Compound used as autophagy regulator, and preparation method therefor and uses thereof

Abstract

The present invention relates to a compound used as an autophagy regulator, and a preparation method therefor and uses thereof. Particularly, provided is a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof, which is an autophagy regulator and particularly, a mammalian ATG8 homologue regulator.

Description

[0001] Compounds for use as autophagy modulators, and methods of making and using the same

[0002] The present application relates to the field of biological medicine, in particular to a class of autophagy modulators, especially mammalian ATG8 homolog modulators and uses thereof.

[0003] BACKGROUND

[0004] Cellular autophagy is a pathway of intracellular degradation, which transports intracellular damaged or dysfunctional proteins and organelles to lysosomes for digestion and degradation. In biological evolution, cellular autophagy is a conserved process, from yeast to plant cells to mammalian cells.

[0005] Existing studies have shown that cellular autophagy plays an important role in maintaining physiological functions such as providing nutrition during starvation, removing cellular contents, antigen presentation, and plays an important role in cancer, infectious diseases, neurodegenerative diseases, etc. Cellular autophagy plays a double-edged sword role in the occurrence and development of tumors: in the early stage of tumor occurrence, autophagy defects can increase genomic instability and promote carcinogenic processes; in the rapid growth and metastasis stage of tumor, autophagy can resist stress conditions to inhibit anoikis and maintain tumor cell survival. Although the relationship between autophagy and tumors is different in different stages of tumor occurrence and development, the development of cellular autophagy modulators for advanced and chemotherapy-resistant cancers will have great value.

[0006] Currently, there are more than 30 clinical trials on autophagy modulators, such as the use of hydroxychloroquine, chloroquine alone or in combination with other antitumor drugs to evaluate the therapeutic effect of autophagy inhibition on refractory and recurrent solid tumors, and the related results can be inquired on the website of clinicaltrial.gov. However, due to the lack of clear molecular targets, the side effects of lysosome inhibitors and the unclear direction of chemical space modification will seriously limit the further development of such autophagy inhibitors.

[0007] Currently, the small molecule modulators targeting autophagy are mainly limited to mTOR and lysosome modulators. The research on small molecule modulators targeting autophagy-related proteins, such as ATG4 and ULK1, is still in the early stage of development. There is no report on modulators of the most important autophagy-related protein ATG8 and its mammalian homologous protein LC3, GABARAP and GATE-16 subfamily. In human body, LC3 family has LC3A, LC3B and LC3C, GABARAP family has GABARAPL and GABARAPL1, and GATE-16 family has GABARAPL2. Among the mammalian homologous proteins of ATG8, LC3B is undoubtedly the most in-depth one, which is considered as a marker of autophagy. There is no report on modulators of LC3B, and it is urgent to develop modulators of LC3B for treating related diseases.

[0008] SUMMARY

[0009] The present application provides a compound represented by general formula ① or a pharmaceutically acceptable salt thereof:

[0010]

[0011] wherein - X and Y are each independently selected from O, S, NR a , NOH and CH 2 ;

[0012] U and V are each independently selected from C, S, SO and POR a ;

[0013] W, Z and T are each independently selected from O, S, SO, SO2, N, NR a , CO, C, CR a , and CH2;

[0014] m is 0, 1, 2 or 3; preferably 0 or 1;

[0015] n is 0, 1, 2 or 3; preferably 0 or 1;

[0016] selected from hydrogen, deuterium, C1-6alkyl, C1-6hydroxyalkyl, C1-6haloalkyl, unsubstituted or substituted phenyl;

[0017] 3-7 membered heterocycloalkenyl; K is a covalent bond, NR a , CRcRe' or CRJ^CRcRc,;

[0018] M is a covalent bond, a divalent 3-10 membered heterocycloalkyl, a divalent 3-7 membered heterocycloalkenyl or a divalent 5-10 membered heteroaryl;

[0019] Q is hydrogen, C1-6alkyl, C1-6hydroxyalkyl, -(CH2) p -C(O)R b , -(CH2) p -C(O)HR b , -(CH2) p -C(S)R b , -(CH2) p -C(S)NHR b , -(CH2) p -SO2R b , -(CH2) p -SO2NHR b ,

[0020] p is 0, 1, 2 or 3; preferably 0 or 1;

[0021] each R e and Rc' are independently selected from hydrogen, hydroxyl, amino, RaRa', halogen, cyano, nitro, carboxyl, formyl, amido, ester, C1-6haloalkyl, C1-6hydroxyalkyl, C1-6heteroalkyl, C1-6alkoxy, C1-6alkoxyalkyl, C2-6alkenyl, C2-6alkynyl, C6-10aryl, 5-10 membered heteroaryl, C3-10cycloalkyl, 3-10 membered heterocycloalkyl, 3-7 membered heterocycloalkenyl, C1-6alkyl C6-10aryl, 5-10 membered heteroaryl C1-6alkyl or C1-6alkyl 5-10 membered heteroaryl; preferably from hydrogen, hydroxyl, amino, NRaRa', halogen, carboxyl, formyl, amido, ester, C1-6haloalkyl, C1-6hydroxyalkyl, C1-6heteroalkyl, C1-6alkoxy, C3-10cycloalkyl, 3-10 membered heterocycloalkyl, substituted or unsubstituted phenyl or pyridyl;

[0022] R3, R4and each independently are selected from hydrogen, hydroxyl, amino, halogen, cyano, nitro, carboxyl, formyl, amido, -NH-COR bC1-6alkyl, C2-6alkenyl, C2-6alkynyl, unsubstituted or substituted -CONH-(C6-10aryl), unsubstituted or substituted -CH=CH-(C6-10aryl), unsubstituted or substituted C6-10aryl, unsubstituted or substituted 5-10 membered heteroaryl, unsubstituted or substituted C3-10cycloalkyl, unsubstituted or substituted 3-10 membered heterocycloalkyl, unsubstituted or substituted 3-7 membered heterocycloalkenyl, unsubstituted or substituted C6-10aryl C1-6alkyl, unsubstituted or substituted C1-6alkyl C6-10aryl, unsubstituted or substituted 5-10 membered heteroaryl C1-6alkyl, and unsubstituted or substituted C1-6alkyl 5-10 membered heteroaryl;

[0023] or two adjacent groups of R3, R4and R5may be joined to form an unsubstituted or substituted C6-10aryl, unsubstituted or substituted 5-10 membered heteroaryl, unsubstituted or substituted C3-10cycloalkyl, or unsubstituted or substituted 3-10 membered heterocycloalkyl; wherein each R b is independently C1-6alkyl, C2-6alkenyl, NHR a , R a R a is unsubstituted or substituted phenyl or 3-7 membered heterocyclyl;

[0024] each R a and R a is independently hydrogen or C1-6alkyl;

[0025] unsubstituted or substituted means that the group is either not substituted or substituted with one or more substituents selected from the group consisting of hydroxy, amino, cyano, nitro, carboxy, halogen, C1-6alkyl, C1-6haloalkyl, or C1-6hydroxyalkyl, or two adjacent substituents can be joined to form a C6-10aryl, C5-10heteroaryl, C3-10cycloalkyl, or C3-10heterocycloalkyl;

[0026] and the following conditions are met:

[0027] (1) when Y, Z or T is substituted with one of R3, R4and R5, the Y, Z or T is N or CH;

[0028] (2) when W, Z or T is substituted with one of R3, R4and R5and that group is attached to another of R3, R4and R5to form an unsubstituted or substituted C6-10aryl or unsubstituted or substituted 5-10 membered heteroaryl, then that W, Z or T is C; for example, when W is substituted and R3is attached to adjacent R4to form an unsubstituted or substituted C6-10aryl or unsubstituted or substituted 5-10 membered heteroaryl, then W is C;

[0029] (3) when W, Z or T is substituted with two of R3, R4and R5, then that W, Z or T is (.

[0030] Preferably, in general formula CI):

[0031] X and Y are each independently selected from O, S or H;

[0032] U and V are each independently selected from C or S;

[0033] W, Z and T are each independently selected from O, N, R a , CO, C, CR a , CH2;

[0034] m is 0, 1 or 2;

[0035] n is 0, 1 or 2;

[0036] selected from hydrogen and deuterium;

[0037] 3-7 membered heterocycloalkenyl;

[0038] K is a covalent bond, NR a , CR e R e , or CRcRcRcRc;

[0039] M is a covalent bond, CH, bivalent 3-10 membered heterocycloalkyl, bivalent 3-7 membered heterocycloalkenyl or bivalent 5-10 membered heteroaryl;

[0040] Q is hydrogen, C1-6alkyl, C1-6hydroxyalkyl, -(CH2) p -C(O)R b , -(CH2) p -C(O)NHR b , -(CH2) p -C(S)R b , -(CH2) p -C(S)NHRb , -(CH2) p -S02R b , -(CH2) p -S02NHR b , wherein,

[0041] p is 0, 1, 2 or 3; preferably 0 or 1;

[0042] each R e and Rc' are independently selected from hydrogen, hydroxyl, amino, RaRa', halogen, cyano, nitro, carboxyl, formyl, amido, ester, C1-6haloalkyl, C1-6hydroxyalkyl, C1-6heteroalkyl, C1-6alkoxy, C1-6alkoxyalkyl, C2-6alkenyl, C2-6alkynyl, C6-10aryl, 5-10 membered heteroaryl, C3-10cycloalkyl, 3-10 membered heterocycloalkyl, 3-7 membered heterocycloalkenyl, C1-6alkyl C6-10aryl, 5-10 membered heteroaryl C1-6alkyl or C1-6alkyl 5-10 membered heteroaryl; preferably from hydrogen, hydroxyl, amino, NRaRa', halogen, carboxyl, formyl, amido, ester, C1-6haloalkyl, Cl-6hydroxyalkyl, C1-6heteroalkyl, C1-6alkoxy, C3-10cycloalkyl, 3-10 membered heterocycloalkyl, substituted or unsubstituted phenyl or pyridyl;

[0043] R3, R4and R5are each independently selected from hydrogen, hydroxyl, amino, halogen, cyano, nitro, carboxyl, formyl, amido, H-COR b , ester, C1-6alkyl, C1-6haloalkyl, C1-6hydroxyalkyl, C1-6heteroalkyl, C1-6alkoxy, C1-6alkoxyalkyl, C2-6alkenyl, C2-6alkynyl, unsubstituted or substituted -COH- (C6-10aryl;), unsubstituted or substituted -CH=CH-(C6-10aryl;), unsubstituted or substituted C6-10aryl, unsubstituted or substituted 5-10 membered heteroaryl, unsubstituted or substituted C3-10cycloalkyl, unsubstituted or substituted 3-10 membered heterocycloalkyl, unsubstituted or substituted 3-7 membered heterocycloalkenyl, unsubstituted or substituted C6-10aryl C1-6alkyl, unsubstituted or substituted C1-6alkyl C6-10aryl, unsubstituted or substituted 5-10 membered heteroaryl C1-6alkyl or unsubstituted or substituted C1-6alkyl 5-10 membered heteroaryl;

[0044] or two adjacent R3, R4and R5groups can be joined to form an unsubstituted or substituted C6-10aryl, unsubstituted or substituted 5-10 membered heteroaryl, unsubstituted or substituted C3-10cycloalkyl or unsubstituted or substituted 3-10 membered heterocycloalkyl; wherein each R b independently is C1-6alkyl, C2-6alkenyl, NHR a , R a R a , unsubstituted or substituted phenyl or 3-7 membered heterocyclyl;

[0045] each R a independently is hydrogen or C1-6alkyl;

[0046] unsubstituted or substituted means that the group is either unsubstituted or substituted with one or more substituents selected from the group consisting of hydroxy, amino, cyano, nitro, carboxy, halogen, C1-6alkyl, C1-6haloalkyl and C1-6hydroxyalkyl, or two adjacent substituents can be joined to form a C6-10aryl, 5-10 membered heteroaryl, C3-10cycloalkyl or 3-10 membered heterocycloalkyl; and provided that

[0047] (1) when X, Z or T is substituted with one of R3, R4and R5, then X, Z or T is N or CH;

[0048] (2) when W, Z or T is substituted with one of R3, R4and R5and this group is joined to another adjacent group of R3, R4and R5to form an unsubstituted or substituted C6-10aryl or unsubstituted or substituted 5-10 membered heteroaryl, then X, Z or T is C;

[0049] (3) when X, Z or T is substituted with two of R3, R4and R5, then X, Z or T is

[0050] Z, X, Λ, in another embodiment of the application, said R2in general formula (I) is selected from the group consisting of: Ν ,

[0051]

[0052] , R

[0053] wherein A is a divalent 3-10 membered nitrogen containing heterocyclyl or a divalent 3-7 membered nitrogen containing heterocycloalkenyl;

[0054] Rc, Rc' and R c Each group is independently selected from hydrogen, hydroxyl, amino, NRaRa', halogen, cyano, nitro, carboxyl, 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 heteroaryl, C3-10 cycloalkyl, 3-10 heterocycloalkyl, 3-7 heterocycloalkenyl, C1-6 alkylC6-10 aryl, 5-10 heteroarylC1-6 alkyl or C1-6 alkyl5-10 heteroaryl; preferably selected from hydrogen, hydroxyl, amino, NRaRa', halogen, carboxyl, formyl, amide, ester, C1-6 haloalkyl. C1-6 hydroxyalkyl, C1-6 heteroalkyl, C1-6 alkoxy, C3-10 cycloalkyl, 3-10 heterocyclic alkyl, substituted or unsubstituted phenyl or pyridyl;

[0055] Each and R a 'Independently hydrogen or C1-6 alkyl.'

[0056]

[0057] Wherein, Rc, R cl DR c2 Selected from hydrogen, hydroxyl, amino, RaRa', halogen, cyano, nitro, carboxyl, formyl, amide, ester, C1-6 alkyl, C1-6 hydroxyalkyl, C1-6 heteroalkyl, C1-6 alkyloxy, C1-6 alkoxyalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, 5-10 heteroaryl, C3-10 cycloalkyl, 3-10 heterocyclic alkyl, 3-7 heterocyclic alkenyl, C1-6 alkylC6-10 aryl, 5-10 heteroarylC1-6 alkyl or C1-6 alkyl5-10 heteroaryl; preferably selected from hydrogen, hydroxyl, amino, NRaRa', halogen, carboxyl, formyl, amide, ester, C1-6 haloalkyl. C1-6 hydroxyalkyl, C1-6 heteroalkyl, C1-6 alkoxy, C3-10 cycloalkyl, 3-10 heterocyclic alkyl, substituted or unsubstituted phenyl or pyridyl;

[0058] Alternatively, it can connect with Rc2 to form C6-10 aryl, 5-10 heteroaryl, C3-10 cycloalkenyl and 3-10 heterocyclic alkyl groups;

[0059] Each! ^ and R aindependently hydrogen or C1-6alkyl.

[0060] In one embodiment, the compound of Formula (I) is selected from a compound of Formula (la) or (lb)

[0061] (la)

[0062] wherein X and Y are each independently selected from O, S or NH;

[0063] W, Z and T are each independently selected from O, N, NR a , CO, C, CR a , or CH 2 ;

[0064] m is 0, 1 or 2;

[0065] n is 0, 1 or 2;

[0066] selected from hydrogen and deuterium;

[0067] NA— NA4—

[0068] J is NR a , NOR a , O, S or NH, wherein J is a divalent 3-10 membered heterocycloalkyl group containing at least one nitrogen atom or a divalent 3-7 membered heterocycloalkenyl group;

[0069] selected from: hydrogen, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C1-6alkylamino, C6-10aryl or 5-10 membered heteroaryl, C3-10cycloalkyl, 3-10 membered heterocycloalkyl, -(CH2) m -M-Q,

[0070] wherein 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;

[0071] Q is hydrogen, C1-6alkyl, C1-6hydroxyalkyl, -(CH2) p -C(O)R b , -(CH2) p -C(O)NHR b , -(CH2) p -C(S)R b , -(CH2)p-C(S)NHR b , -(CH2)p-SO2R b , -(CH2) p -SO2NHRb ,

[0072] p is 0, 1, 2 or 3; preferably 0 or 1;

[0073] R3, R4and R5are each independently selected from the group consisting of hydrogen, hydroxyl, amino, halogen, cyano, nitro, carboxyl, formyl, amido, H-COR b , ester, C1-6alkyl, C1-6haloalkyl, C1-6hydroxyalkyl, C1-6heteroalkyl, C1-6alkoxy, C1-6alkoxyalkyl, C2-6alkenyl, C2-6alkynyl, unsubstituted or substituted -CO H-(C6-10aryl), unsubstituted or substituted -CH=CH-(C6-10aryl); unsubstituted or substituted C6-10aryl, unsubstituted or substituted 5-10 membered heteroaryl, unsubstituted or substituted C3-10cycloalkyl, unsubstituted or substituted 3-10 membered heterocycloalkyl, unsubstituted or substituted 3-7 membered heterocycloalkenyl, unsubstituted or substituted C6-10aryl C1-6alkyl, unsubstituted or substituted C1-6alkyl C6-10aryl, unsubstituted or substituted 5-10 membered heteroaryl C1-6alkyl or unsubstituted or substituted C1-6alkyl 5-10 membered heteroaryl;

[0074] or two adjacent groups of R3, R4and R5may be joined to form unsubstituted or substituted C6-10aryl, unsubstituted or substituted 5-10 membered heteroaryl, unsubstituted or substituted C3-10cycloalkyl or unsubstituted or substituted 3-10 membered heterocycloalkyl; wherein each R b is independently C1-6alkyl, C2-6alkenyl, NHR a , R a R a , unsubstituted or substituted phenyl or 3-7 membered heterocyclyl;

[0075] each R and R a is independently hydrogen or C1-6alkyl;

[0076] unsubstituted or substituted means that the group is unsubstituted or substituted with one or more substituents selected from the group consisting of hydroxyl, amino, cyano, nitro, carboxyl, halogen, C1-6alkyl, C1-6haloalkyl and C1-6hydroxyalkyl, or two adjacent substituents can be joined to form C6-10aryl, 5-10 membered heteroaryl, C3-10cycloalkyl or 3-10 membered heterocycloalkyl; and subject to the following proviso:

[0077] (1) when Y, Z or T is substituted with one of R3, R4and R5, Y, Z or T is N or CH;

[0078] (2) when W, Z or T is substituted with one of R3, R4and R5and this group is attached to another adjacent group of R3, R4and R5to form an unsubstituted or substituted C6-10aryl or unsubstituted or substituted 5-10 membered heteroaryl, Y, Z or T is C;

[0079] (3) when Y, Z or T is substituted with two of R3, and R5, Y, Z or T is

[0080] In another embodiment of the application, the compound of general formula (X) is selected from the group consisting of the following general formulae (Ha), (lib), (lie) and (lid)

[0081]

[0082] wherein X and Y are independently O, S, NH;

[0083] W, Z and T are each independently selected from the group consisting of O, N, R a , CO, C, CR a , or CH2

[0084] n is 0, 1, 2 or 3;

[0085] and deuterium; is a divalent 3-10 membered nitrogen-containing heterocycloalkyl or a divalent 3-7 membered nitrogen-containing heterocycloalkenyl;

[0086] J is selected from the group consisting of Ra, NOR a , O and S;

[0087] K is a covalent bond, NR a , CR e R e , or CReRfCRcRd; Q is hydrogen, Cl-6alkyl, Cl-6hydroxyalkyl, -(CH2) p -C(O)R b , -(CH2) p -C(O) HR b , -(CH2) p -C(S)R b , -(CH2) p -C(S)NHR b , -(CH2) p -SO2Rb -(CH2) p -S02NHR b ,

[0088] p is 0, 1, 2 or 3; preferably 0 or 1;

[0089] Rc, Rc' and Re" are each independently selected from hydrogen, hydroxyl, amino, NRaRa', halogen, cyano, nitro, carboxyl, formyl, amido, ester, C1-6haloalkyl, C1-6hydroxyalkyl, C1-6heteroalkyl, C1-6alkoxy, C1-6alkoxyalkyl, C2-6alkenyl, C2-6alkynyl, C6-10aryl, 5-10 membered heteroaryl, C3-10cycloalkyl, 3-10 membered heterocycloalkyl, 3-7 membered heterocycloalkenyl, C1-6alkyl C6-10aryl, 5-10 membered heteroaryl C1-6alkyl or C1-6alkyl 5-10 membered heteroaryl; preferably from hydrogen, hydroxyl, amino, NRaRa', halogen, carboxyl, formyl, amido, ester, C1-6haloalkyl, C1-6hydroxyalkyl, C1-6heteroalkyl, C1-6alkoxy, C3-10cycloalkyl, 3-10 membered heterocycloalkyl, substituted or unsubstituted phenyl or pyridyl;

[0090] and are each independently selected from hydrogen, hydroxyl, amino, halogen, cyano, nitro, carboxyl, formyl, amido, NH-COR b , ester, C1-6alkyl, C1-6haloalkyl, C1-6hydroxyalkyl, C1-6heteroalkyl, C1-6alkoxy, C1-6alkoxyalkyl, C2-6alkenyl, C2-6alkynyl, unsubstituted or substituted -CO H-(C6-10aryl), unsubstituted or substituted -CH=CH-(C6-10aryl), unsubstituted or substituted C6-10aryl, unsubstituted or substituted 5-10 membered heteroaryl, unsubstituted or substituted C3-10cycloalkyl, unsubstituted or substituted 3-10 membered heterocycloalkyl, unsubstituted or substituted 3-7 membered heterocycloalkenyl, unsubstituted or substituted C6-10aryl C1-6alkyl, unsubstituted or substituted C1-6alkyl C6-10aryl, unsubstituted or substituted 5-10 membered heteroaryl C1-6alkyl or unsubstituted or substituted C1-6alkyl 5-10 membered heteroaryl;

[0091] or R3and R4are linked to form unsubstituted or substituted C6-10aryl, unsubstituted or substituted 5-10 membered heteroaryl, unsubstituted or substituted C3-10cycloalkyl or unsubstituted or substituted 3-10 membered heterocycloalkyl;

[0092] wherein each R b independently is C1-6alkyl, C2-6alkenyl, NHR a , R a R a , unsubstituted or substituted phenyl or 3-7 membered heterocyclyl;

[0093] each and Ra' independently is hydrogen or C1-6alkyl;

[0094] unsubstituted or substituted means that the group is either unsubstituted or substituted by one or more substituents selected from the group consisting of hydroxy, amino, cyano, nitro, carboxy, halogen, C1-6alkyl, C1-6haloalkyl and C1-6hydroxyalkyl, or two adjacent substituents can be joined to form a C6-10aryl, 5-10 membered heteroaryl, C3-10cycloalkyl or 3-10 membered heterocyclyl; and provided that

[0095] (1) W, Z or T is N or CH when substituted by one of R3and R4;

[0096] (2) W, Z or T is C when substituted by one of R3and R4and and together form a C6-10aryl or 5-10 membered heteroaryl;

[0097] (3) W, Z or T is N when substituted by both R3and R4;

[0098] In another embodiment of the present application, the compound of general formula (X) is selected from the group consisting of compounds of general formulae (IIIa), (IIIb), (IIIc) and (IIId) as depicted below : (IIIa), (IIIb),

[0099]

[0100] wherein R1is selected from the group consisting of hydrogen, deuterium, C1-6alkyl, C1-6hydroxyalkyl, C1-6haloalkyl, unsubstituted or substituted phenyl; preferably from hydrogen and deuterium; preferably is hydrogen;

[0101] J is selected from the group consisting of NRa, NORa, O or S;

[0102] , NRa, CH, or CReRfCRgRh,; bivalent 3-10 membered nitrogen-containing heterocycloalkyl or bivalent 3-7 membered nitrogen-containing heterocycloalkenyl;

[0103] Q is hydrogen, C1-6alkyl, C1-6hydroxyalkyl, -(CH2) p -C(O)R b , -(CH2) p -C(O)NHR b , -(CH2) p -C(S)R b , -(CH2) p -C(S)NHR b , -(CH2) p -SO2R b , or -(CH2) p -SO2HR b ,

[0104] p is 0, 1, 2 or 3; preferably 0 or 1;

[0105] each R e ,, and are independently selected from hydrogen, hydroxyl, amino, NRaRa', halogen, cyano, nitro, carboxyl, formyl, amido, ester, C1-6haloalkyl, C1-6hydroxyalkyl, C1-6heteroalkyl, C1-6alkoxy, C1-6alkoxyalkyl, C2-6alkenyl, C2-6alkynyl, C6-10aryl, 5-10 membered heteroaryl, C3-10cycloalkyl, 3-10 membered heterocycloalkyl, 3-7 membered heterocycloalkenyl, C1-6alkyl C6-10aryl, 5-10 membered heteroaryl C1-6alkyl or C1-6alkyl 5-10 membered heteroaryl; preferably from hydrogen, hydroxyl, amino, NRaRa', halogen, carboxyl, formyl, amido, ester, C1-6haloalkyl, C1-6hydroxyalkyl, C1-6heteroalkyl, C1-6alkoxy, C3-10cycloalkyl, 3-10 membered heterocycloalkyl, substituted or unsubstituted phenyl or pyridyl;

[0106] and R4are each independently selected from hydrogen, hydroxyl, amino, halogen, cyano, nitro, carboxyl, formyl, amido, NH-COR b, ester, C1-6alkyl, C1-6haloalkyl, C1-6hydroxyalkyl, C1-6heteroalkyl, C1-6alkoxy, C1-6alkoxyalkyl, C2-6alkenyl, C2-6alkynyl, unsubstituted or substituted -CO H-(C6-10aryl), unsubstituted or substituted -CH=CH-(C6-10aryl);, unsubstituted or unsubstituted or substituted C6-10aryl, unsubstituted or substituted 5-10 membered heteroaryl, unsubstituted or substituted C3-10cycloalkyl, unsubstituted or substituted 3-10 membered heterocycloalkyl, unsubstituted or substituted 3-7 membered heterocycloalkenyl, unsubstituted or substituted C6-10aryl C1-6alkyl, unsubstituted or substituted C1-6alkyl C6-10aryl, unsubstituted or substituted 5-10 membered heteroaryl C1-6alkyl or unsubstituted or substituted C1-6alkyl 5-10 membered heteroaryl;

[0107] or R3and the bond form together unsubstituted or substituted C6-10aryl, unsubstituted or substituted 5-10 membered heteroaryl, unsubstituted or substituted C3-10cycloalkyl or unsubstituted or substituted 3-10 membered heterocycloalkyl;

[0108] wherein each R b independently is C1-6alkyl, C2-6alkenyl, H a , R a R a , unsubstituted or substituted phenyl or 3-7 membered heterocyclyl;

[0109] each and R a independently is hydrogen or C1-6alkyl;

[0110] 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, carboxyl, halogen, C1-6alkyl, C1-6haloalkyl and C1-6hydroxyalkyl, or two adjacent substituents can be joined to form a C6-10aryl, 5-10 membered heteroaryl, C3-10cycloalkyl or 3-10 membered heterocycloalkyl.

[0111] In another embodiment of the present application, the compounds of general formula (I) are selected from the group consisting of compounds of general formula (IVa), (IVb), (IVc) and

[0112] (IVd) as shown below: (IVc),

[0113]

[0114] wherein R is selected from the group consisting of hydrogen, deuterium, Ci-6alkyl, Ci-6hydroxyalkyl, Ci-6haloalkyl, unsubstituted or substituted phenyl; preferably from the group consisting of hydrogen and deuterium; preferably hydrogen;

[0115] J is NR a , NORa, 0 or S;

[0116] , NR a , CR e R e , or CReRc RcRc,; is a bivalent 3-10 membered nitrogen containing heterocycloalkyl or a bivalent 3-7 membered nitrogen containing heterocycloalkenyl;

[0117] Q is hydrogen, Ci-6alkyl, Ci-6hydroxyalkyl, -(CH2) p -C(0)R b , -(CH2) p -C(0) HR b , -(CH2) p -C(S)R b , -(CH2) P -C(S)NHR b , -(CH2) p -S02R b , -(CH2) P -S02NHR b ,

[0118] p is 0, 1, 2 or 3; preferably 0 or 1;

[0119] Rc, Rc'and Rc"are each independently selected from the group consisting of hydrogen, hydroxyl, amino, RaRa', halogen, cyano, nitro, carboxyl, formyl, amido, ester, Ci-6haloalkyl, Ci-6hydroxyalkyl, Ci-6heteroalkyl, Ci-6alkoxy, Ci-6alkoxyalkyl, C2-6alkenyl, C2-6alkynyl, C6-10aryl, 5-10 membered heteroaryl, C3-10cycloalkyl, 3-10 membered heterocycloalkyl, 3-7 membered heterocycloalkenyl, Ci-6alkyl C6-10aryl, 5-10 membered heteroaryl Ci-6alkyl or Ci-6alkyl 5-10 membered heteroaryl; preferably from the group consisting of hydrogen, hydroxyl, amino, NRaRa', halogen, carboxyl, formyl, amido, ester, Ci-6haloalkyl, Ci-6hydroxyalkyl, Ci-6heteroalkyl, Ci-6alkoxy, C3-10cycloalkyl, 3-10 membered heterocycloalkyl, substituted or unsubstituted phenyl or pyridyl;

[0120] selected from the group consisting of hydrogen, hydroxy, amino, halogen, cyano, nitro, carboxyl, formyl, acylamino, NH-COR b , ester, C1-6alkyl, C1-6haloalkyl, C1-6hydroxyalkyl, C1-6heteroalkyl, C1-6alkoxy, C1-6alkoxyalkyl, C2-6alkenyl, C2-6alkynyl, unsubstituted or substituted -CO H-(C6-10aryl); unsubstituted or substituted -CH=CH-(C6-10aryl); unsubstituted or substituted C6-10aryl; unsubstituted or substituted 5-10 membered heteroaryl; unsubstituted or substituted C3-10cycloalkyl; unsubstituted or substituted 3-10 membered heterocycloalkyl; unsubstituted or substituted 3-7 membered heterocycloalkenyl; unsubstituted or substituted C6-10aryl C1-6alkyl; unsubstituted or substituted C1-6alkyl C6-10aryl; unsubstituted or substituted 5-10 membered heteroaryl C1-6alkyl; or unsubstituted or substituted C1-6alkyl 5-10 membered heteroaryl;

[0121] wherein each R b is independently C1-6alkyl, C2-6alkenyl, NHR a , R a R a is unsubstituted or substituted phenyl or 3-7 membered heterocyclyl;

[0122] each and R a is independently hydrogen or C1-6alkyl;

[0123] 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, carboxyl, halogen, C1-6alkyl, C1-6haloalkyl and C1-6hydroxyalkyl, or two adjacent substituents can be joined to form a C6-10aryl, 5-10 membered heteroaryl, C3-10cycloalkyl or 3-10 membered heterocycloalkyl;

[0124] R4is selected from the group consisting of hydrogen, hydroxy and C1-6alkyl.

[0125] In another specific embodiment of the application, the general formula (I), (la), (lb), (Ila), (lib), (lie lid),,

[0126]

[0127] wherein each Rc, R el , R c2Rc' and Re" are independently selected from hydrogen, hydroxyl, amino, NRaRa', halogen, cyano, nitro, carboxyl, formyl, amido, ester, C1-6haloalkyl, C1-6hydroxyalkyl, C1-6heteroalkyl, C1-6alkoxy, C1-6alkoxyalkyl, C2-6alkenyl, C2-6alkynyl, C6-10aryl, 5-10 membered heteroaryl, C3-10cycloalkyl, 3-10 membered heterocycloalkyl, 3-7 membered heterocycloalkenyl, C1-6alkyl C6-10aryl, 5-10 membered heteroaryl C1-6alkyl or C1-6alkyl 5-10 membered heteroaryl; preferably selected from hydrogen, hydroxyl, amino, NRaRa', halogen, carboxyl, formyl, amido, ester, C1-6haloalkyl, C1-6hydroxyalkyl, C1-6heteroalkyl, C1-6alkoxy, C3-10cycloalkyl, 3-10 membered heterocycloalkyl, substituted or unsubstituted phenyl or pyridyl;

[0128] each R1and R2is independently hydrogen, halogen, cyano, nitro, C1-6alkyl, C1-6haloalkyl, C1-6hydroxyalkyl, C1-6heteroalkyl, C1-6alkoxy, C3-10cycloalkyl, 3-10 membered heterocycloalkyl, substituted or unsubstituted phenyl or pyridyl; a R1and R2are independently hydrogen or C1-6alkyl.

[0129] or R1and R2may be joined to form a C6-10aryl, 5-10 membered heteroaryl, C3-10cycloalkyl or 3-10 membered heterocycloalkyl ring;

[0130]

[0131] wherein X1is F, Cl, Br, I or trifluoromethyl;

[0132] X2is H, F, Cl, Br or I;

[0133] Rci, Rc3or R4is each independently selected from hydrogen, hydroxyl, amino, NRaRa', halogen, cyano, nitro, carboxyl, formyl, amido, ester, C1-6haloalkyl, C1-6hydroxyalkyl, C1-6heteroalkyl, C1-6alkoxy, C1-6alkoxyalkyl, C2-6alkenyl, C2-6alkynyl, C6-10aryl, 5-10 membered heteroaryl, C3-10cycloalkyl, 3-10 membered heterocycloalkyl, 3-7 membered heterocycloalkenyl, C1-6alkyl C6-10aryl, 5-10 membered heteroaryl C1-6alkyl or C1-6alkyl 5-10 membered heteroaryl; preferably from hydrogen, hydroxyl, amino, NRaRa', halogen, carboxyl, formyl, amido, ester, C1-6haloalkyl, C1-6hydroxyalkyl, C1-6heteroalkyl, C1-6alkoxy, C3-10cycloalkyl, 3-10 membered heterocycloalkyl, substituted or unsubstituted phenyl or pyridyl;

[0134] or Rci and R02, or R03and R04may be linked to form C6-10aryl, 5-10 membered heteroaryl, C3-10cycloalkyl and 3-10 membered heterocycloalkyl;

[0135] each R a is independently hydrogen or C1-6alkyl.

[0136] In another particular embodiment of the application, said R4and R5in general formula (I) are hydrogen.

[0137] In another particular embodiment of the application, the compounds of general formula (I) are selected from the following compounds of general formulae (Va), (Vb) and (Vc):

[0138]

[0139] wherein: W is selected from: O, NRaand CHR a ;

[0140] J is NR a , NORa, O or S;

[0141] K is a covalent bond, NR a , CH' or CR e Rc, CR c Rc,;

[0142] is selected from the group consisting of hydrogen, deuterium, Ci-6alkyl, Ci-6hydroxyalkyl, Ci-6haloalkyl, unsubstituted or substituted phenyl; preferably from the group consisting of hydrogen and deuterium; preferably is hydrogen; A ring is a divalent 3-10 membered nitrogen containing heterocycloalkyl or a divalent 3-7 membered nitrogen containing heterocycloalkenyl;

[0143] B ring is unsubstituted or substituted C6-10aryl or 5-10 membered heteroaryl; preferably, B ring is unsubstituted or substituted C6-10aryl, more preferably B ring is unsubstituted or substituted phenyl;

[0144] Rc, Rc, and Rc, are each independently selected from the group consisting of hydrogen, hydroxyl, amino, NRaRa', halogen, cyano, nitro, carboxyl, formyl, amido, ester, Ci-6haloalkyl, Ci-6hydroxyalkyl, Ci-6heteroalkyl, Ci-6alkoxy, Ci-6alkoxyalkyl, C2-6alkenyl, C2-6alkynyl, C6-10aryl, 5-10 membered heteroaryl, C3-10cycloalkyl, 3-10 membered heterocycloalkyl, 3-7 membered heterocycloalkenyl, Ci-6alkyl C6-10aryl, 5-10 membered heteroaryl Ci-6alkyl or Ci-6alkyl 5-10 membered heteroaryl; preferably from the group consisting of hydrogen, hydroxyl, amino, NRaRa', halogen, carboxyl, formyl, amido, ester, Ci-6haloalkyl, Ci-6hydroxyalkyl, Ci-6heteroalkyl, Ci-6alkoxy, C3-10cycloalkyl, 3-10 membered heterocycloalkyl, substituted or unsubstituted phenyl or pyridyl;

[0145] each R a is independently selected from the group consisting of hydrogen and Ci-6alkyl.

[0146] In another specific embodiment of the application, the compound of the application or a pharmaceutically acceptable salt thereof is preferably selected from the following compounds or salts:

[0147] / 3: 0 980s18i AV

[0148]

[0149]

[0150] / 3: 0 980s18i AV

[0151]

[0152] / 3: 0 980s18i AV

[0153]

[0154]

[0155]

[0156]

[0157]

[0158]

[0159]

[0160]

[0161]

[0162]

[0163]

[0164]

[0165]

[0166]

[0167]

[0168]

[0169]

[0170]

[0171]

[0172]

[0173]

[0174]

[0175]

[0176] ​​​​​​​​​​​​In another embodiment of the present application, the present application provides a pharmaceutical composition comprising a compound according to the present application or a pharmaceutically acceptable salt thereof. The pharmaceutical composition can further comprise a pharmaceutical adjuvant.

[0177] In another embodiment of the present application, the present application provides the use of a compound according to the present application or a pharmaceutically acceptable salt thereof for the preparation of a medicament for modulating autophagy.

[0178] In another embodiment of the present application, the medicament for modulating autophagy is a medicament for modulating a mammalian ATG8 homolog.

[0179] In another embodiment of the present application, the medicament for modulating autophagy is a medicament for preventing or treating a disease associated with autophagy, in particular a mammalian ATG8 homolog.

[0180] In another embodiment of the present application, the present application provides a method for modulating autophagy, comprising administering to a subject in need thereof a compound according to the present application or a pharmaceutically acceptable salt thereof. In another embodiment of the present application, the method for modulating autophagy is a method for modulating a mammalian ATG8 homolog.

[0181] In another embodiment of the present application, the method for modulating autophagy is a method for preventing or treating a disease associated with autophagy, in particular a mammalian ATG8 homolog.

[0182] In another embodiment of the present application, the mammalian ATG8 homolog is LC3B.

[0183] In another embodiment of the present application, the disease associated with autophagy, in particular a mammalian ATG8 homolog is selected from the group consisting of a tumor, a cardiovascular disease, an autoimmune disease, a neurodegenerative disease, hypertension, a bone tissue cell and bone disease, Crohn's disease, acute kidney injury, cerebral ischemia, retinal disease, bronchial asthma, Vici syndrome, and an infectious disease.

[0184] In another embodiment of the present application, the tumor is selected from the group consisting of liver cancer, lung cancer, pancreatic cancer, breast cancer, cervical cancer, endometrial cancer, colon cancer, stomach cancer, lung cancer, nasopharyngeal cancer, ovarian cancer, prostate cancer, leukemia, lymphoma, myeloma.

[0185] In the use of the medicament for the preparation of the medicament for modulating autophagy of cells and the method for modulating autophagy of cells according to the present application, some preferred compounds are selected from the group consisting of the compounds of general formula Ob), the compounds of general formula (lid), the compounds of general formula (lid), the compounds of general formula (IVd), and the compounds of general formula (Vc).

[0186] (Vc) compounds, wherein the descriptions of general formula (Ib), general formula (lid), general formula (lid), general formula (IVd), and general formula (Vc) are the same as above; or some preferred compounds are selected from the group consisting of compound 2, compound 3, compound 241, compound 264, compound 449, compound 462, compound 463, and compound 464.

[0187] It should be understood that the foregoing general description and the following detailed description of the present application are both exemplary and explanatory, and are intended to provide further explanation of the claimed application.

[0188] DETAILED DESCRIPTION

[0189] The embodiments of the present application will be described in detail below.

[0190] The terms used in the present application have their general meanings in the art. The chemical names, common names, and chemical structures can be used interchangeably to describe the same structure. These definitions apply regardless of whether the term is used alone or in combination with other terms. Thus, the definition of "C1-6alkyl" applies to "C1-6alkyl" as well as the "C1-6alkyl" portion of "C1-6alkoxy", "C1-6haloalkyl", "C6-10aryl C1-6alkyl", "C1-6alkyl C6-10aryl", "C1-6alkoxy", and the like.

[0191] A "pharmaceutical composition" refers to a composition suitable for administering to a patient. The composition can contain only a compound of the present application or a mixture of compounds of the present application, or a salt, solvate, prodrug, isomer, or tautomer of a compound of the present application, or the compound of the present application in combination with one or more pharmaceutically acceptable carriers or excipients. A "patient" includes both human and non-human animals. The pharmaceutical composition can be in a variety of forms, such as tablets, capsules, powders, syrups, solutions, suspensions, and aerosols, and can be present in a suitable solid or liquid carrier or diluent and a suitable sterile device for injection or infusion.

[0192] The pharmaceutical compositions of the present application can be prepared by conventional methods in the pharmaceutical art. The formulations are prepared in unit dosage form of 0.05-200 mg of the compound of formula (I), preferably 0.1 mg-100 mg of the compound of formula (I) per unit dosage form.

[0193] The compounds and pharmaceutical compositions of the present application can be used clinically on mammals, including humans and animals, by oral, nasal, dermal, pulmonary, or gastrointestinal routes of administration. Oral administration is most preferred. The optimal daily dose is 0.01-200 mg / kg body weight, administered in a single dose or in divided doses of 0.01-100 mg / kg body weight. Regardless of the route of administration, the optimal dose for an individual is determined by the specific treatment. Generally, the dose is started from a small amount and gradually increased until the optimal dose is found.

[0194] "Halo" (or halogen) means fluorine, chlorine, bromine, or iodine.

[0195] "C1-6alkyl" means a straight or branched chain alkyl group containing 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms. Branched means one or more lower C1-6alkyl groups, such as methyl, ethyl, or propyl, are attached to the straight chain alkyl group. Preferred C1-6alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, and t-butyl.

[0196] "C1-6haloalkyl" means a C1-6alkyl group as defined above containing one or more halogen atom substituents.

[0197] "C1-6heteroalkyl" means a C1-6alkyl group as defined above containing one or more substituents selected from the group consisting of O, S, N, -(S=0)-, -(O=S=O)-, and the like.

[0198] "C2-6alkenyl" means a straight or branched chain alkenyl group containing 2 to 6 carbon atoms, preferably 2 to 4 carbon atoms. Branched means one or more lower C1-6alkyl groups are attached to the straight chain C2-6alkenyl chain. Preferred C2-6alkenyl groups include, but are not limited to, ethenyl, propenyl, n-butenyl, 3-methylbutenyl, n-pentenyl, and the like.

[0199] "C1-6alkylene" means a divalent group obtained by removing one hydrogen atom from a C1-6alkyl group as defined above. Preferred C1-6alkylene groups include, but are not limited to, methylene, ethylene, and propylene. Generally, it can be optionally and equivalently represented herein as -(C1-6alkyl)-, e.g., -CH2CH2- is ethylene.

[0200] "C2-6alkynyl" means a straight or branched chain alkynyl group containing 2 to 6 carbon atoms, preferably containing 2 to 6 carbon atoms, more preferably containing 2 to 4 carbon atoms. Branched means one or more alkyl groups containing 2 to 4 carbon atoms are attached to the straight chain alkynyl chain. Preferred C2-6alkynyl groups include, but are not limited to, ethynyl, propynyl, 2-butynyl, and 3-methylbutynyl, and the like.

[0201] "C2-6alkenyl" means a straight or branched chain alkenyl group containing 2 to 6 carbon atoms, preferably containing 2 to 6 carbon atoms, more preferably containing 2 to 4 carbon atoms. Branched means one or more alkyl groups containing 2 to 4 carbon atoms are attached to the straight chain alkenyl chain. Preferred C2-6alkenyl groups include, but are not limited to, -CH=CH2, -C(CH3)=CH2, -CH=CHCH3, and the like.

[0202] "C6-10aryl" means an aromatic monocyclic or polycyclic ring system containing 6 to 10 carbon atoms. Preferred C6-10aryl groups include, but are not limited to, phenyl and naphthyl.

[0203] "C6-10arylene" means a divalent radical derived from a C6-10aryl group as defined above by removal of one hydrogen atom, for example,

[0204] "5-10 membered heteroaryl" means an aromatic monocyclic or polycyclic ring group containing 5 to 10 ring atoms, said 5-10 membered heteroaryl group containing 1 to 4 heteroatoms selected from N, O, and S. Preferred 5-10 membered heteroaryl groups contain 5 to 6 ring atoms. The nitrogen atom of a 5-10 membered heteroaryl group can optionally be oxidized to the corresponding N-oxide. The term "5-10 membered heteroaryl" also includes fused ring systems of the above defined C6-10aryl groups. Preferred 5-10 membered heteroaryl groups include, but are not limited to, pyridyl, pyrazinyl, furanyl, thienyl, pyrimidinyl, pyridone, oxazolyl, isothiazolyl, oxazolyl, oxadiazolyl, thiazolyl, thiadiazolyl, pyrazolyl, furazanyl, pyrrolyl, triazolyl, 1,2,4-thiadiazolyl, pyridazinyl, quinoxalinyl, phthalazinyl, oxindolyl, imidazo[l,2-a]pyridyl, imidazo[2,l-b]thiazolyl, benzofurazanyl, indolyl, azaindolyl, benzimidazolyl, benzothienyl, quinolinyl, imidazolyl, thienopyridyl, quinazolinyl, thienopyrimidinyl, pyrrolopyridyl, imidazopyridines, isoquinolinyl, benzoxazinyl, 1,2,4-triazinyl, benzothiazolyl, and the like, and oxides thereof. The term "5-10 membered heteroaryl" also means partially saturated 5-10 membered heteroaryl groups, for example, tetrahydroisoquinolinyl, tetrahydroquinolinyl, and the like.

[0205] "C3-10cycloalkyl" means a non-aromatic monocyclic or polycyclic group containing 3 to 10 carbon atoms, preferably 3 to 6 carbon atoms. Preferred monocyclic C3-10cycloalkyl groups include, but are not limited to, cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like. Preferred polycyclic cycloalkyl groups include, but are not limited to, [l,l]-bicyclopentyl, 1-decaloyl, norbornyl, adamantyl, and the like.

[0206] "C3-10cycloalkenyl" means a non-aromatic monocyclic or polycyclic group containing 3 to 10 carbon atoms, which contains at least one carbon-carbon double bond within the ring, preferably containing 3 to 7 ring atoms, more preferably containing 5 to 7 ring atoms. Preferably the C3-10cycloalkenyl groups include, but are not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cyclopentenyl, cycloheptenyl-l,3-dienyl, norbornenyl, and the like.

[0207] "3-10 membered heterocycloalkyl" (or "3-10 membered heterocyclyl") means a non-aromatic saturated monocyclic or polycyclic group containing 3 to 10 ring atoms, preferably 5 to 10 ring atoms, preferably 5 to 6 ring atoms, wherein the 3-10 membered heterocyclyl contains 1 to 4 heteroatoms selected from N, O, and S, and no two heteroatoms are adjacent in the ring system. The nitrogen or sulfur atom of the 3-10 membered heterocyclyl group can optionally be oxidized to the corresponding N-oxide, S-oxide, or S,S-dioxide. Thus, the term "oxide" in the present application means the corresponding N-oxide, S-oxide, or S,S-dioxide. The "3-10 membered heterocyclyl" also includes two available hydrogen atoms on the same carbon atom of the ring system being simultaneously replaced with a single group =0 (e.g., a carbonyl group;), such =0 group can be referred to as an "oxo" in the present application. Preferred monocyclic 3-10 membered heterocycloalkyl groups include, but are not limited to, piperidinyl, oxetanyl, pyrrolinyl, piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, 1,4-dioxanyl, tetrahydrofuranyl, tetrahydrothienyl, lactam groups (such as pyrrolidonyl;), lactone groups of 3 to 10 ring atoms, and oxides thereof.

[0208] "3-7 membered heterocycloalkenyl" refers to a non-aromatic monocyclic or polycyclic group containing 3 to 7 ring atoms, preferably 5 to 6 ring atoms, wherein the 3-7 membered heterocycloalkenyl group contains 1 to 4 heteroatoms selected from N, O, and S, and which contains at least one carbon-carbon double bond or carbon-nitrogen double bond. There are no adjacent oxygen and / or sulfur atoms in the ring system. The prefix aza, oxa or thia before the 3-7 membered heterocycloalkenyl root name means that at least a nitrogen, oxygen or sulfur atom, respectively, is a ring atom. The nitrogen or sulfur atom of a 3-7 membered heterocycloalkenyl group can optionally be oxidized to the corresponding N-oxide, S-oxide or S-sulfoxide or S-dioxide. Preferred 3-7 membered heterocycloalkenyl groups include, but are not limited to, 1,2,3,4-tetrahydropyridinyl, 1,2-dihydropyridinyl, 1,4-dihydropyridinyl, 1,2,3,6-tetrahydropyridinyl, 1,4,5,6-tetrahydropyrimidinyl, 2-pyrrolinyl, 3-pyrrolinyl, 2-imidazolinyl, 2-pyrazolinyl, dihydroimidazolyl, dihydrooxazolyl, dihydrooxadiazolyl, dihydrothiazolyl, 3,4-dihydro-2H-pyranyl, dihydrofuranyl, fluorodi hydrofuranyl groups and oxides thereof. The "3-7 membered heterocycloalkenyl" can also be one in which two available hydrogen atoms on the same carbon atom of the ring system are simultaneously replaced by a single group =0 (i.e., forming a carbonyl group).

[0209] "C6-10aryl C1-6alkyl" (or "C6-10aryl C1-6alkyl") refers to a radical formed by connecting a C6-10aryl group as defined above to a C1-6alkyl group. Preferred C6-10aryl C1-6alkyl groups include, but are not limited to, benzyl, 2-phenylethyl, and naphthylmethyl. The C6-10aryl C1-6alkyl group is bonded to the parent moiety through the C1-6alkyl group. Similarly, "5-10 membered heteroaryl C1-6alkyl", "C3-10cycloalkyl C1-6alkyl", "C2-6cycloalkenyl C1-6alkyl", "3-10 membered heterocycloalkyl C1-6alkyl", "3-7 membered heterocycloalkenyl C1-6alkyl", and the like refer to 5-10 membered heteroaryl, C2-6cycloalkenyl, 3-10 membered heterocycloalkyl, 3-7 membered heterocycloalkenyl, and the like, as described herein, bonded to the parent moiety through a C1-6alkyl group.

[0210] "C6-10aryl C1-6alkyl" (or "C6-10aryl C1-6alkyl") refers to a radical formed by connecting a C6-10aryl group as defined above to a C1-6alkyl group. Preferred C6-10aryl C1-6alkyl groups include, but are not limited to, benzyl, 2-phenylethyl, and naphthylmethyl. The C6-10aryl C1-6alkyl group is bonded to the parent moiety through the C1-6alkyl group. Similarly, "5-10 membered heteroaryl C1-6alkyl", "C3-10cycloalkyl C1-6alkyl", "C2-6cycloalkenyl C1-6alkyl", "3-10 membered heterocycloalkyl C1-6alkyl", "3-7 membered heterocycloalkenyl C1-6alkyl", and the like refer to 5-10 membered heteroaryl, C2-6cycloalkenyl, 3-10 membered heterocycloalkyl, 3-7 membered heterocycloalkenyl, and the like, as described herein, bonded to the parent moiety through a C1-6alkyl group.

[0211] "C6-ioaryl C1-6alkyl" refers to groups derived from C6-ioaryl groups as defined above attached through an C1-6alkyl group. Preferred C6-ioaryl C1-6alkyl groups include, but are not limited to, phenylmethyl and naphthylmethyl. The C6-ioaryl C1-6alkyl group is attached to the parent moiety through the C1-6alkyl group.

[0212] "C1-6alkyl" refers to a straight, branched, or cyclic hydrocarbon groups having from one to six carbon atoms and includes methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, n-pentyl, n-hexyl, and cyclohexyl. Preferred C1-6alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, and t-butyl.

[0213] "C1-6alkoxy" refers to a C1-6alkyl-O- group attached through oxygen to the parent moiety, wherein C1-6alkyl is as described above. Preferred C1-6alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propyloxy, i-propyloxy, and n-butyloxy.

[0214] "C1-6alkoxyalkyl" refers to groups derived from C1-6alkoxy groups as defined herein and C1-6alkyl groups, attached through the C1-6alkyl group to the parent moiety.

[0215] "C1-6alkyl" refers to a straight, branched, or cyclic hydrocarbon groups having from one to six carbon atoms and includes methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, n-pentyl, n-hexyl, and cyclohexyl. Preferred C1-6alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, and t-butyl.

[0216] "Carboxamide" or "carboxylic acid amide" refers to the group -C(O)NRxRy, wherein Rxand R y R y , and R y and R y are hydrogen, C1-6alkyl, C6-10aryl, C6-10aryl C1-6alkyl, or C3-10cycloalkyl.

[0217] Any of the foregoing functional groups of the application can be unsubstituted or substituted with a substituent group described herein. The term "substituted" (or substitution) means the replacement of one or more hydrogen atoms on the designated atom with a group selected from the specified groups, provided that the substitution results in a stable compound. Only stable compounds are within the scope of the application. The combination of substituents and / or variables must be allowed, in terms of valency and the normal definition of the chemistry of the application; "stable compound" or "stable structure" is meant to indicate a compound that is sufficiently robust to survive isolation to useful purity from a reaction mixture and to be formulated into an effective therapeutic agent.

[0218] The term "unsubstituted or substituted" means that a particular group is either not substituted or substituted with one or more substituents. Substituents include, without limitation, hydrogen, hydroxyl, amino, cyano, nitro, carboxyl, halogen, Ci-6alkyl, Ci-6haloalkyl, or Ci-6hydroxyalkyl. Two adjacent substituents can be joined to form a C6-10aryl, 5-10 membered heteroaryl, C3-10cycloalkyl, or 3-10 membered heterocycloalkyl. Substitution on C6-10aryl, 5-10 membered heteroaryl, C3-10cycloalkyl, 3-10 membered heterocycloalkyl, 3-7 membered heterocycloalkenyl, and the like groups includes substitution on any ring moiety of the group.

[0219] In the present application, if a group is "a covalent bond", it is meant that the group "does not exist" and the two groups attached by the covalent bond are attached by a covalent bond. For example, in the substituent "-J-K-M-Q", if K is a covalent bond, then the substituent becomes "-J_M-Q".

[0220] Tautomers refer to compounds that result from the phenomenon of the transfer of a proton from one atom to another in a molecule. Tautomers also refer to two or more isomeric forms in equilibrium that are readily converted from one isomeric form to another. 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.

[0221] In particular, the compounds of the present application include all tautomers thereof, e.g., keto-enol tautomers. For convenience, in the detailed description of the application and in the claims, these tautomers and mixtures thereof are shown in the keto form, (Example 11,

[0222] 112, and Hercon B 415) are shown below.

[0223]

[0224] 415

[0225] For convenience, only one tautomer of each compound is shown in the present application. It should be noted that the compounds of the present application include all tautomers.

[0226] Stereoisomers refer to compounds having the same molecular formula, the same arrangement of atoms but a different arrangement of atoms in space resulting in isomerism. Stereoisomerism includes cis-trans isomerism, conformational isomerism, enantiomeric isomerism and diastereomeric isomerism, among others. Cis-trans isomerism refers to isomerism due to the inability of the two carbon atoms attached to a double bond to rotate freely about the sigma bond, typically referring to alkenes, but also C=N double bonds, N=N double bonds and cyclic compounds. Enantiomeric isomers refer to stereoisomers that are mirror images of one another. Diastereomeric isomers refer to stereoisomers that have two or more chiral centers and are not mirror images of one another. Unless otherwise stated, this specification is intended to include both individual stereoisomers and mixtures thereof.

[0227] Specifically, the compounds of the present application include all isomers thereof, such as diastereomers and cis / trans (Z / E) isomers. An example of a cis-trans isomer of Compound 101 disclosed herein is shown below.

[0228]

[0229] For convenience, only one isomer of each compound is exemplified in the present application. It should be noted that the compounds of the present application include all stereoisomers.

[0230] The compounds of the present application can 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, among others. Examples of metal chelates are given in Example 38, as described herein. It should be noted that the compounds of the present application include all metal chelates.

[0231] The term "pharmaceutically acceptable salt" refers to a substance that is suitable for use with humans and / or animals without undue adverse side effects (such as toxicity, irritation, and allergic response) commensurate with a reasonable benefit / risk ratio, and is acceptable to a medical doctor at the time of manufacture, for example, salts of inorganic and organic acids, which can be obtained during the final isolation and purification of the compounds of the present application, or by reaction of the free acid or base function with a suitable base or acid, respectively. Suitable salts of acids include, but are not limited to, inorganic acids such as hydrochloric, phosphoric, or sulfuric acids, or organic acids such as citric, ascorbic, citric, tartaric, lactic, maleic, malonic, fumaric, glycolic, succinic, propionic, acetic, or methanesulfonic acids, among others. Suitable salts of bases 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, among others, and organic bases such as aminoethanol, among others.

[0232] The term "effective amount" refers to the amount of a compound of the present application contained in the composition administered sufficient to modulate (e.g., inhibit or agonize, etc.) a mammalian ATG8 homolog.

[0233] The compounds of the present application can be prepared by various methods known in the art, and the following reaction schemes are alternatives for preparing the compounds of the present application.

[0234] General Reaction Schemes

[0235]

[0236] The definitions of the groups or substituents in the above schemes are the same as those of Formula ①. The compounds can be prepared by methods described in some references known to those of ordinary skill in the art. These references include, for example: 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.

[0237] Examples

[0238] The application will be further described in conjunction with specific examples. It should be understood that these examples are intended to illustrate the application and are not intended to limit the scope of the application, and the application is not limited to these examples. Those skilled in the art will readily understand that the compounds can be prepared using known variations of the conditions and procedures of the following preparations. The starting reactants used in the application are commercially available unless otherwise specified.

[0239] Abbreviations: acetonitrile (MeCN, ACN); aqueous solution (aq.); benzyl bromide (BnBr); di-tert-butyl dicarbonate (Boc2O); methyl tert-butyl ether (t-BuOMe); potassium tert-butoxide (t-BuOK); sodium tert-butoxide (t-BuONa); cerium ammonium nitrate (CAN); concentrated / highly concentrated (con.); dichloromethane (DCM); diisobutylaluminum hydride (DIBAL-H;); diisopropylethylamine (DI(P)EA); 4-dimethylaminopyridine (DMAP); N,N-dimethylformamide dimethyl acetal (DMF-DMA); dimethylformamide (DMF); dimethyl sulfoxide (DMSO); ethyl acetate (EA or EtOAc); equivalent (eq.); ethanol (EtOH); sodium ethoxide (EtONa); gram / milligram (g / mg); 2-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU); hour (h, hr, hrs); acetic acid (HOAc); liter / milliliter (L / mL) ; liquid chromatography-mass spectrometry (LCMS); lithium diisopropylamide (LDA); methanol (MeOH); mole / millimole (mol / mmol); mass spectrometry (MS); methanesulfonyl chloride (MsCl); minute(s) (min(s)); sodium acetate (NaOAc); nitrogen (N2); N-bromosuccinimide (NBS); N-methylmorpholine oxide (NMO); nuclear magnetic resonance (NMR); palladium on carbon (Pd / C); petroleum ether (PE); benzoyl chloride (PhCOCl); toluene (PhMe); triphenylphosphine (PPh3); pyridine (Py); 1H-benzotriazol-1-yl-oxytris-pyrrolidino-phosphonium hexafluorophosphate (PyBOP); preparative thin layer chromatography (Pre-TLC); room temperature (RT, rt); triethylamine (TEA); tetrahydrofuran (THF); thin layer chromatography (TLC); trimethylsilyl chloride (TMSCl); 1,1'-bis(diphenylphosphino)ferrocene palladium dichloride 21.

[0240] (Pd(dppf)₂Cl₂). June 21, 2018. General synthesis method:

[0241] Unless otherwise specified, all reactions are carried out in an inert gas atmosphere (such as argon or nitrogen), and commercially available reagents and anhydrous solvents used do not require further treatment.

[0242] Mass spectrometry was recorded using a liquid chromatography-mass spectrometry (LC-MS) system (Agilent 6120B single quadrupole LC-MS system). Nuclear magnetic resonance (NMR) spectra (such as proton NMR, carbon NMR) were also recorded. 13 C) Phosphorus spectrum ( 31 P) and fluorine spectrum ( 19 F) NMR spectra were recorded using a Bruker AMX-400, Gemini-300, or AX-600 NMR spectra in deuterated solvents such as deuterated chloroform, deuterated methanol, deuterated water, or deuterated dimethyl sulfoxide, with the deuterated solvent peak serving as the reference standard. The chemical shift δ is expressed in ppm, and the coupling constant (J or J) is expressed in Hertz (Hz). Coupled split peaks in the NMR spectrum are represented as: broad singlet (brs), singlet (d), doublet (dd), triplet (t), quartet (q), and multiplet (m).

[0243] Example 1: Synthesis of compound 2-(4-(2-aminoethyl)piperazin-1-yl)ethanol-1-ol

[0244] Step 1: Synthesis of compound 2-(2-(4-(2-hydroxyethyl)piperazin-1-yl)ethyl)isoindoline-1,3-dione

[0245] Compound 2-(2-bromoethyl)isodihydroindole-1,3-dione (20.0 g, 78 mmol), compound 2-(piperazinyl)ethanol-1-ol (10.2 g, 78 mmol), and potassium carbonate (22.0 g, 156 mmol) were dissolved in 100 mL of acetonitrile. The mixture was refluxed for 3 hours. After the reaction was complete, the mixture was cooled to room temperature, filtered, and the residue was washed with acetonitrile (100 mL). The filtrate was collected, concentrated, and purified by column chromatography to give 13.45 g of the target compound, with a yield of 57%.

[0246] Step 2: Synthesis of compound 2-(4-(2-aminoethyl;)piperazine-1-yl)ethanol-1-ol

[0247] compound2 - 2 -[ 4 -( 2 [-hydroxy-ethyl]-piperazine-1-yl]-ethyl}-isoindole-I, 3 -Diketone(1) 3 . 4 43.67 mmol) and hydrazine hydrate (80%, 6 mL) were dissolved in ethanol (130 mL) and refluxed for 4 hours. After the reaction was complete, the mixture was cooled to room temperature, filtered, and the residue was washed with cold ethanol (10 mL x 2). The filtrate was collected and concentrated to obtain 6.5 g of crude product, which was used directly in the next reaction without further purification.

[0248] Example 2: Compound 5-(((2-(4-(2-hydroxyethyl;)piperazin-1-yl)ethyl)amino)methylene)-2,2-dimethyl-1,3-dioxane-4,6-dione (compound)

[0249] 5-(methoxymethylene)-2,2-dimethyl-1,3-dioxane-4,6-dione (186 mg, 1 mmol) was dissolved in 5 mL of ethanol, and 2-(4-(2-aminoethyl)piperazin-1-yl)ethanol-1-ol (259.5 mg, 1.5 mmol) was added. The mixture was reacted at room temperature for 15 minutes, concentrated to obtain a crude product, and purified by column chromatography to obtain 220 mg of the target compound, with a yield of 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).

[0250] Example 3: Synthesis of Compound 2-(aminomethylene)-5-phenylcyclohexane-1,3-dione (Compound 2) - Correction Page (Detailed Rules, Clause 91) ISA / CN Compound 2-dimethylaminomethylene-5-phenylcyclohexane-1,3-dione (1.1 g, 4.52 mmol) was dissolved in ammonia in methanol (7 N, 50 mL), stirred at room temperature for 1 hour, concentrated to obtain a crude product, and separated by column chromatography to obtain 900 mg of the target compound, with a yield of 93%. Compound 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].

[0251] Example 4: Synthesis of compound 2-(hydroxymethylene)-5-phenylcyclohexane-l,3-dione (compound 3)

[0252]

[0253] Compound 2-(dimethylamino)methylene)-5-phenylcyclohexane-l,3-dione (244 mg, lmmol) was dissolved in 5 mL of methanol, and concentrated hydrochloric acid (lmL) was added dropwise. The reaction was allowed to proceed at room temperature for 30 minutes. The crude product was concentrated and purified by column chromatography to give the target compound 3 (162 mg, 75% yield). Compound 3: IH NMR (400 MHz, DMSO-d6) δ 9.58 (s, IH), 7.27-7.30 (m, 4H), 7.16-7.19 (m, IH), 3.14-3.20 (m, IH), 2.51 (d, J = 16.8 Hz, IH), 2.47 (d, J = 9.2 Hz, IH), 2.31 (dd, J = 16.0, 4.0 Hz, 2H); LCMS: 217.1 [M+l].

[0254] Synthesis of compound 5-(2-bromophenyl)-2-(hydroxymethylene)-l,3-dione (compound 4)

[0255] Compound 4 was synthesized by the same method as compound 3. Compound 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].

[0256] Example 5: Synthesis of compound - ((methylthio)methylene)-5-phenylcyclohexane-1,3-dione (Compound 4A)

[0257]

[0258] Compound 2-((dimethylamino)methylene)-5-phenylcyclohexane-1,3-dione (200 mg, 0.823 mmol) was dissolved in 5 mL of absolute ethanol and 5 mL of DCM, ImL of acetic acid and sodium methanethiolate (115 mg, 1.64 mmol) were added at room temperature, the mixture was stirred in a sealed tube at room temperature for 16 hours. ImL of acetic acid and sodium methanethiolate (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 dichloromethane (DCM) was used for extraction. The organic phase was washed with water and saturated brine in sequence, dried over anhydrous sodium sulfate, and concentrated to obtain a crude product, which was separated by column chromatography to obtain 15 mg of the target compound 4A at a yield of 7%. Compound 4A: 1H NMR (400 MHz, DMSO-d6) δ 8.75 (s, IH), 7.33-7.19 (m, 5H), 3.46-3.37 (m, IH), 2.95-2.86 (m, 2H), 2.72-2.64 (m, 2H), 2.60 (s, 3H); MS: 247.1 [M+l]

[0259] Example 6: Synthesis of compound 5- -2- ((phenyl -1,3-dione (Compound 5)

[0260] Compound 2-((dimethylamino)methylene)-5-phenylcyclohexane-l,3-dione (200 mg 0.82 mmol), aniline (60 mg 0.65 mmol) and acetic acid (0.5 mL) were dissolved in 10 mL of ethanol, and the reaction was refluxed for 1 hour. After cooling to room temperature, the crude product was concentrated and separated by column chromatography to obtain the target compound 150 mg, yield 79%. Compound 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]

[0261] Example 7: Synthesis of compounds 6 and 7

[0262] The synthesis method of compounds 6 and 7 is the same as that of compound 5, as shown in Table 1.

[0263] Table 1: Compounds 6 and 7

[0264] Example 8: Synthesis of compound 2-(((2-(4-(2-hydroxyethyl)piperazin-l-yl)ethyl)amino)methylene)-5-phenylcyclohexane-l,3-dione (compound 8)

[0265]

[0266] Step 1: Synthesis of compound 2-((dimethylamino)methylene)-5-phenylcyclohexane-l,3-dione

[0267] Compound 5-phenylcyclohexane-l,3-dione (5.0 g 26.6 mmol) was dissolved in chloroform (25 mL), and N,N-dimethylformamide dimethyl acetal (DMF-DMA) (5 mL) was added. The mixture was reacted at room temperature for 1 hour. After the reaction was completed, the reaction solution was concentrated, and the concentrate was slurried with 10% ethyl acetate (EA) / petroleum ether (PE) to precipitate, filtered, and the filter residue was dried to obtain the target compound 4.81 g, yield 74%

[0268] Step 2: Compound 2-(((2-(4-(2-hydroxyethyl)piperazin-l-yl)ethyl)amino)methylene)-5-phenylcyclohexane-l,3-dione

[0269] Synthesis of compound 8

[0270] Compound 2-(4-(2-aminoethyl)piperazin-l-yl)ethanol (200 mg 1.15 mmol) was dissolved in 5 mL of ethanol, and compound 2-((dimethylamino)methylene)-5- phenylcyclohexane-l,3-dione (365 mg, 1.5 mmol) was added, and the reaction was allowed to proceed at room temperature for 30 minutes.

[0271] 42

[0272] Compound 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].

[0273] Example 9: Compounds 9-12, 14-15

[0274] The synthesis of compounds 9-12 and 14-15 was performed as for compound 8, except that the corresponding substituted 1,3-cyclohexanedione or other ketone with a reactive methylene group was used (e.g. Example 9-1), as shown in Table 2.

[0275] Table 2: Compounds 9-12 and 14-15

[0276] 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

[0277] 43

[0278] Correction page (Rule 91) ISA / CN Compound (2S, 6'R)-7-chloro-2',4,6-trimethoxy-6'-methyl-3H-spiro[benzofuran-2,1'-cyclohexane]-2'-ene-3,4'-dione (1.0 g, 2.84 mmol) and cerium ammonium nitrate (1.55 g, 2.84 mmol) were dissolved in a mixed solvent of acetonitrile (40 mL) and water (40 mL) and heated to reflux for 6 hours. After completion of the reaction, it was cooled to room temperature, poured into water, extracted with EA, and the organic phase was washed with water and saturated brine in turn, dried over anhydrous sodium sulfate, and concentrated to obtain a crude product. The target compound 880 mg was obtained by column chromatography separation with a yield of 91%.

[0279] Example 10: Synthesis of compound 2-(((2-(4-(2-hydroxyethyl)piperazin-1-yl)ethyl)amino)methylene)-5-(1H-pyrrolo[2,3-b]pyridin-4-yl)cyclohexane-1,3-dione (Compound 17)

[0280]

[0281] Step 1: Synthesis of compound 4-bromo-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine

[0282] Compound 4-bromo-1H-pyrrolo[2,3-b]pyridine (3.0 g, 15.23 mmol) was dissolved in anhydrous tetrahydrofuran (THF) (50 mL) under nitrogen protection. At 0°C, 60% sodium hydride (800 mg, 20 mmol) was added to the above mixture in batches, and after stirring at this temperature for 30 minutes, phenylsulfonyl chloride (3.53 g, 20 mmol) was added. The resulting mixture was reacted at room temperature for 1 hour. After completion of the reaction, the reaction mixture was slowly quenched with ice water at 0°C, extracted with EA, and the organic phase was washed with water, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by column chromatography to obtain the target compound 4.3 g with a yield of 84%.

[0283] Step 2: Synthesis of compound 1-(phenylsulfonyl)-4-vinyl-1H-pyrrolo[2,3-b]pyridine

[0284] Compound 4-bromo-l-(phenylsulfonyl)-lH-pyrrolo[2,3-b]pyridine (4.3 g, 12.8 mmol) was dissolved in 50 mL of dioxane and 10 mL of water under nitrogen protection, and Pd(dppf)2Cl2(470 mg, 0.64 mmol), potassium ethylene trifluoroborate (2.57 g, 19.2 mmol) and N,N-diisopropylethylamine (DIPEA) (3.23 g, 25 mmol) were added in sequence. The mixture was heated to reflux for 2 hours, cooled to room temperature after the reaction was completed, poured into ice water, extracted with EA, and the organic phase was washed with water and saturated brine respectively, dried, concentrated to obtain the crude product, and the target compound 2.52 g was separated by column chromatography with a yield of 70%.

[0285] Step 3: Synthesis of compound l-(phenylsulfonyl)-lH-pyrrolo[2,3-b]pyridine-4-carbaldehyde

[0286] Compound l-(phenylsulfonyl)-4-ethenyl-lH-pyrrolo[2,3-b]pyridine (2.52 g, 8.86 mmol) was dissolved in 50 mL of acetone and 10 mL of water, and N-methyl-N-oxymorpholine (1.56 g, 13.3 mmol) and potassium osmium dihydrate (100 mg) were added. After reacting at room temperature for 2 hours, sodium periodate 7.56 g, 35.44 mmol) was added in portions to the above reaction solution, and then the reaction was continued at room temperature for 1 hour. After the reaction was completed, it was poured into water, extracted with EA, and the organic phase was washed with water and saturated brine respectively, dried, concentrated to obtain the crude product, and the target compound 1.52 g was separated by column chromatography with a yield of 60%.

[0287] Step 4: Synthesis of compound 4-(l-(phenylsulfonyl)-lH-pyrrolo[2,3-b]pyridin-4-yl)butan-3-en-2-one Compound l-(phenylsulfonyl)-lH-pyrrolo[2,3-b]pyridine-4-carbaldehyde (1.52 g, 5.3 mmol) and l-triphenylphosphine-2-propanone (2.55 g, 8 mmol) were added to 30 mL of anhydrous THF respectively, and refluxed for 2 hours. After the reaction was completed, it was cooled to room temperature and concentrated to obtain the crude product, and the target compound 1.52 g was separated by column chromatography with a yield of 88%.

[0288] Step 5: Synthesis of compound 5-(lH-pyrrolo[2,3-b]pyridin-4-yl)cyclohexane-l,3-dione

[0289] To a solution of sodium ethoxide (412 mg, 6.06 mmol) in ethanol (20 mL) was added diethyl malonate (970 mg, 6.06 mmol) and stirred at room temperature for 10 min. A solution of 4-0 phenylsulfonyl 1H-pyrrolo[2,3-b]pyridine-4-yl)but-3-en-2-one (1.52 g, 4.66 mmol) in ethanol (10 mL) was added dropwise and heated to reflux for 1 h. The reaction mixture was cooled to room temperature, added 50 mL of water, extracted with EA (50 mL), the aqueous phase was adjusted to pH = 2-3 with 3N hydrochloric acid, heated to reflux for 30 min. The reaction mixture was cooled to room temperature, extracted with EA, and the combined organic phase was washed with water and saturated brine, dried and concentrated. The crude product was separated by column chromatography to give the target compound 620 mg, yield 58.3%.

[0290] Step 6: Synthesis of compound 2-(((2-(4-(2-hydroxyethyl)piperazin-1-yl)ethyl)amino)methylene)-5-(1H-pyrrolo[2,3-b]pyridin-4-yl)cyclohexane-1,3-dione

[0291] Procedure as in Example 2. Compound 1H NMR (400 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].

[0292] Example 11: Compounds 18-32

[0293] The synthesis of compounds 18-32 was performed as for compound 17 except that the corresponding bromo C6-10 aryl or aldehyde was used (as in Examples 11-1 to 11-5), as shown in Table 3.

[0294] Table 3: Compounds 18-32

[0295] Structure Name Hydrogen spectrum (1H NMR), Mass spectrum (MS)

[0296] 2-(((2-(4-(2-hydroxyethyl)) ] ¹H NMR (400 MHz, CDCl₃) δ 11.28 -piperazin-1-yl)ethyl)amino11 +08 (m, 1H), 9.50 (s, 1H), 8.32 (d, J)

[0297] 18 ο = 4.0 Hz, 1H), 8.20 (d, J = 14.3 Hz, yl)methylene) -5-(1H-1H), 7.97 (d, J = 7.8 Hz, 1H), δ 7.14 -pyrrolo[2,3-b]pyridine 7.07 (m, 2H), 3.85 - 3.62 (m, 3H), 3.52 -3-yl)cyclohexane-1,3-di(m, 2H), 3.02 - 2.65 (m, 17H); MS: ketone 412.2 [M+l] ,

[0298] ] ¹H NMR (400 MHz, DMSO-c₆) δ

[0299] 2-(((2-(4-(2-hydroxyethyl) 11.03 - 10.91 (m, 1H), 8.34 - 8.01 (m, piperazine-1-yl)ethyl)amino2H), 7.51 (d, J = 3.5 Hz, 1H), 7.00 (d, J

[0300] = 5.0 Hz, 1H), 6.64 (d, J = 3.5 Hz, 1H), yl)methylene)-5-(1-(2-

[0301] 19 4.40 (t, J = 5.4 Hz, 3H), 3.83 - 3.65 (methoxyethyl)-1H-pyridine (m, 3H), 3.58 (dd, J = 11.6, 5.8 Hz, pyro[2,3-b]pyridine-4-4H), 3.49 (dd, J = 11.4, 5.9 Hz, 3H), cyclohexane-1,3-dione 3.23 (s, 2H), 2.97 - 2.76 (m, 2H), 2.69

[0302] - 2.23 (m, 12H); MS: 470.1 [M+l].

[0303] ]H NMR (400 MHz, DMSO-i / 6) δ

[0304] 2-(((2-(4-(2-hydroxyethyl) 11.09 - 10.83 (m, 1H), 9.09 (dd, J = piperazine-1-yl)ethyl)amino 2.0, 1.0 Hz, 1H), 8.47 (dd, J = 12.3, 4.7)

[0305] 20-yl)methylene)-5-(1,10- Hz, 2H), 8.17 (d, J = 14+6 Hz, 1H), phenanthroline-3-yl)cyclohexane 7.95 (s, 2H), 7.77 (dd, J = 7.6, 6.9 Hz,

[0306] -1,3-dione (2H), 5.20 - 4.90 (m, 1H), 3.94 - 3.52

[0307] (m, 6H), 3.14 - 2.83 (m, 7H), 2.85 - 9

[0308]

[0309] ZY8 and 8Y0Z OAV ~. 2-(((2-(4-(2-hydroxyethyl) 】H NMR (400 MHz, CD3OD) δ 8.07(s, piperazine-1-yl)ethyl)amino1H), 7.34-7.25(m, 4H), 7.18-7.14(m,

[0310] 29 (1-methyl)methylene)-5-methyl (1H), 3.79 (t, J = 5.6 Hz, 2H), 3.53-3.49

[0311] -5-Phenyloncyclohexane-1,3- (m, 2H), 3.06-2.96 (m, 8H), 2.77-2.58 diketone (m, 8H), 1.36 (s, 3H)

[0312] 5-((3aR, 4R, 6R,

[0313] 6aR)-2,2-dimethyl

[0314] •6-(6-morpholino-9H-purin-9-yl)tetrahydrofuran-3-ol (400 MHz, CD30D) δ 8.25 (s, 1H), 8.17 (m, 2H), 6.14 (d, J = 2.6 Hz,

[0315] 1H), 5.42 - 5.31 (m, 1H), 5.08 - 4.99

[0316] 30 m [3,4-D] [1,3]dioxane

[0317] (m, 1H), 4.26 (s, 4H), 3.95 (m, 1H), 3.84 - 3.68 (m, 6H), 3.57 (m, 2H), 2.90 (m, 6H), 2.61 (s, 7H), 2.46 (m, 5H), 1.57 (s, 3H), 1.37 (s, 3H) -1,3-diketone

[0318] -1,3-diketone

[0319] 2-(((2-(4-(2-hydroxyethyl)piperazin-1-yl)ethyl)amino)methyl)pyridine-1,3-dione (400 MHz, CD30D) δ 8.26 (s, 1H), 7.14 (m, 2H), 7.03 - 6.88 (m, 1H), 4.62 (d, J = 5.1 Hz, 2H), 3.97 (d, J = 5.1 Hz, 2H), 3.75 (m, 4H), 3.64 (m, 4H), 3.62 (m, 2H), 3.59 (m, 2H), 2.92 - 2.41 (m, 17H); MS: 402.4 [M+l].

[0320] 31H-methyl)-5-(phenoxymethyl)cyclohexane-1,3-dione

[0321] (t, J = 5.8 Hz, 2H), 3.63 (t, J = 5.8 Hz, 2H), 2.92 - 2.41 (m, 17H); MS: 402.4 [M+l].

[0322] 'HNMR (400 MHz, CD30D) δ 8.22 (s,

[0323] 5-((3-fluorophenoxy)methyl 1H), 7.24 (dd, J = 15.2, 8.1 Hz, 1H), yl) -2-(((2-(4-(2-hydroxyethyl) 6.73 (d, J = 8.2 Hz, 1H), 6.70 - 6.59

[0324] 32-yl)piperazin-1-yl)ethyl) (m, 2H), 3.94 (d, J = 5.1 Hz, 2H), 3.77 amino)methylene)cyclohexane (t, J = 5.6 Hz, 2H), 3.59 (t, J = 5.7 Hz, -1,3-dione 2H), 2.98-2.91 (m, 5H), 2.79 - 2.32

[0325] (m, 12H); MS: 420.4 [M+l].

[0326] Synthesis of ¾6t ll-l: Intermediate 11-1: 4-Bromo-l-(2-methoxyethyl)-1H-pyrrolo[2,3-b]pyridine

[0327] 4-Bromo-7-azaindole (3 g, 15.2 mmol) was dissolved in 30 mL of anhydrous N,N-dimethylformamide (DMF), and sodium hydroxide (60%, 800 mg, 20 mmol) was slowly added at 0 °C for 30 minutes. Then, 2-bromoethyl methyl ether (2.78 g, 20 mmol) was added. ? The reaction was brought to room temperature and carried out for 4 hours. After the reaction was complete, the mixture was slowly poured into ice water, extracted with EA, and the organic phase was washed successively with water and saturated brine, dried, and concentrated. The crude product was separated by column chromatography to obtain 3.12 g of the target compound, with a yield of 80%.

[0328] ¾6fi 11-2: Synthesis of intermediate 11-2: 2-Cyclopropyl-4,5-Dimethoxybenzaldehyde

[0329] Under nitrogen, 6-bromoveratraldehyde (lg, 4.08 mmol), cyclopropylboronic acid (515 mg, 6 mmol), sodium carbonate (1.06 g, 10 mmol) and tetrakis(triphenylphosphine)palladium (100 mg, 0.086 mmol) were added to dioxane (15 mL) and water (5 mL) and the reaction was refluxed overnight. The reaction was allowed to cool to room temperature, poured into ice water and extracted with EA. The organic phase was washed with water and brine, dried and concentrated. The crude product was separated by column chromatography to give the target compound 560 mg, 66% yield.

[0330]

[0331] Step 1 : Synthesis of compound 8-chloroimidazo[l,2-a]pyrazine

[0332] 2-Bromo-l,l-diethoxyethane (22.7 g, 0.115 mol) was heated to reflux in 48% aqueous hydrogen bromide (4.45 mL) for 2 hours and then poured into a solution of sodium bicarbonate (74.5 g) in isopropanol 200 mL. The mixture was stirred for 30 minutes, filtered and to the filtrate was added 3-chloropyrazin-2-amine (5.0 g, 38.6 mmol) and the mixture was stirred at 85 °C for 4 hours. Concentration, addition of saturated sodium carbonate solution and extraction with DCM, drying of the combined organic layers and concentration gave a crude product 5.7 g which was recrystallised from diethyl ether and used directly in the next step without further purification.

[0333] Step 2: Synthesis of compound 3-bromo-8-chloroimidazo[l,2-a]pyrazine

[0334] To a solution of 8-chloroimidazo[l,2-a]pyrazine (5.7 g) in DCM (100 mL) was added BS (6.6 g, 37 mmol) in portions at room temperature and the reaction was stirred at room temperature for 2 hours. The reaction mixture was poured into water and extracted with DCM. The organic phase was washed with water, brine, dried and concentrated to give a crude product 8.0 g which was used directly in the next step without further purification.

[0335] Step 3: Synthesis of compound bromoimidazo[l,2-a]pyrazin-8-yl)morpholine

[0336] A mixture of 3-bromo-8-chloroimidazo[l,2-a]pyrazine (8.0 g), DIPEA (5.7 g, 44 mmol) and morpholine (6.44 g, 74 mmol) was reacted at 80 °C for 4 h. The reaction was completed by pouring into water, extracted with DCM, the organic phase was washed with water, brine, dried, concentrated and separated by column chromatography to give the target compound 5.71 g, yield 52%.

[0337] Example 11-4: Synthesis of intermediate 11-4: (3aS,4S,6R,6aR)-2,2-dimethyl-6-(6-morpholino-9H-purin-9-yl)tetrahydrofuro[3,4-D][l,3]dioxole-4-carbaldehyde

[0338]

[0339] Step 1: Synthesis of compound ((3aR,4R,6R,6aR)-2,2-dimethyl-6-(6-morpholino-9H-purin-9-yl)tetrahydrofuro[3,4-d][l,3]dioxol-4-yl)methanol

[0340] A solution of 6-chloropurine riboside (3.0 g, 10.46 mmol), 2,2-dimethoxypropane (5.2 g, 50 mmol) and p-toluenesulfonic acid monohydrate (1.99 g, 10.46 mmol) in acetone (120 mL) was refluxed for 2 h. Upon completion of the reaction, the reaction mixture was poured into ice water, the pH was adjusted to 8-9, extracted with DCM, the organic phase was washed with water, dried over sodium sulfate and concentrated to give the target compound 3.31 g, yield 96%.

[0341] Step 2: Synthesis of compound ((3aR,4R,6R,6aR)-2,2-dimethyl-6-(6-morpholino-9H-purin-9-yl)tetrahydrofuro[3,4-d][l,3]dioxol-4-yl)methanol

[0342] Compound ((3aR, 4R, 6R, 6aR)-2,2-dimethyl-6-(6-morpholino-9H-purin-9-yl)tetrahydrofuro[3,4-d][l,3]dioxol-4-yl)methanol (700 mg, 1.85 mmol) was dissolved in DCM, and Dess-Martin Oxidizing Reagent (2.5 mmol) was slowly added at 0 °C. The reaction solution was stirred at room temperature for 2 hours. Water was added for dilution, and the mixture was extracted with DCM. The organic phase was washed with saturated brine, dried, and concentrated. The crude product was separated by column chromatography to obtain 508 mg of the target compound at a yield of 73%.

[0343] Step 3: Synthesis of compound (3aS, 4S, 6R, 6aR)-2,2-dimethyl-6-(6-morpholino-9H-purin-9-yl)tetrahydrofuro[3,4-d][l,3]dioxole-4-carbaldehyde

[0344] ((3aR, 4R, 6R, 6aR)-2,2-dimethyl-6-(6-morpholino-9H-purin-9-yl)tetrahydrofuro[3,4-d][l,3]dioxol-4-yl)methanol (700 mg, 1.85 mmol) was dissolved in DCM, and Dess-Martin Oxidizing Reagent (2.5 mmol) was slowly added at 0 °C. The reaction solution was stirred at room temperature for 2 hours. Water was added for dilution, and the mixture was extracted with DCM. The organic phase was washed with saturated brine, dried, and concentrated. The crude product was separated by column chromatography to obtain 508 mg of the target compound at a yield of 73%.

[0345] Example 11-5 -5: Synthesis of 2-phenoxyacetaldehyde

[0346] Step 1: Synthesis of compound (2,2-diethoxyethoxy)benzene

[0347] Phenol (0.94 g, lO mmol), chloroacetaldehyde diethyl acetal (1.52 g, lO mmol), potassium carbonate (2.77 g, 20 mmol), and potassium iodide (500 mg) were dissolved in DMF (15 mL), and the mixture was stirred at 100 °C overnight. After the reaction was completed, the reaction mixture was cooled to room temperature, poured into ice water, extracted with EA, and the organic phase was washed with water, dried over sodium sulfate, and concentrated. The crude product was separated and purified by column chromatography to obtain 1.21 g of the target compound at a yield of 58%.

[0348] Step 2: Synthesis of compound 2-phenoxyacetaldehyde

[0349] (2,2-Diethoxyethoxy)benzene (0.84 g, 4 mmol) was dissolved in a mixture solution of acetic acid (5 mL), IN hydrochloric acid solution (2.5 mL) and ethanol (EtOH) pOmL) and heated to reflux for 3 hours. The reaction was completed and cooled to room temperature, poured into ice water, extracted with EA, the organic phase was washed with water, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by column chromatography to give the target compound 468 mg, yield 86%.

[0350] Example 12: Synthesis of compound 5-(4-(9H-purin-6-yl)phenyl)-2-(((2-(4-(2- hydroxyethyl)piperazin-1-yl)ethyl)amino)methylene)-1,3-dione (Compound 33)

[0351]

[0352] Step 1: Synthesis of compound 6-chloro-9-(tetrahydro-2H-pyran-2-yl)-9H-purine

[0353] 49

[0354] The correction page (Rule 91) ISA / CN heated 6-chloro-9H-purine (4.50 g, 30 mmol), p-toluenesulfonic acid monohydrate (1.14 g, 6.0 mmol) and 3,4-dihydro-2H-pyran (5.05 g, 60 mmol) in EA (200 mL) to reflux for 5 hours. The reaction was completed and cooled to room temperature, poured into ice water, extracted with EA, the organic phase was washed with water, dried over sodium sulfate, concentrated, and the crude product was purified by column chromatography to give the target compound 5.72 g, yield 80%.

[0355] Step 2: Synthesis of compound 4-(9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)benzaldehyde

[0356] A mixture of 6-chloro-9-(tetrahydro-2H-pyran-2-yl)-9H-purine (5.7 g, 24 mmol), sodium carbonate (5.3 g, 50 mmol), 4-formylbenzeneboronic acid (7.5 g, 50 mmol), and tetrakis(triphenylphosphine)palladium (690 mg, 0.6 mmol) in a mixture of dioxane (200 mL) and water (20 mL) was refluxed overnight. After the reaction was completed, the mixture was cooled to room temperature, poured into ice water, extracted with EA, washed with water, dried over sodium sulfate, concentrated, and purified by column chromatography to give the target compound 5.51 g in 74% yield.

[0357] Steps 3, 4, and 5: The same as the procedures of Example 9

[0358] Step 6: Synthesis of compound 5-(4-(9H-purin-6-yl)phenyl)-2-(((2-(4-(2- hydroxyethyl)piperazin-1-yl)ethyl)amino)methylene)cyclohexane-1,3-dione

[0359] A mixture of 2-(((2-(4-(2-hydroxyethyl)piperazin-1-yl)ethyl)amino)methylene)-5-(4-(9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)phenyl)cyclohexane-1,3-dione (160.0 mg, 0.28 mmol) was dissolved in ethanol (3 mL) and DCM (5 mL), and diluted with dilute hydrochloric acid (1 M, 2 mL). After the dropwise addition was completed, the mixture was stirred at room temperature for 6 hours. After the reaction was completed, the mixture was adjusted to alkaline with saturated aqueous sodium bicarbonate solution, extracted with DCM, washed with saturated brine, dried, concentrated, and purified by preparative plate to give the target compound 46 mg in 33% yield. Compound 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].

[0360] Example 12A: Synthesis of compound 2-(((2-(4-(2-hydroxyethyl)piperazin-l- yl)ethyl)amino)methylene)-5-(3-(2-(2-methoxyethoxy)ethoxy)phenyl)cyclohexane-l,3- dione (Compound 34)

[0361] TsO

[0362] KOH

[0363] HPLC

[0364] Step 1: Synthesis of compound 3-(2-(2-methoxyethoxy)ethoxy)benzaldehyde

[0365] 3-hydroxybenzaldehyde (2.00 g, 16.4 mmol), 4-methylbenzenesulfonic acid 2-(2- methoxyethoxy)ethyl ester (4.94 g, 18 mmol) and potassium carbonate (4.53 g, 32.8 mmol) were dissolved in acetonitrile (50 mL) and the reaction was refluxed for 3 hours. The reaction was cooled to room temperature, poured into ice water, extracted with EA, the organic phase was washed with water, dried over sodium sulfate, concentrated and the crude product was purified by column chromatography to give the target compound 1.7 g, yield 46%.

[0366] Step 2: Synthesis of compound 4-(3-(2-(2-methoxyethoxy)ethoxy)phenyl)butan-3- en-2-one

[0367] 50

[0368] 3-hydroxybenzaldehyde (7 g, 31.21 mmol) was dissolved in acetone (20 mL) and water (10 mL), 20 mL of 1% sodium hydroxide solution was added, the mixture was heated to reflux for 2 hours, cooled to room temperature, poured into ice water, extracted with EA. The combined organic phase was washed with water and saturated brine, dried and concentrated. The crude product was purified by column chromatography to give 6.16 g, yield 75%.

[0369] Steps 3, 4 and 5: Synthesis of compound 2-(((2-(4-(2-hydroxyethyl)piperazin-l- yl)ethyl)amino)methylene)-5-(3-(2-(2-methoxyethoxy)ethoxy)phenyl)cyclohexane-l,3- dione

[0370] Steps 3, 4 and 5: The procedure was the same as in Example 9. Compound 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].

[0371] Example 13: Synthesis of compounds 35-59, 61-84

[0372] The synthesis of compounds 35-84 was performed as for compound 34, except that the corresponding benzaldehyde, aromatic aldehyde or substituted 1,3-cyclohexanedione was used (e.g. Examples 13-1 to 13-11), as shown in Table 4.

[0373] Table 4: Compounds 35-59, 61-84

[0374] Z

[0375]

[0376] Z18and Z20OAV

[0377]

[0378] .

[0379] 69 (a ε a3and a7 t

[0380] Z18and Z20OAV

[0381]

[0382] Z18and Z20OAV Example 13-1: Synthesis of intermediate 13-1: 4-(4-methylpiperazin-l-yl)pyridine

[0383] A solution of 6-chloro-3-nitrobenzaldehyde (5 g, 35.32 mmol) and N- methylpiperazine (15.68 L, 141.28 mmol) in DMF was heated to 100 °C for 1 h. The reaction was cooled to room temperature, poured into ice water, extracted with EA, and the combined organic phase was washed with water and saturated brine, dried, and concentrated. The crude product was separated by column chromatography to give the target compound 6.32 g in 87% yield.

[0384] Example 13-2: Intermediate 13-2: Synthesis of 1-adamantanecarboxaldehyde

[0385] Step 1: Synthesis of methyl 1-adamantane carboxylate

[0386] Methyl 1-adamantane carboxylate (3 g, 15.5 mml) was dissolved in 80 ml of toluene under nitrogen protection, and the temperature was lowered to -78 °C. Diisobutylaluminum hydride (1.5 M in toluene, 10.3 mL) was added dropwise, and the temperature was raised to room temperature after the dropwise addition was completed. The reaction was quenched by slowly adding 4N hydrochloric acid, poured into ice water, and extracted with EA. The combined organic phase was washed with saturated brine, dried, and concentrated. The crude product was separated by column chromatography to give the target compound 2.1 g in 82% yield.

[0387] 57

[0388] The reaction was completed, the reaction mixture was cooled to room temperature, poured into ice water, extracted with DCM, and the organic phase was washed with saturated sodium bicarbonate, water, and brine, dried with sodium sulfate, and concentrated to give the target compound crude product 4.8 g in 89% yield.

[0389] Step 2: Synthesis of 1-adamantanecarboxaldehyde

[0390] Methyl 1-adamantane carboxylate (3 g, 15.5 mml) was dissolved in 80 ml of toluene under nitrogen protection, and the temperature was lowered to -78 °C. Diisobutylaluminum hydride (1.5 M in toluene, 10.3 mL) was added dropwise, and the temperature was raised to room temperature after the dropwise addition was completed. The reaction was quenched by slowly adding 4N hydrochloric acid, poured into ice water, and extracted with EA. The combined organic phase was washed with saturated brine, dried, and concentrated. The crude product was separated by column chromatography to give the target compound 2.1 g in 82% yield.

[0391] Example 13-3: Intermediate 13-3: Synthesis of 4-(morpholine-4-carbonyl)benzaldehyde

[0392] 4-Formylbenzoic acid (5.0 g, 33.3 mmol) was dissolved in anhydrous DMF (10 mL), followed by the sequential addition of 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (HATU) (17.12 g, 45 mmol) and DIPEA (6.45 g, 50 mmol). The mixture was reacted at room temperature for 30 minutes, then morpholine (3.92 g, 45 mmol) was added, and the reaction was continued at room temperature for 1 hour. After the reaction was complete, the mixture was poured into ice water, extracted with EA, washed with water, dried over sodium sulfate, concentrated, and the crude product was separated by column chromatography to obtain 5.0 g of the target compound, with a yield of 68%.

[0393] Example 13-13-4-(pyridin-4-yloxy)benzaldehyde

[0394] 4-Bromopyridine (3.1 g, 40 mmol), 3-hydroxybenzaldehyde (40 mmol), and cesium carbonate (26.1 g, 80 mmol) were dissolved in 80 mL of DMF and reacted overnight at 100 °C. After the reaction was complete, the mixture was cooled to room temperature, poured into ice water, extracted with EA, and the organic phase was washed successively with water and brine, dried, and concentrated. The crude product was separated by column chromatography to give 1.99 g of the target compound, with a yield of 25%.

[0395] Example 13-5: Synthesis of 5-(pyridin-4-yl)thiophene-2-carboxaldehyde

[0396] Under nitrogen protection, 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, 1.0 mmol), and triphenylphosphine (520.0 mg, 2.0 mmol) were dissolved in a mixed solvent of dioxane and water (v / V = 3 : The mixture was refluxed overnight in 80 mL of water. After the reaction was complete, the reaction mixture was cooled to room temperature and poured into ice water. It was extracted with EA, the combined organic phases were washed with water, dried under sodium sulfate, and the crude product was purified by column chromatography to give 3.2 g of the target compound, with a yield of 85%.

[0397] Synthesis of 4-(pyridin-4-yl)benzaldehyde (Example 13-6: -6: 61)

[0398] Under nitrogen protection, 4-bromobenzaldehyde (2.78g, 15mmol), 4-pyridineboronic acid (2.46g, 20mmol), sodium carbonate (3.18g, 0mmol) and tetrakis(triphenylphosphine)palladium (722mg, 0.62mmol) were dissolved in dioxane (40mL) and water (10mL), the mixture was refluxed overnight. The reaction was cooled to room temperature and poured into ice water, EA extraction, the organic phase was washed with water, dried, concentrated. The crude product was separated by column chromatography to obtain the target compound 2.23g, yield 81%.

[0399] Example 13-7 -7: Synthesis of compound 4- (thiazol-2-yl) benzaldehyde

[0400] Under nitrogen protection, 2-bromothiazole (3.0g, 18.3mmol), 4-formylbenzeneboronic acid (3.3g, 22mmol), sodium carbonate (3.88g, 36.6mmol) and tetrakis(triphenylphosphine)palladium (1.0g, 0.865mmol) were dissolved in toluene / ethanol / water (50mL, v:v=3:1:1) mixed solvent, refluxed overnight. The reaction was cooled to room temperature, poured into water, EA extraction, the organic layer was dried with sodium sulfate, concentrated, column chromatography to obtain the target compound 2.24g, yield 65%.

[0401] Example 13- -8: Synthesis of 10-(2-methoxyethyl) -10H-phenothiazine-3-carbaldehyde

[0402]

[0403] Step 1: Synthesis of compound 10-(2-methoxyethyl) -10H-phenothiazine

[0404] Under nitrogen protection, sodium hydride (2.4g, 2eq) was added to a solution of phenothiazine (6g, 1eq) in DMF (60mL) at 0°C, stirred for 30 minutes, 2-bromoethyl methyl ether (6.3g, 1.5eq) was added and stirred at room temperature for 2 hours. The reaction was quenched with water, DCM extraction, the organic layer was dried, concentrated, the crude product was separated by column chromatography to obtain the target compound 9g.

[0405] Step 2: Synthesis of compound 10-(2-methoxyethyl) -10H-phenothiazine-3-carbaldehyde

[0406] Phosphorous oxychloride (10.2 mL, 5 eq) was added dropwise to dry DMF (8 g, 5 eq) at 0 °C under nitrogen. After the addition was complete, the mixture was stirred until a colorless solid was formed, then the solid was dissolved in 1,2-dichloroethane (50 mL) and stirring was continued for 1 h. A solution of 10-(2-methoxyethyl)-10H-phenothiazine (5.6 g, 1 eq) in 1,2-dichloroethane was added dropwise and stirring was continued at 90 °C for 2 h. After the reaction was complete, the mixture was cooled to room temperature, 20% aqueous sodium hydroxide solution was added to adjust the pH to 7, and the aqueous phase was extracted with DCM. The combined organic phases were dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by column chromatography to give the title compound 5.3 g.

[0407] -9: Synthesis of intermediate 13-9: tert-butyl (4-formylbenzo[d]thiazol-2- yl)carbamate

[0408] Step 1: Synthesis of tert-butyl (4-methylbenzo[d]thiazol-2-yl)carbamate

[0409] Tert-butyl dicarbonate (10.0 g, 45.7 mmol) and DMAP (0.67 g, 5.5 mmol) were added to a solution of 4-methylbenzo[d]thiazol-2-amine (3.0 g, 18.3 mmol) in DCM (80 mL) at room temperature and the reaction was allowed to proceed overnight. After the reaction was complete, the reaction mixture was poured into ice water and extracted with DCM. The combined organic phases were washed with water, dried over sodium sulfate, concentrated, and the crude product was purified by column chromatography to give the title compound 5.2 g in 78% yield.

[0410] Step 2: Synthesis of tert-butyl (4-(dibromomethyl)benzo[d]thiazol-2-yl)carbamate (4-methylbenzo[d]thiazol-2-yl)carbamate e (5.2 g, 14.3 mmol), NBS (5.08 g, 28.5 mmol), and AIBN (330 mg, 2 mmol) were dissolved in carbon tetrachloride (30 mL) and the reaction was allowed to proceed at reflux overnight. After the reaction was complete, the reaction mixture was poured into ice water and extracted with DCM. The combined organic phases were washed with water, dried over sodium sulfate, and concentrated to give the crude product 4.5 g, which was used directly in the next step without further purification.

[0411] Step 3: Synthesis of tert-butyl (4-formylbenzo[d]thiazol-2-yl)carbamate

[0412] Dissolve compound tert-butyl (4-(dibromomethyl)benzo[d]thiazol-2-yl)carbamate (4.5 g crude) and silver nitrate (12.2 g, 71.5 mmol) in a mixed solvent of toluene (50 mL) and DMSO (5 mL), and react at 60 °C for 2 hours. After completion of the reaction, pour the reaction mixture into ice water, extract with EA, wash the combined organic phase with water, dry over sodium sulfate, and concentrate. Purify the crude product by column chromatography to obtain the target compound 1.8 g at a yield of 45.2%.

[0413] Example 13-10: Synthesis of Intermediate 13-10: 4-(4-(6-ethoxy-9H-purin-9-yl)phenyl)butan-3-en-2-one

[0414] CI

[0415] τ Ν

[0416] k :>

[0417] Step 1: Synthesis of compound (4-(6-chloro-9H-purin-9-yl)phenyl)methanol

[0418] Dissolve 6-chloro-9H-purine (1.54 g, 10.0 mmol), copper acetate (3.63 g, 20 mmol), 4-(hydroxymethyl)benzoic acid (3.63 g, 20 mmol), 1,10-phenanthroline (3.60 g, 20 mmol), and 4A molecular sieves (1.0 g) in a dry DMF (50 mL) solution, and react at 40 °C overnight. After completion of the reaction, pour the reaction mixture into ice water, extract with EA, wash the organic phase with water, dry over sodium sulfate, and concentrate. Purify the crude product by column chromatography to obtain the target compound 1.49 g at a yield of 57%.

[0419] Step 2: Synthesis of compound 4-(6-chloro-9H-purin-9-yl)benzaldehyde

[0420] Dissolve (4-(6-chloro-9H-purin-9-yl)phenyl)methanol (900 mg, 3.5 mmol) and manganese dioxide (6.1 g, 70 mmol) in 50 mL of DCM, and stir at room temperature for 1 hour. Filter, wash the residue with DCM, collect the filtrate, and concentrate to obtain the crude product 900 mg, which is used directly in the next step without purification.

[0421] Step 3: Synthesis of compound 4-(4-(6-ethoxy-9H-purin-9-yl)phenyl)butan-3-en-2-one

[0422] To a solution of 4-(6-chloro-9H-purin-9-yl)benzaldehyde (900 mg, 3.5 mmol) in 125 mL of ethanol was added saturated aqueous sodium bicarbonate solution (5 mL) and heated to reflux for 5 h. Upon completion of the reaction, the reaction mixture was cooled to room temperature, poured into ice water and extracted with DCM. The combined organic layers were dried over anhydrous sodium sulfate and concentrated. The crude product was purified by column chromatography to give the title compound 490 mg in 46% yield.

[0423] Example 13-11 : Synthesis of intermediate 13-11 : 4-(2-(pyridin-4-yloxy)ethoxy)benzaldehyde

[0424] Step 1 : Synthesis of compound 4-(2-bromoethoxy)benzaldehyde

[0425] To a solution of 4-hydroxybenzaldehyde (3.0 g, 24.6 mmol), potassium carbonate (6.90 g, 50 mmol) and 1,2-dibromoethane (9.4 g, 50 mmol) in 85 mL of EtOH was added and refluxed overnight. Upon completion of the reaction, the reaction mixture was cooled to room temperature, poured into ice water and extracted with EA. The combined organic layers were washed with water, dried over anhydrous sodium sulfate and concentrated. The crude product was purified by column chromatography to give the title compound 1.8 g in 32% yield.

[0426] 60

[0427] To a solution of 4-(2-bromoethoxy)benzaldehyde (1.80 g, 7.86 mmol), cesium carbonate (4.89 g, 15 mmol) and 4-hydroxypyridine (950 mg, 10 mmol) in 125 mL of ethanol was added and refluxed overnight. Upon completion of the reaction, the reaction mixture was cooled to room temperature, poured into ice water and extracted with EA. The combined organic layers were dried over anhydrous sodium sulfate and concentrated. The crude product was purified by column chromatography to give the title compound 400 mg in 21% yield.

[0428] Step 2: Synthesis of compound 4-(2-(pyridin-4-yloxy)ethoxy)benzaldehyde

[0429] To a solution of 4-(2-bromoethoxy)benzaldehyde (1.80 g, 7.86 mmol), cesium carbonate (4.89 g, 15 mmol) and 4-hydroxypyridine (950 mg, 10 mmol) in 125 mL of ethanol was added and refluxed overnight. Upon completion of the reaction, the reaction mixture was cooled to room temperature, poured into ice water and extracted with EA. The combined organic layers were dried over anhydrous sodium sulfate and concentrated. The crude product was purified by column chromatography to give the title compound 400 mg in 21% yield.

[0430] Example 14: Synthesis of compound 5-(2-amino-benzo[d]thiazol-4-yl)-2-(((2-(4-(2- hydroxyethyl)piperazin-1-yl)ethyl)amino)methylene)-1,3-dione (compound 85)

[0431]

[0432] The compound N'-(4-(4-((((2-(4-((2-hydroxyethyl)piperazin-1-yl)ethyl)amino)methylene)-3,5-cyclohexyl)benzo[d]thiazo-2-yl)-N,N-dimethylformamidin (100 mg, 0.2 mmol) and zinc chloride (1.36 g, 10 mmol) were dissolved in 5 mL of anhydrous ethanol and refluxed overnight. After the reaction was complete, the mixture was cooled, poured into ice water, extracted with EA, dried over anhydrous sodium sulfate, concentrated, and the crude product was separated by column chromatography to give 40 mg of the target compound, with a yield of 45%. Compound 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].

[0433] Example 15: Compound 7-(((2-(4-(2-hydroxyethyl)piperazinyl)ethyl)amino)methylene)-spiro[3.5]nonane-6,8-dione (Chemical)

[0434] , Step 1: Synthesis of compound 2-cyclobutylene ethyl acetate

[0435] Under nitrogen protection, sodium hydrogen (60%, 1.60g, 40mm) was added at 0°C. O l) Add ethyl 3-(diethoxyphosphono)-3-oxopropionate (8.96 g, 40 mmol) to anhydrous THF solution (50 mL), and stir at this temperature for 30 minutes. Then add cyclobutanone (2.8 g, 40 mmol) to anhydrous THF solution (10 mL). Stir the mixture at this temperature for 2 hours, then slowly add water (0 mL). Stir the resulting mixture at room temperature for another 30 minutes. After the reaction is complete, pour the reaction mixture into ice water, extract with EA, wash the combined organic phases with water, dry with sodium sulfate, and concentrate. The crude product is purified by column chromatography to give 4.62 g of the target compound, with a yield of 82.5%.

[0436] Step 2: Synthesis of the compound spiro[3.5]nonane-6,8-dione

[0437] Under nitrogen protection, sodium hydride (60%, 960 mg, 24 mmol) was added to a solution of diethyl 3-oxopentanedioate (2.53 g, 12 mmol) in anhydrous THF (50 mL) and stirred at this temperature for 30 min. Then a solution of 2-cyclobutylethylene acetate (1.4 g, 10 mmol) in anhydrous THF (10 mL) was added and the reaction was carried out at room temperature for 2 h. Then a solution of sodium ethoxide (816 mg, 12 mmol) in anhydrous ethanol (5 mL) was added. The above mixture was refluxed for 5 h, cooled to 50 °C and a 20% KOH solution (10 mL) was added. The resulting mixture was stirred at this temperature overnight, cooled to room temperature, extracted with EA, the aqueous phase was adjusted to 1-2 and stirred at 70 °C for 2 h. Cooled to room temperature, extracted with DCM. The combined organic phase was washed with water, dried over sulfate and concentrated. The crude product was separated and purified by column chromatography to give the target compound 483 mg, yield 32%.

[0438] 61

[0439] The procedure was the same as that of Example 2. Compound 86:

[0440] Step 3: Synthesis of compound 7-(((2-(4-(2-hydroxyethyl)piperazin-1-yl)ethyl)amino)methylene)spiro[3.5]nonane-6,8-dione

[0441] The procedure was the same as that of Example 2. Compound 86: 1 HNMR (CD3OD, 400 MHz) δ 8.16 (s, 1H), 3.67 (t, J = 6.0 Hz, 2H), 3.56 (t, J = 6.0 Hz, 2H), 2.59-2.53 (m, 16H), 1.95-1.82 (m, 6H); MS: 336.5 [M+l].

[0442] Example 16: Compounds 87-94

[0443] The procedure for the synthesis of compounds 87-94 was the same as that of compound 86 except that the corresponding aldehyde, ketone or substituted propenoate was used (e.g. Examples 16-1 and 16-2) as shown in Table 5.

[0444] Table 5: Compounds 87-94

[0445] Example 16-1 : Synthesis of Intermediate 16-1 : (Morpholinosulfonyl)phenyl; ethyl acrylate

[0446] Step 1 : Synthesis of compound 4-(4-bromophenyl)sulfonylmorpholine

[0447] Dissolve 4-bromobenzenesulfonyl chloride (5.0 g, 19.6 mmol), triethylamine (TEA) (2.98 mL) and morpholine (1.88 g, 21.53 mmol) in DCM (10 mL) and react at room temperature for 30 minutes. Pour the reaction mixture into water and extract with DCM. Wash the combined organic phase with 1 N hydrochloric acid, water and brine, dry and concentrate to give the crude product 5.21 g, which is used directly in the next step without further purification.

[0448] Step 2: Synthesis of compound ethyl 3-(4-(morpholinosulfonyl)phenyl)acrylate

[0449] Under nitrogen protection, add 4-(4-bromophenyl)sulfonylmorpholine (1.0 g, 6.53 mmol), ethyl acrylate (849 mg, 8.49 mmol), palladium acetate (43.88 mg, 0.2 mmol) and triphenylphosphine (68.89 mg, 0.26 mmol) into 3 mL of triethylamine, stir in a sealed tube at 150 degrees for 6 hours. Cool, pour into water and extract with EA. Dry the combined organic phase with anhydrous sodium sulfate, concentrate and separate the crude product by column chromatography to give 1.8 g, 85% yield.

[0450] Example 16-2: Synthesis of Intermediate 16-3: 6-(2-morpholinoethoxy)nicotinaldehyde

[0451] Human Cl Human. OH Human o OMs

[0452] Step 1 : Synthesis of compound 6-(2-hydroxyethoxy)nicotinaldehyde

[0453] Sodium tert-butoxide (3.49 g, 36.3 mmol) was added to 1,2-ethanediol (30 mL) at room temperature, after stirring for 30 minutes, 6-chloronicotinaldehyde (4.0 g, 28.3 mmol) was added, the resulting mixture was stirred at room temperature overnight, then heated to 80 °C and stirred for another 2 hours, the reaction was completed. The reaction mixture was cooled to room temperature, poured into ice water, extracted with EA, the organic phase was washed with water, dried, concentrated, and the crude product was separated and purified by column chromatography to give the target compound 4.01 g, yield 85%. Step 2: Synthesis of compound 2-((5-formylpyridin-2-yl)oxy)ethyl methanesulfonate

[0454] 6-(2-Hydroxyethoxy)nicotinaldehyde (4 g, 24 mmol) and TEA (4 mL) were added to DCM (90 mL), a solution of methanesulfonyl chloride (P.66 g, 32 mmol) in dichloromethane was added dropwise at 0 °C, and the reaction was stirred at this temperature for 30 minutes after the dropwise addition was completed. The reaction was poured into water and extracted with EA. The combined organic phase was dried over anhydrous sodium sulfate and concentrated to give a crude product 5.21 g, which was used directly in the next step without further purification.

[0455] Step 3: Preparation of compound 6-(2-morpholinoethoxy)nicotinaldehyde

[0456] 2-((5-Formylpyridin-2-yl)oxy)ethyl methanesulfonate (5.21 g, crude), morpholine (4.35 g, 50 mmol), and potassium carbonate (6.91 g, 50 mmol) were added to 80 mL of acetonitrile and refluxed overnight. After cooling, it was poured into water and extracted with EA. The organic phase was dried over anhydrous sodium sulfate and concentrated. The crude product was separated by column chromatography to give the target compound 2.92 g, yield 51%.

[0457] Example 17: Compound 3-(((2-(4-(2-hydroxyethyl)piperazin-1-yl)ethyl)amino)methylene)-6-phenyl- dihydro-2H-pyran-2,4(3H)-dione

[0458] Step 1: Preparation of compound 6-phenyldihydro-2H-pyran-2,4(3H)-dione

[0459] Ethyl acetoacetate (13.01 g, 0.1 mol), potassium carbonate (27.64 g, 0.2 mol) and benzaldehyde (10.1 mL, 0+ l mol) were dissolved in ethanol (100 mL) and reacted at 45 °C for 22 hours, filtered, the filter residue was washed with ethanol, the collected filtrate was poured into water, washed with PE. The aqueous phase was collected, acidified with 6N hydrochloric acid to pH 2-3, extracted with EA, the organic phase was washed with water, dried over sodium sulfate, concentrated, and the crude product was purified by column chromatography to obtain the target compound 8.87 g, yield 46.7%.

[0460] Step 2: Synthesis of compound 3-(((2-(4-(2-hydroxyethyl)piperazin-l-yl)ethyl)amino)methylene)-6-phenyl-2,4(3H)-dihydropyran-2,4-dione

[0461] Synthetic procedure same as example 2. Compound 95: 1 HNMR (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].

[0462] Example 17A: 3-(((2-(4-(2-hydroxyethyl)piperazin-l-yl)ethyl)amino)methylene)-6-phenylpiperidine-2,4-dione (Compound 96

[0463] Step 1: Synthesis of compound ethyl 3-((3-ethoxy-3-oxo-l-phenylpropyl)amino)-3-oxopropionate Ethyl 3-amino-3-phenylpropanoate (4.31 g, 22.23 mmol), malonic acid monoethyl ester (4.47 g, 33.84 mmol),

[0464] DIPEA (7.7 g, 55.8 mmol) and lH-benzotriazol-l- yloxytris(pyrrolidino)phosphonium hexafluorophosphate (PyBOP) (17.42 g,

[0465] 33.84 mmol) was added to 30 mL of DMF and reacted at room temperature for 2 hours until the reaction was complete. The mixture was then poured into water, extracted with EA, dried over anhydrous sodium sulfate, concentrated, and the crude product was separated by column chromatography to obtain 6.05 g of the target compound, with a yield of 88%.

[0466] Step 2: Synthesis of compound 6-phenylpiperidine-2,4-dione

[0467] 64

[0468] Correction Page (Detailed Rules, Clause 91) ISA / CN At 0°C, a toluene solution (16 mL) of ethyl 3-(X3-ethoxy-3-oxo-1-phenylpropyl)amino)-3-oxopropionate (2.0 g, 6.51 mmol) was added dropwise to an anhydrous ethanol solution (16 mL) of sodium ethoxide (0.66 g, 9.77 mmol), and the mixture was refluxed for 1 hour. After the reaction was complete, the reaction mixture was poured into water, the pH was adjusted to 1-2, and the mixture was extracted. The organic phase was washed with water and brine, dried, concentrated, and the crude product was dissolved in acetonitrile-water (...). V:V The mixture was prepared in a 100:1 (16 mL) solvent mixture and refluxed overnight. After the reaction was complete, the mixture was cooled to room temperature, poured into ice water, extracted with EA, washed with water, dried over sodium sulfate, and concentrated. The crude product was purified by column chromatography to obtain 622 mg of the target compound, with a yield of 50%. Compound 96: ! HNMR (400 MHz, CD3OD) δ 8.09 (s, 0.3H), 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 ]

[0469] Example 18: Synthesis of compound 4-(((2-(4-(2-hydroxyethyl)piperazin-1-yl)ethyl)amino)methylene)-1-phenylpiperidine-3,5-dione (;Compound 97;)

[0470]

[0471] Step 1: Synthesis of ethyl phenylglycine ester

[0472] Aniline (5.0 g 53.69 mmol), ethyl bromoacetate (10.76 g 64.43 mmol) and sodium acetate (5.29 g 64.43 mmol) were dissolved in absolute ethanol (120 mL) and refluxed for 2 h. After completion of the reaction, it was concentrated and the crude product was purified by column chromatography to get the desired compound 7.4 g, yield 77%

[0473] Step 2: Synthesis of compound N-(2-oxopropyl)-N-phenylglycine ethyl ester

[0474] Phenylglycine ethyl ester (2.3 g 12.83 mmol), bromoacetone (2.11 g 25.67 mmol) and DIPEA (4.57 mL 25.67 mmol) were taken in DMF (50 mL) and heated at 110 °C for 4 h. Additional bromoacetone (1.06 g 12.8 mmol) was added and heating was continued at 110 °C for 4 h. It was cooled to room temperature, poured into water and extracted with EA. The combined organic phase was dried over anhydrous sodium sulfate, concentrated and the crude product was purified by column chromatography to get the desired compound 1.3 g, yield 43%

[0475] Step 3: Synthesis of compound l-phenylpiperidine-3,5-dione

[0476] A solution of potassium tert-butoxide in THF (2 mol L 3.8 mL) was added dropwise to a solution of compound N-(2-oxopropyl)-N-phenylglycine ethyl ester (1.2 g 5.1 mmol) in dry THF (50 mL) at 0 °C. The reaction mixture was stirred at room temperature for 3 h. After completion of the reaction, it was quenched by dropwise addition of 20% acetic acid and poured into ice-cold water. It was extracted with EA and the organic phase was dried over anhydrous sodium sulfate. The crude product was purified by column chromatography to get the desired compound 600 mg, yield 62%

[0477] Step 4: Procedure same as example 2. Compound 97:1H NMR (400 MHz, CD3OD) δ 8.22 (s, 1H), 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]

[0478] Example 19: Synthesis of compound 3-(((2-(4-(2-hydroxyethyl)piperazin-1-yl)ethyl)amino)methylene)-1-phenylpiperidine-2,4-dione (compound 99)

[0479] 65

[0480] Correction sheet (Rule 91) ISA / CN

[0481] Step 1: Synthesis of compound ethyl 3-(phenylamino)propanoate

[0482] Dissolve aniline (2.8 g, 30 mmol) and ethyl acrylate (3.6 g, 36 mmol) in 2 mL acetic acid, react at 95 °C overnight. After the reaction is completed, cool to room temperature, pour into ice water, adjust the pH to 9-10 with a saturated sodium carbonate solution, extract with EA, wash the organic phase with water, dry, concentrate, and separate the crude product by column chromatography to obtain the target compound 5.3 g, yield 91%.

[0483] Step 2: Synthesis of compound ethyl 3-((3-ethoxy-3-oxopropyl)(phenyl)amino)-3-oxopropanoate

[0484] Dissolve ethyl 3-(phenylamino)propanoate (5.3 g, 27.4 mmol), monoethyl malonate chloride (5.35 g, 35.6 mmol), and DIPEA (7.09 g, 54.8 mmol) in DCM (35 mL), react at room temperature for 1 hour. After the reaction is completed, pour the reaction mixture into ice water, extract with EA, wash the organic phase with water, dry, concentrate, and separate the crude product by column chromatography to obtain the target compound 2.1 g, yield 25%.

[0485] Step 3: Synthesis of compound ethyl 2,4-dioxo-1-phenylpiperidine-3-carboxylate

[0486] Dissolve ethyl 3-((3-ethoxy-3-oxopropyl)(phenyl)amino)-3-oxopropanoate (2.00 g, 6.5 mmol) and sodium ethoxide (0.88 g, 13 mmol) in 15 mL anhydrous ethanol, react at room temperature for 2 hours, and after the reaction is completed, pour the reaction mixture into ice water, adjust the pH of the aqueous phase to 3-4 with 2N hydrochloric acid, extract with EA, wash the organic phase with water, dry with sodium sulfate, concentrate, and separate the crude product by column chromatography to obtain the target compound 780 mg, yield 46%.

[0487] Step 4: Synthesis of compound 1 -phenylpiperidine-2,4-dione

[0488] Ethyl-2,4-dioxo-l-phenylpiperidine-3-carboxylate (780 mg, 3.0 mmol) and acetic acid (0.7 mL) in water (7 mL) was reacted at 90 °C for 18 h. Upon completion of the reaction, the reaction mixture was poured into ice water, extracted with EA, the organic phase was washed with water, dried, concentrated, and the crude product was separated by column chromatography to give the target compound 510 mg, yield 90%.

[0489] Step 5 : Synthesis of compound 3 -((( 2 -( 4 -( 2 -((2-(4-(2-hydroxyethyl)piperazin-l-yl)ethyl)amino)methylene)-l- phenylpiperidine-4-carboxylic acid 2 , 4 -2,4-dione

[0490] The procedure for this step was the same as in Example 2. Compound 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].

[0491] Example 20: Synthesis of compound 4-(4-fluorophenyl)-2-(((2-(4-(2- hydroxyethyl)piperazin-l-yl)ethyl)amino)methylene)cyclohexane-l,3-dione

[0492]

[0493] Step 1: Synthesis of compound 4-(4-fluorophenyl)cyclohexane-l,3-dione

[0494] Compound l-(4-fluorophenyl)propan-2-one (2.0 g, 13.14 mmol), ethyl acrylate (1.45 g, 14.46 mmol) and sodium ethoxide (893.5 mg, 13.14 mmol) were dissolved in anhydrous ethanol 20 mL, refluxed overnight. After the reaction was completed, it was cooled to room temperature and poured into ice water, adjusted to pH 3-4 with 2N hydrochloric acid, EA extracted, the organic phase was washed with water, dried over sodium sulfate, concentrated, and the crude product was separated and purified by column chromatography to obtain 620 mg of the target compound, with a yield of 23%

[0495] Step 2: Synthesis of compound 4-(4-fluorophenyl)-2-(((2-(4-(2- hydroxyethyl)piperazin-l-yl)ethyl)amino)methylene)cyclohexane-l,3-dione

[0496] The operating procedure was the same as in Example 2. Compound 100: l H 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]

[0497] Example 21 : Compound 4-benzyl-2-(((2-(4-(2-hydroxyethyl)piperazin-l- yl)ethyl)amino)methylene)-6-phenylcyclohexane-l,3-dione (Compound 21)

[0498]

[0499] Step 1 : Synthesis of compound 5-benzyl-4-phenylcyclohexane-l,3-dione

[0500] Under nitrogen protection, potassium tert-butoxide (1.61 g, 14.3 mmol) was added to a solution of benzylacetone (2.5 mL 15.5 mmol) in anhydrous THF (20 mL) at 0 °C, stirred for 10 minutes, then methyl cinnamate (2 g 12.3 mmol) was added, and then stirring was continued for 30 minutes. After the reaction was completed, the reaction liquid was poured into water, adjusted to pH 6-7 with 2N dilute hydrochloric acid, EA was extracted, the organic phase was dried, and concentrated to obtain 3.61 g of crude product, which was directly used in the next step reaction.

[0501] Step 2: Synthesis of compound 4-azabicyclo[2.2.2]oct-5-yl-2-(((2-(4-(2- hydroxyethyl)piperazin-1-yl)ethyl)amino)methylene)-6-phenylcyclohexane-1,3-dione

[0502] Procedure step as example 2. Compound 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] +

[0503] Example 22: Synthesis of compound 4-(((2-(4-(2-hydroxyethyl)piperazin-1- yl)ethyl)amino)methylene)-1-(4-methoxybenzyl)piperazine-3,5-dione (compound 102)

[0504]

[0505] Step 1: Synthesis of compound ethyl (4-methoxybenzyl)glycinate ethyl ester

[0506] A solution of ethyl 2-bromoacetate (5.00 g 29.94 mmol) in anhydrous THF (20 mL) was added dropwise to a solution of p-methoxybenzylamine (9.04 g 66 mmol) in anhydrous THF (120 mL) at room temperature over 2 hours and the reaction was allowed to proceed overnight at room temperature. Upon completion of the reaction, the reaction mixture was poured into water and the pH was adjusted to 9-10 with saturated sodium carbonate. The EA was extracted and the organic phase was washed with water, dried over sodium sulfate and concentrated. The crude product was purified by column chromatography to give the target compound 3.12 g in 47% yield.

[0507] 67

[0508] Correction sheet (Rule 91) ISA / CN NO / VSI W 3Γ

[0509] 89

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[0524] ' )顯 2邈資具寸) ¾2 Step 3: Synthesis of 1-benzoyl-3,5-dione

[0525] At 0 °C, a THF solution of potassium tert-butoxide (1 mol / L, 11 mL) was added dropwise to an anhydrous THF solution (60 mL) of ethyl N-benzoyl-N-(2-oxopropyl)glycinate (1.9 g, 7.22 mmol). The reaction was carried out at room temperature for 3 hours. After completion of the reaction, the reaction mixture was poured into 10% acetic acid solution, extracted with EA, the organic phase was dried over anhydrous sodium sulfate, concentrated, and the crude product was separated by column chromatography to obtain 1.03 g of the target compound with a yield of 66%.

[0526] Step 4: Synthesis of 1-benzoyl-4-(((2-(4-(2-hydroxyethyl)piperazin-1-yl)ethyl)amino)methylene)piperidine-3,5-dione

[0527] The last step was performed as described in Example 8. Compound 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), 3.73 (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].

[0528] Example 26: Synthesis of compound 2-(((2-(4-(2-hydroxyethyl)piperazin-l- yl)ethyl)amino)methylene)-5-(morpholine-4-carbonyl)cyclohexane-l,3-dione (Compound 106)

[0529]

[0530] Step 1: Synthesis of compound 3-methoxy-5-oxocyclohex-3-ene-l-carboxylic acid

[0531] Compound 3,5-dioxocyclohexane carboxylic acid (780 mg, 5 mmol), p-toluenesulfonic acid monohydrate (95 mg, 0.5 mmol) were dissolved in 6 mL of methanol and refluxed for 2 hours. The reaction was cooled to room temperature and EA was added to the mixture. The precipitate was filtered to give 420 mg of crude product which was used directly in the next step without further purification.

[0532] Step 2: Synthesis of compound 3-methoxy-5-(morpholine-4-carbonyl)cyclohex-2- en-l-one

[0533] Compound 3-methoxy-5-oxocyclohex-3-ene-l-carboxylic acid (340 mg, crude), morpholine (310 mg, 2.4 mmol), DIPEA (390 mg, 3 mmol) and HATU (1.14 g, 3 mmol) were added to 12 mL of dry DMF and stirred at room temperature overnight. The reaction was poured into water and extracted with EA. The organic phase was dried over anhydrous sodium sulfate, concentrated and the crude product was separated by column chromatography to give the target compound 100 mg in 15% yield.

[0534] Step 3: Synthesis of compound 5-(morpholine-4-carbonyl)cyclohexane-l,3-dione

[0535] To a solution of 3-methoxy-5-(morpholine-4-carbonyl)cyclohex-2-en-1-one (132 mg, 0.55 mmol) and cerium ammonium nitrate (110 mg, 0.2 mmol) in acetonitrile (4 mL) and water (4 mL) was heated to reflux for 3 h. After completion of the reaction, the reaction mixture was cooled to room temperature and poured into water. The organic phase was separated and dried over anhydrous sodium sulfate. The crude product was purified by column chromatography to give the title compound 112 mg in 90% yield.

[0536] Step 4: Synthesis of compound 2-(((2-(4-(2-hydroxyethyl)piperazin-1-yl)ethyl)amino)methylene)-5-(morpholine-4-carbonyl)cyclohexane-1,3-dione

[0537] Procedure step was same as example 2. Compound 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,

[0538] 69

[0539] Correction page (Rule 91) ISA / CN 2H), 2.75 - 2.42 (m, 10H).

[0540] Example 27: Synthesis of compound 3-(((2-(4-(2-hydroxyethyl)piperazin-1-yl)ethyl)amino)methylene)quinoline-2,4(1H,3H)-dione (Compound 107)

[0541] Step 1: Synthesis of compound methyl 3-oxo-3-(phenylamino)propanoate

[0542] To a solution of aniline (1.00 g, 10.74 mmol) and TEA (1.42 g, 14 mmol) in ethyl acetate was added monomethyl malonate chloride (1.84 g, 13.5 mmol) dropwise at 0 °C. After the addition was complete, the reaction mixture was stirred at room temperature for 30 min. After completion of the reaction, the reaction mixture was poured into water. The organic phase was washed with water, dried over sodium sulfate and concentrated. The crude product was purified by column chromatography to give the title compound 1.75 g in 85% yield.

[0543] Step 2: Synthesis of compound 3-oxo-3-(phenylamino)propanoic acid

[0544] A mixture solution of methyl 3-oxo-3-(phenylamino)propanoate (1.00 g, 5.18 mmol) and sodium hydroxide (415 mg, 10.37 mmol) in methanol / water (v:v=3:1, 20 mL) was stirred at room temperature for 1 h. After the reaction was completed, the reaction mixture was poured into water and extracted with EA. The pH value of the aqueous phase was adjusted to 5-6 and extracted with DCM. The combined organic phase was washed with water, dried over sodium sulfate and concentrated to give the crude product 820 mg, which was used directly in the next step.

[0545] Step 3: Synthesis of compound quinoline-2-(1H, 3H)-dione

[0546] 3-oxo-3-(phenylamino)propanoic acid (537 mg, crude) was added to 6 mL of methanesulfonic acid and heated to 50 °C. Phosphorus pentoxide (852 mg) was added portionwise and the reaction solution was then raised to 75 °C and stirred for 2 h. The temperature was lowered to room temperature and the mixture was slowly poured into ice water. The pH value of the aqueous phase was adjusted to 7-8 with saturated aqueous sodium carbonate solution. The precipitated solid was collected by filtration and dried to give the crude product 220 mg in a yield of 40%, which was used directly in the next step without purification.

[0547] Step 4: Synthesis of compound 3-(((2-(4-(2-hydroxyethyl)piperazin-1-yl)ethyl)amino)methylene)quinoline-2,4(1H, 3H)-dione

[0548] The operating steps were the same as in Example 2. Compound 107: l U 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)。

[0549] Example 28: Compound 2-(1-((2-(4-(2-hydroxyethyl)piperazin-1-yl)ethyl)amino)ethylidene)-5-phenylcyclohexane-1,3-dione (Compound 1

[0550]

[0551] Step 1 : Synthesis of compound 2-acetyl-5-phenyl-1,3-cyclohexanedione

[0552] Acetyl chloride (4.2 g, 53.5 mmol) was added dropwise to a mixture of 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) at room temperature and the reaction was refluxed for 2 hours. The reaction was completed

[0553] 70

[0554] Correction page (Rule 91) ISA CN was cooled to room temperature, poured into ice water, DCM extraction, the organic phase was washed with water, dried with sodium sulfate, concentrated, and the crude product was purified by column chromatography to obtain the target compound 8.51 g with a yield of 70%.

[0555] Step 2: Synthesis of compound 2-(1-((2-(4-(2-hydroxyethyl)piperazin-1-yl)ethyl)amino)ethylidene)-5-phenylcyclohexane-1,3-dione

[0556] 2-acetyl-5-phenyl-1,3-cyclohexanedione (90 mg, 0.39 mmol) and 2-(4-(2-aminoethyl)piperazin-1-yl)ethan-1-ol (81 mg, 0.47 mmol) were dissolved in 5 mL of ethanol and heated to reflux for 1 hour. It was cooled, concentrated, and the crude product was separated by preparative plate to obtain the target compound 80 mg with a yield of 44%. Compound 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)

[0557] The synthesis method of compounds 109-112 was the same as that of compound 107, as shown in Table 6.

[0558] Table 6: Compounds 109-112

[0559] Example 30: Compound 2-(((2-(4-(2-hydroxyethyl)piperazin-l-yl)ethyl)amino)methylene)- 4a,9, 10, 10a-tetrahydropyrrolo

[0560] Step 1 : Synthesis of compound ethyl 3-(2-bromophenyl)acrylate

[0561] Dissolve 2-bromobenzaldehyde (2.0 g, 10.8 mmol), triethyl phosphonoacetate (2.66 g, 11.9 mmol) and lithium hydroxide (285 mg, 11.9 mmol) in anhydrous THF solution (14 mL) and react at room temperature for 3.5 hours. After completion of the reaction, pour the reaction mixture into ice water, extract with DCM, wash the organic phase with water, dry over sodium sulfate, concentrate, and purify the crude product by column chromatography to obtain the target compound 2.59 g in a yield of 94%.

[0562] 71

[0563] Step 2: Synthesis of compound ethyl 3-(2-(4-oxopentyl)phenyl)acrylate

[0564] Dissolve compound ethyl 3-(2-bromophenyl)acrylate (1.00 g, 3.92 mmol), pent-4-en-2-ol (843 mg, 9.8 mmol), palladium acetate (44 mg, 0.2 mmol), DIPEA (4.00 g, 31 mmol) and lithium chloride (167 mg, 3.94 mmol) in dry DMF solution (100 mL) under nitrogen protection and react at 80°C for 48 hours. After completion of the reaction, cool to room temperature, pour into ice water, extract with methyl tert-butyl ether, wash the organic phase with water, dry over sodium sulfate, concentrate, and purify the crude product by column chromatography to obtain the target compound 612 mg in a yield of 60%.

[0565] Step 3: Synthesis of compound 4a,9, 10, 10a-tetrahydropyrrolo[1,3(2H,4H)-dione

[0566] Ethyl 3-(2-(4-oxopentyl)phenyl)acrylate (195 mg, 0.75 mmol) and sodium hydride (60%, 100 mg, 2.5 mmol) were dissolved in anhydrous THF solution (12 mL) and reacted at room temperature overnight. After the reaction was completed, the reaction mixture was poured into IN hydrochloric acid (20 mL) at 0 °C, extracted with EA, and the organic phase was washed with water, dried over sodium sulfate, concentrated, and the crude product was separated and purified by column chromatography to obtain 74 mg of the target compound at a yield of 46%.

[0567] Step 4: Synthesis of compound 2-(((2-(4-(2-hydroxyethyl)piperazin-l-yl)ethyl)amino)methylene)- 4a,9,10,10a-tetrahydropyrrolo[l,3(2H,4H)-dione

[0568] The procedure was the same as in Example 2. Compound 113:1H NMR (400 MHz, CD3OD) δ 8.26 (s, 1H), 7.30 (d, J = 7.6 Hz, 1H), 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).

[0569] Example 30B: Synthesis of compound 5-((2R,3S,4R,5R)-3,4-dihydroxy-5-(6-morpholino-9H-purin-9-yl)tetrahydrofuran-2-yl)-2-(((2-(4-(2-hydroxyethyl)piperazin-l-yl)ethyl)amino)methylene)cyclohexane-l,3-dione (Compound 114)

[0570]

[0571] 5-(3AR,4R,6R,6AR 2,2-dimethyl-6-(6-morpholino-9H-purin-9-yl)tetrahydrofuro[3,4- D][l, 3 ]dioxole- 4 -yl)- 2 -((( 2 -( 4 -( 2 -((2-(4-(2-hydroxyethyl)piperazin-l-yl)ethyl)amino)methylene)cyclohexane-l, 3- diketone (120 mg, 0.187 mmol) was added to 1 mL formic acid and 1 mL water, heated to 50 °C for 4 hours. The reaction was completed, cooled to room temperature, poured into ice water, adjusted to pH 9-10, extracted with DCM, the organic phase was dried with anhydrous sodium sulfate, concentrated, and the crude product was separated by preparative plate to give the target compound 73 mg, yield 65%. Compound 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).

[0572] Example 31: Synthesis of compound 4-benzyl-2-(((2-(4-(2-hydroxyethyl)piperazin-1- yl)ethyl)amino)-methylene)cyclopentan-1,3-dione (compound 115)

[0573] Correction page (Rule 91) ISA / CN

[0574] Step 1: Synthesis of compound 5-benzyl-3-ethoxycyclopent-2-en-1-one

[0575] Under nitrogen protection, LDA (1 mol / L THF solution, 5 mL, 5 mmol) was added dropwise to a solution of 3-ethoxycyclopent-2-en-1-one (500 mg, 4 mmol) in anhydrous THF (15 mL) at -60 °C. After stirring at this temperature for 30 minutes, benzyl bromide (855 mg, 5 mmol) was added, and the reaction was continued for 3 hours. After the reaction was completed, the reaction mixture was poured into saturated aqueous ammonium chloride solution, extracted with DCM, and the organic phase was washed with water, dried with sodium sulfate, concentrated, and the crude product was separated and purified by column chromatography to give the target compound 540 mg, yield 63%.

[0576] Step 2: Synthesis of compound 4-benzylcyclopentane-1,3-dione

[0577] Step 1 : Synthesis of compound 5-benzyl-3-ethoxycyclopent-2-en-l-one

[0578] Step 3: Synthesis of compound 4-benzyl-2-(((2-(4-(2-hydroxyethyl)piperazin-l- yl)ethyl)amino)methylene)-cyclopentane-l,3-dione

[0579] Procedure step as example 2. Compound 115: ! H NMR (400 MHz, CD3OD) δ 7.86 (s, 1H), 7.27-7.17 (m, 5H), 3.71 (t, J = 6.0 Hz, 2H), 3.59 (t, J = 6.0 Hz, 2H), 3.18-3.14 (m, 1H), 2.94-2.88 (m, 1H), 2.74-2.60 (m, 13H), 2.51-2.45 (m, 1H), 2.24-2.18 (m, 1H); MS: 372.2 [M+l]·.

[0580] Example 32: Compound 2-(((2-(4-(2-hydroxyethyl)piperazin-l-yl)ethyl)amino)methylene)- 4-methyl-5-phenylcyclohexane-l,3-dione

[0581]

[0582] Step 1 : Synthesis of compound 4-methyl-5-phenyl-l,3-cyclohexanedione

[0583] Under nitrogen protection, potassium tert-butoxide (831 mg, 7.4 mmol) was added to butan-2-one (5 mL) at 0 °C, after stirring at this temperature for 10 minutes, methyl cinnamate (1.00 g, 6.17 mmol) was added. The reaction mixture was warmed to room temperature and reacted for 30 minutes. The reaction was completed. The reaction mixture was poured into ice water, the pH was adjusted to 7 with 1 N hydrochloric acid, EA was extracted, the organic phase was washed with water, dried, concentrated, and the crude product was separated by column chromatography to obtain the target compound 510 mg, yield 41%.

[0584] Step 2: Synthesis of compound 2-(((2-(4-(2-hydroxyethyl)piperazin-l- yl)ethyl)amino)methylene)-4-methyl-5-phenylcyclohexane-l,3-dione

[0585] Procedure same as example 2. Compound 116:1H MR (400 MHz, CD3OD) δ 8.35 - 8.13 (m, 1H),

[0586] 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,

[0587] J = 12.6, 6.6 Hz, 3H); MS: 386.2 [M+l ].

[0588] Example 33: Synthesis of compound l-(hydroxymethyl)-4-phenylpiperidine-2,6-dione (compound 117)

[0589] 73

[0590] Correction page (Rule 91) ISA / CN

[0591] Step 1 : Synthesis of compound 4-phenylpiperidine-2,6-dione

[0592] A mixture of 3-phenylpentandioic acid (5.0 g, 24 mmol) and urea (25 g) was reacted at 160 °C for 3 hours. After the reaction was completed, the reaction mixture was slowly poured into ice water, extracted with EA, and the organic phase was washed with water, dried over sodium sulfate, and concentrated. The crude product was separated by column chromatography to give the target compound 3.6 g in a yield of 79%.

[0593] Step 2: Synthesis of compound l-(hydroxymethyl)-4-phenylpiperidine-2,6-dione

[0594] A mixture of 4-phenylpiperidine-2,6-dione (800 mg, 4.22 mmol) and 35% formaldehyde solution (101 mL) was heated to 100 °C until all the solid was dissolved. After the reaction was completed, it was cooled to room temperature, poured into water, extracted with EA, and the combined organic phase was dried over anhydrous sodium sulfate, concentrated, and the crude product was separated by column chromatography to give the target compound 513 mg in a yield of 55%. Compound 117: !HNMR (DMSO-d6) δ 7.31 - 7.34 (m, 5H), 6.10 (t, J = 7.6 Hz, 1H), 5.06 (d, J = 7.6 Hz, 2H), 3.41 - 3.33 (m, 1H), 2.97 - 2.90 (m, 2H), 2.82 - 2.77 (m, 2H), MS: 220.1 [M + 1].

[0595] Example 34: Synthesis of Compounds 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 and 349 - 414

[0596] Except for using the corresponding substituted 1,3 - cyclohexanedione or other similar compounds with an active methylene group (such as in Example 9 - 1), the synthesis method of the following compounds is the same as above (such as Compound 8), as shown in Table 7.

[0597] Table 7

[0598]

[0599] 74

[0600] Correction Sheet (Rule 91) ISA / CN

[0601]

[0602] ΖΪ8 and 8Ϊ0Ζ OAV LL

[0603]

[0604] 9M7Z.80 / 8T0ZN3 / X3d ΖΪ8 and 8Ϊ0Ζ OAV 8 / ,

[0605]

[0606] ΖΪ8 and 8Ϊ0Ζ OAV 6L

[0607]

[0608] ΖΪ8 and 8Ϊ0Ζ OAV 1HNMR (400 MHz, DMSO - d6) δ 11.24 - 1 - Η. 11.13 (m, IH), 8.31 (s, 2H), 8.21 (d, J =

[0609] 14.2 Hz, IH), 8.00 (s, IH), 7.32 (d, J = 4.4

[0610] ((2,6-dioxo-4-benzene)

[0611] Hz, 4H), 7.27 - 7.19 (m, IH), 4.70 (p, J = cyclohexylene)methyl

[0612] 174 7.2 Hz (IH), 4.45 - 4.35 (m, IH), 4.33 - yl) -L-alanine hydrochloride

[0613] ±h 4.24 (m, IH), 3.58 (dd, J= 9.2, 3.7 Hz, IH),

[0614] 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).

[0615] 'HNMR (400 MHz, DMS0-d6) δ 10.88 - 10.77 (m, IH), 8.32 (s, 3H), 8.10 (d, J =

[0616] 2-((((2-aminoethyl) 14.4 Hz, 1H), 7.32 (d, J = 4.3 Hz, 4H), 7.28 (amino)methylene)-5- (dd, J = 37.6, 4.3 Hz, 5H), 7.23 (d, J = 4.3)

[0617] 175

[0618] Phenylcyclohexane-1,3- Hz, IH), 3.73 (d, J = 6.1 Hz, 2H), 3.31 (tt, J diketone hydrochloride = 11.5, 4.0 Hz, IH), 3.06 (dd, J = 11.4, 5.6 Hz).

[0619] Hz, 2H), 2.73 (dt, J = 28.6, 14.1 Hz, 2H), 2.53 (d, J= 13.3 Hz, 2H).

[0620] 'HNMR (400 MHz, CDC13) δ 11.21 (s, IH),

[0621] N-(2-(((2,6-dioxo-4-phenylcyclohexylene) 8.14 (d, J = 14.0 Hz, 1H), 7.35 (t, J = 7.4 Hz, 2H), 7.24 (t, J = 6.7 Hz, 3H), 6.03 (s, ...

[0622] 176

[0623] Methyl (amino) ethyl (IH), 3.59 (dd, J = 11.7, 5.8 Hz, 2H), 3.49 Acetamide (dd, J = 11.5, 5.7 Hz, 2H), 3.42 - 3.30 (m,

[0624] IH), 2.82 - 2.59 (m, 4H), 2.02 (s, 3H).

[0625] 'HNMR (400 MHz, CDC13) δ 11.22 (s, IH),

[0626] (2-(((2,6-dioxo)

[0627] Boc 8.12 (d, J = 13.9 Hz, IH), 7.34 (t, J = 7.4-phenylcyclohexylene)

[0628] Hz, 2H), 7.27 - 7.20 (m, 3H), 3.58 (s, 2H),

[0629] 177 Methyl)amino)ethyl

[0630] 3.46 (t, J = 5.7 Hz, 2H), 3.41 - 3.29 (m, yl) (methyl)aminomethyl

[0631] IH), 2.89 (s, 3H), 2.81 - 2.60 (m, 4H), 1.46 tert-butyl ester

[0632] (s, 9H).

[0633] iHNMR (400 MHz, DMS0-d6) δ 11.14 - 11.02 (m, IH), 8.31 (s, 3H), 7.97 (d, J =

[0634] ((2,6-dioxo-4-benzene 14.0 Hz, 1H), 7.40 - 7.06 (m, 10H), 4.94 cyclohexylene)methyl

[0635] (td, J = 8.9, 4.6 Hz, IH), 4.41 (dd, J = 12.1,

[0636] 178-yl)-L-phenylalanine salt

[0637] 3.2 Hz, IH), 4.29 (dd, J = 12.1, 2.6 Hz, IH), 2-aminoethyl acid salt of 2-aminoethyl acid salt

[0638] 3.26 (ddd, J = 19.7, 11.0, 3.5 Hz, 2H), 3.13 ester

[0639] (s, 2H), 2.82 - 2.61 (m, 2H), 2.54 (s, IH),

[0640] 2.44 (s, 2H).

[0641] ((methoxyamino) 1H NMR (400 MHz, DMSO d6) 812.36 (br,

[0642] 2-

[0643] 180 methylene (s,

[0644] )-5-phenyl ring (IH), 8.16(s, IH), 7.32-7.20(m, 5H), 3.83

[0645] 3H), 3.41–3.33 (m, 1H), 2.84–2.77 (m, 2H), hexane-1,3-dione 2.61–2.57 (m, 2H); MS: 246.1 [M+1].

[0646] 2-(((2-(4-(2-hydroxyethyl)piperazin-l-yl)ethyl)amino)methyl)-5-phenylcyclohexane- 1,3-dione [M+l]. 182

[0647] 182 2-(((2-(4-(2-hydroxyethyl)piperazin-l-yl)ethyl)amino)methyl)-5-phenylcyclohexane- 1,3-dione [M+l]. 182

[0648]

[0649] Z18and Z20are OAV

[0650] Z18and Z20are OAV

[0651] 0 2-(((2-(dimethylamino)ethyl)amino)methyl)-5-phenylcyclohexane-l,3-dione [M+l]. 182

[0652] = 6.1 Hz, 2H), 2.28 (d, J = 2.1 Hz, 6H)

[0653] 'HNMR (400 MHz, CD3OD) δ 8.22 (s, IH),

[0654] 0 H ° ((2,6-dioxo-4-benzene 7.37 - 7.26 (m, 4H), 7.26 - 7.19 (m, IH), cyclohexylene)methyl) 4.29 (s, 2H), 3.96 (s, 2H), 3.42 - 3.33 (m, glycylglycine IH), 2.80 (ddd, J = 23.7, 16.8, 11.6 Hz, 2H),

[0655] 2.71 - 2.63 (m, 2H)

[0656] 'HNMR (300 MHz, CDC13) δ 11.24 (s, IH),

[0657] H 2-((((2-(4-isobutyryl 8.19 (d, J = 14.4 Hz, IH), 7.38 - 7.29 (m, oo ylpiperazin-1-yl)ethyl 2H), 7.26 (s, IH), 7.23 (d, J = 8.0 Hz, 2H), yl)amino)methylene 3.67 (s, 2H), 3.60 - 3.47 (m, 4H), 3.35 (s, yl)-5-phenylcyclohexane IH), 2.83 - 2.70 (m, 4H), 2.64 (dd, J = 11.8, -1,3-dione 5.7 Hz, 2H), 2.49 (s, 4H), 1.12 (d, J = 6.7

[0658] Hz, 6H)

[0659] 'HNMR (300 MHz, CDC13) δ 11.26 (s, IH),

[0660] H 5-Phenylacetyl-2-((((2-(4- 8.19 (d, J = 14.4 Hz, 1H), 7.34 (t, J = 7.3 Hz, 2H), 7.23 (d, J = 8.4 Hz, 3H), 3.69 (s, yl)ethyl)amino)imide

[0661] 4H), 3.52 (d, J = 5.9 Hz, 2H), 3.35 (s, IH), methyl)cyclohexane-1,3-

[0662] 0 2.75 (q, J = 8.6 Hz, 4H), 2.63 (dd, J = 13.9, diketone)

[0663] 7.8 Hz, 2H), 2.49 (s, 4H), 1.27 (s, 9H).

[0664] 'HNMR (300 MHz, CDC13) δ 11.39 (s, IH), 8.19 (d, J = 14.7 Hz, IH), 7.33 (d, J = 7.3

[0665] H 2-(((2-(4-(3-methyl)

[0666] Hz, 2H), 7.26 (s, IH), 7.23 (d, J = 7.8 Hz, butyryl)piperazine-1-2H), 3.67 (s, 2H), 3.53 (s, 4H), 3.36 (s, IH), butyryl)piperazine-1-2H), butyryl)ethyl)amino)imide)butyryl ...

[0667] 2.77 - 2.69 (m, 2H), 2.69 - 2.58 (m, 2H), (methyl)-5-phenylcyclohexane

[0668] 2.49 (s, 4H), 2.20 (d, J = 6.7 Hz, 2H), 2.15 - α-1,3-dione

[0669] 2.03 (m, IH), 1.77 - 1.51 (m, 2H), 0.96 (d, J = 6.3 Hz, 6H)

[0670] 'HNMR (300 MHz, CDC13) δ 11.30(m, IH),

[0671] H 4-(2-(((2,6-dioxo

[0672] 8.17 (d, J = 14.9 Hz, IH), 7.26 - 7.24 (m, o ί ,ο - 4 -Phenylonhexyl)

[0673] IH), 7.13 (s, 4H), 3.51 (d, J = 6.0 Hz, 2H), methyl)amino)ethyl

[0674] 3.30 (s, 5H), 2.81 (s, 6H), 2.72 (d, J = 6.8 yl) -N,N-dimethyl

[0675] Hz, 3H), 2.66 - 2.57 (m, 2H), 2.49 (s, 4H), piperazine-1-carboxamide

[0676] 2.33 (s, 2H)

[0677] 'HNMR (300 MHz, CDC13) δ 11.25 (s, IH),

[0678] 5-phenyl-2-(((2-(4- 8.19 (d, J = 14.3 Hz, IH), 7+40 - 7.29 (m, propionylpiperazin-1-yl: 2H), 7.23 (d, J = 8.2 Hz, 3H), 3.66 (s, 2H), ethyl)amino)methyl 3.51 (s, 4H), 3.36 (s, IH), 2.75 (d, J = 7.3 Hz, 2H), 2.64 (dd, J = 12.2, 6.2 Hz, 2H), ketone 2.49 (s, 4H), 2.34 (q, J = 7.5 Hz, 2H), 1.25

[0679] (s, 2H), 1.14 (t, J = 7.4 Hz, 3H) 'HNMR (300 MHz, CDC13) δ 11.25 (s, IH),

[0680] 2-(((2-(4-benzoyl 8.21 (d, J = 14.7 Hz, IH), 8.10 (d, J = 7.6 Hz, piperazin-1-yl)ethyl)methyl 7.48 (d, J = 7.7 Hz, IH), 7.40 (s,

[0681] 216 amino)methyl)-5- 4H), 7.32 (d, J = 7.1 Hz, IH), 7.23 (d, J = 7.7 Hz, 2H), 3.85 (s, 2H), 3.54 (d, J = 5.8 diketone Hz, 4H), 3.36 (s, IH), 2.84 - 2.69 (m, 4H),

[0682] 2.64 (d, J = 13.3 Hz, 4H), 2 48 (s 2H)

[0683] 'HNMR (300 MHz, CDC13) δ 11.26 (s, IH),

[0684] H 2-(((2-(4-(4-nitro 8.29 (d, J = 8+4 Hz, 2H), 8.19 (d, J = 14.3 benzoyl)piperazine-1- Hz, IH), 7.57 (d, J = 8.5 Hz, 2H), 7.33 (d, J

[0685] 217 (methyl)ethyl)amino)imide = 7.1 Hz, 2H), 7.22 (s, 3H), 3.86 (s, 2H), y H NO2methyl)-5-phenylcyclohexane 3.53 (d J = 5.8 Hz, 4H), 3.42 (s, 2H), 3.38 - alkyl-1,3-dione 3.28 (m, 1H), 2.83 - 2.69 (m, 4H), 2.65 (d, J

[0686] = 6.0 Hz, 4H), 2.47 (s, 2H)

[0687] 'HNMR (300 MHz, CDC13) δ 11.22 (s, IH),

[0688] 2-(((2-(4-(methylsulfonyl)

[0689] 8.18 (d, J = 14.3 Hz, IH), 7.37 - 7.30 (m, acyl)piperazin-1-yl)

[0690] 2H), 7.23 (d, J = 7.9 Hz, 3H), 3.60 - 3.46

[0691] 218 Ethyl)amino)methylene

[0692] (m 2H), 3.36 (d, J = 5.5 Hz, IH), 3.28 (s, yl)-5-phenylcyclohexane

[0693] 4H), 2.79 (s, 3H), 2.75 (d, J = 7.5 Hz, 2H), -1,3-dione

[0694] 2.72 - 2.63 (m, 4H), 2.67 - 2.59 (m, 4H)

[0695] 'HNMR (300 MHz, CDC13) δ 11.25 (s, IH),

[0696] 2-(((2-(4-(4-chlorobenzene)

[0697] 8.18 (d, J = 14.3 Hz, 1H), 7.37 (d, J = 6.6 formyl)piperazine-1- Hz, 5H), 7.24 (d, J = 12.4 Hz, 4H), 3.81 (s,

[0698] 219 (methyl) ethyl) amino) imide

[0699] 2H), 3.51 (s, 4H), 3.40 - 3.29 (m, IH), 2.83 (methyl)-5-phenylcyclohexane

[0700] - 2.67 (m, 4H), 2+65 (s, 2H), 2.62 - 2.35 (m, α-1,3-dione)

[0701] 4H)

[0702] 'HNMR (300 MHz, CDC13) δ 11.26 (s, IH),

[0703] H 2-(((2-(4-(4-bromobenzene 8.18 (d, J = 14.1 Hz, IH), 7.55 (d, J = 7.7 formyl)piperazine-1- Hz, 2H), 7.38 - 7.27 (m, 4H), 7.23 (d, J = ...

[0704] 220 methyl)ethyl)amino)imide 7.4 Hz, 3H), 3.81 (s, 2H), 3.52 (d, J = 5.7 methyl)-5-phenylcyclohexane Hz, 4H), 3.36 (s, 1H), 2.82 - 2.68 (m, 4H), alkyl-1,3-dione 2.65 (d, J = 6.4 Hz, 2H), 2.51 (d, J = 29.1

[0705] Hz, 4H)

[0706] 5-phenyl 'HNMR (300 MHz, CDC13) δ 11.19 (s, IH), -2-(((2-(4-(2-phenyl 8.16 (d, J = 14.4 Hz, IH), 7.38 - 7.28 (m, 5H), 7.23 (d, J = 7.7 Hz, 5H), 3.73 (s, 2H),

[0707] 221

[0708] yl)ethyl)amino)methyl)-5-phenylcyclohexane-l,3-dione

[0709] yl)ethyl)amino)methyl)-5-phenylcyclohexane-l,3-dione

[0710] 'HNMR (300 MHz, CDC13) δ 11.26 (s, IH),

[0711] 2-((((2-(4-nicotinoyl 8.66 (s, 2H), 8.18 (d, J = 14.4 Hz, IH), 7.75 (d, J = 7.9 Hz, IH), 7.35 (dd, J = 15.1, 7.6 (d, J = 7.9 Hz, IH), 7.23 (d, J = 7.7 Hz, 5H), 3.73 (s, 2H),

[0712] 222 Hz, 4H), 7.25 - 7.19 (m, 2H), 3.86 (s, 2H), 3.52 (d, J = 5.4 Hz, 4H), 3.38 (s, IH), 2.85 -

[0713] yl)ethyl)amino)methyl)-5-phenylcyclohexane-l,3-dione

[0714] yl)ethyl)amino)methyl)-5-phenylcyclohexane-l,3-dione 'HNMR (300 MHz, CDC13) δ 11.20 (s, 2Η),

[0715] 2-(((2-(4-(3-hydroxyprop

[0716] 8.16 (d, J = 14.4 Hz, IH), 7.18 - 7.06 (m, yl)piperazine-1-yl)ethyl

[0717] 4H), 3.84 - 3.72 (m, 2H), 3.49 (dd, J= 11.6,

[0718] 230-methyl-amino-methylene

[0719] 5.8 Hz, 2H), 3.31 (d, J = 5.9 Hz, IH), 2.87 (-yl) -5- (p-tolyl)

[0720] 2.50 (m, 14H), 2.33 (s, 3H), 1.85 - 1.72 (m, cyclohexane-1,3-dione)

[0721] 2H)

[0722] 4-(2-(((2,6-dioxo)H NMR (300 MHz, CDCl3) δ 11.28 (m, —4-(p-tolyl)amino(IH), 8.17 (d, J = 14.2 Hz, IH), 7.32 (d, J = cyclohexyl)methyl)amino(7.8 Hz, 3H), 7.13 (d, J = 3.2 Hz, 6H), 3.87

[0723] 231

[0724] (yl)ethyl)-N-phenyl (s, 4H), 3.50 (s, 2H), 3.36 - 3.26 (m, 1H), piperazine-1-thiocarboxyl 2.81 - 2.65 (m, 4H), 2.64 (s, 2H), 2.57 (s, amine 4H), 2.33 (s, 3H)

[0725] 'HNMR (300 MHz, CDC13) δ 11.21 (s, IH),

[0726] H 8.18 (d, J = 14.4 Hz, IH), 7+ 14 (d, J = 10.6

[0727] 2-(((2-(4-Acryloyl Hz, 4H), 6.55 (dd, J = 16.4, 10.9 Hz, IH), piperazine-1-yl)ethyl) 6.28 (d, J = 16.8 Hz, IH), 5.69 (d, J = 10.5)

[0728] 232 (amino) methylene (Hz, IH), 3.73 (s, 2H), 3.57 (d, J = 22.5 Hz, yl) -5- (p-tolyl) 2H), 3.57 - 3.43 (m, IH), 3.30 (d, J = 6.0 cyclohexane-1,3-dione (Hz, 2H), 2.83 - 2.65 (m, 4H), 2.63 (t, J = 6.0 Hz, yl) -5- (p-tolyl) 2H), 3.57 - 3.43 (m, IH), 3.30 (d, J = 6.0 Hz, yl) -5- (p-tolyl) 2H), 3.57 - 3.43 (m, IH), 3.30 (d, J = 6.0 Hz, yl) -5- (p-tolyl) 2H), 3.57 - 3.43 (m, IH), 3.30 (d, J = 6.0 Hz, yl) -5- (p-tolyl) 2H), 3.73 (s, 2H), 3.73 (s, 2H), 3.57 (d, J = 22.5 ...

[0729] 5.4 Hz, 2H), 2.55 - 2.42 (m, 4H), 2.33 (s, 3H)

[0730] 】H NMR (300 MHz, CDC13) δ 11.28 (m,

[0731] 2-(((2-(4-methylpropene IH), 8.18 (d, J = 14.0 Hz, IH), 7.15 (d, J = acylpiperazin-1-yl)ethyl 10.7 Hz, 4H), 5.19 (s, IH), 5.02 (s, IH),

[0732] 233yl)amino)methylene 3.63 (s, 4H), 3.52 (d, J = 5.8 Hz, 2H), 3.31yl)-5-(p-Tolyl) (s, 1H), 2.80 - 2.69 (m, 4H), 2.62 (d, J = 5.6 Hz, 2H), 2.49 (s, 4H), 2.33 (s, 3H), 1.94 (s,

[0733] 3H)

[0734] 'HNMR (300 MHz, CDC13) δ 11.20 (s, IH),

[0735] 5-Phenylacetyl-2-(((2-(piperazine) 8.17 (d, J = 14.0 Hz, IH), 7.32 (d, J = 7.3)

[0736] Hz, 2H), 7.24 (t, J = 6.7 Hz, 3H), 3.48 (d, J

[0737] 236

[0738] alkyl:)methylene:)cyclohexane = 7.0 Hz, 2H), 3.41 (s, 4H), 3.41 (s, 2H), -1,3-dione 3.08 (s, 2H), 2.74 (d, J = 7.1 Hz, 2H), 2.64

[0739] (s, 4H), 2.52 (s, IH)

[0740] 2-(((2-(piperazin-1-yl) 'H NMR (300 MHz, CDCl3) δ 11.31 - 11.16 il k / NH

[0741] Ethyl)amino)methylene (m, 2H), 8.14 (s, 1H), 7.13 (s, 4H), 3.51 (s, 2H)

[0742] 237

[0743] (base) - 5 - (p-Tolyl) 3H), 3.38 - 3.27 (m, 2H), 3.12 (s, 4H), 2.71 cyclohexane-1,3-dione (s, 4H), 2.43 (s, 6H), 2.33 (s, 3H)

[0744] N 2-(((2-(4-ethylpiperazine) ¹H NMR (300 MHz, CDCl₃) δ 11.20 (s, 1H),

[0745] -1-yl)ethyl)amino) 8.16 (d, J = 14.3 Hz, 1H), 7.13 (s, 4H), 3.45

[0746] 238 methylene)-5-(p-methyl (t, J = 23.7 Hz, 2H), 3.31 (d, J = 5.3 Hz, phenyl)cyclohexane-1,3-1H), 2.83 - 2.53 (m, 16H), 2.32 (s, 3H), dione 1.20 (t, J = 7.2 Hz, 3H)

[0747]

[0748] For 8 and 8 is 0. OAV H 5 - (4 - chlorophenyl)'HNMR (300 MHz, CDC13) δ 11.22 (s, IH),

[0749] C Jl a L N N J group) - 2 - (((2 - (4 - (morpholine 8.17 (d, J = 14.5 Hz, IH), 7.29 (t, J = 7.7

[0750] - 4 - carbonyl) piperazine - 1 - Hz, 2H), 7.15 (d, J = 8.4 Hz, 2H), 3.66 (d, J

[0751] 249

[0752] yl) ethyl) amino) methylene = 4.4 Hz, 4H), 3.51 (d, J = 6.0 Hz, 2H), 3.34 methyl) cyclohexane - 1,3 - (s, 5H), 3.25 (d, J = 4.3 Hz, 4H), 2.79 - 2.55 z diketone (m, 6H), 2.49 (s, 4H)

[0753] 'HNMR (400 MHz, CDC13) δ 8.09 (s, IH),

[0754] 5 - (2,3 - dihydrobenzofur 7.09 (s, IH), 6.99 (d, J = 8.1 Hz, IH), 6.75 ( S 0

[0755] furan - 5 - yl) - 2 - ((dimethyl (d, J = 8.iz, IH), 4.58 (t, J = 8.7 Hz, 2H),

[0756] 251

[0757] ylamino) methylene) cyclo 3.44 (d, J = 5.0 Hz, 3H), 3.31 (ddd, J = 16.2, hexane - 1,3 - dione 11.6, 4 + 4 Hz, IH), 3.26 - 3.16 (m, 5H), 2.70

[0758] (qd, J = 16.6, 8.1 Hz, 4H)

[0759] 'H NMR (400 MHz, CDCl3) δ 8.10 (d, J = o 4-(4-((dimethylamine)

[0760] 5.5 Hz, IH), 8.02 (d, J = 7.9, 6 1 Hz, 2H), methyl)methylene)-3,5-di

[0761] 252 7.37 - 7.30 (d, 2H), 3.96 - 3.84 (s, 3H), oxocyclohexyl)benzyl

[0762] 3.44 (t, J = 8.5 Hz, 4H), 3.24 (s, J = 5.6 Hz, methyl ester)

[0763] 3H), 2.74 (m, J= 16.9, 5.3 Hz, 4H)

[0764] 3-(4-((dimethylamino)methylene)-3,5-dimethylamino(4,5-dimethylamino)H NMR (400 MHz, CDCl3) δ 8.11 (s, IH), 7.97 (s, IH), 7.94 (d, J = 7.1 Hz, IH), 7.49 -

[0765] 253

[0766] (Oxycyclohexyl)benzyl 7.40 (m, 2H), 3.94 (s, 3H), 3.52 - 3.35 (m,

[0767] COOMe methyl ester (4H), 3.25 (s, 3H), 2.84 - 2.63 (m, 4H)

[0768] 2-((dimethylamino) 'H NMR (400 MHz, CDCl3) δ 8.10 (s, 1H), methylene)-5-(4-(trimethylamino) 7.61 (d J = 8+0 Hz, 2H), 7.38 (d, J = 7.9 Hz,

[0769] 254

[0770] (Fluoromethyl)phenyl)cyclohexane (2H), 3.45 (s, 4H), 3.24 (s, 3H), 2.84 - 2.62 1,3-dione (m 5H)

[0771] o 2- ((dimethylamino) 'H NMR (400 MHz, CDCl3) δ 8.10 (s, 1H), methylene)-5-(3-(trimethyl)-5-(m, 2H), 7.54 - 7.49 (m, 2H), 7.48 (d, J = 7.8 Hz,

[0772] 255

[0773] (Fluoromethyl)phenyl)cyclohexane (IH), 7.46 (s, IH), 3.51 - 3.35 (m, 4H), 3.24 α-1,3-dione (s, 3H), 2.75 (qd, J = 16.5, 8.1 Hz, 4H)

[0774] 'HNMR (400 MHz, CDC13) δ 8.07 (s, IH),

[0775] N-(4-(4-((dimethyl)

[0776] 7.94 (s, IH), 7.47 (d, J = 6.8 Hz, 2H), 7.18 (amino)methylene)-3,5-

[0777] 256 (d, J = 6.1 Hz, 2H), 3.40 (s, 3H), 3.33 (m, cyclohexyl)phenyl)ethyl

[0778] IH), 3.21 (s, 3H), 2.69 (q, J = 15.7 Hz, 4H), amide

[0779] 2.16 (s, 3H)

[0780] 'HNMR (400 MHz, CDC13) δ 8.56 (s, IH),

[0781] 2-((dimethylamino)

[0782] 8.53 (d, J = 4.5 Hz, IH), 8.11 (s, IH), 7.59 (methylene)-5-(pyridine)

[0783] 257 (d, J = 7.9 Hz, IH), 7.32 - 7.29 (m, IH),

[0784] -3-yl)cyclohexane-1,3- 3.46 (s, 3H), 3.41 (dd, J = 11.2, 4.8 Hz, 1H), diketone

[0785] 3.25 (s, 3H), 2.82 - 2.71 (m, 4H)

[0786] 'HNMR (400 MHz, CDC13) δ 11.26 (s, IH), 8.21 (d, J = 14.4 Hz, IH), 8.03 (d, J = 8.2

[0787] 4-(4-(((2-morpholinoethyl

[0788] Hz, 2H), 7.33 (d, J = 8.2 Hz, 2H), 3.93 (s, group)amino)methylene

[0789] 258 3H), 3.80 - 3.72 (m, 4H), 3.55 (dd, J = 11.9, group)-3,5-dioxocyclohex

[0790] 6.0 Hz, 2H), 3.46 (dd, J = 10.8, 5.8 Hz, IH), group)methyl benzoate

[0791] 2.84 - 2.66 (m, 4H), 2.63 (t, J = 5.9 Hz, 2H), 2.53 (d, J = 4.1 Hz, 4H) 06

[0792]

[0793] ΖΪ8而 8Ϊ0Ζ OAV Z6

[0794]

[0795] 9M7Z.80 / 8T0ZN3 / X3d ΖΪ8而 8Ϊ0Ζ OAV

[0796]

[0797] 9M7Z.80 / 8T0ZN3 / X3d ΖΪ8而 8Ϊ0Ζ OAV 86

[0798]

[0799] 9M7Z.80 / 8T0ZN3 / X3d ΖΪ8而 8Ϊ0Ζ OAV 66

[0800]

[0801] Z18 and Z80 OAV 001

[0802]

[0803] Z18 and Z80 OAV 001

[0804]

[0805] Z18 and Z80 OAV

[0806] Z18 and Z80 OAV eoi

[0807]

[0808] Z18 and Z80 OAV 501

[0809]

[0810] 9M7Z.80 / 8T0ZN3 / X3d Z18 and Z80 OAV 4-(hydroxy(phenyl)methyl

[0811] 'H NMR (400 MHz, CD3OD) δ 7.77 (s, -2-(((2-(4-(2-hydroxy

[0812] IH), 7.26 (m, 5H), 5.13 (d, J = 6.0 Hz, IH), ethyl)piperazin-1-yl

[0813] 3.69 (t, J = 6.0 Hz, 2H), 3.55 (t, J = 5.7 Hz, ethyl)amino)methy

[0814] 2H), 3.13 (m, IH), 2.69 - 2.46 (m, 12H), ethyl)cyclopentane-1,3-di

[0815] 2.33 (m, 2H); MS: 388.2 [M+1].

[0816] ketone

[0817] 5-(5-bromo-1H-indole)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 = hydroxyethyl)piperazine-1- 3.2 Hz, IH), 6.38 (d, J = 2.4 Hz, IH), 3.90 - o m (m, 1H) 3.81 (t, J = 5.9 Hz, 2H), 3.72 (t, J = 5.9 Hz, 2H), 3.62 (m, 16H) cyclohexane-1,3- (t, J = 5.6 Hz, 2H), 2.72 (m, 16H); MS: diketone 491.1 [M+1].

[0818] 5-(2-bromo-5-hydroxybenzene)

[0819] ¾ NMR (400 MHz, CD3OD) δ 8.27 (s, kJ r group) -2-(((2-(4-(2-hydroxy)

[0820] IH), 7.36 (d, J = 8.6 Hz, IH), 6.78 (d, J =

[0821] 〇r (ethyl)piperazine-1-yl)

[0822] 2.9 Hz, IH), 6.60 (dd, J = 8.7, 2.8 Hz, IH), ethyl)amino)methylene

[0823] 1 3.80 - 3.57 (m, 4H), 2.77 (m, 13H); MS:

[0824] L-(cyclohexane-1,3-di)

[0825] 467+0 [M+1],

[0826] ketone

[0827] H 5-(4-chloro-1H-indole)

[0828] **¹H 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 (t, J = hydroxyethyl)piperazine-1- (m, 2H), 4.22 - 4.12 (m, IH), 3.77 (t, J = yl)ethyl)amino)imide

[0829] 5.7 Hz (2H), 3.63 (m, 2H), 3.03 - 2.63 (m, methyl)cyclohexane-1,3-

[0830] H 16H); MS: 445.1 [M+1].

[0831] diketone

[0832] 】H NMR (400 MHz, CD3OD) δ 8.55 (s,

[0833] 7-Chloro-3-(((5-(diethylIH), 7.97 (d, J = 8.5 Hz, IH), 7.18 (d, J = ylamino)pentan- 2 -2,4(1H, 3H)-diketone (1.7 Hz, IH), 7.12 (dd, J = 8.5, 1.8 Hz, IH), amino)methylene)quinoline 3.81 (s, IH), 3.06 (m, 6H), 1.75 (d, J = 5.6 Hz, 4H), 1.43 (d, J = 6.6 Hz, 3H), 1.30 - 1.18 (m, 6H); MS: 364.1 [M+1].

[0834] 】H NMR (400 MHz, CD3OD) δ 8.28 (s,

[0835] 2- ( 4- ( 2- ( ( ( 4- IH), 7.43 (d, J = 8.4 Hz, 2H), 7.26 (dd, J =

[0836] (1H-indol-4-yl)

[0837] 14.2 (5.7 Hz, 2H), 7.13 (d, J = 8.0 Hz, 2H), -2,6-dioxocyclic ring

[0838] 7.06 (t, J = 7.7 Hz, 1H), 6.88 (d, J = 7.3 Hz, 1H), 6.53 (d, J = 2.6 Hz, 1H), 3.79 (m, 1H), 3.63 (m, 2H), 3.16 (s, 2H), 2.99 - 2.85 (m, 2H), 2.82 (m, 2H), 2.65 (s, 9H), 2.29 (s, 3H). 2-(((2-(dimethylamino)ethyl)amino)-N-(p-tolyl)acetamide

[0839] 1H), 6.53 (d, J = 2.6 Hz, 1H), 3.79 (m, 1H), (ethyl)piperazin-1-yl

[0840] 3.63 (m, 2H), 3.16 (s, 2H), 2.99 - 2.85 (m, -N-(p-tolyl)

[0841] 2H), 2.82 (m, 2H), 2.65 (s, 9H), 2.29 (s, acetamide

[0842] 3H).

[0843] 2-(((2-(dimethylamino)ethyl)amino)-N-(p-tolyl)acetamide 1H NMR (400 MHz, CDCl3) δ 11.25 (s, 1H),

[0844] 8.21 (d, J = 14.4 Hz, 1H), 7.31 (s, 1H), 7.25,

[0845] c i o H methylene)-5-(2,3,6-trichlorophenyl)cyclohexane-1,3-dione 7.17 (m, 1H), 4.41 (s, 1H), 3.68 - 3.43 (m, 4H), 2.58 (t, J = 5.9 Hz, 2H), 2.48 (d, J = 16.7 Hz, 2H), 2.31 (s, 6H). 801

[0846]

[0847] 9M7Z.80 / 8T0ZN3 / X3d ΖΪ8而 8Ϊ0Ζ OAV 601

[0848]

[0849] 9M7Z.80 / 8T0ZN3 / X3d ΖΪ8而 8Ϊ0Ζ OAV Synthesis of Compounds 415 - 452 of Example 35

[0850] The synthesis of compounds 415-452 is identical to that of Example 4 or 8 (as for compounds 3 and 8) except that the corresponding substituted 1,3-cyclohexanedione is used, as shown in Table 8.

[0851] Table 8: Compounds 415-452

[0852] en

[0853]

[0854] Z18and Z20are OAV ill

[0855]

[0856] Z18and Z20are OAV Example 36 Compound 5 - ((( 2 - ( 4 - ( 2 - hydroxyethyl) piperazin-1-yl) ethyl) amino) methylene) thiazolidine - 2 , 4 Synthesis of 5- ( ( (dimethylamino) methylene) -2, 4- thiazolidinedione (Compound 200)

[0857]

[0858] Step 1: Synthesis of 5- ( ( (dimethylamino) methylene) -2, 4- thiazolidinedione

[0859] A mixture of 2, 4-thiazolidinedione (2.8 g, 23.93 mmol), triethoxymethane (4 mL) and acetic anhydride (6 mL) was heated to reflux overnight. Upon completion of the reaction, the mixture was cooled to room temperature and solid was precipitated. The solid was filtered, the filtrate was collected and concentrated to give the crude product which was used directly in the next step without further purification.

[0860] Step 2: Synthesis of 5- ( ( (dimethylamino) methylene) -2, 4- thiazolidinedione (Compound 200)

[0861] Example 37 Synthesis of 4- ( (dimethylamino) methylene) -2- methyl-2-phenylcyclobutane-1, 3-dione (Compound 201)

[0862] Step 1 : Synthesis of 2-phenylpropanoyl chloride

[0863] Under nitrogen protection, add dropwise to 2-phenylpropanoic acid (2 g, 13.3 mmol) in DCM (20 mL) at 0 °C, add dropwise a catalytic amount of DMF, reflux the mixture for 2 hours and concentrate to obtain 2-phenylpropanoyl chloride crude, which is directly used in the next step.

[0864] Step 2: Synthesis of compound 3-ethoxy-4-methyl-4-phenylcyclobut-2-en-1-one

[0865] Under nitrogen protection, add dropwise to 2-phenylpropanoyl chloride (13.3 mmol) in ether (40 mL), add dropwise to the above mixture TEA (2 g, 19.8 mmol), after stirring at room temperature for 30 minutes, heat the suspension to reflux for 24 hours. After the reaction is completed, cool the obtained mixture, filter, concentrate the filtrate, and purify by column chromatography to obtain the target compound 600 mg.

[0866] Step 3: Synthesis of compound 2-methyl-2-phenylcyclobutane-1,3-dione

[0867] Dissolve compound 3-ethoxy-4-methyl-4-phenylcyclobut-2-en-1-one (350 mg, 1.73 mmol) in a mixture of 2M hydrochloric acid (5 mL) and THF (3 mL), and stir vigorously at room temperature for 48 hours. After the reaction is completed, extract with DCM, dry and concentrate the combined organic layers to obtain crude product 250 mg, which is directly used in the next step.

[0868] Step 4: Synthesis of compound 4-((dimethylamino)methylene)-2-methyl-2-phenylcyclobutane-1,3-dione (compound 201)

[0869] The operating steps are the same as in Example 8 (compound 8). Compound 201: Ή NMR (400 MHz, CDC13) δ 7.56 - 7.48 (m,

[0870] 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).

[0871] Example 38: Synthesis of compound 2-(((2-(dimethylamino)ethyl)amino)methylene)-5- phenylcyclohexan-1,3-dione) nickel (II) chloride

[0872] (II) Complex Synthesis

[0873] Compound 119

[0874] To a solution of sodium (264 mg, 11 mmol) in methanol (20 mL) was added dropwise a solution of compound 119 (2.86 g, 10 mmol) in methanol (7.5 mL) and stirred at room temperature for 10 minutes. To the above mixture was added a solution of nickel (II) chloride-1,2-dimethoxyethane (2.63 g, 12 mmol) in methanol (10 mL). The mixture was heated to 40 °C and stirred for 2 hours. Concentration, the concentrated crude was diluted with acetone and refluxed for 1 hour, cooled, filtered off the solid, washed with acetone and dried to give the target compound Ug, yield 29 0 MS (ESI): [M - Cl] + : 343.3; [M + CI] ": 413+2.

[0875] Example 39: Synthesis of 2-(benzyloxy-methylene)-5-phenylcyclohexan-1,3-dione sodium salt (compound 463)

[0876]

[0877] To a solution of compound 3 (294 mg) in water (8 mL) was added NaOH solid (57 mg, 1.4 mmol) and stirred at room temperature overnight. The reaction mixture was concentrated and slurry with ether to give the yellow solid product (compound 463) 267 mg, yield 83%.

[0878] In compound 463, Na forms a coordination bond with benzyloxy.

[0879] Example 40: Synthesis of compounds 453-462 and 464

[0880] The synthesis of compounds 453-462 and 464 was carried out as described in Example 39 except that the corresponding diketone compound and base were used as shown in Table 9.

[0881] Table 9: Compounds 453-464 Correction Page (Rule 91) ISA / CN

[0882] In the above compounds, Li, Na or K forms a coordinate bond with the carbonyl oxygen.

[0883] Example 41 : The modulation of autophagy-related protein LC3B by the compounds of the application was tested using the fluorescence polarization (FP) method. Fluorescence polarization (FP) method test experiment

[0884] The histone GST-LC3B (final concentration 180 nM) (SEQ ID NO: 1) and the N-terminal FITC-labelled peptide (SEQ ID NO: 2, sequence: FITC-GGDDDWTHLSSKEVD-NH2, final concentration 18 nM) were placed in FP buffer (50 mM HEPES pH 7.5, 0.1 mg / mL BSA, 1 mM DTT) to which the compounds were added, diluted using a gradient of FP buffer, and then the above mixture was incubated at 25 °C in the dark. The fluorescence polarization values were monitored (PerkinElmer Envision, emission wavelength 480 nm; absorption wavelength 535 nm), and the IC 5Q values were calculated using the GraphPad Prism 6.0 program, and the test results are shown in Table 8.

[0885] The IC 5Q values of the compounds indicate: 100 μΜ < IC 50 < 10 μΜ is considered to be low activity on LC3B (+); 15 μΜ < IC 50 < 3 μΜ is considered to be moderate activity on LC3B (C++); 3 μΜ < IC 50 < 15 μΜ is considered to be high activity on LC3B (+++); IC 50 < 3 μΜ is considered to have high activity on LC3B (++++). The IC values of the compounds of the application are shown in Table 10.

[0886] Table 10: IC50 values of the compounds

[0887] No. IC 50 (μΜ) No. IC 50 (μΜ) No. IC 50 (μΜ) No. IC 50 (μΜ)

[0888] 1 + 2 +++ 4A +++ 7 +++ 8 ++++ 9 +

[0889] 10 + 11 + 12 + 14 + 15 +++ 17 +++

[0890] 18 +++ 19 ++ 20 + 21 ++ 22 + 23 +++

[0891] 24 + + 25 + 26 ++ 27 ++ 28 +++ 29 +

[0892] 30 + 31 +++ 32 +++ 33 ++ 34 ++++ 35 ++

[0893] 36 + 37 39 40 41 +++ 42 +++

[0894] 43 +++ 44 ++ 45 ++ 46 47 +++ 48

[0895] 49 50 51 ++ 52 ++ 53 ++ 54

[0896] 55 ++ 56 +++ 57 ++ 58 ++ 59 + 61 ++++

[0897] 62 +++ 63 ++ 64 + 65 + 66 ++++ 67 +

[0898] 68 69 ++ 70 + 71 ++ 72 73

[0899] 74 + + 75 +++ 76 ++ 77 ++ 78 ++ 79 +

[0900] 80 ++ 81 ++ 82 ++ 83 ++ 84 ++ 85 ++

[0901] 86 ++ 87 ++ 88 +++ 89 + 90 + 91 ++

[0902] 92 ++ 93 +++ 94 ++ 95 ++ 96 + 97 ++

[0903] 99 + 100 ++ 101 ++ 102 ++ 103 ++ 104 ++

[0904] 106 + 107 ++ 108 + 109 + 110 + 111 +

[0905] 112 ++ 113 + 114 + 115 +++ 116 ++++ 119 ++++

[0906] 120 121 ++ 122 + 123 + 124 + 125 +

[0907] 126 ++ 127 ++ 128 + 129 ++ 131 ++ 132 +

[0908] 133 + 134 + 135 + 136 + 137 +++ 138 +

[0909] 139 + 140 ++ 141 +++ 142 ++ 143 ++ 145 +

[0910] 146 ++ 147 ++ 148 149 150 155 ++

[0911] 156 +++ 158 + 160 十十 161 + 162 十十 163 十

[0912] 164 +++ 165 + 169 +++ 170 +++ 171 +++ 172 +++

[0913] 173 ++ 174 ++ 175 +++ 176 + 177 + 178 ++

[0914] 180 + 182 + 183 + 184 + 185 ++++ 186 +++

[0915] 187 188 +++ 189 190 ++ 191 192 +++

[0916] 193 ++ 194 ++ 195 +++ 196 +++ 197 ++++ 198 ++

[0917] For 8 and 8 is 0. OAV 412 ++++ 413 +++ 414 +++ 415 416 417

[0918] 418 419 420 421 422 423

[0919] 424 +++ 425 ++ 426 ++++ 427 +++ 428 +++ 429 ++++

[0920] 430 431 +++ 432 433 434 435

[0921] 436 +++ 437 +++ 438 +++ 439 +++ 440 441

[0922] 442 ++ 443 ++ 444 +++ 445 ++ 446 +++ 447 +++

[0923] 448 +++ 449 ++ 450 ++ 451 452 453

[0924] 454 +++ 455 +++ 456 +++ 457 458 459

[0925] 460 461 +++ 462 +++ 463 +++ 464 +++ The compounds of the present application exhibit activity against LC3B, and some compounds have high activity against LC3B. These compounds are also active against other mammalian homologues of ATG8. Thus, these compounds can modulate LC3B and other mammalian homologues of ATG8 for the treatment of diseases associated with autophagy.

[0926] It is understood that various modifications or changes in light thereof can be made by those skilled in the art and such equivalent forms are to be included within the scope of the application. It is therefore intended that the preferred embodiments recited herein be considered as illustrative only and not as limiting the scope of the application.

Claims

CLAIM 1. A compound of general formula ① or a pharmaceutically acceptable salt thereof. in- X and Y are each independently selected from the group consisting of O, 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 O, S, SO, SO2, N, NR a , CO, C, CR a , and CH2; m can be 0, 1, 2, or 3; n is 0, 1, 2, or 3; Selected from hydrogen, deuterium, C1-6 alkyl, C1-6 hydroxyalkyl, C1-6 haloalkyl, phenyl, and substituted phenyl; R2 is represented as -JKMQ, where — NA 4— — NA , J is NR a , NOR a , 0, S or, wherein ^ is a divalent 3-10 membered heterocycloalkyl group or a divalent 3-7 membered heterocycloalkenyl group containing at least one nitrogen atom; K is a covalent bond, NR a , CRcR c . or CR e Rc, CR c R c , M is a covalent bond, 0^, divalent 3-10 membered heterocyclic alkyl, divalent 3-7 membered heterocyclic alkenyl or divalent 5-10 membered heteroaromatic Q is hydrogen, C1-6alkyl, C1-6hydroxyalkyl, -(CH2) p -C(O)R b , -(CH2) p -C(O)NHR b , -(CH2) p -C(S)R b , -(CH2) p -C(S)NHR b , -(CH2)p-SO2R b , -(CH2) p -SO2NHR b , p is 0, 1, 2, or 3; Each R e Rc' is independently selected from hydrogen, hydroxyl, amino, RaRa', halogen, cyano, nitro, carboxyl, formyl, amide, ester, C1-6 haloalkyl, C1-6 hydroxyalkyl, C1-6 heteroalkyl, C1-6 alkyloxy, C1-6 alkoxyalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, 5-10 heteroaryl, C3-10 cycloalkyl, 3-10 heterocycloalkyl, 3-7 heterocycloalkenyl, C1-6 alkylC6-10 aryl, 5-10 heteroarylC1-6 alkyl or C1-6 alkyl5-10 heteroaryl; preferably selected from hydrogen, hydroxyl, amino, NRaRa', halogen, carboxyl, formyl, amide, ester, C1-6 Halogenated alkyl, C1-6 hydroxyalkyl, C1-6 heteroalkyl, C1-6 alkoxy, C3-10 cycloalkyl, 3-10 heterocyclic alkyl, substituted or unsubstituted phenyl or pyridyl; R3, FUand each independently are selected from the group consisting of hydrogen, hydroxyl, amino, halogen, cyano, nitro, carboxyl, formyl, amido, -NH-COR b , ester, C1-6alkyl, C1-6haloalkyl, C1-6hydroxyalkyl, C1-6heteroalkyl, C1-6 alkyl group, C1-6 alkoxyalkyl group, C2-6 alkenyl group, C2-6 alkynyl group, unsubstituted or substituted -CO H- (C6-10 aryl group), unsubstituted or substituted -CH=CH- (C6-10 aryl group), unsubstituted or substituted C6-10 aryl group, unsubstituted or substituted 5-10 heteroaryl group, unsubstituted or substituted C3-10 cycloalkyl group, unsubstituted or substituted 3-10 heterocyclic alkyl group, unsubstituted or substituted 3-7 heterocyclic alkenyl group, unsubstituted or substituted C6-10 aryl C1-6 alkyl group, unsubstituted or substituted C1-6 alkyl C6-10 aryl group, unsubstituted or substituted 5-10 heteroaryl C1-6 alkyl group, and unsubstituted or substituted C1-6 alkyl 5-10 heteroaryl group; or two adjacent groups of R3, R4and R5may join to form an unsubstituted or substituted C6-10 aryl, unsubstituted or substituted 5-10 membered heteroaryl, unsubstituted or substituted C3-10 cycloalkyl, or unsubstituted or substituted 3-10 membered heterocycloalkyl; wherein, each R is independently H, C1-6alkyl, C2-6alkenyl, NHR b is independently H, C1-6alkyl, C2-6alkenyl, NHR a , R a R a , unsubstituted or substituted phenyl or 3-7 membered heterocyclyl; each R and R a independently hydrogen or C1-6alkyl, Unsubstituted or substituted means that the group is not substituted or is substituted by one or more substituents selected from hydroxyl, amino, cyano, nitro, carboxyl, halogen, C1-6 alkyl, C1-6 haloalkyl or C1-6 hydroxyalkyl, or two adjacent substituents can be linked to form C6-10 aryl, C5-10 heteroaryl, C3-10 cycloalkenyl or C3-10 heterocycloalkenyl; And it meets the following conditions - (1) When \¥, Z or T is replaced by one of R3, and, the \¥, Z or T is N or CH; (2) When W, Z, or T is substituted by one of the groups R3, R4, and R5, and that group is connected to another adjacent group among R3, R4, and R5 to form an unsubstituted or substituted C6-10 aryl or an unsubstituted or substituted 5-10 heteroaryl, then W, Z, or T is C; (3) When ^¥, Z or T is replaced by two of R3, R4 and R5, then ^¥, Z or T is .

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein, X and Y are each independently selected from 0, S, or KH; U and V are each independently selected from C or S; W, Z and T are each independently selected from O, N, NR a , CO, C, CR a , CH2; m is 1 or 2; n is 0, 1, or 2; Selected from hydrogen and deuterium; R2 is represented as -JKMQ, where It is a divalent 3-10 membered heterocyclic alkyl group or a divalent 3-7 membered heterocyclic alkenyl group containing at least one nitrogen atom; K is a covalent bond, NR a , CR e R e , or CReRc RcRc,; M is a covalent bond, a divalent 3-10 membered heterocycloalkyl, a divalent 3-7 membered heterocycloalkenyl or a divalent 5-10 membered heteroaryl; Q is hydrogen, C1-6alkyl, C1-6hydroxyalkyl, -(CH2) p -C(O)R b , -(CH2) p -C(O)NHR b , -(CH2) p -C(S)R b , -(CH2) p -C(S)NHR b , -(CH2) p -SO2R b , -(CH2) p -SO2NHR b , wherein, p is 0, 1, 2 or 3; Each R e Rc' is independently selected from hydrogen, hydroxyl, amino, RaRa', halogen, cyano, nitro, carboxyl, formyl, amide, ester, C1-6 haloalkyl, C1-6 hydroxyalkyl, C1-6 heteroalkyl, C1-6 alkyloxy, C1-6 alkoxyalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, 5-10 heteroaryl, C3-10 cycloalkyl, 3-10 heterocycloalkyl, 3-7 heterocycloalkenyl, C1-6 alkylC6-10 aryl, 5-10 heteroarylC1-6 alkyl or C1-6 alkyl5-10 heteroaryl; preferably selected from hydrogen, hydroxyl, amino, NRaRa', halogen, carboxyl, formyl, amide, ester. C1-6 halogenated alkyl group, C1-6 hydroxyalkyl group, C1-6 heteroalkyl group, C1-6 alkyloxy group, C3-10 cyclic alkyl group, 3-10 membered heterocyclic alkyl group, substituted or unsubstituted phenyl or pyridinyl group; R3, E and R5are each independently selected from the group consisting of hydrogen, hydroxyl, amino, halogen, cyano, nitro, carboxyl, formyl, amido, H-COR b , ester, C1-6alkyl, C1-6haloalkyl, C1-6hydroxyalkyl, C1-6heteroalkyl, C1-6alkoxy, C1-6alkoxyalkyl, C2-6alkenyl, C2-6alkynyl, unsubstituted or substituted -CO H-(C6-10aryl), unsubstituted or substituted -CH=CH-(C6-10aryl), unsubstituted or substituted C6-10aryl, unsubstituted or substituted 5-10 membered heteroaryl, unsubstituted or substituted C3-10cycloalkyl, unsubstituted or substituted 3-10 membered heterocycloalkyl, unsubstituted or substituted 3-7 membered heterocycloalkenyl, unsubstituted or substituted C6-10aryl C1-6alkyl, unsubstituted or substituted C1-6alkyl C6-10aryl, unsubstituted or substituted 5-10 membered heteroaryl C1-6alkyl or unsubstituted or substituted C1-6alkyl 5-10 membered heteroaryl; or two adjacent groups in R4and R5may be joined to form an unsubstituted or substituted C6-10 aryl, unsubstituted or substituted 5-10 membered heteroaryl, unsubstituted or substituted C3-10 cycloalkyl, or unsubstituted or substituted 3-10 membered heterocycloalkyl; wherein each R b independently is C1-6alkyl, C2-6alkenyl, NHR a , R a R a , unsubstituted or substituted phenyl, or 3-7 membered heterocycloalkyl; each R and R a independently hydrogen or C1-6alkyl; unsubstituted or substituted means that the group is either unsubstituted or substituted with one or more substituents selected from the group consisting of hydroxy, amino, cyano, nitro, carboxy, halogen, C1-6alkyl, C1-6haloalkyl and C1-6hydroxyalkyl, or two adjacent substituents can be joined to form a C6-10aryl, 5-10 membered heteroaryl, C3-10cycloalkyl or 3-10 membered heterocycloalkyl; and provided that: (1) when Y, Z or T is substituted with one of R3, R4and R5, then Y, Z or T is N or CH; (2) when W, Z or T is substituted with one of R3, R4and R5and this group is joined to another adjacent group of R3, R4and R5to form an unsubstituted or substituted C6-10aryl or unsubstituted or substituted 5-10 membered heteroaryl, then Y, Z or T is C; (3) when Y, Z or T is substituted with two of R3, R4and R5, then Y, Z or T is.

3. The compound or pharmaceutically acceptable salt thereof of claim 1, wherein R2is selected from the group consisting of : , and wherein A is a divalent 3-10 membered nitrogen-containing heterocycloalkyl or a divalent 3-7 membered nitrogen-containing heterocycloalkenyl; Rc, Rc' and R e "each independently selected from the group consisting of hydrogen, hydroxyl, amino, NRaRa', halogen, cyano, nitro, carboxyl, formyl, amido, ester, C1-6haloalkyl, C1-6hydroxyalkyl, C1-6heteroalkyl, C1-6alkoxy, C1-6alkoxyalkyl, C2-6alkenyl, C2-6alkynyl, C6-10aryl, 5-10 membered heteroaryl, C3-10cycloalkyl, 3-10 membered heterocycloalkyl, 3-7 membered heterocycloalkenyl, C1-6alkyl C6-10aryl, 5-10 membered heteroaryl C1-6alkyl and C1-6alkyl 5-10 membered heteroaryl; preferably selected from the group consisting of hydrogen, hydroxyl, amino, NRaRa', halogen, carboxyl, formyl, amido, ester, C1-6haloalkyl, C1-6hydroxyalkyl, C1-6heteroalkyl, C1-6alkoxy, C3-10cycloalkyl, 3-10 membered heterocycloalkyl, substituted or unsubstituted phenyl or pyridyl; each R a independently hydrogen or Ci-6alkyl.

4. The compound or pharmaceutically acceptable salt thereof of claim 1, wherein said R2is selected from the group consisting of : wherein Rc is selected from the group consisting of hydrogen, hydroxy, amino, cyano, nitro, carboxy, halogen, C1-6alkyl, C1-6haloalkyl and C1-6hydroxyalkyl; Rc1and Rc2are each independently selected from the group consisting of hydrogen, hydroxy, amino, RaRa', halogen, cyano, nitro, carboxy, formyl, amido, ester, C1-6alkyl, C1-6hydroxyalkyl, C1-6heteroalkyl, C1-6alkoxy, C1-6alkoxyalkyl, C2-6alkenyl, C2-6alkynyl, C6-10aryl, 5-10 membered heteroaryl, C3-10cycloalkyl, 3-10 membered heterocycloalkyl, 3-7 membered heterocycloalkenyl, C1-6alkyl C6-10aryl, 5-10 membered heteroaryl C1-6alkyl or C1-6alkyl 5-10 membered heteroaryl; preferably selected from the group consisting of hydrogen, hydroxy, amino, NRaRa', halogen, carboxy, formyl, amido, ester, C1-6haloalkyl, C1-6hydroxyalkyl, C1-6heteroalkyl, C1-6alkoxy, C3-10cycloalkyl, 3-10 membered heterocycloalkyl, substituted or unsubstituted phenyl or pyridyl; or R el and R e2 to form C6-10 aryl, 5-10 membered heteroaryl, C3-10 cycloalkyl, and 3-10 membered heterocycloalkyl; each R a independently is hydrogen or C1-6alkyl.

5. The compound or pharmaceutically acceptable salt thereof of claim 1, wherein, the compound of general formula ① is selected from the following general formulae wherein X and Y are each independently selected from the group consisting of O, S or NH; W, Z and T are each independently selected from O, N, NR a , CO, m is 0, 1 or 2; n is 0, 1 or 2; selected from the group consisting of hydrogen and deuterium; -NA-NA J is NR a , NOR a , 0, S or, wherein is a divalent 3-10 membered heterocycloalkyl group or a divalent 3-7 membered heterocycloalkenyl group containing at least one nitrogen atom; R2' is selected from the group consisting of: hydrogen, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C1-6alkylamino, C6-10aryl or 5-10 membered heteroaryl, C3-10cycloalkyl, 3-10 membered heterocycloalkyl, - (CH2) m -M-Q, wherein M is a covalent bond, a divalent 3-10 membered heterocycloalkyl, a divalent 3-7 membered heterocycloalkenyl, or a divalent 5-10 membered heteroaryl; Q is hydrogen, C1-6alkyl, C1-6hydroxyalkyl, -(CH2) p -C(O)R b , -(CH2) p -C(O)NHR b , -(CH2) p -C(S)R b , -(CH2) p -C(S)NHR b , -(CH2) p -SO2R b , -(CH2) p -SO2NHR b , p is 0, 1, 2 or 3; R3, R4and R5are each independently selected from hydrogen, hydroxyl, amino, halogen, cyano, nitro, carboxyl, formyl, amido, H-COR b , ester, C1-6alkyl, C1-6haloalkyl, C1-6hydroxyalkyl, C1-6heteroalkyl, C1-6 C1-6alkoxyalkyl, C2-6alkenyl, C2-6alkynyl, unsubstituted or substituted -COH-(C6-10aryl), wherein X and Y are independently O, S, NH; W, Z and T are each independently selected from O, N, R a , CO, C, CR a , or CH : n is 0, 1, 2 or 3; selected from hydrogen and deuterium; is a divalent 3-10 membered nitrogen-containing heterocycloalkyl or a divalent 3-7 membered nitrogen-containing heterocycloalkenyl; J is selected from the group consisting of Ra, NOR a , O and S; K is a covalent bond, NR a , CR.R e , or CR.CReRc, Q is hydrogen, C1-6alkyl, C1-6hydroxyalkyl, -(CH2) p -C(O)R b , -(CH2) p -C(O)NHR b , -(CH2) p -C(S)R b , -(CH2) p -C(S)NHR b , -(CH2) p -SO2R b , -(CH2) p -SO2NHR b , p is 0, 1, 2 or 3; Rc, Rc' and W are each independently selected from the group consisting of hydrogen, hydroxyl, amino, NRaRa', halogen, cyano, nitro, carboxyl, formyl, amido, ester, C1-6haloalkyl, C1-6hydroxyalkyl, C1-6heteroalkyl, C1-6alkoxy, C1-6alkoxyalkyl, C2-6alkenyl, C2-6alkynyl, C6-10aryl, 5-10 membered heteroaryl, C3-10cycloalkyl, 3-10 membered heterocycloalkyl, 3-7 membered heterocycloalkenyl, C1-6alkyl C6-10aryl, 5-10 membered heteroaryl C1-6alkyl or C1-6alkyl 5-10 membered heteroaryl; preferably selected from the group consisting of hydrogen, hydroxyl, amino, NRaRa', halogen, carboxyl, formyl, amido, ester, C1-6haloalkyl, C1-6hydroxyalkyl, C1-6heteroalkyl, C1-6alkoxy, C3-10cycloalkyl, 3-10 membered heterocycloalkyl, substituted or unsubstituted phenyl or pyridyl; and R4are each independently selected from the group consisting of hydrogen, hydroxyl, amino, halogen, cyano, nitro, carboxyl, formyl, acylamino, NH-COR b , ester, C1-6alkyl, C1-6haloalkyl, C1-6hydroxyalkyl, C1-6heteroalkyl, C1-6alkoxy, C1-6alkoxyalkyl, C2-6alkenyl, C2-6alkynyl, unsubstituted or substituted -CO H-(C6-10aryl), unsubstituted or substituted -CH=CH-(C6-10aryl), unsubstituted or substituted C6-10aryl, unsubstituted or substituted 5-10 membered heteroaryl, unsubstituted or substituted C3-10cycloalkyl, unsubstituted or substituted 3-10 membered heterocycloalkyl, unsubstituted or substituted 3-7 membered heterocycloalkenyl, unsubstituted or substituted C6-10aryl C1-6alkyl, unsubstituted or substituted C1-6alkyl C6-10aryl, unsubstituted or substituted 5-10 membered heteroaryl C1-6alkyl, or unsubstituted or substituted C1-6alkyl 5-10 membered heteroaryl; or R3 and R4 are connected to form unsubstituted or substituted C6-10aryl, unsubstituted or substituted 5-10 membered heteroaryl, unsubstituted or substituted C3-10cycloalkyl or unsubstituted or substituted 3-10 membered heterocycloalkyl; wherein each R b independently is C1-6alkyl, C2-6alkenyl, NHR a , R a R a , unsubstituted or substituted phenyl or 3-7 membered heterocyclyl; each R and R a independently hydrogen or C1-6alkyl; unsubstituted or substituted means that the group is unsubstituted or substituted with one or more substituents selected from the group consisting of hydroxyl, amino, cyano, nitro, carboxyl, halogen, C1-6alkyl, C1-6haloalkyl and C1-6hydroxyalkyl, or two adjacent substituents can be connected to form C6-10aryl, 5-10 membered heteroaryl, C3-10cycloalkyl or 3-10 membered heterocycloalkyl; and with the proviso that (1) when W, Z or T is substituted with one of R3 and R4, the W, Z or T is N or CH; (2) when W, Z or T is substituted with one of R3 and R3 and connected to form C6-10aryl or 5-10 membered heteroaryl, the W, Z or T is C; (3) when W, Z or T is substituted with both R3 and R4, the W, Z or T is 7. The compound or pharmaceutically acceptable salt thereof of claim 1, wherein, the compound of general formula I is selected from the group consisting of compounds of general formula (IIIa), (IIIb), (IIIc) and (III d) as follows: R1is selected from the group consisting of hydrogen, deuterium, C1-6alkyl, C1-6hydroxyalkyl, C1-6heteroalkyl, C1-6alkoxy, C3-10cycloalkyl, 3-10 membered heterocycloalkyl, substituted or unsubstituted phenyl or pyridinyl; J is selected from NRa, NORa, O or S; K is a covalent bond, NR a , CR e R., or CR.Rc, CR c Rc,; is a divalent 3-10 membered nitrogen-containing heterocycloalkyl or a divalent 3-7 membered nitrogen-containing heterocycloalkenyl; Q is hydrogen, C1-6alkyl, C1-6hydroxyalkyl, -(CH2) p -C(O)R b , -(CH2) p -C(O)NHR b , -(CH2) p -C(S)R b , -(CH2) p -C(S)NHR b , -(CH2) p -SO2R b , or -(CH2) p -SO2HR b , p is 0, 1, 2 or 3; Each R e Rc, and Rc' are independently selected from hydrogen, hydroxyl, amino, NRaRa', halogen, cyano, nitro, carboxyl, formyl, amide, ester, C1-6 alkyl, C1-6 hydroxyalkyl, C1-6 heteroalkyl, C1-6 alkyloxy, C1-6 alkoxyalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, 5-10 heteroaryl, C3-10 cycloalkyl, 3-10 heterocyclic alkyl, 3-7 heterocyclic alkenyl, C1-6 alkylC6-10 aryl, 5-10 heteroarylC1-6 alkyl or C1-6 alkyl5-10 heteroaryl; preferably selected from hydrogen, hydroxyl, amino, NRaRa', halogen, carboxyl, formyl, amide, ester, C1-6 haloalkyl, C1-6hydroxyalkyl, C1-6heteroalkyl, C1-6alkoxy, C3-10cycloalkyl, 3-10 membered heterocycloalkyl, substituted or unsubstituted phenyl or pyridinyl; and each independently selected from the group consisting of hydrogen, hydroxyl, amino, halogen, cyano, nitro, carboxyl, formyl, amido, NH-COR b , ester, C1-6alkyl, C1-6haloalkyl, C1-6hydroxyalkyl, C1-6heteroalkyl, C1-6alkoxy, C1-6alkoxyalkyl, C2-6alkenyl, C2-6alkynyl, unsubstituted or substituted -CO H- (C6-10aryl); unsubstituted or substituted -CH=CH-(C6-10aryl); unsubstituted or unsubstituted or substituted C6-10aryl; unsubstituted or substituted 5-10 membered heteroaryl; unsubstituted or substituted C3-10cycloalkyl; unsubstituted or substituted 3-10 membered heterocycloalkyl; unsubstituted or substituted 3-7 membered heterocycloalkenyl; unsubstituted or substituted C6-10aryl C1-6alkyl; unsubstituted or substituted C1-6alkyl C6-10aryl; unsubstituted or substituted 5-10 membered heteroaryl C1-6alkyl; or unsubstituted or substituted C1-6alkyl 5-10 membered heteroaryl; or R3and R4are joined to form an unsubstituted or substituted C6-10aryl, unsubstituted or substituted 5-10 membered heteroaryl, unsubstituted or substituted C3-10cycloalkyl or unsubstituted or substituted 3-10 membered heterocycloalkyl; wherein each R b independently is C1-6alkyl, C2-6alkenyl, NHR a , R a R a , unsubstituted or substituted phenyl or 3-7 membered heterocyclyl; each R and R a independently hydrogen or C1-6alkyl; unsubstituted or substituted means that the group is either unsubstituted or substituted by one or more substituents selected from the group consisting of hydroxyl, amino, cyano, nitro, carboxyl, halogen, C1-6alkyl, C1-6haloalkyl and C1-6hydroxyalkyl, or two adjacent substituents can be joined to form a C6-10aryl, 5-10 membered heteroaryl, C3-10cycloalkyl or 3-10 membered heterocycloalkyl.

8. The compound or pharmaceutically acceptable salt thereof of claim 1, wherein, The compound of general formula I is selected from the group consisting of compounds of the following general formulae (IVa), (IVb), (IVc) and (IVd): R1is selected from the group consisting of hydrogen, deuterium, C1-6alkyl, C1-6hydroxyalkyl, C1-6heteroalkyl, C1-6alkoxy, C3-10cycloalkyl, 3-10 membered heterocycloalkyl, substituted or unsubstituted phenyl or pyridinyl; J is NR a , NORa, 0 or S; K is a covalent bond, NR a , CR e R., or CR.Rc, CR c Rc,; is a divalent 3-10 membered nitrogen-containing heterocycloalkyl or a divalent 3-7 membered nitrogen-containing heterocycloalkenyl; Q is hydrogen, C1-6alkyl, C1-6hydroxyalkyl, -(CH2) p -C(O)R b , -(CH2) p -C(O)NHR b , -(CH2) p -C(S)R b , -(CH2) p -C(S)NHR b , -(CH2) p -SO2R b , -(CH2) p -SO2NHR b , p is 0, 1, 2 or 3; Rc, R e , and Re" are each independently selected from hydrogen, hydroxyl, amino, NRaRa', halogen, cyano, nitro, carboxyl, formyl, amido, ester, C1-6haloalkyl, C1-6hydroxyalkyl, C1-6heteroalkyl, C1-6alkoxy, C3-10cycloalkyl, 3-10 membered heterocycloalkyl, substituted or unsubstituted phenyl or pyridinyl; preferably from hydrogen, hydroxyl, amino, NRaRa', halogen, carboxyl, formyl, amido, ester, C1-6haloalkyl, C1-6hydroxyalkyl, C1-6heteroalkyl, C1-6alkoxy, C3-10cycloalkyl, 3-10 membered heterocycloalkyl, substituted or unsubstituted phenyl or pyridinyl; selected from the group consisting of hydrogen, hydroxyl, amino, halogen, cyano, nitro, carboxyl, formyl, acylamino, NH-COR b , ester, C1-6alkyl, C1-6haloalkyl, C1-6hydroxyalkyl, C1-6heteroalkyl, C1-6alkoxy, C1-6alkoxyalkyl, C2-6alkenyl, C2-6alkynyl, unsubstituted or substituted -CO H-(C6-10aryl), unsubstituted or substituted -CH=CH-(C6-10aryl), unsubstituted or substituted C6-10aryl, unsubstituted or substituted 5-10 membered heteroaryl, unsubstituted or substituted C3-10cycloalkyl, unsubstituted or substituted 3-10 membered heterocycloalkyl, unsubstituted or substituted 3-7 membered heterocycloalkenyl, unsubstituted or substituted C6-10aryl C1-6alkyl, unsubstituted or substituted C1-6alkyl C6-10aryl, unsubstituted or substituted 5-10 membered heteroaryl C1-6alkyl, or unsubstituted or substituted C1-6alkyl 5-10 membered heteroaryl; wherein each R b independently is C1-6alkyl, C2-6alkenyl, NHR a , R a R a , unsubstituted or substituted phenyl or 3-7 membered heterocyclyl; each R and R a independently hydrogen or C1-6alkyl; unsubstituted or substituted means that the group is either unsubstituted or substituted by one or more substituents selected from the group consisting of hydroxyl, amino, cyano, nitro, carboxyl, halogen, C1-6alkyl, C1-6haloalkyl and C1-6hydroxyalkyl, or two adjacent substituents can be joined to form a C6-10aryl, 5-10 membered heteroaryl, C3-10cycloalkyl or 3-10 membered heterocycloalkyl; R4is selected from the group consisting of hydrogen, hydroxyl and C1-6alkyl.

9. The compound or pharmaceutically acceptable salt thereof of any one of claims 1-8, wherein, the group consisting of Among them, each Rc, R el R e2 Rc' and Re" are selected from hydrogen, hydroxyl, amino, NRaRa', halogen, cyano, nitro, carboxyl, formyl, amide, ester, C1-6 haloalkyl, C1-6 hydroxyalkyl, C1-6 heteroalkyl, C1-6 alkoxy, C1-6 alkoxyalkyl, C2-6 thallyl, C2-6 alkynyl, C6-10 aryl, 5-10 heteroaryl, C3-10 cycloalkyl, 3-10 heterocyclic alkyl, 3-7 heterocyclic alkenyl, C1-6 alkylC6-10 aryl, 5-10 heteroarylC1-6 alkyl or C1-6 alkyl5-10 heteroaryl; preferably selected from hydrogen, hydroxyl, amino, RaRa', halogen, carboxyl, formyl, amide, ester. C1-6 haloalkyl, C1-6 hydroxyalkyl, C1-6 heteroalkyl, C1-6 alkoxy, C3-10 cycloalkyl, 3-10 heterocyclic alkyl, substituted or unsubstituted phenyl or pyridyl; or R el and R e2 to form a C6-10 aryl, 5-10 membered heteroaryl, C3-10 cycloalkyl, or 3-10 membered heterocycloalkyl; each R a and R a independently is hydrogen or C1-6alkyl.

10. The compound or pharmaceutically acceptable salt thereof of any one of claims 1-8, wherein, R3is selected from the group consisting of: Xi is F, Cl, Br, I or trifluoromethyl; X2is H, F, CI, Br or I; Rci, Rc2, Rc3or R4are each independently selected from the group consisting of hydrogen, hydroxyl, amino, NRaRa', halogen, cyano, nitro, carboxyl, formyl, amido, ester, C1-6haloalkyl, C1-6hydroxyalkyl, C1-6heteroalkyl, C1-6alkoxy, C1-6alkoxyalkyl, C2-6alkenyl, C2-6alkynyl, C6-10aryl, 5-10 membered heteroaryl, C3-10cycloalkyl, 3-10 C1-6alkyl, C1-6hydroxyalkyl, C1-6heteroalkyl, C1-6alkoxy, C3-10cycloalkyl, 3-10 membered heterocycloalkyl, substituted or unsubstituted phenyl or pyridyl; or R1and R2, or R2and R1, or R3and R4may be joined to form a C6-10aryl, 5-10 membered heteroaryl, C3-10cycloalkyl, and 3-10 membered heterocycloalkyl; each R a independently hydrogen or C1-6alkyl.

11. The compound or pharmaceutically acceptable salt thereof of claim 1, 2, or 5, wherein, R4and R5in general formula (I) are hydrogen.

12. The compound or pharmaceutically acceptable salt thereof of claim 1, wherein, The compound of general formula (I) is selected from the group consisting of compounds of general formulae (Va), (Vb) and (Vc): wherein: W is selected from: O, NRa, and CHR a ; J is NR a , NORa, 0 or S; K is a covalent bond, NR a , CH' or is hydrogen, deuterium, C1-6alkyl, C1-6hydroxyalkyl, C1-6haloalkyl, unsubstituted or substituted phenyl; preferably selected from hydrogen and deuterium; preferably hydrogen, A ring is a divalent 3-10 membered nitrogen-containing heterocycloalkyl or a divalent 3-7 membered nitrogen-containing heterocycloalkenyl; B ring is unsubstituted or substituted C6-10aryl or 5-10 membered heteroaryl; preferably, B ring is unsubstituted or substituted C6-10aryl, more preferably B ring is unsubstituted or substituted phenyl; Rc, Rc. and R c each independently is selected from hydrogen, hydroxyl, amino, NRaRa', halogen, cyano, nitro, carboxyl, formyl, amido, ester, C1-6haloalkyl, C1-6hydroxyalkyl, C1-6heteroalkyl, C1-6alkoxy, C1-6alkoxyalkyl, C2-6alkenyl, C2-6alkynyl, C6-10aryl, 5-10 membered heteroaryl, C3-10cycloalkyl, 3-10 membered heterocycloalkyl, 3-7 membered heterocycloalkenyl, C1-6alkyl C6-10aryl, 5-10 membered heteroaryl C1-6alkyl or C1-6alkyl 5-10 membered heteroaryl; preferably from hydrogen, hydroxyl, amino, NRaRa', halogen, carboxyl, formyl, amido, ester, C1-6haloalkyl, C1-6hydroxyalkyl, C1-6heteroalkyl, C1-6alkoxy, C3-10cycloalkyl, 3-10 membered heterocycloalkyl, substituted or unsubstituted phenyl or pyridyl; Each R a It is independently selected from hydrogen and C1-6 alkyl.

13. The compound or pharmaceutically acceptable salt thereof according to claim 1, which is selected from the following compounds or salts : Z8and Z8OAV 8£ΐ Z8and Z8OAV 6£ΐ M7Z.80 / 8T0ZN3 / X3d Z8and Z8OAV C Z8and Z8OAV Z8and Z8OAV M7Z.80 / 8T0ZN3 / X3d Z8and Z8OAV 80 9P\ Z8and Z8OAV 80 Z8and Z8OAV 6PI Z8and Z8OAV Oil Z8and Z8OAV / 3 / :ϋ O 980sl£ ίϊ8ίAV Z8and Z8OAV 14. A pharmaceutical composition comprising a compound according to any one of claims 1-13, or a pharmaceutically acceptable salt thereof.

15. Use of a compound according to any one of claims 1-13, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for modulating autophagy.

16. The use according to claim 15, wherein, The medicament for modulating autophagy is a medicament for modulating a mammalian ATG8 homolog.

17. The use according to claim 15, wherein, The medicament for modulating autophagy is a medicament for preventing or treating a disease associated with autophagy, in particular with a mammalian ATG8 homolog.

18. The use according to claim 16 or 17, wherein, The mammalian ATG8 homolog is LC3B 19. The use according to claim 17, wherein, The disease associated with autophagy, in particular with mammalian ATG8 homologues, to be prevented or treated is selected from the group consisting of: tumours, cardiovascular diseases, autoimmune diseases, neurodegenerative diseases, hypertension, bone tissue cells and bone diseases, Crohn's disease, acute kidney injury, cerebral ischaemia, retinal diseases, bronchial asthma, Vici syndrome, and infectious diseases.

20. The use according to claim 19, wherein, The tumour is selected from the group consisting of liver cancer, lung cancer, pancreatic cancer, breast cancer, cervical cancer, endometrial cancer, large intestine cancer, stomach cancer, lung cancer, nasopharyngeal cancer, ovarian cancer, prostate cancer, leukaemia, lymphoma, myeloma.

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