Compound for degrading target protein

Abstract

Provided are a compound represented by formula (A) or a pharmaceutically acceptable salt, a pharmaceutical composition comprising same, and the use thereof, which is particularly suitable for preparing a drug for treating or preventing abnormal cell proliferation diseases. Z—L—PTM (A)

Description

[Corrected 21.08.2024 in accordance with Rule 26] Compounds for target protein degradation

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This disclosure claims priority to and the benefit of the following Chinese patent applications filed with the State Intellectual Property Office of China: Chinese Patent Application No. 202310933855.9 filed on July 26, 2023, and Chinese Patent Application No. 202310977576.2 filed on August 3, 2023. The entirety of the above patent applications is incorporated herein by reference in their entirety. Technical Field

[0003] The present disclosure belongs to the field of medical technology, and specifically relates to a compound capable of degrading a target protein, or a pharmaceutically acceptable salt thereof. The compound has biological activities such as anti-proliferation of tumor cells and can be used to treat related diseases. Background Art

[0004] The ubiquitin-proteasome system (UPS) is one of the important protein degradation pathways in human cells, mainly including two major processes: ubiquitination of substrate proteins and degradation of ubiquitin-tagged proteins by proteasomes. Abnormal function of the ubiquitin-proteasome system can affect cell cycle regulation, cell growth, proliferation, apoptosis, DNA repair, and other cell signaling processes, and is closely related to the occurrence and development of malignant tumors, cardiovascular diseases, neurodegenerative diseases and other diseases. Targeted protein degradation chimera PROTAC (Proteolysis targeting chimeras) is a new technology for targeted degradation of target proteins developed based on the cell's own ubiquitin-proteasome system (UPS). PROTAC molecules are bifunctional molecules that can not only bind to target proteins, but also recruit E3 ubiquitin ligases to ubiquitinate the target proteins, and then degrade the target proteins through the proteasomes.

[0005] There are over 600 E3 ubiquitin ligases in the human body, but the E3 ubiquitin ligase ligands currently used by PROTACs in preclinical and clinical studies are concentrated in VHL and CRBN. Due to the potential for acquired drug resistance and the limited universality of degradation substrates, the search for novel E3 ubiquitin ligase-targeting ligands has become a hot topic. Furthermore, traditional bifunctional small-molecule PROTACs targeting E3 ubiquitin ligases have drawbacks, such as the limited distribution of E3 ubiquitin ligases in the human body, the inability to target proteins lacking ubiquitinated lysine residues, and the potential for degradation of target proteins by traditional PROTACs to be inhibited by deubiquitinating enzymes. Therefore, we are committed to developing novel small-molecule target protein degraders that are independent of E3 ubiquitin ligases.

[0006] Summary of the Invention

[0007] The present disclosure discloses a new class of compounds that can be used to degrade target proteins. They can also be referred to as "target protein degraders." The "Z" moiety herein can regulate and / or promote proteasomal degradation of the target protein, and in some cases can be referred to as a regulator and / or promoter of proteasomal degradation. Without being bound by theory, the Z moiety can regulate and / or promote the degradation of the target protein, for example, by acting to bring the target protein into proximity with the proteasome and / or by other means to mark the target protein for proteasomal degradation within the cell. The compounds described in this disclosure have been shown to be effective degraders for a variety of target proteins.

[0008] The present disclosure provides a compound represented by formula (A) or a pharmaceutically acceptable salt or a stereoisomer thereof:

[0009] Z-L-PTM

[0010] (A)

[0011] Wherein, Z is selected from the structure shown in formula (I):

[0012] in, represents the attachment site to L;

[0013] Ring A is selected from 4-8 membered heterocyclic group, C6-C 10 Aryl or 5-10 membered heteroaryl;

[0014] X is selected from CR 3 R 3’ NR 4 , CR 4 R 4’ C(O)NR 1 or CR 4 R 4’ CR 5 R 5’ ;

[0015] W is selected from C(O) or S(O)2;

[0016] Q is selected from (CR A R B ) q ; R A 、R B Independently selected from H, halogen or C1-C6 alkyl;

[0017] q is selected from 0, 1, 2, 3;

[0018] G is selected from C3-C6 cycloalkyl, 4-8 membered heterocyclic group, C6-C 10Aryl, 5-10 membered heteroaryl, the C3-C6 cycloalkyl, 4-8 membered heterocyclic group, C6-C 10 Aryl, 5-10 membered heteroaryl are optionally replaced by R 1a replace;

[0019] R 1a is selected from halogen, CN, OH, NH2, C1-C6 alkyl, C1-C6 alkoxy or C3-C6 cycloalkyl;

[0020] R 1 Selected from H or C1-C6 alkyl;

[0021] R 2 is selected from C1-C6 alkyl or C3-C6 cycloalkyl, wherein the C1-C6 alkyl or C3-C6 cycloalkyl is optionally replaced by R 2a replace;

[0022] R 2a is selected from halogen, CN, OH or NH2;

[0023] R 3’ Selected from H or C1-C6 alkyl;

[0024] R 3 Selected from optionally R 3a Substituted C1-C6 alkyl;

[0025] R 3a Selected from C(O)NH2, C3-C6 cycloalkyl, 4-8 membered heterocyclic group, C6-C 10 Aryl or 5-10 membered heteroaryl, the C3-C6 cycloalkyl, 4-8 membered heterocyclic group, C6-C 10 Aryl or 5-10 membered heteroaryl is optionally substituted with halogen, CN, OH, NH2 or C1-C6 alkyl;

[0026] Or, R 3 、R 3’ The atom to which it is attached forms a C3-C6 cycloalkyl or a 4-6 membered heterocyclyl, wherein the C3-C6 cycloalkyl or the 4-6 membered heterocyclyl is optionally substituted with OH, NH2, halogen or C1-C6 alkyl;

[0027] Or, R 3 、R 2 and the atoms to which they are attached together form a 7-10 membered bicyclic heterocyclic group, the 7-10 membered bicyclic heterocyclic group is optionally replaced by R 3b replace;

[0028] Or, R 3 、R 2 and the atoms to which they are attached together form an optionally R 3bsubstituted 5-6 membered heterocyclic group, and R 3’ 、R 6 and the atoms to which they are attached together form a 5-6 membered saturated or unsaturated carbon ring;

[0029] Or, R 3 、R 2 and their respective connected atoms together form the R 3b When the 5-6 membered heterocyclic group is substituted, and R 3b 、R 6 and the atoms to which they are attached together form a 5-6 membered saturated or unsaturated carbon ring;

[0030] R 3b is selected from OH, NH2, halogen or C1-C6 alkyl; R 4 is selected from C1-C6 alkyl or C3-C6 cycloalkyl, wherein the C1-C6 alkyl or C3-C6 cycloalkyl is optionally replaced by R 4a replace;

[0031] R 4’ is selected from H, C1-C6 alkyl or C3-C6 cycloalkyl, wherein the C1-C6 alkyl or C3-C6 cycloalkyl is optionally replaced by R 4a replace;

[0032] R 5 、R 5’ independently selected from H, halogen, C1-C6 alkyl, said C1-C6 alkyl being optionally replaced by R 5a replace;

[0033] R 4a 、R 5a independently selected from OH, NH2, halogen, C1-C6 alkyl, C3-C6 cycloalkyl or 4-6 membered heterocyclyl, wherein the C1-C6 alkyl, C3-C6 cycloalkyl or 4-6 membered heterocyclyl is optionally substituted with halogen, CN, OH, NH2 or C1-C6 alkyl;

[0034] R 6 Selected from H, halogen, C1-C6 alkyl or C1-C6 alkoxy;

[0035] Provided that, when X is CH(CH2)2CH3, then W is selected from S(O)2 or Q is selected from (CR A R B ) q and q is selected from 1, 2 or 3;

[0036] L represents a linker unit that covalently binds at least one Z and at least one PTM;

[0037] The PTM is selected from the target protein binding ligand.

[0038] In some embodiments, Z is selected from the structure shown in formula (I), wherein,

[0039] represents the attachment site to L;

[0040] Ring A is selected from 4-8 membered heterocyclic group, C6-C 10 Aryl or 5-10 membered heteroaryl;

[0041] X is selected from CR 3 R 3’ NR 4 , CR 4 R 4’ C(O)NR 1 or CR 4 R 4’ CR 5 R 5’ ;

[0042] W is selected from C(O) or S(O)2;

[0043] Q is selected from (CR A R B ) q ; R A 、R B Independently selected from H, halogen or C1-C6 alkyl;

[0044] q is selected from 0, 1, 2, 3;

[0045] G is selected from C3-C6 cycloalkyl, 4-8 membered heterocyclic group, C6-C 10 Aryl, 5-10 membered heteroaryl, the C3-C6 cycloalkyl, 4-8 membered heterocyclic group, C6-C 10 Aryl, 5-10 membered heteroaryl are optionally replaced by R 1a replace;

[0046] R 1a is selected from halogen, CN, OH, NH2, C1-C6 alkyl, C1-C6 alkoxy or C3-C6 cycloalkyl;

[0047] R 1 Selected from H or C1-C6 alkyl;

[0048] R 2 is selected from C1-C6 alkyl or C3-C6 cycloalkyl, wherein the C1-C6 alkyl or C3-C6 cycloalkyl is optionally replaced by R 2a replace;

[0049] R 2a is selected from halogen, CN, OH or NH2;

[0050] R 3’Selected from H or C1-C6 alkyl;

[0051] R 3 Selected from optionally R 3a Substituted C1-C6 alkyl;

[0052] R 3a Selected from C(O)NH2, C3-C6 cycloalkyl, 4-8 membered heterocyclic group, C6-C 10 Aryl or 5-10 membered heteroaryl, the C3-C6 cycloalkyl, 4-8 membered heterocyclic group, C6-C 10 Aryl or 5-10 membered heteroaryl is optionally substituted with halogen, CN, OH, NH2 or C1-C6 alkyl;

[0053] Or, R 3 、R 3’ The atom to which it is attached forms a C3-C6 cycloalkyl or a 4-6 membered heterocyclyl, wherein the C3-C6 cycloalkyl or the 4-6 membered heterocyclyl is optionally substituted with OH, NH2, halogen or C1-C6 alkyl;

[0054] R 4 is selected from C1-C6 alkyl or C3-C6 cycloalkyl, wherein the C1-C6 alkyl or C3-C6 cycloalkyl is optionally replaced by R 4a replace;

[0055] R 4’ is selected from H, C1-C6 alkyl or C3-C6 cycloalkyl, wherein the C1-C6 alkyl or C3-C6 cycloalkyl is optionally replaced by R 4a replace;

[0056] R 5 、R 5’ independently selected from H, halogen, C1-C6 alkyl, said C1-C6 alkyl being optionally replaced by R 5a replace;

[0057] R 4a 、R 5a independently selected from OH, NH2, halogen, C1-C6 alkyl, C3-C6 cycloalkyl or 4-6 membered heterocyclyl, wherein the C1-C6 alkyl, C3-C6 cycloalkyl or 4-6 membered heterocyclyl is optionally substituted with halogen, CN, OH, NH2 or C1-C6 alkyl;

[0058] R 6 Selected from H, halogen, C1-C6 alkyl or C1-C6 alkoxy;

[0059] Provided that, when X is CH(CH2)2CH3, then W is selected from S(O)2 or Q is selected from (CR A R B ) qand q is selected from 1, 2 or 3.

[0060] In some embodiments, X is selected from NR 4 , CR 4 R 4’ C(O)NH or CR 4 R 4’ CR 5 R 5’ .

[0061] In some embodiments, X is selected from NR 4 or CR 4 R 4’ C(O)NH.

[0062] In some embodiments, X is NR 4 .

[0063] In some embodiments, X is CR 4 R 4’ C(O)NH.

[0064] In some embodiments, X is CR 3 R 3’ .

[0065] In some embodiments, X is selected from CHR 3 , the R 3 Selected from R 3a Substituted C1-C6 alkyl.

[0066] In some embodiments, X is selected from CHR 3 , the R 3 、R 2 and the atoms to which they are attached together form a 7-10 membered bicyclic heterocyclic group, the 7-10 membered bicyclic heterocyclic group is optionally replaced by R 3b replace.

[0067] In some embodiments, X is selected from CHR 3 , the R 3 、R 2 and the atoms to which they are attached together form an optionally R 3b Substituted with the following groups:

[0068] In some embodiments, Selected from the following structural units:

[0069] In some embodiments, X is selected from CH(CH2)2CH3C(O)NH, CH(CH2)2CH3, N(CH2)2CH3, CH(CH2)2CH3CF2, CH(CH2)2CONH2,

[0070] In some embodiments, X is selected from CH(CH2)2CH3C(O)NH, CH(CH2)2CH3, N(CH2)2CH3, or CH(CH2)2CONH2.

[0071] In some embodiments, X is CH(CH2)2CH3C(O)NH.

[0072] In some embodiments, X is CH(CH2)2CH3.

[0073] In some embodiments, W is selected from C(O).

[0074] In some embodiments, W is selected from S(O)2.

[0075] In some embodiments, Ring A is selected from C6-C 10 aryl or 5-10 membered heteroaryl.

[0076] In some embodiments, Ring A is selected from phenyl or 5-6 membered heteroaryl.

[0077] In some embodiments, Ring A is selected from phenyl.

[0078] In some embodiments, R 1 Selected from H or C1-C3 alkyl.

[0079] In some embodiments, R 1 Selected from H.

[0080] In some embodiments, q is selected from 0 or 1.

[0081] In some embodiments, q is selected from 0.

[0082] In some embodiments, Q is selected from CR A R B .

[0083] In some embodiments, Q is selected from a bond, CH2, or C(CH3)2.

[0084] In some embodiments, Q is selected from CH2 or C(CH3)2.

[0085] In some embodiments, Q is a bond.

[0086] In some embodiments, R A 、RB Independently selected from H or C1-C6 alkyl.

[0087] In some embodiments, R A 、R B Independently selected from H or methyl.

[0088] In some embodiments, G is selected from 4-8 membered heterocyclyl, C6-C 10 Aryl or 5-10 membered heteroaryl, the 4-8 membered heterocyclic group, C6-C 10 Aryl or 5-10 membered heteroaryl is optionally replaced by R 1a replace.

[0089] In some embodiments, G is selected from 4-6 membered heterocyclyl, phenyl or 5-6 membered heteroaryl, wherein the 4-6 membered heterocyclyl, phenyl or 5-6 membered heteroaryl is optionally replaced by R 1a replace.

[0090] In some embodiments, G is selected from piperazinyl, phenyl, or thiazolyl, wherein the piperazinyl, phenyl, or thiazolyl is optionally replaced by R 1a replace.

[0091] In some embodiments, G is selected from 4-6 membered heterocyclyl or phenyl, wherein the 4-6 membered heterocyclyl or phenyl is optionally replaced by R 1a replace.

[0092] In some embodiments, G is selected from piperazinyl or phenyl, said piperazinyl or phenyl being optionally replaced by R 1a replace.

[0093] In some embodiments, G is selected from 5-6 membered heteroaryl, wherein the 5-6 membered heteroaryl is optionally replaced by R 1a replace.

[0094] In some embodiments, G is selected from thiazolyl, which is optionally replaced by R 1a replace.

[0095] In some embodiments, R 1a Selected from C1-C6 alkyl or C3-C6 cycloalkyl.

[0096] In some embodiments, R 1a is selected from methyl or cyclopropyl.

[0097] In some embodiments, R 2 is a C1-C6 alkyl group, wherein the C1-C6 alkyl group is optionally replaced by R 2a replace.

[0098] In some embodiments, R 2 For CH3.

[0099] In some embodiments, R 3’ For H.

[0100] In some embodiments, R 3 It is -(CH2)2CH3.

[0101] In some embodiments, R 3 To be R 3a Substituted C1-C6 alkyl.

[0102] In some embodiments, R 3 To be R 3a Substituted methyl.

[0103] In some embodiments, R 3a Selected from C(O)NH2, 4-8 membered heterocyclyl or 5-6 membered heteroaryl, wherein the 4-8 membered heterocyclyl or 5-6 membered heteroaryl is optionally substituted with halogen, CN, OH, NH2 or C1-C6 alkyl.

[0104] In some embodiments, R 3a Selected from C(O)NH2, morpholinyl or 1,2,4-triazolyl.

[0105] In some embodiments, R 3 、R 3’ The atom to which it is attached forms a C3-C6 cycloalkyl group, which is optionally substituted with OH, NH2, halogen or C1-C6 alkyl.

[0106] In some embodiments, R 3 、R 3’ The atom to which it is attached forms a C3-C6 cycloalkyl group, which is substituted by OH, NH2, halogen or C1-C6 alkyl.

[0107] In some embodiments, R 3 、R 3’ The atom to which it is attached forms a C3-C4 cycloalkyl group, which is optionally substituted with OH, NH2, halogen or C1-C6 alkyl.

[0108] In some embodiments, R 3 、R 3’ The atom to which it is attached forms a cyclobutyl group which is optionally substituted with halogen or C1-C6 alkyl.

[0109] In some embodiments, R 4 is a C1-C6 alkyl group, wherein the C1-C6 alkyl group is optionally replaced by R 4a replace.

[0110] In some embodiments, R4 It is a C1-C6 alkyl group.

[0111] In some embodiments, R 4 It is -(CH2)2CH3.

[0112] In some embodiments, R 4’ For H.

[0113] In some embodiments, R 5 、R 5’ are independently selected from halogen.

[0114] In some embodiments, R 5 、R 5’ Independently selected from F.

[0115] In some embodiments, R 6 is selected from H or methoxy.

[0116] In some embodiments, R 6 For H.

[0117] In some embodiments, Z is selected from the structure represented by formula (Ia):

[0118] Among them, Q, G, R 1 、R 2 、R 4 、R 4’ 、R 6 , Ring A is as defined above.

[0119] In some embodiments, Z is selected from the structure represented by formula (Ib):

[0120] Among them, Q, G, R 2 、R 4 、R 6 , Ring A is as defined above.

[0121] In some embodiments, Z is selected from the structure represented by formula (Ic):

[0122] Among them, Q, G, R 2 、R 4 、R 4’ 、R 5 、R 5’ 、R 6 , Ring A is as defined above.

[0123] In some embodiments, Z is selected from the structure represented by formula (Id):

[0124] Among them, G, RA 、R B 、R 2 、R 3 、R 6 , Ring A is as defined above.

[0125] In some embodiments, Z is selected from the structure represented by formula (Ie):

[0126] Among them, R 3 Selected from R 3a Substituted C1-C6 alkyl;

[0127] G, R 2 、R 3a 、R 6 , Ring A is as defined above.

[0128] In another aspect, the present disclosure provides a compound represented by formula (A) or a pharmaceutically acceptable salt or a stereoisomer thereof:

[0129] Z-L-PTM

[0130] (A)

[0131] Wherein, Z is selected from the structure shown in formula (II):

[0132] in, represents the connection point of L;

[0133] Indicates a single bond or a double bond;

[0134] W* is selected from C(O) or S(O)2;

[0135] Ring A* is selected from 4-8 membered heterocyclic group, C6-C 10 Aryl or 5-10 membered heteroaryl;

[0136] R 1* -(C1-C6 alkylene)-C3-C6 cycloalkyl, -(C1-C6 alkylene)-4-8 membered heterocyclic group, -(C1-C6 alkylene)-C6-C 10 Aryl, -(C1-C6 alkylene)-5-10 membered heteroaryl, C3-C6 cycloalkyl, 4-8 membered heterocyclic group, C6-C 10 Aryl or 5-10 membered heteroaryl, the -(C1-C6 alkylene)-C3-C6 cycloalkyl, -(C1-C6 alkylene)-4-8 membered heterocyclic group, -(C1-C6 alkylene)-C6-C 10 Aryl, -(C1-C6 alkylene)-5-10 membered heteroaryl, C3-C6 cycloalkyl, 4-8 membered heterocyclic group, C6-C 10Aryl or 5-10 membered heteroaryl is optionally replaced by R 1a* replace;

[0137] R 1a* is selected from halogen, CN, OH, NH2, C1-C6 alkyl, C1-C6 alkoxy or C3-C6 cycloalkyl;

[0138] m is selected from 0, 1, 2 or 3;

[0139] X*Selected from CR 3* or N;

[0140] X 2* Selected from CR x1 R x2 , CR x1 or NH;

[0141] X 3* Selected from CR x3 R x4 , CR x3 or NH;

[0142] R x1 、R x2 、R x3 、R x4 independently selected from H, halogen, CN, OH, NH2, C1-C6 alkyl, C1-C6 alkoxy or C2-C6 alkenyl;

[0143] R 3* is selected from H, OH, NH2, C1-C6 alkyl or C2-C6 alkenyl;

[0144] R 4* Selected from H, C1-C6 alkyl, C1-C6 alkoxy or C2-C6 alkenyl;

[0145] R 5* is selected from H, halogen, CN, OH, NH2, C1-C6 alkyl or C1-C6 alkoxy;

[0146] And R x1 、R x2 、R x3 、R x4 、R 3* 、R 4* At least one of the following conditions must be met:

[0147] (a)R x1 、R x2 The atoms to which it is attached form a C3-C6 cycloalkyl group or a 4-6 membered heterocyclic group;

[0148] (b)R x3 、R x4The atoms to which it is attached form a C3-C6 cycloalkyl group or a 4-6 membered heterocyclic group;

[0149] (c)R x1 、R x3 The atoms to which it is attached form a C3-C6 cycloalkyl group, a 4-6 membered heterocyclyl group, a phenyl group or a 5-6 membered heteroaryl group;

[0150] (d)R x1 、R 4* The atoms to which it is attached form a 5-7 membered heterocyclic group or a C5-C7 cycloalkenyl group;

[0151] (e)R 3* 、R 4* The atoms to which it is attached form a 5-7 membered heterocyclic group or a C5-C7 cycloalkenyl group;

[0152] L represents a linker unit that covalently binds at least one Z and at least one PTM;

[0153] The PTM is selected from the target protein binding ligand.

[0154] In some embodiments, X* is selected from CR 3* .

[0155] In some embodiments, X* is selected from CH.

[0156] In some embodiments, W* is selected from C(O).

[0157] In some embodiments, W* is selected from S(O)2.

[0158] In some embodiments, Ring A* is selected from C6-C 10 aryl or 5-10 membered heteroaryl.

[0159] In some embodiments, Ring A* is selected from phenyl or 5-6 membered heteroaryl.

[0160] In some embodiments, Ring A* is selected from phenyl.

[0161] In some embodiments, R 5* is selected from H or methoxy.

[0162] In some embodiments, R 5* Selected from H.

[0163] In some embodiments, R 1* -(C1-C6 alkylene)-C3-C6 cycloalkyl, -(C1-C6 alkylene)-4-8 membered heterocyclic group, -(C1-C6 alkylene)-C6-C 10Aryl, -(C1-C6 alkylene)-5-10 membered heteroaryl, C3-C6 cycloalkyl, 4-8 membered heterocyclyl or 5-10 membered heteroaryl, the -(C1-C6 alkylene)-C3-C6 cycloalkyl, -(C1-C6 alkylene)-4-8 membered heterocyclyl, -(C1-C6 alkylene)-C6-C 10 Aryl, -(C1-C6 alkylene)-5-10 membered heteroaryl, C3-C6 cycloalkyl, 4-8 membered heterocyclyl or 5-10 membered heteroaryl are optionally replaced by R 1a* replace.

[0164] In some embodiments, R 1* Selected from C3-C6 cycloalkyl, 4-8 membered heterocyclic group, C6-C 10 Aryl or 5-10 membered heteroaryl, the C3-C6 cycloalkyl, 4-8 membered heterocyclic group, C6-C 10 Aryl or 5-10 membered heteroaryl is optionally replaced by R 1a* replace.

[0165] In some embodiments, R 1* is selected from C3-C6 cycloalkyl, 4-8 membered heterocyclyl or 5-10 membered heteroaryl, wherein the C3-C6 cycloalkyl, 4-8 membered heterocyclyl or 5-10 membered heteroaryl is optionally replaced by R 1a* replace.

[0166] In some embodiments, R 1* is selected from 5-10 membered heteroaryl, wherein the 5-10 membered heteroaryl is optionally replaced by R 1a* replace.

[0167] In some embodiments, R 1* is selected from 5-6 membered heteroaryl, wherein the 5-6 membered heteroaryl is optionally replaced by R 1a* replace.

[0168] In some embodiments, R 1* is selected from thiazolyl, said thiazolyl being optionally substituted by R 1a* replace.

[0169] In some embodiments, R 1a* Selected from halogen, CN, OH, NH2, C1-C6 alkyl or C3-C6 cycloalkyl.

[0170] In some embodiments, R x1 、R x3 The atom to which it is connected forms a C3-C6 cycloalkyl group or a phenyl group.

[0171] In some embodiments, R x1 、R x3 The atom to which it is attached forms a phenyl group.

[0172] In some embodiments, R x1 、R 4* The atoms to which it is attached form a C5-C7 cycloalkenyl group.

[0173] In some embodiments, R 3* 、R 4* The atoms to which it is attached form a C5-C7 cycloalkenyl group.

[0174] In some embodiments, R x1 、R x2 The atom to which it is attached forms a cyclopropyl group, a cyclopentyl group or a 1,3-dithiolanyl group.

[0175] In some embodiments, m is selected from 1 or 2.

[0176] In some embodiments, m is selected from 1.

[0177] In some embodiments, X 2* Selected from CR x1 R x2 or CR x1 , X 3* Selected from CR x3 R x4 or CR x3 .

[0178] In some embodiments, L is selected from a linking unit that covalently binds one Z and one PTM.

[0179] In some embodiments, L is selected from

[0180] Wherein, M1 and M2 are independently selected from a bond, -NR 20 -, -C(O)-, -C(O)O-, -SO2-, -S(O)-, -O-, -S-, -C(=S)-, -C(O)NR 20 -、-NR 20 C(O)O-、-NR 20 S(O)2-, 2-10 membered heteroalkylene, C1-C 10 Alkylene, C2-C 10 Alkenylene, C2-C 10 Alkynylidene, C3-C 10 Cycloalkylene, 4-10 membered heterocyclylene, C6-C 10 Arylene or 5-10 membered heteroarylene, the 2-10 membered heteroalkylene, C1-C 10 Alkylene, C2-C 10 Alkenylene, C2-C 10 Alkynylidene, C3-C 10Cycloalkylene, 4-10 membered heterocyclylene, C6-C 10 Arylene or 5-10 membered heteroarylene is optionally replaced by R 21 replace;

[0181] R 10 、R 11 、R 12 、R 13 、R 14 、R 15 、R 16 independently selected from a bond, -(O-CH2CH2) k -, -C(O)-, -C(O)O-, -SO2-, -S(O)-, -O-, -S-, -C(S)-, -C(=NR 20 )-、-C(O)NR 20 -、-NR 20 -、-NR 20 C(O)O-、-NR 20 S(O)2-、-P(O)R 20 -、-P(O)(OR 20 )O-、-P(O)(OR 20 )-, 2-10 membered heteroalkylene, C1-C 10 Alkylene, C2-C 10 Alkenylene, C2-C 10 Alkynylidene, C3-C 10 Cycloalkylene, 4-10 membered heterocyclylene, C6-C 10 Arylene or 5-10 membered heteroarylene, the 2-10 membered heteroalkylene, C1-C 10 Alkylene, C2-C 10 Alkenylene, C2-C 10 Alkynylidene, C3-C 10 Cycloalkylene, 4-10 membered heterocyclylene, C6-C 10 Arylene or 5-10 membered heteroarylene is optionally replaced by R 21 replace;

[0182] k is independently selected from 1, 2, 3, 4, 5 or 6;

[0183] R 20 Selected from H, halogen, CN, OH, NH2, C1-C 10 Alkyl, C3-C 10 Cycloalkyl, 4-8 membered heterocyclic group, C6-C 10 Aryl or 5-10 membered heteroaryl, the OH, NH2, C1-C 10 Alkyl, C3-C 10 Cycloalkyl, 4-8 membered heterocyclic group, C6-C 10Aryl or 5-10 membered heteroaryl is optionally replaced by R f replace;

[0184] R 21 Selected from halogen, CN, OH, NH2, C1-C 10 Alkyl, C3-C 10 Cycloalkyl, 4-8 membered heterocyclic group, C6-C 10 Aryl or 5-10 membered heteroaryl, the OH, NH2, C1-C 10 Alkyl, C3-C 10 Cycloalkyl, 4-8 membered heterocyclic group, C6-C 10 Aryl or 5-10 membered heteroaryl is optionally replaced by R f replace;

[0185] Every R f Independently selected from halogen, CN, OH, NH2 or C1-C6 alkyl.

[0186] In some embodiments, R 20 Selected from H or C1-C 10 Alkyl, the C1-C 10 The alkyl group is optionally replaced by R f replace.

[0187] In some embodiments, R 21 Selected from halogen, CN, OH, NH2, NO2 or C1-C 10 Alkylene, the C1-C 10 The alkyl group is optionally replaced by R f replace.

[0188] In some embodiments, L is selected from Among them, M1, M2, R 10 、R 11 、R 12 、R 13 、R 14 As defined above.

[0189] In some embodiments, L is selected from Among them, M1, M2, R 10 、R 11 、R 12 As defined above.

[0190] In some embodiments, L is selected from Among them, R 10 、R 11 、R 12 、R 13 、R 14 independently selected from a bond, -(O-CH2CH2) k-, -C(O)-, -C(O)O-, -O-, -C(O)NR 20 -、-NR 20 -、-NR 20 C(O)O-、-NR 20 S(O)2-、C1-C 10 Alkylene, C2-C 10 Alkenylene, C2-C 10 Alkynylidene, 4-9 membered heterocyclylene, C6-C 10 Arylene or 5-10 membered heteroarylene, the C1-C 10 Alkylene, C2-C 10 Alkenylene, C2-C 10 Alkynylidene, 4-9 membered heterocyclylene, C6-C 10 Arylene or 5-10 membered heteroarylene is optionally replaced by R 21 Replacement; M1, M2, k, R 20 and R 21 As defined above.

[0191] In some embodiments, L is selected from Among them, R 11 、R 12 、R 13 , independently selected from a bond, -(O-CH2CH2) k -、C1-C 10 Alkylene or C2-C 10 Alkenylene, the C1-C 10 Alkylene or C2-C 10 The alkenylene group is optionally replaced by R 21 Replacement; R 10 、R 14 , M1, M2 are independently selected from a bond, -C(O)-, -C(O)O-, -C(O)NR 20 -、-O-、-NR 20 -、-NR 20 C(O)O-、-NR 20 S(O)2-、C1-C 10 Alkylene, C2-C 10 Alkenylene, C2-C 10 Alkyne, 4-9 membered heterocyclyl or 5-10 membered heteroaryl, the C1-C 10 Alkylene, C2-C 10 Alkenylene, C2-C 10 Alkyne, 4-9 membered heterocyclyl or 5-10 membered heteroarylene are optionally replaced by R 21 Replacement; R 20 、R 21 and k are as defined above.

[0192] In some embodiments, M1 and M2 are independently selected from a bond, -NR 20 -, -C(O)-, -C(O)O-, -SO2-, -S(O)-, -O-, -S-, -C(=S)-, -C(O)NR 20 -、-NR 20 C(O)O-、-NR 20 S(O)2-, 2-10 membered heteroalkylene, C1-C 10 Alkylene, C2-C 10 Alkenylene, C2-C 10 Alkynylidene, C3-C 10 Cycloalkylene, 4-9 membered heterocyclylene, C6-C 10 Arylene or 5-10 membered heteroarylene, the 2-10 membered heteroalkylene, C1-C 10 Alkylene, C2-C 10 Alkenylene, C2-C 10 Alkynylidene, C3-C 10 Cycloalkylene, 4-9 membered heterocyclylene, C6-C 10 Arylene or 5-10 membered heteroarylene is optionally replaced by R 21 replace.

[0193] In some embodiments, M1 and M2 are independently selected from a bond, -NR 20 -, -C(O)-, -C(O)O-, -O-, -S-, -C(O)NR 20 -, 2-10 membered heteroalkylene, C1-C 10 Alkylene, C2-C 10 Alkenylene, C2-C 10 Alkynylidene, C3-C 10 Cycloalkylene, 4-10 membered heterocyclylene, C6-C 10 Arylene or 5-10 membered heteroarylene, the 2-10 membered heteroalkylene, C1-C 10 Alkylene, C2-C 10 Alkenylene, C2-C 10 Alkynylidene, C3-C 10 Cycloalkylene, 4-10 membered heterocyclylene, C6-C 10 Arylene or 5-10 membered heteroarylene is optionally replaced by R 21 replace.

[0194] In some embodiments, M1 and M2 are independently selected from a bond, -NR 20 -, -C(O)-, -C(O)O-, -O-, -S-, -C(O)NR 20 -, 2-10 membered heteroalkylene, C1-C 10Alkylene, C2-C 10 Alkenylene, C2-C 10 Alkynylidene, C3-C 10 Cycloalkylene, 4-9 membered heterocyclylene, C6-C 10 Arylene or 5-10 membered heteroarylene, the 2-10 membered heteroalkylene, C1-C 10 Alkylene, C2-C 10 Alkenylene, C2-C 10 Alkynylidene, C3-C 10 Cycloalkylene, 4-9 membered heterocyclylene, C6-C 10 Arylene or 5-10 membered heteroarylene is optionally replaced by R 21 replace.

[0195] In some embodiments, M1 and M2 are independently selected from a bond, -NR 20 -, -C(O)-, -C(O)O-, -O-, -C(O)NR 20 -、C1-C 10 Alkylene, C2-C 10 Alkenylene, C2-C 10 Alkynylidene, 4-10 membered heterocyclylene, C6-C 10 Arylene or 5-10 membered heteroarylene, the C1-C 10 Alkylene, C2-C 10 Alkenylene, C2-C 10 Alkynylidene, C3-C 10 Cycloalkylene, 4-10 membered heterocyclylene, C6-C 10 Arylene or 5-10 membered heteroarylene is optionally replaced by R 21 replace.

[0196] In some embodiments, M1 and M2 are independently selected from a bond, -NR 20 -, -C(O)-, -C(O)O-, -O-, -C(O)NR 20 -、C1-C 10 Alkylene, C2-C 10 Alkenylene, C2-C 10 Alkynylidene, 4-9 membered heterocyclylene, C6-C 10 Arylene or 5-10 membered heteroarylene, the C1-C 10 Alkylene, C2-C 10 Alkenylene, C2-C 10 Alkynylidene, C3-C 10 Cycloalkylene, 4-9 membered heterocyclylene, C6-C 10 Arylene or 5-10 membered heteroarylene is optionally replaced by R 21 replace.

[0197] In some embodiments, R 10 、R 11 、R 12 、R 13 、R 14 、R 15 、R 16 independently selected from a bond, -(O-CH2CH2) k -, -C(O)-, -C(O)O-, -SO2-, -S(O)-, -O-, -S-, -C(S)-, -C(=NR 20 )-、-C(O)NR 20 -、-NR 20 -、-NR 20 C(O)O-、-NR 20 S(O)2-、-P(O)R 20 -、-P(O)(OR 20 )O-、-P(O)(OR 20 )-, 2-10 membered heteroalkylene, C1-C 10 Alkylene, C2-C 10 Alkenylene, C2-C 10 Alkynylidene, C3-C 10 Cycloalkylene, 4-9 membered heterocyclylene, C6-C 10 Arylene or 5-10 membered heteroarylene, the 2-10 membered heteroalkylene, C1-C 10 Alkylene, C2-C 10 Alkenylene, C2-C 10 Alkynylidene, C3-C 10 Cycloalkylene, 4-9 membered heterocyclylene, C6-C 10 Arylene or 5-10 membered heteroarylene is optionally replaced by R 21 replace.

[0198] In some embodiments, R 10 、R 11 、R 12 、R 13 、R 14 、R 15 、R 16 independently selected from a bond, -(O-CH2CH2) k -, -C(O)-, -C(O)O-, -SO2-, -S(O)-, -O-, -S-, -C(O)NR 20 -、-NR 20 -, 2-10 membered heteroalkylene, C1-C 10 Alkylene, C2-C 10 Alkenylene, C2-C 10 Alkynylidene, C3-C10 Cycloalkylene, 4-9 membered heterocyclylene, C6-C 10 Arylene or 5-10 membered heteroarylene, the 2-10 membered heteroalkylene, C1-C 10 Alkylene, C2-C 10 Alkenylene, C2-C 10 Alkynylidene, C3-C 10 Cycloalkylene, 4-9 membered heterocyclylene, C6-C 10 Arylene or 5-10 membered heteroarylene is optionally replaced by R 21 replace.

[0199] In some embodiments, R 10 、R 11 、R 12 、R 13 、R 14 、R 15 、R 16 independently selected from a bond, -(O-CH2CH2) k -, -C(O)-, -C(O)O-, -O-, -C(O)NR 20 -、-NR 20 -, C1-C6 alkylene, C2-C6 alkenylene, C2-C6 alkynylene, C3-C6 cycloalkylene, 4-9 membered heterocyclylene, C6-C 10 Arylene or 5-6 membered heteroarylene, the C1-C6 alkylene, C2-C6 alkenylene, C2-C6 alkynylene, C3-C6 cycloalkylene, 4-9 membered heterocyclylene, C6-C 10 Arylene or 5-6 membered heteroarylene is optionally replaced by R 21 replace.

[0200] In some embodiments, L is selected from the following structural units:

[0201] -NR 20 -C1-C 10 Alkylene-(OCH2CH2) k -NHC(O)-C1-C 10 Alkylene-O-,

[0202] -NR 20 -C1-C 10 Alkylene-C(O)NR 20 -CH2-,

[0203] -NR 20 -C1-C 10 Alkylene-(OCH2CH2) k -C(O)NR 20 -、

[0204] -C(O)-C1-C 10 Alkylene-(OCH2CH2) k -C(O)NR 20 -、

[0205] -C(O)-C1-C 10 Alkylene-(OCH2CH2) k -C(O)O-,

[0206] -NR 20 -C1-C 10 Alkylene-(OCH2CH2) k -C(O)-,

[0207] -C(O)-C1-C 10 Alkylene-C1-C 10 Alkylene-,

[0208] -C(O)-C1-C 10 Alkylene-C1-C 10 Alkylene-C2-C6 alkynylene-,

[0209] -C(O)-C1-C 10 Alkylene-C1-C 10 Alkylene-(4-10 membered heterocyclylene)-,

[0210] -C(O)-C1-C 10 Alkylene-C1-C 10 Alkylene-(5-10 membered heteroarylene)-,

[0211] -C(O)-C1-C 10 Alkylene-C1-C 10 Alkylene-C(O)NR 20 -(4-10 membered heterocyclylene)-,

[0212] -C(O)-C1-C 10 Alkylene-C1-C 10 Alkylene-C(O)O-,

[0213] -C(O)-C1-C 10 Alkylene-C2-C 10 Alkenylene-(4-10 membered heterocyclylene)-O-,

[0214] -C(O)-(C3-C 10 Cycloalkylene)-C1-C 10 Alkylene-O-,

[0215] -C(O)-(C3-C 10Cycloalkylene)-C1-C 10 Alkylene-NR 20 -、

[0216] -C(O)-(C3-C 10 Cycloalkylene)-C1-C 10 Alkylene-NR 20 -C1-C6 alkylene-,

[0217] Among them, R 20 , k are as defined above.

[0218] In some embodiments, L is selected from the following structural units:

[0219] -NH-(CH2) r -(OCH2CH2) k -NHC(O)-(CH2) r -O-,

[0220] -NH-(CH2) w -C(O)NH-CH2-,

[0221] -NH-(CH2) r -(OCH2CH2) k -C(O)NH-,

[0222] -C(O)-(CH2) r -(OCH2CH2) k -C(O)NH-,

[0223] -C(O)-(CH2) r -(OCH2CH2) k -C(O)O-,

[0224] -NH-(CH2) r -(OCH2CH2) k -C(O)-,

[0225] -C(O)-(CH2) w -(CH2) r -、

[0226] -C(O)-(CH2) w -(CH2) r -C≡C-,

[0227] -C(O)-(CH2) w -(CH2) r -(4-10 membered heterocyclylene)-,

[0228] -C(O)-(CH2)w -(CH2) r -(5-6 membered heteroarylene)-,

[0229] -C(O)-(CH2) w -(CH2) r -C(O)NH-(4-6 membered heterocyclylene)-,

[0230] -C(O)-(CH2) w -(CH2) r -C(O)O-,

[0231] -C(O)-(CH2)r-(CH=CHCH2CH2)2-(4-6 membered heterocyclylene)-O-,

[0232] -C(O)-(C3-C6 cycloalkylene)-(CH2) r -O-,

[0233] -C(O)-(C3-C6 cycloalkylene)-(CH2) r -NH-,

[0234] -C(O)-(C3-C6 cycloalkylene)-(CH2) r -NR 20 -(CH2) r -,

[0235] w is selected from 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10;

[0236] r is selected from 1, 2, 3, 4, 5 or 6;

[0237] k is selected from 1, 2, 3, 4 or 5.

[0238] In some embodiments, L is selected from the following structural units:

[0239] In some embodiments, the PTM is selected from the binding ligands of the following target proteins: ALK, AR, BET1, BRAF, BRCA2, BRD4, BRD9, BTK, BRM, CDK, CBL, CCNE1, CCNE2, CCR4, CCR7, CCR9, CD47, CLDN18, CYP, DDR1, DMPK, EGFR, ERBB2, ERBB3, ERBB4, FGFR1, FGFR2, FGFR3, FGFR4, GSPT1, JAK1, JAK3, KIF18A, KRAS, LCK, MET, NTRK1, NTRK2, NTRK3, PCSK9, PKMYT1, PARP7, PARP14, RAD51, RBM10, RET, RORA, STAT3, SOS1, TYK2, USP1, ARID1B, PTPN2.

[0240] In some embodiments, the PTM is selected from the binding ligands of the following target proteins: ALK, AR, BET1, BRAF, BRCA2, BRD4, BRD9, BRM, CDK, CBL, CCNE1, CCNE2, CCR4, CCR7, CCR9, CD47, CLDN18, CYP, DDR1, DMPK, EGFR, ERBB2, ERBB3, ERBB4, FGFR1, FGFR2, FGFR3, FGFR4, GSPT1, KIF18A, KRAS, LCK, MET, NTRK1, NTRK2, NTRK3, PCSK9, PKMYT1, PARP7, PARP14, RAD51, RBM10, RET, RORA, STAT3, SOS1, TYK2, USP1.

[0241] In some embodiments, the PTM is selected from the group consisting of binding partners of the following target proteins: BRD4, BRM, or ARID1B.

[0242] In some embodiments, the PTM is selected from the binding ligand of the following target protein: BRD4.

[0243] In some embodiments, the PTM is selected from the following structural groups:

[0244] In some embodiments, the compound represented by formula (A) or a pharmaceutically acceptable salt thereof is selected from the following compounds or pharmaceutically acceptable salts or stereoisomers thereof:

[0245] In another aspect, the present disclosure provides a pharmaceutical composition comprising a compound represented by formula (A) of the present disclosure, or a pharmaceutically acceptable salt or stereoisomer thereof, and a pharmaceutically acceptable excipient.

[0246] On the other hand, the present disclosure provides a method for treating a disease caused by abnormal cell proliferation in a mammal, comprising administering a therapeutically effective amount of a compound represented by formula (A) or a pharmaceutically acceptable salt or stereoisomer thereof, or a pharmaceutical composition thereof to a mammal, preferably a human, in need of such treatment.

[0247] In another aspect, the present disclosure provides use of a compound represented by formula (A) or a pharmaceutically acceptable salt or stereoisomer thereof, or a pharmaceutical composition thereof, in the preparation of a medicament for preventing or treating abnormal cell proliferation diseases.

[0248] In another aspect, the present disclosure provides use of a compound represented by formula (A) or a pharmaceutically acceptable salt or stereoisomer thereof, or a pharmaceutical composition thereof, in preventing or treating abnormal cell proliferation diseases.

[0249] In another aspect, the present disclosure provides a compound represented by formula (A) or a pharmaceutically acceptable salt or stereoisomer thereof, or a pharmaceutical composition thereof for preventing or treating abnormal cell proliferation diseases.

[0250] In some embodiments, the abnormal cell proliferation disorder is selected from cancer.

[0251] In some embodiments, the cancer is selected from a solid tumor, an adenocarcinoma, or a hematological cancer.

[0252] On the other hand, the present invention also provides a compound represented by formula (I-1) or a pharmaceutically acceptable salt or a stereoisomer thereof,

[0253] in,

[0254] Ring A is selected from 4-8 membered heterocyclic group, C6-C 10 Aryl or 5-10 membered heteroaryl;

[0255] X is selected from CR 3 R 3’ NR 4 , CR 4 R 4’ C(O)NR 1 or CR 4 R 4’ CR 5 R 5’ ;

[0256] W is selected from C(O) or S(O)2;

[0257] Q is selected from (CR A R B ) q ; R A 、R BIndependently selected from H, halogen or C1-C6 alkyl;

[0258] q is selected from 0, 1, 2, 3

[0259] G is selected from C3-C6 cycloalkyl, 4-8 membered heterocyclic group, C6-C 10 Aryl, 5-10 membered heteroaryl, the C3-C6 cycloalkyl, 4-8 membered heterocyclic group, C6-C 10 Aryl, 5-10 membered heteroaryl are optionally replaced by R 1a replace;

[0260] R 1a is selected from halogen, CN, OH, NH2, C1-C6 alkyl, C1-C6 alkoxy or C3-C6 cycloalkyl;

[0261] R 1 Selected from H or C1-C6 alkyl;

[0262] R 2 Selected from C1-C6 alkyl, C3-C6 cycloalkyl, 4-8 membered heterocyclic group, C6-C 10 Aryl or 5-10 membered heteroaryl, the C1-C6 alkyl, C3-C6 cycloalkyl, 4-8 membered heterocyclic group, C6-C 10 Aryl or 5-10 membered heteroaryl is optionally replaced by R 2a replace;

[0263] R 2a is selected from halogen, CN, OH or NH2;

[0264] R 3’ Selected from H or C1-C6 alkyl;

[0265] R 3 Selected from optionally R 3a Substituted C1-C6 alkyl;

[0266] R 3a Selected from C(O)NH2, C3-C6 cycloalkyl, 4-8 membered heterocyclic group, C6-C 10 Aryl or 5-10 membered heteroaryl, the C3-C6 cycloalkyl, 4-8 membered heterocyclic group, C6-C 10 Aryl or 5-10 membered heteroaryl is optionally substituted with halogen, CN, OH, NH2 or C1-C6 alkyl;

[0267] or R 3 、R 3’ The atom to which it is attached forms a C3-C6 cycloalkyl or a 4-6 membered heterocyclyl, wherein the C3-C6 cycloalkyl or the 4-6 membered heterocyclyl is optionally substituted with OH, NH2, halogen or C1-C6 alkyl;

[0268] R4 is selected from C1-C6 alkyl or C3-C6 cycloalkyl, wherein the C1-C6 alkyl or C3-C6 cycloalkyl is optionally replaced by R 4a replace;

[0269] R 4’ is selected from H, C1-C6 alkyl or C3-C6 cycloalkyl, wherein the C1-C6 alkyl or C3-C6 cycloalkyl is optionally replaced by R 4a replace;

[0270] R 5 、R 5’ independently selected from H, halogen, C1-C6 alkyl, said C1-C6 alkyl being optionally replaced by R 5a replace;

[0271] R 4a 、R 5a independently selected from OH, NH2, halogen, C1-C6 alkyl, C3-C6 cycloalkyl or 4-6 membered heterocyclyl, wherein the C1-C6 alkyl, C3-C6 cycloalkyl or 4-6 membered heterocyclyl is optionally substituted with halogen, CN, OH, NH2 or C1-C6 alkyl;

[0272] R 6 Selected from H, halogen, C1-C6 alkyl or C1-C6 alkoxy;

[0273] The condition is that when R 3’ Selected from H, R 3 When selected from -(CH2)2CH3, W is selected from S(O)2 or Q is selected from (CR A R B ) q and q is selected from 1, 2 or 3;

[0274] L is as defined above.

[0275] In some embodiments, the compound of formula (I-1) or a pharmaceutically acceptable salt thereof or a stereoisomer thereof is selected from the structure represented by formula (Ia-1):

[0276] Among them, Q, G, R 1 、R 2 、R 4 、R 4’ 、R 6 , Ring A, and L are as defined above.

[0277] In some embodiments, the compound of formula (I-1) or a pharmaceutically acceptable salt or stereoisomer thereof is selected from the structure represented by formula (Ib-1):

[0278] Among them, Q, G, R 2 、R 4 、R 6 , Ring A, and L are as defined above.

[0279] In some embodiments, the compound of formula (I-1) or a pharmaceutically acceptable salt or stereoisomer thereof is selected from the structure represented by formula (Ic-1):

[0280] Among them, Q, G, R 2 、R 4 、R 4’ 、R 5 、R 5’ 、R 6 , Ring A, and L are as defined above.

[0281] In some embodiments, the compound of formula (I-1) or a pharmaceutically acceptable salt thereof or a stereoisomer thereof is selected from the structure represented by formula (Id-1):

[0282] Among them, G, R A 、R B 、R 2 、R 3 、R 6 , Ring A, and L are as defined above.

[0283] In some embodiments, the compound of formula (I-1) or a pharmaceutically acceptable salt or stereoisomer thereof is selected from the structure represented by formula (Ie-1):

[0284] Among them, R 3 Selected from R 3a Substituted C1-C6 alkyl;

[0285] G, R 2 、R 3a 、R 6 , Ring A, and L are as defined above.

[0286] On the other hand, the present invention also provides a compound represented by formula (I-2) or a pharmaceutically acceptable salt or a stereoisomer thereof,

[0287] in,

[0288] Ring A is selected from 4-8 membered heterocyclic group, C6-C 10 Aryl or 5-10 membered heteroaryl;

[0289] X is selected from CR 3 R 3’ NR 4, CR 4 R 4’ C(O)NR 1 or CR 4 R 4’ CR 5 R 5’ ;

[0290] W is selected from C(O) or S(O)2;

[0291] Q is selected from (CR A R B ) q ; R A 、R B Independently selected from H, halogen or C1-C6 alkyl;

[0292] q is selected from 0, 1, 2, 3

[0293] G is selected from C3-C6 cycloalkyl, 4-8 membered heterocyclic group, C6-C 10 Aryl, 5-10 membered heteroaryl, the C3-C6 cycloalkyl, 4-8 membered heterocyclic group, C6-C 10 Aryl, 5-10 membered heteroaryl are optionally replaced by R 1a replace;

[0294] R 1a is selected from halogen, CN, OH, NH2, C1-C6 alkyl, C1-C6 alkoxy or C3-C6 cycloalkyl;

[0295] R 1 Selected from H or C1-C6 alkyl;

[0296] R 2 Selected from C1-C6 alkyl, C3-C6 cycloalkyl, 4-8 membered heterocyclic group, C6-C 10 Aryl or 5-10 membered heteroaryl, the C1-C6 alkyl, C3-C6 cycloalkyl, 4-8 membered heterocyclic group, C6-C 10 Aryl or 5-10 membered heteroaryl is optionally replaced by R 2a replace;

[0297] R 2a is selected from halogen, CN, OH or NH2;

[0298] R 3’ Selected from H or C1-C6 alkyl;

[0299] R 3 Selected from - optionally R 3a Substituted C1-C6 alkyl;

[0300] R 3aSelected from C(O)NH2, C3-C6 cycloalkyl, 4-8 membered heterocyclic group, C6-C 10 Aryl or 5-10 membered heteroaryl, the C3-C6 cycloalkyl, 4-8 membered heterocyclic group, C6-C 10 Aryl or 5-10 membered heteroaryl is optionally substituted with halogen, CN, OH, NH2 or C1-C6 alkyl;

[0301] or R 3 、R 3’ The atom to which it is attached forms a C3-C6 cycloalkyl or a 4-6 membered heterocyclyl, wherein the C3-C6 cycloalkyl or the 4-6 membered heterocyclyl is optionally substituted with OH, NH2, halogen or C1-C6 alkyl;

[0302] R 4 is selected from C1-C6 alkyl or C3-C6 cycloalkyl, wherein the C1-C6 alkyl or C3-C6 cycloalkyl is optionally replaced by R 4a replace;

[0303] R 4’ is selected from H, C1-C6 alkyl or C3-C6 cycloalkyl, wherein the C1-C6 alkyl or C3-C6 cycloalkyl is optionally replaced by R 4a replace;

[0304] R 5 、R 5’ independently selected from H, halogen, C1-C6 alkyl, said C1-C6 alkyl being optionally replaced by R 5a replace;

[0305] R 4a 、R 5a independently selected from OH, NH2, halogen, C1-C6 alkyl, C3-C6 cycloalkyl or 4-6 membered heterocyclyl, wherein the C1-C6 alkyl, C3-C6 cycloalkyl or 4-6 membered heterocyclyl is optionally substituted with halogen, CN, OH, NH2 or C1-C6 alkyl;

[0306] R 6 Selected from H, halogen, C1-C6 alkyl or C1-C6 alkoxy;

[0307] The condition is that when R 3’ Selected from H, R 3 When selected from -(CH2)2CH3, W is selected from S(O)2 or Q is selected from (CR A R B ) q and q is selected from 1, 2 or 3.

[0308] In some embodiments, the compound represented by formula (I-2) or a pharmaceutically acceptable salt thereof or a stereoisomer thereof is selected from the structure represented by formula (Ia-2):

[0309] Among them, Q, G, R 1 、R 2 、R 4 、R 4’ 、R 6 , Ring A is as defined above.

[0310] In some embodiments, the compound of the structure represented by formula (I-2) or a pharmaceutically acceptable salt thereof or a stereoisomer thereof is selected from the structure represented by formula (Ib-2):

[0311] Among them, Q, G, R 2 、R 4 、R 6 , Ring A is as defined above.

[0312] In some embodiments, the compound of formula (I-2) or a pharmaceutically acceptable salt thereof or a stereoisomer thereof is selected from the structure represented by formula (Ic-2):

[0313] Among them, Q, G, R 2 、R 4 、R 4’ 、R 5 、R 5’ 、R 6 , Ring A is as defined above.

[0314] In some embodiments, the compound of formula (I-2) or a pharmaceutically acceptable salt thereof or a stereoisomer thereof is selected from the structure represented by formula (Id-2):

[0315] Among them, G, R A 、R B 、R 2 、R 3 、R 6 , Ring A is as defined above.

[0316] In some embodiments, the compound of formula (I-2) or a pharmaceutically acceptable salt thereof or a stereoisomer thereof is selected from the structure represented by formula (Ie-2):

[0317] Among them, R 3 Selected from R 3a Substituted C1-C6 alkyl;

[0318] G, R 2 、R 3a 、R 6 , Ring A is as defined above.

[0319] In some embodiments, the compound represented by formula (I-2) or a pharmaceutically acceptable salt thereof or a stereoisomer thereof is selected from the following compounds or a pharmaceutically acceptable salt thereof or a stereoisomer thereof:

[0320] On the other hand, the present invention also provides a compound represented by formula (II-1) or a pharmaceutically acceptable salt or a stereoisomer thereof,

[0321] in, represents the connection point of L;

[0322] Indicates a single bond or a double bond;

[0323] W* is selected from C(O) or S(O)2;

[0324] Ring A* is selected from 4-8 membered heterocyclic group, C6-C 10 Aryl or 5-10 membered heteroaryl;

[0325] R 1* -(C1-C6 alkylene)-C3-C6 cycloalkyl, -(C1-C6 alkylene)-4-8 membered heterocyclic group, -(C1-C6 alkylene)-C6-C 10 Aryl, -(C1-C6 alkylene)-5-10 membered heteroaryl, C3-C6 cycloalkyl, 4-8 membered heterocyclic group, C6-C 10 Aryl or 5-10 membered heteroaryl, the -(C1-C6 alkylene)-C3-C6 cycloalkyl, -(C1-C6 alkylene)-4-8 membered heterocyclic group, -(C1-C6 alkylene)-C6-C 10 Aryl, -(C1-C6 alkylene)-5-10 membered heteroaryl, C3-C6 cycloalkyl, 4-8 membered heterocyclic group, C6-C 10 Aryl or 5-10 membered heteroaryl is optionally replaced by R 1a* replace;

[0326] R 1a* is selected from halogen, CN, OH, NH2, C1-C6 alkyl, C1-C6 alkoxy or C3-C6 cycloalkyl;

[0327] m is selected from 0, 1, 2 or 3;

[0328] X*Selected from CR 3* or N;

[0329] X 2* Selected from CR x1 R x2 , CR x1 or NH;

[0330] X 3* Selected from CR x3 R x4 , CR x3 or NH;

[0331] R x1 、R x2 、R x3 、R x4 independently selected from H, halogen, CN, OH, NH2, C1-C6 alkyl, C1-C6 alkoxy or C2-C6 alkenyl;

[0332] R 3* is selected from H, OH, NH2, C1-C6 alkyl or C2-C6 alkenyl;

[0333] R 4* Selected from H, C1-C6 alkyl, C1-C6 alkoxy or C2-C6 alkenyl;

[0334] R 5* is selected from H, halogen, CN, OH, NH2, C1-C6 alkyl or C1-C6 alkoxy;

[0335] And R x1 、R x2 、R x3 、R x4 、R 3* 、R 4* At least one of the following conditions must be met:

[0336] (a)R x1 、R x2 The atoms to which it is attached form a C3-C6 cycloalkyl group or a 4-6 membered heterocyclic group;

[0337] (b)R x3 、R x4 The atoms to which it is attached form a C3-C6 cycloalkyl group or a 4-6 membered heterocyclic group;

[0338] (c)R x1 、R x3 The atoms to which it is attached form a C3-C6 cycloalkyl group, a 4-6 membered heterocyclyl group, a phenyl group or a 5-6 membered heteroaryl group;

[0339] (d)R x1 、R 4 The atoms to which it is attached form a 5-7 membered heterocyclic group or a C5-C7 cycloalkenyl group;

[0340] (e)R 3* 、R 4* The atoms to which it is attached form a 5-7 membered heterocyclic group or a C5-C7 cycloalkenyl group;

[0341] L is as defined above.

[0342] In some embodiments, X* is selected from CR 3* .

[0343] In some embodiments, X* is selected from CH.

[0344] In some embodiments, W* is selected from C(O).

[0345] In some embodiments, W* is selected from S(O)2.

[0346] In some embodiments, Ring A* is selected from C6-C 10 aryl or 5-10 membered heteroaryl.

[0347] In some embodiments, Ring A* is selected from phenyl or 5-6 membered heteroaryl.

[0348] In some embodiments, Ring A* is selected from phenyl.

[0349] In some embodiments, R 5* is selected from H or methoxy.

[0350] In some embodiments, R 5* Selected from H.

[0351] In some embodiments, R 1* -(C1-C6 alkylene)-C3-C6 cycloalkyl, -(C1-C6 alkylene)-4-8 membered heterocyclic group, -(C1-C6 alkylene)-C6-C 10 Aryl, -(C1-C6 alkylene)-5-10 membered heteroaryl, C3-C6 cycloalkyl, 4-8 membered heterocyclyl or 5-10 membered heteroaryl, the -(C1-C6 alkylene)-C3-C6 cycloalkyl, -(C1-C6 alkylene)-4-8 membered heterocyclyl, -(C1-C6 alkylene)-C6-C 10 Aryl, -(C1-C6 alkylene)-5-10 membered heteroaryl, C3-C6 cycloalkyl, 4-8 membered heterocyclyl or 5-10 membered heteroaryl are optionally replaced by R 1a* replace.

[0352] In some embodiments, R 1* is selected from C3-C6 cycloalkyl, 4-8 membered heterocyclyl or 5-10 membered heteroaryl, wherein the C3-C6 cycloalkyl, 4-8 membered heterocyclyl or 5-10 membered heteroaryl is optionally replaced by R 1a* replace.

[0353] In some embodiments, R 1* is selected from 5-10 membered heteroaryl, wherein the 5-10 membered heteroaryl is optionally replaced by R 1a* replace.

[0354] In some embodiments, R 1* is selected from 5-6 membered heteroaryl, wherein the 5-6 membered heteroaryl is optionally replaced by R 1a* replace.

[0355] In some embodiments, R 1* is selected from thiazolyl, said thiazolyl being optionally substituted by R 1a* replace.

[0356] In some embodiments, R 1a* Selected from halogen, CN, OH, NH2, C1-C6 alkyl or C3-C6 cycloalkyl.

[0357] In some embodiments, R x1 、R x3 The atom to which it is connected forms a C3-C6 cycloalkyl group or a phenyl group.

[0358] In some embodiments, R x1 、R 4* The atoms to which it is attached form a C5-C7 cycloalkenyl group.

[0359] In some embodiments, R 3* 、R 4* The atoms to which it is attached form a C5-C7 cycloalkenyl group.

[0360] In some embodiments, R x1 、R x2 The atom to which it is attached forms a cyclopropyl group, a cyclopentyl group or a 1,3-dithiolanyl group.

[0361] In some embodiments, m is selected from 1 or 2.

[0362] In some embodiments, m is selected from 1.

[0363] In some embodiments, X 2* Selected from CR x1 R x2 or CR x1 NH;X 3* Selected from CR x3 R x4 or CR x3 .

[0364] On the other hand, the present invention also provides a compound represented by formula (II-2) or a pharmaceutically acceptable salt or a stereoisomer thereof,

[0365] in, Indicates a single bond or a double bond;

[0366] W* is selected from C(O) or S(O)2;

[0367] Ring A* is selected from 4-8 membered heterocyclic group, C6-C 10 Aryl or 5-10 membered heteroaryl;

[0368] R 1* -(C1-C6 alkylene)-C3-C6 cycloalkyl, -(C1-C6 alkylene)-4-8 membered heterocyclic group, -(C1-C6 alkylene)-C6-C 10 Aryl, -(C1-C6 alkylene)-5-10 membered heteroaryl, C3-C6 cycloalkyl, 4-8 membered heterocyclic group, C6-C 10 Aryl or 5-10 membered heteroaryl, the -(C1-C6 alkylene)-C3-C6 cycloalkyl, -(C1-C6 alkylene)-4-8 membered heterocyclic group, -(C1-C6 alkylene)-C6-C 10 Aryl, -(C1-C6 alkylene)-5-10 membered heteroaryl, C3-C6 cycloalkyl, 4-8 membered heterocyclic group, C6-C 10 Aryl or 5-10 membered heteroaryl is optionally replaced by R 1a* replace;

[0369] R 1a* is selected from halogen, CN, OH, NH2, C1-C6 alkyl, C1-C6 alkoxy or C3-C6 cycloalkyl;

[0370] m is selected from 0, 1, 2 or 3;

[0371] X*Selected from CR 3* or N;

[0372] X 2* Selected from CR x1 R x2 , CR x1 or NH;

[0373] X 3* Selected from CR x3 R x4 , CR x3 or NH;

[0374] R x1 、R x2 、R x3 、R x4 independently selected from H, halogen, CN, OH, NH2, C1-C6 alkyl, C1-C6 alkoxy or C2-C6 alkenyl;

[0375] R 3* is selected from H, OH, NH2, C1-C6 alkyl or C2-C6 alkenyl;

[0376] R4* Selected from H, C1-C6 alkyl, C1-C6 alkoxy or C2-C6 alkenyl;

[0377] R 5* is selected from H, halogen, CN, OH, NH2, C1-C6 alkyl or C1-C6 alkoxy;

[0378] And R x1 、R x2 、R x3 、R x4 、R 3* 、R 4* At least one of the following conditions must be met:

[0379] (a)R x1 、R x2 The atoms to which it is attached form a C3-C6 cycloalkyl group or a 4-6 membered heterocyclic group;

[0380] (b)R x3 、R x4 The atoms to which it is attached form a C3-C6 cycloalkyl group or a 4-6 membered heterocyclic group;

[0381] (c)R x1 、R x3 The atoms to which it is attached form a C3-C6 cycloalkyl group, a 4-6 membered heterocyclyl group, a phenyl group or a 5-6 membered heteroaryl group;

[0382] (d)R x1 、R 4* The atoms to which it is attached form a 5-7 membered heterocyclic group or a C5-C7 cycloalkenyl group;

[0383] (e)R 3* 、R 4* The atoms to which it is attached form a 5-7 membered heterocyclic group or a C5-C7 cycloalkenyl group.

[0384] In some embodiments, X* is selected from CR 3* .

[0385] In some embodiments, X* is selected from CH.

[0386] In some embodiments, W* is selected from C(O).

[0387] In some embodiments, W* is selected from S(O)2.

[0388] In some embodiments, Ring A* is selected from C6-C 10 aryl or 5-10 membered heteroaryl.

[0389] In some embodiments, Ring A* is selected from phenyl or 5-6 membered heteroaryl.

[0390] In some embodiments, Ring A* is selected from phenyl.

[0391] In some embodiments, R 5* is selected from H or methoxy.

[0392] In some embodiments, R 5* Selected from H.

[0393] In some embodiments, R 1* -(C1-C6 alkylene)-C3-C6 cycloalkylene, -(C1-C6 alkylene)-4-8 membered heterocyclic group, -(C1-C6 alkylene)-C6-C 10 Aryl, -(C1-C6 alkyl)-5-10 membered heteroaryl, C3-C6 cycloalkyl, 4-8 membered heterocyclyl or 5-10 membered heteroaryl, the -(C1-C6 alkylene)-C3-C6 cycloalkyl, -(C1-C6 alkylene)-4-8 membered heterocyclyl, -(C1-C6 alkylene)-C6-C 10 Aryl, -(C1-C6 alkylene)-5-10 membered heteroaryl, C3-C6 cycloalkyl, 4-8 membered heterocyclyl or 5-10 membered heteroaryl are optionally replaced by R 1a* replace.

[0394] In some embodiments, R 1* is selected from C3-C6 cycloalkyl, 4-8 membered heterocyclyl or 5-10 membered heteroaryl, wherein the C3-C6 cycloalkyl, 4-8 membered heterocyclyl or 5-10 membered heteroaryl is optionally replaced by R 1a* replace.

[0395] In some embodiments, R 1* is selected from 5-10 membered heteroaryl, wherein the 5-10 membered heteroaryl is optionally replaced by R 1a* replace.

[0396] In some embodiments, R 1* is selected from 5-6 membered heteroaryl, wherein the 5-6 membered heteroaryl is optionally replaced by R 1a* replace.

[0397] In some embodiments, R 1* is selected from thiazolyl, said thiazolyl being optionally substituted by R 1a* replace.

[0398] In some embodiments, R 1a* Selected from halogen, CN, OH, NH2, C1-C6 alkyl or C3-C6 cycloalkyl.

[0399] In some embodiments, R x1 、R x3 The atom to which it is connected forms a C3-C6 cycloalkyl group or a phenyl group.

[0400] In some embodiments, R x1 、R 4* The atoms to which it is attached form a C5-C7 cycloalkenyl group.

[0401] In some embodiments, R 3* 、R 4* The atoms to which it is attached form a C5-C7 cycloalkenyl group.

[0402] In some embodiments, R x1 、R x2 The atom to which it is attached forms a cyclopropyl group, a cyclopentyl group or a 1,3-dithiocyclopentyl group.

[0403] In some embodiments, m is selected from 1 or 2.

[0404] In some embodiments, m is selected from 1.

[0405] In some embodiments, X 2* Selected from CR x1 R x2 or CR x1 NH;X 3* Selected from CR x3 R x4 or CR x3 .

[0406] In some embodiments, the compound represented by formula (II-2) or a pharmaceutically acceptable salt thereof or a stereoisomer thereof is selected from the following compounds or a pharmaceutically acceptable salt thereof or a stereoisomer thereof:

[0407] On the other hand, the present invention also provides the use of compounds represented by formula (I-1) or formula (I-2) or formula (II-1) or formula (II-2) or their stereoisomers in the preparation of targeted protein degradation drugs.

[0408] On the other hand, the present invention also provides the use of compounds represented by formula (I-1) or formula (I-2) or formula (II-1) or formula (II-2) or their stereoisomers as intermediates in the preparation of targeted protein degradation drugs.

[0409] Any embodiment of any aspect of the present invention can be combined with other embodiments without contradiction. In addition, in any embodiment of any aspect of the present invention, any technical feature can be applied to the technical feature in other embodiments without contradiction.

[0410] Definitions and Explanations of Terms

[0411] Unless otherwise indicated, the terms used in this disclosure have the following meanings. The definitions of groups and terms described in this disclosure, including their exemplary definitions, preferred definitions, definitions described in tables, and definitions of specific compounds in the Examples, may be combined and coupled with each other in any manner. A particular term should not be considered undefined or unclear unless specifically defined, but should be understood according to its common meaning in the art. When a trade name appears in this document, it is intended to refer to the corresponding commercial product or its active ingredient.

[0412] In this article, double bonds marked with *, i.e. The expression "a compound containing a double bond has cis- and trans-isomers" refers to any one of the cis- and trans-isomers or a mixture thereof.

[0413] In this article Indicates the attachment site.

[0414] The diagrammatic representations of racemates or enantiomerically pure compounds herein are from Maehr, J. Chem. Ed. 1985, 62: 114-120. Unless otherwise indicated, wedge and dotted wedge keys are used. To indicate the absolute configuration of a stereocenter, use black real and imaginary bonds. Indicates the relative configuration of a stereocenter (such as the cis-trans configuration of an alicyclic compound).

[0415] The term "tautomer" refers to functional group isomers resulting from the rapid shift of an atom between two positions in a molecule. Compounds of the present disclosure may exhibit tautomerism. Tautomeric compounds may exist as two or more interconvertible species. Tautomers generally exist in equilibrium, and attempts to isolate a single tautomer typically produce a mixture whose physical and chemical properties are consistent with a mixture of compounds. The position of equilibrium depends on the chemical properties within the molecule. For example, in many aliphatic aldehydes and ketones, such as acetaldehyde, the keto form predominates, while in phenols, the enol form predominates. The present disclosure encompasses all tautomeric forms of the compounds.

[0416] The term "stereoisomer" refers to isomers resulting from different spatial arrangements of atoms in a molecule, including cis-trans isomers, enantiomers and diastereomers.

[0417] The compounds of the present disclosure may have asymmetric atoms such as carbon atoms, sulfur atoms, nitrogen atoms, phosphorus atoms or asymmetric double bonds, and thus the compounds of the present disclosure may exist in specific geometric or stereoisomeric forms. Specific geometric or stereoisomeric forms may be cis and trans isomers, E and Z geometric isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers, (D)-isomers, (L)-isomers, and racemic mixtures or other mixtures thereof, such as enantiomerically or diastereomerically enriched mixtures, all of which are within the definition of compounds of the present disclosure and mixtures thereof. Substituents such as alkyl groups may have additional asymmetric carbon atoms, asymmetric sulfur atoms, asymmetric nitrogen atoms or asymmetric phosphorus atoms, and all of these isomers and mixtures thereof involved in the substituents are also within the definition of compounds of the present disclosure. Compounds of the present disclosure containing an asymmetric atom can be isolated in optically pure or racemic forms. Optically pure forms can be resolved from racemic mixtures or synthesized by using chiral starting materials or reagents.

[0418] The term "substituted" means that any one or more hydrogen atoms on a particular atom are replaced by a substituent, which may include deuterium and hydrogen variants, as long as the valence state of the particular atom is normal and the substituted compound is stable. When the substituent is oxo (i.e., =O), it means that two hydrogen atoms are replaced, and oxo does not occur on aromatic groups.

[0419] The term "optional" or "optionally" refers to that the event or situation described subsequently may or may not occur, and the description includes that the event or situation occurs and that the event or situation does not occur. For example, an ethyl group is "optionally" substituted with halogen, meaning that the ethyl group may be unsubstituted (CH2CH3), monosubstituted (CH2CH2F, CH2CH2Cl, etc.), polysubstituted (CHFCH2F, CH2CHF2, CHFCH2Cl, CH2CHCl2, etc.), or fully substituted (CF2CF3, CF2CCl3, CCl2CCl3, etc.). It will be appreciated by those skilled in the art that for any group comprising one or more substituents, any sterically impossible and / or incomposable replacement or substitution pattern will not be introduced.

[0420] When any variable (such as R a 、R b ) appears more than once in the composition or structure of a compound, its definition is independent in each case. For example, if a group is represented by two R b is replaced, then each R b There are independent options; for the group N (C1-C6 alkyl) 2, when the C1-C6 alkyl is R bWhen substituted, the two C1-C6 alkyl groups have independent R b options.

[0421] When the number of a linking group is 0, such as -(CH2)0-, it means that the linking group is a bond.

[0422] When the linking group mentioned in this article does not specify its connection direction, its connection direction is arbitrary. The X in the sentence is selected from "CR 4 R 4’ C(O)NR 1 ", then X can connect ring A and NR in the direction from left to right. 2 constitute You can also connect rings A and NR from right to left. 2 constitute

[0423] When a substituent's bond crosses two atoms in a ring, the substituent may be bonded to any atom in the ring. Represents R a Can remove OH and The substitution occurs at any position other than the attachment site.

[0424] In this article, C m -C n It means having mn or an integer number of carbon atoms in the range of m to n. For example, "C1-C 10 " means that the group may have 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, 6 carbon atoms, 7 carbon atoms, 8 carbon atoms, 9 carbon atoms or 10 carbon atoms. Similarly, m-membered to n-membered means that the number of ring atoms is m to n, for example, 5-14 membered ring includes 5-membered ring, 6-membered ring, 7-membered ring, 8-membered ring, 9-membered ring, 10-membered ring, 11-membered ring, 12-membered ring, 13-membered ring and 14-membered ring, and also includes any range from m to n, for example, 5-14 membered ring includes 6-14 membered ring, 6-11 membered ring, 5-10 membered ring, 6-10 membered ring, 6-8 membered ring, etc.

[0425] The term "alkyl" refers to a group of the formula C n H 2n+1 The term "C1-C 10The term "alkyl" is understood to mean a straight-chain or branched saturated hydrocarbon radical having 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms. Specific examples of the alkyl radical include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, neopentyl, 1,1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl , 1,1-dimethylbutyl, 2,3-dimethylbutyl, 1,3-dimethylbutyl or 1,2-dimethylbutyl, etc.; the term "C1-C6 alkyl" may be understood to mean an alkyl group having 1, 2, 3, 4, 5 or 6 carbon atoms, specific examples of which include but are not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, neopentyl, hexyl, 2-methylpentyl, etc. The term "C1-C3 alkyl" may be understood to mean a straight-chain or branched saturated alkyl group having 1, 2 or 3 carbon atoms. The "C1-C 10 The term "alkyl" may include "C1-C6 alkyl" or "C1-C3 alkyl" and the like, and the "C1-C6 alkyl" may further include "C1-C3 alkyl".

[0426] The term "alkylene" refers to a radical derived by the removal of two hydrogen atoms from the same carbon atom or from two different carbon atoms of a parent alkane, wherein alkyl is as defined above.

[0427] The term "heteroalkyl" refers to an alkyl group in which one or more -CH2- are replaced by a heteroatom selected from NH, O and S, or one or more -CH- are replaced by N; wherein the alkyl group is as defined above.

[0428] The term "heteroalkylene" refers to a radical having two hydrogen atoms removed from the same carbon atom or two different carbon atoms of a parent heteroalkane, wherein heteroalkyl is as defined above.

[0429] The term "alkoxy" refers to a group generated by the loss of a hydrogen atom from a hydroxyl group of a straight-chain or branched alcohol, and can be understood as "alkyloxy" or "alkyl-O-". The term "C1-C 10 "Alkoxy" can be understood as "C1-C 10 Alkyloxy" or "C1-C 10 The term "C1-C6 alkoxy" can be understood as "C1-C6 alkyloxy" or "C1-C6 alkyl-O-". The "C1-C 10The term "alkoxy" may include "C1-C6 alkoxy" and "C1-C3 alkoxy", and the "C1-C6 alkoxy" may further include "C1-C3 alkoxy".

[0430] The term "alkenyl" refers to a linear or branched unsaturated aliphatic hydrocarbon group consisting of carbon atoms and hydrogen atoms and having at least one double bond. 10 "Alkenyl" is understood to mean a linear or branched unsaturated hydrocarbon radical containing one or more double bonds and having 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms, "C2-C 10 "Alkenyl" is preferably "C2-C6 alkenyl", further preferably "C2-C4 alkenyl", and further preferably C2 or C3 alkenyl. It will be understood that when the alkenyl contains more than one double bond, the double bonds may be separated from each other or conjugated. Specific examples of the alkenyl include, but are not limited to, vinyl, allyl, (E)-2-methylvinyl, (Z)-2-methylvinyl, (E)-but-2-enyl, (Z)-but-2-enyl, (E)-but-1-enyl, (Z)-but-1-enyl, isopropenyl, 2-methylprop-2-enyl, 1-methylprop-2-enyl, 2-methylprop-1-enyl, (E)-1-methylprop-1-enyl or (Z)-1-methylprop-1-enyl, etc.

[0431] The term "alkenylene" refers to a radical derived by the removal of two hydrogen atoms from the same carbon atom or from two different carbon atoms of a parent alkene, wherein alkenyl is as defined above.

[0432] The term "alkynyl" refers to a straight or branched unsaturated aliphatic hydrocarbon group consisting of carbon atoms and hydrogen atoms and having at least one triple bond. 10 "Alkynyl" is understood to mean a linear or branched unsaturated hydrocarbon radical containing one or more triple bonds and having 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms. "C2-C 10 Examples of "alkynyl" include, but are not limited to, ethynyl (-C≡CH), propynyl (-C≡CCH 3、 -CH2C≡CH), but-1-ynyl, but-2-ynyl or but-3-ynyl. "C2-C 10 The term "alkynyl" may include "C2-C3 alkynyl". Examples of "C2-C3 alkynyl" include ethynyl (-C≡CH), prop-1-ynyl (-C≡CCH3), and prop-2-ynyl (-CH2C≡CH).

[0433] The term "alkynylene" refers to a radical derived by the removal of two hydrogen atoms from the same carbon atom or from two different carbon atoms of a parent alkyne, wherein alkynyl is as defined above.

[0434] The term "cycloalkyl" refers to a fully saturated carbon ring that exists in the form of a monocyclic, fused, bridged, or spirocyclic ring. Unless otherwise indicated, the carbon ring is typically a 3- to 10-membered ring. The term "C3-C 10 "Cycloalkyl" is understood to mean a saturated monocyclic, bicyclic, spirocyclic or bridged ring having 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms. Specific examples of the cycloalkyl group include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, norbornyl (bicyclo[2.2.1]heptyl), bicyclo[2.2.2]octyl, adamantyl, spiro[4.5]decyl, and the like. The term "C3-C 10 "Cycloalkyl" may include "C3-C6 cycloalkyl". The term "C3-C6 cycloalkyl" may be understood to mean a saturated monocyclic or bicyclic hydrocarbon ring having 3, 4, 5 or 6 carbon atoms, specific examples of which include but are not limited to cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. The term "C5-C8 cycloalkyl" may be understood to mean a saturated monocyclic or bicyclic hydrocarbon ring having 5, 6, 7 or 8 carbon atoms, and may also be represented as a C5-C8 saturated carbocyclic ring.

[0435] The term "cycloalkylene" refers to a radical derived by the removal of two hydrogen atoms from the same carbon atom or from two different carbon atoms of a parent cycloalkane, wherein cycloalkyl is as defined above.

[0436] The term "heterocyclyl" refers to a fully saturated or partially saturated (heteroaromatic as a whole that is not aromatic) monocyclic, fused, spiro or bridged ring group, which contains 1, 2, 3, 4 or 5 heteroatoms or heteroatomic groups (i.e., heteroatom-containing atomic groups) in its ring atoms, wherein the "heteroatoms or heteroatomic groups" include, but are not limited to, nitrogen atom (N), oxygen atom (O), sulfur atom (S), phosphorus atom (P), boron atom (B), -S(=O)2-, -S(=O)-, -P(=O)2-, -P(=O)-, -NH-, -S(=O)(=NH)-, -C(=O)NH- or -NHC(=O)NH-. The term "3-12 membered heterocyclyl" refers to a heterocyclyl group having 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 ring atoms, and containing 1, 2, 3, 4 or 5 heteroatoms or heteroatomic groups independently selected from the above-mentioned heteroatoms or heteroatomic groups in its ring atoms. “3-12 membered heterocyclic group” includes “4-7 membered heterocyclic group”, wherein specific examples of 4 membered heterocyclic group include but are not limited to azetidinyl, thietanyl or oxetanyl; specific examples of 5 membered heterocyclic group include but are not limited to tetrahydrofuranyl, dioxolyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, pyrrolinyl, 4,5-dihydrooxazolyl or 2,5-dihydro-1H-pyrrolyl; specific examples of 6 membered heterocyclic group include but are not limited to tetrahydropyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl, trithianyl, tetrahydropyridinyl or 4H-[1,3,4]thiadiazinyl; specific examples of 7 membered heterocyclic group include but are not limited to diazepanyl. The heterocyclic group may also be a bicyclic group, wherein specific examples of 5,5-membered bicyclic groups include but are not limited to hexahydrocyclopenta[c]pyrrol-2(1H)-yl; specific examples of 5,6-membered bicyclic groups include but are not limited to hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl, 5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazinyl or 5,6,7,8-tetrahydroimidazo[1,5-a]pyrazinyl. Optionally, the heterocyclic group may be a benzo-fused ring group of the above-mentioned 4-7-membered heterocyclic groups, specific examples of which include but are not limited to dihydroisoquinolinyl and the like. "4-10 membered heterocyclyl" may include "5-10 membered heterocyclyl", "4-7 membered heterocyclyl", "5-6 membered heterocyclyl", "6-8 membered heterocyclyl", "4-10 membered heterocycloalkyl", "5-10 membered heterocycloalkyl", "4-7 membered heterocycloalkyl", "5-6 membered heterocycloalkyl", "6-8 membered heterocycloalkyl", "5-8 membered heterocyclyl", etc. "4-7 membered heterocyclyl" may further include "4-6 membered heterocyclyl", "5-6 membered heterocyclyl", "4-7 membered heterocycloalkyl", "4-6 membered heterocycloalkyl", "5-6 membered heterocyclyl", etc. Although some bicyclic heterocyclyl groups in the present disclosure partially contain a benzene ring or a heteroaromatic ring, the heterocyclyl group as a whole is still non-aromatic.

[0437] The term "heterocyclylene" refers to a radical derived by removing two hydrogen atoms from the same carbon atom or two different carbon atoms of a parent heterocyclic ring, wherein heterocyclyl is as defined above.

[0438] The term "aryl" refers to an all-carbon monocyclic or fused polycyclic aromatic ring group having a conjugated π electron system. The aryl group may have 6-20 carbon atoms, 6-14 carbon atoms, or 6-12 carbon atoms. The term "C6-C 20 "Aryl" is understood to be an aromatic radical having 6 to 20 carbon atoms. In particular, a ring having 6 carbon atoms ("C6 aryl"), such as phenyl; or a ring having 9 carbon atoms ("C9 aryl"), such as indanyl or indenyl; or a ring having 10 carbon atoms ("C 10 or a ring having 13 carbon atoms ("C 13 aryl) such as fluorenyl; or a ring having 14 carbon atoms ("C 14 The term "C6-C 10 "Aryl" is understood to be an aromatic radical having 6 to 10 carbon atoms. In particular, a ring having 6 carbon atoms ("C6 aryl"), such as phenyl; or a ring having 9 carbon atoms ("C9 aryl"), such as indanyl or indenyl; or a ring having 10 carbon atoms ("C 10 The term "C6-C 20 "Aryl" may contain "C6-C 10 Aryl".

[0439] The term "arylene" refers to a radical derived by the removal of two hydrogen atoms from the same carbon atom or from two different carbon atoms of a parent aromatic ring, wherein aryl is as defined above.

[0440] The term "heteroaryl" refers to a monocyclic or fused polycyclic ring system having aromatic character, which contains at least one ring atom selected from N, O, S, and the remaining ring atoms are C. The term "5-10 membered heteroaryl" is understood to include monocyclic or bicyclic aromatic ring systems having 5, 6, 7, 8, 9 or 10 ring atoms, in particular 5 or 6 or 9 or 10 ring atoms, and containing 1, 2, 3, 4 or 5, preferably 1, 2 or 3 heteroatoms independently selected from N, O and S. In particular, the heteroaryl group is selected from thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl or thiadiazolyl, and the like, and benzo derivatives thereof, such as benzofuranyl, benzothienyl, benzothiazolyl, benzoxazolyl, benzisoxazolyl, benzimidazolyl, benzotriazolyl, indazolyl, indolyl or isoindolyl, and the like; or pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl or triazinyl, and the like, and benzo derivatives thereof, such as quinolyl, quinazolinyl or isoquinolyl, and the like; or acinyl, indolizinyl, purinyl, and the like, and benzo derivatives thereof; or cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, pteridinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl or phenoxazinyl, and the like. The term "5-6 membered heteroaryl" refers to an aromatic ring system having 5 or 6 ring atoms, and containing 1, 2 or 3, preferably 1-2 heteroatoms independently selected from N, O and S, and the remaining ring atoms are C aromatic ring groups.

[0441] The term "heteroarylene" refers to a radical derived by the removal of two hydrogen atoms from the same carbon atom or from two different carbon atoms of a parent heteroaryl ring, wherein heteroaryl is as defined above.

[0442] The term "halo" or "halogen" refers to fluorine, chlorine, bromine or iodine.

[0443] The term "therapeutically effective amount" means:

[0444] An amount of a compound of the present disclosure that (i) treats a particular disease, condition, or disorder, (ii) alleviates, ameliorates, or eliminates one or more symptoms of a particular disease, condition, or disorder, or (iii) delays the onset of one or more symptoms of a particular disease, condition, or disorder as described herein.

[0445] The amount of a compound of the disclosure that constitutes a "therapeutically effective amount" varies depending on the compound, the disease state and its severity, the mode of administration, and the age of the mammal to be treated, but can be routinely determined by one skilled in the art based on their own knowledge and this disclosure.

[0446] The term "treatment" means administering the compound or formulation described herein to improve or eliminate a disease or one or more symptoms associated with the disease, and includes:

[0447] (i) inhibiting a disease or disease state, i.e., arresting its development;

[0448] (ii) ameliorating the disease or condition, i.e., causing regression of the disease or condition.

[0449] The term "prevention" means administering a compound or formulation described herein to prevent a disease or one or more symptoms associated with the disease, including preventing the disease or disease state from occurring in a mammal, particularly when such mammal is susceptible to the disease state but has not yet been diagnosed as having the disease state.

[0450] As used herein, examples of the term "mammal" include, but are not limited to, any member of the class Mammalia: humans, non-human primates (e.g., chimpanzees and other apes and monkeys); livestock, such as cattle, horses, sheep, goats, pigs; domestic animals, such as rabbits, dogs, and cats; laboratory animals, including rodents, such as rats, mice, and guinea pigs, etc.

[0451] The term "pharmaceutically acceptable" refers to those compounds, materials, compositions and / or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response or other problems or complications, commensurate with a reasonable benefit / risk ratio.

[0452] The term "pharmaceutically acceptable salt" refers to pharmaceutically acceptable acid addition salts or base addition salts, including salts formed between a compound and an inorganic acid or organic acid, and salts formed between a compound and an inorganic base or an organic base.

[0453] The term "pharmaceutical composition" refers to a mixture of one or more compounds of the present disclosure or their salts and a pharmaceutically acceptable excipient. The purpose of a pharmaceutical composition is to facilitate administration of the compounds of the present disclosure to an organism.

[0454] The term "pharmaceutically acceptable excipient" refers to an excipient that is non-irritating to organisms and does not impair the biological activity and properties of the active compound. Suitable excipients are well known to those skilled in the art and include, for example, carbohydrates, waxes, water-soluble and / or water-swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water, and the like.

[0455] The word "comprise" or "comprises" and its English variations such as comprises or comprising are to be understood as having an open and non-exclusive meaning, ie, "including but not limited to".

[0456] The present disclosure also includes isotopically labeled compounds of the present disclosure that are identical to those described herein, but where one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into the compounds of the present disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine, such as 2 H. 3 H. 11 C. 13 C. 14 C. 13 N. 15 N. 15 O. 17 O. 18 O. 31 P. 32 P. 35 S. 18 F. 123 I. 125 I and 36 Cl et al.

[0457] Certain isotopically labeled compounds of the present disclosure (e.g., 3 H and 14 C-labeled) can be used in compound and / or substrate tissue distribution assays. 3 H) and carbon-14 (i.e. 14 C) isotopes are particularly preferred due to their ease of preparation and detectability. Positron emitting isotopes, such as 15 O. 13 N. 11 C and 18 F can be used in positron emission tomography (PET) studies to determine substrate occupancy. Isotopically labeled compounds of the disclosure can generally be prepared by following procedures analogous to those disclosed in the Schemes and / or Examples below, by substituting an isotopically labeled reagent for a non-isotopically labeled reagent.

[0458] The pharmaceutical compositions of the present disclosure can be prepared by combining the compounds of the present disclosure with suitable pharmaceutically acceptable excipients, and can be formulated into solid, semi-solid, liquid or gaseous preparations, such as tablets, pills, capsules, powders, granules, ointments, emulsions, suspensions, suppositories, injections, inhalants, gels, microspheres and aerosols.

[0459] Typical routes of administration of the disclosed compounds, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof include, but are not limited to, oral, rectal, topical, inhalation, parenteral, sublingual, intravaginal, intranasal, intraocular, intraperitoneal, intramuscular, subcutaneous, and intravenous administration.

[0460] The pharmaceutical composition of the present disclosure can be manufactured by methods well known in the art, such as conventional mixing methods, dissolution methods, granulation methods, emulsification methods, freeze-drying methods, and the like.

[0461] In some embodiments, the pharmaceutical composition is in oral form. For oral administration, the pharmaceutical composition can be formulated by mixing the active compound with pharmaceutically acceptable excipients well known in the art. These excipients enable the compounds of the present disclosure to be formulated into tablets, pills, lozenges, dragees, capsules, liquids, gels, slurries, suspensions, and the like for oral administration to a patient.

[0462] Solid oral compositions can be prepared by conventional mixing, filling, or tableting methods. For example, they can be prepared by mixing the active compound with a solid excipient, optionally grinding the resulting mixture, adding other suitable excipients as needed, and then granulating the mixture to obtain a tablet or dragee core. Suitable excipients include, but are not limited to, binders, diluents, disintegrants, lubricants, glidants, or flavoring agents.

[0463] The pharmaceutical composition may also be suitable for parenteral administration, such as sterile solutions, suspensions or lyophilized products in appropriate unit dosage forms.

[0464] In all the methods of administration of the compounds of formula (I) described herein, the dosage administered per day is 0.01 mg / kg to 1000 mg / kg body weight, in the form of single or divided doses. DETAILED DESCRIPTION

[0465] The invention is described in detail below by way of examples, but this is not intended to limit the present disclosure in any way. While the present disclosure has been described in detail herein, including specific embodiments thereof, it will be apparent to those skilled in the art that various changes and modifications can be made to the specific embodiments of the present disclosure without departing from the spirit and scope of the present disclosure.

[0466] The chemical reactions of the embodiments of the present disclosure are carried out in a suitable solvent that is compatible with the chemical transformations of the present disclosure and the reagents and materials required. In order to obtain the compounds of the present disclosure, it is sometimes necessary for those skilled in the art to modify or select synthetic steps or reaction schemes based on existing embodiments.

[0467] All reagents used in this disclosure were commercially available and used without further purification.

[0468] Unless otherwise specified, the ratio of mixed solvents is the volume mixing ratio. For example, "water:acetonitrile = 1:1" means that during the elution process, the volume ratio of water to acetonitrile in the mixed eluent is 1:1.

[0469] Unless otherwise stated, % refers to wt%.

[0470] Compounds are manually or Software naming, commercially available compounds use supplier catalog names.

[0471] The structures of the compounds were determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). The units of NMR shifts are 10 -6 The solvents for NMR measurements are deuterated dimethyl sulfoxide, deuterated chloroform, deuterated methanol, etc., and tetramethylsilane (TMS) is the internal standard.

[0472] Abbreviations:

[0473] HATU: 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate; DIEA: N,N-diisopropylethylamine; DMF: N,N-dimethylformamide; MeCN: acetonitrile; EtOH: ethanol; Pyrrolidine: tetrahydropyrrole; dioxane: 1,4-dioxane; TEA: triethylamine; THF: tetrahydrofuran; Pd(OAc)2: palladium acetate; X-PHOS: 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl; t-BuOH: tert-BuOH Butanol; 1-Bromopropane: 1-bromopropane; TIPT: tetraisopropyl titanate; DMA: N,N-dimethylacetamide; DMSO: dimethyl sulfoxide; Boc-NH-5PEG-NH2: tert-butyl N-[2-[2-[2-[2-(2-aminoethoxy)ethoxy]ethoxy]ethoxy]ethoxy]ethyl]carbamate; LDA: lithium diisopropylamide; i-PrOH: isopropanol; Xylene: xylene; Toluene or Tol.: toluene; DCM: dichloromethane.

[0474] Example 1: Preparation of 2-(2-cyano-N-methyl-3-(thiazol-2-yl)acrylamide)-N-phenylpentanamide (Compound 3)

[0475] Step 1: 2-Bromo-N-phenylpentanamide (Compound 3-3)

[0476] Compound 3-1 (93 mg, 1 mmol), compound 3-2 (268 mg, 1.5 mmol), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (456 mg, 1.2 mmol), N,N-diisopropylethylamine (193 mg, 1.5 mmol), and N,N-dimethylformamide (2 mL) were added to a flask. The mixture was stirred at room temperature for 3 hours. After the reaction, the mixture was extracted with ethyl acetate and water, and the organic phase was concentrated to obtain the crude product. The product was purified by reverse phase column chromatography (acetonitrile:water = 1:1) to obtain compound 3-3 (224 mg, 88% yield). m / z (ESI): 256 [M+H] + .

[0477] Step 2: 2-(Methylamino)-N-phenylpentanamide (Compound 3-4)

[0478] Compound 3-3 (224 mg, 0.88 mmol), acetonitrile (2 mL), potassium carbonate (364 mg, 2.64 mmol), and methylamine hydrochloride (118 mg, 1.76 mmol) were added to a flask and stirred at 60°C for 3 hours. After the reaction, the mixture was extracted with ethyl acetate and water. The organic phase was concentrated and purified by reverse phase column chromatography (acetonitrile:water = 1:1) to obtain compound 3-4 (172 mg, 95%). m / z (ESI): 207 [M+H] + .

[0479] Step 3: 2-(2-cyano-N-methylacetylamino)-N-phenylpentanamide (Compound 3-5)

[0480] Compound 3-4 (172 mg, 0.83 mmol) was placed in a flask, and 1,4-dioxane (3 mL), N,N-diisopropylethylamine (321 mg, 2.48 mmol), and 3-(3,5-dimethyl-1H-pyrazol-1-yl)-3-oxopropionitrile (202 mg, 1.25 mmol) were added. The mixture was stirred at 90°C for 1 hour. After the reaction, the mixture was extracted with ethyl acetate and water. The organic phase was concentrated to obtain the crude product, which was purified by reverse phase column chromatography (acetonitrile:water = 1:1) to obtain compound 3-5 (172 mg, 64% yield). m / z (ESI): 274 [M+H] + .

[0481] Step 4: 2-(2-cyano-N-methyl-3-(thiazol-2-yl)acrylamido)-N-phenylpentanamide (Compound 3)

[0482] Compound 3-5 (172 mg, 0.63 mmol), ethanol (2 mL), tetrahydropyrrole (22 mg, 0.32 mmol), and thiazole-2-carboxaldehyde (142 mg, 1.26 mmol) were added to a flask. Stir at room temperature for 1 hour. After the reaction, the mixture was extracted with ethyl acetate and water. The organic phase was concentrated to obtain the crude product, which was purified by reverse phase column chromatography (acetonitrile:water = 1:1) to obtain compound 3 (169 mg, 73% yield). m / z (ESI): 369 [M+H] + .

[0483] 1 H NMR(400MHz,DMSO-d6)δ10.11(s,1H),8.16–8.22(m,2H),7.89(s,1H),8.24–7.23(m,5H),5.19–5 .11(m,1H),3.02(s,3H),1.92–1.84(m,J=13.7Hz,2H),1.38–1.30(m,2H),0.84(t,J=7.5Hz,3H).

[0484] Example 2: Preparation of 1-cyano-N-methyl-N-(1-phenylbutyl)-2-(thiazol-2-yl)ethylene-1-sulfonamide (Compound 4)

[0485] Step 1: 1-cyano-N-methyl-N-(1-phenylbutyl)methanesulfonamide (Compound 4-3)

[0486] Compound 4-1 (163 mg, 1 mmol), compound 4-2 (207 mg, 1.5 mmol), sodium hydride (48 mg, 2 mmol), triethylamine (202 mg, 2 mmol), and tetrahydrofuran (3 mL) were added to a flask. The reaction mixture was stirred at room temperature for 2 hours. After completion of the reaction, the mixture was extracted with ethyl acetate and water, and the organic phase was concentrated to obtain the crude product. The crude product was purified by reverse phase column chromatography (acetonitrile:water = 1:1) to obtain compound 4-3 (119 mg, 45% yield). m / z (ESI): 267 [M+H] + .

[0487] Step 2: 1-Cyano-N-methyl-N-(1-phenylbutyl)-2-(thiazol-2-yl)ethylene-1-sulfonamide (Compound 4)

[0488] Compound 4-3 (119 mg, 0.45 mmol), ethanol (2 mL), tetrahydropyrrole (15 mg, 0.22 mmol), and thiazole-2-carboxaldehyde (74 mg, 0.66 mmol) were added to a flask. Stir at room temperature for 1 hour. After the reaction, the mixture was extracted with ethyl acetate and water. The organic phase was concentrated to obtain the crude product, which was purified by reverse-phase column chromatography (acetonitrile:water = 1:1) to obtain compound 4 (109 mg, 67% yield). m / z (ESI): 362 [M+H] + .

[0489] 1 H NMR(400MHz, DMSO-d6)δ8.39(s,1H),8.31(d,J=3.1Hz,1H),8.28(d,J=3.1Hz,1H),7.44–7.23(m,5H),4.94( t,J=7.8Hz,1H),2.85(s,3H),1.97(ddd,J=14.5,8.4,6.6Hz,2H),1.37–1.15(m,2H),0.89(t,J=7.3Hz,3H).

[0490] Example 3: Preparation of 2-cyano-N-methyl-N'-phenyl-N'-propyl-3-(thiazol-2-yl)acryloylhydrazide (Compound 5)

[0491] Step 1: tert-Butyl 1-methyl-2-phenylhydrazine-1-carboxylate (Compound 5-2)

[0492] Compound 5-1 (156 mg, 1 mmol), 1-tert-butyloxycarbonyl-1-methylhydrazine (182 mg, 1.25 mmol), palladium acetate (22 mg, 0.1 mmol), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (84 mg, 0.2 mmol), and sodium hydroxide (56 mg, 1.4 mmol) were added to a flask, and the argon atmosphere was replaced three times. Tert-butanol (3 mL) was added via syringe, and the reaction mixture was stirred at 85°C for 3 hours. After completion of the reaction, the mixture was extracted with ethyl acetate and water, and the organic phase was concentrated to obtain the crude product, which was purified by reverse phase column chromatography (acetonitrile:water = 1:1) to obtain compound 5-2 (93 mg, 42% yield). m / z (ESI): 223 [M+H] + .

[0493] Step 2: 2-Methyl-1-phenyl-1-propylhydrazine (Compound 5-3)

[0494] Compound 5-2 (93 mg, 0.42 mmol), tetrahydrofuran (2 mL), sodium hydride (15 mg, 0.63 mmol), and 1-bromopropane (103 mg, 0.84 mmol) were added to a flask and stirred at room temperature overnight. After the reaction, the mixture was extracted with ethyl acetate and water, and the organic phase was concentrated to obtain the crude intermediate. The intermediate was added to a flask, and tetrahydrofuran (1 mL) and dioxane hydrochloride solution (1 mL, 2 M) were added under an ice bath. The reaction was allowed to proceed at room temperature for 1 hour. After the reaction, the mixture was extracted with ethyl acetate and water, and the organic phase was concentrated to obtain the crude product. The product was purified by reverse phase column chromatography (acetonitrile:water = 1:1) to obtain compound 5-3 (62 mg, 90% yield). m / z (ESI): 165 [M+H] + .

[0495] Step 3: 2-cyano-N-methyl-N'-phenyl-N'-propylacetohydrazide (Compound 5-4)

[0496] Compound 5-3 (62 mg, 0.38 mmol), acetonitrile (3 mL), N,N-diisopropylethylamine (193 mg, 1.5 mmol), and 3-(3,5-dimethyl-1H-pyrazol-1-yl)-3-oxopropionitrile (135 mg, 0.825 mmol) were added to a flask. The mixture was stirred at room temperature for 1 hour. After the reaction, the mixture was extracted with ethyl acetate and water. The organic phase was concentrated to obtain the crude product, which was purified by reverse-phase column chromatography (acetonitrile:water = 1:1) to obtain compound 5-4 (56 mg, 64% yield). m / z (ESI): 232 [M+H] + .

[0497] Step 4: 2-cyano-N-methyl-N'-phenyl-N'-propyl-3-(thiazol-2-yl)acryloylhydrazide (Compound 5)

[0498] Compound 5-4 (56 mg, 0.24 mmol) was dissolved in ethanol (2 mL), and tetrahydropyrrole (8 mg, 0.12 mmol) and thiazole-2-carboxaldehyde (40 mg, 0.36 mmol) were added. The mixture was stirred at room temperature for 1 hour. After the reaction, the mixture was extracted with ethyl acetate and water. The organic phase was concentrated to obtain the crude product, which was purified by reverse phase column chromatography (acetonitrile:water = 1:1) to obtain compound 5 (39 mg, 50% yield). m / z (ESI): 327 [M+H] + .

[0499] 1H NMR(400MHz,DMSO-d6)δ8.33(s,1H),8.24–8.16(m,2H),7.45–7.28(m,2H),7.02–6.83(m,3H) ,3.57(ddd,J=13.3,10.2,6.1Hz,2H),3.03(s,3H),1.70–1.47(m,2H),0.93(t,J=7.3Hz,3H).

[0500] Example 4: Preparation of 2-cyano-N,4-dimethyl-4-(4-methylpiperazin-1-yl)-N-(1-phenylbutyl)pent-2-enamide (Compound 10)

[0501] Step 1: 2-Methyl-2-(4-methylpiperazin-1-yl)propanal (Compound 10-2)

[0502] Compound 10-1 (300 mg, 3.00 mmol), 2-bromo-2-methylpropanal (542.73 mg, 3.59 mmol), and potassium carbonate (827.89 mg, 5.99 mmol) were added to a reaction flask. Acetonitrile (20 mL) was added, and the reaction solution was stirred in an 80°C oil bath for 3 hours. After the reaction, the reaction solution was concentrated and extracted with ethyl acetate and water. The organic phase was dried and separated by normal phase chromatography (petroleum ether:ethyl acetate = 2:1) to obtain compound 10-2 (389 mg, yield 76%). m / z (ESI): 171 [M+H] + .

[0503] Step 2: N-methyl-1-phenylbutan-1-amine (Compound 10-4)

[0504] Compound 10-3 (1.0 g, 6.75 mmol), methylamine hydrochloride (2.73 g, 40.49 mmol), sodium cyanoborohydride (636.05 mg, 10.12 mmol), tetraisopropyl titanate (383.55 mg, 1.35 mmol), and triethylamine (4.10 g, 40.49 mmol) were added to a reaction flask. N,N-dimethylacetamide (10 mL) was added, and the reaction solution was stirred in an 80°C oil bath for 5 hours. After completion of the reaction, compound 10-4 (880 mg, 79% yield) was obtained by reverse phase chromatography (acetonitrile:water = 1:1). m / z (ESI): 164 [M+H] + .

[0505] Step 3: 2-cyano-N-methyl-N-(1-phenylbutyl)acetamide (Compound 10-5)

[0506] Compound 10-4 (25 mg, 153.13 μmol), 3-(3,5-dimethyl-1H-pyrazol-1-yl)-3-oxopropionitrile (37.48 mg, 229.70 μmol), and N,N-diisopropylethylamine (49.48 mg, 382.83 μmol) were added to a reaction flask. N,N-dimethylacetamide (1 mL) was then added, and the reaction mixture was stirred in a 90°C oil bath for 2 hours. After completion of the reaction, compound 10-5 (10.4 mg, 30% yield) was obtained by reverse phase chromatography (acetonitrile:water = 1:1). m / z (ESI): 231 [M+H] + .

[0507] Step 4: 2-Cyano-N,4-dimethyl-4-(4-methylpiperazin-1-yl)-N-(1-phenylbutyl)pent-2-enamide (Compound 10)

[0508] Compound 10-2 (50 mg, 293.68 μmol), compound 10-5 (67.64 mg, 293.68 μmol), and tetrahydropyrrole (20.89 mg, 293.68 μmol) were added to a reaction flask, followed by tetrahydrofuran (3 mL). The mixture was stirred at room temperature for 8 hours. After the reaction, the mixture was separated and purified by reverse phase chromatography (acetonitrile: water = 1:1) to obtain compound 10 (76 mg, yield 67%). m / z (ESI): 383.33 [M+H] + .

[0509] 1 H NMR(400MHz, DMSO-d6)δ7.34(tt,J=12.5,7.6Hz,6H),3.30(s,3H),2.76–2.58(m,3H),2.36(d,J= 24.4Hz,5H),2.15(d,J=8.6Hz,3H),2.05–1.71(m,3H),1.54–1.11(m,8H),0.95(t,J=7.3Hz,3H).

[0510] Example 5: Preparation of N-(3-amino-3-oxo-1-phenylpropyl)-2-cyano-N-methyl-3-(thiazol-2-yl)acrylamide (Compound 11)

[0511] Step 1: 3-(Methylamino)-3-phenylpropionamide (Compound 11-2)

[0512] Compound 11-1 (300 mg, 1.87 mmol) and lithium hydroxide (134.53 mg, 5.62 mmol) were added to a reaction flask, followed by dimethyl sulfoxide (8 mL) and water (2 mL). The reaction solution was stirred in an 80°C oil bath for 4 hours. After completion of the reaction, compound 11-2 (100 mg, 33% yield) was obtained by reverse phase chromatography (acetonitrile:water = 1:1). m / z (ESI): 179 [M+H] + .

[0513] Step 2: 3-(2-cyano-N-methylacetylamino)-3-phenylpropionamide (Compound 11-3)

[0514] Referring to the synthesis method of compound 10-5, compound 11-2 (100 mg, 561.07 μmol) was substituted for compound 10-4 to obtain compound 11-3 (60 mg, yield 43%). m / z (ESI): 246 [M+H] + .

[0515] Step 3: N-(3-amino-3-oxo-1-phenylpropyl)-2-cyano-N-methyl-3-(thiazol-2-yl)acrylamide (Compound 11)

[0516] Compound 11-3 (60 mg, 244.62 μmol), thiazole 2-carboxaldehyde (41.51 mg, 366.93 μmol), and tetrahydropyrrole (44.73 mg, 628.89 μmol) were added to a reaction flask, followed by tetrahydrofuran (2 mL). The reaction mixture was stirred at room temperature for 4 hours. After completion of the reaction, the mixture was purified by reverse phase chromatography (acetonitrile:water = 1:1) to afford compound 11 (10 mg, yield: 12%). m / z (ESI): 341 [M+H] + .

[0517] 1 H NMR(400MHz, DMSO-d6)δ8.21–8.15(m,2H),8.00–7.87(m,1H),7.55(d,J=17.3Hz,1H),7.47–7.15 (m,5H),7.10–6.86(m,1H),6.16–5.87(m,1H),3.15–2.92(m,1H),2.91–2.69(m,3H),2.65(s,1H).

[0518] Example 6: Preparation of 4-((2S,4R)-1-acetyl-4-((4-chlorophenyl)amino)-2-methyl-1,2,3,4-tetrahydroquinolin-6-yl)-N-(1-(4-(2-(2-cyano-N-methyl-3-(thiazol-2-yl)acrylamido)pentanoylamino)phenoxy)-2-oxo-6,9,12,15,18-pentaoxa-3-azaeicosane-20-yl)benzamide (Compound 14)

[0519] Step 1: 4-((2S,4R)-1-acetyl-4-((4-chlorophenyl)amino)-2-methyl-1,2,3,4-tetrahydroquinolin-6-yl)-N-(17-amino-3,6,9,12,15-pentaoxaheptadecanyl)benzamide (Compound 14-11)

[0520] Compound 14-10 (30 mg, 68.98 μmol), tert-butyl N-[2-[2-[2-[2-[2-(2-aminoethoxy)ethoxy]ethoxy]ethoxy]ethoxy]ethyl]carbamate (28.87 mg, 75.88 μmol), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (39.04 mg, 103.47 μmol), N,N-diisopropyl Ethylamine (17.83 mg, 137.96 μmol) was added to a reaction flask, followed by N,N-dimethylformamide (2 mL). The reaction was allowed to react at room temperature for 1 h. After completion of the reaction, the reaction solution was poured into water and extracted with ethyl acetate. The organic phase was dried and concentrated, and then a hydrochloric acid solution of dioxane was added and stirred. The reaction was complete after stirring for 4 h. The mixture was separated by reverse phase chromatography (acetonitrile:water = 1:1) and lyophilized to obtain compound 14-11 (40 mg, yield: 87%). m / z (ESI): 698 [M+H] + .

[0521] Step 2: 2-Bromo-N-(4-hydroxyphenyl)pentanamide (Compound 14-2)

[0522] Compound 14-1 (1.5 g, 13.75 mmol), 2-bromovaleric acid (2.49 g, 13.75 mmol), 2-(7-azophenyltriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (6.22 g, 16.49 mmol), and N,N-diisopropylethylamine (2.66 g, 20.62 mmol) were added to a reaction flask. N,N-dimethylformamide (10 mL) was added and the mixture was reacted at room temperature for 1 hour. After the reaction, the mixture was separated and purified by reverse phase chromatography (acetonitrile:water = 1:1) to obtain compound 14-2 (3.5 g, yield 93%). m / z (ESI): 272 [M+H] + .

[0523] Step 3: N-(4-hydroxyphenyl)-2-(methylamino)pentanamide (Compound 14-3)

[0524] Compound 14-2 (1.0 g, 3.67 mmol), methylamine hydrochloride (272.91 mg, 4.04 mmol), and cesium carbonate (1.80 g, 5.51 mmol) were added to a reaction flask, followed by acetonitrile (10 mL). The mixture was stirred in an 80°C oil bath for 1 hour. After the reaction, the reaction solution was concentrated and purified by reverse phase chromatography (acetonitrile:water = 1:1) to afford compound 14-3 (60 mg, yield: 10%). m / z (ESI): 223 [M+H] + .

[0525] Step 4: tert-Butyl (1-((4-hydroxyphenyl)amino)-1-oxopentan-2-yl)(methyl)carbamate (Compound 14-4)

[0526] Compound 14-3 (62 mg, 278.92 μmol), di-tert-butyl dicarbonate (66.96 mg, 306.82 μmol), and sodium bicarbonate (117.16 mg, 1.39 mmol) were added to a reaction flask, followed by tetrahydrofuran (6 mL) and water (2 mL). The mixture was stirred at room temperature for 2 h. After the reaction, ethyl acetate was added for extraction. The organic phase was dried, concentrated, and separated by normal phase chromatography (petroleum ether:ethyl acetate = 2:1) to obtain compound 14-4 (80 mg, yield: 88%). m / z (ESI): 323 [M+H] + .

[0527] Step 5: Methyl 2-(4-(2-((tert-butoxycarbonyl)(methyl)amino)pentanoylamino)phenoxy)acetate (Compound 14-5)

[0528] Compound 14-4 (90 mg, 279.16 μmol), methyl 2-chloroacetate (45.44 mg, 418.74 μmol), and cesium carbonate (181.91 mg, 558.32 μmol) were added to a reaction flask, followed by acetonitrile (5 mL) and stirring in an 80°C oil bath for 1 h. After completion of the reaction, the reaction solution was concentrated and extracted with ethyl acetate and water. The organic phase was dried and separated by normal phase chromatography (petroleum ether:ethyl acetate = 2:1) to afford compound 14-5 (105 mg, yield: 95%). m / z (ESI): 395 [M+H]+.

[0529] Step 6: 2-(4-(2-((tert-Butoxycarbonyl)(methyl)amino)pentanoylamino)phenoxy)acetic acid (Compound 14-6)

[0530] Compound 14-5 (195 mg, 494.35 μmol) was added to a reaction flask, followed by addition of 20% sodium hydroxide solution and stirring in a 90°C oil bath for 1 h. After completion of the reaction, hydrochloric acid was added to adjust the pH to 7. The product was separated by reverse-phase chromatography (acetonitrile:water = 1:1) and lyophilized to afford compound 14-6 (72 mg, yield: 38%). m / z (ESI): 381 [M+H] + .

[0531] Step 7: Tert-butyl (1-((4-((1-(4-((2S,4R)-1-acetyl-4-((4-chlorophenyl)amino)-2-methyl-1,2,3,4-tetrahydroquinolin-6-yl)phenyl)-1,21-dioxo-5,8,11,14,17-pentaoxa-2,20-diazadocosan-22-yl)oxy)phenyl)amino)-1-oxopentan-2-yl)(methyl)carbamate (Compound 14-7)

[0532] Compound 14-6 (27.28 mg, 71.71 μmol), compound 14-11 (50 mg, 71.71 μmol), 2-(7-azophenyltriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (32.46 mg, 86.05 μmol), and N,N-diisopropylethylamine (18.54 mg, 143.42 μmol) were added to a reaction flask, followed by N,N-dimethylformamide (1 mL). The mixture was reacted at room temperature for 1 h. After the reaction, the mixture was separated by reverse phase chromatography (acetonitrile:water = 1:1) and lyophilized to obtain compound 14-7 (30 mg, yield: 40%). m / z (ESI): 1059 [M+H] + .

[0533] Step 8: 4-((2S,4R)-1-acetyl-4-((4-chlorophenyl)amino)-2-methyl-1,2,3,4-tetrahydroquinolin-6-yl)-N-(1-(4-(2-(methylamino)pentanoylamino)phenoxy)-2-oxo-6,9,12,15,18-pentaoxa-3-azaeicosan-20-yl)benzamide (Compound 14-8)

[0534] Compound 14-7 (62 mg, 59.01 μmol) was added to a reaction flask, followed by a 4M hydrochloric acid / dioxane solution (1 mL). The mixture was allowed to react at room temperature for 2 h. After completion of the reaction, the mixture was separated by reverse phase chromatography (acetonitrile:water = 1:1) and lyophilized to obtain compound 14-8 (25 mg, yield: 92%). m / z (ESI): 959 [M+H]+.

[0535] Step 9: 4-((2S,4R)-1-acetyl-4-((4-chlorophenyl)amino)-2-methyl-1,2,3,4-tetrahydroquinolin-6-yl)-N-(1-(4-(2-(2-cyano-N-methylacetylamino)pentanoylamino)phenoxy)-2-oxo-6,9,12,15,18-pentaoxa-3-azaeicosan-20-yl)benzamide (Compound 14-9)

[0536] Compound 14-8 (27 mg, 28.14 μmol), 3-(3,5-dimethyl-1H-pyrazol-1-yl)-3-oxopropionitrile (6.89 mg, 42.21 μmol), and N,N-diisopropylethylamine (7.27 mg, 56.28 μmol) were added to a reaction flask. Dioxane (2 mL) was added and stirred in an 80°C oil bath for 1 h. After completion of the reaction, the reaction solution was concentrated, separated by reverse phase chromatography (acetonitrile:water = 1:1), and lyophilized to obtain compound 14-9 (25 mg, yield: 86%). m / z (ESI): 1026 [M+H] + .

[0537] Step 9: 4-((2S,4R)-1-acetyl-4-((4-chlorophenyl)amino)-2-methyl-1,2,3,4-tetrahydroquinolin-6-yl)-N-(1-(4-(2-(2-cyano-N-methyl-3-(thiazol-2-yl)acrylamido)pentanoylamino)phenoxy)-2-oxo-6,9,12,15,18-pentaoxa-3-azaeicosan-20-yl)benzamide (Compound 14)

[0538] Compound 14-9 (25 mg, 24.35 μmol), thiazole 2-carboxaldehyde (4.13 mg, 36.53 μmol), and tetrahydropyrrole (4.15 mg, 58.35 μmol) were added to a reaction flask, followed by tetrahydrofuran (1 mL). The reaction solution was stirred at room temperature for 8 h. After completion of the reaction, the product was separated by reverse phase chromatography (acetonitrile:water = 1:1) and lyophilized to obtain compound 14 (2.3 mg, 8.4% yield). m / z (ESI): 1122.04 [M+H] + .

[0539] 1H NMR (400MHz, DMSO-d6) δ8.52(t,J=5.6Hz,1H),8.20(s,1H),8.05(s,1H),7.90(d,J=8.1Hz,2H),7.61(d,J=8.1Hz,3H),7.55–7.4 0(m,4H),7.21(s,2H),7.12(d,J=8.7Hz,2H),6.90(dd,J=8.7,6.3Hz,2H),6.74(d,J=8.7Hz,2H),6.66(s,1H),6.29(d,J=8.0Hz, 1H),5.32(t,J=4.8Hz,1H),4.42(d,J=3.7Hz,2H),3.55–3.40(m,20H),3.27(d,J=6.1Hz,1H),2.64(d,J=22.6Hz,2H),2.14(s,1H ),2.00(q,J=7.1Hz,3H),1.50–1.40(m,3H),1.32–1.17(m,7H),1.09(d,J=6.2Hz,2H),1.01–0.89(m,2H),0.85(t,J=6.7Hz,3H).

[0540] Example 7: 2-(1,2,3,3a,4,8b-hexahydroindeno[1,2-b]pyrrole-1-oxo)-3-(thiazol-2-yl)acrylonitrile (Compound 1)

[0541] Step 1: 2-(1-oxo-2,3-dihydro-1H-inden-2-yl)acetic acid methyl ester (Compound 1-3)

[0542] Under argon at -78°C, lithium diisopropylamide (1.78 g, 16.65 mmol) was added dropwise to a solution of compound 1-1 (2 g, 15.13 mmol) in tetrahydrofuran (40 mL) and stirred for 1 hour. A solution of compound 1-2 (6.95 g, 45.40 mmol) in tetrahydrofuran (5 mL) was added dropwise to the reaction mixture and stirred at -78°C for 16 hours. After the reaction, water (50 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic phase was concentrated to obtain the crude product, which was purified by reverse phase column chromatography (water:acetonitrile = 1:1) to obtain compound 1-3 (3.09 g, 43% yield). m / z (ESI): 205 [M+H] + .

[0543] Step 2: (Z)-2-(1-(oximino)-2,3-dihydro-1H-inden-2-yl)acetic acid methyl ester (Compound 1-4)

[0544] Compound 1-3 (1.33 g, 6.51 mmol) was dissolved in methanol (20 mL) and water (5 mL). Hydroxylamine hydrochloride (1.04 g, 14.98 mmol) and sodium acetate (1.34 g, 16.28 mmol) were added and heated under reflux for 16 hours. After completion of the reaction, the reaction solution was concentrated to obtain the crude product, which was purified by reverse phase column chromatography (water:acetonitrile = 1:1) to obtain compound 1-4 (1.43 g, 70% yield). m / z (ESI): 220 [M+H] + .

[0545] Step 3: 3,3a,4,8b-tetrahydroindeno[1,2-b]pyrrol-2(1H)-one (Compound 1-5)

[0546] Compound 1-4 (1 g, 4.56 mmol) was dissolved in isopropanol (20 mL), and palladium / carbon (50 mg, containing 50% water) was added. The mixture was heated to 50°C and reacted for 16 hours. After completion of the reaction, the reaction mixture was filtered and the filtrate was concentrated to obtain the crude product. The crude product was purified by reverse phase column chromatography (water:acetonitrile = 1:1) to obtain compound 1-5 (0.35 g, 70% yield). m / z (ESI): 174 [M+H] + .

[0547] Step 4: 1,2,3,3a,4,8b-hexahydroindeno[1,2-b]pyrrole (Compound 1-6)

[0548] Compound 1-5 (0.35 g, 2.02 mmol) was dissolved in xylene (5 mL), and a borane dimethyl sulfide solution (1.52 mL, 3.03 mmol) was added. The mixture was heated to 100°C and reacted for 16 hours. After the reaction, methanol (5 mL) was added, and the mixture was stirred at room temperature for 30 minutes. The crude product was concentrated and purified by reverse phase column chromatography (water:acetonitrile = 1:1) to obtain compound 1-6 (0.3 g, 93% yield). m / z (ESI): 160 [M+H] + .

[0549] Step 5: 3-oxo-3-(3,3a,4,8b-tetrahydroindeno[1,2-b]pyrrol-1(2H)-yl)propionitrile (Compound 1-7)

[0550] Compound 1-6 (50 mg, 0.31 mmol) was dissolved in 1,4-dioxane (2 mL), and N,N-diisopropylethylamine (162 mg, 1.26 mmol) and 3-(3,5-dimethyl-1H-pyrazol-1-yl)-3-oxopropionitrile (56 mg, 0.34 mmol) were added. The mixture was heated to 90°C for 1 hour. After completion of the reaction, the crude product was concentrated and purified by reverse phase column chromatography (water:acetonitrile = 1:1) to obtain compound 1-7 (50 mg, 70% yield). m / z (ESI): 227 [M+H] + .

[0551] Step 6: 2-(1,2,3,3a,4,8b-hexahydroindeno[1,2-b]pyrrole-1-oxo)-3-(thiazol-2-yl)acrylonitrile (Compound 1)

[0552] Compound 1-7 (50 mg, 0.22 mmol) was dissolved in tetrahydrofuran (2 mL), and diethylamine (8 mg, 0.11 mmol) and thiazole-2-carboxaldehyde (62 mg, 0.55 mmol) were added. The mixture was heated to 60°C for 2 hours. After completion of the reaction, the crude product was concentrated and purified by reverse phase column chromatography (water:acetonitrile = 1:1) to obtain compound 1 (15 mg, 21% yield). m / z (ESI): 322 [M+H] + .

[0553] 1 H NMR (400MHz, DMSO-d6) δ8.24–8.17(m,2H),8.10(s,1H),7.59(d,J=7.5Hz,1H),7.26(d,J=3.8Hz,2H),7.24–7.14(m,1H),5.58(d, J=6.9Hz,1H),3.87–3.76(m,1H),3.77–3.65(m,1H),3.22–3.11(m,2H),2.87–2.80(m,1H),2.22–2.10(m,1H),1.80–1.68(m,1H).

[0554] Example 8: 2-(2,3,3a,4,5,9b-hexahydro-1H-benzo[g]indole-1-oxo)-3-(thiazol-2-yl)acrylonitrile (Compound 2)

[0555] Step 1: 2-(1-oxo-1,2,3,4-tetrahydronaphthalen-2-yl)acetic acid methyl ester (Compound 2-2)

[0556] Under argon at -78°C, lithium diisopropylamide (1.61 g, 15.05 mmol) was added dropwise to a solution of compound 2-1 (2 g, 13.68 mmol) in tetrahydrofuran (40 mL) and stirred for 1 hour. A solution of compound 1-2 (6.28 g, 41.04 mmol) in tetrahydrofuran (10 mL) was then added dropwise to the reaction mixture and stirred for 16 hours at -78°C. After completion of the reaction, water (50 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic phase was concentrated to obtain the crude product, which was purified by reverse-phase column chromatography (water:acetonitrile = 1:1) to obtain compound 2-2 (2 g, 66% yield). m / z (ESI): 219 [M+H] + .

[0557] Step 2: (Z)-2-(1-(oximino)-1,2,3,4-tetrahydronaphthalen-2-yl)acetic acid methyl ester (Compound 2-3)

[0558] Compound 2-2 (0.4 g, 1.83 mmol) was dissolved in methanol (20 mL) and water (5 mL). Hydroxylamine hydrochloride (0.38 g, 5.5 mmol) and sodium acetate (0.45 g, 5.5 mmol) were added and heated under reflux for 16 hours. After completion of the reaction, the reaction solution was concentrated to obtain the crude product, which was purified by reverse phase column chromatography (water:acetonitrile = 1:1) to obtain compound 2-3 (0.3 g, 70% yield). m / z (ESI): 234 [M+H] + .

[0559] Step 3: 1,3,3a,4,5,9b-hexahydro-2H-benzo[g]indol-2-one (Compound 2-4)

[0560] Compound 2-3 (0.2 g, 0.85 mmol) was dissolved in isopropanol (20 mL), and palladium / carbon (20 mg, containing 50% water) was added. The mixture was heated to 50°C and reacted for 16 hours. After the reaction, the reaction mixture was filtered and the filtrate was concentrated to obtain the crude product. The crude product was purified by reverse phase column chromatography (water:acetonitrile = 1:1) to obtain compound 2-4 (0.1 g, yield 62%). m / z (ESI): 188 [M+H] + .

[0561] Step 4: 2,3,3a,4,5,9b-Hexahydro-1H-benzo[g]indole (Compound 2-5)

[0562] Compound 2-4 (0.2 g, 1.07 mmol) was dissolved in xylene (5 mL), and a solution of borane dimethyl sulfide (0.53 mL, 1.07 mmol) was added. The mixture was heated to 100°C and allowed to react for 16 hours. After the reaction, methanol (5 mL) was added, and the mixture was stirred at room temperature for 30 minutes. The mixture was concentrated to obtain the crude product, which was purified by reverse-phase column chromatography (water:acetonitrile = 1:1) to obtain compound 2-5 (0.05 g, 27% yield). m / z (ESI): 174 [M+H] + .

[0563] Step 5: 3-(2,3,3a,4,5,9b-hexahydro-1H-benzo[g]indol-1-yl)-3-oxopropionitrile (Compound 2-6)

[0564] Compound 2-5 (50 mg, 0.28 mmol) was dissolved in 1,4-dioxane (2 mL), and N,N-diisopropylethylamine (149 mg, 1.15 mmol) and 3-(3,5-dimethyl-1H-pyrazol-1-yl)-3-oxopropionitrile (51 mg, 0.31 mmol) were added. The mixture was heated to 90°C for 1 hour. After completion of the reaction, the crude product was concentrated and purified by reverse phase column chromatography (water:acetonitrile = 1:1) to obtain compound 2-6 (50 mg, 72% yield). m / z (ESI): 241 [M+H] + .

[0565] Step 6: 2-(2,3,3a,4,5,9b-hexahydro-1H-benzo[g]indole-1-oxo)-3-(thiazol-2-yl)acrylonitrile (Compound 2)

[0566] Compound 2-6 (50 mg, 0.20 mmol) was dissolved in tetrahydrofuran (2 mL), and diethylamine (7.6 mg, 0.10 mmol) and thiazole-2-carboxaldehyde (58 mg, 0.52 mmol) were added. The mixture was heated to 60°C for 2 hours. After completion of the reaction, the crude product was concentrated and purified by reverse phase column chromatography (water:acetonitrile = 1:1) to obtain compound 2 (20 mg, 28% yield). m / z (ESI): 336 [M+H] + .

[0567] 1 H NMR (400MHz, DMSO-d6) δ8.23–8.18(m,2H),8.15(s,1H),7.42–7.36(m,1H),7.25–7.12(m,3H),5.34(d,J=7 .8Hz,1H),3.80–3.69(m,2H),2.84–2.73(m,1H),2.70–2.58(m,2H),2.14–1.99(m,2H),1.75–1.59(m,2H).

[0568] Example 9: (2-(1-(4-methoxyphenyl)isoindoline-2-carbonyl)-3-(thiazol-2-yl)acrylonitrile (Compound 6)

[0569] Step 1: 3-Hydroxy-3-(4-methoxyphenyl)isoindolin-1-one (Compound 6-3)

[0570] Compound 6-1 (147 mg, 1 mmol) and tetrahydrofuran (3 mL) were placed in a flask. The reaction mixture was stirred in an ice bath at 0°C and cooled to a low temperature. The argon atmosphere was replaced. After cooling, compound 6-2 (630 mg, 3 mmol) was slowly added, and the reaction mixture was stirred in an ice bath for 1 hour. After the reaction was completed, the reaction mixture was concentrated and extracted with ethyl acetate and water. The organic phase was concentrated to obtain the crude product, which was purified by normal phase column chromatography (petroleum ether:ethyl acetate = 2:1) to obtain compound 6-3 (210 mg, 82% yield). m / z (ESI): 256 [M+H] + .

[0571] Step 2: 1-(4-methoxyphenyl)isoindoline (Compound 6-4)

[0572] Compound 6-3 (210 mg, 0.82 mmol) was placed in a flask and the atmosphere was replaced with nitrogen by vacuum. Toluene (3 mL) and borane dimethyl sulfide solution (5 mL, 2 M) were then added, and the reaction mixture was stirred in a 100°C oil bath for 3 hours. After the reaction was completed, the reaction mixture was placed in a 0°C ice bath with stirring to cool, and methanol was slowly added to quench the reaction. Dilute hydrochloric acid (1 M) was added and stirred and heated to 60°C to dissociate the product. The mixture was extracted with ethyl acetate and water, and the organic phase was concentrated to obtain the crude product, which was purified by reverse phase column chromatography (acetonitrile:water = 1:1) to obtain compound 6-4 (126 mg, 68% yield). m / z (ESI): 226 [M+H] + .

[0573] Step 3: 3-(1-(4-methoxyphenyl)isoindolin-2-yl)-3-oxopropionitrile (Compound 6-5)

[0574] Compound 6-4 (126 mg, 0.55 mmol) was placed in a flask, and 1,4-dioxane (3 mL), N,N-diisopropylethylamine (193 mg, 1.5 mmol), and 3-(3,5-dimethyl-1H-pyrazol-1-yl)-3-oxopropionitrile (84 mg, 0.515 mmol) were added. The mixture was stirred at 90°C for 1 hour. After the reaction, the mixture was extracted with ethyl acetate and water. The organic phase was concentrated to obtain the crude product, which was purified by reverse phase column chromatography (acetonitrile:water = 1:1) to obtain compound 6-5 (122 mg, 81% yield). m / z (ESI): 293 [M+H]+ .

[0575] Step 4: 2-(1-(4-methoxyphenyl)isoindoline-2-carbonyl)-3-(thiazol-2-yl)acrylonitrile (Compound 6)

[0576] Compound 6-5 (122 mg, 0.44 mmol) was placed in a flask and ethanol (2 mL), tetrahydropyrrole (15 mg, 0.22 mmol), and thiazole-2-carboxaldehyde (74 mg, 0.66 mmol) were added. The mixture was stirred at room temperature for 1 hour. After the reaction, the mixture was extracted with ethyl acetate and water. The organic phase was concentrated to obtain the crude product, which was purified by reverse phase column chromatography (acetonitrile:water = 1:1) to obtain compound 6 (122 mg, yield 81%). m / z (ESI): 388 [M+H] + .

[0577] 1 H NMR (400MHz, DMSO-d6) δ8.05–7.96(m,2H),7.76(s,1H),7.48–7.42(m,6H),7.02(d,J=7.6Hz,2H),5.79(s,1H),4.98–4.91(m,2H),3.69(s,3H).

[0578] Example 10: 2-(3-phenyl-3,3a,4,5,6,6-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl)-3-thiazol-2-ylprop-2-enenitrile (Compound 7)

[0579] Step 1: (3aR, 6aS)-1-phenyloctahydrocyclopenta[c]pyrrole (Compound 7-2)

[0580] n-Butyllithium (2.5M, 3.96 mL) was slowly added to a solution of compound 7-1 (1.1 g, 9.89 mmol) in anhydrous tetrahydrofuran (10 mL) at -78°C. The resulting solution was stirred at room temperature for 10 minutes. The solution was then cooled to -78°C and a solution of benzophenone (2.16 g, 11.87 mmol) in tetrahydrofuran (10 mL) was slowly added. The resulting mixture was stirred at -78°C for 1 hour. Phenyllithium (0.75 mmol) was slowly added to the mixture, and the mixture was stirred at -78°C for 8 hours. After the reaction, a small amount of water was added to the reaction solution, followed by extraction with ethyl acetate. The organic phase was collected and dried, and purified by reverse-phase column chromatography (acetonitrile:water = 1:1) to afford compound 7-2 (270 mg, 14% yield). m / z (ESI): 188 [M+H] + .

[0581] Step 2: 3-Oxo-3-((3aR,6aS)-1-phenylhexahydrocyclopenta[c]pyrrol-2(1H)-yl)propionitrile (Compound 7-3)

[0582] Compound 7-2 (260 mg, 1.39 mmol) and 3-(3,5-dimethyl-1H-pyrazol-1-yl)-3-oxopropionitrile (249.19 mg, 1.53 mmol) were added to 1,4-dioxane (5 mL), followed by N,N-diisopropylethylamine (358.85 mg, 2.78 mmol). The reaction was carried out at 90°C and monitored by LCMS. After 4 hours of reaction, the starting material was essentially converted to product. After completion of the reaction, the reaction mixture was poured into water and extracted with ethyl acetate. The organic phase was collected and dried by rotary evaporation. The mixture was purified by reverse phase column chromatography (acetonitrile:water = 1:1) to afford compound 7-3 (320 mg, 90% yield). m / z (ESI): 255 [M+H] + .

[0583] Step 3: 2-(3-phenyl-3,3a,4,5,6,6-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl)-3-thiazol-2-yl-2-propenenitrile (Compound 7)

[0584] Thiazole-2-carboxaldehyde (133.46 mg, 1.18 mmol), compound 7-3 (150 mg, 589.79 μmol), and piperidine (25.11 mg, 294.90 μmol) were added to ethanol (5 mL). The reaction was carried out at room temperature and monitored by LCMS. After overnight reaction, monitoring revealed that all the starting material had disappeared, with most of the product converted. After completion of the reaction, the reaction mixture was poured into water and extracted with ethyl acetate. The organic phase was dried and purified by reverse phase column chromatography (acetonitrile:water = 1:1) to obtain compound 7 (19 mg, 9% yield). m / z (ESI): 350 [M+H] + .

[0585] 1 H NMR(400MHz,Chloroform-d)δ8.20–7.88(m,2H),7.72–7.45(m,2H),7.33(t,J=5.8Hz,2H),7. 24–7.04(m,2H),5.25–5.00(m,1H),3.88–3.40(m,1H),2.91–2.66(m,2H),2.04–1.64(m,7H).

[0586] Example 11: 4-((2S,4R)-1-acetyl-4-((4-chlorophenyl)amino)-2-methyl-1,2,3,4-tetrahydroquinolin-6-yl)-N-(1-(4-(2-(2-cyano-3-(thiazol-2-yl)acryloyl)isoindolin-1-yl)phenoxy)-2-oxo-6,9,12,15,18-pentaoxa-3-azaeicosane-20-yl)benzamide (Compound 13)

[0587] Step 1: 4-((2S,4R)-1-acetyl-4-((4-chlorophenyl)amino)-2-methyl-1,2,3,4-tetrahydroquinolin-6-yl)-N-(17-amino-3,6,9,12,15-pentaoxaheptadecanyl)benzamide (Compound 13-2)

[0588] Compound 13-1 (30 mg, 68.98 μmol), tert-butyl N-[2-[2-[2-[2-[2-(2-aminoethoxy)ethoxy]ethoxy]ethoxy]ethoxy]ethyl]carbamate (28.87 mg, 75.88 μmol), 2-(7-azophenyltriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (39.04 mg, 103.47 μmol), N,N-diisopropylethylamine The 17.83 mg, 137.96 μmol of 1-hydroxy-2-nitropropane-1-yl thiazolinone (17.83 mg, 137.96 μmol) was added to a reaction flask, followed by N,N-dimethylformamide (2 mL) and allowed to react at room temperature for 1 hour. After the reaction, the reaction solution was poured into water and extracted with ethyl acetate. The organic phase was dried, filtered, and the filtrate was concentrated. A hydrochloric acid solution of dioxane was then added and stirred. After stirring for 4 hours, the reaction was complete. Compound 13-2 (40 mg, 87% yield) was obtained by separation and purification via reverse phase chromatography (acetonitrile:water = 1:1). m / z (ESI): 697 [M+H] + .

[0589] Step 2: 3-Hydroxy-3-(4-methoxyphenyl)isoindolin-1-one (Compound 13-4)

[0590] At -78°C under argon protection, compound 13-3 (2.0 g, 13.59 mmol) and (4-methoxyphenyl)magnesium bromide (40.78 mL, 40.78 mmol) were added to a reaction flask, followed by tetrahydrofuran (10 mL). The mixture was then slowly heated to room temperature and stirred for 1 hour. After the reaction was complete, saturated aqueous ammonium chloride (10 mL) was added, followed by extraction with ethyl acetate. The organic phase was dried, filtered, and the filtrate was concentrated and purified by normal phase chromatography (petroleum ether:ethyl acetate = 2:1) to obtain compound 13-4 (3.1 g, yield 89%). m / z (ESI): 256 [M+H] + .

[0591] Step 3: 1-(4-methoxyphenyl)isoindoline (Compound 13-5)

[0592] Under argon protection, compound 13-4 (1.5 g, 5.88 mmol) and a borane dimethyl sulfide solution (11.75 mL, 23.50 mmol) were added to a reaction flask, toluene (20 mL) was added, and the mixture was stirred in an 80°C oil bath for 6 hours. After the reaction, methanol (15 mL) was added to quench the reaction, and ethyl acetate was added for extraction. The organic phase was dried, filtered, and the filtrate was concentrated and purified by normal phase chromatography (petroleum ether:ethyl acetate = 2:1) to obtain compound 13-5 (0.9 g, yield 67%). m / z (ESI): 226 [M+H] + .

[0593] Step 4: 4-(Isoindolin-1-yl)phenol (Compound 13-6)

[0594] Compound 13-5 (820 mg, 3.64 mmol) and boron tribromide (4.56 g, 18.20 mmol) were added to a reaction flask, followed by dichloromethane (20 mL). The mixture was stirred at room temperature for 4 hours. After completion of the reaction, 10 mL of water was added to quench the reaction. The mixture was separated and purified by reverse phase chromatography (acetonitrile:water = 1:1) to obtain compound 13-6 (500 mg, yield 65%). m / z (ESI): 212 [M+H] + .

[0595] Step 5: tert-Butyl 1-(4-hydroxyphenyl)isoindoline-2-carboxylate (Compound 13-7)

[0596] Compound 13-6 (200 mg, 946.71 μmol), di-tert-butyl dicarbonate (247.94 mg, 1.14 mmol), and sodium bicarbonate (397.65 mg, 4.73 mmol) were added to a reaction flask, followed by tetrahydrofuran (6 mL) and water (2 mL). The mixture was stirred at room temperature for 2 hours. After the reaction, ethyl acetate was added for extraction. The organic phase was dried, concentrated, and purified by normal phase chromatography (petroleum ether:ethyl acetate = 2:1) to obtain compound 13-7 (280 mg, yield 94%). m / z (ESI): 312 [M+H] + .

[0597] Step 6: tert-Butyl 1-(4-(2-methoxy-2-oxoethoxy)phenyl)isoindoline-2-carboxylate (Compound 13-8)

[0598] Compound 13-7 (300 mg, 963.47 μmol), methyl 2-chloroacetate (125.47 mg, 1.16 mmol), and cesium carbonate (627.83 mg, 1.93 mmol) were added to a reaction flask, followed by acetonitrile (5 mL) and stirring in an 80°C oil bath for 1 hour. After the reaction, the reaction solution was concentrated and extracted with ethyl acetate and water. The organic phase was dried and filtered. The filtrate was concentrated and purified by normal phase chromatography (petroleum ether:ethyl acetate = 2:1) to obtain compound 13-8 (364 mg, yield 98%). m / z (ESI): 384 [M+H] + .

[0599] Step 7: 2-(4-(2-(tert-Butoxycarbonyl)isoindolin-1-yl)phenoxy)acetic acid (Compound 13-9)

[0600] Compound 13-8 (360 mg, 938.88 μmol) was added to a reaction flask, followed by 20% sodium hydroxide solution (10 mL). The mixture was stirred in a 90°C oil bath for 1 hour. After the reaction, hydrochloric acid (1 M) was added to adjust the pH to 7. The mixture was purified by reverse phase chromatography (acetonitrile:water = 1:1) to afford compound 13-9 (330 mg, 95% yield). m / z (ESI): 370 [M+H] + .

[0601] Step 8: tert-Butyl 1-(4-((1-(4-((2S,4R)-1-acetyl-4-((4-chlorophenyl)amino)-2-methyl-1,2,3,4-tetrahydroquinolin-6-yl)phenyl)-1,21-dioxo-5,8,11,14,17-pentaoxa-2,20-diazadocosan-22-yl)oxy)phenyl)isoindoline-2-carboxylate (Compound 13-10)

[0602] Compound 13-9 (27.34 mg, 74.00 μmol), compound 13-2 (43 mg, 61.67 μmol), 2-(7-azophenyltriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (27.92 mg, 74.0 μmol), and N,N-diisopropylethylamine (15.94 mg, 123.34 μmol) were added to a reaction flask, followed by N,N-dimethylformamide (1 mL). The mixture was reacted at room temperature for 1 h. After completion of the reaction, the mixture was separated and purified by reverse phase chromatography (acetonitrile:water = 1:1) to obtain compound 13-10 (62 mg, yield: 95%). m / z (ESI): 1048 [M+H] + .

[0603] Step 9: 4-((2S,4R)-1-acetyl-4-((4-chlorophenyl)amino)-2-methyl-1,2,3,4-tetrahydroquinolin-6-yl)-N-(1-(4-(isoindolin-1-yl)phenoxy)-2-oxo-6,9,12,15,18-pentaoxa-3-azaeicosan-20-yl)benzamide (Compound 13-11)

[0604] Compound 13-10 (62 mg, 59.01 μmol) was added to a reaction flask, followed by a 4M hydrochloric acid / dioxane solution (1 mL). The mixture was allowed to react at room temperature for 2 hours. After the reaction, the mixture was separated and purified by reverse phase chromatography (acetonitrile:water = 1:1) to obtain compound 13-11 (54 mg, yield 96%). m / z (ESI): 948 [M+H] + .

[0605] Step 10: 4-((2S,4R)-1-acetyl-4-((4-chlorophenyl)amino)-2-methyl-1,2,3,4-tetrahydroquinolin-6-yl)-N-(1-(4-(2-(2-cyanoacetyl)isoindolin-1-yl)phenoxy)-2-oxo-6,9,12,15,18-pentaoxa-3-azaeicosan-20-yl)benzamide (Compound 13-12)

[0606] Compound 13-11 (56 mg, 58.91 μmol), 3-(3,5-dimethyl-1H-pyrazol-1-yl)-3-oxopropionitrile (14.42 mg, 88.37 μmol), and N,N-diisopropylethylamine (15.23 mg, 117.83 μmol) were added to a reaction flask. Dioxane (2 mL) was added and stirred in an 80°C oil bath for 1 hour. After completion of the reaction, the reaction solution was concentrated and purified by reverse phase chromatography (acetonitrile:water = 1:1) to obtain compound 13-12 (50 mg, 83% yield). m / z (ESI): 1015 [M+H] + .

[0607] Step 11: 4-((2S,4R)-1-acetyl-4-((4-chlorophenyl)amino)-2-methyl-1,2,3,4-tetrahydroquinolin-6-yl)-N-(1-(4-(2-(2-cyano-3-(thiazol-2-yl)acryloyl)isoindolin-1-yl)phenoxy)-2-oxo-6,9,12,15,18-pentaoxa-3-azaeicosan-20-yl)benzamide (Compound 13)

[0608] Compound 13-12 (62 mg, 60.93 μmol), thiazole 2-carboxaldehyde (8.27 mg, 73.11 μmol), and tetrahydropyrrole (7.78 mg, 109.39 μmol) were added to a reaction flask. Tetrahydrofuran (1 mL) was added, and the reaction solution was stirred at room temperature for 8 hours. After completion of the reaction, compound 13 (26 mg, 37% yield) was obtained by reverse phase chromatography (acetonitrile:water = 1:1). m / z (ESI): 1110 [M+H] + .

[0609] 1 H NMR (400MHz, DMSO-d6) δ8.51(t,J=5.6Hz,1H),8.42(s,1H),8.31–8.21(m,1H),8.18–8.12(m,1H),8.05(dd,J=10.8,5.1Hz,1H),7.89(d,J=8.3Hz,2H) ,7.67–7.58(m,3H),7.49–7.37(m,3H),7.29(dd,J=22.8,8.8Hz,3H),7.12( d,J=8.7Hz,3H),6.88(dd,J=21.4,8.4Hz,2H),6.74(d,J=8.5Hz,2H),6.36– 6.25(m,1H),5.19(d,J=14.3Hz,1H),5.04–4.86(m,1H),4.71(d,J=7.2Hz,1 H),4.46(d,J=6.3Hz,1H),4.29(d,J=12.2Hz,1H),3.59–3.42(m,20H),2.69 –2.58(m,1H),2.14(s,2H),1.99(p,J=7.0,6.4Hz,1H),1.46(d,J=7.6Hz,1H ),1.24(q,J=9.8,7.9Hz,6H),1.09(d,J=6.3Hz,3H),0.85(t,J=6.5Hz,1H).

[0610] Test Example 1: BRD4 protein degradation activity assay in MV-4-11 cells

[0611] 1. Experimental instruments and materials

[0612] Instruments and Equipment

[0613] Experimental reagents and consumables

[0614] 2. Experimental steps

[0615] (1) Cell plating

[0616] Remove the culture medium from MV-4-11 (CBP60522, Kebai) and add 10 mL of complete culture medium (IMDM medium containing 10% FBS). Perfuse the cells and centrifuge at 1000 rpm for 5 minutes. Count the cells and adjust the cell density to 30,000 cells / mL. Add 90 μL of the cell suspension to a 96-well low-adhesion plate. Add 200 μL of PBS to the edge wells of the 96-well plate. Centrifuge at 1000 rpm for 5 minutes to allow the cells to aggregate into spheres. Place in a cell culture incubator and culture overnight.

[0617] (2) Cell dosing

[0618] Dissolve the disclosed compounds in DMSO to a stock concentration of 10 mM. Perform a 4-fold serial dilution of the compound stock solution to eight concentration points. A negative control with 0.1% DMSO was used. The compound and cell suspension were mixed and incubated at 37°C, 5% CO₂ for 6 hours.

[0619] (3) Western Blot

[0620] Six hours after treatment, the supernatant was discarded, and the cells were washed with 1000 μL of pre-chilled PBS. Then, 100 μL of RIPA lysis buffer (25 mM Tris-HCl, pH 7.5, 150 mM NaCl, 1% NP-40, 1 mM EDTA, pH 8.0, 1 mM PMSF, 1 mM Na₃VO₄, and 1x Protease Inhibitor Cocktail-P2714, Sigma) was added and lysed on ice for 10 min. Cell lysates were collected and centrifuged at 12,000 rpm at 4°C for 30 min. Protein concentration was determined using a Pierce BCA kit for protein quantification. An appropriate amount of 5x SDS-PAGE protein loading buffer was added to the collected protein samples, and the samples were heated in a metal bath at 100°C for 10 min to fully denature the proteins. Protein samples were loaded into the wells of an SDS-PAGE gel and electrophoresed at 120 V for 60 min. After electrophoresis, the gel was transferred to a PVDF membrane using a Bio-bad transfer apparatus. Bands were cut according to the size of the target protein and blocked in 5% BSA (5 g BSA dissolved in 100 mL TBST) for 1 hour at room temperature. Antibodies against BRD4 (1:3000) and β-actin (1:3000) were then added, respectively, and incubated overnight at 4°C. The following day, the antibodies were recovered, and the bands were washed three times with PBST (PBS containing 0.1% Tween-20), each for 10 minutes. After washing, diluted Goat Anti-Rabbit IgG H&L (1:3000) was added and incubated at room temperature for 1 hour. The bands were washed three times with PBST (PBS containing 0.1% Tween-20). Proteins were detected using SuperSignal West Atto ultrasensitive ECL luminescent solution.

[0621] 3. Data Analysis

[0622] The degradation activity of the disclosed compounds on BRD4 protein in MV-4-11 cells was determined by the above test. The grayscale value of the target sample band was read using Image J software, and the protein degradation rate of each sample well was calculated based on the raw data.

[0623] Degradation rate (%) = 100% × (1-sample reading / DMSO reference average reading)

[0624] Sample reading: refers to the signal value of the experimental group;

[0625] DSMO reference average reading: refers to the average signal value of the DSMO control group. The DSMO control group does not receive the test compound, and all other procedures are the same as the experimental group.

[0626] in:

[0627] All raw data were analyzed and processed by GraphPad Prism 9. The concentration-effect curve was fitted with a nonlinear four-parameter curve, and the DC of the compound was calculated. 50 (Concentration when protein degradation is 50%):

[0628] Y=Bottom+(Top-Bottom) / (1+10^((LogDC 50 -X)×HillSlope))

[0629] in:

[0630] X: Log compound concentration;

[0631] Y: degradation rate (%);

[0632] Bottom is the minimum degradation percentage;

[0633] Top is the maximum degradation percentage;

[0634] HillSlope is the slope coefficient of the curve.

[0635] DC measured by the disclosed compounds 50 The values ​​are shown in Table 1.

[0636] Table 1 Degradation activity of the disclosed compounds on BRD4 protein

Claims

1. A compound represented by formula (A) or a pharmaceutically acceptable salt or a stereoisomer thereof: Z-L-PTM (A) in, Z is selected from the structure shown in formula (I): in, represents the attachment site to L; Ring A is selected from 4-8 membered heterocyclic group, C6-C 10 Aryl or 5-10 membered heteroaryl; X is selected from CR 3 R 3’ , NR 4 , CR 4 R 4’ C(O)NR 1 or CR 4 R 4’ CR 5 R 5’ ; W is selected from C(O) or S(O)2; Q is selected from (CR A R B ) q ; R A , R B Independently selected from H, halogen or C1-C6 alkyl; q is selected from 0, 1, 2, 3; G is selected from C3-C6 cycloalkyl, 4-8 membered heterocyclic group, C6-C 10 aryl, 5-10 membered heteroaryl, the C3-C6 cycloalkyl, 4-8 membered heterocyclic group, C6-C 10 Aryl, 5-10 membered heteroaryl are optionally replaced by R 1a replace; R 1a is selected from halogen, CN, OH, NH2, C1-C6 alkyl, C1-C6 alkoxy or C3-C6 cycloalkyl; R 1 Selected from H or C1-C6 alkyl; R 2 is selected from C1-C6 alkyl or C3-C6 cycloalkyl, wherein the C1-C6 alkyl or C3-C6 cycloalkyl is optionally replaced by R 2a replace; R 2a is selected from halogen, CN, OH or NH2; R 3’ Selected from H or C1-C6 alkyl; R 3 Selected from optionally R 3a Substituted C1-C6 alkyl; R 3a Selected from C(O)NH2, C3-C6 cycloalkyl, 4-8 membered heterocyclic group, C6-C 10 aryl or 5-10 membered heteroaryl, the C3-C6 cycloalkyl, 4-8 membered heterocyclic group, C6-C 10 Aryl or 5-10 membered heteroaryl is optionally substituted by halogen, CN, OH, NH2 or C1-C6 alkyl; or R 3 , R 3’ The atom to which it is attached forms a C3-C6 cycloalkyl or a 4-6 membered heterocyclyl, wherein the C3-C6 cycloalkyl or the 4-6 membered heterocyclyl is optionally substituted with OH, NH2, halogen or C1-C6 alkyl; Or, R 3 , R 2 and the atoms to which they are attached together form a 7-10 membered bicyclic heterocyclic group, the 7-10 membered bicyclic heterocyclic group is optionally replaced by R 3b replace; Or, R 3 , R 2 and the atoms to which they are attached together form an optionally R 3b substituted 5-6 membered heterocyclic group, and R 3’ , R 6 and the atoms to which they are connected together form a 5-6 membered saturated or unsaturated carbon ring; Or, R 3 , R 2 and their respective connected atoms together form the R 3b When the 5- to 6-membered heterocyclic group is substituted, and R 3b , R 6 and the atoms to which they are connected together form a 5-6 membered saturated or unsaturated carbon ring; R 3b Selected from OH, NH2, halogen or C1-C6 alkyl; R 4 is selected from C1-C6 alkyl or C3-C6 cycloalkyl, wherein the C1-C6 alkyl or C3-C6 cycloalkyl is optionally replaced by R 4a replace; R 4’ is selected from H, C1-C6 alkyl or C3-C6 cycloalkyl, wherein the C1-C6 alkyl or C3-C6 cycloalkyl is optionally replaced by R 4a replace; R 5 , R 5’ independently selected from H, halogen, C1-C6 alkyl, the C1-C6 alkyl being optionally substituted by R 5a replace; R 4a , R 5a Independently selected from OH, NH2, halogen, C1-C6 alkyl, C3-C6 cycloalkyl or 4-6 membered heterocyclyl, wherein the C1-C6 alkyl, C3-C6 cycloalkyl or 4-6 membered heterocyclyl is optionally substituted with halogen, CN, OH, NH2 or C1-C6 alkyl; R 6 is selected from H, halogen, C1-C6 alkyl or C1-C6 alkoxy; The condition is that when R 3’ Selected from H, R 3 When selected from -(CH2)2CH3, W is selected from S(O)2 or Q is selected from (CR A R B ) q and q is selected from 1, 2 or 3; L represents a linking unit that covalently binds at least one Z and at least one PTM; The PTM is selected from a target protein binding ligand.

2. The compound represented by formula (A) according to claim 1, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein: X is selected from NR 4 , CR 4 R 4’ C(O)NH or CR 4 R 4’ CR 5 R 5’ ; Alternatively, X is selected from NR 4 or CR 4 R 4’ C(O)NH; Alternatively, X is selected from CR 4 R 4’ C(O)NH; Or, X is CR 3 R 3’ ; Alternatively, X is selected from CHR 3 , the R 3 , R 2 and the atoms to which they are attached together form a 7-10 membered bicyclic heterocyclic group, wherein the 7-10 membered The bicyclic heterocyclic group is optionally substituted by R 3b replace.

3. The compound represented by formula (A) according to claim 1, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein: X is selected from CR 3 R 3’ .

4. The compound represented by formula (A) according to claim 1, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein: R 1 Selected from H or C1-C3 alkyl.

5. The compound represented by formula (A) according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein: W is selected from C(O); or, W is selected from S(O)2.

6. The compound of formula (A) according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein: Ring A is selected from C6-C 10 aryl or 5-10 membered heteroaryl; or ring A is selected from phenyl or 5-6 membered heteroaryl; or ring A is selected from phenyl.

7. The compound of formula (A) according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein: G is selected from 4-8 membered heterocyclic group, C6-C 10 aryl or 5-10 membered heteroaryl, the 4-8 membered heterocyclic group, C6-C 10 Aryl or 5-10 membered heteroaryl is optionally replaced by R 1a replace; Alternatively, G is selected from a 4-6 membered heterocyclic group, a phenyl group or a 5-6 membered heteroaryl group, wherein the 4-6 membered heterocyclic group, the phenyl group or the 5-6 membered heteroaryl group is optionally replaced by R 1a replace; Alternatively, G is selected from 5-6 membered heteroaryl, wherein the 5-6 membered heteroaryl is optionally replaced by R 1a or, G is selected from thiazolyl, which is optionally substituted by R 1a replace.

8. The compound of formula (A) according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein: R 2 is selected from C1-C6 alkyl, wherein the C1-C6 alkyl is optionally replaced by R 2a replace.

9. The compound of formula (A) according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein: R 6 Selected from H.

10. The compound represented by formula (A) according to any one of claims 1, 3 or 5-9, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein: R 3’ Selected from H.

11. The compound represented by formula (A) according to any one of claims 1, 3 or 5-10, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein: R 3 Selected from -(CH2)2CH3; Or, R 3 Selected from R 3a Substituted C1-C6 alkyl.

12. The compound of formula (A) according to any one of claims 1, 3 or 5 to 10, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein: R 3 , R 3’ The atom to which it is attached forms a C3-C6 cycloalkyl group which is optionally substituted by OH, NH2, halogen or C1-C6 alkyl.

13. The compound represented by formula (A) according to any one of claims 1, 2, 5 to 9, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein: R 4 is selected from C1-C6 alkyl; or R 4 Selected from -(CH2)2CH3.

14. The compound represented by formula (A) according to any one of claims 1, 2, 5 to 9, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein: R 5 , R 5’ are independently selected from halogen.

15. The compound represented by formula (A) according to any one of claims 1, 2 to 9, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein: Q is selected from CR A R B ; Alternatively, Q is a bond.

16. The compound represented by formula (A) according to any one of claims 1-2 or 4-9 or 13 and 15, or a pharmaceutically acceptable salt thereof or a stereoisomer thereof, wherein: Z is selected from the structure shown in formula (Ia): Among them, Q, G, R 1 , R 2 , R 4 , R 4’ , R 6 , Ring A is as defined in any one of claims 1-2 or 4-9 or 13, 15.

17. The compound of formula (A) according to any one of claims 1-2 or 5-9 or 13, 15, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein: Z is selected from the structure shown in formula (Ib): Among them, Q, G, R 2 , R 4 , R 6 , Ring A is as defined in any one of claims 1-2 or 5-9 or 13, 15.

18. A compound of formula (A) according to any one of claims 1, 2, 5-9 or 13-15, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein: Z is selected from the structure shown in formula (Ic): Among them, Q, G, R 2 , R 4 , R 4’ , R 5 , R 5’ , R 6 , Ring A is as defined in any one of claims 1, 2 or 5-9 or 13-15.

19. The compound of formula (A) according to any one of claims 1, 5 to 9, 11, and 15, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein: Z is selected from the structure shown in formula (Id): Among them, G, R A , R B , R 2 , R 3 , R 6 , Ring A is as defined in any one of claims 1, 5-9, 11, and 15.

20. The compound of formula (A) according to any one of claims 1, 3 or 5-11, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein: Z is selected from the structure shown in formula (Ie): Among them, R 3 Selected from R 3a Substituted C1-C6 alkyl; G.R 2 , R 3a , R 6 , Ring A is as defined in any one of claims 1, 3 or 5-11.

21. The compound of formula (A) or a pharmaceutically acceptable salt or a stereoisomer thereof according to any one of claims 1 to 20, wherein: L is selected from Wherein, M1 and M2 are independently selected from a bond, -NR 20 -, -C(O)-, -C(O)O-, -SO2-, -S(O)-, -O-, -S-, -C(=S)-, -C(O)NR 20 -、-NR 20 C(O)O-、-NR 20 S(O)2-, 2-10 membered alkylene, C1-C 10 Alkylene, C2-C 10 Alkenylene, C2-C 10 Alkynylidene, C3-C 10 Cycloalkylene, 4-10 membered heterocyclylene, C6-C 10 Arylene or 5-10 membered heteroarylene, the 2-10 membered heteroalkylene, C1-C 10 Alkylene, C2-C 10 Alkenylene, C2-C 10 Alkynylidene, C3-C 10 Cycloalkylene, 4-10 membered heterocyclylene, C6-C 10 The arylene group or the 5-10 membered heteroarylene group is optionally substituted by R 21 replace; R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 independently selected from a bond, -(O-CH2CH2) k -, -C(O)-, -C(O)O-, -SO2-, -S(O)-, -O-, -S-, -C(S)-, -C(=NR 20 )-、-C(O)NR 20 -、-NR 20 -、-NR 20 C(O)O-、-NR 20 S(O)2-、-P(O)R 20 -、-P(O)(OR 20 )O-、-P(O)(OR 20 )-, 2-10 membered heteroalkylene, C1-C 10 Alkylene, C2-C 10 Alkenylene, C2-C 10 Alkynylidene, C3-C 10 Cycloalkylene, 4-10 membered heterocyclylene, C6-C 10 Arylene or 5-10 membered heteroarylene, the 2-10 membered heteroalkylene, C1-C 10 Alkylene, C2-C 10 Alkenylene, C2-C 10 Alkynylidene, C3-C 10 Cycloalkylene, 4-10 membered heterocyclylene, C6-C 10 The arylene group or the 5-10 membered heteroarylene group is optionally substituted by R 21 replace; k is independently selected from 1, 2, 3, 4, 5 or 6; R 20 Selected from H, halogen, CN, OH, NH2, C1-C 10 Alkyl, C3-C 10 Cycloalkyl, 4-8 membered heterocyclic group, C6-C 10 Aryl or 5-10 membered heteroaryl, the OH, NH2, C1-C 10 Alkyl, C3-C 10 Cycloalkyl, 4-8 membered heterocyclic group, C6-C 10 Aryl or 5-10 membered heteroaryl is optionally substituted by R f replace; R 21 Selected from halogen, CN, OH, NH2, C1-C 10 Alkyl, C3-C 10 Cycloalkyl, 4-8 membered heterocyclic group, C6-C 10 Aryl or 5-10 membered heteroaryl, the OH, NH2, C1-C 10 Alkyl, C3-C 10 Cycloalkyl, 4-8 membered heterocyclic group, C6-C 10 Aryl or 5-10 membered heteroaryl is optionally substituted by R f replace; Every R f Independently selected from halogen, CN, OH, NH2 or C1-C6 alkyl.

22. The compound of formula (A) or a pharmaceutically acceptable salt or a stereoisomer thereof according to claim 21, wherein: L is selected from Among them, M1, M2, R 10 , R 11 , R 12 , R 13 , R 14 As defined in claim 21; Alternatively, L is selected from Among them, R 10 , R 11 , R 12 , R 13 , R 14 independently selected from a bond, -(O-CH2CH2) k -, -C(O)-, -C(O)O-, -O-, -C(O)NR 20 -、-NR 20 -、-NR 20 C(O)O-、-NR 20 S(O)2-、C1-C 10 Alkylene, C2-C 10 Alkenylene, C2-C 10 Alkyne, 4-9 membered heterocyclyl, C6-C 10 Arylene or 5-10 membered heteroarylene, the C1-C 10 Alkylene, C2-C 10 Alkenylene, C2-C 10 Alkyne, 4-9 membered heterocyclyl, C6-C 10 The arylene group or the 5-10 membered heteroarylene group is optionally substituted by R 21 Replacement; M1, M2, k, R 20 and R 21 As defined in claim 21; Or L is selected from Among them, R 11 , R 12 , R 13 , independently selected from a bond, -(O-CH2CH2) k -、C1-C 10 Alkylene or C2-C 10 Alkenylene, the C1-C 10 Alkylene or C2-C 10 The alkenylene group is optionally substituted by R 21 Replacement; R 10 , R 14 , M1, M2 are independently selected from a bond, -C(O)-, -C(O)O-, -C(O)NR 20 -、-O-、-NR 20 -、-NR 20 C(O)O-、-NR 20 S(O)2-、C1-C 10 Alkylene, C2-C 10 Alkenylene, C2-C 10 Alkyne, 4-9 membered heterocyclyl or 5-10 membered heteroarylene, the C1-C 10 Alkylene, C2-C 10 Alkenylene, C2-C 10 Alkyne, 4-9 membered heterocyclyl or 5-10 membered heteroarylene are optionally substituted by R 21 Replacement; R 20 , R 21 and k as defined in claim 21.

23. The compound of formula (A) or a pharmaceutically acceptable salt or a stereoisomer thereof according to any one of claims 1 to 20, wherein: PTMs are selected from binding ligands of the following target proteins: ALK, AR, BET1, BRAF, BRCA2, BRD4, BRD9, BTK, BRM, CDK, CBL, CCNE1, CCNE2, CCR4, CCR7, CCR9, CD47, CLDN18, CYP, DDR1, DMPK, EGFR, ERBB2, ERBB3, ERBB4, FGFR1, FGFR2, FGFR3, FGFR4, GSPT1, JAK1, JAK3, KIF18A, KRAS, LCK, MET, NTRK1, NTRK2, NTRK3, PCSK9, PKMYT1, PARP7, PARP14, RAD51, RBM10, RET, RORA, STAT3, SOS1, TYK2, USP1, ARID1B, PTPN2.

24. The compound of formula (A) or a pharmaceutically acceptable salt or a stereoisomer thereof according to any one of claims 1 to 20, wherein: The compound represented by formula (A) or its pharmaceutically acceptable salt or its stereoisomer is selected from the following compounds or its pharmaceutically acceptable salt or its stereoisomer:

25. A pharmaceutical composition comprising the compound represented by formula (A) according to any one of claims 1 to 24, or a pharmaceutically acceptable salt or a stereoisomer thereof, and a pharmaceutically acceptable excipient.

26. Use of the compound represented by formula (A) according to any one of claims 1 to 24 or its pharmaceutically acceptable salt or stereoisomer thereof, or the pharmaceutical composition according to claim 25 in the preparation of a drug for preventing or treating abnormal cell proliferation diseases.

27. A method for treating abnormal cell proliferation diseases in mammals, comprising administering to a mammal in need of such treatment a therapeutically effective amount of a compound of formula (A) as described in any one of claims 1 to 24 or a pharmaceutically acceptable salt thereof or a stereoisomer thereof, or a pharmaceutical composition as described in claim 25.

28. A compound having a structure represented by formula (I-1) or a pharmaceutically acceptable salt or a stereoisomer thereof, in, Ring A is selected from 4-8 membered heterocyclic group, C6-C 10 Aryl or 5-10 membered heteroaryl; X is selected from CR 3 R 3’ , NR 4 , CR 4 R 4’ C(O)NR 1 or CR 4 R 4’ CR 5 R 5’ ; W is selected from C(O) or S(O)2; Q is selected from (CR A R B ) q ; R A , R B Independently selected from H, halogen or C1-C6 alkyl; q is selected from 0, 1, 2, 3 G is selected from C3-C6 cycloalkyl, 4-8 membered heterocyclic group, C6-C 10 aryl, 5-10 membered heteroaryl, the C3-C6 cycloalkyl, 4-8 membered heterocyclic group, C6-C 10 Aryl, 5-10 membered heteroaryl are optionally replaced by R 1a replace; R 1a is selected from halogen, CN, OH, NH2, C1-C6 alkyl, C1-C6 alkoxy or C3-C6 cycloalkyl; R 1 Selected from H or C1-C6 alkyl; R 2 Selected from C1-C6 alkyl, C3-C6 cycloalkyl, 4-8 membered heterocyclic group, C6-C 10 aryl or 5-10 membered heteroaryl, the C1-C6 alkyl, C3-C6 cycloalkyl, 4-8 membered heterocyclic, C6-C 10 Aryl or 5-10 membered heteroaryl is optionally replaced by R 2a replace; R 2a is selected from halogen, CN, OH or NH2; R 3’ Selected from H or C1-C6 alkyl; R 3 Selected from optionally R 3a Substituted C1-C6 alkyl; R 3a Selected from C(O)NH2, C3-C6 cycloalkyl, 4-8 membered heterocyclic group, C6-C 10 aryl or 5-10 membered heteroaryl, the C3-C6 cycloalkyl, 4-8 membered heterocyclic group, C6-C 10 Aryl or 5-10 membered heteroaryl is optionally substituted by halogen, CN, OH, NH2 or C1-C6 alkyl; or R 3 , R 3’ The atom to which it is attached forms a C3-C6 cycloalkyl or a 4-6 membered heterocyclyl, wherein the C3-C6 cycloalkyl or the 4-6 membered heterocyclyl is optionally substituted with OH, NH2, halogen or C1-C6 alkyl; R 4 is selected from C1-C6 alkyl or C3-C6 cycloalkyl, wherein the C1-C6 alkyl or C3-C6 cycloalkyl is optionally replaced by R 4a replace; R 4’ is selected from H, C1-C6 alkyl or C3-C6 cycloalkyl, wherein the C1-C6 alkyl or C3-C6 cycloalkyl is optionally replaced by R 4a replace; R 5 , R 5’ independently selected from H, halogen, C1-C6 alkyl, the C1-C6 alkyl being optionally substituted by R 5a replace; R 4a , R 5a Independently selected from OH, NH2, halogen, C1-C6 alkyl, C3-C6 cycloalkyl or 4-6 membered heterocyclyl, wherein the C1-C6 alkyl, C3-C6 cycloalkyl or 4-6 membered heterocyclyl is optionally substituted with halogen, CN, OH, NH2 or C1-C6 alkyl; R 6 Selected from H, halogen, C1-C6 alkyl or C1-C6 alkoxy; The condition is that when R 3’ Selected from H, R 3 When selected from -(CH2)2CH3, W is selected from S(O)2 or Q is selected from (CR A R B ) q and q is selected from 1, 2 or 3; L is as defined in claim 21 or 22.

29. A compound having a structure represented by formula (I-2) or a pharmaceutically acceptable salt or a stereoisomer thereof, in, Ring A is selected from 4-8 membered heterocyclic group, C6-C 10 Aryl or 5-10 membered heteroaryl; X is selected from CR 3 R 3’ , NR 4 , CR 4 R 4’ C(O)NR 1 or CR 4 R 4’ CR 5 R 5’ ; W is selected from C(O) or S(O)2; Q is selected from (CR A R B ) q ; R A , R B Independently selected from H, halogen or C1-C6 alkyl; q is selected from 0, 1, 2, 3 G is selected from C3-C6 cycloalkyl, 4-8 membered heterocyclic group, C6-C 10 aryl, 5-10 membered heteroaryl, the C3-C6 cycloalkyl, 4-8 membered heterocyclic group, C6-C 10 Aryl, 5-10 membered heteroaryl are optionally replaced by R 1a replace; R 1a is selected from halogen, CN, OH, NH2, C1-C6 alkyl, C1-C6 alkoxy or C3-C6 cycloalkyl; R 1 Selected from H or C1-C6 alkyl; R 2 Selected from C1-C6 alkyl, C3-C6 cycloalkyl, 4-8 membered heterocyclic group, C6-C 10 aryl or 5-10 membered heteroaryl, the C1-C6 alkyl, C3-C6 cycloalkyl, 4-8 membered heterocyclic, C6-C 10 Aryl or 5-10 membered heteroaryl is optionally replaced by R 2a replace; R 2a is selected from halogen, CN, OH or NH2; R 3’ Selected from H or C1-C6 alkyl; R 3 Selected from - optionally R 3a Substituted C1-C6 alkyl; R 3a Selected from C(O)NH2, C3-C6 cycloalkyl, 4-8 membered heterocyclic group, C6-C 10 aryl or 5-10 membered heteroaryl, the C3-C6 cycloalkyl, 4-8 membered heterocyclic group, C6-C 10 Aryl or 5-10 membered heteroaryl is optionally substituted by halogen, CN, OH, NH2 or C1-C6 alkyl; or R 3 , R 3’ The atom to which it is attached forms a C3-C6 cycloalkyl or a 4-6 membered heterocyclyl, wherein the C3-C6 cycloalkyl or the 4-6 membered heterocyclyl is optionally substituted with OH, NH2, halogen or C1-C6 alkyl; R 4 is selected from C1-C6 alkyl or C3-C6 cycloalkyl, wherein the C1-C6 alkyl or C3-C6 cycloalkyl is optionally replaced by R 4a replace; R 4’ is selected from H, C1-C6 alkyl or C3-C6 cycloalkyl, wherein the C1-C6 alkyl or C3-C6 cycloalkyl is optionally replaced by R 4a replace; R 5 , R 5’ independently selected from H, halogen, C1-C6 alkyl, the C1-C6 alkyl being optionally substituted by R 5a replace; R 4a , R 5a Independently selected from OH, NH2, halogen, C1-C6 alkyl, C3-C6 cycloalkyl or 4-6 membered heterocyclyl, wherein the C1-C6 alkyl, C3-C6 cycloalkyl or 4-6 membered heterocyclyl is optionally substituted with halogen, CN, OH, NH2 or C1-C6 alkyl; R 6 Selected from H, halogen, C1-C6 alkyl or C1-C6 alkoxy; The condition is that when R 3’ Selected from H, R 3 When selected from -(CH2)2CH3, W is selected from S(O)2 or Q is selected from (CR A R B ) q and q is selected from 1, 2 or 3.

30. The compound of formula (I-2) or its pharmaceutically acceptable salt or its stereoisomer is selected from the following compounds or their pharmaceutically acceptable salts or their stereoisomers:

31. A compound represented by formula (II-1) or a pharmaceutically acceptable salt or a stereoisomer thereof, in, represents the connection point connecting L; Indicates a single bond or a double bond; W* is selected from C(O) or S(O)2; Ring A* is selected from 4-8 membered heterocyclic group, C6-C 10 Aryl or 5-10 membered heteroaryl; R 1* -(C1-C6 alkylene)-C3-C6 cycloalkyl, -(C1-C6 alkylene)-4-8 membered heterocyclic group, -(C1-C6 alkylene)-C6-C 10 Aryl, -(C1-C6 alkylene)-5-10 membered heteroaryl, C3-C6 cycloalkyl, 4-8 membered heterocyclic group, C6-C 10 aryl or 5-10 membered heteroaryl, the -(C1-C6 alkylene)-C3-C6 cycloalkyl, -(C1-C6 alkylene)-4-8 membered heterocyclic group, -(C1-C6 alkylene)-C6-C 10 Aryl, -(C1-C6 alkylene)-5-10 membered heteroaryl, C3-C6 cycloalkyl, 4-8 membered heterocyclic group, C6-C 10 Aryl or 5-10 membered heteroaryl is optionally replaced by R 1a* replace; R 1a* is selected from halogen, CN, OH, NH2, C1-C6 alkyl, C1-C6 alkoxy or C3-C6 cycloalkyl; m is selected from 0, 1, 2 or 3; X*Selected from CR 3* or N; X 2* Selected from CR x1 R x2 , CR x1 or NH; X 3* Selected from CR x3 R x4 , CR x3 or NH; R x1 , R x2 , R x3 , R x4 independently selected from H, halogen, CN, OH, NH2, C1-C6 alkyl, C1-C6 alkoxy or C2-C6 alkenyl; R 3* is selected from H, OH, NH2, C1-C6 alkyl or C2-C6 alkenyl; R 4* is selected from H, C1-C6 alkyl, C1-C6 alkoxy or C2-C6 alkenyl; R 5* is selected from H, halogen, CN, OH, NH2, C1-C6 alkyl or C1-C6 alkoxy; And R x1 , R x2 , R x3 , R x4 , R 3* , R 4* At least one of the following conditions must be met: (a)R x1 , R x2 The atoms to which it is attached form a C3-C6 cycloalkyl group or a 4-6 membered heterocyclic group; (b)R x3 , R x4 The atoms to which it is attached form a C3-C6 cycloalkyl group or a 4-6 membered heterocyclic group; (c)R x1 , R x3 The atoms to which it is attached form a C3-C6 cycloalkyl group, a 4-6 membered heterocyclyl group, a phenyl group or a 5-6 membered heteroaryl group; (d) R x1 , R 4 The atoms to which it is attached form a 5-7 membered heterocyclic group or a C5-C7 cycloalkenyl group; (e)R 3* , R 4* The atoms to which it is attached form a 5-7 membered heterocyclic group or a C5-C7 cycloalkenyl group; L is as defined in claim 21 or 22.

32. A compound represented by formula (II-2) or a pharmaceutically acceptable salt or a stereoisomer thereof, in, Indicates a single bond or a double bond; W* is selected from C(O) or S(O)2; Ring A* is selected from 4-8 membered heterocyclic group, C6-C 10 Aryl or 5-10 membered heteroaryl; R 1* -(C1-C6 alkylene)-C3-C6 cycloalkyl, -(C1-C6 alkylene)-4-8 membered heterocyclic group, -(C1-C6 alkylene)-C6-C 10 Aryl, -(C1-C6 alkylene)-5-10 membered heteroaryl, C3-C6 cycloalkyl, 4-8 membered heterocyclic group, C6-C 10 aryl or 5-10 membered heteroaryl, the -(C1-C6 alkylene)-C3-C6 cycloalkyl, -(C1-C6 alkylene)-4-8 membered heterocyclic group, -(C1-C6 alkylene)-C6-C 10 Aryl, -(C1-C6 alkylene)-5-10 membered heteroaryl, C3-C6 cycloalkyl, 4-8 membered heterocyclic group, C6-C 10 Aryl or 5-10 membered heteroaryl is optionally replaced by R 1a* replace; R 1a* is selected from halogen, CN, OH, NH2, C1-C6 alkyl, C1-C6 alkoxy or C3-C6 cycloalkyl; m is selected from 0, 1, 2 or 3; X*Selected from CR 3* or N; X 2* Selected from CR x1 R x2 , CR x1 or NH; X 3* Selected from CR x3 R x4 , CR x3 or NH; R x1 , R x2 , R x3 , R x4 independently selected from H, halogen, CN, OH, NH2, C1-C6 alkyl, C1-C6 alkoxy or C2-C6 alkenyl; R 3* is selected from H, OH, NH2, C1-C6 alkyl or C2-C6 alkenyl; R 4* is selected from H, C1-C6 alkyl, C1-C6 alkoxy or C2-C6 alkenyl; R 5* is selected from H, halogen, CN, OH, NH2, C1-C6 alkyl or C1-C6 alkoxy; And R x1 , R x2 , R x3 , R x4 , R 3* , R 4* At least one of the following conditions must be met: (a)R x1 , R x2 The atoms to which it is attached form a C3-C6 cycloalkyl group or a 4-6 membered heterocyclic group; (b)R x3 , R x4 The atoms to which it is attached form a C3-C6 cycloalkyl group or a 4-6 membered heterocyclic group; (c)R x1 , R x3 The atom to which it is attached forms a C3-C6 cycloalkyl group, a 4-6 membered heterocyclyl group, a phenyl group or a 5-6 membered heteroaryl group; (d) R x1 , R 4* The atoms to which it is attached form a 5-7 membered heterocyclic group or a C5-C7 cycloalkenyl group; (e)R 3* , R 4* The atoms to which it is attached form a 5-7 membered heterocyclic group or a C5-C7 cycloalkenyl group.

33. The compound of formula (I-2) or its pharmaceutically acceptable salt or its stereoisomer is selected from the following compounds or their pharmaceutically acceptable salts or their stereoisomers:

34. Use of a compound of formula (I-1) according to claim 28, formula (I-2) according to claim 29 or 30, formula (II-1) according to claim 31, or formula (II-2) according to claim 32 or 33, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, in the preparation of a targeted protein degradation drug.

35. Use of a compound of formula (I-1) according to claim 28, formula (I-2) according to claim 29 or 30, formula (II-1) according to claim 31, or formula (II-2) according to claim 32 or 33, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof as an intermediate in the preparation of a targeted protein degradation drug.

Images