CHIMERIC COMPOUND FOR TARGETED DEGRADATION OF ANDROGEN RECEPTOR PROTEIN, PREPARATION METHOD THEREFOR, AND MEDICAL USE THEREOF

Abstract

A chimeric compound for targeted degradation of androgen receptor protein, a preparation method therefor, and a medical use thereof. Specifically, the present invention relates to a spiro compound represented by general formula (I), a preparation method therefor, a pharmaceutical composition containing the spiro compound, and uses thereof as a therapeutic agent, in particular a use as an androgen receptor degradation agent and a use in the preparation of a drug for treating and/or preventing androgen receptor mediated or dependent diseases or conditions.

Description

TECHNICAL FIELD

The present disclosure belongs to the field of pharmaceutics and relates to a novel proteolysis targeting chimera (PROTAC) compound, a preparation method therefor, and pharmaceutical use thereof. Specifically, the present disclosure relates to a spirocyclic compound represented by general formula (I), a preparation method therefor, a pharmaceutical composition comprising the spirocyclic compound, and use thereof as a therapeutic agent, particularly as an androgen receptor degrader, and use thereof in the preparation of a medicament for treating and/or preventing androgen receptor-mediated or -dependent diseases or disorders.

BACKGROUND

PROTACs (PROteolysis TArgeting Chimera) are hybrid bifunctional small-molecule compounds. Their structures contain two different ligands: a ubiquitin ligase E3 ligand and a ligand that binds to a target protein, which are linked by a linker unit. PROTACs draw close the target protein and the ubiquitin ligase E3 in the cell to form a target protein-PROTAC-E3 ternary complex. Subsequently, the E3 ubiquitin ligase labels the target protein with a ubiquitinated protein tag and then initiates the powerful ubiquitination-proteasome system in the cell to specifically degrade the target protein, thereby playing a role in inhibiting the corresponding protein signaling pathway (Cell Biochem Funct. 2019, 37, 21-30). PROTACs have unique advantages over traditional small-molecule inhibitors: 1) PROTACs do not require long and high-strength binding to the target protein, and their degradation of the target protein is similar to catalysis: they can bind and degrade the target protein cyclically, so that the systemic drug exposure and the occurrence of toxic and side effects are reduced; 2) after being degraded, the target protein needs to be re-synthesized to recover its function; therefore, degrading the target protein exhibits a more efficient and lasting anti-tumor effect than inhibiting its activity and will not lead to drug resistance caused by mutation of the target protein; 3) PROTACs also have therapeutic potentials for the targets which are now considered undruggable, such as transcription factors, scaffold proteins, and regulatory proteins.

The discovery of CRBN-type E3 ligase ligands is related to the study of the mechanism of action of thalidomide. In 2010, scientists discovered cereblon, a binding protein of thalidomide, while studying the toxicity of thalidomide (Science 2010, 327, 1345). Cereblon is part of the E3 ubiquitin ligase protein complex. As a substrate receptor, it selectively acts on ubiquitinated proteins. This study indicated that the in vivo binding of thalidomide to cereblon might be the cause of thalidomide's teratogenicity. Subsequent studies found that this compound and related structures could be used as anti-inflammatory agents, anti-angiogenesis agents, and anti-cancer agents. Lenalidomide and pomalidomide obtained by further modifying the thalidomide structure are much safer, and their teratogenic effects are significantly smaller. Lenalidomide was approved for sale by the FDA in 2006. In 2014, two groundbreaking papers published in Science pointed out that lenalidomide acts by degrading two special B-cell transcription factors, Ikaros family zinc finger structure proteins 1 and 3 (IKZF1 and IKZF3), which further reveals that the thalidomide structure may bind to the E3 ubiquitin ligase protein complex of cereblon, thereby playing a role in degrading the target protein (Science, 2014, 343, 301; Science, 2014, 343, 305).

The androgen receptor (AR) is a ligand-dependent trans-transcription regulating protein that belongs to the nuclear receptor superfamily, mainly found in the nucleus. AR molecules that are not bound by the ligand bind to the heat shock protein (HSP); however, upon binding to the ligand, the AR undergoes a conformational change and dissociates from the HSP, and its affinity for DNA increases (activation of the AR). Activated AR molecules bind in dimer form to a specific DNA sequence in the nucleus—the androgen response element (ARE)—and interact with other transcription factors, thereby regulating the expression of relevant genes and producing biological effects. Studies have shown that abnormalities in the AR signaling pathway are closely related to the development and progression of diseases such as prostate cancer, benign prostatic hyperplasia, Kennedy's disease, male infertility, androgen insensitivity syndrome, and male breast cancer.

Prostate cancer is one of the most common malignancies. According to statistics, in 2018, there were nearly 1.3 million new cases and 359 thousand deaths worldwide, accounting for 13.5% of the incidence rate of malignancies in men, ranking second, and 6.7% of the mortality rate of malignancies in men, ranking fifth. A number of AR antagonists have been approved for sale and successfully used in the treatment of castration-resistant prostate cancer, and they have become a major treatment for prostate cancer. However, most patients develop resistance after 0.5-2 years of treatment, which leads to disease progression. In some patients with resistance, cancer cell growth still depends on the AR signaling pathway.

There is a need to develop more effective treatments for prostate cancer. Unlike AR antagonists, PROTACs can degrade the AR, so that they can inhibit the AR signaling pathway more effectively. PROTACs are likely to become a potential treatment for prostate cancer. Disclosed patent applications of AR protein targeted degradation PROTAC compounds include WO2015160845A2, WO2016197032A1, US2015291562A1, WO2018071606A1, WO2019023553A1, WO2016118666A1, WO2018144649A1, WO2020142228A1, WO2020198711A1, WO2021061644A1, and WO2021055756A1.

SUMMARY

The present disclosure aims to provide a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof,

• • wherein:
  • R is aryl or heteroaryl, wherein the aryl and heteroaryl are each independently optionally substituted with one or more substituents selected from the group consisting of halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, —(CH₂)_nNR^aR^b, nitro, hydroxy, hydroxyalkyl, aminoalkyl, alkoxyalkyl, cycloalkylalkyl, heterocyclylalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl;

A is selected from the group consisting of

• • is a single bond or a double bond;
  • one of Q¹, Q², Q³, Q⁴, and Q⁵ is a carbon atom, and the other four are identical or different and are each independently a nitrogen atom or CR¹;
  • each R¹ is identical or different and is independently selected from the group consisting of a hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, aminoalkyl, alkoxyalkyl, cyano, hydroxy, nitro, and —(CH₂)_nNR^cR^d;
  • R¹ is selected from the group consisting of a hydrogen atom, alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, and alkoxyalkyl;
  • R² is selected from the group consisting of a hydrogen atom, halogen, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, hydroxy, cyano, aminoalkyl, and alkoxyalkyl;
  • X¹ is spirocyclyl, wherein the spirocyclyl is optionally substituted with one or more substituents selected from the group consisting of halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, nitro, hydroxy, hydroxyalkyl, aminoalkyl, alkoxyalkyl, cycloalkylalkyl, heterocyclylalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, —OR³, —C(O)R³, —C(O)OR³, —S(O)_mR³, —NR⁴R⁵, —C(O)NR⁴R⁵, —S(O)_mNR⁴R⁵, ═O, and ═S;
  • X² is selected from the group consisting of —C(O)—, —S(O)₂—, and —(CR^2aR^2b)_m1—;
  • X³ is selected from the group consisting of cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl, and heteroaryl are each independently optionally substituted with one or more substituents selected from the group consisting of halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, —(CH₂)_nNR^eR^f, nitro, hydroxy, hydroxyalkyl, aminoalkyl, alkoxyalkyl, cycloalkylalkyl, heterocyclylalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, and ═O;
  • X⁴ is —J¹—J²—J³—J⁴—J⁵—, wherein J¹ is attached to X³;
  • J¹ is selected from the group consisting of —O—, —S—, —NR⁶—, —C(O)—, —S(O)₂—, —(CR⁷R⁸)_m2—, alkenyl, and alkynyl;
  • J² is cycloalkyl or heterocyclyl, wherein the cycloalkyl and heterocyclyl are each independently optionally substituted with one or more substituents selected from the group consisting of halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, —(CH₂)_nNR^gR^h nitro, hydroxy, hydroxyalkyl, aminoalkyl, alkoxyalkyl, cycloalkylalkyl, heterocyclylalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, and ═O;
  • J³ is selected from the group consisting of —O—, —S—, —NR^6a—, —C(O)—, —S(O)₂—, —(CR^7aR^8a)_m3—, alkenyl, alkynyl, cycloalkyl, and heterocyclyl, wherein the cycloalkyl and heterocyclyl are each independently optionally substituted with one or more substituents selected from the group consisting of halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, —(CH₂)_nNR^gR^h, nitro, hydroxy, hydroxyalkyl, aminoalkyl, alkoxyalkyl, cycloalkylalkyl, heterocyclylalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, and ═O;
  • J⁴ is selected from the group consisting of a bond, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl, and heteroaryl are each independently optionally substituted with one or more substituents selected from the group consisting of halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, —(CH₂)_nNR^gR^h, nitro, hydroxy, hydroxyalkyl, aminoalkyl, alkoxyalkyl, cycloalkylalkyl, heterocyclylalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, and ═O;
  • J⁵ is selected from the group consisting of —C(O)NR^6b—, —NR^6bC(O)—, —O—, —S—, —NR⁶—, —C(O)—, —S(O)₂—, —(CR^7bR^8b)_m4—, alkenyl, alkynyl, cycloalkyl, and heterocyclyl, wherein the cycloalkyl and heterocyclyl are each independently optionally substituted with one or more substituents selected from the group consisting of halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, —(CH₂)_nNR^gR^h, nitro, hydroxy, hydroxyalkyl, aminoalkyl, alkoxyalkyl, cycloalkylalkyl, heterocyclylalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, and ═O;
  • R^a, R^b, R^c, R^d, R^e, R^f, R^g, R^h, R⁶, R^6a, and R^6b are identical or different and are each independently selected from the group consisting of a hydrogen atom, alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkoxyalkyl, cycloalkylalkyl, and heterocyclylalkyl;
  • R^2a, R^2b, R⁷, R⁸, R^7a, R^8a, R^7b, and R^8b are identical or different and are each independently selected from the group consisting of a hydrogen atom, halogen, alkyl, alkoxy, hydroxy, amino, cyano, haloalkyl, haloalkoxy, hydroxyalkyl, aminoalkyl, alkoxyalkyl, cycloalkylalkyl, and heterocyclylalkyl;
  • R³ is selected from the group consisting of a hydrogen atom, alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein the alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are each independently optionally substituted with one or more substituents selected from the group consisting of halogen, alkyl, alkoxy, hydroxy, amino, cyano, nitro, haloalkyl, haloalkoxy, hydroxyalkyl, ═O, aminoalkyl, alkoxyalkyl, cycloalkylalkyl, heterocyclylalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl;
  • R⁴ and R⁵ are identical or different and are each independently selected from the group consisting of a hydrogen atom, alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein the alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are each independently optionally substituted with one or more substituents selected from the group consisting of halogen, alkyl, alkoxy, hydroxy, amino, cyano, nitro, haloalkyl, haloalkoxy, hydroxyalkyl, ═O, aminoalkyl, alkoxyalkyl, cycloalkylalkyl, heterocyclylalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl;
  • or R⁴ and R⁵, together with the nitrogen atom to which they are attached, form heterocyclyl, and the heterocyclyl is optionally substituted with one or more substituents selected from the group consisting of halogen, alkyl, alkoxy, hydroxy, amino, cyano, nitro, haloalkyl, haloalkoxy, hydroxyalkyl, ═O, aminoalkyl, alkoxyalkyl, cycloalkylalkyl, heterocyclylalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl;
  • n is 0, 1, 2, or 3;
  • m is 0, 1, or 2;
  • m1 is 0, 1, 2, or 3;
  • m2 is 0, 1, 2, or 3;
  • m3 is 0, 1, 2, or 3; and
  • m4 is 0, 1, 2, or 3.

In some embodiments of the present disclosure, the compound represented by general formula (I) or the pharmaceutically acceptable salt thereof is provided, wherein: R is aryl or heteroaryl, wherein the aryl and heteroaryl are each independently optionally substituted with one or more substituents selected from the group consisting of halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, —(CH₂)_nNR^aR^b, nitro, hydroxy, hydroxyalkyl, aminoalkyl, alkoxyalkyl, cycloalkylalkyl, heterocyclylalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl;

A is selected from the group consisting of

• • is a single bond or a double bond;
  • one of Q¹, Q², Q³, Q⁴, and Q⁵ is a carbon atom, and the other four are identical or different and are each independently a nitrogen atom or CR¹;
  • each R¹ is identical or different and is independently selected from the group consisting of a hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, aminoalkyl, alkoxyalkyl, cyano, hydroxy, nitro, and —(CH₂)_nNR^cR^d;
  • R¹ is selected from the group consisting of a hydrogen atom, alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, and alkoxyalkyl;
  • R² is selected from the group consisting of a hydrogen atom, halogen, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, hydroxy, cyano, aminoalkyl, and alkoxyalkyl;
  • X¹ is spirocyclyl, wherein the spirocyclyl is optionally substituted with one or more substituents selected from the group consisting of halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, nitro, hydroxy, hydroxyalkyl, aminoalkyl, alkoxyalkyl, cycloalkylalkyl, heterocyclylalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, —OR³, —C(O)R³, —C(O)OR³, —S(O)_mR³, —NR⁴R⁵, —C(O)NR⁴R⁵, —S(O)_mNR⁴R⁵, ═O, and ═S;
  • X² is selected from the group consisting of —C(O)—, —S(O)₂—, and —(CR^2aR^2b)_m1—;
  • X³ is selected from the group consisting of cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl, and heteroaryl are each independently optionally substituted with one or more substituents selected from the group consisting of halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, —(CH₂)_nNR^eR^f, nitro, hydroxy, hydroxyalkyl, aminoalkyl, alkoxyalkyl, cycloalkylalkyl, heterocyclylalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, and ═O;
  • X⁴ is —J¹—J²—J³—J⁴—J⁵—, wherein J¹ is attached to X³;
  • J¹ is selected from the group consisting of —O—, —S—, —NR⁶—, —C(O)—, —S(O)₂—, —(CR⁷R⁸)_m2—, alkenyl, and alkynyl;
  • J² is cycloalkyl or heterocyclyl, wherein the cycloalkyl and heterocyclyl are each independently optionally substituted with one or more substituents selected from the group consisting of halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, —(CH₂)_nNR^gR^h nitro, hydroxy, hydroxyalkyl, aminoalkyl, alkoxyalkyl, cycloalkylalkyl, heterocyclylalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, and ═O;
  • J³ is selected from the group consisting of —O—, —S—, —NR^6a—, —C(O)—, —S(O)₂—, —(CR^7aR^8a)_m3—, alkenyl, alkynyl, cycloalkyl, and heterocyclyl, wherein the cycloalkyl and heterocyclyl are each independently optionally substituted with one or more substituents selected from the group consisting of halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, —(CH₂)_nNR^gR^h, nitro, hydroxy, hydroxyalkyl, aminoalkyl, alkoxyalkyl, cycloalkylalkyl, heterocyclylalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, and ═O;
  • J⁴ is selected from the group consisting of a bond, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl, and heteroaryl are each independently optionally substituted with one or more substituents selected from the group consisting of halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, —(CH₂)_nNR^gR^h nitro, hydroxy, hydroxyalkyl, aminoalkyl, alkoxyalkyl, cycloalkylalkyl, heterocyclylalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, and ═O;
  • J⁵ is selected from the group consisting of —C(O)NR^6b—, —NR^6bC(O)—, —O—, —S—, —NR^6b—, —C(O)—, —S(O)₂—, —(CR^7bR^8b)_m4—, alkenyl, alkynyl, cycloalkyl, and heterocyclyl, wherein the cycloalkyl and heterocyclyl are each independently optionally substituted with one or more substituents selected from the group consisting of halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, —(CH₂)_nNR^gR^h, nitro, hydroxy, hydroxyalkyl, aminoalkyl, alkoxyalkyl, cycloalkylalkyl, heterocyclylalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, and ═O;
  • R^a, R^b, R^c, R^d, R^e, R^f, R^g, R^h, R⁶, R^6a, and R^6b are identical or different and are each independently selected from the group consisting of a hydrogen atom, alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkoxyalkyl, cycloalkylalkyl, and heterocyclylalkyl;
  • R^2a, R^2b, R⁷, R⁸, R^7a, R^8a, R^7b, and R^8b are identical or different and are each independently selected from the group consisting of a hydrogen atom, halogen, alkyl, alkoxy, hydroxy, amino, cyano, haloalkyl, haloalkoxy, hydroxyalkyl, aminoalkyl, alkoxyalkyl, cycloalkylalkyl, and heterocyclylalkyl;
  • R³ is selected from the group consisting of a hydrogen atom, alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein the alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are each independently optionally substituted with one or more substituents selected from the group consisting of halogen, alkyl, alkoxy, hydroxy, amino, cyano, nitro, haloalkyl, haloalkoxy, hydroxyalkyl, ═O, aminoalkyl, alkoxyalkyl, cycloalkylalkyl, heterocyclylalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl;
  • R⁴ and R⁵ are identical or different and are each independently selected from the group consisting of a hydrogen atom, alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein the alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are each independently optionally substituted with one or more substituents selected from the group consisting of halogen, alkyl, alkoxy, hydroxy, amino, cyano, nitro, haloalkyl, haloalkoxy, hydroxyalkyl, ═O, aminoalkyl, alkoxyalkyl, cycloalkylalkyl, heterocyclylalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl;
  • or R⁴ and R⁵, together with the nitrogen atom to which they are attached, form heterocyclyl, and the heterocyclyl is optionally substituted with one or more substituents selected from the group consisting of halogen, alkyl, alkoxy, hydroxy, amino, cyano, nitro, haloalkyl, haloalkoxy, hydroxyalkyl, ═O, aminoalkyl, alkoxyalkyl, cycloalkylalkyl, heterocyclylalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl;
  • n is 0, 1, 2, or 3;
  • m is 0, 1, or 2;
  • m1 is 0, 1, 2, or 3;
  • m2 is 0, 1, 2, or 3;
  • m3 is 0, 1, 2, or 3; and
  • m4 is 0, 1, 2, or 3.

In some embodiments of the present disclosure, the compound represented by general formula (I) or the pharmaceutically acceptable salt thereof is provided, wherein R is 6- to 10-membered aryl or 5- to 10-membered heteroaryl, wherein the 6- to 10-membered aryl and 5- to 10-membered heteroaryl are each independently optionally substituted with one or more substituents selected from the group consisting of halogen, C_1-6 alkyl, C_1-6 alkoxy, C_1-6 haloalkyl, C_1-6 haloalkoxy, cyano, —(CH₂)_nNR^aR^b, nitro, hydroxy, C_1-6 hydroxyalkyl, C_1-6 aminoalkyl, C_1-6 alkoxy C_1-6 alkyl, 3- to 8-membered cycloalkyl C_1-6 alkyl, 3- to 8-membered heterocyclyl C_1-6 alkyl, 3- to 8-membered cycloalkyl, and 3- to 8-membered heterocyclyl; R^a and R^b are identical or different and are each independently a hydrogen atom or C_1-6 alkyl; n is 0, 1, 2, or 3;

• • preferably, R is phenyl or 5- or 6-membered heteroaryl, wherein the phenyl and 5- or 6-membered heteroaryl are each independently optionally substituted with one or more substituents selected from the group consisting of halogen, C_1-6 alkyl, C_1-6 alkoxy, C_1-6 haloalkyl, C_1-6 haloalkoxy, cyano, amino, nitro, hydroxy, and C_1-6 hydroxyalkyl;
  • preferably, R is phenyl, wherein the phenyl is optionally substituted with one or more substituents selected from the group consisting of halogen, C_1-6 alkyl, C_1-6 alkoxy, C_1-6 haloalkyl, and cyano;
  • more preferably, R is phenyl, wherein the phenyl is optionally substituted with one or more substituents selected from the group consisting of halogen and cyano; most preferably, R is phenyl, wherein the phenyl is optionally substituted with one or more substituents selected from the group consisting of a chlorine atom and cyano.

In some embodiments of the present disclosure, the compound represented by general formula I or the pharmaceutically acceptable salt thereof is provided, wherein R is

Z¹ is N or CR^3b; Z² is N or CR^3c; R^3a, R^3b, and R^3c are identical or different and are each independently selected from the group consisting of a hydrogen atom, halogen, C_1-6 alkyl, C_1-6 alkoxy, C_1-6 haloalkyl, C_1-6 haloalkoxy, cyano, amino, nitro, hydroxy, and C_1-6 hydroxyalkyl; preferably, R is selected from the group consisting of

more preferably, R is

In some embodiments of the present disclosure, the compound represented by general formula (I) or the pharmaceutically acceptable salt thereof is provided, wherein X¹ is 6-to 14-membered spiroheterocyclyl, wherein the 6- to 14-membered spiroheterocyclyl is optionally substituted with one or more substituents selected from the group consisting of halogen, C_1-6 alkyl, C_1-6 alkoxy, C_1-6 haloalkyl, C_1-6 haloalkoxy, cyano, nitro, hydroxy, C_1-6 hydroxyalkyl, C_1-6 aminoalkyl, C_1-6 alkoxy C_1-6 alkyl, 3- to 8-membered cycloalkyl C_1-6 alkyl, 3- to 8-membered heterocyclyl C_1-6 alkyl, 3- to 8-membered cycloalkyl, 3- to 8-membered heterocyclyl, 6- to 10-membered aryl, 5- to 10-membered heteroaryl, —NR⁴R⁵, ═O, and ═S; R⁴ and R⁵ are identical or different and are each independently a hydrogen atom or C_1-6 alkyl.

In some embodiments of the present disclosure, the compound represented by general formula (I) or the pharmaceutically acceptable salt thereof is provided, wherein X¹ is

• • the bond with * is attached to X²;
  • G¹ is N or CH;
  • G² is N or CH;
  • R^1a, R^1b, R^1c, R^1d, and R^1e are identical or different and are each independently selected from the group consisting of a hydrogen atom, halogen, C_1-6 alkyl, C_1-6 alkoxy, C_1-6 haloalkyl, C_1-6 haloalkoxy, cyano, hydroxy, C_1-6 hydroxyalkyl, C_1-6 aminoalkyl, C_1-6 alkoxy C_1-6 alkyl, 3- to 8-membered cycloalkyl C_1-6 alkyl, 3- to 8-membered heterocyclyl C_1-6 alkyl, 3- to 8-membered cycloalkyl, and —NR⁴R⁵;
  • or, R^1a and R^1b, together with the carbon atom to which they are attached, form 3- to 8-membered cycloalkyl or 3- to 8-membered heterocyclyl, wherein the 3- to 8-membered cycloalkyl and 3- to 8-membered heterocyclyl are each independently optionally substituted with one or more substituents selected from the group consisting of halogen, C_1-6 alkyl, C_1-6 alkoxy, C_1-6 haloalkyl, C_1-6 haloalkoxy, cyano, hydroxy, C_1-6 hydroxyalkyl, C_1-6 aminoalkyl, C_1-6 alkoxy C_1-6 alkyl, 3- to 8-membered cycloalkyl C_1-6 alkyl, 3- to 8-membered heterocyclyl C_1-6 alkyl, 3- to 8-membered cycloalkyl, —NR⁴R⁵, and ═O; or, R^1c and R^1d, together with the carbon atom to which they are attached, form 3- to 8-membered cycloalkyl or 3- to 8-membered heterocyclyl, wherein the 3- to 8-membered cycloalkyl and 3- to 8-membered heterocyclyl are each independently optionally substituted with one or more substituents selected from the group consisting of halogen, C_1-6 alkyl, C_1-6 alkoxy, C_1-6 haloalkyl, C_1-6 haloalkoxy, cyano, hydroxy, C_1-6 hydroxyalkyl, C_1-6 aminoalkyl, C_1-6 alkoxy C_1-6 alkyl, 3- to 8-membered cycloalkyl C_1-6 alkyl, 3- to 8-membered heterocyclyl C_1-6 alkyl, 3- to 8-membered cycloalkyl, —NR⁴R⁵, and ═O;
  • or, R^1a and R^1b, together with the carbon atom to which they are attached, form C═O;
  • or, R^1c and R^1d, together with the carbon atom to which they are attached, form C═O;
  • R⁴ and R⁵ are identical or different and are each independently a hydrogen atom or C_1-6 alkyl;
  • o is 0 or 1;
  • p is 0 or 1;
  • q is 0, 1, 2, or 3;
  • r is 0, 1, 2, or 3;
  • s is 0, 1, 2, 3, or 4;
  • t is 0, 1, 2, 3, or 4; and
  • j is 0, 1, 2, 3, or 4.

In some embodiments of the present disclosure, the compound represented by general formula (I) or the pharmaceutically acceptable salt thereof is provided, wherein X¹ is

the bond with * is attached to X²; R^1a, R^1b, R^1c, and R^1d are identical or different and are each independently selected from the group consisting of a hydrogen atom, halogen, C_1-6 alkyl, C_1-6 alkoxy, C_1-6 haloalkyl, C_1-6 haloalkoxy, cyano, amino, hydroxy, and C_1-6 hydroxyalkyl;

• • or, R^1a and R^1b, together with the carbon atom to which they are attached, form C═O;
  • or, R^1c and R^1d, together with the carbon atom to which they are attached, form C═O;
  • q is 0, 1, 2, or 3; r is 0, 1, 2, or 3; s is 0, 1, 2, 3, or 4; and t is 0, 1, 2, 3, or 4.

In some embodiments of the present disclosure, the compound represented by general formula I or the pharmaceutically acceptable salt thereof is provided, wherein X¹ is

the bond with * is attached to X²; R^1a and R^1b are identical or different and are each independently selected from the group consisting of a hydrogen atom, halogen, C_1-6 alkyl, C_1-6 alkoxy, C_1-6 haloalkyl, C_1-6 haloalkoxy, cyano, amino, hydroxy, and C_1-6 hydroxyalkyl; or, R^1a and R^1b, together with the carbon atom to which they are attached, form C═O.

In some embodiments of the present disclosure, the compound represented by general formula (I) or the pharmaceutically acceptable salt thereof is provided, wherein X¹ is

the bond with * is attached to X²; R^1a is selected from the group consisting of a hydrogen atom, halogen, C_1-6 alkyl, C_1-6 alkoxy, C_1-6 haloalkyl, C_1-6 haloalkoxy, cyano, amino, hydroxy, and C_1-6 hydroxyalkyl, preferably a hydrogen atom or C_1-6 alkyl, further preferably C_1-6 alkyl, and more preferably methyl.

In some embodiments of the present disclosure, the compound represented by general formula I or the pharmaceutically acceptable salt thereof is provided, wherein X¹ is

the bond with * is attached to X²; R^1c and R^1d are identical or different and are each independently selected from the group consisting of a hydrogen atom, halogen, C_1-6 alkyl, C_1-6 alkoxy, C_1-6 haloalkyl, C_1-6 haloalkoxy, cyano, amino, hydroxy, and C_1-6 hydroxyalkyl; or, R^1c and R^1d, together with the carbon atom to which they are attached, form C═O.

In some embodiments of the present disclosure, the compound represented by general formula (I) or the pharmaceutically acceptable salt thereof is provided, wherein X¹ is

the bond with * is attached to X²; R^1c is selected from the group consisting of a hydrogen atom, halogen, C_1-6 alkyl, C_1-6 alkoxy, C_1-6 haloalkyl, C_1-6 haloalkoxy, cyano, amino, hydroxy, and C_1-6 hydroxyalkyl, preferably C_1-6 alkyl, and more preferably methyl.

In some embodiments of the present disclosure, the compound represented by general formula (I) or the pharmaceutically acceptable salt thereof is provided, wherein X is

preferably, X¹ is selected from the group consisting of

more preferably, X¹ is

most preferably, X¹ is

the bond with * is attached to X².

In some embodiments of the present disclosure, the compound represented by general formula (I) or the pharmaceutically acceptable salt thereof is a compound represented by general formula (II) or a pharmaceutically acceptable salt thereof:

• • wherein:
  • R^1a is selected from the group consisting of a hydrogen atom, halogen, C_1-6 alkyl, C_1-6 alkoxy, C_1-6 haloalkyl, C_1-6 haloalkoxy, cyano, amino, hydroxy, and C_1-6 hydroxyalkyl; preferably, R^1a is C_1-6 alkyl; more preferably, R^1a is methyl;
  • Z¹ is N or CR^3b; Z² is N or CR^3c; R^3a, R^3b, and R^3c are identical or different and are each independently selected from the group consisting of a hydrogen atom, halogen, C_1-6 alkyl, C_1-6 alkoxy, C_1-6 haloalkyl, C_1-6 haloalkoxy, cyano, amino, nitro, hydroxy, and C_1-6 hydroxyalkyl; and
  • X², X³, X⁴, and A are as defined in general formula (I).

In some embodiments of the present disclosure, the compounds represented by general formula (I) and general formula (II) or the pharmaceutically acceptable salts thereof are compounds represented by general formula (II-1) or pharmaceutically acceptable salts thereof:

• • wherein:
  • R^1a is selected from the group consisting of halogen, C_1-6 alkyl, C_1-6 alkoxy, C_1-6 haloalkyl, C_1-6 haloalkoxy, cyano, amino, hydroxy, and C_1-6 hydroxyalkyl; preferably, R^1a is C_1-6 alkyl; more preferably, R^1a is methyl; and
  • Z¹, Z², R^3a, X², X³, X⁴, and A are as defined in general formula (II).

In some embodiments of the present disclosure, the compounds represented by general formula (I), general formula (II), and general formula (II-1) or the pharmaceutically acceptable salts thereof are provided, wherein X³ is 6- to 10-membered aryl or 5- to 10-membered heteroaryl, wherein the 6- to 10-membered aryl and 5- to 10-membered heteroaryl are each independently optionally substituted with one or more substituents selected from the group consisting of halogen, C_1-6 alkyl, C_1-6 alkoxy, C_1-6 haloalkyl, C_1-6 haloalkoxy, cyano, —(CH₂)_nNR^eR^f, nitro, hydroxy, C_1-6 hydroxyalkyl, C_1-6 aminoalkyl, C_1-6 alkoxy C_1-6 alkyl, 3- to 8-membered cycloalkyl C_1-6 alkyl, 3- to 8-membered heterocyclyl C_1-6 alkyl, 3- to 8-membered cycloalkyl, 3- to 8-membered heterocyclyl, 6-to 10-membered aryl, and 5- to 10-membered heteroaryl; R^e and R^f are identical or different and are each independently a hydrogen atom or C_1-6 alkyl; and n is 0, 1, 2, or 3; preferably, X³ is 6- to 10-membered aryl or 5- to 10-membered heteroaryl, wherein the 6-to 10-membered aryl and 5- to 10-membered heteroaryl are each independently optionally substituted with one or more substituents selected from the group consisting of halogen, C_1-6 alkyl, C_1-6 alkoxy, C_1-6 haloalkyl, C_1-6 haloalkoxy, cyano, amino, hydroxy, and C_1-6 hydroxyalkyl;

• • more preferably, X³ is selected from the group consisting of phenyl, pyridinyl, pyrimidinyl, pyridazinyl, and pyrazinyl, wherein the phenyl, pyridinyl, pyrimidinyl, pyridazinyl, and pyrazinyl are each independently optionally substituted with one or more substituents selected from the group consisting of halogen, C_1-6 alkyl, and C_1-6 haloalkyl; most preferably, X³ is phenyl or pyridinyl, wherein the phenyl and pyridinyl are each independently optionally substituted with one or more substituents selected from the group consisting of halogen, C_1-6 alkyl, and C_1-6 haloalkyl.

In some embodiments of the present disclosure, the compounds represented by general formula (I), general formula (II), and general formula (II-1) or the pharmaceutically acceptable salts thereof are provided, wherein X³ is phenyl or 6-membered heteroaryl, wherein the phenyl and 6-membered heteroaryl are each independently optionally substituted with one or more halogens; preferably, X³ is selected from the group consisting of phenyl, pyridinyl, pyrimidinyl, pyridazinyl, and pyrazinyl, and the phenyl, pyridinyl, pyrimidinyl, pyridazinyl, and pyrazinyl are each independently optionally substituted with one or more F; more preferably, X³ is phenyl, and the phenyl is optionally substituted with one or more F; most preferably, X³ is phenyl.

In some embodiments of the present disclosure, the compounds represented by general formula (I), general formula (II), and general formula (II-1) or the pharmaceutically acceptable salts thereof are provided, wherein X³ is

the bond with * is attached to X⁴; wherein:

• • W¹ is N or CR^3d; W² is N or CR^3e; W³ is N or CR^3f; W⁴ is N or CR^3g; R^3d, R^3e, R^3f, and R^3g are identical or different and are each independently selected from the group consisting of a hydrogen atom, halogen, C_1-6 alkyl, C_1-6 alkoxy, C_1-6 haloalkyl, C_1-6 haloalkoxy, cyano, —(CH₂)_nNR^eR^f, nitro, hydroxy, C_1-6 hydroxyalkyl, C_1-6 aminoalkyl, C_1-6 alkoxy C_1-6 alkyl, 3- to 8-membered cycloalkyl C_1-6 alkyl, 3- to 8-membered heterocyclyl C_1-6 alkyl, 3- to 8-membered cycloalkyl, 3- to 8-membered heterocyclyl, 6-to 10-membered aryl, and 5- to 10-membered heteroaryl; R^e and R^f are identical or different and are each independently a hydrogen atom or C_1-6 alkyl; and n is 0, 1, 2, or 3; preferably, W¹ is N or CR^3d; W² is N or CR^3e; W³ is N or CR^3f; W⁴ is N or CR^3g; R^3d, R^3e, R^3f, and R^3g are identical or different and are each independently selected from the group consisting of a hydrogen atom, halogen, C_1-6 alkyl, C_1-6 alkoxy, C_1-6 haloalkyl, C_1-6 haloalkoxy, cyano, amino, hydroxy, and C_1-6 hydroxyalkyl;
  • more preferably, W¹ is N or CR^3d; W² is N or CR^3e; W³ is N or CR^3f; W⁴ is N or CR^3g; R^3d, R^3e, R^3f, and R^3g are identical or different and are each independently selected from the group consisting of a hydrogen atom, halogen, C_1-6 alkyl, C_1-6 alkoxy, and C_1-6 haloalkyl;
  • further preferably, W¹ is N or CR^3d; W² is N or CR^3e; W³ is N or CR^3f; W⁴ is N or CR^3g; R^3d, R^3e, R^3f, and R^3g are identical or different and are each independently a hydrogen atom or halogen (the halogen is preferably F);
  • most preferably, W¹ is CR^3d; W² is CR^3e; W³ is CR^3f; W⁴ is CR^3g; R^3d, R^3e, R^3f, and R^3g are identical or different and are each independently a hydrogen atom or halogen (the halogen is preferably F);
  • still most preferably, W¹ is CH; W² is CH; W³ is CH; W⁴ is CH.

In some embodiments of the present disclosure, the compounds represented by general formula (I), general formula (II), and general formula (II-1) or the pharmaceutically acceptable salts thereof are provided, wherein X³ is selected from the group consisting of

the bond with * is attached to X⁴; R^3d, R^3e, R^3f, R^3g, and R^3h are identical or different and are each independently selected from the group consisting of a hydrogen atom, halogen, C_1-6 alkyl, C_1-6 alkoxy, C_1-6 haloalkyl, C_1-6 haloalkoxy, cyano, amino, hydroxy, and C_1-6 hydroxyalkyl; and w is 0, 1, 2, or 3.

In some embodiments of the present disclosure, the compounds represented by general formula (I), general formula (II), and general formula (II-1) or the pharmaceutically acceptable salts thereof are provided, wherein X³ is selected from the group consisting of

R^3d, R^3e, R^3f, and R^3g are identical or different and are each independently selected from the group consisting of a hydrogen atom, halogen, C_1-6 alkyl, C_1-6 alkoxy, C_1-6 haloalkyl, C_1-6 haloalkoxy, cyano, amino, hydroxy, and C_1-6 hydroxyalkyl; preferably from the group consisting of

R^3d, R^3e, R^3f, and R^3g are identical or different and are each independently a hydrogen atom or halogen (preferably F); more preferably from the group consisting of

further preferably from the group consisting of

and most preferably

the bond with * is attached to X⁴.

In some embodiments of the present disclosure, the compounds represented by general formula (I), general formula (II), and general formula (II-1) or the pharmaceutically acceptable salts thereof are provided, wherein J² is 3- to 12-membered cycloalkyl or 3- to 12-membered heterocyclyl, wherein the 3- to 12-membered cycloalkyl and 3- to 12-membered heterocyclyl are each independently optionally substituted with one or more substituents selected from the group consisting of halogen, C_1-6 alkyl, C_1-6 alkoxy, C_1-6 haloalkyl, C_1-6 haloalkoxy, cyano, —(CH)_nNR^gR^h, nitro, hydroxy, C_1-6 hydroxyalkyl, C_1-6 aminoalkyl, C_1-6 alkoxy C_1-6 alkyl, 3- to 8-membered cycloalkyl C_1-6 alkyl, 3- to 8-membered heterocyclyl C_1-6 alkyl, 3- to 8-membered cycloalkyl, 3- to 8-membered heterocyclyl, and ═O; R^g and R^h are identical or different and are each independently a hydrogen atom or C_1-6 alkyl; and n is 0, 1, 2, or 3.

In some embodiments of the present disclosure, the compounds represented by general formula (I), general formula (II), and general formula (II-1) or the pharmaceutically acceptable salts thereof are provided, wherein J² is 3- to 12-membered cycloalkyl or 3- to 12-membered heterocyclyl, and the 3- to 12-membered cycloalkyl and 3- to 12-membered heterocyclyl are each independently optionally substituted with one or more substituents selected from the group consisting of halogen, C_1-6 alkyl, C_1-6 alkoxy, C_1-6 haloalkyl, C_1-6 haloalkoxy, cyano, amino, hydroxy, and ═O;

• • preferably, J² is 3- to 12-membered heterocyclyl, wherein the 3- to 12-membered heterocyclyl is optionally substituted with one or more substituents selected from the group consisting of halogen, C_1-6 alkyl, C_1-6 alkoxy, C_1-6 haloalkyl, C_1-6 haloalkoxy, cyano, amino, hydroxy, and ═O;
  • further preferably, J² is 3- to 8-membered monocyclic heterocyclyl or 7- to 11-membered spiroheterocyclyl, and the 3- to 8-membered monocyclic heterocyclyl and 7- to 11-membered spiroheterocyclyl are each independently optionally substituted with one or more substituents selected from the group consisting of halogen, C_1-6 alkyl, and C_1-6 haloalkyl;
  • still further preferably, J² is 4- to 6-membered monocyclic heterocyclyl or 9- to 11-membered spiroheterocyclyl;
  • more preferably, J² is piperidinyl or piperazinyl.

In some embodiments of the present disclosure, the compounds represented by general formula (I), general formula (II), and general formula (II-1) or the pharmaceutically acceptable salts thereof are provided, wherein J² is selected from the group consisting of the following structures:

wherein the bond with * is attached to J³; each R^2c is identical or different and is independently selected from the group consisting of a hydrogen atom, halogen, C_1-6 alkyl, C_1-6 alkoxy, C_1-6 haloalkyl, C_1-6 haloalkoxy, cyano, amino, hydroxy, and ═O, preferably a hydrogen atom; and k is 0, 1, 2, 3, 4, 5, or 6.

In some embodiments of the present disclosure, the compounds represented by general formula (I), general formula (II), and general formula (II-1) or the pharmaceutically acceptable salts thereof are provided, wherein J² is selected from the group consisting of

wherein the bond with * is attached to J³.

In some embodiments of the present disclosure, the compounds represented by general formula (I), general formula (II), and general formula (II-1) or the pharmaceutically acceptable salts thereof are provided, wherein J² is selected from the group consisting of

each R^2c is identical or different and is independently selected from the group consisting of halogen, C_1-6 alkyl, C_1-6 haloalkyl and ═O; and k is 0, 1 or 2 preferably, J² is selected from the group consisting of

more preferably, J² is

most preferably, J² is

wherein the bond with * is attached to J³.

In some embodiments of the present disclosure, the compounds represented by general formula (I), general formula (II), and general formula (II-1) or the pharmaceutically acceptable salts thereof are provided, wherein R^6a is a hydrogen atom or C_1-6 alkyl; preferably, R^6a is a hydrogen atom or methyl.

In some embodiments of the present disclosure, the compounds represented by general formula (I), general formula (II), and general formula (II-1) or the pharmaceutically acceptable salts thereof are provided, wherein R^7a and R^8a are identical or different and are each independently selected from the group consisting of a hydrogen atom, halogen, C_1-6 alkyl, C_1-6 alkoxy, hydroxy, amino, cyano, C_1-6 haloalkyl, C_1-6 haloalkoxy, and C_1-6 hydroxyalkyl; preferably, R^7a and R^8a are identical or different and are each independently selected from the group consisting of a hydrogen atom, halogen, hydroxy, and C_1-6 alkyl; more preferably, R^7a and R^8a are both hydrogen atoms.

In some embodiments of the present disclosure, the compounds represented by general formula (I), general formula (II), and general formula (II-1) or the pharmaceutically acceptable salts thereof are provided, wherein J³ is selected from the group consisting of —O—, —S—, —NR^6a—, —C(O)—, —S(O)₂—, —(CR^7aR^8a)_m3—, C_2-6 alkenyl, C_2-6 alkynyl, 3- to 12-membered cycloalkyl, and 3- to 12-membered heterocyclyl, wherein the 3- to 12-membered cycloalkyl and 3- to 12-membered heterocyclyl are each independently optionally substituted with one or more substituents selected from the group consisting of halogen, C_1-6 alkyl, C_1-6 alkoxy, C_1-6 haloalkyl, C_1-6 haloalkoxy, cyano, —(CH₂)_nNR^gR^h nitro, hydroxy, C_1-6 hydroxyalkyl, C_1-6 aminoalkyl, C_1-6 alkoxy C_1-6 alkyl, 3- to 8-membered cycloalkyl C_1-6 alkyl, 3- to 8-membered heterocyclyl C_1-6 alkyl, 3- to 8-membered cycloalkyl, 3- to 8-membered heterocyclyl, and ═O; R^g and R^h are identical or different and are each independently a hydrogen atom or C_1-6 alkyl; R^6a is a hydrogen atom or C_1-6 alkyl; R^7a and R^8a are identical or different and are each independently selected from the group consisting of a hydrogen atom, halogen, C_1-6 alkyl, C_1-6 alkoxy, hydroxy, amino, cyano, C_1-6 haloalkyl, C_1-6 haloalkoxy, and C_1-6 hydroxyalkyl; m3 is 0, 1, 2, or 3; n is 0, 1, 2, or 3.

In some embodiments of the present disclosure, the compounds represented by general formula (I), general formula (II), and general formula (II-1) or the pharmaceutically acceptable salts thereof are provided, wherein J³ is selected from the group consisting of —O—, —S—, —NR^a—, —C(O)—, —S(O)₂—, —(CR^7aR^8a)_m3—, C_2-6 alkenyl, C_2-6 alkynyl, 3- to 8-membered cycloalkyl, and 3- to 8-membered heterocyclyl; R^6a is a hydrogen atom or C_1-6 alkyl, preferably a hydrogen atom or methyl; R^7a and R^8a are identical or different and are each independently selected from the group consisting of a hydrogen atom, halogen, hydroxy, and C_1-6 alkyl, preferably a hydrogen atom; m3 is 0, 1, 2, or 3.

In some embodiments of the present disclosure, the compounds represented by general formula (I), general formula (II), and general formula (II-1) or the pharmaceutically acceptable salts thereof are provided, wherein J³ is —(CR^7aR^8a)_m3—; R^7a and R^8a are identical or different and are each independently selected from the group consisting of a hydrogen atom, halogen, hydroxy, and C_1-6 alkyl, preferably a hydrogen atom; and m3 is 0, 1, 2, or 3, preferably 0 or 1.

In some embodiments of the present disclosure, the compounds represented by general formula (I), general formula (II), and general formula (II-1) or the pharmaceutically acceptable salts thereof are provided, wherein J³ is —(CH₂)_m3—; m3 is 0, 1, 2, or 3, preferably 0 or 1.

In some embodiments of the present disclosure, the compounds represented by general formula (I), general formula (II), and general formula (II-1) or the pharmaceutically acceptable salts thereof are provided, wherein J³ is selected from the group consisting of a bond, —O—, —S—, —NH—, —N(CH₃)—, —C(O)—, —S(O)₂—, —CH₂—, —CH(CH₃)—, CH₂CH₂—, —CH₂CH₂CH₂—, and ethynylene; preferably, J¹ is a bond or —CH₂—; more preferably, J³ is —CH₂—.

In some embodiments of the present disclosure, the compounds represented by general formula (I), general formula (II), and general formula (II-1) or the pharmaceutically acceptable salts thereof are provided, wherein J⁴ is selected from the group consisting of a bond, 3- to 12-membered cycloalkyl, 3- to 12-membered heterocyclyl, 6- to 10-membered aryl, and 5- to 10-membered heteroaryl, wherein the 3- to 12-membered cycloalkyl, 3- to 12-membered heterocyclyl, 6- to 10-membered aryl, and 5- to 10-membered heteroaryl are each independently optionally substituted with one or more substituents selected from the group consisting of halogen, C_1-6 alkyl, C_1-6 alkoxy, C_1-6 haloalkyl, C_1-6 haloalkoxy, cyano, —(C)_nNR^gR^h, nitro, hydroxy, C_1-6 hydroxyalkyl, C_1-6 aminoalkyl, C_1-6 alkoxy C_1-6 alkyl, 3- to 8-membered cycloalkyl C_1-6 alkyl, 3- to 8-membered heterocyclyl C_1-6 alkyl, 3- to 8-membered cycloalkyl, 3- to 8-membered heterocyclyl, and ═O; R^g and R^h are identical or different and are each independently a hydrogen atom or C_1-6 alkyl; and n is 0, 1, 2, or 3.

In some embodiments of the present disclosure, the compounds represented by general formula (I), general formula (II), and general formula (II-1) or the pharmaceutically acceptable salts thereof are provided, wherein J⁴ is 3- to 12-membered cycloalkyl or 3- to 12-membered heterocyclyl, and the 3- to 12-membered cycloalkyl and 3- to 12-membered heterocyclyl are each independently optionally substituted with one or more substituents selected from the group consisting of halogen, C_1-6 alkyl, C_1-6 alkoxy, C_1-6 haloalkyl, C_1-6 haloalkoxy, cyano, amino, hydroxy, and ═O;

• • preferably, J⁴ is 3- to 8-membered cycloalkyl or 3- to 8-membered heterocyclyl, and the 3- to 8-membered cycloalkyl and 3- to 8-membered heterocyclyl are each independently optionally substituted with one or more substituents selected from the group consisting of halogen, C_1-6 alkyl, C_1-6 alkoxy, C_1-6 haloalkyl, C_1-6 haloalkoxy, cyano, amino, hydroxy, and ═O;
  • more preferably, J⁴ is 3- to 8-membered heterocyclyl, and the 3- to 8-membered heterocyclyl is optionally substituted with one or more substituents selected from the group consisting of halogen, C_1-6 alkyl, C_1-6 alkoxy, C_1-6 haloalkyl, C_1-6 haloalkoxy, cyano, amino, hydroxy, and ═O;
  • further preferably, J⁴ is 4- to 6-membered heterocyclyl, and the 4- to 6-membered heterocyclyl is optionally substituted with one or more ═O;
  • further preferably, J⁴ is selected from the group consisting of piperazinyl, piperidinyl, and azetidinyl, and the piperazinyl and piperidinyl are each independently optionally substituted with one or more ═O;
  • most preferably, J⁴ is selected from the group consisting of piperazinyl, piperidinyl, and azetidinyl.

In some embodiments of the present disclosure, the compounds represented by general formula (I), general formula (II), and general formula (II-1) or the pharmaceutically acceptable salts thereof are provided, wherein J⁴ is a bond or 4- to 6-membered heterocyclyl, and the 4- to 6-membered heterocyclyl is optionally substituted with one or more ═O; preferably, J⁴ is selected from the group consisting of a bond, piperazinyl, piperidinyl, and azetidinyl, and the piperazinyl and piperidinyl are each independently optionally substituted with one or more ═O; more preferably, J⁴ is selected from the group consisting of a bond,

the bond with * is attached to J⁵.

In some embodiments of the present disclosure, the compounds represented by general formula (I), general formula (II), and general formula (II-1) or the pharmaceutically acceptable salts thereof are provided, wherein J⁴ is selected from the group consisting of the following structures:

the bond with * is attached to J⁵; each R^4a is identical or different and is independently selected from the group consisting of a hydrogen atom, halogen, C_1-6 alkyl, C_1-6 alkoxy, C_1-6 haloalkyl, C_1-6 haloalkoxy, cyano, amino, hydroxy, and ═O, preferably a hydrogen atom; and z is 0, 1, 2, or 3.

In some embodiments of the present disclosure, the compounds represented by general formula (I), general formula (II), and general formula (II-1) or the pharmaceutically acceptable salts thereof are provided, wherein J⁴ is selected from the group consisting of the following structures:

each R^4a is identical or different and is independently selected from the group consisting of a hydrogen atom, halogen, C_1-6 alkyl, C_1-6 alkoxy, C_1-6 haloalkyl, C_1-6 haloalkoxy, cyano, amino, hydroxy, and ═O, preferably a hydrogen atom; and z is 0, 1, 2, or 3; preferably, J⁴ is selected from the group consisting of

more preferably, J⁴ is

the bond with * is attached to J⁵.

In some embodiments of the present disclosure, the compounds represented by general formula (I) and general formula (II) or the pharmaceutically acceptable salts thereof are compounds represented by general formula (G) or pharmaceutically acceptable salts thereof:

• • wherein:
  • R^1a is selected from the group consisting of a hydrogen atom, halogen, C_1-6 alkyl, C_1-6 alkoxy, C_1-6 haloalkyl, C_1-6 haloalkoxy, cyano, amino, hydroxy, and C_1-6 hydroxyalkyl;
  • Z¹ is N or CR^3b; Z² is N or CR^3c; R^3a, R^3b, and R^3c are identical or different and are each independently selected from the group consisting of a hydrogen atom, halogen, C_1-6 alkyl, C_1-6 alkoxy, C_1-6 haloalkyl, C_1-6 haloalkoxy, cyano, amino, nitro, hydroxy, and C_1-6 hydroxyalkyl;
  • ring B and ring C are identical or different and are each independently 3- to 12-membered cycloalkyl or 3- to 12-membered heterocyclyl, and the 3- to 12-membered cycloalkyl and 3- to 12-membered heterocyclyl are each independently optionally substituted with one or more substituents selected from the group consisting of halogen, C_1-6 alkyl, C_1-6 alkoxy, C_1-6 haloalkyl, C_1-6 haloalkoxy, cyano, amino, hydroxy, and ═O;
  • W¹ is N or CR^3d; W² is N or CR^3e; W³ is N or CR^3f; W⁴ is N or CR^3g;
  • R^3d, R^3e, R^3f, and R^3g are identical or different and are each independently selected from the group consisting of a hydrogen atom, halogen, C_1-6 alkyl, C_1-6 alkoxy, C_1-6 haloalkyl, C_1-6 haloalkoxy, cyano, amino, hydroxy, and C_1-6 hydroxyalkyl;
  • and m3, X², J¹, J⁵, and A are as defined in general formula (I).

In some embodiments of the present disclosure, the compounds represented by general formula (I), general formula (II), and general formula (G) or the pharmaceutically acceptable salts thereof are compounds represented by general formula (G-1) or pharmaceutically acceptable salts thereof:

• • wherein:
  • R^1a is selected from the group consisting of halogen, C_1-6 alkyl, C_1-6 alkoxy, C_1-6 haloalkyl, C_1-6 haloalkoxy, cyano, amino, hydroxy, and C_1-6 hydroxyalkyl; and ring B, ring C, R^3a, W¹, W², W³, W⁴, Z¹, Z², m3, X², J¹, J⁵, and A are as defined in general formula (G).

In some embodiments of the present disclosure, the compounds represented by general formula (G) and general formula (G-1) or the pharmaceutically acceptable salts thereof are provided, wherein ring B is 3- to 12-membered heterocyclyl, and the 3- to 12-membered heterocyclyl is optionally substituted with one or more substituents selected from the group consisting of halogen, C_1-6 alkyl, and C_1-6 haloalkyl; preferably, ring B is 3- to 8-membered monocyclic heterocyclyl or 7- to 11-membered spiroheterocyclyl, and the 3- to 8-membered monocyclic heterocyclyl and 7- to 11-membered spiroheterocyclyl are each independently optionally substituted with one or more substituents selected from the group consisting of halogen, C_1-6 alkyl, and C_1-6 haloalkyl; more preferably, ring B is 4- to 6-membered monocyclic heterocyclyl or 9- to 11-membered spiroheterocyclyl; further preferably, ring B is selected from the group consisting of

more preferably, ring B is

most preferably, ring B is

wherein the bond with * is attached to (CH₂)_m3.

In some embodiments of the present disclosure, the compounds represented by general formula (G) and general formula (G-1) or the pharmaceutically acceptable salts thereof are provided, wherein ring C is 4- to 6-membered heterocyclyl, and the 4- to 6-membered heterocyclyl is optionally substituted with one or more ═O; preferably, ring C is selected from the group consisting of piperazinyl, piperidinyl, and azetidinyl, and the piperazinyl and piperidinyl are each independently optionally substituted with one or more ═O; more preferably, ring C is selected from the group consisting of

most preferably, ring C is

the bond with * is attached to J⁵.

In some embodiments of the present disclosure, the compounds represented by general formula (I), general formula (II), general formula (II-1), general formula (G), and general formula (G-1) or the pharmaceutically acceptable salts thereof are provided, wherein R^7b and R^8b are identical or different and are each independently selected from the group consisting of a hydrogen atom, halogen, C_1-6 alkyl, C_1-6 alkoxy, hydroxy, amino, cyano, C_1-6 haloalkyl, C_1-6 haloalkoxy, and C_1-6 hydroxyalkyl; preferably, R^7b and R^8b are identical or different and are each independently selected from the group consisting of a hydrogen atom, halogen, hydroxy, and C_1-6 alkyl; more preferably, R^7b and R^8b are both hydrogen atoms.

In some embodiments of the present disclosure, the compounds represented by general formula (I), general formula (II), general formula (II-1), general formula (G), and general formula (G-1) or the pharmaceutically acceptable salts thereof are provided, wherein R^7b is a hydrogen atom or C_1-6 alkyl; preferably, R^6b is a hydrogen atom or methyl.

In some embodiments of the present disclosure, the compounds represented by general formula (I), general formula (II), general formula (II-1), general formula (G), and general formula (G-1) or the pharmaceutically acceptable salts thereof are provided, wherein JV is selected from the group consisting of —C(O)NR^6b—, —NR^6bC(O)—, —O—, —S—, —NR^6b—, —C(O)—, —S(O)₂—, —(CR^7bR^8b)_m4—, C_2-6 alkenyl, C_2-6 alkynyl, 3- to 12-membered cycloalkyl, and 3- to 12-membered heterocyclyl, wherein the 3- to 12-membered cycloalkyl and 3-to 12-membered heterocyclyl are each independently optionally substituted with one or more substituents selected from the group consisting of halogen, C_1-6 alkyl, C_1-6 alkoxy, C_1-6 haloalkyl, C_1-6 haloalkoxy, cyano, —(CH₂)_nNR^gR^h, nitro, hydroxy, C_1-6 hydroxyalkyl, C_1-6 aminoalkyl, C_1-6 alkoxy C_1-6 alkyl, 3- to 8-membered cycloalkyl C_1-6 alkyl, 3- to 8-membered heterocyclyl C_1-6 alkyl, 3- to 8-membered cycloalkyl, 3- to 8-membered heterocyclyl, and ═O; R^g and R^h are identical or different and are each independently a hydrogen atom or C_1-6 alkyl; n is 0, 1, 2, or 3; R⁶ is a hydrogen atom or C_1-6 alkyl; R^7b and R^8b are identical or different and are each independently selected from the group consisting of a hydrogen atom, halogen, C_1-6 alkyl, C_1-6 alkoxy, hydroxy, amino, cyano, C_1-6 haloalkyl, C_1-6 haloalkoxy, and C_1-6 hydroxyalkyl; m4 is 0, 1, 2, or 3.

In some embodiments of the present disclosure, the compounds of general formula (I), general formula (II), general formula (II-1), general formula (G), and general formula (G-1) or the pharmaceutically acceptable salts thereof are provided, wherein J⁵ is selected from the group consisting of —C(O)NR^6b—, —NR^6bC(O)—, —O—, —S—, —NR^6b—, —C(O)—, —S(O)₂—, —(CR^7bR^8b)_m4—, C_2-6 alkenyl, C_2-6 alkynyl, 3- to 8-membered cycloalkyl, and 3- to 8-membered heterocyclyl; R^6b is a hydrogen atom or C_1-6 alkyl, preferably a hydrogen atom or methyl; R^7b and R^8b are identical or different and are each independently selected from the group consisting of a hydrogen atom, halogen, hydroxy, and C_1-6 alkyl, preferably a hydrogen atom; m4 is 0, 1, 2, or 3, preferably 0 or 1.

In some embodiments of the present disclosure, the compounds represented by general formula (I), general formula (II), general formula (II-1), general formula (G), and general formula (G-1) or the pharmaceutically acceptable salts thereof are provided, wherein JV is a bond.

In some embodiments of the present disclosure, the compounds represented by general formula (I), general formula (II), general formula (II-1), general formula (G), and general formula (G-1) or the pharmaceutically acceptable salts thereof are provided, wherein J⁵ is —C(O)NR⁶— or —NR⁶C(O)—; R⁶ is a hydrogen atom or C_1-6 alkyl; preferably, J⁵ is —C(O)NR⁶— or —NR⁶C(O)—; R⁶ is a hydrogen atom or methyl; more preferably, J⁵ is —C(O)NH—*; the * end is attached to A.

In some embodiments of the present disclosure, the compounds represented by general formula (I), general formula (II), and general formula (G) or the pharmaceutically acceptable salts thereof are compounds represented by general formula (II) or pharmaceutically acceptable salts thereof:

• • wherein:
  • W¹ is N or CR^3d; W² is N or CR^3e; W³ is N or CR^3f; W⁴ is N or CR^3g;
  • R^3d, R^3e, R^3f, and R^3g are identical or different and are each independently selected from the group consisting of a hydrogen atom, halogen, C_1-6 alkyl, C_1-6 alkoxy, C_1-6 haloalkyl, C_1-6 haloalkoxy, cyano, amino, hydroxy, and C_1-6 hydroxyalkyl;
  • Z³, Z⁴, Z⁵, and Z⁶ are identical or different and are each independently a N atom or CH;
  • m3 is 0, 1, 2, or 3;
  • x, x1, y, and y1 are each independently 0, 1, or 2;
  • J⁵ is selected from the group consisting of —C(O)NR^6b—, —NR^6bC(O)—, —O—, —S—, —NR^6b—, —C(O)—, —S(O)₂—, —(CR^7bR^8b)_m4—, C_2-6 alkenyl, C_2-6 alkynyl, 3- to 8-membered cycloalkyl, and 3- to 8-membered heterocyclyl; R^6b is a hydrogen atom or C_1-6 alkyl; R^7b and R^8b are identical or different and are each independently selected from the group consisting of a hydrogen atom, halogen, hydroxy, and C_1-6 alkyl; m4 is 0, 1, 2, or 3; preferably, J⁵ is selected from the group consisting of a bond, 3- to 8-membered heterocyclyl, and 3- to 8 membered cycloalkyl;
  • Z¹, Z², R^1a, R^3a, X², J¹, and A are as defined in general formula (G).

In some embodiments of the present disclosure, the compounds represented by general formula (I), general formula (II), general formula (G), and general formula (III′) or the pharmaceutically acceptable salts thereof are compounds represented by general formula (III′-1 or pharmaceutically acceptable salts thereof:

• • wherein:
  • R^1a is selected from the group consisting of halogen, C_1-6 alkyl, C_1-6 alkoxy, C_1-6 haloalkyl, C_1-6 haloalkoxy, cyano, amino, hydroxy, and C_1-6 hydroxyalkyl; and
  • R^3a, W¹, W², W³, W⁴, Z¹, Z², Z³, Z⁴, Z⁵, Z⁶, x, x1, y, y1, m3, X², J¹, J⁵, and A are as defined in general formula (III′).

In some embodiments of the present disclosure, the compounds represented by general formula (I), general formula (II), general formula (II-1), general formula (G), general formula (G-1), general formula (III′), and general formula (III′-1) or the pharmaceutically acceptable salts thereof are provided, wherein J⁵ is selected from the group consisting of a bond, 3- to 8-membered heterocyclyl, and 3- to 8-membered cycloalkyl; preferably, J⁵ is a bond or piperazinyl; more preferably, J⁵ is a bond.

In some embodiments of the present disclosure, the compounds represented by general formula (I), general formula (II), general formula (II-1), general formula (G), general formula (G-1), general formula (III′), and general formula (III′-1) or the pharmaceutically acceptable salts thereof are provided, wherein J⁵ is selected from the group consisting of a bond, 5- or 6-membered heterocyclyl, and —C(O)NH—*; preferably, J⁵ is selected from the group consisting of a bond, piperazinyl, and —C(O)NH—*; the * end is attached to A; more preferably, J⁵ is a bond.

In some embodiments of the present disclosure, the compounds represented by general formula (I), general formula (II), general formula (G), and general formula (III′) or the pharmaceutically acceptable salts thereof are compounds represented by general formula (III) or pharmaceutically acceptable salts thereof:

• • wherein:
  • W¹ is N or CR^3d; W² is N or CR^3e; W³ is N or CR^3f; W⁴ is N or CR^3g;
  • R^3d, R^3e, R^3f, and R^3g are identical or different and are each independently selected from the group consisting of a hydrogen atom, halogen, C_1-6 alkyl, C_1-6 alkoxy, C_1-6 haloalkyl, C_1-6 haloalkoxy, cyano, amino, hydroxy, and C_1-6 hydroxyalkyl;
  • Z³, Z⁴, Z⁵, and Z⁶ are identical or different and are each independently a N atom or CH, provided that at least one of Z³ and Z⁴ is a N atom;
  • m3 is 0, 1, 2, or 3;
  • x, x1, y, and y1 are each independently 0, 1, or 2;
  • Z¹, Z², R^1a, R^3a, X², J¹, and A are as defined in general formula (G).

In some embodiments of the present disclosure, the compounds represented by general formula (I), general formula (II), general formula (G), general formula (III′), and general formula (III) or the pharmaceutically acceptable salts thereof are compounds represented by general formula (III-1 or pharmaceutically acceptable salts thereof:

• • wherein:
  • R^1a is selected from the group consisting of halogen, C_1-6 alkyl, C_1-6 alkoxy, C_1-6 haloalkyl, C_1-6 haloalkoxy, cyano, amino, hydroxy, and C_1-6 hydroxyalkyl; and
  • R^3a, W¹, W², W³, W⁴, Z¹, Z², Z³, Z⁴, Z⁵, Z⁶, x, x1, y, y1, m3, X², J¹, and A are as defined in general formula (III).

In some embodiments of the present disclosure, the compounds represented by general formula (I), general formula (II), general formula (II-1), general formula (G), general formula (G-1), general formula (III′), general formula (III′-1), general formula (III), and general formula (III-1) or the pharmaceutically acceptable salts thereof are provided, wherein R^2a and R^2b are identical or different and are each independently selected from the group consisting of a hydrogen atom, halogen, C_1-6 alkyl, C_1-6 alkoxy, hydroxy, amino, cyano, C_1-6 haloalkyl, C_1-6 haloalkoxy, and C_1-6 hydroxyalkyl; preferably, R^2a and R^2b are identical or different and are each independently selected from the group consisting of a hydrogen atom, halogen, hydroxy, and C_1-6 alkyl; more preferably, R^2a and R^2b are both hydrogen atoms.

In some embodiments of the present disclosure, the compounds represented by general formula (I), general formula (II), general formula (II-1), general formula (G), general formula (G-1), general formula (III′), general formula (III′-1), general formula (III), and general formula (III-1) or the pharmaceutically acceptable salts thereof are provided, wherein X² is selected from the group consisting of —C(O)—, —S(O)₂—, and —(CR^2aR^2b)_m1—;

• • R^2a and R^2b are identical or different and are each independently selected from the group consisting of a hydrogen atom, halogen, hydroxy, and C_1-6 alkyl, preferably a hydrogen atom; and m1 is 0, 1, 2, or 3.

In some embodiments of the present disclosure, the compounds represented by general formula (I), general formula (II), general formula (II-1), general formula (G), general formula (G-1), general formula (III′), general formula (III′-1), general formula (III), and general formula (III-1) or the pharmaceutically acceptable salts thereof are provided, wherein X² is a bond or —C(O)—; preferably, X² is a bond.

In some embodiments of the present disclosure, the compounds represented by general formula (I), general formula (II), general formula (II-1), general formula (G), general formula (G-1), general formula (III′), general formula (III′-1), general formula (III), and general formula (III-1) or the pharmaceutically acceptable salts thereof are provided, wherein R⁷ and R⁸ are identical or different and are each independently selected from the group consisting of a hydrogen atom, halogen, C_1-6 alkyl, C_1-6 alkoxy, amino, hydroxy, cyano, C_1-6 haloalkyl, C_1-6 haloalkoxy, and C_1-6 hydroxyalkyl; preferably, R⁷ and R⁸ are identical or different and are each independently selected from the group consisting of a hydrogen atom, halogen, hydroxy, and C_1-6 alkyl; more preferably, R⁷ and R⁸ are both hydrogen atoms.

In some embodiments of the present disclosure, the compounds represented by general formula (I), general formula (II), general formula (II-1), general formula (G), general formula (G-1), general formula (III′), general formula (III′-1), general formula (III), and general formula (III-1) or the pharmaceutically acceptable salts thereof are provided, wherein R⁶ is a hydrogen atom or C_1-6 alkyl; preferably, R⁶ is a hydrogen atom or methyl. In some embodiments of the present disclosure, the compounds represented by general formula (I), general formula (II), general formula (II-1), general formula (G), general formula (G-1), general formula (III′), general formula (III′-1), general formula (III), and general formula (III-1) or the pharmaceutically acceptable salts thereof are provided, wherein J¹ is selected from the group consisting of —O—, —S—, —NR¹—, —C(O)—, —S(O)₂—, —(CR⁷R⁸)_m2—, C_2-6 alkenyl, and C_2-6 alkynyl; R⁶ is a hydrogen atom or C_1-6 alkyl, preferably a hydrogen atom or methyl; R⁷ and R⁸ are identical or different and are each independently selected from the group consisting of a hydrogen atom, halogen, hydroxy, and C_1-6 alkyl, preferably a hydrogen atom; and m2 is 0, 1, 2, or 3.

In some embodiments of the present disclosure, the compounds represented by general formula (I), general formula (II), general formula (II-1), general formula (G), general formula (G-1), general formula (III′), general formula (III′-1), general formula (III), and general formula (III-1) or the pharmaceutically acceptable salts thereof are provided, wherein J¹ is selected from the group consisting of a bond, —O—, —S—, —NH—, —N(CH₃)—, —C(O)—, —S(O)₂—, —CH₂—, —CH(CH₃)—, —CH₂CH₂—, —CH₂CH₂CH₂—, and ethynylene; preferably, J¹ is selected from the group consisting of a bond, —O—, —S—, —CH₂—, and —C(O)—; more preferably, J¹ is selected from the group consisting of a bond, —S—, and —C(O)—; further preferably, J¹ is —S— or —C(O)—; most preferably, J¹ is —C(O)—.

In some embodiments of the present disclosure, the compounds represented by general formula (I), general formula (II), general formula (II-1), general formula (G), general formula (G-1), general formula (III′), general formula (III′-1), general formula (III), and general formula (III-1) or the pharmaceutically acceptable salts thereof are provided, wherein X² is —C(O)—; and J¹ is —S—.

In some embodiments of the present disclosure, the compounds represented by general formula (I), general formula (II), general formula (II-1), general formula (G), general formula (G-1), general formula (III′), general formula (III′-1), general formula (III), and general formula (III-1) or the pharmaceutically acceptable salts thereof are provided, wherein X² is a bond; and J¹ is —C(O)—.

In some embodiments of the present disclosure, the compounds represented by general formula (I), general formula (II), and general formula (G) or the pharmaceutically acceptable salts thereof are compounds represented by general formula (X) or pharmaceutically acceptable salts thereof:

• • wherein:
  • W¹ is N or CR^3d; W² is N or CR^3e; W³ is N or CR^3f; W⁴ is N or CR^3g;
  • R^3d, R^3e, R^3f, and R^3g are identical or different and are each independently selected from the group consisting of a hydrogen atom, halogen, C_1-6 alkyl, C_1-6 alkoxy, C_1-6 haloalkyl, C_1-6 haloalkoxy, cyano, amino, hydroxy, and C_1-6 hydroxyalkyl;
  • Z⁴, Z⁵, and Z⁶ are identical or different and are each independently a N atom or CH;
  • m3 is 0, 1, 2, or 3;
  • h, i, u, and v are each independently 0 or 1;
  • x1 and y1 are each independently 0, 1, or 2;
  • Z¹, Z², R^1a, R^3a, and A are as defined in general formula (II).

In some embodiments of the present disclosure, the compounds represented by general formula (I), general formula (II), general formula (G), and general formula (X) or the pharmaceutically acceptable salts thereof are compounds represented by general formula (X-1) or pharmaceutically acceptable salts thereof:

• • wherein:
  • R^1a is selected from the group consisting of halogen, C_1-6 alkyl, C_1-6 alkoxy, C_1-6 haloalkyl, C_1-6 haloalkoxy, cyano, amino, hydroxy, and C_1-6 hydroxyalkyl; and
  • R^3a, W¹, W², W³, W⁴, Z¹, Z², Z⁴, Z⁵, Z⁶, h, i, u, v, x1, y1, m3, and A are as defined in general formula (X).

In some embodiments of the present disclosure, the compounds represented by general formula (I), general formula (II), general formula (II-1), general formula (G), general formula (G-1), general formula (III′), general formula (III′-1), general formula (III), general formula (III-1), general formula (X), and general formula (X-1) or the pharmaceutically acceptable salts thereof are provided, wherein Q² is a carbon atom, and Q¹, Q³, Q⁴, and Q⁵ are identical or different and are each independently a nitrogen atom or CR′;

• • each R¹ is identical or different and is independently selected from the group consisting of a hydrogen atom, halogen, C_1-6 alkyl, C_1-6 alkoxy, C_1-6 haloalkyl, C_1-6 haloalkoxy, C_1-6 hydroxyalkyl, C_1-6 aminoalkyl, C_1-6 alkoxy C_1-6 alkyl, cyano, hydroxy, and —(CH₂)_nNR^cR^d; R^c and R^d are identical or different and are each independently a hydrogen atom or C_1-6 alkyl; and n is 0, 1, 2, or 3;
  • preferably, each R¹ is identical or different and is independently selected from the group consisting of a hydrogen atom, halogen, C_1-6 alkyl, C_1-6 alkoxy, C_1-6 haloalkyl, C_1-6 haloalkoxy, C_1-6 hydroxyalkyl, cyano, hydroxy, and amino;
  • further preferably, each R′ is identical or different and is independently selected from the group consisting of a hydrogen atom, halogen, hydroxy, and C_1-6 alkyl;
  • more preferably, each R′ is identical or different and is independently a hydrogen atom or halogen;
  • most preferably, each R′ is identical or different and is independently a hydrogen atom or fluorine.

In some embodiments of the present disclosure, the compounds represented by general formula (I), general formula (II), general formula (II-1), general formula (G), general formula (G-1), general formula (III′), general formula (III′-1), general formula (III), general formula (III-1), general formula (X), and general formula (X-1) or the pharmaceutically acceptable salts thereof are provided, wherein: Q² is a carbon atom, and Q¹, Q³, Q⁴, and Q⁵ are identical or different and are each independently a nitrogen atom or CR¹; or, Q³ is a carbon atom, and Q¹, Q², Q⁴, and Q⁵ are identical or different and are each independently a nitrogen atom or CR′; wherein: each R′ is identical or different and is independently selected from the group consisting of a hydrogen atom, halogen, C_1-6 alkyl, C_1-6 alkoxy, C_1-6 haloalkyl, C_1-6 haloalkoxy, C_1-6 hydroxyalkyl, C_1-6 aminoalkyl, C_1-6 alkoxy C_1-6 alkyl, cyano, hydroxy, and —(CH₂)_nNR^cR^d; R^c and R^d are identical or different and are each independently a hydrogen atom or C_1-6 alkyl; and n is 0, 1, 2, or 3;

• • preferably, each R′ is identical or different and is independently selected from the group consisting of a hydrogen atom, halogen, C_1-6 alkyl, C_1-6 alkoxy, C_1-6 haloalkyl, C_1-6 haloalkoxy, C_1-6 hydroxyalkyl, cyano, hydroxy, and amino;
  • further preferably, each R′ is identical or different and is independently selected from the group consisting of a hydrogen atom, halogen, hydroxy, and C_1-6 alkyl;
  • more preferably, each R′ is identical or different and is independently a hydrogen atom or halogen;
  • most preferably, each R′ is identical or different and is independently a hydrogen atom or fluorine.

In some embodiments of the present disclosure, the compounds represented by general formula (I), general formula (II), general formula (II-1), general formula (G), general formula (G-1), general formula (III′), general formula (III′-1), general formula (III), general formula (III-1), general formula (X), and general formula (X-1) or the pharmaceutically acceptable salts thereof are provided, wherein R¹ is a hydrogen atom or C_1-6 alkyl; preferably, R¹ is a hydrogen atom.

In some embodiments of the present disclosure, the compounds represented by general formula (I), general formula (II), general formula (II-1), general formula (G), general formula (G-1), general formula (III′), general formula (III′-1), general formula (III), general formula (III-1), general formula (X), and general formula (X-1) or the pharmaceutically acceptable salts thereof are provided, wherein R² is a hydrogen atom or C_1-6 alkyl; preferably, R² is a hydrogen atom.

In some embodiments of the present disclosure, the compounds represented by general formula (I), general formula (II), general formula (II-1), general formula (G), general formula (G-1), general formula (III′), general formula (III′-1), general formula (III), general formula (III-1), general formula (X), and general formula (X-1) or the pharmaceutically acceptable salts thereof are provided, wherein is a single bond.

In some embodiments of the present disclosure, the compounds represented by general formula (I), general formula (II), general formula (II-1), general formula (G), general formula (G-1), general formula (III′), general formula (III′-1), general formula (III), general formula (III-1), general formula (X), and general formula (X-1) or the pharmaceutically acceptable salts thereof are provided, wherein A is

Q¹, Q², Q³, Q⁴, and Q⁵ are as defined in general formula (I); preferably, Q² is a carbon atom, Q¹, Q³, Q⁴, and Q⁵ are each independently CR′, and R′ is a hydrogen atom or halogen; more preferably, Q² is a carbon atom, Q¹, Q³, Q⁴, and Q⁵ are each independently CR′, and R′ is a hydrogen atom or fluorine; most preferably, Q² is a carbon atom, and Q¹, Q³, Q⁴, and Q⁵ are all CH.

In some embodiments of the present disclosure, the compounds represented by general formula (I), general formula (II), general formula (II-1), general formula (G), general formula (G-1), general formula (III′), general formula (III′-1), general formula (III), general formula (III-1), general formula (X), and general formula (X-1) or the pharmaceutically acceptable salts thereof are provided, wherein A is selected from the group consisting of the following structures:

• • Q¹, Q², Q³, Q⁴, and Q⁵ are identical or different and are each independently a nitrogen atom or CR′; each R′ is identical or different and is independently selected from the group consisting of a hydrogen atom, halogen, C_1-6 alkyl, C_1-6 alkoxy, C_1-6 haloalkyl, C_1-6 haloalkoxy, C_1-6 hydroxyalkyl, cyano, hydroxy, and amino, preferably a hydrogen atom, halogen, hydroxy, and C_1-6 alkyl, more preferably a hydrogen atom or halogen, further preferably a hydrogen atom or fluorine, and most preferably a hydrogen atom.

In some embodiments of the present disclosure, the compounds represented by general formula (I), general formula (II), general formula (II-1), general formula (III), formula (G-1), general formula (III′), general formula (III′-1), general formula (III), general formula (III-1), general formula (X), and general formula (X-1) or the pharmaceutically acceptable salts thereof are provided, wherein A is selected from the group consisting of

In some embodiments of the present disclosure, the compounds represented by general formula (I), general formula (II), general formula (II-1), general formula (G), general formula (G-1), general formula (III′), general formula (III′-1), general formula (III), general formula (III-1), general formula (X), and general formula (X-1) or the pharmaceutically acceptable salts thereof are provided, wherein A is selected from the group consisting of

In some embodiments of the present disclosure, the compounds represented by general formula (I), general formula (II), general formula (II-1), general formula (G), general formula (G-1), general formula (III′), general formula (III′-1), general formula (III), general formula (Ill-1), general formula (X), and general formula (X-1) or the pharmaceutically acceptable salts thereof are provided, wherein A is selected from the group consisting of the following structures:

In some embodiments of the present disclosure, the compounds represented by general formula (I), general formula (II), general formula (II-1), general formula (G), general formula (G-1), general formula (III′), general formula (III′-1), general formula (III), general formula (III-1), general formula (X), and general formula (X-1) or the pharmaceutically acceptable salts thereof are provided, wherein A is selected from the group consisting of the following structures:

In some embodiments of the present disclosure, the compounds represented by general formula (I), general formula (II), general formula (II-1), general formula (G), general formula (G-1), general formula (III′), general formula (III′-1), general formula (III), general formula (III-1), general formula (X), and general formula (X-1) or the pharmaceutically acceptable salts thereof are provided, wherein A is selected from the group consisting of the following structures:

more preferably

and most preferably

• • wherein: Q¹, Q³, Q², Q⁴, and Q⁵ are as defined in general formula (I); preferably, Q¹, Q², Q³, Q⁴, and Q⁵ are identical or different and are each independently a nitrogen atom or CR′; each R′ is identical or different and is independently a hydrogen atom or halogen; more preferably, Q¹, Q², Q³, Q⁴, and Q⁵ are CR′; each R′ is identical or different and is independently a hydrogen atom or F; more preferably, Q¹, Q², Q³, Q⁴, and Q⁵ are CH.

In some embodiments of the present disclosure, the compounds represented by general formula (I), general formula (II), general formula (II-1), general formula (G), general formula (G-1), general formula (III′), general formula (III′-1), general formula (III), general formula (III-1), general formula (X), and general formula (X-1) or the pharmaceutically acceptable salts thereof are provided, wherein A is selected from the group consisting of the following structures:

preferably from the group consisting of

In some embodiments of the present disclosure, the compounds represented by general formula (I), general formula (II), general formula (II-1), general formula (G), general formula (G-1), general formula (III′), general formula (III′-1), general formula (III), general formula (III-1), general formula (X), and general formula (X-1) or the pharmaceutically acceptable salts thereof are provided, wherein A is selected from the group consisting of the following structures:

preferably from the group consisting of

more preferably from the group consisting of

In some embodiments of the present disclosure, the compounds represented by general formula (I), general formula (II), general formula (G), general formula (III′), and general formula (III) or the pharmaceutically acceptable salts thereof are compounds represented by general formula (IV′) or pharmaceutically acceptable salts thereof:

• • wherein:
  • Q² is a carbon atom, and Q¹, Q³, Q⁴, and Q⁵ are identical or different and are each independently a nitrogen atom or CR¹; or, Q³ is a carbon atom, and Q¹, Q², Q⁴, and Q⁵ are identical or different and are each independently a nitrogen atom or CR¹;
  • each R¹ is identical or different and is independently selected from the group consisting of a hydrogen atom, halogen, C_1-6 alkyl, C_1-6 alkoxy, C_1-6 haloalkyl, C_1-6 haloalkoxy, C_1-6 hydroxyalkyl, cyano, hydroxy, and amino; and
  • Z¹, Z², R^1a, R^3a, W¹, W², W³, W⁴, Z⁴, Z⁵, Z⁶, m3, x, x1, y, and y1 are as defined in general formula (III′).

In some embodiments of the present disclosure, the compounds represented by general formula (I), general formula (II), general formula (G), general formula (III′), general formula (III), and general formula (IV′) or the pharmaceutically acceptable salts thereof are compounds represented by general formula (IV′-1) or pharmaceutically acceptable salts thereof:

• • wherein:
  • R^1a is selected from the group consisting of halogen, C_1-6 alkyl, C_1-6 alkoxy, C_1-6 haloalkyl, C_1-6 haloalkoxy, cyano, amino, hydroxy, and C_1-6 hydroxyalkyl; preferably, R^1a is C_1-6 alkyl; more preferably, R^1a is methyl;
  • Q¹, Q², Q³, Q⁴, Q⁵, R^3a, W¹, W², W³, W⁴, Z¹, Z², Z⁴, Z⁵, Z⁶, x, x1, y, y1, and m3 are as defined in general formula (IV).

In some embodiments of the present disclosure, the compounds represented by general formula (I), general formula (II), general formula (II-1), general formula (III′), general formula (III′-1), general formula (G), general formula (G-1), general formula (III), general formula (III-1), general formula (IV′), and general formula (IV′-1) or the pharmaceutically acceptable salts thereof are compounds represented by general formula (IV′-1-1) or general formula (IV′-1-2) or pharmaceutically acceptable salts thereof:

• • wherein: Q¹, Q², Q³, Q⁴, Q⁵, R^1a, R^3a, W¹, W², W³, W⁴, Z¹, Z², Z⁴, Z⁵, Z⁶, x, x1, y, y1, and m3 are as defined in general formula (IV′-1).

In some embodiments of the present disclosure, the compounds represented by general formula (I), general formula (II), general formula (G), general formula (III′), general formula (III), and general formula (IV) or the pharmaceutically acceptable salts thereof are compounds represented by general formula (M) or pharmaceutically acceptable salts thereof:

• • wherein:
  • Q¹, Q², Q⁴, Q⁵, R^1a, R^3a, W¹, W², W³, W⁴, Z¹, Z², Z⁴, Z⁵, Z⁶, x, x1, y, y1, and m3 are as defined in general formula (IV′).

In some embodiments of the present disclosure, the compounds represented by general formula (I), general formula (II), general formula (11-1), general formula (G), general formula (G-1), general formula (III′), general formula (III′-1), general formula (III), general formula (III-1), general formula (IV′), general formula (IV′-1), and general formula (M) or the pharmaceutically acceptable salts thereof are compounds represented by general formula (M-1) or pharmaceutically acceptable salts thereof:

• • wherein:
  • R^1a is selected from the group consisting of halogen, C_1-6alkyl, C_1-6 alkoxy, C_1-6 haloalkyl, C_1-6 haloalkoxy, cyano, amino, hydroxy, and C_1-6 hydroxyalkyl; preferably, R^1a is C_1-6 alkyl; more preferably, R^1a is methyl;
  • Q¹, Q², Q⁴, Q⁵, R^3a, W¹, W², W³, W⁴, Z¹, Z², Z⁴, Z⁵, Z⁶, x, x1, y, y1, and m3 are as defined in general formula (M).

In some embodiments of the present disclosure, the compounds represented by general formula (I), general formula (II), general formula (11-1), general formula (G), general formula (G-1), general formula (III′), general formula (III′-1), general formula (III), general formula (III-1), general formula (IV′), general formula (IV′-1), general formula (M), and general formula (M-1) or the pharmaceutically acceptable salts thereof are compounds represented by general formula (M-1-1) or general formula (M-1-2) or pharmaceutically acceptable salts thereof:

• • wherein:
  • Q¹, Q², Q⁴, Q⁵, R^1a, R^3a, W¹, W², W³, W⁴, Z¹, Z², Z⁴, Z⁵, Z⁶, x, x1, y, y1, and m3 are as defined in general formula (M-1).

In some embodiments of the present disclosure, the compounds represented by general formula (I), general formula (II), general formula (G), general formula (III′), and general formula (III) or the pharmaceutically acceptable salts thereof are compounds represented by general formula (IV) or pharmaceutically acceptable salts thereof:

• • wherein:
  • Q¹, Q³, Q⁴, and Q⁵ are identical or different and are each independently a nitrogen atom or CR′;
  • each R′ is identical or different and is independently selected from the group consisting of a hydrogen atom, halogen, C_1-6 alkyl, C_1-6 alkoxy, C_1-6 haloalkyl, C_1-6 haloalkoxy, C_1-6 hydroxyalkyl, cyano, hydroxy, and amino; and
  • Z¹, Z², R^1a, R^3a, W¹, W², W³, W⁴, Z⁴, Z⁵, Z⁶, m3, x, x1, y, and y1 are as defined in general formula (III).

In some embodiments of the present disclosure, the compounds represented by general formula (I), general formula (II), general formula (G), general formula (III′), general formula (III), and general formula (IV) or the pharmaceutically acceptable salts thereof are compounds represented by general formula (IV-1) or pharmaceutically acceptable salts thereof:

• • wherein:
  • R^1a is selected from the group consisting of halogen, C_1-6 alkyl, C_1-6 alkoxy, C_1-6 haloalkyl, C_1-6 haloalkoxy, cyano, amino, hydroxy, and C_1-6 hydroxyalkyl; preferably, R^1a is C_1-6 alkyl; more preferably, R^1a is methyl;
  • Q¹, Q³, Q⁴, Q⁵, R^3a, W¹, W², W³, W⁴, Z¹, Z², Z⁴, Z⁵, Z⁶, x, x1, y, y1, and m3 are as defined in general formula (IV).

In some embodiments of the present disclosure, the compounds represented by general formula (I), general formula (II), general formula (II-1), general formula (G), general formula (G-1), general formula (III′), general formula (III′-1), general formula (III), general formula (III-1), general formula (IV), and general formula (IV-1) or the pharmaceutically acceptable salts thereof are compounds represented by general formula (IV-1-1) or general formula (IV-1-2) or pharmaceutically acceptable salts thereof:

• • wherein:
  • Q¹, Q³, Q⁴, Q³, R^1a, R^3a, W¹, W², W³, W⁴, Z¹, Z², Z⁴, Z⁵, Z⁶, x, x1, y, y1, and m3 are as defined in general formula (IV-1).

In some embodiments of the present disclosure, the compounds represented by general formula (I), general formula (II), general formula (G), general formula (III′), and general formula (III) or the pharmaceutically acceptable salts thereof are compounds represented by general formula V or pharmaceutically acceptable salts thereof:

• • wherein:
  • J¹ is selected from the group consisting of a bond, O, S, —CH₂—, and —C(O)—;
  • Q¹, Q³, Q⁴, and Q⁵ are identical or different and are each independently a nitrogen atom or CR′;
  • each R¹ is identical or different and is independently selected from the group consisting of a hydrogen atom, halogen, C_1-6 alkyl, C_1-6 alkoxy, C_1-6 haloalkyl, C_1-6 haloalkoxy, C_1-6 hydroxyalkyl, cyano, hydroxy, and amino; and
  • Z¹, Z², R^1a, R^3a, W¹, W², W³, W⁴, Z⁵, Z⁶, m3, x, x1, y, and y1 are as defined in general formula (III).

In some embodiments of the present disclosure, the compounds represented by general formula (I), general formula (II), general formula (G), general formula (III′), general formula (III), and general formula (V) or the pharmaceutically acceptable salts thereof are compounds represented by general formula (V-1) or pharmaceutically acceptable salts thereof:

• • wherein:
  • R^1a is selected from the group consisting of halogen, C_1-6 alkyl, C_1-6 alkoxy, C_1-6 haloalkyl, C_1-6 haloalkoxy, cyano, amino, hydroxy, and C_1-6 hydroxyalkyl; preferably, R^1a is C_1-6 alkyl; more preferably, R^1a is methyl;
  • J¹, Q¹, Q³, Q⁴, Q³, R^3a, W¹, W², W³, W⁴, Z¹, Z², Z³, Z⁶, x, x1, y, y1, and m3 are as defined in general formula (V).

In some embodiments of the present disclosure, the compounds represented by general formula (I), general formula (II), general formula (II-1), general formula (G), general formula (G-1), general formula (III′), general formula (III′-1), general formula (III), general formula (III-1), general formula (V), and general formula (V-1) or the pharmaceutically acceptable salts thereof are compounds represented by general formula (V-1-1) or general formula (V-1-2) or pharmaceutically acceptable salts thereof:

• • wherein:
  • J¹, Q¹, Q³, Q⁴, Q⁵, R^1a, R^3a, W¹, W², W³, W⁴, Z¹, Z², Z³, Z⁶, x, x1, y, y1, and m3 are as defined in general formula (V-1).

In some embodiments of the present disclosure, the compounds represented by general formula (II), general formula (II-1), general formula (G), general formula (G-1), general formula (III′), general formula (III′-1), general formula (III), general formula (III-1), general formula (X), general formula (X-1), general formula (IV), general formula (IV′-1), general formula (IV′-1-1), general formula (IV′-1-2), general formula (M), general formula (M-1), general formula (M-1-1), general formula (M-1-2), general formula (IV), general formula (IV-1), general formula (IV-1-1), general formula (IV-1-2), general formula (V), general formula (V-1), general formula (V-1-1), and general formula (V-1-2) or the pharmaceutically acceptable salts thereof are provided, wherein Z¹ is CR^3b; Z² is CR^3c; R^3a, R^3b, and R^3c are identical or different and are each independently selected from the group consisting of a hydrogen atom, halogen, C_1-6 alkyl, C_1-6 alkoxy, C_1-6 haloalkyl, C_1-6 haloalkoxy, cyano, amino, nitro, hydroxy, and C_1-6 hydroxyalkyl;

• • preferably, Z¹ is CR^3b; Z² is CR^3c; R^3a, R^3b, and R^3c are identical or different and are each independently selected from the group consisting of a hydrogen atom, halogen, C_1-6 alkyl, C_1-6 alkoxy, cyano, and C_1-6 haloalkyl; further preferably, Z¹ is CR^3b; Z² is CR^3c; R^3b and R^3c are both hydrogen atoms; R^3a is selected from the group consisting of a hydrogen atom, halogen, C_1-6 alkyl, C_1-6 alkoxy, cyano, and C_1-6 haloalkyl;
  • more preferably, Z¹ is CR^3b; Z² is CR^3c; R^3b and R^3c are both hydrogen atoms; and R^3a is halogen;
  • most preferably, Z¹ is CR^3b; Z² is CR^3c; R^3b and R^3c are both hydrogen atoms; and R^3a is a chlorine atom.

In some embodiments of the present disclosure, the compounds represented by general formula (II), general formula (II-1), general formula (G), general formula (G-1), general formula (III′), general formula (III′-1), general formula (III), general formula (III-1), general formula (X), general formula (X-1), general formula (IV′), general formula (IV′-1), general formula (IV′-1-1), general formula (IV′-1-2), general formula (M), general formula (M-1), general formula (M-1-1), general formula (M-1-2), general formula (IV), general formula (IV-1), general formula (IV-1-1), general formula (IV-1-2), general formula (V), general formula (V-1), general formula (V-1-1), and general formula (V-1-2) or the pharmaceutically acceptable salts thereof are provided, wherein Z¹ is CR^3b; Z² is CR^3c; R^3a is halogen or C_1-6 haloalkyl; R^3b is a hydrogen atom; R^3c is a hydrogen atom or C_1-6 alkyl; preferably, Z¹ is CR^3b; Z² is CR^3c; R^3a is Cl or trifluoromethyl; R^3b is a hydrogen atom; R^3c is a hydrogen atom or methyl.

In some embodiments of the present disclosure, the compounds represented by general formula (II), general formula (II-1), general formula (G), general formula (G-1), general formula (III′), general formula (III′-1), general formula (III), general formula (III-1), general formula (X), general formula (X-1), general formula (IV′), general formula (IV′-1), general formula (IV′-1-1), general formula (IV′-1-2), general formula (M), general formula (M-1), general formula (M-1-1), general formula (M-1-2), general formula (IV), general formula (IV-1), general formula (IV-1-1), general formula (IV-1-2), general formula (V), general formula (V-1), general formula (V-1-1), and general formula (V-1-2) or the pharmaceutically acceptable salts thereof are provided, wherein

is selected from the group consisting of the following structures:is selected from the group consisting of

more preferably,

In some embodiments of the present disclosure, the compounds represented by general formula (G), general formula (G-1), general formula (III′), general formula (III′-1), general formula (III), general formula (III-1), general formula (X), general formula (X-1), general formula (IV′), general formula (IV′-1), general formula (IV′-1-1), general formula (IV′-1-2), general formula (M), general formula (M-1), general formula (M-1-1), general formula (M-1-2), general formula (IV), general formula (IV-1), general formula (IV-1-1), general formula (IV-1-2), general formula (V), general formula (V-1), general formula (V-1-1), and general formula (V-1-2) or the pharmaceutically acceptable salts thereof are provided, wherein W¹ is CR^3d; W² is CR^3e; W³ is CR^3f; W⁴ is N or CR^3g; R^3d, R^3e, R^3f, and R^3g are identical or different and are each independently selected from the group consisting of a hydrogen atom, halogen, C_1-6 alkyl, C_1-6 alkoxy, C_1-6 haloalkyl, C_1-6 haloalkoxy, cyano, amino, hydroxy, and C_1-6 hydroxyalkyl;

• • preferably, W¹ is CR^3d; W² is CR^3e; W³ is CR^3f; W⁴ is N or CR^3g; R^3d, R^3e, R^3f, and R^3g are identical or different and are each independently selected from the group consisting of a hydrogen atom, halogen, C_1-6 alkyl, and C_1-6 haloalkyl.

In some embodiments of the present disclosure, the compounds represented by general formula (G), general formula (G-1), general formula (III′), general formula (III′-1), general formula (III), general formula (III-1), general formula (X), general formula (X-1), general formula (IV′), general formula (IV′-1), general formula (IV′-1-1), general formula (IV′-1-2), general formula (M), general formula (M-1), general formula (M-1-1), general formula (M-1-2), general formula (IV), general formula (IV-1), general formula (IV-1-1), general formula (IV-1-2), general formula (V), general formula (V-1), general formula (V-1-1), and general formula (V-1-2) or the pharmaceutically acceptable salts thereof are provided, wherein W¹ is CR^3d; W² is CR^3e; W³ is CR^3f; W⁴ is CR^3g; R^3d, R^3e, R^3f, and R^3g are identical or different and are each independently selected from the group consisting of a hydrogen atom, halogen, C_1-6 alkyl, C_1-6 alkoxy, C_1-6 haloalkyl, C_1-6 haloalkoxy, cyano, amino, hydroxy, and C_1-6 hydroxyalkyl;

• • preferably, W¹ is CR^3d; W² is CR^3e; W³ is CR^3f; W⁴ is CR^3g; R^3d, R^3e, R^3f, and R^3g are identical or different and are each independently selected from the group consisting of a hydrogen atom, halogen, C_1-6 alkyl, and C_1-6 haloalkyl;
  • more preferably, W¹ is CR^3d; W² is CR^3e; W³ is CR^3f; W⁴ is CR^3g; R^3d, R^3e, R^3f, and R^3g are all hydrogen atoms.

In some embodiments of the present disclosure, the compounds represented by general formula (G), general formula (G-1), general formula (III′), general formula (III′-1), general formula (III), general formula (III-1), general formula (X), general formula (X-1), general formula (IV′), general formula (IV′-1), general formula (IV′-1-1), general formula (IV′-1-2), general formula (M), general formula (M-1), general formula (M-1-1), general formula (M-1-2), general formula (IV), general formula (IV-1), general formula (IV-1-1), general formula (IV-1-2), general formula (V), general formula (V-1), general formula (V-1-1), and general formula (V-1-2) or the pharmaceutically acceptable salts thereof are provided, wherein W¹ is CR^3d; W² is CR^3e; W³ is CR^3f; W⁴ is N; R^3d, R^3e, and R^3f are identical or different and are each independently selected from the group consisting of a hydrogen atom, halogen, C_1-6 alkyl, C_1-6 alkoxy, C_1-6 haloalkyl, C_1-6 haloalkoxy, cyano, amino, hydroxy, and C_1-6 hydroxyalkyl;

• • preferably, W¹ is CR^3d; W² is CR^3e; W³ is CR^3f; W⁴ is N; R^3d, R^3e, and R^3f are identical or different and are each independently selected from the group consisting of a hydrogen atom, halogen, C_1-6 alkyl, and C_1-6 haloalkyl;
  • more preferably, W¹ is CR^3d; W² is CR^3e; W³ is CR^3f; W⁴ is N; R^3d, R^3e, and R^3f are all hydrogen atoms.

In some embodiments of the present disclosure, the compounds represented by general formula (G), general formula (G-1), general formula (III′), general formula (III′-1), general formula (III), general formula (III-1), general formula (X), general formula (X-1), general formula (IV′), general formula (IV′-1), general formula (IV′-1-1), general formula (IV′-1-2), general formula (M), general formula (M-1), general formula (M-1-1), general formula (M-1-2), general formula (IV), general formula (IV-1), general formula (IV-1-1), general formula (IV-1-2), general formula (V), general formula (V-1), general formula (V-1-1), and general formula (V-1-2) or the pharmaceutically acceptable salts thereof are provided, wherein:

• • W¹ is N or CR^3d; W² is N or CR^3e; W³ is N or CR^3f; W⁴ is N or CR^3g; R^3d, R^3e, R^3f, and R^3g are identical or different and are each independently selected from the group consisting of a hydrogen atom, halogen, C_1-6 alkyl, and C_1-6 haloalkyl; preferably, W¹ is CR^3d, W² is CR^3e, W³ is CR^3f, and W⁴ is CR^3g; or,
  • W¹ is CR^3d, W² is CR^3e, W³ is CR^3f, and W⁴ is N; or,
  • W¹ is N, W² is CR^3e, W³ is CR^3f, and W⁴ is N; or,
  • W¹ is CR^3d, W² is N, W³ is CR^3f, and W⁴ is N; or,
  • W¹ is CR^3d, W² is N, W³ is CR^3f, and W⁴ is CR^3g; and R^3d, R^3e, R^3f, and R^3g are identical or different and are each independently selected from the group consisting of a hydrogen atom, halogen, C_1-6 alkyl, and C_1-6 haloalkyl, preferably a hydrogen atom or halogen, more preferably a hydrogen atom or fluorine, and most preferably a hydrogen atom.

In some embodiments of the present disclosure, the compounds represented by general formula (G), general formula (G-1), general formula (III′), general formula (III′-1), general formula (III), general formula (III-1), general formula (X), general formula (X-1), general formula (IV′), general formula (IV′-1), general formula (IV′-1-1), general formula (IV′-1-2), general formula (M), general formula (M-1), general formula (M-1-1), general formula (M-1-2), general formula (IV), general formula (IV-1), general formula (IV-1-1), general formula (IV-1-2), general formula (V), general formula (V-1), general formula (V-1-1), and general formula (V-1-2) or the pharmaceutically acceptable salts thereof are provided, wherein: W¹ is N or CR^3d; W² is N or CR^3e; W³ is N or CR^3f; W⁴ is N or CR^3g; R^3d, R^3e, R^3f, and R^3g are identical or different and are each independently a hydrogen atom or halogen (the halogen is preferably F);

• • preferably, W¹ is CR^3d; W² is CR^3e; W³ is CR^3fW⁴ is CR^3g; R^3d, R^3e, R^3f, and R^3g are identical or different and are each independently a hydrogen atom or halogen;
  • preferably, W¹ is CR^3d; W² is CR^3e; W³ is CR^3fW⁴ is CR^3g; R^3d, R^3e, R^3f, and R^3g are identical or different and are each independently a hydrogen atom or fluorine;
  • further preferably, W¹ is CF or CH; W² is CH; W³ is CH; and W⁴ is CH;
  • most preferably, W¹ is CF; W² is CH; W³ is CH; and W⁴ is CH.

In some embodiments of the present disclosure, the compounds represented by general formula (II), general formula (II-1), general formula (G), general formula (G-1), general formula (III′), general formula (III′-1), general formula (III), general formula (III-1), general formula (X), general formula (X-1), general formula (IV′), general formula (IV-1), general formula (IV′-1-1), general formula (IV′-1-2), general formula (M), general formula (M-1), general formula (M-1-1), general formula (M-1-2), general formula (IV), general formula (IV-1), general formula (IV-1-1), general formula (IV-1-2), general formula (V), general formula (V-1), general formula (V-1-1), and general formula (V-1-2) or the pharmaceutically acceptable salts thereof are provided, wherein R^1a is C_1-6 alkyl, preferably methyl.

In some embodiments of the present disclosure, the compounds represented by general formula (II), general formula (G), general formula (III′), general formula (III), general formula (X), general formula (IV′), general formula (M), general formula (IV), and general formula (V) or the pharmaceutically acceptable salts thereof are provided, wherein R^1a is a hydrogen atom or C_1-6 alkyl; preferably a hydrogen atom or methyl.

In some embodiments of the present disclosure, the compounds represented by general formula (V), general formula (V-1), general formula (V-1-1), and general formula (V-1-2) or the pharmaceutically acceptable salts thereof are provided, wherein J¹ is —S—.

In some embodiments of the present disclosure, the compounds represented by general formula (I), general formula (II), general formula (II-1), general formula (G), general formula (G-1), general formula (III′), general formula (III′-1), general formula (III), general formula (III-1), general formula (X), general formula (X-1), general formula (IV′), general formula (IV′-1), general formula (IV′-1-1), and general formula (IV′-1-2) or the pharmaceutically acceptable salts thereof are provided, wherein Q² is a carbon atom, and Q¹, Q³, Q⁴, and Q⁵ are identical or different and are each independently a nitrogen atom or CR′; or, Q³ is a carbon atom, and Q¹, Q², Q⁴, and Q⁵ are identical or different and are each independently a nitrogen atom or CR′; or, Q′ is a carbon atom, and Q¹, Q², Q³, and Q⁵ are identical or different and are each independently a nitrogen atom or CR′; and R′ is selected from the group consisting of a hydrogen atom, halogen, and C_1-6 alkyl;

• • preferably, Q² is a carbon atom, and Q¹, Q³, Q⁴, and Q⁵ are identical or different and are each independently a nitrogen atom or CR′; or, Q³ is a carbon atom, and Q¹, Q², Q⁴, and Q⁵ are identical or different and are each independently a nitrogen atom or CR′; and R′ is selected from the group consisting of a hydrogen atom, halogen, and C_1-6 alkyl; further preferably, Q³ is a carbon atom, and Q¹, Q², Q⁴, and Q⁵ are identical or different and are each independently a nitrogen atom or CR′; or Q² is a carbon atom, and Q¹, Q³, Q⁴, and Q⁵ are identical or different and are each independently a nitrogen atom or CR′; and R′ is a hydrogen atom or halogen;
  • further preferably, Q³ is a carbon atom, and Q¹, Q², Q⁴, and Q⁵ are identical or different and are each independently a nitrogen atom or CR′; and R′ is a hydrogen atom or halogen;
  • more preferably, Q³ is a carbon atom, and Q¹, Q², Q⁴, and Q⁵ are each independently CR′; and R′ is a hydrogen atom or halogen;
  • more preferably, Q³ is a carbon atom, and Q¹, Q², Q⁴, and Q⁵ are each independently CR′; and R′ is a hydrogen atom or fluorine.
  • more preferably, Q³ is a carbon atom, Q¹, Q⁴, and Q⁵ are CH, and Q² is a hydrogen atom or F;
  • most preferably, Q³ is a carbon atom, and Q¹, Q², Q⁴, and Q⁵ are all CH.

In some embodiments of the present disclosure, the compounds represented by general formula (M), general formula (M-1), general formula (M-1-1), and general formula (M-1-2) or the pharmaceutically acceptable salts thereof are provided, wherein Q¹, Q², Q⁴, and Q⁵ are each independently a nitrogen atom or CR′; and R′ is a hydrogen atom or halogen;

• • preferably, Q¹, Q², Q⁴, and Q⁵ are each independently CR′; and R′ is a hydrogen atom or halogen;
  • more preferably, Q¹, Q², Q⁴, and Q⁵ are each independently CR′; and R′ is a hydrogen atom or fluorine;
  • most preferably, Q¹, Q², Q⁴, and Q⁵ are all CH.

In some embodiments of the present disclosure, the compounds represented by general formula (IV), general formula (IV-1), general formula (IV-1-1), general formula (IV-1-2), general formula (V), general formula (V-1), general formula (V-1-1), and general formula (V-1-2) or the pharmaceutically acceptable salts thereof are provided, wherein: Q¹, Q³, Q⁴, and Q⁵ are each independently a nitrogen atom or CR¹; and R¹ is selected from the group consisting of a hydrogen atom, halogen, and C_1-6 alkyl;

• • preferably, Q¹, Q³, Q⁴, and Q⁵ are each independently CR′; and R′ is a hydrogen atom or halogen;
  • more preferably, Q¹, Q³, Q⁴, and Q⁵ are each independently CR′; and R′ is a hydrogen atom or fluorine;
  • most preferably, Q¹, Q³, Q⁴, and Q⁵ are all CH.

In some embodiments of the present disclosure, the compounds represented by general formula (IV), general formula (V-1), general formula (IV-1-1), general formula (IV-1-2), general formula (V), general formula (V-1), general formula (V-1-1), and general formula (V-1-2) or the pharmaceutically acceptable salts thereof are provided, wherein Q¹, Q³, and Q⁵ are CR⁰; Q⁴ is N or CR⁰¹; R⁰ and R⁰¹ are identical or different and are each independently selected from the group consisting of a hydrogen atom, halogen, C_1-6 alkyl, C_1-6 alkoxy, C_1-6 haloalkyl, C_1-6 haloalkoxy, C_1-6 hydroxyalkyl, cyano, hydroxy, and amino;

• • preferably, Q¹, Q³, and Q⁵ are CR⁰; Q⁴ is N or CR⁰¹; R⁰ is a hydrogen atom; and R⁰¹ is a hydrogen atom or halogen (the halogen is preferably F);
  • more preferably, Q¹, Q³, and Q⁵ are CR⁰; Q⁴ is CR¹⁰; R⁰ is a hydrogen atom; and R⁰¹ is a hydrogen atom or halogen (the halogen is preferably F).

In some embodiments of the present disclosure, the compounds represented by general formula (I), general formula (II), general formula (II-1), general formula (G), general formula (G-1), general formula (III′), general formula (III′-1), general formula (III), general formula (III-1), general formula (X), general formula (X-1), general formula (IV′), general formula (IV′-1), general formula (IV′-1-1), general formula (IV′-1-2), general formula (M), general formula (M-1), general formula (M-1-1), and general formula (M-1-2), general formula (IV), general formula (IV-1), general formula (IV-1-1), general formula (IV-1-2), general formula (V), general formula (V-1), general formula (V-1-1), and general formula (V-1-2) or the pharmaceutically acceptable salts thereof are provided, wherein m3 is 0 or 1; preferably, m3 is 1.

In some embodiments of the present disclosure, the compounds represented by general formula (X), general formula (X-1), general formula (IV′), general formula (IV′-1), general formula (IV′-1-1), general formula (IV′-1-2), general formula (M), general formula (M-1), general formula (M-1-1), and general formula (M-1-2), general formula (IV), general formula (IV-1), general formula (IV-1-1), and general formula (IV-1-2) or the pharmaceutically acceptable salts thereof are provided, wherein Z⁴ is CH, Z⁵ is N, and Z⁶ is N or CH.

In some embodiments of the present disclosure, the compounds represented by general formula (V), general formula (V-1), general formula (V-1-1), and general formula (V-1-2) or the pharmaceutically acceptable salts thereof are provided, wherein Z⁶ is a N atom.

In some embodiments of the present disclosure, the compounds represented by general formula (V), general formula (V-1), general formula (V-1-1), and general formula (V-1-2) or the pharmaceutically acceptable salts thereof are provided, wherein Z³ is CH.

In some embodiments of the present disclosure, the compounds represented by general formula (V), general formula (V-1), general formula (V-1-1), and general formula (V-1-2) or the pharmaceutically acceptable salts thereof are provided, wherein Z³ is CH, and Z⁶ is N.

In some embodiments of the present disclosure, the compounds represented by general formula (III′), general formula (III′-1), general formula (III), general formula (III-1), general formula (IV′), general formula (IV′-1), general formula (IV′-1-1), general formula (IV′-1-2), general formula (M), general formula (M-1), general formula (M-1-1), general formula (M-1-2), general formula (IV), general formula (IV-1), general formula (IV-1), general formula (IV-1-2), general formula (V), general formula (V-1), general formula (V-1-1), and general formula (V-1-2) or the pharmaceutically acceptable salts thereof are provided, wherein x, x1, y, and y1 are each independently 0 or 1; preferably, x, x1, y, and y1 are 1.

In some embodiments of the present disclosure, the compounds represented by general formula (X) and general formula (X-1) or the pharmaceutically acceptable salts thereof are provided, wherein x1 and y1 are each independently 0 or 1; preferably, x1 and y1 are 1.

In some embodiments of the present disclosure, the compounds represented by general formula (I), general formula (II), general formula (G), general formula (III′), general formula (III), and general formula (IV) or the pharmaceutically acceptable salts thereof are compounds represented by general formula (VI) or pharmaceutically acceptable salts thereof:

• • wherein:
  • R^1a is C_1-6 alkyl;
  • Q⁴ is a nitrogen atom or CR⁰¹; R⁰¹ is a hydrogen atom or halogen;
  • W⁴ is N or CR^3g;
  • R^3d, R^3e, R^3f, and R^3g are identical or different and are each independently selected from the group consisting of a hydrogen atom, halogen, C_1-6 alkyl, and C_1-6 haloalkyl;
  • Z⁴ is N or CH;
  • Z⁵ is N or CH;
  • m3 is 0 or 1;
  • x, x1, y, and y1 are each independently 0 or 1.

In some embodiments of the present disclosure, the compounds represented by general formula (I), general formula (II), general formula (G), general formula (III′), general formula (III), general formula (IV), and general formula (VI) or the pharmaceutically acceptable salts thereof are compounds represented by general formula (VI-1) or pharmaceutically acceptable salts thereof:

• • wherein:
  • R^1a, Q⁴, R^3d, R^3e, R^3f, W⁴, Z⁴, Z⁵, m3, x, x1, y, and y1 are as defined in general formula (VI).

In some embodiments of the present disclosure, the compounds represented by general formula (I), general formula (II), general formula (II-1), general formula (G), general formula (G-1), general formula (III′), general formula (III′-1), general formula (III), general formula (III-1), general formula (IV), general formula (IV-1), general formula (VI), and general formula (VI-1) or the pharmaceutically acceptable salts thereof are compounds represented by general formula (VI-1-1) and general formula (VI-1-2) or pharmaceutically acceptable salts thereof:

• • wherein:
  • R^1a, Q⁴, R^3d, R^3e, R^3f, W⁴, Z⁴, Z⁵, m3, x, x1, y, and y1 are as defined in general formula (VI-1).

In some embodiments of the present disclosure, the compounds represented by general formula (I), general formula (II), general formula (G), general formula (III′), general formula (III), and general formula (V) or the pharmaceutically acceptable salts thereof are compounds represented by general formula (VII) or pharmaceutically acceptable salts thereof:

• • wherein:
  • R^1a is C_1-6 alkyl;
  • Q⁴ is a nitrogen atom or CR⁰¹; R⁰¹ is a hydrogen atom or halogen;
  • W⁴ is N or CR^3g;
  • R^3d, R^3e, R^3f, and R^3g are identical or different and are each independently selected from the group consisting of a hydrogen atom, halogen, C_1-6 alkyl, and C_1-6 haloalkyl;
  • m3 is 0 or 1;
  • x, x1, y, and y1 are each independently 0 or 1.

In some embodiments of the present disclosure, the compounds represented by general formula (I), general formula (II), general formula (G), general formula (III′), general formula (III), general formula (V), and general formula (VII) or the pharmaceutically acceptable salts thereof are compounds represented by general formula (VII-1) or pharmaceutically acceptable salts thereof:

• • wherein:
  • R^1a, Q⁴, R^3d, R^3e, R^3f, W⁴, m3, x, x1, y, and y1 are as defined in general formula (VII).

In some embodiments of the present disclosure, the compounds represented by general formula (I), general formula (II), general formula (II-1), general formula (G), general formula (G-1), general formula (III′), general formula (III′-1), general formula (III), general formula (III-1), general formula (V), general formula (V-1), general formula (VII), and general formula (VII-1) or the pharmaceutically acceptable salts thereof are compounds represented by general formula (VII-1-1) and general formula (VII-1-2) or pharmaceutically acceptable salts thereof:

• • wherein:
  • R^1a, Q⁴, R^3d, R^3e, R^3f, W⁴, m3, x, x1, y, and y1 are as defined in general formula (VII-1).

In some embodiments of the present disclosure, the compounds represented by general formula (I), general formula (II), and general formula (II-1) or the pharmaceutically acceptable salts thereof are provided, wherein X⁴ is —J¹—J²—J³—J⁴—J⁵—, wherein J¹ is attached to X³; J¹ is selected from the group consisting of a bond, O, S, —CH₂—, and —C(O)—; J² is 3-to 12-membered heterocyclyl, and the 3- to 12-membered heterocyclyl is optionally substituted with one or more substituents selected from the group consisting of halogen, C_1-6 alkyl, C_1-6 alkoxy, C_1-6 haloalkyl, C_1-6 haloalkoxy, cyano, amino, hydroxy, and ═O;

• • J³ is —(CH₂)_m3—, and m3 is 0 or 1; J⁴ is 3- to 8-membered heterocyclyl, and the 3- to 8-membered heterocyclyl is optionally substituted with one or more substituents selected from the group consisting of halogen, C_1-6 alkyl, C_1-6 alkoxy, C_1-6 haloalkyl, C_1-6 haloalkoxy, cyano, amino, hydroxy, and ═O; J⁵ is selected from the group consisting of a bond, 3- to 8-membered heterocyclyl, and 3- to 8-membered cycloalkyl.

In some embodiments of the present disclosure, the compounds represented by general formula (I), general formula (II), and general formula (II-1) or the pharmaceutically acceptable salts thereof are provided, wherein X⁴ is —J¹—J²—J³—J⁴—J⁵—, wherein J¹ is attached to X³; J¹ is —S— or —C(O)—; J² is 4- to 6-membered monocyclic heterocyclyl or 9- to 11-membered spiroheterocyclyl; J³ is a bond or —CH₂—; J⁴ is a bond or 4- to 6-membered heterocyclyl, and the 4- to 6-membered heterocyclyl is optionally substituted with one or more ═O; J⁵ is selected from the group consisting of a bond, 5- or 6-membered heterocyclyl, and —C(O)NH—*; the * end is attached to A;

• • preferably, X⁴ is —J¹—J²—J³—J⁴—J⁵—, wherein J¹ is attached to X³; J¹ is —S— or —C(O)—; J² is selected from the group consisting of

wherein the bond with * is attached to J³; J³ is a bond or —CH₂—; J⁴ is selected from the group consisting of a bond,

the bond with * is attached to J⁵; J⁵ is selected from the group consisting of a bond, piperazinyl, and —C(O)NH—*; the * end is attached to A;

• • more preferably, X⁴ is —J¹—J²—J³—J⁴—J⁵—, wherein J¹ is attached to X³; J¹ is —C(O)—J² is

wherein the bond with * is attached to J³; J³ is —CH₂—; J⁴ is

the bond with * is attached to J⁵; J⁵ is a bond.

In some embodiments of the present disclosure, the compounds represented by general formula (I), general formula (II), and general formula (II-1) or the pharmaceutically acceptable salts thereof are provided, wherein X⁴ i.e. —J¹—J²—J³—J⁴—J⁵—, is selected from the group consisting of the following structures:

the bond with * is attached to A.

In some embodiments of the present disclosure, the compounds represented by general formula (I), general formula (II), and general formula (II-1) or the pharmaceutically acceptable salts thereof are provided, wherein X⁴, i.e., —J¹—J²—J³—J⁴-J⁵—, is selected from the group consisting of the following structures:

the bond with * is attached to A.

In some embodiments of the present disclosure, the compounds represented by general formula (I), general formula (II), and general formula (II-1) or the pharmaceutically acceptable salts thereof are provided, wherein X⁴, i.e., —J¹—J²—J³—J⁴—J⁵—, is selected from the group consisting of the following structures:

the bond with * is attached to A.

In some embodiments of the present disclosure, the compounds represented by general formula (I), general formula (II), and general formula (II-1) or the pharmaceutically acceptable salts thereof are provided, wherein X⁴, i.e., —J¹—J²—J³—J⁴—J⁵—, is selected from the group consisting of the following structures:

the bond with * is attached to A.

In some embodiments of the present disclosure, the compound represented by general formula (G) or the pharmaceutically acceptable salt thereof is provided, wherein Z¹ is CR^3b; Z² is CR^3c; R^3a is halogen or C_1-6 haloalkyl; R^3b is a hydrogen atom; R^3c is a hydrogen atom or C_1-6 alkyl; R^1a is a hydrogen atom or C_1-6 alkyl; X² is a bond or —C(O)—;

• • W¹ is N or CR^3d; W² is N or CR^3e; W³ is N or CR^3f; W⁴ is N or CR^3g; R^3d, R^3e, R^3f, and R^3g are identical or different and are each independently a hydrogen atom or halogen; J¹ is —S— or —C(O)—; ring B is 4- to 6-membered monocyclic heterocyclyl or 9- to 11-membered spiroheterocyclyl; m3 is 0 or 1; ring C is 4- to 6-membered heterocyclyl, and the 4- to 6-membered heterocyclyl is optionally substituted with one or more ═O; J⁵ is selected from the group consisting of a bond, 5- or 6-membered heterocyclyl, and —C(O)NH—*; the * end is attached to A; A is selected from the group consisting of the following structures:

Q¹, Q², Q³, Q⁴, and Q⁵ are identical or different and are each independently a nitrogen atom or CR′; each R′ is identical or different and is independently a hydrogen atom or halogen.

In some embodiments of the present disclosure, the compound represented by general formula (G-1) or the pharmaceutically acceptable salt thereof is provided, wherein Z¹ is CR^3b; Z² is CR^3c; R^3a is halogen or C_1-6 haloalkyl; R^3b is a hydrogen atom; R^3c is a hydrogen atom or C_1-6 alkyl; R^1a is C_1-6 alkyl; X² is a bond or —C(O)—; W¹ is N or CR^3d;

• • W² is N or CR^3e; W³ is N or CR^3f; W⁴ is N or CR^3g; R^3d, R^3e, R^3f, and R^3g are identical or different and are each independently a hydrogen atom or halogen; J¹ is —S— or —C(O)—; ring B is 4- to 6-membered monocyclic heterocyclyl or 9- to 11-membered spiroheterocyclyl;
  • m3 is 0 or 1; ring C is 4- to 6-membered heterocyclyl, and the 4- to 6-membered heterocyclyl is optionally substituted with one or more ═O; J⁵ is selected from the group consisting of a bond, 5- or 6-membered heterocyclyl, and —C(O)NH—*; the * end is attached to A; A is selected from the group consisting of the following structures:

Q¹, Q², Q³, Q⁴, and Q⁵ are identical or different and are each independently a nitrogen atom or CR′; each R′ is identical or different and is independently a hydrogen atom or halogen.

In some embodiments of the present disclosure, the compounds represented by general formula (M), general formula (M-1), general formula (M-1-1), and general formula M-1-2) or the pharmaceutically acceptable salts thereof are provided, wherein

is selected from the group consisting of

R^1a is C_1-6 alkyl; W¹ is N or CR^3d; W² is N or CR^3e; W³ is N or CR^3f; W⁴ is N or CR^3g; R^3d, R^3e, R^3f, and R^3g are identical or different and are each independently a hydrogen atom or halogen; m3 is 0 or 1; x, x1, y, and y1 are each independently 0 or 1; Z⁴, Z⁵, and Z⁶ are each independently CH or N; Q¹, Q², Q⁴, and Q⁵ are each independently a nitrogen atom or CR′; and R′ is a hydrogen atom or halogen.

In some embodiments of the present disclosure, the compounds represented by general formula (IV), general formula (IV′-1), general formula (IV′-1-1), and general formula (IV′-1-2) or the pharmaceutically acceptable salts thereof are provided, wherein: Z¹ is CR^3b; Z² is CR^3c; R^3b and R^3c are both hydrogen atoms; R^3a is halogen; R^1a is C_1-6 alkyl; W¹ is N or CR^3d; W² is N or CR^3e; W³ is N or CR^3f; W⁴ is N or CR^3g; R^3d, R^3e, R^3f, and R^3g are identical or different and are each independently selected from the group consisting of a hydrogen atom, halogen, C_1-6 alkyl, and C_1-6 haloalkyl; Z⁴ is CH; Z⁵ is N;

• • Z⁶ is N or CH; x, x1, y, and y1 are each independently 0 or 1; m3 is 0 or 1; Q² is a carbon atom, and Q¹, Q³, Q⁴, and Q⁵ are identical or different and are each independently a nitrogen atom or CR′; or, Q³ is a carbon atom, and Q¹, Q², Q⁴, and Q⁵ are identical or different and are each independently a nitrogen atom or CR′; and R′ is selected from the group consisting of a hydrogen atom, halogen, and C_1-6 alkyl.

In some embodiments of the present disclosure, the compounds represented by general formula (IV′), general formula (IV′-1), general formula (IV′-1-1), and general formula (IV′-1-2) or the pharmaceutically acceptable salts thereof are provided, wherein:

R^1a is methyl; W¹ is CR^3d, W² is CR^3e, W³ is CR^3f, and W⁴ is CR^3g; or, W¹ is CR^3d, W² is CR^3e, W³ is CR^3f, and W⁴ is N; or, W¹ is N, W² is CR^3e, W³ is CR^3f, and W⁴ is N; or, W¹ is CR^3d, W² is N, W³ is CR^3f, and W⁴ is N; or, W¹ is CR^3d, W² is N, W³ is CR^3f, and W⁴ is CR^3g; R^3d, R^3e, R^3f, and R^3g are identical or different and are each independently a hydrogen atom or halogen; Z⁴ is CH; Z⁵ is N; Z⁶ is N or CH; x, x1, y, and y1 are each independently is 0 or 1; m3 is 0 or 1; Q³ is a carbon atom, and Q¹, Q², Q⁴, and Q⁵ are identical or different and are each independently a nitrogen atom or CR′; and R′ is a hydrogen atom or halogen.

In some embodiments of the present disclosure, the compounds represented by general formula (IV′), general formula (IV′-1), general formula (IV′-1-1), and general formula (IV′-1-2) or the pharmaceutically acceptable salts thereof are provided, wherein:

R^1a is methyl; W¹ is CF or CH, W² is CH, W³ is CH, and W⁴ is CH; Z⁴ is CH; Z⁵ is N; Z⁶ is N or CH; x, x1, y, and y1 are each independently 0 or 1; m3 is 0 or 1; Q³ is a carbon atom, Q¹, Q², Q⁴, and Q⁵ are each independently CR′, and R′ is a hydrogen atom or halogen.

In some embodiments of the present disclosure, the compounds represented by general formula (X) and general formula (X-1) or the pharmaceutically acceptable salts thereof are provided, wherein:

R^1a is methyl; W¹ is N or CR^3d; W² is N or CR^3f; W³ is N or CR^3f; W⁴ is N or CR^3g; R^3d, R^3e, R^3f, and R^3g are identical or different and are each independently selected from the group consisting of a hydrogen atom or halogen; Z⁴ is CH; Z⁵ is N; Z⁶ is N or CH; h, i, u, v, x1, and y1 are each independently 0 or 1; m3 is 0 or 1; A is

Q² is a carbon atom, Q¹, Q³, Q⁴, and Q⁵ are identical or different and are each independently a nitrogen atom or CR′, and R′ is a hydrogen atom or halogen.

In some embodiments of the present disclosure, the compounds represented by general formula (IV), general formula (IV-1), general formula (IV-1-1), and general formula IV-1-2) or the pharmaceutically acceptable salts thereof are provided, wherein:

R^1a is methyl; W¹ is CR^3d, W² is CR^3e, W³ is CR^3f, and W⁴ is CR^3g; or, W¹ is CR^3d, W² is CR^3e, W³ is CR^3f, and W⁴ is N; or, W¹ is N, W² is CR^3e, W³ is CR^3f, and W⁴ is N; or, W¹ is CR^3d, W² is N, W³ is CR^3f, and W⁴ is N; or, W¹ is CR^3d, W² is N, W³ is CR^3f, and W⁴ is CR^3g; R^3d, R^3e, R^3f, and R^3g are identical or different and are each independently a hydrogen atom or halogen; Z⁴ is CH; Z⁵ is N; Z⁶ is N or CH; x, x1, y, and y1 are each independently is 0 or 1; m3 is 0 or 1; Q¹, Q³, Q⁴, and Q⁵ are each independently CR′; and R′ is a hydrogen atom or halogen.

In some embodiments of the present disclosure, the compounds represented by general formula (V), general formula (V-1), general formula (V-1-1), and general formula (V-1-2 or the pharmaceutically acceptable salts thereof are provided, wherein:

R^1a is methyl; W¹ is CR^3d, W² is CR^3e, W³ is CR^3f, and W⁴ is CR^3g; or, W¹ is CR^3d, W² is CR^3e, W³ is CR^3f, and W⁴ is N; or, W¹ is N, W² is CR^3e, W³ is CR^3f, and W⁴ is N; or, W¹ is CR^3d, W² is N, W³ is CR^3f, and W⁴ is N; or, W¹ is CR^3d, W² is N, W³ is CR^3f, and W⁴ is CR^3g; R^3d, R^3e, R^3f, and R^3g are identical or different and are each independently a hydrogen atom or halogen; J¹ is —S—; Z³ is CH; Z⁶ is N; x, x1, y, and y1 are each independently is 0 or 1; m3 is 0 or 1; Q¹, Q³, Q⁴, and Q⁵ are each independently CR′; and R′ is a hydrogen atom or halogen.

TABLE A
Typical compounds of the present disclosure include, but are not limited to:
No.	Compound structure	Name
		4-(4-(1-(4-(2-(3-Chloro- 4-cyanophenyl)-3-meth- yl-2,8-diazaspiro[4.5] decan-8-yl)benzoyl)- piperidin-4-yl)piperazin- 1-yl)-N-(2,6-dioxopiper- idin-3-yl)-2-fluorobenz- amide
1		4-(4-(1-(4-((S)-2-(3- Chloro-4-cyanophenyl)- 3-methyl-2,8-diazaspiro [4.5]decan-8-yl)benzoyl)- piperidin-4-yl)piperazin- 1-yl)-N-(2,6-dioxopiper- idin-3-yl)-2-fluorobenz- amide 1 (a mixture of diastereomers)
		4-(4-(1-(4-((S)-2-(3- Chloro-4-cyanophenyl)- 3-methyl-2,8-diazaspiro [4.5]decan-8-yl)benzoyl)- piperidin-4-yl)piperazin- 1-yl)-N-((R)-2,6-dioxo- piperidin-3-yl)-2-fluoro- benzamide
		4-(4-(1-(4-((S)-2-(3- Chloro-4-cyanophenyl)- 3-methyl-2,8-diazaspiro [4.5]decan-8-yl)benzoyl) piperidin-4-yl)piperazin- 1-yl)-N-((S)-2,6-dioxo- piperidin-3-yl)-2-fluoro- benzamide
		4-(4-(1-(4-((R)-2-(3- Chloro-4-cyanophenyl)- 3-methyl-2,8-diazaspiro- [4.5]decan-8-yl)benzo- yl)piperidin-4-yl)piper- azin-1-yl)-N-(2,6-dioxo- piperidin-3-yl)-2-fluoro- benzamide
		4-(4-(1-(4-((R)-2-(3- Chloro-4-cyanophenyl)- 3-methyl-2,8-diazaspiro [4.5]decan-8-yl)benzo- yl)piperidin-4-yl)piper- azin-1-yl)-N-((R)-2,6- dioxopiperidin-3-yl)-2- fluorobenzamide
		4-(4-(1-(4-((R)-2-(3- Chloro-4-cyanophenyl)- 3-methyl-2,8-diazaspiro [4.5]decan-8-yl)benzo- yl)piperidin-4-yl)piper- azin-1-yl)-N-((S)-2,6- dioxopiperidin-3-yl)-2- fluorobenzamide
		5-(4-(1-(4-(2-(3-Chloro- 4-cyanophenyl)-3-meth- yl-2,8-diazaspiro[4.5] decan-8-yl)benzoyl)- piperidin-4-yl)piperazin- 1-yl)-N-(2,6-dioxopiper- idin-3-yl)picolinamide
2		5-(4-(1-(4-((S)-2-(3- Chloro-4-cyanophenyl)- 3-methyl-2,8-diazaspiro [4.5]decan-8-yl)benzo- yl)piperidin-4-yl)piper- azin-1-yl)-N-(2,6-dioxo- piperidin-3-yl)picolin- amide 2 (a mixture of diastereomers)
		5-(4-(1-(4-((S)-2-(3- Chloro-4-cyanophenyl)- 3-methyl-2,8-diazaspiro [4.5]decan-8-yl)benzo- yl)piperidin-4-yl)piper- azin-1-yl)-N-((R)-2,6- dioxopiperidin-3-yl)- picolinamide
		5-(4-(1-(4-((S)-2-(3- Chloro-4-cyanophenyl)- 3-methyl-2,8-diazaspiro [4.5]decan-8-yl)benzo- yl)piperidin-4-yl)piper- azin-1-yl)-N-((S)-2,6- dioxopiperidin-3-yl)- picolinamide
		5-(4-(1-(4-((R)-2-(3- Chloro-4-cyanophenyl)- 3-methyl-2,8-diazaspiro [4.5]decan-8-yl)benzo- yl)piperidin-4-yl)piper- azin-1-yl)-N-(2,6-dioxo- piperidin-3-yl)picolin- amide
		5-(4-(1-(4-((R)-2-(3- Chloro-4-cyanophenyl)- 3-methyl-2,8-diazaspiro [4.5]decan-8-yl)benzo- yl)piperidin-4-yl)piper- azin-1-yl)-N-((R)-2,6- dioxopiperidin-3-yl)- picolinamide
		5-(4-(1-(4-((R)-2-(3- Chloro-4-cyanophenyl)- 3-methyl-2,8-diazaspiro [4.5]decan-8-yl)benzo- yl)piperidin-4-yl)piper- azin-1-yl)-N-((S)-2,6- dioxopiperidin-3-yl)- picolinamide
		4-(4-((1-(4-(2-(3-Chloro- 4-cyanophenyl)-3-meth- yl-2,8-diazaspiro[4.5] decan-8-yl)benzoyl)- piperidin-4-yl)methyl)- piperazin-1-yl)-N-(2,6- dioxopiperidin-3-yl)-2- fluorobenzamide
3		4-(4-((1-(4-((S)-2-(3- Chloro-4-cyanophenyl)- 3-methyl-2,8-diazaspiro [4.5]decan-8-yl)benzo- yl)piperidin-4-l)methyl)- piperazin-1-yl)-N-(2,6- dioxopiperidin-3-yl)-2- fluorobenzamide 3 (a mixture of diastereo- mers)
		4-(4-((1-(4-((S)-2-(3- Chloro-4-cyanophenyl)- 3-methyl-2,8-diazaspiro [4.5]decan-8-yl)benzo- yl)piperidin-4-yl)meth- yl)piperazin-1-yl)-N- ((R)-2,6-dioxopiperidin- 3-yl)-2-fluorobenzamide
		4-(4-((1-(4-((S)-2-(3- Chloro-4-cyanophenyl)- 3-methyl-2,8-diazaspiro [4.5]decan-8-yl)benzo- yl)piperidin-4-yl)meth- yl)piperazin-1-yl)-N- ((S)-2,6-dioxopiperidin- 3-yl)-2-fluorobenzamide
		4-(4-((1-(4-((R)-2-(3- Chloro-4-cyanophenyl)- 3-methyl-2,8-diazaspiro [4.5]decan-8-yl)benzo- yl)piperidin-4-yl)meth- yl)piperazin-1-yl)-N- (2,6-dioxopiperidin-3- yl)-2-fluorobenzamide
		4-(4-((1-(4-((R)-2-(3- Chloro-4-cyanophenyl)- 3-methyl-2,8-diazaspiro [4.5]decan-8-yl)benzo- yl)piperidin-4-yl)meth- yl)piperazin-1-yl)-N- ((R)-2,6-dioxopiperidin- 3-yl)-2-fluorobenzamide
		4-(4-((1-(4-((R)-2-(3- Chloro-4-cyanophenyl)- 3-methyl-2,8-diazaspiro [4.5]decan-8-yl)benzo- yl)piperidin-4-yl)meth- yl)piperazin-1-yl)-N- ((S)-2,6-dioxopiperidin- 3-yl)-2-fluorobenzamide
		5-(4-((1-(4-(2-(3-Chloro- 4-cyanophenyl)-3-meth- yl-2,8-diazaspiro[4.5] decan-8-yl)benzoyl)- piperidin-4-yl)methyl)- piperazin-1-yl)-N-(2,6- dioxopiperidin-3-yl)- picolinamide
4		5-(4-((1-(4-((S)-2-(3- Chloro-4-cyanophenyl)- 3-methyl-2,8-diazaspiro [4.5]decan-8-yl)benzo- yl)piperidin-4-yl)meth- yl)piperazin-1-yl)-N- (2,6-dioxopiperidin-3- yl)picolinamide 4 (a mixture of diastereo- mers)
		5-(4-((1-(4-((S)-2-(3- Chloro-4-cyanophenyl)- 3-methyl-2,8-diazaspiro [4.5]decan-8-yl)benzo- yl)piperidin-4-yl)meth- yl)piperazin-1-yl)-N- ((R)-2,6-dioxopiperidin- 3-yl)picolinamide
		5-(4-((1-(4-((S)-2-(3- Chloro-4-cyanophenyl)- 3-methyl-2,8-diazaspiro [4.5]decan-8-yl)benzo- yl)piperidin-4-yl)meth- yl)piperazin-1-yl)-N- ((S)-2,6-dioxopiperidin- 3-yl)picolinamide
		5-(4-((1-(4-((R)-2-(3- Chloro-4-cyanophenyl)- 3-methyl-2,8-diazaspiro [4.5]decan-8-yl)benzo- yl)piperidin-4-yl)meth- yl)piperazin-1-yl)-N- (2,6-dioxopiperidin-3- yl)picolinamide
		5-(4-((1-(4-((R)-2-(3- Chloro-4-cyanophenyl)- 3-methyl-2,8-diazaspiro [4.5]decan-8-yl)benzo- yl)piperidin-4-yl)meth- yl)piperazin-1-yl)-N- ((R)-2,6-dioxopiperidin- 3-yl)picolinamide
		5-(4-((1-(4-((R)-2-(3- Chloro-4-cyanophenyl)- 3-methyl-2,8-diazaspiro [4.5]decan-8-yl)benzo- yl)piperidin-4-yl)meth- yl)piperazin-1-yl)-N- ((S)-2,6-dioxopiperidin- 3-yl)picolinamide
		4-(3-(4-((5-(2-(3-Chloro- 4-cyanophenyl)-3-meth- yl-2,8-diazaspiro[4.5] decane-8-carbonyl)pyr- idin-2-yl)thio)piperidin- 1-yl)azetidin-1-yl)-N- (2,6-dioxopiperidin-3- yl)-2-fluorobenzamide
5		4-(3-(4-((5-((S)-2-(3- Chloro-4-cyanophenyl)- 3-methyl-2,8-diazaspiro [4.5]decane-8-carbonyl)- pyridin-2-yl)thio)piper- idin-1-yl)azetidin-1-yl)- N-(2,6-dioxopiperidin-3- yl)-2-fluorobenzamide 5 (a mixture of diastereo- mers)
		4-(3-(4-((5-((S)-2-(3- Chloro-4-cyanophenyl)- 3-methyl-2,8-diazaspiro [4.5]decane-8-carbonyl)- pyridin-2-yl)thio)piper- idin-1-yl)azetidin-1-yl)- N-((R)-2,6-dioxopiper- idin-3-yl)-2-fluorobenz- amide
		4-(3-(4-((5-((S)-2-(3- Chloro-4-cyanophenyl)- 3-methyl-2,8-diazaspiro [4.5]decane-8-carbonyl)- pyridin-2-yl)thio)piper- idin-1-yl)azetidin-1-yl)- N-((S)-2,6-dioxopiper- idin-3-yl)-2-fluorobenz- amide
		4-(3-(4-((5-((R)-2-(3- Chloro-4-cyanophenyl)- 3-methyl-2,8-diazaspiro [4.5]decane-8-carbonyl)- pyridin-2-yl)thio)piper- idin-1-yl)azetidin-1-yl)- N-(2,6-dioxopiperidin- 3-yl)-2-fluorobenzamide
		4-(3-(4-((5-((R)-2-(3- Chloro-4-cyanophenyl)- 3-methyl-2,8-diazaspiro [4.5]decane-8-carbonyl)- pyridin-2-yl)thio)piperi- din-1-yl)azetidin-1-yl)- N-((R)-2,6-dioxopiper- idin-3-yl)-2-fluorobenz- amide
		4-(3-(4-((5-((R)-2-(3- Chloro-4-cyanophenyl)- 3-methyl-2,8-diazaspiro [4.5]decane-8-carbonyl)- pyridin-2-yl)thio)piper- idin-1-yl)azetidin-1-yl)- N-((S)-2,6-dioxopiper- idin-3-yl)-2-fluorobenz- amide
		2-Chloro-4-(8-(4-(4-(4- (4-(2,4-dioxotetrahydro- pyrimidin-1(2H)-yl)- phenyl)piperazin-1-yl)- [1,4′-bipiperidine]-1′- carbonyl)phenyl)-3- methyl-2,8-diazaspiro [4.5]decan-2-yl)benzo- nitrile
6		(S)-2-Chloro-4-(8-(4-(4- (4-(4-(2,4-dioxotetra- hydropyrimidin-1(2H)- yl)phenyl)piperazin-1- yl)-[1,4′-bipiperidine]- 1′-carbonyl)phenyl)-3- methyl-2,8-diazaspiro [4.5]decan-2-yl)benzo- nitrile 6
		(R)-2-Chloro-4-(8-(4-(4- (4-(4-(2,4-dioxotetra- hydropyrimidin-1(2H)- yl)phenyl)piperazin-1- yl)-[1,4′-bipiperidine]- 1′-carbonyl)phenyl)-3- methyl-2,8-diazaspiro [4.5]decan-2-yl)benzo- nitrile
		2-Chloro-4-(8-(4-(4-(3- (4-(4-(2,4-dioxotetra- hydropyrimidin-1(2H)- yl)phenyl)piperazin-1- yl)azetidin-1-yl)piper- idine-1-carbonyl)phen- yl)-3-methyl-2,8-diaza- spiro[4.5]decan-2-yl)- benzonitrile
7		(S)-2-Chloro-4-(8-(4-(4- (3-(4-(4-(2,4-dioxotetra- hydropyrimidin-1(2H)- yl)phenyl)piperazin-1- yl)azetidin-1-yl)piperi- dine-1-carbonyl)phenyl)- 3-methyl-2,8-diazaspiro [4.5]decan-2-yl)benzo- nitrile 7
		(R)-2-Chloro-4-(8-(4-(4- (3-(4-(4-(2,4-dioxotetra- hydropyrimidin-1(2H)- yl)phenyl)piperazin-1- yl)azetidin-1-yl)piperi- dine-1-carbonyl)phenyl)- 3-methyl-2,8-diazaspiro [4.5]decan-2-yl)benzo- nitrile
		2-Chloro-4-(8-(4-(4-((3- (4-(4-(2,4-dioxotetra- hydropyrimidin-1(2H)- yl)phenyl)piperazin-1- yl)azetidin-1-yl)methyl)- piperidine-1-carbonyl)- phenyl)-3-methyl-2,8- diazaspiro[4.5]decan-2- yl)benzonitrile
8		(S)-2-Chloro-4-(8-(4-(4- ((3-(4-(4-(2,4-dioxotetra- hydropyrimidin-1(2H)- yl)phenyl)piperazin-1- yl)azetidin-1-yl)methyl)- piperidine-1-carbonyl)- phenyl)-3-methyl-2,8- diazaspiro[4.5]decan-2-
		yl)benzonitrile 8
		(R)-2-Chloro-4-(8-(4-(4- ((3-(4-(4-(2,4-dioxotetra- hydropyrimidin-1(2H)- yl)phenyl)piperazin-1- yl)azetidin-1-yl)methyl)- piperidine-1-carbonyl)- phenyl)-3-methyl-2,8- diazaspiro[4.5]decan-2-
		yl)benzonitrile
		2-Chloro-4-(8-(4-(4-((4- (4-(4-(2,4-dioxotetra- hydropyrimidin-1(2H)- yl)phenyl)piperazin-1- yl)piperidin-1-yl)meth- yl)piperidine-1-carbon- yl)phenyl)-3-methyl-2,8- diazaspiro[4.5]decan-2-
		yl)benzonitrile
9		(S)-2-Chloro-4-(8-(4-(4- ((4-(4-(4-(2,4-dioxotetra- hydropyrimidin-1(2H)- yl)phenyl)piperazin-1- yl)piperidin-1-yl)meth- yl)piperidine-1-carbon- yl)phenyl)-3-methyl-2,8- diazaspiro[4.5]decan-2- yl)benzonitrile 9
		(R)-2-Chloro-4-(8-(4-(4- ((4-(4-(4-(2,4-dioxotetra- hydropyrimidin-1(2H)- yl)phenyl)piperazin-1- yl)piperidin-1-yl)meth- yl)piperidine-1-carbon- yl)phenyl)-3-methyl-2,8- diazaspiro[4.5]decan-2-
		yl)benzonitrile
		2-Chloro-4-(8-(4-(4-(4- (3-((2,6-dioxopiperidin- 3-yl)amino)phenyl)piper- azin-1-yl)piperidine-1- carbonyl)phenyl)-3- methyl-2,8-diazaspiro [4.5]decan-2-yl)benzo- nitrile
10		2-Chloro-4-((3S)-8-(4-(4- (4-(3-((2,6-dioxopiperi- din-3-yl)amino)phenyl)- piperazin-1-yl)piperi- dine-1-carbonyl)phenyl)- 3-methyl-2,8-diazaspiro [4.5]decan-2-yl)benzo- nitrile 10 (a mixture of diastereomers)
		2-Chloro-4-((S)-8-(4-(4- (4-(3-(((R)-2,6-dioxo- piperidin-3-yl)amino)- phenyl)piperazin-1-yl)- piperidine-1-carbonyl)- phenyl)-3-methyl-2,8- diazaspiro[4.5]decan-2- yl)benzonitrile
		2-Chloro-4-((S)-8-(4-(4- (4-(3-(((S)-2,6-dioxo- piperidin-3-yl)amino)- phenyl)piperazin-1-yl)- piperidine-1-carbonyl)- phenyl)-3-methyl-2,8- diazaspiro[4.5]decan-2- yl)benzonitrile
		2-Chloro-4-((3R)-8-(4- (4-(4-(3-((2,6-dioxo- piperidin-3-yl)amino)- phenyl)piperazin-1-yl)- piperidine-1-carbonyl)- phenyl)-3-methyl-2,8- diazaspiro[4.5]decan-2- yl)benzonitrile
		2-Chloro-4-((R)-8-(4-(4- (4-(3-(((R)-2,6-dioxo- piperidin-3-yl)amino)- phenyl)piperazin-1-yl)- piperidine-1-carbonyl)- phenyl)-3-methyl-2,8- diazaspiro[4.5]decan-2- yl)benzonitrile
		2-Chloro-4-((R)-8-(4-(4- (4-(3-(((S)-2,6-dioxo- piperidin-3-yl)amino)- phenyl)piperazin-1-yl)- piperidine-1-carbonyl)- phenyl)-3-methyl-2,8- diazaspiro[4.5]decan- 2-yl)benzonitrile
		2-Chloro-4-(8-(4-(4-((4- (3-((2,6-dioxopiperidin- 3-yl)amino)phenyl)piper- azin-1-yl)methyl)piperi- dine-1-carbonyl)phenyl)- 3-methyl-2,8-diazaspiro [4.5]decan-2-yl)benzo- nitrile
11		2-Chloro-4-((3S)-8-(4-(4- ((4-(3-((2,6-dioxopiper- idin-3-yl)amino)phenyl)- piperazin-1-yl)methyl)- piperidine-1-carbonyl)- phenyl)-3-methyl-2,8- diazaspiro[4.5]decan-2- yl)benzonitrile 11 (a mixture of diastereo- mers)
11-2		2-Chloro-4-((S)-8-(4-(4- ((4-(3-(((R)-2,6-dioxo- piperidin-3-yl)amino)- phenyl)piperazin-1-yl)- methyl)piperidine-1- carbonyl)phenyl)-3- methyl-2,8-diazaspiro [4.5]decan-2-yl)benzo- nitrile 11-2
11-1		2-Chloro-4-((S)-8-(4-(4- ((4-(3-(((S)-2,6-dioxo- piperidin-3-yl)amino)- phenyl)piperazin-1-yl)- methyl)piperidine-1- carbonyl)phenyl)-3- methyl-2,8-diazaspiro [4.5]decan-2-yl)benzo- nitrile 11-1
		2-Chloro-4-((3R)-8-(4- (4-((4-(3-((2,6-dioxo- piperidin-3-yl)amino)- phenyl)piperazin-1-yl)- methyl)piperidine-1- carbonyl)phenyl)-3- methyl-2,8-diazaspiro [4.5]decan-2-yl)benzo- nitrile
		2-Chloro-4-((R)-8-(4-(4- ((4-(3-(((R)-2,6-dioxo- piperidin-3-yl)amino)- phenyl)piperazin-1-yl)- methyl)piperidine-1- carbonyl)phenyl)-3- methyl-2,8-diazaspiro [4.5]decan-2-yl)benzo- nitrile
		2-Chloro-4-((R)-8-(4-(4- ((4-(3-(((S)-2,6-dioxo- piperidin-3-yl)amino)- phenyl)piperazin-1-yl)- methyl)piperidine-1- carbonyl)phenyl)-3- methyl-2,8-diazaspiro [4.5]decan-2-yl)benzo- nitrile
		2-Chloro-4-(8-(6-(4-((4- (3-((2,6-dioxopiperidin- 3-yl)amino)phenyl)- piperazin-1-yl)methyl)- piperidine-1-carbonyl)- pyridin-3-yl)-3-methyl- 2,8-diazaspiro[4.5]decan- 2-yl)benzonitrile
12		2-Chloro-4-((3S)-8-(6-(4- ((4-(3-((2,6-dioxopiper- idin-3-yl)amino)phen- yl)piperazin-1-yl)meth- yl)piperidine-1-carbon- yl)pyridin-3-yl)-3-meth- yl-2,8-diazaspiro[4.5] decan-2-yl)benzonitrile 12 (a mixture of dia- stereomers)
12-2		2-Chloro-4-((S)-8-(6-(4- ((4-(3-(((R)-2,6-dioxo- piperidin-3-yl)amino)- phenyl)piperazin-1-yl)- methyl)piperidine-1- carbonyl)pyridin-3-yl)- 3-methyl-2,8-diazaspiro [4.5]decan-2-yl)benzo- nitrile 12-2
12-1		2-Chloro-4-((S)-8-(6-(4- ((4-(3-(((S)-2,6-dioxo- piperidin-3-yl)amino)- phenyl)piperazin-1-yl)- methyl)piperidine-1- carbonyl)pyridin-3-yl)- 3-methyl-2,8-diazaspiro [4.5]decan-2-yl)benzo- nitrile 12-1
		2-Chloro-4-((3R)-8-(6- (4-((4-(3-((2,6-dioxo- piperidin-3-yl)amino)- phenyl)piperazin-1-yl)- methyl)piperidine-1- carbonyl)pyridin-3-yl)- 3-methyl-2,8-diazaspiro [4.5]decan-2-yl)benzo- nitrile
		2-Chloro-4-((R)-8-(6-(4- ((4-(3-(((R)-2,6-dioxo- piperidin-3-yl)amino)- phenyl)piperazin-1-yl)- methyl)piperidine-1- carbonyl)pyridin-3-yl)- 3-methyl-2,8-diazaspiro- [4.5]decan-2-yl)benzo- nitrile
		2-Chloro-4-((R)-8-(6-(4- ((4-(3-(((S)-2,6-dioxo- piperidin-3-yl)amino)- phenyl)piperazin-1-yl)- methyl)piperidine-1- carbonyl)pyridin-3-yl)- 3-methyl-2,8-diazaspiro [4.5]decan-2-yl)benzo- nitrile
		2-Chloro-4-(8-(6-(4-((4- (3-((2,6-dioxopiperidin- 3-yl)amino)phenyl)piper- azin-1-yl)methyl)piper- idine-1-carbonyl)pyrid- azin-3-yl)-3-methyl-2,8- diazaspiro[4.5]decan-2- yl)benzonitrile
13		2-Chloro-4-((3S)-8-(6-(4- ((4-(3-((2,6-dioxopiperi- din-3-yl)amino)phenyl)- piperazin-1-yl)methyl)- piperidine-1-carbonyl)- pyridazin-3-yl)-3-methyl- 2,8-diazaspiro[4.5]decan- 2-yl)benzonitrile 13 (a mixture of diastereo- mers)
		2-Chloro-4-((S)-8-(6-(4- ((4-(3-(((R)-2,6-dioxo- piperidin-3-yl)amino)- phenyl)piperazin-1-yl)- methyl)piperidine-1- carbonyl)pyridazin-3-yl)- 3-methyl-2,8-diazaspiro [4.5]decan-2-yl)benzo- nitrile
		-4-((S)-8-(6-(4-((4-(3- (((S)-2,6-dioxopiperidin- 3-yl)amino)phenyl)piper- azin-1-yl)methyl)piperi- dine-1-carbonyl)pyrid- azin-3-yl)-3-methyl-2,8- diazaspiro[4.5]decan-2- yl)benzonitrile
		2-Chloro-4-((3R)-8-(6- (4-((4-(3-((2,6-dioxo- piperidin-3-yl)amino)- phenyl)piperazin-1-yl)- methyl)piperidine-1- carbonyl)pyridazin-3- yl)-3-methyl-2,8-diaza- spiro[4.5]decan-2-yl)- benzonitrile
		2-Chloro-4-((R)-8-(6-(4- ((4-(3-(((R)-2,6-dioxo- piperidin-3-yl)amino)- phenyl)piperazin-1-yl)- methyl)piperidine-1- carbonyl)pyridazin-3- yl)-3-methyl-2,8-diaza- spiro[4.5]decan-2-yl)- benzonitrile
		-4-((R)-8-(6-(4-((4-(3- (((S)-2,6-dioxopiperidin- 3-yl)amino)phenyl)piper- azin-1-yl)methyl)piper- idine-1-carbonyl)pyrid- azin-3-yl)-3-methyl-2,8- diazaspiro[4.5]decan-2- yl)benzonitrile
		2-Chloro-4-(8-(4-(4-((4- (3-((2,6-dioxopiperidin- 3-yl)amino)phenyl)piper- azin-1-yl)methyl)azeti- dine-1-carbonyl)phenyl)- 3-methyl-2,8-diazaspiro [4.5]decan-2-yl)benzo- nitrile
14		2-Chloro-4-((3S)-8-(4-(4- ((4-(3-((2,6-dioxopiper- idin-3-yl)amino)phenyl)- piperazin-1-yl)methyl)- azetidine-1-carbonyl)- phenyl)-3-methyl-2,8- diazaspiro[4.5]decan-2- yl)benzonitrile 14 (a mixture of diastereo- mers)
		2-Chloro-4-((S)-8-(4-(4- ((4-(3-(((R)-2,6-dioxo- piperidin-3-yl)amino)- phenyl)piperazin-1-yl)- methyl)azetidine-1- carbonyl)phenyl)-3- methyl-2,8-diazaspiro [4.5]decan-2-yl)benzo- nitrile
		2-Chloro-4-((S)-8-(4-(4- ((4-(3-(((S)-2,6-dioxo- piperidin-3-yl)amino)- phenyl)piperazin-1-yl)- methyl)azetidine-1- carbonyl)phenyl)-3- methyl-2,8-diazaspiro [4.5]decan-2-yl)benzo- nitrile
		2-Chloro-4-((3R)-8-(4- (4-((4-(3-((2,6-dioxo- piperidin-3-yl)amino)- phenyl)piperazin-1-yl)- methyl)azetidine-1- carbonyl)phenyl)-3- methyl-2,8-diazaspiro- [4.5]decan-2-yl)benzo- nitrile
		2-Chloro-4-((R)-8-(4-(4- ((4-(3-(((R)-2,6-dioxo- piperidin-3-yl)amino)- phenyl)piperazin-1-yl)- methyl)azetidine-1- carbonyl)phenyl)-3- methyl-2,8-diazaspiro [4.5]decan-2-yl)benzo- nitrile
		2-Chloro-4-((R)-8-(4-(4- ((4-(3-(((S)-2,6-dioxo- piperidin-3-yl)amino)- phenyl)piperazin-1-yl)- methyl)azetidine-1- carbonyl)phenyl)-3- methyl-2,8-diazaspiro [4.5]decan-2-yl)benzo- nitrile
		2-Chloro-4-(8-(4-(4-((4- (3-((2,6-dioxopiperidin- 3-yl)amino)phenyl)piper- azin-1-yl)methyl)piper- idine-1-carbonyl)-2- fluorophenyl)-3-methyl- 2,8-diazaspiro[4.5]decan- 2-yl)benzonitrile
15		2-Chloro-4-((3S)-8-(4-(4- ((4-(3-((2,6-dioxopiper- idin-3-yl)amino)phenyl) piperazin-1-yl)methyl)- piperidine-1-carbonyl)- 2-fluorophenyl)-3-meth- yl-2,8-diazaspiro[4.5] decan-2-yl)benzonitrile 15 (a mixture of dia- stereomers)
15-2		2-Chloro-4-((S)-8-(4-(4- ((4-(3-(((R)-2,6-dioxo- piperidin-3-yl)amino)- phenyl)piperazin-1-yl)- methyl)piperidine-1- carbonyl)-2-fluorophen- yl)-3-methyl-2,8-diaza- spiro[4.5]decan-2-yl)- benzonitrile 15-2
15-1		2-Chloro-4-((S)-8-(4-(4- ((4-(3-(((S)-2,6-dioxo- piperidin-3-yl)amino)- phenyl)piperazin-1-yl)- methyl)piperidine-1- carbonyl)-2-fluorophen- yl)-3-methyl-2,8-diaza- spiro[4.5]decan-2-yl)- benzonitrile 15-1
		2-Chloro-4-((3R)-8-(4- (4-((4-(3-((2,6-dioxo- piperidin-3-yl)amino)- phenyl)piperazin-1-yl)- methyl)piperidine-1- carbonyl)-2-fluorophen- yl)-3-methyl-2,8-diaza- spiro[4.5]decan-2-yl)- benzonitrile
		2-Chloro-4-((R)-8-(4-(4- ((4-(3-(((R)-2,6-dioxo- piperidin-3-yl)amino)- phenyl)piperazin-1-yl)- methyl)piperidine-1- carbonyl)-2-fluorophen- yl)-3-methyl-2,8-diaza- spiro[4.5]decan-2-yl)- benzonitrile
		2-Chloro-4-((R)-8-(4-(4- ((4-(3-(((S)-2,6-dioxo- piperidin-3-yl)amino)- phenyl)piperazin-1-yl)- methyl)piperidine-1- carbonyl)-2-fluorophen- yl)-3-methyl-2,8-diaza- spiro[4.5]decan-2-yl)- benzonitrile
		2-Chloro-4-(8-(4-(4-((4- (3-((2,6-dioxopiperidin- 3-yl)amino)phenyl)piper- azin-1-yl)methyl)piper- idine-1-carbonyl)-3- fluorophenyl)-3-methyl- 2,8-diazaspiro[4.5]decan- 2-yl)benzonitrile
16		2-Chloro-4-((3S)-8-(4-(4- ((4-(3-((2,6-dioxopiper- idin-3-yl)amino)phenyl)- piperazin-1-yl)methyl)- piperidine-1-carbonyl)-3- fluorophenyl)-3-methyl- 2,8-diazaspiro[4.5]decan- 2-yl)benzonitrile 16 (a mixture of diastereo- mers)
		2-Chloro-4-((S)-8-(4-(4- ((4-(3-(((R)-2,6-dioxo- piperidin-3-yl)amino)- phenyl)piperazin-1-yl)- methyl)piperidine-1- carbonyl)-3-fluorophen- yl)-3-methyl-2,8-diaza- spiro[4.5]decan-2-yl)- benzonitrile
		2-Chloro-4-((S)-8-(4-(4- ((4-(3-(((S)-2,6-dioxo- piperidin-3-yl)amino)- phenyl)piperazin-1-yl)- methyl)piperidine-1- carbonyl)-3-fluorophen- yl)-3-methyl-2,8-diaza- spiro[4.5]decan-2-yl)- benzonitrile
		2-Chloro-4-((3R)-8-(4- (4-((4-(3-((2,6-dioxo- piperidin-3-yl)amino)- phenyl)piperazin-1-yl)- methyl)piperidine-1- carbonyl)-3-fluorophen- yl)-3-methyl-2,8-diaza- spiro[4.5]decan-2-yl)- benzonitrile
		2-Chloro-4-((R)-8-(4-(4- ((4-(3-(((R)-2,6-dioxo- piperidin-3-yl)amino)- phenyl)piperazin-1-yl)- methyl)piperidine-1- carbonyl)-3-fluorophen- yl)-3-methyl-2,8-diaza- spiro[4.5]decan-2-yl)- benzonitrile
		2-Chloro-4-((R)-8-(4-(4- ((4-(3-(((S)-2,6-dioxo- piperidin-3-yl)amino)- phenyl)piperazin-1-yl)- methyl)piperidine-1- carbonyl)-3-fluorophen- yl)-3-methyl-2,8-diaza- spiro[4.5]decan-2-yl)- benzonitrile
		2-Chloro-4-(8-(5-(4-((4- (3-((2,6-dioxopiperidin- 3-yl)amino)phenyl)piper- azin-1-yl)methyl)piperi- dine-1-carbonyl)pyrazin- 2-yl)-3-methyl-2,8-diaza- spiro[4.5]decan-2-yl)- benzonitrile
17		2-Chloro-4-((3S)-8-(5-(4- ((4-(3-((2,6-dioxopiper- idin-3-yl)amino)phenyl)- piperazin-1-yl)methyl)- piperidine-1-carbonyl)- pyrazin-2-yl)-3-methyl- 2,8-diazaspiro[4.5]decan- 2-yl)benzonitrile 17 (a mixture of diastereo- mers)
		2-Chloro-4-((S)-8-(5-(4- ((4-(3-(((R)-2,6-dioxo- piperidin-3-yl)amino)- phenyl)piperazin-1-yl)- methyl)piperidine-1- carbonyl)pyrazin-2-yl)- 3-methyl-2,8-diazaspiro [4.5]decan-2-yl)benzo- nitrile
		2-Chloro-4-((S)-8-(5-(4- ((4-(3-(((S)-2,6-dioxo- piperidin-3-yl)amino)- phenyl)piperazin-1-yl)- methyl)piperidine-1- carbonyl)pyrazin-2-yl)- 3-methyl-2,8-diazaspiro [4.5]decan-2-yl)benzo- nitrile
		2-Chloro-4-((3R)-8-(5- (4-((4-(3-((2,6-dioxo- piperidin-3-yl)amino)- phenyl)piperazin-1-yl)- methyl)piperidine-1- carbonyl)pyrazin-2-yl)- 3-methyl-2,8-diazaspiro [4.5]decan-2-yl)benzo- nitrile
		2-Chloro-4-((R)-8-(5-(4- ((4-(3-(((R)-2,6-dioxo- piperidin-3-yl)amino)- phenyl)piperazin-1-yl)- methyl)piperidine-1- carbonyl)pyrazin-2-yl)- 3-methyl-2,8-diazaspiro [4.5]decan-2-yl)benzo- nitrile
		2-Chloro-4-((R)-8-(5-(4- ((4-(3-(((S)-2,6-dioxo- piperidin-3-yl)amino)- phenyl)piperazin-1-yl)- methyl)piperidine-1- carbonyl)pyrazin-2-yl)- 3-methyl-2,8-diazaspiro [4.5]decan-2-yl)benzo- nitrile
		2-Chloro-4-(8-(5-(4-((4- (3-((2,6-dioxopiperidin- 3-yl)amino)phenyl)piper- azin-1-yl)methyl)piper- idine-1-carbonyl)pyridin- 2-yl)-3-methyl-2,8-diaza- spiro[4.5]decan-2-yl)- benzonitrile
18		2-Chloro-4-((3S)-8-(5-(4- ((4-(3-((2,6-dioxopiper- idin-3-yl)amino)phenyl)- piperazin-1-yl)methyl)- piperidine-1-carbonyl)- pyridin-2-yl)-3-methyl- 2,8-diazaspiro[4.5]decan- 2-yl)benzonitrile 18 (a mixture of diastereo- mers)
		2-Chloro-4-((S)-8-(5-(4- ((4-(3-(((R)-2,6-dioxo- piperidin-3-yl)amino)- phenyl)piperazin-1-yl)- methyl)piperidine-1- carbonyl)pyridin-2-yl)- 3-methyl-2,8-diazaspiro [4.5]decan-2-yl)benzo- nitrile
		2-Chloro-4-((S)-8-(5-(4- ((4-(3-(((S)-2,6-dioxo- piperidin-3-yl)amino)- phenyl)piperazin-1-yl)- methyl)piperidine-1- carbonyl)pyridin-2-yl)- 3-methyl-2,8-diazaspiro [4.5]decan-2-yl)benzo- nitrile
		2-Chloro-4-((3R)-8-(5- (4-((4-(3-((2,6-dioxo- piperidin-3-yl)amino)- phenyl)piperazin-1-yl)- methyl)piperidine-1- carbonyl)pyridin-2-yl)- 3-methyl-2,8-diazaspiro [4.5]decan-2-yl)benzo- nitrile
		2-Chloro-4-((R)-8-(5-(4- ((4-(3-(((R)-2,6-dioxo- piperidin-3-yl)amino)- phenyl)piperazin-1-yl)- methyl)piperidine-1- carbonyl)pyridin-2-yl)- 3-methyl-2,8-diazaspiro [4.5]decan-2-yl)benzo- nitrile
		2-Chloro-4-((R)-8-(5-(4- ((4-(3-(((S)-2,6-dioxo- piperidin-3-yl)amino)- phenyl)piperazin-1-yl)- methyl)piperidine-1- carbonyl)pyridin-2-yl)- 3-methyl-2,8-diazaspiro [4.5]decan-2-yl)benzo- nitrile
		2-Chloro-4-(8-(4-(4-((4- (3-((2,6-dioxopiperidin- 3-yl)amino)phenyl)piper- idin-1-yl)methyl)piper- idine-1-carbonyl)phen- yl)-3-methyl-2,8-diaza- spiro[4.5]decan-2-yl)- benzonitrile
19		2-Chloro-4-((3S)-8-(4-(4- ((4-(3-((2,6-dioxopiper- idin-3-yl)amino)phenyl)- piperidin-1-yl)methyl)- piperidine-1-carbonyl)- phenyl)-3-methyl-2,8- diazaspiro[4.5]decan-2- yl)benzonitrile 19 (a mixture of diastereo- mers)
		2-Chloro-4-((S)-8-(4-(4- ((4-(3-(((R)-2,6-dioxo- piperidin-3-yl)amino)- phenyl)piperidin-1-yl)- methyl)piperidine-1- carbonyl)phenyl)-3- methyl-2,8-diazaspiro [4.5]decan-2-yl)benzo- nitrile
		2-Chloro-4-((S)-8-(4-(4- ((4-(3-(((S)-2,6-dioxo- piperidin-3-yl)amino)- phenyl)piperidin-1-yl)- methyl)piperidine-1- carbonyl)phenyl)-3- methyl-2,8-diazaspiro [4.5]decan-2-yl)benzo- nitrile
		2-Chloro-4-((3R)-8-(4- (4-((4-(3-((2,6-dioxo- piperidin-3-yl)amino)- phenyl)piperidin-1-yl)- methyl)piperidine-1- carbonyl)phenyl)-3- methyl-2,8-diazaspiro [4.5]decan-2-yl)benzo- nitrile
		2-Chloro-4-((R)-8-(4-(4- ((4-(3-(((R)-2,6-dioxo- piperidin-3-yl)amino)- phenyl)piperidin-1-yl)- methyl)piperidine-1- carbonyl)phenyl)-3- methyl-2,8-diazaspiro [4.5]decan-2-yl)benzo- nitrile
		2-Chloro-4-((R)-8-(4-(4- ((4-(3-(((S)-2,6-dioxo- piperidin-3-yl)amino)- phenyl)piperidin-1-yl)- methyl)piperidine-1- carbonyl)phenyl)-3- methyl-2,8-diazaspiro [4.5]decan-2-yl)benzo- nitrile
		2-Chloro-4-(8-(6-(4-((4- (3-((2,6-dioxopiperidin- 3-yl)amino)phenyl)piper- idin-1-yl)methyl)piper- idine-1-carbonyl)pyrid- azin-3-yl)-3-methyl-2,8- diazaspiro[4.5]decan-2- yl)benzonitrile
20		2-Chloro-4-((3S)-8-(6-(4- ((4-(3-((2,6-dioxopiper- idin-3-yl)amino)phenyl)- piperidin-1-yl)methyl)- piperidine-1-carbonyl)- pyridazin-3-yl)-3-methyl- 2,8-diazaspiro[4.5]decan- 2-yl)benzonitrile 20 (a mixture of diastereo- mers)
		2-Chloro-4-((S)-8-(6-(4- ((4-(3-(((R)-2,6-dioxo- piperidin-3-yl)amino)- phenyl)piperidin-1-yl)- methyl)piperidine-1- carbonyl)pyridazin-3- yl)-3-methyl-2,8-diaza- spiro[4.5]decan-2-yl)- benzonitrile
		2-Chloro-4-((S)-8-(6-(4- ((4-(3-(((S)-2,6-dioxo- piperidin-3-yl)amino)- phenyl)piperidin-1-yl)- methyl)piperidine-1- carbonyl)pyridazin-3- yl)-3-methyl-2,8-diaza- spiro[4.5]decan-2-yl)- benzonitrile
		2-Chloro-4-((3R)-8-(6- (4-((4-(3-((2,6-dioxo- piperidin-3-yl)amino)- phenyl)piperidin-1-yl)- methyl)piperidine-1- carbonyl)pyridazin-3- yl)-3-methyl-2,8-diaza- spiro[4.5]decan-2-yl)- benzonitrile
		2-Chloro-4-((R)-8-(6-(4- ((4-(3-(((R)-2,6-dioxo- piperidin-3-yl)amino)- phenyl)piperidin-1-yl)- methyl)piperidine-1- carbonyl)pyridazin-3- yl)-3-methyl-2,8-diaza- spiro[4.5]decan-2-yl)- benzonitrile
		2-Chloro-4-((R)-8-(6-(4- ((4-(3-(((S)-2,6-dioxo- piperidin-3-yl)amino)- phenyl)piperidin-1-yl)- methyl)piperidine-1- carbonyl)pyridazin-3- yl)-3-methyl-2,8-diaza- spiro[4.5]decan-2-yl)- benzonitrile
		2-Chloro-4-(8-(6-(3-((4- (3-((2,6-dioxopiperidin- 3-yl)amino)phenyl)- piperidin-1-yl)methyl)- azetidine-1-carbonyl)pyr- idazin-3-yl)-3-methyl- 2,8-diazaspiro[4.5]decan- 2-yl)benzonitrile
21		2-Chloro-4-((3S)-8-(6-(3- ((4-(3-((2,6-dioxopiper- idin-3-yl)amino)phen- yl)piperidin-1-yl)meth- yl)azetidine-1-carbonyl)- pyridazin-3-yl)-3-methyl- 2,8-diazaspiro[4.5]decan- 2-yl)benzonitrile 21 (a mixture of diastereo- mers)
		2-Chloro-4-((S)-8-(6-(3- ((4-(3-(((R)-2,6-dioxo- piperidin-3-yl)amino)- phenyl)piperidin-1-yl)- methyl)azetidine-1- carbonyl)pyridazin-3- yl)-3-methyl-2,8-diaza- spiro[4.5]decan-2-yl)- benzonitrile
		2-Chloro-4-((S)-8-(6-(3- ((4-(3-(((S)-2,6-dioxo- piperidin-3-yl)amino)- phenyl)piperidin-1-yl)- methyl)azetidine-1- carbonyl)pyridazin-3- yl)-3-methyl-2,8-diaza- spiro[4.5]decan-2-yl)- benzonitrile
		2-Chloro-4-((3R)-8-(6- (3-((4-(3-((2,6-dioxo- piperidin-3-yl)amino)- phenyl)piperidin-1-yl)- methyl)azetidine-1-car- bonyl)pyridazin-3-yl)-3- methyl-2,8-diazaspiro [4.5]decan-2-yl)benzo- nitrile
		2-Chloro-4-((R)-8-(6-(3- ((4-(3-(((R)-2,6-dioxo- piperidin-3-yl)amino)- phenyl)piperidin-1-yl)- methyl)azetidine-1-car- bonyl)pyridazin-3-yl)-3- methyl-2,8-diazaspiro [4.5]decan-2-yl)benzo- nitrile
		2-Chloro-4-((R)-8-(6-(3- ((4-(3-(((S)-2,6-dioxo- piperidin-3-yl)amino)- phenyl)piperidin-1-yl)- methyl)azetidine-1-car- bonyl)pyridazin-3-yl)-3- methyl-2,8-diazaspiro [4.5]decan-2-yl)benzo- nitrile
		2-Chloro-4-(8-(6-(3-((4- (3-((2,6-dioxopiperidin- 3-yl)amino)phenyl)piper- azin-1-yl)methyl)azeti- dine-1-carbonyl)pyrid- azin-3-yl)-3-methyl-2,8- diazaspiro[4.5]decan-2- yl)benzonitrile
22		2-Chloro-4-((3S)-8-(6- (3-((4-(3-((2,6-dioxo- piperidin-3-yl)amino)- phenyl)piperazin-1-yl)- methyl)azetidine-1-car- bonyl)pyridazin-3-yl)- 3-methyl-2,8-diazaspiro [4.5]decan-2-yl)benzo- nitrile 22 (a mixture of diastereomers)
		2-Chloro-4-((S)-8-(6-(3- ((4-(3-(((R)-2,6-dioxo- piperidin-3-yl)amino)- phenyl)piperazin-1-yl)- methyl)azetidine-1-car- bonyl)pyridazin-3-yl)-3- methyl-2,8-diazaspiro [4.5]decan-2-yl)benzo- nitrile
		2-Chloro-4-((S)-8-(6-(3- ((4-(3-(((S)-2,6-dioxo- piperidin-3-yl)amino)- phenyl)piperazin-1-yl)- methyl)azetidine-1-car- bonyl)pyridazin-3-yl)-3- methyl-2,8-diazaspiro [4.5]decan-2-yl)benzo- nitrile
		2-Chloro-4-((3R)-8-(6- (3-((4-(3-((2,6-dioxo- piperidin-3-yl)amino)- phenyl)piperazin-1-yl)- methyl)azetidine-1-car- bonyl)pyridazin-3-yl)- 3-methyl-2,8-diazaspiro [4.5]decan-2-yl)benzo- nitrile
		2-Chloro-4-((R)-8-(6-(3- ((4-(3-(((R)-2,6-dioxo- piperidin-3-yl)amino)- phenyl)piperazin-1-yl)- methyl)azetidine-1-car- bonyl)pyridazin-3-yl)-3- methyl-2,8-diazaspiro [4.5]decan-2-yl)benzo- nitrile
		2-Chloro-4-((R)-8-(6-(3- ((4-(3-(((S)-2,6-dioxo- piperidin-3-yl)amino)- phenyl)piperazin-1-yl)- methyl)azetidine-1-car- bonyl)pyridazin-3-yl)-3- methyl-2,8-diazaspiro [4.5]decan-2-yl)benzo- nitrile
		2-Chloro-4-(8-(4-(4-((4- (5-((2,6-dioxopiperidin- 3-yl)amino)-2-fluoro- phenyl)piperazin-1-yl)- methyl)piperidine-1-car- bonyl)phenyl)-3-methyl- 2,8-diazaspiro[4.5]decan- 2-yl)benzonitrile
23		2-Chloro-4-((3S)-8-(4- (4-((4-(5-((2,6-dioxo- piperidin-3-yl)amino)-2- fluorophenyl)piperazin- 1-yl)methyl)piperidine- 1-carbonyl)phenyl)-3- methyl-2,8-diazaspiro [4.5]decan-2-yl)benzo- nitrile 23 (a mixture of diastereomers)
		2-Chloro-4-((S)-8-(4-(4- ((4-(5-(((R)-2,6-dioxo- piperidin-3-yl)amino)-2- fluorophenyl)piperazin- 1-yl)methyl)piperidine- 1-carbonyl)phenyl)-3- methyl-2,8-diazaspiro [4.5]decan-2-yl)benzo- nitrile
		2-Chloro-4-((S)-8-(4-(4- ((4-(5-(((S)-2,6-dioxo- piperidin-3-yl)amino)-2- fluorophenyl)piperazin- 1-yl)methyl)piperidine- 1-carbonyl)phenyl)-3- methyl-2,8-diazaspiro [4.5]decan-2-yl)benzo- nitrile
		2-Chloro-4-((3R)-8-(4- (4-((4-(5-((2,6-dioxo- piperidin-3-yl)amino)-2- fluorophenyl)piperazin- 1-yl)methyl)piperidine- 1-carbonyl)phenyl)-3- methyl-2,8-diazaspiro [4.5]decan-2-yl)benzo- nitrile
		2-Chloro-4-((R)-8-(4-(4- ((4-(5-(((R)-2,6-dioxo- piperidin-3-yl)amino)-2- fluorophenyl)piperazin- 1-yl)methyl)piperidine- 1-carbonyl)phenyl)-3- methyl-2,8-diazaspiro [4.5]decan-2-yl)benzo- nitrile
		2-Chloro-4-((R)-8-(4-(4- ((4-(5-(((S)-2,6-dioxo- piperidin-3-yl)amino)-2- fluorophenyl)piperazin- 1-yl)methyl)piperidine- 1-carbonyl)phenyl)-3- methyl-2,8-diazaspiro [4.5]decan-2-yl)benzo- nitrile
		2-Chloro-4-(8-(4-(4-((4- (4-((2,6-dioxopiperidin- 3-yl)amino)pyridin-2- yl)piperazin-1-yl)meth- yl)piperidine-1-carbon- yl)phenyl)-3-methyl-2,8- diazaspiro[4.5]decan-2- yl)benzonitrile
24		2-Chloro-4-((3S)-8-(4- (4-((4-(4-((2,6-dioxo- piperidin-3-yl)amino)- pyridin-2-yl)piperazin- 1-yl)methyl)piperidine- 1-carbonyl)phenyl)-3- methyl-2,8-diazaspiro [4.5]decan-2-yl)benzo- nitrile 24 (a mixture of diastereomers)
		2-Chloro-4-((S)-8-(4-(4- ((4-(4-(((R)-2,6-dioxo- piperidin-3-yl)amino)- pyridin-2-yl)piperazin- 1-yl)methyl)piperidine- 1-carbonyl)phenyl)-3- methyl-2,8-diazaspiro [4.5]decan-2-yl)benzo- nitrile
		2-Chloro-4-((S)-8-(4-(4- ((4-(4-(((S)-2,6-dioxo- piperidin-3-yl)amino)- pyridin-2-yl)piperazin- 1-yl)methyl)piperidine- 1-carbonyl)phenyl)-3- methyl-2,8-diazaspiro [4.5]decan-2-yl)benzo- nitrile
		2-Chloro-4-((3R)-8-(4- (4-((4-(4-((2,6-dioxo- piperidin-3-yl)amino)- pyridin-2-yl)piperazin- 1-yl)methyl)piperidine- 1-carbonyl)phenyl)-3- methyl-2,8-diazaspiro [4.5]decan-2-yl)benzo- nitrile
		2-Chloro-4-((R)-8-(4-(4- ((4-(4-(((R)-2,6-dioxo- piperidin-3-yl)amino) pyridin-2-yl)piperazin- 1-yl)methyl)piperidine- 1-carbonyl)phenyl)-3- methyl-2,8-diazaspiro [4.5]decan-2-yl)benzo- nitrile
		2-Chloro-4-((R)-8-(4-(4- ((4-(4-(((S)-2,6-dioxo- piperidin-3-yl)amino)- pyridin-2-yl)piperazin- 1-yl)methyl)piperidine- 1-carbonyl)phenyl)-3- methyl-2,8-diazaspiro [4.5]decan-2-yl)benzo- nitrile
		2-Chloro-4-(8-(4-(4-((4- (4-((2,6-dioxopiperidin- 3-yl)amino)phenyl)piper- azin-1-yl)methyl)piper- idine-1-carbonyl)phen- yl)-3-methyl-2,8-diaza- spiro[4.5]decan-2-yl)- benzonitrile
25		2-Chloro-4-((3S)-8-(4- (4-((4-(4-((2,6-dioxo- piperidin-3-yl)amino)- phenyl)piperazin-1-yl)- methyl)piperidine-1-car- bonyl)phenyl)-3-methyl- 2,8-diazaspiro[4.5]decan- 2-yl)benzonitrile 25 (a mixture of diastereo- mers)
		2-Chloro-4-((S)-8-(4-(4- ((4-(4-(((R)-2,6-dioxo- piperidin-3-yl)amino)- phenyl)piperazin-1-yl)- methyl)piperidine-1-car- bonyl)phenyl)-3-methyl- 2,8-diazaspiro[4.5]decan- 2-yl)benzonitrile
		2-Chloro-4-((S)-8-(4-(4- ((4-(4-(((S)-2,6-dioxo- piperidin-3-yl)amino)- phenyl)piperazin-1-yl)- methyl)piperidine-1-car- bonyl)phenyl)-3-methyl- 2,8-diazaspiro[4.5]decan- 2-yl)benzonitrile
		2-Chloro-4-((3R)-8-(4- (4-((4-(4-((2,6-dioxo- piperidin-3-yl)amino)- phenyl)piperazin-1-yl)- methyl)piperidine-1-car- bonyl)phenyl)-3-methyl- 2,8-diazaspiro[4.5]decan- 2-yl)benzonitrile
		2-Chloro-4-((R)-8-(4-(4- ((4-(4-(((R)-2,6-dioxo- piperidin-3-yl)amino)- phenyl)piperazin-1-yl)- methyl)piperidine-1-car- bonyl)phenyl)-3-methyl- 2,8-diazaspiro[4.5]decan- 2-yl)benzonitrile
		2-Chloro-4-((R)-8-(4-(4- ((4-(4-(((S)-2,6-dioxo- piperidin-3-yl)amino)- phenyl)piperazin-1-yl)- methyl)piperidine-1-car- bonyl)phenyl)-3-methyl- 2,8-diazaspiro[4.5]decan- 2-yl)benzonitrile
		2-Chloro-4-(8-(4-(4-((4- (4-((2,6-dioxopiperidin- 3-yl)amino)phenyl)piper- idin-1-yl)methyl)piper- idine-1-carbonyl)phen- yl)-3-methyl-2,8-diaza- spiro[4.5]decan-2-yl)- benzonitrile
26		2-Chloro-4-((3S)-8-(4- (4-((4-(4-((2,6-dioxo- piperidin-3-yl)amino) phenyl)piperidin-1-yl)- methyl)piperidine-1- carbonyl)phenyl)-3- methyl-2,8-diazaspiro [4.5]decan-2-yl)benzo- nitrile 26 (a mixture of diastereomers)
		2-Chloro-4-((S)-8-(4-(4- ((4-(4-(((S)-2,6-dioxo- piperidin-3-yl)amino)- phenyl)piperidin-1-yl)- methyl)piperidine-1-car- bonyl)phenyl)-3-methyl- 2,8-diazaspiro[4.5]decan- 2-yl)benzonitrile
		2-Chloro-4-((S)-8-(4-(4- ((4-(4-(((R)-2,6-dioxo- piperidin-3-yl)amino)- phenyl)piperidin-1-yl)- methyl)piperidine-1-car- bonyl)phenyl)-3-methyl- 2,8-diazaspiro[4.5]decan- 2-yl)benzonitrile
		2-Chloro-4-((3R)-8-(4- (4-((4-(4-((2,6-dioxo- piperidin-3-yl)amino)- phenyl)piperidin-1-yl)- methyl)piperidine-1-car- bonyl)phenyl)-3-methyl- 2,8-diazaspiro[4.5]decan- 2-yl)benzonitrile
		2-Chloro-4-((R)-8-(4-(4- ((4-(4-(((S)-2,6-dioxo- piperidin-3-yl)amino)- phenyl)piperidin-1-yl)- methyl)piperidine-1-car- bonyl)phenyl)-3-methyl- 2,8-diazaspiro[4.5]decan- 2-yl)benzonitrile
		2-Chloro-4-((R)-8-(4-(4- ((4-(4-(((R)-2,6-dioxo- piperidin-3-yl)amino)- phenyl)piperidin-1-yl)- methyl)piperidine-1-car- bonyl)phenyl)-3-methyl- 2,8-diazaspiro[4.5]decan- 2-yl)benzonitrile
		2-Chloro-4-(8-(4-(4-((4- (4-((2,6-dioxopiperidin- 3-yl)amino)-2-fluoro- phenyl)piperidin-1-yl)- methyl)piperidine-1-car- bonyl)phenyl)-3-methyl- 2,8-diazaspiro[4.5]decan- 2-yl)benzonitrile
27		2-Chloro-4-((3S)-8-(4- (4-((4-(4-((2,6-dioxo- piperidin-3-yl)amino)-2- fluorophenyl)piperidin- 1-yl)methyl)piperidine- 1-carbonyl)phenyl)-3- methyl-2,8-diazaspiro [4.5]decan-2-yl)benzo- nitrile 27 (a mixture of diastereomers)
		2-Chloro-4-((S)-8-(4-(4- ((4-(4-(((S)-2,6-dioxo- piperidin-3-yl)amino)-2- fluorophenyl)piperidin- 1-yl)methyl)piperidine- 1-carbonyl)phenyl)-3- methyl-2,8-diazaspiro [4.5]decan-2-yl)benzo- nitrile
		2-Chloro-4-((S)-8-(4-(4- ((4-(4-(((R)-2,6-dioxo- piperidin-3-yl)amino)-2- fluorophenyl)piperidin- 1-yl)methyl)piperidine- 1-carbonyl)phenyl)-3- methyl-2,8-diazaspiro [4.5]decan-2-yl)benzo- nitrile
		2-Chloro-4-((3R)-8-(4- (4-((4-(4-((2,6-dioxo- piperidin-3-yl)amino)-2- fluorophenyl)piperidin- 1-yl)methyl)piperidine- 1-carbonyl)phenyl)-3- methyl-2,8-diazaspiro [4.5]decan-2-yl)benzo- nitrile 27 (a mixture of diastereomers)
		2-Chloro-4-((R)-8-(4-(4- ((4-(4-(((S)-2,6-dioxo- piperidin-3-yl)amino)-2- fluorophenyl)piperidin- 1-yl)methyl)piperidine- 1-carbonyl)phenyl)-3- methyl-2,8-diazaspiro [4.5]decan-2-yl)benzo- nitrile
		2-Chloro-4-((R)-8-(4-(4- ((4-(4-(((R)-2,6-dioxo- piperidin-3-yl)amino)-2- fluorophenyl)piperidin- 1-yl)methyl)piperidine- 1-carbonyl)phenyl)-3- methyl-2,8-diazaspiro [4.5]decan-2-yl)benzo- nitrile
		2-Chloro-4-(8-(4-(2-(4- (4-(2,4-dioxotetrahydro- pyrimidin-1(2H)-yl)- phenyl)piperazin-1-yl)- 7-azaspiro[3.5]nonane- 7-carbonyl)phenyl)-3- methyl-2,8-diazaspiro [4.5]decan-2-yl)benzo- nitrile
28		(S)-2-Chloro-4-(8-(4-(2- (4-(4-(2,4-dioxotetra- hydropyrimidin-1(2H)- yl)phenyl)piperazin-1- yl)-7-azaspiro[3.5] nonane-7-carbonyl)- phenyl)-3-methyl-2,8- diazaspiro[4.5]decan-2- yl)benzonitrile 28
		(R)-2-Chloro-4-(8-(4-(2- (4-(4-(2,4-dioxotetra- hydro-pyrimidin-1(2H)- yl)phenyl)piperazin-1- yl)-7-azaspiro[3.5] nonane-7-carbonyl)- phenyl)-3-methyl-2,8- diazaspiro[4.5]decan-2- yl)benzonitrile
		2-Chloro-4-(8-(4-(9-(4- (4-(2,4-dioxotetrahydro- pyrimidin-1(2H)-yl)- phenyl)piperazin-1-yl)- 3-azaspiro[5.5]undecane- 3-carbonyl)phenyl)-3- methyl-2,8-diazaspiro [4.5]decan-2-yl)benzo- nitrile
29		(S)-2-Chloro-4-(8-(4- (9-(4-(4-(2,4-dioxotetra- hydropyrimidin-1(2H)- yl)phenyl)piperazin-1- yl)-3-azaspiro[5.5]un- decane-3-carbonyl)phen- yl)-3-methyl-2,8-diaza- spiro[4.5]decan-2-yl)- benzonitrile 29
		(R)-2-Chloro-4-(8-(4- (9-(4-(4-(2,4-dioxotetra- hydropyrimidin-1(2H)- yl)phenyl)piperazin-1- yl)-3-azaspiro[5.5]un- decane-3-carbonyl)phen- yl)-3-methyl-2,8-diaza- spiro[4.5]decan-2-yl)- benzonitrile
		2-Chloro-4-(8-(4-(2-(4- (4-(2,4-dioxotetrahydro- pyrimidin-1(2H)-yl)- phenyl)piperazin-1-yl)- 7-azaspiro[3.5]nonane- 7-carbonyl)-2-fluoro- phenyl)-3-methyl-2,8- diazaspiro[4.5]decan-2- yl)benzonitrile
30		(S)-2-Chloro-4-(8-(4-(2- (4-(4-(2,4-dioxotetra- hydropyrimidin-1(2H)- yl)phenyl)piperazin-1- yl)-7-azaspiro[3.5] nonane-7-carbonyl)-2- fluorophenyl)-3-methyl- 2,8-diazaspiro[4.5]decan- 2-yl)benzonitrile 30
		(R)-2-Chloro-4-(8-(4-(2- (4-(4-(2,4-dioxotetra- hydro-pyrimidin-1(2H)- yl)phenyl)piperazin-1- yl)-7-azaspiro[3.5] nonane-7-carbonyl)-2- fluorophenyl)-3-methyl- 2,8-diazaspiro[4.5]decan- 2-yl)benzonitrile
		2-Chloro-4-(8-(4-(2-(4- (4-(2,4-dioxotetrahydro- pyrimidin-1(2H)-yl)- phenyl)piperazin-1-yl)- 7-azaspiro[3.5]nonane- 7-carbonyl)-3-fluoro- phenyl)-3-methyl-2,8- diazaspiro[4.5]decan-2- yl)benzonitrile
31		(S)-2-Chloro-4-(8-(4-(2- (4-(4-(2,4-dioxotetra- hydropyrimidin-1(2H)- yl)phenyl)piperazin-1- yl)-7-azaspiro[3.5] nonane-7-carbonyl)-3- fluorophenyl)-3-methyl- 2,8-diazaspiro[4.5] decan-2-yl)benzonitrile 31
		(R)-2-Chloro-4-(8-(4-(2- (4-(4-(2,4-dioxotetra- hydropyrimidin-1(2H)- yl)phenyl)piperazin-1- yl)-7-azaspiro[3.5] nonane-7-carbonyl)-3- fluorophenyl)-3-methyl- 2,8-diazaspiro[4.5] decan-2-yl)benzonitrile
		2-Chloro-4-(8-(6-(2-(4- (4-(2,4-dioxotetrahydro- pyrimidin-1(2H)-yl)- phenyl)piperazin-1-yl)- 7-azaspiro[3.5]nonane- 7-carbonyl)pyridin-3- yl)-3-methyl-2,8-diaza- spiro[4.5]decan-2-yl)- benzonitrile
32		(S)-2-Chloro-4-(8-(6-(2- (4-(4-(2,4-dioxotetra- hydropyrimidin-1(2H)- yl)phenyl)piperazin-1- yl)-7-azaspiro[3.5] nonane-7-carbonyl)pry- idin-3-yl)-3-methyl-2,8- diazaspiro[4.5]decan-2- yl)benzonitrile 32
		(R)-2-Chloro-4-(8-(6-(2- (4-(4-(2,4-dioxotetra- hydropyrimidin-1(2)- yl)phenyl)piperazin-1- yl)-7-azaspiro[3.5]- nonane-7-carbonyl)pyr- idin-3-yl)-3-methyl-2,8- diazaspiro[4.5]decan-2- yl)benzonitrile
		2-Chloro-4-(8-(5-(2-(4- (4-(2,4-dioxotetrahydro- pyrimidin-1(2H)-yl)- phenyl)piperazin-1-yl)- 7-azaspiro[3.5]nonane- 7-carbonyl)pyridin-2-yl)- 3-methyl-2,8-diazaspiro [4.5]decan-2-yl]benzo- nitrile
33		(S)-2-Chloro-4-(8-(5-(2- (4-(4-(2,4-dioxotetra- hydropyrimidin-1(2H)- yl)phenyl)piperazin-1- yl)-7-azaspiro[3.5] nonane-7-carbonyl)pyr- idin-2-yl)-3-methyl-2,8- diazaspiro[4.5]decan-2- yl]benzonitrile 33
		(R)-2-Chloro-4-(8-(5-(2- (4-(4-(2,4-dioxotetra- hydropyrimidin-1(2H)- yl)phenyl)piperazin-1- yl)-7-azaspiro[3.5] nonane-7-carbonyl)pyr- idin-2-yl)-3-methyl-2,8- diazaspiro[4.5]decan-2- yl]benzonitrile
		2-Chloro-4-(8-(4-(2-(4- (4-(2,6-dioxopiperidin- 3-yl)phenyl)piperazin- 1-yl)-7-azaspiro[3.5] nonane-7-carbonyl)- phenyl)-3-methyl-2,8- diazaspiro[4.5]decan- 2-yl)benzonitrile
34		2-Chloro-4-((3S)-8-(4- (2-(4-(4-(2,6-dioxopiper- idin-3-yl)phenyl)piper- azin-1-yl)-7-azaspiro[3.5] nonane-7-carbonyl)phen- yl)-3-methyl-2,8-diaza- spiro[4.5]decan-2-yl)- benzonitrile 34 (a mix- ture of diastereomers)
		2-Chloro-4-((S)-8-(4-(2- (4-(4-((S)-2,6-dioxo- piperidin-3-yl)phenyl)- piperazin-1-yl)-7-aza- spiro[3.5]nonane-7-car- bonyl)phenyl)-3-methyl- 2,8-diazaspiro[4.5]decan- 2-yl)benzonitrile
		2-Chloro-4-((S)-8-(4-(2- (4-(4-((R)-2,6-dioxo- piperidin-3-yl)phenyl)- piperazin-1-yl)-7-aza- spiro[3.5]nonane-7-car- bonyl)phenyl)-3-methyl- 2,8-diazaspiro[4.5]decan- 2-yl)benzonitrile
		2-Chloro-4-((3R)-8-(4- (2-(4-(4-(2,6-dioxo- piperidin-3-yl)phenyl)- piperazin-1-yl)-7-aza- spiro[3.5]nonane-7-car- bonyl)phenyl)-3-methyl- 2,8-diazaspiro[4.5]decan- 2-yl)benzonitrile
		2-Chloro-4-((R)-8-(4- (2-(4-(4-((S)-2,6-dioxo- piperidin-3-yl)phenyl)- piperazin-1-yl)-7-aza- spiro[3.5]nonane-7-car- bonyl)phenyl)-3-methyl- 2,8-diazaspiro[4.5]decan- 2-yl)benzonitrile
		2-Chloro-4-((R)-8-(4- (2-(4-(4-((R)-2,6-dioxo- piperidin-3-yl)phenyl)- piperazin-1-yl)-7-aza- spiro[3.5]nonane-7-car- bonyl)phenyl)-3-methyl- 2,8-diazaspiro[4.5]decan- 2-yl)benzonitrile
		2-Chloro-4-(8-(4-(2-(4- (3-(2,4-dioxotetrahydro- pyrimidin-1(2H)-yl)- phenyl)piperazin-1-yl)- 7-azaspiro[3.5]nonane- 7-carbonyl)phenyl)-3- methyl-2,8-diazaspiro [4.5]decan-2-yl)benzo- nitrile
35		(S)-2-Chloro-4-(8-(4-(2- (4-(3-(2,4-dioxotetra- hydropyrimidin-1(2H)- yl)phenyl)piperazin-1- yl)-7-azaspiro[3.5] nonane-7-carbonyl)- phenyl)-3-methyl-2,8- diazaspiro[4.5]decan-2- yl)benzonitrile 35
		(R)-2-Chloro-4-(8-(4-(2- (4-(3-(2,4-dioxotetra- hydropyrimidin-1(2H)- yl)phenyl)piperazin-1- yl)-7-azaspiro[3.5] nonane-7-carbonyl)- phenyl)-3-methyl-2,8- diazaspiro[4.5]decan-2- yl)benzonitrile
		2-Chloro-4-(8-(4-(2-(4- (3-((2,6-dioxopiperidin- 3-yl)amino)phenyl)- piperazin-1-yl)-7-aza- spiro[3.5]nonane-7- carbonyl)-2-fluorophen- yl)-3-methyl-2,8-diaza- spiro[4.5]decan-2-yl)- benzonitrile
36		2-Chloro-4-((3S)-8-(4- (2-(4-(3-((2,6-dioxo- piperidin-3-yl)amino)- phenyl)piperazin-1-yl)- 7-azaspiro[3.5]nonane- 7-carbonyl)-2-fluoro- phenyl)-3-methyl-2,8- diazaspiro[4.5]decan-2- yl)benzonitrile 36 (a mixture of diastereo- mers)
		2-Chloro-4-((S)-8-(4-(2- (4-(3-(((R)-2,6-dioxo- piperidin-3-yl)amino)- phenyl)piperazin-1-yl)- 7-azaspiro[3.5]nonane- 7-carbonyl)-2-fluoro- phenyl)-3-methyl-2,8- diazaspiro[4.5]decan-2- yl)benzonitrile
		2-Chloro-4-((S)-8-(4-(2- (4-(3-(((S)-2,6-dioxo- piperidin-3-yl)amino)- phenyl)piperazin-1-yl)- 7-azaspiro[3.5]nonane- 7-carbonyl)-2-fluoro- phenyl)-3-methyl-2,8- diazaspiro[4.5]decan- 2-yl)benzonitrile
		2-Chloro-4-((3R)-8-(4- (2-(4-(3-((2,6-dioxo- piperidin-3-yl)amino)- phenyl)piperazin-1-yl)- 7-azaspiro[3.5]nonane- 7-carbonyl)-2-fluoro- phenyl)-3-methyl-2,8- diazaspiro[4.5]decan-2- yl)benzonitrile
		2-Chloro-4-((R)-8-(4-(2- (4-(3-(((R)-2,6-dioxo- piperidin-3-yl)amino)- phenyl)piperazin-1-yl)- 7-azaspiro[3.5]nonane- 7-carbonyl)-2-fluoro- phenyl)-3-methyl-2,8- diazaspiro[4.5]decan-2- yl)benzonitrile
		2-Chloro-4-((R)-8-(4-(2- (4-(3-(((S)-2,6-dioxo- piperidin-3-yl)amino)- phenyl)piperazin-1-yl)- 7-azaspiro[3.5]nonane- 7-carbonyl)-2-fluoro- phenyl)-3-methyl-2,8- diazaspiro[4.5]decan-2- yl)benzonitrile
		2-Chloro-4-(8-(4-(4-((1- (3-((2,6-dioxopiperidin- 3-yl)amino)phenyl)- piper-idin-4-yl)methyl)- piperazine-1-carbonyl)- phenyl)-3-methyl-2,8- diazaspiro[4.5]decan-2- yl)benzonitrile
37		2-Chloro-4-((3S)-8-(4- (4-((1-(3-((2,6-dioxo- piperidin-3-yl)amino)- phenyl)piperidin-4-yl)- methyl)piperazine-1- carbonyl)phenyl)-3- methyl-2,8-diazaspiro [4.5]decan-2-yl)benzo- nitrile 37 (a mixture of diastereomers)
		2-Chloro-4-((S)-8-(4-(4- ((1-(3-(((R)-2,6-dioxo- piperidin-3-yl)amino)- phenyl)piperidin-4-yl)- methyl)piperazine-1- carbonyl)phenyl)-3- methyl-2,8-diazaspiro [4.5]decan-2-yl)benzo- nitrile
		2-Chloro-4-((S)-8-(4-(4- ((1-(3-(((S)-2,6-dioxo- piperidin-3-yl)amino)- phenyl)piperidin-4-yl)- methyl)piperazine-1- carbonyl)phenyl)-3- methyl-2,8-diazaspiro [4.5]decan-2-yl)benzo- nitrile
		2-Chloro-4-((3R)-8-(4- (4-((1-(3-((2,6-dioxo- piperidin-3-yl)amino) phenyl)piperidin-4-yl)- methyl)piperazine-1- carbonyl)phenyl)-3- methyl-2,8-diazaspiro [4.5]decan-2-yl)benzo- nitrile
		2-Chloro-4-((R)-8-(4-(4- ((1-(3-(((R)-2,6-dioxo- piperidin-3-yl)amino)- phenyl)piperidin-4-yl)- methyl)piperazine-1- carbonyl)phenyl)-3- methyl-2,8-diazaspiro [4.5]decan-2-yl)benzo- nitrile
		2-Chloro-4-((R)-8-(4-(4- ((1-(3-(((S)-2,6-dioxo- piperidin-3-yl)amino)- phenyl)piperidin-4-yl)- methyl)piperazine-1- carbonyl)phenyl)-3- methyl-2,8-diazaspiro [4.5]decan-2-yl)benzo- nitrile
38		±-2-Chloro-4-(8-(4-(4- ((4-(3-((2,6-dioxopiper- idin-3-yl)amino)phen- yl)piperazin-1-yl)meth- yl)piperidine-1-carbon- yl)phenyl)-2,8-diaza- spiro[4.5]decan-2-yl)-3- methylbenzonitrile 38 (a racemate)
		(R)-2-Chloro-4-(8-(4- (4-((4-(3-((2,6-dioxo- piperidin-3-yl)amino)- phenyl)piperazin-1-yl)- methyl)piperidine-1- carbonyl)phenyl)-2,8- diazaspiro[4.5]decan-2- yl)-3-methylbenzonitrile
		(S)-2-Chloro-4-(8-(4- (4-((4-(3-((2,6-dioxo- piperidin-3-yl)amino)- phenyl)piperazin-1-yl)- methyl)piperidine-1- carbonyl)phenyl)-2,8- diazaspiro[4.5]decan-2- yl)-3-methylbenzonitrile
		2-Chloro-4-(8-(4-(4-((4- (2-((2,6-dioxopiperidin- 3-yl)amino)phenyl)piper- azin-1-yl)methyl)piperi- dine-1-carbonyl)phenyl)- 3-methyl-2,8-diazaspiro [4.5]decan-2-yl)benzo- nitrile
39		2-Chloro-4-((3S)-8-(4- (4-((4-(2-((2,6-dioxo- piperidin-3-yl)amino)- phenyl)piperazin-1-yl)- methyl)piperidine-1- carbonyl)phenyl)-3- methyl-2,8-diazaspiro [4.5]decan-2-yl)benzo- nitrile 39 (a mixture of diastereomers)
		2-Chloro-4-((S)-8-(4-(4- ((4-(2-(((R)-2,6-dioxo- piperidin-3-yl)amino)- phenyl)piperazin-1-yl)- methyl)piperidine-1- carbonyl)phenyl)-3- methyl-2,8-diazaspiro [4.5]decan-2-yl)benzo- nitrile
		2-Chloro-4-((S)-8-(4-(4- ((4-(2-(((S)-2,6-dioxo- piperidin-3-yl)amino)- phenyl)piperazin-1-yl)- methyl)piperidine-1- carbonyl)phenyl)-3- methyl-2,8-diazaspiro [4.5]decan-2-yl)benzo- nitrile
		2-Chloro-4-((3R)-8-(4- (4-((4-(2-((2,6-dioxo- piperidin-3-yl)amino)- phenyl)piperazin-1-yl)- methyl)piperidine-1- carbonyl)phenyl)-3- methyl-2,8-diazaspiro [4.5]decan-2-yl)benzo- nitrile
		2-Chloro-4-((R)-8-(4-(4- ((4-(2-(((R)-2,6-dioxo- piperidin-3-yl)amino)- phenyl)piperazin-1-yl)- methyl)piperidine-1- carbonyl)phenyl)-3- methyl-2,8-diazaspiro [4.5]decan-2-yl)benzo- nitrile
		2-Chloro-4-((R)-8-(4-(4- ((4-(2-(((S)-2,6-dioxo- piperidin-3-yl)amino)- phenyl)piperazin-1-yl)- methyl)piperidine-1- carbonyl)phenyl)-3- methyl-2,8-diazaspiro [4.5]decan-2-yl)benzo- nitrile
		2-Chloro-4-(8-(4-(4-((4- (3-((2,6-dioxopiperidin- 3-yl)amino)phenyl)-3- oxopiperazin-1-yl)meth- yl)piperidine-1-carbon- yl)phenyl)-3-methyl-2,8- diazaspiro[4.5]decan-2- yl)benzonitrile
40		2-Chloro-4-((3S)-8-(4- (4-((4-(3-((2,6-dioxo- piperidin-3-yl)amino)- phenyl)-3-oxopiperazin- 1-yl)methyl)piperidine- 1-carbonyl)phenyl)-3- methyl-2,8-diazaspiro [4.5]decan-2-yl)benzo- nitrile 40 (a mixture of diastereomers)
		2-Chloro-4-((S)-8-(4-(4- ((4-(3-(((R)-2,6-dioxo- piperidin-3-yl)amino)- phenyl)-3-oxopiperazin- 1-yl)methyl)piperidine- 1-carbonyl)phenyl)-3- methyl-2,8-diazaspiro [4.5]decan-2-yl)benzo-
		nitrile
		2-Chloro-4-((S)-8-(4-(4- ((4-(3-(((S)-2,6-dioxo- piperidin-3-yl)amino)- phenyl)-3-oxopiperazin- 1-yl)methyl)piperidine- 1-carbonyl)phenyl)-3- methyl-2,8-diazaspiro [4.5]decan-2-yl)benzo- nitrile
		2-Chloro-4-((3R)-8-(4- (4-((4-(3-((2,6-dioxo- piperidin-3-yl)amino)- phenyl)-3-oxopiperazin- 1-yl)methyl)piperidine- 1-carbonyl)phenyl)-3- methyl-2,8-diazaspiro [4.5]decan-2-yl)benzo- nitrile
		2-Chloro-4-((R)-8-(4-(4- ((4-(3-(((R)-2,6-dioxo- piperidin-3-yl)amino)- phenyl)-3-oxopiperazin- 1-yl)methyl)piperidine- 1-carbonyl)phenyl)-3- methyl-2,8-diazaspiro [4.5]decan-2-yl)benzo- nitrile
		2-Chloro-4-((R)-8-(4-(4- ((4-(3-(((S)-2,6-dioxo- piperidin-3-yl)amino)- phenyl)-3-oxopiperazin- 1-yl)methyl)piperidine- 1-carbonyl)phenyl)-3- methyl-2,8-diazaspiro [4.5]decan-2-yl)benzo- nitrile
		4-(8-(4-(4-((4-(3-((2,6- Dioxopiperidin-3-yl)- amino)phenyl)piperazin- 1-yl)methyl)piperidine- 1-carbonyl)phenyl)-3- methyl-2,8-diazaspiro [4.5]decan-2-yl)-2- (trifluoromethyl)benzo- nitrile
41		4-((3S)-8-(4-(4-((4-(3- ((2,6-Dioxopiperidin-3- yl)amino)phenyl)piper- azin-1-yl)methyl)piperi- dine-1-carbonyl)phenyl)- 3-methyl-2,8-diazaspiro [4.5]decan-2-yl)-2- (trifluoromethyl)benzo- nitrile 41 (a mixture of diastereomers)
		4-((S)-8-(4-(4-((4-(3- (((R)-2,6-Dioxopiperi- din-3-yl)amino)phenyl)- piperazin-1-yl)methyl)- piperidine-1-carbonyl)- phenyl)-3-methyl-2,8- diazaspiro[4.5]decan-2- yl)-2-(trifluoromethyl)- benzonitrile
		4-((S)-8-(4-(4-((4-(3- (((S)-2,6-Dioxopiperi- din-3-yl)amino)phenyl)- piperazin-1-yl)methyl)- piperidine-1-carbonyl)- phenyl)-3-methyl-2,8- diazaspiro[4.5]decan-2- yl)-2-(trifluoromethyl)- benzonitrile
		4-((3R)-8-(4-(4-((4-(3- ((2,6-Dioxopiperidin-3- yl)amino)phenyl)piper- azin-1-yl)methyl)piper- idine-1-carbonyl)phen- yl)-3-methyl-2,8-diaza- spiro[4.5]decan-2-yl)-2- (trifluoromethyl)benzo- nitrile
		4-((R)-8-(4-(4-((4-(3- (((R)-2,6-Dioxopiper- idin-3-yl)amino)phen- yl)piperazin-1-yl)meth- yl)piperidine-1-carbon- yl)phenyl)-3-methyl-2,8- diazaspiro[4.5]decan-2- yl)-2-(trifluoromethyl)- benzonitrile
		4-((R)-8-(4-(4-((4-(3- (((S)-2,6-Dioxopiperi- din-3-yl)amino)phenyl)- piperazin-1-yl)methyl)- piperidine-1-carbonyl)- phenyl)-3-methyl-2,8- diazaspiro[4.5]decan-2- yl)-2-(trifluoromethyl)- benzonitrile
		2-(4-(4-(2-(3-Chloro-4- cyanophenyl)-3-methyl- 2,8-diazaspiro[4.5]decan- 8-yl)benzoyl)piperazin- 1-yl)-N-(3-((2,6-dioxo- piperidin-3-yl)amino)- phenyl)acetamide
42		2-(4-(4-((S)-2-(3-Chloro- 4-cyanophenyl)-3-meth- yl-2,8-diazaspiro[4.5] decan-8-yl)benzoyl)- piperazin-1-yl)-N-(3- ((2,6-dioxopiperidin-3- yl)amino)phenyl)acet- amide 42 (a mixture of diastereomers)
		2-(4-(4-((S)-2-(3-Chloro- 4-cyanophenyl)-3-meth- yl-2,8-diazaspiro[4.5] decan-8-yl)benzoyl)- piperazin-1-yl)-N-(3- (((R)-2,6-dioxopiperi- din-3-yl)amino)phen- yl)acetamide
		2-(4-(4-((S)-2-(3-Chloro- 4-cyanophenyl)-3-meth- yl-2,8-diazaspiro[4.5] decan-8-yl)benzoyl)- piperazin-1-yl)-N-(3- (((S)-2,6-dioxopiperi- din-3-yl)amino)phenyl)- acetamide
		2-(4-(4-((R)-2-(3-Chloro- 4-cyanophenyl)-3-meth- yl-2,8-diazaspiro[4.5] decan-8-yl)benzoyl)- piperazin-1-yl)-N-(3- ((2,6-dioxopiperidin-3- yl)amino)phenyl)acet- amide
		2-(4-(4-((R)-2-(3-Chloro- 4-cyanophenyl)-3-meth- yl-2,8-diazaspiro[4.5] decan-8-yl)benzoyl)- piperazin-1-yl)-N-(3- (((R)-2,6-dioxopiperi- din-3-yl)amino)phenyl)- acetamide
		2-(4-(4-((R)-2-(3-Chloro- 4-cyanophenyl)-3-meth- yl-2,8-diazaspiro[4.5] decan-8-yl)benzoyl)- piperazin-1-yl)-N-(3- (((S)-2,6-dioxopiperi- din-3-yl)amino)phenyl)- acetamide
		4-(4-((1-(4-(2-(3-Chloro- 4-cyanophenyl)-3-meth- yl-2,8-diazaspiro[4.5] decan-8-yl)benzoyl)- piperidin-4-yl)methyl)- piperazin-1-yl)-N-(2,6- dioxopiperidin-3-yl)- benzamide
43		4-(4-((1-(4-((S)-2-(3- Chloro-4-cyanophenyl)- 3-methyl-2,8-diazaspiro [4.5]decan-8-yl)benzo- yl)piperidin-4-yl)meth- yl)piperazin-1-yl)-N- (2,6-dioxopiperidin-3- yl)benzamide 43 (a mixture of diastereo- mers)
		4-(4-((1-(4-((S)-2-(3- Chloro-4-cyanophenyl)- 3-methyl-2,8-diazaspiro [4.5]decan-8-yl)benzo- yl)piperidin-4-yl)meth- yl)piperazin-1-yl)-N- ((R)-2,6-dioxopiperidin- 3-yl)benzamide
		4-(4-((1-(4-((S)-2-(3- Chloro-4-cyanophenyl)- 3-methyl-2,8-diazaspiro [4.5]decan-8-yl)benzo- yl)piperidin-4-yl)meth- yl)piperazin-1-yl)-N- ((S)-2,6-dioxopiperidin- 3-yl)benzamide
		4-(4-((1-(4-((R)-2-(3- Chloro-4-cyanophenyl)- 3-methyl-2,8-diazaspiro [4.5]decan-8-yl)benzo- yl)piperidin-4-yl)meth- yl)piperazin-1-yl)-N- (2,6-dioxopiperidin-3- yl)benzamide
		4-(4-((1-(4-((R)-2-(3- Chloro-4-cyanophenyl)- 3-methyl-2,8-diazaspiro [4.5]decan-8-yl)benzo- yl)piperidin-4-yl)meth- yl)piperazin-1-yl)-N- ((R)-2,6-dioxopiperidin- 3-yl)benzamide
		4-(4-((1-(4-((R)-2-(3- Chloro-4-cyanophenyl)- 3-methyl-2,8-diazaspiro [4.5]decan-8-yl)benzo- yl)piperidin-4-yl)meth- yl)piperazin-1-yl)-N- ((S)-2,6-dioxopiperidin- 3-yl)benzamide

Further, the present disclosure provides a compound represented by general formula (XB) or a salt thereof:

• • wherein:
  • Z⁴, Z⁵, Z⁶, h, i, u, v, x1, y1, m3, and A are as defined in general formula (X).

Further, the present disclosure provides a compound represented by general formula (MB) or a salt thereof:

• • wherein:
  • Q¹, Q², Q⁴, Q⁵, Z⁴, Z⁵, Z⁶, x, x1, y, y1, and m3 are as defined in general formula (M).

Further, the present disclosure provides a compound represented by general formula (VA) or a salt thereof:

• • wherein:
  • J¹, R^1a, R^3a, W¹, W², W³, W⁴, Z¹, Z², Z³, x, and y are as defined in general formula (V).

Further, the present disclosure provides a compound represented by general formula (V-1A) or a salt thereof:

• • wherein:
  • J¹, R^1a, R^3a, W¹, W², W³, W⁴, Z¹, Z², Z³, x, and y are as defined in general formula (V-1).

Further, the present disclosure provides a compound represented by general formula (VIIA) or a salt thereof:

• • wherein:
  • R^1a, R^3d, R^3e, R^3f, W⁴, x, and y are as defined in general formula (VII).

Further, the present disclosure provides a compound represented by general formula (VII-1A) or a salt thereof:

• • wherein:
  • R^1a, R^3d, R^3e, R^3f, W⁴, x, and y are as defined in general formula (VII-1).

Further, the present disclosure provides a compound represented by general formula (VB) or a salt thereof:

• • wherein:
  • Q¹, Q³, Q⁴, Q⁵, Z⁶, x1, and y1 are as defined in general formula (V).

Further, the present disclosure provides a compound represented by general formula (VIIB) or a salt thereof:

• • wherein:
  • Q⁴, x1, and y1 are as defined in general formula (VII).

TABLE B
Typical intermediate compounds of the present disclosure include, but are not
limited to:
No.	Compound structure	Name
1c		tert-Butyl (±)-4-(4-((2,6-dioxopiperidin-3- yl)aminocarbonyl)-3- fluorophenyl)piperazine-1-carboxylate 1c
1d		(±)-N-(2,6-Dioxopiperidin-3-yl)-2-fluoro-4- (piperazin-1-yl)benzamide hydrochloride 1d
		(±)-N-(2,6-Dioxopiperidin-3-yl)-2-fluoro-4- (piperazin-1-yl)benzamide
		(R)-N-(2,6-Dioxopiperidin-3-yl)-2-fluoro-4- (piperazin-1-yl)benzamide
		(S)-N-(2,6-Dioxopiperidin-3-yl)-2-fluoro-4- (piperazin-1-yl)benzamide
1f		tert-Butyl (±)-4-(4-(4-((2,6-dioxopiperidin- 3-yl)aminocarbonyl)-3- fluorophenyl)piperazin-1-yl)piperidine-1- carboxylate 1f
1g		(±)-N-(2,6-Dioxopiperidin-3-yl)-2-fluoro-4- (4-(piperidin-4-yl)piperazin-1- yl)benzamide dihydrochloride 1g
		(±)-N-(2,6-Dioxopiperidin-3-yl)-2-fluoro-4- (4-(piperidin-4-yl)piperazin-1- yl)benzamide
		(R)-N-(2,6-Dioxopiperidin-3-yl)-2-fluoro-4- (4-(piperidin-4-yl)piperazin-1- yl)benzamide
		(S)-N-(2,6-Dioxopiperidin-3-yl)-2-fluoro-4- (4-(piperidin-4-yl)piperazin-1- yl)benzamide
2d		tert-Butyl (±)-4-(4-(6-((2,6-dioxopiperidin- 3-yl)aminocarbonyl)pyridin-3-yl)piperazin- 1-yl)piperidine-1-carboxylate 2d
2e		(±)-N-(2,6-Dioxopiperidin-3-yl)-5-(4- (piperidin-4-yl)piperazin-1-yl)picolinamide trihydrochloride 2e
		(+)-N-(2,6-Dioxopiperidin-3-yl)-5-(4- (piperidin-4-yl)piperazin-1-yl)picolinamide
		(R)-N-(2,6-Dioxopiperidin-3-yl)-5-(4- (piperidin-4-yl)piperazin-1-yl)picolinamide
		(S)-N-(2,6-Dioxopiperidin-3-yl)-5-(4- (piperidin-4-yl)piperazin-1-yl)picolinamide
3b		tert-Butyl (±)-4-((4-(4-((2,6-dioxopiperidin- 3-yl)aminocarbonyl)-3- fluorophenyl)piperazin-1- yl)methyl)piperidine-1-carboxylate 3b
3c		(±)-N-(2,6-Dioxopiperidin-3-yl)-2-fluoro-4- (4-(piperidin-4-yl)methyl)piperazin-1- yl)benzamide dihydrochloride 3c
		(±)-N-(2,6-Dioxopiperidin-3-yl)-2-fluoro-4- (4-(piperidin-4-yl)methyl)piperazin-1- yl)benzamide
		(R)-N-(2,6-Dioxopiperidin-3-yl)-2-fluoro-4- (4-(piperidin-4-yl)methyl)piperazin-1- yl)benzamide
		(S)-N-(2,6-Dioxopiperidin-3-yl)-2-fluoro-4- (4-(piperidin-4-yl)methyl)piperazin-1- yl)benzamide
4a		tert-Butyl (±)-4-((4-(6-((2,6-dioxopiperidin- 3-yl)aminocarbonyl)pyridin-3-yl)piperazin- 1-yl)methyl)piperidine-1-carboxylate 4a
4b		(±)-N-(2,6-Dioxopiperidin-3-yl)-5-(4- (piperidin-4-yl)methyl)piperazin-1- yl)picolinamide trihydrochloride 4b
		(±)-N-(2,6-Dioxopiperidin-3-yl)-5-(4- (piperidin-4-yl)methyl)piperazin-1- yl)picolinamide
		(R)-N-(2,6-Dioxopiperidin-3-yl)-5-(4- (piperidin-4-yl)methyl)piperazin-1- yl)picolinamide
		(S)-N-(2,6-Dioxopiperidin-3-yl)-5-(4- (piperidin-4-yl)methyl)piperazin-1- yl)picolinamide
5e		tert-Butyl (S)-4-((5-(2-(3-chloro-4- cyanophenyl)-3-methyl-2,8- diazaspiro[4.5]decane-8-carbonyl)pyridin- 2-yl)thio)piperidine-1-carboxylate 5e
5f		(S)-2-Chloro-4-(3-methyl-8-(6-(piperidin-4- ylthio)nicotinoyl)-2,8-diazaspiro[4.5]decan- 2-yl)benzonitrile hydrochloride 5f
		(S)-2-Chloro-4-(3-methyl-8-(6-(piperidin-4- ylthio)nicotinoyl)-2,8-diazaspiro[4.5]decan- 2-yl)benzonitrile
		2-Chloro-4-(3-methyl-8-(6-(piperidin-4- ylthio)nicotinoyl)-2,8-diazaspiro[4.5]decan- 2-yl)benzonitrile
		(R)-2-Chloro-4-(3-methyl-8-(6-(piperidin- 4-ylthio)nicotinoyl)-2,8- diazaspiro[4.5]decan-2-yl)benzonitrile
5l		(±)-N-(2,6-Dioxopiperidin-3-yl)-2-fluoro-4- (3-oxoazetidin-1-yl)benzamide 5l
		(R)-N-(2,6-Dioxopiperidin-3-yl)-2-fluoro-4- (3-oxoazetidin-1-yl)benzamide
		(S)-N-(2,6-Dioxopiperidin-3-yl)-2-fluoro-4- (3-oxoazetidin-1-yl)benzamide
6b		tert-Butyl 4-(4-(4-(2,4- dioxotetrahydropyrimidin-1(2H)- yl)phenyl)piperazin-1-yl)piperidine-1- carboxylate 6b
6c		1-(4-(4-(Piperidin-4-yl)piperazin-1- yl)phenyl)dihydropyrimidine-2,4(1H,3H)- dione dihydrochloride 6c
		1-(4-(4-(Piperidin-4-yl)piperazin-1- yl)phenyl)dihydropyrimidine-2,4(1H,3H)- dione
6d		tert-Butyl 4-(4-(4-(2,4- dioxotetrahydropyrimidin-1(2H)- yl)phenyl)piperazin-1-yl)-[1,4′- bipiperidine]-1′-carboxylate 6d
6e		1-(4-(4-([1,4′-Bipiperidin]-4-yl)piperazin-1- yl)phenyl)dihydropyrimidine-2,4(1H,3H)- dione trihydrochloride 6e
		1-(4-(4-([1,4′-Bipiperidin]-4-yl)piperazin-1- yl)phenyl)dihydropyrimidine-2,4(1H,3H)- dione
7b		tert-Butyl 3-(4-(4-(2,4- dioxotetrahydropyrimidin-1(2H)- yl)phenyl)piperazin-1-yl)azetidine-1- carboxylate 7b
7c		1-(4-(4-(Azetidin-3-yl)piperazin-1- yl)phenyl)dihydropyrimidine-2,4(1H,3H)- dione bistrifluoroacetate 7c
		1-(4-(4-(Azetidin-3-yl)piperazin-1- yl)phenyl)dihydropyrimidine-2,4(1H,3H)- dione
7d		tert-Butyl 4-(3-(4-(4-(2,4- dioxotetrahydropyrimidin-1(2H)- yl)phenyl)piperazin-1-yl)azetidin-1- yl)piperidine-1-carboxylate 7d
7e		1-(4-(4-(1-(Piperidin-4-yl)azetidin-3- yl)piperazin-1- yl)phenyl)dihydropyrimidine-2,4(1H,3H)- dione trihydrochloride 7e
		1-(4-(4-(1-(Piperidin-4-yl)azetidin-3- yl)piperazin-1- yl)phenyl)dihydropyrimidine-2,4(1H,3H)- dione
10b		tert-Butyl (±)-4-(4-(3-((2,6-dioxopiperidin- 3-yl)amino)phenyl)piperazin-1- yl)piperidine-1-carboxylate 10b
10c		(±)-3-((3-(4-(Piperidin-4-yl)piperazin-1- yl)phenyl)amino)piperidine-2,6-dione dihydrochloride 10c
		(±)-3-((3-(4-(Piperidin-4-yl)piperazin-1- yl)phenyl)amino)piperidine-2,6-dione
		(R)-3-((3-(4-(Piperidin-4-yl)piperazin-1- yl)phenyl)amino)piperidine-2,6-dione
		(S)-3-((3-(4-(Piperidin-4-yl)piperazin-1- yl)phenyl)amino)piperidine-2,6-dione
11a		tert-Butyl (±)-4-((4-(3-((2,6-dioxopiperidin- 3-yl)amino)phenyl)piperazin-1- yl)methyl)piperidine-1-carboxylate 11a
11b		(±)-3-((3-(4-(Piperidin-4- ylmethyl)piperazin-1- yl)phenyl)amino)piperidine-2,6-dione dihydrochloride 11b
		(±)-3-((3-(4-(Piperidin-4- ylmethyl)piperazin-1- yl)phenyl)amino)piperidine-2,6-dione
		(R)-3-((3-(4-(Piperidin-4- ylmethyl)piperazin-1- yl)phenyl)amino)piperidine-2,6-dione
		(S)-3-((3-(4-(Piperidin-4- ylmethyl)piperazin-1- yl)phenyl)amino)piperidine-2,6-dione
14a		tert-Butyl (±)-3-((4-(3-((2,6-dioxopiperidin- 3-yl)amino)phenyl)piperazin-1- yl)methyl)azetidine-1-carboxylate 14a
14b		(±)-3-((3-(4-(Azetidin-3- ylmethyl)piperazin-1- yl)phenyl)amino)piperidine-2,6-dione bistrifluoroacetate 14b
		(±)-3-((3-(4-(Azetidin-3- ylmethyl)piperazin-1- yl)phenyl)amino)piperidine-2,6-dione
		(R)-3-((3-(4-(Azetidin-3- ylmethyl)piperazin-1- yl)phenyl)amino)piperidine-2,6-dione
		(S)-3-((3-(4-(Azetidin-3- ylmethyl)piperazin-1- yl)phenyl)amino)piperidine-2,6-dione
16a		tert-Butyl (S)-4-(2-(3-chloro-4- cyanophenyl)-3-methyl-2,8- diazaspiro[4.5]decan-8-yl)-2- fluorobenzoate 16a
		4-(2-(3-Chloro-4-cyanophenyl)-3-methyl- 2,8-diazaspiro[4.5]decan-8-yl)-2- fluorobenzoic acid
16b		(S)-4-(2-(3-Chloro-4-cyanophenyl)-3- methyl-2,8-diazaspiro[4.5]decan-8-yl)-2- fluorobenzoic acid 16b
		(R)-4-(2-(3-Chloro-4-cyanophenyl)-3- methyl-2,8-diazaspiro[4.5]decan-8-yl)-2- fluorobenzoic acid
		5-(2-(3-Chloro-4-cyanophenyl)-3-methyl- 2,8-diazaspiro[4.5]decan-8-yl)pyrazine-2- carboxylic acid
17b		(S)-5-(2-(3-Chloro-4-cyanophenyl)-3- methyl-2,8-diazaspiro[4.5]decan-8- yl)pyrazine-2-carboxylic acid 17b
		(R)-5-(2-(3-Chloro-4-cyanophenyl)-3- methyl-2,8-diazaspiro[4.5]decan-8- yl)pyrazine-2-carboxylic acid
19b		tert-Butyl (±)-4-((4-(3-((2,6-dioxopiperidin- 3-yl)amino)phenyl)piperidin-1- yl)methyl)piperidine-1-carboxylate 19b
19c		(±)-3-((3-(1-(Piperidin-4- ylmethyl)piperidin-4- yl)phenyl)amino)piperidine-2,6-dione dihydrochloride 19c
		(±)-3-((3-(1-(Piperidin-4- ylmethyl)piperidin-4- yl)phenyl)amino)piperidine-2,6-dione
		(R)-3-((3-(1-(Piperidin-4- ylmethyl)piperidin-4- yl)phenyl)amino)piperidine-2,6-dione
		(S)-3-((3-(1-(Piperidin-4- ylmethyl)piperidin-4- yl)phenyl)amino)piperidine-2,6-dione
21a		tert-Butyl (±)-3-((4-(3-((2,6-dioxopiperidin- 3-yl)amino)phenyl)piperidin-1- yl)methyl)azetidine-1-carboxylate 21a
21b		(±)-3-((3-(1-(Azetidin-3- ylmethyl)piperidin-4- yl)phenyl)amino)piperidine-2,6-dione bistrifluoroacetate 21b
		(±)-3-((3-(1-(Azetidin-3- ylmethyl)piperidin-4- yl)phenyl)amino)piperidine-2,6-dione
		(R)-3-((3-(1-(Azetidin-3- ylmethyl)piperidin-4- yl)phenyl)amino)piperidine-2,6-dione
		(S)-3-((3-(1-(Azetidin-3- ylmethyl)piperidin-4- yl)phenyl)amino)piperidine-2,6-dione
23d		tert-Butyl (±)-4-(5-((2,6-dioxopiperidin-3- yl)amino)-2-fluorophenyl)piperazine-1- carboxylate 23d
23e		(±)-3-((4-Fluoro-3-(piperazin-1- yl)phenyl)amino)piperidine-2,6-dione hydrochloride 23e
		(±)-3-((4-Fluoro-3-(piperazin-1- yl)phenyl)amino)piperidine-2,6-dione
		(R)-3-((4-Fluoro-3-(piperazin-1- yl)phenyl)amino)piperidine-2,6-dione
		(S)-3-((4-Fluoro-3-(piperazin-1- yl)phenyl)amino)piperidine-2,6-dione
23f		tert-Butyl (±)-4-((4-(5-((2,6-dioxopiperidin- 3-yl)amino)-2-fluorophenyl)piperazin-1- yl)methyl)piperidine-1-carboxylate 23f
23g		(±)-3-((4-Fluoro-3-(4-(piperidin-4- ylmethyl)piperazin-1- yl)phenyl)amino)piperidine-2,6-dione dihydrochloride 23g
		(±)-3-((4-Fluoro-3-(4-(piperidin-4- ylmethyl)piperazin-1- yl)phenyl)amino)piperidine-2,6-dione
		(R)-3-((4-Fluoro-3-(4-(piperidin-4- ylmethyl)piperazin-1- yl)phenyl)amino)piperidine-2,6-dione
		(S)-3-((4-Fluoro-3-(4-(piperidin-4- ylmethyl)piperazin-1- yl)phenyl)amino)piperidine-2,6-dione
24f		tert-Butyl 4-(4-((2,6-dioxo-1,2,5,6- tetrahydropyridin-3-yl)amino)pyridin-2- yl)piperazine-1-carboxylate 24f
24g		tert-Butyl (±)-4-(4-((2,6-dioxopiperidin-3- yl)amino)pyridin-2-yl)piperazine-1- carboxylate 24g
24h		(±)-3-((2-(Piperazin-1-yl)pyridin-4- yl)amino)piperidine-2,6-dione bistrifluoroacetate 24h
		(±)-3-((2-(Piperazin-1-yl)pyridin-4- yl)amino)piperidine-2,6-dione
		(R)-3-((2-(Piperazin-1-yl)pyridin-4- yl)amino)piperidine-2,6-dione
		(S)-3-((2-(Piperazin-1-yl)pyridin-4- yl)amino)piperidine-2,6-dione
26b		tert-Butyl (±)-4-((4-(4-((2,6-dioxopiperidin- 3-yl)amino)phenyl)piperidin-1- yl)methyl)piperidine-1-carboxylate 26b
26c		(±)-3-((4-(1-(Piperidin-4- ylmethyl)piperidin-4- yl)phenyl)amino)piperidine-2,6-dione dihydrochloride 26c
		(±)-3-((4-(1-(Piperidin-4- ylmethyl)piperidin-4- yl)phenyl)amino)piperidine-2,6-dione
		(R)-3-((4-(1-(Piperidin-4- ylmethyl)piperidin-4- yl)phenyl)amino)piperidine-2,6-dione
		(S)-3-((4-(1-(Piperidin-4- ylmethyl)piperidin-4- yl)phenyl)amino)piperidine-2,6-dione
27b		tert-Butyl (±)-4-((4-(4-((2,6-dioxopiperidin- 3-yl)amino)-2-fluorophenyl)piperidin-1- yl)methyl)piperidine-1-carboxylate 27b
27c		(±)-3-((3-Fluoro-4-(1-(piperidin-4- ylmethyl)piperidin-4- yl)phenyl)amino)piperidine-2,6-dione dihydrochloride 27c
		(±)-3-((3-Fluoro-4-(1-(piperidin-4- ylmethyl)piperidin-4- yl)phenyl)amino)piperidine-2,6-dione
		(R)-3-((3-Fluoro-4-(1-(piperidin-4- ylmethyl)piperidin-4- yl)phenyl)amino)piperidine-2,6-dione
		(S)-3-((3-Fluoro-4-(1-(piperidin-4- ylmethyl)piperidin-4- yl)phenyl)amino)piperidine-2,6-dione
28c		(S)-2-Chloro-4-(3-methyl-8-(4-(2-oxo-7- azaspiro[3.5]nonane-7-carbonyl)phenyl)- 2,8-diazaspiro[4.5]decan-2-yl)benzonitrile 28c
		2-Chloro-4-(3-methyl-8-(4-(2-oxo-7- azaspiro[3.5]nonane-7-carbonyl)phenyl)- 2,8-diazaspiro[4.5]decan-2-yl)benzonitrile
		(R)-2-Chloro-4-(3-methyl-8-(4-(2-oxo-7- azaspiro[3.5]nonane-7-carbonyl)phenyl)- 2,8-diazaspiro[4.5]decan-2-yl)benzonitrile
29b		tert-Butyl 9-(4-(4-(2,4- dioxotetrahydropyrimidin-1(2//)- yl)phenyl)piperazin-1-yl)-3- azaspiro[5.5]undecane-3-carboxylate 29b
29c		1-(4-(4-(3-Azaspiro[5.5]undecan-9- yl)piperazin-1- yl)phenyl)dihydropyrimidine-2,4(1H,3H)- dione dihydrochloride 29c
		1-(4-(4-(3-Azaspiro[5.5]undecan-9- yl)piperazin-1- yl)phenyl)dihydropyrimidine-2,4(1H,3H)- dione
		2-Chloro-4-(8-(2-fluoro-4-(2-oxo-7- azaspiro[3.5]nonane-7-carbonyl)phenyl)-3- methyl-2,8-diazaspiro[4.5]decan-2- yl)benzonitrile
30a		(S)-2-Chloro-4-(8-(2-fluoro-4-(2-oxo-7- azaspiro[3.5]nonane-7-carbonyl)phenyl)-3- methyl-2,8-diazaspiro[4.5]decan-2- yl)benzonitrile 30a
		(R)-2-Chloro-4-(8-(2-fluoro-4-(2-oxo-7- azaspiro[3.5]nonane-7-carbonyl)phenyl)-3- methyl-2,8-diazaspiro[4.5]decan-2- yl)benzonitrile 30a
31a		tert-Butyl 2-(4-(4-(2,4- dioxotetrahydropyrimidin-1(2H)- yl)phenyl)piperazin-1-yl)-7- azaspiro[3.5]nonane-7-carboxylate 31a
31b		1-(4-(4-(7-Azaspiro[3.5]nonan-2- yl)piperazin-1- yl)phenyl)dihydropyrimidine-2,4(1H,3H)- dione bistrifluoroacetate 31b
		1-(4-(4-(7-Azaspiro[3.5]nonan-2- yl)piperazin-1- yl)phenyl)dihydropyrimidine-2,4(1H,3H)- dione
		2-Chloro-4-(3-methyl-8-(6-(2-oxo-7- azaspiro[3.5]nonane-7-carbonyl)pyridin-3- yl)-2,8-diazaspiro[4.5]decan-2- yl)benzonitrile
32a		(S)-2-Chloro-4-(3-methyl-8-(6-(2-oxo-7- azaspiro[3.5]nonane-7-carbonyl)pyridin-3- yl)-2,8-diazaspiro[4.5]decan-2- yl)benzonitrile 32a
		(R)-2-Chloro-4-(3-methyl-8-(6-(2-oxo-7- azaspiro[3.5]nonane-7-carbonyl)pyridin-3- yl)-2,8-diazaspiro[4.5]decan-2- yl)benzonitrile
35c		1-(3-(Piperazin-1- yl)phenyl)dihydropyrimidine-2,4(1H,3H)- dione trifluoroacetate 35c
		1-(3-(Piperazin-1- yl)phenyl)dihydropyrimidine-2,4(1H,3H)- dione
39d		tert-Butyl (+)-4-(2-((2,6-dioxopiperidin-3- yl)amino)phenyl)piperazine-1-carboxylate 39d
39e		(±)-3-((2-(Piperazin-1- yl)phenyl)amino)piperidine-2,6-dione hydrochloride 39e
		(±)-3-((2-(Piperazin-1- yl)phenyl)amino)piperidine-2,6-dione
		(R)-3-((2-(Piperazin-1- yl)phenyl)amino)piperidine-2,6-dione
		(S)-3-((2-(Piperazin-1- yl)phenyl)amino)piperidine-2,6-dione
40e		tert-Butyl (±)-4-(3-((2,6-dioxopiperidin-3- yl)amino)phenyl)-3-oxopiperazine-1- carboxylate 40e
40f		(±)-3-((3-(2-Oxopiperazin-1- yl)phenyl)amino)piperidine-2,6-dione trifluoroacetate 40f
		(±)-3-((3-(2-Oxopiperazin-1- yl)phenyl)amino)piperidine-2,6-dione
		(R)-3-((3-(2-Oxopiperazin-1- yl)phenyl)amino)piperidine-2,6-dione
		(S)-3-((3-(2-Oxopiperazin-1- yl)phenyl)amino)piperidine-2,6-dione

Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (III′) or a pharmaceutically acceptable salt thereof, comprising:

conducting a condensation reaction of a compound represented by general formula (III′A) or a salt thereof with a compound represented by general formula (III′B) or a salt thereof (preferably hydrochloride and trifluoroacetate) to give the compound represented by general formula (III′) or the pharmaceutically acceptable salt thereof;

• • wherein:
  • J¹ is —C(O)—;
  • Z³ is N;
  • A, R^1a, R^3a, J⁵, X², W¹, W², W³, W⁴, Z¹, Z², Z⁴, Z⁵, Z⁶, x, x1, y, y1, and m3 are as defined in general formula (III′).

Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (III′) or a pharmaceutically acceptable salt thereof, comprising:

conducting a reductive amination reaction of a compound represented by general formula (III′C) or a salt thereof with a compound represented by general formula (III′E) or a salt thereof (preferably hydrochloride and trifluoroacetate) to give the compound represented by general formula (III′) or the pharmaceutically acceptable salt thereof, where m3 is 1, 2, or 3;

• • or, conducting a reductive amination reaction of a compound represented by general formula (III′D) or a salt thereof with a compound represented by general formula (III′E) or a salt thereof (preferably hydrochloride and trifluoroacetate) to give the compound represented by general formula (III′) or the pharmaceutically acceptable salt thereof, where m3 is 0;
  • wherein:
  • m6 is 0, 1, or 2;
  • Z⁴ is CH;
  • Z⁵ is N;
  • A, J¹, J⁵, X², R^1a, R^3a, W¹, W², W³, W⁴, Z¹, Z², Z³, Z⁶, x, x1, y, and y1 are as defined in general formula (III′).

Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (III′) or a pharmaceutically acceptable salt thereof, comprising:

conducting a reductive amination reaction of a compound represented by general formula (III′F) or a salt thereof (preferably hydrochloride and trifluoroacetate) with a compound represented by general formula (III′G) or a salt thereof to give the compound represented by general formula (III′) or the pharmaceutically acceptable salt thereof, where m3 is 0;

• • or, conducting a reductive amination reaction of a compound represented by general formula (III′F) or a salt thereof (preferably hydrochloride and trifluoroacetate) with a compound represented by general formula (III′H) or a salt thereof to give the compound represented by general formula (III′) or the pharmaceutically acceptable salt thereof, where m3 is 1, 2, or 3;
  • wherein:
  • m6 is 0, 1, or 2;
  • Z⁴ is N;
  • Z⁵ is CH;
  • A, J¹, J⁵, X², R^1a, R^3a, W¹, W², W³, W⁴, Z¹, Z², Z³, Z⁶, x, x1, y, and y1 are as defined in general formula (III′).

Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (X) or a pharmaceutically acceptable salt thereof, comprising the following step:

conducting a condensation reaction of a compound represented by general formula (IVA) or a salt thereof with a compound represented by general formula (XB) or a salt thereof (preferably hydrochloride and trifluoroacetate) to give the compound represented by general formula (X) or the pharmaceutically acceptable salt thereof;

• • wherein:
  • R^1a, R^3a, W¹, W², W³, W⁴, Z¹, Z², Z⁴, Z⁵, Z⁶, h, i, u, v, x1, y1, m3, and A are as defined in general formula (X).

Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (X-1) or a pharmaceutically acceptable salt thereof, comprising the following step:

conducting a condensation reaction of a compound represented by general formula (IV-1A) or a salt thereof with a compound represented by general formula (XB) or a salt thereof (preferably hydrochloride and trifluoroacetate) to give the compound represented by general formula (X-1) or the pharmaceutically acceptable salt thereof;

• • wherein:
  • R^1a, R^3a, W¹, W², W³, W⁴, Z¹, Z², Z⁴, Z⁵, Z⁶, h, i, u, v, x1, y1, m3, and A are as defined in general formula (X-1).

Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (X) or a pharmaceutically acceptable salt thereof, comprising the following step:

conducting a reductive amination reaction of a compound represented by general formula (XC) or a salt thereof with a compound represented by general formula (XF) or a salt thereof (preferably hydrochloride and trifluoroacetate) to give the compound represented by general formula (X) or the pharmaceutically acceptable salt thereof, where m3 is 0;

• • or, conducting a reductive amination reaction of a compound represented by general formula (XD) or a salt thereof with a compound represented by general formula (XF) or a salt thereof (preferably hydrochloride and trifluoroacetate) to give the compound represented by general formula (X) or the pharmaceutically acceptable salt thereof, where m3 is 1, 2, or 3;
  • wherein:
  • m6 is 0, 1, or 2;
  • Z⁴ is CH;
  • Z⁵ is N;
  • R^1a, R^3a, W¹, W², W³, W⁴, Z¹, Z², Z⁶, h, i, u, v, x1, y1, and A are as defined in general formula (X).

Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (X-1) or a pharmaceutically acceptable salt thereof, comprising the following step:

conducting a reductive amination reaction of a compound represented by general formula (X-1C) or a salt thereof with a compound represented by general formula (XF) or a salt thereof (preferably hydrochloride and trifluoroacetate) to give the compound represented by general formula (X-1) or the pharmaceutically acceptable salt thereof, where m3 is 0;

• • or, conducting a reductive amination reaction of a compound represented by general formula (X-1D) or a salt thereof with a compound represented by general formula (XF) or a salt thereof (preferably hydrochloride and trifluoroacetate) to give the compound represented by general formula (X-1) or the pharmaceutically acceptable salt thereof, where m3 is 1, 2, or 3;
  • wherein:
  • m6 is 0, 1, or 2;
  • Z⁴ is CH;
  • Z⁵ is N;
  • R^1a, R^3a, W¹, W², W³, W⁴, Z¹, Z², Z⁶, h, i, u, v, x1, y1, and A are as defined in general formula (X-1).

Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (IV′) or a pharmaceutically acceptable salt thereof, comprising:

conducting a condensation reaction of a compound represented by general formula (IVA) or a salt thereof with a compound represented by general formula (IVB′) or a salt thereof (preferably hydrochloride and trifluoroacetate) to give the compound represented by general formula (IV′) or the pharmaceutically acceptable salt thereof;

• • wherein:
  • R^1a, Q¹, Q², Q³, Q⁴, Q⁵, R^3a, W¹, W², W³, W⁴, Z¹, Z², Z⁴, Z⁵, Z⁶, x, x1, y, y1, and m3 are as defined in general formula (IV).

Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (IV′-1) or a pharmaceutically acceptable salt thereof, comprising:

conducting a condensation reaction of a compound represented by general formula (IV-1A) or a salt thereof with a compound represented by general formula (IVB′) or a salt thereof (preferably hydrochloride and trifluoroacetate) to give the compound represented by general formula (IV′-1) or the pharmaceutically acceptable salt thereof;

• • wherein:
  • R^1a, Q¹, Q², Q³, Q⁴, Q⁵, R^3a, W¹, W², W³, W⁴, Z¹, Z², Z⁴, Z⁵, Z⁶, x, x1, y, y1, and m3 are as defined in general formula (IV′-1).

Another aspect of the present disclosure relates to a method for preparing compounds represented by general formula (IV′-1-1) and general formula (IV′-1-2) or pharmaceutically acceptable salts thereof, comprising:

chirally resolving a compound represented by general formula (IV′-1) or a pharmaceutically acceptable salt thereof to give the compounds represented by general formula (IV′-1-1) and general formula (IV′-1-2) or the pharmaceutically acceptable salts thereof;

• • wherein:
  • R^1a, Q¹, Q², Q³, Q⁴, Q⁵, R^3a, W¹, W², W³, W⁴, Z¹, Z², Z⁴, Z⁵, Z⁶, X, x1, y, y1, and m3 are as defined in general formula (IV′-1).

Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (M) or a pharmaceutically acceptable salt thereof, comprising:

conducting a condensation reaction of a compound represented by general formula (IVA) or a salt thereof with a compound represented by general formula (MB) or a salt thereof (preferably hydrochloride and trifluoroacetate) to give the compound represented by general formula (M) or the pharmaceutically acceptable salt thereof,

• • wherein:
  • R^1a, Q¹, Q², Q⁴, Q⁵, R^3a, W¹, W², W³, W⁴, Z¹, Z², Z⁴, Z⁵, Z⁶, x, x1, y, y1, and m3 are as defined in general formula (M).

Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (M-1) or a pharmaceutically acceptable salt thereof, comprising:

conducting a condensation reaction of a compound represented by general formula (IV-IA) or a salt thereof with a compound represented by general formula (MB) or a salt thereof (preferably hydrochloride and trifluoroacetate) to give the compound represented by general formula (M-1) or the pharmaceutically acceptable salt thereof;

• • wherein:
  • R^1a, Q¹, Q², Q⁴, Q⁵, R^3a, W¹, W², W³, W⁴, Z¹, Z², Z⁴, Z⁵, Z⁶, x, x1, y, y1, and m3 are as defined in general formula (M-1).

Another aspect of the present disclosure relates to a method for preparing compounds represented by general formula (M-1-1) and general formula (M-1-2) or pharmaceutically acceptable salts thereof, comprising:

chirally resolving a compound represented by general formula (M-1) or a pharmaceutically acceptable salt thereof to give the compounds represented by general formula (M-1-1) and general formula (M-1-2) or the pharmaceutically acceptable salts thereof;

• • wherein:
  • R^1a, Q¹, Q², Q⁴, Q⁵, R^3a, W¹, W², W³, W⁴, Z¹, Z², Z⁴, Z⁵, Z⁶, x, x1, y, y1, and m3 are as defined in general formula (M-1).

Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (IV) or a pharmaceutically acceptable salt thereof, comprising:

conducting a condensation reaction of a compound represented by general formula (IVA) or a salt thereof with a compound represented by general formula (IVB) or a salt thereof (preferably hydrochloride and trifluoroacetate) to give the compound represented by general formula (IV) or the pharmaceutically acceptable salt thereof;

• • wherein:
  • R^1a, Q¹, Q³, Q⁴, Q⁵, R^3a, W¹, W², W³, W⁴, Z¹, Z², Z⁴, Z⁵, Z⁶, x, x1, y, y1, and m3 are as defined in general formula (IV).

Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (IV-1) or a pharmaceutically acceptable salt thereof, comprising:

conducting a condensation reaction of a compound represented by general formula (IV-1A) or a salt thereof with a compound represented by general formula (IVB) or a salt thereof (preferably hydrochloride and trifluoroacetate) to give the compound represented by general formula (IV-1) or the pharmaceutically acceptable salt thereof;

• • wherein:
  • R^1a, Q¹, Q³, Q⁴, Q⁵, R^3a, W¹, W², W³, W⁴, Z¹, Z², Z⁴, Z⁵, Z⁶, x, x1, y, y1, and m3 are as defined in general formula (IV-1).

Another aspect of the present disclosure relates to a method for preparing compounds represented by general formula (IV-1-1) and general formula (IV-1-2) or pharmaceutically acceptable salts thereof, comprising:

chirally resolving a compound represented by general formula (IV-1) or a pharmaceutically acceptable salt thereof to give the compounds represented by general formula (IV-1-1) and general formula (IV-1-2) or the pharmaceutically acceptable salts thereof;

• • wherein:
  • R^1a, Q¹, Q³, Q⁴, Q⁵, R^3a, W¹, W², W³, W⁴, Z¹, Z², Z⁴, Z⁵, Z⁶, x, x1, y, y1, and m3 are as defined in general formula (IV-1).

Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (V) or a pharmaceutically acceptable salt thereof, comprising:

conducting a reductive amination reaction of a compound represented by general formula (VA) or a salt thereof (preferably hydrochloride and trifluoroacetate) with a compound represented by general formula (VB) or a salt thereof to give the compound represented by general formula (V) or the pharmaceutically acceptable salt thereof, where m3 is 0;

• • or, conducting a reductive amination reaction of a compound represented by general formula (VA) or a salt thereof (preferably hydrochloride and trifluoroacetate) with a compound represented by general formula (VB′) or a salt thereof to give the compound represented by general formula (V) or the pharmaceutically acceptable salt thereof, where m3 is 1, 2, or 3;
  • wherein:
  • m6 is 0, 1, or 2;
  • J¹, R^1a, Q¹, Q³, Q⁴, Q⁵, R^3a, W¹, W², W³, W⁴, Z¹, Z², Z³, Z⁶, x, x1, y, and y1 are as defined in general formula (V).

Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (V-1) or a pharmaceutically acceptable salt thereof, comprising:

conducting a reductive amination reaction of a compound represented by general formula (V-1A) or a salt thereof (preferably hydrochloride and trifluoroacetate) with a compound represented by general formula (VB) or a salt thereof to give the compound represented by general formula (V-1) or the pharmaceutically acceptable salt thereof, where m3 is 0;

• • or, conducting a reductive amination reaction of a compound represented by general formula (V-1A) or a salt thereof (preferably hydrochloride and trifluoroacetate) with a compound represented by general formula (VB′) or a salt thereof to give the compound represented by general formula (V-1) or the pharmaceutically acceptable salt thereof, where m3 is 1, 2, or 3;
  • wherein:
  • m6 is 0, 1, or 2;
  • J¹, R^1a, Q¹, Q³, Q⁴, Q⁵, R^3a, W¹, W², W³, W⁴, Z¹, Z², Z³, Z⁶, x, x1, y, and y1 are as defined in general formula (V-1).

Another aspect of the present disclosure relates to a method for preparing compounds represented by general formula (V-1-1) and general formula (V-1-2) or pharmaceutically acceptable salts thereof, comprising:

chirally resolving a compound represented by general formula (V-1) or a pharmaceutically acceptable salt thereof to give the compounds represented by general formula (V-1-1) and general formula (V-1-2) or the pharmaceutically acceptable salts thereof;

• • wherein:
  • J¹, R^1a, Q¹, Q³, Q⁴, Q⁵, R^3a, W¹, W², W³, W⁴, Z¹, Z², Z³, Z⁶, x, x1, y, y1, and m3 are as defined in general formula (V-1).

Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (VI) or a pharmaceutically acceptable salt thereof, comprising:

conducting a condensation reaction of a compound represented by general formula (VIA) or a salt thereof with a compound represented by general formula (VIB) or a salt thereof (preferably hydrochloride and trifluoroacetate) to give the compound represented by general formula (VI) or the pharmaceutically acceptable salt thereof;

• • wherein:
  • R^1a, R^3d, R^3e, R^3f, W⁴, Z⁴, Z⁵, x, x1, y, y1, m3, and Q⁴ are as defined in general formula (VI).

Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (VI-1) or a pharmaceutically acceptable salt thereof, comprising:

conducting a condensation reaction of a compound represented by general formula (VI-1A) or a salt thereof with a compound represented by general formula (VIB) or a salt thereof (preferably hydrochloride and trifluoroacetate) to give the compound represented by general formula (VI-1) or the pharmaceutically acceptable salt thereof;

• • wherein:
  • R^1a, R^3d, R^3e, R^3f, W⁴, Z⁴, Z⁵, x, x1, y, y1, m3, and Q⁴ are as defined in general formula (VI-1).

Another aspect of the present disclosure relates to a method for preparing compounds represented by general formula (VI-1-1) and general formula (VI-1-2) or pharmaceutically acceptable salts thereof, comprising:

chirally resolving a compound represented by general formula (VI-1) or a pharmaceutically acceptable salt thereof to give the compounds represented by general formula (VI-1-1) and general formula (VI-1-2) or the pharmaceutically acceptable salts thereof,

• • wherein:
  • R^1a, R^3d, R^3e, R^3f, W⁴, Z⁴, Z⁵, x, x1, y, y1, m3, and Q⁴ are as defined in general formula (VI-1).

Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (VII) or a pharmaceutically acceptable salt thereof, comprising:

conducting a reductive amination reaction of a compound represented by general formula (VIIA) or a salt thereof (preferably hydrochloride and trifluoroacetate) with a compound represented by general formula (VIIB) or a salt thereof to give the compound represented by general formula (VII) or the pharmaceutically acceptable salt thereof, where m3 is 0;

• • or, conducting a reductive amination reaction of a compound represented by general formula (VIIA) or a salt thereof (preferably hydrochloride and trifluoroacetate) with a compound represented by general formula (VIIB′) or a salt thereof to give the compound represented by general formula (VII) or the pharmaceutically acceptable salt thereof, where m3 is 1, 2, or 3;
  • wherein:
  • m6 is 0, 1, or 2;
  • R^1a, Q⁴, R^3d, R^3e, R^3f, W⁴, x, x1, y, and y1 are as defined in general formula (VII).

Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (VII-1) or a pharmaceutically acceptable salt thereof, comprising:

conducting a reductive amination reaction of a compound represented by general formula (VII-1A) or a salt thereof (preferably hydrochloride and trifluoroacetate) with a compound represented by general formula (VIIB) or a salt thereof to give the compound represented by general formula (VII-1) or the pharmaceutically acceptable salt thereof, where m3 is 0;

• • or, conducting a reductive amination reaction of a compound represented by general formula (VII-1A) or a salt thereof (preferably hydrochloride and trifluoroacetate) with a compound represented by general formula (VIIB′) or a salt thereof to give the compound represented by general formula (VII-1) or the pharmaceutically acceptable salt thereof, where m3 is 1, 2, or 3;
  • wherein:
  • m6 is 0, 1, or 2;
  • R^1a, Q⁴, R^3d, R^3e, R^3f, W⁴, x, x1, y, and y1 are as defined in general formula (VII-1).

Another aspect of the present disclosure relates to a method for preparing compounds represented by general formula (VII-1-1) and general formula (VII-1-2) or pharmaceutically acceptable salts thereof, comprising:

chirally resolving a compound represented by general formula (VII-1) or a pharmaceutically acceptable salt thereof to give the compounds represented by general formula (VII-1-1) and general formula (VII-1-2) or the pharmaceutically acceptable salts thereof,

• • wherein:
  • R^1a, Q⁴, R^3d, R^3e, R^3f, W⁴, m3, x, x1, y, and y1 are as defined in general formula (VII-1).

Another aspect of the present disclosure relates to a pharmaceutical composition comprising the compounds represented by general formula (I), general formula (II), general formula (II-1), general formula (G), general formula (G-1), general formula (III′), general formula (III′-1), general formula (III), general formula (III-1), general formula (X), general formula (X-1), general formula (IV′), general formula (IV′-1), general formula (IV′-1-1), general formula (IV′-1-2), general formula (M), general formula (M-1), general formula (M-1-1), general formula (M-1-2), general formula (IV), general formula (IV-1), general formula (IV-1-1), general formula (IV-1-2), general formula (V), general formula (V-1), general formula (V-1-1), general formula (V-1-2), general formula (VI), general formula (VI-1), general formula (VI-1-1), general formula (VI-1-2), general formula (VII), general formula (VII-1), general formula (VII-1-1), and general formula (VII-1-2) described above in the present disclosure or the compounds shown in Table A or pharmaceutically acceptable salts thereof, and one or more pharmaceutically acceptable carriers, diluents, or excipients.

The present disclosure further relates to use of the compounds represented by general formula (I), general formula (II), general formula (II-1), general formula (G), general formula (G-1), general formula (III′), general formula (III′-1), general formula (III), general formula (III-1), general formula (X), general formula (X-1), general formula (IV′), general formula (IV′-1), general formula (IV′-1-1), general formula (IV′-1-2), general formula (M), general formula (M-1), general formula (M-1-1), general formula (M-1-2), general formula (IV), general formula (IV-1), general formula (IV-1-1), general formula (IV-1-2), general formula (V), general formula (V-1), general formula (V-1-1), general formula (V-1-2), general formula (VI), general formula (VI-1), general formula (VI-1-1), general formula (VI-1-2), general formula (VII), general formula (VII-1), general formula (VII-1-1), and general formula (VII-1-2) described above or the compounds shown in Table A or pharmaceutically acceptable salts thereof, or the pharmaceutical composition comprising same, in the preparation of a medicament for regulating the ubiquitination and degradation of the androgen receptor (AR) protein in a subject.

The present disclosure further relates to use of the compounds represented by general formula (I), general formula (II), general formula (II-1), general formula (G), general formula (G-1), general formula (III′), general formula (III′-1), general formula (III), general formula (III-1), general formula (X), general formula (X-1), general formula (IV′), general formula (IV′-1), general formula (IV′-1-1), general formula (IV′-1-2), general formula (M), general formula (M-1), general formula (M-1-1), general formula (M-1-2), general formula (IV), general formula (IV-1), general formula (IV-1-1), general formula (IV-1-2), general formula (V), general formula (V-1), general formula (V-1-1), general formula (V-1-2), general formula (VI), general formula (VI-1), general formula (VI-1-1), general formula (VI-1-2), general formula (VII), general formula (VII-1), general formula (VII-1-1), and general formula (VII-1-2) described above or the compounds shown in Table A or pharmaceutically acceptable salts thereof, or the pharmaceutical composition comprising same, in the preparation of a medicament for treating and/or preventing an androgen receptor-mediated or -dependent disease or disorder, wherein the androgen receptor-mediated or -dependent disease or disorder is preferably selected from the group consisting of tumors, male sexual dysfunction, and Kennedy's disease; more preferably from the group consisting of prostate cancer, prostatic hyperplasia, hirsutism, alopecia, anorexia nervosa, breast cancer, acne, male sexual dysfunction, Kennedy's disease, and AIDS; most preferably prostate cancer; and still most preferably hormone-sensitive prostate cancer or hormone-refractory prostate cancer.

The present disclosure further relates to use of the compounds represented by general formula (I), general formula (II), general formula (II-1), general formula (G), general formula (G-1), general formula (III′), general formula (III′-1), general formula (III), general formula (III-1), general formula (X), general formula (X-1), general formula (IV′), general formula (IV′-1), general formula (IV′-1-1), general formula (IV′-1-2), general formula (M), general formula (M-1), general formula (M-1-1), general formula (M-1-2), general formula (IV), general formula (IV-1), general formula (IV-1-1), general formula (IV-1-2), general formula (V), general formula (V-1), general formula (V-1-1), general formula (V-1-2), general formula (VI), general formula (VI-1), general formula (VI-1-1), general formula (VI-1-2), general formula (VII), general formula (VII-1), general formula (VII-1-1), and general formula (VII-1-2) described above or the compounds shown in Table A or pharmaceutically acceptable salts thereof, or the pharmaceutical composition comprising same, in the preparation of a medicament for treating and/or preventing tumors, male sexual dysfunction, and Kennedy's disease; preferably for treating and/or preventing prostate cancer, prostatic hyperplasia, hirsutism, alopecia, anorexia nervosa, breast cancer, acne, male sexual dysfunction, Kennedy's disease, and AIDS; more preferably for treating and/or preventing prostate cancer; and most preferably for treating and/or preventing hormone-sensitive prostate cancer or hormone-refractory prostate cancer.

The present disclosure also relates to a method for regulating the ubiquitination and degradation of the androgen receptor (AR) protein in a subject, comprising administering to a subject in need thereof a therapeutically effective amount of the compounds represented by general formula (I), general formula (II), general formula (II-1), general formula (G), general formula (G-1), general formula (III′), general formula (III′-1), general formula (III), general formula (III-1), general formula (X), general formula (X-1), general formula (IV′), general formula (IV′-1), general formula (IV′-1-1), general formula (IV′-1-2), general formula (M), general formula (M-1), general formula (M-1-1), general formula (M-1-2), general formula (IV), general formula (IV-1), general formula (IV-1-1), general formula (IV-1-2), general formula (V), general formula (V-1), general formula (V-1-1), general formula (V-1-2), general formula (VI), general formula (VI-1), general formula (VI-1-1), general formula (VI-1-2), general formula (VII), general formula (VII-1), general formula (VII-1-1), and general formula (VII-1-2) described above or the compounds shown in Table A or pharmaceutically acceptable salts thereof, or the pharmaceutical composition comprising same.

The present disclosure also relates to a method for treating and/or preventing an androgen receptor-mediated or -dependent disease or disorder, comprising administering to a subject in need thereof a therapeutically effective amount of the compounds represented by general formula (I), general formula (II), general formula (II-1), general formula (G), general formula (G-1), general formula (III′), general formula (III′-1), general formula (III), general formula (III-1), general formula (X), general formula (X-1), general formula (IV′), general formula (IV′-1), general formula (IV′-1-1), general formula (IV′-1-2), general formula (M), general formula (M-1), general formula (M-1-1), general formula (M-1-2), general formula (IV), general formula (IV-1), general formula (IV-1-1), general formula (IV-1-2), general formula (V), general formula (V-1), general formula (V-1-1), general formula (V-1-2), general formula (VI), general formula (VI-1), general formula (VI-1-1), general formula (VI-1-2), general formula (VII), general formula (VII-1), general formula (VII-1-1), and general formula (VII-1-2) described above or the compounds shown in Table A or pharmaceutically acceptable salts thereof, or the pharmaceutical composition comprising same, wherein the androgen receptor-mediated or -dependent disease or disorder is preferably selected from the group consisting of tumors, male sexual dysfunction, and Kennedy's disease; more preferably from the group consisting of prostate cancer, prostatic hyperplasia, hirsutism, alopecia, anorexia nervosa, breast cancer, acne, male sexual dysfunction, Kennedy's disease, and AIDS; most preferably prostate cancer; and still most preferably hormone-sensitive prostate cancer or hormone-refractory prostate cancer.

The present disclosure also relates to a method for treating and/or preventing tumors, male sexual dysfunction, and Kennedy's disease, preferably for treating and/or preventing prostate cancer, prostatic hyperplasia, hirsutism, alopecia, anorexia nervosa, breast cancer, acne, male sexual dysfunction, Kennedy's disease, and AIDS, more preferably for treating and/or preventing prostate cancer, and most preferably for treating and/or preventing hormone-sensitive prostate cancer or hormone-refractory prostate cancer, comprising administering to a patient in need thereof a therapeutically effective amount of the compounds represented by general formula (I), general formula (II), general formula (II-1), general formula (G), general formula (G-1), general formula (III′), general formula (III′-1), general formula (III), general formula (III-1), general formula (X), general formula (X-1), general formula (IV′), general formula (IV′-1), general formula (IV′-1-1), general formula (IV′-1-2), general formula (M), general formula (M-1), general formula (M-1-1), general formula (M-1-2), general formula (IV), general formula (IV-1), general formula (IV-1-1), general formula (IV-1-2), general formula (V), general formula (V-1), general formula (V-1-1), general formula (V-1-2), general formula (VI), general formula (VI-1), general formula (VI-1-1), general formula (VI-1-2), general formula (VII), general formula (VII-1), general formula (VII-1-1), and general formula (VII-1-2) described above or the compounds shown in Table A or pharmaceutically acceptable salts thereof, or the pharmaceutical composition comprising same.

The present disclosure further relates to the compounds represented by general formula (I), general formula (II), general formula (II-1), general formula (G), general formula (G-1), general formula (III′), general formula (III′-1), general formula (III), general formula (III-1), general formula (X), general formula (X-1), general formula (IV′), general formula (IV′-1), general formula (IV′-1-1), general formula (IV′-1-2), general formula (M), general formula (M-1), general formula (M-1-1), general formula (M-1-2), general formula (IV), general formula (IV-1), general formula (IV-1-1), general formula (IV-1-2), general formula (V), general formula (V-1), general formula (V-1-1), general formula (V-1-2), general formula (VI), general formula (VI-1), general formula (VI-1-1), general formula (VI-1-2), general formula (VII), general formula (VII-1), general formula (VII-1-1), and general formula (VII-1-2) described above or the compounds shown in Table A or pharmaceutically acceptable salts thereof, or the pharmaceutical composition comprising same, for use as a medicament.

The present disclosure further relates to the compounds represented by general formula (I), general formula (II), general formula (II-1), general formula (G), general formula (G-1), general formula (III′), general formula (III′-1), general formula (III), general formula (III-1), general formula (X), general formula (X-1), general formula (IV′), general formula (IV′-1), general formula (IV′-1-1), general formula (IV′-1-2), general formula (M), general formula (M-1), general formula (M-1-1), general formula (M-1-2), general formula (IV), general formula (IV-1), general formula (IV-1-1), general formula (IV-1-2), general formula (V), general formula (V-1), general formula (V-1-1), general formula (V-1-2), general formula (VI), general formula (VI-1), general formula (VI-1-1), general formula (VI-1-2), general formula (VII), general formula (VII-1), general formula (VII-1-1), and general formula (VII-1-2) described above or the compounds shown in Table A or pharmaceutically acceptable salts thereof, or the pharmaceutical composition comprising same, for use as a medicament for regulating the ubiquitination and degradation of the androgen receptor (AR) protein in a subject.

The present disclosure further relates to the compounds represented by general formula (I), general formula (II), general formula (II-1), general formula (G), general formula (G-1), general formula (III′), general formula (III′-1), general formula (III), general formula (III-1), general formula (X), general formula (X-1), general formula (IV′), general formula (IV′-1), general formula (IV′-1-1), general formula (IV′-1-2), general formula (M), general formula (M-1), general formula (M-1-1), general formula (M-1-2), general formula (IV), general formula (IV-1), general formula (IV-1-1), general formula (IV-1-2), general formula (V), general formula (V-1), general formula (V-1-1), general formula (V-1-2), general formula (VI), general formula (VI-1), general formula (VI-1-1), general formula (VI-1-2), general formula (VII), general formula (VII-1), general formula (VII-1-1), and general formula (VII-1-2) described above or the compounds shown in Table A or pharmaceutically acceptable salts thereof, or the pharmaceutical composition comprising same, for use as a medicament for treating and/or preventing an androgen receptor-mediated or -dependent disease or disorder, wherein the androgen receptor-mediated or -dependent disease or disorder is preferably selected from the group consisting of tumors, male sexual dysfunction, and Kennedy's disease; more preferably from the group consisting of prostate cancer, prostatic hyperplasia, hirsutism, alopecia, anorexia nervosa, breast cancer, acne, male sexual dysfunction, Kennedy's disease, and AIDS; most preferably prostate cancer; and still most preferably hormone-sensitive prostate cancer or hormone-refractory prostate cancer.

The present disclosure further relates to the compounds represented by general formula (I), general formula (II), general formula (II-1), general formula (G), general formula (G-1), general formula (III′), general formula (III′-1), general formula (III), general formula (III-1), general formula (X), general formula (X-1), general formula (IV′), general formula (IV′-1), general formula (IV′-1-1), general formula (IV′-1-2), general formula (M), general formula (M-1), general formula (M-1-1), general formula (M-1-2), general formula (IV), general formula (V-1), general formula (IV-1-1), general formula (IV-1-2), general formula (V), general formula (V-1), general formula (V-1-1), general formula (V-1-2), general formula (VI), general formula (VI-1), general formula (VI-1-1), general formula (VI-1-2), general formula (VII), general formula (VII-1), general formula (VII-1-1), and general formula (VII-1-2) described above or the compounds shown in Table A or pharmaceutically acceptable salts thereof, or the pharmaceutical composition comprising same, for use as a medicament for treating and/or preventing tumors, male sexual dysfunction, and Kennedy's disease; preferably for treating and/or preventing prostate cancer, prostatic hyperplasia, hirsutism, alopecia, anorexia nervosa, breast cancer, acne, male sexual dysfunction, Kennedy's disease, and AIDS; more preferably for treating and/or preventing prostate cancer; and most preferably for treating and/or preventing hormone-sensitive prostate cancer or hormone-refractory prostate cancer.

The present disclosure further relates to the compounds represented by general formula (I), general formula (II), general formula (II-1), general formula (G), general formula (G-1), general formula (III′), general formula (III′-1), general formula (III), general formula (III-1), general formula (X), general formula (X-1), general formula (IV′), general formula (IV′-1), general formula (IV′-1-1), general formula (IV′-1-2), general formula (M), general formula (M-1), general formula (M-1-1), general formula (M-1-2), general formula (IV), general formula (V-1), general formula (IV-1-1), general formula (IV-1-2), general formula (V), general formula (V-1), general formula (V-1-1), general formula (V-1-2), general formula (VI), general formula (VI-1), general formula (VI-1-1), general formula (VI-1-2), general formula (VII), general formula (VII-1), general formula (VII-1-1), and general formula (VII-1-2) described above or the compounds shown in Table A or pharmaceutically acceptable salts thereof, or the pharmaceutical composition comprising same, for use in regulating the ubiquitination and degradation of the androgen receptor (AR) protein in a subject.

The present disclosure further relates to the compounds represented by general formula (I), general formula (II), general formula (II-1), general formula (G), general formula (G-1), general formula (III′), general formula (III′-1), general formula (III), general formula (III-1), general formula (X), general formula (X-1), general formula (IV′), general formula (IV′-1), general formula (IV′-1-1), general formula (IV′-1-2), general formula (M), general formula (M-1), general formula (M-1-1), general formula (M-1-2), general formula (IV), general formula (V-1), general formula (IV-1-1), general formula (IV-1-2), general formula (V), general formula (V-1), general formula (V-1-1), general formula (V-1-2), general formula (VI), general formula (VI-1), general formula (VI-1-1), general formula (VI-1-2), general formula (VII), general formula (VII-1), general formula (VII-1-1), and general formula (VII-1-2) described above or the compounds shown in Table A or pharmaceutically acceptable salts thereof, or the pharmaceutical composition comprising same, for use in treating and/or preventing an androgen receptor-mediated or -dependent disease or disorder, wherein the androgen receptor-mediated or -dependent disease or disorder is preferably selected from the group consisting of tumors, male sexual dysfunction, and Kennedy's disease; more preferably from the group consisting of prostate cancer, prostatic hyperplasia, hirsutism, alopecia, anorexia nervosa, breast cancer, acne, male sexual dysfunction, Kennedy's disease, and AIDS; most preferably prostate cancer; and still most preferably hormone-sensitive prostate cancer or hormone-refractory prostate cancer.

The present disclosure further relates to the compounds represented by general formula (I), general formula (II), general formula (II-1), general formula (G), general formula (G-1), general formula (III′), general formula (III′-1), general formula (III), general formula (III-1), general formula (X), general formula (X-1), general formula (IV′), general formula (IV′-1), general formula (IV′-1-1), general formula (IV′-1-2), general formula (M), general formula (M-1), general formula (M-1-1), general formula (M-1-2), general formula (IV), general formula (IV-1), general formula (IV-1-1), general formula (IV-1-2), general formula (V), general formula (V-1), general formula (V-1-1), general formula (V-1-2), general formula (VI), general formula (VI-1), general formula (VI-1-1), general formula (VI-1-2), general formula (VII), general formula (VII-1), general formula (VII-1-1), and general formula (VII-1-2) described above or the compounds shown in Table A or pharmaceutically acceptable salts thereof, or the pharmaceutical composition comprising same, for use in treating and/or preventing tumors, male sexual dysfunction, and Kennedy's disease; preferably for use in treating and/or preventing prostate cancer, prostatic hyperplasia, hirsutism, alopecia, anorexia nervosa, breast cancer, acne, male sexual dysfunction, Kennedy's disease, and AIDS; more preferably for use in treating and/or preventing prostate cancer; and most preferably for use in treating and/or preventing hormone-sensitive prostate cancer or hormone-refractory prostate cancer.

In certain embodiments, the disease or disorder is asthma, multiple sclerosis, cancer, Kennedy's disease, ciliopathy, cleft palate, diabetes, heart disease, hypertension, inflammatory bowel disease, mental retardation, mood disorder, obesity, refractive error, infertility, Angelman syndrome, Canavan disease, coeliac disease, Charcot-Marie-Tooth disease, cystic fibrosis, Duchenne muscular dystrophy, hemochromatosis, hemophilia, Klinefelter syndrome, neurofibroma, phenylketonuria, polycystic kidney disease, (PKD1) or 4(PKD2) Prader-Willi syndrome, sickle cell disease, Tay-Sachs disease, or Turner syndrome. The cancer is squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, hepatocellular carcinoma, renal cell carcinoma, bladder cancer, intestinal cancer, breast cancer, cervical cancer, colon cancer, esophageal cancer, head cancer, kidney cancer, liver cancer, lung cancer, neck cancer, ovarian cancer, pancreatic cancer, prostate cancer, gastric cancer, leukemia, benign and malignant lymphomas (particularly Burkitt's lymphoma and non-Hodgkin lymphoma), benign and malignant melanomas, myeloproliferative diseases, sarcomas (including Ewing's sarcoma, angiosarcoma, Kaposi's sarcoma, liposarcoma, myosarcoma, peripheral neuroepithelioma, synovial sarcoma, neuroglioma, astrocytoma, oligodendroglioma, ependymoma, glioblastoma, neuroblastoma, ganglioneuroma, ganglioma, medulloblastoma, pinealocyte tumors, meningioma, meningeal sarcoma, neurofibroma, and schwannomas), endometrial cancer, testicular cancer, thyroid cancer, carcinosarcoma, Hodgkin disease, Wilms' tumor, or teratocarcinoma. In certain embodiments, the disease to be treated is cancer, e.g., prostate cancer or Kennedy's disease.

The active compound may be formulated into a form suitable for administration by any suitable route, preferably in the form of a unit dose, or in the form of a single dose that can be self-administered by a patient. The unit dose of the compound or composition of the present disclosure may be expressed in the form of a tablet, capsule, cachet, vial, powder, granule, lozenge, suppository, regenerating powder, or liquid formulation.

As a general guide, a suitable unit dose may be 0.1-1000 mg. The pharmaceutical composition of the present disclosure may comprise, in addition to the active compound, one or more auxiliary materials selected from the group consisting of a filler (diluent), a binder, a wetting agent, a disintegrant, or an excipient or the like.

Depending on the method of administration, the composition may comprise 0.1 to 99 wt. % of the active compound.

The pharmaceutical composition comprising the active ingredient may be in a form suitable for oral administration, for example, in the form of a tablet, dragee, lozenge, aqueous or oil suspension, dispersible powder or granule, emulsion, hard or soft capsule, or syrup or elixir. An oral composition may be prepared by following any method known in the art for preparing pharmaceutical compositions, and such a composition may comprise one or more ingredients selected from the group consisting of a sweetener, a corrigent, a colorant, and a preservative, so as to provide a pharmaceutical formulation that is pleasing to the eye and palatable. The tablet comprises the active ingredient, and non-toxic pharmaceutically acceptable excipients that are used for mixing and are suitable for the preparation of the tablet. These excipients may be an inert excipient, a granulating agent, a disintegrant, a binder, and a lubricant. 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, thereby providing a sustained-release effect over an extended period of time.

An oral formulation may also be provided in the form of a soft gelatin capsule in which the active ingredient is mixed with an inert solid diluent or with a water-soluble carrier or oil vehicle.

An aqueous suspension comprises the active substance and an excipient that is used for mixing and is suitable for the preparation of the aqueous suspension. Such an excipient is a suspending agent, a dispersant, or a wetting agent. The aqueous suspension may also comprise one or more preservatives, one or more colorants, one or more corrigents, and one or more sweeteners.

An oil suspension may be formulated by suspending the active ingredient in a vegetable oil, or in a mineral oil. The oil suspension may comprise a thickening agent. The sweeteners and corrigents described above may be added to provide a palatable formulation. Antioxidants may also be added to preserve the compositions.

The pharmaceutical composition of the present disclosure may also be in the form of an oil-in-water emulsion. The oil phase may be a vegetable oil or a mineral oil, or a mixture thereof. Suitable emulsifiers may be naturally occurring phospholipids, and the emulsion may also comprise a sweetener, a corrigent, a preservative, and an antioxidant. Such a formulation may also comprise a palliative, a preservative, a colorant, and an antioxidant. The pharmaceutical composition of the present disclosure may be in the form of a sterile injectable aqueous solution. Acceptable vehicles or solvents that can be used include water, Ringer's solution, and isotonic sodium chloride solution. A sterile injectable formulation may be a sterile injectable oil-in-water microemulsion in which an active ingredient is dissolved in an oil phase. The injection or microemulsion can be locally injected into the bloodstream of a patient in large quantities. Alternatively, it may be desirable to administer the solution and microemulsion in such a way as to maintain a constant circulating concentration of the compound of the present disclosure. To maintain such a constant concentration, a continuous intravenous delivery device may be used. An example of such a device is a Deltec CADD-PLUS. TM. 5400 intravenous injection pump.

The pharmaceutical composition of the present disclosure may be in the form of a sterile injectable aqueous or oil suspension for intramuscular and subcutaneous administration. The suspension can be prepared according to the prior art using suitable dispersants or wetting agents and suspending agents. The sterile injectable formulation may also be a sterile injection or suspension prepared in a parenterally acceptable non-toxic diluent or solvent. In addition, a sterile fixed oil may be conventionally used as a solvent or a suspending medium. For this purpose, any blend fixed oil may be used. In addition, fatty acids may also be used to prepare injections.

The compound of the present disclosure may be administered in the form of a suppository for rectal administration. Such a pharmaceutical composition can be prepared by mixing a drug with a suitable non-irritating excipient which is a solid at ambient temperature but a liquid in the rectum and therefore will melt in the rectum to release the drug. As is well known to those skilled in the art, the dosage of the drug depends on a variety of factors, including, but not limited to, the activity of the particular compound used, the age of the patient, the body weight of the patient, the health condition of the patient, the behavior of the patient, the diet of the patient, the time of administration, the route of administration, the rate of excretion, the combination of drugs, the severity of the disease, and the like. In addition, the optimal treatment regimen, such as the mode of treatment, the daily dose of the compound, or the type of pharmaceutically acceptable salts, can be verified according to conventional treatment regimens.

Terminology

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

The term “alkyl” refers to a saturated straight-chain or branched-chain 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., C_1-20 alkyl). The alkyl is preferably an alkyl group having 1 to 12 carbon atoms (i.e., C_1-12 alkyl), and more preferably an alkyl group having to 6 carbon atoms (i.e., C_1-6 alkyl). 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, various branched-chain isomers thereof, and the like. Alkyl may be substituted or unsubstituted, and when it is substituted, it may be substituted at any accessible point of attachment, and the substituent is preferably selected from the group consisting of one or more of a D atom, halogen, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl.

The term “alkenyl” refers to an alkyl group containing at least one carbon-carbon double bond in the molecule, wherein the alkyl group is as defined above, and it has 2 to 12 (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12) carbon atoms (i.e., C_2-12 alkenyl). The alkenyl is preferably an alkenyl group having 2 to 6 carbon atoms (i.e., C_2-6 alkenyl). Non-limiting examples include: ethenyl, propenyl, isopropenyl, butenyl, and the like. Alkenyl may be substituted or unsubstituted, and when it is substituted, it may be substituted at any accessible point of attachment, and the substituent is preferably selected from the group consisting of one or more of a D atom, alkoxy, halogen, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl.

The term “alkynyl” refers to an alkyl group containing at least one carbon-carbon triple bond in the molecule, wherein the alkyl group is as defined above, and it has 2 to 12 (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12) carbon atoms (i.e., C_2-12 alkynyl). The alkynyl is preferably an alkynyl group having 2 to 6 carbon atoms (i.e., C_2-6 alkynyl). Non-limiting examples include: ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like. Alkynyl may be substituted or unsubstituted, and when it is substituted, it may be substituted at any accessible point of attachment, and the substituent is preferably selected from the group consisting of one or more of a D atom, alkoxy, halogen, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl.

The term “alkoxy” refers to —O—(alkyl), wherein the alkyl is as defined above. Non-limiting examples include: methoxy, ethoxy, propoxy, butoxy, and the like. Alkoxy may be substituted or unsubstituted, and when it is substituted, it may be substituted at any accessible point of attachment, and the substituent is preferably selected from the group consisting of one or more of a D atom, halogen, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl.

The term “cycloalkyl” refers to a saturated or partially unsaturated monocyclic all-carbon ring (i.e., monocyclic cycloalkyl) or polycyclic system (i.e., polycyclic cycloalkyl) having 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 group having 3 to 12 ring atoms (i.e., 3- to 12-membered cycloalkyl), more preferably a cycloalkyl group having 3 to 8 ring atoms (i.e., 3- to 8-membered cycloalkyl), and most preferably a cycloalkyl group having 3 to 6 ring atoms (i.e., 3- to 6-membered cycloalkyl). Non-limiting examples of the monocyclic cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, and the like.

The polycyclic cycloalkyl includes: spirocycloalkyl, fused cycloalkyl, and bridged cycloalkyl.

The term “spirocycloalkyl” refers to a polycyclic system in which a carbon atom (referred to as a spiro atom) is shared between rings, which may contain in the rings one or more double bonds or may contain in the rings one or more heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur (the nitrogen may be optionally oxidized to form a nitrogen oxide; the sulfur may be optionally substituted with oxo to form a sulfoxide or sulfone, excluding —O—O—, —O—S—, or —S—S—), provided that at least one all-carbon ring is contained and the point of attachment is on the all-carbon ring; and 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 spirocycloalkyl). The spirocycloalkyl is preferably a spirocycloalkyl group having 6 to 14 ring atoms (i.e., 6- to 14-membered spirocycloalkyl), and more preferably a spirocycloalkyl group having 7 to 10 ring atoms (i.e., 7- to 10-membered spirocycloalkyl). The spirocycloalkyl includes monospirocycloalkyl and polyspirocycloalkyl (e.g., bispirocycloalkyl), preferably monospirocycloalkyl or bispirocycloalkyl, and 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 monospirocycloalkyl. Non-limiting examples include:

wherein the point of attachment may be at an position;

and the like.

The term “fused cycloalkyl” refers to a polycyclic system in which two adjacent carbon atoms are shared between rings, which is formed by fusing a monocyclic cycloalkyl group with one or more monocyclic cycloalkyl groups, or fusing a monocyclic cycloalkyl group with one or more of a heterocyclyl group, an aryl group, or a heteroaryl group, wherein the point of attachment is on a monocyclic cycloalkyl group; and which may contain in the rings 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). The fused cycloalkyl is preferably a fused cycloalkyl group having 6 to 14 ring atoms (i.e., 6- to 14-membered fused cycloalkyl), and more preferably a fused cycloalkyl group having 7 to ring atoms (i.e., 7- to 10-membered fused cycloalkyl). The fused cycloalkyl includes bicyclic fused cycloalkyl and polycyclic fused cycloalkyl (e.g., tricyclic fused cycloalkyl and tetracyclic fused cycloalkyl), preferably bicyclic fused cycloalkyl or tricyclic fused cycloalkyl, and 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 cycloalkyl. Non-limiting examples include:

wherein the point of attachment may be at any position;

and the like.

The term “bridged cycloalkyl” refers to an all-carbon polycyclic system in which two carbon atoms that are not directly connected are shared between rings, which may contain in the rings 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 group having 6 to 14 carbon atoms (i.e., 6- to 14-membered bridged cycloalkyl), and more preferably a bridged cycloalkyl group 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 and tetracyclic bridged cycloalkyl), preferably bicyclic bridged cycloalkyl or tricyclic bridged cycloalkyl. Non-limiting examples include:

wherein the point of attachment may be at any position.

Cycloalkyl may be substituted or unsubstituted, and when it is substituted, it may be substituted at any accessible point of attachment, and the substituent is preferably selected from the group consisting of one or more of a D atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, oxo, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl.

The term “heterocyclyl” refers to a saturated or partially unsaturated monocyclic heterocyclic (i.e., monocyclic heterocyclyl) or polycyclic heterocyclic system (i.e., polycyclic heterocyclyl), which contains in the ring(s) at least one (e.g., 1, 2, 3, or 4) heteroatom selected from the group consisting of nitrogen, oxygen, and sulfur (the nitrogen may be optionally oxidized to form a nitrogen oxide; the sulfur may be optionally substituted with oxo to form a sulfoxide or sulfone, excluding —O—O—, —O—S—, or —S—S—) and has 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 heterocyclyl). The heterocyclyl is preferably a heterocyclyl group having 3 to 12 ring atoms (i.e., 3- to 12-membered heterocyclyl); further preferably a heterocyclyl group having 3 to 8 ring atoms (i.e., 3- to 8-membered heterocyclyl); more preferably a heterocyclyl group having 3 to 6 ring atoms (i.e., 3- to 6-membered heterocyclyl) or a heterocyclyl group having 4 to 6 ring atoms (i.e., 4- to 6-membered heterocyclyl); and most preferably a heterocyclyl group having 5 or 6 ring atoms (i.e., 5 or 6-membered heterocyclyl).

Non-limiting examples of the monocyclic heterocyclyl include: pyrrolidinyl, tetrahydropyranyl, 1,2,3,6-tetrahydropyridinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, and the like.

The polycyclic heterocyclyl includes spiroheterocyclyl, fused heterocyclyl, and bridged heterocyclyl.

The term “spiroheterocyclyl” refers to a polycyclic heterocyclic system in which an atom (referred to as a spiro atom) is shared between rings, which may contain in the rings one or more double bonds and contains in the rings at least one (e.g., 1, 2, 3, or 4) heteroatom selected from the group consisting of nitrogen, oxygen, and sulfur (the nitrogen may be optionally oxidized to form a nitrogen oxide; the sulfur may be optionally substituted with oxo to form a sulfoxide or sulfone, excluding —O—O—, —O—S—, or —S—S—), provided that at least one monocyclic heterocyclyl group is contained and the point of attachment is on the monocyclic heterocyclyl group; and 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 spiroheterocyclyl). The spiroheterocyclyl is preferably a spiroheterocyclyl group having 6 to 14 ring atoms (i.e., 6- to 14-membered spiroheterocyclyl), further preferably a spiroheterocyclyl group having 7 to 11 ring atoms (i.e., 7- to 11-membered spiroheterocyclyl), and more preferably a spiroheterocyclyl group having 7 to 10 ring atoms (i.e., 7- to 10-membered spiroheterocyclyl) or a spiroheterocyclyl group having 9 to 11 ring atoms (i.e., 9- to 11-membered spiroheterocyclyl). The spiroheterocyclyl includes monospiroheterocyclyl and polyspiroheterocyclyl (e.g., bispiroheterocyclyl), preferably monospiroheterocyclyl or bispiroheterocyclyl, and 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 monospiroheterocyclyl. Non-limiting examples include:

and the like.

The term “fused heterocyclyl” refers to a polycyclic heterocyclic system in which two adjacent atoms are shared between rings, which may contain in the rings one or more double bonds and contains in the rings at least one (e.g., 1, 2, 3, or 4) heteroatom selected from the group consisting of nitrogen, oxygen, and sulfur (the nitrogen may be optionally oxidized to form a nitrogen oxide; the sulfur may be optionally substituted with oxo to form a sulfoxide or sulfone, excluding —O—O—, —O—S—, or —S—S—); which is formed by fusing a monocyclic heterocyclyl group with one or more monocyclic heterocyclyl groups, or fusing a monocyclic heterocyclyl group with one or more of a cycloalkyl group, an aryl group, or a heteroaryl group, wherein the point of attachment is on a monocyclic heterocyclyl group; and 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 fused heterocyclyl). The fused heterocyclyl is preferably a fused heterocyclyl group having 6 to 14 ring atoms (i.e., 6- to 14-membered fused heterocyclyl), and more preferably a fused heterocyclyl group having to 10 ring atoms (i.e., 7- to 10-membered fused heterocyclyl). The fused heterocyclyl includes bicyclic and polycyclic fused heterocyclyl (e.g., tricyclic fused heterocyclyl and tetracyclic fused heterocyclyl), preferably bicyclic fused heterocyclyl or tricyclic fused heterocyclyl, 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 heterocyclyl. Non-limiting examples include:

and the like.

The term “bridged heterocyclyl” refers to a polycyclic heterocyclic system in which two atoms that are not directly connected are shared between rings, which may contain in the rings one or more double bonds and contains in the rings at least one (e.g., 1, 2, 3, or 4) heteroatom selected from the group consisting of nitrogen, oxygen, and sulfur (the nitrogen may be optionally oxidized to form a nitrogen oxide; the sulfur may be optionally substituted with oxo to form a sulfoxide or sulfone, excluding —O—O—, —O—S—, or —S—S—); and 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 bridged heterocyclyl). The bridged heterocyclyl is preferably a bridged heterocyclyl group having 6 to 14 ring atoms (i.e., 6- to 14-membered bridged heterocyclyl), and more preferably a bridged heterocyclyl group having 7 to 10 ring atoms (i.e., 7- to 10-membered bridged heterocyclyl). According to the number of constituent rings, bridged heterocyclyl can be divided into bicyclic bridged heterocyclyl and polycyclic bridged heterocyclyl (e.g., tricyclic bridged heterocyclyl and tetracyclic bridged heterocyclyl), preferably bicyclic bridged heterocyclyl or tricyclic bridged heterocyclyl. Non-limiting examples include:

and the like.

Heterocyclyl may be substituted or unsubstituted, and when it is substituted, it may be substituted at any accessible point of attachment, and the substituent is preferably selected from the group consisting of one or more of a D atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, oxo, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl.

The term “aryl” refers to a monocyclic all-carbon aromatic ring (i.e., monocyclic aryl) or polycyclic aromatic ring system (i.e., polycyclic aryl) having a conjugated a-electron system, which has 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 group having 6 to 10 ring atoms (i.e., 6- to 10-membered aryl). An example of the monocyclic aryl is phenyl. Non-limiting examples of the polycyclic aryl include: naphthyl, anthryl, phenanthryl, and the like. The polycyclic aryl also includes those formed by fusing a phenyl group with one or more of a heterocyclyl group or a cycloalkyl group or fusing a naphthyl group with one or more of a heterocyclyl group or a cycloalkyl group, wherein the point of attachment is on the phenyl group or the naphthyl group, and in the circumstances the number of ring atoms continues to represent the number of ring atoms in the polycyclic aromatic ring system; non-limiting examples include:

and the like.

Aryl may be substituted or unsubstituted, and when it is substituted, it may be substituted at any accessible point of attachment, and the substituent is preferably selected from the group consisting of one or more of a D atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, oxo, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl.

The term “heteroaryl” refers to a monocyclic heteroaromatic ring (i.e., monocyclic heteroaryl) or polycyclic heteroaromatic ring system (i.e., polycyclic heteroaryl) having a conjugated a-electron system, which contains in the ring(s) at least one (e.g., 1, 2, 3, or 4) heteroatom selected from the group consisting of nitrogen, oxygen, and sulfur (the nitrogen may be optionally oxidized to form a nitrogen oxide; the sulfur may be optionally substituted with oxo to form a sulfoxide or sulfone, excluding —O—O—, —O—S—, or —S—S—) and has 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 group is preferably a heteroaryl group having 5 to 10 ring atoms (i.e., 5- to 10-membered heteroaryl), more preferably a heteroaryl group having 5 or 6 ring atoms (i.e., 5- or 6-membered heteroaryl), and most preferably a heteroaryl group having 6 ring atoms (i.e., 6-membered heteroaryl).

Non-limiting examples of the monocyclic heteroaryl include: furanyl, thienyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, furazanyl, pyrrolyl, N-alkylpyrrolyl, pyridinyl, pyrimidinyl, pyridonyl, N-alkylpyridinone (e.g.,

pyrazinyl, pyridazinyl, and the like.

Non-limiting examples of the polycyclic heteroaryl include: indolyl, indazolyl, quinolyl, isoquinolyl, quinoxalinyl, phthalazinyl, benzimidazolyl, benzothienyl, quinazolinyl, benzothiazolyl, carbazolyl, and the like. The polycyclic heteroaryl also includes those formed by fusing a monocyclic heteroaryl group with one or more aryl groups, wherein the point of attachment is on an aromatic ring, and in the circumstances the number of ring atoms continues to represent the number of ring atoms in the polycyclic heteroaromatic ring system. The polycyclic heteroaryl also includes those formed by fusing a monocyclic heteroaryl group with one or more of a cycloalkyl group or a heterocyclyl group, wherein the point of attachment is on the monocyclic heteroaromatic ring, and in the circumstances the number of ring atoms continues to represent the number of ring atoms in the polycyclic heteroaromatic ring system. Non-limiting examples include:

and the like.

Heteroaryl may be substituted or unsubstituted, and when it is substituted, it may be substituted at any accessible point of attachment, and the substituent is preferably selected from the group consisting of one or more of a D atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl.

The term “amino protecting group” refers to an easily removable group that is introduced onto an amino group in order for the amino group to remain unchanged when other parts of the molecule are involved in reactions. Non-limiting examples include: (trimethylsilyl)ethoxymethyl, tetrahydropyranyl, tert-butyloxycarbonyl (Boc), benzyloxycarbonyl (Cbz), fluorenylmethoxycarbonyl (Fmoc), allyloxycarbonyl (Alloc), trimethylsilylethoxycarbonyl (Teoc), methoxycarbonyl, ethoxycarbonyl, phthaloyl (Pht), p-toluenesulfonyl (Tos), trifluoroacetyl (Tfa), trityl (Trt), 2,4-dimethoxybenzyl (DMB), acetyl, benzyl, allyl, p-methoxybenzyl, and the like.

The term “hydroxy protecting group” refers to an easily removable group that is introduced onto a hydroxy group to block or protect the hydroxy group so that reactions take place on other functional groups of the compound. Non-limiting examples include: trimethylsilyl (TMS), triethylsilyl (TES), triisopropylsilyl (TIPS), tert-butyldimethylsilyl (TBS), tert-butyldiphenylsilyl (TBDPS), methyl, tert-butyl, allyl, benzyl, methoxymethyl (MOM), ethoxyethyl, 2-tetrahydropyranyl (THP), formyl, acetyl, benzoyl, p-nitrobenzoyl, and the like.

The term “spirocyclyl” refers to a spirocycloalkyl or spiroheterocyclyl group, wherein the spirocycloalkyl or spiroheterocyclyl group is as defined above.

The term “cycloalkylalkyl” refers to an alkyl group substituted with one or more cycloalkyl groups, wherein the cycloalkyl and alkyl groups are as defined above.

The term “heterocyclylalkyl” refers to an alkyl group substituted with one or more heterocyclyl groups, wherein the heterocyclyl and alkyl groups are as defined above.

The term “aminoalkyl” refers to an alkyl group substituted with one or more amino groups, wherein the alkyl group is as defined above.

The term “alkoxyalkyl” refers to an alkyl group substituted with one or more alkoxy groups, wherein the alkoxy and alkyl groups are as defined above.

The term “haloalkyl” refers to an alkyl group substituted with one or more halogens, wherein the alkyl group is as defined above.

The term “haloalkoxy” refers to an alkoxy group substituted with one or more halogens, wherein the alkoxy group is as defined above.

The term “deuterated alkyl” refers to an alkyl group substituted with one or more deuterium atoms, wherein the alkyl group is as defined above.

The term “hydroxyalkyl” refers to an alkyl group substituted with one or more hydroxy groups, wherein the alkyl group is as defined above.

The term “halogen” refers to fluorine, chlorine, bromine, or iodine.

The term “hydroxy” refers to —OH.

The term “sulfhydryl” refers to —SH.

The term “amino” refers to —NH₂.

The term “cyano” refers to —CN.

The term “nitro” refers to —NO₂.

The term “oxo” refers to “═O”.

The term “carbonyl” refers to C═O.

The term “carboxyl” refers to —C(O)OH.

The term “carboxylate group” refers to —C(O)O(alkyl), —C(O)O(cycloalkyl), (alkyl)C(O)O—, or (cycloalkyl)C(O)O—, wherein the alkyl and cycloalkyl are as defined above.

In the present disclosure, when m1 is 0, X² is a bond.

In the present disclosure, when m2 is 0, J¹ is a bond.

In the present disclosure, when m3 is 0, J³ is a bond.

In the present disclosure, when m4 is 0, J is a bond.

The term “ubiquitin ligase” refers to a family of proteins that facilitate the transfer of ubiquitin to a specific substrate protein, targeting the substrate protein for degradation. For example, cereblon is an E3 ubiquitin ligase protein that alone or in combination with an E2 ubiquitin conjugating enzyme causes the attachment of ubiquitin to a lysine on a target protein and subsequently targets the specific protein substrate for degradation by the proteasome. Thus, E3 ubiquitin ligase alone or in complex with an E2 ubiquitin conjugating enzyme is responsible for the transfer of ubiquitin to target proteins. In general, the ubiquitin ligase is involved in polyubiquitination such that a second ubiquitin is attached to the first ubiquitin, a third ubiquitin is attached to the second ubiquitin, and so forth. Polyubiquitination marks proteins for degradation by the proteasome. However, there are some ubiquitination events that are limited to mono-ubiquitination, in which only a single ubiquitin is added by the ubiquitin ligase to a substrate molecule. Mono-ubiquitinated proteins are not targeted to the proteasome for degradation, but may instead be altered in their cellular location or function, for example, via binding other proteins that have domains capable of binding ubiquitin. To complicate matters further, different lysines on ubiquitin can be targeted by E3 to prepare chains. The most common lysine is Lys48 on the ubiquitin chain. This is the lysine used to prepare polyubiquitin, which is recognized by the proteasome.

The term “target proteins” refers to proteins and peptides having any biological function or activity (including structural, regulatory, hormonal, enzymatic, genetic, immunological, contractile, storage, transportation, and signal transduction). In some embodiments, target proteins include structural proteins, receptors, enzymes, cell surface proteins, and proteins associated with the integrated function of a cell, including proteins involved in: catalytic activity, aromatase activity, motor activity, helicase activity, metabolic processes (anabolism and catabolism), antioxidant activity, proteolysis, biosynthesis, proteins with kinase activity, oxidoreductase activity, transferase activity, hydrolase activity, lyase activity, isomerase activity, ligase activity, enzyme regulator activity, signal transducer activity, structural molecule activity, binding activity (protein and lipid carbohydrate), receptor activity, cell motility, membrane fusion, cell communication, regulation of biological processes, development, cell differentiation, response to stimulus, behavioral proteins, cell adhesion proteins, proteins involved in cell death, proteins involved in transport (including protein transporter activity, nuclear transport, ion transporter activity, channel transporter activity, and carrier activity), permease activity, secretion activity, electron transporter activity, pathogenesis, chaperone regulator activity, nucleic acid binding activity, transcription regulator activity, extracellular organization and biogenesis activity, and translation regulator activity. The proteins include proteins derived from eukaryotes and prokaryotes, including microbes, viruses, fungi and parasites, among numerous others; including humans, microbes, viruses, fungi, and parasites as targets for drug therapy, other animals including domestic animals), microbes for determining targets for antibiotics and other antimicrobials and plants and even viruses, among numerous others.

The compounds of the present disclosure may exist in specific stereoisomeric forms. The term “stereoisomer” refers to isomers that are structurally identical but differ in the arrangement of the atoms in space. It includes cis and trans (or Z and E) isomers, (−)- and (+)-isomers, (R)- and (S)-enantiomers, diastereomers, (D)- and (L)-isomers, tautomers, atropisomers, conformers, and mixtures thereof (e.g., mixtures of racemates and diastereomers). Additional asymmetric atoms may be present in the substituents in the compounds of the present disclosure. All such stereoisomers and mixtures thereof are included within the scope of the present 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. One isomer of a certain compound of the present disclosure may be prepared by asymmetric synthesis or with a chiral auxiliary, or, when the molecule contains a basic functional group (e.g., amino) or an acidic functional group (e.g., carboxyl), a diastereomeric salt is formed with an appropriate optically active acid or base, followed by diastereomeric resolution by conventional methods known in the art to give the pure isomer. In addition, separation of enantiomers and diastereomers is generally accomplished by chromatography.

In the chemical structures of the compounds of the present disclosure, a bond “” represents an unspecified configuration; that is, if chiral isomers exist in the chemical structures, the bond “” may be “” or “”, or both the configurations of “” and “” are included simultaneously. For all carbon-carbon double bonds, both Z- and E-forms are included, even if only one configuration is named.

The compounds of the present disclosure may also exist in different tautomeric forms, and all such forms are included within the scope of the present disclosure. The term “tautomer” or “tautomeric form” refers to a structural isomer that exists in equilibrium and is readily converted from one isomeric form into another. It includes all possible tautomers; that is, it is present in the form of a single isomer or in the form of a mixture of the tautomers in any ratio. Non-limiting examples include: keto-enol, imine-enamine, lactam-lactim, and the like. An example of lactam-lactim in equilibrium is shown below:

For example, reference to pyrazolyl is understood to include any one of the following two structures or a mixture of the two tautomers:

All tautomeric forms fall within the scope of the present disclosure, and the nomenclature of the compounds does not exclude any tautomer.

The compound of the present disclosure may include atropisomers. The term “atropisomers” refers to conformational stereoisomers that result from hindered or greatly slowed rotation about a single bond in a molecule (as a result of the steric interactions with other parts of the molecule and the asymmetry of the substituents at both ends of the single bond), which interconvert sufficiently slowly to allow separation and isolation under predetermined conditions. For example, certain compounds of the present disclosure may exist in the form of a mixture of atropisomers (e.g., an equal ratio mixture, a mixture enriched in one atropisomer) or a purified atropisomer.

The compounds of the present disclosure include all suitable isotopic derivatives of the compounds thereof. The term “isotopic derivative” refers to a compound in which at least one atom is replaced with an atom having the same atomic number but a different atomic mass. Examples of isotopes that can be incorporated into the compounds of the present disclosure include stable and radioactive isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, bromine, iodine, etc., such as ²H (deuterium, D), ³H (tritium, T), ¹¹C, ¹³C, ¹⁴C, ¹⁵N, ¹⁷O, ¹⁸O, ³²P, ³³P, ³³S, ³⁴S, ³⁵S, ³⁶S, ¹⁸F, ³⁶Cl, ⁸² Br, ¹²³I, ¹²⁴I, ¹²⁵, ¹²⁹I, and ¹³¹I respectively; deuterium is preferred.

Compared to non-deuterated drugs, deuterated drugs have the advantages of reduced toxic and side effects, increased drug stability, enhanced efficacy, prolonged biological half-lives, and the like. All isotopic variations of the compounds of the present disclosure, whether radioactive or not, are intended to be included within the scope of the present disclosure. Each available hydrogen atom connected to a carbon atom may be independently replaced with a deuterium atom, wherein replacement of deuterium may be partial or complete, and replacement of partial deuterium refers to replacement of at least one hydrogen atom with at least one deuterium atom.

When a position is specifically assigned deuterium (D), the position should be understood as deuterium with an abundance that is at least 1000 times greater than the natural abundance of deuterium (which is 0.015%) (i.e., at least 15% deuterium incorporation). The deuterium of the compounds in the examples with an abundance greater than the natural abundance of deuterium may be deuterium with an abundance that is at least 1000 times greater (i.e., at least 15% deuterium incorporation), at least 2000 times greater (i.e., at least 30% deuterium incorporation), at least 3000 times greater (i.e., at least 45% deuterium incorporation), at least 3340 times greater (i.e., at least 50.1% deuterium incorporation), at least 3500 times greater (i.e., at least 52.5% deuterium incorporation), at least 4000 times greater (i.e., at least 60% deuterium incorporation), at least 4500 times greater (i.e., at least 67.5% deuterium incorporation), at least 5000 times greater (i.e., at least 75% deuterium incorporation), at least 5500 times greater (i.e., at least 82.5% deuterium incorporation), at least 6000 times greater (i.e., at least 90% deuterium incorporation), at least 6333.3 times greater (i.e., at least 95% deuterium incorporation), at least 6466.7 times greater (i.e., at least 97% deuterium incorporation), at least 6600 times greater (i.e., at least 99% deuterium incorporation), or at least 6633.3 times greater (i.e., at least 99.5% deuterium incorporation), or deuterium with a higher abundance. “Optional” or “optionally” means that the event or circumstance subsequently described may, but does not necessarily, occur and includes an instance where the event or circumstance occurs and an instance where it does not. For example, “C_1-6 alkyl that is optionally substituted with halogen or cyano” includes an instance where the alkyl is substituted with halogen or cyano and an instance where the alkyl is not substituted with halogen or cyano. “Substitution” or “substituted” means that one or more, preferably 1 to 6, and more preferably 1 to 3, hydrogen atoms in the group are independently substituted with a corresponding number of substituents. Those skilled in the art can determine (experimentally or theoretically) possible or impossible substitutions without undue effort. For example, it may be unstable when an amino or hydroxy group having free hydrogen binds to a carbon atom having an unsaturated bond (e.g., an olefin).

“Pharmaceutical composition” refers to a mixture containing one or more of the compounds or the pharmaceutically acceptable salts thereof described herein, and other chemical components, and other components, for example, pharmaceutically acceptable carriers and excipients. The pharmaceutical composition is intended to promote the administration to an organism, so as to facilitate the absorption of the active ingredient, thereby exerting biological activity.

“Pharmaceutically acceptable salt” refers to a salt of the compound of the present disclosure, which may be selected from the group consisting of inorganic or organic salts. Such salts are safe and effective when used in the body of a mammal and possess the requisite biological activity. The salts may be prepared separately during the final separation and purification of the compound, or by reacting an appropriate group with an appropriate 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 inorganic acids and organic acids.

For drugs or pharmacologically active agents, the term “therapeutically effective amount” refers to an amount of the drug or agent sufficient to achieve, or at least partially achieve, the desired effect. The determination of the therapeutically effective amount varies from person to person. It depends on the age and general condition of a subject, as well as the specific active substance used. The appropriate therapeutically effective amount in a case may be determined by those skilled in the art in the light of routine tests.

The term “pharmaceutically acceptable” as used herein means that those compounds, materials, compositions, and/or dosage forms that are, within the scope of reasonable medical judgment, suitable for use in contact with the tissues of patients without excessive toxicity, irritation, allergic reaction, or other problems or complications, and are commensurate with a reasonable benefit/risk ratio and effective for the intended use.

As used herein, the singular forms “a”, “an” and “the” include plural references and vice versa, unless otherwise clearly defined in the context.

When the term “about” is applied to parameters such as pH, concentration, and temperature, it means that the parameter may vary by ±10%, and sometimes more preferably within ±5%. As will be understood by those skilled in the art, when the parameters are not critical, the numbers are generally given for illustrative purposes only and are not intended to be limiting.

Synthetic Methods of the Compounds of the Present Disclosure

To achieve the purposes of the present disclosure, the following technical solutions are adopted in the present disclosure:

Scheme 1

A method for preparing the compound represented by general formula (III′) or the pharmaceutically acceptable salt thereof of the present disclosure, comprising the following step:

conducting a condensation reaction of a compound represented by general formula (III′A) or a salt thereof with a compound represented by general formula (III′B) or a salt thereof (preferably hydrochloride and trifluoroacetate) under alkaline conditions in the presence of a condensing agent to give the compound represented by general formula (III′) or the pharmaceutically acceptable salt thereof;

• • wherein:
  • J¹ is —C(O)—;
  • Z³ is N;
  • A, R^1a, R^3a, J⁵, X², W¹, W², W³, W⁴, Z¹, Z², Z⁴, Z⁵, Z⁶, x, x1, y, y1, and m3 are as defined in general formula (III′).

Scheme 2

A method for preparing the compound represented by general formula (III′) or the pharmaceutically acceptable salt thereof of the present disclosure, comprising the following step:

conducting a reductive amination reaction of a compound represented by general formula (III′C) or a salt thereof with a compound represented by general formula (III′E) or a salt thereof (preferably hydrochloride and trifluoroacetate) under weakly acidic conditions in the presence of a reductant to give the compound represented by general formula (III′) or the pharmaceutically acceptable salt thereof, where m3 is 1, 2, or 3;

• • or, conducting a reductive amination reaction of a compound represented by general formula (III′D) or a salt thereof with a compound represented by general formula (III′E) or a salt thereof (preferably hydrochloride and trifluoroacetate) under weakly acidic conditions in the presence of a reductant to give the compound represented by general formula (III′) or the pharmaceutically acceptable salt thereof, where m3 is 0;
  • wherein:
  • m6 is 0, 1, or 2;
  • Z⁴ is CH;
  • Z⁵ is N;
  • A, J¹, J⁵, X², R^1a, R^3a, W¹, W², W³, W⁴, Z¹, Z², Z³, Z⁶, x, x1, y, and y1 are as defined in general formula (III′).

Scheme 3

A method for preparing the compound represented by general formula (III′) or the pharmaceutically acceptable salt thereof of the present disclosure, comprising the following step:

conducting a reductive amination reaction of a compound represented by general formula (III′F) or a salt thereof (preferably hydrochloride and trifluoroacetate) with a compound represented by general formula (III′G) or a salt thereof under weakly acidic conditions in the presence of a reductant to give the compound represented by general formula (III′) or the pharmaceutically acceptable salt thereof, where m3 is 0;

• • or, conducting a reductive amination reaction of a compound represented by general formula (III′F) or a salt thereof (preferably hydrochloride and trifluoroacetate) with a compound represented by general formula (III′H) or a salt thereof under weakly acidic conditions in the presence of a reductant to give the compound represented by general formula (III′) or the pharmaceutically acceptable salt thereof, where m3 is 1, 2, or 3;
  • wherein:
  • m6 is 0, 1, or 2;
  • Z⁴ is N;
  • Z⁵ is CH;
  • A, J¹, J⁵, X², R^1a, R^3a, W¹, W², W³, W⁴, Z¹, Z², Z³, Z⁶, x, x1, y, and y1 are as defined in general formula (III′).

Scheme 4

A method for preparing the compound represented by general formula (X) or the pharmaceutically acceptable salt thereof of the present disclosure, comprising the following step:

conducting a condensation reaction of a compound represented by general formula (IVA) or a salt thereof with a compound represented by general formula (XB) or a salt thereof (preferably hydrochloride and trifluoroacetate) under alkaline conditions in the presence of a condensing agent to give the compound represented by general formula (X) or the pharmaceutically acceptable salt thereof;

• • wherein:
  • R^1a, R^3a, W¹, W², W³, W⁴, Z¹, Z², Z⁴, Z⁵, Z⁶, h, i, u, v, x1, y1, m3, and A are as defined in general formula (X).

Scheme 5

A method for preparing the compound represented by general formula (X-1) or the pharmaceutically acceptable salt thereof of the present disclosure, comprising the following step:

conducting a condensation reaction of a compound represented by general formula (IV-1A) or a salt thereof with a compound represented by general formula (XB) or a salt thereof (preferably hydrochloride and trifluoroacetate) under alkaline conditions in the presence of a condensing agent to give the compound represented by general formula (X-1) or the pharmaceutically acceptable salt thereof;

• • wherein:
  • R^1a, R^3a, W¹, W², W³, W⁴, Z¹, Z², Z⁴, Z⁵, Z⁶, h, i, u, v, x1, y1, m3, and A are as defined in general formula (X-1).

Scheme 6

A method for preparing the compound represented by general formula (X) or the pharmaceutically acceptable salt thereof of the present disclosure, comprising the following step:

conducting a reductive amination reaction of a compound represented by general formula (XC) or a salt thereof with a compound represented by general formula (XF) or a salt thereof (preferably hydrochloride and trifluoroacetate) under weakly acidic conditions in the presence of a reductant to give the compound represented by general formula (X) or the pharmaceutically acceptable salt thereof, where m3 is 0;

• • or, conducting a reductive amination reaction of a compound represented by general formula (XD) or a salt thereof with a compound represented by general formula (XF) or a salt thereof (preferably hydrochloride and trifluoroacetate) under weakly acidic conditions in the presence of a reductant to give the compound represented by general formula (X) or the pharmaceutically acceptable salt thereof, where m3 is 1, 2, or 3;
  • wherein:
  • m6 is 0, 1, or 2;
  • Z⁴ is CH;
  • Z⁵ is N;
  • R^1a, R^3a, W¹, W², W³, W⁴, Z¹, Z², Z⁶, h, i, u, v, x1, y1, and A are as defined in general formula (X).

Scheme 7

A method for preparing the compound represented by general formula (X-1) or the pharmaceutically acceptable salt thereof of the present disclosure, comprising the

conducting a reductive amination reaction of a compound represented by general formula (X-1C) or a salt thereof with a compound represented by general formula (XF) or a salt thereof (preferably hydrochloride and trifluoroacetate) under weakly acidic conditions in the presence of a reductant to give the compound represented by general formula (X-1) or the pharmaceutically acceptable salt thereof, where m3 is 0;

• • or, conducting a reductive amination reaction of a compound represented by general formula (X-1D) or a salt thereof with a compound represented by general formula (XF) or a salt thereof (preferably hydrochloride and trifluoroacetate) under weakly acidic conditions in the presence of a reductant to give the compound represented by general formula (X-1) or the pharmaceutically acceptable salt thereof, where m3 is 1, 2, or 3;
  • wherein:
  • m6 is 0, 1, or 2;
  • Z⁴ is CH;
  • Z⁵ is N;
  • R^1a, R^3a, W¹, W², W³, W⁴, Z¹, Z², Z⁶, h, i, u, v, x1, y1, and A are as defined in general formula (X-1).

Scheme 8

A method for preparing the compound represented by general formula (IV′) or the pharmaceutically acceptable salt thereof of the present disclosure, comprising the following step:

conducting a condensation reaction of a compound represented by general formula (IVA) or a salt thereof with a compound represented by general formula (IVB′) or a salt thereof (preferably hydrochloride and trifluoroacetate) under alkaline conditions in the presence of a condensing agent to give the compound represented by general formula (IV′) or the pharmaceutically acceptable salt thereof;

• • wherein:
  • R^1a, Q¹, Q², Q³, Q⁴, Q⁵, R^3a, W¹, W², W³, W⁴, Z¹, Z², Z⁴, Z⁵, Z⁶, x, x1, y, y l, and m3 are as defined in general formula (IV′).

Scheme 9

A method for preparing the compound represented by general formula (IV′-1) or the pharmaceutically acceptable salt thereof of the present disclosure, comprising the following step:

conducting a condensation reaction of a compound represented by general formula (IV-1A) or a salt thereof with a compound represented by general formula (IVB′) or a salt thereof (preferably hydrochloride and trifluoroacetate) under alkaline conditions in the presence of a condensing agent to give the compound represented by general formula (IV′-1) or the pharmaceutically acceptable salt thereof;

• • wherein:
  • R^1a, Q¹, Q², Q³, Q⁴, Q⁵, R^3a, W¹, W², W³, W⁴, Z¹, Z², Z⁴, Z⁵, Z⁶, x, x1, y, y1, and m3 are as defined in general formula (IV′-1).

Scheme 10

A method for preparing the compounds represented by general formula (IV′-1-1) and general formula (IV′-1-2) or the pharmaceutically acceptable salts thereof of the present disclosure, comprising the following step:

chirally resolving a compound represented by general formula (IV′-1) or a pharmaceutically acceptable salt thereof to give the compounds represented by general formula (IV′-1-1) and general formula (IV′-1-2) or the pharmaceutically acceptable salts thereof;

• • wherein:
  • R^1a, Q¹, Q², Q³, Q⁴, Q⁵, R^3a, W¹, W², W³, W⁴, Z¹, Z², Z⁴, Z⁵, Z⁶, x, x1, y, y1, and m3 are as defined in general formula (IV′-1).

Scheme 11

A method for preparing the compound represented by general formula (M) or the pharmaceutically acceptable salt thereof of the present disclosure, comprising the following step:

conducting a condensation reaction of a compound represented by general formula (IVA) or a salt thereof with a compound represented by general formula (MB) or a salt thereof (preferably hydrochloride and trifluoroacetate) under alkaline conditions in the presence of a condensing agent to give the compound represented by general formula (M) or the pharmaceutically acceptable salt thereof;

• • wherein:
  • R^1a, Q¹, Q², Q⁴, Q⁵, R^3a, W¹, W², W³, W⁴, Z¹, Z², Z⁴, Z⁵, Z⁶, x, x1, y, y1, and m3 are as defined in general formula (M).

Scheme 12

A method for preparing the compound represented by general formula (M-1) or the pharmaceutically acceptable salt thereof of the present disclosure, comprising the following step:

conducting a condensation reaction of a compound represented by general formula (IV-1A) or a salt thereof with a compound represented by general formula (MB) or a salt thereof (preferably hydrochloride and trifluoroacetate) under alkaline conditions in the presence of a condensing agent to give the compound represented by general formula (M-1) or the pharmaceutically acceptable salt thereof,

• • wherein:
  • R^1a, Q¹, Q², Q⁴, Q⁵, R^3a, W¹, W², W³, W⁴, Z¹, Z², Z⁴, Z⁵, Z⁶, x, x1, y, y1, and m3 are as defined in general formula (M-1).

Scheme 13

A method for preparing the compounds represented by general formula (M-1-1) and general formula (M-1-2) or the pharmaceutically acceptable salts thereof of the present disclosure, comprising the following step:

chirally resolving a compound represented by general formula (M-1) or a pharmaceutically acceptable salt thereof to give the compounds represented by general formula (M-1-1) and general formula (M-1-2) or the pharmaceutically acceptable salts thereof;

• • wherein:
  • R^1a, Q¹, Q², Q⁴, Q⁵, R^3a, W¹, W², W³, W⁴, Z¹, Z², Z⁴, Z⁵, Z⁶, x, x1, y, y1, and m3 are as defined in general formula (M-1).

Scheme 14

A method for preparing the compound represented by general formula (IV) or the pharmaceutically acceptable salt thereof of the present disclosure, comprising the following step:

conducting a condensation reaction of a compound represented by general formula (IVA) or a salt thereof with a compound represented by general formula (IVB) or a salt thereof (preferably hydrochloride and trifluoroacetate) under alkaline conditions in the presence of a condensing agent to give the compound of general formula (IV) or the pharmaceutically acceptable salt thereof;

• • wherein:
  • R^1a, Q¹, Q³, Q⁴, Q⁵, R^3a, W¹, W², W³, W⁴, Z¹, Z², Z⁴, Z⁵, Z⁶, x, x1, y, y1, and m3 are as defined in general formula (IV).

Scheme 15

A method for preparing the compound represented by general formula (IV-1) or the pharmaceutically acceptable salt thereof of the present disclosure, comprising the following step:

conducting a condensation reaction of a compound represented by general formula (IV-1A) or a salt thereof with a compound represented by general formula (IVB) or a salt thereof (preferably hydrochloride and trifluoroacetate) under alkaline conditions in the presence of a condensing agent to give the compound represented by general formula (IV-1) or the pharmaceutically acceptable salt thereof;

• • wherein:
  • R^1a, Q¹, Q³, Q⁴, Q⁵, R^3a, W¹, W², W³, W⁴, Z¹, Z², Z⁴, Z⁵, Z⁶, x, x1, y, y1, and m3 are as defined in general formula (IV-1).

Scheme 16

A method for preparing the compounds represented by general formula (IV-1-1) and general formula (IV-1-2) or the pharmaceutically acceptable salts thereof of the present disclosure, comprising the following step:

chirally resolving a compound represented by general formula (IV-1) or a pharmaceutically acceptable salt thereof to give the compounds represented by general formula (IV-1-1) and general formula (IV-1-2) or the pharmaceutically acceptable salts thereof;

• • wherein:
  • R^1a, Q¹, Q³, Q⁴, Q⁵, R^3a, W¹, W², W³, W⁴, Z¹, Z², Z⁴, Z⁵, Z⁶, x, x1, y, y1, and m3 are as defined in general formula (IV-1).

Scheme 17

A method for preparing the compound represented by general formula (V) or the pharmaceutically acceptable salt thereof of the present disclosure, comprising the following step:

conducting a reductive amination reaction of a compound represented by general formula (VA) or a salt thereof (preferably hydrochloride and trifluoroacetate) with a compound represented by general formula (VB) or a salt thereof under weakly acidic conditions in the presence of a reductant to give the compound represented by general formula (V) or the pharmaceutically acceptable salt thereof, where m3 is 0;

• • or, conducting a reductive amination reaction of a compound represented by general formula (VA) or a salt thereof (preferably hydrochloride and trifluoroacetate) with a compound represented by general formula (VB′) or a salt thereof under weakly acidic conditions in the presence of a reductant to give the compound represented by general formula (V) or the pharmaceutically acceptable salt thereof, where m3 is 1, 2, or 3;
  • wherein:
  • m6 is 0, 1, or 2;
  • J¹, R^1a, Q¹, Q³, Q⁴, Q⁵, R^3a, W¹, W², W³, W⁴, Z¹, Z², Z³, Z⁶, x, x1, y, and y1 are as defined in general formula (V).

Scheme 18

A method for preparing the compound represented by general formula (V-1) or the pharmaceutically acceptable salt thereof of the present disclosure, comprising the following step:

conducting a reductive amination reaction of a compound represented by general formula (V-1A) or a salt thereof (preferably hydrochloride and trifluoroacetate) with a compound represented by general formula (VB) or a salt thereof under weakly acidic conditions in the presence of a reductant to give the compound represented by general formula (V-1) or the pharmaceutically acceptable salt thereof, where m3 is 0;

• • or, conducting a reductive amination reaction of a compound represented by general formula (V-1A) or a salt thereof (preferably hydrochloride and trifluoroacetate) with a compound represented by general formula (VB′) or a salt thereof under weakly acidic conditions in the presence of a reductant to give the compound represented by general formula (V-1) or the pharmaceutically acceptable salt thereof, where m3 is 1, 2, or 3;
  • wherein:
  • m6 is 0, 1, or 2;
  • J¹, R^1a, Q¹, Q³, Q⁴, Q⁵, R^3a, W¹, W², W³, W⁴, Z¹, Z², Z³, Z⁶, x, x1, y, and y1 are as defined in general formula (V-1).

Scheme 19

A method for preparing the compounds represented by general formula (V-1-1) and general formula (V-1-2) or the pharmaceutically acceptable salts thereof of the present disclosure, comprising the following step:

chirally resolving a compound represented by general formula (V-1) or a pharmaceutically acceptable salt thereof to give the compounds represented by general formula (V-1-1) and general formula (V-1-2) or the pharmaceutically acceptable salts thereof;

• • wherein:
  • J¹, R^1a, Q¹, Q³, Q⁴, Q⁵, R^3a, W¹, W², W³, W⁴, Z¹, Z², Z³, Z⁶, x, x1, y, y1, and m3 are as defined in general formula (V-1).

Scheme 20

A method for preparing the compound represented by general formula (VI) or the pharmaceutically acceptable salt thereof of the present disclosure, comprising the following step:

conducting a condensation reaction of a compound represented by general formula (VIA) or a salt thereof with a compound represented by general formula (VIB) or a salt thereof (preferably hydrochloride and trifluoroacetate) under alkaline conditions in the presence of a condensing agent to give the compound represented by general formula (VI) or the pharmaceutically acceptable salt thereof;

• • wherein:
  • R^1a, R^3d, R^3e, R^3f, W⁴, Z⁴, Z⁵, x, x1, y, y1, m3, and Q⁴ are as defined in general formula (VI).

Scheme 21

A method for preparing the compound represented by general formula (VI-1) or the pharmaceutically acceptable salt thereof of the present disclosure, comprising the following step:

conducting a condensation reaction of a compound represented by general formula (VI-1A) or a salt thereof with a compound represented by general formula (VIB) or a salt thereof (preferably hydrochloride and trifluoroacetate) under alkaline conditions in the presence of a condensing agent to give the compound represented by general formula (VI-1) or the pharmaceutically acceptable salt thereof;

• • wherein:
  • R^1a, R^3d, R^3e, R^3f, W⁴, Z⁴, Z⁵, x, x1, y, y1, m3, and Q⁴ are as defined in general formula (VI-1).

Scheme 22

A method for preparing the compounds represented by general formula (VI-1-1) and general formula (VI-1-2) or the pharmaceutically acceptable salts thereof of the present disclosure, comprising the following step:

chirally resolving a compound represented by general formula (VI-1) or a pharmaceutically acceptable salt thereof to give the compounds represented by general formula (VI-1-1) and general formula (VI-1-2) or the pharmaceutically acceptable salts thereof;

• • wherein:
  • R^1a, R^3d, R^3e, R^3f, W⁴, Z⁴, Z⁵, x, x1, y, y1, m3, and Q⁴ are as defined in general formula (VI-1).

Scheme 23

A method for preparing the compound represented by general formula (VII) and or the pharmaceutically acceptable salt thereof of the present disclosure, comprising the following step:

conducting a reductive amination reaction of a compound represented by general formula (VIIA) or a salt thereof (preferably hydrochloride and trifluoroacetate) with a compound represented by general formula (VIIB) or a salt thereof under weakly acidic conditions in the presence of a reductant to give the compound represented by general formula (VII) or the pharmaceutically acceptable salt thereof, where m3 is 0;

• • or, conducting a reductive amination reaction of a compound represented by general formula (VIIA) or a salt thereof (preferably hydrochloride and trifluoroacetate) with a compound represented by general formula (VIIB′) or a salt thereof under weakly acidic conditions in the presence of a reductant to give the compound represented by general formula (VII) or the pharmaceutically acceptable salt thereof, where m3 is 1, 2, or 3;
  • wherein:
  • m6 is 0, 1, or 2;
  • R^1a, Q⁴, R^3d, R^3e, R^3f, W⁴, x, x1, y, and y1 are as defined in general formula (VII).

Scheme 24

A method for preparing the compound represented by general formula (VII-1) or the pharmaceutically acceptable salt thereof of the present disclosure, comprising the following step:

conducting a reductive amination reaction of a compound represented by general formula (VII-1A) or a salt thereof (preferably hydrochloride and trifluoroacetate) with a compound represented by general formula (VIIB) or a salt thereof under weakly acidic conditions in the presence of a reductant to give the compound represented by general formula (VII-1) or the pharmaceutically acceptable salt thereof, where m3 is 0;

• • or, conducting a reductive amination reaction of a compound represented by general formula (VII-1A) or a salt thereof (preferably hydrochloride and trifluoroacetate) with a compound represented by general formula (VIIB′) or a salt thereof under weakly acidic conditions in the presence of a reductant to give the compound represented by general formula (VII-1) or the pharmaceutically acceptable salt thereof, where m3 is 1, 2, or 3;
  • wherein:
  • m6 is 0, 1, or 2;
  • R^1a, Q⁴, R^3d, R^3e, R^3f, W⁴, x, x1, y, and y1 are as defined in general formula (VII-1).

Scheme 25

A method for preparing the compounds represented by general formula (VII-1-1) and general formula (VII-1-2) or the pharmaceutically acceptable salts thereof of the present disclosure, comprising the following step:

chirally resolving a compound represented by general formula (VII-1) or a pharmaceutically acceptable salt thereof to give the compounds represented by general formula (VII-1-1) and general formula (VII-1-2) or the pharmaceutically acceptable salts thereof;

• • wherein:
  • R^1a, Q⁴, R^3d, R^3e, R^3f, W⁴, m3, x, x1, y, and y1 are as defined in general formula (VII-1).

In the above synthesis schemes, the condensing agents include, but are not limited to, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, N,N′-dicyclohexylcarbodiimide, N,N′-diisopropylcarbodiimide, O-benzotriazol-N,N,N′,N′-tetramethyluronium tetrafluoroborate, 1-hydroxybenzotriazole, 1-hydroxy-7-azabenzotriazole, O-benzotriazol-N,N,N′,N′-tetramethyluronium hexafluorophosphate, O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU), 2-(7-oxybenzotriazoleoxide)-N,N,N′,N′-tetramethyluronium hexafluorophosphate, benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate, or benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate; preferably, the condensing agent is O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU).

In the above synthesis schemes, reagents that provide the alkaline conditions include organic bases and inorganic bases; the organic bases include, but are not limited to, triethylamine, N,N-diisopropylethylamine, n-butyllithium, lithium diisopropylamide, potassium acetate, sodium acetate, sodium ethoxide, sodium tert-butoxide, or potassium tert-butoxide; the inorganic bases include, but are not limited to, sodium hydride, potassium phosphate, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, lithium hydroxide monohydrate, lithium hydroxide, and potassium hydroxide; preferably, the reagent that provides the alkaline conditions is N,N-diisopropylethylamine.

In the above synthesis schemes, reagents that provide the weakly acidic conditions include, but are not limited to, acetic acid, Ti(i-PrO)₃, and BF₃·Et₂O; preferably, the agent that provides the weakly acidic conditions is acetic acid; or the weakly acidic conditions are provided by acids produced in the reaction, including, but not limited to, acetic acid.

In the above synthesis schemes, the reductants include, but are not limited to, sodium triacetoxyborohydride, sodium borohydride, lithium borohydride, sodium cyanoborohydride, sodium acetylborohydride, and the like; sodium cyanoborohydride and sodium triacetoxyborohydride are preferred.

The above synthesis schemes are preferably carried out in solvents, 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-dimethylacetamide, N,N-dimethylformamide, and mixtures thereof.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows the efficacy of Example 15-1 and 11-2 or 11-1 (longer retention time) compounds against LNCap-FGC xenograft tumors in castrated CB17-SCID mice.

FIG. 2 shows the effects of Example 15-1 and 11-2 or 11-1 (longer retention time) compounds on the body weight of CB17-SCID mice.

DETAILED DESCRIPTION

The present disclosure is further described below with reference to examples, but these examples are not intended to limit the scope of the present disclosure.

EXAMPLES

The structures of the compounds were determined by nuclear magnetic resonance (NMR) spectroscopy or/and mass spectrometry (MS). NMR shifts (δ) are given in a unit of 10⁻⁶ (ppm). The NMR analyses were performed on a Bruker AVANCE-400 nuclear magnetic resonance instrument or Bruker AVANCE NEO 500M, with dimethyl sulfoxide-D6 (DMSO-d₆), chloroform-D (CDCl₃), and methanol-D4 (CD₃OD) as solvents and tetramethylsilane (TMS) as an internal standard.

The MS analyses were performed on an Agilent 1200/1290 DAD-6110/6120 Quadrupole MS liquid chromatography-mass spectrometry system (manufacturer: Agilent; MS model: 6110/6120 Quadrupole MS),

• • waters ACQuity UPLC-QD/SQD (manufacturer: waters; MS model: waters ACQuity Qda Detector/waters SQ Detector), and
  • THERMO Ultimate 3000-Q Exactive (manufacturer: THERMO; MS model: THERMO Q Exactive).

The high performance liquid chromatography (HPLC) analyses were performed on Agilent HPLC 1200DAD, Agilent HPLC 1200VWD, and Waters HPLC e2695-2489 high performance liquid chromatographs.

The chiral HPLC analyses were performed on an Agilent 1260 DAD high performance liquid chromatograph.

The preparative high performance liquid chromatography steps were performed on Waters 2545-2767, Waters 2767-SQ Detecor2, Shimadzu LC-20AP, and Gilson GX-281 preparative chromatographs.

The preparative chiral chromatography steps were performed on a Shimadzu LC-20AP preparative chromatograph.

The CombiFlash preparative flash chromatograph used was Combiflash Rf200 (TELEDYNE ISCO).

The thin-layer chromatography silica gel plates used were Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plates. The silica gel plates used in the thin-layer chromatography (TLC) analyses had a layer thickness of 0.15 mm-0.2 mm, and those used in the thin-layer chromatography separation and purification had a layer thickness of 0.4 mm-0.5 mm.

In the silica gel column chromatography steps, a 200-300 mesh silica gel (Huanghai, Yantai) was generally used as the carrier.

The kinase mean inhibition rates and IC₅₀ values were measured using a NovoStar microplate reader (BMG, Germany).

The known starting materials in the present disclosure may be synthesized using or by following methods known in the art, or may be purchased from companies such as ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, Accela ChemBio Inc., Chembee Chemicals, and the like.

In the examples, the reactions can all be performed under an argon atmosphere or a nitrogen atmosphere unless otherwise specified.

The argon atmosphere or nitrogen atmosphere means that the reaction flask is connected to a balloon containing about 1 L of argon or nitrogen gas.

The hydrogen atmosphere means that the reaction flask is connected to a balloon containing about 1 L of hydrogen gas.

The pressurized hydrogenation reactions were performed using a Parr 3916EKX hydrogenator and a Qinglan QL-500 hydrogenator, or an HC2-SS hydrogenator.

The hydrogenation reactions generally involved 3 cycles of vacuumization and hydrogen filling.

The microwave reactions were performed using a CEM Discover-S 908860 microwave reactor.

In the examples, the solutions refer to aqueous solutions unless otherwise specified.

In the examples, the reaction temperature was room temperature, i.e., 20° C.-30° C., unless otherwise specified.

The monitoring of the reaction progress in the examples was conducted by thin-layer chromatography (TLC). The developing solvent used in the reactions, the eluent systems used in the column chromatography purification, and the developing solvent systems used in the thin-layer chromatography analyses include: A: a dichloromethane/methanol system, and B: a n-hexane/ethyl acetate system. The volume ratio of the solvents was adjusted according to the polarity of the compound, or by adding a small amount of basic or acidic reagents such as triethylamine and acetic acid.

Example 1

4-(4-(1-(4-((S)-2-(3-Chloro-4-cyanophenyl)-3-methyl-2,8-diazaspiro[4.5]decan-8-yl)benzoyl)piperidin-4-yl)piperazin-1-yl)-N-(2,6-dioxopiperidin-3-yl)-2-fluorobenzamide 1 (a Mixture of Diastereomers

Step 1

tert-Butyl (±)-4-(4-((2,6-dioxopiperidin-3-yl)aminocarbonyl)-3-fluorophenyl)piperazine-1-carboxylate 1c

The compound 4-(4-(tert-butoxycarbonyl)piperazin-1-yl)-2-fluorobenzoic acid 1a (3.0 g, 9.25 mmol, prepared using the well-known method “ChemBioChem, 2014, 15(8), 1111-1120”) was dissolved in N,N-dimethylformamide (25 mL), and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (5.28 g, 13.87 mmol) and N,N-diisopropylethylamine (3.59 g, 27.75 mmol, 4.6 mL) were then added. After 10 minutes of stirring, (±)-3-aminopiperidine-2,6-dione hydrochloride 1b (1.83 g, 11.10 mmol, Bide Pharmatech) was added, and the mixture was stirred for another 2 hours. The reaction mixture was added dropwise to water (30 mL), and saturated brine (about 20 mL) was then added to the water. The mixture was filtered, and the filter cake was washed with water (40 mL), collected, and dried in vacuo to give the title product 1c (3.8 g, yield: 95%).

Step 2

(±)-N-(2,6-Dioxopiperidin-3-yl)-2-fluoro-4-(piperazin-1-yl)benzamide hydrochloride 1d

Compound 1c (3.8 g, 8.75 mmol) was dissolved in dichloromethane (40 mL), and a 4 M solution of hydrogen chloride in 1,4-dioxane (17.5 mL) was added. The mixture was stirred for 2 hours and filtered, and the filter cake was stirred in 50 mL of a mixed solvent of ethyl acetate and methanol (V/V=20:1). The filter cake was repeatedly treated twice to give the title compound 1d (2.53 g, yield: 78%).

MS m/z (ESI): 335.1 [M+1].

Step 3

tert-Butyl (±)-4-(4-(4-((2,6-dioxopiperidin-3-yl)aminocarbonyl)-3-fluorophenyl)piperazin-1-yl)piperidine-1-carboxylate 1f

To a 25 mL three-necked flask were sequentially added dichloromethane (5 mL), methanol (1 mL), and compound 1d (80 mg, 0.21 mmol), followed by anhydrous sodium acetate (89 mg, 1.08 mmol). After 15 minutes of stirring, acetic acid (26 mg, 0.43 mmol) and tert-butyl 4-oxopiperidine-1-carboxylate 1e (86 mg, 0.43 mmol, Bide Pharmatech) were added. After 30 minutes of stirring at room temperature, sodium triacetoxyborohydride (92 mg, 0.43 mmol) was slowly added. After 16 hours of reaction, compound 1e (344 mg, 1.73 mmol) and sodium triacetoxyborohydride (92 mg, 0.43 mmol) were added again, and the mixture was heated to 40° C. and left to react for another hours. 10 mL of a saturated sodium bicarbonate solution was added to the system under ice bath cooling to quench the reaction, and extraction was performed with dichloromethane (20 mL×3). The organic phases were combined, washed with a saturated sodium chloride solution (20 mL×3), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system A to give the title compound 1f (65 mg, yield: 58%).

MS m/z (ESI): 518.8 [M+1].

Step 4

(±)-N-(2,6-Dioxopiperidin-3-yl)-2-fluoro-4-(4-(piperidin-4-yl)piperazin-1-yl)benzamide dihydrochloride 1g

Compound 1f (80 mg, 0.15 mmol) was dissolved in dichloromethane (3 mL), and a 4 M solution of hydrogen chloride in 1,4-dioxane (1.1 mL) was slowly added under an ice bath. The mixture was left to react for 3 hours. The reaction mixture was concentrated under reduced pressure and dried in vacuo to give the title compound 1g as a crude product (75 mg, yield: 100%). The crude product was directly used in the next step without purification.

MS m/z (ESI): 418.3 [M+1].

Step 5

4-(4-(1-(4-((S)-2-(3-Chloro-4-cyanophenyl)-3-methyl-2,8-diazaspiro[4.5]decan-8-yl)benzoyl)piperidin-4-yl)piperazin-1-yl)-N-(2,6-dioxopiperidin-3-yl)-2-fluorobenzamide 1 (a Mixture of Diastereomers

To a 25 mL three-necked flask were sequentially added N,N-dimethylformamide (2 mL), compound 1g (50 mg, 0.10 mmol), and the compound (S)-4-(2-(3-chloro-4-cyanophenyl)-3-methyl-2,8-diazaspiro[4.5]decan-8-yl)benzoic acid 1h (50 mg, 0.078 mmol, prepared using the method disclosed in “Example 10 on page 211 of the specification in the patent application WO2021055756A1”). N,N-Diisopropylethylamine (102 mg, 0.79 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (60 mg, 0.16 mmol) were slowly added under an ice bath, and the system was then warmed to room temperature and left to react for 16 hours. The reaction mixture was filtered and separated and purified by preparative high performance liquid chromatography (Waters 2545, elution system: 10 mmol/L aqueous ammonium bicarbonate solution and acetonitrile, gradient of acetonitrile: 36/6-51%, flow rate: 30 mL/min) to give the title compound 1 (a Mixture of Diastereomers, a 1:1 ratio, 26 mg, yield: 41%).

MS m/z (ESI): 809.3 [M+1].

¹H NMR (500 MHz, DMSO-d₆): δ 10.84 (s, 1H), 8.04 (t, 1H), 7.72-7.52 (m, 2H), 7.26 (d, 2H), 6.95 (d, 2H), 6.87-6.72 (m, 3H), 6.66 (d, 1H), 4.78-4.64 (m, 1H), 4.34-3.92 (m, 3H), 3.52-3.42 (m, 2H), 3.40-3.34 (m, 2H), 3.29-3.12 (m, 5H), 3.02-2.71 (m, 5H), 2.68-2.54 (m, 4H), 2.28-2.18 (m, 1H), 2.10-2.05 (m, 1H), 2.04-1.96 (m, 1H), 1.90-1.66 (m, 4H), 1.64-1.55 (m, 1H), 1.53-1.44 (m, 2H), 1.42-1.32 (m, 2H), 1.30-1.13 (m, 4H).

Example 2

5-(4-(1-(4-((S)-2-(3-Chloro-4-cyanophenyl)-3-methyl-2,8-diazaspiro[4.5]decan-8-yl)benzoyl)piperidin-4-yl)piperazin-1-yl)-N-(2,6-dioxopiperidin-3-yl)picolinamide 2 (a Mixture of Diastereomers

Step 1

tert-Butyl (±)-4-(6-((2,6-dioxopiperidin-3-yl)aminocarbonyl)pyridin-3-yl)piperazine-1-carboxylate 2b

To a 100 mL three-necked flask were sequentially added N,N-dimethylformamide (30 mL), 5-(4-(tert-butoxycarbonyl)piperazin-1-yl)picolinic acid 2a (2.9 g, 9.44 mmol, prepared using the method disclosed in “Example 21 on page 95 of the specification in the patent application WO2012003189A1”), compound 1b (1.86 g, 11.32 mmol), O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (5.38 g, 14.14 mmol), and triethylamine (2.86 g, 28.31 mmol), and the mixture was stirred at room temperature for 1 hour. Water (20 mL) was added to the system, and extraction was performed with ethyl acetate (50 mL×3). The organic phases were combined, washed with a saturated sodium chloride solution (20 mL×2), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was stirred in 50 mL of a mixed solvent of n-heptane and ethyl acetate (V/V=20:1). The mixture was filtered, and the filter cake was collected to give the title compound 2b (2.9 g, yield: 74%).

Step 2

(±)-N-(2,6-Dioxopiperidin-3-yl)-5-(piperazin-1-yl)picolinamide dihydrochloride 2c Compound 2b (2.9 g, 6.95 mmol) was dissolved in dichloromethane (60 mL), and a 4 M solution of hydrogen chloride in 1,4-dioxane (30 mL) was added. The mixture was stirred at room temperature for 3 hours. The reaction mixture was filtered, and the filter cake was washed sequentially with dichloromethane (5 mL) and ethyl acetate (5 mL) and dried in vacuo to give the title compound 2c (2.7 g, yield: 100%).

MS m/z (ESI): 318.1 [M+1].

Step 3

tert-Butyl (±)-4-(4-(6-((2,6-dioxopiperidin-3-yl)aminocarbonyl)pyridin-3-yl)piperazin-1-yl)piperidine-1-carboxylate 2d

To a 25 mL three-necked flask were sequentially added dichloromethane (5 mL), methanol (1 mL), and compound 2c (80 mg, 0.20 mmol), followed by anhydrous sodium acetate (93 mg, 1.13 mmol). After 15 minutes of stirring, acetic acid (28 mg, 0.47 mmol) and compound 1e (90 mg, 0.45 mmol) were added. After 30 minutes of stirring at room temperature, sodium triacetoxyborohydride (96 mg, 0.45 mmol) was slowly added. After hours of reaction, compound 1e (360 mg, 1.80 mmol) and sodium triacetoxyborohydride (96 mg, 0.45 mmol) were added again, and the mixture was heated to 40° C. and left to react for another 12 hours. 10 mL of a saturated sodium bicarbonate solution was added to the system under ice bath cooling to quench the reaction, and extraction was performed with dichloromethane (20 mL×3). The organic phases were combined, washed with a saturated sodium chloride solution (20 mL×3), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system A to give the title compound 2d (63 mg, yield: 63%).

MS m/z (ESI): 501.5 [M+1].

Step 4

(±)-N-(2,6-Dioxopiperidin-3-yl)-5-(4-(piperidin-4-yl)piperazin-1-yl)picolinamide trihydrochloride 2e

Compound 2d (60 mg, 0.12 mmol) was dissolved in dichloromethane (3 mL), and a 4 M solution of hydrogen chloride in 1,4-dioxane (0.9 mL) was slowly added under an ice bath. The mixture was left to react for 2 hours. The reaction mixture was concentrated under reduced pressure and dried in vacuo to give the title compound 2e as a crude product (61 mg, yield: 100%). The crude product was directly used in the next step without purification.

MS m/z (ESI): 401.4 [M+1].

Step 5

5-(4-(1-(4-((S)-2-(3-Chloro-4-cyanophenyl)-3-methyl-2,8-diazaspiro[4.5]decan-8-yl)benzoyl)piperidin-4-yl)piperazin-1-yl)-N-(2,6-dioxopiperidin-3-yl)picolinamide 2 (a Mixture of Diastereomers

To a 25 mL three-necked flask were sequentially added N,N-dimethylformamide (2 mL), compound 2e (52 mg, 0.10 mmol), and compound 1h (50 mg, 0.078 mmol). N,N-Diisopropylethylamine (102 mg, 0.79 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (60 mg, 0.16 mmol) were slowly added under an ice bath, and the system was then warmed to room temperature and left to react for 16 hours. The reaction mixture was filtered and separated and purified by preparative high performance liquid chromatography (Waters 2545, elution system: 10 mmol/L aqueous ammonium bicarbonate solution and acetonitrile, gradient of acetonitrile: 36%-51%, flow rate: 30 mL/min) to give the title compound 2 (a Mixture of Diastereomers, a 1:1 ratio, 32 mg, yield: 51%).

MS m/z (ESI): 792.3 [M+1].

¹H NMR (500 MHz, DMSO-d₆): δ 10.84 (s, 1H), 8.72 (d, 1H), 8.31 (s, 1H), 7.86 (d, 1H), 7.59 (d, 1H), 7.41 (d, 1H), 7.26 (d, 2H), 6.95 (d, 2H), 6.80 (s, 1H), 6.66 (d, 1H), 4.84-4.61 (m, 1H), 4.40-3.88 (m, 3H), 3.60-3.32 (m, 7H), 3.28-3.06 (m, 2H), 3.02-2.72 (m, 3H), 2.71-2.57 (m, 6H), 2.33-2.09 (m, 2H), 2.07-1.94 (m, 1H), 1.91-1.65 (m, 4H), 1.62-1.31 (m, 5H), 1.30-0.98 (m, 4H).

Example 3

4-(4-((1-(4-((S)-2-(3-Chloro-4-cyanophenyl)-3-methyl-2,8-diazaspiro[4.5]decan-8-yl)benzoyl)piperidin-4-yl)methyl)piperazin-1-yl)-N-(2,6-dioxopiperidin-3-yl)-2-fluorobenzamide 3 (a Mixture of Diastereomers

Step 1

tert-Butyl (±)-4-((4-(4-((2,6-dioxopiperidin-3-yl)aminocarbonyl)-3-fluorophenyl)piperazin-1-yl)methyl)piperidine-1-carboxylate 3b

To a 25 mL three-necked flask were sequentially added dichloromethane (4 mL), methanol (1 mL), and compound 1d (80 mg, 0.22 mmol), followed by anhydrous sodium acetate (54 mg, 0.66 mmol). After 15 minutes of stirring, tert-butyl 4-formylpiperidine-1-carboxylate 3a (65 mg, 0.30 mmol, Bide Pharmatech) was added. After 30 minutes of stirring at room temperature, sodium triacetoxyborohydride (92 mg, 0.43 mmol) was slowly added, and the mixture was left to react for 16 hours. 10 mL of a saturated sodium bicarbonate solution was added to the system under ice bath cooling to quench the reaction, and extraction was performed with dichloromethane (20 mL×3). The organic phases were combined, washed with a saturated sodium chloride solution (20 mL×3), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system A to give the title compound 3b (82 mg, yield: 71%).

MS m/z (ESI): 530.2 [M-1].

Step 2

(±)-N-(2,6-Dioxopiperidin-3-yl)-2-fluoro-4-(4-(piperidin-4-yl)methyl)piperazin-1-yl)benzamide dihydrochloride 3c

Compound 3b (82 mg, 0.15 mmol) was dissolved in dichloromethane (3 mL), and a 4 M solution of hydrogen chloride in 1,4-dioxane (0.8 mL) was slowly added under an ice bath. The mixture was left to react for 3 hours. The reaction mixture was concentrated under reduced pressure and dried in vacuo to give the title compound 3c as a crude product (77 mg, yield: 100%). The crude product was directly used in the next step without purification.

MS m/z (ESI): 432.4 [M+1].

Step 3

4-(4-((1-(4-((S)-2-(3-Chloro-4-cyanophenyl)-3-methyl-2,8-diazaspiro[4.5]decan-8-yl)benzoyl)piperidin-4-yl)methyl)piperazin-1-yl)-N-(2,6-dioxopiperidin-3-yl)-2-fluorobenzamide 3 (a Mixture of Diastereomers

To a 25 mL three-necked flask were sequentially added N,N-dimethylformamide (2 mL), compound 3c (51 mg, 0.10 mmol), and compound 1h (50 mg, 0.078 mmol). N,N-Diisopropylethylamine (152 mg, 1.18 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (60 mg, 0.16 mmol) were slowly added under an ice bath, and the system was then warmed to room temperature and left to react for 16 hours. The reaction mixture was filtered and separated and purified by preparative high performance liquid chromatography (Waters 2545, elution system: 10 mmol/L aqueous ammonium bicarbonate solution and acetonitrile, gradient of acetonitrile: 36%-51%, flow rate: 30 mL/min) to give the title compound 3 (a Mixture of Diastereomers, a 1:1 ratio, 48 mg, yield: 74%).

MS m/z (ESI): 823.6 [M+1].

¹H NMR (500 MHz, DMSO-d₆): δ 10.85 (s, 1H), 8.05 (t, 1H), 7.72-7.52 (m, 2H), 7.25 (d, 2H), 6.95 (d, 2H), 6.88-6.72 (m, 3H), 6.66 (d, 1H), 4.80-4.64 (m, 1H), 4.34-3.82 (m, 3H), 3.44 (d, 1H), 3.32-3.05 (m, 7H), 3.03-2.66 (m, 4H), 2.48-2.35 (m, 4H), 2.32-2.07 (m, 4H), 2.05-1.94 (m, 1H), 1.92-1.66 (m, 5H), 1.62-1.37 (m, 4H), 1.35-1.17 (m, 4H), 1.14-0.95 (m, 2H).

Example 4

5-(4-((1-(4-((S)-2-(3-Chloro-4-cyanophenyl)-3-methyl-2,8-diazaspiro[4.5]decan-8-yl)benzoyl)piperidin-4-yl)methyl)piperazin-1-yl)-N-(2,6-dioxopiperidin-3-yl)picolinamide 4 (a Mixture of Diastereomers

Step 1

tert-Butyl (±)-4-((4-(6-((2,6-dioxopiperidin-3-yl)aminocarbonyl)pyridin-3-yl)piperazin-1-yl)methyl)piperidine-1-carboxylate 4a

To a 25 mL three-necked flask were sequentially added dichloromethane (4 mL), methanol (1 mL), and compound 2c (100 mg, 0.28 mmol), followed by anhydrous sodium acetate (70 mg, 0.85 mmol). After 15 minutes of stirring, compound 3a (80 mg, 0.38 mmol) was added. After 30 minutes of stirring at room temperature, sodium triacetoxyborohydride (120 mg, 0.57 mmol) was slowly added, and the mixture was left to react for 16 hours. 10 mL of a saturated sodium bicarbonate solution was added to the system under ice bath cooling to quench the reaction, and extraction was performed with dichloromethane (20 mL×3). The organic phases were combined, washed with a saturated sodium chloride solution (20 mL×3), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system A to give the title compound 4a (125 mg, yield: 85%).

MS m/z (ESI): 515.4 [M+1].

Step 2

(±)-N-(2,6-Dioxopiperidin-3-yl)-5-(4-(piperidin-4-yl)methyl)piperazin-1-yl)picolinamide trihydrochloride 4b

Compound 4a (125 mg, 0.24 mmol) was dissolved in dichloromethane (3 mL), and a 4 M solution of hydrogen chloride in 1,4-dioxane (1.2 mL) was slowly added under an ice bath. The mixture was left to react for 4 hours. The reaction mixture was concentrated under reduced pressure and dried in vacuo to give the title compound 4b as a crude product (126 mg, yield: 100%). The crude product was directly used in the next step without purification.

MS m/z (ESI): 415.5 [M+1].

Step 3

5-(4-((1-(4-((S)-2-(3-Chloro-4-cyanophenyl)-3-methyl-2,8-diazaspiro[4.5]decan-8-yl)benzoyl)piperidin-4-yl)methyl)piperazin-1-yl)-N-(2,6-dioxopiperidin-3-yl)picolinamide 4 (a Mixture of Diastereomers

To a 25 mL three-necked flask were sequentially added N,N-dimethylformamide (2 mL), compound 4b (51 mg, 0.10 mmol), and compound 1h (50 mg, 0.078 mmol). N,N-Diisopropylethylamine (152 mg, 1.18 mmol) and O-(7-azabenzotriazol-1-y)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (60 mg, 0.16 mmol) were slowly added under an ice bath, and the system was then warmed to room temperature and left to react for 16 hours. The reaction mixture was filtered and separated and purified by preparative high performance liquid chromatography (Waters 2545, elution system: 10 mmol/L aqueous ammonium bicarbonate solution and acetonitrile, gradient of acetonitrile: 36%-51%, flow rate: 30 mL/min) to give the title compound 4 (a Mixture of Diastereomers, a 1:1 ratio, 35 mg, yield: 55%).

MS m/z (ESI): 806.2 [M+1].

¹H NMR (500 MHz, DMSO-d₆): δ 10.85 (s, 1H), 8.73 (d, 1H), 8.32 (s, 1H), 7.87 (d, 1H), 7.60 (d, 1H), 7.42 (d, 1H), 7.25 (d, 2H), 6.95 (d, 2H), 6.80 (s, 1H), 6.66 (d, 1H), 4.86-4.63 (m, 1H), 4.28-3.82 (m, 3H), 3.44 (d, 1H), 3.41-3.32 (m, 7H), 3.26-3.10 (m, 2H), 2.98-2.72 (m, 3H), 2.64-2.53 (m, 4H), 2.32-2.14 (m, 4H), 2.07-1.94 (m, 1H), 1.92-1.66 (m, 5H), 1.62-1.56 (m, 1H), 1.52-1.40 (m, 2H), 1.33-1.17 (m, 4H), 1.14-0.98 (m, 2H).

Example 5

4-(3-(4-((5-((S)-2-(3-Chloro-4-cyanophenyl)-3-methyl-2,8-diazaspiro[4.5]decane-8-carbonyl)pyridin-2-yl)thio)piperidin-1-yl)azetidin-1-yl)-N-(2,6-dioxopiperidin-3-yl)-2-fluorobenzamide 5 (a Mixture of Diastereomers

Step 1

(S)-2-Chloro-4-(8-(6-fluoronicotinoyl)-3-methyl-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile 5c

6-Fluoronicotinic acid 5b (139 mg, 0.98 mmol, Bide Pharmatech) was weighed into a 50 mL eggplant-shaped flask. N,N-Dimethylformamide (3 mL) was added, and N,N-diisopropylethylamine (446 mg, 3.45 mmol, 0.86 mL) and O-(7-azabenzotriazole-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (563 mg, 1.48 mmol) were then added. After 15 minutes of stirring, the compound (S)-2-chloro-4-(3-methyl-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile 5a (284 mg, 0.98 mmol, prepared using the method disclosed in “Example 10 on page 211 of the specification in the patent application WO2021055756A1”) was added, and the mixture was left to react for 2 hours. Water (5 mL) was added to the system, and extraction was performed with ethyl acetate (10 mL×3). The organic phases were combined, washed with a saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography with eluent system B to give the title compound 5c (407 mg, yield: 100%).

MS m/z (ESI): 413.2 [M+1].

Step 2

tert-Butyl (S)-4-((5-(2-(3-chloro-4-cyanophenyl)-3-methyl-2,8-diazaspiro[4.5]decane-8-carbonyl)pyridin-2-yl)thio)piperidine-1-carboxylate 5e

Compound 5c (407 mg, 0.98 mmol) and tert-butyl 4-mercaptopiperidine-1-carboxylate 5d (428 mg, 1.96 mmol) were weighed into a 50 mL eggplant-shaped flask. N,N-Dimethylformamide (5 mL) and cesium carbonate (481 mg, 1.48 mmol) were added, and the mixture was then left to react at 110° C. for 5 hours. The heating was stopped. Water (8 mL) was added to the system, and extraction was performed with ethyl acetate (15 mL×3). The organic phases were combined, washed with a saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography with eluent system B to give the title compound 5e (596 mg, yield: 99%).

MS m/z (ESI): 510.1 [M-99].

Step 3

(S)-2-Chloro-4-(3-methyl-8-(6-(piperidin-4-ylthio)nicotinoyl)-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile hydrochloride 5f

Compound 5e (596 mg, 0.98 mmol) was weighed into a 25 mL eggplant-shaped flask, and a 4 M solution of hydrogen chloride in 1,4-dioxane (5 mL) was added. After 2 hours of reaction, the system was concentrated and dried to give the title compound 5f (528 mg, yield: 99%). The crude product was directly used in the next step without purification.

MS m/z (ESI): 510.1 [M+1].

Step 4

Methyl 2-fluoro-4-(3-hydroxyazetidin-1-yl)benzoate 5i

Methyl 2-fluoro-4-bromobenzoate 5g (3 g, 12.9 mmol, Bide Pharmatech) and azetidin-3-ol hydrochloride 5h (1.41 g, 12.87 mmol, Bide Pharmatech) were weighed into a 100 mL eggplant-shaped flask, and palladium acetate (289 mg, 1.289 mmol), 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (962 mg, 1.55 mmol), and cesium carbonate (12.6 g, 38.67 mmol) were sequentially added. 1,4-Dioxane (30 mL) was added, and the mixture was then left to react at 105° C. for 5 hours. After being cooled to room temperature, the reaction mixture was filtered using celite, and the filter cake was washed with ethyl acetate (15 mL×3). The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system B to give the title compound 5i (1.8 g, yield: 62%).

MS m/z (ESI): 226.1 [M+1].

Step 5

2-Fluoro-4-(3-hydroxyazetidin-1-yl)benzoic acid 5j

Compound 5i (600 mg, 2.66 mmol) was weighed into a 50 mL eggplant-shaped flask and dissolved in tetrahydrofuran (10 mL), and a solution of sodium hydroxide (533 mg, 13.32 mmol) in water (2 mL) was then added. The mixture was left to react at 80° C. for 4 hours. After the reaction mixture was cooled to room temperature, 1 M hydrochloric acid was added to the system to adjust the pH to 3-4. The reaction mixture was concentrated under reduced pressure to remove the organic solvent and filtered, and the filter cake was collected to give the title compound 5j (560 mg, 99%).

MS m/z (ESI): 212.3 [M+1].

Step 6

(±)-N-(2,6-Dioxopiperidin-3-yl)-2-fluoro-4-(3-hydroxyazetidin-1-yl)benzamide 5k Compound 5j (653 mg, 3.09 mmol) was weighed into a 50 mL eggplant-shaped flask. N,N-Dimethylformamide (5 mL) was added, and N,N-diisopropylethylamine (1.2 g, 9.28 mmol, 1.61 mL) and O-(7-azabenzotriazole-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (1.76 g, 4.63 mmol) were then added. After 15 minutes of stirring, compound 1b (763 mg, 4.63 mmol) was added. After 2 hours of reaction, water (8 mL) was added to the system, and extraction was performed with ethyl acetate (15 mL×3). The organic phases were combined, washed with a saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography with eluent system A to give the title compound 5k (260 mg, 26%).

MS m/z (ESI): 322.3 [M+1].

Step 7

(±)-N-(2,6-Dioxopiperidin-3-yl)-2-fluoro-4-(3-oxoazetidin-1-yl)benzamide 5l Compound 5k (50 mg, 0.16 mmol) was weighed into a 50 mL eggplant-shaped flask, and dichloromethane (10 mL) and sodium bicarbonate (26 mg, 0.31 mmol) were added. Under conditions of an ice-water bath, Dess-Martin oxidant (73 mg, 0.172 mmol) was added, and the system was naturally warmed to room temperature and left to react for 12 hours. A saturated sodium thiosulfate solution (5 mL) and water (5 mL) were added to the system, and extraction was performed with dichloromethane (10 mL×3). The organic phases were combined, washed with a saturated sodium chloride solution (15 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography with eluent system A to give the title compound 5l (35 mg, 70%).

MS m/z (ESI): 320.1 [M+1].

Step 8

4-(3-(4-((5-((S)-2-(3-Chloro-4-cyanophenyl)-3-methyl-2,8-diazaspiro[4.5]decane-8-carbonyl)pyridin-2-yl)thio)piperidin-1-yl)azetidin-1-yl)-N-(2,6-dioxopiperidin-3-yl)-2-fluorobenzamide 5 (a Mixture of Diastereomers

Compound 5f (18 mg, 0.033 mmol) was weighed into a 25 mL eggplant-shaped flask. Methanol (2 mL) and sodium acetate (13.8 mg, 0.16 mmol) were added, and the mixture was then left to react at 50° C. for 30 minutes. To the reaction system were added compound 5l (32 mg, 0.099 mmol) and acetic acid (4 mg, 0.066 mmol). After 1 hour of reaction, sodium cyanoborohydride (12 mg, 0.02 mmol) was added, and the mixture was left to react for 12 hours. The reaction mixture was filtered and separated and purified by preparative high performance liquid chromatography (Waters-2545, elution system: 10 mmol/L aqueous ammonium bicarbonate solution and acetonitrile, gradient of acetonitrile: 45%-60%, flow rate: 30 mL/min) to give the title compound 5 (a mixture of diastereomers, a 1:1 ratio, 10 mg, yield: 37%).

MS m/z (ESI): 813.2 [M+1].

H NMR (500 MHz, DMSO-d₆): δ 10.83 (s, 1H), 8.45 (s, 1H), 7.98 (t, 1H), 7.78-7.50 (m, 3H), 7.33 (d, 1H), 6.77 (s, 1H), 6.64 (d, 1H), 6.28 (d, 1H), 6.23 (d, 1H), 4.80-4.66 (m, 1H), 4.14-3.95 (m, 3H), 3.93-3.64 (m, 4H), 3.57-3.38 (m, 3H), 2.93-2.60 (m, 4H), 2.32-1.95 (m, 8H), 1.84-1.35 (m, 9H), 1.19 (d, 3H).

Example 6

(S)-2-Chloro-4-(8-(4-(4-(4-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperazin-1-yl)-[1,4′-bipiperidine]-1′-carbonyl)phenyl)-3-methyl-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile 6

Step 1

tert-Butyl 4-(4-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperazin-1-yl)piperidine-1-carboxylate 6b

To a 50 mL reaction flask was added 6 mL of a mixed solvent of 1,2-dichloroethane and methanol (V/V=5/1), followed by 1-(4-(piperazin-1-yl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione hydrochloride 6a (500 mg, 1.61 mmol, prepared using the method disclosed in “Scheme 15 on page 345 of the specification in the patent application WO2020132561 A1”) and anhydrous sodium acetate (660 mg, 8.05 mmol). After 10 minutes of stirring at room temperature, compound 1e (960 mg, 4.82 mmol) was added. After 1 hour of stirring, sodium triacetoxyborohydride (685 mg, 3.23 mmol) was added. After 3 hours of reaction, sodium cyanoborohydride (200 mg, 3.34 mmol) was added. After 3 hours of reaction, compound 1e (960 mg, 4.82 mmol) was added again. After another 12 hours of reaction, a saturated sodium bicarbonate solution (20 mL) was added to quench the reaction, and extraction was performed with 1,2-dichloroethane (50 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography with eluent system A to give the title compound 6b (736 mg, yield: 99%).

MS m/z (ESI): 458.6 [M+1].

Step 2

1-(4-(4-(Piperidin-4-yl)piperazin-1-yl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione dihydrochloride 6c

Compound 6b (736 mg, 1.61 mmol) was dissolved in 5 mL of dichloromethane, and a 4 M solution of hydrogen chloride in 1,4-dioxane (5 mL) was slowly added under an ice bath. The mixture was left to react for 1 hour. The reaction mixture was concentrated under reduced pressure and dried in vacuo to give the title compound 6c as a crude product (692 mg, yield: 99%). The crude product was directly used in the next step without purification.

MS m/z (ESI): 358.3 [M+1].

Step 3

tert-Butyl 4-(4-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperazin-1-yl)-[1,4′-bipiperidine]-1′-carboxylate 6d

To a 50 mL reaction flask were added 10 mL of a mixed solution of 1,2-dichloromethane and methanol (V/V=7/3), compound 6c (300 mg, 0.70 mmol), and anhydrous sodium acetate (350 mg, 4.27 mmol). The mixture was stirred for 30 minutes. Compound 1e (400 mg, 2.01 mmol) was added, and the mixture was stirred for another 10 minutes. Sodium cyanoborohydride (84 mg, 1.40 mmol) was added. After 1 hour of reaction, compound 1e (400 mg, 2.01 mmol) was added again, and the mixture was heated to 50° C. and stirred overnight. The reaction mixture was concentrated under reduced pressure and separated and purified by preparative high performance liquid chromatography (Gilson GX-281, elution system: 10 mmol/L aqueous ammonium bicarbonate solution and acetonitrile, gradient of acetonitrile: 28/6-48%, flow rate: 30 mL/min) to give the title compound 6d (138 mg, yield: 37%).

MS m/z (ESI): 541.4 [M+1].

Step 4

1-(4-(4-([1,4′-Bipiperidin]-4-yl)piperazin-1-yl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione trihydrochloride 6e

Compound 6d (36 mg, 0.066 mmol) was dissolved in 1 mL of dichloromethane, and a 4 M solution of hydrogen chloride in 1,4-dioxane (1 mL) was slowly added under an ice bath. The mixture was left to react for 1 hour. The reaction mixture was concentrated under reduced pressure and dried in vacuo to give the title compound 6e as a crude product (36 mg, yield: 99%). The crude product was directly used in the next step without purification.

MS m/z (ESI): 441.4 [M+1].

Step 5

(S)-2-Chloro-4-(8-(4-(4-(4-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperazin-1-yl)-[1,4′-bipiperidine]-1′-carbonyl)phenyl)-3-methyl-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile 6

To a 25 mL reaction flask were sequentially added 2 mL of N,N-dimethylformamide, compound 1h (35 mg, 0.085 mmol), and compound 6e (42 mg, 0.076 mmol), followed by O-(7-azabenzotriazol-1-yl)-N,N,N′N′-tetramethyluronium hexafluorophosphate (36 mg, 0.095 mmol) and N,N-diisopropylethylamine (60 mg, 0.464 mmol). After 1 hour of reaction, the reaction mixture was filtered and separated and purified by preparative high performance liquid chromatography (Waters 2767-SQ Detecor2, elution system: 10 mmol/L aqueous ammonium bicarbonate solution and acetonitrile, gradient of acetonitrile: 70/6-90%, flow rate: 30 mL/min) to give the title compound 6 (4 mg, yield: 6%).

MS m/z (ESI): 832.4 [M+1].

¹H NMR (500 MHz, DMSO-d₆): δ 10.26 (s, 1H), 7.60 (d, 1H), 7.27 (d, 2H), 7.15 (d, 2H), 7.01-6.85 (m, 4H), 6.80 (d, 1H), 6.66 (dd, 1H), 4.08-3.96 (m, 1H), 3.69 (t, 2H), 3.58-3.35 (m, 6H), 3.28-3.04 (m, 7H), 3.01-2.55 (m, 12H), 2.28-2.18 (m, 1H), 2.10-1.91 (m, 3H), 1.83-1.36 (m, 9H), 1.32-1.12 (m, 5H).

Example 7

(S)-2-Chloro-4-(8-(4-(4-(3-(4-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperazin-1-yl)azetidin-1-yl)piperidine-1-carbonyl)phenyl)-3-methyl-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile 7

Step 1

tert-Butyl 3-(4-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperazin-1-yl)azetidine-1-carboxylate 7b

Compound 6a (500 mg, 1.82 mmol) and tert-butyl 3-oxoazetidine-1-carboxylate 7a (343 mg, 2.0 mmol, Bide Pharmatech) were dissolved in 45 mL of a mixed solvent of dichloromethane and methanol (V/V=2/1). Anhydrous sodium acetate (897 mg, 10.94 mmol) was added, and acetic acid (0.1 mL) was added. The mixture was heated to 60° C. and left to react for 0.5 hours. Sodium triacetoxyborohydride (848 mg, 4.0 mmol) was added, and the mixture was heated to 60° C. and left to react for 12 hours. The reaction mixture was filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography with eluent system A to give the title compound 7b (440 mg, yield: 56%).

MS m/z (ESI): 430.3 [M+1].

Step 2

1-(4-(4-(Azetidin-3-yl)piperazin-1-yl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione bistrifluoroacetate 7c

Compound 7b (440 mg, 1.02 mmol) was dissolved in 15 mL of dichloromethane, and trifluoroacetic acid (3 mL) was added dropwise. After 2 hours of reaction, the reaction mixture was concentrated under reduced pressure and dried in vacuo to give the title compound 7c (570 mg, yield: 100%). The crude product was directly used in the next step without purification.

Step 3

tert-Butyl 4-(3-(4-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperazin-1-yl)azetidin-1-yl)piperidine-1-carboxylate 7d

To a 50 mL reaction flask were sequentially added 6.5 mL of a mixed solution of 1,2-dichloroethane and methanol (V/V=10/3), compound 7c (100 mg, 0.18 mmol), and anhydrous sodium acetate (150 mg, 1.83 mmol). After 30 minutes of stirring, compound 1e (400 mg, 2.01 mmol) was added, and the mixture was heated to 50° C. After 15 minutes of reaction, sodium cyanoborohydride (40 mg, 0.67 mmol) was added, and the mixture was left to react for 12 hours. The solvent was removed by concentration under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system A to give the title compound 7d (50 mg, yield: 54%).

MS m/z (ESI): 513.6 [M+1].

Step 4

1-(4-(4-(1-(Piperidin-4-yl)azetidin-3-yl)piperazin-1-yl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione trihydrochloride 7e

Compound 7d (50 mg, 0.098 mmol) was dissolved in 1 mL of dichloromethane, and a 4 M solution of hydrogen chloride in 1,4-dioxane (2 mL) was slowly added under an ice bath. The mixture was left to react for 1 hour. The reaction mixture was concentrated and dried in vacuo to give the title compound 7e as a crude product (50 mg, yield: 98%). The crude product was directly used in the next step without purification.

MS m/z (ESI): 413.3 [M+1].

Step 5

(S)-2-Chloro-4-(8-(4-(4-(3-(4-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperazin-1-yl)azetidin-1-yl)piperidine-1-carbonyl)phenyl)-3-methyl-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile 7

To a 25 mL reaction flask were sequentially added 2 mL of N,N-dimethylformamide, compound 1h (50 mg, 0.12 mmol), and compound 7e (50 mg, 0.096 mmol), followed by O-(7-azabenzotriazol-1-yl)-N,N,N′N′-tetramethyluronium hexafluorophosphate (50 mg, 0.13 mmol) and N,N-diisopropylethylamine (100 mg, 0.77 mmol). After 1 hour of reaction at room temperature, the reaction mixture was filtered and separated and purified by preparative high performance liquid chromatography (Waters 2767-SQ Detecor2, elution system: 10 mmol/L aqueous ammonium bicarbonate solution and acetonitrile, gradient of acetonitrile: 70/6-90%, flow rate: 30 mL/min) to give the title compound 7 (10 mg, yield: 13%).

MS m/z (ESI): 804.4 [M+1].

¹H NMR (500 MHz, DMSO-d₆): δ 10.26 (s, 1H), 7.59 (d, 1H), 7.23 (d, 2H), 7.14 (d, 2H), 7.01-6.85 (m, 4H), 6.80 (d, 1H), 6.65 (dd, 1H), 4.17-3.96 (m, 1H), 3.94-3.60 (m, 4H), 3.55-3.35 (m, 5H), 3.28-2.98 (m, 8H), 2.94-2.74 (m, 3H), 2.72-2.60 (m, 2H), 2.47-2.31 (m, 4H), 2.30-2.12 (m, 2H), 1.88-1.39 (m, 7H), 1.36-0.98 (m, 6H).

Example 8

(S)-2-Chloro-4-(8-(4-(4-((3-(4-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperazin-1-yl)azetidin-1-yl)methyl)piperidine-1-carbonyl)phenyl)-3-methyl-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile 8

Step 1

Compound 7c (44 mg, 0.079 mmol) was weighed into a 25 mL eggplant-shaped flask, and 8 mL of a mixed solvent of dichloromethane and methanol (V/V=3/1) and anhydrous sodium acetate (81 mg, 0.99 mmol) were added. After 15 minutes of reaction, (S)-2-chloro-4-(8-(4-(4-formylpiperidine-1-carbonyl)phenyl)-3-methyl-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile 8a (50 mg, 0.099 mmol, prepared using the method disclosed in “Example 47 on page 265 of the specification in patent application WO2021055756 A1”) and acetic acid (4 mg, 0.066 mmol) were added to the system.

After 1 hour of reaction, sodium cyanoborohydride (12 mg, 0.19 mmol) was added, and the mixture was left to react for 12 hours. The reaction mixture was filtered and separated and purified by preparative high performance liquid chromatography (Waters-2545, elution system: 10 mmol/L aqueous ammonium bicarbonate solution and acetonitrile, gradient of acetonitrile: 45%-60%, flow rate: 30 mL/min) to give the title compound 8 (20 mg, yield: 31%).

MS m/z (ESI): 818.7 [M+1].

¹H NMR (500 MHz, DMSO-d₆): δ 10.26 (s, 1H), 7.60 (d, 1H), 7.23 (d, 2H), 7.15 (d, 2H), 7.01-6.85 (m, 4H), 6.81 (d, 1H), 6.66 (dd, 1H), 4.07-3.98 (m, 1H), 3.70 (t, 2H), 3.56-3.35 (m, 6H), 3.28-2.98 (m, 7), 2.94-2.74 (m, 3H), 2.72-2.64 (m, 2H), 2.62-2.52 (m, 4H), 2.42-2.20 (m, 6H), 1.88-1.40 (m, 8H), 1.21 (d, 3H), 1.13-0.96 (m, 2H).

Example 9

(S)-2-Chloro-4-(8-(4-(4-((4-(4-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperazin-1-yl)piperidin-1-yl)methyl)piperidine-1-carbonyl)phenyl)-3-methyl-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile 9

Step 1

Compound 6c (44 mg, 0.10 mmol) was weighed into a 25 mL eggplant-shaped flask, and 8 mL of a mixed solvent of dichloromethane and methanol (V/V=3/1) and anhydrous sodium acetate (92 mg, 1.12 mmol) were added. After 15 minutes of reaction, compound 8a (53 mg, 0.10 mmol) and acetic acid (4 mg, 0.066 mmol) were added. After 1 hour of reaction, sodium triacetoxyborohydride (47 mg, 0.22 mmol) was added, and the mixture was left to react for 2 hours. The reaction mixture was filtered and separated and purified by preparative high performance liquid chromatography (Waters-2545, elution system: mmol/L aqueous ammonium bicarbonate solution and acetonitrile, gradient of acetonitrile: 45/6-60%, flow rate: 30 mL/min) to give the title compound 9 (20 mg, yield: 23%).

MS m/z (ESI): 846.5 [M+1].

¹H NMR (500 MHz, DMSO-d₆): δ 10.25 (s, 1H), 7.59 (d, 1H), 7.23 (d, 2H), 7.14 (d, 2H), 7.01-6.85 (m, 4H), 6.80 (d, 1H), 6.66 (dd, 1H), 4.06-3.98 (m, 1H), 3.69 (t, 2H), 3.51-3.38 (m, 2H), 3.26-2.99 (m, 7H), 2.94-2.74 (m, 4H), 2.71-2.66 (m, 2H), 2.71-2.66 (m, 4H), 2.64-2.57 (m, 5H), 1.92-1.62 (m, 10H), 1.61-1.36 (m, 6H), 1.20 (d, 3H), 1.08-0.96 (m, 2H).

Example 10

2-Chloro-4-((3S)-8-(4-(4-(4-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperazin-1-yl)piperidine-1-carbonyl)phenyl)-3-methyl-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile a Mixture of Diastereomers

Step 1

tert-Butyl (±)-4-(4-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperazin-1-yl)piperidine-1-carboxylate 10b

To a 25 mL three-necked flask was added 3 mL of a mixed solution of dichloromethane and methanol (V/V=2/1), followed by (±)-3-((3-(piperazin-1-yl)phenyl)amino)piperidine-2,6-dione hydrochloride 10a (90 mg, 0.25 mmol, prepared using the method disclosed for “Compound 86 on page 266 of the specification in the patent application WO 2018237026 A1”) and anhydrous sodium acetate (103 mg, 1.25 mmol). After 15 minutes of stirring, acetic acid (30 mg, 0.49 mmol) and compound 1e (148 mg, 0.74 mmol) were added. After 30 minutes of stirring at room temperature, sodium cyanoborohydride (38 mg, 0.60 mmol) was slowly added, and the mixture was left to react for 16 hours. 10 mL of a saturated sodium bicarbonate solution was added to the system under ice bath cooling to quench the reaction, and extraction was performed with dichloromethane (20 mL×3). The organic phases were combined, washed with a saturated sodium chloride solution (20 mL×3), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system A to give the title compound 10b (95 mg, yield: 80%).

MS m/z (ESI): 472.8 [M+1].

Step 2

(±)-3-((3-(4-(Piperidin-4-yl)piperazin-1-yl)phenyl)amino)piperidine-2,6-dione dihydrochloride 10c

Compound 10b (90 mg, 0.19 mmol) was dissolved in 2 mL of dichloromethane, and a 4 M solution of hydrogen chloride in 1,4-dioxane (0.5 mL) was slowly added under an ice bath. The mixture was left to react for 4 hours. The reaction mixture was concentrated and dried in vacuo to give the title compound 10c as a crude product (84 mg, yield: 99%). The crude product was directly used in the next step without purification.

MS m/z (ESI): 372.4 [M+1].

Step 3

2-Chloro-4-((3S)-8-(4-(4-(4-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperazin-1-yl)piperidine-1-carbonyl)phenyl)-3-methyl-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile (a Mixture of Diastereomers

To a 25 mL three-necked flask were sequentially added 2 mL of N,N-dimethylformamide, compound 10c (38 mg, 0.085 mmol), and compound 1h (29 mg, 0.071 mmol). N,N-Diisopropylethylamine (136 mg, 1.05 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (53 mg, 0.14 mmol) were slowly added under an ice bath, and the system was then warmed to room temperature and left to react for 16 hours. The reaction mixture was filtered and separated and purified by preparative high performance liquid chromatography (Waters 2545, elution system: 10 mmol/L aqueous ammonium bicarbonate solution and acetonitrile, gradient of acetonitrile: 45/0-95%, flow rate: 30 mL/min) to give the title compound 10 (a Mixture of Diastereomers, a 1:1 ratio, 24 mg, yield: 44%).

MS m/z (ESI): 763.3 [M+1].

¹H NMR (500 MHz, DMSO-d₆): δ 10.76 (s, 1H), 7.59 (d, 1H), 7.26 (d, 2H), 6.95 (d, 2H), 6.90 (t, 1H), 6.80 (d, 1H), 6.66 (dd, 1H), 6.25 (s, 1H), 6.16 (dd, 2H), 5.62 (d, 1H), 4.41-4.24 (m, 1H), 4.19-3.72 (m, 3H), 3.56-3.32 (m, 4H), 3.27-3.12 (m, 2H), 3.10-2.97 (m, 3H), 2.95-2.80 (m, 2H), 2.78-2.69 (m, 1H), 2.67-2.54 (m, 4H), 2.48-2.32 (m, 4H), 2.31-2.16 (m, 1H), 2.15-2.03 (m, 1H), 1.94-1.62 (m, 4H), 1.61-1.32 (m, 4H), 1.30-1.04 (m, 4H).

Example 11

2-Chloro-4-((3S)-8-(4-(4-((4-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperazin-1-yl)methyl)piperidine-1-carbonyl)phenyl)-3-methyl-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile 11 (a Mixture of Diastereomers

Step 1

tert-Butyl (±)-4-((4-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperazin-1-yl)methyl)piperidine-1-carboxylate 11a

To a 25 mL three-necked flask was added 3 mL of a mixed solution of dichloromethane and methanol (V/V=2/1), followed by (±)-3-((3-(piperazin-1-yl)phenyl)amino)piperidine-2,6-dione 10a (90 mg, 0.25 mmol) and anhydrous sodium acetate (102 mg, 1.24 mmol). After 15 minutes of reaction, compound 3a (85 mg, 0.40 mmol) was added. After 30 minutes of reaction, sodium triacetoxyborohydride (106 mg, 0.50 mmol) was slowly added, and the mixture was left to react for 16 hours. 10 mL of a saturated sodium bicarbonate solution was added to the system under ice bath cooling to quench the reaction, and extraction was performed with dichloromethane (20 mL×3). The organic phases were combined, washed with a saturated sodium chloride solution (20 mL×3), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system A to give the title compound 11a (110 mg, yield: 90%).

MS m/z (ESI): 486.6 [M+1].

Step 2

(±)-3-((3-(4-(Piperidin-4-ylmethyl)piperazin-1-yl)phenyl)amino)piperidine-2,6-dione dihydrochloride 11b

Compound 11a (105 mg, 0.22 mmol) was dissolved in 3 mL of dichloromethane, and a 4 M solution of hydrogen chloride in 1,4-dioxane (0.53 mL) was slowly added under an ice bath. The mixture was left to react for 4 hours. The reaction mixture was concentrated and dried in vacuo to give the title compound 11b as a crude product (99 mg, yield: 98%). The crude product was directly used in the next step without purification.

MS m/z (ESI): 386.5 [M+1].

Step 3

2-Chloro-4-((3S)-8-(4-(4-((4-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperazin-1-yl)methyl)piperidine-1-carbonyl)phenyl)-3-methyl-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile 11 (a Mixture of Diastereomers

To a 25 mL three-necked flask were sequentially added 2 mL of N,N-dimethylformamide, compound 11b (42 mg, 0.092 mmol), and compound 1h (29 mg, 0.071 mmol). N,N-Diisopropylethylamine (136 mg, 1.05 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (53 mg, 0.14 mmol) were slowly added under an ice bath, and the system was then warmed to room temperature and left to react for 16 hours. The reaction mixture was filtered and separated and purified by preparative high performance liquid chromatography (Waters 2545, elution system: 10 mmol/L aqueous ammonium bicarbonate solution and acetonitrile, gradient of acetonitrile: 50/0-95%, flow rate: 30 mL/min) to give the title compound 11 (a Mixture of Diastereomers, a 1:1 ratio, 24 mg, yield: 43%).

MS m/z (ESI): 777.3 [M+1].

¹H NMR (500 MHz, DMSO-d₆): δ 10.76 (s, 1H), 7.59 (d, 1H), 7.26 (d, 2H), 6.94 (d, 2H), 6.90 (t, 1H), 6.80 (d, 1H), 6.66 (dd, 1H), 6.25 (s, 1H), 6.16 (dd, 2H), 5.61 (d, 1H), 4.42-4.25 (m, 1H), 4.19-3.74 (m, 3H), 3.56-3.33 (m, 4H), 3.26-3.14 (m, 2H), 3.12-2.97 (m, 4H), 2.95-2.80 (m, 2H), 2.78-2.68 (m, 1H), 2.66-2.52 (m, 2H), 2.48-2.38 (m, 3H), 2.29-1.96 (m, 4H), 1.96-1.66 (m, 5H), 1.62-1.38 (m, 3H), 1.36-1.16 (m, 4H), 1.11-0.97 (m, 2H).

Example 11-1 and Example 11-2

2-Chloro-4-((S)-8-(4-(4-((4-(3-(((S)-2,6-dioxopiperidin-3-yl)amino)phenyl)piperazin-1-yl)methyl)piperidine-1-carbonyl)phenyl)-3-methyl-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile 11-1

2-Chloro-4-((S)-8-(4-(4-((4-(3-(((R)-2,6-dioxopiperidin-3-yl)amino)phenyl)piperazin-1-yl)methyl)piperidine-1-carbonyl)phenyl)-3-methyl-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile 11-2

Compound 11 (100 mg) was resolved by preparative chiral chromatography (separation conditions: Gilson-281, column: Phenomenex Amylose-2, 5 μm, 21.2 mm×250 mm, mobile phase: acetonitrile (0.5% 7 M ammonia (NH₃) in methanol)/ethanol (0.5% 7 M ammonia (NH₃) in methanol)=40/60 (v/v)), flow rate 20 mL/min) to give eluates of 2 compounds. Each of the two eluates was well mixed with formic acid (500 mg), and the solvent was removed by concentration under reduced pressure to give crude products (46 mg, 45 mg). The crude products of the 2 compounds (46 mg, 45 mg) were then separated and purified by preparative high performance liquid chromatography (Waters 2545, elution system: 10 mmol/L aqueous ammonium bicarbonate solution and acetonitrile, gradient of acetonitrile: 60/6-85%, flow rate: 30 m/min) to give the title compounds (30 mg, 27 mg).

Single-configuration compound (shorter retention time) (30 mg, yield: 30%): MS m/z (ESI): 777.3 [M+1].

Chiral HPLC analysis method: retention time 4.27 minutes (Agilent 1260 DAD, column: Phenomenex LUX Amylose-2, (4.6×150 mM), 5 μm; mobile phase: acetonitrile/ethanol/diethylamine)=60/40/0.1 (v/v/v)), flow rate 1 mL/min).

¹H NMR (500 MHz, DMSO-d₆): δ 10.76 (s, 1H), 7.59 (d, 1H), 7.26 (d, 2H), 6.94 (d, 2H), 6.90 (t, 1H), 6.80 (s, 1H), 6.66 (d, 1H), 6.25 (s, 1H), 6.18 (d, 1H), 6.13 (d, 1H), 5.61 (d, 1H), 4.42-4.25 (m, 1H), 4.19-3.74 (m, 3H), 3.56-3.33 (m, 4H), 3.26-3.14 (m, 2H), 3.12-2.97 (m, 4H), 2.95-2.80 (m, 2H), 2.78-2.68 (m, 1H), 2.66-2.52 (m, 1H), 2.48-2.38 (m, 4H), 2.29-1.96 (m, 4H), 1.96-1.66 (m, 5H), 1.62-1.38 (m, 3H), 1.36-1.16 (m, 4H), 1.11-0.97 (m, 2H).

Single-configuration compound (longer retention time) (27 mg, yield: 27%): MS m/z (ESI): 777.3 [M+1].

Chiral HPLC analysis method: retention time 5.24 minutes (Agilent 1260 DAD, column: Phenomenex LUX Amylose-2, (4.6×150 mM), 5 μm; mobile phase: acetonitrile/ethanol/diethylamine)=60/40/0.1 (v/v/v)), flow rate 1 mL/min).

¹H NMR (500 MHz, DMSO-d₆): δ 10.76 (s, 1H), 7.59 (d, 1H), 7.24 (d, 2H), 6.94 (d, 2H), 6.90 (t, 1H), 6.80 (s, 1H), 6.66 (d, 1H), 6.25 (s, 1H), 6.18 (d, 1H), 6.13 (d, 1H), 5.61 (d, 1H), 4.42-4.25 (m, 1H), 4.19-3.74 (m, 3H), 3.56-3.33 (m, 4H), 3.26-3.14 (m, 2H), 3.12-2.97 (m, 4H), 2.95-2.80 (m, 2H), 2.78-2.68 (m, 1H), 2.66-2.52 (m, 1H), 2.48-2.38 (m, 4H), 2.29-1.96 (m, 4H), 1.96-1.66 (m, 5H), 1.62-1.38 (m, 3H), 1.36-1.16 (m, 4H), 1.11-0.97 (m, 2H).

Example 12

2-Chloro-4-((3S)-8-(6-(4-((4-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperazin-1-yl)methyl)piperidine-1-carbonyl)pyridin-3-yl)-3-methyl-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile 12 (a Mixture of Diastereomers

To a 25 mL single-necked flask were sequentially added 2 mL of N,N-dimethylformamide, compound 11b (64 mg, 0.12 mmol), and (S)-5-(2-(3-chloro-4-cyanophenyl)-3-methyl-2,8-diazaspiro[4.5]decan-8-yl)picolinic acid 12a (45 mg, 0.11 mmol, prepared using the method disclosed in “Example 35 on page 245 of the specification in the patent application WO2021055756A1”). N,N-Diisopropylethylamine (84 mg, 0.65 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (83 mg, 0.22 mmol) were slowly added under an ice bath. The cooling bath was removed, and the mixture was left to react for 16 hours. The reaction mixture was filtered and separated and purified by preparative high performance liquid chromatography (Waters 2545, elution system: 10 mmol/L aqueous ammonium bicarbonate solution and acetonitrile, gradient of acetonitrile: 50/6-95%, flow rate: 30 m/min) to give the title compound 12 (a Mixture of Diastereomers, a 1:1 ratio, 48 mg, yield: 56%).

MS m/z (ESI): 778.3 [M+1].

¹H NMR (500 MHz, DMSO-d₆): δ 10.75 (s, 1H), 8.24 (d, 1H), 7.58 (d, 1H), 7.42 (d, 1H), 7.36 (dd, 1H), 6.89 (t, 1H), 6.79 (d, 1H), 6.65 (dd, 1H), 6.24 (s, 1H), 6.17 (d, 1H), 6.12 (d, 1H), 5.60 (d, 1H), 4.51-4.39 (m, 1H), 4.33-4.25 (m, 1H), 4.09-3.97 (m, 2H), 3.48-3.32 (m, 4H), 3.30-3.21 (m, 2H), 3.09-2.96 (m, 4H), 2.79-2.67 (m, 2H), 2.64-2.50 (m, 3H), 2.47-2.41 (m, 3H), 2.28-1.94 (m, 4H), 1.90-1.62 (m, 5H), 1.61-1.42 (m, 3H), 1.31-1.16 (m, 4H), 1.14-0.99 (m, 2H).

Example 12-1 and Example 12-2

2-Chloro-4-((S)-8-(6-(4-((4-(3-(((S)-2,6-dioxopiperidin-3-yl)amino)phenyl)piperazin-1-yl)methyl)piperidine-1-carbonyl)pyridin-3-yl)-3-methyl-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile 12-1

2-Chloro-4-((S)-8-(6-(4-((4-(3-(((R)-2,6-dioxopiperidin-3-yl)amino)phenyl)piperazin-1-yl)methyl)piperidine-1-carbonyl)pyridin-3-yl)-3-methyl-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile 12-2

Compound 12 (500 mg) was resolved by preparative chiral chromatography (separation conditions: Gilson-281, column: Phenomenex Amylose-2, 5 μm, 21.2 mm×250 mm, mobile phase: acetonitrile (0.5% 7 M ammonia (NH₃) in methanol)/ethanol (0.5% 7 M ammonia (NH₃) in methanol)=40/60 (v/v)), flow rate 20 mL/min) to give eluates of two compounds. Each of the two eluates was well mixed with formic acid (1.0 g), and the solvent was removed by concentration under reduced pressure to give crude products (160 mg, 140 mg). The crude products of the two compounds (160 mg, 140 mg) were then separated and purified by preparative high performance liquid chromatography (Waters 2545, elution system: 10 mmol/L aqueous ammonium bicarbonate solution and acetonitrile, gradient of acetonitrile: 50/6-67%, flow rate: 30 mL/min) to give the title compounds (80 mg, 70 mg).

Single-configuration compound (shorter retention time) (80 mg, yield: 16%): MS m/z (ESI): 778.3 [M+1].

Chiral HPLC analysis method: retention time 3.92 minutes (Agilent 1260 DAD, column: Phenomenex LUX Amylose-2, (4.6×150 mM), 5 μm; mobile phase: acetonitrile/ethanol/diethylamine=40/60/0.06 (v/v/v), flow rate 1 mL/min).

¹H NMR (500 MHz, DMSO-d₆): δ 10.75 (s, 1H), 8.25 (d, 1H), 7.59 (d, 1H), 7.43 (d, 1H), 7.37 (dd, 1H), 6.90 (t, 1H), 6.80 (d, 1H), 6.66 (d, 1H), 6.25 (s, 1H), 6.18 (d, 1H), 6.13 (d, 1H), 5.61 (d, 1H), 4.51-4.39 (m, 1H), 4.33-4.25 (m, 1H), 4.09-3.97 (m, 2H), 3.48-3.32 (m, 4H), 3.30-3.21 (m, 2H), 3.09-2.96 (m, 4H), 2.79-2.67 (m, 2H), 2.64-2.50 (m, 3H), 2.47-2.41 (m, 3H), 2.28-1.94 (m, 4H), 1.90-1.62 (m, 5H), 1.61-1.42 (m, 3H), 1.38-1.16 (m, 4H), 1.14-0.99 (m, 2H).

Single-configuration compound (longer retention time) (70 mg, yield: 14%): MS m/z (ESI): 778.3 [M+1].

Chiral HPLC analysis method: retention time 4.74 minutes (Agilent 1260 DAD, column: Phenomenex LUX Amylose-2, (4.6×150 mM), 5 μm; mobile phase: acetonitrile/ethanol/diethylamine=40/60/0.06 (v/v/v), flow rate 1 mL/min).

¹H NMR (500 MHz, DMSO-d₆): δ 10.75 (s, 1H), 8.25 (d, 1H), 7.59 (d, 1H), 7.43 (d, 1H), 7.37 (dd, 1H), 6.90 (t, 1H), 6.80 (d, 1H), 6.66 (d, 1H), 6.25 (s, 1H), 6.18 (d, 1H), 6.13 (d, 1H), 5.61 (d, 1H), 4.51-4.39 (m, 1H), 4.33-4.25 (m, 1H), 4.09-3.94 (m, 2H), 3.52-3.32 (m, 4H), 3.30-3.21 (m, 2H), 3.09-2.96 (m, 4H), 2.79-2.67 (m, 2H), 2.64-2.50 (m, 3H), 2.47-2.41 (m, 3H), 2.28-1.94 (m, 4H), 1.90-1.62 (m, 5H), 1.61-1.42 (m, 3H), 1.38-1.16 (m, 4H), 1.14-0.99 (m, 2H).

Example 13

2-Chloro-4-((3S)-8-(6-(4-((4-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperazin-1-yl)methyl)piperidine-1-carbonyl)pyridazin-3-yl)-3-methyl-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile 13 (a Mixture of Diastereomers

To a 25 mL single-necked flask were sequentially added 2 mL of N,N-dimethylformamide, compound 11b (47 mg, 0.088 mmol), and (S)-6-(2-(3-chloro-4-cyanophenyl)-3-methyl-2,8-diazaspiro[4.5]decan-8-yl)pyridazine-3-carboxylic acid 13a (36 mg, 0.087 mmol, prepared using the method disclosed in “Example 54 on page 273 of the specification in the patent application WO2021055756A1”). N,N-Diisopropylethylamine (90 mg, 0.69 mmol) and O-(7-azabenzotriazol-1-y)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (66 mg, 0.17 mmol) were slowly added under an ice bath. The cooling bath was removed, and the mixture was left to react for 16 hours. The reaction mixture was filtered and separated and purified by preparative high performance liquid chromatography (Waters 2545, elution system: 10 mmol/L aqueous ammonium bicarbonate solution and acetonitrile, gradient of acetonitrile: 50/6-95%, flow rate: 30 mL/min) to give the title compound 13 (a Mixture of Diastereomers, a 1:1 ratio, 45 mg, yield: 66%).

MS m/z (ESI): 779.3 [M+1].

¹H NMR (500 MHz, DMSO-d₆): δ 10.74 (s, 1H), 7.59 (d, 1H), 7.50 (d, 1H), 7.32 (d, 1H), 6.89 (t, 1H), 6.79 (s, 1H), 6.65 (d, 1H), 6.24 (s, 1H), 6.17 (d, 1H), 6.12 (d, 1H), 5.60 (d, 1H), 4.48 (d, 1H), 4.34-4.25 (m, 1H), 4.10-3.95 (m, 2H), 3.87-3.74 (m, 2H), 3.66-3.55 (m, 2H), 3.48 (d, 1H), 3.38-3.32 (m, 1H), 3.13-2.99 (m, 4H), 2.85-2.67 (m, 2H), 2.64-2.50 (m, 3H), 2.48-2.42 (m, 3H), 2.31-1.93 (m, 4H), 1.92-1.63 (m, 5H), 1.62-1.40 (m, 3H), 1.31-1.17 (m, 4H), 1.17-1.02 (m, 2H).

Example 14

2-Chloro-4-((3S)-8-(4-(3-((4-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperazin-1-yl)methyl)azetidine-1-carbonyl)phenyl)-3-methyl-2,8-diazaspiro[4.5]decan-2-benzonitrile 14 (a Mixture of Diastereomers

Step 1

tert-Butyl (±)-3-((4-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperazin-1-yl)methyl)azetidine-1-carboxylate 14a

To a 50 mL single-necked flask was added 4 mL of a mixed solution of dichloromethane and methanol (V/V=3/1), followed by compound 10a (250 mg, 0.77 mmol) and anhydrous sodium acetate (729 mg, 8.67 mmol). After 15 minutes of reaction, tert-butyl 3-formylazetidine-1-carboxylate (324 mg, 1.54 mmol) was added. After 30 minutes of reaction, sodium triacetoxyborohydride (326 mg, 1.54 mmol) was slowly added, and the mixture was left to react for 1 hour. Dichloromethane and methanol were removed by concentration under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system A to give the title compound 14a (205 mg, yield: 58%).

MS m/z (ESI): 458.8 [M+1].

Step 2

(±)-3-((3-(4-(Azetidin-3-ylmethyl)piperazin-1-yl)phenyl)amino)piperidine-2,6-dione bistrifluoroacetate 14b

Compound 14a (100 mg, 0.22 mmol) was dissolved in 3 mL of dichloromethane, and trifluoroacetic acid (1 mL) was slowly added. The mixture was left to react for 1 hour. Dichloromethane and trifluoroacetic acid were removed by concentration under reduced pressure, and the residue was dried in vacuo to give the title compound 14b as a crude product (120 mg, yield: 94%). The crude product was directly used in the next step without purification.

MS m/z (ESI): 358.3 [M+1].

Step 3

2-Chloro-4-((3S)-8-(4-(3-((4-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperazin-1-yl)methyl)azetidine-1-carbonyl)phenyl)-3-methyl-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile 14 (a Mixture of Diastereomers

To a 50 mL single-necked flask were sequentially added 2 mL of N,N-dimethylformamide, compound 1h (75 mg, 0.18 mmol), N,N-diisopropylethylamine (118 mg, 0.91 mmol), and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (104 mg, 0.27 mmol). After 15 minutes of reaction, compound 14b (103 mg, 0.18 mmol) was added, and the mixture was left to react for 30 minutes. The reaction mixture was filtered and separated and purified by preparative high performance liquid chromatography (Waters 2545, elution system: 10 mmol/L aqueous ammonium bicarbonate solution and acetonitrile, gradient of acetonitrile: 48/6-63%, flow rate: 30 mL/min) to give the title compound 14 (a Mixture of Diastereomers, a 1:1 ratio, 70 mg, yield: 63%).

MS m/z (ESI): 749.3 [M+1].

¹H NMR (500 MHz, DMSO-d₆): δ 10.76 (s, 1H), 7.59 (d, 1H), 7.50 (d, 2H), 7.00-6.85 (m, 3H), 6.80 (s, 1H), 6.65 (d, 1H), 6.24 (s, 1H), 6.15 (dd, 2H), 5.62 (s, 1H), 4.49-4.23 (m, 2H), 4.17-3.89 (m, 4H), 3.71-3.58 (m, 1H), 3.52-3.16 (m, 5H), 3.03 (s, 4H), 2.92-2.81 (m, 1H), 2.78-2.33 (m, 6H), 2.28-2.18 (m, 1H), 2.14-1.95 (m, 2H), 1.92-1.79 (m, 2H), 1.78-1.65 (m, 2H), 1.62-1.41 (m, 3H), 1.20 (d, 3H).

Example 15

2-Chloro-4-((3S)-8-(4-(4-((4-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperazin-1-yl)methyl)piperidine-1-carbonyl)-2-fluorophenyl)-3-methyl-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile 15 (a Mixture of Diastereomers

To a 25 mL three-necked flask were sequentially added 2 mL of N,N-dimethylformamide, compound 11b (50 mg, 0.094 mmol), and (S)-4-(2-(3-chloro-4-cyanophenyl)-3-methyl-2,8-diazaspiro[4.5]decan-8-yl)-3-fluorobenzoic acid 15a (45 mg, 0.083 mmol, prepared using the method disclosed in “Example 52 on page 271 of the specification in the patent application WO2021055756A1”). N,N-Diisopropylethylamine (85 mg, 0.66 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (63 mg, 0.16 mmol) were slowly added under an ice bath. The cooling bath was removed, and the mixture was left to react for 16 hours. The reaction mixture was filtered and purified by preparative high performance liquid chromatography (Waters 2545, elution system: 10 mmol/L aqueous ammonium bicarbonate solution and acetonitrile, gradient of acetonitrile: 50/6-95%, flow rate: 30 mL/min) to give the title compound 15 (a mixture of diastereomers, a 1:1 ratio, 36 mg, yield: 54%).

MS m/z (ESI): 795.3 [M+1].

¹H NMR (500 MHz, DMSO-d₆): δ 10.75 (s, 1H), 7.59 (d, 1H), 7.13 (d, 1H), 7.11 (s, 1H), 7.06 (t, 1H), 6.89 (t, 1H), 6.79 (d, 1H), 6.65 (dd, 1H), 6.24 (s, 1H), 6.17 (d, 1H), 6.12 (d, 1H), 5.60 (d, 1H), 4.35-4.25 (m, 1H), 4.07-3.97 (m, 1H), 3.43 (d, 1H), 3.34-3.30 (m, 3H), 3.17-2.92 (m, 8H), 2.78-2.68 (m, 1H), 2.64-2.50 (m, 3H), 2.48-2.40 (m, 4H), 2.28-1.93 (m, 4H), 1.90-1.67 (m, 5H), 1.62-1.48 (m, 3H), 1.27-1.15 (m, 4H), 1.12-0.99 (m, 2H).

Example 15-1 and Example 15-2

2-Chloro-4-((S)-8-(4-(4-((4-(3-(((S)-2,6-dioxopiperidin-3-yl)amino)phenyl)piperazin-1-yl)methyl)piperidine-1-carbonyl)-2-fluorophenyl)-3-methyl-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile 15-1

2-Chloro-4-((S)-8-(4-(4-((4-(3-(((R)-2,6-dioxopiperidin-3-yl)amino)phenyl)piperazin-1-yl)methyl)piperidine-1-carbonyl)-2-fluorophenyl)-3-methyl-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile 15-2

Compound 15 (21 mg) was resolved by preparative chiral chromatography (separation conditions: Gilson-281, column: Phenomenex Amylose-2, 5 μm, 21.2 mm×250 mm, mobile phase: acetonitrile (0.5% 7 M ammonia (NH₃) in methanol)/ethanol (0.5% 7 M ammonia (NH₃) in methanol)=40/60 (v/v)), flow rate 20 mL/min) to give the title compound 15-2 (5 mg) and compound 15-1 (8 mg).

Compound 15-2 (5 mg, yield: 24%), with a shorter retention time: MS m/z (ESI): 795.3 [M+1].

Chiral HPLC analysis method: retention time 3.53 minutes (Agilent 1260 DAD, column: Phenomenex LUX Amylose-2, (4.6×150 mM), 5 μm; mobile phase: acetonitrile/ethanol/diethylamine=40/60/0.06 (v/v/), flow rate 1 mL/min).

¹H NMR (500 MHz, DMSO-d₆): δ 10.75 (s, 1H), 7.59 (d, 1H), 7.14 (d, 1H), 7.12 (s, 1H), 7.06 (t, 1H), 6.90 (t, 1H), 6.79 (d, 1H), 6.65 (dd, 1H), 6.24 (s, 1H), 6.17 (d, 1H), 6.13 (d, 1H), 5.61 (d, 1H), 4.35-4.25 (m, 1H), 4.07-3.97 (m, 1H), 3.43 (d, 1H), 3.37-3.30 (m, 3H), 3.17-2.92 (m, 8H), 2.78-2.68 (m, 1H), 2.64-2.50 (m, 3H), 2.48-2.40 (m, 4H), 2.28-1.93 (m, 4H), 1.90-1.67 (m, 5H), 1.62-1.48 (m, 3H), 1.27-1.15 (m, 4H), 1.12-0.99 (m, 2H).

Compound 15-1 (8 mg, yield: 38%), with a longer retention time: MS m/z (ESI): 795.3 [M+1].

Chiral HPLC analysis method: retention time 4.19 minutes (Agilent 1260 DAD, column: Phenomenex LUX Amylose-2, (4.6×150 mM), 5 μm; mobile phase: acetonitrile/ethanol/diethylamine=40/60/0.06 (v/v/v), flow rate 1 mL/min).

¹H NMR (500 MHz, DMSO-d₆): δ 10.76 (s, 1H), 7.59 (d, 1H), 7.13 (d, 1H), 7.11 (s, 1H), 7.06 (t, 1H), 6.90 (t, 1H), 6.80 (d, 1H), 6.65 (dd, 1H), 6.24 (s, 1H), 6.17 (d, 1H), 6.12 (d, 1H), 5.61 (d, 1H), 4.35-4.25 (m, 1H), 4.07-3.97 (m, 1H), 3.43 (d, 1H), 3.34-3.30 (m, 3H), 3.17-2.92 (m, 8H), 2.78-2.68 (m, 1H), 2.64-2.50 (m, 3H), 2.48-2.40 (m, 4H), 2.28-1.93 (m, 4H), 1.90-1.67 (m, 5H), 1.62-1.48 (m, 3H), 1.27-1.15 (m, 4H), 1.12-0.99 (m, 2H).

Example 16

2-Chloro-4-((3S)-8-(4-(4-((4-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperazin-1-yl)methyl)piperidine-1-carbonyl)-3-fluorophenyl)-3-methyl-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile 16 (a Mixture of Diastereomers

Step 1

tert-Butyl (S)-4-(2-(3-chloro-4-cyanophenyl)-3-methyl-2,8-diazaspiro[4.5]decan-8-yl)-2-fluorobenzoate 16a

To a 25 mL single-necked flask were sequentially added 10 mL of toluene, compound 5a (100 mg, 0.31 mmol), tert-butyl 4-bromo-2-fluorobenzoate (168 mg, 0.61 mmol, Bide Pharmatech), palladium acetate (13 mg, 0.057 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (35 mg, 0.061 mmol), and anhydrous cesium carbonate (299 mg, 0.92 mmol). The system was purged with nitrogen gas 3 times, and the reaction mixture was heated to 85° C. and left to react for 10 hours. The reaction mixture was filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system B to give the title compound 16a (100 mg, yield: 67%).

MS m/z (ESI):484.4 [M+1].

Step 2

(S)-4-(2-(3-Chloro-4-cyanophenyl)-3-methyl-2,8-diazaspiro[4.5]decan-8-yl)-2-fluorobenzoic acid 16b

Compound 16a (98 mg, 0.20 mmol) was dissolved in 3 mL of dichloromethane, and trifluoroacetic acid (461 mg, 4.04 mmol) was slowly added under an ice bath. The mixture was left to react for 2 hours. The reaction mixture was concentrated under reduced pressure and dried in vacuo to give the title compound 16b as a crude product (110 mg, yield: 99%). The crude product was directly used in the next step without purification.

MS m/z (ESI): 428.2 [M+1].

Step 3

2-Chloro-4-((3S)-8-(4-(4-((4-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperazin-1-yl)methyl)piperidine-1-carbonyl)-3-fluorophenyl)-3-methyl-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile 16 (a Mixture of Diastereomers

To a 25 mL single-necked flask were sequentially added 2 mL of N,N-dimethylformamide, compound 11b (53 mg, 0.099 mmol), and (S)-4-(2-(3-chloro-4-cyanophenyl)-3-methyl-2,8-diazaspiro[4.5]decan-8-yl)-2-fluorobenzoic acid 16b (50 mg, 0.092 mmol). N,N-Diisopropylethylamine (95 mg, 0.73 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (70 mg, 0.18 mmol) were slowly added under an ice bath. The cooling bath was removed, and the mixture was left to react for 16 hours. The reaction mixture was filtered and separated and purified by preparative high performance liquid chromatography (Waters 2545, elution system: 10 mmol/L aqueous ammonium bicarbonate solution and acetonitrile, gradient of acetonitrile: 50/6-95%, flow rate: 30 mL/min) to give the title compound 16 (a Mixture of Diastereomers, a 1:1 ratio, 38 mg, yield: 51%).

MS m/z (ESI): 795.8 [M+1].

¹H NMR (500 MHz, DMSO-d₆): δ 10.75 (s, 1H), 7.58 (d, 1H), 7.14 (t, 1H), 6.89 (t, 1H), 6.81-6.70 (m, 3H), 6.64 (dd, 1H), 6.24 (s, 1H), 6.17 (d, 1H), 6.12 (d, 1H), 5.60 (d, 1H), 4.49-4.38 (m, 1H), 4.32-4.24 (m, 1H), 4.06-3.98 (m, 1H), 3.54-3.32 (m, 4H), 3.30-3.16 (m, 3H), 3.09-2.94 (m, 4H), 2.78-2.67 (m, 2H), 2.64-2.50 (m, 3H), 2.48-2.41 (m, 3H), 2.26-1.95 (m, 4H), 1.90-1.62 (m, 5H), 1.60-1.52 (m, 1H), 1.50-1.40 (m, 2H), 1.30-1.15 (m, 4H), 1.08-0.92 (m, 2H).

Example 17

2-Chloro-4-((3S)-8-(5-(4-((4-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperazin-1-yl)methyl)piperidine-1-carbonyl)pyrazin-2-yl)-3-methyl-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile 17 (a Mixture of Diastereomers

Step 1

Methyl (S)-5-(2-(3-chloro-4-cyanophenyl)-3-methyl-2,8-diazaspiro[4.5]decan-8-yl)pyrazine-2-carboxylate 17a

To a 25 mL single-necked flask were sequentially added 10 mL of 1,4-dioxane, compound 5a (100 mg, 0.34 mmol), methyl 5-bromopyrazine-2-carboxylate (134 mg, 0.62 mmol, Bide Pharmatech), tris(dibenzylideneacetone)dipalladium(0) (31 mg, 0.033 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (19 mg, 0.033 mmol), and anhydrous cesium carbonate (281 mg, 0.86 mmol). The system was purged with nitrogen gas 3 times, and the reaction mixture was heated to 100° C. and left to react for 8 hours. The reaction mixture was filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system B to give the title compound 17a (130 mg, yield: 88%).

MS m/z (ESI):426.2 [M+1].

Step 2

(S)-5-(2-(3-Chloro-4-cyanophenyl)-3-methyl-2,8-diazaspiro[4.5]decan-8-yl)pyrazine-2-carboxylic acid 17b

Compound 17a (120 mg, 0.28 mmol) was dissolved in 2 mL of methanol, and a 1 M solution of sodium hydroxide (0.55 mL, 0.55 mmol) was slowly added under an ice bath. The mixture was left to react for 3 hours. The reaction mixture was concentrated under reduced pressure, and the pH of the reaction mixture was adjusted to about 4 with 1 M dilute hydrochloric acid. Filtration was performed, and the filter cake was collected and dried in vacuo to give the title compound 17b as a crude product (115 mg, yield: 99%). The crude product was directly used in the next step without purification.

MS m/z (ESI): 412.1 [M+1].

Step 3

2-Chloro-4-((3S)-8-(5-(4-((4-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperazin-1-yl)methyl)piperidine-1-carbonyl)pyrazin-2-yl)-3-methyl-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile 17 (a Mixture of Diastereomers

To a 25 mL single-necked flask were sequentially added 2 mL of N,N-dimethylformamide, compound 11b (51 mg, 0.096 mmol), and compound 17b (50 mg, 0.097 mmol). N,N-Diisopropylethylamine (100 mg, 0.77 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (73 mg, 0.19 mmol) were slowly added under an ice bath. The cooling bath was removed, and the mixture was left to react for 16 hours. The reaction mixture was filtered and separated and purified by preparative high performance liquid chromatography (Waters 2545, elution system: 10 mmol/L aqueous ammonium bicarbonate solution and acetonitrile, gradient of acetonitrile: 50/6-95%, flow rate: 30 mL/min) to give the title compound 17 (a Mixture of Diastereomers, a 1:1 ratio, 40 mg, yield: 52%).

MS m/z (ESI): 779.3 [M+1].

¹H NMR (500 MHz, DMSO-d₆): δ 10.75 (s, 1H), 8.29 (s, 1H), 8.26 (s, 1H), 7.59 (d, 1H), 6.89 (t, 1H), 6.78 (s, 1H), 6.64 (d, 1H), 6.24 (s, 1H), 6.17 (d, 1H), 6.12 (d, 1H), 5.60 (d, 1H), 4.50-4.36 (m, 1H), 4.34-4.25 (m, 1H), 4.11-3.99 (m, 2H), 3.84-3.74 (m, 2H), 3.65-3.53 (m, 2H), 3.47 (d, 1H), 3.33 (d, 1H), 3.11-2.96 (m, 4H), 2.81-2.67 (m, 2H), 2.64-2.50 (m, 3H), 2.47-2.42 (m, 3H), 2.30-1.93 (m, 4H), 1.91-1.62 (m, 5H), 1.62-1.53 (m, 1H), 1.50-1.39 (m, 2H), 1.32-1.16 (m, 4H), 1.15-0.99 (m, 2H).

Example 18

2-Chloro-4-((3S)-8-(5-(4-((4-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperazin-1-yl)methyl)piperidine-1-carbonyl)pyridin-2-yl)-3-methyl-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile 18 (a Mixture of Diastereomers

To a 25 mL single-necked flask were sequentially added 2 mL of N,N-dimethylformamide, compound 11b (59 mg, 0.11 mmol), and (S)-6-(2-(3-chloro-4-cyanophenyl)-3-methyl-2,8-diazaspiro[4.5]decan-8-yl)nicotinic acid 18a (65 mg, 0.10 mmol, prepared using the method disclosed in “Example 51 on page 268 of the specification in the patent application WO2021055756A1”). N,N-Diisopropylethylamine (131 mg, 1.01 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (77 mg, 0.20 mmol) were slowly added under an ice bath. The cooling bath was removed, and the mixture was left to react for 16 hours. The reaction mixture was filtered and separated and purified by preparative high performance liquid chromatography (Waters 2545, elution system: 10 mmol/L aqueous ammonium bicarbonate solution and acetonitrile, gradient of acetonitrile: 50/6-95%, flow rate: 30 mL/min) to give the title compound 18 (a Mixture of Diastereomers, a 1:1 ratio, 40 mg, yield: 50%).

MS m/z (ESI): 778.8 [M+1].

¹H NMR (500 MHz, DMSO-d₆): δ 10.75 (s, 1H), 8.14 (d, 1H), 7.59 (d, 1H), 7.53 (d, 1H), 6.89 (t, 1H), 6.83 (d, 1H), 6.78 (d, 1H), 6.64 (dd, 1H), 6.24 (s, 1H), 6.17 (d, 1H), 6.12 (d, 1H), 5.60 (d, 1H), 4.33-4.26 (m, 1H), 4.08-3.99 (m, 1H), 3.77-3.66 (m, 2H), 3.57-3.47 (m, 2H), 3.45 (d, 1H), 3.32 (d, 1H), 3.30-3.26 (m, 2H), 3.10-2.96 (m, 4H), 2.95-2.82 (m, 1H), 2.78-2.67 (m, 1H), 2.64-2.50 (m, 2H), 2.47-2.41 (m, 4H), 2.28-1.94 (m, 4H), 1.89-1.61 (m, 5H), 1.61-1.52 (m, 1H), 1.46-1.37 (m, 2H), 1.26-1.15 (m, 4H), 1.12-0.99 (m, 2H).

Example 19

2-Chloro-4-((3S)-8-(4-(4-((4-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperidin-1-yl)methyl)piperidine-1-carbonyl)phenyl)-3-methyl-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile 19 (a Mixture of Diastereomers

Step 1

tert-Butyl (±)-4-((4-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperidin-1-yl)methyl)piperidine-1-carboxylate 19b

To a 50 mL single-necked flask was added 4 mL of a mixed solution of dichloromethane and methanol (V/V=3/1), followed by (±)-3-((3-(piperidin-4-yl)phenyl)amino)piperidine-2,6-dione 19a (500 mg, 1.54 mmol, prepared using the method disclosed for “compound 2-2 on page 348 of the specification in the patent application WO2021127561A1”) and anhydrous sodium acetate (1.30 mg, 15.4 mmol). After 15 minutes of reaction, compound 3a (659 mg, 3.09 mmol) was added. After 30 minutes of reaction, sodium triacetoxyborohydride (654 mg, 3.09 mmol) was slowly added, and the mixture was left to react for 1 hour. Dichloromethane and methanol were removed by concentration under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system A to give the title compound 19b (130 mg, yield: 17%).

MS m/z (ESI): 485.2 [M+1].

Step 2

(±)-3-((3-(1-(Piperidin-4-ylmethyl)piperidin-4-yl)phenyl)amino)piperidine-2,6-dione dihydrochloride 19c

Compound 19b (100 mg, 0.22 mmol) was dissolved in 3 mL of dichloromethane, and a 4 M solution of hydrogen chloride in 1,4-dioxane (1 mL) was slowly added. The mixture was left to react for 1 hour. The reaction mixture was concentrated under reduced pressure and dried in vacuo to give the title compound 19c as a crude product (170 mg, yield: 97%). The crude product was directly used in the next step without purification.

MS m/z (ESI): 385.3 [M+1].

Step 3

2-Chloro-4-((3S)-8-(4-(4-((4-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperidin-1-yl)methyl)piperidine-1-carbonyl)phenyl)-3-methyl-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile 19 (a Mixture of Diastereomers

To a 50 mL single-necked flask were sequentially added 2 mL of N,N-dimethylformamide, compound 1h (50 mg, 0.12 mmol), N,N-diisopropylethylamine (79 mg, 0.61 mmol), and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (70 mg, 0.18 mmol). After 15 minutes of reaction, compound 19c (130 mg, 0.28 mmol) was added, and the mixture was left to react for 30 minutes. The reaction mixture was filtered and separated and purified by preparative high performance liquid chromatography (Waters 2545, elution system: 10 mmol/L aqueous ammonium bicarbonate solution and acetonitrile, gradient of acetonitrile: 60/6-76%, flow rate: 30 mL/min) to give the title compound 19 (a Mixture of Diastereomers, a 1:1 ratio, 30 mg, yield: 32%).

MS m/z (ESI): 776.6 [M+1].

¹H NMR (500 MHz, DMSO-d₆): δ 10.76 (s, 1H), 7.59 (d, 1H), 7.24 (d, 2H), 6.98 (t, 1H), 6.94 (d, 2H), 6.80 (s, 1H), 6.65 (d, 1H), 6.55 (s, 1H), 6.49 (d, 1H), 6.44 (d, 1H), 5.71 (d, 1H), 4.37-4.28 (m, 1H), 4.08-3.98 (m, 1H), 3.51-3.13 (m, 5H), 3.00-2.69 (m, 5H), 2.62-2.53 (m, 1H), 2.38-2.28 (m, 1H), 2.07-2.04 (m, 4H), 2.02-1.42 (m, 18H), 1.20 (d, 3H), 1.12-0.98 (m, 2H).

Example 20

2-Chloro-4-((3S)-8-(6-(4-((4-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperidin-1-yl)methyl)piperidine-1-carbonyl)pyridazin-3-yl)-3-methyl-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile 20 (a Mixture of Diastereomers

To a 50 mL single-necked flask were sequentially added 2 mL of N,N-dimethylformamide, compound 13a (30 mg, 0.072 mmol), N,N-diisopropylethylamine (47 mg, 0.36 mmol), and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (42 mg, 0.093 mmol). After 15 minutes of reaction, compound 19c (43 mg, 0.08 mmol) was added, and the mixture was left to react for 30 minutes. The reaction mixture was filtered and separated and purified by preparative high performance liquid chromatography (Waters 2545, elution system: 10 mmol/L aqueous ammonium bicarbonate solution and acetonitrile, gradient of acetonitrile: 50/6-67%, flow rate: 30 mL/min) to give the title compound 20 (a Mixture of Diastereomers, a 1:1 ratio, 20 mg, yield: 35%).

MS m/z (ESI): 778.3 [M+1].

¹H NMR (500 MHz, DMSO-d₆): δ 10.76 (s, 1H), 7.60 (d, 1H), 7.51 (d, 1H), 7.33 (d, 1H), 6.98 (t, 1H), 6.80 (s, 1H), 6.66 (d, 1H), 6.55 (s, 1H), 6.48 (d, 1H), 6.45 (d, 1H), 5.71 (d, 1H), 4.52-4.46 (m, 1H), 4.36-4.28 (m, 1H), 4.10-3.96 (m, 2H), 3.86-3.76 (m, 2H), 3.67-3.57 (m, 2H), 3.49 (d, 1H), 3.40-3.26 (m, 2H), 3.08 (t, 1H), 2.99-2.88 (m, 2H), 2.84-2.70 (m, 2H), 2.65-2.53 (m, 2H), 2.37-2.25 (m, 2H), 2.20-2.08 (m, 2H), 2.03-1.80 (m, 5H), 1.77-1.55 (m, 7H), 1.51-1.42 (m, 2H), 1.21 (d, 3H), 1.17-1.03 (m, 2H).

Example 21

2-Chloro-4-((3S)-8-(6-(3-((4-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperidin-1-yl)methyl)azetidine-1-carbonyl)pyridazin-3-yl)-3-methyl-2,8-diazaspiro[4.5]decan-2-benzonitrile 21 (a Mixture of Diastereomers

Step 1

tert-Butyl (±)-3-((4-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperidin-1-yl)methyl)azetidine-1-carboxylate 21a

To a 50 mL single-necked flask was added 4 mL of a mixed solution of dichloromethane and methanol (V/V=3/1), followed by compound 19a (390 mg, 1.20 mmol) and anhydrous sodium acetate (505 mg, 6.02 mmol). After 15 minutes of reaction, tert-butyl 3-formylazetidine-1-carboxylate (446 mg, 2.41 mmol, Bide Pharmatech) was added. After 30 minutes of reaction, sodium triacetoxyborohydride (508 mg, 2.41 mmol) was slowly added, and the mixture was left to react for 1 hour. Dichloromethane and methanol were removed by concentration under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system A to give the title compound 21a (100 mg, yield: 22%).

MS m/z (ESI): 457.3 [M+1].

Step 2

(±)-3-((3-(1-(Azetidin-3-ylmethyl)piperidin-4-yl)phenyl)amino)piperidine-2,6-dione bistrifluoroacetate 21b

Compound 21a (95 mg, 0.21 mmol) was dissolved in 3 mL of dichloromethane, and trifluoroacetic acid (0.5 mL) was slowly added. The mixture was left to react for 1 hour. Dichloromethane and trifluoroacetic acid were removed by concentration under reduced pressure, and the residue was dried in vacuo to give the title compound 21b as a crude product (120 mg, yield: 99%). The crude product was directly used in the next step without purification.

MS m/z (ESI): 357.5 [M+1].

Step 3

2-Chloro-4-((3S)-8-(6-(3-((4-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperidin-1-yl)methyl)azetidine-1-carbonyl)pyridazin-3-yl)-3-methyl-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile 21 (a Mixture of Diastereomers

To a 50 mL single-necked flask were sequentially added 2 mL of N,N-dimethylformamide, compound 13a (30 mg, 0.073 mmol), N,N-diisopropylethylamine (47 mg, 0.36 mmol), and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (30 mg, 0.11 mmol). After 15 minutes of reaction, compound 21b (59 mg, 0.10 mmol) was added, and the mixture was left to react for 30 minutes. The reaction mixture was filtered and separated and purified by preparative high performance liquid chromatography (Waters 2545, elution system: 10 mmol/L aqueous ammonium bicarbonate solution and acetonitrile, gradient of acetonitrile: 50/6-67%, flow rate: 30 mL/min) to give the title compound 21 (a Mixture of Diastereomers, a 1:1 ratio, 20 mg, yield: 37%).

MS m/z (ESI): 750.5 [M+1].

¹H NMR (500 MHz, DMSO-d₆): δ 10.76 (s, 1H), 7.75 (d, 1H), 7.60 (d, 1H), 7.32 (d, 1H), 6.98 (t, 1H), 6.80 (s, 1H), 6.66 (d, 1H), 6.56 (s, 1H), 6.48 (d, 1H), 6.45 (d, 1H), 5.71 (d, 1H), 4.64 (t, 1H), 4.37-4.29 (m, 1H), 4.27-4.21 (m, 1H), 4.15 (t, 1H), 4.09-4.00 (m, 1H), 3.91-3.80 (m, 2H), 3.74-3.59 (m, 3H), 3.49 (d, 1H), 3.35 (d, 1H), 2.95-2.84 (m, 2H), 2.80-2.70 (m, 1H), 2.62-2.53 (m, 3H), 2.38-2.28 (m, 2H), 2.14-1.96 (m, 4H), 1.92-1.81 (m, 1H), 1.77-1.56 (m, 7H), 1.50-1.42 (m, 2H), 1.21 (d, 3H).

Example 22

2-Chloro-4-((3S)-8-(6-(3-((4-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperazin-1-yl)methyl)azetidine-1-carbonyl)pyridazin-3-yl)-3-methyl-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile 22 (a Mixture of Diastereomers

To a 50 mL single-necked flask were sequentially added 2 mL of N,N-dimethylformamide, compound 14b (55 mg, 0.079 mmol), and compound 13a (35 mg, 0.068 mmol). N,N-Diisopropylethylamine (70 mg, 0.54 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (47 mg, 0.12 mmol) were slowly added under an ice bath. The cooling bath was removed, and the mixture was left to react for 16 hours. The reaction mixture was filtered and separated and purified by preparative high performance liquid chromatography (Waters 2545, elution system: 10 mmol/L aqueous ammonium bicarbonate solution and acetonitrile, gradient of acetonitrile: 50/6-95%, flow rate: 30 mL/min) to give the title compound 22 (a mixture of diastereomers, a 1:1 ratio, 20 mg, yield: 39%).

MS m/z (ESI): 751.3 [M+1].

¹H NMR (500 MHz, DMSO-d₆): δ 10.74 (s, 1H), 7.74 (d, 1H), 7.59 (d, 1H), 7.31 (d, 1H), 6.89 (t, 1H), 6.79 (s, 1H), 6.65 (d, 1H), 6.24 (s, 1H), 6.17 (d, 1H), 6.13 (d, 1H), 5.61 (d, 1H), 4.64 (t, 1H), 4.34-4.20 (m, 2H), 4.18-4.12 (m, 1H), 4.07-3.99 (m, 1H), 3.89-3.79 (m, 2H), 3.75-3.58 (m, 3H), 3.48 (d, 1H), 3.34 (d, 1H), 3.11-2.99 (m, 4H), 2.94-2.83 (m, 1H), 2.78-2.68 (m, 1H), 2.66-2.50 (m, 5H), 2.30-2.21 (m, 1H), 2.12-2.04 (m, 2H), 2.89-2.79 (m, 1H), 1.75-1.62 (m, 2H), 1.61-1.55 (m, 1H), 1.50-1.41 (m, 2H), 1.28-1.16 (m, 4H).

Example 23

2-Chloro-4-((3S)-8-(4-(4-((4-(5-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperazin-1-yl)methyl)piperidine-1-carbonyl)phenyl)-3-methyl-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile 23 (a Mixture of Diastereomers

tert-Butyl 4-(2-fluoro-5-nitrophenyl)piperazine-1-carboxylate 23b 2-Bromo-1-fluoro-4-nitrobenzene 23a (1.0 g, 4.55 mmol) and tert-butyl piperazine-1-carboxylate (847 mg, 4.55 mmol, Bide Pharmatech) were dissolved in 15 mL of 1,4-dioxane, and cesium carbonate (4.44 g, 13.64 mmol) and methanesulfonato(2-dicyclohexylphosphino-2′,6′-diisopropoxy-1,1′-biphenyl)(2-amino-1,1′-biphenyl-2-yl)palladium(II) (381 mg, 0.454 mmol, Bide Pharmatech) were added. The system was purged with nitrogen gas 3 times, heated to 110° C., and left to react for 12 hours. 10 mL of water was added, and extraction was performed with ethyl acetate (20 mL×3). The organic phase was washed with a saturated sodium chloride solution (10 mL×3), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system B to give the title compound 23b (1.0 g, yield: 68%).

MS m/z (ESI): 270.1 [M-55].

Step 2

tert-Butyl 4-(5-amino-2-fluorophenyl)piperazine-1-carboxylate 23c

Compound 23b (1.0 g, 3.07 mmol) was dissolved in 12 mL of methanol, and 10% wet palladium on carbon (containing 50% water, 327 mg, Accela ChemBio (Shanghai) Co., Ltd.) was then added. The system was purged with hydrogen gas 3 times and left to react for 12 hours under a hydrogen balloon atmosphere. The reaction mixture was filtered using celite. The resulting filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system B to give the title compound 23c (600 mg, yield: 66%).

MS m/z (ESI): 296.2 [M+1].

Step 3

tert-Butyl (±)-4-(5-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperazine-1-carboxylate 23d

Compound 23c (400 mg, 1.35 mmol) was dissolved in 10 mL of acetonitrile, and (4)-3-bromopiperidine-2,6-dione (312 mg, 1.63 mmol) and sodium bicarbonate (455 mg, 5.42 mmol) were then added. After 4 hours of reaction at 85° C., 3-bromopiperidine-2,6-dione (312 mg, 1.63 mmol) was added again. After another 4 hours of reaction, 3-bromopiperidine-2,6-dione (312 mg, 1.63 mmol) was added again, and the mixture was left to react for 4 hours. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system B to give the title compound 23d (400 mg, yield: 73%).

MS m/z (ESI): 407.4 [M+1].

Step 4

(±)-3-((4-Fluoro-3-(piperazin-1-yl)phenyl)amino)piperidine-2,6-dione hydrochloride 23e

Compound 23d (200 mg, 0.49 mmol) was weighed into a 50 mL eggplant-shaped flask, and a 4 M solution of hydrogen chloride in 1,4-dioxane (3 mL) was added. After 2 hours of reaction, the system was concentrated under reduced pressure and dried in vacuo to give the title compound 23e as a crude product (168 mg, yield: 99%). The crude product was directly used in the next step without purification.

MS m/z (ESI): 307.2 [M+1].

Step 5

tert-Butyl (±)-4-((4-(5-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperazin-1-yl)methyl)piperidine-1-carboxylate 23f

To a 25 mL single-necked flask was added 3 mL of a mixed solution of dichloromethane and methanol (V/V=2/1), followed by compound 23e (100 mg, 0.29 mmol) and anhydrous sodium acetate (216 mg, 2.6 mmol). After 15 minutes of reaction, compound 3a (112 mg, 0.53 mmol) was added. After 0.5 hours of reaction, sodium triacetoxyborohydride (112 mg, 0.53 mmol) was slowly added, and the mixture was left to react for 1 hour. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system A to give the title compound 23f (130 mg, yield: 98%).

MS m/z (ESI): 504.9 [M+1].

Step 6

(±)-3-((4-Fluoro-3-(4-(piperidin-4-ylmethyl)piperazin-1-yl)phenyl)amino)piperidine-2,6-dione dihydrochloride 23g

Compound 23f (130 mg, 0.26 mmol) was weighed into a 50 mL eggplant-shaped flask, and a 4 M solution of hydrogen chloride in 1,4-dioxane (3 mL) was added. After 2 hours of reaction, the system was concentrated under reduced pressure and dried in vacuo to give the title compound 23g as a crude product (122 mg, yield: 99%). The crude product was directly used in the next step without purification.

Step 7

2-Chloro-4-((3S)-8-(4-(4-((4-(5-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperazin-1-yl)methyl)piperidine-1-carbonyl)phenyl)-3-methyl-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile 23 (a Mixture of Diastereomers

To a 25 mL single-necked flask were sequentially added 2 mL of N,N-dimethylformamide, compound 23g (80 mg, 0.17 mmol), and compound 1h (69 mg, 0.17 mmol). N,N-Diisopropylethylamine (130 mg, 1.0 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (96 mg, 0.25 mmol) were slowly added under an ice bath. The cooling bath was removed, and the mixture was left to react for 16 hours. The reaction mixture was filtered and separated and purified by preparative high performance liquid chromatography (Waters 2545, elution system: 10 mmol/L aqueous ammonium bicarbonate solution and acetonitrile, gradient of acetonitrile: 60/6-80%, flow rate: 30 mL/min) to give the title compound 23 (a Mixture of Diastereomers, a 1:1 ratio, 35 mg, yield: 26%).

MS m/z (ESI):795.3 [M+1].

¹H NMR (500 MHz, DMSO-d₆): δ 10.75 (s, 1H), 7.58 (d, 1H), 7.23 (d, 2H), 6.93 (d, 2H), 6.85-6.76 (m, 2H), 6.65 (dd, 1H), 6.33 (dd, 1H), 6.19 (dt, 1H), 5.66 (d, 1H), 4.28-4.21 (m, 1H), 4.07-3.99 (m, 1H), 3.42 (d, 1H), 3.38-3.31 (m, 5H), 3.25-3.14 (m, 2H), 3.00-2.80 (m, 5H), 2.76-2.67 (m, 1H), 2.64-2.50 (m, 3H), 2.48-2.44 (m, 3H), 2.26-2.16 (m, 2H), 2.12-1.94 (m, 2H), 1.90-1.65 (m, 5H), 1.60-1.54 (m, 1H), 1.53-1.40 (m, 2H), 1.29-1.16 (m, 4H), 1.11-0.98 (m, 2H).

Example 24

2-Chloro-4-((3S)-8-(4-(4-((4-(4-((2,6-dioxopiperidin-3-yl)amino)pyridin-2-yl)piperazin-1-yl)methyl)piperidine-1-carbonyl)phenyl)-3-methyl-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile 24 (a Mixture of Diastereomers

Step 1

tert-Butyl 4-(4-nitropyridin-2-yl)piperazine-1-carboxylate 24b

To a 50 mL single-necked flask were sequentially added 25 mL of N,N-dimethylformamide, 2-chloro-4-nitropyridine 24a (2.84 g, 17.90 mmol, Bide Pharmatech), and tert-butyl piperazine-1-carboxylate (3.34 g, 19.9 mmol, Bide Pharmatech). N,N-Diisopropylethylamine (4.63 mg, 35.8 mmol) was slowly added, and the system was then heated to 100° C. and left to react for 16 hours. 50 mL of a saturated sodium bicarbonate solution was added to the reaction system under ice bath cooling, and extraction was performed with dichloromethane (50 mL×3). The organic phases were combined, washed with a saturated sodium chloride solution (50 mL×3), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system B to give the title compound 24b (1.3 g, yield: 23%).

MS m/z (ESI): 253.1 [M-55].

Step 2

tert-Butyl 4-(4-aminopyridin-2-yl)piperazine-1-carboxylate 24c

To a 100 mL single-necked flask were sequentially added 30 mL of a mixed solution of ethyl acetate and methanol (V/V=1/1), compound 24b (1.0 g, 3.24 mmol), and 10% palladium on carbon (containing 50% water, 300 mg). The system was then purged with hydrogen gas 3 times and left to react for 2 hours under a hydrogen atmosphere. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give the title compound 24c (902 mg, yield: 99%). The crude product was directly used in the next step without purification.

MS m/z (ESI): 279.2 [M+1].

Step 3

tert-Butyl 4-(4-((2,6-bis(benzyloxy)pyridin-3-yl)amino)pyridin-2-yl)piperazine-1-carboxylate 24e

To a 50 mL single-necked flask were sequentially added 25 mL of toluene, 2,6-bis(benzyloxy)-3-bromopyridine 24d (554 mg, 1.49 mmol, Bide Pharmatech), and compound 24c (278 mg, 1.00 mmol), followed by methanesulfonato(9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene)(2′-amino-1,1′-biphenyl-2-yl)palladium(II) (135 mg, 0.14 mmol) and sodium tert-butoxide (191 mg, 1.99 mmol). The system was heated to 100° C. and left to react for 16 hours under a nitrogen atmosphere. 50 mL of a saturated sodium bicarbonate solution was added to the system under ice bath cooling to quench the reaction, and extraction was performed with dichloromethane (50 mL×3). The organic phases were combined, washed with a saturated sodium chloride solution (50 mL×3), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system A to give the title compound 24e (480 mg, yield: 84%).

MS m/z (ESI): 568.2 [M+1].

Step 4

tert-Butyl 4-(4-((2,6-dioxo-1,2,5,6-tetrahydropyridin-3-yl)amino)pyridin-2-yl)piperazine-1-carboxylate 24f

To a 100 mL single-necked flask were sequentially added 20 mL of a mixed solution of ethyl acetate and ethanol (V/V=3/1), compound 24e (480 mg, 0.84 mmol), and 10% palladium on carbon (containing 50% water, 480 mg, 3.91 mmol). The mixture was left to react at room temperature for 16 hours under a hydrogen atmosphere. The filtrate was concentrated under reduced pressure to give the title compound 24f as a crude product (327 mg, yield: 99%). The crude product was directly used in the next step without purification.

MS m/z (ESI): 388.2 [M+1].

Step 5

tert-Butyl (±)-4-(4-((2,6-dioxopiperidin-3-yl)amino)pyridin-2-yl)piperazine-1-carboxylate 24g

To a 100 mL single-necked flask were sequentially added 48 mL of a mixed solution of tetrahydrofuran and ethanol (V/V=5/1), compound 24g (400 mg, 1.03 mmol), and platinum dioxide (152 mg, 0.67 mmol). The system was purged with hydrogen gas 3 times, heated to 45° C., and left to react for 8 hours under a hydrogen atmosphere. The system was purged with hydrogen gas 3 times and left to react at 45° C. for 8 hours under a hydrogen atmosphere. The filtrate was concentrated under reduced pressure to give the title compound 24g as a crude product (30 mg, yield: 7.6%). The crude product was directly used in the next step without purification.

MS m/z (ESI): 390.2 [M+1].

Step 6

(±)-3-((2-(Piperazin-1-yl)pyridin-4-yl)amino)piperidine-2,6-dione bistrifluoroacetate 24h

To a 50 mL single-necked flask were sequentially added 4 mL of a mixed solution of trifluoroacetic acid and dichloromethane (V/V=¼) and Compound 24g (50 mg, 0.13 mmol). The mixture was left to react for 1 hour. The reaction mixture was concentrated under reduced pressure to give the title compound 24h as a crude product (66 mg, yield: 99%). The crude product was directly used in the next step without purification.

MS m/z (ESI): 290.3 [M+1].

Step 7

2-Chloro-4-((3S)-8-(4-(4-((4-(4-((2,6-dioxopiperidin-3-yl)amino)pyridin-2-yl)piperazin-1-yl)methyl)piperidine-1-carbonyl)phenyl)-3-methyl-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile 24 (a Mixture of Diastereomers

To a 25 mL single-necked flask was added 3 mL of a mixed solution of dichloromethane and methanol (V/V=2/1), followed by compound 24h (39 mg, 0.07 mmol) and anhydrous sodium acetate (49 mg, 0.64 mmol). After 15 minutes of reaction, compound 8a (49 mg, 0.09 mmol) was added. After 30 minutes of reaction, sodium triacetoxyborohydride (32 mg, 0.15 mmol) was slowly added, and the mixture was left to react for 16 hours. 10 mL of a saturated sodium bicarbonate solution was added to the reaction system under ice bath cooling, and extraction was performed with ethyl acetate (50 mL×3). The organic phases were combined, washed with a saturated sodium chloride solution (20 mL×3), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure and separated and purified by preparative high performance liquid chromatography (Waters 2545, elution system: 10 mmol/L aqueous ammonium bicarbonate solution and acetonitrile, gradient of acetonitrile: 50/6-95%, flow rate: 30 mL/min) to give the title compound 24 (a Mixture of Diastereomers, a 1:1 ratio, 10 mg, yield: 17%).

MS m/z (ESI): 778.4 [M+1].

¹H NMR (500 MHz, DMSO-d₆): δ 10.97 (s, 1H), 8.22-7.90 (m, 1H), 7.80-7.48 (m, 2H), 7.24 (d, 2H), 6.95 (d, 2H), 6.80 (s, 1H), 6.66 (d, 1H), 6.40 (s, 1H), 6.14 (s, 1H), 4.85-4.62 (m, 1H), 4.35-3.92 (m, 3H), 3.72-3.40 (m, 4H), 3.39-3.32 (m, 6H), 3.22-3.13 (m, 2H), 3.10-2.58 (m, 5H), 2.48-2.35 (m, 2H), 2.30-1.95 (m, 4H), 1.92-1.65 (m, 4H), 1.62-1.40 (m, 3H), 1.34-1.16 (m, 4H), 1.14-0.95 (m, 2H).

Example 25

2-Chloro-4-((3S)-8-(4-(4-((4-(4-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperazin-1-yl)methyl)piperidine-1-carbonyl)phenyl)-3-methyl-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile 25 (a Mixture of Diastereomers

The compound (±)-3-((4-(piperazin-1-yl)phenyl)amino)piperidine-2,6-dione hydrochloride 25a (25 mg, 0.069 mmol, prepared using the method disclosed in “Example 89 on page 268 of the specification in the patent application WO2018237026A1”) was dissolved in 5 mL of a mixed solvent of methanol and dichloromethane (V/V=4/1), and sodium acetate (25 mg, 0.30 mmol) was added. After 30 minutes of reaction, compound 8a (30 mg, 0.059 mmol) was added. After 15 minutes of reaction, sodium triacetoxyborohydride (26 mg, 0.12 mmol) was added, and the mixture was left to react for 1 hour. The reaction mixture was filtered and separated and purified by preparative high performance liquid chromatography (Waters-2545, elution system: 10 mmol/L aqueous ammonium bicarbonate solution and acetonitrile, gradient of acetonitrile: 50/6-95%, flow rate: 30 mL/min) to give the title compound 25 (a mixture of diastereomers, a 1:1 ratio, 16 mg, yield: 35%).

MS m/z (ESI): 777.3 [M+1].

¹H NMR (500 MHz, DMSO-d₆): δ 10.74 (s, 1H), 7.58 (d, 1H), 7.26-7.20 (m, 2H), 6.96-6.90 (m, 2H), 6.79 (s, 1H), 6.76-6.70 (m, 2H), 6.65 (d, 1H), 6.62-6.55 (m, 2H), 5.36 (d, 1H), 4.21-4.14 (m, 1H), 4.06-3.98 (m, 1H), 3.46-3.33 (m, 4H), 3.30-3.24 (m, 2H), 3.24-3.13 (m, 2H), 2.98-2.84 (m, 4H), 2.77-2.65 (m, 1H), 2.65-2.52 (m, 2H), 2.48-2.42 (m, 5H), 2.27-1.94 (m, 4H), 1.86-1.66 (m, 5H), 1.61-1.53 (m, 1H), 1.52-1.41 (m, 2H), 1.25-1.16 (m, 4H), 1.10-0.97 (m, 2H).

Example 26

2-Chloro-4-((3S)-8-(4-(4-((4-(4-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperidin-1-yl)methyl)piperidine-1-carbonyl)phenyl)-3-methyl-2,8-diazaspiro[4.5]decan-2-benzonitrile 26 (a Mixture of Diastereomers

Step 1

tert-Butyl (±)-4-((4-(4-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperidin-1-yl)methyl)piperidine-1-carboxylate 26b

To a 50 mL single-necked flask was added 8 mL of a mixed solution of dichloromethane and methanol (V/V=4/1), followed by (±)-3-((4-(piperidin-4-yl)phenyl)amino)piperidine-2,6-dione hydrochloride 26a (830 mg, 2.89 mmol, prepared using the method disclosed for “compound 2-2 on page 348 of the specification in the patent application WO2021127561A1”) and anhydrous sodium acetate (731 mg, 8.7 mmol). After 15 minutes of reaction, compound 3a (742 mg, 3.48 mmol) was added.

After 30 minutes of reaction, sodium triacetoxyborohydride (738 mg, 3.48 mmol) was slowly added, and the mixture was left to react for 1 hour. Dichloromethane and methanol were removed by concentration under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system A to give the title compound 26b (500 mg, yield: 59%).

MS m/z (ESI): 485.8 [M+1].

Step 2

(±)-3-((4-(1-(Piperidin-4-ylmethyl)piperidin-4-yl)phenyl)amino)piperidine-2,6-dione dihydrochloride 26c

Compound 26b (500 mg, 1.03 mmol) was dissolved in 10 mL of dichloromethane, and a 4 M solution of hydrogen chloride in 1,4-dioxane (2 mL) was slowly added. The mixture was left to react for 1 hour. The reaction mixture was concentrated under reduced pressure and dried in vacuo to give the title compound 26c as a crude product (450 mg, yield: 95%). The crude product was directly used in the next step without purification.

MS m/z (ESI): 385.3 [M+1].

Step 3

2-Chloro-4-((3S)-8-(4-(4-((4-(4-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperidin-1-yl)methyl)piperidine-1-carbonyl)phenyl)-3-methyl-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile 26 (a Mixture of Diastereomers

To a 50 mL single-necked flask were sequentially added 2 mL of N,N-dimethylformamide, compound 1h (40 mg, 0.10 mmol), N,N-diisopropylethylamine (63 mg, 0.49 mmol), and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (55 mg, 0.14 mmol). After 15 minutes of reaction, compound 26c (53 mg, 0.12 mmol) was added, and the mixture was left to react for 30 minutes. The reaction mixture was filtered and separated and purified by preparative high performance liquid chromatography (Waters 2545, elution system: 10 mmol/L aqueous ammonium bicarbonate solution and acetonitrile, gradient of acetonitrile: 60/6-85%, flow rate: 30 mL/min) to give the title compound 26 (a Mixture of Diastereomers, a 1:1 ratio, 25 mg, yield: 33%).

MS m/z (ESI): 776.3 [M+1].

¹H NMR (500 MHz, DMSO-d₆): δ 10.76 (s, 1H), 7.59 (d, 1H), 7.24 (d, 2H), 6.94 (d, 4H), 6.80 (d, 1H), 6.66 (d, 1H), 6.60 (d, 2H), 5.64 (d, 1H), 4.31-4.21 (m, 1H), 4.08-4.00 (m, 1H), 3.44 (d, 1H), 3.26-3.15 (m, 2H), 3.00-2.68 (m, 5H), 2.64-2.54 (m, 2H), 2.38-2.06 (m, 6H), 2.03-1.91 (m, 3H), 1.87-1.43 (m, 15H), 1.20 (d, 3H), 1.10-1.00 (m, 2H).

Example 27

2-Chloro-4-((3S)-8-(4-(4-((4-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperidin-1-yl)methyl)piperidine-1-carbonyl)phenyl)-3-methyl-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile 27 (a Mixture of Diastereomers

Step 1

tert-Butyl (±)-4-((4-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperidin-1-yl)methyl)piperidine-1-carboxylate 27b

To a 50 mL single-necked flask was added 4 mL of a mixed solution of dichloromethane and methanol (V/V=3/1), followed by (±)-3-((3-fluoro-4-(piperidin-4-yl)phenyl)amino)piperidine-2,6-dione hydrochloride 27a (106 mg, 0.35 mmol, prepared using the method disclosed for “compound 6 on page 353 of the specification in the patent application WO2021127561A1”) and anhydrous sodium acetate (146 mg, 1.74 mmol). After 15 minutes of reaction, compound 3a (148 mg, 0.70 mmol) was added. After 30 minutes of reaction, sodium triacetoxyborohydride (148 mg, 0.70 mmol) was slowly added, and the mixture was left to react for 1 hour. Dichloromethane and methanol were removed by concentration under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system A to give the title compound 27b (150 mg, yield: 86%).

MS m/z (ESI): 503.9 [M+1].

Step 2

(±)-3-((3-Fluoro-4-(1-(piperidin-4-ylmethyl)piperidin-4-yl)phenyl)amino)piperidine-2,6-dione dihydrochloride 27c

Compound 27b (150 mg, 0.30 mmol) was dissolved in 3 mL of dichloromethane, and a 4 M solution of hydrogen chloride in 1,4-dioxane (0.5 mL) was slowly added. The mixture was left to react for 1 hour. The reaction mixture was concentrated under reduced pressure and dried in vacuo to give the title compound 27c as a crude product (140 mg, yield: 99%). The crude product was directly used in the next step without purification.

MS m/z (ESI): 403.4 [M+1].

Step 3

2-Chloro-4-((3S)-8-(4-(4-((4-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperidin-1-yl)methyl)piperidine-1-carbonyl)phenyl)-3-methyl-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile 27 (a Mixture of Diastereomers

To a 50 mL single-necked flask were sequentially added 2 mL of N,N-dimethylformamide, compound 1h (50 mg, 0.12 mmol), N,N-diisopropylethylamine (79 mg, 0.61 mmol), and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (70 mg, 0.18 mmol). After 15 minutes of reaction, compound 27c (70 mg, 0.15 mmol) was added, and the mixture was left to react for 30 minutes. The reaction mixture was filtered and separated and purified by preparative high performance liquid chromatography (Waters 2545, elution system: 10 mmol/L aqueous ammonium bicarbonate solution and acetonitrile, gradient of acetonitrile: 64/6-82%, flow rate: 30 mL/min) to give the title compound 27 (a Mixture of Diastereomers, a 1:1 ratio, 40 mg, yield: 41%).

MS m/z (ESI): 794.3 [M+1].

¹H NMR (500 MHz, DMSO-d₆) δ 10.78 (s, 1H), 7.59 (d, 1H), 7.24 (d, 2H), 6.98 (t, 1H), 6.94 (d, 2H), 6.80 (s, 1H), 6.66 (d, 1H), 6.43 (t, 2H), 5.99 (d, 1H), 4.33-4.25 (m, 1H), 4.07-4.00 (m, 1H), 3.49-3.14 (m, 11H), 2.96-2.80 (m, 3H), 2.78-2.68 (m, 1H), 2.61-2.55 (m, 1H), 2.27-2.10 (m, 1H), 2.16 (d, 2H), 2.11-2.04 (m, 1H), 2.03-1.91 (m, 2H), 1.88-1.67 (m, 6H), 1.65-1.55 (m, 4H), 1.52-1.43 (m, 2H), 1.20 (d, 3H), 1.10-0.97 (m, 2H).

Example 28

(S)-2-Chloro-4-(8-(4-(2-(4-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carbonyl)phenyl)-3-methyl-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile 28

Step 1

7-Azaspiro[3.5]nonan-2-one trifluoroacetate 28b

tert-Butyl 2-oxo-7-azaspiro[3.5]nonane-7-carboxylate 28a (323 mg, 1.35 mmol, Bide Pharmatech) was dissolved in dichloromethane (3 mL), and 1 mL of trifluoroacetic acid was added. The mixture was left to react for 1 hour. The reaction mixture was concentrated under reduced pressure and dried in vacuo to give the title compound 28b as a crude product (237 mg, yield: 99%). The crude product was directly used in the next step without purification.

MS m/z (ESI): 140.2 [M+1].

Step 2

(S)-2-Chloro-4-(3-methyl-8-(4-(2-oxo-7-azaspiro[3.5]nonane-7-carbonyl)phenyl)-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile 28c

To a 25 mL reaction flask were sequentially added 1 h (200 mg, 0.49 mmol), compound 28b (190 mg, 0.75 mmol), and N,N-dimethylformamide (2 mL), followed by O-(7-azabenzotriazol-1-yl)-N,N,N′N′-tetramethyluronium hexafluorophosphate (222 mg, 0.54 mmol) and N,N-diisopropylethylamine (252 mg, 1.95 mmol). After 1 hour of reaction, the reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system A to give the title compound 28c (200 mg, yield: 77%).

MS m/z (ESI): 531.2 [M+1].

Step 3

(S)-2-Chloro-4-(8-(4-(2-(4-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carbonyl)phenyl)-3-methyl-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile 28

Compound 6a (65 mg, 0.21 mmol) was weighed into a 25 mL eggplant-shaped flask, and 8 mL of a mixed solvent of dichloromethane and methanol (V/V=3/1) and anhydrous sodium acetate (93 mg, 1.14 mmol) were added. After 15 minutes of reaction, compound 28c (100 mg, 0.19 mmol) was added to the system. After 1 hour of reaction, sodium triacetoxyborohydride (80 mg, 0.377 mmol) was added, and the mixture was left to react for 1 hour. The reaction mixture was filtered and separated and purified by preparative high performance liquid chromatography (Waters-2545, elution system: 10 mmol/L aqueous ammonium bicarbonate solution and acetonitrile, gradient of acetonitrile: 50/0-70%, flow rate: 30 mL/min) to give the title compound 28 (100 mg, yield: 67%).

MS m/z (ESI): 789.5 [M+1].

¹H NMR (500 MHz, DMSO-d₆) δ 10.25 (s, 1H), 7.59 (d, 1H), 7.23 (d, 2H), 7.14 (d, 2H), 6.93 (t, 4H), 6.80 (s, 1H), 6.66 (d, 1H), 4.07-4.00 (m, 1H), 3.69 (t, 2H), 3.43 (d, 2H), 3.39-3.33 (m, 3H), 3.26-3.16 (m, 2H), 3.12 (s, 4H) 2.76-2.62 (m, 4H), 2.38 (s, 4H), 2.23 (dd, 1H), 2.05-1.95 (m, 3H), 1.78-1.66 (m, 2H), 1.64-1.42 (m, 10H), 1.20 (d, 3H).

Example 29

(S)-2-Chloro-4-(8-(4-(9-(4-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperazin-1-yl)-3-azaspiro[5.5]undecane-3-carbonyl)phenyl)-3-methyl-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile 29

Step 1

tert-Butyl 9-(4-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperazin-1-yl)-3-azaspiro[5.5]undecane-3-carboxylate 29b

To a 50 mL reaction flask was added 6 mL of a mixed solvent of 1,2-dichloroethane and methanol (V/V=5/1), followed by compound 6a (100 mg, 0.32 mmol) and anhydrous sodium acetate (158 mg, 1.93 mmol). After 10 minutes of reaction, tert-butyl 9-oxo-3-azaspiro[5.5]undecane-3-carboxylate 29a (215 mg, 0.80 mmol) was added. After 0.5 hours of reaction, sodium triacetoxyborohydride (137 mg, 0.65 mmol) was added. After hour of reaction, the reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system A to give the title compound 29b (100 mg, yield: 59%).

MS m/z (ESI): 526.3 [M+1].

Step 2

1-(4-(4-(3-Azaspiro[5.5]undecan-9-yl)piperazin-1-yl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione dihydrochloride 29c

Compound 29b (100 mg, 0.19 mmol) was dissolved in a 4 M solution of hydrogen chloride in 1,4-dioxane (3 mL), and the mixture was left to react for 3 hours. The reaction mixture was concentrated and dried in vacuo to give the title compound 29c as a crude product (94 mg, yield: 99%). The crude product was directly used in the next step without purification.

MS m/z (ESI): 426.2 [M+1].

Step 3

(S)-2-Chloro-4-(8-(4-(9-(4-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperazin-1-yl)-3-azaspiro[5.5]undecane-3-carbonyl)phenyl)-3-methyl-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile 29

To a 25 mL reaction flask were sequentially added 3 mL of N,N-dimethylformamide, compound 1h (30 mg, 0.073 mmol), and compound 29c (44 mg, 0.09 mmol), followed by O-(7-azabenzotriazol-1-yl)-N,N,N′N′-tetramethyluronium hexafluorophosphate (42 mg, 0.11 mmol) and N,N-diisopropylethylamine (38 mg, 0.29 mmol). After 1 hour of reaction, the reaction mixture was filtered and separated and purified by preparative high performance liquid chromatography (Waters 2767-SQ Detecor2, elution system: 10 mmol/L aqueous ammonium bicarbonate solution and acetonitrile, gradient of acetonitrile: 50%-70%, flow rate: 30 mL/min) to give the title compound 29 (15 mg, yield: 25%).

MS m/z (ESI): 817.3 [M+1].

¹H NMR (500 MHz, DMSO-d₆): δ 10.24 (s, 1H), 7.58 (d, 1H), 7.23 (d, 2H), 7.13 (d, 2H), 6.96-6.86 (m, 4H), 6.79 (d, 1H), 6.65 (dd, 1H), 4.07-3.97 (m, 1H), 3.73-3.64 (m, 2H), 3.51-3.34 (m, 6H), 3.29-3.04 (m, 7H), 2.92-2.83 (m, 1H), 2.71-2.52 (m, 7H), 2.29-2.17 (m, 2H), 2.05-1.94 (m, 1H), 1.79-1.54 (m, 6H), 1.52-1.25 (m, 7H), 1.19 (d, 3H), 1.16-1.05 (m, 2H).

Example 30

(S)-2-Chloro-4-(8-(4-(2-(4-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carbonyl)-2-fluorophenyl)-3-methyl-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile 30

Step 1

(S)-2-Chloro-4-(8-(2-fluoro-4-(2-oxo-7-azaspiro[3.5]nonane-7-carbonyl)phenyl)-3-methyl-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile 30a

Compound 15a (77 mg, 0.18 mmol) was dissolved in N,N-dimethylformamide (2 mL). Compound 28b (71 mg, 0.28 mmol) was added, and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (82 mg, 0.215 mmol) and N,N-diisopropylethylamine (116 mg, 0.90 mmol) were then added. After 1 hour of reaction, the reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system A to give the title compound 30a (80 mg, yield: 81%).

Step 2

(S)-2-Chloro-4-(8-(4-(2-(4-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carbonyl)-2-fluorophenyl)-3-methyl-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile 30

Compound 6a (53 mg, 0.17 mmol) was weighed into a 25 mL eggplant-shaped flask, and 8 mL of a mixed solvent of dichloromethane and methanol (V/V=3/1) and anhydrous sodium acetate (65 mg, 0.79 mmol) were added. After 15 minutes of reaction, compound 30a (72 mg, 0.13 mmol) was added to the system. After 1 hour of reaction, sodium cyanoborohydride (16 mg, 0.26 mmol) was added, and the mixture was left to react for 1 hour. The reaction mixture was filtered and separated and purified by preparative high performance liquid chromatography (Waters-2545, elution system: 10 mmol/L aqueous ammonium bicarbonate solution and acetonitrile, gradient of acetonitrile: 47%-67%, flow rate: 30 mL/min) to give the title compound 30 (25 mg, yield: 24%).

MS m/z (ESI): 807.3 [M+1].

¹H NMR (500 MHz, DMSO-d₆): δ 10.26 (s, 1H), 7.60 (d, 1H), 7.20-7.12 (m, 4H), 7.07 (t, 1H), 6.93 (d, 2H), 6.80 (s, 1H), 6.66 (d, 1H), 4.09-3.97 (m, 1H), 3.69 (t, 2H), 3.54-3.40 (m, 3H), 3.34-3.32 (m, 3H), 3.16-3.09 (m, 6H), 3.06-3.00 (m, 2H), 2.68 (t, 2H), 2.45-2.30 (m, 3H), 2.28-2.22 (m, 1H), 2.05-1.92 (m, 3H), 1.85-1.72 (m, 2H), 1.68-1.39 (m, 10H), 1.21 (d, 3H).

Example 31

(S)-2-Chloro-4-(8-(4-(2-(4-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carbonyl)-3-fluorophenyl)-3-methyl-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile 31

Step 1

tert-Butyl 2-(4-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate 31a

Compound 6a (277 mg, 0.89 mmol) was weighed into a 25 mL eggplant-shaped flask, and 25 mL of a mixed solvent of dichloromethane and methanol (V/V=4/1) and anhydrous sodium acetate (439 mg, 5.35 mmol) were added. After 15 minutes of reaction, compound 28a (257 mg, 1.07 mmol) was added to the system. After 1 hour of reaction, sodium cyanoborohydride (107 mg, 1.79 mmol) was added, and the mixture was left to react for 12 hours. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system A to give the title compound 31a (330 mg, yield: 74%).

MS m/z (ESI): 498.8 [M+1].

Step 2

1-(4-(4-(7-Azaspiro[3.5]nonan-2-yl)piperazin-1-yl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione bistrifluoroacetate 31b

Compound 31a (330 mg, 0.66 mmol) was added to a 25 mL eggplant-shaped flask. 10 mL of dichloromethane was added, and 2 mL of trifluoroacetic acid was added. The mixture was left to react for 1 hour. The reaction mixture was concentrated under reduced pressure to give the title compound 31b as a crude product (300 mg, yield: 72%). The crude product was directly used in the next step without purification.

MS m/z (ESI): 398.4 [M+1].

Step 3

(S)-2-Chloro-4-(8-(4-(2-(4-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carbonyl)-3-fluorophenyl)-3-methyl-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile 31

Compound 31b (43 mg, 0.069 mmol) was dissolved in N,N-dimethylformamide (3 mL). Compound 16b (30 mg, 0.70 mmol) was added, and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (35 mg, 0.091 mmol) and N,N-diisopropylethylamine (36 mg, 0.28 mmol) were then added. The mixture was left to react for 1 hour. The reaction mixture was filtered and separated and purified by preparative high performance liquid chromatography (Waters-2545, elution system: 10 mmol/L aqueous ammonium bicarbonate solution and acetonitrile, gradient of acetonitrile: 47/0-67%, flow rate: 30 mL/min) to give the title compound 31 (15 mg, yield: 27%).

MS m/z (ESI): 807.3 [M+1].

¹H NMR (500 MHz, DMSO-d₆): δ 10.26 (s, 1H), 7.60 (d, 1H), 7.22-7.10 (m, 3H), 6.93 (d, 2H), 6.84-6.72 (m, 3H), 6.66 (d, 1H), 4.09-3.98 (m, 1H), 3.69 (t, 2H), 3.57-3.32 (m, 6H), 3.27-3.19 (m, 3H), 3.17-3.02 (m, 4H), 2.80-2.62 (m, 3H), 2.45-2.35 (m, 4H), 2.26-2.20 (m, 1H), 2.10-1.94 (m, 2H), 1.80-1.38 (m, 12H), 1.21 (d, 3H).

Example 32

(S)-2-Chloro-4-(8-(6-(2-(4-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carbonyl)pyridin-3-yl)-3-methyl-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile 32

Step 1

(S)-2-Chloro-4-(3-methyl-8-(6-(2-oxo-7-azaspiro[3.5]nonane-7-carbonyl)pyridin-3-yl)-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile 32a

Compound 12a (100 mg, 0.24 mmol) was dissolved in N,N-dimethylformamide (4 mL). Compound 28b (92 mg, 0.36 mmol) was added, and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (111 mg, 0.29 mmol) and N,N-diisopropylethylamine (135 mg, 0.97 mmol) were then added. After 1 hour of reaction, the reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system A to give the title compound 32a (100 mg, yield: 77%).

Step 2

(S)-2-Chloro-4-(8-(6-(2-(4-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carbonyl)pyridin-3-yl)-3-methyl-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile 32

Compound 6a (35 mg, 0.11 mmol) was weighed into a 25 mL eggplant-shaped flask, and 4 mL of a mixed solvent of dichloromethane and methanol (V/V=3/1) and anhydrous sodium acetate (46 mg, 0.56 mmol) were added. After 15 minutes of reaction, compound 32a (50 mg, 0.094 mmol) was added to the system. After 1 hour of reaction, sodium cyanoborohydride (11 mg, 0.18 mmol) was added, and the mixture was left to react for 1 hour. The reaction mixture was filtered and separated and purified by preparative high performance liquid chromatography (Waters-2545, elution system: 10 mmol/L aqueous ammonium bicarbonate solution and acetonitrile, gradient of acetonitrile: 39/6-59%, flow rate: 30 mL/min) to give the title compound 32 (25 mg, yield: 33%).

MS m/z (ESI): 790.3 [M+1].

¹H NMR (500 MHz, DMSO-d₆): δ 10.25 (s, 1H), 8.25 (s, 1H), 7.60 (d, 1H), 7.43 (d, 1H), 7.37 (dd, 1H), 7.14 (d, 2H), 6.92 (d, 2H), 6.80 (d, 1H), 6.66 (dd, 1H), 4.10-3.99 (m, 1H), 3.69 (t, 2H), 3.57-3.40 (m, 6H), 3.29-3.23 (m, 3H), 3.20-3.02 (s, 4H), 2.80-2.61 (m, 3H), 2.45-2.28 (m, 4H), 2.27-2.23 (m, 1H), 2.05-1.94 (m, 2H), 1.82-1.68 (m, 2H), 1.62-1.32 (m, 10H), 1.21 (d, 3H).

Example 33

(S)-2-Chloro-4-(8-(5-(2-(4-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carbonyl)pyridin-2-yl)-3-methyl-2,8-diazaspiro[4.5]decan-2-yl]benzonitrile 33

Compound 18a (30 mg, 0.073 mmol) was dissolved in N,N-dimethylformamide (3 mL), and compound 31b (45 mg, 0.072 mmol), O-(7-azabenzotriazol-1-yl)-N,N,N′,N-tetramethyluronium hexafluorophosphate (36 mg, 0.095 mmol), and N,N-diisopropylethylamine (38 mg, 0.294 mmol) were added. The mixture was left to react for 1 hour. The reaction mixture was filtered and separated and purified by preparative high performance liquid chromatography (Waters-2545, elution system: 10 mmol/L aqueous ammonium bicarbonate solution and acetonitrile, gradient of acetonitrile: 45/0-65%, flow rate: 30 mL/min) to give the title compound 33 (15 mg, yield: 26%).

MS m/z (ESI): 790.3 [M+1].

¹H NMR (500 MHz, DMSO-d₆) S: 10.25 (s, 1H), 8.14 (d, 1H), 7.60 (d, 1H), 7.53 (d, 1H), 7.14 (d, 2H), 6.92 (d, 2H), 6.83 (d, 1H), 6.79 (s, 1H), 6.65 (d, 1H), 4.04 (q, 1H), 3.76-3.72 (m, 1H), 3.69 (t, 2H), 3.57-3.42 (m, 6H), 3.39-3.33 (m, 2H), 3.11 (s, 4H), 2.72 (t, 1H), 2.67 (t, 2H), 2.38 (s, 4H), 2.25 (dd, 1H), 2.04-1.95 (m, 3H), 1.70-1.55 (m, 7H), 1.53-1.44 (m, 2H), 1.43-1.37 (m, 2H), 1.20 (d, 3H).

Example 34

2-Chloro-4-((3S)-8-(4-(2-(4-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carbonyl)phenyl)-3-methyl-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile 34 (a Mixture of Diastereomers

(±)-3-(4-(Piperazin-1-yl)phenyl)piperidine-2,6-dione 34a (a racemate, a 1:1 ratio, 31 mg, 0.113 mmol, prepared using the method disclosed in “Example Ligase 70 on page 104 of the specification in the disclosed patent WO2021083949A1”) was dissolved in a mixed solvent of dichloromethane and methanol (8 mL, V/V=3/1), and anhydrous sodium acetate (47 mg, 0.573 mmol) was added. The mixture was left to react for 10 minutes. Compound 28c (50 mg, 0.094 mmol) was added, and the mixture was left to react for 10 minutes. Sodium cyanoborohydride (11 mg, 0.184 mmol) was added, and the mixture was left to react for 12 hours. The reaction mixture was filtered and separated and purified by preparative high performance liquid chromatography (Waters-2545, elution system: 10 mmol/L aqueous ammonium bicarbonate solution and acetonitrile, gradient of acetonitrile: 50/6-70%, flow rate: 30 mL/min) to give the title compound 34 (a mixture of diastereomers, a 1:1 ratio, 20 mg, yield: 27%).

MS m/z (ESI): 788.3 [M+1].

¹H NMR (500 MHz, DMSO-d₆): δ 10.35 (s, 1H), 7.58 (d, 1H), 7.23 (d, 2H), 7.04 (d, 2H), 6.93 (d, 2H), 6.87 (d, 2H), 6.78 (s, 1H), 6.65 (d, 1H), 4.02 (q, 1H), 3.71 (dd, 3H), 3.35-3.27 (m, 6H), 3.24-3.18 (m, 2H), 3.09 (s, 4H), 2.71 (t, 1H), 2.65-2.58 (m, 1H), 2.48-2.43 (m, 1H), 2.36 (s, 4H), 2.23 (dd, 1H), 2.14-2.09 (m, 1H), 2.03-1.95 (m, 3H), 1.78-1.67 (m, 2H), 1.64-1.52 (m, 5H), 1.50-1.42 (m, 4H), 1.19 (d, 3H).

Example 35

(S)-2-Chloro-4-(8-(4-(2-(4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carbonyl)phenyl)-3-methyl-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile 35

Step 1

tert-Butyl 4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperazine-1-carboxylate 35b

tert-Butyl 4-(3-aminophenyl)piperazine-1-carboxylate 35a (1 g, 3.60 mmol, prepared using the method disclosed in “Example SSTN-552 on page 312 of the specification in the disclosed patent WO2021237112A1”) was dissolved in toluene (5 mL), and acrylic acid (286 mg, 3.97 mmol, Bide Pharmatech) was added. The mixture was heated to 100° C. and left to react for 3 hours. Toluene was removed under reduced pressure, and acetic acid (3 mL) and urea (867 mg, 14.4 mmol) were added. The mixture was heated to 100° C. and left to react for 12 hours. Acetic acid was removed under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system A to give the title compound 35b (150 mg, yield: 11%).

MS m/z (ESI): 375.4 [M+1].

Step 2

1-(3-(Piperazin-1-yl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione trifluoroacetate 35c Compound 35b (150 mg, 0.40 mmol) was added to a 25 mL eggplant-shaped flask, and dichloromethane (10 mL) and trifluoroacetic acid (2 mL) were added. The mixture was left to react for 1 hour. The reaction mixture was concentrated under reduced pressure and dried in vacuo to give the title compound 35c as a crude product (100 mg, yield: 91%). The crude product was directly used in the next step without purification.

MS m/z (ESI): 275.4 [M+1].

Step 3

(S)-2-Chloro-4-(8-(4-(2-(4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carbonyl)phenyl)-3-methyl-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile 35

Compound 28c (50 mg, 0.094 mmol) was weighed into a 25 mL eggplant-shaped flask, and a mixed solvent of dichloromethane and methanol (4 mL, V/V=3/1) and anhydrous sodium acetate (46 mg, 0.49 mmol) were added. After 15 minutes of reaction, compound 35c (37 mg, 0.096 mmol) was added to the system. After 1 hour of reaction, sodium cyanoborohydride (15 mg, 0.25 mmol) was added, and the mixture was left to react for 1 hour. The reaction mixture was filtered and separated and purified by preparative high performance liquid chromatography (Waters-2545, elution system: 10 mmol/L aqueous ammonium bicarbonate solution and acetonitrile, gradient of acetonitrile: 50/6-80%, flow rate: 30 mL/min) to give the title compound 35 (15 mg, yield: 20%).

MS m/z (ESI): 789.7 [M+1].

¹H NMR (500 MHz, DMSO-d₆) δ 10.29 (s, 1H), 7.59 (d, 1H), 7.23 (d, 2H), 7.20 (t, 1H), 6.94 (d, 2H), 6.87 (s, 1H), 6.82-6.77 (m, 2H), 6.71 (dd, 1H), 6.66 (dd, 1H), 4.03 (q, 1H), 3.74 (t, 2H), 3.43 (d, 4H), 3.31-3.26 (m, 2H), 3.25-3.15 (m, 3H), 3.12 (s, 4H), 2.75-2.70 (m, 1H), 2.68 (t, 2H), 2.37 (s, 4H), 2.23 (dd, 1H), 2.04-1.95 (m, 3H), 1.78-1.66 (m, 2H), 1.64-1.53 (m, 5H), 1.51-1.42 (m, 4H), 1.20 (d, 3H).

Example 36

2-Chloro-4-((3S)-8-(4-(2-(4-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carbonyl)-2-fluorophenyl)-3-methyl-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile 36 (a Mixture of Diastereomers

Compound 10a (35 mg, 0.11 mmol) was dissolved in a mixed solvent of dichloromethane and methanol (8 mL, V/V=3/1), and anhydrous sodium acetate (45 mg, 0.55 mmol) was added. After 10 minutes of reaction, compound 30a (50 mg, 0.091 mmol) was added. After 30 minutes of reaction, sodium cyanoborohydride (11 mg, 0.18 mmol) was added, and the mixture was left to react for 12 hours. The reaction mixture was filtered and separated and purified by preparative high performance liquid chromatography (Waters-2545, elution system: 10 mmol/L aqueous ammonium bicarbonate solution and acetonitrile, gradient of acetonitrile: 53%-73%, flow rate: 30 mL/min) to give the title compound 36 (a Mixture of Diastereomers, a 1:1 ratio, 30 mg, yield: 40%).

MS m/z (ESI): 821.3 [M+1].

¹H NMR (500 MHz, DMSO-d₆) δ: 10.76 (s, 1H), 7.60 (d, 1H), 7.19-7.02 (m, 3H), 6.91 (t, 1H), 6.81 (s, 1H), 6.67 (d, 1H), 6.25 (s, 1H), 6.16 (dd, 2H), 5.62 (d, 1H), 4.34-4.27 (m, 1H), 4.04 (q, 1H), 3.45 (d, 4H), 3.17-3.08 (m, 2H), 3.07-2.97 (m, 6H), 2.78-2.69 (m, 2H), 2.64-2.54 (m, 2H), 2.35 (s, 4H), 2.26 (dd, 1H), 2.13-2.05 (m, 1H), 2.04-1.96 (m, 2H), 1.91-1.75 (m, 4H), 1.63-1.52 (m, 7H), 1.51-1.43 (m, 2H), 1.21 (d, 3H).

Example 37

2-Chloro-4-((3S)-8-(4-(4-((1-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperidin-4-yl)methyl)piperazine-1-carbonyl)phenyl)-3-methyl-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile 37 (a Mixture of Diastereomers

Step 1

4-(Dimethoxymethyl)-1-(3-nitrophenyl)piperidine 37c

To a 50 mL single-necked flask were sequentially added 25 mL of dimethyl sulfoxide, m-fluoronitrobenzene 37b (1 g, 7.09 mmol, Accela ChemBio (Shanghai) Co., Ltd.), and 4-(dimethoxymethyl)piperidine 37a (1.7 g, 10.7 mmol, Accela ChemBio (Shanghai) Co., Ltd.). Potassium carbonate (1.46 g, 10.6 mmol) was slowly added, and the reaction flask was then placed in a microwave reactor. The mixture was heated to 120° C. and left to react for 4 hours. 50 mL of a saturated sodium bicarbonate solution was added to the reaction system under ice bath cooling, and extraction was performed with ethyl acetate (50 mL×3). The organic phases were combined, washed with a saturated sodium chloride solution (50 mL×3), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system B to give the title compound 37c (374 mg, yield: 19%).

MS m/z (ESI): 281.1 [M+1].

Step 2

3-(4-(Dimethoxymethyl)piperidin-1-yl)aniline 37d

Compound 37c (370 mg, 1.32 mmol) was dissolved in methanol (5 mL), and 10% dry palladium on carbon (14 mg, Accela ChemBio (Shanghai) Co., Ltd.) was then added. The system was purged with hydrogen gas 3 times and left to react for 12 hours under a hydrogen atmosphere. The reaction mixture was filtered using celite. The resulting filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system B to give the title compound 37d (329 mg, yield: 99%).

MS m/z (ESI): 251.2 [M+1].

Step 3

(±)-3-((3-(4-(Dimethoxymethyl)piperidin-1-yl)phenyl)amino)piperidine-2,6-dione 37e Compound 37d (330 mg, 1.32 mmol) was dissolved in acetonitrile (10 mL). Sodium bicarbonate (554 mg, 6.60 mmol) was added, and (±)-3-bromopiperidine-2,6-dione (303 mg, 1.58 mmol, Jiangsu Aikon Co., Ltd.) was added. The mixture was heated to 80° C. and left to react. After 2 hours of reaction, (±)-3-bromopiperidine-2,6-dione (303 mg, 1.58 mmol) was added again. After 2 hours of reaction, (±)-3-bromopiperidine-2,6-dione (303 mg, 1.58 mmol) was added again, and the mixture was left to react for 12 hours. The reaction mixture was concentrated under reduced pressure and filtered, and the filter cake was washed with ethyl acetate (15 mL). The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system A to give the title compound 37e (a racemate, a 1:1 ratio, 40 mg, yield: 8%).

MS m/z (ESI): 362.6 [M+1].

Step 4

(±)-1-(3-((2,6-Dioxopiperidin-3-yl)amino)phenyl)piperidine-4-carbaldehyde 37f Compound 37e (40 mg, 0.11 mmol) was dissolved in tetrahydrofuran (5 mL), and a 2 M sulfuric acid solution (1 mL) was added. The mixture was heated to 60° C. and left to react for 4 hours in an oil bath. Solid sodium bicarbonate was added to the reaction mixture to adjust the pH of the reaction mixture to 8. Filtration was performed, and the filtrate was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and dried in vacuo to give the title compound 37f as a crude product (a racemate, a 1:1 ratio, 30 mg, yield: 86%). The crude product was directly used in the next step without purification.

MS m/z (ESI): 316.2 [M+1].

Step 5

tert-Butyl (S)-4-(4-(2-(3-chloro-4-cyanophenyl)-3-methyl-2,8-diazaspiro[4.5]decan-8-yl)benzoyl)piperazine-1-carboxylate 37g

Compound 1h (100 mg, 0.24 mmol) was dissolved in N,N-dimethylformamide (2 mL). tert-Butyl piperazine-1-carboxylate (38 mg, 0.36 mmol) was added, and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (139 mg, 0.37 mmol) and N,N-diisopropylethylamine (95 mg, 0.74 mmol) were then added. After 1 hour of reaction, the reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system A to give the title compound 37g (139 mg, yield: 98%).

MS m/z (ESI): 578.2 [M+1].

Step 6

(S)-2-Chloro-4-(3-methyl-8-(4-(piperazine-1-carbonyl)phenyl)-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile hydrochloride 37h

Compound 37g (139 mg, 0.24 mmol) was dissolved in a 4 M solution of hydrogen chloride in 1,4-dioxane (2 mL), and the mixture was left to react for 1 hour. The reaction mixture was concentrated and dried in vacuo to give the title compound 37h as a crude product (123 mg, yield: 99%). The crude product was directly used in the next step without purification.

MS m/z (ESI): 478.2 [M+1].

Step 7

2-Chloro-4-((3S)-8-(4-(4-((1-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperidin-4-yl)methyl)piperazine-1-carbonyl)phenyl)-3-methyl-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile 37

Compound 37h (60 mg, 0.12 mmol) was weighed into a 25 mL eggplant-shaped flask, and 4 mL of a mixed solvent of dichloromethane and methanol (V/V=3/1) and anhydrous sodium acetate (109 mg, 1.30 mmol) were added. After 15 minutes of reaction, compound 37f (41 mg, 0.13 mmol) was added to the system. After 1 hour of reaction, sodium triacetoxyborohydride (55 mg, 0.26 mmol) was added, and the mixture was left to react for 12 hours. The reaction mixture was filtered and separated and purified by preparative high performance liquid chromatography (Waters-2545, elution system: 10 mmol/L aqueous ammonium bicarbonate solution and acetonitrile, gradient of acetonitrile: 39/0-59%, flow rate: 30 mL/min) to give the title compound 37 (a Mixture of Diastereomers, a 1:1 ratio, 5 mg, yield: 5%).

MS m/z (ESI): 777.3 [M+1].

¹H NMR (500 MHz, DMSO-d₆) δ 10.75 (s, 1H), 7.58 (d, 1H), 7.25 (d, 2H), 6.95 (d, 2H), 6.89 (t, 1H), 6.80 (d, 1H), 6.66 (dd, 1H), 6.25 (s, 1H), 6.18 (d, 1H), 6.10 (d, 1H), 5.59 (d, 1H), 4.32-4.26 (m, 1H), 4.04 (q, 1H), 3.59 (d, 2H), 3.49 (s, 3H), 3.43 (d, 2H), 3.39-3.35 (m, 3H), 3.37-3.16 (m, 3H), 2.78-2.69 (m, 1H), 2.65-2.54 (m, 3H), 2.35 (s, 4H), 2.23 (dd, 1H), 2.18 (d, 2H), 2.12-2.06 (m, 1H), 2.03-1.95 (m, 1H), 1.84 (qd, 1H), 1.79-1.62 (m, 5H), 1.57 (dd, 1H), 1.51-1.45 (m, 2H), 1.20 (d, 3H).

Example 38

(±)-2-Chloro-4-(8-(4-(4-((4-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperazin-1-yl)methyl)piperidine-1-carbonyl)phenyl)-2,8-diazaspiro[4.5]decan-2-yl)-3-methylbenzonitrile 38 (a racemate)

To a 25 mL three-necked flask were sequentially added 2 mL of N,N-dimethylformamide, compound 11b (52 mg, 0.11 mmol), and 4-(2-(3-chloro-4-cyano-2-methylphenyl)-2,8-diazaspiro[4.5]decan-8-yl)benzoic acid 38a (55 mg, 0.11 mmol, prepared using the method disclosed in “Example 11 on page 212 of the specification in the disclosed patent WO202155756 A1”). N,N-Diisopropylethylamine (118 mg, 0.91 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (70 mg, 0.18 mmol) were slowly added under an ice bath, and the system was then warmed to room temperature and left to react for 16 hours. The reaction mixture was filtered and separated and purified by preparative high performance liquid chromatography (Waters 2545, elution system: 10 mmol/L aqueous ammonium bicarbonate solution and acetonitrile, gradient of acetonitrile: 55%-95%, flow rate: 30 mL/min) to give the title compound 38 (a racemate, a 1:1 ratio, 35 mg, yield: 39%).

MS m/z (ESI): 777.3 [M+1].

¹H NMR (500 MHz, DMSO-d₆): δ 10.75 (s, 1H), 7.56 (d, 1H), 7.24 (d, 2H), 6.95 (d, 2H), 6.90 (t, 1H), 6.85 (d, 1H), 6.25 (s, 1H), 6.18 (d, 1H), 6.13 (d, 1H), 5.61 (d, 1H), 4.34-4.26 (m, 1H), 4.24-3.69 (m, 3H), 3.46 (t, 2H), 3.30-3.23 (m, 5H), 3.05 (s, 4H), 2.95-2.81 (m, 2H), 2.78-2.69 (m, 1H), 2.61-2.54 (m, 1H), 2.46 (s, 4H), 2.37 (s, 3H), 2.19 (d, 2H), 2.13-2.05 (m, 1H), 1.88-1.78 (m, 4H), 1.77-1.70 (m, 2H), 1.69-1.61 (m, 4H), 1.11-1.01 (m, 2H).

Example 39

2-Chloro-4-((3S)-8-(4-(4-((4-(2-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperazin-1-yl)methyl)piperidine-1-carbonyl)phenyl)-3-methyl-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile 39 (a Mixture of Diastereomers

Step 1

tert-Butyl 4-(2-nitrophenyl)piperazine-1-carboxylate 39b

2-Fluoronitrobenzene 39a (1 g, 7.09 mmol, Bide Pharmatech) and tert-butyl piperazine-1-carboxylate (1.45 g, 7.79 mmol) were dissolved in N,N-dimethylformamide (10 mL), and cesium carbonate (4.62 g, 14.18 mmol) was added. The mixture was heated to 80° C. and left to react for 12 hours. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system B to give the title compound 39b (2.0 g, yield: 92%).

MS m/z (ESI): 308.2 [M+1].

Step 2

tert-Butyl 4-(2-aminophenyl)piperazine-1-carboxylate 39c

Compound 39b (2 g, 6.51 mmol) was dissolved in methanol (20 mL), and 10% dry palladium on carbon (692 mg) was added. The system was purged with hydrogen gas three times and left to react for 12 hours under a hydrogen atmosphere. The reaction mixture was filtered using celite. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system A to give the title compound 39c (1.8 g, yield: 100%).

MS m/z (ESI): 278.2 [M+1].

Step 3

tert-Butyl (±)-4-(2-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperazine-1-carboxylate 39d

Compound 39c (500 mg, 1.80 mmol) was dissolved in acetonitrile (10 mL). Sodium bicarbonate (606 mg, 7.21 mmol) and (±)-3-bromopiperidine-2,6-dione (415 mg, 2.16 mmol) were added. The mixture was heated to 85° C. and left to react for 40 hours. The reaction mixture was filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system A to give the title compound 39d (a racemate, a 1:1 ratio, 360 mg, yield: 51%).

MS m/z (ESI): 389.3 [M+1].

Step 4

(±)-3-((2-(Piperazin-1-yl)phenyl)amino)piperidine-2,6-dione hydrochloride 39e Compound 39d (360 mg, 0.93 mmol) was dissolved in dichloromethane (3 mL), and a 4 M solution of hydrogen chloride in 1,4-dioxane (2 mL) was added. The mixture was left to react for 1 hour. The reaction mixture was concentrated under reduced pressure and dried in vacuo to give the title compound 39e as a crude product (a racemate, a 1:1 ratio, 260 mg, yield: 86%). The crude product was directly used in the next step without purification.

MS m/z (ESI): 289.3 [M+1].

Step 5

2-Chloro-4-((3S)-8-(4-(4-((4-(2-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperazin-1-yl)methyl)piperidine-1-carbonyl)phenyl)-3-methyl-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile 39

Compound 39e (60 mg, 0.18 mmol) and anhydrous sodium acetate (71 mg, 0.87 mmol) were added to a mixed solvent of dichloromethane and methanol (8 mL, V/V=3/1). After 15 minutes of reaction, compound 8a (55 mg, 0.11 mmol) was added, and the mixture was left to react for 15 minutes. Sodium triacetoxyborohydride (46 mg, 0.22 mmol) was added, and the mixture was left to react for 1 hour. The reaction mixture was filtered and separated and purified by preparative high performance liquid chromatography (Waters-2545, elution system: 10 mmol/L aqueous ammonium bicarbonate solution and acetonitrile, gradient of acetonitrile: 55%-85%, flow rate: 30 mL/min) to give the title compound 39 (a Mixture of Diastereomers, a 1:1 ratio, 15 mg, yield: 18%).

MS m/z (ESI): 777.3 [M+1].

¹H NMR (500 MHz, DMSO-d₆) S: 10.92 (s, 1H), 7.59 (d, 1H), 7.24 (d, 2H), 6.98 (d, 1H), 6.96-6.89 (m, 3H), 6.80 (d, 1H), 6.70-6.61 (m, 3H), 5.53 (d, 1H), 4.26-4.19 (m, 1H), 4.04 (q, 1H), 3.44 (d, 1H), 3.39-3.27 (m, 4H), 3.26-3.14 (m, 3H), 2.95-2.78 (m, 5H), 2.73 (s, 2H), 2.56 (d, 2H), 2.31-2.25 (m, 2H), 2.22 (m, 2H), 2.03-1.95 (m, 1H), 1.93-1.79 (m, 3H), 1.78-1.68 (m, 4H), 1.58 (dd, 1H), 1.53-1.41 (m, 3H), 1.20 (d, 3H), 1.12-1.00 (m, 2H).

Example 40

2-Chloro-4-((3S)-8-(4-(4-((4-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)-3-oxopiperazin-1-yl)methyl)piperidine-1-carbonyl)phenyl)-3-methyl-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile 40 (a Mixture of Diastereomers

Step 1

tert-Butyl 4-(3-nitrophenyl)-3-oxopiperazine-1-carboxylate 40c

tert-Butyl 3-oxo-1-piperazinecarboxylate 40a (1.0 g, 4.99 mmol, Bide Pharmatech) was dissolved in 1,4-dioxane (10 mL), and 1-iodo-3-nitrobenzene 40b (1.19 g, 4.79 mmol, Bide Pharmatech), cuprous iodide (143 mg, 0.75 mmol), anhydrous potassium carbonate (1.38 g, 9.99 mmol), and N,N-dimethyl-1,2-cyclohexanediamine (142 mg, 1.00 mmol) were added. The mixture was left to react for 15 minutes under a nitrogen atmosphere, heated to 110° C., and left to react for 16 hours. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system B to give the title compound 40c (750 mg, yield: 47%).

MS m/z (ESI): 266.1 [M-55].

Step 2

tert-Butyl 4-(3-aminophenyl)-3-oxopiperazine-1-carboxylate 40d

To a 100 mL single-necked flask were added a mixed solvent of tetrahydrofuran and methanol (20 mL, V/V=1/1), compound 40c (750 mg, 2.33 mmol), and 10% wet palladium on carbon (containing 50% water, 210 mg, Accela ChemBio (Shanghai) Co., Ltd.). The system was purged with hydrogen gas 3 times and left to react for 3 hours under a hydrogen atmosphere. The reaction mixture was filtered using celite, and the filtrate was concentrated under reduced pressure to give the title compound 40d as a crude product (680 mg, yield: 100%). The crude product was directly used in the next step without purification.

MS m/z (ESI): 292.1 [M+1].

Step 3

tert-Butyl (±)-4-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)-3-oxopiperazine-1-carboxylate 40e

Compound 40d (200 mg, 0.69 mmol) was dissolved in N,N-dimethylformamide (3 mL), and (±)-3-bromopiperidine-2,6-dione (264 mg, 1.37 mmol) was then added. Diisopropylethylamine (266 mg, 2.06 mmol) was added. The mixture was heated to 85° C. and left to react for 4 hours, and (±)-3-bromopiperidine-2,6-dione (264 mg, 1.37 mmol) was added again. After another 4 hours of reaction, (±)-3-bromopiperidine-2,6-dione (264 mg, 1.37 mmol) was added again, and the mixture was left to react for 4 hours. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system A to give the title compound 40e (a racemate, a 1:1 ratio, 50 mg, yield: 18%).

MS m/z (ESI): 403.1 [M+1].

Step 4

(±)-3-((3-(2-Oxopiperazin-1-yl)phenyl)amino)piperidine-2,6-dione trifluoroacetate 40f To a 50 mL single-necked flask were added a mixed solvent of trifluoroacetic acid and dichloromethane (2.5 mL, V/V=¼) and compound 40e (50 mg, 0.12 mmol). The mixture was left to react for 1 hour. The reaction mixture was concentrated under reduced pressure and dried in vacuo to give the title compound 40f as a crude product (a racemate, a 1:1 ratio, 51 mg, yield: 99%). The crude product was directly used in the next step without purification.

MS m/z (ESI): 303.1 [M+1].

Step 5

2-Chloro-4-((3S)-8-(4-(4-((4-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)-3-oxopiperazin-1-yl)methyl)piperidine-1-carbonyl)phenyl)-3-methyl-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile 40

To a 25 mL single-necked flask were added a mixed solvent of dichloromethane and methanol (3 mL, V/V=2/1), compound 40f (52 mg, 0.12 mmol), and anhydrous sodium acetate (34 mg, 0.42 mmol). After 15 minutes of reaction, compound 8a (35 mg, 0.069 mmol) was added. After 30 minutes of reaction, sodium triacetoxyborohydride (29 mg, 0.14 mmol) was slowly added, and the mixture was left to react for 16 hours. 10 mL of a saturated sodium bicarbonate solution (10 mL) was added to the reaction system under ice bath cooling, and extraction was performed with ethyl acetate (15 mL×3). The organic phases were combined, washed with a saturated sodium chloride solution (15 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure and separated and purified by preparative high performance liquid chromatography (Waters 2545, elution system: 10 mmol/L aqueous ammonium bicarbonate solution and acetonitrile, gradient of acetonitrile: 50/6-95%, flow rate: 30 mL/min) to give the title compound 40 (a Mixture of Diastereomers, a 1:1 ratio, 6 mg, yield: 11%).

MS m/z (ESI): 791.3 [M+1].

¹H NMR (500 MHz, DMSO-d₆): δ 10.78 (s, 1H), 7.59 (d, 1H), 7.24 (d, 2H), 7.10-7.05 (m, 1H), 6.94 (d, 2H), 6.80 (d, 1H), 6.66 (dd, 1H), 6.60 (t, 1H), 6.57 (dd, 1H), 6.48 (dd, 1H), 5.96 (s, 1H), 4.37-4.30 (m, 1H), 4.07-4.00 (m, 2H), 3.64-3.51 (m, 2H), 3.44 (d, 1H), 3.39-3.35 (m, 1H), 3.25-3.15 (m, 3H), 3.12 (s, 2H), 2.95-2.84 (m, 2H), 2.79-2.68 (m, 3H), 2.61-2.53 (m, 1H), 2.32-2.19 (m, 3H), 2.12-2.05 (m, 1H), 2.00-1.95 (m, 1H), 1.93-1.81 (m, 2H), 1.79-1.67 (m, 4H), 1.58 (dd, 1H), 1.54-1.43 (m, 3H), 1.20 (d, 3H), 1.13-1.03 (m, 2H).

Example 41

4-((3S)-8-(4-(4-((4-(3-((2,6-Dioxopiperidin-3-yl)amino)phenyl)piperazin-1-yl)methyl)piperidine-1-carbonyl)phenyl)-3-methyl-2,8-diazaspiro[4.5]decan-2-yl)-2-(trifluoromethyl)benzonitrile 41 (a Mixture of Diastereomers

(S)-4-(2-(4-Cyano-3-(trifluoromethyl)phenyl)-3-methyl-2,8-diazaspiro[4.5]decan-8-yl)benzoic acid 41a (30 mg, 0.068 mmol, prepared using the method disclosed in “Example 41 on page 253 of the specification in the disclosed patent WO2021055756A1”) was dissolved in N,N-dimethylformamide (3 mL). Compound 11b (38 mg, 0.083 mmol) was added, and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (39 mg, 0.10 mmol) and N,N-diisopropylethylamine (53 mg, 0.41 mmol) were then added. The mixture was left to react for 1 hour. The reaction mixture was filtered and separated and purified by preparative high performance liquid chromatography (Waters-2545, elution system: 10 mmol/L aqueous ammonium bicarbonate solution and acetonitrile, gradient of acetonitrile: 60/0-80%, flow rate: 30 mL/min) to give the title compound 41 (a Mixture of Diastereomers, a 1:1 ratio, 10 mg, yield: 18%).

MS m/z (ESI): 811.3 [M+1].

¹H NMR (500 MHz, DMSO-d₆): δ 10.76 (s, 1H), 7.77 (d, 1H), 7.24 (d, 2H), 6.99-6.86 (m, 5H), 6.24 (s, 1H), 6.18 (d, 1H), 6.14 (d, 1H), 5.62 (d, 1H), 4.34-4.27 (m, 1H), 4.11 (q, 1H), 3.50 (d, 1H), 3.38 (d, 2H), 3.36-3.33 (m, 1H), 3.30-3.17 (m, 3H), 3.06 (s, 4H), 2.97-2.80 (m, 3H), 2.79-2.67 (m, 2H), 2.65-2.53 (m, 3H), 2.30-2.18 (m, 3H), 2.14-2.07 (m, 1H), 2.04-1.95 (m, 1H), 1.89-1.80 (m, 2H), 1.79-1.69 (m, 4H), 1.60 (dd, 1H), 1.57-1.44 (m, 2H), 1.22 (d, 3H), 1.12-1.02 (m, 2H).

Example 42

2-(4-(4-((S)-2-(3-Chloro-4-cyanophenyl)-3-methyl-2,8-diazaspiro[4.5]decan-8-yl)benzoyl)piperazin-1-yl)-N-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide 42 (a Mixture of Diastereomers

Step 1

Ethyl (S)-2-(4-(4-(2-(3-chloro-4-cyanophenyl)-3-methyl-2,8-diazaspiro[4.5]decan-8-yl)benzoyl)piperazin-1-yl)acetate 42b

Compound 1h (50 mg, 0.12 mmol) and ethyl 2-(piperazin-1-yl)acetate 42a (30 mg, 0.14 mmol, Bide Pharmatech) were dissolved in N,N-dimethylformamide (4 mL), and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (70 mg, 0.18 mmol) and N,N-diisopropylethylamine (65 mg, 0.50 mmol) were added. The mixture was left to react for 1 hour. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system A to give the title compound 42b (68 mg, yield: 99%).

MS m/z (ESI): 564.2 [M+1].

Step 2

(S)-2-(4-(4-(2-(3-Chloro-4-cyanophenyl)-3-methyl-2,8-diazaspiro[4.5]decan-8-yl)benzoyl)piperazin-1-yl)acetic acid 42c

Compound 42b (68 mg, 0.12 mmol) was dissolved in a mixed solvent of tetrahydrofuran and water (6 mL, V/V=1/1), and the mixture was left to react for 1 hour. The pH of the reaction mixture was adjusted to 7 with 1 M dilute hydrochloric acid, and extraction was performed with ethyl acetate (5 mL×3). The organic phases were combined, washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and dried in vacuo to give the title compound 42c as a crude product (65 mg, yield: 99%). The crude product was directly used in the next step without purification.

MS m/z (ESI): 536.2 [M+1].

Step 3

2-(4-(4-((S)-2-(3-Chloro-4-cyanophenyl)-3-methyl-2,8-diazaspiro[4.5]decan-8-yl)benzoyl)piperazin-1-yl)-N-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide 42 Compound 42c (65 mg, 0.12 mmol) was weighed into a 25 mL eggplant-shaped flask, and N,N-dimethylformamide (2 mL), N,N-diisopropylethylamine (63 mg, 0.49 mmol), and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (70 mg, 0.18 mmol) were added. After 15 minutes of reaction, (±)-3-((3-aminophenyl)amino)piperidine-2,6-dione 42d (a racemate, a 1:1 ratio, 35 mg, 0.16 mmol, prepared using the method disclosed in “Example 12 on page 108 of the specification in the disclosed patent WO2020132016A1”) was added, and the mixture was left to react for 30 minutes. The reaction mixture was filtered and separated and purified by preparative high performance liquid chromatography (Waters 2545, elution system: 10 mmol/L aqueous ammonium bicarbonate solution and acetonitrile, gradient of acetonitrile: 64%-82%, flow rate: 30 mL/min) to give the title compound 42 (a mixture of diastereomers, a 1:1 ratio, 15 mg, yield: 17%).

MS m/z (ESI): 737.2 [M+1].

¹H NMR (500 MHz, DMSO-d₆) δ 10.77 (s, 1H), 9.48 (s, 1H), 7.59 (d, 1H), 7.27 (d, 2H), 7.02-6.92 (m, 4H), 6.84-6.78 (m, 2H), 6.66 (m, 1H), 6.39 (d, 1H), 5.87 (d, 1H), 4.28-4.22 (m, 1H), 4.07-4.02 (m, 1H), 3.56 (m, 4H), 3.43 (d, 2H), 3.25-3.19 (m, 2H), 3.14 (s, 2H), 2.76-2.68 (m, 4H), 2.65-2.58 (m, 4H), 2.26-2.19 (m, 1H), 2.13-2.06 (m, 1H), 1.94-1.86 (m, 1H), 1.76-1.68 (m, 3H), 1.58 (dd, 1H), 1.52-1.47 (m, 1H), 1.20 (d, 3H).

Example 43

4-(4-((1-(4-((S)-2-(3-Chloro-4-cyanophenyl)-3-methyl-2,8-diazaspiro[4.5]decan-8-yl)benzoyl)piperidin-4-yl)methyl)piperazin-1-yl)-N-(2,6-dioxopiperidin-3-yl)benzamide 43 (a Mixture of Diastereomers

The synthesis scheme of Example 3 was used, and the starting material of step 1, compound 1d, was replaced with (±)-N-(2,6-dioxopiperidin-3-yl)-4-(piperazin-1-yl)benzamide hydrochloride 43a (prepared using the method disclosed in “Example 9 on page 169 of the specification in the disclosed patent WO2021127443A1”). After separation and purification by preparative high performance liquid chromatography (Waters 2545, elution system: 10 mmol/L aqueous ammonium bicarbonate solution and acetonitrile, gradient of acetonitrile: 55%-95%, flow rate: 30 mL/min), the title compound (a Mixture of Diastereomers, a 1:1 ratio, 36 mg) was obtained.

MS m/z (ESI): 805.7 [M+1].

¹H NMR (500 MHz, DMSO-d₆): δ 10.82 (s, 1H), 8.46 (d, 1H), 7.74 (d, 2H), 7.59 (d, 1H), 7.24 (d, 2H), 7.04-6.87 (m, 4H), 6.80 (d, 1H), 6.65 (dd, 1H), 4.81-4.64 (m, 1H), 4.40-3.72 (m, 3H), 3.43 (d, 1H), 3.38-3.05 (m, 9H), 3.03-2.66 (m, 4H), 2.60-2.41 (m, 4H), 2.30-2.16 (m, 3H), 2.15-2.04 (m, 1H), 2.02-1.66 (m, 6H), 1.57 (dd, 1H), 1.53-1.42 (m, 2H), 1.20 (d, 3H), 1.14-0.98 (m, 2H).

Biological Evaluations

The present disclosure is further described and explained below with reference to test examples. However, these test examples are not intended to limit the scope of the present disclosure.

Test Example 1. Degradation Activity of Compounds Disclosed Herein on Androgen Receptor in LNCaP Cells

Through the in vitro cell assay described below, the degradation activity of the test compounds on the androgen receptor (AR) in the human prostate cancer cell strain can be determined, and their activity can be represented by DC₅₀ values. On the first day of the experiment, LNCaP cells (ATCC, CRL-1740) were seeded in a 96-well plate at a density of 20,000 cells/well using phenol red-free RPMI 1640 medium (Gibco, 11835-030) containing 5% charcoal-stripped fetal bovine serum (Shanghai Biosun Biotechnology Co., Ltd., S-FBS-AU-045), with 200 μL of cell suspension in each well. The plate was incubated in a 37° C., 5% CO₂ cell incubator for three days. On the fourth day, serially diluted test compounds prepared with a plating medium containing 1 nM R1881 (Aladdin, M305037) were added at 22 μL/well. The final concentration of R1881 was 0.1 nM, and the final concentrations of the compounds were 7 concentration points obtained by 6-fold serial dilution starting from 2.5 μM. A blank control cell well containing 0.5% DMSO was set up. The plate was incubated in a 37° C., 5% CO₂ cell incubator for 24 hours. On the fifth day, the 96-well cell culture plate was taken out, and the cell culture supernatant was removed from the plate using a pipette and discarded. The plate was washed with 300 μL of ice-cold PBS once, and 50 μL of 1× lysis buffer diluted with ddH₂O and containing 1 mM PMSF (Cell Signaling Technology, #9803S) was then added. After 1 minute of shaking on a micro-shaker, the cell plate was placed on ice for 15-20 minutes of lysis. The lysate was well mixed by pipetting up and down and then centrifuged at 4000 rpm at 4° C. for 10 minutes. AR protein levels were measured using an AR ELISA kit (Cell Signaling Technology, #12850) according to the instructions. 96 μL of sample dilution and 4 μL of sample lysate or blank lysis buffer were added to a 96-well microplate. The plate was sealed, shaken to mix well the contents, and then incubated in a 37° C. incubator for 2 hours. The liquid in the wells was discarded, and 300 μL of wash buffer was added to each well to wash the plate. After five washes, 100 μL of detection antibody working solution was added. The plate was sealed and incubated in a 37° C. incubator for 1 hour. The liquid in the wells was discarded, and 300 μL of wash buffer was added to each well to wash the plate. After five washes, 100 μL of enzyme conjugate working solution was added. The plate was sealed and then incubated in a 37° C. incubator for 30 minutes. The liquid in the wells was discarded, and 300 μL of wash buffer was added to each well to wash the plate. After five washes, 100 μL of substrate solution was added. The plate was sealed and then incubated at room temperature in the dark for 5 minutes, and 100 μL of stop solution was added to each well. Immediately after the contents were well mixed, the plate was placed on a microplate reader (BMG Labtech, PHERAstar FS), and the OD450 and OD540 values were recorded. The OD540 absorbance values of the corresponding wells were subtracted from the OD450 absorbance values of all the wells to obtain corrected OD450 absorbance values (OD450-correction). The degradation rate of each concentration of the compounds was calculated using the following formula. The maximums (Max) represent the maximum AR degradation rates of the compounds. A curve was fit to the logarithmic concentration and degradation efficiency of each of the compounds using GraphPad Prism, and the DC₅₀ value was calculated.

Degradation rate (%)=(OD450-correction_{blank control}-OD450-correction_compound)/(OD450-correction_{blank control}-OD450-correction_{lysis buffer control})×100%

The biological activity of the compounds of the present disclosure was obtained from the above analysis. The calculated DC₅₀ and Max values are shown in Table 1 below.

TABLE 1
The degradation activity of the compounds of the present
disclosure on the androgen receptor in LNCaP cells
	Example No.	LNCaP DC50 (nM)	Max (%)
	1	10.6	89
	2	5.1	90
	3	22.1	89
	4	20.2	92
	5	30.5	86
	6	5.7	86
	7	1.0	93
	8	1.6	85
	9	12.9	92
	10	2.5	97
	11	7.3	98
	11-1 or 11-2	6.6	96
	(shorter retention
	time)
	11-2 or 11-1	1.6	97
	(longer retention time)
	12	1.3	97
	12-1 or 12-2	3.5	95
	(shorter retention
	time)
	12-2 or 12-1	1.3	97
	(longer retention time)
	13	0.5	96
	14	1.9	96
	15	2.5	96
	15-2	14.2	97
	15-1	4.2	97
	16	3.9	97
	17	3.0	97
	18	5.8	96
	19	1.8	96
	20	0.4	92
	21	0.5	94
	22	0.4	97
	23	6.1	96
	24	9.1	94
	25	1.8	96
	26	2.5	94
	27	7.7	96
	28	5.8	97
	29	12.0	93
	30	4.2	96
	31	8.7	94
	32	1.0	95
	33	2.5	95
	34	5.0	96
	35	5.2	88
	36	5.3	97
	37	7.6	97
	38	11.7	96
	39	13.9	86
	40	7.9	97
	41	17.1	96
	42	4.2	90
	43	9.3	92
	Conclusion: The compounds of the present disclosure have significant degradation activity on the androgen receptor in LNCaP cells.

Test Example 2. Inhibition of LNCaP Proliferation by Compounds Disclosed Herein

Through the in vitro cell assay described below, the proliferation inhibition activity of the test compounds on the human prostate cancer cell strain can be determined, and their activity can be represented by IC₅₀ values. On the first day of the experiment, LNCaP cells (ATCC, CRL-1740) were seeded in a 96-well plate at a density of 7500 cells/well using phenol red-free RPMI 1640 medium (Gibco, 11835-030) containing 5% charcoal-stripped fetal bovine serum (Shanghai Biosun Biotechnology Co., Ltd., S-FBS-AU-045), with 200 μL of cell suspension in each well. The plate was incubated in a 37° C., 5% CO₂ cell incubator for three days. On the fourth day, serially diluted test compounds prepared with a plating medium containing 1 nM R1881 (Aladdin, M305037) were added at 22 μL/well. The final concentration of R1881 was 0.1 nM, and the final concentrations of the compounds were 9 concentration points obtained by 4-fold serial dilution starting from 10 μM. A blank control cell well containing 0.5% DMSO and a cell-free vehicle control well were set up. The plate was incubated in a 37° C., 5% CO₂ cell incubator for six days. On the tenth day, the 96-well cell culture plate was taken out, and 110 μL of cell culture supernatant was removed from each well using a pipette and discarded. Then 50 μL of CellTiter-Glo® Luminescent Cell Viability Assay (Promega, G7573) was added. After 10 minutes of standing at room temperature, luminescence signal values (RLU) were obtained using a multifunctional microplate reader (PerkinElmer, VICTOR 3). The inhibition rate of each concentration of the compounds was calculated using the following formula. The maximums (Max) represent the maximum proliferation inhibition rates of the compounds. A curve was fit to the logarithmic concentration and inhibition rate of each of the compounds using GraphPad Prism, and the IC₅₀ value was calculated.

Inhibition rate (%)=(RLU_{blank control}-RLU_compound)/(RLU_{blank control}-RLU_{vehicle control})×100%

The biological activity of the compounds of the present disclosure was obtained from the above analysis. The calculated IC₅₀ values are shown in Table 2 below.

TABLE 2
The proliferation inhibition activity of the compounds
of the present disclosure on LNCaP cells
	Compound No.	LNCaP IC50 (nM)	Max (%)
	1	183	63
	2	164	62
	3	286	60
	4	135	58
	5	189	72
	6	24.6	50
	7	4.6	53
	8	9.8	31
	9	69	59
	10	93	70
	11	82	68
	11-1 or 11-2	119	72
	(shorter retention time)
	11-2 or 11-1	56	72
	(longer retention time)
	12	48	73
	13	106	56
	14	57	69
	15	65	74
	15-2	74	68
	15-1	15	64
	16	84	70
	17	112	74
	18	123	72
	19	60	68
	20	15	59
	21	16	60
	23	41	76
	24	659	54
	25	24	60
	26	7.8	63
	27	7.9	64
	28	17	61
	29	81	45
	30	7.2	52
	31	12	57
	32	3.1	63
	33	3.5	58
	34	12	60
	35	31	57
	36	35	57
	37	125	73
	38	49	60
	41	98	56
	42	39	50
	Conclusion: The compounds of the present disclosure have good proliferation inhibition activity on LNCaP cells.

Test Example 3. Pharmacokinetic Evaluation

Comparative Example 1 (synthesized by reference to Example 307 of the patent WO2021055756A1) has the following structure:

ARV-110 (synthesized by reference to Example 406 of the patent WO2018071606A1) has the following structure:

I. SD rat testing

1. Abstract

SD rats were used as test animals. The plasma concentrations of compounds of the present disclosure in SD rats at different time points after intragastric (i.g.) administration were determined using an LC/MS/MS method. The pharmacokinetic behavior of the compounds of the present disclosure in SD rats was studied, and their pharmacokinetic profiles were evaluated.

2. Protocol

2.1. Test Compounds

• • Example 11 compound;
  • Example 11-2 or 11-1 (longer retention time);
  • Example 12 compound;
  • Example 15 compound;
  • Example 15-1 compound;
  • Example 23 compound;
  • Example 28 compound; and
  • Comparative Example 1 compound.

2.2. Test Animals

32 SD rats, provided by Vital River Laboratory Animal Co., Ltd., with an equal number of males and females, were evenly divided into 8 groups. The animals were fasted overnight and then intragastrically dosed.

2.3. Compound Solution Preparation

A certain amount of test compound was weighed out and dissolved in 5% DMSO+5% tween 80+90% normal saline to prepare a 0.2 mg/mL clear solution.

2.4. Administration

The dose administered was 2.0 mg/kg, and the volume was 10.0 mL/kg.

3. Procedure

0.2-mL blood samples were collected from the orbit before administration and 0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0, 11.0, and 24.0 hours after administration. The blood samples were placed into EDTA-K2 anticoagulation test tubes and centrifuged at 10,000 rpm for 1 minute (4° C.), and plasma was separated within 1 hour and stored at −20° C. before analysis. The procedure starting from the blood collection to the centrifugation was performed under ice-bath conditions. Access to food was given 2 hours after administration.

After administration of different concentrations of the test compounds, the plasma concentrations of the test compounds in the SD rats were determined: 25 μL of each of the SD rat plasma samples of the various time points after administration was taken; 200 μL of acetonitrile was added to precipitate protein, and 50 μL of camptothecin (100 ng/mL) was added; after 5 minutes of vortexing and 10 minutes of centrifugation at 4000 rpm, 30 μL of the supernatant was taken and diluted with 120 μL of water, and 1 μL of the dilution was taken for LC/MS/MS analysis.

4. Pharmacokinetic Parameters

TABLE 3
Pharmacokinetic parameters of the compounds of the present disclosure in SD rats
						Apparent
		Plasma	Area under		Clearance	distribution
	Route of	concentration	curve	Half-life	rate	volume
Compound	administration/dose	Cmax	AUC0-t	T½	CL/F	Vz/F
No.	(mg/kg)	(ng/mL)	(h*ng/mL)	(h)	(mL/min/kg)	(mL/kg)
11	i.g./2.0	69.4	644	6.75	60.2	34816
11-2 or 11-1	i.g./2.0	77.1	685	6.26	63.7	39568
(longer
retention
time)
12	i.g./2.0	37.4	304	5.19	139	63103
15	i.g./2.0	227	2137	6.75	14.6	8504
15-1	i.g./2.0	110	1126	6.66	39.5	23003
23	i.g./2.0	81.6	703	5.93	51.2	26276
28	i.g./2.0	25.5	315	7.17	108	66596
Comparative	i.g./2.0	2.98	22	4.9	1166	506710
Example 1
Conclusion: The compounds of the present disclosure exhibited larger areas under the curves, longer half-lives, and lower clearance rates in SD rats than Comparative Example 1, have excellent pharmacokinetic absorption activity, and have significant pharmacokinetic advantages.

II. Dog Testing

1. Abstract

Beagles were used as test animals. The plasma concentrations of a compound of the present disclosure in beagles at different time points after intragastric (i.g.) administration were determined using an LC/MS/MS method. The pharmacokinetic behavior of the compound of the present disclosure in beagles was studied, and its pharmacokinetic profile was evaluated.

2. Protocol

2.1. Test Compounds

• • Example 15-1 compound; and
  • Compound ARV-110.2.2. Test Animals beagles, provided by Jiangsu Johnbio Biotechnology Co., Ltd., with an equal number of males and females, were evenly divided into 2 groups. The animals were fasted overnight and then intragastrically dosed.

2.3. Compound Solution Preparation

A certain amount of test compound was weighed out and dissolved in 5% DMSO+30% PG+30% PEG400+35% normal saline to prepare a 0.4 mg/mL solution.

2.4. Administration

The dose administered was 2.0 mg/kg, and the volume was 5.0 mL/kg.

3. Procedure

0.5-mL blood samples were collected from the forelimb vein before administration and 0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0, 11.0, and 24.0 hours after administration. The blood samples were placed into EDTA-K2 anticoagulation test tubes and centrifuged at 10,000 rpm for 2 minutes (4° C.), and plasma was separated within 1 hour and stored at −80° C. before analysis. The procedure starting from the blood collection to the centrifugation was performed under ice-bath conditions. Access to food was given 3 hours after administration.

After administration of different concentrations of the test compounds, the plasma concentrations of the test compounds in the beagles were determined: 50 μL of each of the beagle plasma samples of the various time points after administration was taken, and 25 μL of camptothecin (1 μg/mL) and 450 μL of acetonitrile were added to precipitate protein; after vortexing and 10 minutes of centrifugation at 3700 rpm, 0.5 μL of the supernatant was taken for LC/MS/MS analysis.

4. Pharmacokinetic Parameters

TABLE 4
Pharmacokinetic parameters of the compound of the present disclosure in beagles
						Apparent
		Plasma	Area under		Clearance	distribution
	Route of	concentration	curve	Half-life	rate	volume
Compound	administration/dose	Cmax	AUC0-t	T½	CL/F	Vz/F
No.	(mg/kg)	(ng/mL)	(h*ng/mL)	(h)	(mL/min/kg)	(mL/kg)
15-1	i.g./2.0	75.6	1137	22.5	15.8	29843
ARV-110	i.g./2.0	13.0	239	48.8	70.9	278328
Conclusion: The compound of the present disclosure exhibited a larger area under the curve and a lower clearance rate in beagles than compound ARV-110, has excellent pharmacokinetic absorption activity, and has significant pharmacokinetic advantages.

III. Monkey Testing

1. Abstract

Cynomolgus monkeys were used as test animals. The plasma concentrations of a compound of the present disclosure in cynomolgus monkeys at different time points after intragastric (i.g.) administration were determined using an LC/MS/MS method. The pharmacokinetic behavior of the compound of the present disclosure in cynomolgus monkeys was studied, and its pharmacokinetic profile was evaluated.

2. Protocol

2.1. Test Compounds

• • Example 15-1 compound; and
  • ARV-110.

2.2. Test Animals

8 cynomolgus monkeys, provided by Shanghai Medicilon Inc., with an equal number of males and females, were evenly divided into 2 groups. The animals were fasted overnight and then intragastrically dosed.

2.3. Compound Solution Preparation

A certain amount of test compound was weighed out and dissolved in 5% DMSO+30% PG+30% PEG400+35% normal saline to prepare a 0.4 mg/mL clear solution.

2.4. Administration

The dose administered was 2.0 mg/kg, and the volume was 5.0 mL/kg.

3. Procedure

1-mL blood samples were collected from the forelimb vein before administration and 0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0, 12.0, and 24.0 hours after administration. The blood samples were placed into EDTA-K2 anticoagulation test tubes and centrifuged at 2200 g for 10 minutes (2-8° C.), and plasma was separated within 1 hour and stored at −80° C. before analysis. The procedure starting from the blood collection to the centrifugation was performed under ice-bath conditions. Access to food and ad libitum access to water were given 3 hours after administration.

After administration of different concentrations of the test compounds, the plasma concentrations of the test compounds in the cynomolgus monkeys were determined: 20 μL of each of the cynomolgus monkey plasma samples of the various time points after administration was taken, and 400 μL of methanol was added to precipitate protein (containing 10 ng/mL verapamil); after 1 minute of vortexing and 7 minutes of centrifugation at 18,000 g, 5 μL of the supernatant was taken for LC/MS/MS analysis.

4. Pharmacokinetic Parameters

TABLE 5
Pharmacokinetic parameters of the compound of the present disclosure in cynomolgus monkeys
						Apparent
		Plasma	Area under		Clearance	distribution
	Route of	concentration	curve	Half-life	rate	volume
Compound	administration/dose	Cmax	AUC0-t	T½	CL/F	Vz/F
No.	(mg/kg)	(ng/mL)	(h*ng/mL)	(h)	(mL/min/kg)	(mL/kg)
15-1	i.g./2.0	200.5	2086.0	14.6	11.0	14494.8
ARV-110	i.g./2.0	15.9	282.0	42.0	44.6	165179.6
Conclusion: The compound of the present disclosure exhibited a larger area under the curve and a lower clearance rate in cynomolgus monkeys than ARV-110, has excellent pharmacokinetic absorption activity, and has significant pharmacokinetic advantages.

Test Example 4. Pharmacodynamic Testing

1. Objective

To evaluate the inhibition of the growth of castration-resistant prostate cancer LNCap-FGC subcutaneous xenograft tumors in male CB17-SCID mice by compounds of the present disclosure.

2. Test Compounds

• • Example 15-1 compound;
  • Example 11-2 or 11-1 (longer retention time) compound;
  • ARV-110; and
  • 20% PEG400+75% (10% TPGS)+5% (1% HPMC K100LV) solution.

3. Method and Materials

3.1. Test Animals and Housing Conditions

Test animals: CB17-SCID male mice, purchased from Beijing Vital River Laboratory Animal Technology Co., Ltd. (certificate No. SCXK(Beijing)2016-0006; animal certification No. 110011220107542683), weighing about 20.54-26.72 g on purchase. Housing conditions: 5 animals/cage, a 12/12-hour light/dark cycle, a constant temperature of 23±1° C. with humidity at 50 to 60%, ad libitum access to food and water.

3.2. Grouping of Animals

Following acclimatization, the CB17-SCID mice were grouped and dosed as shown in Table 6 below.

TABLE 6
The animal groups and administration regimen
for the in vivo pharmacodynamic testing
	Number of
Group	animals	Route of administration
Vehicle control	8	20% PEG400 + 75% (10% TPGS) +
		5% (1% HPMC K100LV) solution (i.g./qd)
ARV-110	8	1 mpk (i.g./qd)
ARV-110	8	10 mpk (i.g./qd)
Example 15-1	8	1.5 mpk (i.g./qd)
Example 15-1	8	5 mpk (i.g./qd)
Example 15-1	8	15 mpk (i.g./qd)
11-2 or 11-1	8	1.5 mpk (i.g./qd)
(longer
retention time)
11-2 or 11-1	8	5 mpk (i.g./qd)
(longer
retention time)
11-2 or 11-1	8	15 mpk (i.g./qd)
(longer
retention time)
Notes:
qd stands for “once a day”; i.g. stands for intragastric administration.

3.3. Method

0.2 mL (10×10⁶ cells+Matrigel) of LNCaP FGC cells (Matrigel was added, in a 1:1 ratio by volume) in the logarithmic growth phase was subcutaneously inoculated into the right upper limb of each mouse. When the mean tumor volume reached 77 mm³, male mice with stable tumor growth were selected and subjected to orchiectomy followed by three days of analgesic care. When the mean tumor volume reached 172 mm³, grouping and administration were started. The mice were randomized into 9 groups of 8 according to tumor volume and body weight, as shown in Table 6. The day of grouping was defined as DO, and intragastric administration was started and performed once a day for 21 days. The 21th day after administration was defined as D21 (Table 7). For tumor-bearing mice, the tumor volume was measured with a vernier caliper and the body weight was measured with a balance twice a week, and data were recorded.

3.4. Statistical Analysis

All data were plotted and statistically analyzed using Excel and GraphPad Prism 8 software.

The calculation formula for tumor volume (V) was: V=½×a×b², where a and b represent length and width, respectively.

Relative tumor proliferation rate T/C(%)=(T-T₀)/(C-C₀)×100 (%), where T and C represent the tumor volumes of a treatment group and the control group at the end of the experiment; T₀ and C₀ represent the tumor volumes at the beginning of the experiment. Tumor growth inhibition rate TGI(%)=1−T/C (%).

4. Results

Data on the efficacy of Example 15-1 and 11-2 or 11-1 (longer retention time) compounds against LNCap-FGC xenograft tumors in castrated CB17-SCID mice are shown in Table 7 and FIG. 1.

The effects of Example 15-1 and 11-2 or 11-1 (longer retention time) compounds on the body weight of CB17-SCID mice are shown in FIG. 2.

TABLE 7
The efficacy of the compounds of the present disclosure against
LNCap-FGC xenograft tumors in castrated CB17-SCID mice
	Route		TGI		Number of
	Dose	Mean tumor volume (mm3)	(%)	p	remaining
Group	Administration	(mpk)	D 0	SEM	D 21	SEM	D 21	(vs. vehicle control)	animals/group
Vehicle	qd/21 d	i.g., 0	172	11	1,606	187	/	/	8/8
control
ARV-110	qd/21 d	i.g., 1	172	10	789	193	57	<0.0001	8/8
ARV-110	qd/21 d	i.g., 10	172	10	293	43	92	<0.0001	8/8
Example 15-1	qd/21 d	i.g., 1.5	172	10	255	64	94	<0.0001	8/8
Example 15-1	qd/21 d	i.g., 5	172	11	188	32	99	<0.0001	8/8
Example 15-1	qd/21 d	i.g., 15	172	11	117	17	104	<0.0001	8/8
11-2 or 11-1	qd/21 d	i.g., 1.5	172	11	587	131	71	<0.0001	8/8
(longer
retention time)
11-2 or 11-1	qd/21 d	i.g., 5	172	10	147	35	102	<0.0001	8/8
(longer
retention time)
11-2 or 11-1	qd/21 d	i.g., 15	172	10	120	10	104	<0.0001	8/8
(longer
retention time)
Notes:
qd stands for “once a day”; d stands for day; i.g. stands for intragastric administration; SEM stands for standard error of measurement.

5. Conclusion

After 21 days of once-daily administration, Example 15-1 compound exhibited a tumor growth inhibition rate of 94% in the low-dose 1.5 mpk group, a tumor growth inhibition rate of 99% in the medium-dose 5 mpk group, and a tumor growth inhibition rate of 104% in the high-dose 15 mpk group, and showed little effect on the body weight of the mice. After 21 days of once-daily administration, Example 11-2 or 11-1 (longer retention time) exhibited a tumor growth inhibition rate of 71% in the low-dose 1.5 mpk group, a tumor growth inhibition rate of 102% in the medium-dose 5 mpk group, and a tumor growth inhibition rate of 104% in the high-dose 15 mpk group, and showed little effect on the body weight of the mice.

After 21 days of once-daily administration under the same conditions, ARV-110 exhibited a tumor growth inhibition rate of 57% in the low-dose 1 mpk group and a tumor growth inhibition rate of 92% in the high-dose 10 mpk group. Example 15-1 and Examples 11-2 or 11-1 (longer retention time) have some advantages over ARV-110.

Claims

1. A compound represented by general formula (I) or a pharmaceutically acceptable salt thereof,

2. The compound represented by general formula (I) or the pharmaceutically acceptable salt thereof according to claim 1, wherein R is phenyl or 5- or 6-membered heteroaryl, wherein the phenyl and 5- or 6-membered heteroaryl are each independently optionally substituted with one or more substituents selected from the group consisting of halogen, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C1-6 haloalkoxy, cyano, amino, nitro, hydroxy, and C1-6 hydroxyalkyl.

3. The compound represented by general formula (I) or the pharmaceutically acceptable salt thereof according to claim 1, wherein: X1 is

4. (canceled)

5. The compound represented by general formula (I) or the pharmaceutically acceptable salt thereof according to claim 1, wherein J2 is 3- to 12-membered heterocyclyl, wherein the 3- to 12-membered heterocyclyl is optionally substituted with one or more substituents selected from the group consisting of halogen, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C1-6 haloalkoxy, cyano, amino, hydroxy, and ═O; and/or J3 is selected from —O—, —S—, —NR6a—, —C(O)—, —S(O)2—, —(CR7aR8a)m3—, C2-6 alkenyl, C2-6 alkynyl, 3- to 8-membered cycloalkyl, and 3- to 8-membered heterocyclyl; R6a is a hydrogen atom or C1-6 alkyl; R7a and R8a are identical or different and are each independently selected from a hydrogen atom, halogen, hydroxy, and C1-6 alkyl; m3 is 0, 1, 2, or 3; and/or J4 is 3- to 8-membered cycloalkyl or 3- to 8-membered heterocyclyl, wherein the 3- to 8-membered cycloalkyl and 3- to 8-membered heterocyclyl are each independently optionally substituted with one or more substituents selected from halogen, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C1-6 haloalkoxy, cyano, amino, hydroxy, and ═O.

6. (canceled)

7. (canceled)

8. The compound represented by general formula (I) or the pharmaceutically acceptable salt thereof according to claim 1, being a compound represented by general formula (G) or a pharmaceutically acceptable salt thereof:

9. The compound represented by general formula (I) or the pharmaceutically acceptable salt thereof according to claim 8, being a compound represented by general formula (III′) or a pharmaceutically acceptable salt thereof:

10. The compound represented by general formula (I) or the pharmaceutically acceptable salt thereof according to claim 8, being a compound represented by general formula (III) or a pharmaceutically acceptable salt thereof:

11. The compound represented by general formula (I) or the pharmaceutically acceptable salt thereof according to claim 1, wherein X2 is selected from the group consisting of —C(O)—, —S(O)2—, and —(CR2aR2b)m1—; R2a and R2b are identical or different and are each independently selected from the group consisting of a hydrogen atom, halogen, hydroxy, and C1-6 alkyl; m1 is 0, 1, 2, or 3; and/or J1 is selected from —O—, —S—, —NR6—, —C(O)—, —S(O)2—, —(CR7R8)m2, C2-6 alkenyl, and C2-6 alkynyl; R6 is a hydrogen atom or C1-6 alkyl; R7 and R8 are identical or different and are each independently selected from a hydrogen atom, halogen, hydroxy, and C1-6 alkyl; m2 is 0, 1, 2, or 3; and/or J5 is selected from a bond, 3- to 8-membered heterocyclyl, and 3- to 8-membered cycloalkyl.

12. (canceled)

13. The compound represented by general formula (I) or the pharmaceutically acceptable salt thereof according to claim 9, being a compound represented by general formula (IV′-1) or a pharmaceutically acceptable salt thereof:

14. The compound represented by general formula (I) or the pharmaceutically acceptable salt thereof according to claim 8, wherein R1a is C1-6 alkyl; and/or Z1 is CR3b; Z2 is CR3c; R3a, R3b, and R3e are identical or different and are each independently selected from the group consisting of a hydrogen atom, halogen, C1-6 alkyl, C1-6 alkoxy, cyano, and C1-6 haloalkyl; and/or W1 is N or CR3d; W2 is N or CR3e, W3 is N or CR3f; W4 is N or CR3g; R3d, R3e, R3f, and R3g are identical or different and are each independently a hydrogen atom or halogen.

15. (canceled)

16. The compound represented by general formula (I) or the pharmaceutically acceptable salt thereof according to claim 1, being selected from the group consisting of the following compounds:

17. A compound represented by general formula (MB) or a salt thereof,

18. A compound, being selected from the group consisting of the following compounds:

19. A method for preparing the compound represented by general formula (IV′-1) or the pharmaceutically acceptable salt thereof according to claim 13, comprising:

20. A pharmaceutical composition, wherein the pharmaceutical composition comprises the compound or the pharmaceutically acceptable salt thereof according to claim 1, and one or more pharmaceutically acceptable carriers, diluents, or excipients.

21. A method for regulating the ubiquitination and degradation of the androgen receptor (AR) protein in a subject comprising administering to a subject in need thereof a therapeutically effective amount of the pharmaceutical composition according to claim 20.

22. A method for treating and/or preventing an androgen receptor-mediated or -dependent disease or disorder, comprising administering to a subject in need thereof a therapeutically effective amount of the pharmaceutical composition according to claim 20, wherein the estrogen receptor-mediated or -dependent disease or disorder is selected from the group consisting of a tumor, male sexual dysfunction, and Kennedy's disease.

23. The method according to claim 22, wherein the estrogen receptor-mediated or dependent disease or disorder is selected from the group consisting of prostate cancer, prostatic hyperplasia, hirsutism, alopecia, anorexia nervosa, breast cancer, acne, male sexual dysfunction, Kennedy's disease, and AIDS.

24. The method according to claim 22 wherein the estrogen receptor-mediated or dependent disease or disorder is hormone-sensitive prostate cancer, hormone-refractory prostate cancer or castration-resistant prostate cancer.

25. The compound represented by general formula (I) or the pharmaceutically acceptable salt thereof according to claim 1, wherein: R is selected from