Fused ring compound and application thereof

Abstract

The invention provides a compound shown in a formula (I) or pharmaceutically acceptable salt, a pharmaceutical composition containing the compound or the pharmaceutically acceptable salt and application of the compound or the pharmaceutically acceptable salt, and the compound or the pharmaceutically acceptable salt is particularly suitable for preparing drugs for treating or preventing abnormal cell proliferation diseases. The invention relates to LM-L-PTM (I).

Description

A class of fused ring compounds and uses thereof

[0001] This disclosure claims the priority of the prior application filed with the State Intellectual Property Office of China on September 29, 2022, with patent application number 202211201634.4 and invention name “A class of condensed ring compounds and their uses”; the priority of the prior application filed with the State Intellectual Property Office of China on February 20, 2023, with patent application number 2023101388032 and invention name “A class of condensed ring compounds and their uses”; the full text of the above-mentioned prior application is incorporated into this disclosure by reference. Technical Field

[0002] The present disclosure belongs to the field of medical technology, and specifically relates to a protein-targeted degradation chimeric (PROTAC) compound containing a polycyclic cereblon E3 ubiquitin ligase ligand, or a pharmaceutically acceptable salt thereof, which has biological activities such as anti-proliferation of tumor cells and can be used to treat related diseases. Background Art

[0003] CRBN (Cereblon) is a protein encoded by the CRBN gene in humans. CRBN is widely expressed in the testes, spleen, prostate, liver, pancreas, placenta, kidneys, lungs, skeletal muscle, ovaries, small intestine, peripheral blood leukocytes, colon, brain, and retina. Its expression in the brain (including the retina) and testes is significantly higher than in other tissues.

[0004] CRBN, as an important target for anti-tumor and immunomodulatory drugs, has been shown to be effective in treating a variety of hematological malignancies, including multiple myeloma and chronic lymphocytic leukemia, as well as autoimmune diseases such as systemic lupus erythematosus. However, existing doxorubicin-based drugs have significant side effects, particularly peripheral neuropathy. There is a need to develop new CRBN modulators to improve clinical efficacy, reduce side effects, and facilitate long-term use in patients.

[0005] The ubiquitin-proteasome pathway (UPP) is a key pathway for regulating key regulatory proteins and degrading misfolded or abnormal proteins. Ubiquitin molecules are covalently linked to terminal lysine residues via E3 ubiquitin ligases to mark proteins for proteasomal degradation, where the protein is digested into small peptides and ultimately into its constituent amino acids, which serve as building blocks for new proteins. UPP is important for multiple cellular processes and, if defective or unbalanced, can lead to the pathogenesis of various diseases. It has been shown that defective proteasome degradation is associated with a variety of clinical conditions, including Alzheimer's disease, Parkinson's disease, Huntington's disease, muscular dystrophy, cardiovascular disease, and cancer. Targeted protein degradation chimera PROTAC (Proteolysis targeting chimeras) is a new type of targeted degradation technology for target proteins developed based on the cell's own ubiquitin-proteasome system (UPS). PROTAC molecules are bifunctional molecules that can both bind to target proteins and recruit E3 ubiquitin ligases to ubiquitinate the target protein, which is then degraded by the proteasome. Therefore, CRBN ligands can also be used to prepare bifunctional PROTAC compounds for the treatment of related diseases.

[0006] Summary of the Invention

[0007] The present disclosure provides a compound represented by formula (I) or a pharmaceutically acceptable salt thereof: CLM-L-PTM (I)

[0008] in,

[0009] CLM is selected from the structure shown in formula (II):

[0010] Ring B is selected from a 5-6 membered heteroaromatic ring or a 5-8 membered heterocyclic ring;

[0011] Ring C is selected from a 5-6 membered heteroaromatic ring, a 5-8 membered heterocyclic ring, a benzene ring, a C5-C8 saturated or partially saturated carbocyclic ring;

[0012] Every R 1 、R 2 Independently selected from halogen, =O, CN, NO2, -OR b 、-N(R b )2、-S(O)R b 、-SO2R b , 2-10 membered heteroalkyl, C1-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, C3-C 10 Cycloalkyl, 4-8 membered heterocyclic group, C6-C 10Aryl or 5-10 membered heteroaryl, the 2-10 membered heteroalkyl, C1-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, C3-C 10 Cycloalkyl, 4-8 membered heterocyclic group, C6-C 10 Aryl or 5-10 membered heteroaryl is optionally replaced by R a replace;

[0013] Every R 4 independently selected from halogen, CN, NO2, OH, NH2, 2-10 membered heteroalkyl, 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, 2-10 membered heteroalkyl, 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 a replace;

[0014] Every R a independently selected from halogen, CN, OH, NH2, 2-10 membered heteroalkyl, C1-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, C3-C 10 Cycloalkyl or 4-8 membered heterocyclic group, the 2-10 membered heteroalkyl, C1-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, C3-C 10 Cycloalkyl or 4-8 membered heterocyclic group is optionally replaced by R c replace;

[0015] Every R b independently selected from H, halogen, CN, OH, NH2, 2-10 membered heteroalkyl, C1-C 10 Alkyl, C3-C 10 Cycloalkyl or 4-8 membered heterocyclic group, said OH, NH2, 2-10 membered heteroalkyl, C1-C 10 Alkyl, C3-C 10 Cycloalkyl or 4-8 membered heterocyclic group is optionally replaced by R c replace;

[0016] Every R c independently selected from halogen, CN, OH, NH2, 2-10 membered heteroalkyl, C1-C 10Alkyl, C3-C 10 Cycloalkyl or 4-8 membered heterocyclic group, the OH, NH2, 2-10 membered heteroalkyl, C1-C 10 Alkyl, C3-C 10 Cycloalkyl or 4-8 membered heterocyclic group is optionally replaced by R d replace;

[0017] Every R d Independently selected from halogen, CN, OH, NH2 or C1-C6 alkyl;

[0018] n is independently selected from 0, 1, 2, 3 or 4;

[0019] m and p are independently selected from 0, 1, 2, 3, 4, 5 or 6;

[0020] L represents the connection unit between CLM and PTM;

[0021] The PTM is selected from a binding moiety to a target protein.

[0022] In some embodiments, Ring B is selected from a 5-6 membered heteroaryl ring or a 5-6 membered heterocyclic ring.

[0023] In some embodiments, Ring B is selected from a 5-6 membered heteroaryl ring.

[0024] In some embodiments, Ring C is selected from a 5-6 membered heteroaryl ring, a 5-6 membered heterocyclic ring, a benzene ring, a C5-C6 saturated or partially saturated carbocyclic ring.

[0025] In some embodiments, Ring C is selected from a 5-6 membered heteroaryl ring or a benzene ring.

[0026] In some embodiments, Ring C is selected from a benzene ring.

[0027] In some embodiments, CLM is selected from the structure represented by formula (III):

[0028] Wherein, X is selected from N or CH, and the CH is optionally replaced by R 2 Substitution; Ring C, R 1 、R 2 、R 4 , m, n are as defined above.

[0029] In some embodiments, CLM is selected from the structure shown in formula (III-1):

[0030] Wherein, X is selected from N or CH, and the CH is optionally replaced by R 2 Substituted; Y1, Y2, Y3, Y4 are independently selected from N or CH, the CH is optionally replaced by R 1 Replacement; R 1、R 2 、R 4 , n are as defined above.

[0031] In some embodiments, R 1 、R 2 independently selected from halogen, CN, OH, NH2, C1-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl or C3-C 10 Cycloalkyl, the OH, NH2, C1-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl or C3-C 10 The cycloalkyl group is optionally replaced by R a replace.

[0032] In some embodiments, each R 4 independently selected from halogen, CN, OH, NH2 or C1-C6 alkyl, wherein the OH, NH2 or C1-C6 alkyl is optionally replaced by R a replace.

[0033] In some embodiments, each R a independently selected from halogen, CN, OH, NH2, C1-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, C3-C 10 Cycloalkyl or 4-8 membered heterocyclic group, the C1-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, C3-C 10 Cycloalkyl or 4-8 membered heterocyclic group is optionally replaced by R c replace.

[0034] In some embodiments, each R a independently selected from halogen, CN, OH, NH2 or C1-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl, wherein the C1-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl is optionally replaced by R c replace.

[0035] In some embodiments, each R a are independently selected from halogen or C1-C6 alkyl, the C1-C6 alkyl being optionally replaced by R c replace.

[0036] In some embodiments, each R a Independently selected from F, Cl or CH3.

[0037] In some embodiments, each R b are independently selected from H or C1-C6 alkyl, the C1-C6 alkyl being optionally replaced by R c replace.

[0038] In some embodiments, each R c Independently selected from halogen, CN, OH, NH2 or C1-C6 alkyl.

[0039] In some embodiments, m and p are independently selected from 0, 1, 2, 3 or 4.

[0040] In some embodiments, m and p are independently selected from 0, 1 or 2.

[0041] In some embodiments, m and p are independently selected from 0 or 1.

[0042] In some embodiments, m and p are independently selected from 0.

[0043] In some embodiments, n is selected from 0 or 1.

[0044] In some embodiments, n is selected from 0.

[0045] In some embodiments, L is selected from

[0046] 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 10 Cycloalkylene, 4-10 membered heterocyclylene, C6-C 10 Arylene or 5-10 membered heteroarylene is optionally replaced by R 21 replace;

[0047] R10 、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;

[0048] k is independently selected from 1, 2, 3, 4, 5 or 6;

[0049] 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 replaced by R f replace;

[0050] R 21Selected 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;

[0051] Every R f Independently selected from halogen, CN, OH, NH2 or C1-C6 alkyl.

[0052] 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.

[0053] 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.

[0054] In some embodiments, L is selected from Among them, M1, M2, R 10 、R 11 、R 12 、R 13 、R 14 As defined above.

[0055] In some embodiments, L is selected from Among them, M1, M2, R 10 、R 11 、R 12 As defined above.

[0056] 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 -、-NR20 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, R 20 and k are as defined above.

[0057] 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 , k are as defined above.

[0058] 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.

[0059] 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.

[0060] 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-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.

[0061] 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.

[0062] 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.

[0063] In some embodiments, M1 and M2 are independently selected from -NH-, -CH2-, -C≡C-, -C(O)-, -C(O)O-, -O-, -C(O)NH-, 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.

[0064] 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-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.

[0065] 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.

[0066] 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, 4-6 membered heterocyclylene, phenylene or 5-6 membered heteroarylene, wherein the C1-C6 alkylene, C2-C6 alkenylene, C2-C6 alkynylene, C3-C6 cycloalkylene, 4-6 membered heterocyclylene, phenylene or 5-6 membered heteroarylene is optionally replaced by R 21 In some embodiments, L is selected from:

[0067] -NR 20 -C1-C 10 Alkylene-C(O)NR 20 -CH2-,

[0068] -NR 20 -C1-C 10 Alkylene-(OCH2CH2) k -C(O)NR 20 -、

[0069] -C(O)-C1-C 10 Alkylene-(OCH2CH2) k -C(O)NR 20 -、

[0070] -C(O)-C1-C 10 Alkylene-(OCH2CH2) k -C(O)O-,

[0071] -NR 20 -C1-C 10 Alkylene-(OCH2CH2) k -C(O)-,

[0072] -C(O)-C1-C 10 Alkylene-C1-C 10 Alkylene-,

[0073] -C(O)-C1-C 10 Alkylene-C1-C 10 Alkylene-C2-C6 alkynylene-,

[0074] -C(O)-C1-C 10 Alkylene-C1-C 10 Alkylene-(4-10 membered heterocyclylene)-,

[0075] -C(O)-C1-C 10 Alkylene-C1-C 10 Alkylene-(5-10 membered heteroarylene)-,

[0076] -C(O)-C1-C10 Alkylene-C1-C 10 Alkylene-C(O)NR 20 -(4-10 membered heterocyclylene)-,

[0077] -C(O)-C1-C 10 Alkylene-C1-C 10 Alkylene-C(O)O-,

[0078] -C(O)-C1-C 10 Alkylene-C2-C 10 Alkenylene-(4-10 membered heterocyclylene)-O-,

[0079] -C(O)-(C3-C 10 Cycloalkylene)-C1-C 10 Alkylene-O-,

[0080] -C(O)-(C3-C 10 Cycloalkylene)-C1-C 10 Alkylene-NR 20 -、

[0081] -C(O)-(C3-C 10 Cycloalkylene)-C1-C 10 Alkylene-NR 20 -C1-C6 alkylene-,

[0082] R 20 , k are as defined above.

[0083] In some embodiments, L is selected from:

[0084] -NH-(CH2) w -C(O)NH-CH2-,

[0085] -NH-(CH2)r-(OCH2CH2) k -C(O)NH-,

[0086] -C(O)-(CH2)r-(OCH2CH2) k -C(O)NH-,

[0087] -C(O)-(CH2)r-(OCH2CH2) k -C(O)O-,

[0088] -NH-(CH2)r-(OCH2CH2) k -C(O)-,

[0089] -C(O)-(CH2) w -(CH2)r-,

[0090] -C(O)-(CH2) w -(CH2)rC≡C-,

[0091] -C(O)-(CH2) w -(CH2)r-(4-10 membered heterocyclylene)-,

[0092] -C(O)-(CH2) w -(CH2)r-(5-6 membered heteroarylene)-,

[0093] -C(O)-(CH2) w -(CH2)rC(O)NH-(4-6 membered heterocyclylene)-,

[0094] -C(O)-(CH2) w -(CH2)rC(O)O-,

[0095] -C(O)-(CH2)r-(CH=CHCH2CH2)2-(4-6 membered heterocyclylene)-O-,

[0096] -C(O)-(C3-C6 cycloalkylene)-(CH2)rO-,

[0097] -C(O)-(C3-C6 cycloalkylene)-(CH2)r-NH-,

[0098] -C(O)-(C3-C6 cycloalkylene)-(CH2)r-NR 20 -(CH2)r-,

[0099] w is selected from 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10;

[0100] r is selected from 1, 2, 3, 4, 5 or 6;

[0101] k is selected from 1, 2, 3 or 4.

[0102] In some embodiments, L is selected from:

[0103] In some embodiments, the PTM is selected from the binding portion of the following targeting 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 or USP14.

[0104] In some embodiments, the PTM is selected from the binding portion of the following targeting 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 or USP14.

[0105] In some embodiments, the PTM is selected from the binding portion of the following targeting proteins: BRD4 or STAT3.

[0106] In some embodiments, the PTM is selected from the following structural groups:

[0107] In some embodiments, the compound represented by formula (I) or a pharmaceutically acceptable salt thereof is selected from the following compounds or a pharmaceutically acceptable salt thereof:

[0108] In another aspect, the present disclosure provides a pharmaceutical composition comprising a compound represented by formula (I) of the present disclosure or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

[0109] In another aspect, 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 of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof to a mammal, preferably a human, in need of such treatment.

[0110] In another aspect, the present disclosure provides use of a compound represented by formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, in the preparation of a medicament for preventing or treating abnormal cell proliferation diseases.

[0111] In another aspect, the present disclosure provides use of a compound represented by formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, in preventing or treating abnormal cell proliferation diseases.

[0112] In another aspect, the present disclosure provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for preventing or treating abnormal cell proliferation diseases.

[0113] In some embodiments, the abnormal cell proliferation disorder is selected from cancer.

[0114] In some embodiments, the cancer is selected from a solid tumor, an adenocarcinoma, or a hematological cancer.

[0115] On the other hand, the present disclosure also provides a compound represented by formula (IV) or a pharmaceutically acceptable salt thereof:

[0116] Among them, ring B, ring C, R 1 、R 2 、R 4 , m, n, p, and L are as defined above.

[0117] In some embodiments, the compound represented by formula (IV) or a pharmaceutically acceptable salt thereof is selected from the compound represented by formula (IV-1) or a pharmaceutically acceptable salt thereof:

[0118] Wherein, X is selected from N or CH, and the CH is optionally replaced by R 2 Substitution; Ring C, R 1 、R 2 、R 4 , m, n, and L are as defined above.

[0119] In some embodiments, the compound represented by formula (IV) or a pharmaceutically acceptable salt thereof is selected from the compound represented by formula (IV-1a) or a pharmaceutically acceptable salt thereof:

[0120] Wherein, X is selected from N or CH, and the CH is optionally replaced by R 2Substituted; Y1, Y2, Y3, Y4 are independently selected from N or CH, the CH is optionally replaced by R 1 Replacement; R 1 、R 2 、R 4 , n, and L are as defined above.

[0121] On the other hand, the present disclosure also provides a compound represented by formula (V) or a pharmaceutically acceptable salt thereof:

[0122] Among them, ring B, ring C, R 1 、R 2 、R 4 , m, n, p are as defined above.

[0123] In some embodiments, the compound represented by formula (V) or a pharmaceutically acceptable salt thereof is selected from the compound represented by formula (V-1) or a pharmaceutically acceptable salt thereof:

[0124] Wherein, X is selected from N or CH, and the CH is optionally replaced by R 2 Substitution; Ring C, R 1 、R 2 、R 4 , m, n are as defined above.

[0125] In some embodiments, the compound represented by formula (V) or a pharmaceutically acceptable salt thereof is selected from the compound represented by formula (V-1a) or a pharmaceutically acceptable salt thereof:

[0126] Wherein, X is selected from N or CH, and the CH is optionally replaced by R 2 Substituted; Y1, Y2, Y3, Y4 are independently selected from N or CH, the CH is optionally replaced by R 1 Replacement; R 1 、R 2 、R 4 , n are as defined above.

[0127] In some embodiments, the compound represented by formula (IV) or formula (V) or a pharmaceutically acceptable salt thereof is selected from the following compounds or pharmaceutically acceptable salts thereof:

[0128] On the other hand, the present disclosure also provides the use of the compound represented by formula (IV) or formula (V) or a pharmaceutically acceptable salt thereof in the preparation of a target protein degradation drug.

[0129] On the other hand, the present disclosure also provides the use of the compound represented by formula (IV) or formula (V) or a pharmaceutically acceptable salt thereof as an intermediate in the preparation of a target protein degradation drug.

[0130] In the absence of conflict, it should be understood that the above embodiments can be arbitrarily combined to form a technical solution including the features of the combined embodiments. Such a combined technical solution is within the scope of the present disclosure.

[0131] Definitions and Explanations of Terms

[0132] 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 definitions as examples, 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 as undefined or unclear unless specifically defined, but should be understood according to its ordinary 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.

[0133] In this article Indicates the connection site. of when When not connected to a fixed ring or atom, it means that it can be connected to a group after losing the hydrogen atom at any position in the structure within "[]" containing a replaceable hydrogen atom (including a hydrogen atom directly connected to a ring atom, a hydrogen atom on a non-hydrogen substituent of a ring atom, and a hydrogen atom in a further substituent on the substituent), for example middle The connection positions include but are not limited to Y1, Y2, Y3, Y4, X and their substituents.

[0134] 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).

[0135] The term "tautomer" refers to functional group isomers resulting from the rapid shift of an atom in a molecule between two positions. The 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 usually result in 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.

[0136] The term "stereoisomer" refers to isomers resulting from different spatial arrangements of atoms in a molecule, including cis-trans isomers, enantiomers and diastereomers.

[0137] The compounds of the present invention may have asymmetric atoms such as carbon atoms, sulfur atoms, nitrogen atoms, phosphorus atoms or asymmetric double bonds, so that the compounds of the present invention 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 mixtures enriched in enantiomers or diastereomers, all of which are within the definition of the compounds of the present invention and mixtures thereof. Additional asymmetric carbon atoms, asymmetric sulfur atoms, asymmetric nitrogen atoms or asymmetric phosphorus atoms may be present in substituents such as alkyl groups, and all of which are within the definition of the compounds of the present invention and mixtures thereof. 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.

[0138] The term "substituted" refers to the replacement of any one or more hydrogen atoms on a particular atom by a substituent, as long as the valence state of the particular atom is normal and the substituted compound is stable. When the substituent is an oxo (i.e., =O), it means that two hydrogen atoms are replaced. Oxo does not occur on aromatic groups.

[0139] 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.

[0140] 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.

[0141] When one of the variables is selected from a chemical bond or does not exist, it means that the two groups it connects are directly connected. For example, when L in ALZ represents a bond, it means that the structure is actually AZ.

[0142] When the linking group mentioned in this article does not specify its connection direction, its connection direction is arbitrary. L in 1 When selected from "C1-C3 alkylene-O", L 1 You can connect rings Q and R from left to right. 1 Constitute "ring Q-C1-C3 alkylene-OR 1 ", you can also connect rings Q and R from right to left 1 Constitute the "ring QO-C1-C3 alkylene-R 1 ”.

[0143] When a substituent's bond crosses two atoms in a ring, the substituent may be bonded to any atom in the ring. Represents R 5 Substitution can occur at any position on the benzene ring.

[0144] In this article, C m -C n It means having an integer number of carbon atoms in the range mn. For example, "C1-C 10” means that the group can 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.

[0145] The term "alkyl" refers to a group of the formula C n H 2n+1 The term "C1-C 10 The 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".

[0146] The term "alkylene" refers to a residue derived from an alkyl group by further removing a hydrogen atom.

[0147] The term "heteroalkyl" refers to an alkyl group containing 1, 2, 3, 4, or 5 heteroatoms or heteroatoms, including but not limited to N, O, S, B, P, -S(=O)2-, -S(=O)-, -NH-, etc. The term "2-10 membered heteroalkyl" is understood to mean a heteroalkyl group having 2, 3, 4, 5, 6, 7, 8, 9, or 10 atoms (carbon and heteroatoms excluding hydrogen). The term "2-6 membered heteroalkyl" is understood to mean a heteroalkyl group having 2, 3, 4, 5, or 6 atoms (carbon and heteroatoms excluding hydrogen). The heteroalkyl group can be attached to other groups via heteroatoms or carbon atoms therein. The heteroatom can be located at any interior position of the heteroalkyl group (including the position at which the heteroalkyl group is attached to other groups), that is, the heteroalkyl group does not include hydroxyalkyl groups (e.g., -CH2OH, -CH(CH3)OH), aminoalkyl groups (e.g., -CH2NH2, -CH(CH3)NH2), etc. Examples of heteroalkyl groups include, but are not limited to, -OCH3, -OCH2CH3, -OCH2(CH3)2, -CH2-CH2-O-CH3, -NHCH3, -N(CH3)2, -NHCH2CH3, -CH2-CH2-NH-CH3, -OCH2-CH2-NH-CH3, -OCH2-CH2-NH-CH3, -OCH2-CH2-NH-CH(CH3)2, -SCH3, -SCH2CH3, -S(=O)-CH3, -CH2-S(=O)2-CH3, -CH2-C(=O)NH-CH2-O-CH3.

[0148] The term "heteroalkylene" refers to a residue derived from a heteroalkyl group by further removing a hydrogen atom.

[0149] 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.

[0150] The term "alkenylene" refers to a residue derived from an alkenyl group by further removing a hydrogen atom.

[0151] 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).

[0152] The term "alkynylene" refers to a residue derived from an alkynyl group by further removing a hydrogen atom.

[0153] 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 include but are not limited to cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

[0154] The term "cycloalkylene" refers to a residue derived from a cycloalkyl group by further removing a hydrogen atom.

[0155] The term "cycloalkenyl" refers to a non-aromatic carbocyclic ring having at least one double bond that is not fully saturated and exists in the form of a monocyclic, fused, bridged, or spirocyclic ring. Unless otherwise indicated, the carbocyclic ring is typically a 5- to 8-membered ring. Specific examples of the cycloalkenyl group include, but are not limited to, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl, or cycloheptadienyl.

[0156] The term "heterocyclyl" refers to a fully saturated or partially saturated (heteroaromatic as a whole that is not aromatic) monocyclic, fused, spirocyclic 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 "3-10 membered heterocyclyl" refers to a heterocyclyl group having 3, 4, 5, 6, 7, 8, 9 or 10 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. “3-10 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", 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 heterocycloalkyl", 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.

[0157] The term "heterocyclylene" refers to a residue derived from a heterocyclyl group by further removing a hydrogen atom.

[0158] 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".

[0159] The term "arylene" refers to a residue derived from an aryl group by further removing a hydrogen atom.

[0160] 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.

[0161] The term "heteroarylene" refers to a residue derived from a heteroaryl group by further removing a hydrogen atom.

[0162] The term "halo" or "halogen" refers to fluorine, chlorine, bromine or iodine.

[0163] The term "therapeutically effective amount" means

[0164] 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.

[0165] 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.

[0166] 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.

[0167] 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.

[0168] 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.

[0169] 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.

[0170] 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".

[0171] 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.

[0172] 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 as15 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.

[0173] 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.

[0174] 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.

[0175] 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.

[0176] 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.

[0177] 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.

[0178] The pharmaceutical composition may also be suitable for parenteral administration, such as sterile solutions, suspensions or lyophilized products in appropriate unit dosage forms.

[0179] In all methods of administration described herein, the compounds of formula I are administered at a dosage of 0.01 mg / kg to 200 mg / kg body weight per day in single or divided doses. DETAILED DESCRIPTION

[0180] The present disclosure is described in detail below with reference to the following examples, but the following examples should not be construed as limiting the scope of the present disclosure. 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. All reagents used in the present disclosure are commercially available and can be used without further purification.

[0181] Unless otherwise specified, the ratio of mixed solvents is the volume ratio. For example, "water / acetonitrile = 1:1" means that the volume ratio of water to acetonitrile is 1:1.

[0182] Compounds are manually or Software naming, commercially available compounds use supplier catalog names.

[0183] 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 (ppm). The solvents for NMR determination are deuterated dimethyl sulfoxide, deuterated chloroform, deuterated methanol, etc., and the internal standard is tetramethylsilane (TMS); "IC 50 ” refers to the half-maximal inhibitory concentration, which is the concentration at which half of the maximum inhibitory effect is achieved.

[0184] Abbreviations:

[0185] CDI: N,N'-carbonyldiimidazole; THF: tetrahydrofuran; NH2OH·HCl: hydroxylamine hydrochloride; EtOH: ethanol; LAH: lithium aluminum tetrahydride; DMF: N,N-dimethylformamide; EDCI: 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride; HOBt: 1-hydroxybenzotriazole; TEA: triethylamine; DCM: dichloromethane; Pd(OAc)2: palladium acetate; Cs2CO3: cesium carbonate; Butyldi-1-adamantylphosphine: n-butyldi(1-adamantyl)phosphine; dioxane: 1,4-dioxane; HATU: 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate.

[0186] Example 1: 3-(3-oxo-1H-imidazo[1,5-a]indol-2(3H)-yl)piperidine-2,6-dione

[0187] Step 1: 1,2-dihydro-3H-imidazo[1,5-a]indol-3-one (Compound 1-2)

[0188] Compound 1-1 (400 mg, 2.73 mmol) and N,N'-carbonyldiimidazole (488 mg, 3.01 mmol) were placed in a dry, sealed tube. Tetrahydrofuran (3 mL) was added and the tube was sealed. The reaction mixture was stirred in a 90°C oil bath for 12 h. After the reaction, the reaction mixture was concentrated to obtain the crude product, which was purified by reverse-phase column chromatography (water:acetonitrile = 1:1, 0.1% formic acid) to obtain compound 1-2 (170 mg, 36% yield). m / z (ESI): 173 [M+H] + .

[0189] Step 2: 3-(3-oxo-1H-imidazo[1,5-a]indol-2(3H)-yl)piperidine-2,6-dione (Compound 1)

[0190] Under nitrogen, compound 1-2 (80 mg, 0.46 mmol) was dissolved in tetrahydrofuran (2 mL) and cooled to 0°C. Sodium hydride (55.7 mg, 2.32 mmol) was added and stirred at this temperature for 0.5 h. A solution of 3-bromopiperidine-2,6-dione (107.0 mg, 0.55 mmol) in tetrahydrofuran (2 mL) was then added dropwise to the reaction mixture. After the addition was complete, the reaction was continued at this temperature for 10 min. The reaction mixture was then stirred in an oil bath at 60°C for 4 h. After the reaction, the reaction mixture was cooled to 0°C and quenched by the addition of acetic acid (105.0 mg, 1.75 mmol) and saturated ammonium chloride solution (5 mL). The reaction mixture was concentrated to obtain the crude product, which was purified by reverse-phase column chromatography (water:acetonitrile = 1:1, 0.1% formic acid) to obtain compound 1 (17.5 mg, 13% yield). m / z (ESI): 284 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ11.04(s,1H),7.84(d,J=7.8Hz,1H),7.64(d,J=7.6Hz,1H),7.25(dt,J=15.6,7.4Hz,2H),6.52(s,1H),4.96(dd,J=1 3.5,5.1Hz,1H),4.59(d,J=16.5Hz,1H),4.42(d,J=16.4Hz,1H),2.97–2.86(m,1H),2.61(d,J=17.4Hz,1H),2.43–2.30(m,1H),2.10(s,1H).

[0191] Example 2: 6-(2-((S)-4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine -6-yl)acetamido)-N-((2-(2,6-dioxopiperidin-3-yl)-3-oxo-2,3-dihydro-1H-imidazo[1,5-a]indol-6-yl)methyl)hexanamide

[0192] Step 1: 6-Bromo-1H-indole-2-carbaldehyde oxime (Compound 2-2)

[0193] 6-Bromo-1H-indole-2-carbaldehyde (Compound 2-1, 1500 mg, 6.69 mmol), hydroxylamine hydrochloride (697 mg, 10.0 mmol), and sodium bicarbonate (1123 mg, 13.38 mmol) were placed in a flask. Ethanol (15 mL) and water (10 mL) were added, and the reaction solution was stirred in a 70°C oil bath for 3 hours. After the reaction was completed, the reaction solution was concentrated and extracted with ethyl acetate and water. The organic phase was dried and concentrated to give Compound 2-2 (1515 mg, 95% yield). m / z (ESI): 239 [M+H] + .

[0194] Step 2: (6-Bromo-1H-indol-2-yl)methanamine (Compound 2-3)

[0195] 6-Bromo-1H-indole-2-carbaldehyde oxime (compound 2-2, 1515 mg, 6.33 mmol) was placed in a flask, and anhydrous tetrahydrofuran (25 mL) was added. The reaction solution was stirred in an ice bath at 0°C and cooled. After cooling, lithium aluminum tetrahydride (360 mg, 9.50 mmol) was slowly added. After complete addition, the reaction solution was stirred in an oil bath at 70°C for 2 h. After completion of the reaction, the reaction solution was stirred in an ice bath at 0°C and quenched by slowly adding sodium sulfate decahydrate. After quenching, the reaction solution was filtered, and the filtrate 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 (water:acetonitrile = 1:1, 0.1% formic acid) to obtain compound 2-3 (973 mg, 73% yield). m / z (ESI): 225 [M+H] + .

[0196] Step 3: 6-bromo-1,2-dihydro-3H-imidazo[1,5-a]indol-3-one (Compound 2-4)

[0197] Compound 2-3 (973 mg, 4.32 mmol) was placed in a dry, sealed tube. The air in the reaction tube was replaced with argon. Tetrahydrofuran (3 mL) was added and the tube was sealed. The reaction solution was stirred in an ethanol-dry ice bath to cool. N,N'-carbonyldiimidazole (770 mg, 4.75 mmol) was placed in a dry flask and dissolved in tetrahydrofuran (3 mL). The N,N'-carbonyldiimidazole solution was slowly added dropwise to the reaction solution. After the addition was complete, the temperature was naturally raised to room temperature and stirred for 1 hour. The reaction solution was then placed in a 95°C oil bath and stirred for 16 hours. After the reaction, the reaction solution was concentrated to obtain the crude product, which was purified by normal phase column chromatography (petroleum ether:ethyl acetate = 1:1) to obtain compound 2-4 (800 mg, 74% yield). m / z (ESI): 251 [M+H] + .

[0198] Step 4: Dimethyl 2-(6-bromo-3-oxo-1H-imidazo[1,5-a]indol-2(3H)-yl)glutarate (Compound 2-5)

[0199] Compound 2-4 (800 mg, 3.19 mmol) and sodium hydride (114.7 mg, 4.78 mmol) were placed in a dry reaction tube. The air in the reaction tube was replaced with argon and the reaction tube was cooled in an ethanol-dry ice bath. N,N-dimethylformamide (2 mL) was added to the reaction tube. The reaction solution was naturally warmed to room temperature and stirred for half an hour. The mixture was then stirred in an ice-water bath. Dimethyl 2-bromoglutarate (1140 mg, 4.78 mmol) was added dropwise to the reaction solution. Stirring was continued in the ice-water bath for half an hour and then at room temperature for one hour. After completion of the reaction, acetic acid (287 mg, 4.78 mmol) was added to quench the reaction. The reaction solution was purified by reverse-phase column chromatography (water:acetonitrile = 1:1, 0.1% formic acid) to obtain compound 2-5 (500 mg, 41% yield). m / z (ESI): 409 [M+H] + .

[0200] Step 5: 2-(6-bromo-3-oxo-1H-imidazo[1,5-a]indol-2(3H)-yl)glutaric acid (Compound 2-6)

[0201] Compound 2-5 (500 mg, 1.22 mmol) and lithium hydroxide (117 mg, 4.89 mmol) were placed in a flask, tetrahydrofuran (4 mL) and water (2 mL) were added, and the mixture was stirred at room temperature for 3 to 5 hours. After the reaction, hydrochloric acid (3N) was added to adjust the pH of the reaction solution to 3 to 5. The reaction solution was concentrated and purified by reverse phase column chromatography (water:acetonitrile = 1:1, 0.1% formic acid) to obtain compound 2-6 (419 mg, 90% yield). m / z (ESI): 381 [M+H] + .

[0202] Step 6: 3-(6-bromo-3-oxo-1H-imidazo[1,5-a]indol-2(3H)-yl)piperidine-2,6-dione (Compound 2-7)

[0203] Compound 2-6 (419 mg, 1.10 mmol), trifluoroacetamide (185 mg, 1.64 mmol), 1-hydroxybenzotriazole (326.5 mg, 2.41 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (737.6 mg, 3.85 mmol) were placed in a dry reaction tube. The air in the reaction tube was replaced with argon and the reaction tube was cooled in an ethanol-dry ice bath. Dichloromethane (10 mL) and triethylamine (500 mg, 4.95 mmol) were added to the reaction tube. The reaction solution was naturally warmed to room temperature and stirred for half an hour. The reaction solution was then stirred in a 35°C oil bath for 5 hours. After completion of the reaction, the reaction solution was concentrated and purified by reverse phase column chromatography (water:acetonitrile = 1:1, 0.1% formic acid) to obtain compound 2-7 (318 mg, 80% yield). m / z (ESI): 362 [M+H] + .

[0204] Step 7: Tert-butyl ((2-(2,6-dioxopiperidin-3-yl)-3-oxo-2,3-dihydro-1H-imidazo[1,5-a]indol-6-yl)methyl)carbamate (Compound 2-8)

[0205] Compound 2-7 (80 mg, 0.22 mmol), palladium acetate (4.96 mg, 0.022 mmol), n-butyldi(1-adamantyl)phosphine (15.8 mg, 0.044 mmol), potassium [(tert-butoxycarbonylamino)methyl]trifluoroborate (68.1 mg, 0.29 mmol), and cesium carbonate (215 mg, 0.66 mmol) were placed in a reaction tube. The atmosphere in the reaction tube was replaced with argon. 1,4-Dioxane (1 mL) and water (0.1 mL) were added to the reaction tube. The reaction tube was stirred in a 100°C oil bath for 5-8 hours. After completion of the reaction, the reaction solution was purified by reverse phase column chromatography (water:acetonitrile = 1:1, 0.1% formic acid) to obtain compound 2-8 (54.0 mg, 59% yield). m / z (ESI): 413 [M+H] + .

[0206] Step 8: Tert-butyl (6-(((2-(2,6-dioxopiperidin-3-yl)-3-oxo-2,3-dihydro-1H-imidazo[1,5-a]indol-6-yl)methyl)amino)-6-oxohexyl)carbamate (Compound 2-9)

[0207] Compound 2-8 (13 mg, 0.032 mmol) was placed in a reaction tube. The air in the reaction tube was replaced with argon. 1,4-dioxane (0.5 mL) and 1,4-dioxane-hydrochloride (4 M) (0.5 mL) were added to the reaction tube. The reaction tube was stirred in a 25°C oil bath for 5 hours. After the reaction, the solvent in the reaction solution was spin-dried and then vacuumed for 2 hours to obtain the intermediate. The resulting intermediate, tert-butyloxycarbonyl-6-aminohexanoic acid (10.9 mg, 0.047 mmol), and (7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (17.8 mg, 0.047 mmol) were placed in a reaction tube. The atmosphere was replaced with argon. Triethylamine (6.4 mg, 0.063 mmol) and N,N-dimethylformamide (1 mL) were added to the reaction tube. The reaction tube was stirred at room temperature for 2-3 hours. After completion of the reaction, the reaction solution was purified by reverse-phase column chromatography (water:acetonitrile = 1:1, 0.1% formic acid) to obtain compound 2-9 (12 mg, 72% yield). m / z (ESI): 526 [M+H] + .

[0208] Step 9: 6-(2-((S)-4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine -6-yl)acetamido)-N-((2-(2,6-dioxopiperidin-3-yl)-3-oxo-2,3-dihydro-1H-imidazo[1,5-a]indol-6-yl)methyl)hexanamide (Compound 2)

[0209] Compound 2-9 (12 mg, 0.023 mmol) was placed in a reaction tube. The air in the reaction tube was replaced with argon. 1,4-Dioxane (0.5 mL) and 1,4-Dioxane-hydrochloride (4 M) (0.5 mL) were added to the reaction tube. The reaction tube was stirred in a 25°C oil bath for 5 hours. After the reaction, the solvent in the reaction solution was spin-dried and then vacuumed for 2 hours to obtain the intermediate. The obtained intermediate, compound 2-10 (11.0 mg, 0.027 mmol), and (7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (12.9 mg, 0.034 mmol) were placed in a reaction tube. The air in the reaction tube was replaced with argon. Triethylamine (4.6 mg, 0.046 mmol) and N,N-dimethylformamide (1.0 mL) were added to the reaction tube. The reaction tube was stirred at room temperature for 2-3 hours. After the reaction was completed, the reaction solution was purified by reverse phase column chromatography (water:acetonitrile = 1:1, 0.1% formic acid) to obtain compound 2 (2.0 mg, yield 11%). m / z (ESI): 808 [M+H] +.

[0210] 1 H NMR (400MHz, DMSO-d6) δ11.06(s,1H),8.42(d,J=19.8Hz,2H),8.19(s,1H),7.76(s,1H),7.57( d,J=8.1Hz,3H),7.52–7.38(m,1H),7.14(d,J=8.3Hz,1H),6.49(s,1H),4.97(dd,J=13.5,5.2H z,1H),4.58(d,J=16.5Hz,1H),4.50(t,J=7.1Hz,1H),4.44–4.35(m,2H),3.29–3.03(m,6H),2. 99–2.84(m,2H),2.59(s,3H),2.50(s,3H),2.40(s,3H),2.18–2.03(m,3H),1.59–1.21(m,6H).

[0211] Example 3: 6-(2-((S)-4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine -6-yl)acetamido)-N-((2-(2,6-dioxopiperidin-3-yl)-3-oxo-2,3-dihydro-1H-imidazo[1,5-a]indol-7-yl)methyl)hexanamide

[0212] Step 1: 5-Bromo-1H-indole-2-carbaldehyde oxime (Compound 3-2)

[0213] 5-Bromo-1H-indole-2-carbaldehyde (Compound 3-1, 1000 mg, 4.46 mmol), hydroxylamine hydrochloride (465 mg, 6.69 mmol), and sodium bicarbonate (749 mg, 8.92 mmol) were placed in a flask. Ethanol (15 mL) and water (10 mL) were added, and the reaction solution was stirred in a 70°C oil bath for 3 h. After the reaction, the reaction solution was concentrated and extracted with ethyl acetate and water. The organic phase was dried and concentrated to give Compound 3-2 (1010 mg, 95% yield). m / z (ESI): 239 [M+H] + .

[0214] Step 2: (5-Bromo-1H-indol-2-yl)methanamine (Compound 3-3)

[0215] 5-Bromo-1H-indole-2-carbaldehyde oxime (compound 3-2, 1010 mg, 4.22 mmol) was placed in a flask, and anhydrous tetrahydrofuran (25 mL) was added. The reaction solution was stirred in an ice bath at 0°C and cooled. After cooling, lithium aluminum tetrahydride (240 mg, 6.33 mmol) was slowly added. After complete addition, the reaction solution was stirred in an oil bath at 70°C for 2 h. After completion of the reaction, the reaction solution was stirred in an ice bath at 0°C and cooled. Sodium sulfate decahydrate was slowly added to quench the reaction. After quenching, the reaction solution was filtered, and the filtrate 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 (water:acetonitrile = 1:1, 0.1% formic acid) to obtain compound 3-3 (694 mg, 73% yield). m / z (ESI): 225 [M+H] + .

[0216] Step 3: 7-bromo-1,2-dihydro-3H-imidazo[1,5-a]indol-3-one (Compound 3-4)

[0217] Compound 3-3 (694 mg, 3.08 mmol) was placed in a dry, sealed tube. The air in the reaction tube was replaced with argon. Tetrahydrofuran (3 mL) was added and the tube was sealed. The reaction solution was stirred in an ethanol-dry ice bath to cool. N,N'-Carbonyldiimidazole (550 mg, 3.39 mmol) was placed in a dry flask and dissolved in tetrahydrofuran (3 mL). The N,N'-Carbonyldiimidazole solution was slowly added dropwise to the reaction solution. After the addition was complete, the mixture was naturally warmed to room temperature and stirred for 1 hour. The reaction solution was then placed in a 95°C oil bath and stirred for 16 hours. After the reaction, the reaction solution was concentrated to obtain the crude product, which was purified by normal phase column chromatography (water:acetonitrile = 1:1, 0.1% formic acid) to obtain compound 3-4 (526 mg, 68% yield). m / z (ESI): 251 [M+H] + .

[0218] Step 4: Dimethyl 2-(7-bromo-3-oxo-1H-imidazo[1,5-a]indol-2(3H)-yl)glutarate (Compound 3-5)

[0219] Compound 3-4 (526 mg, 2.10 mmol) and sodium hydride (75.2 mg, 3.14 mmol) were placed in a dry reaction tube. The air in the reaction tube was replaced with argon and the reaction tube was cooled in an ethanol-dry ice bath. N,N-dimethylformamide (2 mL) was added to the reaction tube. The reaction solution was naturally warmed to room temperature and stirred for half an hour. The mixture was then stirred in an ice-water bath. Dimethyl 2-bromoglutarate (749 mg, 3.14 mmol) was added dropwise to the reaction solution. Stirring was continued in the ice-water bath for half an hour and then at room temperature for one hour. After completion of the reaction, acetic acid (250 mg, 4.2 mmol) was added to quench the reaction. The reaction solution was purified by reverse-phase column chromatography (water:acetonitrile = 1:1, 0.1% formic acid) to obtain compound 3-5 (686 mg, 80% yield). m / z (ESI): 409 [M+H] + .

[0220] Step 5: 2-(7-bromo-3-oxo-1H-imidazo[1,5-a]indol-2(3H)-yl)glutaric acid (Compound 3-6)

[0221] Compound 3-5 (686 mg, 1.68 mmol) and lithium hydroxide (161 mg, 6.72 mmol) were placed in a flask, tetrahydrofuran (4 mL) and water (2 mL) were added, and the mixture was stirred at room temperature for 3 to 5 hours. After the reaction, hydrochloric acid (3N) was added to adjust the pH of the reaction solution to 3 to 5. The reaction solution was concentrated and purified by reverse phase column chromatography (water:acetonitrile = 1:1, 0.1% formic acid) to obtain compound 3-6 (575 mg, 90% yield). m / z (ESI): 381 [M+H] + .

[0222] Step 6: 3-(7-bromo-3-oxo-1H-imidazo[1,5-a]indol-2(3H)-yl)piperidine-2,6-dione (Compound 3-7)

[0223] Compound 3-6 (575 mg, 1.51 mmol), trifluoroacetamide (255 mg, 2.26 mmol), 1-hydroxybenzotriazole (448 mg, 3.32 mmol), and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (1012 mg, 5.28 mmol) were placed in a dry reaction tube. The air in the reaction tube was replaced with argon and the reaction tube was cooled in an ethanol-dry ice bath. Dichloromethane (10 mL) and triethylamine (687 mg, 6.80 mmol) were added to the reaction tube. The reaction solution was naturally warmed to room temperature and stirred for half an hour. The reaction solution was then stirred in a 35°C oil bath for 5 hours. After completion of the reaction, the reaction solution was concentrated and purified by reverse phase column chromatography (water:acetonitrile = 1:1, containing 0.1% formic acid) to obtain compound 3-7 (448 mg, 82% yield). m / z (ESI): 362 [M+H]+ .

[0224] Step 7: Tert-butyl ((2-(2,6-dioxopiperidin-3-yl)-3-oxo-2,3-dihydro-1H-imidazo[1,5-a]indol-7-yl)methyl)carbamate (Compound 3-8)

[0225] Compound 3-7 (448 mg, 1.24 mmol), palladium acetate (20.6 mg, 0.09 mmol), n-butyldi(1-adamantyl)phosphine (88.9 mg), potassium [(tert-butoxycarbonylamino)methyl]trifluoroborate (382 mg, 1.61 mmol), and cesium carbonate (808 mg, 2.48 mmol) were placed in a reaction tube. The atmosphere in the reaction tube was replaced with argon. 1,4-Dioxane (3 mL) and water (0.3 mL) were added to the reaction tube. The reaction tube was stirred in a 100°C oil bath for 5-8 hours. After completion of the reaction, the reaction solution was purified by reverse phase column chromatography (water:acetonitrile = 1:1, 0.1% formic acid) to obtain compound 3-8 (296 mg, 58% yield). m / z (ESI): 413 [M+H] + .

[0226] Step 8: Tert-butyl (6-(((2-(2,6-dioxopiperidin-3-yl)-3-oxo-2,3-dihydro-1H-imidazo[1,5-a]indol-7-yl)methyl)amino)-6-carbonylhexyl)carbamate (Compound 3-9)

[0227] Compound 3-8 (13.0 mg, 0.032 mmol) was placed in a reaction tube. The air in the reaction tube was replaced with argon. 1,4-dioxane (0.5 mL) and 1,4-dioxane-hydrochloride (4 M) (0.5 mL) were added to the reaction tube. The reaction tube was stirred in a 25°C oil bath for 5 hours. After the reaction, the solvent in the reaction solution was dried and then vacuumed for 2 hours to obtain the intermediate. The resulting intermediate, tert-butyloxycarbonyl-6-aminohexanoic acid (10.9 mg, 0.047 mmol), and (7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (17.8 mg, 0.047 mmol) were placed in a reaction tube. The atmosphere was replaced with argon. Triethylamine (6.4 mg, 0.06 mmol) and N,N-dimethylformamide (1.0 mL) were added to the reaction tube. The reaction tube was stirred at room temperature for 2-3 hours. After completion of the reaction, the reaction solution was purified by reverse-phase column chromatography (water:acetonitrile = 1:1, 0.1% formic acid) to obtain compound 3-9 (10.0 mg, 60% yield). m / z (ESI): 526 [M+H] + .

[0228] Step 9: 6-(2-((S)-4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine -6-yl)acetamido)-N-((2-(2,6-dioxopiperidin-3-yl)-3-oxo-2,3-dihydro-1H-imidazo[1,5-a]indol-7-yl)methyl)hexanamide (Compound 3)

[0229] Compound 3-9 (10.0 mg, 0.019 mmol) was placed in a reaction tube. The air in the reaction tube was replaced with argon. 1,4-Dioxane (0.5 mL) and 1,4-Dioxane-hydrochloride (4 M) (0.5 mL) were added to the reaction tube. The reaction tube was stirred in an oil bath at 25°C for 5 hours. After the reaction, the solvent in the reaction solution was spin-dried and then pumped with a vacuum oil pump for 2 hours to obtain the intermediate. The obtained intermediate, compound 2-10 (9.2 mg, 0.023 mmol), and (7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (10.8 mg, 0.028 mmol) were placed in a reaction tube. The air in the reaction tube was replaced with argon. Triethylamine (3.8 mg, 0.038 mmol) and N,N-dimethylformamide (1.0 mL) were added to the reaction tube. The reaction tube was stirred at room temperature for 2-3 hours. After the reaction was completed, the reaction solution was purified by reverse phase column chromatography (water:acetonitrile = 1:1, 0.1% formic acid) to obtain compound 3 (1.5 mg, yield 10%). m / z (ESI): 808 [M+H] + .

[0230] 1 H NMR(400MHz, DMSO-d6)11.06(s,1H),8.36(t,J=5.9Hz,1H),8.21(t,J=5.7Hz,1H),7.78(d,J=8.3Hz,1 H),7.52–7.45(m,3H),7.41(d,J=8.3Hz,2H),7.17(d,J=8.5Hz,1H),6.51(s,1H),4.96(dd,J=13.3,5.1 Hz,1H),4.62–4.32(m,4H),3.26–3.06(m,5H),2.96–2.87(m,1H),2.59(s,3H),2.50(s,3H),2.40(s,3 H),2.16(t,J=7.4Hz,2H),1.65–1.53(m,3H),1.49–1.41(t,J=7.4Hz,3H),1.34–1.28(d,J=7.2Hz,3H).

[0231] Example 4: 3-(1-oxo-1H-benzo[d]imidazo[1,5-a]imidazol-2(3H)-yl)piperidine-2,6-dione

[0232] Referring to the synthesis method of Example 1, the starting material compound 1-1 was replaced with (1H-benzimidazole-2-methylene)amine to prepare compound 4 (9 mg, yield 6%). m / z (ESI): 285 [M+H] + .

[0233] 1 H NMR(400MHz,DMSO-d6)δ11.08(s,1H),8.43(s,1H),7.86–7.73(m,2H),7.40–7.37(m,1H) ,5.04(dd,J=13.2,5.0Hz,1H),4.74–4.53(m,2H),2.95–2.88(m,2H),2.40–2.32(m,2H).

[0234] Compounds other than the compounds synthesized in Examples 1-4 can be synthesized by referring to the synthesis routes and source materials in Examples 1-4.

[0235] Biological activity and related properties test examples

[0236] Test Example 1: Cereblon binding experiment

[0237] 1. Experimental instruments and materials

[0238] The detection kit used in the experiment (HTRF Human Cereblon Binding Kits) is a This assay quantitatively measures Cereblon WT ligand. The assay is based on HTRF technology. A specifically labeled GST antibody (Euroum Cryptate, donor) simultaneously binds to GST-tagged human Cereblon WT ligand and the XL665-labeled lenalidomide tracer (acceptor). Excitation of the donor by a light source triggers fluorescence resonance energy transfer (FRET) to the acceptor, which emits fluorescence at a specific wavelength of 665 nm. Addition of the compound competes with the XL665-labeled lenalidomide, preventing FRET. The FRET signal ratio is inversely proportional to compound concentration.

[0239] Other reagents and consumables required for the experiment are as follows:

[0240] 2. Experimental steps

[0241] The disclosed compounds were dissolved in DMSO with a stock concentration of 10 mM. The compound stock solution was gradiently diluted using the dose-response program of the compound dilution and sample injector. The total experimental system of the dilution program was 20 μL, the starting concentration of the test compound was 100 μM, the starting concentration of the standard was 200 μM, 4-fold dilution, 8 concentration points, and the DMSO content was 1%. After the program was completed, 5 μL of 1×9# diluent in the kit was added to each well, followed by 5 μL of GST-labeled human Cereblon WT ligand, mixed thoroughly, and then 10 μL of HTRF detection reagent was added and incubated at room temperature for 3 hours. The HTRF signal in each well was measured using an Envision plate reader. 100% binding inhibition was defined as the signal ratio under treatment with 200 μM standard lenalidomide.

[0242] 3. Data Analysis

[0243] Calculate the ratio of the acceptor and donor emission signals for each well:

[0244] Ratio = 665nm signal / 620nm signal

[0245] Coefficient of variation (%) = standard deviation / mean ratio

[0246] Cereblon binding inhibition rate % = 100% - 100% × (Sample-L) / (HL)

[0247] in:

[0248] Sample=Ave (test sample group);

[0249] H = Ave (DMSO-treated group);

[0250] L=Ave (200 μM lenalidomide standard treatment group).

[0251] Data analysis was performed using GraphPad Prism 9. Concentration-effect curves were fitted using a nonlinear four-parameter curve, and the IC of the compounds was calculated. 50 :

[0252] Y=Bottom+(Top-Bottom) / (1+10^((LogIC 50 -X)*HillSlope))

[0253] in:

[0254] X: Log compound concentration;

[0255] Y: inhibition percentage (%);

[0256] Bottom is the minimum inhibition percentage;

[0257] Top is the maximum inhibition percentage;

[0258] HillSlope is the slope coefficient of the curve.

[0259] The binding ability of the disclosed compounds to Cereblon was determined by the above test, and the measured IC 50 See Table 1 for values.

[0260] Table 1

[0261] A:IC 50 <1μM; B:1μM≤IC 50 <10μM; C:10μM≤IC 50 <100 μM; D:IC 50 ≥100μM.

[0262] Test Example 2: Anti-proliferative activity test on MV-4-11 cells

[0263] 1. Experimental instruments and materials

[0264] Instruments and Equipment

[0265] Experimental reagents and consumables

[0266] 2. Experimental steps

[0267] (1) Cell plating

[0268] Remove the culture medium of the target cells MV-4-11 (CBP60522, Kebai), rinse once with PBS, and then add trypsin (Trypsin-EDTA (0.25%)) to digest for 5 minutes. After digestion, add 10mL of complete culture medium (IMDM containing 10% FBS) to neutralize the trypsin, pipette the cells, collect the cells, centrifuge at 1000rpm for 5 minutes, count the cells, and adjust the cell density to 30,000 / mL. Take 90μL of the cell suspension and add it to a 96-well plate. Add 200μL of PBS to the edge wells of the 96-well plate. Centrifuge at 1000rpm for 5 minutes to aggregate the cells into spheres, and place them in a cell culture incubator for overnight culture.

[0269] (2) Cell dosing

[0270] The disclosed compounds were dissolved in DMSO, and the stock solution concentration was 10 mM. Before administration, the compound stock solution was gradient diluted with DMSO, with a total of 8 gradient working solution concentrations of 1000, 200, 40, 8, 1.6, 0.32, 0.064, and 0.0128 μM. Take 2 μL of each working solution of different concentrations, add it to a dilution plate of 198 μL culture medium, and mix it by pipetting. Take 10 μL of culture medium containing the compound from the dilution plate and add it to the cell plate containing 90 μL of cell suspension laid the day before. The final concentration of each gradient compound is 1000, 200, 40, 8, 1.6, 0.32, 0.064, and 0.0128 nM. The positive control compound is dBET6. Add the diluted compound, 10 μL per well, and culture at 37 ° C, 5% CO2 for 3 days.

[0271] (3) Cell Viability Assay

[0272] Remove the cells from the incubator and allow them to return to room temperature for 30 minutes. Add 50 μL of Cell Viability Assay reagent was shaken and mixed for 10 minutes before reading the plate on an Envision microplate reader.

[0273] 3. Data Analysis

[0274] The anti-proliferative activity of the disclosed compounds on MV-4-11 cells was determined by the above test, and the cell growth inhibition rate of each sample well was calculated based on the raw data.

[0275] Inhibition rate (%) = 100% × (1-sample reading / DMSO reference average reading)

[0276] Sample reading: refers to the signal value of the experimental group;

[0277] DMSO reference average reading: refers to the average signal value of the DMSO control group. The DMSO control group does not receive the test compound, and all other procedures are the same as the experimental group.

[0278] Data analysis was performed using GraphPad Prism 9. Concentration-effect curves were fitted using a nonlinear four-parameter curve, and the IC of the compounds was calculated. 50 :

[0279] Y=Bottom+(Top-Bottom) / (1+10^((LogIC 50 -X)×HillSlope))

[0280] in:

[0281] X: Log compound concentration;

[0282] Y: inhibition rate (%);

[0283] Bottom is the minimum inhibition percentage;

[0284] Top is the maximum inhibition percentage;

[0285] HillSlope is the slope coefficient of the curve.

[0286] The anti-proliferative activities of the disclosed compounds on MV-4-11 cells are shown in Table 2.

[0287] Table 2 Antiproliferative activity of the disclosed compounds on MV-4-11 cells

[0288] Test Example 3: BRD4 protein degradation activity assay in MV-4-11 cells

[0289] 1. Experimental instruments and materials

[0290] Instruments and Equipment

[0291] Experimental reagents and consumables

[0292] 2. Experimental steps

[0293] (1) Cell plating

[0294] Remove the culture medium from MV-4-11 (CBP60522, Kebai) cells, rinse once with PBS, and then digest with trypsin (0.25%) for 5 minutes. After digestion, add 10 mL of complete culture medium (IMDM containing 10% FBS) to neutralize the trypsin. Pipette the cells, collect them, centrifuge at 1000 rpm for 5 minutes, count the cells, and adjust the cell density to 500,000 cells / mL. Add 2 mL of the cell suspension to a 12-well plate and culture overnight in a cell culture incubator.

[0295] (2) Cell dosing

[0296] 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.

[0297] (3) Western Blot

[0298] 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 100°C metal bath 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.

[0299] 3. Data Analysis

[0300] 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.

[0301] Degradation rate (%) = 100% × (1-sample reading / DMSO reference reading)

[0302] Sample reading: refers to the signal value of the experimental group;

[0303] DSMO reference reading: This refers to the signal value of the DSMO control group. The DSMO control group does not contain the test compound, and all other procedures are the same as the experimental group.

[0304] in:

[0305] 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 :

[0306] Y=Bottom+(Top-Bottom) / (1+10^((LogDC 50 -X)×HillSlope))

[0307] in:

[0308] X: Log compound concentration;

[0309] Y: degradation rate (%);

[0310] Bottom is the minimum degradation percentage;

[0311] Top is the maximum degradation percentage;

[0312] HillSlope is the slope coefficient of the curve.

[0313] DC measured by the disclosed compounds 50 The values ​​are shown in Table 3.

[0314] Table 3 BRD4 protein degradation activity of the disclosed compounds

Claims

1. A compound represented by formula (I) or a pharmaceutically acceptable salt thereof: CLM-L-PTM (I) in, CLM is selected from the structure shown in formula (II): Ring B is selected from a 5-6 membered heteroaromatic ring or a 5-8 membered heterocyclic ring; Ring C is selected from a 5-6 membered heteroaromatic ring, a 5-8 membered heterocyclic ring, a benzene ring, a C5-C8 saturated or partially saturated carbocyclic ring; Every R 1 、R 2 Independently selected from halogen, =O, CN, NO2, -OR b 、-N(R b )2、-S(O)R b 、-SO2R b , 2-10 membered heteroalkyl, C1-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, C3-C 10 Cycloalkyl, 4-8 membered heterocyclic group, C6-C 10 Aryl or 5-10 membered heteroaryl, the 2-10 membered heteroalkyl, C1-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, C3-C 10 Cycloalkyl, 4-8 membered heterocyclic group, C6-C 10 Aryl or 5-10 membered heteroaryl is optionally replaced by R a replace; Every R 4 independently selected from halogen, CN, NO2, OH, NH2, 2-10 membered heteroalkyl, 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, 2-10 membered heteroalkyl, 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 a replace; Every R a independently selected from halogen, CN, OH, NH2, 2-10 membered heteroalkyl, C1-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, C3-C 10 Cycloalkyl or 4-8 membered heterocyclic group, the 2-10 membered heteroalkyl, C1-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, C3-C 10 Cycloalkyl or 4-8 membered heterocyclic group is optionally replaced by R c replace; Every R b independently selected from H, halogen, CN, OH, NH2, 2-10 membered heteroalkyl, C1-C 10 Alkyl, C3-C 10 Cycloalkyl or 4-8 membered heterocyclic group, the OH, NH2, 2-10 membered heteroalkyl, C1-C 10 Alkyl, C3-C 10 Cycloalkyl or 4-8 membered heterocyclic group is optionally replaced by R c replace; Every R c independently selected from halogen, CN, OH, NH2, 2-10 membered heteroalkyl, C1-C 10 Alkyl, C3-C 10 Cycloalkyl or 4-8 membered heterocyclic group, the OH, NH2, 2-10 membered heteroalkyl, C1-C 10 Alkyl, C3-C 10 Cycloalkyl or 4-8 membered heterocyclic group is optionally replaced by R d replace; Every R d Independently selected from halogen, CN, OH, NH2 or C1-C6 alkyl; n is independently selected from 0, 1, 2, 3 or 4; m and p are independently selected from 0, 1, 2, 3, 4, 5 or 6; L represents the connection unit between CLM and PTM; The PTM is selected from a moiety that binds to a target protein.

2. The compound of formula (I) or a pharmaceutically acceptable salt according to claim 1, wherein Ring B is selected from a 5-6 membered heteroaryl ring or a 5-6 membered heterocyclic ring.

3. The compound of formula (I) or a pharmaceutically acceptable salt according to claim 1 or 2, wherein: Ring C is selected from a 5-6 membered heteroaromatic ring, a 5-6 membered heterocyclic ring, a benzene ring, a C5-C6 saturated or partially saturated carbon ring; or, Ring C is selected from a 5-6 membered heteroaromatic ring or a benzene ring.

4. The compound of formula (I) or a pharmaceutically acceptable salt according to any one of claims 1 to 3, wherein: CLM is selected from the structure shown in formula (III): Wherein, X is selected from N or CH, and the CH is optionally replaced by R 2 Substitution; Ring C, R 1 、R 2 、R 4 , m, n are as defined in claims 1-3.

5. The compound of formula (I) or a pharmaceutically acceptable salt according to any one of claims 1 to 4, wherein: CLM is selected from the structure shown in formula (III-1): Wherein, X is selected from N or CH, and the CH is optionally replaced by R 2 Substituted; Y1, Y2, Y3, Y4 are independently selected from N or CH, the CH is optionally replaced by R 1 Replacement; R 1 、R 2 、R 4 , n as defined in any one of claims 1-4.

6. The compound of formula (I) or a pharmaceutically acceptable salt according to any one of claims 1 to 5, wherein: R 1 、R 2 independently selected from halogen, CN, OH, NH2, C1-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl or C3-C 10 Cycloalkyl, said OH, NH2, C1-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl or C3-C 10 The cycloalkyl group is optionally replaced by R a replace.

7. The compound of formula (I) or a pharmaceutically acceptable salt according to any one of claims 1 to 6, wherein: Every R 4 independently selected from halogen, CN, OH, NH2 or C1-C6 alkyl, wherein the OH, NH2 or C1-C6 alkyl is optionally replaced by R a replace.

8. The compound of formula (I) or a pharmaceutically acceptable salt according to any one of claims 1 to 7, wherein: Every R a independently selected from halogen, CN, OH, NH2, C1-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, C3-C 10 Cycloalkyl or 4-8 membered heterocyclic group, the C1-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, C3-C 10 Cycloalkyl or 4-8 membered heterocyclic group is optionally replaced by R c replace.

9. The compound of formula (I) or a pharmaceutically acceptable salt according to any one of claims 1 to 8, wherein: m and p are independently selected from 0, 1, 2, 3 or 4; or m and p are independently selected from 0, 1 or 2; Alternatively, m and p are independently selected from 0 or 1.

10. The compound of formula (I) or a pharmaceutically acceptable salt according to any one of claims 1 to 9, wherein: n is selected from 0 or 1; Alternatively, n is selected from 0.

11. The compound of formula (I) or a pharmaceutically acceptable salt according to any one of claims 1 to 10, 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 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; 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; 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 replaced 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 replaced by R f replace; Every R f Independently selected from halogen, CN, OH, NH2 or C1-C6 alkyl.

12. The compound of formula (I) or a pharmaceutically acceptable salt according to any one of claims 11, wherein: L is selected from Among them, M1, M2, R 10 、R 11 、R 12 、R 13 、R 14 As defined in claim 11.

13. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 12, wherein: 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, R 20 and k as defined in claim 11 or 12.

14. The compound of formula (I) or a pharmaceutically acceptable salt according to any one of claims 11 to 13, wherein: M1, 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; Or M1, 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, 4-9 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.

15. The compound of formula (I) or a pharmaceutically acceptable salt according to any one of claims 1 to 11, wherein: 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; or 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-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.

16. The compound of formula (I) or a pharmaceutically acceptable salt according to any one of claims 1 to 15, wherein: L is selected from: -NR 20 -C1-C 10 Alkylene-C(O)NR 20 -CH2-, -NR 20 -C1-C 10 Alkylene-(OCH2CH2) k -C(O)NR 20 -、 -C(O)-C1-C 10 Alkylene-(OCH2CH2) k -C(O)NR 20 -、 -C(O)-C1-C 10 Alkylene-(OCH2CH2) k -C(O)O-, -NR 20 -C1-C 10 Alkylene-(OCH2CH2) k -C(O)-, -C(O)-C1-C 10 Alkylene-C1-C 10 Alkylene-, -C(O)-C1-C 10 Alkylene-C1-C 10 Alkylene-C2-C6 alkynylene-, -C(O)-C1-C 10 Alkylene-C1-C 10 Alkylene-(4-10 membered heterocyclylene)-, -C(O)-C1-C 10 Alkylene-C1-C 10 Alkylene-(5-10 membered heteroarylene)-, -C(O)-C1-C 10 Alkylene-C1-C 10 Alkylene-C(O)NR 20 -(4-10 membered heterocyclylene)-, -C(O)-C1-C 10 Alkylene-C1-C 10 Alkylene-C(O)O-, -C(O)-C1-C 10 Alkylene-C2-C 10 Alkenylene-(4-10 membered heterocyclylene)-O-, -C(O)-(C3-C 10 Cycloalkylene)-C1-C 10 Alkylene-O-, -C(O)-(C3-C 10 Cycloalkylene)-C1-C 10 Alkylene-NR 20 -、 -C(O)-(C3-C 10 Cycloalkylene)-C1-C 10 Alkylene-NR 20 -C1-C6 alkylene-, R 20 , k as defined in any one of claims 1-15.

17. The compound of formula (I) or a pharmaceutically acceptable salt according to any one of claims 1 to 15, wherein: The PTM is selected from the binding portion 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 or USP14; Preferably, the PTM is selected from the binding portion of the following targeting proteins: BRD4 or STAT3.

18. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, selected from the following compounds or pharmaceutically acceptable salts thereof, 19. A pharmaceutical composition comprising the compound of formula (I) according to any one of claims 1 to 18 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

20. Use of the compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 18, or the pharmaceutical composition according to claim 19, in the preparation of a medicament for preventing or treating abnormal cell proliferation diseases.

21. 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 (I) according to any one of claims 1 to 18 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 19.

22. The use of claim 20 or the method of claim 21, wherein the abnormal cell proliferation disorder is selected from cancer.

23. A compound represented by formula (IV) or a pharmaceutically acceptable salt thereof: in, Ring B, Ring C, R 1 、R 2 、R 4 , m, n, p, L are as defined in any one of claims 1-16.

24. The compound of formula (IV) or a pharmaceutically acceptable salt thereof according to claim 23 is selected from the compound of formula (IV-1) or a pharmaceutically acceptable salt thereof: in, X is selected from N or CH, said CH optionally replaced by R 2 Substitution; Ring C, R 1 、R 2 、R 4 , m, n, L are as defined in claim 23 above.

25. The compound of formula (IV) according to claim 23 or formula (IV-1) according to claim 24, or a pharmaceutically acceptable salt thereof, selected from the compound of formula (IV-1a) or a pharmaceutically acceptable salt thereof: in, X is selected from N or CH, said CH optionally replaced by R 2 Substituted; Y1, Y2, Y3, Y4 are independently selected from N or CH, the CH is optionally replaced by R 1 Replacement; R 1 、R 2 、R 4 , n, L as defined in claim 23 or 24.

26. A compound represented by formula (V) or a pharmaceutically acceptable salt thereof: in, Ring B, Ring C, R 1 、R 2 、R 4 , m, n, p are as defined in any one of claims 1-16.

27. The compound of formula (V) or a pharmaceutically acceptable salt thereof according to claim 26 is selected from the compound of formula (V-1) or a pharmaceutically acceptable salt thereof: in, X is selected from N or CH, said CH optionally replaced by R 2 Substitution; Ring C, R 1 、R 2 、R 4 , m, n as defined in claim 26.

28. The compound of formula (V) according to claim 26 or formula (V-1) according to claim 27, or a pharmaceutically acceptable salt thereof, is selected from the compound of formula (V-1a) or a pharmaceutically acceptable salt thereof: in, X is selected from N or CH, said CH optionally replaced by R 2 Substituted; Y1, Y2, Y3, Y4 are independently selected from N or CH, the CH is optionally replaced by R 1 Replacement; R 1 、R 2 、R 4 , n as defined in claim 26 or 27.

29. Use of a compound of formula (IV) according to any one of claims 23 to 25 or a compound of formula (V) according to any one of claims 26 to 28, or a pharmaceutically acceptable salt thereof, in the preparation of a target protein degradation drug.

30. Use of the compound of formula (IV) according to any one of claims 23 to 25 or any one of claims 26 to 28 or a pharmaceutically acceptable salt thereof as an intermediate in the preparation of a target protein degradation drug.

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