留物经prep-TLC(石油醚：乙酸乙酯＝1:1)纯化得化合物27.1(140mg，产率：99％)为无色油状物。
m/z:[M+H]+376
实施例37：化合物28.3的合成
Figure PCTCN2017083031-appb-000087
步骤1：化合物28.1的合成
将化合物16.60(1.55g，3.99mmol)和碘化钠(1.79g，8.93mmol)加入到吡啶(15 mL)中，体系于115℃加热搅拌过夜。待冷至室温后减压浓缩，所得残留物溶于水中，用甲基叔丁基醚萃取除掉杂质。水相用2N盐酸调pH＝2，然后用二氯甲烷萃取。合并有机相，有机层用饱和食盐水洗涤，无水硫酸钠干燥。过滤，浓缩得到化合物28.1(1.15g，产率：80％)为白色固体。
m/z:[M+H]+360
步骤2：化合物28.2的合成
将草酰氯(0.81g，6.39mmol)加到二氯甲烷(20mL)中，随后加入两滴N,N-二甲基甲酰胺并在室温下搅拌15分钟。随后将溶解在二氯甲烷(20mL)的化合物28.1(1.15g，3.19mmol)滴加到该体系中。室温下搅拌40分钟后，减压浓缩得到化合物1.4(1.21g，产率：100％)为黄色油状物。
步骤3：化合物28.3的合成
-30℃下，向化合物28.2(1.21g，3.19mmol)的四氢呋喃(50mL)溶液中滴加甲基溴化镁的乙醚溶液(2.1mL，6.30mmol，3M)。将反应体系在-30℃下搅拌1.5小时后用饱和氯化铵水溶液淬灭，乙酸乙酯萃取。合并有机相，有机层用饱和食盐水洗涤，无水硫酸钠干燥。过滤，浓缩，所得残留物经硅胶柱层析纯化(二氯甲烷/甲醇＝10/1)得到化合物28.3(1.0g，产率：87％)为黄色油状物。
m/z:[M+H]+358
实施例38：化合物28.4的合成
化合物28.4根据实施例37化合物28.3的合成方法，将化合物16.60替换为化合物16.61得到：
Figure PCTCN2017083031-appb-000088
m/z:[M+H]+359
实施例39：化合物29.1的合成
Figure PCTCN2017083031-appb-000089
将化合物16.45(100mg，0.314mmol)和劳森试剂(380mg，0.942mmol)溶解到甲苯(3mL)中，该体系于110℃搅拌回流7天。减压浓缩，所得残留物经prep-TLC(二氯甲烷/甲醇＝20/1)纯化得化合物29.1(75mg，产率：71％)为浅褐色固体。
m/z:[M+H]+334
实施例40：化合物29.2的合成
化合物29.2根据实施例39化合物29.1的合成方法，将化合物16.45替换为化合物16.64得到：
Figure PCTCN2017083031-appb-000090
m/z:[M+H]+335
实施例41：化合物30.1的合成
Figure PCTCN2017083031-appb-000091
向化合物22.4(500mg，1.51mmol)和五硫化二磷(1.01g，4.53mmol)的混合物中加入吡啶(20mL)，反应混合物于110℃搅拌2小时后升温至130℃继续搅拌2小时。减压浓缩，所得残留物分散到氨水(10mL)中，搅拌10分钟。过滤，收集滤饼，再次分散到氨水(10mL)中，继续搅拌10分钟。过滤，收集滤饼，真空干燥得化合物30.1(410mg，产率：78％)为灰色固体。
m/z:[M+H]+347
实施例42：化合物30.2～30.6的合成
化合物30.2～30.6根据实施例41化合物30.1的合成方法，将化合物22.4替换为化合物16.42、16.62、16.68、16.74或16.75得到：
编号 名称 MS
30.2 6-溴-2-(嘧啶-2-基甲基)异喹啉-1(2H)-硫酮 m/z:[M+H]+332
30.3 6-溴-2-((4,6-二甲氧基嘧啶-2-基)甲基)异喹啉-1(2H)-硫酮 m/z:[M+H]+392
30.4 6-溴-2-(吡嗪-2-基甲基)异喹啉-1(2H)-硫酮 m/z:[M+H]+332
30.5 6-溴-2-(吡嗪-2-基甲基)酞嗪-1(2H)-硫酮 m/z:[M+H]+333
30.6 6-溴-2-((4,6-二甲氧基嘧啶-2-基)甲基)酞嗪-1(2H)-硫酮 m/z:[M+H]+393
实施例43：化合物1-1-1的合成
Figure PCTCN2017083031-appb-000092
步骤1：化合物1-1的合成
氮气保护下，向化合物1.20(101mg，0.19mmol)的四氢呋喃(5mL)溶液中依次加入6-溴异喹啉-1(2H)-酮(44mg，0.2mmol)、碳酸钠水溶液(2.5mL，2.0M)和Pd(dppf)2Cl2(10mg)，加毕，反应体系用氮气置换三次，70℃下搅拌20分钟～2小时，直到TLC检测反应完成。向反应体系中加入水(10mL)淬灭反应，混合物用乙酸乙酯(10mL×2)萃取，合并有机相，有机相用饱和食盐水洗涤，分离有机相，用无水硫酸钠干燥，过滤、浓缩，得到的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1-1(44mg，产率：43％)为无色油状物。
步骤2：化合物1-1-1的合成
冰浴条件下，向化合物1-1-1(20mg，0.04mmol)的二氯甲烷(2mL)溶液中滴加三氟乙酸(2mL)，加毕，反应体系在0℃下搅拌20分钟。减压除去溶剂，得到的残留物用50％的乙酸乙酯石油醚溶液洗涤，过滤，得到化合物1-1-1(9.4mg，产率：44％)为白色固体。
1H NMR(400MHz,CD3OD):δ8.37(d,J＝8.0Hz,1H),7.95(s,1H),7.84(d,J＝8.0Hz,1H),7.54(s,1H),7.46(s,2H),7.21(d,J＝8.0Hz,1H),6.91(s,1H),6.77(d,J＝8.0Hz,1H),3.43(t,J＝7.0Hz,4H),3.30(s,2H),1.76-1.61(m,4H),1.08-0.79(m,6H)；m/z:[M+H]+429。
实施例44：化合物1-1-2～1-1-4的合成
化合物1-1-2～1-1-4根据实施例43化合物1-1-1的合成方法，将步骤1中的化合物1.20替换为化合物1.8，和相应的化合物15.1、15.9或15.10反应得到：
Figure PCTCN2017083031-appb-000093
Figure PCTCN2017083031-appb-000094
实施例45：化合物1-2-1～1-2-51的合成
化合物1-2-1～1-2-51根据实施例43化合物1-1-1的合成方法，将步骤1中的6-溴异喹啉-1(2H)-酮替换为相应的化合物15.1、15.5、15.6、15.7、15.8、16.1、16.2、16.3、16.9、16.11、16.12、16.13、16.16、16.22、16.25、17.1、17.2、18.1、18.2、20.3、22.3 26.1、16.33、16.34、16.35、16.37、16.38、16.40、16.41、16.42、16.43、16.45、16.46、16.47、16.48、16.49、16.50、16.51、16.52、16.53、16.54、16.59、16.62、16.68、16.69、16.70、16.71、16.72、27.1、28.3和化合物1.20反应得到：
Figure PCTCN2017083031-appb-000095
Figure PCTCN2017083031-appb-000096
Figure PCTCN2017083031-appb-000097
Figure PCTCN2017083031-appb-000098
Figure PCTCN2017083031-appb-000099
Figure PCTCN2017083031-appb-000100
Figure PCTCN2017083031-appb-000101
Figure PCTCN2017083031-appb-000102
1H NMR(400MHz,CD3OD):δ8.68(s,1H),8.10(dd,J＝8.0,4.0Hz,1H),7.82-7.76(m,3H),7.67(d,J＝8.0Hz,1H),7.44(d,J＝8.0Hz,1H),7.12(s,1H),6.78(d,J＝4.0Hz,1H),4.22(t,J＝5.2Hz,2H),3.93(t,J＝5.2Hz,2H),3.50(br.s,4H),3.42-3.37(m,2H),1.73-1.65(m,4H),0.95(br.s,6H)；m/z:[M+H]+473。
实施例46：化合物1-2-52的合成
Figure PCTCN2017083031-appb-000103
化合物2-1根据实施例43化合物1-1的合成方法，将步骤1中的6-溴异喹啉-1(2H)-酮替换为相应的化合物16.59和化合物1.20反应得到。
向化合物2-1(100mg，0.15mmol)的二氯甲烷(3.0mL)溶液中滴加三氟乙酸(1.5mL)，反应体系在室温下搅拌1.5小时。减压浓缩，残留物用乙醇重结晶得到化合物1-2-52(50mg，产率：53％)为白色固体。
1H NMR(400MHz,DMSO-d6):δ9.88(s,1H),9.12(s,1H),8.35(d,J＝8.8Hz,1H),8.03(d,J＝1.6Hz,1H),7.89-7.80(m,3H),7.72(d,J＝8.4Hz,1H),7.48(d,J＝7.2Hz,1H), 7.06(s,1H),6.74(d,J＝7.2Hz,1H),4.37(d,J＝12.4Hz,2H),3.57(s,2H),3.35(s,6H),1.61-1.54(m,4H),0.91-0.82(m,6H)；m/z:[M+H]+523。
实施例47：化合物1-3-1～1-3-2的合成
化合物1-3-1～1-3-2根据实施例43化合物1-1-1的合成方法，将步骤1中的6-溴异喹啉-1(2H)-酮替换为相应的化合物15.4或19.1和化合物1.20反应得到：
Figure PCTCN2017083031-appb-000104
Figure PCTCN2017083031-appb-000105
实施例48：化合物1-4-1～1-4-2的合成
化合物1-4-1～1-4-2根据实施例43化合物1-1-1的合成方法，将步骤1中的6-溴异喹啉-1(2H)-酮替换为相应的化合物15.3或17.3和化合物1.20反应得到：
Figure PCTCN2017083031-appb-000106
Figure PCTCN2017083031-appb-000107
实施例49：化合物1-5-1和1-5-2的合成
化合物1-5-1和1-5-2根据实施例43化合物1-1-1的合成方法，将步骤1中的6-溴异喹啉-1(2H)-酮替换为相应的化合物15.9或15.10和化合物1.20反应得到：
Figure PCTCN2017083031-appb-000108
Figure PCTCN2017083031-appb-000109
实施例50：化合物1-6-1～1-6-2的合成
化合物1-6-1和1-6-2根据实施例43化合物1-1-1的合成方法，将步骤1中的6-溴异喹啉-1(2H)-酮替换为相应的化合物19.2或21.5和化合物1.20反应得到：
Figure PCTCN2017083031-appb-000110
Figure PCTCN2017083031-appb-000111
实施例51：化合物1-7-1～1-7-6的合成
化合物1-7-1～1-7-6根据实施例43化合物1-1-1的合成方法，将第一步中的6-溴异喹啉-1(2H)-酮替换为相应的化合物16.18、16.20、17.5、18.3、22.1或20.5和化合物1.20反应得到：
Figure PCTCN2017083031-appb-000112
Figure PCTCN2017083031-appb-000113
Figure PCTCN2017083031-appb-000114
实施例52：化合物1-8-1～1-8-22的合成
化合物1-8-1～1-8-22根据实施例43化合物1-1-1的合成方法，将第一步中的6-溴异喹啉-1(2H)-酮替换为相应的化合物18.4、16.21、16.24、17.4、22.4、22.5、16.32、20.6、16.36、16.39、22.11、22.6、16.44、16.60、16.63、16.64、28.4、16.66、16.67、16.73或16.75和化合物1.20反应得到：
Figure PCTCN2017083031-appb-000115
Figure PCTCN2017083031-appb-000116
Figure PCTCN2017083031-appb-000117
Figure PCTCN2017083031-appb-000118
实施例53：化合物1-9-1～1-9-6的合成
化合物1-9-1～1-9-6根据实施例43化合物1-1-1的合成方法，将第一步中的6-溴异喹啉-1(2H)-酮替换为相应的化合物17.3、23.1、24.1、24.2、25.1或20.4和化合物1.20反应得到：
Figure PCTCN2017083031-appb-000119
Figure PCTCN2017083031-appb-000120
Figure PCTCN2017083031-appb-000121
实施例54：化合物1-10-1～1-10-11的合成
化合物1-10-1～1-10-11根据实施例43化合物1-1-1的合成方法，将第一步中的6-溴异喹啉-1(2H)-酮替和化合物1.20分别替换为相应的化合物18.1、22.4、16.22、22.3、24.1、16.21、16.34、16.18、16.33、22.2或22.1和1.22反应得到：
Figure PCTCN2017083031-appb-000122
Figure PCTCN2017083031-appb-000123
Figure PCTCN2017083031-appb-000124
实施例56：化合物1-11-1的合成
化合物1-11-1根据实施例43化合物1-1-1的合成方法，将步骤1中的6-溴异喹啉-1(2H)-酮和化合物1.20分别替换为相应的化合物18.1和1.21反应得到：
Figure PCTCN2017083031-appb-000125
1H NMR(400MHz,CD3OD):δ8.42(d,J＝8.4Hz,1H),7.91(s,1H),7.75(d,J＝8.4Hz,1H),7.62(d,J＝6.8Hz,1H),7.51(d,J＝11.2Hz,1H),7.39(d,J＝7.6Hz,1H),7.08(s,1H),6.77(d,J＝7.2Hz,1H),4.76(s,2H),3.55-3.41(m,4H),3.32(overlapping with solvent,2H),1.77-1.65(m,4H),1.05-0.85(m,6H)；m/z:[M+H]+504。
实施例57：化合物1-12-1的合成
化合物1-12-1根据实施例43化合物1-1-1的合成方法，将步骤1中的6-溴异喹啉-1(2H)-酮替和化合物1.20分别替换为相应的化合物18.4和1.19反应得到：
Figure PCTCN2017083031-appb-000126
1H NMR(400MHz,CD3OD):δ8.40(d,J＝8.0Hz,1H),7.98(s,1H),7.90-7.79(m,2H),7.78-7.65(m,2H),7.37(d,J＝8.0Hz,1H),7.16(s,1H),6.79(d,J＝8.0Hz,1H),4.75(s,2H),3.71-3.44(m,6H),3.25-3.23(m,2H),1.76-1.64(m,2H),1.03-0.80(m,3H)；m/z:[M+H]+488。
实施例58：化合物1-14-1～1-14-8的合成
化合物1-14-1～1-14-8根据实施例43化合物1-1-1的合成方法，将步骤1中的6-溴异喹啉-1(2H)-酮替换为化合物29.1、29.2、30.1、30.2、30.3、30.4、30.5或30.6和化合物1.20反应得到：
Figure PCTCN2017083031-appb-000127
Figure PCTCN2017083031-appb-000128
Figure PCTCN2017083031-appb-000129
实施例59：化合物1-4-10的合成
Figure PCTCN2017083031-appb-000130
步骤1：化合物1-3的合成
化合物1-2按照实施例43化合物1-1的合成方法，用起始原料1.20和16.4合成得到。
将化合物1-2(15mg，0.022mmol)溶解在四氢呋喃(5mL)中，加入四丁基氟化铵(8.5mg，0.033mmol)，然后在室温下搅拌2小时。加入饱和碳酸氢钠水溶液中(10mL)，用乙酸乙酯(10mL×2)萃取，合并有机层。有机相用饱和食盐水洗涤，用无水硫酸钠干燥。过滤，减压蒸馏除去溶剂，得到的残留物用薄层层析硅胶板(乙酸乙酯)纯化得化合物1-3(12mg，产率：96％)为黄色固体。
m/z:[M+H]+575
步骤2：化合物1-4-10的合成
将化合物1-3(12mg，0.021mmol)溶入二氯甲烷(2mL)中。然后在冰水浴下，滴加三氟乙酸(1mL)，接着撤掉冰浴在室温下搅拌1小时。将反应液直接减压旋干，用prep-HPLC纯化得到化合物1-4-10为黄色固体(1.55mg，产率：16％)。
1H NMR(400MHz,CD3OD):δ8.07-8.04(m,1H),7.78-7.74(m,1H),7.72-7.67(m,2H),7.67-7.62(m,2H),7.09(s,1H),3.84-3.69(m,6H),3.55-3.40(m,4H),3.38-3.33(m,2H),3.16-3.11(m,2H),1.76-1.65(m,4H),1.02-0.88(m,6H)；m/z:[M+H]+475。
实施例60：化合物2-1-1的合成
Figure PCTCN2017083031-appb-000131
步骤1：化合物2-1的合成
氮气保护下，向化合物1.12(30mg，0.07mmol)的四氢呋喃(1mL)溶液中依次加入碳酸钠水溶液(2.0M，0.5mL)、Pd(dppf)Cl2(10mg，0.01mmol)和化合物15.2(30mg，0.10mmol)。加毕，反应体系用氮气置换三次，80℃下搅拌30分钟。向反应体系中加入水(10mL)淬灭反应，混合物用乙酸乙酯(10mL×2)萃取，合并有机相，有机相用饱和食盐水洗涤，分离有机相，用无水硫酸钠干燥，过滤、浓缩，得到的残留物用硅胶柱层析(乙酸乙酯：石油醚＝1:1)纯化得到化合物2-1(35mg，产率：97％)为白色固体。
步骤2：化合物2-1-1的合成
冰浴条件下，向化合物2-1(35mg，0.07mmol)的二氯甲烷(1mL)溶液中滴加三氟乙酸(1mL)，加毕，反应体系在20℃下搅拌2小时。向反应体系中加入水(10mL)淬灭反应，用乙酸乙酯(10mL×2)萃取，合并有机相，有机相用饱和食盐水洗涤，分离有机相，用无水硫酸钠干燥，过滤、浓缩，得到的残留物用prep-HPLC纯化得到化合物2-1-1(15mg，产率：55％)为白色固体。
1H NMR(400MHz,CD3OD):δ8.42(d,J＝8.2Hz,1H),7.97(s,1H),7.88-7.80(m,2H),7.75(s,1H),7.70(d,J＝8.0Hz,1H),7.45(d,J＝7.2Hz,1H),7.16(s,1H),6.80(d,J＝7.2Hz,1H),4.11(q,J＝7.2Hz,2H),3.73(s,8H),3.38(s,2H),1.38(t,J＝7.2Hz,3H)；m/z:[M+H]+443。
实施例61：化合物2-1-2～2-1-4的合成
化合物2-1-2～2-1-4根据实施例60化合物2-1-1的合成方法，将步骤1中的化合物1.12替换为相应的化合物1.9、1.11或1.13和化合物15.2反应得到：
Figure PCTCN2017083031-appb-000132
Figure PCTCN2017083031-appb-000133
Figure PCTCN2017083031-appb-000134
实施例62：化合物2-2-1～2-2-4的合成
化合物2-2-1～2-2-4根据实施例60化合物2-1-1的合成方法，将步骤1中的化合物1.12替换为相应的化合物1.14、1.15、1.16或1.17和化合物22.7反应得到：
Figure PCTCN2017083031-appb-000135
Figure PCTCN2017083031-appb-000136
实施例63：化合物2-3-1～2-3-3的合成
化合物2-3-1～2-3-3根据实施例60化合物2-1-1的合成方法，将步骤1中的化合物1.12替换为相应的化合物1.15、1.16或1.17和化合物22.8反应得到：
Figure PCTCN2017083031-appb-000137
Figure PCTCN2017083031-appb-000138
Figure PCTCN2017083031-appb-000139
生物测试实施例
实施例1：TLR8的细胞活性检测
在此项实验中，如式I所示化合物的TLR8生物活性测定采用细胞测试进行检测。该法在表达有TLR8或其他TLR家族成员如TLR4、TLR7和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，从而反应TLR8激动剂的活性。
详细的实验方法如下：
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％CO2。
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1.5hr，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EC50。
实施例2：TLR7的细胞活性检测
在此项实验中，如式I所示化合物的TLR7生物活性测定采用细胞测试进行检测。该法在表达有TLR7或其他TLR家族成员如TLR4、和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激动剂的活性。
详细的实验方法如下：
HEK-BLUE-hTLR7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％CO2。
化合物试验浓度为1.5nM至50μM共10个浓度梯度。加入已知活性的TLR7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1.5hr，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EC50。
TLR7和TLR8EC50值报告的范围为：-表示﹥50μM，--表示10-50μM，+表示1-10μM，++表示0.1-1μM，+++表示<0.1μM，/表示未测定。
编号 TLR8EC50 TLR7EC50 编号 TLR8EC50 TLR7EC50
1-1-1 + / 1-7-2 ++ -
1-2-1 + / 1-7-3 +++ /
1-2-2 ++ / 1-7-4 +++ -
1-2-3 ++ / 1-7-5 +++ /
1-2-5 ++ / 1-7-6 ++ /
1-2-6 +++ / 1-8-1 +++ -
1-2-7 ++ / 1-8-2 +++ -
1-2-8 +++ - 1-8-3 +++ -
1-2-9 +++ - 1-8-4 +++ -
1-2-10 +++ - 1-8-5 +++ -
1-2-11 +++ / 1-8-6 +++ /
1-2-12 ++ / 1-8-7 +++ /
1-2-13 +++ - 1-8-8 +++ /
1-2-14 +++ - 1-8-9 +++ /
1-2-15 + / 1-8-10 +++ /
1-2-16 +++ - 1-8-11 +++ /
1-2-17 +++ - 1-8-12 +++ --
1-2-18 +++ - 1-8-13 +++ /
1-2-19 +++ - 1-8-14 +++ /
1-2-20 ++ / 1-8-15 +++ --
1-2-21 +++ - 1-8-17 +++ /
1-2-22 +++ - 1-8-18 +++ /
1-2-23 +++ - 1-8-19 ++ /
1-2-24 +++ / 1-8-20 +++ /
1-2-25 +++ / 1-8-21 +++ /
1-2-26 +++ / 1-8-22 +++ /
1-2-27 ++ / 1-9-1 +++ -
1-2-28 +++ -- 1-9-2 +++ -
1-2-29 ++ / 1-9-3 ++ /
1-2-30 +++ / 1-9-4 ++ -
1-2-31 +++ -- 1-9-5 ++ /
1-2-32 +++ + 1-9-6 +++ /
1-2-33 +++ - 1-10-1 +++ -
1-2-34 +++ / 1-10-2 +++ /
1-2-35 +++ - 1-10-3 +++ /
1-2-36 +++ -- 1-10-4 +++ /
1-2-37 +++ / 1-10-5 +++ /
1-2-38 + / 1-10-6 +++ /
1-2-39 +++ / 1-10-7 +++ /
1-2-40 +++ - 1-10-8 +++ /
1-2-41 +++ / 1-10-9 +++ +
1-2-42 + / 1-10-10 ++ /
1-2-43 ++ - 1-11-1 + -
1-2-44 +++ / 1-12-1 ++ /
1-2-45 +++ -- 1-14-1 +++ /
1-2-46 +++ / 1-14-2 +++ /
1-2-47 ++ / 1-14-3 +++ /
1-2-49 +++ / 1-14-4 ++ /
1-2-50 ++ / 1-14-5 +++ /
1-2-51 + / 1-14-6 +++ /
1-3-1 +++ / 1-14-7 ++ /
1-3-2 +++ - 1-14-8 +++ -
1-4-1 ++ / 2-2-1 ++ /
1-4-2 +++ - 2-2-2 +++ --
1-4-10 ++ - 2-2-3 ++ /
1-5-1 + / 2-2-4 +++ /
1-5-2 + / 2-3-1 +++ /
1-6-1 ++ / 2-3-2 +++ /
1-6-2 ++ / 2-3-3 +++ /
1-7-1 ++ / 阳性对照 ++ /
注：阳性对照为VTX-2337(motolimod)，化学名称为：2-氨基-N,N-二丙基-8-(4-(吡咯烷-1-羰基)苯基)-3H-苯并[b]氮杂卓-4-甲酰胺。
其中，化合物1-2-21、1-2-24、1-2-25、1-2-26、1-2-30、1-2-31、1-2-33、1-2-34、1-2-35、1-2-39、1-2-40、1-2-41、1-2-44、1-8-4、1-8-5、1-8-6、1-8-8、1-8-9、1-8-12、1-8-15、1-8-17、1-8-20、1-8-22、1-10-3、1-10-6、1-10-7、1-10-9、1-14-1、1-14-2、1-14-3、1-14-8、2-2-4、2-3-2和2-3-3的TLR8EC50值均小于0.01μM。
虽然以上描述了本发明的具体实施方式，但是本领域的技术人员应当理解，这些仅是举例说明，在不背离本发明的原理和实质的前提下，可以对这些实施方式做出多种变更或修改。因此，本发明的保护范围由所附权利要求书限定。

Claims (17)

  1. 一种如式(I)所示化合物、其异构体、前药、稳定的同位素衍生物或药学上可接受的盐；
    Figure PCTCN2017083031-appb-100001
    其中，L为-C(O)-、-C(S)-或-S(O)2-；
    L1为连接键、C2-6亚烯基、C2-6亚炔基、-(CRaRb)m-、-(CRaRb)uO(CRaRb)v-、-(CRaRb)uC(O)(CRaRb)v-、-(CRaRb)uC(O)O(CRaRb)v-、-(CRaRb)uOC(O)(CRaRb)v-、-(CRaRb)uN(Rc)C(O)(CRaRb)v-、-(CRaRb)uN(Rc)C(O)N(Rc)(CRaRb)v-、-(CRaRb)uC(O)N(Rc)(CRaRb)v-、-(CRaRb)uC(S)(CRaRb)v、-(CRaRb)uS(O)0-2(CRaRb)v、-(CRaRb)uS(O)1-2N(Rc)(CRaRb)v、-(CRaRb)uN(Rc)S(O)2N(Rc)(CRaRb)v或-(CRaRb)uN(Rc)S(O)1-2(CRaRb)v；
    R选自二环、三环或四环并环基团，所述并环基团为未取代或者选择性地被如下一个或多个基团取代在任意位置：卤素、烷基、卤代烷基、卤代烷氧基、烯基、炔基、Cy1、-L2-Cy1、-CN、-NO2、-SRd、-ORd、-OC(O)Rd、-OC(O)ORd、-OC(O)NRdRe、-C(O)ORd、-C(O)Rd、-C(O)NRdRe、-C(O)NRdS(O)2Re、-C(O)N(Rd)ORe、-C(＝NH)Re、-C(＝NH)NRdRe、-NRdRe、-NRdC(O)Re、-N(Rd)C(O)ORe、-N(Rd)C(O)NRdRe、-NRdS(O)2Re、-NRdC(＝NH)Re、-NRdC(＝NH)NRdRe、-S(O)1-2Re、-S(O)2NRdRe和-NRdS(O)2NRdRe；其中所述烷基、烯基或炔基为未取代或者选择性地被如下一个或多个取代基取代在任意位置：-CN、-NO2、-SRd、-ORd、-OC(O)Rd、-OC(O)ORd、-OC(O)NRdRe、-C(O)ORd、-C(O)Rd、-C(O)NRdRe、-C(O)NRdS(O)2Re、-NRdRe、-NRdC(O)Re、-N(Rd)C(O)ORe、-N(Rd)C(O)NRdRe、-NRdC(＝NH)Re、-NRdC(＝NH)NRdRe、-NRdS(O)2Re、-NRdS(O)2NRdRe、-N(Rd)C(O)N(Rd)S(O)2Re、-S(O)1-2Re、-S(O)2NRdRe、-S(O)(＝NCN)Re、-S(O)(＝NRd)Re、-S(O)(＝NSO2Rd)Re、-S(O)2N(Rd)C(O)Re、-S(O)2N(Rd)C(O)NRdRe、-P(O)(ORd)2、-OP(O)(ORd)2或-B(ORd)2；
    L2为连接键、C2-6亚烯基、C2-6亚炔基、-(CRa1Rb1)m-、-(CRa1Rb1)uO(CRa1Rb1)v-、
    -(CRa1Rb1)uC(O)(CRa1Rb1)v-、-(CRa1Rb1)uC(O)O(CRa1Rb1)v-、-(CRa1Rb1)uOC(O)(CRa1Rb1)v-、-(CRa1Rb1)uN(Rc1)C(O)(CRa1Rb1)v-、-(CRaRb)uC(O)N(Rc1)(CRa1Rb1)v-、-(CRa1Rb1)uN(Rc)C(O)N(Rc1)(CRa1Rb1)v-、-(CRa1Rb1)uC(S)(CRa1Rb1)v、-(CRa1Rb1)uS(O)0-2(CRa1Rb1)v、-(CRa1Rb1)uS(O)1-2N(Rc1)(CRa1Rb1)v、-(CRa1Rb1)uN(Rc1)S(O)2N(Rc1)(CRa1Rb1)v或-(CRa1Rb1)uN(Rc1)S(O)1-2(CRa1Rb1)v；
    每个Cy1独立地为环烷基、杂环烷基、芳基或者杂芳基；所述Cy1为未取代或者选择性地被如下一个或多个基团取代在任意位置：卤素、烷基、卤代烷基、卤代烷氧基、羟基烷基、氨基烷基、烯基、炔基、-CN、-NO2、-SRd2、-ORd2、-OC(O)Rd2、-OC(O)ORd2、-OC(O)NRd2Re2、-C(O)ORd2、-C(O)Rd2、-C(O)NRd2Re2、-NRd2Re2、-NRd2C(O)Re2、-N(Rd2)C(O)ORe2、-N(Rd2)C(O)NRd2Re2、-NRd2S(O)2Re2、-NRd2C(＝NH)Re2、-NRd2C(＝NH)NRd2Re2、-S(O)1-2Re2、-S(O)2NRd2Re2和-NRd2S(O)2NRd2Re2；
    R1、R2和R3分别独立地选自氢、氘、烷基、烯基、炔基、环烷基、杂环烷基、芳基、和杂芳基，所述烷基、烯基、炔基、环烷基、杂环烷基、芳基或杂芳基为未取代或者选择性地被如下1～3个基团取代在任意位置：卤素、烷基、卤代烷基、卤代烷氧基、羟基烷基、氨基烷基、烯基、炔基、-CN、-NO2、-SRd2、-ORd2、-OC(O)Rd2、-OC(O)ORd2、-OC(O)NRd2Re2、-C(O)ORd2、-C(O)Rd2、-C(O)NRd2Re2、-NRd2Re2、-NRd2C(O)Re2、-N(Rd2)C(O)ORe2、-N(Rd2)C(O)NRd2Re2、-NRd2S(O)2Re2、-NRd2C(＝NH)Re2、-NRd2C(＝NH)NRd2Re2、-S(O)1-2Re2、-S(O)2NRd2Re2和-NRd2S(O)2NRd2Re2；
    或者，R2和R3与它们共同连接的C原子一起形成C3-8环烷基或3-8元的杂环烷基；所述C3-8环烷基或3-8元杂环烷基为未取代或者选择性地被如下1～3个基团取代在任意位置：卤素、烷基、卤代烷基、卤代烷氧基、羟基烷基、氨基烷基、烯基、炔基、-CN、-NO2、-SRd2、-ORd2、-OC(O)Rd2、-OC(O)ORd2、-OC(O)NRd2Re2、-C(O)ORd2、-C(O)Rd2、-C(O)NRd2Re2、-NRd2Re2、-NRd2C(O)Re2、-N(Rd2)C(O)ORe2、-N(Rd2)C(O)NRd2Re2、-NRd2S(O)2Re2、-NRd2C(＝NH)Re2、-NRd2C(＝NH)NRd2Re2、-S(O)1-2Re2、-S(O)2NRd2Re2和-NRd2S(O)2NRd2Re2；
    R4、R5和R6分别独立地选自氢、氘、卤素、氨基、氰基、硝基、C1-6烷基、卤代C1-6烷基、卤代C1-6烷氧基、C1-6烷氧基、C2-6烯基、C2-6炔基、羟基C1-6烷基、C3-8环烷基、3-8元杂环烷基、苯基和5-6元杂芳基；
    RA选自-ORd1或-NRd1Re1；
    RB选自-NRd1Re1；
    每个Ra、每个Rb、每个Ra1和每个Rb1分别独立地选自氢、氘、卤素、C1-6烷基、C1-6烷氧基、C2-6烯基、C2-6炔基、C3-8环烷基、3-8元杂环烷基、C6-10芳基、5-6元杂芳基、C3-8环烷基C1-6烷基、3-8元杂环烷基C1-6烷基、苯基C1-6烷基或5-6元杂芳基C1-6烷基；所述C1-6烷基、C1-6烷氧基、C2-6烯基、C2-6炔基、C3-8环烷基、3-8元杂环烷基、C6-10芳基或5-6元杂芳基为未取代或者选择性地被1～3个选自卤素、羟基、氨基、羧基、C2-6烯基、C2-6炔基、C1-6烷基、卤代C1-6烷基、C1-6烷氧基和卤代C1-6烷氧基中的一种或多种取代基取代在任意位置；
    或者，Ra和Rb、或Ra1和Rb1与它们共同连接的C原子一起形成的C3-8环烷基或3-8元杂环烷基；
    每个Rc和每个Rc1分别独立地选自氢、C1-4烷基、C3-8环烷基或3-8元杂环烷基；
    每个Rd、每个Re、每个Rd1和每个Re1分别独立地选自氢、C1-6烷基、C2-6烯基、C2-6炔基、C3-8环烷基、3-8元杂环烷基、C6-10芳基、5-6元杂芳基、C3-8环烷基C1-6烷基、3-8元杂环烷基C1-6烷基、苯基C1-6烷基或5-6元杂芳基C1-6烷基；所述Rd、Re、Rd1或Re1为未取代或者选择性地被1～3个选自卤素、羟基、氨基、羧基、C1-6烷基、C1-6烷氧基、C1-6烷氨基、卤代C1-6烷基、卤代C1-6烷氧基、C2-6烯基和C2-6炔基中的一种或多种取代基取代在任意位置；
    或者，Rd和Re、或Rd1和Re1与它们共同连接的N原子一起形成3-8元的杂环烷基；所述杂环烷基还可以进一步含有1～3个选自N、O、S的杂原子；所述杂环烷基为未取代或者进一步被1～3个选自卤素、氨基、羟基、羧基、氰基、C1-6烷基、卤代C1-6烷基、C2-6烯基、C2-6炔基、C1-3烷基、氨基C1-3烷基、-ORd2、-OC(O)Rd2、-OC(O)ORd2、-OC(O)NRd2Re2、-C(O)ORd2、-C(O)Rd2、-C(O)NRd2Re2、-NRd2Re2、-NRd2C(O)Re2、-N(Rd2)C(O)ORe2、-N(Rd2)C(O)NRd2Re2、-NRd2S(O)2Re2、-NRd2C(＝NH)Re2、-NRd2C(＝NH)NRd2Re2、-NRd2S(O)2NRd2Re2、-S(O)1-2Rd2和-S(O)2NRd2Re2中的一种或多种取代基取代在任意位置；
    每个Rd2和每个Re2分别独立地选自氢、C1-6烷基、C2-6烯基、C2-6炔基、C3-8环烷基、3-8元杂环烷基、C6-10芳基、5-6元杂芳基、C3-8环烷基C1-6烷基、3-8元杂环烷基C1-6烷基、苯基C1-6烷基或5-6元杂芳基C1-6烷基；所述Rd2或Re2为未取代或者选择性地被1～3个选自卤素、羟基、氨基、羧基、C1-6烷基、C1-6烷氧基、C1-6烷氨基、卤代C1-6烷基、卤代C1-6烷氧基、C2-6烯基、C2-6炔基中的一种或多种取代基取代在任意位置；或者，Rd2和Re2与它们共同连接的N原子一起形成3-8元杂环烷基；
    每个u独立地为0、1、2或3；
    每个v独立地为0、1、2或3；
    每个m独立地为1、2、3、4、5或6。
  2. 如权利要求1所述的如式(I)所示化合物、其异构体、前药、稳定的同位素衍生物或药学上可接受的盐，其中R1、R2和R3分别独立地选自H；R4、R5和R6分别独立地选自H、D、F、Cl、Br、-CN、-NH2、-CH3、-OCH3、-OCF3、-CH2F、-CHF2或-CF3。
  3. 如权利要求1所述的如式(I)所示化合物、其异构体、前药、稳定的同位素衍生物或药学上可接受的盐，其中L1为连接键、-CH2-、-NH-、-O-、-CH2O-或-OCH2-。
  4. 如权利要求1所述的如式(I)所示化合物、其异构体、前药、稳定的同位素衍生物或药学上可接受的盐，其中Rd1和Re1分别独立地选自氢、C1-6烷基、卤代C1-6烷基、C3-8环烷基或3-8元杂环烷基；所述Rd1或Re1为未取代，或者选择性被1个羟基取代在任意位置；
    或者Rd1和Re1与它们共同连接的N原子一起形成C3-8杂环烷基；所述杂环烷基还可 以进一步含有1～3个选自N、O、S的杂原子；所述杂环烷基为未取代或者进一步被1个选自C1-4烷基、卤代C1-3烷基、羟基C1-3烷基或氨基C1-3烷基的取代基取代在任意位置。
  5. 如权利要求1所述的如式(I)所示化合物、其异构体、前药、稳定的同位素衍生物或药学上可接受的盐，其中RB为-NH2。
  6. 如权利要求1所述的如式(I)所示化合物、其异构体、前药、稳定的同位素衍生物或药学上可接受的盐，其中R为8-20元取代或者未取代的双环、三环或四环并环基团，优选如下R-1～R-19任一结构：
    Figure PCTCN2017083031-appb-100002
    每个R7和R7a分别独立选自氢、卤素、烷基、卤代烷基、烯基、炔基、Cy1、-L2-Cy1、-SRd、-ORd、-C(O)ORd、-C(O)Rd、-C(O)NRdRe、-C(O)NRdS(O)2Re、-C(＝NH)Re、-C(＝NH)NRdRe、-S(O)2Re和-S(O)2NRdRe；其中所述烷基、烯基或炔基为未取代或者选择性地被如下一个或多个取代基取代在任意位置：-CN、-NO2、-SRd、-ORd、-OC(O)Rd、-OC(O)ORd、-OC(O)NRdRe、-C(O)ORd、-C(O)Rd、-C(O)NRdRe、-C(O)NRdS(O)2Re、-NRdRe、-NRdC(O)Re、-N(Rd)C(O)ORe、-N(Rd)C(O)NRdRe、-NRdC(＝NH)Re、-NRdC(＝NH)NRdRe、-NRdS(O)2Re、-NRdS(O)2NRdRe、-N(Rd)C(O)N(Rd)S(O)2Re、-S(O)1-2Re、-S(O)2NRdRe、 -S(O)(＝NCN)Re、-S(O)(＝NRd)Re、-S(O)(＝NSO2Rd)Re、-S(O)2N(Rd)C(O)Re、-S(O)2N(Rd)C(O)NRdRe、-P(O)(ORd)2、-OP(O)(ORd)2或-B(ORd)2；
    每个R8独立地为氢、卤素、烷基、卤代烷基、卤代烷氧基、烯基、炔基、Cy1、-L2-Cy1、-CN、-NO2、-SRd、-ORd、-OC(O)Rd、-OC(O)ORd、-OC(O)NRdRe、-C(O)ORd、-C(O)Rd、-C(O)NRdRe、-C(O)NRdS(O)2Re、-C(＝NH)Re、-C(＝NH)NRdRe、-NRdRe、-NRdC(O)Re、-N(Rd)C(O)ORe、-N(Rd)C(O)NRdRe、-NRdS(O)2Re、-NRdC(＝NH)Re、-NRdC(＝NH)NRdRe、-S(O)1-2Re、-S(O)2NRdRe和-NRdS(O)2NRdRe；其中所述烷基、烯基或炔基为未取代或者选择性地被如下一个或多个取代基取代在任意位置：-CN、-NO2、-SRd、-ORd、-OC(O)Rd、-OC(O)ORd、-OC(O)NRdRe、-C(O)ORd、-C(O)Rd、-C(O)NRdRe、-C(O)NRdS(O)2Re、-NRdRe、-NRdC(O)Re、-N(Rd)C(O)ORe、-N(Rd)C(O)NRdRe、-NRdC(＝NH)Re、-NRdC(＝NH)NRdRe、-NRdS(O)2Re、-NRdS(O)2NRdRe、-N(Rd)C(O)N(Rd)S(O)2Re、-S(O)1-2Re、-S(O)2NRdRe、-S(O)2N(Rd)C(O)Re或-S(O)2N(Rd)C(O)NRdRe；
    每个n独立地为1、2或3；
    其中，L2、Cy1、Rd和Re的定义如权利要求1所述。
  7. 如权利要求6所述的如式(I)所示化合物、其异构体、前药、稳定的同位素衍生物或药学上可接受的盐，其中，
    每个R7独立地为氢、C1-6烷基、卤代C1-6烷基、C2-6烯基、C2-6炔基、Cy1、-L2-Cy1、-SRd、-ORd、-C(O)ORd、-C(O)Rd、-C(O)NRdRe、-C(＝NH)Re、-C(＝NH)NRdRe、-S(O)2Re或-S(O)2NRdRe；其中所述C1-6烷基、C2-6烯基或C2-6炔基为未取代或者选择性地被如下1～3个取代基取代在任意位置：-CN、-NO2、-CN、-SRd、-ORd、-OC(O)Rd、-OC(O)ORd、-OC(O)NRdRe、-C(O)ORd、-C(O)Rd、-C(O)NRdRe、-NRdRe、-NRdC(O)Re、-N(Rd)C(O)ORe、-N(Rd)C(O)NRdRe、-NRdS(O)2Re、-NRdC(＝NH)Re、-NRdC(＝NH)NRdRe、-S(O)1-2Re、-S(O)2NRdRe、-S(O)(＝NCN)Re、-S(O)(＝NRd)Re、-S(O)(＝NSO2Rd)Re、-NRdS(O)2NRdRe或-P(O)(ORd)2、-OP(O)(ORd)2或-B(ORd)2；
    和/或，每个R7a独立地为氢或C1-6烷基；
    和/或，每个R8独立地为氢、甲基、乙基、正丙基、叔丁基、异丙基、异丁基、正丁基、-CN、-NO2、-NH2、-CF3、-OCF3、-CH3、-OCH3、F、Cl或Br；
    和/或，L2为连接键、-CH2-、-CH2CH2-、-CH2CH2CH2-、-CH2CH2C(CH3)2-、-CH2CH2CH2CH2-或-CH2CH(CH3)CH2-；
    和/或，每个Cy1独立地为C3-10环烷基、3-10元杂环烷基、C6-10芳基或者5-10元杂芳基；所述Cy1为未取代或者选择性地被如下1～3个基团取代在任意位置：F、Cl、Br、C1-4烷基、卤代C1-3烷基、卤代C1-3烷氧基、羟基C1-3烷基、氨基C1-3烷基、C2-6烯基、C2-6炔基、-CN、-NO2、-SRd2、-ORd2、-OC(O)Rd2、-OC(O)ORd2、-OC(O)NRd2Re2、-C(O)ORd2、-C(O)Rd2、-C(O)NRd2Re2、-NRd2Re2、-NRd2C(O)Re2、-N(Rd2)C(O)ORe2、-N(Rd2)C(O)NRd2Re2、 -NRd2S(O)2Re2、-NRd2C(＝NH)Re2、-NRd2C(＝NH)NRd2Re2、-S(O)1-2Re2、-S(O)2NRd2Re2和-NRd2S(O)2NRd2Re2；
    和/或，每个Rd、每个Re、每个Rd2和每个Re2分别独立地选自氢、C1-6烷基、C1-6卤代烷基、C2-6烯基、C2-6炔基、C3-8环烷基、3-8元杂环烷基、C6-10芳基、5-6元杂芳基、C3-8环烷基C1-6烷基、3-8元杂环烷基C1-6烷基、苯基C1-6烷基或5-6元杂芳基C1-6烷基；所述Rd、Re、Rd2和Re2为未取代或者选择性地被1～3个选自卤素、羟基、氨基、羧基、C1-4烷基、C1-3卤代烷基、C1-3卤代烷氧基、C1-3烷氧基、C1-3烷氨基、C2-6烯基和C2-6炔基中的一种或多种取代基取代在任意位置；
    或者，Rd和Re与它们共同连接的N原子一起形成3-8元的杂环烷基；所述杂环烷基还可以进一步含有1～3个选自N、O、S的杂原子；
    或者，Rd2和Re2与它们共同连接的N原子一起形成3-8元杂环烷基。
  8. 如权利要求6或7所述的如式(I)所示化合物、其异构体、前药、稳定的同位素衍生物或药学上可接受的盐，其中每个R7独立地为氢、甲基、乙基、正丙基、叔丁基、异丙基、异丁基、正丁基、新戊基、特戊基、环丙基、环丁基、环戊基、环己基、苯基、吡啶基、嘧啶基、苄基、
    Figure PCTCN2017083031-appb-100003
    Figure PCTCN2017083031-appb-100004
    Figure PCTCN2017083031-appb-100005
    Figure PCTCN2017083031-appb-100006
  9. 如权利要求1～8中至少一项所述的如式(I)所示化合物、其异构体、前药、稳定的同位素衍生物或药学上可接受的盐，其中，其为通式(IA)、(IB)、(IC)、(ID)、(IE)、(IF)、(IG)、(IH)、(II)、(IJ)、(IK)或(IL)所示化合物、其异构体、前药、稳定的同位素衍生物或药学上可接受的盐：
    通式(IA)所示的化合物、其异构体、前药、稳定的同位素衍生物或药学上可接受的盐：
    Figure PCTCN2017083031-appb-100007
    其中，
    Figure PCTCN2017083031-appb-100008
    为单键或双键；
    Y为O或S；
    U为N、C(R8)或C(O)，V为N、C(R8)或N(R7a)；并且，
    Figure PCTCN2017083031-appb-100009
    U和V为如下任一组合：
    1)
    Figure PCTCN2017083031-appb-100010
    为双键，U为N，V为C(R8)；
    2)
    Figure PCTCN2017083031-appb-100011
    为双键，U为C(R8)，V为N；
    3)
    Figure PCTCN2017083031-appb-100012
    为双键，U为C(R8)，V为C(R8)；
    4)
    Figure PCTCN2017083031-appb-100013
    为单键，U为C(R8)，V为C(R8)；
    5)
    Figure PCTCN2017083031-appb-100014
    为单键，U为C(O)，V为N(R7a)；
    n为1；
    L1、Rd1、Re1、R4、R5、R6、R7和R8的定义如权利要求1～8任一项所述；
    通式(IB)或(IC)所示化合物、其异构体、前药、稳定的同位素衍生物或药学上 可接受的盐：
    Figure PCTCN2017083031-appb-100015
    其中，
    Figure PCTCN2017083031-appb-100016
    为单键或双键；
    Rd1、Re1、R4、R5、R6、R7、R8和Y的定义如权利要求1～8任一项所述；
    通式(ID)或(IE)所示化合物、其异构体、前药、稳定的同位素衍生物或药学上可接受的盐：
    Figure PCTCN2017083031-appb-100017
    其中，Rd1、Re1、R4、R5、R6、R7、R8和Y的定义如权利要求1～8任一项所述；
    通式(IF)或(IG)所示化合物、其异构体、前药、稳定的同位素衍生物或药学上可接受的盐：
    Figure PCTCN2017083031-appb-100018
    其中，Rd1、Re1、R4、R5、R6、R7、R8和Y的定义如权利要求1～8任一项所述；
    通式(IH)或(II)所示化合物、其异构体、前药、稳定的同位素衍生物或药学上可接受的盐：
    Figure PCTCN2017083031-appb-100019
    其中，Rd1、Re1、R4、R5、R6、R7和R7a的定义如权利要求1～8任一项所述；
    通式(IJ)所示化合物、其异构体、前药、稳定的同位素衍生物或药学上可接受的盐：
    Figure PCTCN2017083031-appb-100020
    其中，
    Figure PCTCN2017083031-appb-100021
    为单键或双键；Z为N(R7a)或S；
    n为1或2；
    L1、Rd1、Re1、R4、R5、R6、R7和R8的定义如权利要求1～8任一项所述；
    通式(IK)或(IL)所示化合物、其异构体、前药、稳定的同位素衍生物或药学上可接受的盐：
    Figure PCTCN2017083031-appb-100022
    其中，Z为NH、N(CH3)或S；
    Rd1、Re1、R4、R5、R6、R7和R8的定义如权利要求1～8任一项所述。
  10. 如权利要求1所述的如式(I)所示化合物、其异构体、前药、稳定的同位素衍生物或药学上可接受的盐，其中所述的如式(I)所示的化合物为如下任一化合物：
    Figure PCTCN2017083031-appb-100023
    Figure PCTCN2017083031-appb-100024
    Figure PCTCN2017083031-appb-100025
    Figure PCTCN2017083031-appb-100026
    Figure PCTCN2017083031-appb-100027
    Figure PCTCN2017083031-appb-100028
    Figure PCTCN2017083031-appb-100029
    Figure PCTCN2017083031-appb-100030
    Figure PCTCN2017083031-appb-100031
    Figure PCTCN2017083031-appb-100032
    Figure PCTCN2017083031-appb-100033
    Figure PCTCN2017083031-appb-100034
  11. 一种如权利要求1～10中至少一项所述如式(I)所示化合物、其异构体、前药、稳定的同位素衍生物或药学上可接受的盐的制备方法，其中，所述如式(I)所示化合物的制备方法为如下任一方法：
    方法1包括下列步骤：将如式I-a所示的化合物与
    Figure PCTCN2017083031-appb-100035
    进行如下所示的suzuki偶联反应，制得所述如式(I)所示化合物；
    Figure PCTCN2017083031-appb-100036
    方法2包括下列步骤：将如式I-b所示的化合物与R-M进行如下所示的suzuki偶联反应，制得所述如式(I)所示化合物；
    Figure PCTCN2017083031-appb-100037
    其中，M为溴、氯、碘或-OS(O)2CF3；所述R1、R3、R4、R5、R6、RA、RB、R和L的定义均同如权利要求1～10任一项所述。
  12. 一种药物组合物，其包括治疗有效量的如权利要求1～10中至少一项所述的如式(I)所述化合物、其异构体、前药、稳定的同位素衍生物或药学上可接受的盐以及药学上可接受的辅料。
  13. 一种如权利要求1～10中至少一项所述的如式(I)所示化合物、其异构体、前药、稳定的同位素衍生物或药学上可接受的盐在制备TLRs调节剂中的应用。
  14. 一种如权利要求1～10中至少一项所述的如式(I)所示化合物、其异构体、前药、稳定的同位素衍生物或药学上可接受的盐在制备治疗、缓解和/或预防由TLRs介导的相关疾病的药物中的应用。
  15. 如权利要求14所述的应用，其中，所述药物进一步和一种或多种其它种类的治疗剂和/或治疗方法联合使用，用于治疗、缓解和/或预防由TLRs介导的相关疾病。
  16. 根据权利要求14或15所述的应用，其中，所述的疾病为癌症、病毒感染、炎症、自身免疫性疾病、移植排斥和移植抗宿主病中的一种或多种。
  17. 如权利要求13～16中至少一项所述的应用，其中，所述的TLRs为TLR7和/或TLR8。
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