Compound for use in targeted degradation of androgen receptors, and method

Abstract

The present disclosure relates to a bifunctional compound suitable for use in the degradation (and inhibition) of androgen receptors. Specifically, the present disclosure relates to a compound, wherein one end of the compound contains a moiety which binds to an E3 ubiquitin ligase, and the other end contains a moiety which binds to an androgen receptor, such that the androgen receptor is located close to the ubiquitin ligase so as to implement the degradation (and inhibition) of the androgen receptor. The present disclosure exhibits pharmacological activity which is related to a compound related to the compound of the present disclosure and is consistent with androgen receptor degradation / inhibition.

Description

Compounds and methods for androgen receptor targeted degradation

[0001] This application claims priority to Chinese Patent Application No. 202410898869.6, filed on July 5, 2024, No. 202411250492X, filed on September 6, 2024, No. 2024112961573, filed on September 18, 2024, No. 202411444178.5, filed on October 16, 2024, No. 2024118602606, filed on December 17, 2024, No. 2025103489925, filed on March 24, 2025, No. 2025105334257, filed on April 26, 2025, the entire contents of which are incorporated herein by reference. TECHNICAL FIELD

[0002] The present disclosure relates to bifunctional compounds comprising an androgen receptor binding moiety and an E3 ubiquitin ligase binding moiety, pharmaceutical compositions thereof, and medical uses of the compounds, pharmaceutical compositions. BACKGROUND

[0003] The concept of protein degradation targeting chimera (PROTAC) technology was first proposed by Craig Crews et al. in 2001 (Proc. Natl. Acad. Sci. USA, 2001, 98, 8584). A PROTAC molecule is a bifunctional molecule, one end of which contains a ligand that binds to an E3 ubiquitin ligase, and the other end contains a ligand that binds to a target protein, and the two parts are connected by a linker unit. By pulling closer through the linker unit, the E3 ligase and the target protein are very close, which in turn causes the polyubiquitination of the target protein and the degradation of the proteasome. Compared with traditional small molecule drugs, PROTAC only needs to be transiently combined with the target protein to complete the process of ubiquitin transfer to achieve irreversible degradation of the target protein, so that PROTAC has stronger degradation effect and more persistent drug efficacy, higher selectivity for target proteins, and can overcome the drug resistance caused by target protein variation of traditional small molecule inhibitors.

[0004] Currently, the ligands of E3 ubiquitin ligases such as cereblon (CRBN), von Hippel-Lindau (VHL), mouse double minute homolog 2 (MDM2), inhibitor of apoptosis (IAP) are mainly used in the development of PROTAC technology. Among them, the CRBN type of E3 ligase ligand is widely used, the discovery process of this kind of ligand is closely related to the study of the mechanism of action of thalidomide, researchers found that cereblon is a thalidomide binding protein in the process of studying the toxicity of thalidomide, and cereblon is part of the E3 ubiquitin ligase protein complex, which can act as a substrate receptor to selectively act on ubiquitinated proteins. In addition, lenalidomide and pomalidomide modified from thalidomide have also been confirmed to be able to bind cereblon. Based on this, the CRBN ligand is widely used in the field of PROTAC, and new and highly selective CRBN ligands are also urgently needed to be developed.

[0005] Androgen receptor (AR) is a steroid-induced transcription factor that regulates many genes that promote tumor growth (N. Lallous, Int. J. Mol. Sci. 14 (2013), 12496-12519). Prostate cancer is a typical disease mainly driven by androgen receptor. Androgen deprivation therapy (ADT) is one of the conventional treatment methods for prostate cancer, such as surgical castration (bilateral orchiectomy) or drug castration (such as injection of goserelin), ADT therapy has a significant effect in the early stage of treatment, but as the disease progresses, the androgen receptor (AR) mutates, the mutated AR is more sensitive to low levels of androgens, thus driving the disease to progress to castration-resistant prostate cancer (CRPC). Currently approved oral drugs for the treatment of metastatic castration-resistant prostate cancer mainly include abiraterone and enzalutamide. Among them, abiraterone is a new androgen biosynthesis inhibitor, and enzalutamide is an androgen receptor inhibitor that can competitively inhibit the binding of androgens to the receptor. However, these drugs become ineffective in advanced prostate cancer with AR gene amplification, mutation and alternative splicing (Lottrup, G.; J. Clin. Endocrinol. Metab. 2013, 98, 2223-2229). Therefore, there is an urgent need for new AR selective degraders in the clinic. SUMMARY

[0006] The present disclosure relies on the protein degradation targeting chimera (PROTAC) technology to obtain a selective AR degrader (SARD) that can not only inhibit the androgen receptor and block the process of androgen receptor signaling, but also degrade the receptor itself, which can bring more benefits to prostate cancer patients than known AR inhibitors.

[0007] The first aspect of the present disclosure provides a compound represented by Formula 1, or an isomer, an isotopic derivative, a polymorph, a prodrug, a pharmaceutically acceptable salt, or a solvate thereof:

[0008] PTM-L-CLM (Formula 1);

[0009] wherein PTM is an androgen receptor binding moiety;

[0010] L is a bond or -(B L ) q -;

[0011] B L each occurrence is the same or different, and each is independently selected from: CR L1 R L2 , O, S, S(O), SO2, NR L3 , SO2NR L3 , S(O)NR L3 , C(O)NR L3 , NR L3 C(O)NR L4 , NR L3 SO2NR L4 , C(O), CR L1 =CR L2 , C≡C, SiR L1 R L2 , P(O)R L1 , P(O)OR L1 , NR L3 C(=NCN)NR L4 , NR L3 C(=NCN), NR L3 C(=CNO2)NR L4 , monocycloalkylene, monoheterocyclylene, bridged cyclylene, spiro cyclylene, arylene, and heteroarylene, wherein the monocycloalkylene, monoheterocyclylene, bridged cyclylene, spiro cyclylene, arylene, and heteroarylene are optionally substituted with 0, 1, 2, 3, 4, 5, or 6 R L1 groups; L2 in one embodiment, R

[0012] R L1 , R L2 , R L3 , and R L4 each occurrence is independently selected from oxo (=O), H, halogen, C 1-8 alkyl, -O-C 1-8 alkyl, -S-C 1-8 alkyl, -NH-C 1-8 alkyl, N(C 1-8 alkyl)2, C3-11 cycloalkyl, C 6-10 Aryl, C 5-10 heteroaryl, C 3-11 Heterocyclic groups, -OC 3-8 cycloalkyl, -OC 3-11 Heterocyclic groups, -OC 6-10 Aryl, -OC 5-10 heteroaryl, -SC 3-8 cycloalkyl, -NH-C 3-8 cycloalkyl, -N(C) 3-8 cycloalkyl)2, -N(C 3-8 cycloalkyl)(C 1-8 alkyl), -NH-C 3-8 Heterocyclic groups, -N(C) 3-8 Heterocyclic group)2, -N(C 3-8 Heterocyclic group)(C 1-8 alkyl), -NH-C 6-10 Aryl, -N(C 6-10 Aryl)(C 1-8 alkyl), -NH-C 5-10 heteroaryl, -N(C 5-10 (C) 1-8 Alkyl groups, -OH, -NH2, -SH, SO2, P(O)(OC) 1-8 Alkyl)(C 1-8 Alkyl), -P(O)(OC 1-8 Alkyl)2、-C≡CC 1-8 Alkyl group, -C≡CH, -CH=CH-(C 1-8 alkyl), -C(C 1-8 Alkyl)=CH-(C 1-8 alkyl), -C(C 1-8 Alkyl) = C(C 1-8 Alkyl group 2, -Si(OH)3, -Si(C) 1-8 Alkyl)3、-Si(OH)(C 1-8 Alkyl)2、-C(O)-C 1-8 Alkyl, -C(O)2H, -CN, -NO2, -SO2, -SF5, -SO2NH-C 1-8 Alkyl group, -SO2N(C) 1- 8-alkyl)2、-S(O)NH-C 1-8 Alkyl, -S(O)N(C) 1-8 Alkyl)2、-C(O)NH-C 1-8 Alkyl, -C(O)N(C) 1-8 Alkyl)2, -N(C 1-8 alkyl)C(O)NH(C 1- 8-alkyl), -N(C)1-8 alkyl)C(O)N(C 1-8 alkyl)2、-NHC(O)NH(C 1-8 Alkyl), -NHC(O)N(C 1-8 Alkyl)2, -NHC(O)NH2, -N(C 1-8 alkyl)SO2NH(C 1-8 alkyl), -N(C) 1-8 Alkyl)SO2N(C 1-8 Alkyl)2、-NHSO2NH(C 1-8 Alkyl), -NHSO2 N(C 1-8 Alkyl)2 and -NHSO2NH2, optionally, the C 1-8 Alkyl, C 3-11 cycloalkyl, C 3-11 Heterocyclic group, C 6-10 Aryl and C 5-10 Each heteroaryl group is independently selected from halogens, alkyl groups, heteroalkyl groups, alkenyl groups, alkoxy groups, hydroxyl groups, haloalkyl groups, hydroxyalkyl groups, cyano groups, amino groups, nitro groups, cycloalkyl groups, heterocyclic groups, halocycloalkyl groups, haloheteroalkyl groups, alkyl-NH groups, and C groups. 6-10 Aryl, C 5-10 heteroaryl, halogenated C 6-10 Aryl and halogenated C 5-10 One or more substituents in the heteroaryl group are substituted; and

[0013] q is an integer greater than or equal to 1;

[0014] CLM is selected from:

[0015] in:

[0016] Each time A1 appears, it is independently selected from CR. a and N;

[0017] A2 and A4 are each independently selected from C(O) and C(R) each time they appear. a )2;

[0018] A3 is independently assigned to NR each time it appears. a ;

[0019] A5 and A6 are each selected independently from single bonds and NR each time they appear. a and C(R) a )2;

[0020] Each time A7 appears, it is independently selected from C(O) and C(R). a )2;

[0021] R1and R2together form when the CLM is of Formula 2, Formula 4, Formula 5, or Formula 7 R1and R2together form when the CLM is of Formula 3 R3, R4, and R5are each independently selected at each occurrence from H, a deuterium atom, halogen, C 1-6 alkyl, C 1-6 deuteroalkyl, C 1-6 heteroalkyl, alkenyl, alkynyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, hydroxy, C 1-6 hydroxyalkyl, nitro, cyano, amino, -C(O)NH-C 1-6 alkyl, -C(O)N(C 1-6 alkyl)2, -N(C 1-6 alkyl)C(O)NH(C 1-6 alkyl), -N(C 1-6 alkyl)C(O)N(C 1- 6alkyl)2, -NHC(O)NH(C 1-6 alkyl), -NHC(O)N(C 1-6 alkyl)2, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein said C 1-6 alkyl, C 1-6 deuteroalkyl, C 1-6 heteroalkyl, alkenyl, alkynyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl are each independently optionally substituted with one or more substituents selected from halogen, alkyl, heteroalkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, alkenyl, alkynyl, alkyl-NH, -C(O)NH-C 1-6 alkyl, -C(O)N(C 1-6 alkyl)2, -N(C 1-6 alkyl)C(O)NH(C 1-6 alkyl), -N(C 1- 6alkyl)C(O)N(C 1-6 alkyl)2, -NHC(O)NH(C 1-6 alkyl), -NHC(O)N(C 1-6 alkyl)2, aryl, and heteroaryl; in one embodiment, R3, R4, and R5are each independently selected from H, a deuterium atom, F, Cl, Br, I, C 1-6 alkyl, C 1-6 deuteroalkyl, C 1-6 heteroalkyl, alkenyl, alkynyl, C 1-6alkyl, C 1-6 haloalkyl, C 1-6 haloalkoxy, hydroxy, C 1-6 hydroxyalkyl, and amino; in one embodiment, R3, R4, and R5are each independently selected from H, a deuterium atom, F, Cl, Br, I, C 1-3 alkyl, C 1-3 deuteroalkyl, alkenyl, alkynyl, C 1-3 alkoxy, C1-3haloalkyl, C 1-3 haloalkoxy, hydroxy, C 1-3 hydroxyalkyl, and amino; and when CLMis Formula 7, R3, R4are not H;

[0022] or

[0023] when CLMis Formula 2, Formula 4, or Formula 5, R2and R3together form when CLMis Formula 3, R2and R3together form R1, R4, and R5are each independently at each occurrence selected from H, a deuterium atom, halogen, C 1-6 alkyl, C 1-6 deuteroalkyl, carboxyl, C 1-6 heteroalkyl, alkenyl, alkynyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, hydroxy, C 1-6 hydroxyalkyl, nitro, cyano, amino, C 1-6 alkyl-NH, C 1-6 alkyl-C(O), C 1-6 alkyloxy C(O), C 1-6 alkyl-NH-C(O), cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein said C 1-6 alkyl, C 1-6 deuteroalkyl, C 1-6 heteroalkyl, alkenyl, alkynyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl are each independently optionally substituted with a member selected from halogen, alkyl, heteroalkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, alkenyl, alkynyl, alkyl-NH, -C(O)NH-C 1-6 alkyl, -C(O)N(C 1- 6alkyl)2, -N(C 1-6 alkyl)C(O)NH(C 1-6 alkyl), -N(C 1-6 alkyl)C(O)N(C 1-6 alkyl)2, -NHC(O)NH(C1-6 alkyl), -NHC(O)N(C 1-6 alkyl)2, aryl, and heteroaryl; in one embodiment, R1, R4, and R5are each independently selected from H, a deuterium atom, F, Cl, Br, I, C 1-6 alkyl, C 1-6 deuteroalkyl, C 1-6 heteroalkyl, alkenyl, alkynyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, hydroxy, C 1-6 hydroxyalkyl, and amino; in one embodiment, R1, R4, and R5are each independently selected from H, a deuterium atom, F, Cl, Br, I, C 1-3 alkyl, C 1-3 deuteroalkyl, alkenyl, alkynyl, C 1-3 alkoxy, C 1-3 haloalkyl, C 1-3 haloalkoxy, hydroxy, C 1-3 hydroxyalkyl, and amino;

[0024] or

[0025] when CLM is of Formula 2, R3and R4together form when CLM is of Formula 3, R3and R4together form R1, R2, and R5are each independently at each occurrence selected from H, a deuterium atom, halogen, C 1-6 alkyl, C 1-6 deuteroalkyl, carboxyl, C 1-6 heteroalkyl, alkenyl, alkynyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, hydroxy, C 1-6 hydroxyalkyl, nitro, cyano, amino, C 1-6 alkyl-NH, C 1-6 alkyl C(O), C 1-6 alkyloxy C(O), C 1-6 alkyl-NH-C(O), cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein said C 1-6 alkyl, C 1-6 deuteroalkyl, C 1-6 heteroalkyl, alkenyl, alkynyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6haloalkyl, C 1-6 alkyl, -C(O)N(C 1-6 alkyl)2, -N(C 1-6 alkyl)C(O)NH(C 1- 6alkyl), -N(C 1-6 alkyl)C(O)N(C 1-6 alkyl)2, -NHC(O)NH(C 1-6 alkyl), -NHC(O)N(C 1-6 alkyl)2, aryl, and heteroaryl; in one embodiment, R1, R2, and R5are each independently selected from H, a deuterium atom, F, Cl, Br, I, C 1-6 alkyl, C 1-6 deuteroalkyl, C 1-6 heteroalkyl, alkenyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, hydroxy, C 1-6 hydroxyalkyl, and amino; in one embodiment, R1, R2, and R5are each independently selected from H, a deuterium atom, F, Cl, Br, I, C 1-3 alkyl, C 1-3 deuteroalkyl, alkenyl, C 1-3 alkoxy, C 1-3 haloalkyl, C 1-3 haloalkoxy, hydroxy, C 1-3 hydroxyalkyl, and amino;

[0026] or

[0027] when CLM is of Formula 2, R4and R5together form when CLM is of Formula 3, R4and R5together form R1, R2, and R3are each independently selected at each occurrence from H, a deuterium atom, halogen, C 1-6 alkyl, C 1-6 deuteroalkyl, carboxyl, C 1-6 heteroalkyl, alkenyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, hydroxy, C 1-6 hydroxyalkyl, nitro, cyano, amino, C 1-6 alkyl-NH, C 1-6 alkylC(O), C 1-6alkyl, C 1-6 alkyl, C 1-6 alkyl, C 1-6 deuteroalkyl, C 1-6 heteroalkyl, alkenyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl are each independently optionally substituted with one or more substituents selected from the group consisting of halogen, alkyl, heteroalkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, alkenyl, alkynyl, alkyl-NH, -C(O)NH-C 1-6 alkyl, -C(O)N(C 1-6 alkyl)2, -N(C 1-6 alkyl)C(O)NH(C 1- 6alkyl), -N(C 1-6 alkyl)C(O)N(C 1-6 alkyl)2, -NHC(O)NH(C 1-6 alkyl), -NHC(O)N(C 1-6 alkyl)2, aryl, and heteroaryl; in one embodiment, R1, R2, and R3are each independently selected from the group consisting of H, deuterium atom, F, Cl, Br, I, C 1-6 alkyl, C 1-6 deuteroalkyl, C 1-6 heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, hydroxy, C 1-6 hydroxyalkyl, and amino; in one embodiment, R1, R2, and R3are each independently selected from the group consisting of H, deuterium atom, F, Cl, Br, I, C 1-3 alkyl, C 1-3 deuteroalkyl, alkenyl, alkynyl, C 1-3 alkoxy, C 1-3 haloalkyl, C 1-3 haloalkoxy, hydroxy, C 1-3 hydroxyalkyl, and amino;

[0028] B2is independently selected at each occurrence from C(R a )2, NR a , O, and S;

[0029] B4and B5are each independently selected at each occurrence from CR a , and N;

[0030] C3is independently selected for each occurrence from CR a and N;

[0031] n2, n3, n4, n5, n6, and n7 are each independently selected for each occurrence from 0, 1, 2, and 3; n8 is each independently selected for each occurrence from 1, 2, and 3;

[0032] B1and B3are each independently selected for each occurrence from C(R a )2, O, and C(O);

[0033] B6is selected from C(R a )2and O;

[0034] C1and C2are each independently selected for each occurrence from C(R a )2;

[0035] when the ring on which B3is located and the ring on which C1is located share B4and B5, at least one of B1, B2, B3, and B6is selected from NRa, O, and S;

[0036] R a is independently selected for each occurrence from H, a deuterium atom, a halogen, a C 1-6 alkyl group, a deuterated C 1-6 alkyl group, a carboxyl group, a C 1-6 heteroalkyl group, a C 2-6 alkenyl group, a C 2-6 alkynyl group, a -C(O)-C 1-6 alkyl group, a C 1-6 alkoxy group, a halogenated C 1-6 alkyl group, a halogenated C 1-6 alkoxy group, a hydroxyl group, a C 1-6 hydroxyalkyl group, a nitro group, a cyano group, an amino group, a C 1-6 alkyl-NH group, a C 1-6 alkyl C(O) group, a C 1-6 alkyloxy C(O) group, a C 1-6 alkyl-NH-C(O) group, a 3-10 membered cycloalkyl group, a 3-10 membered heterocyclyl group, a 6-10 membered aryl group, and a 5-10 membered heteroaryl group, wherein each of said alkyl, heteroalkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl groups is independently optionally substituted with one or more substituents selected from halogen, alkyl, heteroalkyl, alkoxy, halogenated alkyl, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, alkenyl, alkynyl, alkyl-NH, alkyl C(O), alkyloxy C(O), alkyl-NH-C(O), aryl, and heteroaryl;

[0037] said PTM is selected from the following structures:

[0038] wherein F6, F 16 , and F21 each independently selected from a combination of one or more of single bond, -NH-, -N(CH3)-, -S(O)-, -S-, -O-, -S(O)2-, alkylene, haloalkylene, heteroalkylene, alkoxyalkylene, heteroalkoxyalkylene, alkenylene, alkynylene, -C(=O)-, -O-C(=O)-, -C(=O)-O-, -C(=O)-NH-, and -NH-C(=O)-, wherein the alkylene, alkoxyalkylene, and alkenylene are optionally substituted with 0, 1, 2, 3, 4, 5, or 6 R da substituents;

[0039] F A1 selected from 6-10 membered aryl and 5-10 membered heteroaryl, wherein the 6-10 membered aryl and 5-10 membered heteroaryl are optionally substituted with 0, 1, 2, 3, 4, 5, or 6 R da substituents;

[0040] F A2 selected from 3-15 membered cycloalkylene, 5-15 membered spirocycloalkylene, 3-15 membered heterocyclylene, and 5-15 membered heterospirocyclylene, and the 3-15 membered cycloalkylene, 5-15 membered spirocycloalkylene, 3-15 membered heterocyclylene, and 5-15 membered heterospirocyclylene are optionally substituted with 0, 1, 2, 3, 4, 5, or 6 R ca substituents; in one embodiment, F A2 selected from 3-15 membered cycloalkylene, 5-15 membered spirocycloalkylene, 3-15 membered heterocyclylene, and 5-15 membered heterospirocyclylene, and the 3-15 membered cycloalkylene, 5-15 membered spirocycloalkylene, 3-15 membered heterocyclylene, and 5-15 membered heterospirocyclylene are optionally substituted with 0, 1, 2, 3, 4, 5, or 6 R ca substituents;

[0041] F A3 selected from 6-10 membered arylene and 5-10 membered heteroarylene, the 6-10 membered arylene and 5-10 membered heteroarylene are optionally substituted with 0, 1, 2, 3, 4, 5, or 6 R da substituents;

[0042] R da independently at each occurrence selected from halogen, C 1-6 alkyl, -O-C 1-6 haloalkyl, C 1-6 haloalkyl, C 1-6 heteroalkyl, C 1-6 alkoxy, C 1-6 heteroalkoxy, C 3-7 cycloalkyl, C 3-7 heterocyclyl, C 6-8 aryl, C 5-8heteroaryl, -OH, -NH2, -CN, -SO2 C 1-6 alkyl and -NO2;

[0043] R ca independently selected for each occurrence from halogen, C 1-6 alkyl, C 1-6 haloalkyl, -O-C 1-6 haloalkyl, C 1-6 heteroalkyl, C 1-6 alkoxy, C 1-6 alkylhydroxy, C 1-6 heteroalkoxy, C 3-7 cycloalkyl, C 3-7 heterocyclyl, C 6-8 aryl, C 5-8 heteroaryl, oxo (=O), thio (=S), C 1-6 alkylene N(C 1- 3alkyl)2, OH, NH2, CN and NO2;

[0044] when CLM is F is 8-10 membered heteroarylene; A3 is 8-10 membered heteroarylene;

[0045] when CLM is and R2 and R3 together form F is 8-10 membered heteroarylene; A2 is 4-6 membered cycloalkylene;

[0046] when CLM is R2 and R3 together form and n2+n3+n4 is 0 or 1, F A2 is 5-15 membered heterospirocyclylene, optionally substituted with 0, 1, 2, 3, 4, 5 or 6 R ca ;

[0047] denotes a point of attachment; and

[0048] the compound of Formula 1 is not any one of the following structures:

[0049] The second aspect of the present disclosure provides a compound as shown in Formula 1-1, or an isomer, an isotopic derivative, a polymorph, a prodrug, a pharmaceutically acceptable salt or a solvate thereof:

[0050] PTM-L-CLM (Formula 1-1);

[0051] wherein PTM is an androgen receptor binding moiety;

[0052] L is a bond or -(B L ) q -:

[0053] B L each occurrence is the same or different, and each is independently selected from: CR L1 R L2 , O, S, S(O), SO2, NR L3 , SO2NR L3 , S(O)NR L3 , C(O)NR L3 , NR L3 C(O)NR L4 , NR L3 SO2NR L4 , C(O), CR L1 =CR L2 , C≡C, SiR L1 R L2 , P(O)R L1 , P(O)OR L1 , NR L3 C(=NCN)NR L4 , NR L3 C(=NCN), NR L3 C(=CNO2)NR L4 , monocycloalkylene, monoheterocyclylene, bridged cyclylene, spiro cyclylene, arylene, and heteroarylene, wherein the monocycloalkylene, monoheterocyclylene, bridged cyclylene, spiro cyclylene, arylene, and heteroarylene are optionally substituted with 0, 1, 2, 3, 4, 5, or 6 R L1 and / or R L2 groups;

[0054] R L1 , R L2 , R L3 , and R L4 each occurrence is independently selected from H, halogen, C 1-8 alkyl, -O-C 1-8 alkyl, -S-C 1-8 alkyl, -NH-C 1-8 alkyl, N(C 1-8 alkyl)2, C 3-11 cycloalkyl, C 6-10 aryl, C 5-10 heteroaryl, C 3-11 heterocyclyl, -O-C 3-8 cycloalkyl, -O-C 3-11 heterocyclyl, -O-C 6-10 aryl, -O-C 5-10 heteroaryl, -S-C 3-8cycloalkyl, -NH-C 3-8 cycloalkyl, -N(C 3-8 cycloalkyl)2, -N(C 3-8 cycloalkyl)(C 1-8 alkyl), -NH-C 3-8 heterocyclyl, -N(C 3-8 heterocyclyl)2, -N(C 3-8 heterocyclyl)(C 1-8 alkyl), -NH-C 6-10 aryl, -N(C 6-10 aryl)(C 1-8 alkyl), -NH-C 5-10 heteroaryl, -N(C 5-10 heteroaryl)(C 1-8 alkyl), -OH, -NH2, -SH, SO2P(O)(O-C 1-8 alkyl)(C 1-8 alkyl), -P(O)(O-C 1-8 alkyl)2, -C≡C-C 1-8 alkyl, -C≡CH, -CH=CH-(C 1-8 alkyl), -C(C 1-8 alkyl)=CH-(C 1-8 alkyl), -C(C 1-8 alkyl)=C(C 1-8 alkyl)2, -Si(OH)3, -Si(C 1-8 alkyl)3, -Si(OH)(C 1-8 alkyl)2, -C(O)-C 1-8 alkyl, -C(O)2H, -CN, -NO2, -SO2, -SF5, -SO2NH-C 1-8 alkyl, -SO2N(C 1-8 alkyl)2, -SONH-C 1-8 alkyl, -SON(C 1-8 alkyl)2, -C(O)NH-C 1-8 alkyl, -C(O)N(C 1-8 alkyl)2, -N(C 1-8 alkyl)C(O)NH(C 1-8 alkyl), -N(C 1-8 alkyl)C(O)N(C 1-8 alkyl)2, -NHC(O)NH(C 1-8 alkyl), -NHC(O)N(C 1-8 alkyl)2, -NHC(O)NH2, -N(C 1-8 alkyl)SO2NH(C 1- 8alkyl), -N(C 1-8alkyl)2, -NHSO2NH(C 1-8 alkyl)2, -NHSO2NH(C 1-8 alkyl)2, -NHSO2NH(C 1-8 alkyl)2, and -NHSO2NH2, optionally, said C 1-8 alkyl, C 3-11 cycloalkyl, C 3-11 heterocyclyl, C 6-10 aryl, and C 5-10 heteroaryl are each independently substituted with one or more substituents selected from the group consisting of halogen, alkyl, heteroalkyl, alkenyl, alkynyl, alkoxy, hydroxy, haloalkyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, halocycloalkyl, haloheteroalkyl, alkyl-NH, C 6-10 aryl, C 5-10 heteroaryl, haloC 6-10 aryl, and haloC 5-10 heteroaryl; and

[0055] q is an integer greater than or equal to 1 ;

[0056] CLM is selected from the group consisting of:

[0057] wherein:

[0058] each occurrence of A1is independently selected from the group consisting of CR a and N;

[0059] each occurrence of A2and A4is independently selected from the group consisting of C(O) and C(R a )2;

[0060] each occurrence of A3is independently NR a ;

[0061] each occurrence of A5and A6is independently selected from the group consisting of a single bond, NR a , and C(R a )2;

[0062] when CLMis of Formula 2, Formula 4, or Formula 5, R1and R2together form when CLMis of Formula 3, R1and R2together form each occurrence of R3, R4, and R5is independently selected from the group consisting of H, a deuterium atom, halogen, C 1-6 alkyl, C 1-6 deuteroalkyl, carboxyl, C 1-6 heteroalkyl, alkenyl, alkynyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, hydroxy, C 1-6hydroxyalkyl, nitro, cyano, amino, -C(O)NH-C 1-6 alkyl, -C(O)N(C 1-6 alkyl)2, -N(C 1-6 alkyl)C(O)NH(C 1-6 alkyl), -N(C 1-6 alkyl)C(O)N(C 1- alkyl)2, -NHC(O)NH(C 1-6 alkyl), -NHC(O)N(C 1-6 alkyl)2, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein said C 1-6 alkyl, C 1-6 deuteroalkyl, C 1-6 heteroalkyl, alkenyl, alkynyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl are each independently optionally substituted with one or more substituents selected from the group consisting of halogen, alkyl, heteroalkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, alkenyl, alkynyl, alkyl-NH, -C(O)NH-C 1-6 alkyl, -C(O)N(C 1-6 alkyl)2, -N(C 1-6 alkyl)C(O)NH(C 1-6 alkyl), -N(C 1- alkyl)C(O)N(C 1-6 alkyl)2, -NHC(O)NH(C 1-6 alkyl), -NHC(O)N(C 1-6 alkyl)2, aryl, and heteroaryl; in one embodiment, R3, R4, and R5are each independently selected from the group consisting of H, deuterium atom, F, Cl, Br, I, C 1-6 alkyl, C 1-6 deuteroalkyl, C 1-6 heteroalkyl, alkenyl, alkynyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, hydroxy, C 1-6 hydroxyalkyl, and amino; in one embodiment, R3, R4, and R5are each independently selected from the group consisting of H, deuterium atom, F, Cl, Br, I, C 1-3 alkyl, C 1-3 deuteroalkyl, alkenyl, alkynyl, C 1-3 alkoxy, C1-3haloalkyl, C 1-3 haloalkoxy, hydroxy, C 1-3 hydroxyalkyl, and amino;

[0063] or

[0064] R2and R3together form R2and R3together form R1, R4, and R5are each independently at each occurrence selected from the group consisting of H, a deuterium atom, F, Cl, Br, I, C 1-6 alkyl, C 1-6 deuteroalkyl, C 1-6 heteroalkyl, alkenyl, alkynyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, hydroxy, C 1-6 hydroxyalkyl, nitro, cyano, amino, C 1-6 alkyl-NH, C 1-6 alkyl C(O), C 1-6 alkyloxy C(O), C 1-6 alkyl NHC(O), cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein said C 1-6 alkyl, C 1-6 deuteroalkyl, C 1-6 heteroalkyl, alkenyl, alkynyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl are each independently optionally substituted with one or more substituents selected from the group consisting of halogen, alkyl, heteroalkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, alkenyl, alkynyl, alkyl-NH, -C(O)NH-C 1-6 alkyl, -C(O)N(C 1-6 alkyl)2, -N(C 1- 6alkyl)C(O)NH(C 1-6 alkyl), -N(C 1-6 alkyl)C(O)N(C 1-6 alkyl)2, -NHC(O)NH(C 1-6 alkyl), -NHC(O)N(C 1-6 alkyl)2, aryl, and heteroaryl; in one embodiment, R1, R4, and R5are each independently selected from the group consisting of H, a deuterium atom, F, Cl, Br, I, C 1-6 alkyl, C 1-6 deuteroalkyl, C 1-6 heteroalkyl, alkenyl, alkynyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, hydroxy, C 1-6hydroxyalkyl, and amino; in one embodiment, R1, R4, and R5are each independently selected from H, a deuterium atom, F, Cl, Br, I, C 1-3 alkyl, C 1-3 deuteroalkyl, alkenyl, alkynyl, C 1-3 alkoxy, C 1-3 haloalkyl, C 1-3 haloalkoxy, hydroxy, C 1-3 hydroxyalkyl, and amino; in one embodiment, when CLMis Formula 2, R2and R3together form and n2+n3+n4is 0 or 1, F A2 is a 5-15 membered heterospirocyclyl optionally substituted with 0, 1, 2, 3, 4, 5, or 6 R ca substituents;

[0065] or

[0066] when CLMis Formula 2, R3and R4together form when CLMis Formula 3, R3and R4together form R1, R2, and R5are each independently selected at each occurrence from H, a deuterium atom, halogen, C 1-6 alkyl, C 1-6 deuteroalkyl, carboxyl, C 1-6 heteroalkyl, alkenyl, alkynyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, hydroxy, C 1-6 hydroxyalkyl, nitro, cyano, amino, C 1-6 alkyl-NH, C 1-6 alkyl C(O), C 1-6 alkyloxy C(O), C 1-6 alkyl NHC(O), cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein the C 1-6 alkyl, C 1-6 deuteroalkyl, C 1-6 heteroalkyl, alkenyl, alkynyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl are each independently optionally substituted with 0, 1, 2, 3, or 4 substituents selected from halogen, alkyl, heteroalkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, alkenyl, alkynyl, alkyl-NH, -C(O)NH-C 1-6 alkyl, -C(O)N(C 1-6 alkyl)2, -N(C 1-6 alkyl)C(O)NH(C 1- 6alkyl), -N(C1-6 alkyl)C(O)N(C 1-6 alkyl)2、-NHC(O)NH(C 1-6 Alkyl), -NHC(O)N(C 1-6 The alkyl group is substituted with one or more substituents selected from alkyl, aryl, and heteroaryl groups; in one embodiment, R1, R2, and R5 are each independently selected from H, deuterium, F, Cl, Br, I, and C. 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 heteroalkyl, alkenyl, ynyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy, hydroxyl, C 1-6 Hydroxyalkyl and amino groups; in one embodiment, R1, R2, and R5 are each independently selected from H, deuterium, F, Cl, Br, I, and C. 1-3 Alkyl, C 1-3 Deuterated alkyl, alkenyl, alkynyl, C 1-3 Alkoxy, C 1-3 Haloalkyl, C 1-3 Halogenated alkoxy, hydroxyl, C 1-3 Hydroxyalkyl and amino;

[0067] or

[0068] When CLM is Equation 2, R4 and R5 are formed together. When CLM is Equation 3, R4 and R5 can be formed together. R1, R2, and R3 are each independently selected from H, deuterium, halogen, and C atoms, respectively. 1-6 Alkyl, C 1-6 Deuterated alkyl, carboxyl, C 1-6 heteroalkyl, alkenyl, ynyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy, hydroxyl, C 1-6 Hydroxyalkyl, nitro, cyano, amino, C 1-6 Alkyl-NH, C 1-6 Alkyl C(O), C 1-6 Alkyloxy C(O), C 1-6 Alkyl NHC(O), cycloalkyl, heterocyclic, aryl, and heteroaryl, wherein the C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 heteroalkyl, alkenyl, ynyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6The haloalkoxy, cycloalkyl, heterocyclic, aryl, and heteroaryl groups are each independently selected from halogen, alkyl, heteroalkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, alkenyl, alkynyl, alkyl-NH, -C(O)NH-C 1-6 Alkyl, -C(O)N(C) 1-6 Alkyl)2, -N(C 1-6 alkyl)C(O)NH(C 1-6 alkyl), -N(C) 1-6 alkyl)C(O)N(C 1-6 alkyl)2、-NHC(O)NH(C 1-6 Alkyl), -NHC(O)N(C 1-6 The alkyl group is substituted with one or more substituents selected from alkyl, aryl, and heteroaryl groups; in one embodiment, R1, R2, and R3 are each independently selected from H, deuterium, F, Cl, Br, I, C1-6 alkyl, C 1-6 Deuterated alkyl, C 1-6 Heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 The compounds are halogenated alkoxy, hydroxyl, C1-6 hydroxyalkyl, and amino; in one embodiment, R1, R2, and R3 are each independently selected from H, deuterium, F, Cl, Br, I, and C. 1-3 Alkyl, C 1-3 Deuterated alkyl, alkenyl, alkynyl, C 1-3 Alkoxy, C 1-3 Haloalkyl, C 1-3 Halogenated alkoxy, hydroxyl, C 1-3 Hydroxyalkyl and amino;

[0069] B2 is selected independently from C(R) each time it appears. a 2. NR a O and S;

[0070] B4 and B5 are each selected independently from CR each time they appear. a and N;

[0071] C3 is selected independently from CR each time it appears. a and N;

[0072] n2, n3, n4, n5, n6, and n7 are each independently selected from 0, 1, 2, and 3 each time they appear; n8 is each independently selected from 1, 2, and 3 each time it appears.

[0073] B1 and B3 are each selected independently from C(R) each time they appear. a 2. O and C(O);

[0074] B6is selected from C(R a )2and O;

[0075] C1and C2are each independently at each occurrence selected from C(R a )2;

[0076] when B4and B5are present, at least one of B1, B2, B3and B6is selected from NR a , O and S;

[0077] R a is independently at each occurrence selected from H, a deuterium atom, halogen, C 1-6 alkyl, deuterated C 1-6 alkyl, carboxyl, C 1-6 heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl, -C(O)-C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkyl, halogenated C 1-6 alkoxy, hydroxyl, C 1-6 hydroxyalkyl, nitro, cyano, amino, C 1-6 alkyl-NH, C 1-6 alkyl C(O), C 1-6 alkyl oxy C(O), C 1-6 alkyl NHC(O), 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl, and 5-10 membered heteroaryl, wherein each of said alkyl, heteroalkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl is independently optionally substituted with one or more substituents selected from halogen, alkyl, heteroalkyl, alkoxy, halogenated alkyl, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, alkenyl, alkynyl, alkyl-NH, alkyl C(O), alkyl oxy C(O), alkyl NHC(O), aryl, and heteroaryl;

[0078] said PTM is selected from the following structures:

[0079] wherein F6, F 16 and F 21each independently selected from a combination of one or more of single bond, -NH-, -N(CH3)-, -S(O)-, -S-, -O-, -S(O)2-, alkylene, haloalkylene, heteroalkylene, alkoxyalkylene, heteroalkoxyalkylene, alkenylene, alkynylene, -C(=O)-, -O-C(=O)-, -C(=O)-O-, -C(=O)-NH-, and -NH-C(=O)-, wherein the alkylene, alkoxyalkylene, and alkenylene are optionally substituted with 0, 1, 2, 3, 4, 5, or 6 R da substituted;

[0080] F A1 selected from 6-10 membered aryl and 5-10 membered heteroaryl, wherein the 6-10 membered aryl and 5-10 membered heteroaryl are optionally substituted with 0, 1, 2, 3, 4, 5, or 6 R da substituted;

[0081] F A2 selected from 3-15 membered cycloalkylene, 5-15 membered spirocycloalkylene, 3-15 membered heterocyclylene, and 5-15 membered heterospirocyclylene, and the 3-15 membered cycloalkylene, 5-15 membered spirocycloalkylene, 3-15 membered heterocyclylene, and 5-15 membered heterospirocyclylene are optionally substituted with 0, 1, 2, 3, 4, 5, or 6 R ca substituted; in one embodiment, F A2 selected from 3-15 membered cycloalkylene, 5-15 membered spirocycloalkylene, 3-15 membered heterocyclylene, and 5-15 membered heterospirocyclylene, and the 3-15 membered cycloalkylene, 5-15 membered spirocycloalkylene, 3-15 membered heterocyclylene, and 5-15 membered heterospirocyclylene are optionally substituted with 0, 1, 2, 3, 4, 5, or 6 R ca substituted;

[0082] F A3 selected from 6-10 membered arylene and 5-10 membered heteroarylene, the 6-10 membered arylene and 5-10 membered heteroarylene are optionally substituted with 0, 1, 2, 3, 4, 5, or 6 R da substituted;

[0083] R da independently at each occurrence selected from H, halogen, C 1-6 alkyl, -O-C 1-6 haloalkyl, C 1-6 haloalkyl, C 1-6 heteroalkyl, C 1-6 alkoxy, C 1- 6heteroalkoxy, C 3-7 cycloalkyl, C 3-7 heterocyclyl, C 6-8 aryl, C 5-8 heteroaryl, -OH, -NH2, -CN, -SO2 C1-6 Alkyl groups and -NO2;

[0084] R ca Each time it appears, it is independently selected from H, halogen, C. 1-6 Alkyl, C 1-6 Halogenated alkyl groups, -OC 1-6 Haloalkyl, C 1-6 Heteroalkyl, C 1-6 Alkoxy, C 1- 6-alkylhydroxyl, C 1-6 Zykaloxy, C 3-7 cycloalkyl, C 3-7 Heterocyclic group, C 6-8 Aryl, C 5-8 heteroaryl, oxo (=O), thio (=S), C 1-6 Alkylene N(C) 1-3 Alkyl groups, OH, NH2, CN, and NO2; and

[0085] The compound of formula 1-1 is not one of the following structures:

[0086] In one implementation, B L Each occurrence is independently selected from: CR L1 R L2 O, S, S(O), SO2, NR L3 C(O), C≡C, 3-15-membered monocycloalkylene, 3-15-membered monoheterocyclic group containing 1, 2, 3, 4 or 5 heteroatoms independently selected from N, O and S, 5-15-membered bridged cycloalkyl group containing 0, 1, 2, 3, 4 or 5 heteroatoms independently selected from N, O and S, 5-15-membered spirocyclic group containing 0, 1, 2, 3, 4 or 5 heteroatoms independently selected from N, O and S, 6-15-membered aryl group and 5-15-membered heteroaryl group containing 0, 1, 2, 3, 4 or 5 heteroatoms independently selected from N, O and S, wherein the 3-15-membered monocycloalkylene, 3-15-membered monoheterocyclic group, 5-15-membered bridged cycloalkyl group, 5-15-membered spirocyclic group, 6-15-membered aryl group and 5-15-membered heteroaryl group are optionally separated by 0, 1, 2 or 3 R L1 and / or R L2 Group substitution; in one embodiment, B L Each occurrence is independently selected from: CR L1 R L2 O, S, S(O), SO2, NR L3, C(O), CºC, 3-8 membered alkylenemonocycloalkyl, 3-8 membered alkylenomono heterocyclyl containing 1, 2, or 3 heteroatoms independently selected from N, O, and S, 5-12 membered alkylenabicyclyl containing 0-3 heteroatoms independently selected from N, O, and S, 5-12 membered alkylenaspirocyclyl containing 0-3 heteroatoms independently selected from N, O, and S, 6-12 membered arylene, and 5-12 membered heteroarylene containing 1, 2, or 3 heteroatoms independently selected from N, O, and S, wherein the 3-8 membered alkylenemonocycloalkyl, 3-8 membered alkylenomono heterocyclyl, 5-12 membered alkylenabicyclyl, 5-12 membered alkylenaspirocyclyl, 6-12 membered arylene, and 5-12 membered heteroarylene are optionally substituted with 0, 1, 2, or 3 R L1 and / or R L2 groups; in one embodiment, B L is independently selected at each occurrence from: CR L1 R L2 , O, S, S(O), SO2, NR L3 , C(O), CºC, 3-8 membered alkylenemonocycloalkyl, 3-6 membered alkylenomono heterocyclyl containing 1, 2, or 3 heteroatoms independently selected from N, O, and S, 5-12 membered alkylenabicyclyl containing 0-3 heteroatoms independently selected from N, O, and S, 5-12 membered alkylenaspirocyclyl containing 0-3 heteroatoms independently selected from N, O, and S, 6-12 membered arylene, and 5-12 membered heteroarylene containing 1, 2, or 3 heteroatoms independently selected from N, O, and S, wherein the 3-8 membered alkylenemonocycloalkyl, 3-8 membered alkylenomono heterocyclyl, 5-12 membered alkylenabicyclyl, 5-12 membered alkylenaspirocyclyl, 6-12 membered arylene, and 5-12 membered heteroarylene are optionally substituted with 0, 1, 2, or 3 R L1 and / or R L2 groups.

[0087] In one embodiment, R L1 , R L2 , R L3 , and R L4 are each independently selected at each occurrence from oxo, H, halogen, C 1-6 alkyl, -O-C 1- 6alkyl, -S-C 1-6 alkyl, -NH-C 1-6 alkyl, N(C 1-6 alkyl)2, C 3-11 cycloalkyl, C 6-10 aryl, C 5-10 heteroaryl, C 3-11 heterocyclyl, -O-C 3-8 cycloalkyl, -O-C 3-11 heterocyclyl, -O-C 6-10 aryl, -O-C 5-10 heteroaryl, -S-C3-8 cycloalkyl, -NH-C 3-8 cycloalkyl, -N(C 3-8 cycloalkyl)2, -N(C 3-8 cycloalkyl)(C 1-6 alkyl), -NH-C 3-8 heterocyclyl, -N(C 3-8 heterocyclyl)2, -N(C 3-8 heterocyclyl)(C 1-6 alkyl), -NH-C 6-10 aryl, -N(C 6-10 aryl)(C 1- 6alkyl), -NH-C 5-10 heteroaryl, -N(C 5-10 heteroaryl)(C 1-6 alkyl), -OH, -NH2, -SH, SO2 P(O)(O-C 1-6 alkyl)(C 1-6 alkyl), -P(O)(O-C 1-6 alkyl)2, -C≡C-C 1-6 alkyl, -C≡CH, -CH=CH-(C 1-6 alkyl), -C(C 1-6 alkyl)=CH-(C 1-6 alkyl), -C(C 1-6 alkyl)=C(C 1-6 alkyl)2, -Si(OH)3, -Si(C 1-6 alkyl)3, -Si(OH)(C 1-6 alkyl)2, -C(O)-C 1-6 alkyl, -C(O)2H, -CN, -NO2, -SO2, -SF5, -SO2NH-C 1-6 alkyl, -SO2N(C 1-6 alkyl)2, -S(O)NH-C 1-6 alkyl, -S(O)N(C 1-6 alkyl)2, -C(O)NH-C 1-6 alkyl, -C(O)N(C 1-6 alkyl)2, -N(C 1- 6alkyl)C(O)NH(C 1-6 alkyl), -N(C 1-6 alkyl)C(O)N(C 1-6 alkyl)2, -NHC(O)NH(C 1-6 alkyl), -NHC(O)N(C 1-6 alkyl)2, -NHC(O)NH2, -N(C 1-6 alkyl)SO2NH(C 1-6 alkyl), -N(C1-6 alkyl)2, -NHSO2NH(C 1-6 alkyl)2, -NHSO2NH(C 1-6 alkyl), -NHSO2N(C 1-6 alkyl)2, and -NHSO2NH2, optionally, said C 1-6 alkyl, C 3-11 cycloalkyl, C 3-11 heterocyclyl, C 6-10 aryl, and C 5-10 heteroaryl are each independently substituted with one or more substituents selected from the group consisting of halogen, alkyl, heteroalkyl, alkenyl, alkynyl, alkoxy, hydroxy, haloalkyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, halocycloalkyl, haloheteroalkyl, alkyl-NH, aryl, heteroaryl, haloaryl, and haloheteroaryl.

[0088] In one embodiment, q is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20; in one embodiment, q is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

[0089] In one embodiment, A2and A4are each independently C(O).

[0090] In one embodiment, A3is each occurrence independently selected from the group consisting of NH and N-C 1-3 alkyl; in one embodiment, A3is each occurrence independently selected from the group consisting of NH and N-methyl.

[0091] In one embodiment, A5and A6are each independently C(R a )2; in one embodiment, A5and A6are each independently CH2.

[0092] In one embodiment, n2+n3+n4=0, n2+n3+n4=1, or n2+n3+n4=2.

[0093] In one embodiment, n5+n6=2 or n5+n6=3.

[0094] In one embodiment, n7+n8=2, n7+n8=3, n7+n8=4, or n7+n8=5.

[0095] In one embodiment, the CLM is selected from the group consisting of:

[0096] wherein R1, R2, R3, R4, R5, R a, C1, C2, C3, B1, B2, B3, B4, B5, B6, n2, n3, n4, n5, n6, n7, and n8 are defined as previously defined;

[0097] In one embodiment, R1, R2, R3, R4, and R5are each independently at each occurrence selected from the group consisting of H, F, Cl, Br, I, C 1-3 alkyl, C 1-3 alkoxy, hydroxyl, and amino;

[0098] B2is independently at each occurrence selected from the group consisting of C(R a )2, NR a , and O;

[0099] B1and B3are each independently at each occurrence selected from the group consisting of C(R a )2, O, and C(O);

[0100] B4and B5are each independently at each occurrence one of N and the other of CR a ;

[0101] B6is selected from the group consisting of C(R a )2and O;

[0102] C1and C2are each independently at each occurrence selected from the group consisting of C(R a )2;

[0103] C3is independently at each occurrence selected from the group consisting of N;

[0104] R a is independently at each occurrence selected from the group consisting of H, F, Cl, Br, I, C 1-3 alkyl, C 1-3 alkoxy, hydroxyl, amino, and -C(O)-C 1-3 alkyl; and

[0105] n2, n3, n4, n5, n6, and n7are each independently at each occurrence selected from the group consisting of 0, 1, 2, and 3, and n8is selected from the group consisting of 1, 2, and 3; in one embodiment, n2+n3+n4=0, n2+n3+n4=1, or n2+n3+n4=2; in one embodiment, n5+n6=2 or n5+n6=3.

[0106] In one embodiment, the CLM is selected from the group consisting of:

[0107] In one embodiment, B L is independently at each occurrence selected from one or more of the following structures: -O-, -S-, -S(O)-, -SO2-, -CH2-, -C(O)-, -NH-, For the attachment site.

[0108] In one embodiment, L is selected from a covalent bond, -CH2-, -(CH2)2-, -(CH2)3-, -(CH2)4-, -(CH2)5-, -(CH2)6-, -(CH2)7-, -(CH2)8-, -NH-CH2-, -NH-(CH2)2-, -NH-(CH2)3-, -NH-(CH2)4-, -NH-(CH2)5-, -NH-(CH2)6-, -NH-(CH2)7-, -NH-(CH2)8-, -C(O)-NH-CH2-, -C(O)-NH-(CH2)2-, -C(O)-NH-(CH2)3-, -C(O)-NH-(CH2)4-, -C(O)-NH-(CH2)5-, -C(O)-NH-(CH2)6-, -C(O)-NH-(CH2)7-, -C(O)-NH-(CH2)8-, -CH2-NH-, -(CH2)2-NH-, -(CH2)3-NH-, -(CH2)4-NH-, -(CH2)5-NH-, -(CH2)6-NH-, -(CH2)7-NH-, -(CH2)8-NH-, -NH-CH2-NH-, -NH-(CH2)2-NH-, -NH-(CH2)3-NH-, -NH-(CH2)4-NH-, -NH-(CH2)5-NH-, -NH-(CH2)6-NH-, -NH-(CH2)7-NH-, -NH-(CH2)8-NH-, -(CH2-CH2-O)-CH2-CH2-, -(CH2-CH2-O)2-CH2-CH2-, -(CH2-CH2-O)3-CH2-CH2-, -NH-(CH2-CH2-O)-CH2-CH2-, -NH-(CH2-CH2-O)2-CH2-CH2-, -NH-(CH2-CH2-O)3-CH2-CH2-, -C(O)-NH-(CH2-CH2-O)-CH2-CH2-, -C(O)-NH-(CH2-CH2-O)2-CH2-CH2-, -C(O)-NH-(CH2-CH2-O)3-CH2-CH2-, -(CH2-CH2-O)-CH2-CH2-NH-, -(CH2-CH2-O)2-CH2-CH2-NH-, -(CH2-CH2-O)3-CH2-CH2-NH-, -NH-(CH2-CH2-O)-CH2-CH2-NH-, -NH-(CH2-CH2-O)2-CH2-CH2-NH-, -NH-(CH2-CH2-O)3-CH2-CH2-NH-, -C(O)-NH-(CH2-CH2-O)-CH2-CH2-NH-, -C(O)-NH-(CH2-CH2-O)2-CH2-CH2-NH-, -C(O)-NH-(CH2-CH2-O)3-CH2-CH2-NH-, -CH2-CH2-S-, -CH2-CH2-S-CH2-CH2-, -CH2-CH2-S-CH2-CH2-S-, -CH2-CH2-S-CH2-CH2-S-CH2-CH2-, -CH2-CH2-S-CH2-CH2-S-CH2-CH2-S-, -CH2-CH2-S-CH2-CH2-S-CH2-CH2-S-CH2-CH2-, -CH2-CH2-S-CH2-CH2-S-CH2-CH2-S-CH2-CH2-S-, -CH2-CH2-S-CH2-CH2-S-CH2-CH2-S-CH2-CH2-S-CH2-CH2-, -CH2-CH2-S-CH2-CH2-S-CH2-CH2-S-CH2-CH2-S-CH2-CH2-S-, -CH2-CH2-S-CH2-CH2-S-CH2-CH2-S-CH2-CH2-S-CH2-CH2-S-CH2-CH2-, -CH2-CH2-S-CH2-CH2-S-CH2-CH2-S-CH2-CH2-S-CH2-CH2-S-CH2-CH2-S-, -CH2-CH2-S-CH2-CH2-S-CH2-CH2-S-CH2-CH2-S-CH2-CH2-S-CH2-CH2-S-CH2-CH2-, -CH2-CH2-S-CH2-CH2-S-CH2-CH2-S-CH2-CH2-S-CH2-CH2-S-CH2-CH2-S-CH2-CH2-S-, -CH2-CH2-S-CH2-CH2-S-CH2-CH2-S-CH2-CH2-S-CH2-CH2-S-CH2-CH2-S-CH2-CH2-S-, -CH2-CH2-S-CH2-CH2-S-CH2-CH2-S-CH2-CH2-S-CH2-CH2-S-CH2-CH2-S-CH2-CH2-S-, -CH2-CH2-S-CH2-CH2-S-CH2-CH2-S-CH2-CH2-S-CH2-CH2-S-CH2-CH2-S-CH2-CH2-S-, -CH2-CH2-S-CH2-CH2-S-CH2-CH2-S-CH2-CH2-S-CH2-CH2-S-CH2-CH2-S-CH2-CH2-S-, -CH2-CH2-S-CH2-CH2-S-CH2-CH2-S-CH2-CH2-S-CH2-CH2-S-CH2-CH2-S-CH2-CH2-S-, -CH2-CH2-S-CH2-CH2-S-CH2-CH2-S-CH2-CH2-S-CH2-CH2-S-CH2-CH2-S-CH2-CH2-S-, -CH2-CH2-S-CH2-CH2-S-CH2-CH2-S-CH2-CH2-S-CH2-CH2-S-CH2-CH2-S-CH2-CH2-S-, -CH2-CH2-S-CH2-CH2-S-CH2-CH2-S-CH2-CH2-S-CH2-CH2-S-CH2-CH2-S-CH2-CH2-S-, -CH2-CH2-S-CH2-CH2-S-CH2-CH2-S-CH2-CH2-S-CH2-CH2-S-CH2-CH2-S-CH2-CH2-S-, -CH2-CH2-S-CH2-CH2-S-CH2-CH2-S-CH2-CH2-S-CH2-CH2-S-CH2-CH2-S-CH2-CH2-S-, -CH2-CH2-S-CH2-CH2-S-CH2-CH2-S-CH2-CH2-S-CH2-CH2-S-CH2-CH2-S-CH2-CH2-S-, -CH2-CH2-S-CH2-CH2-S-CH2-CH2-S-CH2-CH2-S-CH2-CH2-S-CH2-CH2-S-CH2-CH2-S-, -CH2-CH2-S-CH2-CH2-S-CH2-CH2-S-CH2-CH2-S-CH2-CH2-S-CH2-CH2-S-CH2-CH2-S-, -CH2-CH2-S-CH2-CH2-S-CH2-CH2-S-CH2-CH2-S-CH2-CH2-S-CH2-CH2-S-CH2-CH2-S-, -CH2-CH2-S-CH2-CH2-S-CH2-CH2-S-CH2-CH2-S-CH2-CH2-S-CH2-CH2-S-CH2-CH2-S-, -CH2-CH2-S-CH2-CH2-S-CH2-CH2-S-CH2-CH2-S-CH2-CH2-S-CH2-CH2-S-CH2-CH2-S-, -CH2-CH2-S-CH2-CH2-S-CH2-CH2-S-CH2-CH2-S-CH2-CH2-S-CH2-CH2-S-CH2-CH2-S-, -CH2-CH2-S-CH2-CH2-S-CH2-CH2-S-CH2-CH2-S-CH2-CH2-S-CH2-CH2-S-CH2-CH2-S-, -CH2-CH2-S-CH2-CH2-S-CH2-CH2-S-CH2-CH2-S-CH2-CH2-S-CH2-CH2-S-CH2-CH2-S-, -CH2-CH2-S-CH2-CH2-S-CH2-CH2-S--C(O)-NH-(CH2-CH2-O)3-CH2-CH2-NH-, -CH2-CH2-(O-CH2-CH2)-, -CH2-CH2-(O-CH2-CH2)2-, -CH2-CH2-(O-CH2-CH2)3-, -NH-CH2-CH2-(O-CH2-CH2)-, -NH-CH2-CH2-(O-CH2-CH2)2-, -NH-CH2-CH2-(O-CH2-CH2)3-, -C(O)-NH-CH2-CH2-(O-CH2-CH2)-, -C(O)-NH-CH2-CH2-(O-CH2-CH2)2-, -C(O)-NH-CH2-CH2-(O-CH2-CH2)3-, -CH2-CH2-(O-CH2-CH2)-NH-, -CH2-CH2-(O-CH2-CH2)2-NH-, -CH2-CH2-(O-CH2-CH2)3-NH-, -NH-CH2-CH2-(O-CH2-CH2)-NH-, -NH-CH2-CH2-(O-CH2-CH2)2-NH-, -NH-CH2-CH2-(O-CH2-CH2)3-NH-, -NH-CH2-CH2-O-CH2-CH2-C(O)-, -C(O)-CH2-CH2-O-CH2-CH2-NH-, -NH-(CH2)4-C(O)-, -NH-(CH2)5-C(O)-, -NH-(CH2)6-C(O)-, -C(O)-(CH2)4-NH-, -C(O)-(CH2)5-NH-, -C(O)-(CH2)6-NH-, -NH-(CH2-CH2-O)-(CH2)3-, -NH-(CH2-CH2-O)-(CH2)4-, -NH-(CH2-CH2-O)-(CH2)5-, -NH-(CH2-CH2-O)-(CH2)6-, -(CH2)3-(O-CH2-CH2)-NH-, -(CH2)4-(O-CH2-CH2)-NH-, -(CH2)5-(O-CH2-CH2)-NH-, -(CH2)6-(O-CH2-CH2)-NH-, -CH2-CH2-O-(CH2)2-C(O)-, -CH2-CH2-O-(CH2)3-C(O)-, -CH2-CH2-O-(CH2)4-C(O)-, -C(O)-(CH2)2-O-CH2-CH2-, -C(O)-(CH2)3-O-CH2-CH2-, -C(O)-(CH2)4-O-CH2-CH2-, -C(O)-(CH2)2-, -C(O)-(CH2)3-, -C(O)-(CH2)4-, -C(O)-(CH2)5-, -C(O)-(CH2)6-,-(CH2)2-C(O)-, -(CH2)3-C(O)-, -(CH2)4-C(O)-, -(CH2)5-C(O)-, -(CH2)6-C(O)-, -C(O)-(CH2)2-C(O)-, -C(O)-(CH2)3-C(O)-, -C(O)-(CH2)4-C(O)-, -C(O)-(CH2)5-C(O)-, -C(O)-(CH2)6-C(O)-, -CH2-C(O)-CH2-, -CH2-C(O)-(CH2)2-, -CH2-C(O)-(CH2)3-, -CH2-C(O)-(CH2)4-, -(CH2)2-C(O)-CH2-, -(CH2)2-C(O)-(CH2)2-, -(CH2)2-C(O)-(CH2)3-, -(CH2)2-C(O)-(CH2)4-, -(CH2)3-C(O)-CH2-, -(CH2)3-C(O)-(CH2)2-, -(CH2)3-C(O)-(CH2)3-, -(CH2)3-C(O)-(CH2)4-, -(CH2)4-C(O)-CH2-, -(CH2)4-C(O)-(CH2)2-, -(CH2)4-C(O)-(CH2)3-, -(CH2)4-C(O)-(CH2)4-, -CH2-O-CH2-, -CH2-O-(CH2)2-, -CH2-O-(CH2)3-, -CH2-O-(CH2)4-, -(CH2)2-O-CH2-, -(CH2)2-O-(CH2)2-, -(CH2)2-O-(CH2)3-, -(CH2)2-O-(CH2)4-, -(CH2)3-O-CH2-, -(CH2)3-O-(CH2)2-, -(CH2)3-O-(CH2)3-, -(CH2)3-O-(CH2)4-, -(CH2)4-O-CH2-, -(CH2)4-O-(CH2)2-, -(CH2)4-O-(CH2)3-, -(CH2)4-O-(CH2)4-, -O-CH2-, -O-(CH2)2-, -O-(CH2)3-, -O-(CH2)4-, -O-(CH2)5-, -O-(CH2)6-,

[0109] In one embodiment, the PTM is selected from the following structure:

[0110] wherein F6, F 16 and F 21are each independently selected from a single bond, -NH-, -N(CH3)-, -S(O)-, -S-, -O-, -S(O)2-, -C(=O)-, -O-C(=O)-, and -NH-C(=O)-;

[0111] F A1 is phenyl or pyridyl, which phenyl or pyridyl is optionally substituted with 0, 1, 2, 3, 4, or 5 R da substituents; in one embodiment, F A1 is phenyl, which phenyl is optionally substituted with 2, 3, 4, or 5 R da substituents, and at least one R da is CN;

[0112] F A2 is selected from 4-6 membered single cycloalkylene, 7-11 membered spiro cycloalkylene, 4-6 membered single heterocyclylene containing 1, 2, 3, or 4 heteroatoms each independently selected from N, O, and S, and 7-11 membered heterospirocyclylene containing 1, 2, 3, or 4 heteroatoms each independently selected from N, O, and S, said 4-6 membered single cycloalkylene, 7-11 membered spiro cycloalkylene, 4-6 membered single heterocyclylene, and 7-11 membered heterospirocyclylene being optionally substituted with 0, 1, 2, 3, 4, 5, or 6 R ca substituents; in one embodiment, F A2 is selected from 4-, 5-, or 6-membered single cycloalkylene, 4-, 5-, or 6-membered single heterocyclylene containing 1, 2, 3, or 4 heteroatoms each independently selected from N, O, and S, and 9-, 10-, or 11-membered heterospirocyclylene containing 1, 2, 3, or 4 heteroatoms each independently selected from N, O, and S, said 4-, 5-, or 6-membered single cycloalkylene, 4-, 5-, or 6-membered single heterocyclylene, and 9-, 10-, or 11-membered heterospirocyclylene being optionally substituted with 0, 1, 2, 3, 4, 5, or 6 R ca substituents; in one embodiment, F A2 is selected from 4-, 5-, or 6-membered single cycloalkylene, and 10-membered heterospirocyclylene containing 1, 2, or 3 N atoms, and said 4-, 5-, or 6-membered single cycloalkylene, and 10-membered heterospirocyclylene containing 1, 2, or 3 N atoms being optionally substituted with 0, 1, 2, 3, 4, 5, or 6 R ca substituents;

[0113] F A3 is phenylene substituted with 0, 1, 2, 3, or 4 R da substituents, or is 6-membered heteroarylene containing 1, 2, or 3 heteroatoms each independently selected from N, O, and S, substituted with 0, 1, 2, or 3 R da substituents, or is 10-membered bicyclic heteroarylene containing 1, 2, or 3 heteroatoms each independently selected from N, O, and S; da substituents;

[0114] Rda independently at each occurrence selected from H, F, CI, Br, I, C 1-3 alkyl, O-C 1-3 haloalkyl, C 1-3 haloalkyl, C 1-3 heteroalkyl, C 1-3 alkoxy, C 1-3 heteroalkoxy, C 3-7 cycloalkyl, C 3-7 heterocyclyl, C 6-8 aryl, C 5-8 heteroaryl, OH, NH2, CN, SO2 C 1-3 alkyl and NO2; in one embodiment, R da independently at each occurrence selected from H, F, CI, Br, I, CH3, C2H5, OCH3, OCH2CH3, CF3, CHF2, O-CF3, O-CHF2, O-CH2F, OH, NH2, CN, SO2CH3, and NO2; in one embodiment, R da independently at each occurrence selected from F, CI, Br, I, CH3, C2H5, OCH3, OCH2CH3, CF3, CHF2, O-CF3, O-CHF2, O-CH2F, OH, NH2, CN, SO2CH3, and NO2; and

[0115] R ca independently at each occurrence selected from H, F, CI, Br, I, C 1-3 alkyl, C 1-3 alkylhydroxy, -O-C 1-3 haloalkyl, C 1-3 haloalkyl, C 1-3 heteroalkyl, C 1-3 alkoxy, C 1-3 heteroalkoxy, C 3-7 cycloalkyl, C 3-7 heterocyclyl, C 6-8 aryl, C 5-8 heteroaryl, oxo (=0), thioxo (=S), C 1-3 alkyl N(C 1-3 alkyl)2, OH, NH2, CN, and NO2; in one embodiment, R ca independently at each occurrence selected from H, F, CI, Br, I, oxo (=0), thioxo (=S), CH3, C2H5, CH2OH, CH2N(CH3)2, 3-membered cycloalkyl, CHF2, CH2-CHF2, OCH3, CF3, OH, NH2, CN, and NO2; in one embodiment, R caindependently at each occurrence selected from the group consisting of F, CI, Br, I, oxo, CH3, C2H5, CH2OH, CH2N(CH3)2, 3-membered cycloalkyl, CHF2, CH2-CHF2, OCH3, CF3, OH, NH2, CN, and NO2.

[0116] independently at each occurrence selected from the group consisting of F, CI, Br, I, oxo, CH3, C2H5, CH2OH, CH2N(CH3)2, 3-membered cycloalkyl, CHF2, CH2-CHF2, OCH3, CF3, OH, NH2, CN, and NO2. A1 selected from the group consisting of phenyl and pyridyl, said phenyl and pyridyl being optionally substituted with 1, 2, 3, or 4 substituents independently selected from the group consisting of F, CI, Br, I, CN, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 haloalkyl, and -O-C 1-3 haloalkyl; in one embodiment, F A1 selected from the group consisting of phenyl and pyridyl, said phenyl and pyridyl being optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of F, CI, Br, CN, CH3, OCH3, CH2F, CHF2, CF3, O-CH2F, O-CHF2, and O-CF3; in one embodiment, F A1 selected from the group consisting of in which the wavy line indicates F A1 is the point of attachment to F6.

[0117] independently at each occurrence selected from the group consisting of F, CI, Br, I, oxo, CH3, C2H5, CH2OH, CH2N(CH3)2, 3-membered cycloalkyl, CHF2, CH2-CHF2, OCH3, CF3, OH, NH2, CN, and NO2. A2 selected from the group consisting of: said optionally substituted with 1, 2, 3, or 4 substituents independently selected from the group consisting of F, CI, Br, I, oxo, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkylhydroxy, C 1-3 alkyl-NH2, C 1-3 alkylNH(C 1-3 alkyl), C 1-3 alkylN(C 1-3 alkyl)2, and C 3-6 cycloalkyl; in one embodiment, F optionally substituted with 1, 2, 3, or 4 substituents independently selected from the group consisting of F, CH3, C2H5, oxo, CH2F, CHF2, CF3, CH2-CH2F, CH2-HCF2, CH2-CF3, CH2OH, CH2 N(CH3)2, and cyclopropyl; in one embodiment, F A2 selected from the group consisting of: F represents F A2 F6is a point of attachment to F6or F 16 , respectively;

[0118] In one embodiment, F6is independently selected at each occurrence from a single bond, -NH-, -N(CH3)-, -O-, -C(=O)-, -O-C(=O)-, and -NH-C(=O)-; in one embodiment, F6is independently a single bond, -O-, or -N(CH3)- at each occurrence; in one embodiment, F6is -O-.

[0119] In one embodiment, F 16 is independently selected at each occurrence from a single bond, -NH-, -N(CH3)-, -S(O)-, -S-, -O-, -S(O)2-, -C(=O)-, -O-C(=O)-, and -NH-C(=O)-; in one embodiment, F 16 is independently a single bond or C(O) at each occurrence; in one embodiment, F In one embodiment, F 16 is

[0120] In one embodiment, F 21 is independently selected at each occurrence from a single bond, -NH-, -N(CH3)-, -S(O)-, -S-, -O-, -S(O)2-, -C(=O)-, -O-C(=O)-, and -NH-C(=O)-; in one embodiment, F 21 is independently a single bond or C(O) at each occurrence; in one embodiment, F 21 is a single bond.

[0121] In one embodiment, when F A2 is , F6is -O- or -N(CH3)-, F 16 is , F6and F A2 is , F6and F 16 are single bonds; when F A2 is , F6is a single bond, F 16 is

[0122] In one embodiment, F A3 is selected from phenyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, and pyridopyrrolidinyl, wherein the phenyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, and pyridopyrrolidinyl are optionally substituted with 1, 2, 3, or 4 substituents independently selected from F, Cl, Br, I, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 haloalkyl, -O-C 1-3 haloalkyl and -SO2 C 1-3 alkyl; in one embodiment, the phenyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl and pyridopyrrolidinyl groups are optionally substituted with 1, 2 or 3 substituents independently selected from F, CI, Br, CH3, C2H5, OCH3, O-CH2CH3, CH2F, CHF2, CF3, CH2-CH2F, CH2-CHF2, CH2-CF3, OCH2F, OCHF2, OCF3and -SO2CH3; in one embodiment, the F A3 is selected from: In this wavy line indicates the point of attachment of F A3 to F 16 or F 21 respectively.

[0123] In one embodiment, F 21 is or a single bond.

[0124] In one embodiment, the F A1 in the PTM is selected from wherein, R da1 , R da2 , R da3 , R da4 and R da5 are independently at each occurrence selected from H, F, CI, Br, I, C 1-3 alkyl, -O-C 1-3 haloalkyl, C 1-3 haloalkyl, C 1-3 heteroalkyl, C 1-3 alkoxy, C 1-3 heteroalkoxy, C 3-7 cycloalkyl, C 3-7 heterocyclyl, C 6-8 aryl, C 5-8 heteroaryl, OH, NH2, CN, SO2 C 1-3 alkyl and NO2; in one embodiment, R da1 , R da2 , R da3 , R da4 , and R da5 are independently at each occurrence selected from H, F, CI, Br, CN, CH3, OCH3, CH2F, CHF2, CF3, O-CH2F, O-CHF2and O-CF3;

[0125] In one embodiment, F in the PTM is A2 selected from the group consisting of:

[0126] wherein R ca1 , R ca2 , R ca3 and R ca4 are each, independently at each occurrence, selected from the group consisting of H, F, Cl, Br, I, C 1-3 alkyl, C 1-3 alkylhydroxy, -O-C 1-3 haloalkyl, C 1-3 haloalkyl, C 1-3 heteroalkyl, C 1-3 alkoxy, C 1-3 heteroalkoxy, C 3-7 cycloalkyl, C 3-7 heterocyclyl, C 6-8 aryl, C 5-8 heteroaryl, C 1-3 alkylN(C 1-3 alkyl)2, OH, NH2, CN, and NO2; in one embodiment, R ca1 , R ca2 , R ca3 and R ca4 are each, independently at each occurrence, selected from the group consisting of H, F, CH3, C2H5, oxo, CH2F, CHF2, CF3, CH2-CH2F, CH2-HCF2, CH2-CF3, CH2OH, CH2 N(CH3)2, and cyclopropyl; or

[0127] one of R ca1 and R ca2 is oxo or thioxo, and the other is absent; one of R ca3 and R ca4 is oxo or thioxo, and the other is absent;

[0128] hi, h2, h3, h4, h5, and h6 are each independently 0, 1, or 2;

[0129] In one embodiment, F in the PTM is A3 selected from the group consisting of:

[0130] wherein Y 1 is N or CR da6 ; Y 2 is N or CR da7 ; Y 3 is N or CR da8 ; Y 4N or CR da9 ;

[0131] R da6 , R da7 , R da8 , and R da9 are each independently selected at each occurrence from H, F, Cl, Br, I, C 1-3 alkyl, -O-C 1-3 haloalkyl, C 1-3 haloalkyl, C 1-3 heteroalkyl, C 1-3 alkoxy, C 1-3 heteroalkoxy, C 3-7 cycloalkyl, C 3-7 heterocyclyl, C 6-8 aryl, C 5-8 heteroaryl, OH, NH2, CN, SO2 C 1- 3alkyl, and NO2; in one embodiment, R da6 , R da7 , R da8 , and R da9 are each independently selected at each occurrence from H, F, Cl, Br, CH3, C2H5, OCH3, O-CH2CH3, CH2F, CHF2, CF3, CH2-CH2F, CH2-CHF2, CH2-CF3, OCH2F, OCHF2, OCF3, and -SO2CH3.

[0132] In one embodiment, is selected from:

[0133] In one embodiment, the PTM is selected from:

[0134] In one embodiment, the PTM is selected from:

[0135] In one embodiment, the CLM is selected from the structures shown in Formula 2-1, Formula 2-2, Formula 2-3, and Formula 2-4:

[0136] wherein R1, R2, R3, R4, and R5are each independently selected at each occurrence from H, F, Cl, Br, I, C 1-3 alkyl, C 1-3 alkoxy, hydroxyl, and amino;

[0137] B2is independently at each occurrence O;

[0138] B1and B3are each independently at each occurrence selected from CH2, NH, C(C 1-3 alkyl)2, and N(C 1-3 alkyl);

[0139] one of B4and B5is N and the other is CH;

[0140] B6is independently at each occurrence selected from CH2and O;

[0141] C1and C2are each independently at each occurrence selected from CH2and C(C 1-3 alkyl)2;

[0142] C3is independently at each occurrence N;

[0143] R a is independently at each occurrence selected from H, F, Cl, Br, I, C 1-3 alkyl, C 1-3 alkoxy, hydroxyl, amino, and -C(O)-C 1-3 alkyl;

[0144] n2, n3, n4, n5, and n6are each independently at each occurrence selected from 0, 1, and 2; in one embodiment, n2+n3+n4=1 or n2+n3+n4=2; n5+n6=2 or n5+n6=3; in one embodiment, n2=0, n3=2, n4=0, n2=0, n5=1, and n6=2;

[0145] the PTM is selected from the following structures:

[0146] wherein F6, F 16 , and F 21 are each independently selected from a single bond, -NH-, -S(O)-, -S-, -O-, -S(O)2-, -C(=O)-, -O-C(=O)-, and -NH-C(=O)-;

[0147] F A1 is phenyl optionally substituted with 2, 3, 4, or 5 R da , and at least one R da is -CN;

[0148] F A2 is selected from 4-, 5-, or 6-membered cycloalkylene and 10-membered heterospirocyclylene containing 1, 2, or 3 N atoms, and the 4-, 5-, or 6-membered cycloalkylene and 10-membered heterospirocyclylene containing 1, 2, or 3 N atoms is optionally substituted with 0, 1, 2, 3, 4, 5, or 6 Rca replace;

[0149] F A3 For 0, 1, 2, 3 or 4 R da The substituted phenylene group may be substituted with 0, 1, 2 or 3 R groups. da Substituted with one, two, or three six-membered heteroaryl groups, each independently selected from N, O, and S heteroatoms;

[0150] R da Each time it appears, it is independently selected from F, Cl, Br, I, CH3, C2H5, OCH3, CF3, CHF2, O-CF3, O-CHF2, O-CH2F, OH, NH2, CN, and NO2;

[0151] R ca Each time it appears, it is independently selected from F, Cl, Br, I, oxo group (=O), CH3, C2H5, CH2OH-CH2N(CH3)2, 3-membered cycloalkyl, CF2H, CH2-CF2H, OCH3, CF3, OH, NH2, CN and NO2;

[0152] In one implementation, the F in the PTM A1 Selected from: The wavy line here represents F. A1 Connection point with F6;

[0153] In one implementation, the F in the PTM A2 Selected from: The wavy line here represents F. A2 With F6 or F respectively 16 The connection point;

[0154] In one implementation, F6 is -O-, -N(CH3-), or a single bond; in another implementation, F 16 for Or a single bond; in one implementation, when F A2 for When F6 is -O- or -N(CH3)-, F 16 for When F A2 for At that time, F6 and F 16 It is a single bond;

[0155] In one implementation, the F in the PTM A3 Selected from: This wavy line represents F.A3 a linking point to F 16 or F 21 ;

[0156] In one embodiment, F 21 is or a single bond;

[0157] In one embodiment, L is selected from

[0158] The third aspect of the present disclosure provides a compound represented by Formula 1-2, or an isomer, an isotopic derivative, a polymorph, a prodrug, a pharmaceutically acceptable salt or a solvate thereof:

[0159] PTM-L-CLM (Formula 1-2);

[0160] wherein PTM is an androgen receptor binding moiety;

[0161] said CLM has a structure selected from Formula 2-1, Formula 2-2, Formula 2-3 and Formula 2-4:

[0162] wherein R1, R2, R3, R4and R5are each independently selected at each occurrence from H, F, Cl, Br, I, C 1-3 alkyl, C 1-3 alkoxy, hydroxyl and amino;

[0163] B2is independently at each occurrence O;

[0164] B1and B3are each independently selected at each occurrence from CH2, NH, C(C 1-3 alkyl)2and N(C 1-3 alkyl);

[0165] B4and B5are each N at each occurrence, and the other is CH; in one embodiment, B5is N at each occurrence, and B4is CH at each occurrence;

[0166] B6is independently selected at each occurrence from CH2and O;

[0167] C1and C2are each independently selected at each occurrence from CH2and C(C 1-3 alkyl)2;

[0168] C3is independently N at each occurrence;

[0169] R a is independently selected at each occurrence from H, F, Cl, Br, I, C 1-3 alkyl, C 1-3Alkoxy, hydroxy, amino, and -C(O)-C 1-3 alkyl;

[0170] n2, n3, n4, n5, and n6 are each independently selected from 0, 1, and 2 each time they appear; in one implementation, n2+n3+n4=1 or n2+n3+n4=2; and n5+n6=2 or n5+n6=3; in another implementation, n2=0, n3=2, n4=0, n2=0, n5=1, and n6=2.

[0171] In one implementation, L is selected from...

[0172] and

[0173] The PTM is selected from the following structures:

[0174] Among them, F6, F 16 and F 21 Each is independently selected from single bonds, -NH-, -S(O)-, -S-, -O-, -S(O)2-, -C(=O)-, -OC(=O)- and -NH-C(=O)-;

[0175] F A1 It is a phenyl group, optionally surrounded by 2, 3, 4 or 5 R groups. da Replace, and at least one R da CN;

[0176] F A2 Selected from 4, 5, or 6-membered cyclohexane groups and 10-membered heterospirocyclic groups containing 1, 2, or 3 N atoms, wherein the 4, 5, or 6-membered cyclohexane groups and the 10-membered heterospirocyclic groups containing 1, 2, or 3 N atoms are optionally surrounded by 1, 2, 3, 4, 5, or 6 R atoms. ca replace;

[0177] F A3 For 0, 1, 2, 3 or 4 R da The substituted phenylene group may be substituted with 1, 2, or 3 R groups. da Substituted with one, two, or three six-membered heteroaryl groups, each independently selected from N, O, and S heteroatoms;

[0178] R da Each occurrence is independently selected from F, Cl, Br, I, -CH3, -C2H5, -OCH3, -CF3, -C F2 H, -O-CF3, -O-CHF2, -O-CH2F, -OH, -NH2, -CN and -NO2;

[0179] R caindependently at each occurrence selected from the group consisting of F, Cl, Br, I, oxo (=0), CH3, C2H5, CH2OH, CH2N(CH3)2, 3-membered cycloalkyl, -CF2H, -CH2-CF2H, OCH3, CF3, OH, NH2, CN, and NO2;

[0180] In one embodiment, F A1 is selected from the group consisting of: In this wavy line indicates F A1 is a point of attachment to F6;

[0181] F A2 is selected from the group consisting of: In this wavy line indicates F A2 is a point of attachment to F6or F 16 , respectively;

[0182] F6is -0-, -N(CH3)-, or a single bond;

[0183] F 16 is or a single bond;

[0184] In one embodiment, when F A2 is F6is -0- or -N(CH3)-, F 16 is F6and F A2 are single bonds when F 16 is

[0185] F A3 is selected from the group consisting of: In this wavy line indicates F A3 is a point of attachment to F 16 or F 21 , respectively;

[0186] F 21 is or a single bond; and

[0187] The compound of formula 1-2 is not any one of the following structures:

[0188] In another aspect of the present disclosure, a compound is provided, having the structure of formula 1-3:

[0189] PTM-L-CLM (formula 1-3);

[0190] ​wherein PTM is

[0191] wherein F6, F 16 and F 21 are each independently selected from the group of one or more of a single bond, -NH-, -N(CH3)-, -S(O)-, -S-, -O-, -S(O)2-, alkylene, haloalkylene, heteroalkylene, alkylenoxy, heteroalkylenoxy, alkenylene, alkynylene, -C(=O)-, -O-C(=O)-, -C(=O)-O-, -C(=O)-NH-, and -NH-C(=O)-, wherein said alkylene, alkylenoxy, alkenylene are optionally substituted with 0, 1, 2, 3, 4, 5, or 6 R da ; in one embodiment, F6, F 16 and F 21 are each independently selected from the group of one or more of a single bond, -NH-, -S(O)-, -S-, -O-, -S(O)2-, -C(=O)-, -O-C(=O)-, and -NH-C(=O)-;

[0192] F A1 is selected from the group consisting of 6-10 membered aryl and 5-10 membered heteroaryl, wherein said 6-10 membered aryl and 5-10 membered heteroaryl are optionally substituted with 0, 1, 2, 3, 4, 5, or 6 R da ; in one embodiment, F A1 is phenyl optionally substituted with 0, 1, 2, 3, 4, or 5 R da ; in one embodiment, F A1 is phenyl optionally substituted with 2, 3, 4, or 5 R da ; in one embodiment, F da is -CN;

[0193] F A2 is selected from the group consisting of 3-15 membered cycloalkylene, 5-15 membered spirocycloalkylene, 3-15 membered heterocyclylene, and 5-15 membered heterospirocyclylene, and said 3-15 membered cycloalkylene, 5-15 membered spirocycloalkylene, 3-15 membered heterocyclylene, and 5-15 membered heterospirocyclylene are optionally substituted with 0, 1, 2, 3, 4, 5, or 6 R ca ; in one embodiment, F A2 is selected from the group consisting of 4-6 membered cycloalkylene, 7-11 membered spirocycloalkylene, 4-6 membered heterocyclylene containing 1, 2, 3, or 4 heteroatoms each independently selected from the group consisting of N, O, and S, and 7-11 membered heterospirocyclylene containing 1, 2, 3, or 4 heteroatoms each independently selected from the group consisting of N, O, and S, said 4-6 membered cycloalkylene, 7-11 membered spirocycloalkylene, 4-6 membered heterocyclylene, and 7-11 membered heterospirocyclylene are optionally substituted with 0, 1, 2, 3, 4, 5, or 6 R casubstituted; in one embodiment, F A2 is selected from 4-, 5-, or 6-membered cycloalkylene and 10-membered heterospirocyclylene containing 1, 2, or 3 N atoms, and said 4-, 5-, or 6-membered cycloalkylene and 10-membered heterospirocyclylene containing 1, 2, or 3 N atoms is optionally substituted with 0, 1, 2, 3, 4, 5, or 6 R ca substituted;

[0194] F A3 is selected from 6-10 membered arylene and 5-10 membered heteroarylene, said 6-10 membered arylene and 5-10 membered heteroarylene is optionally substituted with 0, 1, 2, 3, 4, 5, or 6 R da substituted; in one embodiment, F A3 is phenylene substituted with 0, 1, 2, 3, or 4 R da substituted phenylene or is 6-membered heteroarylene containing 1, 2, or 3 heteroatoms each independently selected from N, O, and S, substituted with 0, 1, 2, or 3 R da substituted phenylene or is 6-membered heteroarylene containing 1, 2, or 3 heteroatoms each independently selected from N, O, and S, substituted with 0, 1, 2, or 3 R da substituted phenylene or is 6-membered heteroarylene containing 1, 2, or 3 heteroatoms each independently selected from N, O, and S, substituted with 0, 1, 2, or 3 R

[0195] R da is independently selected at each occurrence from H, halogen, C 1-6 alkyl, -O-C 1-6 haloalkyl, C 1-6 haloalkyl, C 1-6 heteroalkyl, C 1-6 alkoxy, C 1- heteroalkoxy, C 3-7 cycloalkyl, C 3-7 heterocyclyl, C 6-8 aryl, C 5-8 heteroaryl, -OH, -NH2, -CN, -SO2 C 1-6 alkyl, and -NO2; in one embodiment, R da is independently selected at each occurrence from H, F, Cl, Br, I, C 1-3 alkyl, -O-C 1-3 haloalkyl, C 1-3 haloalkyl, C 1-3 heteroalkyl, C 1-3 alkoxy, C 1-3 heteroalkoxy, C 3-7 cycloalkyl, C 3-7 heterocyclyl, C 6-8 aryl, C 5-8 heteroaryl, -OH, -NH2, -CN, -SO2 C 1-3 alkyl, and -NO2; in one embodiment, R daindependently at each occurrence selected from the group consisting of H, F, CI, Br, I, -CH3, -C2H5, -OCH3, -OCH2CH3, -CF3, -CF2H, -O-CF3, -O-CHF2, -O-CH2F, -OH, -NH2, -CN, -SO2CH3, and -NO2;

[0196] R da independently at each occurrence selected from the group consisting of H, halogen, C 1-6 alkyl, -O-C 1-6 haloalkyl, C 1-6 haloalkyl, C 1-6 heteroalkyl, C 1-6 alkoxy, C 1-6 heteroalkoxy, C 3-7 cycloalkyl, C 3-7 heterocyclyl, C 6-8 aryl, C 5-8 heteroaryl, -OH, -NH2, -CN, and -NO2; in one embodiment, R da independently at each occurrence selected from the group consisting of H, F, CI, Br, I, C 1-3 alkyl, -O-C 1-3 haloalkyl, C 1-3 haloalkyl, C 1-3 heteroalkyl, C 1-3 alkoxy, C 1-3 heteroalkoxy, C 3-7 cycloalkyl, C 3-7 heterocyclyl, C 6-8 aryl, C 5-8 heteroaryl, -OH, -NH2, -CN, and -NO2; in one embodiment, R da independently at each occurrence selected from the group consisting of H, F, CI, Br, I, -CH3, -C2H5, -OCH3, -CF3, -CF2H, -O-CF3, -O-CHF2, -O-CH2F, -OH, -NH2, -CN, and -NO2;

[0197] R ca independently at each occurrence selected from the group consisting of H, halogen, C 1-6 alkyl, C 1-6 haloalkyl, -O-C 1-6 haloalkyl, C 1-6 heteroalkyl, C 1-6 alkoxy, C 1- 6alkylhydroxy, C 1-6 heteroalkoxy, C 3-7 cycloalkyl, C 3-7 heterocyclyl, C 6-8 aryl, C 5-8heteroaryl, oxo (=0), thioxo (=S), C 1-6 alkyl N(C 1-3 alkyl)2, OH, NH2, CN and NO2; in one embodiment, R ca independently for each occurrence H, F, Cl, Br, I, oxo (=0), thioxo (=S), CH3, C2H5, CH2OH, CH2N(CH3)2, 3-membered cycloalkyl, -CF2H, -CH2-CF2H, OCH3, CF3, OH, NH2, CN and NO2; 1-3 alkyl, C 1-3 alkyl hydroxy, -0-C 1-3 haloalkyl, C 1-3 haloalkyl, C 1-3 heteroalkyl, C 1-3 alkoxy, C 1-3 heteroalkoxy, C 3-7 cycloalkyl, C 3-7 heterocyclyl, C 6-8 aryl, C 5-8 heteroaryl, oxo (=0), thioxo (=S), C 1-3 alkyl N(C 1-3 alkyl)2, -OH, -NH2, -CN and -NO2; in one embodiment, R ca independently for each occurrence H, F, Cl, Br, I, oxo (=0), thioxo (=S), CH3, C2H5, CH2OH, CH2N(CH3)2, 3-membered cycloalkyl, -CF2H, -CH2-CF2H, OCH3, CF3, OH, NH2, CN and NO2;

[0198] L is a bond or -(B L ) q :

[0199] B L each occurrence is the same or different, and each is independently selected from: CR L1 R L2 , O, S, SO, SO2, NR L3 , SO2NR L3 , SONR L3 , C(O)NR L3 , NR L3 C(O)NR L4 , NR L3 SO2NR L4 , C(O), CR L1 =CR L2 , C≡C, SiR L1 R L2 , P(O)R L1 , P(O)OR L1 , NR L3 C(=NCN)NR L4 , NR L3C(=NCN), NR L3 C(=CNO2)NR L4 monocycloalkylene, monoheterocyclylene, bridged cyclylene, spiro cyclylene, arylene, and heteroarylene, wherein the monocycloalkylene, monoheterocyclylene, bridged cyclylene, spiro cyclylene, arylene, and heteroarylene are optionally substituted with 0, 1, 2, 3, 4, 5, or 6 R L1 and / or R L2 groups;

[0200] R L1 , R L2 , R L3 , and R L4 are each independently at each occurrence selected from oxo (=0), H, halogen, C 1-8 alkyl, -O-C 1-8 alkyl, -S-C 1-8 alkyl, -NH-C 1-8 alkyl, N(C 1-8 alkyl)2, C 3-11 cycloalkyl, C 6-10 aryl, C 5-10 heteroaryl, C 3-11 heterocyclyl, -O-C 3-8 cycloalkyl, -O-C 3-11 heterocyclyl, -O-C 6-10 aryl, -O-C 5-10 heteroaryl, -S-C 3-8 cycloalkyl, -NH-C 3-8 cycloalkyl, -N(C 3-8 cycloalkyl)2, -N(C 3-8 cycloalkyl)(C 1-8 alkyl), -NH-C 3-8 heterocyclyl, -N(C 3-8 heterocyclyl)2, -N(C 3-8 heterocyclyl)(C 1-8 alkyl), -NH-C 6-10 aryl, -N(C 6-10 aryl)(C 1-8 alkyl), -NH-C 5-10 heteroaryl, -N(C 5-10 heteroaryl)(C 1-8 alkyl), -OH, -NH2, -SH, SO2 P(O)(O-C 1-8 alkyl)(C 1-8 alkyl), -P(O)(O-C 1-8 alkyl)2, -C≡C-C 1-8 alkyl, -C≡CH, -CH=CH-(C 1-8 alkyl), -C(C 1-8Alkyl)=CH-(C 1-8 alkyl), -C(C 1-8 Alkyl) = C(C 1-8 Alkyl group 2, -Si(OH)3, -Si(C) 1-8 Alkyl)3、-Si(OH)(C 1-8 Alkyl)2、-C(O)-C 1-8 Alkyl, -C(O)2H, -CN, -CF3, -CHF2, -CH2F, -NO2, -SO2, -SF5, -SO2NH-C 1-8 Alkyl group, -SO2N(C) 1-8 Alkyl)2、-S(O)NH-C 1-8 Alkyl, -S(O)N(C) 1-8 Alkyl)2、-C(O)NH-C 1-8 Alkyl, -C(O)N(C) 1-8 Alkyl)2, -N(C 1-8 alkyl)C(O)NH(C 1-8 alkyl), -N(C) 1-8 alkyl)C(O)N(C 1-8 alkyl)2、-NHC(O)NH(C 1-8 Alkyl), -NHC(O)N(C 1-8 Alkyl)2, -NHC(O)NH2, -N(C 1-8 alkyl)SO2NH(C 1-8 alkyl), -N(C) 1-8 Alkyl)SO2N(C 1-8 Alkyl)2、-NHSO2NH(C 1-8 Alkyl), -NHSO2 N(C 1- 8-alkyl)2 and -NHSO2NH2, optionally, the C 1-8 Alkyl, C 3-11 cycloalkyl, C 3-11 Heterocyclic group, C 6-10 Aryl and C 5-10 Each heteroaryl group is independently selected from halogen, alkyl, heteroalkyl, alkenyl, alkoxy, hydroxy, haloalkyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, halocycloalkyl, haloheteroalkyl, alkylamino, C 6-10 Aryl, C 5-10 heteroaryl, halogenated C 6-10 Aryl and halogenated C 5-10 One or more substituents in the heteroaryl group are substituted;

[0201] In one implementation, R L1 R L2 R L3 and RL4 each occurrence is selected from the group consisting of H, halogen, C 1-8 alkyl, -O-C 1-8 alkyl, -S-C 1- 8alkyl, -NH-C 1-8 alkyl, N(C 1-8 alkyl)2, C 3-11 cycloalkyl, C 6-10 aryl, C 5-10 heteroaryl, C 3-11 heterocyclyl, -O-C 3-8 cycloalkyl, -O-C 3- 11 heterocyclyl, -O-C 6-10 aryl, -O-C 5-10 heteroaryl, -S-C 3-8 cycloalkyl, -NH-C 3-8 cycloalkyl, -N(C 3-8 cycloalkyl)2, -N(C 3-8 cycloalkyl)(C 1- 8alkyl), -NH-C 3-8 heterocyclyl, -N(C 3-8 heterocyclyl)2, -N(C 3-8 heterocyclyl)(C 1-8 alkyl), -NH-C 6-10 aryl, -N(C 6-10 aryl)(C 1-8 alkyl), -NH-C 5-10 heteroaryl, -N(C 5-10 heteroaryl)(C 1-8 alkyl), -OH, -NH2, -SH, SO2 P(O)(O-C 1-8 alkyl)(C 1-8 alkyl), -P(O)(O-C 1-8 alkyl)2, -C≡C-C 1-8 alkyl, -C≡CH, -CH=CH-(C 1-8 alkyl), -C(C 1-8 alkyl)=CH-(C 1-8 alkyl), -C(C 1-8 alkyl)=C(C 1-8 alkyl)2, -Si(OH)3, -Si(C 1-8 alkyl)3, -Si(OH)(C 1-8 alkyl)2, -C(O)-C 1-8 alkyl, -C(O)2H, -CN, -CF3, -CHF2, -CH2F, -NO2, -SO2, -SF5, -SO2NH-C 1-8 alkyl, -SO2N(C1-8 alkyl, -S(O)N(C 1-8 alkyl, -S(O)N(C 1-8 alkyl, -C(O)NH-C 1-8 alkyl, -C(O)N(C 1- alkyl)2, -N(C 1-8 alkyl)C(O)NH(C 1-8 alkyl), -N(C 1-8 alkyl)C(O)N(C 1-8 alkyl)2, -NHC(O)NH(C 1-8 alkyl), -NHC(O)N(C 1-8 alkyl)2, -NHC(O)NH2, -N(C 1-8 alkyl)SO2NH(C 1-8 alkyl), -N(C 1-8 alkyl)SO2N(C 1-8 alkyl)2, -NHSO2NH(C 1-8 alkyl), -NHSO2N(C 1-8 alkyl)2, and -NHSO2NH2, optionally substituted with one or more substituents independently selected from halo, alkyl, heteroalkyl, alkenyl, alkynyl, alkoxy, hydroxy, haloalkyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, halocycloalkyl, haloheteroalkyl, alkylamino, C 1-8 alkyl, C 3-11 cycloalkyl, C 3-11 heterocyclyl, C 6-10 aryl, and C 5-10 heteroaryl, each independently optionally substituted with one or more substituents independently selected from halo, alkyl, heteroalkyl, alkenyl, alkynyl, alkoxy, hydroxy, haloalkyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, halocycloalkyl, haloheteroalkyl, alkylamino, C 6-10 aryl, C 5-10 heteroaryl, haloC 6-10 aryl, and haloC 5-10 heteroaryl, each independently optionally substituted with one or more substituents independently selected from halo, alkyl, heteroalkyl, alkenyl, alkynyl, alkoxy, hydroxy, haloalkyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, halocycloalkyl, haloheteroalkyl, alkylamino, C

[0202] q is an integer greater than or equal to 1; in one embodiment, q is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20;

[0203] CLM is selected from:

[0204] wherein:

[0205] A1is independently selected from CR a and N;

[0206] A2and A4are each independently selected from C(O) and C(R a )2;

[0207] A3 is selected from NR a ;

[0208] A5 and A6 are each independently selected from single bonds, NR a and C(R) a )2;

[0209] A7 is selected from C(O) and C(R). a )2;

[0210] When CLM is Equation 2, Equation 4, Equation 5, or Equation 7, R1 and R2 can be formed together. When CLM is Equation 3, R1 and R2 can be formed together. R3, R4, and R5 are each independently selected from H, deuterium, halogen, and C atoms, respectively. 1-6 Alkyl, C 1-6 Deuterated alkyl, carboxyl, C 1-6 heteroalkyl, alkenyl, ynyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy, hydroxyl, C 1- 6-hydroxyalkyl, nitro, cyano, amino, -C(O)NH-C 1-6 Alkyl, -C(O)N(C) 1-6 Alkyl)2, -N(C 1-6 alkyl)C(O)NH(C 1-6 alkyl), -N(C) 1-6 alkyl)C(O)N(C 1-6 alkyl)2、-NHC(O)NH(C 1-6 Alkyl), -NHC(O)N(C 1-6 Alkyl)2, cycloalkyl, heterocyclic, aryl and heteroaryl, wherein the C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 heteroalkyl, alkenyl, ynyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 The haloalkoxy, cycloalkyl, heterocyclic, aryl, and heteroaryl groups are each independently selected from halogen, alkyl, heteroalkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, alkenyl, alkynyl, alkylamino, -C(O)NH-C 1-6 Alkyl, -C(O)N(C) 1-6 Alkyl)2, -N(C 1-6 alkyl)C(O)NH(C 1- 6-alkyl), -N(C) 1-6 alkyl)C(O)N(C 1-6 alkyl)2、-NHC(O)NH(C1-6 alkyl), -NHC(O)N(C 1-6 alkyl)2, aryl, and heteroaryl; in one embodiment, R3, R4, and R5are each independently selected from H, deuterium atom, F, Cl, Br, I, C 1-6 alkyl, C 1-6 deuteroalkyl, C 1-6 heteroalkyl, alkenyl, alkynyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, hydroxy, C 1-6 hydroxyalkyl, and amino; in one embodiment, R3, R4, and R5are each independently selected from H, deuterium atom, F, Cl, Br, I, C 1-3 alkyl, C 1-3 deuteroalkyl, alkenyl, alkynyl, C 1-3 alkoxy, C 1-3 haloalkyl, C 1-3 haloalkoxy, hydroxy, C 1-3 hydroxyalkyl, and amino;

[0211] or

[0212] when CLM is of Formula 2, Formula 4, Formula 5, R2and R3together can form when CLM is of Formula 3, R2and R3together can form R1, R4, and R5are each independently selected at each occurrence from H, deuterium atom, halogen, C 1- 6alkyl, C 1-6 deuteroalkyl, carboxyl, C 1-6 heteroalkyl, alkenyl, alkynyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, hydroxy, C 1-6 hydroxyalkyl, nitro, cyano, amino, C 1-6 alkylamino, C 1-6 alkylacyl, C 1-6 alkyloxyacyl, C 1-6 alkylaminoacyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein said C 1-6 alkyl, C 1-6 deuteroalkyl, C 1-6 heteroalkyl, alkenyl, alkynyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, alkenyl, alkynyl, alkylamino, -C(O)NH-C 1-6 alkyl, -C(O)N(C 1-6 alkyl)2, -N(C 1-6 alkyl)C(O)NH(C 1-6 alkyl), -N(C 1-6 alkyl)C(O)N(C 1-6 alkyl)2, -NHC(O)NH(C 1-6 alkyl), -NHC(O)N(C 1-6 alkyl)2, aryl, and heteroaryl; in one embodiment, R1, R4, and R5are each independently selected from H, a deuterium atom, F, Cl, Br, I, C 1-6 alkyl, C 1-6 deuteroalkyl, C 1-6 heteroalkyl, alkenyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, hydroxy, C 1-6 hydroxyalkyl, and amino; in one embodiment, R1, R4, and R5are each independently selected from H, a deuterium atom, F, Cl, Br, I, C 1-3 alkyl, C 1-3 deuteroalkyl, alkenyl, C 1-3 alkoxy, C 1-3 haloalkyl, C 1-3 haloalkoxy, hydroxy, C 1-3 hydroxyalkyl, and amino;

[0213] or

[0214] when CLM is of Formula 2, R3and R4can together form when CLM is of Formula 3, R3and R4can together form R1, R2, and R5are each independently at each occurrence selected from H, a deuterium atom, halogen, C 1-6 alkyl, C 1-6 deuteroalkyl, carboxyl, C 1-6 heteroalkyl, alkenyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, hydroxy, C 1-6 hydroxyalkyl, nitro, cyano, amino, C 1-6 alkylamino, C 1-6 alkylacyl, C 1-6alkylcarbonyl, C 1-6 alkylamino, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein said C 1-6 alkyl, C 1-6 deuteroalkyl, C 1-6 heteroalkyl, alkenyl, alkynyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl are each independently optionally substituted with one or more substituents selected from the group consisting of halogen, alkyl, heteroalkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, alkenyl, alkynyl, alkylamino, -C(O)NH-C 1-6 alkyl, -C(O)N(C 1-6 alkyl)2, -N(C 1- 6alkyl)C(O)NH(C 1-6 alkyl), -N(C 1-6 alkyl)C(O)N(C 1-6 alkyl)2, -NHC(O)NH(C 1-6 alkyl), -NHC(O)N(C 1-6 alkyl)2, aryl, and heteroaryl; in one embodiment, R1, R2, and R5are each independently selected from the group consisting of H, deuterium atom, F, Cl, Br, I, C 1-6 alkyl, C 1-6 deuteroalkyl, C 1-6 heteroalkyl, alkenyl, alkynyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, hydroxy, C 1-6 hydroxyalkyl, and amino; in one embodiment, R1, R2, and R5are each independently selected from the group consisting of H, deuterium atom, F, Cl, Br, I, C 1-3 alkyl, C 1-3 deuteroalkyl, alkenyl, alkynyl, C 1-3 alkoxy, C 1-3 haloalkyl, C 1-3 haloalkoxy, hydroxy, C 1-3 hydroxyalkyl, and amino;

[0215] or

[0216] when CLM is of Formula 2, R4and R5together can form when CLM is of Formula 3, R4and R5together can form R1, R2, and R3are each independently at each occurrence selected from the group consisting of H, deuterium atom, halogen, C 1-6 alkyl, C 1- 6deuteroalkyl, carboxyl, C1-6 heteroalkyl, alkenyl, ynyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy, hydroxyl, C 1-6 Hydroxyalkyl, nitro, cyano, amino, C 1-6 Alkylamino, C 1-6 Alkyl acyl, C 1-6 Alkyloxyacyl, C 1-6 Alkylaminoacyl, cycloalkyl, heterocyclic, aryl, and heteroaryl, wherein the C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 heteroalkyl, alkenyl, ynyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 The haloalkoxy, cycloalkyl, heterocyclic, aryl, and heteroaryl groups are each independently selected from halogen, alkyl, heteroalkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, alkenyl, alkynyl, alkylamino, -C(O)NH-C 1-6 Alkyl, -C(O)N(C) 1-6 Alkyl)2, -N(C 1- 6alkyl)C(O)NH(C 1-6 alkyl), -N(C) 1-6 alkyl)C(O)N(C 1-6 alkyl)2、-NHC(O)NH(C 1-6 Alkyl), -NHC(O)N(C 1-6 The alkyl group is substituted with one or more substituents selected from alkyl, aryl, and heteroaryl groups; in one embodiment, R1, R2, and R3 are each independently selected from H, deuterium, F, Cl, Br, I, and C. 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy, hydroxyl, C 1-6 Hydroxyalkyl and amino groups; in one embodiment, R1, R2, and R3 are each independently selected from H, deuterium, F, Cl, Br, I, and C. 1-3 Alkyl, C 1-3 Deuterated alkyl, alkenyl, alkynyl, C 1-3 Alkoxy, C 1-3 Haloalkyl, C 1-3 Halogenated alkoxy, hydroxyl, C 1-3 Hydroxyalkyl and amino;

[0217] B2 is selected independently from C(R) each time it appears. a 2. NR a O and S;

[0218] B4 and B5 are each selected independently from CR each time they appear. a and N;

[0219] C3 is selected independently from CR each time it appears. a and N;

[0220] n2, n3, n4, n5, n6, and n7 are each independently selected from 0, 1, 2, and 3 when they appear; n8 is selected from 1, 2, and 3.

[0221] B1 and B3 are each selected independently from C(R) each time they appear. a 2. O and C(O);

[0222] B6 is selected from C(R) a )2 and O;

[0223] C1 and C2 are each selected independently from C(R) each time they appear. a )2;

[0224] When B4 and B5 are present, at least one of B1, B2, B3 and B6 is selected from NRa, O and S;

[0225] R a Each occurrence is independently selected from H, deuterium, halogen, and C. 1-6 Alkyl, deuterated C 1-6 Alkyl, carboxyl, C 1-6 Heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, -C(O)-C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkoxy, hydroxy, C 1-6 Hydroxyalkyl, nitro, cyano, amino, C 1-6 Alkylamino, C 1-6 Alkyl acyl, C 1-6 Alkyloxyacyl, C 1-6alkyl, heteroalkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl are each independently optionally substituted with one or more substituents selected from halogen, alkyl, heteroalkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, alkenyl, alkynyl, alkylamino, alkylacyl, alkyloxyacyl, alkylaminoacyl, aryl, and heteroaryl; in one embodiment, R a each occurrence is independently selected from H, a deuterium atom, F, Cl, Br, I, C 1-6 alkyl, C 1-6 deuteroalkyl, alkenyl, alkynyl, C 1-6 heteroalkyl, C 2-6 alkenyl, C 2- alkynyl, C 1-6 alkoxy, haloC 1-6 alkyl, haloC 1-6 alkoxy, hydroxy, C 1-6 hydroxyalkyl, -C(O)-C 1-3 alkyl and amino;

[0226] denotes the point of attachment;

[0227] when CLM is of Formula 7, R3, R4 are not H; and

[0228] the compound of Formula 1-3 is not:

[0229] In one embodiment, CLM is of Formula 2: R2and R3can together form R1, R4, and R5are each independently selected at each occurrence from H, a deuterium atom, F, Cl, Br, I, C 1-3 alkyl, C 1-3 deuteroalkyl, alkenyl, alkynyl, C 1-3 alkoxy, C 1-3 haloalkyl, C 1-3 haloalkoxy, hydroxy, C 1-3 hydroxyalkyl and amino;

[0230] or

[0231] R3and R4can together form R1, R2and R5are each independently selected from H, a deuterium atom, F, Cl, Br, I, C 1-3 alkyl, C 1-3 deuteroalkyl, alkenyl, alkynyl, C 1-3 alkoxy, C1-3 Haloalkyl, C 1-3 Halogenated alkoxy, hydroxyl, C 1-3 Hydroxyalkyl and amino;

[0232] or

[0233] R4 and R5 can be formed together. R1, R2, and R3 are each independently selected from H, deuterium, F, Cl, Br, I, and C atoms. 1-3 Alkyl, C 1-3 Deuterated alkyl, alkenyl, alkynyl, C 1-3 Alkoxy, C 1-3 Haloalkyl, C 1-3 Halogenated alkoxy, hydroxyl, C 1-3 Hydroxyalkyl and amino;

[0234] B1 and B3 are each selected independently from C(R) each time they appear. a 2. O and C(O);

[0235] B2 is selected independently from C(R) each time it appears. a 2. NR a O and S;

[0236] B4 and B5 are each selected independently from CR each time they appear. a and N;

[0237] B6 is selected from C(R) a )2 and O;

[0238] When B4 and B5 are present, at least one of B1, B2, B3, and B6 is selected from NR. a O and S;

[0239] C3 is selected independently from CR each time it appears. a and N;

[0240] C1 and C2 are each selected independently from C(R) each time they appear. a )2;

[0241] n2, n3, n4, n5, n6, and n7 are each independently selected from 0, 1, 2, and 3 when they appear; n8 is selected from 1, 2, and 3.

[0242] n2+n3+n4=0, n2+n3+n4=1 or n2+n3+n4=2;

[0243] n5+n6=2 or n5+n6=3;

[0244] n7+n8=2, n7+n8=3, n7+n8=4 or n7+n8=5;

[0245] R a independently at each occurrence selected from H, a deuterium atom, F, Cl, Br, I, C 1-6 alkyl, C 1-6 deuteroalkyl, C 1-6 heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, haloC 1-6 alkyl, haloC 1-6 alkoxy, hydroxy, C 1-6 hydroxyalkyl, -C(O)-C 1-3 alkyl and amino.

[0246] In one embodiment, the CLM is selected from R2and R3can together form R1, R4, and R5are each independently at each occurrence selected from H, a deuterium atom, F, Cl, Br, I, C 1-3 alkyl, C 1-3 deuteroalkyl, alkenyl, alkynyl, C 1-3 alkoxy, C 1-3 haloalkyl, C 1-3 haloalkoxy, hydroxy, C 1-3 hydroxyalkyl and amino;

[0247] or

[0248] R3and R4can together form R1, R2, and R5are each independently selected from H, a deuterium atom, F, Cl, Br, I, C 1-3 alkyl, C 1-3 deuteroalkyl, alkenyl, alkynyl, C 1-3 alkoxy, C 1-3 haloalkyl, C 1-3 haloalkoxy, hydroxy, C 1-3 hydroxyalkyl and amino;

[0249] or

[0250] R4and R5can together form R1, R2, and R3are each independently selected from H, a deuterium atom, F, Cl, Br, I, C 1-3 alkyl, C 1-3 deuteroalkyl, alkenyl, alkynyl, C 1-3 alkoxy, C 1-3 haloalkyl, C 1-3 haloalkoxy, hydroxy, C 1-3 hydroxyalkyl and amino;

[0251] B1and B3are each independently at each occurrence selected from C(Ra )2, O and C(O);

[0252] B2is, at each occurrence, independently selected from C(R a )2, NR a , O and S;

[0253] B4and B5are each independently selected at each occurrence from CR a and N;

[0254] B6is selected from C(R a )2and O;

[0255] when B4and B5are present, at least one of B1, B2, B3and B6is selected from NR a , O and S;

[0256] C3is, at each occurrence, independently selected from CR a and N;

[0257] C1and C2are each independently selected at each occurrence from C(R a )2;

[0258] n2, n3, n4, n5, n6, and n7are each independently selected at each occurrence from 0, 1, 2 and 3; n8is selected from 1, 2 and 3;

[0259] n2+n3+n4= 0, n2+n3+n4= 1 or n2+n3+n4= 2;

[0260] n5+n6= 2 or n5+n6= 3;

[0261] n7+n8= 2, n7+n8= 3, n7+n8= 4 or n7+n8= 5;

[0262] R a is, at each occurrence, independently selected from H, a deuterium atom, F, Cl, Br, I, C 1-6 alkyl, C 1-6 deuteroalkyl, C 1-6 heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, haloC 1-6 alkyl, haloC 1-6 alkoxy, hydroxy, C 1-6 hydroxyalkyl, -C(O)-C 1-3 alkyl and amino.

[0263] In one embodiment, CLM is selected from R2and R3can together form R1 and R5 are each independently selected from H, deuterium, F, Cl, Br, I, and C when they appear. 1-3 Alkyl, C 1-3 Deuterated alkyl, alkenyl, alkynyl, C 1-3 Alkoxy, C 1-3 Haloalkyl, C 1-3 Halogenated alkoxy, hydroxyl, C 1-3 Hydroxyalkyl and amino;

[0264] B1 and B3 are each selected independently from C(R) each time they appear. a 2. O and C(O);

[0265] B2 is selected independently from C(R) each time it appears. a 2. NR a O and S;

[0266] B4 and B5 are each selected independently from CR each time they appear. a and N;

[0267] B6 is selected from C(R) a )2 and O;

[0268] When B4 and B5 are present, at least one of B1, B2, B3, and B6 is selected from NR. a O and S;

[0269] C3 is selected independently from CR each time it appears. a and N;

[0270] C1 and C2 are each selected independently from C(R) each time they appear. a )2;

[0271] n2, n3, n4, n5, n6, and n7 are each independently selected from 0, 1, 2, and 3 when they appear; n8 is selected from 1, 2, and 3.

[0272] n2+n3+n4=0, n2+n3+n4=1 or n2+n3+n4=2;

[0273] n5+n6=2 or n5+n6=3;

[0274] n7+n8=2, n7+n8=3, n7+n8=4 or n7+n8=5;

[0275] R a Each time it appears, it is independently selected from H, deuterium, F, Cl, Br, I, and C. 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C1-6 alkoxy, haloC 1-6 alkyl, haloC 1-6 alkoxy, hydroxy, C 1-6 hydroxyalkyl, -C(O)-C 1-3 alkyl and amino.

[0276] In one embodiment, the CLM is selected from R2and R3may together form R1is each occurrence independently selected from H, a deuterium atom, F, Cl, Br, I, C 1-3 alkyl, C 1-3 deuteroalkyl, alkenyl, alkynyl, C 1-3 alkoxy, C 1-3 haloalkyl, C 1-3 haloalkoxy, hydroxy, C 1-3 hydroxyalkyl and amino;

[0277] or

[0278] R1and R2may together form R3is each independently selected from H, a deuterium atom, F, Cl, Br, I, C 1-3 alkyl, C 1-3 deuteroalkyl, alkenyl, alkynyl, C 1-3 alkoxy, C 1-3 haloalkyl, C 1-3 haloalkoxy, hydroxy, C 1-3 hydroxyalkyl and amino;

[0279] B1and B3are each occurrence independently selected from C(R a )2, O and C(O);

[0280] B2is independently at each occurrence selected from C(R a )2, NR a , O and S;

[0281] B4and B5are each occurrence independently selected from CR a and N;

[0282] B6is selected from C(R a )2and O;

[0283] when B4and B5are present, at least one of B1, B2, B3and B6is selected from NR a , O and S;

[0284] C3is independently at each occurrence selected from CR a and N;

[0285] C1and C2are each independently at each occurrence selected from C(R a )2;

[0286] n2, n3, n4, n5, n6, and n7 are each independently at each occurrence selected from 0, 1, 2, and 3; n8 is selected from 1, 2, and 3;

[0287] n2+n3+n4= 0, n2+n3+n4= 1, or n2+n3+n4= 2;

[0288] n5+n6= 2 or n5+n6= 3;

[0289] n7+n8= 2, n7+n8= 3, n7+n8= 4, or n7+n8= 5;

[0290] R a is independently at each occurrence selected from H, a deuterium atom, F, Cl, Br, I, C 1-6 alkyl, C 1-6 deuteroalkyl, C 1-6 heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, haloC 1-6 alkyl, haloC 1-6 alkoxy, hydroxy, C 1-6 hydroxyalkyl, -C(O)-C 1-3 alkyl, and amino.

[0291] In one embodiment, CLM is selected from

[0292] In one embodiment, CLM is selected from

[0293] In one embodiment, CLM is selected from

[0294] In one embodiment, CLM is

[0295] In one embodiment, CLM is selected from

[0296] In one embodiment, CLM is selected from

[0297] In one embodiment, CLM is In one embodiment, the compound is selected from:

[0298] and the compounds of Table A;

[0299] In one embodiment, the compound is selected from the compounds of Table A.

[0300] The fourth aspect of the present application provides a compound represented by Formula A-1 or Formula A-2, or a salt thereof,

[0301] wherein, R da1 , R da2 , R da3 , R da4 and R da5 are independently selected at each occurrence from H, F, Cl, Br, I, C 1-3 alkyl, -O-C 1-3 haloalkyl, C 1-3 haloalkyl, C 1-3 heteroalkyl, C 1-3 alkoxy, C 1-3 heteroalkoxy, C 3-7 cycloalkyl, C 3-7 heterocyclyl, C6-8 aryl, C 5-8 heteroaryl, OH, NH2, CN, SO2 C 1-3 alkyl and NO2; in one embodiment, R da1 , R da2 , R da3 , R da4 , R da5 is independently at each occurrence selected from H, F, Cl, Br, CN, CH3, OCH3, CH2F, CHF2, CF3, O-CH2F, O-CHF2, and O-CF3;

[0302] R ca1 , R ca2 , R ca3 , R ca4 , R ca5 , and R ca6 is independently at each occurrence selected from H, F, Cl, Br, I, C 1-3 alkyl, C 1-3 alkylhydroxy, -O-C 1-3 haloalkyl, C 1-3 haloalkyl, C 1-3 heteroalkyl, C 1-3 alkoxy, C 1-3 heteroalkoxy, C 3-7 cycloalkyl, C 3-7 heterocyclyl, C 6-8 aryl, C 5-8 heteroaryl, C 1-3 alkyl N(C 1-3 alkyl)2, OH, NH2, CN, and NO2; in one embodiment, R ca1 , R ca2 , R ca3 , R ca4 , R ca5 , and R ca6 is independently at each occurrence selected from H, F, CH3, C2H5, CH2F, CHF2, CF3, CH2-CH2F, CH2-HCF2, CH2-CF3, CH2OH, CH2 N(CH3)2, and cyclopropyl; or R ca1 and R ca2 one of R ca3 and R ca4 is oxo or thioxo, the other being absent; in one embodiment, R ca1 , R ca2 , R ca3 , R ca4 is independently at each occurrence methyl; in one embodiment, R ca5 is H, Rca6 is methyl, CF3;

[0303] Y 1 is N or CR da6 ; Y 2 is N or CR da7 ; Y 3 is N or CR da8 ; Y 4 is N or CR da9 ;

[0304] R da6 , R da7 , R da8 , and R da9 are each, independently at each occurrence, selected from the group consisting of H, F, Cl, Br, I, C 1-3 alkyl, O-C 1-3 haloalkyl, C 1-3 haloalkyl, C 1-3 heteroalkyl, C 1-3 alkoxy, C 1-3 heteroalkoxy, C 3-7 cycloalkyl, C 3-7 heterocyclyl, C 6-8 aryl, C 5-8 heteroaryl, OH, NH2, CN, SO2 C 1- 3alkyl, and NO2; in one embodiment, R da6 , R da7 , R da8 , and R da9 are each, independently at each occurrence, selected from the group consisting of H, F, Cl, Br, CH3, C2H5, OCH3, O-CH2CH3, CH2F, CHF2, CF3, CH2-CH2F, CH2-CHF2, CH2-CF3, OCH2F, OCHF2, OCF3, and -SO2CH3;

[0305] provided that at least one occurrence of R da6 , R da7 , R da8 , and R da9 is selected from the group consisting of Cl, Br, I, C 1-3 alkyl, -O-C 1-3 haloalkyl, C 1-3 haloalkyl, C 1-3 heteroalkyl, C 1-3 alkoxy, C 1-3 heteroalkoxy, C 3-7 cycloalkyl, C 3-7 heterocyclyl, C 6-8 aryl, C 5-8 heteroaryl, OH, NH2, CN, SO2 C 1-3alkyl and NO2; in one embodiment, R da6 , R da7 , R da8 , and R da9 at least one occurrence is independently selected from the group consisting of Cl, Br, CH3, C2H5, OCH3, O-CH2CH3, CH2F, CHF2, CF3, CH2-CH2F, CH2-CHF2, CH2-CF3, OCH2F, OCHF2, OCF3, and -SO2CH3; in one embodiment, R da6 , R da7 , R da8 , and R da9 at least one occurrence is independently selected from the group consisting of Cl, Br, CH3, OCH3, OCF3, and -SO2CH3; in one embodiment, R da9 at each occurrence is independently selected from the group consisting of Cl, Br, CH3, C2H5, OCH3, O-CH2CH3, CH2F, CHF2, CF3, CH2-CH2F, CH2-CHF2, CH2-CF3, OCH2F, OCHF2, OCF3, and -SO2CH3; in one embodiment, R da9 at each occurrence is independently selected from the group consisting of Cl, Br, CH3, OCH3, OCF3, and -SO2CH3; in one embodiment, R da9 at each occurrence is independently selected from the group consisting of Cl, Br, O-CH2CH3, -CH2CH3; in one embodiment, R da9 at each occurrence is independently selected from the group consisting of Cl, Br;

[0306] T is selected from the group consisting of a leaving group; in one embodiment, T is selected from the group consisting of H, a deuterium atom, F, Cl, Br, I, C1-C6alkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl, hydroxyl, carboxyl, nitro, cyano, amino, and -ON=NH, said C1-C6alkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, 3-10 membered cycloalkyl, and 3-10 membered heterocycloalkyl optionally substituted with one or more substituents independently selected from the group consisting of deuterium, F, Cl, Br, I, C1-C6alkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, hydroxyl, carboxyl, 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl, and amino; in one embodiment, T is selected from the group consisting of F, Cl, Br, I, Ms, Tf, TsCl, Ts, COOH, C(O)OCH3, C(O)OCH3, CH2NO2, CH2 ON=NH, and CH2NH2;

[0307] In one embodiment, the compound is selected from:

[0308] In one embodiment, T is selected from F, CI, Br, I, and COOH.

[0309] In a fifth aspect, the present application provides a pharmaceutical composition comprising a compound as described herein, or an isomer, an isotopic derivative, a polymorph, a prodrug, a pharmaceutically acceptable salt or a solvate thereof, or a compound as described herein, or a salt thereof, and a pharmaceutically acceptable carrier or excipient.

[0310] In a sixth aspect, the present application provides a compound as described herein, or an isomer, an isotopic derivative, a polymorph, a prodrug, a pharmaceutically acceptable salt or a solvate thereof, or a compound as described herein, or a salt thereof, or a pharmaceutical composition as described herein, for use in the treatment or prevention of a disease; in one embodiment, wherein the disease is a disease treated by degrading androgen receptor protein or a disease associated with accumulation and / or aggregation of androgen receptor protein; in one embodiment, the disease is cancer; in one embodiment, the cancer is prostate cancer.

[0311] In a seventh aspect, the present application provides the use of a compound as described herein, or an isomer, an isotopic derivative, a polymorph, a prodrug, a pharmaceutically acceptable salt or a solvate thereof, or a compound as described herein, or a salt thereof, or a pharmaceutical composition as described herein, in the manufacture of a medicament for the treatment or prevention of a disease; in one embodiment, wherein the disease is a disease treated by degrading androgen receptor protein or a disease associated with accumulation and / or aggregation of androgen receptor protein; in one embodiment, the disease is cancer; in one embodiment, the cancer is prostate cancer.

[0312] In an eighth aspect, the present application provides a method of treating or preventing a disease, comprising administering to a subject in need thereof a therapeutically effective amount of a compound as described herein, or an isomer, an isotopic derivative, a polymorph, a prodrug, a pharmaceutically acceptable salt or a solvate thereof, or a compound as described herein, or a salt thereof, or a pharmaceutical composition as described herein; wherein the disease is a disease treated by degrading androgen receptor protein or a disease associated with accumulation and / or aggregation of androgen receptor protein; in one embodiment, the cancer is prostate cancer. DETAILED DESCRIPTION

[0313] TERMS AND DEFINITIONS

[0314] The term "alkyl" refers to saturated aliphatic hydrocarbon groups which are straight-chain or branched groups, preferably alkyl groups containing 1 to 20 carbon atoms, more preferably alkyl groups containing 1 to 12 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12) carbon atoms, and even more preferably alkyl groups containing 1 to 6 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2,3-dimethylpentyl, 2,4-dimethylpentyl, 2,2-dimethylpentyl, 3,3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2,5-dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2,2-diethylpentyl, n-decyl, 3,3-diethylhexyl, 2,2-diethylhexyl, and various branched isomers thereof, and the like. More preferred are lower alkyl groups containing 1 to 6 carbon atoms, non-limiting examples of which include methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-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, and the like. The alkyl group can be substituted or unsubstituted, and when substituted, the substituents can be substituted at any available attachment point, the substituents preferably being independently optionally selected from one or more of D atoms, halogen, alkyl, alkoxy, haloalkyl, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl.

[0315] The term "heteroalkyl" refers to one or more -CH2- groups in the alkyl radical are replaced by a heteroatom selected from the group consisting of NH, O and S or one or more -CH- groups are replaced by a N atom; wherein the alkyl radical is as defined above; heteroalkyl is preferably Ci-C6heteroalkyl, wherein 1, 2, 3 or 4 heteroatoms are contained, more preferably Ci-C3heteroalkyl, the heteroalkyl radical can be substituted or non-substituted, when substituted, the substituents can be substituted at any available point of attachment, the substituents are preferably independently optionally substituted with one or more substituents selected from the group consisting of D atoms, halogen, alkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl.

[0316] The term "alkoxy" refers to -O-(alkyl) and -O-(non-substituted cycloalkyl), wherein alkyl or cycloalkyl are defined herein. Alkoxy is preferably Ci-C6alkoxy, more preferably Ci-C3alkoxy; non-limiting examples of alkoxy include: methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentoxy, cyclohexoxy. Alkoxy can be optionally substituted or non-substituted, when substituted, the substituents are preferably one or more groups independently selected from the group consisting of D atoms, halogen, alkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl.

[0317] The term "alkenyl" refers to an alkyl compound containing a carbon-carbon double bond in the molecule, wherein alkyl is as defined above. Alkenyl can be substituted or non-substituted, alkenyl is preferably C2-C6alkenyl, more preferably C2-C4alkenyl; when substituted, the substituents are preferably one or more groups independently selected from the group consisting of D atoms, alkyl, alkoxy, halogen, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl.

[0318] The term "alkynyl" refers to an alkyl compound containing a carbon-carbon triple bond in the molecule, wherein alkyl is as defined above. Alkynyl can be substituted or non-substituted, alkynyl is preferably C2-C6alkynyl, more preferably C2-C4alkynyl; when substituted, the substituents are preferably one or more groups independently selected from the group consisting of D atoms, alkyl, alkoxy, halogen, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl.

[0319] The term "cycloalkyl" refers to saturated or partially unsaturated monocyclic cyclic hydrocarbon substituents, the cycloalkyl ring comprising 3 to 20 carbon atoms, preferably comprising 3 to 12 carbon atoms, more preferably comprising 3 to 8 (e.g., 3, 4, 5, 6, 7, and 8) carbon atoms, more preferably comprising 4 to 7 carbon atoms. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, and the like. Cycloalkyl groups can be substituted or unsubstituted, and when substituted, the substituents can be substituted at any available point of attachment, the substituents preferably being independently and optionally selected from one or more of D atoms, halogen, alkyl, alkoxy, haloalkyl, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl.

[0320] The term "heterocycloalkyl" or "heterocyclyl" refers to saturated or partially unsaturated monocyclic cyclic hydrocarbon substituents comprising 3 to 20 ring atoms, wherein one or more of the ring atoms is a heteroatom selected from nitrogen, oxygen, or S(O) m (m is an integer from 0 to 2) ring members, the remaining ring atoms being carbon. Preferably, the ring comprises 3 to 12 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12) ring atoms, wherein 1 to 4 (e.g., 1, 2, 3, and 4) are heteroatoms; more preferably, the ring comprises 3 to 8 ring atoms, wherein 1 to 3 are heteroatoms; more preferably, the ring comprises 3 to 6 ring atoms, wherein 1 to 3 are heteroatoms; most preferably, the ring comprises 5 or 6 ring atoms, wherein 1 to 3 are heteroatoms. Non-limiting examples of monocyclic heterocycloalkyl groups include pyrrolidinyl, tetrahydropyranyl, 1,2,3,6-tetrahydropyridinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, and the like. Heterocycloalkyl or heterocyclyl groups can be substituted or unsubstituted, and when substituted, the substituents can be substituted at any available point of attachment, the substituents preferably being independently and optionally selected from one or more of D atoms, halogen, alkyl, alkoxy, haloalkyl, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl.

[0321] The term "spirocycloalkyl" or "spirocyclyl" refers to a bicyclic structure formed by the attachment of two saturated or partially unsaturated cycloalkyl groups through a common ring carbon atom. Spirocycloalkyl or spirocyclyl groups can be substituted or unsubstituted, and when substituted, the substituents can be substituted at any available point of attachment, the substituents preferably being independently and optionally selected from one or more of D atoms, halogen, alkyl, alkoxy, haloalkyl, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl.

[0322] The term "spiroheterocycloalkyl" or "spiroheterocyclyl" refers to a bicyclic structure formed by the attachment of two saturated or partially unsaturated heterocyclyl groups through a common ring carbon atom, or a bicyclic structure formed by the attachment of a saturated heterocycloalkyl group and a partially unsaturated cycloalkyl group through a common ring carbon atom. A spiroheterocycloalkyl or spiroheterocyclyl group can be substituted or unsubstituted, and when substituted, the substituents can be substituted at any available point of attachment, and are preferably independently and optionally selected from one or more of D atoms, halogen, alkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl.

[0323] The term "aryl" refers to a 6- to 14-membered all-carbon monocyclic or fused polycyclic (fused polycyclic is a ring sharing pairs of adjacent carbon atoms) groups with a conjugated pi-electron system, preferably 6- to 10-membered, such as phenyl and naphthyl. The aryl ring includes aryl rings fused to a heteroaryl, heterocyclyl, spirocycloalkyl, spiroheterocycloalkyl, or cycloalkyl ring as described above, wherein the ring that is attached to the parent structure is the aryl ring. An aryl group can be substituted or unsubstituted, and when substituted, the substituents can be substituted at any available point of attachment, and are preferably independently and optionally selected from one or more of D atoms, halogen, alkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl.

[0324] The term "heteroaryl" refers to a heteroaromatic system comprising 1 to 4 (e.g., 1, 2, 3, and 4) heteroatoms, 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur, and nitrogen. A heteroaryl group is preferably 5- to 10-membered (e.g., 5, 6, 7, 8, 9, or 10-membered), more preferably 5- or 6-membered, such as furanyl, thienyl, pyridyl, pyrrolyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, and the like. The heteroaryl ring includes heteroaryl rings fused to an aryl, heterocyclyl, or cycloalkyl ring as described above, wherein the ring that is attached to the parent structure is the heteroaryl ring. A heteroaryl group can be substituted or unsubstituted, and when substituted, the substituents can be substituted at any available point of attachment, and are preferably independently and optionally selected from one or more of D atoms, halogen, alkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl.

[0325] The term "haloalkyl" refers to an alkyl group, as defined above, substituted with one or more halogens (e.g., fluorine, chlorine, bromine, or iodine).

[0326] The term "hydroxyalkyl" refers to an alkyl group, as defined above, substituted with one or more hydroxyl groups.

[0327] The term "halogen" means fluorine, chlorine, bromine, or iodine.

[0328] The term "amino" means -NH2.

[0329] The term "cyano" means -CN.

[0330] The term "nitro" means -NO2.

[0331] The term "acyl" means C(O).

[0332] The term "oxo" means =O.

[0333] Unless otherwise indicated, the term "compounds of the present invention or the present disclosure" refers to compounds of Formula 1, Formula 1-1, Formula 1-2, or Formula 1-3 and subformulae thereof, and isomers, such as stereoisomers (including diastereomers, enantiomers, and racemates), geometric isomers, conformational isomers (including rotamers and atropisomers), tautomers, isotopically labeled compounds (including deuterium substitutions), and inherently formed moieties (e.g., polymorphs, solvates, and / or hydrates). When moieties are present that are capable of forming salts, salts are also included, particularly pharmaceutically acceptable salts.

[0334] Those skilled in the art will recognize that the compounds of the present disclosure can contain chiral centers and therefore can exist in different isomeric forms. The term "isomers" as used herein refers to different compounds that have the same molecular formula but differ in the arrangement of atoms or in the configuration of a molecule.

[0335] "Enantiomer" is a pair of stereoisomers that are non-superimposable mirror images of each other. A 1 : 1 mixture of a pair of enantiomers is a "racemic" mixture. The term is used to indicate a suitable racemic mixture. When stereochemistry of a compound is specified, a single stereoisomer having a known relative and absolute configuration about all chiral centers is indicated by the conventional R-S system (e.g., (1S,2S)) for single stereoisomers having a known relative and absolute configuration about two chiral centers; a single stereoisomer having a known relative but unknown absolute configuration is indicated by an asterisk (e.g., (1R*,2R*)); and a racemate of two letters (e.g., (1RS,2RS) as a racemic mixture of (1R,2R) and (1S,2S); (1RS,2SR) as a racemic mixture of (1R,2S) and (1S,2R)). "Diastereomer" is a stereoisomer that has at least two asymmetric atoms, but they are not mirror images of each other. Absolute stereochemistry is specified using the Cahn-Ingold-Prelog R-S system. When a compound is a pure enantiomer, the stereochemistry at each chiral carbon can be specified by either R or S notation. Resolved compounds whose absolute configuration is unknown can be designated (+) or (-) by the direction the plane of polarized light is rotated by the compound. Alternatively, a resolved compound can be defined by the corresponding retention time of the corresponding enantiomer / diastereomer by chiral HPLC.

[0336] Certain compounds described herein contain one or more asymmetric centers or axes and can thus give rise to enantiomers, diastereomers, and other stereoisomeric forms in addition to the absolute stereochemistry specified herein. In these situations, the present disclosure specifically includes each possible enantiomeric, diastereomeric, and other stereoisomeric form as

[0337] Geometric isomers arise when a compound contains a double bond or some other feature that imparts an amount of structural rigidity to the molecule. If the compound contains a double bond, its substituents can be in the E or Z configuration. If the compound contains a double substituted cycloalkyl, the cycloalkyl substituent can have a cis- or trans- configuration.

[0338] Conformational isomers (or conformers) are isomers that differ by rotation about one or more bonds. Rotamers are conformational isomers that differ by rotation about only one bond.

[0339] The term "atropisomers" refers to structural isomers based on axial or planar chirality, which results from restricted rotation in the molecule.

[0340] Unless otherwise stated, the compounds of the disclosure are intended to include all such possible isomers, including racemic mixtures, optionally in pure form and intermediate mixtures. Optically active (R)- and (S)-isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques (e.g., separation on chiral SFC or HPLC chromatographic columns, such as CHIRALPAK® and CHIRALCEL® available from DAICEL Corp., or other equivalent columns, using appropriate solvents or mixed solvents to achieve good separation).

[0341] The compounds of the disclosure can be isolated in optically active or racemic forms. The optically active forms can be prepared by resolution of racemic forms or by synthesis from optically active starting material. All processes used to

[0342] Depending on the process conditions, the end products of the disclosure are obtained in free (neutral) or salt form. Both the free forms and the salts of these end products are within the scope of the disclosure. If desired, the compound in one form can be converted into another form. A free base or acid can be converted into a salt; a salt can be converted into the free compound or another salt; mixtures of isomeric compounds of the disclosure can be separated into the individual isomers.

[0343] Pharmaceutically acceptable salts are preferred. However, other salts may, for example, be useful in the preparation of the isolated or purified steps employed in the making process and are thus intended to be within the scope of the disclosure.

[0344] As used herein, “pharmaceutically acceptable salt” refers to a derivative of the disclosed compounds wherein the parent compound is modified by making acid or base salts thereof. For example, pharmaceutically acceptable salts include, but are not limited to, acetate, aspartate, benzoate, besylate, bicarbonate / carbonate, bisulfate / sulfate, camsylate, decanoate, chloride / hydrochloride, chlorobenzylate, citrate, edisylate, fumarate, gluconate, glucoheptonate, glucuronate, glutamate, glutarate, glycolate, hippurate, hydroiodide / iodide, isethionate, lactate, lactobionate, laurylsulfate, malate, maleate, malonate / hydroxymalonate, mandelate, methylsulfate, mucate, naphthoate, napsylate, nicotinate, nitrate, octadecanoate, oleate, oxalate, palmitate, pamoate, phenylacetate, phosphate / diphosphate / hydrogen phosphate, polygalacturonate, propionate, salicylate, stearate, succinate, sulfamate, sulfosalicylate, tartrate, tosylate, trifluoroacetate, and xinafoate forms.

[0345] Pharmaceutically acceptable acid addition salts can be formed with inorganic acids and organic acids. Inorganic acids from which salts can be derived include, for example, hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, mandelic acid, ethanesulfonic acid, toluenesulfonic acid, sulfosalicylic acid, and the like.

[0346] Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases. Inorganic bases from which salts can be derived include, for example, ammonium salts and metals in columns I - XII of the Periodic Table. In certain embodiments, salts are derived from sodium, potassium, ammonium, calcium, magnesium, iron, silver, zinc, and copper; particularly suitable salts include ammonium, potassium, sodium, calcium, and magnesium salts. Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, basic ion-exchange resins, and the like. Certain organic amines include isopropylamine, benzathine, choline, diethanolamine, diethylamine, lysine, meglumine, piperazine, and tromethamine.

[0347] Pharmaceutically acceptable salts of the present disclosure can be synthesized from the parent compound that contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. Lists of suitable salts are found in Remington: The Science and Practice of Pharmacy, 22ndEdition, Allen, L.V., Jr., Ed.; Pharmaceutical Press: London, UK (2012), the disclosure of which is hereby incorporated by reference.

[0348] Compounds of the present disclosure containing a group capable of acting as a hydrogen bond donor and / or acceptor can form co-crystals with suitable co-crystal formers. These co-crystals can be prepared from compounds of the present disclosure by known co-crystal forming methods. Such methods include grinding, heating, co-subliming, co-melting the compound of the present disclosure with the co-crystal former under crystallization conditions or contacting a compound of Formula (I) with the co-crystal former in solution and isolating the co-crystal formed thereby. Suitable co-crystal formers include those described in WO 2004 / 078163. The present disclosure thus also provides co-crystals comprising a compound of the present disclosure.

[0349] Any formula given herein is also intended to represent unlabelled forms as well as isotopically label led forms of the compounds. Isotopically labeled compounds have structures depicted by the formulas given herein except for the fact that one or more atoms are replaced by an atom having a selected atomic mass or mass number. Examples of isotopes that can be 2 H, 3 H, 11 C, 13 C, 14 C, 15 N, 18 F, 31 P, 32 P, 35 S, 36 Cl, 125 I. The present disclosure includes various isotopically labeled compounds as described herein, for example, those into which radioactive isotopes such as 3 H and 14 C are present, or those into which non-radioactive isotopes such as 2 H and 13 C are present. Such isotopically labeled compounds are useful in metabolic studies (with 14 C), reaction kinetic studies (with, for example 2 H or 3 H), in drug or substrate tissue distribution studies, or in radiotherapy. In particular, those compounds into which 18 F is present are particularly desirable for PET or SPECT studies.

[0350] Additionally, substitution with heavier isotopes such as deuterium (i.e. 2H or D) substitution can offer certain therapeutic advantages resulting from, for example, increased metabolic stability, or increased half-life or reduced dosage requirements or improved therapeutic index in vivo. It will be appreciated that deuterium is considered a substituent according to the present disclosure. The concentration of such heavier isotopes, particularly deuterium, can be defined by an isotopic enrichment factor. The term "isotopic enrichment factor" as used herein means the ratio between the isotopic abundance of a particular isotope and the natural abundance. If a substituent in a compound of the present disclosure is represented by deuterium, such a compound has an isotopic enrichment factor for each designated deuterium atom of at least 3500 (52.5% deuterium incorporation for each designated deuterium atom), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium incorporation), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation).

[0351] Isotopically-labeled compounds of the present disclosure can generally be prepared by conventional techniques known to those skilled in the art or by the methods and procedures described in the Schemes or in the Examples disclosed herein and manufacturers' instructions (or adapted from the techniques described therein) using an appropriate isotopically-labeled reagent in place of the non-isotopically labeled reagent that is otherwise employed. Such compounds have a variety of potential uses, for example, as standards and reagents in determining the ability of potential pharmaceutical compounds to bind to target proteins or receptors, or for imaging substances that bind to the biological receptors of the present disclosure in vivo or in vitro.

[0352] The term "solvate" means the physical association of one or more solvent molecules with a compound of the present disclosure, whether or not the solvent is organic or inorganic. The physical association can include hydrogen bonding. In certain instances the solvate will be capable of isolation, for example, where one or more solvent molecules are incorporated in the crystal lattice of the solid state form of the compound. The solvent molecules can be present in a regular or an orderly arrangement and / or in an orderly orientation for example as hydrates, ethanolates, methanolates and isopropanolates. Methods of solvation are generally known in the art.

[0353] 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 ubiquitin to be attached to a lysine on a target protein and subsequently targets the specific protein substrate for degradation by the proteasome. Thus, the E3 ubiquitin ligase, alone or in complex with an E2 ubiquitin conjugating enzyme, is the cause of the transfer of ubiquitin to the target protein. In general, ubiquitin ligases are involved in polyubiquitination, so that a second ubiquitin is attached to the first, a third to the second, and so on. Polyubiquitination marks the protein 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 to the substrate molecule by the ubiquitin ligase. Mono-ubiquitinated proteins are not targeted to the proteasome for degradation, but can instead be altered in their cellular location or function, for example via binding to other proteins that have domains capable of binding ubiquitin. To make things more complicated, different lysines on ubiquitin can be targeted by E3s to make chains. The most common lysine is Lys48 on the ubiquitin chain. This is the lysine that is used to make polyubiquitin, which is recognized by the proteasome.

[0354] The term "target protein" refers to proteins and peptides having any biological function or activity, including structural, regulatory, hormonal, enzymatic, genetic, immune, contractile, storage, transport, and signal transduction. In some embodiments, target proteins include structural proteins, receptors, enzymes, cell surface proteins, proteins associated with a cell's integrated function, including proteins involved in catalytic activity, aromatase activity, motility activity, helicase activity, metabolic processes (anabolic and catabolic), antioxidant activity, proteolysis, biosynthesis, proteins with kinase activity, oxidoreductase activity, transferase activity, hydrolase activity, lyase activity, isomerase activity, ligase activity, enzyme modulator activity, signal transducer activity, structural molecule activity, binding activity (protein, lipid carbohydrate), receptor activity, cell motility, membrane fusion, cell communication, biological process regulation, development, cell differentiation, response to stimulus, behavioral protein, cell adhesion protein, proteins involved in cell death, proteins involved in transport (including protein transport activity, nuclear transport, ion transport activity, channel transport activity, carrier activity), permease activity, secretion activity, electron transport activity, pathogenesis, chaperone regulator activity, nucleic acid binding activity, transcription regulator activity, extracellular structure and biological origin activity, translation regulator activity. The proteins include proteins from eukaryotes and prokaryotes, including microorganisms, viruses, fungi, and parasites, and numerous others, including humans, microorganisms, viruses, fungi, and parasites as targets for drug therapy, other animals including domesticated animals, microorganisms and other antimicrobial agents for which targets are used to determine antibiotics, and plants and even viruses and numerous others. In the present disclosure, the target protein is preferably an androgen receptor protein.

[0355] "Optional" or "optionally" means that the subsequently described event or circumstance can or can not occur, and that the description includes instances where the event or circumstance occurs and instances where it does not. For example, "optionally substituted cyclopropyl" means that the cyclopropyl group can or can not be substituted, and that the description includes instances where the cyclopropyl group is substituted and instances where the cyclopropyl group is not substituted.

[0356] "Substituted" means that one or more hydrogen atoms, preferably up to 5, more preferably 1 to 3, of a group are independently of each other replaced with a corresponding number of substituents, as chemically allowable. It goes without saying that substituents are only in their possible chemical positions, which can or cannot be possible, as can be determined by one skilled in the art without undue effort (experimentally or theoretically).

[0357] The following examples are provided by way of illustration, and not by way of limitation.

[0358] Abbreviations used herein are as follows:

[0359] MeOH is methanol; H2SO4 is concentrated sulfuric acid; NIS is N-iodosuccinimide; TFA is trifluoroacetic acid; Pd is palladium; Sn is tin; Pyrrolidine is tetrahydro- pyrrole; -OH is hydroxyl; Boc is tert-butyloxycarbonyl; NaBH4 is sodium borohydride; Et3SiH is triethylsilane; H2 is hydrogen; LiOH is lithium hydroxide; NaOAc is sodium acetate; AcOH is acetic acid; PE is petroleum ether; EA is ethyl acetate; CDCl3 is deuterated chloroform; HNO3 is nitric acid; HBF4 is tetrafluoroboric acid; NaNO2 is sodium nitrite; NBS is N-bromosuccinimide; KOtBu is potassium tert-butoxide; NaH is sodium hydride; B2pin2 is pinacolboronic acid; Oxone is potassium peroxymonosulfate; Cbz is carbobenzyloxy; PPh3 is triphenylphosphine; CBr4 is carbon tetrabromide; Zn is zinc; NH4Cl is ammonium chloride; B is boron; Br is bromine; (TMS)3SiH is tri- (trimethylsilyl)silane; AlBN is azobisisobutyronitrile; DMF is N,N-dimethylformamide; K2CO3 is potassium carbonate; TBAB is tetrabutylammonium bromide; Bn is benzyl; LiAlH4 is lithium aluminum hydride; BH3 is borane; THF is tetrahydrofuran; H2O2 is hydrogen peroxide; DMP is Dess-Martin periodinane; PBr3 is phosphorus tribromide; Pd(OAc)2 is palladium acetate; BF3Et2O is boron trifluoride etherate; S is sulfur; MsCl is methanesulfonyl chloride; TEA is triethylamine; DBU is 1,8-diazabicyclo[5.4.0]undec-7-ene; NaHCO3 is sodium bicarbonate; Malonic acid is malonic acid; PPA is polyphosphoric acid; HBr is hydrogen bromide; Tf2O is triflic anhydride; Pd / C is palladium on carbon; DMSO is dimethyl sulfoxide; UPLC is ultra performance liquid chromatography; MgCl2 is magnesium chloride; NADPH is nicotinamide adenine dinucleotide phosphate; NaBH3CN is sodium cyanoborohydride; DIPEA is N,N-diisopropylethylamine; Dioxane is dioxane; NaBH(OAc)3 is sodium triacetoxyborohydride; DIEA is N,N-diisopropylethylamine.

[0360] Examples

[0361] The following examples are directed to the intermediate compounds and final products identified in the specification and synthetic schemes. The following examples are used to describe the preparation of the compounds of the present application in detail, but the chemical reactions described are disclosed by their general applicability to the preparation of compounds within the scope of the application as described. At times, the reactions described can not be applicable to every compound within the scope of the application as described. A person skilled in the art would readily identify compounds where this would occur. In these instances, the reactions described can be successfully performed by routine modifications known to those skilled in the art. In all preparative methods, all starting materials are known or can be readily prepared from known materials.

[0362] The starting materials, chemical reagents, solvents used in the present disclosure are commercially available, purchased from Anjieji Chemical, Shanghai Bidai Pharmaceutical, Beijing Ino Kai, Jiangsu Aikang, China National Pharmaceutical Group, Beijing Bailingwei, Yunnan Xinlanke, etc.

[0363] The structure of the compound is determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). The determination of nuclear magnetic resonance (NMR) is carried out by Bruke AVANCE-400 / 600 nuclear magnetic instrument, and deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), deuterated methanol (CD3OD) are used as deuterated solvents, and tetramethylsilane (TMS) is used as internal standard. The determination of mass spectrometry (MS) uses Waters Acquity Plus device. High performance liquid preparation uses Waters 2489 device. Medium pressure rapid preparation chromatograph uses COMBIFLASH NEXTGEN 300+ device. Thin layer chromatography silica gel plate uses Silica gel 60 thin layer chromatography silica gel plate (aluminum plate, containing fluorescence). The silica gel used in the silica gel column chromatography (100-200 mesh, 200-300 mesh) is purchased from Ino Kai.

[0364] The reaction progress detection in the examples adopts thin layer chromatography (TLC), and the system of developing agent used for monitoring the reaction and eluent used for purifying the compound by column chromatography includes: petroleum ether / ethyl acetate system, dichloromethane / methanol system.

[0365] The preparation of the exemplary compounds in the present application is as follows, for example:

[0366] Example 1: synthesis method AR-T-1

[0367] Synthesis of AR-P-25

[0368] First step: synthesis of compound tert-butyl (S)-4-((9-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1,2,4,4a,5,6-hexahydro-3H-benzo[b]pyrazino[1,2-d][1,4]oxazepin-3-yl)methyl)piperidine-1-carboxylate

[0369] In a glass vial, (S)-1-(2,3,4,4a,5,6-hexahydro-1H-benzo[b]pyrazino[1,2- d][1,4]oxazepin-9-yl)dihydropyrimidine-2,4(1H,3H)-dione 25 (100 mg, 0.32 mmol) and 4- formylpiperidine-1-carboxylic acid tert-butyl ester (101.12 mg, 0.47 mmol) were added sequentially, solvent THF (2 mL) was added, Ti(O-iPr)4 (179.68 mg, 0.63 mmol), stirred at 60 °C for 1 h, then NaBH3CN (39.73 mg, 0.63 mmol) was added, continued to stir at 60 °C for 1 h, after the reaction was completed, concentrated and treated, then purified by preparative thin layer chromatography (DCM:MeOH = 10:1) to obtain white solid compound (S)-4-((9-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1,2,4,4a,5,6- hexahydro-3H-benzo[b]pyrazino[1,2-d][1,4]oxazepin-3-yl)methyl)piperidine-1-carboxylic acid tert-butyl ester (112 mg, 68.98%).

[0370] 1 H NMR (400 MHz, DMSO-d6) δ 10.30 (s, 1H), 6.94 (d, J = 8.6 Hz, 1H), 6.85 (dd, J = 8.5, 2.5 Hz, 1H), 6.74 (d, J = 2.4 Hz, 1H), 4.38 (td, J = 10.6, 3.3 Hz, 1H), 4.12 (dt, J = 11.0, 4.3 Hz, 1H), 3.93 (d, J = 12.9 Hz, 2H), 3.69 (t, J = 6.7 Hz, 2H), 3.18 - 3.00 (m, 3H), 2.66 (t, J = 6.7 Hz, 4H), 2.54 (s, 2H), 2.33 - 2.25 (m, 1H), 2.16 (t, J = 7.8 Hz, 3H), 1.98 (ddt, J = 17.2, 11.7, 5.8 Hz, 2H), 1.76 - 1.63 (m, 3H), 1.39 (s, 9H), 0.95 (qd, J = 12.3, 3.8 Hz, 2H).

[0371] LCMS (ESI): [M+H] + = 514.49

[0372] Second Step: Synthesis of compound (S)-1-(3-(piperidin-4-ylmethyl)-2,3,4,4a,5,6- hexahydro-1H-benzo[b]pyrazino[1,2-d][1,4]oxazepin-9-yl)dihydropyrimidine-2,4(1H,3H)- dione

[0373] In a 50 mL vial, (S)-4-((9-(2,4-dioxotetrahydropyrimidin-1 (2H)-yl)-1,2,4,4a,5,6- hexahydro-3H-benzo[b]pyrazino[1,2-d][1,4]oxazocin-3-yl)methyl)piperidine-1-carboxylate (112 mg, 0.22 mmol), dichloromethane 5 mL, trifluoroacetic acid 1 mL, stirred at room temperature for 0.5 h. After the reaction was completed, concentrated and treated, then purified by reverse phase Flash (MeCN in Water = 35%) to give white solid compound (S)-1-(3-(piperidin-4-ylmethyl)-2,3,4,4a,5,6-hexahydro-1H- benzo[b]pyrazino[1,2-d][1,4]oxazocin-9-yl)dihydropyrimidine-2,4(1H,3H)-dione (80 mg, 88.72%).

[0374] 1 H NMR (400 MHz, DMSO-d6) δ 10.32 (s, 1H), 9.12 (s, 1H), 7.03 - 6.89 (m, 2H), 6.82 (d, J = 2.2 Hz, 1H), 4.51 (t, J = 10.0 Hz, 1H), 4.10 (ddd, J = 8.9, 5.9, 2.9 Hz, 1H), 3.71 (t, J = 6.7 Hz, 2H), 3.67 - 3.46 (m, 4H), 3.26 (dd, J = 9.4, 5.9 Hz, 3H), 3.16 - 2.95 (m, 4H), 2.84 (q, J = 12.1 Hz, 2H), 2.67 (t, J = 6.7 Hz, 2H), 2.23 - 2.09 (m, 2H), 1.99 (d, J = 13.2 Hz, 2H), 1.83 - 1.73 (m, 1H), 1.48 (q, J = 12.6 Hz, 2H).

[0375] LCMS (ESI): [M+H] + = 414.35

[0376] Third step: synthesis of compound (2-chloro-4-((S)-8-(4-(4-((S)-9-(2,4-dioxotetrahydropyrimidin-1 (2H)-yl)-1,2,4,4a,5,6-hexahydro-3H-benzo[b]pyrazino[1,2-d][1,4]oxazocin-3-yl)methyl)piperidine-1-carbonyl)phenyl)-3-methyl-2,8-diazaspiro[4.5]dec-2-yl)benzonitrile

[0377] In a glass vial was placed ((S)-1-(3-(piperidin-4-ylmethyl)-2,3,4,4a,5,6- hexahydro-1H-benzo[b]pyrazino[1,2-d][1,4]oxazepin-9-yl)dihydropyrimidine-2,4(1H,3H)- dione (20 mg, 0.048 mmol), solvent DMF (1 mL) was added, (S)-4-(2-(3-chloro-4- cyanophenyl)-3-methyl-2,8-diazaspiro[4.5]dec-8-yl)benzoic acid (19.83 mg, 0.048 mmol), EDCI (18.54 mg, 0.097 mmol), HOBT (13.07 mg, 0.097 mmol) and DIEA (18.75 mg, 145 mmol), and the reaction was allowed to proceed at room temperature for 2 h. After the reaction was completed, the compound (2-chloro-4-((S)-8-(4-(4-((S)-9-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1,2,4,4a,5,6- hexahydro-3H-benzo[b]pyrazino[1,2-d][1,4]oxazepin-3-yl)methyl)piperidin-1- carbonyl)phenyl)-3-methyl-2,8-diazaspiro[4.5]dec-2-yl)benzonitrile (25 mg, 64.18%) was obtained as a white solid by high performance liquid chromatography purification.

[0378] 1H NMR (600 MHz, DMSO) δ 10.34 (s, 1H), 7.61 (d, J = 8.9 Hz, 1H), 7.27 (d, J = 8.5 Hz, 2H), 7.02 - 6.92 (m, 4H), 6.81 (dd, J = 9.6, 2.0 Hz, 2H), 6.67 (d, J = 8.9 Hz, 1H), 4.52 (t, J = 9.9 Hz, 1H), 4.11 (d, J = 4.8 Hz, 1H), 4.05 (dd, J = 13.2, 6.6 Hz, 2H), 3.71 (dd, J = 12.6, 6.2 Hz, 3H), 3.61 (d, J = 9.9 Hz, 2H), 3.51 (d, J = 9.8 Hz, 2H), 3.44 (d, J = 10.8 Hz, 1H), 3.37 (d, J = 10.5 Hz, 2H), 3.33 (d, J = 10.6 Hz, 2H), 3.26 - 3.18 (m, 3H), 3.16 - 3.07 (m, 4H), 2.93 (s, 2H), 2.68 (t, J = 6.6 Hz, 2H), 2.24 (dd, J = 12.7, 7.8 Hz, 1H), 2.14 (s, 2H), 1.81 (d, J = 13.2 Hz, 1H), 1.74 (dd, J = 13.4, 7.9 Hz, 2H), 1.58 (dd, J = 12.8, 6.5 Hz, 1H), 1.53 - 1.49 (m, 2H), 1.28 - 1.23 (m, 3H), 1.21 (d, J = 6.0 Hz, 3H).

[0379] LCMS (ESI): [M+H] + = 805.56

[0380] Example 2: Synthesis method AR-T-2

[0381] Synthesis of AR-P-98

[0382] First step: synthesis of compound tert-butyl 4-((6-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-3H-spiro[benzofuran-2,4'-piperidin]-1'-yl)methyl)piperidine-1-carboxylate

[0383] Prepared according to the first step of Example 1.

[0384] LCMS (ESI): [M+H] + = 499.49

[0385] Second step: synthesis of compound 1-(1'-(piperidin-4-ylmethyl)-3H-spiro[benzofuran-2,4'-piperidin]-6-yl)dihydropyrimidine-2,4(1H,3H)-dione

[0386] Prepared according to the procedure of Example 1, second step.

[0387] LCMS (ESI): [M+H] + = 399.49

[0388] Third step: Synthesis of compound N-((1 r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-6-(4-((6-(2,4-dioxotetrahydropyrimidin-1 (2H)-yl)-3H-spiro[benzofuran-2,4'-piperidin]-1'- yl)methyl)piperidin-1-yl)pyridazine-3-carboxamide

[0389] In a glass vial, N-((1 r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-6-(4-((6-(2,4- dioxotetrahydropyrimidin-1 (2H)-yl)-3H-spiro[benzofuran-2,4'-piperidin]-1'- yl)methyl)piperidin-1-yl)pyridazine-3-carboxamide (20 mg, 0.050 mmol), solvent DMSO (1 mL), 6-chloro-N-((1 r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)pyridazine-3- carboxamide (19.64 mg, 0.050 mmol), DIEA (19.46 mg, 0.15 mmol) were added and the reaction was carried out at 80 °C for 2 h. After completion of the reaction, the crude was purified by high performance liquid preparative purification to get compound N-((1 r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-6-(4-((6-(2,4-dioxotetrahydropyrimidin-1 (2H)-yl)-3H-spiro[benzofuran-2,4'-piperidin]-1'- yl)methyl)piperidin-1-yl)pyridazine-3-carboxamide (23 mg, 60.84%) as a white solid.

[0390]

[0391] 1 ​H NMR (600 MHz, DMSO-d6) δ 10.37 (s, 1H), 8.62 (d, J = 8.1 Hz, 1H), 7.91 - 7.80 (m, 2H), 7.46 - 7.36 (m, 2H), 7.23 (dd, J = 8.1, 4.3 Hz, 1H), 7.14 (dd, J = 8.8, 2.4 Hz, 1H), 6.84 - 6.73 (m, 2H), 4.54 (tt, J = 10.6, 4.1 Hz, 3H), 3.89 - 3.84 (m, 1H), 3.76 - 3.71 (m, 2H), 3.24 - 3.02 (m, 8H), 2.69 (t, J = 6.7 Hz, 2H), 2.27 - 2.18 (m, 1H), 2.15 - 2.06 (m, 5H), 2.07 - 1.96 (m, 1H), 1.89 (ddd, J = 22.3, 11.2, 7.2 Hz, 4H), 1.64 (qd, J = 13.2, 3.1 Hz, 2H), 1.56 - 1.47 (m, 2H), 1.24 (dtd, J = 16.6, 12.1, 11.6, 7.1 Hz, 4H).

[0392] LCMS (ESI): [M+H] + = 753.47

[0393] Example 3: Synthesis Method AR-T-3

[0394] Synthesis of AR-P-94

[0395] First Step: Synthesis of compound tert-butyl 4-(4-((6-(2,4-dioxotetrahydropyrimidin- 1(2H)-yl)-2H-spiro[benzofuran-3,4'-piperidin]-1'-yl)methyl)piperidin-1-yl)benzoate

[0396] Prepared according to the first step of Example 1.

[0397] LCMS (ESI): [M+H] + = 575.56

[0398] Second Step: Synthesis of compound 4-(4-((6-(2,4-dioxotetrahydropyrimidin- 1(2H)-yl)-2H-spiro[benzofuran-3,4'-piperidin]-1'-yl)methyl)piperidin-1-yl)benzoic acid

[0399] Prepared according to the second step of Example 1.

[0400] LCMS (ESI): [M+H] + = 519.48

[0401] Step 3: Synthesis of compound N-((1 r,3r)-3-(4-cyano-3-methoxyphenoxy)-2,2,4,4- tetramethylcyclobutyl)-4-(4-((6-(2,4-dioxotetrahydropyrimidin-1 (2H)-yl)-2H-spiro[benzofuran- 3,4'-piperidin]-1'-yl)methyl)piperidin-1-yl)benzamide

[0402] Prepared according to the procedure described in Step 3 of Reference Example 1.

[0403] 1 H NMR (400 MHz, CD3OD) δ 7.78 (d, J = 8.9 Hz, 2H), 7.55 (d, J = 8.6 Hz, 1H), 7.23 (d, J = 8.0 Hz, 1H), 7.07 (d, J = 8.7 Hz, 2H), 6.94 (dd, J = 7.9, 1.9 Hz, 1H), 6.86 (d, J = 1.9 Hz, 1H), 6.65 (d, J = 2.2 Hz, 1H), 6.58 (dd, J = 8.7, 2.2 Hz, 1H), 4.60 (s, 2H), 4.29 (s, 1H), 4.16 (s, 1H), 3.98 (d, J = 14.6 Hz, 2H), 3.95 (s, 3H), 3.85 (t, J = 6.7 Hz, 2H), 3.72 (d, J = 12.7 Hz, 2H), 3.32 (s, 2H), 3.15 (t, J = 8.8 Hz, 3H), 2.96 (t, J = 12.3 Hz, 2H), 2.82 (t, J = 6.7 Hz, 2H), 2.36 - 2.24 (m, 2H), 2.23 - 2.14 (m, 1H), 2.07 (d, J = 14.5 Hz, 2H), 1.97 (d, J = 12.8 Hz, 2H), 1.59 - 1.44 (m, 2H), 1.28 (d, J = 19.7 Hz, 12H).

[0404] LCMS (ESI): [M+H] + = 775.56

[0405] Example 4: Synthesis Method AR-T-4

[0406] Synthesis of AR-P-66

[0407] Step 1: Synthesis of compound 1-(4-bromophenyl)-4-(dimethoxymethyl)piperidine

[0408] In a 100 mL vial, add 4-(dimethoxymethyl)piperidine (1.00 g, 6.28 mmol), 1,4- dibromobenzene (4.44 g, 18.84 mmol), Pd(OAc)2 (141.00 mg, 0.628 mmol), BINAP (782.13 mg, 1.26 mmol) and Cs2CO3 (6.14 g, 18.84 mmol) in turn, add solvent dioxane (10 mL), stir the reaction at 110 °C for 2 h under N2 atmosphere, after the reaction is completed, filter and concentrate, then purify by column chromatography (EA:PE = 1:5) to obtain compound 1-(4-bromophenyl)-4- (dimethoxymethyl)piperidine (820 mg, 41.55%) as a yellow solid.

[0409] LCMS (ESI): [M+H] + = 315.26

[0410] Second step: synthesis of compound (S)-4-(8-(4-(4-(dimethoxymethyl)piperidin-1-yl)phenyl)- 3-methyl-2,8-diazaspiro[4.5]dec-2-yl)-2-methoxybenzonitrile

[0411] In a vial, add 1-(4-bromophenyl)-4-(dimethoxymethyl)piperidine (500 mg, 1.59 mmol), (S)-2-methoxy-4-(3-methyl-2,8-diazaspiro[4.5]dec-2-yl)benzonitrile (454.12 mg, 1.59 mmol), Pd2(dba)3 (145.71 mg, 0.16 mmol), X-Phos (151.72 mg, 0.32 mmol) and Cs2CO3 (1.56 g, 4.77 mmol) in turn, add solvent dioxane (5 mL), stir the reaction at 110 °C for 12 h under N2 atmosphere, after the reaction is completed, filter and concentrate, then purify by preparative thin layer column chromatography (EA:PE = 1:1) to obtain compound (S)-4-(8-(4-(tetra-(dimethoxymethyl)piperidin-1-yl)phenyl)-3-methyl-2,8- diazaspiro[4.5]dec-2-yl)-2-methoxybenzonitrile (323 mg, 39.13%) as a yellow solid.

[0412] LCMS (ESI): [M+H] + = 519.56

[0413] Third step: synthesis of compound (S)-4-(8-(4-(4-formylpiperidin-1-yl)phenyl)-3-methyl- 2,8-diazaspiro[4.5]dec-2-yl)-2-methoxybenzonitrile

[0414] In a flask, add (S)-4-(8-(4-(4-(dimethoxymethyl)piperidin-l-yl)phenyl)-3-methyl-2,8- diazaspiro[4.5]dec-2-yl)-2-methoxybenzonitrile (300 mg, 0.58 mmol) and TFA (1.00 mL) and H20 (0.2 mL), add solvent DCM (0.5 mL), stir the reaction at room temperature for 1 h, after the reaction is completed, concentrate, spin dry to get the crude blue solid compound (S)-4-(8-(4-(4-formylpiperidin-l-yl)phenyl)-3-methyl-2,8- diazaspiro[4.5]dec-2-yl)-2-methoxybenzonitrile (310 mg).

[0415] LCMS (ESI): [M+H] + = 473.39

[0416] Fourth step: synthesis of compound 4-((S)-8-(4-(S)-9-(2,4-dioxotetrahydropyrimidin- 1(2H)-yl)-l,2,4,4a,5,6-hexahydro-3H-benzo[b]pyrazino[l,2-d][l,4]oxazepin-3-yl)methyl)piperidin- 1-yl)phenyl)-3-methyl-2,8-diazaspiro[4.5]dec-2-yl)-2-methoxybenzonitrile

[0417] Prepared according to the first step of Example 1.

[0418] 1 H NMR (400 MHz, CD3OD) δ 7.46 (d, J = 8.8 Hz, 2H), 7.35 (d, J = 8.7 Hz, 1H), 7.23 (d, J = 9.1 Hz, 2H), 7.09 - 6.99 (m, 2H), 6.92 (d, J = 2.4 Hz, 1H), 6.34 (dd, J = 8.8, 2.1 Hz, 1H), 6.25 (d, J = 2.1 Hz, 1H), 4.57 (s, 1H), 4.25 - 4.09 (m, 2H), 3.94 (s, 3H), 3.90 - 3.79 (m, 4H), 3.59 (dd, J = 10.6, 6.0 Hz, 6H), 3.50 (d, J = 10.5 Hz, 4H), 3.24 (d, J = 7.0 Hz, 2H), 3.06 (q, J = 12.2 Hz, 2H), 2.81 (t, J = 6.7 Hz, 2H), 2.46 (t, J = 10.5 Hz, 1H), 2.32 - 1.99 (m, 7H), 1.97 - 1.83 (m, 3H), 1.77 (dd, J = 13.0, 6.9 Hz, 1H), 1.59 (q, J = 11.6 Hz, 2H), 1.39 - 1.29 (m, 5H).

[0419] LCMS (ESI): [M+H] + = 773.66

[0420] Example 5: Synthesis method AR-T-5

[0421] Synthesis of AR-P-51

[0422] First step: Synthesis of compound tert-butyl 4-(methylamino)piperidine-1- carboxylate

[0423] Into a glass vial, tert-butyl 4-oxopiperidine-1-carboxylate (500 mg, 2.51 mmol) and methylamine (155.87 mg, 5.02 mmol) were added sequentially, solvent 1,2-dichloroethane (10 mL) was added, then NaBH(OAc)3 (1.60 g, 7.53 mmol) was added, the reaction was stirred at room temperature for 2 h, after the reaction was completed, concentrated treatment, then purified by column chromatography (EA:PE = 1:1) to obtain compound tert-butyl 4-(methylamino)piperidine-1-carboxylate (314 mg, 58.39%) as colorless oil.

[0424] Second step: Synthesis of compound tert-butyl 4-((7-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)spiro[chromane-2,1'-cyclohexane]-4'-yl)(methyl)amino)piperidine-1-carboxylate

[0425] Prepared according to the first step of Example 1.

[0426] LCMS (ESI): [M+H] + = 527.49

[0427] Third step: Synthesis of compound 1-(4'-(methyl(piperidin-4-yl)amino)spiro[chromane-2,1'-cyclohexane]-7-yl)dihydropyrimidine-2,4(1H,3H)-dione

[0428] Prepared according to the second step of Example 1.

[0429] LCMS (ESI): [M+H] + = 427.49

[0430] Fourth step: Synthesis of compound (S)-2-chloro-4-(8-(4-(4-(7-(2-4-dioxotetrahydropyrimidin-1(2H)-yl)spiro[chromane-2,1'-cyclohexane]-4'-yl)(methyl)amino)piperidine-1-carbonyl)phenyl)-3-methyl-2,8-diazaspiro[4.5]dec-2-yl)benzonitrile

[0431] Prepared according to the third step of Example 1.

[0432] 1 H NMR (600 MHz, DMSO-d6) δ 10.32 (s, 1H), 7.59 (d, J = 8.9 Hz, 1H), 7.28 (d, J = 8.5 Hz, 2H), 7.07 (d, J = 8.3 Hz, 1H), 6.96 (d, J = 8.5 Hz, 2H), 6.79 (d, J = 2.3 Hz, 1H), 6.76 (dd, J = 8.1, 2.2 Hz, 1H), 6.67 (d, J = 2.2 Hz, 1H), 6.65 (dd, J = 9.0, 2.3 Hz, 1H), 4.03 (d, J = 6.7 Hz, 1H), 3.70 (t, J = 6.7 Hz, 4H), 3.43 (d, J = 10.7 Hz, 4H), 3.31 (d, J = 10.8 Hz, 2H), 3.25 - 3.18 (m, 3H), 2.72 (d, J = 4.9 Hz, 3H), 2.69 (t, J = 6.7 Hz, 2H), 2.66 (t, J = 6.7 Hz, 2H), 2.23 (dd, J = 12.8, 7.7 Hz, 1H), 2.04 - 1.99 (m, 2H), 1.95 (q, J = 7.2 Hz, 4H), 1.90 (d, J = 11.0 Hz, 2H), 1.77 - 1.69 (m, 3H), 1.65 (dd, J = 17.3, 8.8 Hz, 4H), 1.57 (dd, J = 12.9, 6.6 Hz, 2H), 1.49 (dt, J = 9.6, 4.9 Hz, 2H), 1.19 (d, J = 6.0 Hz, 4H).

[0433] LCMS (ESI): [M+H] + = 818.66

[0434] Example 6: Synthesis Method AR-T-6

[0435] Synthesis of AR-P-59

[0436] First Step: Synthesis of compound 2-chloro-4-((S)-8-(4-(1s,4s)-4- (dimethoxymethyl)cyclohexyl)oxy)piperidine-1-carbonyl)phenyl)-3-methyl-2,8- diazaspiro[4.5]dec-2-yl)benzonitrile

[0437] Prepared according to the procedure of Example 1, third step.

[0438] LCMS (ESI): [M+H] + = 650.39

[0439] Second Step: Synthesis of compound 2-chloro-4-((S)-8-(4-(4-(1s,4s)-4- formylcyclohexyl)oxy)piperidine-1-carbonyl)phenyl)-3-methyl-2,8-diazaspiro[4.5]dec- 2-yl)benzonitrile

[0440] Prepared according to the procedure described in the second step of Example 1.

[0441] LCMS (ESI): [M+H] + = 604.19

[0442] Third Step: 2-chloro-4-((S)-8-(4-(4-(1S,4r)-4-(((S)-9-(2,4-dioxotetrahydropyrimidin- 1(2H)-yl)-1,2,4,4a,5,6-hexahydro-3H-benzo[b]pyrazino[1,2-d][1,4]oxazepin-3-yl)methyl) cyclohexyl)oxy)piperidine-1-carbonyl)phenyl)-3-methyl-2,8-diazaspiro[4.5]dec-2- yl)benzonitrile

[0443] Prepared according to the procedure described in the first step of Example 1.

[0444] 1H NMR (600 MHz, DMSO-d6) δ 10.34 (s, 1H), 7.61 (d, J = 8.9 Hz, 1H), 7.26 (d, J = 8.6 Hz, 2H), 7.01 - 6.97 (m, 2H), 6.95 (dd, J = 8.8, 2.4 Hz, 2H), 6.81 (dd, J = 7.8, 2.3 Hz, 2H), 6.67 (dd, J = 8.9, 2.2 Hz, 1H), 4.52 (t, J = 9.7 Hz, 2H), 4.14 - 4.09 (m, 2H), 4.04 (dd, J = 13.3, 6.6 Hz, 2H), 3.70 (dt, J = 12.1, 6.2 Hz, 3H), 3.58 (d, J = 11.0 Hz, 1H), 3.46 (t, J = 11.1 Hz, 2H), 3.40 - 3.35 (m, 3H), 3.33 (dd, J = 16.7, 5.8 Hz, 4H), 3.21 (dt, J = 21.5, 7.0 Hz, 4H), 3.13 (d, J = 12.0 Hz, 1H), 3.08 - 3.00 (m, 3H), 2.68 (t, J = 6.7 Hz, 2H), 2.24 (dd, J = 12.7, 7.7 Hz, 1H), 2.15 - 2.09 (m, 1H), 1.96 (d, J = 11.1 Hz, 2H), 1.84 - 1.72 (m, 7H), 1.58 (dd, J = 12.8, 6.5 Hz, 1H), 1.50 (dd, J = 10.6, 6.4 Hz, 2H), 1.38 (d, J = 8.8 Hz, 2H), 1.24 (s, 1H), 1.21 (d, J = 6.1 Hz, 3H), 1.17 (d, J = 10.6 Hz, 1H), 1.07 - 0.99 (m, 2H).

[0445] LCMS (ESI): [M+H] + = 903.75

[0446] Example 7: Synthesis Method AR-T-7

[0447] Synthesis of AR-P-114

[0448] First Step: Synthesis of compound 2-((3-bromo-4-hydroxyphenyl)amino)-2- methylacrylonitrile

[0449] Into a 250 mL three-necked flask, 4-amino-2-bromophenol (10 g, 53.18 mmol) was taken, to which dichloromethane 100 mL, acetone 25 mL was added. Trimethylsilyl triflate (591 mg, 2.66 mmol) and trimethylsilyl cyanide (7.39 g, 74.46 mmol) were added at room temperature and stirred for 12 h at room temperature. After completion of the reaction, concentrated and worked up, which was purified by column chromatography (EA: PE = 1:1) to get compound 2-((3-bromo-4-hydroxyphenyl)amino)-2-methylacrylonitrile as yellow solid (6 g, 44.22 %).

[0450] 1 H NMR (600 MHz, DMSO-d6) δ 9.62 (s, 1H), 7.05 (d, J = 2.7 Hz, 1H), 6.85 (d, J = 8.6 Hz, 1H), 6.80 (dd, J = 8.7, 2.6 Hz, 1H), 5.51 (s, 1H), 1.55 (s, 6H).

[0451] LCMS (ESI): [M+H] + = 255.17

[0452] Second Step: Synthesis of compound 4-(3-(3-bromo-4-hydroxyphenyl)-4,4-dimethyl-5- oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile Into a 250 mL three-necked flask, 2-((3-bromo-4-hydroxyphenyl)amino)-2-methylacrylonitrile (6 g, 23.52 mmol) was taken, to which DMF 50 mL, 4-isothiocyanato-2- (trifluoromethyl)benzonitrile (5.0 g, 25.87 mmol) was added and stirred for 1 h at room temperature. Methanol 50 mL and 2M aqueous hydrochloric acid 50 mL was added at room temperature and stirred for 2 h at 70 °C. After completion of the reaction, water was added and extracted with ethyl acetate, which was dried, concentrated and purified by column chromatography (EA: PE = 1:1) to get compound 4-(3-(3-bromo-4-hydroxyphenyl)-4,4-dimethyl-5-oxo-2- thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile as yellow solid (6 g, 52.68 %).

[0453] 1 H NMR (600 MHz, DMSO-d6) δ 10.79 (s, 1H), 8.39 (d, J = 8.2 Hz, 1H), 8.27 (d, J = 1.9 Hz, 1H), 8.06 (dd, J = 8.2, 1.9 Hz, 1H), 7.53 (d, J = 2.4 Hz, 1H), 7.20 (dd, J = 8.6, 2.5 Hz, 1H), 7.10 (d, J = 8.6 Hz, 1H), 1.50 (s, 6H).

[0454] LCMS (ESI): [M+H] = 482.09 +

[0455] Step 3: Synthesis of compound 2-bromo-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5- dimethyl-4-oxo-2-thioxoimidazolidin-l-yl)phenyl acetate

[0456] (6 g, 12.39 mmol) was added into a 250 mL three-necked flask, 100 mL of dichloromethane was added, acetyl chloride (1.17 g, 14.82 mmol) was added under ice-bath condition, N,N- diisopropylethylamine (3.20 g, 24.78 mmol) was added, and stirred at room temperature for 3 hours. After the reaction was completed, water was added and extracted with ethyl acetate, and the organic phase was dried and concentrated, and then purified by column chromatography (40% EA, 60% PE) to obtain yellow solid compound 2-bromo-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2- thioxoimidazolidin-l-yl)phenyl acetate (6.28 g, 96.31%).

[0457] 1 H NMR (600 MHz, DMSO-d6) δ 8.41 (d, J = 8.2 Hz, 1H), 8.28 (d, J = 1.9 Hz, 1H), 8.08 (dd, J = 8.1, 1.9 Hz, 1H), 7.82 (d, J = 2.3 Hz, 1H), 7.53 (d, J = 8.5 Hz, 1H), 7.49 (dd, J = 8.5, 2.3 Hz, 1H), 2.38 (s, 3H), 1.54 (s, 6H).

[0458] LCMS (ESI): [M+H] = 527.29 +

[0459] Step 4: Synthesis of compound 4-(3-(4-hydroxy-3-vinylphenyl)-4,4-dimethyl-5-oxo-2- thioxoimidazolidin-l-yl)-2-(trifluoromethyl)benzonitrile

[0460] ​​Compound 4-(3-(3-ethyl-4-hydroxyphenyl)-4,4-dimethyl-5-oxo-2- thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile was synthesized according to the following procedure. 2-Bromo-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5- dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)phenyl acetate (4.5 g, 8.55 mmol) was added to a 250 mL three-necked flask, 1,4-dioxane / water (5:2) 70 mL, 4,4,5,5- tetramethyl-2-vinyl-1,3,2-dioxaborolane (2.63 g, 17.1 mmol), potassium phosphate (3.63 g, 17.1 mmol), Pd(dppf)Cl2(625.60 mg, 0.85 mmol). Stirring at 80 °C for 16 hours under nitrogen protection. After the reaction was completed, water was added and extracted with ethyl acetate, and the organic phase was dried and concentrated, then purified by column chromatography (50% EA, 50% PE) to obtain yellow solid compound 4-(3-(4-hydroxy-3-vinylphenyl)-4,4-dimethyl-5-oxo-2- thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile (3 g, 81.33%).

[0461] 1 H NMR (600 MHz, DMSO-d6) δ 10.19 (s, 1H), 8.39 (d, J = 8.2 Hz, 1H), 8.29 (d, J = 1.9 Hz, 1H), 8.08 (dd, J = 8.2, 1.9 Hz, 1H), 7.39 (d, J = 2.5 Hz, 1H), 7.09 (dd, J = 8.5, 2.6 Hz, 1H), 7.00 - 6.90 (m, 2H), 5.78 (dd, J = 17.8, 1.5 Hz, 1H), 5.29 (dd, J = 11.2, 1.4 Hz, 1H), 1.50 (s, 6H).

[0462] LCMS (ESI): [M+H] + = 432.29

[0463] Fifth step: synthesis of compound 4-(3-(3-ethyl-4-hydroxyphenyl)-4,4-dimethyl-5- oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile

[0464] To a 50 mL round bottom flask was added 4-(3-(4-hydroxy-3- ethylphenyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2- (trifluoromethyl)benzonitrile (340 mg, 784.41 μmol), N,N- dimethylformamide 5 mL, potassium carbonate (325 mg, 2.35 mmol), 1,2-dibromoethane (1.47 g, 7.84 mmol) and stirred at 80 °C for 16 h. After the reaction was completed, quenched with water and extracted with ethyl acetate, the organic phase was dried and concentrated to give a white solid compound 4-(3-(4-(2-bromoethoxy)-3- ethylphenyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2- (trifluoromethyl)benzonitrile (80 mg, 18.87 %).

[0465] 1 H NMR (600 MHz, DMSO-d6) δ 9.79 (s, 1H), 8.38 (d, J = 8.2 Hz, 1H), 8.29 (d, J = 1.9 Hz, 1H), 8.07 (dd, J = 8.2, 1.9 Hz, 1H), 7.04 (d, J = 2.6 Hz, 1H), 6.99 (dd, J = 8.4, 2.6 Hz, 1H), 6.91 (d, J = 8.4 Hz, 1H), 2.57 (q, J = 7.6 Hz, 2H), 1.48 (s, 6H), 1.15 (t, J = 7.5 Hz, 3H).

[0466] LCMS (ESI): [M+H] + = 434.39

[0467] Sixth step: synthesis of compound 4-(3-(4-(2-bromoethoxy)-3- ethylphenyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2- (trifluoromethyl)benzonitrile

[0468] To a 50 mL round bottom flask was added 4-(3-(4-hydroxy-3- ethylphenyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2- (trifluoromethyl)benzonitrile (340 mg, 784.41 μmol), N,N- dimethylformamide 5 mL, potassium carbonate (325 mg, 2.35 mmol), 1,2-dibromoethane (1.47 g, 7.84 mmol) and stirred at 80 °C for 16 h. After the reaction was completed, quenched with water and extracted with ethyl acetate, the organic phase was dried and concentrated to give a white solid compound 4-(3-(4-(2-bromoethoxy)-3- ethylphenyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2- (trifluoromethyl)benzonitrile (80 mg, 18.87 %).

[0469] (340 mg, 784.41 μmol), N,N-dimethylformamide 5 mL, potassium carbonate (325 mg, 2.35 mmol), 1,2-dibromoethane (1.47 g, 7.84 mmol) and stirred at 80 °C for 16 h. After the reaction was completed, quenched with water and extracted with ethyl acetate, the organic phase was dried and concentrated to give a white solid compound 4-(3-(4-(2-bromoethoxy)-3- ethylphenyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2- (trifluoromethyl)benzonitrile (80 mg, 18.87 %).

[0470] 1 H NMR (400 MHz, DMSO-d6) δ 8.39 (d, J = 8.2 Hz, 1H), 8.30 (d, J = 1.9 Hz, 1H), 8.08 (dd, J = 8.3, 2.0 Hz, 1H), 7.17 (d, J = 8.1 Hz, 2H), 7.12 - 7.08 (m, 1H), 4.43 - 4.37 (m, 2H), 3.90 - 3.84 (m, 2H), 2.66 (q, J = 7.5 Hz, 2H), 1.50 (s, 6H), 1.19 (t, J = 7.5 Hz, 3H).

[0471] LCMS (ESI): [M+H] + = 540.28

[0472] Step 7: Synthesis of compound (S)-4-(3-(4-(2-(4-((9-(2,4-dioxotetrahydropyridin-1(2H)-yl)- 1,2,4,4a,5,6-hexahydro-3H-benzo[b]pyrazolo[l,2-d][l,4]oxazepin-3-yl)methyl)piperidin- 1-yl)ethoxy)-3-ethylphenyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-l-yl)-2- (trifluoromethyl)benzonitrile

[0473] Prepared according to the procedure described in Example 2, Step 3.

[0474] 1 H NMR (400 MHz, DMSO-d6) δ 10.31 (s, 1H), 8.40 (d, J = 8.3 Hz, 1H), 8.29 (d, J = 1.9 Hz, 1H), 8.08 (dd, J = 8.2, 2.0 Hz, 1H), 7.26 - 7.14 (m, 4H), 6.81 (s, 1H), 6.66 (s, 1H), 4.43 (s, 2H), 4.14 (s, 2H), 3.73 - 3.58 (m, 6H), 3.15 (d, J = 15.6 Hz, 6H), 2.71 - 2.61 (m, 4H), 2.33 (p, J = 1.9 Hz, 1H), 2.00 (q, J = 7.0 Hz, 5H), 1.50 (s, 8H), 1.24 (d, J = 3.3 Hz, 7H).

[0475] LCMS (ESI): [M+H] + = 873.66

[0476] Example 8: Synthesis Method AR-T-8

[0477] Synthesis of AR-P-178

[0478] First Step: Synthesis of compound tert-butyl 2-(((1 r,4r)-4-(3-chloro-4- cyanophenoxy)cyclohexyl)carbamoyl)-7,8-dihydro-1,6-naphthyridine-6(5H)- carboxylate

[0479] Prepared according to the procedure described in Reference Example 1, Step 3.

[0480] LCMS (ESI): [M+H] + = 512.49

[0481] Second Step: Synthesis of compound N-((1 r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)- 5,6,7,8-tetrahydro-1,6-naphthyridine-2-carboxamide

[0482] Prepared according to the procedure described in Reference Example 1, Step 2.

[0483] LCMS (ESI): [M+H] + = 411.69

[0484] Third Step: Synthesis of compound 5-(4-((1 r,4r)-4-(dimethoxymethyl)cyclohexyl)oxy)piperidin- 1 -yl)-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione

[0485] Into a glass vial was added 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindole-1,3-dione (100 mg, 0.36 mmol), solvent DMF (2 mL), (4-(((1 r,4r)-4-(dimethoxymethyl)cyclohexyl)oxy)piperidine (93.18 mg, 0.36 mmol), potassium carbonate (150.10 mg, 1.09 mmol), and the reaction was allowed to proceed at 120 °C for 2 h. After completion of the reaction, the reaction mixture was purified by column chromatography to obtain compound 5-(4-((1 r,4r)-4-(dimethoxymethyl)cyclohexyl)oxy)piperidin-1 -yl)-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione (124 mg, 66.69%) as a white solid.

[0486] LCMS (ESI): [M+H] + = 514.39

[0487] Fourth Step: Synthesis of compound (1 r,4r)-4-(1 -(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl)piperidin-4-yl)oxy)cyclohexan-1 -carboxaldehyde

[0488] Prepared according to the procedure described in Reference Example 1, Step 2.

[0489] LCMS (ESI): [M+H]+ = 468.39

[0490] Step 5: Synthesis of compound N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-6-((((1r,4r)-4-((1-(2-(2-6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)oxy)cyclohexyl)methyl)-5,6,7,8-tetrahydro-1,6-naphthyridine-2-carboxamide

[0491] Prepared according to the procedure described in Step 1 of Example 1.

[0492] 1 H NMR (600 MHz, DMSO-d6) δ 8.38 (d, J = 8.3 Hz, 1H), 7.94 (d, J = 7.9 Hz, 1H), 7.86 (dd, J = 21.7, 8.4 Hz, 2H), 7.67 (d, J = 8.5 Hz, 1H), 7.36 (dd, J = 18.9, 2.4 Hz, 2H), 7.26 (dd, J = 8.7, 2.4 Hz, 1H), 7.14 (dd, J = 8.8, 2.5 Hz, 1H), 5.07 (dd, J = 12.8, 5.4 Hz, 1H), 4.74 (d, J = 16.1 Hz, 1H), 4.54 (tt, J = 10.1, 4.3 Hz, 1H), 4.48 - 4.38 (m, 1H), 3.92 - 3.84 (m, 2H), 3.80 (dt, J = 13.4, 4.8 Hz, 2H), 3.70 (dt, J = 26.4, 4.0 Hz, 2H), 3.35 - 2.92 (m, 4H), 2.89 (ddd, J = 17.0, 13.8, 5.5 Hz, 1H), 2.65 - 2.57 (m, 2H), 2.15 - 2.08 (m, 2H), 2.01 (td, J = 13.0, 10.9, 5.1 Hz, 2H), 1.95 - 1.83 (m, 4H), 1.83 - 1.72 (m, 2H), 1.66 (s, 1H), 1.63 (d, J = 12.8 Hz, 2H), 1.59 - 1.54 (m, 2H), 1.52 (dd, J = 7.5, 4.2 Hz, 2H), 1.51 - 1.47 (m, 2H), 1.47 - 1.43 (m, 1H), 1.40 (d, J = 12.0 Hz, 2H), 1.25 (d, J = 13.0 Hz, 4H).

[0493] LCMS (ESI): [M+H] + = 862.66

[0494] Example 9: Synthesis Method AR-T-9

[0495] Synthesis of AR-P-277

[0496] First Step: Synthesis of compound 4-(3-(4-(3-bromopropoxy)-3-ethylphenyl)-4,4- dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile

[0497] In a glass vial, 4-(3-(3-ethyl-4-hydroxyphenyl)-4,4-dimethyl-5-oxo-2- thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile (50 mg, 0.12 mmol) was added sequentially, solvent DMF (1 mL) was added, 1,3-dibromopropane (49.81 mg, 0.23 mmol), potassium carbonate (47.83 mg, 0.35 mmol), and the reaction was allowed to proceed at room temperature for 2 h. After the reaction was completed, the product was purified by column chromatography to obtain compound 4-(3-(4-(3-bromopropoxy)-3-ethylphenyl)-4,4-dimethyl-5-oxo-2- thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile (20 mg, 30.50%) as a white solid.

[0498] LCMS (ESI): [M+H] + = 569.39

[0499] Second Step: Synthesis of compound 4-(3-(4-(3-((S)-10-(((S)-2,6-dioxopiperidin-3- ylamino)-1,2,4,4a,5,6-hexahydro-3H-benzo[b]pyrazolo[1,2-d][1,4]oxazepin-3-yl)propoxy)- 3-ethylphenyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2- (trifluoromethyl)benzonitrile

[0500] In a glass vial, 4-(3-(4-(3-bromopropoxy)-3-ethylphenyl)-4,4-dimethyl-5-oxo-2- thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile (20 mg, 0.035 mmol) was added sequentially, DMSO (0.5 mL) was added, (S)-3-(((S)-2,3,4,4a,5,6-hexahydro-1H- benzo[b]pyrazinyl[1,2-d][1,4]oxazepin-10-yl)amino)piperidine-2,6-dione (11.62 mg, 0.035 mmol), N,N-diisopropylethylamine (13.64 mg, 0.105 mmol), 80 °C for 2 h, after the reaction was completed, white solid compound 4-(3-(4-(3-((S)-10-(((S)-2,6-dioxopiperidin-3-ylamino)-1,2,4,4a,5,6-hexahydro-3H- benzo[b]pyrazolo[1,2-d][1,4]oxazepin-3-yl)propoxy)-3-ethylphenyl)-4,4-dimethyl-5-oxo-2- thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile (5 mg, 17.37%) was obtained by high performance liquid preparation purification.

[0501] 1 H NMR (600 MHz, DMSO) δ 8.94 - 8.86 (m, 1H), 8.85 - 8.77 (m, 1H), 8.39 (d, J = 8.2 Hz, 1H), 8.30 (d, J = 1.4 Hz, 1H), 8.08 (dd, J = 8.2, 1.5 Hz, 1H), 7.18 - 7.11 (m, 2H), 7.03 (d, J = 8.6 Hz, 1H), 6.60 (d, J = 8.5 Hz, 1H), 6.36 (s, 1H), 6.25 (dd, J = 8.5, 2.5 Hz, 1H), 4.33 (dd, J = 11.2, 4.6 Hz, 1H), 4.20 - 4.14 (m, 1H), 4.03 (t, J = 6.2 Hz, 2H), 3.98 - 3.94 (m, 1H), 3.90 - 3.84 (m, 2H), 3.37 - 3.28 (m, 3H), 3.24 - 3.16 (m, 2H), 3.15 - 3.08 (m, 1H), 3.05 - 2.97 (m, 1H), 2.90 - 2.80 (m, 1H), 2.80 - 2.71 (m, 1H), 2.69 - 2.59 (m, 2H), 2.15 - 2.07 (m, 1H), 2.03 - 1.80 (m, 5H), 1.50 (s, 6H), 1.21 - 1.12 (m, 3H).

[0502] LCMS (ESI): [M+H] + = 804.66

[0503] Example 10: Synthesis Method AR-T-10

[0504] Synthesis of AR-P-289

[0505] First Step: Synthesis of compound tert-butyl 4-(4-(((lS,4S)-4- (dimethoxymethyl)cyclohexyl)oxy)piperidin-l-yl)benzoate was prepared according to the third step of Reference Example 8.

[0506] LCMS (ESI): [M+H] + = 434.29

[0507] Second Step: Synthesis of compound tert-butyl 4-(4-(((lS,4S)-4- (dimethoxymethyl)cyclohexyl)oxy)piperidin-l-yl)benzoate was prepared according to the third step of Reference Example 8.

[0508] Prepared according to the second step of Reference Example 1.

[0509] LCMS (ESI): [M+H] + = 332.49

[0510] Third Step: Synthesis of compound 4-(4-(((lR,4S)-4-(((S)-9-(2,4- dioxotetrahydropyrimidin-l(2H)-yl)-l,2,4,4a,5,6-hexahydro-3H- benzo[b]pyrazino[l,2-d][l,2-d][l,4]oxazepin-3-yl)methyl)cyclohexyl)oxy)piperidin-l- yl)benzoic acid

[0511] Prepared according to the first step of Reference Example 1.

[0512] LCMS (ESI): [M+H] + = 632.69

[0513] Fourth Step: Synthesis of compound N-((lR,3R)-3-(4-cyano-3- methoxyphenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-(4-(((lS,4R)-4-(((S)-9-(2,4- dioxotetrahydropyrimidin-l(2H)-yl)-l,2,4,4a,5,6-hexahydro-3H- benzo[b]pyrazino[l,2-d][l,2-d][l,4]oxazepin-3-yl)methyl)cyclohexyl)oxy)piperidin-l- yl)benzamide

[0514] Prepared according to the third step of Reference Example 1.

[0515] 1H NMR (600 MHz, DMSO-d6) δ 10.32 (s, 1H), 7.75 (d, J = 8.5 Hz, 2H), 7.65 (d, J = 8.6 Hz, 1H), 7.51 (d, J = 9.2 Hz, 1H), 7.01 - 6.94 (m, 4H), 6.82 (d, J = 2.5 Hz, 1H), 6.64 (d, J = 2.2 Hz, 1H), 6.54 (m, J = 8.7, 2.2 Hz, 1H), 4.54 - 4.49 (m, 1H), 4.28 (s, 1H), 4.12 (m, J = 9.2, 6.1, 3.3 Hz, 1H), 4.06 (d, J = 9.1 Hz, 1H), 3.91 (s, 3H), 3.72 (p, J = 6.1 Hz, 2H), 3.68 - 3.64 (m, 3H), 3.58 (d, J = 11.8 Hz, 2H), 3.32 (s, 3H), 3.14 (s, 2H), 3.08 - 2.99 (m, 5H), 2.68 (t, J = 6.8 Hz, 2H), 2.16 - 2.09 (m, 1H), 1.99 (m, J = 16.9, 13.3, 5.7 Hz, 3H), 1.90 - 1.84 (m, 3H), 1.83 (q, J = 2.7 Hz, 1H), 1.81 - 1.77 (m, 2H), 1.47 (m, J = 14.8, 9.4, 4.7 Hz, 3H), 1.26 - 1.24 (m, 2H), 1.23 (s, 6H), 1.15 (s, 6H)

[0516] LCMS (ESI): [M+H] + = 888.86.

[0517] Example 11: Synthesis Method AR-T-11

[0518] Synthesis of AR-P-187

[0519] First Step: Intermediate-3

[0520] Intermediate-1 (25 g, 102.73 mmol, 1.0 eq.) was dissolved in dry toluene (300 mL) and the system was placed at 0 °C, after 10 minutes NaH (9.25 g, 231.15 mmol, 2.25 eq.) was added to the system and stirring was continued at 0 °C for 30 minutes, then intermediate-2 (15.53 g, 102.73 mmol, 1.0 eq.) was added to the reaction system, after 30 minutes the reaction system was slowly warmed to room temperature and stirring was continued for 30 minutes. After the completion of the reaction, the reaction was quenched with saturated NH4C1 solution (100 mL) under ice bath, extracted with ethyl acetate, washed with saturated brine, the organic phases were combined and dried over anhydrous sodium sulfate. The organic phase was concentrated and the crude product obtained was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1:1) to obtain compound intermediate-3 (26 g, 67.6%) as an oil.

[0521] 1 H NMR (600 MHz, DMSO-d6) δ 7.82 (d, J = 5.9 Hz, 1H), 7.64 (d, J = 8.6 Hz, 1H), 6.63 (d, J = 2.2 Hz, 1H), 6.53 (dd, J = 8.6, 2.2 Hz, 1H), 4.31 (s, 1H), 3.90 (s, 3H), 3.07 (d, J = 5.4 Hz, 1H), 1.40 (s, 9H) 1.32 (s, 6H), 1.11 (s, 6H).

[0522] LCMS (ESI) [M+H] + = 375.49.

[0523] Second step: compound intermediate-4

[0524] Compound intermediate-3 (44 g, 117.5 mmol) was dissolved in ethyl acetate (200 mL), hydrochloric acid-ethyl acetate solution (200 mL) was added, and the reaction system was stirred at room temperature for 2 h. After the completion of the reaction, the reaction liquid was directly concentrated under reduced pressure to obtain white solid compound intermediate-4 (35 g, 96%).

[0525] 1 H NMR (600 MHz, DMSO-d6) δ 7.82 (d, J = 5.9 Hz, 1H), 7.64 (d, J = 8.6 Hz, 1H), 6.63 (d, J = 2.2 Hz, 1H), 6.53 (dd, J = 8.6, 2.2 Hz, 1H), 4.31 (s, 1H), 3.90 (s, 3H), 3.07 (d, J = 5.4 Hz, 1H), 1.40 (s, 9H) 1.32 (s, 6H), 1.11 (s, 6H).

[0526] LCMS (ESI) [M+H] += 275.37.

[0527] Third Step: Compound Intermediate-7

[0528] Intermediate-5 (50 g, 265.14 mmol, 1.0 eq.), Intermediate-6 (46.44 g, 291.65 mmol, 1.1 eq.) and potassium carbonate (109.9 g, 795.41 mmol, 3.0 eq.) were dissolved in dry dimethyl sulfoxide (300 mL) and the reaction system was heated to 120 °C for 3 hours. After the reaction was completed, a saturated NH4Cl solution (300 mL) was added and stirred for 10 minutes, extracted with ethyl acetate, and the organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. The organic phase was concentrated to obtain a white solid product (75 g) which was directly used in the next step reaction.

[0529] The above obtained crude product was dissolved in a MeOH-THF-H2O (600 mL, 1:1:1) mixed solvent, sodium hydroxide (36.6 g, 915.18 mmol, 4.0 eq.) was slowly added and stirred at room temperature for 2 hours. After the reaction was completed, the pH was adjusted to 5-6 with 5% aqueous HCl solution, extracted with ethyl acetate, and the organic phase was combined and dried over anhydrous sodium sulfate. After concentration, the crude product was purified by C18 reverse phase column chromatography (water: acetonitrile (containing 1% trifluoroacetic acid) = 1:1) to obtain yellow solid compound Intermediate-7 (63.8 g, 88.9%).

[0530] 1 H NMR (400 MHz, DMSO-d6) δ 7.90-7.75 (m, 2H), 7.15 (d, J = 8.5 Hz, 1H), 4.11 (d, J = 6.4 Hz, 1H), 3.40 (dq, J = 12.1, 2.5, 2.1 Hz, 3H), 3.28 (s, 6H), 2.68-2.57 (m, 2H), 1.72 (tq, J = 10.3, 6.9, 5.3 Hz, 3H), 1.49-1.31 (m, 2H).

[0531] LCMS (ESI) [M+H] + = 314.28.

[0532] Fourth Step: Compound Intermediate-8

[0533] Compound intermediate-7 (22 g, 70.11 mmol, 1.0 eq.), intermediate-4 (28.85 g, 105.17 mmol, 1.5 eq.) and HATU (53.42 g, 140.23 mmol, 2.0 eq.) were dissolved in dry N,N-dimethylformamide (200 mL), then N,N-diisopropylethylamine (DIEA, 45.32 g, 350.57 mmol, 5.0 eq.) was added and stirred at room temperature for 2 hours. After the reaction was completed, water was added and extracted with ethyl acetate, the organic phase was combined, concentrated and the crude product obtained was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1:1) to obtain compound intermediate-8 (18.1 g, 45.28%) as a yellow solid.

[0534] 1 H NMR (400 MHz, DMSO-d6) δ 7.95 (s, 1H), 7.89 (d, J = 2.1 Hz, 1H), 7.84 - 7.75 (m, 2H), 7.64 (d, J = 8.6 Hz, 1H), 7.17 (d, J = 8.4 Hz, 1H), 6.63 (d, J = 2.2 Hz, 1H), 6.53 (dd, J = 8.7, 2.2 Hz, 1H), 5.75 (s, 1H), 4.26 (s, 1H), 4.13 (d, J = 6.3 Hz, 1H), 4.06 (d, J = 7.3 Hz, 1H), 3.90 (s, 3H), 3.38 (d, J = 5.4 Hz, 1H), 3.28 (s, 6H), 2.69 - 2.58 (m, 2H), 1.74 (d, J = 11.3 Hz, 3H), 1.41 (qd, J = 13.2, 12.6, 4.1 Hz, 2H), 1.22 (s, 6H), 1.14 (s, 6H).

[0535] LCMS (ESI) [M+H] + = 570.38.

[0536] Fifth step: Compound intermediate-9

[0537] Compound intermediate-8 (35 g, 61.39 mmol) was dissolved in formic acid (100 mL) and stirred at room temperature for 2 hours. After the reaction was completed, the reaction solution was directly concentrated to obtain blue solid product intermediate-9 (38 g).

[0538] 1H NMR (400 MHz, DMSO-d6) δ 9.67 (s, 1H), 7.90 (d, J = 2.1 Hz, 1H), 7.86 - 7.76 (m, 2H), 7.65 (d, J = 8.6 Hz, 1H), 7.21 (d, J = 8.4 Hz, 1H), 6.64 (d, J = 2.2 Hz, 1H), 6.54 (dd, J = 8.7, 2.2 Hz, 1H), 4.27 (s, 1H), 4.06 (d, J = 9.2 Hz, 1H), 3.91 (s, 3H), 3.30 (d, J = 9.7 Hz, 2H), 2.82 (t, J = 10.5 Hz, 2H), 2.04 - 1.94 (m, 2H), 1.75 - 1.61 (m, 2H), 1.23 (s, 6H), 1.15 (s, 6H).

[0539] LCMS (ESI) [M+H+18] + = 542.38.

[0540] Sixth Step: Compound AR-P-187

[0541] Compound Intermediate-9 (7 g, 15.8 mmol, 1.0 eq.) and Intermediate-10 (11.6 g, 15.8 mmol, 1.0 eq.) were dissolved in dimethyl sulfoxide (50 mL), sodium triacetoxyborohydride (14.07 g, 66.38 mmol, 3.0 eq.) was added and stirred at room temperature for 1 h. After the reaction was completed, the reaction solution was directly purified by C18 reverse phase column chromatography (water: acetonitrile (containing 1‰ trifluoroacetic acid) = 1:1) to obtain white solid compound AR-P-187 (9.8 g, 53.72%).

[0542] 1H NMR (400 MHz, Methanol-d4) δ 8.45 (s, 2H), 7.69 - 7.67 (d, J = 8.8 Hz, 1H), 7.09 - 7.01 (m, 2H), 6.98 (d, J = 2.2 Hz, 1H), 6.93 - 6.88 (m, 2H), 4.57 (t, J = 9.8 Hz, 1H), 4.22 - 4.13 (m, 3H), 4.06 - 3.88 (m, 5H), 3.83 - 3.81 (t, J = 6.8 Hz, 2H), 3.73 - 3.71 (d, J = 11.8 Hz, 1H), 3.61 - 3.41 (m, 6H), 3.25 - 3.15 (m, 6H), 2.81 (t, J = 6.7 Hz, 2H), 2.43 (dd, J = 12.9, 7.6 Hz, 1H), 2.29 (m, 2H), 1.99 - 1.67 (m, 6H), 1.56 (m, 2H), 1.41 - 1.37 (m, 2H), 1.33 - 1.32 (d, J = 6.1 Hz, 3H).

[0543] LCMS (ESI) [M / 2 + H] = 421.6. + = 421.6.

[0544] The synthesis of the compounds of Table A was carried out according to the above Preparation, with the difference that the conventional groups were replaced.

[0545] Table A:

[0546] Degrading activity of AR protein in LNCaP cells

[0547] AR-positive human prostate cancer cells LNCaP FGC (cell source: ATCC) were cultured in RPMI 1640 (ATCC catalog number 30-2001) containing 10% FBS (Hyclone catalog number SH30406.05) at 1.5 x 10 5The cells were placed in a carbon dioxide incubator (ESCO) overnight, and then 1 μL / well of the prepared compound solution of different concentrations and the positive control sample ARV-766 (source: Anergen) solution were added to the six-well microculture plates (Thermo catalog number 140675) to make the final concentration of the compound and the positive control sample reach 100 nM and 10 nM, and a corresponding DMSO solvent control was set up, and incubated for 8 h. After 8 h of incubation, the culture medium was removed, the cells were washed with PBS, and then RIPA lysis solution containing 1% Protease Inhibitor Cocktail was added, and after lysis and centrifugation, total protein extract was obtained, and the protein concentration in the extract was detected by the BCA method. SDS-PAGE was used for protein electrophoresis, and then the proteins were transferred to a PVDF (Millipore Sigma catalog number PSRP010R5) membrane at a constant voltage of 100 V for 60 min, and the PVDF membrane was placed in a 5% milk 1xTBST solution and blocked at room temperature for 1 h. The primary antibody solution (Anti-Androgen receptor, Cell Signaling Technology catalog number: 5153S; 1:2000 dilution) was prepared, and incubated overnight at 4°C. Discard the primary antibody solution, and wash the PVDF membrane with 1xTBST for 5 min each time, for a total of three times. Prepare the secondary antibody solution (Thermo catalog number SA5-35571; 1:7500 dilution), and incubate the secondary antibody dilution at room temperature for 1 h. Discard the secondary antibody solution, and wash the PVDF membrane with 1xTBST for 5 min each time, for a total of three times. Western membrane imaging was performed using a dual-color infrared laser imaging system (Licor catalog number Odyssey CLX). The bands were analyzed for gray scale using the software Image Studio. The GAPDH protein band was detected simultaneously as an internal reference for each sample. The AR protein degradation rate of the compound and the positive control sample was calculated according to the gray scale of the protein band.

[0548] Table 1 The degradation rate of the disclosed compound on AR protein in LNCaP cells

[0549] Note: "-" means no test result.

[0550] Conclusion: The disclosed compound has a significant degradation effect on AR protein in LNCAP cells.

[0551] AR positive human prostate cancer cells VCaP (cell source: ATCC) were seeded at 3 x 10 5 / well in a six-well microplate (Thermo Cat# 140675). After incubation in a carbon dioxide incubator (ESCO) overnight, different concentrations of the compounds of the present disclosure and the positive control ARV-766 (purchased from AnorMed) were added to the cells at a volume of 1 μL / well, so that the final concentration of the compounds and the positive control was 5 nM and 50 nM, respectively, with the corresponding DMSO vehicle control. After 8 h of incubation, the medium was removed, and the cells were washed with PBS, and then RIPA lysis buffer containing 1% Protease Inhibitor Cocktail was added. After lysis and centrifugation, the total protein extract was obtained, and the protein concentration in the extract was determined by the BCA method. SDS-PAGE was used for protein electrophoresis, and then the proteins were transferred to a PVDF (Millipore Sigma Cat# PSRP010R5) membrane at a constant voltage of 100 V for 60 min. The PVDF membrane was placed in a 5% milk 1 x TBST solution and blocked at room temperature for 1 h. The primary antibody solution (Anti-Androgen receptor, Cell Signaling Technology Cat# 5153S; 1:2000 dilution) was prepared and incubated at 4°C overnight. The primary antibody solution was discarded, and the PVDF membrane was washed with 1 x TBST for 5 min each time, for a total of three times. The secondary antibody solution (Thermo Cat# SA5-35571; 1:7500 dilution) was prepared and incubated at room temperature for 1 h. The secondary antibody solution was discarded, and the PVDF membrane was washed with 1 x TBST for 5 min each time, for a total of three times. Western membrane imaging was performed using a dual-color infrared laser imaging system (Licor Cat# Odyssey CLX). The bands were analyzed for gray scale using the software Image Studio. The GAPDH protein band was detected simultaneously as an internal control for each sample. The AR protein degradation rate of the compounds and the positive control was calculated according to the gray scale of the protein band. The AR protein degradation rates of the compounds of the present disclosure in VCaP cells are shown in Table 2 below.

[0552] Table 2 AR protein degradation rates of the compounds of the present disclosure in VCaP cells

[0553] Note: “-” indicates no test results.

[0554] Conclusion: The compound disclosed in the application has obvious degradation effect on AR protein in VCaP cells.

[0555] Test Example 3 Inhibitory activity on proliferation of LNCaP cells

[0556] LNCaP FGC cells (ATCC, CLR-1740) were cultured with complete RPMI 1640 medium (ATCC, 30-2001) containing 10% fetal bovine serum (Hyclone, SH30406.05). LNCaP FGC cells were seeded in a 96-well plate at a density of 5,000 cells per well in 100 μL of cell suspension using RPMI 1640 medium containing 10% fetal bovine serum, and placed in a 37°C, 5% CO2 cell incubator overnight.

[0557] 1) 100 μL / well of medium containing different concentrations of the compound to be tested were transferred to a 96-well cell culture plate, and the compound was diluted 5-fold to 9 concentration gradients (90.0 μM, 30.0 μM, 10.0 μM, 3.33 μM, 1.11 μM, 0.370 μM, 0.123 μM, 0.0411 μM, 0.0137 μM), and 200 μL of RPMI 1640 medium containing 10% fetal bovine serum was added as a blank control, and placed in a 37°C, 5% CO2 cell incubator for 96 h. The 96-well cell culture plate was removed, 1 / 10 volume of WST-8 (Beytime, C0040) reagent was added to each well, and the absorbance at 450 nm was detected using an enzyme marker (TECAN, F50). The 50% proliferation inhibition concentration (IC 50 value) was calculated according to the concentration and absorbance values of the compound by Logistic regression using Graphpad Prism software.

[0558] 2) Inhibitory activity on proliferation in the presence of R1881: The compound was diluted 5-fold to 9 concentration gradients (90.0 μM, 30.0 μM, 10.0 μM, 3.33 μM, 1.11 μM, 0.370 μM, 0.123 μM, 0.0411 μM, 0.0137 μM), and 100 μL of CTG (Promega, G7572) was added to each well of a 96-well cell culture plate containing different concentrations of the compound with a final concentration of 0.1 nM R1881 (ABMole, M8128), and placed in a 37°C, 5% CO2 cell incubator for 96 h. The 96-well cell culture plate was removed, 100 μL of CTG (Promega, G7572) was added to each well, and the plate was incubated at room temperature for 15 min. The luminescence signal was recorded using an enzyme marker (TECAN, F50). The 50% proliferation inhibition concentration (IC 50The IC50 values of the compounds of the present application for inhibiting the proliferation of LNCaP cells are shown in Tables 3-4 below. 50 The IC50 values of the compounds of the present application for inhibiting the proliferation of LNCaP cells are shown in Tables 3-4 below.

[0559] The IC50 values of the compounds of the present application for inhibiting the proliferation of LNCaP cells are shown in Tables 3-4 below. 50 The IC50 values of the compounds of the present application for inhibiting the proliferation of LNCaP cells are shown in Tables 3-4 below.

[0560] The IC50 values of the compounds of the present application for inhibiting the proliferation of LNCaP cells are shown in Tables 3-4 below. 50 The IC50 values of the compounds of the present application for inhibiting the proliferation of LNCaP cells are shown in Tables 3-4 below.

[0561] Conclusion: The compounds of the present application have obvious inhibitory effect on the proliferation of LNCaP cells.

[0562] Test Example 4 Inhibitory activity on the proliferation of VCaP cells

[0563] VCaP cells (ATCC, CRL-2876) were cultured with DMEM (Gibco, 11995-065) complete medium containing 10% fetal bovine serum (Hyclone, SH30406.05). VCaP cells were seeded in 96-well plates at a density of 15,000 cells per well in 100 μL of cell suspension using DMEM medium containing 10% fetal bovine serum, and placed in a 37°C, 5% CO2 cell incubator overnight.

[0564] 1) 100 μL / well of medium containing different concentrations of the compound of the present application to be tested were transferred to a 96-well cell culture plate, and the compound was diluted 5-fold to 9 concentration gradients (50.0 μM, 10.0 μM, 2.00 μM, 0.400 μM, 0.080 μM, 0.0160 μM, 0.00320 μM, 0.000640 μM, 0.0001280 μM), and 200 μL of DMEM medium containing 10% fetal bovine serum was added as a blank control, and placed in a 37°C, 5% CO2 cell incubator for 168 h. The 96-well cell culture plate was removed, 1 / 10 volume of WST-8 (Beytime, C0040) reagent was added to each well, and the absorbance at 450 nm was detected using an enzyme marker (TECAN, F50), and the 50% proliferation inhibition concentration (IC50) was calculated according to the concentration of the compound and the absorbance value by Logistic regression using Graphpad Prism software. 50 The IC50 values of the compounds of the present application for inhibiting the proliferation of LNCaP cells are shown in Tables 3-4 below.

[0565] 2) Inhibitory activity of proliferation in the presence of R1881: the compound is diluted 5 times to 9 concentration gradients (50.0 μM, 10.0 μM, 2.00 μM, 0.400 μM, 0.080 μM, 0.0160 μM, 0.00320 μM, 0.000640 μM, 0.0001280 μM), and the compound containing a final concentration of 0.1 nM R1881 (ABMole, M8128) is transferred to a 96-well cell culture plate, and is cultured at 37°C in a cell incubator with 5% CO2 for 120 h. The 96-well cell culture plate is removed, 1 / 10 volume of WST-8 (Beytime, C0040) reagent is added to each well, and the absorbance at 450 nm is detected using an enzyme label meter (TECAN, F50). The 50% proliferation inhibition concentration (IC 50 value) is calculated according to the concentration of the compound and the absorbance value by Logistic regression using Graphpad Prism software.

[0566] The consistent IC 50 values of the compounds disclosed in the present application on VCaP cell proliferation are shown in Tables 5-6.

[0567] Table 5 IC 50 values of the compounds disclosed in the present application on VCaP cell proliferation

[0568] Table 6 IC 50 values of the compounds disclosed in the present application on VCaP cell proliferation in the presence of R1881

[0569] Conclusion: The compounds of the present application have obvious inhibitory effect on the proliferation of VCaP cells.

[0570] Test Example 5 Pharmacokinetic study

[0571] 1) Test method for overall PK of mice

[0572] 1) After oral administration by gavage of mice (this test example or expression is oral administration), blood is taken from the retro-orbital plexus at 15 min, 30 min, 1 h, 2 h, 4 h, 7 h, 24 h, and 48 h, respectively. After intravenous administration, blood is taken from the retro-orbital plexus at 5 min, 15 min, 30 min, 1 h, 2 h, 4 h, 7 h, 24 h, and 48 h, respectively. The whole blood is collected into an anticoagulant tube containing EDTA.

[0573] 2) Within 1 hour after the whole blood collection is completed, the supernatant is centrifuged, and centrifuged at 4°C, 4000 rpm for 10 min. The supernatant plasma sample is frozen at -80°C for standby.

[0574] 3) Analysis before taking sample plasma and blank plasma, thawing on ice or 4℃ refrigerator.

[0575] 4) Preparation of standard curve sample: the test compound was diluted with DMSO to the required concentration, 5 μL of the compound solution was added to 45 μL of mouse blank plasma, 200 μL of internal standard acetonitrile (IS, 50 nM labetalol and 500 nM terfenadine) was added to precipitate the protein, and centrifugation was performed at 3200 rpm for 40 min. Eight to ten concentration gradients were set for the standard curve.

[0576] 5) The quality control sample was prepared according to the preparation method of the standard curve, and the lower limit of quantification and high, medium and low four quality control samples were set. Each concentration of the quality control sample was in triplicate.

[0577] 6) 50 μL of sample plasma at different times was taken, and 200 μL of internal standard acetonitrile was added to precipitate the protein.

[0578] 7) After centrifugation of the standard curve sample, the quality control sample and the plasma sample at different time points, 100L of supernatant was diluted with water at a ratio of 1:1, and then subjected to LC-MS / MS quantitative analysis. The blood drug concentration at different times was calculated by Excel. The PK parameters in the following table were calculated by Phoenix WinNonlin tool, and the specific experimental results are shown in Tables 7-8.

[0579] Table 7 Pharmacokinetic parameters of an example compound molecule in mice (i.v.)

[0580] Table 8 Pharmacokinetic parameters of an example compound molecule in mice (p.o.)

[0581] Note: "-" means not applicable; i.v. is intravenous administration; p.o. is oral administration; Cl obs is systemic clearance, V ss_obs is steady-state distribution volume, C0is the extrapolated zero-time blood drug concentration, T max is the time to peak, C max is the peak concentration, AUC last is the area under the concentration-time curve from zero time to the last quantifiable concentration, AUC INF_obs is the area under the curve from time zero to infinity, F( 0-last ) is the bioavailability.

[0582] Conclusion: The compound of the present application has a long half-life, and the half-life of some compounds is better than that of the positive control drug. The compound of the present application has good oral bioavailability in mice.

[0583] 2, Comprehensive PK test method of rats

[0584] 1) After oral administration (test example or expression as oral administration) of the compound to the rats without fasting, blood was collected from the retro-orbital plexus at 15 min, 30 min, 1 h, 2 h, 4 h, 7 h, 24 h and 48 h, respectively. After intravenous administration, blood was collected from the retro-orbital plexus at 5 min, 15 min, 30 min, 1 h, 2 h, 4 h, 7 h, 24 h and 48 h, respectively. The whole blood was collected into an anticoagulation tube containing EDTA.

[0585] 2) Within 1 h after the whole blood collection, the supernatant was obtained by centrifugation at 4℃ and 4000 rpm for 10 min. The supernatant, i.e., the plasma sample, was stored in a freezer at -80℃ for later use.

[0586] 3) Before analysis, the sample plasma and blank plasma were taken out and thawed on ice or in a refrigerator at 4℃.

[0587] 4) The compound to be tested was diluted with DMSO to a desired concentration, 5 μL of the compound solution was added to 45 μL of blank plasma of the rat, 200 μL of an internal standard acetonitrile (IS, 50 nM labetalol and 500 nM terfenadine) was added to precipitate the protein, and centrifugation was performed at 16000 rpm for 20 min. An 8-10 concentration gradient was set for the standard curve.

[0588] 5) The quality control samples were prepared according to the preparation method of the standard curve, and a lower limit of quantification and four high, medium and low quality control samples were set. Each concentration of the quality control sample was in triplicate.

[0589] 6) 50 μL of the sample plasma at different time points was taken, and 200 μL of the internal standard acetonitrile was added to precipitate the protein.

[0590] 7) After centrifugation of the standard curve sample, the quality control sample and the plasma sample at different time points, 100 L of the supernatant was diluted with water at a ratio of 1:1, and then subjected to LC-MS / MS quantitative analysis. The blood drug concentration of the compound at different time points was calculated by using Excel. The PK parameters in the following table were calculated by using Phoenix WinNonlin tool. The specific experimental results are shown in Table 9.

[0591] Table 9: Pharmacokinetic parameters of the example compound molecules in rats

[0592] Conclusion: The compound of the present application has a long half-life, and the half-life of some of the compounds is better than that of the positive control drug. The compound of the present application has good oral bioavailability in rats.

[0593] 3. Test method for comprehensive PK of beagle dogs

[0594] 1) Experimental animals

[0595] Species / strain: beagle. Number of animals and gender: 6 in total, randomly divided into 2 groups according to weight, 3 in each group, male.

[0596] Animal weight: about 6-8 kg.

[0597] Animal source: Xingnuogu (Jiangsu) Biotechnology Co., Ltd.

[0598] 2) Administration method

[0599] Preparation of test substances: i.v.: DMSO: PEG200: physiological saline = 10:70:20; p.o.: PDO: 0.5% CMC-Na (containing 0.2% SDS) = 20:80.

[0600] Administration route and frequency: intravenous injection and oral gavage; single administration.

[0601] Administration volume: intravenous administration (i.v.): 2 mL / kg; oral administration (p.o.): 5 mL / kg.

[0602] 3) Sample collection

[0603] Sample collection time points: i.v. group: before administration and 5 min, 15 min, 30 min, 1 h, 2 h, 4 h, 6 h, 8 h, 24 h, 48 h, 72 h, 96 h after administration; p.o. group: before administration and 15 min, 30 min, 1 h, 2 h, 4 h, 6 h, 8 h, 24 h, 48 h, 72 h, 96 h after administration.

[0604] The PK parameters in the following table were calculated by detecting according to the steps in the above mouse comprehensive PK test part

[0605] Table 10 shows the comprehensive PK pharmacokinetic parameters of beagle dogs of example compound molecules and positive molecules

[0606] Conclusion: The compound of the present application has a long half-life, and the half-life of some compounds is better than that of the positive control drug. And the compound of the present application has good oral bioavailability in beagle dogs.

[0607] Test Example 6 Animal efficacy experiment

[0608] 1. Tumor inhibition effect of LNCaP xenotransplantation model

[0609] 7-week-old NOD SCID male mice (Sibeifubio Technology Co., Ltd.) were subcutaneously injected with 200 μL of LNCaP cells (containing 50% ABW high-concentration matrix glue, cat#: 082724) on the right side of the back, and the number of injected cells was 1×10 7cells / animal. The tumor growth was observed regularly, and when the tumor grew to an average volume of 200 mm3, the mice were randomly divided into groups, and the drug administration was started. The drug was administered once a day for 21 days (qd x 21), and the oral administration volume of each animal was 10 mL / kg, and the administration solvent was DMSO:PEG200:30% SEB-β-CD = 5:20:75. In the efficacy experiment, the tumor volume was measured three times a week, and the tumor volume T = (long diameter x short diameter2) / 2, and all the measurements were in millimeters. The body weight of the mice was recorded three times a week. 3 The drug administration was started when the tumor grew to an average volume of 200 mm3. The drug was administered once a day for 21 days (qd x 21), and the oral administration volume of each animal was 10 mL / kg, and the administration solvent was DMSO:PEG200:30% SEB-β-CD = 5:20:75. In the efficacy experiment, the tumor volume was measured three times a week, and the tumor volume T = (long diameter x short diameter2) / 2, and all the measurements were in millimeters. The body weight of the mice was recorded three times a week.

[0610] The tumor growth inhibition (TGI) was calculated as follows, TGI% = [1-(T i -T0) / (C i -C0)]x100, T i is the average tumor volume of the treatment group on the ith day, T0 is the average tumor volume of the treatment group when the grouping is performed, C i is the average tumor volume of the vehicle group on the ith day, C0 is the average tumor volume of the vehicle group when the grouping is performed, and the tumor volume unit is mm 3 After the 21st day of administration, the whole blood was taken from the orbit at 1, 2, 4, 6, 8, 24 h, respectively, to test the efficacy endpoint PK, and the tumor was taken to test the drug concentration in the tumor. The AR protein degradation level (WB) in the tumor of the LNCaP tumor-bearing mice was tested at 6 h and 24 h after the last administration.

[0611] Table 11 Tumor inhibition rate, AR protein degradation level in the tumor, drug concentration in the plasma and tumor after 24 h of the positive molecules and drug molecules

[0612] Conclusion: The compound of the present application has the effect of inhibiting tumor growth, and the effect of inhibiting tumor growth is better than that of the positive drug ARV-766 under the same dose. The compound of the present application has good safety, and no animal death event occurs in the process of the efficacy experiment, and the animals in the efficacy group have no abnormal reaction compared with the control group, and the low-dose group and the high-dose group have a good dose relationship.

[0613] The present application has been described by the above examples and test examples, but it should be understood that the above examples and test examples are only for the purpose of illustration and description, and are not intended to limit the present application to the scope of the described examples and test examples. In addition, those skilled in the art can understand that the present application is not limited to the above examples and test examples, and more various modifications and modifications can be made according to the teachings of the present application, which all fall within the scope of the present application. The protection scope of the present application is defined by the attached claims and their equivalent scope.

Claims

1. A compound of Formula 1, or an isomer, isotopic derivative, polymorph, prodrug, pharmaceutically acceptable salt, or solvate thereof: PTM-L-CLM (Formula 1); wherein: PTM is an androgen receptor binding moiety; and q is an integer greater than or equal to 1; wherein: or or or n2, n3, n4, n5, n6, and n7 are each independently at each occurrence 0, 1, 2, and 3; n8 is each independently at each occurrence 1, 2, and 3; B1, B2, B3, and B6 are each independently selected from the group consisting of NRa, O, and S; B4 and B5 are each independently selected from the group consisting of CH, N, and C-Ra; B1 and B2 are not both O; B3 is not O when B3 is attached to a ring that shares B4 and B5 with the ring to which C1 is attached; B1, B2, B3, and B6 are at least one selected from the group consisting of NRa, O, and S when the ring to which B3 is attached and the ring to which C1 is attached share B4 and B5; and represents a point of attachment; and 2. A compound of Formula 1-1, or an isomer, isotopic derivative, polymorph, prodrug, pharmaceutically acceptable salt, or solvate thereof: PTM-L-CLM (Formula 1-1); wherein: PTM is an androgen receptor binding moiety; and q is an integer greater than or equal to 1; wherein: or or or n2, n3, n4, n5, n6, and n7 are each independently at each occurrence 0, 1, 2, and 3; n8 is each independently at each occurrence 1, 2, and 3; B1, B2, B3, and B6 are each independently selected from the group consisting of NRa, O, and S; B4 and B5 are each independently selected from the group consisting of CH, N, and C-Ra; B1 and B2 are not both O; B3 is not O when B3 is attached to a ring that shares B4 and B5 with the ring to which C1 is attached; B1, B2, B3, and B6 are at least one selected from the group consisting of NRa, O, and S when the ring to which B3 is attached and the ring to which C1 is attached share B4 and B5; and represents a point of attachment.

3. The compound of claim 1 or 2, wherein: q is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20; preferably, q is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; and / or A2 and A4 are each independently C(O); and / or n2+n3+n4=0, n2+n3+n4=1, or n2+n3+n4=2; and / or n5+n6=2 or n5+n6=3; and / or n7+n8=2, n7+n8=3, n7+n8=4, or n7+n8=5. wherein Preferably: C3 is independently at each occurrence N; n2, n3, n4, n5, n6, and n7 are each independently at each occurrence 0, 1, 2, and 3, n8 is selected from 1, 2, and 3; preferably, n2+n3+n4=0, n2+n3+n4=1, or n2+n3+n4=2; preferably, n5+n6=2 or n5+n6=3. L is a bond or -(B L ) q -; B L at each occurrence, the same or different, and each independently selected from: CR L1 R L2 , O, S, S(O), SO2, NR L3 , SO2NR L3 , S(O)NR L3 , C(O)NR L3 , NR L3 C(O)NR L4 , NR L3 SO2NR L4 , C(O), CR L1 =CR L2 , C≡C, SiR L1 R L2 , P(O)R L1 , P(O)OR L1 , NR L3 C(=NCN)NR L4 , NR L3 C(=NCN), NR L3 C(=CNO2)NR L4 , cycloalkylene, heterocyclylene, bridged cycloalkylene, spiro cycloalkylene, arylene, and heteroarylene, wherein the cycloalkylene, heterocyclylene, bridged cycloalkylene, spiro cycloalkylene, arylene, and heteroarylene are optionally substituted with 0, 1, 2, 3, 4, 5, or 6 R L1 and / or R L2 groups; R L1 , R L2 , R L3 and R L4 are each independently at each occurrence selected from the group consisting of oxo (=0), H, halogen, C 1-8 alkyl, -O-C 1-8 alkyl, -S-C 1-8 alkyl, -NH-C 1-8 alkyl, N(C 1-8 alkyl)2, C 3-11 cycloalkyl, C 6-10 aryl, C 5-10 heteroaryl, C 3-11 heterocyclyl, -O-C 3-8 cycloalkyl, -O-C 3-11 heterocyclyl, -O-C 6-10 aryl, -O-C 5-10 heteroaryl, -S-C 3-8 cycloalkyl, -NH-C 3-8 cycloalkyl, -N(C 3-8 cycloalkyl)2, -N(C 3-8 cycloalkyl)(C 1-8 alkyl), -NH-C 3-8 heterocyclyl, -N(C 3-8 heterocyclyl)2, -N(C 3-8 heterocyclyl)(C 1-8 alkyl), -NH-C 6-10 aryl, -N(C 6-10 aryl)(C 1-8 alkyl), -NH-C 5-10 heteroaryl, -N(C 5-10 heteroaryl)(C 1-8 alkyl), -OH, -NH2, -SH, SO2 P(O)(O-C 1-8 alkyl)(C 1-8 alkyl), -P(O)(O-C 1-8 alkyl)2, -C≡C-C 1-8 alkyl, -C≡CH, -CH=CH-(C 1-8 alkyl), -C(C 1-8 alkyl)=CH-(C 1-8 alkyl), -C(C 1-8 alkyl)=C(C 1-8 alkyl)2, -Si(OH)3, -Si(C 1-8 alkyl)3, -Si(OH)(C 1-8 alkyl)2, -C(O)-C 1-8 alkyl, -C(O)2H, -CN, -NO2, -SO2, -SF5, -SO2NH-C 1-8 Alkyl group, -SO2N(C) 1- 8-alkyl)2、-S(O)NH-C 1-8 Alkyl, -S(O)N(C) 1-8 Alkyl)2、-C(O)NH-C 1-8 Alkyl, -C(O)N(C) 1-8 Alkyl)2, -N(C 1-8 alkyl)C(O)NH(C 1- 8-alkyl), -N(C) 1-8 alkyl)C(O)N(C 1-8 alkyl)2、-NHC(O)NH(C 1-8 Alkyl), -NHC(O)N(C 1-8 Alkyl)2, -NHC(O)NH2, -N(C 1-8 alkyl)SO2NH(C 1-8 alkyl), -N(C) 1-8 Alkyl)SO2N(C 1-8 Alkyl)2、-NHSO2NH(C 1-8 Alkyl), -NHSO2 N(C 1-8 Alkyl)2 and -NHSO2NH2, optionally, the C 1-8 Alkyl, C 3-11 cycloalkyl, C 3-11 Heterocyclic group, C 6-10 Aryl and C 5-10 Each heteroaryl group is independently selected from halogens, alkyl groups, heteroalkyl groups, alkenyl groups, alkoxy groups, hydroxyl groups, haloalkyl groups, hydroxyalkyl groups, cyano groups, amino groups, nitro groups, cycloalkyl groups, heterocyclic groups, halocycloalkyl groups, haloheteroalkyl groups, alkyl-NH groups, and C groups. 6-10 Aryl, C 5-10 heteroaryl, halogenated C 6-10 Aryl and halogenated C 5-10 One or more substituents in the heteroaryl group are substituted; F6 is independently at each occurrence a single bond, -NH-, -N(CH3)-, -O-, -C(=O)-, -O-C(=O)-, and -NH-C(=O)-; preferably, F6 is independently at each occurrence a single bond, -O-, or -N(CH3)-, more preferably -O-; and / or and / or The CLM is selected from: and / or A1is independently selected for each occurrence from CR a and N; A2and A4are each independently selected for each occurrence from C(O) and C(R a )2; A3each occurrence is independently NR a ; A5and A6are each independently for each occurrence selected from a single bond, NR a and C(R a )2; A7is independently selected at each occurrence from C(O) and C(R a )2; R1and R2together form, when CLM is of Formula 2, Formula 4, Formula 5, or Formula 7 when the CLM is of formula 3, R1and R2together form R3, R4and R5are each independently at each occurrence selected from the group consisting of H, deuterium atom, halogen, C 1-6 alkyl, C 1-6 deuteroalkyl, carboxyl, C 1-6 heteroalkyl, alkenyl, alkynyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, hydroxyl, C 1-6 hydroxyalkyl, nitro, cyano, amino, -C(O)NH-C 1-6 alkyl, -C(O)N(C 1-6 alkyl)2, -N(C 1-6 alkyl)C(O)NH(C 1-6 alkyl), -N(C 1-6 alkyl)C(O)N(C 1- 6alkyl)2, -NHC(O)NH(C 1-6 alkyl), -NHC(O)N(C 1-6 alkyl)2, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein said C 1-6 alkyl, C 1-6 deuteroalkyl, C 1-6 heteroalkyl, alkenyl, alkynyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally substituted with one or more substituents selected from the group consisting of halogen, alkyl, heteroalkyl, alkoxy, haloalkyl, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, alkenyl, alkynyl, alkyl-NH, -C(O)NH-C 1-6 alkyl, -C(O)N(C 1-6 alkyl)2, -N(C 1-6 alkyl)C(O)NH(C 1-6 alkyl), -N(C 1- 6alkyl)C(O)N(C 1-6 alkyl)2, -NHC(O)NH(C 1-6 alkyl), -NHC(O)N(C 1-6 alkyl)2, aryl and heteroaryl; preferably, R3, R4and R5are each independently selected from the group consisting of H, deuterium atom, F, Cl, Br, I, C 1-6 alkyl, C 1-6 deuteroalkyl, C 1-6 heteroalkyl, alkenyl, alkynyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, hydroxyl, C 1-6 Hydroxyl alkyl and amino; more preferably, R3, R4 and R5 are each independently selected from H, deuterium, F, Cl, Br, I, C. 1-3 Alkyl, C 1-3 Deuterated alkyl, alkenyl, alkynyl, C 1-3 Alkoxy, C 1-3 Haloalkyl, C 1-3 Halogenated alkoxy, hydroxyl, C 1-3 Hydroxyalkyl and amino; and when CLM is formula 7, R3 and R4 are not H; or a single bond. R2and R3together form, when CLM is of formula 2, formula 4 or formula 5 when the CLM is of formula 3, R2and R3together form R1, R4and R5are each independently at each occurrence selected from the group consisting of H, a deuterium atom, halogen, C 1-6 alkyl, C 1-6 deuteroalkyl, carboxyl, C 1-6 heteroalkyl, alkenyl, alkynyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, hydroxyl, C 1-6 hydroxyalkyl, nitro, cyano, amino, C 1-6 alkyl-NH, C 1-6 alkyl-C(O), C 1-6 alkyloxyl C(O), C 1-6 alkyl-NH-C(O), cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein the C 1-6 alkyl, C 1-6 deuteroalkyl, C 1-6 heteroalkyl, alkenyl, alkynyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl are each independently optionally substituted with one or more substituents selected from the group consisting of halogen, alkyl, heteroalkyl, alkoxy, haloalkyl, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, alkenyl, alkynyl, alkyl-NH, -C(O)NH-C 1-6 alkyl, -C(O)N(C 1- 6alkyl)2, -N(C 1-6 alkyl)C(O)NH(C 1-6 alkyl), -N(C 1-6 alkyl)C(O)N(C 1-6 alkyl)2, -NHC(O)NH(C 1-6 alkyl), -NHC(O)N(C 1-6 alkyl)2, aryl, and heteroaryl; preferably, R1, R4and R5are each independently selected from the group consisting of H, a deuterium atom, F, Cl, Br, I, C 1-6 alkyl, C 1-6 deuteroalkyl, C 1-6 heteroalkyl, alkenyl, alkynyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, hydroxyl, C 1-6 hydroxyalkyl and amino; more preferably, R1, R4and R5are each independently selected from the group consisting of H, a deuterium atom, F, Cl, Br, I, C 1-3 alkyl, C 1-3 deuteroalkyl, alkenyl, alkynyl, C 1-3 alkoxy, C 1-3 haloalkyl, C 1-3 haloalkoxy, hydroxy, C 1-3 hydroxyalkyl and amino; h1, h2, h3, h4, h5, and h6 are each independently 0, 1, or 2; and / or when the CLM is of formula 2, R3and R4together form when the CLM is of formula 3, R3and R4together form R1, R2, and R5are each independently at each occurrence selected from the group consisting of H, a deuterium atom, halogen, C 1-6 alkyl, C 1-6 deuteroalkyl, carboxyl, C 1-6 heteroalkyl, alkenyl, alkynyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, hydroxyl, C 1-6 hydroxyalkyl, nitro, cyano, amino, C 1-6 alkyl-NH, C 1-6 alkylC(O), C 1-6 alkyloxylC(O), C 1-6 alkyl-NH-C(O), cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein the C 1-6 alkyl, C 1-6 deuteroalkyl, C 1-6 heteroalkyl, alkenyl, alkynyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl are each independently optionally substituted with one or more substituents selected from the group consisting of halogen, alkyl, heteroalkyl, alkoxy, haloalkyl, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, alkenyl, alkynyl, alkyl-NH, -C(O)NH-C 1-6 alkyl, -C(O)N(C 1-6 alkyl)2, -N(C 1-6 alkyl)C(O)NH(C 1- 6alkyl), -N(C 1-6 alkyl)C(O)N(C 1-6 alkyl)2, -NHC(O)NH(C 1-6 alkyl), -NHC(O)N(C 1-6 alkyl)2, aryl, and heteroaryl; preferably, R1, R2, and R5are each independently selected from the group consisting of H, a deuterium atom, F, Cl, Br, I, C 1-6 alkyl, C 1-6 deuteroalkyl, C 1-6 heteroalkyl, alkenyl, alkynyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, hydroxyl, C 1-6 hydroxyalkyl, and amino; more preferably, R1, R2, and R5are each independently selected from the group consisting of H, a deuterium atom, F, Cl, Br, I, C 1-3 alkyl, C 1-3 deuteroalkyl, alkenyl, alkynyl, C 1-3 alkoxy, C 1-3 haloalkyl, C 1-3 haloalkoxy, hydroxy, C 1-3 hydroxyalkyl and amino; B2 is independently at each occurrence O; when the CLM is of formula 2, R4and R5together form when the CLM is of formula 3, R4and R5together form R1, R2, and R3are each independently at each occurrence selected from the group consisting of H, a deuterium atom, halogen, C 1-6 alkyl, C 1-6 deuteroalkyl, C 1-6 heteroalkyl, alkenyl, alkynyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, hydroxy, C 1-6 hydroxyalkyl, nitro, cyano, amino, C 1-6 alkyl-NH, C 1-6 alkylC(O), C 1-6 alkyloxylC(O), C 1-6 alkylNHC(O), cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein the C 1-6 alkyl, C 1-6 deuteroalkyl, C 1-6 heteroalkyl, alkenyl, alkynyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl are each independently optionally substituted with one or more substituents selected from the group consisting of halogen, alkyl, heteroalkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, alkenyl, alkynyl, alkyl-NH, -C(O)NH-C 1-6 alkyl, -C(O)N(C 1-6 alkyl)2, -N(C 1-6 alkyl)C(O)NH(C 1- 6alkyl), -N(C 1-6 alkyl)C(O)N(C 1-6 alkyl)2, -NHC(O)NH(C 1-6 alkyl), -NHC(O)N(C 1-6 alkyl)2, aryl, and heteroaryl; preferably, R1, R2, and R3are each independently selected from the group consisting of H, a deuterium atom, F, Cl, Br, I, C 1-6 alkyl, C 1-6 deuteroalkyl, C 1-6 heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, hydroxy, C 1-6 hydroxyalkyl, and amino; more preferably, R1, R2, and R3are each independently selected from the group consisting of H, a deuterium atom, F, Cl, Br, I, C 1-3 alkyl, C 1-3 deuteroalkyl, alkenyl, alkynyl, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 haloalkoxy, hydroxy, C 1-3 hydroxyalkyl and amino; B2is independently at each occurrence selected from C(R a )2, NR a , O, and S; B4and B5are each independently selected for each occurrence from CR a and N; C3is independently selected for each occurrence from CR a and N; one of B4 and B5 is N, the other is CH; B1and B3are each independently selected at each occurrence from C(R a )2, O, and C(O); B6is selected from C(R a )2and O; C1and C2are each independently selected for each occurrence from C(R a )2; B6 is independently at each occurrence CH2 and O; R a independently at each occurrence selected from H, a deuterium atom, halogen, C 1-6 alkyl, deuterated C 1-6 alkyl, carboxyl, C 1-6 heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl, -C(O)-C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkyl, halogenated C 1-6 alkoxy, hydroxyl, C 1-6 hydroxyalkyl, nitro, cyano, amino, C 1-6 alkyl-NH, C 1-6 alkyl C(O), C 1-6 alkyloxy C(O), C 1-6 alkyl-NH-C(O), 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl, and 5-10 membered heteroaryl, wherein each of said alkyl, heteroalkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl is independently optionally substituted with one or more substituents selected from halogen, alkyl, heteroalkyl, alkoxy, halogenated alkyl, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, alkenyl, alkynyl, alkyl-NH, alkyl C(O), alkyloxy C(O), alkyl-NH-C(O), aryl, and heteroaryl; The PTM is selected from the following structures: Among them, F6, F 16 and F 21 Each is independently selected from one or more combinations of single bonds, -NH-, -N(CH3)-, -S(O)-, -S-, -O-, -S(O)2-, alkylene, haloalkylene, heteroalkylene, alkeneoxy, heteroalkeneoxy, alkenyl, ynylene, -C(=O)-, -OC(=O)-, -C(=O)-O-, -C(=O)-NH-, and -NH-C(=O)-, wherein the alkylene, alkeneoxy, and alkenyl groups are optionally represented by 0, 1, 2, 3, 4, 5, or 6 R groups. da replace; F A1 selected from 6-10 membered aryl and 5-10 membered heteroaryl, wherein the 6-10 membered aryl and 5-10 membered heteroaryl are optionally substituted with 0, 1, 2, 3, 4, 5, or 6 R da substituents; F A2 selected from 3-15 membered cycloalkylene, 5-15 membered spirocycloalkylene, 3-15 membered heterocyclylene, and 5-15 membered heterospirocyclylene, and said 3-15 membered cycloalkylene, 5-15 membered spirocycloalkylene, 3-15 membered heterocyclylene, and 5-15 membered heterospirocyclylene is optionally substituted with 0, 1, 2, 3, 4, 5, or 6 R ca substituents; preferably, F A2 selected from 3-15 membered cycloalkylene, 5-15 membered spirocycloalkylene, 3-15 membered heterocyclylene, and 5-15 membered heterospirocyclylene, and said 3-15 membered cycloalkylene, 5-15 membered spirocycloalkylene, 3-15 membered heterocyclylene, and 5-15 membered heterospirocyclylene is optionally substituted with 0, 1, 2, 3, 4, 5, or 6 R ca substituents; F A3 is selected from 6-10 membered arylene and 5-10 membered heteroarylene, said 6-10 membered arylene and 5-10 membered heteroarylene being optionally substituted with 0, 1, 2, 3, 4, 5, or 6 R da substituents; R da independently at each occurrence selected from halogen, C 1-6 alkyl, -O-C 1-6 haloalkyl, C 1-6 haloalkyl, C 1-6 heteroalkyl, C 1-6 alkoxy, C 1-6 heteroalkoxy, C 3-7 cycloalkyl, C 3-7 heterocyclyl, C 6-8 aryl, C 5-8 heteroaryl, -OH, -NH2, -CN, -SO2C 1-6 alkyl and -NO2; R ca independently at each occurrence selected from halogen, C 1-6 alkyl, C 1-6 haloalkyl, -O-C 1-6 haloalkyl, C 1-6 heteroalkyl, C 1-6 alkoxy, C 1-6 alkylhydroxy, C 1-6 heteroalkoxy, C 3-7 cycloalkyl, C 3-7 heterocyclyl, C 6-8 aryl, C 5-8 heteroaryl, oxo (=0), thioxo (=S), C 1-6 alkylene N(C 1- 3alkyl)2, OH, NH2, CN, and NO2; When the CLM is F A3 is 8-10 membered heteroarylene; When the CLM is and R2and R3together form F A2 R is 4-6 membered cycloalkylene; When the CLM is R2and R3together form and n2+n3+n4 is 0 or 1, F A2 5-15 membered heterospirocyclyl optionally substituted with 0, 1, 2, 3, 4, 5, or 6 R ca substituents; C3 is independently at each occurrence N; The compound of Formula 1 is not any of the following structures: ​ ​ wherein, ​ L is a bond or -(B L ) q -: B L at each occurrence, the same or different, and each independently selected from: CR L1 R L2 , O, S, S(O), SO2, NR L3 , SO2NR L3 , S(O)NR L3 , C(O)NR L3 , NR L3 C(O)NR L4 , NR L3 SO2NR L4 , C(O), CR L1 =CR L2 , C≡C, SiR L1 R L2 , P(O)R L1 , P(O)OR L1 , NR L3 C(=NCN)NR L4 , NR L3 C(=NCN), NR L3 C(=CNO2)NR L4 , monocycloalkylene, monoheterocyclylene, bridged cyclylene, spiro cyclylene, arylene, and heteroarylene, wherein the monocycloalkylene, monoheterocyclylene, bridged cyclylene, spiro cyclylene, arylene, and heteroarylene are optionally substituted with 0, 1, 2, 3, 4, 5, or 6 R L1 and / or R L2 groups; R L1 , R L2 , R L3 , and R L4 are each independently at each occurrence selected from H, halogen, C 1-8 alkyl, -O-C 1-8 alkyl, -S-C 1-8 alkyl, -NH-C 1-8 alkyl, N(C 1-8 alkyl)2, C 3-11 cycloalkyl, C 6-10 aryl, C 5-10 heteroaryl, C 3-11 heterocyclyl, -O-C 3-8 cycloalkyl, -O-C 3-11 heterocyclyl, -O-C 6-10 aryl, -O-C 5-10 heteroaryl, -S-C 3-8 cycloalkyl, -NH-C 3-8 cycloalkyl, -N(C 3-8 cycloalkyl)2, -N(C 3-8 cycloalkyl)(C 1-8 alkyl), -NH-C 3-8 heterocyclyl, -N(C 3-8 heterocyclyl)2, -N(C 3-8 heterocyclyl)(C 1-8 alkyl), -NH-C 6-10 aryl, -N(C 6-10 aryl)(C 1-8 alkyl), -NH-C 5-10 heteroaryl, -N(C 5-10 heteroaryl)(C 1-8 alkyl), -OH, -NH2, -SH, SO2P(O)(O-C 1-8 alkyl)(C 1-8 alkyl), -P(O)(O-C 1-8 alkyl)2, -C≡C-C 1-8 alkyl, -C≡CH, -CH=CH-(C 1-8 alkyl), -C(C 1-8 alkyl)=CH-(C 1-8 alkyl), -C(C 1-8 alkyl)=C(C 1-8 alkyl)2, -Si(OH)3, -Si(C 1-8 alkyl)3, -Si(OH)(C 1-8 alkyl)2, -C(O)-C 1-8 alkyl, -C(O)2H, -CN, -NO2, -SO2, -SF5, -SO2NH-C 1-8 Alkyl group, -SO2N(C) 1-8 Alkyl)2、-SONH-C 1-8 Alkyl, -SON(C) 1-8 Alkyl)2、-C(O)NH-C 1-8 Alkyl, -C(O)N(C) 1-8 Alkyl)2, -N(C 1-8 alkyl)C(O)NH(C 1-8 alkyl), -N(C) 1-8 alkyl)C(O)N(C 1-8 alkyl)2、-NHC(O)NH(C 1-8 Alkyl), -NHC(O)N(C 1-8 Alkyl)2, -NHC(O)NH2, -N(C 1-8 alkyl)SO2NH(C 1- 8-alkyl), -N(C) 1-8 Alkyl)SO2N(C 1-8 Alkyl)2、-NHSO2NH(C 1-8 Alkyl), -NHSO2 N(C 1-8 Alkyl)2 and -NHSO2NH2, optionally, the C 1-8 Alkyl, C 3-11 cycloalkyl, C 3-11 Heterocyclic group, C 6-10 Aryl and C 5-10 Each heteroaryl group is independently selected from halogens, alkyl groups, heteroalkyl groups, alkenyl groups, alkoxy groups, hydroxyl groups, haloalkyl groups, hydroxyalkyl groups, cyano groups, amino groups, nitro groups, cycloalkyl groups, heterocyclic groups, halocycloalkyl groups, haloheteroalkyl groups, alkyl-NH groups, and C groups. 6-10 Aryl, C 5-10 heteroaryl, halogenated C 6-10 Aryl and halogenated C 5-10 One or more substituents in the heteroaryl group are substituted; ​ ​ The CLM is selected from: ​ A1is independently selected for each occurrence from CR a and N; A2and A4are each independently selected for each occurrence from C(O) and C(R a )2; A3each occurrence independently is NR a ; A5and A6are each independently for each occurrence selected from a single bond, NR a and C(R a )2; R1and R2together form, when CLM is of formula 2, formula 4 or formula 5 when the CLM is of formula 3, R1and R2together form R3, R4, and R5are each independently selected at each occurrence from H, deuterium atom, halogen, C 1-6 alkyl, C 1-6 deuteroalkyl, C 1-6 heteroalkyl, alkenyl, alkynyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, hydroxy, C 1-6 hydroxyalkyl, nitro, cyano, amino, -C(O)NH-C 1-6 alkyl, -C(O)N(C 1-6 alkyl)2, -N(C 1-6 alkyl)C(O)NH(C 1-6 alkyl), -N(C 1-6 alkyl)C(O)N(C 1- 6alkyl)2, -NHC(O)NH(C 1-6 alkyl), -NHC(O)N(C 1-6 alkyl)2, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein said C 1-6 alkyl, C 1-6 deuteroalkyl, C 1-6 heteroalkyl, alkenyl, alkynyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl are each independently optionally substituted with one or more substituents selected from halogen, alkyl, heteroalkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, alkenyl, alkynyl, alkyl-NH, -C(O)NH-C 1-6 alkyl, -C(O)N(C 1-6 alkyl)2, -N(C 1-6 alkyl)C(O)NH(C 1-6 alkyl), -N(C 1- 6alkyl)C(O)N(C 1-6 alkyl)2, -NHC(O)NH(C 1-6 alkyl), -NHC(O)N(C 1-6 alkyl)2, aryl, and heteroaryl; preferably, R3, R4, and R5are each independently selected from H, deuterium atom, F, Cl, Br, I, C 1-6 alkyl, C 1-6 deuteroalkyl, C 1-6 heteroalkyl, alkenyl, alkynyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, hydroxy, C 1-6 Hydroxyl alkyl and amino; more preferably, R3, R4 and R5 are each independently selected from H, deuterium, F, Cl, Br, I, C. 1-3 Alkyl, C 1-3 Deuterated alkyl, alkenyl, alkynyl, C 1-3 Alkoxy, C 1-3 Haloalkyl, C 1-3 Halogenated alkoxy, hydroxyl, C 1-3 Hydroxyalkyl and amino; ​ R2and R3together form, when CLM is of formula 2, formula 4 or formula 5 when the CLM is of formula 3, R2and R3together form R1, R4, and R5are each independently selected at each occurrence from H, a deuterium atom, halogen, C 1-6 alkyl, C 1-6 deuteroalkyl, C 1-6 heteroalkyl, alkenyl, alkynyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, hydroxy, C 1-6 hydroxyalkyl, nitro, cyano, amino, C 1-6 alkyl-NH, C 1-6 alkylC(O), C 1-6 alkyloxylC(O), C 1-6 alkylNHC(O), cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein the C 1-6 alkyl, C 1-6 deuteroalkyl, C 1-6 heteroalkyl, alkenyl, alkynyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl are each independently optionally substituted with one or more substituents selected from halogen, alkyl, heteroalkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, alkenyl, alkynyl, alkyl-NH, -C(O)NH-C 1-6 alkyl, -C(O)N(C 1-6 alkyl)2, -N(C 1- 6alkyl)C(O)NH(C 1-6 alkyl), -N(C 1-6 alkyl)C(O)N(C 1-6 alkyl)2, -NHC(O)NH(C 1-6 alkyl), -NHC(O)N(C 1-6 alkyl)2, aryl, and heteroaryl; preferably, R1, R4, and R5are each independently selected from H, a deuterium atom, F, Cl, Br, I, C 1-6 alkyl, C 1-6 deuteroalkyl, C 1-6 heteroalkyl, alkenyl, alkynyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, hydroxy, C 1-6 hydroxyalkyl, and amino; more preferably, R1, R4, and R5are each independently selected from H, a deuterium atom, F, Cl, Br, I, C 1-3 alkyl, C 1-3 deuteroalkyl, alkenyl, alkynyl, C 1-3 alkoxy, C 1-3 haloalkyl, C 1-3 haloalkoxy, hydroxy, C 1-3 hydroxyalkyl and amino; preferably, when CLMis of formula 2, R2and R3together form and n2+n3+n4 is 0 or 1, F A2 5-15 membered heterospirocyclyl optionally substituted with 0, 1, 2, 3, 4, 5, or 6 R ca substituents; ​ when the CLM is of formula 2, R3and R4together form when the CLM is of formula 3, R3and R4together form R1, R2, and R5are each independently at each occurrence selected from the group consisting of H, a deuterium atom, halogen, C 1-6 alkyl, C 1-6 deuteroalkyl, C 1-6 heteroalkyl, alkenyl, alkynyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, hydroxy, C 1-6 hydroxyalkyl, nitro, cyano, amino, C 1-6 alkyl-NH, C 1-6 alkylC(O), C 1-6 alkyloxylC(O), C 1-6 alkylNHC(O), cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein the C 1-6 alkyl, C 1-6 deuteroalkyl, C 1-6 heteroalkyl, alkenyl, alkynyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl are each independently optionally substituted with one or more substituents selected from the group consisting of halogen, alkyl, heteroalkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, alkenyl, alkynyl, alkyl-NH, -C(O)NH-C 1-6 alkyl, -C(O)N(C 1-6 alkyl)2, -N(C 1-6 alkyl)C(O)NH(C 1- 6alkyl), -N(C 1-6 alkyl)C(O)N(C 1-6 alkyl)2, -NHC(O)NH(C 1-6 alkyl), -NHC(O)N(C 1-6 alkyl)2, aryl, and heteroaryl; preferably, R1, R2, and R5are each independently selected from the group consisting of H, a deuterium atom, F, Cl, Br, I, C 1-6 alkyl, C 1-6 deuteroalkyl, C 1-6 heteroalkyl, alkenyl, alkynyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, hydroxy, C 1-6 hydroxyalkyl, and amino; more preferably, R1, R2, and R5are each independently selected from the group consisting of H, a deuterium atom, F, Cl, Br, I, C 1-3 alkyl, C 1-3 deuteroalkyl, alkenyl, alkynyl, C 1-3 alkoxy, C 1-3 haloalkyl, C 1-3 haloalkoxy, hydroxy, C 1-3 hydroxyalkyl and amino; ​ when the CLM is of formula 2, R4and R5together form When the CLM is of formula 3, R4and R5can together form R1, R2, and R3 are each independently selected from H, deuterium, halogen, and C atoms, respectively. 1-6 Alkyl, C 1-6 Deuterated alkyl, carboxyl, C 1-6 heteroalkyl, alkenyl, ynyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy, hydroxyl, C 1-6 Hydroxyalkyl, nitro, cyano, amino, C 1-6 Alkyl-NH, C 1-6 Alkyl C(O), C 1-6 Alkyloxy C(O), C 1-6 Alkyl NHC(O), cycloalkyl, heterocyclic, aryl, and heteroaryl, wherein the C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 heteroalkyl, alkenyl, ynyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 The haloalkoxy, cycloalkyl, heterocyclic, aryl, and heteroaryl groups are each independently selected from halogen, alkyl, heteroalkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, alkenyl, alkynyl, alkyl-NH, -C(O)NH-C 1-6 Alkyl, -C(O)N(C) 1-6 Alkyl)2, -N(C 1-6 alkyl)C(O)NH(C 1-6 alkyl), -N(C) 1-6 alkyl)C(O)N(C 1-6 alkyl)2、-NHC(O)NH(C 1-6 Alkyl), -NHC(O)N(C 1-6 The alkyl group is substituted with one or more substituents selected from alkyl, aryl, and heteroaryl groups; preferably, R1, R2, and R3 are each independently selected from H, deuterium, F, Cl, Br, I, and C. 1-6 Alkyl, C1-6 deuterated alkyl, C 1-6 Heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy, hydroxyl, C 1-6 Hydroxyl alkyl and amino; more preferably, R1, R2 and R3 are each independently selected from H, deuterium, F, Cl, Br, I, C 1-3 Alkyl, C 1-3 Deuterated alkyl, alkenyl, alkynyl, C 1-3 Alkoxy, C 1-3 haloalkyl, C 1-3 haloalkoxy, hydroxy, C 1-3 hydroxyalkyl and amino; B2is independently at each occurrence selected from C(R a )2, NR a , O, and S; B4and B5are each independently selected for each occurrence from CR a and N; C3is independently selected for each occurrence from CR a and N; ​ B1and B3are each independently selected at each occurrence from C(R a )2, O, and C(O); B6is selected from C(R a )2and O; C1and C2are each independently selected for each occurrence from C(R a )2; B1, B2, B3, and B6, at least one of which is selected from NR a , O, and S; R a independently at each occurrence selected from H, a deuterium atom, halogen, C 1-6 alkyl, deuterated C 1-6 alkyl, carboxyl, C 1-6 heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl, -C(O)-C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkyl, halogenated C 1-6 alkoxy, hydroxyl, C 1-6 hydroxyalkyl, nitro, cyano, amino, C 1-6 alkyl-NH, C 1-6 alkyl C(O), C 1-6 alkyloxy C(O), C 1-6 alkyl NHC(O), 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl, and 5-10 membered heteroaryl, wherein each of the alkyl, heteroalkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl is independently optionally substituted with one or more substituents selected from halogen, alkyl, heteroalkyl, alkoxy, halogenated alkyl, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, alkenyl, alkynyl, alkyl-NH, alkyl C(O), alkyloxy C(O), alkyl NHC(O), aryl, and heteroaryl; The PTM is selected from the following structures: wherein F6, F 16 and F 21 each independently is selected from the group of one or more of a single bond, -NH-, -N(CH3)-, -S(O)-, -S-, -O-, -S(O)2-, alkylene, haloalkylene, heteroalkylene, alkoxyalkylene, heteroalkoxyalkylene, alkenylene, alkynylene, -C(=O)-, -O-C(=O)-, -C(=O)-O-, -C(=O)-NH-, and -NH-C(=O)-, wherein the alkylene, alkoxyalkylene, and alkenylene are optionally substituted with 0, 1, 2, 3, 4, 5, or 6 R da substituents; F A1 selected from 6-10 membered aryl and 5-10 membered heteroaryl, wherein the 6-10 membered aryl and 5-10 membered heteroaryl are optionally substituted with 0, 1, 2, 3, 4, 5, or 6 R da substituents; F A2 is selected from 3-15 membered cycloalkylene, 5-15 membered spirocycloalkylene, 3-15 membered heterocyclylene, and 5-15 membered heterospirocyclylene, and the 3-15 membered cycloalkylene, 5-15 membered spirocycloalkylene, 3-15 membered heterocyclylene, and 5-15 membered heterospirocyclylene is optionally substituted with 0, 1, 2, 3, 4, 5, or 6 R ca is selected from 3-15 membered cycloalkylene, 5-15 membered spirocycloalkylene, 3-15 membered heterocyclylene, and 5-15 membered heterospirocyclylene, and the 3-15 membered cycloalkylene, 5-15 membered spirocycloalkylene, 3-15 membered heterocyclylene, and 5-15 membered heterospirocyclylene is optionally substituted with 0, 1, 2, 3, 4, 5, or 6 R A2 is selected from 3-15 membered cycloalkylene, 5-15 membered spirocycloalkylene, 3-15 membered heterocyclylene, and 5-15 membered heterospirocyclylene, and the 3-15 membered cycloalkylene, 5-15 membered spirocycloalkylene, 3-15 membered heterocyclylene, and 5-15 membered heterospirocyclylene is optionally substituted with 0, 1, 2, 3, 4, 5, or 6 R ca is selected from 3-15 membered cycloalkylene, 5-15 membered spirocycloalkylene, 3-15 membered heterocyclylene, and 5-15 membered heterospirocyclylene, and the 3-15 membered cycloalkylene F A3 selected from 6-10 membered arylene and 5-10 membered heteroarylene, said 6-10 membered arylene and 5-10 membered heteroarylene optionally substituted with 0, 1, 2, 3, 4, 5, or 6 R da substituents; R da independently at each occurrence selected from H, halogen, C 1-6 alkyl, -O-C 1-6 haloalkyl, C 1-6 haloalkyl, C 1-6 heteroalkyl, C 1-6 alkoxy, C 1- 6heteroalkoxy, C 3-7 cycloalkyl, C 3-7 heterocyclyl, C 6-8 aryl, C 5-8 heteroaryl, -OH, -NH2, -CN, -SO2C 1-6 alkyl and -NO2; R ca independently at each occurrence selected from H, halogen, C 1-6 alkyl, C 1-6 haloalkyl, -O-C 1-6 haloalkyl, C 1-6 heteroalkyl, C 1-6 alkoxy, C 1- 6alkylhydroxy, C 1-6 heteroalkoxy, C 3-7 cycloalkyl, C 3-7 heterocyclyl, C 6-8 aryl, C 5-8 heteroaryl, oxo (=0), thioxo (=S), C 1-6 alkylene N(C 1-3 alkyl)2, OH, NH2, CN, and NO2; and The compound of formula 1-1 is not any one of the following structures: ​ B L each occurrence is selected independently from: CR L1 R L2 , O, S, S(O), SO2, NR L3 , C(O), CºC, 3-15 membered cycloalkylene, 3-15 membered heterocycloalkylene containing 1, 2, 3, 4, or 5 heteroatoms independently selected from N, O, and S, 5-15 membered bridged cycloalkylene containing 0, 1, 2, 3, 4, or 5 heteroatoms independently selected from N, O, and S, 5-15 membered spirocycloalkylene containing 0, 1, 2, 3, 4, or 5 heteroatoms independently selected from N, O, and S, 6-15 membered arylene, and 5-15 membered heteroarylene containing 0, 1, 2, 3, 4, or 5 heteroatoms independently selected from N, O, and S, wherein the 3-15 membered cycloalkylene, 3-15 membered heterocycloalkylene, 5-15 membered bridged cycloalkylene, 5-15 membered spirocycloalkylene, 6-15 membered arylene, and 5-15 membered heteroarylene are optionally substituted with 0, 1, 2, or 3 R L1 and / or R L2 groups; preferably, B L each occurrence is selected independently from: CR L1 R L2 , O, S, S(O), SO2, NR L3 , C(O), CºC, 3-8 membered cycloalkylene, 3-8 membered heterocycloalkylene containing 1-3 heteroatoms independently selected from N, O, and S, 5-12 membered bridged cycloalkylene containing 0-3 heteroatoms independently selected from N, O, and S, 5-12 membered spirocycloalkylene containing 0-3 heteroatoms independently selected from N, O, and S, 6-12 membered arylene, and 5-12 membered heteroarylene containing 1-3 heteroatoms independently selected from N, O, and S, wherein the 3-8 membered cycloalkylene, 3-8 membered heterocycloalkylene, 5-12 membered bridged cycloalkylene, 5-12 membered spirocycloalkylene, 6-12 membered arylene, and 5-12 membered heteroarylene are optionally substituted with 0, 1, 2, or 3 R L1 and / or R L2 groups; preferably, B L each occurrence is selected independently from: CR L1 R L2 , O, S, S(O), SO2, NR L3 C(O), CºC, 3-8 membered aliphatic, 3-8 membered heteroaliphatic containing 1, 2, or 3 heteroatoms independently selected from N, O, and S, 5-12 membered bridged aliphatic containing 0-3 heteroatoms independently selected from N, O, and S, 5-12 membered spiroaliphatic containing 0-3 heteroatoms independently selected from N, O, and S, 6-12 membered aryl, and 5-12 membered heteroaryl containing 1-3 heteroatoms independently selected from N, O, and S, wherein the 3-8 membered aliphatic, 3-8 membered heteroaliphatic, 5-12 membered bridged aliphatic, 5-12 membered spiroaliphatic, 6-12 membered aryl, and 5-12 membered heteroaryl are optionally substituted with 0, 1, 2, or 3 R L1 and / or R L2 groups; and / or R L1 , R L2 , R L3 , and R L4 are each independently at each occurrence selected from oxo, H, halogen, C 1-6 1-6alkyl, -O-C 1-6 1-6alkyl, -S-C 1-6 1-6alkyl, -NH-C 1-6 1-6alkyl, N(C 1-6 1-6alkyl)2, C 3-11 2-6cycloalkyl, C 6-10 6aryl, C 5-10 6heteroaryl, C 3-11 1-6heterocyclyl, -O-C 3-8 2-6cycloalkyl, -O-C 3-11 1-6heterocyclyl, -O-C 6-10 6aryl, -O-C 5-10 6heteroaryl, -S-C 3-8 2-6cycloalkyl, -NH-C 3-8 2-6cycloalkyl, -N(C 3-8 2-6cycloalkyl)2, -N(C 3-8 2-6cycloalkyl)(C 1-6 1-6alkyl), -NH-C 3-8 1-6heterocyclyl, -N(C 3-8 1-6heterocyclyl)2, -N(C 3-8 1-6heterocyclyl)(C 1-6 1-6alkyl), -NH-C 6-10 6aryl, -N(C 6-10 6aryl)(C 1-6 1-6alkyl), -NH-C 5-10 6heteroaryl, -N(C 5-10 6heteroaryl)(C 1-6 1-6alkyl), -OH, -NH2, -SH, SO2 P(O)(O-C 1-6 1-6alkyl)(C 1-6 1-6alkyl), -P(O)(O-C 1-6 1-6alkyl)2, -C≡C-C 1- 6alkyl, -C≡CH, -CH=CH-(C 1-6 1-6alkyl), -C(C 1-6 1-6alkyl)=CH-(C 1-6 1-6alkyl), -C(C 1-6 1-6alkyl)=C(C 1-6 1-6alkyl)2, -Si(OH)3, -Si(C 1- 1-6alkyl)3, -Si(OH)(C 1-6 1-6alkyl)2, -C(O)-C 1-6 1-6alkyl, -C(O)2H, -CN, -NO2, -SO2, -SF5, -SO2NH-C 1-6 alkyl, -SO2N(C 1-6 alkyl)2, -S(O)NH-C 1-6 alkyl, -S(O)N(C 1-6 alkyl)2, -C(O)NH-C 1-6 alkyl, -C(O)N(C 1-6 alkyl)2, -N(C 1-6 alkyl)C(O)NH(C 1-6 alkyl), -N(C 1-6 alkyl)C(O)N(C 1-6 alkyl)2, -NHC(O)NH(C 1-6 alkyl), -NHC(O)N(C 1-6 alkyl)2, -NHC(O)NH2, -N(C 1-6 alkyl)SO2NH(C 1-6 alkyl), -N(C 1-6 alkyl)SO2N(C 1-6 alkyl)2, -NHSO2NH(C 1-6 alkyl), -NHSO2 N(C 1-6 alkyl)2, and -NHSO2NH2, optionally, said C 1-6 alkyl, C 3-11 cycloalkyl, C 3-11 heterocyclyl, C 6-10 aryl, and C 5-10 heteroaryl are each independently substituted with one or more substituents selected from halogen, alkyl, heteroalkyl, alkenyl, alkynyl, alkoxy, hydroxy, haloalkyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, halocycloalkyl, haloheteroalkyl, alkyl-NH, aryl, heteroaryl, haloaryl, and haloheteroaryl; and / or ​ ​ A3is at each occurrence independently selected from the group consisting of NH and N-C 1-3 alkyl; preferably, A3is at each occurrence independently selected from the group consisting of NH and N-methyl; and / or A5and A6are each independently C(R a )2; preferably A5and A6are each independently CH2; and / or ​ ​ ​ 4. The compound of any one of claims 1-3, wherein, The CLM is selected from the group consisting of: wherein R1, R2, R3, R4, R5, R a , C1, C2, C3, B1, B2, B3, B4, B5, B6, n2, n3, n4, n5, n6, n7 and n8 are as defined in claim 1 or 2; ​ R1, R2, R3, R4, and R5are each independently at each occurrence selected from the group consisting of H, F, Cl, Br, I, C 1-3 alkyl, C 1-3 alkoxy, hydroxyl, and amino; B2is independently at each occurrence selected from C(R a )2, NR a and O; B1and B3are each independently selected at each occurrence from C(R a )2, O, and C(O); B4and B5are each, at each occurrence, one N and the other CR a ; B6is selected from C(R a )2and O; C1and C2are each independently selected for each occurrence from C(R a )2; ​ R a independently at each occurrence selected from H, F, Cl, Br, I, C 1-3 alkyl, C 1-3 alkoxy, hydroxyl, amino, and -C(O)-C 1-3 alkyl; and ​ 5. The compound of any one of claims 1-4, wherein, The CLM is selected from the group consisting of:

6. The compound of any one of claims 1-5, wherein, B L Each occurrence is independently selected from one or more of the following structures: -O-, -S-, -S(O)-, -SO2-, -CH2-, -C(O)-, -NH-, This is the connection site.

7. The compound of any one of claims 1-6, wherein, L is selected from a covalent bond, -CH2-, -(CH2)2-, -(CH2)3-, -(CH2)4-, -(CH2)5-, -(CH2)6-, -(CH2)7-, -(CH2)8-, -NH-CH2-, -NH-(CH2)2-, -NH-(CH2)3-, -NH-(CH2)4-, -NH-(CH2)5-, -NH-(CH2)6-, -NH-(CH2)7-, -NH-(CH2)8-, -C(O)-NH-CH2-, -C(O)-NH-(CH2)2-, -C(O)-NH-(CH2)3-, -C(O)-NH-(CH2)4-, -C(O)-NH-(CH2)5-, -C(O)-NH-(CH2)6-, -C(O)-NH-(CH2)7-, -C(O)-NH-(CH2)8-, -CH2-NH-, -(CH2)2-NH-, -(CH2)3-NH-, -(CH2)4-NH-, -(CH2)5-NH-, -(CH2)6-NH-, -(CH2)7-NH-, -(CH2)8-NH-, -NH-CH2-NH-, -NH-(CH2)2-NH-, -NH-(CH2)3-NH-, -NH-(CH2)4-NH-, -NH-(CH2)5-NH-, -NH-(CH2)6-NH-, -NH-(CH2)7-NH-, -NH-(CH2)8-NH-, -(CH2-CH2-O)-CH2-CH2-, -(CH2-CH2-O)2-CH2-CH2-, -(CH2-CH2-O)3-CH2-CH2-, -NH-(CH2-CH2-O)-CH2-CH2-, -NH-(CH2-CH2-O)2-CH2-CH2-, -NH-(CH2-CH2-O)3-CH2-CH2-, -C(O)-NH-(CH2-CH2-O)-CH2-CH2-, -C(O)-NH-(CH2-CH2-O)2-CH2-CH2-, -C(O)-NH-(CH2-CH2-O)3-CH2-CH2-, -(CH2-CH2-O)-CH2-CH2-NH-, -(CH2-CH2-O)2-CH2-CH2-NH-, -(CH2-CH2-O)3-CH2-CH2-NH-, -NH-(CH2-CH2-O)-CH2-CH2-NH-, -NH-(CH2-CH2-O)2-CH2-CH2-NH-, -NH-(CH2-CH2-O)3-CH2-CH2-NH-, -C(O)-NH-(CH2-CH2-O)-CH2-CH2-NH-, -C(O)-NH-(CH2-CH2-O)2-CH2-CH2-NH-, -C(O)-NH-(CH2-CH2-O)3-CH2-CH2-NH-, -CH2-CH2-O-, -CH2-CH2-O-CH2-CH2-, -CH2-CH2-O-CH2-CH2-O-, -CH2-CH2-O-CH2-CH2-O-CH2-CH2-, -CH2-CH2-O-CH2-CH2-O-CH2-CH2-O-, -CH2-CH2-O-CH2-CH2-O-CH2-CH2-O-CH2-CH2-, -CH2-CH2-O-CH2-CH2-O-CH2-CH2-O-CH2-CH2-O-, -CH2-CH2-O-CH2-CH2-O-CH2-CH2-O-CH2-CH2-O-CH2-CH2-, -CH2-CH2-O-CH2-CH2-O-CH2-CH2-O-CH2-CH2-O-CH2-CH2-O-, -CH2-CH2-O-CH2-CH2-O-CH2-CH2-O-CH2-CH2-O-CH2-CH2-O-CH2-CH2-, -CH2-CH2-O-CH2-CH2-O-CH2-CH2-O-CH2-CH2-O-CH2-CH2-O-CH2-CH2-O-, -CH2-CH2-O-CH2-CH2-O-CH2-CH2-O-CH2-CH2-O-CH2-CH2-O-CH2-CH2-O-CH2-CH2-, -CH2-CH2-O-CH2-CH2-O-CH2-CH2-O-CH2-CH2-O-CH2-CH2-O-CH2-CH2-O-CH2-CH2-O-, -CH2-CH2-O-CH2-CH2-O-CH2-CH2-O-CH2-CH2-O-CH2-CH2-O-CH2-CH2-O-CH2-CH2-O-CH2-CH2-, -CH2-CH2-O-CH2-CH2-O-CH2-CH2-O-CH2-CH2-O-CH2-CH2-O-CH2-CH2-O-CH2-CH2-O-CH2-CH2-O-, -CH2-CH2-O-CH2-CH2-O-CH2-CH2-O-CH2-CH2-O-CH2-CH2-O-CH2-CH2-O-CH2-CH2-O-CH2-CH2-O-CH2-CH2-, -CH2-CH2-O-CH2-CH2-O-CH2-CH2-O-CH2-CH2-O-CH2-CH2-O-CH2-CH2-O-CH2-CH2-O-CH2-CH2-O-CH2-CH2-O-, -CH2-CH2-O-CH2-CH2-O-CH2-CH2-O-CH2-CH2-O-CH2-CH2-O-CH2-CH2-O-CH2-CH2-O-CH2-CH2-O-CH2-CH2-O-, -CH2-CH2-O-CH2-CH2-O-CH2-CH2-O-CH2-CH2-O-CH2-CH2-O-CH2-CH2-O-CH2-CH2-O-CH2-CH2-O-CH2-CH2-O-, -CH2-CH2-O-CH2-CH2-O-CH2-CH2-O-CH2-CH2-O-CH2-CH2-O-CH2-CH2-O-CH2-CH2-O-CH2-CH2-O-CH2-CH2-O-, -CH2-CH2-O-CH2-CH2-O-CH2-CH2-O-CH2-CH2-O-CH2-CH2-O-CH2-CH2-O-CH2-CH2-O-CH2-CH2-O-CH2-CH2-O-, -CH2-CH2-O-CH2-CH2-O-CH2-CH2-O-CH2-CH2-O-CH2-CH2-O-CH2-CH2-O-CH2-CH2-O-CH2-CH2-O-CH2-CH2-O-, -CH2-CH2-O-CH2-CH2-O-CH2-CH2-O-CH2-CH2-O-CH2-CH2-O-CH2-CH2-O-CH2-CH2-O-CH2-CH2-O-CH2-CH2-O-, -CH2-CH2-O-CH2-CH2-O-CH2-CH2-O-CH2-CH2-O-CH2-CH2-O-CH2-CH2-O-CH2-CH2-O-CH2-CH2-O-CH2-CH2-O-, -CH2-CH2-O-CH2-CH2-O-CH2-CH2-O-CH2-CH2-O-CH2-CH2-O-CH2-CH2-O-CH2-CH2-O-CH2-CH2-O-CH2-CH2-O-, -CH2-CH2-O-CH2-CH2-O-CH2-CH2-O-CH2-CH2-O-CH2-CH2-O-CH2-CH2-O-CH2-CH2-O-CH2-CH2-O-CH2-CH2-O-, -CH2-CH2-O-CH2-CH2-O-CH2-CH2-O-CH2-CH2-O-CH2-CH2-O-CH2-CH2-O-CH2-CH2-O-CH2-CH2-O-CH2-CH2-O-, -CH2-CH2-O-CH2-CH2-O-CH2-CH2-O-CH2-CH2-O-CH2-CH2-O-CH2-CH2-O-CH2-CH2-O-CH2-CH2-O-CH2-CH2-O-, -CH2-CH2-O-CH2-CH2-O-CH2-CH2-O-CH2-CH2-O-CH2--C(O)-NH-(CH2-CH2-O)3-CH2-CH2-NH-, -CH2-CH2-(O-CH2-CH2)-, -CH2-CH2-(O-CH2-CH2)2-, -CH2-CH2-(O-CH2-CH2)3-, -NH-CH2-CH2-(O-CH2-CH2)-, -NH-CH2-CH2-(O-CH2-CH2)2-, -NH-CH2-CH2-(O-CH2-CH2)3-, -C(O)-NH-CH2-CH2-(O-CH2-CH2)-, -C(O)-NH-CH2-CH2-(O-CH2-CH2)2-, -C(O)-NH-CH2-CH2-(O-CH2-CH2)3-, -CH2-CH2-(O-CH2-CH2)-NH-, -CH2-CH2-(O-CH2-CH2)2-NH-, -CH2-CH2-(O-CH2-CH2)3-NH-, -NH-CH2-CH2-(O-CH2-CH2)-NH-, -NH-CH2-CH2-(O-CH2-CH2)2-NH-, -NH-CH2-CH2-(O-CH2-CH2)3-NH-, -NH-CH2-CH2-O-CH2-CH2-C(O)-, -C(O)-CH2-CH2-O-CH2-CH2-NH-, -NH-(CH2)4-C(O)-, -NH-(CH2)5-C(O)-, -NH-(CH2)6-C(O)-, -C(O)-(CH2)4-NH-, -C(O)-(CH2)5-NH-, -C(O)-(CH2)6-NH-, -NH-(CH2-CH2-O)-(CH2)3-, -NH-(CH2-CH2-O)-(CH2)4-, -NH-(CH2-CH2-O)-(CH2)5-, -NH-(CH2-CH2-O)-(CH2)6-, -(CH2)3-(O-CH2-CH2)-NH-, -(CH2)4-(O-CH2-CH2)-NH-, -(CH2)5-(O-CH2-CH2)-NH-, -(CH2)6-(O-CH2-CH2)-NH-, -CH2-CH2-O-(CH2)2-C(O)-, -CH2-CH2-O-(CH2)3-C(O)-, -CH2-CH2-O-(CH2)4-C(O)-, -C(O)-(CH2)2-O-CH2-CH2-, -C(O)-(CH2)3-O-CH2-CH2-, -C(O)-(CH2)4-O-CH2-CH2-, -C(O)-(CH2)2-, -C(O)-(CH2)3-, -C(O)-(CH2)4-, -C(O)-(CH2)5-, -C(O)-(CH2)6-,-(CH2)2-C(O)-, -(CH2)3-C(O)-, -(CH2)4-C(O)-, -(CH2)5-C(O)-, -(CH2)6-C(O)-, -C(O)-(CH2)2-C(O)-, -C(O)-(CH2)3-C(O)-, -C(O)-(CH2)4-C(O)-, -C(O)-(CH2)5-C(O)-, -C(O)-(CH2)6-C(O)-, -CH2-C(O)-CH2-, -CH2-C(O)-(CH2)2-, -CH2-C(O)-(CH2)3-, -CH2-C(O)-(CH2)4-, -(CH2)2-C(O)-CH2-, -(CH2)2-C(O)-(CH2)2-, -(CH2)2-C(O)-(CH2)3-, -(CH2)2-C(O)-(CH2)4-, -(CH2)3-C(O)-CH2-, -(CH2)3-C(O)-(CH2)2-, -(CH2)3-C(O)-(CH2)3-, -(CH2)3-C(O)-(CH2)4-, -(CH2)4-C(O)-CH2-, -(CH2)4-C(O)-(CH2)2-, -(CH2)4-C(O)-(CH2)3-, -(CH2)4-C(O)-(CH2)4-, -CH2-O-CH2-, -CH2-O-(CH2)2-, -CH2-O-(CH2)3-, -CH2-O-(CH2)4-, -(CH2)2-O-CH2-, -(CH2)2-O-(CH2)2-, -(CH2)2-O-(CH2)3-, -(CH2)2-O-(CH2)4-, -(CH2)3-O-CH2-, -(CH2)3-O-(CH2)2-, -(CH2)3-O-(CH2)3-, -(CH2)3-O-(CH2)4-, -(CH2)4-O-CH2-, -(CH2)4-O-(CH2)2-, -(CH2)4-O-(CH2)3-, -(CH2)4-O-(CH2)4-, -O-CH2-, -O-(CH2)2-, -O-(CH2)3-, -O-(CH2)4-, -O-(CH2)5-, -O-(CH2)6-, 8. The compound of any one of claims 1-7, wherein, The PTM is selected from the following structures: F6, F 16 and F 21 each independently is selected from a single bond, -NH-, -N(CH3)-, -S(O)-, -S-, -O-, -S(O)2-, -C(=O)-, -O-C(=O)-, and -NH-C(=O)-; F A1 is phenyl or pyridyl, which phenyl or pyridyl is optionally substituted with 0, 1, 2, 3, 4, or 5 R da substituents; preferably, F A1 is phenyl, which phenyl is optionally substituted with 2, 3, 4, or 5 R da substituents, and at least one R da is CN; F A2 The group is selected from 4-6-membered monocyclic alkylene, 7-11-membered spirocyclic alkylene, 4-6-membered monocyclic heterocyclic groups containing 1, 2, 3 or 4 heteroatoms independently selected from N, O and S, and 7-11-membered heterocyclic heterocyclic groups containing 1, 2, 3 or 4 heteroatoms independently selected from N, O and S, wherein the 4-6-membered monocyclic alkylene, 7-11-membered spirocyclic alkylene, 4-6-membered monocyclic heterocyclic group and 7-11-membered heterocyclic heterocyclic group are optionally separated by 0, 1, 2, 3, 4, 5 or 6 R groups. ca Replacement; preferably, F A2 The group consists of 4, 5, or 6-membered monocyclic alkyl groups, 4, 5, or 6-membered monocyclic heterocyclic groups containing 1, 2, 3, or 4 heteroatoms each independently selected from N, O, and S, and 9, 10, or 11-membered heterospirocyclic groups containing 1, 2, 3, or 4 heteroatoms each independently selected from N, O, and S, wherein the 4, 5, or 6-membered monocyclic alkyl groups, 4, 5, or 6-membered monocyclic heterocyclic groups, and 9, 10, or 11-membered heterospirocyclic groups are optionally surrounded by 0, 1, 2, 3, 4, 5, or 6 R groups. ca Replacement; preferably, F A2 Selected from 4, 5, or 6-membered monocyclic alkylene groups and 10-membered heterospirocyclic groups containing 1, 2, or 3 N atoms, wherein the 4, 5, or 6-membered monocyclic alkylene groups and the 10-membered heterospirocyclic groups containing 1, 2, or 3 N atoms are optionally surrounded by 0, 1, 2, 3, 4, 5, or 6 R atoms. ca replace; F A3 substituted phenylene or a 6-membered heteroarylene containing 1, 2, or 3 heteroatoms each independently selected from N, O, and S, which is substituted by 0, 1, 2, or 3 R da substituted phenylene or a 6-membered heteroarylene containing 1, 2, or 3 heteroatoms each independently selected from N, O, and S, which is substituted by 0, 1, 2, or 3 R da substituted phenylene or a 6-membered heteroarylene containing 1, 2, or 3 heteroatoms each independently selected from N, O, and S, which is substituted by 0, 1, 2, or 3 R da substituted phenylene or a 6-membered heteroarylene containing 1, 2, or 3 heteroatoms each independently selected from N, O, and S, which is substituted by 0, 1, 2, or 3 R R da independently at each occurrence selected from H, F, Cl, Br, I, C 1-3 alkyl, O-C 1-3 haloalkyl, C 1-3 haloalkyl, C 1-3 heteroalkyl, C 1-3 alkoxy, C 1-3 heteroalkoxy, C 3-7 cycloalkyl, C 3-7 heterocyclyl, C 6-8 aryl, C 5-8 heteroaryl, OH, NH2, CN, SO2C 1-3 alkyl and NO2; preferably, R da independently at each occurrence selected from H, F, Cl, Br, I, CH3, C2H5, OCH3, OCH2CH3, CF3, CHF2, O-CF3, O-CHF2, O-CH2F, OH, NH2, CN, SO2CH3, and NO2; preferably, R da independently at each occurrence selected from F, Cl, Br, I, CH3, C2H5, OCH3, OCH2CH3, CF3, CHF2, O-CF3, O-CHF2, O-CH2F, OH, NH2, CN, SO2CH3, and NO2; and R ca independently at each occurrence selected from the group consisting of H, F, CI, Br, I, C 1-3 alkyl, C 1-3 alkylhydroxy, -O-C 1-3 haloalkyl, C 1-3 haloalkyl, C 1-3 heteroalkyl, C 1-3 alkoxy, C 1-3 heteroalkoxy, C 3-7 cycloalkyl, C 3-7 heterocyclyl, C 6-8 aryl, C 5-8 heteroaryl, oxo (=0), thioxo (=S), C 1-3 alkyl N(C 1-3 alkyl)2, OH, NH2, CN, and NO2; preferably, R ca independently at each occurrence selected from the group consisting of H, F, CI, Br, I, oxo (=0), thioxo (=S), CH3, C2H5, CH2OH, CH2N(CH3)2, 3-membered cycloalkyl, CHF2, CH2-CHF2, OCH3, CF3, OH, NH2, CN, and NO2; preferably, R ca independently at each occurrence selected from the group consisting of F, CI, Br, I, oxo (=0), thioxo (=S), CH3, C2H5, CH2OH, CH2N(CH3)2, 3-membered cycloalkyl, CHF2, CH2-CHF2, OCH3, CF3, OH, NH2, CN, and NO2.

9. The compound of claim 8, wherein, F in said PTM is in the para position A1 selected from F, CI, Br, I, CN, CH3, OCH3, CH2F, CHF2, CF3, O-CH2F, O-CHF2, and O-CF3; preferably, F in said PTM is in the para position 1-3 alkyl, C 1-3 alkoxy, C 1-3 haloalkyl and -O-C 1-3 haloalkyl; preferably, F in said PTM is in the para position A1 selected from F, CI, Br, I, CN, CH3, OCH3, CH2F, CHF2, CF3, O-CH2F, O-CHF2, and O-CF3; preferably, F in said PTM is in the para position A1 selected from F in said PTM is in the para position A1 the point of attachment to F6; and / or F in said PTM A2 selected from: The optionally substituted with 1, 2, 3 or 4 substituents independently selected from the group consisting of F, CI, Br, I, oxo, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkylhydroxy, C 1-3 alkyl-NH2, C 1-3 alkylNH(C 1-3 alkyl), C 1-3 alkylN(C 1-3 alkyl)2and C 3-6 cycloalkyl; preferably optionally substituted with 1, 2, 3 or 4 substituents independently selected from the group consisting of F, CH3, C2H5, oxo, CH2F, CHF2, CF3, CH2-CH2F, CH2-HCF2, CH2-CF3, CH2OH, CH2N(CH3)2and cyclopropyl; preferably, F A2 is selected from the group consisting of: Here the wavy line represents F A2 respectively to a connection point of F6 or F 16 ; and / or ​ F 16 is independently at each occurrence selected from a single bond, -NH-, -N(CH3)-, -S(O)-, -S-, -O-, -S(O)2-, -C(=O)-, -O-C(=O)-, and -NH-C(=O)-; preferably, F 16 is independently at each occurrence a single bond or More preferred are ​ F 21 is independently at each occurrence selected from a single bond, -NH-, -N(CH3)-, -S(O)-, -S-, -O-, -S(O)2-, -C(=O)-, -O-C(=O)-, and -NH-C(=O)-; preferably, F 21 is independently at each occurrence a single bond or C(O), more preferably a single bond; Preferably, when F A2 is F6 is -O- or -N(CH3)-, F 16 is When F A2 is At that time, F6 and F 16 It is a single bond; when F A2 for F6 is a single bond, F 16 is ​ F in said PTM A3 selected from the group consisting of F, Cl, Br, I, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 haloalkyl, -O-C 1-3 haloalkyl and -SO2 C 1-3 alkyl; preferably optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of F, Cl, Br, CH3, C2H5, OCH3, O-CH2CH3, CH2F, CHF2, CF3, CH2-CH2F, CH2-CHF2, CH2-CF3, OCH2F, OCHF2, OCF3and -SO2CH3; preferably F in said PTM A3 selected from the group consisting of: Here the wavy line represents F A3 respectively to the connection points of F 16 or F 21 ; and / or F 21 for ​ 10. The compound of claim 8, wherein, F in said PTM A1 selected from wherein R da1 , R da2 , R da3 , R da4 and R da5 are independently at each occurrence selected from H, F, CI, Br, I, C 1-3 alkyl, -O-C 1-3 haloalkyl, C 1-3 haloalkyl, C 1-3 heteroalkyl, C 1-3 alkoxy, C 1-3 heteroalkoxy, C 3-7 cycloalkyl, C 3-7 heterocyclyl, C 6-8 aryl, C 5-8 heteroaryl, OH, NH2, CN, SO2 C 1-3 alkyl and NO2; preferably, R da1 , R da2 , R da3 , R da4 , and R da5 are independently at each occurrence selected from H, F, CI, Br, CN, CH3, OCH3, CH2F, CHF2, CF3, O-CH2F, O-CHF2, and O-CF3; and / or F in said PTM A2 selected from: wherein R ca1 , R ca2 , R ca3 and R ca4 are independently at each occurrence selected from the group consisting of H, F, CI, Br, I, C 1-3 alkyl, C 1-3 alkylhydroxy, -O-C 1-3 haloalkyl, C 1-3 haloalkyl, C 1-3 heteroalkyl, C 1-3 alkoxy, C 1-3 heteroalkoxy, C 3-7 cycloalkyl, C 3-7 heterocyclyl, C 6-8 aryl, C 5-8 heteroaryl, C 1-3 alkylN(C 1-3 alkyl)2, OH, NH2, CN and NO2; preferably, R ca1 , R ca2 , R ca3 and R ca4 are independently at each occurrence selected from the group consisting of H, F, CH3, C2H5, oxo, CH2F, CHF2, CF3, CH2-CH2F, CH2-HCF2, CH2-CF3, CH2OH, CH2N(CH3)2and cyclopropyl; or R ca1 and one of R ca2 is oxo or thioxo, the other being absent; R ca3 and one of R ca4 is oxo or thioxo, the other being absent; ​ F in said PTM A3 selected from: wherein Y 1 is N or CR da6 ; Y 2 is N or CR da7 ; Y 3 is N or CR da8 ; Y 4 is N or CR da9 ; R da6 , R da7 , R da8 and R da9 are independently at each occurrence selected from the group consisting of H, F, Cl, Br, I, C 1-3 alkyl, -O-C 1-3 haloalkyl, C 1-3 haloalkyl, C 1-3 heteroalkyl, C 1-3 alkoxy, C 1-3 heteroalkoxy, C 3-7 cycloalkyl, C 3-7 heterocyclyl, C 6-8 aryl, C 5-8 heteroaryl, OH, NH2, CN, SO2 C 1- 3alkyl and NO2; preferably, R da6 , R da7 , R da8 and R da9 are independently at each occurrence selected from the group consisting of H, F, Cl, Br, CH3, C2H5, OCH3, O-CH2CH3, CH2F, CHF2, CF3, CH2-CH2F, CH2-CHF2, CH2-CF3, OCH2F, OCHF2, OCF3and -SO2CH3.

11. The compound of claim 10, wherein, selected from: Preferably, the PTM is selected from the group consisting of:

12. The compound of any one of claims 1-11, wherein, The PTM is selected from:

13. The compound of claim 1, wherein, The CLM is selected from the group consisting of structures shown in Formula 2-1, Formula 2-2, Formula 2-3, and Formula 2-4: wherein R1, R2, R3, R4, and R5are each independently at each occurrence selected from the group consisting of H, F, Cl, Br, I, C 1-3 alkyl, C 1-3 alkoxy, hydroxyl, and amino; ​ B1and B3are each independently for each occurrence selected from CH2, NH, C(C 1-3 alkyl)2, and N(C 1-3 alkyl); ​ ​ C1and C2are each independently at each occurrence selected from CH2and C(C 1-3 alkyl)2; ​ R a independently at each occurrence selected from H, F, Cl, Br, I, C 1-3 alkyl, C 1-3 alkoxy, hydroxyl, amino, and -C(O)-C 1-3 alkyl; n2, n3, n4, n5, and n6 are each independently at each occurrence selected from 0, 1, and 2; preferably, n2+n3+n4 = 1 or n2+n3+n4 = 2; and n5+n6 = 2 or n5+n6 = 3; more preferably n2 = 0, n3 = 2, n4 = 0, n2 = 0, n5 = 1, and n6 = 2; The PTM is selected from the following structures: wherein F6, F 16 and F 21 each independently is selected from a single bond, -NH-, -S(O)-, -S-, -O-, -S(O)2-, -C(=O)-, -O-C(=O)-, and -NH-C(=O)-; F A1 is phenyl, which is optionally substituted with 2, 3, 4, or 5 R da substituents, and at least one R da is -CN; F A2 selected from 4-, 5-, or 6-membered cycloalkylene and 10-membered heterospirocyclylene containing 1, 2, or 3 N atoms, and said 4-, 5-, or 6-membered cycloalkylene and 10-membered heterospirocyclylene containing 1, 2, or 3 N atoms is optionally substituted with 0, 1, 2, 3, 4, 5, or 6 R ca substituents; F A3 is phenylene substituted by 0, 1, 2, 3 or 4 R da is phenylene substituted by 0, 1, 2 or 3 R da is 6-membered heteroarylene containing 1, 2 or 3 heteroatoms each independently selected from N, O, and S; R da independently at each occurrence selected from the group consisting of F, Cl, Br, I, CH3, C2H5, OCH3, CF3, CHF2, O-CF3, O-CHF2, O-CH2F, OH, NH2, CN, and NO2; R ca independently at each occurrence selected from the group consisting of F, CI, Br, I, oxo (=0), CH3, C2H5, CH2OH-CH2N(CH3)2, 3-membered cycloalkyl, CF2H, CH2-CF2H, OCH3, CF3, OH, NH2, CN, and NO2; Preferably, F in said PTM is selected from: A1 selected from: Here the wavy line represents F A1 Connection point to F6; and / or F in said PTM A2 selected from: Here the wavy line represents F A2 respectively to a connection point of F6 or F 16 ; and / or F6 is -0-, -N(CH3)- or a single bond; and / or F 16 is or a single bond; preferably, when F A2 is F6 is -O- or -N(CH3)-, F 16 is When F A2 is F6and F 16 is a single bond; and / or F in said PTM A3 selected from: This wavy line indicates F A3 respectively to the connection point of F 16 or F 21 ; and / or F 21 for or a single bond; L is selected from 14. A compound of Formula 1-2, or an isomer, isotopic derivative, polymorph, prodrug, pharmaceutically acceptable salt, or solvate thereof: PTM-L-CLM (Formula 1-2); wherein PTM is an androgen receptor binding moiety; The CLM has a structure selected from the following Formula 2-1, Formula 2-2, Formula 2-3, and Formula 2-4: wherein R1, R2, R3, R4, and R5are each independently at each occurrence selected from the group consisting of H, F, Cl, Br, I, C 1-3 alkyl, C 1-3 alkoxy, hydroxyl, and amino; B2 is, at each occurrence, independently O; B1and B3are each independently for each occurrence selected from CH2, NH, C(C 1-3 alkyl)2, and N(C 1-3 alkyl); B4 and B5 are, at each occurrence, one of N and the other of CH; preferably B5 is, at each occurrence, N and B4 is, at each occurrence, CH; B6 is, at each occurrence, independently selected from CH2 and O; C1and C2are each independently at each occurrence selected from CH2and C(C 1-3 alkyl)2; C3 is, at each occurrence, independently N; R a independently at each occurrence selected from H, F, CI, Br, I, C 1-3 alkyl, C 1-3 alkoxy, hydroxy, amino and -C(O)-C 1-3 alkyl; n2, n3, n4, n5, and n6 are each independently at each occurrence selected from 0, 1, and 2; preferably, n2+n3+n4 = 1 or n2+n3+n4 = 2; and n5+n6 = 2 or n5+n6 = 3; more preferably n2 = 0, n3 = 2, n4 = 0, n2 = 0, n5 = 1, and n6 = 2; L is selected from and The PTM is selected from the following structures: wherein F6, F 16 and F 21 are each independently selected from a single bond, -NH-, -S(O)-, -S-, -O-, -S(O)2-, -C(=O)-, -O-C(=O)-, and -NH-C(=O)-; F A1 is phenyl, which is optionally substituted with 2, 3, 4 or 5 R da substituents, and at least one R da is CN; F A2 selected from 4-, 5-, or 6-membered cycloalkylene and 10-membered heterospirocyclylene containing 1, 2, or 3 N atoms, and said 4-, 5-, or 6-membered cycloalkylene and 10-membered heterospirocyclylene containing 1, 2, or 3 N atoms is optionally substituted with 1, 2, 3, 4, 5, or 6 R ca substituents; F A3 is phenylene substituted by 0, 1, 2, 3 or 4 R da is phenylene substituted by 1, 2 or 3 R da is 6-membered heteroarylene containing 1, 2 or 3 heteroatoms each independently selected from N, O, and S; R da independently at each occurrence selected from the group consisting of F, Cl, Br, I, -CH3, -C2H5, -OCH3, -CF3, -CF2H, -O-CF3, -O-CHF2, -O-CH2F, -OH, -NH2, -CN, and -NO2; R ca independently at each occurrence selected from the group consisting of F, CI, Br, I, oxo (=0), CH3, C2H5, CH2OH, CH2N(CH3)2, 3-membered cycloalkyl, -CF2H, -CH2-CF2H, OCH3, CF3, OH, NH2, CN, and NO2; Preferably: F A1 selected from the group consisting of: Here the wavy line represents F A1 Connection point to F6; F A2 selected from: Here the wavy line represents F A2 respectively to the connection point of F6 or F 16 respectively to the connection point of F6 or F F6 is -O-, -N(CH3)-, or a single bond; F 16 for or a single bond; preferably, when F A2 is F6 is -O- or -N(CH3)-, F 16 is When F A2 is F6and F 16 is a single bond; F A3 selected from the group consisting of: This wavy line indicates F A3 respectively to the connection point of F 16 or F 21 ; and F 21 for or a single bond; and The compound of formula 1-2 is not any of the following structures:

15. A compound of Formula 1-3, having the structure: PTM-L-CLM (Formula 1-3); wherein PTM is F6, F 16 and F 21 each independently is selected from the group of one or more of a single bond, -NH-, -N(CH3)-, -S(O)-, -S-, -0-, -S(O)2-, alkylene, haloalkylene, heteroalkylene, alkylenoxy, heteroalkylenoxy, alkenylene, alkynylene, -C(=0)-, -0-C(=0)-, -C(=0)-0-, -C(=0)-NH-, and -NH-C(=0)-, wherein said alkylene, alkylenoxy, alkenylene is optionally substituted with 0, 1, 2, 3, 4, 5, or 6 R da substituents; preferably, F6, F 16 and F 21 each independently is selected from the group of one or more of a single bond, -NH-, -S(O)-, -S-, -0-, -S(O)2-, -C(=0)-, -0-C(=0)-, and -NH-C(=0)-; F A1 selected from 6-10 membered aryl and 5-10 membered heteroaryl, wherein said 6-10 membered aryl and 5-10 membered heteroaryl are optionally substituted with 0, 1, 2, 3, 4, 5, or 6 R da substituents; preferably, F A1 is phenyl, said phenyl being optionally substituted with 0, 1, 2, 3, 4, or 5 R da substituents; more preferably, F A1 is phenyl, said phenyl being optionally substituted with 2, 3, 4, or 5 R da substituents, and at least one R da is -CN; F A2 selected from 3-15 membered cycloalkylene, 5-15 membered spirocycloalkylene, 3-15 membered heterocyclylene, and 5-15 membered heterospirocyclylene, and said 3-15 membered cycloalkylene, 5-15 membered spirocycloalkylene, 3-15 membered heterocyclylene, and 5-15 membered heterospirocyclylene is optionally substituted with 0, 1, 2, 3, 4, 5, or 6 R ca substituents; preferably, F A2 selected from 4-6 membered cycloalkylene, 7-11 membered spirocycloalkylene, 4-6 membered heterocyclylene containing 1, 2, 3, or 4 heteroatoms each independently selected from N, O, and S, and 7-11 membered heterospirocyclylene containing 1, 2, 3, or 4 heteroatoms each independently selected from N, O, and S, said 4-6 membered cycloalkylene, 7-11 membered spirocycloalkylene, 4-6 membered heterocyclylene, and 7-11 membered heterospirocyclylene is optionally substituted with 0, 1, 2, 3, 4, 5, or 6 R ca substituents; more preferably, F A2 selected from 4-, 5-, or 6-membered cycloalkylene and 10-membered heterospirocyclylene containing 1, 2, or 3 N atoms, and said 4-, 5-, or 6-membered cycloalkylene and 10-membered heterospirocyclylene containing 1, 2, or 3 N atoms is optionally substituted with 0, 1, 2, 3, 4, 5, or 6 R ca substituents; F A3 Selected from 6-10 arylene and 5-10 heteroarylene, wherein the 6-10 arylene and 5-10 heteroarylene are optionally surrounded by 0, 1, 2, 3, 4, 5 or 6 R groups. da Replacement; preferably, F A3 For 0, 1, 2, 3 or 4 R da The substituted phenylene group may be substituted with 0, 1, 2 or 3 R groups. da The substituted 6-membered heteroaryl group containing 1, 2, or 3 heteroatoms independently selected from N, O, and S, or the substituted 6-membered heteroaryl group containing 0, 1, 2, or 3 R atoms. da Substituted with one, two, or three 10-membered bicyclic heteroaryl groups, each independently selected from N, O, and S heteroatoms; R da independently at each occurrence selected from H, halogen, C 1-6 alkyl, -O-C 1-6 haloalkyl, C 1-6 haloalkyl, C 1-6 heteroalkyl, C 1-6 alkoxy, C 1- heteroalkoxy, C 3-7 cycloalkyl, C 3-7 heterocyclyl, C 6-8 aryl, C 5-8 heteroaryl, -OH, -NH2, -CN, -SO2 C 1-6 alkyl and -NO2; preferably, R da independently at each occurrence selected from H, F, Cl, Br, I, C 1-3 alkyl, -O-C 1-3 haloalkyl, C 1-3 haloalkyl, C 1-3 heteroalkyl, C 1-3 alkoxy, C 1-3 heteroalkoxy, C 3-7 cycloalkyl, C 3-7 heterocyclyl, C 6-8 aryl, C 5-8 heteroaryl, -OH, -NH2, -CN, -SO2 C 1-3 alkyl and -NO2; more preferably, R da independently at each occurrence selected from H, F, Cl, Br, I, -CH3, -C2H5, -OCH3, -OCH2CH3, -CF3, -CF2 H, -O-CF3, -O-CHF2, -O-CH2F, -OH, -NH2, -CN, -SO2CH3, and -NO2; Preferably, R da Each time it appears, it is independently selected from H, halogen, C. 1-6 Alkyl, -OC 1-6 Haloalkyl, C 1-6 Haloalkyl, C 1-6 Heteroalkyl, C 1-6 Alkoxy, C 1-6 Zykaloxy, C 3-7 cycloalkyl, C 3-7 Heterocyclic group, C 6-8 Aryl, C 5-8 Heteroaryl, -OH, -NH2, -CN and -NO2; preferably, R da Each time it appears, it is independently selected from H, F, Cl, Br, I, C. 1-3 Alkyl, -OC 1-3 Haloalkyl, C 1-3 Haloalkyl, C 1-3 Heteroalkyl, C 1-3 Alkoxy, C 1- 3-hexaalkoxy, C 3-7 cycloalkyl, C 3-7 Heterocyclic group, C 6-8 Aryl, C 5-8 Heteroaryl, -OH, -NH2, -CN and -NO2; more preferably, R da Each occurrence is independently selected from H, F, Cl, Br, I, -CH3, -C2H5, -OCH3, -CF3, -CF2H, -O-CF3, -O-CHF2, -O-CH2F, -OH, -NH2, -CN, and -NO2; R ca independently at each occurrence selected from H, halogen, C 1-6 alkyl, C 1-6 haloalkyl, -O-C 1-6 haloalkyl, C 1-6 heteroalkyl, C 1-6 alkoxy, C 1- 6alkylhydroxy, C 1-6 heteroalkoxy, C 3-7 cycloalkyl, C 3-7 heterocyclyl, C 6-8 aryl, C 5-8 heteroaryl, oxo (=0), thioxo (=S), C 1-6 alkyl N(C 1-3 alkyl)2, OH, NH2, CN and NO2; preferably, R ca independently at each occurrence selected from H, F, Cl, Br, I, C 1-3 alkyl, C 1-3 alkylhydroxy, -O-C 1-3 haloalkyl, C 1-3 haloalkyl, C 1-3 heteroalkyl, C 1-3 alkoxy, C 1-3 heteroalkoxy, C 3-7 cycloalkyl, C 3-7 heterocyclyl, C 6-8 aryl, C 5-8 heteroaryl, oxo (=0), thioxo (=S), C 1-3 alkyl N(C 1-3 alkyl)2, -OH, -NH2, -CN and -NO2; more preferably, R ca independently at each occurrence selected from H, F, Cl, Br, I, oxo (=0), thioxo (=S), CH3, C2H5, CH2OH, CH2N(CH3)2, 3-membered cycloalkyl, -CF2H, -CH2-CF2H, OCH3, CF3, OH, NH2, CN and NO2; L is a bond or -(B L ) q -: B L at each occurrence, the same or different, and each independently selected from: CR L1 R L2 , O, S, SO, SO2, NR L3 , SO2NR L3 , SONR L3 , C(O)NR L3 , NR L3 C(O)NR L4 , NR L3 SO2NR L4 , C(O), CR L1 =CR L2 , C≡C, SiR L1 R L2 , P(O)R L1 , P(O)OR L1 , NR L3 C(=NCN)NR L4 , NR L3 C(=NCN), NR L3 C(=CNO2)NR L4 , cycloalkylene, heterocyclylene, bridged cycloalkylene, spiro cycloalkylene, arylene, and heteroarylene, wherein the cycloalkylene, heterocyclylene, bridged cycloalkylene, spiro cycloalkylene, arylene, and heteroarylene are optionally substituted with 0, 1, 2, 3, 4, 5, or 6 R L1 and / or R L2 groups; R L1 R L2 R L3 and R L4 Each time it appears, it is independently selected from oxygen groups (=O), H, halogens, and C. 1-8 Alkyl, -OC 1-8 Alkyl, -SC 1-8 Alkyl, -NH-C 1-8 Alkyl, N(C) 1-8 Alkyl)2, C 3-11 cycloalkyl, C 6-10 Aryl, C 5-10 heteroaryl, C 3-11 Heterocyclic groups, -OC 3-8 cycloalkyl, -OC 3-11 Heterocyclic groups, -OC 6-10 Aryl, -OC 5-10 heteroaryl, -SC 3-8 cycloalkyl, -NH-C 3-8 cycloalkyl, -N(C) 3-8 cycloalkyl)2, -N(C 3-8 cycloalkyl)(C 1-8 alkyl), -NH-C 3-8 Heterocyclic groups, -N(C) 3-8 Heterocyclic group)2, -N(C 3-8 Heterocyclic group)(C 1-8 alkyl), -NH-C 6-10 Aryl, -N(C 6-10 Aryl)(C 1-8 alkyl), -NH-C 5-10 heteroaryl, -N(C 5-10 (C) 1-8 Alkyl groups, -OH, -NH2, -SH, SO2, P(O)(OC) 1-8 Alkyl)(C 1-8 Alkyl), -P(O)(OC 1-8 Alkyl)2、-C≡CC 1-8 Alkyl group, -C≡CH, -CH=CH-(C 1-8 alkyl), -C(C 1-8 Alkyl)=CH-(C 1-8 alkyl), -C(C 1-8 Alkyl) = C(C 1-8 Alkyl group 2, -Si(OH)3, -Si(C) 1-8 Alkyl)3、-Si(OH)(C 1-8 Alkyl)2、-C(O)-C 1-8 alkyl, -C(O)2H, -CN, -CF3, -CHF2, -CH2F, -NO2, -SO2, -SF5, -SO2NH-C 1-8 alkyl, -SO2N(C 1-8 alkyl)2, -S(O)NH-C 1-8 alkyl, -S(O)N(C 1-8 alkyl)2, -C(O)NH-C 1-8 alkyl, -C(O)N(C 1-8 alkyl)2, -N(C 1-8 alkyl)C(O)NH(C 1-8 alkyl), -N(C 1-8 alkyl)C(O)N(C 1-8 alkyl)2, -NHC(O)NH(C 1-8 alkyl), -NHC(O)N(C 1-8 alkyl)2, -NHC(O)NH2, -N(C 1-8 alkyl)SO2NH(C 1-8 alkyl), -N(C 1-8 alkyl)SO2N(C 1-8 alkyl)2, -NHSO2NH(C 1-8 alkyl), -NHSO2 N(C 1- 8alkyl)2, and -NHSO2NH2, optionally, said C 1-8 alkyl, C 3-11 cycloalkyl, C 3-11 heterocyclyl, C 6-10 aryl, and C 5-10 heteroaryl are each independently substituted with one or more substituents selected from halogen, alkyl, heteroalkyl, alkenyl, alkynyl, alkoxy, hydroxy, haloalkyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, halocycloalkyl, haloheteroalkyl, alkylamino, C 6-10 aryl, C 5-10 heteroaryl, haloC 6-10 aryl, and haloC 5-10 heteroaryl; Preferably, R L1 R L2 R L3 and R L4 Each time it appears, it is independently selected from H, halogen, and C. 1-8 Alkyl, -OC 1-8 Alkyl, -SC 1-8 Alkyl, -NH-C 1-8 Alkyl, N(C) 1-8 Alkyl)2, C 3-11 cycloalkyl, C 6-10 Aryl, C 5-10 heteroaryl, C 3-11 Heterocyclic groups, -OC 3-8 cycloalkyl, -OC 3-11 Heterocyclic groups, -OC 6-10 Aryl, -OC 5-10 heteroaryl, -SC 3-8 cycloalkyl, -NH-C 3-8 cycloalkyl, -N(C) 3-8 cycloalkyl)2, -N(C 3-8 cycloalkyl)(C 1-8 alkyl), -NH-C 3-8 Heterocyclic groups, -N(C) 3-8 Heterocyclic group)2, -N(C 3-8 Heterocyclic group)(C 1-8 alkyl), -NH-C 6-10 Aryl, -N(C 6-10 Aryl)(C 1-8 alkyl), -NH-C 5-10 heteroaryl, -N(C 5-10 (C) 1-8 Alkyl groups, -OH, -NH2, -SH, SO2, P(O)(OC) 1-8 Alkyl)(C 1-8 Alkyl), -P(O)(OC 1-8 Alkyl)2、-C≡CC 1-8 Alkyl group, -C≡CH, -CH=CH-(C 1-8 alkyl), -C(C 1-8 Alkyl)=CH-(C 1-8 alkyl), -C(C 1-8 Alkyl) = C(C 1-8 Alkyl group 2, -Si(OH)3, -Si(C) 1-8 Alkyl)3、-Si(OH)(C 1-8 Alkyl)2、-C(O)-C 1-8 alkyl, -C(O)2H, -CN, -CF3, -CHF2, -CH2F, -NO2, -SO2, -SF5, -SO2NH-C 1-8 alkyl, -SO2N(C 1-8 alkyl)2, -S(O)NH-C 1-8 alkyl, -S(O)N(C 1-8 alkyl)2, -C(O)NH-C 1-8 alkyl, -C(O)N(C 1-8 alkyl)2, -N(C 1-8 alkyl)C(O)NH(C 1-8 alkyl), -N(C 1-8 alkyl)C(O)N(C 1-8 alkyl)2, -NHC(O)NH(C 1-8 alkyl), -NHC(O)N(C 1-8 alkyl)2, -NHC(O)NH2, -N(C 1-8 alkyl)SO2NH(C 1-8 alkyl), -N(C 1-8 alkyl)SO2N(C 1-8 alkyl)2, -NHSO2NH(C 1-8 alkyl), -NHSO2 N(C 1- 8alkyl)2, and -NHSO2NH2, optionally, said C 1-8 alkyl, C 3-11 cycloalkyl, C 3-11 heterocyclyl, C 6-10 aryl, and C 5-10 heteroaryl are each independently substituted with one or more substituents selected from halogen, alkyl, heteroalkyl, alkenyl, alkynyl, alkoxy, hydroxy, haloalkyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, halocycloalkyl, haloheteroalkyl, alkylamino, C 6-10 aryl, C 5-10 heteroaryl, haloC 6-10 aryl, and haloC 5-10 heteroaryl; and q is an integer greater than or equal to 1; preferably, q is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20; The CLM is selected from: wherein: A1is independently selected from CR a and N; A2and A4are each independently selected from C(O) and C(R a )2; A3is selected from NR a ; A5and A6are each independently selected from a single bond, NR a and C(R a )2; A7is selected from C(O) and C(R a )2; When the CLM is of Formula 2, Formula 4, Formula 5, Formula 7, R1and R2can together form When the CLM is of formula 3, R1and R2can together form R3, R4, and R5are each independently selected at each occurrence from H, deuterium atom, halogen, C 1-6 alkyl, C 1-6 deuteroalkyl, carboxyl, C 1-6 heteroalkyl, alkenyl, alkynyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, hydroxyl, C 1- 6hydroxyalkyl, nitro, cyano, amino, -C(O)NH-C 1-6 alkyl, -C(O)N(C 1-6 alkyl)2, -N(C 1-6 alkyl)C(O)NH(C 1-6 alkyl), -N(C 1-6 alkyl)C(O)N(C 1-6 alkyl)2, -NHC(O)NH(C 1-6 alkyl), -NHC(O)N(C 1-6 alkyl)2, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein said C 1-6 alkyl, C 1-6 deuteroalkyl, C 1-6 heteroalkyl, alkenyl, alkynyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl are each independently optionally substituted with one or more substituents selected from halogen, alkyl, heteroalkyl, alkoxy, haloalkyl, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, alkenyl, alkynyl, alkylamino, -C(O)NH-C 1-6 alkyl, -C(O)N(C 1-6 alkyl)2, -N(C 1-6 alkyl)C(O)NH(C 1- 6alkyl), -N(C 1-6 alkyl)C(O)N(C 1-6 alkyl)2, -NHC(O)NH(C 1-6 alkyl), -NHC(O)N(C 1-6 alkyl)2, aryl, and heteroaryl; preferably, R3, R4, and R5are each independently selected from H, deuterium atom, F, Cl, Br, I, C 1-6 alkyl, C 1-6 deuteroalkyl, C 1-6 heteroalkyl, alkenyl, alkynyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, hydroxyl, C 1-6 Hydroxyl alkyl and amino; more preferably, R3, R4 and R5 are each independently selected from H, deuterium, F, Cl, Br, I, C. 1-3 Alkyl, C 1-3 Deuterated alkyl, alkenyl, alkynyl, C 1-3 Alkoxy, C 1-3 Haloalkyl, C 1-3 Halogenated alkoxy, hydroxyl, C 1-3 Hydroxyalkyl and amino; or When the CLM is of Formula 2, Formula 4, Formula 5, R2and R3can together form When the CLM is of formula 3, R2and R3can together form R1, R4, and R5are each independently selected at each occurrence from H, a deuterium atom, halogen, C 1- 6alkyl, C 1-6 deuteroalkyl, carboxyl, C 1-6 heteroalkyl, alkenyl, alkynyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, hydroxyl, C 1-6 hydroxyalkyl, nitro, cyano, amino, C 1-6 alkylamino, C 1-6 alkylacyl, C 1-6 alkyloxyacyl, C 1-6 alkylaminoacyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein the C 1-6 alkyl, C 1-6 deuteroalkyl, C 1-6 heteroalkyl, alkenyl, alkynyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl are each independently optionally substituted with one or more substituents selected from halogen, alkyl, heteroalkyl, alkoxy, haloalkyl, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, alkenyl, alkynyl, alkylamino, -C(O)NH-C 1-6 alkyl, -C(O)N(C 1-6 alkyl)2, -N(C 1-6 alkyl)C(O)NH(C 1-6 alkyl), -N(C 1-6 alkyl)C(O)N(C 1-6 alkyl)2, -NHC(O)NH(C 1-6 alkyl), -NHC(O)N(C 1-6 alkyl)2, aryl, and heteroaryl; preferably, R1, R4, and R5are each independently selected from H, a deuterium atom, F, Cl, Br, I, C 1-6 alkyl, C 1-6 deuteroalkyl, C 1-6 heteroalkyl, alkenyl, alkynyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, hydroxyl, C 1-6 hydroxyalkyl, and amino; more preferably, R1, R4, and R5are each independently selected from H, a deuterium atom, F, Cl, Br, I, C 1-3 alkyl, C 1-3 deuteroalkyl, alkenyl, alkynyl, C 1-3 alkoxy, C 1-3 haloalkyl, C 1-3 haloalkyl, haloalkoxy, hydroxy, C 1-3 hydroxyalkyl, and amino; or When the CLM is of formula 2, R3and R4can together form When the CLM is of formula 3, R3and R4can together form R1, R2, and R5are each independently selected at each occurrence from H, a deuterium atom, halogen, C 1-6 alkyl, C 1-6 deuteroalkyl, C 1-6 heteroalkyl, alkenyl, alkynyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, hydroxy, C 1-6 hydroxyalkyl, nitro, cyano, amino, C 1-6 alkylamino, C 1-6 alkylacyl, C 1-6 alkyloxyacyl, C 1-6 alkylaminoacyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein the C 1-6 alkyl, C 1-6 deuteroalkyl, C 1-6 heteroalkyl, alkenyl, alkynyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl are each independently optionally substituted with one or more substituents selected from halogen, alkyl, heteroalkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, alkenyl, alkynyl, alkylamino, -C(O)NH-C 1-6 alkyl, -C(O)N(C 1-6 alkyl)2, -N(C 1- 6alkyl)C(O)NH(C 1-6 alkyl), -N(C 1-6 alkyl)C(O)N(C 1-6 alkyl)2, -NHC(O)NH(C 1-6 alkyl), -NHC(O)N(C 1-6 alkyl)2, aryl, and heteroaryl; preferably, R1, R2, and R5are each independently selected from H, a deuterium atom, F, Cl, Br, I, C 1-6 alkyl, C 1-6 deuteroalkyl, C 1-6 heteroalkyl, alkenyl, alkynyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, hydroxy, C 1-6 hydroxyalkyl, and amino; more preferably, R1, R2, and R5are each independently selected from H, a deuterium atom, F, Cl, Br, I, C 1-3 alkyl, C 1-3 deuteroalkyl, alkenyl, alkynyl, C 1-3 alkoxy, C 1-3 haloalkyl, C 1-3 haloalkyl, haloalkoxy, hydroxy, C 1-3 hydroxyalkyl, and amino; or When the CLM is of formula 2, R4and R5can together form When the CLM is of formula 3, R4and R5can together form R1, R2, and R3are each independently selected at each occurrence from H, a deuterium atom, halogen, C 1-6 alkyl, C 1- deuteroalkyl, C 1-6 heteroalkyl, alkenyl, alkynyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, hydroxy, C 1-6 hydroxyalkyl, nitro, cyano, amino, C 1-6 alkylamino, C 1-6 alkylacyl, C 1-6 alkyloxyacyl, C 1-6 alkylaminoacyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein the C 1-6 alkyl, C 1-6 deuteroalkyl, C 1-6 heteroalkyl, alkenyl, alkynyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl are each independently optionally substituted with one or more substituents selected from halogen, alkyl, heteroalkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, alkenyl, alkynyl, alkylamino, -C(O)NH-C 1-6 alkyl, -C(O)N(C 1-6 alkyl)2, -N(C 1- alkyl)C(O)NH(C 1-6 alkyl), -N(C 1-6 alkyl)C(O)N(C 1-6 alkyl)2, -NHC(O)NH(C 1-6 alkyl), -NHC(O)N(C 1-6 alkyl)2, aryl, and heteroaryl; preferably, R1, R2, and R3are each independently selected from H, a deuterium atom, F, Cl, Br, I, C 1-6 alkyl, C 1-6 deuteroalkyl, C 1-6 heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, hydroxy, C 1-6 hydroxyalkyl, and amino; more preferably, R1, R2, and R3are each independently selected from H, a deuterium atom, F, Cl, Br, I, C 1-3 alkyl, C 1-3 deuteroalkyl, alkenyl, alkynyl, C 1-3 alkoxy, C 1-3 haloalkyl, C 1-3 haloalkoxy, hydroxy, C 1-3 hydroxyalkyl and amino; B2is independently at each occurrence selected from C(R a )2, NR a , O, and S; B4and B5are each independently selected for each occurrence from CR a and N; C3is independently selected for each occurrence from CR a and N; n2, n3, n4, n5, n6, and n7 are each independently at each occurrence selected from 0, 1, 2, and 3; n8 is selected from 1, 2, and 3; B1and B3are each independently selected at each occurrence from C(R a )2, O, and C(O); B6is selected from C(R a )2and O; C1and C2are each independently selected for each occurrence from C(R a )2; when B4 and B5 are present, at least one of B1, B2, B3, and B6 is selected from NRa, O, and S; R a independently at each occurrence selected from H, a deuterium atom, F, Cl, Br, I, C 1-6 alkyl, deuterated C 1-6 alkyl, carboxyl, C 1-6 heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl, -C(O)-C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkyl, halo C 1-6 alkoxy, hydroxyl, C 1-6 hydroxyalkyl, nitro, cyano, amino, C 1-6 alkylamino, C 1-6 alkylacyl, C 1-6 alkyloxyacyl, C 1-6 alkylaminoacyl, 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl, and 5-10 membered heteroaryl, wherein each of said alkyl, heteroalkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl is independently optionally substituted with one or more substituents selected from halogen, alkyl, heteroalkyl, alkoxy, haloalkyl, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, alkenyl, alkynyl, alkylamino, alkylacyl, alkyloxyacyl, alkylaminoacyl, aryl, and heteroaryl; preferably, R a independently at each occurrence selected from H, a deuterium atom, F, Cl, Br, I, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C1-6alkoxy, halo C 1-6 alkyl, halo C 1-6 alkoxy, hydroxyl, C 1-6 hydroxyalkyl, -C(O)-C 1-3 alkyl and amino; represents a point of attachment; when CLM is Formula 7, R3, R4 are not H; and The compound of formula 1-3 is not:

16. The compound of any one of claims 1-15, selected from: and the compounds of Table A. Preferably, the compound is selected from the compounds of Table A.

17. A compound represented by Formula A-1 or Formula A-2, or a salt thereof, wherein R da1 , R da2 , R da3 , R da4 and R da5 are independently at each occurrence selected from the group consisting of H, F, Cl, Br, I, C 1-3 alkyl, -O-C 1-3 haloalkyl, C 1-3 haloalkyl, C 1-3 heteroalkyl, C 1-3 alkoxy, C 1-3 heteroalkoxy, C 3-7 cycloalkyl, C 3-7 heterocyclyl, C 6-8 aryl, C 5-8 heteroaryl, OH, NH2, CN, SO2C 1-3 alkyl and NO2; preferably, R da1 , R da2 , R da3 , R da4 , R da5 are independently at each occurrence selected from the group consisting of H, F, Cl, Br, CN, CH3, OCH3, CH2F, CHF2, CF3, O-CH2F, O-CHF2and O-CF3; R ca1 , R ca2 , R ca3 , R ca4 , R ca5 , and R ca6 are at each occurrence independently selected from the group consisting of H, F, Cl, Br, I, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 haloalkyl, C 1-3 haloalkyl, C 1-3 heteroalkyl, C 1-3 alkoxy, C 1-3 heteroalkoxy, C 3-7 cycloalkyl, C 3-7 heterocyclyl, C 6-8 aryl, C 5-8 heteroaryl, C 1-3 alkyl N(C 1-3 alkyl)2, OH, NH2, CN, and NO2; preferably, R ca1 , R ca2 , R ca3 , R ca4 , R ca5 , and R ca6 are at each occurrence independently selected from the group consisting of H, F, CH3, C2H5, CH2F, CHF2, CF3, CH2-CH2F, CH2-HCF2, CH2-CF3, CH2OH, CH2N(CH3)2, and cyclopropyl; or one of R ca1 and R ca2 is oxo or thioxo and the other is absent; one of R ca3 and R ca4 is oxo or thioxo and the other is absent; preferably, R ca1 , R ca2 , R ca3 , R ca4 are at each occurrence independently methyl; preferably, R ca5 is H and R ca6 is methyl, CF3; Y 1 is N or CR da6 ; Y 2 is N or CR da7 ; Y 3 is N or CR da8 ; Y 4 is N or CR da9 ; R da6 , R da7 , R da8 and R da9 are independently at each occurrence selected from the group consisting of H, F, Cl, Br, I, C 1-3 alkyl, O-C 1-3 haloalkyl, C 1-3 haloalkyl, C 1-3 heteroalkyl, C 1-3 alkoxy, O-C 1-3 heteroalkoxy, C 3-7 cycloalkyl, C 3-7 heterocyclyl, C 6-8 aryl, C 5-8 heteroaryl, OH, NH2, CN, SO2 C 1- 3alkyl and NO2; preferably, R da6 , R da7 , R da8 and R da9 are independently at each occurrence selected from the group consisting of H, F, Cl, Br, CH3, C2H5, OCH3, O-CH2CH3, CH2F, CHF2, CF3, CH2-CH2F, CH2-CHF2, CH2-CF3, OCH2F, OCHF2, OCF3and -SO2CH3; provided that R da6 , R da7 , R da8 and R da9 are at each occurrence at least one independently selected from the group consisting of Cl, Br, I, C 1-3 alkyl, -O-C 1-3 haloalkyl, C 1-3 haloalkyl, C 1-3 heteroalkyl, C 1-3 alkoxy, C 1-3 heteroalkoxy, C 3-7 cycloalkyl, C 3-7 heterocyclyl, C 6-8 aryl, C 5-8 heteroaryl, OH, NH2, CN, SO2C 1-3 alkyl and NO2; preferably R da6 , R da7 , R da8 and R da9 are at each occurrence at least one independently independently selected from the group consisting of Cl, Br, CH3, C2H5, OCH3, O-CH2CH3, CH2F, CHF2, CF3, CH2-CH2F, CH2-CHF2, CH2-CF3, OCH2F, OCHF2, OCF3 and -SO2CH3; preferably R da6 , R da7 , R da8 and R da9 are at each occurrence at least one independently selected from the group consisting of Cl, Br, CH3, OCH3, OCF3 and -SO2CH3; preferably R da9 are at each occurrence independently selected from the group consisting of Cl, Br, CH3, C2H5, OCH3, O-CH2CH3, CH2F, CHF2, CF3, CH2-CH2F, CH2-CHF2, CH2-CF3, OCH2F, OCHF2, OCF3 and -SO2CH3; preferably R da9 are at each occurrence independently selected from the group consisting of Cl, Br, CH3, OCH3, OCF3 and SO2CH3; preferably R da9 are at each occurrence independently selected from the group consisting of Cl, Br, O-CH2CH3, -CH2CH3; preferably R da9 are at each occurrence independently selected from the group consisting of Cl, Br; T is selected from the group consisting of a leaving group; preferably, T is selected from the group consisting of H, a deuterium atom, F, Cl, Br, I, Ci-C6alkyl, Ci-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, Ci-C6alkoxy, 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl, hydroxyl, carboxyl, nitro, cyano, amino, and -ON=NH, said Ci-C6alkyl, Ci-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, Ci-C6alkoxy, 3-10 membered cycloalkyl, and 3-10 membered heterocycloalkyl optionally substituted with one or more substituents independently selected from deuterium, F, Cl, Br, I, Ci-C6alkyl, Ci-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, Ci-C6alkoxy, hydroxyl, carboxyl, 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl, and amino; preferably, T is selected from the group consisting of F, Cl, Br, I, Ms, Tf, TsCl, Ts, COOH, C(O)OCH3, C(O)OCH3, CH2NO2, CH2 ON=NH, and CH2NH2; Preferably, the compound is selected from: and / or T is selected from the group consisting of F, Cl, Br, I, and COOH.

18. A pharmaceutical composition comprising a compound of any one of claims 1-16, or an isomer, isotopic derivative, polymorph, prodrug, pharmaceutically acceptable salt, or solvate thereof, or a compound of claim 17, or a salt thereof, and a pharmaceutically acceptable carrier or excipient.

19. A compound of any one of claims 1-16, or an isomer, isotopic derivative, polymorph, prodrug, pharmaceutically acceptable salt, or solvate thereof, or a compound of claim 17, or a salt thereof, or a pharmaceutical composition of claim 18, for use in the treatment or prevention of a disease; preferably, wherein the disease is a disease treated by degrading androgen receptor protein or a disease associated with accumulation and / or aggregation of androgen receptor protein; preferably, the disease is cancer; preferably, the cancer is prostate cancer.

20. Use of a compound of any one of claims 1-16, or an isomer, isotopic derivative, polymorph, prodrug, pharmaceutically acceptable salt, or solvate thereof, or a compound of claim 17, or a salt thereof, or a pharmaceutical composition of claim 18, in the manufacture of a medicament for the treatment or prevention of a disease; preferably, wherein the disease is a disease treated by degrading androgen receptor protein or a disease associated with accumulation and / or aggregation of androgen receptor protein; preferably, the disease is cancer; preferably, the cancer is prostate cancer.

21. A method of treating or preventing a disease comprising administering to a subject in need thereof a therapeutically effective amount of a compound of any one of claims 1-16, or an isomer, isotopic derivative, polymorph, prodrug, pharmaceutically acceptable salt or solvate thereof, or an isomer, isotopic derivative, polymorph, prodrug, pharmaceutically acceptable salt or solvate thereof, or a compound of claim 17, or a salt thereof, or a pharmaceutical composition of claim 18; wherein the disease is a disease treated by degrading androgen receptor protein or a disease associated with accumulation and / or aggregation of androgen receptor protein; preferably, the cancer is prostate cancer.

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