WO2018214812A1 - 用作自噬调节剂的化合物及其制备方法和用途 - Google Patents

用作自噬调节剂的化合物及其制备方法和用途 Download PDF

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WO2018214812A1
WO2018214812A1 PCT/CN2018/087446 CN2018087446W WO2018214812A1 WO 2018214812 A1 WO2018214812 A1 WO 2018214812A1 CN 2018087446 W CN2018087446 W CN 2018087446W WO 2018214812 A1 WO2018214812 A1 WO 2018214812A1
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membered
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PCT/CN2018/087446
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English (en)
French (fr)
Inventor
罗成
谢雨礼
周兵
姚志艺
乐立艳
万伟
张碧东
张元元
蒋华良
陈凯先
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苏州偶领生物医药有限公司
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Application filed by 苏州偶领生物医药有限公司 filed Critical 苏州偶领生物医药有限公司
Priority to US16/614,465 priority Critical patent/US11319303B2/en
Priority to BR112019024376-3A priority patent/BR112019024376A2/pt
Priority to CN202310882957.2A priority patent/CN116969904A/zh
Priority to EP18805508.1A priority patent/EP3632903B1/en
Priority to CN201880033785.9A priority patent/CN111148740B/zh
Priority to CA3061209A priority patent/CA3061209A1/en
Priority to JP2019565459A priority patent/JP7237017B2/ja
Priority to MX2019013816A priority patent/MX2019013816A/es
Priority to AU2018274378A priority patent/AU2018274378B2/en
Priority to KR1020197036203A priority patent/KR102580087B1/ko
Publication of WO2018214812A1 publication Critical patent/WO2018214812A1/zh

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    • C07D473/26—Heterocyclic compounds containing purine ring systems with an oxygen, sulphur, or nitrogen atom directly attached in position 2 or 6, but not in both
    • C07D473/32—Nitrogen atom
    • C07D473/34—Nitrogen atom attached in position 6, e.g. adenine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
    • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
    • C07H19/16—Purine radicals
    • C07H19/167—Purine radicals with ribosyl as the saccharide radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/04—Systems containing only non-condensed rings with a four-membered ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/14—The ring being saturated

Definitions

  • the invention relates to the field of biomedicine, and in particular to a class of autophagy regulators, in particular mammalian ATG8 homolog regulators and uses thereof.
  • Autophagy is a pathway for intracellular degradation. It is a process in which proteins and organelles that are damaged or lose function in the cell are transported to lysosomes for digestion and degradation. In biological evolution, autophagy is a conserved process, from yeast to plant cells to mammalian cells.
  • autophagy plays an important role in providing nutrients, clearing cell contents, antigen presentation, etc. while maintaining physiological functions such as starvation, and plays an important role in cancer, infectious diseases, and neurodegenerative diseases. character of. Autophagy plays a double-edged sword in the development of tumors: In the early stage of tumorigenesis, autophagy defects increase genomic instability and promote carcinogenesis; rapid tumor growth and metastasis, autophagy can resist stress Conditions inhibit anoikis and maintain tumor cell survival. Although the relationship between autophagy and tumors varies at different stages of tumor development, the development of autophagy regulators will be of great value for advanced cancers and chemotherapy-resistant cancers.
  • small molecule modulators targeting autophagy are mainly limited to mTOR and lysosomal modulators, and studies on small molecule modulators such as ATG4 and ULK1 are still in the early stages of development.
  • the most important autophagy-related proteins, ATG8 and its mammalian homologous family of proteins, LC3, GABARAP and GATE-16 subfamily have not been reported.
  • the LC3 family has LC3A, LC3B, and LC3C
  • the GABARAP family has GABARAPL and GABARAPLl
  • the GATE-16 family has GABARAPL2.
  • LC3B is undoubtedly the most intensive research, and it is considered to be a marker of autophagy. There have been no reports on modulators of LC3B, and the development of modulators of LC3B is urgent for the treatment of related diseases.
  • the present invention provides a compound of the formula 1 or a pharmaceutically acceptable salt thereof -
  • X and Y are each independently selected from the group consisting of 0, S, NR a , NOH and CH 2 ;
  • U and V are each independently selected from C, S, SO and POR a ;
  • W, Z and T are each independently selected from the group consisting of 0, S, SO, S0 2 , N, NR a , CO, C, CR a , and CH 2 ;
  • n 0, 1, 2 or 3; preferably 0 or 1;
  • n 0, 1, 2 or 3; preferably 0 or 1;
  • K is a covalent bond, NR a , CRcRe' or CRJ ⁇ CRcRc;
  • M is a covalent bond, a divalent 3-10 membered heterocycloalkyl group, a divalent 3-7 membered heterocycloalkenyl group or a divalent 5-10 membered heteroaryl group;
  • Q is hydrogen, C1-6 alkyl, C1-6 hydroxyalkyl, -(CH 2 ) p -C(0)R b , -(CH 2 ) p -C(0) HR b , -(CH 2 ) p -C(S)R b , -(CH 2 ) p -C(S)NHR b , -(CH 2 ) p -S0 2 R b , -(CH 2 ) p -S0 2 NHR b ,
  • p is 0, 1, 2 or 3; preferably 0 or 1;
  • R e and Rc' is independently selected from the group consisting of hydrogen, hydroxy, amino, RaRa', halogen, cyano, nitro, carboxy, formyl, amide, ester, C1-6 halogenated fluorenyl, C1-6 hydroxy Alkyl, C1-6 heteroalkyl, C1-6 alkoxy, C1-6 alkoxyalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, 5-10 membered heteroaryl Base, C3-10 cycloalkyl, 3-10 membered heterocyclic fluorenyl, 3-7 membered heterocycloalkenyl, C1-6 fluorenyl C6-10 aryl, 5-10 membered heteroaryl C1-6 alkyl Or a C1-6 mercapto 5-10 membered heteroaryl; preferably selected from the group consisting of hydrogen, hydroxy, amino, NRaRa', halogen, carboxy, formyl, amide, ester, C1-6 hal
  • R 3 , R 4 and each independently selected from the group consisting of hydrogen, hydroxy, amino, halogen, cyano, nitro, carboxy, formyl, amide, -NH-COR b , ester, C1-6 fluorenyl, C1-6 Haloalkyl, C1-6 hydroxydecyl, C1-6 heteroalkyl, C1-6 decyloxy, C1-6 alkoxyfluorenyl, C2-6 alkenyl, C2-6 alkynyl, unsubstituted or substituted -CONH-(C6-10 aryl), unsubstituted or substituted -CH CH-(C6-10 aryl;), unsubstituted or substituted C6-10 aryl, unsubstituted or substituted 5-10 member Heteroaryl, unsubstituted or substituted C3-10 cyclodecyl, unsubstituted or substituted 3-10 membered heterocyclic fluorenyl, unsubstituted or
  • R 3 , R 4 and R 5 may be bonded to form an unsubstituted or substituted C 6-10 aryl group, an unsubstituted or substituted 5-10 membered heteroaryl group, an unsubstituted or substituted C 3 3 10 fluorenyl or unsubstituted or substituted 3-10 membered heterocycloalkyl; wherein each R b is independently C 1-6 alkyl, C 2-6 alkenyl, NHR a , R a R a ', unsubstituted Or substituted phenyl or 3-7 membered heterocyclic group;
  • R a and R a ' is independently hydrogen or C1-6 fluorenyl
  • Unsubstituted or substituted means that the group is unsubstituted or substituted by one or more substituents selected from the group consisting of hydroxy, amino, cyano, nitro, carboxy, halogen, C1-6 fluorenyl, C 1- 6 halodecyl or C 1-6 hydroxyalkyl, or two adjacent substituents may be bonded to form a C6-10 aryl group, a C5-10 heteroaryl group, a C3-10 cycloalkyl group or a C3-10 heterocycloalkane Base
  • X and Y are each independently selected from 0, S or H;
  • U and V are each independently selected from C or S;
  • W, Z and T are each independently selected from the group consisting of 0, N, R a , CO, C, CR a , and CH 2 ;
  • n is. , 1 or 2;
  • n 0, 1 or 2;
  • K is a covalent bond, NR a , CR e R e , or CReRc RcRc,;
  • M is a covalent bond, CH, a divalent 3-10 membered heterocycloalkyl group, a divalent 3-7 membered heterocycloalkenyl group or a divalent 5-10 membered heteroaryl group;
  • Q is hydrogen, C1-6 fluorenyl, C1-6 hydroxy fluorenyl, -(CH 2 ) p -C(0)R b , -(CH 2 ) p -C(0) HR b , -(CH 2 ) p -C(S)R b , -(CH 2 ) p -C(S)NHR b , -(CH 2 ) p -S0 2 R b , -(CH 2 ) p -S0 2 NHR b , wherein
  • p is 0, 1, 2 or 3; preferably 0 or 1;
  • R e and Rc' is independently selected from the group consisting of hydrogen, hydroxy, amino, RaRa', halogen, cyano, nitro, carboxy, formyl, amide, ester, C1-6 haloalkyl, C1-6 hydroxyalkyl , C1-6 heteroalkyl, C1-6 alkoxy, C1-6 alkoxyfluorenyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, 5-10 membered heteroaryl, C3-10 cyclodecyl, 3-10 membered heterocycloalkyl, 3-7 membered heterocycloalkenyl, C1-6 alkyl C6-10 aryl, 5-10 membered heteroaryl C1-6 fluorenyl or C1 -6-mercapto 5-10 membered heteroaryl; preferably selected from the group consisting of hydrogen, hydroxy, amino, NRaRa', halogen, carboxy, formyl, amide, ester, C1-6 halogen,
  • R 3 , R 4 and R 5 may be bonded to form an unsubstituted or substituted C 6-10 aryl group, an unsubstituted or substituted 5-10 membered heteroaryl group, an unsubstituted or substituted C 3 3 10 fluorenyl or unsubstituted or substituted 3-10 membered heterocycloalkyl; wherein each R b is independently C 1-6 alkyl, C 2-6 alkenyl, NHR a , R a R a ', unsubstituted Or substituted phenyl or 3-7 membered heterocyclic group;
  • Each and R a ' is independently hydrogen or C1-6 fluorenyl
  • Unsubstituted or substituted means that the group is unsubstituted or substituted by one or more substituents selected from the group consisting of hydroxy, amino, cyano, nitro, carboxy, halogen, C1-6 alkyl, C 1- 6 haloalkyl and C 1-6 hydroxy fluorenyl, or two adjacent substituents may be bonded to form a C6-10 aryl group, a 5-10 membered heteroaryl group, a C3-10 cycloalkyl group or a 3-10 membered heterocyclic ring Base; and meet the following conditions -
  • R 2 is selected from the following groups: ⁇ ,
  • A is a divalent 3-10 membered nitrogen-containing heterocyclic fluorenyl group or a divalent 3-7 membered nitrogen-containing heterocycloalkenyl group;
  • Rc, Rc' and R c " are each independently selected from the group consisting of hydrogen, hydroxy, amino, NRaRa', halogen, cyano, nitro, carboxy, formyl, amide, ester, C1-6 haloalkyl, C1-6 Hydroxyalkyl, C1-6 heteroalkyl, C1-6 alkoxy, C1-6 alkoxyalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, 5-10 member Aryl, C3-10 cycloalkyl, 3-10 membered heterocycloalkyl, 3-7 membered heterocycloalkenyl, C1-6 fluorenyl C6-10 aryl, 5-10 membered heteroaryl C1-6 alkane Or a C1-6 alkyl 5-10 membered heteroaryl; preferably selected from the group consisting of hydrogen, hydroxy, amino, NRaRa', halogen, carboxy, formyl, amide, ester, C1-6 halogenated flu
  • Each and R a ' is independently hydrogen or C1-6 fluorenyl.
  • Rc, R cl DR c2 is selected from the group consisting of hydrogen, hydroxy, amino, RaRa', halogen, cyano, nitro, carboxy, formyl Base, amide group, ester group, C1-6 hydrazino group, C1-6 hydroxyalkyl group, C1-6 heteroalkyl group, C1-6 decyloxy group, C1-6 alkoxyalkyl group, C2-6 alkenyl group , C2-6 alkynyl, C6-10 aryl, 5-10 membered heteroaryl, C3-10 cyclodecyl, 3-10 membered heterocycloalkyl, 3-7 membered heterocycloalkenyl, C1-6 alkane a C6-10 aryl group, a 5-10 membered heteroaryl C1-6 alkyl group or a C1-6 fluorenyl 5-10 membered heteroaryl group; preferably selected from the group consisting of hydrogen, hydroxy, amino, NRaRa', halogen,
  • Or can be linked to Rc 2 to form a C6-10 aryl group, a 5-10 membered heteroaryl group, a C3-10 cyclodecyl group and a 3-10 membered heterocyclic group;
  • each! ⁇ and R a ' are independently hydrogen or C1-6 fluorenyl.
  • the compound of formula (I) is selected from the group consisting of compounds of formula (la) or (lb) below.
  • X and Y are each independently selected from 0, S or NH;
  • W, Z and T are each independently selected from 0, N, NR a , CO, C, CR a , or CH 2 ;
  • n is. , 1 or 2;
  • n 0, 1 or 2;
  • J is NR a , NOR a , 0, S or, wherein J is a divalent 3-10 membered heterocyclic fluorenyl group containing at least one nitrogen atom or a divalent 3-7 membered heterocycloalkenyl group;
  • M is a covalent bond, a divalent 3-10 membered heterocycloalkyl group, a divalent 3-7 membered heterocycloalkenyl group or a divalent 5-10 membered heteroaryl group;
  • Q is hydrogen, C1-6 alkyl, C1-6 hydroxy fluorenyl, -(CH 2 ) p -C(0)R b , -(CH 2 ) p -C(0)NHR b , -(CH 2 ) p -C(S)R b , -(CH 2 )pC(S)NHR b , -(CH 2 )p-S0 2 R b , -(CH 2 ) p -S0 2 NHR b ,
  • p is 0, 1, 2 or 3; preferably 0 or 1;
  • R 3 , R 4 and R 5 may be bonded to form an unsubstituted or substituted C 6-10 aryl group, an unsubstituted or substituted 5-10 membered heteroaryl group, an unsubstituted or substituted C 3 3 10 fluorenyl or unsubstituted or substituted 3-10 membered heterocyclic fluorenyl; wherein each R b is independently C 1-6 alkyl, C 2-6 alkenyl, NHR a , R a R a ', unsubstituted Or substituted phenyl or 3-7 membered heterocyclic group;
  • Each of ⁇ and R a ' is independently hydrogen or C1-6 fluorenyl
  • Unsubstituted or substituted means that the group is unsubstituted or substituted by one or more substituents selected from the group consisting of hydroxy, amino, cyano, nitro, carboxy, halogen, C1-6, C1- 6 halodecyl and C 1-6 hydroxy fluorenyl, or two adjacent substituents may be bonded to form a C6-10 aryl group, a 5-10 membered heteroaryl group, a C3-10 cycloalkyl group or a 3-10 membered hetero ⁇ ⁇ ; and meet the following conditions:
  • the compound of formula (X) is selected from the group consisting of the following formulae IIa), (lib), (lie) and (lid)
  • X and Y are independently 0, S, NH;
  • W, Z and T are each independently selected from 0, N, R a , CO, C, CR a , or CH 2
  • n 0, 1, 2 or 3;
  • J is selected from the group consisting of Ra, NOR a , 0 and S;
  • K is a covalent bond, NR a , CR e R e , or CReR ⁇ CRcR ⁇ ;
  • Q is hydrogen, Cl-6 fluorenyl, Cl-6 hydroxy fluorenyl, -(CH 2 ) p -C(0)R b , -(CH 2 ) p -C(0) HR b , -(CH 2 ) p -C(S)R b , -(CH 2 ) p -C(S)NHR b , -(CH 2 ) p -S0 2 R b , -(CH 2 ) p -S0 2 NHR b ,
  • p is 0, 1, 2 or 3; preferably 0 or 1;
  • Rc, Rc' and Re are each independently selected from the group consisting of hydrogen, hydroxy, amino, NRaRa', halogen, cyano, nitro, carboxy, formyl, amide, ester, C1-6 haloalkyl, C1-6 hydroxy Alkyl, C1-6 heteroalkyl, C1-6 alkoxy, C1-6 decyloxy, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, 5-10 membered heteroaryl Base, C3-10 cyclodecyl, 3-10 membered heterocyclic fluorenyl, 3-7 membered heterocycloalkenyl, C1-6 alkyl C6-10 aryl, 5-10 membered heteroaryl C1-6 alkyl Or a C1-6 alkyl 5-10 membered heteroaryl; preferably selected from the group consisting of hydrogen, hydroxy, amino, NRaRa', halogen, carboxy, formyl, amide, ester, C1-6 haloal
  • R 3 and R 4 are bonded to form an unsubstituted or substituted C 6-10 aryl group, an unsubstituted or substituted 5-10 membered heteroaryl group, an unsubstituted or substituted C 3-10 cyclodecyl group or an unsubstituted or substituted 3- 10-membered heterocyclic fluorenyl;
  • each R b is independently C1-6 fluorenyl, C 2-6 alkenyl, NHR a , R a R a ', unsubstituted or substituted phenyl or 3-7 membered heterocyclic group;
  • Each and Ra' are independently hydrogen or C1-6 fluorenyl
  • Unsubstituted or substituted means that the group is unsubstituted or substituted by one or more substituents selected from the group consisting of hydroxy, amino, cyano, nitro, carboxy, halogen, C1-6 alkyl, C 1- 6 haloalkyl and C 1-6 hydroxy fluorenyl, or two adjacent substituents may be bonded to form a C6-10 aryl group, a 5-10 membered heteroaryl group, a C3-10 cycloalkyl group or a 3-10 membered heterocyclic ring Base; and meet the following conditions -
  • the compound of formula (X) is selected from the group consisting of the following formulae IIIa), (IIIb), (IIIc) and (Hid): Compound : (Ilia), (Illb),
  • 1 is selected from the group consisting of hydrogen, hydrazine, C1-6 fluorenyl, C1-6 hydroxy fluorenyl, C1-6 halogenated fluorenyl, unsubstituted or substituted phenyl; preferably selected from hydrogen and hydrazine; preferably hydrogen;
  • J is selected from NRa, NORa, O or S;
  • Q is hydrogen, C1-6 alkyl, C1-6 hydroxy fluorenyl, -(CH 2 ) p -C(0)R b , -(CH 2 ) p -C(0) HR b , -(CH 2 ) p -C(S)R b , -(CH 2 ) p -C(S)NHR b , -(CH 2 ) p -S0 2 R b , or -(CH 2 ) p -S0 2 HR b ,
  • p is 0, 1, 2 or 3; preferably 0 or 1;
  • Each R e , ! ⁇ And! ⁇ "Independently selected from hydrogen, hydroxy, amino, NRaRa', halogen, cyano, nitro, carboxy, formyl, amide, ester, C1-6 alkyl, C1-6 hydroxyalkyl, C1- 6heteroalkyl, C1-6 alkoxy, C1-6 alkoxyfluorenyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, 5-10 membered heteroaryl, C3-10 Cyclodecyl, 3-10 membered heterocyclic fluorenyl, 3-7 membered heterocycloalkenyl, C1-6 fluorenyl C6-10 aryl, 5-10 membered heteroaryl C1-6 fluorenyl or C1-6 ⁇ 5-10 membered heteroaryl; preferably selected from the group consisting of hydrogen, hydroxy, amino, NRaRa', halogen, carboxy, formyl, amide, ester, C1-6
  • R 3 are bonded to form an unsubstituted or substituted C6-10 aryl group, an unsubstituted or substituted 5-10 membered heteroaryl group, an unsubstituted or substituted C3-10 cycloalkyl group or an unsubstituted or substituted 3-10 Monocyclic sulfhydryl group;
  • each R b is independently C 1-6 alkyl, C 2-6 alkenyl, HR a , R a R a ', unsubstituted or substituted phenyl or 3-7 membered heterocyclic group;
  • Each and R a ' is independently hydrogen or C1-6 fluorenyl
  • Unsubstituted or substituted means that the group is unsubstituted or substituted by one or more substituents selected from the group consisting of hydroxy, amino, cyano, nitro, carboxy, halogen, C1-6 fluorenyl, C 1 -6 halodecyl and C 1-6 hydroxyalkyl, or two adjacent substituents may be bonded to form a C6-10 aryl group, a 5-10 membered heteroaryl group, a C3-10 cycloalkyl group or a 3-10 member. Heterocyclic fluorenyl.
  • the compound of formula (I) is selected from the group consisting of the following general formulae (IVa), (IVb:), (IVc) and
  • J is NR a , NORa, 0 or S;
  • NR a NR a , CR e R e , or CReRc RcRc,; a divalent 3-10 membered nitrogen-containing heterocycloalkyl group or a divalent 3-7 membered nitrogen-containing heterocycloalkenyl group;
  • Q is hydrogen, C1-6 fluorenyl, C1-6 hydroxy fluorenyl, -(CH 2 ) p -C(0)R b , -(CH 2 ) p -C(0) HR b , -(CH 2 ) p -C(S)R b , -(CH 2 ) P -C(S)NHR b , -(CH 2 ) p -S0 2 R b , -(CH 2 ) P -S0 2 NHR b ,
  • p is 0, 1, 2 or 3; preferably 0 or 1;
  • Rc, Rc' and Rc" are each independently selected from the group consisting of hydrogen, hydroxy, amino, RaRa', halogen, cyano, nitro, carboxy, formyl, amide, ester, C1-6 halogenated fluorenyl, C1 -6 hydroxy fluorenyl, C1-6 heterofluorenyl, C1-6 decyloxy, C1-6 fluorenyl fluorenyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, 5-10 Monoheteroaryl, C3-10 cyclodecyl, 3-10 membered heterocyclic fluorenyl, 3-7 membered heterocycloalkenyl, C1-6 alkyl C6-10 aryl, 5-10 membered heteroaryl C1- 6 alkyl or C1-6 alkyl 5-10 membered heteroaryl; preferably selected from the group consisting of hydrogen, hydroxy, amino, NRaRa', halogen, carboxy, for
  • each R b is independently C 1-6 alkyl, C 2-6 alkenyl, NHR a , R a R a ', unsubstituted or substituted phenyl or 3-7 membered heterocyclic;
  • Each and R a ' is independently hydrogen or C 1-6 alkyl
  • Unsubstituted or substituted means that the group is unsubstituted or substituted by one or more substituents selected from the group consisting of hydroxy, amino, cyano, nitro, carboxy, halogen, C1-6 alkyl, C 1- 6 haloalkyl and C 1-6 hydroxy fluorenyl, or two adjacent substituents may be bonded to form a C6-10 aryl group, a 5-10 membered heteroaryl group, a C3-10 cyclodecyl group or a 3-10 membered heterocyclic ring.
  • substituents selected from the group consisting of hydroxy, amino, cyano, nitro, carboxy, halogen, C1-6 alkyl, C 1- 6 haloalkyl and C 1-6 hydroxy fluorenyl, or two adjacent substituents may be bonded to form a C6-10 aryl group, a 5-10 membered heteroaryl group, a C3-10 cyclodecyl group or a 3-10
  • R4 is selected from the group consisting of hydrogen, hydroxy and C1-6 fluorenyl.
  • each Rc, R el , R c2 , Rc' and Re are independently selected from the group consisting of hydrogen, hydroxy, amino, NRaRa', halogen, cyano, nitro, carboxy, formyl, amide, ester, C1- 6 haloalkyl, C1-6 hydroxyalkyl, C1-6 heterofluorenyl, C1-6 decyloxy, C1-6 decyloxyalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl Base, 5-10 membered heteroaryl, C3-10 cycloalkyl, 3-10 membered heterocyclic fluorenyl, 3-7 membered heterocycloalkenyl, C1-6 fluorenyl C6-10 aryl, 5-10.
  • Heteroaryl C1-6 fluorenyl or C1-6 fluorenyl 5-10 membered heteroaryl preferably selected from the group consisting of hydrogen, hydroxy, amino, RaRa', halogen, carboxy, formyl, amide, ester, C1-6 Haloalkyl, C1-6 hydroxyalkyl, C1-6 heterofluorenyl, C1-6 decyloxy, C3-10 cyclononyl, 3-10 membered heterocycloalkyl, substituted or unsubstituted phenyl or pyridyl ;
  • Each of R and R a ' is independently hydrogen or C1-6 alkyl.
  • X 1 is F, Cl, Br, I or a trifluoromethyl group
  • X 2 is H, F, Cl, Br or I
  • Rci, Rc3 or R. 4 each independently selected from the group consisting of hydrogen, hydroxy, amino, NRaRa', halogen, cyano, nitro, carboxy, formyl, amide, ester, C1-6 halogenated fluorenyl, C1-6 hydroxyalkyl, C1 -6 heteroalkyl, C1-6 alkoxy, C1-6 alkoxyalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, 5-10 membered heteroaryl, C3- 10 cycloalkyl, 3-10 membered heterocyclic fluorenyl, 3-7 membered heterocycloalkenyl, C1-6 alkyl C6-10 aryl, 5-10 membered heteroaryl C1-6 fluorenyl or C1-6 Alkyl 5-10 membered heteroaryl; preferably selected from the group consisting of hydrogen, hydroxy, amino, NRaRa', halogen, carboxy, formyl, amide, ester
  • Rc3 and Rc 4 may be bonded to form a C6-10 aryl group, a 5-10 membered heteroaryl group, a C3-10 cyclodecyl group and a 3-10 membered heterocyclic ring. ⁇ ;
  • Each of R and R a ' is independently hydrogen or C1-6 alkyl.
  • R 4 and in the formula (I) are hydrogen.
  • the compound of formula (I) is selected from the group consisting of the following formula (Va), (Vb) and (Vc):
  • W is selected from the group consisting of: 0, NRa and CHR a ;
  • J is NR a , NORa, O or S;
  • K is a covalent bond, NR a , CH' or CR e Rc, CR c Rc,;
  • Ring A is a divalent 3-10 membered nitrogen-containing heterocyclic fluorenyl group or a divalent 3-7 membered nitrogen-containing heterocycloalkenyl group;
  • the B ring is an unsubstituted or substituted C6-10 aryl group or a 5-10 membered heteroaryl group; preferably, the B ring is an unsubstituted or substituted C6-10 aryl group, more preferably the B ring is an unsubstituted or substituted benzene group.
  • Rc, Rc, and! Each independently selected from the group consisting of hydrogen, hydroxy, amino, NRaRa', halogen, cyano, nitro, carboxy, formyl, amide, ester, C1-6 haloalkyl, C1-6 hydroxyalkyl, C1-6 Heteroalkyl, C1-6 alkoxy, C1-6 ⁇ oxyalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, 5-10 membered heteroaryl, C3-10 ring Mercapto, 3-10 membered heterocyclic fluorenyl, 3-7 membered heterocycloalkenyl, C1-6 alkyl C6-10 aryl, 5-10 membered heteroaryl C1-6 alkyl or C1-6 alkyl 5-10 membered heteroaryl; preferably selected from the group consisting of hydrogen, hydroxy, amino, NRaRa', halogen, carboxyl, formyl, amide, ester, C1-6 haloalkyl
  • Each R a is independently selected from the group consisting of hydrogen and C 1 -6 fluorenyl.
  • the compound of the invention or a pharmaceutically acceptable salt thereof is preferably selected from the following compounds or salts:
  • the invention provides a pharmaceutical composition comprising a compound according to the invention or a pharmaceutically acceptable salt thereof.
  • the pharmaceutical composition may also comprise a pharmaceutical excipient.
  • the invention provides the use of a compound according to the invention, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for modulating autophagy in a cell.
  • the agent that modulates autophagy is a drug that modulates a mammalian ATG8 homolog.
  • the agent for modulating autophagy is a medicament for preventing or treating a disease associated with autophagy, particularly a mammalian ATG8 homolog.
  • the invention provides a method of modulating autophagy in a subject comprising administering a compound according to the invention, or a pharmaceutically acceptable salt thereof, to a subject in need thereof.
  • the method of modulating autophagy is a method of modulating a mammalian ATG8 homolog.
  • the method of modulating autophagy is a method of preventing or treating a disease associated with autophagy, particularly a mammalian ATG8 homolog.
  • the mammalian ATG8 homolog is LC3B.
  • the prevention or treatment of a disease associated with autophagy is selected from the group consisting of a tumor, a cardiovascular disease, an autoimmune disease, Degenerative diseases, hypertension, bone tissue and bone diseases, Crohn's disease, acute kidney injury, cerebral ischemia, retinal disease, bronchial asthma, Vici syndrome, and infectious diseases.
  • the tumor is selected from the group consisting of liver cancer, lung cancer, pancreatic cancer, breast cancer, cervical cancer, endometrial cancer, colorectal cancer, gastric cancer, lung cancer, nasopharyngeal cancer, ovarian cancer, prostate cancer , leukemia, lymphoma, myeloma.
  • some preferred compounds are selected from the group consisting of a compound of the formula Ob), a compound of the formula end), a compound of the formula and; ClVd) compound, and formula
  • C1-6 alkyl refers to "C1-6 fluorenyl” and "C1-6 hydroxy fluorenyl”, “C1-6 halogenated fluorenyl”, “C6-10 aryl C1-6 alkane”
  • C1-6 fluorenyl moiety such as “C1-6 alkyl C6-10 aryl", “C1-6 methoxy”, and the like.
  • “Pharmaceutical composition” means a composition suitable for administration to a patient.
  • the composition may contain only a compound of the invention or a mixture containing a compound of the invention, or a salt, solvate, prodrug, isomer or tautomer of the compound of the invention, or may contain one or A compound of the invention in combination with a plurality of pharmaceutically acceptable carriers or adjuvants.
  • "Patient” includes both human and non-human animals.
  • the pharmaceutical composition may be in various forms such as tablets, capsules, powders, syrups, solutions, suspensions and aerosols, and the like, and may be present in a suitable solid or liquid carrier or diluent and suitable for use In the sterilizing device for injection or drip.
  • the compound dosage form comprises from 0.05 to 200 mg of the compound of the formula (I), preferably, the unit dosage of the formulation comprises from 0.1 mg to 100 mg of the compound of the formula (I).
  • the compounds and pharmaceutical compositions of the invention can be used clinically in mammals, including humans and animals, through the mouth, nose, Route of administration for the skin, lungs, or gastrointestinal tract, and the like. Most preferably oral.
  • the best preferred daily dose is 0.01 - 200 mg / kg body weight, taken once, or 0.01-100 mg / kg body weight.
  • the optimal dosage for the individual should be based on the particular treatment. Usually starting with a small dose, gradually increasing the dose until the most suitable agent is found
  • Halogen (or halo) means fluoro, chloro, bromo or iodo.
  • C1-6 fluorenyl group means a straight-chain or branched alkyl group having 1 to 6 carbon atoms, preferably a linear or branched fluorenyl group having 1 to 4 carbon atoms. Branched means that one or more mercapto groups of 1 to 4 carbon atoms such as a methyl group, an ethyl group or a propyl group are bonded to a linear alkyl group.
  • Preferred C1-6 thiol groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, and t-butyl groups.
  • C1-6 haloalkyl means a C1-6 fluorenyl group as defined above containing one or more substituents of a halogen atom.
  • C2-6 alkenyl group means a linear or branched alkenyl group having 2 to 6 carbon atoms, preferably 2 to 4 carbon atoms. Branched means that one or more lower C1-6 thiol groups are attached to a linear C2-6 alkenyl chain.
  • Preferred C2-6 alkenyl groups include, but are not limited to, ethenyl, propenyl, n-butenyl, 3-methylbutenyl, n-pentenyl and the like.
  • C1-6 anthracene group means a divalent group obtained by removing one hydrogen atom from the C1-6 alkyl group defined above.
  • Preferred C1-6 alkylene groups include, but are not limited to, methylene, ethylene, propylene, and the like. In general, it may equally be optionally and denoted herein as - (alkyl with a C1-6) -, for example, -CH 2 CH 2 - is ethylene.
  • C2-6 alkynyl group means a straight or branched alkynyl group having 2 to 6 carbon atoms, preferably 2 to 6 carbon atoms, more preferably 2 to 4 carbon atoms. Branched means that one or more thiol groups having 2 to 4 carbon atoms are attached to the linear alkynyl chain.
  • Preferred C2-6 alkynyl groups include, but are not limited to, ethynyl, propynyl, 2-butynyl, 3-methylbutynyl and the like.
  • substituted C2-6 alkenyl group means a difunctional group obtained by removing one hydrogen atom from the C2-6 alkenyl group defined above.
  • C6-10 aryl means an aromatic monocyclic or polycyclic ring system containing from 6 to 10 carbon atoms.
  • Preferred C6-10 aryl groups include, but are not limited to, phenyl and naphthyl.
  • C6-10 arylene means a divalent group obtained by removing one hydrogen atom from the C6-10 aryl group defined above, for example
  • 5-10 membered heteroaryl means an aromatic monocyclic or polycyclic group having 5 to 10 ring atoms, and the 5-10 membered heteroaryl group includes 1 to 4 of N, 0 and S. A hetero atom.
  • Preferred 5-10 membered heteroaryl groups contain 5 to 6 ring atoms.
  • the nitrogen atom of the 5-10 membered heteroaryl group can be optionally oxidized to the corresponding N-oxide.
  • the term "5-10 membered heteroaryl” also includes a C6-10 aryl fused ring as defined above.
  • Preferred 5-10 membered heteroaryl groups include, but are not limited to, pyridinyl, pyrazinyl, furyl, thienyl, pyrimidinyl, pyridone, oxazolyl, isothiazolyl, oxazolyl, oxadiazolyl, thiazole Base, thiadiazolyl, pyrazolyl, furazanyl, pyrrolyl, triazolyl, 1,2,4-thiadiazolyl, pyridazinyl, quinoxalinyl, pyridazinyl, Hydroxamyl, imidazo[l,2-a]pyridyl, imidazo[2,1-b]thiazolyl, benzofurazanyl, fluorenyl, azaindole, benzo Imidazolyl, benzothienyl, quinolyl, imidazolyl, thienopyridyl, quinazolinyl
  • C3-10 cycloalkyl group means a non-aromatic monocyclic or polycyclic group having 3 to 10 carbon atoms, preferably 3 to 6 carbon atoms.
  • Preferred monocyclic C3-10 cyclodecyl groups include, but are not limited to, cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl and the like.
  • Preferred polycyclic fluorenyl groups include, but are not limited to, [1 ⁇ 1]-dicyclopentamethylene, 1-decanoyl, norbornyl, adamantyl and the like.
  • C3-10 cycloalkenyl means a non-aromatic monocyclic or polycyclic group containing from 3 to 10 carbon atoms which contains at least one intra-carbon-carbon double bond, preferably from 3 to 7 ring atoms, More preferably, it contains 5 to 7 ring atoms.
  • the C3-10 cycloalkenyl group includes, but is not limited to, a cyclopropenyl group, a cyclobutenyl group, a cyclopentenyl group, a cyclohexenyl group, a cyclopentenyl group, a cycloheptanium-1,3-dienyl group, Norbornyl and the like.
  • the "3-10 membered heterocyclic fluorenyl group” (or “3-10 membered heterocyclic group”) means a non-aryl group having 3 to 10 ring atoms, preferably 5 to 10 ring atoms, preferably 5 to 6 ring atoms. a saturated monocyclic or polycyclic group, wherein the 3-10 membered heterocyclic group contains 1 to 4 hetero atoms selected from N, 0 and S, and the two heteroatoms in the ring system do not adjacent.
  • the nitrogen or sulfur atom of the 3-10 membered heterocyclic group can be optionally oxidized to the corresponding N-oxide, S-oxide or S,S-dioxide.
  • oxide refers to the corresponding N-oxide, S-oxide or S,S-dioxide.
  • Preferred monocyclic 3-10 membered heterocyclic fluorenyl groups include, but are not limited to, piperidinyl, oxetanyl, pyrrolyl, piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, 1,4- Dioxo C1-6 fluorenyl, tetrahydrofuranyl, tetrahydrothiophenyl, lactam (eg pyrrolidinyl;), lactone groups of 3 to 10 ring atoms and oxides thereof.
  • the "3-7 membered heterocycloalkenyl group” means a non-aromatic monocyclic or polycyclic group having 3 to 7 ring atoms, preferably 5 to 6 ring atoms, wherein the 3-7 membered heterocyclic alkene
  • the group contains 1 to 4 hetero atoms selected from N, 0 and S, and it contains at least one carbon-carbon double bond or carbon-nitrogen double bond. There are no adjacent oxygen and/or sulfur atoms present in the ring system.
  • the prefix aza, oxa or thia before the 3-7 membered heterocycloalkenyl name means that at least one nitrogen, oxygen or sulfur atom respectively acts as a ring atom.
  • the nitrogen or sulfur atom of the 3-7 membered heterocycloalkenyl can be optionally oxidized to the corresponding N-oxide, S-oxide or 8, S-dioxide.
  • Preferred 3-7 membered heterocycloalkenyl groups include, but are not limited to, 1,2,3,4-tetrahydropyridyl, 1,2-dihydropyridyl, 1,4-dihydropyridyl, 1,2,3 ,6-tetrahydropyridyl, 1,4,5,6-tetrahydropyrimidinyl, 2-pyrroline, 3-pyrroline, 2-imidazolinyl, 2-pyrazolyl, dihydroimidazolyl And a dihydrooxazolyl group, a dihydrooxadiazolyl group, a dihydrothiazolyl group, a 3,4-dihydro-2H-pyranyl group, a dihydrofuranyl group, a fluorodihydro
  • C6-10 aryl C1-6 fluorenyl (or “C6-10 aryl C1-6 alkyl”) means a group formed by linking a C6-10 aryl group and a C1-6 fluorenyl group as defined above.
  • Preferred C6-10 aryl C1-6 alkyl groups include, but are not limited to, benzyl, 2-phenethyl and naphthylmethyl.
  • the C6-10 aryl C1-6 fluorenyl group is bonded to the parent moiety through a C1-6 alkyl group.
  • C1-6 Mercapto C6-10 aryl means a group formed by linking a C1-6 alkyl group as defined above and a C6-10 aryl group.
  • Preferred C1-6 alkyl C6-10 aryl groups include, but are not limited to, tolyl.
  • the C1-6 alkyl C6-10 aryl group is bonded to the parent moiety through a C6-10 aryl group.
  • the "5-10 membered heteroaryl C1-6 fluorenyl group” means a group formed by linking a 5-10 membered heteroaryl group as defined above and a C1-6 fluorenyl group.
  • Preferred C6-10 aryl C1-6 alkyl groups include, but are not limited to, pyridylmethyl and quinolin-3-ylmethyl.
  • the 5-10 membered heteroaryl C1-6 fluorenyl group is bonded to the parent moiety through a C1-6 fluorenyl group.
  • C1-6 hydroxy fluorenyl group means a C1-6 fluorenyl group substituted by a hydroxy group, wherein the C1-6 fluorenyl group is as described above.
  • Preferred C1-6 hydroxy fluorenyl groups include, but are not limited to, hydroxymethyl and 2-hydroxyethyl.
  • C1-6 methoxy means a C1-6 fluorenyl-0- group bonded to the parent moiety through oxygen, wherein the C1-6 alkyl group is as defined above.
  • Preferred C1-6 alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy and n-butoxy.
  • C1-6 alkoxyalkyl group means a group derived from a C1-6 methoxy group and a C1-6 fluorenyl group as defined in the present invention, and is bonded to the parent moiety through a C1-6 alkyl group.
  • Ester group means -C(0)ORx, which is C1-6 mercapto, C6-10 aryl, C6-10 aryl C1-6 alkyl and C3-10 cycloalkyl.
  • Preferred ester groups include, but are not limited to, methyl ester groups, ethyl ester groups, isopropyl ester groups, tert-butyl ester groups, phenyl ester groups.
  • “Amido” means -C(0) R y R y , wherein R y and R y are hydrogen, C 1 -6 fluorenyl, C 6-10 aryl, C 6-10 aryl C 1-6 alkyl Or C3-10 cycloalkyl.
  • any of the foregoing functional groups of the present invention may be unsubstituted or substituted with a substituent as described herein.
  • substituted refers to the replacement of one or more hydrogen atoms on a given atom with a group selected from a specified group, provided that the normal valence of the specified atom is not exceeded and that the substitution results in a stable Compound.
  • the combination of substituents and/or variables is permissible only when the combination forms a stabilizing compound; "stable compound” or “stable structure” means having the ability to be separated from the reaction mixture to a useful purity and configured to be effective A compound with sufficient stability for a therapeutic agent.
  • unsubstituted or substituted means that a particular group is unsubstituted or substituted with one or more substituents.
  • the substituent includes, without limitation, hydrogen, hydroxy, amino, cyano, nitro, carboxy, halogen, C1-6 alkyl, C1-6 haloalkyl or C1-6 hydroxyindenyl. Two adjacent substituents may be bonded to form a C6-10 aryl group, a 5-10 membered heteroaryl group, a C3-10 cyclodecyl group or a 3-10 membered heterocyclic fluorenyl group.
  • a tautomer refers to a compound produced by the phenomenon that a proton of one atom in a molecule is transferred to another atom. Tautomers also mean that two or more are readily converted from one isomeric form to another. The isomeric form of the state.
  • One of ordinary skill in the art will recognize the possibility of all tautomeric ring atom arrangements. All such isomeric forms of these compounds are expressly included in the present disclosure.
  • the compounds of the invention include all tautomers thereof, such as keto-enol tautomers.
  • these tautomers and mixtures thereof are partially structured (Example 11,
  • a stereoisomer refers to an isomer of a compound having the same molecular formula and having the same atomic bonding order but different spatial arrangement in the molecule.
  • Enantiomers are stereoisomers that are mirror images of each other; diastereomers refer to molecules having two or more centers of chirality and intermolecular non-mirrored relationship Stereoisomers. Unless otherwise indicated, the specification is intended to include individual stereoisomers and mixtures thereof.
  • the compounds of the invention include all isomers thereof, such as diastereomers and cis/trans (Z/E) isomers.
  • cis-trans isomers of compound 101 disclosed herein are shown below .
  • the compounds of the invention may form metal chelates with one or more metal ions.
  • Metal ions include, but are not limited to, copper, iron, magnesium, calcium, zinc, nickel, and platinum.
  • An example of a metal chelate compound is given in Example 38 as described herein. It should be noted that the compounds of the invention include all metal chelates.
  • pharmaceutically acceptable salts refers to substances which are suitable for use in humans and/or animals without excessive adverse side effects (e.g., toxicity, irritation, and allergic reactions), i.e., having a reasonable benefit/risk ratio.
  • Pharmaceutically acceptable salts include inorganic and organic salts which may be obtained during the final isolation and purification of the compounds of the invention or by the reaction of the free acid or base function with a suitable base or acid.
  • Acids suitable for salt formation include, but are not limited to, inorganic acids such as hydrochloric acid, phosphoric acid or sulfuric acid, or organic acids such as capric acid, ascorbic acid, citric acid, tartaric acid, lactic acid, maleic acid, malonic acid, fumaric acid, glycolic acid.
  • Bases suitable for the formation of salts include, but are not limited to, inorganic bases such as sodium carbonate, sodium hydroxide, potassium carbonate, potassium hydroxide, lithium hydroxide, calcium acetate, calcium chloride or magnesium chloride, and the like, and organic bases such as aminoethanol and the like.
  • an effective amount means that the amount of the compound of the invention contained in the composition to be administered is sufficient to modulate (e.g., inhibit or agonize, etc.;) a mammalian ATG8 homolog.
  • the compounds of the present invention can be prepared by various methods known in the art which are known in the art, and the following reaction schemes are optional for the preparation of the compounds of the present invention.
  • Mass spectrometry was recorded by liquid chromatography-mass spectrometry (LC-MS) (Agilent 6120B single quadrupole liquid chromatography-mass spectrometer). Nuclear magnetic resonance spectroscopy (such as hydrogen spectrum ( , carbon spectrum ( 13 C), phosphorus spectrum ( 31 P) and fluorine spectrum ( 19 F)) using Bruker AMX-400, Gemini-300 or A X-600 NMR Recorded in deuterated solvents such as deuterated chloroform, deuterated methanol, deuterated water or deuterated dimethyl sulfoxide and referenced to deuterated solvent peaks.
  • deuterated solvents such as deuterated chloroform, deuterated methanol, deuterated water or deuterated dimethyl sulfoxide and referenced to deuterated solvent peaks.
  • the unit of chemical shift ⁇ is ppm
  • coupling constant (J or The unit of J) is Hertz Hz, Hertz)
  • the coupling split peaks in the nuclear magnetic spectrum are expressed as: wide single peak (brs), single peak;), doublet (d), double doublet (dd), triplet (t), quartet (q) and multiplet (m).
  • Step 1 Synthesis of the compound 2-(2-(4-(2-hydroxyethyl)piperazine-1-yl)ethyl)isoindoline-1,3-dione
  • Step 2 Synthesis of the compound 2-(4-(2-Aminoethyl;) piperazine-]-yl)ethan-1-ol
  • Example 2 Compound 5-(((2-(4-(2-hydroxyethyl))piperazin-1-yl)ethyl)amino)methylene)-2,2-dimethyl-1, 3-dioxin-4,6-dione (compound)
  • Example 3 Synthesis of Compound 2-(Aminomethylene)-5-phenylcyclohexane-1,3-dione (Compound 2) Correction Page (Rule 91) ISA/CN
  • the compound 2-dimethylaminomethylene-5-phenylcyclohexane-1,3-dione (1.1 g, 4.52 mmol) was dissolved in aqueous methanol (7 N, 50 mL).
  • the compound 2-((dimethylamino)methylene)-5-phenylcyclohexane-1,3-dione (200 mg, 0.823 mmol) was dissolved in 5 mL absolute ethanol and 5 mL DCM. ImL acetic acid and sodium thiomethoxide (115 mg, 1.64 mmol), and the mixture was stirred at room temperature for 16 hr. Additional 1 mL of acetic acid and sodium thiomethoxide (115 mg, 1.64 mmol) were added and stirring was continued for 16 hours. After the reaction was completed, the reaction solution was poured into water and extracted with dichloromethane (DCM).
  • DCM dichloromethane
  • Example 8 Compound 2-(((2-(4-(2-hydroxyethyl)piperazin-1-yl)ethyl)amino)methylene)-5-phenylcyclohexane-1 3- Synthesis of diketone (compound 8)
  • Step 1 Synthesis of the compound 2-((Dimethylamino)methylene)-5-phenylcyclohexane-1 3-dione
  • Step 2 Compound 2-(((2-(4-(2-hydroxyethyl)piperazin-1-yl)ethyl)amino)methylene)-5-phenylcyclohexanium-1,3- Diketone
  • the compounds 9-12 and 14-15 are synthesized in the same manner as the compound 8, as shown in Table 2. Shown.
  • Example 9-1 Intermediate 3-1: (2S, 2'R)-7-chloro-4,6-dimethoxy-2'-methyl-3H-spiro [benzofuran-2,1 '-cyclohexane] 3,4-',6'-trione
  • Example 10 Compound 2-(((2-(4-(2-hydroxyethyl)piperazin-1-yl)ethyl)amino)methylene)-5-(1 ⁇ -pyrrolo[2, - Synthesis of b]pyridin-4-yl)cyclohexanyl-1,3-dione (compound 17)
  • Step 1 Synthesis of the compound 4-bromo-1-(phenylsulfonyl >1H-pyrrolo[2,3-b]pyridine
  • Step 2 Synthesis of the compound 1 - (phenylsulfonyl)-4-ethyl C2-6 alkenyl-1 H-pyrrolo[2,3-b]pyridine
  • Step 3 Synthesis of the compound 1 - (phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine-4-carbaldehyde
  • Step 4 Synthesis of the compound 4-(1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)but-3-en-2-one 91) ISA/CN
  • Compound 1-(;phenylsulfonyl;)-1H-pyrrolo[2,3-b]pyridine-4-carbaldehyde (1.52 g, 5.3 mmol) and 1-triphenylphosphino-2-propanone (2.55 g) 8 mmol) was separately added to 30 mL of anhydrous THF, and the reaction was refluxed for 2 hours. After the reaction was completed, the mixture was concentrated to dryness.
  • Step 5 Synthesis of the compound 5-(1 ⁇ -pyrrolo[2,3-b]pyridin-4-yl)cyclohexanyl-1,3-dione
  • Step 6 Compound 2-(((2-(4-(2-hydroxyethyl))piperazin-1-yl)ethyl)amino)methylene)-5-(1 ⁇ -pyrrolo[2,3 , b] pyridin-4-yl;) synthesis of cyclohexene-1,3-dione
  • Step 1 Compound ((3aR, 4R, 6R, 6aR)-2,2-dimethyl-6-(6-morpholino-9H-indol-9-yl)tetrahydrofuro[3,4-d] [ 1,3]dioxo-4-yl;) Synthesis of methanol
  • 6-chloropurine nucleoside (3.0 g, 10.46 mmol), 2,2-dimethoxypropionamidine (5.2 g, 50 mmol) and p-toluenesulfonic acid monohydrate (1.99 g, 10.46 mmol) in acetone (120 ml)
  • acetone 120 ml
  • Step 2 Compound ((3aR, 4R, 6R, 6aR)-2,2-dimethyl-6-(6-morpholino-9H-indol-9-yl)tetrahydrofuro[3,4-d] [ Synthesis of 1,3]dioxo-4-yl)methanol
  • Step 3 Compound (3aS, 4S, 6R, 6aR)-2,2-dimethyl-6-(6-morpholino-9H-indol-9-yl)tetrahydrofuro[3,4-d] [1 Synthesis of 3,dioxol-4-carbaldehyde
  • Example 12 Compound 5-(4-(9H-indol-6-yl)phenyl)-2-(((2-(4-(2-hydroxyethyl)piperazin-1-yl)ethyl)) Synthesis of Amino)methylene)-1,3-Dione (Compound 33)
  • Step 1 Synthesis of the compound 6-chloro-9-(tetrahydro-2H-pyran-2-yl)-9H-indole
  • Step 2 Synthesis of the compound 4-(9-(tetrahydro-2H-pyran-2-yl)-9H-indol-6-yl)benzaldehyde
  • 6-Chloro-9-(tetrahydro-2H-pyran-2-yl)-9H-indole (5.7 g, 24 mmol) sodium carbonate (5.3 g, 50 mmol)
  • 4- aldehyde phenylboronic acid (7.5 g, 50 mmol)
  • tetrakis(triphenylphosphine)palladium (690 mg, 0.6 mmol) was dissolved in a mixed solution of dioxane (200 mL) and water (20 mL) and refluxed overnight. After completion of the reaction, the mixture was cooled to room temperature, poured into ice water, extracted with EtOAc, EtOAc evaporated.
  • Steps 3, 4, and 5 The same steps as in Embodiment 9
  • Step 6 Compound 5-(4-(9H-indol-6-yl)phenyl)-2-(((2-(4-(2-hydroxyethyl)piperazin-1-yl)ethyl)amino) Synthesis of methylene)cyclohexane-1,3-dione
  • Example 12A Compound 2-(((2-(4-(2-hydroxyethyl)piperazinyl)ethyl)amino)methylene)-5-(3-(2-(2-methoxy) Ethoxy)ethoxy)phenyl)cyclohexanyl-1,3-dione (compound 34) o
  • Step 1 Synthesis of the compound 3-(2-(2-methoxyethoxy)ethoxy)benzaldehyde
  • Step 2 Synthesis of the compound 4-(3-(2-(2-methoxyethoxy)ethoxy)phenyl)but-3-en-2-one
  • Steps 3, 4 and 5 Compound 2-(((2-(4-(2-hydroxyethyl)piperazinyl)ethyl)amino)methylene)-5-(3-(2-(2-) Synthesis of methoxyethoxy)ethoxy)phenyl)cyclohexane-1,3-dione
  • Steps 3, 4 and 5 The operation steps are the same as those in the embodiment 9.
  • the compound 35-84 is synthesized in the same manner as the compound 34, as shown in Table 4. .
  • Methyl 1-adamantanecarboxylate (3 g, 15.5 mml) was dissolved in 80 ml of toluene under nitrogen, cooled to -78 ° C, and diisobutylaluminum hydride (1.5 M in toluene, 10.3 mL;) was added dropwise. The mixture was allowed to react to room temperature for 1 hour. The reaction was quenched by dropwise addition of 4N hydrochloric acid, poured into ice water and extracted with EA. The combined organic phases were washed with brine, dried and evaporated. The crude product was isolated by column chromatography to give the title compound 2. lg, yield 82%.
  • 5-bromo-2-thiophenecarboxaldehyde (3.80 g, 20.0 mmol).
  • 4-pyridineboronic acid (3.0 g, 24.0 mmol) > sodium carbonate (3.18 g, 30.0 mmol)
  • palladium acetate 224.0 mg, l .Ommol
  • triphenylphosphine 520.0 mg, 2.0 mmol
  • the reaction mixture was cooled to room temperature and poured into ice water, EtOAc was evaporated, and then evaporated.
  • Step 1 Synthesis of the compound (4-methylbenzo[d]thiazol-2-yl)carbamic acid tert-butyl ester
  • Step 2 Synthesis of the compound (4-(Dibromomethyl)benzo[d]thiazol-2-yl)carbamic acid tert-butyl ester.
  • Correction page (Rule 91) ISA/CN (4-Methylbenzo[d]thiazol-2-yl)carbamic acid tert-butyl ester e (5.2 g, 14.3 mmol), NBS (5.08 g, 28.5 mmol) and AIBN (330 mg, 2 mmol) were dissolved in tetrachloro In 30 mL of carbon, the reaction was refluxed overnight. After completion of the reaction, the reaction mixture was poured into EtOAc EtOAc EtOAc.
  • Step 3 Synthesis of the compound (4-formylbenzo[d]thiazol-2-yl)carbamic acid tert-butyl ester
  • 6-Chloro-9H-indole (1.54 g, 10 mmol), copper acetate (3.63 g, 20 mmol), 4-(hydroxymethyl)benzeneboronic acid (3.63 g, 20 mmol), 1,10-phenanthroline ( 3.60 g, 20 mmol) and 4A molecular sieves (1.0 g) were placed in dry DMF (50 mL) and allowed to react overnight at 40 °C. After the reaction was completed, it was poured into ice water, extracted with EA, and the organic phase was washed with water, dried over sodium sulfate and evaporated. The crude product was purified by column chromatography to yield the title compound 1.49 g, yield 57%.
  • Step 3 Synthesis of the compound 4-(4-(6-ethoxy-9H-indol-9-yl)phenyl)but-3-en-2-one
  • Example 15 Compound 7-(((2-(4-(2-hydroxyethyl))piperazinyl)ethyl)amino)methylene)-spiro[3.5]decane-6,8-dione (chemical
  • Step 1 Synthesis of the compound 2-cyclobutylene ethyl acetate
  • Step 2 Synthesis of the compound snail [3.5] ⁇ -6,8-dione
  • Step 3 Compound 7-(((2-(4-(2-hydroxyethyl)piperazin-1-yl)ethyl)amino)methylene)spiro[3.5]decane-6,8-dione Synthesis
  • the compound 87-94 was synthesized in the same manner as the compound 86, as shown in Table 5.
  • Step 1 Synthesis of the compound 4- «4-bromophenyl;)sulfonyl)morpholine
  • Step 2 Synthesis of the compound 3-(4-(morpholinosulfonyl)phenyl) acrylate
  • 6-(2-Hydroxyethoxy)nicotinyl (4 g, 24 mmol) and TEA (4 mL) were added to DCM (90 mL), m.sub. The solution was stirred at this temperature for 30 minutes and the reaction was completed. The reaction solution was poured into water and extracted with EA. The combined organic layers were dried with anhydrous sodium sulfate and evaporated.
  • Example 17 Compound 3-(((2-(4-(2-hydroxyethyl)piperazine-]-yl)ethyl)amino)methylene)-6-phenyldihydro-2H-pyran -2,4(3H)-
  • Step 1 Preparation of the compound 6-phenyldihydro-2H-pyran-2,4(3H)-dione
  • Step 2 Compound 3-(((2-(4-(2-hydroxyethyl)piperazin-1-yl)ethyl)amino)methylene)-6-phenyldihydro-2H-pyran- Synthesis of 2,4(3H)-dione
  • Example 17A 3-(((2-(4-(2-hydroxyethyl)piperazin-1 -yl)ethyl)amino)methylene)-6-phenylpiperidine-2,4-di Ketone (compound 96
  • Step 1 Synthesis of the compound 3-((3-ethoxy-3-oxo-1-phenylpropyl)amino)-3-oxopropionic acid ethyl ester 3-amino-3-phenylpropionic acid Ethyl ester (4.31 g, 22.23 mmol), monoethyl malonate (4.47 g, 33.84 mmol),
  • Example 18 Compound 4-(((2-(4-(2-hydroxyethyl)piperazin-1-yl)ethyl)amino)methylene)-1 -phenylpiperidine-3,5- Synthesis of diketone (; compound 97;)
  • Step 2 Synthesis of the compound N-(2-oxopropyl)-N-phenylglycine ethyl ester
  • Phenylglycine ethyl ester (2.3 g 12.83 mmol), bromoacetone (2.1 1 g 25.67 mmol) and DIPEA (4.57 mL 25.67 mmol) were added to DMF (50 mL), and reacted at 10 ° C for 4 hours, supplemented with bromoacetone ( 1.06 g 12.8 mmol), continue to react at 1 10 ° C for 4 hours.
  • the mixture was poured into water, and extracted with EA.
  • the combined organic phase was dried over anhydrous sodium sulfate and evaporated.
  • Step 4 and 5 The procedure is the same as in Example 2.
  • Step 1 Synthesis of the compound ethyl 3-(phenylamino)propionate
  • Step 2 Synthesis of the compound 3-((3-ethoxy-3-oxopropyl)(phenyl)amino)-3-oxopropionate
  • Step 3 Synthesis of ethyl ester of compound ethyl-2,4-dioxo-l-phenylpiperidine-3-carboxylate
  • Step 5 Compound 3 -((( 2- ( 4- ( 2 -hydroxyethyl)piperazin-1-yl)ethyl)amino)methylene)-1-phenylpiperyl 1 ⁇ 2- 2 , 4 - 2 Ketone synthesis
  • Example 20 Compound 4-(4-fluorophenyl)-2-(((2-(4-(2-hydroxyethyl)piperazine-1-yl)ethyl)amino)methylene)cyclohexane -1,3-
  • Step 1 Synthesis of the compound 4-(4-fluorophenyl)cyclohexanyl -1 ,3-dione
  • Step 2 Compound 4-(4-fluorophenyl)-2-(((2-(4-(2-hydroxyethyl)piperazin-1-yl)ethyl)amino)methylene)cyclohexane- Synthesis of 1, 3-dione
  • Example 21 Compound 4-benzyl-2-(((2-(4-(2-hydroxyethyl))piperazinyl)ethyl)amino)methylene)-6-phenylcyclohexane- 1,3-diketone
  • Step 1 Synthesis of the compound 5-benzyl-4-phenylcyclohexanyl-1,3-dione
  • Step 2 Compound 4-benzyl-2-((2-(4-(2-hydroxyethyl)piperazin-1 -yl)ethyl)amino)methylene)-6-phenylcyclohexane Synthesis of -1,3-dione
  • Step 1 Synthesis of the compound ethyl (4-methoxybenzyl) glycine ethyl ester
  • Step 4 Compound 1-benzoyl-4-(((2-(4-(2-hydroxyethyl)piperazin-1 -yl)ethyl)amino)methylene)piperidine-3,5- Synthesis of diketone
  • Example 26 Compound 2-(((2-(4-(2-hydroxyethyl)piperazin-1-yl)ethyl)amino)methylene)-5-(morpholin-4-carbonyl) ring Synthesis of hexane-dione (compound 106)
  • Step 1 Synthesis of the compound 3-methoxy-5-oxocyclohex-3-ene-1-carboxylic acid
  • Step 2 Synthesis of the compound 3-methoxy-5-(morpholine-4-carbonyl)cyclohexane-2-dec-1-one
  • Step 4 Compound 2-(((2-(4-(2-hydroxyethyl))piperazinyl)ethyl)amino)methylene)-5-(indol-4-carbonyl)cyclohexane- Synthesis of 1,3-diketone
  • Example 27 Compound 3-(((2-(4-(2-hydroxyethyl)piperazin-1-yl)ethyl)amino)methylene)quinoline-2,4(1H, 3H)- Synthesis of diketone (; compound 107)
  • Step 1 Synthesis of the compound 3-oxo-3-(phenylamino)propionic acid methyl ester
  • Monomethyl malonyl chloride (1.84 g, 13.5 mmol) was added dropwise to an aniline solution of aniline (1.00 g, 10.74 mmol) and TEA (1.42 g, 14 mmol) at 0 ° C. Stir at room temperature for 30 minutes. After completion of the reaction, the reaction mixture was poured into water, EtOAc was evaporated, evaporated, evaporated, evaporated, evaporated. .
  • Step 3 Synthesis of the compound quinoline-2 1H, 3H)-dione
  • Step 4 Compound 3-(((2-(4-(2-hydroxyethyl)piperazin-1-yl)ethyl)amino)methylene)quinoline-2,4(1H, 3H)- Ketone synthesis
  • Example 28 Compound 2-(l-((2-(4-(2-hydroxyethyl)piperazin-1 -yl)ethyl)amino)ethylidene)-5-phenylcyclohexan-1 , 3-diketone (Compound 1
  • Acetyl chloride (4.2 g, 53.5 mmol) was added dropwise to 5-phenyl-1,3-cyclohexanedione (10.0 g, 53.1 mmol), DMAP (2.00 g, 16.4 mmol) and DIPEA (7.75 g). , 60 mmol) of the mixture was refluxed for 2 hours. Reaction completed
  • Step 2 Compound 2-(1-((2-(4-(2-hydroxyethyl)piperazin-1-yl)ethyl)amino)ethylidene)-5-phenylcyclohexan-1, Synthesis of 3-diketone
  • Compound 109-112 was synthesized in the same manner as Compound 107, as shown in Table 6.
  • Example 30 Compound 2-(((2-(4-(2-hydroxyethyl)piperazin-1-yl)ethyl)amino)methylene)-4a,9,10,10a-tetrahydrophenanthrene Single
  • Step 1 Synthesis of the compound ethyl 3-(2-bromophenyl)acrylate
  • Step 4 Compound 2-(((2-(4-(2-hydroxyethyl)piperazin-1-yl)ethyl)amino)methylene)-4a,9,10,10a-tetrahydrophenanthroline Synthesis of porphyrin-1,3(2H, 4H)-dione
  • Example 30B Compound 5-((2R, 3S, 4R, 5R)-3,4-dihydroxy-5-(6-morpholino-9H-indol-9-yl)tetrahydrofuran-2-yl)-2 Synthesis of - «(2-p- -1-yl)ethyl)amino)methylene)cyclohexanyl-1,3-dione (Compound 1 14)
  • Example 31 Compound 4-benzyl-2-(((2-(4-(2-hydroxyethyl)piperazin-1-yl)ethyl)amino)-methylene)cyclopentan-1, Synthesis of 3-diketone (; compound 115)
  • Step 1 Synthesis of the compound 5-benzyl-3-ethoxycyclopent-2-en-1-one
  • Step 3 Compound 4-benzyl-2-(((2-(4-(2-hydroxyethyl)piperazin-1-yl)ethyl)amino)methylene)-cyclopentan-1,3 -Diketone synthesis
  • Example 32 Compound 2-(((2-(4-(2-hydroxyethyl)piperazin-1 -yl)ethyl)amino)methylene)-4-methyl-5-phenylcyclohexane Alkane-1,3-two
  • Step 2 Compound 2-(((2-(4-(2-hydroxyethyl)piperazin-1 -yl)ethyl)amino)methylene)-4-methyl-5-phenylcyclohexane -1,3-dione synthesis
  • Example 34 Compounds 119-129, 131-143, 145-150, 155-156, 158, 160-165, 169-180, 182-197, 200-233, 236-243, 245-260, 262-274 Synthesis of 276-291, 293-311, 315, 317-318, 320-347 and 349-414
  • Oxocyclohexyl)benzene 7.40 (m, 2H), 3.94 (s, 3H), 3.52 - 3.35 (m,
  • Compound 415-452 was synthesized in the same manner as in Example 4 or 8 except for the corresponding substituted 1, 3-cyclohexanedione (e.g., Compounds 3 and 8), as shown in Table 8.
  • Step 1 Synthesis of 5-(; ethoxymethylene)-2,4-thiazolidinedione
  • Step 2 The synthesis procedure of the compound 5-(3 ⁇ 42-(4-(2-hydroxyethyl)piperazin-1-yl)ethyl)amino)methylene)thiazolium-2,4-dione
  • Example 2 (Compound 1)
  • Step 4 Synthesis of the compound 4-((dimethylamino)methylene)-2-methyl-2-phenylcyclobutane-1,3-dione (Compound 201)
  • Example 38 Compound 2-(((2-(Dimethylamino)ethyl)amino)methylene)-5-phenylcyclohexanyl-1,3-dione) Nickel chloride
  • Na forms a coordinate bond with a mercaptooxy group.
  • Li, Na or K forms a coordinate bond with the carbonyl oxygen.
  • Example 41 Modulation of the autophagy-associated protein LC3B by the compounds of the present invention was tested using the fluorescence polarization (FP) method. Fluorescence polarization (FP) test
  • Histone GST-LC3B final concentration 180 nM
  • SEQ ID NO: 1 ⁇ terminal FITC-labeled peptide
  • SEQ ID NO: 2 sequence: FITC-GGDDDWTHLSSKEVD-NH 2 , final concentration 18 nM
  • FP buffer 50 mM
  • HEPES pH 7.5, O.lmg/mL BSA, 1 mM DTT HEPES pH 7.5, O.lmg/mL BSA, 1 mM DTT
  • the IC 5Q value of the compound is expressed as: ⁇ ⁇ IC 50 ⁇ ImM is considered to be less active for LC3B (; +); compound 15 ⁇ ⁇ IC 50 ⁇ ⁇ is considered to be moderately active for LC3B C++); 3 ⁇ ⁇ IC 50 ⁇ 15 ⁇ is considered to be LC3B activity is high (+++); IC 50 ⁇ 3 ⁇ is considered to be highly active against LC3B (++++;).
  • the IC values of the compounds of the present invention are shown in Table 10.
  • the compounds of the present invention exhibit activity against LC3B, and some compounds have high activity against LC3B. These compounds are also active against other mammalian homologs of ATG8. Thus, these compounds can modulate LC3B and other mammalian homologs of ATG8 for the treatment of diseases associated with autophagy.

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Abstract

涉及用作自噬调节剂的化合物及其制备方法和用途，具体而言提供了一种通式(I)所示化合物或其药学上可接受的盐，其是一类自噬调节剂，特别是哺乳动物ATG8同源物调节剂。

Description

用作自噬调节剂的化合物及其制备方法和用途 技术领域
本发明涉及生物医药领域， 具体涉及一类自噬调节剂， 特别是哺乳动物 ATG8同源物调 节剂及其用途。
背景技术
细胞自噬是一种细胞内降解的通路，是将细胞内受损或失去功能的蛋白质以及细胞器运 输至溶酶体， 并进行消化和降解的过程。 在生物进化中， 细胞自噬是一种保守的过程， 从酵 母到植物细胞再到哺乳动物细胞， 都存在这样的过程。
现有的研究表明， 细胞自噬在维持生理功能如饥饿时提供营养、清除细胞内容物、抗原 呈递等方面起着重要的作用，并在癌症、感染性疾病、神经退行性疾病等扮演着重要的角色。 细胞自噬在肿瘤的发生发展中起到双刃剑的作用： 在肿瘤发生早期， 自噬缺陷会增加基因组 的不稳定性， 促进癌变过程； 肿瘤快速生长和转移阶段， 自噬可以抵抗应激条件抑制失巢凋 亡， 维持肿瘤细胞生存。 虽然自噬与肿瘤之间的关系在肿瘤发生发展的不同阶段有所不同， 但针对进展晚期以及化疗耐药的癌症， 细胞自噬调节剂的开发将有重大的价值。
目前共有 30余项关于调节自噬的药物临床试验， 例如单独使用羟氯喹、 氯喹或与其他 抗肿瘤药物联用评价细胞自噬的抑制对难治性、复发性为主的实体瘤的治疗效果，相关结果 可在 clinicaltrial.gov官网査询。 不过， 由于缺乏明确的分子靶标， 抗溶酶体抑制剂的副作用 以及化学空间改造的方向不明会严重限制该类细胞自噬抑制剂的进一步发展。
目前靶向细胞自噬的小分子调节剂主要限于 mTOR和溶酶体调节剂， 针对细胞自噬相 关蛋白， 如 ATG4和 ULK1的小分子调控剂的研究依然处于开发的早期。而最重要的细胞自 噬相关蛋白， ATG8及其哺乳动物同源家族蛋白 LC3, GABARAP和 GATE-16子家族的调控 剂均未有任何报道。 在人体内， LC3 家族有 LC3A、 LC3B、 LC3C， GABARAP 家族有 GABARAPL和 GABARAPLl , GATE-16家族有 GABARAPL2。在 ATG8的哺乳动物同源蛋 白中， LC3B无疑是研宄得最为深入的一个， 它被认为是细胞自噬的标志物。 目前尚未有任 何针对 LC3B的调控剂的报道， 开发 LC3B的调控剂对于治疗相关疾病的来说十分迫切。
发明内容
本发明提供了一种通式①所示化合物或其药学上可接受的盐-
Figure imgf000002_0001
其中- X和 Y各自独立地选自 0， S， NRa， NOH和 CH2 ;
U和 V各自独立地选自 C， S， SO和 PORa;
W、 Z和 T各自独立地选自 0， S， SO, S02， N， NRa， CO, C， CRa， 和 CH2;
m为 0， 1， 2或 3 ; 优选为 0或 1 ;
n为 0， 1， 2或 3 ; 优选为 0或 1 ;
选自氢， 氘， C1-6浣基， C1-6羟基垸基， C1-6卤代垸基， 未取代或取代的苯基;
Figure imgf000003_0001
3-7元杂环烯基； K为共价键， NRa， CRcRe' 或 CRJ^CRcRc，；
M为共价键，
Figure imgf000003_0002
二价 3-10元杂环烷基， 二价 3-7元杂环烯基或二价 5-10元杂芳 基；
Q为氢， C1-6烷基， C1-6羟基烷基， -(CH2)p-C(0)Rb， -(CH2)p-C(0) HRb， -(CH2)p-C(S)Rb， -(CH2)p-C(S)NHRb， -(CH2)p-S02Rb， -(CH2)p-S02NHRb，
p为 0， 1， 2或 3 ; 优选为 0或 1 ;
各 Re和 Rc'独立地选自氢， 羟基， 氨基， RaRa'， 卤素， 氰基， 硝基， 羧基， 甲酰基， 酰胺基， 酯基， C1-6卤代垸基， C1-6羟基烷基， C1-6杂烷基， C1-6垸氧基， C1-6烷氧基 烷基， C2-6烯基， C2-6炔基， C6-10芳基， 5-10元杂芳基， C3-10环烷基， 3-10元杂环垸基， 3-7元杂环烯基， C1-6垸基 C6-10芳基， 5-10元杂芳基 C1-6烷基或 C1-6垸基 5-10元杂芳 基； 优选选自氢， 羟基， 氨基， NRaRa'， 卤素， 羧基， 甲酰基， 酰胺基， 酯基， C1-6 卤代 垸基， C1-6羟基垸基， C1-6杂垸基， C1-6烷氧基， C3-10环垸基， 3-10元杂环烷基， 取代 或未取代的苯基或吡啶基；
R3、 R4和 各自独立地选自氢， 羟基， 氨基， 卤素， 氰基， 硝基， 羧基， 甲酰基， 酰 胺基， -NH-CORb， 酯基， C1-6垸基， C1-6卤代烷基， C1-6羟基垸基， C1-6杂烷基， C1-6 垸氧基， C1-6烷氧基垸基， C2-6烯基， C2-6炔基， 未取代或取代的 -CONH-(C6-10芳基)， 未取代或取代的 -CH=CH-(C6-10芳基；)， 未取代或取代的 C6-10芳基， 未取代或取代的 5-10 元杂芳基， 未取代或取代的 C3-10环垸基， 未取代或取代的 3-10元杂环垸基， 未取代或取 代的 3-7元杂环烯基， 未取代或取代的 C6-10芳基 C1-6烷基， 未取代或取代的 C1-6垸基 C6-10芳基， 未取代或取代的 5-10元杂芳基 C1-6垸基， 和未取代或取代的 C1-6垸基 5-10 元杂芳基；
或者 R3、 R4和 R5中的两个相邻基团可以连接形成未取代或取代的 C6-10芳基， 未取代 或取代的 5-10元杂芳基，未取代或取代的 C3-10环垸基或未取代或取代的 3-10元杂环烷基； 其中， 各 Rb独立地为 C1-6烷基， C2-6烯基， NHRa， RaRa'， 未取代或取代的苯基或 3-7元杂环基；
各 Ra和 Ra '独立地为氢或 C1-6垸基；
未取代或取代表示该基团未被取代或者被一个或多个取代基取代，所述取代基选自羟基， 氨基， 氰基， 硝基， 羧基， 卤素， C1-6垸基， C 1-6卤代垸基或 C 1-6羟基烷基， 或者二个相 邻取代基可以连接形成 C6-10芳基， C5-10杂芳基， C3-10环烷基或 C3-10杂环烷基；
并且满足如下条件：
( 1 ) 当\¥、 Z或 T上被 R3、 R4和 R5中的一个取代时， 该\¥、 Z或 T是 N或 CH;
(2) 当 W、 Z或 T上被 R3、 R4和 R5中的一个基团取代且该基团与 、 和 R5中的 另一个相邻基团连接形成未取代或取代的 C6-10芳基或未取代或取代的 5-10元杂芳基时， 该 W、Z或 T是 C;例如，当 W被 取代且 R3与相邻的 R4连接形成未取代或取代的 C6-10 芳基或未取代或取代的 5-10元杂芳基时， W是 C;
( 3 ) 当^¥、 Z或 T上被 R3、 R4和 R5中的二个取代时， 该^¥、 Z或 1"是( 。
优选地， 通式 CI)中：
X和 Y各自独立地选自 0， S或 H;
U和 V各自独立地选自 C或 S;
W、 Z和 T各自独立地选自 0， N， Ra， CO, C， CRa， 禾 Π CH2;
m为。， 1或 2;
n为 0， 1或 2;
选自氢和氘；
Figure imgf000004_0001
3-7元杂环烯基；
K为共价键， NRa, CReRe, 或 CReRc RcRc，；
M为共价键， CH，， 二价 3-10元杂环烷基， 二价 3-7元杂环烯基或二价 5-10元杂芳 基；
Q为氢， C1-6垸基， C1-6羟基垸基， -(CH2)p-C(0)Rb， -(CH2)p-C(0) HRb , -(CH2)p-C(S)Rb， -(CH2)p-C(S)NHRb, -(CH2)p-S02Rb， -(CH2)p-S02NHRb, 其中，
p为 0， 1， 2或 3 ; 优选为 0或 1 ;
各 Re和 Rc'独立地选自氢， 羟基， 氨基， RaRa'， 卤素， 氰基， 硝基， 羧基， 甲酰基， 酰胺基， 酯基， C1-6卤代烷基， C1-6羟基烷基， C1-6杂烷基， C1-6垸氧基， C1-6烷氧基 垸基， C2-6烯基， C2-6炔基， C6-10芳基， 5-10元杂芳基， C3-10环垸基， 3-10元杂环烷基， 3-7元杂环烯基， C1-6烷基 C6-10芳基， 5-10元杂芳基 C1-6垸基或 C1-6垸基 5-10元杂芳 基； 优选选自氢， 羟基， 氨基， NRaRa'， 卤素， 羧基， 甲酰基， 酰胺基， 酯基， C1-6 卤代 垸基， Cl-6羟基烷基， C1-6杂垸基， C1-6垸氧基， C3-10环垸基， 3-10元杂环烷基， 取代 或未取代的苯基或吡啶基；
R3、 R4和 R5各自独立地选自氢， 羟基， 氨基， 卤素， 氰基， 硝基， 羧基， 甲酰基， 酰 胺基， H-CORb， 酯基， C1-6烷基， C1-6卤代烷基， C1-6羟基垸基， C1-6杂垸基， C1-6 垸氧基， C1-6烷氧基烷基， C2-6烯基， C2-6炔基， 未取代或取代的 -CO H- (； C6-10芳基)， 未取代或取代的 -CH=CH-(C6-10芳基；)， 未取代或取代的 C6-10芳基， 未取代或取代的 5-10 元杂芳基， 未取代或取代的 C3-10环垸基， 未取代或取代的 3-10元杂环垸基， 未取代或取 代的 3-7元杂环烯基， 未取代或取代的 C6-10芳基 C1-6垸基， 未取代或取代的 C1-6烷基 C6-10芳基， 未取代或取代的 5-10元杂芳基 C1-6垸基或未取代或取代的 C1-6垸基 5-10元 杂芳基；
或者 R3、 R4和 R5中的两个相邻基团可以连接形成未取代或取代的 C6-10芳基， 未取代 或取代的 5-10元杂芳基，未取代或取代的 C3-10环垸基或未取代或取代的 3-10元杂环烷基； 其中， 各 Rb独立地为 C1-6烷基， C2-6烯基， NHRa， RaRa'， 未取代或取代的苯基或 3-7元杂环基；
各 和 Ra '独立地为氢或 C1-6垸基；
未取代或取代表示该基团未被取代或者被一个或多个取代基取代，所述取代基选自羟基， 氨基， 氰基， 硝基， 羧基， 卤素， C1-6烷基， C 1-6卤代烷基和 C 1-6羟基垸基， 或者二个相 邻取代基可以连接形成 C6-10芳基， 5-10元杂芳基， C3-10环烷基或 3-10元杂环垸基； 并且满足如下条件-
( 1 ) 当^¥、 Z或 T上被 R3、 R4和 R5中的一个取代时， 该^¥、 Z或 T是 N或 CH;
(2) 当 W、 Z或 T上被 R3、 R4和 R5中的一个基团取代且该基团与 R3、 R4和 R5中的 另一个相邻基团连接形成未取代或取代的 C6-10芳基或未取代或取代的 5-10元杂芳基时， 该\¥、 Z或 T是 C;
( 3 ) 当^¥、 Z或 T上被 R3、 R4和 R5中的二个取代时， 该^¥、 Z或 1是( 。
Z儿、、 Λ、 在本发明的另一具体实施方案中， 通式 (I)中所述 R2选自如下基团： Ν ,
Figure imgf000005_0001
Figure imgf000006_0001
， 禾口 ；
其中， A为二价 3-10元含氮杂环垸基或二价 3-7元含氮杂环烯基；
Rc, Rc'和 Rc"各自独立地选自氢， 羟基， 氨基， NRaRa'， 卤素， 氰基， 硝基， 羧基， 甲 酰基， 酰胺基， 酯基， C1-6 卤代烷基， C1-6羟基烷基， C1-6杂烷基， C1-6烷氧基， C1-6 院氧基烷基， C2-6烯基， C2-6炔基， C6-10芳基， 5-10元杂芳基， C3-10环烷基， 3-10元杂 环烷基， 3-7元杂环烯基， C1-6垸基 C6-10芳基， 5-10元杂芳基 C1-6烷基或 C1-6烷基 5-10 元杂芳基； 优选选自氢， 羟基， 氨基， NRaRa'， 卤素， 羧基， 甲酰基， 酰胺基， 酯基， C1-6 卤代垸基， C1-6羟基垸基， C1-6杂垸基， C1-6烷氧基， C3-10环垸基， 3-10元杂环烷基， 取代或未取代的苯基或吡啶基；
各 和 Ra'独立地为氢或 C1-6垸基。
Figure imgf000006_0002
其中， Rc， Rcl D Rc2选自氢， 羟基， 氨基， RaRa'， 卤素， 氰基， 硝基， 羧基， 甲酰 基， 酰胺基， 酯基， C1-6 代垸基， C1-6羟基烷基， C1-6杂烷基， C1-6垸氧基， C1-6烷 氧基烷基， C2-6烯基， C2-6炔基， C6-10芳基， 5-10元杂芳基， C3-10环垸基， 3-10元杂环 烷基， 3-7元杂环烯基， C1-6烷基 C6-10芳基， 5-10元杂芳基 C1-6烷基或 C1-6垸基 5-10 元杂芳基； 优选选自氢， 羟基， 氨基， NRaRa'， 卤素， 羧基， 甲酰基， 酰胺基， 酯基， C1-6 卤代垸基， C1-6羟基烷基， C1-6杂垸基， C1-6烷氧基， C3-10环烷基， 3-10元杂环烷基， 取代或未取代的苯基或吡啶基；
或者 和 Rc2可以连接形成 C6-10芳基， 5-10元杂芳基， C3-10环垸基和 3-10元杂环 烧基；
各！^和 Ra '独立地为氢或 C1-6垸基。
一具体实施方案中，通式 (I)化合物选自如下通式（la)或（lb)所示化合物
Figure imgf000007_0001
(lb )
其中， X和 Y各自独立地选自 0， S或 NH;
W、 Z和 T各自独立地选自 0， N， NRa, CO, C， CRa, 或 CH2 ;
m为。， 1或 2;
n为 0， 1或 2;
选自氢和氘；
_N A — — N A 4—
J为 NRa， NORa, 0， S或 ， 其中 J 为含至少一个氮原子的二价 3-10 元杂环垸基或二价 3-7元杂环烯基；
'选自： 氢， C1-6烷基、 C1-6卤代烷基、 C1-6烷氧基、 C1-6烷胺基、 C6-10芳基或 5-10元杂芳基， C3-10环垸基， 3-10元杂环烷基， - (CH2) m-M-Q，
其中， M为共价键，二价 3-10元杂环烷基，二价 3-7元杂环烯基或二价 5-10元杂芳基；
Q为氢， C1-6烷基， C1-6羟基垸基， -(CH2)p-C(0)Rb， -(CH2)p-C(0)NHRb， -(CH2)p-C(S)Rb， -(CH2)p-C(S)NHRb， -(CH2)p-S02Rb， -(CH2)p-S02NHRb,
p为 0， 1， 2或 3 ; 优选为 0或 1 ;
R3、 ！^和 R5各自独立地选自氢， 羟基， 氨基， 卤素， 氰基， 硝基， 羧基， 甲酰基， 酰 胺基， H-CORb， 酯基， C1-6垸基， C1-6卤代垸基， C1-6羟基烷基， C1-6杂烷基， C1-6 烷氧基， C1-6垸氧基烷基， C2-6烯基， C2-6炔基， 未取代或取代的 -CO H-(C6-10芳基)， 未取代或取代的 -CH=CH-(C6-10芳基；)， 未取代或取代的 C6-10芳基， 未取代或取代的 5-10 元杂芳基， 未取代或取代的 C3-10环烷基， 未取代或取代的 3-10元杂环垸基， 未取代或取 代的 3-7元杂环烯基， 未取代或取代的 C6-10芳基 C1-6烷基， 未取代或取代的 C1-6烷基 C6-10芳基， 未取代或取代的 5-10元杂芳基 C1-6垸基或未取代或取代的 C1-6烷基 5-10元 杂芳基；
或者 R3、 R4和 R5中的两个相邻基团可以连接形成未取代或取代的 C6-10芳基， 未取代 或取代的 5-10元杂芳基，未取代或取代的 C3-10环垸基或未取代或取代的 3-10元杂环垸基； 其中， 各 Rb独立地为 C1-6烷基， C2-6烯基， NHRa， RaRa'， 未取代或取代的苯基或 3-7元杂环基；
各 ^和 Ra '独立地为氢或 C1-6垸基；
未取代或取代表示该基团未被取代或者被一个或多个取代基取代，所述取代基选自羟基， 氨基， 氰基， 硝基， 羧基， 卤素， C1-6院基， C 1-6卤代垸基和 C 1-6羟基垸基， 或者二个相 邻取代基可以连接形成 C6-10芳基， 5-10元杂芳基， C3-10环烷基或 3-10元杂环垸基； 并且满足如下条件：
( 1 ) 当^¥、 Z或 T上被 R3、 R4和 R5中的一个取代时， 该^¥、 Z或 T是 N或 CH;
(2) 当 W、 Z或 T上被 R3、 R4和 R5中的一个基团取代且该基团与 R3、 R4和 R5中的 另一个相邻基团连接形成未取代或取代的 C6-10芳基或未取代或取代的 5-10元杂芳基时， 该\¥、 Z或 T是 C;
( 3 ) 当\¥、 Z或 T上被 R3、 和 中的二个取代时， 该\¥、 Z或丁是（。
在本发明的另一具体实施方案中，通式 (X)化合物选自如下通式 IIa)、 (lib ), (lie)和 (lid)
Figure imgf000008_0001
其中， X和 Y独立地是 0， S， NH;
W、 Z和 T各自独立地选自 0, N, Ra， CO, C， CRa, 或 CH2
n为 0， 1， 2或 3 ;
和氘；
Figure imgf000008_0002
为二价 3-10元含氮杂环垸基或二价 3-7元含氮杂环烯基;
J选自 Ra， NORa， 0和 S;
K为共价键， NRa，CReRe， 或 CReR^CRcR^; Q为氢， Cl-6垸基， Cl-6羟基垸基， -(CH2)p-C(0)Rb， -(CH2)p-C(0) HRb , -(CH2)p-C(S)Rb， -(CH2)p-C(S)NHRb, -(CH2)p-S02Rb， -(CH2)p-S02NHRb,
p为 0， 1， 2或 3 ; 优选为 0或 1 ;
Rc， Rc'和 Re"各自独立地选自氢， 羟基， 氨基， NRaRa'， 卤素， 氰基， 硝基， 羧基， 甲 酰基， 酰胺基， 酯基， C1-6 卤代烷基， C1-6羟基烷基， C1-6杂烷基， C1-6烷氧基， C1-6 垸氧基烷基， C2-6烯基， C2-6炔基， C6-10芳基， 5-10元杂芳基， C3-10环垸基， 3-10元杂 环垸基， 3-7元杂环烯基， C1-6烷基 C6-10芳基， 5-10元杂芳基 C1-6烷基或 C1-6烷基 5-10 元杂芳基； 优选选自氢， 羟基， 氨基， NRaRa'， 卤素， 羧基， 甲酰基， 酰胺基， 酯基， C1-6 卤代烷基， C1-6羟基烷基， C1-6杂垸基， C1-6烷氧基， C3-10环垸基， 3-10元杂环垸基， 取代或未取代的苯基或吡啶基；
和 各自独立地选自氢， 羟基， 氨基， 卤素， 氰基， 硝基， 羧基， 甲酰基， 酰胺基， NH-CORb， 酯基， C1-6烷基， C1-6卤代烷基， C1-6羟基烷基， C1-6杂烷基， C1-6烷氧基， C1-6烷氧基垸基， C2-6烯基， C2-6炔基， 未取代或取代的 -CO H-(C6-10芳基)， 未取代或 取代的 -CH=CH-(C6-10芳基)，未取代或取代的 C6-10芳基，未取代或取代的 5-10元杂芳基， 未取代或取代的 C3-10环垸基，未取代或取代的 3-10元杂环垸基，未取代或取代的 3-7元杂 环烯基， 未取代或取代的 C6-10芳基 C1-6垸基， 未取代或取代的 C1-6垸基 C6-10芳基， 未 取代或取代的 5-10元杂芳基 C1-6垸基或未取代或取代的 C1-6垸基 5-10元杂芳基；
或者 R3和 R4连接形成未取代或取代的 C6-10芳基， 未取代或取代的 5-10元杂芳基， 未 取代或取代的 C3-10环垸基或未取代或取代的 3-10元杂环垸基；
其中， 各 Rb独立地为 C1-6垸基， C2-6烯基， NHRa， RaRa'， 未取代或取代的苯基或 3-7元杂环基；
各 和 Ra'独立地为氢或 C1-6垸基；
未取代或取代表示该基团未被取代或者被一个或多个取代基取代， 所述取代基选自羟基， 氨基， 氰基， 硝基， 羧基， 卤素， C1-6烷基， C 1-6卤代烷基和 C 1-6羟基垸基， 或者二个相 邻取代基可以连接形成 C6-10芳基， 5-10元杂芳基， C3-10环烷基或 3-10元杂环垸基； 并且满足如下条件-
( 1 ) W、 Z或 T上被 R3和 R4中一个取代时， 该\¥、 Z或 T是 N或 CH;
(2) W、 Z或 T上被 R3和 中一个取代且 和 连接形成 C6-10芳基或 5-10元杂 芳基时， 该\¥、 Z或 T是 C;
( 3 ) W、 Z或 T上同时被 R3和 R4取代时， 该\¥、 Z或 1"是(。
在本发明的另一具体实施方案中， 通式 (X)化合物选自如下通式IIIa)、 （IIIb )、 ( IIIc ) 和 (Hid)所:示化合物:
Figure imgf000010_0001
(Ilia), (Illb ) ,
Figure imgf000010_0002
其中， 1^选自氢， 氘， C1-6垸基， C1-6羟基垸基， C1-6卤代垸基， 未取代或取代的苯 基； 优选选自氢和氘； 优选为氢；
J选自 NRa， NORa, O或 S;
， NI^ CH, 或 CReR^CRcRc，；
Figure imgf000010_0003
为二价 3-10元含氮杂环烷基或二价 3-7元含氮杂环烯基;
Q为氢， C1-6烷基， C1-6羟基垸基， -(CH2)p-C(0)Rb， -(CH2)p-C(0) HRb， -(CH2)p-C(S)Rb， -(CH2)p-C(S)NHRb， -(CH2)p-S02Rb， 或 -(CH2)p-S02 HRb，
p为 0， 1， 2或 3 ; 优选为 0或 1 ;
各 Re， ！^和！^ "独立地选自氢， 羟基， 氨基， NRaRa'， 卤素， 氰基， 硝基， 羧基， 甲酰 基， 酰胺基， 酯基， C1-6 代烷基， C1-6羟基烷基， C1-6杂烷基， C1-6垸氧基， C1-6烷 氧基垸基， C2-6烯基， C2-6炔基， C6-10芳基， 5-10元杂芳基， C3-10环垸基， 3-10元杂环 垸基， 3-7元杂环烯基， C1-6垸基 C6-10芳基， 5-10元杂芳基 C1-6垸基或 C1-6垸基 5-10 元杂芳基； 优选选自氢， 羟基， 氨基， NRaRa'， 卤素， 羧基， 甲酰基， 酰胺基， 酯基， C1-6 卤代垸基， C1-6羟基烷基， C1-6杂垸基， C1-6烷氧基， C3-10环垸基， 3-10元杂环烷基， 取代或未取代的苯基或吡啶基；
和 R4各自独立地选自氢， 羟基， 氨基， 卤素， 氰基， 硝基， 羧基， 甲酰基， 酰胺基， NH-CORb, 酯基， C1-6烷基， C1-6卤代垸基， C1-6羟基垸基， C1-6杂烷基， C1-6烷氧基， C1-6烷氧基烷基， C2-6烯基， C2-6炔基， 未取代或取代的 -CO H-(C6-10芳基)， 未取代或 取代的 -CH=CH-(C6-10芳基；)， 未取代或未取代或取代的 C6-10芳基， 未取代或取代的 5-10 元杂芳基， 未取代或取代的 C3-10环垸基， 未取代或取代的 3-10元杂环垸基， 未取代或取 代的 3-7元杂环烯基， 未取代或取代的 C6-10芳基 C1-6烷基， 未取代或取代的 C1-6垸基 C6-10芳基， 未取代或取代的 5-10元杂芳基 C1-6烷基或未取代或取代的 C1-6垸基 5-10元 杂芳基；
或者 R3和 连接形成未取代或取代的 C6-10芳基， 未取代或取代的 5-10元杂芳基， 未 取代或取代的 C3-10环烷基或未取代或取代的 3-10元杂环垸基；
其中， 各 Rb独立地为 C1-6烷基， C2-6烯基， HRa， RaRa'， 未取代或取代的苯基或 3-7元杂环基；
各 和 Ra '独立地为氢或 C1-6垸基；
未取代或取代表示该基团未被取代或这被一个或多个取代基取代， 所述取代基选自羟基， 氨基， 氰基， 硝基， 羧基， 卤素， C1-6垸基， C 1-6卤代垸基和 C 1-6羟基烷基， 或者二个相 邻取代基可以连接形成 C6-10芳基， 5-10元杂芳基， C3-10环烷基或 3-10元杂环垸基。
在本发明的另一具体实施方案中， 通式 (I)化合物选自如下通式 (IVa)、 （IVb：)、 (IVc) 和
(IVd)所示化合物:
Figure imgf000011_0001
(IVc),
Figure imgf000011_0002
其中， 选自氢， 氘， C1-6烷基， C1-6羟基烷基， C1-6卤代烷基， 未取代或取代的苯 基； 优选选自氢和氘； 优选为氢；
J为 NRa， NORa， 0或 S;
， NRa，CReRe， 或 CReRc RcRc，；
Figure imgf000011_0003
为二价 3-10元含氮杂环烷基或二价 3-7元含氮杂环烯基;
Q为氢， C1-6垸基， C1-6羟基垸基， -(CH2)p-C(0)Rb， -(CH2)p-C(0) HRb , -(CH2)p-C(S)Rb， -(CH2)P-C(S)NHRb, -(CH2)p-S02Rb， -(CH2)P-S02NHRb,
p为 0， 1， 2或 3 ; 优选为 0或 1 ;
Rc， Rc'禾卩 Rc"各自独立地选自氢， 羟基， 氨基， RaRa'， 卤素， 氰基， 硝基， 羧基， 甲酰基， 酰胺基， 酯基， C1-6卤代垸基， C1-6羟基垸基， C1-6杂垸基， C1-6垸氧基， C1-6 垸氧基垸基， C2-6烯基， C2-6炔基， C6-10芳基， 5-10元杂芳基， C3-10环垸基， 3-10元杂 环垸基， 3-7元杂环烯基， C1-6烷基 C6-10芳基， 5-10元杂芳基 C1-6烷基或 C1-6烷基 5-10 元杂芳基； 优选选自氢， 羟基， 氨基， NRaRa'， 卤素， 羧基， 甲酰基， 酰胺基， 酯基， C1-6 卤代烷基， C1-6羟基烷基， C1-6杂垸基， C1-6烷氧基， C3-10环垸基， 3-10元杂环垸基， 取代或未取代的苯基或吡啶基；
选自氢， 羟基， 氨基， 卤素， 氰基， 硝基， 羧基， 甲酰基， 酰胺基， NH-CORb， 酯基， C1-6烷基， C1-6卤代烷基， C1-6羟基烷基， C1-6杂垸基， C1-6垸氧基， C1-6烷氧基烷基， C2-6烯基， C2-6炔基，未取代或取代的 -CO H-(C6-10芳基；)，未取代或取代的 -CH=CH-(C6-10 芳基)，未取代或取代的 C6-10芳基，未取代或取代的 5-10元杂芳基，未取代或取代的 C3-10 环垸基， 未取代或取代的 3-10元杂环垸基， 未取代或取代的 3-7元杂环烯基， 未取代或取代 的 C6-10芳基 Cl-6烷基， 未取代或取代的 C1-6垸基 C6-10芳基， 未取代或取代的 5-10元 杂芳基 C1-6垸基或未取代或取代的 C1-6烷基 5-10元杂芳基；
其中， 各 Rb独立地为 C1-6烷基， C2-6烯基， NHRa， RaRa'， 未取代或取代的苯基或 3-7元杂环基；
各 和 Ra '独立地为氢或 C 1-6烷基；
未取代或取代表示该基团未被取代或者被一个或多个取代基取代， 所述取代基选自羟基， 氨基， 氰基， 硝基， 羧基， 卤素， C1-6烷基， C 1-6卤代烷基和 C 1-6羟基垸基， 或者二个相 邻取代基可以连接形成 C6-10芳基， 5-10元杂芳基， C3-10环垸基或 3-10元杂环垸基；
R4选自氢， 羟基和 C1-6垸基。
在本发明的另一具体实施方案中， 通式 (I), (la), (lb), (Ila), (lib), (lie lid), ,
Figure imgf000012_0001
其中， 各 Rc， Rel、 Rc2、 Rc'和 Re"独立地选自氢， 羟基， 氨基， NRaRa'， 卤素， 氰基， 硝基， 羧基， 甲酰基， 酰胺基， 酯基， C1-6卤代烷基， C1-6羟基烷基， C1-6杂垸基， C1-6 垸氧基， C1-6垸氧基烷基， C2-6烯基， C2-6炔基， C6-10芳基， 5-10元杂芳基， C3-10环 烷基， 3-10元杂环垸基， 3-7元杂环烯基， C1-6垸基 C6-10芳基， 5-10元杂芳基 C1-6垸基 或 C1-6垸基 5-10元杂芳基； 优选选自氢， 羟基， 氨基， RaRa'， 卤素， 羧基， 甲酰基， 酰 胺基， 酯基， C1-6卤代烷基， C1-6羟基烷基， C1-6杂垸基， C1-6垸氧基， C3-10环垸基， 3-10元杂环烷基， 取代或未取代的苯基或吡啶基；
各 ^和 Ra'独立地为氢或 C1-6烷基。
或者 和 Rc2可以连接形成 C6-10芳基， 5-10元杂芳基， C3-10环烷基或 3-10元杂环 在本发明的另一具体实施方案中， 通式 (1)， (la), (lb), (Ila), (lib), (lie), (lid), (Ilia), (Illb),
Figure imgf000013_0001
其中， X1为F， Cl， Br, I或三氟甲基；
X2为 H， F， Cl， Br或 I;
Rci、 Rc3或 R。4各自独立地选自氢， 羟基， 氨基， NRaRa'， 卤素， 氰基， 硝基， 羧 基， 甲酰基， 酰胺基， 酯基， C1-6卤代垸基， C1-6羟基烷基， C1-6杂烷基， C1-6烷氧基， C1-6烷氧基烷基， C2-6烯基， C2-6炔基， C6-10芳基， 5-10元杂芳基， C3-10环烷基， 3-10 元杂环垸基， 3-7元杂环烯基， C1-6烷基 C6-10芳基， 5-10元杂芳基 C1-6垸基或 C1-6烷基 5-10元杂芳基； 优选选自氢， 羟基， 氨基， NRaRa'， 卤素， 羧基， 甲酰基， 酰胺基， 酯基， C1-6卤代烷基， C1-6羟基垸基， C1-6杂烷基， C1-6烷氧基， C3-10环烷基， 3-10元杂环烷 基， 取代或未取代的苯基或吡啶基；
或者 1^和1^2， 或 2和1^3， 或 Rc3和 Rc4可以连接形成 C6-10芳基， 5-10元杂芳基， C3-10环垸基和 3-10元杂环垸基；
各 ^和 Ra'独立地为氢或 C1-6烷基。
在本发明的另一具体实施方案中， 通式 (I)中所述 R4和 为氢。
在本发明的另一具体实施方案中， 通式 (I)化合物选自如下通式 (Va)，（Vb)和 （Vc)所示 化合物：
Figure imgf000013_0002
其中： W选自： 0， NRa和 CHRa;
J为 NRa， NORa, O或 S;
K为共价键， NRa, CH' 或 CReRc，CRcRc，；
选自氢， 氘， C1-6垸基， C1-6羟基垸基， C1-6卤代垸基， 未取代或取代的苯基； 优 选选自氢和氘； 优选为氢； A环为二价 3-10元含氮杂环垸基或二价 3-7元含氮杂环烯基；
B环为未取代或取代的 C6-10芳基或 5-10元杂芳基； 优选地， B环为未取代或取代的 C6-10芳基， 更优选 B环为未取代或取代的苯基；
Rc， Rc,和！^各自独立地选自氢， 羟基， 氨基， NRaRa'， 卤素， 氰基， 硝基， 羧基， 甲 酰基， 酰胺基， 酯基， C1-6 卤代烷基， C1-6羟基烷基， C1-6杂烷基， C1-6烷氧基， C1-6 垸氧基烷基， C2-6烯基， C2-6炔基， C6-10芳基， 5-10元杂芳基， C3-10环垸基， 3-10元杂 环垸基， 3-7元杂环烯基， C1-6烷基 C6-10芳基， 5-10元杂芳基 C1-6烷基或 C1-6烷基 5-10 元杂芳基； 优选选自氢， 羟基， 氨基， NRaRa'， 卤素， 羧基， 甲酰基， 酰胺基， 酯基， C1-6 卤代烷基， C1-6羟基烷基， C1-6杂垸基， C1-6烷氧基， C3-10环垸基， 3-10元杂环垸基， 取代或未取代的苯基或吡啶基；
各 Ra独立地选自氢和 C 1 -6垸基。
在本发明的另一具体实施方案中，本发明化合物或其药学上可接受的盐优选选自以下化 合物或盐：
Figure imgf000014_0001
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在本发明的另一具体实施方案中，本发明提供了一种药物组合物， 其包含根据本发明的 化合物或其药学上可接受的盐。 所述药物组合物还可以包含药学辅料。
在本发明的另一具体实施方案中，本发明提供了根据本发明的化合物或其药学上可接受 的盐在制备调节细胞自噬的药物中的用途。
在本发明的另一具体实施方案中，所述调节细胞自噬的药物是调节哺乳动物 ATG8同源 物的药物。
在本发明的另一具体实施方案中， 所述调节细胞自噬的药物是预防或治疗与细胞自噬， 尤其是与哺乳动物 ATG8同源物相关的疾病的药物。
在本发明的另一具体实施方案中，本发明提供了调节细胞自噬的方法， 其包括向有此需 要的对象施用根据本发明的化合物或其药学上可接受的盐。 在本发明的另一具体实施方案中，所述调节细胞自噬的方法是调节哺乳动物 ATG8同源 物的方法。
在本发明的另一具体实施方案中， 所述调节细胞自噬的方法是预防或治疗与细胞自噬， 尤其是与哺乳动物 ATG8同源物相关的疾病的方法。
在本发明的另一具体实施方案中， 所述哺乳动物 ATG8同源物是 LC3B。
在本发明的另一具体实施方案中，所述预防或治疗与细胞自噬，尤其是与哺乳动物 ATG8 同源物相关的疾病选自以下的疾病：肿瘤，心血管疾病，自身免疫性疾病，祌经退行性疾病， 高血压， 骨组织细胞及骨类疾病， 克罗恩氏病， 急性肾损伤， 脑缺血， 视网膜疾病， 支气管 哮喘， Vici综合征， 以及感染性疾病。
在本发明的另一具体实施方案中，所述肿瘤选自肝癌、肺癌、胰腺癌、乳腺癌、宫颈癌、 子宫内膜癌、大肠癌、 胃癌、肺癌、鼻咽癌、卵巢癌、前列腺癌、 白血病、淋巴瘤、骨髓瘤。
在根据本发明的制备调节细胞自噬的药物的用途和调节细胞自噬的方法中，一些优选的 化合物选自通式 Ob)化合物， 通式 end)化合物， 通式 and;)化合物， 通式 ClVd)化合物， 和通式
(Vc)化合物， 其中， 通式 (Ib)， 通式 (lid；)， 通式 (Hid；)， 通式 (IVd)， 和通式 (Vc)的描述同上； 或者一些优选的化合物选自化合物 2， 化合物 3， 化合物 241， 化合物 264， 化合物 449， 化 合物 462， 化合物 463， 和化合物 464。
应理解， 本发明的前述一般性描述和以下详细描述都是示例性和说明性的， 旨在提供对 所要求保护的本发明的进一步说明。
具体实施方式
以下将详细描述本发明的实施例。
本发明使用的术语具有其在本技术领域的一般含义。化学名称、通用名称和化学结构可 以互换使用以描述相同的结构。无论术语是单独使用还是与其他术语组合使用， 这些定义都 适用。因此， "C1-6烷基"的定义适用于 "C1-6垸基"以及" C1-6羟基垸基"、 "C1-6卤代垸基"、 "C6-10芳基 C1-6烷基"、 "C1-6烷基 C6-10芳基"、 "C1-6垸氧基 "等的 "C1-6垸基"部分。
"药物组合物 "是指适合于患者用药的组合物。所述组合物可以只含有本发明化合物或含 有本发明化合物的混合物， 或含有本发明化合物的盐、 溶剂合物、 前体药物、 异构体或互变 异构体， 或含有与一种或多种药学上可接受的载体或辅料合用的本发明化合物。 "患者 "包括 人类和非人类的动物。 所述药物组合物可以是多种形式， 如片剂、 胶囊、 粉剂、 糖浆、 溶液 状、悬浮液和气雾剂等， 并可以存在于适宜的固体或液体的载体或稀释液中以及适宜的用于 注射或滴注的消毒器具中。
本发明的药物组合物的各种剂型可按照药学领域的常规制备方法制备。其制剂配方的单 位剂量中包含 0.05-200mg通式（I)化合物，优选地，制剂配方的单位剂量中包含 O.lmg-lOOmg 通式 （I) 化合物。
本发明的化合物和药物组合物可对哺乳动物临床使用，包括人和动物，可以通过口、鼻、 皮肤、 肺、 或者胃肠道等的给药途径。 最优选为口服。 最佳优选日剂量为 0.01 -200 mg/kg体 重， 一次性服用， 或 0.01-100 mg/kg体重分次服用。 不管用何种服用方法， 个人的最佳剂量 应依据具体的治疗而定。通常情况下是从小剂量开始，逐渐增加剂量一直到找到最适合的剂
"卤素" (或卤代基)是指氟、 氯、 溴或碘。
"C1-6垸基"是指含有 1至 6个碳原子的直链或支链烷基，优选为 1至 4个碳原子的直链 或支链垸基。支链是指一个或多个 1至 4个碳原子的垸基如甲基、 乙基或丙基等与直链烷基 连接。 优选的 C1-6垸基包括但不限于甲基、 乙基、 正丙基、 异丙基、 正丁基、 异丁基和叔 丁基等。
"C1-6卤代烷基"是指如上定义的 C1-6垸基中含有一个或多个卤素原子取代基。
"C1-6杂烷基 "是指如上定义的 C1-6烷基中含有一个或多个选自以下基团中的取代基： 0、 S、 N、 -(S=0)-、 -(0=S=0)-等。
"C2-6烯基"是指含有 2至 6个碳原子的直链或支链的烯基， 优选含有 2至 4个碳原子。 支链是指一个或多个低级 C1-6垸基连接到直链 C2-6烯基链上。 优选的 C2-6烯基包括但不 限于乙烯基、 丙烯基、 正丁烯基、 3-甲基丁烯基、 正戊烯基等。
"C1-6亚垸基 "是指通过从上述定义的 C1-6烷基除去一个氢原子得到的二价基团。 优选 的 C1-6亚烷基包括但不限于亚甲基、 亚乙基和亚丙基等。 一般地， 其可以任选且等同地在 此表示为 -(C1-6垸基) -， 例如 -CH2CH2-是亚乙基。
"C2-6炔基"是指含有 2至 6个碳原子的直链或支链炔基，优选含有 2至 6个碳原子，更 优选含有 2至 4个碳原子。支链表示一个或多个含有 2至 4个碳原子的垸基连接到直链炔基 链上。 优选的 C2-6炔基包括但不限于乙炔基、 丙炔基、 2-丁炔基和 3-甲基丁炔基等。
"亚 C2-6烯基"是指通过从上述定义的 C2-6烯基中除去一个氢原子而获得的双官能团。 优选的亚 C2-6烯基包括但不限于 -CH=CH-， -C(CH3)=CH -， -CH=CHCH2-等。
"C6-10芳基"是指含有 6至 10个碳原子的芳族单环或多环系统。优选的 C6-10芳基包括 但不限于苯基和萘基。
"C6-10亚芳基 "是指通过从上述定义的 C6-10芳基除去一个氢原子得到的二价基团， 例
Figure imgf000035_0001
"5-10元杂芳基"是指含有 5至 10个环原子的芳族单环或多环基团， 所述 5-10元杂芳基 包含选 N、 0和 S中的 1至 4个杂原子。优选的 5-10元杂芳基含有 5至 6个环原子。 5-10 元杂芳基的氮原子可以任选地被氧化成相应的 N-氧化物。 术语" 5-10元杂芳基"还包括与上 述定义的 C6-10芳基稠环。 优选的 5-10元杂芳基包括但不限于吡啶基、 吡嗪基、 呋喃基、 噻吩基、 嘧啶基、 吡啶酮、 噁唑基、 异噻唑基、 噁唑基、 噁二唑基、 噻唑基、 噻二唑基、 吡 唑基、 呋咕基 (furazanyl)、 吡咯基、 三唑基、 1,2,4-噻二唑基、 哒嗪基、 喹喔啉基、 酞嗪基、 羟吲哚基、 咪唑并 [l，2-a]吡啶基、 咪唑并 [2,1-b]噻唑基、 苯并呋咕基 (benzofurazanyl)、 吲哚 基、 氮杂吲哚基、 苯并咪唑基、 苯并噻吩基、 喹啉基、 咪唑基、 噻吩并吡啶基、 喹唑啉基、 噻吩并嘧啶基、 吡咯并吡啶基、 咪唑并吡啶、 异喹啉基、 苯并吖嗪基、 1,2,4-三嗪基、 苯并 噻唑基其氧化物等。 术语" 5-10元杂芳基"也指部分饱和的 5-10元杂芳基， 例如四氢异喹啉 基， 四氢喹啉基等。
"C3-10环烷基 "是指含有 3至 10个碳原子，优选 3至 6个碳原子的非芳族单环或多环基 团。 优选的单环 C3-10环垸基包括但不限于环丙基、 环戊基、 环己基、 环庚基等。 优选的多 环环垸基包括但不限于 [1丄 1]-双环戊垸基、 1-癸酰基、 降冰片基、 金刚垸基等。
"C3-10环烯基 "是指含有 3至 10个碳原子的非芳族单环或多环基团，其含有至少一个环 内碳-碳双键， 优选含有 3至 7个环原子， 更优选含有 5至 7个环原子。 优选地所述 C3-10 环烯基包括但不限于环丙烯基、 环丁烯基、 环戊烯基、 环己烯基、 环戊烯基、 环庚垸 -1,3- 二烯基、 降冰片烯基等。
"3-10元杂环垸基" (或" 3-10元杂环基")是指含有 3至 10个环原子， 优选 5至 10个环原 子， 优选 5至 6个环原子的非芳族饱和单环或多环基团， 其中， 所述 3-10元杂环基包含选 自 N、 0和 S中的 1至 4个杂原子， 且环体系中两个的杂原子不会相邻。 所述 3-10元杂环 基的氮或硫原子可以任选地氧化成相应的 N-氧化物、 S-氧化物或 S， S-二氧化物。 因此本发 明中术语"氧化物 "是指相应的 N-氧化物、 S-氧化物或 S， S-二氧化物。 "3-10元杂环基"还包 括环体系的相同碳原子上的两个可用氢原子同时被单一的基团 =0 取代 (例如羰基；)， 这样的 =0基团在本发明中可以称为"氧代"。 优选的单环 3-10元杂环垸基包括但不限于哌啶基、 氧 杂环丁垸基、 吡咯基、 哌嗪基、 吗啉基、 硫代吗啉基、 噻唑烷基、 1,4-二噁 C1-6垸基、 四氢 呋喃基、 四氢噻吩基、 内酰胺基 (如吡咯垸酮基；)、 3至 10个环原子的内酯基及其氧化物。
"3-7元杂环烯基"是指含有 3至 7个环原子， 优选 5至 6个环原子的非芳族单环或多环 基团， 其中， 所述 3-7元杂环烯基包含选自 N、 0和 S中的 1至 4个杂原子， 并且其含有至 少一个碳-碳双键或碳-氮双键。 环体系中不存在相邻的氧和 /或硫原子。 在 3-7元杂环烯基根 名之前的前缀氮杂、 氧杂或硫杂是指至少一个氮、 氧或硫原子分别地作为环原子。 3-7元杂 环烯基的氮或硫原子可以任选被氧化成相应的 N-氧化物、 S-氧化物或8， S-二氧化物。优选 的 3-7元杂环烯基包含但不限于 1,2,3,4-四氢吡啶基、 1,2-二氢吡啶基、 1,4-二氢吡啶基、 1,2,3,6- 四氢吡啶基、 1,4,5,6-四氢嘧啶基、 2-吡咯啉基、 3-吡咯啉基、 2-咪唑啉基、 2-吡唑啉基、 二 氢咪唑基、 二氢噁唑基、 二氢恶二唑基、 二氢噻唑基、 3，4-二氢 -2H-吡喃基、 二氢呋喃基、 氟代二氢呋喃基基及其氧化物等。 "3-7元杂环烯基"还可是环体系中相同碳原子上的两个可 用氢原子同时被单一的基团 =0取代 (即形成羰基)。
"C6-10芳基 C1-6垸基" (或" C6-10芳基 C1-6烷基")是指由上述定义的 C6-10芳基和 C1-6 垸基连接形成的基团。优选的 C6-10芳基 C1-6烷基包括但不限于苄基、 2-苯乙基和萘甲基。 所述 C6-10芳基 C1-6垸基通过 C1-6烷基与母体部分键接。类似地， "5-10元杂芳基 C1-6垸 基"， "C3-10环垸基 C1-6烷基"， "C2-6环烯基 C1-6垸基"， "3-10元杂环垸基 C1-6垸基"， "3-7元杂环烯基 C1-6垸基"等是指如本发明所述的 5-10元杂芳基， C2-6环烯基， 3-10元杂 环烷基， 3-7元杂环烯基等通过 C1-6烷基与母体部分键接。
"C1-6垸基 C6-10芳基"是指由上述定义的 C1-6烷基和 C6-10芳基连接形成的基团。 优 选 C1-6烷基 C6-10芳基包括但不限于甲苯基。所述 C1-6烷基 C6-10芳基通过 C6-10芳基与 母体部分键接。
"5-10元杂芳基 C1-6垸基"是指由上述定义的 5-10元杂芳基和 C1-6垸基连接形成的基 团。 优选的 C6-10芳基 C1-6烷基基团包括但不限于吡啶基甲基和喹啉 -3-基甲基。 所述 5-10 元杂芳基 C1-6垸基通过 C1-6垸基与母体部分键接。
"C1-6羟基垸基"是指被羟基取代的 C1-6垸基基团， 其中 C1-6垸基如上所述。 优选的 C1-6羟基垸基包括但不限于羟甲基和 2-羟乙基。
"C1-6垸氧基 "是指 C1-6垸基 -0-基团， 通过氧与母体部分键接， 其中 C1-6烷基如上所 述。 优选的 C1-6烷氧基包括但不限于甲氧基、 乙氧基、 正丙氧基、 异丙氧基和正丁氧基。
"C1-6烷氧基烷基"是指衍生自本发明所定义的 C1-6垸氧基和 C1-6垸基的基团， 通过 C1-6烷基与母体部分键接。
"酯基 "是指 -C(0)ORx，其中 是 C1-6垸基、 C6-10芳基、 C6-10芳基 C1-6烷基和 C3-10 环烷基。 优选的酯基包括但不限于甲酯基， 乙酯基， 异丙酯基， 叔丁酯基， 苯酯基。
"酰胺基"是指 -C(0) RyRy，， 其中 Ry和 Ry，是氢， C 1 -6垸基、 C6-10芳基、 C6-10芳基 C1-6烷基或 C3-10环烷基。
本发明任何前述官能团可以是未经取代或被本发明所述取代基取代。 术语"取代的" (或 取代)是指将指定原子上的一个或多个氢原子替换为从指定基团中选择的基团， 条件是不超 出指定原子的正常价态， 并且取代产生稳定的化合物。 只有当所述组合形成稳定化合物时， 所述取代基和 /或变量的组合才是允许的； "稳定化合物 "或"稳定结构"是指具有能够从反应混 合物中分离至有用纯度和配置成有效治疔剂的具有充分稳定性的化合物。
术语"未取代或取代 "表示特定基团未被取代或被一个或多个取代基取代。 取代基包括， 不局限于， 氢， 羟基， 氨基， 氰基， 硝基， 羧基， 卤素， C1-6烷基， C1-6卤代烷基或 C1-6 羟基垸基。 二个相邻取代基可以连接形成 C6-10芳基， 5-10元杂芳基， C3-10环垸基或 3-10 元杂环垸基。 C6-10芳基， 5-10元杂芳基， C3-10环垸基， 3-10元杂环烷基， 3-7元杂环烯 基等基团上的取代包括在基团的任何环部分的取代。
在本申请中， 如果一个基团是"共价键"， 那表明这个基团"不存在"， 二个相连的基团通 过一个共价键相连。 比如说， 在 " -J-K-M-Q"取代基中， 如果 K是共价键， 那这个取代基就 成为 "-J_M-Q"。
互变异构体是指由于分子中一个原子的质子转移到另一个原子上的现象产生的化合物。 互变异构体还指容易从一种异构体形式转化为另一种异构体形式的两种或更多种处于平衡 状态的异构体形式。本领域普通技术人员应认识到所有互变异构环原子排列的可能性。这些 化合物的所有这些异构形式明确地包括在本发明公开内容中。
具体而言， 本发明的化合物包括其所有互变异构体， 例如酮 -烯醇互变异构体。 为方便 起见，在本发明的详细叙述和权利要求中，这些互变异构体和其混合物部分结构 (实施例 11，
112, 禾 B 415)如下所示。
Figure imgf000038_0001
415
为方便起见， 在本发明中仅示例出了每种化合物的一种互变异构体。 应当注意， 本发明 的化合物包括所有互变异构体。
立体异构体是指化合物具有相同分子式，分子中原子连接次序相同但空间排列不同而引 起的同分异构。 立体异构包括顺反异构、 构象异构、对映异构和非对映异构等， 其中顺反异 构是指由于双键相连的两个碳原子不能绕 σ键作相对的自由旋转引起的，一般指烯烃的双键， 也有 C=N双键， N=N双键及环状等化合物的顺反异构。 对映异构体是指互为镜像关系的立 体异构体； 非对映异构体是指分子具有两个或多个手性中心， 并且分子间为非镜像的关系的 立体异构体。 除非另有说明， 本说明书旨在包括单独的立体异构体及其混合物。
具体而言，本发明的化合物包括其所有异构体，例如非对映异构体和顺 /反 (Z/E)异构体 本发明公开的化合物 101的顺反异构体的实例如下所示。
Figure imgf000039_0001
为方便起见， 在本发明中仅示例了每种化合物的一种异构体。应当注意， 本发明的化合 物包括所有的立体异构体。
本发明的化合物可以与一种或多种金属离子形成金属螯合物。金属离子包括但不限于铜， 铁， 镁， 钙， 锌， 镍和铂等。 如本发明所述， 金属螯合物的实例在实施例 38中给出。 应当 注意， 本发明的化合物包括所有的金属螯合物。
术语"药学上可接受的盐"是指适用于人和 /或动物而无过度不良副反应 (如毒性、剌激和变 态反应)， 即有合理的效益 /风险比的物质。药学上可接受的盐包括无机盐和有机盐， 它们可以 在本发明化合物的最终分离和纯化期间获得， 或者通过游离酸或碱官能团与合适的碱或酸反 应成盐。 适合形成盐的酸包括但不限于： 无机酸如盐酸、 磷酸或硫酸， 或有机酸如枸橼酸、 抗坏血酸、 柠檬酸、 酒石酸、 乳酸、 马来酸、 丙二酸、 富马酸、 乙醇酸、 琥珀酸、 丙酸、 乙 酸或甲磺酸等。 适合形成盐的碱包括但不限于： 无机碱如碳酸钠、 氢氧化钠、 碳酸钾、 氢氧 化钾、 氢氧化锂、 醋酸钙、 氯化钙或氯化镁等， 有机碱如氨基乙醇等。
术语"有效量"是指施用的组合物中所含的本发明化合物的量足以调节 (例如抑制或激动 等;)哺乳动物 ATG8同源物。
本发明化合物可以通过本领域中类似己知的各种方法制备，下述反应流程为制备本发明 化合物的可选方案。
一般反应流程
Figure imgf000040_0001
Figure imgf000040_0002
上述方案中的基团或取代基定义与通式①定义相同。化合物可以通过本领域普通技术人 员已知的一些参考文献中描述的方法来制备。 这些参考文献包括例如： Bioorganic & Medicinal Chemistry Letters, 24(16), 3764-3771, 2014; Chemistry-A European Journal, 20(9), 2445-2448, 2014; Bioorganic & Medicinal Chemistry, 20(2), 1029-1045, 2012; Journal of Organic Chemistry, 82(5), 2630-2640, 2017; Tetrahedron Letters, 49 (2008), 4725-4727; Journal of Organic Chemistry, 78(9), 4563-4567, 2013; Heterocycles, 28(2), 1015-35, 1989; Journal of Medicinal Chemistry, 57(10), 3924-3938, 2014; Journal of Organic Chemistry, 66(24), 8000-8009, 2001; and Tetrahedron Letters, 56(45), 6287-6289, 2015.
实施例
下面结合具体实施例， 进一步阐述本发明。 应理解， 这些实施例仅用于说明本发明而不 用于限制本发明的范围， 且本发明不限于这些实施例。 本领域的技术人员将容易理解的是， 可使用以下制备方法的条件和过程的己知变型来制备这些化合物。本发明中用到的起始反应 物未经特别说明， 均为商业购买。
缩写： 乙腈 (MeCN， ACN); 水溶液 (aq.); 溴化苄 (BnBr); 二碳酸二叔丁酯 (Boc^O); 甲 基叔丁基醚 (t-BuOMe); 叔丁醇钾 (t-BuOK); 叔丁醇钠 (t-BuONa); 硝酸铈铵 (CAN); 浓缩的 / 高浓度的 (con.); 二氯甲垸 (DCM); 二异丁基氢化铝 (DIBAL-H;); 二异丙基乙胺 (DI(P)EA); 4-二甲基氨基吡啶 (DMAP) ; Ν,Ν-二甲基甲酰胺二甲基缩醛 (DMF-DMA) ; 二甲基甲酰胺 (DMF);二甲基亚砜 (DMSO);乙酸乙酯 (ΕΑ或 EtOAc);当量 (eq.);乙醇 (EtOH);乙醇钠 (EtONa); 克 /毫克 (g/mg); 2-(7-偶氮苯并三氮唑) -Ν,Ν,Ν',Ν'-四甲基脲六氟磷酸酯 (HATU);小时 (h, hr, hrs); 醋酸 CHOAc); 升 /毫升 (L/mL); 液相色谱 -质谱联用仪 (LCMS); 二异丙基氨基锂 (LDA); 甲醇 (MeOH);摩尔 /毫摩尔 (mol/mmol);质谱 (MS);甲磺酰氯 (MsCl);分钟 (min(s));醋酸钠 (NaOAc); 氮气 (N2 氮溴代丁二酰亚胺 ( BS N-甲基吗啉氧化物 ( MO 核磁共振 (NMR);钯碳 (Pd/C); 石油醚 (PE); 苯甲酰氯 (PhCOCl); 甲苯 (PhMe); 三苯基膦 (PPh3 吡啶 (Py); 1H-苯并三唑 -1- 氧三吡咯啉嗡六氟磷酸 (PyBOP); 制备型薄层色谱 (Pre-TLC); 室温 (RT， rt); 三乙胺 (TEA); 四氢呋喃THF); 薄层色谱 CTLC); 三甲基氯硅烷TMSC1) ； 1，Γ-双二苯基膦二茂铁二氯化钯 21. 6
(Pd(dppf)2Cl2)。 月 2018 (21. 06. 2018) 一般合成方法：
除非另有说明， 否则所有反应均在惰性气体 (如氩气或氮气)环境下进行， 使用的市售试 剂和无水溶剂无需进行进一步处理。
质谱用液相色谱 -质谱联用仪 (LC-MS)记录 (安捷伦 6120B型单四级杆液相色谱-质谱联用 仪)。 核磁共振谱 (如氢谱 ( 、 碳谱 (13C)、 磷谱 (31P)和氟谱 (19F)等)用 BrukerAMX-400 型、 Gemini-300型或 A X-600型核磁共振仪记录， 在氘代氯仿、氘代甲醇、氘代水或氘代二甲 亚砜等氘代溶剂中记录并以氘代溶剂峰为参考标准。 化学位移 δ的单位为 ppm， 耦合常数 (J 或 J)的单位为赫兹Hz, Hertz), 核磁谱中耦合裂分峰表示为： 宽单峰 (brs)、 单峰 ；)、 二重峰 (d)、 双二重峰 (dd)、 三重峰 (t)、 四重峰 (q)和多重峰 (m)。
实施例 1 : 化合物 2-(4-(2-氨基乙基)哌嗪 -1-基；)乙 -1-醇的合成
Figure imgf000041_0001
步骤 1 : 化合物 2-(2-(4-(2-羟乙基)哌嗪 -1 -基)乙基)异吲哚啉 -1 ,3-二酮的合成
将化合物 2-(2-溴乙基)异二氢吲哚 -1 ,3-二酮 (20.0g， 78mmol),化合物 2- (；哌嗪- 基)乙 -1 - 醇 (10.2g， 78mmol)和碳酸钾 (22.0 g， 156mmol)溶解于 l OOmL乙腈中， 上述混合物回流反应 3小时。 反应完毕， 冷却至室温， 过滤， 滤渣用乙腈 pOmL)洗涤， 收集滤液， 浓缩， 经柱层 析分离纯化得目标化合物 13.45g， 产率 57 %。
步骤 2: 化合物 2-(4-(2-氨基乙基;)哌嗪 -】-基)乙 -1-醇的合成
将化合物 2- ί2-[4-(2-羟基 - 乙基） - 哌嗪 -1 -基] - 乙基 } - 异吲哚 -I,3-二酮 (13.4 ， 43.67mmol)和水合肼 (80 %， 6mL)溶解于乙醇 (130mL)中回流反应 4小时。反应完毕， 冷却至 室温， 过滤， 滤渣用冷乙醇 p0mLx2)洗涤。收集滤液， 浓縮得粗品 6.5g， 不经进一步纯化直 接用于下一步反应。
实施例 2:化合物 5-(((2-(4-(2-羟乙基；)哌嗪 -1-基)乙基)氨基)亚甲基 )-2，2-二甲基 -1,3-二噁 垸 -4,6-二酮 (化合物
Figure imgf000041_0002
将化合物 5- (甲氧基亚甲基) -2,2-二甲基 -1 ,3-二噁烷 -4,6-二酮 (186 mg， 1 mmol)溶于 5mL 乙醇， 加入 2-(4-(2-氨基乙基)哌嗪 -1-基)乙 -1-醇 (259.5 mg,， 1.5mmol) , 室温反应 15分钟， 浓缩得粗品， 经柱层析分离纯化得目标化合物 220mg， 产率 67.2°/。。 ' H NMR (400 MHz, CD3OD) δ 8.22 (s, 1H), 3.67 (t, J = 6.0 Hz, 1H), 3.58 (t, J = 5.9 Hz, 1H), 2.57 (dt, J = 24.7, 6.0 Hz 1 H)， 1.66 (s, 1 H); LCMS: 328.4 (M+l)。
实施例 3: 化合物 2- (氨基亚甲基 )-5-苯基环己烷 -1，3-二酮 (化合物 2)的合成 更正页 （细则第 91条） ISA/CN
Figure imgf000042_0001
将化合物 2-二甲氨基亚甲基 -5-苯基环己烷 -1,3-二酮 (1.1 g, 4.52 mmol)溶于氨的甲醇溶 液 (7 N， 50mL)， 室温搅拌 1小时， 浓縮得粗品， 经柱层析分离得目标化合物 900mg， 产率 93%。 化合物 2: ]H NMR (400 MHz, CD3OD) δ 10.12 (br, IH), 8.24 (br, IH), 8.02 (q, J =8.8 Hz, IH), 7.32-7.29 (m, 4H), 7.23-7.17 (m, IH), 3.31-3.25 (m, IH), 2.77-2.63 (m, 2H), 2.51-2.45 (m, 2H); MS: 216.1 [M+l]。
实施例 4: 化合 2- (羟基亚甲基 )-5-苯基环己垸 -1,3-二酮 (化合物 3)的合成
Figure imgf000042_0002
将化合物 2- 二甲基氨基)亚甲基 )-5-苯基环己烷 -1,3-二酮 (244 mg， lmmol)溶于 5mL甲 醇，滴加浓盐酸 (lmL)，室温反应 30分钟。浓缩得粗品，经柱层析分离得目标化合物 162mg， 产率 75%。化合物 3 : !H MR (400 MHz, DMSO-d6) δ 9.58 (s， I H), 7.27-7.30 (m, 4H)， 7.16-7.19 (m, IH), 3.14-3.20 (m, IH), 2.51 (d, J = 16.8Hz, IH), 2.47 (d, J = 9.2Hz, IH), 2.31(dd, J = 16.0, 4.0Hz, 2H); LCMS: 217.1 [M+l ]。
化合物 5-(2-溴苯基 )-2- (羟基亚甲 -1，3-二酮 (化合物 4)的合成
Figure imgf000042_0003
化合物 4的合成方法同化合物 3。 化合物 4: !H NMR (400 MHz, DMSO-d6) δ 9.34 (dd, J = 9.1, 1.9 Hz, IH), 7.60 (d, J= 7.6 Hz, IH), 7.49 - 7.29 (m, 2H), 7.16 (d, J= 7.0 Hz, IH), 3.57 (m, 2H), 2.82 - 2.56 (m, 2H), 2.41 (d, J= 1.8 Hz, I H); MS: 297.0 [M+l]。
实施例 5： 化合物 - ((甲硫基)亚甲基 )-5-苯基环己烷 -1,3-二酮 (化合物 4A)的合成
Figure imgf000042_0004
将化合物 2- ((二甲基氨基)亚甲基 )-5-苯基环己烷 -1，3-二酮 (200 mg, 0.823 mmol)溶于 5mL 无水乙醇和 5mL DCM中， 室温加入 ImL醋酸和甲硫醇钠 (115mg， 1.64mmol), 混合物在封 管中室温搅拌 16小时。 补加 ImL醋酸和甲硫醇钠 (115mg， 1.64mmol), 继续搅拌 16小时。 反应完毕将反应液倒入水中， 二氯甲垸 （DCM) 萃取。 合并有机相依次用水和饱和食盐水 洗涤， 无水硫酸钠干燥， 浓缩得粗品， 经柱层析分离得目标化合物 15mg， 产率 7%。 化合物 4A: 1H NMR (400 MHz, DMSO-d6) δ 8.75 (s, IH), 7.33-7.19 (m, 5H), 3.46-3.37 (m， IH), 更正页 （细则第 91条） ISA/CN 2.95-2.86 (m, 2H), 2.72-2.64 (m, 2H), 2.60(s, 3H); MS: 247.1 [M+l]
实施例 6: 化合物 5- -2- ((苯基 -1,3-二酮 (化合物 5)的合成
Figure imgf000043_0001
将化合物 2 - ((二甲基氨基)亚甲基 )-5-苯基环己垸 -1,3-二酮 (200 mg 0.82mmol), 苯胺 (60mg 0.65mmol)和醋酸 (0.5mL)溶解于 lOmL乙醇中， 回流反应 1小时。 冷却至室温， 浓 缩得粗品， 经柱层析分离得到目标化合物 150mg， 产率 79%。化合物 5 : ¾ NMR (400 MHz, DMSO-d6) δ 8.72 (s, IH), 7.49-7.41 (m, 4H), 7.35-7.28 (m, 5H), 7.25-7.22 (m, IH), 3.46-3.40 (m, IH), 2.95-2.70 (m, 4H); MS: 292.1 [M+l ]
实施例 7: 化合物 6和 7的合成
化合物 6和 7的合成方法同化合物 5， 如表 1所示.
表 1 : 化合物 6和 7
Figure imgf000043_0003
实施例 8: 化合物 2-(((2-(4-(2-羟乙基)哌嗪 -1-基)乙基)氨基)亚甲基 )-5-苯基环己烷 -1 3-二 酮 (化合物 8)的合成
Figure imgf000043_0002
步骤 1 : 化合物 2- ((二甲基氨基)亚甲基 )-5-苯基环己烷 -1 3-二酮的合成
将化合物 5-苯基环己烷 -1 ,3-二酮 (5.0 g 26.6 mmol)溶于氯仿 (25mL)中， 加入 Ν,Ν-二甲基 甲酰胺二甲基缩醛 （DMF-DMA) (5mL), 上述混合物于室温下反应 1 小时。 反应完毕， 反 应液浓缩， 浓缩物用 10 %乙酸乙酯 （EA) /石油醚（PE)匀浆析出沉淀， 过滤， 将滤渣干燥 即得目标化合物 4.81g， 产率 74 %
步骤 2: 化合物 2-(((2-(4-(2-羟乙基)哌嗪 -1-基)乙基)氨基)亚甲基 )-5-苯基环己垸 -1,3-二酮
(化合物 8)的合成
将化合物 2-(4-(2-氨基乙基)哌嗪 -1-基)乙 - 醇 (200 mg 1.15mmol)溶于 5mL乙醇， 加入 化合物 2 - ((二甲基氨基)亚甲基 )-5-苯基环己院 -1 ,3-二酮 (365mg, 1.5mmol),室温反应 30分钟，
42
更正页 （细则第 91条） ISA/CN 产生固体， 过滤， 滤渣用乙醇洗涤， 收集滤渣， 干燥得目标化合物 312mg， 产率 73%。 化合 物 8: 'HNMR (400 MHz, CD3OD) δ 8.25 (s, 1H), 7.34-7.20 (m， 5H), 3.80 (t, J= 5.6 Hz, 2H), 3.61 (t， J= 5.6 Hz, 2H), 3.40-3.30 (m, 1H), 3.06 (br, 4H), 2.98 (t, J = 4.4 Hz, 2H), 2.85-2.64 (m, 10H), MS: 372.3 [M+l]。
实施例 9: 化合物 9-12， 14-15
除了使用相应的取代 1,3-环己二酮或其他具有活泼亚甲基的酮外 (例如实施例 9-1)，化合 物 9-12和 14-15的合成方法同化合物 8， 如表 2所示。
表 2: 化合物 9-12和 14-15
Figure imgf000044_0002
实施例 9-1: 中间体 3-1: (2S, 2'R)-7-氯 -4,6-二甲氧基 -2'-甲基 -3H-螺 [苯并呋喃 -2,1'-环 己烷] 3,4-',6'-三酮的
Figure imgf000044_0001
43
更正页 （细则第 91条） ISA/CN 化合物 (2S， 6'R)-7-氯 -2',4，6-三甲氧基 -6'-甲基 -3H-螺 [苯并呋喃 -2,1'-环己烷 ]-2'-烯 -3,4'- 二酮 (1.0 g , 2.84 mmol)和硝酸铈铰 (1.55g， 2.84mmol)溶解于乙腈 (40mL)和水 (40mL)混合溶剂 中加热回流 6小时。 反应完毕， 降至室温， 倒入水中， EA萃取， 有机相并依次用水和饱和 食盐水洗涤， 无水硫酸钠千燥， 浓缩得粗品， 经柱层析分离得到目标化合物 880mg， 产率 91 %。
实施例 10: 化合物 2-(((2-(4-(2-羟乙基)哌嗪 -1-基)乙基)氨基)亚甲基 )-5-(1Η- 吡咯并 [2, -b]吡啶 -4-基)环己垸 -1,3-二酮 (化合物 17)的合成
Figure imgf000045_0001
步骤 1： 化合物 4-溴 -1-(苯基磺酰基 >1H-吡咯并 [2,3-b]吡啶的合成
氮气保护下，将化合物 4-溴 -1H-吡咯并 [2，3-b]吡啶 (3.0g， 15.23mmol)溶于无水四氢呋喃 ( THF ) (50mL)中， 在 0°C下， 向上述混合液分批加入 60 %氢化钠 (800mg， 20mmol)并在该 温度下搅拌 30分钟后，加入苯磺酰氯 (3.53g， 20mmol),将所得混合物在室温下反应 1小时。 反应完毕， 将反应混合物用冰水在 0°C缓慢淬灭， EA萃取， 有机相用水洗涤， 无水硫酸钠 干燥， 浓缩， 粗品经柱层析分离纯化得目标化合物 4.3g， 产率 84 %。
步骤 2: 化合物 1 - (苯基磺酰基 )-4-乙 C2-6烯基 -1 H-吡咯并 [2,3-b]吡啶的合成
氮气保护下，将化合物 4-溴 -1 -(苯基磺酰基) -1H-吡咯并 [2,3-b]吡啶 (4.3g, 12.8 mmol)溶于 50mL二氧六环和 l OmL水中， 依次加入 Pd(dppf)2Cl2 (470 mg, 0.64 mmol)、 乙烯三氟硼酸钾 (2.57g, 19.2mmol)和 Ν,Ν-二异丙基乙胺 （DIPEA) (3.23 g, 25 mmol)。 上述混合物加热回流 2 小时， 反应完毕降至室温， 倒入冰水中， EA萃取， 有机相分别用水和饱和食盐水洗涤， 干 燥， 浓缩得粗品， 经柱层析分离得目标化合物 2.52g， 产率 70%。
步骤 3 : 化合物 1 - (苯基磺酰基) -1H-吡咯并 [2,3-b]吡啶 -4-甲醛的合成
将化合物 1 - (苯基磺酰基 )-4-乙 C2-6烯基 -1H-吡咯并 [2,3-b]吡啶 (2.52g， 8.86 mmol)溶于 50mL丙酮和 10mL水，加入 N-甲基 -N-氧化吗啉 (1.56g， 13.3mmol)和二水合锇酸钾 (100mg)， 室温反应 2小时后， 向上述反应液分批加入高碘酸钠 7.56g， 35.44mmol), 然后继续室温反 应 1小时。 反应完毕倒入水中， EA萃取， 有机相分别用水和饱和食盐水洗绦， 千燥， 浓缩 得粗品， 经柱层析分离得到目标化合物 1.52g， 产率 60%。
步骤 4: 化合物 4-(1- (苯基磺酰基) -1 H-吡咯并 [2，3-b]吡啶 -4-基)丁 -3-烯 -2-酮的合成 更正页 （细则第 91条） ISA/CN 将化合物 1- (；苯基磺酰基；) -1H-吡咯并 [2，3-b]吡啶 -4-甲醛 (1.52g， 5.3mmol)和 1-三苯基膦 -2-丙酮 (2.55g， 8mmol)分别加入到 30mL无水 THF中， 回流反应 2小时。 反应完毕降至室 温， 浓缩得粗品， 经柱层析分离得到目标化合物 1.52g， 产率 88%。
步骤 5 : 化合物 5-(1Η-吡咯并 [2，3-b]吡啶 -4-基)环己垸 -1，3-二酮的合成
将丙二酸二乙酯 (970 mg, 6.06mmol)加入到乙醇钠 (412mg， 6.06mmol)的乙醇 (20mL)溶 液中，室温搅拌 10分钟，滴加 4-O苯基磺酰基 1Η-吡咯并 [2，3-b]吡啶 -4-基)丁 -3-烯 -2-酮 (1.52 g， 4.66mmol)的乙醇 (10mL)溶液， 加热回流 1小时。 降至室温， 加 50mL水， 用 EA(50mL) 萃取， 水相用 3N盐酸调节至 pH=2-3， 加热回流 30分钟。 降至室温， 用 EA萃取， 合并的 有机相依次用水和饱和食盐水洗涤，干燥，浓缩。粗品经柱层析分离得到目标化合物 620mg， 产率 58.3%。
步骤 6 : 化合物 2-(((2-(4-(2-羟乙基；)哌嗪 -1-基)乙基)氨基)亚甲基 )-5-(1Η-吡咯并 [2,3,b] 吡啶 -4-基;)环己烧 - 1 ,3 -二酮的合成
操作步骤同实施例 2。化合物 n- iH MR OO MHz, CDC13) δ 11.31 - 11.15 (m， 1H)， 9.81 (s， 1H), 8.27 (dd, J = 18.6, 9.6 Hz, 2H), 7.35 (d, J= 3.4 Hz, 1H), 6.95 (d, J = 5.0 Hz, 1H), 6.56 (d, J= 3.5 Hz, 1H), 3.92 - 3.77 (m, 1H), 3.73 - 3.64 (m, 2H), 3.60 - 3.46 (m, 2H), 3.07 - 2.53 (m, 17H); MS: 412.4 [M+l]。
实施例 11 : 化合物 18-32
除了使用相应的溴代 C6-10芳基或醛 (；如实施例 11-1至 11-5)， 化合物 18-32的合成方 法同化合物 17， 如表 3所示.
表 3 : 化合物 18-32
# 结构 名称 氢谱 ('HNMR)，质谱 (MS)
2-(((2-(4-(2-羟乙基） ]H NMR (400 MHz, CDC13) δ 11.28 - 哌嗪 -1-基）乙基）氨 11 +08 (m, 1H), 9.50 (s, 1H), 8.32 (d, J 广
18 ο = 4.0 Hz, 1H), 8.20 (d, J = 14.3 Hz, 基）亚甲基） -5-(1Η- 1H), 7.97 (d, J = 7.8 Hz, 1H), δ 7.14 - 吡咯并 [2,3-b]吡啶 7.07 (m, 2H), 3.85 - 3.62 (m, 3H), 3.52 -3-基)环己烷 -1,3-二 (m, 2H), 3.02 - 2.65 (m, 17H); MS: 酮 412.2 [M+l] ,
]H NMR (400 MHz, DMSO-c 6) δ
2-(((2-(4-(2-羟乙基) 11.03 - 10.91 (m, 1H), 8.34 - 8.01 (m, 哌嗪 -1-基）乙基）氨 2H), 7.51 (d, J= 3.5 Hz, 1H), 7.00 (d, J
= 5.0 Hz, 1H), 6.64 (d, J= 3.5 Hz, 1H), 基）亚甲基）-5-(1-(2-
19 4.40 (t, J = 5.4 Hz, 3H), 3.83 - 3.65 甲氧基乙基) -1H-吡 (m, 3H), 3.58 (dd, J = 11.6, 5.8 Hz, 咯并 [2,3-b]吡啶 -4- 4H), 3.49 (dd, J = 11.4, 5.9 Hz, 3H), 基)环己垸 -1,3-二酮 3.23 (s, 2H), 2.97 - 2.76 (m, 2H), 2.69
- 2.23 (m, 12H); MS: 470.1 [M+l].
]H NMR (400 MHz, DMSO-i/6) δ
2-(((2-(4-(2-羟乙基） 11.09 - 10.83 (m, 1H), 9.09 (dd, J = 哌嗪 -1-基）乙基）氨 2.0, 1.0 Hz, 1H), 8.47 (dd, J= 12.3, 4.7
20 基）亚甲基 )-5-(1,10- Hz, 2H), 8.17 (d, J = 14+6 Hz, 1H), 菲咯啉 -3-基)环己垸 7.95 (s, 2H), 7.77 (dd, J = 7.6， 6.9 Hz,
Figure imgf000046_0001
-1,3-二酮 2H), 5.20 - 4.90 (m, 1H), 3.94 - 3.52
(m, 6H), 3.14 - 2.83 (m, 7H), 2.85 - 9
Figure imgf000047_0001
ΖΪ8而 8Ϊ0Ζ OAV 〜。 2-(((2-(4-(2-羟乙基） 】H NMR (400 MHz, CD3OD) δ 8.07(s, 哌嗪 -1-基）乙基）氨 1Η), 7.34-7.25(m, 4H), 7.18-7.14(m,
29 丄 基）亚甲基 )-5-甲基 1H), 3.79(t, J= 5.6Hz, 2H), 3.53-3.49
-5-苯基环己烷 -1,3- (m, 2H), 3.06-2.96(m, 8H), 2.77-2.58 二酮 (m, 8H), 1.36 (s, 3H)
5-((3aR， 4R， 6R，
6aR)-2,2- 二 甲 基
•6-(6-吗啉代 -9H-嘌 'HNM (400 MHz, CD30D) δ 8.25 (s, 呤 -9-基)四氢呋喃并 1H), 8.17 (m, 2H), 6.14 (d, J = 2.6 Hz,
1H), 5.42 - 5.31 (m, 1H), 5.08 - 4.99
30 m [3,4-D] [1,3]二氧杂
(m, 1H), 4.26 (s, 4H), 3.95 (m, 1H), 环 戊 烯 -4- 。 3.84 - 3.68 (m, 6H), 3.57 (m, 2H), 2.90 基) -2-(«2-(4-(2-羟乙 - 2 70 (m, 6H)， 2.61 (s, 7H), 2.46 (m, 基:)哌嗪 -1-基:)乙基） 5H), 1.57 (s, 3H), 1.37 (s, 3H) 氨基)亚甲基)环己垸
-1,3-二酮
2-(((2-(4-(2-羟乙基） 'HNM (400 MHz, CD3OD) δ 8.26 (s, 哌嗪 7.14 (m, 2H), 7.03 - 6.88 -1-基）乙基）氨 1H), 7.41 - a。 C (m, 3H), 3.97 (d, J = 5.1 Hz, 2H), 3.75
31 H 基)亚甲基 )-5- (苯氧
(t, J = 5.8 Hz, 2H), 3.63 (t, J = 5.8 Hz, 基甲基)环己垸 -1,3- 2H), 2.92 - 2.41 (m, 17H); MS: 402.4 二酮 [M+l].
'HNMR (400 MHz, CD3OD) δ 8.22 (s,
5-((3-氟苯氧基）甲 1H), 7.24 (dd, J = 15.2, 8.1 Hz, 1H), 基) -2-(((2-(4-(2-羟乙 6.73 (d, J = 8.2 Hz, 1H), 6.70 - 6.59
32 基）哌嗪 -1-基）乙基） (m, 2H), 3.94 (d, J = 5.1 Hz, 2H), 3.77 氨基)亚甲基)环己垸 (t, J = 5.6 Hz, 2H), 3.59 (t, J = 5.7 Hz, -1,3-二酮 2H), 2.98-2.91 (m, 5H), 2.79 - 2.32
(m, 12H); MS: 420.4 [M+l] .
¾6t ll-l: 中间体 11-1 : 4-溴 -l-(2-甲氧基乙基) -1H-吡咯并 [2，3-b]吡啶的合成
Figure imgf000048_0001
将 4-溴- 7-氮杂吲哚 (3g， 15.2mmol)溶于 30mL无水 N，N-二甲基甲酰胺（DMF )中， 0 °C 下缓慢加入钠氢 (60%， 800mg， 20mmol),该温度下反应 30分钟。加入 2-溴乙基甲基醚 (2.78g， 20mmol)? 升至室温反应 4小时。 反应完毕缓慢倒入冰水中， EA萃取， 有机相依次用水和 饱和食盐水洗搽， 干燥， 浓缩。 粗品经柱层析分离得目标化合物 3.12g， 产率 80%。
¾6fi 11-2： 中间体 11-2: 2-环丙基 -4,5-二甲氧基苯甲醛的合成
Figure imgf000048_0002
氮气保护下，将 6-溴藜芦醛 lg， 4.08mmol)、环丙基硼酸515mg， 6mmoi;>、碳酸钠 (1.06g， lOmmol)和四 (三苯基膦)钯 (100mg， 0.086mmol)加入到二氧六环 (15mL)和水 (5mL)中， 回流反 应过夜。反应完毕降至室温，倒入冰水中， EA萃取，有机相依次用水和食盐水洗涤， 干燥， 浓缩。 粗品经柱层析分离得目标化合物 560mg， 产率 66%。 实施例
Figure imgf000049_0001
步骤 1 : 化合物 8-氯咪唑并 [1,2-a]吡嗪的合成
将 2-溴 -1,1-二乙氧基乙烷 (22.7g， 0.115mol)在 48 %溴化氢 (4.45mL)水溶液中加热回流 2小时， 然后倒入碳酸氢钠 (74.5g)的异丙醇溶液 200mL中。 混合物搅拌 30分钟， 过滤， 向 滤液中加入 3-氯吡嗪 -2-胺 (5.0g， 38.6mmol), 将混合物在 85 °C下搅拌 4小时。浓缩， 加入饱 和的碳酸钠溶液并用 DCM萃取， 将合并的有机层干燥， 浓缩， 粗品用乙醚重结晶， 得粗品 5.7g, 其不经进一步纯化直接用于下一步反应。
步骤 2: 化合物 3-溴 -8-氯咪唑并 [l，2-a]吡嗪的合成
室温下向 8-氯咪唑并 [1,2-a]吡嗪 (5.7g)的 DCM(lOOmL)溶液中分批加入 BS(6.6g， 37mmol), 室温反应 2小时。 反应完毕将反应混合物倒入水中， DCM萃取， 有机相用水、 盐水洗涤， 干燥， 浓缩得粗品 8.0g， 其不经进一步纯化直接用于下一步反应。
步骤 3 : 化合物 溴咪唑并 [l，2-a]吡嗪 -8-基)吗啉的合成
将 3-溴 -8-氯咪唑并 [1,2-a]吡嗪 (8.0g)、 DIPEA(5.7g, 44mmol)和吗啉 (6.44g， 74mmol) 的混合物在 80°C下反应 4小时。 反应完毕倒入水中， DCM萃取， 有机相用水， 盐水洗涤， 干燥， 浓缩， 经柱层析分离得目标化合物 5.71g， 产率 52%。
实施树 11-4： 中间体 11-4: (3aS,4S，6R,6aR)-2,2-二甲基 -6-(6-吗啉代 -9H-嘌呤 -9-基）四氢 呋喃并 [3，4-D] [1,3]二氧杂环戊烯 -4-甲醛的合成
Figure imgf000049_0002
步骤 1 : 化合物 ((3aR， 4R， 6R， 6aR)-2,2-二甲基 -6-(6-吗啉代 -9H-嘌呤 -9-基)四氢呋喃并 [3,4-d] [1，3]二氧代 -4基；)甲醇的合成
将 6-氯嘌吟核苷 (3.0g， 10.46mmol)、 2,2-二甲氧基丙垸 (5.2g， 50mmol)和一水合对甲 苯磺酸 (1.99g， 10.46mmol)的丙酮 (120ml;)溶液回流 2小时， 反应完毕， 将反应混合物倒入冰 水中， 调节 pH至 8-9， 用 DCM萃取， 有机相用水洗涤， 硫酸钠干燥， 浓缩得到目标化合物 3.31g， 产率 96%。
步骤 2: 化合物 ((3aR， 4R， 6R， 6aR)-2,2-二甲基 -6-(6-吗啉代 -9H-嘌呤 -9-基)四氢呋喃并 [3,4-d] [1,3]二氧代 -4基)甲醇的合成
将化合物 （(33«_，4^61，6311)- 6-(6-氯 -9H-嘌吟 -9-基) -2，2-二甲基四氢呋喃并 [3，4-D] [1,3] 二氧杂环戊烯 -4-基）甲醇（1.00 g, 3.06 mmol), 吗啉 (610 mg, 7.0 mmol)和 DIPEA (900 mg, 7.0 mmol)溶于乙腈 (20 mL) 中， 回流反应 2小时， 反应完毕将反应混合物冷却至室温， 倒入冰 水中， EA萃取， 有机相用水洗涤， 无水硫酸钠干燥， 浓缩， 粗品经柱层析分离纯化得目标 化合物 912mg， 产率 80%。
步骤 3：化合物 (3aS， 4S， 6R， 6aR)-2,2-二甲基 -6-(6-吗啉代 -9H-嘌呤 -9-基)四氢呋喃并 [3,4-d] [1,3]间二氧杂环戊烯 -4-甲醛的合成
将 ((3aR， 4R， 6R， 6aR)-2,2-二甲基 -6-(6-吗啉代 -9H-嘌呤 -9-基）四氢呋喃并 [3,4-d] [U] 二氧代 -4 基）甲醇 (700mg， 1.85mmol)溶于 DCM 中， 0 °C 下缓慢加入戴斯 -马丁氧化剂 (2.5mmol),反应液升至室温搅拌 2小时。加水稀释， DCM萃取，有机相用饱和食盐水洗涤， 干燥， 浓縮。 粗品经柱层析分离得目标化合物 508mg， 产率 73%。
实施例 11-5 -5 : 2-苯氧基乙醛的合成
Figure imgf000050_0001
步骤 1 : 化合物 (2，2-二乙氧基乙氧基)苯的合成
将苯酚 (0.94g， lOmmol), 氯乙醛缩二乙醇 (1.52g， l Ommol) , 碳酸钾 (2.77g， 20mmol) 和碘化钾 (500mg)溶解于 DMF(15mL)中， 上述混合物在 100°C下搅拌过夜。 反应完毕， 将反 应混合物冷却至室温， 倒入冰水中， 用 EA萃取， 有机相用水洗涤， 硫酸钠干燥， 浓缩， 粗 品经柱层析分离纯化得目标化合物 1.21 g， 产率 58%。
步骤 2: 化合物 2-苯氧基乙醛的合成
将 (2,2-二乙氧基乙氧基)苯 (0.84g， 4mmol)溶解于醋酸 (5mL)、 IN盐酸溶液 (2.5mL)和 乙醇（EtOH) pOmL)的混合溶液中， 加热回流 3小时。反应完毕冷却至室温， 倒入冰水中， EA萃取， 有机相用水洗涤， 无水硫酸钠干燥， 浓缩， 粗品经柱层析分离纯化得目标化合物 468mg， 产率 86%。
实施例 12: 化合物 5-(4-(9H-嘌呤 -6-基)苯基) -2-(((2-(4-(2-羟乙基)哌嗪 -1-基)乙基)氨基)亚 甲基) -1 ,3-二酮 (化合物 33)的合成
Figure imgf000050_0002
步骤 1 : 化合物 6-氯 -9- (四氢 -2H-吡喃 -2-基) -9H-嘌呤的合成
49
更正页 （细则第 91条） ISA/CN 将 6-氯 -9H-嘌呤 (4.50g， 30mmol)、 一水合对甲苯磺酸（1.14g， 6.0mmol)和 3,4-二氢 -2H- 吡喃 (5.05g， 60mmoi;i的 EA溶液 (200mL)加热回流 5小时。 反应完毕冷却至室温， 倒入冰水 中， EA萃取， 有机相用水洗涤， 硫酸钠干燥， 浓縮， 粗品经柱层析分离纯化得目标化合物 5.72g, 产率 80%。
步骤 2: 化合物 4-(9- (四氢 -2H-吡喃 -2-基) -9H-嘌呤 -6-基)苯甲醛的合成
将 6-氯 -9- (四氢 -2H-吡喃 -2-基) -9H-嘌呤 (5.7g， 24mmol) 碳酸钠 (5.3g， 50mmol) 4-醛 基苯硼酸 (7.5 g， 50mmol)和四（三苯基膦)钯 (690mg， 0.6mmol)溶于二氧六环 (200mL)和水 (20mL)的混合溶液中， 回流反应过夜。 反应完毕冷却至室温， 倒入冰水中， EA萃取， 有机 相用水洗涤， 硫酸钠干燥， 浓缩， 粗品经柱层析分离纯化得目标化合物 5.51g， 产率 74%。
步骤 3、 4和 5 : 同实施例 9的操作步骤
步骤 6: 化合物 5-(4-(9H-嘌呤 -6-基)苯基) -2-(((2-(4-(2-羟乙基)哌嗪 -1-基)乙基)氨基)亚甲 基)环己烷 -1,3-二酮的合成
将 2-( (2-(4-(2-羟乙基)哌嗪 -1-基)乙基)氨基)亚甲基 )-5-(4-(9- (四氢 -2H-吡喃 -2-基) -9H-嘌 呤 -6-基)苯基)环己烷 -1,3-二酮 (160.0mg， 0.28mmol)溶于乙醇 (3mL)和 DCM(5mL)中，滴加稀盐 酸 (1 M， 2mL), 滴毕， 反应液室温搅拌 6小时， 反应完毕用饱和碳酸氢钠水溶液调 PH至碱 性， DCM萃取， 有机相用饱和食盐水洗涤， 干燥， 浓缩， 粗品经制备板分离得到目标化合 物 46mg， 产率 33%。 化合物 33 : 1H NMR (400 MHz, DMSO-i/6) δ 13.59 (s, 1 H), 11.20 - 10.79 (m, 1H), 9.08 - 8.52 (m, 4H), 8.13 (d, J= 14.6 Hz, 1H), 7.53 (d, J= 8.0 Hz, 2H), 4.55― 4.21 (m, 1H), 3.70 - 3.12 (m, 8H), 2.95 - 2.66 (m, 2H), 2.62 - 2.10 (m, 11 H); MS: 490.3 [M+l]。
实施例 12A: 化合物 2-(((2-(4-(2-羟乙基)哌嗪基)乙基)氨基)亚甲基 )-5-(3-(2-(2-甲氧基乙 氧基)乙氧基)苯基)环己焼 -1,3-二酮 (化合物 34)的 o
TsO
«酸钾
¾仿
Figure imgf000051_0001
步骤 1 : 化合物 3-(2-(2-甲氧基乙氧基)乙氧基)苯甲醛的合成
将 3-羟基苯甲醛 (2.00g， 16,4mmol)、4-甲基苯磺酸 2-(2-甲氧基乙氧基)乙酯 (4.94g， 18mmol) 和碳酸钾 (4.53g， 32.8mm0l)溶于乙腈 (50mL)中， 回流反应 3小时。反应完毕冷却至室温， 倒 入冰水中， EA萃取， 有机相用水洗涤， 硫酸钠干燥， 浓缩， 粗品经柱层析分离纯化得目标 化合物 1.7g， 产率 46°/0。
步骤 2: 化合物 4-(3-(2-(2-甲氧基乙氧基)乙氧基)苯基)丁 -3-烯 -2-酮的合成
50
更正页 （细则第 91条） ISA/CN 将 3-0(2-甲氧基乙氧基；)乙氧基；)苯甲醛 (7g， 31.21mmol)溶于丙酮 (20mL)和水 (10mL)中， 加入 20mL l%氢氧化钠溶液， 上述混合物加热回流 2小时， 降至室温， 倒入冰水中， EA萃 取。合并的有机相依次用水和饱和食盐水洗涤，干燥，浓缩。粗品经柱层析分离得到 6.16g， 产率 75%。
步骤 3、 4和 5 : 化合物 2-(((2-(4-(2-羟乙基)哌嗪基)乙基)氨基)亚甲基 )-5-(3-(2-(2-甲氧基 乙氧基)乙氧基)苯基)环己烷 -1,3-二酮的合成
步骤 3、 4禾卩 5 : 操作步骤同实施例 9。化合物 34: XHNMR (400 MHz, CD3OD) δ 8.24 (s, 1H), 7.23(t, J = 8.0 Hz, 1H), 6.88-6.80 (m, 3H), 4.11 (t， J = 4.8 Hz, 2H), 3.82 (t， J = 4.8 Hz, 2H), 3.74 (t， J = 5.6 Hz, 2H), 3.70-3.67 (m, 2H), 3.60(t, J = 5.6 Hz, 2H), 3.57-3.55(m, 2H), 3.36 (m, 3H), 3.35-3.34(m, 1H), 2.81-2.61(m, 16H); MS: 491.6 [M+l]。
实施例 13: 化合物 35-59， 61-84的合成
除了使用相应的苯甲醛、 芳香醛或取代的 1， 3-环己二酮外 (例如实施例 13-1至 13-11)， 化合物 35-84的合成方法同化合物 34， 如表 4所示。
表 4: 化合物 35-59， 61-84
Figure imgf000052_0001
Z
Figure imgf000053_0001
ΖΪ8而 8Ϊ0Ζ OAV
Figure imgf000054_0001
。
6Ζ'6 9 (αθεα3 'ζ謂 0017)腦應 t
ΖΪ8而 8Ϊ0Ζ OAV
Figure imgf000055_0001
ΖΪ8而 8Ϊ0Ζ OAV
Figure imgf000056_0001
Figure imgf000057_0001
Figure imgf000058_0001
实施例 13-1: 中间体 13-1: -(4-甲基哌嗪 -1-基)吡啶)的合成
Figure imgf000058_0002
将 6-氯 -3-口比啶甲醛 (5g， 35.32mmol)和 N-甲基哌嗪（15.68L, I41.28mmol)的 DMF溶液 加热至 100 °C反应 1小时。 反应完毕冷却至室温， 倒入冰水中， EA萃取， 合并的有机相依 次用水和饱和食盐水洗涤， 干燥，浓縮。粗品经柱层析分离得目标化合物 6.32g，产率 87°/。。
实施例 1 -2: 中间体 13-2: 1-金刚烷甲醛的合成
Figure imgf000058_0003
步骤 1: 1-金刚烷甲酸甲酯的合成
1-金刚垸甲酸 (5.00g， 27.74mmol)和浓硫酸 (0.5ml)溶解于 50mL甲醇中，回流反应过夜。
57
更正页 （细则第 91条） ISA/CN 反应完毕， 将反应混合物冷却至室温， 倒入冰水中， DCM萃取， 有机相用饱和碳酸氢钠、 水和盐水洗涤， 硫酸钠干燥， 浓缩得到目标化合物粗品 4.8g， 产率 89%。
步骤 2: 1-金刚垸甲醛的合成
氮气保护下， 将 1-金刚烷甲酸甲酯 (3g， 15.5mml)溶于 80ml甲苯， 降温至 -78 °C， 滴加 二异丁基氢化铝 (1.5 M的甲苯溶液， 10.3mL；)， 滴毕升至室温反应 1小时。缓慢滴加 4N盐酸 淬灭反应， 倒入冰水中， EA萃取。 合并的有机相用饱和食盐水洗涤， 干燥， 浓缩。 粗品经 柱层析分离得到目标化合物 2. lg， 产率 82%。
例 13-3: 中 -3 : 4- (吗啉 -4-羰基)苯甲醛的合成
Figure imgf000059_0001
将 4-甲酰基苯甲酸 (5.0g， 33.3mmol)溶于无水 DMF(lOmL)中， 依次加入 2-(7-偶氮苯并 三氮唑) -Ν,Ν,Ν',Ν'-四甲基脲六氟磷酸酯（HATU)(17.12g， 45mmol)禾卩 DIPEA(6.45g, 50mmol)， 室温反应 30分钟， 加入吗啉 (3.92g， 45mmol), 上述混合物室温继续反应 1小时。 反应完毕 倒入冰水中， EA萃取， 有机相用水洗涤， 硫酸钠干燥， 浓缩， 粗品经柱层析分离得目标化 合物 5.0g， 产率 68%。
例 13- 13-4 - (吡啶 -4-基氧基)苯甲醛
Figure imgf000059_0002
将 4-溴吡啶 (3.1g， 40mmol)、 3-羟基苯甲醛 (40mmol)和碳酸铯 (26.1g， 80mmol)溶于 80mL DMF中， 100 °C反应过夜。 反应完毕冷却至室温， 倒入冰水中， EA萃取， 有机相依次用水 和食盐水洗涤， 干燥， 浓缩。 粗品经柱层析分离得目标化合物 1.99g， 产率 25%。
实施例 13-5: -5 : 5- (；吡啶 -4-基)噻吩 -2-甲醛的合成
Figure imgf000059_0003
氮气保护下， 将 5-溴 -2-噻吩甲醛 (3.80g， 20.0mmol). 4-吡啶硼酸 (3.0g， 24.0mmol)> 碳 酸钠 (3.18g， 30.0mmol)、 醋酸钯 (224.0mg， l .Ommol)和三苯基膦 (520.0mg， 2.0mmol)溶解于 二氧六环和水的混合溶剂(v / V = 3 : l ; 80mL)中， 回流反应过夜。 反应完毕， 将反应混合物冷 却至室温并倒入冰水中， EA萃取， 合并的有机相用水洗涤， 硫酸钠下燥， 粗品经柱层析分 离纯化得目标化合物 3.2g， 产率 85%。
¾61例 13-6: -6: 4- (吡啶 -4-基)苯甲醛的合成
Figure imgf000059_0004
氮气保护下，将 4-溴苯甲醛 (2.78g， 15mmol)、4-吡啶硼酸 (2.46g，20mmol)、碳酸钠 (3.18g， 0mmol)和四 (三苯基膦)钯 (722mg， 0.62mmol)溶于二氧六环 (40mL)和水 (10mL)中， 混合物回 流反应过夜。反应完毕冷却至室温并倒入冰水中， EA萃取，有机相用水洗涤，千燥，浓缩。 粗品经柱层析分离得目标化合物 2.23g， 产率 81%。
实施例 13-7 -7: 化合物 4- (噻唑 -2-基)苯甲醛的合成
Figure imgf000060_0001
在氮气保护下， 将 2-溴噻唑 (3.0g， 18.3mmol) . 4-甲醛基苯硼酸 (3.3g， 22mmol).碳酸钠 (3.88g， 36.6mmol)和四（三苯基膦)钯（1.0g， 0.865mmol)溶于甲苯 /乙醇 /水 (50mL， v:v=3 : l : l) 混合溶剂中， 回流反应过夜。 反应完毕冷却至室温， 倒入水中， EA萃取， 有机层用硫酸钠 干燥， 浓缩， 柱层析得目标化合物 2.24g， 产率 65%。
实施例 13- -8 : 10-(2-甲氧基乙基) -10H-吩噻嗪 -3-甲醛的合成
Figure imgf000060_0002
步骤 1 : 化合物 10-(2-甲氧基乙基) -10H-吩噻嗪的合成
氮气保护， 0°C下将钠氢 (2.4g， 2eq)分批加入到吩噻嗪 (6g， l eq)的 DMF(60mL)溶液中， 搅拌 30分钟， 加入 2-溴乙基甲基醚 (6.3g， 1.5eq)后室温搅拌 2小时。 加水淬灭反应， DCM 萃取， 有机层干燥， 浓缩， 粗品经柱层析分离得目标化合物 9g。
步骤 2: 化合物 10-(2-甲氧基乙基) -10H-吩噻嗪 -3-甲醛的合成
氮气保护下， 0°C滴加三氯氧磷 (10.2mL， 5eq)至无水 DMF (8g, 5eq;)中。 滴毕， 搅拌直到 有无色固体生成， 随后加入 1,2-二氯乙烷 (50mL)溶解固体， 继续搅拌 1小时。 滴加 10-(2-甲 氧基乙基) -10H-吩噻嗪 (5.6g， l eq)的 1,2-二氯乙垸溶液， 并在 90°C搅拌 2小时。 反应完毕， 降至室温， 加入 20%氢氧化钠水溶液调节 pH=7， 水相用 DCM萃取。 合并的有机相用无水 硫酸钠干燥， 浓縮， 粗品经柱层析分离得目标化合物 5.3g。
-9: 中间体 13-9: 化合物 (4-甲酰基苯并 [d]噻唑 -2-基)氨基甲酸叔丁酯的合成
Figure imgf000060_0003
步骤 1 : 化合物 (4-甲基苯并 [d]噻唑 -2-基)氨基甲酸叔丁酯的合成
将 4-甲基苯并 [d]噻唑 -2-胺 (3.0g， 18.3mmol)、 二碳酸二叔丁酯（lO.Og , 45.7mmol)和 DMAP(0.67g, 5.5mmol)溶解在 DCM(80mL)中， 室温反应过夜。 反应完毕， 将反应混合物倒 入冰水中， DCM萃取， 合并的有机相用水洗涤， 硫酸钠干燥， 浓缩， 粗品经柱层析分离纯 化得目标化合物 5.2g， 产率 78%。
步骤 2: 化合物 (4- (二溴甲基)苯并 [d]噻唑 -2-基)氨基甲酸叔丁酯的合成 更正页 （细则第 91条） ISA/CN 将 (4-甲基苯并 [d]噻唑 -2-基)氨基甲酸叔丁酯 e(5.2g， 14.3mmol)、 NBS(5.08g， 28.5mmol) 和 AIBN(330mg， 2mmol)溶解于四氯化碳 30mL中， 回流反应过夜。 反应完毕， 将反应混合 物倒入冰水中， DCM萃取， 合并的有机相用水洗涤， 硫酸盐干燥， 浓缩得粗产物 4.5g， 其 不经进一步纯化直接用于下一步反应。
步骤 3 : 化合物 (4-甲酰基苯并 [d]噻唑 -2-基)氨基甲酸叔丁酯的合成
将化合物 (4- (；二溴甲基)苯并 [d]噻唑 -2-基)氨基甲酸叔丁酯 (4.5g粗品)和硝酸银 (12.2g， 71.5mmol)溶解于甲苯 (50mL)和 DMSO(5mL)混合溶剂中， 60°C反应 2小时。反应完毕，将反 应混合物倒入冰水中， EA萃取， 合并的有机相用水洗涤， 硫酸钠干燥， 浓缩。 粗品经柱层 析分离纯化得目标化合物 1.8g， 产率 45.2%。
实施例 13-10: 中间体 13-10: 4-(4-(6-乙氧基 -9H-嘌呤 -9-基)苯基)丁 -3-烯 -2-酮的合成
CI
τ Ν
k :>
Figure imgf000061_0001
步骤 1 : 化合物 (4-(6-氯 -9H-噤呤 -9-基)苯基)甲醇的合成
将 6-氯 -9H-嘌呤 (1.54g， lO.Ommol),醋酸铜 (3.63g， 20mmol)、 4- (羟甲基)苯硼酸 (3.63g， 20mmol)、 1,10-菲咯啉 (3.60g， 20mmol)和 4A分子筛（l .Og)置于干燥 DMF(50mL)溶液中， 40°C 反应过夜。 反应完毕倒入冰水中， EA萃取， 有机相用水洗涤， 硫酸钠干燥， 浓缩。 粗品经 柱层析分离纯化得目标化合物 1.49g， 产率 57%。
步骤 2: 化合物 4-(6-氯 -9H-嘌呤 -9-基)苯甲醛的合成
将 (4-(6-氯 -9H-嘌呤 -9-基)苯基）甲醇 (900mg， 3.5mmol)和二氧化锰 (6.1g , 70mmol)置于 SOmL DCM中，室温搅拌 1小时。过滤，滤渣用 DCM洗涤，收集滤液并浓缩得粗品 900mg， 其不经纯化直接用于下一步反应。
步骤 3 : 化合物 4-(4-(6-乙氧基 -9H-嘌呤 -9-基)苯基)丁 -3-烯 -2-酮的合成
将 4-(6-氯 -9H-嘌呤 -9-基)苯甲醛 (900mg， 3.5mmol)和饱和碳酸氢钠水溶液 (5ml)加入丙酮 (30mL)和乙醇 (20mL)中，加热回流 5小时。反应完毕， 降至室温，倒入冰水中， DCM萃取。 合并的有机相用无水硫酸钠干燥，浓缩，粗品经柱层析分离得目标化合物 490mg，产率 46%。
实施例 13-11 : 中间体 13-11 : 4-(2- (吡啶 -4-基氧基)乙氧基)苯甲醛的合成
Figure imgf000061_0002
步骤 1 : 化合物 4-(2-溴乙氧基)苯甲醛的合成
将 4-羟基苯甲醛 (3.0g，24.6mmol)、碳酸钾 (6.90g， 50mmol)和 1,2-二溴乙烷 (9.4g， 50ramol)
60
更正页 （细则第 91条） ISA/CN 溶解于 EtOHC85mL)中， 回流反应过夜。 反应完毕， 将反应混合物倒入冰水中， EA萃取， 合并的有机相用水洗涤， 硫酸钠干燥， 浓缩。 粗品经柱层析分离得目标化合物 1.8g， 产率 32%。
步骤 2: 化合物 4-(2- (吡啶 -4-基氧基)乙氧基)苯甲醛的合成
将 4-(2-溴乙氧基)苯甲醛 (1.80g， 7.86mmol)、碳酸铯 (4.89g， 15mmol)和 4-羟基吡啶 (950mg， lOmmol)溶于 125mL乙醇中， 回流反应过夜。反应完毕， 降至室温，倒入冰水中， EA萃取， 合并的有机相用无水硫酸钠干燥，浓缩，粗品经柱层析分离得目标化合物 400mg，产率 21%。
实施例 14:化合物 5-(2-氨基苯并 [d]噻唑 -4-基) -2-(((2-(4-(2-羟乙基)哌嗪 -1-基)乙基)氨基) 亚甲基) -1,3-二酮 (化合物 85)的合成
Figure imgf000062_0001
将化合物 N'-(4-(4-(((2-(4-(2-羟乙基)哌嗪 -1-基)乙基)氨基)亚甲基 )-3,5-代环己基)苯并 [d] 噻唑 -2-基) -N， N-二甲基甲脒 (lOOmg, 0.2mmol)和氯化锌 (1.36g， l Ommol)溶于 5mL无水乙 醇中， 回流反应过夜。 反应完毕， 冷却， 倒入冰水中， EA萃取， 合并的有机相用无水硫酸 钠干燥， 浓缩，粗品经柱层析分离得目标化合物 40mg，产率 45%。化合物 85: 1H NMR (400 MHz, CD3OD) δ 8.27 (s, 1H), 7.48 (d, J = 7.7 Hz, 1H), 7.14 (d, J = 7.4 Hz, 1H), 7.03 (t, J = 7.7 Hz, 1H), 3.92 (s, 1H), 3.75 (t, J = 5.6 Hz, 2H), 3.62 (t, J = 5.8 Hz, 2H), 3.10 - 2.49 (m, 16H); MS: 444.2 [M+l]。
实施例 15： 化合物 7-(((2-(4-(2-羟乙基)哌嗪小基)乙基)氨基)亚甲基) -螺 [3.5]壬烷 -6,8-二 酮 (化
,
Figure imgf000062_0002
步骤 1 : 化合物 2-环亚丁基乙酸乙酯的合成
氮气保护， 在 0°C下将钠氢 (60 %， 1.60g， 40mmOl)加入 3- (二乙氧基膦基) -3-氧代丙酸乙 酯 (8.96g，40mmol)的无水 THF溶液 (50mL)中，并在该温度下搅拌 30分钟后，加入环丁酮 (2.8g， 40mmoi;>的无水 THF溶液 (10mL)。上述混合物在该温度下搅拌 2小时，然后缓慢加入水 G OmL)， 将所得混合物在室温下再搅拌 30分钟。 反应完毕， 将反应混合物倒入冰水中， EA萃取， 合 并的有机相用水洗涤， 硫酸钠千燥， 浓缩。 粗品经柱层析分离纯化得目标化合物 4.62g， 产 率 82.5%。
步骤 2: 化合物螺 [3.5]壬垸 -6,8-二酮的合成
氮气保护， 在（TC下， 钠氢 (60 %， 960mg, 24mmol)加入 3-氧代戊二酸二乙酯 (2.53g，
61
更正页 （细则第 91条） ISA/CN 12.5mmol)的无水 THF(50mL)溶液中， 并该温度下搅拌 30分钟后， 加入 2-环丁基亚乙基酯 乙酸乙酯 (1.4g， lOmmol)的无水 THF(lOmL)溶液，室温反应 2小时，然后加入乙醇钠 (816mg， 12mmol)的无水乙醇溶液 5mL。 上述混合物回流反应 5小时， 冷却至 50°C， 加入 20 %KOH 溶液 (10mL)。 将所得混合物在该温度下搅拌过夜， 反应完毕冷却至室温， EA萃取， 将水相 调节至 1-2， 并在 70°C下搅拌 2小时。冷却至室温， DCM萃取。将合并的有机相用水洗涤， 硫酸盐干燥， 浓缩。 粗品经柱层析分离纯化得目标化合物 483mg， 产率 32%。
步骤 3 : 化合物 7-(((2-(4-(2-羟乙基)哌嗪 -1-基)乙基)氨基)亚甲基)螺 [3.5]壬烷 -6,8-二酮的 合成
操作步骤同实施例 2。 化合物 86: 1HNMR (CD3OD, 400ΜΗζ) δ 8.16 (s, 1H), 3.67 (t, J = 6.0Hz, 2H), 3.56 (t, J= 6.0Hz, 2H), 2.59-2.53 (m, 16H), 1.95-1.82 (m, 6H); MS: 336.5 [M+l]。
实施例 16: 化合物 87-94
除了使用相应的醛、 酮或取代的丙烯酸酯外 (例如实施例 16-1和 16-2)， 化合物 87-94的 合成方法同化合物 86， 如表 5所示。
表 5 : 化合物 87-94
Figure imgf000063_0001
Figure imgf000064_0001
实施例 16-1 : 中间体 16-1 : 吗啉代磺酰基)苯基；) -丙烯酸乙酯的合成
Figure imgf000064_0002
步骤 1 : 化合物 4-«4-溴苯基；)磺酰基)吗啉的合成
将 4-溴苯磺酰氯 (5.0g， 19.6mmol)、 三乙胺 （TEA) (2.98mL)和吗啉 (1.88g， 21.53mmol) 溶解在 DCM OmL)中，室温反应 30分钟，反应完毕。将反应混合物倒入水中， DCM萃取。 合并的有机相用 1N盐酸、 水和盐水洗涤， 干燥， 浓缩得粗品 5.21g， 其不经进一步纯化直 接用于下一步反应。
步骤 2: 化合物 3-(4- (吗啉代磺酰基；)苯基)丙烯酸乙酯的合成
氮气保护下， 将 4-¾4-溴苯基)磺酰基；)吗啉 p.0g， 6.53mmol)、 丙烯酸乙酯 (849mg， 8.49mmol)、 醋酸钯 (43.88mg， 0.2mmol)和三苯基膦 (68.89mg， 0.26mmol)加入到 3mL三乙胺 中， 封管中于 150度搅拌 6小时。 冷却， 倒入水中， EA萃取。 合并的有机相用无水硫酸钠 干燥， 浓缩， 粗品经柱层析分离得到 1.8g， 产率 85%。
¾6！例 16-2: 中间体 16-3 : 6-(2-吗啉代乙氧基)烟醛的合成
Figure imgf000064_0003
人 Cl 人。〜OH 人 o〜OMs
步骤 1 : 化合物 6-(2-羟基乙氧基；)烟醛的合成
在室温下将叔丁醇钠 (3.49g， 36.3mmol)加入到 1，2-乙二醇 (30mL)中， 搅拌 30分钟后， 加入 6-氯烟醛 (4.0g， 28.3mmol), 所得混合物在室温下搅拌过夜， 然后升温至 80 °C再搅拌 2 小时， 反应完毕。 将反应混合物冷却至室温， 倒入冰水中， EA萃取， 有机相用水洗涤， 干 燥， 浓缩， 粗品经柱层析分离纯化得目标化合物 4.01g， 产率 85%。 步骤 2: 化合物 2-((5-甲酰基吡啶 -2-基)氧基；)乙基甲磺酸酯的合成
将 6-(2-羟基乙氧基)烟醛 (4g， 24mmol)和 TEA(4mL)加入到 DCM(90mL)中， 于 0°C滴加 甲磺酰氯 P.66g， 32mmol)的二氯甲烷溶液， 滴毕保持在该温度下搅拌 30分钟， 反应完毕。 反应液倒入水中， EA萃取。合并的有机相用无水硫酸钠干燥， 浓缩得粗品 5.21g， 不经进一 步纯化直接用于下一步反应。
步骤 3 : 化合物 6-(2-吗啉代乙氧基)烟醛的制备
将 2-((5-甲酰基吡啶 -2-基)氧基)乙基甲磺酸酯 (5.21g， 粗品)、 吗啉 (4.35g， 50mmol)和碳 酸钾 (6.91g， 50mmol)加入 80mL乙腈中， 回流反应过夜。 冷却， 倒入水中， EA萃取， 有机 相用无水硫酸钠干燥， 浓缩， 粗品经柱层析分离得目标化合物 2.92g， 产率 51%。
实施例 17:化合物 3-(((2-(4-(2-羟乙基)哌嗪-] -基)乙基)氨基)亚甲基 )-6-苯基二氢 -2H-吡喃 -2,4(3H)-
Figure imgf000065_0001
步骤 1 : 化合物 6-苯基二氢 -2H-吡喃 -2，4(3H)-二酮的制备
将乙酰乙酸乙酯（13.01g， 0.1 mol)、 碳酸钾 (27.64g， 0.2mol)和苯甲醛 (10.1mL， 0+ l mol) 溶解于乙醇 (l OOmL)中， 45°C下反应 22小时，过滤，滤渣用乙醇洗涤，收集的滤液倒入水中， PE洗涤。 收集水相， 用 6N盐酸酸化至 pH 2-3， EA萃取， 有机相用水洗涤， 硫酸钠干燥， 浓缩， 粗品经柱层析分离纯化得目标化合物 8.87g， 产率 46.7%。
步骤 2: 化合物 3-(((2-(4-(2-羟乙基)哌嗪 -1-基)乙基)氨基)亚甲基 )-6-苯基二氢 -2H-吡喃 -2,4(3H)-二酮的合成
合成步骤同实施例 2。 化合物 95: 1HNMR (400 MHz, CD3OD) δ 8.31 (s, 0.33Η), 8.18 (s, 0.67H), 7.46-7.32 (m, 5H), 5.53 (dd, J= 7.2Hz, 2.4Hz, 1 H), 3.68 (t, J= 6.0Hz, 2H), 3.61-3.58 (m, 2H), 2.98-2.86 (m, 1H), 2.72-2.54 (m, 14H); MS: 374.4 [M+l].
实施例 17A: 3-(((2-(4-(2-羟乙基)哌嗪 -1 -基)乙基)氨基)亚甲基 )-6-苯基哌啶 -2，4-二酮 (化合 物 96
Figure imgf000065_0002
步骤 1 : 化合物 3-((3-乙氧基 -3-氧代 -1-苯基丙基)氨基) -3-氧代丙酸乙酯的合成 将 3-氨基 -3-苯基丙酸乙酯 （4.31g， 22.23mmol)、 丙二酸单乙酯 (4.47g， 33.84mmol)、
DIPEA(7.7g， 55.8mmol)禾卩 1H-苯并三唑 -1 -氧三吡咯啉嗡六氟磷酸 （PyBOP ) (17.42g ,
33.84mmol)加入 DMF(30mL)中， 室温反应 2小时， 反应完毕。倒入水中， EA萃取， 有机相 用无水硫酸钠干燥， 浓縮， 粗品经柱层析分离得目标化合物 6.05g， 产率 88%。
步骤 2: 化合物 6-苯基哌啶 -2,4-二酮的合成
64
更正页 （细则第 91条） ISA/CN 在 0°C下， 将化合物 3-(X3-乙氧基 -3-氧代 -1-苯基丙基)氨基) -3-氧代丙酸乙酯 2.0 g 6.51 mmol)的甲苯溶液 (16mL)滴加至乙醇钠 (0.66g 9.77mmol)的无水乙醇溶液 (16mL)中， 回流反 应 1小时。 反应完毕， 将反应混合物倒入水中， pH调节至 1 -2 EA萃取， 有机相用水和盐 水洗涤， 干燥， 浓缩， 所得粗品溶于乙腈 I水 (V:V=100: 1 16mL)混合溶剂中， 并回流过夜。 反应完毕冷却至室温， 倒入冰水中， EA萃取， 有机相用水洗涤， 硫酸钠干燥， 浓缩所得粗 品经柱层析分离纯化得目标化合物 622mg，产率 50%。化合物 96: !HNMR (400 MHz, CD3OD) δ 8.09 (s, 0.3Η), 8.04 (s, 0.7H), 7.34-7.24 (m, 5H), 4.75-4.72 (m, 1 H)， 3.72 (t, J =5.6Hz, 2H), 3.55-3.52 (m 2H), 2.87-2.57 (m, 15H), MS: 373.3 [M+l ]
实施例 18:化合物 4-(((2-(4-(2-羟乙基)哌嗪 -1-基)乙基)氨基)亚甲基 )-1 -苯基哌啶 -3,5-二酮 (；化合物 97；)的合成
Figure imgf000066_0001
步骤 1 : 苯基甘氨酸乙酯的合成
将苯胺 (5.0g 53.69mmol)、溴乙酸乙酯（10.76g 64.43mmol)和醋酸钠 (5.29g 64.43ramol) 溶于无水乙醇 (120mL)中， 回流反应 2小时。 反应完毕， 浓縮， 粗品经柱层析分离纯化得目 标化合物 7.4g， 产率 77%
步骤 2: 化合物 N-(2-氧代丙基) -N-苯基甘氨酸乙酯的合成
将苯基甘氨酸乙酯 (2.3g 12.83mmol)、 溴丙酮 (2.1 1g 25.67mmol)和 DIPEA(4.57mL 25.67mmol)加入到 DMF(50mL)中， 1 10°C反应 4小时， 补加溴丙酮（1.06g 12.8mmol), 继续 在 1 10°C反应 4小时。 降至室温， 倒入水中， EA萃取， 合并的有机相用无水硫酸钠千燥， 浓缩， 粗品经柱层析分离得目标化合物 1.3g， 产率 43%
步骤 3 : 化合物 1 -苯基哌啶 -3,5-二酮的合成
在 0°C下，将叔丁醇钾的 THF溶液 (2mol L 3.8mL)滴加至化合物 N-(2-氧代丙基) -N-苯基 甘氨酸乙酯 (1.2g 5.1 mmol)的无水 THF溶液 (50mL)中， 上述反应液于室温搅拌 3小时。 反 应完毕， 滴加 20%醋酸淬灭反应， 倒入冰水中， EA萃取， 有机相用无水硫酸钠干燥， 粗品 经柱层析分离得目标化合物 600mg， 产率 62%
步骤 4禾 Π 5 :操作步骤同实施例 2。化合物 97: 'UNMR (400 MHz, CD3OD) δ 8.22 (s, 1Η), 7.26 (t, J = 8.0 Hz, 2H), 6.98 (d, J = 8.0 Hz, 2H), 6.88 (t, J = 7.3 Hz, 1H), 4.03 (d, J = 10.9 Hz, 4H)， 3.75 (t, J = 5.8 Hz, 2H), 3.61 (t, J = 5.7 Hz, 2H), 2.66 (dd J = 23.9, 18.2 Hz, 12H); MS: 373.3 [M+l]
实施例 19:化合物 3-(((2-(4-(2-羟乙基)哌嗪 -1-基)乙基)氨基)亚甲基 )-1 -苯基哌啶 -2 4-二酮 (化合物 99)的合成
65
更正页 （细则第 91条） ISA/CN
Figure imgf000067_0001
步骤 1 : 化合物 3- (苯基氨基)丙酸乙酯的合成
将苯胺 (2.8g， 30mmol) 丙烯酸乙酯 (3.6g， 36mmol)溶解于 2mL醋酸中， 95 °C反应过夜。 反应完毕冷却至室温， 倒入冰水中， 用饱和碳酸钠溶液调 PH至 9-10， EA萃取， 有机相用 水洗涤， 干燥， 浓缩， 粗品经柱层析分离得目标化合物 5.3g， 产率 91°/0。
步骤 2: 化合物 3-((3-乙氧基 -3-氧代丙基) (苯基)氨基) -3-氧代丙酸乙酯的合成
将 3- (苯基氨基)丙酸乙酯 (5.3g， 27.4mmol)、 丙二酸单乙酯酰氯 (5.35g， 35.6mmol)和 DIPEA(7.09g, 54.8mmol)溶解于 DCM(35mL)中， 室温反应 1小时。 反应完毕， 将反应混合 物倒入冰水中， EA萃取， 有机相用水洗涤， 干燥， 浓缩， 粗品经柱层析分离得目标化合物 2.1g, 产率 25%。
步骤 3 : 化合物乙基 -2,4-二氧代 -1 -苯基哌啶 -3-羧酸乙酯的合成
化合物 3-((3-乙氧基 -3-氧代丙基) (苯基)氨基) -3-氧代丙酸乙酯 (2.00 g, 6.5 mmol)和乙醇钠 (0.88g, 13mmol)溶解于 15mL无水乙醇中， 室温反应 2小时， 反应完毕。将反应混合物倒入 冰水中， 水相用 2N盐酸调 PH至 3-4， EA萃取， 有机相用水洗涤， 硫酸钠干燥， 浓缩， 粗 品经柱层析分离纯化得目标化合物 780mg， 产率 46°/。。
步骤 4: 化合物 1 -苯基哌啶 -2,4-二酮的合成
将乙基 -2,4-二氧代 -1-苯基哌啶 -3-羧酸乙酯 (780mg， 3.0mmol)和醋酸 (0.7mL)的水溶液 (7mL)在 90°C下反应 18小时。 反应完毕， 将反应混合物倒入冰水中， EA萃取， 有机相用水 洗涤， 干燥， 浓缩， 粗品经柱层析分离得目标化合物 51 Omg， 产率 90%。
步骤 5：化合物 3-(((2-(4-(2-羟乙基)哌嗪 -1-基)乙基)氨基)亚甲基 )-1-苯基哌 ½-2,4-二酮的 合成
本步操作步骤同实施例 2。 化合物 99: 1H NMR (400 MHz, CD3OD) δ 8.13 (d, J = 7.1 Hz, 1H), 7.48 - 7.33 (m, 2H), 7.34 - 7.15 (m, 3H), 3.90 - 3.72 (m, 2H), 3.71 - 3.61 (m, 2H), 3.60 - 3.46 (m, 2H), 2.83 - 2.38 (m, 14H); MS: 373.3 [M+l]。
实施例 20 : 化合物 4-(4-氟苯基 )-2-(((2-(4-(2-羟乙基)哌嗪 -1 -基)乙基)氨基)亚甲基)环己 -1，3-
Figure imgf000067_0002
步骤 1 : 化合物 4-(4-氟苯基)环己浣 -1 ,3-二酮的合成
化合物 1-(4-氟苯基)丙 -2-酮 (2.0g， 13.14mmol)、 丙烯酸乙酯 (1.45g， 14.46mmol)和乙醇 钠 (893.5mg， 13.14mmol)溶解于无水乙醇 20mL中， 回流反应过夜。 反应完毕， 冷却至室温 更正页 （细则第 91条） ISA/CN 并倒入冰水中， 用 2N盐酸调 PH至 3-4 EA萃取， 有机相用水洗涤， 硫酸钠干燥， 浓缩， 粗品经柱层析分离纯化得目标化合物 620mg， 产率 23%
步骤 2: 化合物 4-(4-氟苯基 )-2-(((2-(4-(2-羟乙基)哌嗪 -1-基)乙基)氨基)亚甲基)环己 -1 ,3- 二酮的合成
操作步骤同实施例 2。化合物 100: lH NMR (400 MHz, CD3OD) δ 8.30 (d, J = 8.8 Hz, 1H), 7.28― 7.16 (m, 2H), 7.06 (t J = 8.0 Hz, 2H)， 3.81― 3.66 (m, 3H), 3.62 (t, J = 5.8 Hz, 2H), 2.86 - 2.43 (m, 14H), 2.27 - 2.15 (m 2H). MS: 390.4 [M+l]
实施例 21 : 化合物 4-苄基 -2-(((2-(4-(2-羟乙基)哌嗪小基)乙基)氨基)亚甲基 )-6-苯基环己 烷 -1,3-二酮 (化
Figure imgf000068_0001
步骤 1 : 化合物 5-苄基 -4-苯基环己垸 -1,3-二酮的合成
氮气保护， 在 0°C下， 将叔丁醇钾 (1.61 g, 14.3mmol)加入苄基丙酮 (2.5mL 15.5mmol)的 无水 THF(20mL)溶液中， 搅拌 10分钟后， 加入肉桂酸甲酯 (2g 12.3mmol), 然后继续搅拌 30分钟，反应完毕将反应液倒入水中，用 2N稀盐酸调节 pH至 6-7 EA萃取，有机相干燥， 浓缩得到 3.61g粗品， 直接用于下一步反应。
步骤 2: 化合物 4-节基 -2-(((2-(4-(2-羟乙基)哌嗪 -1 -基)乙基)氨基)亚甲基 )-6-苯基环己烷 -1 ,3-二酮的合成
操作步骤同实施例 2。化合物 101 !H NMR (400 MHz, CD3OD) δ 8.24 (d, J = 5.6 Hz, 1H), 7.39 - 6.98 (m, 9H), 6.91 (d, J = 7.4 Hz, 1H), 3.72 (t, J = 5.8 Hz, 2H), 3.60 (t, J = 5.7 Hz, 2H), 3.46-3.40 (m, 1H), 3.24 - 3.01 (m, 3H), 2.95 - 2.56 (m, 13H), 2.49 (dd, J = 13.8, 7.6 Hz, 1 H); MS: 462.3 [M+l] +
实施例 22: 化合物 4-(((2-(4-(2-羟乙基)哌嗪 -1 -基)乙基)氨基)亚甲基 )-l -(4-甲氧基苄基)哌 -3,5-二酮 (化合物 102)的合成
Figure imgf000068_0002
步骤 1 : 化合物乙基 (4-甲氧基苄基)甘氨酸乙酯的合成
室温下， 2-溴乙酸乙酯 (5.00g 29.94mmol)的无水 THF溶液 (20mL)在 2小时内滴加至对 甲氧基苄胺胺 (9.04g 66mm0l)的无水 THF 溶液 (120mL)中， 室温反应过夜。 反应完毕， 将 反应混合物倒入水中， 用饱和碳酸钠调 PH至 9-10 EA萃取， 有机相用水洗涤， 硫酸钠干 燥， 浓缩， 粗品经柱层析分离纯化得目标化合物 3.12g， 产率 47%
67
更正页 （细则第 91条） ISA/CN NO/VSI W 3Γ
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Figure imgf000069_0008
' )顯 2邈資具 寸) ¾2 步骤 3 : 化合物 1-苯甲酰 -3,5-二酮的合成
在 0Ό下， 将叔丁醇钾的 THF溶液 (lmol/L， 1 1 mL)滴加至乙基 N-苯甲酰基 -N-(2-氧 代丙基；)甘氨酸乙酯 (1.9g， 7.22mmol)的无水 THF溶液 60mL中， 于室温反应 3小时。反应完 毕， 将反应液倒入 10%醋酸溶液中， EA萃取， 有机相用无水硫酸钠干燥， 浓缩， 粗品经柱 层析分离得目标化合物 1.03g， 产率 66°/。。
步骤 4: 化合物 1-苯甲酰基 -4-(((2-(4-(2-羟乙基)哌嗪 -1 -基)乙基)氨基)亚甲基)哌啶 -3,5-二 酮的合成
最后一步操作步骤同实施例 8。 化合物 104: Ή NMR (400 MHz, CD3OD) δ 8.25 (s, 1H), 7.57 - 7.45 (m, 3H), 7.42 (dd， J= 8.0, 1.5 Hz, 2H)， 4.47 (s， 2H)， 4.18 (s， 2H), 373 (t, J = 5.8 Hz, 2H), 3.62 (t, J= 5.8 Hz, 2H), 2.83 - 2.58 (m, 12H); MS: 401.4 [M+l]。
实施例 26:化合物 2-(((2-(4-(2-羟乙基)哌嗪 -1-基)乙基)氨基)亚甲基 )-5- (吗啉 -4-羰基)环己 烧 - -二酮 (化合物 106)的合成
Figure imgf000070_0001
步骤 1 : 化合物 3-甲氧基 -5-氧代环己 -3-烯 -1-羧酸的合成
将化合物 3,5-二氧代环己烷羧酸 (780mg， 5mmol)、 一水合对甲苯磺酸 (95mg， 0.5mmol) 溶解于 6mL甲醇中， 回流反应 2小时。 反应完毕冷却至室温， 将 EA加入到混合物中， 析 出沉淀， 过滤得粗品 420mg， 其不经进一步纯化直接用于下一步反应。
步骤 2: 化合物 3-甲氧基 -5- (吗啉 -4-羰基)环己 -2-炼 -1-酮的合成
将 3-甲氧基 -5-氧代环己 -3-烯 -1 -羧酸 (340mg， 粗品）、 吗啡啉 (310mg， 2.4mmol) , DIPEA(390mg， 3mmol)和 HATU(1.14g， 3mmol)加入到 12mL无水 DMF中，室温搅拌过夜。 反应完毕， 倒入水中， EA萃取， 有机相用无水硫酸钠干燥， 浓缩， 粗品经柱层析分离得目 标化合物 M0mg， 产率 15°/。。
步骤 3 : 化合物 5- (吗啉 -4-羰基)环己浣 -1,3-二酮的合成
将 3-甲氧基 -5- (吗啉 -4-羰基)环己 -2-烯 -1 -酮（132mg， 0.55mmol)和硝酸铈铰（110mg， 0.2mmol)加入到乙腈 (4mL)和水 (4mL)中， 加热回流 3小时。 反应完毕， 降至室温， 将反应液 倒入水中， EA萃取， 合并的有机相用无水硫酸钠干燥， 浓缩， 粗品经柱层析分离得目标化 合物 112mg， 产率 90%。
步骤 4: 化合物 2-(((2-(4-(2-羟乙基)哌嗪小基)乙基)氨基)亚甲基 )-5- (吗咻 -4-羰基)环己烷 -1，3-二酮的合成
操作步骤同实施例 2。化合物 106: !H MR (400 MHz, CD30D) δ 8.19 (s, 1H), 3.75 (t, J = 5.7 Hz, 2H), 3.65 (dd, J= 13.9, 4.5 Hz, 4H), 3.61 - 3.47 (m, 7H), 2.88 (s, 3H), 2.81 (t, J= 5.8 Hz,
69
更正页 （细则第 91条） ISA/CN 2H), 2.75 - 2.42 (m, 10H)。
实施例 27: 化合物 3-(((2-(4-(2-羟乙基)哌嗪 -1 -基)乙基)氨基)亚甲基)喹啉 -2,4(1H， 3H)- 二酮 (；化合物 107)的合成
Figure imgf000071_0001
步骤 1： 化合物 3-氧代 -3- (苯基氨基)丙酸甲酯的合成
在 0°C下， 将丙二酸单甲酯酰氯 (1.84 g， 13.5 mmol)滴加至苯胺 (1.00g， 10.74mmol)和 TEA(1.42g, 14mmol)的乙酸乙酯溶液中， 滴毕， 在室温下搅拌 30分钟。 反应完毕， 将反应 混合物倒入水中， EA萃取， 有机相用水洗涤， 硫酸钠干燥， 浓缩， 粗品经柱层析分离得目 标化合物 1.75g， 产率 85°/。。
步骤 2: 化合物 3-氧代 -3- (苯基氨基)丙酸的合成
将 3-氧代 -3- (苯基氨基)丙酸甲酯 (1.00g， 5.18mmd)和氢氧化钠 (415mg， 10.37mmol) 的甲醇 /水 (v: v= 3 : 1， 20mL)混合溶液在室温下搅拌 1小时。反应完毕， 将反应混合物倒入 水中， EA萃取。 将水相的 PH值调节至 5-6， DCM萃取。 将合并的有机相用水洗涤， 硫酸 钠干燥， 浓缩得粗品 820mg， 直接用于下一步反应。
步骤 3 : 化合物喹啉 -2 1H, 3H)-二酮的合成
将 3-氧代 -3- (苯基氨基)丙酸 (537mg， 粗品;)加入到 6mL甲磺酸中， 加热至 50°C， 分批 加入五氧化二磷 (852mg 反应液随后升至 75 °C搅拌 2小时。 降至室温， 缓慢倒入冰水中， 水相用饱和碳酸钠水溶液调节 pH至 7-8。 将析出的固体过滤， 收集， 干燥得粗品 220mg， 产率 40%， 无需纯化直接用于下一步反应。
步骤 4: 化合物 3-(((2-(4-(2-羟乙基)哌嗪 -1-基)乙基)氨基)亚甲基)喹啉 -2，4(1H， 3H)-二酮 的合成
操作步骤同实施例 2。 化合物 107: lU NMR (400 MHz, CD3OD) δ 8.57 (d, J = 36.5 Hz, 1H), 8.04 (d, J = 7.5 Hz, 1H)， 7.53 (t， J = 6.9 Hz, 1H), 7.16 (t, J = 8J Hz, 2H), 3.73 (m, 4H), 2.69 (m, 11 H)。
实施例 28:化合物 2-(l -((2-(4-(2-羟乙基)哌嗪 -1 -基)乙基)氨基)亚乙基 )-5-苯基环己垸 -1 ,3- 二酮 (化合物 1
Figure imgf000071_0002
步骤 1 : 化合物 2-乙酰基 -5-苯基 -1,3-环己二酮的合成
室温下， 将乙酰氯 (4.2g， 53.5 mmol)滴加至 5-苯基 -1 ,3-环己二酮 (10.0g， 53.1mmol)、 DMAP(2.00g, 16.4mmol)和 DIPEA(7.75g， 60mmol)混合物中， 回流反应 2小时。 反应完毕
70
更正页 （细则第 91条） ISA CN 冷却至室温， 倒入冰水中， DCM萃取， 有机相用水洗涤， 硫酸钠干燥， 浓缩， 粗品经柱层 析分离纯化得目标化合物 8.5 lg， 产率 70%。
步骤 2: 化合物 2-(1-((2-(4-(2-羟乙基)哌嗪 -1-基)乙基)氨基)亚乙基 )-5-苯基环己垸 -1，3-二 酮的合成
将 2-乙酰基 -5-苯基 -1，3-环己二酮 (90mg， 0.39mmol)和 2-(4-(2-氨基乙基)! ^嗪 -1-基)乙 -1-醇 (81mg， 0.47mmd)溶解于 5mL乙醇中， 加热回流 1小时。 冷却， 浓縮， 粗品经制备板 分离得目标化合物 80mg， 产率 44°/。。 化合物 108: !H NMR (400 MHz, DMSO-d6) δ 13.18 (s, 1Η), 7.37 - 7.26 (m, 4H), 7.26 - 7.19 (m, 1H), 5.00 (s, 1H), 3.68 (s, 2H), 3.57 (d, J= 5.4 Hz, 2H), 3.31 - 3.18 (m, 2H), 2.91 (s, 4H), 2.77 - 2.58 (m, 7H), 2.56 (d, J= 4 1 Hz, 2H), 2.53 (s, 3H)
化合物 109-112的合成方法同化合物 107， 如表 6所示。
表 6： 化合物 109-112
Figure imgf000072_0002
实施例 30: 化合物 2-(((2-(4-(2-羟乙基)哌嗪 -1-基)乙基)氨基)亚甲基 )-4a,9, 10,10a-四氢菲 咯
Figure imgf000072_0001
步骤 1 : 化合物 3-(2-溴苯基)丙烯酸乙酯的合成
将 2-溴苯甲醛 (2.0g， 10.8mmol)、磷酰基乙酸三乙酯 (2.66g， 11.9mmol)和氢氧化锂 (285mg， 11.9mmol)溶于无水 THF溶液 (14mL)， 室温反应 3.5小时， 反应完毕将反应混合物倒入冰水 中， DCM萃取， 有机相用水洗涤， 硫酸钠干燥， 浓縮， 粗品经柱层析分离纯化得目标化合 物 2.59g， 产率 94%。
71
更正页 （细则第 91条） ISA CN 步骤 2: 化合物 3-(2-(4-氧代戊基)苯基)丙烯酸乙酯的合成
氮气保护下，将化合物 3-(2-溴苯基)丙烯酸乙酯 (l .OOg, 3.92 mmol) 戊 -4-烯 -2-醇 (843 mg, 9.8 mmol)， 醋酸钯 (44mg， 0.2mmol)、 DIPEA(4.00g， 31mmol)和氯化锂 (167mg， 3.94mmol) 溶解于干燥 DMF溶液 (ΙΟΟπιΙ 中， 80°C下反应 48小时。 反应完毕， 冷却至室温， 倒入冰水 中， 用甲基叔丁基醚萃取， 有机相用水洗涤， 硫酸钠干燥， 浓缩， 粗品经柱层析分离纯化得 目标化合物 612mg， 产率 60%。
步骤 3 : 化合物 4a,9,10, 10a-四氢菲咯啉 -1,3(2H， 4H)-二酮的合成
将 3-(2-(4-氧代戊基)苯基)丙烯酸乙酯（195mg， 0.75mmol)和钠氢 (60%， 100mg， 2.5mmol) 溶解于无水 THF溶液 (12mL)中， 室温反应过夜。反应完毕， 0°C下将反应混合物在缓慢倒入 1N盐酸 (20mL)中， EA萃取， 有机相用水洗涤， 硫酸钠干燥， 浓缩， 粗品经柱层析分离纯化 得目标化合物 74mg， 产率 46%。
步骤 4:化合物 2-(((2-(4-(2-羟乙基)哌嗪 -1-基)乙基)氨基)亚甲基 )-4a,9, 10,10a-四氢菲咯啉 -1,3(2H, 4H)-二酮的合成
操作步骤同实施例 2。化合物 113： ¾ NMR (400 MHz, CD3OD) δ 8.26 (s, 1H)， 7.30 (d, J = 7.6 Hz, I H), 7.13 (m, 3H), 3.88 - 3.77 (m, 2H), 3.63 (t, J = 5.7 Hz, 2H), 3.28 - 2.72 (m, 12H), 2.72 - 2.64 (m, 2H), 2.61 - 2.35 (m, 3H), 1.62 - 1.47 (m， 1H)。
实施例 30B: 化合物 5-((2R， 3S， 4R， 5R)-3,4-二羟基 -5-(6-吗啉代 -9H-嘌呤 -9-基)四氢呋 喃 -2-基) -2-«(2-p- -1-基)乙基)氨基)亚甲基)环己垸 -1,3-二酮 (；化合物 1 14)的合成
Figure imgf000073_0001
将 5-( 3AR， 4R， 6R， 6AR 2,2-二甲基 -6-(6-吗啉代 -9H-嘌呤 -9-基)四氢呋喃并 [3,4-D] [1，3]二氧杂环戊烯 -4-基) -2-(((2-(4-(2-羟乙基)哌嗪 -1 -基）乙基)氨基)亚甲基)环己 -I,3-二酮 (120mg, 0.187mmol)加入到 lmL甲酸和 lmL ^K中， 加热至 50°C反应 4小时。反应完毕降至 室温， 倒入冰水中， 调节 pH至 9-10， DCM萃取， 有机相用无水硫酸钠干燥， 浓缩， 粗品 经制备板分离得目标化合物 73mg，产率 65°/。。化合物 114: NMR (400 MHz, CD3OD) δ 8.24 (s, IH), 8.19 (s, IH), 8.15 (s, 1H)， 5.94 (d, J = 4.9 Hz, IH), 4.72 (t, J = 5.3 Hz, IH), 4.38 (s, IH), 4.26 (s, 4H), 3.88 (t, J = 5.7 Hz, IH), 3.82 - 3.75 (m, 4H), 3.70 (t， J= 5.9 Hz, 2H), 3.57 (t, J= 5.8 Hz, 2H), 2.71 - 2.36 (m, 17H)。
实施例 31 : 化合物 4-苄基 -2-(((2-(4-(2-羟乙基)哌嗪 -1-基)乙基)氨基) -亚甲基)环戊垸 -1 ,3- 二酮 (；化合物 115)的合成
更正页 （细则第 91条） ISA/CN
Figure imgf000074_0001
步骤 1 : 化合物 5-苄基 -3-乙氧基环戊 -2-烯 -1-酮的合成
氮气保护， 在 -60°C下， 将 LDA(l mol / L的 THF溶液， 5mL, 5mmol)滴加至 3-乙氧 基环戊 -2-烯 -1 -酮 (500mg， 4mmol)的无水 THF溶液 (15mL)中， 在此温度下搅拌 30分钟后加 入苄溴 (855mg， 5mmol)， 继续反应 3 小时。 反应完毕， 将反应混合物倒入饱和氯化铵水溶 液中， DCM萃取， 有机相用水洗涤， 硫酸钠干燥， 浓缩， 粗品经柱层析分离纯化得目标化 合物 540mg， 产率 63%。
步骤 2: 化合物 4-苄基环戊烷 -1 ,3-二酮的合成
将 5-苄基 -3-乙氧基环戊 -2-烯 -1-酮 (300mg， 1.38mmol)和硝酸铈铵 (152mg， 0.27mmol)加 入到 5mL乙腈和 5mL水中， 加热回流 4小时。反应完毕降至室温，倒入水中， DCM萃取， 有机相干燥， 浓缩， 粗品经柱层析分离得到 160mg， 产率 62°/。。
步骤 3 :化合物 4-苄基 -2-(((2-(4-(2-羟乙基)哌嗪 -1-基)乙基)氨基)亚甲基)-环戊垸 -1,3-二酮 的合成
操作步骤同实施例 2。化合物 115 : !H NMR (400 MHz, CD3OD) δ 7.86 (s， 1 Η), 7.27-7.17 (m, 5H), 3.71 (t, J = 6.0Hz, 2H), 3.59 (t, J = 6.0Hz, 2H), 3.18-3.14 (m, 1H), 2.94-2.88 (m, 1H), 2.74-2.60 (m, 13H), 2.51-2.45 (ra, 1 H), 2.24-2.18 (m, 1H); MS: 372.2 [Μ+1]·。
实施例 32: 化合物 2-(((2-(4-(2-羟乙基)哌嗪 -1 -基)乙基)氨基)亚甲基 )-4-甲基 -5-苯基环己 烷 -1,3-二
Figure imgf000074_0002
步骤 1 : 化合物 4-甲基 -5-苯基 -1,3-环己二酮的合成
氮气保护， 在 0°C下将叔丁醇钾 (831mg， 7.4mmol)加入到丁 -2-酮 (5mL)中， 在该温度下 搅拌 10分钟后，加入肉桂酸甲酯 (1.00g， 6.17mmol)。将反应混合物升温至室温反应 30分钟， 反应完毕。 将反应混合物倒入冰水中， 用 1N盐酸将 PH调节至 7， EA萃取， 有机相用水洗 涤， 干燥， 浓缩， 粗品经柱层析分离得目标化合物 510mg， 产率 41%。
步骤 2: 化合物 2-(((2-(4-(2-羟乙基)哌嗪 -1 -基)乙基)氨基)亚甲基 )-4-甲基 -5-苯基环己烷 -1,3-二酮的合成
操作步骤同实施例 2。 化合物 116: ¾ MR (400 MHz, CD3OD) δ 8.35 - 8.13 (m, 1H),
7.44 - 7.08 (m, 5H), 3.67 (t，J = 6.0 Hz, 2H), 3.63 - 3.55 (m, 2H), 3.06 - 2.43 (m, 16H), 0.97 (dd,
J= 12.6, 6.6 Hz, 3H); MS: 386.2 [M+l ]。
实施例 33: 化合物 1- (羟甲基) -4-苯基哌啶 -2,6-二酮 (化合物 117)的合成
73
更正页 （细则第 91条） ISA/CN
Figure imgf000075_0001
步骤 1 : 化合物 4-苯基哌啶 -2,6-二酮的合成
将 3-苯基戊二酸 (5.0g， 24mm0l)和脲 (25g)的混合物在 160°C下反应 3小时， 反应完毕， 将反应混合物缓慢倒入冰水中， EA萃取， 有机相用水洗涤， 硫酸钠干燥， 浓缩， 粗品经柱 层析分离得目标化合物 3.6g， 产率 79%。
步骤 2: 化合物 1- (羟基甲基) -4-苯基哌啶 -2，6-二酮的合成
将 4-苯基哌啶 -2,6-二酮 (800mg， 4.22mmol)和 35°/。甲醛溶液(101^1^)加热至 100°C， 直到 所有固体溶解。反应完毕降至室温，倒入水中， EA萃取，合并的有机相，无水硫酸钠干燥， 浓缩， 粗品经柱层析分离得目标化合物 513mg， 产率 55%。化合物 117: !HNMR (DMSO-i/6) δ 7.31 -7.34(m, 5H), 6.10(t, J =7.6Hz, IH), 5.06(d, J =7.6Hz, 2H), 3.41 -3.33(m, IH), 2.97-2.90(m, 2H), 2.82-2.77(m, 2H), MS: 220.1 [M+l]。
实施例 34: 化合物 119-129, 131 -143, 145-150, 155-156, 158, 160-165, 169-180, 182-197, 200-233, 236-243, 245-260, 262-274, 276-291, 293-311, 315, 317-318, 320-347和 349-414的合 成
除了使用相应的取代 1， 3-环己二酮或其他具有活性亚甲基的类似化合物 (如实施例 9-1)， 下列化合物的合成方法同上（如化合物 8)， 如表 7所示。
表 7
Figure imgf000075_0002
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更正页 （细则第 91条） ISA/CN
Figure imgf000076_0001
Figure imgf000077_0001
ΖΪ8而 8Ϊ0Ζ OAV LL
Figure imgf000078_0001
9M7Z.80/8T0ZN3/X3d ΖΪ8而 8Ϊ0Ζ OAV 8/,
Figure imgf000079_0001
ΖΪ8而 8Ϊ0Ζ OAV 6L
Figure imgf000080_0001
ΖΪ8而 8Ϊ0Ζ OAV iHNMR (400 MHz, DMS0-d6) δ 11.24 - 广 Η。 11.13 (m, IH), 8.31 (s, 2H), 8.21 (d, J =
14.2 Hz, IH), 8.00 (s, IH), 7.32 (d, J = 4.4
((2,6-二氧代 -4-苯
Hz, 4H), 7.27 - 7.19 (m, IH), 4.70 (p, J = 基亚环己基）甲
174 7.2 Hz, IH), 4.45 - 4.35 (m, IH), 4.33 - 基) -L-丙氨酸盐酸
±h 4.24 (m, IH), 3.58 (dd, J= 9.2, 3.7 Hz, IH),
3.35 - 3 30 (m, IH), 3+ 10 (d, J = 4+5 Hz, 2H), 2.93 - 2.66 (m, 3H), 2.59 - 2.53 (m, IH), 1.53 (d, J= 7.1 Hz, 3H).
'HNMR (400 MHz, DMS0-d6) δ 10.88 - 10.77 (m, IH), 8.32 (s, 3H), 8.10 (d, J =
2-((((2-氨基乙基） 14.4 Hz, IH), 7.32 (d, J= 4.3 Hz, 4H), 7.28 氨基）亚甲基 )-5- (dd, J = 37.6, 4.3 Hz, 5H), 7.23 (d, J = 4.3
175
苯基环己垸 -1,3- Hz, IH), 3.73 (d, J = 6.1 Hz, 2H), 3.31 (tt, J 二酮盐酸盐 = 11.5, 4.0 Hz, IH), 3.06 (dd, J = 11.4, 5.6
Hz, 2H), 2.73 (dt, J = 28.6, 14.1 Hz, 2H), 2.53 (d, J= 13.3 Hz, 2H).
'HNMR (400 MHz, CDC13) δ 11.21 (s, IH),
N-(2-(((2,6-二氧代 8.14 (d, J = 14.0 Hz, IH), 7.35 (t, J = 7.4 -4-苯基亚环己基） Hz, 2H), 7.24 (t, J = 6.7 Hz, 3H), 6.03 (s,
176
甲基）氨基）乙基） IH), 3.59 (dd, J = 11.7, 5.8 Hz, 2H), 3.49 乙酰胺 (dd, J = 11.5, 5.7 Hz, 2H), 3.42 - 3.30 (m,
IH), 2.82 - 2.59 (m, 4H), 2.02 (s, 3H).
'HNMR (400 MHz, CDC13) δ 11.22 (s, IH),
(2-(((2,6-二氧代
Boc 8.12 (d, J = 13.9 Hz, IH), 7.34 (t, J = 7.4 -4-苯基亚环己基）
Hz, 2H), 7.27 - 7.20 (m, 3H), 3.58 (s, 2H),
177 甲基）氨基）乙
3.46 (t, J = 5.7 Hz, 2H), 3.41 - 3.29 (m, 基)（甲基）氨基甲
IH), 2.89 (s, 3H), 2.81 - 2.60 (m, 4H), 1.46 酸叔丁酯
(s, 9H).
iHNMR (400 MHz, DMS0-d6) δ 11.14 - 11.02 (m, IH), 8.31 (s, 3H), 7.97 (d, J =
((2,6-二氧代 -4-苯 14.0 Hz, IH), 7.40 - 7.06 (m, 10H), 4.94 基亚环己基）甲
(td, J = 8.9, 4.6 Hz, IH), 4.41 (dd, J = 12.1,
178 基) -L-苯丙氨酸盐
3.2 Hz, IH), 4.29 (dd, J = 12.1, 2.6 Hz, IH), 酸盐的 2-氨基乙
3.26 (ddd, J = 19.7, 11.0, 3.5 Hz, 2H), 3.13 基酯
Figure imgf000081_0001
(s, 2H), 2.82 - 2.61 (m, 2H), 2.54 (s, IH),
2.44 (s, 2H).
((甲氧基氨基） H NMR (400 MHz, DMSO d6) 812.36(br,
2-
180 亚甲基 (s,
)-5-苯基环 IH), 8.16(s, IH), 7.32-7.20(m, 5H), 3.83
3H), 3.41- 3.33(m, IH), 2.84- 2.77(m, 2H), 己垸 -1,3-二酮 2.61-2.57(m, 2H); MS: 246.1 [M+1].
2-(((2-(4-(2-羟 乙 'H NMR (400 MHz, CD3OD) δ 8.19(s, IH), 〜 基）哌嗪 -1-基）乙 3.68 (t, J= 6.1 Hz, 2H), 3.58 ((t, J= 5.9 Hz,
182 基）氨基）亚甲 2H), 2.94 (m, IH), 2.67-2.47(m, 11H), 2.35 基） -5,5-二甲基环 (d, J= 14.8 Hz, 4H) 1 04 (s, 6H); MS: 324.2 己烷 -1,3-二酮 [M+1]. ΐ8
Figure imgf000082_0001
ΖΪ8而 8Ϊ0Ζ OAV
Figure imgf000083_0001
Figure imgf000084_0001
ΖΪ8而 8Ϊ0Ζ OAV 】Η ΝΜΙ (400 ΜΗζ， cdcl3) δ 1 1.31, 11.13
0 2-(((2-(二甲基氨 (2s, IH), 8.24, 8.17(2d, J= 14.7 Hz, IH), 基）乙基）氨基）亚 7.37 - 7.27 (m, 5H), 5.08, 4.96 (2dd, J = 甲基) -4-氟 -5-苯基 8.6, 2.8 Hz, IH), 3.65 - 3.48 (m, 3H), 3.18 - 环己垸 -1,3-二酮 3.07 (m, IH), 2.81 - 2.69 (m, IH), 2.55 (t, J
= 6.1 Hz, 2H), 2.28 (d, J = 2.1 Hz, 6H)
'HNMR (400 MHz, CD3OD) δ 8.22 (s, IH),
0 H ° ((2,6-二氧代 -4-苯 7.37 - 7.26 (m, 4H), 7.26 - 7.19 (m, IH), 基亚环己基）甲基） 4.29 (s, 2H), 3.96 (s, 2H), 3.42 - 3.33 (m, 甘氨酰甘氨酸 IH), 2.80 (ddd, J = 23.7, 16.8, 11.6 Hz, 2H),
2.71 - 2.63 (m, 2H)
'HNMR (300 MHz, CDC13) δ 11.24 (s, IH),
H 2-((((2-(4-异丁酰 8.19 (d, J = 14.4 Hz, IH), 7.38 - 7.29 (m, o o 基哌嗪 -1 -基）乙 2H), 7.26 (s, IH), 7.23 (d, J = 8.0 Hz, 2H), 基）氨基）亚甲 3.67 (s, 2H), 3.60 - 3.47 (m, 4H), 3.35 (s, 基) -5-苯基环己垸 IH), 2.83 - 2.70 (m, 4H), 2.64 (dd, J = 11.8, -1,3-二酮 5.7 Hz, 2H), 2.49 (s, 4H), 1.12 (d, J = 6.7
Hz, 6H)
'HNMR (300 MHz, CDC13) δ 11.26 (s, IH),
H 5-苯基 -2-((((2-(4- 8.19 (d, J = 14.4 Hz, IH), 7.34 (t, J = 7.3 ^。 新戊酰基哌嗪 -1- Hz, 2H), 7.23 (d, J = 8.4 Hz, 3H), 3.69 (s, 基）乙基）氨基）亚
4H), 3.52 (d, J = 5.9 Hz, 2H), 3.35 (s, IH), 甲基)环己垸 -1,3-
0 2.75 (q, J = 8.6 Hz, 4H), 2.63 (dd, J = 13.9, 二酮
7.8 Hz, 2H), 2.49 (s, 4H), 1.27 (s, 9H).
'HNMR (300 MHz, CDC13) δ 11.39 (s, IH), 8.19 (d, J = 14.7 Hz, IH), 7.33 (d, J = 7.3
H 2-(((2-(4-(3- 甲 基
Hz, 2H), 7.26 (s, IH), 7.23 (d, J = 7.8 Hz, 丁酰基）哌嗪 -1- 2H), 3.67 (s, 2H), 3.53 (s, 4H), 3.36 (s, IH), 基）乙基）氨基）亚
2.77 - 2.69 (m, 2H), 2.69 - 2.58 (m, 2H), 甲基) -5-苯基环己
2.49 (s, 4H), 2.20 (d, J = 6.7 Hz, 2H), 2.15 - 垸 -1,3-二酮
2.03 (m, IH), 1.77 - 1.51 (m, 2H), 0.96 (d, J = 6.3 Hz, 6H)
'HNMR (300 MHz, CDC13) δ 11.30(m, IH),
H 4-(2-(((2,6-二氧代
8.17 (d, J = 14.9 Hz, IH), 7.26 - 7.24 (m, o ί ,ο -4-苯基亚环己基）
IH), 7.13 (s, 4H), 3.51 (d, J = 6.0 Hz, 2H), 甲基）氨基）乙
3.30 (s, 5H), 2.81 (s， 6H)， 2.72 (d, J = 6.8 基) -N， N-二甲基
Hz, 3H), 2.66 - 2.57 (m, 2H), 2.49 (s, 4H), 哌嗪 -1-甲酰胺
2.33 (s, 2H)
'HNMR (300 MHz, CDC13) δ 11.25 (s, IH),
5-苯基 -2-(((2-(4- 8.19 (d, J = 14.3 Hz, IH), 7+40 - 7.29 (m, 丙酰基哌嗪 -1-基:） 2H), 7.23 (d, J = 8.2 Hz, 3H), 3.66 (s, 2H), 乙基）氨基）亚甲 3.51 (s, 4H), 3.36 (s, IH), 2.75 (d, J = 7.3 基）环己垸 -1,3-二 Hz, 2H), 2.64 (dd, J = 12.2, 6.2 Hz, 2H),
Figure imgf000085_0001
酮 2.49 (s, 4H), 2.34 (q, J = 7.5 Hz, 2H), 1.25
(s, 2H), 1.14 (t, J = 7.4 Hz, 3H) 'HNMR (300 MHz, CDC13) δ 11.25 (s, IH),
2-(((2-(4-苯甲酰基 8.21 (d, J = 14.7 Hz, IH), 8.10 (d, J = 7.6 哌嗪 -1-基）乙基） Hz, 2H), 7.48 (d, J = 7.7 Hz, IH), 7.40 (s,
216 氨基）亚甲基）-5- 4H), 7.32 (d, J = 7.1 Hz, IH), 7.23 (d, J = 苯基环己垸 -1,3- 7.7 Hz, 2H), 3.85 (s, 2H), 3.54 (d, J = 5.8
Figure imgf000086_0001
二酮 Hz, 4H), 3.36 (s, IH), 2.84 - 2.69 (m, 4H),
2.64 (d, J = 13.3 Hz, 4H), 2 48 (s 2H)
'HNMR (300 MHz, CDC13) δ 11.26 (s, IH),
H 2-(((2-(4-(4-硝基 8.29 (d, J = 8+4 Hz, 2H), 8.19 (d, J = 14.3 苯甲酰基)哌嗪 -1- Hz, IH), 7.57 (d, J = 8.5 Hz, 2H), 7.33 (d, J
217 基）乙基）氨基）亚 = 7.1 Hz, 2H), 7.22 (s, 3H), 3.86 (s, 2H), y H N02 甲基) -5-苯基环己 3.53 (d J = 5.8 Hz, 4H), 3.42 (s, 2H), 3.38 - 烷 -1,3-二酮 3.28 (m, IH), 2.83 - 2.69 (m, 4H), 2.65 (d, J
= 6.0 Hz, 4H), 2.47 (s, 2H)
'HNMR (300 MHz, CDC13) δ 11.22 (s, IH),
2-(((2-(4-(甲基磺
8.18 (d, J = 14.3 Hz, IH), 7.37 - 7.30 (m, 酰基）哌嗪 -1-基）
2H), 7.23 (d, J = 7.9 Hz, 3H), 3.60 - 3.46
218 乙基）氨基）亚甲
(m 2H), 3.36 (d, J = 5.5 Hz, IH), 3.28 (s, 基) -5-苯基环己垸
4H), 2.79 (s, 3H), 2.75 (d, J = 7.5 Hz, 2H), -1,3-二酮
2.72 - 2.63 (m, 4H), 2.67 - 2.59 (m, 4H)
'HNMR (300 MHz, CDC13) δ 11.25 (s, IH),
2-(((2-(4-(4-氯苯
8.18 (d, J = 14.3 Hz, IH), 7.37 (d, J = 6.6 甲酰基）哌嗪 -1- Hz, 5H), 7.24 (d, J = 12.4 Hz, 4H), 3.81 (s,
219 基）乙基）氨基）亚
2H), 3.51 (s, 4H), 3.40 - 3.29 (m, IH), 2.83 甲基) -5-苯基环己
Figure imgf000086_0002
- 2.67 (m, 4H), 2+65 (s, 2H), 2.62 - 2.35 (m, 垸 -1,3-二酮
4H)
'HNMR (300 MHz, CDC13) δ 11.26 (s, IH),
H 2-(((2-(4-(4-溴苯 8.18 (d, J = 14.1 Hz, IH), 7.55 (d, J = 7.7 甲酰基）哌嗪 -1- Hz, 2H), 7.38 - 7.27 (m, 4H), 7.23 (d, J =
220 基）乙基）氨基）亚 7.4 Hz, 3H), 3.81 (s, 2H), 3.52 (d, J = 5.7 甲基) -5-苯基环己 Hz, 4H), 3.36 (s, IH), 2.82 - 2.68 (m, 4H), 垸 -1,3-二酮 2.65 (d, J = 6.4 Hz, 2H), 2.51 (d, J = 29.1
Hz, 4H)
5- 苯 基 'HNMR (300 MHz, CDC13) δ 11.19 (s, IH), -2-(((2-(4-(2-苯基 8.16 (d, J = 14.4 Hz, IH), 7.38 - 7.28 (m, 乙酰基）哌嗪 -1- 5H), 7.23 (d, J = 7.7 Hz, 5H), 3.73 (s, 2H),
221
基）乙基）氨基）亚 3.69 (s, 2H), 3.48 (d, J = 5.4 Hz, 4H), 3.35 甲基)环己烷 -1,3- (s, IH), 2.81 - 2.63 (m, 4H), 2.57 (t, J = 5.6
Figure imgf000086_0003
二酮 Hz, 2H), 2.45 (s, 2H), 2.30 (s, 2H)
'HNMR (300 MHz, CDC13) δ 11.26 (s, IH),
2-((((2-(4-烟酰基 8.66 (s, 2H), 8.18 (d, J = 14.4 Hz, IH), 7.75 哌嗪 -1-基）乙基） (d, J = 7.9 Hz, IH), 7.35 (dd, J = 15.1, 7.6
222 氨基）亚甲基）-5- Hz, 4H), 7.25 - 7.19 (m, 2H), 3.86 (s, 2H), 苯基环己烷 -1,3- 3.52 (d, J = 5.4 Hz, 4H), 3.38 (s, IH), 2.85 -
0 二酮 2.70 (m, 4H), 2.65 (d, J = 6.0 Hz, 4H), 2.51
(t, J= 29.8 Hz, 2H)
Figure imgf000087_0001
'HNMR (300 MHz, CDC13) δ 11.20 (s, 2Η),
2-(((2-(4-(3-羟丙
8.16 (d, J = 14.4 Hz, IH), 7.18 - 7.06 (m, 基）哌嗪 -1-基）乙
4H), 3.84 - 3.72 (m, 2H), 3.49 (dd, J= 11.6,
230 基）氨基）亚甲
5.8 Hz, 2H), 3.31 (d, J = 5.9 Hz, IH), 2.87 - 基) -5- (对甲苯基）
2.50 (m, 14H), 2.33 (s, 3H), 1.85 - 1.72 (m, 环己烷 -1,3-二酮
2H)
4-(2-(((2,6-二氧代 'HNMR (300 MHz, CDC13) δ 11.28 (m, —4- (对甲苯基）亚 IH), 8.17 (d, J = 14.2 Hz, IH), 7.32 (d, J = 环己基）甲基）氨 7.8 Hz, 3H), 7.13 (d, J = 3.2 Hz, 6H), 3.87
231
基）乙基) -N-苯基 (s, 4H), 3.50 (s, 2H), 3.36 - 3.26 (m, IH), 哌嗪 -1-硫代甲酰 2.81 - 2.65 (m, 4H), 2.64 (s, 2H), 2.57 (s, 胺 4H), 2.33 (s, 3H)
'HNMR (300 MHz, CDC13) δ 11.21 (s, IH),
H 8.18 (d, J = 14.4 Hz, IH), 7+ 14 (d, J = 10.6
2-(((2-(4-丙烯酰基 Hz, 4H), 6.55 (dd, J = 16.4， 10.9 Hz, IH), 哌嗪 -1-基）乙基） 6.28 (d, J = 16.8 Hz, IH), 5.69 (d, J = 10.5
232 氨 基 ） 亚 甲 Hz, IH), 3.73 (s, 2H), 3.57 (d, J = 22.5 Hz, 基) -5- (对甲苯基) 2H), 3.57 - 3.43 (m， IH), 3.30 (d, J = 6.0 环己烷 -1,3-二酮 Hz, 2H), 2.83 - 2.65 (m, 4H), 2.63 (t, J =
5.4 Hz, 2H), 2.55 - 2.42 (m, 4H), 2.33 (s, 3H)
】H NMR (300 MHz, CDC13) δ 11.28 (m,
2-(((2-(4-甲基丙烯 IH), 8.18 (d, J = 14.0 Hz, IH), 7.15 (d, J = 酰基哌嗪 -1-基）乙 10.7 Hz, 4H), 5.19 (s, IH), 5.02 (s, IH),
233 基）氨基）亚甲 3.63 (s, 4H), 3.52 (d, J = 5.8 Hz, 2H), 3.31 基) -5- (对甲苯基) (s, IH), 2.80 - 2.69 (m, 4H), 2.62 (d, J= 5.6 环己垸 -1,3-二酮 Hz, 2H), 2.49 (s, 4H), 2.33 (s, 3H), 1.94 (s,
3H)
'HNMR (300 MHz, CDC13) δ 11.20 (s, IH),
5-苯基 -2-(((2- (哌 8.17 (d, J = 14.0 Hz, IH), 7.32 (d, J = 7.3
Hz, 2H), 7.24 (t, J = 6.7 Hz, 3H), 3.48 (d, J
236
基：)亚甲基:)环己垸 = 7.0 Hz, 2H), 3.41 (s, 4H), 3.41 (s, 2H),
Figure imgf000088_0001
-1,3-二酮 3.08 (s, 2H), 2.74 (d, J = 7.1 Hz, 2H), 2.64
(s, 4H), 2.52 (s, IH)
2-(((2- (哌嗪 -1-基） 'HNMR (300 MHz, CDC13) δ 11.31 - 11.16 il k/NH
乙基）氨基）亚甲 (m， 2H), 8.14 (s， IH), 7.13 (s, 4H), 3.51 (s,
237
基) -5- (对甲苯基） 3H), 3.38 - 3.27 (m, 2H), 3.12 (s, 4H), 2.71 环己烷 -1,3-二酮 (s, 4H), 2.43 (s, 6H), 2.33 (s, 3H)
N 、、 2-(((2-(4-乙基哌嗪 'HNMR (300 MHz, CDC13) δ 11.20 (s, IH),
-1-基）乙基)氨基） 8.16 (d, J = 14.3 Hz, IH), 7.13 (s, 4H), 3.45
238 亚甲基）-5- (对甲 (t, J = 23.7 Hz, 2H), 3.31 (d, J = 5.3 Hz, 苯基)环己烷 -1,3- IH), 2.83 - 2.53 (m, 16H), 2.32 (s, 3H), 二酮 1.20 (t, J= 7.2 Hz, 3H)
Figure imgf000089_0001
ΖΪ8而 8Ϊ0Ζ OAV H 5 -(4- 氯 苯 'HNMR (300 MHz, CDC13) δ 11.22 (s, IH),
C Jl a L N N J 基) -2-(((2-(4- (吗啉 8.17 (d, J = 14.5 Hz, IH), 7.29 (t, J = 7.7
-4-羰基）哌嗪 -1- Hz, 2H), 7.15 (d, J = 8.4 Hz, 2H), 3.66 (d, J
249
基）乙基）氨基）亚 = 4.4 Hz, 4H), 3.51 (d, J = 6.0 Hz, 2H), 3.34 甲基)环己烷 -1,3- (s, 5H), 3.25 (d, J= 4.3 Hz, 4H), 2.79 - 2.55 z 二酮 (m, 6H), 2.49 (s, 4H)
'HNMR (400 MHz, CDC13) δ 8.09 (s, IH),
5-(2,3-二氢苯并呋 7.09 (s, IH), 6.99 (d, J = 8.1 Hz, IH), 6.75 ( S 0
喃 -5-基) -2- ((二甲 (d, J= 8.2 Hz, IH), 4.58 (t, J = 8.7 Hz, 2H),
251
基氨基)亚甲基)环 3.44 (d, J = 5.0 Hz, 3H), 3.31 (ddd, J= 16.2, 己垸 -1,3-二酮 11.6, 4+4 Hz, IH), 3.26 - 3.16 (m, 5H), 2.70
(qd, J= 16.6, 8.1 Hz, 4H)
'HNMR (400 MHz, CDC13) δ 8.10 (d, J = o 4-(4-((二甲基氨
5.5 Hz, IH), 8.02 (d, J = 7.9, 6 1 Hz, 2H), 基)亚甲基 )-3,5-二
252 7.37 - 7.30 (d, 2H), 3.96 - 3.84 (s, 3H), 氧代环己基)苯甲
3.44 (t, J = 8.5 Hz, 4H), 3.24 (s, J = 5.6 Hz, 酸甲酯
3H), 2.74 (m, J= 16.9, 5.3 Hz, 4H)
3-(4-((二甲基氨 'HNMR (400 MHz, CDC13) δ 8.11 (s, IH), 基)亚甲基 )-3,5-二 7.97 (s, IH), 7.94 (d, J = 7.1 Hz, IH), 7.49 -
253
氧代环己基)苯甲 7.40 (m, 2H), 3.94 (s, 3H), 3.52 - 3.35 (m,
COOMe 酸甲酯 4H), 3.25 (s, 3H), 2.84 - 2.63 (m, 4H)
2- ((二甲基氨基） 'HNMR (400 MHz, CDC13) δ 8.10 (s, IH), 亚甲基）-5-(4-(三 7.61 (d J = 8+0 Hz, 2H), 7.38 (d, J = 7.9 Hz,
254
氟甲基)苯基)环己 2H), 3.45 (s, 4H), 3.24 (s, 3H), 2.84 - 2.62
Figure imgf000090_0001
垸 -1,3-二酮 (m 5H)
o 2- ((二甲基氨基） 'HNMR (400 MHz, CDC13) δ 8.10 (s, IH), 亚甲基）-5-(3-(三 7.54 - 7.49 (m, 2H), 7.48 (d, J = 7.8 Hz,
255
氟甲基)苯基)环己 IH), 7.46 (s, IH), 3.51 - 3.35 (m, 4H), 3.24 垸 -1,3-二酮 (s, 3H), 2.75 (qd, J= 16.5, 8.1 Hz, 4H)
'HNMR (400 MHz, CDC13) δ 8.07 (s, IH),
N-(4-(4-((二甲基
7.94 (s, IH), 7.47 (d, J = 6.8 Hz, 2H), 7.18 氨基)亚甲基 )-3,5-
256 (d, J = 6.1 Hz, 2H), 3.40 (s, 3H), 3.33 (m, 代环己基)苯基)乙
IH), 3.21 (s, 3H), 2.69 (q, J = 15.7 Hz, 4H), 酰胺
2.16 (s, 3H)
'HNMR (400 MHz, CDC13) δ 8.56 (s, IH),
2- ((二甲基氨基）
8.53 (d, J = 4.5 Hz, IH), 8.11 (s, IH), 7.59 亚甲基）-5- (吡啶
257 (d, J = 7.9 Hz, IH), 7.32 - 7.29 (m, IH),
-3-基)环己烷 -1,3- 3.46 (s, 3H), 3.41 (dd, J= 11.2, 4.8 Hz, IH), 二酮
3.25 (s, 3H), 2.82 - 2.71 (m, 4H)
'HNMR (400 MHz, CDC13) δ 11.26 (s, IH), 8.21 (d, J = 14.4 Hz, IH), 8.03 (d, J = 8.2
4-(4-(((2-吗啉代乙
Hz, 2H), 7.33 (d, J = 8.2 Hz, 2H), 3.93 (s, 基）氨基）亚甲
258 3H), 3.80 - 3.72 (m, 4H), 3.55 (dd, J = 11.9, 基) -3,5-二氧环己
6.0 Hz, 2H), 3.46 (dd, J = 10.8, 5.8 Hz, IH), 基)苯甲酸甲酯
2.84 - 2.66 (m, 4H), 2.63 (t, J = 5.9 Hz, 2H), 2.53 (d, J= 4.1 Hz, 4H) 06
Figure imgf000091_0001
ΖΪ8而 8Ϊ0Ζ OAV
Figure imgf000092_0001
Z6
Figure imgf000093_0001
9M7Z.80/8T0ZN3/X3d ΖΪ8而 8Ϊ0Ζ OAV
Figure imgf000094_0001
Figure imgf000095_0001
Figure imgf000096_0001
Figure imgf000097_0001
9M7Z.80/8T0ZN3/X3d ΖΪ8而 8Ϊ0Ζ OAV
Figure imgf000098_0001
86
Figure imgf000099_0001
9M7Z.80/8T0ZN3/X3d ΖΪ8而 8Ϊ0Ζ OAV 66
Figure imgf000100_0001
ΖΪ8而 8Ϊ0Ζ OAV 001
Figure imgf000101_0001
ΖΪ8而 8Ϊ0Ζ OAV ιοι
Figure imgf000102_0001
ΖΪ8而 8Ϊ0Ζ OAV
Figure imgf000103_0001
ΖΪ8而 8Ϊ0Ζ OAV eoi
Figure imgf000104_0001
ΖΪ8而 8Ϊ0Ζ OAV
Figure imgf000105_0001
501
Figure imgf000106_0001
9M7Z.80/8T0ZN3/X3d ΖΪ8而 8Ϊ0Ζ OAV
Figure imgf000107_0001
4- (羟基（苯基）甲
'HNMR (400 MHz, CD3OD ) δ 7.77 (s, 基) -2-(((2-(4-(2-羟
IH), 7.26 (m, 5H), 5.13 (d, J = 6.0 Hz, IH), 乙基）哌嗪 -1-基）
3.69 (t, J = 6.0 Hz, 2H), 3.55 (t, J = 5.7 Hz, 乙基）氨基）亚甲
2H), 3.13 (m, IH), 2.69 - 2.46 (m, 12H), 基）环戊垸 -1,3-二
Figure imgf000108_0001
2.33 (m, 2H); MS: 388.2 [M+1].
酮
5 -(5-溴 -1H-吲哚 】H NMR (400 MHz, CD3OD) δ 8.27 (s, -6-S)-2-(((2-(4-(2- IH), 7.78 (s, IH), 7.37 (s, IH), 7.25 (d, J = 羟乙基）哌嗪 -1- 3.2 Hz, IH), 6.38 (d, J = 2.4 Hz, IH), 3.90 - o m 基）乙基）氨基）亚 3.81 (m, IH), 3.72 (t, J = 5.9 Hz, 2H), 3.62 甲基)环己烷 -1,3- (t, J = 5.6 Hz, 2H), 2.72 (m, 16H); MS: 二酮 491.1 [M+1].
5-(2-溴 -5-羟基苯
¾ NMR (400 MHz, CD3OD) δ 8.27 (s, k J r 基) -2-(((2-(4-(2-羟
IH), 7.36 (d, J = 8.6 Hz, IH), 6.78 (d, J =
〇 r 乙基）哌嗪 -1-基）
2.9 Hz, IH), 6.60 (dd, J = 8.7, 2.8 Hz, IH), 乙基）氨基）亚甲
1 3.80 - 3.57 (m, 4H), 2.77 (m, 13H); MS:
L 基）环己烷 -1,3-二
467+0 [M+1],
酮
H 5 -(4-氯 -1H-吲哚
】H NMR (400 MHz, CD3OD) δ 8.27 (s, -3-¾)-2-(((2-(4-(2- IH), 7.36 - 7.26 (m, IH), 7.14 (s, IH), 7.03 Y U 羟乙基）哌嗪 -1- (m, 2H), 4.22 - 4.12 (m, IH), 3.77 (t, J = 基）乙基）氨基）亚
5.7 Hz, 2H), 3.63 (m, 2H), 3.03 - 2.63 (m, 甲基)环己垸 -1,3-
H 16H); MS: 445.1 [M+1] .
二酮
】H NMR (400 MHz, CD3OD) δ 8.55 (s,
7-氯 -3-(((5- (二乙 IH), 7.97 (d, J = 8.5 Hz, IH), 7.18 (d, J = 基氨基）戊 -2-基） 1.7 Hz, IH), 7.12 (dd, J = 8.5, 1.8 Hz, IH), 氨基)亚甲基)喹啉 3.81 (s, IH), 3.06 (m, 6H), 1.75 (d, J = 5.6 -2,4(1H, 3H)-二酮 Hz, 4H), 1.43 (d, J = 6.6 Hz, 3H), 1.30 - 1.18 (m, 6H); MS: 364.1 [M+1].
】H NMR (400 MHz, CD3OD) δ 8.28 (s,
2- ( 4- ( 2- ( ( ( 4- IH), 7.43 (d， J = 8.4 Hz, 2H), 7.26 (dd, J =
( 1H-吲哚 -4-基）
14.2, 5.7 Hz, 2H), 7.13 (d, J = 8.0 Hz, 2H), -2,6-二氧代亚环
7.06 (t, J= 7.7 Hz, IH), 6.88 (d, J = 7.3 Hz, 己基）甲基）氨基）
IH), 6.53 (d, J = 2.6 Hz, IH), 3.79 (m, IH), 乙基） 哌嗪 -1-基）
3.63 (m, 2H), 3.16 (s, 2H), 2.99 - 2.85 (m,
Figure imgf000108_0002
-N- (对甲苯基）
2H), 2.82 (m, 2H), 2.65 (s, 9H), 2.29 (s, 乙酰胺
3H).
2- ( ( ( 2- (二甲基 】H NMR (400 MHz, CDC13) δ 11.25 (s, IH),
Jl 氨基）乙基）氨基） 8.21 (d, J = 14.4 Hz, IH), 7.31 (s, IH), 7.25 、
ci o H 亚甲基）-5- (2,3,6- - 7.17 (m, IH), 4.41 (s, IH), 3.68 - 3.43 (m, 三氯苯基）环己垸 4H), 2.58 (t, J = 5.9 Hz, 2H), 2.48 (d, J = -1,3-二酮 16.7 Hz, 2H), 2.31 (s, 6H). 801
Figure imgf000109_0001
9M7Z.80/8T0ZN3/X3d ΖΪ8而 8Ϊ0Ζ OAV 601
Figure imgf000110_0001
9M7Z.80/8T0ZN3/X3d ΖΪ8而 8Ϊ0Ζ OAV
Figure imgf000111_0001
实施例 35化合物 415-452的合成
除了使用相应的取代 1， 3-环己二酮外， 化合物 415-452 的合成方法与实施例 4或 8相 同 （如化合物 3和 8)， 如表 8所示。
表 8 : 化合物 415-452
Figure imgf000111_0002
Figure imgf000112_0001
Figure imgf000113_0001
en
Figure imgf000114_0001
ΖΪ8而 8Ϊ0Ζ OAV
Figure imgf000115_0001
ill
Figure imgf000116_0001
ΖΪ8而 8Ϊ0Ζ OAV
Figure imgf000117_0001
实施例 36化合物 5- (((2- (4- (2-羟乙基)哌嗪- 1-基)乙基)氨基)亚甲基)噻唑烷 - 2，4-二酉同 (化合 物 200)的合成
Figure imgf000117_0002
步骤 1 : 5- (；乙氧基亚甲基) -2,4-噻唑烷二酮的合成
将 2，4-噻唑烷二酮 (2.8g， 23.93mmol),三乙氧基甲垸 (4mL)和乙酸酐 (6mL)的混合物加 热回流过夜， 反应完毕， 冷却至室温析出固体， 过滤， 收集滤液并浓缩， 得到目标化合物粗 品， 不经纯化直接用于下一步反应。
步骤 2: 化合物 5-(¾2-(4-(2-羟乙基)哌嗪 -1-基)乙基)氨基)亚甲基)噻唑垸 -2，4-二酮的合成 操作步骤同实施例 2(化合物 1)
实施例 37化合物 4- ((二甲基氨基)亚甲基 )-2-甲基 -2-苯基环丁垸 -1,3-二酮 (化合物 201)的 合成
Figure imgf000117_0003
步骤 1 : 2-苯基丙酰氯的合成
氮气保护， 在 0°C下， 氯化亚砜 (4.8g， 40.3mmol)滴加至 2-苯基丙酸 (2g， 13.3mmol) 的 DCM(20mL)溶液， 滴毕， 加入催化量 DMF， 将混合物回流反应 2小时并浓缩， 得到 2- 苯基丙酰氯粗品， 直接用于下一步反应。
步骤 2: 化合物 3-乙氧基 -4-甲基 -4-苯基环丁 -2-烯 -1-酮的合成
氮气保护下， 将乙氧基乙炔 (3.72g， 26.6mmol， 50%w / w己垸溶液)滴加至 2-苯基丙 酰氯 (13.3mmol)的乙醚 (40mL)溶液中， 向上述混合物滴加 TEA(2g， 19.8mmol), 室温搅拌 30 分钟后，将悬浮液加热回流反应 24小时。反应完毕，将所得混合物冷却，过滤，滤液浓缩， 通过柱层析分离纯化得目标化合物 600mg。
步骤 3 : 化合物 2-甲基 -2-苯基环丁垸 -1，3-二酮的合成
将化合物 3-乙氧基 -4-甲基 -4-苯基环丁 -2-炼-1-酮 (350mg， 1.73mmol)溶解在 2M盐酸 (5mL)和 THF(3mL)混合液中， 室温剧烈搅拌 48小时， 反应完毕， 用 DCM萃取， 将合并的 有机层干燥并浓缩， 得粗品 250mg， 直接用于下一步反应。
步骤 4: 化合物 4- ((二甲基氨基)亚甲基 )-2-甲基 -2-苯基环丁烷 -1,3-二酮 (化合物 201)的合 成
操作步骤同实施例 8(化合物 8)。化合物 201： Ή NMR (400 MHz, CDC13) δ 7.56 - 7.48 (m,
2H), 7.31 (m, 2H), 7.21 (m, 1H), 7.04 (s, 1H), 3.64 (s, 3H), 3.27 (s, 3H), 1.59 (s, 3H)。
实施例 38:化合物 2-(((2-(二甲基氨基)乙基)氨基)亚甲基 )-5-苯基环己垸 -1,3-二酮)氯化镍
(Π)络合物的合成
Figure imgf000118_0001
化合物 119
将化合物 119(2.86g， lOmmol)的甲醇溶液 (7.5mL)滴加至钠 (264mg， llmmol)的甲醇溶液 (20mL)中，室温下搅拌 10分钟，然后向上述混合液中加入氯化镍 (Π)-1，2-二甲氧基乙烷 (2.63g， 12mmoi;)的甲醇溶液 (10mL)。将混合物加热至 40°C并搅拌 2小时。浓縮， 将浓缩的粗品用丙 酮稀释并回流 1小时， 冷却， 滤出固体， 过滤， 滤渣用丙酮洗涤并干燥得目标化合物 Ug， 产率 290/0。 MS(ESI): [M-C1] +： 343.3; [M + CI] "： 413+2。
实施例 39: 2- (径基亚 - 5-苯基环己烧 -1,3-二酮钠盐 （化合物 463 ) 的合成
Figure imgf000118_0002
将化合物 3 (294mg)加到水 （ 8ml) 中， 加入 NaOH固体 （57mg，）室温搅拌过夜， 反 应液浓縮后乙醚打浆， 过滤， 得到黄色固体产物 （化合物 463 ) 267mg, 收率 83°/。。
在化合物 463中， Na与漦基氧形成配位键。
实施例 40化合物 453-462和 464的合成
除了使用对应的二酮化合物和碱以外， 化合物 453-462和 464 的合成方法与实施例 39 同， 如表 9所示。
表 9: 化合物 453-464 更正页 （细则第 91条） ISA/CN
Figure imgf000119_0001
Figure imgf000120_0001
在上述化合物中， Li、 Na或 K与羰基氧形成配位键。
实施例 41： 利用荧光偏振 (FP)法测试本发明的化合物对自噬相关蛋白 LC3B的调节。 荧光偏振 (FP)法测试实验
组蛋白 GST-LC3B (终浓度 180nM)(SEQ ID NO: l)和 Ν末端 FITC标记肽 (SEQ ID NO:2， 序列： FITC-GGDDDWTHLSSKEVD-NH2，终浓度 18nM)置于 FP缓冲液 (50mM HEPES pH7.5， O. lmg/ mL BSA, ImM DTT)中， 向其中加入使用 FP缓冲液梯度稀释的化合物， 然后将上述 混合物于 25 °C下在避光孵育。 监测荧光偏振值 (PerkinElmer Envision, 发射光波长 480rnn; 吸收光波长 535nm)， 并用 GraphPad Prism 6.0程序计算 IC5Q值， 测试结果如表 8所示。
化合物的 IC5Q值表示方法： ΙΟΟμΜ < IC50 < ImM被认为对 LC3B的活性较低 (；+); 化合 物 15μΜ < IC50 < ΙΟΟμΜ被认为是对 LC3B的活性中等 C++); 3μΜ < IC50 < 15μΜ被认为对 LC3B活性较高 (+++); IC50 < 3μΜ被认为对 LC3B具有高活性 (++++；)。 本发明化合物的 IC 值如表 10所示。
表 10：化合物 IC5o
编号 IC50 (μΜ) 编号 ICso (μΜ) 编号 IC50 (μΜ) 编号 ICso (μΜ) 编号 IC50 (μΜ) 编号 IC50 (μΜ)
1 + 2 +++ 4Α +++ 7 +++ 8 ++++ 9 +
10 + 11 + 12 + 14 + 15 +++ 17 +++
18 +++ 19 ++ 20 + 21 ++ 22 + 23 +++
24 + + 25 + 26 ++ 27 ++ 28 +++ 29 +
30 + 31 +++ 32 +++ 33 ++ 34 ++++ 35 ++
36 + 37 39 40 41 +++ 42 +++
43 +++ 44 ++ 45 ++ 46 47 +++ 48
49 50 51 ++ 52 ++ 53 ++ 54
55 ++ 56 +++ 57 ++ 58 ++ 59 + 61 ++++
62 +++ 63 ++ 64 + 65 + 66 ++++ 67 +
68 69 ++ 70 + 71 ++ 72 73
74 + + 75 +++ 76 ++ 77 ++ 78 ++ 79 +
80 ++ 81 ++ 82 ++ 83 ++ 84 ++ 85 ++
86 ++ 87 ++ 88 +++ 89 + 90 + 91 ++
92 ++ 93 +++ 94 ++ 95 ++ 96 + 97 ++
99 + 100 ++ 101 ++ 102 ++ 103 ++ 104 ++
106 + 107 ++ 108 + 109 + 110 + 111 +
112 ++ 113 + 114 + 115 +++ 116 ++++ 119 ++++
120 121 ++ 122 + 123 + 124 + 125 +
126 ++ 127 ++ 128 + 129 ++ 131 ++ 132 +
133 + 134 + 135 + 136 + 137 +++ 138 +
139 + 140 ++ 141 +++ 142 ++ 143 ++ 145 +
146 ++ 147 ++ 148 149 150 155 ++
156 +++ 158 + 160 十十 161 + 162 十十 163 十
164 +++ 165 + 169 +++ 170 +++ 171 +++ 172 +++
173 ++ 174 ++ 175 +++ 176 + 177 + 178 ++
180 + 182 + 183 + 184 + 185 ++++ 186 +++
187 188 +++ 189 190 ++ 191 192 +++
193 ++ 194 ++ 195 +++ 196 +++ 197 ++++ 198 ++
Figure imgf000122_0001
ΖΪ8而 8Ϊ0Ζ OAV 412 ++++ 413 +++ 414 +++ 415 416 417
418 419 420 421 422 423
424 +++ 425 ++ 426 ++++ 427 +++ 428 +++ 429 ++++
430 431 +++ 432 433 434 435
436 +++ 437 +++ 438 +++ 439 +++ 440 441
442 ++ 443 ++ 444 +++ 445 ++ 446 +++ 447 ++++
448 +++ 449 ++ 450 ++ 451 452 453
454 +++ 455 +++ 456 +++ 457 458 459
460 461 ++++ 462 +++ 463 +++ 464 +++ 本发明的化合物表现出对 LC3B的活性， 并且一些化合物对 LC3B具有高活性。 这些化 合物对 ATG8 的其它哺乳动物同源物也是有活性的。 因此， 这些化合物可以调节 LC3B和 ATG8的其他哺乳动物同源物， 用于治疗与自噬相关的疾病。
应理解， 在不脱离本发明范围和精神的情况下， 本领域技术人员可以对本发明进行各种 改动或修改， 这对于本领域技术人员是显而易见的， 这些等价形式同样落于本申请所附权利 要求书所限定的范围。

Claims

权 利 要 求
1、 一种通式①所示化合物或其药学上可接受的盐-
Figure imgf000124_0001
其中-
X和 Y各自独立地选自 0， S， NRa， NOH和 CH2 ;
U和 V各自独立地选自 C， S， SO和 PORa;
W、 Z和 T各自独立地选自 0， S， SO, S02， N， NRa, CO , C， CRa， 和 CH2;
m为 0， 1， 2或 3 ;
n为 0， 1， 2或 3 ;
选自氢， 氘， C1 -6烷基， C1-6羟基垸基， C1-6卤代垸基， 苯基和取代的苯基； R2表示为 -J-K-M-Q, 其中
— N A 4— — N A ,
J为 NRa， NORa， 0， S或 ， 其中 ^ 为含至少一个氮原子的二价 3-10 元杂环烷基或二价 3-7元杂环烯基；
K为共价键， NRa， CRcRc. 或 CReRc，CRcRc，；
M为共价键， 0^ ，， 二价 3-10元杂环烷基， 二价 3-7元杂环烯基或二价 5-10元杂芳
Q为氢， C1 -6垸基， C1-6羟基垸基， -(CH2)p-C(0)Rb， -(CH2)p-C(0) HRb , -(CH2)p-C(S)Rb， -(CH2)p-C(S)NHRb, -(CH2)p-S02Rb， -(CH2)p-S02NHRb,
p为 0， 1， 2或 3 ;
各 Re和 Rc'独立地选自氢， 羟基， 氨基， RaRa'， 卤素， 氰基， 硝基， 羧基， 甲酰基， 酰胺基， 酯基， C1-6卤代垸基， C1-6羟基烷基， C1-6杂垸基， C1-6垸氧基， C1 -6烷氧基 垸基， C2-6烯基， C2-6炔基， C6-10芳基， 5-10元杂芳基， C3-10环烷基， 3-10元杂环烷基， 3-7元杂环烯基， C1-6垸基 C6-10芳基， 5-10元杂芳基 C1-6烷基或 C1-6垸基 5-10元杂芳 基； 优选选自氢， 羟基， 氨基， NRaRa'， 卤素， 羧基， 甲酰基， 酰胺基， 酯基， C1-6 卤代 烷基， C1-6羟基烷基， C1 -6杂垸基， C1-6烷氧基， C3-10环垸基， 3-10元杂环垸基， 取代 或未取代的苯基或吡啶基；
R3、 FU和 各自独立地选自氢， 羟基， 氨基， 卤素， 氰基， 硝基， 羧基， 甲酰基， 酰 胺基， -NH-CORb， 酯基， C1-6烷基， C1-6卤代烷基， C1-6羟基垸基， C1 -6杂烷基， C1-6 垸氧基， C1-6烷氧基烷基， C2-6烯基， C2-6炔基， 未取代或取代的 -CO H-(C6-10芳基)， 未取代或取代的 -CH=CH-(C6-10芳基 )， 未取代或取代的 C6-10芳基， 未取代或取代的 5-10 元杂芳基， 未取代或取代的 C3-10环烷基， 未取代或取代的 3-10元杂环烷基， 未取代或取 代的 3-7元杂环烯基， 未取代或取代的 C6-10芳基 C1-6烷基， 未取代或取代的 C1-6烷基 C6-10芳基， 未取代或取代的 5-10元杂芳基 C1-6烷基， 和未取代或取代的 C1-6垸基 5-10 元杂芳基；
或者 R3、 R4和 R5中的两个相邻基团可以连接形成未取代或取代的 C6-10芳基， 未取代 或取代的 5-10元杂芳基，未取代或取代的 C3-10环垸基或未取代或取代的 3-10元杂环烷基； 其中， 各 Rb独立地为 C1-6垸基， C2-6烯基， NHRa， RaRa'， 未取代或取代的苯基或 3-7元杂环基；
各 和 Ra '独立地为氢或 C1-6垸基，
未取代或取代表示该基团未被取代或者被一个或多个取代基取代，所述取代基选自羟基， 氨基， 氰基， 硝基， 羧基， 卤素， C1-6烷基， C 1-6卤代烷基或 C 1-6羟基烷基， 或者二个相 邻取代基可以连接形成 C6-10芳基， C5-10杂芳基， C3-10环垸基或 C3-10杂环垸基；
并且满足如下条件-
( 1 ) 当\¥、 Z或 T上被 R3、 和 中的一个取代时， 该\¥、 Z或 T是 N或 CH;
(2) 当 W、 Z或 T上被 R3、 R4和 R5中的一个基团取代且该基团与 、 和 R5中的 另一个相邻基团连接形成未取代或取代的 C6-10芳基或未取代或取代的 5-10元杂芳基时， 该\¥、 Z或 T是 C;
( 3 ) 当^¥、 Z或 T上被 R3、 R4和 R5中的二个取代时， 该^¥、 Z或丁是。。
2、 根据权利要求 1所述的化合物或其药学上可接受的盐， 其中，
X和 Y各自独立地选自 0， S或 KH;
U和 V各自独立地选自 C或 S;
W、 Z和 T各自独立地选自 0， N， NRa， CO, C， CRa， 禾 Π CH2;
m为。， 1或 2;
n为 0， 1或 2;
选自氢和氘；
R2表示为 -J-K-M-Q, 其中
Figure imgf000125_0001
为含至少一个氮原子的二价 3-10元杂环垸基或二价 3-7元杂环烯基;
K为共价键， NRa，CReRe， 或 CReRc RcRc，； M为共价键，
Figure imgf000126_0001
二价 3-10元杂环烷基， 二价 3-7元杂环烯基或二价 5-10元杂芳 基；
Q为氢， C1-6烷基， C1-6羟基烷基， -(CH2)p-C(0)Rb， -(CH2)p-C(0) HRb , -(CH2)p-C(S)Rb， -(CH2)p-C(S)NHRb, -(CH2)p-S02Rb， -(CH2)p-S02NHRb, 其中，
p为 0， 1， 2或 3 ;
各 Re和 Rc'独立地选自氢， 羟基， 氨基， RaRa'， 卤素， 氰基， 硝基， 羧基， 甲酰基， 酰胺基， 酯基， C1-6卤代垸基， C1-6羟基烷基， C1-6杂垸基， C1-6垸氧基， C1-6烷氧基 垸基， C2-6烯基， C2-6炔基， C6-10芳基， 5-10元杂芳基， C3-10环烷基， 3-10元杂环烷基， 3-7元杂环烯基， C1-6垸基 C6-10芳基， 5-10元杂芳基 C1-6垸基或 C1-6垸基 5-10元杂芳 基； 优选选自氢， 羟基， 氨基， NRaRa'， 卤素， 羧基， 甲酰基， 酰胺基， 酯基， C1-6 卤代 垸基， C1-6羟基垸基， C1-6杂垸基， C1-6垸氧基， C3-10环垸基， 3-10元杂环垸基， 取代 或未取代的苯基或吡啶基；
R3、 E 和 R5各自独立地选自氢， 羟基， 氨基， 卤素， 氰基， 硝基， 羧基， 甲酰基， 酰 胺基， H-CORb， 酯基， C1-6垸基， C1-6卤代垸基， C1-6羟基烷基， C1-6杂烷基， C1-6 垸氧基， C1-6烷氧基烷基， C2-6烯基， C2-6炔基， 未取代或取代的 -CO H-(C6-10芳基)， 未取代或取代的 -CH=CH-(C6-10芳基 )， 未取代或取代的 C6-10芳基， 未取代或取代的 5-10 元杂芳基， 未取代或取代的 C3-10环烷基， 未取代或取代的 3-10元杂环烷基， 未取代或取 代的 3-7元杂环烯基， 未取代或取代的 C6-10芳基 C1-6垸基， 未取代或取代的 C1-6垸基 C6-10芳基， 未取代或取代的 5-10元杂芳基 C1-6烷基或未取代或取代的 C1-6烷基 5-10元 杂芳基；
或者 、 和 R5中的两个相邻基团可以连接形成未取代或取代的 C6-10芳基， 未取代 或取代的 5-10元杂芳基，未取代或取代的 C3-10环垸基或未取代或取代的 3-10元杂环垸基； 其中， 各 Rb独立地为 C1-6垸基， C2-6烯基， NHRa， RaRa'， 未取代或取代的苯基或 3-7元杂环基；
各 和 Ra'独立地为氢或 C1-6垸基；
未取代或取代表示该基团未被取代或者被一个或多个取代基取代，所述取代基选自羟基， 氨基， 氰基， 硝基， 羧基， 卤素， C1-6烧基， C 1-6卤代垸基和 C 1-6羟基烷基， 或者二个相 邻取代基可以连接形成 C6-10芳基， 5-10元杂芳基， C3-10环烷基或 3-10元杂环垸基； 并且满足如下条件：
( 1 ) 当\¥、 Z或 T上被 R3、 R4和 R5中的一个取代时， 该\¥、 Z或 T是 N或 CH;
(2) 当 W、 Z或 T上被 R3、 R4和 R5中的一个基团取代且该基团与 R3、 R4和 R5中的 另一个相邻基团连接形成未取代或取代的 C6-10芳基或未取代或取代的 5-10元杂芳基时， 该\¥、 Z或 T是 C;
( 3 ) 当^¥、 Z或 T上被 R3、 R4和 R5中的二个取代时， 该^¥、 Z或丁是。。 3、根据权利要求 1所述的化合物或其药学上可接受的盐，其中，所述 R2选自如下基团 :
Figure imgf000127_0001
Figure imgf000127_0002
Figure imgf000127_0003
， 和 、、·.·' ；
其中， A为二价 3-10元含氮杂环垸基或二价 3-7元含氮杂环烯基；
Rc, Rc'和 Re"各自独立地选自氢， 羟基， 氨基， NRaRa'， 卤素， 氰基， 硝基， 羧基， 甲 酰基， 酰胺基， 酯基， C1-6 卤代烷基， C1-6羟基垸基， C1-6杂垸基， C1-6垸氧基， C1-6 垸氧基垸基， C2-6烯基， C2-6炔基， C6-10芳基， 5-10元杂芳基， C3-10环烷基， 3-10元杂 环烷基， 3-7元杂环烯基， C1-6垸基 C6-10芳基， 5-10元杂芳基 C1-6垸基和 C1-6垸基 5-10 元杂芳基； 优选选自氢， 羟基， 氨基， NRaRa'， 卤素， 羧基， 甲酰基， 酰胺基， 酯基， C1-6 卤代烷基， C1-6羟基烷基， C1-6杂垸基， C1-6烷氧基， C3-10环烷基， 3-10元杂环烷基， 取代或未取代的苯基或吡啶基；
各 ^和 Ra '独立地为氢或 C 1-6烷基。 4、根据权利要求 1所述的化合物或其药学上可接受的盐，其中，所述 R2选自如下基团:
Figure imgf000128_0001
其中， Rc选自氢， 羟基， 氨基， 氰基， 硝基， 羧基， 卤素， C1-6焼基， C1-6卤代垸基 或 C1-6羟基垸基；
！^和 Rc2各自独立地选自氢， 羟基， 氨基， RaRa'， 卤素， 氰基， 硝基， 羧基， 甲酰 基， 酰胺基， 酯基， C1-6 代垸基， C1-6羟基垸基， C1-6杂烷基， C1-6垸氧基， C1-6垸 氧基烷基， C2-6烯基， C2-6炔基， C6-10芳基， 5-10元杂芳基， C3-10环垸基， 3-10元杂环 垸基， 3-7元杂环烯基， C1-6烷基 C6-10芳基， 5-10元杂芳基 C1-6垸基或 C1-6垸基 5-10 元杂芳基； 优选选自氢， 羟基， 氨基， NRaRa'， 卤素， 羧基， 甲酰基， 酰胺基， 酯基， C1-6 卤代垸基， C1-6羟基垸基， C1-6杂垸基， C1-6垸氧基， C3-10环烷基， 3-10元杂环垸基， 取代或未取代的苯基或吡啶基；
或者 Rel和 Re2连接形成 C6-10芳基， 5-10元杂芳基， C3-10环垸基和 3-10元杂环烷基； 各 1^和 Ra'独立地为氢或 C1-6烷基。
5、 根据权利要求 1所述的化合物或其药学上可接受的盐， 其中， 通式①化合物选自如 下通
Figure imgf000128_0002
其中， X和 Y各自独立地选自 0， S或 NH;
W、 Z和 T各自独立地选自 0， N， NRa， CO，
m为 0， 1或 2;
n为 0， 1或 2;
选自氢和氘；
-N A -N A
J为 NRa， NORa, 0， S或 ， 其中 为含至少一个氮原子的二价 3-10 元杂环烷基或二价 3-7元杂环烯基；
R2'选自： 氢， C1-6垸基、 C1-6卤代垸基、 C1-6垸氧基、 C1-6烷胺基、 C6-10芳基或
5-10元杂芳基， C3-10环烷基， 3-10元杂环烷基， - (CH2) m-M-Q， 其中， M为共价键，二价 3-10元杂环烷基，二价 3-7元杂环烯基或二价 5-10元杂芳基； Q为氢， C1-6垸基， C1-6羟基垸基， -(CH2)p-C(0)Rb， -(CH2)p-C(0) HRb， -(CH2)p-C(S)Rb， -(CH2)p-C(S)NHRb， -(CH2)p-S02Rb， -(CH2)p-S02NHRb，
p为 0， 1， 2或 3 ;
R3、 R4和 R5各自独立地选自氢， 羟基， 氨基， 卤素， 氰基， 硝基， 羧基， 甲酰基， 酰 胺基， H-CORb， 酯基， C1-6垸基， C1-6卤代烷基， C1-6羟基垸基， C1-6杂垸基， C1-6
-6烷氧基垸基， C2-6烯基， C2-6炔基， 未取代或取代的 -CO H-(C6-10芳基)，
Figure imgf000129_0001
Figure imgf000130_0001
其中， X和 Y独立地是 0， S， NH;
W、 Z和 T各自独立地选自 O, N, Ra， CO, C， CRa, 或 CH:
n为 0， 1， 2或 3;
选自氢和氘；
Figure imgf000130_0002
为二价 3-10元含氮杂环烷基或二价 3-7元含氮杂环烯基;
J选自 Ra， NORa， O和 S;
K为共价键， NRa，CR。Re， 或 CR ^CReRc，；
Q为氢， C1-6垸基， C1-6羟基垸基， -(CH2)p-C(0)Rb, -(C¾)p-C(0) HRb， -(CH2)p-C(S)Rb， -(CH2)p-C(S)NHRb， -(CH2)p-S02Rb， -(CH2)p-S02NHRb，
p为 0， 1， 2或 3;
Rc, Rc'和 W各自独立地选自氢， 羟基， 氨基， NRaRa'， 卤素， 氰基， 硝基， 羧基， 甲酰基， 酰胺基， 酯基， C1-6卤代垸基， C1-6羟基垸基， C1-6杂垸基， C1-6垸氧基， C1-6 烷氧基垸基， C2-6烯基， C2-6炔基， C6-10芳基， 5-10元杂芳基， C3-10环垸基， 3-10元杂 环烷基， 3-7元杂环烯基， C1-6烷基 C6-10芳基， 5-10元杂芳基 C1-6烷基或 C1-6烷基 5-10 元杂芳基； 优选选自氢， 羟基， 氨基， NRaRa'， 卤素， 羧基， 甲酰基， 酰胺基， 酯基， C1-6 卤代垸基， C1-6羟基烷基， C1-6杂垸基， C1-6烷氧基， C3-10环烷基， 3-10元杂环烷基， 取代或未取代的苯基或吡啶基；
和 R4各自独立地选自氢， 羟基， 氨基， 卤素， 氰基， 硝基， 羧基， 甲酰基， 酰胺基， NH-CORb， 酯基， C1-6烷基， C1-6卤代垸基， C1-6羟基垸基， C1-6杂烷基， C1-6烷氧基， C1-6垸氧基烷基， C2-6烯基， C2-6炔基， 未取代或取代的 -CO H-(C6-10芳基)， 未取代或 取代的 -CH=CH-(C6-10芳基)，未取代或取代的 C6-10芳基，未取代或取代的 5-10元杂芳基， 未取代或取代的 C3-10环烷基，未取代或取代的 3-10元杂环垸基，未取代或取代的 3-7元杂 环烯基， 未取代或取代的 C6-10芳基 C1-6垸基， 未取代或取代的 C1-6垸基 C6-10芳基， 未 取代或取代的 5-10元杂芳基 C1-6垸基或未取代或取代的 C1-6烷基 5-10元杂芳基；
或者 和 R4连接形成未取代或取代的 C6-10芳基， 未取代或取代的 5-10元杂芳基， 未 取代或取代的 C3-10环垸基或未取代或取代的 3-10元杂环垸基；
其中， 各 Rb独立地为 C1-6垸基， C2-6烯基， NHRa， RaRa'， 未取代或取代的苯基或 3-7元杂环基； 各 和 Ra '独立地为氢或 C1-6垸基；
未取代或取代表示该基团未被取代或者被一个或多个取代基取代， 所述取代基选自羟基， 氨基， 氰基， 硝基， 羧基， 卤素， C1-6烷基， C 1-6卤代烷基和 C 1-6羟基烷基， 或者二个相 邻取代基可以连接形成 C6-10芳基， 5-10元杂芳基， C3-10环垸基或 3-10元杂环垸基； 并且满足如下条件-
( 1 ) W、 Z或 T上被 R3和 R4中一个取代时， 该\¥、 Z或 T是 N或 CH;
(2) W、 Z或 T上被 R3和 中一个取代且 R3和 连接形成 C6-10芳基或 5-10元杂 芳基时， 该\¥、 Z或 T是 C;
( 3 ) W、 Z或 T上同时被 R3和 R4取代时， 该^¥、 Z或丁是(。
7、 根据权利要求 1所述的化合物或其药学上可接受的盐， 其中， 通式①化合物选自如 下通式 (IIIa)、 （IIIb )、 (IIIc)禾口 (Hid)所示化合物：
Figure imgf000131_0001
其中， 1^选自氢， 氘， C1-6垸基， C1-6羟基垸基， C1-6卤代垸基， 未取代或取代的苯 基； 优选选自氢和氘； 优选为氢；
J选自 NRa， NORa, O或 S;
K为共价键， NRa, CReR。， 或 CR。Rc，CRcRc，；
Figure imgf000131_0002
为二价 3-10元含氮杂环烷基或二价 3-7元含氮杂环烯基;
Q为氢， CI -6垸基， CI -6羟基垸基， -(CH2)p-C(0)Rb， -(CH2)p-C(0) HRb , -(CH2)p-C(S)Rb， -(CH2)p-C(S)NHRb, -(CH2)p-S02Rb， 或 -(C¾)p-S02 HRb，
p为 0， 1， 2或 3 ;
各 Re， Rc,和 Rc"独立地选自氢， 羟基， 氨基， NRaRa'， 卤素， 氰基， 硝基， 羧基， 甲酰 基， 酰胺基， 酯基， Cl-6 代烷基， C1-6羟基烷基， C1-6杂烷基， C1-6垸氧基， C1-6烷 氧基垸基， C2-6烯基， C2-6炔基， C6-10芳基， 5-10元杂芳基， C3-10环烷基， 3-10元杂环 垸基， 3-7元杂环烯基， C1-6垸基 C6-10芳基， 5-10元杂芳基 C1-6烷基或 C1-6烷基 5-10 元杂芳基； 优选选自氢， 羟基， 氨基， NRaRa'， 卤素， 羧基， 甲酰基， 酰胺基， 酯基， C1-6 卤代垸基， C1-6羟基烷基， C1-6杂垸基， C1-6垸氧基， C3-10环垸基， 3-10元杂环烷基， 取代或未取代的苯基或吡啶基；
和 各自独立地选自氢， 羟基， 氨基， 卤素， 氰基， 硝基， 羧基， 甲酰基， 酰胺基， NH-CORb, 酯基， C1-6垸基， C1-6卤代烷基， C1-6羟基垸基， C1-6杂垸基， C1-6烷氧基， C1-6烷氧基烷基， C2-6烯基， C2-6炔基， 未取代或取代的 -CO H- (； C6-10芳基)， 未取代或 取代的 -CH=CH-(C6-10芳基；)， 未取代或未取代或取代的 C6-10芳基， 未取代或取代的 5-10 元杂芳基， 未取代或取代的 C3-10环垸基， 未取代或取代的 3-10元杂环垸基， 未取代或取 代的 3-7元杂环烯基， 未取代或取代的 C6-10芳基 C1-6垸基， 未取代或取代的 C1-6烷基 C6-10芳基， 未取代或取代的 5-10元杂芳基 C1-6垸基或未取代或取代的 C1-6垸基 5-10元 杂芳基；
或者 和 R4连接形成未取代或取代的 C6-10芳基， 未取代或取代的 5-10元杂芳基， 未 取代或取代的 C3-10环垸基或未取代或取代的 3-10元杂环烷基；
其中， 各 Rb独立地为 C1-6烷基， C2-6烯基， NHRa， RaRa'， 未取代或取代的苯基或 3-7元杂环基；
各 和 Ra '独立地为氢或 C1-6垸基；
未取代或取代表示该基团未被取代或这被一个或多个取代基取代， 所述取代基选自羟基， 氨基， 氰基， 硝基， 羧基， 卤素， C1-6烷基， C 1-6卤代烷基和 C 1-6羟基垸基， 或者二个相 邻取代基可以连接形成 C6-10芳基， 5-10元杂芳基， C3-10环烷基或 3-10元杂环垸基。
8、 根据权利要求 1所述的化合物或其药学上可接受的盐， 其中， 通式①化合物选自如 下通式 (IVa)、 （IVb)、 (IVc) 禾口 (IVd)所示化合物：
Figure imgf000132_0001
其中， 1^选自氢， 氘， C1-6垸基， C1-6羟基垸基， C1-6卤代垸基， 未取代或取代的苯 基； 优选选自氢和氘； 优选为氢；
J为 NRa， NORa， 0或 S;
K为共价键， NRa, CReR。， 或 CR。Rc，CRcRc，； 为二价 3-10元含氮杂环垸基或二价 3-7元含氮杂环烯基;
Q为氢， C1-6烷基， C1-6羟基烷基， -(CH2)p-C(0)Rb， -(CH2)p-C(0)NHRb， -(CH2)p-C(S)Rb， -(CH2)p-C(S)NHRb， -(CH2)p-S02Rb， -(CH2)p-S02NHRb，
p为 0， 1， 2或 3 ;
Rc, Re,和 Re"各自独立地选自氢， 羟基， 氨基， NRaRa'， 卤素， 氰基， 硝基， 羧基， 甲 酰基， 酰胺基， 酯基， C1-6 卤代垸基， C1-6羟基垸基， C1-6杂垸基， C1-6烷氧基， C1-6 烷氧基垸基， C2-6烯基， C2-6炔基， C6-10芳基， 5-10元杂芳基， C3-10环垸基， 3-10元杂 环垸基， 3-7元杂环烯基， C1-6烷基 C6-10芳基， 5-10元杂芳基 C1-6烷基或 C1-6烷基 5-10 元杂芳基； 优选选自氢， 羟基， 氨基， NRaRa'， 卤素， 羧基， 甲酰基， 酰胺基， 酯基， C1-6 卤代垸基， C1-6羟基烷基， C1-6杂垸基， C1-6烷氧基， C3-10环烷基， 3-10元杂环垸基， 取代或未取代的苯基或吡啶基；
选自氢， 羟基， 氨基， 卤素， 氰基， 硝基， 羧基， 甲酰基， 酰胺基， NH-CORb， 酯基， C1-6烷基， C1-6卤代垸基， C1-6羟基垸基， C1-6杂垸基， C1-6垸氧基， C1-6垸氧基烷基， C2-6烯基， C2-6炔基，未取代或取代的 -CO H-(C6-10芳基)，未取代或取代的 -CH=CH-(C6-10 芳基)，未取代或取代的 C6-10芳基，未取代或取代的 5-10元杂芳基，未取代或取代的 C3-10 环烷基， 未取代或取代的 3-10元杂环垸基， 未取代或取代的 3-7元杂环烯基， 未取代或取代 的 C6-10芳基 C1-6烷基， 未取代或取代的 C1-6烷基 C6-10芳基， 未取代或取代的 5-10元 杂芳基 C1-6垸基或未取代或取代的 C1-6垸基 5-10元杂芳基；
其中， 各 Rb独立地为 C1-6垸基， C2-6烯基， NHRa， RaRa'， 未取代或取代的苯基或 3-7元杂环基；
各 和 Ra'独立地为氢或 C1-6垸基；
未取代或取代表示该基团未被取代或者被一个或多个取代基取代， 所述取代基选自羟基， 氨基， 氰基， 硝基， 羧基， 卤素， C1-6烧基， C 1-6卤代垸基和 C 1-6羟基烷基， 或者二个相 邻取代基可以连接形成 C6-10芳基， 5-10元杂芳基， C3-10环烷基或 3-10元杂环垸基；
R4选自氢， 羟基和 C1-6垸基。
9、 根据权利要求 1-8中任一项所述的化合物或其药学上可接受的盐， 其中， 所述 选 自如下基
Figure imgf000133_0001
Figure imgf000134_0001
其中， 各 Rc， Rel， Re2， Rc'和 Re"独 2：地选自氢， 羟基， 氨基， NRaRa'， 卤素， 氰基， 硝基， 羧基， 甲酰基， 酰胺基， 酯基， C1-6卤代垸基， C1-6羟基垸基， C1-6杂垸基， C1-6 烧氧基， C1-6烷氧基烷基， C2-6爆基， C2-6炔基， C6-10芳基， 5-10元杂芳基， C3-10环 烧基， 3-10元杂环烷基， 3-7元杂环烯基， C1-6烷基 C6-10芳基， 5-10元杂芳基 C1-6烷基 或 C1-6烷基 5-10元杂芳基； 优选选自氢， 羟基， 氨基， RaRa'， 卤素， 羧基， 甲酰基， 酰 胺基， 酯基， C1-6卤代垸基， C1-6羟基烷基， C1-6杂垸基， C1-6烷氧基， C3-10环垸基， 3-10元杂环垸基， 取代或未取代的苯基或吡啶基；
或者 Rel和 Re2连接形成 C6-10芳基， 5-10元杂芳基， C3-10环垸基或 3-10元杂环垸基； 各 Ra和 Ra'独立地为氢或 C1-6垸基。
10、 根据权利要求 1-8 中任一项所述的化合物或其药学上可接受的盐， 其中， 所述 R3 选自如下基团-
Figure imgf000134_0002
其中， Xi为 F， Cl， Br, I或三氟甲基；
X2为 H， F， CI, Br或 I;
Rci、 Rc2、 Rc3或 R。4各自独立地选自氢， 羟基， 氨基， NRaRa'， 卤素， 氰基， 硝基， 羧 基， 甲酰基， 酰胺基， 酯基， C1-6卤代垸基， C1-6羟基垸基， C1-6杂烷基， C1-6垸氧基， C1-6烷氧基烷基， C2-6烯基， C2-6炔基， C6-10芳基， 5-10元杂芳基， C3-10环烷基， 3-10 元杂环垸基， 3-7元杂环烯基， C1-6烷基 C6-10芳基， 5-10元杂芳基 C1-6垸基或 C1-6烷基 5-10元杂芳基； 优选选自氢， 羟基， 氨基， NRaRa'， 卤素， 羧基， 甲酰基， 酰胺基， 酯基， C1-6卤代烷基， C1-6羟基烷基， C1-6杂烷基， C1-6烷氧基， C3-10环烷基， 3-10元杂环烷 基， 取代或未取代的苯基或吡啶基；
或者 1^和 2， 或 2和1^3， 或 Rc3和 Rc4可以连接形成 C6-10芳基， 5-10元杂芳基， C3-10环烷基和 3-10元杂环垸基；
各 ^和 Ra '独立地为氢或 C 1-6垸基，。
11、 根据权利要求 1、 2或 5所述的化合物或其药学上可接受的盐， 其中， 通式 (I)中所 述 R4和 R5为氢。
12、根据权利要求 1所述的化合物或其药学上可接受的盐， 其中， 通式①化合物选自如 下通式 (Va), (Vb)和 (Vc)所示化合物：
Figure imgf000135_0001
其中： W选自： 0， NRa和 CHRa;
J为 NRa， NORa， 0或 S;
K为共价键， NRa, CH' 或
Figure imgf000135_0002
为氢， 氘， C1-6烷基， C1-6羟基垸基， C1-6卤代垸基， 未取代或取代的苯基； 优选 选自氢和氘； 优选为氢，
A环为二价 3-10元含氮杂环垸基或二价 3-7元含氮杂环烯基；
B环为未取代或取代的 C6-10芳基或 5-10元杂芳基； 优选地， B环为未取代或取代的 C6-10芳基， 更优选 B环为未取代或取代的苯基；
Rc, Rc.和 Rc,.各自独立地选自氢， 羟基， 氨基， NRaRa'， 卤素， 氰基， 硝基， 羧基， 甲 酰基， 酰胺基， 酯基， C1-6 卤代烷基， C1-6羟基垸基， C1-6杂垸基， C1-6垸氧基， C1-6 垸氧基垸基， C2-6烯基， C2-6炔基， C6-10芳基， 5-10元杂芳基， C3-10环烷基， 3-10元杂 环烷基， 3-7元杂环烯基， C1-6垸基 C6-10芳基， 5-10元杂芳基 C1-6烷基或 C1-6垸基 5-10 元杂芳基； 优选选自氢， 羟基， 氨基， NRaRa'， 卤素， 羧基， 甲酰基， 酰胺基， 酯基， C1-6 卤代垸基， C1-6羟基垸基， C1-6杂垸基， C1-6垸氧基， C3-10环烷基， 3-10元杂环垸基， 取代或未取代的苯基或吡啶基；
各 Ra独立地选自氢和 C 1 -6烷基。
13、 根据权利要求 1所述的化合物或其药学上可接受的盐， 其选自以下化合物或盐:
Figure imgf000136_0001
Figure imgf000137_0001
Figure imgf000138_0001
ΖΪ8而 8Ϊ0Ζ OAV 8£ΐ
Figure imgf000139_0001
ΖΪ8而 8Ϊ0Ζ OAV 6£ΐ
Figure imgf000140_0001
M7Z.80/8T0ZN3/X3d ΖΪ8而 8Ϊ0Ζ OAV C
Figure imgf000141_0001
ΖΪ8而 8Ϊ0Ζ OAV
Figure imgf000142_0001
ΖΪ8而 8Ϊ0Ζ OAV
Figure imgf000143_0001
M7Z.80/8T0ZN3/X3d ΖΪ8而 8Ϊ0Ζ OAV
Figure imgf000144_0001
ΖΪ8而 8Ϊ0Ζ OAV
Figure imgf000145_0001
Figure imgf000146_0001
9P\
Figure imgf000147_0001
ΖΪ8而 8Ϊ0Ζ OAV
Figure imgf000148_0001
ΖΪ8而 8Ϊ0Ζ OAV
Figure imgf000149_0001
ΖΪ8而 8Ϊ0Ζ OAV 6PI
Figure imgf000150_0001
ΖΪ8而 8Ϊ0Ζ OAV Oil
Figure imgf000151_0001
ΖΪ8而 8Ϊ0Ζ OAV /3/:ϋ O 980sl£ ίϊ8ίAV
Figure imgf000152_0001
Figure imgf000153_0001
Figure imgf000154_0001
ΖΪ8而 8Ϊ0Ζ OAV
Figure imgf000155_0001
14、 一种药物组合物， 其包含根据权利要求 1-13 中任一项所述的化合物或其药学上可 接受的盐。
15、 根据权利要求 1-13 中任一项所述的化合物或其药学上可接受的盐在制备调节细胞 自噬的药物中的用途。
16、 根据权利要求 15 的用途， 其中， 所述调节细胞自噬的药物是调节哺乳动物 ATG8 同源物的药物。
17、 根据权利要求 15的用途， 其中， 所述调节细胞自噬的药物是预防或治疗与细胞自 噬， 尤其是与哺乳动物 ATG8同源物， 相关的疾病的药物。
18、 根据权利要求 16或 17的用途， 其中， 所述哺乳动物 ATG8同源物是 LC3B
19、 根据权利要求 17的用途， 其中， 所述预防或治疗与细胞自噬， 尤其是与哺乳动物 ATG8同源物， 相关的疾病选自以下的疾病： 肿瘤， 心血管疾病， 自身免疫性疾病， 神经退 行性疾病， 高血压， 骨组织细胞及骨类疾病， 克罗恩氏病， 急性肾损伤， 脑缺血， 视网膜疾 病， 支气管哮喘， Vici综合征， 以及感染性疾病。
20、 根据权利要求 19的用途， 其中， 所述肿瘤选自肝癌、 肺癌、 胰腺癌、 乳腺癌、 宫 颈癌、 子宫内膜癌、 大肠癌、 胃癌、 肺癌、 鼻咽癌、 卵巢癌、 前列腺癌、 白血病、 淋巴瘤、 骨髓瘤。
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