A class of isoindolone-imide ring-1,3-dione-2-ene compounds, composition and use thereof

Abstract

The present invention provides a class of isoindolone-imide ring-1,3-dione-2-ene compounds, a preparation method, pharmaceutical composition and use thereof. Specifically, the present invention provides a class of compounds of the following formula (I) or a pharmaceutically acceptable salt thereof, wherein Ar is an isoindolinone-imide group represented by the formula (II); L is absent or is a divalent, trivalent or tetravalent linking group; and X is a group represented by the formula (III). Definitions of the other groups are as described in the specification. The compounds of formula (I) are a class of autophagy modulators, particularly mammalian ATG8 homolog modulators.

Description

Isoindolinone-imide ring-1,3-diketone-2-ene compounds, compositions and uses thereof TECHNICAL FIELD

[0001] The present application relates to the field of biological medicine, in particular to a kind of autophagy regulator, especially mammalian ATG8 homolog regulator, its preparation method, pharmaceutical composition and purpose. BACKGROUND

[0002] Cellular autophagy is a kind of intracellular degradation pathway, which is a process of transporting damaged or lost functional proteins and organelles in cells to lysosomes and carrying out digestion and degradation. In biological evolution, cellular autophagy is a conservative process, which exists from yeast to plant cells to mammals.

[0003] 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.

[0004] Diseases related to cellular autophagy include cellular autophagy-related diseases such as liver cancer, lung cancer, pancreatic cancer, breast cancer, cervical cancer, endometrial cancer, colon cancer, gastric cancer, lung cancer, nasopharyngeal cancer, ovarian cancer, prostate cancer, leukemia, lymphoma, myeloma, etc., and other related diseases including cardiovascular diseases, autoimmune diseases, neurodegenerative diseases, hypertension, bone tissue cells and bone diseases, Crohn's disease, acute kidney injury, cerebral ischemia, retinal disease, bronchial asthma, Vici syndrome, amyotrophic lateral sclerosis and various infectious diseases.

[0005] At present, there are more than 30 clinical trials to evaluate the therapeutic effect of autophagy inhibition on refractory and recurrent solid tumors by using hydroxychloroquine, chloroquine alone or in combination with other anti-tumor drugs. The relevant results can be queried on the official website of clinicaltrial.gov. However, due to the lack of clear molecular targets, the side effects of lysosome inhibitors and the unclear direction of chemical space modification will seriously limit the further development of this kind of autophagy inhibitors. It is urgent to develop new regulators that directly act on important proteins in the cellular autophagy pathway for the treatment of related diseases. The development prospect of the regulator of mammalian ATG8 homolog protein represented by targeting LC3B is promising.

[0006] Lenalidomide, as an immunomodulator, has been approved for multiple myeloma, myelodysplastic syndrome and mantle cell lymphoma, and indications in clinical research stage also include non-Hodgkin's lymphoma, large B-cell lymphoma, follicular lymphoma, T-cell lymphoma, mucosa-associated lymphoid tissue lymphoma, plasma cell myeloma, chronic lymphocytic leukemia (CLL), acute myeloid leukemia (AML), non-small cell lung cancer, liver cancer, kidney cancer, ovarian cancer, squamous cell carcinoma, malignant glioma, thyroid tumor, POEMS syndrome, neurofibromatosis type 1, prostate cancer, bladder cancer, systemic lupus erythematosus, anemia, HIV-1 infection, autism, primary amyloidosis, Crohn's disease and pain syndrome type 1, etc.

[0007] Since the indications targeted by the autophagy modulator and the indications targeted by lenalidomide are both very extensive and overlap each other more, the possible application range of the small molecule inhibitor with the activity of lenalidomide and its analogues and the activity of autophagy-related proteins such as mammalian ATG8 homolog family proteins is wide, and the prospect is promising.

[0008] SUMMARY

[0009] The present application provides a class of autophagy modulators, in particular, mammalian ATG8 homolog modulators, preparation methods, pharmaceutical compositions and uses thereof.

[0010] In one aspect, the present application provides a compound of the following general formula (I) or a pharmaceutically acceptable salt thereof,

[0011] Ar-L(-X)p (I)

[0012] wherein p is 1, 2 or 3;

[0013] Ar is an isoindolinone-imide group represented by the general formula (II),

[0014]

[0015] wherein one of A and B is C=O and the other is C=O or CH2;

[0016] R1 is selected from the group consisting of hydrogen, deuterium, halogen, and C1-C4 alkyl;

[0017] one of R6, R7, R8 and R9 is a divalent group selected from the group consisting of O, S, SO2, and NH, connected to L or directly to X, and the remaining three of R6, R7, R8 and R9 are each independently selected from the group consisting of hydrogen, deuterium, halogen, C1-C4 alkyl, unsubstituted or substituted phenyl, and unsubstituted or substituted 5-10 membered heteroaryl; and R 10 is hydrogen;

[0018] or R6, R7, R8and R9are each independently selected from the group consisting of hydrogen, deuterium, halogen, C1-C4alkyl, unsubstituted or substituted phenyl, unsubstituted or substituted 5-10 membered heteroaryl, and NR b1 R b’ wherein R b1 and R b’ are each independently selected from the group consisting of hydrogen, C1-C4alkyl, unsubstituted or substituted phenyl and unsubstituted or substituted 5-10 membered heteroaryl; R 10 is absent, the nitrogen to which R 10 is attached is directly attached to L or X;

[0019] L is absent or is a divalent, trivalent or tetravalent linking group; and p is 1 when L is absent or is a divalent linking group; p is 2 when L is a trivalent linking group; p is 3 when L is a tetravalent linking group; and the 2 or 3 X to which L is linked are the same or different when p is 2 or 3;

[0020] X is a group of the general formula (III):

[0021]

[0022] wherein,

[0023] R2is selected from the group consisting of hydrogen, deuterium, halogen, C1-C6alkyl, unsubstituted or substituted phenyl and unsubstituted or substituted 5-10 membered heteroaryl;

[0024] W and T are each independently absent, -C(R a1 )(R a1 ’)-, -C(R a1 )(R a1 ’)C(R a2 )(R a2 ’))-, a3 -O-, -S- or -NR a1 ; wherein R a1 , R a2 , R a2 , R a3 are each independently hydrogen, deuterium, hydroxyl, amino, halogen, CN, CO2R a4 , CONR a5 R a5C1-C6alkyl, C1-C10heteroalkyl, C2-C4alkenyl, C2-C4alkynyl, unsubstituted or substituted -CONH-(C6-C10)aryl, unsubstituted or substituted -CH=CH-(C6-C10)aryl, unsubstituted or substituted C6-10aryl, unsubstituted or substituted 5-10 membered heteroaryl, unsubstituted or substituted C3-C10cycloalkyl, unsubstituted or substituted 3-10 membered heterocycloalkyl, unsubstituted or substituted 3-7 membered heterocycloalkenyl, unsubstituted or substituted C6-C10aryl C1-C6alkyl, unsubstituted or substituted C1-C6alkyl C6-C10aryl, unsubstituted or substituted 5-10 membered heteroaryl C1-C6alkyl, or unsubstituted or substituted C1-C6alkyl 5-10 membered heteroaryl;

[0025] Z is selected from N, O, or CR d ; wherein R d is hydrogen, deuterium, halogen, C1-C4alkyl, or C6-C12aryl; and R3is absent when Z is O;

[0026] R3is selected from hydrogen, deuterium, hydroxyl, amino, halogen, CN, CO2R e1 ', CONR e2 R e2 ', C1-C6alkyl, C1-C10heteroalkyl, C2-C4alkenyl, C2-C4alkynyl, -O(C6-C10)aryl, unsubstituted or substituted -S(C6-C10)aryl, unsubstituted or substituted -NH(C6-C10)aryl, unsubstituted or substituted -NHC(=O)(C6-C10)aryl, unsubstituted or substituted -CONH-(C6-C10)aryl, unsubstituted or substituted -CH=CH-(C6-C10)aryl, unsubstituted or substituted C6-10aryl, unsubstituted or substituted 5-10 membered heteroaryl, unsubstituted or substituted C3-C10cycloalkyl, unsubstituted or substituted 3-10 membered heterocycloalkyl, unsubstituted or substituted 3-7 membered heterocycloalkenyl, unsubstituted or substituted C6-C10aryl C1-6alkyl, unsubstituted or substituted C1-6alkyl C6-C10aryl, unsubstituted or substituted 5-10 membered heteroaryl C1-C6alkyl, or unsubstituted or substituted C1-C6alkyl 5-10 membered heteroaryl; R3and an adjacent W, T can be joined to form unsubstituted or substituted C6-C10aryl, unsubstituted or substituted 5-10 membered heteroaryl, 5-10 membered cycloalkyl, or 5-10 membered heterocycloalkyl; R e1 , e1 and R e2 are each independently hydrogen, hydroxyl, C1-C6alkyl;

[0027] Q is absent, O, N(R f ), S, or SO2, wherein R fis selected from the group consisting of hydrogen or C1-C4alkyl;

[0028] "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-C6alkyl, C1-C6haloalkyl and C1-C6hydroxyalkyl,

[0029] denotes the point of attachment.

[0030] In one embodiment, in general formula (I), Ar is a group according to general formula (IIa):

[0031]

[0032] wherein:

[0033] B is C=O or CH2;

[0034] R1is selected from the group consisting of hydrogen, deuterium, halogen and C1-C4alkyl;

[0035] R 10 is H, Y1is NH or O, and is attached to L or directly to X;

[0036] or R 10 is absent, R 10 is attached to L or directly to X; Y1is H, NH2or halogen;

[0037] or Ar is selected from the group consisting of:

[0038]

[0039] denotes the point of attachment.

[0040] In another embodiment, in general formula (I), X is selected from the group consisting of the following general formulae (IIIa) and (IIIb):

[0041]

[0042] wherein:

[0043] R2is selected from the group consisting of hydrogen, deuterium, halogen, C1-C4alkyl, and unsubstituted or substituted phenyl;

[0044] Q is selected from the group consisting of absent, NH and O;

[0045] W is selected from the group consisting of CR g1 R g1’ , O, NR g2 ; wherein R g1 , R g1’ and Rg2 Each is independently hydrogen, C1-C6 alkyl, CO2R g3 or CONR g4 R g4’ ;R g3 R g4 and R g4’ Each is independently hydrogen or C1-C6 alkyl;

[0046] R3 is selected from unsubstituted or substituted -CONH-(C6-C10)aryl, -CO2-(C6-C10)aryl, unsubstituted or substituted -CH=CH-(C6-C10)aryl, unsubstituted or substituted C6-C10aryl, unsubstituted or substituted 5-10 heteroaryl, unsubstituted or substituted C3-C10 cycloalkyl, unsubstituted or substituted 3-10 heterocyclic alkyl, unsubstituted or substituted 3-7 heterocyclic alkenyl, unsubstituted or substituted C1-C6 alkyl C6-C10aryl, unsubstituted or substituted -O(C6-C10)aryl, unsubstituted or substituted -S(C6-C10)aryl, unsubstituted or substituted -NH(C6-C10)aryl, unsubstituted or substituted -NHC(=O)(C6-C10)aryl, or unsubstituted or substituted C1-C6 alkyl 5-10 heteroaryl;

[0047] Z is selected from CR e3 N; Re3 is selected from hydrogen, C1-C6 alkyl, C1-C10 heteroalkyl, C2-C4 alkenyl, C2-C4 alkynyl, and unsubstituted or substituted C6-C10 aryl;

[0048] The C ring is an unsubstituted or substituted C6-C10 aryl group, or an unsubstituted or substituted 5-10 heteroaryl group;

[0049] "Unsubstituted or substituted" means that the group is either unsubstituted or substituted by one or more substituents selected from hydroxyl, amino, cyano, nitro, carboxyl, halogen, C1-C6 alkyl, C1-C6 haloalkyl, and C1-C6 hydroxyalkyl.

[0050] This indicates a connection from that point.

[0051] In another specific embodiment, in general formula (I), R3 is selected from the following groups:

[0052]

[0053] in,

[0054] X1 is hydrogen, halogen, or CF3;

[0055] X2 is hydrogen, halogen, or CF3;

[0056] Rc1 c2 c3 c4 c5 c6 each independently is selected from the group consisting of hydrogen, deuterium, hydroxyl, halogen, cyano, nitro, formyl, C02R h h1 R h1’ h2 R h2’ C1-C4alkyl, C1-C10heteroalkyl, C2-C4alkenyl, C2-C4alkynyl, unsubstituted or substituted C6-C10aryl, unsubstituted or substituted 5-10 membered heteroaryl, unsubstituted or substituted C3-C10cycloalkyl, unsubstituted or substituted 3-10 membered heterocycloalkyl, unsubstituted or substituted 3-7 membered heterocycloalkenyl, unsubstituted or substituted C6-C10aryl C1-6alkyl, unsubstituted or substituted C1-6alkyl C6-C10aryl, unsubstituted or substituted 5-10 membered heteroaryl C1-C6alkyl, and unsubstituted or substituted C1-C6alkyl 5-10 membered heteroaryl; wherein R h h1 h1’ h2 h2’ each independently is selected from the group consisting of hydrogen and C1-C4alkyl;

[0057] or R c1 and R c2 , or R c2 and R c3 , or R c3 and R c4， , or R c5 and R c6 together with the ring atoms in the ring to which they are attached form an unsubstituted or substituted C6-10aryl, or an unsubstituted or substituted 5-10 membered heteroaryl;

[0058] "unsubstituted or substituted" means that the group is either not substituted or is substituted with one or more substituents selected from the group consisting of hydroxyl, amino, cyano, nitro, carboxyl, halogen, C1-C6alkyl, C1-C6haloalkyl, and C1-C6hydroxyalkyl;

[0059] Alternatively, R3is selected from the group consisting of:

[0060] and H, denotes the point of attachment.

[0061] In another particular embodiment, in general formula (I), X is selected from the group consisting of:

[0062] In another particular embodiment, in general formula (I), X is selected from the group consisting of:​​​​​​​​​​

[0063]

[0064] wherein, indicates the point of attachment.

[0065] In another embodiment, L is absent in general formula (I), or is a divalent group according to general formula (IV) or a trivalent group according to general formula (V):

[0066]

[0067]

[0068] wherein,

[0069] J and M are each independently absent, NR i , O, S, SO2, C(=O) or C(=S), wherein R i is hydrogen, C1-C4 alkyl or C6-C10 aryl;

[0070] K is absent, C1-C10 alkylene, C3-C10 cycloalkylene, C1-C6 heteroalkylene, C2-C6 alkenylene, C2-C6 alkynylene, unsubstituted or substituted C6-C10 arylene, unsubstituted or substituted 5-10 membered heteroarylene, unsubstituted or substituted C3-C8 cycloalkylene, unsubstituted or substituted 3-10 membered non-aromatic heterocyclylene, a peptidyl group consisting of 2-8 identical or different amino acids, or wherein two, three or four groups, identical or different, are combined freely;

[0071] K1 is a trivalent group selected from C1-C10 alkyl, C3-C10 cycloalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, unsubstituted or substituted C6-C10 aryl, unsubstituted or substituted 5-10 membered heteroaryl, unsubstituted or substituted C3-C8 cycloalkyl, unsubstituted or substituted 3-10 membered non-aromatic heterocyclyl, a peptidyl group consisting of 2-8 identical or different amino acids, and wherein two, three or four groups, identical or different, are combined freely;

[0072] "unsubstituted or substituted" means that the group is unsubstituted or substituted with one or more substituents selected from the group consisting of hydroxy, amino, cyano, nitro, carboxy, halogen, C1-C6 alkyl, C1-C6 haloalkyl and C1-C6 hydroxyalkyl;

[0073] Preferably, the divalent or trivalent groups according to general formula (IV) and (V) are selected from the following groups and combinations between identical or different groups:

[0074]

[0075] wherein m, n are each independently 0, 1, 2, 3, 4 or 5;

[0076] X b , X c , X h and X i are each independently absent, O, S or NH;

[0077] R 22 , R 23 , R 24 , R 25 , R 26 , R 27 , R 29 , R 32 , R 33 and R 34 are each independently absent, C1-C10alkylene, C3-C10cycloalkylene, C1-C6heteroalkylene, C2-C6alkenylene, C2-C6alkynylene, unsubstituted or substituted C6-C10arylene, unsubstituted or substituted 5-10 membered heteroarylene, unsubstituted or substituted C3-C8cycloalkylene, unsubstituted or substituted 3-10 membered non-aromatic heterocyclylene, or wherein two, three or four of the same or different radicals are combined;

[0078] R 30 and R 31 are each independently H, C1-C10alkyl, C3-C10cycloalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, unsubstituted or substituted C6-C10aryl, unsubstituted or substituted 5-10 membered heteroaryl, unsubstituted or substituted C3-C8cycloalkyl, unsubstituted or substituted 3-10 membered non-aromatic heterocyclyl, or wherein two, three or four of the same or different radicals are combined;

[0079] Ar1and Ar2are each independently unsubstituted or substituted C6-C10arylene, or unsubstituted or substituted 5-10 membered heteroarylene;

[0080] D and E rings are each independently unsubstituted or substituted 3-10 membered nitrogen-containing heterocyclic ring;

[0081] "unsubstituted or substituted" means that the radical is unsubstituted or substituted by one or more hydroxyl, amino, cyano, nitro, carboxyl, halogen, C1-C6alkyl, C1-C6haloalkyl or C1-C6hydroxyalkyl.

[0082] Preferably, the divalent and trivalent radicals of the above general formulae IV and V are selected from the following radicals:

[0083] Preferably, the divalent and trivalent radicals of the above general formulae IV and V are selected from the following radicals:

[0084]

[0085] terminal linker Ar, terminal linker fragment X.

[0086] In another embodiment, the compound of general formula (I) is selected from the group consisting of compounds of general formula (VI), (VII), (VIII), (IX), (X) and (XI):

[0087]

[0088]

[0089] wherein A, B, R1, R2, R3, Q, L, W, T, Z are as defined in the respective claims;

[0090] Y2is H, NH2or halogen;

[0091] Y3is NH or O.

[0092] In another embodiment, the compound of general formula (I) is selected from the group consisting of:

[0093]

[0094]

[0095]

[0096]

[0097]

[0098]

[0099]

[0100]

[0101]

[0102]

[0103]

[0104] The present application also provides a pharmaceutical composition comprising a compound according to the present application or a pharmaceutically acceptable salt thereof, and optionally a pharmaceutical adjuvant.

[0105] The present application also provides the use of a compound according to the present application or a pharmaceutically acceptable salt thereof for the preparation of an autophagy modulator, in particular a modulator of a mammalian ATG8 homolog, for the preparation of a medicament for the prevention or treatment of a disease associated with cellular autophagy.

[0106] The present application also provides a method for modulating autophagy, comprising administering to a subject in need thereof a compound according to the present application or a pharmaceutically acceptable salt thereof or a pharmaceutical composition according to the present application.

[0107] The present application also provides a method for modulating a mammalian ATG8 homolog, comprising administering to a subject in need thereof a compound according to the present application or a pharmaceutically acceptable salt thereof or a pharmaceutical composition according to the present application.

[0108] The present application also provides a method for preventing or treating a disease associated with cellular autophagy, comprising administering to a subject in need thereof a compound according to the present application or a pharmaceutically acceptable salt thereof or a pharmaceutical composition according to the present application.

[0109] The disease associated with cellular autophagy can be selected from the group consisting of a tumor, a cancer, 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, amyotrophic lateral sclerosis and an infectious disease, and the cancer can be selected from the group consisting of liver cancer, lung cancer, pancreatic cancer, breast cancer, cervical cancer, endometrial cancer, colon cancer, gastric cancer, lung cancer, nasopharyngeal cancer, ovarian cancer, prostate cancer, leukemia, lymphoma, myeloma, preferably from the group consisting of lymphoma, multiple myeloma, leukemia, lung cancer, breast cancer and pancreatic cancer. BRIEF DESCRIPTION OF DRAWINGS

[0110] Figure 1 is a graph showing the body weight of mice in each group in the in vivo efficacy test of Example 25 of the present application over time;

[0111] Figure 2 is a graph showing the change in body weight of mice in each group in the in vivo efficacy test of Example 25 of the present application over time;

[0112] Figure 3 is a graph showing the tumor volume of mice in each group in the in vivo efficacy test of Example 25 of the present application over time;

[0113] Figure 4 is a graph showing the change in tumor volume of mice in each group in the in vivo efficacy test of Example 25 of the present application over time. DETAILED DESCRIPTION

[0114] The present application will now be described in detail. It is to be understood that various alterations and modifications can be made to the application without departing from the spirit and scope thereof. It is also to be understood that the following example is illustrative only and not restrictive of the scope of the application as set forth in the appended claims.

[0115] The terms used in the present application have their ordinary meanings in the art and will be employed as such if not otherwise indicated. Chemical names, common names, and chemical structures can be used interchangeably to describe the same structure. These definitions apply regardless of whether a term is used by itself or in combination with other terms, where the indi vidual meanings are known or can be inferred. Thus, the definition of "alkyl" applies to "alkyl" as well as the "alkyl" portion of "hydroxyalkyl," "haloalkyl," "arylalkyl," "alkylaryl," "alkoxy," and the like.

[0116] A "pharmaceutical composition" refers to a composition suitable for administering to a subject. 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 in combination with one or more pharmaceutically acceptable carriers or excipients. A "subject" 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.

[0117] The pharmaceutical compositions of the present application can be prepared by conventional methods in the pharmaceutical art. The formulation of the unit dose contains 0.05 to 200 mg of the compound of the general formula (I), preferably, the formulation of the unit dose contains 0.1 mg to 100 mg of the compound of the general formula (I).

[0118] 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. Oral administration is most preferred. The optimal daily dose is 0.01 to 200 mg / kg of body weight, administered at one time or divided into several times. Regardless of the method of administration, the optimal dose for an individual should be determined according to the specific treatment. Generally, the dose should be started from a small amount and gradually increased until the optimal dose is found.

[0119] "Halogen" (or halo) refers to fluorine, chlorine, bromine, or iodine.

[0120] "Alkyl" refers to an aliphatic saturated hydrocarbon group, which is preferably a straight or branched chain alkyl group containing from 1 to 10 carbon atoms, preferably 1 to 6 carbon atoms, more preferably 1 to 4 carbon atoms. Branched is meant that one or more alkyl groups containing from 1 to 4 carbon atoms, such as methyl, ethyl, or propyl, etc., are attached to the straight chain alkyl group. Preferred alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, and t-butyl, etc.

[0121] "Haloalkyl" refers to an alkyl group as defined above wherein one or more of the hydrogen atoms on the alkyl group are replaced with a halogen as defined above.

[0122] "Heteroalkyl" refers to an alkyl group as defined above wherein one or more of the carbon atoms are replaced by a moiety independently selected from -0-, -S-, -(S=0)-, -(0=S=0)-, -N(H), and -N-, etc. Preferred heteroalkyl groups include, but are not limited to, -0-alkyl, -S-alkyl, -(S=0)-alkyl, -(0=S=0)-alkyl, -N(H)alkyl, and -N(alkyl)2, etc.

[0123] "Alkenyl" refers to an aliphatic hydrocarbon group containing at least one carbon-carbon double bond, which can be straight or branched and contains from 2 to 10 carbon atoms in the straight or branched chain, preferably 2 to 6 carbon atoms, more preferably 2 to 4 carbon atoms. Branched is meant that one or more lower alkyl groups are attached to the straight chain alkenyl chain. Preferred alkenyl groups include, but are not limited to, ethenyl, propenyl, n-butenyl, 3-methylbut-2-enyl, n-pentenyl, octenyl, decenyl, etc.

[0124] "Alkylene" refers to a divalent group obtained by removing one hydrogen atom from an alkyl group as defined above. Preferred alkylene groups include, but are not limited to, methylene, ethylene, and propylene, etc. Generally, it can be optionally and equivalently represented herein as -(alkyl)-, e.g., -CH2CH2- is ethylene.

[0125] "Aryl" refers to an aromatic carbocyclic group of from 6 to 12 carbon atoms having a single ring (such as phenyl) or multiple condensed rings (such as naphthyl) but not more than two rings in the condensed ring system. Preferred aryl groups include, but are not limited to, phenyl, 1-naphthyl, 2-naphthyl, 1-anthryl, 2-anthryl, and 9-anthryl, etc.

[0126] "Arylalkyl" refers to an alkyl group as defined above wherein one of the hydrogen atoms is replaced with an aryl group as defined above. Preferred arylalkyl groups include, but are not limited to, benzyl, 1-phenylethyl, 2-phenylethyl, 2-naphthylethyl, 2-anthracylethyl, etc.

[0127] "Aryl" means a carbocyclic aromatic monocyclic or polycyclic ring system containing from 6 to 14 carbon atoms, preferably 6 to 10 carbon atoms in the ring. Aryl groups can be optionally substituted with one or more "substituents," which are the same or different, as defined herein. Preferred aryl groups include, but are not limited to, phenyl and naphthyl. "Monocyclic aryl" means phenyl.

[0128] "Arylene" means a divalent functional radical obtained by removing two hydrogen atoms from an aryl group as defined above. For example, is para-phenylene.

[0129] "Heteroaryl" means an aromatic monocyclic or polycyclic ring system containing from 5 to 14 ring atoms, preferably 5 to 10 ring atoms, wherein one or more of the ring atoms is an element other than carbon, such as nitrogen, oxygen, or sulfur, used alone or in combination. Preferred heteroaryls contain from 5 to 6 ring atoms. "Heteroaryl" groups can be optionally substituted with one or more substituents, which can be the same or different, as defined herein. The prefixes azo, oxa, or thia before the name of a heteroaryl radical mean that at least one nitrogen, oxygen, or sulfur atom, respectively, is independently a ring atom. Nitrogen atoms of heteroaryl groups can optionally be oxidized to the corresponding N-oxide. The term "heteroaryl" also includes heteroaryl groups as defined above fused to aryl groups as defined above. Preferred heteroaryl groups include, but are not limited to, pyridyl, pyrazinyl, furanyl, thienyl, pyrimidinyl, pyridonyl (including N-substituted pyridonyl), isoxazolyl, isothiazolyl, oxazolyl, oxadiazolyl, thiazolyl, thiadiazolyl, pyrazolyl, furazanyl, pyrrolyl, triazolyl, 1,2,4-thiadiazolyl, pyridazinyl, quinoxalinyl, phthalazinyl, oxindolyl, imidazo[l,2-a]pyridinyl, imidazo[2,l-b]thiazolyl, benzofurazanyl, indolyl, azaindolyl, benzimidazolyl, benzothiophenyl, quinolinyl, imidazolyl, thienopyridinyl, quinazolinyl, thienopyrimidinyl, pyrrolopyridinyl, imidazopyridine, isoquinolinyl, benzoxazinyl, 1,2,4-triazinyl, benzothiazolyl, and the like. The term "heteroaryl" also refers to partially saturated heteroaryls, such as tetrahydroisoquinolinyl, tetrahydroquinolinyl, and the like. The term "monocyclic heteroaryl" means a monocyclic form of a heterocycle as described above and includes 4- to 7-membered monocyclic heteroaryls containing from 1 to 4 ring heteroatoms independently selected from N, O, and S and oxides thereof. The point of attachment to the parent moiety is any available ring carbon or ring heteroatom. Preferred monocyclic heteroaryls include, but are not limited to, pyridyl, pyrazinyl, furanyl, thienyl, pyrimidinyl, pyridazinyl, pyridonyl, thiazolyl, isothiazolyl, oxazolyl, oxadiazolyl, isoxazolyl, pyrazolyl, furazanyl, pyrrolyl, pyrazolyl, triazolyl, thiadiazolyl (e.g., 1,2,4-thiadiazolyl), imidazolyl, and triazinyl (e.g., 1,2,4-triazinyl), and oxides thereof.

[0130] "Cycloalkyl" refers to a non-aromatic monocyclic or polycyclic ring system containing 3 to 10 carbon atoms, preferably 3 to 6 carbon atoms. Cycloalkyl groups can be optionally substituted with one or more substituents, which can be the same or different, as described herein. Monocyclic cycloalkyl groups refer to monocyclic forms of cycloalkyl groups described herein. Preferred monocyclic cycloalkyl 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-decaloyl, norbornyl, adamantyl, and the like.

[0131] "Cycloalkenyl" refers to a non-aromatic monocyclic or polycyclic ring system containing 3 to 10 carbon atoms, which contains at least one carbon-carbon double bond within the ring. Preferred cycloalkenyl rings contain 3 to 7 ring atoms. Cycloalkenyl groups can be optionally substituted with one or more substituents, which can be the same or different, as described herein. The term "monocyclic cycloalkenyl" refers to monocyclic forms of cycloalkenyl groups described herein, and includes non-aromatic 3- to 7-membered monocyclic cycloalkenyl groups containing one or more carbon-carbon double bonds. Preferred monocyclic cycloalkenyl groups include, but are not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cyclopentenyl, cycloheptane-1,3-dienyl, and the like. Preferred polycyclic cycloalkenyl groups include, but are not limited to, norbornenyl.

[0132] "Heterocycloalkyl" (or "heterocyclyl") refers to a non-aromatic saturated monocyclic or polycyclic ring system containing 3 to 10 ring atoms, preferably 5 to 10 ring atoms, wherein one or more atoms within the ring system is an element other than carbon, such as nitrogen, oxygen, or sulfur, alone or in combination. There are no adjacent oxygen and / or sulfur atoms present in the ring system. Preferred heterocyclyl groups contain 5 to 6 ring atoms. Heterocyclyl groups can be optionally substituted with one or more substituents, which can be the same or different, as described herein. The nitrogen or sulfur atoms of the heterocyclyl group can optionally be oxidized to the corresponding N-oxide, S-oxide, or S,S-dioxide. Thus, the term "oxide" in the present application refers to the corresponding N-oxide, S-oxide, or S,S-dioxide. "Heterocyclyl" also includes instances where two available hydrogen atoms on the same carbon atom of the ring system are simultaneously replaced by a single group =0 (e.g., carbonyl), such =0 group can be referred to as an "oxo" in the present application. The term "monocyclic heterocycloalkyl" refers to monocyclic forms of heterocycloalkyl groups described herein, including 4- to 7-membered monocyclic heterocycloalkyl groups containing 1 to 4 ring heteroatoms independently selected from N, N-oxide, O, S, S-oxide, S(O), and S(O)2. Preferred monocyclic 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, and oxides thereof.

[0133] "Heterocyclic alkenyl" refers to a non-aromatic monocyclic or polycyclic system containing 3 to 10 ring atoms, preferably 3 to 7 ring atoms, wherein one or more atoms in the ring system are elements other than carbon, such as nitrogen, oxygen, or sulfur alone, or combinations thereof, and it contains at least one carbon-carbon double bond or carbon-nitrogen double bond. Adjacent oxygen and / or sulfur atoms are absent from the ring system. Preferred heterocyclic alkenyl groups contain 5 to 6 ring atoms. The prefixes aza, oxa, or thiaza before the root name of the heterocyclic alkenyl group indicate that at least one nitrogen, oxygen, or sulfur atom is a ring atom, respectively. The heterocyclic alkenyl group may optionally be substituted by one or more of the same or different substituents as described in this invention. The nitrogen or sulfur atom of the heterocyclic alkenyl group may optionally be oxidized to the corresponding N-oxide, S-oxide, or S,S-dioxide. Preferred heterocyclic alkenyl groups include, but are not limited to, 1,2,3,4-tetrahydropyridyl, 1,2-dihydropyridyl, 1,4-dihydropyridyl, 1,2,3,6-tetrahydropyridyl, 1,4,5,6-tetrahydropyrimidinyl, 2-pyrrolinyl, 3-pyrrolinyl, 2-imidazolinyl, 2-pyrazolinyl, dihydroimidazolinyl, dihydrooxazolyl, dihydrooxadiazolyl, dihydrothiazolinyl, 3,4-dihydro-2H-pyranyl, dihydrofuranyl, fluorodihydrofuranyl, etc. A "heterocyclic alkenyl" can also be a substituted ring system in which two available hydrogen atoms on the same carbon atom are simultaneously substituted by a single group =O (e.g., a carbonyl group). The term "monocyclic heterocyclic alkenyl" refers to the monocyclic form of the heterocyclic alkenyl described in this invention, including 4- to 7-membered monocyclic heterocyclic alkenyls containing 1 to 4 cyclic heteroatoms, wherein the cyclic heteroatoms are independently selected from N, N-dioxide, O, S, S-oxide, S(O) and S(O)2. Preferred monocyclic heterocyclic alkenyls include, but are not limited to, 1,2,3,4-tetrahydropyridyl, 1,2-dihydropyridyl, 1,4-dihydropyridyl, 1,2,3,6-tetrahydropyridyl, 1,4,5,6-tetrahydropyrimidinyl, 2-pyrrolinyl, 3-pyrrolinyl, 2-imidazolinyl, 2-pyrazolinyl, dihydroimidazolinyl, dihydrooxazolyl, dihydrooxadiazolyl, dihydrothiazolinyl, 3,4-dihydro-2H-pyranyl, dihydrofuranyl, fluorodihydrofuranyl, dihydrothiophenyl, and dihydrothiaranyl and their oxides.

[0134] "Aryloxy" refers to an aryl-O- group, wherein aryl is as previously described. Preferred aryloxy groups include, but are not limited to, phenyloxy, 1- naphthyloxy, and 2-naphthyloxy. The point of attachment is through the oxygen. "Aryloxyalkyl" refers to a group derived by removing the hydrogen atom of an alcohol group from an aryloxy group as defined herein. The point of attachment is through the alkyl group.

[0135] "Aryloxy" refers to an aryl-O- group, wherein aryl is as previously described. Preferred aryloxy groups include, but are not limited to, phenyloxy, 1- naphthyloxy, and 2-naphthyloxy. The point of attachment is through the oxygen. "Aryloxyalkyl" refers to a group derived by removing the hydrogen atom of an alcohol group from an aryloxy group as defined herein. The point of attachment is through the alkyl group.

[0136] "Aryloxy" refers to an aryl-O- group, wherein aryl is as previously described. Preferred aryloxy groups include, but are not limited to, phenyloxy, 1- naphthyloxy, and 2-naphthyloxy. The point of attachment is through the oxygen. "Aryloxyalkyl" refers to a group derived by removing the hydrogen atom of an alcohol group from an aryloxy group as defined herein. The point of attachment is through the alkyl group.

[0137] "Aryloxy" refers to an aryl-O- group, wherein aryl is as previously described. Preferred aryloxy groups include, but are not limited to, phenyloxy, 1- naphthyloxy, and 2-naphthyloxy. The point of attachment is through the oxygen. "Aryloxyalkyl" refers to a group derived by removing the hydrogen atom of an alcohol group from an aryloxy group as defined herein. The point of attachment is through the alkyl group.

[0138] Any of the foregoing functional groups of the application can be unsubstituted or substituted with a substituent group as described herein. The term "substituted" means that one or more hydrogen atoms on the designated atom is replaced with a group selected from the designated group, provided that the substitution results in a stable compound. Combinations of substituents and / or variables are permissible only if the presence of such combinations results in stable compounds.

[0139] The term "unsubstituted or substituted" means that the specified group is either not substituted or is substituted with one or more substituents.

[0140] Substitution on cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, heteroarylalkyl, aryl-fused cycloalkylalkyl, and the like groups includes substitution on any ring portion and / or alkyl portion of the group.

[0141] Tautomers refer to compounds that result from the phenomenon of a proton in a molecule shifting from one atom to another. Tautomers also refer to two or more isomeric forms in equilibrium that are readily interconvertible 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.

[0142] Specifically, the compounds of the present application include all tautomers thereof, for example keto-enol tautomers. For convenience, in the detailed description of the application and in the claims, these tautomers and partial structures (Example 1) for mixtures thereof are shown below.

[0143]

[0144] 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.

[0145] Stereoisomers refer to compounds that have the same molecular formula but different spatial arrangements of atoms, resulting in compounds that are not superimposable on one another. Stereoisomerism includes cis-trans isomerism, conformational isomerism, enantiomerism, and diastereomerism, among others. Cis-trans isomerism refers to the fact that two carbon atoms bonded by a double bond cannot rotate about the sigma bond to give the relative free rotation, and is generally used for alkenes, but also for C=N double bonds, N=N double bonds, and cyclic compounds. Enantiomers refer to stereoisomers that are mirror images of one another; diastereomers refer to stereoisomers that are not mirror images of one another, i.e., having two or more chiral centers and are not mirror images of one another. Unless otherwise specified, the present description is intended to include individual stereoisomers as well as mixtures thereof.

[0146] Specifically, the compounds of the present application include all isomers thereof, for example diastereomers and cis / trans (Z / E) isomers.

[0147] 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.

[0148] The compounds of the present application can form metal chelates with one or more metal ions. Metal ions include, but are not limited to, copper, iron, magnesium, calcium, zinc, nickel, and platinum, among others. The compounds of the present application include all metal chelates.

[0149] 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 Federal, State, and local governments. Pharmaceutically acceptable salts include inorganic and organic salts, which 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, phosphoric, or sulfuric acids, or salts of organic acids such as citric, ascorbic, citric, tartaric, lactic, maleic, malonic, fumaric, glycolic, succinic, propionic, acetic, or methanesulfonic acids, 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.

[0150] The term "effective amount" refers to the amount of a compound of the present application contained in the composition administered which is sufficient to modulate (e.g., inhibit or agonize, etc.) a mammalian ATG8 homolog.

[0151] The compounds of the present application can be prepared by a variety of methods known in the art, and the following reaction schemes are alternative routes for preparing the compounds of the present application. Those skilled in the art will readily understand that known variations of the conditions and processes described below can be used to prepare these compounds. The starting reactants used in the present application are commercially available unless otherwise stated.

[0152] For example, the compounds of the present application can be synthesized using one of the following general synthetic methods:

[0153] General Synthetic Method One:

[0154]

[0155] General Synthetic Method Two:

[0156]

[0157] General Synthetic Method Three:

[0158]

[0159] General Synthetic Method Four:

[0160]

[0161] General Synthetic Method Five:

[0162]

[0163] General Synthetic Method Six:

[0164]

[0165] The definitions of the groups or substituents in the above general synthetic methods are the same as the foregoing definitions. The intermediates can be prepared by methods described in some references known to those of ordinary skill in the art. These references include, for example:

[0166] Bioorganic & Medicinal Chemistry Letters, 24(16), 3764-3771, 2014;

[0167] Chemistry-A European Journal, 20(9), 2445-2448, 2014;

[0168] Bioorganic & Medicinal Chemistry, 20(2), 1029-1045, 2012;

[0169] Journal of Organic Chemistry, 82(5), 2630-2640, 2017;

[0170] Tetrahedron Letters, 49 (2008), 4725-4727; Journal of Organic Chemistry, 78(9), 4563-4567, 2013;

[0171] Heterocycles, 28(2), 1015-35, 1989; Journal of Medicinal Chemistry, 57(10), 3924-3938, 2014;

[0172] Journal of Organic Chemistry, 66(24), 8000-8009, 2001; and Tetrahedron Letters, 56(45), 6287-6289, 2015;

[0173] The Journal of Immunology, pp. 380-386, 1999; J. Org. Chem., vol. 53, pp. 1167-1170, 1988;

[0174] Progress in Medicinal Chemistry, vol. 22, pp. 166-242 (1985); J. Med. Chem., pp. 2858-2865 (1997);

[0175] Chem. Pharm. Bull., 46(7), pp. 1165-1168 (1998);

[0176] Bioorganic & Medicinal Chem. Letters 9, pp. 1625-1630 (1999);

[0177] J. Med. Chem., pp. 3044-3045 (1996);

[0178] Journal of Medicinal Chemistry, vol. 39, No. 17, pp. 3238-3240 (1996);

[0179] Bioorganic & Medicinal Chemistry Letters 8, pp. 2669-2674 (1998);

[0180] Bioorganic & Medicinal Chemistry Letters 7, pp. 1071-1076 (1998);

[0181] Immunopharmacology 35, pp. 203-212 (1997).

[0182] Examples

[0183] The present application is further illustrated by the following examples. It should be understood that these examples are included merely to further illustrate the application and should not be considered in any way limiting to the scope of the application.

[0184] Abbreviations: nuclear magnetic resonance (NMR); triethylamine (TEA); mass spectrometry (MS); dimethylformamide (DMF); N,N-dimethylformamide dimethyl acetal (DMF-DMA); diisopropylethylamine (DIPEA); N-methylpyrrolidone (NMP); lenalidomide; benzyl carbamate (Cbz), sodium sulfate (Na2S04); tert-butyl carbamate (Boc); 2-(7-oxabenzo-triazol-l-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU)

[0185] liquid chromatography-mass spectrometry (LCMS); thin layer chromatography (TLC); milligram / gram / kilogram (mg / g / kg); mole / millimole (mol / mmol); milliliter / liter (ml / L); equivalent (eq).

[0186] General synthetic conditions:

[0187] Unless otherwise specified, all reactions are carried out in an inert gas atmosphere (such as argon or nitrogen), and commercially available reagents and anhydrous solvents used require no further treatment.

[0188] The liquid chromatography-mass spectrometry (LC-MS) system was an Agilent 6120B single quadrupole LC-MS system. Solvent system gradient: 2–98% B, 1.5 min, flow rate 1.2 mL / min; eluent A: water / 0.1% TFA, eluent B: ACN / 0.1% TFA. Column: Kinetex C18 2.6 μm 2.1 x 50 mm (Phenomenex), column temperature 50 °C. LC / MS UPLC system (column: Acquity C18BEH 1.7 μm, 2.1 x 50 mm at 50 °C; eluent A: water + 0.1% formic acid; eluent B: ACN. Gradient: 2–98% B, 1.4 min – flow rate 1.0 mL / min; HPLC: method group: 10–95%; run time: 10 min).

[0189] Nuclear magnetic resonance spectroscopy (such as proton spectrum) 1 H), carbon spectrum ( 13 C) Phosphorus spectrum ( 31 P) and fluorine spectrum ( 19 F) NMR spectra were recorded using a Bruker AMX-400, Gemini-300, or AMX-600 NMR spectra in deuterated solvents such as deuterated chloroform, deuterated methanol, deuterated water, or deuterated dimethyl sulfoxide, with the deuterated solvent peak serving as the reference standard. The chemical shift δ is expressed in ppm, and the coupling constant (J) is expressed in Hertz (Hz). Coupled split peaks in the NMR spectrum are represented as: broad singlet (brs), singlet (s), doublet (d), twin doublet (dd), triplet (t), quartet (q), and multiplet (m).

[0190] Example 1: Synthesis of Compound 1

[0191]

[0192] Step 1: 5-Phenyl-1,3-cyclohexanedione (30.0 g, 159.4 mmol) was dissolved in chloroform (100 mL). N,N-dimethylformamide dimethyl acetal (DMFDMA, 20 mL) was slowly added at room temperature. After stirring for 1 hour, TLC showed that the reaction was complete. The reaction solution was poured into ice water, and the chloroform phase was separated. The aqueous phase was extracted with dichloromethane. The combined organic phases were washed with water, brine, dried (Na2SO4), and concentrated. The crude product was separated by column chromatography to obtain the target intermediate 1-1 (30.4 g, yield 78.4%).

[0193] Step 2: Lenalidomide (910 mg, 3.5 mmol), intermediate 1-1 (1.10 g, 4.5 mmol) were dissolved in a mixture of ethanol (20 mL) / dichloromethane (15 mL), the reaction was heated to reflux for 1 hour, TLC showed the reaction was complete. The reaction was filtered hot, the solid was washed with ethanol (10 mL) for 3 times, dried, then slurry in methanol (20 mL) and stirred for 2 hours; filtered, the crude product was dissolved in dichloromethane (20 mL) and slurry for 1 hour, filtered and dried to give the target compound 1 (1.42 g, yield 89%).

[0194] 1 H NMR (400 MHz, DMSO-d6): δ 12.87 (d, J = 13.6 Hz, 1H), 10.99 (s, 1H), 8.58 (d, J = 13.6 Hz, 1H), 7.89 (dd, J = 6.8, 1.2 Hz, 1H), 7.63-7.57 (m, 2H), 7.32-7.29 (m, 4H), 7.23-7.20 (m, 1H), 5.17-5.12 (m, 1H), 4.62-4.44 (m, 2H), 3.43-3.38 (m, 1H), 2.95-2.78 (m, 3H), 2.68-2.55 (m, 3H), 2.45-2.40 (m, 1H), 1.99-1.96 (m, 1H). MS: 458.5 (M+l).

[0195] Example 2: Synthesis of compounds 2-41, 110-121, 124, 126-128, 130-132, 134-156

[0196] The synthesis of compounds 2-41, 110-121, 124, 126-128, 130-132, 134-156 was performed as for compound 1, as described in Table 1:

[0197] Table 1

[0198]

[0199]

[0200]

[0201]

[0202]

[0203]

[0204]

[0205]

[0206]

[0207]

[0208] Example 3: Synthesis of compound 42

[0209]

[0210] Step 1: N-Boc-glycine (405 mg, 2.31 mmol) was dissolved in dry DMF (10 ml), HATU (1.10 g, 2.9 mmol) and DIPEA (516 mg, 4 mmol) were added at room temperature, after stirring for 20 minutes, lenalidomide (500 mg, 1.93 mmol) was added and stirring was continued for 2 hours; TLC showed that the raw material was completely reacted. The reaction liquid was poured into water, extracted with EtOAc, the organic phase was washed with water, brine, dried, concentrated, and the crude product was separated by column chromatography to obtain intermediate 42-1 (511 mg, 64%).

[0211] Step 2: Intermediate 42-1 (500 mg, 1.2 mmol) was dissolved in dichloromethane (DCM, 10 ml), trifluoroacetic acid (TFA, 10 ml) was added, and the reaction was stirred at room temperature for 1 hour. TLC showed that the reaction was complete, and the TFA was removed by reduced pressure distillation. The crude product was dissolved in ethanol (30 ml), and the pH was adjusted to basic by adding an appropriate amount of N,N-diisopropyl ethylamine (DIPEA); then intermediate 1-1 (365 mg, 1.5 mmol) was added and stirred at room temperature for 1 hour; TLC showed that the reaction was basically complete, the reaction liquid was poured into ice water, and the solid was filtered and washed with ethanol 3 times, and washed with water 3 times, and dried to obtain compound 42 (150 mg, 24.3%).

[0212] 1 H NMR (400 MHz, DMSO-d6) δ 11.07 - 10.89 (m, 2H), 10.11 (s, 1H), 8.13 (d, J = 14.5 Hz, 1H), 7.82 (dd, J = 7.0, 1.8 Hz, 1H), 7.59 - 7.44 (m, 2H), 7.42 - 7.13 (m, 5H), 5.15 (dd, J = 13.3, 5.1 Hz, 1H), 4.52 - 4.26 (m, 4H), 3.31 (s, 1H), 3.00 - 2.50 (m, 6H), 2.41 - 2.21 (m, 1H), 2.10 - 1.98 (m, 1H). MS: 515.1 (M+1).

[0213] Example 4: Synthesis of compounds 43-49, 54-57, 59-61, 64, 65, 93, 122-123, 157-158 The synthesis of compounds 43-49, 54-57, 59-61, 64, 65, 93, 122-123, 157-158 was carried out as for compound 42, as shown in Table 2:

[0214] Table 2:

[0215]

[0216]

[0217]

[0218]

[0219] Example 5: Synthesis of compound 50

[0220]

[0221] Step 1: The synthesis was carried out as for Example 3, Step 1.

[0222] Step 2: Intermediate 50-1 (500 mg, 1.22 mmol) was dissolved in ethanol (20 ml) / water (10 ml), saturated ammonium chloride (3 mL) was added, iron powder (560 mg, 10 mmol) was added and refluxed at 80 degrees for 1 hour; TLC showed the reaction was complete, the reaction was hot filtered through celite, the filter cake was washed with EtOAc, the organic phase was separated, the aqueous phase was extracted with EtOAc, the combined organic phase was washed with water, brine, dried, concentrated, and the crude product was separated by column chromatography to give intermediate 50-2 (200 mg, 43%).

[0223] Step 3: As for Example 1, Step 2. Compound 50, 1 H NMR (400 MHz, DMSO-d6) δ 12.73 (d, J = 13.5 Hz, 1H), 10.97 (s, 1H), 10.37 (s, 1H), 8.61 (d, J = 13.5 Hz, 1H), 8.04 (d, J = 8.5 Hz, 2H), 7.70 (t, J = 8.3 Hz, 3H), 7.64 - 7.47 (m, 2H), 7.44 - 7.12 (m, 5H), 5.26 - 4.99 (m, 1H), 4.56 - 4.26 (m, 2H), 3.42 (s, 1H), 2.88 (ddd, J = 40.5, 16.2, 11.3 Hz, 3H), 2.74 - 2.51 (m, 3H), 2.39 (d, J = 13.0 Hz, 1H), 2.00 (s, 1H). MS: 577.3 (M+l).

[0224] Example 6: Synthesis of compounds 51-53, 58, 62, 63, 66

[0225] The synthesis of compounds 51-53, 58, 62, 63, 66 was carried out as for compound 50, as shown in Table 3:

[0226] Table 3:

[0227]

[0228]

[0229] Example 7: Synthesis of compound 73

[0230]

[0231] Step 1: 5-phenyl-1,3-cyclohexanedione (10 g, 53.1 mmol), DIPEA (7.11 g, 55 mmol) and 4-dimethylaminopyridine (2.0 g, 16.4 mmol) were dissolved in 1,2-dichloroethane (140 ml), acetyl chloride (4.32 g, 55 mmol) was added dropwise at RT, then the reaction was carried out at 60 °C for 2 h. TLC showed that the reaction was complete, the reaction solution was poured into ice water, the organic layer was separated, the aqueous phase was extracted with dichloromethane, the organic phase was washed with water, brine, dried, and concentrated. The crude product was separated by column chromatography to obtain intermediate 73-1 (7.31 g, yield 60%).

[0232] Step 2: Intermediate 73-1 (360 mg, 1.56 mmol) and lenalidomide (200 mg, 0.77 mmol) were dissolved in ethanol / chloroform (10 mL / 10 mL) and heated to reflux for 2 h. TLC showed that the reaction was complete, and the crude product was separated by column chromatography on silica gel to obtain compound 73 (90 mg, 25%).

[0233] 1 H NMR (400 MHz, DMSO_d6): δ 15.04 (s, 1H), 11.01 (s, 1H), 7.70-7.65 (m, 3H), 7.35-7.24 (m, 5H), 5.18-5.13 m, 1H), 4.40 (q, J = 39.2 Hz, 2H), 2.90-2.86 (m, 3H), 2.67-2.51 (m, 3H), 2.48 (s, 3H), 2.46-2.40 (m, 1H), 2.01-1.95 (m, 1H). MS: 472.1 (M+1)

[0234] Example 8: Synthesis of compounds 74-76

[0235] Method of synthesis of compounds 74-76 is same as compound 73 as described in table 4;

[0236] Table 4:

[0237]

[0238] Example 9: Synthesis of compound 77

[0239]

[0240] Step 1: Triphosgene (1.14 g, 3.84 mmol) was dissolved in dichloromethane (20 ml) and 2-azidoethanamine (1.0 g, 11.61 mmol) was added dropwise slowly at -10 °C. After stirring for half an hour at -10 °C, TEA (2.34 g, 23 mmol) was added and the reaction was continued for 1 hour. The reaction mixture was then added dropwise slowly to a solution of lenalidomide (2.0 g, 7.7 mmol) in N,N-dimethylacetamide (20 ml) and the reaction was continued at 65 °C for 1 hour. The reaction mixture was poured into ice water and the aqueous phase was extracted with EtOAc. The organic phase was washed with water, brine, dried, and concentrated. The crude product was separated by column chromatography to obtain intermediate 77-1 (2.01 g, 70%).

[0241] Step 2: Intermediate 77-1 (2.0 g, 5.38 mmol) was dissolved in ethanol (50 ml) and 10% Pd / C (200 mg) was added. Hydrogenation was carried out at RT for 1 hour with stirring. TLC showed that the reaction was complete. The Pd / C was removed by filtration. Intermediate 1-1 (423 mg, 1.74 mmol) was then added and stirring was continued at room temperature for 1 hour. A solid was separated which was filtered and washed with ethanol three times. The solid was dried to obtain compound 77 (533 mg, 68%).

[0242] 1 H NMR (400 MHz, DMSO_d6): δ 11.02-10.89 (m, 2H), 8.41 (s, 1H), 8.06 (d, J = 16.0 Hz, 1H), 7.93 (d, J = 8.4 Hz, 1H), 7.42-7.20 (m, 7H), 6.50 (br, 1H), 5.14 (dd, J = 13.2.4.8 Hz, 1H), 4.30 (q, J = 13.2 Hz, 2H), 3.56 (br, 2H), 3.37 (br, 1H), 3.25-3.16 (m, 2H), 2.96-2.87 (m, 1H), 2.75-2.57 (m, 4H), 2.46-2.30 (m, 1H). MS: 544.2 (M+1).

[0243] Example 10: Synthesis of compounds 71, 72, 78-90

[0244] The synthesis of compounds 71, 72, 78-90 was performed as described for compound 77 in Table 5:

[0245] Table 5

[0246]

[0247]

[0248] Example 11: Synthesis of compound 67

[0249]

[0250] Step 1: 2-Aminonicotinic acid (5.00 g, 36.2 mmol) was slowly added to dichlorosulfoxide (50 mL). After stirring at 80 °C for 2 h, the dichlorosulfoxide was removed directly under reduced pressure. The crude acyl chloride was added portionwise to a solution of lenalidomide (2.00 g, 7.72 mmol), DIPEA (3.8 mL) in N,N-dimethylacetamide (20 mL) at RT, and the reaction was stirred at room temperature for 2 h. The reaction was poured into ice water, and extracted with ethyl acetate. The organic phase was washed with water, brine, dried, and concentrated. The crude product was separated by column chromatography to give intermediate 67-1 (620 mg, 21%).

[0251] Step 2: Intermediate 67-1 (200 mg, 0.526 mmol), intermediate 1-1 (300 mg, 1.23 mmol), and acetic acid (60 mg, 1 mmol) were dissolved in methanol (20 mL) / dichloromethane (20 mL). The reaction was heated at 45 °C overnight. The solid was filtered, washed with ethanol, and washed with dichloromethane, and dried to give compound 67 (32 mg, 10%).

[0252] 1 H NMR (400 MHz, DMSO-d6): δ 13.63 (d, J = 12.4 Hz, 1H), 10.99 (s, 1H), 10.80 (s, 1H), 9.24 (d, J = 12.8 Hz, 1H), 8.64 (d, J = 8.4 Hz, 1H), 8.41 (d, J = 8.4 Hz, 1H), 7.73-7.60 (m, 3H), 7.48-7.44 (m, 1H), 7.32-7.21 (m, 6H), 5.20-5.14 (m, 1H), 4.58-4.40 (m, 2H), 3.44-3.36 (m, 2H), 2.92-2.80 (m, 3H), 2.67-2.63 (m, 3H), 2.04-1.98 (m, 1H). MS: 578.2 (M+l).

[0253] Example 12: Synthesis of compound 91

[0254]

[0255] Step 1 : 1 -(2-azidoethyl)piperazine (0.93 g, 6.0 mmol) was dissolved in tetrahydrofuran (20 mL), succinic anhydride (0.5 g, 5.0 mmol) was added at room temperature, stirred at room temperature for 3 h, TLC showed the starting material was consumed, concentrated to give intermediate 91-1 (1.46 g, crude) was used directly in the next step.

[0256] Step 2: Intermediate 91-1 (1.46 g, crude), DIPEA (1.6 mL, 10.0 mmol), lenalidomide (1.00 g, 3.86 mmol) was dissolved in dry DMF (20 mL), HATU (2.8 g, 7.5 mmol) was added at RT, stirred overnight. The reaction was poured into ice water, extracted with EtOAc, the organic phase was washed with water, brine, dried, concentrated. The crude product was separated by column chromatography to give intermediate 91-2 (615 mg, 32%).

[0257] Step 3: The synthesis was carried out according to the procedure described in Example 10, step 2.

[0258] Compound 91, 1 H NMR (400 MHz, CD3OD): δ 8.27 (s, 1 H), 7.71 (d, J = 8.0 Hz, 1 H), 7.65 (d, J = 8.0 Hz, 1 H), 7.51 (t, J = 8.0 Hz, 1 H), 7.32-7.22 (m, 5H), 5.18 (q, J = 8.0 Hz, 1 H), 4.47 (d, J = 3.2 Hz, 1 H), 3.63-3.59 (m, 6H), 3.39-3.34 (m, 1 H), 2.80-2.49 (m, 17H), 2.21-2.18 (m, 1 H). MS: 669.2 (M+1).

[0259] Example 13: Synthesis of compound 92

[0260]

[0261] Step 1 : 4-Formylbenzoic acid (1.50 g, 10.0 mmol), DIPEA (3.87 g, 30.0 mmol), lenalidomide (2.10 g, 8.1 mmol) was dissolved in dry DMF (20 mL), HATU (5.70 g, 15.0 mmol) was added at RT, stirred overnight. The reaction was poured into ice water, extracted with ethyl acetate, the organic phase was washed with water, brine, dried, concentrated. The crude product was separated by column chromatography to give intermediate 92-1 (613 mg, 20%).

[0262] Step 2: Intermediate 92-1 (400 mg, 1.02 mmol) and l-(2-azidoethyl)piperazine (174 mg, 1.13 mmol), acetic acid (90 mg, 1.5 mmol) were dissolved in dichloromethane (50 mL) / methanol (10 mL), after stirring at room temperature for half an hour, sodium cyanoborohydride (126 mg, 2.04 mmol) was added, and stirring was continued at room temperature overnight. The reaction solution was poured into ice water, extracted with dichloromethane, the organic phase was washed with water, washed with brine, dried, and concentrated. The crude product was separated by column chromatography to obtain intermediate 92-2 (140 mg, 26%).

[0263] Step 3: The synthesis method was the same as that in Example 12, step 2.

[0264] Compound 92, 1 H NMR (400 MHz, CD3OD): δ 8.24 (s, 1H), 7.96 (d, J = 8.0 Hz, 1H), 7.74-7.67 (m, 2H), 7.61-7.50 (m, 3H), 7.31-7.21 (m, 5H), 5.17-5.13 (m, 1H), 4.54 (s, 2H), 3.68 (s, 2H), 3.61-3.58 (m, 2H), 3.36-3.39 (m, 1H), 2.85-2.59 (m, 17H) 2.21-2.19 (m, 1H). MS: 703.3 (M+l).

[0265] Example 14: Synthesis of compound 94

[0266] The synthesis of compound 94 was the same as that of compound 92, as described in Table 6 below:

[0267] Table 6

[0268]

[0269] Example 15: Synthesis of compound 101

[0270]

[0271] Step 1: Thalidomide (2.58 g, 10 mmol) was dissolved in anhydrous DMF (100 mL), and sodium hydride (60%, 440 mg, 11 mmol) was added slowly in batches under ice water bath cooling conditions. After stirring at room temperature for 30 minutes, the starting material 101-1 (3.67 g, 13 mmol) was added, and the reaction solution was stirred at room temperature overnight. The reaction solution was poured into ice water, extracted with ethyl acetate, and the organic phase was washed with water, washed with brine, dried, and concentrated. The crude product was separated by column chromatography to obtain intermediate 101-2 (807 mg, 16%).

[0272] Step 2: 101-2 (807 mg, 1.6 mmol) was dissolved in methanol (35 mL), 10% Pd / C (80 mg) was added, and the reaction was stirred under hydrogen (0.2 MPa) at room temperature for 24 h. TLC showed the reaction was complete, the Pd / C was filtered off, and the filtrate was added to N-Cbz- aminoacetaldehyde (710 mg, 3.6 mmol), acetic acid (120 mg, 2.0 mmol), and stirred at room temperature for 10 min. Sodium cyanoborohydride (302 mg, 4.8 mmol) was added, and the reaction was stirred at room temperature for 2 h. The reaction was poured into ice water, and extracted with EtOAc. The organic phase was washed with water, brine, dried, and concentrated. The crude product was purified by column chromatography to give intermediate 95-3 (271 mg, 31%).

[0273] Step 3: The synthesis was performed according to the procedure described in Example 12, Step 2.

[0274] Compound 101: MS: 612.4 (M+1).

[0275] Example 16: Synthesis of compounds 100, 102, 103

[0276] The synthesis of compounds 100, 102, 103 was performed according to the procedure described for compound 101, as described in Table 7:

[0277] Table 7

[0278]

[0279]

[0280] Example 17: Synthesis of compound 105

[0281]

[0282] Step 1: The starting material 105-1 (4.414 g, 16.10 mmol), triphenylphosphine (6.33 g, 24.13 mmol) and benzyl hydroxyacetate (2.51 mL, 17.7 mmol) were dissolved in anhydrous tetrahydrofuran (180 mL) and diisopropyl azodicarboxylate (3.49 mL, 17.7 mmol) was added slowly at 0 °C. After stirring for 5 min, the reaction was allowed to warm to room temperature and stirred overnight. The reaction was poured into ice water and extracted with dichloromethane. The organic phase was washed with water, brine, dried, and concentrated. The crude product was purified by column chromatography to give intermediate 105-2 (4.1 g, 60%).

[0283] Step 2: Intermediate 105-2 (4.1 g, 9.71 mmol) was dissolved in 5:2 ethyl acetate / dichloromethane (200 mL) and 10% Pd / C (460 mg) was added and the reaction was stirred under hydrogen for 3 hours. TLC showed the reaction was complete and methanol (200 mL) was added and the product was dissolved by heating to reflux. The Pd / C was removed by filtration and washed with hot methanol. The organic phase was concentrated to give intermediate 105-3 (3.23 g 100%).

[0284] Step 3: Intermediate 105-3 (1.0 g, 3.0 mmol), 1-(2-azidoethyl)piperazine (620 mg, 4.0 mmol), DIPEA (1.03 g, 8.0 mmol) were dissolved in dry DMF (25 mL) and HATU (1.9 g, 5.0 mmol) was added at RT and the reaction was stirred overnight. The reaction was poured into ice water and extracted with EtOAc. The organic phase was washed with water, brine, dried and concentrated. The crude product was purified by column chromatography to give intermediate 105-4 (720 mg, 51%).

[0285] Step 3: The synthesis was carried out as described in Example 10, step 2.

[0286] Compound 105: MS: 642.4 (M+1).

[0287] Example 18: Synthesis of compounds 104, 106

[0288] The synthesis of compounds 104, 106 was carried out as for compound 105 as described in Table 8:

[0289] Table 8:

[0290]

[0291] Example 19: Synthesis of compound 108

[0292]

[0293] Step 1: Lenalidomide (780 mg, 3.0 mmol), N-Cbz-aminoacetaldehyde (770 mg, 4 mmol) were dissolved in dry DMF (25 mL) and heated to 80 degrees and stirred for 6 hours. The reaction was then cooled to RT and sodium borohydride (190 mg, 5 mmol) was added in portions and stirred for 30 minutes. The reaction was poured into ice water and extracted with ethyl acetate. The organic phase was washed with water, brine, dried and concentrated. The crude product was purified by column chromatography to give intermediate 108-2 (360 mg, 27%).

[0294] Step 2: The synthesis was carried out as described in Example 10, step 2.

[0295] Compound 108, MS: 501.3 (M+1).

[0296] Example 20: Synthesis of compound 107, 133

[0297] The synthesis of compound 107, 133 was performed as described for compound 108, as described in Table 9:

[0298] Table 9:

[0299]

[0300] Example 21: Synthesis of compound 109

[0301]

[0302] Step 1: Intermediate 109-3 (340 mg, 25%) was obtained by dissolving starting material 109-1 (830 mg, 3 mmol), starting material 109-2 (1.0 g, 5 mmol), DIPEA (775 mg, 6 mmol) in anhydrous NMP (20 ml) and heating at 90 degrees overnight. The reaction was poured into ice water and extracted with EtOAc. The organic phase was washed with water, brine, dried, concentrated. The crude product was separated by column chromatography.

[0303] Step 2: The synthesis was performed as described in Example 10, step 2.

[0304] Compound 109, MS: 627.5 (M+1).

[0305] Example 22: Synthesis of compound 125

[0306] The synthesis of compound 125 was performed as described for compound 109, as described in Table 10:

[0307] Table 10:

[0308]

[0309] Example 23: Molecular level experiments of compounds 1-67, 71-94, 100-158 or salts thereof targeting LC3B at the molecular level

[0310] By constructing a prokaryotic expression system, we successfully expressed and purified LC3B protein, and established a preliminary screening and verification platform using fluorescence polarization experiment to determine the activity of purchased and synthesized small compound library. Recombinant protein GST-LC3B (final concentration 180 nM) (SEQ ID NO: 1) and N-terminal FITC labeled peptide (SEQ ID NO: 2, final concentration 18 nM) were placed in FP buffer (50 mM HEPES pH 7.5, 0.1 mg / ml BSA and 1 mM DTT), and then the compound was added to the above mixture using FP buffer for continuous gradient dilution, and then the above mixture was incubated at 25°C in the dark. The fluorescence polarization value (PerkinElmer Envision, emission wavelength 480 nm; absorption wavelength 535 nm) was monitored, and the IC 50 values were calculated using the GraphPad Prism 6.0 program, and the test results are shown in Table 11.

[0311] Table 11 summarizes the inhibition activity data of the example compounds on LC3B (wherein 1 mM ≥ IC 50 > 100 μM is considered to have low activity on LC3B (+); 15 μM < IC 50 ≤ 100 μM is considered to have moderate activity on LC3B (++); 3 μM < IC 50 ≤ 15 μM is considered to have high activity on LC3B (+++); IC 50 ≤ 3 μM is considered to have high activity on LC3B (+++))

[0312] Table 11

[0313]

[0314] Example 24 Inhibition of the proliferation of tumor cells by compounds 1-68, 71-94, 100-158 or salts thereof

[0315] The proliferation inhibition effects of compounds 1-68, 71-94, 100-158 on lymphoma, multiple myeloma, leukemia, lung cancer, breast cancer, pancreatic cancer and other tumor cells were investigated. Different cell lines were cultured in a 37°C, 5% CO2 incubator using the corresponding complete medium. After cell counting, 2000-10000 cells / 100ul were inoculated in a 96-well plate according to the cell volume and growth rate, and then the suspension cells were treated with drugs, and the adherent cells were treated with drugs after adhering. The CellTiter-Glo method was used to detect the change in cell viability after 72 hours of drug treatment, and the cell survival rate at different concentrations was calculated. The calculation formula is: survival rate (%) = (drug well RLU-blank well RLU) / (control well RLU-blank well RLU) x 100.

[0316] Method for expressing the tumor cell proliferation inhibitory activity of the compound: the tumor cell proliferation inhibitory activity of the compound is evaluated according to the cell survival rate at the concentration of 50 μM of the compound, and is considered to be low (+) when 60≤ survival rate (%) < 90, to be moderate (++) when 30 > survival rate (%)≤ 60, and to be high (+++) when survival rate (%)≤ 30. The test results are shown in Table 12, and the compounds of the present application have different degrees of proliferation inhibitory effects on the aforementioned various tumor cells.

[0317] Table 12: Tumor cell proliferation inhibitory activity of compounds 1-67, 71-94, 100-158 or salts thereof

[0318] Compound SU-DHL6 RPMI-8226 K562 A549 MDA-MB-453 BxPC-31 +++++++++++++++++ 2 ++++++++++++++ 3 ++++++++++ 4 ++++++++++ 5 +++++++++++ 6 ++++ 7 +++++++++++++ 8 +++++++++++ 9 +++++++++++ 10 ++++++++++ 11 +++++++++ 12 ++++ 13 +++++++++++++ 14 ++++++++++++ 15 +++++++++++ 16 +++++++++ 17 ++++++++++ 18 +++++++++ 19 +++++++++++ 20 ++++++++++ 21 +++++++++ 22 +++++++++ 23 ++++++++++++++++ 24 ++++++++++++ 25 +++

[0319] 26++++++27++++++++++++++++28+++++++++++++++++29++++++++++++++++30++++++++++++++++31++++++++++++++++32+++++++++++++++33++++++++++++++++34++++++++++++35++++++++++++++++36+++++++++37++++++++++38+++++++++++++++++39++++++++++++40+++++++++++41++++++++++42+++++++++43++++++++++++44++++++++++++++45++++++46++++++++++++47+++++++++++48++++++++++++++++49++++ +++++50+++++++++51++++++++52++++++++++++53+++++++++++++++54++++++++++++++55++++++++++++56++++++++++++57++++++++58+++++++59+++++++++++++++60++++++ +++61+++++++++62+++++++++++++63++++++++++64++++++++ ++++65++++++++++++++++66+++++++++++++67+++++++++++++++71++++++++++++++++

[0320] 72++++++++++73++++++++++++++74++++++75++++++++++++++++76++++++++++++ ++77++++++++++++78++++++++++++79++++++++++80+++++++++++++81+++++++++++++82+++++++++++83+++++++84++++++++++++++85++++++++++86+++++++++++++87++++++++++++++88+++++++++++++89++++++++++++90++++++++++++++91+++++++++++92+++++++++++93+++++++++++++94++++++++++++++++100+++++++++++++101++++++++++++++102+++++++++++++++103++++++++++++104+++++++++++++++++105++++++++++106++++++++++107+++++++++++++108++++++++++++109+++++++++++110++++++++++111++++++++++++++112++++++++++113+++++++++++114+++++++++115+++++++++++116+++++++++++117+++++++++118+++++++119+++++++++++

[0321] 120++++++++++121++++++++++++122++++++++++123++++++++++++++++124+++++++++125+++++++++++++126+++++++++127++++++++128++++++++++++++++129+++++++++++130++++++++++++++131++++++ ++++132++++++++++++133++++++++134+++++++++135++++++++++++++136++++++ ++++137++++++++++++138++++++++++++++139++++++++++++++140++++++++++++++++141++++++++++++++142++++++++++++++143++++++++++++++144++++++++++++++145++++++++++++++146++++++++++++++147++++++++++++++++148++++++++++++++149++++++++++++++150++++++++++++++151++++++++++++++152++++++++++++++++153++++++++++++++154++++++++++++++155++++++++++++++156++++++++++++++157++++++++++++++++158++++++++++++++

[0322] Example 25 Pharmacodynamic study of Compound 1 in a xenograft tumor mouse model of multiple myeloma

[0323] The in vivo anti-tumor efficacy of Compound 1, lenalidomide, dexamethasone, and Compound 1 or lenalidomide in combination with dexamethasone was evaluated in a human multiple myeloma RPMI8226 cell xenograft tumor model.

[0324] The experimental animals were female CB17 SCID mice. Human-derived RPMI8226 cells were cultured in RPMI1640 medium containing 10% heat-inactivated fetal bovine serum and 1% penicillin-streptomycin double antibiotic at 37°C in a 5% CO2 incubator. When the cells were in the exponential growth phase, the cells were harvested, counted, and subcutaneously inoculated into the right back of each mouse. When the average tumor volume reached about 150 mm3, the animals were grouped and dosed. The grouping method was as follows: the animals were weighed and the tumor volume was measured before dosing. The animals were grouped according to the tumor volume using a block design. The dosing regimen is shown in Table 13. 3 Table 13: Dosing regimen of Compound 1, lenalidomide, dexamethasone, and Compound 1 or lenalidomide in combination with dexamethasone in a human multiple myeloma RPMI8226 cell xenograft tumor model.

[0325] Tumor growth inhibition was investigated. The tumor diameters were measured with vernier caliper. The tumor volume was calculated by the formula: V = 0.5 x a x b 2 , where a and b represent the long diameter and short diameter of the tumor, respectively. The tumor inhibition effect of the compound was evaluated by T / C (%). T / C (%) = T RTV / C RTV x 100% (T RTV : RTV of treatment group; C RTV : RTV of negative control group). The relative tumor volume RTV was calculated by RTV = V t / V0. Where V0 is the tumor volume measured at the time of grouping (i.e. day 0), and V t is the tumor volume at each measurement. The percentage value of T / C (%) reflects the tumor growth inhibition rate. The tumor weight effect was evaluated by TGI (%), and the tumor weight inhibition rate (TGI) % = (TWc-TW T ) / TWc x 100%, TWc: tumor weight of control group, TW T : tumor weight of treatment group. The body weight of tumor-bearing mice in each group was recorded and the results are shown in Figures 1 and 2 and Table 14. The effect of the compound on the tumor volume of tumor-bearing mice is shown in Figures 3 and 4 and Table 15.

[0326] The results show that the compound Compound 1 does not affect the body weight of tumor-bearing mice during the entire administration period (the decrease in body weight in the combination group with dexamethasone is due to dexamethasone). The tumor inhibition effect of Compound 1 at a dose of 17.7 mg / kg (which is 1 / 3 of the molar dose of lenalidomide) is comparable to that of lenalidomide at a dose of 30 mg / kg. When the dose of Compound 1 is 53 mg / kg (which is the same molar dose as lenalidomide), its tumor inhibition effect is significantly stronger than that of lenalidomide. Meanwhile, in the combination group with dexamethasone, Compound 1 also shows a stronger tumor inhibition effect than lenalidomide. Therefore, the compound has a significant in vivo anti-tumor efficacy in the human multiple myeloma RPMI8226 cell xenograft tumor model, and the efficacy is stronger than that of the marketed drug lenalidomide.

[0327] Table 13 Grouping of animals and administration scheme for in vivo efficacy experiment

[0328]

[0329] p.o: by gavage

[0330] i.p: intraperitoneal injection

[0331] Table 14 Body weight of tumor-bearing mice in each group

[0332]

[0333] p.o: oral administration i.p: intraperitoneal administration

[0334] Note: *Relative change in body weight (RCBW) reflects the impact of the drug on the animal's body weight. The time of the first administration is defined as day 1 and RCBW (%) is calculated from the body weight at the time of grouping on day 1. Formula: RCBW (%) = (body weight on a given day of administration - body weight on day 1 of administration) / body weight on day 1 of administration x 100%

[0335] Table 15 Effect of test compounds on tumor volume in RPMI8226 tumor-bearing mice

[0336]

[0337] Note: # T / C% = T RTV / C RTV *100% (T RTV : treated group RTV; C RTV : negative control group RTV, RTV = Vt / V1. Where V1 is the tumor volume measured at the time of grouping (i.e. day 1) and Vt is the tumor volume at each measurement.

Claims

1. A compound of the following general formula (I) or a pharmaceutically acceptable salt thereof, Ar-L(-X)p (I) wherein, p is 1, 2 or 3; Ar is an isoindolinone-imide group represented by the general formula (II), wherein one of A and B is C═O and the other is C═O or CH2; R1 is selected from hydrogen, deuterium, halogen, and C1-C4 alkyl; One of R6, R7, R8 and R9 is a divalent group selected from O, S, SO2, and NH, which is connected to L or directly to X, and the remaining three of R6, R7, R8 and R9 are each independently selected from hydrogen, deuterium, halogen, C1-C4 alkyl, unsubstituted or substituted phenyl, and unsubstituted or substituted 5-10 membered heteroaryl; and R 10 is hydrogen; Alternatively, each of R6, R7, R8, and R9 is independently selected from hydrogen, deuterium, halogen, C1-C4 alkyl, unsubstituted or substituted phenyl, unsubstituted or substituted 5-10 membered heteroaryl, and NR b1 R b’ , where R b1 and R b’ are each independently selected from hydrogen, C1-C4 alkyl, unsubstituted or substituted phenyl, and unsubstituted or substituted 5-10 membered heteroaryl; R 10 is absent, and the nitrogen atom linked to R 10 is directly linked to L or X; L is absent or is a divalent, trivalent or tetravalent linking group; and when L is absent or is a divalent linking group, p is 1; when L is a trivalent linking group, p is 2; when L is a tetravalent linking group, p is 3; when p is 2 or 3, the two or three Xs linked by L are the same or different; X is a group represented by the general formula (III): wherein, R2 is selected from hydrogen, deuterium, halogen, C1-C6 alkyl, unsubstituted or substituted phenyl and unsubstituted or substituted 5-10-membered heteroaryl; W and T are each independently absent, -C(R a1 )(R a1’ )-, -C(R a1 )(R a1’ )C(R a2 )(R a2’ ))-, -O-, -S- or -NR a3 -; wherein R a1 , R a1 ’, R a2 , R a2 ’, and R a3 are each independently hydrogen, deuterium, hydroxy, amino, halogen, CN, CO2R a4’ , CONR a5 R a5‘ , C1-C6 alkyl, C1-C10 heteroalkyl, C2-C4 alkenyl, C2-C4 alkynyl, unsubstituted or substituted -CONH-(C6-C10) aryl, unsubstituted or substituted -CH=CH-(C6-C10) aryl, unsubstituted or substituted C6-10 aryl, unsubstituted or substituted 5-10 membered heteroaryl, unsubstituted or substituted C3-10 cycloalkyl, unsubstituted or substituted 3-10 membered heterocycloalkyl, unsubstituted or substituted 3-7 membered heterocycloalkenyl, unsubstituted or substituted C6-C10 aryl C1-C6 alkyl, unsubstituted or substituted C1-C6 alkyl C6-C10 aryl, unsubstituted or substituted 5-10 membered heteroaryl C1-6 alkyl or unsubstituted or substituted C1-C6 alkyl 5-10 membered heteroaryl; Z is selected from N, O or CR d ; wherein R d is hydrogen, deuterium, halogen, C1-C4 alkyl or C6-C12 aryl; and when Z is O, R3 does not exist; R3 is selected from hydrogen, deuterium, hydroxyl, amino, halogen, CN, CO2R e1’ , CONR e2 R e2‘ , C1-C6 alkyl, C1-C10 heteroalkyl, C2-C4 alkenyl, C2-C4 alkynyl, -O(C6-C10) aryl, unsubstituted or substituted -S(C6-C10) aryl, unsubstituted or substituted -NH(C6-C10) aryl, unsubstituted or substituted -NHC(=O)(C6-C10) aryl, unsubstituted or substituted -CONH-(C6-C10) aryl, unsubstituted or substituted -CH=CH-(C6-C10) aryl, unsubstituted or substituted C6-10 aryl, unsubstituted or substituted 5-10 membered heteroaryl, unsubstituted or substituted C3-C10 cycloalkyl, unsubstituted or substituted 3-10 membered heterocycloalkyl, unsubstituted or substituted 3-7 membered heterocycloalkenyl, unsubstituted or substituted C6-C10 aryl C1-C6 alkyl, unsubstituted or substituted C1-C6 alkyl C6-C10 aryl, unsubstituted or substituted 5-10 membered heteroaryl C1-C6 alkyl or unsubstituted or substituted C1-C6 alkyl 5-10 membered heteroaryl; R3 can be linked with adjacent W, T to form an unsubstituted or substituted C6-C10 aryl, unsubstituted or substituted 5-10 membered heteroaryl, 5-10 membered cycloalkyl or 5-10 membered heterocycloalkyl; R e1 , R e1’ and R e2’ are each independently hydrogen, hydroxyl, C1-C6 alkyl; Q is absent, O, N(R f ), S or SO2, where R f is selected from hydrogen or C1-C4 alkyl; "Unsubstituted or substituted" means that the group is unsubstituted or substituted by one or more substituents selected from hydroxy, amino, cyano, nitro, carboxy, halogen, C1-C6 alkyl, C1-C6 haloalkyl and C1-C6 hydroxyalkyl; represents connection from this position.

2. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein, Ar is a group represented by the general formula (IIa): wherein: B is C═O or CH2; R1 is selected from hydrogen, deuterium, halogen and C1-C4 alkyl; R 10 is H, Y1 is NH or O, and is connected to L or directly to X; Or R 10 Does not exist, R 10 The connected N is directly connected to L or directly connected to X; Y1 is H, NH2 or halogen; or Ar is selected from the following groups: represents connection from this position.

3. The compound or a pharmaceutically acceptable salt thereof according to claim 1 or 2, wherein, X is selected from the groups represented by the following general formulas (IIIa) and (IIIb): wherein: R2 is selected from hydrogen, deuterium, halogen, C1-C4 alkyl, and unsubstituted or substituted phenyl; Q is selected from absent, NH and O; W is selected from CR g1 R g1’ , O, NR g2 ; wherein R g1 , R g1’ and R g2 are each independently hydrogen, C1-C6 alkyl, CO2R g3 or CONR g4 R g4’ ; R g3 , R g4 and R g4’ are each independently hydrogen or C1-C6 alkyl; R3 is selected from unsubstituted or substituted -CONH-(C6-C10) aryl, -CO2-(C6-C10) aryl, unsubstituted or substituted -CH═CH-(C6-C10) aryl, unsubstituted or substituted C6-C10 aryl, unsubstituted or substituted 5-10-membered heteroaryl, unsubstituted or substituted C3-C10 cycloalkyl, unsubstituted or substituted 3-10-membered heterocycloalkyl, unsubstituted or substituted 3-7-membered heterocycloalkenyl, unsubstituted or substituted C1-C6 alkyl C6-C10 aryl, unsubstituted or substituted -O(C6-C10) aryl, unsubstituted or substituted -S(C6-C10) aryl, unsubstituted or substituted -NH(C6-C10) aryl, unsubstituted or substituted -NHC(═O)(C6-C10) aryl, or unsubstituted or substituted C1-C6 alkyl 5-10-membered heteroaryl; Z is selected from C and N; e3 Re3 is selected from hydrogen, C1-C6 alkyl, C1-C10 heteroalkyl, C2-C4 alkenyl, C2-C4 alkynyl, and unsubstituted or substituted C6-10 aryl; Ring C is unsubstituted or substituted C6-C10 aryl, or unsubstituted or substituted 5-10-membered heteroaryl; "Unsubstituted or substituted" means that the group is unsubstituted or substituted by one or more substituents selected from hydroxy, amino, cyano, nitro, carboxy, halogen, C1-C6 alkyl, C1-C6 haloalkyl and C1-C6 hydroxyalkyl; represents connection from this position.

4. The compound according to claim 1 or 3, or a pharmaceutically acceptable salt thereof, wherein, R3 is selected from the following groups: wherein, X1 is hydrogen, halogen or CF3; X2 is hydrogen, halogen or CF3; R c1 、R c2 、R c3 、R c4 、R c5 and R c6 are each independently selected from hydrogen, deuterium, hydroxy, halogen, cyano, nitro, formyl, CO₂R h , CONR h1 R h1’ , NR h2 R h2’ , C₁-C₄ alkyl, C₁-C₁₀ heteroalkyl, C₂-C₄ alkenyl, C₂-C₄ alkynyl, unsubstituted or substituted C₆-₁₀ aryl, unsubstituted or substituted 5-10-membered heteroaryl, unsubstituted or substituted C₃-C₁₀ cycloalkyl, unsubstituted or substituted 3-10-membered heterocycloalkyl, unsubstituted or substituted 3-7-membered heterocycloalkenyl, unsubstituted or substituted C₆-C₁₀ aryl C₁-C₆ alkyl, unsubstituted or substituted C₁-C₆ alkyl C₆-C₁₀ aryl, unsubstituted or substituted 5-10-membered heteroaryl C₁-C₆ alkyl, and unsubstituted or substituted C₁-C₆ alkyl 5-10-membered heteroaryl; wherein R h , R h1 , R h1’ , R h2 and R h2’ are each independently selected from hydrogen and C₁-C₄ alkyl; or R c1 and R c2 or R c2 and R c3 or R c3 and R c4， or R c5 and R c6 together with the ring atoms on the ring connected thereto form an unsubstituted or substituted C6-C10 aryl group, or an unsubstituted or substituted 5- to 10-membered heteroaryl group; "Unsubstituted or substituted" means that the group is unsubstituted or substituted by one or more substituents selected from hydroxy, amino, cyano, nitro, carboxy, halogen, C1-C6 alkyl, C1-C6 haloalkyl and C1-C6 hydroxyalkyl; or, R3 is selected from the following groups: and H, Indicates connection from this point.

5. The compound according to any one of claims 1, 3 and 4, or a pharmaceutically acceptable salt thereof, wherein X is selected from the following groups: wherein, Indicates connection from this point.

6. The compound according to any one of claims 1 - 5, or a pharmaceutically acceptable salt thereof, wherein, L does not exist, or is a divalent group represented by the general formula (IV) or a trivalent group represented by the general formula (V): Wherein, J and M are each independently absent, NR i , O, S, SO2, C(=O) or C(=S), where R i is hydrogen, C1-C4 alkyl or C6-C10 aryl; K is absent, C1-C10 alkylene, C3-C10 cycloalkylene, C1-C6 heteroalkylene, C2-C6 alkenylene, C2-C6 alkynylene, unsubstituted or substituted C6-C10 arylene, unsubstituted or substituted 5-10 membered heteroarylene, unsubstituted or substituted C3-C8 cycloalkylene, unsubstituted or substituted 3-10 membered non-aromatic heterocyclic group, a sub-peptide group composed of 2-8 identical or different amino acids, or a free combination of two, three or four groups that are the same or different; K1 is a trivalent group selected from C1-C10 alkyl, C3-C10 cycloalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, unsubstituted or substituted C6-C10 aryl, unsubstituted or substituted 5-10 membered heteroaryl, unsubstituted or substituted C3-C8 cycloalkyl, unsubstituted or substituted 3-10 membered non-aromatic heterocyclic group, a peptide group composed of 2-8 identical or different amino acids, and a free combination of two, three or four groups that are the same or different; "Unsubstituted or substituted" means that the group is unsubstituted or substituted by one or more substituents selected from hydroxyl, amino, cyano, nitro, carboxyl, halogen, C1-C6 alkyl, C1-C6 haloalkyl and C1-C6 hydroxyalkyl; Preferably, the divalent or trivalent groups represented by the above general formulas (IV) and (V) are selected from the following groups and combinations between the following same or different groups: Wherein, m and n are each independently 0, 1, 2, 3, 4 or 5; X b 、 X c 、 X h and X i each independently is absent, O, S or NH; R 22 、R 23 、R 24 、R 25 、R 26 、R 27 、R 29 、R 32 、R 33 and R 34 each independently is absent, a C1-C10 alkylene group, a C3-C10 cycloalkylene group, a C1-C6 heteroalkylene group, a C2-C6 alkenylene group, a C2-C6 alkynylene group, an unsubstituted or substituted C6-C10 arylene group, an unsubstituted or substituted 5-10 membered heteroarylene group, an unsubstituted or substituted C3-C8 cycloalkylene group, an unsubstituted or substituted 3-10 membered non-aromatic heterocyclic group, or a free combination of two, three or four groups which are the same or different; R 30 and R 31 each independently is H, C1-C10 alkyl, C3-C10 cycloalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, unsubstituted or substituted C6-C10 aryl, unsubstituted or substituted 5-10 membered heteroaryl, unsubstituted or substituted C3-C8 cycloalkyl, unsubstituted or substituted 3-10 membered non-aromatic heterocyclic group, or two, three or four groups which are the same or different are freely combined; Ar1 and Ar2 are each independently unsubstituted or substituted C6-C10 arylene, or unsubstituted or substituted 5-10 membered heteroarylene; The D and E rings are each independently an unsubstituted or substituted 3-10 membered nitrogen-containing heterocycle; "Unsubstituted or substituted" means that the group is unsubstituted or substituted by one or more hydroxyl, amino, cyano, nitro, carboxyl, halogen, C1-C6 alkyl, C1-C6 haloalkyl or C1-C6 hydroxyalkyl; Preferably, the divalent and trivalent groups represented by the above general formulas IV and V are selected from the following groups: Terminal link Ar, Terminal linking fragment X.

7. The compound according to any one of claims 1-6 or a pharmaceutically acceptable salt thereof, wherein, The compound is selected from the compounds represented by the following general formulas (VI), (VII), (VIII), (IX), (X) and (XI): Wherein, A, B, R1, R2, R3, Q, L, W, T, Z are the same as defined in the corresponding claims; Y2 is H, NH2 or halogen; Y3 is NH or O.

8. The compound according to any one of claims 1-7 or a pharmaceutically acceptable salt thereof, wherein, The compound is selected from:

9. A pharmaceutical composition comprising the compound according to any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof, and optionally a pharmaceutical excipient.

10. Use of the compound according to any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof for the preparation of an autophagy regulator, particularly a regulator of mammalian ATG8 homologs, for the preparation of a medicament for preventing or treating a disease associated with cellular autophagy, said disease associated with cellular autophagy being selected from the group consisting of tumors, cancers, cardiovascular diseases, autoimmune diseases, neurodegenerative diseases, hypertension, bone tissue and bone diseases, Crohn's disease, acute kidney injury, cerebral ischemia, retinal diseases, bronchial asthma, Vici syndrome, amyotrophic lateral sclerosis, and infectious diseases, said cancers being selected from the group consisting of liver cancer, lung cancer, pancreatic cancer, breast cancer, cervical cancer, endometrial cancer, colorectal cancer, gastric cancer, lung cancer, nasopharyngeal cancer, ovarian cancer, prostate cancer, leukemia, lymphoma, myeloma, preferably selected from the group consisting of lymphoma, multiple myeloma, leukemia, lung cancer, breast cancer, and pancreatic cancer.

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