Novel protein degrader and antibody-protein degrader conjugate

Abstract

A novel protein degrader and an antibody-protein degrader conjugate. Specifically, the present invention relates to compounds represented by general formula (1) and a preparation method therefor, and the use of the compounds of general formula (1) and isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates thereof as protein degraders.

Description

Novel protein degraders and antibody-protein degrader conjugates

[0001] This application claims priority to Chinese patent application No. 202410140237.3, filed on January 31, 2024. This application incorporates the entire text of the aforementioned Chinese patent application. Technical Field

[0002] The present invention belongs to the field of medicinal chemistry, and more specifically, relates to a class of GSPT1 protein degraders, a preparation method thereof, and the use of such compounds in preparing drugs for treating or preventing blood cancers and solid tumors. Background Art

[0003] The success of immunomodulatory drugs (IMiDs) such as lenalidomide has established protein degradation as an effective therapeutic strategy. These drugs, acting as molecular glues, can form stable ternary complexes with the ubiquitin E3 ligase substrate adaptor cereblon (CRBN) and ubiquitinated substrate proteins, thereby promoting protein ubiquitination and degradation. Lenalidomide inhibits cancer cell proliferation and regulates immunity by degrading various proteins, including Aiolos and Ikaros. Molecular glues such as lenalidomide have achieved significant success as treatments for multiple myeloma. Currently, much research and effort is focused on identifying new molecular glues to degrade other pathogenic proteins, particularly undruggable targets.

[0004] GSPT1 (G1 to S Phase Transition 1) is a translation termination factor that recognizes stop codons by binding to eRF1 and allows the protein to separate from the ribosome after translation. GSPT1 is abnormally expressed in a variety of tumor cells and is closely associated with the occurrence and progression of many common malignancies, such as acute myeloid leukemia (AML), breast cancer, gastric cancer, and colorectal cancer. Degradation of GSPT1 protein can inhibit tumor cell proliferation or induce tumor cell apoptosis. Therefore, small molecule degraders of GSPT1 have the potential to treat a variety of malignant tumors. However, existing GSPT1 degraders have poor selectivity for normal cells and high on-target toxicity, and to date, no drugs have been approved for marketing. Summary of the Invention

[0005] The present invention unexpectedly discovered a class of GSPT1 molecular glue degraders that are selective for normal cells. These compounds possess sufficient protein degradation activity, allowing for development as small-molecule GSPT1 degraders. Furthermore, their structures contain chemical functional groups suitable for antibody coupling, allowing for convenient preparation into antibody-protein degrader conjugates. The conjugation of antibodies and GSPT1 protein degraders combines the specificity of antibodies for tumor cell surface antigen binding with the inhibitory and cytotoxic effects of GSPT1 degraders, further enhancing the drug's selectivity for normal cells and reducing its toxicity.

[0006] Specifically, the present invention provides a compound represented by general formula (1) or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates:

[0007] In the general formula (1):

[0008] R is selected from Where * represents that the end is connected to ring A;

[0009] Ring A is (C6-C14)aryl, (5-14 membered)heteroaryl or (C3-C14)cycloalkyl;

[0010] Ring B is (C6-C14)arylene, (5-14 membered)heteroarylene or (C3-C14)cycloalkylene;

[0011] U is optionally a chemical bond, -NR 15 - or (C1-C8)alkylene, wherein the (C1-C8)alkylene may be substituted by 1, 2, 3, 4, 5 or 6 halogen, (C1-C8)alkyl, (C1-C8)alkoxy, (C1-C8)haloalkyl, (C1-C8)haloalkoxy, (C3-C14)cycloalkyl or (3-14 membered)heterocycloalkyl, or two substituents on the same carbon atom of the (C1-C8)alkylene and the carbon atom to which they are attached form a (C3-C10)cycloalkyl or (3-10 membered)heterocycloalkyl;

[0012] X is optionally -OH, -SH or -NHR 16 ;

[0013] V is optionally a chemical bond, -O-, -S- or -NR 17 -;

[0014] W is optionally a chemical bond, -O-, -S- or -NR 18 -;

[0015] G is optionally a chemical bond, -O-, -S- or -NR 19 -;

[0016] T is optionally a chemical bond, -O-, -S- or -NR 20 -;

[0017] Q is optionally a chemical bond, -O-, -S- or -NR 21 -;

[0018] Each R 1 R is independently optionally hydrogen, deuterium, halogen, cyano, nitro, (C1-C8) alkyl, (C1-C8) haloalkyl, (C1-C8) alkoxy, (C3-C14) cycloalkyl, (3-14 membered) heterocycloalkyl, (C6-C14) aryl or (5-14 membered) heteroaryl, wherein said (C1-C8) alkyl, (C1-C8) haloalkyl, (C1-C8) alkoxy, (C3-C14) cycloalkyl, (3-14 membered) heterocycloalkyl, (C6-C14) aryl or (5-14 membered) heteroaryl can be independently optionally replaced by 1, 2, 3, 4, 5 or 6 R a replace;

[0019] R a each independently represents hydrogen, deuterium, halogen, cyano, nitro, (C1-C8)alkyl, (C1-C8)haloalkyl, (C1-C8)alkoxy, (C1-C8)haloalkoxy, (C3-C14)cycloalkyl, (3-14 membered)heterocycloalkyl, (C6-C14)aryl, or (5-14 membered)heteroaryl;

[0020] Each R 2 R is independently optionally hydrogen, deuterium, halogen, cyano, nitro, (C1-C8) alkyl, (C1-C8) haloalkyl, (C1-C8) alkoxy, (C3-C14) cycloalkyl, (3-14 membered) heterocycloalkyl, (C6-C14) aryl or (5-14 membered) heteroaryl, wherein said (C1-C8) alkyl, (C1-C8) haloalkyl, (C1-C8) alkoxy, (C3-C14) cycloalkyl, (3-14 membered) heterocycloalkyl, (C6-C14) aryl or (5-14 membered) heteroaryl can be independently optionally replaced by 1, 2, 3, 4, 5 or 6 R b replace;

[0021] R b each independently represents hydrogen, deuterium, halogen, cyano, nitro, (C1-C8)alkyl, (C1-C8)haloalkyl, (C1-C8)alkoxy, (C1-C8)haloalkoxy, (C3-C14)cycloalkyl, (3-14 membered)heterocycloalkyl, (C6-C14)aryl, or (5-14 membered)heteroaryl;

[0022] Each R 3 independently selected from hydrogen, deuterium, halogen, cyano, nitro, -ORc , (C1-C8)alkyl, (C1-C8)haloalkyl, (C1-C8)alkoxy, (C3-C14)cycloalkyl, (3-14-membered)heterocycloalkyl, (C6-C14)aryl or (5-14-membered)heteroaryl, wherein said (C1-C8)alkyl, (C1-C8)haloalkyl, (C1-C8)alkoxy, (C3-C14)cycloalkyl, (3-14-membered)heterocycloalkyl, (C6-C14)aryl or (5-14-membered)heteroaryl can each independently be optionally substituted by 1, 2, 3, 4, 5 or 6 R c replace;

[0023] R c each independently represents hydrogen, deuterium, halogen, cyano, nitro, (C1-C8)alkyl, (C1-C8)haloalkyl, (C1-C8)alkoxy, (C1-C8)haloalkoxy, (C3-C14)cycloalkyl, (3-14 membered)heterocycloalkyl, (C6-C14)aryl, or (5-14 membered)heteroaryl;

[0024] Each R 4 independently selected from hydrogen, deuterium, halogen, cyano, nitro, -OR d , (C1-C8)alkyl, (C1-C8)haloalkyl, (C1-C8)alkoxy, (C3-C14)cycloalkyl, (3-14-membered)heterocycloalkyl, (C6-C14)aryl or (5-14-membered)heteroaryl, wherein said (C1-C8)alkyl, (C1-C8)haloalkyl, (C1-C8)alkoxy, (C3-C14)cycloalkyl, (3-14-membered)heterocycloalkyl, (C6-C14)aryl or (5-14-membered)heteroaryl can each independently be optionally substituted by 1, 2, 3, 4, 5 or 6 R d replace;

[0025] R d each independently represents hydrogen, deuterium, halogen, cyano, nitro, (C1-C8)alkyl, (C1-C8)haloalkyl, (C1-C8)alkoxy, (C1-C8)haloalkoxy, (C3-C14)cycloalkyl, (3-14 membered)heterocycloalkyl, (C6-C14)aryl, or (5-14 membered)heteroaryl;

[0026] R 5 、R 6each independently optionally represents hydrogen, deuterium, (C1-C8)alkyl, (C1-C8)haloalkyl, (C3-C14)cycloalkyl, (3-14 membered)heterocycloalkyl, (C6-C14)aryl, or (5-14 membered)heteroaryl, wherein said (C1-C8)alkyl, (C1-C8)haloalkyl, (C3-C14)cycloalkyl, (3-14 membered)heterocycloalkyl, (C6-C14)aryl, or (5-14 membered)heteroaryl may each independently optionally be replaced by 1, 2, 3, 4, 5, or 6 R e replace;

[0027] R e is optionally hydrogen, deuterium, halogen, cyano, nitro, (C1-C8)alkyl, (C1-C8)haloalkyl, (C1-C8)alkoxy, (C1-C8)haloalkoxy, (C3-C14)cycloalkyl, (3-14 membered)heterocycloalkyl, (C6-C14)aryl or (5-14 membered)heteroaryl;

[0028] Or, R 5 and R 6 The carbon atoms to which they are commonly attached form a (C3-C10) cycloalkyl or (3-10 membered) heterocycloalkyl, wherein the (C3-C10) cycloalkyl or (3-10 membered) heterocycloalkyl may be independently optionally substituted with 1, 2, 3, 4, 5 or 6 R f replace;

[0029] R f is optionally hydrogen, deuterium, halogen, cyano, nitro, (C1-C8)alkyl, (C1-C8)haloalkyl, (C1-C8)alkoxy, (C1-C8)haloalkoxy, (C3-C14)cycloalkyl, (3-14 membered)heterocycloalkyl, (C6-C14)aryl or (5-14 membered)heteroaryl;

[0030] R 7 、R 8 、R 9 、R 10 、R 11 、R 12 、R 13 、R 14 each independently optionally represents hydrogen, deuterium, halogen, cyano, nitro, (C1-C8)alkyl, (C1-C8)haloalkyl, (C1-C8)alkoxy, (C3-C14)cycloalkyl, (3-14-membered)heterocycloalkyl, (C6-C14)aryl, or (5-14-membered)heteroaryl, wherein said (C1-C8)alkyl, (C1-C8)haloalkyl, (C1-C8)alkoxy, (C3-C14)cycloalkyl, (3-14-membered)heterocycloalkyl, (C6-C14)aryl, or (5-14-membered)heteroaryl may each independently optionally be replaced by 1, 2, 3, 4, 5, or 6 Rg replace;

[0031] R g is optionally hydrogen, deuterium, halogen, cyano, nitro, (C1-C8)alkyl, (C1-C8)haloalkyl, (C1-C8)alkoxy, (C1-C8)haloalkoxy, (C3-C14)cycloalkyl, (3-14 membered)heterocycloalkyl, (C6-C14)aryl or (5-14 membered)heteroaryl;

[0032] R 7 and R 8 、R 9 and R 10 、R 11 and R 12 、R 13 and R 14 The carbon atoms connected thereto may independently and optionally form a (C3-C10) cycloalkyl or (3-10 membered) heterocycloalkyl, wherein the (C3-C10) cycloalkyl or (3-10 membered) heterocycloalkyl may be independently and optionally substituted by 1, 2, 3, 4, 5 or 6 R h replace;

[0033] R h is optionally hydrogen, deuterium, halogen, cyano, nitro, (C1-C8)alkyl, (C1-C8)haloalkyl, (C1-C8)alkoxy, (C1-C8)haloalkoxy, (C3-C14)cycloalkyl, (3-14 membered)heterocycloalkyl, (C6-C14)aryl or (5-14 membered)heteroaryl;

[0034] R 15 、R 16 、R 17 、R 18 、R 19 、R 20 、R 21 each independently optionally hydrogen, (C1-C8)alkyl, (C1-C8)haloalkyl, (C3-C14)cycloalkyl, (3-14 membered)heterocycloalkyl, (C6-C14)aryl or (5-14 membered)heteroaryl, wherein said (C1-C8)alkyl, (C1-C8)haloalkyl, (C3-C14)cycloalkyl, (3-14 membered)heterocycloalkyl, (C6-C14)aryl or (5-14 membered)heteroaryl may each independently optionally be substituted by 1, 2, 3, 4, 5 or 6 R i replace;

[0035] R iis hydrogen, deuterium, halogen, cyano, nitro, (C1-C8)alkyl, (C1-C8)haloalkyl, (C1-C8)alkoxy, (C1-C8)haloalkoxy, (C3-C14)cycloalkyl, (3-14 membered)heterocycloalkyl, (C6-C14)aryl or (5-14 membered)heteroaryl;

[0036] a is an integer selected from 0, 1, 2 or 3;

[0037] b is an integer selected from 0, 1 or 2;

[0038] c and d are each independently selected from an integer of 0, 1, 2, 3 or 4;

[0039] m, n, p, q, s are each independently selected from an integer of 0, 1, 2, 3, 4, 5, 6, 7 or 8.

[0040] In another preferred embodiment, wherein in the general formula (1), each R 1 Independently selected are hydrogen, deuterium, halogen, cyano, nitro, (C1-C6) alkyl, (C1-C6) haloalkyl, (C1-C6) alkoxy, (C1-C6) haloalkoxy, (C3-C8) cycloalkyl, and (3-8 membered) heterocycloalkyl.

[0041] In another preferred embodiment, wherein in the general formula (1), R 1 For hydrogen, deuterium, F, Cl, Br, cyano, nitro, -CH3, -CD3, -CF3, -CH2CH3, -CH2CH2CH3, -CH(Me)2, -CH(CF3)2, -C(Me)3, -OMe, -OCF3.

[0042] In another preferred embodiment, wherein in the general formula (1), each R 2 Independently selected are hydrogen, deuterium, halogen, cyano, nitro, (C1-C6) alkyl, (C1-C6) haloalkyl, (C1-C6) alkoxy, (C1-C6) haloalkoxy, (C3-C8) cycloalkyl, and (3-8 membered) heterocycloalkyl.

[0043] In another preferred embodiment, wherein in the general formula (1), R 2 For hydrogen, deuterium, F, Cl, Br, cyano, nitro, -CH3, -CD3, -CF3, -CH2CH3, -CH2CH2CH3, -CH(Me)2, -CH(CF3)2, -C(Me)3, -OMe, -OCF3.

[0044] In another preferred embodiment, wherein in the general formula (1), R 5 、R 6Each is independently selected from hydrogen, deuterium, (C1-C6) alkyl, and (C3-C8) cycloalkyl; s is selected from an integer of 1 or 2.

[0045] In another preferred embodiment, wherein in the general formula (1), R 5 、R 6 Each independently selected from hydrogen, deuterium, -Me, -CD3, -CH2CH3,

[0046] In another preferred embodiment, wherein in the general formula (1), R 5 、R 6 is hydrogen; s is 1.

[0047] In another preferred embodiment, wherein in the general formula (1), R 5 and R 6 The carbon atoms that can be commonly attached thereto independently and optionally form a (C3-C8) cycloalkyl group or a (3-8 membered) heterocycloalkyl group, wherein the (C3-C8) cycloalkyl group or the (3-8 membered) heterocycloalkyl group is replaced by hydrogen, deuterium, F, Cl, Br, cyano, -CH3, -CD3, -CF3, -CH(Me)2, -OMe, -OCF3 substituted.

[0048] In another preferred embodiment, wherein in the general formula (1), R 5 and R 6 The carbon atoms that can be connected to each other independently and optionally form

[0049] In another preferred embodiment, wherein in the general formula (1), U is a chemical bond, -NR 15 -, -CF2-, (C1-C4) alkylene, R 15 is hydrogen, (C1-C3)alkyl or (C3-C6)cycloalkyl.

[0050] In another preferred embodiment, wherein in the general formula (1), U is a chemical bond, -CH2-, -CH2CH2-, -CF2-, -NH-, -C(CH3)2-,

[0051] In another preferred embodiment, in the general formula (1), ring A is a (C6-C14) aryl group, preferably a phenyl group.

[0052] In another preferred embodiment, wherein in the general formula (1), each R 3 independently selected from hydrogen, deuterium, F, Cl, Br, I, cyano, nitro, -OR c, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C3-C8)cycloalkyl, (3-8 membered)heterocycloalkyl, (C6-C14)aryl or (5-14 membered)heteroaryl, wherein the (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C3-C8)cycloalkyl, (3-8 membered)heterocycloalkyl, (C6-C14)aryl or (5-14 membered)heteroaryl The (5-14 membered)heteroaryl or (5-14 membered)heteroaryl groups may each independently be optionally substituted with 1, 2, 3, 4, 5 or 6 of the following groups: hydrogen, deuterium, F, Cl, Br, I, cyano, nitro, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C3-C8)cycloalkyl, (3-8 membered)heterocycloalkyl, (C6-C14)aryl or (5-14 membered)heteroaryl.

[0053] In another preferred embodiment, wherein in the general formula (1), each R 3 independently selected from hydrogen, deuterium, F, Cl, Br, cyano, nitro, -CH3, -CD3, -CF3, -CHF2, -CH2F, -CH2CH3, -CH2CH2CH3, -CH(Me)2, -CH(CF3)2, -C(Me)3, -OMe, -OCF3, -OCF2H, -OCFH2, -OCH2CH3, -OCH2CH2CH3, -OCH(CH3)2, -OCH(CF3)2, -OC(CH3)3, -O(CH2)2OMe, -Ph, -Bn.

[0054] In another preferred embodiment, in the general formula (1), the B ring is a (C6-C14)arylene group, preferably a phenylene group.

[0055] In another preferred embodiment, wherein in the general formula (1), each R 4 independently selected from hydrogen, deuterium, F, Cl, Br, I, cyano, nitro, -OR d, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C3-C8)cycloalkyl, (3-8 membered)heterocycloalkyl, (C6-C14)aryl or (5-14 membered)heteroaryl, wherein the (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C3-C8)cycloalkyl, (3-8 membered)heterocycloalkyl, (C6-C14)aryl or (5-14 membered)heteroaryl The (5-14 membered)heteroaryl or (5-14 membered)heteroaryl groups may each independently be optionally substituted with 1, 2, 3, 4, 5 or 6 of the following groups: hydrogen, deuterium, F, Cl, Br, I, cyano, nitro, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C3-C8)cycloalkyl, (3-8 membered)heterocycloalkyl, (C6-C14)aryl or (5-14 membered)heteroaryl.

[0056] In another preferred embodiment, wherein in the general formula (1), each R 4 independently selected from hydrogen, deuterium, F, Cl, Br, cyano, nitro, -O-(C3-C6)cycloalkyl, (C1-C3)alkyl, (C1-C3)haloalkyl, (C1-C3)alkoxy, (C3-C6)cycloalkyl, (3-6 membered)heterocycloalkyl, wherein said (C1-C3)alkyl, (C1-C3)haloalkyl, (C1-C3)alkoxy, (C3-C6)cycloalkyl, (3-6 membered)heterocycloalkyl The R groups may each be independently optionally substituted with 1, 2, 3, 4, 5 or 6 of the following groups: hydrogen, deuterium, F, Cl, Br, I, cyano, nitro, (C1-C6) alkyl, (C1-C6) haloalkyl, (C1-C6) alkoxy, (C3-C8) cycloalkyl, (3-8 membered) heterocycloalkyl, (C6-C14) aryl or (5-14 membered) heteroaryl; preferably 1, 2, 3, 4, 5 or 6 of hydrogen, deuterium, F; each R 4 are independently preferably hydrogen, deuterium, F, Cl, Br, cyano, nitro, -CH3, -CD3, -CF3, -CHF2, -CH2F, -OMe, -OCF3,

[0057] In another preferred embodiment, wherein in the general formula (1), each R 7 、R 8 、R 9 、R 10 、R 11 、R 12 、R 13 、R 14 m, n, p, q are each independently selected from an integer of 0, 1, 2, 3, 4, 5 or 6.

[0058] In another preferred embodiment, wherein in the general formula (1), each R 7 、R 8 、R 9 、R 10 、R 11 、R 12 、R 13 、R 14 independently selected from hydrogen, deuterium, F, Cl, -Me, -CD3, -CH2CH3,

[0059] In another preferred embodiment, wherein in the general formula (1), R 7 and R 8 、R 9 and R 10 、R 11 and R 12 、R 13 and R 14 The carbon atoms to which they are commonly attached may independently and optionally form a (C3-C6) cycloalkyl group or a (3-6 membered) heterocycloalkyl group, wherein the (C3-C6) cycloalkyl group or the (3-6 membered) heterocycloalkyl group is replaced by hydrogen, deuterium, F, Cl, Br, cyano, -CH3, -CD3, -CF3, -CH(Me)2, -OMe, -OCF3 substituted.

[0060] In another preferred embodiment, wherein in the general formula (1), R 7 and R 8 、R 9 and R 10 、R 11 and R 12 、R 13 and R 14 The carbon atoms connected thereto can independently and optionally form

[0061] In another preferred embodiment, wherein in the general formula (1), V is optionally a chemical bond, -O-, -S-, -NR 17 -;R 17 Optionally, it is hydrogen, (C1-C6)alkyl, (C3-C8)cycloalkyl, -Ph or -Bn.

[0062] In another preferred embodiment, wherein in the general formula (1), W is optionally a chemical bond, -O-, -S-, -NR 18 -;R 18 Optionally, hydrogen, (C1-C6)alkyl, (C3-C8)cycloalkyl, -Ph or -Bn;

[0063] In another preferred embodiment, wherein in the general formula (1), the structural unit for * indicates that this end is connected to ring A;

[0064] V is optionally -O-, -S-, or -NR 17 -;

[0065] R 17 Optionally, it is hydrogen, (C1-C3) alkyl, (C3-C6) cycloalkyl, (C3-C6) heterocycloalkyl, -Ph, -Bn; preferably, hydrogen, -Me, -Et,

[0066] R 7 or R 8 Each is independently selected from hydrogen, (C1-C3) alkyl;

[0067] R 7 and R 8 The carbon atoms connected thereto may optionally form a (C3-C6) cycloalkyl group or a (3-6 membered) heterocycloalkyl group, preferably

[0068] n is an integer selected from 1, 2, 3, 4, 5 or 6; n is preferably an integer of 1, 2, 3 or 4; and n is more preferably an integer of 3 or 4.

[0069] In another preferred embodiment, wherein in the general formula (1), the structural unit for * indicates that the end is connected to ring A.

[0070] In another preferred embodiment, wherein in the general formula (1), the structural unit for * indicates that this end is connected to ring A;

[0071] V is optionally -O-, -S-, or -NR 17 -;

[0072] W is optionally -O-, -S-, or -NR 18 -;

[0073] R 17 Optionally, it is hydrogen, (C1-C3) alkyl, (C3-C6) cycloalkyl, (C3-C6) heterocycloalkyl; preferably, hydrogen, -Me, -Et,

[0074] R 18Optionally, it is hydrogen, (C1-C3) alkyl, (C3-C6) cycloalkyl, (C3-C6) heterocycloalkyl; preferably, hydrogen, -Me, -Et,

[0075] R 9 or R 10 Each is independently selected from hydrogen, (C1-C3) alkyl;

[0076] R 9 and R 10 The carbon atoms connected thereto may optionally form a (C3-C6) cycloalkyl group or a (3-6 membered) heterocycloalkyl group, preferably

[0077] p is optionally selected from an integer of 2, 3, 4, 5 or 6; p is preferably an integer of 2, 3 or 4; and p is more preferably an integer of 2 or 3.

[0078] In another preferred embodiment, wherein in the general formula (1), the structural unit for * indicates that the end is connected to ring A.

[0079] In another preferred embodiment, wherein in the general formula (1), the structural unit for * indicates that this end is connected to ring A;

[0080] W is optionally -O-, -S-, or -NR 18 -;

[0081] R 18 Optionally, it is hydrogen, (C1-C3) alkyl, (C3-C6) cycloalkyl, (3-6 membered) heterocycloalkyl; preferably, hydrogen, -Me, -Et,

[0082] R 7 、R 8 、R 9 、R 10 Each is independently selected from hydrogen, (C1-C3) alkyl; preferably H, -Me;

[0083] R 7 and R 8 、R 9 and R 10 The carbon atoms connected thereto can independently and optionally form a (C3-C6) cycloalkyl group or a (3-6 membered) heterocycloalkyl group, preferably

[0084] n is optionally an integer of 1, 2, 3, or 4; n is preferably an integer of 2 or 3;

[0085] p is optionally an integer of 2, 3, or 4; preferably, p is an integer of 2 or 3.

[0086] -

[0087] In another preferred embodiment, wherein in the general formula (1), the structural unit for * indicates that the end is connected to ring A.

[0088] In another preferred embodiment, wherein in the general formula (1), T is optionally a chemical bond, -O-, -S-, -NR 20 -;R 20 It is optionally hydrogen, (C1-C6) alkyl, (C3-C8) cycloalkyl, (C3-C8) heterocycloalkyl, -Ph or -Bn; T is preferably a chemical bond, -O-, -NH-, or -NMe-.

[0089] In another preferred embodiment, wherein in the general formula (1), X is optionally -OH, -SH, -NHR 16 ; R 16 Optionally, it is hydrogen, (C1-C6)alkyl, (C3-C8)cycloalkyl, (C3-C8)heterocycloalkyl, -Ph or -Bn.

[0090] In another preferred embodiment, wherein in the general formula (1), the structural unit for * represents that the end is connected to the carbonyl group;

[0091] X is optionally -OH, -SH, or -NHR 16 ;

[0092] R 16 Optionally, it is hydrogen, (C1-C3) alkyl, (C3-C6) cycloalkyl, (C3-C6) heterocycloalkyl; preferably, hydrogen, -Me, -Et,

[0093] R 13 or R 14 Each is independently selected from hydrogen, (C1-C6) alkyl, (C3-C6) cycloalkyl; preferably hydrogen, -Me, -Et,

[0094] R 13 and R 14The carbon atoms connected thereto may optionally form a (C3-C6) cycloalkyl group or a (3-6 membered) heterocycloalkyl group, preferably

[0095] m is optionally an integer of 1, 2, 3, 4, 5, or 6; preferably, m is an integer of 1, 2, 3, or 4.

[0096] In another preferred embodiment, wherein in the general formula (1), for *Indicates that the end is connected to T.

[0097] In another preferred embodiment, wherein in the general formula (1), the structural unit for * indicates that this end is connected to ring A;

[0098] R 7 、R 8 、R 9 、R 10 Each is independently selected from hydrogen, -Me;

[0099] R 7 and R 8 、R 9 and R 10 The carbon atoms connected thereto can independently and optionally form

[0100] R 13 、R 14 Each independently selected from hydrogen, -Me,

[0101] X is optionally -OH, -SH, -NH2, -NHMe;

[0102] m is optionally an integer of 1, 2 or 3.

[0103] In another preferred embodiment, wherein in the general formula (1), Q is optionally a chemical bond, -O-, -S-, -NR 21 -;R 21 Optionally, it is hydrogen, (C1-C6)alkyl, (C3-C8)cycloalkyl, (3-6 membered)heterocycloalkyl, -Ph or -Bn.

[0104] In another preferred embodiment, wherein in the general formula (1), R 11 、R 12 Each is independently hydrogen, (C1-C6)alkyl, (C3-C6)cycloalkyl, (3-6 membered)heterocycloalkyl; q is an integer of 0, 1, 2, 3, 4, 5 or 6.

[0105] In another preferred embodiment, wherein in the general formula (1), R 11 and R 12 The carbon atoms to which they are commonly attached may independently and optionally form a (C3-C6)cycloalkyl group or a (3-6 membered)heterocycloalkyl group.

[0106] In another preferred embodiment, wherein in the general formula (1), G is optionally a chemical bond, -O-, -S-, -NR 19 -;R 19 Optionally, it is hydrogen, (C1-C6)alkyl, (C3-C8)cycloalkyl, (3-6 membered)heterocycloalkyl, -Ph or -Bn.

[0107] In another preferred embodiment, wherein in the general formula (1), The structural unit is * indicates that this end is connected to ring A;

[0108] R 4 For hydrogen, F, Cl, nitro, -CH3, -CF3, -OMe, -OCF3,

[0109] W is -NR 18 -;R 18 For hydrogen, -Me, -Et,

[0110] R 7 、R 8 、R 9 、R 10 Each is independently selected from hydrogen, -Me;

[0111] R 7 and R 8 、R 9 and R 10 The carbon atoms connected thereto can independently and optionally form

[0112] d is an integer of 1 or 2;

[0113] n is an integer of 2 or 3;

[0114] p is an integer of 2, 3 or 4.

[0115] In another preferred embodiment, wherein in the general formula (1), The structural unit is * indicates that this end is connected to ring A;

[0116] Q is optionally a chemical bond, O, -NR 21 -;

[0117] R21 For hydrogen, -Me, -Et,

[0118] R 4 For hydrogen, F, Cl, nitro, -CH3, -CF3, -OMe, -OCF3,

[0119] R 7 、R 8 、R 9 、R 10 、R 11 、R 12 Each is independently selected from hydrogen, -Me;

[0120] R 7 and R 8 、R 9 and R 10 、R 11 and R 12 The carbon atoms connected thereto can independently and optionally form

[0121] d is an integer of 1 or 2;

[0122] n and p are each independently an integer of 2 or 3;

[0123] q is an integer of 1, 2, 3 or 4.

[0124] In another preferred embodiment, wherein in the general formula (1), The structural unit is * indicates that this end is connected to ring A;

[0125] W is -NR 18 -;R 18 For hydrogen, -Me, -Et,

[0126] Q is optionally a chemical bond, O, -NR 21 -;

[0127] R 21 For hydrogen, -Me, -Et, -Ph or -Bn;

[0128] T is a chemical bond, -O-, -NH-, or -NMe-;

[0129] X is optionally -OH, -SH, or -NHR 16 ;

[0130] R 16 For hydrogen, -Me, -Et,

[0131] R 7 、R 8 、R 9 、R 10 、R 11 、R 12 、R 13 、R 14 Each independently selected from hydrogen, -Me, -Et,

[0132] R 7 and R 8 、R 9 and R 10 、R 11 and R 12 、R 13 and R 14 The carbon atoms connected thereto can independently and optionally form

[0133] n and p are each independently an integer of 2 or 3;

[0134] q is optionally an integer of 0, 1, 2, 3 or 4;

[0135] m is optionally an integer of 1, 2, 3 or 4.

[0136] In another preferred embodiment, wherein in the general formula (1), The structural unit is * indicates that this end is connected to ring A;

[0137] Q is optionally a chemical bond, O, -NR 21 -;

[0138] R 21 For hydrogen, -Me, -Et,

[0139] T is a chemical bond, -O-, -NH-, or -NMe-;

[0140] X is optionally -OH, -SH, or -NHR 16 ;

[0141] R 16 For hydrogen, -Me, -Et,

[0142] R 7 、R 8 、R 9 、R 10 、R 11 、R 12 、R 13 、R 14Each independently selected from hydrogen, -Me, -Et,

[0143] R 7 and R 8 、R 9 and R 10 、R 11 and R 12 、R 13 and R 14 The carbon atoms connected thereto can independently and optionally form

[0144] n and p are each independently an integer of 2 or 3;

[0145] q is optionally an integer of 0, 1, 2, 3 or 4;

[0146] m is optionally an integer of 1, 2, 3 or 4.

[0147] In another preferred embodiment, the general formula (1) has a structure as shown in the general formula (2):

[0148] where R 1 、R 2 、R 3 、R 5 、R 6 、R 7 、R 8 、R 9 、R 10 , U, V, W, a, b, c, n, p and s are defined as described above and illustrated in the specific embodiments.

[0149] In another preferred embodiment, the general formula (1) has a structure as shown in general formula (3):

[0150] where R 1 、R 2 、R 3 、R 5 、R 6 、R 7 、R 8 、R 9 、R 10 、R 13 、R 14 , U, V, W, T, X, a, b, c, m, n, p and s are defined as above and illustrated in the specific embodiments.

[0151] In another preferred embodiment, the general formula (1) has a structure as shown in the general formula (4):

[0152] where R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 、R 8 、R 9 、R 10 、R 11 、R 12 , U, V, W, Q, G, a, b, c, d, n, p, q and s are defined as described above and illustrated in the specific embodiments.

[0153] In another preferred embodiment, the general formula (1) has a structure as shown in general formula (5):

[0154] where R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 、R 8 、R 9 、R 10 、R 11 、R 12 、R 13 、R 14 , U, V, W, Q, G, T, X, a, b, c, d, m, n, p, q and s are defined as described above and illustrated in the specific embodiments.

[0155] In another embodiment of the present invention, the compound of formula (1) has one of the following structures:

[0156] Another object of the present invention is to provide a pharmaceutical composition comprising a pharmaceutically acceptable carrier, diluent and / or excipient, and a compound of the general formula (1) of the present invention, or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates as active ingredients.

[0157] Another object of the present invention is to provide the use of the compound represented by general formula (1) of the present invention, or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates, or solvates, or the pharmaceutical composition thereof, for preparing a medicament for treating, regulating, or preventing a disease associated with GSPT1 protein degradation. The disease is preferably cancer, and the cancer is a hematological cancer or a solid tumor.

[0158] It is to be understood that both the foregoing general description and the following detailed description of the present invention are exemplary and explanatory and are intended to provide further explanation of the invention as claimed. BRIEF DESCRIPTION OF THE DRAWINGS

[0159] FIG1 is the experimental result of degradation of GSPT1 protein by compound 5-1-8 in Biological Example 1 of the present invention.

[0160] Synthesis of compounds

[0161] The following specifically describes the preparation methods of the compound of general formula (1) of the present invention, but these specific methods do not constitute any limitation to the present invention.

[0162] The compounds of formula (1) described above can be synthesized using standard synthetic techniques or known techniques in combination with the methods described herein. In addition, the solvents, temperatures and other reaction conditions mentioned herein may vary. The starting materials used in the synthesis of the compounds can be synthesized or obtained from commercial sources. The compounds described herein and other related compounds having different substituents can be synthesized using known techniques and starting materials, including those found in March, ADVANCED ORGANIC CHEMISTRY 4 th Ed., (Wiley 1992); Carey and Sundberg, ADVANCED ORGANIC CHEMISTRY 4 th Ed., Vols.A and B (Plenum 2000, 2001), Green and Wuts, PROTECTIVE GROUPS IN ORGANIC SYNTHESIS 3 rd Ed., (Wiley 1999). The general methods for the preparation of compounds can be modified by using appropriate reagents and conditions to introduce various groups into the formulae provided herein.

[0163] In one aspect, the compounds described herein are prepared according to methods known in the art. However, the process conditions, such as reactants, solvents, bases, amounts of the compounds used, reaction temperatures, and reaction times, are not limited to the following explanations. The compounds of the present invention can also be conveniently prepared by optionally combining various synthetic methods described herein or known in the art, and such combinations can be readily performed by those skilled in the art.

[0164] Further forms of compounds

[0165] "Pharmaceutically acceptable" as used herein refers to a substance, such as a carrier or diluent, that does not abrogate the biological activity or properties of the compound and is relatively non-toxic, i.e., a substance that does not cause undesirable biological effects or interact in a deleterious manner with any of its components when administered to a subject.

[0166] The term "pharmaceutically acceptable salt" refers to a form of a compound that does not cause significant irritation to the organism to which it is administered and does not abrogate the biological activity and properties of the compound. In certain specific aspects, pharmaceutically acceptable salts are obtained by reacting a compound of the formula with an acid or base, wherein the acid or base includes, but is not limited to, those found in Stahl and Wermuth, Handbook of Pharmaceutical Salts: Properties, Selection, and Use 1. st Acids and Bases in Ed., (Wiley, 2002).

[0167] It should be understood that references to pharmaceutically acceptable salts include solvent-added forms or crystallized forms, particularly solvates or polymorphs. Solvates contain stoichiometric or non-stoichiometric amounts of solvent and are selectively formed during crystallization with pharmaceutically acceptable solvents such as water, ethanol, etc. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is ethanol. Solvates of compounds of formula (1) are conveniently prepared or formed according to the methods described herein. For example, hydrates of compounds of formula (1) are conveniently prepared by recrystallization from a mixed solvent of water / organic solvent, using organic solvents including, but not limited to, tetrahydrofuran, acetone, ethanol or methanol. In addition, the compounds mentioned herein can exist in unsolvated and solvated forms. In general, for the purposes of the compounds and methods provided herein, the solvated forms are considered to be equivalent to the unsolvated forms.

[0168] In other embodiments, the compound of formula (1) is prepared in different forms, including but not limited to, amorphous, crushed and nano-particle forms. In addition, the compound of formula (1) includes crystalline forms and can also be polymorphic. Polymorphs include different lattice arrangements of the same elemental composition of the compound. Polymorphs generally have different X-ray diffraction spectra, infrared spectra, melting points, density, hardness, crystal form, optical and electrical properties, stability and solubility. Different factors such as recrystallization solvent, crystallization rate and storage temperature may cause a single crystalline form to dominate.

[0169] In another aspect, compounds of formula (1) may have chiral centers and / or axial chirality and thus occur as racemates, racemic mixtures, single enantiomers, diastereomeric compounds and single diastereomers, and cis-trans isomers. Each chiral center or axial chirality will independently produce two optical isomers, and all possible optical isomers and diastereomeric mixtures as well as pure or partially purified compounds are included within the scope of the present invention. The present invention is intended to include all such isomeric forms of these compounds.

[0170] The compounds of the present invention may contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute the compound. For example, the compounds may be labeled with radioactive isotopes, such as tritium ( 3 H), oxygen-18 ( 18 O), iodine-125 ( 125 I) and C-14( 14 C). For example, deuterated compounds can be formed by replacing hydrogen atoms with heavy hydrogen. The bond formed by deuterium and carbon is stronger than the bond formed by ordinary hydrogen and carbon. Compared with non-deuterated drugs, deuterated drugs generally have advantages such as reduced toxic side effects, increased drug stability, enhanced efficacy, and prolonged drug half-life in vivo. All isotopic variations of the compounds of the present invention, whether radioactive or not, are included within the scope of this invention.

[0171] Unless otherwise specified, any reference to an atom in the compounds of the present invention refers to its stable atomic isotope. Unless otherwise specified, when a position in a molecular structure is designated as "H" or "hydrogen," such position should be understood to have the natural abundance of the hydrogen isotope. Similarly, when a position is designated as "D" or "deuterium," such position should be understood to have a deuterium isotope abundance at least 3000 times its natural abundance (the natural abundance of the deuterium isotope is 0.015%).

[0172] More preferably, the deuterium atom abundance at each deuterated site of the deuterated compound of the present invention is at least 3500 times its natural abundance (52.2% deuterium atom enrichment). More preferably, it is at least 4500 times (67.5% deuterium atom enrichment). More preferably, it is at least 5000 times (75% deuterium atom enrichment). More preferably, it is at least 6000 times (90% deuterium atom enrichment). More preferably, it is at least 6333 times (95% deuterium atom enrichment). More preferably, it is at least 6466.7 times (97% deuterium atom enrichment). More preferably, it is at least 6600 times (99% deuterium atom enrichment). More preferably, it is at least 6633.3 times (99.5% deuterium atom enrichment).

[0173] the term

[0174] Unless otherwise specified, the terms used in this application, including the specification and claims, are defined as follows. It must be noted that in the specification and the appended claims, unless otherwise clearly indicated in the text, the singular form "a" includes the plural meaning. Unless otherwise specified, the substituents in this application (such as alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, etc.) are all optionally substituted, that is, they can be substituted substituents or unsubstituted substituents. Unless otherwise specified, conventional methods such as mass spectrometry, nuclear magnetic resonance, HPLC, protein chemistry, biochemistry, recombinant DNA technology and pharmacology are used. In this application, unless otherwise specified, the use of "or" or "and" means "and / or".

[0175] Unless otherwise specified, "alkyl" refers to a saturated aliphatic hydrocarbon group, including straight and branched groups of 1 to 6 carbon atoms. Preferred are lower alkyl groups containing 1 to 4 carbon atoms, such as methyl, ethyl, propyl, 2-propyl, n-butyl, isobutyl, and tert-butyl. More preferred are lower alkyl groups containing 1 to 3 carbon atoms, such as methyl, ethyl, propyl, and 2-propyl. As used herein, "alkyl" includes unsubstituted and substituted alkyl groups, especially alkyl groups substituted with one or more halogens. Preferred alkyl groups are selected from CH3, CH3CH2, CF3, CHF2, CF3CH2, CF3(CH3)CH, i Pr, n Pr, i Bu, n Bu or t Bu.

[0176] Unless otherwise specified, "alkylene" refers to a divalent alkyl group as defined above. Examples of alkylene groups include, but are not limited to, methylene and ethylene.

[0177] Unless otherwise specified, "alkenyl" refers to an unsaturated aliphatic hydrocarbon group containing a carbon-carbon double bond, including straight or branched groups of 1 to 14 carbon atoms. Preferred are lower alkenyl groups containing 1 to 4 carbon atoms, such as ethenyl, 1-propenyl, 1-butenyl, or 2-methylpropenyl. More preferred are lower alkenyl groups containing 1 to 2 carbon atoms.

[0178] Unless otherwise specified, "alkenylene" refers to a divalent alkenyl group as defined above.

[0179] Unless otherwise specified, "alkynyl" refers to an unsaturated aliphatic hydrocarbon group containing a carbon-carbon triple bond, including straight-chain and branched groups having 1 to 14 carbon atoms. Preferred are lower alkynyl groups having 1 to 4 carbon atoms, such as ethynyl, 1-propynyl, or 1-butynyl. More preferred are lower alkynyl groups having 1 to 2 carbon atoms.

[0180] Unless otherwise specified, "alkynylene" refers to a divalent alkynyl group as defined above.

[0181] Unless otherwise specified, "cycloalkyl" refers to a non-aromatic hydrocarbon ring system (monocyclic, bicyclic or polycyclic), preferably containing 3 to 14 ring carbon atoms (C 3-14 In some embodiments, the cycloalkyl group has 3-10 ring carbon atoms (C 3-10 In some embodiments, a cycloalkyl group has 3-8 ring carbon atoms (C 3-8 In some embodiments, the cycloalkyl group has 3-7 ring carbon atoms (C 3-7 In some embodiments, the cycloalkyl group has 3-6 ring carbon atoms (C 3-6 In some embodiments, the cycloalkyl group has 4-6 ring carbon atoms (C 4-6 In some embodiments, the cycloalkyl group has 5-6 ring carbon atoms (C 5-6 In some embodiments, a cycloalkyl group has 5-10 ring carbon atoms (C 5-10Cycloalkyl). If the carbocyclic ring contains at least one double bond, the partially unsaturated cycloalkyl group may be referred to as a "cycloalkenyl group," or if the carbocyclic ring contains at least one triple bond, the partially unsaturated cycloalkyl group may be referred to as a "cycloalkynyl group." Cycloalkyl groups may include monocyclic or polycyclic (e.g., having 2, 3, or 4 fused rings) groups and spirocycles. In some embodiments, the cycloalkyl group is monocyclic. In some embodiments, the cycloalkyl group is bicyclic. In some embodiments, the cycloalkyl group is monocyclic or bicyclic. In some embodiments, the cycloalkyl group is tricyclic. The ring-forming carbon atoms of the cycloalkyl group may optionally be oxidized to form an oxo or thio group. Cycloalkyl groups also include cycloalkylene groups. In some embodiments, the cycloalkyl group contains 0, 1, or 2 double bonds. In some embodiments, the cycloalkyl group contains 1 or 2 double bonds (partially unsaturated cycloalkyl groups). In some embodiments, the cycloalkyl group may be fused with an aryl group, a heteroaryl group, a cycloalkyl group, and a heterocycloalkyl group. In some embodiments, the cycloalkyl group may be fused with an aryl group, a cycloalkyl group, and a heterocycloalkyl group. In some embodiments, cycloalkyl groups can be fused with aryl groups and heterocycloalkyl groups. In some embodiments, cycloalkyl groups can be fused with aryl groups and cycloalkyl groups. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptatrienyl, norbornyl, norpinyl, norcaryl, bicyclo[1.1.1]pentanyl, bicyclo[2.1.1]hexanyl, and the like.

[0182] Unless otherwise specified, "cycloalkylene" refers to a divalent cycloalkyl group as defined above.

[0183] Unless otherwise specified, "alkoxy" refers to an alkyl group bonded to the rest of the molecule through an ether oxygen atom. Representative alkoxy groups are those having 1 to 6 carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, and tert-butoxy. As used herein, "alkoxy" includes unsubstituted and substituted alkoxy groups, especially those substituted with one or more halogens. Preferred alkoxy groups are selected from OCH3, OCF3, CHF2O, CF3CH2O, i- PrO, n- PrO, i- BuO, n- BuO or t- BuO.

[0184] Unless otherwise specified, "aryl" refers to a hydrocarbon aromatic group. Aryl is monocyclic or polycyclic, for example, a monocyclic aryl ring fused to one or more carbocyclic aromatic groups. Examples of aryl include, but are not limited to, phenyl, naphthyl, and phenanthrenyl.

[0185] Unless otherwise specified, "aryloxy" refers to an aryl group bonded to the rest of the molecule through an ethereal oxygen atom. Examples of aryloxy groups include, but are not limited to, phenoxy and naphthoxy.

[0186] Unless otherwise specified, "arylene" refers to a divalent aromatic radical as defined above. Examples of arylene groups include, but are not limited to, 1,4-phenylene, 1,3-phenylene, 1,2-phenylene, naphthylene, and phenanthrenylene.

[0187] Unless otherwise specified, "heteroaryl" refers to a substituted or unsubstituted aromatic group containing one or more heteroatoms, the heteroatoms being independently selected from O, N or S, preferably 1, 2, 3 or 4 heteroatoms, preferably a 5-14 membered aromatic group containing 1-4 heteroatoms selected from oxygen, sulfur and nitrogen, more preferably a 5-9 membered aromatic group containing 1-2 heteroatoms selected from oxygen, sulfur or nitrogen, more preferably a 5-6 membered aromatic group containing 1-3 heteroatoms selected from oxygen, sulfur or nitrogen. The heteroaryl group is monocyclic or polycyclic. The monocyclic heteroaryl group is preferably a 5-6 membered aromatic group containing 1-3 heteroatoms selected from oxygen, nitrogen or sulfur. More preferably, it is a 5-6 membered aromatic group containing 1-2 heteroatoms selected from oxygen, nitrogen or sulfur. More preferably, it is a 5-6 membered aromatic group containing 1 heteroatom selected from oxygen, nitrogen or sulfur. In some embodiments, the monocyclic heteroaryl ring is fused with one or more carbocyclic aromatic groups or other monocyclic heterocycloalkyl groups. Examples of heteroaryl groups include, but are not limited to, pyridyl, pyridazinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, quinolyl, isoquinolyl, quinazolinyl, furanyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl, isothiazolyl, pyrrolyl, indolyl, benzimidazolyl, benzofuranyl, benzothiazolyl, benzothienyl, benzoxazolyl, benzopyridinyl, pyrrolopyrimidinyl, 1H-pyrrolo[3,2-b]pyridinyl, 1H-pyrrolo[2,3-c]pyridinyl, 1H-pyrrolo[3,2-c]pyridinyl, 1H-pyrrolo[2,3-b]pyridinyl,

[0188] Unless otherwise specified, "heteroarylene" refers to a divalent heteroaryl group as defined above.

[0189] Unless otherwise specified, "heterocycloalkyl" refers to a non-aromatic ring or ring system, which may optionally contain one or more alkenylene groups as part of the ring structure, having at least one heteroatom ring member independently selected from boron, phosphorus, nitrogen, sulfur, oxygen and selenium, preferably a saturated or partially unsaturated ring containing 1-4 heteroatoms selected from oxygen, sulfur or nitrogen, more preferably a saturated or partially unsaturated ring containing 1-2 heteroatoms selected from oxygen, sulfur or nitrogen. In some embodiments, heterocycloalkyl is a 5-14 membered non-aromatic ring containing ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen or sulfur (5-14 membered heterocycloalkyl). In some embodiments, heterocycloalkyl is a 3-9 membered non-aromatic ring containing ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen or sulfur (3-9 membered heterocycloalkyl). In some embodiments, heterocycloalkyl is a 5-8 membered non-aromatic ring containing ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, or sulfur (5-8 membered heterocycloalkyl). In some embodiments, heterocycloalkyl is a 5-6 membered non-aromatic ring containing ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, or sulfur (5-6 membered heterocycloalkyl). In some embodiments, 5-6 membered heterocycloalkyl contains 1-3 ring heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, 5-6 membered heterocycloalkyl contains 1-2 ring heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, 5-6 membered heterocycloalkyl contains 1 ring heteroatom independently selected from nitrogen, oxygen, and sulfur. In some embodiments, heterocycloalkyl is a 10-13 membered non-aromatic ring containing ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, or sulfur (10-13 membered heterocycloalkyl). In some embodiments, 10-13 membered heterocycloalkyl groups contain 1-3 ring heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, 10-13 membered heterocycloalkyl groups contain 1-2 ring heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, 10-13 membered heterocycloalkyl groups contain 1 ring heteroatom independently selected from nitrogen, oxygen, and sulfur. If the heterocycloalkyl group contains at least one double bond, the partially unsaturated heterocycloalkyl group may be referred to as a "heterocycloalkenyl group," or if the heterocycloalkyl group contains at least one triple bond, the partially unsaturated heterocycloalkyl group may be referred to as a "heterocycloalkynyl group." Heterocycloalkyl groups may include monocyclic, bicyclic, spirocyclic, or polycyclic (e.g., having two fused or bridged rings) ring systems. In some embodiments, heterocycloalkyl groups are monocyclic groups having 1, 2, or 3 heteroatoms independently selected from nitrogen, sulfur, and oxygen. The ring-forming carbon atoms and heteroatoms of the heterocycloalkyl group may be optionally oxidized to form oxo or thio or other oxidized bonds (e.g., C(O), S(O), C(S) or S(O) 2, N-oxide, etc.), or the nitrogen atom may be quaternized. The heterocycloalkyl group may be connected via ring-forming carbon atoms or ring-forming heteroatoms. In some embodiments, the heterocycloalkyl group contains 0 to 3 double bonds.In some embodiments, heterocycloalkyl contains 0 to 2 double bonds. Also included in the definition of heterocycloalkyl are moieties (also referred to as partially unsaturated heterocycles) with one or more aromatic rings fused to the heterocycloalkyl ring (i.e., sharing a key therewith), such as benzo derivatives of piperidine, morpholine, azacycloheptane or tetrahydrothienyl, and pyrido derivatives of piperidine, morpholine, azacycloheptane or tetrahydrothienyl. Heterocycloalkyl containing fused aromatic rings can be connected via any ring-forming atoms, including ring-forming atoms of the fused aromatic ring. Examples of heterocycloalkyl groups include, but are not limited to, azetidinyl, azepanyl, dihydrobenzofuranyl, dihydrofuranyl, dihydropyranyl, N-morpholinyl, 3-oxa-9-azaspiro[5.5]undecyl, 1-oxa-8-azaspiro[4.5]decyl, piperidinyl, piperazinyl, oxopiperazinyl, pyranyl, pyrrolidinyl, quinuclyl, tetrahydrofuranyl, tetrahydropyranyl, 1,2,3,4-tetrahydroquinolinyl, tropanediyl, 4,5,6,7-tetrahydrothiazolo[5,4-c]pyridinyl, 4,5,6,7-tetrahydro-1H-imidazole , 4-nitro-2-nitro-1-pyridine, 4 ...1-pyridine, 4-nitro-1-pyridine, 4-nitro-1-pyridine, 4-nitro-1-pyridine, 4-nitro-1-pyridine, 4-nitro-1-pyridine, 4-nitro-1-pyridine, 4-nitro-1-pyridine, 4-nitro-1-pyridine, 4-nitro-1-pyridine, 4-nitro-1-pyridine, 4-nitro-1-pyridine, 4-nitro-1-pyridine, 4-nitro-1-pyridine, 4-nitro-1-pyridine,

[0190] Unless otherwise specified, "heterocycloalkylene" refers to a divalent heterocycloalkyl group as defined above.

[0191] Unless otherwise specified, "oxo" refers to =0; for example, a carbonyl group substituted with an oxo group is a "carbonyl group." "; the group formed by sulfur being replaced by an oxo group is called "sulfinyl" ", the group formed by sulfur being substituted by two oxo groups is called "sulfonyl" ”.

[0192] Unless otherwise specified, "halogen" (or halo) refers to fluorine, chlorine, bromine or iodine. The term "halo" (or "halogen substituted") appearing before the name of a group indicates that the group is partially or fully halogenated, that is, substituted by F, Cl, Br or I in any combination, preferably substituted by F or Cl.

[0193] Unless otherwise specified, the term "substituted" refers to a substituent group other than one or more hydrogen atoms on a specified atom or group that is substituted by one or more hydrogen atoms, without exceeding the normal valence of the specified atom. For example, one or more hydrogen atoms of an alkyl, alkylene, alkenyl, alkynyl, hydroxyl or amido group can be substituted by one or more substituent groups. Wherein the substituent group includes but is not limited to alkyl, alkenyl, alkynyl, alkoxy, acyl, amino, amido, amidino, aryl, azido, carbamoyl, carboxyl, carboxylate, cyano, guanidino, halogen, haloalkyl, heteroalkyl, heteroaryl, heterocyclic radical, hydroxyl, hydrazino, imino, oxo, nitro, alkylsulfinyl, sulfonic acid, alkylsulfonyl, thiocyanate, mercaptan, thioketone or its combination. The definition of "substituted" does not include similar indefinite structures obtained by defining a substituent group having a further substituent group attached to infinity (for example, a substituted aryl group itself substituted by a substituted aryl group with a substituted alkyl group, which is further substituted by a substituted heteroalkyl group, etc.). Unless otherwise specified, the maximum number of consecutive substitutions in the compounds described herein is three. For example, a substituted aryl group is continuously substituted by two other substituted aryls to an aryl group substituted by ((substituted aryl) substituted aryl). Similarly, the above definition does not include substitution patterns that are not allowed (for example, a methyl group substituted by 5 fluorines or a heteroaryl group with two adjacent oxygen ring atoms). This substitution pattern that is not allowed is well known to those skilled in the art. Whenever used to modify a chemical group, "substituted" can describe other chemical groups defined herein. For example, the term "substituted aryl" includes but is not limited to "alkyl aryl". Unless otherwise specified, if a group is described as optionally substituted, any substituent of the group itself is unsubstituted.

[0194] "Optional" or "optionally" means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where said event or circumstance occurs and instances where it does not.

[0195] Unless otherwise specified, "acyl" refers to -C(=O)-R, where R is selected from optionally substituted alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, or heterocycloalkyl.

[0196] Unless otherwise specified, it will be understood that the word "comprise", or variations such as "comprises" or "comprising", imply the inclusion of a stated element or integer, or group of elements or integers, but not the exclusion of any other element or integer, or group of elements or integers.

[0197] The substituent "-O-CH2-O-" refers to the substituent in which two oxygen atoms are connected to two adjacent carbon atoms of a heterocycloalkyl, aryl or heteroaryl group, for example:

[0198] When the number of a linking group is 0, such as -(CH2)0-, it means that the linking group is a single bond.

[0199] When one of the variables is selected from a chemical bond, it means that the two groups it connects are directly connected. For example, when L in XLY represents a chemical bond, it means that the structure is actually XY.

[0200] The term "membered ring" includes any cyclic structure. The term "membered" refers to the number of atoms that make up the ring. For example, cyclohexyl, pyridyl, pyranyl, and thiopyranyl are six-membered rings, while cyclopentyl, pyrrolyl, furanyl, and thiophenyl are five-membered rings.

[0201] The term "fragment" refers to a specific part or functional group of a molecule. A chemical fragment is generally considered to be a chemical entity contained in or attached to a molecule.

[0202] The term "isomer" means any tautomer, stereoisomer, atropisomer, isotopomer, enantiomer or diastereomer of any compound of the present invention. The compounds of the present invention may have one or more chiral centers or double bonds and therefore exist in stereoisomeric form, for example, as double bond isomers (i.e., E / Z geometric isomers) or diastereomers (e.g., enantiomers (i.e., (+) or (-)) or cis / trans isomers). Therefore, the compounds of the present invention encompass all corresponding stereoisomers, i.e., stereoisomerically pure (e.g., geometrically pure, enantiomerically pure or diastereomerically pure) forms as well as enantiomers and stereoisomer mixtures, such as racemates. Enantiomeric and stereoisomeric mixtures of the compounds of the present invention can be separated into their component enantiomers or stereoisomers by well-known methods, such as chiral gas chromatography, chiral high performance liquid chromatography, and crystallization of the compounds as chiral salt complexes or crystallization of the compounds in chiral solvents. Enantiomers and stereoisomers can also be obtained from stereoisomerically pure or enantiomerically pure intermediates, reagents and catalysts by well-known asymmetric synthetic methods.

[0203] The term "isotopomers" refers to different molecules whose structures differ only in one isotope but are otherwise identical.

[0204] The term "atropisomer" refers to a conformational stereoisomer produced when rotation about a single bond within a molecule is prevented or greatly slowed due to steric interactions with other parts of the molecule and the substituents at either end of the single bond are asymmetric, i.e., atropisomers do not require a stereocenter. When the barrier to rotation about the single bond is sufficiently high and the interconversion between conformations is sufficiently slow, separation of the individual isomers is permitted (LaPlante et al., J. Med. Chem. 2011, 54, 20, 7005), preferably by chiral resolution.

[0205] Unless otherwise specified, when a group has one or more linkable sites, any one or more sites of the group can be linked to other groups through chemical bonds. When the linking mode of the chemical bond is non-positional and there is an H atom at the linkable site, when the chemical bond is connected, the number of H atoms at the site will decrease accordingly with the number of chemical bonds connected, and the group will become a group with the corresponding valence. For example, "pyridyl" means "Oxazolyl" means

[0206] Unless otherwise specified, use a solid wedge key. and dotted wedge key To indicate the absolute configuration of a stereocenter, use a straight solid bond and straight dashed bond Indicate the relative configuration of stereocenters with a wavy line Indicates a wedge-shaped solid key or dotted wedge key Or use a wavy line Indicates a straight solid bond or straight dashed key

[0207] Unless otherwise stated, Indicates a single bond or a double bond.

[0208] The term "small molecule toxin" refers to a small molecular weight cytotoxic compound with a molecular weight not exceeding 2500 Daltons that is cytotoxic to mammalian cells, or refers to a small molecular weight protein degrader with a molecular weight not exceeding 2500 Daltons that targets and degrades specific proteins in mammalian cells; in some embodiments, "small molecule toxin" refers to a small molecular weight protein degrader that has a degradative effect on GSPT1 protein.

[0209] The term "DAR" or "drug-antibody ratio" refers to the ratio of small molecule compound or novel protein degrader to antibody in a conjugate, i.e., the average number of small molecule compound or novel protein degrader attached per antibody. In some embodiments, the DAR of the conjugate is a number between 1 and 10. In some embodiments, the DAR of the conjugate is a number of 1, 2, 3, 4, 5, 6, 7, or 8. In some embodiments, the DAR of the conjugate is 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9, or 10.

[0210] The term "antibody" refers to a full-length immunoglobulin molecule or an immunologically active fragment of an immunoglobulin molecule. The immunoglobulin can be of any type (e.g., IgG, IgE, IgM, IgD, or IgA), any subtype (e.g., IgG1, IgG2, IgG3, IgG4, IgA1, or IgA2), or any subclass. In some embodiments, the immunoglobulin can be derived from any species. In some embodiments, the immunoglobulin is derived from humans, rodents, or rabbits.

[0211] The term "single domain antibody" or "nanobody" refers to an antibody fragment consisting of a single variable antibody domain with a molecular weight of approximately 12 kDa to 15 kDa. Single domain antibodies include but are not limited to V H H fragment or V NAR fragment.

[0212] The term "antibody fragment" refers to a portion of an intact antibody, typically the antigen binding domain or variable domain. Antibody fragments include, but are not limited to, Fab, Fab', F(ab').sub2 or Fv fragments, bispecific antibodies (diabodies), linear antibodies, fragments obtained by Fab expression libraries, anti-idiotypic antibodies, complementary determining regions (CDRs), or any of the above fragments that can bind to an antigen epitope, which fragment can immunospecifically bind to an antigen of a tumor cell, a viral antigen, or an antigen of a microorganism. Single-chain antibody molecules (single-chain antibodies) and multispecific antibodies (multispecific antibodies) are generated from antibody fragments. The constant domain can be a native sequence constant domain (native sequence constant domain) or a variable amino acid sequence structure (amino acid sequence variant)

[0213] The term "monoclonal antibody" refers to an antibody obtained from a group of highly homogeneous antibodies, in which each antibody has a highly similar structure except for a small number of naturally occurring mutations. Monoclonal antibodies are highly specific and can bind to a certain antigen with high specificity. Unlike polyclonal antibodies that can bind to multiple antigenic epitopes, each monoclonal antibody can only bind to a single antigenic epitope. In some embodiments, monoclonal antibodies are prepared by hybridoma method or recombinant DNA method. In some embodiments, monoclonal antibodies are prepared by phage display. Monoclonal antibodies include chimeric antibodies, which refer to antibodies in which part of the light chain or heavy chain is consistent with or similar to the corresponding structural sequence of a certain type or subtype of antibody, and the remaining light chain or heavy chain of the antibody is consistent with or similar to the corresponding structural sequence of another type or subtype of antibody. In some embodiments, chimeric antibodies are primatized antibodies composed of variable domain antigen-binding sequences derived from non-human primates and human constant region sequences.

[0214] In some embodiments, the monoclonal antibodies are chimeric antibodies or humanized antibodies. Chimeric antibodies can be composed of mouse variable domains and human constant domains. Although humanized antibodies contain some non-human parts, their main structure is derived from human antibodies. For example, humanized antibodies contain a completely human constant domain and a variable domain that is partially derived from human sources. The non-human, synthetic parts of humanized antibodies are usually derived from the CDRs regions of rodent antibodies, which are important for antibody recognition and binding to specific antigens. Rodent antibodies cannot usually be administered to humans for a long time because they can cause highly dangerous immune responses in the human body. This reaction is referred to as the human anti-rodent antibody (HAMA, human anti-murine antibody) reaction.

[0215] "Chimeric" or "humanized" antibodies can reduce the likelihood of a human anti-rodent antibody (HAMA) response by reducing the non-human portion of the antibody. They can also stimulate immune responses, such as antibody-dependent cellular cytotoxicity (ADCC).

[0216] The term "antibody" also refers to natural or synthetic immunoglobulins and protein fragments. The term "antibody" also includes proteins containing binding domains similar to those of immunoglobulins. The term "antibody" also includes polypeptides containing a framework region from an immunoglobulin gene or fragment that are capable of specifically binding to an antigen. The term "antibody" is used to refer to all antibodies (whole antibodies), polyclonal antibodies (polyclonal antibodies), monoclonal antibodies (monoclonal antibodies), recombinant antibodies (recombinant antibodies), and protein fragments. The term "antibody" also refers to single-chain antibodies (single-chain antibodies), humanized antibodies (humanized antibodies), rodent antibodies (murine antibodies), chimeric antibodies (chimeric antibodies), anti-idiotypic antibodies (antibody fragments, such as scFv, (scFv)2, Fab, Fab', F(ab')2, F(ab1)2, Fv, dAb or Fd fragments), bispecific antibodies (diabodies), and antibody-related polypeptides. The term "antibody" is also used to refer to bispecific antibodies and multispecific antibodies. In some embodiments, the biologically active molecule is an antibody or a molecule containing an antigen-binding fragment.

[0217] The terms "antibody-drug conjugate," "antibody-protein degrader conjugate," "antibody-drug conjugate," "degrader-antibody conjugate," "ADC," and "DAC" are used interchangeably herein. The terms "antibody-drug conjugate," "antibody-protein degrader conjugate," "antibody-drug conjugate," "degrader-antibody conjugate," "ADC," and "DAC" refer to one or more therapeutic molecules, such as drugs, novel protein degraders, or pharmaceutical ingredients, covalently attached to an antibody to form a conjugate. In some embodiments, the biologically active molecule is an "antibody-drug conjugate." In some embodiments, the biologically active molecule is an "antibody-protein degrader conjugate."

[0218] The terms "conjugating" and "linking" are used interchangeably. The terms "conjugating" and "linking" refer to covalently or non-covalently linking a therapeutic molecule, such as a drug, novel protein degrader, or pharmaceutical ingredient, to an antibody.

[0219] The term "amino acid sequence variant" refers to a polypeptide structure that contains an amino acid sequence that differs to a certain extent from that of a native polypeptide. In some embodiments, the variable amino acid sequence variant generally has at least 70% sequence identity in amino acid sequence with the receptor binding domain of at least one native antibody or the ligand binding domain of at least one native receptor. In some embodiments, the variable amino acid sequence variant generally has at least 80% sequence identity in amino acid sequence with the receptor binding domain of at least one native antibody or the ligand binding domain of at least one native receptor. In some embodiments, the variable amino acid sequence variant generally has at least 90% sequence identity in amino acid sequence with the receptor binding domain of at least one native antibody or the ligand binding domain of at least one native receptor. A variable amino acid sequence variant refers to an amino acid residue substitution, deletion, and / or insertion at a position in a native amino acid sequence.

[0220] The term "sequence identity" refers to the degree of similarity between amino acid sequence variants.

[0221] The term "Fc receptor" or "FcR" refers to a receptor that binds to the Fc region of an antibody. In some embodiments, the FcR is a native sequence human FcR. In some embodiments, the FcR is a gamma receptor that binds to an IgG antibody, including the Fc.gamma.RI receptor, the Fc.gamma.RII receptor, and the Fc.gamma.RIII receptor, as well as allelic variants and alternatively spiced forms of the above three types of receptors. The Fc.gamma.RII receptor includes Fc.gamma.RIIA and Fc.gamma.RIIB, two receptor subtypes with similar amino acid sequences but with differences in the amino acid sequence of the cytoplasmic domain. Fc.gamma.RIIA contains an ITAM fragment (immunoreceptor tyrosine-based activation motif) in the cytoplasmic domain. Fc.gamma.RIIB contains an ITTM segment (immunoreceptor tyrosine-based inhibition motif) in its cytoplasmic domain. In some embodiments, the term "FcR" also refers to other, currently unreported FcRs. In some embodiments, the term "FcR" also refers to the neonatal receptor, FcRn, responsible for transporting IgGs to the embryo.

[0222] The term "complement dependent cytotoxicity" or "CDC" refers to the ability of a molecule to lyse target cells in the presence of complement. The complement activation pathway is initiated by the binding of C1q, the first component of the complement system, to a molecular complex containing an antigen (e.g., an antibody molecule in complex with the antigen).

[0223] The term "native antibodies" refers to heterotetrameric glycoproteins with a molecular weight of approximately 150 kDa, which are composed of two identical light chains and two identical heavy chains. Each light chain is covalently linked to a heavy chain by a disulfide bond, and the number of disulfide bonds varies depending on the heavy chain of different types of immunoglobulins. Each heavy chain has a variable region (VH) at one end, followed by several constant domains. Each light chain has a variable region (VL) at one end and a constant region at the other end. The constant region of the light chain is aligned with the first constant region of the heavy chain, and the variable region of the light chain (VL) is aligned with the variable region of the heavy chain (VH). Some specific amino acid residues form an interface between the variable regions of the light and heavy chains.

[0224] The term "variable" refers to the wide diversity of partial amino acid sequences in the variable region of an antibody, which plays an important role in the specific binding of the antibody to the corresponding antigen. Variability is not evenly distributed in the variable region of an antibody, but is mainly concentrated in the three hypervariable regions of the light chain and heavy chain. The highly conserved part of the variable region is called the framework region. The variable region in each natural heavy chain and light chain contains four framework structures, most of which are in a β-pleated conformation, which are connected by three hypervariable regions in a loop conformation. The highly variable region and framework region of the antibody contribute to the formation of the antigen-binding region of the antibody. Although the constant region has no direct effect on the binding of the antibody to the antigen, it has a variety of effector functions, such as participating in antibody-dependent cellular cytotoxicity.

[0225] The term "hypervariable region" refers to the amino acid residues of an antibody that play an important role in antibody-antigen binding. A hypervariable region generally includes amino acid residues from the complementary determining region (CDR) (e.g., residues 24-34 (L1), 50-56 (L2), and 89-97 (L3) of the light chain variable region and residues 31-35 (H1), 50-65 (H2), and 95-102 (H3) of the heavy chain variable region) and / or amino acid residues from the hypervariable loop (e.g., residues 26-32 (L1), 50-52 (L2), and 91-96 (L3) of the light chain variable region and residues 26-32 (H1), 53-55 (H2), and 96-101 (H3) of the heavy chain variable region). The term "framework region" amino acid residues herein refers to the amino acid residues in the variable domain excluding the amino acid residues in the hypervariable regions.

[0226] Papain digestion of antibodies produces two identical antigen-binding fragments, called "Fab" fragments, each with a single antigen-binding site, and an "Fc" fragment. Pepsin digestion of antibodies produces an F(ab')2 fragment, each with two antigen-binding sites and capable of cross-linking with antigens.

[0227] The term "Fv" refers to the smallest antibody fragment with complete antigen recognition ability and antigen binding site. This region is a dimer, with each monomer consisting of the variable regions of a heavy chain and a light chain tightly linked by non-covalent bonding. In its structure, the three highly variable regions in each variable domain interact to form an antigen binding site on the surface of the VH-VL dimer. Therefore, the six highly variable regions in an antibody determine the antibody's specificity for the antigen. However, even a single variable domain or a half Fv structure containing only three highly variable regions has the ability to recognize and bind to an antigen, although the binding force is lower than that of the complete binding site.

[0228] The Fab fragment also contains the constant region of the light chain and the first constant region (CH1) of the heavy chain. The Fab' fragment is based on the Fab fragment, with some amino acid residues added to the carbon-terminus of the heavy chain CH1 domain. Fab'-SH is a degradation product of Fab', in which the cysteine ​​residues in the constant domains have at least one free sulfhydryl group. F(ab')2 fragments are produced by linking two Fab' fragments via cysteines in the hinge region.

[0229] The term "light chain" refers to the light chain portion of an antibody. Vertebrate antibody light chains can be divided into two categories based on the difference in constant domain amino acid sequences: kappa (.kappa.) and lamda (.lamda.).

[0230] The term "single-chain Fv" or "scFv" refers to an antibody fragment that contains both heavy and light chain domains, with these domains contained within a single polypeptide chain. The Fv polypeptide can also consist of a single polypeptide chain linking the VH and VL chains, giving the scFv the necessary structure for antigen binding.

[0231] The term "bispecific antibodies" (diabodies) refers to antibody fragments with two antigen-binding sites. These antibody fragments are composed of a variable heavy chain domain (VH) connected to a variable light chain domain (VL) to form a single polypeptide chain (VH-VL).

[0232] "Humanized" forms of non-human (e.g., rodent) antibodies are chimeric antibodies that contain minimal non-human immunoglobulin proteins. Humanization refers to a process by which murine antigen-binding information is transferred to a non-immunogenic human antibody receptor, thereby generating drugs with various therapeutic effects. This humanization process typically involves transferring six murine complementarity-determining regions (CDRs) onto the framework structure of a human antibody. These CDR-incorporated antibodies typically do not retain their original binding ability to their antigens, and binding is generally significantly reduced. In addition to the CDRs, non-human antibody framework residues must also be introduced to maintain the proper CDR conformation. Transferring key mouse framework residues to the human receptor to support the structural conformation of the grafted CDRs can restore the antibody's antigen-binding ability. For the most part, humanized antibodies are human immunoglobulins (called recipient antibodies or recipient antibodies) whose amino acid residues in the hypervariable regions are replaced by the hypervariable regions of non-human antibodies (called donor antibodies or donor antibodies). Non-human antibodies with the desired specificity, binding ability and loading capacity are derived from mice, rats, rabbits or non-human primates. In some embodiments, the framework residues of human immunoglobulins are replaced by corresponding non-human framework residues. In addition, humanized antibodies have amino acid residues that are neither derived from the recipient antibody nor from the donor antibody. These modifications to the antibodies improve the performance of the antibodies. Generally, humanized antibodies have at least one, and usually two, variable domains, in which all or almost all of the hypervariable polypeptide chains are variable polypeptide chains of non-human immunoglobulins, and all or almost all of the framework regions are framework regions of human immunoglobulin sequences. In some embodiments, humanized antibodies may also have at least a portion of an immunoglobulin constant domain (Fc), usually a portion of a human immunoglobulin constant domain (Fc).

[0233] Specific pharmaceutical and medical terms

[0234] The term "acceptable," as used herein, means that a prescribed ingredient or active ingredient has no undue adverse effect on health and well-being for the general purpose of treatment.

[0235] The terms "treat," "treatment," or "therapy" as used herein include alleviating, inhibiting, or ameliorating the symptoms of a disease or condition; inhibiting the development of complications; ameliorating or preventing underlying metabolic syndrome; inhibiting the development of a disease or symptom, such as controlling the progression of a disease or condition; alleviating a disease or symptom; causing a regression of a disease or symptom; alleviating complications caused by a disease or symptom, or preventing or treating signs caused by a disease or symptom. As used herein, a compound or pharmaceutical composition, upon administration, can improve a disease, symptom, or condition, particularly by improving its severity, delaying its onset, slowing its progression, or reducing its duration. Whether the administration is fixed or temporary, continuous or intermittent, the circumstances attributable to or related to the administration can be explained.

[0236] "Active ingredient" refers to the compound of formula (1), as well as pharmaceutically acceptable inorganic or organic salts of the compound of formula (1). The compounds of the present invention may contain one or more asymmetric centers (chiral centers or axial chirality) and therefore appear in the form of racemates, racemic mixtures, single enantiomers, diastereomeric compounds and single diastereomers. The asymmetric centers that may exist depend on the properties of the various substituents on the molecule. Each such asymmetric center will independently produce two optical isomers, and all possible optical isomers and diastereomeric mixtures as well as pure or partially pure compounds are included within the scope of the present invention. The present invention is meant to include all such isomeric forms of these compounds.

[0237] The terms "compound," "composition," "agent," or "medicine or medicament" are used interchangeably herein and refer to a compound or composition that, when administered to a subject (human or animal), induces a desired pharmaceutical and / or physiological response through local and / or systemic action.

[0238] The term "administered," "administering," or "administration" as used herein refers to the direct administration of the compound or composition, or the administration of a prodrug, derivative, or analog of the active compound.

[0239] Although the numerical ranges and parameters used to define the broader scope of the present invention are approximate, the numerical values ​​of the specific examples are presented herein as precisely as possible. However, any numerical value inherently and inevitably contains standard deviations resulting from individual testing methods. As used herein, "about" generally refers to the actual value being within plus or minus 10%, 5%, 1%, or 0.5% of a particular value or range. Alternatively, the term "about" means that the actual value falls within an acceptable standard error of the mean, as determined by one skilled in the art. Except in the experimental examples, or unless otherwise expressly indicated, all ranges, amounts, values, and percentages used herein (e.g., to describe material amounts, time periods, temperatures, operating conditions, quantitative ratios, and the like) are to be understood as modified by the word "about." Therefore, unless otherwise indicated, the numerical parameters disclosed in this specification and the appended claims are approximate and may be modified as needed. At a minimum, these numerical parameters should be understood to include the number of significant digits indicated and to include normal rounding.

[0240] Unless otherwise defined in this specification, the scientific and technical terms used herein have the same meanings as commonly understood by those skilled in the art. In addition, unless otherwise defined in this specification, singular terms used in this specification include the plural form of the term, and plural terms also include the singular form of the term, unless otherwise defined in the context.

[0241] Therapeutic uses

[0242] The present invention provides methods for treating diseases using the compounds of formula (1) or pharmaceutical compositions of the present invention, including but not limited to conditions treatable by GSPT1 protein degraders (eg, cancer).

[0243] In some embodiments, a method for treating cancer is provided, comprising administering to a subject in need thereof an effective amount of any of the aforementioned pharmaceutical compositions comprising a compound of formula (1). In other embodiments, the cancer is a blood cancer and a solid tumor, including but not limited to leukemia, breast cancer, lung cancer, pancreatic cancer, colon cancer, bladder cancer, brain cancer, urothelial cancer, prostate cancer, liver cancer, ovarian cancer, head and neck cancer, gastric cancer, mesothelioma, or all cancer metastases. Preferably, non-small cell lung cancer, small cell lung cancer, high-grade neuroendocrine cancer, diffuse large B-cell lymphoma, acute myeloid leukemia, breast cancer, gastric cancer, colorectal cancer.

[0244] Route of administration

[0245] The compounds of the present invention and their pharmaceutically acceptable salts can be formulated into various formulations containing a safe and effective amount of the compounds of the present invention or their pharmaceutically acceptable salts and a pharmacologically acceptable excipient or carrier. "Safe and effective amount" means an amount of the compound sufficient to significantly improve the condition without causing serious side effects. The safe and effective amount of the compound will be determined based on the patient's age, condition, and duration of treatment, among other factors.

[0246] "Pharmaceutically acceptable excipients or carriers" refer to: one or more compatible solid or liquid fillers or gel substances, which are suitable for human use and must have sufficient purity and sufficiently low toxicity. "Compatibility" here means that the components in the composition can be mixed with the compounds of the present invention and with each other without significantly reducing the efficacy of the compounds. Some examples of pharmacologically acceptable excipients or carriers include cellulose and its derivatives (such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid, magnesium stearate), calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerol, mannitol, sorbitol, etc.), emulsifiers (such as ), wetting agents (such as sodium lauryl sulfate), colorants, flavorings, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.

[0247] The compounds of the present invention may be administered orally, rectally, parenterally (intravenously, intramuscularly or subcutaneously), or topically.

[0248] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In these solid dosage forms, the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with the following ingredients: (a) fillers or extenders, for example, starches, lactose, sucrose, glucose, mannitol, and silicic acid; (b) binders, for example, hydroxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose, and acacia; (c) humectants, for example, glycerol; (d) disintegrants, for example, agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) solubilizers, for example, paraffin; (f) absorption accelerators, for example, quaternary ammonium compounds; (g) wetting agents, for example, cetyl alcohol and glyceryl monostearate; (h) adsorbents, for example, kaolin; and (i) lubricants, for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, or mixtures thereof. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents.

[0249] Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared using coatings and shell materials, such as enteric coatings and other materials known in the art. They may contain opacifying agents, and the release of the active compound or compounds in such compositions can be delayed in a certain portion of the digestive tract. Examples of useful encapsulating components are polymeric substances and waxes. If desired, the active compound can also be microencapsulated with one or more of the above-mentioned excipients.

[0250] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures. In addition to the active compound, the liquid dosage form may contain an inert diluent conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropyl alcohol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butylene glycol, dimethylformamide, and oils, particularly cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil, or mixtures thereof.

[0251] Besides such inert diluents, the composition may also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

[0252] Suspensions, in addition to the active compounds, may contain suspending agents such as, for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances.

[0253] Compositions for parenteral injection may comprise physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and non-aqueous carriers, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof.

[0254] Dosage forms for topical administration of the compounds of this invention include ointments, powders, patches, sprays and inhalants. The active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants that may be required.

[0255] The compounds of the present invention can be administered alone or in combination with other pharmaceutically acceptable compounds. When using a pharmaceutical composition, a safe and effective amount of the compounds of the present invention is applied to a mammal (e.g., a human) in need of treatment, wherein the dosage is a pharmaceutically effective dosage. For a 60 kg human, the daily dosage is generally 1 to 2000 mg, preferably 50 to 1000 mg. Of course, the specific dosage should also take into account factors such as the route of administration and the patient's health status, all of which are within the skill of a skilled physician.

[0256] The features described above, or in the embodiments, may be combined in any combination. All features disclosed in this specification may be used in any combination, and each feature disclosed in this specification may be replaced by any alternative feature that serves the same, equivalent, or similar purpose. Therefore, unless otherwise specified, the features disclosed are merely general examples of equivalent or similar features. DETAILED DESCRIPTION

[0257] The following description will elaborate on various specific aspects, characteristics, and advantages of the above-mentioned compounds, methods, and pharmaceutical compositions so that the present invention will be readily apparent. It should be understood that the following detailed description and examples describe specific embodiments and are provided for reference only. After reading the present description, those skilled in the art may make various changes or modifications to the present invention, and such equivalents are within the scope of the present invention.

[0258] In all embodiments, 1 H-NMR was recorded on a Vian Mercury 400 nuclear magnetic resonance instrument, and chemical shifts are expressed in δ (ppm). Silica gel used for separation was 200-300 mesh unless otherwise specified, and the eluent ratios were by volume.

[0259] The present invention uses the following abbreviations: AcOH (or HOAc) for acetic acid; Ar for argon; BH3-MeS for borane dimethyl sulfide complex; Boc2O for di-tert-butyl dicarbonate; CDCl3 for deuterated chloroform; Cs2CO3 for cesium carbonate; DCC for dicyclohexylcarbodiimide; DCM for dichloromethane; DIEA for diisopropylethylamine; DMF for dimethylformamide; DMSO for dimethyl sulfoxide; EA for ethyl acetate; EDTA for ethylenediaminetetraacetic acid; EtOH for ethanol; h for hours; H2 for hydrogen; HATU for O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; HOBT for 1-hydroxybenzotriazole; NaOH for sodium hydroxide; KOH for potassium hydroxide; LAH for lithium aluminum hydride; LC- MS stands for liquid chromatography-mass spectrometry; LiHMDS stands for lithium bis(trimethylsilyl)amide; MeCN stands for acetonitrile; MeI stands for iodomethane; MeOH stands for methanol; min stands for minute; mL stands for milliliter; MS stands for mass spectrometry; NaH stands for sodium hydride; Na2SO3 stands for sodium sulfite; Na2SO4 stands for sodium sulfate; NH4Cl stands for ammonium chloride; NMR stands for nuclear magnetic resonance; Pd / C stands for palladium on carbon; Pd(OAc)2 stands for palladium acetate / palladium acetate; PE stands for petroleum ether; SOCl2 stands for dichlorothionyl; t-BuOK stands for potassium tert-butoxide; TBAF stands for tetrabutylammonium fluoride; TEA stands for triethylamine; TFA (or CF3COOH) stands for trifluoroacetic acid; THF stands for tetrahydrofuran; Toluene stands for toluene; xant-phos stands for 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene.

[0260] Preparation Example 1A1-a Synthesis

[0261] Step 1: Synthesis of A1-a

[0262] S-1 (8 g, 32.2 mmol) was dissolved in THF (80 mL) under argon. NaH (6.46 g, 161 mmol, 60% in mineral oil) was added portionwise under ice-cooling and stirred at room temperature for 1 h. Subsequently, a THF solution of S-2 (15.46 g, 80.5 mmol) (20 mL) was slowly added dropwise under ice-cooling and stirred at 60°C under argon for 4 h. After the reaction was completed as monitored by LC-MS, a saturated NH4Cl solution (100 mL) was slowly added under ice bath conditions to quench the reaction. The mixture was extracted with ethyl acetate (100 mL*3). The organic phases were combined, washed sequentially with water (50 mL) and saturated brine (50 mL), dried over anhydrous sodium sulfate, concentrated, and slurried with dichloromethane / methyl tert-butyl ether (1 / 5, 300 mL) for 0.5 h. The mixture was filtered, and the filter cake was rinsed with 100 mL of dichloromethane / methyl tert-butyl ether (1 / 5, 100 mL). The filter cake was dried to give A1-a (8.1 g, 70%) as a yellow solid. LC-MS: 359.1 [M+H] + .

[0263] Step 2: Synthesis of A2-a

[0264] To a 100 mL three-necked flask, add A1-a (2 g, 5.57 mmol), S-3 (1.98 g, 8.36 mmol), Pd(OAc)2 (250 mg, 1.114 mmol), the ligand n-butyldi(1-adamantyl)phosphine (400 mg, 1.114 mmol, CAS: 321921-71-5), and Cs2CO3 (3.63 g, 11.14 mmol). The mixture was dissolved in dioxane / water (4 / 1, 20 mL). The argon atmosphere was purged three times, and the mixture was stirred at 100°C for 1 h. After the reaction was completed, the reaction solution was filtered through celite and concentrated. Water (50 mL) was added and extracted with ethyl acetate (100 mL*3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated. The crude product was separated by column chromatography (dichloromethane / ethyl acetate = 25 / 75) to give a yellow solid A2-a (0.76 g, 34%). LC-MS: 410.3 [M+H] + .

[0265] Step 3: Synthesis of A3-a

[0266] A2-a (0.76 g, 1.86 mmol) was dissolved in 1,4-dioxane (2 mL). 4M hydrochloric acid / 1,4-dioxane solution (5 mL) was added dropwise in an ice bath and stirred at room temperature for 1 h. LC-MS indicated the reaction was complete. The product was concentrated to afford A3-a hydrochloride (0.62 g, 96%) as a yellow solid. LC-MS: 310.2 [M+H] + .

[0267] Similar to the synthesis of A3-a, the intermediates listed in Table 1 below can be obtained.

[0268] Table 1

[0269] Example 1 Synthesis of Compound 2-1-1

[0270] Step 1: Synthesis of B1-a

[0271] S-4 (2.5 g, 10 mmol) was dissolved in DMF (10 mL), and 30% ethanolic methylamine (1.14 g, 11 mmol) and DIEA (3.88 g, 30 mmol) were added. HATU (4.18 g, 11 mmol) was added under ice-cooling conditions, and the mixture was slowly warmed to room temperature and stirred for 2 h. LCMS indicated the reaction was complete. The crude product was separated by reverse-phase column chromatography (MeCN / H2O with 0.1% formic acid = 10 / 90 to 30 / 70) to afford B1-a (2.23 g, 85%) as a colorless oil. LC-MS: 262.1 [M+H] + .

[0272] Step 2: Synthesis of B2-a

[0273] B1-a (2.23 g, 8.5 mmol) was dissolved in THF (30 mL) in a 100 mL three-necked flask. BH3-MeS solution (2 M in THF, 12.8 mL) was added dropwise under ice-cooling and stirred at room temperature for 48 h under argon protection. LC-MS indicated the reaction was complete. Excess 4 M hydrochloric acid / 1,4-dioxane solution was added dropwise under ice-cooling to quench the mixture (until bubbles ceased). The mixture was concentrated to obtain a colorless oily crude product, which was dissolved in THF (15 mL). Boc2O (2.18 g, 10 mmol) was added under ice-cooling, followed by DIEA (3.87 g, 30 mmol) dropwise. The mixture was stirred at room temperature for 1 h. LCMS indicated the reaction was complete. The product was concentrated and the crude product was separated by column chromatography (ethyl acetate / petroleum ether = 5 / 95 to 15 / 85) to obtain B2-a (1.8 g, 61%) as a colorless oil. LC-MS: 348.1 [M+H] + .

[0274] Step 3: Synthesis of B3-a

[0275] To a 50 mL three-necked flask, B2-a (1.74 g, 5 mmol) was dissolved in anhydrous DMF (10 mL). Pd(OAc)2 (112 mg, 0.5 mmol), xant-phos (289 mg, 0.5 mmol), and DCC (1.03 g, 5 mmol) were added, followed by formic acid (1.15 g, 25 mmol) and triethylamine (1.01 g, 10 mmol). The argon atmosphere was rapidly purged three times, and the mixture was stirred at 80°C for 1 hour. LC-MS indicated the reaction was complete. The crude product was isolated by reverse-phase column chromatography (MeCN / H2O with 0.1% formic acid = 30 / 70 to 70 / 30) to afford B3-a (1.11 g, 71%) as a colorless oil. LC-MS: 314.2 [M+H] + .

[0276] Step 4: Synthesis of 2-1-1

[0277] B3-a (157 mg, 0.5 mmol), the hydrochloride salt of A3-a (173 mg, 0.5 mmol), and DIEA (194 mg, 1.5 mmol) were dissolved in DMF (2 mL). HATU (228 mg, 0.6 mmol) was added in an ice bath and allowed to react at room temperature for 1 h. LC-MS indicated the reaction was complete. The crude product was isolated by reverse-phase column chromatography (MeCN / H2O with 0.1% formic acid = 30 / 70 to 70 / 30) to afford a yellow solid (218 mg).

[0278] The above yellow solid (218 mg) was dissolved in 1,4-dioxane (2 mL), and a 4M hydrochloric acid / 1,4-dioxane solution (4 mL) was added under ice-cooling conditions. The mixture was stirred at room temperature for 1 h. LC-MS monitored the reaction completion, and the mixture was directly concentrated to give the hydrochloride salt of 2-1-1 (193 mg, 72%) as a yellow solid. LC-MS: 505.2 [M+H] + .

[0279] Example 2 Synthesis of Compound 2-3-15

[0280] Step 1: Synthesis of C1-a

[0281] S-4 (10 g, 40 mmol) was dissolved in THF (100 mL) in a 250 mL three-necked flask. BH3-MeS solution (2 M in THF, 40 mL) was added dropwise under an ice bath. The mixture was stirred at 50°C for 3 h under argon. LC-MS indicated the reaction was complete. The mixture was cooled to room temperature and quenched with methanol dropwise under an ice bath. The reaction was concentrated, and the crude product was isolated by column chromatography (ethyl acetate / petroleum ether = 1 / 50-1 / 20) to afford C1-a (9.0 g, 95%) as a colorless oil. LC-MS: 235.1 [M+H] + .

[0282] Step 2: Synthesis of C2-a

[0283] To a 250 mL three-necked flask, C1-a (8 g, 34 mmol) dissolved in toluene (80 mL) was added, followed by tert-butyl bromoacetate (13.3 g, 68 mmol), NaOH (4.1 g dissolved in 10 mL of water, 102 mmol), and tetrabutylammonium iodide (10 g, 27.2 mmol). The mixture was stirred at room temperature overnight under argon. LC-MS indicated completion of the reaction. The mixture was concentrated and poured into ice water (100 mL). Extraction was performed with dichloromethane (100 mL). The organic phases were combined, washed sequentially with water (100 mL) and saturated brine (100 mL), dried, and concentrated. The crude product was isolated by column chromatography (petroleum ether) to afford C2-a (8.9 g, 75%) as a colorless oil. LC-MS: 349.2 [M+H] + .

[0284] Step 3: Synthesis of C3-a

[0285] C2-a (7.0 g, 20.0 mmol) was dissolved in DCM (20 mL). TFA (7 mL) was added dropwise in an ice bath and stirred at room temperature for 1 h. LC-MS indicated the reaction was complete. The product was concentrated to give a colorless oily crude product (6.0 g, 99%). LC-MS: 293.[M+H] + .

[0286] The crude product (4.1 g, 14 mmol) was dissolved in N-methylpyrrolidone (20 mL), and 30% ethanolic methylamine (1.59 g, 15.4 mmol) and DIEA (5.4 g, 42 mmol) were added. HATU (5.85 g, 15.4 mmol) was added in an ice bath, and the mixture was slowly warmed to room temperature and stirred for 2 h. LC-MS indicated the reaction was complete. The crude product was isolated by reverse-phase column chromatography (MeCN / H2O with 0.1% formic acid = 10 / 90 to 30 / 70) to afford C3-a (3.1 g, 72%) as a colorless oil. LC-MS: 306.1 [M+H] + .

[0287] Step 4: Synthesis of C4-a

[0288] C3-a (2.9 g, 9.5 mmol) was dissolved in THF (30 mL) in a 100 mL three-necked flask. BH3-MeS solution (2 M in THF, 14.2 mL) was added dropwise under ice-cooling and stirred at room temperature for 48 h under argon. LC-MS indicated the reaction was complete. Excess 4.0 M HCl / 1,4-dioxane solution was added dropwise under ice-cooling to quench the mixture (until bubbling ceased). The mixture was concentrated to afford a colorless crude oil, which was dissolved in THF (15 mL). Boc2O (2.18 g, 10 mmol) was added under ice-cooling, followed by DIEA (3.87 g, 30 mmol) dropwise. The mixture was stirred at room temperature for 1 h. LC-MS indicated the reaction was complete. The mixture was concentrated and the crude product was isolated by column chromatography (ethyl acetate / petroleum ether = 10 / 90 to 50 / 50) to afford C4-a (2.4 g, 65%) as a colorless oil. LC-MS: 392.3 [M+H] + .

[0289] Step 5: Synthesis of C5-a

[0290] C4-a (2.4 g, 6 mmol) was dissolved in anhydrous DMF (10 mL) in a 50 mL three-necked flask. Pd(OAc)2 (136 mg, 0.6 mmol), xant-phos (347 mg, 0.6 mmol), and DCC (1.24 g, 6 mmol) were then added, followed by formic acid (1.38 g, 30 mmol) and triethylamine (1.22 g, 12 mmol). The argon atmosphere was rapidly purged three times, and the mixture was stirred at 80°C for 1 h. LC-MS indicated the reaction was complete. The crude product was isolated by reverse-phase column chromatography (MeCN / H2O with 0.1% formic acid = 30 / 70 to 70 / 30) to afford C5-a (1.4 g, 65%) as a colorless oil. LC-MS: 358.3 [M+H] + .

[0291] Step 5: Synthesis of 2-3-15

[0292] C5-a (208 mg, 0.582 mmol), A3-a (200 mg, 0.582 mmol), and DIEA (227 mg, 1.75 mmol) were dissolved in DMF (4 mL). HATU (265 mg, 0.7 mmol) was added under ice-cooling conditions, and the mixture was stirred at room temperature for 1 h. LC-MS indicated the reaction was complete. The crude product was isolated by reverse-phase column chromatography (MeCN / H₂O with 0.1% formic acid = 30 / 70 to 70 / 30) to afford a yellow solid (250 mg).

[0293] The above yellow solid (250 mg) was dissolved in 1,4-dioxane (2 mL). 4M hydrochloric acid / 1,4-dioxane solution (4 mL) was added under ice-cooling conditions and stirred at room temperature for 1 h. LC-MS monitored the reaction completion and the product was directly concentrated to give the 2-hydrochloride salt of a yellow solid (220 mg, 64%). LC-MS: 549.2 [M+H] + .

[0294] Example 3 Synthesis of Compound 2-3-50

[0295] Step 1: Synthesis of D1-a

[0296] S-4 (10 g, 40 mmol) was dissolved in DCM (100 mL). SOCl2 (10 mL) was slowly added dropwise under an ice bath. The mixture was stirred at 40°C for 1 h under argon. LC-MS indicated the reaction was complete. Excess methanol was then added dropwise under an ice bath until bubbling ceased. The mixture was concentrated, and the crude product was separated by column chromatography (ethyl acetate / petroleum ether = 1 / 99 to 5 / 95) to afford D1-a (10 g, 95%) as a colorless oil. LC-MS: 263.1 [M+H] + .

[0297] Step 2: Synthesis of D2-a

[0298] D1-a (5.5 g, 18.97 mmol) was dissolved in THF (25 mL). Under argon, a LiHMDS solution (2 M in THF, 28.5 mL) was slowly added at -78°C. The mixture was stirred at -78°C for 1 h, followed by the dropwise addition of MeI (8 g, 57 mmol). After the addition was complete, the temperature was slowly raised to room temperature and stirred for 3 h. LC-MS monitored the reaction completion. The mixture was quenched with saturated ammonium chloride solution (50 mL) and extracted with ethyl acetate (100 mL*3). The organic phases were combined, washed sequentially with water (100 mL) and saturated brine (100 mL), dried, and concentrated. The crude product was purified by column chromatography (ethyl acetate / petroleum ether = 5 / 95-10 / 90) to afford D2-a (2.95 g, 54%) as a colorless oil. LC-MS: 291.1 [M+H]+ .

[0299] Step 3: Synthesis of D3-a

[0300] D2-a (2.95 g, 10.2 mmol) was dissolved in THF (30 mL). Lithium aluminum tetrahydride solution (2.5 M in THF, 4.9 mL) was added dropwise under ice-cooling conditions. The temperature was slowly warmed to room temperature and stirred for 1 h. LC-MS monitored the reaction completion. Water (0.46 mL), 15% aqueous NaOH solution (0.92 mL), and water (1.38 mL) were added sequentially under ice-cooling conditions to quench the reaction. The mixture was filtered, washed with ethyl acetate, and the combined organic phases were concentrated. The crude product was purified by column chromatography (ethyl acetate / petroleum ether = 2 / 98 to 10 / 90) to afford D3-a (2.23 g, 83%) as a colorless oil. LC-MS: 263.1 [M+H] + .

[0301] Step 4: Synthesis of D4-a

[0302] In a 250 mL three-necked flask, D3-a (2.23 g, 8.46 mmol) was dissolved in toluene (30 mL). Tert-butyl bromoacetate (12.9 g, 66 mmol) and tetrabutylammonium iodide (2.51 g, 6.81 mmol) were added. NaOH solution (3.38 g, 84.6 mmol dissolved in 30 mL of water) was added under ice-cooling. Stirring was continued at room temperature under argon overnight. LC-MS indicated the reaction was complete. The mixture was concentrated and poured into ice water (50 mL). The mixture was then extracted with ethyl acetate (100 mL x 3). The organic phases were combined, washed sequentially with water (100 mL) and saturated brine (100 mL), dried over anhydrous sodium sulfate, and concentrated. The crude product was isolated by column chromatography (ethyl acetate / petroleum ether = 1 / 99 to 5 / 95) to afford D4-a (545 mg, 17%) as a colorless oil. LC-MS: 377.1 [M+H] + .

[0303] Step 5: Synthesis of D5-a

[0304] D4-a (545 mg, 1.44 mmol) was dissolved in DCM (5 mL) and TFA (1 mL) was added dropwise under ice-cooling conditions. The mixture was stirred at room temperature for 1 h. LC-MS indicated the reaction was complete. The product was concentrated to give a colorless oily crude product (442 mg).

[0305] The crude product (442 mg, 1.38 mmol) was dissolved in N-methylpyrrolidone (3 mL), and 30% ethanolic methylamine (157 mg, 1.52 mmol) and DIEA (357 mg, 2.76 mmol) were added. HATU (630 mg, 1.656 mmol) was added under ice-cooling conditions, and the mixture was slowly warmed to room temperature and stirred for 2 h. LC-MS indicated the reaction was complete. The crude product was isolated by reverse-phase column chromatography (MeCN / H2O with 0.1% formic acid = 10 / 90 to 70 / 30) to afford D5-a (388 mg, 80%) as a colorless oil. LC-MS: 334.1 [M+H] + .

[0306] Step 6: Synthesis of D6-a

[0307] D5-a (388 mg, 1.162 mmol) dissolved in THF (5 mL) was added to a 100 mL three-necked flask. BH3-MeS solution (2 M in THF, 1.75 mL) was added dropwise under ice-cooling. The mixture was stirred at 60°C under argon for 48 h. LC-MS indicated completion of the reaction. The mixture was quenched by dropwise addition of an excess of 4.0 M HCl / 1,4-dioxane solution under ice-cooling (until bubbling ceased). The mixture was concentrated to afford a colorless crude oil, which was dissolved in THF (5 mL). Boc2O (381 mg, 1.743 mmol) was added under ice-cooling, followed by the dropwise addition of DIEA (300 mg, 2.324 mmol). The mixture was stirred at room temperature for 1 h. LC-MS showed that the reaction was complete, and the product was concentrated. The crude product was separated by column chromatography (EA / PE = 5 / 95-10 / 90) to give D6-a (395 mg, 81%) as a colorless oil. LC-MS: 442.1 [M+Na] + .

[0308] Step 7: Synthesis of D7-a

[0309] D6-a (390 mg, 0.928 mmol) was dissolved in DMF (5 mL) in a 50 mL three-necked flask. Pd(OAc)2 (10.5 mg, 0.046 mmol), xant-phos (26.6 mg, 0.046 mmol), and DCC (191 mg, 0.928 mmol) were then added. Formic acid (213 mg, 4.64 mmol) and triethylamine (187 mg, 1.856 mmol) were then added sequentially. After rapid evacuation of argon three times, the mixture was stirred at 80°C for 1 h. LC-MS indicated the reaction was complete. The crude product was isolated by reverse-phase column chromatography (MeCN / H2O with 0.1% formic acid = 30 / 70 to 70 / 30) to afford D7-a (320 mg, 89%) as a colorless oil. LC-MS: 408.2 [M+Na]+ .

[0310] Step 8: Synthesis of 2-3-50

[0311] D7-a (320 mg, 0.83 mmol), the hydrochloride salt of A3-a (286 mg, 0.83 mmol), and DIEA (215 mg, 1.66 mmol) were dissolved in DMF (4 mL). HATU (378 mg, 0.996 mmol) was added in an ice bath and allowed to react at room temperature for 1 h. LC-MS indicated the reaction was complete. The crude product was isolated by reverse-phase column chromatography (MeCN / H2O with 0.1% formic acid = 10 / 90 to 30 / 70) to afford a yellow solid (148 mg, 25%). LC-MS: 677.3 [M+H] + .

[0312] The above yellow solid (100 mg, 0.148 mmol) was dissolved in 1,4-dioxane (1 mL). 4M hydrochloric acid / 1,4-dioxane solution (2 mL) was added under ice-cooling conditions and stirred at room temperature for 1 h. LC-MS monitored the reaction completion and the mixture was directly concentrated to afford the hydrochloride salt of 2-3-50 (85 mg, 94%) as a yellow solid. LC-MS: 577.2 [M+H] + .

[0313] Example 4 Synthesis of Compound 2-3-51

[0314] Step 1: Synthesis of E1-a

[0315] D1-a (5 g, 18.97 mmol) was dissolved in DMF (50 mL). Under argon, 60% NaH (1.67 g, 41.8 mmol, 60% in mineral oil) was added portionwise on ice. The mixture was stirred on ice for 1 h. 1,2-dibromoethane (3.93 g, 20.87 mmol) was then added dropwise. After the addition was complete, the mixture was slowly warmed to room temperature and stirred overnight. LC-MS monitored the reaction completion. The mixture was quenched with saturated ammonium chloride solution (50 mL) and extracted with ethyl acetate (100 mL x 3). The organic phases were combined, washed sequentially with water (100 mL) and saturated brine (100 mL), dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by column chromatography (ethyl acetate / petroleum ether = 1 / 99 to 5 / 95) to afford E1-a (1.54 g, 28%) as a colorless oil. LC-MS: 289.1 [M+H] + .

[0316] Step 2: Synthesis of E2-a

[0317] E1-a (1.53 g, 5.28 mmol) was dissolved in THF (10 mL). LAH (1 M in THF, 5.3 mL) was added dropwise under ice-cooling conditions. The mixture was slowly warmed to room temperature and stirred for 1 h. LC-MS monitored the reaction completion. Water (0.2 mL), 15% aqueous NaOH (0.4 mL), and water (0.6 mL) were added sequentially under ice-cooling conditions to quench the reaction. The mixture was filtered, washed with ethyl acetate, and the combined organic phases were concentrated. The crude product was purified by column chromatography (ethyl acetate / petroleum ether = 2 / 98 to 10 / 90) to afford E2-a (1.04 g, 75%) as a colorless oil. LC-MS: 261.1 [M+H] + .

[0318] Step 3: Synthesis of E3-a

[0319] To a 250 mL three-necked flask, E2-a (1.04 g, 3.98 mmol) was dissolved in toluene (20 mL). Tert-butyl bromoacetate (6.2 g, 31.84 mmol) and tetrabutylammonium iodide (1.5 g, 3.98 mmol) were added. Aqueous NaOH (1.6 g, 39.8 mmol dissolved in 30 mL of water) was added under ice-cooling. The mixture was stirred at room temperature overnight under argon. LC-MS indicated the reaction was complete. The mixture was concentrated and poured into ice water (50 mL). The mixture was then extracted with ethyl acetate (100 mL x 3). The organic phases were combined, washed sequentially with water (100 mL) and saturated brine (100 mL), dried over anhydrous sodium sulfate, and concentrated. The crude product was isolated by column chromatography (ethyl acetate / petroleum ether = 1 / 99 to 5 / 95) to afford E3-a (420 mg, 28%) as a colorless oil. LC-MS: 375.1 [M+H] + .

[0320] Step 4: Synthesis of E4-a

[0321] E3-a (420 mg, 1.117 mmol) was dissolved in DCM (5 mL) and TFA (1 mL) was added dropwise under ice-cooling conditions. The mixture was stirred at room temperature for 1 hour. LC-MS indicated the reaction was complete. The product was concentrated and the crude product was separated by reversed-phase chromatography (MeCN / H2O with 0.1% formic acid = 20 / 80 to 60 / 40) to afford a colorless oil (171 mg, 48%). LC-MS: 319.2 [M+H] + .

[0322] The above compound (171 mg, 0.536 mmol) was dissolved in N-methylpyrrolidone (1 mL), and 30% ethanolic methylamine (56 mg, 0.536 mmol) and DIEA (138 mg, 1.072 mmol) were added. HATU (244 mg, 0.643 mmol) was added under ice-cooling conditions, and the mixture was slowly warmed to room temperature and stirred for 1 h. LCMS indicated the reaction was complete. The crude product was isolated by reverse-phase column chromatography (MeCN / H2O with 0.1% formic acid = 10 / 90 to 50 / 50) to afford E4-a (145 mg, 82%) as a colorless oil. LC-MS: 332.1 [M+H] + .

[0323] Step 5: Synthesis of E5-a

[0324] To a 100 mL three-necked flask, E4-a (145 mg, 0.436 mmol) dissolved in THF (2 mL) was added dropwise. BH₃-MeS solution (2 M in THF, 1.31 mL) was added dropwise under ice-cooling, and the mixture was stirred at 60°C for 1 h under argon. LC-MS indicated completion of the reaction. The mixture was quenched by dropwise addition of an excess of 4.0 M HCl / 1,4-dioxane solution under ice-cooling (until bubbling ceased). The mixture was concentrated to afford a colorless crude oil, which was dissolved in THF (3 mL). Boc₂O (142 mg, 0.651 mmol) was added dropwise under ice-cooling, followed by DIEA (112 mg, 0.866 mmol), and stirred at room temperature for 1 h. LC-MS showed that the reaction was complete, and the product was concentrated. The crude product was separated by column chromatography (ethyl acetate / petroleum ether = 5 / 95-10 / 90) to give colorless oil E5-a (118 mg, 65%), LC-MS: 440.1 [M+Na] + .

[0325] Step 6: Synthesis of E6-a

[0326] To a 50 mL three-necked flask, E5-a (118 mg, 0.282 mmol) dissolved in DMF (3 mL) was added. Pd(OAc)2 (3.2 mg, 0.014 mmol), xant-phos (8.15 mg, 0.014 mmol), and DCC (58 mg, 0.282 mmol) were then added. Formic acid (65 mg, 1.409 mmol) and triethylamine (57 mg, 0.564 mmol) were then added. After rapid evacuation of argon three times, the mixture was stirred at 80°C for 1 h. LC-MS indicated the reaction was complete. The crude product was isolated by reverse-phase column chromatography (MeCN / H2O with 0.1% formic acid = 30 / 70 to 70 / 30) to afford E6-a (100 mg, 92%) as a colorless oil. LC-MS: 384.2 [M+H]+ .

[0327] Step 7: Synthesis of 2-3-51

[0328] E6-a (100 mg, 0.26 mmol), the hydrochloride salt of A3-a (90.1 mg, 0.26 mmol), and DIEA (68 mg, 0.52 mmol) were dissolved in DMF (2 mL). HATU (118 mg, 0.312 mmol) was added under ice-cooling conditions and allowed to react at room temperature for 1 h. LC-MS indicated the reaction was complete. The crude product was isolated by reverse-phase column chromatography (MeCN / H2O with 0.1% formic acid = 10 / 90 to 60 / 40) to afford a yellow solid (148 mg, 84%). LC-MS: 697.3 [M+Na] + .

[0329] The above yellow solid (148 mg, 0.219 mmol) was dissolved in 1,4-dioxane (1 mL). 4M hydrochloric acid-1,4-dioxane solution (3 mL) was added under ice-cooling conditions and stirred at room temperature for 1 h. LC-MS monitored the reaction completion and the product was concentrated to give the hydrochloride salt of 2-3-51 (126 mg, 95%) as a yellow solid. LC-MS: 575.23 [M+H] + .

[0330] Example 5 Synthesis of Compound 2-5-2

[0331] Step 1: Synthesis of F1-a

[0332] S-5 (5.0 g, 23.19 mmol) was dissolved in THF (75 mL) in a 250 mL three-necked flask. BH₃-MeS solution (2 M in THF, 23.2 mL) was added dropwise under an ice bath. The mixture was stirred at 70°C for 2 h under argon. LC-MS indicated the reaction was complete. The mixture was cooled to room temperature and quenched with methanol dropwise under an ice bath. The reaction was concentrated, and the crude product was isolated by reverse-phase column chromatography (MeCN / H₂O with 0.1% formic acid = 30 / 70 to 60 / 40) to afford F1-a (4.3 g, 92%) as a yellow solid. LC-MS: 224.1 [M+Na] + .

[0333] Step 2: Synthesis of F2-a

[0334] In a 250 mL three-necked flask, F1-a (4.3 g, 21.38 mmol) was dissolved in toluene (120 mL). Tert-butyl bromoacetate (29.1 g, 149 mmol) and tetrabutylammonium hydrogen sulfate (5.8 g, 17.06 mmol) were added dropwise. Aqueous NaOH (5.3 g, 132 mmol dissolved in 20 mL of water) was added dropwise under an ice bath. Stirring was continued at room temperature under argon overnight. LC-MS indicated the reaction was complete. The mixture was concentrated, poured into ice water (50 mL), and extracted with ethyl acetate (100 mL x 3). The organic phases were combined, washed sequentially with water (100 mL) and saturated brine (100 mL), dried over anhydrous sodium sulfate, and concentrated. The crude product was isolated by reverse-phase column chromatography (MeCN / H2O with 0.1% formic acid = 30 / 70-80 / 20) to afford F2-a (3.7 g, 55%) as a yellow oil. LC-MS: 338.1 [M+Na] + .

[0335] Step 3: Synthesis of F3-a

[0336] F2-a (3.7 g, 11.72 mmol) was dissolved in DCM (20 mL). TFA (5 mL) was added dropwise in an ice bath and stirred at room temperature for 1 h. LC-MS indicated completion of the reaction. The crude product was concentrated and dissolved in DMF (20 mL). 30% ethanolic methylamine solution (1.24 g, 12 mmol) and DIEA (3.0 g, 23.44 mmol) were added. HATU (5.3 g, 14.1 mmol) was added in an ice bath and the mixture was slowly warmed to room temperature and stirred for 1 h. LC-MS showed the reaction was complete. The system was poured into ice water (100 mL) and extracted with ethyl acetate (100 mL*3). The organic phases were combined, washed sequentially with water (100 mL) and saturated brine (100 mL), dried over anhydrous sodium sulfate, and concentrated. The crude product was separated by reverse column chromatography (MeCN / H2O with 0.1% formic acid = 10 / 90 to 50 / 50) to obtain a yellow oil F3-a (2.8 g, 88%). LC-MS: 273.1 [M+H] + .

[0337] Step 4: Synthesis of F4-a

[0338] To a 100 mL three-necked flask, F3-a (2.8 g, 10.27 mmol) dissolved in THF (40 mL) was added dropwise. BH3-MeS solution (2 M in THF, 10.3 mL) was added dropwise under ice-cooling, and the mixture was stirred at 60°C for 2 h under argon. LC-MS indicated completion of the reaction. The mixture was quenched by dropwise addition of an excess of 4.0 M HCl / 1,4-dioxane solution under ice-cooling (until bubbling ceased). The mixture was concentrated to afford a colorless crude oil, which was dissolved in DCM (20 mL). Boc2O (4.1 g, 18.5 mmol) was added dropwise under ice-cooling, followed by DIEA (3.87 g, 30 mmol), and stirred at room temperature overnight. LC-MS showed that the reaction was complete, and the product was concentrated. The crude product was separated by reverse column chromatography (MeCN / H2O with 0.1% formic acid = 10 / 90-70 / 30) to give F4-a (1.3 g, 35%) as a colorless oil. LC-MS: 359.3 [M+H] + .

[0339] Step 5: Synthesis of F5-a

[0340] F4-a (1.2 g, 3.34 mmol) and ammonium chloride (1.8 g, 33 mmol) were dissolved in ethanol / water (20 mL / 10 mL). Iron powder (1.87 g, 33.4 mmol) was added and stirred at 60°C for 1 h. LC-MS indicated the reaction was complete. The mixture was filtered, the residue washed with ethanol, and the solution concentrated. The crude product was separated by reverse-phase column chromatography (MeCN / H2O with 0.1% formic acid = 10 / 90 to 50 / 50) to afford F5-a (0.85 g, 77%) as a colorless oil. LC-MS: 329.3 [M+H] + .

[0341] Step 6: Synthesis of 2-5-2

[0342] F5-a (328 mg, 1.0 mmol) was dissolved in N-methylpyrrolidone (3 mL). Triphosgene (100 mg, 0.34 mmol) was added under ice-cooling conditions. After stirring for 20 minutes under ice-cooling conditions, DIEA (387 mg, 3.0 mmol) and the hydrochloride salt of A3-a (346 mg, 1.0 mmol) were added sequentially. The mixture was slowly warmed to room temperature and stirred for 1 hour. LC-MS indicated the reaction was complete. The crude product was isolated by reverse-phase column chromatography (MeCN / H2O with 0.1% formic acid = 10 / 90 to 60 / 40) to afford a yellow solid (0.45 g, 68%). LC-MS: 664.3 [M+H] + .

[0343] The above yellow solid (0.45 g, 0.68 mmol) was dissolved in 1,4-dioxane (2 mL). 4M hydrochloric acid / 1,4-dioxane solution (4 mL) was added under ice-cooling conditions and stirred at room temperature for 1 h. LC-MS monitored the reaction completion and the product was directly concentrated to give the hydrochloride salt of 2-5-2 (364 mg, 95%) as a yellow solid. LC-MS: 564.3 [M+H] + .

[0344] Similar syntheses to 2-1-1, 2-3-15, 2-3-50, 2-3-51, and 2-5-2 can yield the compounds listed in Table 2 below.

[0345] Table 2

[0346] Example 6 Synthesis of Compound 3-1-1

[0347] The hydrochloride salt of 2-3-15 (58.6 mg, 0.1 mmol), S-6 (8.4 mg, 0.11 mmol), and DIEA (38.8 mg, 0.3 mmol) were dissolved in DMF (2 mL). HATU (41.8 mg, 0.11 mmol) was added in an ice bath and allowed to react at room temperature for 1 h. LC-MS indicated the reaction was complete. The crude product was isolated by reverse-phase column chromatography (MeCN / H2O with 0.1% formic acid = 10 / 90 to 60 / 40) to afford a yellow solid (45.5 mg, 75%). LC-MS: 629.3 [M+Na] + .

[0348] Similar to the synthesis of 3-1-1, the compounds listed in Table 3 below can be obtained.

[0349] Table 3

[0350] Example 7 Synthesis of Compound 4-1-1

[0351] Step 1: Synthesis of G1-a

[0352] The hydrochloride salt of 2-3-15 (100 mg, 0.17 mmol), S-7 (45 mg, 0.19 mmol), and DIEA (70 mg, 0.55 mmol) were dissolved in DMF (2 mL). HATU (83 mg, 0.22 mmol) was added under ice-cooling conditions, and the mixture was stirred at room temperature for 1 h. LC-MS indicated the reaction was complete. The crude product was isolated by reverse-phase column chromatography (MeCN / H2O with 0.1% formic acid = 10 / 90 to 60 / 40) to afford a yellow solid (90 mg, 68%). LC-MS: 768.4 [M+H] + .

[0353] Step 2: Synthesis of 4-1-1

[0354] G1-a (90 mg, 0.117 mmol) was dissolved in 1,4-dioxane (1 mL). 4M hydrochloric acid-1,4-dioxane solution (1 mL) was added under ice-cooling conditions and stirred at room temperature for 1 h. The reaction was monitored by LC-MS. The crude product was isolated by reverse-phase column chromatography (MeCN / H2O with 0.1% formic acid = 10 / 90 to 40 / 60) to afford a yellow solid (41 mg, 52%). LC-MS: 668.4 [M+H] + .

[0355] Similar to the synthesis of 4-1-1, the compounds listed in Table 4 below can be obtained.

[0356] Table 4

[0357] Example 8 Synthesis of Compound 5-1-1

[0358] 4-1-1 (33.4 mg, 0.05 mmol), S-6 (7.6 mg, 0.1 mmol), and DIEA (19.4 mg, 0.15 mmol) were dissolved in DMF (1 mL). HATU (22.8 mg, 0.06 mmol) was added under ice-cooling conditions and stirred at room temperature for 1 h. LC-MS indicated the reaction was complete. The crude product was separated by reverse-phase column chromatography (MeCN / H2O with 0.1% formic acid = 10 / 90 to 60 / 40) to afford 5-1-1 (23.2 mg, 64%) as a yellow solid. LC-MS: 726.5 [M+H] + .

[0359] Example 9 Synthesis of Compound 5-1-8

[0360] Step 1: Synthesis of H1-a

[0361] S-6 (2 g, 26.3 mmol) and DIEA (10.2 g, 79 mmol) were dissolved in DCM (50 mL). tert-Butyldiphenylsilyl chloride (18.1 g, 65.7 mmol) was added portionwise in an ice bath, and the mixture was stirred for 2 h. TLC indicated completion of the reaction. The mixture was concentrated to remove most of the DCM, added to water (50 mL), and extracted with petroleum ether (50 mL x 3). The organic phases were combined, washed with 0.5 M dilute hydrochloric acid solution (50 mL), concentrated, and dissolved in THF / water (20 mL / 20 mL). Potassium carbonate (3.6 g, 26.3 mmol) was added, and the mixture was stirred at room temperature overnight. The mixture was concentrated and extracted with ethyl acetate. Dilute hydrochloric acid was added to the aqueous phase to adjust the pH to 5. The mixture was extracted with ethyl acetate (50 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to afford H1-a (6.7 g, 82%) as a colorless oil, which was used directly in the next step.

[0362] Step 2: Synthesis of H2-a

[0363] H1-a (700 mg, 2.226 mmol), p-aminobenzyl alcohol (274 mg, 2.226 mmol), and DIEA (575 mg, 4.45 mmol) were dissolved in DMF (5 mL). HATU (1.0 g, 2.63 mmol) was added under ice-cooling conditions, and the mixture was stirred at room temperature for 2 h. LC-MS indicated the reaction was complete. The crude product was separated by reverse-phase column chromatography (MeCN / H2O with 0.1% formic acid = 10 / 90 to 70 / 30) to afford H2-a (710 mg, 76%) as a colorless oil. LC-MS: 442.2 [M+Na] + .

[0364] Step 3: Synthesis of H3-a

[0365] H2-a (400 mg, 0.95 mmol) and di(p-nitrobenzene) carbonate (NPC, 580 mg, 1.91 mmol) were dissolved in DMF (5 mL). DIEA (246 mg, 1.91 mmol) was added in an ice bath and stirred at room temperature for 2 h. LC-MS indicated the reaction was complete. The crude product was separated by reverse-phase column chromatography (MeCN / H2O with 0.1% formic acid = 30 / 70 to 90 / 10) to afford H3-a (200 mg, 36%) as a colorless oil. LC-MS: 607.2 [M+Na] + .

[0366] Step 4: Synthesis of H4-a

[0367] H3-a (70 mg, 0.12 mmol) and the hydrochloride salt of 2-3-15 (70 mg, 0.12 mmol) were dissolved in DMF (3 mL). HOBt (31 mg, 0.24 mmol) and DIEA (31 mg, 0.24 mmol) were added sequentially under ice-cooling conditions, and the mixture was stirred at room temperature for 1 h. LC-MS indicated the reaction was complete. The crude product was separated by reverse-phase column chromatography (MeCN / H2O with 0.1% formic acid = 30 / 70 to 90 / 10) to afford H4-a (60 mg, 50%) as a colorless oil. LC-MS: 994.5 [M+H] + .

[0368] Step 5: Synthesis of 5-1-8

[0369] H4-a (60 mg, 0.06 mmol) was dissolved in THF (4 mL). TBAF tetrahydrofuran solution (1 N, 0.5 mL) was added under ice-cooling and stirred for 2 h under ice-cooling. LC-MS indicated the reaction was complete. The crude product was separated by reverse-phase column chromatography (MeCN / H2O with 0.1% formic acid = 10 / 90 to 50 / 50) to afford 5-1-8 (30 mg, 66%) as a yellow solid. LC-MS: 778.3 [M+Na] + .

[0370] 1H NMR (400MHz, DMSO-d6) δ11.13(s,1H),9.68(s,1H),9.13(t,J=6.0Hz,1H),8.44(d,J=8.4Hz,1H),8.09(d,J=6.8Hz,1H),7.9(d,J=1. 6Hz,1H),7.85(t,J=7.6Hz,1H),7.75(d,J=8.0Hz,1H),7.67-7.64(m,2H),7.47(d,J=7.2Hz,1H),7.44-7.38(m,1H),7.27-7.24(m,2H ),7.10(d,J=7.6Hz,1H),5.65(t,J=6.4Hz,1H),5.44(dd,J=12.8,5.2Hz,1H),4.95(s,2H),4.88(d,J=5.6Hz,2H),3.96(d,J=5.6Hz, 2H),3.62-3.55(m,2H),3.49-3.45(m,2H),3.28(s,3H),2.98-2.89(m,3H),2.79-2.76(m,3H),2.66-2.61(m,1H),2.09-2.05(m,1H).

[0371] Similar synthesis to 5-1-1 and 5-1-8 can obtain the compounds listed in Table 5 below.

[0372] Table 5

[0373] Example 10 Preparation of Antibody-Drug Conjugate (ADC-6)

[0374] Step 1: Preparation of compound 6

[0375] The hydrochloride salt of 2-3-15 (58.6 mg, 0.1 mmol) and HOBt (13.5 mg, 0.1 mmol) were dissolved in DMF (2 mL). S-10 (73.7 mg, 0.1 mmol) and DIEA (38.8 mg, 0.3 mmol) were added sequentially in an ice bath. The mixture was slowly warmed to room temperature and reacted for 1 h. LC-MS indicated the reaction was complete. The crude product was isolated by reverse-phase column chromatography (MeCN / H2O with 0.1% formic acid = 10 / 90 to 70 / 30) to afford a yellow solid (70.1 mg, 61%). LC-MS: 1169.6 [M+Na] + .

[0376] Step 2: Preparation of compound ADC-6

[0377] At 37°C, a solution of trastuzumab in PBS buffer (2 mL, pH 7.0, 50 mM PBS, 1 mM EDTA buffer, 10.8 mg / mL, 146 nmol) was added with a prepared aqueous solution of tris(2-carboxyethyl)phosphine (5 mg / mL, 110 μL, 15 eq) and incubated at 37°C for 1 hour. The antibody solution was transferred to an ultrafiltration centrifuge tube and diluted with 10 mM citric acid, 1 mM EDTA, pH 5.0 buffered saline (15 mL). The solution was then ultrafiltered and centrifuged (12 min, 4500 rpm) for a total of 6 times. After ultrafiltration and concentration, the pH was adjusted to 6.5 with 1M sodium citrate buffer solution. 94.6 μL (4.0 eq, 1 mg / mL) of DHAA solution was added to the antibody solution and allowed to react at 4°C for 2 h. After completion of the reaction (the reaction solution was slightly turbid), the solution was transferred to an ultrafiltration centrifuge tube and diluted to 15 mL with 10 mM citric acid, 1 mM EDTA, pH 5.0 buffer solution. After ultrafiltration and centrifugation (12 min, 4500 rpm) for a total of 6 times, the solution was transferred to a centrifuge tube to obtain 3.46 mL of sample. The sample solution was measured and the sample concentration was determined using a UV-visible spectrophotometer. The sample recovery rate was determined to be 91% and the concentration was 5.37 mg / mL.

[0378] 1.70 mL of the above antibody solution (containing 9.10 mg of antibody) was added to a test tube, and the pH was adjusted to 6.0 with 1 M sodium citrate buffer. 76.2 μL (5 mg / mL, 5.5 eq) of compound 6 in DMSO was added to the antibody solution, mixed thoroughly, and allowed to react at room temperature for 90 min. After completion of the reaction, the solution was filtered through a 0.22 μM filter and transferred to an ultrafiltration centrifuge tube. The solution was diluted to 15 mL with 6% sucrose-histidine buffer and ultrafiltration centrifuged six times (12 min, 4500 rpm) to obtain the ADC-6 buffer solution, which was then stored frozen at 4°C. Average value calculated by UV-HPLC: n = 4.3.

[0379] Example 11 Preparation of Antibody-Drug Conjugate (ADC-7)

[0380] Step 1: Preparation of compound 7

[0381] The hydrochloride salt of 2-3-23 (58.0 mg, 0.1 mmol) and HOBt (13.5 mg, 0.1 mmol) were dissolved in DMF (2 mL). S-10 (73.7 mg, 0.1 mmol) and DIEA (38.8 mg, 0.3 mmol) were added sequentially under ice-cooling conditions. The mixture was slowly warmed to room temperature and reacted for 1 h. LC-MS indicated the reaction was complete. The crude product was isolated by reverse-phase column chromatography (MeCN / H2O with 0.1% formic acid = 10 / 90 to 70 / 30) to afford a yellow solid (65.1 mg, 57%). LC-MS: 1165.6 [M+Na] + .

[0382] Step 2: Preparation of compound ADC-7

[0383] To a PBS buffer solution (4 mL, pH 7.0, 50 mM, containing 1 mM EDTA, 10.8 mg / mL, 292 nmol) of the antibody trastuzumab was added 252 μL of an aqueous solution of tris(2-carboxyethyl)phosphine hydrochloride (CAS: 51805-45-9) (5 mg / mL) at 37°C and incubated at 37°C for 1 hour. The antibody solution was transferred to an ultrafiltration centrifuge tube and diluted to 15 mL with citrate buffer (pH 5.0, 10 mM, containing 1 mM EDTA). The solution was then ultrafiltered and concentrated six times (12 min, 4500 rpm) to yield 6.94 mL of sample. The sample concentration was determined using a UV-visible spectrophotometer, yielding a recovery of 91% and a concentration of 5.90 mg / mL. 6.82 mL of the above sample (containing 40.2 mg of antibody) was adjusted to pH 6.5 with 1 M sodium citrate buffer. 189 μL of a 1 mg / mL aqueous solution of dehydroascorbic acid (CAS: 490-83-5) was added to the antibody solution and allowed to react at 4°C for 2 h. The solution was transferred to an ultrafiltration centrifuge tube and diluted to 15 mL with 10 mM citrate buffer (pH 5.0, containing 1 mM EDTA). After ultrafiltration and centrifugation six times (12 min at 4500 rpm), the solution was transferred to a centrifuge tube to yield 6.92 mL of sample. The sample concentration was determined using a UV-Vis spectrophotometer, yielding a recovery of 91% and a concentration of 5.37 mg / mL.

[0384] 1.70 mL of the above antibody solution (containing 9.10 mg of antibody) was added to a test tube. The pH was adjusted to 6.0 with 1 M sodium citrate buffer. 77.2 μL of a 5 mg / mL DMSO solution of compound 7 was added to the antibody solution, mixed thoroughly, and allowed to react at room temperature for 90 min. After completion of the reaction, the solution was filtered through a 0.22 μM filter and transferred to an ultrafiltration centrifuge tube. The solution was diluted to 15 mL with histidine buffer (pH 6.0, 25 mM, containing 6% sucrose). Ultrafiltration and centrifugation were performed six times (12 min, 4500 rpm) to obtain the ADC-7 buffer solution, which was then stored frozen at 4°C. Average value calculated by UV-HPLC: n = 4.1.

[0385] Example 12 Preparation of Antibody-Drug Conjugate (ADC-8)

[0386] Step 1: Preparation of compound 8

[0387] The hydrochloride salt of 2-5-2 (60 mg, 0.1 mmol) and HOBt (13.5 mg, 0.1 mmol) were dissolved in DMF (2 mL). S-10 (73.7 mg, 0.1 mmol) and DIEA (38.8 mg, 0.3 mmol) were added sequentially in an ice bath. The mixture was slowly warmed to room temperature and allowed to react for 1 h. LC-MS indicated the reaction was complete. The crude product was isolated by reverse-phase column chromatography (MeCN / H2O with 0.1% formic acid = 10 / 90 to 70 / 30) to afford a yellow solid (60.2 mg, 52%). LC-MS: 1186.5 [M+Na] + .

[0388] Step 2: Preparation of compound ADC-8

[0389] To a PBS buffer solution (4 mL, pH 7.0, 50 mM, containing 1 mM EDTA, 10.8 mg / mL, 292 nmol) of the antibody trastuzumab was added 252 μL of an aqueous solution of tris(2-carboxyethyl)phosphine hydrochloride (CAS: 51805-45-9) (5 mg / mL) at 37°C and incubated at 37°C for 1 hour. The antibody solution was transferred to an ultrafiltration centrifuge tube and diluted to 15 mL with citrate buffer (pH 5.0, 10 mM, containing 1 mM EDTA). The solution was then ultrafiltered and concentrated six times (12 min, 4500 rpm) to yield 6.94 mL of sample. The sample concentration was determined using a UV-visible spectrophotometer, yielding a recovery of 91% and a concentration of 5.90 mg / mL. 6.82 mL of the above sample (containing 40.2 mg of antibody) was adjusted to pH 6.5 with 1 M sodium citrate buffer. 189 μL of a 1 mg / mL aqueous solution of dehydroascorbic acid (CAS: 490-83-5) was added to the antibody solution and allowed to react at 4°C for 2 h. The solution was transferred to an ultrafiltration centrifuge tube and diluted to 15 mL with 10 mM citrate buffer (pH 5.0, containing 1 mM EDTA). After ultrafiltration and centrifugation six times (12 min at 4500 rpm), the solution was transferred to a centrifuge tube to yield 6.92 mL of sample. The sample concentration was determined using a UV-Vis spectrophotometer, yielding a recovery of 91% and a concentration of 5.37 mg / mL.

[0390] 1.70 mL of the above antibody solution (containing 9.10 mg of antibody) was added to a test tube. The pH was adjusted to 6.0 with 1 M sodium citrate buffer. 78.6 μL of a 5 mg / mL DMSO solution of compound 8 was added to the antibody solution, mixed thoroughly, and allowed to react at room temperature for 90 min. After completion of the reaction, the solution was filtered through a 0.22 μM filter and transferred to an ultrafiltration centrifuge tube. The solution was diluted to 15 mL with histidine buffer (pH 6.0, 25 mM, containing 6% sucrose). Ultrafiltration and centrifugation were performed six times (12 min, 4500 rpm) to obtain the ADC-8 buffer solution, which was then stored frozen at 4°C. Average value calculated by UV-HPLC: n = 4.4.

[0391] Example 13 Preparation of Antibody-Drug Conjugate (ADC-9)

[0392] Step 1: Preparation of compound S11-c

[0393] Step 1: Synthesis of S-11c

[0394] S-11a (500 mg, 0.81 mmol), p-aminobenzyl alcohol S-11b (110 mg, 0.89 mmol), and N,N-diisopropylethylamine (262 mg, 2.03 mmol) were dissolved in DMF (4 mL). HATU (462 mg, 1.22 mmol) was added under ice-cooling conditions and the mixture was allowed to react at room temperature for 1.5 h. LC-MS indicated the reaction was complete. The crude product was separated by reverse-phase column chromatography (MeCN / H2O with 0.1% formic acid = 10 / 90 to 80 / 20) to afford S-11c (330 mg, 56%) as a white solid. LC-MS: 722.3 [M+H] + .

[0395] Step 2: Synthesis of S-11

[0396] S-11c (160 mg, 0.22 mmol) was dissolved in DMF (2 mL). DIEA (57 mg, 0.44 mmol) and di(p-nitrobenzene) carbonate (135 mg, 0.44 mmol) were added sequentially under ice-cooling conditions. The mixture was slowly warmed to room temperature and stirred for 1.5 h. LC-MS indicated the reaction was complete. 10 mL of saturated aqueous ammonium chloride was added to quench the reaction. The mixture was extracted with ethyl acetate (20 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated. The crude product was separated by column chromatography (ethyl acetate / methanol = 95 / 5-90 / 10) to afford S-11 (161 mg, 82%) as a white solid. LC-MS: 887.3 [M+H] + .

[0397] Step 3: Preparation of compound 9

[0398] The hydrochloride salt of 2-3-15 (58.6 mg, 0.1 mmol) and HOBt (13.5 mg, 0.1 mmol) were dissolved in DMF (2 mL). S-11 (88.7 mg, 0.1 mmol) and DIEA (38.8 mg, 0.3 mmol) were added sequentially in an ice bath. The mixture was slowly warmed to room temperature and reacted for 1 h. LC-MS indicated the reaction was complete. The crude product was isolated by reverse-phase column chromatography (MeCN / H2O with 0.1% formic acid = 10 / 90 to 70 / 30) to afford a yellow solid (64.2 mg, 50%). LC-MS: 1318.6 [M+Na] + . 1H NMR (400MHz, DMSO-d6) δ11.11(s,1H),9.75(s,1H),9.11(t,J=5.6Hz,1H),8.70(t,J=6.8Hz,1H) ,8.43(d,J=8.4Hz,1H),8.33(t,J=5.6Hz,1H),8.13-8.08(m,2H),8.05(t,J=6.0Hz,1H),7.99(t, J=6.0Hz,1H),7.89(d,J=2.0Hz,1H),7.84(t,J=7.6Hz,1H),7.75(d,J=8.4Hz,1H),7.63(d,J=7.6 Hz,2H),7.47(d,J=7.6Hz,1H),7.43-7.38(m,1H),7.25-7.20(m,6H),7.19-7.13(m,1H),7.09(d, J=7.6Hz,1H),6.96(s,2H),5.43(dd,J=12.8,5.2Hz,1H),4.94(s,2H),4.87(d,J=5.6Hz,2H),4. 64(d,J=5.6Hz,2H),4.50-4.45(m,1H),4.02(s,2H),3.79-3.69(m,3H),3.65(d,J=6.0Hz,2H),3. 61-3.55(m,3H),3.48-3.43(m,2H),3.28(s,3H),3.05(dd,J=13.6,4.8Hz,1H),2.97-2.89(m,3H) ,2.82-2.74(m,5H),2.68-2.60(m,1H),2.10-2.05(m,3H),1.49-1.39(m,4H),1.20-1.12(m,2H).

[0399] Step 4: Preparation of compound ADC-9

[0400] To a PBS buffer solution (4 mL, pH 7.0, 50 mM, containing 1 mM EDTA, 10.8 mg / mL, 292 nmol) of the antibody trastuzumab was added 252 μL of an aqueous solution of tris(2-carboxyethyl)phosphine hydrochloride (CAS: 51805-45-9) (5 mg / mL) at 37°C and incubated at 37°C for 1 hour. The antibody solution was transferred to an ultrafiltration centrifuge tube and diluted to 15 mL with citrate buffer (pH 5.0, 10 mM, containing 1 mM EDTA). The solution was then ultrafiltered and concentrated six times (12 min, 4500 rpm) to yield 6.94 mL of sample. The sample concentration was determined using a UV-visible spectrophotometer, yielding a recovery of 91% and a concentration of 5.90 mg / mL. 6.82 mL of the above sample (containing 40.2 mg of antibody) was adjusted to pH 6.5 with 1 M sodium citrate buffer. 189 μL of a 1 mg / mL aqueous solution of dehydroascorbic acid (CAS: 490-83-5) was added to the antibody solution and allowed to react at 4°C for 2 h. The solution was transferred to an ultrafiltration centrifuge tube and diluted to 15 mL with 10 mM citrate buffer (pH 5.0, containing 1 mM EDTA). After ultrafiltration and centrifugation six times (12 min at 4500 rpm), the solution was transferred to a centrifuge tube to yield 6.92 mL of sample. The sample concentration was determined using a UV-Vis spectrophotometer, yielding a recovery of 91% and a concentration of 5.37 mg / mL.

[0401] 1.70 mL of the above antibody solution (containing 9.10 mg of antibody) was added to a test tube. The pH was adjusted to 6.0 with 1 M sodium citrate buffer. 87.6 μL of a 5 mg / mL DMSO solution of compound 9 was added to the antibody solution, mixed thoroughly, and allowed to react at room temperature for 90 min. After completion of the reaction, the solution was filtered through a 0.22 μM filter and transferred to an ultrafiltration centrifuge tube. The solution was diluted to 15 mL with histidine buffer (pH 6.0, 25 mM, containing 6% sucrose). Ultrafiltration and centrifugation were performed six times (12 min, 4500 rpm) to obtain the ADC-9 buffer solution, which was then stored frozen at 4°C. Average value calculated by UV-HPLC: n = 4.3.

[0402] Biological Example 1 Degradation of GSPT1 Protein by the Compounds of the Present Invention

[0403] 12,000 cells / well were plated and treated with 5-1-8 for 24 hours. The cells were then fixed with 1% PFA at room temperature for 15 minutes, permeabilized with 0.2% TritonX-100 at room temperature for 15 minutes, and incubated with 3% BSA at 37 degrees for 30 minutes, followed by incubation with primary antibody at 4 degrees. The next day, secondary antibody was incubated at room temperature for 2 hours and ECL was added for color development. The signal value of the experimental plate was detected by Lums fluorescence on a microplate reader. The EC value of the compound for degradation of GSPT1 protein was calculated. 50 The results are shown in Figure 1 and Table 6.

[0404] Biological Example 2 In vitro inhibition of 293T cell proliferation by the compounds of the present invention

[0405] 100 293T cells per well were seeded in a 384-well plate (Corning REF: 3764). After overnight attachment, serially diluted compounds were added. After incubation for seven days, Cell Titer-Lumi (Biyuntian C0068XL) was added to measure the ATP content in the cells, evaluate cell growth, and calculate the IC value of the compound for inhibiting cell growth. 50 .

[0406] Biological Example 3 In vitro inhibition of HCC1569 cell proliferation by the compounds of the present invention

[0407] 500 HCC1569 cells per well were seeded in 384-well plates. After overnight attachment, serially diluted compounds were added and incubated for seven days. Cell ATP levels were measured by CTG to evaluate cell growth. The percentage of growth inhibition and IC of the compound were calculated compared with the DMSO group. 50 The specific results are shown in Tables 6 and 7 below.

[0408] At the same time, the IC values ​​of the compounds for inhibiting 293T cell proliferation and HCC1569 cell proliferation were calculated based on the results of the 293T cell proliferation inhibition experiment. 50 Selectivity Index (R 293T / HCC1569 ).

[0409] The specific results are shown in Table 6 below.

[0410] Table 6 Inhibitory activity of the compounds of the present invention on HCC1569 cells (IC 50 , nM), GSPT1 protein degradation (EC 50 , nM), inhibition activity selection index of 293T cell proliferation and HCC1569 cell proliferation (R 293T / HCC1569 ) +++ indicates IC 50 Less than or equal to 0.5nM; ++ indicates IC50 0.5nM to 5nM; + indicates IC 50 Greater than 5nM ***Indicates EC 50 Less than or equal to 0.5nM; ** indicates EC 50 0.5nM to 5nM; * indicates EC 50 Greater than 5 nM R 293T / HCC569 ≥100 is A; 10 <R 293T / HCC569 <100 is B; R 293T / HCC569 ≤10 is C

[0411] Table 7 Inhibitory activity of the compounds of the present invention on HCC1569 cells (IC 50 ,nM) +++ indicates IC 50 Less than or equal to 0.5 nM ++ indicates IC 50 0.5nM to 5nM + indicates IC 50 Greater than 5nM

[0412] Biological Example 3 In vitro antitumor activity of the antibody-drug conjugate of the present invention

[0413] HCC1569 cells, which highly express HER2, were selected as the cell line for in vitro activity testing in this experiment to evaluate the dose-effect of the antibody-drug conjugate of the present invention on cell killing. 500 HCC1569 cells per well were seeded in a 384-well plate. After overnight adherence, serially diluted compounds were added and incubated for seven days. Cell ATP levels were measured by CTG to evaluate cell growth, and the percentage of compound inhibition and IC were calculated. 50 The specific results are shown in Table 8 below.

[0414] Table 8 In vitro antitumor activity of the antibody-drug conjugates of the present invention

[0415] The compounds of the present invention have strong in vitro anti-proliferation activity against HCC1569 cells. In particular, the compounds of the general formula (1) of the present invention are suitable as small molecule toxins for ADCs because they contain OH or NHMe groups in their side chains that are easy to connect.

[0416] Although the above describes specific embodiments of the present invention, it should be understood by those skilled in the art that these are merely illustrative and that various changes or modifications may be made to these embodiments without departing from the principles and essence of the present invention. Therefore, the scope of protection of the present invention is defined by the appended claims.

Claims

1. A compound represented by the general formula (1) or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates: In the general formula (1): R is selected from Where * represents that the end is connected to ring A; Ring A is (C6-C14)aryl, (5-14 membered)heteroaryl or (C3-C14)cycloalkyl; Ring B is (C6-C14)arylene, (5-14 membered)heteroarylene or (C3-C14)cycloalkylene; U is optionally a chemical bond, -NR 15 - or (C1-C8)alkylene, wherein the (C1-C8)alkylene may be substituted by 1, 2, 3, 4, 5 or 6 halogen, (C1-C8)alkyl, (C1-C8)alkoxy, (C1-C8)haloalkyl, (C1-C8)haloalkoxy, (C3-C14)cycloalkyl or (3-14 membered)heterocycloalkyl, or two substituents on the same carbon atom of the (C1-C8)alkylene and the carbon atom to which they are attached form a (C3-C10)cycloalkyl or (3-10 membered)heterocycloalkyl; X is optionally -OH, -SH or -NHR 16 ; V is optionally a chemical bond, -O-, -S- or -NR 17 -; W is optionally a chemical bond, -O-, -S- or -NR 18 -; G is optionally a chemical bond, -O-, -S- or -NR 19 -; T is optionally a chemical bond, -O-, -S- or -NR 20 -; Q is optionally a chemical bond, -O-, -S- or -NR 21 -; Each R 1 R is independently optionally hydrogen, deuterium, halogen, cyano, nitro, (C1-C8) alkyl, (C1-C8) haloalkyl, (C1-C8) alkoxy, (C3-C14) cycloalkyl, (3-14 membered) heterocycloalkyl, (C6-C14) aryl or (5-14 membered) heteroaryl, wherein said (C1-C8) alkyl, (C1-C8) haloalkyl, (C1-C8) alkoxy, (C3-C14) cycloalkyl, (3-14 membered) heterocycloalkyl, (C6-C14) aryl or (5-14 membered) heteroaryl can be independently optionally replaced by 1, 2, 3, 4, 5 or 6 R a replace; R a each independently represents hydrogen, deuterium, halogen, cyano, nitro, (C1-C8)alkyl, (C1-C8)haloalkyl, (C1-C8)alkoxy, (C1-C8)haloalkoxy, (C3-C14)cycloalkyl, (3-14 membered)heterocycloalkyl, (C6-C14)aryl, or (5-14 membered)heteroaryl; Each R 2 R is independently optionally hydrogen, deuterium, halogen, cyano, nitro, (C1-C8) alkyl, (C1-C8) haloalkyl, (C1-C8) alkoxy, (C3-C14) cycloalkyl, (3-14 membered) heterocycloalkyl, (C6-C14) aryl or (5-14 membered) heteroaryl, wherein said (C1-C8) alkyl, (C1-C8) haloalkyl, (C1-C8) alkoxy, (C3-C14) cycloalkyl, (3-14 membered) heterocycloalkyl, (C6-C14) aryl or (5-14 membered) heteroaryl can be independently optionally replaced by 1, 2, 3, 4, 5 or 6 R b replace; R b each independently represents hydrogen, deuterium, halogen, cyano, nitro, (C1-C8)alkyl, (C1-C8)haloalkyl, (C1-C8)alkoxy, (C1-C8)haloalkoxy, (C3-C14)cycloalkyl, (3-14 membered)heterocycloalkyl, (C6-C14)aryl, or (5-14 membered)heteroaryl; Each R 3 independently selected from hydrogen, deuterium, halogen, cyano, nitro, -OR c , (C1-C8)alkyl, (C1-C8)haloalkyl, (C1-C8)alkoxy, (C3-C14)cycloalkyl, (3-14-membered)heterocycloalkyl, (C6-C14)aryl or (5-14-membered)heteroaryl, wherein said (C1-C8)alkyl, (C1-C8)haloalkyl, (C1-C8)alkoxy, (C3-C14)cycloalkyl, (3-14-membered)heterocycloalkyl, (C6-C14)aryl or (5-14-membered)heteroaryl can each independently be optionally substituted by 1, 2, 3, 4, 5 or 6 R c replace; R c each independently represents hydrogen, deuterium, halogen, cyano, nitro, (C1-C8)alkyl, (C1-C8)haloalkyl, (C1-C8)alkoxy, (C1-C8)haloalkoxy, (C3-C14)cycloalkyl, (3-14 membered)heterocycloalkyl, (C6-C14)aryl, or (5-14 membered)heteroaryl; Each R 4 independently selected from hydrogen, deuterium, halogen, cyano, nitro, -OR d , (C1-C8)alkyl, (C1-C8)haloalkyl, (C1-C8)alkoxy, (C3-C14)cycloalkyl, (3-14-membered)heterocycloalkyl, (C6-C14)aryl or (5-14-membered)heteroaryl, wherein said (C1-C8)alkyl, (C1-C8)haloalkyl, (C1-C8)alkoxy, (C3-C14)cycloalkyl, (3-14-membered)heterocycloalkyl, (C6-C14)aryl or (5-14-membered)heteroaryl can each independently be optionally substituted by 1, 2, 3, 4, 5 or 6 R d replace; R d each independently represents hydrogen, deuterium, halogen, cyano, nitro, (C1-C8)alkyl, (C1-C8)haloalkyl, (C1-C8)alkoxy, (C1-C8)haloalkoxy, (C3-C14)cycloalkyl, (3-14 membered)heterocycloalkyl, (C6-C14)aryl, or (5-14 membered)heteroaryl; R 5 、R 6 each independently optionally represents hydrogen, deuterium, (C1-C8)alkyl, (C1-C8)haloalkyl, (C3-C14)cycloalkyl, (3-14 membered)heterocycloalkyl, (C6-C14)aryl, or (5-14 membered)heteroaryl, wherein said (C1-C8)alkyl, (C1-C8)haloalkyl, (C3-C14)cycloalkyl, (3-14 membered)heterocycloalkyl, (C6-C14)aryl, or (5-14 membered)heteroaryl may each independently optionally be replaced by 1, 2, 3, 4, 5, or 6 R e replace; R e is optionally hydrogen, deuterium, halogen, cyano, nitro, (C1-C8)alkyl, (C1-C8)haloalkyl, (C1-C8)alkoxy, (C1-C8)haloalkoxy, (C3-C14)cycloalkyl, (3-14 membered)heterocycloalkyl, (C6-C14)aryl or (5-14 membered)heteroaryl; Or, R 5 and R 6 The carbon atoms to which they are commonly attached form a (C3-C10) cycloalkyl or (3-10 membered) heterocycloalkyl, wherein the (C3-C10) cycloalkyl or (3-10 membered) heterocycloalkyl may be independently optionally substituted with 1, 2, 3, 4, 5 or 6 R f replace; R f is optionally hydrogen, deuterium, halogen, cyano, nitro, (C1-C8)alkyl, (C1-C8)haloalkyl, (C1-C8)alkoxy, (C1-C8)haloalkoxy, (C3-C14)cycloalkyl, (3-14 membered)heterocycloalkyl, (C6-C14)aryl or (5-14 membered)heteroaryl; R 7 、R 8 、R 9 、R 10 、R 11 、R 12 、R 13 、R 14 each independently optionally represents hydrogen, deuterium, halogen, cyano, nitro, (C1-C8)alkyl, (C1-C8)haloalkyl, (C1-C8)alkoxy, (C3-C14)cycloalkyl, (3-14-membered)heterocycloalkyl, (C6-C14)aryl, or (5-14-membered)heteroaryl, wherein said (C1-C8)alkyl, (C1-C8)haloalkyl, (C1-C8)alkoxy, (C3-C14)cycloalkyl, (3-14-membered)heterocycloalkyl, (C6-C14)aryl, or (5-14-membered)heteroaryl may each independently optionally be replaced by 1, 2, 3, 4, 5, or 6 R g replace; R g is optionally hydrogen, deuterium, halogen, cyano, nitro, (C1-C8)alkyl, (C1-C8)haloalkyl, (C1-C8)alkoxy, (C1-C8)haloalkoxy, (C3-C14)cycloalkyl, (3-14 membered)heterocycloalkyl, (C6-C14)aryl or (5-14 membered)heteroaryl; R 7 and R 8 、R 9 and R 10 、R 11 and R 12 、R 13 and R 14 The carbon atoms connected thereto may independently and optionally form a (C3-C10) cycloalkyl or (3-10 membered) heterocycloalkyl, wherein the (C3-C10) cycloalkyl or (3-10 membered) heterocycloalkyl may be independently and optionally substituted by 1, 2, 3, 4, 5 or 6 R h replace; R h is optionally hydrogen, deuterium, halogen, cyano, nitro, (C1-C8)alkyl, (C1-C8)haloalkyl, (C1-C8)alkoxy, (C1-C8)haloalkoxy, (C3-C14)cycloalkyl, (3-14 membered)heterocycloalkyl, (C6-C14)aryl or (5-14 membered)heteroaryl; R 15 、R 16 、R 17 、R 18 、R 19 、R 20 、R 21 each independently optionally hydrogen, (C1-C8)alkyl, (C1-C8)haloalkyl, (C3-C14)cycloalkyl, (3-14 membered)heterocycloalkyl, (C6-C14)aryl or (5-14 membered)heteroaryl, wherein said (C1-C8)alkyl, (C1-C8)haloalkyl, (C3-C14)cycloalkyl, (3-14 membered)heterocycloalkyl, (C6-C14)aryl or (5-14 membered)heteroaryl may each independently optionally be substituted by 1, 2, 3, 4, 5 or 6 R i replace; R i is hydrogen, deuterium, halogen, cyano, nitro, (C1-C8)alkyl, (C1-C8)haloalkyl, (C1-C8)alkoxy, (C1-C8)haloalkoxy, (C3-C14)cycloalkyl, (3-14 membered)heterocycloalkyl, (C6-C14)aryl or (5-14 membered)heteroaryl; a is an integer selected from 0, 1, 2 or 3; b is an integer selected from 0, 1 or 2; c and d are each independently selected from an integer of 0, 1, 2, 3 or 4; m, n, p, q, s are each independently selected from an integer of 0, 1, 2, 3, 4, 5, 6, 7 or 8.

2. The compound according to claim 1 or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates, wherein in the general formula (1), each R 1 Independently selected are hydrogen, deuterium, halogen, cyano, nitro, (C1-C6) alkyl, (C1-C6) haloalkyl, (C1-C6) alkoxy, (C1-C6) haloalkoxy, (C3-C8) cycloalkyl, and (3-8 membered) heterocycloalkyl.

3. The compound according to claim 2 or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates, wherein in the general formula (1), R 1 For hydrogen, deuterium, F, Cl, Br, cyano, nitro, -CH3, -CD3, -CF3, -CH2CH3, -CH2CH2CH3, -CH(Me)2, -CH(CF3)2, -C(Me)3, -OMe, -OCF3.

4. The compound according to any one of claims 1 to 3 or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates, wherein in the general formula (1), each R 2 Independently selected are hydrogen, deuterium, halogen, cyano, nitro, (C1-C6) alkyl, (C1-C6) haloalkyl, (C1-C6) alkoxy, (C1-C6) haloalkoxy, (C3-C8) cycloalkyl, and (3-8 membered) heterocycloalkyl.

5. The compound according to any one of claims 4 or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates, wherein in the general formula (1), R 2 For hydrogen, deuterium, F, Cl, Br, cyano, nitro, -CH3, -CD3, -CF3, -CH2CH3, -CH2CH2CH3, -CH(Me)2, -CH(CF3)2, -C(Me)3, -OMe, -OCF3.

6. The compound according to any one of claims 1 to 5, or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates, wherein in the general formula (1), R 5 、R 6 Each is independently selected from hydrogen, deuterium, (C1-C6) alkyl, and (C3-C8) cycloalkyl; s is selected from an integer of 1 or 2.

7. The compound according to claim 6 or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates, wherein in the general formula (1), R 5 、R 6 Each independently selected from hydrogen, deuterium, -Me, -CD3, -CH2CH3, 8. The compound according to claim 7 or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates, wherein in the general formula (1), R 5 、R 6 is hydrogen; s is 1.

9. The compound according to any one of claims 1 to 5 or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates, wherein in the general formula (1), R 5 and R 6 The carbon atoms that can be commonly attached thereto independently and optionally form a (C3-C8) cycloalkyl group or a (3-8 membered) heterocycloalkyl group, wherein the (C3-C8) cycloalkyl group or the (3-8 membered) heterocycloalkyl group is replaced by hydrogen, deuterium, F, Cl, Br, cyano, -CH3, -CD3, -CF3, -CH(Me)2, -OMe, -OCF3 substituted.

10. The compound according to claim 9 or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates, wherein in the general formula (1), R 5 and R 6 The carbon atoms that can be connected to each other independently and optionally form 11. The compound according to any one of claims 1 to 10 or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates, wherein in the general formula (1), U is a chemical bond, -NR 15 -, -CF2-, (C1-C4) alkylene, R 15 is hydrogen, (C1-C3)alkyl or (C3-C6)cycloalkyl.

12. The compound according to claim 11 or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates, wherein in the general formula (1), U is a chemical bond, -CH2-, -CH2CH2-, -CF2-, -NH-, -C(CH3)2-, 13. The compound according to any one of claims 1 to 12 or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates, wherein in the general formula (1), ring A is a (C6-C14) aryl group, preferably a phenyl group.

14. The compound according to any one of claims 1 to 13 or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates, wherein in the general formula (1), each R 3 independently selected from hydrogen, deuterium, F, Cl, Br, I, cyano, nitro, -OR c , (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C3-C8)cycloalkyl, (3-8 membered)heterocycloalkyl, (C6-C14)aryl or (5-14 membered)heteroaryl, wherein the (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C3-C8)cycloalkyl, (3-8 membered)heterocycloalkyl, (C6-C14)aryl or (5-14 membered)heteroaryl The (5-14 membered)heteroaryl or (5-14 membered)heteroaryl groups may each independently be optionally substituted with 1, 2, 3, 4, 5 or 6 of the following groups: hydrogen, deuterium, F, Cl, Br, I, cyano, nitro, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C3-C8)cycloalkyl, (3-8 membered)heterocycloalkyl, (C6-C14)aryl or (5-14 membered)heteroaryl.

15. The compound according to claim 14 or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates, wherein in the general formula (1), each R 3 independently selected from hydrogen, deuterium, F, Cl, Br, cyano, nitro, -CH3, -CD3, -CF3, -CHF2, -CH2F, -CH2CH3, -CH2CH2CH3, -CH(Me)2, -CH(CF3)2, -C(Me)3, -OMe, -OCF3, -OCF2H, -OCFH2, -OCH2CH3, -OCH2CH2CH3, -OCH(CH3)2, -OCH(CF3)2, -OC(CH3)3, -O(CH2)2OMe, -Ph, -Bn.

16. The compound according to any one of claims 1 to 15 or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates, wherein in the general formula (1), ring B is a (C6-C14)arylene group, preferably a phenylene group.

17. The compound according to any one of claims 1 to 16, or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates, wherein in the general formula (1), each R 4 independently selected from hydrogen, deuterium, F, Cl, Br, I, cyano, nitro, -OR d , (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C3-C8)cycloalkyl, (3-8 membered)heterocycloalkyl, (C6-C14)aryl or (5-14 membered)heteroaryl, wherein the (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C3-C8)cycloalkyl, (3-8 membered)heterocycloalkyl, (C6-C14)aryl or (5-14 membered)heteroaryl The (5-14 membered)heteroaryl or (5-14 membered)heteroaryl groups may each independently be optionally substituted with 1, 2, 3, 4, 5 or 6 of the following groups: hydrogen, deuterium, F, Cl, Br, I, cyano, nitro, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C3-C8)cycloalkyl, (3-8 membered)heterocycloalkyl, (C6-C14)aryl or (5-14 membered)heteroaryl.

18. The compound according to claim 17 or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates, wherein in the general formula (1), each R 4 independently selected from hydrogen, deuterium, F, Cl, Br, cyano, nitro, -O-(C3-C6)cycloalkyl, (C1-C3)alkyl, (C1-C3)haloalkyl, (C1-C3)alkoxy, (C3-C6)cycloalkyl, (3-6 membered)heterocycloalkyl, wherein said (C1-C3)alkyl, (C1-C3)haloalkyl, (C1-C3)alkoxy, (C3-C6)cycloalkyl, (3-6 membered)heterocycloalkyl The R groups may each be independently optionally substituted with 1, 2, 3, 4, 5 or 6 of the following groups: hydrogen, deuterium, F, Cl, Br, I, cyano, nitro, (C1-C6) alkyl, (C1-C6) haloalkyl, (C1-C6) alkoxy, (C3-C8) cycloalkyl, (3-8 membered) heterocycloalkyl, (C6-C14) aryl or (5-14 membered) heteroaryl; preferably 1, 2, 3, 4, 5 or 6 of hydrogen, deuterium, F; each R 4 are independently preferably hydrogen, deuterium, F, Cl, Br, cyano, nitro, -CH3, -CD3, -CF3, -CHF2, -CH2F, -OMe, -OCF3, 19. The compound according to any one of claims 1 to 18, or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates, wherein in the general formula (1), each R 7 、R 8 、R 9 、R 10 、R 11 、R 12 、R 13 、R 14 m, n, p, q are each independently selected from an integer of 0, 1, 2, 3, 4, 5 or 6.

20. The compound according to claim 19 or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates, wherein in the general formula (1), each R 7 、R 8 、R 9 、R 10 、R 11 、R 12 、R 13 、R 14 independently selected from hydrogen, deuterium, F, Cl, -Me, -CD3, -CH2CH3, 21. The compound according to any one of claims 1 to 20, or any isomer, crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein in the general formula (1), R 7 and R 8 、R 9 and R 10 、R 11 and R 12 、R 13 and R 14 The carbon atoms to which they are commonly attached may independently and optionally form a (C3-C6) cycloalkyl group or a (3-6 membered) heterocycloalkyl group, wherein the (C3-C6) cycloalkyl group or the (3-6 membered) heterocycloalkyl group is replaced by hydrogen, deuterium, F, Cl, Br, cyano, -CH3, -CD3, -CF3, -CH(Me)2, -OMe, -OCF3 substituted.

22. The compound according to claim 21 or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates, wherein in the general formula (1), R 7 and R 8 、R 9 and R 10 、R 11 and R 12 、R 13 and R 14 The carbon atoms connected thereto can independently and optionally form 23. The compound according to any one of claims 1 to 22, or any of its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates, wherein in the general formula (1), V is optionally a chemical bond, -O-, -S-, -NR 17 -;R 17 Optionally, it is hydrogen, (C1-C6)alkyl, (C3-C8)cycloalkyl, -Ph or -Bn.

24. The compound according to any one of claims 1 to 23 or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates, wherein in the general formula (1), W is optionally a chemical bond, -O-, -S-, -NR 18 -;R 18 Optionally, it is hydrogen, (C1-C6)alkyl, (C3-C8)cycloalkyl, -Ph or -Bn.

25. The compound according to any one of claims 1 to 24 or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates, wherein in the general formula (1), the structural unit for * indicates that this end is connected to ring A; V is optionally -O-, -S-, or -NR 17 -; R 17 Optionally, it is hydrogen, (C1-C3) alkyl, (C3-C6) cycloalkyl, (C3-C6) heterocycloalkyl, -Ph, -Bn; preferably, hydrogen, -Me, -Et, R 7 or R 8 Each is independently selected from hydrogen, (C1-C3) alkyl; R 7 and R 8 The carbon atoms connected thereto may optionally form a (C3-C6) cycloalkyl group or a (3-6 membered) heterocycloalkyl group, preferably n is an integer selected from 1, 2, 3, 4, 5 or 6; n is preferably an integer of 1, 2, 3 or 4; and n is more preferably an integer of 3 or 4.

26. The compound according to claim 25 or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates, wherein in the general formula (1), the structural unit for * indicates that the end is connected to ring A.

27. The compound according to any one of claims 1 to 24 or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates, wherein in the general formula (1), the structural unit for * indicates that this end is connected to ring A; V is optionally -O-, -S-, or -NR 17 -; W is optionally -O-, -S-, or -NR 18 -; R 17 Optionally, it is hydrogen, (C1-C3) alkyl, (C3-C6) cycloalkyl, (C3-C6) heterocycloalkyl; preferably, hydrogen, -Me, -Et, R 18 Optionally, it is hydrogen, (C1-C3) alkyl, (C3-C6) cycloalkyl, (C3-C6) heterocycloalkyl; preferably, hydrogen, -Me, -Et, R 9 or R 10 Each is independently selected from hydrogen, (C1-C3) alkyl; R 9 and R 10 The carbon atoms connected thereto may optionally form a (C3-C6) cycloalkyl group or a (3-6 membered) heterocycloalkyl group, preferably p is optionally selected from an integer of 2, 3, 4, 5 or 6; p is preferably an integer of 2, 3 or 4; and p is more preferably an integer of 2 or 3.

28. The compound according to claim 27 or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates, wherein in the general formula (1), the structural unit for * indicates that the end is connected to ring A.

29. The compound according to any one of claims 1 to 24, or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates, wherein in the general formula (1), the structural unit for * indicates that this end is connected to ring A; W is optionally -O-, -S-, or -NR 18 -; R 18 Optionally, it is hydrogen, (C1-C3) alkyl, (C3-C6) cycloalkyl, (3-6 membered) heterocycloalkyl; preferably, hydrogen, -Me, -Et, R 7 、R 8 、R 9 、R 10 Each is independently selected from hydrogen, (C1-C3) alkyl; preferably H, -Me; R 7 and R 8 、R 9 and R 10 The carbon atoms connected thereto can independently and optionally form a (C3-C6) cycloalkyl group or a (3-6 membered) heterocycloalkyl group, preferably n is optionally an integer of 1, 2, 3, or 4; n is preferably an integer of 2 or 3; p is optionally an integer of 2, 3, or 4; preferably, p is an integer of 2 or 3.

30. The compound according to claim 29 or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates, wherein in the general formula (1), the structural unit for * indicates that the end is connected to ring A.

31. The compound according to any one of claims 1 to 30 or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates, wherein in the general formula (1), T is optionally a chemical bond, -O-, -S-, -NR 20 -;R 20 It is optionally hydrogen, (C1-C6) alkyl, (C3-C8) cycloalkyl, (C3-C8) heterocycloalkyl, -Ph or -Bn; T is preferably a chemical bond, -O-, -NH-, or -NMe-.

32. The compound according to any one of claims 1 to 31 or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates, wherein in the general formula (1), X is optionally -OH, -SH, -NHR 16 ; R 16 Optionally, it is hydrogen, (C1-C6)alkyl, (C3-C8)cycloalkyl, (C3-C8)heterocycloalkyl, -Ph or -Bn.

33. The compound according to any one of claims 1 to 32 or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates, wherein in the general formula (1), the structural unit for * represents that the end is connected to the carbonyl group; X is optionally -OH, -SH, or -NHR 16 ; R 16 Optionally, it is hydrogen, (C1-C3) alkyl, (C3-C6) cycloalkyl, (C3-C6) heterocycloalkyl; preferably, hydrogen, -Me, -Et, R 13 or R 14 Each is independently selected from hydrogen, (C1-C6) alkyl, (C3-C6) cycloalkyl; preferably hydrogen, -Me, -Et, R 13 and R 14 The carbon atoms connected thereto may optionally form a (C3-C6) cycloalkyl group or a (3-6 membered) heterocycloalkyl group, preferably m is optionally an integer of 1, 2, 3, 4, 5, or 6; preferably, m is an integer of 1, 2, 3, or 4.

34. The compound according to any one of claims 1 to 33, or any isomer, crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein in the general formula (1), for *Indicates that the end is connected to T.

35. The compound according to any one of claims 1 to 34 or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates, wherein in the general formula (1), the structural unit * indicates that this end is connected to ring A; R 7 、R 8 、R 9 、R 10 Each is independently selected from hydrogen, -Me; R 7 and R 8 、R 9 and R 10 The carbon atoms connected thereto can independently and optionally form R 13 、R 14 Each independently selected from hydrogen, -Me, X is optionally -OH, -SH, -NH2, -NHMe; m is optionally an integer of 1, 2 or 3.

36. The compound according to any one of claims 1 to 35 or its isomers, crystalline forms, pharmaceutically acceptable salts, hydrates or solvates, wherein in the general formula (1), Q is optionally a chemical bond, -O-, -S-, -NR 21 -;R 21 Optionally, it is hydrogen, (C1-C6)alkyl, (C3-C8)cycloalkyl, (3-6 membered)heterocycloalkyl, -Ph or -Bn.

37. The compound according to any one of claims 1 to 36, or any isomer, crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein in the general formula (1), R 11 、R 12 Each is independently hydrogen, (C1-C6)alkyl, (C3-C6)cycloalkyl, (3-6 membered)heterocycloalkyl; q is an integer of 0, 1, 2, 3, 4, 5 or 6.

38. The compound according to any one of claims 1 to 37 or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates, wherein in the general formula (1), R 11 and R 12 The carbon atoms to which they are commonly attached may independently and optionally form a (C3-C6)cycloalkyl group or a (3-6 membered)heterocycloalkyl group.

39. The compound according to any one of claims 1 to 38 or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates, wherein in the general formula (1), G is optionally a chemical bond, -O-, -S-, -NR 19 -;R 19 Optionally, it is hydrogen, (C1-C6)alkyl, (C3-C8)cycloalkyl, (3-6 membered)heterocycloalkyl, -Ph or -Bn.

40. The compound according to any one of claims 1 to 39 or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates, wherein in the general formula (1), The structural unit is * indicates that this end is connected to ring A; R 4 For hydrogen, F, Cl, nitro, -CH3, -CF3, -OMe, -OCF3, W is -NR 18 -;R 18 For hydrogen, -Me, -Et, R 7 、R 8 、R 9 、R 10 Each is independently selected from hydrogen, -Me; R 7 and R 8 、R 9 and R 10 The carbon atoms connected thereto can independently and optionally form d is an integer of 1 or 2; n is an integer of 2 or 3; p is an integer of 2, 3 or 4.

41. The compound according to any one of claims 1 to 39 or any of its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates, wherein in the general formula (1), The structural unit is * indicates that this end is connected to ring A; Q is optionally a chemical bond, O, -NR 21 -; R 21 For hydrogen, -Me, -Et, R 4 For hydrogen, F, Cl, nitro, -CH3, -CF3, -OMe, -OCF3, R 7 、R 8 、R 9 、R 10 、R 11 、R 12 Each is independently selected from hydrogen, -Me; R 7 and R 8 、R 9 and R 10 、R 11 and R 12 The carbon atoms connected thereto can independently and optionally form d is an integer of 1 or 2; n and p are each independently an integer of 2 or 3; q is an integer of 1, 2, 3 or 4.

42. The compound according to any one of claims 1 to 41 or any of its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates, wherein in the general formula (1), The structural unit is * indicates that this end is connected to ring A; W is -NR 18 -;R 18 For hydrogen, -Me, -Et, Q is optionally a chemical bond, O, -NR 21 -; R 21 For hydrogen, -Me, -Et, -Ph or -Bn; T is a chemical bond, -O-, -NH-, or -NMe-; X is optionally -OH, -SH, or -NHR 16 ; R 16 For hydrogen, -Me, -Et, R 7 、R 8 、R 9 、R 10 、R 11 、R 12 、R 13 、R 14 Each independently selected from hydrogen, -Me, -Et, R 7 and R 8 、R 9 and R 10 、R 11 and R 12 、R 13 and R 14 The carbon atoms connected thereto can independently and optionally form n and p are each independently an integer of 2 or 3; q is optionally an integer of 0, 1, 2, 3 or 4; m is optionally an integer of 1, 2, 3 or 4.

43. The compound according to any one of claims 1 to 41 or any of its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates, wherein in the general formula (1), The structural unit is * indicates that this end is connected to ring A; Q is optionally a chemical bond, O, -NR 21 -; R 21 For hydrogen, -Me, -Et, T is a chemical bond, -O-, -NH-, or -NMe-; X is optionally -OH, -SH, or -NHR 16 ; R 16 For hydrogen, -Me, -Et, R 7 、R 8 、R 9 、R 10 、R 11 、R 12 、R 13 、R 14 Each independently selected from hydrogen, -Me, -Et, R 7 and R 8 、R 9 and R 10 、R 11 and R 12 、R 13 and R 14 The carbon atoms connected thereto can independently and optionally form n and p are each independently an integer of 2 or 3; q is optionally an integer of 0, 1, 2, 3 or 4; m is optionally an integer of 1, 2, 3 or 4.

44. The compound according to any one of claims 1 to 43 or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates, wherein the general formula (1) is 45. The compound according to any one of claims 1 to 43 or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates, wherein the general formula (1) is 46. The compound according to any one of claims 1 to 43 or its isomers, crystalline forms, pharmaceutically acceptable salts, hydrates or solvates, wherein the general formula (1) is 47. The compound according to any one of claims 1 to 43 or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates, wherein the general formula (1) is 48. The compound of any one of claims 1 to 47, or any isomer, crystalline form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein the compound has one of the following structures:

49. Use of the compound according to any one of claims 1 to 48 or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates as a small molecule toxin in the preparation of an antibody-drug conjugate.

50. A pharmaceutical composition, characterized in that It contains a pharmaceutically acceptable excipient or carrier, and the compound according to any one of claims 1 to 48 or its individual isomers, individual crystal forms, pharmaceutically acceptable salts, hydrates or solvates.

51. Use of the compound according to any one of claims 1 to 48 or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates, or the pharmaceutical composition according to claim 50 in the preparation of a GSPT1 protein degrader.

52. The use according to claim 51 for treating a cell proliferative disease, wherein the disease is cancer, and the cancer is a blood cancer and a solid tumor, preferably non-small cell lung cancer, small cell lung cancer, high-grade neuroendocrine carcinoma, diffuse large B-cell lymphoma, acute myeloid leukemia, breast cancer, gastric cancer, colorectal cancer.

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