Stat degraders and uses thereof

Abstract

Provided are compounds of Formula (I): and pharmaceutically acceptable satis and compositions thereof, which are useful for treating a variety of conditions associated with STAT3 and / or STAT6.

Description

STAT DEGRADERS AND USES THEREOF BACKGROUND

[0001] The Signal Transducer and Activator of Transcription (STAT) family of proteins consists of transcription factors that play an essential role in the regulation of cell processes, such as proliferation, differentiation, apoptosis and angiogenesis. Seven STAT genes have been identified in the human genome: STAT1, STAT2, STAT3, STAT4, STAT5a, STAT5b, and STAT6.

[0002] STAT3 has received particular attention because it is strongly associated with the promotion of tumor growth and immune evasion, and the only STAT family member whose genetic deletion results in embryonic lethality. Indeed, aberrantly elevated STAT3 activity has been estimated to occur in more than 70% of human cancers. Activated STAT3 mediates critical gene expression changes and molecular events that dysregulate cell growth and apoptosis, promote angiogenesis, invasion, metastasis, and the development of resistance to apoptosis, and suppress the host’s immune surveillance of the tumor, thereby making constitutively-active STAT3 a critical mediator of carcinogenesis and tumor progression.

[0003] Another STAT protein that has gained recent interest is STAT6. Recent studies have shown that STAT6 signaling is essential for IL-4- and IL-13-induced epithelial mesenchymal transition (EMT) and aggressiveness of colorectal cancer cells (CRC) cells. STAT6 is involved in several aspects of inflammatory disease and other related conditions. SUMMARY

[0004] Given their role in the regulation of cell processes, modulating the activity of one or more STAT proteins, particularly STAT3 and / or STAT6, represent a pivotal area of investigation for the treatment of cancer, inflammatory conditions, and other therapeutic needs.

[0005] Targeted protein degradation has become an advancing area as seen with rapid progression of PROTACs (proteolysis targeting chimeras) to clinic. PROTACs are protein degraders, which utilize the cell’s own waste disposal machinery to eliminate, instead of inhibit, a target protein. PROTACs are bifunctional in that they simultaneously bind a target protein and an E3 ligase protein. This event subsequently ubiquitylates the target, marking it for proteasomal degradation. This, and related processes, represent a new therapeutic modality for the treatment of diseases.

[0006] The present invention provides novel bifunctional compounds for degradation of STAT3 and / or STAT6 by recruiting them to E3 uniquitin ligase for degradation. Theadvantages of using the methods of the invention are that a broad range of targets that may be modulalted by recruiting E3 ubiquitin ligase for degradation.

[0007] In certain aspects, the invention provides effective degraders of the STAT3 and / or STAT6. The degraders of STAT3 and / or STAT6 have general Formula A:)

[0008] wherein, TBM is target binding moiety; DM is degradation moiety; and L is a linker between TBM and DM. A TBM is a moiety that binds to a target protein that should be degraded. In certain embodiments, the TBM is the moiety that binds to STAT3 and / or STAT6. The degradation moiety is responsible for induding degradation of the target. In certain embodiments, the degradation moiety acts by recruitment of ubiquiting E3 ligase to the target attached to TBM, and thus results in degradation of the target.

[0009] In certain aspects, the compounds of the invention provide that the TBM moiety comprises a STAT3 and / or STAT6 binding moiety. The STAT3 and / or STAT6 binding moeity are inhibitors and / or modulators of STAT3 and / or STAT6. In certain embodiments, the STAT3 and / or STAT6 binding are compounds provided in WO 2023 / 164680, which is incorporated by reference in its entirey.

[0010] In certain embodiments, the STAT3 and / or STAT6 binding moiety is a compound of Formula (I’):wherein: q is 0 or 1 and t is 0, 1, or 2, provided that at least one of q or t is 1; p is 1 or 2; X is selected from S, SO2, -S(=O)=NH, and NR8;R1is selected from an 8- to 10-membered fused bicyclic heteroaryl substituted with – CR1aR2aP(O)OR1bOR2b, –CR1aR2aP(O)[OR1b][NH(AA)C(O)ORT], –P(O)OR1bOR2b, - [P(O)[NHRTy][NH(AA)C(O)ORT], or –P(O)[OR1b][NH(AA)C(O)ORT]; an 8- to 10- membered fused bicyclic heterocyclyl substituted with –CR1aR2aP(O)OR1bOR2b, – CR1aR2aP(O)[OR1b][NH(AA)C(O)ORT], –P(O)OR1bOR2b, - [P(O)[NHRTy][NH(AA)C(O)ORT], or –P(O)[OR1b][NH(AA)C(O)ORT]; an aryl substituted with –CR1aR2aP(O)OR1bOR2b, –CR1aR2aP(O)[OR1b][NH(AA)C(O)ORT], –P(O)OR1bOR2b, - [P(O)[NHRTy][NH(AA)C(O)ORT], or –P(O)[OR1b][NH(AA)C(O)ORT], wherein said aryl may be further optionally substituted with 1 or 2 groups independently selected from cyano, (C1-C4)alkoxy, and halo; a -(C1-C4)alkyl(aryl) wherein said aryl portion of -(C1-C4)alkyl(aryl) is substituted with –CR1aR2aP(O)OR1bOR2b, –CR1aR2aP(O)[OR1b][NH(AA)C(O)ORT], – P(O)OR1bOR2b, -[P(O)[NHRTy][NH(AA)C(O)ORT], - [P(O)[NH(AA)C(O)ORT][NH(AA)C(O)ORT], or –P(O)[OR1b][NH(AA)C(O)ORT]; and a - (C2-C4)alkenyl(aryl) wherein said aryl portion of -(C2-C4)alkenyl(aryl) is substituted with – CR1aR2aP(O)OR1bOR2b, –CR1aR2aP(O)[OR1b][NH(AA)C(O)ORT], –P(O)OR1bOR2b, - [P(O)[NHRTy][NH(AA)C(O)ORT], or –P(O)[OR1b][NH(AA)C(O)ORT]; R1aand R2aare each independently selected from hydrogen, cyano, (C1-C4)alkyl, hydroxy(C1-C4)alkyl and fluoro; or R1aand R2ataken together with the carbon they are attached form oxo; R1band R2bare each independently selected from hydrogen, (C1-C4)alkyl, halo(C1- C4)alkyl, -[(C1-C4)alkyl]-OC(O)-[(C1-C4)alkyl], -[(C1-C4)alkyl]-C(O)O-[(C1-C4)alkyl], -[(C1- C4)alkyl]-O-[(C1-C20)alkyl], -[(C1-C4)alkyl]-OC(O)-[halo(C1-C4)alkyl], [(C1-C4)alkyl]- OC(O)O-[5- to 7-membered heterocyclyl], [(C1-C4)alkyl]-OC(O)-[5- to 7-membered heterocyclyl], -[(C1-C4)alkyl]-OC(O)-[(C1-C4)alkyl]-OH, -[(C1-C4)alkyl]-OC(O)-[(C1- C4)alkyl]-O-[(C1-C4)alkyl], -[(C1-C4)alkyl]-OC(O)O-[(C1-C4)alkyl], -[(C1-C4)alkyl]-OC(O)O- [halo(C1-C4)alkyl], -[(C1-C4)alkyl]-OC(O)O-[(C1-C4)alkyl]-OH, -[(C1-C4)alkyl]-OC(O)O- [(C1-C4)alkyl]-O-[(C1-C4)alkyl], -[(C1-C4)alkyl]-SC(O)-[(C1-C4)alkyl], -[(C1-C4)alkyl]- SC(O)-[halo(C1-C4)alkyl], -[(C1-C4)alkyl]-SC(O)-[(C1-C4)alkyl]-OH, -[(C1-C4)alkyl]-SC(O)- [(C1-C4)alkyl]-O-[(C1-C4)alkyl], -[(C1-C4)alkyl]-OC(O)NH(C1-C4)alkyl], -[(C1-C4)alkyl]- OC(O)N[(C1-C4)alkyl]2, and aryl, wherein said 5- to 6- membered heteroaryl and aryl are each optionally and independently substituted with, as valency permits, 1 to 2 groups selected from halo, cyano, and (C1-C4)alkyl and wherein said 5- to 7-membered heterocyclyl of [(C1- C4)alkyl]-OC(O)O-[5- to 7-membered heterocyclyl] and [(C1-C4)alkyl]-OC(O)-[5- to 7-membered heterocyclyl] are each optionally and independently substituted with, as valency permits 1 to 2 groups selected from C(O)ORh; R2is selected from hydrogen, halo, (C1-C4)alkyl, halo(C1-C4)alkyl, (C1-C4)alkoxy, halo(C1-C4)alkoxy, hydroxy(C1-C4)alkyl, cyano, and hydroxyl; R3and R4are each independently selected from hydrogen, halo, (C1-C4)alkyl, halo(C1- C4)alkyl, hydroxy(C1-C4)alkyl, -(C1-C4)alkylphenyl, (C1-C4)alkoxy, halo(C1-C4)alkoxy, -(C1- C4)alkyl(C1-C4)alkoxy, hydroxyl, cyano, -NRaRb, phenyl, (C3-C6)cycloalkyl, 5- to 6- membered heteroaryl, and 4- to 6-membered heterocyclyl, wherein said phenyl, (C3- C6)cycloalkyl, 5- to 6-membered heteroaryl, and 4- to 6-membered heterocyclyl are each optionally substituted with, as valency permits, 1 to 3 groups selected from RS; R5and R6are each independently selected from hydrogen, phenyl, and (C1-C4)alkyl; R7is selected from (C1-C4)alkyl, phenyl, 4- to 9-membered monocyclic or bicyclic heterocyclyl, and 5- to 10-membered monocyclic or bicyclic heteroaryl, wherein said (C1- C4)alkyl is optionally substituted with, as valency permits, 1 to 3 groups selected from RYand said phenyl, 4- to 9-membered monocyclic or bicyclic heterocyclyl, and 5- to 10-membered monocyclic or bicyclic heteroaryl are each optionally substituted with, as valency permits, 1 to 3 groups selected from RZ; or R6and R7together with the nitrogen atom to which they are attached form a 4- to 14- membered monocyclic or bicyclic heterocyclyl or a 5- to 12-membered monocyclic or bicyclic heteroaryl, each of which being optionally substituted with, as valency permits, 1 to 3 groups selected from RQ; R8is selected from hydrogen, (C1-C4)alkyl, halo(C1-C4)alkyl, (C3-C6)cycloalkyl, 5- to 7-membered heterocyclyl, -(C1-C4)[5- to 7-membered heterocyclyl], 5- to 10-membered heteroaryl, -(C1-C4)[5- to 10-membered heteroaryl], phenyl, -(C1-C4)alkylphenyl, –C(O)RHa, – C(O)ORHa, -C(O)NRHaRHb, -C(O)ORHa, -SORHaRHband -SO2RHa, wherein said (C3- C6)cycloalkyl, 5- to 7-membered heterocyclyl, 5- to 10-membered heteroaryl, phenyl, the phenyl on (C1-C4)alkylphenyl, the 5- to 7-membered heterocyclyl on -(C1-C4)[5- to 7- membered heterocyclyl], and the 5- to 6-membered heteroaryl on -(C1-C4)[5- to 6-membered heteroaryl] are each optionally substituted with, as valency permits, 1 to 3 groups selected from RU; RHais selected from (C1-C10)alkyl, (C2-C10)alkenyl, (C2-C10)alkynyl, phenyl, 5- to 10- membered monocyclic or bicyclic heteroaryl, and 4- to 10-membered monocyclic or bicyclic heterocyclyl, wherein said (C1-C10)alkyl, (C2-C10)alkenyl, (C2-C10)alkynyl are each optionally substituted with, as valency permits, 1 to 2 groups selected from ROand wherein said 5-to 10-membered monocyclic or bicyclic heteroaryl and said 4-to 10-membered monocyclic or bicyclic heterocyclyl are each optionally substituted with, as valency permits, 1 to 3 groups selected from halo, (C1-C4)alkyl, halo(C1-C4)alkyl, (C1-C4)alkoxy, halo(C1-C4)alkoxy, oxo, cyano, and 4- to 6-membered heterocyclyl optionally substituted with C1-C4alkyl; ROis selected from halo, (C1-C4)alkoxy, OH, phenyl, NH2, -NH(C1-C10)alkyl, -N[(C1- C10)alkyl], (C3-6cycloalkyl), 4- to 10-membered monocyclic or fused bicyclic heterocyclyl and 5-to 10-membered monocyclic or bicyclic heteroaryl, wherein said 5- to 10-membered monocyclic or bicyclic heteroaryl and said 4-to 10-membered monocyclic or bicyclic heterocyclyl are each optionally substituted with, as valency permits, 1 to 3 groups selected from halo, (C1-C4)alkyl, halo(C1-C4)alkyl, (C1-C4)alkoxy, halo(C1-C4)alkoxy, oxo, and cyano; RHbis hydrogen or (C1-C4)alkyl; AA is the residue of an alpha or beta natural or non-natural amino acid; RTand RTyare each independently selected from (C1-C4)alkyl, benzyl, and phenyl, wherein said phenyl is optionally substituted with 1 or 2 groups selected from halo, (C1- C4)alkyl, and halo(C1-C4)alkyl; RQand RUare each independently selected from halo, (C2-C4)alkenyl, (C1-C4)alkyl, (C1-C4)alkoxy, halo(C1-C4)alkoxy, cyano, phenyl, hydroxyl, 4- to 9-membered monocyclic or bicyclic heterocyclyl, 5- to 10-membered monocyclic or bicyclic heteroaryl, (C3-C6)cycloalkyl, oxo, imino, -ORe, -C(O)Rg, -C(O)ORe, -NRcC(O)Re, -C(O)NRcRd, -NRaRb, -S(O)ReRf, - S(O)2Rf, -S(O)=NH(C1-C4)alkyl, -S(O)NReRf, and -S(O)2NReRf, wherein said (C2-C4)alkenyl and (C1-C4)alkyl are each optionally and independently substituted with, as valency permits, 1 to 3 groups selected from RM, and wherein said phenyl, 5- to 10- membered monocyclic or bicyclic heteroaryl, (C3-C6)cycloalkyl, and 4- to 9-membered monocyclic or bicyclic heterocyclyl are each optionally and independently substituted with, as valency permits, 1 to 3 groups selected from RF; RYis selected from halo, (C1-C4)alkoxy, halo(C1-C4)alkoxy, cyano, -C(O)Rg, - C(O)ORe, -NHC(O)Re, -NRaRb, -S(O)ReRf, -S(O)2Rf, -S(O)NReRf, -S(O)=NH(C1-C4)alkyl, - S(O)2NReRf, hydroxyl, phenyl, 4- to 6-membered heterocyclyl, and 5- to 10-membered monocyclic or bicyclic heteroaryl, wherein said phenyl, 4- to 6-membered heterocyclyl, and 5- to 10-membered monocyclic or bicyclic heteroaryl are each optionally substituted with, as valency permits, 1 to 3 groups selected from RX; RMand RJare each independently selected from halo, (C1-C4)alkyl, (C1-C4)alkoxy, halo(C1-C4)alkoxy, cyano, -C(O)Rg, -C(O)ORe, -NHC(O)Re, -C(O)NRcRd, -NRaRb, - S(O)ReRf, -S(O)2Rf, -S(O)NReRf, -S(O)=NH(C1-C4)alkyl, -S(O)2NReRf, hydroxyl, phenyl, 4-to 6-membered heterocyclyl, and 5- to 10-membered monocyclic or bicyclic heteroaryl, wherein said phenyl, 4- to 6-membered heterocyclyl, and 5- to 10-membered monocyclic or bicyclic heteroaryl are each optionally substituted with, as valency permits, 1 to 3 groups selected from RX; RF, RS, RX, and RZare each independently selected from halo, cyano, (C1-C4)alkyl, (C3-C6cycloalkyl), halo(C1-C4)alkyl, -(C1-C4)alkyl(C1-C4)alkoxy, hydroxy(C1-C4)alkyl, -(C1- C4)alkylphenyl, -(C1-C4)alkylheteroaryl, (C2-C4)alkenyl, halo(C2-C4)alkenyl, (C2-C4)alkynyl, halo(C2-C4)alkynyl, (C1-C4)alkoxy, halo(C1-C4)alkoxy, -ORe, oxo, imino, phenyl, 4- to 6- membered heterocyclyl, -S(O)ReRf, -S(O)2Rf, -S(O)=NH(C1-C4)alkyl, -S(O)NReRf, and - S(O)2NReRf, -C(O)ORe, -NRcC(O)Re, -(C1-C4alkyl)C(O)Rg, -C(O)Rg, -(C1- C4alkyl)C(O)NRcRd, -C(O)NRcRd, -NO2, and -NRaRb, wherein the (C1-C4)alkyl is optionally substituted with cyano, wherein said phenyl, said 4- to 6-membered heterocyclyl, and said phenyl for -(C1-C4)alkylphenyl are each optionally and independently substituted with, as valency permits 1 to 3 groups selected from halo, cyano, oxo, (C1-C10)alkyl, (C2-C10)alkenyl, (C2-C10)alkynyl, halo(C1-C10)alkyl, (C1-C10)alkoxy, and halo(C1-C10)alkoxy, wherein said (C1-C10)alkyl, (C2-C10)alkenyl and (C2-C10)alkynyl are each optionally substituted with, as valency permits a 5-to 10-membered monocyclic or bicyclic heteroaryl or a 4-to 10- membered monocyclic or bicyclic heterocyclyl each of said 5-to 10-membered monocyclic and bicyclic heteroaryl or a 4-to 10-membered monocyclic or bicyclic heterocyclyl being optionally substituted with oxo or a 5- to 7-membered heterocyclyl that is optionally substituted with 1 to 2 oxo; and Ra, Rb, Rc, Rd, Re, Rf,Rg, and Rhare each independently selected from, as valency permits, hydrogen, (C1-C4)alkyl, (C2-C4)alkynyl, -(C1-C4)alkylphenyl, phenyl, (C3- C6)cycloalkyl, 4- to 6-membered heterocyclyl and 5- to 6-membered heteroaryl, wherein said (C1-C4)alkyl is optionally substituted with, as valency permits, 1 to 3 groups selected from RJ, and said phenyl, (C3-C6)cycloalkyl, 4- to 6-membered heterocyclyl, and 5- to 6-membered heteroaryl are each independently optionally substituted with, as valency permits, 1 to 3 groups selected from halo, cyano, (C1-C4)alkyl, halo(C1-C4)alkyl, (C1-C4)alkoxy, halo(C1-C4)alkoxy, hydroxyl, phenyl, and benzyl.

[0011] Provided herein are compounds having the structural Formula I:and pharmaceutically acceptable salts and compositions thereof, wherein: q is 0 or 1 and t is 0, 1, or 2, provided that at least one of q or t is 1; p is 1 or 2; X is selected from S, SO2, -S(=O)=NH, -NR8, and -NR9; R1is selected from an 8- to 10-membered fused bicyclic heteroaryl substituted with – CR1aR2aP(O)OR1bOR2b, –CR1aR2aP(O)[OR1b][NH(AA)C(O)ORT], –P(O)OR1bOR2b, - [P(O)[NHRTy][NH(AA)C(O)ORT], or –P(O)[OR1b][NH(AA)C(O)ORT]; an 8- to 10- membered fused bicyclic heterocyclyl substituted with –CR1aR2aP(O)OR1bOR2b, – CR1aR2aP(O)[OR1b][NH(AA)C(O)ORT], –P(O)OR1bOR2b, - [P(O)[NHRTy][NH(AA)C(O)ORT], or –P(O)[OR1b][NH(AA)C(O)ORT]; an aryl substituted with –CR1aR2aP(O)OR1bOR2b, –CR1aR2aP(O)[OR1b][NH(AA)C(O)ORT], –P(O)OR1bOR2b, - [P(O)[NHRTy][NH(AA)C(O)ORT], or –P(O)[OR1b][NH(AA)C(O)ORT], wherein said aryl may be further optionally substituted with 1 or 2 groups independently selected from cyano, (C1-C4)alkoxy, and halo; a -(C1-C4)alkyl(aryl) wherein said aryl portion of -(C1-C4)alkyl(aryl) is substituted with –CR1aR2aP(O)OR1bOR2b, –CR1aR2aP(O)[OR1b][NH(AA)C(O)ORT], – P(O)OR1bOR2b, -[P(O)[NHRTy][NH(AA)C(O)ORT], - [P(O)[NH(AA)C(O)ORT][NH(AA)C(O)ORT], or –P(O)[OR1b][NH(AA)C(O)ORT]; and a - (C2-C4)alkenyl(aryl) wherein said aryl portion of -(C2-C4)alkenyl(aryl) is substituted with – CR1aR2aP(O)OR1bOR2b, –CR1aR2aP(O)[OR1b][NH(AA)C(O)ORT], –P(O)OR1bOR2b, - [P(O)[NHRTy][NH(AA)C(O)ORT], or –P(O)[OR1b][NH(AA)C(O)ORT]; R1aand R2aare each independently selected from hydrogen, cyano, (C1-C4)alkyl, hydroxy(C1-C4)alkyl and fluoro; or R1aand R2ataken together with the carbon they are attached form oxo; R1band R2bare each independently selected from hydrogen, (C1-C4)alkyl, halo(C1- C4)alkyl, -[(C1-C4)alkyl]-OC(O)-[(C1-C4)alkyl], -[(C1-C4)alkyl]-C(O)O-[(C1-C4)alkyl], -[(C1- C4)alkyl]-O-[(C1-C20)alkyl], -[(C1-C4)alkyl]-OC(O)-[halo(C1-C4)alkyl], [(C1-C4)alkyl]- OC(O)O-[5- to 7-membered heterocyclyl], [(C1-C4)alkyl]-OC(O)-[5- to 7-membered heterocyclyl], -[(C1-C4)alkyl]-OC(O)-[(C1-C4)alkyl]-OH, -[(C1-C4)alkyl]-OC(O)-[(C1-C4)alkyl]-O-[(C1-C4)alkyl], -[(C1-C4)alkyl]-OC(O)O-[(C1-C4)alkyl], -[(C1-C4)alkyl]-OC(O)O- [halo(C1-C4)alkyl], -[(C1-C4)alkyl]-OC(O)O-[(C1-C4)alkyl]-OH, -[(C1-C4)alkyl]-OC(O)O- [(C1-C4)alkyl]-O-[(C1-C4)alkyl], -[(C1-C4)alkyl]-SC(O)-[(C1-C4)alkyl], -[(C1-C4)alkyl]- SC(O)-[halo(C1-C4)alkyl], -[(C1-C4)alkyl]-SC(O)-[(C1-C4)alkyl]-OH, -[(C1-C4)alkyl]-SC(O)- [(C1-C4)alkyl]-O-[(C1-C4)alkyl], -[(C1-C4)alkyl]-OC(O)NH(C1-C4)alkyl], -[(C1-C4)alkyl]- OC(O)N[(C1-C4)alkyl]2, and aryl, wherein said 5- to 6- membered heteroaryl and aryl are each optionally and independently substituted with, as valency permits, 1 to 2 groups selected from halo, cyano, and (C1-C4)alkyl and wherein said 5- to 7-membered heterocyclyl of [(C1- C4)alkyl]-OC(O)O-[5- to 7-membered heterocyclyl] and [(C1-C4)alkyl]-OC(O)-[5- to 7- membered heterocyclyl] are each optionally and independently substituted with, as valency permits 1 to 2 groups selected from C(O)ORh; R2is selected from hydrogen, halo, (C1-C4)alkyl, halo(C1-C4)alkyl, (C1-C4)alkoxy, halo(C1-C4)alkoxy, hydroxy(C1-C4)alkyl, cyano, and hydroxyl; R3and R4are each independently selected from hydrogen, halo, (C1-C4)alkyl, halo(C1- C4)alkyl, hydroxy(C1-C4)alkyl, -(C1-C4)alkylphenyl, (C1-C4)alkoxy, halo(C1-C4)alkoxy, -(C1- C4)alkyl(C1-C4)alkoxy, hydroxyl, cyano, -NRaRb, phenyl, (C3-C6)cycloalkyl, 5- to 6- membered heteroaryl, and 4- to 6-membered heterocyclyl, wherein said phenyl, (C3- C6)cycloalkyl, 5- to 6-membered heteroaryl, and 4- to 6-membered heterocyclyl are each optionally substituted with, as valency permits, 1 to 3 groups selected from RS; R5and R6are each independently selected from hydrogen, phenyl, and (C1-C4)alkyl; R7is selected from E, -R10AE, (C1-C4)alkyl, phenyl, 4- to 9-membered monocyclic or bicyclic heterocyclyl, and 5- to 10-membered monocyclic or bicyclic heteroaryl, wherein said (C1-C4)alkyl is optionally substituted with, as valency permits, 1 to 3 groups selected from RYand said phenyl, 4- to 9-membered monocyclic or bicyclic heterocyclyl, and 5- to 10-membered monocyclic or bicyclic heteroaryl are each optionally substituted with, as valency permits, R11and / or 1 to 3 groups selected from RZ; or R6and R7together with the nitrogen atom to which they are attached form a 4- to 14- membered monocyclic or bicyclic heterocyclyl or a 5- to 12-membered monocyclic or bicyclic heteroaryl, each of which being optionally substituted with, as valency permits, R12and / or 1 to 3 groups selected from RQ; R8is selected from hydrogen, (C1-C4)alkyl, halo(C1-C4)alkyl, (C3-C6)cycloalkyl, 5- to 7-membered heterocyclyl, -(C1-C4)[5- to 7-membered heterocyclyl], 5- to 10-membered heteroaryl, -(C1-C4)[5- to 10-membered heteroaryl], phenyl, -(C1-C4)alkylphenyl, –C(O)RHa, – C(O)ORHa, -C(O)NRHaRHb, -C(O)ORHa, -SORHaRHband -SO2RHa, wherein said (C3-C6)cycloalkyl, 5- to 7-membered heterocyclyl, 5- to 10-membered heteroaryl, phenyl, the phenyl on (C1-C4)alkylphenyl, the 5- to 7-membered heterocyclyl on -(C1-C4)[5- to 7- membered heterocyclyl], and the 5- to 6-membered heteroaryl on -(C1-C4)[5- to 6-membered heteroaryl] are each optionally substituted with, as valency permits, 1 to 3 groups selected from RU; R9is selected from –R10E and –C(O)R10E; R10, R10A, R10B, R10C, and R10Dare each independently a chemical spacer unit; R11is selected from –NHC(O)R10BE, -OR10BE, phenyl, (C3-C6)cycloalkyl, 5- to 6- membered heteroaryl, and 4- to 6-membered heterocyclyl each of said phenyl, (C3- C6)cycloalkyl, 5- to 6-membered heteroaryl, and 4- to 6-membered heterocyclyl being substituted with -OR10BE, -NHR10BE, -[N(C1-C4)alkyl]R10BE, or R10BE, and wherein said 4- to 6-membered heterocyclyl is optionally substituted further with oxo; R12is selected from –NHC(O)R10CE, -OR10CE, phenyl, (C3-C6)cycloalkyl, 5- to 6- membered heteroaryl, and 4- to 6-membered heterocyclyl each of said phenyl, (C3- C6)cycloalkyl, 5- to 6-membered heteroaryl, and 4- to 6-membered heterocyclyl being substituted with -OR10CE, -NHR10CE, -[N(C1-C4)alkyl]R10CE, or R10CE, and wherein said 4- to 6-membered heterocyclyl is optionally substituted further with oxo; R13is selected from –NHC(O)R10DE, -OR10DE, phenyl, (C3-C6)cycloalkyl, 5- to 6- membered heteroaryl, and 4- to 6-membered heterocyclyl each of said phenyl, (C3- C6)cycloalkyl, 5- to 6-membered heteroaryl, and 4- to 6-membered heterocyclyl being substituted with -OR10DE, -NHR10DE, -[N(C1-C4)alkyl]R10DE, or R10DE, and wherein said 4- to 6-membered heterocyclyl is optionally substituted further with oxo; E is a chemical moiety that binds to E3 ligase; RHais selected from (C1-C10)alkyl, (C2-C10)alkenyl, (C2-C10)alkynyl, phenyl, 5- to 10- membered monocyclic or bicyclic heteroaryl, and 4- to 10-membered monocyclic or bicyclic heterocyclyl, wherein said (C1-C10)alkyl, (C2-C10)alkenyl, (C2-C10)alkynyl are each optionally substituted with, as valency permits, 1 to 2 groups selected from ROand wherein said 5-to 10- membered monocyclic or bicyclic heteroaryl and said 4-to 10-membered monocyclic or bicyclic heterocyclyl are each optionally substituted with, as valency permits, 1 to 3 groups selected from halo, (C1-C4)alkyl, halo(C1-C4)alkyl, (C1-C4)alkoxy, halo(C1-C4)alkoxy, oxo, cyano, and 4- to 6-membered heterocyclyl optionally substituted with C1-C4alkyl; ROis selected from halo, (C1-C4)alkoxy, OH, phenyl, NH2, -NH(C1-C10)alkyl, -N[(C1- C10)alkyl], (C3-6cycloalkyl), 4- to 10-membered monocyclic or fused bicyclic heterocyclyl and 5-to 10-membered monocyclic or bicyclic heteroaryl, wherein said 5- to 10-memberedmonocyclic or bicyclic heteroaryl and said 4-to 10-membered monocyclic or bicyclic heterocyclyl are each optionally substituted with, as valency permits, 1 to 3 groups selected from halo, (C1-C4)alkyl, halo(C1-C4)alkyl, (C1-C4)alkoxy, halo(C1-C4)alkoxy, oxo, and cyano; RHbis hydrogen or (C1-C4)alkyl; AA is the residue of an alpha or beta natural or non-natural amino acid; RTand RTyare each independently selected from (C1-C4)alkyl, benzyl, and phenyl, wherein said phenyl is optionally substituted with 1 or 2 groups selected from halo, (C1- C4)alkyl, and halo(C1-C4)alkyl; RQand RUare each independently selected from halo, (C2-C4)alkenyl, (C1-C4)alkyl, (C1-C4)alkoxy, halo(C1-C4)alkoxy, cyano, phenyl, hydroxyl, 4- to 9-membered monocyclic or bicyclic heterocyclyl, 5- to 10-membered monocyclic or bicyclic heteroaryl, (C3-C6)cycloalkyl, oxo, imino, -ORe, -C(O)Rg, -C(O)ORe, -NRcC(O)Re, -C(O)NRcRd, -NRaRb, -S(O)ReRf, - S(O)2Rf, -S(O)=NH(C1-C4)alkyl, -S(O)NReRf, and -S(O)2NReRf, wherein said (C2-C4)alkenyl and (C1-C4)alkyl are each optionally and independently substituted with, as valency permits, 1 to 3 groups selected from RM, and wherein said phenyl, 5- to 10- membered monocyclic or bicyclic heteroaryl, (C3-C6)cycloalkyl, and 4- to 9-membered monocyclic or bicyclic heterocyclyl are each optionally and independently substituted with, as valency permits, 1 to 3 groups selected from RF; RYis selected from halo, (C1-C4)alkoxy, halo(C1-C4)alkoxy, cyano, -C(O)Rg, - C(O)ORe, -NHC(O)Re, -NRaRb, -S(O)ReRf, -S(O)2Rf, -S(O)NReRf, -S(O)=NH(C1-C4)alkyl, - S(O)2NReRf, hydroxyl, phenyl, 4- to 6-membered heterocyclyl, and 5- to 10-membered monocyclic or bicyclic heteroaryl, wherein said phenyl, 4- to 6-membered heterocyclyl, and 5- to 10-membered monocyclic or bicyclic heteroaryl are each optionally substituted with, as valency permits, 1 to 3 groups selected from RX; RMand RJare each independently selected from halo, (C1-C4)alkyl, (C1-C4)alkoxy, halo(C1-C4)alkoxy, cyano, -C(O)Rg, -C(O)ORe, -NHC(O)Re, -C(O)NRcRd, -NRaRb, - S(O)ReRf, -S(O)2Rf, -S(O)NReRf, -S(O)=NH(C1-C4)alkyl, -S(O)2NReRf, hydroxyl, phenyl, 4- to 6-membered heterocyclyl, and 5- to 10-membered monocyclic or bicyclic heteroaryl, wherein said phenyl, 4- to 6-membered heterocyclyl, and 5- to 10-membered monocyclic or bicyclic heteroaryl are each optionally substituted with, as valency permits, 1 to 3 groups selected from RX; RF, RS, and RXare each independently selected from halo, cyano, (C1-C4)alkyl, (C3- C6cycloalkyl), halo(C1-C4)alkyl, -(C1-C4)alkyl(C1-C4)alkoxy, hydroxy(C1-C4)alkyl, -(C1- C4)alkylphenyl, -(C1-C4)alkylheteroaryl, (C2-C4)alkenyl, halo(C2-C4)alkenyl, (C2-C4)alkynyl,halo(C2-C4)alkynyl, (C1-C4)alkoxy, halo(C1-C4)alkoxy, -ORe, oxo, imino, phenyl, 4- to 6- membered heterocyclyl, -S(O)ReRf, -S(O)2Rf, -S(O)=NH(C1-C4)alkyl, -S(O)NReRf, and - S(O)2NReRf, -C(O)ORe, -NRcC(O)Re, -(C1-C4alkyl)C(O)Rg, -C(O)Rg, -(C1- C4alkyl)C(O)NRcRd, -C(O)NRcRd, -NO2, and -NRaRb, wherein the (C1-C4)alkyl is optionally substituted with cyano, wherein said phenyl, said 4- to 6-membered heterocyclyl, and said phenyl for -(C1-C4)alkylphenyl are each optionally and independently substituted with, as valency permits 1 to 3 groups selected from halo, cyano, oxo, (C1-C10)alkyl, (C2-C10)alkenyl, (C2-C10)alkynyl, halo(C1-C10)alkyl, (C1-C10)alkoxy, and halo(C1-C10)alkoxy, wherein said (C1- C10)alkyl, (C2-C10)alkenyl and (C2-C10)alkynyl are each optionally substituted with, as valency permits a 5-to 10-membered monocyclic or bicyclic heteroaryl or a 4-to 10-membered monocyclic or bicyclic heterocyclyl each of said 5-to 10-membered monocyclic and bicyclic heteroaryl or a 4-to 10-membered monocyclic or bicyclic heterocyclyl being optionally substituted with oxo or a 5- to 7-membered heterocyclyl that is optionally substituted with 1 to 2 oxo; RZis selected from halo, cyano, (C1-C4)alkyl, (C3-C6cycloalkyl), halo(C1-C4)alkyl, - (C1-C4)alkyl(C1-C4)alkoxy, hydroxy(C1-C4)alkyl, -(C1-C4)alkylphenyl, -(C1- C4)alkylheteroaryl, (C2-C4)alkenyl, halo(C2-C4)alkenyl, (C2-C4)alkynyl, halo(C2-C4)alkynyl, (C1-C4)alkoxy, halo(C1-C4)alkoxy, -ORe, oxo, imino, phenyl, 4- to 6-membered heterocyclyl, -S(O)ReRf, -S(O)2Rf, -S(O)=NH(C1-C4)alkyl, -S(O)NReRf, and -S(O)2NReRf, -C(O)ORe, - NRcC(O)Re, -(C1-C4alkyl)C(O)Rg, -C(O)Rg, -(C1-C4alkyl)C(O)NRcRd, -C(O)NRcRd, -NO2, and -NRaRb, wherein the (C1-C4)alkyl is optionally substituted with cyano, wherein said phenyl, said 4- to 6-membered heterocyclyl, and said phenyl for -(C1-C4)alkylphenyl are each optionally and independently substituted with, as valency permits R13and / or 1 to 3 groups selected from halo, cyano, oxo, (C1-C10)alkyl, (C2-C10)alkenyl, (C2-C10)alkynyl, halo(C1- C10)alkyl, (C1-C10)alkoxy, and halo(C1-C10)alkoxy, wherein said (C1-C10)alkyl, (C2- C10)alkenyl and (C2-C10)alkynyl are each optionally substituted with, as valency permits a 5-to 10-membered monocyclic or bicyclic heteroaryl or a 4-to 10-membered monocyclic or bicyclic heterocyclyl each of said 5-to 10-membered monocyclic and bicyclic heteroaryl or a 4-to 10- membered monocyclic or bicyclic heterocyclyl being optionally substituted with oxo or a 5- to 7-membered heterocyclyl that is optionally substituted with 1 to 2 oxo; Ra, Rb, Rc, Rd, Re, Rf, Rg, and Rhare each independently selected from, as valency permits, hydrogen, (C1-C4)alkyl, (C2-C4)alkynyl, -(C1-C4)alkylphenyl, phenyl, (C3-C6)cycloalkyl, 4- to 6-membered heterocyclyl and 5- to 6-membered heteroaryl, wherein said (C1-C4)alkyl is optionally substituted with, as valency permits, 1 to 3 groups selected from RJ, and said phenyl,(C3-C6)cycloalkyl, 4- to 6-membered heterocyclyl, and 5- to 6-membered heteroaryl are each independently optionally substituted with, as valency permits, 1 to 3 groups selected from halo, cyano, (C1-C4)alkyl, halo(C1-C4)alkyl, (C1-C4)alkoxy, halo(C1-C4)alkoxy, hydroxyl, phenyl, and benzyl.

[0012] In one aspect, the disclosed compounds of Formula I and pharmaceutically acceptable salts thereof act as protein degraders of STAT3 and / or STAT6, and are useful in a variety of therapeutic applications such as, for example, in treating cancer and inflammatory conditions.

[0013] Pharmaceutical compositions comprising the compounds and pharmaceutically acceptable salts of Formula I, as well as methods for their preparation are also included.

[0014] Methods of treating conditions responsive to the degradation of STAT3 and / or STAT6 using the described compounds, pharmaceutically acceptable salts, and compositions thereof are also included. DETAILED DESCRIPTION 1. General Description of Compounds

[0015] The present invention provides novel bifunctional compounds for degradation of STAT3 and / or STAT6 by recruiting them to E3 uniquitin ligase for degradation. The advantage of using the methods of the invention are that a broad range of targets that may be modulalted by recruiting E3 ubiquitin ligase for degradation.

[0016] In certain aspects, the invention provides effective degraders of the STAT3 and / or STAT6. The degraders of STAT3 and / or STAT6 have general Formula A:

[0017] wherein, TBM is target binding moiety; DM is degradation moiety; and L is a linker between TBM and DM. A TBM is a moiety that binds to a target protein that should be degraded. In certain embodiments, the TBM is the moiety that binds to STAT3 and / or STAT6. The degradation moiety is responsible for induding degradation of the target. In certain embodiments, the degradation moiety acts by recruitment of ubiquiting E3 ligase to the target attached to TBM, and thus results in degradation of the target.

[0018] In certain aspects, the compounds of the invention provide that the TBM moiety comprises a STAT3 and / or STAT6 binding moiety. The STAT3 and / or STAT6 binding moeity are inhibitors and / or modulators of STAT3 and / or STAT6. In certain embodiments, the STAT3 and / or STAT6 binding are compounds provided in WO 2023 / 164680, which is incorporated by reference in its entirey.

[0019] In a first embodiment, the invention provides compounds wherein the TBM is a compound of Formula (I’):wherein R1, R2, R3, R4, R5, R6, R7, X, q, t, and q are described above.

[0020] In a second embodiment, provided herein is a compound of structural Formula I:; or a pharmaceutically acceptable salt thereof, wherein: q is 0 or 1 and t is 0, 1, or 2, provided that at least one of q or t is 1; p is 1 or 2; X is selected from S, SO2, -S(=O)=NH, -NR8, and -NR9; R1is selected from an 8- to 10-membered fused bicyclic heteroaryl substituted with – CR1aR2aP(O)OR1bOR2b, –CR1aR2aP(O)[OR1b][NH(AA)C(O)ORT], –P(O)OR1bOR2b, - [P(O)[NHRTy][NH(AA)C(O)ORT], or –P(O)[OR1b][NH(AA)C(O)ORT]; an 8- to 10- membered fused bicyclic heterocyclyl substituted with –CR1aR2aP(O)OR1bOR2b, – CR1aR2aP(O)[OR1b][NH(AA)C(O)ORT], –P(O)OR1bOR2b, - [P(O)[NHRTy][NH(AA)C(O)ORT], or –P(O)[OR1b][NH(AA)C(O)ORT]; an aryl substituted with –CR1aR2aP(O)OR1bOR2b, –CR1aR2aP(O)[OR1b][NH(AA)C(O)ORT], –P(O)OR1bOR2b, - [P(O)[NHRTy][NH(AA)C(O)ORT], or –P(O)[OR1b][NH(AA)C(O)ORT], wherein said arylmay be further optionally substituted with 1 or 2 groups independently selected from cyano, (C1-C4)alkoxy, and halo; a -(C1-C4)alkyl(aryl) wherein said aryl portion of -(C1-C4)alkyl(aryl) is substituted with –CR1aR2aP(O)OR1bOR2b, –CR1aR2aP(O)[OR1b][NH(AA)C(O)ORT], – P(O)OR1bOR2b, -[P(O)[NHRTy][NH(AA)C(O)ORT], - [P(O)[NH(AA)C(O)ORT][NH(AA)C(O)ORT], or –P(O)[OR1b][NH(AA)C(O)ORT]; and a - (C2-C4)alkenyl(aryl) wherein said aryl portion of -(C2-C4)alkenyl(aryl) is substituted with – CR1aR2aP(O)OR1bOR2b, –CR1aR2aP(O)[OR1b][NH(AA)C(O)ORT], –P(O)OR1bOR2b, - [P(O)[NHRTy][NH(AA)C(O)ORT], or –P(O)[OR1b][NH(AA)C(O)ORT]; R1aand R2aare each independently selected from hydrogen, cyano, (C1-C4)alkyl, hydroxy(C1-C4)alkyl and fluoro; or R1aand R2ataken together with the carbon they are attached form oxo; R1band R2bare each independently selected from hydrogen, (C1-C4)alkyl, halo(C1- C4)alkyl, -[(C1-C4)alkyl]-OC(O)-[(C1-C4)alkyl], -[(C1-C4)alkyl]-C(O)O-[(C1-C4)alkyl], -[(C1- C4)alkyl]-O-[(C1-C20)alkyl], -[(C1-C4)alkyl]-OC(O)-[halo(C1-C4)alkyl], [(C1-C4)alkyl]- OC(O)O-[5- to 7-membered heterocyclyl], [(C1-C4)alkyl]-OC(O)-[5- to 7-membered heterocyclyl], -[(C1-C4)alkyl]-OC(O)-[(C1-C4)alkyl]-OH, -[(C1-C4)alkyl]-OC(O)-[(C1- C4)alkyl]-O-[(C1-C4)alkyl], -[(C1-C4)alkyl]-OC(O)O-[(C1-C4)alkyl], -[(C1-C4)alkyl]-OC(O)O- [halo(C1-C4)alkyl], -[(C1-C4)alkyl]-OC(O)O-[(C1-C4)alkyl]-OH, -[(C1-C4)alkyl]-OC(O)O- [(C1-C4)alkyl]-O-[(C1-C4)alkyl], -[(C1-C4)alkyl]-SC(O)-[(C1-C4)alkyl], -[(C1-C4)alkyl]- SC(O)-[halo(C1-C4)alkyl], -[(C1-C4)alkyl]-SC(O)-[(C1-C4)alkyl]-OH, -[(C1-C4)alkyl]-SC(O)- [(C1-C4)alkyl]-O-[(C1-C4)alkyl], -[(C1-C4)alkyl]-OC(O)NH(C1-C4)alkyl], -[(C1-C4)alkyl]- OC(O)N[(C1-C4)alkyl]2, and aryl, wherein said 5- to 6- membered heteroaryl and aryl are each optionally and independently substituted with, as valency permits, 1 to 2 groups selected from halo, cyano, and (C1-C4)alkyl and wherein said 5- to 7-membered heterocyclyl of [(C1- C4)alkyl]-OC(O)O-[5- to 7-membered heterocyclyl] and [(C1-C4)alkyl]-OC(O)-[5- to 7- membered heterocyclyl] are each optionally and independently substituted with, as valency permits 1 to 2 groups selected from C(O)ORh; R2is selected from hydrogen, halo, (C1-C4)alkyl, halo(C1-C4)alkyl, (C1-C4)alkoxy, halo(C1-C4)alkoxy, hydroxy(C1-C4)alkyl, cyano, and hydroxyl; R3and R4are each independently selected from hydrogen, halo, (C1-C4)alkyl, halo(C1- C4)alkyl, hydroxy(C1-C4)alkyl, -(C1-C4)alkylphenyl, (C1-C4)alkoxy, halo(C1-C4)alkoxy, -(C1- C4)alkyl(C1-C4)alkoxy, hydroxyl, cyano, -NRaRb, phenyl, (C3-C6)cycloalkyl, 5- to 6- membered heteroaryl, and 4- to 6-membered heterocyclyl, wherein said phenyl, (C3-C6)cycloalkyl, 5- to 6-membered heteroaryl, and 4- to 6-membered heterocyclyl are each optionally substituted with, as valency permits, 1 to 3 groups selected from RS; R5and R6are each independently selected from hydrogen, phenyl, and (C1-C4)alkyl; R7is selected from E, -R10AE, (C1-C4)alkyl, phenyl, 4- to 9-membered monocyclic or bicyclic heterocyclyl, and 5- to 10-membered monocyclic or bicyclic heteroaryl, wherein said (C1-C4)alkyl is optionally substituted with, as valency permits, 1 to 3 groups selected from RYand said phenyl, 4- to 9-membered monocyclic or bicyclic heterocyclyl, and 5- to 10-membered monocyclic or bicyclic heteroaryl are each optionally substituted with, as valency permits, R11and / or 1 to 3 groups selected from RZ; or R6and R7together with the nitrogen atom to which they are attached form a 4- to 14- membered monocyclic or bicyclic heterocyclyl or a 5- to 12-membered monocyclic or bicyclic heteroaryl, each of which being optionally substituted with, as valency permits, R12and / or 1 to 3 groups selected from RQ; R8is selected from hydrogen, (C1-C4)alkyl, halo(C1-C4)alkyl, (C3-C6)cycloalkyl, 5- to 7-membered heterocyclyl, -(C1-C4)[5- to 7-membered heterocyclyl], 5- to 10-membered heteroaryl, -(C1-C4)[5- to 10-membered heteroaryl], phenyl, -(C1-C4)alkylphenyl, –C(O)RHa, – C(O)ORHa, -C(O)NRHaRHb, -C(O)ORHa, -SORHaRHband -SO2RHa, wherein said (C3- C6)cycloalkyl, 5- to 7-membered heterocyclyl, 5- to 10-membered heteroaryl, phenyl, the phenyl on (C1-C4)alkylphenyl, the 5- to 7-membered heterocyclyl on -(C1-C4)[5- to 7- membered heterocyclyl], and the 5- to 6-membered heteroaryl on -(C1-C4)[5- to 6-membered heteroaryl] are each optionally substituted with, as valency permits, 1 to 3 groups selected from RU; R9is selected from –R10E and –C(O)R10E; R10, R10A, R10B, R10C, and R10Dare each independently a chemical spacer unit; R11is selected from –NHC(O)R10BE, -OR10BE, phenyl, (C3-C6)cycloalkyl, 5- to 6- membered heteroaryl, and 4- to 6-membered heterocyclyl each of said phenyl, (C3- C6)cycloalkyl, 5- to 6-membered heteroaryl, and 4- to 6-membered heterocyclyl being substituted with -OR10BE, -NHR10BE, -[N(C1-C4)alkyl]R10BE, or R10BE, and wherein said 4- to 6-membered heterocyclyl is optionally substituted further with oxo; R12is selected from –NHC(O)R10CE, -OR10CE, phenyl, (C3-C6)cycloalkyl, 5- to 6- membered heteroaryl, and 4- to 6-membered heterocyclyl each of said phenyl, (C3- C6)cycloalkyl, 5- to 6-membered heteroaryl, and 4- to 6-membered heterocyclyl being substituted with -OR10CE, -NHR10CE, -[N(C1-C4)alkyl]R10CE, or R10CE, and wherein said 4- to 6-membered heterocyclyl is optionally substituted further with oxo;R13is selected from –NHC(O)R10DE, -OR10DE, phenyl, (C3-C6)cycloalkyl, 5- to 6- membered heteroaryl, and 4- to 6-membered heterocyclyl each of said phenyl, (C3- C6)cycloalkyl, 5- to 6-membered heteroaryl, and 4- to 6-membered heterocyclyl being substituted with -OR10DE, -NHR10DE, -[N(C1-C4)alkyl]R10DE, or R10DE, and wherein said 4- to 6-membered heterocyclyl is optionally substituted further with oxo; E is a chemical moiety that binds to E3 ligase; RHais selected from (C1-C10)alkyl, (C2-C10)alkenyl, (C2-C10)alkynyl, phenyl, 5- to 10- membered monocyclic or bicyclic heteroaryl, and 4- to 10-membered monocyclic or bicyclic heterocyclyl, wherein said (C1-C10)alkyl, (C2-C10)alkenyl, (C2-C10)alkynyl are each optionally substituted with, as valency permits, 1 to 2 groups selected from ROand wherein said 5-to 10- membered monocyclic or bicyclic heteroaryl and said 4-to 10-membered monocyclic or bicyclic heterocyclyl are each optionally substituted with, as valency permits, 1 to 3 groups selected from halo, (C1-C4)alkyl, halo(C1-C4)alkyl, (C1-C4)alkoxy, halo(C1-C4)alkoxy, oxo, cyano, and 4- to 6-membered heterocyclyl optionally substituted with C1-C4alkyl; ROis selected from halo, (C1-C4)alkoxy, OH, phenyl, NH2, -NH(C1-C10)alkyl, -N[(C1- C10)alkyl], (C3-6cycloalkyl), 4- to 10-membered monocyclic or fused bicyclic heterocyclyl and 5-to 10-membered monocyclic or bicyclic heteroaryl, wherein said 5- to 10-membered monocyclic or bicyclic heteroaryl and said 4-to 10-membered monocyclic or bicyclic heterocyclyl are each optionally substituted with, as valency permits, 1 to 3 groups selected from halo, (C1-C4)alkyl, halo(C1-C4)alkyl, (C1-C4)alkoxy, halo(C1-C4)alkoxy, oxo, and cyano; RHbis hydrogen or (C1-C4)alkyl; AA is the residue of an alpha or beta natural or non-natural amino acid; RTand RTyare each independently selected from (C1-C4)alkyl, benzyl, and phenyl, wherein said phenyl is optionally substituted with 1 or 2 groups selected from halo, (C1- C4)alkyl, and halo(C1-C4)alkyl; RQand RUare each independently selected from halo, (C2-C4)alkenyl, (C1-C4)alkyl, (C1-C4)alkoxy, halo(C1-C4)alkoxy, cyano, phenyl, hydroxyl, 4- to 9-membered monocyclic or bicyclic heterocyclyl, 5- to 10-membered monocyclic or bicyclic heteroaryl, (C3-C6)cycloalkyl, oxo, imino, -ORe, -C(O)Rg, -C(O)ORe, -NRcC(O)Re, -C(O)NRcRd, -NRaRb, -S(O)ReRf, - S(O)2Rf, -S(O)=NH(C1-C4)alkyl, -S(O)NReRf, and -S(O)2NReRf, wherein said (C2-C4)alkenyl and (C1-C4)alkyl are each optionally and independently substituted with, as valency permits, 1 to 3 groups selected from RM, and wherein said phenyl, 5- to 10- membered monocyclic or bicyclic heteroaryl, (C3-C6)cycloalkyl, and 4- to 9-membered monocyclic or bicyclicheterocyclyl are each optionally and independently substituted with, as valency permits, 1 to 3 groups selected from RF; RYis selected from halo, (C1-C4)alkoxy, halo(C1-C4)alkoxy, cyano, -C(O)Rg, - C(O)ORe, -NHC(O)Re, -NRaRb, -S(O)ReRf, -S(O)2Rf, -S(O)NReRf, -S(O)=NH(C1-C4)alkyl, - S(O)2NReRf, hydroxyl, phenyl, 4- to 6-membered heterocyclyl, and 5- to 10-membered monocyclic or bicyclic heteroaryl, wherein said phenyl, 4- to 6-membered heterocyclyl, and 5- to 10-membered monocyclic or bicyclic heteroaryl are each optionally substituted with, as valency permits, 1 to 3 groups selected from RX; RMand RJare each independently selected from halo, (C1-C4)alkyl, (C1-C4)alkoxy, halo(C1-C4)alkoxy, cyano, -C(O)Rg, -C(O)ORe, -NHC(O)Re, -C(O)NRcRd, -NRaRb, - S(O)ReRf, -S(O)2Rf, -S(O)NReRf, -S(O)=NH(C1-C4)alkyl, -S(O)2NReRf, hydroxyl, phenyl, 4- to 6-membered heterocyclyl, and 5- to 10-membered monocyclic or bicyclic heteroaryl, wherein said phenyl, 4- to 6-membered heterocyclyl, and 5- to 10-membered monocyclic or bicyclic heteroaryl are each optionally substituted with, as valency permits, 1 to 3 groups selected from RX; RF, RS, and RXare each independently selected from halo, cyano, (C1-C4)alkyl, (C3- C6cycloalkyl), halo(C1-C4)alkyl, -(C1-C4)alkyl(C1-C4)alkoxy, hydroxy(C1-C4)alkyl, -(C1- C4)alkylphenyl, -(C1-C4)alkylheteroaryl, (C2-C4)alkenyl, halo(C2-C4)alkenyl, (C2-C4)alkynyl, halo(C2-C4)alkynyl, (C1-C4)alkoxy, halo(C1-C4)alkoxy, -ORe, oxo, imino, phenyl, 4- to 6- membered heterocyclyl, -S(O)ReRf, -S(O)2Rf, -S(O)=NH(C1-C4)alkyl, -S(O)NReRf, and - S(O)2NReRf, -C(O)ORe, -NRcC(O)Re, -(C1-C4alkyl)C(O)Rg, -C(O)Rg, -(C1- C4alkyl)C(O)NRcRd, -C(O)NRcRd, -NO2, and -NRaRb, wherein the (C1-C4)alkyl is optionally substituted with cyano, wherein said phenyl, said 4- to 6-membered heterocyclyl, and said phenyl for -(C1-C4)alkylphenyl are each optionally and independently substituted with, as valency permits 1 to 3 groups selected from halo, cyano, oxo, (C1-C10)alkyl, (C2-C10)alkenyl, (C2-C10)alkynyl, halo(C1-C10)alkyl, (C1-C10)alkoxy, and halo(C1-C10)alkoxy, wherein said (C1- C10)alkyl, (C2-C10)alkenyl and (C2-C10)alkynyl are each optionally substituted with, as valency permits a 5-to 10-membered monocyclic or bicyclic heteroaryl or a 4-to 10-membered monocyclic or bicyclic heterocyclyl each of said 5-to 10-membered monocyclic and bicyclic heteroaryl or a 4-to 10-membered monocyclic or bicyclic heterocyclyl being optionally substituted with oxo or a 5- to 7-membered heterocyclyl that is optionally substituted with 1 to 2 oxo; RZis selected from halo, cyano, (C1-C4)alkyl, (C3-C6cycloalkyl), halo(C1-C4)alkyl, - (C1-C4)alkyl(C1-C4)alkoxy, hydroxy(C1-C4)alkyl, -(C1-C4)alkylphenyl, -(C1-C4)alkylheteroaryl, (C2-C4)alkenyl, halo(C2-C4)alkenyl, (C2-C4)alkynyl, halo(C2-C4)alkynyl, (C1-C4)alkoxy, halo(C1-C4)alkoxy, -ORe, oxo, imino, phenyl, 4- to 6-membered heterocyclyl, -S(O)ReRf, -S(O)2Rf, -S(O)=NH(C1-C4)alkyl, -S(O)NReRf, and -S(O)2NReRf, -C(O)ORe, - NRcC(O)Re, -(C1-C4alkyl)C(O)Rg, -C(O)Rg, -(C1-C4alkyl)C(O)NRcRd, -C(O)NRcRd, -NO2, and -NRaRb, wherein the (C1-C4)alkyl is optionally substituted with cyano, wherein said phenyl, said 4- to 6-membered heterocyclyl, and said phenyl for -(C1-C4)alkylphenyl are each optionally and independently substituted with, as valency permits R13and / or 1 to 3 groups selected from halo, cyano, oxo, (C1-C10)alkyl, (C2-C10)alkenyl, (C2-C10)alkynyl, halo(C1- C10)alkyl, (C1-C10)alkoxy, and halo(C1-C10)alkoxy, wherein said (C1-C10)alkyl, (C2- C10)alkenyl and (C2-C10)alkynyl are each optionally substituted with, as valency permits a 5-to 10-membered monocyclic or bicyclic heteroaryl or a 4-to 10-membered monocyclic or bicyclic heterocyclyl each of said 5-to 10-membered monocyclic and bicyclic heteroaryl or a 4-to 10- membered monocyclic or bicyclic heterocyclyl being optionally substituted with oxo or a 5- to 7-membered heterocyclyl that is optionally substituted with 1 to 2 oxo; Ra, Rb, Rc, Rd, Re, Rf, Rg, and Rhare each independently selected from, as valency permits, hydrogen, (C1-C4)alkyl, (C2-C4)alkynyl, -(C1-C4)alkylphenyl, phenyl, (C3-C6)cycloalkyl, 4- to 6-membered heterocyclyl and 5- to 6-membered heteroaryl, wherein said (C1-C4)alkyl is optionally substituted with, as valency permits, 1 to 3 groups selected from RJ, and said phenyl, (C3-C6)cycloalkyl, 4- to 6-membered heterocyclyl, and 5- to 6-membered heteroaryl are each independently optionally substituted with, as valency permits, 1 to 3 groups selected from halo, cyano, (C1-C4)alkyl, halo(C1-C4)alkyl, (C1-C4)alkoxy, halo(C1-C4)alkoxy, hydroxyl, phenyl, and benzyl. 2. Definitions

[0021] When used in connection to describe a chemical group that may have multiple points of attachment, a hyphen (-) designates the point of attachment of that group to the variable to which it is defined. For example, -NRcC(O)Remeans that the point of attachment for this group occurs on the nitrogen atom.

[0022] The terms “halo” and “halogen” refer to an atom selected from fluorine (fluoro, -F), chlorine (chloro, -Cl), bromine (bromo, -Br), and iodine (iodo, -I).

[0023] Unless otherwise specified, the term “alkyl” when used alone or as part of a larger moiety, such as “haloalkyl”, and the like, means saturated straight-chain or branched monovalent hydrocarbon radical.

[0024] The term “haloalkyl” includes mono, poly, and perhaloalkyl groups where the halogens are independently selected from fluorine, chlorine, bromine, and iodine.

[0025] “Alkoxy” means an alkyl radical attached through an oxygen linking atom, represented by –O-alkyl. For example, “(C1-C4)alkoxy” includes methoxy, ethoxy, proproxy, and butoxy.

[0026] “Haloalkoxy” is a haloalkyl group which is attached to another moiety via an oxygen atom such as, e.g., –OCHF2or –OCF3.

[0027] The term “oxo” means the group =O.

[0028] The term “imino” means the group =NH.

[0029] Unless otherwise specified, the term “heteroaryl” refers to a 5- to 12-membered aromatic radical containing 1-4 heteroatoms selected from N, O, and S. In some instances, nitrogen atoms in a heteroaryl may be quaternized. The term “heteroaryl” may be used interchangeably with the terms “heteroaryl ring”, “heteroaryl group”, or “heteroaromatic”. A heteroaryl group may be mono- or bi-cyclic. Monocyclic heteroaryl includes, for example, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, etc. Bi-cyclic heteroaryls include groups in which a monocyclic heteroaryl ring is fused to one or more aryl or heteroaryl rings. Nonlimiting examples include indolyl, benzooxazolyl, benzooxodiazolyl, indazolyl, benzimidazolyl, benzthiazolyl, benzothiopheneyl, quinolinyl, quinazolinyl, quinoxalinyl, pyrrolopyridinyl, pyrrolopyrimidinyl, pyrrolopyridinyl, thienopyridinyl, thienopyrimidinyl, indolizinyl, purinyl, cinnolinyl, naphthyridinyl, and pteridinyl. It will be understood that when specified, optional substituents on a heteroaryl group may be present on any substitutable position and, include, e.g., the position at which the heteroaryl is attached (where valency permits).

[0030] Unless otherwise specified, the term “heterocyclyl” means a 4- to 12-membered saturated or partially unsaturated heterocyclic ring containing 1 to 4 heteroatoms independently selected from N, O, and S. The terms “heterocycle”, “heterocyclyl”, “heterocyclyl ring”, “heterocyclic group”, “heterocyclic moiety”, and “heterocyclic radical”, are used interchangeably herein. A heterocyclyl ring can be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure. A heterocyclyl group may be mono- or bicyclic (e.g., a bridged, fused, or spiro bicyclic ring). Examples of monocyclic saturated or partially unsaturated heterocyclic radicals include, without limitation, azetidinyl, tetrahydrofuranyl, tetrahydrothienyl, terahydropyranyl, pyrrolidinyl, pyrrolidonyl, piperidinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, morpholinyl, dihydrofuranyl, dihydropyranyl, dihydropyridinyl, tetrahydropyridinyl, dihydropyrimidinyl, tetrahydropyrimidinyl, dihydrooxadizolyl, and dihydroisoxazolyl. Bi-cyclic heterocyclyl groups include, e.g.,unsaturated heterocyclic radicals fused to another unsaturated heterocyclic radical, cycloalkyl, aryl, or heteroaryl ring, such as for example, benzodioxolyl, dihydrobenzodioxinyl, dihydrobenzofuranyl, dihydrobenzothiophenyl, 5-oxa-2,6-diazaspiro[3.4]oct-6-enyl, 6-thia- 2,7-diazaspiro[3.4]octanyl, 2,6-diazaspiro[3.3]heptanyl, spiro[indoline-3,3'-pyrrolidine]-yl, thiochromanyl, and the like. It will be understood that when specified, optional substituents on a heterocyclyl group may be present on any substitutable position and, include, e.g., the position at which the heterocyclyl is attached (where valency permits).

[0031] The term “spiro” refers to two rings that shares one ring atom (e.g., carbon).

[0032] The term “fused” refers to two rings that share two adjacent ring atoms with one another.

[0033] The term “bridged” refers to two rings that share three adjacent ring atoms with one another.

[0034] The term “aryl” refers to an aromatic carbocyclic single ring or two fused ring system containing 6 to 10 carbon atoms. Examples include phenyl, indanyl, tetrahydronaphthalene, and naphthyl. In one aspect, the aryl is phenyl or naphthyl.

[0035] The terms “cycloalkyl”, used alone or as part of a larger moiety, refers to a saturated cyclic aliphatic monocyclic or bicyclic ring system, as described herein, having from, unless otherwise specified, 3 to 10 carbon ring atoms. Monocyclic cycloalkyl groups include, without limitation, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cycloheptenyl, and cyclooctyl. It will be understood that when specified, optional substituents on a cycloalkyl or cycloaliphatic group may be present on any substitutable position and, include, e.g., the position at which the cycloalkyl group is attached.

[0036] The term alkylene refers to a refers to a bivalent radical of a saturated, straight or branched chain hydrocarbon (e.g., CH2) of the specified length.

[0037] The term alkynylene refers to an alkylene group that has at least one triple bond within the chain e.g., -(CH2)5CCH-.

[0038] The “residue of an amino acid” is the moiety remaining after formation of a bond between a reactive group in another compound (e.g., an amino group) and the carboxylic acid in the amino acid, after formation of a bond between a reactive group in another compound (e.g., a carboxylic acid) and the amino group in the amino acid, or both. As a consequence of the bond(s) formation, the carboxylic acid in the amino acid no longer has the OH group and instead has a bond between the carbonyl group and the reactive group in the compound; the amino group has only one hydrogen atom and instead has a bond between the reactive group in the other compound and the nitrogen of the amino group; or both. For example, the “residueof an alpha amino acid” can be depicted structurally as NH2CR’R-C(O)-, -NHCR’R-C(O)OH or -NHCR’R-C(O)-; and the “residue of an beta amino acid” can be depicted structurally as or NH2CR’RCH2-C(O)-, -NHCR’RCH2-C(O)OH or -NHCR’RCH2-C(O)-, where R’ is H or C1- C6 alkyl and R is H or C1-C6 alkyl optionally substituted with 1 to 3 groups selected from halo, (C1-C3)alkoxy, OH, NH2, -NH(C1-C4alkyl), -N[(C1-C4alkyl)]2, SH, S(C1-C4alkyl), imino, COOH, -COO(C1-C4alkyl), -CO(C1-C4alkyl), -CONH(C1-C4alkyl)phenyl, phenyl, and 5- to 10-membered heteroaryl, wherein said C1-C6alkyl may also be optionally interrupted by a sulfur or nitrogen heteroatom and wherein said phenyl is optionally substituted with 1 to 3 groups selected from OH, cyano, (C1-C4alkyl), and halo(C1-C4alkyl); or R is taken together with the nitrogen atoms from the alpha or beta amino acid residue to form a 4- to 6-membered heterocyclyl. For naturally occurring alpha amino acid (i.e., amino acids that occur in nature), R’ is H and R is selected from hydrogen, methyl, isopropyl, -CH2CH(CH3)2, -(CH2)2SCH3, - CH(CH3)(CH2CH3), CH2OH, -CH(OH)(CH3), CH2SH, -CH2C(O)NH2, -(CH2)2C(O)NH2, benzyl, p-hydroxybenzyl, -CH2(indolyl), -(CH2)4NH2, -(CH2)3NHC(=NH2)NH2, - CH2(imidazolyl), -(CH2)COOH, and -(CH2)2COOH; or R taken together with the nitrogen atom of the alpha or beta amio acid residue forms a pyrrolidinyl ring.

[0039] Non-natural amino acids are known in the art and include e.g., alpha-alkyl amino acids (e.g., alpha methyl), alpha-alkylalkoxy amino acids (e.g., alpha -CH2OCH3), N-methyl amino acids, homo-amino acids, etc.

[0040] A chemical spacer unit refers to refers to a cleavable or non-cleavable that joins the E3 ligase binder to the remainder of the molecule described herein. In one aspect, the chemical spacer is uncleavable in vivo. In one aspect, the chemical spacer comprises one or more cyclic ring systems. In another aspect, the chemical spacer comprises an alkyl chain optionally substituted by and / or interrupted with one or more chemical groups. In one aspect, the chemical spacer comprises optimal spatial and chemical properties to effectuate optimal therapeutic activity.

[0041] A chemical moiety that binds to E3 ligase refers to a chemical structure that binds to the pocket or surface of E3 ligase. E3 ligase binders are known in the art and include, but are not limited to CRBN, VHL, IAP, or MDM2 based E3 binders. See e.g., Angewandte Chemie International Edition 59(36), May 2020, DOI:10.1002 / anie.202004310; Medicinal Chemistry Communication 10(10), August 2019, DOI:10.1039 / C9MD00272C; and Molecules 2022, 27(19), 6515; https: / / doi.org / 10.3390 / molecules27196515.

[0042] Compounds having one or more chiral centers can exist in various stereoisomeric forms. Stereoisomers are compounds that differ only in their spatial arrangement.Stereoisomers include all diastereomeric, enantiomeric, and epimeric forms as well as racemates and mixtures thereof. A “geometric isomer” refers to isomers that differ in the orientation of substituent group in relationship to a carbon-carbon double bond, a cycloalkyl ring, or a bridged bicyclic system. Atoms (other than H) on each side of a carbon-carbon double bond may be in an E (substituents are on opposite sides of the carbon-carbon double bond) or Z (substituents are oriented on the same side) configuration. “Cis” refers to substituents oriented on the same side of the ring, whereas “trans” refers to substituents oriented on opposite sides of the ring.

[0043] When the stereochemical configuration at a chiral center in a compound having one or more chiral centers is depicted by its chemical name (e.g., where the configuration is indicated in the chemical name by “R” or “S”) or structure (e.g., the configuration is indicated by “wedge” bonds), the enrichment of the indicated configuration relative to the opposite configuration is greater than 50%, 60%, 70%, 80%, 90%, 99% or 99.9%. “Enrichment of the indicated configuration relative to the opposite configuration” is a mole percent and is determined by dividing the number of compounds with the indicated stereochemical configuration at the chiral center(s) by the total number of all of the compounds with the same or opposite stereochemical configuration in a mixture.

[0044] When a geometric isomer is depicted by name or structure, the enrichment of the indicated isomer relative to the opposite isomer is greater than 50%, 60%, 70%, 80%, 90%, 99% or 99.9%. “Enrichment of the indicated isomer relative to the opposite isomer” is a mole percent and is determined by dividing the number of compounds with the indicated geometrical configuration by the total number of all of the compounds with the same or opposite geometrical configuration in a mixture.

[0045] When a disclosed compound is named or depicted by structure without indicating stereochemistry, it is understood that the name or the structure encompasses one of the possible stereoisomers or geometric isomers free of the others, or a mixture of the encompassed stereoisomers or geometric isomers.

[0046] The terms “subject” and “patient” may be used interchangeably, and means a mammal in need of treatment, e.g., companion animals (e.g., dogs, cats, and the like), farm animals (e.g., cows, pigs, horses, sheep, goats and the like) and laboratory animals (e.g., rats, mice, guinea pigs and the like). Typically, the subject is a human in need of treatment.

[0047] As used herein, the terms “treatment,” “treat,” and “treating” refer to reversing, alleviating, delaying the onset of, or inhibiting the progress of a disease or disorder, or one or more symptoms thereof, as described herein. In some aspects, treatment may be administeredafter one or more symptoms have developed, i.e., therapeutic treatment. In other aspects, treatment may be administered in the absence of symptoms. For example, treatment may be administered to a susceptible individual prior to the onset of symptoms (e.g., in light of a history of symptoms and / or in light of exposure to a particular organism, or other susceptibility factors), i.e., prophylactic treatment. Treatment may also be continued after symptoms have resolved, for example to delay their recurrence.

[0048] The term “pharmaceutically acceptable carrier” refers to a non-toxic carrier, adjuvant, or vehicle that does not destroy the pharmacological activity of the compound with which it is formulated. Pharmaceutically acceptable carriers, adjuvants or vehicles that may be used in the compositions described herein include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene- polyoxypropylene-block polymers, polyethylene glycol and wool fat.

[0049] For use in medicines, the salts of the compounds described herein refer to non-toxic “pharmaceutically acceptable salts.” Pharmaceutically acceptable salt forms include pharmaceutically acceptable acidic / anionic or basic / cationic salts. Suitable pharmaceutically acceptable acid addition salts of the compounds described herein include e.g., salts of inorganic acids (such as hydrochloric acid, hydrobromic, phosphoric, nitric, and sulfuric acids) and of organic acids (such as, acetic acid, benzenesulfonic, benzoic, methanesulfonic, and p- toluenesulfonic acids). Compounds of the present teachings with acidic groups such as carboxylic acids can form pharmaceutically acceptable salts with pharmaceutically acceptable base(s). Suitable pharmaceutically acceptable basic salts include e.g., ammonium salts, alkali metal salts (such as sodium and potassium salts) and alkaline earth metal salts (such as magnesium and calcium salts). Compounds with a quaternary ammonium group also contain a counteranion such as chloride, bromide, iodide, acetate, perchlorate and the like. Other examples of such salts include hydrochlorides, hydrobromides, sulfates, methanesulfonates, nitrates, benzoates and salts with amino acids such as glutamic acid.

[0050] The term “effective amount” or “therapeutically effective amount” refers to an amount of a compound described herein that is sufficient to achieve the desired therapeutic effect (such as treatment of a condition recited herein) under the conditions of administration.3. General Description of the Compounds of the Invention

[0051] In certain aspects, the invention provides effective degraders of the STAT3 and / or STAT6. The degraders of STAT3 and / or STAT6 have general Formula A:

[0052] wherein, TBM is target binding moiety; DM is degradation moiety; and L is a linker between TBM and DM. A TBM is a moiety that binds to a target protein that should be degraded. In certain embodiments, the TBM is the moiety that binds to STAT3 and / or STAT6. The degradation moiety is responsible for induding degradation of the target. In certain embodiments, the degradation moiety acts by recruitment of ubiquiting E3 ligase to the target attached to TBM, and thus results in degradation of the target.

[0053] In certain aspects, the compounds of the invention provide that the TBM moiety comprises a STAT3 and / or STAT6 binding moiety. The STAT3 and / or STAT6 binding moeity are inhibitors and / or modulators of STAT3 and / or STAT6. In certain embodiments, the STAT3 and / or STAT6 binding are compounds provided in WO 2023 / 164680, which is incorporated by reference in its entirey.

[0054] In certain embodiments, the STAT3 and / or STAT6 binding moiety is a compound of Formula (I’): wherein:q is 0 or 1 and t is 0, 1, or 2, provided that at least one of q or t is 1; p is 1 or 2; X is selected from S, SO2, -S(=O)=NH, and NR8; R1is selected from an 8- to 10-membered fused bicyclic heteroaryl substituted with – CR1aR2aP(O)OR1bOR2b, –CR1aR2aP(O)[OR1b][NH(AA)C(O)ORT], –P(O)OR1bOR2b, -[P(O)[NHRTy][NH(AA)C(O)ORT], or –P(O)[OR1b][NH(AA)C(O)ORT]; an 8- to 10- membered fused bicyclic heterocyclyl substituted with –CR1aR2aP(O)OR1bOR2b, – CR1aR2aP(O)[OR1b][NH(AA)C(O)ORT], –P(O)OR1bOR2b, - [P(O)[NHRTy][NH(AA)C(O)ORT], or –P(O)[OR1b][NH(AA)C(O)ORT]; an aryl substituted with –CR1aR2aP(O)OR1bOR2b, –CR1aR2aP(O)[OR1b][NH(AA)C(O)ORT], –P(O)OR1bOR2b, - [P(O)[NHRTy][NH(AA)C(O)ORT], or –P(O)[OR1b][NH(AA)C(O)ORT], wherein said aryl may be further optionally substituted with 1 or 2 groups independently selected from cyano, (C1-C4)alkoxy, and halo; a -(C1-C4)alkyl(aryl) wherein said aryl portion of -(C1-C4)alkyl(aryl) is substituted with –CR1aR2aP(O)OR1bOR2b, –CR1aR2aP(O)[OR1b][NH(AA)C(O)ORT], – P(O)OR1bOR2b, -[P(O)[NHRTy][NH(AA)C(O)ORT], - [P(O)[NH(AA)C(O)ORT][NH(AA)C(O)ORT], or –P(O)[OR1b][NH(AA)C(O)ORT]; and a - (C2-C4)alkenyl(aryl) wherein said aryl portion of -(C2-C4)alkenyl(aryl) is substituted with – CR1aR2aP(O)OR1bOR2b, –CR1aR2aP(O)[OR1b][NH(AA)C(O)ORT], –P(O)OR1bOR2b, - [P(O)[NHRTy][NH(AA)C(O)ORT], or –P(O)[OR1b][NH(AA)C(O)ORT]; R1aand R2aare each independently selected from hydrogen, cyano, (C1-C4)alkyl, hydroxy(C1-C4)alkyl and fluoro; or R1aand R2ataken together with the carbon they are attached form oxo; R1band R2bare each independently selected from hydrogen, (C1-C4)alkyl, halo(C1- C4)alkyl, -[(C1-C4)alkyl]-OC(O)-[(C1-C4)alkyl], -[(C1-C4)alkyl]-C(O)O-[(C1-C4)alkyl], -[(C1- C4)alkyl]-O-[(C1-C20)alkyl], -[(C1-C4)alkyl]-OC(O)-[halo(C1-C4)alkyl], [(C1-C4)alkyl]- OC(O)O-[5- to 7-membered heterocyclyl], [(C1-C4)alkyl]-OC(O)-[5- to 7-membered heterocyclyl], -[(C1-C4)alkyl]-OC(O)-[(C1-C4)alkyl]-OH, -[(C1-C4)alkyl]-OC(O)-[(C1- C4)alkyl]-O-[(C1-C4)alkyl], -[(C1-C4)alkyl]-OC(O)O-[(C1-C4)alkyl], -[(C1-C4)alkyl]-OC(O)O- [halo(C1-C4)alkyl], -[(C1-C4)alkyl]-OC(O)O-[(C1-C4)alkyl]-OH, -[(C1-C4)alkyl]-OC(O)O- [(C1-C4)alkyl]-O-[(C1-C4)alkyl], -[(C1-C4)alkyl]-SC(O)-[(C1-C4)alkyl], -[(C1-C4)alkyl]- SC(O)-[halo(C1-C4)alkyl], -[(C1-C4)alkyl]-SC(O)-[(C1-C4)alkyl]-OH, -[(C1-C4)alkyl]-SC(O)- [(C1-C4)alkyl]-O-[(C1-C4)alkyl], -[(C1-C4)alkyl]-OC(O)NH(C1-C4)alkyl], -[(C1-C4)alkyl]- OC(O)N[(C1-C4)alkyl]2, and aryl, wherein said 5- to 6- membered heteroaryl and aryl are each optionally and independently substituted with, as valency permits, 1 to 2 groups selected from halo, cyano, and (C1-C4)alkyl and wherein said 5- to 7-membered heterocyclyl of [(C1- C4)alkyl]-OC(O)O-[5- to 7-membered heterocyclyl] and [(C1-C4)alkyl]-OC(O)-[5- to 7- membered heterocyclyl] are each optionally and independently substituted with, as valency permits 1 to 2 groups selected from C(O)ORh;R2is selected from hydrogen, halo, (C1-C4)alkyl, halo(C1-C4)alkyl, (C1-C4)alkoxy, halo(C1-C4)alkoxy, hydroxy(C1-C4)alkyl, cyano, and hydroxyl; R3and R4are each independently selected from hydrogen, halo, (C1-C4)alkyl, halo(C1- C4)alkyl, hydroxy(C1-C4)alkyl, -(C1-C4)alkylphenyl, (C1-C4)alkoxy, halo(C1-C4)alkoxy, -(C1- C4)alkyl(C1-C4)alkoxy, hydroxyl, cyano, -NRaRb, phenyl, (C3-C6)cycloalkyl, 5- to 6- membered heteroaryl, and 4- to 6-membered heterocyclyl, wherein said phenyl, (C3- C6)cycloalkyl, 5- to 6-membered heteroaryl, and 4- to 6-membered heterocyclyl are each optionally substituted with, as valency permits, 1 to 3 groups selected from RS; R5and R6are each independently selected from hydrogen, phenyl, and (C1-C4)alkyl; R7is selected from (C1-C4)alkyl, phenyl, 4- to 9-membered monocyclic or bicyclic heterocyclyl, and 5- to 10-membered monocyclic or bicyclic heteroaryl, wherein said (C1- C4)alkyl is optionally substituted with, as valency permits, 1 to 3 groups selected from RYand said phenyl, 4- to 9-membered monocyclic or bicyclic heterocyclyl, and 5- to 10-membered monocyclic or bicyclic heteroaryl are each optionally substituted with, as valency permits, 1 to 3 groups selected from RZ; or R6and R7together with the nitrogen atom to which they are attached form a 4- to 14- membered monocyclic or bicyclic heterocyclyl or a 5- to 12-membered monocyclic or bicyclic heteroaryl, each of which being optionally substituted with, as valency permits, 1 to 3 groups selected from RQ; R8is selected from hydrogen, (C1-C4)alkyl, halo(C1-C4)alkyl, (C3-C6)cycloalkyl, 5- to 7-membered heterocyclyl, -(C1-C4)[5- to 7-membered heterocyclyl], 5- to 10-membered heteroaryl, -(C1-C4)[5- to 10-membered heteroaryl], phenyl, -(C1-C4)alkylphenyl, –C(O)RHa, – C(O)ORHa, -C(O)NRHaRHb, -C(O)ORHa, -SORHaRHband -SO2RHa, wherein said (C3- C6)cycloalkyl, 5- to 7-membered heterocyclyl, 5- to 10-membered heteroaryl, phenyl, the phenyl on (C1-C4)alkylphenyl, the 5- to 7-membered heterocyclyl on -(C1-C4)[5- to 7- membered heterocyclyl], and the 5- to 6-membered heteroaryl on -(C1-C4)[5- to 6-membered heteroaryl] are each optionally substituted with, as valency permits, 1 to 3 groups selected from RU; RHais selected from (C1-C10)alkyl, (C2-C10)alkenyl, (C2-C10)alkynyl, phenyl, 5- to 10- membered monocyclic or bicyclic heteroaryl, and 4- to 10-membered monocyclic or bicyclic heterocyclyl, wherein said (C1-C10)alkyl, (C2-C10)alkenyl, (C2-C10)alkynyl are each optionally substituted with, as valency permits, 1 to 2 groups selected from ROand wherein said 5-to 10- membered monocyclic or bicyclic heteroaryl and said 4-to 10-membered monocyclic or bicyclic heterocyclyl are each optionally substituted with, as valency permits, 1 to 3 groupsselected from halo, (C1-C4)alkyl, halo(C1-C4)alkyl, (C1-C4)alkoxy, halo(C1-C4)alkoxy, oxo, cyano, and 4- to 6-membered heterocyclyl optionally substituted with C1-C4alkyl; ROis selected from halo, (C1-C4)alkoxy, OH, phenyl, NH2, -NH(C1-C10)alkyl, -N[(C1- C10)alkyl], (C3-6cycloalkyl), 4- to 10-membered monocyclic or fused bicyclic heterocyclyl and 5-to 10-membered monocyclic or bicyclic heteroaryl, wherein said 5- to 10-membered monocyclic or bicyclic heteroaryl and said 4-to 10-membered monocyclic or bicyclic heterocyclyl are each optionally substituted with, as valency permits, 1 to 3 groups selected from halo, (C1-C4)alkyl, halo(C1-C4)alkyl, (C1-C4)alkoxy, halo(C1-C4)alkoxy, oxo, and cyano; RHbis hydrogen or (C1-C4)alkyl; AA is the residue of an alpha or beta natural or non-natural amino acid; RTand RTyare each independently selected from (C1-C4)alkyl, benzyl, and phenyl, wherein said phenyl is optionally substituted with 1 or 2 groups selected from halo, (C1- C4)alkyl, and halo(C1-C4)alkyl; RQand RUare each independently selected from halo, (C2-C4)alkenyl, (C1-C4)alkyl, (C1-C4)alkoxy, halo(C1-C4)alkoxy, cyano, phenyl, hydroxyl, 4- to 9-membered monocyclic or bicyclic heterocyclyl, 5- to 10-membered monocyclic or bicyclic heteroaryl, (C3-C6)cycloalkyl, oxo, imino, -ORe, -C(O)Rg, -C(O)ORe, -NRcC(O)Re, -C(O)NRcRd, -NRaRb, -S(O)ReRf, - S(O)2Rf, -S(O)=NH(C1-C4)alkyl, -S(O)NReRf, and -S(O)2NReRf, wherein said (C2-C4)alkenyl and (C1-C4)alkyl are each optionally and independently substituted with, as valency permits, 1 to 3 groups selected from RM, and wherein said phenyl, 5- to 10- membered monocyclic or bicyclic heteroaryl, (C3-C6)cycloalkyl, and 4- to 9-membered monocyclic or bicyclic heterocyclyl are each optionally and independently substituted with, as valency permits, 1 to 3 groups selected from RF; RYis selected from halo, (C1-C4)alkoxy, halo(C1-C4)alkoxy, cyano, -C(O)Rg, - C(O)ORe, -NHC(O)Re, -NRaRb, -S(O)ReRf, -S(O)2Rf, -S(O)NReRf, -S(O)=NH(C1-C4)alkyl, - S(O)2NReRf, hydroxyl, phenyl, 4- to 6-membered heterocyclyl, and 5- to 10-membered monocyclic or bicyclic heteroaryl, wherein said phenyl, 4- to 6-membered heterocyclyl, and 5- to 10-membered monocyclic or bicyclic heteroaryl are each optionally substituted with, as valency permits, 1 to 3 groups selected from RX; RMand RJare each independently selected from halo, (C1-C4)alkyl, (C1-C4)alkoxy, halo(C1-C4)alkoxy, cyano, -C(O)Rg, -C(O)ORe, -NHC(O)Re, -C(O)NRcRd, -NRaRb, - S(O)ReRf, -S(O)2Rf, -S(O)NReRf, -S(O)=NH(C1-C4)alkyl, -S(O)2NReRf, hydroxyl, phenyl, 4- to 6-membered heterocyclyl, and 5- to 10-membered monocyclic or bicyclic heteroaryl, wherein said phenyl, 4- to 6-membered heterocyclyl, and 5- to 10-membered monocyclic orbicyclic heteroaryl are each optionally substituted with, as valency permits, 1 to 3 groups selected from RX; RF, RS, RX, and RZare each independently selected from halo, cyano, (C1-C4)alkyl, (C3-C6cycloalkyl), halo(C1-C4)alkyl, -(C1-C4)alkyl(C1-C4)alkoxy, hydroxy(C1-C4)alkyl, -(C1- C4)alkylphenyl, -(C1-C4)alkylheteroaryl, (C2-C4)alkenyl, halo(C2-C4)alkenyl, (C2-C4)alkynyl, halo(C2-C4)alkynyl, (C1-C4)alkoxy, halo(C1-C4)alkoxy, -ORe, oxo, imino, phenyl, 4- to 6- membered heterocyclyl, -S(O)ReRf, -S(O)2Rf, -S(O)=NH(C1-C4)alkyl, -S(O)NReRf, and - S(O)2NReRf, -C(O)ORe, -NRcC(O)Re, -(C1-C4alkyl)C(O)Rg, -C(O)Rg, -(C1- C4alkyl)C(O)NRcRd, -C(O)NRcRd, -NO2, and -NRaRb, wherein the (C1-C4)alkyl is optionally substituted with cyano, wherein said phenyl, said 4- to 6-membered heterocyclyl, and said phenyl for -(C1-C4)alkylphenyl are each optionally and independently substituted with, as valency permits 1 to 3 groups selected from halo, cyano, oxo, (C1-C10)alkyl, (C2-C10)alkenyl, (C2-C10)alkynyl, halo(C1-C10)alkyl, (C1-C10)alkoxy, and halo(C1-C10)alkoxy, wherein said (C1-C10)alkyl, (C2-C10)alkenyl and (C2-C10)alkynyl are each optionally substituted with, as valency permits a 5-to 10-membered monocyclic or bicyclic heteroaryl or a 4-to 10- membered monocyclic or bicyclic heterocyclyl each of said 5-to 10-membered monocyclic and bicyclic heteroaryl or a 4-to 10-membered monocyclic or bicyclic heterocyclyl being optionally substituted with oxo or a 5- to 7-membered heterocyclyl that is optionally substituted with 1 to 2 oxo; and Ra, Rb, Rc, Rd, Re, Rf, Rg, and Rhare each independently selected from, as valency permits, hydrogen, (C1-C4)alkyl, (C2-C4)alkynyl, -(C1-C4)alkylphenyl, phenyl, (C3- C6)cycloalkyl, 4- to 6-membered heterocyclyl and 5- to 6-membered heteroaryl, wherein said (C1-C4)alkyl is optionally substituted with, as valency permits, 1 to 3 groups selected from RJ, and said phenyl, (C3-C6)cycloalkyl, 4- to 6-membered heterocyclyl, and 5- to 6-membered heteroaryl are each independently optionally substituted with, as valency permits, 1 to 3 groups selected from halo, cyano, (C1-C4)alkyl, halo(C1-C4)alkyl, (C1-C4)alkoxy, halo(C1- C4)alkoxy, hydroxyl, phenyl, and benzyl.

[0055] In certain embodiments from the present invention, the L and DM moieties are described herein. In certain embodiments, the L and DM moieties are provided in WO 2024 / 064080, which is incorporated by reference in its entirety.

[0056] In some embodiments, DM is an E3 ligase ligand well known to one of ordinary skill in the art including those described in M. Toure, C. M. Crews, Angew. Chem. Int. Ed., 2016, 55, 1966, T. Uehara et al. Nature Chemical Biology, 2017, 13, 675, WO 2017 / 176708, US 2017 / 0281784, WO 2017 / 161119, WO 2017 / 176957, WO 2017 / 176958, WO2015 / 160845, US 2015 / 0291562, WO 2016 / 197032, WO 2016 / 105518, US 2018 / 0009779, WO 2017 / 007612, 2018 / 0134684, WO 2013 / 106643, US 2014 / 0356322, WO 2002 / 020740, US 2002 / 0068063, WO 2012 / 078559, US 2014 / 0302523, WO 2012 / 003281, US 2013 / 0190340, US 2016 / 0022642, WO 2014 / 063061, US 2015 / 0274738, WO 2016 / 118666, US 2016 / 0214972, WO 2016 / 149668, US 2016 / 0272639, WO 2016 / 169989, US 2018 / 0118733, WO 2016 / 197114, US 2018 / 0147202, WO 2017 / 011371, US 2017 / 0008904, WO 2017 / 011590, US 2017 / 0037004, WO 2017 / 079267, US 2017 / 0121321, WO 2017 / 117473, WO 2017 / 117474, WO 2013 / 106646, WO 2014 / 108452, WO 2017 / 197036, US 2019 / 0076540, WO 2017 / 197046, US 2019 / 0076542, WO 2017 / 197051, US 2019 / 0076539, WO 2017 / 197055, US 2019 / 0076541, and WO 2017 / 197056, the entirety of each of which is herein incorporated by reference.

[0057] In certain embodiments, L is attached to a modifiable carbon, oxygen, or nitro substitution or replacement group on one or both of DM and TBM.

[0058] In certain embodiments, the DM is a cereblon E3 ubiquitin ligase binding moiety (hereinafter also referred to as LBM).

[0059] In some embodiments, LBM is selected from the group consisting of: , , , ,,, , , ,

[0060] In some embodiments, LBM is E3 Ubiquitin ligase binding moiety recited in Varfolomeev, E. et al., IAP Antagonists Induce Autoubiquitination of c-IAPs, NF-κB activation, and TNFα- Dependent Apoptosis, Cell, 2007, 131(4): 669-81, such as, for example:wherein L is attached to a modifiable carbon, oxygen, nitrogen or sulfur atom.

[0061] In certain embodiments, LBM is selected from the group consisting of:

[0062] In certain embodiments, the LBM is selected from the group consisting of:

[0063] In certain embodiments, LBM is selected from the group consisting of:

[0064] As describd herein, L is a bivalent moiety that connects TBM and DM.

[0065] In certain embodiments, L is a bivalent moiety that connects TBM to a lysine mimetic.

[0066] In certain embodiments, L is a covalent bond or a bivalent, saturated or partially unsaturated, straight or branched C1-50hydrocarbon chain, wherein 0-6 methylene units of L may optionally be replaced by -Cy-, -CHF-, -CF2-, -O-, -NR-, –SiR2–, –Si(OH)R–, –Si(OH)2– , –P(O)OR–, –P(O)R–, –P(O)NR2–, -S-, -OC(O)-, -C(O)O-, -C(O)-, -S(O)-, -S(O)2-, -wherein: each -Cy- is independently an optionally substituted bivalent ring selected from phenylenyl, an 8-10 membered bicyclic arylenyl, a 4-7 membered saturated or partially unsaturated carbocyclylenyl, a 6-11 membered saturated or partially unsaturated spiro carbocyclylenyl, an 8-10 membered bicyclic saturated or partially unsaturated carbocyclylenyl, a 4-7 membered saturated or partially unsaturated heterocyclylenyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 6-11 membered saturated orpartially unsaturated spiro heterocyclylenyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, an 8-10 membered bicyclic saturated or partially unsaturated heterocyclylenyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered heteroarylenyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and an 8-10 membered bicyclic heteroarylenyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur, each R is independently hydrogen, or an optionally substituted group selected from C1-6 aliphatic, phenyl, a 4-7 membered saturated or partially unsaturated heterocyclic having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or: two R groups on the same nitrogen are optionally taken together with their intervening atoms to forn1 a 4-7 membered saturated, partially unsaturated, or heteroaryl ring having 0-3 heteroatoms, in addition to the nitrogen, independently selected from nitrogen, oxygen, and sulfur, and; r is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

[0067] In some embodiments, each -Cy- is independently an optionally substituted bivalent phenylenyl. In some embodiments, each -Cy- is independently an optionally substituted 8-10 membered bicyclic arylenyl. In some embodiments, each -Cy- is independently an optionally substituted 4-7 membered saturated or partially unsaturated carbocyclylenyl. In some embodiments, each -Cy- is independently an optionally substituted 6-11 membered saturated or partially unsaturated spiro-carbocyclylenyl. In some embodiments, each -Cy- is independently an optionally substituted 8-10 membered bicyclic saturated or partially unsaturated carbocyclylenyl. In some embodiments, each -Cy is independently an optionally substituted 4-7 membered saturated or partially unsaturated heterocyclylenyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, each -Cy- is independently an optionally substituted 6-11 membered saturated or partially unsaturated spiro-heterocyclylenyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, each -Cy- is independently an optionally substituted 8-10 membered bicyclic saturated or partially unsaturated heterocyclylenyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, each -Cy- is independently an optionally substituted 5-6 membered heteroarylenyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, each -Cy- is independently an optionally substituted 8-10membered bicyclic heteroarylenyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0068] In some embodiments, -Cy- is substituted with C1-6alkyl (e.g., methyl, ethyl, isopropyl). In some embodiments, -Cy- is substituted with oxo. In some embodiments, -Cy- is substituted with halogen. In some embodiments, -Cy- is substituted with fluoro. In some embodiments, -Cy- is substituted with geminal difluoro. In some embodiments, -Cy- is substituted with -OH. In some embodiments, -Cy- is substituted with -NR2.

[0069] In some embodiments, r is 0. In some embodiments, r is 1. In some embodiments, r is 2. In some embodiments, r is 3. In some embodiments, r is 4. In some embodiments, r is 5. In some embodiments, r is 6. In some embodiments, r is 7. In some embodiments, r is 8. In some embodiments, r is 9. In some embodiments, r is 10.

[0070] In some embodiments, L is -NR-(C1-10 aliphatic)-. In some embodiments, L is -(C1-10aliphatic)- NR-(C1-10aliphatic)-. In some embodiments, L is -(C1-10aliphatic)-NR- (CH2CH2O)1-10CH2CH2-. In some embodiments, L is -Cy-NR-(C1-10 aliphatic)-. In some embodiments, L is -Cy-(C1-10 aliphatic)-NR-. In some embodiments, L is -Cy-(C1-10 aliphatic)- NR-(C1-10 aliphatic)-. In some embodiments, L is -(C1-10 aliphatic)-Cy-NR-(C1-10 aliphatic)-. In some embodiments, L is -(C1-10 aliphatic)-Cy-(C1-10 aliphatic)-NR-. In some embodiments, L is -(C1-10aliphatic)-Cy-(C1-10aliphatic)-NR-(C1-10aliphatic)-. In some embodiments, L is -Cy- (C1-10 aliphatic)-Cy-NR-. In some embodiments, L is -Cy-(C1-10 aliphatic)-NR-Cy-. In some embodiments, L is -Cy-(C1-10 aliphatic)-Cy-NR-(C1-10 aliphatic)-. In some embodiments, L is - Cy-(C1-10 aliphatic)-NR-Cy-(C1-10 aliphatic)-.

[0071] In some embodiments, L is -CONR-(C1-10aliphatic)-. In some embodiments, L is - (C1-10 aliphatic)-CONR-(C1-10 aliphatic)-. In some embodiments, L is -(C1-10 aliphatic)-CONR- (CH2CH2O)1- 10CH2CH2-. In some embodiments, L is -Cy-CONR-(C1-10aliphatic). In some embodiments, L is -Cy-(C1- 10 aliphatic)-CONR-. In some embodiments, L is -Cy-(C1-10 aliphatic)-CONR-(C1-10aliphatic)-. In some embodiments, L is -(C1-10aliphatic)-Cy-CONR- (C1-10 aliphatic)-. In some embodiments, L is -(C1-10 aliphatic)-Cy-(C1-10 aliphatic)-CONR-. In some embodiments, L is -(C1-10aliphatic)-Cy-(C1-10aliphatic)- CONR-(C1-10aliphatic)-. In some embodiments, L is -Cy-(C1-10 aliphatic)-Cy-CONR-. In some embodiments, L is -Cy-(C1-10aliphatic)-CONR-Cy-. In some embodiments, L is -Cy-(C1-10aliphatic)-Cy- CONR-(C1-10aliphatic)-. In some embodiments, L is -Cy-(C1-10 aliphatic)-CONR-Cy-(C1-10 aliphatic)-.

[0072] In certain embodiments, L is any bivalent linker provided in WO 2024 / 064080, incorporated herein by reference in its entirey.4. Compounds

[0073] In a first embodiment, provided is a compound of structural Formula I:or a pharmaceutically acceptable salt thereof, wherein the variables are as described above.

[0074] In a second embodiment, X in the compound of Formula I, or pharmaceutically acceptable salt thereof, is NR9; R7is selected from (C1-C4)alkyl, phenyl, 4- to 9-membered monocyclic or bicyclic heterocyclyl, and 5- to 10-membered monocyclic or bicyclic heteroaryl, wherein said (C1- C4)alkyl is optionally substituted with, as valency permits, 1 to 3 groups selected from RYand said phenyl, 4- to 9-membered monocyclic or bicyclic heterocyclyl, and 5- to 10-membered monocyclic or bicyclic heteroaryl are each optionally substituted with, as valency permits, 1 to 3 groups selected from RZ; or R6and R7together with the nitrogen atom to which they are attached form a 4- to 14- membered monocyclic or bicyclic heterocyclyl or a 5- to 12-membered monocyclic or bicyclic heteroaryl, each of which being optionally substituted with, as valency permits, 1 to 3 groups selected from RQ; and RZis selected from halo, cyano, (C1-C4)alkyl, (C3-C6cycloalkyl), halo(C1-C4)alkyl, - (C1-C4)alkyl(C1-C4)alkoxy, hydroxy(C1-C4)alkyl, -(C1-C4)alkylphenyl, -(C1- C4)alkylheteroaryl, (C2-C4)alkenyl, halo(C2-C4)alkenyl, (C2-C4)alkynyl, halo(C2-C4)alkynyl, (C1-C4)alkoxy, halo(C1-C4)alkoxy, -ORe, oxo, imino, phenyl, 4- to 6-membered heterocyclyl, -S(O)ReRf, -S(O)2Rf, -S(O)=NH(C1-C4)alkyl, -S(O)NReRf, and -S(O)2NReRf, -C(O)ORe, - NRcC(O)Re, -(C1-C4alkyl)C(O)Rg, -C(O)Rg, -(C1-C4alkyl)C(O)NRcRd, -C(O)NRcRd, -NO2, and -NRaRb, wherein the (C1-C4)alkyl is optionally substituted with cyano, wherein said phenyl, said 4- to 6-membered heterocyclyl, and said phenyl for -(C1-C4)alkylphenyl are each optionally and independently substituted with, as valency permits 1 to 3 groups selected from halo, cyano, oxo, (C1-C10)alkyl, (C2-C10)alkenyl, (C2-C10)alkynyl, halo(C1-C10)alkyl, (C1- C10)alkoxy, and halo(C1-C10)alkoxy, wherein said (C1-C10)alkyl, (C2-C10)alkenyl and (C2- C10)alkynyl are each optionally substituted with, as valency permits a 5-to 10-membered monocyclic or bicyclic heteroaryl or a 4-to 10-membered monocyclic or bicyclic heterocyclyleach of said 5-to 10-membered monocyclic and bicyclic heteroaryl or a 4-to 10-membered monocyclic or bicyclic heterocyclyl being optionally substituted with oxo or a 5- to 7- membered heterocyclyl that is optionally substituted with 1 to 2 oxo, wherein the remaining variables are as described above for Formula I. Alternatively, as part of a second embodiment, X in the compound of Formula I, or pharmaceutically acceptable salt thereof, is X is selected from S, SO2, -S(=O)=NH, -NR8; R7is selected from E, -R10AE, (C1-C4)alkyl, phenyl, 4- to 9-membered monocyclic or bicyclic heterocyclyl, and 5- to 10-membered monocyclic or bicyclic heteroaryl, wherein said (C1-C4)alkyl is optionally substituted with, as valency permits, 1 to 3 groups selected from RYand said phenyl, 4- to 9-membered monocyclic or bicyclic heterocyclyl, and 5- to 10-membered monocyclic or bicyclic heteroaryl are each optionally substituted with, as valency permits, 1 to 3 groups selected from RZ; or R6and R7together with the nitrogen atom to which they are attached form a 4- to 14- membered monocyclic or bicyclic heterocyclyl or a 5- to 12-membered monocyclic or bicyclic heteroaryl, each of which being optionally substituted with, as valency permits, 1 to 3 groups selected from RQ; and RZis selected from halo, cyano, (C1-C4)alkyl, (C3-C6cycloalkyl), halo(C1-C4)alkyl, - (C1-C4)alkyl(C1-C4)alkoxy, hydroxy(C1-C4)alkyl, -(C1-C4)alkylphenyl, -(C1- C4)alkylheteroaryl, (C2-C4)alkenyl, halo(C2-C4)alkenyl, (C2-C4)alkynyl, halo(C2-C4)alkynyl, (C1-C4)alkoxy, halo(C1-C4)alkoxy, -ORe, oxo, imino, phenyl, 4- to 6-membered heterocyclyl, -S(O)ReRf, -S(O)2Rf, -S(O)=NH(C1-C4)alkyl, -S(O)NReRf, and -S(O)2NReRf, -C(O)ORe, - NRcC(O)Re, -(C1-C4alkyl)C(O)Rg, -C(O)Rg, -(C1-C4alkyl)C(O)NRcRd, -C(O)NRcRd, -NO2, and -NRaRb, wherein the (C1-C4)alkyl is optionally substituted with cyano, wherein said phenyl, said 4- to 6-membered heterocyclyl, and said phenyl for -(C1-C4)alkylphenyl are each optionally and independently substituted with, as valency permits 1 to 3 groups selected from halo, cyano, oxo, (C1-C10)alkyl, (C2-C10)alkenyl, (C2-C10)alkynyl, halo(C1-C10)alkyl, (C1- C10)alkoxy, and halo(C1-C10)alkoxy, wherein said (C1-C10)alkyl, (C2-C10)alkenyl and (C2- C10)alkynyl are each optionally substituted with, as valency permits a 5-to 10-membered monocyclic or bicyclic heteroaryl or a 4-to 10-membered monocyclic or bicyclic heterocyclyl each of said 5-to 10-membered monocyclic and bicyclic heteroaryl or a 4-to 10-membered monocyclic or bicyclic heterocyclyl being optionally substituted with oxo or a 5- to 7- membered heterocyclyl that is optionally substituted with 1 to 2 oxo, wherein the remaining variables are as described above for Formula I. In another alternative, as part of a secondembodiment, in Formula I or pharmaceutically acceptable salt thereof, X is selected from S, SO2, -S(=O)=NH, -NR8; R7is selected from (C1-C4)alkyl, phenyl, 4- to 9-membered monocyclic or bicyclic heterocyclyl, and 5- to 10-membered monocyclic or bicyclic heteroaryl, wherein said (C1- C4)alkyl is optionally substituted with, as valency permits, 1 to 3 groups selected from RYand said phenyl, 4- to 9-membered monocyclic or bicyclic heterocyclyl, and 5- to 10-membered monocyclic or bicyclic heteroaryl are each optionally substituted with, as valency permits, R11and / or 1 to 3 groups selected from RZ; or R6and R7together with the nitrogen atom to which they are attached form a 4- to 14- membered monocyclic or bicyclic heterocyclyl or a 5- to 12-membered monocyclic or bicyclic heteroaryl, each of which being optionally substituted with, as valency permits, 1 to 3 groups selected from RQ; and RZis selected from halo, cyano, (C1-C4)alkyl, (C3-C6cycloalkyl), halo(C1-C4)alkyl, - (C1-C4)alkyl(C1-C4)alkoxy, hydroxy(C1-C4)alkyl, -(C1-C4)alkylphenyl, -(C1- C4)alkylheteroaryl, (C2-C4)alkenyl, halo(C2-C4)alkenyl, (C2-C4)alkynyl, halo(C2-C4)alkynyl, (C1-C4)alkoxy, halo(C1-C4)alkoxy, -ORe, oxo, imino, phenyl, 4- to 6-membered heterocyclyl, -S(O)ReRf, -S(O)2Rf, -S(O)=NH(C1-C4)alkyl, -S(O)NReRf, and -S(O)2NReRf, -C(O)ORe, - NRcC(O)Re, -(C1-C4alkyl)C(O)Rg, -C(O)Rg, -(C1-C4alkyl)C(O)NRcRd, -C(O)NRcRd, -NO2, and -NRaRb, wherein the (C1-C4)alkyl is optionally substituted with cyano, wherein said phenyl, said 4- to 6-membered heterocyclyl, and said phenyl for -(C1-C4)alkylphenyl are each optionally and independently substituted with, as valency permits 1 to 3 groups selected from halo, cyano, oxo, (C1-C10)alkyl, (C2-C10)alkenyl, (C2-C10)alkynyl, halo(C1-C10)alkyl, (C1- C10)alkoxy, and halo(C1-C10)alkoxy, wherein said (C1-C10)alkyl, (C2-C10)alkenyl and (C2- C10)alkynyl are each optionally substituted with, as valency permits a 5-to 10-membered monocyclic or bicyclic heteroaryl or a 4-to 10-membered monocyclic or bicyclic heterocyclyl each of said 5-to 10-membered monocyclic and bicyclic heteroaryl or a 4-to 10-membered monocyclic or bicyclic heterocyclyl being optionally substituted with oxo or a 5- to 7- membered heterocyclyl that is optionally substituted with 1 to 2 oxo, wherein the remaining variables are as described above for Formula I. In another alternative, as part of a second embodiment, in Formula I or pharmaceutically acceptable salt thereof, X is selected from S, SO2, -S(=O)=NH, -NR8; R7is selected from (C1-C4)alkyl, phenyl, 4- to 9-membered monocyclic or bicyclic heterocyclyl, and 5- to 10-membered monocyclic or bicyclic heteroaryl, wherein said (C1- C4)alkyl is optionally substituted with, as valency permits, 1 to 3 groups selected from RYandsaid phenyl, 4- to 9-membered monocyclic or bicyclic heterocyclyl, and 5- to 10-membered monocyclic or bicyclic heteroaryl are each optionally substituted with, as valency permits, 1 to 3 groups selected from RZ; or R6and R7together with the nitrogen atom to which they are attached form a 4- to 14- membered monocyclic or bicyclic heterocyclyl or a 5- to 12-membered monocyclic or bicyclic heteroaryl, each of which being optionally substituted with, as valency permits, R12and / or 1 to 3 groups selected from RQ; and RZis selected from halo, cyano, (C1-C4)alkyl, (C3-C6cycloalkyl), halo(C1-C4)alkyl, - (C1-C4)alkyl(C1-C4)alkoxy, hydroxy(C1-C4)alkyl, -(C1-C4)alkylphenyl, -(C1- C4)alkylheteroaryl, (C2-C4)alkenyl, halo(C2-C4)alkenyl, (C2-C4)alkynyl, halo(C2-C4)alkynyl, (C1-C4)alkoxy, halo(C1-C4)alkoxy, -ORe, oxo, imino, phenyl, 4- to 6-membered heterocyclyl, -S(O)ReRf, -S(O)2Rf, -S(O)=NH(C1-C4)alkyl, -S(O)NReRf, and -S(O)2NReRf, -C(O)ORe, - NRcC(O)Re, -(C1-C4alkyl)C(O)Rg, -C(O)Rg, -(C1-C4alkyl)C(O)NRcRd, -C(O)NRcRd, -NO2, and -NRaRb, wherein the (C1-C4)alkyl is optionally substituted with cyano, wherein said phenyl, said 4- to 6-membered heterocyclyl, and said phenyl for -(C1-C4)alkylphenyl are each optionally and independently substituted with, as valency permits 1 to 3 groups selected from halo, cyano, oxo, (C1-C10)alkyl, (C2-C10)alkenyl, (C2-C10)alkynyl, halo(C1-C10)alkyl, (C1- C10)alkoxy, and halo(C1-C10)alkoxy, wherein said (C1-C10)alkyl, (C2-C10)alkenyl and (C2- C10)alkynyl are each optionally substituted with, as valency permits a 5-to 10-membered monocyclic or bicyclic heteroaryl or a 4-to 10-membered monocyclic or bicyclic heterocyclyl each of said 5-to 10-membered monocyclic and bicyclic heteroaryl or a 4-to 10-membered monocyclic or bicyclic heterocyclyl being optionally substituted with oxo or a 5- to 7- membered heterocyclyl that is optionally substituted with 1 to 2 oxo, wherein the remaining variables are as described above for Formula I. In another alternative, as part of a second embodiment, in Formula I or pharmaceutically acceptable salt thereof, X is selected from S, SO2, -S(=O)=NH, -NR8; R7is selected from (C1-C4)alkyl, phenyl, 4- to 9-membered monocyclic or bicyclic heterocyclyl, and 5- to 10-membered monocyclic or bicyclic heteroaryl, wherein said (C1- C4)alkyl is optionally substituted with, as valency permits, 1 to 3 groups selected from RYand said phenyl, 4- to 9-membered monocyclic or bicyclic heterocyclyl, and 5- to 10-membered monocyclic or bicyclic heteroaryl are each optionally substituted with, as valency permits, 1 to 3 groups selected from RZ; or R6and R7together with the nitrogen atom to which they are attached form a 4- to 14- membered monocyclic or bicyclic heterocyclyl or a 5- to 12-membered monocyclic or bicyclicheteroaryl, each of which being optionally substituted with, as valency permits, 1 to 3 groups selected from RQ; and RZis selected from halo, cyano, (C1-C4)alkyl, (C3-C6cycloalkyl), halo(C1-C4)alkyl, - (C1-C4)alkyl(C1-C4)alkoxy, hydroxy(C1-C4)alkyl, -(C1-C4)alkylphenyl, -(C1- C4)alkylheteroaryl, (C2-C4)alkenyl, halo(C2-C4)alkenyl, (C2-C4)alkynyl, halo(C2-C4)alkynyl, (C1-C4)alkoxy, halo(C1-C4)alkoxy, -ORe, oxo, imino, phenyl, 4- to 6-membered heterocyclyl, -S(O)ReRf, -S(O)2Rf, -S(O)=NH(C1-C4)alkyl, -S(O)NReRf, and -S(O)2NReRf, -C(O)ORe, - NRcC(O)Re, -(C1-C4alkyl)C(O)Rg, -C(O)Rg, -(C1-C4alkyl)C(O)NRcRd, -C(O)NRcRd, -NO2, and -NRaRb, wherein the (C1-C4)alkyl is optionally substituted with cyano, wherein said phenyl, said 4- to 6-membered heterocyclyl, and said phenyl for -(C1-C4)alkylphenyl are each optionally and independently substituted with, as valency permits 1 to 3 groups selected from halo, cyano, oxo, (C1-C10)alkyl, (C2-C10)alkenyl, (C2-C10)alkynyl, halo(C1-C10)alkyl, (C1- C10)alkoxy, and halo(C1-C10)alkoxy, wherein said (C1-C10)alkyl, (C2-C10)alkenyl and (C2- C10)alkynyl are each optionally substituted with, as valency permits a 5-to 10-membered monocyclic or bicyclic heteroaryl or a 4-to 10-membered monocyclic or bicyclic heterocyclyl each of said 5-to 10-membered monocyclic and bicyclic heteroaryl or a 4-to 10-membered monocyclic or bicyclic heterocyclyl being optionally substituted with oxo or a 5- to 7- membered heterocyclyl that is optionally substituted with 1 to 2 oxo, wherein the remaining variables are as described above for Formula I.

[0075] In a third embodiment, the compound of Formula I is of the structural Formula II:or pharmaceutically acceptable salt thereof, wherein the variables are as described above for Formula I or the second embodiment.

[0076] In a fourth embodiment, p in the compound of Formula I or II, or pharmaceutically acceptable salt thereof, is 1, wherein the remaining variables are as described above for Formula I or the second embodiment.

[0077] In a fifth embodiment, R2in the compound of Formula I or II, or pharmaceutically acceptable salt thereof, is hydrogen, wherein the remaining variables are as described above for Formula I or any one of the second or fourth embodiments.

[0078] In a sixth embodiment, R3in the compound of Formula I or II, or pharmaceutically acceptable salt thereof, is hydrogen, wherein the remaining variables are as described above for Formula I or any one of the second, fourth or fifth embodiments.

[0079] In a seventh embodiment, R4in the compound of Formula I or II, or pharmaceutically acceptable salt thereof, is hydrogen, wherein the remaining variables are as described above for Formula I or any one of the second and fourth to sixth embodiments.

[0080] In an eighth embodiment, q in the compound of Formula I or II, or pharmaceutically acceptable salt thereof, is 0 and t is 2, wherein the remaining variables are as described above for Formula I or any one of the second and fourth to seventh embodiments. Alternatively, as part of an eighth embodiment, q in the compound of Formula I or II, or pharmaceutically acceptable salt thereof, is 1 and t is 1, wherein the remaining variables are as described above for Formula I or any one of the second and fourth to seventh embodiments. In another alternative, as part of an eighth embodiment, q in the compound of Formula I or II, or pharmaceutically acceptable salt thereof, is 0 and t is 1, wherein the remaining variables are as described above for Formula I or any one of the second and fourth to seventh embodiments.

[0081] In a ninth embodiment, the compound of Formula I is of the structural Formula III, I I II III ,or pharmaceutically acceptable salt thereof, wherein the variables are as described above for Formula I or the second embodiment.

[0082] In a tenth embodiment, R5in the compound of structural Formula I, II, III, IV, V, VI, VII, or VIII, or pharmaceutically acceptable salt thereof, is hydrogen, wherein the remaining variables are as described above for Formula I or any one of the second and fourth to eighth embodiments.

[0083] In an eleventh embodiment, R1in the compound of structural Formula I, II, III, IV, V, VI, VII, or VIII, or pharmaceutically acceptable salt thereof, is selected from 8- to 10- membered fused bicyclic heteroaryl and aryl, each of which are substituted with – CR1aR2aP(O)OR1bOR2b, wherein the remaining variables are as described above for Formula I or any one of the second, fourth to eighth, and tenth embodiments. Alternatively, as part of an eleventh embodiment, R1in the compound of structural Formula I, II, III, IV, V, VI, VII, or VIII, or pharmaceutically acceptable salt thereof, is selected from benzothiophenyl, indolyl, naphthalenyl, thienopyridinyl, benzothiazoyl, quinolinyl, isoquinolinyl, 4,5,6,7- tetrahydropyrrolopyridinyl, 5,6,7,8-tetrahydroimidazopyrazinyl, each of which are substituted with –CR1aR2aP(O)OR1bOR2b, wherein the remaining variables are as described above for Formula I or any one of the second, fourth to eighth, and tenth embodiments. In another alternative, as part of an eleventh embodiment, R1in the compound of structural Formula I, II, III, IV, V, VI, VII, or VIII, or pharmaceutically acceptable salt thereof, is selected fromvariables are as described above for Formula I or any one of the second, fourth to eighth, and tenth embodiments. In another alternative, as part of an eleventh embodiment, R1in the compound of structural Formula I, II, III, IV, V, VI, VII, or VIII, or pharmaceutically acceptable salt thereof,, or, wherein the remaining variables are as described above for Formula I or any one of the second, fourth to eighth, and tenth embodiments.

[0084] In a twelfth embodiment, R1ain the compound of structural Formula I, II, III, IV, V, VI, VII, or VIII, or pharmaceutically acceptable salt thereof, is hydrogen and R2ais fluoro or R1ais fluoro and R2ais fluoro, wherein the remaining variables are as described above for Formula I or any one of the second, fourth to eighth, tenth, and eleventh embodiments. Alternatively, as part of an twelfth embodiment, R1ain the compound of structural Formula I, II, III, IV, V, VI, VII, or VIII, or pharmaceutically acceptable salt thereof, is fluoro and R2ais fluoro, wherein the remaining variables are as described above for Formula I or any one of the second, fourth to eighth, tenth, and eleventh embodiments.

[0085] In a thirteenth embodiment, R1band R2bin the compound of structural Formula I, II, III, IV, V, VI, VII, or VIII, or pharmaceutically acceptable salt thereof, are each independently selected from hydrogen, (C1-C4)alkyl, -[(C1-C4)alkyl]-OC(O)-[(C1-C4)alkyl], - [(C1-C4)alkyl]-OC(O)O-[(C1-C4)alkyl], -[(C1-C4)alkyl]-SC(O)-[(C1-C4)alkyl], -[(C1- C4)alkyl]-SC(O)-[halo(C1-C4)alkyl], -[(C1-C4)alkyl]-OC(O)NR2cR2d], [(C1-C4)alkyl]- OC(O)O-[5- to 7-membered heterocyclyl], and phenyl, wherein the 5- to 7-membered heterocyclyl of [(C1-C4)alkyl]-OC(O)O-[5- to 7-membered heterocyclyl] is optionally substituted with C(O)OR2c, wherein any of the (C1-C)4alkyl groups are optionally substituted with 1 or 2 (C1-C4)alkyl, wherein the remaining variables are as described above for Formula I or any one of the second, fourth to eighth, and tenth to twelfth embodiments. Alternatively, as part of a thirteenth embodiment, R1band R2bin the compound of structural Formula I, II, III, IV, V, VI, VII, or VIII, or pharmaceutically acceptable salt thereof, are each -[(C1- C4)alkyl]-OC(O)-[(C1-C4)alkyl], wherein the remaining variables are as described above for Formula I or any one of the second, fourth to eighth, and tenth to twelfth embodiments. In another alternative, as part as part of a thirteenth embodiment, R1band R2bin the compound of structural Formula I, II, III, IV, V, VI, VII, or VIII, or pharmaceutically acceptable salt thereof, are each hydrogen, wherein the remaining variables are as described above for Formula I or any one of the second, fourth to eighth, and tenth to twelfth embodiments.

[0086] In a fourteenth embodiment, –CR1aR2aP(O)OR1bOR2bin the compound of structural Formula I, II, III, IV, V, VI, VII, or VIII, or pharmaceutically acceptable salt thereof, isselected from, , ,the remaining variables are as described above for Formula I or any one of the second, fourth to eighth, and tenth to thirteenth embodiments. Alternatively, as part of a fourteenth embodiment, –CR1aR2aP(O)OR1bOR2bin the compound of structural Formula I, II, III, IV, V, VI, VII, or VIII, or pharmaceutically acceptable salt thereof, is selected from, ,,,, wherein the remaining variables are as described above for Formula I or any one of the second, fourth to eighth, and tenth to thirteenth embodiments.

[0087] In a fifteenth embodiment, R6in the compound of structural Formula I, II, III, IV, V, VI, VII, or VIII, or pharmaceutically acceptable salt thereof, is selected from hydrogen and (C1-C4)alkyl, wherein the remaining variables are as described above for Formula I or any one of the second, fourth to eighth, and tenth to fourteenth embodiments.

[0088] In a sixteenth embodiment, R7in the compound of structural Formula I, II, III, IV, V, VI, VII, or VIII, or pharmaceutically acceptable salt thereof, is selected from E, -R10AE, and phenyl, wherein the remaining variables are as described above for Formula I or any one of the second, fourth to eighth, and tenth to fifteenth embodiments. Alternatively, as part of a sixteenth embodiment, R7in the compound of structural Formula I, II, III, IV, V, VI, VII, or VIII, or pharmaceutically acceptable salt thereof, is phenyl substituted with R11, wherein the remaining variables are as described above for Formula I or any one of the second, fourth to eighth, and tenth to fifteenth embodiments.

[0089] In a seventeenth embodiment, R11in the compound of structural Formula I, II, III, IV, V, VI, VII, or VIII, or pharmaceutically acceptable salt thereof, is –NHC(O)R10BE, wherein the remaining variables are as described above for Formula I or any one of the second, fourth to eighth, and tenth to sixteenth embodiments.

[0090] In an eighteenth embodiment, R6and R7in the compound of structural Formula I, II, III, IV, V, VI, VII, or VIII, or pharmaceutically acceptable salt thereof, together with thenitrogen atom to which they are attached form a 4- to 6-membered monocyclic heterocyclyl optionally substituted with, as valency permits, R12and / or 1 to 3 groups selected from RQ, wherein the remaining variables are as described above for Formula I or any one of the second, fourth to eighth, and tenth to seventeenth embodiments. Alternatively, as part of a eighteenth embodiment, R6and R7in the compound of structural Formula I, II, III, IV, V, VI, VII, or VIII, or pharmaceutically acceptable salt thereof, together with the nitrogen atom to which they are attached form azetidinyl, pyrrolidyl, or piperidinyl, each optionally substituted with, as valency permits, R12and / or 1 to 3 groups selected from RQ, wherein the remaining variables are as described above for Formula I or any one of the second, fourth to eighth, and tenth to seventeenth embodiments.

[0091] In a nineteenth embodiment, RQin the compound of structural Formula I, II, III, IV, V, VI, VII, or VIII, or pharmaceutically acceptable salt thereof, is cyano, phenyl, or 5- to 7-membered monocyclic heteroaryl optionally substituted with, as valency permits, 1 to 3 groups selected from RF, wherein the remaining variables are as described above for Formula I or any one of the second, fourth to eighth, and tenth to eighteenth embodiments. Alternatively, as part of a nineteenth embodiment, RQin the compound of structural Formula I, II, III, IV, V, VI, VII, or VIII, or pharmaceutically acceptable salt thereof, is cyano, phenyl, or pyridinyl optionally substituted with, as valency permits, 1 to 3 groups selected from RF, wherein the remaining variables are as described above for Formula I or any one of the second, fourth to eighth, and tenth to eighteenth embodiments.

[0092] In a twentieth embodiment, RFin the compound of structural Formula I, II, III, IV, V, VI, VII, or VIII, or pharmaceutically acceptable salt thereof, is -NRaRb, wherein the remaining variables are as described above for Formula I or any one of the second, fourth to eighth, and tenth to nineteenth embodiments.

[0093] In a twenty-first embodiment, R12in the compound of structural Formula I, II, III, IV, V, VI, VII, or VIII, or pharmaceutically acceptable salt thereof, is E, wherein the remaining variables are as described above for Formula I or any one of the second, fourth to eighth, and tenth to twentieth embodiments.

[0094] In a twenty-second embodiment, R8in the compound of structural Formula I, II, III, IV, V, VI, VII, or VIII, or pharmaceutically acceptable salt thereof, is –C(O)RHa, wherein the remaining variables are as described above for Formula I or any one of the second, fourth to eighth, and tenth to twenty-first embodiments.

[0095] In a twenty-third embodiment, RHain the compound of structural Formula I, II, III, IV, V, VI, VII, or VIII, or pharmaceutically acceptable salt thereof, is 8- to 10-memberedbicyclic heteroaryl optionally substituted with C1-C4alkyl, wherein the remaining variables are as described above for Formula I or any one of the second, fourth to eighth, and tenth to twenty- second embodiments. Alternatively, as part of a twenty-third embodiment, RHain the compound of structural Formula I, II, III, IV, V, VI, VII, or VIII, or pharmaceutically acceptable salt thereof, is indazolyl or benzoisoxazolyl, each optionally substituted with C1- C4alkyl, wherein the remaining variables are as described above for Formula I or any one of the second, fourth to eighth, and tenth to twenty-second embodiments.

[0096] In a twenty-fourth embodiment, R9in the compound of structural Formula I, II, III, IV, V, VI, VII, or VIII, or pharmaceutically acceptable salt thereof, is selected from –R10E and –C(O)R10E, wherein the remaining variables are as described above for Formula I or any one of the second, fourth to eighth, and tenth to twenty-third embodiments.

[0097] In a twenty-fifth embodiment, R10, R10A, R10B, R10C, and R10Din the compound of structural Formula I, II, III, IV, V, VI, VII, or VIII, or pharmaceutically acceptable salt thereof, are each independently selected from (C1-C10)alkylene and (C2-C10)alkynelene each optionally substituted with one or more groups selected from halo and oxo, and wherein said (C1-C6)alkylene and (C2-C10)alkynelene may also be optionally interrupted by one or more heteroatoms selected from S, N, and O, and / or optionally interrupted by one or more rings selected from 5- to 7-membered heteroaryl, (C3-C6)cycloakyl, phenyl, and 4- to 7-membered heterocyclyl. Alternatively, as part of a twenty-fifth embodiment, R10, R10A, R10B, R10C, and R10Din the compound of structural Formula I, II, III, IV, V, VI, VII, or VIII, or pharmaceutically acceptable salt thereof, are each independently selected from (C1- C10)alkylene and (C2-C10)alkynelene, wherein the remaining variables are as described above for Formula I or any one of the second, fourth to eighth, and tenth to twenty-fourth embodiments. In another alternative, as part of as part of a twenty-fifth embodiment, R10, R10A, R10B, R10C, and R10Din the compound of structural Formula I, II, III, IV, V, VI, VII, or VIII, or pharmaceutically acceptable salt thereof, are each independently selected from (C1- C10)alkylene and (C2-C10)alkynelene,,, CH2, and (CH2)2, (CH2)3, (CH2)4, wherein the remaining variables are as described above for Formula I or any one of the second, fourth to eighth, and tenth to twenty-fourth embodiments.

[0098] In a twenty-sixth embodiment, E in the compound of structural Formula I, II, III, IV, V, VI, VII, or VIII, or pharmaceutically acceptable salt thereof is selected from a CRBN, VHL, IAP, or MDM2 based E3 binder, wherein the remaining variables are as described above for Formula I or any one of the second, fourth to eighth, and tenth to twenty-fifth embodiments. Alternatively, as part of a twenty-sixth embodiment, E in the compound of structural Formula I, II, III, IV, V, VI, VII, or VIII, or pharmaceutically acceptable salt thereof is selected from , ,wherein: Y and Y1are each independently is O or CH2; D is O, NH, or a bond; U is absent or C(O); and R is halo or cyano, wherein the remaining variables are as described above for Formula I or any one of the second, fourth to eighth, and tenth to twenty-fifth embodiments. In another alternative, as part of a as part of a twenty-sixth embodiment, E in the compound of structural Formula I, II, III, IV, V, VI, VII, or VIII, or pharmaceutically acceptable salt

[0099] Compounds having the Formula I are further disclosed in the Exemplification and are included in the present disclosure. Pharmaceutically acceptable salts thereof as well as the neutral forms are included. 4. Uses, Formulation and Administration

[0100] The compounds and compositions described herein are generally useful for modulating the activity of STAT proteins, in particular STAT3 and / or STAT6. In some aspects, the compounds, pharmaceutical acceptable salts, and pharmaceutical compositions described herein degrade STAT3 and / or STAT6.

[0101] In some aspects, the compounds and pharmaceutical compositions described herein are useful in a condition responsive to the modulation (or degradation) of STAT3 and / or STAT6. Thus, provided herein are methods of treating a condition responsive to the modulation (e.g., degradation) of STAT3 and / or STAT6 in a subject, comprising administering to a subject in need thereof, a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a disclosed compound or pharmaceutically acceptable salt thereof.

[0102] Also provided is the use of a compound described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a disclosed compound or pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treating a condition responsive to the modulation (e.g., degradation) of STAT3 and / or STAT6. Also provided is a compound described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a disclosed compound or pharmaceutically acceptablesalt thereof, for use in treating a condition responsive to the modulation (e.g., degradation) of STAT3 and / or STAT6.

[0103] In one aspect, the condition responsive to the modulation (e.g., degradation) of STAT3 and / or STAT6 include, but are not limited to, cancer, a neurodegenative disorder, a viral disease, an autoimmune disease, an inflammatory disorder, a hereditary disorder, a hormone-related disease, a metabolic disorder, conditions associated with organ transplantation, immunodeficiency disorders, a destructive bone disorder, a proliferative disorder, an infectious disease, a condition associated with cell death, thrombin-induced platelet aggregation, liver disease, pathologic immune conditions involving T cell activation, a cardiovascular disorder, or a CNS disorder.

[0104] In another aspect, the condition responsive to the modulation (e.g., degradation) of STAT3 and / or STAT6 include, but are not limited to, cancer (see, e.g., Turkson & Jove, Oncogene 2000, 19:6613-6626), diabetes (see. e.g., Gurzov et al., FEBS 2016, 283:3002), cardiovascular disease (see, e.g., Grote et al., Vasc. Pharmacol. 2005, 43:2005), viral disease (see, e.g., Gao et al., J Hepatol.2012, 57(2):430), autoimmune diseases such as lupus (see, e.g., Goropevsek et al., Clin. Rev. Alleg. & Immun.2017, 52(2):164), and rheumatoid arthritis (see, e.g., Walker & Smith, J. Rheumat.2005, 32(9): 1650), autoinflammatory syndromes (see, e.g., Rauch et al., Jak-Stat 2013, 2(l):e23820), atherosclerosis (see, e.g., Ortiz-Munoz et al., Arterio., Thromho., Vase. Bio. 2009, 29:525), psoriasis (see, e.g., Andres et al., Exp. Derm. 2013, 22(5):323), allergic disorders (see, e.g., Oh et al., Eur. Respir. Rev. 2019, 19(115):46), inflammatory bowel disease (see. e.g., Sugimoto, World J Gastroenterol. 2008, 14(33):5110), inflammation (see, e.g., Tamiya et al., Arierio. Thrombo., Vasc. Bio. 2011, 31:980), acute and chronic gout and gouty arthritis, neurological disorders (see, e.g., Campbell, Brain Res. Rev. 2005, 48(2): 166), metabolic syndrome, immunodeficiency disorders such as AIDS and HIV (see, e.g., O’Shea et al., N. Engl. J.Med.2013, 368:161), destructive bone disorders (see, e.g., Jatiani et al., Genes & Can. 2011, 1(10):979), osteoarthritis, proliferative disorders, Waldenstrom’s Macroglobulinemia (see, e.g., Hodge et al., Blood 2014, 123(7):1055) infectious diseases, conditions associated with cell death, pathologic immune conditions involving T cell activation, and CNS disorders.

[0105] Proliferative disorders, include, but are not limited to a benign or malignant tumor, solid tumor, liquid tumor, carcinoma of the brain, kidney, liver, adrenal gland, bladder, breast, stomach, gastric tumors, ovaries, colon, rectum, prostate, pancreas, lung, vagina, cervix, testis, genitourinary tract, esophagus, larynx, skin, bone or thyroid, sarcoma, glioblastomas, neuroblastomas, multiple myeloma, gastrointestinal cancer, especially colon carcinoma orcolorectal adenoma, a tumor of the neck and head, an epidermal hyperproliferation, psoriasis, prostate hyperplasia, a neoplasia, a neoplasia of epithelial character, adenoma, adenocarcinoma, keratoacanthoma, epidermoid carcinoma, large cell carcinoma, non-small- cell lung carcinoma, lymphomas, Hodgkins and Non-Hodgkins, a mammary carcinoma, follicular carcinoma, undifferentiated carcinoma, papillary carcinoma, seminoma, melanoma, an IL-I driven disorder, an MyD88 driven disorder, Smoldering of indolent multiple myeloma, or hematological malignancies (including leukemia, diffuse large B-cell lymphoma (DLBCL), ABC DLBCL, chronic lymphocytic leukemia (CLL), chronic lymphocytic lymphoma, primary effusion lymphoma, Burkitt lymphoma / leukemia, acute lymphocytic leukemia, B-cell prolymphocytic leukemia, lymphoplasmacytic lymphoma, Waldenstrom’s macroglobulinemia (WM), splenic marginal zone lymphoma, multiple myeloma, plasmacytoma, intravascular large B-cell lymphoma).

[0106] In some embodiments, the cancer to be treated is selected from glioma, breast cancer, prostate cancer, head and neck squamous cell carcinoma, skin melanomas, ovarian cancer, malignant peripheral nerve sheath tumors (MPNST), and pancreatic cancer. In other embodiments, the cancer to be treated is cancer selected from glioma, breast cancer, prostate cancer, head and neck squamous cell carcinoma, skin melanomas, ovarian cancer, malignant peripheral nerve shealth tumors (MPNST), pancreatic cancer, non-small cell lung cancer (NSCLC) including EGFR-mutant NSCLC, urothelial cancer, liver cancer, bile duct cancer, kidney cancer, colon cancer, esophageal cancer, gastric cancer, gastrointestinal stromal tumors, and hematological malignancies include lymphomas, leukemias, myelomas, myeloproliferative neoplasms and myelodysplastic syndromes. In other embodiments, the cancer is selected from solid tumors (e.g., prostate cancer, renal cancer, hepatic cancer, pancreatic cancer, gastric cancer, breast cancer, lung cancer, cancers of the head and neck, thyroid cancer, glioblastoma, Kaposi's sarcoma, Castleman's disease, uterine leiomyosarcoma, melanoma etc.), hematological cancers (e.g., lymphoma, leukemia such as acute lymphoblastic leukemia (ALL), acute myelogenous leukemia (AML) or multiple myeloma), and skin cancer such as cutaneous T-cell lymphoma (CTCL) and cutaneous B-cell lymphoma. Example CTCLs include Sezary syndrome and mycosis fungoides.

[0107] Compounds, salts, and compositions described herein are also useful in the treatment of inflammatory or obstructive airways diseases, resulting, for example, in reduction of tissue damage, airways inflammation, bronchial hyperreactivity, remodeling or disease progression. Inflammatory or obstructive airways diseases include asthma of whatever type or genesis including both intrinsic (non-allergic) asthma and extrinsic (allergic) asthma, mildasthma, moderate asthma, severe asthma, bronchitic asthma, exercise-induced asthma, occupational asthma and asthma induced following bacterial infection. Treatment of asthma is also to be understood as embracing treatment of subjects, e.g. of less than 4 or 5 years of age, exhibiting wheezing symptoms and diagnosed or diagnosable as "wheezy infants", an established patient category of major medical concern and now often identified as incipient or early-phase asthmatics.

[0108] Compounds, salts, and compositions described herein are also useful in the treatment of heteroimmune diseases including, but are not limited to, graft versus host disease, transplantation, transfusion, anaphylaxis, allergies (e.g., allergies to plant pollens, latex, drugs, foods, insect poisons, animal hair, animal dander, dust mites, or cockroach calyx), type I hypersensitivity, allergic conjunctivitis, allergic rhinitis, and atopic dermatitis.

[0109] Compounds, salts, and compositions described herein are also useful in the treatment of other inflammatory or obstructive airways diseases and conditions to which the present invention is applicable and include acute lung injury (ALI), adult / acute respiratory distress syndrome (ARDS), chronic obstructive pulmonary, airways or lung disease (COPD, COAD or COLD), including chronic bronchitis or dyspnea associated therewith, emphysema, as well as exacerbation of airways hyperreactivity consequent to other drug therapy, in particular other inhaled drug therapy. Compounds, salts, and compositions described herein are also useful in the treatment of bronchitis including, but not limited to, acute, arachidic, catarrhal, croupus, chronic or phthinoid bronchitis. Compounds, salts, and compositions described herein are also useful in the treatment of pneumoconiosis (an inflammatory, commonly occupational, disease of the lungs, frequently accompanied by airways obstruction, whether chronic or acute, and occasioned by repeated inhalation of dusts) of whatever type or genesis, including, for example, aluminosis, anthracosis, asbestosis, chalicosis, ptilosis, siderosis, silicosis, tabacosis and byssinosis.

[0110] Compounds, salts, and compositions described herein are also useful in the treatment of inflammatory or allergic conditions of the skin, for example psoriasis, contact dermatitis, atopic dermatitis, alopecia areata, erythema multiforma, dermatitis herpetiformis, scleroderma, vitiligo, hypersensitivity angiitis, urticaria, bullous pemphigoid, lupus erythematosus, systemic lupus erythematosus, pemphigus vulgaris, pemphigus foliaceus, paraneoplastic pemphigus, epidermolysis bullosa acquisita, acne vulgaris, and other inflammatory or allergic conditions of the skin.

[0111] Compounds, salts, and compositions described herein are also useful in the treatment of other diseases or conditions, such as diseases or conditions having aninflammatory component, for example, treatment of diseases and conditions of the eye such as ocular allergy, conjunctivitis, keratoconjunctivitis sicca, and vernal conjunctivitis, diseases affecting the nose including allergic rhinitis, and inflammatory disease in which autoimmune reactions are implicated or having an autoimmune component or etiology, including autoimmune hematological disorders (e.g. hemolytic anemia, aplastic anemia, pure red cell anemia and idiopathic thrombocytopenia), systemic lupus erythematosus, rheumatoid arthritis, polychondritis, scleroderma, Wegener granulamatosis, dermatomyositis, chronic active hepatitis, myasthenia gravis, Steven-Johnson syndrome, idiopathic sprue, autoimmune inflammatory bowel disease (e.g. ulcerative colitis and Crohn's disease), irritable bowel syndrome, celiac disease, periodontitis, hyaline membrane disease, kidney disease, glomerular disease, alcoholic liver disease, multiple sclerosis, endocrine opthalmopathy, Grave's disease, sarcoidosis, alveolitis, chronic hypersensitivity pneumonitis, multiple sclerosis, primary biliary cirrhosis, uveitis (anterior and posterior), Sjogren’s syndrome, keratoconjunctivitis sicca and vernal keratoconjunctivitis, interstitial lung fibrosis, psoriatic arthritis, systemic juvenile idiopathic arthritis, cryopyrin-associated periodic syndrome, nephritis, vasculitis, diverticulitis, interstitial cystitis, glomerulonephritis (with and without nephrotic syndrome, e.g. including idiopathic nephrotic syndrome or minal change nephropathy), chronic granulomatous disease, endometriosis, leptospiriosis renal disease, glaucoma, retinal disease, ageing, headache, pain, complex regional pain syndrome, cardiac hypertrophy, musclewasting, catabolic disorders, obesity, fetal growth retardation, hyperchlolesterolemia, heart disease, chronic heart failure, mesothelioma, anhidrotic ectodermal dysplasia, Behcet’s disease, incontinentia pigmenti, Paget’s disease, pancreatitis, hereditary periodic fever syndrome, asthma (allergic and non- allergic, mild, moderate, severe, bronchitic, and exercise-induced), acute lung injury, acute respiratory distress syndrome, eosinophilia, hypersensitivities, anaphylaxis, nasal sinusitis, ocular allergy, silica induced diseases, COPD (reduction of damage, airways inflammation, bronchial hyperreactivity, remodeling or disease progression), pulmonary disease, cystic fibrosis, acidinduced lung injury, pulmonary hypertension, polyneuropathy, cataracts, muscle inflammation in conjunction with systemic sclerosis, inclusion body myositis, myasthenia gravis, thyroiditis, Addison’s disease, lichen planus, Type 1 diabetes, or Type 2 diabetes, appendicitis, atopic dermatitis, asthma, allergy, blepharitis, bronchiolitis, bronchitis, bursitis, cervicitis, cholangitis, cholecystitis, chronic graft rejection, colitis, conjunctivitis, Crohn’s disease, cystitis, dacryoadenitis, dermatitis, dermatomyositis, encephalitis, encephalomyelitis, endocarditis, endometritis, enteritis, enterocolitis, epicondylitis, epididymitis, fasciitis, fibrositis, gastritis, gastroenteritis, Henoch-Schonlein purpura, hepatitis, hidradenitissuppurativa, immunoglobulin A nephropathy, interstitial lung disease, laryngitis, mastitis, meningitis, myelitis myocarditis, myositis, nephritis, oophoritis, orchitis, osteitis, otitis, pancreatitis, parotitis, pericarditis, peritonitis, pharyngitis, pleuritis, phlebitis, pneumonitis, pneumonia, polymyositis, proctitis, prostatitis, pyelonephritis, rhinitis, salpingitis, sinusitis, stomatitis, synovitis, tendonitis, tonsillitis, ulcerative colitis, uveitis, vaginitis, vasculitis, or vulvitis.

[0112] In some embodiments, cardiovascular diseases which can be treated according to the present methods include, but are not limited to, restenosis, cardiomegaly, atherosclerosis, myocardial infarction, ischemic stroke, congestive heart failure, angina pectoris, reocclusion after angioplasty, restenosis after angioplasty, reocclusion after aortocoronary bypass, restenosis after aortocoronary bypass, stroke, transitory ischemia, a peripheral arterial occlusive disorder, pulmonary embolism, and deep venous thrombosis.

[0113] In some embodiments, the neurodegenerative disease which can be treated according to the present methods include, but are not limited to, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, cerebral ischemia, and neurodegenerative disease caused by traumatic injury, glutamate neurotoxicity, hypoxia, epilepsy, treatment of diabetes, metabolic syndrome, obesity, organ transplantation and graft versus host disease.

[0114] In certain aspects, a pharmaceutical composition described herein is formulated for administration to a patient in need of such composition. Pharmaceutical compositions described herein may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir. The term "parenteral" as used herein includes subcutaneous, intravenous, intramuscular, intra-articular, intra-synovial, intrasternal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion techniques. In some embodiments, the compositions are administered orally, intraperitoneally or intravenously. Sterile injectable forms of the pharmaceutical compositions described herein may be aqueous or oleaginous suspension. These suspensions may be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents.

[0115] In some aspects, the pharmaceutical compositions are administered orally.

[0116] A specific dosage and treatment regimen for any particular patient will depend upon a variety of factors, including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination, and the judgment of the treating physician and the severity of the particular disease beingtreated. The amount of a compound described herein in the composition will also depend upon the particular compound in the pharmaceutical composition. EXEMPLIFICATION Preparation of Compounds

[0117] The compounds claimed herein were prepared following the procedures outlined in the following schemes. Compound names were generated using the software built into ChemDraw. To the extent that there are discrepancies between the name of a compound and its depicted structure, the depicted chemical structure is to be taken as the appropriate compound.

[0118] The following intermediates can be prepared according to the protocols described in PCT / US2023 / 063318: 5-((diethoxyphosphoryl)difluoromethyl)-1H-indole-2-carboxylic acid; (difluoro(2-((4-nitrophenoxy)carbonyl)benzo[b]thiophen-5-yl)methyl)phosphonic acid; (difluoro(7-((perfluorophenoxy)carbonyl)naphthalen-2-yl)methyl)phosphonic acid; 7-((diethoxyphosphoryl)difluoromethyl)-2-naphthoic acid; perfluorophenyl 7-((bis(2-(butyrylthio)ethoxy)phosphoryl)difluoromethyl)-2- naphthoate; perfluorophenyl 7-((bis(2-((3-methylbutanoyl)thio)ethoxy) phosphoryl) difluoromethyl)-2-naphthoate; (difluoro(7-((perfluorophenoxy)carbonyl)naphthalen-2-yl)methyl)phosphonic acid; (fluoro(7-((perfluorophenoxy)carbonyl)naphthalen-2-yl)methyl)phosphonic acid; ((7-((perfluorophenoxy)carbonyl)naphthalen-2-yl)methyl)phosphonic acid; 7-(fluoro((((S)-1-oxo-1-propoxypropan-2-yl)amino)(phenoxy)phosphoryl)methyl)-2- naphthoic acid; and 7-(((((S)-1-oxo-1-propoxypropan-2-yl)amino)(phenoxy)phosphoryl)methyl)-2- naphthoic acid.

[0119] Tert-butyl 3-(4-fluoropyridin-3-yl)azetidine-1-carboxylate can be prepared according to the protocols described in PCT / US2023 / 010447.

[0120] Preparation of 8-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin4-yl)oct-7-ynoic acid

[0121] Step 1: Methyl 3-bromo-2-(bromomethyl)benzoate

[0122] To the solution of methyl 3-bromo-2-methylbenzoate (5 g, 21.39 mmol) in carbon tetrachloride (anhydrous) (65 mL, 671.9 mmol) under N2atmosphere was added N- bromosuccinimide (4.30 g, 23.92 mmol) and benzoyl peroxide (500.0 mg, 2.023 mmol). The reaction mixture was heated at reflux (90 ºC) and stirred at this temperature for 4 h. The precipitate was filtered off and the solvent was removed on a rotary evaporator. The crude material was purified by flash-chromatography using a 80 g silica gel cartridge eluting with a gradient of 0 to 20% EtOAc in heptanes in 15 CV to afford methyl 3-bromo-2- (bromomethyl)benzoate (6.6 g, 89%) as a colorless oil. LCMS (ESI): m / z = 308.9 (M+H)+.1H NMR (400 MHz, CDCl3) δ 7.92 (d, J = 7.8 Hz, 1H), 7.80 (d, J = 7.8 Hz, 1H), 7.32 - 7.23 (m, 1H), 5.17 (s, 2H), 4.00 (s, 3H).

[0123] Step 2: 3-(4-Bromo-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0124] A mixture of methyl 3-bromo-2-(bromomethyl)benzoate (6.6 g, 20.36 mmol), 3- aminopiperidine-2,6-dione HCl salt (4.1 g, 24.41 mmol) and N,N-diisopropylethylamine (18 mL, 102.3 mmol) in acetonitrile (70 mL) was heated to 90ºC for 18 h. The reaction mixture was filtered and the filter cake was washed with ether to give 3-(4-bromo-1-oxoisoindolin-2- yl)piperidine-2,6-dione (5.3 g, 80%) as a purple solid. LCMS (ESI): m / z = 323.0 (M+H)+.1H NMR (400 MHz, DMSO-d6) δ 11.01 (s, 1H), 7.87 (d, J = 7.8 Hz, 1H), 7.77 (d, J = 7.1 Hz, 1H), 7.51 (t, J = 7.7 Hz, 1H), 5.15 (dd, J = 13.2, 5.1 Hz, 1H), 4.46 - 4.22 (m, 2H), 2.97 - 2.86 (m, 1H), 2.59 (d, J = 17.4 Hz, 1H), 2.54 - 2.41 (m, 1H), 2.07 - 1.98 (m, 1H).

[0125] Step 3: Oct-7-ynoic acid

[0126] Preparation of Jones’ reagent: chromium trioxide (2.05 g, 20.6 mmol, 1.6 eq) was dissolved in water (4 mL) (dark red solution) and sulfuric acid (1.8 mL) was added (precipitate). Minimal amount of water (15 drops) was added until a dark red solution was observed.

[0127] 7-Octyn-1-ol (2 g, 12.9 mmol, 1 eq) was dissolved in acetone (40 mL) then Jones’ reagent was added dropwise (careful: highly exothermic). Upon addition of Jones’ reagent, the solution turned green and by the end of the addition, a red mixture with green precipitate was observed. The reaction was stirred for 2 h and then quenched with dropwise addition of i-PrOH (reaction turned green). The reaction was diluted with MTBE and filtered over Celite. Silica gel was added to the filtrate and the latter was evaporated to dryness. The crude residue was purified by flash-chromatography on a 40 g silica gel cartridge eluting with 0-75% EtOAc in heptanes to give dec-9-ynoic acid (1.99 g, 92%) as a yellow oil.1H NMR (400 MHz, CDCl3) δ 11.42 (br. s., 1H), 2.37 (t, J = 7.6 Hz, 2H), 2.20 (td, J = 7.0, 2.7 Hz, 2H), 1.97 - 1.92 (m, 1H), 1.71 - 1.61 (m, 2H), 1.60 - 1.51 (m, 2H), 1.50 - 1.42 (m, 2H).

[0128] Step 4: 8-(2-(2,6-Dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oct-7-ynoic acid

[0129] Triethylamine (1.60 mL, 11.44 mmol) was added to a mixture of 3-(4-bromo-1- oxoisoindolin-2-yl)piperidine-2,6-dione (200 mg, 0.618 mmol), oct-7-ynoic acid (95.0 mg, 0.677 mmol), copper(I) iodide (30.0 mg, 0.156 mmol) and trans- dichlorobis(triphenylphosphine) palladium(II) (55.0 mg, 0.078 mmol) in N,N- dimethylformamide (3 mL). The resulting mixture was purged and refilled with nitrogen three times and then stirred at 80°C for 18 h under nitrogen. The reaction mixture was directly purified by reverse phase chromatography using a 50 g C18cartridge eluting with a gradient of acetonitrile in water (5% for 4 CV then 5 to 100% in 18 CV) to give 8-(2-(2,6-dioxopiperidin- 3-yl)-1-oxoisoindolin-4-yl)oct-7-ynoic acid (145 mg, 56%) as a brown solid. LCMS (ESI): m / z = 383.2 (M+H)+.1H NMR (400 MHz, DMSO-d6) δ 10.99 (br. s., 1H), 7.70 (d, J = 7.8 Hz, 1H), 7.63 (d, J = 7.3 Hz, 1H), 7.54 - 7.49 (m, 1H), 5.13 (dd, J = 13.0, 4.9 Hz, 1H), 4.48 - 4.26 (m, 2H), 2.96 - 2.85 (m, 1H), 2.59 (d, J = 18.6 Hz, 1H), 2.49 - 2.40 (m, 3H), 2.33 - 2.12 (m, 3H), 2.02 (d, J = 5.1 Hz, 1H), 1.62 - 1.51 (m, 4H), 1.48 - 1.40 (m, 2H).

[0130] Preparation of [(2-{[(5S,8S,10aR)-3-{8-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3- dihydro-1H-isoindol-4-yl]oct-7-ynoyl}-8-[methyl(phenyl)carbamoyl]-6-oxo- decahydropyrrolo[1,2-a][1,5]diazocin-5-yl]carbamoyl}-1H-indol-5- yl)difluoromethyl]phosphonic acid (Compound 1)

[0131] Step 1: 3-Benzyl 8-methyl (5S,8S,10aR)-5-{[(tert-butoxy)carbonyl]amino}-6-oxo- decahydropyrrolo[1,2-a][1,5]diazocine-3,8-dicarboxylate

[0132] Benzyl chloroformate (582 µL, 4.08 mmol, 1.4 eq) and sodium bicarbonate (735 mg, 8.76 mmol, 3 eq) were added to a solution of methyl (5S,8S,10aR)-5-{[(tert- butoxy)carbonyl]amino}-6-oxo-decahydropyrrolo[1,2-a][1,5]diazocine-8-carboxylate (1 g, 2.92 mmol, 1 eq) in anhydrous dioxane (30 mL). The mixture was stirred at room temperature for 18 h. The reaction mixture was filtered through Celite and then the filtrate was concentrated to give crude 3-benzyl 8-methyl (5S,8S,10aR)-5-{[(tert-butoxy)carbonyl]amino}-6-oxo-decahydropyrrolo[1,2-a][1,5]diazocine-3,8-dicarboxylate as a clear oil. The crude product was used for the next step without further purification. LCMS (ESI): m / z = 376.2 (M-Boc+2H)+, 420.2 (M-t-Bu+2H)+.

[0133] Step 2: (5S,8S,10aR)-3-[(Benzyloxy)carbonyl]-5-{[(tert-butoxy)carbonyl]amino}- 6-oxo-decahydropyrrolo[1,2-a][1,5]diazocine-8-carboxylic acid

[0134] To a solution of crude 3-benzyl 8-methyl (5S,8S,10aR)-5-{[(tert- butoxy)carbonyl]amino}-6-oxo-decahydropyrrolo[1,2-a][1,5]diazocine-3,8-dicarboxylate (1.4 g, 2.94 mmol, 1 eq) in tetrahydrofuran (8 mL) and water (2 mL) was added lithium hydroxide monohydrate (370 mg, 8.82 mmol, 3 eq). The reaction mixture was stirred for 4 h at room temperature. The reaction mixture was quenched with the addition of 1 N aqueous HCl solution (20 mL) and then the product was extracted with DCM (3 x 30 mL). The combined organic extracts were dried with sodium sulfate, filtered and concentrated under reduced pressure. The crude residue was directly purified by reverse phase chromatography using a 50 g C18 cartridge eluting with a gradient of acetonitrile in water (5% for 3 CV then 5 to 100% in 18 CV) to give (5S,8S,10aR)-3-[(benzyloxy)carbonyl]-5-{[(tert-butoxy)carbonyl]amino}-6- oxo-decahydropyrrolo[1,2-a][1,5]diazocine-8-carboxylic acid (1.07 g, 80% over 2 steps) as a white solid. LCMS (ESI): m / z = 362.2 (M-Boc+2H)+, 406.2 (M-t-Bu+2H)+.1H NMR (400 MHz, DMSO-d6) δ 12.39 (br. s., 1H), 7.41 - 7.26 (m, 5H), 7.04 - 6.85 (m, 1H), 5.12 - 4.98 (m, 2H), 4.54 - 4.40 (m, 1H), 4.27 - 4.15 (m, 2H), 3.64 - 3.37 (m, 4H), 2.25 (dt, J = 12.0, 7.7 Hz, 1H), 2.11 - 1.97 (m, 1H), 1.92 - 1.78 (m, 2H), 1.76 - 1.57 (m, 2H), 1.40 - 1.27 (m, 9H).

[0135] Step 3: Benzyl (5S,8S,10aR)-5-{[(tert-butoxy)carbonyl]amino}-8- [methyl(phenyl)carbamoyl]-6-oxo-decahydropyrrolo[1,2-a][1,5]diazocine-3-carboxylate

[0136] To a solution of (5S,8S,10aR)-3-[(benzyloxy)carbonyl]-5-{[(tert- butoxy)carbonyl]amino}-6-oxo-decahydropyrrolo[1,2-a][1,5]diazocine-8-carboxylic acid (500 mg, 1.08 mmol, 1 eq) in 1,2-dichloroethane (10 mL) were added N-methylaniline (173 µL, 1.61 mmol, 1.5 eq), a 50% w / w solution of T3P in EtOAc (1.02 mL, 1.61 mmol, 1.5 eq) and N,N-diisopropylethylamine (1.12 mL, 6.47 mmol, 6 eq). The reaction mixture was stirred for 18 h. The solvent was evaporated and the crude residue was directly purified by reverse phase chromatography on a 50 g C18 cartridge eluting with 5-100% acetonitrile in water. The combined fractions were concentrated under reduced pressure. The isolated product was re- purified by normal phase chromatography using a 24 g silica gel cartridge eluting with a gradient of EtOAc in heptanes (0 to 100% in 18 CV) then with MeOH in DCM (0 to 10% in 6 CV) to give benzyl (5S,8S,10aR)-5-{[(tert-butoxy)carbonyl]amino}-8-[methyl(phenyl)carbamoyl]-6-oxo-decahydropyrrolo[1,2-a][1,5]diazocine-3-carboxylate (311 mg, 52%) as a yellow solid. LCMS (ESI): m / z = 551.2 (M+H)+.

[0137] Step 4: tert-Butyl N-[(5S,8S,10aR)-8-[methyl(phenyl)carbamoyl]-6-oxo- decahydropyrrolo[1,2-a][1,5]diazocin-5-yl]carbamate

[0138] 10% Palladium on carbon (50% wet) (238 mg, 113 µmol, 0.2 eq) was added to a mixture of benzyl (5S,8S,10aR)-5-{[(tert-butoxy)carbonyl]amino}-8- [methyl(phenyl)carbamoyl]-6-oxo-decahydropyrrolo[1,2-a][1,5]diazocine-3-carboxylate (311 mg, 564 µmol, 1 eq) in methanol (15 mL). Hydrogen was bubbled into the suspension for 2 min. and then the reaction mixture was stirred under 1 atm. of hydrogen for 18 h. The reaction mixture was filtered on Celite and the pad was rinsed with MeOH. The filtrate was concentrated in vacuo. The crude residue was purified by reverse phase chromatography on a 50 g C18 cartridge eluting with 5-80% acetonitrile in water. The combined fractions were concentrated under reduced pressure to give tert-butyl N-[(5S,8S,10aR)-8-[methyl(phenyl)carbamoyl]-6- oxo-decahydropyrrolo[1,2-a][1,5]diazocin-5-yl]carbamate (125 mg, 53%) as a white solid. LCMS (ESI): m / z = 417.2 (M+H)+.

[0139] Step 5: tert-Butyl N-[(5S,8S,10aR)-3-{8-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3- dihydro-1H-isoindol-4-yl]oct-7-ynoyl}-8-[methyl(phenyl)carbamoyl]-6-oxo- decahydropyrrolo[1,2-a][1,5]diazocin-5-yl]carbamate

[0140] To a solution of tert-butyl N-[(5S,8S,10aR)-8-[methyl(phenyl)carbamoyl]-6-oxo- decahydropyrrolo[1,2-a][1,5]diazocin-5-yl]carbamate (125 mg, 300 µmol, 1 eq) and 8-[2-(2,6- dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-yl]oct-7-ynoic acid (126 mg, 330 µmol, 1.1 eq) in N,N-dimethylformamide (5 mL) and N,N-diisopropylethylamine (311 µL, 1.79 mmol) was added HATU (148 mg, 390 µmol, 1.3 eq). The resulting brown solution was stirred for 30 min. at room temperature. The reaction mixture was directly purified by reverse phase chromatography on a 50 g C18 cartridge eluting with 5-100% acetonitrile in water. The combined fractions were concentrated under reduced pressure to give tert-butyl N- [(5S,8S,10aR)-3-{8-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-yl]oct-7- ynoyl}-8-[methyl(phenyl)carbamoyl]-6-oxo-decahydropyrrolo[1,2-a][1,5]diazocin-5- yl]carbamate (123 mg, 52%) as a beige solid. LCMS (ESI): m / z = 781.4 (M+H)+.

[0141] Step 6: (5S,8S,10aR)-5-amino-3-{8-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3- dihydro-1H-isoindol-4-yl]oct-7-ynoyl}-N-methyl-6-oxo-N-phenyl-decahydropyrrolo[1,2- a][1,5]diazocine-8-carboxamide

[0142] To a solution of tert-butyl N-[(5S,8S,10aR)-3-{8-[2-(2,6-dioxopiperidin-3-yl)-1- oxo-2,3-dihydro-1H-isoindol-4-yl]oct-7-ynoyl}-8-[methyl(phenyl)carbamoyl]-6-oxo-decahydropyrrolo[1,2-a][1,5]diazocin-5-yl]carbamate (25 mg, 32.0 µmol, 1 eq) in methylene chloride (1 mL) was added trifluoroacetic acid (0.5 mL). The resulting yellow solution was stirred for 1 h at room temperature. The reaction mixture was concentrated under reduced pressure. The crude TFA salt was used directly for the next step without further purification. LCMS (ESI): m / z = 681.3 (M+H)+.

[0143] Step 7: Diethyl [(2-{[(5S,8S,10aR)-3-{8-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3- dihydro-1H-isoindol-4-yl]oct-7-ynoyl}-8-[methyl(phenyl)carbamoyl]-6-oxo- decahydropyrrolo[1,2-a][1,5]diazocin-5-yl]carbamoyl}-1H-indol-5- yl)difluoromethyl]phosphonate

[0144] To a solution of crude (5S,8S,10aR)-5-amino-3-{8-[2-(2,6-dioxopiperidin-3-yl)-1- oxo-2,3-dihydro-1H-isoindol-4-yl]oct-7-ynoyl}-N-methyl-6-oxo-N-phenyl- decahydropyrrolo[1,2-a][1,5]diazocine-8-carboxamide TFA salt (25.4 mg, 32.0 µmol, 1 eq) and 5-[(diethoxyphosphoryl)difluoromethyl]-1H-indole-2-carboxylic acid (12.3 mg, 35.5 µmol, 1.1 eq) in N,N-dimethylformamide (2 mL) and N,N-diisopropylethylamine (33.5 µL, 193 µmol, 6 eq) was added HATU (15.9 mg, 41.9 µmol, 1.3 eq). The resulting yellow solution was stirred for 30 min. at room temperature. The reaction mixture was directly purified by reverse phase chromatography on a 50 g C18 cartridge eluting with 5-100% acetonitrile in water. The combined fractions were concentrated under reduced pressure and then dried under high vacuum to give diethyl [(2-{[(5S,8S,10aR)-3-{8-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3- dihydro-1H-isoindol-4-yl]oct-7-ynoyl}-8-[methyl(phenyl)carbamoyl]-6-oxo- decahydropyrrolo[1,2-a][1,5]diazocin-5-yl]carbamoyl}-1H-indol-5- yl)difluoromethyl]phosphonate (22.0 mg, 67%) as a yellow solid. LCMS (ESI): m / z = 1011.4 (M+H)+.

[0145] Step 8: [(2-{[(5S,8S,10aR)-3-{8-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro- 1H-isoindol-4-yl]oct-7-ynoyl}-8-[methyl(phenyl)carbamoyl]-6-oxo-decahydropyrrolo[1,2- a][1,5]diazocin-5-yl]carbamoyl}-1H-indol-5-yl)difluoromethyl]phosphonic acid

[0146] To a solution of diethyl [(2-{[(5S,8S,10aR)-3-{8-[2-(2,6-dioxopiperidin-3-yl)-1- oxo-2,3-dihydro-1H-isoindol-4-yl]oct-7-ynoyl}-8-[methyl(phenyl)carbamoyl]-6-oxo- decahydropyrrolo[1,2-a][1,5]diazocin-5-yl]carbamoyl}-1H-indol-5- yl)difluoromethyl]phosphonate (22 mg, 21.7 µmol, 1 eq) in methylene chloride (3 mL) at 0°C was added N,O-bis(trimethylsilyl)trifluoroacetamide (17.2 µL, 65.1 µmol, 3 eq) and trimethylsilyl iodide (26.0 µL, 130 µmol, 6 eq). The reaction mixture was stirred for 15 min. at 0°C. The solvent was removed under reduced pressure at 0°C. DMSO (1 mL) was added.

[0147] The crude residue was purified by reverse phase chromatography on a 50 g C18cartridge eluting with 5-40% acetonitrile in water. The combined fractions were directly freeze- dried to give [(2-{[(5S,8S,10aR)-3-{8-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H- isoindol-4-yl]oct-7-ynoyl}-8-[methyl(phenyl)carbamoyl]-6-oxo-decahydropyrrolo[1,2- a][1,5]diazocin-5-yl]carbamoyl}-1H-indol-5-yl)difluoromethyl]phosphonic acid (Compound 16.7 mg, 32%) as a white solid. LCMS (ESI): m / z = 954.3 (M+H)+.NMR (400 MHz, CD3OD) δ 7.96 - 7.88 (m, 1H), 7.75 - 7.34 (m, 10H), 7.27 - 7.16 (m, 1H), 5.20 - 4.96 (m, 2H), 4.53 - 4.47 (m, 1H), 4.37 - 4.35 (m, 1H), 4.26 - 4.20 (m, 1H), 4.05 - 4.00 (m, 1H), 3.85 - 3.81 (m, 1H), 3.75 - 3.45 (m, 2H), 3.28 - 3.18 (m, 3H), 2.92 - 2.79 (m, 1H), 2.77 - 2.62 (m, 2H), 2.54 - 2.50 (m, 3H), 2.21 - 2.09 (m, 1H), 2.04 - 1.85 (m, 4H), 1.79 - 1.54 (m, 7H), 1.39 - 1.31 (m, 3H).

[0148] Preparation of 5-((bis((pivaloyloxy)methoxy)phosphoryl)difluoromethyl)-1H- indole-2-carboxylic acid

[0149] Step 1: 1-(tert-Butyl) 2-ethyl 5-methyl-1H-indole-1,2-dicarboxylate

[0150] To a suspension of sodium hydride (60% dispersion in mineral oil) (1.60 g, 40 mmol) in tetrahydrofuran (anhydrous) (400 mL) under N2 atmosphere at 0ºC was added ethyl5-methylindole-2-carboxylate (4 g, 19.09 mmol) over 15 min. The reaction mixture was allowed to stir at 0ºC for 30 min. Then di-tert-butyl dicarbonate (6 g, 27.22 mmol) was added in one portion. The reaction mixture was stirred at room temperature for 18 h. The reaction mixture was treated with ice-water (200 mL). The product was extracted with ethyl acetate (3 x 150 mL). The combined extracts were washed with brine (2 x 100 mL), dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give crude 1-(tert-butyl) 2-ethyl 5-methyl-1H-indole-1,2-dicarboxylate (7.6 g, 131%) as an orange oil. The crude product was used for the next step without any further purification.1H NMR (400 MHz, CDCl3) δ 7.96 (d, J = 8.6 Hz, 1H), 7.38 (s, 1H), 7.24 (d, J = 8.6 Hz, 1H), 7.06 - 7.00 (m, 1H), 4.38 (q, J = 7.2 Hz, 2H), 2.44 (s, 3H), 1.63 (s, 9H), 1.40 (t, J = 7.2 Hz, 3H).

[0151] Step 2: 1-(tert-Butyl) 2-ethyl 5-(bromomethyl)-1H-indole-1,2-dicarboxylate

[0152] To a solution of 1-(tert-butyl) 2-ethyl 5-methyl-1H-indole-1,2-dicarboxylate (7.6 g, 25.0 mmol) in anhydrous carbon tetrachloride (125 mL) under N2atmosphere was added N- bromosuccinimide (4.5 g, 25.0 mmol) and benzoyl peroxide (250 mg, 1.01 mmol). The reaction mixture was heated at reflux (78ºC) and stirred at this temperature for 18 h. The precipitate was filtered off and the solvent was removed on a rotary evaporator. The crude material was purified by flash-chromatography on a 40 g silica gel cartridge (with a pre-column of 50 g of silica gel) using a gradient of 0 to 40% EtOAc in heptanes in 18 CV to afford 1-(tert-butyl) 2- ethyl 5-(bromomethyl)-1H-indole-1,2-dicarboxylate (7.1 g, 54%) as a yellow oil. The isolated product contained a mixture of brominated and di-brominated product in a ratio of ≈75:25. LCMS (ESI): m / z = 326.0 [M-C4H9+2H]+.1H NMR (400 MHz, CDCl3) δ 8.06 (d, J = 8.8 Hz, 1H), 7.66 - 7.60 (m, 1H), 7.46 (dd, J = 8.8, 1.7 Hz, 1H), 7.07 (s, 1H), 4.65 - 4.60 (m, 2H), 4.43 - 4.37 (m, 2H), 1.64 (s, 9H), 1.41 (t, J = 7.2 Hz, 3H).

[0153] Step 3: 1-(tert-Butyl) 2-ethyl 5-((diethoxyphosphoryl)methyl)-1H-indole-1,2- dicarboxylate

[0154] 1-(tert-Butyl) 2-ethyl 5-(bromomethyl)-1H-indole-1,2-dicarboxylate (7.1 g, 13.54 mmol) and triethyl phosphite (3.1 mL, 17.74 mmol) were placed in a round bottomed flask equipped with a magnetic stirring bar. The reaction mixture was heated at 100°C and stirred at this temperature for 6 h. The reaction mixture was directly purified through reverse phase chromatography on a 275 g C18cartridge using a gradient of 5-100% acetonitrile in water. The fractions containing the product were concentrated under reduced pressure to afford 1-(tert- butyl) 2-ethyl 5-((diethoxyphosphoryl)methyl)-1H-indole-1,2-dicarboxylate (4.8 g, 81%) as a brown oil. LCMS (ESI): m / z = 440.1 (M+H)+.1H NMR (400 MHz, CDCl3) δ 8.02 (d, J = 8.6 Hz, 1H), 7.55 - 7.52 (m, 1H), 7.35 (dt, J = 8.6, 2.0 Hz, 1H), 7.05 (s, 1H), 4.38 (q, J = 7.3 Hz,2H), 4.07 - 3.92 (m, 4H), 3.29 - 3.19 (m, 2H), 1.63 (s, 9H), 1.40 (t, J = 7.1 Hz, 3H), 1.24 (t, J = 7.1 Hz, 6H).

[0155] Step 4: Benzyl 5-((diethoxyphosphoryl)methyl)-1H-indole-2-carboxylate

[0156] A mixture of 1-(tert-butyl) 2-ethyl 5-((diethoxyphosphoryl)methyl)-1H-indole-1,2- dicarboxylate (4.3 g, 9.77 mmol), benzyl alcohol (22 mL, 212.0 mmol) and titanium (IV) isopropoxide (300 μL, 2.59 mmol) were placed in a round bottomed flask equipped with a magnetic stirring bar. The reaction mixture was heated at 100°C for 18 h. The reaction mixture was cooled down to 35°C and quenched with 1 N aqueous HCl solution (20 mL). The product was extracted with EtOAc (2 x 100 mL) and the combined organic extracts were washed with brine (2 x 100 mL), dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was directly purified by reverse phase chromatography using a 150 g C18 cartridge eluting with a gradient of acetonitrile in water (5% for 3 CV then 5 to 100% in 18 CV) to give benzyl 5-((diethoxyphosphoryl)methyl)-1H-indole-2-carboxylate (3.1 g, 74%) as a yellow oil. LCMS (ESI): m / z = 402.1 [M+H]+.1H NMR (400 MHz, CDCl3) δ 9.11 (br. s., 1H), 7.64 (br. s., 1H), 7.53 - 7.48 (m, 2H), 7.48 - 7.36 (m, 5H), 7.32 (d, J = 6.6 Hz, 1H), 5.44 (s, 2H), 4.11 - 3.97 (m, 4H), 3.33 - 3.24 (m, 2H), 1.27 (t, J = 7.0 Hz, 6H).

[0157] Step 5: Dibenzyl 5-((diethoxyphosphoryl)methyl)-1H-indole-1,2-dicarboxylate

[0158] To a suspension of sodium hydride (60% dispersion in mineral oil) (950 mg, 23.75 mmol) in tetrahydrofuran (anhydrous) (110 mL) under N2 atmosphere at 0°C was added benzyl 5-((diethoxyphosphoryl)methyl)-1H-indole-2-carboxylate (3.1 g, 7.19 mmol) in tetrahydrofuran (anhydrous) (10 mL) over 5 min. The reaction mixture was allowed to stir at 0°C for 10 min. Then benzyl chloroformate (1.6 mL, 10.87 mmol) was added dropwise. The reaction mixture was stirred at room temperature for 18 h. The reaction mixture was treated with ice-water (100 mL). The product was extracted with EtOAc (3 x 100 mL). The combined extracts were washed with brine (2 x 100 mL), dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude material was directly purified by reverse phase chromatography using a 150 g C18 cartridge eluting with a gradient of acetonitrile in water (5% for 3 CV then 5 to 100% in 18 CV) to give dibenzyl 5- ((diethoxyphosphoryl)methyl)-1H-indole-1,2-dicarboxylate (3.67 g, 88%) as a yellow oil. LCMS (ESI): m / z = 536.2 [M+H]+.1H NMR (400 MHz, CDCl3) δ 8.01 (d, J = 8.6 Hz, 1H), 7.54 (br. s., 1H), 7.43 - 7.33 (m, 11H), 7.13 (s, 1H), 5.35 (s, 2H), 5.22 (s, 2H), 4.07 - 3.91 (m, 4H), 3.27 - 3.17 (m, 2H), 1.23 (t, J = 7.0 Hz, 6H).

[0159] Step 6: Dibenzyl 5-((diethoxyphosphoryl)difluoromethyl)-1H-indole-1,2- dicarboxylate

[0160] A mixture of dibenzyl 5-((diethoxyphosphoryl)methyl)-1H-indole-1,2- dicarboxylate (360 mg, 0.6400 mmol) and Accufluor NFSI (620 mg, 1.927 mmol) in tetrahydrofuran (anhydrous) (10 mL) were placed in a round bottomed flask equipped with a magnetic stirring bar. The reaction mixture was cooled down to −78°C (dry ice + acetone). To this solution was added sodium bis(trimethylsilylamide) (1 M in THF) (2 mL, 2 mmol) over 10 min. The reaction mixture was stirred at -78°C for 2 h before warming up to room temperature over 3 h. The reaction mixture was quenched with saturated NH4Cl aqueous solution (20 mL). The product was extracted with EtOAc (3 x 40 mL). The combined extracts were washed with brine (2 x 50 mL), dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude residue was directly purified by reverse phase chromatography using a 50 g C18 cartridge eluting with a gradient of acetonitrile in water (5% for 3 CV then 5 to 100% in 18 CV) to give to give dibenzyl 5- ((diethoxyphosphoryl)difluoromethyl)-1H-indole-1,2-dicarboxylate (300 mg, 82%) as a yellow oil. LCMS (ESI): m / z = 572.1 [M+H]+.1H NMR (400 MHz, CDCl3) δ 8.15 (d, J = 8.8 Hz, 1H), 7.89 (s, 1H), 7.67 (d, J = 9.0 Hz, 1H), 7.46 - 7.32 (m, 10H), 7.23 - 7.18 (m, 1H), 5.37 (s, 2H), 5.23 (s, 2H), 4.26 - 4.06 (m, 4H), 1.30 (t, J = 7.1 Hz, 6H).

[0161] Step 7: ({1,2-bis[(Benzyloxy)carbonyl]-1H-indol-5-yl}difluoromethyl)phosphonic acid

[0162] 1,2-Dibenzyl 5-[(diethoxyphosphoryl)difluoromethyl]-1H-indole-1,2- dicarboxylate (1.9 g, 3.32 mmol) was dissolved in methylene chloride (15 mL) and cooled to 0°C. N,O-Bis(trimethylsilyl)trifluoroacetamide (5.28 mL, 19.9 mmol) was added followed by a solution of iodotrimethylsilane (1 M in DCM, freshly prepared) (13.2 mL, 13.2 mmol) which was added dropwise at 0°C. The reaction mixture was stirred at 0°C for 20 min. and the solvent was then removed under vacuum at 0°C. The crude product was dissolved in a mixture of water:CH3CN:TFA (2:1:0.1) and directly purified by reverse phase chromatography using a 50 g C18cartridge eluting with a gradient of acetonitrile in water (5% for 4 CV then 5 to 100% in 18 CV) to give ({1,2-bis[(benzyloxy)carbonyl]-1H-indol-5-yl}difluoromethyl)phosphonic acid (1.16 g, 68%) as an orange solid.1H NMR (400 MHz, DMSO-d6) δ 7.99 - 7.85 (m, 2H), 7.65 (d, J = 9.0 Hz, 1H), 7.53 - 7.27 (m, 10H), 6.69 (br. s., 3H), 5.41 (s, 2H), 5.22 (s, 2H).

[0163] Step 8: 1,2-Dibenzyl 5-{[bis({[(2,2-dimethylpropanoyl)oxy]methoxy})phosphoryl] difluoromethyl}-1H-indole-1,2-dicarboxylate

[0164] Sodium hydroxide (185 mg, 4.64 mmol) in H2O (2 mL) was added dropwise to a stirred suspension of ({1,2-bis[(benzyloxy)carbonyl]-1H-indol-5- yl}difluoromethyl)phosphonic acid (1.20 g, 2.32 mmol) in H2O (6 mL). When the mixturebecame clear (pH!9), silver nitrate (985 mg, 5.80 mmol) was added. After 2 h at 0°C, the gray precipitate was collected by filtration and dried under vacuum. The powder was suspended in dry toluene (14 mL) and iodomethyl 2,2-dimethylpropanoate (1.68 g, 6.96 mmol) was added. The mixture was stirred for 24 h at room temperature. After filtration, the solvent was removed in vacuo. The crude residue was directly purified by normal phase chromatography using a 40 g silica gel cartridge eluting with a gradient of EtOAc in heptanes (0 to 60% in 18 CV) to give 1,2-dibenzyl 5-{[bis({[(2,2-dimethylpropanoyl)oxy]methoxy})phosphoryl]difluoromethyl}- 1H-indole-1,2-dicarboxylate (820 mg, 48%) as a brown oil.1H NMR (400 MHz, DMSO-d6) δ 8.17 - 8.08 (m, 1H), 7.99 - 7.92 (m, 1H), 7.60 (d, J = 8.8 Hz, 1H), 7.52 - 7.30 (m, 11H), 5.74 - 5.59 (m, 4H), 5.46 - 5.41 (m, 2H), 5.28 - 5.20 (m, 2H), 1.13 - 1.06 (m, 18H).

[0165] Step 9: 5-{[bis({[(2,2- Dimethylpropanoyl)oxy]methoxy})phosphoryl]difluoromethyl}-1H-indole-2-carboxylic acid

[0166] 10% Palladium on carbon (50% wet) (350 mg, 164 µmol) was added to a mixture of 1,2-dibenzyl 5-{[bis({[(2,2-dimethylpropanoyl)oxy]methoxy})phosphoryl] difluoromethyl}-1H-indole-1,2-dicarboxylate (820 mg, 1.10 mmol) in anhydrous tetrahydrofuran (20 mL). Hydrogen was bubbled into the suspension for 2 min. and then the reaction mixture was stirred under 1 atm. of hydrogen for 18 h. The reaction mixture was filtered on a Celite pad and the pad was rinsed with Me-THF. The filtrate was concentrated in vacuo. The crude residue was purified by reverse phase chromatography using a 50 g C18cartridge eluting with a gradient of acetonitrile in water (5% for 3 CV then 5 to 100% in 18 CV) to give 5-{[bis({[(2,2- dimethylpropanoyl)oxy]methoxy})phosphoryl]difluoromethyl}- 1H-indole-2-carboxylic acid (444 mg, 78%) as a light green solid.1H NMR (400 MHz, DMSO-d6) δ 13.18 (br. s., 1H), 12.12 (s, 1H), 7.88 (s, 1H), 7.55 (d, J = 8.6 Hz, 1H), 7.37 (d, J = 9.0 Hz, 1H), 7.21 (s, 1H), 5.72 - 5.61 (m, 4H), 1.15 - 1.09 (m, 18H).

[0167] Preparation of ((((2-(((5S,8S,10aR)-3-(8-(2-(2,6-Dioxopiperidin-3-yl)-1- oxoisoindolin-4-yl)oct-7- ynoyl)-8-(methyl(phenyl)carbamoyl)-6- oxodecahydropyrrolo[1,2-a][1,5]diazocin-5- yl)carbamoyl)-1H-indol-5- yl)difluoromethyl)phosphoryl)bis(oxy))bis(methylene) bis(2,2-dimethylpropanoate) (Compound 2)

[0168] Step 1: (5S,8S,10aR)-5-Amino-3-{8-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3- dihydro-1H-isoindol-4-yl]oct-7-ynoyl}-N-methyl-6-oxo-N-phenyl-decahydropyrrolo[1,2- a][1,5]diazocine-8-carboxamide

[0169] To a solution of tert-butyl N-[(5S,8S,10aR)-3-{8-[2-(2,6-dioxopiperidin-3-yl)-1- oxo-2,3-dihydro-1H-isoindol-4-yl]oct-7-ynoyl}-8-[methyl(phenyl)carbamoyl]-6-oxo- decahydropyrrolo[1,2-a][1,5]diazocin-5-yl]carbamate (60 mg, 76.8 µmol, 1 eq) in methylene chloride (2 mL) was added trifluoroacetic acid (1 mL). The resulting yellow solution was stirred for 1 h at room temperature. The reaction mixture was concentrated under reduced pressure. The crude TFA salt was used directly for the next step without further purification. LCMS (ESI): m / z = 681.3 (M+H)+.

[0170] Step 2: ((((2-(((5S,8S,10aR)-3-(8-(2-(2,6-Dioxopiperidin-3-yl)-1-oxoisoindolin-4- yl)oct-7- ynoyl)-8-(methyl(phenyl)carbamoyl)-6-oxodecahydropyrrolo[1,2-a][1,5]diazocin-5- yl)carbamoyl)-1H-indol-5-yl)difluoromethyl)phosphoryl)bis(oxy))bis(methylene) bis(2,2- dimethylpropanoate)

[0171] To a solution of (5S,8S,10aR)-5-amino-3-{8-[2-(2,6-dioxopiperidin-3-yl)-1-oxo- 2,3-dihydro-1H-isoindol-4-yl]oct-7-ynoyl}-N-methyl-6-oxo-N-phenyl-decahydropyrrolo[1,2- a][1,5]diazocine-8-carboxamide TFA salt (61 mg, 76.8 µmol, 1 eq) in N,N-dimethylformamide (3 mL) was added N,N-diisopropylethylamine (79.5 µL, 457 µmol, 6 eq). The reaction mixture was stirred for 5 min. and then 5-{[bis({[(2,2- dimethylpropanoyl)oxy]methoxy})phosphoryl]difluoromethyl}-1H-indole-2-carboxylic acid (47.5 mg, 91.5 µmol, 1.2 eq) and HATU (37.6 mg, 99.1 µmol, 1.3 eq) were added. The resultingyellow solution was stirred for 30 min. at room temperature. The reaction mixture was directly purified by reverse phase chromatography on a 30 g C18 cartridge eluting with 5-100% acetonitrile in water (5% acetonitrile in water 3 CV, 5-100% acetonitrile in water 2 CV then 100% acetonitrile in 7 CV). The combined fractions were concentrated. The isolated product was re-purified by flash-chromatography on a 12 g silica gel cartridge eluting with 0-20% DCM in methanol to give ((((2-(((5S,8S,10aR)-3-(8-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4- yl)oct-7-ynoyl)-8-(methyl(phenyl)carbamoyl)-6-oxodecahydropyrrolo[1,2-a][1,5]diazocin-5- yl)carbamoyl)-1H-indol-5-yl)difluoromethyl)phosphoryl)bis(oxy))bis(methylene) bis(2,2- dimethylpropanoate) (Compound 2, 45.0 mg, 50%) as a beige solid. LCMS (ESI): m / z = 1182.4 (M+H)+.1H NMR (400 MHz, CD3OD) δ 7.92 - 7.84 (m, 1H), 7.74 - 7.32 (m, 10H), 7.28 - 7.20 (m, 1H), 5.76 - 5.66 (m, 4H), 5.27 - 4.90 (m, 2H), 4.51 - 4.47 (m, 1H), 4.41 - 4.36 (m, 1H), 4.27 - 4.15 (m, 1H), 4.12 - 3.92 (m, 1H), 3.90 - 3.75 (m, 1H), 3.67 - 3.57 (m, 1H), 3.56 - 3.37 (m, 1H), 3.28 - 3.18 (m, 3H), 2.91 - 2.80 (m, 1H), 2.75 - 2.67 (m, 2H), 2.58 - 2.44 (m, 3H), 2.20 - 2.09 (m, 1H), 2.06 - 1.81 (m, 6H), 1.80 - 1.58 (m, 6H), 1.36 - 1.27 (m, 1H), 1.21 - 1.17 (m, 19H).

[0172] Preparation of ((2-(((5S,8S,10aR)-3-acetyl-8-((4'-(8-(2-(2,6-dioxopiperidin-3- yl)-1-oxoisoindolin-4-yl)oct-7-ynamido)-[1,1'-biphenyl]-4-yl)carbamoyl)-6- oxodecahydropyrrolo[1,2-a][1,5]diazocin-5-yl)carbamoyl)-1H-indol-5- yl)difluoromethyl)phosphonic acid (Compound 3)

[0173] Step 1: tert-Butyl (4'-amino-[1,1'-biphenyl]-4-yl)carbamate

[0174] To a stirred solution of benzidine (500 mg, 2.71 mmol, 1 eq) in a mixture of DMF (3 mL), THF (10 mL) and H2O (1.5 mL) were added potassium carbonate (317 mg, 2.30 mmol, 0.85 eq) and di-tert-butyl dicarbonate (471 mg, 2.16 mmol, 0.8 eq) at room temperature. The resulting mixture was stirred for 18 h at room temperature. The reaction mixture was then diluted with water (50 mL) and the product was extracted with EtOAc (3 x 20 mL). The organic layers were combined, washed with brine (2 x 10 mL), dried with anhydrous sodium sulfate and concentrated under reduced pressure. The crude residue was purified by reverse phase chromatography on a 50 g C18cartridge eluting with 5-100% acetonitrile in water. The combined fractions were concentrated under reduced pressure to give tert-butyl (4'-amino- [1,1'-biphenyl]-4-yl)carbamate (420 mg, 55%) as a yellow solid. LCMS (ESI): m / z = 285.2 (M+H)+.

[0175] Step 2: tert-Butyl (4'-(8-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oct-7- ynamido)-[1,1'-biphenyl]-4-yl)carbamate

[0176] To a solution of 8-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-4- yl]oct-7-ynoic acid (50 mg, 130 µmol, 1 eq) and tert-butyl (4'-amino-[1,1'-biphenyl]-4- yl)carbamate (44.0 mg, 155 µmol, 1.2 eq) in N,N-dimethylformamide (2 mL) and N,N- diisopropylethylamine (134 µL, 779 µmol, 6 eq) was added HATU (64.2 mg, 169 µmol, 1.3 eq). The resulting brown solution was stirred for 30 min. at room temperature. The reaction mixture was directly purified by reverse phase chromatography on a 50 g C18 cartridge eluting with 5-100% acetonitrile in water. The combined fractions were concentrated under reduced pressure to give tert-butyl (4'-(8-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oct-7- ynamido)-[1,1'-biphenyl]-4-yl)carbamate (40.0 mg, 47%) as a beige solid. LCMS (ESI): m / z = 649.3 (M+H)+.

[0177] Step 3: N-(4'-Amino-[1,1'-biphenyl]-4-yl)-8-(2-(2,6-dioxopiperidin-3-yl)-1- oxoisoindolin-4-yl)oct-7-ynamide

[0178] To a solution of tert-butyl (4'-(8-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4- yl)oct-7-ynamido)-[1,1'-biphenyl]-4-yl)carbamate (40 mg, 61.6 µmol, 1 eq) in methylene chloride (2 mL) was added trifluoroacetic acid (1 mL). The resulting yellow solution was stirred for 1 h at room temperature. The reaction mixture was concentrated under reduced pressure. The crude TFA salt was used directly for the next step without further purification. LCMS (ESI): m / z = 549.2 (M+H)+.

[0179] Step 4: tert-Butyl ((5S,8S,10aR)-3-acetyl-8-((4'-(8-(2-(2,6-dioxopiperidin-3-yl)-1- oxoisoindolin-4-yl)oct-7-ynamido)-[1,1'-biphenyl]-4-yl)carbamoyl)-6- oxodecahydropyrrolo[1,2-a][1,5]diazocin-5-yl)carbamate

[0180] To a solution of (5S,8S,10aR)-3-acetyl-5-{[(tert-butoxy)carbonyl]amino}-6-oxo- decahydropyrrolo[1,2-a][1,5]diazocine-8-carboxylic acid (25 mg, 67.6 µmol, 1 eq) and N-(4'- amino-[1,1'-biphenyl]-4-yl)-8-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oct-7- ynamide TFA salt (44.8 mg, 67.6 µmol, 1 eq) in N,N-dimethylformamide (2 mL) and N,N- diisopropylethylamine (70.4 µL, 405 µmol, 6 eq) was added HATU (33.3 mg, 87.8 µmol, 1.3 eq). The resulting brown solution was stirred for 2 h at room temperature. The reaction mixture was directly purified by reverse phase chromatography on a 50 g C18 cartridge eluting with 5- 80% acetonitrile in water. The combined fractions were concentrated under reduced pressure to give tert-butyl ((5S,8S,10aR)-3-acetyl-8-((4'-(8-(2-(2,6-dioxopiperidin-3-yl)-1- oxoisoindolin-4-yl)oct-7-ynamido)-[1,1'-biphenyl]-4-yl)carbamoyl)-6- oxodecahydropyrrolo[1,2-a][1,5]diazocin-5-yl)carbamate (41.0 mg, 67%) as a beige solid. LCMS (ESI): m / z = 901.6 (M+H)+.

[0181] Step 5: (5S,8S,10aR)-3-Acetyl-5-amino-N-(4'-(8-(2-(2,6-dioxopiperidin-3-yl)-1- oxoisoindolin-4-yl)oct-7-ynamido)-[1,1'-biphenyl]-4-yl)-6-oxodecahydropyrrolo[1,2- a][1,5]diazocine-8-carboxamide

[0182] To a solution of tert-butyl ((5S,8S,10aR)-3-acetyl-8-((4'-(8-(2-(2,6-dioxopiperidin- 3-yl)-1-oxoisoindolin-4-yl)oct-7-ynamido)-[1,1'-biphenyl]-4-yl)carbamoyl)-6- oxodecahydropyrrolo[1,2-a][1,5]diazocin-5-yl)carbamate (40 mg, 44.4 µmol, 1 eq) in methylene chloride (2 mL) was added trifluoroacetic acid (1 mL). The resulting yellow solution was stirred for 1 h at room temperature. The reaction mixture was concentrated under reduced pressure. The crude TFA salt was used directly for the next step without further purification. LCMS (ESI): m / z = 800.4 (M+H)+.

[0183] Step 6: Diethyl ((2-(((5S,8S,10aR)-3-acetyl-8-((4'-(8-(2-(2,6-dioxopiperidin-3-yl)- 1-oxoisoindolin-4-yl)oct-7-ynamido)-[1,1'-biphenyl]-4-yl)carbamoyl)-6- oxodecahydropyrrolo[1,2-a][1,5]diazocin-5-yl)carbamoyl)-1H-indol-5- yl)difluoromethyl)phosphonate

[0184] To a solution of 5-[(diethoxyphosphoryl)difluoromethyl]-1H-indole-2-carboxylic acid (10.9 mg, 31.6 µmol, 1.1 eq) and (5S,8S,10aR)-3-acetyl-5-amino-N-(4'-(8-(2-(2,6- dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oct-7-ynamido)-[1,1'-biphenyl]-4-yl)-6- oxodecahydropyrrolo[1,2-a][1,5]diazocine-8-carboxamide (26.3 mg, 28.8 µmol, 1 eq) in N,N- dimethylformamide (2 mL) and N,N-diisopropylethylamine (29.9 µL, 172 µmol, 6 eq) wasadded HATU (14.2 mg, 37.4 µmol, 1.3 eq). The resulting brown solution was stirred for 2 h at room temperature. The reaction mixture was directly purified by reverse phase chromatography on a 50 g C18cartridge eluting with 5-80% acetonitrile in water (with 0.1% formic acid). The product was repurified purified by reverse phase chromatography on a 50 g C18 cartridge eluting with 5-80% acetonitrile in water (with 0.1% formic acid). The combined fractions were concentrated under reduced pressure to give diethyl ((2-(((5S,8S,10aR)-3-acetyl-8-((4'-(8-(2- (2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oct-7-ynamido)-[1,1'-biphenyl]-4- yl)carbamoyl)-6-oxodecahydropyrrolo[1,2-a][1,5]diazocin-5-yl)carbamoyl)-1H-indol-5- yl)difluoromethyl)phosphonate (15.0 mg, 46.%) as a white solid. LCMS (ESI): m / z = 1130.4 (M+H)+.

[0185] Step 7: ((2-(((5S,8S,10aR)-3-Acetyl-8-((4'-(8-(2-(2,6-dioxopiperidin-3-yl)-1- oxoisoindolin-4-yl)oct-7-ynamido)-[1,1'-biphenyl]-4-yl)carbamoyl)-6- oxodecahydropyrrolo[1,2-a][1,5]diazocin-5-yl)carbamoyl)-1H-indol-5- yl)difluoromethyl)phosphonic acid

[0186] To a solution of diethyl ((2-(((5S,8S,10aR)-3-acetyl-8-((4'-(8-(2-(2,6- dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oct-7-ynamido)-[1,1'-biphenyl]-4-yl)carbamoyl)-6- oxodecahydropyrrolo[1,2-a][1,5]diazocin-5-yl)carbamoyl)-1H-indol-5- yl)difluoromethyl)phosphonate (15 mg, 12.3 µmol, 1 eq) in methylene chloride (5 mL) at 0°C was added N,O-bis(trimethylsilyl)trifluoroacetamide (19.5 mL, 73.8 µmol, 6 eq) followed by a 1 M solution of trimethylsilyl iodide in DCM (49.2 µL, 49.2 µmol, 4 eq). The reaction mixture was stirred for 15 min. at 0°C. The reaction mixture was quenched with the addition of a 2:1 mixture of H2O and acetonitrile (with 0.1% TFA) (0.5 mL). The solvent was removed under reduced pressure at 0°C. The crude residue was purified by reverse phase chromatography on a 30 g C18cartridge eluting with 5-40% acetonitrile in water. The combined fractions were directly freeze-dried to give ((2-(((5S,8S,10aR)-3-acetyl-8-((4'-(8-(2-(2,6-dioxopiperidin-3- yl)-1-oxoisoindolin-4-yl)oct-7-ynamido)-[1,1'-biphenyl]-4-yl)carbamoyl)-6- oxodecahydropyrrolo[1,2-a][1,5]diazocin-5-yl)carbamoyl)-1H-indol-5- yl)difluoromethyl)phosphonic acid (Compound 3, 5.9 mg, 45%) as a white solid. LCMS (ESI): m / z = 1073.4 (M+H)+.1H NMR (400 MHz, CD3OD:D2O 1:0.1) δ 7.94 (s, 1H), 7.68 - 7.59 (m, 3H), 7.57 - 7.38 (m, 10H), 7.31 - 7.26 (m, 1H), 5.27 - 5.22 (m, 1H), 5.12 -5.08 (m, 1H), 4.67 - 4.60 (m, 1H), 4.50 - 4.38 (m, 3H), 3.97 - 3.62 (m, 4H), 2.95 - 2.77 (m, 2H), 2.57 - 2.50 (m, 2H), 2.50 - 2.36 (m, 4H), 2.26 - 2.24 (m, 3H), 2.21 - 2.06 (m, 3H), 2.04 - 1.87 (m, 2H), 1.85 - 1.75 (m, 2H), 1.72 - 1.67 (m, 2H), 1.62 - 1.55 (m, 2H), 1.38 - 1.22 (m, 1H).

[0187] Preparation of ((((2-(((5S,8S,10aR)-3-acetyl-8-((4'-(8-(2-(2,6-dioxopiperidin-3- yl)-1-oxoisoindolin4-yl)oct-7-ynamido)-[1,1'-biphenyl]-4-yl)carbamoyl)-6- oxodecahydropyrrolo[1,2-a][1,5]diazocin-5-yl)carbamoyl)-1H-indol-5- yl)difluoromethyl)phosphoryl)bis(oxy))bis(methylene) bis(2,2-dimethylpropanoate) (Compound 4)

[0188] Step 1: (5S,8S,10aR)-3-Acetyl-5-amino-N-(4'-(8-(2-(2,6-dioxopiperidin-3-yl)-1- oxoisoindolin-4-yl)oct-7-ynamido)-[1,1'-biphenyl]-4-yl)-6-oxodecahydropyrrolo[1,2- a][1,5]diazocine-8-carboxamide

[0189] To a solution of tert-butyl ((5S,8S,10aR)-3-acetyl-8-((4'-(8-(2-(2,6-dioxopiperidin- 3-yl)-1-oxoisoindolin-4-yl)oct-7-ynamido)-[1,1'-biphenyl]-4-yl)carbamoyl)-6- oxodecahydropyrrolo[1,2-a][1,5]diazocin-5-yl)carbamate (200 mg, 222 µmol, 1 eq) in methylene chloride (5 mL) was added trifluoroacetic acid (2 mL). The resulting yellowish solution was stirred for 1 h at room temperature. The reaction was concentrated under reduced pressure. The crude residue was purified by reverse phase chromatography on a 50 g C18 cartridge eluting with 5-60% acetonitrile in water. The combined fractions were concentrated under reduced pressure to give (5S,8S,10aR)-3-acetyl-5-amino-N-(4'-(8-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oct-7-ynamido)-[1,1'-biphenyl]-4-yl)-6- oxodecahydropyrrolo[1,2-a][1,5]diazocine-8-carboxamide (80 mg, 45%) as a white solid. LCMS (ESI): m / z = 800.4 (M+H)+.

[0190] Step 2: ((((2-(((5S,8S,10aR)-3-Acetyl-8-((4'-(8-(2-(2,6-dioxopiperidin-3-yl)-1- oxoisoindolin4-yl)oct-7-ynamido)-[1,1'-biphenyl]-4-yl)carbamoyl)-6- oxodecahydropyrrolo[1,2-a][1,5]diazocin-5-yl)carbamoyl)-1H-indol-5- yl)difluoromethyl)phosphoryl)bis(oxy))bis(methylene) bis(2,2-dimethylpropanoate)

[0191] To a solution of (5S,8S,10aR)-3-acetyl-5-amino-N-(4'-(8-(2-(2,6-dioxopiperidin-3- yl)-1-oxoisoindolin-4-yl)oct-7-ynamido)-[1,1'-biphenyl]-4-yl)-6-oxodecahydropyrrolo[1,2- a][1,5]diazocine-8-carboxamide TFA salt (40 mg, 43.8 µmol, 1 eq) in N,N-dimethylforamide (2 mL) was added N,N-diisopropylethylamine (52.1 µL, 300 µmol, 6.8 eq). The reaction mixture was stirred for 5 min. then 5-{[bis({[(2,2- dimethylpropanoyl)oxy]methoxy})phosphoryl]difluoromethyl}-1H-indole-2-carboxylic acid (28.5 mg, 55.0 µmol, 1.25 eq) and HATU (24.7 mg, 65.0 µmol, 1.5 eq) were added. The resulting yellow solution was stirred for 30 min. at room temperature. The reaction mixture was directly purified by reverse phase chromatography on a 30 g C18 cartridge eluting with 5- 100% acetonitrile in water (5% acetonitrile in water 3 CV, 5-100% acetonitrile in water 2 CV then 100% acetonitrile in 7 CV). The combined fractions were concentrated. The isolated product was purified by flash-chromatography on a 12 g silica gel cartridge eluting with 0-20% DCM in methanol to give ((((2-(((5S,8S,10aR)-3-acetyl-8-((4'-(8-(2-(2,6-dioxopiperidin-3-yl)- 1-oxoisoindolin4-yl)oct-7-ynamido)-[1,1'-biphenyl]-4-yl)carbamoyl)-6- oxodecahydropyrrolo[1,2-a][1,5]diazocin-5-yl)carbamoyl)-1H-indol-5- yl)difluoromethyl)phosphoryl)bis(oxy))bis(methylene) bis(2,2-dimethylpropanoate) (Compound 4, 22.9 mg, 40%) as a beige solid. LCMS (ESI): m / z = 1301.5 (M+H)+.1H NMR (400 MHz, CD3OD) δ 7.88 (br. s., 1H), 7.71 - 7.62 (m, 3H), 7.59 - 7.36 (m, 10H), 7.29 - 7.23 (m, 1H), 5.76 - 5.62 (m, 4H), 5.255.10 (m, 2H), 4.68 - 4.57 (m, 1H), 4.52 - 4.38 (m, 3H), 4.03 - 3.58 (m, 4H), 2.94 - 2.82 (m, 1H), 2.81 - 2.71 (m, 1H), 2.59 - 2.47 (m, 3H), 2.462.34 (m, 3H), 2.28 - 2.06 (m, 7H), 2.02 - 1.84 (m, 2H), 1.84 - 1.74 (m, 2H), 1.74 - 1.66 (m, 2H), 1.67 - 1.62 (m, 2H), 1.18 (s, 18H).

[0192] Preparation of ((2-(((5S,8S,10aR)-3-(8-(2-(2,6-dioxopiperidin-3-yl)-1- oxoisoindolin-4-yl)oct-7-ynoyl)-6-oxo-8-(3-(pyridin-3-yl)azetidine-1- carbonyl)decahydropyrrolo[1,2-a][1,5]diazocin-5-yl)carbamoyl)benzo[b]thiophen-5- yl)difluoromethyl)phosphonic acid (Compound 5)

[0193] Step 1: Preparation of (5S,8S,10aR)-methyl 5-((tert-butoxycarbonyl)amino)-3- (oct-7-ynoyl)-6-oxodecahydropyrrolo[1,2-a][1,5]diazocine-8-carboxylate

[0194] To a solution of oct-7-ynoic acid (0.30 g, 2.20 mmol, 1 eq) in DCM (5 mL) was added HATU (2.50 g, 6.60 mmol, 3 eq) and ethylbis(propan-2-yl)amine (0.33 g, 2.60 mmol, 1.2 eq). The mixture was stirred at 25 °C for 10 minutes. Then, a solution of methyl (5S,8S,10aR)-5-((tert-butoxycarbonyl)amino)-6-oxodecahydropyrrolo[1,2-a][1,5]diazocine- 8-carboxylate (0.80 g, 2.40 mmol, 1.1 eq) in DCM (2 mL) was added to the mixture. Themixture was stirred at 25 °C for 2 hour to give a yellow mixture. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography to give (5S,8S,10aR)-methyl 5-((tert-butoxycarbonyl)amino)- 3-(oct-7-ynoyl)-6-oxodecahydro pyrrolo[1,2-a][1,5]diazocine-8-carboxylate (0.6 g, 58.6% yield, 1.30 mmol) as a white solid. LCMS (ESI) m / z = 464.3.1H NMR (400 MHz, CHLOROFORM-d) δ 4.55 - 4.45 (m, 1H), 3.98 - 3.82 (m, 1H), 3.79 - 3.73 (m, 2H), 3.73 - 3.65 (m, 2H), 3.47 - 3.25 (m, 1H), 3.20 - 3.10 (m, 3H), 2.64 ( s, 1H), 2.43 - 2.32 (m, 1H), 2.24 - 2.18 (m, 1H), 2.17 - 2.06 (m, 1H), 2.03 - 1.91 (m, 1H), 1.93 (t, J = 2.4 Hz, 1H), 1.88 - 1.77 (m, 1H), 1.75 - 1.64 (m, 1H), 1.59 ( d, J = 7.0 Hz, 1H), 1.48 - 1.46 (m, 4H), 1.46 - 1.44 (m, 9H), 1.42 (s, 4H)

[0195] Step 2: Preparation of (5S,8S,10aR)-5-((tert-butoxycarbonyl)amino)-3-(oct-7- ynoyl)-6-oxodecahydropyrrolo[1,2-a][1,5]diazocine-8-carboxylic acid

[0196] To a solution of (5S,8S,10aR)-methyl 5-((tert-butoxycarbonyl)amino)-3-(oct-7- ynoyl)-6-oxodecahydropyrrolo[1,2-a][1,5]diazocine-8-carboxylate (0.60 g, 1.30 mmol, 1 eq) in methanol (1 mL), THF (1 mL) and H2O (1 mL) was added lithium hydroxide (0.11 g, 2.60 mmol, 2 eq). The mixture was stirred at 25 °C for 1 hour to give a yellow mixture. The reaction mixture was filtered and concentrated under reduced pressure to give a residue which was purified by prep-HPLC (column: Waters bridge 150 × 25 mm × 10 um; mobile phase: [water (NH4HCO3) - ACN]; B%: 0% - 30%, 11 min) then lyophilized to give (5S,8S,10aR)-5-((tert- butoxycarbonyl)amino)-3-(oct-7-ynoyl)-6-oxodecahydropyrrolo [1,2-a][1,5]diazocine-8- carboxylic acid (0.2 g, 41% yield, 0.45 mmol) as a white solid. LCMS (ESI) m / z = 450.1

[0197] Step 3: Preparation of (5S,8S,10aR)-5-((tert-butoxycarbonyl)amino)-3-(8-(2-(2,6- dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oct-7-ynoyl)-6-oxodecahydropyrrolo[1,2- a][1,5]diazocine-8-carboxylic acid

[0198] To a solution of (5S,8S,10aR)-5-((tert-butoxycarbonyl)amino)-3-(oct-7-ynoyl)-6- oxodecahydropyrrolo[1,2-a][1,5]diazocine-8-carboxylic acid (0.2 g, 0.45 mmol, 1 eq) in DMF (1 mL) was added 3-(4-bromo-1-oxoisoindolin-2-yl)piperidine-2,6-dione (0.14 g, 0.45 mmol, 1 eq) and copper iodide (17 mg, 89 µmol, 0.2 eq), then triethylamine (0.14 g, 1.4 mmol, 3 eq) and bis((cyclopenta-1,3-dien-1-yl)diphenylphosphane) dihydrochloride iron palladium (33 mg, 45 µmol, 0.1 eq) was added in the mixture at 25 °C under N2atmosphere. Then the mixture was stirred at 80 °C for 3 hours to give a brown solution. The reaction mixture was quenched by water (20 mL) and adjusted to pH = 2~3 with the addition of 1M HCl aqueous solution, then extracted with ethyl acetate 60 mL (20 mL × 3). The combined organic layer was washed with brine 20 mL, dried over Na2SO4, filtered and concentrated under reduced pressure to give aresidue. The residue was purified by column chromatography to give (5S,8S,10aR)-5-((tert- butoxycarbonyl)amino)-3-(8-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oct-7-ynoyl)- 6-oxodecahydropyrrolo[1,2-a][1,5]diazocine-8-carboxylic acid (0.17 g, 55% yield, 0.25 mmol) as a white solid. LCMS (ESI) m / z = 692.6

[0199] Step 4: Preparation of tert-butyl ((5S,8S,10aR)-3-(8-(2-(2,6-dioxopiperidin-3-yl)- 1-oxoisoindolin-4-yl)oct-7-ynoyl)-6-oxo-8-(3-(pyridin-3-yl)azetidine-1- carbonyl)decahydropyrrolo[1,2-a][1,5]diazocin-5-yl)carbamate

[0200] To a solution of (5S,8S,10aR)-5-((tert-butoxycarbonyl)amino)-3-(8-(2-(2,6- dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oct-7-ynoyl)-6-oxodecahydropyrrolo[1,2- a][1,5]diazocine-8-carboxylic acid (60 mg, 87 µmol, 1 eq) in DCM (1 mL) was added Chloro- N,N,N′,N′-tetramethylformamidinium hexafluorophosphate (29 mg, 0.10 mmol, 1.2 eq) and 1- methyl-1H-imidazole (22 mg, 0.26 mmol, 3 eq). The mixture was stirred at 25 °C for 10 minutes and then 3-(azetidin-3-yl)pyridine (12 mg, 87 µmol, 1 eq) was added in the mixture, the mixture was stirred at 25 °C for 1 hour to give a yellow solution. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography to give tert-butyl ((5S,8S,10aR)-3-(8-(2-(2,6-dioxopiperidin- 3-yl)-1-oxoisoindolin-4-yl)oct-7-ynoyl)-6-oxo-8-(3-(pyridin-3-yl)azetidine-1- carbonyl)decahydropyrrolo[1,2-a][1,5]diazocin-5-yl)carbamate (40 mg, 57.10% yield, 49 µmol) as a white solid. LCMS (ESI) m / z = 808.3

[0201] Step 5: Preparation of 3-(4-(8-((5S,8S,10aR)-5-amino-6-oxo-8-(3-(pyridin-3- yl)azetidine-1-carbonyl)octahydropyrrolo[1,2-a][1,5]diazocin-3(4H)-yl)-8-oxooct-1-yn-1- yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0202] To a solution of tert-butyl ((5S,8S,10aR)-3-(8-(2-(2,6-dioxopiperidin-3-yl)-1- oxoisoindolin-4-yl)oct-7-ynoyl)-6-oxo-8-(3-(pyridin-3-yl)azetidine-1- carbonyl)decahydropyrrolo[1,2-a][1,5]diazocin-5-yl)carbamate (80 mg, 99 µmol, 1 eq) in DCM (0.5 mL) and TFA (0.3 mL) was stirred at 25 °C for 0.5 hour to give a yellow solution. The reaction mixture was filtered and concentrated under reduced pressure to give 3-(4-(8- ((5S,8S,10aR)-5-amino-6-oxo-8-(3-(pyridin-3-yl)azetidine-1-carbonyl)octahydropyrrolo[1,2- a][1,5]diazocin-3(4H)-yl)-8-oxooct-1-yn-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (80 mg, crude) as a yellow oil.

[0203] Step 6: Preparation of ((2-(((5S,8S,10aR)-3-(8-(2-(2,6-dioxopiperidin-3-yl)-1- oxoisoindolin-4-yl)oct-7-ynoyl)-6-oxo-8-(3-(pyridin-3-yl)azetidine-1- carbonyl)decahydropyrrolo[1,2-a][1,5]diazocin-5-yl)carbamoyl)benzo[b]thiophen-5- yl)difluoromethyl)phosphonic acid

[0204] To a solution of 3-(4-(8-((5S,8S,10aR)-5-amino-6-oxo-8-(3-(pyridin-3- yl)azetidine-1-carbonyl)octahydropyrrolo[1,2-a][1,5]diazocin-3(4H)-yl)-8-oxooct-1-yn-1-yl)- 1-oxoisoindolin-2-yl)piperidine-2,6-dione (70 mg, 99 µmol, 1.0 eq) in DCM (1 mL) was added (difluoro(2-((4-nitrophenoxy)carbonyl)benzo[b]thiophen-5-yl)methyl)phosphonic acid (51 mg, 0.12 mmol, 1.2 eq), ethylbis(propan-2-yl)amine (16 mg, 0.12 mmol, 1.2 eq) and 1H-1,2,3- benzotriazol-1-ol (40 mg, 0.30 mmol, 3 eq). The mixture was stirred at 25 °C for 10 minutes to give a yellow solution. The reaction mixture filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex Luna C18 150 × 25 mm × 10 um; mobile phase: [water (0.1% TFA) - ACN]; B%: 32% - 62%, 10 min). The solution was lyophilized to give ((2-(((5S,8S,10aR)-3-(8-(2-(2,6-dioxopiperidin-3-yl)-1- oxoisoindolin-4-yl)oct-7-ynoyl)-6-oxo-8-(3-(pyridin-3-yl)azetidine-1- carbonyl)decahydropyrrolo[1,2-a][1,5]diazocin-5-yl)carbamoyl)benzo[b]thiophen-5- yl)difluoromethyl)phosphonic acid (Compound 5, 13 mg, 12.80% yield, 13 µmol) as a white solid. LCMS (ESI) m / z = 998.2.1H NMR (400 MHz, DMSO-d6) δ 10.98 (s, 1H), 8.83 - 8.65 (m, 1H), 8.63 - 8.43 (m, 2H), 8.31 (d, J = 10.0 Hz, 1H), 8.19 - 8.06 (m, 2H), 7.95 - 7.84 (m, 1H), 7.64 (s, 3H), 7.53 - 7.40 (m, 2H), 7.24 - 6.96 (m, 1H), 5.16 - 5.09 (m, 1H), 5.06 - 4.95 (m, 1H), 4.89 - 4.80 (m, 1H), 4.64 - 4.56 (m, 1H), 4.38 (s, 8H), 3.97 - 3.85 (m, 5H), 3.77 (s, 1H), 3.68 (s, 1H), 3.49 - 3.42 (m, 2H), 2.95 - 2.86 (m, 1H), 2.28 - 2.16 (m, 1H), 2.11 - 1.45 (m, 12H).

[0205] Preparation of ((2-(((5S,8S,10aR)-8-((rel-3S,4R)-3-cyano-4- phenylpyrrolidine-1-carbonyl)-3-(8-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4- yl)oct-7-ynoyl)-6-oxodecahydropyrrolo[1,2-a][1,5]diazocin-5- yl)carbamoyl)benzo[b]thiophen-5-yl)difluoromethyl)phosphonic acid (Compound 6)

[0206] Step 1: Preparation of tert-butyl ((5S,8S,10aR)-8-((rel-3S,4R)-3-cyano-4- phenylpyrrolidine-1-carbonyl)-3-(8-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oct-7- ynoyl)-6-oxodecahydropyrrolo[1,2-a][1,5]diazocin-5-yl)carbamate

[0207] To a solution of (5S,8S,10aR)-5-{[(tert-butoxy)carbonyl]amino}-3-{8-[2-(2,6- dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-yl]oct-7-ynoyl}-6- oxodecahydropyrrolo[1,2-a][1,5]diazocine-8-carboxylic acid (0.10 g, 0.14 mmol, 1 eq) in DCM (0.5 mL) was added DIEA (56 mg, 0.43 mmol, 3 eq) and HATU (60 mg, 0.16 mmol, 1.1 eq). The mixture was stirred at 25 °C for 10 minutes and then rac-(3S,4R)-4-phenylpyrrolidine- 3-carbonitrile (33 mg, 0.19 mmol, 1.3 eq) was added in the mixture, the mixture was stirred at 25 °C for 1 hour to give a yellow solution. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography to give tert-butyl ((5S,8S,10aR)-8-((rel-3S,4R)-3-cyano-4-phenylpyrrolidine- 1-carbonyl)-3-(8-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oct-7-ynoyl)-6-oxodecahydropyrrolo[1,2-a][1,5]diazocin-5-yl)carbamate (54 mg, 45% yield) as a white solid. LCMS (ESI) m / z = 846.3

[0208] Step 2: Preparation of (3S,4R)-1-((5S,8S,10aR)-5-amino-3-(8-(2-(2,6- dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oct-7-ynoyl)-6-oxodecahydropyrrolo[1,2- a][1,5]diazocine-8-carbonyl)-4-phenylpyrrolidine-3-carbonitrile

[0209] To a solution of tert-butyl ((5S,8S,10aR)-8-((rel-3S,4R)-3-cyano-4- phenylpyrrolidine-1-carbonyl)-3-(8-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oct-7- ynoyl)-6-oxodecahydropyrrolo[1,2-a][1,5]diazocin-5-yl)carbamate (70 mg, 83 µmol, 1 eq) in DCM (0.6 mL) and TFA (0.3 mL) as stirred at 25 °C for 30 minutes to give a yellow solution. The reaction mixture was filtered and concentrated under reduced pressure to give (rel-3S,4R)- 1-((5S,8S,10aR)-5-amino-3-(8-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oct-7- ynoyl)-6-oxodecahydropyrrolo[1,2-a][1,5]diazocine-8-carbonyl)-4-phenylpyrrolidine-3- carbonitrile (70 mg, crude) as a yellow oil. LCMS (ESI) m / z = 746.4

[0210] Step 3: Preparation of ((2-(((5S,8S,10aR)-8-((rel-3S,4R)-3-cyano-4- phenylpyrrolidine-1-carbonyl)-3-(8-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oct-7- ynoyl)-6-oxodecahydropyrrolo[1,2-a][1,5]diazocin-5-yl)carbamoyl)benzo[b]thiophen-5- yl)difluoromethyl)phosphonic acid

[0211] To a solution of (rel-3S,4R)-1-((5S,8S,10aR)-5-amino-3-(8-(2-(2,6- dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oct-7-ynoyl)-6-oxodecahydropyrrolo[1,2- a][1,5]diazocine-8-carbonyl)-4-phenylpyrrolidine-3-carbonitrile (50 mg, 67 µmol, 1 eq) in DCM (1 mL) was added (difluoro(2-((4-nitrophenoxy)carbonyl)benzo[b]thiophen-5- yl)methyl)phosphonic acid (35 mg, 81 µmol, 1.2 eq), 1H-1,2,3-benzotriazol-1-ol (9.0 mg, 67 µmol, 1.0 eq) and ethylbis(propan-2-yl)amine (30 mg, 0.20 mmol, 3 eq). The mixture was stirred at 25 °C for 10 minutes to give a yellow solution. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep- HPLC (column: Phenomenex Luna C18150 × 25 mm × 10 um; mobile phase: [water (0.1% TFA) - ACN]; B%: 32% - 62%, 10 min) to lyophilized to give ((2-(((5S,8S,10aR)-8-((rel-3S,4R)-3- cyano-4-phenylpyrrolidine-1-carbonyl)-3-(8-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4- yl)oct-7-ynoyl)-6-oxodecahydropyrrolo[1,2-a][1,5]diazocin-5- yl)carbamoyl)benzo[b]thiophen-5-yl)difluoromethyl)phosphonic acid (Compound 6, 12 mg, 17% yield) as a white solid. LCMS (ESI) m / z = 1036.51H NMR (400 MHz, DMSO-d6) δ 10.98 (s, 2H), 9.06 - 8.59 (m, 1H), 8.33 - 8.27 (m, 1H), 8.13 - 8.06 (m, 2H), 7.72 - 7.67 (m, 1H), 7.64 - 7.58 (m, 2H), 7.51 - 7.46 (m, 1H), 7.44 - 7.37 (m, 4H), 7.36 - 7.31 (m, 1H), 7.26 - 6.94 (m, 1H), 5.17 - 5.09 (m, 1H), 4.98 ( d, J = 4.0 Hz, 1H), 4.91 - 4.69 (m, 1H), 4.68 - 4.49 (m, 2H),4.48 - 4.41 (m, 1H), 4.36 - 4.32 (m, 1H), 4.31 - 4.16 (m, 3H), 4.12 - 4.05 (m, 1H), 4.02 - 3.97 (m, 1H), 3.90 ( d, J = 3.2 Hz, 1H), 3.80 ( s, 1H), 3.71 - 3.65 (m, 3H), 2.95 - 2.81 (m, 2H), 2.06 - 1.89 (m, 4H), 1.86 - 1.68 (m, 4H), 1.67 - 1.57 (m, 5H), 1.54 - 1.39 (m, 3H), 1.29 - 1.11 (m, 1H).

[0212] Preparation of (5S,8S,10aR)-5-((tert-butoxycarbonyl)amino)-3-(5-methyl-1H- indazole-3-carbonyl)-6-oxodecahydropyrrolo[1,2-a][1,5]diazocine-8-carboxylic acid

[0213] STEP A: methyl (5S,8S,10aR)-5-((tert-butoxycarbonyl)amino)-3-(5-methyl-1H- indazole-3-carbonyl)-6-oxodecahydropyrrolo[1,2-a][1,5]diazocine-8-carboxylate

[0214] To a solution of methyl (5S,8S,10aR)-5-((tert-butoxycarbonyl)amino)-6- oxodecahydropyrrolo[1,2-a][1,5]diazocine-8-carboxylate (1 g, 2.93 mmol, 1.0 eq.) and 7- ((bis(2-(butyrylthio)ethoxy)phosphoryl)difluoromethyl)-2-naphthoic acid (516 mg, 2.93 mmol, 1.0 eq.) in DMF (20 mL) were added HATU (1.22 g, 3.22 mmol, 1.1 eq.) and DIEA (1.13 g, 8.79 mmol, 3.0 eq.) at room temperature. The resulting mixture was stirred at room temperature for 2 hrs. After completion, the reaction mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel to give methyl (5S,8S,10aR)-5-((tert-butoxycarbonyl)amino)-3-(5-methyl-1H-indazole-3-carbonyl)-6- oxodecahydropyrrolo[1,2-a][1,5]diazocine-8-carboxylate (1.1 g, 2.20 mmol, 75%) as a white solid. LCMS (ESI): m / z = 500 [M+H]+.

[0215] STEP B: (5S,8S,10aR)-5-((tert-butoxycarbonyl)amino)-3-(5-methyl-1H-indazole- 3-carbonyl)-6-oxodecahydropyrrolo[1,2-a][1,5]diazocine-8-carboxylic acid

[0216] To a solution of methyl (5S,8S,10aR)-5-((tert-butoxycarbonyl)amino)-3-(5-methyl- 1H-indazole-3-carbonyl)-6-oxodecahydropyrrolo[1,2-a][1,5]diazocine-8-carboxylate (1.1 g, 2.20 mmol, 1.0 eq.) in THF (20 mL) and H2O (7 mL) was added LiOH (277 mg, 6.60 mmol, 3.0 eq.) at room temperature. The resulting mixture was stirred at room temperature for 2 hrs. After completion, the reaction mixture was cooled down in an ice bath, then neutralized carefully with HCl (1N, aq.) until the pH was adjusted to pH = 2-3. The resulting mixture was extracted with EtOAc (20 mL x 3), and the combined organic layers were washed with brine (10 mL x 2), dried over with anhydrous Na2SO4, then concentrated under reduced pressure to give crude (5S,8S,10aR)-5-((tert-butoxycarbonyl)amino)-3-(5-methyl-1H-indazole-3-carbonyl)-6-oxodecahydropyrrolo[1,2-a][1,5]diazocine-8-carboxylic acid (930 mg, quant.) as a white solid, which was directly used without further purification. LCMS (ESI): m / z = 486 [M+H]+.

[0217] The following intermediates in Table 1 were prepared according to the procedure described above for (5S,8S,10aR)-5-((tert-butoxycarbonyl)amino)-3-(5-methyl-1H-indazole- 3-carbonyl)-6-oxodecahydropyrrolo[1,2-a][1,5]diazocine-8-carboxylic acid utilizing the appropriate starting materials and modifications. Table 1

[0218] Preparation of ((difluoro(7-(((5S,8S,10aR)-8-((9-(((S)-1-((2S,4R)-4-hydroxy-2- (((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1- oxobutan-2-yl)amino)-9-oxononyl)carbamoyl)-3-(5-methyl-1H-indazole-3-carbonyl)-6- oxodecahydropyrrolo[1,2-a][1,5]diazocin-5-yl)carbamoyl)naphthalen-2- yl)methyl)phosphonic acid (Compound 7) and S,S'-((((difluoro(7-(((5S,8S,10aR)-8-((9- (((S)-1-((2S,4R)-4-hydroxy-2-(((S)-1-(4-(4-methylthiazol-5- yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-9- oxononyl)carbamoyl)-3-(5-methyl-1H-indazole-3-carbonyl)-6-oxodecahydropyrrolo[1,2- a][1,5]diazocin-5-yl)carbamoyl)naphthalen-2-yl)methyl)phosphoryl)bis(oxy))bis(ethane- 2,1-diyl)) dibutanethioate (Compound 8)

[0219] STEP A: tert-butyl (9-(((S)-1-((2S,4R)-4-hydroxy-2-(((S)-1-(4-(4-methylthiazol-5- yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-9- oxononyl)carbamate

[0220] To a solution of (2S,4R)-1-((S)-2-amino-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)- 1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (150 mg, 0.34 mmol, 1.0 eq.) and 9-((tert-butoxycarbonyl)amino)nonanoic acid (92 mg, 0.34 mmol, 1.0 eq.) in DMF (2 mL) were added DIEA (132 mg, 1.02 mmol, 3.0 eq.) and HATU (155 mg, 0.41 mmol, 1.2 eq.), and the resulting mixture was stirred at room temperature for 12 hrs. After completion, the reaction mixture was purified by C18 column to afford tert-butyl (9-(((S)-1-((2S,4R)-4- hydroxy-2-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)-3,3- dimethyl-1-oxobutan-2-yl)amino)-9-oxononyl)carbamate (143 mg, 0.21 mmol, 60%) as a yellow solid. LCMS (ESI): m / z = 700 [M+H]+.

[0221] STEP B: (2S,4R)-1-((S)-2-(9-aminononanamido)-3,3-dimethylbutanoyl)-4- hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide

[0222] To a solution of tert-butyl (9-(((S)-1-((2S,4R)-4-hydroxy-2-(((S)-1-(4-(4- methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2- yl)amino)-9-oxononyl)carbamate (250 mg, 0.36 mmol, 1.0 eq.) in DCM (3 mL) was added TFA (1 mL), and the resulting mixture was stirred at room temperature for 1 hr. After completion, the reaction mixture was concentrated under reduced pressure to give crude (2S,4R)-1-((S)-2-(9-aminononanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4- methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (250 mg, quant.) as a yellow solid, which was used in next step directly without further purification. LCMS (ESI): m / z = 600 [M+H]+.

[0223] STEP C: tert-butyl ((5S,8S,10aR)-8-((9-(((S)-1-((2S,4R)-4-hydroxy-2-(((S)-1-(4- (4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2- yl)amino)-9-oxononyl)carbamoyl)-3-(5-methyl-1H-indazole-3-carbonyl)-6- oxodecahydropyrrolo[1,2-a][1,5]diazocin-5-yl)carbamate

[0224] To a solution of (2S,4R)-1-((S)-2-(9-aminononanamido)-3,3-dimethylbutanoyl)-4- hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (250 mg, 0.42 mmol, 1.0 eq.) and (5S,8S,10aR)-5-((tert-butoxycarbonyl)amino)-3-(5-methyl-1H- indazole-3-carbonyl)-6-oxodecahydropyrrolo[1,2-a][1,5]diazocine-8-carboxylic acid (204 mg, 0.42 mmol, 1.0 eq.) in DMF (2 mL) were added DIEA (163 mg, 1.26 mmol, 3.0 eq.), EDCI (161 mg, 0.84 mmol, 2.0 eq.), and HOBt (113 mg, 0.84 mmol, 2.0 eq.). The resulting mixture was stirred at room temperature for 12 hrs. After completion, the reaction mixture was purified by C18 column to afford tert-butyl ((5S,8S,10aR)-8-((9-(((S)-1-((2S,4R)-4-hydroxy-2-(((S)-1- (4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan- 2-yl)amino)-9-oxononyl)carbamoyl)-3-(5-methyl-1H-indazole-3-carbonyl)-6-oxodecahydropyrrolo[1,2-a][1,5]diazocin-5-yl)carbamate (270 mg, 0.25 mmol, 60%) as a yellow solid. LCMS (ESI): m / z = 1067 [M+H]+.

[0225] STEP D: (5S,8S,10aR)-5-amino-N-(9-(((S)-1-((2S,4R)-4-hydroxy-2-(((S)-1-(4-(4- methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2- yl)amino)-9-oxononyl)-3-(5-methyl-1H-indazole-3-carbonyl)-6-oxodecahydropyrrolo[1,2- a][1,5]diazocine-8-carboxamide

[0226] To a solution of tert-butyl ((5S,8S,10aR)-8-((9-(((S)-1-((2S,4R)-4-hydroxy-2-(((S)- 1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1- oxobutan-2-yl)amino)-9-oxononyl)carbamoyl)-3-(5-methyl-1H-indazole-3-carbonyl)-6- oxodecahydropyrrolo[1,2-a][1,5]diazocin-5-yl)carbamate (150 mg, 0.14 mmol, 1.0 eq.) in DCM (1 mL) was added TFA (0.3 mL), and the resulting mixture was stirred at room temperature for 1 hr. After completion, the reaction mixture was concentrated under reduced pressure to give crude (5S,8S,10aR)-5-amino-N-(9-(((S)-1-((2S,4R)-4-hydroxy-2-(((S)-1-(4- (4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2- yl)amino)-9-oxononyl)-3-(5-methyl-1H-indazole-3-carbonyl)-6-oxodecahydropyrrolo[1,2- a][1,5]diazocine-8-carboxamide (140 mg, quant.) as a colorless oil, which was used in next step directly without further purification. LCMS (ESI): m / z = 967 [M+H]+.

[0227] STEP E: (difluoro(7-(((5S,8S,10aR)-8-((9-(((S)-1-((2S,4R)-4-hydroxy-2-(((S)-1- (4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2- yl)amino)-9-oxononyl)carbamoyl)-3-(5-methyl-1H-indazole-3-carbonyl)-6- oxodecahydropyrrolo[1,2-a][1,5]diazocin-5-yl)carbamoyl)naphthalen-2- yl)methyl)phosphonic acid

[0228] To a solution of (5S,8S,10aR)-5-amino-N-(9-(((S)-1-((2S,4R)-4-hydroxy-2-(((S)- 1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1- oxobutan-2-yl)amino)-9-oxononyl)-3-(5-methyl-1H-indazole-3-carbonyl)-6- oxodecahydropyrrolo[1,2-a][1,5]diazocine-8-carboxamide (60 mg, 62.0 µmol, 1.0 eq.) and (difluoro(7-((perfluorophenoxy)carbonyl)naphthalen-2-yl)methyl)phosphonic acid (29.0 mg, 62.0 µmol, 1.0 eq.) in DMF (1 mL) was added DIEA (23.9 mg, 186 µmol, 3.0 eq.) at room temperature. The resulting mixture was stirred at room temperature for 2 hrs. After completion, the reaction mixture was purified by prep-HPLC to give ((difluoro(7-(((5S,8S,10aR)-8-((9- (((S)-1-((2S,4R)-4-hydroxy-2-(((S)-1-(4-(4-methylthiazol-5- yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-9- oxononyl)carbamoyl)-3-(5-methyl-1H-indazole-3-carbonyl)-6-oxodecahydropyrrolo[1,2-a][1,5]diazocin-5-yl)carbamoyl)naphthalen-2-yl)methyl)phosphonic acid (Compound 7, 21.4 mg, 17.1 µmol, 28%) as a white solid.

[0229] 1H NMR (400 MHz, CDCl3) δ 8.68 (s, 1H), 8.48-8.32 (m, 1H), 8.23-8.05 (m, 1H), 8.03-7.94 (m, 1H), 7.93-7.33 (m, 6H), 7.31-7.29 (m, 2H), 7.19-7.09 (m, 1H), 6.70-6.55 (m, 1H), 5.72-5.54 (m, 1H), 5.07-4.95 (m, 1H), 4.76-4.57 (m, 3H), 4.50-4.38 (m, 2H), 4.09- 4.00 (m, 1H), 3.63-3.41 (m, 5H), 3.00-2.85 (m, 4H), 2.52-2.40 (m, 6H), 2.31-1.96 (m, 8H), 1.85-1.74 (m, 1H), 1.47-1.26 (m, 20H), 1.11-1.05 (m, 2H), 0.98 (s, 9H). LCMS (ESI): m / z = 626.5 [M / 2+H]+.

[0230] STEP F: S,S'-((((difluoro(7-(((5S,8S,10aR)-8-((9-(((S)-1-((2S,4R)-4-hydroxy-2- (((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1- oxobutan-2-yl)amino)-9-oxononyl)carbamoyl)-3-(5-methyl-1H-indazole-3-carbonyl)-6- oxodecahydropyrrolo[1,2-a][1,5]diazocin-5-yl)carbamoyl)naphthalen-2- yl)methyl)phosphoryl)bis(oxy))bis(ethane-2,1-diyl)) dibutanethioate

[0231] To a solution of (5S,8S,10aR)-5-amino-N-(8-(2-(2,6-dioxopiperidin-3-yl)-1- oxoisoindolin-4-yl)oct-7-yn-1-yl)-3-(5-methyl-1H-indazole-3-carbonyl)-6- oxodecahydropyrrolo[1,2-a][1,5]diazocine-8-carboxamide (60 mg, 62.0 µmol, 1.0 eq.) and perfluorophenyl 7-((bis(2-(butyrylthio)ethoxy)phosphoryl)difluoromethyl)-2-naphthoate (45.1 mg, 62.0 µmol, 1.0 eq.) in DMF (2 mL) was added DIEA (23.9 mg, 186 µmol, 3.0 eq.) at room temperature. The resulting mixture was stirred at room temperature for 1 hr. After completion, the reaction mixture was purified by prep-HPLC to give S,S'-((((difluoro(7-(((5S,8S,10aR)-8- ((9-(((S)-1-((2S,4R)-4-hydroxy-2-(((S)-1-(4-(4-methylthiazol-5- yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-9- oxononyl)carbamoyl)-3-(5-methyl-1H-indazole-3-carbonyl)-6-oxodecahydropyrrolo[1,2- a][1,5]diazocin-5-yl)carbamoyl)naphthalen-2-yl)methyl)phosphoryl)bis(oxy))bis(ethane-2,1- diyl)) dibutanethioate (Compound 8, 13.5 mg, 8.94 µmol, 14%) as a white solid.1H NMR (400 MHz, CDCl3) δ 8.87-8.75 (m, 1H), 8.52 (s, 1H), 8.30-8.17 (m, 2H), 8.09-7.86 (m, 5H), 7.80-7.65 (m, 2H), 7.37-7.31 (m, 3H), 7.22-7.15 (m, 1H), 6.53-6.28 (m, 2H), 5.80-5.67 (m, 1H), 4.97-4.86 (m, 2H), 4.74-4.64 (m, 2H), 4.53-4.45 (m, 2H), 4.32-4.08 (m, 8H), 3.75-3.60 (m, 2H), 3.21-3.08 (m, 5H), 3.00-2.94 (m, 1H), 2.58-2.51 (m, 8H), 2.47-2.16 (m, 12H), 2.11- 1.93 (m, 5H), 1.89-1.75 (m, 2H), 1.73-1.63 (m, 5H), 1.46-1.26 (m, 8H), 1.05 (s, 9H), 0.97-0.93 (m, 8H). LCMS (ESI): m / z = 1511.8 [M+H]+.

[0232] Preparation of ((7-(((5S,8S,10aR)-8-((8-(2-(2,6-dioxopiperidin-3-yl)-1- oxoisoindolin-4-yl)oct-7-yn-1-yl)carbamoyl)-3-(5-methyl-1H-indazole-3-carbonyl)-6- oxodecahydropyrrolo[1,2-a][1,5]diazocin-5-yl)carbamoyl)naphthalen-2-yl)difluoromethyl)phosphonic acid (Compound 9) and S,S'-(((((7-(((5S,8S,10aR)-8-((8- (2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oct-7-yn-1-yl)carbamoyl)-3-(5-methyl- 1H-indazole-3-carbonyl)-6-oxodecahydropyrrolo[1,2-a][1,5]diazocin-5- yl)carbamoyl)naphthalen-2-yl)difluoromethyl)phosphoryl)bis(oxy))bis(ethane-2,1-diyl)) dibutanethioate (Compound 10)

[0233] STEP A: 8-bromooct-1-yne

[0234] To a solution of oct-7-yn-1-ol (1 g, 7.94 mmol, 1.0 eq.) and PPh3 (4.16 g, 15.9 mmol, 2.0 eq.) in dry DCM (50 mL) was added CBr4(2.86 mg,8.73 mmol, 1.1 eq) slowly at room temperature under nitrogen. The mixture was stirred at 40 °C for 1 hr. After completion, the reaction mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel to afford 8-bromooct-1-yne (750 mg, 3.97 mmol, 50%) as a yellow oil. LC-MS (ESI) m / z = 189 [M+H]+.

[0235] STEP B: 2-(oct-7-yn-1-yl)isoindoline-1,3-dione

[0236] To a solution of isoindoline-1,3-dione (531 mg, 3.61 mmol, 1.0 eq.) and K2CO3(1.50 g, 10.8 mmol, 3.0 eq.) in DMF ( mL) was added 8-bromooct-1-yne (750 mg, 3.97 mmol, 1.1 eq) slowly at room temperature under nitrogen. The mixture was stirred at 60 °C for 2 hrs. After completion, the reaction mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel to afford 2-(oct-7-yn-1-yl)isoindoline-1,3-dione (531 mg, 2.08 mmol, 58%) as a yellow oil. LC-MS (ESI) m / z = 256 [M+H]+.

[0237] STEP C: oct-7-yn-1-amine

[0238] To a solution of 2-(oct-7-yn-1-yl)isoindoline-1,3-dione (1.6 g, 6.26 mmol, 1.0 eq.) in EtOH (50 mL) was added hydrazine hydrate (1.09 g, 21.9 mmol, 3.5 eq.). The mixture was stirred at 80 °C for 4 hrs. After completion, the reaction mixture was concentrated under reduced pressure. KOH (40 mL, 1N, aq.) was added, then extracted with DCM (50 mL x 2). The organic layers were combined and washed with brine (150 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel to afford oct-7-yn-1-amine (600 mg, 4.79 mmol, 77%) as a green oil. LC-MS (ESI) m / z = 126 [M+H]+.

[0239] STEP D: tert-butyl oct-7-yn-1-ylcarbamate

[0240] To a solution of oct-7-yn-1-amine (250 mg, 1.99 mmol, 1.0 eq.) and Na₂CO₃ (421 mg, 3.98 mmol, 2.0 eq.) in THF (4.5 mL) was added Boc2O (650 mg, 2.98 mmol, 1.5 eq.). The mixture was stirred at 25 °C for 12 hrs. After completion, the reaction mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel to afford tert-butyl oct-7-yn-1-ylcarbamate (320 mg, 1.42 mmol, 71%) as a yellow oil. LC-MS (ESI) m / z = 226 [M+H]+.

[0241] STEP E: tert-butyl (8-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oct-7-yn- 1-yl)carbamate

[0242] To a solution of 3-(4-bromo-1-oxoisoindolin-2-yl)piperidine-2,6-dione (250 mg, 773 µmol, 1.0 eq.), tert-butyl oct-7-yn-1-ylcarbamate (208 mg, 927 µmol, 1.2 eq.) and Cs2CO3(750 mg, 2.31 mmol, 3.0 eq.) in DMF (15 mL) were added Pd(PPh3)2Cl2 (108 mg, 154 µmol, 0.2 eq.) and CuI (29.2 mg, 154 µmol, 0.2 eq.). The resulting mixture was stirred at 80 °C for 12 hrs. After completion, the reaction mixture was filtered and the filtrate was purified by prep- HPLC to give tert-butyl (8-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oct-7-yn-1- yl)carbamate (136 mg, 290 µmol, 38%) as a white solid. LC-MS (ESI) m / z = 466.2 [M-H]-.

[0243] STEP F: 3-(4-(8-aminooct-1-yn-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0244] To a solution of tert-butyl (8-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4- yl)oct-7-yn-1-yl)carbamate (160 mg, 342 µmol, 1.0 eq.) in DCM (1.5 mL) was added TFA (0.5 mL), and the resulting mixture was stirred at room temperature for 1 hr. After completion, the reaction mixture was concentrated under reduced pressure to give crude 3-(4-(8-aminooct-1- yn-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (120 mg, quant.) as a yellow solid, which was used in next step directly without further purification. LCMS (ESI): m / z = 368.2 [M+H]+.

[0245] STEP G: tert-butyl ((5S,8S,10aR)-8-((8-(2-(2,6-dioxopiperidin-3-yl)-1- oxoisoindolin-4-yl)oct-7-yn-1-yl)carbamoyl)-3-(5-methyl-1H-indazole-3-carbonyl)-6- oxodecahydropyrrolo[1,2-a][1,5]diazocin-5-yl)carbamate

[0246] To a solution of 3-(4-(8-aminooct-1-yn-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6- dione (120 mg, 326 µmol, 1.0 eq.) and (5S,8S,10aR)-5-((tert-butoxycarbonyl)amino)-3-(5- methyl-1H-indazole-3-carbonyl)-6-oxodecahydropyrrolo[1,2-a][1,5]diazocine-8-carboxylic acid (173 mg, 358 µmol, 1.1 eq.) in DMF (2 mL) were added DIEA (3126 mg, 978 µmol, 3.0 eq.), EDCI (125 mg, 652 µmol, 2.0 eq.), and HOBt (88.0 mg, 652 µmol, 2.0 eq.). The resulting mixture was stirred at room temperature for 12 hrs. After completion, the reaction mixture was purified by prep-HPLC to afford tert-butyl ((5S,8S,10aR)-8-((8-(2-(2,6-dioxopiperidin-3-yl)- 1-oxoisoindolin-4-yl)oct-7-yn-1-yl)carbamoyl)-3-(5-methyl-1H-indazole-3-carbonyl)-6- oxodecahydropyrrolo[1,2-a][1,5]diazocin-5-yl)carbamate (160 mg, 191 µmol, 59%) as a yellow solid. LCMS (ESI): m / z = 835.1 [M+H]+.

[0247] STEP H: (5S,8S,10aR)-5-amino-N-(8-(2-(2,6-dioxopiperidin-3-yl)-1- oxoisoindolin-4-yl)oct-7-yn-1-yl)-3-(5-methyl-1H-indazole-3-carbonyl)-6- oxodecahydropyrrolo[1,2-a][1,5]diazocine-8-carboxamide

[0248] To a solution of tert-butyl ((5S,8S,10aR)-8-((8-(2-(2,6-dioxopiperidin-3-yl)-1- oxoisoindolin-4-yl)oct-7-yn-1-yl)carbamoyl)-3-(5-methyl-1H-indazole-3-carbonyl)-6- oxodecahydropyrrolo[1,2-a][1,5]diazocin-5-yl)carbamate (60 mg, 71.8 µmol, 1.0 eq.) in DCM (1 mL) was added TFA (0.4 mL), and the resulting mixture was stirred at room temperature for 1 hr. After completion, the reaction mixture was concentrated under reduced pressure to give crude (5S,8S,10aR)-5-amino-N-(8-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oct-7- yn-1-yl)-3-(5-methyl-1H-indazole-3-carbonyl)-6-oxodecahydropyrrolo[1,2-a][1,5]diazocine- 8-carboxamide (45.0 mg, 61.2 µmol, 85%.) as a red solid, which was used directly without further purification. LCMS (ESI): m / z = 735.0 [M+H]+.

[0249] STEP I: ((7-(((5S,8S,10aR)-8-((8-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4- yl)oct-7-yn-1-yl)carbamoyl)-3-(5-methyl-1H-indazole-3-carbonyl)-6- oxodecahydropyrrolo[1,2-a][1,5]diazocin-5-yl)carbamoyl)naphthalen-2- yl)difluoromethyl)phosphonic acid

[0250] To a solution of (5S,8S,10aR)-5-amino-N-(8-(2-(2,6-dioxopiperidin-3-yl)-1- oxoisoindolin-4-yl)oct-7-yn-1-yl)-3-(5-methyl-1H-indazole-3-carbonyl)-6- oxodecahydropyrrolo[1,2-a][1,5]diazocine-8-carboxamide (45 mg, 61.2 µmol, 1.0 eq.) and (difluoro(7-((perfluorophenoxy)carbonyl)naphthalen-2-yl)methyl)phosphonic acid (28.6 mg, 61.2 µmol, 1.0 eq.) in DMF (2 mL) was added DIEA (23.6 mg, 183 µmol, 3.0 eq.) at roomtemperature. The resulting mixture was stirred at room temperature for 1 hr. After completion, the reaction mixture was purified by prep-HPLC to give ((7-(((5S,8S,10aR)-8-((8-(2-(2,6- dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oct-7-yn-1-yl)carbamoyl)-3-(5-methyl-1H- indazole-3-carbonyl)-6-oxodecahydropyrrolo[1,2-a][1,5]diazocin-5- yl)carbamoyl)naphthalen-2-yl)difluoromethyl)phosphonic acid (Compound 9, 21.0 mg, 20.6 µmol, 34%) as a white solid.

[0251] 1H NMR (400 MHz, DMSO-d6) δ 13.60-13.28 (m, 1H), 11.11-10.91 (m, 1H), 9.04-8.75 (m, 1H), 8.72-8.58 (m, 1H), 8.26-8.16 (m, 1H), 8.13-7.99 (m, 3H), 7.97-7.55 (m, 5H), 7.54-7.38 (m, 2H), 7.29-7.17 (m, 1H), 5.26-5.01 (m, 2H), 4.74-4.62 (m, 1H), 4.46-4.25 (m, 4H), 4.17-4.03 (m, 1H), 3.95-3.53 (m, 3H), 3.13-2.82 (m, 3H), 2.48-2.39 (m, 5H), 2.22- 1.97 (m, 4H), 1.95-1.68 (m, 3H), 1.67-1.16 (m, 9H).

[0252] LCMS (ESI): m / z = 1019.3 [M+H]+.

[0253] STEP J: S,S'-(((((7-(((5S,8S,10aR)-8-((8-(2-(2,6-dioxopiperidin-3-yl)-1- oxoisoindolin-4-yl)oct-7-yn-1-yl)carbamoyl)-3-(5-methyl-1H-indazole-3-carbonyl)-6- oxodecahydropyrrolo[1,2-a][1,5]diazocin-5-yl)carbamoyl)naphthalen-2- yl)difluoromethyl)phosphoryl)bis(oxy))bis(ethane-2,1-diyl)) dibutanethioate

[0254] To a solution of (5S,8S,10aR)-5-amino-N-(8-(2-(2,6-dioxopiperidin-3-yl)-1- oxoisoindolin-4-yl)oct-7-yn-1-yl)-3-(5-methyl-1H-indazole-3-carbonyl)-6- oxodecahydropyrrolo[1,2-a][1,5]diazocine-8-carboxamide (45 mg, 61.2 µmol, 1.0 eq.) and perfluorophenyl 7-((bis(2-(butyrylthio)ethoxy)phosphoryl)difluoromethyl)-2-naphthoate (44.5 mg, 61.2 µmol, 1.0 eq.) in DMF (2 mL) was added DIEA (23.6 mg, 183 µmol, 3.0 eq.) at room temperature. The resulting mixture was stirred at room temperature for 1 hr. After completion, the reaction mixture was purified by prep-HPLC to give S,S'-(((((7-(((5S,8S,10aR)-8-((8-(2- (2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oct-7-yn-1-yl)carbamoyl)-3-(5-methyl-1H- indazole-3-carbonyl)-6-oxodecahydropyrrolo[1,2-a][1,5]diazocin-5- yl)carbamoyl)naphthalen-2-yl)difluoromethyl)phosphoryl)bis(oxy))bis(ethane-2,1-diyl)) dibutanethioate (Compound 10, 10.0 mg, 7.81 µmol, 13%) as a white solid.

[0255] 1H NMR (400 MHz, CDCl3) δ 10.36-9.91 (m, 1H), 8.71-8.32 (m, 1H), 8.29-8.13 (m, 1H), 8.11-7.62 (m, 6H), 7.60-7.38 (m, 2H), 7.24-7.15 (m, 1H), 6.79-6.38 (m, 1H), 5.79- 5.48 (m, 1H), 5.46-3.70 (m, 12H), 3.22-3.03 (m, 4H), 2.98-2.72 (m, 2H), 2.69-2.55 (m, 1H), 2.55-2.48 (m, 4H), 2.47-2.43 (m, 3H), 2.43-1.69 (m, 11H), 1.69-1.58 (m, 4H), 1.58-0.98 (m, 9H), 0.96-0.86 (m, 6H).

[0256] LCMS (ESI): m / z = 1279.3 [M+H]+.

[0257] Preparation of ((7-(((5S,8S,10aR)-8-((8-(2-(2,6-dioxopiperidin-3-yl)-1- oxoisoindolin-4-yl)oct-7-yn-1-yl)(methyl)carbamoyl)-3-(5-methyl-1H-indazole-3- carbonyl)-6-oxodecahydropyrrolo[1,2-a][1,5]diazocin-5-yl)carbamoyl)naphthalen-2- yl)difluoromethyl)phosphonic acid (Compound 11) and S,S'-(((((7-(((5S,8S,10aR)-8-((8- (2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oct-7-yn-1-yl)(methyl)carbamoyl)-3-(5- methyl-1H-indazole-3-carbonyl)-6-oxodecahydropyrrolo[1,2-a][1,5]diazocin-5- yl)carbamoyl)naphthalen-2-yl)difluoromethyl)phosphoryl)bis(oxy))bis(ethane-2,1-diyl)) dibutanethioate (Compound 12)

[0258] STEP A: tert-butyl methyl(oct-7-yn-1-yl)carbamate

[0259] To a solution of tert-butyl oct-7-yn-1-ylcarbamate (1.2 g, 5.33 mmol, 1.0 eq.) in dry DMF (20 mL) was added NaH (188 mg, 5.86 mmol, 1.1 eq) slowly at 0 °C under nitrogen. The mixture was stirred for additional 30 min at 0 °C, then MeI (1.51 g, 10.7 mmol, 2.0 eq.) was added dropwise. After addition, the reaction mixture was allowed to warm to room temperature and stirred for 14 hrs. After completion, the reaction mixture was quenched by adding H2O (20 mL), then extracted with EtOAc (150 mL x 3). The organic layers were combined and washed with brine (150 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel to afford tert-butyl methyl(oct-7-yn-1-yl)carbamate (1.1 g, 4.60 mmol, 86%) as a yellow oil. LC-MS (ESI) m / z = 240 [M+H]+.

[0260] STEP B: tert-butyl (8-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oct-7-yn- 1-yl)(methyl)carbamate

[0261] A solution of 3-(4-bromo-1-oxoisoindolin-2-yl)piperidine-2,6-dione (650 mg, 2.01mmol, 1.0 eq.), tert-butyl methyl(oct-7-yn-1-yl)carbamate (576 mg, 2.41 mmol, 1.2 eq.), Cs2CO3 (1.96 g, 6.03 mmol, 3.0 eq.) in DMF (15 mL) was stirred at room temperature under N2, then Pd(PPh3)2Cl2 (140 mg, 0.20 mmol,0.1 eq.) and CuI (76 mg, 0.40 mmol, 0.2 eq.) were added, and the resulting mixture was stirred at 80 °C for 12 hrs. After completion, the reaction mixture was diluted with H2O (40 mL) and extracted with EtOAc (30 mL x 3). The organic layers were combined and washed with brine (10 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel to afford tert-butyl (8-(2-(2,6-dioxopiperidin-3-yl)-1- oxoisoindolin-4-yl)oct-7-yn-1-yl)(methyl)carbamate (330 mg, 0.69 mmol, 34%) as a white solid. LCMS (ESI): m / z = 482 [M+H]+.

[0262] STEP C: 3-(4-(8-(methylamino)oct-1-yn-1-yl)-1-oxoisoindolin-2-yl)piperidine- 2,6-dione

[0263] To a solution of tert-butyl (8-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4- yl)oct-7-yn-1-yl)(methyl)carbamate (330 mg, 0.69 mmol, 1.0 eq.) in DCM (3 mL) was added TFA (1 mL), and the resulting mixture was stirred at room temperature for 2 hrs. After completion, the reaction mixture was cooled down in an ice bath, then neutralized carefully with NaHCO3(aq.) until the pH was adjusted to pH = 8-9. The resulting mixture was extracted with DCM (10 mL x 3), and the combined organic layers were washed with brine (10 mL x 2), dried over with anhydrous Na2SO4, then concentrated under reduced pressure to give crude 3- (4-(8-(methylamino)oct-1-yn-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (260 mg,quant.) as a white solid, which was used in next step directly without further purification. LCMS (ESI): m / z = 382 [M+H]+.

[0264] STEP D: tert-butyl ((5S,8S,10aR)-8-((8-(2-(2,6-dioxopiperidin-3-yl)-1- oxoisoindolin-4-yl)oct-7-yn-1-yl)(methyl)carbamoyl)-3-(5-methyl-1H-indazole-3-carbonyl)- 6-oxodecahydropyrrolo[1,2-a][1,5]diazocin-5-yl)carbamate

[0265] To a solution of 3-(4-(8-(methylamino)oct-1-yn-1-yl)-1-oxoisoindolin-2- yl)piperidine-2,6-dione (260 mg, 0.68 mmol, 1.2 eq.) and (5S,8S,10aR)-5-((tert- butoxycarbonyl)amino)-3-(5-methyl-1H-indazole-3-carbonyl)-6-oxodecahydropyrrolo[1,2- a][1,5]diazocine-8-carboxylic acid (210 mg, 0.56 mmol, 1.0 eq.) in DMF (10 mL) were added DIEA (361 mg, 2.80 mmol, 5.0 eq.), EDCI (108 mg, 0.56 mmol, 1.0 eq.), and HOBt (76 mg, 0.56 mmol, 1.0 eq.), and the resulting mixture was stirred at room temperature for 2 hrs. After completion, the reaction was diluted with H2O (20 mL) and extracted with EtOAc (10 mL x 3). The organic layers were combined and washed with brine (10 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel to afford tert-butyl ((5S,8S,10aR)-8-((8-(2-(2,6-dioxopiperidin- 3-yl)-1-oxoisoindolin-4-yl)oct-7-yn-1-yl)(methyl)carbamoyl)-3-(5-methyl-1H-indazole-3- carbonyl)-6-oxodecahydropyrrolo[1,2-a][1,5]diazocin-5-yl)carbamate (80 mg, 94.3 µmol, 17%) as a white solid. LCMS (ESI): m / z = 849 [M+H]+.

[0266] STEP E: (5S,8S,10aR)-5-amino-N-(8-(2-(2,6-dioxopiperidin-3-yl)-1- oxoisoindolin-4-yl)oct-7-yn-1-yl)-N-methyl-3-(5-methyl-1H-indazole-3-carbonyl)-6- oxodecahydropyrrolo[1,2-a][1,5]diazocine-8-carboxamide

[0267] To a solution of tert-butyl ((5S,8S,10aR)-8-((8-(2-(2,6-dioxopiperidin-3-yl)-1- oxoisoindolin-4-yl)oct-7-yn-1-yl)(methyl)carbamoyl)-3-(5-methyl-1H-indazole-3-carbonyl)- 6-oxodecahydropyrrolo[1,2-a][1,5]diazocin-5-yl)carbamate (80 mg, 94.3 µmol, 1.0 eq.) in DCM (3 mL) was added TFA (1 mL), and the resulting mixture was stirred at room temperature for 2 hrs. After completion, the reaction mixture was concentrated under reduced pressure to give crude (5S,8S,10aR)-5-amino-N-(8-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4- yl)oct-7-yn-1-yl)-N-methyl-3-(5-methyl-1H-indazole-3-carbonyl)-6- oxodecahydropyrrolo[1,2-a][1,5]diazocine-8-carboxamide (70 mg, quant.) as a white solid, which was used in next step directly without further purification. LCMS (ESI): m / z = 749 [M+H]+.

[0268] STEP F: ((7-(((5S,8S,10aR)-8-((8-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4- yl)oct-7-yn-1-yl)(methyl)carbamoyl)-3-(5-methyl-1H-indazole-3-carbonyl)-6-oxodecahydropyrrolo[1,2-a][1,5]diazocin-5-yl)carbamoyl)naphthalen-2- yl)difluoromethyl)phosphonic acid

[0269] To a solution of (5S,8S,10aR)-5-amino-N-(8-(2-(2,6-dioxopiperidin-3-yl)-1- oxoisoindolin-4-yl)oct-7-yn-1-yl)-N-methyl-3-(5-methyl-1H-indazole-3-carbonyl)-6- oxodecahydropyrrolo[1,2-a][1,5]diazocine-8-carboxamide (42 mg, 56.1 µmol, 1.1 eq.) and (difluoro(7-((perfluorophenoxy)carbonyl)naphthalen-2-yl)methyl)phosphonic acid (24 mg, 51.0 µmol, 1.0 eq.) in DMF (2 mL) was added DIEA (33 mg,0.25 mmol, 5.0 eq.) at room temperature. The resulting mixture was stirred at room temperature for an additional 2 hrs. After completion, the reaction mixture was concentrated under reduced pressure. The residue was purified by RP-prep HPLC to give ((7-(((5S,8S,10aR)-8-((8-(2-(2,6-dioxopiperidin-3-yl)- 1-oxoisoindolin-4-yl)oct-7-yn-1-yl)(methyl)carbamoyl)-3-(5-methyl-1H-indazole-3- carbonyl)-6-oxodecahydropyrrolo[1,2-a][1,5]diazocin-5-yl)carbamoyl)naphthalen-2- yl)difluoromethyl)phosphonic acid (Compound 11, 28 mg, 27.1 µmol, 53%) as a white solid.

[0270] 1H NMR (400 MHz, DMSO-d6) δ 13.57-13.28 (m, 1H), 11.04-10.91 (m, 1H), 8.97-8.69 (m, 1H), 8.69-8.57 (m, 1H), 8.24-8.12 (m, 1H), 8.11-7.81 (m, 4H), 7.78-7.37 (m, 5H), 7.27-7.19 (m, 1H), 5.24-5.01 (m, 2H), 4.82-4.76 (m, 1H), 4.45-4.14 (m, 5H), 3.90- 3.80(m, 1H), 3.66-3.56 (m, 2H), 3.37-3.29 (m, 2H), 3.22-3.12 (m, 1H), 3.03-2.77 (m, 4H), 2.63-2.54 (m, 1H), 2.47-2.40 (m, 4H), 2.31-1.87 (m, 4H), 1.84-1.63 (m, 3H), 1.59-1.48 (m, 2H), 1.46-1.20 (m, 6H).

[0271] LCMS (ESI): m / z = 1031.2 [M-H]-.

[0272] STEP G: S,S'-(((((7-(((5S,8S,10aR)-8-((8-(2-(2,6-dioxopiperidin-3-yl)-1- oxoisoindolin-4-yl)oct-7-yn-1-yl)(methyl)carbamoyl)-3-(5-methyl-1H-indazole-3-carbonyl)- 6-oxodecahydropyrrolo[1,2-a][1,5]diazocin-5-yl)carbamoyl)naphthalen-2- yl)difluoromethyl)phosphoryl)bis(oxy))bis(ethane-2,1-diyl)) dibutanethioate

[0273] To a solution of (5S,8S,10aR)-5-amino-N-(8-(2-(2,6-dioxopiperidin-3-yl)-1- oxoisoindolin-4-yl)oct-7-yn-1-yl)-N-methyl-3-(5-methyl-1H-indazole-3-carbonyl)-6- oxodecahydropyrrolo[1,2-a][1,5]diazocine-8-carboxamide (70 mg, 0.18 mmol, 1.1 eq.) and 7- ((bis(2-(butyrylthio)ethoxy)phosphoryl)difluoromethyl)-2-naphthoic acid (92 mg, 0.16 mmol, 1.0 eq.) in DMF (2 mL) were added HATU (68 mg, 0.18 mmol, 1.1 eq.) and DIEA (103 mg, 0.80 mmol, 5.0 eq.) at room temperature. The resulting mixture was stirred at room temperature for an additional 2 hrs. After completion, the reaction mixture was concentrated under reduced pressure. The residue was purified by RP-prep HPLC to give S,S'-(((((7-(((5S,8S,10aR)-8-((8- (2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oct-7-yn-1-yl)(methyl)carbamoyl)-3-(5- methyl-1H-indazole-3-carbonyl)-6-oxodecahydropyrrolo[1,2-a][1,5]diazocin-5-yl)carbamoyl)naphthalen-2-yl)difluoromethyl)phosphoryl)bis(oxy))bis(ethane-2,1-diyl)) dibutanethioate (Compound 12, 13.7 mg, 10.6 µmol, 6%) as a white solid.

[0274] 1H NMR (400 MHz, CDCl3) δ 10.61-9.53 (m, 1H), 9.49-8.77 (m, 1H), 8.54-8.32 (m, 1H), 8.30-8.19 (m, 1H), 8.16 (d, J = 8.7 Hz, 1H), 8.02-7.64 (m, 6H), 7.57-7.46 (m, 1H), 7.45-7.27 (m, 2H), 7.18 (s, 1H), 5.86-5.45 (m, 1H), 5.42-4.10 (m, 11H), 3.68-3.39 (m, 2H), 3.21-3.05 (m, 6H), 3.01-2.91 (m, 1H), 2.85-2.62 (m, 2H), 2.53-2.48 (m, 4H), 2.47-2.43 (m, 3H), 2.37-1.80 (m, 11H), 1.68-1.27 (m, 13H), 0.97-0.86 (m, 6H).

[0275] LCMS (ESI): m / z = 1293.3 [M+H]+.

[0276] Preparation of propyl (((7-(((5S,8S,10aR)-8-((8-(2-(2,6-dioxopiperidin-3-yl)-1- oxoisoindolin-4-yl)oct-7-yn-1-yl)(methyl)carbamoyl)-3-(5-methyl-1H-indazole-3- carbonyl)-6-oxodecahydropyrrolo[1,2-a][1,5]diazocin-5-yl)carbamoyl)naphthalen-2- yl)fluoromethyl)(phenoxy)phosphoryl)-L-alaninate (Compound 13) and ((7- (((5S,8S,10aR)-8-((8-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oct-7-yn-1- yl)(methyl)carbamoyl)-3-(5-methyl-1H-indazole-3-carbonyl)-6- oxodecahydropyrrolo[1,2-a][1,5]diazocin-5-yl)carbamoyl)naphthalen-2- yl)fluoromethyl)phosphonic acid (Compound 14)

[0277] STEP A: propyl (((7-(((5S,8S,10aR)-8-((8-(2-(2,6-dioxopiperidin-3-yl)-1- oxoisoindolin-4-yl)oct-7-yn-1-yl)(methyl)carbamoyl)-3-(5-methyl-1H-indazole-3-carbonyl)- 6-oxodecahydropyrrolo[1,2-a][1,5]diazocin-5-yl)carbamoyl)naphthalen-2- yl)fluoromethyl)(phenoxy)phosphoryl)-L-alaninate

[0278] To a solution of (5S,8S,10aR)-5-amino-N-(8-(2-(2,6-dioxopiperidin-3-yl)-1- oxoisoindolin-4-yl)oct-7-yn-1-yl)-N-methyl-3-(5-methyl-1H-indazole-3-carbonyl)-6- oxodecahydropyrrolo[1,2-a][1,5]diazocine-8-carboxamide (48 mg, 64.2 µmol, 1.0 eq.) and 7- (fluoro((((S)-1-oxo-1-propoxypropan-2-yl)amino)(phenoxy)phosphoryl)methyl)-2-naphthoic acid (30 mg, 64.2 µmol, 1.0 eq.) in DMF (2 mL) were added HATU (29 mg, 77.0 µmol, 1.2 eq.) and DIEA (41 mg, 321 µmol, 5.0 eq.) at room temperature. The resulting mixture was stirred at room temperature for 2 hrs. After completion, the reaction mixture was concentrated under reduced pressure. The residue was purified by RP-prep HPLC to give propyl (((7- (((5S,8S,10aR)-8-((8-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oct-7-yn-1-yl)(methyl)carbamoyl)-3-(5-methyl-1H-indazole-3-carbonyl)-6-oxodecahydropyrrolo[1,2- a][1,5]diazocin-5-yl)carbamoyl)naphthalen-2-yl)fluoromethyl)(phenoxy)phosphoryl)-L- alaninate (Compound 13, 10 mg, 8.3 µmol, 13%) as a white solid.

[0279] 1H NMR (400 MHz, CDCl3) δ 8.36-8.26 (m, 1H), 8.16-7.60 (m, 8H), 7.59-7.27 (m, 4H), 7.26-6.97 (m, 6H), 6.16-5.92 (m, 1H), 5.84-5.60 (m, 1H), 5.31-5.09 (m, 1H), 4.87- 4.76 (m, 1H), 4.58-3.94 (m, 8H), 3.71-3.19 (m, 4H), 3.15-3.05 (m, 2H), 2.97-2.68 (m, 3H), 2.52-2.38 (m, 5H), 2.28-2.11 (m, 4H), 1.98-1.75 (m, 4H), 1.64-1.37 (m, 9H), 1.37-1.24 (m, 4H), 0.93-0.81 (m, 3H).

[0280] LCMS (ESI): m / z = 1204.4 [M+H]+.

[0281] STEP B: ((7-(((5S,8S,10aR)-8-((8-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4- yl)oct-7-yn-1-yl)(methyl)carbamoyl)-3-(5-methyl-1H-indazole-3-carbonyl)-6- oxodecahydropyrrolo[1,2-a][1,5]diazocin-5-yl)carbamoyl)naphthalen-2- yl)fluoromethyl)phosphonic acid

[0282] To a solution of (5S,8S,10aR)-5-amino-N-(8-(2-(2,6-dioxopiperidin-3-yl)-1- oxoisoindolin-4-yl)oct-7-yn-1-yl)-N-methyl-3-(5-methyl-1H-indazole-3-carbonyl)-6- oxodecahydropyrrolo[1,2-a][1,5]diazocine-8-carboxamide (48 mg, 64.2 µmol, 1.0 eq.) and (fluoro(7-((perfluorophenoxy)carbonyl)naphthalen-2-yl)methyl)phosphonic acid (29 mg, 64.2 µmol, 1.0 eq.) in DMF (2 mL) was added DIEA (41 mg, 321 µmol, 5.0 eq.) at room temperature. The resulting mixture was stirred at room temperature for 2 hrs. After completion, the reaction mixture was concentrated under reduced pressure. The residue was purified by RP- prep HPLC to give ((7-(((5S,8S,10aR)-8-((8-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4- yl)oct-7-yn-1-yl)(methyl)carbamoyl)-3-(5-methyl-1H-indazole-3-carbonyl)-6- oxodecahydropyrrolo[1,2-a][1,5]diazocin-5-yl)carbamoyl)naphthalen-2- yl)fluoromethyl)phosphonic acid (Compound 14, 18.6 mg, 18.3 µmol, 29%) as a white solid.

[0283] 1H NMR (400 MHz, DMSO-d6) δ 13.64-13.18 (m, 1H), 10.98 (s, 1H), 9.00-8.30 (m, 2H), 8.16-7.78 (m, 5H), 7.75-7.38 (m, 5H), 7.31-7.15 (m, 1H), 6.05-5.80 (m, 1H), 5.29- 4.98 (m, 2H), 4.87-4.67 (m, 2H), 4.60-4.09 (m, 5H), 3.90-3.82 (m, 1H), 3.62-3.57 (m, 2H), 3.51-3.44 (m, 3H), 3.21-3.17 (m, 1H), 3.05-2.98 (m, 2H), 2.95-2.75 (m, 3H), 2.68-2.58 (m, 1H), 2.42 (m, 3H), 2.22-1.93 (m, 3H), 1.85-1.61 (m, 3H), 1.59-1.50 (m, 2H), 1.47-1.33 (m, 3H), 1.30-1.04 (m, 2H).

[0284] LCMS (ESI): m / z = 1013.5 [M-H]-.

[0285] Preparation of ((7-(((5S,8S,10aR)-8-((8-(2-(2,6-dioxopiperidin-3-yl)-1- oxoisoindolin-4-yl)oct-7-yn-1-yl)(methyl)carbamoyl)-3-(5-methyl-1H-indazole-3- carbonyl)-6-oxodecahydropyrrolo[1,2-a][1,5]diazocin-5-yl)carbamoyl)naphthalen-2-yl)methyl)phosphonic acid (Compound 15) and propyl (((7-(((5S,8S,10aR)-8-((8-(2-(2,6- dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oct-7-yn-1-yl)(methyl)carbamoyl)-3-(5-methyl- 1H-indazole-3-carbonyl)-6-oxodecahydropyrrolo[1,2-a][1,5]diazocin-5- yl)carbamoyl)naphthalen-2-yl)methyl)(phenoxy)phosphoryl)-L-alaninate (Compound 16)

[0286] STEP A: ((7-(((5S,8S,10aR)-8-((8-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4- yl)oct-7-yn-1-yl)(methyl)carbamoyl)-3-(5-methyl-1H-indazole-3-carbonyl)-6- oxodecahydropyrrolo[1,2-a][1,5]diazocin-5-yl)carbamoyl)naphthalen-2- yl)methyl)phosphonic acid

[0287] To a solution of (5S,8S,10aR)-5-amino-N-(8-(2-(2,6-dioxopiperidin-3-yl)-1- oxoisoindolin-4-yl)oct-7-yn-1-yl)-N-methyl-3-(5-methyl-1H-indazole-3-carbonyl)-6- oxodecahydropyrrolo[1,2-a][1,5]diazocine-8-carboxamide (57.1 mg, 76.3 µmol, 1.1 eq.) and ((7-((perfluorophenoxy)carbonyl)naphthalen-2-yl)methyl)phosphonic acid (30 mg, 69.4 µmol,1.0 eq.) in DMF (1 mL) was added DIEA (26.8 mg, 208 µmol, 3.0 eq.) at room temperature. The resulting mixture was stirred at room temperature for 1 hr. After completion, the reaction mixture was concentrated under reduced pressure. The residue was purified by RP-prep HPLC to give ((7-(((5S,8S,10aR)-8-((8-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oct-7-yn- 1-yl)(methyl)carbamoyl)-3-(5-methyl-1H-indazole-3-carbonyl)-6-oxodecahydropyrrolo[1,2- a][1,5]diazocin-5-yl)carbamoyl)naphthalen-2-yl)methyl)phosphonic acid (Compound 15, 11.0 mg, 11.0 µmol, 15.9 %) as a white solid.

[0288] 1H NMR (400 MHz, DMSO-d6) δ 13.66-13.15 (m, 1H), 10.98 (s, 1H), 8.89-8.62 (m, 1H), 8.52-8.37 (m, 1H), 8.01-7.36 (m, 10H), 7.27-7.21 (m, 1H), 5.35-4.94 (m, 4H), 4.92- 4.72 (m, 3H), 4.63-4.12 (m, 5H), 3.92-3.46 (m, 3H), 3.26-2.75 (m, 7H), 2.64-2.53 (m, 1H), 2.48-2.45 (m, 1H), 2.44-2.41 (m, 3H), 2.35-2.24 (m, 1H), 2.17-1.95 (m, 3H), 1.87-1.64 (m, 3H), 1.61-1.51 (m, 3H), 1.49-1.39 (m, 3H), 1.35-1.26 (m, 2H). (TFA salt).

[0289] LCMS (ESI): m / z = 997.3 [M+H]+.

[0290] STEP B: propyl (((7-(((5S,8S,10aR)-8-((8-(2-(2,6-dioxopiperidin-3-yl)-1- oxoisoindolin-4-yl)oct-7-yn-1-yl)(methyl)carbamoyl)-3-(5-methyl-1H-indazole-3-carbonyl)- 6-oxodecahydropyrrolo[1,2-a][1,5]diazocin-5-yl)carbamoyl)naphthalen-2- yl)methyl)(phenoxy)phosphoryl)-L-alaninate

[0291] To a solution of (5S,8S,10aR)-5-amino-N-(8-(2-(2,6-dioxopiperidin-3-yl)-1- oxoisoindolin-4-yl)oct-7-yn-1-yl)-N-methyl-3-(5-methyl-1H-indazole-3-carbonyl)-6- oxodecahydropyrrolo[1,2-a][1,5]diazocine-8-carboxamide (40 mg, 53.5 µmol, 1.1 eq.) and 7- (((((S)-1-oxo-1-propoxypropan-2-yl)amino)(phenoxy)phosphoryl)methyl)-2-naphthoic acid (22 mg, 48.6 µmol, 1.0 eq.) in DMF (2 mL) were added HATU (20 mg, 53.5 µmol, 1.1 eq.) and DIEA (31.3 mg, 243 µmol, 5.0 eq.) at room temperature. The resulting mixture was stirred at room temperature for 2 hrs. After completion, the reaction mixture was concentrated under reduced pressure. The residue was purified by RP-prep HPLC to give propyl (((7- (((5S,8S,10aR)-8-((8-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oct-7-yn-1- yl)(methyl)carbamoyl)-3-(5-methyl-1H-indazole-3-carbonyl)-6-oxodecahydropyrrolo[1,2- a][1,5]diazocin-5-yl)carbamoyl)naphthalen-2-yl)methyl)(phenoxy)phosphoryl)-L-alaninate (Compound 16, 10 mg, 8.44 µmol, 17%) as a white solid.

[0292] 1H NMR (400 MHz, CDCl3) δ 8.33-8.22 (m, 1H), 8.12-7.31 (m, 12H), 7.24-7.01 (m, 6H), 5.87-5.56 (m, 1H), 5.21-5.07 (m, 1H), 4.84-4.74 (m, 1H), 4.61-4.34 (m, 3H), 4.31- 4.14 (m, 1H), 4.05-3.81 (m, 4H), 3.68-3.22 (m, 7H), 3.10 (d, J = 13.7 Hz, 2H), 3.02-2.90 (m, 1H), 2.80-2.67 (m, 1H), 2.49-2.43 (m, 3H), 2.38-2.18 (m, 4H), 2.16-1.77 (m, 12H), 1.67-1.60 (m, 2H), 1.40-1.31 (m, 2H), 1.18-1.06 (m, 3H), 0.86-0.80 (m, 3H).

[0293] LCMS (ESI): m / z = 1186.7 [M+H]+.

[0294] Preparation of S-(2-((((7-(((5S,8S,10aR)-8-((8-(2-(2,6-dioxopiperidin-3-yl)-1- oxoisoindolin-4-yl)oct-7-yn-1-yl)(methyl)carbamoyl)-3-(5-methylbenzo[d]isoxazole-3- carbonyl)-6-oxodecahydropyrrolo[1,2-a][1,5]diazocin-5-yl)carbamoyl)naphthalen-2- yl)difluoromethyl)(hydroxy)phosphoryl)oxy)ethyl) 2,2-dimethylpropanethioate (Compound 17)

[0295] STEP A: S-(2-((((7-(((5S,8S,10aR)-8-((8-(2-(2,6-dioxopiperidin-3-yl)-1- oxoisoindolin-4-yl)oct-7-yn-1-yl)(methyl)carbamoyl)-3-(5-methylbenzo[d]isoxazole-3- carbonyl)-6-oxodecahydropyrrolo[1,2-a][1,5]diazocin-5-yl)carbamoyl)naphthalen-2- yl)difluoromethyl)(hydroxy)phosphoryl)oxy)ethyl) 2,2-dimethylpropanethioate

[0296] To a solution of (5S,8S,10aR)-5-amino-N-(8-(2-(2,6-dioxopiperidin-3-yl)-1- oxoisoindolin-4-yl)oct-7-yn-1-yl)-N-methyl-3-(5-methylbenzo[d]isoxazole-3-carbonyl)-6- oxodecahydropyrrolo[1,2-a][1,5]diazocine-8-carboxamide (50 mg, 66.7 µmol, 1.0 eq.) and perfluorophenyl 7-(difluoro(hydroxy(2-(pivaloylthio)ethoxy)phosphoryl)methyl)-2- naphthoate (41 mg, 66.7 µmol, 1.0 eq.) in DMF (2 mL) was added DIEA (26 mg, 200 µmol, 3 eq.) at room temperature. The reaction solution was stirred at room temperature for 1 hr. After completion, the reaction solution was purified by RP-prep-HPLC to afford S-(2-((((7- (((5S,8S,10aR)-8-((8-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oct-7-yn-1- yl)(methyl)carbamoyl)-3-(5-methylbenzo[d]isoxazole-3-carbonyl)-6- oxodecahydropyrrolo[1,2-a][1,5]diazocin-5-yl)carbamoyl)naphthalen-2- yl)difluoromethyl)(hydroxy)phosphoryl)oxy)ethyl) 2,2-dimethylpropanethioate (Compound 17, 17 mg, 14.4 µmol, 22%) as a white solid.

[0297] 1H NMR (400 MHz, DMSO-d6) δ 11.02-10.96 (m, 1H), 8.76-7.42 (m, 13H), 5.31-5.11 (m, 2H), 4.76-4.72 (m, 1H), 4.61-4.56 (m, 2H), 4.46-4.40 (m, 2H), 4.36-4.23 (m, 2H), 4.07-3.93 (m, 4H), 3.35-3.28 (m, 1H), 3.18-2.86 (m, 5H), 2.78-2.74 (m, 1H), 2.63-2.55 (m, 1H), 2.48-2.38 (m, 6H), 2.36-2.09 (m, 3H), 2.05-1.78 (m, 3H), 1.68-1.20 (m, 9H), 1.18- 1.11 (m, 9H).

[0298] LCMS (ESI): m / z = 1178.4 [M+H]+.

[0299] Preparation of S,S'-(((((7-(((5S,8S,10aR)-8-((8-(2-(2,6-dioxopiperidin-3-yl)-1- oxoisoindolin-4-yl)oct-7-yn-1-yl)(methyl)carbamoyl)-3-(5-methylbenzo[d]isoxazole-3- carbonyl)-6-oxodecahydropyrrolo[1,2-a][1,5]diazocin-5-yl)carbamoyl)naphthalen-2- yl)difluoromethyl)phosphoryl)bis(oxy))bis(ethane-2,1-diyl)) bis(2,2- dimethylpropanethioate) (Compound 18)

[0300] STEP A: S,S'-(((((7-(((5S,8S,10aR)-8-((8-(2-(2,6-dioxopiperidin-3-yl)-1- oxoisoindolin-4-yl)oct-7-yn-1-yl)(methyl)carbamoyl)-3-(5-methylbenzo[d]isoxazole-3- carbonyl)-6-oxodecahydropyrrolo[1,2-a][1,5]diazocin-5-yl)carbamoyl)naphthalen-2- yl)difluoromethyl)phosphoryl)bis(oxy))bis(ethane-2,1-diyl)) bis(2,2-dimethylpropanethioate)

[0301] To a solution of (5S,8S,10aR)-5-amino-N-(8-(2-(2,6-dioxopiperidin-3-yl)-1- oxoisoindolin-4-yl)oct-7-yn-1-yl)-N-methyl-3-(5-methylbenzo[d]isoxazole-3-carbonyl)-6- oxodecahydropyrrolo[1,2-a][1,5]diazocine-8-carboxamide (500 mg, 0.67 mmol, 1.0 eq.) and perfluorophenyl 7-((bis(2-(pivaloylthio)ethoxy)phosphoryl)difluoromethyl)-2-naphthoate (504 mg, 0.67 mmol, 1.0 eq.) in DMF (15 mL ) was added DIEA (432 mg, 3.35 mmol, 5.0 eq.) at room temperature. The reaction solution was stirred at room temperature for 2 hrs. After completion, the reaction solution was concentrated under reduced pressure. The residue waspurified by prep-HPLC to afford S,S'-(((((7-(((5S,8S,10aR)-8-((8-(2-(2,6-dioxopiperidin-3- yl)-1-oxoisoindolin-4-yl)oct-7-yn-1-yl)(methyl)carbamoyl)-3-(5-methylbenzo[d]isoxazole-3- carbonyl)-6-oxodecahydropyrrolo[1,2-a][1,5]diazocin-5-yl)carbamoyl)naphthalen-2- yl)difluoromethyl)phosphoryl)bis(oxy))bis(ethane-2,1-diyl)) bis(2,2-dimethylpropanethioate) (Compound 18, 415 mg, 0.31 mmol, 47%) as a white solid.

[0302] 1H NMR (400 MHz, CDCl3) δ 10.31-8.70 (m, 1H), 8.61-8.32 (m, 1H), 8.30-7.57 (m, 8H), 7.56-7.36 (m, 4H), 5.64-5.26 (m, 1H), 5.26-5.03 (m, 1H), 4.89-4.72 (m, 1H), 4.71- 4.33 (m, 3H), 4.33-4.08 (m, 6H), 4.03-3.68 (m, 1H), 3.41-3.30 (m, 1H), 3.21-3.03 (m, 6H), 2.96-2.68 (m, 3H), 2.49-2.40 (m, 4H), 2.39-1.70 (m, 12H), 1.66-1.25 (m, 7H), 1.24-1.14 (m, 18H).

[0303] LCMS (ESI): m / z = 1322.6 [M+H]+.

[0304] Preparation of ((((7-(((5S,8S,10aR)-8-((8-(2-(2,6-dioxopiperidin-3-yl)-1- oxoisoindolin-4-yl)oct-7-yn-1-yl)(methyl)carbamoyl)-3-(5-methylbenzo[d]isoxazole-3- carbonyl)-6-oxodecahydropyrrolo[1,2-a][1,5]diazocin-5-yl)carbamoyl)naphthalen-2- yl)difluoromethyl)phosphoryl)bis(oxy))bis(methylene) diisopropyl bis(carbonate) (Compound 19) and ((((7-(((5S,8S,10aR)-8-((8-(2-(2,6-dioxopiperidin-3-yl)-1- oxoisoindolin-4-yl)oct-7-yn-1-yl)(methyl)carbamoyl)-3-(5-methylbenzo[d]isoxazole-3- carbonyl)-6-oxodecahydropyrrolo[1,2-a][1,5]diazocin-5-yl)carbamoyl)naphthalen-2- yl)difluoromethyl)(hydroxy)phosphoryl)oxy)methyl isopropyl carbonate (Compound 20)

[0305] STEP A: perfluorophenyl 7-((diethoxyphosphoryl)difluoromethyl)-2-naphthoate

[0306] Oxalyl chloride (7.53 g, 76.8 mmol, 5.0 eq.) was added dropwise to the solution of 7-((diethoxyphosphoryl)difluoromethyl)-2-naphthoic acid (5.5 g, 15.4 mmol, 1.0 eq.) in dry DCM (120 mL) and DMF (2 drops) at 0 °C. The reaction mixture was warmed to roomtemperature, then stirred for an additional 2 hrs. The reaction was monitored by pipetting out a small amount of crude sample and quenching it with MeOH to ensure acid chloride had been formed completely. After completion, the excess oxalyl chloride and solvent were removed under reduced pressure. The residue was re-dissolved in anhydrous DCM (120 mL) then added to a mixture of 2,3,4,5,6-pentafluorophenol (2.98 g, 16.2 mmol, 1.05 eq.), triethylamine (7.77 g, 76.8 mmol, 5.0 eq.) in anhydrous DCM (100 mL) at 0 °C. The reaction was allowed to warm to room temperature, and stirred for an additional 1 hr. The reaction progress was monitored by LCMS, and after completion, the reaction was concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel to afford perfluorophenyl 7-((diethoxyphosphoryl)difluoromethyl)-2-naphthoate (7.1 g, 13.5 mmol, 88%) as a white solid. LCMS (ESI): m / z = 525 [M+H]+.

[0307] STEP B: (difluoro(7-((perfluorophenoxy)carbonyl)naphthalen-2- yl)methyl)phosphonic acid

[0308] To a solution of perfluorophenyl 7-((diethoxyphosphoryl)difluoromethyl)-2- naphthoate (7.1 g, 13.5 mmol, 1.0 eq.) in DCM (100 mL) was added TMSBr (20 mL) at room temperature. The solution was stirred at room temperature overnight. After completion, the solvent was removed under reduced pressure and the residue was purified by flash column chromatography on silica gel to give (difluoro(7-((perfluorophenoxy)carbonyl)naphthalen-2- yl)methyl)phosphonic acid (5.8 g, 12.4 mmol, 92%). LCMS (ESI): m / z = 469 [M+H]+.

[0309] STEP C: perfluorophenyl 7- ((bis(((isopropoxycarbonyl)oxy)methoxy)phosphoryl)difluoromethyl)-2-naphthoate

[0310] To a solution of (difluoro(7-((perfluorophenoxy)carbonyl)naphthalen-2- yl)methyl)phosphonic acid (2.1 g, 4.49 mmol, 1.0 eq.) in a mixture of deionized H2O (20 mL) and THF (10 mL) was added Amberlite IR120® resin (Na+form) (10 g). The resulting mixture was stirred at room temperature for 1 hr, then the excess of the resin was removed by filtration. AgNO3(3.05 g, 17.96 mmol, 4.0 eq.) in deionized H2O (30 mL) was then added to the resulting solution. After addition, the resulting mixture was stirred at room temperature for an additional 1 hr. During this period, the silver salt formed as a white precipitate, which was collected via filtration. The filter cake was washed with cool H2O (30 mL x3), and the silver salt was further dried under reduced pressure to get a dry powder.The isolated Ag salt was suspended in ACN (10 mL), and iodomethyl isopropyl carbonate (3.29 g, 13.5 mmol, 3.0 eq.) was added dropwise. After addition, the resulting mixture was stirred at room temperature for an additional 12 hrs. The reaction progress was monitored by LCMS, and after completion, the unreacted silver salt was recovered by filtration, and the filtrate was concentrated under reduced pressure. Theresulting residue was purified by flash column chromatography on silica gel to give perfluorophenyl 7-((bis(((isopropoxycarbonyl)oxy)methoxy)phosphoryl)difluoromethyl)-2- naphthoate (1.4 g, 2.0 mmol, 45%) and perfluorophenyl 7- (difluoro(hydroxy(((isopropoxycarbonyl)oxy)methoxy)phosphoryl)methyl)-2-naphthoate (150 mg) as a white solid. LCMS (ESI) m / z = 701 [M+H]+.

[0311] STEP D: ((((7-(((5S,8S,10aR)-8-((8-(2-(2,6-dioxopiperidin-3-yl)-1- oxoisoindolin-4-yl)oct-7-yn-1-yl)(methyl)carbamoyl)-3-(5-methylbenzo[d]isoxazole-3- carbonyl)-6-oxodecahydropyrrolo[1,2-a][1,5]diazocin-5-yl)carbamoyl)naphthalen-2- yl)difluoromethyl)phosphoryl)bis(oxy))bis(methylene) diisopropyl bis(carbonate)

[0312] To a solution of perfluorophenyl 7- ((bis(((isopropoxycarbonyl)oxy)methoxy)phosphoryl)difluoromethyl)-2-naphthoate (660 mg, 0.94 mmol, 1.0 eq.) and 3-(4-(8-(methylamino)oct-1-yn-1-yl)-1-oxoisoindolin-2-yl)piperidine- 2,6-dione (359 mg, 0.94 mmol, 1.0 eq.) in DMF (15 mL) was added DIEA (606 mg, 4.70 mmol, 5.0 eq.) at room temperature. The reaction solution was stirred at room temperature for 1 hr, then concentrated under reduced pressure. The residue was purified by prep-HPLC to afford ((((7-(((5S,8S,10aR)-8-((8-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oct-7-yn-1- yl)(methyl)carbamoyl)-3-(5-methylbenzo[d]isoxazole-3-carbonyl)-6- oxodecahydropyrrolo[1,2-a][1,5]diazocin-5-yl)carbamoyl)naphthalen-2- yl)difluoromethyl)phosphoryl)bis(oxy))bis(methylene) diisopropyl bis(carbonate) (Compound 19, 405 mg, 032 mmol, 34%) as a white solid.

[0313] 1H NMR (400 MHz, CDCl3) δ 8.56-7.63 (m, 9H), 7.58-7.34 (m, 4H), 5.82-5.60 (m, 4H), 5.58-5.04 (m, 2H), 4.97-4.74 (m, 3H), 4.71-3.61 (m, 7H), 3.50-3.02 (m, 4H), 2.94- 2.72 (m, 3H), 2.50-2.40 (m, 4H), 2.38-1.85 (m, 10H), 1.69-1.36 (m, 6H), 1.31-1.15 (m, 13H).

[0314] LCMS (ESI): m / z = 1266.3 [M+H]+.

[0315] STEP E: ((((7-(((5S,8S,10aR)-8-((8-(2-(2,6-dioxopiperidin-3-yl)-1- oxoisoindolin-4-yl)oct-7-yn-1-yl)(methyl)carbamoyl)-3-(5-methylbenzo[d]isoxazole-3- carbonyl)-6-oxodecahydropyrrolo[1,2-a][1,5]diazocin-5-yl)carbamoyl)naphthalen-2- yl)difluoromethyl)(hydroxy)phosphoryl)oxy)methyl isopropyl carbonate

[0316] To a solution of perfluorophenyl 7- (difluoro(hydroxy(((isopropoxycarbonyl)oxy)methoxy)phosphoryl)methyl)-2-naphthoate (30 mg, 51.3 µmol, 1.0 eq.) and 3-(4-(8-(methylamino)oct-1-yn-1-yl)-1-oxoisoindolin-2- yl)piperidine-2,6-dione (19.5 mg, 51.3 µmol, 1.0 eq.) in DMF (5 mL ) was added DIEA (33 mg, 0.26 mmol, 5.0 eq.) at room temperature. The reaction solution was stirred at room temperature for 1 hr, then concentrated under reduced pressure. The residue was purified byC18 column to afford ((((7-(((5S,8S,10aR)-8-((8-(2-(2,6-dioxopiperidin-3-yl)-1- oxoisoindolin-4-yl)oct-7-yn-1-yl)(methyl)carbamoyl)-3-(5-methylbenzo[d]isoxazole-3- carbonyl)-6-oxodecahydropyrrolo[1,2-a][1,5]diazocin-5-yl)carbamoyl)naphthalen-2- yl)difluoromethyl)(hydroxy)phosphoryl)oxy)methyl isopropyl carbonate (Compound 20, 7.0 mg, 6.10 µmol, 12%) as a white solid.

[0317] 1H NMR (400 MHz, DMSO-d6) δ 11.11-10.93 (m, 1H), 8.82-8.47 (m, 1H), 8.24- 8.10 (m, 1H), 8.08-7.85 (m, 4H), 7.82-7.40 (m, 7H), 5.48-5.37 (m, 2H), 5.33-5.05 (m, 2H), 4.80-4.68 (m, 2H), 4.51-4.37 (m, 2H), 4.34-4.23 (m, 1H), 4.08-3.91 (m, 3H), 3.90-3.78 (m, 1H), 3.34-3.08 (m, 2H), 3.01-2.97 (m, 1H), 2.95-2.84 (m, 1H), 2.79-2.73 (m, 1H), 2.52 (s, 3H), 2.46-2.38 (m, 7H), 2.06-1.94 (m, 2H), 1.85-1.70 (m, 2H), 1.58-1.46 (m, 3H), 1.45-1.29 (m, 4H), 1.25-1.19 (m, 8H). (TFA salt).

[0318] LCMS (ESI): m / z = 1150.1 [M+H]+.

[0319] Preparation of S,S'-(((((7-(((5S,8S,10aR)-8-((8-(2-(2,6-dioxopiperidin-3-yl)-1- oxoisoindolin-4-yl)oct-7-yn-1-yl)(methyl)carbamoyl)-3-(5-methylbenzo[d]isoxazole-3- carbonyl)-6-oxodecahydropyrrolo[1,2-a][1,5]diazocin-5-yl)carbamoyl)naphthalen-2- yl)difluoromethyl)phosphoryl)bis(oxy))bis(ethane-2,1-diyl)) bis(3-methylbutanethioate) (Compound 21) and ((7-(((5S,8S,10aR)-8-((8-(2-(2,6-dioxopiperidin-3-yl)-1- oxoisoindolin-4-yl)oct-7-yn-1-yl)(methyl)carbamoyl)-3-(5-methylbenzo[d]isoxazole-3- carbonyl)-6-oxodecahydropyrrolo[1,2-a][1,5]diazocin-5-yl)carbamoyl)naphthalen-2- yl)difluoromethyl)phosphonic acid (Compound 22)

[0320] STEP A: tert-butyl ((5S,8S,10aR)-8-((8-(2-(2,6-dioxopiperidin-3-yl)-1- oxoisoindolin-4-yl)oct-7-yn-1-yl)(methyl)carbamoyl)-3-(5-methylbenzo[d]isoxazole-3- carbonyl)-6-oxodecahydropyrrolo[1,2-a][1,5]diazocin-5-yl)carbamate

[0321] To a solution of 3-(4-(8-(methylamino)oct-1-yn-1-yl)-1-oxoisoindolin-2- yl)piperidine-2,6-dione (2 g, 5.25 mmol, 1.0 eq.) and (5S,8S,10aR)-5-((tert- butoxycarbonyl)amino)-3-(5-methylbenzo[d]isoxazole-3-carbonyl)-6- oxodecahydropyrrolo[1,2-a][1,5]diazocine-8-carboxylic acid (2.55 g, 5.25 mmol, 1.0 eq.) inDMF (50 mL ) were added DIEA (3.39 g, 26.3 mmol, 5.0 eq.) and HATU (2.19 g, 5.78 mmol, 1.1 eq.) at room temperature. The reaction solution was stirred at room temperature for 2 hrs. After completion, the reaction solution was concentrated under reduced pressure. The residue was purified by C18 column to afford tert-butyl ((5S,8S,10aR)-8-((8-(2-(2,6-dioxopiperidin-3- yl)-1-oxoisoindolin-4-yl)oct-7-yn-1-yl)(methyl)carbamoyl)-3-(5-methylbenzo[d]isoxazole-3- carbonyl)-6-oxodecahydropyrrolo[1,2-a][1,5]diazocin-5-yl)carbamate (1.67 g, 1.97 mmol, 37%) as a white solid. LCMS (ESI): m / z = 850 [M+H]+.

[0322] STEP B: (5S,8S,10aR)-5-amino-N-(8-(2-(2,6-dioxopiperidin-3-yl)-1- oxoisoindolin-4-yl)oct-7-yn-1-yl)-N-methyl-3-(5-methylbenzo[d]isoxazole-3-carbonyl)-6- oxodecahydropyrrolo[1,2-a][1,5]diazocine-8-carboxamide

[0323] To a solution of tert-butyl ((5S,8S,10aR)-8-((8-(2-(2,6-dioxopiperidin-3-yl)-1- oxoisoindolin-4-yl)oct-7-yn-1-yl)(methyl)carbamoyl)-3-(5-methylbenzo[d]isoxazole-3- carbonyl)-6-oxodecahydropyrrolo[1,2-a][1,5]diazocin-5-yl)carbamate (700 mg, 0.82 mmol, 1.0 eq.) in DCM (10 mL) was added TFA (3 mL), and the resulting mixture was stirred at room temperature for 2 hrs. After completion, the reaction mixture was concentrated under reduced pressure to give crude (5S,8S,10aR)-5-amino-N-(8-(2-(2,6-dioxopiperidin-3-yl)-1- oxoisoindolin-4-yl)oct-7-yn-1-yl)-N-methyl-3-(5-methylbenzo[d]isoxazole-3-carbonyl)-6- oxodecahydropyrrolo[1,2-a][1,5]diazocine-8-carboxamide (617 mg, quant.) (TFA salt) as a white solid, which was used in next step directly without further purification. LCMS (ESI): m / z = 750 [M+H]+.

[0324] STEP C: S,S'-(((((7-(((5S,8S,10aR)-8-((8-(2-(2,6-dioxopiperidin-3-yl)-1- oxoisoindolin-4-yl)oct-7-yn-1-yl)(methyl)carbamoyl)-3-(5-methylbenzo[d]isoxazole-3- carbonyl)-6-oxodecahydropyrrolo[1,2-a][1,5]diazocin-5-yl)carbamoyl)naphthalen-2- yl)difluoromethyl)phosphoryl)bis(oxy))bis(ethane-2,1-diyl)) bis(3-methylbutanethioate)

[0325] To a solution of (5S,8S,10aR)-5-amino-N-(8-(2-(2,6-dioxopiperidin-3-yl)-1- oxoisoindolin-4-yl)oct-7-yn-1-yl)-N-methyl-3-(5-methylbenzo[d]isoxazole-3-carbonyl)-6- oxodecahydropyrrolo[1,2-a][1,5]diazocine-8-carboxamide (530 mg, 706 µmol, 1.0 eq.) and perfluorophenyl 7-((bis(2-((3-methylbutanoyl)thio)ethoxy)phosphoryl)difluoromethyl)-2- naphthoate (560 mg, 741 µmol, 1.05 eq.) in DMF (9 mL) were added DIEA (272 mg, 2.11 mmol, 3.0 eq.) and DMAP (8 mg, 70.6 µmol, 0.1 eq.) at room temperature. The reaction solution was stirred at room temperature for 1 hr. After completion, the reaction solution was diluted with water (30 mL) and extracted with EtOAc (50 mL × 3). The combined organic layers were washed with brine (30 mL × 2), dried over dried over with anhydrous Na2SO4, then concentrated under reduced pressure. The residue was purified by flash columnchromatography on silica gel to afford S,S'-(((((7-(((5S,8S,10aR)-8-((8-(2-(2,6- dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oct-7-yn-1-yl)(methyl)carbamoyl)-3-(5- methylbenzo[d]isoxazole-3-carbonyl)-6-oxodecahydropyrrolo[1,2-a][1,5]diazocin-5- yl)carbamoyl)naphthalen-2-yl)difluoromethyl)phosphoryl)bis(oxy))bis(ethane-2,1-diyl)) bis(3-methylbutanethioate) (Compound 21, 507 mg, 383 µmol, 54%) as a yellow solid.

[0326] 1H NMR (400 MHz, DMSO-d6) δ 11.02-10.96 (m, 1H), 8.74-8.61 (m, 1H), 8.33- 8.00 (m, 4H), 7.96-7.88 (m, 1H), 7.79-7.39 (m, 7H), 5.36-5.06 (m, 2H), 4.82-4.67 (m, 1H), 4.53-3.76 (m, 11H), 3.25-2.62 (m, 10H), 2.62-2.55 (m, 1H), 2.47-2.38 (m, 9H), 2.34-1.09 (m, 18H), 0.89-0.81 (m, 12H).

[0327] LCMS (ESI): m / z = 1322.5 [M+H]+.

[0328] STEP D: ((7-(((5S,8S,10aR)-8-((8-(2-(2,6-dioxopiperidin-3-yl)-1- oxoisoindolin-4-yl)oct-7-yn-1-yl)(methyl)carbamoyl)-3-(5-methylbenzo[d]isoxazole-3- carbonyl)-6-oxodecahydropyrrolo[1,2-a][1,5]diazocin-5-yl)carbamoyl)naphthalen-2- yl)difluoromethyl)phosphonic acid

[0329] To a solution of (5S,8S,10aR)-5-amino-N-(8-(2-(2,6-dioxopiperidin-3-yl)-1- oxoisoindolin-4-yl)oct-7-yn-1-yl)-N-methyl-3-(5-methylbenzo[d]isoxazole-3-carbonyl)-6- oxodecahydropyrrolo[1,2-a][1,5]diazocine-8-carboxamide (617 mg, 822 µmol, 1.0 eq.) and (difluoro(7-((perfluorophenoxy)carbonyl)naphthalen-2-yl)methyl)phosphonic acid (384 mg, 822 µmol, 1.0 eq.) in DMF (15 mL) were added DIEA (317 mg, 2.46 mmol, 3.0 eq.) and DMAP (10.0 mg, 82.2 µmol, 0.1 eq.) at room temperature. The reaction solution was stirred at room temperature for 2 hrs. After completion,the reaction solution was concentrated under reduced pressure. The residue was purified by RP-pre-HPLC to afford ((7-(((5S,8S,10aR)-8-((8-(2- (2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oct-7-yn-1-yl)(methyl)carbamoyl)-3-(5- methylbenzo[d]isoxazole-3-carbonyl)-6-oxodecahydropyrrolo[1,2-a][1,5]diazocin-5- yl)carbamoyl)naphthalen-2-yl)difluoromethyl)phosphonic acid (Compound 22, 162 mg, 157 µmol, 19%) as a white solid.

[0330] 1H NMR (400 MHz, DMSO-d6) δ 11.07-10.92 (m, 1H), 8.97-8.54 (m, 2H), 8.27- 8.13 (m, 1H), 8.12-7.88 (m, 4H), 7.76-7.64 (m, 3H), 7.63-7.42 (m, 3H), 5.31-5.21 (m, 1H), 5.17-5.10 (m, 1H), 4.78-4.71 (m, 1H), 4.48-4.40 (m, 2H), 4.35-4.26 (m, 2H), 4.05-3.97 (m, 2H), 3.90-3.82 (m, 1H), 3.39-3.23 (m, 2H), 3.18-3.05 (m, 1H), 3.04-2.84 (m, 3H), 2.78-2.53 (m, 3H), 2.48-2.36 (m, 6H), 2.33-2.24 (m, 1H), 2.21-2.10 (m, 1H), 2.04-1.98 (m, 1H), 1.91 (m, 1H), 1.83-1.70 (m, 2H), 1.67-1.59 (m, 1H), 1.56-1.49 (m, 2H), 1.41-1.30 (m, 3H), 1.19-1.09 (m, 1H). (TFA salt).

[0331] LCMS (ESI): m / z = 1034.1 [M+H]+.

[0332] Preparation of S-(2-((((7-(((5S,8S,10aR)-8-((8-(2-(2,6-dioxopiperidin-3-yl)-1- oxoisoindolin-4-yl)oct-7-yn-1-yl)(methyl)carbamoyl)-3-(5-methylbenzo[d]isoxazole-3- carbonyl)-6-oxodecahydropyrrolo[1,2-a][1,5]diazocin-5-yl)carbamoyl)naphthalen-2- yl)difluoromethyl)(hydroxy)phosphoryl)oxy)ethyl) 3-methylbutanethioate (Compound 23)

[0333] STEP A: S-(2-((((7-(((5S,8S,10aR)-8-((8-(2-(2,6-dioxopiperidin-3-yl)-1- oxoisoindolin-4-yl)oct-7-yn-1-yl)(methyl)carbamoyl)-3-(5-methylbenzo[d]isoxazole-3- carbonyl)-6-oxodecahydropyrrolo[1,2-a][1,5]diazocin-5-yl)carbamoyl)naphthalen-2- yl)difluoromethyl)(hydroxy)phosphoryl)oxy)ethyl) 3-methylbutanethioate

[0334] To a solution of (5S,8S,10aR)-5-amino-N-(8-(2-(2,6-dioxopiperidin-3-yl)-1- oxoisoindolin-4-yl)oct-7-yn-1-yl)-N-methyl-3-(5-methylbenzo[d]isoxazole-3-carbonyl)-6- oxodecahydropyrrolo[1,2-a][1,5]diazocine-8-carboxamide (51.3 mg, 68.5 µmol, 1.0 eq.) and perfluorophenyl 7-(difluoro(hydroxy(2-((3-methylbutanoyl)thio)ethoxy)phosphoryl)methyl)- 2-naphthoate (42 mg, 68.5 µmol, 1.0 eq.) in DMF (2 mL) was added DIEA (26.4 mg, 205 µmol, 3 eq.) at room temperature. The reaction solution was stirred at room temperature for 1 hr. After completion, the reaction solution was purified by RP-pre-HPLC to afford S-(2-((((7- (((5S,8S,10aR)-8-((8-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oct-7-yn-1- yl)(methyl)carbamoyl)-3-(5-methylbenzo[d]isoxazole-3-carbonyl)-6- oxodecahydropyrrolo[1,2-a][1,5]diazocin-5-yl)carbamoyl)naphthalen-2- yl)difluoromethyl)(hydroxy)phosphoryl)oxy)ethyl) 3-methylbutanethioate (Compound 23, 15.0 mg, 12.7 µmol, 19%) as a white solid.

[0335] 1H NMR (400 MHz, CDCl3) δ 8.38-7.30 (m, 12H), 7.26-7.23 (m, 1H), 5.54-5.24 (m, 1H), 5.18-4.77 (m, 2H), 4.52-4.18 (m, 5H), 3.73-3.39 (m, 5H), 3.22-2.99 (m, 5H), 2.85- 2.64 (m, 3H), 2.53-1.74 (m, 18H), 1.46-1.28 (m, 6H), 0.96-0.86 (m, 6H).

[0336] LCMS (ESI): m / z = 1178.5 [M+H]+.

[0337] Preparation of ((4-((E)-3-(((5S,8S,10aR)-8-([1,1'-biphenyl]-4-ylcarbamoyl)-3- (8-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oct-7-ynoyl)-6- oxodecahydropyrrolo[1,2-a][1,5]diazocin-5-yl)amino)-3-oxoprop-1-en-1- yl)phenyl)difluoromethyl)phosphonic acid (Compound 24) and S,S'-(((((4-((E)-3- (((5S,8S,10aR)-8-([1,1'-biphenyl]-4-ylcarbamoyl)-3-(8-(2-(2,6-dioxopiperidin-3-yl)-1- oxoisoindolin-4-yl)oct-7-ynoyl)-6-oxodecahydropyrrolo[1,2-a][1,5]diazocin-5-yl)amino)- 3-oxoprop-1-en-1-yl)phenyl)difluoromethyl)phosphoryl)bis(oxy))bis(ethane-2,1-diyl)) dibutanethioate (Compound 25)

[0338] STEP A: benzyl (5S,8S,10aR)-8-([1,1'-biphenyl]-4-ylcarbamoyl)-5-((tert- butoxycarbonyl)amino)-6-oxooctahydropyrrolo[1,2-a][1,5]diazocine-3(4H)-carboxylate

[0339] To a solution of (5S,8S,10aR)-3-((benzyloxy)carbonyl)-5-((tert- butoxycarbonyl)amino)-6-oxodecahydropyrrolo[1,2-a][1,5]diazocine-8-carboxylic acid (800 mg, 1.73 mmol, 1.0 eq.) and [1,1'-biphenyl]-4-amine (292 mg, 1.73 mmol, 1.0 eq.) in DMF (10 mL) were added DIEA (670 mg, 5.19 mmol, 3.0 eq.) and CMPI (443 mg, 1.73 mmol, 1.0 eq.), and the resulting mixture was stirred at room temperature for 2 hrs. After completion, the reaction was diluted with H2O (20 mL) and extracted with EtOAc (10 mL x 3). The organic layers were combined and washed with brine (10 mL), dried over anhydrous Na2SO4and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel to afford benzyl (5S,8S,10aR)-8-([1,1'-biphenyl]-4- ylcarbamoyl)-5-((tert-butoxycarbonyl)amino)-6-oxooctahydropyrrolo[1,2-a][1,5]diazocine- 3(4H)-carboxylate (800 mg, 1.31 mmol, 76%) as a white solid. LCMS (ESI): m / z = 613 [M+H]+.

[0340] STEP B: tert-butyl ((5S,8S,10aR)-8-([1,1'-biphenyl]-4-ylcarbamoyl)-6- oxodecahydropyrrolo[1,2-a][1,5]diazocin-5-yl)carbamate

[0341] To a solution of benzyl (5S,8S,10aR)-8-([1,1'-biphenyl]-4-ylcarbamoyl)-5-((tert- butoxycarbonyl)amino)-6-oxooctahydropyrrolo[1,2-a][1,5]diazocine-3(4H)-carboxylate (800 mg, 1.31 mmol, 1.0 eq. ) in MeOH (80 mL) was added Pd / C (400 mg) under nitrogen. The suspension was degassed under vacuum and purged with H2several times. The resulting mixture was stirred at room temperature for 14 hrs. After completion, the suspension was filtered through a pad of Celite®, the filter cake was washed with MeOH (20 mL). The combined filtrates were concentrated to dryness to give tert-butyl ((5S,8S,10aR)-8-([1,1'- biphenyl]-4-ylcarbamoyl)-6-oxodecahydropyrrolo[1,2-a][1,5]diazocin-5-yl)carbamate (550 mg, quant.) as a white solid. LCMS (ESI): m / z = 479 [M+H]+.

[0342] STEP C: tert-butyl ((5S,8S,10aR)-8-([1,1'-biphenyl]-4-ylcarbamoyl)-3-(8-(2-(2,6- dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oct-7-ynoyl)-6-oxodecahydropyrrolo[1,2- a][1,5]diazocin-5-yl)carbamate

[0343] To a solution of tert-butyl ((5S,8S,10aR)-8-([1,1'-biphenyl]-4-ylcarbamoyl)-6- oxodecahydropyrrolo[1,2-a][1,5]diazocin-5-yl)carbamate (120 mg, 0.25 mmol, 1.1 eq.) and 8- (2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oct-7-ynoic acid (90 mg, 0.23 mmol, 1.0 eq.) in DMF (2 mL) were added HATU (95 mg, 0.25 mmol, 1.1 eq.) and DIEA (89 mg, 0.69 mmol, 3.0 eq.) at room temperature. The resulting mixture was stirred at room temperature for 2 hrs. After completion, the reaction mixture was concentrated under reduced pressure. The residue was purified by C18-column to give tert-butyl ((5S,8S,10aR)-8-([1,1'-biphenyl]-4- ylcarbamoyl)-3-(8-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oct-7-ynoyl)-6-oxodecahydropyrrolo[1,2-a][1,5]diazocin-5-yl)carbamate (170 mg, 0.20 mmol, 88%) as a white solid. LCMS (ESI): m / z = 843 [M+H]+.

[0344] STEP D: (5S,8S,10aR)-N-([1,1'-biphenyl]-4-yl)-5-amino-3-(8-(2-(2,6- dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oct-7-ynoyl)-6-oxodecahydropyrrolo[1,2- a][1,5]diazocine-8-carboxamide

[0345] To a solution of tert-butyl ((5S,8S,10aR)-8-([1,1'-biphenyl]-4-ylcarbamoyl)-3-(8- (2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oct-7-ynoyl)-6-oxodecahydropyrrolo[1,2- a][1,5]diazocin-5-yl)carbamate (60 mg, 71.3 µmol, 1.0 eq.) in DCM (3 mL) was added TFA (1 mL), and the resulting mixture was stirred at room temperature for 2 hrs. After completion, the reaction mixture was concentrated under reduced pressure to give crude (5S,8S,10aR)-N- ([1,1'-biphenyl]-4-yl)-5-amino-3-(8-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oct-7- ynoyl)-6-oxodecahydropyrrolo[1,2-a][1,5]diazocine-8-carboxamide (50 mg, quant.) as a white solid, which was used in next step directly without further purification. LCMS (ESI): m / z = 743 [M+H]+.

[0346] STEP E: ((4-((E)-3-(((5S,8S,10aR)-8-([1,1'-biphenyl]-4-ylcarbamoyl)-3-(8-(2- (2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oct-7-ynoyl)-6-oxodecahydropyrrolo[1,2- a][1,5]diazocin-5-yl)amino)-3-oxoprop-1-en-1-yl)phenyl)difluoromethyl)phosphonic acid

[0347] To a solution of (5S,8S,10aR)-N-([1,1'-biphenyl]-4-yl)-5-amino-3-(8-(2-(2,6- dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oct-7-ynoyl)-6-oxodecahydropyrrolo[1,2- a][1,5]diazocine-8-carboxamide (50 mg, 67.4 µmol, 1.0 eq.) and (E)-(difluoro(4-(3-oxo-3- (perfluorophenoxy)prop-1-en-1-yl)phenyl)methyl)phosphonic acid (30 mg, 67.4 µmol, 1.0 eq.) in DMF (2 mL) was added DIEA (44 mg, 0.34 mmol, 5.0 eq.) at room temperature. The resulting mixture was stirred at room temperature for additional 2 hrs. After completion, the reaction mixture was concentrated under reduced pressure. The residue was purified by RP- prep HPLC to give ((4-((E)-3-(((5S,8S,10aR)-8-([1,1'-biphenyl]-4-ylcarbamoyl)-3-(8-(2-(2,6- dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oct-7-ynoyl)-6-oxodecahydropyrrolo[1,2- a][1,5]diazocin-5-yl)amino)-3-oxoprop-1-en-1-yl)phenyl)difluoromethyl)phosphonic acid (Compound 24, 18.1 mg, 18.0 µmol, 27%) as a white solid.

[0348] 1H NMR (400 MHz, DMSO-d6) δ 10.99 (s, 1H), 10.32-10.15 (m, 1H), 8.54-8.20 (m, 1H), 7.79-7.23 (m, 17H), 7.03-6.83 (m, 1H), 5.18-5.07 (m, 1H), 4.96-4.85 (m, 1H), 4.53- 4.42 (m, 2H), 4.35-4.24 (m, 2H), 4.01-3.94 (m, 2H), 3.80-3.68 (m, 3H), 3.43-3.20 (m, 2H), 2.94-2.85 (m, 1H), 2.38-1.10 (m, 16H).

[0349] LCMS (ESI): m / z = 1003.4 [M+H]+.

[0350] STEP F: S,S'-(((((4-((E)-3-(((5S,8S,10aR)-8-([1,1'-biphenyl]-4-ylcarbamoyl)-3-(8- (2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oct-7-ynoyl)-6-oxodecahydropyrrolo[1,2- a][1,5]diazocin-5-yl)amino)-3-oxoprop-1-en-1- yl)phenyl)difluoromethyl)phosphoryl)bis(oxy))bis(ethane-2,1-diyl)) dibutanethioate

[0351] To a solution of (5S,8S,10aR)-N-([1,1'-biphenyl]-4-yl)-5-amino-3-(8-(2-(2,6- dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oct-7-ynoyl)-6-oxodecahydropyrrolo[1,2- a][1,5]diazocine-8-carboxamide (50 mg, 67.4 µmol, 1.0 eq.) and perfluorophenyl (E)-3-(4- ((bis(2-(butyrylthio)ethoxy)phosphoryl)difluoromethyl)phenyl)acrylate (48 mg, 67.4 µmol, 1.0 eq.) in DMF (2 mL) was added DIEA (44 mg, 0.34 mmol, 5.0 eq.) at room temperature. The resulting mixture was stirred at room temperature for 2 hrs. After completion, the reaction mixture was concentrated under reduced pressure. The residue was purified by RP-prep HPLC to give S,S'-(((((4-((E)-3-(((5S,8S,10aR)-8-([1,1'-biphenyl]-4-ylcarbamoyl)-3-(8-(2-(2,6- dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oct-7-ynoyl)-6-oxodecahydropyrrolo[1,2- a][1,5]diazocin-5-yl)amino)-3-oxoprop-1-en-1- yl)phenyl)difluoromethyl)phosphoryl)bis(oxy))bis(ethane-2,1-diyl)) dibutanethioate (Compound 25, 18.8 mg, 14.9 µmol, 22%) as a white solid.

[0352] 1H NMR (400 MHz, CDCl3) δ 8.85-8.50 (m, 1H), 7.82-7.74 (m, 1H), 7.70-7.45 (m, 11H), 7.45-7.28 (m, 6H), 6.84-6.53 (m, 1H), 5.36-5.25 (m, 1H), 5.03-4.69 (m, 1H), 4.65- 4.11 (m, 8H), 3.99-3.59 (m, 2H), 3.48-3.04 (m, 6H), 2.94-2.72 (m, 2H), 2.58-2.01 (m, 15H), 1.74-1.61 (m, 6H), 1.55-1.25 (m, 5H), 0.99-0.91 (m, 6H).

[0353] LCMS (ESI): m / z = 1263.4 [M+H]+.

[0354] Preparation of propyl (((7-(((5S,8S,10aR)-8-((8-(2-(2,6-dioxopiperidin-3-yl)-1- oxoisoindolin-4-yl)oct-7-yn-1-yl)(methyl)carbamoyl)-3-(5-methylbenzo[d]isoxazole-3- carbonyl)-6-oxodecahydropyrrolo[1,2-a][1,5]diazocin-5-yl)carbamoyl)naphthalen-2- yl)fluoromethyl)(phenoxy)phosphoryl)-L-alaninate (Compound 26)

[0355] STEP A: propyl (((7-(((5S,8S,10aR)-8-((8-(2-(2,6-dioxopiperidin-3-yl)-1- oxoisoindolin-4-yl)oct-7-yn-1-yl)(methyl)carbamoyl)-3-(5-methylbenzo[d]isoxazole-3- carbonyl)-6-oxodecahydropyrrolo[1,2-a][1,5]diazocin-5-yl)carbamoyl)naphthalen-2- yl)fluoromethyl)(phenoxy)phosphoryl)-L-alaninate

[0356] To a solution of 7-(fluoro((((S)-1-oxo-1-propoxypropan-2- yl)amino)(phenoxy)phosphoryl)methyl)-2-naphthoic acid (317 mg, 0.67 mmol, 1.0 eq.), (5S,8S,10aR)-5-amino-N-(8-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oct-7-yn-1- yl)-N-methyl-3-(5-methylbenzo[d]isoxazole-3-carbonyl)-6-oxodecahydropyrrolo[1,2- a][1,5]diazocine-8-carboxamide (500 mg, 0.67 mmol, 1.0 eq.) and DIEA (432 mg, 3.35 mmol, 5.0 eq.) in DMF (15 mL ) was added HATU (306 mg, 0.80 mmol, 1.2 eq.) at room temperature. The reaction solution was stirred at room temperature for 1 hr. After completion, the reaction solution was concentrated under reduced pressure. The residue was purified by prep-HPLC to afford propyl (((7-(((5S,8S,10aR)-8-((8-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4- yl)oct-7-yn-1-yl)(methyl)carbamoyl)-3-(5-methylbenzo[d]isoxazole-3-carbonyl)-6- oxodecahydropyrrolo[1,2-a][1,5]diazocin-5-yl)carbamoyl)naphthalen-2- yl)fluoromethyl)(phenoxy)phosphoryl)-L-alaninate (Compound 26, 420 mg, 035 mmol, 52%) as a white solid.

[0357] 1H NMR (400 MHz, DMSO-d6) δ 11.11-10.88 (m, 1H), 9.09-8.64 (m, 1H), 8.64- 8.42 (m, 1H), 8.25-7.86 (m, 5H), 7.82-7.40 (m, 6H), 7.39-7.07 (m, 5H), 6.41-6.10 (m, 2H), 5.35-4.69 (m, 3H), 4.53-4.24 (m, 3H), 4.22-3.59 (m, 7H), 3.36-3.22 (m, 2H), 3.16-2.86 (m, 3H), 2.79-2.71 (m, 1H), 2.64-2.53 (m, 1H), 2.48-1.22 (m, 22H), 1.19-1.05 (m, 3H), 1.03-0.90 (m, 1H), 0.87-0.69 (m, 3H).

[0358] LCMS (ESI): m / z = 1205.5 [M+H]+.

[0359] Preparation of (difluoro(7-(((5S,8S,10aR)-8-((2-(((S)-1-((2S,4R)-4-hydroxy-2- (((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1- oxobutan-2-yl)amino)-2-oxoethyl)(methyl)carbamoyl)-3-(5-methylbenzo[d]isoxazole-3- carbonyl)-6-oxodecahydropyrrolo[1,2-a][1,5]diazocin-5-yl)carbamoyl)naphthalen-2- yl)methyl)phosphonic acid (Compound 27)

[0360] STEP A: tert-butyl (2-(((S)-1-((2S,4R)-4-hydroxy-2-(((S)-1-(4-(4-methylthiazol-5- yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-2- oxoethyl)(methyl)carbamate

[0361] To a solution of (2S,4R)-1-((S)-2-amino-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)- 1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (120 mg, 0.27 mmol, 1.0 eq.) and N-(tert-butoxycarbonyl)-N-methylglycine ( 51 mg, 0.27 mmol, 1.0 eq.) in DMA (3 mL) were added HATU (113 mg, 0.30 mmol, 1.1 eq.) and DIEA (104 mg, 0.81 mmol, 3.0 eq.), and the resulting mixture was stirred at room temperature for 2 hrs. After completion, the reaction was diluted with H2O (10 mL) and extracted with EtOAc (10 mL x 3). The organic layers were combined and washed with brine (10 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel to afford tert-butyl (2-(((S)-1-((2S,4R)-4-hydroxy-2-(((S)-1-(4- (4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2- yl)amino)-2-oxoethyl)(methyl)carbamate (110 mg, 0.18 mmol, 67%) as a white solid. LCMS (ESI): m / z = 616 [M+H]+.

[0362] STEP B: (2S,4R)-1-((S)-3,3-dimethyl-2-(2-(methylamino)acetamido)butanoyl)-4- hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide

[0363] To a solution of tert-butyl (2-(((S)-1-((2S,4R)-4-hydroxy-2-(((S)-1-(4-(4- methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2- yl)amino)-2-oxoethyl)(methyl)carbamate (110 mg, 0.18 mmol, 1.0 eq.) in DCM (3 mL) was added TFA (1 mL), and the resulting mixture was stirred at room temperature for 2 hrs. After completion, the reaction mixture was concentrated under reduced pressure to give crude (2S,4R)-1-((S)-3,3-dimethyl-2-(2-(methylamino)acetamido)butanoyl)-4-hydroxy-N-((S)-1- (4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (90 mg, quant.) (TFA salt) as a white solid, which was used in next step directly without further purification. LCMS (ESI): m / z = 516 [M+H]+.

[0364] STEP C: tert-butyl ((5S,8S,10aR)-8-((2-(((S)-1-((2S,4R)-4-hydroxy-2-(((S)-1-(4-(4- methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2- yl)amino)-2-oxoethyl)(methyl)carbamoyl)-3-(5-methylbenzo[d]isoxazole-3-carbonyl)-6- oxodecahydropyrrolo[1,2-a][1,5]diazocin-5-yl)carbamate

[0365] To a solution of (2S,4R)-1-((S)-3,3-dimethyl-2-(2- (methylamino)acetamido)butanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5- yl)phenyl)ethyl)pyrrolidine-2-carboxamide (90 mg, 0.17 mmol, 1.0 eq.) and (5S,8S,10aR)-5- ((tert-butoxycarbonyl)amino)-3-(5-methylbenzo[d]isoxazole-3-carbonyl)-6-oxodecahydropyrrolo[1,2-a][1,5]diazocine-8-carboxylic acid (83 mg, 0.17 mmol, 1.0 eq.) in DMA (3 mL) were added HATU (71 mg, 0.19 mmol, 1.1 eq.) and DIEA (66 mg, 0.51 mmol, 3.0 eq.), and the resulting mixture was stirred at room temperature for 2 hrs. After completion, the reaction was diluted with H2O (10 mL) and extracted with EtOAc (10 mL x 3). The organic layers were combined and washed with brine (10 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel to afford tert-butyl ((5S,8S,10aR)-8-((2-(((S)-1-((2S,4R)-4- hydroxy-2-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)-3,3- dimethyl-1-oxobutan-2-yl)amino)-2-oxoethyl)(methyl)carbamoyl)-3-(5- methylbenzo[d]isoxazole-3-carbonyl)-6-oxodecahydropyrrolo[1,2-a][1,5]diazocin-5- yl)carbamate (90 mg, 91.6 µmol, 54%) as a white solid. LCMS (ESI): m / z = 984 [M+H]+.

[0366] STEP D: (5S,8S,10aR)-5-amino-N-(2-(((S)-1-((2S,4R)-4-hydroxy-2-(((S)-1-(4-(4- methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2- yl)amino)-2-oxoethyl)-N-methyl-3-(5-methylbenzo[d]isoxazole-3-carbonyl)-6- oxodecahydropyrrolo[1,2-a][1,5]diazocine-8-carboxamide

[0367] To a solution of tert-butyl ((5S,8S,10aR)-8-((2-(((S)-1-((2S,4R)-4-hydroxy-2-(((S)- 1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1- oxobutan-2-yl)amino)-2-oxoethyl)(methyl)carbamoyl)-3-(5-methylbenzo[d]isoxazole-3- carbonyl)-6-oxodecahydropyrrolo[1,2-a][1,5]diazocin-5-yl)carbamate (90 mg, 91.6 µmol, 1.0 eq.) in DCM (3 mL) was added TFA (1 mL), and the resulting mixture was stirred at room temperature for 2 hrs. After completion, the reaction mixture was concentrated under reduced pressure to give crude (5S,8S,10aR)-5-amino-N-(2-(((S)-1-((2S,4R)-4-hydroxy-2-(((S)-1-(4- (4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2- yl)amino)-2-oxoethyl)-N-methyl-3-(5-methylbenzo[d]isoxazole-3-carbonyl)-6- oxodecahydropyrrolo[1,2-a][1,5]diazocine-8-carboxamide (80 mg, quant.) (TFA salt) as a white solid, which was used in next step directly without further purification. LCMS (ESI): m / z = 884 [M+H]+.

[0368] STEP E: (difluoro(7-(((5S,8S,10aR)-8-((2-(((S)-1-((2S,4R)-4-hydroxy-2-(((S)-1-(4- (4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2- yl)amino)-2-oxoethyl)(methyl)carbamoyl)-3-(5-methylbenzo[d]isoxazole-3-carbonyl)-6- oxodecahydropyrrolo[1,2-a][1,5]diazocin-5-yl)carbamoyl)naphthalen-2- yl)methyl)phosphonic acid

[0369] To a solution of (5S,8S,10aR)-5-amino-N-(2-(((S)-1-((2S,4R)-4-hydroxy-2-(((S)- 1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-2-oxoethyl)-N-methyl-3-(5-methylbenzo[d]isoxazole-3-carbonyl)-6- oxodecahydropyrrolo[1,2-a][1,5]diazocine-8-carboxamide (80 mg, 90.6 µmol, 1.0 eq.) and (difluoro(7-((perfluorophenoxy)carbonyl)naphthalen-2-yl)methyl)phosphonic acid (42 mg, 90.6 µmol, 1.0 eq.) in DMA (2 mL) was added DIEA (58 mg, 0.45 mmol, 5.0 eq.) at room temperature. The resulting mixture was stirred at room temperature for additional 2 hrs. After completion, the reaction mixture was purified by RP-prep HPLC to give (difluoro(7- (((5S,8S,10aR)-8-((2-(((S)-1-((2S,4R)-4-hydroxy-2-(((S)-1-(4-(4-methylthiazol-5- yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-2- oxoethyl)(methyl)carbamoyl)-3-(5-methylbenzo[d]isoxazole-3-carbonyl)-6- oxodecahydropyrrolo[1,2-a][1,5]diazocin-5-yl)carbamoyl)naphthalen-2- yl)methyl)phosphonic acid (Compound 27, 36 mg, 30.8 µmol, 34%) as a white solid.

[0370] 1H NMR (400 MHz, DMSO-d6) δ 9.03-8.96 (m, 1H), 8.80-8.28 (m, 3H), 8.26- 7.65 (m, 8H), 7.56-7.50 (m, 1H), 7.48-7.34 (m, 4H), 5.29-5.18 (m, 1H), 4.94-4.84 (m, 2H), 4.54-4.47 (m, 4H), 4.30-4.28 (m, 1H), 4.16-3.80 (m, 6H), 3.77-3.51 (m, 3H), 3.03-3.00 (m, 1H), 2.82-2.79 (m, 1H), 2.47-2.41 (m, 6H), 2.37-1.74 (m, 8H), 1.44-1.28 (m, 3H), 0.99-0.86 (m, 9H). (TFA salt).

[0371] LCMS (ESI): m / z = 1169.4 [M+H]+.

[0372] Preparation of ((7-(((5S,8S,10aR)-8-((4-(2-(2,6-dioxopiperidin-3-yl)-1- oxoisoindolin-4-yl)but-3-yn-1-yl)(methyl)carbamoyl)-3-(5-methylbenzo[d]isoxazole-3- carbonyl)-6-oxodecahydropyrrolo[1,2-a][1,5]diazocin-5-yl)carbamoyl)naphthalen-2- yl)difluoromethyl)phosphonic acid (Compound 28)

[0373] STEP A: tert-butyl but-3-yn-1-yl(methyl)carbamate

[0374] To a solution of tert-butyl but-3-yn-1-ylcarbamate (200 mg, 1.18 mmol, 1.0 eq.) in dry DMF (5 mL) was added NaH (52 mg, 1.30 mmol, 1.1 eq) slowly at 0 °C under nitrogen. The mixture was stirred for additional 30 min at 0 °C, then MeI (335 mg, 2.36 mmol, 2.0 eq.) was added drop-wisely. After addition complete addition of MeI, the reaction mixture was allowed to warm to room temperature and stirred for 3 hrs. The reaction mixture was quenched by adding H2O (5 mL), then extracted with EtOAc (10 mL x 3). The organic layers were combined and washed with brine (10 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel to afford tert-butyl but-3-yn-1-yl(methyl)carbamate (180 mg, 0.98 mmol, 83%) as a yellow oil. LC-MS (ESI) m / z = 184 [M+H]+.

[0375] STEP B: tert-butyl (4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)but-3-yn- 1-yl)(methyl)carbamate

[0376] To a solution of 3-(4-bromo-1-oxoisoindolin-2-yl)piperidine-2,6-dione (263 mg, 0.82 mmol, 1.0 eq.), tert-butyl but-3-yn-1-yl(methyl)carbamate (180 mg, 0.98 mmol, 1.2 eq.), Cs2CO3(800 mg, 2.46 mmol, 3.0 eq.) in DMF (10 mL) were added Pd(PPh3)2Cl2( 41 mg, 0..08 mmol, 0.1 eq.) and CuI (31 mg, 0.16 mmol, 0.2 eq.), and the resulting mixture was stirred at 80 °C for additional 12 hrs. After completion, the reaction mixture was diluted with H2O (10 mL) and extracted with EtOAc (10 mL x 3). The organic layers were combined and washed with brine (10 mL), dried over anhydrous Na2SO4and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel to afford tert-butyl (4- (2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)but-3-yn-1-yl)(methyl)carbamate (240 mg, 0.56 mmol, 69%) as a white solid. LCMS (ESI): m / z = 426 [M+H]+.

[0377] STEP C: 3-(4-(4-(methylamino)but-1-yn-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6- dione

[0378] To a solution of tert-butyl (4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4- yl)but-3-yn-1-yl)(methyl)carbamate (150 mg, 0.35 mmol, 1.0 eq.) in DCM (3 mL) was added TFA (1 mL), and the resulting mixture was stirred at room temperature for 2 hrs. After completion, the reaction mixture was concentrated under reduced pressure to give crude 3-(4- (4-(methylamino)but-1-yn-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (110 mg, quant.) as a white solid, which was used in next step directly without further purification. LCMS (ESI): m / z = 326 [M+H]+.

[0379] STEP D: tert-butyl ((5S,8S,10aR)-8-((4-(2-(2,6-dioxopiperidin-3-yl)-1- oxoisoindolin-4-yl)but-3-yn-1-yl)(methyl)carbamoyl)-3-(5-methylbenzo[d]isoxazole-3- carbonyl)-6-oxodecahydropyrrolo[1,2-a][1,5]diazocin-5-yl)carbamate

[0380] To a solution of 3-(4-(4-(methylamino)but-1-yn-1-yl)-1-oxoisoindolin-2- yl)piperidine-2,6-dione (110 mg 0.33 mmol, 1.0 eq.) and (5S,8S,10aR)-5-((tert- butoxycarbonyl)amino)-3-(5-methylbenzo[d]isoxazole-3-carbonyl)-6- oxodecahydropyrrolo[1,2-a][1,5]diazocine-8-carboxylic acid (165 mg, 0.33 mmol, 1.0 eq.) in DMA (5 mL) were added DIEA (213 mg, 1.65 mmol, 5.0 eq.) and HATU (138 mg, 0.36 mmol, 1.1 eq.), and the resulting mixture was stirred at room temperature for 2 hrs. After completion, the reaction was diluted with H2O (10 mL) and extracted with EtOAc (10 mL x 3). The organic layers were combined and washed with brine (10 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel to afford tert-butyl ((5S,8S,10aR)-8-((4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)but-3-yn-1-yl)(methyl)carbamoyl)-3-(5-methylbenzo[d]isoxazole- 3-carbonyl)-6-oxodecahydropyrrolo[1,2-a][1,5]diazocin-5-yl)carbamate (65 mg, 82.0 µmol, 25%) as a white solid. LCMS (ESI): m / z = 794 [M+H]+.

[0381] STEP E: (5S,8S,10aR)-5-amino-N-(4-(2-(2,6-dioxopiperidin-3-yl)-1- oxoisoindolin-4-yl)but-3-yn-1-yl)-N-methyl-3-(5-methylbenzo[d]isoxazole-3-carbonyl)-6- oxodecahydropyrrolo[1,2-a][1,5]diazocine-8-carboxamide

[0382] To a solution of tert-butyl ((5S,8S,10aR)-8-((4-(2-(2,6-dioxopiperidin-3-yl)-1- oxoisoindolin-4-yl)but-3-yn-1-yl)(methyl)carbamoyl)-3-(5-methylbenzo[d]isoxazole-3- carbonyl)-6-oxodecahydropyrrolo[1,2-a][1,5]diazocin-5-yl)carbamate (65 mg, 82.0 µmol, 1.0 eq.) in DCM (3 mL) was added TFA (1 mL), and the resulting mixture was stirred at room temperature for 2 hrs. After completion, the reaction mixture was concentrated under reduced pressure to give crude (5S,8S,10aR)-5-amino-N-(4-(2-(2,6-dioxopiperidin-3-yl)-1- oxoisoindolin-4-yl)but-3-yn-1-yl)-N-methyl-3-(5-methylbenzo[d]isoxazole-3-carbonyl)-6- oxodecahydropyrrolo[1,2-a][1,5]diazocine-8-carboxamide (50 mg, quant.) (TFA salt) as a white solid, which was used in next step directly without further purification. LCMS (ESI): m / z = 694 [M+H]+.

[0383] STEP F: ((7-(((5S,8S,10aR)-8-((4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4- yl)but-3-yn-1-yl)(methyl)carbamoyl)-3-(5-methylbenzo[d]isoxazole-3-carbonyl)-6- oxodecahydropyrrolo[1,2-a][1,5]diazocin-5-yl)carbamoyl)naphthalen-2- yl)difluoromethyl)phosphonic acid

[0384] To a solution of (5S,8S,10aR)-5-amino-N-(4-(2-(2,6-dioxopiperidin-3-yl)-1- oxoisoindolin-4-yl)but-3-yn-1-yl)-N-methyl-3-(5-methylbenzo[d]isoxazole-3-carbonyl)-6- oxodecahydropyrrolo[1,2-a][1,5]diazocine-8-carboxamide (50 mg, 72.2 µmol, 1.1 eq.) and (difluoro(7-((perfluorophenoxy)carbonyl)naphthalen-2-yl)methyl)phosphonic acid (31 mg, 65.6 µmol, 1.0 eq.) in DMA (2 mL) was added DIEA (42.3 mg, 328 µmol, 5.0 eq.) at room temperature. The resulting mixture was stirred at room temperature for 2 hrs. After completion, the reaction mixture was concentrated under reduced pressure. The residue was purified by RP- prep HPLC to give ((7-(((5S,8S,10aR)-8-((4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4- yl)but-3-yn-1-yl)(methyl)carbamoyl)-3-(5-methylbenzo[d]isoxazole-3-carbonyl)-6- oxodecahydropyrrolo[1,2-a][1,5]diazocin-5-yl)carbamoyl)naphthalen-2- yl)difluoromethyl)phosphonic acid (Compound 28, 26 mg, 26.6 µmol, 41%) as a white solid.

[0385] 1H NMR (400 MHz, DMSO-d6) δ 11.04-10.93 (m, 1H), 9.01-8.69 (m, 1H), 8.69- 8.55 (m, 1H), 8.24-8.13 (m, 1H), 8.13-7.93 (m, 4H), 7.78-7.39 (m, 6H), 5.34-5.08 (m, 2H), 4.82-4.73 (m, 1H), 4.50-4.39 (m, 2H), 4.36-4.25 (m, 2H), 4.01-3.96 (m, 2H), 3.87-3.80 (m,2H), 3.68-3.58 (m, 2H), 3.35-3.22 (m, 1H), 3.17-3.04 (m, 2H), 2.90-2.82 (m, 2H), 2.63-2.57 (m, 1H), 2.53-2.52 (m, 2H), 2.46-2.41 (m, 3H), 2.29-1.47 (m, 6H).

[0386] LCMS (ESI): m / z = 978.2 [M+H]+.

[0387] Preparation of(difluoro(7-(((5S,8S,10aR)-8-((4-(((S)-1-((2S,4R)-4-hydroxy-2- (((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1- oxobutan-2-yl)amino)-4-oxobutyl)(methyl)carbamoyl)-3-(5-methylbenzo[d]isoxazole-3- carbonyl)-6-oxodecahydropyrrolo[1,2-a][1,5]diazocin-5-yl)carbamoyl)naphthalen-2- yl)methyl)phosphonic acid (Compound 29)

[0388] STEP A: tert-butyl (4-(((S)-1-((2S,4R)-4-hydroxy-2-(((S)-1-(4-(4-methylthiazol-5- yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-4- oxobutyl)(methyl)carbamate

[0389] To a solution of (2S,4R)-1-((S)-2-amino-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)- 1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (150 mg, 0.34 mmol, 1.0 eq.) and 4-((tert-butoxycarbonyl)(methyl)amino)butanoic acid (74 mg, 0.34mmol, 1.0 eq.) inDMA (3 mL) were added HATU (142 mg, 0.37 mmol, 1.1 eq.) and DIEA (132 mg, 1.02 mmol, 3.0 eq.), and the resulting mixture was stirred at room temperature for 2 hrs. After completion, the reaction was diluted with H2O (10 mL) and extracted with EtOAc (10 mL x 3). The organic layers were combined and washed with brine (10 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel to afford tert-butyl (4-(((S)-1-((2S,4R)-4-hydroxy-2-(((S)-1-(4- (4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2- yl)amino)-4-oxobutyl)(methyl)carbamate (140 mg, 0.22 mmol, 65%) as a white solid. LCMS (ESI): m / z = 644 [M+H]+.

[0390] STEP B: (2S,4R)-1-((S)-3,3-dimethyl-2-(4-(methylamino)butanamido)butanoyl)-4- hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide

[0391] To a solution of tert-butyl (4-(((S)-1-((2S,4R)-4-hydroxy-2-(((S)-1-(4-(4- methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2- yl)amino)-4-oxobutyl)(methyl)carbamate (140 mg, 0.22 mmol, 1.0 eq.) in DCM (3 mL) was added TFA (1 mL), and the resulting mixture was stirred at room temperature for 2 hrs. After completion, the reaction mixture was concentrated under reduced pressure to give crude (2S,4R)-1-((S)-3,3-dimethyl-2-(4-(methylamino)butanamido)butanoyl)-4-hydroxy-N-((S)-1- (4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (110 mg, quant.) (TFA salt) as a white solid, which was used in next step directly without further purification. LCMS (ESI): m / z = 544 [M+H]+.

[0392] STEP C: tert-butyl ((5S,8S,10aR)-8-((4-(((S)-1-((2S,4R)-4-hydroxy-2-(((S)-1-(4-(4- methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2- yl)amino)-4-oxobutyl)(methyl)carbamoyl)-3-(5-methylbenzo[d]isoxazole-3-carbonyl)-6- oxodecahydropyrrolo[1,2-a][1,5]diazocin-5-yl)carbamate

[0393] To a solution of (2S,4R)-1-((S)-3,3-dimethyl-2-(4- (methylamino)butanamido)butanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5- yl)phenyl)ethyl)pyrrolidine-2-carboxamide (110 mg, 0.20 mmol, 1.0 eq.) and (5S,8S,10aR)-5- ((tert-butoxycarbonyl)amino)-3-(5-methylbenzo[d]isoxazole-3-carbonyl)-6- oxodecahydropyrrolo[1,2-a][1,5]diazocine-8-carboxylic acid (98 mg, 0.20 mmol, 1.0 eq.) in DMA (3 mL) were added HATU (84 mg, 0.22 mmol, 1.1 eq.) and DIEA (77 mg, 0.6 mmol, 3.0 eq.), and the resulting mixture was stirred at room temperature for 2 hrs. After completion, the reaction was diluted with H2O (10 mL) and extracted with EtOAc (10 mL x 3). The organic layers were combined and washed with brine (10 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by flash columnchromatography on silica gel to afford tert-butyl ((5S,8S,10aR)-8-((4-(((S)-1-((2S,4R)-4- hydroxy-2-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)-3,3- dimethyl-1-oxobutan-2-yl)amino)-4-oxobutyl)(methyl)carbamoyl)-3-(5- methylbenzo[d]isoxazole-3-carbonyl)-6-oxodecahydropyrrolo[1,2-a][1,5]diazocin-5- yl)carbamate (120 mg, 0.12 mmol, 59%) as a white solid. LCMS (ESI): m / z = 1012 [M+H]+.

[0394] STEP D: (5S,8S,10aR)-5-amino-N-(4-(((S)-1-((2S,4R)-4-hydroxy-2-(((S)-1-(4-(4- methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2- yl)amino)-4-oxobutyl)-N-methyl-3-(5-methylbenzo[d]isoxazole-3-carbonyl)-6- oxodecahydropyrrolo[1,2-a][1,5]diazocine-8-carboxamide

[0395] To a solution of tert-butyl ((5S,8S,10aR)-8-((4-(((S)-1-((2S,4R)-4-hydroxy-2-(((S)- 1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1- oxobutan-2-yl)amino)-4-oxobutyl)(methyl)carbamoyl)-3-(5-methylbenzo[d]isoxazole-3- carbonyl)-6-oxodecahydropyrrolo[1,2-a][1,5]diazocin-5-yl)carbamate (90 mg, 89.0 µmol, 1.0 eq.) in DCM (3 mL) was added TFA (1 mL), and the resulting mixture was stirred at room temperature for 2 hrs. After completion, the reaction mixture was concentrated under reduced pressure to give crude (5S,8S,10aR)-5-amino-N-(4-(((S)-1-((2S,4R)-4-hydroxy-2-(((S)-1-(4- (4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2- yl)amino)-4-oxobutyl)-N-methyl-3-(5-methylbenzo[d]isoxazole-3-carbonyl)-6- oxodecahydropyrrolo[1,2-a][1,5]diazocine-8-carboxamide (78 mg, quant.) (TFA salt) as a white solid, which was used in next step directly without further purification. LCMS (ESI): m / z = 912 [M+H]+.

[0396] STEP E: (difluoro(7-(((5S,8S,10aR)-8-((4-(((S)-1-((2S,4R)-4-hydroxy-2-(((S)-1-(4- (4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2- yl)amino)-4-oxobutyl)(methyl)carbamoyl)-3-(5-methylbenzo[d]isoxazole-3-carbonyl)-6- oxodecahydropyrrolo[1,2-a][1,5]diazocin-5-yl)carbamoyl)naphthalen-2- yl)methyl)phosphonic acid

[0397] To a solution of (5S,8S,10aR)-5-amino-N-(4-(((S)-1-((2S,4R)-4-hydroxy-2-(((S)- 1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1- oxobutan-2-yl)amino)-4-oxobutyl)-N-methyl-3-(5-methylbenzo[d]isoxazole-3-carbonyl)-6- oxodecahydropyrrolo[1,2-a][1,5]diazocine-8-carboxamide (78 mg, 85.6 µmol, 1.0 eq.) and (difluoro(7-((perfluorophenoxy)carbonyl)naphthalen-2-yl)methyl)phosphonic acid (40 mg, 85.6 µmol, 1.0 eq.) in DMA (2 mL) was added DIEA (55 mg, 0.43 mmol, 5.0 eq.) at room temperature. The resulting mixture was stirred at room temperature for additional 2 hrs. After completion, the reaction mixture was purified by RP-prep HPLC to give (difluoro(7-(((5S,8S,10aR)-8-((4-(((S)-1-((2S,4R)-4-hydroxy-2-(((S)-1-(4-(4-methylthiazol-5- yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-4- oxobutyl)(methyl)carbamoyl)-3-(5-methylbenzo[d]isoxazole-3-carbonyl)-6- oxodecahydropyrrolo[1,2-a][1,5]diazocin-5-yl)carbamoyl)naphthalen-2- yl)methyl)phosphonic acid (Compound 29, 27 mg, 22.6 µmol, 26%) as a white solid.

[0398] 1H NMR (400 MHz, DMSO-d6) δ 9.03-8.97 (m, 1H), 8.94-8.53 (m, 2H), 8.41- 7.64 (m, 9H), 7.58-7.50 (m, 1H), 7.48-7.29 (m, 4H), 5.31-5.23 (m, 1H), 4.92-4.88 (m, 2H), 4.78-4.76 (m, 1H), 4.53-4.23 (m, 5H), 4.17-3.78 (m, 4H), 3.68-3.48 (m, 2H), 3.37-3.12 (m, 2H), 3.02-3.00 (m, 1H), 2.79-2.75 (m, 1H), 2.48-2.42 (m, 6H), 2.34-1.98 (m, 6H), 1.89-1.42 (m, 6H), 1.40-1.22 (m, 3H), 1.02-0.76 (m, 9H). (TFA salt).

[0399] LCMS (ESI): m / z = 1197.0 [M+H]+.

[0400] Preparation of ((7-(((5S,8S,10aR)-8-((4-(4-(2,6-dioxopiperidin-3- yl)phenoxy)butyl)(methyl)carbamoyl)-3-(5-methylbenzo[d]isoxazole-3-carbonyl)-6- oxodecahydropyrrolo[1,2-a][1,5]diazocin-5-yl)carbamoyl)naphthalen-2- yl)difluoromethyl)phosphonic acid (Compound 30)

[0401] STEP A: 4-(2,6-bis(benzyloxy)pyridin-3-yl)phenol

[0402] To solution of (4-hydroxyphenyl)boronic acid (206 mg, 1.50 mmol, 1.1 eq.), 2,6- bis(benzyloxy)-3-bromopyridine (500 mg, 1.36 mmol, 1.0 eq.), and K2CO3 (621 mg, 4.50 mmol, 3.0 eq.) in dioxane / H2O (15 mL / 3 mL), was added Pd(dppf)Cl2(99 mg, 0.14 mmol, 0.1 eq), and the resulting mixture was stirred at 100 °C for 12 hrs under N2. After completion, the reaction mixture was diluted with H2O (10 mL) and extracted with EtOAc (10 mL x 3). The organic layers were combined and washed with brine (10 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel to afford 4-(2,6-bis(benzyloxy)pyridin-3-yl)phenol (230 mg, 0.60 mmol, 44%) as a white solid. LCMS (ESI): m / z = 384 [M+H]+.

[0403] STEP B: tert-butyl (4-(4-(2,6-bis(benzyloxy)pyridin-3- yl)phenoxy)butyl)(methyl)carbamate

[0404] To a solution of 4-(2,6-bis(benzyloxy)pyridin-3-yl)phenol (600 mg, 1.57 mmol, 1.0 eq.) and K2CO3(649 mg, 4.70 mmol, 3.0 eq.) in DMF (10 mL) was added 4-((tert- butoxycarbonyl)(methyl)amino)butyl 4-methylbenzenesulfonate (841 mg, 2.36 mmol, 1.5 eq.), and the resulting mixture was stirred at 50 °C for 1 hr. After completion, the reaction mixture was diluted with H2O (10 mL) and extracted with EtOAc (10 mL x 3). The organic layers were combined and washed with brine (10 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel to afford tert-butyl (4-(4-(2,6-bis(benzyloxy)pyridin-3- yl)phenoxy)butyl)(methyl)carbamate (400 mg, 0.70 mmol, 45%) as a white solid. LCMS (ESI): m / z = 569 [M+H]+.

[0405] STEP C: tert-butyl (4-(4-(2,6-dioxopiperidin-3- yl)phenoxy)butyl)(methyl)carbamate

[0406] To a solution of tert-butyl (4-(4-(2,6-bis(benzyloxy)pyridin-3- yl)phenoxy)butyl)(methyl)carbamate (400 mg, 0.70 mmol, 1 eq.) in MeOH (50 mL) was added Pd / C (200 mg) under nitrogen. The suspension was degassed under vacuum and purged with H2 several times. The resulting mixture was stirred at room temperature for 14 hrs. After completion, the suspension was filtered through a pad of Celite®, the filter cake was washed with MeOH (20 mL). The combined filtrates were concentrated to dryness to give tert-butyl (4-(4-(2,6-dioxopiperidin-3-yl)phenoxy)butyl)(methyl)carbamate (200 mg, 0.51 mmol, 73%) as a white solid. LCMS (ESI): m / z = 391 [M+H]+.

[0407] STEP D: 3-(4-(4-(methylamino)butoxy)phenyl)piperidine-2,6-dione

[0408] To a solution of tert-butyl (4-(4-(2,6-dioxopiperidin-3- yl)phenoxy)butyl)(methyl)carbamate (200 mg, 0.51 mmol, 1.0 eq.) in DCM (3 mL) was addedTFA (1 mL), and the resulting mixture was stirred at room temperature for 2 hrs. After completion, the reaction mixture was concentrated under reduced pressure to give crude 3-(4- (4-(methylamino)butoxy)phenyl)piperidine-2,6-dione (200 mg, quant.) (TFA salt) as a white solid, which was used in next step directly without further purification. LCMS (ESI): m / z = 291 [M+H]+.

[0409] STEP E: tert-butyl ((5S,8S,10aR)-8-((4-(4-(2,6-dioxopiperidin-3- yl)phenoxy)butyl)(methyl)carbamoyl)-3-(5-methylbenzo[d]isoxazole-3-carbonyl)-6- oxodecahydropyrrolo[1,2-a][1,5]diazocin-5-yl)carbamate

[0410] To a solution of 3-(4-(4-(methylamino)butoxy)phenyl)piperidine-2,6-dione (200 mg, 0.69 mmol, 1.0 eq.) and (5S,8S,10aR)-5-((tert-butoxycarbonyl)amino)-3-(5- methylbenzo[d]isoxazole-3-carbonyl)-6-oxodecahydropyrrolo[1,2-a][1,5]diazocine-8- carboxylic acid (335 mg, 0.69 mmol, 1.0 eq.) in DMF (3 mL) were added HATU (288 mg, 0.76 mmol, 1.1 eq.) and DIEA (294 mg, 2.28 mmol, 3.0 eq.), and the resulting mixture was stirred at room temperature for 2 hrs. After completion, the reaction was diluted with H2O (10 mL) and extracted with EtOAc (10 mL x 3). The organic layers were combined and washed with brine (10 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel to afford tert-butyl ((5S,8S,10aR)-8-((4-(4-(2,6-dioxopiperidin-3-yl)phenoxy)butyl)(methyl)carbamoyl)-3-(5- methylbenzo[d]isoxazole-3-carbonyl)-6-oxodecahydropyrrolo[1,2-a][1,5]diazocin-5- yl)carbamate (150 mg, 97.8 µmol, 14%) as a white solid. LCMS (ESI): m / z = 759 [M+H]+.

[0411] STEP F : (5S,8S,10aR)-5-amino-N-(4-(4-(2,6-dioxopiperidin-3-yl)phenoxy)butyl)- N-methyl-3-(5-methylbenzo[d]isoxazole-3-carbonyl)-6-oxodecahydropyrrolo[1,2- a][1,5]diazocine-8-carboxamide

[0412] To a solution of tert-butyl ((5S,8S,10aR)-8-((4-(4-(2,6-dioxopiperidin-3- yl)phenoxy)butyl)(methyl)carbamoyl)-3-(5-methylbenzo[d]isoxazole-3-carbonyl)-6- oxodecahydropyrrolo[1,2-a][1,5]diazocin-5-yl)carbamate (150 mg, 97.8 µmol, 1.0 eq.) in DCM (3 mL) was added TFA (1 mL), and the resulting mixture was stirred at room temperature for 2 hrs. After completion, the reaction mixture was concentrated under reduced pressure to give crude (5S,8S,10aR)-5-amino-N-(4-(4-(2,6-dioxopiperidin-3-yl)phenoxy)butyl)-N- methyl-3-(5-methylbenzo[d]isoxazole-3-carbonyl)-6-oxodecahydropyrrolo[1,2- a][1,5]diazocine-8-carboxamide (150 mg, quant.) (TFA salt) as a white solid, which was used in next step directly without further purification. LCMS (ESI): m / z = 658 [M+H]+.

[0413] STEP G: ((7-(((5S,8S,10aR)-8-((4-(4-(2,6-dioxopiperidin-3- yl)phenoxy)butyl)(methyl)carbamoyl)-3-(5-methylbenzo[d]isoxazole-3-carbonyl)-6-oxodecahydropyrrolo[1,2-a][1,5]diazocin-5-yl)carbamoyl)naphthalen-2- yl)difluoromethyl)phosphonic acid

[0414] To a solution of (5S,8S,10aR)-5-amino-N-(4-(4-(2,6-dioxopiperidin-3- yl)phenoxy)butyl)-N-methyl-3-(5-methylbenzo[d]isoxazole-3-carbonyl)-6- oxodecahydropyrrolo[1,2-a][1,5]diazocine-8-carboxamide (150 mg, 0.10 mmol, 1.0 eq.) and (difluoro(7-((perfluorophenoxy)carbonyl)naphthalen-2-yl)methyl)phosphonic acid (49 mg, 0.10 mmol, 1.0 eq.) in DMF (2 mL) was added DIEA (65 mg, 0.5 mmol, 5.0 eq.) at room temperature. The resulting mixture was stirred at room temperature for additional 2 hrs. After completion, the reaction mixture was purified by RP-prep HPLC to give ((7-(((5S,8S,10aR)-8- ((4-(4-(2,6-dioxopiperidin-3-yl)phenoxy)butyl)(methyl)carbamoyl)-3-(5- methylbenzo[d]isoxazole-3-carbonyl)-6-oxodecahydropyrrolo[1,2-a][1,5]diazocin-5- yl)carbamoyl)naphthalen-2-yl)difluoromethyl)phosphonic acid (Compound 30, 27 mg, 28.7 µmol, 29%) as a white solid.

[0415] 1H NMR (400 MHz, DMSO-d6) δ 10.77 (d, J = 5.2 Hz, 1H), 9.00-8.68 (m, 1H), 8.59 (s, 1H), 8.28-7.83 (m, 5H), 7.80-7.60 (m, 2H), 7.58-7.42 (m, 1H), 7.14-7.04 (m, 1H), 7.02- 6.91 (m, 1H), 6.90-6.71 (m, 2H), 5.33-5.16 (m, 1H), 4.82-4.72 (m, 1H), 4.49-4.43 (m, 1H), 3.98-3.66 (m, 7H), 3.43-3.16 (m, 2H), 3.05-2.74 (m, 3H), 2.69-2.58 (m, 1H), 2.55-2.52 (m, 1H), 2.47-2.40 (m, 3H), 2.35-1.37 (m, 12H).

[0416] LCMS (ESI): m / z = 943.2 [M+H]+.

[0417] Preparation of ((7-(((5S,8S,10aR)-8-((4-(2-(((2S,4R)-1-((S)-2-acetamido-3,3- dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)methyl)-5-(4-methylthiazol-5- yl)phenoxy)butyl)(methyl)carbamoyl)-3-(5-methylbenzo[d]isoxazole-3-carbonyl)-6- oxodecahydropyrrolo[1,2-a][1,5]diazocin-5-yl)carbamoyl)naphthalen-2- yl)difluoromethyl)phosphonic acid (Compound 31)

[0418]

[0419] STEP A: 2-(aminomethyl)-5-(4-methylthiazol-5-yl)phenol

[0420] To a solution of 2-hydroxy-4-(4-methylthiazol-5-yl)benzonitrile (800 mg, 3.70 mmol, 1.0 eq.) in dry THF (5 mL) was added LiAlH4 (422 mg, 11.1 mmol, 3.0 eq) slowly at 0 °C under nitrogen. After addition, the reaction mixture was allowed to warm to room temperature and stirred for 3 hrs. After completion, the reaction mixture was quenched by adding 15% NaOH (4 mL) and filtered, the filtrate was then extracted with EtOAc (10 mL x 3). The organic layers were combined and washed with brine (10 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel to afford 2-(aminomethyl)-5-(4-methylthiazol-5-yl)phenol (310 mg, 1.40 mmol, 38%) as a yellow oil. LC-MS (ESI) m / z = 221 [M+H]+.

[0421] STEP B: 4-((tert-butoxycarbonyl)(methyl)amino)butyl 4-methylbenzenesulfonate

[0422] To a solution of tert-butyl (4-hydroxybutyl)(methyl)carbamate (800 mg, 3.94 mmol, 1.0 eq.) and TEA (1.19 g, 11.8 mmol, 3.0 eq.) in dry DCM (5 mL) was added TsCl (399mg, 2.10 mmol, 1.5 eq.) slowly at 0 °C under nitrogen. After addition, the reaction mixture was allowed to warm to room temperature and stirred for 3 hrs. After completion, the reaction mixture was quenched by adding H2O (4 mL), then extracted with DCM (10 mL x 3). The organic layers were combined and washed with brine (10 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure to afford 4-((tert- butoxycarbonyl)(methyl)amino)butyl 4-methylbenzenesulfonate (1.4 g, quant.) as a yellow oil. LC-MS (ESI) m / z = 358 [M+H]+.

[0423] STEP C: methyl (2S,4R)-1-((S)-2-((tert-butoxycarbonyl)amino)-3,3- dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxylate

[0424] To a solution of methyl (2S,4R)-4-hydroxypyrrolidine-2-carboxylate hydrochloride (1.8 g, 9.94 mmol, 1.0 eq.) and (S)-2-((tert-butoxycarbonyl)amino)-3,3-dimethylbutanoic acid (2.30 g, 9.94 mmol, 1.0 eq.) in DMF (100 mL) were added HATU (4.15 g, 10.9 mmol, 1.1 eq.) and DIEA (3.85 g, 29.8 mmol, 3.0 eq.), and the resulting mixture was stirred at room temperature for 2 hrs. After completion, the reaction was diluted with H2O (100 mL) and extracted with EtOAc (100 mL x 3). The organic layers were combined and washed with brine (100 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel to afford methyl (2S,4R)-1-((S)-2- ((tert-butoxycarbonyl)amino)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxylate (3 g, 8.38 mmol, 84%) as a white solid. LCMS (ESI): m / z = 359 [M+H]+.

[0425] STEP D: (2S,4R)-1-((S)-2-((tert-butoxycarbonyl)amino)-3,3-dimethylbutanoyl)-4- hydroxypyrrolidine-2-carboxylic acid

[0426] To a solution of methyl (2S,4R)-1-((S)-2-((tert-butoxycarbonyl)amino)-3,3- dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxylate (3 g, 8.38 mmol, 1.0 eq.) in THF / H2O (20 mL / 7 mL) was added LiOH (1.05 g, 25.1 mmol, 1.5 eq.), and the resulting mixture was stirred at room temperature for 2 hrs. After completion, the reaction mixture was cooled down in an ice bath, then neutralized carefully with HCl (aq., 1 N) until the pH was adjusted to pH = 2-3. The resulting mixture was extracted with EtOAc (30 mL x 3), and the combined organic layers were washed with brine (10 mL x 2), dried over with anhydrous Na2SO4, then concentrated under reduced pressure to give crude (2S,4R)-1-((S)-2-((tert- butoxycarbonyl)amino)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxylic acid (2.5 g, quant.) as a white solid, which was used in next step directly without further purification. LCMS (ESI): m / z = 345 [M+H]+.

[0427] STEP E: tert-butyl ((S)-1-((2S,4R)-4-hydroxy-2-((2-hydroxy-4-(4-methylthiazol-5- yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)carbamate

[0428] To a solution of (2S,4R)-1-((S)-2-((tert-butoxycarbonyl)amino)-3,3- dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxylic acid (310 mg, 0.90 mmol, 1.0 eq.) and 2-(aminomethyl)-5-(4-methylthiazol-5-yl)phenol (198 mg, 0.90 mmol, 1.0 eq.) in DMF ( mL) were added HATU ( 376 mg, 0.99 mmol, 1.1 eq.) and DIEA (348 mg, 2.70 mmol, 3.0 eq.), and the resulting mixture was stirred at room temperature for 2 hrs. After completion, the reaction was diluted with H2O (10 mL) and extracted with EtOAc (10 mL x 3). The organic layers were combined and washed with brine (10 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel to afford tert-butyl ((S)-1-((2S,4R)-4-hydroxy-2-((2-hydroxy-4-(4-methylthiazol-5- yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)carbamate (360 mg, 0.65 mmol, 72%) as a white solid. LCMS (ESI): m / z = 547 [M+H]+.

[0429] STEP F: (2S,4R)-1-((S)-2-amino-3,3-dimethylbutanoyl)-4-hydroxy-N-(2-hydroxy- 4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide

[0430] To a solution of tert-butyl ((S)-1-((2S,4R)-4-hydroxy-2-((2-hydroxy-4-(4- methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2- yl)carbamate (360 mg, 0.65 mmol, 1.0 eq.) in DCM (3 mL) was added TFA (1 mL), and the resulting mixture was stirred at room temperature for 2 hrs. After completion, the reaction mixture was concentrated under reduced pressure to give crude (2S,4R)-1-((S)-2-amino-3,3- dimethylbutanoyl)-4-hydroxy-N-(2-hydroxy-4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2- carboxamide (300 mg, quant.) (TFA salt) as a white solid, which was used in next step directly without further purification. LCMS (ESI): m / z = 447 [M+H]+.

[0431] STEP G: (2S,4R)-1-((S)-2-acetamido-3,3-dimethylbutanoyl)-4-hydroxy-N-(2- hydroxy-4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide

[0432] To a solution of (2S,4R)-1-((S)-2-amino-3,3-dimethylbutanoyl)-4-hydroxy-N-(2- hydroxy-4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (300 mg, 0.67 mmol, 1.0 eq.) and NaHCO3(169 mg, 2.01 mmol, 3.0 eq.) in THF / H2O (5 mL / 1 mL) was added Ac2O (75 mg, 0.74 mmol, 1.1 eq.), and the resulting mixture was stirred at room temperature for 2 hrs. After completion, the reaction mixture was diluted with H2O (10 mL) and extracted with EtOAc (10 mL x 3). The organic layers were combined and washed with brine (10 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel to afford (2S,4R)-1-((S)-2-acetamido-3,3- dimethylbutanoyl)-4-hydroxy-N-(2-hydroxy-4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2- carboxamide (200 mg, quant.) as an oil. LCMS (ESI): m / z = 489 [M+H]+.

[0433] STEP H: tert-butyl (4-(2-(((2S,4R)-1-((S)-2-acetamido-3,3-dimethylbutanoyl)-4- hydroxypyrrolidine-2-carboxamido)methyl)-5-(4-methylthiazol-5- yl)phenoxy)butyl)(methyl)carbamate

[0434] To a solution of (2S,4R)-1-((S)-2-acetamido-3,3-dimethylbutanoyl)-4-hydroxy-N- (2-hydroxy-4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (200 mg, 0.41 mmol, 1.0 eq.) and K2CO3 (170 mg, 1.23 mmol, 3.0 eq.) in DMF (5 mL) was added 4-((tert- butoxycarbonyl)(methyl)amino)butyl 4-methylbenzenesulfonate (220 mg, 0.62 mmol, 1.5 eq.), and the resulting mixture was stirred at 90 °C for 1 hr. After completion, the reaction mixture was diluted with H2O (10 mL) and extracted with EtOAc (10 mL x 3). The organic layers were combined and washed with brine (10 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel to afford tert-butyl (4-(2-(((2S,4R)-1-((S)-2-acetamido-3,3-dimethylbutanoyl)-4- hydroxypyrrolidine-2-carboxamido)methyl)-5-(4-methylthiazol-5- yl)phenoxy)butyl)(methyl)carbamate (103 mg, 0.21 mmol, 51%) as an oil. LCMS (ESI): m / z = 674 [M+H]+.

[0435] STEP I: (2S,4R)-1-((S)-2-acetamido-3,3-dimethylbutanoyl)-4-hydroxy-N-(2-(4- (methylamino)butoxy)-4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide

[0436] To a solution of tert-butyl (4-(2-(((2S,4R)-1-((S)-2-acetamido-3,3- dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)methyl)-5-(4-methylthiazol-5- yl)phenoxy)butyl)(methyl)carbamate (60 mg, 89.2 µmol, 1.0 eq.) in DCM (3 mL) was added TFA (1 mL), and the resulting mixture was stirred at room temperature for 2 hrs. After completion, the reaction mixture was concentrated under reduced pressure to give crude (2S,4R)-1-((S)-2-acetamido-3,3-dimethylbutanoyl)-4-hydroxy-N-(2-(4- (methylamino)butoxy)-4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (60 mg, quant.) (TFA salt) as a white solid, which was used in next step directly without further purification. LCMS (ESI): m / z = 574 [M+H]+.

[0437] STEP J: tert-butyl ((5S,8S,10aR)-8-((4-(2-(((2S,4R)-1-((S)-2-acetamido-3,3- dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)methyl)-5-(4-methylthiazol-5- yl)phenoxy)butyl)(methyl)carbamoyl)-3-(5-methylbenzo[d]isoxazole-3-carbonyl)-6- oxodecahydropyrrolo[1,2-a][1,5]diazocin-5-yl)carbamate

[0438] To a solution of (2S,4R)-1-((S)-2-acetamido-3,3-dimethylbutanoyl)-4-hydroxy-N- (2-(4-(methylamino)butoxy)-4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (60 mg, 0.10 mmol, 1.0 eq.) and (5S,8S,10aR)-5-((tert-butoxycarbonyl)amino)-3-(5- methylbenzo[d]isoxazole-3-carbonyl)-6-oxodecahydropyrrolo[1,2-a][1,5]diazocine-8-carboxylic acid (49 mg, 0.10 mmol, 1.0 eq.) in DMF (3 mL) were added HATU (42 mg, 0.11 mmol, 1.1 eq.) and DIEA (43 mg, 0.33 mmol, 3.0 eq.), and the resulting mixture was stirred at room temperature for 2 hrs. After completion, the reaction was diluted with H2O (10 mL) and extracted with EtOAc (10 mL x 3). The organic layers were combined and washed with brine (10 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel to afford tert-butyl ((5S,8S,10aR)- 8-((4-(2-(((2S,4R)-1-((S)-2-acetamido-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2- carboxamido)methyl)-5-(4-methylthiazol-5-yl)phenoxy)butyl)(methyl)carbamoyl)-3-(5- methylbenzo[d]isoxazole-3-carbonyl)-6-oxodecahydropyrrolo[1,2-a][1,5]diazocin-5- yl)carbamate (57 mg, 55 µmol, 55%) as a white solid. LCMS (ESI): m / z = 1043 [M+H]+.

[0439] STEP K: (5S,8S,10aR)-N-(4-(2-(((2S,4R)-1-((S)-2-acetamido-3,3- dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)methyl)-5-(4-methylthiazol-5- yl)phenoxy)butyl)-5-amino-N-methyl-3-(5-methylbenzo[d]isoxazole-3-carbonyl)-6- oxodecahydropyrrolo[1,2-a][1,5]diazocine-8-carboxamide

[0440] To a solution of tert-butyl ((5S,8S,10aR)-8-((4-(2-(((2S,4R)-1-((S)-2-acetamido- 3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)methyl)-5-(4-methylthiazol-5- yl)phenoxy)butyl)(methyl)carbamoyl)-3-(5-methylbenzo[d]isoxazole-3-carbonyl)-6- oxodecahydropyrrolo[1,2-a][1,5]diazocin-5-yl)carbamate (57 mg, 55 µmol, 1.0 eq.) in DCM (3 mL) was added TFA (1 mL), and the resulting mixture was stirred at room temperature for 2 hrs. After completion, the reaction mixture was concentrated under reduced pressure to give crude (5S,8S,10aR)-N-(4-(2-(((2S,4R)-1-((S)-2-acetamido-3,3-dimethylbutanoyl)-4- hydroxypyrrolidine-2-carboxamido)methyl)-5-(4-methylthiazol-5-yl)phenoxy)butyl)-5- amino-N-methyl-3-(5-methylbenzo[d]isoxazole-3-carbonyl)-6-oxodecahydropyrrolo[1,2- a][1,5]diazocine-8-carboxamide (45 mg, quant.) (TFA salt) as a white solid, which was used in next step directly without further purification. LCMS (ESI): m / z = 943 [M+H]+.

[0441] STEP L: ((7-(((5S,8S,10aR)-8-((4-(2-(((2S,4R)-1-((S)-2-acetamido-3,3- dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)methyl)-5-(4-methylthiazol-5- yl)phenoxy)butyl)(methyl)carbamoyl)-3-(5-methylbenzo[d]isoxazole-3-carbonyl)-6- oxodecahydropyrrolo[1,2-a][1,5]diazocin-5-yl)carbamoyl)naphthalen-2- yl)difluoromethyl)phosphonic acid

[0442] To a solution of (5S,8S,10aR)-N-(4-(2-(((2S,4R)-1-((S)-2-acetamido-3,3- dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)methyl)-5-(4-methylthiazol-5- yl)phenoxy)butyl)-5-amino-N-methyl-3-(5-methylbenzo[d]isoxazole-3-carbonyl)-6- oxodecahydropyrrolo[1,2-a][1,5]diazocine-8-carboxamide (45 mg, 47.8 µmol, 1.0 eq.) and(difluoro(7-((perfluorophenoxy)carbonyl)naphthalen-2-yl)methyl)phosphonic acid (22 mg, 47.8 µmol, 1.0 eq.) in DMF (2 mL) was added DIEA (31 mg, 239 µmol, 5.0 eq.) at room temperature. The resulting mixture was stirred at room temperature for additional 2 hrs. After completion, the reaction mixture was purified by RP-prep HPLC to give ((7-(((5S,8S,10aR)-8- ((4-(2-(((2S,4R)-1-((S)-2-acetamido-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2- carboxamido)methyl)-5-(4-methylthiazol-5-yl)phenoxy)butyl)(methyl)carbamoyl)-3-(5- methylbenzo[d]isoxazole-3-carbonyl)-6-oxodecahydropyrrolo[1,2-a][1,5]diazocin-5- yl)carbamoyl)naphthalen-2-yl)difluoromethyl)phosphonic acid (Compound 31, 30 mg, 24.5 µmol, 51%) as a white solid.

[0443] 1H NMR (400 MHz, CDCl3) δ 9.00-8.94 (m, 1H), 8.83-8.69 (m, 1H), 8.58 (s, 1H), 8.51-8.35 (m, 1H), 8.24-7.89 (m, 6H), 7.78-7.59 (m, 2H), 7.57-7.30 (m, 2H), 7.00-6.83 (m, 2H), 5.30-5.19 (m, 1H), 4.82-4.71 (m, 2H), 4.53-4.45 (m, 3H), 4.33-4.26 (m, 2H), 4.16-4.07 (m, 2H), 4.03-3.97 (m, 2H), 3.89-3.82 (m, 1H), 3.64 (s, 2H), 3.52-3.15 (m, 3H), 3.04-2.75 (m, 3H), 2.47-2.38 (m, 6H), 2.34-1.92 (m, 5H), 1.90-1.86 (m, 3H), 1.85-1.41 (m, 7H), 1.02-0.72 (m, 9H). (TFA salt).

[0444] LCMS (ESI): m / z = 1226.8 [M+H]+.

[0445] Preparation of (difluoro(7-(((5S,8S,10aR)-8-((2-((5-(1-((2S,4R)-4-hydroxy-2- (((R)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)-3-methyl-1- oxobutan-2-yl)isoxazol-3-yl)oxy)ethyl)carbamoyl)-3-(5-methylbenzo[d]isoxazole-3- carbonyl)-6-oxodecahydropyrrolo[1,2-a][1,5]diazocin-5-yl)carbamoyl)naphthalen-2- yl)methyl)phosphonic acid (Compound 32)

[0446] STEP A: 2-((tert-butoxycarbonyl)amino)ethyl 4-methylbenzenesulfonate

[0447] To solution of tert-butyl (2-hydroxyethyl)carbamate (500 mg, 3.11 mmol, 1.0 eq.), TEA (941 mg, 9.32 mmol, 3.0 eq.) and DMAP (38 mg, 0.31 mmol, 0.1 eq.) in DCM (11 mL) was added TsCl (891 mg, 4.67 mmol, 1.5 eq.) at 0 °C and the resulting mixture was warmed up to room temperature and stirred for for 3 hrs under N2. After completion, the reaction mixture was quenched by adding H2O (10 mL), then extracted with EtOAc (15 mL x 3). The organic layers were combined and washed with brine (15 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel to afford 2-((tert-butoxycarbonyl)amino)ethyl 4- methylbenzenesulfonate (500 mg, 1.59 mmol, 51%) as a yellow oil. LC-MS (ESI) m / z = 316 [M+H]+

[0448] STEP B: methyl 2-(3-(2-((tert-butoxycarbonyl)amino)ethoxy)isoxazol-5-yl)-3- methylbutanoate

[0449] To a solution of methyl 2-(3-hydroxyisoxazol-5-yl)-3-methylbutanoate (198 mg, 0.63 mmol, 1.0 eq.) and K2CO3(261 mg, 1.89 mmol, 3.0 eq.) in DMF (10 mL) was added 2- ((tert-butoxycarbonyl)amino)ethyl 4-methylbenzenesulfonate (400 mg, 1.26 mmol, 2.0 eq.) at room temperature. The resulting mixture was stirred at room temperature for 2 hrs. Aftercompletion, the reaction mixture was purified by C18 column chromatography to give methyl 2-(3-(2-((tert-butoxycarbonyl)amino)ethoxy)isoxazol-5-yl)-3-methylbutanoate (200 mg, 0.58 mmol, 93%) as a white solid. LC-MS (ESI) m / z = 343 [M+H]+

[0450] STEP C: 2-(3-(2-((tert-butoxycarbonyl)amino)ethoxy)isoxazol-5-yl)-3- methylbutanoic acid

[0451] To a stirring solution of methyl 2-(3-(2-((tert- butoxycarbonyl)amino)ethoxy)isoxazol-5-yl)-3-methylbutanoate (200 mg, 0.58 mmol, 1.0 eq.) in MeOH / H2O (5 mL / 0.5 mL) was added LiOH H2O (75 mg, 1.74 mmol, 3.0 eq.) at room temperature. The reaction mixture was stirred at room temperature for 4 hrs. The resulting solution was acidified to pH~5 with 1 N HCl aqueous solution and concentrated under reduced pressure. The residue was purified by C18 column chromatography to afford 2-(3-(2-((tert-butoxycarbonyl)amino)ethoxy)isoxazol-5-yl)-3-methylbutanoic acid (180 mg, 0.55 mmol, 95%) as a white solid. LCMS (ESI): m / z = 329 [M+H]+.

[0452] STEP D: tert-butyl (2-((5-(1-((2S,4R)-4-hydroxy-2-(((R)-1-(4-(4-methylthiazol-5- yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-yl)isoxazol-3- yl)oxy)ethyl)carbamate

[0453] To a solution of 2-(3-(2-((tert-butoxycarbonyl)amino)ethoxy)isoxazol-5-yl)-3- methylbutanoic acid (180 mg, 0.55 mmol, 1.0 eq.) and (2S,4R)-4-hydroxy-N-((R)-1-(4-(4- methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (182 mg, 0.55 mmol, 1.0 eq.) in DMF (3 mL) were added HATU (230 mg, 0.61 mmol, 1.1 eq.) and DIEA (213 mg, 1.65 mmol, 3.0 eq.), and the resulting mixture was stirred at room temperature for 2 hrs. After completion, the reaction was diluted with H2O (10 mL) and extracted with EtOAc (10 mL x 3). The organic layers were combined and washed with brine (10 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel to afford tert-butyl (2-((5-(1-((2S,4R)-4-hydroxy-2-(((R)-1-(4- (4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2- yl)isoxazol-3-yl)oxy)ethyl)carbamate (250 mg, 0.39 mmol, 71%) as a white solid. LCMS (ESI): m / z = 642 [M+H]+.

[0454] STEP E: (2S,4R)-1-(2-(3-(2-aminoethoxy)isoxazol-5-yl)-3-methylbutanoyl)-4- hydroxy-N-((R)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide

[0455] To a solution of tert-butyl (2-((5-(1-((2S,4R)-4-hydroxy-2-(((R)-1-(4-(4- methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2- yl)isoxazol-3-yl)oxy)ethyl)carbamate (250 mg, 0.39 mmol, 1.0 eq.) in DCM (3 mL) was added TFA (1 mL), and the resulting mixture was stirred at room temperature for 2 hrs. Aftercompletion, the reaction mixture was concentrated under reduced pressure to give crude (2S,4R)-1-(2-(3-(2-aminoethoxy)isoxazol-5-yl)-3-methylbutanoyl)-4-hydroxy-N-((R)-1-(4- (4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (200 mg, quant.) (TFA salt) as a white solid, which was used in next step directly without further purification. LCMS (ESI): m / z = 542 [M+H]+.

[0456] STEP F: tert-butyl ((5S,8S,10aR)-8-((2-((5-(1-((2S,4R)-4-hydroxy-2-(((R)-1-(4-(4- methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2- yl)isoxazol-3-yl)oxy)ethyl)carbamoyl)-3-(5-methylbenzo[d]isoxazole-3-carbonyl)-6- oxodecahydropyrrolo[1,2-a][1,5]diazocin-5-yl)carbamate

[0457] To a solution of (2S,4R)-1-(2-(3-(2-aminoethoxy)isoxazol-5-yl)-3- methylbutanoyl)-4-hydroxy-N-((R)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2- carboxamide (200 mg, 0.37 mmol, 1.0 eq.) and (5S,8S,10aR)-5-((tert- butoxycarbonyl)amino)-3-(5-methylbenzo[d]isoxazole-3-carbonyl)-6- oxodecahydropyrrolo[1,2-a][1,5]diazocine-8-carboxylic acid (180 mg, 0.37 mmol, 1.0 eq.) in DMF (3 mL) were added HATU (155 mg, 0.41 mmol, 1.1 eq.) and DIEA (143 mg, 1.11 mmol, 3.0 eq.), and the resulting mixture was stirred at room temperature for 2 hrs. After completion, the reaction was diluted with H2O (10 mL) and extracted with EtOAc (10 mL x 3). The organic layers were combined and washed with brine (10 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel to afford tert-butyl ((5S,8S,10aR)-8-((2-((5-(1-((2S,4R)-4- hydroxy-2-(((R)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)-3- methyl-1-oxobutan-2-yl)isoxazol-3-yl)oxy)ethyl)carbamoyl)-3-(5-methylbenzo[d]isoxazole- 3-carbonyl)-6-oxodecahydropyrrolo[1,2-a][1,5]diazocin-5-yl)carbamate (200 mg, 0.20 mmol, 54%) as a white solid. LCMS (ESI): m / z = 1010 [M+H]+.

[0458] STEP G: (5S,8S,10aR)-5-amino-N-(2-((5-(1-((2S,4R)-4-hydroxy-2-(((R)-1-(4-(4- methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2- yl)isoxazol-3-yl)oxy)ethyl)-3-(5-methylbenzo[d]isoxazole-3-carbonyl)-6- oxodecahydropyrrolo[1,2-a][1,5]diazocine-8-carboxamide

[0459] To a solution of tert-butyl ((5S,8S,10aR)-8-((2-((5-(1-((2S,4R)-4-hydroxy-2-(((R)- 1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2- yl)isoxazol-3-yl)oxy)ethyl)carbamoyl)-3-(5-methylbenzo[d]isoxazole-3-carbonyl)-6- oxodecahydropyrrolo[1,2-a][1,5]diazocin-5-yl)carbamate (200 mg, 0.20 mmol, 1.0 eq.) in DCM (3 mL) was added TFA (1 mL), and the resulting mixture was stirred at room temperature for 2 hrs. After completion, the reaction mixture was concentrated under reducedpressure to give crude (5S,8S,10aR)-5-amino-N-(2-((5-(1-((2S,4R)-4-hydroxy-2-(((R)-1-(4- (4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2- yl)isoxazol-3-yl)oxy)ethyl)-3-(5-methylbenzo[d]isoxazole-3-carbonyl)-6- oxodecahydropyrrolo[1,2-a][1,5]diazocine-8-carboxamide (45 mg, quant.) (TFA salt) as a white solid, which was used in next step directly without further purification. LCMS (ESI): m / z = 910 [M+H]+.

[0460] STEP H: (difluoro(7-(((5S,8S,10aR)-8-((2-((5-(1-((2S,4R)-4-hydroxy-2-(((R)-1-(4- (4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2- yl)isoxazol-3-yl)oxy)ethyl)carbamoyl)-3-(5-methylbenzo[d]isoxazole-3-carbonyl)-6- oxodecahydropyrrolo[1,2-a][1,5]diazocin-5-yl)carbamoyl)naphthalen-2- yl)methyl)phosphonic acid

[0461] To a solution of (5S,8S,10aR)-5-amino-N-(2-((5-(1-((2S,4R)-4-hydroxy-2-(((R)- 1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2- yl)isoxazol-3-yl)oxy)ethyl)-3-(5-methylbenzo[d]isoxazole-3-carbonyl)-6- oxodecahydropyrrolo[1,2-a][1,5]diazocine-8-carboxamide (45 mg, 49.5 µmol, 1.0 eq.) and (difluoro(7-((perfluorophenoxy)carbonyl)naphthalen-2-yl)methyl)phosphonic acid (23.2 mg, 49.5 µmol, 1.0 eq.) in DMF (2 mL) was added DIEA (32 mg, 248 µmol, 5.0 eq.) at room temperature. The resulting mixture was stirred at room temperature for additional 2 hrs. After completion, the reaction mixture was purified by RP-prep HPLC to give (difluoro(7- (((5S,8S,10aR)-8-((2-((5-(1-((2S,4R)-4-hydroxy-2-(((R)-1-(4-(4-methylthiazol-5- yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-yl)isoxazol-3- yl)oxy)ethyl)carbamoyl)-3-(5-methylbenzo[d]isoxazole-3-carbonyl)-6- oxodecahydropyrrolo[1,2-a][1,5]diazocin-5-yl)carbamoyl)naphthalen-2- yl)methyl)phosphonic acid (Compound 32, 36.7 mg, 30.8 µmol, 62%) as a white solid.

[0462] 1H NMR (400 MHz, DMSO-d6) δ 9.05-8.88 (m, 1H), 8.86-8.64 (m, 1H), 8.58 (s, 1H), 8.46-8.30 (m, 1H), 8.28-8.13 (m, 2H), 8.11-7.90 (m, 4H), 7.79-7.68 (m, 1H), 7.67-7.59 (m, 1H), 7.57-7.33 (m, 5H), 6.18-5.78 (m, 1H), 5.39-5.07 (m, 1H), 5.02-4.73 (m, 1H), 4.53- 4.24 (m, 5H), 4.16-4.04 (m, 3H), 4.00-3.89 (m, 4H), 3.50-3.18 (m, 4H), 2.47-2.34 (m, 6H), 2.33-1.64 (m, 9H), 1.49-1.27 (m, 3H), 1.07-0.68 (m, 5H), 0.51-0.28 (m, 1H).

[0463] LCMS (ESI): m / z = 1194.5 [M+H]+.

[0464] Preparation of (difluoro(7-(((5S,8S,10aR)-8-(4-(5-(1-((2S,4R)-4-hydroxy-2- (((R)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)-3-methyl-1- oxobutan-2-yl)isoxazol-3-yl)piperazine-1-carbonyl)-3-(5-methylbenzo[d]isoxazole-3-carbonyl)-6-oxodecahydropyrrolo[1,2-a][1,5]diazocin-5-yl)carbamoyl)naphthalen-2- yl)methyl)phosphonic acid (Compound 33)

[0465] STEP A: 4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiazole

[0466] To solution of 5-bromo-4-methylthiazole (2 g, 11.3 mmol, 1.0 eq.), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (3.44 g, 13.6 mmol, 1.2 eq.), and KOAc (3.29 g, 33.9 mmol, 3.0 eq.) in dioxane (110 mL), was added Pd(dppf)Cl2 (820 mg,1.13 mmol, 0.1 eq), and the resulting mixture was stirred at 90 °C for 3 hrs under N2. After completion, the reaction mixture was filtered and the filtrate was concentrated under reduced pressure to afford crude 4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiazole (2.5 g, quant.) as an oil, which was used in next step directly without further purification. LCMS (ESI): m / z = 226 [M+H]+.

[0467] STEP B: tert-butyl (R)-(1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamate

[0468] To solution of tert-butyl (R)-(1-(4-bromophenyl)ethyl)carbamate (2.2 g, 7.4 mmol, 1.0 eq.), 4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiazole (2.5 g, 11.1 mmol, 1.5 eq.) and K2CO3(3.06 g, 22.2 mmol, 3.0 eq.) in dioxane / H2O (70 mL / 14 mL), was added Pd(dppf)Cl2 (537 mg, 0.74 mmol, 0.1 eq.), and the resulting mixture was stirred at 90 °C for 12 hrs under N2. After completion, the reaction mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel to afford tert-butyl (R)-(1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamate (1.5 g, 4.72 mmol, 64%) as a white solid. LCMS (ESI): m / z = 319 [M+H]+.

[0469] STEP C: (R)-1-(4-(4-methylthiazol-5-yl)phenyl)ethan-1-amine

[0470] To a solution of tert-butyl (R)-(1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamate (1.5 g, 4.72 mmol, 1.0 eq.) in DCM (10 mL) was added TFA (3 mL), and the resulting mixture was stirred at room temperature for 2 hrs. After completion, the reaction mixture was concentrated under reduced pressure to give crude (R)-1-(4-(4-methylthiazol-5- yl)phenyl)ethan-1-amine (800 mg, quant.) (TFA salt) as a white solid, which was used in next step directly without further purification. LCMS (ESI): m / z = 219 [M+H]+.

[0471] STEP D: tert-butyl (2S,4R)-4-hydroxy-2-(((R)-1-(4-(4-methylthiazol-5- yl)phenyl)ethyl)carbamoyl)pyrrolidine-1-carboxylate

[0472] To a solution of (R)-1-(4-(4-methylthiazol-5-yl)phenyl)ethan-1-amine (800 mg, 3.65 mmol, 1.0 eq.) and (2S,4R)-1-(tert-butoxycarbonyl)-4-hydroxypyrrolidine-2-carboxylic acid (843 mg, 3.65 mmol, 1.0 eq.) in DMF (40 mL) were added HOBt (493 mg, 3.65 mmol, 1.0 eq.), EDCI (701 mg, 3.65 mmol, 1.0 eq.), and DIEA (1.41 g, 11.0 mmol, 3.0 eq.), and the resulting mixture was stirred at room temperature for 2 hrs. After completion, the reaction was diluted with H2O (40 mL) and extracted with EtOAc (50 mL x 3). The organic layers were combined and washed with brine (40 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel to afford te...

Claims

Claims:

1. A compound having the structural formula I:or a pharmaceutically acceptable salt thereof, wherein: q is 0 or 1 and t is 0, 1, or 2, provided that at least one of q or t is 1; p is 1 or 2; X is selected from S, SO2, -S(=O)=NH, -NR8, and -NR9; R1is selected from an 8- to 10-membered fused bicyclic heteroaryl substituted with – CR1aR2aP(O)OR1bOR2b, –CR1aR2aP(O)[OR1b][NH(AA)C(O)ORT], –P(O)OR1bOR2b, - [P(O)[NHRTy][NH(AA)C(O)ORT], or –P(O)[OR1b][NH(AA)C(O)ORT]; an 8- to 10- membered fused bicyclic heterocyclyl substituted with –CR1aR2aP(O)OR1bOR2b, – CR1aR2aP(O)[OR1b][NH(AA)C(O)ORT], –P(O)OR1bOR2b, - [P(O)[NHRTy][NH(AA)C(O)ORT], or –P(O)[OR1b][NH(AA)C(O)ORT]; an aryl substituted with –CR1aR2aP(O)OR1bOR2b, –CR1aR2aP(O)[OR1b][NH(AA)C(O)ORT], –P(O)OR1bOR2b, - [P(O)[NHRTy][NH(AA)C(O)ORT], or –P(O)[OR1b][NH(AA)C(O)ORT], wherein said aryl may be further optionally substituted with 1 or 2 groups independently selected from cyano, (C1-C4)alkoxy, and halo; a -(C1-C4)alkyl(aryl) wherein said aryl portion of -(C1-C4)alkyl(aryl) is substituted with –CR1aR2aP(O)OR1bOR2b, –CR1aR2aP(O)[OR1b][NH(AA)C(O)ORT], – P(O)OR1bOR2b, -[P(O)[NHRTy][NH(AA)C(O)ORT], - [P(O)[NH(AA)C(O)ORT][NH(AA)C(O)ORT], or –P(O)[OR1b][NH(AA)C(O)ORT]; and a - (C2-C4)alkenyl(aryl) wherein said aryl portion of -(C2-C4)alkenyl(aryl) is substituted with – CR1aR2aP(O)OR1bOR2b, –CR1aR2aP(O)[OR1b][NH(AA)C(O)ORT], –P(O)OR1bOR2b, - [P(O)[NHRTy][NH(AA)C(O)ORT], or –P(O)[OR1b][NH(AA)C(O)ORT]; R1aand R2aare each independently selected from hydrogen, cyano, (C1-C4)alkyl, hydroxy(C1-C4)alkyl and fluoro; or R1aand R2ataken together with the carbon they are attached form oxo; R1band R2bare each independently selected from hydrogen, (C1-C4)alkyl, halo(C1- C4)alkyl, -[(C1-C4)alkyl]-OC(O)-[(C1-C4)alkyl], -[(C1-C4)alkyl]-C(O)O-[(C1-C4)alkyl], -[(C1-C4)alkyl]-O-[(C1-C20)alkyl], -[(C1-C4)alkyl]-OC(O)-[halo(C1-C4)alkyl], [(C1-C4)alkyl]- OC(O)O-[5- to 7-membered heterocyclyl], [(C1-C4)alkyl]-OC(O)-[5- to 7-membered heterocyclyl], -[(C1-C4)alkyl]-OC(O)-[(C1-C4)alkyl]-OH, -[(C1-C4)alkyl]-OC(O)-[(C1- C4)alkyl]-O-[(C1-C4)alkyl], -[(C1-C4)alkyl]-OC(O)O-[(C1-C4)alkyl], -[(C1-C4)alkyl]-OC(O)O- [halo(C1-C4)alkyl], -[(C1-C4)alkyl]-OC(O)O-[(C1-C4)alkyl]-OH, -[(C1-C4)alkyl]-OC(O)O- [(C1-C4)alkyl]-O-[(C1-C4)alkyl], -[(C1-C4)alkyl]-SC(O)-[(C1-C4)alkyl], -[(C1-C4)alkyl]- SC(O)-[halo(C1-C4)alkyl], -[(C1-C4)alkyl]-SC(O)-[(C1-C4)alkyl]-OH, -[(C1-C4)alkyl]-SC(O)- [(C1-C4)alkyl]-O-[(C1-C4)alkyl], -[(C1-C4)alkyl]-OC(O)NH(C1-C4)alkyl], -[(C1-C4)alkyl]- OC(O)N[(C1-C4)alkyl]2, and aryl, wherein said 5- to 6- membered heteroaryl and aryl are each optionally and independently substituted with, as valency permits, 1 to 2 groups selected from halo, cyano, and (C1-C4)alkyl and wherein said 5- to 7-membered heterocyclyl of [(C1- C4)alkyl]-OC(O)O-[5- to 7-membered heterocyclyl] and [(C1-C4)alkyl]-OC(O)-[5- to 7- membered heterocyclyl] are each optionally and independently substituted with, as valency permits 1 to 2 groups selected from C(O)ORh; R2is selected from hydrogen, halo, (C1-C4)alkyl, halo(C1-C4)alkyl, (C1-C4)alkoxy, halo(C1-C4)alkoxy, hydroxy(C1-C4)alkyl, cyano, and hydroxyl; R3and R4are each independently selected from hydrogen, halo, (C1-C4)alkyl, halo(C1- C4)alkyl, hydroxy(C1-C4)alkyl, -(C1-C4)alkylphenyl, (C1-C4)alkoxy, halo(C1-C4)alkoxy, -(C1- C4)alkyl(C1-C4)alkoxy, hydroxyl, cyano, -NRaRb, phenyl, (C3-C6)cycloalkyl, 5- to 6- membered heteroaryl, and 4- to 6-membered heterocyclyl, wherein said phenyl, (C3- C6)cycloalkyl, 5- to 6-membered heteroaryl, and 4- to 6-membered heterocyclyl are each optionally substituted with, as valency permits, 1 to 3 groups selected from RS; R5and R6are each independently selected from hydrogen, phenyl, and (C1-C4)alkyl; R7is selected from E, -R10AE, (C1-C4)alkyl, phenyl, 4- to 9-membered monocyclic or bicyclic heterocyclyl, and 5- to 10-membered monocyclic or bicyclic heteroaryl, wherein said (C1-C4)alkyl is optionally substituted with, as valency permits, 1 to 3 groups selected from RYand said phenyl, 4- to 9-membered monocyclic or bicyclic heterocyclyl, and 5- to 10-membered monocyclic or bicyclic heteroaryl are each optionally substituted with, as valency permits, R11and / or 1 to 3 groups selected from RZ; or R6and R7together with the nitrogen atom to which they are attached form a 4- to 14- membered monocyclic or bicyclic heterocyclyl or a 5- to 12-membered monocyclic or bicyclic heteroaryl, each of which being optionally substituted with, as valency permits, R12and / or 1 to 3 groups selected from RQ;R8is selected from hydrogen, (C1-C4)alkyl, halo(C1-C4)alkyl, (C3-C6)cycloalkyl, 5- to 7-membered heterocyclyl, -(C1-C4)[5- to 7-membered heterocyclyl], 5- to 10-membered heteroaryl, -(C1-C4)[5- to 10-membered heteroaryl], phenyl, -(C1-C4)alkylphenyl, –C(O)RHa, – C(O)ORHa, -C(O)NRHaRHb, -C(O)ORHa, -SORHaRHband -SO2RHa, wherein said (C3- C6)cycloalkyl, 5- to 7-membered heterocyclyl, 5- to 10-membered heteroaryl, phenyl, the phenyl on (C1-C4)alkylphenyl, the 5- to 7-membered heterocyclyl on -(C1-C4)[5- to 7- membered heterocyclyl], and the 5- to 6-membered heteroaryl on -(C1-C4)[5- to 6-membered heteroaryl] are each optionally substituted with, as valency permits, 1 to 3 groups selected from RU; R9is selected from –R10E and –C(O)R10E; R10, R10A, R10B, R10C, and R10Dare each independently a chemical spacer unit; R11is selected from –NHC(O)R10BE, -OR10BE, phenyl, (C3-C6)cycloalkyl, 5- to 6- membered heteroaryl, and 4- to 6-membered heterocyclyl each of said phenyl, (C3- C6)cycloalkyl, 5- to 6-membered heteroaryl, and 4- to 6-membered heterocyclyl being substituted with -OR10BE, -NHR10BE, -[N(C1-C4)alkyl]R10BE, or R10BE, and wherein said 4- to 6-membered heterocyclyl is optionally substituted further with oxo; R12is selected from –NHC(O)R10CE, -OR10CE, phenyl, (C3-C6)cycloalkyl, 5- to 6- membered heteroaryl, and 4- to 6-membered heterocyclyl each of said phenyl, (C3- C6)cycloalkyl, 5- to 6-membered heteroaryl, and 4- to 6-membered heterocyclyl being substituted with -OR10CE, -NHR10CE, -[N(C1-C4)alkyl]R10CE, or R10CE, and wherein said 4- to 6-membered heterocyclyl is optionally substituted further with oxo; R13is selected from –NHC(O)R10DE, -OR10DE, phenyl, (C3-C6)cycloalkyl, 5- to 6- membered heteroaryl, and 4- to 6-membered heterocyclyl each of said phenyl, (C3- C6)cycloalkyl, 5- to 6-membered heteroaryl, and 4- to 6-membered heterocyclyl being substituted with -OR10DE, -NHR10DE, -[N(C1-C4)alkyl]R10DE, or R10DE, and wherein said 4- to 6-membered heterocyclyl is optionally substituted further with oxo; E is a chemical moiety that binds to E3 ligase; RHais selected from (C1-C10)alkyl, (C2-C10)alkenyl, (C2-C10)alkynyl, phenyl, 5- to 10- membered monocyclic or bicyclic heteroaryl, and 4- to 10-membered monocyclic or bicyclic heterocyclyl, wherein said (C1-C10)alkyl, (C2-C10)alkenyl, (C2-C10)alkynyl are each optionally substituted with, as valency permits, 1 to 2 groups selected from ROand wherein said 5-to 10- membered monocyclic or bicyclic heteroaryl and said 4-to 10-membered monocyclic or bicyclic heterocyclyl are each optionally substituted with, as valency permits, 1 to 3 groupsselected from halo, (C1-C4)alkyl, halo(C1-C4)alkyl, (C1-C4)alkoxy, halo(C1-C4)alkoxy, oxo, cyano, and 4- to 6-membered heterocyclyl optionally substituted with C1-C4alkyl; ROis selected from halo, (C1-C4)alkoxy, OH, phenyl, NH2, -NH(C1-C10)alkyl, -N[(C1- C10)alkyl], (C3-6cycloalkyl), 4- to 10-membered monocyclic or fused bicyclic heterocyclyl and 5-to 10-membered monocyclic or bicyclic heteroaryl, wherein said 5- to 10-membered monocyclic or bicyclic heteroaryl and said 4-to 10-membered monocyclic or bicyclic heterocyclyl are each optionally substituted with, as valency permits, 1 to 3 groups selected from halo, (C1-C4)alkyl, halo(C1-C4)alkyl, (C1-C4)alkoxy, halo(C1-C4)alkoxy, oxo, and cyano; RHbis hydrogen or (C1-C4)alkyl; AA is the residue of an alpha or beta natural or non-natural amino acid; RTand RTyare each independently selected from (C1-C4)alkyl, benzyl, and phenyl, wherein said phenyl is optionally substituted with 1 or 2 groups selected from halo, (C1- C4)alkyl, and halo(C1-C4)alkyl; RQand RUare each independently selected from halo, (C2-C4)alkenyl, (C1-C4)alkyl, (C1-C4)alkoxy, halo(C1-C4)alkoxy, cyano, phenyl, hydroxyl, 4- to 9-membered monocyclic or bicyclic heterocyclyl, 5- to 10-membered monocyclic or bicyclic heteroaryl, (C3-C6)cycloalkyl, oxo, imino, -ORe, -C(O)Rg, -C(O)ORe, -NRcC(O)Re, -C(O)NRcRd, -NRaRb, -S(O)ReRf, - S(O)2Rf, -S(O)=NH(C1-C4)alkyl, -S(O)NReRf, and -S(O)2NReRf, wherein said (C2-C4)alkenyl and (C1-C4)alkyl are each optionally and independently substituted with, as valency permits, 1 to 3 groups selected from RM, and wherein said phenyl, 5- to 10- membered monocyclic or bicyclic heteroaryl, (C3-C6)cycloalkyl, and 4- to 9-membered monocyclic or bicyclic heterocyclyl are each optionally and independently substituted with, as valency permits, 1 to 3 groups selected from RF; RYis selected from halo, (C1-C4)alkoxy, halo(C1-C4)alkoxy, cyano, -C(O)Rg, - C(O)ORe, -NHC(O)Re, -NRaRb, -S(O)ReRf, -S(O)2Rf, -S(O)NReRf, -S(O)=NH(C1-C4)alkyl, - S(O)2NReRf, hydroxyl, phenyl, 4- to 6-membered heterocyclyl, and 5- to 10-membered monocyclic or bicyclic heteroaryl, wherein said phenyl, 4- to 6-membered heterocyclyl, and 5- to 10-membered monocyclic or bicyclic heteroaryl are each optionally substituted with, as valency permits, 1 to 3 groups selected from RX; RMand RJare each independently selected from halo, (C1-C4)alkyl, (C1-C4)alkoxy, halo(C1-C4)alkoxy, cyano, -C(O)Rg, -C(O)ORe, -NHC(O)Re, -C(O)NRcRd, -NRaRb, - S(O)ReRf, -S(O)2Rf, -S(O)NReRf, -S(O)=NH(C1-C4)alkyl, -S(O)2NReRf, hydroxyl, phenyl, 4- to 6-membered heterocyclyl, and 5- to 10-membered monocyclic or bicyclic heteroaryl, wherein said phenyl, 4- to 6-membered heterocyclyl, and 5- to 10-membered monocyclic orbicyclic heteroaryl are each optionally substituted with, as valency permits, 1 to 3 groups selected from RX; RF, RS, and RXare each independently selected from halo, cyano, (C1-C4)alkyl, (C3- C6cycloalkyl), halo(C1-C4)alkyl, -(C1-C4)alkyl(C1-C4)alkoxy, hydroxy(C1-C4)alkyl, -(C1- C4)alkylphenyl, -(C1-C4)alkylheteroaryl, (C2-C4)alkenyl, halo(C2-C4)alkenyl, (C2-C4)alkynyl, halo(C2-C4)alkynyl, (C1-C4)alkoxy, halo(C1-C4)alkoxy, -ORe, oxo, imino, phenyl, 4- to 6- membered heterocyclyl, -S(O)ReRf, -S(O)2Rf, -S(O)=NH(C1-C4)alkyl, -S(O)NReRf, and - S(O)2NReRf, -C(O)ORe, -NRcC(O)Re, -(C1-C4alkyl)C(O)Rg, -C(O)Rg, -(C1- C4alkyl)C(O)NRcRd, -C(O)NRcRd, -NO2, and -NRaRb, wherein the (C1-C4)alkyl is optionally substituted with cyano, wherein said phenyl, said 4- to 6-membered heterocyclyl, and said phenyl for -(C1-C4)alkylphenyl are each optionally and independently substituted with, as valency permits 1 to 3 groups selected from halo, cyano, oxo, (C1-C10)alkyl, (C2-C10)alkenyl, (C2-C10)alkynyl, halo(C1-C10)alkyl, (C1-C10)alkoxy, and halo(C1-C10)alkoxy, wherein said (C1- C10)alkyl, (C2-C10)alkenyl and (C2-C10)alkynyl are each optionally substituted with, as valency permits a 5-to 10-membered monocyclic or bicyclic heteroaryl or a 4-to 10-membered monocyclic or bicyclic heterocyclyl each of said 5-to 10-membered monocyclic and bicyclic heteroaryl or a 4-to 10-membered monocyclic or bicyclic heterocyclyl being optionally substituted with oxo or a 5- to 7-membered heterocyclyl that is optionally substituted with 1 to 2 oxo; RZis selected from halo, cyano, (C1-C4)alkyl, (C3-C6cycloalkyl), halo(C1-C4)alkyl, - (C1-C4)alkyl(C1-C4)alkoxy, hydroxy(C1-C4)alkyl, -(C1-C4)alkylphenyl, -(C1- C4)alkylheteroaryl, (C2-C4)alkenyl, halo(C2-C4)alkenyl, (C2-C4)alkynyl, halo(C2-C4)alkynyl, (C1-C4)alkoxy, halo(C1-C4)alkoxy, -ORe, oxo, imino, phenyl, 4- to 6-membered heterocyclyl, -S(O)ReRf, -S(O)2Rf, -S(O)=NH(C1-C4)alkyl, -S(O)NReRf, and -S(O)2NReRf, -C(O)ORe, - NRcC(O)Re, -(C1-C4alkyl)C(O)Rg, -C(O)Rg, -(C1-C4alkyl)C(O)NRcRd, -C(O)NRcRd, -NO2, and -NRaRb, wherein the (C1-C4)alkyl is optionally substituted with cyano, wherein said phenyl, said 4- to 6-membered heterocyclyl, and said phenyl for -(C1-C4)alkylphenyl are each optionally and independently substituted with, as valency permits R13and / or 1 to 3 groups selected from halo, cyano, oxo, (C1-C10)alkyl, (C2-C10)alkenyl, (C2-C10)alkynyl, halo(C1- C10)alkyl, (C1-C10)alkoxy, and halo(C1-C10)alkoxy, wherein said (C1-C10)alkyl, (C2- C10)alkenyl and (C2-C10)alkynyl are each optionally substituted with, as valency permits a 5-to 10-membered monocyclic or bicyclic heteroaryl or a 4-to 10-membered monocyclic or bicyclic heterocyclyl each of said 5-to 10-membered monocyclic and bicyclic heteroaryl or a 4-to 10-membered monocyclic or bicyclic heterocyclyl being optionally substituted with oxo or a 5- to 7-membered heterocyclyl that is optionally substituted with 1 to 2 oxo; Ra, Rb, Rc, Rd, Re, Rf,Rg, and Rhare each independently selected from, as valency permits, hydrogen, (C1-C4)alkyl, (C2-C4)alkynyl, -(C1-C4)alkylphenyl, phenyl, (C3- C6)cycloalkyl, 4- to 6-membered heterocyclyl and 5- to 6-membered heteroaryl, wherein said (C1-C4)alkyl is optionally substituted with, as valency permits, 1 to 3 groups selected from RJ, and said phenyl, (C3-C6)cycloalkyl, 4- to 6-membered heterocyclyl, and 5- to 6-membered heteroaryl are each independently optionally substituted with, as valency permits, 1 to 3 groups selected from halo, cyano, (C1-C4)alkyl, halo(C1-C4)alkyl, (C1-C4)alkoxy, halo(C1- C4)alkoxy, hydroxyl, phenyl, and benzyl.

2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein X is NR9; R7is selected from (C1-C4)alkyl, phenyl, 4- to 9-membered monocyclic or bicyclic heterocyclyl, and 5- to 10-membered monocyclic or bicyclic heteroaryl, wherein said (C1- C4)alkyl is optionally substituted with, as valency permits, 1 to 3 groups selected from RYand said phenyl, 4- to 9-membered monocyclic or bicyclic heterocyclyl, and 5- to 10-membered monocyclic or bicyclic heteroaryl are each optionally substituted with, as valency permits, 1 to 3 groups selected from RZ; or R6and R7together with the nitrogen atom to which they are attached form a 4- to 14- membered monocyclic or bicyclic heterocyclyl or a 5- to 12-membered monocyclic or bicyclic heteroaryl, each of which being optionally substituted with, as valency permits, 1 to 3 groups selected from RQ; and RZis selected from halo, cyano, (C1-C4)alkyl, (C3-C6cycloalkyl), halo(C1-C4)alkyl, - (C1-C4)alkyl(C1-C4)alkoxy, hydroxy(C1-C4)alkyl, -(C1-C4)alkylphenyl, -(C1- C4)alkylheteroaryl, (C2-C4)alkenyl, halo(C2-C4)alkenyl, (C2-C4)alkynyl, halo(C2-C4)alkynyl, (C1-C4)alkoxy, halo(C1-C4)alkoxy, -ORe, oxo, imino, phenyl, 4- to 6-membered heterocyclyl, -S(O)ReRf, -S(O)2Rf, -S(O)=NH(C1-C4)alkyl, -S(O)NReRf, and -S(O)2NReRf, -C(O)ORe, - NRcC(O)Re, -(C1-C4alkyl)C(O)Rg, -C(O)Rg, -(C1-C4alkyl)C(O)NRcRd, -C(O)NRcRd, -NO2, and -NRaRb, wherein the (C1-C4)alkyl is optionally substituted with cyano, wherein said phenyl, said 4- to 6-membered heterocyclyl, and said phenyl for -(C1-C4)alkylphenyl are each optionally and independently substituted with, as valency permits 1 to 3 groups selected from halo, cyano, oxo, (C1-C10)alkyl, (C2-C10)alkenyl, (C2-C10)alkynyl, halo(C1-C10)alkyl, (C1- C10)alkoxy, and halo(C1-C10)alkoxy, wherein said (C1-C10)alkyl, (C2-C10)alkenyl and (C2-C10)alkynyl are each optionally substituted with, as valency permits a 5-to 10-membered monocyclic or bicyclic heteroaryl or a 4-to 10-membered monocyclic or bicyclic heterocyclyl each of said 5-to 10-membered monocyclic and bicyclic heteroaryl or a 4-to 10-membered monocyclic or bicyclic heterocyclyl being optionally substituted with oxo or a 5- to 7- membered heterocyclyl that is optionally substituted with 1 to 2 oxo.

3. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein X is selected from S, SO2, -S(=O)=NH, -NR8; R7is selected from E, -R10AE, (C1-C4)alkyl, phenyl, 4- to 9-membered monocyclic or bicyclic heterocyclyl, and 5- to 10-membered monocyclic or bicyclic heteroaryl, wherein said (C1-C4)alkyl is optionally substituted with, as valency permits, 1 to 3 groups selected from RYand said phenyl, 4- to 9-membered monocyclic or bicyclic heterocyclyl, and 5- to 10-membered monocyclic or bicyclic heteroaryl are each optionally substituted with, as valency permits, 1 to 3 groups selected from RZ; or R6and R7together with the nitrogen atom to which they are attached form a 4- to 14- membered monocyclic or bicyclic heterocyclyl or a 5- to 12-membered monocyclic or bicyclic heteroaryl, each of which being optionally substituted with, as valency permits, 1 to 3 groups selected from RQ; and RZis selected from halo, cyano, (C1-C4)alkyl, (C3-C6cycloalkyl), halo(C1-C4)alkyl, - (C1-C4)alkyl(C1-C4)alkoxy, hydroxy(C1-C4)alkyl, -(C1-C4)alkylphenyl, -(C1- C4)alkylheteroaryl, (C2-C4)alkenyl, halo(C2-C4)alkenyl, (C2-C4)alkynyl, halo(C2-C4)alkynyl, (C1-C4)alkoxy, halo(C1-C4)alkoxy, -ORe, oxo, imino, phenyl, 4- to 6-membered heterocyclyl, -S(O)ReRf, -S(O)2Rf, -S(O)=NH(C1-C4)alkyl, -S(O)NReRf, and -S(O)2NReRf, -C(O)ORe, - NRcC(O)Re, -(C1-C4alkyl)C(O)Rg, -C(O)Rg, -(C1-C4alkyl)C(O)NRcRd, -C(O)NRcRd, -NO2, and -NRaRb, wherein the (C1-C4)alkyl is optionally substituted with cyano, wherein said phenyl, said 4- to 6-membered heterocyclyl, and said phenyl for -(C1-C4)alkylphenyl are each optionally and independently substituted with, as valency permits 1 to 3 groups selected from halo, cyano, oxo, (C1-C10)alkyl, (C2-C10)alkenyl, (C2-C10)alkynyl, halo(C1-C10)alkyl, (C1- C10)alkoxy, and halo(C1-C10)alkoxy, wherein said (C1-C10)alkyl, (C2-C10)alkenyl and (C2- C10)alkynyl are each optionally substituted with, as valency permits a 5-to 10-membered monocyclic or bicyclic heteroaryl or a 4-to 10-membered monocyclic or bicyclic heterocyclyl each of said 5-to 10-membered monocyclic and bicyclic heteroaryl or a 4-to 10-membered monocyclic or bicyclic heterocyclyl being optionally substituted with oxo or a 5- to 7- membered heterocyclyl that is optionally substituted with 1 to 2 oxo.

4. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein X is selected from S, SO2, -S(=O)=NH, -NR8; R7is selected from (C1-C4)alkyl, phenyl, 4- to 9-membered monocyclic or bicyclic heterocyclyl, and 5- to 10-membered monocyclic or bicyclic heteroaryl, wherein said (C1- C4)alkyl is optionally substituted with, as valency permits, 1 to 3 groups selected from RYand said phenyl, 4- to 9-membered monocyclic or bicyclic heterocyclyl, and 5- to 10-membered monocyclic or bicyclic heteroaryl are each optionally substituted with, as valency permits, R11and / or 1 to 3 groups selected from RZ; or R6and R7together with the nitrogen atom to which they are attached form a 4- to 14- membered monocyclic or bicyclic heterocyclyl or a 5- to 12-membered monocyclic or bicyclic heteroaryl, each of which being optionally substituted with, as valency permits, 1 to 3 groups selected from RQ; and RZis selected from halo, cyano, (C1-C4)alkyl, (C3-C6cycloalkyl), halo(C1-C4)alkyl, - (C1-C4)alkyl(C1-C4)alkoxy, hydroxy(C1-C4)alkyl, -(C1-C4)alkylphenyl, -(C1- C4)alkylheteroaryl, (C2-C4)alkenyl, halo(C2-C4)alkenyl, (C2-C4)alkynyl, halo(C2-C4)alkynyl, (C1-C4)alkoxy, halo(C1-C4)alkoxy, -ORe, oxo, imino, phenyl, 4- to 6-membered heterocyclyl, -S(O)ReRf, -S(O)2Rf, -S(O)=NH(C1-C4)alkyl, -S(O)NReRf, and -S(O)2NReRf, -C(O)ORe, - NRcC(O)Re, -(C1-C4alkyl)C(O)Rg, -C(O)Rg, -(C1-C4alkyl)C(O)NRcRd, -C(O)NRcRd, -NO2, and -NRaRb, wherein the (C1-C4)alkyl is optionally substituted with cyano, wherein said phenyl, said 4- to 6-membered heterocyclyl, and said phenyl for -(C1-C4)alkylphenyl are each optionally and independently substituted with, as valency permits 1 to 3 groups selected from halo, cyano, oxo, (C1-C10)alkyl, (C2-C10)alkenyl, (C2-C10)alkynyl, halo(C1-C10)alkyl, (C1- C10)alkoxy, and halo(C1-C10)alkoxy, wherein said (C1-C10)alkyl, (C2-C10)alkenyl and (C2- C10)alkynyl are each optionally substituted with, as valency permits a 5-to 10-membered monocyclic or bicyclic heteroaryl or a 4-to 10-membered monocyclic or bicyclic heterocyclyl each of said 5-to 10-membered monocyclic and bicyclic heteroaryl or a 4-to 10-membered monocyclic or bicyclic heterocyclyl being optionally substituted with oxo or a 5- to 7- membered heterocyclyl that is optionally substituted with 1 to 2 oxo.

5. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein X is selected from S, SO2, -S(=O)=NH, -NR8; R7is selected from (C1-C4)alkyl, phenyl, 4- to 9-membered monocyclic or bicyclic heterocyclyl, and 5- to 10-membered monocyclic or bicyclic heteroaryl, wherein said (C1-C4)alkyl is optionally substituted with, as valency permits, 1 to 3 groups selected from RYand said phenyl, 4- to 9-membered monocyclic or bicyclic heterocyclyl, and 5- to 10-membered monocyclic or bicyclic heteroaryl are each optionally substituted with, as valency permits, 1 to 3 groups selected from RZ; or R6and R7together with the nitrogen atom to which they are attached form a 4- to 14- membered monocyclic or bicyclic heterocyclyl or a 5- to 12-membered monocyclic or bicyclic heteroaryl, each of which being optionally substituted with, as valency permits, R12and / or 1 to 3 groups selected from RQ; and RZis selected from halo, cyano, (C1-C4)alkyl, (C3-C6cycloalkyl), halo(C1-C4)alkyl, - (C1-C4)alkyl(C1-C4)alkoxy, hydroxy(C1-C4)alkyl, -(C1-C4)alkylphenyl, -(C1- C4)alkylheteroaryl, (C2-C4)alkenyl, halo(C2-C4)alkenyl, (C2-C4)alkynyl, halo(C2-C4)alkynyl, (C1-C4)alkoxy, halo(C1-C4)alkoxy, -ORe, oxo, imino, phenyl, 4- to 6-membered heterocyclyl, -S(O)ReRf, -S(O)2Rf, -S(O)=NH(C1-C4)alkyl, -S(O)NReRf, and -S(O)2NReRf, -C(O)ORe, - NRcC(O)Re, -(C1-C4alkyl)C(O)Rg, -C(O)Rg, -(C1-C4alkyl)C(O)NRcRd, -C(O)NRcRd, -NO2, and -NRaRb, wherein the (C1-C4)alkyl is optionally substituted with cyano, wherein said phenyl, said 4- to 6-membered heterocyclyl, and said phenyl for -(C1-C4)alkylphenyl are each optionally and independently substituted with, as valency permits 1 to 3 groups selected from halo, cyano, oxo, (C1-C10)alkyl, (C2-C10)alkenyl, (C2-C10)alkynyl, halo(C1-C10)alkyl, (C1- C10)alkoxy, and halo(C1-C10)alkoxy, wherein said (C1-C10)alkyl, (C2-C10)alkenyl and (C2- C10)alkynyl are each optionally substituted with, as valency permits a 5-to 10-membered monocyclic or bicyclic heteroaryl or a 4-to 10-membered monocyclic or bicyclic heterocyclyl each of said 5-to 10-membered monocyclic and bicyclic heteroaryl or a 4-to 10-membered monocyclic or bicyclic heterocyclyl being optionally substituted with oxo or a 5- to 7- membered heterocyclyl that is optionally substituted with 1 to 2 oxo.

6. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein X is selected from S, SO2, -S(=O)=NH, -NR8; R7is selected from (C1-C4)alkyl, phenyl, 4- to 9-membered monocyclic or bicyclic heterocyclyl, and 5- to 10-membered monocyclic or bicyclic heteroaryl, wherein said (C1- C4)alkyl is optionally substituted with, as valency permits, 1 to 3 groups selected from RYand said phenyl, 4- to 9-membered monocyclic or bicyclic heterocyclyl, and 5- to 10-membered monocyclic or bicyclic heteroaryl are each optionally substituted with, as valency permits, 1 to 3 groups selected from RZ; orR6and R7together with the nitrogen atom to which they are attached form a 4- to 14- membered monocyclic or bicyclic heterocyclyl or a 5- to 12-membered monocyclic or bicyclic heteroaryl, each of which being optionally substituted with, as valency permits, 1 to 3 groups selected from RQ; and RZis selected from halo, cyano, (C1-C4)alkyl, (C3-C6cycloalkyl), halo(C1-C4)alkyl, - (C1-C4)alkyl(C1-C4)alkoxy, hydroxy(C1-C4)alkyl, -(C1-C4)alkylphenyl, -(C1- C4)alkylheteroaryl, (C2-C4)alkenyl, halo(C2-C4)alkenyl, (C2-C4)alkynyl, halo(C2-C4)alkynyl, (C1-C4)alkoxy, halo(C1-C4)alkoxy, -ORe, oxo, imino, phenyl, 4- to 6-membered heterocyclyl, -S(O)ReRf, -S(O)2Rf, -S(O)=NH(C1-C4)alkyl, -S(O)NReRf, and -S(O)2NReRf, -C(O)ORe, - NRcC(O)Re, -(C1-C4alkyl)C(O)Rg, -C(O)Rg, -(C1-C4alkyl)C(O)NRcRd, -C(O)NRcRd, -NO2, and -NRaRb, wherein the (C1-C4)alkyl is optionally substituted with cyano, wherein said phenyl, said 4- to 6-membered heterocyclyl, and said phenyl for -(C1-C4)alkylphenyl are each optionally and independently substituted with, as valency permits 1 to 3 groups selected from halo, cyano, oxo, (C1-C10)alkyl, (C2-C10)alkenyl, (C2-C10)alkynyl, halo(C1-C10)alkyl, (C1- C10)alkoxy, and halo(C1-C10)alkoxy, wherein said (C1-C10)alkyl, (C2-C10)alkenyl and (C2- C10)alkynyl are each optionally substituted with, as valency permits a 5-to 10-membered monocyclic or bicyclic heteroaryl or a 4-to 10-membered monocyclic or bicyclic heterocyclyl each of said 5-to 10-membered monocyclic and bicyclic heteroaryl or a 4-to 10-membered monocyclic or bicyclic heterocyclyl being optionally substituted with oxo or a 5- to 7- membered heterocyclyl that is optionally substituted with 1 to 2 oxo.

7. The compound of any one of Claims 1 to 6, wherein the compound is of the structural formula II:or a pharmaceutically acceptable salt thereof.

8. The compound of any one of Claims 1 to 7, or a pharmaceutically acceptable salt thereof, wherein p is 1.

9. The compound of any one of Claims 1 to 8, or a pharmaceutically acceptable salt thereof, wherein R2is hydrogen.

10. The compound of any one of Claims 1 to 9, or a pharmaceutically acceptable salt thereof, wherein R3is hydrogen.

11. The compound of any one of Claims 1 to 10, or a pharmaceutically acceptable salt thereof, wherein R4is hydrogen.

12. The compound of any one of Claims 1 to 11, or a pharmaceutically acceptable salt thereof, wherein q is 1 and t is 1.

13. The compound of any one of Claims 1 to 12, or a pharmaceutically acceptable salt thereof, wherein q is 0 and t is 2.

14. The compound of any one of Claims 1 to 13, wherein the compound is of the structural formula III, IV, V, VI, VII, VIII, IIIa, VIa, or VIIIa:,(VIIIa); or a pharmaceutically acceptable salt thereof.

15. The compound of any one of Claims 1 to 14, wherein the compound is of the structural formula.

16. The compound of any one of Claims 1 to 15, or a pharmaceutically acceptable salt thereof, wherein R5is hydrogen.

17. The compound of any one of Claims 1 to 16, or a pharmaceutically acceptable salt thereof, wherein R1is selected from 8- to 10-membered fused bicyclic heteroaryl, aryl, and (C2-C4)alkenyl(aryl), wherein said 8- to 10-membered fused bicyclic heteroaryl, aryl, and aryl portion of (C2-C4)alkenyl(aryl) are each substituted with –CR1aR2aP(O)OR1bOR2b.

18. The compound of any one of Claims 1 to 17, or a pharmaceutically acceptable salt thereof, wherein, R1is selected from (C2-C4)alkenyl(phenyl) benzothiophenyl, indolyl, naphthalenyl, thienopyridinyl, benzothiazoyl, quinolinyl, isoquinolinyl, 4,5,6,7- tetrahydropyrrolopyridinyl, 5,6,7,8-tetrahydroimidazopyrazinyl, each of which are substituted with –CR1aR2aP(O)OR1bOR2b.

19. The compound of any one of Claims 1 to 18, or a pharmaceutically acceptable salt20. The compound of any one of Claims 1 to 19, or a pharmaceutically acceptable salt r21. The compound of any one of Claims 1 to 20, or a pharmaceutically acceptable salt thereof, wherein R1ais hydrogen and R2ais fluoro or R1ais fluoro and R2ais fluoro.

22. The compound of any one of Claims 1 to 21, or a pharmaceutically acceptable salt thereof, wherein R1aand R2aare fluoro.

23. The compound of any one of Claims 1 to 22, or a pharmaceutically acceptable salt thereof, wherein R1band R2bare each independently selected from hydrogen, (C1-C4)alkyl, - [(C1-C4)alkyl]-OC(O)-[(C1-C4)alkyl], -[(C1-C4)alkyl]-OC(O)O-[(C1-C4)alkyl], -[(C1- C4)alkyl]-SC(O)-[(C1-C4)alkyl], -[(C1-C4)alkyl]-SC(O)-[halo(C1-C4)alkyl], -[(C1-C4)alkyl]- OC(O)NR2cR2d], [(C1-C4)alkyl]-OC(O)O-[5- to 7-membered heterocyclyl], and phenyl, wherein the 5- to 7-membered heterocyclyl of [(C1-C4)alkyl]-OC(O)O-[5- to 7-membered heterocyclyl] is optionally substituted with C(O)OR2c, wherein any of the (C1-C)4alkyl groups are optionally substituted with 1 or 2 (C1-C4)alkyl.

24. The compound of any one of Claims 1 to 23, or a pharmaceutically acceptable salt thereof, wherein R1band R2bare each -[(C1-C4)alkyl]-OC(O)-[(C1-C4)alkyl].

25. The compound of any one of Claims 1 to 23, or a pharmaceutically acceptable salt thereof, wherein R1band R2bare hydrogen.

26. The compound of any one of Claims 1 to 20 and 23, or a pharmaceutically acceptable salt thereof, wherein –CR1aR2aP(O)OR1bOR2bis selected from, ,,.

27. The compound of any one of Claims 1 to 20, 21, and 26, or a pharmaceutically acceptable salt thereof, wherein –CR1aR2aP(O)OR1bOR2bis selected from, ,,28. The compound of any one of Claims 1 to 27, or a pharmaceutically acceptable salt thereof, wherein R6is selected from hydrogen and (C1-C4)alkyl.

29. The compound of any one of Claims 1 to 28, or a pharmaceutically acceptable salt thereof, wherein R7is selected from E, -R10AE, and phenyl.

30. The compound of any one of Claims 1, 4, and 7 to 28, or a pharmaceutically acceptable salt thereof, wherein R7is phenyl substituted with R11.

31. The compound of any one of Claims 1, 4, and 7 to 28, or a pharmaceutically acceptable salt thereof, wherein R11is –NHC(O)R10BE.

32. The compound of any one of Claims 1 to 31, or a pharmaceutically acceptable salt thereof, wherein R6and R7together with the nitrogen atom to which they are attached form a 4- to 6-membered monocyclic heterocyclyl optionally substituted with, as valency permits, R12and / or 1 to 3 groups selected from RQ.

33. The compound of any one of Claims 1 to 32, or a pharmaceutically acceptable salt thereof, wherein R6and R7together with the nitrogen atom to which they are attached form azetidinyl, pyrrolidyl, or piperidinyl, each optionally substituted with, as valency permits, R12and / or 1 to 3 groups selected from RQ.

34. The compound of any one of Claims 1 to 27, 32, and 33, or a pharmaceutically acceptable salt thereof, wherein RQis cyano, phenyl, or 5- to 7-membered monocyclic heteroaryl optionally substituted with, as valency permits, 1 to 3 groups selected from RF.

35. The compound of any one of Claims 1 to 27 and 32 to 34, or a pharmaceutically acceptable salt thereof, wherein RQis cyano, phenyl, or pyridinyl optionally substituted with, as valency permits, 1 to 3 groups selected from RF.

36. The compound of any one of Claims 1 to 27 and 32 to 35, or a pharmaceutically acceptable salt thereof, wherein RFis -NRaRb.

37. The compound of any one of Claims 1 to 27 and 33, or a pharmaceutically acceptable salt thereof, wherein R12is E.

38. The compound of any one of Claims 1 to 37, or a pharmaceutically acceptable salt thereof, wherein R8is –C(O)RHa.

39. The compound of any one of Claims 1 to 38, or a pharmaceutically acceptable salt thereof, wherein RHais 8- to 10-membered bicyclic heteroaryl optionally substituted with C1- C4alkyl.

40. The compound of any one of Claims 1 to 39, or a pharmaceutically acceptable salt thereof, wherein RHais indazolyl or benzoisoxazolyl, each optionally substituted with C1- C4alkyl.

41. The compound of any one of Claims 1, 2, and 7 to 37, or a pharmaceutically acceptable salt thereof, wherein R9is selected from –R10E and –C(O)R10E.

42. The compound of any one of Claims 1 to 41, wherein R10, R10A, R10B, R10C, and R10Dare each independently selected from (C1-C10)alkylene and (C2-C10)alkynelene each optionally substituted with one or more groups selected from halo and oxo, and wherein said (C1- C6)alkylene and (C2-C10)alkynelene may also be optionally interrupted by one or more heteroatoms selected from S, N, and O, and / or optionally interrupted by one or more ringsselected from 5- to 7-membered heteroaryl, (C3-C6)cycloakyl, phenyl, and 4- to 7-membered heterocyclyl.

43. The compound of any one of Claims 1 to 42, wherein R10, R10A, R10B, R10C, and R10Dare each independently selected from (C1-C10)alkylene and (C2-C10)alkynelene.

44. The compound of any one of Claims 1 to 43, wherein R10, R10A, R10B, R10C, and R10Dare each independently selected from (C1-C10)alkylene and (C2-C10)alkynelene,, CH2, and (CH2)2, (CH2)3, (CH2)4.

45. The compound of any one of Claims 1 to 44, or pharmaceutically acceptable salt thereof, wherein E is selected from a CRBN, VHL, IAP, or MDM2 based E3 binder.

46. The compound of any one of Claims 1 to 45, or pharmaceutically acceptable salt,Y and Y1are each independently is O or CH2; D is O, NH, or a bond; U is absent or C(O); and R is halo or cyano.

47. The compound of any one of Claims 1 to 46, or pharmaceutically acceptable salt thereof, wherein E is selected from,.

48. The compound of Claim 1, or pharmaceutically acceptable salt thereof, wherein the compound is selected selected from,,,,,,,,, ,,,,, ,, ,,.

49. A pharmaceutically acceptable composition comprising the compound of any one of Claims 1 to 48, or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier.

50. A method of treating a condition responsive to the modulation of STAT3 or STAT6 in a subject comprising administering to the subject a therapeutically effective amount of the compound of any one of Claims 1 to 48 or a pharmaceutically acceptable salt thereof, or the pharmaceutically acceptable composition of Claim 49.

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