Pyrimidine derivative as well as preparation method and medical application thereof

Abstract

The invention relates to a pyrimidine derivative, a preparation method thereof and application of the pyrimidine derivative in medicine. Specifically, the invention relates to a polycyclic compound as shown in a general formula (I), a preparation method of the polycyclic compound, a pharmaceutical composition containing the pyrimidine derivative and application of the pharmaceutical composition as a therapeutic agent, especially application of the pharmaceutical composition as a BCL6 inhibitor or a degradation agent and application of the pharmaceutical composition in preparation of drugs for treating and / or preventing BCL6-mediated or dependent diseases or symptoms. Wherein each group in the general formula (I) is defined in the specification.

Description

TECHNICAL FIELD

[0001] The present disclosure belongs to the field of medicine, and relates to a pyrimidine derivative represented by general formula (I), a preparation method thereof, a pharmaceutical composition containing the polycyclic compound, and the use thereof as a therapeutic agent, particularly as a BCL6 inhibitor or degrader and in the preparation of a medicament for treating and / or preventing a BCL6-mediated or -dependent disease or disorder. BACKGROUND

[0002] BCL6 (B-cell lymphoma 6) is a member of the BTB / POZ zinc finger family, containing an N-terminal BTB / POZ domain and a C-terminal zinc finger. As a transcription factor for T follicular helper (Tfh) cells, BCL6 is essential for germinal center formation and antibody affinity maturation of naive B cells. BCL6 was originally discovered as an oncogene in diffuse large B-cell lymphomas (DIBCLs), and its role is associated with many types of diseases, including B acute lymphoblastic leukemia, chronic myeloid leukemia, breast cancer, and non-small cell lung cancer (NSCLC). The N-terminal BTB / POZ binds and recruits co-repressors, such as SMRT, NCOR1, BCOR, to form type I and type II histone deacetylase complexes, and the C-terminal zinc finger binds to specific DNA recognition sequences. By forming a complex with the target gene sequence, BCL6 can reduce the RNA expression of the target gene, including some key tumor suppressors. Overexpression of BCL6 can lead to ectopic suppression of cell cycle proteins and DNA repair checkpoint proteins, resulting in uncontrolled cell proliferation and tumorigenesis, which is common in malignancies such as non-Hodgkin lymphoma (NHL). GC responses to some diseases can lead to an increase in disease-specific autoantibodies, and inhibition or degradation of BCL6 has potential therapeutic applications. Structural features of the co-crystal structure of the BCL6 TB / POZ domain and its co-repressor suggest that the binding between the two occurs in a side groove formed at the interface between BCL6 BB / POZ homodimers. Therefore, specific ligands targeting this groove site were studied, and the discovery of ligands with affinity for this groove enabled BCL6 to become a drug target.

[0003] Protein degradation is a highly regulated and essential process to maintain cellular homeostasis. Selective recognition and removal of damaged, misfolded, or excess proteins is achieved through the ubiquitin-proteasome pathway (UPP). The UPP is central to the regulation of almost all cellular processes. Ubiquitination of proteins is accomplished by E3 ubiquitin ligases, enzymes that bind to proteins and add ubiquitin molecules to proteins, thereby marking them for proteasomal degradation. A promising therapy uses proteolysis against chimeras, commonly known as PROTACs, to remove unwanted proteins through protein degradation. PROTAS are ligand-directed degraders that bind E3 ligases and target proteins to be degraded together. These bivalent molecules are typically composed of an E3 ligase ligand connected to a small molecule that binds to the target protein through a linker moiety. PROTACs position E3 ligases at the proper distance and orientation from the target protein, allowing the latter to be ubiquitinated. Ubiquitinated target proteins are subsequently recognized by proteasomes, which in turn are degraded. In summary, PROTAC chimeric molecules can be utilized to degrade BCL6 by linking a ligand against the BCL6 groove and an E3 ligand together through a linker.

[0004] Published compound patent applications include WO2023212147A1, WO2023244917A1, WO2023244918A1, WO2024086759A1, or WO2023232133A1, etc. SUMMARY

[0005] The purpose of the present disclosure is to provide a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof,

[0006]

[0007] wherein:

[0008] Z is selected from O, S, (CR 2 R 3 ) z and NR 4 ;

[0009] Z 1 , Z 2 , Z 3 and Z 4 one of Z a , Z 5 ;

[0010] L a and L bthe same or different, and each is independently selected from the group consisting of a bond, alkylene, alkenylene, alkynylene, cycloalkyl, heterocyclyl, (CR c R d ) a , O, S, NR b , C(O), C(O)NR b , and NR b C(O);

[0011] L c is selected from the group consisting of a bond, (CR c R d ) a , O, S, NR b , C(O), C(O)NR b , and NR b C(O);

[0012] Ring A is selected from the group consisting of polycycloalkyl, polycycloheteroalkyl, polycycloaryl, and polycycloheteroaryl; wherein each of said polycycloalkyl, polycycloheteroalkyl, polycycloaryl, and polycycloheteroaryl is independently optionally substituted with one or more R 8 ;

[0013] Ring B is selected from the group consisting of is connected to L b ;

[0014] One of Q 1 , Q 2 , Q 3 , and Q 4 is a carbon atom and is connected to L b , and the remaining three are the same or different, and each is independently selected from the group consisting of N, CH, and CR 9 ;

[0015] One of G 1 , G 2 , G 3 , G 4 , and G 5 is a carbon atom and is connected to L b , and the remaining four are the same or different, and each is independently selected from the group consisting of N, CH, and CR 9 ;

[0016] U is N or CR 10 ;

[0017] Y 1 , Y 2 , and Y 3 are the same or different, and each is independently selected from the group consisting of a bond, (CR c R d ) b , O, S, NR b , and C(O);

[0018] X is N or CR 13 ;

[0019] is a double or single bond;

[0020] R 1 , R 4 , R 11 , R 14 , R a , and R b are the same or different and each is independently selected from the group consisting of a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group, a haloalkyl group, a hydroxyalkyl group, an alkoxyalkyl group, a hydroxyl group, an alkoxy group, -alkylene-NR 17 R 18 , a cycloalkyl group, a heterocyclyl group, an aryl group, a heteroaryl group, a cycloalkylalkyl group, a heterocyclylalkyl group, an arylalkyl group, and a heteroarylalkyl group; wherein each of the alkyl group, the alkenyl group, the alkynyl group, the alkoxyalkyl group, the alkoxy group, the cycloalkyl group, the heterocyclyl group, the aryl group, the heteroaryl group, the cycloalkylalkyl group, the heterocyclylalkyl group, the arylalkyl group, and the heteroarylalkyl group is independently optionally substituted with one or more R 0 ;

[0021] R 2 , R 3 , R 13 , R 15 , R c , and R d are the same or different and each is independently selected from the group consisting of a hydrogen atom, a halogen, an alkyl group, an alkenyl group, an alkynyl group, a haloalkyl group, a hydroxyalkyl group, an alkoxy group, a haloalkoxy group, an alkoxyalkyl group, an aminoalkyl group, a cyano group, an amino group, a hydroxyl group, a nitro group, -OR 16 , -NR 17 R 18 , -C(O)R 16 , -C(O)OR 16 , -C(O)NR 17 R 18 , a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group; wherein each of the alkyl group, the alkenyl group, the alkynyl group, the alkoxy group, the alkoxyalkyl group, the cycloalkyl group, the heterocyclyl group, the aryl group, and the heteroaryl group is independently optionally substituted with one or more R 0 ;

[0022] or, R 2 and R 3 together with the atoms to which they are attached form a cycloalkyl group or a heterocyclyl group, each of which is independently optionally substituted with one or more R 0 ;

[0023] or, R c and R dTogether with the attached atoms, they form a cycloalkyl or heterocyclic group, each of which is independently and optionally influenced by one or more R atoms. 0 replace;

[0024] R 5 and R 9 The same or different, and each independently selected from halogen, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkoxyalkyl, aminoalkyl, cyano, amino, hydroxyl, nitro, -OR 16 -NR 17 R 18 -C(O)R 16 -C(O)OR 16 -C(O)NR 17 R 18 alkyl, heterocyclic, aryl, and heteroaryl; wherein each of the alkyl, alkenyl, alkoxy, alkoxyalkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups is independently and optionally composed of one or more R 0 replace;

[0025] R 6 R 7 R 10 and R 12 The same or different, and each independently selected from hydrogen atom, halogen, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkoxyalkyl, aminoalkyl, cyano, amino, hydroxyl, nitro, -OR 16 -NR 17 R 18 -C(O)R 16 -C(O)OR 16 -C(O)NR 17 R 18 alkyl, heterocyclic, aryl, and heteroaryl; wherein each of the alkyl, alkenyl, alkoxy, alkoxyalkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups is independently and optionally composed of one or more R 0 replace;

[0026] Each R 8 The same or different, and each independently selected from halogen, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkoxyalkyl, aminoalkyl, cyano, amino, hydroxyl, nitro, -OR 16 -NR 17 R 18 -C(O)R 16 -C(O)OR 16 -C(O)NR 17 R 18 -OC(O)NR17 R 18 -OC(O)R 21 -OC(O)OR 16 -NR 19 C(O)R 16 -NR 19 C(O)OR 16 -C(=NR) 20 )NR 17 R 18 -S(O) v R 16 -S(O) v NR 17 R 18 -NR 19 S(O) v R 16 -NR 19 S(O) v NR 17 R 18 =O, =S, =CR 21 R 22 alkyl, heterocyclic, aryl, and heteroaryl; wherein each of the alkyl, alkenyl, alkoxy, alkoxyalkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups is independently and optionally composed of one or more R 0 replace;

[0027] R 16 R 17 and R 18 The elements may be the same or different each time they appear, and are each independently selected from hydrogen atoms, alkyl, alkenyl, ynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl; wherein the alkyl, alkenyl, ynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl elements are each independently selected by one or more R atoms. 0 Replace; or R 17 and R 18 Together with the attached nitrogen atom, a nitrogen-containing heterocyclic group is formed, wherein the nitrogen-containing heterocyclic group is optionally surrounded by one or more R atoms. 0 replace;

[0028] R 19 They may be the same or different each time they appear, and each is independently selected from hydrogen atoms, alkyl groups and cycloalkyl groups;

[0029] R 20 They may be the same or different each time they appear, and each is independently selected from hydrogen atoms, alkyl, alkoxy, hydroxy and cycloalkyl;

[0030] R 21 and R 22They may be the same or different each time they appear, and each is independently selected from hydrogen atoms, halogens, alkyl groups, haloalkyl groups, hydroxyalkyl groups, and cycloalkyl groups; or, R 21 and R 22 Together with the carbon atoms attached to it, they form cycloalkyl groups;

[0031] R 0 Each of the following groups may be the same or different in each occurrence and is independently selected from =O, =S, =CH2, =CHF, =CF2, halogen, hydroxyl, alkenyl, alkynyl, cyano, nitro, amino, -NHalkyl, -N(alkyl)2, -C(O)Oalkyl, -C(O)OH, -C(O)NH2, -C(O)NH(alkyl), -C(O)N(alkyl)2, -C(O)halogen, -C(O)alkyl, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkoxyalkyl, aminoalkyl, -S(alkyl), cycloalkyl, cycloalkylalkyl, cycloalkyloxy, heterocyclic, heterocyclic alkyl, heterocyclic oxy, aryl, arylalkyl, aryloxy, heteroaryl, heteroarylalkyl and heteroaryloxy;

[0032] z can be 0, 1, 2, or 3;

[0033] a and b may be the same or different, and each is independently 0, 1, 2, 3, 4 or 5;

[0034] v can be 0, 1, or 2.

[0035] In some embodiments of this disclosure, the compound represented by general formula (I) is not a compound disclosed in WO2023212147A1; in some embodiments, the compound represented by general formula (I) is not one of the following compounds:

[0036] In some embodiments of this disclosure, the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof, wherein Z is CR 2 R 3 or NR 4 ;R 2 R 3 and R 4 As defined in general formula (I); in some implementations, Z is CR 2 R 3 ;R 2 and R 3 As defined in general formula (I); in some implementations, Z is NR 4 ;R 4 As defined in general formula (I); in some implementations, Z is CH2.

[0037] In some embodiments of this disclosure, the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof, wherein z is 1 or 2; in some embodiments, z is 1.

[0038] In some embodiments of this disclosure, the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof, wherein R 4 It is a hydrogen atom or a carbon atom. 1-6 Alkyl; in some embodiments, R 4 C 1-6 Alkyl; in some embodiments, R 4 For hydrogen atoms; in some implementations, R 4 It can be methyl or ethyl.

[0039] In some embodiments of this disclosure, the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof, wherein Z 1 Z 2 Z 3 and Z 4 One of them is a carbon atom and is related to NR. a Connected, the other three are the same or different, and each is independently CH or CR. 5 ;R 5 As defined in general formula (I); in some implementations, Z 2 It is a carbon atom and is related to NR a Connected, Z 1 and Z 3 Whether the two are the same or different, and each is independently CH or CR 5 Z 4 Selected from N, CH and CR 5 ;R 5 As defined in general formula (I); in some implementations, Z 2 It is a carbon atom and is related to NR a Connected, Z 1 Z 3 and Z 4 Whether the two are the same or different, and each is independently CH or CR 5 ;R 5 As defined in general formula (I); in some implementations, Z 2 It is a carbon atom and is related to NR a Connected, Z 1 Z 3 and Z 4 CH; in some implementations, Z 3 It is a carbon atom and is related to NR a Connected, Z 1 Z 2 and Z 4 They may be the same or different, and each is independently selected from N, CH and CR. 5 ;R5 As defined in general formula (I); in some implementations, Z 3 It is a carbon atom and is related to NR a Connected, Z 1 Z 2 and Z 4 Whether the two are the same or different, and each is independently CH or CR 5 ;R 5 As defined in general formula (I); in some implementations, Z 3 It is a carbon atom and is related to NR a Connected, Z 1 Z 2 and Z 4 For CH.

[0040] In some embodiments of this disclosure, the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof, wherein for Z 4 R 1 R 2 R 3 R 5 and m are as defined in general formula (II); in some implementations, for R 1 R 5 and m1 as defined in general formula (III); in some implementations, Same or different, and each selected independently In some implementation schemes, for

[0041] In some embodiments of this disclosure, the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof, wherein L a For key or NR b ;R b As defined in general formula (I); in some implementations, L a For bond or NH; in some implementations, L a For key.

[0042] In some embodiments of this disclosure, the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof, wherein L b For key or NR b ;R b As defined in general formula (I); in some implementations, L b For bond or NH; in some implementations, L b For key.

[0043] In some embodiments of this disclosure, the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof, wherein L c For key or NR b ;R b As defined in general formula (I); in some implementations, L c For bond or NH; in some implementations, L c For key.

[0044] In some embodiments of this disclosure, the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof, wherein L a For key; L b For key.

[0045] In some embodiments of this disclosure, the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof, wherein Q 2 It is a carbon atom and is related to L b Connected, Q 1 Q 3 and Q 4 They may be the same or different, and each is independently selected from N, CH and CR. 9 ;R 9 As defined in general formula (I); in some implementations, Q 2 It is a carbon atom and is related to L b Connected, Q 1 Q 3 and Q 4 For CH; in some implementations, Q 2 It is a carbon atom and is related to L b Connected, Q 1 For N; Q 3 and Q 4 For CH; in some implementations, Q 2 It is a carbon atom and is related to L b Connected, Q 3 For N; Q 1 and Q 4 For CH.

[0046] In some embodiments of this disclosure, the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof, wherein U is N; in some embodiments, U is N or CH.

[0047] In some embodiments of this disclosure, the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof, wherein R 10 Selected from hydrogen atoms, halogens, C 1-6 Alkyl and C 1-6 Halogenated alkyl; in some embodiments, R 10 It is a hydrogen atom.

[0048] In some embodiments of this disclosure, the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof, wherein R 12 Selected from hydrogen atoms, halogens, C 1-6 Alkyl and C 1-6 Halogenated alkyl; in some embodiments, R 12 It is a hydrogen atom.

[0049] In some embodiments of this disclosure, the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof, wherein Y 1 It is CH2 or C(O); in some implementations, Y 1 It is C(O).

[0050] In some embodiments of this disclosure, the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof, wherein Y 2 It is CH2 or C(O).

[0051] In some embodiments of this disclosure, the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof, wherein Y 3 It is CH2 or C(O).

[0052] In some embodiments of this disclosure, the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof, wherein R b It is a hydrogen atom or a carbon atom. 1-6 Alkyl; in some embodiments, R b It is a hydrogen atom.

[0053] In some embodiments of this disclosure, the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof, wherein R c and R d They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl; in some embodiments, R c and R d It is a hydrogen atom.

[0054] In some embodiments of this disclosure, the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof, wherein a is 1 or 2; in some embodiments, a is 1.

[0055] In some embodiments of this disclosure, the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof, wherein b is 1 or 2; in some embodiments, b is 1.

[0056] In some embodiments of this disclosure, the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof, wherein ring B is Q 1 Q 2 Q 3 Q4 , U and R 11 As defined in general formula (I); in some implementations, ring B is Q 1 Q 3 Q 4 and R 11 As defined in general formula (II); *end and L b Connection; in some implementations, ring B is R 9 , k and R 11 As defined in general formula (III); *end and L b connect.

[0057] In some implementation schemes disclosed herein, ring B, Same or different, and each selected independently *End and L b Or ring A connection; in some implementations, ring B, for *End and L b Or ring A connection.

[0058] In some embodiments of this disclosure, the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof is a compound represented by general formula (II) or a pharmaceutically acceptable salt thereof.

[0059]

[0060] in:

[0061] m is 0, 1, or 2;

[0062] Z 4 Selected from N, CH and CR 5 ;

[0063] Q 1 Q 3 and Q 4 They may be the same or different, and each is independently selected from N, CH and CR. 9 ;

[0064] R 1 To R 3 R 5 R a R 6 R 7 Ring A, R 9 R 11 X, R 14 R 15 and As defined in general formula (I).

[0065] In some embodiments of this disclosure, the compound represented by general formula (I) or (II) or a pharmaceutically acceptable salt thereof, wherein R a It is a hydrogen atom or a carbon atom. 1-6 Alkyl; in some embodiments, R a It is a hydrogen atom.

[0066] In some embodiments of this disclosure, the compound represented by general formula (I) or (II) or a pharmaceutically acceptable salt thereof, wherein R 2 and R 3 They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, hydroxyl, and cyano groups; or, R 2 and R 3 Together with the carbon atom attached to it, they form a 3- to 6-membered cycloalkyl group; in some embodiments, R 2 and R 3 They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl; in some embodiments, R 2 and R 3 They may be the same or different, and each is independently a hydrogen atom or a halogen; in some embodiments, R 2 and R 3 For F; in some implementations, R 2 and R 3 It is a hydrogen atom.

[0067] In some embodiments of this disclosure, the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof, wherein Z 1 It is a carbon atom and is related to NR a Connection; in some implementations, Z 1 For CH or N; in some implementations, Z 1 For CH or CR 5 ;R 5 As defined in general formula (I); in some implementations, Z 1 For CH.

[0068] In some embodiments of this disclosure, the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof, wherein Z 2 It is a carbon atom and is related to NR a Connection; in some implementations, Z 2 For CH or N; in some implementations, Z 2 For CH or CR 5 ;R 5As defined in general formula (I); in some implementations, Z 2 For CH.

[0069] In some embodiments of this disclosure, the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof, wherein Z 3 It is a carbon atom and is related to NR a Connection; in some implementations, Z 3 For CH or N; in some implementations, Z 3 For CH or CR 5 ;R 5 As defined in general formula (I); in some implementations, Z 3 For CH.

[0070] In some embodiments of this disclosure, the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof, wherein Z 4 It is a carbon atom and is related to NR a Connection; in some implementations, Z 4 For CH or N; in some implementations, Z 4 For CH or CR 5 ;R 5 As defined in general formula (I); in some implementations, Z 4 CH; in some implementations, Z 4 Let N be the number of elements in the array.

[0071] In some embodiments of this disclosure, the compound shown in (II) or a pharmaceutically acceptable salt thereof, wherein Z 4 For CH or N; in some implementations, Z 4 For CH or CR 5 ;R 5 As defined in general formula (I); in some implementations, Z 4 CH; in some implementations, Z 4 Let N be the number of elements in the array.

[0072] In some embodiments of this disclosure, the compound represented by general formula (I) or (II) or a pharmaceutically acceptable salt thereof, wherein R 7 Selected from hydrogen atoms, halogens, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, hydroxyl, and cyano groups; in some embodiments, R 7 Selected from hydrogen atoms, halogens and C 1-6 Alkyl; in some embodiments, R 7 It is a hydrogen atom.

[0073] In some embodiments of this disclosure, the compound represented by general formula (I) or (II) or a pharmaceutically acceptable salt thereof, wherein Q 1 Q 3 and Q 4 Whether the two are the same or different, and each is independently CH or CR 9 ;R 9 As defined in general formula (I); in some implementations, Q 1 Q 3 and Q 4 For CH.

[0074] In some embodiments of this disclosure, the compound represented by general formula (I) or (II) or a pharmaceutically acceptable salt thereof, wherein Q 1 For N or CH; in some implementations, Q 1 For CH or CR 9 ;R 9 As defined in general formula (I); in some implementations, Q 1 For CH or CR 9 ;R 9 It is halogen; in some implementations, Q 1 For CH.

[0075] In some embodiments of this disclosure, the compound represented by general formula (I) or (II) or a pharmaceutically acceptable salt thereof, wherein Q 3 For N or CH; in some implementations, Q 3 For CH or CR 9 ;R 9 As defined in general formula (I); in some implementations, Q 3 For CH or CR 9 ;R 9 It is halogen; in some implementations, Q 3 For CH.

[0076] In some embodiments of this disclosure, the compound represented by general formula (I) or (II) or a pharmaceutically acceptable salt thereof, wherein Q 4 For N or CH; in some implementations, Q 4 For CH or CR 9 ;R 9 As defined in general formula (I); in some implementations, Q 4 For CH or CR 9 ;R 9 It is halogen; in some implementations, Q 4 For CH.

[0077] In some embodiments of this disclosure, the compound represented by general formula (I) or (II) or a pharmaceutically acceptable salt thereof, wherein X is N or CH; in some embodiments, X is CR 13 ;R 13 As defined in general formula (I); in some implementations, X is CH; in some implementations, X is N.

[0078] In some embodiments of this disclosure, the compound represented by general formula (I) or (II) or a pharmaceutically acceptable salt thereof, wherein R 13 It is a hydrogen atom or a carbon atom. 1-6 Alkyl; in some embodiments, R 13 For hydrogen atoms; in some implementations, R 13 It is a methyl group.

[0079] In some embodiments of this disclosure, the compound represented by general formula (I) or (II) or a pharmaceutically acceptable salt thereof, wherein R 14 It is a hydrogen atom or a carbon atom. 1-6 Alkyl; in some embodiments, R 14 For hydrogen atoms; in some implementations, R 14 It is a methyl group.

[0080] In some embodiments of this disclosure, the compound represented by general formula (I) or (II) or a pharmaceutically acceptable salt thereof, wherein R 15 It is a hydrogen atom or a halogen; in some implementations, R 15 It is a hydrogen atom.

[0081] In some embodiments of this disclosure, the compound represented by general formula (I) or (II) or a pharmaceutically acceptable salt thereof, wherein It is a single key; in some implementations, It is a double bond.

[0082] In some embodiments of this disclosure, the compound represented by general formula (I) or (II) or a pharmaceutically acceptable salt thereof, wherein Selected from In some implementation schemes, Selected from In some implementation schemes, for In some implementation schemes, for

[0083] In some embodiments of this disclosure, the compound represented by general formula (I) or (II) or a pharmaceutically acceptable salt thereof is a compound represented by general formula (III) or a pharmaceutically acceptable salt thereof.

[0084]

[0085] in:

[0086] k can be 0, 1, 2, or 3;

[0087] m1 can be 0, 1, 2, or 3;

[0088] R 1 R 5 R 6 Ring A, R 9 and R 11 As defined in general formula (I).

[0089] In some embodiments of this disclosure, the compound represented by general formula (I), (II) or (III) or a pharmaceutically acceptable salt thereof, wherein for *End and L a Or linked by a pyrimidine ring; ring A0 is a nitrogen-containing fused heterocyclic group or a nitrogen-containing polycyclic heteroaryl group, wherein the nitrogen-containing fused heterocyclic group and the nitrogen-containing polycyclic heteroaryl group are optionally connected by one or more R 8 Replace; R 8 As defined in general formula (I).

[0090] In some embodiments of this disclosure, the compounds represented by general formulas (I), (II), or (III), or pharmaceutically acceptable salts thereof, wherein ring A is a 7- to 11-membered fused heterocyclic group or a 7- to 11-membered spiroheterocyclic group, wherein the 7- to 11-membered fused heterocyclic group and the 7- to 11-membered spiroheterocyclic group are each independently and optionally independently constituting one or more R 8 Replace; R 8 As defined in general formula (I);

[0091] In some embodiments, ring A is a 7- to 11-membered bicyclic fused heterocyclic group or a 7- to 11-membered monospirocyclic heterocyclic group, wherein the 7- to 11-membered bicyclic fused heterocyclic group and the 7- to 11-membered monospirocyclic heterocyclic group are each independently and optionally converted by one or more R 8 Replace; R 8 As defined in general formula (I);

[0092] In some implementations, ring A is optionally controlled by one or more R... 8 Substituted 7- to 11-membered fused heterocyclic groups; R 8 As defined in general formula (I);

[0093] In some implementations, ring A is optionally controlled by one or more R... 8 Substituted 7- to 11-membered bicyclic fused heterocyclic groups; R 8 As defined in general formula (I);

[0094] In some implementations, ring A is optionally controlled by one or more R... 8 Substituted 9-membered bicyclic fused heterocyclic group; R 8 As defined in general formula (I);

[0095] In some implementations, ring A is optionally controlled by one or more R... 8 Replaced 7- to 11-membered bicyclic fused heterocyclic groups; each R 8 They may be the same or different, and each is independently selected from oxo groups, halogens, and C. 1-6 Alkyl and C 1-6 Halogenated alkyl groups;

[0096] In some embodiments, ring A is a 4- to 7-membered heterocyclic group fused with a 5- or 6-membered heterocyclic group; the 4- to 7-membered heterocyclic group fused with the 5- or 6-membered heterocyclic group is optionally surrounded by one or more R groups. 8 Replace; R 8 As defined in general formula (I);

[0097] In some embodiments, ring A is a 5-membered heterocyclic fused to a 6-membered heterocyclic group; the 5-membered heterocyclic fused to a 6-membered heterocyclic group is optionally coupled to one or more R groups. 8 Replace; R 8 As defined in general formula (I);

[0098] In some embodiments, ring A is a 5- or 6-membered heteroaryl-fused 5- or 6-membered heterocyclic group, wherein the 5- or 6-membered heteroaryl-fused 5- or 6-membered heterocyclic group is optionally surrounded by one or more R 8 Replace; R 8 As defined in general formula (I);

[0099] In some embodiments, ring A is a 5-membered heteroaryl-fused 6-membered heterocyclic group, wherein the 5-membered heteroaryl-fused 6-membered heterocyclic group is optionally surrounded by one or more R 8 Replace; R 8 As defined in general formula (I);

[0100] In some implementations, ring A is Ring A1 is a 4- to 7-membered heterocyclic group or a 5- or 6-membered heteroaryl group; the 4- to 7-membered heterocyclic group and the 5- or 6-membered heteroaryl group are each independently and optionally converted by one or more R groups. 8 Replace; R 8 As defined in general formula (I); *end and L a Or linked by a pyrimidine ring;

[0101] In some implementations, ring A is selected from... *End and L a Or linked by a pyrimidine ring.

[0102] In some embodiments of this disclosure, ring A1 is a 5-membered heterocyclic group or a 5-membered heteroaryl group; the 5-membered heterocyclic group and the 5-membered heteroaryl group are each independently and optionally converted by one or more R groups. 8 Replace; R 8 As defined in general formula (I); in some implementations, ring A1 is optionally bounded by one or more R 8 Substituted 5-membered heterocyclic group; R 8 As defined in general formula (I); in some implementations, ring A1 is optionally bounded by one or more R 8 Substituted 5-membered heteroaryl; R 8 As defined in general formula (I); in some embodiments, ring A1 is 3-oxohexahydroimidazolyl; in some embodiments, ring A1 is selected from pyrazolyl, triazolyl, imidazolyl and pyrroleyl.

[0103] In some embodiments of this disclosure, the compound represented by general formula (I), (II), or (III) or a pharmaceutically acceptable salt thereof, wherein ring A is optionally surrounded by one or more R 8 Replaced 7- to 11-membered monospirocyclic heterocyclic groups; R 8 As defined in general formula (I); in some implementations, ring A is X 1 For N or CR X1 ;X 2 For N or CR X2 ;R X1 and R X2 They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl, C 1-6 Halogenated alkyl groups and C 1-6 Hydroxyalkyl; n1, n2, n3, and n4 may be the same or different, and each is independently 0, 1, 2, or 3; *terminus with L a Or linked by a pyrimidine ring; in some embodiments, ring A is *End and L a Or linked by a pyrimidine ring.

[0104] In some embodiments disclosed herein, X 1 For N or CH; in some implementations, X 1 For N; in some implementations, X 1 For CH.

[0105] In some embodiments disclosed herein, X 2 For N or CH; in some implementations, X 2 For N; in some implementations, X 2 For CH.

[0106] In some embodiments disclosed herein, X 1For N; X 2 For N; in some implementations, X 1 For N; X 2 For CH; in some implementations, X 1 For CH; X 2 Let N be the number of elements in the array.

[0107] In some embodiments disclosed herein, R X1 and R X2 It is a hydrogen atom.

[0108] In some embodiments of this disclosure, n1, n2, n3, and n4 may be the same or different, and each is independently 0, 1, or 2; in other embodiments, n1, n2, n3, and n4 may be the same or different, and each is independently 0 or 1.

[0109] In some embodiments of this disclosure, the compounds represented by general formulas (I), (II), or (III) or their pharmaceutically acceptable salts, wherein each R 8 They may be the same or different, and each is independently selected from oxo groups, halogens, and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, cyano, and hydroxyl groups; in some embodiments, each R 8 They may be the same or different, and each is independently selected from oxo groups, halogens, and C. 1-6 Alkyl and C 1-6 Halogenated alkyl; in some embodiments, R 8 For oxygen groups; in some embodiments, each R 8 They may be the same or different, and each is independently selected from halogens, C 1-6 Alkyl and C 1-6 Halogenated alkyl groups.

[0110] In some embodiments of this disclosure, the compound represented by general formula (I), (II) or (III) or a pharmaceutically acceptable salt thereof, wherein R 1 Selected from hydrogen atoms, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy C 1-6 Alkyl, -C 1-6 Alkylene-NHC 1-6 Alkyl, 3- to 6-membered cycloalkyl C 1-6 Alkyl groups and 3 to 6-membered heterocyclic C groups 1-6 Alkyl; in some embodiments, R 1 It is a hydrogen atom or a carbon atom. 1-6Alkyl; in some embodiments, R 1 C 1-6 Alkyl; in some embodiments, R 1 It is an ethyl group.

[0111] In some embodiments of this disclosure, the compounds represented by general formulas (I), (II), or (III) or their pharmaceutically acceptable salts, wherein each R 5 They may be the same or different, and each is independently selected from halogens, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy and C 1-6 Halogenated alkoxy groups; in some embodiments, each R 5 They may be the same or different, and each is independently selected from halogens, C 1-6 Alkyl and C 1-6 Halogenated alkyl groups; in some embodiments, each R 5 They may be the same or different, and each is independently a halogen; in some implementations, R 5 It is F.

[0112] In some embodiments of this disclosure, the compound represented by general formula (I) or (II) or a pharmaceutically acceptable salt thereof is used, wherein m is 0 or 1; in some embodiments, m is 0.

[0113] In some embodiments of this disclosure, the compound represented by general formula (I), (II) or (III) or a pharmaceutically acceptable salt thereof, wherein m1 is 0 or 1; in some embodiments, m1 is 0.

[0114] In some embodiments of this disclosure, the compound represented by general formula (I), (II) or (III) or a pharmaceutically acceptable salt thereof, wherein R 6 Selected from hydrogen atom, halogen, cyano group, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy and C 1-6 Haloalkoxy; in some embodiments, R 6 It is halogen or cyano; in some embodiments, R 6 For halogen; in some implementations, R 6 It is Cl.

[0115] In some embodiments of this disclosure, the compounds represented by general formulas (I), (II), or (III) or their pharmaceutically acceptable salts, wherein each R 9 They may be the same or different, and each is independently selected from halogens, C 1-6 Alkyl, C1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy and C 1-6 Halogenated alkoxy groups; in some embodiments, each R 9 They may be the same or different, and each is independently a halogen; in some implementations, R 9 It is F.

[0116] In some embodiments of this disclosure, the compound represented by general formula (I), (II) or (III) or its pharmaceutically acceptable salt is used, wherein k is 0 or 1; in some embodiments, k is 0; in some embodiments, k is 1.

[0117] In some embodiments of this disclosure, the compound represented by general formula (I), (II) or (III) or a pharmaceutically acceptable salt thereof, wherein R 11 Selected from hydrogen atoms, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups and C 1-6 Hydroxyalkyl; in some embodiments, R 11 C 1-6 Alkyl; in some embodiments, R 11 It is a methyl group.

[0118] In some embodiments of this disclosure, the compound represented by general formula (III) or a pharmaceutically acceptable salt thereof, wherein for In some implementation schemes, for In some implementation schemes, for

[0119] In some embodiments of this disclosure, the compound represented by general formula (I), (II) or (III) or a pharmaceutically acceptable salt thereof, wherein R 16 It is a hydrogen atom or a carbon atom. 1-6 Alkyl; in some embodiments, R 16 C 1-6 alkyl.

[0120] In some embodiments of this disclosure, the compound represented by general formula (I), (II) or (III) or a pharmaceutically acceptable salt thereof, wherein R 17 and R 18 They may be the same or different, and each is independently a hydrogen atom or a carbon atom. 1-6 alkyl.

[0121] In some embodiments of this disclosure, the compound represented by general formula (I), (II) or (III) or a pharmaceutically acceptable salt thereof, wherein R 19 It is a hydrogen atom.

[0122] In some embodiments of this disclosure, the compound represented by general formula (I), (II) or (III) or a pharmaceutically acceptable salt thereof, wherein R 20 Selected from hydrogen atoms, C 1-6 Alkyl, C 1-6 Alkyl and hydroxyl groups.

[0123] In some embodiments of this disclosure, the compound represented by general formula (I), (II) or (III) or a pharmaceutically acceptable salt thereof, wherein R 21 and R 22 They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl; in some embodiments, R 21 and R 22 They may be the same or different, and each is independently a hydrogen atom or a halogen.

[0124] In some embodiments of this disclosure, the compound represented by general formula (I), (II) or (III) or a pharmaceutically acceptable salt thereof is used, wherein v is 0; in some embodiments, v is 1; and in some embodiments, v is 2.

[0125] In some embodiments of this disclosure, the compound represented by general formula (II) or a pharmaceutically acceptable salt thereof, wherein R 1 C 1-6 Alkyl; R 2 and R 3 They may be the same or different, and each is independently a hydrogen atom or a halogen; R 5 It is a halogen; m is 0 or 1; Z 4 For CH or N; R a It is a hydrogen atom or a carbon atom. 1-6 Alkyl; R 6 It is a halogen or cyano group; R 7 Selected from hydrogen atoms, halogens and C 1-6 Alkyl; cycloA is optionally surrounded by one or more R 8 Replaced 7- to 11-membered bicyclic fused heterocyclic groups; each R 8 They may be the same or different, and each is independently selected from oxo groups, halogens, and C. 1-6 Alkyl and C 1-6 Halogenated alkyl; Q 1 Q 3 and Q 4 For CH; R 11 C 1-6 Alkyl; X is N or CH; It is a single bond; R 14 For hydrogen atoms; R 15 It is a hydrogen atom.

[0126] In some embodiments of this disclosure, the compound represented by general formula (III) or a pharmaceutically acceptable salt thereof, wherein R 1 C 1-6 Alkyl; R 5 It is a halogen; m1 is 0 or 1; R 6 It is a halogen; ring A is optionally surrounded by one or more R 8 Replaced 7- to 11-membered bicyclic fused heterocyclic groups; each R 8 They may be the same or different, and each is independently selected from oxo groups, halogens, and C. 1-6 Alkyl and C 1-6 Halogenated alkyl; R 9 Halogen; k is 0 or 1; R 11 C 1-6 alkyl.

[0127] In some embodiments of this disclosure, the compound represented by general formula (III) or a pharmaceutically acceptable salt thereof, wherein R 1 C 1-6 Alkyl; R 5 It is a halogen; m1 is 0 or 1; R 6 It is a halogen; ring A is *The end is connected to a pyrimidine ring; ring A1 is a 5-membered heterocyclic group or a 5-membered heteroaryl group, each of which is independently and optionally converted by one or more R... 8 Replace; each R 8 They may be the same or different, and each is independently selected from oxo groups, halogens, and C. 1-6 Alkyl and C 1-6 Halogenated alkyl; R 9 Halogen; k is 0 or 1; R 11 C 1-6 alkyl.

[0128] In some embodiments of this disclosure, the compound represented by general formula (III) or a pharmaceutically acceptable salt thereof, wherein R 1 C 1-6 Alkyl; R 5 It is a halogen; m1 is 0 or 1; R 6 It is a halogen; ring A is selected from... *The end is connected to the pyrimidine ring; R 9 Halogen; k is 0 or 1; R 11 C 1-6 alkyl.

[0129] In some embodiments of this disclosure, the compound represented by general formula (III) or a pharmaceutically acceptable salt thereof, wherein R 1 C 1-6 Alkyl; m1 is 0; R 6 It is a halogen; ring A is selected from... *The end is connected to the pyrimidine ring; k is 0; R 11 C 1-6 alkyl.

[0130] Table A lists typical compounds disclosed herein, including but not limited to:

[0131]

[0132]

[0133] Furthermore, this disclosure provides a compound of general formula (IIA) or a salt thereof:

[0134]

[0135] in:

[0136] Ring A0 is a nitrogen-containing fused heterocyclic group or a nitrogen-containing polycyclic heteroaryl group, wherein the nitrogen-containing fused heterocyclic group and the nitrogen-containing polycyclic heteroaryl group are optionally converted by one or more R groups. 8 replace;

[0137] R 8 Q 1 Q 3 Q 4 R 11 X, R 14 R 15 and As defined in general formula (II).

[0138] This disclosure provides a compound of general formula (IIIA) or a salt thereof:

[0139]

[0140] in:

[0141] Ring A0 is a nitrogen-containing fused heterocyclic group or a nitrogen-containing polycyclic heteroaryl group, wherein each nitrogen-containing fused heterocyclic group and nitrogen-containing polycyclic heteroaryl group is independently and optionally converted by one or more R groups. 8 replace;

[0142] R 8 R 9 R 11 And k is as defined in general formula (III).

[0143] Table B lists typical intermediate compounds disclosed herein, including but not limited to:

[0144]

[0145]

[0146] Another aspect of this disclosure relates to a method for preparing a compound of general formula (II) or a pharmaceutically acceptable salt thereof, comprising:

[0147]

[0148] The compound of general formula (IIA) or its salt undergoes a nucleophilic substitution reaction with the compound of general formula (IIB) or its salt to give the compound of general formula (II) or its pharmaceutically usable salt.

[0149] in:

[0150] In general formula (II) for

[0151] Ring A0 is a nitrogen-containing polycyclic heterocyclic group or a nitrogen-containing polycyclic heteroaryl group, wherein the nitrogen-containing polycyclic heterocyclic group and the nitrogen-containing polycyclic heteroaryl group are each independently and optionally converted by one or more R groups. 8 Substitution; and the * end is connected to the pyrimidine ring;

[0152] R LP For leaving groups; in some embodiments, R LP For halogen; in some implementations, R LP For F;

[0153] R 1 To R 3 Z 4 R 5 m, R a R 6 R 7 R 8 Q 1 Q 3 Q 4 R 11 X, R 14 R 15 and As defined in general formula (II).

[0154] Another aspect of this disclosure relates to a method for preparing a compound of general formula (III) or a pharmaceutically acceptable salt thereof, comprising:

[0155]

[0156] The compound of general formula (IIIA) or its salt undergoes a nucleophilic substitution reaction with the compound of general formula (IIIB) or its salt to give the compound of general formula (III) or its pharmaceutically usable salt.

[0157] in:

[0158] In general formula (III) for

[0159] Ring A0 is a nitrogen-containing polycyclic heterocyclic group or a nitrogen-containing polycyclic heteroaryl group, wherein the nitrogen-containing polycyclic heterocyclic group and the nitrogen-containing polycyclic heteroaryl group are each independently and optionally converted by one or more R groups. 8 Substitution; and the * end is connected to the pyrimidine ring;

[0160] R LP For leaving groups; in some embodiments, R LP For halogen; in some implementations, R LP For F;

[0161] R 1 R 5 m1, R 6 R 8 R 9 , k and R 11 As defined in general formula (III).

[0162] In some embodiments of this disclosure, ring A0 is a nitrogen-containing 7- to 11-membered fused heterocyclic group or a nitrogen-containing 7- to 11-membered spiroheterocyclic group, wherein the nitrogen-containing 7- to 11-membered fused heterocyclic group and the nitrogen-containing 7- to 11-membered spiroheterocyclic group are each independently and optionally independently substituted by one or more R 8 Replace; R 8 As defined in general formula (I);

[0163] In some embodiments, ring A0 is a nitrogen-containing 7- to 11-membered bicyclic fused heterocyclic group or a nitrogen-containing 7- to 11-membered monospirocyclic heterocyclic group, wherein the nitrogen-containing 7- to 11-membered bicyclic fused heterocyclic group and the nitrogen-containing 7- to 11-membered monospirocyclic heterocyclic group are each independently and optionally converted by one or more R 8 Replace; R 8 As defined in general formula (I);

[0164] In some implementations, ring A0 is optionally controlled by one or more R... 8 Substituted nitrogen-containing 7- to 11-membered fused heterocyclic groups; R 8 As defined in general formula (I);

[0165] In some implementations, ring A0 is optionally controlled by one or more R... 8 Substituted nitrogen-containing 7- to 11-membered bicyclic fused heterocyclic groups; R 8 As defined in general formula (I);

[0166] In some implementations, ring A0 is optionally controlled by one or more R... 8 Substituted nitrogen-containing 9-membered bicyclic fused heterocyclic group; R 8 As defined in general formula (I);

[0167] In some implementations, ring A0 is optionally controlled by one or more R...8 Substituted nitrogen-containing 7- to 11-membered bicyclic fused heterocyclic groups; each R 8 They may be the same or different, and each is independently selected from oxo groups, halogens, and C. 1-6 Alkyl and C 1-6 Halogenated alkyl groups;

[0168] In some embodiments, ring A0 is a 4- to 7-membered heterocyclic group fused with a nitrogen-containing 5- or 6-membered heterocyclic group; the 4- to 7-membered heterocyclic group fused with the nitrogen-containing 5- or 6-membered heterocyclic group is optionally surrounded by one or more R groups. 8 Replace; R 8 As defined in general formula (I);

[0169] In some embodiments, ring A0 is a 5-membered heterocyclic group fused with a nitrogen-containing 6-membered heterocyclic group; the 5-membered heterocyclic group fused with the nitrogen-containing 6-membered heterocyclic group is optionally coupled with one or more R... 8 Replace; R 8 As defined in general formula (I);

[0170] In some embodiments, ring A0 is a 5- or 6-membered heteroaryl fused nitrogen-containing 5- or 6-membered heterocyclic group, wherein the 5- or 6-membered heteroaryl fused nitrogen-containing 5- or 6-membered heterocyclic group is optionally surrounded by one or more R 8 Replace; R 8 As defined in general formula (I);

[0171] In some embodiments, ring A0 is a 5-membered heteroaryl fused with a nitrogen-containing 6-membered heterocyclic group, wherein the 5-membered heteroaryl fused with the 6-membered heterocyclic group is optionally surrounded by one or more R 8 Replace; R 8 As defined in general formula (I);

[0172] In some implementations, ring A0 is Ring A1 is a 4- to 7-membered heterocyclic group or a 5- or 6-membered heteroaryl group; the 4- to 7-membered heterocyclic group and the 5- or 6-membered heteroaryl group are each independently and optionally converted by one or more R groups. 8 Replace; R 8 As defined in general formula (I); *end and L a Or linked by a pyrimidine ring;

[0173] In some implementations, ring A0 is selected from... *End L a Or it may be linked to a pyrimidine ring;

[0174] In some implementations, ring A0 is optionally controlled by one or more R... 8 Substituted nitrogen-containing 7- to 11-membered monospirocyclic heterocyclic groups; R 8 As defined in general formula (I);

[0175] In some implementations, ring A0 is X 1 For N or CR X1 ;X 2 For N; R X1 Selected from hydrogen atoms, halogens, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups and C 1-6 Hydroxyalkyl; n1, n2, n3, and n4 may be the same or different, and each is independently 0, 1, 2, or 3; *terminus with L a Or linked by a pyrimidine ring;

[0176] In some implementations, ring A0 is *End and L a Or linked by a pyrimidine ring.

[0177] Another aspect of this disclosure relates to a pharmaceutical composition comprising a compound of formula (I), formula (II), formula (III) or Table A of this disclosure or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients.

[0178] This disclosure further relates to the use of compounds of general formula (I), general formula (II), general formula (III) or Table A, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising them, in the preparation of medicaments for inhibiting or degrading BCL6.

[0179] This disclosure further relates to the use of compounds of general formula (I), general formula (II), general formula (III) or Table A, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising them, in the preparation of a medicament for regulating the ubiquitination and degradation of BCL6 protein in a subject.

[0180] This disclosure further relates to the use of compounds of the above general formula (I), general formula (II), general formula (III) or Table A, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising them, in the preparation of medicaments for the treatment and / or prevention of diseases or conditions mediated or dependent on BCL6.

[0181] This disclosure further relates to the use of compounds of general formula (I), general formula (II), general formula (III) or Table A, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising them, in the preparation of medicaments for the treatment and / or prevention of tumors or autoimmune diseases.

[0182] This disclosure also relates to a method for regulating the ubiquitination and degradation of BCL6 protein in a subject, comprising administering to a desired patient a compound of the above general formula (I), general formula (II), general formula (III) or Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the above.

[0183] This disclosure also relates to a method for inhibiting or degrading BCL6 in a subject, comprising administering to a desired patient a compound of the above general formula (I), general formula (II), general formula (III) or Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the above.

[0184] This disclosure also relates to a method of treating and / or preventing diseases or conditions mediated or dependent on BCL6, comprising administering to a desired patient a compound of the above general formula (I), general formula (II), general formula (III) or Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the above.

[0185] This disclosure also relates to a method of treating and / or preventing tumors or autoimmune diseases, comprising administering to a desired patient a compound of the above general formula (I), general formula (II), general formula (III) or Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the above.

[0186] This disclosure further relates to a compound of the above general formula (I), general formula (II), general formula (III) or Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the above, which is used as a medicine.

[0187] This disclosure further relates to a compound of the above general formula (I), general formula (II), general formula (III) or Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the above, which is used as a drug for regulating the ubiquitination and degradation of BCL6 protein in a subject.

[0188] This disclosure further relates to a compound of the above general formula (I), general formula (II), general formula (III) or Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the above, which is used as a medicine for treating and / or preventing diseases or conditions mediated or dependent on BCL6.

[0189] This disclosure further relates to compounds of the above general formula (I), general formula (II), general formula (III) or Table A, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising thereof, for regulating BCL6 protein ubiquitination and degradation in a subject.

[0190] This disclosure further relates to compounds of the above general formula (I), general formula (II), general formula (III) or Table A, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising thereof, for use in inhibiting or degrading BCL6 in a subject.

[0191] This disclosure further relates to compounds of the above general formula (I), general formula (II), general formula (III) or Table A, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising thereof, for the treatment and / or prevention of diseases or conditions mediated or dependent on BCL6.

[0192] This disclosure further relates to compounds of the above general formula (I), general formula (II), general formula (III) or Table A, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising them, for the treatment and / or prevention of tumors or autoimmune diseases.

[0193] In some embodiments, the diseases or conditions mediated or dependent on BCL6 described in this disclosure are tumors or autoimmune diseases; in some embodiments, the diseases or conditions mediated or dependent on BCL6 described in this disclosure are tumors; in some embodiments, the diseases or conditions mediated or dependent on BCL6 described in the disclosure are selected from lymphoma, leukemia, breast cancer, and lung cancer; in some embodiments, the diseases or conditions mediated or dependent on BCL6 described in the disclosure are lymphoma or leukemia; in some embodiments, the diseases or conditions mediated or dependent on BCL6 described in the disclosure are lymphoma.

[0194] In some embodiments, the tumors described in this disclosure are selected from lymphoma, leukemia, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, hepatocellular carcinoma, renal cell carcinoma, bladder cancer, colorectal cancer, breast cancer, cervical cancer, colon cancer, esophageal cancer, kidney cancer, liver cancer, lung cancer, head and neck cancer, ovarian cancer, pancreatic cancer, prostate cancer, gastric cancer, melanoma, sarcoma, Ewing sarcoma, angiosarcoma, Kaposi's sarcoma, liposarcoma, sarcoma, and peripheral neuroepithelial tumor. Neuroepithelial tumor, synovial sarcoma, glioma, astrocytoma, glioblastoma, neuroblastoma, ganglioglioma, medulloblastoma, pineal cell carcinoma, meningioma, meningeal sarcoma, neurofibroma and schwannoma, prostate cancer, endometrial cancer, testicular cancer, thyroid cancer, astrocytoma, carcinosarcoma, Hodgkin's disease, nephroblastoma and teratoma; in some embodiments, the tumors described in this disclosure are selected from leukemia, lymphoma, breast cancer and lung cancer; in some embodiments, the tumors described in this disclosure are leukemia or lymphoma; in some embodiments, the tumors described in this disclosure are lymphoma.

[0195] In some embodiments, the autoimmune diseases described in this disclosure are selected from systemic lupus erythematosus (SLE), ankylosing spondylitis, Chagas disease, chronic obstructive pulmonary disease, dermatomyositis, type 1 diabetes mellitus, endometriosis, Goodpasture's syndrome, Graves' disease, Guillain-Barré syndrome (GBS), Hashimoto's disease, hidradenitis suppurativa, and Kawasaki disease. Diseases, IgA nephropathy, idiopathic thrombocytopenic purpura, interstitial cystitis (IC), mixed connective tissue disease (MCTD), morphine scleroderma, multiple sclerosis, chronic spontaneous urticaria (CSU), neuromuscular rigidity, psoriasis, psoriatic arthritis, psoriasis, polymyositis, primary biliary cirrhosis, relapsing polychondritis, rheumatoid arthritis, sarcoidosis, scleroderma, Sjögren's syndrome, stiffness syndrome, ulcerative colitis, vasculitis, vitiligo, and Wegener's granulomatosis. Atosis), atopic dermatitis, asthma, insulin-dependent diabetes mellitus, Hashimoto's thyroiditis, pernicious anemia, myasthenia gravis, pemphigus vulgaris, and Crohn's disease; in some embodiments, the autoimmune diseases described in this disclosure are selected from systemic lupus erythematosus (SLE), rheumatoid arthritis, scleroderma, and Guillain-Barré syndrome (GBS); in some embodiments, the autoimmune diseases described in this disclosure are selected from atopic dermatitis, asthma, insulin-dependent diabetes mellitus, Hashimoto's thyroiditis, pernicious anemia, myasthenia gravis, pemphigus vulgaris, and Crohn's disease.

[0196] In some implementations, the tumor described in this disclosure is cancer.

[0197] In some embodiments, the tumors described in this disclosure are hematologic malignancies.

[0198] In some implementations, the lung cancer described in this disclosure is non-small cell lung cancer (NSCLC).

[0199] In some embodiments, the lymphoma described in this disclosure is selected from non-Hodgkin lymphoma (NHL), diffuse large B-cell lymphoma (DIBCLs), Burkitt lymphoma, T-cell lymphoblastic lymphoma (T-LL), peripheral T-cell lymphoma, lymphoblastic lymphoma, Pre-B lymphoma, B-cell lymphoma, B-cell ALL, follicular lymphoma, marginal zone lymphoma (MZL), mantle cell lymphoma (MCL), small lymphocytic lymphoma (SLL), intravascular large B-cell lymphoma, and Waldenström macroglobulinemia (WM); in some embodiments, the lymphoma described in this disclosure is B-cell lymphoma; in some embodiments, the lymphoma described in this disclosure is diffuse large B-cell lymphoma; in some embodiments, the lymphoma described in this disclosure is non-Hodgkin lymphoma (NHL); in some embodiments, the lymphoma described in this disclosure is relapsed / refractory non-Hodgkin lymphoma.

[0200] In some embodiments, the leukemia described in this disclosure is selected from T-cell acute lymphoblastic leukemia (T-ALL), adult T-cell leukemia, precursor B-cell acute lymphoblastic leukemia (Pre-B ALL), B-cell acute lymphoblastic leukemia, chronic myeloid leukemia, chronic lymphocytic leukemia (CLL), B-cell leukemia, and chronic myeloid leukemia.

[0201] The active compound can be formulated into a form suitable for administration via any appropriate route, preferably in a unit dose manner or in a manner that allows the patient to self-administer a single dose. The unit dose of the disclosed compound or composition can be expressed as a tablet, capsule, sachet, bottled liquid, powder, granule, lozenge, suppository, regenerated powder, or liquid formulation.

[0202] As a general guideline, a suitable unit dose can be 0.1–1000 mg.

[0203] In addition to the active compound, the pharmaceutical compositions disclosed herein may contain one or more excipients selected from the following: fillers (diluents), binders, wetting agents, disintegrants, or excipients. Depending on the method of administration, the composition may contain 0.1 to 99% by weight of the active compound.

[0204] As a general guideline, the active compounds disclosed herein are preferably expressed in unit dose form, or in a manner that allows patients to self-administer a single dose. The unit dose of the disclosed compounds or compositions may be expressed as tablets, capsules, sachets, bottled liquids, powders, granules, lozenges, suppositories, regenerated powders, or liquid formulations. Suitable unit doses may range from 0.1 to 1000 mg.

[0205] In addition to the active compound, the pharmaceutical compositions disclosed herein may contain one or more excipients selected from the following: fillers (diluents), binders, wetting agents, disintegrants, or excipients. Depending on the method of administration, the composition may contain 0.1 to 99% by weight of the active compound.

[0206] In some embodiments, the unit dose of the pharmaceutical composition is 0.001 mg to 1000 mg.

[0207] In some embodiments, the pharmaceutical composition contains 0.01-99.99% of the aforementioned compound or its pharmaceutically acceptable salt or isotopic substitution, based on the total weight of the composition. 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.

[0208] 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.

[0209] The pharmaceutically acceptable salts of the compounds described in this disclosure may be selected from inorganic or organic salts.

[0210] Pharmaceutical compositions containing active ingredients may be in forms suitable for oral administration, such as tablets, sugar lozenges, tablets, aqueous or oil suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs. Oral compositions may be prepared according to any method known in the art for preparing pharmaceutical compositions, and such compositions may contain one or more ingredients selected from sweeteners, flavoring agents, coloring agents, and preservatives to provide an appealing and palatable pharmaceutical formulation.

[0211] Tablets contain an active ingredient and non-toxic, pharmaceutically acceptable excipients suitable for tablet preparation, used for mixing. These excipients may be inert excipients, granulating agents, disintegrants, binders, and lubricants. These tablets may be uncoated or coated using known techniques that mask the taste of the drug or delay disintegration and absorption in the gastrointestinal tract, thus providing sustained release over a longer period.

[0212] Oral formulations can also be provided using soft gelatin capsules in which the active ingredient is mixed with an inert solid diluent or in which the active ingredient is mixed with a water-soluble carrier or an oil solvent.

[0213] Aqueous suspensions contain active substances and excipients suitable for preparing aqueous suspensions for mixing. These excipients are suspending agents, dispersing agents, or wetting agents. Aqueous suspensions may also contain one or more preservatives, one or more coloring agents, one or more flavoring agents, and one or more sweeteners.

[0214] Oil suspensions are formulated by suspending the active ingredient in vegetable or mineral oil. Oil suspensions may contain thickeners. Sweeteners and flavoring agents mentioned above may be added to provide palatable formulations. These compositions may be preserved by adding antioxidants.

[0215] The pharmaceutical compositions disclosed herein may also be in the form of an oil-in-water emulsion. The oil phase may be vegetable oil, mineral oil, or a mixture thereof. Suitable emulsifiers may be naturally occurring phospholipids, and the emulsion may also contain sweeteners, flavoring agents, preservatives, and antioxidants. Such formulations may also contain modifiers, preservatives, colorants, and antioxidants.

[0216] The pharmaceutical compositions disclosed herein may be in the form of sterile injectable aqueous solutions. Acceptable solvents or media that can be used include water, Ringer's solution, and isotonic sodium chloride solution. The sterile injectable formulation may be a sterile injectable oil-in-water microemulsion in which the active ingredient is dissolved in the oil phase, which can be injected into the patient's bloodstream via local large-volume injection. Alternatively, the solution and microemulsion are preferably administered in a manner that maintains a constant circulating concentration of the compounds disclosed herein. To maintain such a constant concentration, a continuous intravenous delivery device may be used. An example of such a device is the Deltec CADD-PLUS™ 5400 intravenous infusion pump.

[0217] The pharmaceutical compositions disclosed herein may be in the form of sterile injectable aqueous or oil suspensions for intramuscular and subcutaneous administration. These suspensions may be formulated using suitable dispersants or wetting agents and suspending agents according to known techniques. The sterile injectable formulations may also be sterile injectable solutions or suspensions prepared in parenteral acceptable non-toxic diluents or solvents. Furthermore, sterile fixative oils can be conveniently used as solvents or suspension media. Any blended fixative oil may be used for this purpose. Additionally, fatty acids may also be used to prepare injectable formulations.

[0218] The disclosed compounds can be administered in suppository form for rectal administration. These pharmaceutical compositions can be prepared by mixing the drug with a suitable, non-irritating excipient that is solid at normal temperatures but liquid in the rectum, and thus dissolves in the rectum to release the drug.

[0219] As is well known to those skilled in the art, the dosage of a drug depends on a variety of factors, including but not limited to: the activity of the specific compound used, the patient's age, the patient's weight, the patient's health status, the patient's behavior, the patient's diet, the timing of administration, the route of administration, the rate of excretion, the combination of drugs, the severity of the disease, etc.; in addition, the optimal treatment mode, such as the treatment pattern, the daily dosage of the compound, or the type of medicinal salt can be validated based on conventional treatment protocols.

[0220] TERMS

[0221] Unless otherwise stated, the terms used in the specification and claims have the following meanings.

[0222] The term "alkyl" refers to a saturated, straight-chain or branched aliphatic hydrocarbon group having 1 to 20 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) carbon atoms (i.e., C2). 1-20 Alkyl group). The alkyl group is preferably an alkyl group having 1 to 12 carbon atoms (i.e., C12). 1-12 Alkyl groups, more preferably alkyl groups having 1 to 6 carbon atoms (i.e., C14-C6 ... 1-6Alkyl groups). 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, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2 3-Dimethylpentyl, 2,4-Dimethylpentyl, 2,2-Dimethylpentyl, 3,3-Dimethylpentyl, 2-Ethylpentyl, 3-Ethylpentyl, n-Octyl, 2,3-Dimethylhexyl, 2,4-Dimethylhexyl, 2,5-Dimethylhexyl, 2,2-Dimethylhexyl, 3,3-Dimethylhexyl, 4,4-Dimethylhexyl, 2-Ethylhexyl, 3-Ethylhexyl, 4-Ethylhexyl, 2-Methyl-2-Ethylpentyl, 2-Methyl-3-Ethylpentyl, n-Nonyl, 2-Methyl-2-Ethylhexyl, 2-Methyl-3-Ethylhexyl, 2,2-Diethylpentyl, n-Decyl, 3,3-Diethylhexyl, 2,2-Diethylhexyl, and their various branched isomers, etc. Alkyl groups can be substituted or unsubstituted. When substituted, they can be substituted at any usable connection point. The substituents are preferably selected from one or more of the following: D atom, halogen, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclic oxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0223] The term "alkylene" refers to a divalent alkyl group, wherein the alkyl group, as defined above, has 1 to 20 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) carbon atoms (i.e., C2). 1-20 Alkylenes). The alkylene group is preferably an alkylene group having 1 to 10 carbon atoms (i.e., C10). 1-10 Alkylenes, preferably alkylenes having 1 to 8 carbon atoms (i.e., C164-C ... 1-8 Alkylenes, more preferably alkylenes having 2 to 7 carbon atoms (i.e., C164-C ... 2-7 Alkylenes or alkylenes having 1, 2 or 3 carbon atoms (i.e., C14) 1-6Alkylenes. Non-limiting examples include: -CH2-, -CH(CH3)-, -C(CH3)2-, -CH2CH2-, -CH(CH2CH3)-, -CH2CH(CH3)-, -CH2C(CH3)2-, -CH2CH2CH2-, -CH2CH2CH2CH2-, etc. Alkylenes can be substituted or unsubstituted, and when substituted, they can be substituted at any usable linking point. Substituents are preferably selected from one or more of the following: D atom, halogen, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclic oxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0224] The term "alkenyl" refers to an alkyl group in which the molecule contains at least one carbon-carbon double bond, wherein the alkyl group is defined as described above and has 2 to 12 (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12) carbon atoms (i.e., C atoms). 2-12 Alkenyl). The alkenyl group is preferably an alkenyl group having 2 to 6 carbon atoms (i.e., C). 2-6 Alkenyl). Non-limiting examples include vinyl, propenyl, isopropenyl, butenyl, etc. Alkenyl groups can be substituted or unsubstituted, and when substituted, they can be substituted at any usable connection point. Substituents are preferably selected from one or more of the following: D atom, alkoxy, halogen, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclic oxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0225] The term "alkynyl" refers to an alkyl group in a molecule that contains at least one carbon-carbon triple bond, wherein the alkyl group is defined as described above and has 2 to 12 (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12) carbon atoms (i.e., C64, C74, C84, C9 ... 2-12 The alkynyl group is preferably an alkynyl group having 2 to 6 carbon atoms (i.e., C64). 2-6 (Alynyl). Non-limiting examples include: ethynyl, propynyl, butynyl, pentyynyl, hexynyl, etc. The alkynyl group can be substituted or unsubstituted, and when substituted, it can be substituted at any usable linker. The substituent is preferably selected from one or more of the following: D atom, alkoxy, halogen, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclic oxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0226] The term "alkoxy" refers to -O-(alkyl), where alkyl is defined as described above. Non-limiting examples include methoxy, ethoxy, propoxy, and butoxy, etc. Alkoxy groups can be substituted or unsubstituted, and when substituted, they can be substituted at any usable linker. The substituent is preferably selected from one or more of the following: D atom, halogen, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclic oxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0227] The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic carbocyclic ring (i.e., monocyclic cycloalkyl) or polycyclic system (i.e., polycyclic cycloalkyl) having 3 to 20 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) ring atoms (i.e., 3 to 20 membered cycloalkyl). The cycloalkyl is preferably a cycloalkyl having 3 to 12 ring atoms (i.e., 3 to 12 membered cycloalkyl) or a cycloalkyl having 4 to 11 ring atoms (i.e., 4 to 11 membered cycloalkyl), more preferably a cycloalkyl having 3 to 8 ring atoms (i.e., 3 to 8 membered cycloalkyl), and most preferably a cycloalkyl having 3 to 6 ring atoms (i.e., 3 to 6 membered cycloalkyl).

[0228] Non-limiting examples of the monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cyclohepttrienyl, and cyclooctyl.

[0229] The polycyclic alkyl groups include: spirocyclic alkyl groups, fused cyclic alkyl groups, and bridged cyclic alkyl groups.

[0230] The term "spirocycloalkyl" refers to a polycyclic system in which rings share a single carbon atom (called a spiro atom), and the ring may contain one or more double bonds, or one or more heteroatoms selected from nitrogen, oxygen, and sulfur (the nitrogen may optionally be oxidized to form nitrogen oxides; the sulfur may optionally be oxidized to form sulfoxides or sulfones, but excluding -OO-, -OS-, or -SS-), provided that it contains at least one full carbon ring with a bonding point on that full carbon ring, having 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) ring atoms (i.e., 5 to 20-membered spirocycloalkyl). The spirocycloalkyl is preferably a spirocycloalkyl having 6 to 14 ring atoms (i.e., 6 to 14-membered spirocycloalkyl), more preferably a spirocycloalkyl having 7 to 10 ring atoms (i.e., 7 to 10-membered spirocycloalkyl). The spirocyclic alkyl group includes monospirocyclic alkyl and polyspirocyclic alkyl (such as bispirocyclic alkyl, etc.), preferably monospirocyclic alkyl or bispirocyclic alkyl, more preferably 3 / 4, 3 / 5, 3 / 6, 4 / 4, 4 / 5, 4 / 6, 5 / 3, 5 / 4, 5 / 5, 5 / 6, 5 / 7, 6 / 3, 6 / 4, 6 / 5, 6 / 6, 6 / 7, 7 / 5 or 7 / 6 monospirocyclic alkyl. Non-limiting examples include:

[0231] Its connection point can be anywhere;

[0232] wait.

[0233] The term "fused cycloalkyl" refers to a polycyclic system in which two adjacent carbon atoms are shared between rings. This system is a monocyclic cycloalkyl group fused with one or more monocyclic cycloalkyl groups, or a monocyclic cycloalkyl group fused with one or more heterocyclic, aryl, or heteroaryl groups, wherein the bonding point is on the monocyclic cycloalkyl group. The ring may contain one or more double bonds and has 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) ring atoms (i.e., 5 to 20-membered fused cycloalkyl groups). The fused cycloalkyl group is preferably a fused cycloalkyl group having 6 to 14 ring atoms (i.e., 6 to 14-membered fused cycloalkyl groups), and more preferably a fused cycloalkyl group having 7 to 10 ring atoms (i.e., 7 to 10-membered fused cycloalkyl groups). The fused cyclic alkyl group includes bicyclic fused cyclic alkyl groups and polycyclic fused cyclic alkyl groups (such as tricyclic fused cyclic alkyl groups, tetracyclic fused cyclic alkyl groups, etc.), preferably bicyclic fused cyclic alkyl groups or tricyclic fused cyclic alkyl groups, more preferably ternary / quadrivalent, ternary / pentary, ternary / hexavalent, quadrivalent / quadrivalent, quadrivalent / pentary, quadrivalent / hexavalent, pentary / pentary ... or pentary / pentary bicyclic fused cyclic alkyl groups. Non-limiting examples include: Its connection point can be anywhere; wait.

[0234] The term "bridged cycloalkyl" refers to a fully carbon polycyclic system in which two non-directly connected carbon atoms are shared between rings, and the ring may contain one or more double bonds and has 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) carbon atoms (i.e., 5 to 20-membered bridged cycloalkyl). The bridged cycloalkyl is preferably a bridged cycloalkyl having 6 to 14 carbon atoms (i.e., 6 to 14-membered bridged cycloalkyl), more preferably a bridged cycloalkyl having 7 to 10 carbon atoms (i.e., 7 to 10-membered bridged cycloalkyl). The bridged cycloalkyl includes bicyclic bridged cycloalkyl and polycyclic bridged cycloalkyl (e.g., tricyclic bridged cycloalkyl, tetracyclic bridged cycloalkyl, etc.), preferably bicyclic or tricyclic bridged cycloalkyl. Non-limiting examples include: Its connection point can be anywhere.

[0235] The cycloalkyl group can be substituted or unsubstituted. When substituted, it can be substituted at any usable connection point. The substituent is preferably selected from one or more of the following: D atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, alkylthio, haloalkylthio, cycloalkylthio, heterocyclic thio, heterocyclic oxy, hydroxy, hydroxyalkyl, oxo, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0236] The term "heterocyclic group" refers to a saturated or partially unsaturated monocyclic heterocycle (i.e., monocyclic heterocyclic group) or polycyclic heterocyclic system (i.e., polycyclic heterocyclic group) containing at least one (e.g., 1, 2, 3 or 4) heteroatoms selected from nitrogen, oxygen and sulfur (the nitrogen may optionally be oxidized, i.e., to form nitrogen oxides; the sulfur may optionally be oxidized, i.e., to form sulfoxides or sulfones, but excluding -OO-, -OS- or -SS-), and having 3 to 20 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) ring atoms (i.e., 3 to 20 membered heterocyclic groups). The heterocyclic group is preferably a heterocyclic group having 3 to 12 ring atoms (i.e., a 3 to 12-membered heterocyclic group) or a heterocyclic group having 4 to 11 ring atoms (i.e., a 4 to 11-membered heterocyclic group); more preferably a heterocyclic group having 3 to 8 ring atoms (i.e., a 3 to 8-membered heterocyclic group); more preferably a heterocyclic group having 3 to 6 ring atoms (i.e., a 3 to 6-membered heterocyclic group); and most preferably a heterocyclic group having 5 or 6 ring atoms (i.e., a 5 or 6-membered heterocyclic group).

[0237] Non-limiting examples of the monocyclic heterocyclic group include: pyrrolidinyl, tetrahydropyranyl, 1,2,3,6-tetrahydropyridyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, and homopiperazinyl, etc.

[0238] The polycyclic heterocyclic groups include spirocyclic heterocyclic groups, fused heterocyclic groups, and bridged heterocyclic groups.

[0239] The term "spiroheterocyclic group" refers to a polycyclic heterocyclic system in which rings share a single atom (called a spiro atom), which may contain one or more double bonds and at least one (e.g., 1, 2, 3, or 4) heteroatoms selected from nitrogen, oxygen, and sulfur (the nitrogen may optionally be oxidized to form nitrogen oxides; the sulfur may optionally be oxidized to form sulfoxides or sulfones, but excluding -OO-, -OS-, or -SS-), provided that at least one monocyclic heterocyclic group is present and the bonding point is on the monocyclic heterocyclic group, which has 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) ring atoms (i.e., 5 to 20-membered spiroheterocyclic groups). The spiroheterocyclic group is preferably a spiroheterocyclic group having 6 to 14 ring atoms (i.e., a 6 to 14-membered spiroheterocyclic group), more preferably a spiroheterocyclic group having 7 to 11 ring atoms (i.e., a 7 to 11-membered spiroheterocyclic group). The spiroheterocyclic group includes mono-spiroheterocyclic groups and multi-spiroheterocyclic groups (such as bi-spiroheterocyclic groups), preferably mono-spiroheterocyclic groups or bi-spiroheterocyclic groups, more preferably 3-membered / 4-membered, 3-membered / 5-membered, 3-membered / 6-membered, 4-membered / 4-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 3-membered, 5-membered / 4-membered, 5-membered / 5-membered, 5-membered / 6-membered, 5-membered / 7-membered, 6-membered / 3-membered, 6-membered / 4-membered, 6-membered / 5-membered, 6-membered / 6-membered, 6-membered / 7-membered, 7-membered / 5-membered, or 7-membered / 6-membered mono-spiroheterocyclic groups. Non-limiting examples include:

[0240]

[0241] wait.

[0242] The term "fused heterocyclic group" refers to a polycyclic heterocyclic system in which two adjacent atoms are shared between rings. The ring may contain one or more double bonds and at least one (e.g., 1, 2, 3, or 4) heteroatoms selected from nitrogen, oxygen, and sulfur (the nitrogen may optionally be oxidized to form nitrogen oxides; the sulfur may optionally be oxidized to form sulfoxides or sulfones, but excluding -OO-, -OS-, or -SS-). It is a monocyclic heterocyclic group fused with one or more monocyclic heterocyclic groups, or a monocyclic heterocyclic group fused with one or more cycloalkyl, aryl, or heteroaryl groups, wherein the bonding point is on the monocyclic heterocyclic group and has 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) ring atoms (i.e., 5 to 20 membered fused heterocyclic groups). The fused heterocyclic group is preferably a fused heterocyclic group having 6 to 14 ring atoms (i.e., a 6 to 14-membered fused heterocyclic group), more preferably a fused heterocyclic group having 7 to 11 ring atoms (i.e., a 7 to 11-membered fused heterocyclic group). The fused heterocyclic group includes bicyclic and polycyclic fused heterocyclic groups (such as tricyclic fused heterocyclic groups, tetracyclic fused heterocyclic groups, etc.), preferably bicyclic or tricyclic fused heterocyclic groups, more preferably 3-membered / 4-membered, 3-membered / 5-membered, 3-membered / 6-membered, 4-membered / 4-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 3-membered, 5-membered / 4-membered, 5-membered / 5-membered, 5-membered / 6-membered, 5-membered / 7-membered, 6-membered / 3-membered, 6-membered / 4-membered, 6-membered / 5-membered, 6-membered / 6-membered, 6-membered / 7-membered, 7-membered / 5-membered, or 7-membered / 6-membered bicyclic fused heterocyclic groups. Non-limiting examples include:

[0243] wait.

[0244] The term "bridged heterocyclic group" refers to a polycyclic heterocyclic system in which two non-directly connected atoms are shared between the rings. The rings may contain one or more double bonds, and the rings contain at least one (e.g., 1, 2, 3, or 4) heteroatoms selected from nitrogen, oxygen, and sulfur (the nitrogen may optionally be oxidized to form nitrogen oxides; the sulfur may optionally be oxidized to form sulfoxides or sulfones, but excluding -OO-, -OS-, or -SS-). The system has 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) ring atoms (i.e., a 5- to 20-membered bridged heterocyclic group). The bridged heterocyclic group is preferably a bridged heterocyclic group with 6 to 14 ring atoms (i.e., a 6- to 14-membered bridged heterocyclic group), and more preferably a bridged heterocyclic group with 7 to 10 ring atoms (i.e., a 7- to 10-membered bridged heterocyclic group). Based on the number of constituent rings, heterocyclic groups can be classified into bicyclic bridged heterocyclic groups and multicyclic bridged heterocyclic groups (such as tricyclic bridged heterocyclic groups, tetracyclic bridged heterocyclic groups, etc.), with bicyclic bridged heterocyclic groups or tricyclic bridged heterocyclic groups being preferred. Non-limiting examples include:

[0245] wait.

[0246] The heterocyclic group can be substituted or unsubstituted. When substituted, it can be substituted at any usable connection point. The substituent is preferably selected from one or more of the following: D atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclic oxy, alkylthio, haloalkylthio, cycloalkylthio, heterocyclic thio, hydroxy, hydroxyalkyl, oxo, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0247] The term "aryl" refers to a monocyclic all-carbon aromatic ring (i.e., monocyclic aryl) or a polycyclic aromatic ring system (i.e., polycyclic aryl) having a conjugated π-electron system, having 6 to 14 (e.g., 6, 7, 8, 9, 10, 11, 12, 13, or 14) ring atoms (i.e., 6 to 14-membered aryl). The aryl is preferably an aryl having 6 to 10 ring atoms (i.e., 6 to 10-membered aryl). The monocyclic aryl is, for example, phenyl. Non-limiting examples of the polycyclic aryl include naphthyl, anthraceneyl, phenanthrene, etc. The polycyclic aryl further includes fusion of the phenyl with one or more heterocyclic groups or cycloalkyl groups, or fusion of the naphthyl with one or more heterocyclic groups or cycloalkyl groups, wherein the bonding point is on the phenyl or naphthyl group, and in this case, the number of ring atoms continues to represent the number of ring atoms in the polycyclic aromatic ring system, non-limiting examples including:

[0248] wait.

[0249] The aryl group can be substituted or unsubstituted. When substituted, it can be substituted at any usable connection point. The substituent is preferably selected from one or more of the following: D atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclic oxy, hydroxyl, alkylthio, haloalkylthio, cycloalkylthio, heterocyclic thio, hydroxyalkyl, oxo, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0250] The term "heteroaryl" refers to a monocyclic heteroaryl ring (i.e., monocyclic heteroaryl) or a polycyclic heteroaryl ring system (i.e., polycyclic heteroaryl) having a conjugated π-electron system, wherein the ring contains at least one (e.g., 1, 2, 3, or 4) heteroatoms selected from nitrogen, oxygen, and sulfur (the nitrogen may optionally be oxidized, i.e., to form nitrogen oxides; the sulfur may optionally be oxidized, i.e., to form sulfoxides or sulfones, but excluding -OO-, -OS-, or -SS-), having 5 to 14 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14) ring atoms (i.e., 5 to 14-membered heteroaryl). The heteroaryl is preferably a heteroaryl having 5 to 10 ring atoms (i.e., 5 to 10-membered heteroaryl), more preferably a heteroaryl having 5 or 6 ring atoms (i.e., 5 or 6-membered heteroaryl).

[0251] Non-limiting examples of the aforementioned monocyclic heteroaryl groups include: furanyl, thiopheneyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, furazonyl, pyrroleyl, N-alkylpyrroleyl, pyridyl, pyrimidinyl, pyridoneyl, N-alkylpyridone (e.g.) (etc.), pyrazinyl, pyridazinyl, etc.

[0252] Non-limiting examples of the polycyclic heteroaryl groups include: indolyl, indazole, quinolinyl, isoquinolinyl, quinoxalinyl, phthalazinyl, benzimidazolyl, benzothiophene, quinazolinyl, benzothiazolyl, carbazole, etc. The polycyclic heteroaryl groups also include monocyclic heteroaryl groups fused with one or more aryl groups, wherein the connecting point is on the aromatic ring, and in this case, the number of ring atoms continues to represent the number of ring atoms in the polycyclic heteroaryl ring system. The polycyclic heteroaryl groups also include monocyclic heteroaryl groups fused with one or more cycloalkyl or heterocyclic groups, wherein the connecting point is on the monocyclic heteroaryl ring, and in this case, the number of ring atoms continues to represent the number of ring atoms in the polycyclic heteroaryl ring system. Non-limiting examples include:

[0253]

[0254] wait.

[0255] The heteroaryl group can be substituted or unsubstituted. When substituted, it can be substituted at any usable connection point. The substituent is preferably selected from one or more of the following: D atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclic oxy, hydroxyl, alkylthio, haloalkylthio, cycloalkylthio, heterocyclic thio, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0256] The aforementioned cycloalkyl, heterocyclic, aryl, and heteroaryl groups include residues derived from removing one hydrogen atom from a parent ring atom, or residues derived from removing two hydrogen atoms from the same ring atom or two different ring atoms of the parent ring, i.e., "cycloalkylene", "heterocyclicene", "arylene", and "heteroarylene". Non-limiting examples include: wait.

[0257] When a polycyclic system formed by the fusion of a monocyclic heterocyclic group with a cycloalkyl, aryl, or heteroaryl group is divalent, the polycyclic system is considered a "fused heterocyclic group" as long as one of the linking sites is on the monocyclic heterocyclic group; non-limiting examples include:

[0258] The term "cycloalkylalkyl" refers to an alkyl group that is substituted by one or more cycloalkyl groups, wherein the cycloalkyl and alkyl groups are as defined above.

[0259] The term "heterocyclic alkyl" refers to an alkyl group that is substituted by one or more heterocyclic groups, wherein the heterocyclic group and the alkyl group are as defined above.

[0260] The term "arylalkyl" refers to an alkyl group that is substituted with one or more aryl groups, wherein the aryl and alkyl groups are as defined above.

[0261] The term "heteroarylalkyl" refers to an alkyl group that is substituted by one or more heteroaryl groups, wherein the heteroaryl and alkyl groups are as defined above.

[0262] The term "cycloalkyloxy" refers to -O-cycloalkyl, where the cycloalkyl is as defined above.

[0263] The term "heterocyclic oxygen group" refers to an -O-heterocyclic group, wherein the heterocyclic group is as defined above.

[0264] The term "aryloxy group" refers to -O-aryl, where the aryl group is as defined above.

[0265] The term "heteroaryloxy" refers to -O-heteroaryl, where the heteroaryl is as defined above.

[0266] The term "aminoalkyl" refers to an alkyl group that is substituted with one or more amino groups, wherein the alkyl group is as defined above.

[0267] The term "alkoxyalkyl" refers to an alkyl group that is substituted with one or more alkoxy groups, wherein the alkoxy groups and alkyl groups are as defined above.

[0268] The term "halogenated alkyl" refers to an alkyl group that has been substituted with one or more halogens, wherein the alkyl group is as defined above.

[0269] The term "haloalkoxy" refers to an alkoxy group that is substituted by one or more halogens, wherein the alkoxy group is as defined above.

[0270] The term "hydroxyalkyl" refers to an alkyl group that is replaced by one or more hydroxyl groups, wherein the alkyl group is as defined above.

[0271] The term "halogen" refers to fluorine, chlorine, bromine, or iodine.

[0272] The term "hydroxyl group" refers to -OH.

[0273] The term "thiol" refers to -SH.

[0274] The term "amino" refers to -NH2.

[0275] The term "cyano" refers to -CN.

[0276] The term "nitro" refers to -NO2.

[0277] The term "oxo" or "oxo group" refers to "=O".

[0278] The term "carbonyl" refers to C=O.

[0279] The term "alkylthio" refers to -S-alkyl, where the alkyl group is as defined above.

[0280] The term "haloalkylthio" refers to an alkylthio group that is replaced by one or more halogens, wherein the alkylthio group is as defined above.

[0281] The term "cycloalkylthio" refers to -S-cycloalkyl, where the cycloalkyl group is as defined above.

[0282] The term "heterocyclic thio" refers to a -S-heterocyclic group, where the heterocyclic group is as defined above.

[0283] A "leaving group," or simply a group, is an atom or functional group that breaks off from a larger molecule in a chemical reaction. It's a term used in nucleophilic substitution and elimination reactions. In a nucleophilic substitution reaction, the reactant attacked by the nucleophile is called the substrate, and the atom or group of atoms that breaks off with a pair of electrons from the substrate molecule is called the leaving group. Groups that readily accept electrons and have a strong ability to accept negative charges are desirable leaving groups. The smaller the pKa of the conjugate acid of the leaving group, the easier it is for the leaving group to break off from other molecules. This is because a smaller pKa means the leaving group doesn't need to bond with other atoms and has a stronger tendency to exist as an anion (or an electrically neutral leaving group). Common leaving groups include, but are not limited to, halogens, -OTs, or -OH.

[0284] The compounds disclosed herein can exist in specific stereoisomer forms. The term "stereoisomer" refers to isomers with the same structure but different spatial arrangements of atoms. These include cis and trans (or Z and E) isomers, (-)- and (+)- isomers, (R)- and (S)- enantiomers, diastereomers, (D)- and (L)- isomers, tautomers, blocked isomers, conformational isomers, and mixtures thereof (such as racemic mixtures and mixtures of diastereomers). Substituents in the compounds disclosed herein may contain additional asymmetric atoms. All such stereoisomers and mixtures thereof are included within the scope of this disclosure. Optically active (-)- and (+)- isomers, (R)- and (S)- enantiomers, and (D)- and (L)- isomers can be prepared by chiral synthesis, chiral reagents, or other conventional techniques. This disclosure discloses an isomer of a compound, which can be prepared by asymmetric synthesis or with chiral auxiliaries, or, when the molecule contains a basic functional group (such as an amino group) or an acidic functional group (such as a carboxyl group), by forming a salt of the diastereomer with a suitable optically active acid or base, followed by diastereomer resolution using conventional methods known in the art to obtain the pure isomer. Furthermore, the separation of enantiomers and diastereomers is typically performed by chromatography.

[0285] 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 Or simultaneously include and Two configurations. For all carbon-carbon double bonds, even if only one configuration is named, both the Z-type and E-type are included.

[0286] The compounds disclosed herein may exist in various tautomer forms, and all such forms are included within the scope of this disclosure. The terms "tautomer" or "tautomer form" refer to a structural isomer that exists in equilibrium and readily transforms from one isomer to another. This includes all possible tautomers, i.e., existing as a single isomer or as a mixture of said tautomers in any proportion. Non-limiting examples include: keto-enols, imine-enamines, lactam-lactamimides, etc. Examples of lactam-lactamimide equilibrium are shown below:

[0287]

[0288] When referring to the pyrazolyl group, it should be understood to include any one or a mixture of two tautomers of the following two structures:

[0289]

[0290] All tautomers are within the scope of this disclosure, and the naming of compounds does not exclude any tautomers.

[0291] The compounds disclosed herein may comprise transisomers. The term "transisomer" refers to a conformational stereoisomer resulting from restricted or significantly slowed rotation around a single bond in a molecule (as a result of steric interactions with other parts of the molecule and asymmetric substituents at the ends of the single bond), whose interconversion is slow enough to allow separation and isolation under predetermined conditions. For example, some compounds of this disclosure may exist as mixtures of transisomers (e.g., equal-proportion mixtures, mixtures enriched with one transisomer, etc.) or as a purified transisomer.

[0292] The compounds disclosed herein include all suitable isotopic derivatives thereof. The term "isotopic derivative" refers to a compound in which at least one atom is replaced by an atom having the same atomic number but a different atomic mass. Examples of isotopes that may be introduced into the compounds of this disclosure include stable and radioactive isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, bromine, and iodine, for example, […]. 2 H (deuterium, D) 3H (tritium, T) 11 C 13 C 14 C 15 N、 17 O、 18 O、 32 p、 33 p、 33 S, 34 S, 35 S, 36 S, 18 F, 36 Cl、 82 Br、 123 I, 124 I, 125 I, 129 I and 131 Grade I, with deuterium as the preferred grade.

[0293] Compared to undeuterated drugs, deuterated drugs offer advantages such as reduced toxicity, increased drug stability, enhanced efficacy, and prolonged biological half-life. All isotopic variations of the compounds disclosed herein, regardless of radioactivity, are included within the scope of this disclosure. Each available hydrogen atom bonded to a carbon atom can be independently replaced by a deuterium atom, wherein the deuterium substitution can be partial or complete; partial deuterium substitution refers to the replacement of at least one hydrogen atom with at least one deuterium atom.

[0294] When a site is specifically designated as deuterium D, the site should be understood as having a deuterium abundance of at least 1,000 times greater than the natural abundance of deuterium (which is 0.015%) (i.e., at least 15% deuterium incorporation). The compounds in the examples having a natural abundance greater than deuterium can be at least 1000 times abundant deuterium (i.e., at least 15% deuterium doping), at least 2000 times abundant deuterium (i.e., at least 30% deuterium doping), at least 3000 times abundant deuterium (i.e., at least 45% deuterium doping), at least 3340 times abundant deuterium (i.e., at least 50.1% deuterium doping), at least 3500 times abundant deuterium (i.e., at least 52.5% deuterium doping), at least 4000 times abundant deuterium (i.e., at least 60% deuterium doping), or at least 4500 times abundant deuterium (i.e., at least 67.5% deuterium doping). The abundance of deuterium is at least 5000 times (i.e., at least 75% deuterium doping), at least 5500 times (i.e., at least 82.5% deuterium doping), at least 6000 times (i.e., at least 90% deuterium doping), at least 6333.3 times (i.e., at least 95% deuterium doping), at least 6466.7 times (i.e., at least 97% deuterium doping), at least 6600 times (i.e., at least 99% deuterium doping), at least 6633.3 times (i.e., at least 99.5% deuterium doping), or higher.

[0295] "Optional" or "optional" means that the event or situation described below may but is not necessarily to occur; it includes both the possibility that the event or situation may occur or not occur. For example, "C that is optionally substituted with a halogen or cyano group..." 1-6 "Alkyl" includes cases where the alkyl group is substituted with a halogen or cyano group and cases where the alkyl group is not substituted with a halogen or cyano group.

[0296] "Substitution" or "substituted" refers to one or more hydrogen atoms in a group, preferably 1 to 6, more preferably 1 to 3 hydrogen atoms, which are independently substituted by the corresponding number of substituents. Those skilled in the art can determine possible or impossible substitutions without much effort (through experimentation or theory). For example, an amino or hydroxyl group with free hydrogen may be unstable when combined with a carbon atom having an unsaturated bond (such as an alkene).

[0297] "Pharmaceutical composition" means a mixture containing one or more of the compounds described herein or their pharmaceutically acceptable salts, along with other chemical components, such as 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.

[0298] "Pharmacologically acceptable salt" refers to the salt of the compounds disclosed herein, which may be selected from inorganic or organic salts. Such salts are safe and effective when used in mammals and possess the expected biological activity. They can be prepared separately during the final isolation and purification of the compound, or by reacting a suitable group with a suitable base or acid. Bases commonly used to form pharmaceutically acceptable salts include inorganic bases, such as sodium hydroxide and potassium hydroxide, and organic bases, such as ammonia. Acids commonly used to form pharmaceutically acceptable salts include both inorganic and organic acids.

[0299] For the purposes of pharmaceuticals or pharmacologically active agents, the term "therapeutic effective amount" refers to the amount of a drug or agent sufficient to achieve or at least partially achieve the intended effect. The determination of the therapeutic effective amount varies from person to person, depending on the recipient's age and general condition, as well as the specific active substance. The appropriate therapeutic effective amount in a given case can be determined by a person skilled in the art based on routine testing.

[0300] As used herein, the term "pharmaceutically acceptable" means that these compounds, materials, compositions, and / or dosage forms are suitable for contact with patient tissues without excessive toxicity, irritation, allergic reactions, or other problems or complications, within reasonable medical judgment, have a reasonable benefit / risk ratio, and are effective for their intended use.

[0301] As used herein, the singular forms of “a,” “an,” and “the” include plural references, and vice versa, unless the context clearly indicates otherwise.

[0302] When the term "about" is applied to parameters such as pH, concentration, temperature, etc., it indicates that the parameter can vary by ±10%, and sometimes more preferably within ±5%. As those skilled in the art will understand, when a parameter is not critical, figures are usually given for illustrative purposes only, not as limitations.

[0303] Synthetic methods for the compounds of the disclosure

[0304] In order to achieve the purpose of this disclosure, the following technical solution is adopted:

[0305] Option 1

[0306] This disclosure includes a method for preparing compounds of general formula (II) or pharmaceutically acceptable salts thereof, comprising the following steps:

[0307]

[0308] A compound of general formula (IIA) or a salt thereof undergoes a nucleophilic substitution reaction with a compound of general formula (IIB) or a salt thereof under basic conditions to give a compound of general formula (II) or a pharmaceutically usable salt thereof.

[0309] in:

[0310] In general formula (II) for

[0311] Ring A0 is a nitrogen-containing polycyclic heterocyclic group or a nitrogen-containing polycyclic heteroaryl group, wherein the nitrogen-containing polycyclic heterocyclic group and the nitrogen-containing polycyclic heteroaryl group are each independently and optionally converted by one or more R groups. 8 Substitution; and the * end is connected to the pyrimidine ring;

[0312] R LP For leaving groups; in some embodiments, R LP For halogen; in some implementations, R LP For F;

[0313] R 1 To R 3 Z 4 R 5 m, R a R 6 R 7 R 8 Q 1 Q 3 Q 4 R 11 X, R 14 R 15 and As defined in general formula (II).

[0314] Option 2

[0315] This disclosure includes a method for preparing compounds of formula (III) or pharmaceutically acceptable salts thereof, comprising the following steps:

[0316]

[0317] A compound of general formula (IIIA) or a salt thereof undergoes a nucleophilic substitution reaction with a compound of general formula (IIIB) or a salt thereof under basic conditions to give a compound of general formula (III) or a pharmaceutically usable salt thereof.

[0318] in:

[0319] In general formula (III) for

[0320] Ring A0 is a nitrogen-containing polycyclic heterocyclic group or a nitrogen-containing polycyclic heteroaryl group, wherein the nitrogen-containing polycyclic heterocyclic group and the nitrogen-containing polycyclic heteroaryl group are each independently and optionally converted by one or more R groups. 8 Substitution; and the * end is connected to the pyrimidine ring;

[0321] R LP For leaving groups; in some embodiments, R LP For halogen; in some implementations, R LP For F;

[0322] R 1 R 5 m1, R 6 R 8 R 9 , k and R 11 As defined in general formula (III).

[0323] The reagents providing alkaline conditions in the above synthesis scheme include organic and inorganic bases. The organic bases include, but are not limited to, triethylamine, N,N-diisopropylethylamine, n-butyllithium, diisopropylaminolithium, potassium acetate, sodium tert-butoxide, potassium tert-butoxide, tetrabutylammonium fluoride, tetrahydrofuran solution of tetrabutylammonium fluoride, or 1,8-diazabicycloundec-7-ene. The inorganic bases include, but are not limited to, sodium hydride, potassium phosphate, sodium carbonate, sodium acetate, potassium acetate, potassium carbonate, cesium carbonate, sodium hydroxide, lithium hydroxide, cesium fluoride, and potassium hydroxide; preferably, N,N-diisopropylethylamine.

[0324] The above synthesis is preferably carried out in a solvent, including but not limited to: ethylene glycol dimethyl ether, acetic acid, methanol, ethanol, acetonitrile, n-butanol, toluene, tetrahydrofuran, dichloromethane, petroleum ether, ethyl acetate, n-hexane, dimethyl sulfoxide, 1,4-dioxane, water, N,N-dimethylformamide, N,N-dimethylacetamide, and mixtures thereof. Detailed Implementation

[0325] The following embodiments are used to further describe this disclosure, but these embodiments are not intended to limit the scope of this disclosure.

[0326] Example

[0327] 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).

[0328] 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).

[0329] waters ACQuity UPLC-QD / SQD (Manufacturer: waters, MS model: waters ACQuity QdaDetector / waters SQ Detector)

[0330] THERMO Ultimate 3000-Q Exactive (Manufacturer: THERMO, MS Model: THERMOQExactive)

[0331] High-performance liquid chromatography (HPLC) analysis was performed using an Agilent HPLC 1200DAD, an Agilent HPLC 1200VWD, and a Waters HPLCe2695-2489 HPLC system.

[0332] Chiral HPLC analysis was performed using an Agilent 1260DAD high-performance liquid chromatograph.

[0333] High performance liquid chromatography (HPLC) was performed using Waters 2545-2767, Waters 2767-SQ Detecor2, Shimadzu LC-20AP, and Gilson GX-281 preparative chromatographs.

[0334] Chiral preparation was performed using a Shimadzu LC-20AP preparative chromatograph.

[0335] The CombiFlash rapid preparation system uses a CombiFlash Rf200 (TELEDYNE ISCO).

[0336] 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.

[0337] Silica gel column chromatography generally uses Yantai Huanghai silica gel with a mesh size of 200-300 as the carrier.

[0338] Mean inhibition rate of kinases and IC 50 The values ​​were determined using a NovoStar microplate reader (BMG GmbH, Germany).

[0339] 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, AccelaChemBio Inc, and Darui Chemicals.

[0340] Unless otherwise specified in the examples, all reactions can be carried out under an argon or nitrogen atmosphere.

[0341] Argon or nitrogen atmosphere refers to a reaction flask connected to an argon or nitrogen gas balloon with a volume of approximately 1L.

[0342] A hydrogen atmosphere refers to a reaction flask connected to a hydrogen balloon with a volume of approximately 1L.

[0343] The pressurized hydrogenation reaction was performed using a Parr 3916EKX hydrogenator and a Qinglan QL-500 hydrogen generator or an HC2-SS hydrogenator.

[0344] The hydrogenation reaction is usually carried out under vacuum, filled with hydrogen gas, and repeated 3 times.

[0345] The microwave reaction was performed using a CEM Discover-S 908860 microwave reactor.

[0346] Unless otherwise specified in the examples, "solution" refers to an aqueous solution.

[0347] Unless otherwise specified in the examples, the reaction temperature is room temperature.

[0348] 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, and C: petroleum ether / 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.

[0349] Example 1

[0350] 3-(6-(7-(5-chloro-4-((1-ethyl-2-oxoindoline-5-yl)amino)pyrimidin-2-yl)-3-oxohexahydroimidazo[1,5-a]pyrazin-2(3H)-yl)-1-methyl-1H-indazol-3-yl)piperidin-2,6-dione

[0351]

[0352]

[0353] first step

[0354] 2-((1,3-dioxoisoindoline-2-yl)methyl)piperazine-1,4-dicarboxylic acid ditert-butyl ester 1c

[0355] Di-tert-butyl 2-(hydroxymethyl)piperazine-1,4-dicarboxylic acid 1a (2 g, 6.3 mmol, Bio-Tech Pharmaceuticals) was dissolved in tetrahydrofuran (30 mL, Adamas), and isoindoline-1,3-dione 1b (1.2 g, 8.2 mmol, Shaoyuan) and triphenylphosphine (2.2 g, 8.2 mmol, Adamas) were added. Diisopropyl azodicarbonate (1.7 g, 8.2 mmol, Shaoyuan) was added under stirring at 0 °C, and the reaction was carried out at room temperature for 2 hours. 30 mL of water was added, and the mixture was extracted with ethyl acetate (30 mL × 3). The organic phases were combined, washed with 30 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The filtrate was purified by column chromatography using eluent system C to give the title compound 1c (2.4 g, yield: 85.2%). MS m / z (ESI): 446.1 [M+1].

[0356] Step 2

[0357] 2-(aminomethyl)piperazine-1,4-dicarboxylic acid di-tert-butyl ester 1d

[0358] Compound 1c (2.4 g, 5.4 mmol) was dissolved in ethanol (10 mL, Sinopharm), and methylamine ethanol (10 mL, Sinopharm) was added. The mixture was refluxed for 4 hours. After cooling to room temperature, the solution was concentrated, 50 mL of water was added, and the pH was adjusted to 3 with 2N hydrochloric acid. The solution was extracted with methyl tert-butyl ether (30 mL × 3). The pH was adjusted to 10 with 2N sodium hydroxide aqueous solution, and the solution was extracted with ethyl acetate (30 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness to give compound 1d (1.2 g, yield: 70.6%).

[0359] MSm / z(ESI):316.1[M+1].

[0360] Step 3

[0361] 3-O-hexahydroimidazo[1,5-a]pyrazine-7(1H)-carboxylic acid tert-butyl ester 1e

[0362] Compound 1d (1.2 g, 3.8 mmol) was dissolved in tetrahydrofuran (15 mL, Adamas), and sodium hydride (291 mg, 7.6 mmol, Sinopharm) was added with stirring at 0 °C. The reaction was carried out at 80 °C for 4 hours. 30 mL of ice water was added, and the mixture was extracted with ethyl acetate (30 mL × 3). The organic phases were combined, washed with 30 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give the title compound 1e (820 mg, yield: 89.3%).

[0363] Step 4

[0364] 3-(2,6-bis(benzyloxy)pyridin-3-yl)-6-bromo-1-methyl-1H-indazole 1h

[0365] 1 g (5 g, 14.8 mmol, Bio-Tech Pharmaceuticals) of 6-bromo-3-iodo-1-methyl-1H-indazole was dissolved in 1,4-dioxane (80 mL, Adamas) and 20 mL of water. 1 f (7.4 g, 17.8 mmol, Bio-Tech Pharmaceuticals), 1,1-bis(diphenylphosphine)ferrocene palladium dichloride (1.1 g, 1.5 mmol, Bio-Tech Pharmaceuticals), and cesium carbonate (9.7 g, 29.7 mmol, Bio-Tech Pharmaceuticals) were added. The reaction was carried out at 100 °C for 16 hours under nitrogen protection. Cool to room temperature, add 20 mL of water, extract with ethyl acetate (50 mL × 3), combine the organic phases, wash with 50 mL of saturated sodium chloride solution, dry with anhydrous sodium sulfate, filter, concentrate the filtrate, and purify by column chromatography with eluent system C to give the title compound 1h (4.3 g, yield: 57.9%).

[0366] MSm / z(ESI):502.0[M+2].

[0367] Step 5

[0368] 2-(3-(2,6-bis(benzyloxy)pyridin-3-yl)-1-methyl-1H-indazol-6-yl)-3-oxohexahydroimidazo[1,5-a]pyrazine-7(1H)-carboxylic acid tert-butyl ester 1i

[0369] Compound 1h (124.4 mg, 0.25 mmol) was dissolved in 1,4-dioxane (3 mL, Adamas), and compound 1e (50 mg, 0.21 mmol), palladium acetate (4.7 mg, 0.02 mmol, Adamas), 4,5-bisdiphenylphosphine-9,9-dimethyloxanthracene (18 mg, 0.03 mmol, Bio-Tech Pharmaceuticals), and cesium carbonate (135 mg, 0.41 mmol, Bio-Tech Pharmaceuticals) were added. The reaction was carried out at 90 °C for 16 hours under nitrogen protection. After cooling to room temperature, the mixture was concentrated, and the residue was purified by column chromatography with eluent system C to give the title compound 1i (88 mg, yield: 64.2%). MS m / z (ESI): 661.4 [M+1]

[0370] Step 6

[0371] 2-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-6-yl)-3-oxohexahydroimidazo[1,5-a]pyrazine-7(1H)-carboxylic acid tert-butyl ester

[0372] Compound 1i (88 mg, 0.13 mmol) was dissolved in 10 mL of a mixed solvent of tetrahydrofuran and methanol (V / V = 4:6). Palladium on carbon (36.8 mg, 0.17 mmol, Bio-Tech) and palladium hydroxide (37.4 mg, 0.13 mmol, Shaoyuan) were added. The system was reacted at 70 °C for 16 hours under a hydrogen atmosphere. After cooling to room temperature, the mixture was filtered, and the filtrate was concentrated to give the title compound 1j (63 mg, yield: 98.0%).

[0373] MSm / z(ESI): 483.3 [M+1]

[0374] Step 7

[0375] 3-(1-Methyl-6-(3-oxohexahydroimidazo[1,5-a]pyrazin-2(3H)-yl)-1H-indazol-3-yl)piperidin-2,6-dione 1k

[0376] Compound 1j (63 mg, 0.13 mmol) was dissolved in dichloromethane (2 mL, Sinopharm), and trifluoroacetic acid (0.5 mL, Adamas) was added. The reaction mixture was reacted at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, and 10 mL of saturated sodium bicarbonate was added. The mixture was extracted with ethyl acetate (10 mL × 3). The combined organic phases were washed with 10 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the title compound 1k (48 mg, yield: 96.1%). MS m / z (ESI): 383.2 [M+1]

[0377] Step 8

[0378] 3-(6-(7-(5-chloro-4-((1-ethyl-2-oxoindoline-5-yl)amino)pyrimidin-2-yl)-3-oxohexahydroimidazo[1,5-a]pyrazin-2(3H)-yl)-1-methyl-1H-indazol-3-yl)piperidin-2,6-dione

[0379] Compound 1k (48 mg, 0.13 mmol) was dissolved in dimethyl sulfoxide (4 mL, Adamas), and 5-((5-chloro-2-fluoropyrimidin-4-yl)amino)-1-ethylindoline-2-one 1l (46.2 mg, 0.15 mmol, prepared by the method disclosed in Example S89 on page 197 of patent application “WO2023212147A1”) and N,N-diisopropylethylamine (48.7 mg, 0.38 mmol, Adamas) were added. The mixture was reacted at 100 °C for 4 hours. After cooling to room temperature, the mixture was concentrated, 5 mL of water was added, and the mixture was extracted with dichloromethane (5 mL × 3). The organic phases were combined, washed with 5 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by column chromatography using eluent system A to give title compound 1 (20 mg, yield: 23.8%).

[0380] MSm / z(ESI): 669.6 [M+1]

[0381] 1H NMR (500MHz, Methanol-d4): δ7.99(s,1H),7.73-7.67(m,1H),7.63-7.55(m,3H),7.54-7.49( m,1H),7.07-7.02(m,1H),4.69-4.63(m,1H),4.17-4.10(m,1H),4.01(s,3H),3.95-3.90(m,1H ),3.88-3.80(m,3H),3.76-3.69(m,1H),3.63(s,2H),3.11-3.02(m,1H),3.00-2.87(m,2H),2 .83-2.73(m,2H),2.51-2.45(m,1H),2.38-2.29(m,1H),2.24-2.18(m,2H),1.31-1.28(m,3H).

[0382] Example 1-P1

[0383] 3-(6-((R)-7-(5-chloro-4-((1-ethyl-2-oxoindoline-5-yl)amino)pyrimidin-2-yl)-3-oxohexahydroimidazo[1,5-a]pyrazin-2(3H)-yl)-1-methyl-1H-indazol-3-yl)piperidin-2,6-dione 1-P1

[0384]

[0385] Using the synthetic route of Example 1, the starting compound 1e was replaced with (S)-3-oxohexahydroimidazole[1,5-a]pyrazine-7(1H)-carboxylic acid tert-butyl ester to obtain the title compound 1-P1.

[0386] MSm / z (ESI): 669.5 [M+1]

[0387] 1H NMR (500MHz, DMSO-d4): δ10.89(s,1H),8.77(s,1H),8.07(s,1H),7.67-7.57(m,4H),7.49- 7.47(m,1H),7.04-7.02(m,1H),4.65-4.63(m,1H),4.58-4.56(m,1H),4.35-4.32(m,1H),4. 06-4.04(m,1H),3.95-3.93(m,3H),3.84-3.81(m,2H),3.74-3.67(m,3H),3.61(s,2H),2.9 5-2.82(m,3H),2.66-2.62(m,2H),2.38-2.36(m,1H),2.21-2.18(m,1H),1.19-1.17(m,3H).

[0388] Example 1-P2

[0389] 3-(6-((S)-7-(5-chloro-4-((1-ethyl-2-oxoindoline-5-yl)amino)pyrimidin-2-yl)-3-oxohexahydroimidazo[1,5-a]pyrazin-2(3H)-yl)-1-methyl-1H-indazol-3-yl)piperidin-2,6-dione 1-P2

[0390]

[0391] Using the synthetic route of Example 1, the starting compound 1e was replaced with (R)-3-oxohexahydroimidazole[1,5-a]pyrazine-7(1H)-carboxylic acid tert-butyl ester to obtain the title compound 1-P2.

[0392] MSm / z(ESI): 669.7 [M+1]

[0393] 1 H NMR (500MHz, Methanol-d4): δ7.99(s,1H),7.72-7.67(m,1H),7.62-7.55(m,3H),7. 54-7.49(m,1H),7.07-7.02(m,1H),4.68-4.62(m,1H),4.40-4.33(m,1H),4.16-4.09 (m,1H),4.01(s,3H),3.95-3.80(m,5H),3.75-3.69(m,1H),3.62(s,2H),3.11-3.01 (m,1H),3.01-2.66(m,4H),2.54-2.43(m,1H),2.38-2.29(m,1H),1.31-1.27(m,3H).

[0394] Biological evaluation

[0395] The following test examples further describe and explain this disclosure, but these test examples are not intended to limit the scope of this disclosure.

[0396] Test Example 1: Degradation activity of the disclosed compound against BCL6 in OCI-LY1 human B-cell lymphoma.

[0397] OCI-LY1 cells were centrifuged (300 g / min, 3 min), the supernatant was discarded, and the cell pellet was resuspended in fresh culture medium. Cell counts were performed. A cell suspension with a density of 5E5 / ml was prepared and mixed thoroughly. 50 μL of the suspension was added to each well of a 96-well round-bottom plate, along with 140 μL of fresh culture medium. The plate was incubated at 37°C. A 20 mM stock solution of the compound was prepared using DMSO and then 4-fold diluted in a 96-well round-bottom plate to an initial concentration of 5 mM. This was repeated 4-fold with DMSO, resulting in 11 concentration points. DMSO blank wells served as a control. The resulting DMSO solution was then diluted 50-fold: 3 μL of the DMSO solution was added to 147 μL of fresh culture medium and shaken for 10 min to mix. 10 μL of the solution was added to each well of the plate, with duplicates, to a final DMSO concentration of 0.1%. The plate was incubated at 37°C for 24 hours. Cell lysis was performed 24 hours later: The cell plate was removed from the 37°C incubator and centrifuged at 400g / min for 5 min. 160 μL of supernatant was discarded from each well, and 10 μL of 5X lysis buffer was added to each well of the remaining cells. The cells were shaken for 5 min and then sonicated for 5 min to fully lyse the cells. The lysed cell plate was centrifuged at 800g / min for 5 min, and the supernatant was transferred to a new 96-well round-bottom plate. The BCL6 protein content was measured using the MSD method.

[0398] One day prior to testing, MSD 96-well plates were coated with PBS buffer containing 1 μg / mL goat-derived BCL6 antibody and incubated overnight at 4°C. Before testing, the coating solution was discarded, and 150 μL of 5% BSA phosphate buffer was added to each well for blocking for 1 hour. The plates were washed three times with PBS and 0.05% Tween 20 wash buffer. 25 μL of lysed cell sample or BCL6 standard curve solution was added to each well, and the plates were incubated with shaking at 500 rpm for 1.5 hours. The sample was discarded, and the plates were washed three times. 25 μL of primary antibody solution containing 0.8 μg / mL rabbit-derived BCL6 antibody was added, and the plates were incubated with shaking at 500 rpm for 1 hour. The primary antibody was discarded, and the plates were washed three times. 25 μL of secondary antibody solution containing 1 μg / mL SULFO-TAG-labeled anti-rabbit antibody was added, and the plates were incubated with shaking at 500 rpm in the dark for 1 hour. The secondary antibody was discarded, and the plates were washed three times. 150 μL of 1X MSD detection buffer was added to each well, and the signal value was read using a MESO SECTOR S600.

[0399] The BCL6 content in the samples was calculated based on the BCL6 standard curve. DMSO-treated wells were used as positive control wells, and blank cell lysis buffer wells were used as negative control wells. The inhibition rate was calculated as: (positive control wells - test compound) / (positive control wells - negative control wells) * 100%. Inhibition curves were plotted using Graphpad software based on the compound concentration points and corresponding inhibition rates, and the concentration of the compound at which the inhibition rate was 50% (IC50) was calculated. 50 value.

[0400] Table 1. Degradation activity of the disclosed compounds against BCL6 in OCI-LY1 human B-cell lymphoma.

[0401] No. DC 50 nM]]> Dmax % 1 0.68 96.09 1-P1 0.18 98.7

[0402] Conclusion: The compound disclosed herein exhibits good degradation activity against intracellular BCL6.

[0403] Test Example 2: The inhibitory activity of the disclosed compound on the proliferation of OCI-LY1 human B-cell lymphoma.

[0404] Centrifuge OCI-LY1 cells (300 g / min, 3 min), discard the supernatant, resuspend the cell pellet in fresh culture medium, and count the cells. Prepare a cell suspension with a cell density of 5E4 / ml and mix well. Add 50 μL per well to a 96-well plate, along with 187.5 μL of fresh culture medium, for a total cell count of 2500. Incubate at 37°C. Dilute the compound with DMSO to a 20x solution. Prepare a 20 mM stock solution with DMSO, then dilute with DMSO in 96-well plates to an initial concentration of 10 μM (the highest final concentration is 10 nM). Perform 3-fold dilutions with DMSO to obtain 9 concentration points.

[0405] The obtained DMSO solution was diluted 50-fold to obtain a 20× compound solution: 3 μL of DMSO compound solution was added to 147 μL of fresh culture medium and mixed by pipetting 15 times. The 20× compound solution was added to cell culture plates at 12.5 μL / well, in triplicate, with a final DMSO concentration of 0.1%. DMSO blank wells served as blank controls, and wells treated with the highest concentration of the positive reference compound served as positive controls. The plates were shaken at 350 rpm for 5 minutes to mix. The cell culture plates were incubated at 37°C for 5 days. On the fifth day, cell counts were performed on the DMSO-treated wells, and the dilution factor to 2500 cells per well was calculated. All cell wells were diluted to this factor and transferred to new 96-well black plates. Fresh culture medium was added to bring the total volume to 237.5 μL. The compound solution was prepared as described above and added to new black 96-well plates at the same concentration as on the first day at 12.5 μL. The plates were incubated at 37°C for 4 days.

[0406] CellTiter-Glo assay for cell viability: After centrifuging a 96-well cell culture plate (300 g / min, 5 min), discard 150 μL of supernatant, add 100 μL of CTG reagent, vortex for 5 min, and then incubate in the dark for 10 min. Measure the bioluminescent fluorescence signal value using an EnVision microplate reader.

[0407] DMSO-treated wells served as blank control wells, and blank cell culture medium wells served as negative control wells. The inhibition rate was calculated as (1 - (blank control wells - test compound) / (blank control wells - negative control wells)) * 100%. Inhibition curves were plotted using Graphpad Prism software based on the compound concentration points and corresponding inhibition rates, and the IC50 concentration (the concentration at which the inhibition rate was 50%) was calculated. 50 Value. The maximum inhibition rate for each compound is the IMax% value.

[0408] Table 2. Inhibitory activity of the disclosed compounds against the proliferation of OCI-LY1 tumor cells.

[0409] Example No. IC 50 (nM) Imax % 1-P1 4.71 97.43

[0410] Conclusion: The compound disclosed herein exhibits good inhibitory activity against the proliferation of OCI-LY1 tumor cells.

Claims

1. A compound of general formula (I) or a pharmaceutically acceptable salt thereof, in: Z is selected from O, S, (CR) 2 R 3 ) z and NR 4 ; Z 1 Z 2 Z 3 and Z 4 One of them is a carbon atom and is related to NR. a Connected, the other three are the same or different, and each is independently selected from N, CH and CR. 5 ; L a and L b They may be the same or different, and each is independently selected from bonds, alkylene groups, alkenyl groups, alkynyl groups, cycloalkyl groups, heterocyclic groups, (CR) c R d ) a O, S, NR b C(O), C(O)NR b and NR b C(O); L c Selected from key, (CR) c R d ) a O, S, NR b C(O), C(O)NR b and NR b C(O); Ring A is selected from polycyclic alkyl, polycyclic heterocyclic, polycyclic aryl, and polycyclic heteroaryl groups; wherein each of the polycyclic alkyl, polycyclic heterocyclic, polycyclic aryl, and polycyclic heteroaryl groups is independently selected by one or more R groups. 8 replace; Ring B is selected from *End and L b connect; Q 1 Q 2 Q 3 and Q 4 One of them is a carbon atom and is related to L b Connected, the other three are the same or different, and each is independently selected from N, CH and CR. 9 ; G 1 G 2 G 3 G 4 and G 5 One of them is a carbon atom and is related to L b Connected, the other four are the same or different, and each is independently selected from N, CH and CR. 9 ; U is N or CR 10 ; Y 1 Y 2 and Y 3 Same or different, and each is independently selected from the key, (CR c R d ) b O, S, NR b and C(O); X is N or CR 13 ; It can be a double bond or a single bond; R 1 R 4 R 11 R 14 R a and R b They may be the same or different, and each is independently selected from hydrogen atom, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, hydroxyl, alkoxy, -alkylene-NR 17 R 18 cycloalkyl, heterocyclic, aryl, heteroaryl, cycloalkylalkyl, heterocyclic alkyl, arylalkyl, and heteroarylalkyl; wherein the alkyl, alkenyl, alkynyl, alkoxyalkyl, alkoxy, cycloalkyl, heterocyclic, aryl, heteroaryl, cycloalkylalkyl, heterocyclic alkyl, arylalkyl, and heteroarylalkyl are each independently and optionally selected by one or more R 0 replace; R 2 R 3 R 13 R 15 R c and R d The same or different, and each independently selected from hydrogen atom, halogen, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkoxyalkyl, aminoalkyl, cyano, amino, hydroxyl, nitro, -OR 16 -NR 17 R 18 -C(O)R 16 -C(O)OR 16 -C(O)NR 17 R 18 cycloalkyl, heterocyclic, aryl, and heteroaryl; wherein each of the alkyl, alkenyl, alkoxy, alkoxyalkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups is independently and optionally composed of one or more R 0 replace; Or, R 2 and R 3 Together with the attached atoms, they form a cycloalkyl or heterocyclic group, each of which is independently and optionally influenced by one or more R atoms. 0 replace; Or, R c and R d Together with the attached atoms, they form a cycloalkyl or heterocyclic group, each of which is independently and optionally influenced by one or more R atoms. 0 replace; R 5 and R 9 The same or different, and each independently selected from halogen, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkoxyalkyl, aminoalkyl, cyano, amino, hydroxyl, nitro, -OR 16 -NR 17 R 18 -C(O)R 16 -C(O)OR 16 -C(O)NR 17 R 18 cycloalkyl, heterocyclic, aryl, and heteroaryl; wherein each of the alkyl, alkenyl, alkoxy, alkoxyalkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups is independently and optionally composed of one or more R 0 replace; R 6 R 7 R 10 and R 12 The same or different, and each independently selected from hydrogen atom, halogen, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkoxyalkyl, aminoalkyl, cyano, amino, hydroxyl, nitro, -OR 16 -NR 17 R 18 -C(O)R 16 -C(O)OR 16 -C(O)NR 17 R 18 cycloalkyl, heterocyclic, aryl, and heteroaryl; wherein each of the alkyl, alkenyl, alkoxy, alkoxyalkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups is independently and optionally composed of one or more R 0 replace; Each R 8 The same or different, and each independently selected from halogen, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkoxyalkyl, aminoalkyl, cyano, amino, hydroxyl, nitro, -OR 16 -NR 17 R 18 -C(O)R 16 -C(O)OR 16 -C(O)NR 17 R 18 -OC(O)NR 17 R 18 -OC(O)R 21 -OC(O)OR 16 -NR 19 C(O)R 16 -NR 19 C(O)OR 16 -C(=NR) 20 )NR 17 R 18 -S(O) v R 16 -S(O) v NR 17 R 18 -NR 19 S(O) v R 16 -NR 19 S(O) v NR 17 R 18 =O, =S, =CR 21 R 22 cycloalkyl, heterocyclic, aryl, and heteroaryl; wherein each of the alkyl, alkenyl, alkoxy, alkoxyalkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups is independently and optionally composed of one or more R 0 replace; R 16 R 17 and R 18 The elements may be the same or different each time they appear, and are each independently selected from hydrogen atoms, alkyl, alkenyl, ynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl; wherein the alkyl, alkenyl, ynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl elements are each independently selected by one or more R atoms. 0 Replace; or R 17 and R 18 Together with the attached nitrogen atom, a nitrogen-containing heterocyclic group is formed, wherein the nitrogen-containing heterocyclic group is optionally surrounded by one or more R atoms. 0 replace; R 19 They may be the same or different each time they appear, and each is independently selected from hydrogen atoms, alkyl groups and cycloalkyl groups; R 20 They may be the same or different each time they appear, and each is independently selected from hydrogen atoms, alkyl, alkoxy, hydroxy and cycloalkyl; R 21 and R 22 They may be the same or different each time they appear, and each is independently selected from hydrogen atoms, halogens, alkyl groups, haloalkyl groups, hydroxyalkyl groups, and cycloalkyl groups; or, R 21 and R 22 Together with the carbon atoms attached to it, they form cycloalkyl groups; R 0 Each of the following groups is selected independently from the following groups: =O, =S, =CH2, =CHF, =CF2, halogen, hydroxyl, alkenyl, alkynyl, cyano, nitro, amino, -NHalkyl, -N(alkyl)2, -C(O)Oalkyl, -C(O)OH, -C(O)NH2, -C(O)NH(alkyl), -C(O)N(alkyl)2, -C(O)halogen, -C(O)alkyl, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkoxyalkyl, aminoalkyl, -S(alkyl), cycloalkyl, cycloalkylalkyl, cycloalkyloxy, heterocyclic, heterocyclic alkyl, heterocyclic oxy, aryl, arylalkyl, aryloxy, heteroaryl, heteroarylalkyl and heteroaryloxy; z can be 0, 1, 2, or 3; a and b may be the same or different, and each is independently 0, 1, 2, 3, 4 or 5; v can be 0, 1, or 2.

2. The compound of general formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, is a compound of general formula (II) or a pharmaceutically acceptable salt thereof. in: m is 0, 1, or 2; Z 4 Selected from N, CH and CR 5 ; Q 1 Q 3 and Q 4 They may be the same or different, and each is independently selected from N, CH and CR. 9 ;R 1 To R 3 R 5 R a R 6 R 7 Ring A, R 9 R 11 X, R 14 R 15 and As defined in claim 1.

3. The compound of general formula (I) according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein the compound is of general formula (III) or a pharmaceutically acceptable salt thereof. in: k can be 0, 1, 2, or 3; m1 can be 0, 1, 2, or 3; R 1 R 5 R 6 Ring A, R 9 and R 11 As defined in claim 1.

4. The compound of general formula (I) according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein ring A is optionally surrounded by one or more R 8 Replaced 7- to 11-membered bicyclic fused heterocyclic groups; each R 8 They may be the same or different, and each is independently selected from oxo groups, halogens, and C. 1-6 Alkyl and C 1-6 Halogenated alkyl; preferably, ring A is selected from... *End and L a Or linked by a pyrimidine ring.

5. The compound of general formula (I) according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein R 1 Selected from hydrogen atoms, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy C 1-6 Alkyl, -C 1-6 Alkylene-NHC 1-6 Alkyl, 3- to 6-membered cycloalkyl C 1-6 Alkyl groups and 3 to 6-membered heterocyclic C groups 1-6 Alkyl; preferably, R 1 C 1-6 Alkyl; more preferably, R 1 It is an ethyl group.

6. The compound of general formula (I) according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, wherein each R 5 They may be the same or different, and each is independently selected from halogens, C 1-6 Alkyl and C 1-6 Halogenated alkyl; preferably, R 5 It is F.

7. The compound of general formula (I) according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein R 6 Selected from hydrogen atom, halogen, cyano group, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy and C 1-6 Halogenated alkoxy groups; preferably, R 6 It is halogen or cyano; more preferably, R 6 It is a halogen.

8. The compound of formula (I) according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, wherein each R 9 They may be the same or different, and each is independently selected from halogens, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy and C 1-6 Halogenated alkoxy groups; preferably, each R 9 They may be the same or different, and each is an independent halogen.

9. The compound of formula (I) according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, wherein R 11 Selected from hydrogen atoms, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups and C 1-6 Hydroxyalkyl; preferably, R 11 C 1-6 Alkyl; more preferably, R 11 It is methyl.

10. The compound of formula (I) according to any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, selected from the group consisting of:

11. A compound of general formula (IIA) or a salt thereof, in: Ring A0 is a nitrogen-containing fused heterocyclic group or a nitrogen-containing polycyclic heteroaryl group, wherein each nitrogen-containing fused heterocyclic group and nitrogen-containing polycyclic heteroaryl group is independently and optionally converted by one or more R groups. 8 replace; R 8 Q 1 Q 3 Q 4 R 11 X, R 14 R 15 and As defined in claim 2.

12. The compound of general formula (IIA) according to claim 11, or a salt thereof, wherein the compound is selected from the group consisting of:

13. A method for preparing a compound of general formula (II) according to claim 2 or a pharmaceutically acceptable salt thereof, comprising: The compound of general formula (IIA) or its salt undergoes a nucleophilic substitution reaction with the compound of general formula (IIB) or its salt to give the compound of general formula (II) or its pharmaceutically usable salt. in: In general formula (II) for Ring A0 is a nitrogen-containing polycyclic heterocyclic group or a nitrogen-containing polycyclic heteroaryl group, wherein the nitrogen-containing polycyclic heterocyclic group and the nitrogen-containing polycyclic heteroaryl group are each independently and optionally converted by one or more R groups. 8 Substitution; and the * end is connected to the pyrimidine ring; R LP It is a leaving group; preferably, R LP Halogen; more preferably, R LP For F; R 1 To R 3 Z 4 R 5 m, R a R 6 R 7 R 8 Q 1 Q 3 Q 4 R 11 X, R 14 R 15 and As defined in claim 2.

14. A pharmaceutical composition comprising a compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 10, and one or more pharmaceutically acceptable carriers, diluents or excipients.

15. Use of the compound of any one of claims 1 to 10 or a pharmaceutically acceptable salt thereof or the pharmaceutical composition of claim 14 in the preparation of a medicament for inhibiting or degrading BCL6.

16. Use of the compound of any one of claims 1 to 10 or a pharmaceutically acceptable salt thereof or the pharmaceutical composition of claim 14 in the preparation of a medicament for treating and / or preventing diseases or conditions mediated or dependent on BCL6.

17. Use of the compound of any one of claims 1 to 10 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 14, in the preparation of a medicament for treating and / or preventing tumors or autoimmune diseases; wherein the tumor is preferably selected from lymphoma, leukemia, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, hepatocellular carcinoma, renal cell carcinoma, bladder cancer, intestinal cancer, breast cancer, cervical cancer, colon cancer, esophageal cancer, kidney cancer, liver cancer, lung cancer, head and neck cancer, ovarian cancer, pancreatic cancer, prostate cancer, gastric cancer, melanoma, sarcoma, Ewing sarcoma, angiosarcoma, Kaposi's sarcoma, liposarcoma, sarcoma, peripheral neuroepithelial tumor (PED). Neuroepithelioma, synovial sarcoma, glioma, astrocytoma, glioblastoma, neuroblastoma, ganglioglioma, medulloblastoma, pineal cell carcinoma, meningioma, meningeal sarcoma, neurofibroma and schwannoma, prostate cancer, endometrial cancer, testicular cancer, thyroid cancer, astrocytoma, carcinosarcoma, Hodgkin's disease, nephroblastoma and teratoma; more preferably selected from lymphoma, leukemia, breast cancer and lung cancer.

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