Compounds as autophagy modulators, processes for their preparation and uses thereof

Abstract

The present application relates to compounds for use as autophagy modulators and methods and uses thereof, in particular, there is provided a compound of general formula (I) or a pharmaceutically acceptable salt thereof, which is a class of autophagy modulators, in particular, mammalian ATG8 homolog modulators.

Description

[0001] This application is a divisional application of application No. 201880033785.9, filed on May 18, 2018, entitled "Compounds for use as autophagy modulators and methods of making and using the same". TECHNICAL FIELD

[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. BACKGROUND

[0003] Cellular autophagy is a pathway of intracellular degradation, which is a process of transporting intracellular damaged or dysfunctional proteins and organelles to lysosomes for digestion and degradation. In biological evolution, cellular autophagy is a conservative process, which exists from yeast to plant cells to mammalian cells.

[0004] 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, etc., 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 deficiency increases genomic instability and promotes carcinogenesis; 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.

[0005] Currently, there are more than 30 clinical trials on autophagy modulators, such as the use of hydroxychloroquine, chloroquine alone or in combination with other anti-tumor drugs to evaluate the therapeutic effect of autophagy inhibition on refractory and recurrent solid tumors, and the related results can be queried on the clinicaltrial.gov website. However, due to the lack of clear molecular targets, the side effects of anti-lysosome inhibitors and the unclear direction of chemical space modification will seriously limit the further development of this type of autophagy inhibitors.

[0006] 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. SUMMARY

[0007] The present application provides a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof:

[0008]

[0009] wherein:

[0010] X and Y are each independently selected from O, S, NR a , NOH and CH2;

[0011] U and V are each independently selected from C, S, SO and POR a ;

[0012] W, Z and T are each independently selected from O, S, SO, SO2, N, NR a , CO, C, CR a , and CH2;

[0013] m is 0, 1, 2 or 3; preferably 0 or 1;

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

[0015] R1 is selected from hydrogen, deuterium, C1-6alkyl, C1-6hydroxyalkyl, C1-6haloalkyl, unsubstituted or substituted phenyl;

[0016] R2 is represented as -J-K-M-Q, wherein

[0017] J is NR a , NOR a , O, S or wherein

[0018] R is a divalent 3-10 membered heterocycloalkyl or a divalent 3-7 membered heterocycloalkenyl group containing at least one nitrogen atom;

[0019] K is a covalent bond, NR a , CR c R c’ or CR c R c’ CR c R c’ ;

[0020] M is a covalent bond, CR c R c’ , a divalent 3-10 membered heterocycloalkyl, a divalent 3-7 membered heterocycloalkenyl or a divalent 5-10 membered heteroaryl group;

[0021] 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 ,

[0022] p is 0, 1, 2 or 3; preferably 0 or 1;

[0023] each R c and Rc' 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, C1-6alkylC6-10aryl, 5-10 membered heteroarylC1-6alkyl or C1-6alkyl5-10 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;

[0024] R3, R4and R5are 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 -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;

[0025] 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;

[0026] wherein each R b is independently C1-6alkyl, C2-6alkenyl, NHR a , NR a R a is unsubstituted or substituted phenyl or 3-7 membered heterocyclyl;

[0027] each R a and R a is independently hydrogen or C1-6alkyl;

[0028] unsubstituted or substituted means that the group is either not substituted or substituted with one or more substituents selected from the group consisting of hydroxyl, amino, cyano, nitro, carboxyl, 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;

[0029] and the following conditions are met:

[0030] (1) when W, Z or T is substituted with one of R3, R4and R5, the W, Z or T is N or CH;

[0031] (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, then the W, Z or T is C; for example, when W is substituted with R3and R3is attached to adjacent R4to form an unsubstituted or substituted C6-10aryl or unsubstituted or substituted 5-10 membered heteroaryl, then W is C;

[0032] (3) when W, Z or T is substituted with two of R3, R4and R5, then the W, Z or T is C.

[0033] Preferably, in general formula (I):

[0034] X and Y are each independently selected from O, S or NH;

[0035] U and V are each independently selected from C or S;

[0036] W, Z and T are each independently selected from O, N, NR a , CO, C, CR a , and CH2;

[0037] m is 0, 1 or 2;

[0038] n is 0, 1 or 2;

[0039] R1is selected from hydrogen and deuterium;

[0040] R2is represented as -J-K-M-Q, wherein

[0041] J is NR a , NOR a , O, S or wherein

[0042] is a divalent 3-10 membered heterocycloalkyl or divalent 3-7 membered heterocycloalkenyl containing at least one nitrogen atom;

[0043] K is a covalent bond, NR a , CR c R c’ or CR c R c’ CR c R c’ ;

[0044] M is a covalent bond, CR c R c’ , divalent 3-10 membered heterocycloalkyl, divalent 3-7 membered heterocycloalkenyl or divalent 5-10 membered heteroaryl;

[0045] 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,

[0046] p is 0, 1, 2 or 3; preferably 0 or 1;

[0047] each R c and Rc' are independently selected from 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-6alkylC6-10aryl, 5-10 membered heteroarylCi-6alkyl or Ci-6alkyl5-10 membered heteroaryl; preferably from 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;

[0048] R3, R4 and R5 are each independently selected from hydrogen, hydroxyl, amino, halogen, cyano, nitro, carboxyl, formyl, amido, NH-COR b , ester, Ci-6alkyl, Ci-6haloalkyl, Ci-6hydroxyalkyl, Ci-6heteroalkyl, Ci-6alkoxy, Ci-6alkoxyalkyl, 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 C6-10arylCi-6alkyl, unsubstituted or substituted Ci-6alkylC6-10aryl, unsubstituted or substituted 5-10 membered heteroarylCi-6alkyl or unsubstituted or substituted Ci-6alkyl5-10 membered heteroaryl;

[0049] or two adjacent 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;

[0050] wherein each R b is independently C1-6alkyl, C2-6alkenyl, NHR a , NR a R a , unsubstituted or substituted phenyl or 3-7 membered heterocyclyl;

[0051] each R a and R a is independently hydrogen or C1-6alkyl;

[0052] 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;

[0053] and the following conditions are met:

[0054] (1) when W, Z or T is substituted with one of R3, R4and R5, the W, Z or T is N or CH;

[0055] (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, the W, Z or T is C;

[0056] (3) when W, Z or T is substituted with two of R3, R4and R5, the W, Z or T is C.

[0057] In another embodiment of the application, R2in general formula (I) is selected from the group consisting of:

[0058]

[0059] wherein A is a divalent 3-10 membered nitrogen containing heterocycloalkyl or a divalent 3-7 membered nitrogen containing heterocycloalkenyl;

[0060] R c , R c and R chydrogen, 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-6alkylC6-10aryl, 5-10 membered heteroarylCi-6alkyl, or Ci-6alkyl5-10 membered heteroaryl; preferably selected from 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;

[0061] each R a and R a are independently hydrogen or Ci-6alkyl.

[0062] In another specific embodiment of the application, R2in general formula (I) is selected from the group consisting of:

[0063] wherein R c , R c1 and R c2 are selected from 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-6alkylC6-10aryl, 5-10 membered heteroarylCi-6alkyl, or Ci-6alkyl5-10 membered heteroaryl; preferably selected from 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;

[0064] or R c1 and R c2 may be linked to form a C6-10aryl, 5-10 membered heteroaryl, C3-10cycloalkyl, and 3-10 membered heterocycloalkyl;

[0065] each R a and R a are independently hydrogen or Ci-6alkyl.

[0066] In another embodiment of the application, the compound of general formula (I) is selected from the group consisting of compounds of general formula (Ia) or (Ib)

[0067] wherein X and Y are each independently selected from O, S or NH;

[0068] W, Z and T are each independently selected from O, N, NR a , CO, C, CR a , or CH2;

[0069] m is 0, 1 or 2;

[0070] n is 0, 1 or 2;

[0071] R1is selected from hydrogen and deuterium;

[0072] J is NR a , NOR a , O, S or wherein is a divalent 3-10 membered heterocycloalkyl or a divalent 3-7 membered heterocycloalkenyl comprising at least one nitrogen atom;

[0073] R2' is 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,

[0074] 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;

[0075] 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 ,

[0076] p is 0, 1, 2 or 3; preferably 0 or 1;

[0077] R3, R4and R5are 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 -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 or unsubstituted or substituted C1-6alkyl 5-10 membered heteroaryl;

[0078] 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;

[0079] wherein each R b is independently C1-6alkyl, C2-6alkenyl, NHR a , NR a R a is unsubstituted or substituted phenyl or 3-7 membered heterocyclyl;

[0080] each R a and R a is independently hydrogen or C1-6alkyl;

[0081] unsubstituted or substituted means that the group is either 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 a C6-10aryl, 5-10 membered heteroaryl, C3-10cycloalkyl or 3-10 membered heterocycloalkyl;

[0082] and the following conditions are met:

[0083] (1) when W, Z or T is substituted with one of R3, R4and R5, the W, Z or T is N or CH;

[0084] (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, then W, Z or T is C;

[0085] (3) when W, Z or T is substituted with two of R3, R4and R5, then W, Z or T is C.

[0086] In another embodiment of the application, the compound of Formula (I) is selected from the group consisting of compounds of Formulae (IIa), (IIb), (IIc) and (IId) as follows:

[0087] wherein X and Y are independently O, S, NH;

[0088] W, Z and T are each independently selected from O, N, NR a , CO, C, CR a , or CH2;

[0089] n is 0, 1, 2 or 3;

[0090] R1is selected from the group consisting of hydrogen and deuterium;

[0091] is a divalent 3-10 membered nitrogen-containing heterocycloalkyl or a divalent 3-7 membered nitrogen-containing heterocycloalkenyl;

[0092] J is selected from NRa, NOR a , O and S;

[0093] K is a covalent bond, NR a , CR c R c’ or CR c R c’ CR c R c’ ;

[0094] 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 ,

[0095] p is 0, 1, 2 or 3; preferably 0 or 1;

[0096] R c , Rc' and R c are each independently selected from 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-6alkylC6-10aryl, 5-10 membered heteroarylCi-6alkyl or Ci-6alkyl5-10 membered heteroaryl; preferably from 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;

[0097] R3and R4are each independently selected from hydrogen, hydroxyl, amino, halogen, cyano, nitro, carboxyl, formyl, amido, NH-COR b , ester, Ci-6alkyl, Ci-6haloalkyl, Ci-6hydroxyalkyl, Ci-6heteroalkyl, Ci-6alkoxy, Ci-6alkoxyalkyl, 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 C6-10arylCi-6alkyl, unsubstituted or substituted Ci-6alkylC6-10aryl, unsubstituted or substituted 5-10 membered heteroarylCi-6alkyl or unsubstituted or substituted Ci-6alkyl5-10 membered heteroaryl;

[0098] 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;

[0099] wherein each R b is independently Ci-6alkyl, C2-6alkenyl, NHR a , NR a R aunsubstituted or substituted phenyl or 3-7 membered heterocyclyl;

[0100] each R a and R a independently is hydrogen or Ci-6alkyl;

[0101] 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, Ci-6alkyl, Ci-6haloalkyl and Ci-6hydroxyalkyl, or two adjacent substituents can be joined to form a C6-10aryl, 5-10 membered heteroaryl, C3-10cycloalkyl or 3-10 membered heterocycloalkyl;

[0102] and the following conditions are met:

[0103] (1) when W, Z or T is substituted with one of R3and R4, the W, Z or T is N or CH;

[0104] (2) when W, Z or T is substituted with one of R3and R4and R3and R4are joined to form a C6-10aryl or 5-10 membered heteroaryl, the W, Z or T is C;

[0105] (3) when W, Z or T is substituted with both R3and R4, the W, Z or T is C.

[0106] In another specific embodiment of the present application, the compound of general formula (I) is selected from the group consisting of compounds of general formulae (Ilia), (Illb), (IIIc) and (IIId) as follows:

[0107] wherein R1is 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;

[0108] J is selected from the group consisting of NRa, NORa, O or S;

[0109] K is a covalent bond, NR a , CR c R c’ or CR c R c’ CR c R c’ ;

[0110] is a divalent 3-10 membered nitrogen-containing heterocycloalkyl or a divalent 3-7 membered nitrogen-containing heterocycloalkenyl;

[0111] Q is hydrogen, Ci-6alkyl, Ci-6hydroxyalkyl, -(CH2) p -C(O)Rb , -(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 -SO2NHR b ,

[0112] p is 0, 1, 2 or 3; preferably 0 or 1;

[0113] each R c , R c' and R c” is independently selected from 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-6alkylC6-10aryl, 5-10 membered heteroarylCi-6alkyl or Ci-6alkyl5-10 membered heteroaryl; preferably from 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;

[0114] R3and R4are each independently selected from hydrogen, hydroxyl, amino, halogen, cyano, nitro, carboxyl, formyl, amido, NH-COR b , ester, Ci-6alkyl, Ci-6haloalkyl, Ci-6hydroxyalkyl, Ci-6heteroalkyl, Ci-6alkoxy, Ci-6alkoxyalkyl, 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 C6-10arylCi-6alkyl, unsubstituted or substituted Ci-6alkylC6-10aryl, unsubstituted or substituted 5-10 membered heteroarylCi-6alkyl or unsubstituted or substituted Ci-6alkyl5-10 membered heteroaryl;

[0115] or R3and R4are linked 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;

[0116] wherein each R b independently is C1-6alkyl, C2-6alkenyl, NHR a , NR a R a , unsubstituted or substituted phenyl or 3-7 membered heterocyclyl;

[0117] each R a and R a independently is hydrogen or C1-6alkyl;

[0118] 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 linked to form a C6-10aryl, 5-10 membered heteroaryl, C3-10cycloalkyl or 3-10 membered heterocycloalkyl.

[0119] In another embodiment of the present application, the compound of general formula (I) is selected from the group consisting of compounds of general formulae (IVa), (IVb), (IVc) and (IVd) as follows:

[0120] wherein R1is selected from the group consisting of hydrogen, deuterium, C1-6alkyl, C1-6hydroxyalkyl, C1-6haloalkyl, unsubstituted or substituted phenyl; preferably from the group consisting of hydrogen and deuterium; preferably is hydrogen;

[0121] J is NR a , NORa, O or S;

[0122] K is a covalent bond, NR a , CR c R c’ or CR c R c’ CR c R c’ ;

[0123] is a bivalent 3-10 membered nitrogen containing heterocycloalkyl or a bivalent 3-7 membered nitrogen containing heterocycloalkenyl;

[0124] 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 ,

[0125] p is 0, 1, 2 or 3; preferably 0 or 1;

[0126] R c , Rc' and R c” are each independently selected from 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 heterocyclenyl, Ci-6alkylC6-10aryl, 5-10 membered heteroarylCi-6alkyl or Ci-6alkyl5-10 membered heteroaryl; preferably from 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;

[0127] R3is selected from hydrogen, hydroxyl, amino, halogen, cyano, nitro, carboxyl, formyl, amido, NH-COR b , ester, Ci-6alkyl, Ci-6haloalkyl, Ci-6hydroxyalkyl, Ci-6heteroalkyl, Ci-6alkoxy, Ci-6alkoxyalkyl, 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 heterocyclenyl, unsubstituted or substituted C6-10arylCi-6alkyl, unsubstituted or substituted Ci-6alkylC6-10aryl, unsubstituted or substituted 5-10 membered heteroarylCi-6alkyl or unsubstituted or substituted Ci-6alkyl5-10 membered heteroaryl;

[0128] wherein each R b is independently Ci-6alkyl, C2-6alkenyl, NHRa , NR a R a , unsubstituted or substituted phenyl or 3-7 membered heterocyclyl;

[0129] each R a and R a is independently hydrogen or Ci-6alkyl;

[0130] 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, Ci-6alkyl, Ci-6haloalkyl and Ci-6hydroxyalkyl, or two adjacent substituents can be joined to form a C6-10aryl, 5-10 membered heteroaryl, C3-10cycloalkyl or 3-10 membered heterocycloalkyl group;

[0131] R4is selected from the group consisting of hydrogen, hydroxy and Ci-6alkyl.

[0132] In another specific embodiment of the application, R3in the general formula (I), (la), (lb), (IIa), (lib), (lie), (lid), (Ilia), (Illb), (IIIc), (Illd), (IVa), (IVb), (IVc), (IVd) is selected from the group consisting of:

[0133] wherein each R c , R c1 , R c2 , R c and R c is independently selected from the group consisting of hydrogen, hydroxy, amino, NRaRa', halogen, cyano, nitro, carboxy, 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-6alkylC6-10aryl, 5-10 membered heteroarylCi-6alkyl or Ci-6alkyl5-10 membered heteroaryl; preferably from the group consisting of hydrogen, hydroxy, amino, NRaRa', halogen, carboxy, formyl, amido, ester, Ci-6haloalkyl, Ci-6hydroxyalkyl, Ci-6heteroalkyl, Ci-6alkoxy, C3-10cycloalkyl, 3-10 membered heterocycloalkyl, substituted or unsubstituted phenyl or pyridyl;

[0134] each R a and R a is independently hydrogen or Ci-6alkyl.

[0135] or Rc1 and R c2 may be joined to form a C6-10 aryl, 5-10 membered heteroaryl, C3-10 cycloalkyl or 3-10 membered heterocycloalkyl.

[0136] In another embodiment of the application, R3in the general formula (I), (Ia), (Ib), (IIa), (IIb), (IIc), (IId), (IIIa), (IIIb), (IIIc), (IIId), (IVa), (IVb), (IVc), (IVd) is selected from the group consisting of:

[0137] wherein X1is F, Cl, Br, I or trifluoromethyl;

[0138] X2is H, F, Cl, Br or I;

[0139] c1 , R c2 , R c3 or R c4 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, C1-6alkylC6-10aryl, 5-10 membered heteroarylC1-6alkyl or C1-6alkyl5-10 membered heteroaryl; preferably 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;

[0140] or R c1 and R c2 , or R c2 and R c3 , or R c3 and R c4 may be joined to form a C6-10 aryl, 5-10 membered heteroaryl, C3-10 cycloalkyl and 3-10 membered heterocycloalkyl;

[0141] each R a and R a are independently hydrogen or C1-6alkyl.

[0142] In another embodiment of the application, R4and R5in the general formula (I) are hydrogen.​

[0143] In another embodiment of the application, the compound of general formula (I) is selected from the group consisting of compounds of general formula (Va), (Vb) and (Vc):

[0144]

[0145] wherein: W is selected from the group consisting of: O, NRaand CHR a ;

[0146] J is NR a , NORa, O or S;

[0147] K is a covalent bond, NR a , CR c R c’ or CR c R c’ CR c R c’ ;

[0148] R1is selected from the group consisting of hydrogen, deuterium, C1-6alkyl, C1-6hydroxyalkyl, C1-6haloalkyl, unsubstituted or substituted phenyl; preferably from the group consisting of hydrogen and deuterium; preferably hydrogen;

[0149] A ring is a divalent 3-10 membered nitrogen containing heterocycloalkyl or a divalent 3-7 membered nitrogen containing heterocycloalkenyl;

[0150] B ring is an unsubstituted or substituted C6-10aryl or 5-10 membered heteroaryl; preferably B ring is an unsubstituted or substituted C6-10aryl, more preferably B ring is an unsubstituted or substituted phenyl;

[0151] R c , R c' and R c” 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, C1-6alkylC6-10aryl, 5-10 membered heteroarylC1-6alkyl or C1-6alkyl5-10 membered heteroaryl; preferably 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;

[0152] each R ais independently selected from hydrogen and Ci-6alkyl.

[0153] 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:

[0154]

[0155]

[0156]

[0157]

[0158]

[0159]

[0160]

[0161]

[0162]

[0163]

[0164]

[0165]

[0166]

[0167]

[0168]

[0169]

[0170]

[0171]

[0172]

[0173]

[0174] In another specific embodiment of the application, the application provides a pharmaceutical composition comprising a compound according to the application or a pharmaceutically acceptable salt thereof. The pharmaceutical composition can further comprise a pharmaceutical adjuvant.

[0175] In another embodiment of the application, the application provides the use of a compound according to the application, or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for modulating autophagy.

[0176] In another embodiment of the application, the medicament for modulating autophagy is a medicament for modulating a mammalian ATG8 homolog.

[0177] In another embodiment of the application, the medicament for modulating autophagy is a medicament for preventing or treating a disease associated with autophagy, in particular with a mammalian ATG8 homolog.

[0178] In another embodiment of the application, the application provides a method for modulating autophagy, comprising administering to a subject in need thereof a compound according to the application, or a pharmaceutically acceptable salt thereof.

[0179] In another embodiment of the application, the method for modulating autophagy is a method for modulating a mammalian ATG8 homolog.

[0180] In another embodiment of the application, the method for modulating autophagy is a method for preventing or treating a disease associated with autophagy, in particular with a mammalian ATG8 homolog.

[0181] In another embodiment of the application, the mammalian ATG8 homolog is LC3B.

[0182] In another embodiment of the application, the disease associated with autophagy, in particular with 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.

[0183] In another embodiment of the application, the tumor is selected from the group consisting of a liver cancer, a lung cancer, a pancreatic cancer, a breast cancer, a cervical cancer, an endometrial cancer, a colon cancer, a stomach cancer, a lung cancer, a nasopharyngeal cancer, an ovarian cancer, a prostate cancer, a leukemia, a lymphoma, a myeloma.

[0184] In the use of the preparation of the medicament for regulating autophagy of cells and the method for regulating autophagy of cells according to the present application, some preferred compounds are selected from the compounds of general formula (Ib), the compounds of general formula (IId), the compounds of general formula (IIId), the compounds of general formula (IVd), and the compounds of general formula (Vc), wherein the descriptions of general formula (Ib), general formula (IId), general formula (IIId), general formula (IVd), and general formula (Vc) are the same as above; or some preferred compounds are selected from compound 2, compound 3, compound 241, compound 264, compound 449, compound 462, compound 463, and compound 464.

[0185] It is to be understood that both the foregoing general description and the following detailed description of the present application are exemplary and explanatory and are intended to provide further explanation of the application as claimed. DETAILED DESCRIPTION

[0186] The embodiments of the present application will be described in detail below.

[0187] The terms used in the present application have their general meanings in the art. 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 to the "C1-6alkyl" portion of "C1-6hydroxyalkyl", "C1-6haloalkyl", "C6-10arylC1-6alkyl", "C1-6alkylC6-10aryl", "C1-6alkoxy", and the like.

[0188] A "pharmaceutical composition" refers to a composition suitable for administration 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 suitable solid or liquid carriers or diluents and suitable sterile equipment for injection or infusion.

[0189] The various dosage forms of the pharmaceutical composition of the present application can be prepared according to the conventional methods in the field of pharmacy. The unit dose of the preparation formula contains 0.05-200 mg of the compound of general formula (I), preferably, the unit dose of the preparation formula contains 0.1 mg-100 mg of the compound of general formula (I).

[0190] The compounds and pharmaceutical compositions of the present application can be used clinically on mammals, including humans and animals, and can be administered by oral, nasal, dermal, pulmonary, or gastrointestinal routes of administration. Oral administration is most preferred. Optimal dosages are typically within the range of 0.01 to 200 mg / kg body weight, administered singly or in divided doses, of from 0.01 to 100 mg / kg body weight. Regardless of the route of administration, the optimal dosage will depend on the reactivity of the individual, the severity of the disease, and the therapeutic regimen being followed.

[0191] "Halo" (or halogen) means fluorine, chlorine, bromine, or iodine.

[0192] "C1-6alkyl" means straight or branched chain alkyl groups containing from 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms. Branched means that one or more lower alkyl 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.

[0193] "C1-6haloalkyl" means a C1-6alkyl group as defined above containing one or more halogen atom substituents.

[0194] "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=O)-, -(O=S=O)-, and the like.

[0195] "C2-6alkenyl" means straight or branched chain alkenyl groups containing from 2 to 6 carbon atoms, preferably 2 to 4 carbon atoms. Branched means that 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.

[0196] "C1-6alkylene" means a divalent radical resulting from the removal of 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. In general, it can be optionally and equivalently represented herein as -(C1-6alkyl)-, e.g., -CH2CH2- is ethylene.

[0197] "C2-6alkynyl" means straight or branched chain alkynyl groups containing from 2 to 6 carbon atoms, preferably 2 to 6 carbon atoms, more preferably 2 to 4 carbon atoms. Branched means that one or more alkyl groups containing from 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.

[0198] "C2-6alkenyl" refers to a bivalent radical derived from a C2-6alkene as defined above by the removal of one hydrogen atom. Preferred C2-6alkenyl groups include, but are not limited to, -CH=CH-, -C(CH3)=CH-, -CH=CHCH2-, and the like.

[0199] "C6-10aryl" refers to a monocyclic or polycyclic aromatic ring system containing 6 to 10 carbon atoms. Preferred C6-10aryl groups include, but are not limited to, phenyl and naphthyl.

[0200] "C6-10arylene" refers to a divalent radical derived from a C6-10aryl group as defined above by the removal of one hydrogen atom, for example is a reference to phenylene.

[0201] "5-10 membered heteroaryl" refers to a monocyclic or polycyclic aromatic radical containing 5 to 10 ring atoms, said 5-10 membered heteroaryl 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 atoms 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, thienopyrimidyl, pyrrolopyridyl, imidazopyridine, isoquinolinyl, benzoxazinyl, 1,2,4-triazinyl, benzothiazolyl, and the like. The term "5-10 membered heteroaryl" also refers to partially saturated 5-10 membered heteroaryl groups such as tetrahydroisoquinolinyl, tetrahydroquinolinyl, and the like.

[0202] "C3-10cycloalkyl" refers to a non-aromatic monocyclic or polycyclic radical 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, [1.1.1]- bicyclopentyl, 1-decalinyl, norbornyl, adamantyl, and the like.

[0203] "C3-10 cycloalkenyl" 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 3 to 7 ring atoms, more preferably 5 to 7 ring atoms. Preferably the C3-10 cycloalkenyl group includes, but is not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cyclopentenyl, cycloheptan-1,3-dienyl, norbornenyl and the like.

[0204] "3-10 membered heterocycloalkyl" (or "3-10 membered heterocyclyl") means a non-aromatic saturated monocyclic or polycyclic ring radical containing 3 to 10 ring atoms, preferably 5 to 10 ring atoms, preferably 5 to 6 ring atoms, wherein the 3-10 membered heterocyclyl group contains 1 to 4 heteroatoms selected from N, O and S, and no two of which 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 invention 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 by a single group =0 (i.e. forming a carbonyl group). Such =0 group can be referred to as "oxo" in the present invention. Preferred monocyclic 3-10 membered heterocycloalkyl groups include, but are not limited to, piperidinyl, oxetanyl, pyrrolinyl, piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, 1,4-dioxanyl, tetrahydrofuranyl, tetrahydrothiophenyl, lactam groups (such as pyrrolidinonyl), lactone groups of 3 to 10 ring atoms and oxides thereof.

[0205] "3-7 membered heterocycloalkenyl" means a non-aromatic monocyclic or polycyclic ring radical 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. The prefix aza, oxa or thia preceding the 3-7 membered heterocycloalkenyl radical denotes the presence of at least one nitrogen, oxygen or sulfur atom, respectively, as a ring atom. The nitrogen or sulfur atom of the 3-7 membered heterocycloalkenyl group can optionally be oxidized to the corresponding N-oxide, S-oxide or S,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, fluorodihydrofuranyl groups and oxides thereof. The "3-7 membered heterocycloalkenyl" can also be a group 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).

[0206] "C6-10arylC1-6alkyl" (or "C6-10arylC1-6alkyl") refers to groups resulting from the attachment of a C6-10aryl and a C1-6alkyl as defined above. Preferred C6-10arylC1-6alkyl groups include, but are not limited to, benzyl, 2-phenylethyl, and naphthylmethyl. The C6-10arylC1-6alkyl is attached to the parent moiety through the C1-6alkyl. Similarly, "5-10 membered heteroarylC1-6alkyl", "C2-6cycloalkylC1-6alkyl", "C2-6cycloalkenylC1-6alkyl", "3-10 membered heterocycloalkylC1-6alkyl", "3-7 membered heterocycloalkenylC1-6alkyl" 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, attached to the parent moiety through a C1-6alkyl.

[0207] "C1-6alkylC6-10aryl" refers to groups resulting from the attachment of a C1-6alkyl and a C6-10aryl as defined above. Preferred C1-6alkylC6-10aryl groups include, but are not limited to, tolyl. The C1-6alkylC6-10aryl is attached to the parent moiety through the C6-10aryl.

[0208] "5-10 membered heteroarylC1-6alkyl" refers to groups resulting from the attachment of a 5-10 membered heteroaryl and a C1-6alkyl as defined above. Preferred C6-10arylC1-6alkyl groups include, but are not limited to, pyridylmethyl and quinolin-3-ylmethyl. The 5-10 membered heteroarylC1-6alkyl is attached to the parent moiety through the C1-6alkyl.

[0209] "C1-6hydroxyalkyl" refers to a C1-6alkyl group, as described above, substituted with a hydroxyl group. Preferred C1-6hydroxyalkyl groups include, but are not limited to, hydroxymethyl and 2-hydroxyethyl.

[0210] "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, isopropyloxy, and n-butyloxy.

[0211] "C1-6alkoxyalkyl" refers to a radical derived by replacing one of the hydrogens of a C1-6alkyl group, as defined herein, with a C1-6alkoxy group, as defined herein, attached through C1-6alkyl to the parent moiety.

[0212] "Carbonyl" refers to a -C(O)- group. x is C1-6alkyl, C6-10aryl, C6-10arylC1-6alkyl, and C3-10cycloalkyl. Preferred ester groups include, but are not limited to, methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl, tert-butoxycarbonyl, phenoxycarbonyl.

[0213] "Amido" refers to -C(O)NR y R y’ wherein R y and R y’ are hydrogen, Ci-6alkyl, C6-10aryl, C6-10arylCi-6alkyl, or C3-10cycloalkyl.

[0214] Any of the foregoing functional groups of the present application can be unsubstituted or substituted with substituents 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 group, 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 result in a stable compound; by "stable compound" is meant a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.

[0215] The term "unsubstituted or substituted" means that the specified group is either unsubstituted or substituted with one or more substituents. Substituents include, but are not limited to, 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.

[0216] In the present application, if a group is "a covalent bond", it is meant that the group "is absent" and the two attached groups 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".

[0217] 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 convertible 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.

[0218] 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 partial structures of mixtures thereof (Examples 11, 112, and 415) are shown below.

[0219]

[0220] For convenience, only one tautomer of each compound is exemplified in the present application. It should be noted that the compounds of the present application include all tautomers.

[0221] Stereoisomers refer to compounds which have the same molecular formula but different spatial arrangements of atoms. Stereoisomerism includes cis-trans isomerism, conformational isomerism, enantiomeric and diastereomeric isomerism, etc. Cis-trans isomerism refers to the isomerism due to the inability of the two carbon atoms attached to a double bond to rotate freely about the sigma bond, generally referring to alkenes, but also C=N double bonds, N=N double bonds and cyclic compounds. Enantiomers refer to stereoisomers which are mirror images of one another; diastereomers refer to stereoisomers which are not mirror images of one another, i.e., having two or more chiral centers and existing as nonmirror-image related isomers. Unless otherwise specified, this specification intends to include both individual stereoisomers and mixtures thereof.

[0222] In particular, the compounds of the present application include all isomers thereof, such as diastereomers and cis / trans (Z / E) isomers.

[0223] Examples of cis-trans isomers of compound 101 disclosed in the present application are shown below.

[0224]

[0225] 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.

[0226] 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, etc. 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.

[0227] The term "pharmaceutically acceptable salt" refers to a substance which 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 the m edical community. Pharmaceutically acceptable salts include inorganic and organic salts that can be obtained during final isolation and purification of the compounds of the present application, or by reacting a free acid or base function with a suitable base or acid, respectively. Suitable salts include, but are not limited to, salts of inorganic acids such as hydrochloric acid, phosphoric acid, or sulfuric acid, or salts of organic acids such as citric acid, ascorbic acid, citric acid, tartaric acid, lactic acid, maleic acid, malonic acid, fumaric acid, glycolic acid, succinic acid, propionic acid, acetic acid, or methanesulfonic acid, and the like. Suitable 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, and the like, and organic bases such as aminoethanol, and the like.

[0228] 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.

[0229] The compounds of the present application can be prepared by a variety of methods known in the art, and the following reaction schemes are alternatives for preparing the compounds of the present application.

[0230] General Reaction Scheme

[0231]

[0232] The definitions of the groups or substituents in the above schemes are the same as those of the general formula (I). The compounds can be prepared by the 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.

[0233] Examples

[0234] The application will be further described in conjunction with specific examples. It should be understood that these examples are only used to illustrate the application and not used 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 these compounds can be prepared using known variations of the conditions and procedures of the following preparation methods. The starting reactants used in the application are commercially available unless specifically stated otherwise.

[0235] 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 / high (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-l-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU); hour(s) (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-l-yl-l, l,3,3-tetramethyluronium 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 (Pd(dppf)2Cl2).

[0236] General Synthetic Methods:

[0237] Unless otherwise indicated, all reactions were carried out under an inert atmosphere using commercially available reagents and anhydrous solvents without further purification.

[0238] Mass spectra were recorded using liquid chromatography-mass spectrometry (LC-MS) (Agilent 6120B single quadrupole liquid chromatography-mass spectrometry). Nuclear magnetic resonance spectra (such as hydrogen spectra (1H), carbon spectra (13C), phosphorus spectra (31P) and fluorine spectra (19F)) were recorded on a Bruker Avance III 400 MHz spectrometer. 1 H), a Bruker Avance III 100 MHz spectrometer or a Bruker Avance III 500 MHz spectrometer. 13 C), a Bruker Avance III 100 MHz spectrometer or a Bruker Avance III 500 MHz spectrometer. 31 P), a Bruker Avance III 100 MHz spectrometer or a Bruker Avance III 500 MHz spectrometer. 19F) etc.) were recorded on a Bruker AMX-400, Gemini-300 or AMX-600 NMR spectrometer, in deuterated chloroform, deuterated methanol, deuterated water or deuterated dimethylsulfoxide, etc. deuterated solvents, and referenced to the deuterated solvent peak. The chemical shifts (δ) are in ppm, the coupling constants (J or Hz) are in Hertz (Hz), and the coupling splitting patterns in the NMR spectra are indicated as: broad singlet (brs), singlet (s), doublet (d), doublet of doublets (dd), triplet (t), quartet (q), and multiplet (m).

[0239] Example 1: Synthesis of compound 2-(4-(2-aminoethyl)piperazin-1-yl)ethan-1-ol

[0240]

[0241] Step 1: Synthesis of compound 2-(2-(4-(2-hydroxyethyl)piperazin-1-yl)ethyl)isoindoline-1,3-dione

[0242] Compound 2-(2-bromoethyl)isoindoline-1,3-dione (20.0 g, 78 mmol), compound 2-(piperazin-1-yl)ethan-1-ol (10.2 g, 78 mmol) and potassium carbonate (22.0 g, 156 mmol) were dissolved in 100 mL of acetonitrile, and the mixture was refluxed for 3 hours. After the reaction was completed, it was cooled to room temperature, filtered, the residue was washed with acetonitrile (20 mL), the filtrate was collected and concentrated, and the target compound was separated and purified by column chromatography to obtain 13.45 g with a yield of 57%.

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

[0244] Compound 2-{2-[4-(2-hydroxy-ethyl)-piperazin-1-yl]-ethyl}-isoindoline-1,3-dione (13.45 g, 43.67 mmol) and hydrazine hydrate (80%, 6 mL) were dissolved in ethanol (130 mL) and refluxed for 4 hours. After the reaction was completed, it was cooled to room temperature, filtered, and the residue was washed with cold ethanol (20 mL x 2). The filtrate was collected and concentrated to obtain 6.5 g of a crude product, which was directly used in the next step without further purification.

[0245] Example 2: Synthesis of compound 5-(((2-(4-(2-hydroxyethyl)piperazin-1-yl)ethyl)amino)methylene)-2,2-dimethyl-1,3-dioxane-4,6-dione (Compound 1)

[0246]

[0247] Compound 5-(methoxymethylene)-2,2-dimethyl-1,3-dioxane-4,6-dione (186 mg, 1 mmol) was dissolved in 5 mL of ethanol, 2-(4-(2-aminoethyl)piperazin-1-yl)ethan-1-ol (259.5 mg, 1.5 mmol) was added, and the reaction was allowed to proceed at room temperature for 15 minutes. The crude product was concentrated and purified by column chromatography to obtain the target compound 220 mg, in a yield of 67.2%. 1 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, 1H), 1.66 (s, 1H); LCMS: 328.4 (M+1).

[0248] Example 3: Synthesis of compound 2-(aminomethylene)-5-phenylcyclohexane-1,3-dione (compound 2)

[0249]

[0250] Compound 2-dimethylaminomethylene-5-phenylcyclohexane-1,3-dione (1.1 g, 4.52 mmol) was dissolved in ammonia methanol solution (7 N, 50 mL), stirred at room temperature for 1 hour, and concentrated to obtain the crude product, which was separated by column chromatography to obtain the target compound 900 mg, in a yield of 93%. Compound 2: 1 H NMR (400 MHz, CD3OD) δ 10.12 (br, 1H), 8.24 (br, 1H), 8.02 (q, J = 8.8 Hz, 1H), 7.32-7.29 (m, 4H), 7.23-7.17 (m, 1H), 3.31-3.25 (m, 1H), 2.77-2.63 (m, 2H), 2.51-2.45 (m, 2H); MS: 216.1 [M+1].

[0251] Example 4: Synthesis of compound 2-(hydroxymethylene)-5-phenylcyclohexane-1,3-dione (compound 3)

[0252]

[0253] Compound 2-((dimethylamino)methylene)-5-phenylcyclohexane-1,3-dione (244 mg, 1 mmol) was dissolved in 5 mL of methanol, and concentrated hydrochloric acid (1 mL) 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 obtain the target compound 162 mg, in a yield of 75%. Compound 3: 1H NMR (400 MHz, DMSO-d6) δ 9.58 (s, 1H), 7.27-7.30 (m, 4H), 7.16-7.19 (m, 1H), 3.14-3.20 (m, 1H), 2.51 (d, J = 16.8 Hz, 1H), 2.47 (d, J = 9.2 Hz, 1H), 2.31 (dd, J = 16.0, 4.0 Hz, 2H); LCMS: 217.1 [M+1].

[0254] Synthesis of compound 5-(2-bromophenyl)-2-(hydroxymethylene)cyclohexane-1,3-dione (compound 4)

[0255]

[0256] Synthesis of compound 4 was same as compound 3. Compound 4: 1 H NMR (400 MHz, DMSO-d6) δ 9.34 (dd, J = 9.1, 1.9 Hz, 1H), 7.60 (d, J = 7.6 Hz, 1H), 7.49 - 7.29 (m, 2H), 7.16 (d, J = 7.0 Hz, 1H), 3.57 (m, 2H), 2.82 - 2.56 (m, 2H), 2.41 (d, J = 1.8 Hz, 1H); MS: 297.0 [M+1].

[0257] Example 5: Synthesis of compound 2-((methylthio)methylene)-5-phenylcyclohexane-1,3-dione (compound 4A)

[0258]

[0259] 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, 1 mL of acetic acid and sodium methanethiolate (115 mg, 1.64 mmol) was added at room temperature, the mixture was stirred in a sealed tube at room temperature for 16 hours. 1 mL of acetic acid and sodium methanethiolate (115 mg, 1.64 mmol) was added, and stirring was continued for 16 hours. After the reaction was completed, the reaction solution was poured into water, and dichloromethane (DCM) was extracted. The organic phase was washed with water and saturated brine successively, dried over anhydrous sodium sulfate, and concentrated to give a crude product, which was separated by column chromatography to give 15 mg of the target compound 4A, with a yield of 7%. Compound 4A: 1 H NMR (400 MHz, DMSO-d6) δ 9.34 (dd, J = 9.1, 1.9 Hz, 1H), 7.60 (d, J = 7.6 Hz, 1H), 7.49 - 7.29 (m, 2H), 7.16 (d, J = 7.0 Hz, 1H), 3.57 (m, 2H), 2.82 - 2.56 (m, 2H), 2.41 (d, J = 1.8 Hz, 1H); MS: 297.0 [M+1].

[0260] Example 6: Synthesis of compound 5-phenyl-2-((phenylamino)methylene)cyclohexane-1,3-dione (compound 5)

[0261]

[0262] Compound 2-((dimethylamino)methylene)-5-phenylcyclohexane-1,3-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 150 mg of the target compound 5 with a yield of 79%. 1 HNMR (400 MHz, DMSO-d6) δ 8.72 (s, 1H), 7.49-7.41 (m, 4H), 7.35-7.28 (m, 5H), 7.25-7.22 (m, 1H), 3.46-3.40 (m, 1H), 2.95-2.70 (m, 4H); MS: 292.1 [M+1].

[0263] Example 7: Synthesis of compounds 6 and 7

[0264] The synthesis method of compounds 6 and 7 is the same as that of compound 5, as shown in Table 1.

[0265] Table 1: Compounds 6 and 7

[0266]

[0267] Example 8: Synthesis of compound 2-(((2-(4-(2-hydroxyethyl)piperazin-1-yl)ethyl)amino)methylene)-5-phenylcyclohexane-1,3-dione (compound 8)

[0268]

[0269] Step 1: Synthesis of compound 2-((dimethylamino)methylene)-5-phenylcyclohexane-1,3-dione

[0270] Compound 5-phenylcyclohexane-1,3-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 precipitate was separated by homogenization of the concentrated product with 10% ethyl acetate (EA) / petroleum ether (PE). The filter residue was dried to obtain 4.81 g of the target compound with a yield of 74%.

[0271] Step 2: Synthesis of compound 2-(((2-(4-(2-hydroxyethyl)piperazin-1-yl)ethyl)amino)methylene)-5-phenylcyclohexane-1,3-dione (Compound 8)

[0272] Compound 2-(4-(2-aminoethyl)piperazin-1-yl)ethan-1-ol (200 mg, 1.15 mmol) was dissolved in 5 mL of ethanol, and compound 2-((dimethylamino)methylene)-5-phenylcyclohexane-1,3-dione (365 mg, 1.5 mmol) was added. The reaction was allowed to proceed at room temperature for 30 minutes to produce a solid, which was filtered, washed with ethanol, and the filter cake was collected and dried to yield 312 mg of the target compound 8 with a yield of 73%. 1 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+1].

[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]

[0277] Example 9-1: Synthesis of intermediate 3-1: (2S,2'R)-7-chloro-4,6-dimethoxy-2'- methyl-3H-spiro[benzofuran-2,1'-cyclohexane] 3,4',6'-trione

[0278]

[0279] 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 the reaction was completed, 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, which was separated by column chromatography to obtain 880 mg of the target compound at a yield of 91%.

[0280] Example 10: Synthesis of compound 2-(((2-(4-(2-hydroxyethyl)piperazin-1-yl)ethyl)amino)methylene)-5-(1H-

[0281] Synthesis of compound 2-(((2-(4-(2-hydroxyethyl)piperazin-1-yl)ethyl)amino)methylene)-5-(1H-

[0282]

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

[0284] 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, 60% sodium hydride (800 mg, 20 mmol) was added to the above mixture in batches at 0°C, and after stirring at this temperature for 30 minutes, phenylsulfonyl chloride (3.53 g, 20 mmol) was added, and the resulting mixture was reacted at room temperature for 1 hour. After the reaction was completed, 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 4.3 g of the target compound at a yield of 84%.

[0285] Step 2: Synthesis of compound 1-(phenylsulfonyl)-4-vinyl-1H-pyrrolo[2,3-b]pyridine

[0286] 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 successively. The mixture was heated to reflux for 2 hours. After the reaction was completed, it was cooled to room temperature and poured into ice water. The product was extracted with EA. The organic phase was washed with water and saturated brine successively, dried and concentrated to obtain a crude product. The target compound was separated by column chromatography to obtain 2.52 g in a yield of 70%.

[0287] Step 3: Synthesis of compound l-(phenylsulfonyl)-lH-pyrrolo[2,3-b]pyridine-4- carboxaldehyde

[0288] Compound l-(phenylsulfonyl)-4-ethC2-6enyl-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- morpholine oxide (1.56 g, 13.3 mmol) and potassium osmium dihydrate (100 mg) were added. After reaction at room temperature for 2 hours, sodium periodate (7.56 g, 35.44 mmol) was added to the reaction solution in portions, and then the reaction was continued at room temperature for 1 hour. After the reaction was completed, the product was poured into water and extracted with EA. The organic phase was washed with water and saturated brine successively, dried and concentrated to obtain a crude product. The target compound was separated by column chromatography to obtain 1.52 g in a yield of 60%.

[0289] Step 4: Synthesis of compound 4-(l-(phenylsulfonyl)-lH-pyrrolo[2,3-b]pyridin-4- yl)but-3-en-2-one

[0290] Compound l-(phenylsulfonyl)-lH-pyrrolo[2,3-b]pyridine-4-carboxaldehyde (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 the reaction was continued at reflux for 2 hours. After the reaction was completed, the product was cooled to room temperature and concentrated to obtain a crude product. The target compound was separated by column chromatography to obtain 1.52 g in a yield of 88%.

[0291] Step 5: Synthesis of compound 5-(lH-pyrrolo[2,3-b]pyridin-4-yl)cyclohexane-l,3- dione

[0292] Step 1: Synthesis of compound 4-(1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)but-3-en-2-one

[0293] 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

[0294] The operating procedure is the same as Example 2. Compound 17: 1 H NMR (400 MHz, CDCl3) 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+1].

[0295] Example 11: Compounds 18-32

[0296] The synthesis of compounds 18-32 is the same as compound 17 except using the corresponding bromo C6-10 aryl or aldehyde (as in Example 11-1 to 11-5), as shown in Table 3.

[0297] Table 3: Compounds 18-32

[0298]

[0299]

[0300]

[0301] Example 11-1: Synthesis of intermediate 11-1: 4-bromo-1-(2-methoxyethyl)-1H-pyrrolo[2,3-b]pyridine

[0302]

[0303] To a solution of 4-bromo-7-azaindole (3 g, 15.2 mmol) in 30 mL of dry N,N- dimethylformamide (DMF) was added sodium hydride (60%, 800 mg, 20 mmol) slowly at 0 °C and the reaction was allowed to proceed for 30 min at this temperature. 2- Bromoethyl methyl ether (2.78 g, 20 mmol) was added and the reaction was allowed to proceed for 4 h at room temperature. The reaction was completed by pouring into ice water and extracted with EA. The organic phase was washed with water and saturated brine, dried and concentrated. The crude product was purified by column chromatography to give the title compound 3.12 g in 80% yield.

[0304] Example 11-2: Synthesis of intermediate 11-2: 2-cyclopropyl-4,5-dimethoxybenzaldehyde

[0305]

[0306] To a solution of 4-bromo-7-azaindole (3 g, 15.2 mmol) in 30 mL of dry N,N- dimethylformamide (DMF) was added sodium hydride (60%, 800 mg, 20 mmol) slowly at 0 °C and the reaction was allowed to proceed for 30 min at this temperature. 2- Bromoethyl methyl ether (2.78 g, 20 mmol) was added and the reaction was allowed to proceed for 4 h at room temperature. The reaction was completed by pouring into ice water and extracted with EA. The organic phase was washed with water and saturated brine, dried and concentrated. The crude product was purified by column chromatography to give the title compound 3.12 g in 80% yield.

[0307] Example 11-3: Synthesis of intermediate 11-3: 4-(3-bromoimidazo[l,2- a]pyrazin-8-yl)morpholine

[0308]

[0309] Step 1: Synthesis of compound 8-chloroimidazo[l,2-a]pyrazine

[0310] To a solution of 4-bromo-7-azaindole (3 g, 15.2 mmol) in 30 mL of dry N,N- dimethylformamide (DMF) was added sodium hydride (60%, 800 mg, 20 mmol) slowly at 0 °C and the reaction was allowed to proceed for 30 min at this temperature. 2- Bromoethyl methyl ether (2.78 g, 20 mmol) was added and the reaction was allowed to proceed for 4 h at room temperature. The reaction was completed by pouring into ice water and extracted with EA. The organic phase was washed with water and saturated brine, dried and concentrated. The crude product was purified by column chromatography to give the title compound 3.12 g in 80% yield.

[0311] Step 2: Synthesis of compound 3-bromo-8-chloroimidazo[l,2- a]pyrazine

[0312] To a solution of 8-chloroimidazo[l,2-a]pyrazine (5.7 g) in DCM (100 mL) was added NBS (6.6 g, 37 mmol) in portions at room temperature and the reaction was stirred at room temperature for 2 h. The reaction was completed by pouring the reaction mixture into water and extracted with DCM. The organic layer was washed with water, brine, dried and concentrated to get the crude product 8.0 g which was used as such for the next step without further purification.

[0313] Step 3: Synthesis of compound 4-(3-bromoimidazo[l,2-a]pyrazin-8- yl)morpholine

[0314] 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 heated at 80 °C for 4 h. The reaction was completed by pouring the reaction mixture into water and extracted with DCM. The organic layer was washed with water, brine, dried and concentrated. The crude product was purified by column chromatography to get the desired compound 5.71 g in 52% yield.

[0315] 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

[0316]

[0317] 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

[0318] 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. The reaction was completed by pouring the reaction mixture into ice water and adjusting the pH to 8-9. The reaction mixture was extracted with DCM. The organic layer was washed with water, dried over sodium sulfate and concentrated to get the desired compound 3.31 g in 96% yield.

[0319] 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

[0320] Compound ((3aR,4R,6R,6aR)-6-(6-chloro-9H-purin-9-yl)-2,2-dimethyltetrahydrofuro[3,4- d][l,3]dioxol-4-yl)methanol (1.00 g, 3.06 mmol), morpholine (610 mg, 7.0 mmol) and DIPEA (900 mg, 7.0 mmol) were dissolved in acetonitrile (20 mL) and refluxed for 2 hours. After completion of the reaction, the reaction mixture was 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 separated and purified by column chromatography to obtain 912 mg of the target compound at a yield of 80%.

[0321] 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

[0322] ((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 agent (2.5 mmol) was slowly added at 0°C. The reaction solution was stirred at room temperature for 2 hours. After completion of the reaction, water was added for dilution, and the reaction mixture was extracted with DCM. The organic phase was washed with saturated brine, dried, and concentrated. The crude product was separated and purified by column chromatography to obtain 508 mg of the target compound at a yield of 73%.

[0323] Example 11-5: Synthesis of intermediate 11-5: 2-phenoxyacetaldehyde

[0324]

[0325] Step 1: Synthesis of compound (2,2-diethoxyethoxy)benzene

[0326] Phenol (0.94 g, 10 mmol), chloroacetaldehyde diethyl acetal (1.52 g, 10 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 completion of the reaction, the reaction mixture was cooled to room temperature, poured into ice water, and extracted with EA. 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%.

[0327] Step 2: Synthesis of compound 2-phenoxyacetaldehyde

[0328] Dissolve (2,2-diethoxyethoxy)benzene (0.84 g, 4 mmol) in a mixture solution of acetic acid (5 mL), 1 N hydrochloric acid solution (2.5 mL), and ethanol (EtOH) (20 mL), and heat to reflux for 3 hours. Cool the reaction to room temperature, pour into ice water, extract with EA, wash the organic phase with water, dry over anhydrous sodium sulfate, concentrate, and purify the crude product by column chromatography to obtain the target compound 468 mg at a yield of 86%.

[0329] Example 12: 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 (Compound 33)

[0330]

[0331] Step 1: Synthesis of compound 6-chloro-9-(tetrahydro-2H-pyran-2-yl)-9H-purine

[0332] Dissolve 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), and heat to reflux for 5 hours. Cool the reaction to room temperature, pour into ice water, extract with EA, wash the organic phase with water, dry over sodium sulfate, concentrate, and purify the crude product by column chromatography to obtain the target compound 5.72 g at a yield of 80%.

[0333] Step 2: Synthesis of compound 4-(9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)benzaldehyde

[0334] Dissolve 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 solution of dioxane (200 mL) and water (20 mL), and reflux the reaction overnight. Cool the reaction to room temperature, pour into ice water, extract with EA, wash the organic phase with water, dry over sodium sulfate, concentrate, and purify the crude product by column chromatography to obtain the target compound 5.51 g at a yield of 74%.

[0335] Steps 3, 4, and 5: Same as the procedures of Example 9

[0336] 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

[0337] Step 1 : Synthesis of compound 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 (Compound 34) 1 H NMR (400 MHz, DMSO-d6) δ 13.59 (s, 1 H), 11.20 - 10.79 (m, 1 H), 9.08 - 8.52 (m, 4 H), 8.13 (d, J = 14.6 Hz, 1 H), 7.53 (d, J = 8.0 Hz, 2 H), 4.55 - 4.21 (m, 1 H), 3.70 - 3.12 (m, 8 H), 2.95 - 2.66 (m, 2 H), 2.62 - 2.10 (m, 11 H); MS: 490.3 [M+1].

[0338] Example 12A: Synthesis of compound 2-(((2-(4-(2-hydroxyethyl)piperazin-1- yl)ethyl)amino)methylene)-5-(3-(2-(2-methoxyethoxy)ethoxy)phenyl)cyclohexane- 1,3-dione (Compound 34)

[0339]

[0340] Step 1 : Synthesis of compound 3-(2-(2-methoxyethoxy)ethoxy)benzaldehyde

[0341] Step 1 : Synthesis of compound 3-(2-(2-methoxyethoxy)ethoxy)benzaldehyde

[0342] Step 2: Synthesis of compound 4-(3-(2-(2-methoxyethoxy)ethoxy)phenyl)but-3- en-2-one

[0343] Dissolve 3-(2-(2-methoxyethoxy)ethoxy)benzaldehyde (7 g, 31.21 mmol) in acetone (20 mL) and water (10 mL), add 20 mL of 1% sodium hydroxide solution, heat the mixture to reflux for 2 hours, cool to room temperature, pour into ice water, extract with EA. The combined organic phase is washed successively with water and saturated brine, dried, and concentrated. The crude product is separated by column chromatography to obtain 6.16 g, yield 75%.

[0344] Step 3, 4 and 5: Synthesis of compound 2-(((2-(4-(2-hydroxyethyl)piperazinyl)ethyl)amino)methylene)-5-(3-(2-(2-methoxyethoxy)ethoxy)phenyl)cyclohexane-1,3-dione

[0345] Step 3, 4 and 5: The operation steps are the same as Example 9. Compound 34: 1 HNMR (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+1].

[0346] Example 13: Synthesis of compounds 35-59, 61-84

[0347] Except for using the corresponding benzaldehyde, aromatic aldehyde or substituted 1,3-cyclohexanedione (for example, Examples 13-1 to 13-11), the synthesis method of compounds 35-84 is the same as compound 34, as shown in Table 4.

[0348] Table 4: Compounds 35-59, 61-84

[0349]

[0350]

[0351]

[0352]

[0353]

[0354]

[0355]

[0356] Example 13-1: Synthesis of Intermediate 13-1: (6-(4-methylpiperazin-1-yl)pyridine)

[0357]

[0358] A solution of 6-chloro-3-pyridinecarboxaldehyde (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 completed and cooled to room temperature, poured into ice water, extracted with EA, the combined organic phase was washed with water and saturated brine successively, dried and concentrated. The crude product was separated by column chromatography to give the target compound 6.32 g in 87% yield.

[0359] Example 13-2: Synthesis of Intermediate 13-2: 1-adamantanecarboxaldehyde

[0360]

[0361] Step 1: Synthesis of methyl 1-adamantane carboxylate

[0362] Methyl 1-adamantane carboxylate (3 g, 15.5 mml) was dissolved in 80 ml of toluene under nitrogen protection, cooled to -78 °C, and diisobutylaluminum hydride (1.5 M solution in toluene, 10.3 mL) was added dropwise. After the dropwise addition was completed, the reaction was allowed to warm to room temperature and react for 1 h. The reaction was quenched by slowly adding 4 N 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.

[0363] Step 2: Synthesis of 1-adamantane carboxaldehyde

[0364] Methyl 1-adamantane carboxylate (3 g, 15.5 mml) was dissolved in 80 ml of toluene under nitrogen protection, cooled to -78 °C, and diisobutylaluminum hydride (1.5 M solution in toluene, 10.3 mL) was added dropwise. After the dropwise addition was completed, the reaction was allowed to warm to room temperature and react for 1 h. The reaction was quenched by slowly adding 4 N 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.

[0365] Example 13-3: Synthesis of Intermediate 13-3: 4-(morpholine-4-carbonyl)benzaldehyde

[0366]

[0367] Dissolve 4-formylbenzoic acid (5.0 g, 33.3 mmol) in anhydrous DMF (10 mL), and sequentially add 2-(7-azobenzotriazol)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU) (17.12 g, 45 mmol) and DIPEA (6.45 g, 50 mmol), and react at room temperature for 30 minutes. Add morpholine (3.92 g, 45 mmol), and continue to react the mixture at room temperature for 1 hour. After completion of the reaction, pour into ice water, extract with EA, wash the organic phase with water, dry over sodium sulfate, and concentrate. Isolate the crude product by column chromatography to obtain 5.0 g of the target compound at a yield of 68%.

[0368] Example 13-4: Synthesis of Intermediate 13-4: 3-(pyridin-4-yloxy)benzaldehyde

[0369]

[0370] Dissolve 4-bromopyridine (3.1 g, 40 mmol), 3-hydroxybenzaldehyde (40 mmol), and cesium carbonate (26.1 g, 80 mmol) in 80 mL of DMF, and react at 100°C overnight. After completion of the reaction, cool to room temperature, pour into ice water, extract with EA, wash the organic phase sequentially with water and brine, dry, and concentrate. Isolate the crude product by column chromatography to obtain 1.99 g of the target compound at a yield of 25%.

[0371] Example 13-5: Synthesis of Intermediate 13-5: 5-(pyridin-4-yl)thiophene-2-carbaldehyde

[0372]

[0373] Dissolve 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) in a mixed solvent of dioxane and water (v / v = 3:1; 80 mL) under nitrogen protection, and reflux-react overnight. After completion of the reaction, cool the reaction mixture to room temperature, pour into ice water, extract with EA, wash the combined organic phase with water, dry over sodium sulfate, and purify the crude product by column chromatography to obtain 3.2 g of the target compound at a yield of 85%.

[0374] Example 13-6: Synthesis of Intermediate 13-6: 4-(pyridin-4-yl)benzaldehyde

[0375]

[0376] A mixture of 4-bromobenzaldehyde (2.78 g, 15 mmol), 4-pyridineboronic acid (2.46 g, 20 mmol), sodium carbonate (3.18 g, 30 mmol) and tetrakis(triphenylphosphine)palladium (722 mg, 0.62 mmol) was dissolved in dioxane (40 mL) and water (10 mL) under nitrogen protection, and the mixture was refluxed overnight. After the reaction was completed, the mixture was cooled to room temperature and poured into ice water, extracted with EA, and the organic phase was washed with water, dried, and concentrated. The crude product was separated by column chromatography to obtain the target compound 2.23 g in a yield of 81%.

[0377] Example 13-7: Synthesis of intermediate 13-7: compound 4-(thiazol-2-yl)benzaldehyde

[0378]

[0379] A mixture of 2-bromothiazole (3.0 g, 18.3 mmol), 4-formylphenylboronic acid (3.3 g, 22 mmol), sodium carbonate (3.88 g, 36.6 mmol) and tetrakis(triphenylphosphine)palladium (1.0 g, 0.865 mmol) was dissolved in a mixture of toluene / ethanol / water (50 mL, v:v = 3:1:1) under nitrogen protection, and the mixture was refluxed overnight. After the reaction was completed, the mixture was cooled to room temperature, poured into water, extracted with EA, and the organic layer was dried with sodium sulfate, concentrated, and column chromatography to obtain the target compound 2.24 g in a yield of 65%.

[0380] Example 13-8: Synthesis of intermediate 13-8: 10-(2-methoxyethyl)-10H-phenothiazine-3- carboxaldehyde

[0381]

[0382] Step 1: Synthesis of compound 10-(2-methoxyethyl)-10H-phenothiazine

[0383] Sodium hydride (2.4 g, 2 eq) was added to a solution of phenothiazine (6 g, 1 eq) in DMF (60 mL) under nitrogen protection at 0°C, stirred for 30 minutes, and then 2-bromoethyl methyl ether (6.3 g, 1.5 eq) was added and stirred at room temperature for 2 hours. The reaction was quenched by adding water, extracted with DCM, and the organic layer was dried, concentrated, and the crude product was separated by column chromatography to obtain the target compound 9 g.

[0384] Step 2: Synthesis of compound 10-(2-methoxyethyl)-10H-phenothiazine-3-carboxaldehyde

[0385] Phosphorous oxychloride (10.2 mL, 5 eq) was added dropwise to dry DMF (8 g, 5 eq) at 0 °C under nitrogen atmosphere. 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 NaOH solution was added to adjust the pH to 7, and the aqueous phase was extracted with DCM. The combined organic phase was dried over anhydrous sodium sulfate and concentrated. The crude product was purified by column chromatography to give the title compound 5.3 g.

[0386] Example 13-9: Synthesis of intermediate 13-9: tert-butyl (4-formylbenzo[d]thiazol-2- yl)carbamate

[0387]

[0388] Step 1: Synthesis of tert-butyl (4-methylbenzo[d]thiazol-2-yl)carbamate

[0389] Tert-butyl (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 refluxed overnight. After the reaction was complete, the reaction mixture was poured into ice water and extracted with DCM. The combined organic phase was washed with water, dried over anhydrous sodium sulfate and concentrated to give the crude product 4.5 g, which was used in the next step without further purification.

[0390] Step 2: Synthesis of tert-butyl (4-(dibromomethyl)benzo[d]thiazol-2-yl)carbamate

[0391] Tert-butyl (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 refluxed overnight. After the reaction was complete, the reaction mixture was poured into ice water and extracted with DCM. The combined organic phase was washed with water, dried over anhydrous sodium sulfate and concentrated to give the crude product 4.5 g, which was used in the next step without further purification.

[0392] Step 3: Synthesis of tert-butyl (4-formylbenzo[d]thiazol-2-yl)carbamate

[0393] 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%.

[0394] Example 13-10: Synthesis of intermediate 13-10: 4-(4-(6-ethoxy-9H-purin-9-yl)phenyl)butan-3-en-2-one

[0395]

[0396] Step 1: Synthesis of compound (4-(6-chloro-9H-purin-9-yl)phenyl)methanol

[0397] 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%.

[0398] Step 2: Synthesis of compound 4-(6-chloro-9H-purin-9-yl)benzaldehyde

[0399] Dissolve (4-(6-chloro-9H-purin-9-yl)phenyl)methanol (900 mg, 3.5 mmol) and manganese dioxide (6.1 g, 70 mmol) in 80 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 reaction without purification.

[0400] Step 3: Synthesis of compound 4-(4-(6-ethoxy-9H-purin-9-yl)phenyl)butan-3-en-2-one

[0401] To a solution of 4-(6-chloro-9H-purin-9-yl)benzaldehyde (900 mg, 3.5 mmol) in 30 mL of acetone and 20 mL of ethanol was added saturated aqueous sodium bicarbonate solution (5 mL) and heated to reflux for 5 h. The reaction was completed, cooled to room temperature, poured into ice water and extracted with DCM. The combined organic phase was 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.

[0402] Example 13-11: Synthesis of intermediate 13-11: 4-(2-(pyridin-4-yloxy)ethoxy)benzaldehyde

[0403]

[0404] Step 1: Synthesis of compound 4-(2-bromoethoxy)benzaldehyde

[0405] 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 EtOH (85 mL) was heated to reflux overnight. The reaction was completed, the reaction mixture was poured into ice water and extracted with EA. The combined 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 1.8 g in 32% yield.

[0406] Step 2: Synthesis of compound 4-(2-(pyridin-4-yloxy)ethoxy)benzaldehyde

[0407] 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 heated to reflux overnight. The reaction was completed, cooled to room temperature, poured into ice water and extracted with EA. The combined organic phase was 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.

[0408] Example 14: Synthesis of compound 5-(2-aminobenzo[d]thiazol-4-yl)-2-(((2-(4-(2- hydroxyethyl)piperazin-1-yl)ethyl)amino)methylene)cyclohexane-1,3-dione (compound 85)

[0409]

[0410] Compound N'-(4-(4-(((2-(4-(2-hydroxyethyl)piperazin-l-yl)ethyl)amino)methylene)- 3,5-dicyclohexyl)benzo[d]thiazol-2-yl)-N,N-dimethylformamidine (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 completion of the reaction, it was cooled, poured into ice water, extracted with EA, the combined organic phase was dried over anhydrous sodium sulfate and concentrated. The crude product was separated by column chromatography to obtain 40 mg of the target compound with a yield of 45%. Compound 85: 1 H 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].

[0411] Example 15: Preparation of compound 7-(((2-(4-(2-hydroxyethyl)piperazin-l- yl)ethyl)amino)methylene)-spiro[3.5]nonane-6,8-dione (Compound 86)

[0412]

[0413] Step 1: Synthesis of compound ethyl 2-cyclobutylidenylacetate

[0414] Sodium hydride (60%, 1.60 g, 40 mmol) was added to a solution of ethyl 3- (diethoxyphosphoryl)-3-oxopropylate (8.96 g, 40 mmol) in anhydrous THF (50 mL) under nitrogen at 0 °C and after stirring for 30 min at this temperature, a solution of cyclobutanone (2.8 g, 40 mmol) in anhydrous THF (10 mL) was added. The mixture was stirred at this temperature for 2 h, then water (10 mL) was added slowly and the resulting mixture was stirred at room temperature for another 30 min. After completion of the reaction, the reaction mixture was poured into ice water, extracted with EA, the combined organic phase was washed with water, dried over sodium sulfate and concentrated. The crude product was purified by column chromatography to obtain 4.62 g of the target compound with a yield of 82.5%.

[0415] Step 2: Synthesis of compound spiro[3.5]nonane-6,8-dione

[0416] Nitrogen atmosphere, sodium hydride (60%, 960 mg, 24 mmol) was added to a solution of diethyl 3-oxopentanedioate (2.53 g, 12.5 mmol) in anhydrous THF (50 mL) at 0 °C and stirred at this temperature for 30 min, then added a solution of 2-cyclobutylethylene acetate ethyl ester (1.4 g, 10 mmol) in anhydrous THF (10 mL), reacted at room temperature for 2 h, then added a solution of sodium ethoxide (816 mg, 12 mmol) in anhydrous ethanol 5 mL. The above mixture was refluxed for 5 h, cooled to 50 °C, added 20% KOH solution (10 mL). The resulting mixture was stirred at this temperature overnight, cooled to room temperature, EA extraction, the water phase was adjusted to 1-2, and stirred at 70 °C for 2 h. Cooled to room temperature, DCM extraction. The combined organic phase was washed with water, dried with sulfate, concentrated. The crude product was separated and purified by column chromatography to obtain the target compound 483 mg, yield 32%.

[0417] Step 3: Synthesis of compound 7-(((2-(4-(2-hydroxyethyl)piperazin-1-yl)ethyl)amino)methylene)spiro[3.5]nonane-6,8-dione

[0418] The operating procedure was the same as 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+1].

[0419] Example 16: Compounds 87-94

[0420] The synthesis method of compounds 87-94 was the same as 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.

[0421] Table 5: Compounds 87-94

[0422]

[0423]

[0424] Example 16-1: Synthesis of intermediate 16-1: ethyl 3-(4-(morpholinosulfonyl)phenyl)- propenoate

[0425]

[0426] Step 1: Synthesis of compound 4-((4-bromophenyl)sulfonyl)morpholine

[0427] 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 (50 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 in the next step without further purification.

[0428] Step 2: Synthesis of compound ethyl 3-(4-(morpholinosulfonyl)phenyl)acrylate

[0429] Under nitrogen protection, add 4-((4-bromophenyl)sulfonyl)morpholine (2.0 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, extract with EA. Dry the combined organic phase with anhydrous sodium sulfate, concentrate, and separate the crude product by column chromatography to obtain 1.8 g, yield 85%.

[0430] Example 16-2: Intermediate 16-3: Synthesis of 6-(2-morpholinoethoxy)nicotinaldehyde

[0431]

[0432] Step 1: Synthesis of compound 6-(2-hydroxyethoxy)nicotinaldehyde

[0433] Add sodium tert-butoxide (3.49 g, 36.3 mmol) to 1,2-ethanediol (30 mL) at room temperature, stir for 30 minutes, then add 6-chloronicotinaldehyde (4.0 g, 28.3 mmol), stir the resulting mixture at room temperature overnight, then warm to 80 degrees and stir for another 2 hours. Cool the reaction mixture to room temperature, pour into ice water, extract with EA, wash the organic phase with water, dry and concentrate. Purify the crude product by column chromatography to obtain the target compound 4.01 g, yield 85%.

[0434] Step 2: Synthesis of compound 2-((5-formylpyridin-2-yl)oxy)ethyl methanesulfonate

[0435] To a solution of 6-(2-hydroxyethoxy)nicotinaldehyde (4 g, 24 mmol) and TEA (4 mL) in DCM (90 mL) was added dropwise a solution of methanesulfonyl chloride (3.66 g, 32 mmol) in DCM at 0 °C. After the addition was complete, the reaction was stirred at 0 °C for 30 min. The reaction was then quenched with water and extracted with EA. The combined organic phase was dried over anhydrous Na2SO4 and concentrated to give the crude product 5.21 g, which was used in the next step without further purification.

[0436] Step 3: Preparation of compound 6-(2-morpholinoethoxy)nicotinaldehyde

[0437] To a solution of 2-((5-formylpyridin-2-yl)oxy)ethyl methanesulfonate (5.21 g, crude) in 80 mL of acetonitrile was added morpholine (4.35 g, 50 mmol) and K2CO3 (6.91 g, 50 mmol). The reaction was refluxed overnight. After cooling, the reaction was poured into water and extracted with EA. The organic phase was dried over anhydrous Na2SO4 and concentrated. The crude product was purified by column chromatography to give the target compound 2.92 g in 51% yield.

[0438] Example 17: Synthesis of compound 3-(((2-(4-(2-hydroxyethyl)piperazin-1-yl)ethyl)amino)methylene)-6-phenyldihydro-2H-pyran-2,4(3H)-dione (Compound 95)

[0439]

[0440] Step 1: Preparation of compound 6-phenyldihydro-2H-pyran-2,4(3H)-dione

[0441] Ethyl acetoacetate (13.01 g, 0.1 mol), K2CO3 (27.64 g, 0.2 mol) and benzaldehyde (10.1 mL, 0.1 mol) were dissolved in ethanol (100 mL) and the reaction was stirred at 45 °C for 22 h. The reaction was filtered and the filtrate was collected and poured into water and washed with PE. The aqueous phase was collected and acidified with 6N HCl to pH 2-3 and extracted with EA. The organic phase was washed with water, dried over Na2SO4 and concentrated. The crude product was purified by column chromatography to give the target compound 8.87 g in 46.7% yield.

[0442] Step 2: Synthesis of compound 3-(((2-(4-(2-hydroxyethyl)piperazin-1-yl)ethyl)amino)methylene)-6-phenyldihydro-2H-pyran-2,4(3H)-dione

[0443] Synthesis steps were the same as in Example 2. Compound 95: 1HNMR (400 MHz, CD3OD) δ 8.31 (s, 0.33H), 8.18 (s, 0.67H), 7.46-7.32 (m, 5H), 5.53 (dd, J = 7.2 Hz, 2.4 Hz, 1H), 3.68 (t, J = 6.0 Hz, 2H), 3.61-3.58 (m, 2H), 2.98-2.86 (m, 1H), 2.72-2.54 (m, 14H); MS: 374.4 [M+1].

[0444] Example 17A: Synthesis of 3-(((2-(4-(2-hydroxyethyl)piperazin-1-yl)ethyl)amino)methylene)-6- phenylpiperidine-2,4-dione (Compound 96)

[0445]

[0446] Step 1: Synthesis of compound ethyl 3-((3-ethoxy-3-oxo-1-phenylpropyl)amino)-3- oxopropanoate

[0447] Ethyl 3-amino-3-phenylpropanoate (4.31 g, 22.23 mmol), monoethyl malonate (4.47 g, 33.84 mmol), DIPEA (7.7 g, 55.8 mmol) and 1H-benzotriazole-1- oxytripyrrolidinophosphonium hexafluorophosphate (PyBOP) (17.42 g, 33.84 mmol) were added into DMF (30 mL) and reacted at room temperature for 2 hours. The reaction was completed. Pour into water, EA extraction, the organic phase was dried with anhydrous sodium sulfate, concentrated, the crude product was separated by column chromatography to obtain the target compound 6.05 g, yield 88%.

[0448] Step 2: Synthesis of compound 6-phenylpiperidine-2,4-dione

[0449] A toluene solution (16 mL) of compound ethyl 3-((3-ethoxy-3-oxo-1-phenylpropyl)amino)-3- oxopropanoate (2.0 g, 6.51 mmol) was added dropwise to a solution of sodium ethoxide (0.66 g, 9.77 mmol) in anhydrous ethanol (16 mL) at 0 °C, and refluxed for 1 hour. The reaction was completed, the reaction mixture was poured into water, pH was adjusted to 1-2, EA extraction, the organic phase was washed with water and brine, dried, concentrated, the obtained crude product was dissolved in acetonitrile / water (v:v = 100:1, 16 mL) mixed solvent and refluxed overnight. The reaction was completed and cooled to room temperature, poured into ice water, EA extraction, the organic phase was washed with water, dried with sodium sulfate, concentrated, the obtained crude product was separated and purified by column chromatography to obtain the target compound 622 mg, yield 50%. Compound 96: 1HNMR (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, 1H), 3.72 (t, J = 5.6 Hz, 2H), 3.55-3.52 (m, 2H), 2.87-2.57 (m, 15H), MS: 373.3 [M+l].

[0450] Example 18: Synthesis of compound 4-(((2-(4-(2-hydroxyethyl)piperazin-1- yl)ethyl)amino)methylene)-1-phenylpiperidine-3,5-dione (Compound 97)

[0451]

[0452] Step 1: Synthesis of phenylglycine ethyl ester

[0453] 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 anhydrous ethanol (120 mL) and refluxed for 2 hours. After completion of the reaction, it was concentrated and the crude product was purified by column chromatography to obtain the target compound 7.4 g in 77% yield.

[0454] Step 2: Synthesis of compound N-(2-oxopropyl)-N-phenylglycine ethyl ester

[0455] 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 added to DMF (50 mL) and refluxed at 110 °C for 4 hours. Bromoacetone (1.06 g, 12.8 mmol) was added and refluxed at 110 °C for another 4 hours. After cooling to room temperature, it was 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 obtain the target compound 1.3 g in 43% yield.

[0456] Step 3: Synthesis of compound 1-phenylpiperidine-3,5-dione

[0457] A THF solution (2 mol / L, 3.8 mL) of potassium tert-butoxide was added dropwise to a solution of compound N-(2-oxopropyl)-N-phenylglycine ethyl ester (1.2 g, 5.1 mmol) in anhydrous THF (50 mL) at 0 °C. The reaction was stirred at room temperature for 3 hours. After completion of the reaction, it was quenched by adding 20% acetic acid and poured into ice water. The organic phase was extracted with EA and dried over anhydrous sodium sulfate. The crude product was purified by column chromatography to obtain the target compound 600 mg in 62% yield.

[0458] Steps 4 and 5: Operate the same as Example 2. Compound 97: 1 HNMR (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].

[0459] Example 19: Synthesis of compound 3-(((2-(4-(2-hydroxyethyl)piperazin-l- yl)ethyl)amino)methylene)-l-phenylpiperidine-2,4-dione (Compound 99)

[0460]

[0461] Step 1: Synthesis of compound ethyl 3-(phenylamino)propanoate

[0462] Dissolve aniline (2.8 g, 30 mmol), ethyl acrylate (3.6 g, 36 mmol) in 2 mL acetic acid, react at 95 °C overnight. Cool to room temperature after the reaction is complete, pour into ice water, adjust the pH to 9-10 with saturated sodium carbonate solution, extract with EA, wash the organic phase with water, dry, concentrate, and separate the target compound 5.3 g, yield 91% by column chromatography.

[0463] Step 2: Synthesis of compound ethyl 3-((3-ethoxy-3-oxopropyl)(phenyl)amino)-3- oxopropanoate

[0464] 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 complete, pour the reaction mixture into ice water, extract with EA, wash the organic phase with water, dry, concentrate, and separate the target compound 2.1 g, yield 25% by column chromatography.

[0465] Step 3: Synthesis of compound ethyl-2,4-dioxo-l-phenylpiperidine-3-carboxylate

[0466] Compound 3-((3-ethoxy-3-oxopropyl)(phenyl)amino)-3-oxopropanoic acid ethyl ester (2.00 g, 6.5 mmol) and sodium ethoxide (0.88 g, 13 mmol) were dissolved in 15 mL of anhydrous ethanol, and the reaction was allowed to proceed at room temperature for 2 hours. After the reaction was completed, the reaction mixture was poured into ice water, and the aqueous phase was adjusted to pH 3-4 with 2N hydrochloric acid. The organic phase was extracted with water, dried over sodium sulfate, and concentrated. The crude product was separated and purified by column chromatography to obtain 780 mg of the target compound at a yield of 46%.

[0467] Step 4: Synthesis of compound 1-phenylpiperidine-2,4-dione

[0468] An aqueous solution (7 mL) of ethyl 2,4-dioxo-1-phenylpiperidine-3-carboxylate (780 mg, 3.0 mmol) and acetic acid (0.7 mL) was reacted at 90°C for 18 hours. After the reaction was completed, the reaction mixture was poured into ice water, and the organic phase was extracted with water, dried, and concentrated. The crude product was separated and purified by column chromatography to obtain 510 mg of the target compound at a yield of 90%.

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

[0470] The procedure of this step was the same as in Example 2. Compound 99: 1 H 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+1].

[0471] Example 20: Synthesis of compound 4-(4-fluorophenyl)-2-(((2-(4-(2-hydroxyethyl)piperazin-1-yl)ethyl)amino)methylene)cyclohexane-1,3-dione (Compound 100)

[0472]

[0473] Step 1: Synthesis of compound 4-(4-fluorophenyl)cyclohexane-1,3-dione

[0474] 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 20 mL of anhydrous ethanol and refluxed overnight. After completion of the reaction, it was cooled to room temperature and poured into ice water and pH was adjusted to 3-4 with 2N hydrochloric acid and extracted with EA. The organic phase was washed with water, dried over sodium sulfate and concentrated. The crude product was purified by column chromatography to obtain 620 mg of the target compound with a yield of 23%.

[0475] Step 2: Synthesis of compound 4-(4-fluorophenyl)-2-(((2-(4-(2- hydroxy ethyl)piperazin- 1 -yl)ethyl)amino)methylene)cyclohexane- 1,3-dione

[0476] Procedure step was same as example 2. Compound 100: 1 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].

[0477] Example 21: Synthesis of compound 4-benzyl-2-(((2-(4-(2-hydroxyethyl)piperazin- 1 - yl)ethyl)amino)methylene)-6-phenylcyclohexane- 1,3-dione (Compound 101)

[0478]

[0479] Step 1: Synthesis of compound 5-benzyl-4-phenylcyclohexane- 1,3-dione

[0480] 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) under nitrogen protection. After stirring for 10 min, methyl cinnamate (2 g, 12.3 mmol) was added, and stirring was continued for 30 min. After completion of the reaction, the reaction solution was poured into water, and the pH was adjusted to 6-7 with 2N dilute hydrochloric acid. The organic phase was extracted with EA, dried, and concentrated to obtain 3.61 g of crude product, which was directly used in the next step.

[0481] Step 2: Synthesis of compound 4-benzyl-2-(((2-(4-(2-hydroxyethyl)piperazin- 1 - yl)ethyl)amino)methylene)-6-phenylcyclohexane- 1,3-dione

[0482] The procedure was same as example 2. Compound 101: 1 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, 1H); MS: 462.3 [M+l].

[0483] Example 22: Synthesis of compound 4-(((2-(4-(2-hydroxyethyl)piperazin-1- yl)ethyl)amino)methylene)-1-(4-methoxybenzyl)piperidine-3,5-dione (Compound 102)

[0484]

[0485] Step 1: Synthesis of compound ethyl (4-methoxybenzyl)glycine ethyl ester

[0486] 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 solution. 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.

[0487] Step 2: Synthesis of compound N-(4-methoxybenzyl)-N-(2-oxo-propyl) glycine ethyl ester

[0488] Ethyl (4-methoxybenzyl) glycine ethyl ester (3 g, 13.44 mmol), bromoacetone (7.36 g, 53.75 mmol) and sodium bicarbonate (2.26 g, 26.87 mmol) were added to 50 mL of anhydrous ethanol and heated to reflux for 4 hours. Upon cooling to room temperature, the reaction mixture was concentrated and the crude product was purified by column chromatography to give the target compound 700 mg in 19% yield.

[0489] Step 3: Synthesis of compound 1-(4-methoxybenzyl)piperidine-3,5-dione

[0490] A solution of potassium tert-butoxide in THF (1 mol / L, 4 mL) was added dropwise to a solution of N-(4-methoxybenzyl)-N-(2-oxopropyl)glycine ethyl ester (700 mg, 2.51 mmol) in anhydrous THF (30 mL) at 0 °C, and the reaction was allowed to proceed at room temperature for 3 hours. The reaction was poured into 10% acetic acid aqueous solution, extracted with EA, and the organic phase was dried over anhydrous sodium sulfate and concentrated. The crude product was separated by column chromatography to give the target compound 220 mg, in a yield of 38%.

[0491] Step 4: Synthesis of compound 4-(((2-(4-(2-hydroxyethyl)piperazin-1-yl)ethyl)amino)methylene)-1-(4-methoxybenzyl)piperidine-3,5-dione

[0492] The operating procedure was the same as in Example 2. Compound 102: 1 HNMR (400 MHz, CD3OD) δ 8.19 (s, 1H), 7.24 (d, J = 8.2 Hz, 2H), 6.89 (d, J = 8.3 Hz, 2H), 3.86-3.73 (m, 5H), 3.60 (s, 4H), 3.31 (s, 2H), 3.14 (d, J = 33.6 Hz, 8H), 2.72 (m, 6H); MS: 417.4 [M+1].

[0493] Example 23: Synthesis of compound 1-benzyl-4-(((2-(4-(2-hydroxyethyl)piperazin-1-yl)ethyl)amino)methylene)-piperidine-3,5-dione (compound 103)

[0494]

[0495] The synthesis method of compound 103 was the same as in Example 22 (compound 102) except that benzylamine was used. Compound 103: 1 HNMR (400 MHz, CD3OD) δ 8.22 (s, 1H), 7.40-7.26 (m, 5H), 3.72 (t, J = 5.9 Hz, 2H), 3.69 (s, 2H), 3.62 (t, J = 5.8 Hz, 2H), 3.34 (s, 2H), 3.23 (d, J = 6.6 Hz, 1H), 2.80-2.54 (m, 10H); MS: 387.4 [M+1].

[0496] Example 24: Synthesis of compound 1-benzoyl-4-(((2-(4-(2-hydroxyethyl)piperazin-1-yl)ethyl)amino)methylene)-piperidine-3,5-dione (compound 104)

[0497]

[0498] Step 1 : Synthesis of compound ethyl (2-oxopropyl) glycine ethyl ester hydrochloride

[0499] Ethyl N-benzyl-N-(2-oxopropyl) glycine ethyl ester (4.00 g, 16.04 mmol), 10% palladium on carbon (500 mg) and 5 mL of hydrochloric acid were dissolved in 100 mL of ethanol, hydrogen was replaced, and the reaction was carried out at room temperature for 4 hours. After the reaction was completed, the palladium on carbon was removed by filtration, the filter residue was washed with ethanol, and the filtrate was collected and concentrated to obtain 3.4 g of a crude product, which was directly used in the next step reaction.

[0500] Step 2: Synthesis of compound ethyl N-benzoyl-N-(2-oxopropyl) glycine ethyl ester

[0501] TEA (4 mL, 29 mmol) was added to a DCM solution (100 mL) of (2-oxopropyl) glycine hydrochloride (2.78 g, crude) at room temperature, followed by the addition of benzoyl chloride (1.65 mL, 14.23 mmol) to the above mixture, and the reaction was carried out at room temperature for 4 hours. After the reaction was completed, it was poured into water, extracted with DCM, 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 1.92 g of the target compound with a yield of 56%.

[0502] Step 3: Synthesis of compound 1-benzoyl-3,5-diketone

[0503] A THF solution (1 mol / L, 11 mL) of potassium tert-butoxide was added dropwise to a solution of ethyl N-benzoyl-N-(2-oxopropyl) glycine ethyl ester (1.9 g, 7.22 mmol) in anhydrous THF 60 mL at 0°C, and the reaction was carried out at room temperature for 3 hours. After the reaction was completed, the reaction liquid was poured into a 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%.

[0504] Step 4: Synthesis of compound 1-benzoyl-4-(((2-(4-(2-hydroxyethyl)piperazin-1-yl)ethyl)amino)methyl)piperidine-3,5-dione

[0505] The last step was operated as in Example 8. Compound 104: 1 H 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+1].

[0506] Example 26: Synthesis of compound 2-(((2-(4-(2-hydroxyethyl)piperazin-1- yl)ethyl)amino)methylene)-5-(morpholine-4-carbonyl)cyclohexane-1,3-dione (Compound 106)

[0507]

[0508] Step 1: Synthesis of compound 3-methoxy-5-oxocyclohex-3-ene-1-carboxylic acid

[0509] Compound 3,5-dioxocyclohexanecarboxylic 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. After the reaction was completed, it was cooled to room temperature, EA was added to the mixture, and a precipitate was separated out, which was filtered to obtain a crude product 420 mg, which was directly used in the next step without further purification.

[0510] Step 2: Synthesis of compound 3-methoxy-5-(morpholine-4-carbonyl)cyclohex-2-en-1- one

[0511] 3-methoxy-5-oxocyclohex-3-ene-1-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 anhydrous DMF, and stirred at room temperature overnight. After the reaction was completed, it was poured into water, extracted with EA, and the organic phase was dried with anhydrous sodium sulfate, concentrated, and the crude product was separated by column chromatography to obtain the target compound 140 mg in a yield of 15%.

[0512] Step 3: Synthesis of compound 5-(morpholine-4-carbonyl)cyclohexane-1,3-dione

[0513] 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) were added to acetonitrile (4 mL) and water (4 mL), and heated to reflux for 3 hours. After the reaction was completed, it was cooled to room temperature, the reaction solution was poured into water, extracted with EA, and the combined organic phase was dried with anhydrous sodium sulfate, concentrated, and the crude product was separated by column chromatography to obtain the target compound 112 mg in a yield of 90%.

[0514] Step 4: Synthesis of compound 2-(((2-(4-(2-hydroxyethyl)piperazin-1- yl)ethyl)amino)methylene)-5-(morpholine-4-carbonyl)cyclohexane-1,3-dione

[0515] The operation steps were the same as in Example 2. Compound 106: 1H NMR (400 MHz, CD3OD) 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, 2H), 2.75 - 2.42 (m, 10H).

[0516] Example 27: Synthesis of compound 3-(((2-(4-(2-hydroxyethyl)piperazin-1- yl)ethyl)amino)methylene)quinoline-2,4(1H,3H)-dione (Compound 107)

[0517]

[0518] Step 1: Synthesis of compound methyl 3-oxo-3-(phenylamino)propanoate

[0519] Methyl malonate chloride (1.84 g, 13.5 mmol) was added dropwise to a solution of aniline (1.00 g, 10.74 mmol) and TEA (1.42 g, 14 mmol) in ethyl acetate at 0 °C, and stirred at room temperature for 30 min after dropwise addition. After the reaction was completed, the reaction mixture was poured into 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 1.75 g in 85% yield.

[0520] Step 2: Synthesis of compound 3-oxo-3-(phenylamino)propanoic acid

[0521] 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 directly used in the next step.

[0522] Step 3: Synthesis of compound quinoline-2,4(1H,3H)-dione

[0523] 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. The reaction solution was then raised to 75 °C and stirred for 2 h. After cooling to room temperature, it was slowly poured into ice water, and the aqueous phase was adjusted to pH 7-8 with saturated aqueous sodium carbonate solution. The precipitated solid was filtered, collected, and dried to give the crude product 220 mg in 40% yield, which was directly used in the next step without purification.

[0524] Step 4: Synthesis of compound 3-(((2-(4-(2-hydroxyethyl)piperazin-1- yl)ethyl)amino)methylene)quinoline-2,4(1H,3H)-dione

[0525] Procedure step same as example 2. Compound 107: 1 H 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 = 8.7 Hz, 2H), 3.73 (m, 4H), 2.69 (m, 11H).

[0526] Example 28: Synthesis of compound 2-(1-((2-(4-(2-hydroxyethyl)piperazin-1- yl)ethyl)amino)ethylidene)-5-phenylcyclohexane-1,3-dione (Compound 108)

[0527]

[0528] Step 1: Synthesis of compound 2-acetyl-5-phenyl-1,3-cyclohexanedione

[0529] Acetyl chloride (4.2 g, 53.5 mmol) was added drop wise 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 h. The reaction was cooled to room temperature and poured into ice water and extracted with DCM. The organic layer was washed with water, dried over sodium sulfate and concentrated. The crude was purified by column chromatography to get the target compound 8.51 g in 70% yield.

[0530] Step 2: Synthesis of compound 2-(1-((2-(4-(2-hydroxyethyl)piperazin-1- yl)ethyl)amino)ethylidene)-5-phenylcyclohexane-1,3-dione

[0531] 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 h. It was cooled, concentrated and the crude was purified by preparative plate to get the target compound 80 mg in 44% yield. Compound 108: 1H NMR (400 MHz, DMSO-d6) δ 13.18 (s, 1H), 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).

[0532] The synthesis of compounds 109-112 was carried out as for compound 107, as shown in Table 6.

[0533] Table 6: Compounds 109-112

[0534]

[0535] Example 30: Synthesis of compound 2-(((2-(4-(2-hydroxyethyl)piperazin-1- yl)ethyl)amino)methylene)-4a,9,10,10a-tetrahydrophenanthrolin-1,3(2H,4H)-dione (compound 113)

[0536]

[0537] Step 1: Synthesis of compound ethyl 3-(2-bromophenyl)acrylate

[0538] To a solution of 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 dry THF (14 mL) was added at room temperature for 3.5 hours. The reaction mixture was poured into ice water and extracted with DCM. 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 2.59 g in 94% yield.

[0539] Step 2: Synthesis of compound ethyl 3-(2-(4-oxopentyl)phenyl)acrylate

[0540] Compound 3-(2-bromophenyl) ethyl 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) were dissolved in dry DMF (100 mL) and the reaction was carried out at 80 °C for 48 h under nitrogen atmosphere. After completion of the reaction, the reaction mixture was cooled to room temperature and poured into ice-cold water. The organic compound was extracted with methyl tert-butyl ether and the organic layer was washed with water, dried over sodium sulfate and concentrated. The crude product was purified by column chromatography to obtain the title compound 612 mg, yield 60%.

[0541] Step 3: Synthesis of compound 4a,9,10,10a-tetrahydrophenalene-1,3(2H,4H)-dione

[0542] Compound 3-(2-(4-oxopentyl)phenyl) ethyl acrylate (195 mg, 0.75 mmol) and sodium hydride (60%, 100 mg, 2.5 mmol) were dissolved in dry THF (12 mL) and the reaction was carried out at room temperature overnight. After completion of the reaction, the reaction mixture was cooled to 0 °C and poured into 1 N hydrochloric acid (20 mL) slowly. The organic compound was extracted with ethyl acetate and the organic layer was washed with water, dried over sodium sulfate and concentrated. The crude product was purified by column chromatography to obtain the title compound 74 mg, yield 46%.

[0543] Step 4: Synthesis of compound 2-(((2-(4-(2-hydroxyethyl)piperazin-1-yl)ethyl)amino)methylene)- 4a,9,10,10a-tetrahydrophenalene-1,3(2H,4H)-dione

[0544] Procedure step was same as example 2. Compound 113: 1 H 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).

[0545] 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-(2-hydroxyethyl)piperazin-1-yl)ethyl)amino)methylene)cyclohexane- 1,3-dione (Compound 114)

[0546]

[0547] Step 1 : Synthesis of compound 5-benzyl-3-ethoxycyclopent-2-en-l-one 1 H NMR (400 MHz, CD3OD) δ 8.24 (s, 1H), 8.19 (s, 1H), 8.15 (s, 1H), 5.94 (d, J = 4.9 Hz, 1H), 4.72 (t, J = 5.3 Hz, 1H), 4.38 (s, 1H), 4.26 (s, 4H), 3.88 (t, J = 5.7 Hz, 1H), 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).

[0548] Example 31 : Synthesis of compound 4-benzyl-2-(((2-(4-(2- hydroxyethyl)piperazin-l-yl)ethyl)amino)methyl)cyclopentane-l,3-dione (Compound 115)

[0549]

[0550] Step 1 : Synthesis of compound 5-benzyl-3-ethoxycyclopent-2-en-l-one

[0551] Under nitrogen protection, LDA (1 mol / L THF solution, 5 mL, 5 mmol) was added dropwise to a solution of 3-ethoxycyclopent-2-en-l-one (500 mg, 4 mmol) in anhydrous THF (15 mL) at -60 °C. After stirring at this temperature for 30 min, benzyl bromide (855 mg, 5 mmol) was added, and the reaction was continued for 3 h. 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 over sodium sulfate, concentrated, and the crude product was purified by column chromatography to give the target compound 540 mg in 63% yield.

[0552] Step 2: Synthesis of compound 4-benzylcyclopentane-l,3-dione

[0553] Step 1 : Synthesis of compound 5-benzyl-3-ethoxycyclopent-2-en-1-one

[0554] Step 3: Synthesis of compound 4-benzyl-2-(((2-(4-(2-hydroxyethyl)piperazin-1- yl)ethyl)amino)methylene)-cyclopentane-1,3-dione

[0555] Procedure same as example 2. Compound 115: 1 H NMR (400 MHz, CD3OD) δ 7.86 (s, 1 H), 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, 1 H), 2.94-2.88 (m, 1 H), 2.74-2.60 (m, 13H), 2.51-2.45 (m, 1 H), 2.24-2.18 (m, 1 H); MS: 372.2 [M+1].

[0556] Example 32: Synthesis of compound 2-(((2-(4-(2-hydroxyethyl)piperazin-1- yl)ethyl)amino)methylene)-4-methyl-5-phenylcyclohexane-1,3-dione (Compound 116)

[0557]

[0558] Step 1 : Synthesis of compound 4-methyl-5-phenyl-1,3-cyclohexanedione

[0559] Step 1 : Synthesis of compound 4-methyl-5-phenyl-1,3-cyclohexanedione

[0560] Step 2: Synthesis of compound 2-(((2-(4-(2-hydroxyethyl)piperazin-1- yl)ethyl)amino)methylene)-4-methyl-5-phenylcyclohexane-1,3-dione

[0561] Procedure same as example 2. Compound 116: 1H NMR (400 MHz, CD3OD) δ 8.35 - 8.13 (m, 1H), 7.44 - 7.08 (m, 5H), 3.67 (t, J = 6.0 Hz, 2H), 3.63 - 3.55 (m, 2H), 3.06 - 2.43 (m, 16H), 0.97 (dd, J = 12.6, 6.6 Hz, 3H); MS: 386.2 [M+l].

[0562] Example 33: Synthesis of compound l-(hydroxymethyl)-4-phenylpiperidine-2,6-dione (compound 117)

[0563]

[0564] Step 1: Synthesis of compound 4-phenylpiperidine-2,6-dione

[0565] A mixture of 3-phenylpentandioic acid (5.0 g, 24 mmol) and urea (25 g) was reacted at 160 °C for 3 h. After the reaction was completed, the reaction mixture was slowly poured into ice water, extracted with EA, the organic phase was washed with water, dried over sodium sulfate, concentrated, and the crude product was separated by column chromatography to give the target compound 3.6 g in a yield of 79%.

[0566] Step 2: Synthesis of compound l-(hydroxymethyl)-4-phenylpiperidine-2,6-dione

[0567] 4-phenylpiperidine-2,6-dione (800 mg, 4.22 mmol) and 35% formaldehyde solution (10 mL) were 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, 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: 1 H NMR (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+l].

[0568] 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

[0569] In addition to using the corresponding substituted 1,3-cyclohexanediones or other active methylene-containing analogs (e.g., Example 9-1), the following compounds were synthesized as described above (e.g., Compound 8) as shown in Table 7.

[0570] Table 7

[0571]

[0572]

[0573]

[0574]

[0575]

[0576]

[0577]

[0578]

[0579]

[0580]

[0581]

[0582]

[0583]

[0584]

[0585]

[0586]

[0587]

[0588]

[0589]

[0590]

[0591]

[0592]

[0593]

[0594]

[0595]

[0596]

[0597]

[0598]

[0599]

[0600]

[0601]

[0602]

[0603]

[0604]

[0605]

[0606]

[0607]

[0608] Synthesis of compounds 415-452

[0609] The synthesis of compounds 415-452 was identical to that of Example 4 or 8 (e.g., compounds 3 and 8) except that the corresponding substituted 1,3-cyclohexanedione was used, as shown in Table 8.

[0610] Table 8: Compounds 415-452

[0611]

[0612]

[0613]

[0614]

[0615]

[0616]

[0617]

[0618] Example 36 Synthesis of compound 5-(((2-(4-(2-hydroxyethyl)piperazin-1- yl)ethyl)amino)methyl)thiazolidine-2,4-dione (Compound 200)

[0619]

[0620] Step 1: Synthesis of 5-(ethoxymethyl)-2,4-thiazolidinedione

[0621] 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 and the filtrate was concentrated to give the crude product which was used directly for the next step without further purification.

[0622] Step 2: Synthesis of compound 5-(((2-(4-(2-hydroxyethyl)piperazin-1- yl)ethyl)amino)methyl)thiazolidine-2,4-dione

[0623] Example 37 Synthesis of compound 4-((dimethylamino)methyl)-2-methyl-2- phenylcyclobutane-1,3-dione (Compound 201)

[0624]

[0625] Step 1: Synthesis of 2-phenylpropanoyl chloride

[0626] Under nitrogen protection, at 0 °C, a solution of thionyl chloride (4.8 g, 40.3 mmol) was added dropwise to a solution of 2-phenylpropanoic acid (2 g, 13.3 mmol) in DCM (20 mL). After the addition was completed, a catalytic amount of DMF was added and the mixture was refluxed for 2 h and concentrated to give the crude 2-phenylpropanoyl chloride which was used directly for the next step.

[0627] Step 2: Synthesis of compound 3-ethoxy-4-methyl-4-phenylcyclobut-2-en-1-one

[0628] Under nitrogen protection, ethoxyacetylene (3.72 g, 26.6 mmol, 50% w / w in hexane) was added dropwise to a solution of 2-phenylpropanoyl chloride (13.3 mmol) in ether (40 mL). To the above mixture, TEA (2 g, 19.8 mmol) was added dropwise. After stirring at room temperature for 30 min, the suspension was heated to reflux for 24 h. Upon completion of the reaction, the mixture was cooled, filtered and the filtrate was concentrated. The crude product was purified by column chromatography to give the target compound 600 mg.

[0629] Step 3: Synthesis of compound 2-methyl-2-phenylcyclobutane-1,3-dione

[0630] Compound 3-ethoxy-4-methyl-4-phenylcyclobut-2-en-l-one (350 mg, 1.73 mmol) was dissolved in a mixture of 2M hydrochloric acid (5 mL) and THF (3 mL), stirred vigorously at room temperature for 48 hours, the reaction was completed, extracted with DCM, the combined organic layers were dried and concentrated to give 250 mg of crude which was used directly in the next step.

[0631] Step 4: Synthesis of compound 4-((dimethylamino)methylene)-2-methyl-2- phenylcyclobutane-l,3-dione (Compound 201)

[0632] The procedure was same as Example 8 (Compound 8). Compound 201: 1 HNMR (400 MHz, CDC13) δ 7.56-7.48 (m, 2H), 7.31 (m, 2H), 7.21 (m, IH), 7.04 (s, IH), 3.64 (s, 3H), 3.27 (s, 3H), 1.59 (s, 3H).

[0633] Example 38: Synthesis of compound 2-(((2-(dimethylamino)ethyl)amino)methylene)- 5-phenylcyclohexane-l,3-dione) nickel (II) chloride complex

[0634]

[0635] Compound 119 (2.86 g, 10 mmol) in methanol (7.5 mL) was added dropwise to a solution of sodium (264 mg, 11 mmol) in methanol (20 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 was followed by dilution of the concentrated crude with acetone and refluxing for 1 hour. The mixture was cooled, the solid was filtered off, washed with acetone and dried to give the target compound 1.1 g in 29% yield. MS (ESI): [M-Cl] + : 343.3; [M+Cl] - : 413.2.

[0636] Example 39: Synthesis of compound 2-(hydroxymethylene)-5-phenylcyclohexane-l,3- dione sodium salt (Compound 463)

[0637]

[0638] Compound 3 (294 mg) was added to water (8 ml), NaOH solid (57 mg) was added, stirred at room temperature overnight, the reaction solution was concentrated, and then washed with ether, filtered to obtain the product (compound 463) as a yellow solid (267 mg, yield 83%).

[0639] In compound 463, Na forms a coordination bond with the carbonyl oxygen.

[0640] Example 40: Synthesis of compounds 453-462 and 464

[0641] The synthesis of compounds 453-462 and 464 was carried out as in Example 39, except that the corresponding diketone compound and base were used, as shown in Table 9.

[0642] Table 9: Compounds 453-464

[0643]

[0644]

[0645] In the above compounds, Li, Na or K forms a coordination bond with the carbonyl oxygen.

[0646] Example 41: Testing of the compounds of the application for the modulation of autophagy-related protein LC3B using the fluorescence polarization (FP) method.

[0647] Fluorescence polarization (FP) method test experiment

[0648] Histone GST-LC3B (final concentration 180 nM) (SEQ ID NO: 1) and N-terminal FITC-labeled 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 mixture was incubated at 25°C in the dark. The fluorescence polarization value was monitored (PerkinElmer Envision, emission wavelength 480 nm; absorption wavelength 535 nm), and the IC 50 values were calculated using the GraphPad Prism 6.0 program, and the test results are shown in Table 8.

[0649] IC 50 values of the compounds indicate the method: 100 μM < IC 50 ≤ 1 mM is considered to be low activity (+) for LC3B; 15 μM < IC 50 ≤ 100 μM is considered to be moderate activity (++) for LC3B; 3 μM < IC 50≤ 15 μΜ was considered to be high activity (+++) for LC3B activity; IC 50 ≤ 3 μΜ was considered to have high activity (++++) for LC3B. The IC 50 values of the compounds of the present application are shown in Table 10.

[0650] Table 10: Compound IC 50

[0651]

[0652]

[0653]

[0654] The compounds of the present application exhibit activity for LC3B, and some compounds have high activity for LC3B. These compounds are also active for 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.

[0655] 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

1. A compound represented by the following formula or a pharmaceutically acceptable salt thereof:

2. A pharmaceutical composition comprising the compound of claim 1 or a pharmaceutically acceptable salt thereof.

3. Use of the compound of claim 1 or a pharmaceutically acceptable salt thereof or the pharmaceutical composition of claim 2 in the manufacture of a medicament for modulating autophagy.

4. Use according to claim 3, wherein, The medicament for modulating autophagy is a medicament for modulating a mammalian ATG8 homolog.

5. Use according to claim 4, wherein, The medicament for modulating autophagy is a medicament for preventing or treating a disease associated with autophagy.

6. Use according to claim 4 or 5, wherein, The mammalian ATG8 homolog is LC3B.

7. The use according to claim 5, wherein, The disease associated with autophagy is selected from the group consisting of a tumor, a cardiovascular disease, an autoimmune disease, a neurodegenerative disease, hypertension, a bone tissue cell and a bone disease, Crohn's disease, acute kidney injury, cerebral ischemia, a retinal disease, bronchial asthma, Vici syndrome, and an infectious disease.

8. Use according to claim 7, wherein, The tumor is selected from the group consisting of liver cancer, lung cancer, pancreatic cancer, breast cancer, cervical cancer, endometrial cancer, large intestine cancer, stomach cancer, nasopharyngeal cancer, ovarian cancer, prostate cancer, leukemia, lymphoma, myeloma.

Images