BRM selective degradation agent compounds

Abstract

The present disclosure relates to protein degradation targeting chimera (PROTAC) molecules, further to BRM selective degradation agent compounds, and specifically provides compounds of formula (I) or pharmaceutically acceptable salts thereof, the compounds having the substituents and structural characteristics described herein. Also described are pharmaceutical compositions comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, and the use of said compound or a pharmaceutically acceptable salt thereof in medicine.

Description

BRM selective degrader compounds

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims the benefit of and priority to the following Chinese invention patent application, the entire contents of which are hereby incorporated by reference into this application:

[0003] Patent application No. 202310371071.1 submitted to the State Intellectual Property Office of China on April 7, 2023. Technical Field

[0004] The present disclosure relates to compounds or pharmaceutically acceptable salts thereof that are selective degraders of BRMs, methods for preparing the same, pharmaceutical compositions containing the same, and uses of the same in preventing or treating diseases or conditions mediated by BRMs. Background Art

[0005] SWI / SNF is a crucial nucleosome remodeling complex that hydrolyzes ATP to generate energy, which is used to break down the interactions between DNA and histones within nucleosomes, thereby regulating gene expression and repairing genetic damage. Epigenetic abnormalities have been shown to be a major cause of the development and progression of many chronic diseases, such as cancer. Mutations in SWI / SNF complex components are found in approximately 20% of cancers. BRM (SMARCA2) and BRG1 (SMARCA4) are both ATPase subunits of the SWI / SNF complex and are core components. Their primary function is to hydrolyze ATP to provide energy for nucleosome mobilization, regulating gene transcription, DNA replication, and DNA damage repair. The two proteins share the same but mutually exclusive functions within the complex and cannot coexist in the same SWI / SNF complex. Simultaneous inhibition of BRM and BRG1 protein function leads to cell death, a phenomenon known as synthetic lethality. BRG1 deficiency occurs in a variety of tumors, including lung, gastric, and pancreatic cancers, which are highly malignant and have limited therapeutic options. For example, BRG1 mutations occur in 5-10% of non-small cell lung cancer (NSCLC) and are mutually exclusive with the most prevalent driver genes in NSCLC, such as EGFR, ALK, MET, ROS1, and RET. Tumor cells with BRG1 mutations or functional loss are highly dependent on BRMs and are therefore more sensitive to BRM inhibitors, resulting in a synergistic lethal effect. Normal cells, however, are well-tolerated by BRM inhibitors, making BRMs a potential specific tumor target.

[0006] Protein degradation targeting chimeras (PROTACs) are an emerging technology with great prospects, which are expected to turn many "undruggable" potential targets into "druggable". Traditional small molecule drugs are often powerless against proteins without enzyme functions, which account for about 80% of human proteins, because these drugs usually need to bind to enzymes or receptors to work. PROTACs are composed of three parts: a ligand (anchor) that recruits E3 ubiquitin ligase, a ligand molecule (warhead) that binds to the target protein (protein of interest, POI), and a linker (linker) that connects the two parts. Traditional small molecules need to exert their pharmacological effects by occupying key sites of the target protein (i.e., occupancy-driven), so a certain drug concentration in the body needs to be maintained, and the requirements for small molecule binding sites are high. PROTACs achieve pharmacodynamic effects by degrading the target protein, and theoretically do not require very high drug concentrations.

[0007] BRM and BRG1 proteins have two main functional regions, the ATPase region and the bromodomain. The amino acid residue homology of the corresponding functional regions of these two proteins is greater than 90%. Small molecule inhibitors are difficult to achieve selectivity for BRM and BRG1, and therefore have strong killing ability against normal cells. Clinically, there is an urgent need for BRM protein degradation PROTAC molecules with excellent stability and activity and good selectivity for BRG1.

[0008] Summary of the Invention

[0009] In one aspect, a compound of formula (I) or a pharmaceutically acceptable salt thereof is provided, TL——Linker——DIM (I)

[0010] in:

[0011] The DIM is a ligand compound capable of binding to cereblon-type E3 ubiquitin ligase;

[0012] The Linker is a connecting group that covalently binds at least one TL and at least one DIM;

[0013] The TL is a group as shown below:

[0014] in:

[0015] R 1 Selected from H, -C(O)R a OR-P(O)(OR b )2; where Ra and R b Each is independently selected from H, C1-C6 alkyl, C3-C6 cycloalkyl or 4-8 membered heterocyclic group, wherein the C1-C6 alkyl, C3-C6 cycloalkyl or 4-8 membered heterocyclic group is optionally replaced by R 1a replace;

[0016] R 2 Selected from H, deuterium, halogen, CN, COOH, NO2, NH2, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, C6-C 10 Aryl, 5-10 membered heteroaryl or 4-8 membered heterocyclic group, the NH2, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, C6-C 10 Aryl, 5-10 membered heteroaryl or 4-8 membered heterocyclic group is optionally replaced by R 2a replace;

[0017] R 3 Selected from deuterium, halogen, CN, COOH, NO2, NH2, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, C6-C 10 Aryl, 5-10 membered heteroaryl or 4-8 membered heterocyclic group, the NH2, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, C6-C 10 Aryl, 5-10 membered heteroaryl or 4-8 membered heterocyclic group is optionally replaced by R 3a replace;

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

[0019] n is selected from 0, 1 or 2;

[0020] Each W is independently selected from -CR c R d -, -C(O)-, -S(O)- or -S(O)2-, and when n is 2, at least one W is -CR c R d -;

[0021] R c and R d are independently selected from H, deuterium, halogen, OH, C1-C6 alkyl, C3-C6 cycloalkyl or 4-8 membered heterocyclic group, wherein the OH, C1-C6 alkyl, C3-C6 cycloalkyl or 4-8 membered heterocyclic group is optionally replaced by R 4a Replacement; or R c 、R d and the atoms to which they are attached together form a C3-C6 cycloalkyl or a 4-8 membered heterocyclic group, wherein the C3-C6 cycloalkyl or the 4-8 membered heterocyclic group is optionally replaced by R 5a replace;

[0022] represents a single bond or a double bond;

[0023] Y and Z are independently selected from CR or N, said R being selected from absence, H or deuterium;

[0024] Ring A is selected from a 5-7 membered heterocyclic ring, a 5-6 membered heteroaromatic ring or a benzene ring, wherein the 5-7 membered heterocyclic ring, the 5-6 membered heteroaromatic ring or the benzene ring is optionally replaced by R 6a replace;

[0025] R 1a 、R 2a 、R 3a 、R 4a 、R 5a and R 6a are independently selected from deuterium, halogen, =O, OH, CN, NH2, C1-C6 alkyl, C3-C6 cycloalkyl, 4-8 membered heterocyclyl, C6-C 10 Aryl or 5-10 membered heteroaryl, the OH, NH2, C1-C6 alkyl, C3-C6 cycloalkyl, 4-8 membered heterocyclic group, C6-C 10 Aryl or 5-10 membered heteroaryl is optionally replaced by R 1b replace;

[0026] R 1b is selected from halogen, OH, NH2, =O or C1-C3 alkyl;

[0027] Provided that: when ring A is optionally replaced by R 6a substituted 5-7 membered heterocyclic ring or optionally R 6a When the 5-6 membered heteroaromatic ring is substituted, n is 1 or 2, and at least one W is -CR c R d -, the R c 、R d and the atoms to which they are attached together form a C3-C6 cycloalkyl or a 4-8 membered heterocyclic group, wherein the C3-C6 cycloalkyl or the 4-8 membered heterocyclic group is optionally replaced by R 5a replace.

[0028] In another aspect, a pharmaceutical composition is provided, comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0029] In another aspect, provided is a use of a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described herein, in the preparation of a medicament for preventing or treating a BRM-mediated disease, wherein the BRM-mediated disease is preferably a tumor.

[0030] In another aspect, provided is a compound of formula (I) as described herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described herein for use in preventing or treating a BRM-mediated disease.

[0031] In another aspect, provided is a use of a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein, in preventing or treating a disease mediated by BRM.

[0032] In another aspect, provided is a method for treating a disease mediated by BRM, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein. DETAILED DESCRIPTION

[0033] The present disclosure is described in detail below by way of specific embodiments, but this does not imply any adverse limitations on the present disclosure. Various specific embodiments of the present disclosure have been described herein in detail, and it will be apparent to those skilled in the art that various changes and modifications can be made to the specific embodiments of the present disclosure without departing from the spirit and scope of the present disclosure.

[0034] The present disclosure relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof: TL——Linker——DIM (I)

[0035] The DIM is a ligand compound capable of binding to cereblon-type E3 ubiquitin ligase;

[0036] The Linker is a connecting group that covalently binds at least one TL and at least one DIM;

[0037] The TL is a group as shown below:

[0038] in:

[0039] R 1 Selected from H, -C(O)R a OR-P(O)(OR b )2; where R a and R b Each independently selected from H, C1-C6 alkyl, C3-C6 cycloalkyl or 4-8 membered heterocyclic group, wherein the C1-C6 alkyl, C3-C6 cycloalkyl or 4-8 membered heterocyclic group is optionally replaced by R 1a replace;

[0040] R 2 Selected from H, deuterium, halogen, CN, COOH, NO2, NH2, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, C6-C10 Aryl, 5-10 membered heteroaryl or 4-8 membered heterocyclic group, the NH2, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, C6-C 10 Aryl, 5-10 membered heteroaryl or 4-8 membered heterocyclic group is optionally replaced by R 2a replace;

[0041] R 3 Selected from deuterium, halogen, CN, COOH, NO2, NH2, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, C6-C 10 Aryl, 5-10 membered heteroaryl or 4-8 membered heterocyclic group, the NH2, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, C6-C 10 Aryl, 5-10 membered heteroaryl or 4-8 membered heterocyclic group is optionally replaced by R 3a replace;

[0042] m is selected from 0, 1, 2, 3 or 4;

[0043] n is selected from 0, 1 or 2;

[0044] Each W is independently selected from -CR c R d -, -C(O)-, -S(O)- or -S(O)2-, and when n is 2, at least one W is -CR c R d -;

[0045] R c and R d are independently selected from H, deuterium, halogen, OH, C1-C6 alkyl, C3-C6 cycloalkyl or 4-8 membered heterocyclic group, wherein the OH, C1-C6 alkyl, C3-C6 cycloalkyl or 4-8 membered heterocyclic group is optionally replaced by R 4a Replacement; or R c 、R d and the atoms to which they are attached together form a C3-C6 cycloalkyl or a 4-8 membered heterocyclic group, wherein the C3-C6 cycloalkyl or the 4-8 membered heterocyclic group is optionally replaced by R 5a replace;

[0046] represents a single bond or a double bond;

[0047] Y and Z are independently selected from CR or N, said R being selected from absence, H or deuterium;

[0048] Ring A is selected from a 5-7 membered heterocyclic ring, a 5-6 membered heteroaromatic ring or a benzene ring, wherein the 5-7 membered heterocyclic ring, the 5-6 membered heteroaromatic ring or the benzene ring is optionally replaced by R 6a replace;

[0049] R 1a 、R 2a 、R 3a 、R 4a 、R 5a and R 6a are independently selected from deuterium, halogen, =O, OH, CN, NH2, C1-C6 alkyl, C3-C6 cycloalkyl, 4-8 membered heterocyclyl, C6-C 10 Aryl or 5-10 membered heteroaryl, the OH, NH2, C1-C6 alkyl, C3-C6 cycloalkyl, 4-8 membered heterocyclic group, C6-C 10 Aryl or 5-10 membered heteroaryl is optionally replaced by R 1b replace;

[0050] R 1b is selected from halogen, OH, NH2, =O or C1-C3 alkyl;

[0051] Provided that: when ring A is optionally replaced by R 6a substituted 5-7 membered heterocyclic ring or optionally R 6a When the 5-6 membered heteroaromatic ring is substituted, n is 1 or 2, and at least one W is -CR c R d -, the R c 、R d and the atoms to which they are attached together form a C3-C6 cycloalkyl or a 4-8 membered heterocyclic group, wherein the C3-C6 cycloalkyl or the 4-8 membered heterocyclic group is optionally replaced by R 5a replace.

[0052] In some embodiments, is C=C, and ring A is selected from a 5-6 membered heteroaromatic ring or a benzene ring, wherein the 5-6 membered heteroaromatic ring or the benzene ring is optionally replaced by R 6a substituted; provided that: when ring A is optionally replaced by R 6a When the 5-6 membered heteroaromatic ring is substituted, n is 1 or 2, and at least one W is -CR c R d -, the R c 、R d and the atoms to which they are attached together form a C3-C6 cycloalkyl or a 4-8 membered heterocyclic group, wherein the C3-C6 cycloalkyl or the 4-8 membered heterocyclic group is optionally replaced by R 5a replace.

[0053] In some embodiments, is C=C, and ring A is optionally replaced by R 6a Substituted 5-6 membered heteroaromatic ring, n is 1 or 2, and at least one W is -CR c R d -, the R c 、R dand the atoms to which they are attached together form a C3-C6 cycloalkyl or a 4-6 membered heterocyclic group, wherein the C3-C6 cycloalkyl or the 4-6 membered heterocyclic group is optionally replaced by R 5a replace.

[0054] In some embodiments, is C=C, and ring A is optionally replaced by R 6a Substituted 5-6 membered heteroaromatic ring, n is 1, W is -CR c R d -, the R c 、R d and its connected atoms together form an optionally R 5a Substituted C3-C6 cycloalkyl.

[0055] In some embodiments, represents a single bond, Y and Z are independently selected from CR or N, said R is selected from absent or H, and ring A is optionally replaced by R 6a Substituted 5-7 membered heterocycle, n is 1 or 2, and at least one W is -CR c R d -, the R c 、R d and the atoms to which they are attached together form a C3-C6 cycloalkyl or a 4-8 membered heterocyclic group, wherein the C3-C6 cycloalkyl or the 4-8 membered heterocyclic group is optionally replaced by R 5a replace.

[0056] In some embodiments, Ring A is optionally substituted with R 6a Substituted benzene ring.

[0057] In some embodiments, Ring A is a benzene ring.

[0058] In some embodiments, each W is independently selected from -CR c R d - or -C(O)-, and when n is 2, one W is selected from -CR c R d - or -C(O)-, the other W is -CR c R d -.

[0059] In some embodiments, n is 1 and W is selected from -CR c R d -or -C(O)-.

[0060] In some embodiments, R c and R d are independently selected from H, deuterium, halogen, OH or C1-C6 alkyl, wherein the OH or C1-C6 alkyl is optionally replaced by R 4a Replacement; or Rc 、R d and the atoms to which they are attached together form a C3-C6 cycloalkyl or a 4-6 membered heterocyclic group, wherein the C3-C6 cycloalkyl or the 4-6 membered heterocyclic group is optionally replaced by R 5a replace.

[0061] In some embodiments, R c and R d Each independently selected from H, OH or C1-C6 alkyl, said OH or C1-C6 alkyl being optionally replaced by R 4a replace.

[0062] In some embodiments, n is 1 and W is -C(O)-.

[0063] In some embodiments, n is 0.

[0064] In some embodiments, R 1 Selected from H, -C(O)R a OR-P(O)(OR b )2; where R a and R b Each independently selected from H or optionally R 1a Substituted C1-C6 alkyl.

[0065] In some embodiments, R 1 Selected from H.

[0066] In some embodiments, R 2 is selected from H, deuterium, halogen, NH2, C1-C3 alkyl or C1-C3 alkoxy, wherein the NH2, C1-C3 alkyl or C1-C3 alkoxy is optionally replaced by R 2a replace.

[0067] In some embodiments, R 2 Selected from H or deuterium.

[0068] In some embodiments, R 2 For H.

[0069] In some embodiments, R 3 is selected from deuterium, halogen, CN, COOH, NO2, NH2, C1-C6 alkyl or C1-C6 alkoxy, wherein the NH2, C1-C6 alkyl or C1-C6 alkoxy is optionally replaced by R 3a replace.

[0070] In some embodiments, R 3 is selected from deuterium, halogen, NH2, C1-C3 alkyl or C1-C3 alkoxy, wherein the NH2, C1-C3 alkyl or C1-C3 alkoxy is optionally replaced by R 3a replace.

[0071] In some embodiments, R 3 Selected from deuterium or halogen.

[0072] In some embodiments, m is selected from 0, 1 or 2.

[0073] In some embodiments, m is 0.

[0074] In some embodiments, R 1a 、R 2a 、R 3a 、R 4a 、R 5a and R 6a are independently selected from deuterium, halogen, =O, OH, NH2, C1-C6 alkyl, C3-C6 cycloalkyl, 4-6 membered heterocyclyl, C6-C 10 Aryl or 5-6 membered heteroaryl, the OH, NH2, C1-C6 alkyl, C3-C6 cycloalkyl, 4-6 membered heterocyclic group, C6-C 10 Aryl or 5-6 membered heteroaryl is optionally replaced by R 1b replace.

[0075] In some embodiments, R 1a 、R 2a 、R 3a 、R 4a 、R 5a and R 6a are independently selected from deuterium, halogen, =O, OH, NH2, C1-C6 alkyl, C3-C6 cycloalkyl or 4-6 membered heterocyclic group, wherein the OH, NH2, C1-C6 alkyl, C3-C6 cycloalkyl or 4-6 membered heterocyclic group is optionally replaced by R 1b replace.

[0076] In some embodiments, R 1a 、R 2a 、R 3a 、R 4a 、R 5a and R 6a Each independently selected from deuterium, halogen, =O, OH, NH2 or C1-C6 alkyl, wherein the OH, NH2 or C1-C6 alkyl is optionally replaced by R 1b replace.

[0077] In some embodiments, R 1b Selected from halogen, OH, NH2 or C1-C3 alkyl.

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

[0079] In some embodiments, the TL is further selected from the group shown below: Among them, the R 1 、R 2 、R 3 , W, m and n are as defined above.

[0080] In some embodiments, the TL is selected from the following structures:

[0081] In some embodiments, the TL is selected from the following structures:

[0082] In some embodiments, the TL is selected from

[0083] In some embodiments, the linker is a connecting group that covalently binds a TL and a DIM.

[0084] In some embodiments, the linker is selected from -L A -、-L B -、-R 1L -、-R 2L -、-Q 1 -、-Q 2 -、

[0085] Where: -L A -、-L B - independently selected from a bond, -O-, -S-, -NR 3’ -、-CR 4’ R 5’ -、-CR 4’ R 5’ -NR 3’ -、-CR 4’ R 5’ -O-, -C(O)-, -CR 4’ R 5’ -C(O)-, -S(O)-, -S(O)2-, -C(S)-, -C(O)O- or -C(O)NR 6’ -;

[0086] R 1L and R 2L are independently selected from a bond, -C(O)-, alkylene, heteroalkylene, alkenylene and alkynylene, wherein said alkylene, heteroalkylene, alkenylene and alkynylene are optionally substituted with a group selected from the group consisting of halogen, alkyl, alkoxy, haloalkyl, OH, hydroxyalkyl, CN, NH2, =O, cycloalkyl, heterocyclyl, aryl, heteroaryl;

[0087] Q 1 , Q 2 , Q 3 and Q 4 are independently selected from cycloalkyl, heterocyclyl, aryl, heteroaryl or cycloalkenyl, wherein the cycloalkyl, heterocyclyl, aryl, heteroaryl and cycloalkenyl are each independently optionally substituted by a group selected from the group consisting of halogen, alkyl, alkoxy, haloalkyl, OH, hydroxyalkyl, CN, NH2, =O, cycloalkyl, heterocyclyl, aryl, heteroaryl;

[0088] R 3’ is selected from H, alkyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl;

[0089] R 4’ and R 5’ Each is independently selected from H, halogen, alkyl, alkoxy, haloalkyl, OH, hydroxyalkyl, CN, NH2, =O, cycloalkyl, heterocyclyl, aryl or heteroaryl;

[0090] R 6’ is selected from H, alkyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl.

[0091] In some embodiments, the linker is selected from the following structures:

[0092] In some embodiments, the linker is selected from the following structures:

[0093] In some embodiments, the linker is selected from the following structures:

[0094] In some embodiments, the DIM is selected from the structure shown in formula (DIM-1) or (DIM-2):

[0095] in:

[0096] Selected from

[0097] Y' is a bond, or Y' is selected from Y A 、O、NH、NR E 、C(O)O、C(O)NR E '、NR E 'C(O), Y A -NH, Y A -NR E 、Y A -C(O), Y A -C(O)O、Y A -OC(O),Y A -C(O)NR E ' or Y A -NR E 'C(O), wherein the Y A is selected from C1-C6 alkylene, C2-C6 alkenylene or C2-C6 alkynylene;

[0098] X' is selected from C(O) or C(R A )2;X A -X B Selected from C(R A )=N or C(R A )2-C(R A )2;

[0099] Every R A independently selected from H or C1-C3 alkyl, said C1-C3 alkyl being optionally replaced by C6-C 10 substituted with aryl or 5-10 membered heteroaryl;

[0100] Every R A 'Independently selected from C1-C3 alkyl;

[0101] Every R B are independently selected from H or C1-C3 alkyl, or two R B Together with the atoms to which it is attached, it forms a C(O), a C3-C6 cycloalkyl, a C3-C6 cycloalkenyl, or a 4-6 membered heterocyclyl;

[0102] R C Selected from H, halogen or C1-C3 alkyl;

[0103] Every R D Independently selected from halogen, NO2, NH2, OH, COOH, C1-C6 alkyl or C1-C6 alkoxy;

[0104] Every R Eindependently selected from C1-C6 alkyl, C2-C6 alkenyl, C3-C8 cycloalkyl, 3-8 membered heterocycloalkyl, C(O)-C1-C6 alkyl, C(O)-C2-C6 alkenyl, C(O)-C3-C8 cycloalkyl or C(O)-3-8 membered heterocycloalkyl, wherein R E Optionally substituted by a group selected from the group consisting of halogen, N(R a )2、NHC(O)R a 、NHC(O)OR a , OR b , C3-C8 cycloalkyl, 3-8 membered heterocycloalkyl, C6-C 10 aryl or 5-10 membered heteroaryl, wherein the C3-C8 cycloalkyl, 3-8 membered heterocycloalkyl, C6-C 10 The aryl or 5-10 membered heteroaryl is optionally further substituted by a group selected from the group consisting of halogen, NH2, CN, NO2, OH, COOH, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy or C1-C6 haloalkoxy;

[0105] R E ' is selected from H, C1-C6 alkyl, C2-C6 alkenyl, C3-C8 cycloalkyl or 3-8 membered heterocycloalkyl, wherein the C1-C6 alkyl, C2-C6 alkenyl, C3-C8 cycloalkyl or 3-8 membered heterocycloalkyl is optionally substituted by a group selected from the following: halogen, N (R a )2、NHC(O)R a 、NHC(O)OR a , OR b , C3-C8 cycloalkyl, 3-8 membered heterocycloalkyl, C6-C 10 aryl or 5-10 membered heteroaryl, wherein the C3-C8 cycloalkyl, 3-8 membered heterocycloalkyl, C6-C 10 The aryl or 5-10 membered heteroaryl is optionally further substituted by a group selected from the group consisting of halogen, NH2, CN, NO2, OH, COOH, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy or C1-C6 haloalkoxy;

[0106] Every R a Independently selected from H or C1-C6 alkyl;

[0107] R b Selected from H or p-toluenesulfonyl;

[0108] t is selected from 0 or 1;

[0109] m1 is selected from 0, 1, 2 or 3;

[0110] p is selected from 0, 1 or 2.

[0111] In some embodiments, the DIM is further selected from the structure represented by formula (DIM-3) or (DIM-4):

[0112] Wherein, the rings A, Y', R A 、R A '、R B 、R C 、R D , m1 and p are as defined above.

[0113] In some embodiments, the DIM is further selected from the structure represented by formula (DIM-5), (DIM-6), (DIM-7) or (DIM-8):

[0114] Wherein, the Y', X', X A -X B 、R A 、R A '、R B 、R C 、R D , m1 and p are as defined above.

[0115] In some embodiments, the DIM is further selected from the structure represented by formula (DIM-9) or (DIM-10):

[0116] Wherein, the Y', X', X A -X B 、R A 、R A '、R B 、R C 、R D , m1 and p are as defined above.

[0117] In some embodiments, the DIM is selected from the structure shown in formula (DIM-11):

[0118] in:

[0119] X C is selected from a bond, -CH2-, -CHCF3-, -SO2-, -S(O)-, -P(O)R'-, -P(O)OR'-, -P(O)NR'2-, -C(O)-, -C(S-) or

[0120] X D selected from C, N or Si;

[0121] X Eis selected from a bond, -CR'2-, -NR'-, -O-, -S- or -SiR'2-;

[0122] R F Does not exist, or R F is selected from H, deuterium, halogen, CN, -OR', -SR', -S(O)R', -S(O)2R', -NR'2, -P(O)(OR')2, -P(O)(NR'2)OR', -P(O)(NR'2)2, -Si(OH)2R', -Si(OH)R'2, -SiR'3 or C1-C4 alkyl;

[0123] Every R G Independently selected from H, deuterium, R H , Halogen, CN, -NO2, -OR', -SR', -NR'2, -SiR'3, -S(O)2R', -S(O)2NR'2, -S(O)R', -C(O)R', -C(O)OR', -C(O)NR'2, -C(O)N(R')OR', -C(R')2N(R' )C(O)R', -C(R')2N(R')C(O)NR'2, -OC(O)R', -OC(O)NR'2, -OP(O)R'2, -OP(O)(OR')2, -OP(O)(OR')NR'2, -OP(O)(NR'2)2, -N(R')C(O)OR', -N(R')C(O)R', -N(R')C(O)NR'2, -N(R')S(O)2R', -NP(O)R'2, -N(R')P(O)(OR')2, -N(R')P(O)(OR')NR'2 or -N(R')P(O)(NR'2)2;

[0124] Every R H Independently selected from C1-C6 alkyl, phenyl, 4-7 membered heterocyclyl or 5-6 membered heteroaryl;

[0125] Ring E, Ring F, and Ring G are independently selected from phenyl, 6-membered heteroaryl, C5-C7 cycloalkyl, C5-C7 cycloalkenyl, 5-7-membered heterocyclyl, or 5-6-membered heteroaryl, wherein Ring E, Ring F, and Ring G are each optionally further substituted with ═O;

[0126] L 1 is selected from a bond, C1-C3 alkylene, C2-C3 alkenylene or C2-C3 alkynylene, wherein any one or two methylene groups in the C1-C3 alkylene, C2-C3 alkenylene or C2-C3 alkynylene are optionally replaced by -O-, -C(O)-, -C(S)-, -C(R')2-, -CH(R')-, -C(F)2-, -N(R')-, -S- or -S(O)2-;

[0127] Each R' is independently selected from H, C1-C6 alkyl, phenyl, 4-7 membered heterocyclyl or 5-6 membered heteroaryl, or two R' and the atoms to which they are attached together form a 4-7 membered heterocyclyl or 5-6 membered heteroaryl;

[0128] q is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or 16.

[0129] In some embodiments, the DIM is selected from the structure shown in formula (DIM-11'):

[0130] wherein X C 、R F 、R G , q, ring E, ring F and ring G are as defined in formula (DIM-11).

[0131] In some embodiments, the DIM is selected from the structure shown in formula (DIM-12):

[0132] wherein: Ring H is selected from C5-C9 cycloalkyl, C5-C9 cycloalkenyl or 5-9 membered heterocyclyl, wherein said C5-C9 cycloalkyl, C5-C9 cycloalkenyl or 5-9 membered heterocyclyl is optionally substituted with ═O; k is selected from 0, 1, 2, 3 or 4; X C 、X D 、X E 、R F 、R G 、L 1 and Ring E are as defined in Formula (DIM-11).

[0133] In some embodiments, the DIM is selected from the structure shown in (DIM-12'):

[0134] Wherein, the X C 、R F 、R G , k, ring E and ring H are as defined in formula (DIM-12).

[0135] In some embodiments, the DIM is selected from the structure shown in formula (DIM-13):

[0136] Among them, the X C 、X D 、X E 、R F 、R G 、L 1 , Ring E and k are as defined in Formula (DIM-12).

[0137] In some embodiments, the DIM is selected from the structure shown in (DIM-13'):

[0138] Among them, the X C 、R F 、R G , Ring E and k are as defined in Formula (DIM-13).

[0139] In some embodiments, the DIM is selected from the following structures:

[0140] In some embodiments, the DIM is selected from the following structures:

[0141] In some embodiments, the compound of formula (I) of the present disclosure is selected from the following compounds:

[0142] On the other hand, the present disclosure provides a pharmaceutical composition comprising a compound represented by general formula (I) of the present disclosure or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0143] On the other hand, the present disclosure provides a method for treating a disease mediated by BRM in a mammal, comprising administering a therapeutically effective amount of a compound represented by formula (I) of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof to a mammal, preferably a human, in need of such treatment.

[0144] In another aspect, the present disclosure provides a method for treating tumors in mammals, comprising administering a therapeutically effective amount of a compound represented by formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof to a mammal, preferably a human, in need of such treatment.

[0145] 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 a BRM-mediated disease.

[0146] On the other hand, the present disclosure provides use of a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, in the preparation of a medicament for preventing or treating tumors.

[0147] In another aspect, the present disclosure provides the use of a compound represented by formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, in preventing or treating BRM-mediated diseases.

[0148] In another aspect, the present disclosure provides the use of a compound represented by formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, in preventing or treating tumors.

[0149] 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 BRM-mediated diseases.

[0150] 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 tumors.

[0151] In some embodiments, the BRM-mediated disease is selected from a tumor.

[0152] In some embodiments, the tumor is selected from cancer.

[0153] Definitions and Explanations of Terms

[0154] Unless otherwise indicated, the terms used in this disclosure have the following meanings. The definitions of groups and terms described in this disclosure, including their exemplary definitions, preferred definitions, definitions described in tables, and definitions of specific compounds in the Examples, may be combined and coupled with each other in any manner. A particular term should not be considered undefined or unclear unless specifically defined, but should be understood according to its common meaning in the art. When a trade name appears in this document, it is intended to refer to the corresponding commercial product or its active ingredient.

[0155] 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 molecule enclosed by "[]" (including hydrogen atoms directly connected to ring atoms, hydrogen atoms on non-hydrogen substituents of ring atoms, and hydrogen atoms in further substituents on substituents), for example middle The connection position includes but is not limited to R G , Ring E, Ring F, Ring G and their respective substituents, etc., middle The connection position includes ring A and the substituent R on ring A 6a wait.

[0156] The term "capable of binding" means capable of measurably binding to a target (eg, a ligand of an E3 ubiquitin ligase is capable of forming a covalent bond with a cysteine ​​of an E3 ubiquitin ligase, etc.).

[0157] The term "ubiquitin ligase" refers to a family of proteins that facilitate the transfer of ubiquitin to specific substrate proteins, targeting them for degradation. E3 ubiquitin ligases, alone or in complex with E2 ubiquitin ligases, are responsible for transferring ubiquitin to target proteins. Typically, ubiquitin ligases participate in polyubiquitination, where a second ubiquitin is attached to the first; a third ubiquitin is attached to the second, and so on. Polyubiquitination marks proteins for degradation by the proteasome. However, there are some ubiquitination events that are limited to monoubiquitination, in which the ubiquitin ligase only adds a single ubiquitin to the substrate molecule. Monoubiquitinated proteins are not targeted for degradation by the proteasome, but can instead change their cellular location or function, for example, by binding to other proteins with domains capable of binding ubiquitin. Further complicating matters, E3 ubiquitin ligases can target different lysines on ubiquitin to create chains.

[0158] Unless otherwise specified in this document, wedge keys and virtual 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).

[0159] The term "tautomer" refers to functional group isomers resulting from the rapid shift of an atom between two positions in a molecule. Compounds of the present disclosure may exhibit tautomerism. Tautomeric compounds may exist as two or more interconvertible species. Tautomers generally exist in equilibrium, and attempts to isolate a single tautomer typically produce a mixture whose physical and chemical properties are consistent with a mixture of compounds. The position of equilibrium depends on the chemical properties within the molecule. For example, in many aliphatic aldehydes and ketones, such as acetaldehyde, the keto form predominates, while in phenols, the enol form predominates. The present disclosure encompasses all tautomeric forms of the compounds.

[0160] The term "stereoisomer" refers to isomers resulting from different spatial arrangements of atoms in a molecule, including cis-trans isomers, enantiomers and diastereomers.

[0161] The compounds of the present disclosure may have asymmetric atoms such as carbon atoms, sulfur atoms, nitrogen atoms, phosphorus atoms or asymmetric double bonds, and thus the compounds of the present disclosure may exist in specific geometric or stereoisomeric forms. Specific geometric or stereoisomeric forms may be cis and trans isomers, E and Z geometric isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers, (D)-isomers, (L)-isomers, and racemic mixtures or other mixtures thereof, such as enantiomerically or diastereomerically enriched mixtures, all of which are within the definition of compounds of the present disclosure and mixtures thereof. Substituents such as alkyl groups may have additional asymmetric carbon atoms, asymmetric sulfur atoms, asymmetric nitrogen atoms or asymmetric phosphorus atoms, and all of these isomers and mixtures thereof involved in the substituents are also within the definition of compounds of the present disclosure. Compounds of the present disclosure containing an asymmetric atom can be isolated in optically pure or racemic forms. Optically pure forms can be resolved from racemic mixtures or synthesized by using chiral starting materials or reagents.

[0162] The term "substituted" means that any one or more hydrogen atoms on a particular atom are replaced by a substituent, which may include deuterium and hydrogen variants, as long as the valence state of the particular atom is normal and the substituted compound is stable. When the substituent is oxo (i.e., =O), it means that two hydrogen atoms are replaced, and oxo does not occur on aromatic groups.

[0163] 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.

[0164] The term "optionally substituted" means that the group may be substituted or not substituted. Unless otherwise specified, the type and amount of the substituents may be any based on chemical practicability.

[0165] The term "substituted" means that a specific atom or group can be replaced by another specified atom or group. For example, the CH2 in -CH2CH2CH2- can be replaced by O, S or NH to obtain -CH2OCH2-, -OCH2CH2-, -CH2SCH2-, -SCH2CH2-, -CH2NHCH2- or -NHCH2CH2-, etc.

[0166] When any variable (such as R a 、R b ) appears more than once in the composition or structure of a compound, its definition is independent in each case. For example, if a group is represented by two R b is replaced, then each R b There are independent options; for the group N (C1-C6 alkyl) 2, when the C1-C6 alkyl is R b When substituted, the two C1-C6 alkyl groups have independent R b options.

[0167] When the number of a linking group is 0, such as -(CH2)0-, it means that the linking group is a bond.

[0168] 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.

[0169] 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 ”.

[0170] When a substituent's bond crosses two atoms in a ring, the substituent may be bonded to any atom in the ring. Represents R 3 Can remove OR on benzene ring 1 and The substitution occurs at any position other than the attachment site.

[0171] In this article, C m -C nIt means having mn or an integer number of carbon atoms in the range of m to n. For example, "C1-C 10 " means that the group may have 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, 6 carbon atoms, 7 carbon atoms, 8 carbon atoms, 9 carbon atoms or 10 carbon atoms. Similarly, m-membered to n-membered means that the number of ring atoms is m to n, for example, 5-14 membered ring includes 5-membered ring, 6-membered ring, 7-membered ring, 8-membered ring, 9-membered ring, 10-membered ring, 11-membered ring, 12-membered ring, 13-membered ring and 14-membered ring, and also includes any range from n to m, for example, 5-14 membered ring includes 6-14 membered ring, 6-11 membered ring, 5-10 membered ring, 6-10 membered ring, 6-8 membered ring, etc.

[0172] 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 linear or branched saturated monovalent hydrocarbon radical having 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms. Specific examples of such alkyl radicals 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, 1,2-dimethylbutyl, The term "C1-C6 alkyl" can be understood to mean an alkyl group having 1, 2, 3, 4, 5 or 6 carbon atoms, and specific examples 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-C4 alkyl" can be understood to mean a straight-chain or branched saturated monovalent hydrocarbon group having 1, 2, 3 or 4 carbon atoms. The term "C1-C3 alkyl" can be understood to mean a straight-chain or branched saturated monovalent hydrocarbon group having 1, 2 or 3 carbon atoms. The "C1-C 10 The term "alkyl" may include "C1-C6 alkyl", "C1-C4 alkyl" or "C1-C3 alkyl", and the "C1-C6 alkyl" may further include "C1-C4 alkyl" or "C1-C3 alkyl", and the "C1-C4 alkyl" may further include "C1-C3 alkyl".

[0173] The term "heteroalkyl" refers to an alkyl group in which one or more -CH2- are replaced by a heteroatom selected from NH, O and S, or one or more -CH- are replaced by N; wherein the alkyl group is as defined above.

[0174] The term "haloalkyl" refers to a group obtained by further replacing the alkyl group with a halogen, such as "C1-C6 haloalkyl" refers to a C1-C6 alkyl group further replaced with a halogen. The term "hydroxyalkyl" refers to a group obtained by further replacing the alkyl group with an OH group.

[0175] The term "alkylene" refers to a saturated straight or branched aliphatic hydrocarbon group having two residues derived from the same carbon atom or two different carbon atoms of an alkane group by removing two hydrogen atoms, and is a straight or branched group containing 1 to 20 carbon atoms, preferably an alkylene group containing 1 to 12 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12) carbon atoms, and more preferably an alkylene group containing 1 to 6 carbon atoms. Non-limiting examples of alkylene groups include, but are not limited to, methylene, -CH(CH3)-, -CH2CH2-, -CH(CH2CH3)-, -CH2CH(CH3)-, -CH2CH2CH2-, -CH2CH2CH2CH2-, and the like. The term "C1-C6 alkylene" is understood to mean an alkylene group having 1, 2, 3, 4, 5, or 6 carbon atoms. The term "C1-C3 alkylene" is understood to mean an alkylene group having 1, 2 or 3 carbon atoms. Preferably, "C1-C6 alkylene" may include "C1-C3 alkylene". The term "heteroalkylene" refers to an alkylene group in which one or more -CH2- groups are substituted with a heteroatom selected from N, O and S; wherein the alkylene group is as defined above.

[0176] The term "alkoxy" refers to a monovalent group generated by the loss of a hydrogen atom from a hydroxyl group of a straight-chain or branched alcohol, which can be understood as "alkyloxy" or "alkyl-O-", wherein the definition of alkyl is as described above. 10 "Alkoxy" can be understood as "C1-C 10 Alkyloxy" or "C1-C 10 The term "C1-C6 alkoxy" can be understood as "C1-C6 alkyloxy" or "C1-C6 alkyl-O-". "C1-C3 alkoxy" can be understood as "C1-C3 alkyloxy" or "C1-C3 alkyl-O-". The "C1-C 10 The term "alkoxy" may include "C1-C6 alkoxy" and "C1-C3 alkoxy", and the "C1-C6 alkoxy" may further include "C1-C3 alkoxy".

[0177] The term "haloalkoxy" refers to a group obtained by further substituted alkoxy with halogen, such as "C1-C6 haloalkoxy" refers to a C1-C6 alkoxy further substituted with halogen.

[0178] The term "alkenyl" refers to an unsaturated aliphatic hydrocarbon group consisting of carbon atoms and hydrogen atoms, which is a straight or branched chain containing 2 to 20 carbon atoms and has at least one double bond. 10 The term "alkenyl" is understood to mean a linear or branched unsaturated monovalent hydrocarbon radical containing one or more double bonds and having 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms, and the term "C2-C6 alkenyl" is understood to mean a linear or branched unsaturated monovalent hydrocarbon radical containing one or more double bonds and having 2, 3, 4, 5 or 6 carbon atoms. 10 "Alkenyl" is preferably "C2-C6 alkenyl" or "C2-C4 alkenyl", "C2-C6 alkenyl" is further preferably "C2-C4 alkenyl", and further preferably C2 or C3 alkenyl. It should 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.

[0179] The term "alkenylene" refers to a residue derived from two carbon atoms, either identical or distinct, of a parent alkene, wherein alkenyl is as defined above. The term "C2-C6 alkenylene" is understood to include alkenylene groups having from 2 to 6 carbon atoms. The term "C2-C3 alkenylene" is understood to include alkenylene groups having from 2 to 3 carbon atoms. Preferably, "C2-C6 alkenylene" includes "C2-C3 alkenylene."

[0180] The term "alkynyl" refers to a straight or branched unsaturated aliphatic hydrocarbon group consisting of carbon atoms and hydrogen atoms, containing 2 to 20 carbon atoms and having at least one triple bond. 10 The term "alkynyl" is understood to mean a linear or branched unsaturated monovalent hydrocarbon radical containing one or more triple bonds and having 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms. The term "C2-C6 alkynyl" is understood to mean a linear or branched unsaturated monovalent hydrocarbon radical containing one or more triple bonds and having 2, 3, 4, 5 or 6 carbon atoms. Examples of "C2-C6 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 "Alkynyl" may include "C2-C6 alkynyl" or "C2-C3 alkynyl", and "C2-C6 alkynyl" may include "C2-C3 alkynyl". Examples of "C2-C3 alkynyl" include ethynyl (-C≡CH), prop-1-ynyl (-C≡CCH3) or prop-2-ynyl (propargyl).

[0181] The term "alkynylene" refers to a radical having two hydrogen atoms derived from the same carbon atom or two different carbon atoms of a parent alkyne, wherein the definition of alkynyl is as shown above. The term "C2-C6 alkynylene" is understood to mean an alkynylene having 2 to 6 carbon atoms. The term "C2-C3 alkynylene" is understood to mean an alkynylene having 2 or 3 carbon atoms. Preferably, "C2-C6 alkynylene" includes "C2-C3 alkynylene".

[0182] 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 The term "cycloalkyl" shall be understood to mean a saturated monovalent monocyclic, cyclic, spirocyclic or bridged ring having 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms. The term "C3-C8 cycloalkyl" shall be understood to mean a saturated monovalent monocyclic, cyclic, spirocyclic or bridged ring having 3, 4, 5, 6, 7 or 8 carbon atoms. The term "C3-C6 cycloalkyl" shall be understood to mean a saturated monovalent monocyclic, cyclic, spirocyclic or bridged 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-C9 cycloalkyl" shall be understood to mean a saturated monovalent monocyclic , cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, norbornyl (bicyclo[2.2.1]heptyl), bicyclo[2.2.2]octyl, adamantyl, spiro[4.5]decyl, etc. The term "C5-C7 cycloalkyl" is understood to mean a saturated monovalent monocyclic, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, norbornyl (bicyclo[2.2.1]heptyl), bicyclo[2.2.2]octyl, adamantyl, spiro[4.5]decyl, etc. 10 The term "cycloalkyl" may include "C3-C8 cycloalkyl", "C3-C6 cycloalkyl", "C5-C9 cycloalkyl" or "C5-C7 cycloalkyl", the term "C3-C8 cycloalkyl" may include "C3-C6 cycloalkyl" or "C5-C7 cycloalkyl", the term "C5-C9 cycloalkyl" may include "C5-C7 cycloalkyl".

[0183] The term "cycloalkenyl" refers to a non-aromatic carbocyclic ring that is not fully saturated and exists in the form of a monocyclic, fused, bridged or spirocyclic ring. Unless otherwise indicated, the carbocyclic ring is usually a 3- to 10-membered ring. Specific examples of the cycloalkenyl include, but are not limited to, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl or cycloheptadienyl. The term "C5-C 10 The term "cycloalkenyl" refers to a non-aromatic carbocyclic ring that is not fully saturated and exists in the form of a monocyclic, fused ring, bridged ring or spirocyclic ring, and has 5-10 carbon atoms. The term "C5-C9 cycloalkenyl" refers to a non-aromatic carbocyclic ring that is not fully saturated and exists in the form of a monocyclic, fused ring, bridged ring or spirocyclic ring, and has 5-9 carbon atoms. The term "C5-C7 cycloalkenyl" refers to a non-aromatic carbocyclic ring that is not fully saturated and exists in the form of a monocyclic, fused ring, bridged ring or spirocyclic ring, and has 5-7 carbon atoms. The term "C3-C6 cycloalkenyl" refers to a non-aromatic carbocyclic ring that is not fully saturated and exists in the form of a monocyclic, fused ring, bridged ring or spirocyclic ring, and has 3-6 carbon atoms. The term "C5-C 10 The term "cycloalkenyl" may include "C5-C9 cycloalkenyl" or "C5-C7 cycloalkenyl", and the term "C5-C9 cycloalkenyl" may include "C5-C7 cycloalkenyl".

[0184] The term "heterocyclyl" refers to a fully saturated or partially saturated (heteroaromatic group that is not aromatic as a whole) monovalent monocyclic, fused, spiro or bridged ring group containing 1 to 5 heteroatoms or heteroatomic groups (i.e., heteroatomic groups containing heteroatoms) in the 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)- and optionally substituted -NH-, -S(=O)(=NH)-, -C(=O)NH-, -C(=NH)-, -S(=O)2NH-, S(=O)NH- or -NHC(=O)NH-, etc., which usually contain 3 to 20 ring atoms. The term "5-14 membered heterocyclyl" refers to a heterocyclyl group having 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 ring atoms, and wherein the ring atoms contain 1 to 5 heteroatoms or heteroatom groups independently selected from the above-mentioned heteroatoms. "5-14 membered heterocyclyl" may include "6-14 membered heterocyclyl", "6-11 membered heterocyclyl", "6-10 membered heterocyclyl", "6-8 membered heterocyclyl", "5-10 membered heterocyclyl", "5-9 membered heterocyclyl", "5-8 membered heterocyclyl" or "5-7 membered heterocyclyl". The term "5-10 membered heterocyclyl" may include "5-9 membered heterocyclyl", "5-8 membered heterocyclyl", "5-7 membered heterocyclyl", "6-10 membered heterocyclyl" or "6-8 membered heterocyclyl". The term "4-10 membered heterocyclyl" refers to a heterocyclyl having 4, 5, 6, 7, 8, 9 or 10 ring atoms, and the ring atoms thereof contain 1-5 heteroatoms or heteroatom groups independently selected from the above-mentioned. "4-10 membered heterocyclyl" includes "4-7 membered heterocyclyl", wherein specific examples of 4-membered heterocyclyl include but are not limited to azetidinyl or oxetanyl; specific examples of 5-membered heterocyclyl 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 heterocyclyl include but are not limited to The heterocyclic group is limited to tetrahydropyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl, trithianyl, tetrahydropyridinyl, or 4H-[1,3,4]thiadiazinyl; specific examples of 7-membered heterocyclic groups 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 4-7 membered heterocyclic groups, specific examples of which include, but are not limited to, dihydroisoquinolinyl.The “4-10 membered heterocyclyl” may include the ranges of “5-10 membered heterocyclyl”, “5-9 membered heterocyclyl”, “5-8 membered heterocyclyl”, “5-7 membered heterocyclyl”, “5-6 membered heterocyclyl”, “6-10 membered heterocyclyl”, “6-8 membered heterocyclyl”, “4-8 membered heterocyclyl”, “4-7 membered heterocyclyl”, “4-6 membered heterocyclyl”, “4-10 membered heterocycloalkyl”, “5-10 membered heterocycloalkyl”, “4-7 membered heterocycloalkyl”, “5-6 membered heterocycloalkyl”, “6-8 membered heterocycloalkyl”, and the like; and the “4-7 membered heterocyclyl” may further include the ranges of “4-6 membered heterocyclyl”, “5-7 membered heterocyclyl”, “5-6 membered heterocyclyl”, “4-7 membered heterocyclyl”, “4-6 membered heterocycloalkyl”, “5-7 membered heterocycloalkyl”, “5-6 membered heterocycloalkyl”, and the like. Although some bicyclic heterocyclic groups in the present disclosure partially contain a benzene ring or a heteroaromatic ring, the heterocyclic group as a whole is still non-aromatic.

[0185] The term "heterocycloalkyl" refers to a fully saturated monovalent cyclic group in the form of a monocyclic, fused, bridged or spirocyclic ring, wherein the ring atoms of the ring contain 1-5 heteroatoms or heteroatom groups (i.e., heteroatom-containing atomic groups), wherein the "heteroatoms or heteroatom 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)- and optionally substituted -NH-, -S(=O)(=NH)-, -C(=O)NH-, -C(=NH)-, -S(=O)2NH-, S(=O)NH- or -NHC(=O)NH-, etc., which generally contain 3 to 20 ring atoms. The term "3-10 membered heterocycloalkyl" refers to a heterocycloalkyl group having 3, 4, 5, 6, 7, 8, 9 or 10 ring atoms, and containing 1 to 5 heteroatoms or heteroatom groups independently selected from the above-mentioned heteroatoms. “3-10 membered heterocycloalkyl” includes “3-8 membered heterocycloalkyl”, wherein specific examples of 4 membered heterocycloalkyl include but are not limited to azetidinyl, oxetanyl or thietanyl; specific examples of 5 membered heterocycloalkyl include but are not limited to tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, isoxazolidinyl, oxazolidinyl, isothiazolidinyl, thiazolidinyl, imidazolidinyl or tetrahydropyrazolyl; specific examples of 6 membered heterocycloalkyl include but are not limited to piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, piperazinyl, 1,4-thioxanyl, 1,4-dioxanyl, thiomorpholinyl, 1,3-dithianyl or 1,4-dithianyl; specific examples of 7 membered heterocycloalkyl include but are not limited to azepanyl, oxetanyl or thiepanyl.

[0186] 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 a monovalent aromatic monocyclic, bicyclic or tricyclic hydrocarbon ring having 6 to 20 carbon atoms. In particular, it is 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 a monovalent aromatic, all-carbon monocyclic or bicyclic group having 6, 7, 8, 9 or 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 indenyl; or a ring having 10 carbon atoms ("C 10 "aryl"), for example naphthyl.

[0187] The term "heteroaryl" refers to a monocyclic or fused polycyclic ring system having aromatic properties, containing at least one, preferably 1-4, ring atoms selected from N, O, and S, with the remaining ring atoms being carbon atoms. Heteroaryl is preferably a 5- to 10-membered, more preferably a 5- or 6-membered heteroaryl. The term "5- to 10-membered heteroaryl" is understood to include monovalent monocyclic or bicyclic aromatic ring systems having 5, 6, 7, 8, 9, or 10 ring atoms, in particular 5, 6, 9, or 10 ring atoms, and containing 1-5, preferably 1-3, 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 1-3, preferably 1-2 heteroatoms independently selected from N, O and S. The term "6 membered heteroaryl" refers to an aromatic ring system having 6 ring atoms, and containing 1-3, preferably 1-2 heteroatoms independently selected from N, O and S. The term "5-10 membered heteroaryl" may include "5-6 membered heteroaryl" or "6 membered heteroaryl", and the term "5-6 membered heteroaryl" may include "6 membered heteroaryl".

[0188] The term "halo" or "halogen" refers to fluorine, chlorine, bromine or iodine.

[0189] The term "hydroxy" refers to an -OH group.

[0190] The term "cyano" refers to a -CN group.

[0191] The term "amino" refers to a -NH2 group.

[0192] The term "nitro" refers to a -NO2 group.

[0193] The term "therapeutically effective amount" means an amount of a Compound of the Disclosure that (i) treats or prevents a particular disease, condition, or disorder, (ii) alleviates, ameliorates, or eliminates one or more symptoms of a particular disease, condition, or disorder, or (iii) prevents or delays the onset of one or more symptoms of a particular disease, condition, or disorder as described herein. 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.

[0194] 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.

[0195] The term "pharmaceutically acceptable salt" refers to a salt of a pharmaceutically acceptable acid or base, including a salt formed between a compound and an inorganic acid or organic acid, and a salt formed between a compound and an inorganic base or an organic base.

[0196] The term "pharmaceutical composition" refers to a mixture of one or more compounds of the present disclosure or their salts and pharmaceutically acceptable excipients. The purpose of a pharmaceutical composition is to facilitate administration of the compounds of the present disclosure to an organism.

[0197] 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.

[0198] The word "comprise" or "comprises" and its English variations such as comprises or comprising should be understood as having an open and non-exclusive meaning, ie, "including but not limited to".

[0199] 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.

[0200] Certain isotopically labeled compounds of the present disclosure (e.g., 3 H and 14 C-labeled) can be used in compound and / or substrate tissue distribution assays. 3 H) and carbon-14 (i.e. 14 C) isotopes are particularly preferred due to their ease of preparation and detectability. Positron emitting isotopes, such as 15 O. 13 N. 11 C and 18 F can be used in positron emission tomography (PET) studies to determine substrate occupancy. Isotopically-labeled compounds of the disclosure can generally be prepared by following procedures analogous to those disclosed in the Schemes and / or Examples below, by substituting an isotopically-labeled reagent for a non-isotopically-labeled reagent.

[0201] 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.

[0202] Typical routes of administration of the compounds of the present disclosure, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof include, but are not limited to, oral, rectal, topical, inhalation, parenteral, sublingual, vaginal, intranasal, intraocular, intraperitoneal, intramuscular, subcutaneous, and intravenous administration.

[0203] 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.

[0204] 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.

[0205] 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.

[0206] The pharmaceutical composition may also be suitable for parenteral administration, such as sterile solutions, suspensions or lyophilized products in appropriate unit dosage forms.

[0207] The dosage of the compound or composition used in the treatment methods of the present disclosure will generally vary with the severity of the disease, the weight of the patient and the relative efficacy of the compound, but as a general guide, a suitable daily dosage of the compound of formula (I) described herein is 0.01 mg / kg to 1000 mg / kg.

[0208] The compounds of the present disclosure can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining them with other chemical synthesis methods, and equivalent substitutions well known to those skilled in the art. Preferred embodiments include but are not limited to the examples of the present disclosure.

[0209] The chemical reactions of the embodiments of the present disclosure are carried out in a suitable solvent that is compatible with the chemical transformations of the present disclosure and the reagents and materials required. In order to obtain the compounds of the present disclosure, it is sometimes necessary for those skilled in the art to modify or select synthetic steps or reaction schemes based on existing embodiments.

[0210] All reagents used in this disclosure were commercially available and used without further purification.

[0211] Unless otherwise specified, the ratios expressed for mixed solvents are volume ratios. Unless otherwise specified, % refers to wt%.

[0212] 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.

[0213] The eluent mentioned below can be a mixed eluent formed by two or more solvents, and the ratio thereof is the volume ratio of each solvent.

[0214] Explanation of terms or abbreviations:

[0215] Boc: tert-butyloxycarbonyl; MeOH: methanol; HOAc: acetic acid; NaOAc: sodium acetate; KOAc: potassium acetate; Ac2O: acetic anhydride; DCM: dichloromethane; TEA: triethylamine; ACN: acetonitrile; THF: tetrahydrofuran; NaBH(OAc)3: sodium acetate borohydride; DMF: N,N-dimethylformamide; t-BuOH: tert-butyl alcohol; t-BuOK: potassium tert-butoxide; Pd(dppf)Cl2: 1,1-bis(diphenylphosphino)ferrocenepalladium chloride; Pd(OAc2: palladium acetate); dioxane: 1,4-dioxane; toluene: toluene; triphosgene: triphosgene; B2Pin2: bis(pinacol boronate); Py: pyridine; MOMO: methoxymethoxy; HATU: O-(7-azabenzotriazol-1-yl)-N,N,N,N-tetrakis Methyluronium hexafluorophosphate; DIEA: N,N-diisopropylethylamine; BINAP: 1,1'-binaphthyl-2,2'-bisdiphenylphosphine; Ts: p-toluenesulfonyl; TsCl: p-toluenesulfonyl chloride; Tf: trifluoromethanesulfonyl; PMB: p-methoxybenzyl; Ms: methanesulfonyl; Pd-PEPPSI-Ipent-Cl: (SP-4-1)-[1,3-bis[2,6-bis(1-ethylpropyl)phenyl]-4,5-dichloro-1,3-dihydro-2H-imidazol-2-ylidene]dichloro(3-chloropyridine-κN)palladium.

[0216] Example 1: Synthesis of 2-(2-hydroxyphenyl)-8-(piperidin-4-ylamino)pyridazin[3,4-c]isoquinolin-6(5H)-one

[0217] Step 1: Synthesis of tert-butyl 4-(4-bromo-3-methoxycarbonyl-anilino)piperidine-1-carboxylate

[0218] Methyl 5-amino-2-bromobenzoate (500.0 mg, 2.2 mmol) and N-tert-butyloxycarbonyl-4-piperidone (649.6 mg, 3.3 mmol) were dissolved in anhydrous tetrahydrofuran (5 mL) and anhydrous N,N-dimethylformamide (5 mL). Sodium acetate borohydride (1.4 g, 6.5 mmol), acetic acid (391.5 mg, 6.5 mmol, 373.3 μL), and sodium acetate (534.9 mg, 6.5 mmol) were added. The reaction mixture was stirred at 60°C for 16 hours. LCMS confirmed the reaction was complete. Water (10 mL) was added, and the mixture was extracted with ethyl acetate (10 mL*3). The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to dryness under reduced pressure and purified by column chromatography (silica, petroleum ether: tetrahydrofuran = 2:1) to give tert-butyl 4-(4-bromo-3-methoxycarbonyl-anilino)piperidine-1-carboxylate (490.5 mg).

[0219] MS m / z(ESI):357.1,359.1[M-56+H] + .

[0220] Step 2: Synthesis of tert-butyl 4-[3-methoxycarbonyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)anilino]piperidine-1-carboxylate

[0221] Dissolve tert-butyl 4-(4-bromo-3-methoxycarbonyl-anilino)piperidine-1-carboxylate (200.0 mg, 483.9 μmol) and bis-pinacol boronate (184.3 mg, 725.9 μmol) in anhydrous dioxane (2 mL). Add 1,1-bis(diphenylphosphino)ferrocenepalladium dichloride (17.7 mg, 24.2 μmol) and potassium acetate (142.5 mg, 1.5 mmol). Stir the reaction at 80°C for 16 hours. LCMS confirms the reaction is complete. Water (10 mL) was added, and the mixture was extracted with ethyl acetate (25 mL*3). The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to dryness under reduced pressure and purified by column chromatography (silica, petroleum ether: tetrahydrofuran = 2:1) to give tert-butyl 4-[3-methoxycarbonyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)anilino]piperidine-1-carboxylate (245.7 mg).

[0222] MS m / z(ESI):483.0[M+Na] + .

[0223] Step 3: Synthesis of tert-butyl 4-[(2-chloro-6-oxo-5,6-dihydropyridazino[3,4-c]isoquinolin-8-yl)amino]piperidine-1-carboxylate

[0224] Tert-butyl 4-[3-methoxycarbonyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)anilino]piperidine-1-carboxylate (2.0 g, 4.3 mmol) and 4-bromo-6-chloro-pyridazin-3-amine (905.6 mg, 4.3 mmol) were dissolved in anhydrous dioxane (15 mL) and water (5 mL). 1,1-bis(diphenylphosphino)ferrocenepalladium dichloride (158.9 mg, 217.2 μmol) and sodium carbonate (1.4 g, 13.0 mmol) were added. The reaction mixture was stirred at 100°C for 3 hours. LCMS confirmed the reaction was complete. Water (30 mL) was added, and the mixture was extracted with ethyl acetate (30 mL*3). The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to dryness under reduced pressure and purified by column chromatography (silica, petroleum ether: tetrahydrofuran = 2:1) to give tert-butyl 4-[(2-chloro-6-oxo-5,6-dihydropyridazin[3,4-c]isoquinolin-8-yl)amino]piperidine-1-carboxylate (372.3 mg).

[0225] MS m / z(ESI):430.1[M+H] + .

[0226] Step 4: Synthesis of tert-butyl 4-[[2-[2-(methoxymethoxy)phenyl]-6-oxo-5,6-dihydropyridazino[3,4-c]isoquinolin-8-yl]amino]piperidine-1-carboxylate

[0227] Tert-butyl 4-[(2-chloro-6-oxo-5,6-dihydropyridazino[3,4-c]isoquinolin-8-yl)amino]piperidine-1-carboxylate (60 mg, 139.6 μmol) and 2-(methoxymethoxy)phenylboronic acid (33.0 mg, 181.4 μmol) were dissolved in anhydrous dioxane (1.5 mL) and water (0.5 mL). 1,1-bis(diphenylphosphino)ferrocenepalladium dichloride (10.2 mg, 14.0 μmol) and potassium carbonate (57.9 mg, 418.7 μmol) were added. The reaction mixture was stirred at 100°C for 2 hours. LCMS confirmed the reaction was complete. Water (3 mL) was added, and the mixture was extracted three times with ethyl acetate (3 mL). The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to dryness under reduced pressure and purified by thin layer chromatography (silica, petroleum ether:tetrahydrofuran = 1:2) to give tert-butyl 4-[[2-[2-(methoxymethoxy)phenyl]-6-oxo-5,6-dihydropyridazino[3,4-c]isoquinolin-8-yl]amino]piperidine-1-carboxylate (27 mg).

[0228] MS m / z(ESI):532.3[M+H] + .

[0229] Step 5: Synthesis of 2-(2-hydroxyphenyl)-8-(piperidin-4-ylamino)pyridazino[3,4-c]isoquinolin-6(5H)-one

[0230] Tert-butyl 4-[[2-[2-(methoxymethoxy)phenyl]-6-oxo-5,6-dihydropyridazino[3,4-c]isoquinolin-8-yl]amino]piperidine-1-carboxylate (27.0 mg, 50.8 μmol) was dissolved in anhydrous methanol (2 mL), and dioxane hydrochloride (4 M, 127.0 μL) was added. The reaction mixture was stirred at 25°C for 2 hours. The reaction was completed by LCMS. The reaction solution was concentrated, and the residue was purified by HPLC (Phenomenex Luna C18 column, 3 μm silica, 30 mm diameter, 150 mm length; using decreasingly polar mixtures of water (containing 0.225% formic acid) and acetonitrile (acetonitrile ratio 18%-38%) as eluent) to give 2-(2-hydroxyphenyl)-8-(piperidin-4-ylamino)pyridazin[3,4-c]isoquinolin-6(5H)-one (6.4 mg).

[0231] MS m / z(ESI):388.1[M+H] + ;

[0232] 1 H NMR (400MHz, DMSO-d6) δ = 9.00 (s, 1H), 8.68-8.58 (m, 1H), 8.52-8.31 (m, 1H), 8.25 (d, J = 7.7Hz, 1H), 7.48-7.41 (m, 1H), 7.39-7.32 (m, 1H),7.28-7.20(m,1H),7.06-6.98(m,2H),6.97-6.89(m,1H),3.26-3.16(m,3H),2.95-2.82(m,2H),2.11-1.89(m,2H),1.65(s,2H).

[0233] Example 2: Synthesis of 2-(2-hydroxyphenyl)-8-(piperazine-1-carbonyl)pyridazine[3,4-c]isoquinolin-6(5H)-one hydrochloride

[0234] Step 1: Synthesis of methyl 2-chloro-6-oxo-5,6-dihydropyridazino[3,4-c]isoquinoline-8-carboxylate

[0235] 3-Amino-4-bromo-6-chloropyridazine (450.0 mg, 2.2 mmol) and (2,4-bis(methoxycarbonyl)phenyl)boronic acid (565.2 mg, 2.4 mmol) were dissolved in dioxane (8 mL) and water (1.6 mL). Sodium carbonate (457.6 mg, 4.3 mmol) and [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium in dichloromethane (176.3 mg, 215.9 μmol) were added at 20°C. The reaction mixture was stirred at 100°C under nitrogen for 16 hours. LCMS indicated the reaction was complete. The reaction solution was diluted with water (10 mL), extracted with ethyl acetate three times (10 mL*3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by column chromatography (silica, tetrahydrofuran: petroleum ether = 0:1 to 2:1) to give methyl 2-chloro-6-oxo-5,6-dihydropyridazin[3,4-c]isoquinoline-8-carboxylate (183.0 mg).

[0236] MS m / z(ESI):289.9[M+H] + .

[0237] Step 2: Synthesis of methyl 2-[2-(methoxymethoxy)phenyl]-6-oxo-5,6-dihydropyridazino[3,4-c]isoquinoline-8-carboxylate

[0238] Methyl 2-chloro-6-oxo-5,6-dihydropyridazino[3,4-c]isoquinoline-8-carboxylate (160.0 mg, 552.4 μmol) and 2-(methoxymethoxy)phenylboronic acid (150.8 mg, 828.5 μmol) were dissolved in dioxane (8 mL) and water (1.6 mL). Potassium carbonate (152.7 mg, 1.1 mmol) and [1,1-bis(diphenylphosphino)ferrocene]palladium dichloride in dichloromethane (45.1 mg, 55.2 μmol) were added. The reaction mixture was stirred at 100°C under nitrogen for 1.5 hours. LCMS indicated the reaction was complete. The reaction solution was diluted with water (20 mL), extracted three times with ethyl acetate (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by column chromatography (silica, tetrahydrofuran:petroleum ether = 0:1 to 2:1) to give methyl 2-[2-(methoxymethoxy)phenyl]-6-oxo-5,6-dihydropyridazin[3,4-c]isoquinoline-8-carboxylate (172.0 mg).

[0239] MS m / z(ESI):392.1[M+H] + .

[0240] Step 3: Synthesis of 2-[2-(methoxymethoxy)phenyl]-6-oxo-5,6-dihydropyridazino[3,4-c]isoquinoline-8-carboxylic acid

[0241] Methyl 2-[2-(methoxymethoxy)phenyl]-6-oxo-5,6-dihydropyridazino[3,4-c]isoquinoline-8-carboxylate (60.0 mg, 153.3 μmol) was dissolved in tetrahydrofuran (1 mL) and water (1 mL), and sodium hydroxide (18.4 mg, 459.9 μmol) was added. The reaction mixture was reacted at 25°C for 2 hours, and the reaction was complete by LCMS. The reaction mixture was adjusted to pH 7-8 with 1.5 M hydrochloric acid and extracted with ethyl acetate (15 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to yield 2-[2-(methoxymethoxy)phenyl]-6-oxo-5,6-dihydropyridazino[3,4-c]isoquinoline-8-carboxylic acid (60 mg).

[0242] MS m / z(ESI):378.3[M+H] + .

[0243] Step 4: Synthesis of tert-butyl 4-[2-[2-(methoxymethoxy)phenyl]-6-oxo-5,6-dihydropyridazino[3,4-c]isoquinoline-8-carbonyl]piperazine-1-carboxylate

[0244] 2-[2-(Methoxymethoxy)phenyl]-6-oxo-5,6-dihydropyridazino[3,4-c]isoquinoline-8-carboxylic acid (60.0 mg, 159.0 μmol) and 1-Boc-piperazine (35.5 mg, 190.8 μmol) were dissolved in N,N-dimethylformamide (1 mL). N,N-diisopropylethylamine (61.65 mg, 477.01 μmol) and O-(7-azabenzotriazol-1-yl)-N,N,N,N-tetramethyluronium hexafluorophosphonate (60.5 mg, 159.0 μmol) were added. The reaction mixture was reacted at 25°C for 2 hours. The reaction was completed by LCMS. The reaction solution was quenched with water (5 mL), extracted with ethyl acetate (15 mL*3), and the organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (silica, petroleum ether / ethyl acetate = 1 / 1) to give tert-butyl 4-[2-[2-(methoxymethoxy)phenyl]-6-oxo-5,6-dihydropyridazino[3,4-c]isoquinoline-8-carbonyl]piperazine-1-carboxylate (23.0 mg).

[0245] MS m / z(ESI):546.3[M+H] + .

[0246] Step 5: Synthesis of 2-(2-hydroxyphenyl)-8-(piperazine-1-carbonyl)pyridazino[3,4-c]isoquinolin-6(5H)-one hydrochloride

[0247] Tert-butyl 4-[2-[2-(methoxymethoxy)phenyl]-6-oxo-5,6-dihydropyridazino[3,4-c]isoquinoline-8-carbonyl]piperazine-1-carboxylate (10.0 mg, 18.3 μmol) was dissolved in dichloromethane (0.5 mL). Dioxane hydrochloride (4 M, 45.8 μL) was added, and the reaction mixture was allowed to react at 25°C for 12 hours. LCMS confirmed the completion of the reaction. The reaction mixture was concentrated to dryness under reduced pressure to yield 2-(2-hydroxyphenyl)-8-(piperazine-1-carbonyl)pyridazino[3,4-c]isoquinolin-6(5H)-one hydrochloride (4.0 mg).

[0248] MS m / z(ESI):402.1[M+H] + ;

[0249] 1 H NMR (400MHz, DMSO-d6) δ12.85(s,1H),9.41-9.28(m,3H),9.04(d,J=8.4Hz,1H),8.43(d,J=1.3Hz,1H ),8.24(d,J=7.0Hz,1H),8.08(dd,J=1.4,8.3Hz,1H),7.43-7.35(m,1H),7.08-7.01(m,2H),3.89(br s,2H),3.62-3.55(m,2H),3.17(br s,4H).

[0250] Example 3: Synthesis of 2-(2-hydroxyphenyl)-8-(piperazin-1-yl)pyridazino[3,4-c]isoquinolin-6(5H)-one

[0251] Step 1: Synthesis of tert-butyl 4-(4-bromo-3-methoxycarbonylphenyl)piperazine-1-carboxylate

[0252] Methyl 2-bromo-5-iodobenzoate (2.0 g, 5.9 mmol) and N-Boc piperazine (1.2 g, 6.2 mmol) were dissolved in anhydrous toluene (40 mL). Cesium carbonate (3.8 g, 11.7 mmol), 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (365.3 mg, 586.6 μmol), and palladium acetate (131.7 mg, 586.6 μmol) were added. The reaction mixture was stirred at 100°C under a nitrogen atmosphere for 3 hours. The reaction was completed by LCMS detection. The reaction solution was cooled to room temperature, quenched by adding water (20 mL), diluted with water (50 mL) and extracted three times with ethyl acetate (150 mL). The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to dryness under reduced pressure and purified by column chromatography (silica, petroleum ether:tetrahydrofuran = 4:1) to give tert-butyl 4-(4-bromo-3-methoxycarbonylphenyl)piperazine-1-carboxylate (1.85 g).

[0253] MS m / z(ESI):343.2,354.2[M+H-56] + .

[0254] Step 2: Synthesis of tert-butyl 4-(3-(methoxycarbonyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperazine-1-carboxylate

[0255] Tert-butyl 4-(4-bromo-3-methoxycarbonylphenyl)piperazine-1-carboxylate (500.0 mg, 1.3 mmol) and bispinacol borate (477.0 mg, 1.9 mmol) were dissolved in anhydrous dioxane (10 mL). Potassium acetate (307.2 mg, 3.1 mmol) and 1,1-bis(diphenylphosphino)ferrocenepalladium dichloride (45.8 mg, 62.6 μmol) were added. The reaction mixture was stirred at 100°C under a nitrogen atmosphere for 16 hours. The reaction was completed by LCMS detection. The reaction solution was cooled to room temperature, quenched by the addition of water (1 mL), diluted with water (20 mL) and extracted with ethyl acetate (60 mL*3). The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to dryness under reduced pressure and purified by column chromatography (silica, petroleum ether:tetrahydrofuran = 2:1) to give tert-butyl 4-(3-(methoxycarbonyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperazine-1-carboxylate (390.0 mg).

[0256] MS m / z(ESI):447.3[M+H] + .

[0257] Step 3: Synthesis of tert-butyl 4-(2-chloro-6-oxo-5,6-dihydropyridazino[3,4-c]isoquinolin-8-yl)piperazine-1-carboxylate

[0258] Tert-butyl 4-(3-(methoxycarbonyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperazine-1-carboxylate (370.0 mg, 829.0 μmol) and 3-amino-4-bromo-6-chloropyridazine (172.8 mg, 829.0 μmol) were dissolved in anhydrous dioxane (7.5 mL) and water (2.5 mL). Anhydrous sodium carbonate (263.6 mg, 2.5 mmol) and 1,1-bis(diphenylphosphino)ferrocenepalladium dichloride (30.3 mg, 41.5 μmol) were added. The reaction mixture was stirred at 100° C. under a nitrogen atmosphere for 3 hours. LCMS detected that the reaction was complete, and the reaction solution was cooled to room temperature, quenched by adding water (1 mL), diluted with water (20 mL) and extracted three times with ethyl acetate (60 mL). The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to dryness under reduced pressure and purified by column chromatography (silica, petroleum ether:tetrahydrofuran = 1:1) to give tert-butyl 4-(2-chloro-6-oxo-5,6-dihydropyridazino[3,4-c]isoquinolin-8-yl)piperazine-1-carboxylate (137.0 mg).

[0259] MS m / z(ESI):416.2[M+H] + .

[0260] Step 4: Synthesis of tert-butyl 4-(2-(2-(methoxymethoxy)phenyl)-6-oxo-5,6-dihydropyridazino[3,4-c]isoquinolin-8-yl)piperazine-1-carboxylate

[0261] Tert-butyl 4-(2-chloro-6-oxo-5,6-dihydropyridazin[3,4-c]isoquinolin-8-yl)piperazine-1-carboxylate (117.0 mg, 281.3 μmol) and 2-(methoxymethoxy)phenylboronic acid (71.7 mg, 393.9 μmol) were dissolved in anhydrous dioxane (3 mL) and water (1 mL), and anhydrous potassium carbonate (116.7 mg, 844.0 μmol) and 1,1-bis(diphenylphosphino)ferrocenepalladium dichloride (20.6 mg, 28.1 μmol) were added, and the reaction solution was stirred at 100 ° C. under a nitrogen atmosphere for 2 hours. The reaction was completed by LCMS detection, and water (1 mL) was added to quench the reaction, diluted with water (20 mL) and extracted three times with ethyl acetate (60 mL). The organic phase was dried over anhydrous sodium sulfate and filtered, then concentrated to dryness under reduced pressure. The product was purified by column chromatography (silica, petroleum ether:tetrahydrofuran = 3:2) to give tert-butyl 4-(2-(2-(methoxymethoxy)phenyl)-6-oxo-5,6-dihydropyridazino[3,4-c]isoquinolin-8-yl)piperazine-1-carboxylate (107.0 mg).

[0262] MS m / z(ESI):518.3[M+H] + .

[0263] Step 5: Synthesis of 2-(2-hydroxyphenyl)-8-(piperazin-1-yl)pyridazino[3,4-c]isoquinolin-6(5H)-one

[0264] Dissolve tert-butyl 4-(2-(2-(methoxymethoxy)phenyl)-6-oxo-5,6-dihydropyridazino[3,4-c]isoquinolin-8-yl)piperazine-1-carboxylate (107.0 mg, 206.7 μmol) in anhydrous methanol (2 mL). Add dioxane hydrochloride solution (4 M, 516.8 μL). Stir the reaction at 25°C for 16 hours. LCMS analysis indicates the reaction is complete. Concentrate the reaction mixture to dryness under reduced pressure. The product was purified by high performance liquid chromatography (C18 column, 40 mm diameter, 150 mm length; using decreasingly polar mixtures of water (containing 0.05% ammonia and ammonium bicarbonate) and acetonitrile (acetonitrile ratio 23%-63%) as eluent) to give 2-(2-hydroxyphenyl)-8-(piperazin-1-yl)pyridazino[3,4-c]isoquinolin-6(5H)-one (13.0 mg).

[0265] MS m / z(ESI):374.2[M+H] + .

[0266] Example 4: 2-(2,6-dioxopiperidin-3-yl)-5-[4-[[4-[[2-(2-hydroxyphenyl)-6-oxo-5,6-dihydropyridazino[3,4-c]isoquinolin-8-yl]amino]piperidin-1-yl]methyl]piperidin-1-yl]isoindoline-1,3-dione

[0267] 1-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl]piperidine-4-carbaldehyde (12.2 mg, 33.1 μmol) and 2-(2-hydroxyphenyl)-8-(piperidin-4-ylamino)pyridazino[3,4-c]isoquinolin-6(5H)-one (14.1 mg, 36.4 μmol) were dissolved in anhydrous tetrahydrofuran (0.5 mL) and anhydrous N,N-dimethylformamide (0.5 mL). Sodium acetate borohydride (21.0 mg, 99.3 μmol) and acetic acid (6.0 mg, 99.3 μmol, 5.7 μL) were added. The reaction mixture was stirred at 30°C for 2 hours. The reaction was complete by LCMS. The reaction mixture was concentrated to dryness under reduced pressure. The product was purified by high performance liquid chromatography (Boston Prime C18 column, 5 μm silica, 30 mm diameter, 150 mm length; using decreasingly polar mixtures of water (containing 0.225% formic acid) and acetonitrile (acetonitrile ratio 28%-48%) as eluent to give 2-(2,6-dioxopiperidin-3-yl)-5-[4-[[4-[[2-(2-hydroxyphenyl)-6-oxo-5,6-dihydropyridazino[3,4-c]isoquinolin-8-yl]amino]piperidin-1-yl]methyl]piperidin-1-yl]isoindoline-1,3-dione (5.8 mg).

[0268] MS m / z(ESI):741.3[M+H] + ;

[0269] 1 H NMR (400MHz, DMSO-d6) δ = 13.49 (s, 1H), 12.53 (s, 1H), 11.15 (s, 1H), 8.98 (s, 1H), 8.63 (J = 9.1Hz, 1H),8.25(s,1H),7.69-7.61(m,1H),7.44-7.28(m,3H),7.22(d,J=8.8Hz,2H),7.05-6.97(m,2H), 6.83(d,J=7.8Hz,1H),5.11-5.00(m,1H),4.10-3.98(m,2H),3.03-2.80(m,6H),2.62-2.54(m,2H) ),2.21-2.07(m,4H),2.05-1.91(m,3H),1.87-1.75(m,3H),1.55-1.41(m,2H),1.24-1.08(m,2H).

[0270] Example 5: Synthesis of 2-(2,6-dioxopiperidin-3-yl)-5-[4-[[4-[2-(2-hydroxyphenyl)-6-oxo-5H-pyridazino[3,4-c]isoquinoline-8-carbonyl]piperazin-1-yl]methyl]piperidin-1-yl]isoindoline-1,3-dione

[0271] 2-(2-Hydroxyphenyl)-8-(piperazine-1-carbonyl)-5H-pyridazino[3,4-c]isoquinolin-6-one hydrochloride (7.0 mg, 16.0 μmol) and 1-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl]piperidine-4-carbaldehyde (5.9 mg, 16.0 μmol) were dissolved in N,N-dimethylformamide (0.2 mL) and tetrahydrofuran (0.2 mL). Sodium acetate borohydride (13.6 mg, 63.9 μmol), sodium acetate (5.3 mg, 63.9 μmol), and acetic acid (960.0 μg, 16.0 μmol) were added. The reaction mixture was reacted at 25°C for 2 hours. The reaction was completed by LCMS. The reaction mixture was concentrated and purified by preparative liquid chromatography (Boston Prime C18 column: 3 μm silica, 30 mm diameter, 150 mm length; using decreasingly polar mixtures of water (containing 0.05% ammonia) and acetonitrile (acetonitrile ratio 31%-71%) as eluent) to give 2-(2,6-dioxopiperidin-3-yl)-5-[4-[[4-[2-(2-hydroxyphenyl)-6-oxo-5H-pyridazino[3,4-c]isoquinoline-8-carbonyl]piperazin-1-yl]methyl]piperidin-1-yl]isoindoline-1,3-dione (1.7 mg).

[0272] MS m / z(ESI):755.4[M+H] + ;

[0273] 1H NMR (400MHz, DMSO-d6) δ = 12.79 (br s, 1H), 12.70 (br s, 1H), 11.09 (br s,1H),9.32(s,1H),9.05(d,J=8.5Hz,1H),8.32(d,J=1.5Hz,1H),8.27(d,J=7.0Hz,1H),8.03(dd,J=1.4,8.2Hz,1H),7.65(d,J=8.5Hz,1H) ,7.44-7.36(m,1H),7.31(s,1H),7.23(dd,J=1.9,8.7Hz,1H),7.08-7.02(m,2H),5.07(dd,J=5.3,12.9Hz,1H),4.12-3.98(m,2H),3.71(br s,2H),3.02-2.92(m,3H),2.91-2.81(m,1H),2.62-2.57(m,2H),2.37(br s,1H),2.25-2.192(m,2H),2.08-1.93(m,3H),1.86-1.75(m,4H),1.22-1.07(m,3H).

[0274] Example 6: Synthesis of 3-(7-(4-((4-((2-(2-hydroxyphenyl)-6-oxo-5,6-dihydropyridazino[3,4-c]isoquinolin-8-yl)amino)piperidin-1-yl)methyl)piperidin-1-yl)-1-methyl-2-oxo-1,2-dihydro-3H-naphtho[1,2-d]imidazol-3-yl)piperidine-2,6-dione

[0275] Step 1: Synthesis of N-(6-bromonaphthalen-2-yl)-4-methyl-benzenesulfonamide

[0276] 6-Bronaphthalen-2-amine (25.0 g, 112.6 mmol) was dissolved in dichloromethane (170 mL), and p-toluenesulfonyl chloride (42.9 g, 225.1 mmol) and pyridine (26.7 g, 337.7 mmol) were added. The reaction mixture was stirred at 25°C for 12 hours. LCMS confirmed the reaction was complete. Ethyl acetate (150 mL x 2) and water (200 mL) were added to the reaction mixture. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure. The product was purified by column chromatography (silica, petroleum ether / tetrahydrofuran = 7 / 1) to afford N-(6-bromonaphthalen-2-yl)-4-methylbenzenesulfonamide (36.0 g).

[0277] MS m / z(ESI):376.0,378.0[M+H] + .

[0278] Step 2: Synthesis of N-(6-bromo-1-nitronaphthalen-2-yl)-4-methylbenzenesulfonamide

[0279] Dissolve N-(6-bromonaphthalen-2-yl)-4-methylbenzenesulfonamide (20.0 g, 53.2 mmol) in acetic acid (200 mL), add acetic anhydride (54.3 g, 531.5 mmol) and nitric acid (16.8 g, 266.6 mmol). Stir the reaction mixture at 25°C for 2 hours. Completion of the reaction was detected by thin-layer chromatography (petroleum ether / ethyl acetate = 3 / 1). Ice water (100 mL) was added to the reaction mixture to quench the reaction. Ethyl acetate (150 mL*2) and water (200 mL) were added. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure to obtain N-(6-bromo-1-nitronaphthalen-2-yl)-4-methylbenzenesulfonamide (14 g).

[0280] 1 H NMR (400MHz, DMSO-d6) δ = 8.40 (s, 1H), 8.13-8.06 (m, 1H), 7.87-7.78 (m, 1H), 7.74-7.53 (m, 3H), 7.44-7.34 (m, 3H), 2.40-2.33 (m, 3H).

[0281] Step 3: Synthesis of N-(1-amino-6-bromonaphthalen-2-yl)-4-methylbenzenesulfonamide

[0282] N-(6-bromo-1-nitronaphthalen-2-yl)-4-methylbenzenesulfonamide (20.0 g, 47.5 mmol) was dissolved in ethanol (100 mL) and water (100 mL). Iron powder (26.51 g, 474.76 mmol) and ammonium chloride (25.39 g, 474.76 mmol) were added. The reaction mixture was stirred at 70°C for 2 hours. LCMS confirmed the reaction was complete. Ethyl acetate (150 mL x 2) and water (200 mL) were added to the reaction mixture. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure. Purification by column chromatography (silica, petroleum ether / tetrahydrofuran = 3 / 1) afforded N-(1-amino-6-bromonaphthalen-2-yl)-4-methylbenzenesulfonamide (12.0 g).

[0283] MS m / z(ESI):391.0,393.0[M+H] + .

[0284] Step 4: Synthesis of 7-bromo-3-(p-toluenesulfonyl)-1,3-dihydro-2H-naphtho[1,2-d]imidazol-2-one

[0285] Dissolve N-(1-amino-6-bromonaphthalen-2-yl)-4-methylbenzenesulfonamide (11.0 g, 28.1 mmol) in tetrahydrofuran (200 mL). Add triphosgene (4.4 g, 14.8 mmol) at 0°C. After stirring for a while, add triethylamine (8.5 g, 84.3 mmol). Stir the reaction mixture at 25°C for 2 hours. LCMS confirms the reaction is complete. Quench the reaction mixture with saturated sodium bicarbonate solution (100 mL), filter, and rinse the filter cake three times with petroleum ether to obtain 7-bromo-3-(p-toluenesulfonyl)-1,3-dihydro-2H-naphtho[1,2-d]imidazol-2-one (10.1 g).

[0286] MS m / z(ESI):417.0,419.0[M+H] + .

[0287] Step 5: Synthesis of 7-bromo-1-methyl-3-(p-toluenesulfonyl)-1,3-dihydro-2H-naphtho[1,2-d]imidazol-2-one

[0288] Dissolve 7-bromo-3-(p-toluenesulfonyl)-1,3-dihydro-2H-naphtho[1,2-d]imidazol-2-one (10.0 g, 24.0 mmol) in acetonitrile (100 mL), add potassium carbonate (9.9 g, 71.9 mmol) and iodomethane (8.5 g, 59.9 mmol). Stir the reaction mixture at 50°C for 3 hours. LCMS confirms the reaction is complete. Add 100 mL of water to the reaction mixture, filter, and rinse the filter cake three times with petroleum ether to obtain 7-bromo-1-methyl-3-(p-toluenesulfonyl)-1,3-dihydro-2H-naphtho[1,2-d]imidazol-2-one (9.1 g).

[0289] MS m / z(ESI):431.0,433.0[M+H] + .

[0290] Step 6: Synthesis of 7-bromo-1-methyl-1,3-dihydro-2H-naphtho[1,2-d]imidazol-2-one

[0291] Dissolve 7-bromo-1-methyl-3-(p-toluenesulfonyl)-1,3-dihydro-2H-naphtho[1,2-d]imidazol-2-one (948.9 mg, 2.2 mmol) in tert-butanol (10 mL) and add potassium hydroxide (374.6 mg, 6.7 mmol). Stir the reaction mixture at 25°C for 16 hours. LCMS confirms the reaction is complete. Add 100 mL of water to the reaction mixture, filter, and rinse the filter cake three times with ethyl acetate to yield 7-bromo-1-methyl-1,3-dihydro-2H-naphtho[1,2-d]imidazol-2-one (450.0 mg).

[0292] MS m / z(ESI):276.9,278.9[M+H] + .

[0293] Step 7: Synthesis of 3-(7-bromo-1-methyl-2-oxo-1,2-dihydro-3H-naphtho[1,2-d]imidazol-3-yl)-1-(4-methoxybenzyl)piperidine-2,6-dione

[0294] Dissolve 7-bromo-1-methyl-1,3-dihydro-2H-naphtho[1,2-d]imidazol-2-one (4 g, 14.4 mmol) and 1-(4-methoxybenzyl)-2,6-dioxopiperidin-3-yl trifluoromethanesulfonate (6.1 g, 15.9 mmol) in tetrahydrofuran (40 mL). Add potassium tert-butoxide (3.2 g, 28.9 mmol) at -40°C. Stir the reaction mixture at 0°C under N2 protection for 2 hours. LCMS indicates completion of the reaction. Ethyl acetate (50 mL*2) and 60 mL of water were added to the reaction solution, the organic phase was dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated to dryness under reduced pressure and purified by chromatography (silica, petroleum ether / tetrahydrofuran = 3 / 2) to give 3-(7-bromo-1-methyl-2-oxo-1,2-dihydro-3H-naphtho[1,2-d]imidazol-3-yl)-1-(4-methoxybenzyl)piperidine-2,6-dione (3.4 g).

[0295] MS m / z(ESI):508.0,510.0[M+H] + .

[0296] Step 8: Synthesis of 3-(7-bromo-1-methyl-2-oxo-1,2-dihydro-3H-naphtho[1,2-d]imidazol-3-yl)piperidine-2,6-dione

[0297] Dissolve 3-(7-bromo-1-methyl-2-oxo-1,2-dihydro-3H-naphtho[1,2-d]imidazol-3-yl)-1-(4-methoxybenzyl)piperidine-2,6-dione (3.4 g, 6.7 mmol) in toluene (80 mL) and add methanesulfonic acid (30 mL). Stir the reaction mixture at 120°C under nitrogen for 3 hours. LCMS confirms the reaction is complete. Add saturated sodium bicarbonate (100 mL) to the reaction mixture to adjust the pH to 8-9. Filter the mixture, and rinse the filter cake three times with petroleum ether to yield 3-(7-bromo-1-methyl-2-oxo-1,2-dihydro-3H-naphtho[1,2-d]imidazol-3-yl)piperidine-2,6-dione (1.5 g).

[0298] 1H NMR (400MHz, DMSO-d6) δ = 8.40-8.34 (m, 1H), 8.26 (d, J = 2.0Hz, 1H), 7.69-7.65 (m, 1H), 7.65-7.55 (m,1H),7.61-7.55(m,1H),5.60-5.46(m,1H),3.86-3.83(m,3H),3.32(s,2H),2.74-2.56(m,2H).

[0299] Step 9: Synthesis of 3-(7-(4-(dimethoxymethyl)piperidin-1-yl)-1-methyl-2-oxo-1,2-dihydro-3H-naphtho[1,2-d]imidazol-3-yl)piperidine-2,6-dione

[0300] 3-(7-Bromo-1-methyl-2-oxo-1,2-dihydro-3H-naphtho[1,2-d]imidazol-3-yl)piperidine-2,6-dione (50.0 mg, 128.8 μmol) and 4-(dimethoxymethyl)piperidine (41.0 mg, 257.6 μmol) were dissolved in dioxane (1 mL). Under nitrogen, (SP-4-1)-[1,3-bis[2,6-bis(1-ethylpropyl)phenyl]-4,5-dichloro-1,3-dihydro-2H-imidazol-2-ylidene]dichloro(3-chloropyridine-κN)palladium (11.1 mg, 12.9 μmol) and cesium carbonate (126.0 mg, 386.6 μmol) were added. The reaction mixture was reacted at 100°C for 2 hours. LCMS confirmed the reaction was complete. The reaction solution was concentrated under reduced pressure, and the concentrate was extracted with ethyl acetate (3 mL*3) and saturated aqueous ammonium chloride solution (4 mL). The organic phase was concentrated to dryness under reduced pressure, and the concentrate was purified by thin layer chromatography (silica, petroleum ether / tetrahydrofuran = 1:1) to give 3-(7-(4-(dimethoxymethyl)piperidin-1-yl)-1-methyl-2-oxo-1,2-dihydro-3H-naphtho[1,2-d]imidazol-3-yl)piperidine-2,6-dione (40.0 mg).

[0301] MS m / z(ESI):467.1[M+H] + .

[0302] Step 10: Synthesis of 1-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-2-oxo-2,3-dihydro-1H-naphtho[1,2-d]imidazol-7-yl)piperidine-4-carbaldehyde

[0303] 3-(7-(4-(dimethoxymethyl)piperidin-1-yl)-1-methyl-2-oxo-1,2-dihydro-3H-naphtho[1,2-d]imidazol-3-yl)piperidine-2,6-dione (25.0 mg, 53.6 μmol) was dissolved in tetrahydrofuran (1 mL). Hydrochloric acid (2 M, 535.9 μL) was added, and the reaction mixture was stirred at 25°C for 1 hour. LCMS indicated the reaction was complete. The pH of the reaction mixture was adjusted to 8-9 with saturated sodium bicarbonate solution and extracted with ethyl acetate (2 mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure to obtain 1-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-2-oxo-2,3-dihydro-1H-naphtho[1,2-d]imidazol-7-yl)piperidine-4-carbaldehyde (20.0 mg).

[0304] MS m / z(ESI):421.2[M+H] + .

[0305] Step 11: Synthesis of 3-(7-(4-((4-((2-(2-hydroxyphenyl)-6-oxo-5,6-dihydropyridazino[3,4-c]isoquinolin-8-yl)amino)piperidin-1-yl)methyl)piperidin-1-yl)-1-methyl-2-oxo-1,2-dihydro-3H-naphtho[1,2-d]imidazol-3-yl)piperidine-2,6-dione

[0306] 1-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-2-oxo-2,3-dihydro-1H-naphtho[1,2-d]imidazol-7-yl)piperidine-4-carbaldehyde (26.2 mg, 62.4 μmol) and 2-(2-hydroxyphenyl)-8-(piperidin-4-ylamino)pyridazino[3,4-c]isoquinolin-6(5H)-one (19.3 mg, 49.9 μmol) were dissolved in N,N-dimethylformamide (0.5 mL) and tetrahydrofuran (0.5 mL). Sodium acetate (15.4 mg, 187.2 μmol), acetic acid (11.2 mg, 187.1 μmol), and sodium acetate borohydride (26.4 mg, 124.8 μmol) were added. The reaction mixture was stirred at 25°C for 2 hours. LCMS confirmed the reaction was complete. The reaction solution was concentrated to dryness under reduced pressure and purified by preparative liquid chromatography (Phenomenex C18 column: 3 μm silica, 30 mm diameter, 75 mm length; using decreasingly polar mixtures of water (containing 0.05% ammonia) and acetonitrile (acetonitrile ratio 41%-81%) as eluent) to give 3-(7-(4-((4-((2-(2-hydroxyphenyl)-6-oxo-5,6-dihydropyridazino[3,4-c]isoquinolin-8-yl)amino)piperidin-1-yl)methyl)piperidin-1-yl)-1-methyl-2-oxo-1,2-dihydro-3H-naphtho[1,2-d]imidazol-3-yl)piperidine-2,6-dione (2.3 mg).

[0307] MS m / z:792.6[M+H] + ;

[0308] 1 H NMR (400MHz, DMSO-d6) δ = 13.42 (s, 1H), 12.52 (s, J = 4.8Hz, 1H), 11.19 (s, 1H), 9.03 (s, 1H), 8.68-8.60 (m, 1H), 8.30-8 .21(m,2H),7.48(d,J=8.6Hz,1H),7.43-7.38(m,2H),7.35(d,J=8.6Hz,2H),7.27-7.21(m,2H),7.06-6.96(m,2H),6. 88(s,1H),5.52-5.39(m,1H),3.81(s,3H),3.54-3.41(m,2H),2.93-2.83(m,3H),2.77-2.64(m,5H),2.26-2.19(m,2H ),2.17-2.09(m,2H),2.00-1.93(m,2H),1.90-1.80(m,2H),1.76-1.67(m,1H),1.58-1.44(m,2H),1.35-1.20(m,3H).

[0309] Example 7: Synthesis of 3-(4-(1-(2-(4-(2-(2-hydroxyphenyl)-6-oxo-5,6-dihydropyridazino[3,4-c]isoquinoline-8-carbonyl)piperazin-1-yl)-2-oxoethyl)piperidin-4-yl)phenyl)piperidine-2,6-dione

[0310] 2-(2-Hydroxyphenyl)-8-(piperazine-1-carbonyl)pyridazino[3,4-c]isoquinolin-6(5H)-one hydrochloride (8.8 mg, 20.1 μmol) and 2-[4-[4-(2,6-dioxopiperidin-3-yl)phenyl]piperidin-1-yl]acetic acid (6.6 mg, 20.1 μmol) were dissolved in N,N-dimethylformamide (0.5 mL). N,N-diisopropylethylamine (7.1 mg, 54.8 μmol) and O-(7-azabenzotriazol-1-yl)-N,N,N,N-tetramethyluronium hexafluorophosphonate (7.6 mg, 20.1 μmol) were added. The reaction mixture was reacted at 25°C for 2 hours. The reaction was completed by LCMS. The reaction solution was quenched with water (1 mL), extracted with ethyl acetate (1 mL*3), and the organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and purified by preparative liquid chromatography (Phenomenex Gemini NX column: 5 μm silica, 30 mm diameter, 150 mm length; using decreasingly polar mixtures of water (containing 0.225% formic acid) and acetonitrile (acetonitrile ratio 11%-55%) as eluents) to give 3-(4-(1-(2-(4-(2-(2-hydroxyphenyl)-6-oxo-5,6-dihydropyridazino[3,4-c]isoquinoline-8-carbonyl)piperazin-1-yl)-2-oxoethyl)piperidin-4-yl)phenyl)piperidine-2,6-dione (3.4 mg).

[0311] MS m / z(ESI):714.4[M+H] + ;

[0312] 1H NMR(400MHz,DMSO-d6)δ=12.83(br s,1H),12.69(s,1H),10.83(s,1H),9.33(s,1H),9.06(d,J=8.1Hz,1H),8.39(s,1H),8.08(d,J=8.0Hz,1H),7.43-7.37(m,1H),7.27-7.11(m ,4H),7.09-7.03(m,2H),3.87-3.48(m,5H),2.99-2.85(m,4H),2.66- 2.57(m,2H),2.56-2.53(m,2H),2.25-1.95(m,6H),1.83-1.57(m,5H).

[0313] Example 8: Synthesis of 2-(2,6-dioxopiperidin-3-yl)-5-(4-((4-(2-(2-hydroxyphenyl)-6-oxo-5,6-dihydropyridazino[3,4-c]isoquinolin-8-yl)piperazin-1-yl)methyl)piperidin-1-yl)isoindoline-1,3-dione

[0314] 2-(2-Hydroxyphenyl)-8-(piperazin-1-yl)pyridazino[3,4-c]isoquinolin-6(5H)-one (10.0 mg, 26.8 μmol) and 1-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl]piperidine-4-carbaldehyde (9.9 mg, 26.8 μmol) were dissolved in anhydrous tetrahydrofuran (0.25 mL) and anhydrous N,N-dimethylformamide (0.25 mL). Anhydrous sodium acetate (6.6 mg, 80.3 μmol), acetic acid (4.8 mg, 80.3 μmol), and sodium acetate borohydride (17.0 mg, 80.3 μmol) were added. The reaction mixture was stirred at 25°C for 2 hours. The reaction was complete after LCMS detection. The reaction solution was quenched with water (0.5 mL) and concentrated to dryness under reduced pressure. The product was purified by HPLC (Boston Prime C18 column, 5 μm silica, 30 mm diameter, 150 mm length; using decreasingly polar mixtures of water (containing 0.05% ammonia) and acetonitrile (acetonitrile ratio 53%-73%) as eluent) to give 2-(2,6-dioxopiperidin-3-yl)-5-(4-((4-(2-(2-hydroxyphenyl)-6-oxo-5,6-dihydropyridazino[3,4-c]isoquinolin-8-yl)piperazin-1-yl)methyl)piperidin-1-yl)isoindoline-1,3-dione (4.2 mg).

[0315] MS m / z(ESI):727.3[M+H] + ;

[0316] 1 H NMR (400MHz, DMSO-d6) δ = 13.27 (s, 1H), 11.09 (s, 1H), 9.11 (s, 1H), 8.80-8.75 (m, 1H), 8.28 (d, J = 8.1Hz, 1H), 7.70 (d, J = 2.1Hz, 1H), 7. 68-7.62(m,2H),7.40-7.31(m,2H),7.25(d,J=8.4Hz,1H),7.06-7.00(m,2H),5.07(dd,J=5.6,12.9Hz,1H),4.10-4.03(m,2H),3.47(br s,5H),3.10-2.92(m,2H),2.61-2.50(m,5H),2.29-2.20(m,2H),2.06-1.98(m,1H),1.95-1.81(m,3H),1.26-1.13(m,3H).

[0317] Biological activity and related properties test examples

[0318] Test Example 1: TR-FRET Binding Assay

[0319] The assay was performed using the SMARCA2 TR-FRET Assay Kit (BPS Bioscience, cat#40342). 3X BRD TR-FRET Assay buffer was diluted to 1X, and BRM (1:1000), Bromodomain Ligand 2 (1:40), Tb-labeled donor (1:100), and Dye-labeled acceptor (1:100) were diluted accordingly. PFI-3 (Selleck, CAS No. 1819363-80-8) served as a positive control, while a DMSO group served as a negative control, and a group without BRM served as a blank control. Test compounds were prepared in DMSO to a 10 mM stock solution, then serially diluted threefold in ddH₂O. 2 μL of the diluted test compound solution and 3 μL of the BRM solution were added to a 96-well white plate (Cisbio, cat#66PL96025) and incubated at room temperature for 10 minutes. Subsequently, 5 μL of Bromodomain Ligand 2, 5 μL of Tb-labeled donor, and 5 μL of Dye-labeled acceptor solution were added, shaken for 30 seconds, and briefly centrifuged at 1000 rpm / min. After incubation at room temperature for 30 minutes, the mixture was assayed using an Envision multifunctional microplate reader (purchased from PerkinElmer). The TR-FRET ratio (655 nm / 622 nm) was analyzed using GraphPad software. The concentration-effect curve was fitted with a nonlinear four-parameter curve, and the EC of the compound was calculated. 50 , the calculation method is as follows:

[0320] in:

[0321] FRET Sample : FRET value of each well in the compound addition group;

[0322] FRET Blank : FRET value of blank control group;

[0323] FRET DMSO : FRET value of negative control group;

[0324] The binding activity of the compounds of the present disclosure to BRM was tested according to the above test method (EC 50 ), some of the results are summarized in Table 1.

[0325] Table 1

[0326] Test Example 2: Detecting the BRM and BRG1 protein degradation activity of compounds using HiBiT detection technology

[0327] 1. Cell line construction:

[0328] 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 Cas9 Protein v2, A36498, Invitrogen; Lipofectamine TM CRISPRMAX TM Cas9 transfection reagent, CMAX00003, Invitrogen; Opti-MEM TM I Reduced Serum Medium, 31985070, Thermofisher), the required amounts of various reagents, sgRNA, and donor DNA were calculated according to the amount of transfection reagent required for a 6-well plate in the instruction manual, and transfection was performed on SW1573 cells according to the Cas9 transfection protocol. The culture medium was replaced with normal culture medium 24 hours later; culture was continued until 3 days after transfection, and each group of cells was expanded, and 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.

[0329] 2. Cell seeding plate:

[0330] Adjust the cell density (SW1573 BRM / BRG1 knock-in cell line: 9,000 cells / well) in a 384-well plate and incubate overnight at 37°C, 5% CO2. Dissolve the compound in DMSO, dilute it in DMSO and then in culture medium, and transfer it to the cell plate to a final concentration of 1 μM, in 3-fold dilutions. Continue incubation at 37°C, 5% CO2 for 16-18 hours.

[0331] 3. Protein degradation detection:

[0332] 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).

[0333] 4. Degradation of DC 50 calculate

[0334] The final drug concentration was 1000 nM, and the cells were diluted 3-fold to obtain 10 concentration points. The protein degradation rate at each concentration was calculated using EXCEL XLfit5.4.0. Each concentration point had 2 replicates.

[0335] Protein degradation rate (%) = (High control - corresponding well reading) / (High control - Low control) * 100%

[0336] High control = 0.1% DMSO, defined as 0% degradation

[0337] Low control = PBS (no cells), defined as 100% degradation

[0338] The degradation curve is generated by the degradation rate of 10 concentration points, and the degradation DC is calculated 50 and D max The results are shown in Table 2.

[0339] Table 2

[0340] The test results showed that the compounds of Examples 4, 6 and 8 degraded the DC of BRM of SW1573 cells. 50 were smaller than DCs that degraded BRG1 in SW1573 cells 50 , degrading D of BRM in SW1573 cells max were greater than the D of BRG1 that degraded SW1573 cells. maxThe activities of these three compounds in degrading BRM of SW1573 cells were stronger than those in degrading BRG1 of SW1573 cells.

[0341] Each document cited herein, including any cross-referenced patent or patent application and any patent application or patent to which this application claims priority, is hereby incorporated by reference in its entirety unless expressly excluded or otherwise limited. Further, to the extent that any meaning or definition of a term in this document conflicts with any meaning or definition of the same term in a document incorporated by reference, the meaning or definition assigned to that term in this document shall govern.

[0342] Although specific embodiments of the present disclosure have been illustrated and described, those skilled in the art will appreciate that, where feasible, the technical features described in one embodiment may be applied to another embodiment, or combined with the technical features described in another embodiment. Therefore, those skilled in the art will be able to make various changes and modifications to the embodiments of the present disclosure without departing from the spirit and scope of the present disclosure.

Claims

1. A compound represented by formula (I) or a pharmaceutically acceptable salt thereof, TL-Linker-DIM (I) The DIM is a ligand compound capable of binding to cereblon type E3 ubiquitin ligase; The Linker is a linking group that covalently binds at least one TL and at least one DIM; The TL is a group as shown below: in: R 1 Selected from H, -C(O)R a OR-P(O)(OR b )2; where R a and R b Each of them is independently selected from H, C1-C6 alkyl, C3-C6 cycloalkyl or 4-8 membered heterocyclic group, wherein the C1-C6 alkyl, C3-C6 cycloalkyl or 4-8 membered heterocyclic group is optionally replaced by R 1a replace; R 2 Selected from H, deuterium, halogen, CN, COOH, NO2, NH2, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, C6-C 10 aryl, 5-10 membered heteroaryl or 4-8 membered heterocyclic group, the NH2, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, C6-C 10 Aryl, 5-10 membered heteroaryl or 4-8 membered heterocyclic group is optionally replaced by R 2a replace; R 3 Selected from deuterium, halogen, CN, COOH, NO2, NH2, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, C6-C 10 aryl, 5-10 membered heteroaryl or 4-8 membered heterocyclic group, the NH2, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, C6-C 10 Aryl, 5-10 membered heteroaryl or 4-8 membered heterocyclic group is optionally replaced by R 3a replace; m is selected from 0, 1, 2, 3 or 4; n is selected from 0, 1 or 2; Each W is independently selected from -CR c R d -, -C(O)-, -S(O)- or -S(O)2-, and when n is 2, at least one W is -CR c R d -; R c and R d are independently selected from H, deuterium, halogen, OH, C1-C6 alkyl, C3-C6 cycloalkyl or 4-8 membered heterocyclic group, wherein R 4a Replace; or R c , R d and the atoms to which they are connected together form a C3-C6 cycloalkyl or a 4-8 membered heterocyclic group, wherein the C3-C6 cycloalkyl or the 4-8 membered heterocyclic group is optionally replaced by R 5a replace; represents a single bond or a double bond; Y and Z are independently selected from CR or N, said R being selected from absence, H or deuterium; Ring A is selected from a 5-7 membered heterocyclic ring, a 5-6 membered heteroaromatic ring or a benzene ring, wherein the 5-7 membered heterocyclic ring, the 5-6 membered heteroaromatic ring or the benzene ring is optionally replaced by R 6a replace; R 1a , R 2a , R 3a , R 4a , R 5a and R 6a are independently selected from deuterium, halogen, =O, OH, CN, NH2, C1-C6 alkyl, C3-C6 cycloalkyl, 4-8 membered heterocyclyl, C6-C 10 aryl or 5-10 membered heteroaryl, the OH, NH2, C1-C6 alkyl, C3-C6 cycloalkyl, 4-8 membered heterocyclic, C6-C 10 Aryl or 5-10 membered heteroaryl is optionally replaced by R 1b replace; R 1b is selected from halogen, OH, NH2, =O or C1-C3 alkyl; Provided that: when ring A is optionally replaced by R 6a substituted 5-7 membered heterocyclic ring or optionally R 6a When the 5-6 membered heteroaromatic ring is substituted, n is 1 or 2, and at least one W is -CR c R d -, the R c , R d and the atoms to which they are connected together form a C3-C6 cycloalkyl or a 4-8 membered heterocyclic group, wherein the C3-C6 cycloalkyl or the 4-8 membered heterocyclic group is optionally replaced by R 5a replace.

2. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein: is C=C, and ring A is selected from a 5-6 membered heteroaromatic ring or a benzene ring, wherein the 5-6 membered heteroaromatic ring or the benzene ring is optionally replaced by R 6a substituted; provided that: when ring A is optionally replaced by R 6a When the 5-6 membered heteroaromatic ring is substituted, n is 1 or 2, and at least one W is -CR c R d -, the R c , R d and the atoms to which they are connected together form a C3-C6 cycloalkyl or a 4-8 membered heterocyclic group, wherein the C3-C6 cycloalkyl or the 4-8 membered heterocyclic group is optionally replaced by R 5a replace.

3. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein represents a single bond, Y and Z are independently selected from CR or N, said R is selected from not present or H, and ring A is optionally replaced by R 6a Substituted 5-7 membered heterocyclic ring, n is 1 or 2, and at least one W is -CR c R d -, the R c , R d and the atoms to which they are connected together form a C3-C6 cycloalkyl or a 4-8 membered heterocyclic group, wherein the C3-C6 cycloalkyl or the 4-8 membered heterocyclic group is optionally replaced by R 5a replace.

4. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein: Ring A is optionally substituted with R 6a Substituted benzene ring.

5. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein Each W is independently selected from -CR c R d - or -C(O)-, and when n is 2, one W is selected from -CR c R d - or -C(O)-, the other W is -CR c R d -.

6. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein: n is 1 and W is selected from -CR c R d -or -C(O)-.

7. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein: R 1 Selected from H, -C(O)R a OR-P(O)(OR b )2; where R a and R b are independently selected from H or optionally R 1a Substituted C1-C6 alkyl, preferably, R 1 Selected from H.

8. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein R 2 is selected from H, deuterium, halogen, NH2, C1-C3 alkyl or C1-C3 alkoxy, wherein the NH2, C1-C3 alkyl or C1-C3 alkoxy is optionally replaced by R 2a Substituted, preferably, R 2 For H.

9. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein: R 3 is selected from deuterium, halogen, CN, COOH, NO2, NH2, C1-C6 alkyl or C1-C6 alkoxy, wherein the NH2, C1-C6 alkyl or C1-C6 alkoxy is optionally replaced by R 3a Substituted, preferably, R 3 Selected from deuterium or halogen.

10. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein: The TL is further selected from the group shown below: Wherein R 1 , R 2 , R 3 , W, m and n are as defined in claim 1, preferably, said TL is selected from 11. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 10, wherein: The Linker is a connecting group that covalently binds a TL and a DIM.

12. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 11, wherein: The Linker is selected from: -L A -、-L B -、-R 1L -、-R 2L -、-Q 1 -、-Q 2 -、 Where: -L A -、-L B - independently selected from a bond, -O-, -S-, -NR 3’ -、-CR 4’ R 5’ -、-CR 4’ R 5’ -NR 3’ -、-CR 4’ R 5’ -O-, -C(O)-, -CR 4’ R 5’ -C(O)-, -S(O)-, -S(O)2-, -C(S)-, -C(O)O- or -C(O)NR 6’ -; R 1L and R 2L are independently selected from a bond, -C(O)-, alkylene, heteroalkylene, alkenylene and alkynylene, wherein the alkylene, heteroalkylene, alkenylene and alkynylene are optionally substituted with a group selected from the group consisting of halogen, alkyl, alkoxy, haloalkyl, OH, hydroxyalkyl, CN, NH2, =O, cycloalkyl, heterocyclyl, aryl, heteroaryl; Q 1 , Q 2 , Q 3 and Q 4 Each of the cycloalkyl, heterocyclyl, aryl, heteroaryl or cycloalkenyl groups is independently selected from the group consisting of halogen, alkyl, alkoxy, haloalkyl, OH, hydroxyalkyl, CN, NH2, =O, cycloalkyl, heterocyclyl, aryl, heteroaryl; R 3’ is selected from the group consisting of H, alkyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl; R 4’ and R 5’ Each is independently selected from H, halogen, alkyl, alkoxy, haloalkyl, OH, hydroxyalkyl, CN, NH2, =O, cycloalkyl, heterocyclyl, aryl or heteroaryl; R 6’ is selected from H, alkyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl.

13. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 12, wherein: The DIM is selected from the structure shown in formula (DIM-1) or (DIM-2): in: Selected from Y' is a bond, or Y' is selected from Y A , O, NH, NR E 、C(O)O、C(O)NR E '、NR E 'C(O),Y A -NH, Y A -NR E , Y A -C(O),Y A -C(O)O、Y A -OC(O),Y A -C(O)NR E ' or Y A -NR E 'C(O), wherein said Y A is selected from C1-C6 alkylene, C2-C6 alkenylene or C2-C6 alkynylene; X' is selected from C(O) or C(R A )2;X A -X B Selected from C(R A )=NorC(R A )2-C(R A )2; Every R A independently selected from H or C1-C3 alkyl, the C1-C3 alkyl being optionally substituted by C6-C 10 Aryl or 5-10 membered heteroaryl substituted; Every R A 'Independently selected from C1-C3 alkyl; Every R B are independently selected from H or C1-C3 alkyl, or two R B Together with the atoms to which it is attached, it forms C(O), C3-C6 cycloalkyl, C3-C6 cycloalkenyl or 4-6 membered heterocyclyl; R C Selected from H, halogen or C1-C3 alkyl; Every R D Independently selected from halogen, NO2, NH2, OH, COOH, C1-C6 alkyl or C1-C6 alkoxy; Every R E independently selected from C1-C6 alkyl, C2-C6 alkenyl, C3-C8 cycloalkyl, 3-8 membered heterocycloalkyl, C(O)-C1-C6 alkyl, C(O)-C2-C6 alkenyl, C(O)-C3-C8 cycloalkyl or C(O)-3-8 membered heterocycloalkyl, wherein R E Optionally substituted by a group selected from the group consisting of halogen, N(R a )2. NHC(O)R a 、NHC(O)OR a , OR b , C3-C8 cycloalkyl, 3-8 membered heterocycloalkyl, C6-C 10 aryl or 5-10 membered heteroaryl, wherein the C3-C8 cycloalkyl, 3-8 membered heterocycloalkyl, C6-C 10 The aryl or 5-10 membered heteroaryl group is optionally further substituted by a group selected from: Halogen, NH2, CN, NO2, OH, COOH, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy or C1-C6 haloalkoxy; R E ' is selected from H, C1-C6 alkyl, C2-C6 alkenyl, C3-C8 cycloalkyl or 3-8 membered heterocycloalkyl, wherein the C1-C6 alkyl, C2-C6 alkenyl, C3-C8 cycloalkyl or 3-8 membered heterocycloalkyl is optionally substituted by a group selected from the following: halogen, N(R a )2. NHC(O)R a 、NHC(O)OR a , OR b , C3-C8 cycloalkyl, 3-8 membered heterocycloalkyl, C6-C 10 aryl or 5-10 membered heteroaryl, wherein the C3-C8 cycloalkyl, 3-8 membered heterocycloalkyl, C6-C 10 The aryl or 5-10 membered heteroaryl is optionally further substituted by a group selected from the group consisting of halogen, NH2, CN, NO2, OH, COOH, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy or C1-C6 haloalkoxy; Every R a Independently selected from H or C1-C6 alkyl; R b Selected from H or p-toluenesulfonyl; t is selected from 0 or 1; m1 is selected from 0, 1, 2 or 3; p is selected from 0, 1 or 2.

14. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 12, wherein: The DIM is selected from the structure shown in formula (DIM-11): in: X C is selected from a bond, -CH2-, -CHCF3-, -SO2-, -S(O)-, -P(O)R'-, -P(O)OR'-, -P(O)NR'2-, -C(O)-, -C(S-) or X D is selected from C, N or Si; X E is selected from a bond, -CR'2-, -NR'-, -O-, -S- or -SiR'2-; R F Does not exist, or R F is selected from H, deuterium, halogen, CN, -OR', -SR', -S(O)R', -S(O)2R', -NR'2, -P(O)(OR')2, -P(O)(NR'2)OR', -P(O)(NR'2)2, -Si(OH)2R', -Si(OH)R'2, -SiR'3 or C1-C4 alkyl; Each R G is independently selected from H, deuterium, R H , halogen, CN, -NO2, -OR’, -SR’, -NR’2, -SiR’3, -S(O)2R’, -S(O)2NR’2, -S(O)R’, -C(O)R’, -C(O)OR’, -C(O)NR’2, -C(O)N(R’)OR’, -C(R’)2N(R’)C(O)R’, -C(R’)2N(R’)C(O)NR’2, -OC(O)R’, -OC(O)NR’2, -OP(O)R’2, -OP(O)(OR’)2, -OP(O)(OR’)NR’2, -OP(O)(NR’2)2, -N(R’)C(O)OR’, -N(R’)C(O)R’, -N(R’)C(O)NR’2, -N(R’)S(O)2R’, -NP(O)R’2, -N(R’)P(O)(OR’)2, -N(R’)P(O)(OR’)NR’2 or -N(R’)P(O)(NR’2)2; Every R H Independently selected from C1-C6 alkyl, phenyl, 4-7 membered heterocyclyl or 5-6 membered heteroaryl; Ring E, Ring F, Ring G are independently selected from phenyl, 6-membered heteroaryl, C5-C7 cycloalkyl, C5-C7 cycloalkenyl, 5-7-membered heterocyclyl or 5-6-membered heteroaryl, wherein Ring E, Ring F and Ring G are each optionally further substituted by =O; L 1 is selected from a bond, a C1-C3 alkylene, a C2-C3 alkenylene or a C2-C3 alkynylene, wherein any one or two methylene groups in the C1-C3 alkylene, C2-C3 alkenylene or C2-C3 alkynylene are optionally replaced by -O-, -C(O)-, -C(S)-, -C(R')2-, -CH(R')-, -C(F)2-, -N(R')-, -S- or -S(O)2-; Each R' is independently selected from H, C1-C6 alkyl, phenyl, 4-7 membered heterocyclyl or 5-6 membered heteroaryl, or two R' and the atoms to which they are attached together form a 4-7 membered heterocyclyl or 5-6 membered heteroaryl; q is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or 16.

15. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 12, wherein: The DIM is selected from the structure shown in formula (DIM-12): Wherein: Ring H is selected from C5-C9 cycloalkyl, C5-C9 cycloalkenyl or 5-9 membered heterocyclic group, the C5-C9 cycloalkyl, C5-C9 cycloalkenyl or 5-9 membered heterocyclic group The heterocyclic group is optionally substituted by =O; k is selected from 0, 1, 2, 3 or 4; X C , X D , X E , R F , R G , L 1 and Ring E is as defined in claim 14.

16. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 12, wherein: The DIM is selected from the structure shown in formula (DIM-13): Among them, the X C , X D , X E , R F , R G , L 1 , ring E and k are as defined in claim 15.

17. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 16, wherein: The compound has a structure selected from one of the following:

18. A pharmaceutical composition comprising the compound according to any one of claims 1 to 17 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

19. Use of the compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 17 or the pharmaceutical composition according to claim 18 in the preparation of a medicament for preventing or treating a BRM-mediated disease, wherein the BRM-mediated disease is preferably a tumor.

20. The compound according to any one of claims 1 to 17 or a pharmaceutically acceptable salt thereof or the pharmaceutical composition according to claim 18 for use in preventing or treating a BRM-mediated disease, wherein the BRM-mediated disease is preferably a tumor.

21. Use of the compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 17 or the pharmaceutical composition according to claim 18 in preventing or treating a BRM-mediated disease, wherein the BRM-mediated disease is preferably a tumor.

22. A method for treating a disease mediated by BRM, comprising administering to an individual in need thereof a therapeutically effective amount of a compound according to any one of claims 1 to 17 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 18, wherein the BRM-mediated disease is preferably a tumor, and optionally wherein, The individual is a mammal, preferably a human.