Aromatic amide compound having tricyclic skeleton and use thereof

Abstract

An aromatic amide compound having a tricyclic skeleton, which is represented by formula I, or a pharmaceutically acceptable salt thereof and the use thereof.

Description

A tricyclic skeletal aromatic amide compound and its applications Technical Field

[0001] This disclosure pertains to the pharmaceutical field and relates to a tricyclic aromatic amide compound and its applications. Background Technology

[0002] Gene regulation is essential for the proper execution of all biological processes. Each human cell contains over 3.2 billion DNA base pairs compressed into a higher-order chromatin structure, and its dynamic regulation is crucial for ensuring that events occur at the correct time, in the correct location, and in the correct sequence.

[0003] S-witch / sucrose non-fermentable (SWI / SNF) is a chromatin remodeling complex (CRC) that uses the energy from ATP hydrolysis to reposition nucleosomes, thereby regulating DNA acquisition and regulating transcription and DNA replication / repair. It possesses two SWI2-like ATPases: BRG1 (Brahma-associated gene 1) and BRM (Brahma). BRG1, also known as the ATP-dependent chromatin remodeling agent SMARCA4, is overexpressed in some cancerous tumors and is essential for cancer cell proliferation. BRM is called the global transcription activator SNF2L2 and / or the ATP-dependent chromatin remodeling factor SMARCA2. Either SMARCA2 or SMARCA4 must be present in the BAF complex for chromatin remodeling to occur. When either SMARCA2 or SMARCA4 is damaged or lost, they can compensate for each other's function. Functional gene screening has shown a synthetic lethal relationship between SMARCA2 and SMARCA4 (Cancer Cell. 2014; 26, 309-317). Since SMARCA4 is a common mutation in many tumor cells, accounting for approximately 10% of non-small cell lung cancer cases (J.Med.Chem.2018;61,10155–10172), selective inhibition of SMARCA2 in tumor cells characterized by SMARCA4 functional mutations or deletions can significantly slow tumor cell growth.

[0004] Papillon, JPN et al. reported a series of dual ATPase inhibitors of SMARCA2 and SMARCA4. These compounds effectively inhibited the growth of SMARCA4 mutant cancer cell lines (J.Med.Chem.2018;61,10155–10172).

[0005] In addition, other selective SMARCA2 inhibitors have been reported, such as WO2022103899, WO2023220219 and WO2024088351. Currently, there are no SMARCA2 / 4 inhibitors on the market. Furthermore, the compounds disclosed in this paper have not been published in any literature, and these compounds exhibit good selective inhibitory effects on SMARCA2 / 4. Summary of the Invention

[0006] This disclosure provides a compound of formula I or a pharmaceutically acceptable salt thereof.

[0007] Among them, R 1 Selected from hydrogen, halogen, amino, alkyl, alkoxy, cycloalkyl, or heterocycloalkyl, wherein the alkyl, alkoxy, cycloalkyl, or heterocycloalkyl is optionally composed of one or more elements selected from halogen, hydroxyl, cyano, nitro, amino, C 1-6 Alkyl or C 1-6 Alkyl groups are substituted;

[0008] R 2 The group is selected from hydrogen, halogen, amino, alkyl, or alkoxy, wherein the alkyl or alkoxy group is optionally surrounded by one or more groups selected from halogen, hydroxyl, cyano, nitro, amino, C 1-6 Alkyl or C 1-6 Alkyl groups are substituted;

[0009] R 3 The group is selected from hydrogen or alkyl, wherein the alkyl group is optionally divided by one or more radicals selected from halogen, hydroxyl, cyano, nitro, amino, or C. 1-6 Alkyl groups are substituted;

[0010] R 4 R 5 Each is independently selected from hydrogen, halogen, hydroxyl, alkyl, or alkoxy, wherein the alkyl or alkoxy group is optionally selected from one or more of halogen, hydroxyl, cyano, nitro, amino, C 1-6 Alkyl or C 1-6 Alkoxy groups are substituted.

[0011] Or, R 4 R 5 Together with the attached carbon atom, a cycloalkyl or heterocycloalkyl group is formed, wherein the cycloalkyl or heterocycloalkyl group is optionally bonded by one or more elements selected from halogen, hydroxyl, cyano, nitro, amino, C 1-6 Alkyl or C 1- Substituted with 6-alkoxy groups;

[0012] L 1 Selected from optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heteroaryl-alkenyl or optionally substituted heteroaryl-ynyl;

[0013] L 2 Selected from alkyl groups, optionally substituted cycloalkyl groups, optionally substituted heterocycloalkyl groups, optionally substituted aryl groups, or optionally substituted heteroaryl groups;

[0014] R 6 Each is independently selected from halogen, hydroxyl, cyano, nitro, amino, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 3-10 Cycloalkyl, 3- to 10-membered heterocycloalkyl, 6- to 10-membered aryl, 5- to 10-membered heteroaryl, C 3-10 Cycloalkoxy, 3 to 10-membered heterocycloalkoxy, or -OC 2-6 alkenyl, the C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 3-10 Cycloalkyl, 3- to 10-membered heterocycloalkyl, C 3-10 Cycloalkoxy, 3 to 10-membered heterocycloalkoxy, or -OC 2-6 Alkenyl groups are optionally selected from one or more R groups. 1a Replaced

[0015] Or, adjacent R 6 Form C with adjacent atoms 3-10 Cycloalkyl or 3 to 10-membered heterocycloalkyl, wherein the C 3- 10 Cycloalkyl or 3 to 10-membered heterocyclic alkyl groups optionally selected from R 1a Replaced;

[0016] R 1a Each is independently selected from deuterium, halogen, hydroxyl, cyano, nitro, amino, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-10 Cycloalkyl, 3- to 10-membered heterocycloalkyl, wherein C 1-6 Alkyl, C 1-6 Alkoxy, C 3-10 Cycloalkyl groups and 3 to 10-membered heterocyclic alkyl groups may be selected from one or more halogens, oxo groups, hydroxyl groups, cyano groups, nitro groups, amino groups, C groups, etc. 1-6 Alkyl or C 1-6 Alkyl substitution;

[0017] X 1 Selected from N or C;

[0018] Z 1 Selected from N or C;

[0019] Ring A is selected from the optionally substituted C 5-6 Alicyclic rings, optionally substituted 5-6 membered alicyclic rings, optionally substituted aromatic rings, or optionally substituted 5-6 membered heteroaromatic rings;

[0020] X 2 Selected from -S-, -SO-, -SO2- or -S(O)(=NH)-;

[0021] R 7 Selected from hydrogen, halogen, hydroxyl, amino, C 1-6 Alkyl or C 1-6 Alkoxy, the C 1-6 Alkyl or C 1- The 6-alkoxy group is optionally surrounded by one or more groups selected from halogen, oxo, hydroxyl, cyano, nitro, amino, C 1-6 Alkyl or C 1-6 Alkyl groups are substituted;

[0022] R 8 Each is independently selected from halogen, hydroxyl, cyano, nitro, amino, C 1-6 Alkyl or C 1-6 Alkoxy, the C 1-6 Alkyl or C 1-6 Alkyl groups are optionally surrounded by one or more groups selected from halogen, hydroxyl, cyano, nitro, amino, C 1-6 Alkyl or C 1-6 Alkoxy groups are substituted, or two adjacent R groups are substituted. 8 Formation = O;

[0023] X 3 Selected from -O-, -C(R) 2a )2-、-N(R 2b )-、;

[0024] Z 2 Selected from key or -C(R) 3a )2-;

[0025] R 2a Each is independently selected from hydrogen, halogen, hydroxyl, nitro, cyano, amino, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl or 3- to 6-membered heterocycloalkyl, wherein the C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl or 3- to 6-membered heterocyclic alkyl groups may be optionally prefixed with one or more halogens, oxo groups, hydroxyl groups, cyano groups, nitro groups, amino groups, or C groups. 1-6 Alkyl or C 1-6 Alkyl groups are substituted, or, both R groups are substituted. 2a Together with the atoms they are attached to, they form C 3-8Cycloalkyl or 3-8 membered heterocycloalkyl, wherein C 3-8 Cycloalkyl or 3-8 membered heterocyclic alkyl groups may be selected from one or more halogens, hydroxyl, cyano, nitro, amino, C 1-6 Alkyl or C 1-6 Alkyl groups are substituted;

[0026] R 2b Selected from hydrogen or C 1-6 Alkyl, the C 1-6 Alkyl groups may be selected from one or more groups chosen from halogen, oxo, hydroxyl, cyano, nitro, amino, C 1-6 Alkyl or C 1-6 Alkyl groups are substituted;

[0027] R 3a Each is independently selected from hydrogen, halogen, hydroxyl, nitro, cyano, amino, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl or 3- to 6-membered heterocycloalkyl, wherein the C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl or 3- to 6-membered heterocyclic alkyl groups optionally selected from one or more halogens, hydroxyl, cyano, nitro, amino, C 1- 6-alkyl or C 1-6 Alkyl groups are substituted, or, both R groups are substituted. 3a Together with the atoms they are attached to, they form C 3-8 Cycloalkyl or 3-8 membered heterocycloalkyl, wherein C 3-8 Cycloalkyl or 3-8 membered heterocyclic alkyl groups may be selected from one or more halogens, hydroxyl, cyano, nitro, amino, C 1-6 Alkyl or C 1-6 Alkyl groups are substituted;

[0028] m is selected from 0, 1, 2, or 3;

[0029] n is selected from 0, 1, or 2;

[0030] o can be selected from 0, 1, 2, 3 or 4.

[0031] In some embodiments, L in the compound of formula I or a pharmaceutically acceptable salt thereof 1 Selected from C 3-12 Cycloalkyl, 3-12 membered heterocycloalkyl, C 6-10 aryl, 5-10 heteroaryl, 5-10 heteroaryl-alkenyl or 5-10 heteroaryl-alkynyl, wherein C 3-12 Cycloalkyl, 3-12 membered heterocycloalkyl, C 6-10 5-10-membered heteroaryl, 5-10-membered heteroaryl-alkenyl, or 5-10-membered heteroaryl-alkynyl may be selected from one or more of R4a Replaced by, R 4a Each is independently selected from halogen, hydroxyl, cyano, nitro, amino, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-10 Cycloalkyl, 3- to 10-membered heterocycloalkyl, wherein C 1-6 Alkyl, C 1-6 Alkoxy, C 3-10 Cycloalkyl groups and 3 to 10-membered heterocyclic alkyl groups may be selected from one or more halogens, oxo groups, hydroxyl groups, cyano groups, nitro groups, amino groups, C groups, etc. 1-6 Alkyl or C 1-6 Alkyl-substituted.

[0032] In some embodiments, L in the compound of formula I or a pharmaceutically acceptable salt thereof 2 Selected from key, C 3-12 Cycloalkyl, 3-12 membered heterocycloalkyl, C 6-10 Aryl or 5-10 heteroaryl, C 3-12 Cycloalkyl, 3-12 membered heterocycloalkyl, C 6-10 Aryl or 5-10 heteroaryl groups are optionally selected from one or more R groups. 5a Replaced

[0033] R 5a Each is independently selected from halogen, hydroxyl, cyano, nitro, amino, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-10 Cycloalkyl, 3- to 10-membered heterocycloalkyl, wherein C 1-6 Alkyl, C 1-6 Alkoxy, C 3-10 Cycloalkyl groups and 3 to 10-membered heterocyclic alkyl groups may be selected from one or more halogens, oxo groups, hydroxyl groups, cyano groups, nitro groups, amino groups, C groups, etc. 1-6 Alkyl or C 1-6 Alkyl-substituted.

[0034] In some embodiments, L in the compound of formula I or a pharmaceutically acceptable salt thereof 1 Selected from 5-10 heteroaryl groups, wherein the 5-10 heteroaryl group is optionally surrounded by one or more groups selected from R 4a Replaced by, R 4a As defined above.

[0035] In some embodiments, L in the compound of formula I or a pharmaceutically acceptable salt thereof 1 It is selected from 5- to 6-membered heteroaromatic rings containing at least one heteroatom, such as 5- to 6-membered heteroaromatic rings containing at least one N atom.

[0036] In some embodiments, L in the compound of formula I or a pharmaceutically acceptable salt thereof 1 Selected from Where X 4 X 5 X 6 X 7 X 8 X 9 Each is independently selected from N or CR 4aa R 4aa Each is independently selected from hydrogen, halogen, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl or 3- to 6-membered heterocycloalkyl, wherein the C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl or 3- to 6-membered heterocyclic alkyl groups optionally selected from one or more halogens, hydroxyl, cyano, nitro, amino, C 1-6 Alkyl or C 1-6 Alkyl groups are substituted;

[0037] A 1 For -C(R) 4 (R) 5 - The bond connected, A 2 To be with L 2 Connecting keys.

[0038] In some implementation schemes, ZhongX 4 Selected from CR 4aa R 4aa As defined above.

[0039] In some implementation schemes, ZhongX 6 Selected from CR 4aa R 4aa As defined above.

[0040] In some implementation schemes, ZhongX 5 Selected from N.

[0041] In some implementation schemes, ZhongX 7 Selected from CR 4aa R 4aa As defined above.

[0042] In some implementation schemes, ZhongX 5 Selected from N, X 4 X 6 X 7 X 8 X 9 Selected from CR 4aa R4aa As defined above.

[0043] In some implementation schemes, ZhongX 5 X 9 Selected from N, X 4 X 6 X 7 X 8 Selected from CR 4aa R 4aa As defined above.

[0044] In some embodiments, L in the compound of formula I or a pharmaceutically acceptable salt thereof 1 Selected from Where A 1 A 2 As defined above; R 4aa As defined above.

[0045] In some implementation schemes, R 4aa Each is independently selected from hydrogen or halogens (such as fluorine, chlorine, or bromine). In some embodiments, R 4aa Each is independently selected from hydrogen and C. 1-6 Alkyl or C 1-6 Alkoxy, the C 1-6 Alkyl or C 1-6 Alkyl groups are optionally surrounded by one or more groups selected from halogen, hydroxyl, cyano, nitro, amino, C 1-6 Alkyl or C 1-6 Alkyl groups are substituted.

[0046] In some embodiments, L in the compound of formula I or a pharmaceutically acceptable salt thereof 1 Selected from Where A 1 A 2 As defined above.

[0047] In some embodiments, L in the compound of formula I or a pharmaceutically acceptable salt thereof 1 Selected from Where A 1 A 2 As defined above. In some embodiments, L in the compound of Formula I or a pharmaceutically acceptable salt thereof 1 Selected from Where A 1 A 2 As defined above. On the other hand, in some embodiments, L in the compound of Formula I or its pharmaceutically acceptable salt 1Selected from 5-6-membered heteroaryl groups, wherein the 5-6-membered heteroaryl group is optionally surrounded by one or more groups selected from R 4aa Replaced by, R 4aa As defined above.

[0048] In some embodiments, L in the compound of formula I or a pharmaceutically acceptable salt thereof 1 Selected from Where X 4 X 5 X 6 X 10 Each is independently selected from N or CR 4aa R 4aa Each is independently selected from hydrogen, halogen, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl or 3- to 6-membered heterocycloalkyl, wherein the C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl or 3- to 6-membered heterocyclic alkyl groups optionally selected from one or more halogens, hydroxyl, cyano, nitro, amino, C 1-6 Alkyl or C 1-6 Alkyl groups are substituted;

[0049] A 1 For -C(R) 4 (R) 5 - The bond connected, A 2 To be with L 2 Connecting keys.

[0050] In some implementation schemes, ZhongX 4 Selected from CR 4aa R 4aa As defined above.

[0051] In some implementation schemes, ZhongX 6 Selected from CR 4aa R 4aa As defined above.

[0052] In some implementation schemes, ZhongX 5 Selected from N.

[0053] In some implementation schemes, ZhongX 10 Selected from CR 4aa R 4aa As defined above.

[0054] In some implementation schemes, ZhongX4 Selected from N, X 5 X 6 X 10 Selected from CR 4aa R 4aa As defined above.

[0055] In some implementation schemes, ZhongX 10 Selected from N, X 4 X 5 X 6 Selected from CR 4aa R 4aa As defined above.

[0056] In some implementation schemes, ZhongX 6 Selected from N, X 4 X 5 X 10 Selected from CR 4aa R 4aa As defined above.

[0057] In some implementation schemes, ZhongX 5 Selected from N, X 4 X 6 X 10 Selected from CR 4aa R 4aa As defined above.

[0058] In other embodiments, L in the compound of formula I or a pharmaceutically acceptable salt thereof 1 Selected from 5-10-membered heteroaryl-alkenyl or 5-10-membered heteroaryl-alkynyl, wherein the 5-10-membered heteroaryl-alkenyl or 5-10-membered heteroaryl-alkynyl is optionally composed of one or more components selected from R 4aa Replaced by, R 4aa As defined above.

[0059] Some embodiments provide that the compound shown in Formula I is the same as the compound shown in Formula II-1.

[0060] Where R 1 ~R 8 X 1 X 2 X 3 Z 1 Z 2 The rings A, m, n, and o are defined as shown in the compound represented by Formula I; X 4 X 5 X 6 X 7 X8 X 9 Each is independently selected from N or CR 4aa R 4aa Each is independently selected from hydrogen, halogen, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl or 3- to 6-membered heterocyclic alkyl, wherein the alkyl, alkoxy, cycloalkyl, or heterocyclic alkyl is optionally selected from one or more elements selected from halogen, hydroxyl, cyano, nitro, amino, C 1-6 Alkyl or C 1-6 Alkyl groups are substituted.

[0061] Some embodiments provide that the compound shown in Formula I is the same as the compound shown in Formula II-2.

[0062] Where R 1 ~R 8 X 1 X 2 X 3 Z 1 Z 2 The rings A, m, n, and o are defined as shown in the compound represented by Formula I; X 4 X 5 X 6 X 10 Each is independently selected from N or CR 4aa R 4aa Each is independently selected from hydrogen, halogen, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl or 3- to 6-membered heterocycloalkyl, wherein the C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl or 3- to 6-membered heterocyclic alkyl groups optionally selected from one or more halogens, hydroxyl, cyano, nitro, amino, C 1-6 Alkyl or C 1-6 Alkyl groups are substituted.

[0063] On the other hand, in some embodiments, the compound represented by Formula I or Formula II-1 or Formula II-2, or its pharmaceutically acceptable salt, contains -L 2 -(R 6 ) o Selected from X 11 X 12 X 13 X 14 and X 15 Each is independently selected from N or CR 5aa R 5aa Each is independently selected from hydrogen, halogen, cyano, C1-6 Alkyl, C 1-6 Alkoxy, C 3- 6-membered cycloalkyl or 3- to 6-membered heterocycloalkyl, wherein C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl or 3- to 6-membered heterocyclic alkyl groups optionally selected from one or more halogens, hydroxyl, cyano, nitro, amino, C 1-6 Alkyl or C 1-6 Alkoxy groups are substituted, R 6 As defined above.

[0064] In some implementation schemes, ZhongX 11 Selected from N.

[0065] In some implementation schemes, ZhongX 12 Selected from N.

[0066] In some implementation schemes, ZhongX 13 Selected from N.

[0067] In some implementation schemes, ZhongX 11 Selected from N, X 12 X 13 X 14 and X 15 Each independently selected from CR 5aa R 5aa As defined above.

[0068] In some implementation schemes, ZhongX 12 Selected from N, X 11 X 13 X 14 and X 15 Each independently selected from CR 5aa R 5aa As defined above.

[0069] In some implementation schemes, ZhongX 13 Selected from N, X 11 X 12 X 14 and X 15 Each independently selected from CR 5aa R 5aa As defined above.

[0070] In other embodiments, the compound of formula I or II-1 or II-2, or a pharmaceutically acceptable salt thereof, contains -L 2-(R 6 ) o Selected from Where R 6 As defined above.

[0071] In other embodiments, the compound of formula I or II-1 or II-2, or a pharmaceutically acceptable salt thereof, contains -L 2 -(R 6 ) o Selected from

[0072] In other embodiments, the compound of formula I or II-1 or II-2, or a pharmaceutically acceptable salt thereof, contains -L 2 -(R 6 ) o Selected from In other embodiments, the compound of formula I or II-1 or II-2, or a pharmaceutically acceptable salt thereof, contains -L 2 -(R 6 ) o Selected from

[0073] In other embodiments, the compound of formula I or II-1 or II-2, or a pharmaceutically acceptable salt thereof, contains -L 2 -(R 6 ) o Selected from X 11 X 12 X 13 and X 14 Each is independently selected from N or CR 5aa R 5aa Each is independently selected from hydrogen, halogen, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl or 3- to 6-membered heterocycloalkyl, wherein the C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl or 3- to 6-membered heterocyclic alkyl groups optionally selected from one or more halogens, hydroxyl, cyano, nitro, amino, C 1-6 Alkyl or C 1-6 Alkoxy-substituted; ring B is selected from phenyl, 5-6 membered heterocyclic alkyl, or 5-6 membered heteroaryl, R 6 As defined above.

[0074] In some implementation schemes, The middle ring B is selected from phenyl.

[0075] In some implementation schemes, The middle ring B is selected from 5-6 membered heteroaryl groups, such as arbitrarily substituted pyridine rings, pyrazine rings, or pyrimidine rings.

[0076] In some implementation schemes, The intermediate ring B is selected from 5-6 membered heterocyclic alkyl groups.

[0077] In other embodiments, the compound of formula I or II-1 or II-2, or a pharmaceutically acceptable salt thereof, contains -L 2 -(R 6 ) o Selected from Where R 6 As defined above.

[0078] In other embodiments, the compound of formula I or II-1 or II-2, or a pharmaceutically acceptable salt thereof, contains -L 2 -(R 6 ) o Selected from 5-membered heteroaryl groups, such as or

[0079] On the other hand, X in the compound of formula I or formula II-1 or formula II-2 or its pharmaceutically acceptable salt 1 Selected from C.

[0080] In some embodiments, Z in the compound of formula I or formula II-1 or formula II-2 or its pharmaceutically acceptable salt 1 Selected from N.

[0081] In some embodiments, ring A in the compound of formula I, II-1, or II-2, or its pharmaceutically acceptable salt, is selected from 5-6 membered heteroaromatic rings, wherein the 5-6 membered heteroaromatic ring is optionally composed of one or more members selected from R. 6a Replaced by, R 6a Each is independently selected from halogen, hydroxyl, cyano, nitro, amino, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-10 Cycloalkyl, 3- to 10-membered heterocycloalkyl, wherein C 1-6 Alkyl, C 1-6 Alkoxy, C 3-10 Cycloalkyl groups and 3 to 10-membered heterocyclic alkyl groups may be selected from one or more halogens, oxo groups, hydroxyl groups, cyano groups, nitro groups, amino groups, C groups, etc. 1-6 Alkyl or C 1-6 Alkyl-substituted.

[0082] In some embodiments, ring A in the compound of formula I, II-1, or II-2 or its pharmaceutically acceptable salt is selected from... Where “*” indicates a loop site, R 6a As defined above, r is selected from 0, 1, 2, or 3.

[0083] In some embodiments, X in the compound of formula I or formula II-1 or formula II-2 or its pharmaceutically acceptable salt 3 Selected from -C(R) 2a )2-, R 2a As defined above.

[0084] In some embodiments, X in the compound of formula I or formula II-1 or formula II-2 or its pharmaceutically acceptable salt 2 Selected from -S- or -SO2-.

[0085] In some embodiments, X in the compound of formula I or formula II-1 or formula II-2 or its pharmaceutically acceptable salt 2 Selected from -S(O)(=NH)-.

[0086] In some embodiments, Z in the compound of formula I or formula II-1 or formula II-2 or its pharmaceutically acceptable salt 2 Selected from C(R) 3a )2, R 3a As defined above.

[0087] In some embodiments, Z in the compound of formula I or formula II-1 or formula II-2 or its pharmaceutically acceptable salt 2 Selected from key.

[0088] In some embodiments, the compound of formula I or formula II-1 or formula II-2, or a pharmaceutically acceptable salt thereof, is present in... Selected from Where R 1 R 2 R 7 R 8 R 2a m is defined in the compound shown in Formula I; R 6a As defined above, r is selected from 0, 1, 2, or 3.

[0089] In some embodiments, the compound of formula I or formula II-1 or formula II-2, or a pharmaceutically acceptable salt thereof, is present in... for

[0090] In some embodiments, R in the compound of formula I or formula II-1 or formula II-2 or its pharmaceutically acceptable salt 3 Selected from hydrogen or C 1-6 Alkyl, the C 1-6 Alkyl groups may be optionally surrounded by one or more radicals selected from halogen, hydroxyl, cyano, nitro, amino, or C. 1-6 Alkoxy-substituted

[0091] In some embodiments, R in the compound of formula I or formula II-1 or formula II-2 or its pharmaceutically acceptable salt 3 Selected from hydrogen, methyl, ethyl, or propyl. In some embodiments, R in the compound of formula I, II-1, or II-2, or a pharmaceutically acceptable salt thereof. 3 Selected from hydrogen.

[0092] Some embodiments provide a compound of formula I or a pharmaceutically acceptable salt thereof as a compound of formula III-1 or III-2. Where R 1 ~R 8 R 2a , m, n, o are defined as in the compound shown in Formula I; X 4 X 5 X 6 X 7 X 8 X 9 X 10 As defined above; R 6a As defined above, r is selected from 0, 1, 2, or 3.

[0093] In some embodiments, the compound represented by formula III-1 is the compound represented by formula III-1a.

[0094] In some embodiments, the compound represented by formula III-2 is the compound represented by formula III-2a.

[0095] Some embodiments provide a compound of formula I or a pharmaceutically acceptable salt thereof as a compound of formula III-3 or III-4. Where R 1 ~R 8 R 2a , m, n, o are defined as in the compound shown in Formula I; X 4 X 5 X 6 X 7 X 8 X 9 X 10 As defined above; R 6a As defined above, r is selected from 0, 1, 2, or 3.

[0096] In some embodiments, the compound represented by formula III-3 is the compound represented by formula III-3a.

[0097] In some embodiments, the compound represented by formula III-4 is the compound represented by formula III-4a.

[0098] In some embodiments, R in the compound of formula I or formula II-1 or formula II-2 or formula III-1 or formula III-2 or formula III-3 or formula III-4 or a pharmaceutically acceptable salt thereof 4 R 5 Each is independently selected from hydrogen, halogen, hydroxyl, C 1- 6-alkyl or C 1-6 Alkoxy, the C 1-6 Alkyl or C 1-6 Alkyl groups are optionally surrounded by one or more groups selected from halogen, hydroxyl, cyano, nitro, amino, C 1-6 Alkyl or C 1-6 Alkyl groups are substituted.

[0099] In some embodiments, R in the compound of formula I or formula II-1 or formula II-2 or formula III-1 or formula III-2 or formula III-3 or formula III-4 or a pharmaceutically acceptable salt thereof 4 R 5 Each is independently selected from hydrogen, halogen, or C. 1-6 Alkyl (e.g., methyl, ethyl).

[0100] In some embodiments, R in the compound of formula I or formula II-1 or formula II-2 or formula III-1 or formula III-2 or formula III-3 or formula III-4 or a pharmaceutically acceptable salt thereof 4 R 5 Each is independently selected from hydrogen.

[0101] In other embodiments, R in the compound of formula I or II-1 or II-2 or III-1 or III-2 or III-3 or III-4 or a pharmaceutically acceptable salt thereof 4 R 5 Together with the attached carbon atom, they form C 3-6 Cycloalkyl or 3-6 membered heterocycloalkyl, wherein C 3-6 Cycloalkyl or 3-6 membered heterocyclic alkyl groups may be selected from one or more halogens, hydroxyl, cyano, nitro, amino, C 1-6 Alkyl or C 1-6 Alkyl groups are substituted.

[0102] In some embodiments, n = 1 in the compound of formula I or formula II-1 or formula II-2 or formula III-1 or formula III-2 or formula III-3 or formula III-4 or its pharmaceutically acceptable salt.

[0103] In some embodiments, R in the compound of formula I or formula II-1 or formula II-2 or formula III-1 or formula III-2 or formula III-3 or formula III-4 or a pharmaceutically acceptable salt thereof6 Each is independently selected from 3 to 10-membered heterocyclic alkyl groups, wherein the 3 to 10-membered heterocyclic alkyl groups are optionally selected from one or more of R 1a Replaced by, R 1a As defined above.

[0104] In some embodiments, R in the compound of formula I or formula II-1 or formula II-2 or formula III-1 or formula III-2 or formula III-3 or formula III-4 or a pharmaceutically acceptable salt thereof 6 Each is independently selected from 3- to 10-membered heterocyclic alkyl groups containing at least one N atom, for example, 3- to 10-membered heterocyclic alkyl groups containing one or two N atoms.

[0105] In other embodiments, R in the compound of formula I or II-1 or II-2 or III-1 or III-2 or III-3 or III-4 or a pharmaceutically acceptable salt thereof 6 Each is independently selected from halogens (such as fluorine or chlorine), hydroxyl groups, and C. 1-6 Alkyl (such as methyl or ethyl), C 2-6 alkenyl (such as vinyl), C 2-6 Alkyne group (such as ethynyl group), C 1-6 Alkoxy (such as methoxy or ethoxy), C 3-10 Cycloalkyl groups (such as cyclopropyl or cyclobutyl), 3- to 10-membered heterocyclic alkyl groups, wherein the C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 3-10 Cycloalkyl or 3 to 10-membered heterocyclic alkyl groups optionally selected from R 1a Replaced by, R 1a As defined above.

[0106] In other embodiments, R in the compound of formula I or II-1 or II-2 or III-1 or III-2 or III-3 or III-4 or a pharmaceutically acceptable salt thereof 6 Each is independently selected from 6-membered aryl and 5- to 6-membered heteroaryl, wherein the 6-membered aryl and 5- to 6-membered heteroaryl are optionally selected from one or more of R 1a Replaced by, R 1a As defined above.

[0107] In some embodiments, R in the compound of formula I or formula II-1 or formula II-2 or formula III-1 or formula III-2 or formula III-3 or formula III-4 or a pharmaceutically acceptable salt thereof 6 Each is independently selected from halogens, C 1-6 Alkyl, C 3-10 Cycloalkoxy or -OC 2-6alkenyl, the C 1-6 Alkyl, C 3-10 Cycloalkoxy or -OC 2-6 Alkenyl groups are optionally selected from one or more R groups. 1a Replaced by, R 1a Halogen, C 1-6 Alkyl, C 3-10 Cycloalkoxy or -OC 2-6 alkenyl, the C 1-6 Alkyl, C 3-10 Cycloalkoxy or -OC 2-6 Alkenyl groups are optionally selected from one or more R groups. 1a Replaced by, R 1a As defined above.

[0108] In some implementation schemes, R 6 Selected from halogens, C 3-10 Cycloalkyl (including but not limited to spirocyclic, fused or bridged rings) or 3 to 10-membered heterocyclic alkyl (including but not limited to spirocyclic, fused or bridged rings).

[0109] In some embodiments, R in the compound of formula I or formula II-1 or formula II-2 or formula III-1 or formula III-2 or formula III-3 or formula III-4 or a pharmaceutically acceptable salt thereof 6 Selected from (include ), (include ),

[0110] In some embodiments, R in the compound of formula I or formula II-1 or formula II-2 or formula III-1 or formula III-2 or formula III-3 or formula III-4 or a pharmaceutically acceptable salt thereof 6 Selected from C 1-6 Alkyl, the C 1-6 Alkyl groups are optionally selected from one or more of R 1a Replaced by, R 1a As defined above.

[0111] In some embodiments, R in the compound of formula I or formula II-1 or formula II-2 or formula III-1 or formula III-2 or formula III-3 or formula III-4 or a pharmaceutically acceptable salt thereof 6 Selected from C 3-10 Cycloalkoxy, the C 3-10 Cycloalkoxy groups are optionally selected from one or more R groups. 1a Replaced by, R 1a As defined above.

[0112] In other embodiments, R in the compound of formula I or II-1 or II-2 or III-1 or III-2 or III-3 or III-4 or a pharmaceutically acceptable salt thereof 6 Selected from fluorine, chlorine, methyl, deuterated methyl, ethyl, deuterated ethyl, difluoromethyl, trifluoromethyl, methoxy, ethoxy, deuterated methoxy, difluoromethoxy, difluoroethoxy, trifluoromethoxy, trifluoroethoxy, cyclopropylmethyloxy, cyclopropoxy, and cyclobutoxy.

[0113] In some embodiments, the compound represented by Formula I is the compound represented by Formula IV-1.

[0114] Where R 1 ~R 8 R 2a , m, n, o are defined as in the compounds shown in Formula I; R 6a X 4 X 6 X 7 X 8 X 9 X 11 X 12 X 13 X 14 and X 15 As defined above; r is selected from 0, 1, 2, or 3. In some embodiments, X is a compound of formula I or II-1 or II-2 or III-1 or III-2 or III-3 or III-4 or IV-1, or a pharmaceutically acceptable salt thereof. 12 Selected from N.

[0115] In some embodiments, X is a compound of formula I or II-1 or II-2 or III-1 or III-2 or III-3 or III-4 or IV-1 or a pharmaceutically acceptable salt thereof. 11 Selected from N.

[0116] In some embodiments, the compound of formula I or formula II-1 or formula II-2 or formula III-1 or formula III-2 or formula III-3 or formula III-4 or formula IV-1 or the compound of formula IV-2 or a pharmaceutically acceptable salt thereof contains X. 11 X 12 Selected from N.

[0117] In some embodiments, the compound of formula I or formula II-1 or formula II-2 or formula III-1 or formula III-2 or formula III-3 or formula III-4 or formula IV-1 or the compound of formula IV-2 or a pharmaceutically acceptable salt thereof contains X. 13 Selected from N.

[0118] In some embodiments, the compound represented by formula IV-1 is the compound represented by formula IV-1a.

[0119] In some embodiments, the compound represented by Formula I is the same as the compound represented by Formula V-1.

[0120] Where R 1 ~R 8 R 2a , m, n, o are defined as in the compounds shown in Formula I; R 6a X 4 X 6 X 7 X 8 X 9 As defined above, r is selected from 0, 1, 2, or 3.

[0121] In some embodiments, the compound shown in Formula I is the same as the compound shown in Formula V-2.

[0122] Where R 1 ~R 8 R 2a , m, n, o are defined as in the compounds shown in Formula I; R 6a X 4 X 6 X 7 X 8 X 9 As defined above, r is selected from 0, 1, 2, or 3.

[0123] In some embodiments, X in the compound of formula I or formula IV-2 or its pharmaceutically acceptable salt 12 Selected from N.

[0124] In some embodiments, X in the compound of formula I or formula IV-2 or its pharmaceutically acceptable salt 11 Selected from N.

[0125] In some embodiments, X in the compound of formula I or formula IV-2 or its pharmaceutically acceptable salt 11 X 12 Selected from N.

[0126] In some embodiments, X in the compound of formula I or formula IV-2 or its pharmaceutically acceptable salt 13 Selected from N.

[0127] In some embodiments, the compound represented by formula V-1 is the compound represented by formula V-1a.

[0128] On the other hand, in some embodiments, the compound shown in Formula I is the compound shown in Formula IV-2.

[0129] Where R 1 ~R 8 R 2a , m, n, o are defined as in the compounds shown in Formula I; R 6a X 4 X 6 X 7 X 8 X 9 X 11 X 12 X 13 X 14 and X 15 As defined above; r is selected from 0, 1, 2 or 3.

[0130] In some embodiments, the compound represented by formula IV-2 is the compound represented by formula IV-2a.

[0131] In some embodiments, the compound represented by Formula I is the same as the compound represented by Formula V-3.

[0132] Where R 1 ~R 8 R 2a , m, n, o are defined as in the compounds shown in Formula I; R 6a X 4 X 6 X 7 X 8 X 9 As defined above, r is selected from 0, 1, 2, or 3.

[0133] In some embodiments, the compound represented by Formula I is the same as the compound represented by Formula V-4.

[0134] Where R 1 ~R 8 R 2a , m, n, o are defined as in the compounds shown in Formula I; R 6a X 4 X 6 X 7 X 8 X 9 As defined above, r is selected from 0, 1, 2, or 3.

[0135] In some embodiments, R in the compound of formula I or formula II-1 or formula II-2 or formula III-1 or formula III-2 or formula III-3 or formula III-4 or formula IV-1 or formula IV-2 or formula V-1 or formula V-2 or formula V-3 or formula V-4 or a pharmaceutically acceptable salt thereof 1 Selected from hydrogen, halogen, amino, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl or 3-6 membered heterocycloalkyl, wherein C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl or 3-6 membered heterocyclic alkyl groups may be selected from one or more halogens, hydroxyl, cyano, nitro, amino, C 1-6 Alkyl or C 1-6 Alkyl groups are substituted.

[0136] In some embodiments, R in the compound of formula I or formula II-1 or formula II-2 or formula III-1 or formula III-2 or formula III-3 or formula III-4 or formula IV-1 or formula IV-2 or formula V-1 or formula V-2 or formula V-3 or formula V-4 or a pharmaceutically acceptable salt thereof 1 Selected from hydrogen, halogen or C 1-6 Alkyl, the C 1-6 Alkyl groups may be optionally surrounded by one or more groups selected from halogen, hydroxyl, cyano, nitro, amino, C 1-6 Alkyl or C 1-6 Alkyl groups are substituted.

[0137] In some embodiments, R in the compound of formula I or formula II-1 or formula II-2 or formula III-1 or formula III-2 or formula III-3 or formula III-4 or formula IV-1 or formula IV-2 or formula V-1 or formula V-2 or formula V-3 or formula V-4 or a pharmaceutically acceptable salt thereof 1 It is selected from hydrogen, fluorine, methyl, difluoromethyl, trifluoromethyl, ethyl or propyl.

[0138] In some embodiments, R in the compound of formula I or formula II-1 or formula II-2 or formula III-1 or formula III-2 or formula III-3 or formula III-4 or formula IV-1 or formula IV-2 or formula V-1 or formula V-2 or formula V-3 or formula V-4 or a pharmaceutically acceptable salt thereof 2 Selected from hydrogen, halogen, amino, C 1-6 Alkyl or C 1-6 Alkoxy, the C 1-6 Alkyl or C 1-6 Alkyl groups are optionally surrounded by one or more groups selected from halogen, hydroxyl, cyano, nitro, amino, C 1-6 Alkyl or C 1-6 What it replaced.

[0139] In some embodiments, R in the compound of formula I or formula II-1 or formula II-2 or formula III-1 or formula III-2 or formula III-3 or formula III-4 or formula IV-1 or formula IV-2 or formula V-1 or formula V-2 or formula V-3 or formula V-4 or a pharmaceutically acceptable salt thereof 2 Selected from hydrogen, halogen or C 1-6 Alkyl, the C 1-6 Alkyl groups may be optionally surrounded by one or more groups selected from halogen, hydroxyl, cyano, nitro, amino, C 1-6 Alkyl or C 1-6 Alkyl groups are substituted.

[0140] In some embodiments, R in the compound of formula I or formula II-1 or formula II-2 or formula III-1 or formula III-2 or formula III-3 or formula III-4 or formula IV-1 or formula IV-2 or formula V-1 or formula V-2 or formula V-3 or formula V-4 or a pharmaceutically acceptable salt thereof 2 It is selected from hydrogen, fluorine, methyl, difluoromethyl, trifluoromethyl, ethyl or propyl.

[0141] In some embodiments, R in the compound of formula I or formula II-1 or formula II-2 or formula III-1 or formula III-2 or formula III-3 or formula III-4 or formula IV-1 or formula IV-2 or formula V-1 or formula V-2 or formula V-3 or formula V-4 or a pharmaceutically acceptable salt thereof 1a Selected from deuterium, halogens (such as fluorine or chlorine), or C 1-6 Alkyl group (such as methyl or ethyl), wherein the alkyl group is optionally substituted with one or more groups selected from halogen, hydroxyl, cyano, nitro or amino.

[0142] In some embodiments, R in the compound of formula I or formula II-1 or formula II-2 or formula III-1 or formula III-2 or formula III-3 or formula III-4 or formula IV-1 or formula IV-2 or formula V-1 or formula V-2 or formula V-3 or formula V-4 or a pharmaceutically acceptable salt thereof 1a Selected from deuterium, fluorine, chlorine, methyl or ethyl.

[0143] In some embodiments, R in the compound of formula I or formula II-1 or formula II-2 or formula III-1 or formula III-2 or formula III-3 or formula III-4 or formula IV-1 or formula IV-2 or formula V-1 or formula V-2 or formula V-3 or formula V-4 or a pharmaceutically acceptable salt thereof 7 Selected from hydrogen, hydroxyl, halogen (such as fluorine or chlorine) or C 1-6 Alkyl groups (such as methyl or ethyl), the C 1-6 Alkyl groups may be optionally surrounded by one or more groups selected from halogen, hydroxyl, cyano, nitro, amino, C 1-6 Alkyl or C 1-6 Alkyl groups are substituted.

[0144] In some embodiments, R in the compound of formula I or formula II-1 or formula II-2 or formula III-1 or formula III-2 or formula III-3 or formula III-4 or formula IV-1 or formula IV-2 or formula V-1 or formula V-2 or formula V-3 or formula V-4 or a pharmaceutically acceptable salt thereof 7 It is selected from hydrogen, hydroxyl, fluorine, methyl, difluoromethyl, trifluoromethyl, ethyl or propyl.

[0145] In some embodiments, R in the compound of formula I or formula II-1 or formula II-2 or formula III-1 or formula III-2 or formula III-3 or formula III-4 or formula IV-1 or formula IV-2 or formula V-1 or formula V-2 or formula V-3 or formula V-4 or a pharmaceutically acceptable salt thereof 2a Each is independently selected from hydrogen, (such as fluorine or chlorine) or C. 1-6 Alkyl groups (such as methyl or ethyl), the C 1-6 Alkyl groups may be optionally surrounded by one or more groups selected from halogen, hydroxyl, cyano, nitro, amino, C 1-6 Alkyl or C 1-6 Alkyl groups are substituted. In some embodiments, R is a compound of formula I, II-1, II-2, III-1, III-2, III-3, or III-4, or a pharmaceutically acceptable salt thereof. 2a Each is independently selected from hydrogen, fluorine, methyl, difluoromethyl, trifluoromethyl, ethyl, or propyl.

[0146] In some embodiments, R in the compound of formula I or formula II-1 or formula II-2 or formula III-1 or formula III-2 or formula III-3 or formula III-4 or formula IV-1 or formula IV-2 or formula V-1 or formula V-2 or formula V-3 or formula V-4 or a pharmaceutically acceptable salt thereof 3a Each is independently selected from hydrogen, (such as fluorine or chlorine) or C. 1-6 Alkyl groups (such as methyl or ethyl), the C 1-6 Alkyl groups may be optionally surrounded by one or more groups selected from halogen, hydroxyl, cyano, nitro, amino, C 1-6 Alkyl or C 1-6 Alkyl groups are substituted. In some embodiments, R is a compound of formula I, II-1, II-2, III-1, III-2, III-3, or III-4, or a pharmaceutically acceptable salt thereof. 3a Each is independently selected from hydrogen, fluorine, methyl, difluoromethyl, trifluoromethyl, ethyl, or propyl.

[0147] In some embodiments, R in the compound of formula I or formula II-1 or formula II-2 or formula III-1 or formula III-2 or formula III-3 or formula III-4 or formula IV-1 or formula IV-2 or formula V-1 or formula V-2 or formula V-3 or formula V-4 or a pharmaceutically acceptable salt thereof 4a Each is independently selected from hydrogen, (such as fluorine or chlorine) or C. 1-6 Alkyl groups (such as methyl or ethyl), the C 1-6 Alkyl groups may be optionally surrounded by one or more groups selected from halogen, hydroxyl, cyano, nitro, amino, C 1-6 Alkyl or C 1-6 Alkyl groups are substituted. In some embodiments, R is a compound of formula I, II-1, II-2, III-1, III-2, III-3, or III-4, or a pharmaceutically acceptable salt thereof. 4a Each is independently selected from hydrogen, fluorine, methyl, difluoromethyl, trifluoromethyl, ethyl, or propyl.

[0148] In some embodiments, R in the compound of formula I or formula II-1 or formula II-2 or formula III-1 or formula III-2 or formula III-3 or formula III-4 or formula IV-1 or formula IV-2 or formula V-1 or formula V-2 or formula V-3 or formula V-4 or a pharmaceutically acceptable salt thereof 5a Each is independently selected from hydrogen, (such as fluorine or chlorine) or C. 1-6 Alkyl groups (such as methyl or ethyl), the C 1-6 Alkyl groups may be optionally surrounded by one or more groups selected from halogen, hydroxyl, cyano, nitro, amino, C 1-6 Alkyl or C 1-6 Alkyl groups are substituted. In some embodiments, R is a compound of formula I, II-1, II-2, III-1, III-2, III-3, or III-4, or a pharmaceutically acceptable salt thereof. 5a Each is independently selected from hydrogen, fluorine, methyl, difluoromethyl, trifluoromethyl, ethyl, or propyl.

[0149] In some embodiments, R in the compound of formula I or formula II-1 or formula II-2 or formula III-1 or formula III-2 or formula III-3 or formula III-4 or formula IV-1 or formula IV-2 or formula V-1 or formula V-2 or formula V-3 or formula V-4 or a pharmaceutically acceptable salt thereof 6a Each is independently selected from hydrogen, (such as fluorine or chlorine) or C. 1-6 Alkyl groups (such as methyl or ethyl), the C 1-6 Alkyl groups may be optionally surrounded by one or more groups selected from halogen, hydroxyl, cyano, nitro, amino, C 1-6 Alkyl or C 1-6 Alkyl groups are substituted.

[0150] In some embodiments, R in the compound of formula I or formula II-1 or formula II-2 or formula III-1 or formula III-2 or formula III-3 or formula III-4 or a pharmaceutically acceptable salt thereof 6a Each is independently selected from hydrogen, fluorine, methyl, difluoromethyl, trifluoromethyl, ethyl, or propyl.

[0151] In some embodiments, X is a compound of formula I or formula II-1 or formula II-2 or formula III-1 or formula III-2 or formula III-3 or formula III-4 or formula IV-1 or formula IV-2 or formula V-1 or formula V-2 or formula V-3 or formula V-4, or a pharmaceutically acceptable salt thereof. 9 Selected from CR 4aa .

[0152] In some embodiments, X is a compound of formula I or formula II-1 or formula II-2 or formula III-1 or formula III-2 or formula III-3 or formula III-4 or formula IV-1 or formula IV-2 or formula V-1 or formula V-2 or formula V-3 or formula V-4, or a pharmaceutically acceptable salt thereof. 4 X 6 X 7 X 8 Selected from CH.

[0153] In some implementation schemes, R 4aa Each is independently selected from hydrogen, (such as fluorine or chlorine) or C. 1-6 Alkyl groups (such as methyl or ethyl), the C 1-6 Alkyl groups may be optionally surrounded by one or more groups selected from halogen, hydroxyl, cyano, nitro, amino, C 1-6 Alkyl or C 1-6 Alkyl groups are substituted. In some embodiments, R... 4aa Each is independently selected from hydrogen, fluorine, methyl, difluoromethyl, trifluoromethyl, ethyl, or propyl.

[0154] In some implementation schemes, R 5aa Each is independently selected from hydrogen, (such as fluorine or chlorine) or C. 1-6 Alkyl groups (such as methyl or ethyl), the C 1-6 Alkyl groups may be optionally surrounded by one or more groups selected from halogen, hydroxyl, cyano, nitro, amino, C 1-6 Alkyl or C 1-6 Alkyl groups are substituted. In some embodiments, R... 5aa Each is independently selected from hydrogen, fluorine, methyl, difluoromethyl, trifluoromethyl, ethyl, or propyl.

[0155] In some embodiments, m in the compound of formula I or formula II-1 or formula II-2 or formula III-1 or formula III-2 or formula III-3 or formula III-4 or formula IV-1 or IV-2 or V or a pharmaceutically acceptable salt thereof is selected from 0, 1 or 2.

[0156] The compounds disclosed herein include, but are not limited to:

[0157] This disclosure also provides isotopic substitutes of the aforementioned compounds or their pharmaceutically acceptable salts. In some embodiments, the isotopic substitutes are deuterated.

[0158] This disclosure also provides nitrogen oxides of the aforementioned compounds or their pharmaceutically acceptable salts.

[0159] In assays to determine the ATPase catalytic activity of BRM or BRG-1, in some embodiments, the IC50 value of the disclosed compound against SMARCA2 inhibitory activity is from 0.01 to 50 nM. In some embodiments, the IC50 value of the disclosed compound against SMARCA2 inhibitory activity is from 0.1 to 20 nM. In some embodiments, the IC50 value of the disclosed compound against SMARCA2 inhibitory activity is from 1 to 20 nM. Furthermore, in some embodiments, the disclosed compound exhibits selective inhibitory activity against SMARCA2.

[0160] This disclosure also provides a pharmaceutical composition comprising at least one therapeutically effective amount of the aforementioned compound, such as a pharmaceutically acceptable salt of formula I or II-1 or II-2 or III-1 or III-2 or III-3 or III-4, or an isotopic substitute thereof, and a pharmaceutically acceptable excipient.

[0161] In some embodiments, the pharmaceutical composition contains 0.01-99.99% of the aforementioned compound or its pharmaceutically acceptable salt or isotopic substitute, based on the total weight of the composition.

[0162] In some embodiments, the pharmaceutical composition contains 0.1%-99.9% of the aforementioned compound or its pharmaceutically acceptable salt or isotopic substitution. In some embodiments, the pharmaceutical composition contains 0.5%-99.5% of the aforementioned compound or its pharmaceutically acceptable salt or isotopic substitution. In some embodiments, the pharmaceutical composition contains 1%-99% of the aforementioned compound or its pharmaceutically acceptable salt or isotopic substitution. In some embodiments, the pharmaceutical composition contains 2%-98% of the aforementioned compound or its pharmaceutically acceptable salt or isotopic substitution.

[0163] In some embodiments, the pharmaceutical composition contains 0.01% to 99.99% pharmaceutically acceptable excipients based on the total weight of the composition. In some embodiments, the pharmaceutical composition contains 0.1% to 99.9% pharmaceutically acceptable excipients. In some embodiments, the pharmaceutical composition contains 0.5% to 99.5% pharmaceutically acceptable excipients. In some embodiments, the pharmaceutical composition contains 1% to 99% pharmaceutically acceptable excipients. In some embodiments, the pharmaceutical composition contains 2% to 98% pharmaceutically acceptable excipients.

[0164] This disclosure also provides a combination comprising the aforementioned pharmaceutical composition and instructions for use of the pharmaceutical composition.

[0165] This disclosure also provides a method for preventing and / or treating cancer by administering to the individual a therapeutically effective amount of the aforementioned compound or a pharmaceutically acceptable salt thereof, or the aforementioned pharmaceutical composition. In some embodiments, the cancer is selected from lung cancer, colorectal cancer, breast cancer, melanoma, skin cancer, lymphoma, and prostate cancer.

[0166] This disclosure also provides the use of compounds of formula I, II-1, II-2, III-1, III-2, III-3, or III-4, or pharmaceutically acceptable salts thereof, or the aforementioned pharmaceutical compositions, in the preparation of medicaments for the prevention and / or treatment of SMARCA2-related diseases. In some embodiments, SMARCA2-related diseases are selected from lung cancer, colorectal cancer, breast cancer, melanoma, skin cancer, lymphoma, and prostate cancer.

[0167] This disclosure also provides the use of compounds of formula I, II-1, II-2, III-1, III-2, III-3, or III-4, or pharmaceutically acceptable salts thereof, or the aforementioned pharmaceutical compositions, in the preparation of medicaments for the prevention and / or treatment of cancer. In some embodiments, the cancer is selected from lung cancer, colorectal cancer, breast cancer, melanoma, skin cancer, lymphoma, and prostate cancer.

[0168] This disclosure also provides compounds of formula I, II-1, II-2, III-1, III-2, III-3, or III-4, or pharmaceutically acceptable salts thereof, or the aforementioned pharmaceutical compositions, for the prevention and / or treatment of cancer. In some embodiments, the cancer is selected from lung cancer, colorectal cancer, breast cancer, melanoma, skin cancer, lymphoma, and prostate cancer.

[0169] On the other hand, this disclosure also provides a method for preparing the compound of formula I or a pharmaceutically acceptable salt thereof.

[0170] The method includes the step of reacting a compound of formula AA or a salt thereof with a compound of formula BB or a salt thereof to form a compound of formula I.

[0171] Where R 1 ~R 8 X 1 X 2 X 3 Z 1 Z 2 The rings A, m, n, and o are defined as shown in the compound represented by Formula I; PG is a hydroxyl group or a leaving group (such as chlorine).

[0172] In other embodiments, the compound of formula AA or a salt thereof reacts with the compound of formula BB or a salt thereof in the presence of a condensing agent. The condensing agent described in this disclosure is selected from, but not limited to, 2-(7-azobenzotriazole)-tetramethylurea hexafluorophosphate (HATU).

[0173] This disclosure also provides compounds of formula AA or salts thereof. Where R 1 R 2 R 7 R 8 X 1 X 2 X 3 Z 1 Z 2 In compounds of formula I, ring A and m are defined as hydroxyl or leaving group (e.g., chlorine).

[0174] The pharmaceutically acceptable salts of the compounds described in this disclosure may be selected from inorganic or organic salts.

[0175] The compound salts described in this disclosure may be selected from inorganic or organic salts.

[0176] The compounds disclosed herein can exist in specific geometric or stereoisomeric forms. This disclosure envisions all such compounds, including cis and trans isomers, (-)- and (+)- enantiomers, (R)- and (S)- enantiomers, diastereomers, (D)- isomers, (L)- isomers, and racemic mixtures thereof, as well as other mixtures, such as mixtures enriched with enantiomers or diastereomers, all of which are within the scope of this disclosure. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers and mixtures thereof are included within the scope of this disclosure. The compounds containing asymmetric carbon atoms of this disclosure can be isolated in optically active pure form or in racemic form. Optically active pure forms can be resolved from racemic mixtures or synthesized using chiral starting materials or chiral reagents.

[0177] Optically active (R)- and (S)- isomers, as well as D- and L- isomers, can be prepared by chiral synthesis, chiral reagents, or other conventional techniques. To obtain an enantiomer of a compound disclosed herein, it can be prepared by asymmetric synthesis or derivatization with a chiral auxiliary, wherein the resulting diastereomeric mixture is separated and the auxiliary group is cleaved to provide the desired enantiomer in pure form. Alternatively, when the molecule contains a basic functional group (such as an amino group) or an acidic functional group (such as a carboxyl group), a salt of the diastereomeric isomer is formed with a suitable optically active acid or base, followed by diastereomeric resolution using conventional methods known in the art, and then the pure enantiomer is recovered. Furthermore, the separation of enantiomers and diastereomeric isomers is typically accomplished by using chromatography employing a chiral stationary phase and optionally combined with chemical derivatization (e.g., from amines to carbamates).

[0178] In the chemical structure of the compounds described in this disclosure, the bonds... This indicates that the configuration is not specified; that is, if chiral isomers exist in the chemical structure, the bond... It can be Or simultaneously include Two configurations.

[0179] For example Chiral isomers exist, including Two configurations, such as

[0180] The compounds and intermediates disclosed herein may also exist in different tautomer forms, and all such forms are included within the scope of this disclosure. The terms "tautomer" or "tautomer form" refer to structural isomers of different energies that can interconvert via low energy barriers. For example, proton tautomers (also known as proton transfer tautomers) include interconversions via proton migration, such as keto-enol and imine-enamine, lactam-lactamimide isomerization. An example of a lactam-lactamimide equilibrium is between A and B as shown below:

[0181] All tautomers are within the scope of this disclosure. The nomenclature of compounds does not exclude any tautomers.

[0182] This disclosure also includes compounds identical to those described herein, but in which one or more atoms are labeled with isotopes whose atomic weights or mass numbers differ from those commonly found in nature. Examples of isotopes that can be incorporated into compounds of this 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, etc.

[0183] Unless otherwise specified, when a position is specifically designated as deuterium (D), that position should be understood as having a deuterium abundance of at least 1000 times greater than the natural abundance of deuterium (which is 0.015%) (i.e., at least 10% deuterium incorporation). The natural abundance of deuterium in the example compounds can be at least 1000 times, at least 2000 times, at least 3000 times, at least 4000 times, at least 5000 times, at least 6000 times, or even higher. This disclosure also includes various deuterated forms of compounds of formula (I). Each available hydrogen atom bonded to a carbon atom can be independently replaced by a deuterium atom. Those skilled in the art can synthesize the deuterated forms of compounds of formula (I) with reference to relevant literature. Commercially available deuterated starting materials can be used to prepare the deuterated form of the compound of formula (I), or they can be synthesized using conventional techniques with deuterated reagents, including but not limited to deuterated boranes, trideuterated borane tetrahydrofuran solutions, deuterated lithium aluminum hydride, deuterated iodoethane, and deuterated iodomethane.

[0184] "Optionally" means that the event or situation subsequently described may, but does not have to, occur; the description includes the possibility or possibility that the event or situation may or may not occur. For example, "optionally halogenated or cyano-substituted C..." 1-6 "Alkyl" means that halogens or cyano groups may or may not be present. This description includes cases where alkyl groups are substituted by halogens or cyano groups and cases where alkyl groups are not substituted by halogens or cyano groups.

[0185] "Pharmaceutical composition" means a mixture containing one or more of the compounds described herein or their physiologically pharmaceutically acceptable salts or prodrugs, along with other chemical components, such as physiologically pharmaceutically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration to a living organism, thereby promoting the absorption of the active ingredient and its biological activity.

[0186] "Pharmaceutical excipients" include, but are not limited to, any adjuvant, carrier, flow aid, sweetener, diluent, preservative, dye / coloring agent, flavoring agent, surfactant, wetting agent, dispersant, suspending agent, stabilizer, isotonic agent, solvent, or emulsifier that has been approved by the U.S. Food and Drug Administration (FDA) for use in humans or livestock.

[0187] The term "effective amount" or "effective therapeutic amount" as used in this disclosure includes an amount sufficient to improve or prevent symptoms or conditions of a medical condition. An effective amount also means an amount sufficient to allow or facilitate diagnosis. The effective amount for a particular patient or veterinary subject may vary depending on factors such as the condition to be treated, the patient's overall health, the route and dosage of administration, and the severity of side effects. An effective amount may be the maximum dose or administration regimen that avoids significant side effects or toxicity.

[0188] "alkyl" refers to a saturated aliphatic hydrocarbon group, including straight-chain and branched groups with 1 to 6 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, and their various branched isomers. The alkyl group may be substituted or unsubstituted; when substituted, the substituent can be replaced at any usable connection point, preferably one or more of the following groups, including but not limited to halogens, hydroxyl groups, cyano groups, nitro groups, amino groups, and C6 groups. 1-6 Alkyl or C 1-6 Alkyl group.

[0189] "Alkenyl" refers to an unsaturated aliphatic straight-chain or branched hydrocarbon group containing one or more carbon-carbon double bonds. Exemplary alkenyl groups include C2-C6, C2-C4, and C3 alkenyl groups. These include, but are not limited to, vinyl (i.e., vinyl), 1-propenyl, 2-propenyl (i.e., allyl), 2-methyl-1-propenyl, 1-butenyl, 2-butenyl (i.e., crotonyl), etc. Alkenyl groups used in any context herein may optionally be substituted in the same manner as alkyl groups.

[0190] "Alynyl" refers to an unsaturated aliphatic straight-chain or branched hydrocarbon group containing one or more carbon-carbon triple bonds. Exemplary alkynyl groups include C2-C6, C2-C4, and C3 alkynyl groups. These include, but are not limited to, ethynyl, propynyl, butynyl, pentynyl, pentynyl-4-alkynyl, and pentynyl-1,4-diynyl. In any context herein, alkynyl groups may optionally be substituted in the same manner as alkyl groups.

[0191] The term "cycloalkyl" or "alicyclic ring" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent containing 3 to 6 carbon atoms, such as 4 or 5 carbons. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, etc.; polycyclic cycloalkyl groups include spirocyclic, fused-ring, and bridged-ring cycloalkyl groups. Cycloalkyl groups can be substituted or unsubstituted. When substituted, the substituent is preferably one or more of the following groups, independently selected from halogen, oxo, hydroxyl, cyano, nitro, amino, C... 1-6 Alkyl or C 1-6 Alkyl group.

[0192] The term "heterocycloalkyl" or "alicyclic heterocycle" refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon substituent containing 3 to 14 ring atoms, such as 4 or 5 ring atoms, wherein one or more ring atoms are selected from nitrogen, oxygen, or S(O). m Heteroatoms (where m is an integer from 0 to 2), excluding the ring moiety of -OO-, -OS-, or -SS-, with the remaining ring atoms being carbon. Non-limiting examples of "heterocyclic alkyl" include: etc.

[0193] Heterocyclic alkyl groups may be optionally substituted or unsubstituted. When substituted, the substituents are preferably one or more of the following groups, including but not limited to halogen, oxo, hydroxyl, cyano, nitro, amino, C 1-6 Alkyl or C 1-6 Alkyl group.

[0194] In some embodiments, the heterocyclic alkyl group may be fused to an aryl or heteroaryl ring, wherein the ring attached to the parent structure is a heterocyclic alkyl group. Non-limiting examples include:

[0195] In some embodiments, the heterocyclic alkyl group exists in a polycyclic cyclic form, including "spirocyclic", "fused-ring", or "bridged ring".

[0196] The term "spirocyclic" refers to a compound in which two rings share a single atom. Non-limiting examples of spirocyclic alkyl compounds include:

[0197] The term "cyclic" refers to a compound in which two or more rings are fused together by sharing two adjacent atoms. Non-limiting examples of cyclic alkyl groups include:

[0198] The term "bridged ring" refers to a structure formed by two or more ring structures sharing two non-adjacent ring atoms. Depending on the number of rings, bridged alkyl groups can be classified as bicyclic, tricyclic, tetracyclic, or polycyclic, preferably bicyclic, tricyclic, or tetracyclic, and more preferably bicyclic or tricyclic. Non-limiting examples of bridged alkyl groups include:

[0199] The term "alkoxy" refers to -O- (alkyl), where alkyl is defined as described above. Non-limiting examples include: methoxy, ethoxy, propoxy, and butoxy. The alkoxy group can be optionally substituted or unsubstituted; when substituted, the substituent is preferably one or more of the following groups, including but not limited to halogens, hydroxyl groups, cyano groups, nitro groups, amino groups, and C- groups. 1-6 Alkyl or C 1-6 Alkyl group.

[0200] The term "aryl" or "aromatic ring" refers to a 6- to 10-membered all-carbon monocyclic or fused polycyclic (i.e., a ring sharing adjacent carbon atom pairs) group having a conjugated π-electron system, such as phenyl and naphthyl. The aryl ring may be fused to a heteroaryl, heterocycloalkyl, or cycloalkyl ring, wherein the ring attached to the parent structure is an aryl ring, and non-limiting examples include:

[0201] The aryl group can be substituted or unsubstituted. When substituted, the substituent is preferably one or more of the following groups, including but not limited to halogen, hydroxyl, cyano, nitro, amino, C 1-6 Alkyl or C 1-6 Alkyl group.

[0202] The term "heteroaryl" or "heteroary ring" refers to a heteroaryl system comprising 1 to 4 heteroatoms and 5 to 10 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur, and nitrogen. The heteroaryl group is preferably 5 to 10-membered, such as 7-, 8-, or 9-membered, and more preferably 5- or 6-membered. For example, non-limiting examples include:

[0203] The heteroaryl group may be fused to an aryl, heterocyclic, or cycloalkyl ring, wherein the ring attached to the parent structure is a heteroaryl group, and non-limiting examples include:

[0204] The heteroaryl group can be optionally substituted or unsubstituted. When substituted, the substituent is preferably one or more of the following groups, including but not limited to halogen, hydroxyl, cyano, nitro, amino, C 1-6 Alkyl or C 1-6 Alkyl group.

[0205] The term "heterocyclic" refers to a ring composed of atoms other than carbon atoms, including heterocyclic alkyl and heteroaryl groups. "Heterocyclic alkyl" and "heteroaryl" are as defined above.

[0206] A "monovalent group" refers to a compound in which one monovalent atom or group is "formally" removed. A "divalent group" refers to a compound in which two monovalent or one divalent atom or group is "formally" removed. For example, "methylene" represents the part remaining after removing two hydrogen atoms from an alkane molecule.

[0207] In some implementations, the heterocyclic alkyl and heteroaryl groups can be monovalent, divalent, or polyvalent, and those skilled in the art will recognize from the context the number of available valences.

[0208] The term "amino" refers to -N(R) a )2, where R a Each is independently selected from hydrogen and C. 1-6 Alkyl, C 3-6 Cycloalkyl or 3- to 6-membered heterocyclic alkyl groups, wherein the alkyl, cycloalkyl, or heterocyclic alkyl group is optionally selected from one or more elements selected from halogen, hydroxyl, cyano, nitro, C 1-6 Alkyl or C 1-6 Alkyl groups are substituted. In some embodiments, the "amino" can be an unsubstituted amino group (i.e., -NH2) or a substituted amino group (-N(R)). a )2, R a (Not all of it is hydrogen).

[0209] The term "hydroxyl group" refers to the -OH group.

[0210] The term "halogen" refers to fluorine, chlorine, bromine, or iodine.

[0211] The term "cyano" refers to -CN.

[0212] The term "nitro" refers to -NO2.

[0213] The term "oxo" refers to =O.

[0214] "Substituted" refers to one or more hydrogen atoms in a group, preferably up to five, more preferably one to three hydrogen atoms, which are independently substituted by the corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and those skilled in the art can determine (by experiment or theory) possible or impossible substitutions without much effort.

[0215] The "substituents" disclosed herein include, but are not limited to, halogens (such as chlorine and fluorine), hydroxyl groups, cyano groups, nitro groups, amino groups, and C6 groups. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C3-6 Cycloalkyl, 3- to 6-membered heterocycloalkyl, C 3-6 Cycloalkoxy, 3- to 6-membered heterocycloalkoxy, or -OC 2-6 alkenyl, the C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 3-6 Cycloalkyl, 3- to 6-membered heterocycloalkyl, C 3-6 Cycloalkoxy, 3- to 6-membered heterocycloalkoxy, or -OC 2-6 Alkenyl groups may be optionally replaced by one or more halogens, oxo groups, hydroxyl groups, cyano groups, nitro groups, amino groups, or C groups. 1-6 Alkyl or C 1-6 Alkyl-substituted. Detailed Implementation

[0216] The following embodiments are used to further describe this disclosure, but these embodiments are not intended to limit the scope of this disclosure.

[0217] Example

[0218] The structure of the compound was determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). NMR shifts (δ) were expressed in 10⁻¹⁰. -6 The unit (ppm) is given. NMR determination was performed using a Bruker AVANCE-400 NMR spectrometer or a Bruker AVANCE NEO 500M. The solvents used were deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), and deuterated methanol (CD3OD). The internal standard was tetramethylsilane (TMS).

[0219] MS measurements were performed using an Agilent 1200 / 1290DAD-6110 / 6120 Quadrupole MS liquid chromatography-mass spectrometry system (manufacturer: Agilent, MS model: 6110 / 6120 Quadrupole MS).

[0220] waters ACQuity UPLC-QD / SQD (Manufacturer: waters, MS model: waters ACQuity Qda Detector / waters SQ Detector)

[0221] THERMO Ultimate 3000-Q Exactive (Manufacturer: THERMO, MS Model: THERMO Q Exactive)

[0222] High-performance liquid chromatography (HPLC) analysis was performed using an Agilent HPLC 1200DAD, an Agilent HPLC 1200VWD, and a Waters HPLC e2695-2489 HPLC system.

[0223] Chiral HPLC analysis was performed using an Agilent 1260DAD high-performance liquid chromatograph.

[0224] High performance liquid chromatography (HPLC) was performed using Waters 2545-2767, Waters 2767-SQ Detecor2, Shimadzu LC-20AP, and Gilson GX-281 preparative chromatographs.

[0225] Chiral preparation was performed using a Shimadzu LC-20AP preparative chromatograph.

[0226] The CombiFlash rapid preparation system uses a CombiFlash Rf200 (TELEDYNE ISCO).

[0227] Thin-layer chromatography silica gel plates are Yantai Huanghai HSGF254 or Qingdao GF254. The silica gel plates used in thin-layer chromatography (TLC) have a diameter of 0.15 mm to 0.2 mm, and the diameter of the silica gel plates used for thin-layer chromatography separation and purification products is 0.4 mm to 0.5 mm.

[0228] Silica gel column chromatography generally uses Yantai Huanghai silica gel with a mesh size of 200-300 as the carrier.

[0229] Mean inhibition rate of kinases and IC 50 The values ​​were determined using a NovoStar microplate reader (BMG GmbH, Germany).

[0230] The known starting materials disclosed herein can be synthesized using or in accordance with methods known in the art, or can be purchased from companies such as ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, Accela ChemBio Inc, and Darui Chemicals.

[0231] Unless otherwise specified in the examples, all reactions can be carried out under an argon or nitrogen atmosphere.

[0232] Argon or nitrogen atmosphere refers to a reaction flask connected to an argon or nitrogen gas balloon with a volume of approximately 1L.

[0233] A hydrogen atmosphere refers to a reaction flask connected to a hydrogen balloon with a volume of approximately 1L.

[0234] The pressurized hydrogenation reaction was performed using a Parr 3916EKX hydrogenator and a Qinglan QL-500 hydrogen generator or an HC2-SS hydrogenator.

[0235] The hydrogenation reaction is usually carried out under vacuum, filled with hydrogen gas, and repeated 3 times.

[0236] The microwave reaction was performed using a CEM Discover-S 908860 microwave reactor.

[0237] Unless otherwise specified in the examples, "solution" refers to an aqueous solution.

[0238] Unless otherwise specified in the examples, the reaction temperature is room temperature, which is 20℃~30℃.

[0239] The reaction process in the examples was monitored using thin-layer chromatography (TLC). The developing solvent used in the reaction, the eluent system for column chromatography used to purify the compounds, and the developing solvent system for TLC included: A: dichloromethane / methanol system, B: n-hexane / ethyl acetate system. The volume ratio of the solvent was adjusted according to the polarity of the compounds, and small amounts of basic or acidic reagents such as triethylamine and acetic acid could also be added for adjustment.

[0240] Example 1

[0241] N-((2-(2-(cyclopropylmethoxy)-6-(difluoromethyl)pyridin-3-yl)-1,6-naphthidin-7-yl)methyl)-2-fluoro-3,4-dihydro-2H-[1,4]thiazaheptancyclo[2,3,4-hi]indole-9-carboxamide 1,1-dioxide

[0242] first step

[0243] 7-((3-hydroxypropyl)thia)-1H-indole-5-carboxylic acid methyl ester 1b

[0244] Weigh methyl 7-bromo-1H-indole-5-carboxylate 1a (1.08 g, 4.25 mmol, Bio-Dexter Pharmaceuticals) into a 50 mL single-necked flask, add 3-mercapto-1-propanol (628 mg, 6.81 mmol, Bio-Dexter Pharmaceuticals), tris(dibenzylideneacetone)dipalladium (273 mg, 0.29 mmol), 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) (345 mg, 0.59 mmol), N,N-diisopropylethylamine (1.10 g, 8.51 mmol), add 25 mL of 1,4-dioxane, purge with nitrogen three times, and heat to 100 °C for 16 hours. The reaction solution was cooled to room temperature, 20 mL of water was added, and the mixture was extracted with ethyl acetate (40 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution (25 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system B to give title compound 1b (930 mg, yield: 82%).

[0245] MS m / z(ESI):264.1[M-1].

[0246] Step 2

[0247] methyl 3-bromo-7-((3-bromopropyl)thia)-1H-indole-5-carboxylic acid ester 1c

[0248] Compound 1b (520 mg, 1.96 mmol) was weighed into a 50 mL single-necked flask, and 20 mL of dichloromethane was added. Triphenylphosphine (2.05 g, 7.81 mmol) and carbon tetrabromide (2.59 mg, 7.81 mmol) were added at 0 °C, and the reaction was allowed to proceed for 16 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using eluent system B to give the title compound 1c (660 mg, yield: 83%). MS m / z (ESI): 405.9 [M+1].

[0249] Step 3

[0250] 7-Bromo-3,4-dihydro-2H-[1,4]thiazaheptancyclo[2,3,4-hi]indole-9-carboxylic acid methyl ester 1d

[0251] Compound 1b (660 mg, 1.62 mmol) was weighed into a 50 mL single-necked flask, and 12 mL of N,N-dimethylformamide was added. Sodium hydride (130 mg, 3.25 mmol, 60% purity) was added at -10 °C, and the mixture was allowed to react at room temperature for 0.5 hours. The reaction mixture was poured into 30 mL of ice water and extracted with ethyl acetate (40 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution (25 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent system B to give the title compound 1d (510 mg, yield: 96%).

[0252] MS m / z(ESI): 326.0 [M+1].

[0253] Step 4

[0254] 7-Bromo-2-fluoro-3,4-dihydro-2H-[1,4]thiazaheptancyclo[2,3,4-hi]indole-9-carboxylic acid methyl ester 1e

[0255] and

[0256] 7-Bromo-2-fluoro-3,4-dihydro-2H-[1,4]thiazaheptancyclo[2,3,4-hi]indole-9-carboxylic acid methyl ester 1-oxide 1f

[0257] Compound 1d (280 mg, 0.86 mmol) was weighed into a 50 mL single-necked flask, 10 mL of acetonitrile was added, and diethylaminosulfur trifluoride (27 mg, 0.17 mmol) and 1-chloromethyl-4-fluoro-1,4-diazobicyclo[2.2.2]octanebis(tetrafluoroborate) (457 mg, 1.29 mmol) were added dropwise at 0 °C, and the mixture was allowed to rise naturally to room temperature for 1 hour. N,N-diisopropylethylamine (167 mg, 1.29 mmol) was added dropwise at 0 °C, and the reaction was continued for 0.5 hours. 20 mL of saturated sodium bicarbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate (40 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution (25 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a mixture of title compounds 1e and 1f (130 mg). The crude product was used directly in the next reaction without purification.

[0258] MS m / z(ESI):344.1[M+1], 360.1[M+1].

[0259] Step 5

[0260] 1 g of methyl 7-bromo-2-fluoro-3,4-dihydro-2H-[1,4]thiazaheptancyclo[2,3,4-hi]indole-9-carboxylic acid ester 1,1-dioxide

[0261] Weigh a mixture of compounds 1e and 1f (130 mg, 0.37 mmol) into a 25 mL single-necked flask, add 8 mL of dichloromethane, and add m-chloroperoxybenzoic acid (230 mg, 1.13 mmol, 85% purity) at 0 °C. React for 16 hours. Add 20 mL of saturated sodium bicarbonate solution to the reaction mixture, extract with ethyl acetate (20 mL × 3), combine the organic phases, wash with saturated sodium chloride solution (25 mL × 2), dry to anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and purify the residue by silica gel column chromatography with eluent system B to give 1 g (70 mg, yield: 49%) of the title compound.

[0262] MS m / z(ESI): 374.0 [M-1].

[0263] Step 6

[0264] 7-Bromo-2-fluoro-3,4-dihydro-2H-[1,4]thiazaheptancyclo[2,3,4-hi]indole-9-carboxylic acid 1,1-dioxide 1h

[0265] Weigh 1 g (70 mg, 0.19 mmol) of the compound into a 25 mL single-necked flask, add 3 mL of methanol, 3 mL of tetrahydrofuran, and 1 mL of water, stir to dissolve, add lithium hydroxide monohydrate (38 mg, 0.91 mmol), and react for 4 hours. Add 20 mL of water to the reaction solution, adjust the pH to approximately 3 with 1 N hydrochloric acid, extract with ethyl acetate (30 mL × 3), combine the organic phases, wash with saturated sodium chloride solution (15 mL × 3), dry with anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain the crude product, title compound 1h (66 mg, yield: 97%). The crude product was used directly in the next reaction without purification.

[0266] MS m / z(ESI): 360.1 [M-1].

[0267] Step 7

[0268] 2-Fluoro-3,4-dihydro-2H-[1,4]thiazaheptancyclo[2,3,4-hi]indole-9-carboxylic acid 1,1-dioxide

[0269] Weigh 35 mg (0.10 mmol) of compound 1 h into a 25 mL single-necked flask, add 8 mL of ethyl acetate and 20% wet palladium hydroxide on carbon (containing 50% water, 13 mg, 0.09 mmol), purge three times with hydrogen, and react for 2 hours under a hydrogen balloon atmosphere. Filter the reaction solution with diatomaceous earth, concentrate the filtrate under reduced pressure to obtain the crude product, title compound 1i (27 mg, yield: 98%). The crude product was used directly in the next reaction without purification.

[0270] MS m / z(ESI):284.1[M+1].

[0271] Step 8

[0272] N-((2-(2-(cyclopropylmethoxy)-6-(difluoromethyl)pyridin-3-yl)-1,6-naphthidin-7-yl)methyl)-2-fluoro-3,4-dihydro-2H-[1,4]thiazaheptancyclo[2,3,4-hi]indole-9-carboxamide 1,1-dioxide

[0273] Compound 1i (27 mg, 0.09 mmol), (2-(2-(cyclopropylmethoxy)-6-(difluoromethyl)pyridin-3-yl)-1,6-naphthidin-7-yl)methylamine hydrochloride 1j (40 mg, 0.09 mmol, prepared by the method disclosed in compound 332 on page 271 of patent application "WO2023220219A1") were weighed into a 25 mL single-necked flask, 3 mL of N,N-dimethylformamide was added, followed by N,N-diisopropylethylamine (24 mg, 0.18 mmol), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (52 mg, 0.13 mmol), and the reaction was carried out for 0.5 hours. The reaction solution was filtered and purified by high performance liquid chromatography (Shimadzu LC-20AP, elution system: 10 mmol / L ammonium bicarbonate aqueous solution and acetonitrile, acetonitrile gradient: 40%-95%, flow rate: 30 mL / min) to give title compound 1 (16 mg, yield: 28%).

[0274] MS m / z(ESI): 622.2 [M+1].

[0275] 1 H NMR(500MHz,DMSO-d6)δ9.55(t,1H),9.43(s,1H),8.69-8.65(m,2H),8.46(d,1H),8.39 (d,1H),8.28(d,1H),7.83(s,1H),7.68(d,1H),7.43(d,1H),6.95(t,1H),6.81(d,1H), 6.23(ddd,1H),4.85(d,2H),4.79-4.73(m,1H),4.64-4.59(m,1H),4.30(d,2H),3.04-2 .94(m,1H),2.47-2.38(m,1H),1.35-1.28(m,1H),0.57-0.53(m,2H),0.40-0.37(m,2H).

[0276] Example 2

[0277] N-((2-(6-(difluoromethyl)-2-ethoxypyridin-3-yl)-1,6-naphthidin-7-yl)methyl)-2-fluoro-3,4-dihydro-2H-[1,4]thiazaheptancyclo[2,3,4-hi]indole-9-carboxamide 1,1-dioxide

[0278] Using the method of Example 1, the starting material compound 1j in step 8 was replaced with (2-(6-(difluoromethyl)-2-ethoxypyridin-3-yl)-1,6-naphthidin-7-yl)methylamine hydrochloride 2a (prepared using the method disclosed in compound 331 on page 269 of patent application "WO2023220219A1"). The compound was purified by high performance liquid chromatography (Shimadzu LC-20AP, elution system: 10 mmol / L ammonium bicarbonate aqueous solution and acetonitrile, acetonitrile gradient: 40%-95%, flow rate: 30 mL / min) to obtain title compound 2 (15 mg, yield: 51%).

[0279] MS m / z(ESI): 596.1 [M+1].

[0280] 1 H NMR(500MHz,DMSO-d6)δ9.54(t,1H),9.43(s,1H),8.69-8.65(m,2H),8.46(d ,1H),8.39(d,1H),8.25(d,1H),7.83(s,1H),7.69(d,1H),7.43(d,1H),6.96 (t,1H),6.82(d,1H),6.24(ddd,1H),4.85(d,2H),4.79-4.74(m,1H),4.65-4 .60(m,1H),4.50(q,2H),3.05-2.95(m,1H),2.45-2.37(m,1H),1.38(t,3H).

[0281] Example 3

[0282] N-((2-(6-((2S,6R)-2,6-dimethylmorpholinyl)pyridin-2-yl)-1,6-naphthidin-7-yl)methyl]-2-fluoro-3,4-dihydro-2H-[1,4]thiazaheptancyclo[2,3,4-hi]indazole-9-carboxamide-1,1-dioxide

[0283] first step

[0284] 7-((3-hydroxypropyl)thia)-1H-indazole-5-carboxylic acid methyl ester 3b

[0285] 2.50 g (9.80 mmol, Bio-Tech Pharmaceuticals) of methyl 7-bromo-1H-indazole-5-carboxylate 3a was weighed into a 250 mL single-necked flask. 3-Mercapto-1-propanol (1.81 g, 19.64 mmol, Bio-Tech Pharmaceuticals), tris(dibenzylacetone)dipalladium (628 mg, 0.69 mmol), 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) (794 mg, 1.37 mmol), and N,N-diisopropylethylamine (2.54 g, 19.65 mmol) were added. 60 mL of 1,4-dioxane was added, and the mixture was purged three times with nitrogen. The temperature was raised to 100 °C and reacted for 16 hours. The reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent system A to give the title compound 3b (2.6 g, yield: 99%).

[0286] MS m / z(ESI):267.0[M+1].

[0287] Step 2

[0288] 3,4-Dihydro-2H-[1,4]thiazaheptancyclo[2,3,4-hi]indazole-9-carboxylic acid methyl ester 3c

[0289] Compound 3b (2.6 g, 9.8 mmol) was dissolved in toluene (500 mL), and cyanomethylenetri-n-butylphosphine (5 g, 20.72 mmol) was added. The mixture was purged with nitrogen three times, and the temperature was raised to 120 °C for 16 hours. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using eluent system A to give the title compound 3c (1.34 g, yield: 51%).

[0290] MS m / z(ESI):249.0[M+1].

[0291] Step 3

[0292] 2-Fluoro-3,4-dihydro-2H-[1,4]thiazaheptancyclo[2,3,4-hi]indazole-9-carboxylic acid methyl ester 3d

[0293] and

[0294] 2-Fluoro-3,4-dihydro-2H-[1,4]thiazaheptancyclo[2,3,4-hi]indazole-9-carboxylic acid methyl ester 1-oxide 3e

[0295] Compound 3c (700 mg, 2.82 mmol) was dissolved in acetonitrile (30 mL), cooled in an ice bath, and 1-chloromethyl-4-fluoro-1,4-diazobicyclo[2.2.2]octanebis(tetrafluoroborate) (1.5 g, 4.23 mmol) and diethylaminosulfur trifluoride (91 mg, 0.56 mmol) were added. The reaction was allowed to proceed for 10 minutes, then allowed to rise naturally to room temperature for 1 hour. The mixture was then cooled in an ice bath, and N,N-diisopropylethylamine (547 mg, 4.23 mmol) was added. The reaction was allowed to proceed for 10 minutes, then allowed to rise naturally to room temperature for 1 hour. Under ice bath conditions, saturated sodium bicarbonate solution (70 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (40 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution (40 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a mixture (750 mg) of crude products, namely, title compounds 3d and 3e. The crude products were used directly in the next reaction without purification.

[0296] MS m / z(ESI):267.0[M+1], 283.0[M+1].

[0297] Step 4

[0298] 2-Fluoro-3,4-dihydro-2H-[1,4]thiazaheptancyclo[2,3,4-hi]indazole-9-carboxylic acid methyl ester 1,1-dioxide 3f

[0299] A mixture of compounds 3d and 3e (750 mg, 2.82 mmol) was dissolved in dichloromethane (60 mL), and m-chloroperoxybenzoic acid (1.46 g, 8.46 mmol) was added under ice bath cooling. The reaction mixture was reacted at room temperature for 16 hours. Saturated sodium thiosulfate solution (30 mL) and saturated sodium bicarbonate solution (30 mL) were added to the reaction mixture, and the mixture was extracted with dichloromethane (30 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution (30 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent system A to give the title compound 3f (536 mg, yield: 64%).

[0300] MS m / z(ESI):298.9[M+1].

[0301] Step 5

[0302] 3g of 2-fluoro-3,4-dihydro-2H-[1,4]thiazaheptancyclo[2,3,4-hi]indazole-9-carboxylic acid 1,1-dioxide

[0303] Compound 3f (300 mg, 1.0 mmol) was dissolved in 25 mL of a mixed solvent of tetrahydrofuran, methanol, and water (V / V / V = 2:2:1), and lithium hydroxide monohydrate (127 mg, 3.03 mmol) was added. The reaction was allowed to proceed for 16 hours. 2 M hydrochloric acid was added dropwise until the pH of the reaction solution reached 4–5. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using eluent system A to give 3 g (160 mg, yield: 56%) of the title compound.

[0304] MS m / z(ESI):285.0[M+1].

[0305] Step 6

[0306] ((2-(trimethylstanyl)-1,6-naphthid-7-yl)methyl)tert-butyl carbamate 3i

[0307] (1 g, 3.40 mmol, prepared by the method disclosed in Example 26, page 204 of patent application "WO2021155320A1") of tert-butyl carbamate ((2-chloro-1,6-naphthid-7-yl)methyl)carbamate 3 h) was dissolved in 1,4-dioxane (10 mL), and hexamethyldistin (1.34 g, 4.08 mmol) and tetrakis(triphenylphosphine)palladium (197 mg, 0.17 mmol) were added. The mixture was purged with nitrogen three times and heated to 100 °C for 4 h. The reaction solution was used directly in the next step without further treatment.

[0308] MS m / z(ESI):424.0[M+1].

[0309] Step 7 ((2-(6-((2S,6R)-2,6-dimethylmorpholino)pyridin-2-yl)-1,6-naphthidin-7-yl)methyl)tert-butyl carbamate 3k

[0310] (2S,6R)-4-(6-bromopyridin-2-yl)-2,6-dimethylmorpholine 3j (650 mg, 2.40 mmol, prepared by the method disclosed in Example 32 on page 73 of patent application “WO2021155264A1”) and bis(triphenylphosphine)palladium dichloride (84 mg, 0.12 mmol) were added to the reaction solution from the previous step. The mixture was purged with nitrogen three times and heated to 100 °C for 16 hours. The reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent system B to give the title compound 3k (630 mg, yield: 58%).

[0311] MS m / z(ESI): 450.2 [M+1].

[0312] Step 8 (2-(6-((2S,6R)-2,6-dimethylmorpholino)pyridin-2-yl)-1,6-naphthidin-7-yl)methylamine trifluoroacetate 3l

[0313] Compound 3k (60 mg, 0.13 mmol) was dissolved in dichloromethane (3 mL), and trifluoroacetic acid (0.4 mL) was added dropwise. The reaction mixture was allowed to react for 2 hours. The reaction solution was concentrated under reduced pressure to give the crude product, title compound 3l (93 mg, yield: 100%). The crude product was used directly in the next reaction without purification.

[0314] MS m / z(ESI): 350.2 [M+1].

[0315] Step 9

[0316] N-((2-(6-((2S,6R)-2,6-dimethylmorpholino)pyridin-2-yl)-1,6-naphthidin-7-yl)methyl]-2-fluoro-3,4-dihydro

[0317] -2H-[1,4]thiazaheptancyclo[2,3,4-hi]indazole-9-carboxamide 1,1-dioxide

[0318] 3 g (48 mg, 0.14 mmol) and 3 l (93 mg, 0.13 mmol) of compound were dissolved in N,N-dimethylformamide (2.5 mL), and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (77 mg, 0.20 mmol) and N,N-diisopropylethylamine (105 mg, 0.81 mmol) were added. The reaction mixture was reacted for 1 h. The reaction solution was filtered and purified by preparative high-performance liquid chromatography (Waters-2545, elution system: 10 mmol / L ammonium bicarbonate aqueous solution and acetonitrile, acetonitrile gradient: 35%-60%, flow rate: 30 mL / min) to give title compound 3 (37 mg, yield: 45%).

[0319] MS m / z(ESI): 616.2 [M+1].

[0320] 1H NMR(500MHz,DMSO-d6)δ9.67(t,1H),9.41(s,1H),8.92(d,1H),8.69-8.62(m,3 H),8.52(s,1H),7.90(d,1H),7.85(s,1H),7.73(t,1H),7.02(d,1H),6.37(dt, 1H),4.97-4.91(m,1H),4.85(d,2H),4.81-4.76(m,1H),4.31(d,2H),3.71-3.6 4(m,2H),3.12-3.01(m,1H),2.70-2.59(m,1H),1.25-1.23(m,2H),1.21(d,6H).

[0321] Example 3-1

[0322] (S)-N-((2-(6-((2S,6R)-2,6-dimethylmorpholinyl)pyridin-2-yl)-1,6-naphthidin-7-yl)methyl]-2-fluoro-3,4-dihydro-2H-[1,4]thiazaheptancyclo[2,3,4-hi]indazole-9-carboxamide-1,1-dioxide-3-1

[0323] (R)-N-((2-(6-((2S,6R)-2,6-dimethylmorpholinyl)pyridin-2-yl)-1,6-naphthidin-7-yl)methyl]-2-fluoro-3,4-dihydro-2H-[1,4]thiazaheptancyclo[2,3,4-hi]indazole-9-carboxamide-1,1-dioxide-3-2

[0324] first step

[0325] (S)-2-Fluoro-3,4-dihydro-2H-[1,4]thiazaheptancyclo[2,3,4-hi]indazole-9-carboxylic acid 1,1-dioxide 3g-1

[0326] and

[0327] (R)-2-Fluoro-3,4-dihydro-2H-[1,4]thiazaheptan[2,3,4-hi]indazole-9-carboxylic acid 1,1-dioxide 3g-2

[0328] Resolution: 3 g (340 mg) of compound was chirally resolved (separation conditions: Shimadzu LC-20AP, column: CHIRALPAK IG (50 × 300 mM), mobile phase: hexane / 0.1% trifluoroacetic acid (TFA) in ethanol = 55 / 45 (v / v), flow rate 80 mL / min) to obtain 3 g-1 (165 mg) and 3 g-2 (169 mg).

[0329] 3g-1: Single-configuration compound (shorter retention time):

[0330] MS m / z(ESI):285.3[M+1].

[0331] Chiral HPLC analysis method: retention time 10.49 min (Agilent 1290DAD, column: Chiralpak IG (4.6×150mM), 5μm; mobile phase: n-hexane / ethanol (0.1% trifluoroacetic acid) = 55 / 45 (v / v), flow rate 1 mL / min);

[0332] 3g-2: Single-configuration compound (longer retention time):

[0333] MS m / z(ESI):285.3[M+1].

[0334] Chiral HPLC analysis method: retention time 12.80 min (Agilent 1290DAD, column: Chiralpak IG (4.6×150 mM), 5 μm; mobile phase: n-hexane / ethanol (0.1% trifluoroacetic acid) = 55 / 45 (v / v), flow rate 1 mL / min).

[0335] Step 2: (S)-N-((2-(6-((2S,6R)-2,6-dimethylmorpholino)pyridin-2-yl)-1,6-naphthidin-7-yl)methyl)-2-fluoro-3,4-dihydro-2H-[1,4]thiazaheptancyclo[2,3,4-hi]indazole-9-carboxamide-1,1-dioxide-3-1

[0336] and

[0337] (R)-N-((2-(6-((2S,6R)-2,6-dimethylmorpholinyl)pyridin-2-yl)-1,6-naphthidin-7-yl)methyl)-2-fluoro-3,4-dihydro-2H-[1,4]thiazaheptancyclo[2,3,4-hi]indazole-9-carboxamide-1,1-dioxide-3-2

[0338] Compounds 3g-1 (35 mg, 0.12 mmol) and 3l (85 mg, 0.12 mmol) were dissolved in N,N-dimethylformamide (2.5 mL), and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (71 mg, 0.19 mmol) and N,N-diisopropylethylamine (159 mg, 1.23 mmol) were added. The reaction mixture was reacted for 1 hour. The reaction solution was filtered and purified by preparative high-performance liquid chromatography (Waters-2545, elution system: 10 mmol / L ammonium bicarbonate aqueous solution and acetonitrile, acetonitrile gradient: 35%-60%, flow rate: 30 mL / min) to give the title compound 3-1 (51 mg, yield: 67%).

[0339] MS m / z(ESI): 616.2 [M+1].

[0340] 1 H NMR(500MHz,DMSO-d6)δ9.67(t,1H),9.41(s,1H),8.92(s,1H),8.68-8.62( m,3H),8.52(s,1H),7.90(d,1H),7.85(s,1H),7.73(t,1H),7.02(d,1H),6.3 7(dt,1H),4.97-4.91(m,1H),4.85(d,2H),4.81-4.76(m,1H),4.31(d,2H), 3.71-3.65(m,2H),3.12-3.01(m,1H),2.70-2.59(m,1H),1.31-1.21(m,8H).

[0341] Compounds 3g-2 (36 mg, 0.13 mmol) and 3l (88 mg, 0.13 mmol) were dissolved in N,N-dimethylformamide (2.5 mL), and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (73 mg, 0.19 mmol) and N,N-diisopropylethylamine (165 mg, 1.28 mmol) were added. The reaction mixture was reacted for 1 hour. The reaction solution was filtered and purified by preparative high-performance liquid chromatography (Gilson GX-281, elution system: 10 mmol / L ammonium bicarbonate aqueous solution and acetonitrile, acetonitrile gradient: 35%-65%, flow rate: 30 mL / min) to give title compound 3-2 (59 mg, yield: 75%).

[0342] MS m / z(ESI): 616.2 [M+1].

[0343] 1H NMR(500MHz,DMSO-d6)δ9.67(t,1H),9.40(s,1H),8.91(s,1H),8.67-8.61( m,3H),8.51(d,1H),7.90(d,1H),7.84(s,1H),7.73(t,1H),7.02(d,1H),6.3 6(dt,1H),4.96-4.91(m,1H),4.85(d,2H),4.80-4.75(m,1H),4.30(d,2H), 3.70-3.64(m,2H),3.09-3.02(m,1H),2.69-2.59(m,1H),1.25-1.21(m,8H).

[0344] Example 4

[0345] N-((2-(6-((2S,6R)-2,6-dimethylmorpholino)-4-fluoropyridin-2-yl)-1,6-naphthidin-7-yl)methyl)-2-fluoro-3,4-dihydro-2H-[1,4]thiazaheptancyclo[2,3,4-hi]indazole-9-carboxamide-1,1-dioxide-4

[0346] first step

[0347] (2S,6R)-4-(6-bromo-4-nitropyridin-2-yl)-2,6-dimethylmorpholine 4b

[0348] 2,6-Dibromo-4-nitropyridine (1.8 g, 6.36 mmol, Adamas reagent) and cis-2,6-dimethylmorpholine (869 mg, 7.55 mmol, Bioderm) were dissolved in toluene (50 mL) and bubbled under nitrogen for 15 minutes. Palladium acetate (143 mg, 0.64 mmol), 1,1'-binaphthyl-2,2'-bis(diphenylphosphine) (398 mg, 0.64 mmol), and cesium carbonate (3.12 g, 9.58 mmol) were added, and the mixture was purged three times with nitrogen. The temperature was raised to 110 °C and the reaction was carried out for 16 hours. The reaction solution was cooled to room temperature, 50 mL of water was added, and the mixture was extracted with ethyl acetate (50 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution (50 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system B to give the title compound 4b (1.15 g, yield: 57%).

[0349] MS m / z(ESI):316.0[M+1].

[0350] Step 2

[0351] (2S,6R)-4-(6-bromo-4-fluoropyridin-2-yl)-2,6-dimethylmorpholine 4c

[0352] Compound 4b (1.15 g, 3.64 mmol) was weighed into a 120 mL sealed tube, and N,N-dimethylformamide (30 mL) and tetrabutylammonium fluoride (1 M tetrahydrofuran solution, 5.46 mmol) were added. The mixture was heated to 65 °C and sealed for 3 hours. The reaction solution was cooled to room temperature, 30 mL of water was added, and the mixture was extracted with ethyl acetate (40 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution (30 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent system B to give the title compound 4c (744 mg, yield: 71%).

[0353] MS m / z(ESI):289.2[M+1].

[0354] Step 3 ((2-(6-((2S,6R)-2,6-dimethylmorpholino)-4-fluoropyridin-2-yl)-1,6-naphthidin-7-yl)methyl)tert-butyl carbamate 4d

[0355] Compound 4c (197 mg, 0.68 mmol) was added to a 1,4-dioxane solution (3 mL) of compound 3i (287 mg, 0.68 mmol), followed by the addition of palladium dichloride bis(triphenylphosphine) (48 mg, 0.07 mmol). The mixture was purged three times with nitrogen and heated to 100 °C for 16 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using eluent system B to give the title compound 4d (317 mg, yield: 99%).

[0356] MS m / z(ESI):468.2[M+1].

[0357] Step 4

[0358] (2-(6-((2S,6R)-2,6-dimethylmorpholino)-4-fluoropyridin-2-yl)-1,6-naphthidin-7-yl)methylamine trifluoroacetate 4e

[0359] Compound 4d (74 mg, 0.16 mmol) was dissolved in dichloromethane (3 mL), and trifluoroacetic acid (0.5 mL) was added dropwise. The reaction mixture was allowed to react for 1 hour. The reaction solution was concentrated under reduced pressure to give the crude product, title compound 4e (114 mg, yield: 99%). The crude product was used directly in the next reaction without purification.

[0360] MS m / z(ESI): 368.2 [M+1].

[0361] Step 5

[0362] N-((2-(6-((2S,6R)-2,6-dimethylmorpholino)-4-fluoropyridin-2-yl)-1,6-naphthidin-7-yl)methyl)-2-fluoro-3,4-dihydro-2H-[1,4]thiazaheptancyclo[2,3,4-hi]indazole-9-carboxamide-1,1-dioxide-4

[0363] 3 g (15 mg, 0.05 mmol) of compound 4e and 35 mg (0.05 mmol) of compound 4e were weighed into a 25 mL single-necked flask. 3 mL of N,N-dimethylformamide was added, followed by 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (30 mg, 0.08 mmol) and N,N-diisopropylethylamine (34 mg, 0.26 mmol). The mixture was reacted for 1 hour. The reaction solution was filtered and purified by preparative high-performance liquid chromatography (GILSON-281, elution system: 10 mmol / L ammonium bicarbonate aqueous solution and acetonitrile, acetonitrile gradient: 40%-75%, flow rate: 30 mL / min) to give title compound 4 (10 mg, yield: 30%).

[0364] MS m / z(ESI): 634.2 [M+1].

[0365] 1 H NMR(500MHz,DMSO-d6)δ9.68(t,1H),9.44(s,1H),8.92(d,1H),8.71(d,1H),8. 63-8.61(m,2H),8.53(s,1H),7.88(s,1H),7.64(dd,1H),6.90(dd,1H),6.37(dt ,1H),4.97-4.92(m,1H),4.86(d,2H),4.81-4.76(m,1H),4.35(d,2H),3.68-3.6 4(m,2H),3.11-3.03(m,1H),2.67-2.62(m,1H),2.57-2.55(m,2H),1.21(d,6H).

[0366] Example 4-1

[0367] (R)-N-((2-(6-((2S,6R)-2,6-dimethylmorpholino)-4-fluoropyridin-2-yl)-1,6-naphthidin-7-yl)methyl)-2-fluoro-3,4-dihydro-2H-[1,4]thiazaheptancyclo[2,3,4-hi]indazole-9-carboxamide-1,1-dioxide-4-1

[0368] 3 g of compound 4-2 (40 mg, 0.104 mmol) and 4e (101 mg, 0.142 mmol) were weighed into a 25 mL single-necked flask. 5 mL of N,N-dimethylformamide was added, followed by 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (51 mg, 0.134 mmol) and N,N-diisopropylethylamine (67 mg, 0.518 mmol). The reaction mixture was reacted for 1 hour. The reaction solution was filtered and purified by preparative high-performance liquid chromatography (GILSON-281, elution system: 10 mmol / L ammonium bicarbonate aqueous solution and acetonitrile, acetonitrile gradient: 40%-75%, flow rate: 30 mL / min) to give the title compound 4-1 (28 mg, yield: 42%).

[0369] MS m / z(ESI): 634.2 [M+1].

[0370] 1 H NMR(500MHz,DMSO-d6)δ9.68(t,1H),9.44(s,1H),8.92(s,1H),8.71(d,1H),8.63 -8.61(m,2H),8.53(s,1H),7.88(s,1H),7.65(dd,1H),6.90(dd,1H),6.37(dt,1H ),4.97-4.92(m,1H),4.86(d,2H),4.81-4.77(m,1H),4.36-4.33(m,2H),3.68-3. 64(m,2H),3.11-3.03(m,1H),2.65-2.62(m,1H),2.57-2.55(m,2H),1.21(d,6H).

[0371] Example 5

[0372] (R)-N-((6-(6-(((2S,6R)-2,6-dimethylmorpholinyl)pyridin-2-yl)-5-fluoroisoquinolin-3-yl)methyl)-2-fluoro-3,4-dihydro-2H-[1,4]thiazaheptancyclo[2,3,4-hi]indazole-9-carboxamide-1,1-dioxide

[0373] first step

[0374] (6-(6-((2S,6R)-2,6-dimethylmorpholino)pyridin-2-yl)-5-fluoroisoquinoline-3-yl)methylamine trifluoroacetate 5b

[0375] ((6-(6-(((2S,6R)-2,6-dimethylmorpholinyl)pyridin-2-yl)-5-fluoroisoquinoline-3-yl)methyl)tert-butyl carbamate 5a (38 mg, 0.08 mmol, prepared by the method disclosed on page 31 of patent application "WO2025068354A1, intermediate 6")) was dissolved in dichloromethane (3 mL), and trifluoroacetic acid (0.4 mL) was added dropwise. The reaction mixture was reacted for 2 hours. The reaction solution was concentrated under reduced pressure to obtain the crude product, title compound 5b (67 mg, yield: 100%). The crude product was used directly in the next reaction without purification.

[0376] MS m / z(ESI): 367.2 [M+1].

[0377] Step 2: (R)-N-((6-(6-(((2S,6R)-2,6-dimethylmorpholino)pyridin-2-yl)-5-fluoroisoquinoline-3-yl)methyl)-2-fluoro-3,4-dihydro-2H-[1,4]thiazaheptancyclo[2,3,4-hi]indazole-9-carboxamide-1,1-dioxide

[0378] Compounds 3g-2 (23 mg, 0.08 mmol) and 5b (67 mg, 0.08 mmol) were dissolved in N,N-dimethylformamide (2.5 mL), and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (47 mg, 0.12 mmol) and N,N-diisopropylethylamine (105 mg, 0.81 mmol) were added. The reaction mixture was reacted for 1 hour. The reaction solution was filtered and purified by preparative high-performance liquid chromatography (Waters-2545, elution system: 10 mmol / L ammonium bicarbonate aqueous solution and acetonitrile, acetonitrile gradient: 40%-70%, flow rate: 30 mL / min) to give title compound 5 (26 mg, yield: 50%).

[0379] MS m / z(ESI): 633.2 [M+1]. 1H NMR(500MHz,DMSO-d6)δ9.65(t,1H),9.40(s,1H),8.88(s,1H),8.60(s,1H),8.51(s ,1H),8.19(t,1H),8.06(d,1H),7.92(s,1H),7.70(t,1H),7.29(d,1H),6.93(d,1H), 6.36(dt,1H),4.95-4.90(m,1H),4.84(d,2H),4.79-4.75(m,1H),4.24(d,2H),3.67 -3.61(m,2H),3.11-3.00(m,1H),2.68-2.59(m,1H),2.48-2.43(m,2H),1.18(d,6H).

[0380] Biological evaluation

[0381] The following test examples further describe and explain this disclosure, but these test examples are not intended to limit the scope of this disclosure.

[0382] Test Example 1: Cell Proliferation Inhibition Experiment

[0383] The in vitro cell experiments described below can determine the inhibitory activity of the test compound on the proliferation of human lung cancer cells A549 and NCI-H520. This activity can be measured using IC50 assays. 50Values ​​are used to represent the results. On the first day of the experiment, A549 cells and NCI-H520 cells were seeded in 96-well cell culture plates (Corning, 3903) at densities of 400 cells / well and 2000 cells / well, respectively, using Ham's F-12K (Gibco, 21127-030) medium containing 10% FBS (Corning, 35-081-CV) and RPMI1640 (Meilunbio, PWL047) medium containing 10% FBS, respectively. Each well contained 200 μL of cell suspension, and the plates were incubated overnight at 37°C in a 5% CO2 cell culture incubator. On the second day, a compound was added to the cell culture plate using a Tecan D300e. The final concentration of the compound was determined by a 4-fold serial dilution starting from 10 μM, resulting in 9 concentration points. Wells containing only DMSO were set as solvent control wells, and wells containing only culture medium and DMSO were set as blank control wells. The DMSO content in all wells was 0.5%. The well plates were incubated at 37°C and 5% CO2 for five days. On the seventh day, the cell culture plates were removed, and the cells were passaged into new 96-well cell culture plates at a specific ratio. The cell culture plates were then incubated at 37°C and 5% CO2 for 4 hours, after which the compound was added again to treat the cells. The well plates were then incubated at 37°C and 5% CO2 for another five days. On the twelfth day, the 96-well cell culture plates were removed, 100 μL of culture supernatant was aspirated from each well and discarded, and 50 μL of luminescent cell viability assay reagent was added. The Luminescent Cell Viability Assay (Promega, G7573) was prepared by shaking in the dark for 5 minutes and then incubating at room temperature for 10 minutes. The luminescence signal (RLU) was then read using a microplate reader (PerkinElmer, EnVision2105). The inhibition rate of each compound concentration was calculated using the following formula, where the maximum value represents the maximum inhibition rate of cell proliferation. A curve was fitted using GraphPad Prism based on the logarithmic concentration and inhibition rate of the compound, and the IC50 was calculated. 50 Value. Inhibition rate (%) = (RLU) 溶媒对照 -RLU 化合物 ) / (RLU 溶媒对照 -RLU 空白对照 )×100%

[0384] The activity of the compound disclosed herein is obtained from the above analysis, and the calculated IC50 value is... 50 value.

[0385] Table 1. Inhibitory activity of the disclosed compounds against the proliferation of A549 and NCI-H520 cells.

[0386] Conclusion: The compound disclosed herein exhibits significant inhibitory activity against the proliferation of A549 cells, but weaker inhibitory activity against the proliferation of NCI-H520 cells, demonstrating significant selectivity.

[0387] Test Example 2: SMARCA2 and SMARCA4 Enzyme Activity Inhibition Experiment

[0388] The in vitro biochemical experiments described below can determine the inhibitory activity of the test compound on the activities of SMARCA2 and SMARCA4 enzymes. This activity can be measured using the IC50 assay. 50 Values ​​are expressed as [values]. Experimental buffer solutions containing 20 mM HEPES (pH 8.0), 1 mM MgCl2, 20 mM KCl, 1 mM DTT, 0.005% Tween 20, and 0.01% BSA were prepared. UltraPure was diluted with the experimental buffer solution. TM Prepare working solutions for the DNA and enzyme using Salmon Sperm DNA Solution (Invitrogen, 15632-011), SMARCA2, or SMARCA4 protein. Add 2 μL of DNA working solution and 2 μL of SMARCA2 or SMARCA4 enzyme working solution or experimental buffer to each well of a 384-well plate (Corning, 4513). Then, using a Tecan D300e, add the compound to the wells at nine concentration points, starting from 10 μM (SMARCA2 protein) or 30 μM (SMARCA4 protein) and serially diluted 4-fold. Wells containing DMSO serve as solvent controls, while wells containing only DNA, ATP, and DMSO (without enzyme) serve as blank controls. All wells contain 0.5% DMSO. Pre-incubate the plate at 25°C for 10 minutes. Dilute ADP-Glo ​​with experimental buffer. TMPrepare the ATP working solution using the ATP from the Kinase Assay kit (Promega, V9102). Add 1 μL of ATP working solution to each well of a 384-well plate. Therefore, in a 5 μL enzyme reaction system, the final concentrations of enzyme, DNA, and ATP are 10 nM, 20 nM, and 400 μM, respectively. Incubate the plate at 25°C for 1 hour. After 1 hour, add 5 μL of ADP-Glo ​​from the kit to each well of the 384-well plate and incubate at 25°C for 40 minutes. After 40 minutes, remove the 384-well plate and add 10 μL of Kinase Detection Reagent from the kit to each well. Incubate the plate at 25°C in the dark for 40 minutes. Read the luminescence signal value (RLU) using a microplate reader (BMG LABTECH, PHERAstar FSX). Calculate the inhibition rate of each compound concentration using the following formula, where the maximum value is the maximum inhibition rate of the compound on enzyme activity. The IC was calculated using GraphPad Prism to perform curve fitting based on the compound's logarithmic concentration and inhibition rate. 50 Value. Inhibition rate (%) = (RLU) 溶媒对照 -RLU 化合物 ) / (RLU 溶媒对照 -RLU 空白对照 )×100%

[0389] The activity of the compound disclosed herein is obtained from the above analysis, and the calculated IC50 value is... 50 The values ​​are shown in the table below:

[0390] Table 2. Inhibitory activity of the disclosed compounds against SMARCA2 enzyme activity.

[0391] Conclusion: The disclosed compound exhibits significant inhibitory activity against SMARCA2 enzyme activity, but weaker inhibitory activity against SMARCA4 enzyme activity, demonstrating selectivity.

[0392] Test Example 3: Reporter Gene Experiment

[0393] The in vitro cell experiments described below can determine the inhibitory effect of the test compound on the reporter gene activity of human lung cancer cells A549-MMTV-luc and human breast cancer cells MDA-SMARCA2-KO, and can be performed using IC50. 50The values ​​are expressed as follows: A549-MMTV-luc cells are obtained by transfecting the MMTV-luc reporter gene into A549 cells (ATCC), and MDA-SMARCA2-KO cells are obtained by knocking out SMARCA2 in MDA cells (ATCC). On the first day of the experiment, A549-MMTV-luc cells and MDA-SMARCA2-KO cells were seeded in 96-well cell culture plates (Corning, 3903) at densities of 15,000 cells / well and 25,000 cells / well, respectively, using Ham's F-12K (Gibco, 21127-030) medium containing 5% activated charcoal-treated serum (CS-FBS) (Biosun, BS-0004-500) and Leibovitz's L-15 (Gibco, 11415064) medium containing 5% CS-FBS, respectively. Each well contained 200 μL of cell suspension. A549-MMTV-luc cells were incubated overnight in a 37°C, 5% CO2 cell culture incubator (the same below), and MDA-SMARCA2-KO cells were incubated overnight in a 37°C, CO2-free cell culture incubator (the same below). The next day, the compound was added to the cell culture plate using a Tecan D300e. The final concentration of the compound was determined by a 4-fold serial dilution starting at 10 μM, with nine concentration points. Dexamethasone was added simultaneously. Wells containing only DMSO and dexamethasone were designated as solvent controls, and wells containing only DMSO were designated as blank controls. The DMSO concentration in all wells was 0.5%. The plate was incubated at 37°C in either a 5% CO2 or CO2-free incubator for 6 hours. After 6 hours, the 96-well cell culture plate was removed, and 100 μL of culture supernatant was aspirated from each well and discarded. 50 μL of the ONE-Glo Luciferase Assay System (Promega, E6120) was added, and the plate was shaken in the dark for 5 minutes, then incubated at room temperature for 10 minutes. The luminescence signal (RLU) value was read using a microplate reader (BMG LABTECH, PHERAstar FSX). The inhibition rate of each compound concentration was calculated using the following formula, where the maximum value represents the maximum inhibition rate of the compound on cell transcriptional activity. The IC was calculated using GraphPad Prism to perform curve fitting based on the compound's logarithmic concentration and inhibition rate. 50 Value. Inhibition rate (%) = (RLU) 溶媒对照 -RLU 化合物 ) / (RLU 溶媒对照 -RLU 空白对照 )×100%

[0394] The activity of the compound disclosed herein is obtained from the above analysis, and the calculated IC50 value is... 50 The values ​​are shown in the table below:

[0395] Table 3. Inhibitory activity of the disclosed compounds on transcriptional levels in A549-MMTV-luc and MDA-SMARCA2-KO cells. Note: " / " was not detected.

[0396] Conclusion: The disclosed compound has significant inhibitory activity on the transcriptional level of A549-MMTV-luc cells, but weaker inhibitory activity on the transcriptional level of MDA-SMARCA2-KO cells, demonstrating significant selectivity.

[0397] Test Example 4: Inhibitory Activity of Different Compounds on hERG Channels

[0398] 1. Experimental Methods

[0399] 1.1) Cell Culture

[0400] CHO hERG cells (provided by B'SYS) were grown in culture dishes containing culture medium (Ham's F12 medium, 10% fetal bovine serum, 100 μg / mL hygromycin B, 100 μg / mL geneticin) and incubated at 37°C in a 5% CO2 incubator. 24 to 48 hours before electrophysiological experiments, CHO hERG cells were transferred to round glass slides placed in culture dishes and cultured under the same medium and conditions. The density of CHO hERG cells on each round slide was required to ensure that the vast majority of cells were independent and singular.

[0401] 1.2) Whole-cell recording

[0402] The hERG inhibitory activity of the test sample was tested at different concentrations (30, 10, 3, 1, 0.3, and 0.1 μM). Before the experiment, stock solutions were prepared by serial dilution with DMSO to 10, 3, 1, 0.3, and 0.1 mM, and then diluted to the final concentration with extracellular fluid (2 mM CaCl2, 1 mM MgCl2, 4 mM KCl, 145 mM NaCl, 10 mM Glucose, 10 mM HEPES, pH 7.4, osmolarity ~305 mOsm).

[0403] Whole-cell current recording was performed using a manual patch-clamp system (HEKA EPC-10 signal amplifier and digital conversion system, purchased from HEKA Electronics, Germany). Circular slides with CHO hERG cells were placed in an electrophysiological recording chamber under an inverted microscope, continuously perfused with extracellular fluid (approximately 1 mL / min). The procedure employed standard whole-cell patch-clamp current recording techniques. Cells were clamped at -80 mV, then depolarized to +20 mV to activate hERG potassium channels, and after 5 seconds, clamped again to -50 mV to eliminate inactivation and generate a tail current. The peak tail current was used as the magnitude of the hERG current. After the recorded hERG current stabilized under continuous extracellular fluid perfusion in the recording chamber, the test compound was superimposed until the inhibitory effect of the compound on the hERG current reached a stable state. To test multiple concentrations of the same compound on a single cell, it is necessary to reach a steady state between different concentrations, then flush with extracellular fluid until the hERG current returns to the level before the compound was added.

[0404] 1.3) Results Analysis

[0405] Experimental data were analyzed using HEKA Patchmaster (V2x73.2), Microsoft Excel, and Graphpad Prism 10.0.

[0406] Compare with Example 1: It was synthesized according to the method reported in Example 332 of WO2023220219A1.

[0407] The IC obtained from experiments with the disclosed compound 50 The values ​​are shown in the table below:

[0408] Table 4. Inhibitory activity of the compounds disclosed herein against hERG channels.

[0409] Conclusion: The compound disclosed in this study exhibits relatively weak inhibitory activity against hERG channels, which is a certain advantage.

Claims

1. The compound shown in Formula I or a pharmaceutically acceptable salt thereof in, R 1 Selected from hydrogen, halogen, amino, alkyl, alkoxy, cycloalkyl, or heterocycloalkyl, wherein the alkyl, alkoxy, cycloalkyl, or heterocycloalkyl is optionally composed of one or more elements selected from halogen, hydroxyl, cyano, nitro, amino, C 1-6 Alkyl or C 1-6 Alkyl groups are substituted; R 2 The group is selected from hydrogen, halogen, amino, alkyl, or alkoxy, wherein the alkyl or alkoxy group is optionally surrounded by one or more groups selected from halogen, hydroxyl, cyano, nitro, amino, C 1-6 Alkyl or C 1-6 Alkyl groups are substituted; R 3 The group is selected from hydrogen or alkyl, wherein the alkyl group is optionally divided by one or more radicals selected from halogen, hydroxyl, cyano, nitro, amino, or C. 1-6 Alkyl groups are substituted; R 4 R 5 Each is independently selected from hydrogen, halogen, hydroxyl, alkyl, or alkoxy, wherein the alkyl or alkoxy group is optionally selected from one or more of halogen, hydroxyl, cyano, nitro, amino, C 1-6 Alkyl or C 1-6 Alkoxy groups are substituted. Or, R 4 R 5 Together with the attached carbon atom, a cycloalkyl or heterocycloalkyl group is formed, wherein the cycloalkyl or heterocycloalkyl group is optionally bonded by one or more elements selected from halogen, hydroxyl, cyano, nitro, amino, C 1-6 Alkyl or C 1- Substituted with 6-alkoxy groups; L 1 Selected from optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heteroaryl-alkenyl or optionally substituted heteroaryl-ynyl; L 2 Selected from alkyl groups, optionally substituted cycloalkyl groups, optionally substituted heterocycloalkyl groups, optionally substituted aryl groups, or optionally substituted heteroaryl groups; R 6 Each is independently selected from halogen, hydroxyl, cyano, nitro, amino, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 3-10 Cycloalkyl, 3- to 10-membered heterocycloalkyl, 6- to 10-membered aryl, 5- to 10-membered heteroaryl, C 3-10 Cycloalkoxy, 3 to 10-membered heterocycloalkoxy, or -OC 2-6 alkenyl, the C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 3-10 Cycloalkyl, 3- to 10-membered heterocycloalkyl, 6- to 10-membered aryl, 5- to 10-membered heteroaryl, C 3-10 Cycloalkoxy, 3 to 10-membered heterocycloalkoxy, or -OC 2-6 Alkenyl groups are optionally selected from one or more R groups. 1a Replaced Or, adjacent R 6 Form C with adjacent atoms 3-10 Cycloalkyl or 3 to 10-membered heterocycloalkyl, wherein the C 3- 10 Cycloalkyl or 3 to 10-membered heterocyclic alkyl groups optionally selected from R 1a Replaced; R 1a Each is independently selected from deuterium, halogen, hydroxyl, cyano, nitro, amino, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-10 Cycloalkyl, 3- to 10-membered heterocycloalkyl, wherein C 1-6 Alkyl, C 1-6 Alkoxy, C 3-10 Cycloalkyl groups and 3 to 10-membered heterocyclic alkyl groups may be selected from one or more halogens, oxo groups, hydroxyl groups, cyano groups, nitro groups, amino groups, C groups, etc. 1-6 Alkyl or C 1-6 Alkyl substitution; X 1 Selected from N or C; Z 1 Selected from N or C; Ring A is selected from the optionally substituted C 5-6 Alicyclic rings, optionally substituted 5-6 membered alicyclic rings, optionally substituted aromatic rings, or optionally substituted 5-6 membered heteroaromatic rings; X 2 Selected from -S-, -SO-, -SO2- or -S(O)(=NH)-; R 7 Selected from hydrogen, halogen, hydroxyl, amino, C 1-6 Alkyl or C 1-6 Alkoxy, the C 1-6 Alkyl or C 1- The 6-alkoxy group is optionally surrounded by one or more groups selected from halogen, oxo, hydroxyl, cyano, nitro, amino, C 1-6 Alkyl or C 1-6 Alkyl groups are substituted; R 8 Each is independently selected from halogen, hydroxyl, cyano, nitro, amino, C 1-6 Alkyl or C 1-6 Alkoxy, the C 1-6 Alkyl or C 1-6 Alkyl groups are optionally surrounded by one or more groups selected from halogen, hydroxyl, cyano, nitro, amino, C 1-6 Alkyl or C 1-6 Alkoxy groups are substituted, or two adjacent R groups are substituted. 8 Formation = O; X 3 Selected from -O-, -C(R) 2a )2-、-N(R 2b )-; Z 2 Selected from key or -C(R) 3a )2-; R 2a Each is independently selected from hydrogen, halogen, hydroxyl, nitro, cyano, amino, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl or 3- to 6-membered heterocycloalkyl, wherein the C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl or 3- to 6-membered heterocyclic alkyl groups may be optionally prefixed with one or more halogens, oxo groups, hydroxyl groups, cyano groups, nitro groups, amino groups, or C groups. 1-6 Alkyl or C 1-6 Alkyl groups are substituted, or both R groups are substituted. 2a Together with the atoms they are attached to, they form C 3-8 Cycloalkyl or 3-8 membered heterocycloalkyl, wherein C 3-8 Cycloalkyl or 3-8 membered heterocyclic alkyl groups may be selected from one or more halogens, hydroxyl, cyano, nitro, amino, C 1-6 Alkyl or C 1-6 Alkyl groups are substituted; R 2b Selected from hydrogen or C 1-6 Alkyl, the C 1-6 Alkyl groups may be selected from one or more groups chosen from halogen, oxo, hydroxyl, cyano, nitro, amino, C 1-6 Alkyl or C 1-6 Alkyl groups are substituted; R 3a Each is independently selected from hydrogen, halogen, hydroxyl, nitro, cyano, amino, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl or 3- to 6-membered heterocycloalkyl, wherein the C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl or 3- to 6-membered heterocyclic alkyl groups optionally selected from one or more halogens, hydroxyl, cyano, nitro, amino, C 1- 6-alkyl or C 1-6 Alkyl groups are substituted, or both R groups are substituted. 3a Together with the atoms they are attached to, they form C 3-8 Cycloalkyl or 3-8 membered heterocycloalkyl, wherein C 3-8 Cycloalkyl or 3-8 membered heterocyclic alkyl groups may be selected from one or more halogens, hydroxyl, cyano, nitro, amino, C 1-6 Alkyl or C 1-6 Alkyl groups are substituted; m is selected from 0, 1, 2, or 3; n is selected from 0, 1, or 2; o can be selected from 0, 1, 2, 3 or 4.

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein L 1 Selected from C 3-12 Cycloalkyl, 3-12 membered heterocycloalkyl, C 6-10 aryl, 5-10 heteroaryl, 5-10 heteroaryl-alkenyl or 5-10 heteroaryl-alkynyl, wherein C 3-12 Cycloalkyl, 3-12 membered heterocycloalkyl, C 6-10 5-10-membered heteroaryl, 5-10-membered heteroaryl-alkenyl, or 5-10-membered heteroaryl-alkynyl may be selected from one or more of R 4a Replaced R 4a Each is independently selected from halogen, hydroxyl, cyano, nitro, amino, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-10 Cycloalkyl, 3- to 10-membered heterocycloalkyl, wherein C 1-6 Alkyl, C 1-6 Alkoxy, C 3-10 Cycloalkyl groups and 3 to 10-membered heterocyclic alkyl groups may be selected from one or more halogens, oxo groups, hydroxyl groups, cyano groups, nitro groups, amino groups, C groups, etc. 1-6 Alkyl or C 1-6 Alkyl-substituted.

3. The compound or a pharmaceutically acceptable salt thereof according to claim 1 or 2, wherein L 2 Selected from key, C 3-12 Cycloalkyl, 3-12 membered heterocycloalkyl, C 6-10 Aryl or 5-10 heteroaryl, C 3-12 Cycloalkyl, 3-12 membered heterocycloalkyl, C 6-10 Aryl or 5-10 heteroaryl groups are optionally selected from one or more R groups. 5a Replaced R 5a Each is independently selected from halogen, hydroxyl, cyano, nitro, amino, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-10 Cycloalkyl, 3- to 10-membered heterocycloalkyl, wherein C 1-6 Alkyl, C 1-6 Alkoxy, C 3-10 Cycloalkyl groups and 3 to 10-membered heterocyclic alkyl groups may be selected from one or more halogens, oxo groups, hydroxyl groups, cyano groups, nitro groups, amino groups, C groups, etc. 1-6 Alkyl or C 1-6 Alkyl-substituted.

4. The compound or its pharmaceutically acceptable salt according to any one of claims 1-3, wherein L 1 Selected from 5-10 heteroaryl groups, wherein the 5-10 heteroaryl group is optionally surrounded by one or more groups selected from R 4a Replaced by, R 4a As defined in claim 2; Furthermore, L 1 Preferred Where X 4 X 5 X 6 X 7 X 8 X 9 Each is independently selected from N or CR 4aa R 4aa Each is independently selected from hydrogen, halogen, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl or 3- to 6-membered heterocycloalkyl, wherein the C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl or 3- to 6-membered heterocyclic alkyl groups optionally selected from one or more halogens, hydroxyl, cyano, nitro, amino, C 1-6 Alkyl or C 1-6 Alkyl groups are substituted; A 1 For -C(R) 4 (R) 5 - The bond connected, A 2 To be with L 2 Connecting keys.

5. The compound according to claim 4, or a pharmaceutically acceptable salt thereof, wherein L 1 Selected from Where A 1 A 2 As defined in claim 4, R 4aa As defined in claim 1; further, L 1 Preferred More Where A 1 A 2 As defined in claim 4.

6. The compound or its pharmaceutically acceptable salt according to any one of claims 1-3, wherein L 1 Selected from 5-6-membered heteroaryl groups, wherein the 5-6-membered heteroaryl group is optionally surrounded by one or more groups selected from R 4a Replaced by, R 4a As defined in claim 2; Furthermore, L 1 Preferred Where X 4 X 5 X 6 X 10 Each is independently selected from N or CR 4aa R 4aa Each is independently selected from hydrogen, halogen, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl or 3- to 6-membered heterocycloalkyl, wherein the C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl or 3- to 6-membered heterocyclic alkyl groups optionally selected from one or more halogens, hydroxyl, cyano, nitro, amino, C 1-6 Alkyl or C 1- Substituted with 6-alkoxy groups; A 1 For -C(R) 4 (R) 5 - The bond connected, A 2 To be with L 2 Connecting keys.

7. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-4, wherein the compound represented by formula I is the compound represented by formula II-1. Where R 1 ~R 8 X 1 X 2 X 3 Z 1 Z 2 A, m, n, o are defined as in claim 1; X 4 X 5 X 6 X 7 X 8 X 9 As defined in claim 4.

8. The compound or a pharmaceutically acceptable salt thereof according to claims 1-3 or 6, wherein the compound of formula I is the compound of formula II-2. Where R 1 ~R 8 X 1 X 2 X 3 Z 1 Z 2 A, m, n, o are defined as in claim 1; X 4 X 5 X 6 X 10 As defined in claim 6.

9. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-8, wherein -L 2 -(R 6 ) o Selected from X 11 X 12 X 13 X 14 and X 15 Each is independently selected from N or CR 5aa R 5aa Each is independently selected from hydrogen, halogen, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl or 3- to 6-membered heterocycloalkyl, wherein the C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl or 3- to 6-membered heterocyclic alkyl groups optionally selected from one or more halogens, hydroxyl, cyano, nitro, amino, C 1-6 Alkyl or C 1-6 Alkoxy-substituted, R 6 o is defined as in claim 1; Furthermore, -L 2 -(R 6 ) o Preferred Where R 6 o is as defined in claim 1.

10. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-8, wherein -L 2 -(R 6 ) o Selected from X 11 X 12 X 13 and X 14 Each is independently selected from N or CR 5aa R 5aa Each is independently selected from hydrogen, halogen, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl or 3- to 6-membered heterocycloalkyl, wherein the C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl or 3- to 6-membered heterocyclic alkyl groups optionally selected from one or more halogens, hydroxyl, cyano, nitro, amino, C 1-6 Alkyl or C 1-6 Alkoxy-substituted; ring B is selected from phenyl, 5-6 membered heterocyclic alkyl, or 5-6 membered heteroaryl, R 6 o is defined as in claim 1; Furthermore, -L 2 -(R 6 ) o Preferred R 6 o is as defined in claim 1.

11. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 4-10, wherein X 4 Selected from CR 4aa R 4aa As defined in claim 4.

12. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 4-11, wherein X 6 Selected from CR 4aa R 4aa As defined in claim 3.

13. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-12, wherein X 1 Selected from C.

14. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-13, wherein Z 1 Selected from N.

15. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-14, wherein ring A is selected from 5-6 membered heteroaromatic rings, said 5-6 membered heteroaromatic ring being optionally surrounded by one or more members selected from R. 6a Replaced by, R 6a Each is independently selected from halogen, hydroxyl, cyano, nitro, amino, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-10 Cycloalkyl, 3- to 10-membered heterocycloalkyl, wherein C 1-6 Alkyl, C 1-6 Alkoxy, C 3-10 Cycloalkyl groups and 3 to 10-membered heterocyclic alkyl groups may be selected from one or more halogens, oxo groups, hydroxyl groups, cyano groups, nitro groups, amino groups, C groups, etc. 1-6 Alkyl or C 1-6 Alkyl-substituted.

16. The compound according to any one of claims 1-13 or 15, or a pharmaceutically acceptable salt thereof, wherein ring A is selected from... Where "*" indicates a loop site, R 6a As defined in claim 15, r is selected from 0, 1, 2 or 3.

17. The compound or its pharmaceutical salt according to any one of claims 1-18, wherein X 3 Selected from -C(R) 2a )2-.

18. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-17, wherein X 2 Selected from -S- or -SO2-.

19. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-18, wherein Z 2 Selected from key.

20. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-19, wherein... Selected from Where R 1 R 2 R 7 R 8 R 2a m is defined as in claim 1; R 6a As defined in claim 15, r is selected from 0, 1, 2 or 3.

21. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-20, wherein R 3 It is selected from hydrogen, methyl, ethyl or propyl, with hydrogen being preferred.

22. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-10, wherein the compound represented by formula I is selected from the compounds represented by formula III-1 or III-2 or III-3 or III-4. Where R 1 ~R 8 R 2a m, n, o are defined as in claim 1; X 4 X 5 X 6 X 7 X 8 X 9 As defined in claim 4; X 10 As defined in claim 6; R 6a As defined in claim 15; r is selected from 0, 1, 2 or 3.

23. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-22, wherein R 4 R 5 Each is independently selected from hydrogen, halogen, or C. 1-6 Alkyl group, preferably hydrogen.

24. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 6 Each is independently selected from halogens, hydroxyl groups, and C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 3-10 Cycloalkyl, 3- to 10-membered heterocycloalkyl, 6-membered aryl, 5- to 6-membered heteroaryl, wherein C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 3-10 Cycloalkyl, 3 to 10-membered heterocycloalkyl, 6-membered aryl, or 5 to 6-membered heteroaryl, optionally selected from one or more R 1a Replaced by, R 1a As defined in claim 1.

25. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-24, wherein R 6 Each is independently selected from halogens, C 1-6 Alkyl, C 3-10 Cycloalkoxy or -OC 2-6 alkenyl, the C 1-6 Alkyl, C 3-10 Cycloalkoxy or -OC 2-6 Alkenyl groups are optionally selected from one or more R groups. 1a Replaced by, R 1a As defined in claim 1.

26. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-24, wherein R 6 Each is independently selected from fluorine, chlorine, methyl, deuterated methyl, ethyl, deuterated ethyl, difluoromethyl, trifluoromethyl, methoxy, ethoxy, deuterated methoxy, difluoromethoxy, trifluoromethoxy, difluoroethoxy, trifluoroethoxy, cyclopropylmethyloxy, cyclopropoxy, and cyclobutoxy.

27. The compound or a pharmaceutically acceptable salt thereof according to claims 1-26, wherein the compound of formula I is selected from the compound of formula IV-1 or the compound of formula IV-2. Where R 1 ~R 8 R 2a m, n, o are defined as in claim 1; R 6a As defined in claim 15; X 4 X 6 X 7 X 8 X 9 As defined in claim 4; X 11 X 12 X 13 X 14 and X 15 As defined in claim 9; r is selected from 0, 1, 2 or 3.

28. The compound or a pharmaceutically acceptable salt thereof according to claim 9 or 27, wherein X 11 or X 12 Selected from N.

29. The compound or a pharmaceutically acceptable salt thereof according to claim 1 or 27, wherein the compound of formula I is selected from the compound of formula V-1, the compound of formula V-2, the compound of formula V-3, or the compound of formula V-4. Where R 1 ~R 8 R 2a m, n, o are defined as in claim 1; R 6a As defined in claim 15; X 4 X 6 X 7 X 8 X 9 As defined in claim 4; r is selected from 0, 1, 2 or 3.

30. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-29, wherein R 1 Selected from hydrogen, halogen or C 1-6 Alkyl group, wherein the alkyl group is optionally oxidized by one or more radicals selected from halogen, hydroxyl, cyano, nitro, amino, C 1-6 Alkyl or C 1-6 Alkyl groups are substituted; further, R 1 The preferred compounds are hydrogen, fluorine, methyl, difluoromethyl, trifluoromethyl, ethyl, or propyl.

31. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-30, wherein R 2 Selected from hydrogen, halogen or C 1-6 Alkyl group, wherein the alkyl group is optionally oxidized by one or more radicals selected from halogen, hydroxyl, cyano, nitro, amino, C 1-6 Alkyl or C 1-6 Alkyl groups are substituted; further, R 2 The preferred compounds are hydrogen, fluorine, methyl, difluoromethyl, trifluoromethyl, ethyl, or propyl.

32. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 1a Selected from deuterium, halogens or C 1-6 Alkyl group, wherein the alkyl group is optionally substituted with one or more groups selected from halogen, hydroxyl, cyano, nitro, or amino; further, R 1a Preferred compounds include deuterium, fluorine, chlorine, bromine, methyl, difluoromethyl, trifluoromethyl, ethyl, or propyl.

33. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-32, wherein R 7 Selected from hydrogen, hydroxyl, halogen or C 1-6 Alkyl group, wherein the alkyl group is optionally oxidized by one or more radicals selected from halogen, hydroxyl, cyano, nitro, amino, C 1-6 Alkyl or C 1-6 Alkyl groups are substituted; further, R 7 The preferred compounds are hydrogen, fluorine, hydroxyl, methyl, difluoromethyl, trifluoromethyl, ethyl, or propyl.

34. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-33, wherein R 2a Each is independently selected from hydrogen, halogen, or C. 1-6 Alkyl group, wherein the alkyl group is optionally oxidized by one or more radicals selected from halogen, hydroxyl, cyano, nitro, amino, C 1-6 Alkyl or C 1-6 Alkyl groups are substituted; further, R 2a Each of the following is preferred independently: hydrogen, fluorine, methyl, difluoromethyl, trifluoromethyl, ethyl, or propyl.

35. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-34, wherein R 3a Each is independently selected from hydrogen, halogen, or C. 1-6 Alkyl group, wherein the alkyl group is optionally oxidized by one or more radicals selected from halogen, hydroxyl, cyano, nitro, amino, C 1-6 Alkyl or C 1-6 Alkyl groups are substituted; further, R 3a Each of the following is preferred independently: hydrogen, fluorine, methyl, difluoromethyl, trifluoromethyl, ethyl, or propyl.

36. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-35, wherein R 4a Each is independently selected from hydrogen, halogen, or C. 1-6 Alkyl group, wherein the alkyl group is optionally oxidized by one or more radicals selected from halogen, hydroxyl, cyano, nitro, amino, C 1-6 Alkyl or C 1-6 Alkyl groups are substituted; further, R 4a Each of the following is preferred independently: hydrogen, fluorine, methyl, difluoromethyl, trifluoromethyl, ethyl, or propyl.

37. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-36, wherein R 5a Each is independently selected from hydrogen, halogen, or C. 1-6 Alkyl group, wherein the alkyl group is optionally oxidized by one or more radicals selected from halogen, hydroxyl, cyano, nitro, amino, C 1-6 Alkyl or C 1-6 Alkyl groups are substituted; further, R 5a Each of the following is preferred independently: hydrogen, fluorine, methyl, difluoromethyl, trifluoromethyl, ethyl, or propyl.

38. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 15-37, wherein R 6a Each is independently selected from hydrogen, halogen, or C. 1-6 Alkyl group, wherein the alkyl group is optionally oxidized by one or more radicals selected from halogen, hydroxyl, cyano, nitro, amino, C 1-6 Alkyl or C 1-6 Alkyl groups are substituted; further, R 6a Each of the following is preferred independently: hydrogen, fluorine, methyl, difluoromethyl, trifluoromethyl, ethyl, or propyl.

39. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is selected from:

40. A pharmaceutical composition comprising at least a therapeutically effective amount of the compound as claimed in any one of claims 1-39 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

41. A method for preventing and / or treating cancer, comprising administering to the individual an effective therapeutic amount of a compound as claimed in any one of claims 1-39 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition as claimed in claim 40, wherein the cancer is preferably lung cancer, colorectal cancer, breast cancer, melanoma, skin cancer, lymphoma, or prostate cancer.

42. Use of the compound of any one of claims 1-39 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 40, in the preparation of a medicament for the prevention and / or treatment of diseases associated with SMARCA2.

43. Use of the compound of any one of claims 1-39 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 40, in the preparation of a medicament for the prevention and / or treatment of cancer, preferably lung cancer, colorectal cancer, breast cancer, melanoma, skin cancer, lymphoma, or prostate cancer.

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