Multi-fused-ring compound and application thereof

Abstract

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

Description

Polycyclic compounds and their uses

[0001] This disclosure claims the priority of a prior application filed with the State Intellectual Property Office of China on September 14, 2022, with patent application number 202211119510.1, entitled “Poly-paracyclic compounds, pharmaceutical compositions and uses thereof”; a prior application filed with the State Intellectual Property Office of China on September 20, 2022, with patent application number 202211141718.3, entitled “Poly-paracyclic compounds and uses thereof”; and a prior application filed with the State Intellectual Property Office of China on November 24, 2022, with patent application number 202211484237.2, entitled “Poly-paracyclic compounds and uses thereof”. The entire text of the above-mentioned prior applications 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] The CLM structure is as follows:

[0010] is selected from a single bond or a double bond;

[0011] Z is selected from C(R 3 )2、NR 3 or O;

[0012] Ring B 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;

[0013] 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;

[0014] Every R 1 、R 2 、R 5 Independently selected from halogen, =O, CN, NO2, -OR b 、-N(R b )2、-S(O)R b 、-SO2Rb , 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;

[0015] Every R 3 Independently selected from H, 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;

[0016] or R 1 、R 3 The atoms to which it is attached together form a C5-C8 saturated or partially saturated carbocyclic ring, a 5-6 membered heteroaromatic ring or a 5-8 membered heterocyclic ring, wherein the C5-C8 saturated or partially saturated carbocyclic ring, a 5-6 membered heteroaromatic ring or a 5-8 membered heterocyclic ring is optionally replaced by R 5 replace;

[0017] 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 10Aryl 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;

[0018] 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;

[0019] 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;

[0020] 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, 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 d replace;

[0021] Every R d Independently selected from halogen, CN, OH, NH2 or C1-C6 alkyl;

[0022] n is independently selected from 0, 1, 2, 3 or 4;

[0023] m and p are independently selected from 0, 1, 2, 3, 4, 5 or 6;

[0024] L represents the connection unit between CLM and PTM;

[0025] The PTM is selected from a binding moiety to a target protein.

[0026] In some embodiments, Z is selected from NR 3 or O.

[0027] In some embodiments, Z is selected from NR 3 .

[0028] In some embodiments, Z is selected from NCH3.

[0029] In some embodiments, Ring B 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.

[0030] In some embodiments, Ring B is selected from a 5-6 membered heteroaryl ring or a benzene ring.

[0031] In some embodiments, ring B is selected from a pyridine ring or a benzene ring. In some embodiments, 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.

[0032] In some embodiments, Ring C is selected from a 5-6 membered heteroaryl ring or a benzene ring.

[0033] In some embodiments, Ring C is selected from a benzene ring, a pyridine ring, a pyrrole ring, or a thiazole ring.

[0034] In some embodiments, Ring C is selected from a benzene ring or a pyridine ring.

[0035] In some embodiments, Ring C is selected from a benzene ring.

[0036] In some embodiments, the CLM is selected from the structure represented by formula (II):

[0037] Wherein, X1 and X2 are independently selected from N or CH, and the CH is optionally replaced by R 2 Substitution; Ring C, Z, R 1 、R 2 、R 4 , m, n are as defined above.

[0038] In some embodiments, CLM is selected from the structures shown in formula (II-1a) and (II-1b):

[0039] Wherein, X1 and X2 are independently 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 R1 replace; Selected from a single bond or a double bond; Q1, Q2, Q3 are independently selected from O, S, NH, CH2, N or CH, wherein NH, CH2, CH are optionally replaced by R 1 Replacement; Z, R 1 、R 2 、R 4 , n are as defined above.

[0040] In some embodiments, is selected from a double bond, Q1 is selected from O, S, NH or CH2, Q2, Q3 are independently selected from N or CH, and the NH, CH2, CH are optionally replaced by R 1 replace.

[0041] 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.

[0042] In some embodiments, R 3 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.

[0043] In some embodiments, each R3 Independently selected from H, 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.

[0044] In some embodiments, each R 3 Independently selected from H, C1-C 10 Alkyl or C3-C 10 Cycloalkyl, the C1-C 10 Alkyl or C3-C 10 The cycloalkyl group is optionally replaced by R a replace.

[0045] In some embodiments, each R 3 independently selected from C1-C6 alkyl, said C1-C6 alkyl being optionally replaced by R a replace.

[0046] In some embodiments, each R 3 Independently selected from CH3.

[0047] In some embodiments, R 1 、R 3 The atoms to which it is attached together form a 5-, 6-, 7- or 8-membered heterocyclic ring, wherein the 5-, 6-, 7- or 8-membered heterocyclic ring is optionally replaced by R 5 replace.

[0048] In some embodiments, R 1 、R 3 The atoms to which it is attached together form a 5-, 6-, 7- or 8-membered heterocyclic ring, wherein the 5-, 6-, 7- or 8-membered heterocyclic ring contains 1, 2 or 3 heteroatoms or heteroatomic groups selected from N, O or S, and the 5-, 6-, 7- or 8-membered heterocyclic ring is optionally replaced by R 5 replace.

[0049] In some embodiments, each R 5 Independently selected from halogen, =O, CN, OH, NH2, C1-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl or C3-C 10 Cycloalkyl, the OH, NH2, C1-C10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl or C3-C 10 The cycloalkyl group is optionally replaced by R a replace.

[0050] In some embodiments, each R 5 Independently selected from =O, C1-C 10 Alkyl or C3-C 10 Cycloalkyl, the C1-C 10 Alkyl or C3-C 10 The cycloalkyl group is optionally replaced by R a replace.

[0051] In some embodiments, each R 5 independently selected from =O or C1-C6 alkyl, said C1-C6 alkyl being optionally replaced by R a replace.

[0052] In some embodiments, each R 5 is selected from C1-C6 alkyl, wherein the C1-C6 alkyl is optionally replaced by R a replace.

[0053] In some embodiments, R 5 Selected from CH3.

[0054] 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.

[0055] 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.

[0056] In some embodiments, each R aindependently 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.

[0057] 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.

[0058] In some embodiments, each R a Independently selected from F, Cl or CH3.

[0059] 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.

[0060] In some embodiments, each R c Independently selected from halogen, CN, OH, NH2 or C1-C6 alkyl.

[0061] In some embodiments, m and p are independently selected from 0, 1, 2, 3 or 4.

[0062] In some embodiments, m and p are independently selected from 0, 1 or 2.

[0063] In some embodiments, m and p are independently selected from 1 or 2.

[0064] In some embodiments, m and p are both selected from 0.

[0065] In some embodiments, n is selected from 0 or 1.

[0066] In some embodiments, n is selected from 0.

[0067] In some embodiments, L is selected from

[0068] 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-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;

[0069] 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;

[0070] k is independently selected from 1, 2, 3, 4, 5 or 6;

[0071] R 20Selected 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;

[0072] 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;

[0073] Every R f Independently selected from halogen, CN, OH, NH2 or C1-C6 alkyl.

[0074] 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.

[0075] In some embodiments, R 21 Selected from halogen, CN, OH, NH2, NO2 or C1-C 10 Alkyl, the C1-C 10 The alkyl group is optionally replaced by R f replace.

[0076] In some embodiments, L is selected from Among them, M1, M2, R 10 、R 11 、R 12 、R 13 、R 14 As defined above.

[0077] In some embodiments, L is selected from Among them, M1, M2, R 10 、R 11 、R12 , as defined above.

[0078] In some embodiments, L is selected from Among them, R 10 、R 11 、R 12 、R 13 、R 14 independently selected from a bond, -(O-CH2CH2) k -, -C(O)-, -C(O)O-, -O-, -C(O)NR 20 -、-NR 20 -、-NR 20 C(O)O-、-NR 20 S(O)2-、C1-C 10 Alkylene, C2-C 10 Alkenylene, C2-C 10 Alkynylidene, 4-9 membered heterocyclylene, C6-C 10 Arylene or 5-10 membered heteroarylene, the C1-C 10 Alkylene, C2-C 10 Alkenylene, C2-C 10 Alkynylidene, 4-9 membered heterocyclylene, C6-C 10 Arylene or 5-10 membered heteroarylene is optionally replaced by R 21 Replacement; M1, M2, R 20 、R 21 and k are as defined above.

[0079] In some embodiments, L is selected from in,

[0080] 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 replace;

[0081] 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-C10 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; where k, R 20 、R 21 As defined above.

[0082] 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, 4-9 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 Replacement; wherein, R 20 、R 21 As defined above.

[0083] 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 10Arylene or 5-10 membered heteroarylene is optionally replaced by R 21 replace.

[0084] 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 Substitution, where k, R 20 、R 21 As defined above.

[0085] 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 10Arylene or 5-6 membered heteroarylene is optionally replaced by R 21 Substitution, where k, R 20 、R 21 As defined above.

[0086] In some embodiments, L is selected from the following structures:

[0087] -C(O)-(O-CH2CH2) k -C1-C 10 Alkylene-C(O)NR 20 -、

[0088] -NR 20 -(O-CH2CH2) k -C1-C 10 Alkylene-C(O)NR 20 -、

[0089] -NR 20 -(O-CH2CH2) k -C1-C 10 Alkylene-C(O)-,

[0090] -C(O)-C1-C 10 Alkylene-C1-C 10 Alkylene-,

[0091] -C(O)-C1-C 10 Alkylene-C2-C 10 Alkynylidene-,

[0092] -C(O)-C1-C 10 Alkylene-C1-C 10 Alkylene-4-9 membered heterocyclylene-,

[0093] -C(O)-C1-C 10 Alkylene-C1-C 10 Alkylene-5-10 membered heteroarylene-,

[0094] -C(O)-C1-C 10 Alkylene-C1-C 10 Alkylene-C(O)-4-9 membered heterocyclylene-,

[0095] -C(O)-C1-C 10 Alkylene-C1-C 10 Alkylene-C(O)NR 20 -4-9 membered heterocyclylene-,

[0096] -C(O)-C1-C 10 Alkylene-C1-C 10Alkylene-C(O)O-,

[0097] -C(O)-C1-C 10 Alkylene-C2-C 10 Alkenylene-4-9 membered heterocyclylene-O-,

[0098] -C(O)-C1-C 10 Alkylene-C1-C 10 Alkylene-4-9 membered heterocyclylene-C(O)-,

[0099] -C(O)-C3-C 10 Cycloalkylene-C1-C 10 Alkylene-O-,

[0100] -C(O)-C3-C 10 Cycloalkylene-C1-C 10 Alkylene-NR 20 -、

[0101] -C(O)-C3-C 10 Cycloalkylene-C1-C 10 Alkylene-NR 20 -C1-C 10 Alkylene-,

[0102] -NR 20 -C1-C 10 Alkylene-C(O)NR 20 -C1-C 10 Alkylene-,

[0103] -C1-C 10 Alkylene-4-9 membered heterocyclylene-C1-C6 alkylene-4-9 membered heterocyclylene-,

[0104] Among them, k, R 20 As defined above.

[0105] In some embodiments, L is selected from the following structures:

[0106] -C(O)-(O-CH2CH2) k -C1-C6 alkylene-C(O)NH-,

[0107] -NH-(O-CH2CH2) k -C1-C6 alkylene-C(O)NH-,

[0108] -NH-(O-CH2CH2) k -C1-C6 alkylene-C(O)-,

[0109] -C(O)-C1-C10 Alkylene-C1-C6 alkylene-,

[0110] -C(O)-C1-C 10 Alkylene-C2-C6 alkynylene-,

[0111] -C(O)-C1-C 10 Alkylene-C1-C6 alkylene-4-9 membered heterocyclic group-,

[0112] -C(O)-C1-C 10 Alkylene-C1-C6 alkylene-5-6 membered heteroarylene-,

[0113] -C(O)-C1-C 10 Alkylene-C1-C6 alkylene-C(O)-4-9 membered heterocyclylene-,

[0114] -C(O)-C1-C 10 Alkylene-C1-C6 alkylene-C(O)NH-4-9 membered heterocyclylene-,

[0115] -C(O)-C1-C 10 Alkylene-C1-C6 alkylene-C(O)O-,

[0116] -C(O)-C1-C6 alkylene-C2-C6 alkenylene-4-6 membered heterocyclylene-O-,

[0117] -C(O)-C1-C 10 Alkylene-C1-C6 alkylene-4-6 membered heterocyclylene-C(O)-,

[0118] -C(O)-C3-C6 cycloalkylene-C1-C6 alkylene-O-,

[0119] -C(O)-C3-C6 cycloalkylene-C1-C6 alkylene-NH-,

[0120] -C(O)-C3-C6 cycloalkylene-C1-C6 alkylene-NH-C1-C6 alkylene-,

[0121] -NH-C1-C6 alkylene-C(O)NH-C1-C6 alkylene-,

[0122] -C1-C6 alkylene-4-6 membered heterocyclylene-C1-C6 alkylene-4-6 membered heterocyclylene-,

[0123] wherein k is as defined above.

[0124] In some embodiments, L is selected from the following structures:

[0125] 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, 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.

[0126] In some embodiments, the PTM is selected from the binding portion of the following targeting proteins: ALK, AR, BET1, BRAF, BRCA2, BRD4, BRD9, BTK, 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.

[0127] In some embodiments, the PTM is selected from the binding portion of the following targeting proteins: BRM, BRD4, or STAT3.

[0128] In some embodiments, the PTM is selected from the binding portion of the following targeting proteins: BRD4 or STAT3.

[0129] In some embodiments, the PTM is selected from the group consisting of binding moieties of the following targeting proteins: BRM or BRD4.

[0130] In some embodiments, the PTM is selected from the following structural groups:

[0131] 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:

[0132] 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.

[0133] 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.

[0134] 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.

[0135] 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.

[0136] 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.

[0137] In some embodiments, the abnormal cell proliferation disorder is selected from cancer.

[0138] In some embodiments, the cancer is selected from a solid tumor, an adenocarcinoma, or a hematological cancer.

[0139] On the other hand, the present disclosure also provides a compound represented by formula (III) or a pharmaceutically acceptable salt thereof:

[0140] Wherein, X1 and X2 are independently selected from N or CH, and the CH is optionally replaced by R 2 Replacement; Z, R 1 、R 2 、R 4 , m, n, L are as defined above;

[0141] Ring C is selected from a 5-6 membered heteroaromatic ring or a benzene ring;

[0142] Provided that the following compounds or pharmaceutically acceptable salts thereof are not included:

[0143] In some embodiments, the compound represented by formula (III) or a pharmaceutically acceptable salt thereof is selected from the compound represented by formula (III-1a) or formula (III-1b) or a pharmaceutically acceptable salt thereof:

[0144] Wherein, X1 and X2 are independently 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 replace; Selected from double bonds; Q1, Q2, Q3 are independently selected from O, S, NH, CH2, N or CH, wherein NH, CH2, CH are optionally replaced by R 1 Substitution; Z, R 1 、R 2 、R 4 , n, L are as defined above;

[0145] Provided that the following compounds or pharmaceutically acceptable salts thereof are not included:

[0146] In some embodiments, the compound represented by formula (III) or a pharmaceutically acceptable salt thereof is selected from the following compounds or a pharmaceutically acceptable salt thereof:

[0147] On the other hand, the present disclosure also provides a compound represented by formula (IV) or a pharmaceutically acceptable salt thereof:

[0148] Wherein, X1 and X2 are independently selected from N or CH, and the CH is optionally replaced by R 2 Substitution; Z, R 1 、R 2 、R 4 , m, n are as defined above;

[0149] Ring C is selected from a 5-6 membered heteroaromatic ring or a benzene ring;

[0150] Provided that the following compounds or pharmaceutically acceptable salts thereof are not included:

[0151] 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 formula (IV-1b) or a pharmaceutically acceptable salt thereof:

[0152] Wherein, X1 and X2 are independently 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 replace; Selected from double bonds; Q1, Q2, Q3 are independently selected from O, S, NH, CH2, N or CH, wherein NH, CH2, CH are optionally replaced by R 1 Substitution; Z, R1 、R 2 、R 4 , n is as defined above;

[0153] Provided that the following compounds or pharmaceutically acceptable salts thereof are not included:

[0154] On the other hand, the present disclosure also provides a compound represented by formula (V) or a pharmaceutically acceptable salt thereof,

[0155] in,

[0156] Z* is selected from C(R 3* )2、NR 3* or O;

[0157] Ring B* 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;

[0158] 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;

[0159] Every R 1* 、R 2* 、R 3* 、R 5* Independently selected from the following groups:

[0160] (a) 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;

[0161] or,

[0162] (b)

[0163] M 1* Selected from bond, -NR b* -, -C(O)-, -C(O)O-, -SO2-, -S(O)-, -O-, -S-, -C(O)NR b* -、-C(=NR b* )-, 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, 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, 5-10 membered heteroarylene are optionally replaced by R a* replace;

[0164] R 10* 、R 11* 、R 12* 、R 13* 、R 14* are independently selected from a bond, -NR b* -, -C(O)-, -C(O)O-, -SO2-, -S(O)-, -O-, -S-, -NR b* C(O)-, -C(=NR b* )-、-C(S)-、-P(O)(OR b* )O-、-P(O)(OR b* )-, 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, 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, 5-10 membered heteroarylene are optionally replaced by R a* replace;

[0165] R 20*Selected from H, halogen, CN, -OR b* 、-N(R b*) 2. -S(O)R b* 、-SO2R b* 、-C(O)R b* 、-C(O)OR b* 、-OC(O)R b* 、-C(O)N(R b*) 2. -NR b* C(O)R b* , 2-10 membered heteroalkyl, C1-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, C3-C 10 Cycloalkyl, 4-9 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, 4-9 membered heterocyclic group, C6-C 10 Aryl or 5-10 membered heteroaryl is optionally replaced by R a* replace;

[0166] or R 1* 、R 3* The atoms to which it is attached together form a C5-C8 saturated or partially saturated carbocyclic ring, a 5-6 membered heteroaromatic ring or a 5-8 membered heterocyclic ring, wherein the C5-C8 saturated or partially saturated carbocyclic ring, a 5-6 membered heteroaromatic ring or a 5-8 membered heterocyclic ring is optionally replaced by R 5* replace;

[0167] Every R 4* Selected from halogen, CN, 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;

[0168] Every R a* independently selected from halogen, CN, OH, NH2, 2-10 membered heteroalkyl, C1-C 10 Alkyl, C3-C 10Cycloalkyl, 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 c* replace;

[0169] Every R b* independently selected from H, halogen, CN, 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 c* replace;

[0170] 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;

[0171] Every R d* Independently selected from halogen, CN, OH, NH2 or C1-C6 alkyl;

[0172] n* is independently selected from 0, 1, 2, 3 or 4;

[0173] m* and p* are independently selected from 0, 1, 2, 3, 4, 5 or 6.

[0174] In some embodiments, Z* is selected from NR 3* or O.

[0175] In some embodiments, Ring B* 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.

[0176] In some embodiments, Ring B* is selected from a 5-6 membered heteroaryl ring or a benzene ring.

[0177] In some embodiments, Ring B* is selected from a pyridine ring or a benzene ring.

[0178] 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.

[0179] In some embodiments, Ring C* is selected from a 5-6 membered heteroaryl ring or a benzene ring.

[0180] In some embodiments, ring C* is selected from a benzene ring, a pyridine ring, a pyrrole ring, or a thiazole ring.

[0181] In some embodiments, R 1* 、R 2* Independently selected from halogen, CN, NO2, -OR b* 、-N(R b* )2、-S(O)R b* 、-SO2R b* 、C1-C 10 Alkyl or C3-C 10 Cycloalkyl, the C1-C 10 Alkyl or C3-C 10 The cycloalkyl group is optionally replaced by R a* replace.

[0182] In some embodiments, R 1* 、R 2* independently selected from halogen, CN, OH, NH2, 2-10 membered heteroalkyl, C1-C 10 Alkyl or C3-C 10 Cycloalkyl, the 2-10 membered heteroalkyl, C1-C 10 Alkyl or C3-C 10 The cycloalkyl group is optionally replaced by R a* replace.

[0183] In some embodiments, R 3* Selected from halogen, CN, OH, NH2, 2-10 membered heteroalkyl, C1-C 10 Alkyl or C3-C 10 Cycloalkyl, the 2-10 membered heteroalkyl, C1-C 10 Alkyl or C3-C 10 The cycloalkyl group is optionally replaced by R a* replace.

[0184] In some embodiments, R 3* is selected from 2-6 membered heteroalkyl, C1-C6 alkyl or C3-C6 cycloalkyl, wherein the 2-6 membered heteroalkyl, C1-C6 alkyl or C3-C6 cycloalkyl is optionally replaced by R a* replace.

[0185] In some embodiments, R 3* is selected from C1-C6 alkyl or C3-C6 cycloalkyl, wherein the C1-C6 alkyl or C3-C6 cycloalkyl is optionally replaced by R a* replace.

[0186] In some embodiments, R 3* Independently selected from CH3, CH2CH3, CH(CH3)2, CHCF3 or cyclopropyl.

[0187] In some embodiments, R 5* Selected from halogen, =O, CN, OH, NH2, C1-C 10 Alkyl or C3-C 10 Cycloalkyl, the C1-C 10 Alkyl or C3-C 10 The cycloalkyl group is optionally replaced by R a* replace.

[0188] In some embodiments, R 5* is selected from halogen, =O, CN, OH, NH2, C1-C6 alkyl or C3-C6 cycloalkyl, wherein the C1-C6 alkyl or C3-C6 cycloalkyl is optionally replaced by R a* replace.

[0189] In some embodiments, R 5* is selected from =O or C1-C6 alkyl, the C1-C6 alkyl is optionally replaced by R a* replace.

[0190] In some embodiments, R 1* Selected from Among them, M 1* 、R 10* 、R 11* 、R 12* 、R 13* 、R 20* As defined above.

[0191] In some embodiments, R 1* Selected from Among them, M 1* 、R 10* 、R 11* 、R 12* 、R 20* As defined above.

[0192] In some embodiments, R 2* Selected from Among them, M 1* 、R 10* 、R 11* 、R 12* 、R 13*、R 20* As defined above.

[0193] In some embodiments, R 2* Selected from Among them, M 1* 、R 10* 、R 11* 、R 12* 、R 20* As defined above.

[0194] In some embodiments, R 3* Selected from Among them, M 1* 、R 10* 、R 11* 、R 12* 、R 13* 、R 20* As defined above.

[0195] In some embodiments, R 3* Selected from Among them, M 1* 、R 10* 、R 11* 、R 12* 、R 20* As defined above.

[0196] In some embodiments, R 5* Selected from Among them, M 1* 、R 10* 、R 11* 、R 12* 、R 13* 、R 20* As defined above.

[0197] In some embodiments, R 5* Selected from Among them, M 1* 、R 10* 、R 11* 、R 12* 、R 20* As defined above.

[0198] In some embodiments, R 1* 、R 2* 、R 3* 、R 5* Independently selected from Among them, R 11* 、R 12* 、R 13* independently selected from a bond, -C(O)-, -C(O)O-, -O-, -S-, -C(O)NRb* -or-NR b* -;M 1* 、R 10* 、R 14* 、R 20* 、R b* As defined above.

[0199] In some embodiments, R 1* 、R 2* 、R 3* 、R 5* Independently selected from Among them, M 1* 、R 10* 、R 11* 、R 13* 、R 14* 、R 20* As defined above.

[0200] In some embodiments, R 1* 、R 2* 、R 3* 、R 5* Independently selected from Among them, R 11* 、R 13* independently selected from a bond, -C(O)-, -C(O)O-, -O-, -S-, -C(O)NR b* -or-NR b* -;M 1* 、R 10* 、R 14* 、R 20* 、R b* As defined above.

[0201] In some embodiments, M 1* is selected from a bond, -NH-, -CH2-, -CH2CH2-, -C(O)-, -C(O)O-, -O-, -S- or -C(O)NH-.

[0202] In some embodiments, M 1* Selected from -CH2- or -CH2CH2-.

[0203] In some embodiments, R 10* 、R 11* 、R 12* 、R 13* 、R 14* independently selected from a bond, -C(O)-, -C(O)O-, -O-, -S-, -C(O)NR b* -、-NR b* -, 2-10 membered heteroalkylene, C1-C 10Alkylene, C2-C 10 Alkenylene, C2-C 10 Alkynylidene, 4-9 membered heterocyclylene, C6-C 10 Arylene, 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, 5-10 membered heteroarylene are optionally replaced by R a* replace.

[0204] In some embodiments, R 20* Selected from H, 2-10 membered heteroalkyl, C1-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, C3-C 10 Cycloalkyl, 4-9 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, 4-9 membered heterocyclic group, C6-C 10 Aryl or 5-10 membered heteroaryl is optionally replaced by R a* replace.

[0205] In some embodiments, R 20* Selected from H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 Cycloalkyl, 4-9 membered heterocyclic group, C6-C 10 Aryl or 5-10 membered heteroaryl, the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 Cycloalkyl, 4-9 membered heterocyclic group, C6-C 10 Aryl or 5-10 membered heteroaryl is optionally replaced by R a* replace.

[0206] In some embodiments, R 1* 、R 3* The atoms to which it is attached together form a 5-, 6-, 7- or 8-membered heterocyclic ring, wherein the 5-, 6-, 7- or 8-membered heterocyclic ring is optionally replaced by R 5* replace.

[0207] In some embodiments, R 1* 、R 3*The atoms to which it is attached together form a 5-, 6-, 7- or 8-membered heterocyclic ring, wherein the 5-, 6-, 7- or 8-membered heterocyclic ring contains 1, 2 or 3 heteroatoms or heteroatomic groups selected from N, O or S, and the 5-, 6-, 7- or 8-membered heterocyclic ring is optionally replaced by R 5* replace.

[0208] In some embodiments, R 4* independently selected from halogen, CN, OH, NH2, 2-10 membered heteroalkyl or C1-C 10 Alkyl, the OH, NH2, 2-10 membered heteroalkyl or C1-C 10 The alkyl group is optionally replaced by R a* replace.

[0209] In some embodiments, each R a* independently selected from halogen, CN, OH, NH2, C1-C 10 Alkyl, C3-C 10 Cycloalkyl or 4-8 membered heterocyclic group, the OH, NH2, C1-C 10 Alkyl, C3-C 10 Cycloalkyl or 4-8 membered heterocyclic group is optionally replaced by R c* replace.

[0210] In some embodiments, each R a* independently selected from halogen, CN, OH, NH2 or C1-C 10 Alkyl, the OH, NH2, C1-C 10 The alkyl group is optionally replaced by R c* replace.

[0211] 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.

[0212] In some embodiments, each R a* Independently selected from F, Cl, CH3 or CF3.

[0213] In some embodiments, each R b* Independently selected from H, C1-C6 alkyl, C3-C 10 Cycloalkyl, 4-8 membered heterocyclic group, C6-C 10 Aryl or 5-10 membered heteroaryl, the C1-C6 alkyl, C3-C 10 Cycloalkyl, 4-8 membered heterocyclic group, C6-C 10 Aryl or 5-10 membered heteroaryl is optionally replaced by R c* replace.

[0214] 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.

[0215] In some embodiments, each R c* Independently selected from halogen, CN, OH, NH2 or C1-C6 alkyl.

[0216] In some embodiments, m* and p* are independently selected from 0, 1, 2, 3, or 4.

[0217] In some embodiments, m* and p* are independently selected from 1, 2, 3, or 4.

[0218] In some embodiments, m* and p* are independently selected from 1 or 2.

[0219] In some embodiments, n* is selected from 0 or 1.

[0220] In some embodiments, n* is selected from 0.

[0221] In some embodiments, the compound of formula (V) or a pharmaceutically acceptable salt thereof of the present disclosure is selected from the compound of formula (VI) or a pharmaceutically acceptable salt thereof,

[0222] Among them, X 1* 、X 2* independently selected from N or CH, said CH optionally replaced by R 2* Substitution; Ring C, Z*, R 1* 、R 2* 、R 4* , m*, n* are as defined above.

[0223] In some embodiments, the compound of formula (VI) or a pharmaceutically acceptable salt thereof of the present disclosure is selected from the compound of formula (VI-1a) or (VI-1b) or a pharmaceutically acceptable salt thereof,

[0224] Among them, X 1* 、X 2* independently selected from N or CH, said CH optionally replaced by R 2* Replace; Y 1* 、Y 2* 、Y 3* 、Y 4* independently selected from N or CH, said CH optionally replaced by R 1* Replace; Q 1* , Q 2* , Q 3*Independently selected from O, S, NH, CH2, N or CH, wherein NH, CH2, CH are optionally replaced by R 1* Replacement; Z*, R 1* 、R 2* 、R 4* , n* is as defined above.

[0225] 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.

[0226] In some embodiments, the compound of formula (III) or formula (IV) or formula (V) or a pharmaceutically acceptable salt thereof is selected from the following compounds or a pharmaceutically acceptable salt thereof,

[0227] In another aspect, the present disclosure provides a pharmaceutical composition comprising a compound represented by formula (V) of the present disclosure or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

[0228] 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 (V) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof to a mammal, preferably a human, in need of such treatment.

[0229] In another aspect, the present disclosure provides use of a compound represented by formula (V) 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.

[0230] In another aspect, the present disclosure provides use of a compound represented by formula (V) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, in preventing or treating abnormal cell proliferation diseases.

[0231] In another aspect, the present disclosure provides a compound represented by formula (V) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for preventing or treating abnormal cell proliferation diseases.

[0232] In some embodiments, the abnormal cell proliferation disorder is selected from cancer.

[0233] In some embodiments, the cancer is selected from a solid tumor, an adenocarcinoma, or a hematological tumor.

[0234] On the other hand, the present disclosure also provides the use of the compounds represented by formula (III), formula (IV), formula (V) or pharmaceutically acceptable salts thereof in the preparation of target protein degradation drugs.

[0235] On the other hand, the present disclosure also provides the use of compounds represented by formula (III), formula (IV), formula (V) or pharmaceutically acceptable salts thereof as intermediates in the preparation of target protein degradation drugs.

[0236] 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.

[0237] Definitions and Explanations of Terms

[0238] 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.

[0239] 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 position includes but is not limited to Y 1 、Y 2 、Y 3 、Y 4 、X 1 、X 2 , Z and their substituents, etc.

[0240] 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).

[0241] 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.

[0242] The term "stereoisomer" refers to isomers resulting from different spatial arrangements of atoms in a molecule, including cis-trans isomers, enantiomers and diastereomers.

[0243] 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.

[0244] 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.

[0245] 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.

[0246] 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.

[0247] 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.

[0248] 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 ”.

[0249] 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.

[0250] 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.

[0251] In this paper, the bonds depicted by solid and dashed lines represents a single bond or a double bond. For example, the structural unit Include

[0252] 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".

[0253] The term "alkylene" refers to a divalent group derived from an "alkyl" group as defined herein.

[0254] 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.

[0255] The term "heteroalkylene" refers to a divalent radical derived from a "heteroalkyl" group as defined herein.

[0256] 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.

[0257] The term "alkenylene" refers to a divalent group derived from an "alkenyl" group as defined herein.

[0258] 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).

[0259] The term "alkynylene" refers to a divalent group derived from an "alkynyl" group as defined herein.

[0260] The term "cycloalkyl" refers to a fully saturated carbon ring that exists in the form of a monocyclic, fused, bridged, or spirocyclic ring. Unless otherwise indicated, the carbon ring is typically a 3- to 10-membered ring. The term "C3-C 10 "Cycloalkyl" is understood to mean a saturated monocyclic, bicyclic, spirocyclic or bridged ring having 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms. Specific examples of the cycloalkyl group include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, norbornyl (bicyclo[2.2.1]heptyl), bicyclo[2.2.2]octyl, adamantyl, spiro[4.5]decyl, and the like. The term "C3-C 10 "Cycloalkyl" may include "C3-C6 cycloalkyl". The term "C3-C6 cycloalkyl" may be understood to mean a saturated monocyclic or bicyclic hydrocarbon ring having 3, 4, 5 or 6 carbon atoms, specific examples of which include but are not limited to cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. The term "C5-C8 cycloalkyl" may be understood to mean a saturated monocyclic or bicyclic hydrocarbon ring having 5, 6, 7 or 8 carbon atoms, and may also be represented as a C5-C8 saturated carbocyclic ring.

[0261] The term "cycloalkylene" refers to a divalent group derived from a "cycloalkyl" group as defined herein.

[0262] 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., and "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.

[0263] The term "heterocyclylene" refers to a divalent radical derived from a "heterocyclyl" group as defined herein.

[0264] 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".

[0265] The term "arylene" refers to a divalent group derived from an "aryl" group as defined herein.

[0266] 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.

[0267] The term "heteroarylene" refers to a divalent radical derived from a "heteroaryl" group as defined herein.

[0268] The term "halo" or "halogen" refers to fluorine, chlorine, bromine or iodine.

[0269] The term "therapeutically effective amount" means:

[0270] 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.

[0271] 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.

[0272] 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.

[0273] 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.

[0274] 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.

[0275] 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.

[0276] 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".

[0277] 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.

[0278] 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.

[0279] 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.

[0280] 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.

[0281] 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.

[0282] 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.

[0283] 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.

[0284] The pharmaceutical composition may also be suitable for parenteral administration, such as sterile solutions, suspensions or lyophilized products in appropriate unit dosage forms.

[0285] In all methods of administration of the compounds of formula (I) described herein, the dosage administered per day is 0.01 mg / kg to 200 mg / kg body weight, in the form of single or divided doses. DETAILED DESCRIPTION

[0286] 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.

[0287] 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.

[0288] Unless otherwise specified, the ratios expressed for mixed solvents are volume ratios.

[0289] Unless otherwise stated, % refers to wt%.

[0290] The eluent mentioned below can be a mixed eluent formed by two or more solvents, and the ratio is the volume ratio of each solvent. For example, "water:acetonitrile = 1:1" means that during the elution process, the volume ratio of water and acetonitrile in the mixed eluent is 1:1.

[0291] Abbreviations:

[0292] ACN: acetonitrile; TEA: triethylamine; DPPA: diphenylphosphoryl azide; DMF: N,N-dimethylformamide; THF: tetrahydrofuran; HOBT: 1-hydroxybenzotriazole; DCM: dichloromethane; Trifluoroacetamide: trifluoroacetamide; EDCI: 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride; 2-MeTHF: 2-methyltetrahydrofuran; Glyoxal: glyoxal; t-BuOK or KOtBu: potassium tert-butoxide; toluene: toluene; MsOH: methanesulfonic acid; Pd(OAc)2: palladium acetate; Catacxium: n-butylbis(1-adamantyl)phosphine; Dioxane: 1,4-dioxane; DIEA: N,N-diisopropylethylamine; HATU: 2-(7-Azobenzotriazole)-tetramethyluronium hexafluorophosphate; NBS: N-bromosuccinimide; Ephos Pd G4: (methanesulfonic acid {biscyclohexyl (3-isopropoxy-2', 4', 6'-triisopropyl-[1,1'-biphenyl]-2-yl) phosphane} (2'-methylamino-1,1'-biphenyl-2-yl) palladium; Ephos: dicyclohexyl (3-ethylpropoxy-2', 4', 6'-triisopropyl-[1,1'-biphenyl]-2-yl) phosphane; triphosgene: triphosgene; TFA: triphosgene Fluoroacetic acid; TfOH: trifluoromethanesulfonic acid; Pd-PEPPSI-IPent-Cl: [1,3-bis(2,6-di-3-pentylphenyl)imidazol-2-ylidene](3-chloropyridyl)palladium(II) dichloride; FA: formic acid; AcOH: acetic acid; NaOAc: sodium acetate; NaBH(OAc)3: sodium acetate borohydride; PMB: p-methoxybenzyl; OTf: trifluoromethanesulfonate.

[0293] Example 1: 3-(1-methyl-2-oxo-1,2-dihydro-3H-naphtho[1,2-d]imidazol-3-yl)piperidine-2,6-dione

[0294] Step 1: 1-(Methylamino)-2-naphthoic acid (Compound 1-2)

[0295] Compound 1-1 (0.5 g, 2.67 mmol) and sodium carbonate (424 mg, 4.01 mmol) were dissolved in acetonitrile (10 mL), followed by the addition of iodomethane (341 mg, 2.40 mmol). The reaction mixture was stirred in a 90°C oil bath for 1 h. After completion of the reaction, the reaction mixture was concentrated to obtain the crude product, which was purified by reverse phase column chromatography (eluent: water:acetonitrile = 1:1) to obtain compound 1-2 (100 mg, yield 18%). m / z (ESI): 202 [M+H] + .

[0296] Step 2: 1-Methyl-1,3-dihydro-2H-naphtho[1,2-d]imidazol-2-one (Compound 1-3)

[0297] Under nitrogen, triethylamine (60 mg, 0.59 mmol) was added to a solution of compound 1-2 (40 mg, 0.20 mmol) in N,N-dimethylformamide (2 mL). The mixture was stirred at room temperature for 0.5 h. Diphenylphosphoryl azide (58 mg, 0.24 mmol) was then added, and the mixture was stirred in a 60°C oil bath for 1 h. After the reaction, the reaction mixture was concentrated to obtain the crude product, which was purified by reverse-phase column chromatography (eluent: water:acetonitrile = 1:1) to obtain compound 1-3 (39 mg, 99% yield). m / z (ESI): 199 [M+H] + .

[0298] Step 3: Dimethyl 2-(1-methyl-2-oxo-1,2-dihydro-3H-naphtho[1,2-d]imidazol-3-yl)glutarate (Compound 1-4)

[0299] Under nitrogen, sodium hydride (10 mg, 0.25 mmol) was slowly added to a solution of compound 1-3 (39 mg, 0.19 mmol) in N,N-dimethylformamide (2 mL). The mixture was stirred at room temperature for 15 minutes. Dimethyl 2-bromoglutarate (70 mg, 0.29 mmol) was then added, and the reaction was allowed to proceed at room temperature for 1 hour. After the reaction, water (0.5 mL) was added to the reaction solution to obtain the crude product, which was purified by reverse-phase column chromatography (eluent: water:acetonitrile = 1:1) to obtain compound 1-4 (60 mg, 85% yield). m / z (ESI): 357 [M+H] + .

[0300] Step 4: 2-(1-methyl-2-oxo-1,2-dihydro-3H-naphtho[1,2-d]imidazol-3-yl)pentanedioic acid (Compound 1-5)

[0301] Compound 1-4 (60 mg, 0.16 mmol) was dissolved in tetrahydrofuran (1 mL) and water (1 mL), and lithium hydroxide (12 mg, 0.50 mmol) was added. The mixture was stirred at room temperature for 2 h. After the reaction, the pH was adjusted to approximately 3 with concentrated hydrochloric acid and lyophilized to obtain the crude product, compound 1-5 (60 mg). m / z (ESI): 329 [M+H] + .

[0302] Step 5: 3-(1-methyl-2-oxo-1,2-dihydro-3H-naphtho[1,2-d]imidazol-3-yl)piperidine-2,6-dione (Compound 1)

[0303] Under nitrogen, compound 1-5 (60 mg, 0.18 mmol), 1-hydroxybenzotriazole (54 mg, 0.40 mmol), and triethylamine (55 mg, 0.54 mmol) were dissolved in dichloromethane (2 mL) at 0°C. Trifluoroacetamide (20 mg, 0.18 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (73 mg, 0.38 mmol) were then added and stirred at room temperature for 48 h. After completion of the reaction, the reaction solution was concentrated to obtain the crude product, which was purified by reverse-phase column chromatography (eluent: water:acetonitrile = 1:1) to obtain compound 1 (5 mg, 8% yield). m / z (ESI): 310 [M+H] + . 1 H NMR (600MHz, DMSO-d6) δ11.15(s,1H),8.43(d,J=8.7Hz,1H),7.98(d,J=8.2Hz,1 H),7.70(d,J=8.7Hz,1H),7.57(t,J=7.7Hz,1H),7.52(d,J=8.8Hz,1H),7.44(t,J =7.5Hz,1H),5.54(dd,J=12.9,5.4Hz,1H),3.88(s,3H),2.94(ddd,J=17.5,13.7 ,5.4Hz,1H),2.81(qd,J=13.0,4.3Hz,1H),2.70–2.61(m,1H),2.13–2.06(m,1H).

[0304] 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]diazoheptan-6-yl)acetamido)-N-((3-(2,6-dioxopiperidin-3-yl)-1-methyl-2-oxo-2,3-dihydro-1H-naphtho[1,2-d]imidazol-8-yl)methyl)hexanamide

[0305] Step 1: 8-Bromo-1H-benzo[g]indole-2,3-dione (Compound 2-2)

[0306] Under nitrogen, cesium trifluoroacetate (1.1 g, 4.5 mmol) and cupric chloride dihydrate (3.0 g, 18 mmol) were added to a reaction mixture of compound 2-1 (1.0 g, 4.5 mmol) and glyoxal (1.7 g, 9.0 mmol) dissolved in 2-methyltetrahydrofuran (30 mL). The reaction was stirred at 70°C for 5 hours. After completion of the reaction, the reaction mixture was concentrated to obtain the crude product, which was purified by column chromatography (petroleum ether:ethyl acetate = 1:1) to obtain compound 2-2 (0.6 g, yield: 48%). m / z (ESI): 277 [M+H] + .

[0307] Step 2: 8-Bromo-1-methyl-1H-benzo[g]indole-2,3-dione (Compound 2-3)

[0308] Sodium hydride (0.1 g, 2.6 mmol) was slowly added to a reaction solution containing compound 2-2 (0.6 g, 2.1 mmol) in N,N-dimethylformamide (5 mL). The reaction was stirred at 0°C for 0.5 hours, followed by the addition of iodomethane (0.3 g, 2.3 mmol). The reaction was stirred at room temperature for 1 hour. After the reaction was completed, saturated aqueous ammonium chloride (10 mL) was added, and the mixture was extracted with ethyl acetate. The organic phase was concentrated to obtain crude compound 2-3 (0.6 g), which was used directly in the next reaction. m / z (ESI): 290 [M+H] + .

[0309] Step 3: 7-Bromo-1-(methylamino)-2-naphthoic acid (Compound 2-4)

[0310] Compound 2-3 (0.6 g, 2.0 mmol) was dissolved in a 1 M sodium hydroxide aqueous solution (10 mL) and tetrahydrofuran (5 mL), and hydrogen peroxide (1.1 g, 10 mmol) was slowly added. The reaction was allowed to proceed at room temperature for 1 hour. After completion of the reaction, the pH was adjusted to approximately 3 using hydrochloric acid (1 M), and the mixture was extracted with ethyl acetate. The organic phase was concentrated to obtain crude compound 2-4 (0.4 g), which was used directly in the next reaction. m / z (ESI): 280 [M+H] + .

[0311] Step 4: 8-Bromo-1-methyl-1,3-dihydro-2H-naphtho[1,2-d]imidazol-2-one (Compound 2-5)

[0312] Under nitrogen, triethylamine (0.43 g, 4.2 mmol) was added to a reaction solution containing compound 2-4 (0.4 g, 1.4 mmol) in N,N-dimethylformamide (5 mL). The mixture was stirred at room temperature for 0.5 hours. Diphenylphosphoryl azide (0.41 g, 1.7 mmol) was added, and the mixture was stirred at room temperature for 0.5 hours. The mixture was then stirred at 60°C for 1 hour. After completion of the reaction, the mixture was purified by reverse-phase column chromatography (eluent: water:acetonitrile = 1:1) to afford compound 2-5 (0.2 g, yield: 50%). m / z (ESI): 277 [M+H] + .

[0313] Step 5: 3-(8-Bromo-1-methyl-2-oxo-1,2-dihydro-3H-naphtho[1,2-d]imidazol-3-yl)-1-(4-methoxybenzyl)piperidine-2,6-dione (Compound 2-7)

[0314] Under nitrogen, potassium tert-butoxide (91 mg, 0.8 mmol) was added to a reaction solution containing compound 2-5 (150 mg, 0.5 mmol) in tetrahydrofuran (1 mL). The reaction was stirred at 0°C for 0.5 hours. 1-(4-Methoxybenzyl)-2,6-dicarbonylpiperidin-3-yl trifluoromethanesulfonate (2-6, 0.25 g, 0.65 mmol) was dissolved in tetrahydrofuran (2 mL) and slowly added dropwise to the reaction solution. The reaction was stirred at 0°C for 1 hour. After completion of the reaction, the solution was extracted with ethyl acetate, and the organic phase was concentrated to obtain the crude product, which was purified by reverse-phase column chromatography (eluent: water:acetonitrile = 1:1) to obtain compound 2-7 (150 mg, yield: 54%).

[0315] m / z(ESI):508[M+H] + .

[0316] Step 6: 3-(8-Bromo-1-methyl-2-oxo-1,2-dihydro-3H-naphtho[1,2-d]imidazol-3-yl)piperidine-2,6-dione (Compound 2-8)

[0317] Compound 2-7 (150 mg, 0.29 mmol) was dissolved in methanesulfonic acid (0.5 mL) and toluene (1 mL) and stirred at 120°C for 2 hours. After the reaction, ice water (10 mL) was added and the mixture was extracted with ethyl acetate. The organic phase was concentrated to obtain the crude product, which was then slurried in ethyl acetate to obtain compound 2-8 (100 mg, yield: 87%). m / z (ESI): 388 [M+H] + .

[0318] Step 7: Tert-butyl ((3-(2,6-dioxopiperidin-3-yl)-1-methyl-2-oxo-2,3-dihydro-1H-naphtho[1,2-d]imidazol-8-yl)methyl)carbamate (Compound 2-9)

[0319] Under nitrogen, compound 2-8 (10 mg, 0.025 mmol), potassium [(tert-butoxycarbonylamino)methyl]trifluoroborate (7 mg, 0.03 mmol), palladium acetate (1 mg, 0.005 mmol), n-butyldi(1-adamantyl)phosphine (2 mg, 0.007 mmol), and cesium carbonate (25 mg, 0.077 mmol) were dissolved in 1,4-dioxane (2 mL) and water (0.2 mL) and stirred at 100°C for 1 hour. After completion of the reaction, the mixture was purified by reverse phase column chromatography (eluent: water:acetonitrile = 1:1) to obtain compound 2-9 (10 mg, yield: 88%). m / z (ESI): 439 [M+H] + .

[0320] Step 8: 3-(8-(Aminomethyl)-1-methyl-2-oxo-1,2-dihydro-3H-naphtho[1,2-d]imidazol-3-yl)piperidine-2,6-dione (Compound 2-10)

[0321] Add 1 mL of dioxane hydrochloride solution (4 M) to a solution of compound 2-9 (10 mg, 0.022 mmol) in dichloromethane (2 mL) and stir at room temperature for 5 hours. After the reaction, concentrate to obtain the crude product, compound 2-10 (8 mg), which is used directly in the next reaction. m / z (ESI): 339 [M+H] + .

[0322] Step 9: Tert-butyl (6-(((3-(2,6-dioxopiperidin-3-yl)-1-methyl-2-oxo-2,3-dihydro-1H-naphtho[1,2-d]imidazol-8-yl)methyl)amino)-6-oxohexyl)carbamate (Compound 2-11)

[0323] N,N-Diisopropylethylamine (8 mg, 0.064 mmol) was added to a reaction mixture of compound 2-10 (8 mg, 0.021 mmol), 6-tert-butoxycarbonylaminocaproic acid (5 mg, 0.022 mmol), and 2-(7-azobenzotriazole)-tetramethyluronium hexafluorophosphate (8 mg, 0.023 mmol) dissolved in N,N-dimethylformamide (2 mL). The reaction was stirred at room temperature for 1 h. After completion of the reaction, compound 2-11 was purified by reverse-phase column chromatography (eluent: water:acetonitrile = 1:1) to afford compound 2-11 (7 mg, yield: 59%). m / z (ESI): 552 [M+H] + .

[0324] Step 10: 6-amino-N-((3-(2,6-dioxopiperidin-3-yl)-1-methyl-2-oxo-2,3-dihydro-1H-naphtho[1,2-d]imidazol-8-yl)methyl)hexanamide (Compound 2-12)

[0325] Add 1 mL of dioxane hydrochloride solution (4 M) to a solution of compound 2-11 (7 mg, 0.012 mmol) in dichloromethane (2 mL) and stir at room temperature for 2 hours. After the reaction, concentrate to obtain the crude product, compound 2-12 (6 mg), which is used directly in the next reaction. m / z (ESI): 452 [M+H] + .

[0326] Step 11: 6-(2-((S)-4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazoheptan-6-yl)acetamido)-N-((3-(2,6-dioxopiperidin-3-yl)-1-methyl-2-oxo-2,3-dihydro-1H-naphtho[1,2-d]imidazol-8-yl)methyl)hexanamide (Compound 2)

[0327] Compound 2-12 (6 mg, 0.012 mmol), (S)-2-[2,3,9-trimethyl-4-(4-chlorophenyl)-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl]acetic acid (4 mg, 0.011 mmol), and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (4 mg, 0.012 mmol) were dissolved in N,N-dimethylformamide (2 mL). N,N-Diisopropylethylamine (4 mg, 0.033 mmol) was added and the mixture was reacted at 25°C for 1 h. After completion of the reaction, compound 2 was purified by reverse phase column chromatography (eluent: water:acetonitrile = 1:1) to obtain compound 2 (4 mg, 42% yield). m / z (ESI): 834 [M+H] + .

[0328] 1H NMR (400MHz, DMSO-d6) δ11.15(s,1H),8.49–8.40(m,2H),8.24(s,1H),8.19(t,J=5.6Hz,1H),7.92(d,J=8.6Hz,1H),7.64(d,J =8.7Hz,1H),7.51–7.47(m,2H),7.41(d,J=8.4Hz,2H),7.31(dd,J=8.5,1.5Hz,1H),5.52(dd,J=12.7,5.4Hz,1H),4.53–4.46(m ,3H),3.85(s,3H),3.27–3.18(m,3H),3.17–3.02(m,2H),2.67(p,J=1.8Hz,1H),2.59(s,3H),2.40(s,3H),2.33(q,J=1.9Hz,1 H),2.19(t,J=7.5Hz,2H),2.12–2.05(m,1H),1.61(s,3H),1.57(d,J=7.6Hz,2H),1.45(q,J=7.2Hz,2H),1.33(q,J=7.9Hz,2H).

[0329] 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]diazoheptan-6-yl)acetamido)-N-((3-(2,6-dioxopiperidin-3-yl)-1-methyl-2-oxo-2,3-dihydro-1H-naphtho[1,2-d]imidazol-6-yl)methyl)hexanamide

[0330] The starting material compound 2-1 in the synthetic route of Example 2 was replaced with 5-bromo-1-naphthylamine, and the synthetic route of compound 2 was referred to obtain compound 3. m / z (ESI): 834 [M+H] + .

[0331] 1H NMR (400MHz, DMSO-d6) δ11.14(s,1H),8.41–8.31(m,2H),8.18(t,J=5.7Hz,1H),7.81(d,J=9.0Hz,1H),7.57–7.46(m, 4H),7.44–7.39(m,2H),7.36(d,J=7.1Hz,1H),5.59–5.49(m,1H),4.73(d,J=5.6Hz,2H),4.53–4.47(m,1H),3.86(s,3H ),3.28–3.15(m,2H),3.08(p,J=6.9Hz,2H),2.92–2.78(m,1H),2.64(d,J=16.3Hz,2H),2.58(s,3H),2.40(s,3H),2.16 (t,J=7.4Hz,2H),2.10–2.03(m,1H),1.61(s,3H),1.57(t,J=7.5Hz,2H),1.43(q,J=7.3Hz,2H),1.30(q,J=8.0Hz,2H).

[0332] Example 4: 3-(8-(4-((4-(((S)-2-(2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrano-azino[1',2':4,5]pyrano-azino[2,3-c]pyridazin-8-yl)methyl)piperidin-1-yl)methyl)piperidin-1-yl)-1-methyl-2-carbonyl-1,2-dihydro-3H-naphtho[1,2-d]imidazol-3-yl)piperidine-2,6-dione

[0333] Step 1: 3-(8-(4-(dimethoxymethyl)piperidin-1-yl)-1-methyl-2-oxo-1,2-dihydro-3H-naphtho[1,2-d]imidazol-3-yl)piperidine-2,6-dione (Compound 4-1)

[0334] Compound 2-8 (160 mg, 412.14 μmol) and 4-(dimethoxymethyl)piperidine (98.44 mg, 618.21 μmol) were dissolved in dioxane (5 mL). [1,3-Bis(2,6-di-3-pentylphenyl)imidazol-2-ylidene](3-chloropyridyl)dichloropalladium(II) (17.73 mg, 20.61 μmol) and cesium carbonate (268.57 mg, 824.29 μmol) were added. The reaction mixture was stirred at 100°C under nitrogen for 2 hours. LCMS indicated the reaction was complete. The reaction mixture was diluted with water (5 mL) and extracted with ethyl acetate (20 × 3 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The concentrate was purified by column chromatography (tetrahydrofuran:petroleum ether = 1:2) to afford compound 4-1 (97 mg). MS m / z(ESI):467.3[M+H] + .

[0335] Step 2: 1-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-2-oxo-2,3-dihydro-1H-naphtho[1,2-d]imidazol-8-yl)piperidine-4-carbaldehyde (Compound 4-2)

[0336] Compound 4-1 (87 mg, 186.48 μmol) was dissolved in formic acid (2 mL), and the reaction mixture was stirred at 60°C for 2 hours. LCMS showed that the reaction was complete. The reaction mixture was concentrated under reduced pressure to give compound 4-2 (78 mg), which was used directly in the next reaction. MS m / z (ESI): 421.3 [M+H] + .

[0337] Step 3: 3-(8-(4-((4-(((S)-2-(2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrano-azino[1',2':4,5]pyrano-azino[2,3-c]pyridazin-8-yl)methyl)piperidin-1-yl)methyl)piperidin-1-yl)-1-methyl-2-carbonyl-1,2-dihydro-3H-naphtho[1,2-d]imidazol-3-yl)piperidine-2,6-dione (Compound 4)

[0338] Compound 4-3 (15 mg, 35.98 μmol) and compound 4-2 (18.46 mg, 39.57 μmol) were dissolved in N,N-dimethylformamide (1 mL). Acetic acid (6.48 mg, 107.93 μmol), sodium acetate (8.85 mg, 107.93 μmol), and sodium acetate borohydride (22.87 mg, 107.93 μmol) were added. The reaction mixture was incubated at 25°C for 1 hour. LCMS confirmed the reaction was complete. The reaction mixture was quenched with water (0.1 mL) and concentrated to dryness under reduced pressure. Purification by HPLC (Phenomenex Gemini NX, 5 μm silica, 30 mm diameter, 150 mm length) using a mixture of water (containing 0.05% ammonia) and acetonitrile (1:1) as the eluent afforded compound 4 (1.67 mg).

[0339] MS m / z(ESI):785.5[M+H] + .

[0340] 1 H NMR (400MHz, DMSO-d6) δ = 14.75 (br s, 1H), 11.12 (br s, 1H), 7.91 (br d,J=8.1Hz,1H),7.77(d,J=9.2Hz,1H),7.55(s,1H),7.49(d,J=8.1Hz,1H),7.34(br d,J=2.9Hz,1H),7.28-7.18(m,4H),6.87-6.81(m,2H),5.47(dd,J=5.0,12.2Hz,1H),4.04(br d,J=11.0Hz,2H),3.87(s,5H),3.52-3.39(m,7H),3.23-3.11(m,1H),3.02-2 .95(m,2H),2.91-2.74(m,5H),2.23-2.02(m,5H),1.92-1.79(m,4H),1.70(br t, J=10.7Hz, 3H), 1.26 (br d, J=10.6Hz, 2H), 1.14 (br d, J=10.8Hz, 2H).

[0341] Example 5: 1-(3-chloro-4-methylphenyl)-3-((3-(2,6-dioxopiperidin-3-yl)-1-methyl-2-oxo-2,3-dihydro-1H-naphtho[1,2-d]imidazol-8-yl)methyl)urea

[0342] Step 1: 4-nitrophenyl (3-chloro-4-methylphenyl)carbamate (Compound 5-3)

[0343] Compound 5-1 (100 mg, 0.71 mmol) was dissolved in dichloromethane (3 mL), and triethylamine (215 mg, 2.13 mmol) was added. Compound 5-2 (171 mg, 0.85 mmol) was added under ice-cooling. The reaction mixture was warmed to room temperature and stirred for 1 h. After the reaction, the reaction mixture was concentrated and extracted with ethyl acetate and water. The organic phase was concentrated to obtain the crude product, compound 5-3 (134 mg, 62% yield). m / z (ESI): 308 [M+H] + .

[0344] Step 2: 1-(3-chloro-4-methylphenyl)-3-((3-(2,6-dioxopiperidin-3-yl)-1-methyl-2-oxo-2,3-dihydro-1H-naphtho[1,2-d]imidazol-8-yl)methyl)urea (Compound 5)

[0345] Compound 2-10 (132 mg, 0.39 mmol), triphosgene (97 mg, 0.96 mmol), and N,N-dimethylformamide (1 mL) were added to a flask and the atmosphere was replaced with nitrogen by vacuum. A solution of compound 5-3 (100 mg, 0.32 mmol) in N,N-dimethylformamide was added to the flask under ice-cooling and stirred at room temperature for 1 h. After the reaction, the reaction mixture was placed in an ice-cooling bath at 0°C with stirring and then quenched by slow addition of water. The mixture was extracted with ethyl acetate and water, and the organic phase was concentrated to obtain the crude product. This was purified by reverse-phase column chromatography (eluent: water:acetonitrile = 1:1) to obtain compound 5 (142 mg, 88% yield). m / z (ESI): 506 [M+H] + .

[0346] 1 H NMR (400MHz, DMSO-d6) δ11.13(s,1H),8.83(s,1H),8.30(s,1H),7.94(d,J=8.6Hz, 1H),7.72–7.66(m,2H),7.46(d,J=8.8Hz,1H),7.38(d,J=8.5Hz,1H),7.25–7.15(m ,2H),6.89(t,J=6.0Hz,1H),5.52(dd,J=12.6,5.3Hz,1H),4.51(d,J=5.9Hz,2H),3 .86(s,3H),3.00–2.73(m,2H),2.69-2.65(m,1H),2.23(s,3H),2.11-2.05(m,1H).

[0347] Example 6: 1-(3-chloro-4-methylphenyl)-3-((3-(2,6-dioxopiperidin-3-yl)-1-methyl-2-oxo-2,3-dihydro-1H-naphtho[1,2-d]imidazol-7-yl)methyl)urea

[0348] Step 1: 3-(7-(Aminomethyl)-1-methyl-2-carbonyl-1,2-dihydro-3H-naphtho[1,2-d]imidazol-3-yl)piperidine-2,6-dione (Compound 6-1)

[0349] The starting material compound 2-1 in the synthetic route of Example 2 was replaced with 6-bromo-1-naphthylamine, and the synthetic route of compound 2-10 was referred to obtain compound 6-1. m / z (ESI): 339 [M+H] + .

[0350] Step 2: 1-(3-chloro-4-methylphenyl)-3-((3-(2,6-dioxopiperidin-3-yl)-1-methyl-2-oxo-2,3-dihydro-1H-naphthyl[1,2-d]imidazol-7-yl)methyl)urea (Compound 6)

[0351] Referring to the last step of the synthetic route of Example 5, compound 2-10 was replaced with compound 6-1 to synthesize compound 6 (128 mg, yield 79%). m / z (ESI): 506 [M+H] + .

[0352] 1 H NMR (400MHz, DMSO-d6) δ11.12(s,1H),8.72(s,1H),8.39(d,J=8.9Hz,1H),7.8 3(s,1H),7.70–7.62(m,2H),7.55–7.46(m,2H),7.22–7.13(m,2H),6.78(t,J= 6.0Hz, 1H), 5.51 (dd, J=12.6, 5.4Hz, 1H), 4.45 (d, J=6.0Hz, 2H), 3.85 (s, 3H), 2.91(s,1H),2.86–2.72(m,1H),2.67(s,1H),2.23(s,3H),2.12-2.06(m,1H).

[0353] Example 7: 1-(3-chloro-4-methylphenyl)-3-((3-(2,6-dioxopiperidin-3-yl)-1-methyl-2-oxo-2,3-dihydro-1H-naphtho[1,2-d]imidazol-6-yl)methyl)urea

[0354] Step 1: 3-(6-(Aminomethyl)-1-methyl-2-carbonyl-1,2-dihydro-3H-naphtho[1,2-d]imidazol-3-yl)piperidine-2,6-dione (Compound 7-1)

[0355] The starting material compound 2-1 in the synthetic route of Example 2 was replaced with 5-bromo-1-naphthylamine, and the synthetic route of compound 2-10 was referred to obtain compound 7-1. m / z (ESI): 339 [M+H] + .

[0356] Step 2: 1-(3-chloro-4-methylphenyl)-3-((3-(2,6-dioxopiperidin-3-yl)-1-methyl-2-oxo-2,3-dihydro-1H-naphthyl[1,2-d]imidazol-6-yl)methyl)urea (Compound 7)

[0357] Referring to the last step of the synthetic route of Example 5, compound 2-10 was replaced with compound 7-1 to synthesize compound 7 (128 mg, yield 79%). m / z (ESI): 506 [M+H] + .

[0358] 1 H NMR (400MHz, DMSO-d6) δ11.12(s,1H),8.79(s,1H),8.39(d,J=8.7Hz,1H),7.89(d,J=9.0Hz, 1H),7.68(d,J=2.2Hz,1H),7.63–7.50(m,2H),7.43(d,J=7.0Hz,1H),7.17(d,J=8.4Hz,1H),7 .12(dd,J=8.3,2.2Hz,1H),6.85(t,J=5.8Hz,1H),5.54(dd,J=12.7,5.4Hz,1H),4.76(d,J=5. 9Hz,2H),3.87(s,3H),3.01–2.74(m,2H),2.71–2.62(m,1H),2.23(s,3H),2.14–2.03(m,1H).

[0359] Comparative Example 1: 3-(1-methyl-2-oxo-1,2,6,7,8,9-hexahydro-3H-imidazo[4,5-h]isoquinolin-3-yl)piperidine-2,6-dione

[0360] Step 1: tert-Butyl 7-amino-8-bromo-3,4-dihydroisoquinoline-2(1H)-carboxylate (Compound 8-2)

[0361] Compound 8-1 (1 g, 4 mmol) was dissolved in tetrahydrofuran (5 mL). N-bromosuccinimide (778 mg, 4.4 mmol) was added portionwise under ice-cooling. The reaction mixture was stirred at room temperature for 1 hour. After completion of the reaction, the reaction mixture was concentrated and extracted with ethyl acetate and water. The organic phase was concentrated to obtain the crude product, which was purified by reverse-phase column chromatography (eluent: water:acetonitrile = 1:1) to obtain compound 8-2 (1.22 g, yield 91%). m / z (ESI): 327 [M+H] + .

[0362] Step 2: tert-Butyl 7-amino-8-methylamino-3,4-dihydroisoquinoline-2(1H)-carboxylate (Compound 8-3)

[0363] Compound 8-2 (1 g, 3.05 mmol), (methanesulfonic acid {biscyclohexyl (3-isopropoxy-2', 4', 6'-triisopropyl-[1,1'-biphenyl]-2-yl) phosphine} (2'-methylamino-1,1'-biphenyl-2-yl) palladium (280 mg, 0.305 mmol), dicyclohexyl (3-ethylpropoxy-2', 4', 6'-triisopropyl-[1,1'-biphenyl]-2-yl) phosphine (325 mg, 0.610 mmol), potassium tert-butoxide (6.83 g, 61 mmol), Methylamine hydrochloride (2.05 g, 30.5 mmol) was placed in a flask and the atmosphere was replaced with nitrogen by vacuum. 1,4-Dioxane (100 mL) was then added and the reaction mixture was stirred in a 100°C oil bath for 5 hours. After the reaction, the reaction mixture was stirred in a 0°C ice bath and cooled. Water was slowly added to quench the mixture and extracted with ethyl acetate and water. The organic phase was concentrated to obtain the crude product, which was purified by reverse phase column chromatography (eluent: water:acetonitrile = 1:1) to obtain compound 8-3 (524 mg, yield 61%). m / z (ESI): 278 [M+H] + .

[0364] Step 3: tert-Butyl 1-methyl-2-oxo-1,2,3,6,7,9-hexahydro-8H-imidazo[4,5-H]isoquinoline-8-carboxylate (Compound 8-4)

[0365] Compound 8-3 (500 mg, 1.79 mmol) and triethylamine (268 mg, 2.68 mmol) were dissolved in dichloromethane (5 mL). Triphosgene (264 mg, 0.89 mmol) was dissolved in dichloromethane (2 mL) and slowly added to the reaction mixture under ice-cooling. Stir at room temperature for 1 hour. After the reaction, the reaction mixture was concentrated and extracted with ethyl acetate and water. The organic phase was concentrated to obtain the crude product, which was purified by reverse-phase column chromatography (eluent: water:acetonitrile = 1:1) to obtain compound 8-4 (293 mg, yield 54%). m / z (ESI): 304 [M+H] + .

[0366] Step 4: tert-Butyl 3-(1-(4-methoxybenzyl)-2,6-dioxopiperidin-3-yl)-1-methyl-2-oxo-1,2,3,6,7,9-hexahydro-8H-imidazo[4,5-h]isoquinoline-8-carboxylate (Compound 8-5)

[0367] Compound 8-4 (50 mg, 0.16 mmol) and potassium tert-butoxide (53 mg, 0.48 mmol) were dissolved in tetrahydrofuran (2 mL) and stirred under a dry ice bath for 10 minutes. Compound 2-6 (91 mg, 0.24 mmol) was dissolved in tetrahydrofuran (1 mL) and slowly added to the reaction mixture, followed by stirring for 1 hour. After completion of the reaction, ice water was added to quench the reaction, followed by extraction with ethyl acetate and water. The organic phase was concentrated to obtain the crude product, which was purified by reverse phase column chromatography (eluent: water:acetonitrile = 1:1) to obtain compound 8-5 (51 mg, 60% yield). m / z (ESI): 535 [M+H] + .

[0368] Step 5: 3-(1-methyl-2-oxo-1,2,6,7,8,9-hexahydro-3H-imidazo[4,5-h]isoquinolin-3-yl)piperidine-2,6-dione (Compound 8)

[0369] Compound 8-5 (50 mg, 0.093 mmol) was dissolved in trifluoroacetic acid (2 mL), and trifluoromethanesulfonic acid (0.04 mL) was added. The mixture was stirred at 70°C for 2 hours. After the reaction, the mixture was purified by reverse phase column chromatography (eluent: water:acetonitrile = 1:1) to obtain compound 8 (18 mg, yield 60%). m / z (ESI): 315 [M+H] + .

[0370] 1 H NMR (400MHz, DMSO-d6) δ11.08(s,1H),7.08(d,J=8.2Hz,1H),6.92(d,J=8.2Hz,1H),5.36(dd,J=12.6,5.4Hz,1H),4.77(t,J=4.7Hz,2H),3.56(s, 4H),3.38–3.31(m,2H),3.03(t,J=6.2Hz,2H),2.95–2.84(m,1H),2.72( td,J=12.9,4.3Hz,1H),2.63(dt,J=16.4,2.8Hz,1H),2.04–1.96(m,1H).

[0371] Biological activity and related properties test examples

[0372] Test Example 1: Cereblon binding experiment

[0373] 1. Experimental instruments and materials

[0374] 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.

[0375] Other reagents and consumables required for the experiment are as follows:

[0376] 2. Experimental steps

[0377] 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 addition instrument (Echo). 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, and after thorough mixing, 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.

[0378] 3. Data Analysis

[0379] Calculate the ratio of the acceptor and donor emission signals for each well: Ratio = 665 nm signal / 620 nm signal Coefficient of variation (%) = standard deviation / average ratio Cereblon binding inhibition rate (%) = 100% - 100% x (Sample-L) / (HL)

[0380] Wherein: Sample = Ave (test sample group); H = Ave (DMSO-treated group); L = Ave (200 μM lenalidomide standard-treated group).

[0381] 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 : Y=Bottom+(Top-Bottom) / (1+10^((LogIC 50 -X)×HillSlope))

[0382] in:

[0383] X: Log compound concentration;

[0384] Y: inhibition rate (%);

[0385] Bottom is the minimum inhibition percentage;

[0386] Top is the maximum inhibition percentage;

[0387] HillSlope is the slope coefficient of the curve.

[0388] 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.

[0389] Table 1

[0390] Test Example 2: Anti-proliferative activity test on MV-4-11 cells

[0391] 1. Experimental instruments and materials

[0392] Instruments and Equipment

[0393] Experimental reagents and consumables

[0394] 2. Experimental steps

[0395] (1) Cell plating

[0396] 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 + 10% FBS) to neutralize the trypsin, blow 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 cell suspension and add it to a 96-well low-adsorption 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.

[0397] (2) Cell dosing

[0398] The disclosed compounds were dissolved in DMSO, and the stock concentration of the stock solution was 10 mM. Before administration, the compound was diluted 5-fold using DMSO, for a total of 8 gradient working solutions. Take 2 μL of each working solution of different concentrations, add it to a dilution plate with 198 μL of culture medium, and mix well 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 concentrations of each gradient compound are 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.

[0399] (3) Cell Viability Assay

[0400] 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.

[0401] 3. Data Analysis

[0402] The antiproliferative activity of the disclosed compounds on MV-4-11 cells was determined by the above assay, and the cell growth inhibition rate of each sample well was calculated based on the raw data. Inhibition rate (%) = 100% × (1 - sample reading / reference average reading)

[0403] 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 : Y=Bottom+(Top-Bottom) / (1+10^((LogIC 50 -X)×HillSlope))

[0404] in:

[0405] X: Log compound concentration;

[0406] Y: inhibition rate (%);

[0407] Bottom is the minimum inhibition percentage;

[0408] Top is the maximum inhibition percentage;

[0409] HillSlope is the slope coefficient of the curve.

[0410] The anti-proliferative activities of the disclosed compounds on MV-4-11 cells are shown in Table 2.

[0411] Table 2 Antiproliferative activity of the disclosed compounds on MV-4-11 cells

[0412] Test Example 3: BRD4 protein degradation activity assay in MV-4-11 cells

[0413] 1. Experimental instruments and materials

[0414] Instruments and Equipment

[0415] Experimental reagents and consumables

[0416] 2. Experimental steps

[0417] (1) Cell plating

[0418] Remove the culture medium from MV-4-11 (CBP60522, Kebai), rinse once with PBS, and then digest with trypsin (0.25%) for 5 minutes. After digestion, add 10 mL of complete culture medium (IMDM medium containing 10% FBS) to neutralize the trypsin. Pipet the cells, collect them, centrifuge at 1000 rpm for 5 minutes, count the cells, and adjust the cell density to 500,000 cells / mL. Take 2 mL of the cell suspension and add it to a 12-well plate, then culture in a cell culture incubator overnight.

[0419] (2) Cell dosing

[0420] The disclosed compounds were dissolved in DMSO to a stock concentration of 10 mM. The stock solution was serially diluted (4-fold) to eight concentration points. A negative control was prepared using 0.1% DMSO. The compound and cell suspension were mixed and incubated at 37°C, 5% CO₂ for 6 hours.

[0421] (3) Western Blot

[0422] Six hours after treatment, the supernatant was discarded, and the cells were washed with 1000 μL of pre-chilled PBS. Then, 100 μL of RIPA lysis buffer (25 mM Tris-HCl, pH 7.5, 150 mM NaCl, 1% NP-40, 1 mM EDTA, pH 8.0, 1 mM PMSF, 1 mM Na₃VO₄, and 1x Protease Inhibitor Cocktail-P2714, Sigma) was added and lysed on ice for 10 min. Cell lysates were collected and centrifuged at 12,000 rpm at 4°C for 30 min. Protein concentration was determined using a Pierce BCA kit for protein quantification. An appropriate amount of 5x SDS-PAGE protein loading buffer was added to the collected protein samples, and the samples were heated in a metal bath at 100°C for 10 min to fully denature the proteins. Protein samples were loaded into the wells of an SDS-PAGE gel and electrophoresed at 120 V for 60 min. After electrophoresis, the gel was transferred to a PVDF membrane using a Bio-bad transfer apparatus. Bands were cut according to the size of the target protein and blocked in 5% BSA (5 g BSA dissolved in 100 mL TBST) for 1 hour at room temperature. Antibodies against BRD4 (1:3000) and β-actin (1:3000) were then added, respectively, and incubated overnight at 4°C. The following day, the antibodies were recovered, and the bands were washed three times with PBST (PBS containing 0.1% Tween-20), each for 10 minutes. After washing, diluted Goat Anti-Rabbit IgG H&L (1:3000) was added and incubated at room temperature for 1 hour. The bands were washed three times with PBST (PBS containing 0.1% Tween-20). Proteins were detected using SuperSignal West Atto ultrasensitive ECL luminescent solution.

[0423] 3. Data Analysis

[0424] The degradation activity of the disclosed compounds on BRD4 protein in MV-4-11 cells was determined using the above assay. Image J software was used to read the grayscale values ​​of the target sample bands, and the protein degradation rate for each sample well was calculated based on the raw data. Degradation rate (%) = 100% × (1 - sample reading / DMSO reference reading)

[0425] in:

[0426] 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 : Y=Bottom+(Top-Bottom) / (1+10^((LogDC 50-X)×HillSlope))

[0427] Where: X: Log compound concentration;

[0428] Y: degradation rate (%);

[0429] Bottom is the minimum degradation percentage;

[0430] Top is the maximum degradation percentage;

[0431] HillSlope is the slope coefficient of the curve.

[0432] DC measured by the disclosed compounds 50 The values ​​are shown in Table 3.

[0433] Table 3 BRD4 protein degradation activity of the disclosed compounds

[0434] Test Example 4: Detecting the BRM and BRG1 protein degradation activity of compounds using HiBiT detection technology

[0435] 1. Cell line construction:

[0436] HiBiT detection technology was used to detect the effect of compounds on the degradation of BRM and BRG1 proteins. The HiBiT tag was inserted after the start codon or before the stop codon of BRM and BRG1 proteins. When the compound degraded BRM or BRG1 protein, the degradation of BRM and BRG1 protein could be quantified by detecting the expression level of the HiBiT tag. According to the insertion site of HiBiT, sgRNA and donor DNA of BRM and BRG1 were designed; Cas9 transfection reagent (TrueCut TM Cas9Protein v2, A36498, Invitrogen; Lipofectamine TM CRISPRMAX TM Cas9 transfection reagent, CMAX00003, Invitrogen; Opti-MEM TMI Reduced Serum Medium, 31985070, Thermofisher). The required amounts of various reagents, sgRNA, and donor DNA were calculated according to the instructions for the Cas9 transfection reagent. SW1573 cells were transfected according to the Cas9 transfection protocol, and the culture medium was changed to normal culture medium 24 hours later. Culture was continued until 3 days after transfection, and each group of cells was expanded. The expression level of the HiBiT tag in the pool was detected using the Nano Glo HiBiT Lytic Detection System (N3050, Promega). The cell pool with high HiBiT tag expression was seeded in a 96-well plate as a monoclonal clone, and the expression level of the HiBiT tag in the monoclonal clone was detected using the Nano Glo HiBiT Lytic Detection System (N3050, Promega). If the fluorescence value of the HiBiT tag amplified from the monoclonal cells is high at this time, it indicates that this group of cells may have successfully linked to the HiBiT tag. These monoclonal cells were amplified and sequenced to confirm that the HiBiT sequence was successfully connected and homozygous, and then used for subsequent degradation experiments.

[0437] 2. Cell Seeding and Compound Administration:

[0438] SW1573HiBiT knock-in cells constructed using the above method were digested and blown off from the cell culture flask, resuspended in culture medium (DMEM medium (Thermo Fisher, Catalog No. 11995073) containing 10% FBS (Thermo Fisher, Catalog No. 10099141C) and 1% Penicillin-Streptomycin Solution (Thermo Fisher, Catalog No. 15140-122)), and the cell concentration was adjusted (SW1573HiBiT knock-in cells, 9000 cells / well) and seeded in a 384-well plate and cultured overnight at 37°C, 5% CO2. The test compound was prepared into a 10 mM stock solution in DMSO, and a small amount was diluted to 1 mM in DMSO for later use. Prepare 1 mM compound solutions and DMSO. Using Echo 650 Series Acoustic Liquid Handlers (Beckman, Model Echo 650), serially dilute the 1 mM test compound solution three-fold over 10 concentration points. Transfer 30 nL of the compound to a 384-well cell culture plate containing culture medium and dilute 1000-fold to obtain final compound concentrations of 1000, 333.33, 111.11, 37.04, 12.35, 4.12, 1.37, 0.46, 0.15, and 0.05 nM, respectively. Incubate the 384-well cell culture plate with compound at 37°C, 5% CO2 for 16-18 hours.

[0439] 3. Protein degradation detection:

[0440] 15 μL of reaction solution (Nano Glo HiBiT Lytic Detection System (N3050, Promega) configured according to the protocol) was added to each well of a 384-well plate, incubated at room temperature for 10 min, and scanned and analyzed using an Envision multi-function microplate reader (purchased from PerkinElmer).

[0441] 4. Degradation of DC 50 calculate

[0442] EXCEL XLfit5.4.0 was used to calculate the protein degradation rate at each concentration. Each concentration point had 2 replicates to generate a protein degradation curve and calculate DC. 50 and D maxProtein degradation rate (%) = (High control - corresponding well reading) / (High control - Low control) * 100% High control = 0.1% DMSO, defined as 0% degradation Low control = PBS (no cells), defined as 100% degradation

[0443] The degradation curve is generated by the degradation rate of 10 concentration points, and the degradation DC is calculated 50 and D max value.

[0444] Table 4

[0445] The test results showed that compound 4 has the activity of degrading BRM and BRG1 of SW1573 cells.

Claims

1. A compound represented by formula (I) or a pharmaceutically acceptable salt thereof: CLM-L-PTM (I) in, The CLM structure is as follows: is selected from a single bond or a double bond; Z is selected from C(R 3 )2、NR 3 or O; Ring B 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; 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 、R 5 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 3 Independently selected from H, 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; or R 1 、R 3 The atoms to which it is attached together form a C5-C8 saturated or partially saturated carbocyclic ring, a 5-6 membered heteroaromatic ring or a 5-8 membered heterocyclic ring, wherein the C5-C8 saturated or partially saturated carbocyclic ring, a 5-6 membered heteroaromatic ring or a 5-8 membered heterocyclic ring is optionally replaced by R 5 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 binding moiety to a target protein.

2. The compound of formula (I) or a pharmaceutically acceptable salt according to claim 1, wherein Z is selected from NR 3 or O.

3. The compound of formula (I) or a pharmaceutically acceptable salt according to claim 1 or 2, wherein: Ring B 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 carbocyclic ring; Alternatively, ring B 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: 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 carbocyclic ring; Alternatively, ring C is selected from a 5-6 membered heteroaromatic ring or a benzene ring.

5. The compound of formula (I) or a pharmaceutically acceptable salt according to any one of claims 1 to 4, wherein: CLM is a structure shown in formula (II): Wherein, X1 and X2 are independently selected from N or CH, and the CH is optionally replaced by R 2 Substitution; Ring C, Z, R 1 、R 2 、R 4 , m, n are 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: CLM is selected from the structures represented by formula (II-1a) and (II-1b): Wherein, X1 and X2 are independently 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 replace; Selected from a single bond or a double bond; Q1, Q2, Q3 are independently selected from O, S, NH, CH2, N or CH, wherein NH, CH2, CH are optionally replaced by R 1 Substitution; Z, R 1 、R 2 、R 4 , n as defined in any one of claims 1-5.

7. The compound of formula (I) or a pharmaceutically acceptable salt according to any one of claims 1 to 6, 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.

8. The compound of formula (I) or a pharmaceutically acceptable salt according to any one of claims 1 to 7, wherein: R 5 Independently selected from halogen, =O, 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.

9. The compound of formula (I) or a pharmaceutically acceptable salt according to any one of claims 1 to 8, wherein: R 3 Independently selected from H, 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.

10. The compound of formula (I) or a pharmaceutically acceptable salt according to any one of claims 1 to 9, wherein: R 1 、R 3 The atoms to which it is attached together form a 5-, 6-, 7- or 8-membered heterocyclic ring, wherein the 5-, 6-, 7- or 8-membered heterocyclic ring is optionally replaced by R 5 replace.

11. The compound of formula (I) or a pharmaceutically acceptable salt according to any one of claims 1 to 10, 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.

12. The compound of formula (I) or a pharmaceutically acceptable salt according to any one of claims 1 to 11, 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.

13. The compound of formula (I) or a pharmaceutically acceptable salt according to any one of claims 1 to 12, wherein: m and p are independently selected from 0, 1, 2, 3 or 4; Alternatively, m and p are independently selected from 0, 1 or 2.

14. The compound of formula (I) or a pharmaceutically acceptable salt according to any one of claims 1 to 13, wherein: n is selected from 0 or 1; Alternatively, n is selected from 0.

15. The compound of formula (I) or a pharmaceutically acceptable salt according to any one of claims 1 to 14, 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, 4-9 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; 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; 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.

16. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 15, wherein: L is selected from Among them, M1, M2, R 10 、R 11 、R 12 、R 13 、R 14 As defined in claim 15.

17. The compound of formula (I) or pharmaceutically acceptable salt according to claim 15 or 16, 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 、R 21 and k as defined in claim 15.

18. The compound of formula (I) or a pharmaceutically acceptable salt according to any one of claims 15 to 17, wherein: L is selected from Among them, M1, M2, R 10 、R 11 、R 12 As defined in claim 15.

19. The compound of formula (I) or a pharmaceutically acceptable salt according to any one of claims 15 to 18, wherein: M1, M2 are independently selected from a bond, -NR 20 -, -C(O)-, -C(O)O-, -O-, -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 Substitute, where R 20 、R 21 As defined in claim 15.

20. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 15, 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(O)NR 20 -、-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 Substitution, where k, R 20 、R 21 As defined in claim 15.

21. The compound of formula (I) or a pharmaceutically acceptable salt according to any one of claims 1 to 20, wherein: The PTM is selected from the binding portion of the following target proteins: ALK, AR, BET1, BRAF, BRCA2, BRD4, BRD9, BTK, BRM, 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; Preferably, the PTM is selected from the binding portion of the following targeting proteins: BRM, BRD4 or STAT3; More preferably, the PTM is selected from the group consisting of the binding moieties of the following targeting proteins: BRM or BRD4.

22. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, selected from:

23. A pharmaceutical composition comprising the compound of formula (I) according to any one of claims 1 to 22 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

24. Use of the compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 22, or the pharmaceutical composition according to claim 23, in the preparation of a medicament for preventing or treating abnormal cell proliferation diseases.

25. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 22, or the pharmaceutical composition according to claim 23, for preventing or treating abnormal cell proliferation diseases.

26. A method for treating a mammalian abnormal cell proliferation disease, comprising administering to a mammal in need of such treatment a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 22, or the pharmaceutical composition according to claim 23.

27. The use according to claim 24, the compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof according to claim 25, or the method according to claim 26, wherein the abnormal cell proliferation disease is selected from cancer.

28. A compound represented by formula (III) or a pharmaceutically acceptable salt thereof: in, X1 and X2 are independently selected from N or CH, wherein CH is optionally replaced by R 2 Substitution; Z, R 1 、R 2 、R 4 , m, n, L are as defined in any one of claims 1-2 or 7-20; Ring C is selected from a 5-6 membered heteroaromatic ring or a benzene ring; Provided that the following compounds or pharmaceutically acceptable salts thereof are not included:

29. The compound of formula (III) according to claim 28 or a pharmaceutically acceptable salt thereof is selected from the compound of formula (III-1a) or formula (III-1b) or a pharmaceutically acceptable salt thereof: in, X1 and X2 are independently selected from N or CH, wherein 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 replace; Selected from double bonds; Q1, Q2, Q3 are independently selected from O, S, NH, CH2, N or CH, wherein NH, CH2, CH are optionally replaced by R 1 Substitution; Z, R 1 、R 2 、R 4 , n, L as defined in any one of claims 1-2 or 7-20; Provided that the following compounds or pharmaceutically acceptable salts thereof are not included:

30. A compound represented by formula (IV) or a pharmaceutically acceptable salt thereof: in, X1 and X2 are independently selected from N or CH, wherein CH is optionally replaced by R 2 Substitution; Z, R 1 、R 2 、R 4 , m, n As defined in any one of claims 1 to 2 or 7 to 20; Ring C is selected from a 5-6 membered heteroaromatic ring or a benzene ring; Provided that the following compounds or pharmaceutically acceptable salts thereof are not included:

31. The compound of formula (IV) according to claim 30 or a pharmaceutically acceptable salt thereof is selected from the compound of formula (IV-1a) or formula (IV-1b) or a pharmaceutically acceptable salt thereof: in, X1 and X2 are independently selected from N or CH, wherein 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 replace; Selected from double bonds; Q1, Q2, Q3 are independently selected from O, S, NH, CH2, N or CH, wherein NH, CH2, CH are optionally replaced by R 1 Substitution; Z, R 1 、R 2 、R 4 , n as defined in any one of claims 1-2 or 7-20; Provided that the following compounds or pharmaceutically acceptable salts thereof are not included:

32. A compound represented by formula (V) or a pharmaceutically acceptable salt thereof, in, Z* is selected from C(R 3* )2、NR 3* or O; Ring B* 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; 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* 、R 3* 、R 5* Independently selected from the following groups: (a) 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; or, (b) M 1* Selected from bond, -NR b* -, -C(O)-, -C(O)O-, -SO2-, -S(O)-, -O-, -S-, -C(O)NR b* -、-C(=NR b* )-, 2-10 membered heteroalkylene, C1-C 10 Alkylene, C2-C 10 Alkenylene, C2-C 10 Alkynylidene, C3-C 10 Cycloalkylene, 4-9 membered Heterocyclic group, C6-C 10 Arylene, 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, 5-10 membered heteroarylene are optionally replaced by R a* replace; R 10* 、R 11* 、R 12* 、R 13* 、R 14* are independently selected from a bond, -NR b* -, -C(O)-, -C(O)O-, -SO2-, -S(O)-, -O-, -S-, -NR b* C(O)-, -C(=NR b* )-、-C(S)-、-P(O)(OR b* )O-、-P(O)(OR b* )-, 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, 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, 5-10 membered heteroarylene are optionally replaced by R a* replace; R 20* Selected from H, halogen, CN, -OR b* 、-N(R b*) 2. -S(O)R b* 、-SO2R b* 、-C(O)R b* 、-C(O)OR b* 、-OC(O)R b* 、-C(O)N(R b*) 2. -NR b* C(O)R b* , 2-10 membered heteroalkyl, C1-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, C3-C 10 Cycloalkyl, 4-9 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, 4-9 membered heterocyclic group, C6-C 10 Aryl or 5-10 membered heteroaryl is optionally replaced by R a* replace; or R 1* 、R 3* The atoms to which it is attached together form a C5-C8 saturated or partially saturated carbocyclic ring, a 5-6 membered heteroaromatic ring or a 5-8 membered heterocyclic ring, wherein the C5-C8 saturated or partially saturated carbocyclic ring, a 5-6 membered heteroaromatic ring or a 5-8 membered heterocyclic ring is optionally replaced by R 5* replace; Every R 4* Selected from halogen, CN, 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, 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 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, 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 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.

33. The compound of formula (III) according to claim 28, formula (IV) according to claim 30, or formula (V) according to claim 32, or a compound or a pharmaceutically acceptable salt thereof is selected from the following compounds or pharmaceutically acceptable salts thereof:

34. Use of a compound of formula (III) according to claims 28-29, formula (IV) according to claims 30-31, formula (V) according to claim 32, or claim 33, or a pharmaceutically acceptable salt thereof, in the preparation of a target protein degradation drug.

35. Use of a compound of formula (III) according to claims 28-29, formula (IV) according to claims 30-31, formula (V) according to claim 32, or claim 33, or a pharmaceutically acceptable salt thereof, as an intermediate in the preparation of a target protein degradation drug.

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