ESTROGEN RECEPTOR ALPHA DEGRADERS AND METHODS OF USE THEREOF CROSS-REFERENCE TO RELATED APPLICATIONS [0001] This application claims the benefit of and priority to U.S. Provisional Application No. 63/355,861 filed June 27, 2022; U.S. Provisional Application No. 63/398,067 filed August 15, 2022; U.S. Provisional Application No.63/405,388 filed September 9, 2022; and U.S. Provisional Application No. 63/435,063 filed December 23, 2022, the contents of each of which are incorporated herein by reference in their entirety TECHNICAL FIELD OF THE INVENTION [0002] The present invention relates to compounds and methods useful for the modulation of estrogen receptor alpha (“ERα”) via ubiquitination and/or degradation by compounds according to the present invention. The invention also provides pharmaceutically acceptable compositions comprising compounds of the present invention and methods of using said compositions in the treatment of various disorders BACKGROUND OF THE INVENTION [0003] The Estrogen Receptors (ER) are members of the nuclear hormone receptor superfamily. Two classes of ER exist: estrogen receptor alpha (ERα) and estrogen receptor beta (ERȕ), encoded by the ESR1 and the ESR2 genes respectively. ERα and ERȕ are ligand-activated transcription regulators activated by the hormone estrogen (e.g. 17ȕ-estradiol). The ligand of ER, estrogen, is synthesized by the enzyme aromatase. [0004] In the absence of estrogen, ERs are largely inactive and located in the cytosol of the cell. Upon estrogen binding, ERs migrate to the nucleus, form dimers and bind to specific genomic sequences called Estrogen Response Elements (ERE). ERs further recruit co-regulators to form a multi-protein complex that regulates the transcription of multiple target genes involved in the cellular proliferation and differentiation in target tissues. [0005] Under physiological conditions, ERα expression is mainly restricted to reproductive tissues such as uterus, ovary, breast as well as bone and white adipose tissue. ERα is also expressed in more than 70% of breast cancer and is a major contributor to the pathophysiology of this cancer. Tumors harboring high levels of ERα are classified as ER-positive breast cancer The etiological role of estrogen and ERα in breast cancer is well established and modulation of the ERα signaling pathway through endocrine therapy is a cornerstone of ER+ breast cancer treatment. [0006] Currently, several strategies for inhibiting the estrogen/ ERα signaling pathway in breast cancer exist: 1- Aromatase Inhibitors (AI), that act upstream of the ERα signaling pathway by blocking estrogen production through inhibition of the aromatase enzyme and decreasing the levels of circulating estrogen; 2- Selective Estrogen Receptor Modulators (SERM) bind directly to ERα and competitively inhibit estrogen binding and thus antagonizing ERα activity; 3- Selective Estrogen Receptor Downregulators or Degradors (SERD) that both antagonize and degrade ERα. This process is mediated by induced-conformational changes and ERα protein degradation through the proteasome pathway; 4- Proteolysis-Targeting Chimeras (PROTAC) are heterobifunctional molecules that selectively recruit an E3 ubiquitin ligase to the ERα protein through induced proximity and mediate ubiquitination and proteasomal degradation of ERα. [0007] Ubiquitin-Proteasome Pathway (UPP) is a critical pathway that regulates key regulator proteins and degrades misfolded or abnormal proteins. UPP is central to multiple cellular processes, and if defective or imbalanced, it leads to pathogenesis of a variety of diseases. The covalent attachment of ubiquitin to specific protein substrates is achieved through the action of E3 ubiquitin ligases. [0008] There are over 600 E3 ubiquitin ligases which facilitate the ubiquitination of different proteins in vivo, which can be divided into four families: HECT-domain E3s, U-box E3s, monomeric RING E3s and multi-subunit E3s. See generally Li et al. (PLOS One, 2008, 3, 1487) titled “Genome-wide and functional annotation of human E3 ubiquitin ligases identifies MULAN, a mitochondrial E3 that regulates the organelle’s dynamics and signaling.”; Bemdsen et al. (Nat. Struct. Mol. Biol., 2014, 21, 301-307) titled “New insights into ubiquitin E3 ligase mechanism”; Deshaies et al. (Ann. Rev. Biochem., 2009, 78, 399-434) titled “RING domain E3 ubiquitin ligases.”; Spratt et al. (Biochem. 2014, 458, 421-437) titled “RBR E3 ubiquitin ligases: new structures, new insights, new questions.”; and Wang et al. (Nat. Rev. Cancer., 2014, 14, 233-347) titled “Roles of F-box proteins in cancer.” [0009] UPP plays a key role in the degradation of short-lived and regulatory proteins important in a variety of basic cellular processes, including regulation of the cell cycle, modulation of cell surface receptors and ion channels, and antigen presentation. The pathway has been implicated in several forms of malignancy in the pathogenesis of several genetic diseases (including cystic fibrosis, Angelman’s syndrome, and Liddle syndrome), in immune surveillance/viral pathogenesis, and in the pathology of muscle wasting. Many diseases are associated with an abnormal UPP and negatively affect cell cycle and division, the cellular response to stress and to extracellular modulators, morphogenesis of neuronal networks, modulation of cell surface receptors, ion channels, the secretory pathway, DNA repair and biogenesis of organelles. [0010] Aberrations in the process have recently been implicated in the pathogenesis of several diseases, both inherited and acquired. These diseases fall into two major groups: (a) those that result from loss of function with the resultant stabilization of certain proteins, and (b) those that result from gain of function, i.e. abnormal or accelerated degradation of the protein target. [0011] The UPP is used to induce selective protein degradation, including use of fusion proteins to artificially ubiquitinate target proteins and synthetic small-molecule probes to induce proteasome-dependent degradation. Bifunctional compounds composed of a target protein binding ligand and an E3 ubiquitin ligase ligand induce proteasome-mediated degradation of selected proteins via their recruitment to E3 ubiquitin ligase and subsequent ubiquitination. These drug- like molecules offer the possibility of temporal control over protein expression. Such compounds are capable of inducing the inactivation of a protein of interest upon addition to cells or administration to an animal or human, and could be useful as biochemical reagents and lead to a new paradigm for the treatment of diseases by removing pathogenic or oncogenic proteins (Crews C, Chemistry & Biology, 2010, l7(6):551-555; Schnnekloth JS Jr., Chembiochem, 2005, 6(l):40- 46). [0012] De-novo and acquired resistance to endocrine therapies can arise through distinct mechanisms such as ERα coregulators overexpression or post-translational modification of ERα and its coregulators upon activation of intercellular signaling pathways. All contribute to hypersensitivity of ERα to low circulating estrogen levels. Additionally genomic alterations such as point mutations in the ESR1 gene or chromosomal translocation can result in the ability to bind to DNA in the absence of ligand and confer hormone independence in ERα mutated cancer cells. Since most of the endocrine therapy resistance mechanisms identified rely on ERα-dependent mechanisms, strategies aimed at downregulating ERα (both wild-type and mutant) through targeted protein degradation may overcome resistance and provide better treatment options. [0013] An ongoing need exists in the art for effective treatments for disease, especially hyperplasias and cancers such as breast cancer However non-specific effects and the inability to target and modulate certain classes of proteins altogether, such as transcription factors, remain as obstacles to the development of effective anti-cancer agents. As such, small molecule therapeutic agents that leverage E3 ligase mediated protein degradation to target cancer-associated proteins such as estrogen receptor alpha (“ERα”) hold promise as therapeutic agents. Accordingly, there remains a need to find bifunctional compounds that are ERα degraders useful as therapeutic agents. SUMMARY OF THE INVENTION [0014] The present application relates to novel bifunctional compounds, which function to recruit ERα to E3 Ubiquitin Ligase for degradation, and methods of preparation and uses thereof. In particular, the present disclosure provides bifunctional compounds, which find utility as modulators of targeted ubiquitination of ERα, which is then degraded and/or otherwise inhibited by the bifunctional compounds as described herein. An advantage of the compounds provided herein is that a broad range of pharmacological activities is possible, consistent with the degradation/inhibition of ERα. In addition, the description provides methods of using an effective amount of the compounds as described herein for the treatment or amelioration of a disease condition, such as cancer, e.g., breast cancer. [0015] The present application further relates to targeted degradation of ERα through the use of bifunctional molecules, including bifunctional molecules that link a cereblon-binding moiety to a ligand that binds ERα. [0016] It has now been found that compounds of this invention, and pharmaceutically acceptable compositions thereof, are effective as degraders of ERα. Such compounds have the general formula I-1: or a pharmaceutically acceptable salt thereof, wherein each variable is as defined and described herein. [0017] In an embodiment, provided is a compound of formula I-3’: I-3’ or a pharmaceutically acceptable salt thereof, wherein: the -L-LBM moiety to a modifiable carbon, oxygen, nitrogen, or sulfur atom of the ERBM moiety; X ¹ is N, NH, CH, CH ₂ , CH(R ^A1 ) or C(R ^A1 ) ₂ or C(R ^A1 ) as allowed by the other substituents; X ² is N(R ^A2 ), O, CH ₂ , CH(R ^A3 ), or C(R ^A3 ) ₂ ; X ³ is N(R ^A4 ), O, CH ₂ , CH(R ^A5 ), or C(R ^A5 ) ₂ ; provided that X ¹ and X ² or X ² and X ³ are not both heteroatoms; each instance of R ¹ , R ² , R ⁴ , R ⁵ , R ⁶ , R ^A1 , R ^A2 , R ^A3 R ^A4 and R ^A5 is independently R ^A or R ^B , and is substituted by 0-4 instances of R ^C ; each instance of R ³ is independently R ^A or R ^B , and is substituted by 0-4 instances of R ^C , or two R ³ groups are optionally taken together to form a 5-8 membered partially unsaturated or aryl fused ring having 0-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each instance of R ^A is independently oxo, deuterium, halogen, –CN, –NO ₂ , –OR, –SF ₅ , –SR, –NR ₂ , –S(O) ₂ R, –S(O) ₂ NR ₂ , –S(O) ₂ F, –S(O)R, –S(O)NR ₂ , –S(O)(NR)R, –S(O)(NCN)R, –S(NCN)R, –C(O)R, –C(O)OR, –C(O)NR ₂ , –C(O)N(R)OR, –OC(O)R, –OC(O)NR ₂ , –N(R)C(O)OR, –N(R)C(O)R, –N(R)C(O)NR ₂ , –N(R)C(NR)NR ₂ , –N(R)S(O) ₂ NR ₂ , –N(R)S(O) ₂ R, –P(O)R ₂ , –P(O)(R)OR, or –B(OR) _2; each instance of R ^B is independently a C _1-6 aliphatic chain; phenyl; naphthyl; cubanyl; adamantyl; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 5-12 membered saturated or partially unsaturated bicyclic carbocyclic ring; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each instance of R ^C is independently oxo, deuterium, halogen, –CN, –NO ₂ , –OR, –SF ₅ , –SR, –NR ₂ , –S(O) ₂ R, –S(O) ₂ NR ₂ , –S(O) ₂ F, –S(O)R, –S(O)NR ₂ , –S(O)(NR)R, –C(O)R, –C(O)OR, – C(O)NR ₂ , –C(O)N(R)OR, –OC(O)R, –OC(O)NR ₂ , –N(R)C(O)OR, –N(R)C(O)R, – N(R)C(O)NR ₂ , –N(R)C(NR)NR ₂ , –N(R)S(O) ₂ NR ₂ , –N(R)S(O) ₂ R, –P(O)R ₂ , –P(O)(R)OR, – B(OR) ₂ ,or an optionally substituted group selected from C _1-6 aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and each instance of R is independently hydrogen, or an optionally substituted group selected from C _{1- 6} aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic 6 membered monocyclic 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 form an optionally substituted 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; Ring A and Ring B are each independently phenyl; 1,1'-biphenyl; naphthyl; tetrahydronaphthalenyl; dihydroindenyl; benzocyclobutenyl; cubanyl; adamantyl; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 5-12 membered saturated or partially unsaturated bicyclic carbocyclic ring; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Ring C is a spiro-fused 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a spiro-fused 5-12 membered saturated or partially unsaturated bicyclic carbocyclic ring; a spiro-fused 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a spiro-fused 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; L is a covalent bond or a bivalent, saturated or unsaturated, straight or branched C _1-50 hydrocarbon chain, wherein 0-6 methylene units of L are independently replaced by –Cy–, –CH(R)–, –C(R) ₂ –, –O–, –NR–, –S–, –OC(O)–, –C(O)O–, –C(O)–, –S(O)–, –S(O) ₂ –, –NRS(O) ₂ –, –S(O) ₂ NR–, –

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 5-11 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 5-11 membered saturated or partially 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 6-10 membered bridged 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, or an 8-10 membered bicyclic heteroarylenyl having 1- 5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; , , m is 0, 1, 2, 3, or 4; n is 0, 1, 2, 3, or 4; p is 0, 1, 2, 3, or 4; each of q is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; r is 0, 1, 2, 3, or 4; s is 0, 1, 2, 3, or 4; and t is 0, 1, 2, 3, or 4. [0018] In an embodiment, provided is a compound of formula I-3’: or a pharmaceutically acceptable salt thereof, wherein:

the -L-LBM moiety to a modifiable carbon, oxygen, nitrogen, or sulfur atom of the ERBM moiety; X ¹ is N, NH, CH, CH ₂ , CH(R ^A1 ) or C(R ^A1 ) ₂ or C(R ^A1 ) as allowed by the other substituents; X ² is N(R ^A2 ), O, CH ₂ , CH(R ^A3 ), or C(R ^A3 ) ₂ ; X ³ is N(R ^A4 ), O, CH2, CH(R ^A5 ), or C(R ^A5 )2; provided that X ¹ and X ² or X ² and X ³ are not both heteroatoms; each instance of R ¹ , R ² , R ⁴ , R ⁵ , R ⁶ , R ^A1 , R ^A2 , R ^A3 R ^A5 and R ^A5 is independently R ^A or R ^B , and is substituted by 0-4 instances of R ^C ; each instance of R ³ is independently R ^A or R ^B , and is substituted by 0-4 instances of R ^C , or two R ³ groups are optionally taken together to form a 5-8 membered partially unsaturated or aryl fused ring having 0-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each instance of R ^A is independently oxo, deuterium, halogen, –CN, –NO2, –OR, –SF5, –SR, –NR2, –S(O)2R, –S(O)2NR2, –S(O)2F, –S(O)R, –S(O)NR2, –S(O)(NR)R, –S(O)(NCN)R, –S(NCN)R, –C(O)R, –C(O)OR, –C(O)NR ₂ , –C(O)N(R)OR, –OC(O)R, –OC(O)NR ₂ , –N(R)C(O)OR, –N(R)C(O)R, –N(R)C(O)NR ₂ , –N(R)C(NR)NR ₂ , –N(R)S(O) ₂ NR ₂ , –N(R)S(O) ₂ R, –P(O)R ₂ , –P(O)(R)OR, or –B(OR) _2; each instance of R ^B is independently a C _1-6 aliphatic chain; phenyl; naphthyl; cubanyl; adamantyl; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 5-12 membered saturated or partially unsaturated bicyclic carbocyclic ring; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each instance of R ^C is independently oxo, deuterium, halogen, –CN, –NO2, –OR, –SF5, –SR, –NR2, –S(O)2R, –S(O)2NR2, –S(O)2F, –S(O)R, –S(O)NR2, –S(O)(NR)R, –C(O)R, –C(O)OR, – C(O)NR ₂ , –C(O)N(R)OR, –OC(O)R, –OC(O)NR ₂ , –N(R)C(O)OR, –N(R)C(O)R, – N(R)C(O)NR ₂ , –N(R)C(NR)NR ₂ , –N(R)S(O) ₂ NR ₂ , –N(R)S(O) ₂ R, –P(O)R ₂ , –P(O)(R)OR, – B(OR) ₂ ,or an optionally substituted group selected from C _1-6 aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and each instance of R is independently hydrogen, or an optionally substituted group selected from C _{1- 6} aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5- 6 membered monocyclic 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 form an optionally substituted 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; Ring A and Ring B are each independently phenyl; 1,1'-biphenyl; naphthyl; tetrahydronaphthalenyl; dihydroindenyl; benzocyclobutenyl; cubanyl; adamantyl; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 5-12 membered saturated or partially unsaturated bicyclic carbocyclic ring; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Ring C is a spiro-fused 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a spiro-fused 5-12 membered saturated or partially unsaturated bicyclic carbocyclic ring; a spiro-fused 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a spiro-fused 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; L is a covalent bond or a bivalent, saturated or unsaturated, straight or branched C _1-50 hydrocarbon chain, wherein 0-6 methylene units of L are independently replaced by –Cy–, –CH(R)–, –C(R) ₂ –, –O–, –NR–, –S–, –OC(O)–, –C(O)O–, –C(O)–, –S(O)–, –S(O) ₂ –, –NRS(O) ₂ –, –S(O) ₂ NR–, – , 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 5-11 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 5-11 membered saturated or partially 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 6-10 membered bridged 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, or an 8-10 membered bicyclic heteroarylenyl having 1- 5 heteroatoms independently selected from nitrogen, oxygen, or sulfur;

n is 0 1 2 3 or 4; p is 0, 1, 2, 3, or 4; each of q is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; r is 0, 1, 2, 3, or 4; s is 0, 1, 2, 3, or 4; and t is 0, 1, 2, 3, or 4, wherein X ¹ is CH or N, X ² is CH ₂ ; Ring B is phenyl; Ring A is phenyl or a 6 membered monocyclic heteroaryl ring having 1-3 nitrogen heteroatoms; at least one R ³ is –OH or –OMe; p is 1, 2, or 3; m is 0, 1 or 2; R ¹ is selected from –F and –Cl; n is 0, 1 or 2; and R ² is selected from –OH, –Me, –OMe, –F, –Br, –CF3 and – ⁱ Pr; then LBM is not stereoisomer thereof. [0019] Compounds of the present invention, and pharmaceutically acceptable compositions thereof, are useful for treating a variety of diseases, disorders, or conditions, associated with regulation of signaling pathways implicating ERα. Such diseases, disorders, or conditions include those described herein. [0020] Compounds provided by this invention are also useful for the study of ERα enzymes in biological and pathological phenomena; the study of intracellular signal transduction pathways occurring in bodily tissues; and the comparative evaluation of new ERα inhibitors or ERα degraders or other regulators of ERα-mediated transcription in vitro or in vivo. [0021] In some embodiments, the present disclosure provides a pharmaceutical composition comprising a compound of formula I-1, I-1’, I-2, I-2’, I-3 or I-3’ or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, adjuvant, or diluent. [0022] In some embodiments, the present disclosure provides a method of treating an ERa- mediated disorder comprising administering to a patient in need thereof a compound of formula I- 1, I-1’, I-2, I-2’, I-3 or I-3’, or composition comprising said compound. [0023] In some embodiments, the present disclosure provides a process for providing a compound of formula I-1, I-1’, I-2, I-2’, I-3 or I-3’, or synthetic intermediates thereof. [0024] In some embodiments, the present disclosure provides a process for providing pharmaceutical compositions comprising compounds of formula I-1, I-1’, I-2, I-2’, I-3 or I-3’. DETAILED DESCRIPTION 1. General Description of Certain Embodiments of the Disclosure [0025] Compounds of the present disclosure, and pharmaceutical compositions thereof, are useful as degraders of ErĮ. [0026] I b di t th t di l id d f f l I 1 or a pharmaceutically acceptable salt thereof, wherein: , indicates the site of attachment of the -L-LBM moiety to a modifiable carbon, oxygen, nitrogen, or sulfur atom of the ERBM moiety; X ¹ is N, CH, or C(R ^A1 ); X ² is N(R ^A2 ), O, CH ₂ , CH(R ^A3 ), or C(R ^A3 ) ₂ ; provided that X ¹ and X ² are not both heteroatoms; each instance of R ¹ , R ² , R ^A1 , R ^A2 , and R ^A3 is independently R ^A or R ^B , and is substituted by 0-4 instances of R ^C ; each instance of R ³ is independently R ^A or R ^B , and is substituted by 0-4 instances of R ^C , or two R ³ groups are optionally taken together to form a 5-8 membered partially unsaturated or aryl fused ring having 0-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each instance of R ^A is independently oxo, deuterium, halogen, –CN, –NO ₂ , –OR, –SF ₅ , –SR, –NR2, –S(O)2R, –S(O)2NR2, –S(O)2F, –S(O)R, –S(O)NR2, –S(O)(NR)R, –S(O)(NCN)R, S(NCN)R C(O)R C(O)OR C(O)NR2 C(O)N(R)OR OC(O)R OC(O)NR2 –N(R)C(O)OR, –N(R)C(O)R, –N(R)C(O)NR2, –N(R)C(NR)NR2, –N(R)S(O)2NR2, –N(R)S(O)2R, –P(O)R2, –P(O)(R)OR, or –B(OR)2; each instance of R ^B is independently a C _1-6 aliphatic chain; phenyl; naphthyl; cubanyl; adamantyl; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 5-12 membered saturated or partially unsaturated bicyclic carbocyclic ring; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each instance of R ^C is independently oxo, deuterium, halogen, –CN, –NO ₂ , –OR, –SF ₅ , –SR, –NR ₂ , –S(O) ₂ R, –S(O) ₂ NR ₂ , –S(O) ₂ F, –S(O)R, –S(O)NR ₂ , –S(O)(NR)R, –C(O)R, –C(O)OR, – C(O)NR ₂ , –C(O)N(R)OR, –OC(O)R, –OC(O)NR ₂ , –N(R)C(O)OR, –N(R)C(O)R, – N(R)C(O)NR2, –N(R)C(NR)NR2, –N(R)S(O)2NR2, –N(R)S(O)2R, –P(O)R2, –P(O)(R)OR, – B(OR)2, or an optionally substituted group selected from C1-6 aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and each instance of R is independently hydrogen, or an optionally substituted group selected from C _{1- 6} aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5- 6 membered monocyclic 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 form an optionally substituted 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; Ring A and Ring B are each independently 1,1'-biphenyl; phenyl; naphthyl; membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 5-12 membered saturated or partially unsaturated bicyclic carbocyclic ring; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; L is a bivalent moiety that connects ERBM to LBM; LBM is a ligase binding moiety; m is 0, 1, 2, 3, or 4; n is 0, 1, 2, 3, or 4; and p is 0, 1, 2, 3, or 4. [0027] In some embodiments, the present disclosure provides a compound of formula I-2: or a pharmaceutically acceptable salt thereof, wherein: ERBM is selected from indicates the site of attachment of the - L-LBM moiety to a modifiable carbon, oxygen, nitrogen, or sulfur atom of the ERBM moiety; X ¹ is N, CH, or C(R ^A1 ); X ² is N(R ^A2 ), O, CH ₂ , CH(R ^A3 ), or C(R ^A3 ) ₂ ; provided that X ¹ and X ² are not both heteroatoms; each instance of R ¹ , R ² , R ⁴ , R ⁵ , R ^A1 , R ^A2 , and R ^A3 is independently R ^A or R ^B , and is substituted by 0-4 instances of R ^C ; each instance of R ³ is independently R ^A or R ^B , and is substituted by 0-4 instances of R ^C , or two R ³ groups are optionally taken together to form a 5-8 membered partially unsaturated or aryl fused ring having 0-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each instance of R ^A is independently oxo, deuterium, halogen, –CN, –NO2, –OR, –SF5, –SR, –NR ₂ , –S(O) ₂ R, –S(O) ₂ NR ₂ , –S(O) ₂ F, –S(O)R, –S(O)NR ₂ , –S(O)(NR)R, –S(O)(NCN)R, –S(NCN)R, –C(O)R, –C(O)OR, –C(O)NR ₂ , –C(O)N(R)OR, –OC(O)R, –OC(O)NR ₂ , –N(R)C(O)OR, –N(R)C(O)R, –N(R)C(O)NR ₂ , –N(R)C(NR)NR ₂ , –N(R)S(O) ₂ NR ₂ , –N(R)S(O) ₂ R, –P(O)R ₂ , –P(O)(R)OR, or –B(OR) _2; each instance of R ^B is independently a C _1-6 aliphatic chain; phenyl; naphthyl; cubanyl; adamantyl; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 5-12 membered saturated or partially unsaturated bicyclic carbocyclic ring; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each instance of R ^C is independently oxo, deuterium, halogen, –CN, –NO2, –OR, –SF5, –SR, –NR2, –S(O)2R, –S(O)2NR2, –S(O)2F, –S(O)R, –S(O)NR2, –S(O)(NR)R, –C(O)R, –C(O)OR, – C(O)NR ₂ , –C(O)N(R)OR, –OC(O)R, –OC(O)NR ₂ , –N(R)C(O)OR, –N(R)C(O)R, – N(R)C(O)NR ₂ , –N(R)C(NR)NR ₂ , –N(R)S(O) ₂ NR ₂ , –N(R)S(O) ₂ R, –P(O)R ₂ , –P(O)(R)OR, – B(OR) ₂ ,or an optionally substituted group selected from C _1-6 aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and each instance of R is independently hydrogen, or an optionally substituted group selected from C _{1- 6} aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5- 6 membered monocyclic 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 form an optionally substituted 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; Ring A and Ring B are each independently 1,1'-biphenyl; phenyl; naphthyl; tetrahydronaphthalenyl; dihydroindenyl; benzocyclobutenyl; cubanyl; adamantyl; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 5-12 membered saturated or partially unsaturated bicyclic carbocyclic ring; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; L is a bivalent moiety that connects ERBM to LBM; , , , , n is 0, 1, 2, 3, or 4; p is 0, 1, 2, 3, or 4; r is 0, 1, 2, 3, or 4; and s is 0, 1, 2, 3, or 4. [0028] In some embodiments, provided is a compound of formula I-3: or a pharmaceutically acceptable salt thereof, wherein: ERBM is selected from , indicates the site of attachment of the -L-LBM moiety to a modifiable carbon, oxygen, nitrogen, or sulfur atom of the ERBM moiety; X ¹ is N, CH, or C(R ^A1 ); X ² is N(R ^A2 ), O, CH ₂ , CH(R ^A3 ), or C(R ^A3 ) ₂ ; provided that X ¹ and X ² are not both heteroatoms; each instance of R ¹ , R ² , R ⁴ , R ⁵ , R ^A1 , R ^A2 , and R ^A3 is independently R ^A or R ^B , and is substituted by 0-4 instances of R ^C ; each instance of R ³ is independently R ^A or R ^B , and is substituted by 0-4 instances of R ^C , or two R ³ groups are optionally taken together to form a 5-8 membered partially unsaturated or aryl fused ring having 0-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each instance of R ^A is independently oxo, deuterium, halogen, –CN, –NO ₂ , –OR, –SF ₅ , –SR, –NR ₂ , –S(O) ₂ R, –S(O) ₂ NR ₂ , –S(O) ₂ F, –S(O)R, –S(O)NR ₂ , –S(O)(NR)R, –S(O)(NCN)R, –N(R)C(O)OR, –N(R)C(O)R, –N(R)C(O)NR2, –N(R)C(NR)NR2, –N(R)S(O)2NR2, –N(R)S(O)2R, –P(O)R2, –P(O)(R)OR, or –B(OR)2; each instance of R ^B is independently a C _1-6 aliphatic chain; phenyl; naphthyl; cubanyl; adamantyl; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 5-12 membered saturated or partially unsaturated bicyclic carbocyclic ring; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each instance of R ^C is independently oxo, deuterium, halogen, –CN, –NO ₂ , –OR, –SF ₅ , –SR, –NR ₂ , –S(O) ₂ R, –S(O) ₂ NR ₂ , –S(O) ₂ F, –S(O)R, –S(O)NR ₂ , –S(O)(NR)R, –C(O)R, –C(O)OR, – C(O)NR ₂ , –C(O)N(R)OR, –OC(O)R, –OC(O)NR ₂ , –N(R)C(O)OR, –N(R)C(O)R, – N(R)C(O)NR2, –N(R)C(NR)NR2, –N(R)S(O)2NR2, –N(R)S(O)2R, –P(O)R2, –P(O)(R)OR, – B(OR)2, or an optionally substituted group selected from C1-6 aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and each instance of R is independently hydrogen, or an optionally substituted group selected from C _{1- 6} aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5- 6 membered monocyclic 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 form an optionally substituted 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; Ring A and Ring B are each independently 1,1'-biphenyl; phenyl; naphthyl; membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 5-12 membered saturated or partially unsaturated bicyclic carbocyclic ring; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; L is a covalent bond or a bivalent, saturated or unsaturated, straight or branched C _1-50 hydrocarbon chain, wherein 0-6 methylene units of L are independently replaced by –Cy–, –CH(R)–, –C(R) ₂ –, 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 5-11 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 5-11 membered saturated or partially 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 6-10 membered bridged 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, or an 8-10 membered bicyclic heteroarylenyl having 1- 5 h t t i d d tl l t d f it lf , , , , n is 0, 1, 2, 3, or 4; p is 0, 1, 2, 3, or 4; each of q is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; r is 0, 1, 2, 3, or 4; and s is 0, 1, 2, 3, or 4. [0029] In an embodiment, provided is a compound of formula I-3’: or a pharmaceutically acceptable salt thereof, wherein: -L-LBM moiety to a modifiable carbon, oxygen, nitrogen, or sulfur atom of the ERBM moiety; X ¹ is N, NH, CH, CH ₂ , CH(R ^A1 ) or C(R ^A1 ) ₂ or C(R ^A1 ) as allowed by the other substituents; X ² is N(R ^A2 ), O, CH ₂ , CH(R ^A3 ), or C(R ^A3 ) ₂ ; X ³ is N(R ^A4 ), O, CH2, CH(R ^A5 ), or C(R ^A5 )2; provided that X ¹ and X ² or X ² and X ³ are not both heteroatoms; each instance of R ¹ , R ² , R ⁴ , R ⁵ , R ⁶ , R ^A1 , R ^A2 , R ^A3 , R ^A4 , and R ^A5 is independently R ^A or R ^B , and is substituted by 0-4 instances of R ^C ; each instance of R ³ is independently R ^A or R ^B , and is substituted by 0-4 instances of R ^C , or two R ³ groups are optionally taken together to form a 5-8 membered partially unsaturated or aryl fused ring having 0-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each instance of R ^A is independently oxo, deuterium, halogen, –CN, –NO ₂ , –OR, –SF ₅ , –SR, –NR ₂ , –S(O) ₂ R, –S(O) ₂ NR ₂ , –S(O) ₂ F, –S(O)R, –S(O)NR ₂ , –S(O)(NR)R, –S(O)(NCN)R, –S(NCN)R, –C(O)R, –C(O)OR, –C(O)NR ₂ , –C(O)N(R)OR, –OC(O)R, –OC(O)NR ₂ , –N(R)C(O)OR, –N(R)C(O)R, –N(R)C(O)NR ₂ , –N(R)C(NR)NR ₂ , –N(R)S(O) ₂ NR ₂ , –N(R)S(O) ₂ R, –P(O)R ₂ , –P(O)(R)OR, or –B(OR) _2; each instance of R ^B is independently a C _1-6 aliphatic chain; phenyl; naphthyl; cubanyl; adamantyl; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 5-12 membered saturated or partially unsaturated bicyclic carbocyclic ring; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each instance of R ^C is independently oxo, deuterium, halogen, –CN, –NO ₂ , –OR, –SF ₅ , –SR, –NR ₂ , –S(O) ₂ R, –S(O) ₂ NR ₂ , –S(O) ₂ F, –S(O)R, –S(O)NR ₂ , –S(O)(NR)R, –C(O)R, –C(O)OR, –C(O)NR2, –C(O)N(R)OR, –OC(O)R, –OC(O)NR2, –N(R)C(O)OR, –N(R)C(O)R, –N(R)C(O)NR ₂ , –N(R)C(NR)NR ₂ , –N(R)S(O) ₂ NR ₂ , –N(R)S(O) ₂ R, –P(O)R ₂ , – P(O)(R)OR, –B(OR) ₂ , or an optionally substituted group selected from C _1-6 aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and each instance of R is independently hydrogen, or an optionally substituted group selected from C _{1- 6} aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5- 6 membered monocyclic 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 form an optionally substituted 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; Ring A and Ring B are each independently 1,1'-biphenyl; phenyl; naphthyl; tetrahydronaphthalenyl; dihydroindenyl; benzocyclobutenyl; cubanyl; adamantyl; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 5-12 membered saturated or partially unsaturated bicyclic carbocyclic ring; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Ring C is a spiro-fused 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a spiro-fused 5-12 membered saturated or partially unsaturated bicyclic carbocyclic ring; a spiro-fused 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a spiro-fused 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; L is a covalent bond or a bivalent, saturated or unsaturated, straight or branched C _1-50 hydrocarbon chain, wherein 0-6 methylene units of L are independently replaced by –Cy–, –CH(R)–, –C(R) ₂ –, –O–, –NR–, –S–, –OC(O)–, –C(O)O–, –C(O)–, –S(O)–, –S(O) ₂ –, –NRS(O) ₂ –, –S(O) ₂ NR–, –

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 5-11 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 5-11 membered saturated or partially 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 6-10 membered bridged 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, or an 8-10 membered bicyclic heteroarylenyl having 1- 5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; , , ; m is 0, 1, 2, 3, or 4; n is 0, 1, 2, 3, or 4; p is 0, 1, 2, 3, or 4; each of q is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; r is 0, 1, 2, 3, or 4; s is 0, 1, 2, 3, or 4; and t is 0, 1, 2, 3, or 4. 2. Compounds and Definitions [0030] Compounds of the present disclosure include those described generally herein, and are further illustrated by the classes, subclasses, and species disclosed herein. As used herein, the following definitions shall apply unless otherwise indicated. For purposes of this disclosure, the chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75 ^th Ed. Additionally, general principles of organic chemistry are described in “Organic Chemistry”, Thomas Sorrell, University Science Books, Sausalito: 1999, and “March’s Advanced Organic Chemistry”, 5 ^th Ed., Ed.: Smith, M.B. and March, J., John Wiley & Sons, New York: 2001, the entire contents of which are hereby incorporated by reference. [0031] The term “aliphatic” or “aliphatic group”, as used herein, means a straight-chain (i.e., unbranched) or branched, substituted or unsubstituted hydrocarbon chain that is completely saturated or that contains one or more units of unsaturation, or a monocyclic hydrocarbon or bicyclic hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic (also referred to herein as “carbocycle” or “cycloaliphatic”), that has a single point of attachment to the rest of the molecule. Unless otherwise specified, aliphatic groups contain 1-6 aliphatic carbon atoms. In some embodiments, aliphatic groups contain 1-5 aliphatic carbon atoms. In other embodiments, aliphatic groups contain 1-4 aliphatic carbon atoms. In still other embodiments, aliphatic groups contain 1-3 aliphatic carbon atoms, and in yet other embodiments, aliphatic groups contain 1-2 aliphatic carbon atoms. In some embodiments, “cycloaliphatic” (or “carbocycle”) refers to a monocyclic C ₃ -C ₆ hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic, that has a single point of attachment to the rest of the molecule. Suitable aliphatic groups include, but are not limited to, linear or branched, substituted or unsubstituted alkyl, alkenyl, alkynyl groups and hybrids thereof such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl or (cycloalkyl)alkenyl. [0032] The terms “carbocyclyl” or “carbocyclic group”, unless otherwise defined, refer to a saturated or partially unsaturated, but not aromatic, 3-10 membered monocyclic or 5-14 membered polycyclic ring system, including bridged, spiro or fused rings, and whose ring system includes exclusively carbon atoms. [0033] The term “alkyl”, unless otherwise indicated, as used herein, refers to a monovalent aliphatic hydrocarbon radical having a straight chain, branched chain, monocyclic moiety, or polycyclic moiety or combinations thereof, wherein the radical is optionally substituted at one or more carbons of the straight chain, branched chain, monocyclic moiety, or polycyclic moiety or combinations thereof with one or more substituents at each carbon, wherein the one or more substituents are independently C ₁ -C ₁₀ alkyl. Examples of “alkyl” groups include methyl, ethyl, propyl, isopropyl, butyl, iso-butyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, norbornyl, and the like. [0034] The term “lower alkyl” refers to a C1-4 straight or branched alkyl group. Exemplary lower alkyl groups are methyl ethyl propyl isopropyl butyl isobutyl and tert-butyl [0035] The term “lower haloalkyl” refers to a C1-4 straight or branched alkyl group that is substituted with one or more halogen atoms. [0036] The term “heteroatom” means one or more of oxygen, sulfur, nitrogen, phosphorus, or silicon (including, any oxidized form of nitrogen, sulfur, phosphorus, or silicon; the quaternized form of any basic nitrogen or; a substitutable nitrogen of a heterocyclic ring, for example N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl) or NR ⁺ (as in N-substituted pyrrolidinyl)). [0037] The term “unsaturated,” as used herein, means that a moiety has one or more units of unsaturation. [0038] As used herein, the term “C _1-8 (or C _1-6 , or C _1-4 ) bivalent saturated or unsaturated, straight or branched, hydrocarbon chain”, refers to bivalent alkylene, alkenylene, and alkynylene chains that are straight or branched as defined herein. [0039] The term “alkylene” refers to a bivalent alkyl group. An “alkylene chain” is a polymethylene group, i.e., –(CH ₂ ) _n –, wherein n is a positive integer, preferably from 1 to 6, from 1 to 4, from 1 to 3, from 1 to 2, or from 2 to 3. A substituted alkylene chain is a polymethylene group in which one or more methylene hydrogen atoms are replaced with a substituent. Suitable substituents include those described below for a substituted aliphatic group. [0040] The term “alkenylene” refers to a bivalent alkenyl group. A substituted alkenylene chain is a polymethylene group containing at least one double bond in which one or more hydrogen atoms are replaced with a substituent. Suitable substituents include those described below for a substituted aliphatic group. [0041] The term “halogen” means F, Cl, Br, or I. [0042] The term “aryl,” used alone or as part of a larger moiety as in “aralkyl,” “aralkoxy,” or “aryloxyalkyl,” refers to monocyclic or bicyclic ring systems having a total of five to fourteen ring members, wherein at least one ring in the system is aromatic and wherein each ring in the system contains 3 to 7 ring members. The term “aryl” may be used interchangeably with the term “aryl ring.” In certain embodiments of the present disclosure, “aryl” refers to an aromatic ring system which includes, but is not limited to, phenyl, biphenyl, naphthyl, anthracyl and the like, which may bear one or more substituents. [0043] The terms “heteroaryl” or “heteroaromatic”, unless otherwise defined, as used herein refers t li ti 56 b d i t i i h t t f l one to three heteroatoms, such as nitrogen, oxygen, and sulfur, or an 8-10 membered polycyclic ring system containing one or more heteroatoms, wherein at least one ring in the polycyclic ring system is aromatic, and the point of attachment of the polycyclic ring system is through a ring atom on an aromatic ring. A heteroaryl ring may be linked to adjacent radicals though carbon or nitrogen. Examples of heteroaryl rings include but are not limited to furan, thiophene, pyrrole, thiazole, oxazole, isothiazole, isoxazole, imidazole, pyrazole, triazole, pyridine, pyrimidine, indole, etc. For example, unless otherwise defined, 1,2,3,4-tetrahydroquinoline is a heteroaryl ring if its point of attachment is through the benzo ring, e.g.: . [0044] The terms “heterocyclyl” or “heterocyclic group”, unless otherwise defined, refer to a saturated or partially unsaturated 3-10 membered monocyclic or 7-14 membered polycyclic ring system, including bridged or fused rings, and whose ring system includes one to four heteroatoms, such as nitrogen, oxygen, and sulfur. A heterocyclyl ring may be linked to adjacent radicals through carbon or nitrogen. [0045] The term “partially unsaturated” in the context of rings, unless otherwise defined, refers to a monocyclic ring, or a component ring within a polycyclic (e.g. bicyclic, tricyclic, etc.) ring system, wherein the component ring contains at least one degree of unsaturation in addition to those provided by the ring itself, but is not aromatic. Examples of partially unsaturated rings include, but are not limited to, 3,4-dihydro-2H-pyran, 3-pyrroline, 2-thiazoline, etc. Where a partially unsaturated ring is part of a polycyclic ring system, the other component rings in the polycyclic ring system may be saturated, partially unsaturated, or aromatic, but the point of attachment of the polycyclic ring system is on a partially unsaturated component ring. For example, unless otherwise defined, 1,2,3,4-tetrahydroquinoline is a partially unsaturated ring if its point of attachment is through the piperidino ring, e.g.: . [0046] The term “saturated” in the context of rings, unless otherwise defined, refers to a 3-10 b d li i 7 14 b d l li ( bi li t i li t ) i system, wherein the monocyclic ring or the component ring that is the point of attachment for the polycyclic ring system contains no additional degrees of unsaturation in addition to that provided by the ring itself. Examples of monocyclic saturated rings include, but are not limited to, azetidine, oxetane, cyclohexane, etc. Where a saturated ring is part of a polycyclic ring system, the other component rings in the polycyclic ring system may be saturated, partially unsaturated, or aromatic, but the point of attachment of the polycyclic ring system is on a saturated component ring. For example, unless otherwise defined, 2-azaspiro[3.4]oct-6-ene is a saturated ring if its point of attachment is through the azetidino ring, e.g.: . [0047] The terms “alkylene”, “arylene”, “cycloalkylene”, “heteroarylene”, “heterocycloalkylene”, and the other similar terms with the suffix “-ylene” as used herein refers to a divalently bonded version of the group that the suffix modifies. For example, “alkylene” is a divalent alkyl group connecting the groups to which it is attached. [0048] As used herein, the term “bridged bicyclic” refers to any bicyclic ring system, i.e. carbocyclic or heterocyclic, saturated or partially unsaturated, having at least one bridge. As defined by IUPAC, a “bridge” is an unbranched chain of atoms or an atom or a valence bond connecting two bridgeheads, where a “bridgehead” is any skeletal atom of the ring system which is bonded to three or more skeletal atoms (excluding hydrogen). In some embodiments, a bridged bicyclic group has 7-12 ring members and 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Such bridged bicyclic groups are well known in the art and include those groups set forth below where each group is attached to the rest of the molecule at any substitutable carbon or nitrogen atom. Unless otherwise specified, a bridged bicyclic group is optionally substituted with one or more substituents as set forth for aliphatic groups. Additionally or alternatively, any substitutable nitrogen of a bridged bicyclic group is optionally substituted. Exemplary bridged bicyclics include:

[0049] The suffix ^ylenyl,^ as used herein, refers to a bi-valent radical (i.e., a radical with two attachment points) of the moiety to which ^ylenyl^ is appended. For example, the term ^heterocyclylenyl,^ as used herein, refers to a heterocycle with two points of attachment to the rest of the molecule. One or both points of attachment could be through carbon atoms or heteroatoms. In another example, the term ^phenylenyl,^ as used herein, refers to a divalent form of an optionally substituted phenyl group by itself or in part of another group, and the term ^cycloalkylenyl,^ as used herein, refers to a divalent form of an optionally substituted cycloalkyl group by itself or part of another group. [0050] As described herein, compounds of the disclosure may contain “optionally substituted” moieties. In general, the term “substituted,” whether preceded by the term “optionally” or not, means that one or more hydrogens of the designated moiety are replaced with a suitable substituent. Unless otherwise indicated, an “optionally substituted” group may have a suitable substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at every position. Combinations of substituents envisioned by this disclosure are preferably those that result in the formation of stable or chemically feasible compounds. The term “stable,” as used herein, refers to compounds that are not substantially altered when subjected to conditions to allow for their production, detection, and, in certain embodiments, their recovery, purification, and use for one or more of the purposes disclosed herein. [0051] Suitable monovalent substituents on a substitutable carbon atom of an “optionally substituted” group are independently halogen; –(CH2)0–4Rq; –(CH2)0–4ORq; –O(CH2)0-4R ^o , –O– (CH ₂ ) _0–4 C(O)OR°; –(CH ₂ ) _0–4 CH(ORq) ₂ ; –(CH ₂ ) _0–4 SRq; –(CH ₂ ) _0–4 Ph, which may be substituted with R°; –(CH ₂ ) _0–4 O(CH ₂ ) _0–1 Ph which may be substituted with R°; –CH=CHPh, which may be substituted with R°; –(CH ₂ ) _0–4 O(CH ₂ ) _0–1 -pyridyl which may be substituted with R°; –NO ₂ ; –CN; –N ₃ ; -(CH ₂ ) _0–4 N(Rq) ₂ ; –(CH ₂ ) _0–4 N(Rq)C(O)Rq; –N(Rq)C(S)Rq; –(CH ₂ ) _0–4 N(Rq)C(O)NRq ₂ ; –N(Rq)C(S)NRq ₂ ; –(CH ₂ ) _0–4 N(Rq)C(O)ORq; –N(Rq)N(Rq)C(O)Rq; –N(Rq)N(Rq)C(O)NRq ₂ ; –N(Rq)N(Rq)C(O)ORq; –(CH ₂ ) _0–4 C(O)Rq; –C(S)Rq; –(CH ₂ ) _0–4 C(O)ORq; –(CH ₂ ) _0–4 C(O)SRq; -(CH ₂ ) _0–4 C(O)OSiRq ₃ ; –(CH ₂ ) _0–4 OC(O)Rq; – OC(O)(CH ₂ ) _0–4 SR°; –SC(S)SR°; –(CH ₂ ) _0–4 SC(O)Rq; –(CH ₂ ) _0–4 C(O)NRq ₂ ; –C(S)NRq ₂ ; –(C _1–4 straight or branched alkylene)O–N(Rq) ₂ ; or –(C _1–4 straight or branched alkylene)C(O)O– N(Rq) ₂ , wherein each Rq may be substituted as defined below and is independently hydrogen, C _{1– 6} aliphatic, –CH ₂ Ph, –O(CH ₂ ) _0–1 Ph, –CH ₂ -(5-6 membered heteroaryl ring), or a 5–6–membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the definition above, two independent occurrences of Rq, taken together with their intervening atom(s), form a 3–12–membered saturated, partially unsaturated, or aryl mono– or bicyclic ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, which may be substituted as defined below. [0052] Suitable monovalent substituents on Rq (or the ring formed by taking two independent occurrences of Rq together with their intervening atoms), are independently halogen, –(CH ₂ ) _0–2 R ^z , –(haloR ^z ), –(CH ₂ ) _0–2 OH, –(CH ₂ ) _0–2 OR ^z , –(CH ₂ ) _0–2 CH(OR ^z ) ₂ ; -O(haloR ^z ), –CN, –N ₃ , –(CH ₂ ) _0–2 C(O)R ^z , –(CH ₂ ) _0–2 C(O)OH, –(CH ₂ ) _0–2 C(O)OR ^z , –(CH ₂ ) _0–2 SR ^z , -C(O)SR ^z , –(C1–4 straight or branched alkylene)C(O)OR ^z , or –SSR ^z wherein each R ^z is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently selected from C _1–4 aliphatic, –CH ₂ Ph, –O(CH ₂ ) _0–1 Ph, or a 5–6–membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents on a saturated carbon atom of Rq include =O and [0053] Suitable divalent substituents on a saturated carbon atom of an “optionally substituted” group include the following: =O, =S, =NNR ^* ₂ , =NNHC(O)R ^* , =NNHC(O)OR ^* , =NNHS(O) ₂ R ^* , =NR ^* , wherei ^* n each independent occurrence of R is selected from hydrogen, C _1–6 aliphatic which may be substituted as defined below, or an unsubstituted 5–6–membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents that are bound to vicinal substitutable carbons of an “optionally substituted” group include: –O(CR ^* 2)2– ₃ O–, wherein each independent occurrence of R ^* is selected from hydrogen, C _1–6 aliphatic which may be substituted as defined below, or an unsubstituted 5–6–membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. [0054] Suitable substituents on the aliphatic group of R ^* include halogen, –R ^z , -(haloR ^z ), –OH, –OR ^z , –O(haloR ^z ), –CN, –C(O)OH, –C(O)OR ^z , –NH2, –NHR ^z , –NR ^z ₂ , or –NO ₂ , wherein each R ^z is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently C _1–4 aliphatic, –CH ₂ Ph, –O(CH ₂ ) _0–1 Ph, or a 5–6– membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. [0055] Suitable substituents on a substitutable nitrogen of an “optionally substituted” group include –R ^† , –NR ^† 2, –C(O)R ^† , –C(O)OR ^† , –C(O)C(O)R ^† , –C(O)CH2C(O)R ^† , –S(O)2R ^† , -S(O)2NR ^† 2, –C(S)NR ^† 2, –C(NH)NR ^† 2, or –N(R ^† )S(O)2R ^† ; wherein each R ^† is independently hydrogen, C _1–6 aliphatic which may be substituted as defined below, unsubstituted –OPh, or an unsubstituted 5–6–membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the definition above, two independent occurrences of R ^† , taken together with their intervening atom(s) form an unsubstituted 3–12–membered saturated, partially unsaturated, or aryl mono– or bicyclic ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. [0056] Suitable substituents on the aliphatic group of R ^† are independently halogen, –R ^z , -(haloR ^z ), –OH, –OR ^z , –O(haloR ^z ), –CN, –C(O)OH, –C(O)OR ^z , –NH ₂ , –NHR ^z , –NR ^z ₂ , or –NO ₂ , wherein each R ^z is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently C _1–4 aliphatic, –CH ₂ Ph, –O(CH ₂ ) _0–1 Ph, or a 5–6– membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. [0057] The term “isomer” as used herein refers to a compound having the identical chemical formula but different structural or optical configurations. The term “stereoisomer” as used herein refers to and includes isomeric molecules that have the same molecular formula but differ in positioning of atoms and/or functional groups in the space. All stereoisomers of the present compounds (e.g., those which may exist due to asymmetric carbons on various substituents), including enantiomeric forms and diastereomeric forms, are contemplated within the scope of this disclosure. Therefore, unless otherwise stated, single stereochemical isomers as well as mixtures of enantiomeric, diastereomeric, and geometric (or conformational) isomers of the present compounds are within the scope of the disclosure. [0058] The term “tautomer” as used herein refers to one of two or more structural isomers which exist in equilibrium and which are readily converted from one isomeric form to another. It is understood that tautomers encompass valence tautomers and proton tautomers (also known as prototropic tautomers). Valence tautomers include interconversions by reorganization of some of the bonding electrons. Proton tautomers include interconversions via migration of a proton, such as keto-enol and imine-enamine isomerizations. Unless otherwise stated, all tautomers of the compounds of the disclosure are within the scope of the disclosure. [0059] The term “isotopic substitution” as used herein refers to the substitution of an atom with its isotope. The term “isotope” as used herein refers to an atom having the same atomic number as that of atoms dominant in nature but having a mass number (neutron number) different from the mass number of the atoms dominant in nature. It is understood that a compound with an isotopic substitution refers to a compound in which at least one atom contained therein is substituted with its isotope. Atoms that can be substituted with its isotope include, but are not limited to hydrogen carbon and oxygen Examples of the isotope of a hydrogen atom include ² H (also represented as D) and ³ H. Examples of the isotope of a carbon atom include ¹³ C and ¹⁴ C. Examples of the isotope of an oxygen atom include ¹⁸ O. Unless otherwise stated, all isotopic substitution of the compounds of the disclosure are within the scope of the disclosure. Such compounds are useful, for example, as analytical tools, as probes in biological assays, or as therapeutic agents in accordance with the present disclosure. In certain embodiments, for example, a warhead moiety, R ^W , of a provided compound comprises one or more deuterium atoms. [0060] As used herein, the term “pharmaceutically acceptable salt” refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio. Exemplary pharmaceutically acceptable salts are found, e.g., in Berge, et al. (J. Pharm. Sci. 1977, 66(1), 1; and Gould, P.L., Int. J. Pharmaceutics 1986, 33, 201-217; (each hereby incorporated by reference in its entirety). [0061] Pharmaceutically acceptable salts of the compounds of this disclosure include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2–hydroxy–ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2–naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3–phenylpropionate, phosphate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p–toluenesulfonate, undecanoate, valerate salts, and the like. [0062] Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N ⁺ (C _1–4 alkyl) ₄ salts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, loweralkyl sulfonate and aryl sulfonate. [0063] Pharmaceutically acceptable salts are also intended to encompass hemi-salts, wherein the ratio of compound:acid is respectively 2:1. Exemplary hemi-salts are those salts derived from acids comprising two carboxylic acid groups, such as malic acid, fumaric acid, maleic acid, succinic acid, tartaric acid, glutaric acid, oxalic acid, adipic acid and citric acid. Other exemplary hemi-salts are those salts derived from diprotic mineral acids such as sulfuric acid. Exemplary preferred hemi-salts include, but are not limited to, hemimaleate, hemifumarate, and hemisuccinate. [0064] As used herein the term “about” is used herein to mean approximately, roughly, around, or in the region of. When the term “about” is used in conjunction with a numerical range, it modifies that range by extending the boundaries above and below the numerical values set forth. In general, the term “about” is used herein to modify a numerical value above and below the stated value by a variance of 20 percent up or down (higher or lower). [0065] An “effective amount”, “sufficient amount” or “therapeutically effective amount” as used herein is an amount of a compound that is sufficient to effect beneficial or desired results, including clinical results. As such, the effective amount may be sufficient, e.g., to reduce or ameliorate the severity and/or duration of afflictions related to ERα signaling, or one or more symptoms thereof, prevent the advancement of conditions or symptoms related to afflictions related to ERα signaling, or enhance or otherwise improve the prophylactic or therapeutic effect(s) of another therapy. An effective amount also includes the amount of the compound that avoids or substantially attenuates undesirable side effects. [0066] As used herein and as well understood in the art, “treatment” is an approach for obtaining beneficial or desired results, including clinical results. Beneficial or desired clinical results may include, but are not limited to, alleviation or amelioration of one or more symptoms or conditions, diminution of extent of disease or affliction, a stabilized (i.e., not worsening) state of disease or affliction, preventing spread of disease or affliction, delay or slowing of disease or affliction progression, amelioration or palliation of the disease or affliction state and remission (whether partial or total), whether detectable or undetectable. “Treatment” can also mean prolonging survival as compared to expected survival if not receiving treatment. In some embodiments, treatment may be administered after one or more symptoms have developed In other embodiments, 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 genetic or other susceptibility factors). Treatment may also be continued after symptoms have resolved, for example to prevent or delay their recurrence. [0067] The phrase “in need thereof” refers to the need for symptomatic or asymptomatic relief from conditions related to ERα singaling or that may otherwise be relieved by the compounds and/or compositions of the disclosure. 3. Description of Exemplary Embodiments [0068] As described above, in some embodiments, the present disclosure provides a compound of formula I-1: or a pharmaceutically acceptable salt thereof, wherein: , indicates the site of attachment of the -L-LBM moiety to a modifiable carbon, oxygen, nitrogen, or sulfur atom of the ERBM moiety; X ¹ is N, CH, or C(R ^A1 ); provided that X ¹ and X ² are not both heteroatoms; each instance of R ¹ , R ² , R ^A1 , R ^A2 , and R ^A3 is independently R ^A or R ^B , and is substituted by 0-4 instances of R ^C ; each instance of R ³ is independently R ^A or R ^B , and is substituted by 0-4 instances of R ^C , or two R ³ groups are optionally taken together to form a 5-8 membered partially unsaturated or aryl fused ring having 0-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each instance of R ^A is independently oxo, deuterium, halogen, –CN, –NO ₂ , –OR, –SF ₅ , –SR, –NR ₂ , –S(O) ₂ R, –S(O) ₂ NR ₂ , –S(O) ₂ F, –S(O)R, –S(O)NR ₂ , –S(O)(NR)R, –S(O)(NCN)R, –S(NCN)R, –C(O)R, –C(O)OR, –C(O)NR ₂ , –C(O)N(R)OR, –OC(O)R, –OC(O)NR ₂ , –N(R)C(O)OR, –N(R)C(O)R, –N(R)C(O)NR ₂ , –N(R)C(NR)NR ₂ , –N(R)S(O) ₂ NR ₂ , –N(R)S(O) ₂ R, –P(O)R ₂ , –P(O)(R)OR, or –B(OR) _2; each instance of R ^B is independently a C _1-6 aliphatic chain; phenyl; naphthyl; cubanyl; adamantyl; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 5-12 membered saturated or partially unsaturated bicyclic carbocyclic ring; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each instance of R ^C is independently oxo, deuterium, halogen, –CN, –NO ₂ , –OR, –SF ₅ , –SR, –NR ₂ , –S(O) ₂ R, –S(O) ₂ NR ₂ , –S(O) ₂ F, –S(O)R, –S(O)NR ₂ , –S(O)(NR)R, –C(O)R, –C(O)OR, – C(O)NR ₂ , –C(O)N(R)OR, –OC(O)R, –OC(O)NR ₂ , –N(R)C(O)OR, –N(R)C(O)R, – N(R)C(O)NR ₂ , –N(R)C(NR)NR ₂ , –N(R)S(O) ₂ NR ₂ , –N(R)S(O) ₂ R, –P(O)R ₂ , –P(O)(R)OR, – B(OR) ₂ , or an optionally substituted group selected from C _1-6 aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and each instance of R is independently hydrogen, or an optionally substituted group selected from C1- 6 aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5- 6 membered monocyclic 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 form an optionally substituted 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; Ring A and Ring B are each independently 1,1'-biphenyl; phenyl; naphthyl; tetrahydronaphthalenyl; dihydroindenyl; benzocyclobutenyl; cubanyl; adamantyl; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 5-12 membered saturated or partially unsaturated bicyclic carbocyclic ring; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; L is a bivalent moiety that connects ERBM to LBM; LBM is a ligase binding moiety; m is 0, 1, 2, 3, or 4; n is 0, 1, 2, 3, or 4; and p is 0, 1, 2, 3, or 4. [0069] As described above, in some embodiments, the present disclosure provides a compound of formula I-1’: I-1’ or a pharmaceutically acceptable salt thereof, wherein: the -L-LBM moiety to a modifiable carbon, oxygen, nitrogen, or sulfur atom of the ERBM moiety; X ¹ is N, NH, CH, CH ₂ , CH(R ^A1 ) or C(R ^A1 ) ₂ or C(R ^A1 ) as allowed by the other substituents; X ² is N(R ^A2 ), O, CH ₂ , CH(R ^A3 ), or C(R ^A3 ) ₂ ; X ³ is N(R ^A4 ), O, CH ₂ , CH(R ^A5 ), or C(R ^A5 ) ₂ ; provided that X ¹ and X ² or X ² and X ³ are not both heteroatoms; each instance of R ¹ , R ² , R ⁶ , R ^A1 , R ^A2 R ^A3 , R ^A4 and R ^A5 is independently R ^A or R ^B , and is substituted by 0-4 instances of R ^C ; each instance of R ³ is independently R ^A or R ^B , and is substituted by 0-4 instances of R ^C , or two R ³ groups are optionally taken together to form a 5-8 membered partially unsaturated or aryl fused ring having 0-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each instance of R ^A is independently oxo, deuterium, halogen, –CN, –NO ₂ , –OR, –SF ₅ , –SR, –NR ₂ , –S(O) ₂ R, –S(O) ₂ NR ₂ , –S(O) ₂ F, –S(O)R, –S(O)NR ₂ , –S(O)(NR)R, –S(O)(NCN)R, –S(NCN)R, –C(O)R, –C(O)OR, –C(O)NR ₂ , –C(O)N(R)OR, –OC(O)R, –OC(O)NR ₂ , –N(R)C(O)OR, –N(R)C(O)R, –N(R)C(O)NR2, –N(R)C(NR)NR2, –N(R)S(O)2NR2, –N(R)S(O)2R, –P(O)R2, –P(O)(R)OR, or –B(OR)2; each instance of R ^B is independently a C _1-6 aliphatic chain; phenyl; naphthyl; cubanyl; adamantyl; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 5-12 membered saturated or partially unsaturated bicyclic carbocyclic ring; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each instance of R ^C is independently oxo, deuterium, halogen, –CN, –NO ₂ , –OR, –SF ₅ , –SR, –NR ₂ , –S(O) ₂ R, –S(O) ₂ NR ₂ , –S(O) ₂ F, –S(O)R, –S(O)NR ₂ , –S(O)(NR)R, –C(O)R, –C(O)OR, – C(O)NR ₂ , –C(O)N(R)OR, –OC(O)R, –OC(O)NR ₂ , –N(R)C(O)OR, –N(R)C(O)R, – N(R)C(O)NR ₂ , –N(R)C(NR)NR ₂ , –N(R)S(O) ₂ NR ₂ , –N(R)S(O) ₂ R, –P(O)R ₂ , –P(O)(R)OR, – B(OR) ₂ , or an optionally substituted group selected from C _1-6 aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and each instance of R is independently hydrogen, or an optionally substituted group selected from C _{1- 6} aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5- 6 membered monocyclic 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 form an optionally substituted 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; Ring A and Ring B are each independently 1,1'-biphenyl; phenyl; naphthyl; tetrahydronaphthalenyl; dihydroindenyl; benzocyclobutenyl; cubanyl; adamantyl; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 5-12 membered saturated or partially unsaturated bicyclic carbocyclic ring; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Ring C is a spiro-fused 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a spiro-fused 5-12 membered saturated or partially unsaturated bicyclic carbocyclic ring; a spiro-fused 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a spiro-fused 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; L is a bivalent moiety that connects ERBM to LBM; LBM is a ligase binding moiety; m is 0, 1, 2, 3, or 4; n is 0, 1, 2, 3, or 4; p is 0, 1, 2, 3, or 4; and t is 0, 1, 2, 3 or 4. [0070] In some embodiments, LBM is an E3 ligase ligand. Such E3 ligase ligands are well known to one of ordinary skill in the art and include 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 2017/161119, US 2021/0177825 (LBM corresponds to the cereblon E3 Ubiquitin Ligase binding moiety CLM); WO 2017/176957, WO 2017/176958, WO 2017/180417, US 2019/0119289, US 2019/0169195, US 2019/0127387, US 2021/0002289 (LBM corresponds to B); WO 2015/160845, WO 2016/197032, WO 2019/199816, US 2015/0291562, US 2016/0058872, US 2018/0228907, US 2020/0155689, US 2020/0155690, US 2022/0089570 (LBM corresponds to ULM); WO 2016/105518, US 2018/0009779, WO 2017/007612, 2018/0134684 (LBM corresponds to Degron); WO 2013/106643, US 2014/0356322 (LBM corresponds to ULM); WO 2002/020740, US 2002/0068063 (LBM corresponds to A); WO 2016/118666, US 2016/0214972 (LBM corresponds to ULM); WO 2016/149668, US 2016/0272639 (LBM corresponds to ULM); WO 2016/169989, US 2018/0118733 (LBM corresponds to IAP binder); WO 2016/197114, US 2018/0147202 (LBM corresponds to ULM); WO 2017/011371, US 2017/0008904 (LBM corresponds to ULM); WO 2017/011590, US 2017/0037004 (LBM corresponds to ULM); WO 2017/079267, US 2017/0121321 (LBM corresponds to ULM); WO 2017/117473, US 2020/0216454 (LBM corresponds to Degron); WO 2017/117474, US 2019/0016703 (LBM corresponds to Degron); WO 2017/197036, US 2019/0076540 (LBM corresponds to Degron); WO 2017/197046, US 2019/0076542 (LBM corresponds to Degron); WO 2017/197051, US 2019/0076539 (LBM corresponds to Degron); WO 2017/197055, US 2019/0076541 (LBM corresponds to Degron); WO 2017/197056 (LBM corresponds to Degron), WO 2022/081928 (LBM corresponds to Degron); WO 2019/060742, US 2021/0238193 (LBM corresponds to UBM); WO 2019/140380, US 2021/0002296 (LBM corresponds to UBM); WO 2020/010177, US 2020/0010468 (LBM corresponds to CRBN ligand); WO 2020/010227 (LBM corresponds to UBM); and WO 2021/011634 (LBM corresponds to UBM); the entirety of each of which is herein incorporated by reference. [0071] In some embodiments, L is a bivalent moiety that connects ERBM to LBM. Such L moieties are well known to one of ordinary skill in the art and include 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 (L corresponds to the connector C); WO 2017/161119, US 2021/0177825 (L corresponds to the linker L); WO 2017/176957, WO 2017/176958, WO 2017/180417, US 2019/0119289, US 2019/0169195, US 2019/0127387, US 2021/0002289 (L corresponds to L); WO 2015/160845, WO 2016/197032, WO 2019/199816, US 2015/0291562, US 2016/0058872, US 2018/0228907, US 2020/0155689, US 2020/0155690, US 2022/0089570 (L d t th h i l li k L) WO 2016/105518 US 2018/0009779 WO 2017/007612, 2018/0134684 (L corresponds to Linker); WO 2013/106643, US 2014/0356322 (L corresponds to linker group L); WO 2016/118666, US 2016/0214972 (L corresponds to L); WO 2016/149668, US 2016/0272639 (L corresponds to Linker); WO 2016/169989, US 2018/0118733 (L corresponds to L); WO 2016/197114, US 2018/0147202 (L corresponds to L); WO 2017/011371, US 2017/0008904 (L corresponds to L); WO 2017/011590, US 2017/0037004 (L corresponds to L); WO 2017/079267, US 2017/0121321 (L corresponds to L); WO 2017/117473, US 2020/0216454 (L corresponds to Linker); WO 2017/117474, US 2019/0016703 (L corresponds to Linker); WO 2017/197036, US 2019/0076540 (L corresponds to Linker); WO 2017/197046, US 2019/0076542 (L corresponds to Linker); WO 2017/197051, US 2019/0076539 (L corresponds to Linker); WO 2017/197055, US 2019/0076541 (L corresponds to Linker); WO 2017/197056 (LBM corresponds to Degron); WO 2022/081928 (L corresponds to Linker and/or Spacer); WO 2019/060742, US 2021/0238193 (L corresponds to L); WO 2019/140380, US 2021/0002296 (L corresponds to L); WO 2020/010227 (L corresponds to L); and WO 2021/011634 (L corresponds to L); the entirety of each of which is herein incorporated by reference. [0072] In some embodiments, the present disclosure provides a compound of formula I-2: or a pharmaceutically acceptable salt thereof, wherein: ERBM selected from , indicates the site of attachment of the -L-LBM moiety to a modifiable carbon, oxygen, nitrogen, or sulfur atom of the ERBM moiety; X ¹ is N, CH, or C(R ^A1 ); X ² is N(R ^A2 ), O, CH ₂ , CH(R ^A3 ), or C(R ^A3 ) ₂ ; provided that X ¹ and X ² are not both heteroatoms; each instance of R ¹ , R ² , R ⁴ , R ⁵ , R ^A1 , R ^A2 , and R ^A3 is independently R ^A or R ^B , and is substituted by 0-4 instances of R ^C ; each instance of R ³ is independently R ^A or R ^B , and is substituted by 0-4 instances of R ^C , or two R ³ groups are optionally taken together to form a 5-8 membered partially unsaturated or aryl fused ring having 0-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each instance of R ^A is independently oxo, deuterium, halogen, –CN, –NO2, –OR, –SF5, –SR, –NR ₂ , –S(O) ₂ R, –S(O) ₂ NR ₂ , –S(O) ₂ F, –S(O)R, –S(O)NR ₂ , –S(O)(NR)R, –S(O)(NCN)R, –S(NCN)R, –C(O)R, –C(O)OR, –C(O)NR ₂ , –C(O)N(R)OR, –OC(O)R, –OC(O)NR ₂ , –N(R)C(O)OR, –N(R)C(O)R, –N(R)C(O)NR ₂ , –N(R)C(NR)NR ₂ , –N(R)S(O) ₂ NR ₂ , –N(R)S(O) ₂ R, –P(O)R ₂ , –P(O)(R)OR, or –B(OR) _2; each instance of R ^B is independently a C _1-6 aliphatic chain; phenyl; naphthyl; cubanyl; adamantyl; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 5-12 membered saturated or partially unsaturated bicyclic carbocyclic ring; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each instance of R ^C is independently oxo, deuterium, halogen, –CN, –NO2, –OR, –SF5, –SR, –NR2, –S(O)2R, –S(O)2NR2, –S(O)2F, –S(O)R, –S(O)NR2, –S(O)(NR)R, –C(O)R, –C(O)OR, – C(O)NR ₂ , –C(O)N(R)OR, –OC(O)R, –OC(O)NR ₂ , –N(R)C(O)OR, –N(R)C(O)R, – N(R)C(O)NR ₂ , –N(R)C(NR)NR ₂ , –N(R)S(O) ₂ NR ₂ , –N(R)S(O) ₂ R, –P(O)R ₂ , –P(O)(R)OR, – B(OR) ₂ ,or an optionally substituted group selected from C _1-6 aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and each instance of R is independently hydrogen, or an optionally substituted group selected from C _{1- 6} aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5- 6 membered monocyclic 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 form an optionally substituted 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; Ring A and Ring B are each independently 1,1'-biphenyl; phenyl; naphthyl; tetrahydronaphthalenyl; dihydroindenyl; benzocyclobutenyl; cubanyl; adamantyl; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 5-12 membered saturated or partially unsaturated bicyclic carbocyclic ring; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; L is a bivalent moiety that connects ERBM to LBM; , , , , m is 0, 1, 2, 3, or 4; n is 0, 1, 2, 3, or 4; p is 0, 1, 2, 3, or 4; r is 0, 1, 2, 3, or 4; and s is 0, 1, 2, 3, or 4. [0073] In some embodiments, the present disclosure provides a compound of formula I-2’: or a pharmaceutically acceptable salt thereof, wherein: -L-LBM moiety to a modifiable carbon, oxygen, nitrogen, or sulfur atom of the ERBM moiety; X ¹ is N, NH, CH, CH ₂ , CH(R ^A1 ) or C(R ^A1 ) ₂ or C(R ^A1 ) as allowed by the other substituents; X ² is N(R ^A2 ), O, CH ₂ , CH(R ^A3 ), or C(R ^A3 ) ₂ ; X ³ is N(R ^A4 ), O, CH ₂ , CH(R ^A5 ), or C(R ^A5 ) ₂ ; Provided that X ¹ and X ² or X ² and X ³ are not both heteroatoms; each instance of R ¹ , R ² , R ⁴ , R ⁵ , R ⁶ , R ^A1 , R ^A2 , R ^A3 . R ^A4 and R ^A5 is independently R ^A or R ^B , and is substituted by 0-4 instances of R ^C ; each instance of R ³ is independently R ^A or R ^B , and is substituted by 0-4 instances of R ^C , or two R ³ groups are optionally taken together to form a 5-8 membered partially unsaturated or aryl fused ring having 0-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each instance of R ^A is independently oxo, deuterium, halogen, –CN, –NO2, –OR, –SF5, –SR, –NR2, –S(O)2R, –S(O)2NR2, –S(O)2F, –S(O)R, –S(O)NR2, –S(O)(NR)R, –S(O)(NCN)R, –S(NCN)R, –C(O)R, –C(O)OR, –C(O)NR ₂ , –C(O)N(R)OR, –OC(O)R, –OC(O)NR ₂ , –N(R)C(O)OR, –N(R)C(O)R, –N(R)C(O)NR ₂ , –N(R)C(NR)NR ₂ , –N(R)S(O) ₂ NR ₂ , –N(R)S(O) ₂ R, –P(O)R ₂ , –P(O)(R)OR, or –B(OR) _2; each instance of R ^B is independently a C _1-6 aliphatic chain; phenyl; naphthyl; cubanyl; adamantyl; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 5-12 membered saturated or partially unsaturated bicyclic carbocyclic ring; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each instance of R ^C is independently oxo, deuterium, halogen, –CN, –NO2, –OR, –SF5, –SR, –NR2, –S(O)2R, –S(O)2NR2, –S(O)2F, –S(O)R, –S(O)NR2, –S(O)(NR)R, –C(O)R, –C(O)OR, – C(O)NR ₂ , –C(O)N(R)OR, –OC(O)R, –OC(O)NR ₂ , –N(R)C(O)OR, –N(R)C(O)R, – N(R)C(O)NR ₂ , –N(R)C(NR)NR ₂ , –N(R)S(O) ₂ NR ₂ , –N(R)S(O) ₂ R, –P(O)R ₂ , –P(O)(R)OR, – B(OR) ₂ ,or an optionally substituted group selected from C _1-6 aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and each instance of R is independently hydrogen, or an optionally substituted group selected from C _{1- 6} aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5- 6 membered monocyclic 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 form an optionally substituted 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; Ring A and Ring B are each independently phenyl; 1,1'-biphenyl; naphthyl; tetrahydronaphthalenyl; dihydroindenyl; benzocyclobutenyl; cubanyl; adamantyl; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 5-12 membered saturated or partially unsaturated bicyclic carbocyclic ring; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Ring C is a spiro-fused 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a spiro-fused 5-12 membered saturated or partially unsaturated bicyclic carbocyclic ring; a spiro-fused 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a spiro-fused 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; L is a bivalent moiety that connects ERBM to LBM; LBM is selected from , , , , m is 0, 1, 2, 3, or 4; n is 0, 1, 2, 3, or 4; p is 0, 1, 2, 3, or 4; r is 0, 1, 2, 3, or 4; s is 0, 1, 2, 3, or 4; and t is 0, 1, 2, 3 or 4. [0074] In some embodiments, the present disclosure provides a compound of formula I-3: or a pharmaceutically acceptable salt thereof, wherein:

, the site of attachment of the - L-LBM moiety to a modifiable carbon, oxygen, nitrogen, or sulfur atom of the ERBM moiety; X ¹ is N, CH, or C(R ^A1 ); X ² is N(R ^A2 ), O, CH ₂ , CH(R ^A3 ), or C(R ^A3 ) ₂ ; provided that X ¹ and X ² are not both heteroatoms; each instance of R ¹ , R ² , R ⁴ , R ⁵ , R ^A1 , R ^A2 , and R ^A3 is independently R ^A or R ^B , and is substituted by 0-4 instances of R ^C ; each instance of R ³ is independently R ^A or R ^B , and is substituted by 0-4 instances of R ^C , or two R ³ groups are optionally taken together to form a 5-8 membered partially unsaturated or aryl fused ring having 0-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each instance of R ^A is independently oxo, deuterium, halogen, –CN, –NO ₂ , –OR, –SF ₅ , –SR, –NR2, –S(O)2R, –S(O)2NR2, –S(O)2F, –S(O)R, –S(O)NR2, –S(O)(NR)R, –S(O)(NCN)R, –S(NCN)R, –C(O)R, –C(O)OR, –C(O)NR2, –C(O)N(R)OR, –OC(O)R, –OC(O)NR2, –N(R)C(O)OR, –N(R)C(O)R, –N(R)C(O)NR ₂ , –N(R)C(NR)NR ₂ , –N(R)S(O) ₂ NR ₂ , –N(R)S(O) ₂ R, –P(O)R ₂ , –P(O)(R)OR, or –B(OR) _2; each instance of R ^B is independently a C _1-6 aliphatic chain; phenyl; naphthyl; cubanyl; adamantyl; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 5-12 membered saturated or partially unsaturated bicyclic carbocyclic ring; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each instance of R ^C is independently oxo, deuterium, halogen, –CN, –NO2, –OR, –SF5, –SR, –NR2, –S(O)2R, –S(O)2NR2, –S(O)2F, –S(O)R, –S(O)NR2, –S(O)(NR)R, –C(O)R, –C(O)OR, – C(O)NR ₂ , –C(O)N(R)OR, –OC(O)R, –OC(O)NR ₂ , –N(R)C(O)OR, –N(R)C(O)R, – N(R)C(O)NR ₂ , –N(R)C(NR)NR ₂ , –N(R)S(O) ₂ NR ₂ , –N(R)S(O) ₂ R, –P(O)R ₂ , –P(O)(R)OR, – B(OR) ₂ or an optionally substituted group selected from C _1-6 aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and each instance of R is independently hydrogen, or an optionally substituted group selected from C1- 6 aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5- 6 membered monocyclic 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 form an optionally substituted 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; Ring A and Ring B are each independently phenyl; 1,1'-biphenyl; naphthyl; tetrahydronaphthalenyl; dihydroindenyl; benzocyclobutenyl; cubanyl; adamantyl; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 5-12 membered saturated or partially unsaturated bicyclic carbocyclic ring; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; L is a covalent bond or a bivalent, saturated or unsaturated, straight or branched C _1-50 hydrocarbon chain, wherein 0-6 methylene units of L are independently replaced by –Cy–, –CH(R)–, –C(R) ₂ –, 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 5-11 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 5-11 membered saturated or partially 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 6-10 membered bridged 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, or an 8-10 membered bicyclic heteroarylenyl having 1- 5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; , , , , m is 0, 1, 2, 3, or 4; n is 0, 1, 2, 3, or 4; p is 0, 1, 2, 3, or 4; each of q is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; r is 0, 1, 2, 3, or 4; and s is 0, 1, 2, 3, or 4. [0075] In an embodiment, provided is a compound of formula I-3’: or a pharmaceutically acceptable salt thereof, wherein: -L-LBM moiety to a modifiable carbon, oxygen, nitrogen, or sulfur atom of the ERBM moiety; X ¹ is N, NH, CH, CH ₂ , CH(R ^A1 ) or C(R ^A1 ) ₂ or C(R ^A1 ) as allowed by the other substituents; X ² is N(R ^A2 ), O, CH ₂ , CH(R ^A3 ), or C(R ^A3 ) ₂ ; X ³ is N(R ^A4 ), O, CH2, CH(R ^A5 ), or C(R ^A5 )2; provided that X ¹ and X ² or X ² and X ³ are not both heteroatoms; each instance of R ¹ , R ² , R ⁴ , R ⁵ , R ⁶ , R ^A1 , R ^A2 , R ^A3 , R ^A4 , and R ^A5 is independently R ^A or R ^B , and is substituted by 0-4 instances of R ^C ; each instance of R ³ is independently R ^A or R ^B , and is substituted by 0-4 instances of R ^C , or two R ³ groups are optionally taken together to form a 5-8 membered partially unsaturated or aryl fused ring having 0-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each instance of R ^A is independently oxo, deuterium, halogen, –CN, –NO ₂ , –OR, –SF ₅ , –SR, –NR ₂ , –S(O) ₂ R, –S(O) ₂ NR ₂ , –S(O) ₂ F, –S(O)R, –S(O)NR ₂ , –S(O)(NR)R, –S(O)(NCN)R, –S(NCN)R, –C(O)R, –C(O)OR, –C(O)NR ₂ , –C(O)N(R)OR, –OC(O)R, –OC(O)NR ₂ , –N(R)C(O)OR, –N(R)C(O)R, –N(R)C(O)NR ₂ , –N(R)C(NR)NR ₂ , –N(R)S(O) ₂ NR ₂ , –N(R)S(O) ₂ R, –P(O)R ₂ , –P(O)(R)OR, or –B(OR) ₂ ; each instance of R ^B is independently a C _1-6 aliphatic chain; phenyl; naphthyl; cubanyl; adamantyl; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 5-12 membered saturated or partially unsaturated bicyclic carbocyclic ring; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each instance of R ^C is independently oxo, deuterium, halogen, –CN, –NO ₂ , –OR, –SF ₅ , –SR, –NR ₂ , –S(O) ₂ R, –S(O) ₂ NR ₂ , –S(O) ₂ F, –S(O)R, –S(O)NR ₂ , –S(O)(NR)R, –C(O)R, –C(O)OR, – C(O)NR ₂ , –C(O)N(R)OR, –OC(O)R, –OC(O)NR ₂ , –N(R)C(O)OR, –N(R)C(O)R, – N(R)C(O)NR ₂ , –N(R)C(NR)NR ₂ , –N(R)S(O) ₂ NR ₂ , –N(R)S(O) ₂ R, –P(O)R ₂ , –P(O)(R)OR, – B(OR) ₂ , or an optionally substituted group selected from C _1-6 aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and each instance of R is independently hydrogen, or an optionally substituted group selected from C _{1- 6} aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic 6 membered monocyclic 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 form an optionally substituted 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; Ring A and Ring B are each independently phenyl; 1,1'-biphenyl; naphthyl; tetrahydronaphthalenyl; dihydroindenyl; benzocyclobutenyl; cubanyl; adamantyl; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 5-12 membered saturated or partially unsaturated bicyclic carbocyclic ring; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Ring C is a spiro-fused 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a spiro-fused 5-12 membered saturated or partially unsaturated bicyclic carbocyclic ring; a spiro-fused 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a spiro-fused 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; L is a covalent bond or a bivalent, saturated or unsaturated, straight or branched C _1-50 hydrocarbon chain, wherein 0-6 methylene units of L are independently replaced by –Cy–, –CH(R)–, –C(R) ₂ –, –O–, –NR–, –S–, –OC(O)–, –C(O)O–, –C(O)–, –S(O)–, –S(O) ₂ –, –NRS(O) ₂ –, –S(O) ₂ NR–, –

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 5-11 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 5-11 membered saturated or partially 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 6-10 membered bridged 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, or an 8-10 membered bicyclic heteroarylenyl having 1- 5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; , , m is 0, 1, 2, 3, or 4; n is 0, 1, 2, 3, or 4; p is 0, 1, 2, 3, or 4; each of q is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; r is 0, 1, 2, 3, or 4; s is 0, 1, 2, 3, or 4; and t is 0, 1, 2, 3, or 4. [0076] In some embodiments, the present disclosure provides a compound of formula I-1, I-1’, I- 2, I-2’, I-3 or I-3’ or any subgenera thereof, provided that when ERBM is wherein X ¹ is CH or N, X ² is CH ₂ ; Ring B is phenyl; Ring A is phenyl or a 6 membered monocyclic heteroaryl ring having 1-3 nitrogen heteroatoms; at least one R ³ is –OH or –OMe; p is 1, 2, or 3; m is 0, 1 or 2; R ¹ is selected from –F and –Cl; n is 0, 1 or 2; and R ² is selected from –OH, –Me, –OMe, –F, –Br, –CF ₃ and – ⁱ Pr; then LBM is not stereoisomer thereof. [0077] In some embodiments, the present disclosure provides a compound of formula I-1, I-1’, I- 2, I-2’, I-3 or I-3’ or any subgenera thereof, provided that when ERBM is wherein X ¹ is CH or N, X ² is CH ₂ ; Ring B is phenyl; Ring A is phenyl or a 6 membered monocyclic heteroaryl ring having 1-3 nitrogen heteroatoms; then R ³ is not –OH or –OMe. [0078] In some embodiments, the present disclosure provides a compound of formula I-1, I-1’, I- 2, I-2’, I-3 or I-3’ or any subgenera thereof, provided that:when ERBM is X ² is CH ₂ ; Ring B is phenyl; then Ring A is not phenyl or a 6 membered monocyclic heteroaryl ring having 1-3 nitrogen heteroatoms. [0079] In some embodiments, the present disclosure provides a compound of formula I-1, I-1’, I- 2, I-2’, I-3 or I-3’, provided that Ring A is other than phenyl or a 6 membered monocyclic heteroaryl ring having 1-3 nitrogen heteroatoms when ERBM is Ring B is phenyl. [0080] As defined generally above, ERBM is an ERα binding moiety capable of binding to ERα^^^

indicates the site of attachment of the -L-LBM moiety to a modifiable carbon, oxygen, nitrogen, or sulfur atom of the ERBM moiety and wherein X ₁ , X ₂ , X ₃ , Ring A, Ring B, Ring C, R ¹ , R ² , R ³ , R ⁶ , m, n, p and t are as defined in any of the embodiments described herein. .

. [0085] In some embodiments, ERBM is selected from the group consisting of , , , , , , , , , , , , , , , , , , , ,

some embodiments, some embodiments, ERBM is

e e

embodiments, In some embodiments, ERBM is

embodiments, ERBM . In some embodiments, ERBM is

e some embodiments, ERBM is In some e . In some embodiments, ERBM is s some embodiments, ERBM is . In some embodiments, ERBM is

e _e some embodiments, ERBM is . In some embodiments, ERBM In some embodiments, ERBM is

embodiments, . In some embodiments, ERBM is

embodiments, ERBM is . In some embodiments, ERBM is

_{embodiments, ERBM . In some embodiments, ERBM is embodiments, ERBM is} . In some embodiments, ERBM is embodiments, embodiments, ERBM is

, . ,

embodiments, . In some embodiments, ERBM is embodiments, In some embodiments, ERBM is e , ,

e . In some embodiments, E . In some embodiments, ERBM is embodiments, ERBM is . In some embodiments, ERBM is

. In some embodiments, ERBM is

e e some embodiments, ERBM is _{embodiments, ERBM is} . In some embodiments, ERBM is _{In some} e e embodiments, ERBM i . In some embodiments, ERBM is

embodiments, ERBM is . In some embodiments, ERBM is

e

embodiments, ERBM . In some embodiments, ERBM is some

embodiments, ERBM is . In some embodiments, ERBM is

embodiments, ERBM . In some embodiments, ERBM is embodiments, ERBM is . In some embodiments, ERBM is

_embodiments, . In some embodiments, ERBM is embodiments, ERBM is . In some embodiments, ERBM is

embodiments, ERBM is . In some embodiments, ERBM is

embodiments, ERBM i In some embodiments, ERBM is _{. In some} embodiments, ERBM is . In some embodiments, ERBM is . In some embodiments, ERBM is . In some embodiments, ERBM is some b di t ERBM i I b di t ERBM i

embodiments, ERBM is . In some embodiments, ERBM is

embodiments, ERBM is . In some embodiments, ERBM is . In some embodiments, ERBM is embodiments, ERBM is . In some embodiments, ERBM is

s embodiments, ERBM is . In some embodiments, ERBM is

some embodiments, . In some embodiments, ERBM is embodiments, ERBM . In some embodiments, ERBM is [0087] In some embodiments, ERBM is selected from the groups depicted in the compounds in Table 1 or Table 2. [0088] As defined generally above, X ¹ is N, NH, CH, CH ₂ , CH(R ^A1 ),C(R ^A1 ) ₂ or C(R ^A1 ) as allowed by the other substituents. In some embodiments, X ¹ is CH ₂ . [0089] In some embodiments, X ¹ is CH(R ^A1 ). [0090] In some embodiments, X ¹ is C(R ^A1 ). [0091] In some embodiments, is C(R ^A1 ) ₂ . [0092] In some embodiments, X ¹ is N, CH, or C(R ^A1 ). [0093] In some embodiments, X ¹ is N. In some embodiments, X ¹ is NH. In some embodiments, X ¹ is CH. In some embodiments, X ¹ is C(R ^A1 ). [0094] In some embodiments, X ¹ is selected from the groups depicted in the compounds in Table 1 or Table 2. [0095] As defined generally above, X ² is N(R ^A2 ), O, CH2, CH(R ^A3 ), or C(R ^A3 )2. [0096] In some embodiments, X ² is N(R ^A2 ). In some embodiments, X ² is O. In some embodiments, X ² is CH ₂ . In some embodiments, X ² is CH(R ^A3 ). In some embodiments, X ² is C(R ^A3 ) ₂ . [0097] In some embodiments, X ² is selected from the groups depicted in the compounds in Table 1 or Table 2. [0098] As generally defined herein, X ³ is N(R ^A4 ), O, CH ₂ , CH(R ^A5 ), or C(R ^A5 ) ₂ . [0099] In some embodiments, X ³ is O, CH ₂ , CH(R ^A5 ) or C(R ^A5 ) _2. [0100] In some embodiments, X ³ is O. [0101] In some embodiments, X ³ is CH _2. [0102] In some embodiments, X ³ is CH(R ^A5 ) _. [0103] In some embodiments, X ³ is C(R ^A5 ) _2. [0104] As defined generally above, each instance of R ¹ , R ² , R ⁴ , R ⁵ , R ⁶ , R ^A1 , R ^A2 , R ^A3 R ^A4 , and R ^A5 is independently R ^A or R ^B , and is substituted by 0-4 instances of R ^C . [0105] In some embodiments, R ¹ is R ^A substituted by 0-4 instances of R ^C . In some embodiments, R ¹ is R ^B substituted by 04 instances of R ^C [0106] In some embodiments, each R ¹ is independently selected from deuterium, C1-6 aliphatic chain substituted with 0-3 instances of halo, halogen, –CN, –SR, –OR, –NR2, –S(O)2R, –S(O)2NR2, –S(O)R, –S(O)NR ₂ , –S(O)(NR)R, –C(O)OR, –C(O)NR ₂ , –C(O)N(R)OR, –OC(O)NR ₂ , – N(R)C(O)OR, –N(R)C(O)R, –N(R)C(O)NR ₂ , N(R)S(O) ₂ NR ₂ and –N(R)S(O) ₂ R, wherein R is H or a C _1-6 aliphatic chain substituted with 0-3 instances of halo. [0107] In some embodiments, each R ¹ is independently selected from –Me, –Et, –F, –Cl, –SCF ₃ , –OCF3, –CF3, –CN, –OH, –OMe, –NH2, –NHMe and –NMe2. [0108] In some embodiments, R ¹ is selected from –F and –Me. [0109] In some embodiments, R ¹ is –F. In some embodiments, R ¹ is –Me. [0110] In some embodiments, R ¹ is selected from the groups depicted in the compounds in Table 1 or Table 2. [0111] In some embodiments, R ² is R ^A substituted by 0-4 instances of R ^C . In some embodiments, R ² is R ^B substituted by 0-4 instances of R ^C . [0112] In some embodiments, each R ² is independently selected from deuterium, C _1-6 aliphatic chain substituted with 0-3 instances of halo, halogen, –CN, –OR, –NR2, –S(O)2R, –S(O)2NR2, – S(O)R, –S(O)NR ₂ , –S(O)(NR)R, –C(O)OR, –C(O)NR ₂ , –C(O)N(R)OR, –OC(O)NR ₂ , – N(R)C(O)OR, –N(R)C(O)R, –N(R)C(O)NR ₂ , –N(R)S(O) ₂ NR ₂ and –N(R)S(O) ₂ R, wherein R is H or a C _1-6 aliphatic chain. [0113] In some embodiments, each R ² is independently selected from –Me, –Et, –F, –Cl, –CF ₃ , – CN, –OH, –OMe, –NH ₂ , –NHMe and –NMe ₂ . [0114] In some embodiments, each R ² is independently selected from –Me, –F and –CF ₃ . [0115] In some embodiments, R ² is fluoro. In some embodiments, R ² is methyl. In some embodiments, R ² is trifluoromethyl. [0116] In some embodiments, R ² is selected from the groups depicted in the compounds in Table 1 or Table 2. [0117] In some embodiments, R ⁴ is R ^A substituted by 0-4 instances of R ^C . In some embodiments, R ⁴ is R ^B substituted by 0-4 instances of R ^C . [0118] In some embodiments, each R ⁴ is independently selected from deuterium, C1-6 aliphatic S(O)R, –S(O)NR2, –S(O)(NR)R, –C(O)NR2, –C(O)N(R)OR, –OC(O)NR2, –N(R)C(O)OR, – N(R)C(O)R, –N(R)C(O)NR2, –N(R)S(O)2NR2 and –N(R)S(O)2R, wherein R is H or a C1-6 aliphatic chain. [0119] In some embodiments, each R ⁴ is independently selected from –Me, –Et, –F, –Cl, –CF ₃ , – CN, –OH, –OMe, –NH ₂ , –NHMe and –NMe ₂ . [0120] In some embodiments, R ⁴ is –F. [0121] In some embodiments, R ⁴ is selected from the groups depicted in the compounds in Table 1 or Table 2. [0122] In some embodiments, R ⁵ is R ^A substituted by 0-4 instances of R ^C . In some embodiments, R ⁵ is R ^B substituted by 0-4 instances of R ^C . [0123] In some embodiments, each R ⁵ is independently selected from deuterium, C _1-6 aliphatic chain substituted with 0-3 instances of halo, halogen, –CN, –OR, –NR ₂ , –S(O) ₂ R, –S(O) ₂ NR ₂ , – S(O)R, –S(O)NR ₂ , –S(O)(NR)R, –C(O)NR ₂ , –C(O)N(R)OR, –OC(O)NR ₂ , –N(R)C(O)OR, – N(R)C(O)R, –N(R)C(O)NR ₂ , –N(R)S(O) ₂ NR ₂ and –N(R)S(O) ₂ R, wherein R is H or a C _1-6 aliphatic chain. [0124] In some embodiments, each R ⁵ is independently selected from –Me, –Et, –F, –Cl, –CF ₃ , –CN, –OH, –OMe, –NH ₂ , –NHMe and –NMe ₂ . [0125] In some embodiments, each R ⁵ is independently selected from –Me and –F. [0126] In some embodiments, R ⁵ is selected from the groups depicted in the compounds in Table 1 or Table 2. [0127] In some embodiments, each R ⁶ is independently selected from –Me, –Et, –F, –Cl, –CF3, – CO2H, –CN, –OH, –OMe, –NH2, –NHMe and –NMe2 [0128] In some embodiments, each R ⁶ is independently selected from –Me, and –F. [0129] In some embodiments, R ⁶ is selected from the groups depicted in the compounds in Table 1 or Table 2. [0130] In some embodiments, R ^A1 is R ^A substituted by 0-4 instances of R ^C . In some embodiments, R ^A1 is R ^B substituted by 0-4 instances of R ^C . [0131] In some embodiments, each R ^A1 is independently selected from deuterium, C _1-6 aliphatic S(O)2NR2, –S(O)R, –S(O)NR2, –S(O)(NR)R, –C(O)NR2, –C(O)N(R)OR, –OC(O)NR2, – N(R)C(O)OR, –N(R)C(O)R, –N(R)C(O)NR2, –N(R)S(O)2NR2 and –N(R)S(O)2R, wherein R is H or a C _1-6 aliphatic chain. [0132] In some embodiments, each R ^A1 is independently selected from deuterium, a C _1-6 aliphatic chain substituted with 0-3 instances of halo or hydroxy and halogen. [0133] In some embodiments, each R ^A1 is selected from a C _1-6 aliphatic chain substituted with 0- 3 instances of halo or hydroxy and halogen. [0134] In some embodiments, each R ^A1 is a C1-6 aliphatic chain substituted with 0-3 instances of halo or hydroxy. [0135] In some embodiments, each R ^A1 is selected from –F, –Me, –Et, – ⁱ Pr, –CH=CH–C(CH ₃ ) ₃ , C(CH ₃ ) ₂ OH, –CH ₂ CH ₂ –C(CH ₃ ) ₂ OH, –CH ₂ CF ₃ , –CH ₂ -cyclopropyl, –CH(CH ₃ )-cyclopropyl, and –CH ₂ -cyclopentyl. [0136] In some embodiments, each R ^A1 is selected from –F, –Me, –Et, – ⁱ Pr, –CH=CH–C(CH ₃ ) ₃ , –CH ₂ –C(CH ₃ ) ₃ , –CH ₂ CH ₂ –C(CH ₃ ) ₃ , –C(CH ₃ ) ₃ , –CH ₂ –CH(CH ₃ ) ₂ , –CH ₂ CH ₂ –C(CH ₃ ) ₂ OH and – CH ₂ -cyclopentyl. [0137] In some embodiments, each R ^A1 is selected from –Me, –Et, – ⁱ Pr, –CH=CH–C(CH ₃ ) ₃ , – CH ₂ –C(CH ₃ ) ₃ , –CH ₂ CH ₂ –C(CH ₃ ) ₃ , –C(CH ₃ ) ₃ , –CH ₂ –CH(CH ₃ ) ₂ , –CH ₂ CH ₂ –C(CH ₃ ) ₂ OH and – CH ₂ -cyclopentyl. [0138] In some embodiments, each R ^A1 is independently selected from –Me, –Et, –F, –Cl, –CF ₃ , –CN, –OH, –OMe, –-NH2, –NHMe and –NMe2. [0139] In some embodiments, each R ^A1 is independently selected from –Me, –F, –OH and –OMe. In some embodiments, each R ^A1 is independently selected from –Me and –F. In some embodiments, each R ^A1 is independently –F. In some embodiments, each R ^A1 is independently –Me. [0140] In some embodiments, R ^A1 is selected from the groups depicted in the compounds in Table 1 or Table 2. [0141] In some embodiments, R ^A2 is R ^A substituted by 0-4 instances of R ^C . In some embodiments, R ^A2 is R ^B substituted by 0-4 instances of R ^C . [0142] In some embodiments, R ^A2 is selected from the groups depicted in the compounds in Table 1 or Table 2. [0143] In some embodiments, each R ^A2 is independently selected from deuterium, C _1-6 aliphatic chain substituted with 0-3 instances of halo, –S(O) ₂ R, –S(O) ₂ NR ₂ , –S(O)R, –S(O)NR ₂ , – S(O)(NR)R, –C(O)NR ₂ , –C(O)OR, and –C(O)R, wherein R is H or a C _1-6 aliphatic chain. [0144] In some embodiments, each R ^A2 is independently selected from –Me, –Et, –CH ₂ CF ₃ , – S(O) ₂ Me, –S(O) ₂ NMe ₂ , –S(O)Me, –S(O)NMe ₂ , –C(O)NMe ₂ , –C(O)NR ₂ , –C(O)OMe, and – C(O)Me. [0145] In some embodiments, each R ^A2 is independently selected from –Me, –CH ₂ CF ₃ , and – C(O)Me. In some embodiments, each R ^A2 is independently selected from –Me and –C(O)Me. In some embodiments, each R ^A1 is independently –C(O)Me. In some embodiments, each R ^A1 is independently –Me. [0146] In some embodiments, R ^A3 is R ^A substituted by 0-4 instances of R ^C . In some embodiments, R ^A3 is R ^B substituted by 0-4 instances of R ^C . [0147] In some embodiments, each R ^A3 is independently selected from deuterium, C _1-6 aliphatic chain substituted with 0-3 instances of halo, halogen, –CN, –OR, –NR ₂ , –S(O) ₂ R, –S(O) ₂ NR ₂ , – S(O)R, –S(O)NR ₂ , –S(O)(NR)R, –C(O)NR ₂ , –C(O)N(R)OR, –OC(O)NR ₂ , –N(R)C(O)OR, – N(R)C(O)R, –N(R)C(O)NR ₂ , –N(R)S(O) ₂ NR ₂ and –N(R)S(O) ₂ R, wherein R is H or a C _1-6 aliphatic chain. [0148] In some embodiments, each R ^A3 is independently selected from –Me, –Et, –F, –Cl, –CF ₃ , –CN, –OH, –OMe, –NH ₂ , –NHMe and –NMe ₂ . [0149] In some embodiments, each R ^A3 is independently selected from –Me, –F, –OH and –OMe. In some embodiments, each R ^A3 is independently selected from –Me and –F. In some embodiments, each R ^A3 is independently –F. In some embodiments, each R ^A3 is independently –Me. [0150] In some embodiments, R ^A3 is selected from the groups depicted in the compounds in Table 1 or Table 2. [0151] As defined generally above, R ³ is independently R ^A or R ^B , and is substituted by 0-4 instances of R ^C , or two R ³ groups are optionally taken together to form a 5-8 membered partially unsaturated or aryl fused ring having 0-2 heteroatoms independently selected from nitrogen, [0152] In some embodiments, R ³ is R ^A substituted by 0-4 instances of R ^C . In some embodiments, R ³ is R ^B substituted by 0-4 instances of R ^C . In some embodiments, two R ³ groups are taken together to form a 5-8 membered partially unsaturated or aryl fused ring having 0-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. [0153] In some embodiments, each R ³ is independently selected from deuterium, C _1-6 aliphatic chain substituted with 0-3 instances of halo, halogen, –CN, –OR, –NR ₂ , –S(O) ₂ R, –S(O) ₂ NR ₂ , – S(O)R, –S(O)NR2, –S(O)(NR)R, –C(O)OR, –C(O)NR2, –C(O)N(R)OR, –OC(O)NR2, – N(R)C(O)OR, –N(R)C(O)R, –N(R)C(O)NR2, –N(R)S(O)2NR2 and –N(R)S(O)2R, wherein R is H or a C _1-6 aliphatic chain. [0154] In some embodiments, each R ³ is independently selected from –Me, –Et, –F, –Br, –B(OH), –Cl, –CF ₃ ,–CO ₂ H, –CN, –OH, –OMe, –NH ₂ , –NHMe and –NMe ₂ . [0155] In some embodiments, each R ³ is independently selected from –Me, –Br, –B(OH), –Cl, – CF ₃ ,–CO ₂ H, –CN, –OH, –OMe and –NH _2. [0156] In some embodiments, R ³ is selected from –F, –OH, and –CO ₂ H. [0157] some embodiments, R ³ is selected from –F and –OH. [0158] In some embodiments, R ³ is –OH. In some embodiments, R ³ is –CO ₂ H. In some embodiments, R ³ is fluoro. In some embodiments, two R ³ groups are taken together to form . In some embodiments, R ³ is selected from –Me, –F, –OH, and –CO ₂ H. In some embodiments, R ³ is selected from –Me, –CF ₃ and –F. In some embodiments, R ³ is selected from –Me and –F. In some embodiments, R ³ is –Me. In some embodiments R ³ is –CF3. In some embodiments, R ³ is selected from the groups depicted in the compounds in Table 1 or Table 2. [0159] As defined generally above, each instance of R ^A is independently oxo, deuterium, halogen, –CN, –NO ₂ , –OR, –SF ₅ , –SR, –NR ₂ , –S(O) ₂ R, –S(O) ₂ NR ₂ , –S(O) ₂ F, –S(O)R, –S(O)NR ₂ , – S(O)(NR)R, –S(O)(NCN)R, –S(NCN)R, –C(O)R, –C(O)OR, –C(O)NR ₂ , –C(O)N(R)OR, – OC(O)R, –OC(O)NR ₂ , –N(R)C(O)OR, –N(R)C(O)R, –N(R)C(O)NR ₂ , –N(R)C(NR)NR ₂ , – N(R)S(O) ₂ NR ₂ , –N(R)S(O) ₂ R, –P(O)R ₂ , –P(O)(R)OR, or –B(OR) ₂ . [0160] In some embodiments, R ^A is oxo, deuterium, halogen, –CN, –NO ₂ , –OR, –SF ₅ , –SR, –NR ₂ , –S(O) ₂ R, –S(O) ₂ NR ₂ , –S(O) ₂ F, –S(O)R, –S(O)NR ₂ , –S(O)(NR)R, –S(O)(NCN)R, –S(NCN)R, – N(R)C(O)R, –N(R)C(O)NR2, –N(R)C(NR)NR2, –N(R)S(O)2NR2, –N(R)S(O)2R, –P(O)R2, – P(O)(R)OR, or –B(OR)2. [0161] In some embodiments, R ^A is independently selected from deuterium, halogen, –CN, –OR, –NR ₂ , –S(O) ₂ R, –S(O) ₂ NR ₂ , –S(O)R, –S(O)NR ₂ , –S(O)(NR)R, –C(O)OR, –C(O)NR ₂ , – C(O)N(R)OR, –OC(O)NR ₂ , –N(R)C(O)OR, –N(R)C(O)R, –N(R)C(O)NR ₂ , –N(R)S(O) ₂ NR ₂ and –N(R)S(O) ₂ R, wherein R is H or a C _1-6 aliphatic chain. [0162] In some embodiments, R ^A is –F. In some embodiments, R ^A is –OH. In some embodiments, R ^A is –CO ₂ H. [0163] In some embodiments, R ^A is selected from the groups depicted in the compounds in Table 1 or Table 2. [0164] As defined generally above, each instance of R ^B is independently a C _1-6 aliphatic chain; phenyl; naphthyl; cubanyl; adamantyl; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 5-12 membered saturated or partially unsaturated bicyclic carbocyclic ring; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. [0165] In some embodiments, R ^B is a C _1-6 aliphatic chain; phenyl; naphthyl; cubanyl; adamantyl; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 5-12 membered saturated or partially unsaturated bicyclic carbocyclic ring; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. [0166] In some embodiments, each R ^B is C1-6 aliphatic chain substituted with 0-3 instances of halo. [0167] In some embodiments, R ^B is methyl. In some embodiments, R ^B together with its R ^C sunstituents is trifluoromethyl. [0168] In some embodiments, R ^B is selected from the groups depicted in the compounds in Table 1 or Table 2. [0169] As defined generally above, each instance of R ^C is independently oxo, deuterium, halogen, –CN, –NO ₂ , –OR, –SF ₅ , –SR, –NR ₂ , –S(O) ₂ R, –S(O) ₂ NR ₂ , –S(O) ₂ F, –S(O)R, –S(O)NR ₂ , – S(O)(NR)R, –C(O)R, –C(O)OR, –C(O)NR ₂ , –C(O)N(R)OR, –OC(O)R, –OC(O)NR ₂ , – N(R)C(O)OR, –N(R)C(O)R,–N(R)C(O)NR ₂ , –N(R)C(NR)NR ₂ , –N(R)S(O) ₂ NR ₂ , –N(R)S(O) ₂ R, –P(O)R ₂ , –P(O)(R)OR, –B(OR) ₂ ,or an optionally substituted group selected from C _1-6 aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1- 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. [0170] In some embodiments, R ^C is oxo, deuterium, halogen, –CN, –NO ₂ , –OR, –SF ₅ , –SR, –NR ₂ , –S(O) ₂ R, –S(O) ₂ NR ₂ , –S(O) ₂ F, –S(O)R, –S(O)NR ₂ , –S(O)(NR)R, –C(O)R, –C(O)OR, –C(O)NR ₂ , –C(O)N(R)OR, –OC(O)R, –OC(O)NR ₂ , –N(R)C(O)OR, –N(R)C(O)R, –N(R)C(O)NR ₂ , –N(R)C(NR)NR ₂ , –N(R)S(O) ₂ NR ₂ , –N(R)S(O) ₂ R, –P(O)R ₂ , –P(O)(R)OR, –B(OR) ₂ , or an optionally substituted group selected from C _1-6 aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. [0171] In some embodiments, R ^C is halo. In some embodiments, R ^C is –F. [0172] In some embodiments, R ^C is selected from the groups depicted in the compounds in Table 1 or Table 2. [0173] As defined generally above, each instance of R is independently hydrogen, or an optionally substituted group selected from C _1-6 aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered monocyclic 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 form an optionally substituted 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. [0174] In some embodiments, R is hydrogen, or an optionally substituted group selected from C _{1- 6} aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered monocyclic 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 form an optionally substituted 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. [0175] In some embodiments, R is selected from H or a C _1-6 aliphatic chain. In some embodiments R is a C _1-6 aliphatic chain. [0176] In some embodiments, R is selected from H, –Me, –Et, –Pr, – ⁱ Pr and – ^t Bu. In some embodiments, R is selected from H and –Me. In some embodiments, R is –Me. In some embodiments, R is H. [0177] In some embodiments, R is selected from the groups depicted in the compounds in Table 1 or Table 2. [0178] As defined generally above, Ring A and Ring B are each independently phenyl; 1,1'- biphenyl; naphthyl; tetrahydronaphthalenyl; dihydroindenyl; benzocyclobutenyl; cubanyl; adamantyl; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 5-12 membered saturated or partially unsaturated bicyclic carbocyclic ring; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. [0179] As defined generally above, Ring A and Ring B are each independently phenyl; naphthyl; tetrahydronaphthalenyl; dihydroindenyl; benzocyclobutenyl; cubanyl; adamantyl; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, selected from nitrogen, oxygen, and sulfur; a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 5-12 membered saturated or partially unsaturated bicyclic carbocyclic ring; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. [0180] In some embodiments, Ring A is phenyl; naphthyl; cubanyl; adamantyl; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 5-12 membered saturated or partially unsaturated bicyclic carbocyclic ring; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. [0181] In some embodiments, Ring A is phenyl; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. [0182] In some embodiments, Ring A is phenyl; a 5 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. [0183] In some embodiments, Ring A is a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur (e.g.¸ furanyl, thiophenyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, oxadiazolyl, oxathiazolyl). [0184] In some embodiments, Ring A is a 5-membered membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur (e.g. f¸uranyl, thiophenyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, oxadiazolyl, oxathiazolyl). [0185] In some embodiments, Ring A is selected from phenyl, furanyl, thiophenyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, oxadiazolyl and oxathiazolyl. [0186] In some embodiments, Ring A is selected from phenyl, pyrazolyl, and pyridinyl. In some embodiments, Ring A is selected from phenyl and pyrazolyl. [0187] In some embodiments, Ring A is phenyl. In some embodiments, Ring A is pyrazolyl. In some embodiments, Ring A is pyridinyl. [0188] In some embodiments, Ring A together with its R ¹ substituents is selected from connects to L and the bottom attachment point connects to the six-member ring of the ERBM moiety. [0189] In some embodiments, Ring A together with its R ¹ substituents is selected from wherein the top attachment point connects to L and the bottom attachment point connects to the six-member ring of the ERBM moiety [0190] In some embodiments, Ring A together with its R ¹ substituents is selected from wherein the top attachment point connects to L and the bottom attachment point connects to the six-member ring of the ERBM moiety. [0191] In some embodiments, Ring A together with its R ¹ substituents is selected from , wherein the top attachment point connects to L and the bottom attachment point connects to the six-member ring of the ERBM moiety. [0192] In some embodiments, Ring A together with its R ¹ substituents is selected from wherein the top attachment point connects to L and the bottom attachment point connects to the six-member ring of the ERBM moiety. [0193] In some embodiments, Ring A together with its R ¹ substituents is selected from wherein the top attachment point connects to L and the bottom attachment point connects to the six-member ring of the ERBM moiety. [0194] In some embodiments, Ring A together with its R ¹ substituents wherein the top attachment point connects to L and the bottom attachment point connects to the six-member ring of the ERBM moiety In some embodiments Ring A together with its R ¹ substituents wherein the top attachment point connects to L and the bottom attachment point connects to the six-member ring of the ERBM moiety. In some embodiments, Ring A together with its R ¹ substituents , wherein the top attachment point connects to L and the bottom attachment point connects to the six-member ring of the ERBM moiety. In some embodiments, Ring A together with its R ¹ substituents is , wherein the top attachment point connects to L and the bottom attachment point connects to the six-member ring of the ERBM moiety. In some embodiments, Ring A together with its R ¹ substituents , wherein the top attachment point connects to L and the bottom attachment point connects to the six-member ring of the ERBM moiety. In some embodiments, Ring A together with its R ¹ substituents wherein the top attachment point connects to L and the bottom attachment point connects to the six-member ring of the ERBM moiety. In some embodiments, Ring A together with its R ¹ substituents is , wherein the top attachment point connects to L and the bottom attachment point connects to the six-member ring of the ERBM moiety. In some embodiments, Ring A together with its R ¹ substituents , wherein the top attachment point connects to L and the bottom attachment point connects to the six-member ring of the ERBM moiety. In some embodiments, Ring A together with its R ¹ substituents wherein the top attachment point connects to L and the bottom attachment point connects to the six-member ring of the ERBM moiety. In some embodiments, Ring A together with its R ¹ substituents is , wherein the top attachment point connects to L and the bottom attachment point connects to the six-member ring of the ERBM moiety. In some embodiments, Ring A together with its R ¹ substituents , wherein the top attachment point connects to L and the bottom attachment point connects to the six-member ring of the ERBM moiety. In some embodiments, Ring A together with its R ¹ substituents wherein the top attachment point connects to L and the bottom attachment point connects to the six-member ring of the ERBM moiety. In some embodiments, Ring A together with its R ¹ substituents is , wherein the top attachment point connects to L and the bottom attachment point connects to the six-member ring of the ERBM moiety. In some embodiments, Ring A together ith it R ¹ b tit t h i th t tt h t i t t t L d th bottom attachment point connects to the six-member ring of the ERBM moiety. In some embodiments, Ring A together with its R ¹ substituents wherein the top attachment point connects to L and the bottom attachment point connects to the six-member ring of the ERBM moiety. [0195] In some embodiments, Ring A is selected from the groups depicted in the compounds in Table 1 or Table 2. [0196] In some embodiments, Ring B is phenyl; naphthyl; tetrahydronaphthalenyl; dihydroindenyl; benzocyclobutenyl; cubanyl; adamantyl; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 5-12 membered saturated or partially unsaturated bicyclic carbocyclic ring; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. [0197] In some embodiments, Ring B is phenyl; tetrahydronaphthalenyl; dihydroindenyl; benzocyclobutene; cubanyl; adamantyl; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 5-12 membered saturated or partially unsaturated bicyclic carbocyclic ring; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. [0198] In some embodiments, Ring B is phenyl; tetrahydronaphthalenyl; dihydroindenyl; benzocyclobutenyl; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaryl membered saturated or partially unsaturated monocyclic carbocyclic ring; a 5-12 membered saturated or partially unsaturated bicyclic carbocyclic ring or a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur;. [0199] In some embodiments, Ring B is phenyl; tetrahydronaphthalenyl; dihydroindenyl; benzocyclobutenyl; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; or a 5-12 membered saturated or partially unsaturated bicyclic carbocyclic ring. [0200] In some embodiments, Ring B is phenyl; tetrahydronaphthalenyl; dihydroindenyl; benzocyclobutenyl; a 5 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. [0201] In some embodiments, Ring B is tetrahydronaphthalenyl; dihydroindenyl; or benzocyclobutenyl. In some embodiments, Ring B is tetrahydronaphthalenyl. In some embodiments, Ring B is dihydroindenyl. In some embodiments, Ring B is benzocyclobutenyl. [0202] In some embodiments, Ring B is a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur (e.g.¸ furanyl, thiophenyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, oxadiazolyl, oxathiazolyl). [0203] In some embodiments, Ring B is a an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur (e.g.¸ quinolinyl, isoquinolinyl, benzofuranyl, indolyl, benzimidazolyl, benzothiazolyl, benzothiophenyl, dihydrobenzofuranyl, dihydroisobenzofuranyl, indolinyl, isoindolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl). [0204] In some embodiments, Ring B is a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cycloheptenyl). [0205] In some embodiments, Ring B is 5-12 membered saturated or partially unsaturated bicyclic carbocyclic ring (e.g., spiro [3.3] heptanyl, spiro [3,4] octanyl, adamantyl, dihydroindenyl (e.g., 2,3-dihydro-1H-indenyl), tetrahydronaphthalenyl, benzocyclobutenyl, bicyclo[1.1.1]pentanyl, bicyclo[2.2.0]hexanyl, bicyclo[2.2.1]hept-2-enyl, bicyclo[3.1.1]heptanyl, bicyclo[4.1.0]heptanyl, bicyclo[3.2.0]heptanyl, bicyclo[2.2.1]heptanyl, bicyclo[2.2.2]oct-2-enyl, bicyclo[2.2.2]octanyl, bicyclo[3.3.1]nonanyl). [0206] In some embodiments, Ring B is a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur (e.g., oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl). [0207] In some embodiments, Ring B is selected from phenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cycloheptenyl, bicyclo[1.1.1]pentanyl, bicyclo[2.2.0]hexanyl, bicyclo[2.2.1]hept-2-enyl, bicyclo[3.1.1]heptanyl, bicyclo[4.1.0]heptanyl, bicyclo[3.2.0]heptanyl, bicyclo[2.2.1]heptanyl, bicyclo[2.2.2]oct-2-enyl, bicyclo[2.2.2]octanyl, bicyclo[3.3.1]nonanyl, spiro [3.3] heptanyl, spiro [3,4] octanyl, adamantyl, dihydroindenyl (e.g., 2,3-dihydro-1H-indenyl), tetrahydronaphthalenyl, benzocyclobutenyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, quinolinyl, isoquinolinyl, benzofuranyl, indolyl, benzimidazolyl, benzothiazolyl, benzothiophenyl, dihydrobenzofuranyl, dihydroisobenzofuranyl, indolinyl, isoindolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, furanyl, thiophenyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, oxadiazolyl and oxathiazolyl. [0208] In some embodiments, Ring B is selected from phenyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, bicyclo[1.1.1]pentanyl, bicyclo[2.2.0]hexanyl, bicyclo[2.2.1]hept-2- enyl, bicyclo[3.1.1]heptanyl, bicyclo[4.1.0]heptanyl, bicyclo[3.2.0]heptanyl, bicyclo[2.2.1]heptanyl, bicyclo[2.2.2]oct-2-enyl, bicyclo[2.2.2]octanyl, bicyclo[3.3.1]nonanyl, adamantyl, tetrahydropyranyl, dihydroindenyl (e.g., 2,3-dihydro-1H-indenyl), tetrahydronaphthalenyl, benzocyclobutenyl, dihydrobenzofuranyl, dihydroisobenzofuranyl, indolinyl, isoindolinyl, thiophenyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl and pyrazolyl. [0209] In some embodiments, Ring B is selected from phenyl, cyclopropyl, cyclohexyl, cyclohexenyl, adamantyl, bicyclo[1.1.1]pentanyl, bicyclo[2.2.0]hexanyl, bicyclo[2.2.1]hept-2- enyl, bicyclo[3.1.1]heptanyl, bicyclo[4.1.0]heptanyl, bicyclo[3.2.0]heptanyl, bicyclo[2.2.1]heptanyl, bicyclo[2.2.2]oct-2-enyl, bicyclo[2.2.2]octanyl, bicyclo[3.3.1]nonanyl, tetrahydropyranyl, 2,3-dihydro-1H-indenyl, tetrahydronaphthalenyl, benzocyclobutenyl, pyridinyl, thiophenyl and pyrazolyl. [0210] In some embodiments, Ring B is selected from phenyl, cyclohexyl, cyclohexenyl, adamantyl, tetrahydropyranyl, 2,3-dihydro-1H-indenyl, and pyrazolyl. [0211] In some embodiments, Ring B is phenyl. In some embodiments, Ring B is pyrazolyl. In some embodiments, Ring B is adamantyl. In some embodiments, Ring B is 2,3-dihydro-1H- indenyl. In some embodiments, Ring B is tetrahydrofuranyl.

[0213] In some embodiments, Ring B together with its R ² substituents is . In some embodiments, Ring B together with its R ² substituents is . In some embodiments, Ring B together with its R ² substituents is . In some embodiments, Ring B together with its R ² substituents is . In some embodiments, Ring B together with its R ² substituents is . In some embodiments, Ring B together with its R ² substituents is . , . In Ring B together with its R ² substituents is . In some embodiments, Ring B together with its R ² substituents is . In some embodiments, Ring B together with its R ² substituents is . In some embodiments, Ring B together with its R ² substituents is . In some embodiments, Ring B together with its R ² substituents is . In some embodiments, Ring B together with its R ² substituents is . In some embodiments, Ring B together with its R ² substituents is . In some embodiments, Ring B together with its R ² substituents is . In some embodiments, Ring B together with its R ² substituents is . In some embodiments, Ring B together with its R ² substituents is . In some embodiments, Ring B together with its R ² substituents is . In some embodiments, Ring B together with its R ² substituents is . In some embodiments, Ring B together with its R ² substituents is . In some embodimentsembodiments, Ring B together with its R ² substituents is . In some embodimentsembodiments, Ring B together with its R ² substituents is . In some embodiments, Ring B together with its R ² substituents is . In some embodiments, Ring B together with its R ² substituents is . In some embodiments, Ring B together with its R ² substituents is . In some embodiments, Ring B together with its R ² substituents . In some embodiments, Ring B together with its R ² substituents is . In some embodiments, Ring B together with its R ² substituents is . In some embodiments, Ring B together with its R ² substituents is . In some embodiments, Ring B together with its R ² substituents is embodiments, Ring B together with its R ² substituents is . In some embodiments, Ring B together with its R ² substituents is . In some embodiments, Ring B together substituents is . In some embodiments, Ring B together with its R ² substituents . In some embodiments, Ring B together with its R ² substituents is . embodiments, Ring B together with its R ² substituents is . In some embodiments, Ring B together with its R ² substituents is . In some embodiments, Ring B together with its R ² substituents In some embodiments, Ring B together th its R ² wi substituents is . In some embodiments, Ring B together with its R ² substituents . In some embodiments, Ring B together with its R ² substituents is . In some embodiments, Ring B together with its R ² substituents is . In some embodiments, Ring B together with its R ² substituents is . In some embodiments, Ring together with its R ² substituents is . In some embodiments, Ring together with its R ² substituents is some embodiments, Ring together with its R ² substituents is . In some embodiments, Ring B together with its R ² substituents is . In some embodiments, Ring together with its R ² substituents is . In some embodiments, Ring B together with its R ² substituents is . In some embodiments, Ring together with its R ² substituents is . In some embodiments, Ring B together with its R ² substituents is . [0214] In some embodiments, Ring B together with its R ² substituents . In some embodiments, Ring B together with its R ² substituents is . In some embodiments, Ring B together with its R ² substituents is . [0215] In some embodiments, Ring B together with its R ² substituents is . In some embodiments, Ring B together with its R ² substituents is . In some embodiments, Ring B together with its R ² substituents is . In some embodiments, Ring B together I b di t Ri B t th ith it R ²

In some embodiments, Ring together with its substituents is some embodiments, Ring together with its R ² substituents is some embodiments, Ring B with its R ² substituents is some embodiments, Ring B together with its substituents is n some embodiments, Ring together with its substituents is some embodiments, Ring B with its R ² substituents is some embodiments, Ring B w ² ith its R substituents is some embodiments, Ring together with its R ² substituents is some embodiments, Ring B together with its substituents is n some embodiments, Ring B together with its substituents is some embodiments, Ring B together with its substituents is some embodiments, Ring together with its substituents is some embodiments, Ring together with its R ² substituents is some embodiments, Ring B together with its R ² substituents is some embodiments, Ring B together its substituents is mbodiments, Ring B together with its R ² substituents . In some embodiments, Ring B together with its R ² substituents . In some embodiments, Ring B together with its R ² substituents some embodiments, Ring B together with its R ² substituents some embodiments, Ring B together with its R ² substituents i some embodiments, Ring B together with its R ² substituents is some embodiments, Ring B together with its R ² substituents i embodiments, Ring B together with its R ² substituents i some embodiments, Ring B together with its R ² substituents is . In some embodiments, Ring B together with its R ² substituents is . In some embodiments, Ring B together with its R ² substituents is . In some embodiments, Ring B together with its R ² substituents is . In some embodiments, Ring B together with its substituents . In some embodiments, Ring together with its R ² substituents . In some embodiments, Ring B together with its together with its together with its substituents some embodiments, Ring together with its R ² . In some embodiments, Ring B together with its R ² substituents is . odiments, Ring B together with its R ² substituents is . In some embodiments, Ring B together with its R ² substituents is . In some embodiments, Ring B together with its R ² substituents is . In some embodiments, Ring B together with its R ² substituents is . In some embodiments, Ring B together with its R ² . In some embodiments, Ring B together with its R ² substituents is ²

[0216] In some embodiments, Ring B together with its R ² substituents is embodiments, Ring B together with its R ² substituents is . In some embodiments, Ring B together with its R ² substituents is . [0217] In some embodiments, Ring B is selected from the groups depicted in the compounds in Table 1 or Table 2. [0218] As generally defined herein, Ring C is a spiro-fused 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a spiro-fused 5-12 membered saturated or partially unsaturated bicyclic carbocyclic ring; a spiro-fused 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a spiro-fused 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; [0219] In some embodiments, Ring C together with its R ⁶ substituents is selected from:

[0220] In some embodiments, Ring C together with its R ⁶ substituents is embodiments, Ring C together with its R ⁶ substituents i some embodiments, Ring C together with its R ⁶ substituents i some embodiments, Ring C together some embodiments, Ring C together with its R ⁶ substituents is . In some embodiments, Ring C together with its R ⁶ substituents . In some embodiments, Ring C together with its R ⁶ substituents . In some embodiments, Ring C together with its R ⁶ substituents is some embodiments, Ring C together with its R ⁶ [0221] As defined generally above, L is a bivalent moiety that connects ERBM to LBM. [0222] As defined generally above, L is a covalent bond or a bivalent, saturated or unsaturated, straight or branched C _1-50 hydrocarbon chain, wherein 0-6 methylene units of L are independently replaced by –Cy–, –CH(R)–, –C(R) ₂ –, –O–, –NR–, –S–, –OC(O)–, –C(O)O–, –C(O)–, –S(O)–, – Cy– is independently an optionally substituted bivalent ring selected from phenylenyl, an 8-10 membered bicyclic arylenyl a 47 membered saturated or partially unsaturated carbocyclylenyl a 5-11 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 5-11 membered saturated or partially 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 6-10 membered bridged 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, or an 8-10 membered bicyclic heteroarylenyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur. [0223] In some embodiments, L is a covalent bond. In some embodiments, L is a bivalent, saturated or unsaturated, straight or branched C _1-50 hydrocarbon chain, wherein 0-6 methylene units of L are independently replaced by –Cy–, –CH(R)–, –C(R) ₂ –, –O–, –NR–, –S–, –OC(O)–, – , 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 5-11 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 5-11 membered saturated or partially 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 6-10 membered bridged bicyclic saturated or partially unsaturated heterocyclylenyl having 1-2 h i d d l l d f i d lf 6 b d heteroarylenyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8-10 membered bicyclic heteroarylenyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur. [0224] In some embodiments, L is a bivalent, saturated or unsaturated, straight or branched C _3-5 hydrocarbon chain, wherein 0, 1, 2 or 3 methylene units of L are independently replaced by –Cy–, [0225] In some embodiments, L is a bivalent, saturated or unsaturated, straight or branched C _3-5 hydrocarbon chain, wherein 1, 2 or 3 methylene units of L are independently replaced by –Cy–, – CH(R)–, –C(R) ₂ –, –O– or–NR– . [0226] In some embodiments, L is a bivalent, saturated or unsaturated, straight or branched C _3-5 hydrocarbon chain, wherein 1, 2 or 3 methylene units of L are independently replaced by –Cy– or–NR– . [0227] In some embodiments, each –Cy– is independently an optionally substituted bivalent ring selected from a 4-7 membered saturated or partially unsaturated monocyclic carbocyclylenyl, a 5- 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 monocyclic heterocyclylenyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-11 membered monocyclic saturated or partially 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 and a 6-10 membered bridged bicyclic saturated or partially unsaturated heterocyclylenyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. [0228] In some embodiments, each –Cy– is independently an optionally substituted bivalent ring selected from a 4-7 membered saturated or partially unsaturated monocyclic carbocyclylenyl, a 5- 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 monocyclic heterocyclylenyl containing 1-2 nitrogen atoms, a 5-11 membered monocyclic saturated or partially unsaturated spiro heterocyclylenyl containing 1-2 nitrogen atoms, an 8-10 membered bicyclic saturated or partially unsaturated heterocyclylenyl containing 1-2 nitrogen atoms, and a 6-10 membered bridged bicyclic saturated or partially unsaturated heterocyclylenyl containing 1-2 nitrogen atoms. [0229] In some embodiments, the bivalent ring of each –Cy– is independently substituted with 0, 1 or 2 substituents independently selected from deuterium, C ₁ -C ₄ alkyl, C ₁ -C ₄ haloalkyl, C ₃ -C ₇ cycloalkyl, –O-C ₁ -C ₄ alkyl, halo, cyano, –OH, –NH ₂ , –N(H)(C ₁ -C ₄ alkyl) and –N(C ₁ -C ₄ alkyl) ₂ . [0230] In some embodiments, the bivalent ring of each –Cy– is independently substituted with 0, 1 or 2 substituents independently selected from C ₁ -C ₄ alkyl, C ₁ -C ₄ haloalkyl, C ₃ -C ₇ cycloalkyl, – O-C1-C4 alkyl, halo, cyano, –OH, –NH2, –N(H)(C1-C4 alkyl) and –N(C1-C4 alkyl)2. [0231] In some embodiments, the bivalent ring of each –Cy– is independently substituted with 0, 1 or 2 substituents independently selected from deuterium, –Me, –Et, –Pr, –iPr, cyclopropyl, –CF ₃ , –OMe, –F, –Cl, –CN, –NH ₂ , –NHMe and –NMe ₂ . [0232] In some embodiments, the bivalent ring of each –Cy– is independently substituted with 0, 1 or 2 substituents independently selected from –Me, –Et, –Pr, –iPr, cyclopropyl, –CF ₃ , –OMe, – F, –Cl, –CN, –NH ₂ , –NHMe and –NMe ₂ . [0233] In some embodiments, the bivalent ring of each –Cy– is independently substituted with 0, 1 or 2 substituents independently selected from –Me, –OMe and –F. [0234] In some embodiments, the bivalent ring of each –Cy– is independently substituted with 0, 1 or 2 instances of –Me. [0235] In some embodiments, the bivalent ring of each –Cy– is unsubstituted. [0236] In some embodiments, .

embodiments, , . ,

embodiments, L is . In some embodiments, L is . [0242] In some embodiments, L is . In some embodiments, L is . , . In some embodiments, L is . In some embodiments, L is . In some embodiments, L is . In some embodiments, L is . , . In some embodiments, L is . In some embodiments, L is .

[0243] In some embodiments, L is . In some embodiments, L is . , . In some e . In some embodiments, L is . In some embodiments, L is embodiments, L is . In some embodiments, L is embodiments, L is . In some embodiments, L is . [0244] In some embodiments, L is selected from the groups depicted in the compounds in Table 1 or Table 2. [0245] As defined generally above, LBM is a ligase binding moiety.

[0246] As defined generally above, LBM is selected from , , , , , , , , , , , , , , , and [0247] In some embodiments, LBM is selected from ,

[0250] In some embodiments, LBM is selected from , [ [ [0253] some embodiments, LBM is selected , [ , [ ,

[0256] some embodiments, LBM is selected from , [0261] In some embodiments, some embodiments, LBM i some embodiments, some embodiments, LBM is embodiments, LBM is . In some embodiments, LBM is

In some embodiments, . In some embodiments, LBM is some embodiments, some embodiments, LBM is [0262] In some embodiments, LBM is selected from the groups depicted in the compounds in Table 1 or Table 2. [0263] As defined generally above, m is 0, 1, 2, 3, or 4. In some embodiments, m is 0, 1, 2 or 3. In some embodiments, m is 0, 1 or 2. In some embodiments, m is 0 or 1. [0264] In some embodiments m is 0. In some embodiments m is 1. In some embodiments m is 2. In some embodiments m is 3. In some embodiments m is 4. [0265] In some embodiments, m is selected from the groups depicted in the compounds in Table 1 or Table 2. [0266] As defined generally above, n is 0, 1, 2, 3, or 4. In some embodiments, n is 0, 1, 2 or 3. In some embodiments, n is 0, 1 or 2. In some embodiments, n is 0 or 1. [0267] In some embodiments n is 0. In some embodiments n is 1. In some embodiments n is 2. In some embodiments n is 3. In some embodiments n is 4. [0268] In some embodiments, n is selected from the groups depicted in the compounds in Table 1 or Table 2. [0269] As defined generally above, p is 0, 1, 2, 3, or 4. In some embodiments, p is 0, 1, 2 or 3. In some embodiments, p is 0, 1 or 2. In some embodiments, p is 0 or 1. Of note, when the number of R ³ groups is designated as “p-1” or “p-2”, solely positive integers are contemplated (i.e., “p-1” can be 0, 1, 2 or 3 and “p-2” can be 0, 1 or 2). [0270] In some embodiments p is 0. In some embodiments p is 1. In some embodiments p is 2. In some embodiments p is 3. In some embodiments p is 4. [0271] In some embodiments, p is selected from the groups depicted in the compounds in Table 1 or Table 2. [0272] As defined generally above, each of q is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. [0273] In some embodiments q is 1. In some embodiments q is 2. In some embodiments q is 3. In some embodiments q is 4. In some embodiments q is 5. In some embodiments q is 6. In some embodiments q is 7. In some embodiments q is 8. In some embodiments q is 9. In some embodiments q is 10. [0274] In some embodiments, q is selected from the groups depicted in the compounds in Table 1 or Table 2. [0275] As defined generally above, r is 0, 1, 2, 3, or 4. In some embodiments, r is 0, 1, 2 or 3. In some embodiments, r is 0, 1 or 2. In some embodiments, r is 0 or 1. [0276] 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. [0277] In some embodiments, r is selected from the groups depicted in the compounds in Table 1 or Table 2. [0278] As defined generally above, s is 0, 1, 2, 3, or 4. In some embodiments, s is 0, 1, 2 or 3. In some embodiments, s is 0, 1 or 2. In some embodiments, s is 0 or 1. [0279] In some embodiments s is 0. In some embodiments s is 1. In some embodiments s is 2. In some embodiments s is 3. In some embodiments s is 4. [0280] In some embodiments, s is selected from the groups depicted in the compounds in Table 1 or Table 2. [0281] In certain embodiments, the present invention provides a compound of formula I-1, I-1’, forming a compound of one of formulas II-a, II-b, or II-c, respectively:

or a pharmaceutically acceptable salt thereof, wherein each of Ring A, Ring B, R ¹ , R ² , R ³ , X ¹ , X ² , m, n, p, L, and LBM is as defined in embodiments and classes and subclasses herein. [0282] In some embodiments, when X ¹ is CH or N, X ² is CH and Ring B is phenyl, then ring A is other than phenyl or a 6-membered monocyclic heteroaryl ring containing 1-3 nitrogen heteroatoms. [0283] In some embodiments, the compound is a compound of formula II-a-1, II-b-1, or II-c-1: or a pharmaceutically acceptable salt thereof, wherein each of Ring A, Ring B, R ¹ , R ² , R ³ , X ¹ , X ² , m, n, p, L, and LBM is as defined in embodiments and classes and subclasses herein. In some embodiments, when X ¹ is CH or N, X ² is CH and Ring B is phenyl, then ring A is other than phenyl or a 6-membered monocyclic heteroaryl ring containing 1-3 nitrogen heteroatoms. [0284] In some embodiments, the compound is a compound of formula II-a-1, or a pharmaceutically acceptable salt thereof. In some embodiments, when X ¹ is CH or N, X ² is CH and Ring B is phenyl, then ring A is other than phenyl or a 6-membered monocyclic heteroaryl ring containing 1-3 nitrogen heteroatoms. [0285] In some embodiments, the compound is a compound of formula II-b-1, or a pharmaceutically acceptable salt thereof. In some embodiments, when X ¹ is CH or N, X ² is CH and Ring B is phenyl, then ring A is other than phenyl or a 6-membered monocyclic heteroaryl ring containing 1-3 nitrogen heteroatoms. [0286] In some embodiments, the compound is a compound of formula II-c-1, or a pharmaceutically acceptable salt thereof. In some embodiments, when X ¹ is CH or N, X ² is CH and Ring B is phenyl, then ring A is other than phenyl or a 6-membered monocyclic heteroaryl ring containing 1-3 nitrogen heteroatoms. [0287] In certain embodiments, the present invention provides a compound of formula I-1, I-1’, , thereby forming a compound of one of formulas VIII-a, VIII-b, VIII-c, IX-a, IX-b or IX-c, respectively:

or a pharmaceutically acceptable salt thereof, wherein each of X ¹ , X ² , X ³ , Ring A, Ring C, R ¹ , R ³ , R ⁶ , m, p, t, L, and LBM is as defined in embodiments and classes and subclasses herein. [0288] In some embodiments, the compound is a compound of formula VIII-a, or a pharmaceutically acceptable salt thereof. [0289] In some embodiments, the compound is a compound of formula VIII-b, or a pharmaceutically acceptable salt thereof. [0290] In some embodiments, the compound is a compound of formula VIII-c, or a pharmaceutically acceptable salt thereof. [0291] In some embodiments, the compound is a compound of formula IX-a, or a pharmaceutically acceptable salt thereof. [0292] In some embodiments, the compound is a compound of formula IX-b, or a pharmaceutically acceptable salt thereof. [0293] In some embodiments, the compound is a compound of formula IX-c, or a pharmaceutically acceptable salt thereof. [0294] In some embodiments, the compound is a compound of one of formulas VIII-a-1, VIII-b- 1, or VIII-c-1: or a pharmaceutically acceptable salt thereof, wherein each of X ¹ , X ² , Ring A, R ¹ , R ³ , m, p, L, and LBM is as defined in embodiments and classes and subclasses herein. [0295] In some embodiments, the compound is a compound of formula VIII-a-1, or a pharmaceutically acceptable salt thereof. [0296] In some embodiments, the compound is a compound of formula VIII-b-1, or a pharmaceutically acceptable salt thereof. [0297] In some embodiments, the compound is a compound of formula VIII-c-1, or a pharmaceutically acceptable salt thereof. [0298] In some embodiments, the compound is a compound of one of formulas IX-a-1, IX-b-1 or IX-c-1

or a pharmaceutically acceptable salt thereof, wherein each of X ² , X ³ , Ring A, Ring C, R ¹ , R ³ , R ⁶ , m, p, t, L, and LBM is as defined in embodiments and classes and subclasses herein. [0299] In some embodiments, the compound is a compound of formula IX-a-1, or a pharmaceutically acceptable salt thereof. [0300] In some embodiments, the compound is a compound of formula IX-b-1, or a pharmaceutically acceptable salt thereof. [0301] In some embodiments, the compound is a compound of formula IX-c-1, or a pharmaceutically acceptable salt thereof. [0302] In certain embodiments, the present invention provides a compound of formula I-1, I-1’, I-2, I-2’, I-3 or I-3’, wherein ERBM is ,

forming a compound of one of formulas II-d, II-e, II-f, II-g, II-h, II-i, II-j, II-k, or II-l, respectively:

or a pharmaceutically acceptable salt thereof, wherein each of Ring A, Ring B, R ¹ , R ² , R ³ , m, n, p, L, and LBM is as defined in embodiments and classes and subclasses herein. [0303] In some embodiments, when the compound is of formula II-d, II-e, II-f, II-j, II-k or II-l and Ring B is phenyl, then Ring A is other than phenyl or a 6 membered monocyclic heteroaryl ring having 1-3 nitrogen heteroatoms. [0304] In some embodiments, the compound is a compound of formula II-d, or a pharmaceutically acceptable salt thereof. In some embodiments, when Ring B is phenyl, then Ring A is other than phenyl or a 6 membered monocyclic heteroaryl ring having 1-3 nitrogen heteroatoms. [0305] In some embodiments, the compound is a compound of formula II-e, or a pharmaceutically acceptable salt thereof. In some embodiments, when Ring B is phenyl, then Ring A is other than phenyl or a 6 membered monocyclic heteroaryl ring having 1-3 nitrogen heteroatoms. [0306] In some embodiments, the compound is a compound of formula II-f, or a pharmaceutically acceptable salt thereof. In some embodiments, when Ring B is phenyl, then Ring A is other than phenyl or a 6 membered monocyclic heteroaryl ring having 1-3 nitrogen heteroatoms. [0307] In some embodiments, the compound is a compound of formula II-g, or a pharmaceutically acceptable salt thereof. [0308] In some embodiments, the compound is a compound of formula II-h, or a pharmaceutically acceptable salt thereof. [0309] In some embodiments, the compound is a compound of formula II-i, or a pharmaceutically acceptable salt thereof. [0310] In some embodiments, the compound is a compound of formula II-j, or a pharmaceutically acceptable salt thereof. In some embodiments, when Ring B is phenyl, then Ring A is other than phenyl or a 6 membered monocyclic heteroaryl ring having 1-3 nitrogen heteroatoms. [0311] In some embodiments, the compound is a compound of formula II-k, or a pharmaceutically acceptable salt thereof. In some embodiments, when Ring B is phenyl, then Ring A is other than phenyl or a 6 membered monocyclic heteroaryl ring having 1-3 nitrogen heteroatoms. [0312] In some embodiments, the compound is a compound of formula II-l, or a pharmaceutically acceptable salt thereof. In some embodiments, when Ring B is phenyl, then Ring A is other than phenyl or a 6 membered monocyclic heteroaryl ring having 1-3 nitrogen heteroatoms. [0313] In certain embodiments, the present invention provides a compound of formula I-1, I-1’, I-

forming a compound of one of formulas II-d-A, II-e-A, II-f-A, II-d-B, II-e-B, II-f-B, II-d-C, II- e-C, II-f-C, II-g, II-h, II-I, II-j-A, II-k-A, or II-l-A, respectively:

or a pharmaceutically acceptable salt thereof, wherein each of Ring A, Ring B, R ¹ , R ² , R ³ , m, n, p, L, and LBM is as defined in embodiments and classes and subclasses herein. [0314] In some embodiments, when the compound is of formula II-d-A, II-e-A, II-f-A, II-j-A, II-k-A and II-l-A and Ring B is phenyl, then Ring A is other than phenyl or a 6 membered monocyclic heteroaryl ring having 1-3 nitrogen heteroatoms. [0315] In some embodiments, the compound is a compound of formula II-d-A, or a pharmaceutically acceptable salt thereof. In some embodiments, when Ring B is phenyl, then Ring A is other than phenyl or a 6 membered monocyclic heteroaryl ring having 1-3 nitrogen heteroatoms. [0316] In some embodiments, the compound is a compound of formula II-e-A, or a pharmaceutically acceptable salt thereof. In some embodiments, when Ring B is phenyl, then Ring A is other than phenyl or a 6 membered monocyclic heteroaryl ring having 1-3 nitrogen heteroatoms. [0317] In some embodiments, the compound is a compound of formula II-f-A, or a pharmaceutically acceptable salt thereof. In some embodiments, when Ring B is phenyl, then Ring A is other than phenyl or a 6 membered monocyclic heteroaryl ring having 1-3 nitrogen heteroatoms. [0318] In some embodiments, the compound is a compound of formula II-d-B, or a pharmaceutically acceptable salt thereof. [0319] In some embodiments, the compound is a compound of formula II-e-B, or a pharmaceutically acceptable salt thereof. [0320] In some embodiments, the compound is a compound of formula II-f-B, or a pharmaceutically acceptable salt thereof. [0321] In some embodiments, the compound is a compound of formula II-d-C, or a pharmaceutically acceptable salt thereof. [0322] In some embodiments, the compound is a compound of formula II-e-C, or a pharmaceutically acceptable salt thereof. [0323] In some embodiments, the compound is a compound of formula II-f-C, or a pharmaceutically acceptable salt thereof. [0324] In some embodiments, the compound is a compound of formula II-j-A, or a pharmaceutically acceptable salt thereof. In some embodiments, when Ring B is phenyl, then Ring A is other than phenyl or a 6 membered monocyclic heteroaryl ring having 1-3 nitrogen heteroatoms. [0325] In some embodiments, the compound is a compound of formula II-k-A, or a pharmaceutically acceptable salt thereof. In some embodiments, when Ring B is phenyl, then Ring A is other than phenyl or a 6 membered monocyclic heteroaryl ring having 1-3 nitrogen heteroatoms. [0326] In some embodiments, the compound is a compound of formula II-l-A, or a pharmaceutically acceptable salt thereof. In some embodiments, when Ring B is phenyl, then Ring A is other than phenyl or a 6 membered monocyclic heteroaryl ring having 1-3 nitrogen heteroatoms. [0327] In some embodiments, the compound is a compound of formula II-j-B, or a pharmaceutically acceptable salt thereof. [0328] In some embodiments, the compound is a compound of formula II-k-B, or a pharmaceutically acceptable salt thereof. [0329] In some embodiments, the compound is a compound of formula II-l-B, or a pharmaceutically acceptable salt thereof. [0330] In some embodiments, the compound is a compound of formula or a pharmaceutically acceptable salt thereof. [0331] In some embodiments, the compound is a compound of formula II-k-C, or a pharmaceutically acceptable salt thereof. [0332] In some embodiments, the compound is a compound of formula II-l-C, or a pharmaceutically acceptable salt thereof. [0333] In some embodiments, the compound is a compound of one of formulas II-d-1, II-e-1, II- f-1, II-g-1, II-h-1, II-i-1, II-j-1, II-k-1, or II-l-1: or a pharmaceutically acceptable salt thereof, wherein each of Ring A, Ring B, R1, R2, R3, m, n, p, L, and LBM is as defined in embodiments and classes and subclasses herein. [0334] In some embodiments, when the compound is of formula II-d-1, II-e-1, II-f-1, II-j-1, II- k-1 or II-l-1 and Ring B is phenyl, then Ring A is other than phenyl or a 6 membered monocyclic h t l i h i 1 3 it h t t [0335] In some embodiments, the compound is a compound of formula II-d-1, or a pharmaceutically acceptable salt thereof. In some embodiments, when Ring B is phenyl, then Ring A is other than phenyl or a 6 membered monocyclic heteroaryl ring having 1-3 nitrogen heteroatoms. [0336] In some embodiments, the compound is a compound of formula II-e-1, or a pharmaceutically acceptable salt thereof. In some embodiments, when Ring B is phenyl, then Ring A is other than phenyl or a 6 membered monocyclic heteroaryl ring having 1-3 nitrogen heteroatoms. [0337] In some embodiments, the compound is a compound of formula II-f-1, or a pharmaceutically acceptable salt thereof. In some embodiments, when Ring B is phenyl, then Ring A is other than phenyl or a 6 membered monocyclic heteroaryl ring having 1-3 nitrogen heteroatoms. [0338] In some embodiments, the compound is a compound of formula II-g-1, or a pharmaceutically acceptable salt thereof. [0339] In some embodiments, the compound is a compound of formula II-h-1, or a pharmaceutically acceptable salt thereof. [0340] In some embodiments, the compound is a compound of formula II-i-1, or a pharmaceutically acceptable salt thereof. [0341] In some embodiments, the compound is a compound of formula II-j-1, or a pharmaceutically acceptable salt thereof. In some embodiments, when Ring B is phenyl, then Ring A is other than phenyl or a 6 membered monocyclic heteroaryl ring having 1-3 nitrogen heteroatoms. [0342] In some embodiments, the compound is a compound of formula II-k-1, or a pharmaceutically acceptable salt thereof. In some embodiments, when Ring B is phenyl, then Ring A is other than phenyl or a 6 membered monocyclic heteroaryl ring having 1-3 nitrogen heteroatoms. [0343] In some embodiments, the compound is a compound of formula II-l-1, or a pharmaceutically acceptable salt thereof. In some embodiments, when Ring B is phenyl, then Ring A is other than phenyl or a 6 membered monocyclic heteroaryl ring having 1-3 nitrogen h t t [0344] In some embodiments, the compoundi s a compound of formula II-d-1-A, II-e-1-A, II-f- 1-A, II-d-1-B, II-e-1-B, II-f-1-B, II-d-1-C, II-e-1-C, II-f-1-C, II-j-1-A, II-k-1-A, or II-l-1-A: or a pharmaceutically acceptable salt thereof, wherein each of Ring A, Ring B, R ¹ , R ² , R ³ , m, n, p, L, and LBM is as defined in embodiments and classes and subclasses herein. [0345] In some embodiments, when the compound is of formula II-d-1-A, II-e-1-A, II-f-1-A, II- j-1-A, II-k-1-A and II-l-1-A and Ring B is phenyl, then Ring A is other than phenyl or a 6 membered monocyclic heteroaryl ring having 1-3 nitrogen heteroatoms. [0346] In some embodiments, the compound is a compound of formula II-d-A, or a pharmaceutically acceptable salt thereof. In some embodiments, when Ring B is phenyl, then Ring A is other than phenyl or a 6 membered monocyclic heteroaryl ring having 1-3 nitrogen heteroatoms. [0347] In some embodiments, the compound is a compound of formula II-e-A, or a pharmaceutically acceptable salt thereof. In some embodiments, when Ring B is phenyl, then Ring A is other than phenyl or a 6 membered monocyclic heteroaryl ring having 1-3 nitrogen heteroatoms. [0348] In some embodiments, the compound is a compound of formula II-f-A, or a pharmaceutically acceptable salt thereof. In some embodiments, when Ring B is phenyl, then Ring A is other than phenyl or a 6 membered monocyclic heteroaryl ring having 1-3 nitrogen heteroatoms. [0349] In some embodiments, the compound is a compound of formula II-d-B, or a pharmaceutically acceptable salt thereof. [0350] In some embodiments, the compound is a compound of formula II-e-B, or a pharmaceutically acceptable salt thereof. [0351] In some embodiments, the compound is a compound of formula II-f-B, or a pharmaceutically acceptable salt thereof. [0352] In some embodiments, the compound is a compound of formula II-d-C, or a pharmaceutically acceptable salt thereof. [0353] In some embodiments, the compound is a compound of formula II-e-C, or a pharmaceutically acceptable salt thereof. [0354] In some embodiments, the compound is a compound of formula II-f-C, or a pharmaceutically acceptable salt thereof. [0355] In some embodiments, the compound is a compound of formula II-j-A, or a pharmaceutically acceptable salt thereof. In some embodiments, when Ring B is phenyl, then Ring A is other than phenyl or a 6 membered monocyclic heteroaryl ring having 1-3 nitrogen heteroatoms. [0356] In some embodiments, the compound is a compound of formula II-k-A, or a pharmaceutically acceptable salt thereof. In some embodiments, when Ring B is phenyl, then Ring A is other than phenyl or a 6 membered monocyclic heteroaryl ring having 1-3 nitrogen heteroatoms. [0357] In some embodiments, the compound is a compound of formula II-l-A, or a pharmaceutically acceptable salt thereof. In some embodiments, when Ring B is phenyl, then Ring A is other than phenyl or a 6 membered monocyclic heteroaryl ring having 1-3 nitrogen heteroatoms. [0358] In some embodiments, the compound is a compound of formula II-j-B, or a pharmaceutically acceptable salt thereof. [0359] In some embodiments, the compound is a compound of formula II-k-B, or a pharmaceutically acceptable salt thereof. [0360] In some embodiments, the compound is a compound of formula II-l-B, or a pharmaceutically acceptable salt thereof. [0361] In some embodiments, the compound is a compound of formula or a pharmaceutically acceptable salt thereof. [0362] In some embodiments, the compound is a compound of formula II-k-C, or a pharmaceutically acceptable salt thereof. [0363] In some embodiments, the compound is a compound of formula II-l-C, or a pharmaceutically acceptable salt thereof. [0364] In some embodiments, the compound is a compound of formula I : [0365] In certain embodiments, the present invention provides a compound of formula I-1, I-1’, , , ,

, , thereby forming a compound of one of formulas II-n, II-o, II- p, II-q, II-r, II-s, II-t, II-u or II-v, respectively:

or a pharmaceutically acceptable salt thereof, wherein each of Ring A, R ¹ , R ³ , m, p, L, and LBM is as defined in embodiments and classes and subclasses herein. [0366] In some embodiments, the compound is a compound of formula II-n, or a pharmaceutically acceptable salt thereof. [0367] In some embodiments, the compound is a compound of formula II-o, or a pharmaceutically acceptable salt thereof. [0368] In some embodiments, the compound is a compound of formula II-p, or a pharmaceutically acceptable salt thereof. [0369] In some embodiments, the compound is a compound of formula II-q, or a pharmaceutically acceptable salt thereof. [0370] In some embodiments, the compound is a compound of formula II-r, or a pharmaceutically acceptable salt thereof. [0371] In some embodiments, the compound is a compound of formula II-s, or a pharmaceutically acceptable salt thereof. [0372] In some embodiments, the compound is a compound of formula II-t, or a pharmaceutically acceptable salt thereof. [0373] In some embodiments, the compound is a compound of formula II-u, or a pharmaceutically acceptable salt thereof. [0374] In some embodiments, the compound is a compound of formula II-v, or a pharmaceutically acceptable salt thereof. [0375] In certain embodiments, the present invention provides a compound of formula I-1, I-1’, , ,

a compound of one of formulas II-w, II-x, II-y, II-z, II-aa, II-bb, II-cc, II-dd or II-ee, respectively:

or a pharmaceutically acceptable salt thereof, wherein each of Ring A, Ring C, R ¹ , R ³ , R ⁶ , m, p, t, L, and LBM is as defined in embodiments and classes and subclasses herein. [0376] In some embodiments, the compound is a compound of formula II-w, or a pharmaceutically acceptable salt thereof. [0377] In some embodiments, the compound is a compound of formula II-x, or a pharmaceutically acceptable salt thereof. [0378] In some embodiments, the compound is a compound of formula II-y, or a pharmaceutically acceptable salt thereof. [0379] In some embodiments, the compound is a compound of formula II-z, or a pharmaceutically acceptable salt thereof. [0380] In some embodiments, the compound is a compound of formula II-aa, or a pharmaceutically acceptable salt thereof. [0381] In some embodiments, the compound is a compound of formula II-bb, or a pharmaceutically acceptable salt thereof. [0382] In some embodiments, the compound is a compound of formula II-cc, or a pharmaceutically acceptable salt thereof. [0383] In some embodiments, the compound is a compound of formula II-dd, or a pharmaceutically acceptable salt thereof. [0384] In some embodiments, the compound is a compound of formula II-ee, or a pharmaceutically acceptable salt thereof. [0385] In some embodiments, the compound is a compound of one of formulas II-n-1, II-o-1, II- p-1, II-q-1, II-r-1, II-s-1, II-t-1, II-u-1 or II-v-1: or a pharmaceutically acceptable salt thereof, wherein each of Ring A, R ¹ , R ³ , m, p, L, and LBM is as defined in embodiments and classes and subclasses herein. [0386] In some embodiments, the compound is a compound of formula II-n-1, or a pharmaceutically acceptable salt thereof. [0387] In some embodiments, the compound is a compound of formula II-o-1, or a pharmaceutically acceptable salt thereof. [0388] In some embodiments, the compound is a compound of formula II-p-1, or a pharmaceutically acceptable salt thereof. [0389] In some embodiments, the compound is a compound of formula II-q-1, or a pharmaceutically acceptable salt thereof. [0390] In some embodiments, the compound is a compound of formula II-r-1, or a pharmaceutically acceptable salt thereof. [0391] In some embodiments, the compound is a compound of formula II-s-1, or a pharmaceutically acceptable salt thereof. [0392] In some embodiments, the compound is a compound of formula II-t-1, or a pharmaceutically acceptable salt thereof. [0393] In some embodiments, the compound is a compound of formula II-u-1 or a pharmaceutically acceptable salt thereof. [0394] In some embodiments, the compound is a compound of formula II-v-1 or a pharmaceutically acceptable salt thereof. [0395] In some embodiments, the compound is a compound of one of formulas II-w-1, II-x-1, II- y-1, II-z-1, II-aa-1, II-bb-1, II-cc-1, II-dd-1 or II-ee-1:

or a pharmaceutically acceptable salt thereof, wherein each of Ring A, Ring C, R ¹ , R ³ , R ⁶ , m, p, t, L, and LBM is as defined in embodiments and classes and subclasses herein. [0396] In some embodiments, the compound is a compound of formula II-w-1, or a pharmaceutically acceptable salt thereof. [0397] In some embodiments, the compound is a compound of formula II-x-1, or a pharmaceutically acceptable salt thereof. [0398] In some embodiments, the compound is a compound of formula II-y-1, or a pharmaceutically acceptable salt thereof. [0399] In some embodiments, the compound is a compound of formula II-z-1, or a pharmaceutically acceptable salt thereof. [0400] In some embodiments, the compound is a compound of formula II-aa-1, or a pharmaceutically acceptable salt thereof. [0401] In some embodiments, the compound is a compound of formula II-bb-1, or a pharmaceutically acceptable salt thereof. [0402] In some embodiments, the compound is a compound of formula II-cc-1, or a pharmaceutically acceptable salt thereof. [0403] In some embodiments, the compound is a compound of formula II-dd-1, or a pharmaceutically acceptable salt thereof. [0404] In some embodiments, the compound is a compound of formula II-ee-1 , or a pharmaceutically acceptable salt thereof. [0405] In some embodiments, the compound is a compound of one of formulas II-ff-1, II-gg-1, II-hh-1, II-ii-1, II-jj-1, II-kk-1, II-ll-1, II-mm-1 or II-nn-1: or a pharmaceutically acceptable salt thereof, wherein each of Ring A, R ^A1 , R ¹ , R ³ , m, p, L, and LBM is as defined in embodiments and classes and subclasses herein. [0406] In some embodiments, the compound is a compound of formula II-ff-1, or a pharmaceutically acceptable salt thereof. [0407] In some embodiments, the compound is a compound of formula II-gg-1, or a pharmaceutically acceptable salt thereof. [0408] In some embodiments, the compound is a compound of formula II-hh-1, or a pharmaceutically acceptable salt thereof. [0409] In some embodiments, the compound is a compound of formula II-ii-1, or a pharmaceutically acceptable salt thereof. [0410] In some embodiments, the compound is a compound of formula II-jj-1, or a pharmaceutically acceptable salt thereof. [0411] In some embodiments, the compound is a compound of formula II-kk-1, or a pharmaceutically acceptable salt thereof. [0412] In some embodiments, the compound is a compound of formula II-ll-1, or a pharmaceutically acceptable salt thereof. [0413] In some embodiments, the compound is a compound of formula II-mm-1, or a pharmaceutically acceptable salt thereof. [0414] In some embodiments, the compound is a compound of formula II-nn-1 , or a pharmaceutically acceptable salt thereof. [0415] In certain embodiments, the present invention provides a compound of formula I-1, I-1’, I-2, I-2’, I-3 or I-3’, wherein thereby forming a compound of one of formulas III-a, III-b, or III-c, respectively: III-a III-b III-c or a pharmaceutically acceptable salt thereof, wherein each of Ring B, R ¹ , R ² , R ³ , X ¹ , X ² , m, n, p, L, and LBM is as defined in embodiments and classes and subclasses herein. [0416] In some embodiments of formulas III-a, III-b and III-c, when X ¹ is CH or N and X ² is CH ₂ , then Ring B is other than phenyl. [0417] In some embodiments, the compound is a compound of formula III-a, or a pharmaceutically acceptable salt thereof. In some embodiments, when X ¹ is CH or N and X ² is CH2, then Ring B is other than phenyl. [0418] In some embodiments, the compound is a compound of formula III-b, or a pharmaceutically acceptable salt thereof. In some embodiments, when X ¹ is CH or N and X ² is CH ₂ , then Ring B is other than phenyl. [0419] In some embodiments, the compound is a compound of formula III-c, or a pharmaceutically acceptable salt thereof. In some embodiments, when X ¹ is CH or N and X ² is CH ₂ , then Ring B is other than phenyl. [0420] In certain embodiments, the present invention provides a compound of formula I-1, I-1’, of one of formulas III-a-A, III-b-A, III-c-A, III-a-B, III-b-B, III-c-B, III-a-C, III-b-C and III- c-C, respectively: or a pharmaceutically acceptable salt thereof, wherein each of Ring B, R ¹ , R ² , R ³ , X ¹ , X ² , m, n, p, L, and LBM is as defined in embodiments and classes and subclasses herein. [0421] In some embodiments of formulas III-a-A, III-b-A and III-c-A , when X ¹ is CH or N and X ² is CH ₂ , then Ring B is other than phenyl. [0422] In some embodiments, the compound is a compound of formula III-a-A, or a pharmaceutically acceptable salt thereof. In some embodiments, when X ¹ is CH or N and X ² is CH ₂ , then Ring B is other than phenyl. [0423] In some embodiments, the compound is a compound of formula III-b-A, or a pharmaceutically acceptable salt thereof. In some embodiments, when X ¹ is CH or N and X ² is CH ₂ , then Ring B is other than phenyl. [0424] In some embodiments, the compound is a compound of formula III-c-A, or a pharmaceutically acceptable salt thereof. In some embodiments, when X ¹ is CH or N and X ² is CH ₂ , then Ring B is other than phenyl. [0425] In some embodiments, the compound is a compound of formula III-a-B, or a pharmaceutically acceptable salt thereof. [0426] In some embodiments, the compound is a compound of formula III-b-B, or a pharmaceutically acceptable salt thereof. [0427] In some embodiments, the compound is a compound of formula III-c-B, or a pharmaceutically acceptable salt thereof. [0428] In some embodiments, the compound is a compound of formula III-a-C, or a pharmaceutically acceptable salt thereof. [0429] In some embodiments, the compound is a compound of formula III-b-C, or a pharmaceutically acceptable salt thereof. [0430] In some embodiments, the compound is a compound of formula III-c-C, or a pharmaceutically acceptable salt thereof. [0431] In certain embodiments, the present invention provides a compound of formula I-1, I-1’,

III-j III-k III-l or a pharmaceutically acceptable salt thereof, wherein each of Ring B, R ¹ , R ² , R ³ , m, n, p, L, and LBM is as defined in embodiments and classes and subclasses herein. [0432] In some embodiments, when the compound is of formula III-d, III-e, III-f, III-j, III-k or III-l then Ring B is other than phenyl. [0433] In some embodiments, the compound is a compound of formula III-d, or a pharmaceutically acceptable salt thereof. In some embodiments, Ring B is other than phenyl. [0434] In some embodiments, the compound is a compound of formula III-e, or a pharmaceutically acceptable salt thereof. In some embodiments, Ring B is other than phenyl. [0435] In some embodiments, the compound is a compound of formula III-f, or a pharmaceutically acceptable salt thereof. In some embodiments, Ring B is other than phenyl. [0436] In some embodiments, the compound is a compound of formula III-g, or a pharmaceutically acceptable salt thereof. [0437] In some embodiments, the compound is a compound of formula III-h, or a pharmaceutically acceptable salt thereof. [0438] In some embodiments, the compound is a compound of formula III-i, or a pharmaceutically acceptable salt thereof. [0439] In some embodiments, the compound is a compound of formula III-j, or a pharmaceutically acceptable salt thereof. In some embodiments, Ring B is other than phenyl. [0440] In some embodiments, the compound is a compound of formula III-k, or a pharmaceutically acceptable salt thereof. In some embodiments, Ring B is other than phenyl. [0441] In some embodiments, the compound is a compound of formula III-l, or a pharmaceutically acceptable salt thereof. In some embodiments, Ring B is other than phenyl. In certain embodiments, the present invention provides a compound of formula I-1, I-1’, I-2, I- 2’, I-3 or I-3’, wherein

, thereby forming a compound of one of formulas III-d-A, III-e-A, or III-l-A, respectively:

III-j-A III-k-A III-l-A or a pharmaceutically acceptable salt thereof, wherein each of Ring B, R ¹ , R ² , R ³ , m, n, p, L, and LBM is as defined in embodiments and classes and subclasses herein. [0442] In some embodiments, when the compound is of formula III-d-A, III-e-A, III-f-A, III-j- A, III-k-A, or III-l-A, then Ring B is other than phenyl. [0443] In some embodiments, the compound is a compound of formula III-d-A, or a pharmaceutically acceptable salt thereof. In some embodiments, Ring B is other than phenyl. [0444] In some embodiments, the compound is a compound of formula III-e-A, or a pharmaceutically acceptable salt thereof. In some embodiments, Ring B is other than phenyl. [0445] In some embodiments, the compound is a compound of formula III-f-A, or a pharmaceutically acceptable salt thereof. In some embodiments, Ring B is other than phenyl. [0446] In some embodiments, the compound is a compound of formula III-d-B, or a pharmaceutically acceptable salt thereof. [0447] In some embodiments, the compound is a compound of formula III-e-B, or a pharmaceutically acceptable salt thereof. [0448] In some embodiments, the compound is a compound of formula III-f-B, or a pharmaceutically acceptable salt thereof. [0449] In some embodiments, the compound is a compound of formula III-d-C, or a pharmaceutically acceptable salt thereof. [0450] In some embodiments, the compound is a compound of formula III-e-C, or a pharmaceutically acceptable salt thereof. [0451] In some embodiments, the compound is a compound of formula III-f-C, or a pharmaceutically acceptable salt thereof. [0452] In some embodiments, the compound is a compound of formula III-g, or a pharmaceutically acceptable salt thereof. [0453] In some embodiments, the compound is a compound of formula III-h, or a pharmaceutically acceptable salt thereof. [0454] In some embodiments, the compound is a compound of formula III-i, or a pharmaceutically acceptable salt thereof. [0455] In some embodiments, the compound is a compound of formula III-j-A, or a pharmaceutically acceptable salt thereof. In some embodiments, Ring B is other than phenyl. [0456] In some embodiments, the compound is a compound of formula III-k-A, or a pharmaceutically acceptable salt thereof. In some embodiments, Ring B is other than phenyl. [0457] In some embodiments, the compound is a compound of formula III-l-A, or a pharmaceutically acceptable salt thereof. In some embodiments, Ring B is other than phenyl. [0458] In certain embodiments, the present invention provides a compound of formula I-1, I-1’, one of formulas III-m, III-n, or III-o, respectively:

III-o or a pharmaceutically acceptable salt thereof, wherein each of Ring A, R ¹ , R ² , R ³ , X ¹ , X ² , m, n, p, L, and LBM is as defined in embodiments and classes and subclasses herein. [0459] In some embodiments, when X ¹ is CH or N and X ² is CH ₂ , then Ring A is other than phenyl or a 6 membered monocyclic heteroaryl ring having 1-3 nitrogen heteroatoms. [0460] In some embodiments, the compound is a compound of formula III-m, or a pharmaceutically acceptable salt thereof. In some embodiments, when X ¹ is CH or N and X ² is CH ₂ , then Ring A is other than phenyl or a 6 membered monocyclic heteroaryl ring having 1-3 nitrogen heteroatoms. [0461] In some embodiments, the compound is a compound of formula III-n, or a pharmaceutically acceptable salt thereof. In some embodiments, when X ¹ is CH or N and X ² is CH ₂ , then Ring A is other than phenyl or a 6 membered monocyclic heteroaryl ring having 1-3 nitrogen heteroatoms. [0462] In some embodiments, the compound is a compound of formula III-o, or a pharmaceutically acceptable salt thereof. In some embodiments, when X ¹ is CH or N and X ² is CH ₂ , then Ring A is other than phenyl or a 6 membered monocyclic heteroaryl ring having 1-3 nitrogen heteroatoms. In certain embodiments, the present invention provides a compound of formula I-1, I-1’, I-2, I- thereby forming a compound of one of formulas III-m-A, III-n-A, or III-o-A, III-m-B, III-n-B, III-o-B, III-m-C, III-n-C, or III-o-C:

or a pharmaceutically acceptable salt thereof, wherein each of Ring B, R ¹ , R ² , R ³ , m, n, p, L, and LBM is as defined in embodiments and classes and subclasses herein. [0463] In some embodiments, when the compound is of formulae III-m-A, III-n-A or III-o-A and X ¹ is CH or N and X ² is CH ₂ , then Ring A is other than phenyl or a 6 membered monocyclic heteroaryl ring having 1-3 nitrogen heteroatoms. [0464] In some embodiments, the compound is a compound of formula III-m-A, or a pharmaceutically acceptable salt thereof. In some embodiments, when X ¹ is CH or N and X ² is CH ₂ , then Ring A is other than phenyl or a 6 membered monocyclic heteroaryl ring having 1-3 nitrogen heteroatoms. [0465] In some embodiments, the compound is a compound of formula III-n-A, or a pharmaceutically acceptable salt thereof. In some embodiments, when X ¹ is CH or N and X ² is CH ₂ , then Ring A is other than phenyl or a 6 membered monocyclic heteroaryl ring having 1-3 nitrogen heteroatoms. [0466] In some embodiments, the compound is a compound of formula III-o-A, or a pharmaceutically acceptable salt thereof. In some embodiments, when X ¹ is CH or N and X ² is CH ₂ , then Ring A is other than phenyl or a 6 membered monocyclic heteroaryl ring having 1-3 nitrogen heteroatoms. [0467] In some embodiments, the compound is a compound of formula III-m-B, or a pharmaceutically acceptable salt thereof [0468] In some embodiments, the compound is a compound of formula III-n-B, or a pharmaceutically acceptable salt thereof. [0469] In some embodiments, the compound is a compound of formula III-o-B, or a pharmaceutically acceptable salt thereof. [0470] In some embodiments, the compound is a compound of formula or a pharmaceutically acceptable salt thereof [0471] In some embodiments, the compound is a compound of formula III-n-C, or a pharmaceutically acceptable salt thereof. [0472] In some embodiments, the compound is a compound of formula III-o-C, or a pharmaceutically acceptable salt thereof. [0473] In certain embodiments, the present invention provides a compound of formula I-1, I-1’, III-s, III-t, III-u, III-v, III-w, or III-x, respectively:

III-v III-w III-x or a pharmaceutically acceptable salt thereof, wherein each of Ring A, R ¹ , R ² , R ³ , m, n, p, L, and LBM is as defined in embodiments and classes and subclasses herein. In some embodiments, when the compound is of formulas III-p, III-q, III-r, III-v, III-w or III-x, then Ring A is other than phenyl or a 6 membered monocyclic heteroaryl ring having 1-3 nitrogen heteroatoms. [0474] In some embodiments, the compound is a compound of formula III-p, or a pharmaceutically acceptable salt thereof. In some embodiments, Ring A is other than phenyl or a 6 membered monocyclic heteroaryl ring having 1-3 nitrogen heteroatoms. [0475] In some embodiments, the compound is a compound of formula III-q, or a pharmaceutically acceptable salt thereof. In some embodiments, Ring A is other than phenyl or a 6 membered monocyclic heteroaryl ring having 1-3 nitrogen heteroatoms [0476] In some embodiments, the compound is a compound of formula III-r, or a pharmaceutically acceptable salt thereof. In some embodiments, Ring A is other than phenyl or a 6 membered monocyclic heteroaryl ring having 1-3 nitrogen heteroatoms. [0477] In some embodiments, the compound is a compound of formula III-s, or a pharmaceutically acceptable salt thereof. [0478] In some embodiments, the compound is a compound of formula or a pharmaceutically acceptable salt thereof. [0479] In some embodiments, the compound is a compound of formula III-u, or a pharmaceutically acceptable salt thereof. [0480] In some embodiments, the compound is a compound of formula III-v, or a pharmaceutically acceptable salt thereof. In some embodiments, Ring A is other than phenyl or a 6 membered monocyclic heteroaryl ring having 1-3 nitrogen heteroatoms. [0481] In some embodiments, the compound is a compound of formula III-w, or a pharmaceutically acceptable salt thereof. In some embodiments, Ring A is other than phenyl or a 6 membered monocyclic heteroaryl ring having 1-3 nitrogen heteroatoms. [0482] In some embodiments, the compound is a compound of formula III-x, or a pharmaceutically acceptable salt thereof. In some embodiments, Ring A is other than phenyl or a 6 membered monocyclic heteroaryl ring having 1-3 nitrogen heteroatoms. In certain embodiments, the present invention provides a compound of formula I-1, I-1’, I-2, I- 2’, I-3 or I-3’, wherein

ereby forming a compound of one of formulas III-p-A, III-q-A, III-r-A, III-p-B, III-q-B, III-r-B, III-p-C, III-q-C, III-r-C, III-s, III-t, III-u, III-v-A, III-w- A, or III-x-A, respectively:

III IIIt III

III-v-A III-w-A III-x-A or a pharmaceutically acceptable salt thereof, wherein each of Ring A, R ¹ , R ² , R ³ , m, n, p, L, and LBM is as defined in embodiments and classes and subclasses herein. [0483] In some embodiments, when the compound is of formulas III-p-A, III-q-A, III-r-A, III- v-A, III-w-A or III-x-A, then Ring A is other than phenyl or a 6 membered monocyclic heteroaryl ring having 1-3 nitrogen heteroatoms. [0484] In some embodiments, the compound is a compound of formula III-p-A, or a pharmaceutically acceptable salt thereof. In some embodiments, Ring A is other than phenyl or a 6 membered monocyclic heteroaryl ring having 1-3 nitrogen heteroatoms. [0485] In some embodiments, the compound is a compound of formula III-q-A, or a pharmaceutically acceptable salt thereof. In some embodiments, Ring A is other than phenyl or a 6 membered monocyclic heteroaryl ring having 1-3 nitrogen heteroatoms. [0486] In some embodiments, the compound is a compound of formula III-r-A, or a pharmaceutically acceptable salt thereof. In some embodiments, Ring A is other than phenyl or a 6 membered monocyclic heteroaryl ring having 1-3 nitrogen heteroatoms. [0487] In some embodiments, the compound is a compound of formula III-p-B, or a pharmaceutically acceptable salt thereof. [0488] In some embodiments, the compound is a compound of formula III-q-B, or a pharmaceutically acceptable salt thereof. [0489] In some embodiments, the compound is a compound of formula III-r-B, or a pharmaceutically acceptable salt thereof. [0490] In some embodiments, the compound is a compound of formula III-p-C, or a [0491] In some embodiments, the compound is a compound of formula III-q-C, or a pharmaceutically acceptable salt thereof. [0492] In some embodiments, the compound is a compound of formula III-r-C, or a pharmaceutically acceptable salt thereof. [0493] In some embodiments, the compound is a compound of formula III-v-A, or a pharmaceutically acceptable salt thereof. In some embodiments, Ring A is other than phenyl or a 6 membered monocyclic heteroaryl ring having 1-3 nitrogen heteroatoms. [0494] In some embodiments, the compound is a compound of formula III-w-A, or a pharmaceutically acceptable salt thereof. In some embodiments, Ring A is other than phenyl or a 6 membered monocyclic heteroaryl ring having 1-3 nitrogen heteroatoms. [0495] In some embodiments, the compound is a compound of formula III-x-A, or a pharmaceutically acceptable salt thereof. In some embodiments, Ring A is other than phenyl or a 6 membered monocyclic heteroaryl ring having 1-3 nitrogen heteroatoms. [0496] In certain embodiments, the present invention provides a compound of formula I-1, I-1’, one of formulas IV-a, IV-b, or IV-c, respectively:

IV-c or a pharmaceutically acceptable salt thereof, wherein represents a single or double bond and each of Ring A, R ¹ , R ² , R ³ , X ¹ , X ² , m, n, p, L, and LBM is as defined in embodiments and classes and subclasses herein. [0497] In some embodiments, the compound is a compound of formula IV-a, or a pharmaceutically acceptable salt thereof. [0498] In some embodiments, the compound is a compound of formula IV-b, or a pharmaceutically acceptable salt thereof. [0499] In some embodiments, the compound is a compound of formula IV-b, or a pharmaceutically acceptable salt thereof. [0500] In certain embodiments, the present invention provides a compound of formula I-1, I-1’, I-2, I-2’, I-3 or I-3’, wherein

or a pharmaceutically acceptable salt thereof, wherein represents a single or double bond and each of Ring A, R ¹ , R ² , R ³ , m, n, p, L, and LBM is as defined in embodiments and classes and subclasses herein. [0501] In some embodiments, the compound is a compound of formula IV-d, or a pharmaceutically acceptable salt thereof. [0502] In some embodiments, the compound is a compound of formula IV-e, or a pharmaceutically acceptable salt thereof. [0503] In some embodiments, the compound is a compound of formula IV-f, or a pharmaceutically acceptable salt thereof. [0504] In some embodiments, the compound is a compound of formula IV-g, or a pharmaceutically acceptable salt thereof. [0505] In some embodiments, the compound is a compound of formula IV-h, or a pharmaceutically acceptable salt thereof. [0506] In some embodiments, the compound is a compound of formula IV-i, or a pharmaceutically acceptable salt thereof. [0507] In some embodiments, the compound is a compound of formula IV-j, or a pharmaceutically acceptable salt thereof. [0508] In some embodiments, the compound is a compound of formula IV-k, or a pharmaceutically acceptable salt thereof. [0509] In some embodiments, the compound is a compound of formula IV-l, or a pharmaceutically acceptable salt thereof. [0510] In certain embodiments, the present invention provides a compound of formula I-1, I-1’, one of formulas IV-m, IV-n, or IV-o, respectively: IV-o or a pharmaceutically acceptable salt thereof, wherein each of R ¹ , R ² , R ³ , X ¹ , X ² , m, n, p, L, and LBM is as defined in embodiments and classes and subclasses herein. In some embodiments, when X ¹ is CH or N then X ² is other than CH ₂ . [0511] In some embodiments, the compound is a compound of formula IV-m, or a pharmaceutically acceptable salt thereof. In some embodiments, when X ¹ is CH or N then X ² is other than CH ₂ [0512] In some embodiments, the compound is a compound of formula IV-n, or a pharmaceutically acceptable salt thereof. In some embodiments, when X ¹ is CH or N then X ² is other than CH ₂ . [0513] In some embodiments, the compound is a compound of formula IV-o, or a pharmaceutically acceptable salt thereof. In some embodiments, when X ¹ is CH or N then X ² is other than CH ₂ . [0514] In certain embodiments, the present invention provides a compound of formula I-1, I-1’, IV-o-A, IV-m-B, IV-n-B, IV-o-B, IV-m-C, IV-n-C, or IV-o-C, respectively:

IV-o-B

IV-o-C or a pharmaceutically acceptable salt thereof, wherein each of R ¹ , R ² , R ³ , X ¹ , X ² , m, n, p, L, and LBM is as defined in embodiments and classes and subclasses herein. [0515] In some embodiments, when the compound is of formula IV-m-A, IV-n-A or IV-o-A and X ¹ is CH or N then X ² is other than CH ₂ . [0516] In some embodiments, the compound is a compound of formula IV-m-A, or a pharmaceutically acceptable salt thereof. In some embodiments, when X ¹ is CH or N then X ² is other than CH2. [0517] In some embodiments, the compound is a compound of formula IV-n-A, or a pharmaceutically acceptable salt thereof. In some embodiments, when X ¹ is CH or N then X ² is other than CH ₂ . [0518] In some embodiments, the compound is a compound of formula IV-o-A, or a pharmaceutically acceptable salt thereof. In some embodiments, when X ¹ is CH or N then X ² is other than CH ₂ . [0519] In some embodiments, the compound is a compound of formula IV-m-B, or a pharmaceutically acceptable salt thereof. [0520] In some embodiments, the compound is a compound of formula IV-n-B, or a pharmaceutically acceptable salt thereof. [0521] In some embodiments, the compound is a compound of formula IV-o-B, or a pharmaceutically acceptable salt thereof. [0522] In some embodiments, the compound is a compound of formula IV-m-C, or a pharmaceutically acceptable salt thereof. [0523] In some embodiments, the compound is a compound of formula IV-n-C, or a pharmaceutically acceptable salt thereof. [0524] In some embodiments, the compound is a compound of formula IV-o-C, or a pharmaceutically acceptable salt thereof. [0525] In certain embodiments, the present invention provides a compound of formula I-1, I-1’, , , ,

IV-v IV-w IV-x or a pharmaceutically acceptable salt thereof, wherein each of R ¹ , R ² , R ³ , m, n, p, L, and LBM is as defined in embodiments and classes and subclasses herein. [0526] In some embodiments, the compound is a compound of formula IV-p, or a pharmaceutically acceptable salt thereof. [0527] In some embodiments, the compound is a compound of formula IV-q, or a pharmaceutically acceptable salt thereof. [0528] In some embodiments, the compound is a compound of formula IV-r, or a pharmaceutically acceptable salt thereof. [0529] In some embodiments, the compound is a compound of formula IV-s, or a pharmaceutically acceptable salt thereof. [0530] In some embodiments, the compound is a compound of formula IV-t, or a pharmaceutically acceptable salt thereof. [0531] In some embodiments, the compound is a compound of formula IV-u, or a pharmaceutically acceptable salt thereof. [0532] In some embodiments, the compound is a compound of formula IV-v, or a pharmaceutically acceptable salt thereof. [0533] In some embodiments, the compound is a compound of formula IV-w, or a pharmaceutically acceptable salt thereof. [0534] In some embodiments, the compound is a compound of formula IV-x, or a pharmaceutically acceptable salt thereof. [0535] In certain embodiments, the present invention provides a compound of formula I-1, I-1’,

IVdd IV IVff

or a pharmaceutically acceptable salt thereof, wherein each of R ¹ , R ² , R ³ , m, n, p, L, and LBM is as defined in embodiments and classes and subclasses herein. [0536] In some embodiments, the compound is a compound of formula IV-aa, or a pharmaceutically acceptable salt thereof. [0537] In some embodiments, the compound is a compound of formula IV-bb, or a pharmaceutically acceptable salt thereof. [0538] In some embodiments, the compound is a compound of formula IV-cc, or a pharmaceutically acceptable salt thereof. [0539] In some embodiments, the compound is a compound of formula IV-dd, or a pharmaceutically acceptable salt thereof. [0540] In some embodiments, the compound is a compound of formula IV-ee, or a pharmaceutically acceptable salt thereof. [0541] In some embodiments, the compound is a compound of formula IV-ff, or a pharmaceutically acceptable salt thereof. [0542] In some embodiments, the compound is a compound of formula IV-gg, or a pharmaceutically acceptable salt thereof [0543] In some embodiments, the compound is a compound of formula IV-hh, or a pharmaceutically acceptable salt thereof. [0544] In some embodiments, the compound is a compound of formula IV-ii, or a pharmaceutically acceptable salt thereof. [0545] In some embodiments, the compound is a compound of formula IV-jj, or a pharmaceutically acceptable salt thereof. [0546] In some embodiments, the compound is a compound of formula IV-kk, or a pharmaceutically acceptable salt thereof. [0547] In some embodiments, the compound is a compound of formula IV-ll, or a pharmaceutically acceptable salt thereof. [0548] In certain embodiments, the present invention provides a compound of formula I-1, I-1’, one of formulas V-a, V-b, or V-c, respectively: V-a V-b

or a pharmaceutically acceptable salt thereof, wherein represents a single or double bond and each of R ¹ , R ² , R ³ , X ¹ , X ² , m, n, p, L, and LBM is as defined in embodiments and classes and subclasses herein. [0549] In some embodiments, the compound is a compound of formula V-a, or a pharmaceutically acceptable salt thereof. [0550] In some embodiments, the compound is a compound of formula V-b, or a pharmaceutically acceptable salt thereof. [0551] In some embodiments, the compound is a compound of formula V-c, or a pharmaceutically acceptable salt thereof. [0552] In certain embodiments, the present invention provides a compound of formula I-1, I-1’, , , or a pharmaceutically acceptable salt thereof, wherein represents a single or double bond and each of R ¹ , R ² , R ³ , m, n, p, L, and LBM is as defined in embodiments and classes and subclasses herein. [0553] In some embodiments, the compound is a compound of formula V-d, or a pharmaceutically acceptable salt thereof. [0554] In some embodiments, the compound is a compound of formula V-e, or a pharmaceutically acceptable salt thereof. [0555] In some embodiments, the compound is a compound of formula V-f, or a pharmaceutically acceptable salt thereof. [0556] In some embodiments, the compound is a compound of formula V-g, or a pharmaceutically acceptable salt thereof. [0557] In some embodiments, the compound is a compound of formula V-h, or a pharmaceutically acceptable salt thereof. [0558] In some embodiments, the compound is a compound of formula V-i, or a pharmaceutically acceptable salt thereof. [0559] In some embodiments, the compound is a compound of formula V-j, or a pharmaceutically acceptable salt thereof. [0560] In some embodiments, the compound is a compound of formula V-k, or a pharmaceutically acceptable salt thereof. [0561] In some embodiments, the compound is a compound of formula V-l, or a pharmaceutically acceptable salt thereof. [0562] In certain embodiments, the present invention provides a compound of formula I-1, I-1’, I-2, I-2’, I-3 or I-3’, wherein ERBM is , compound of one of formulas VI-a, VI-b, or VI-c, respectively: or a pharmaceutically acceptable salt thereof, wherein each of Ring A, R ¹ , R ² , R ³ , m, n, p, L, and LBM is as defined in embodiments and classes and subclasses herein. [0563] In certain embodiments, the present invention provides a compound of formula I-1, I-1’, , thereby forming a compound of one of formulas VI-d, VI-e, or VI-f, respectively: or a pharmaceutically acceptable salt thereof, wherein each of Ring A, R ¹ , R ² , R ³ , m, n, p, L, and LBM is as defined in embodiments and classes and subclasses herein. [0564] In certain embodiments, the present invention provides a compound of formula I-1, I-1’, , thereby forming a compound of one of formulas VI-g, VI-h, VI-i, VI-j, VI-k, or VI-l, respectively: or a pharmaceutically acceptable salt thereof, wherein each of Ring A, R ¹ , R ² , R ³ , m, n, p, L, and LBM is as defined in embodiments and classes and subclasses herein. [0565] In certain embodiments, the present invention provides a compound of formula I-1, I-1’, I-2, I-2’, I-3 or I-3’, wherein ERBM is , thereby forming a compound of one of formulas VI-m, VI-n, or VI-o, respectively: VI-m VI-n VI-o or a pharmaceutically acceptable salt thereof, wherein each of Ring A, R ¹ , R ² , R ³ , m, n, p, L, and LBM is as defined in embodiments and classes and subclasses herein. [0566] In some embodiments, the compound is a compound of formula VI-a, or a pharmaceutically acceptable salt thereof. [0567] In some embodiments, the compound is a compound of formula VI-b, or a pharmaceutically acceptable salt thereof. [0568] In some embodiments, the compound is a compound of formula VI-c, or a pharmaceutically acceptable salt thereof. [0569] In some embodiments, the compound is a compound of formula VI-d, or a pharmaceutically acceptable salt thereof. [0570] In some embodiments, the compound is a compound of formula VI-e, or a pharmaceutically acceptable salt thereof. [0571] In some embodiments, the compound is a compound of formula VI-f, or a pharmaceutically acceptable salt thereof. [0572] In some embodiments, the compound is a compound of formula VI-g, or a pharmaceutically acceptable salt thereof. [0573] In some embodiments, the compound is a compound of formula VI-h, or a pharmaceutically acceptable salt thereof. [0574] In some embodiments, the compound is a compound of formula VI-i, or a pharmaceutically acceptable salt thereof. [0575] In some embodiments, the compound is a compound of formula VI-j, or a pharmaceutically acceptable salt thereof. [0576] In some embodiments, the compound is a compound of formula VI-k, or a pharmaceutically acceptable salt thereof. [0577] In some embodiments, the compound is a compound of formula VI-l, or a pharmaceutically acceptable salt thereof. [0578] In some embodiments, the compound is a compound of formula VI-m, or a pharmaceutically acceptable salt thereof. [0579] In some embodiments, the compound is a compound of formula VI-n, or a pharmaceutically acceptable salt thereof. [0580] In some embodiments, the compound is a compound of formula VI-o, or a pharmaceutically acceptable salt thereof. [0581] In certain embodiments, the present invention provides a compound of formula I-1, I-1’, ,

one of formulas II-j-2, II-k-2, or II-l-2, respectively: or a pharmaceutically acceptable salt thereof, wherein each of Ring A, Ring B, R ¹ , R ² , R ³ , m, n, p, L, and LBM is as defined in embodiments and classes and subclasses herein. [0582] In certain embodiments, the present invention provides a compound of formula I-1, I-1’, ,

, thereby forming a compound of one of formulas VII-a, VII-b, VII-c, VII-d, VII-e, or VII-f, respectively:

or a pharmaceutically acceptable salt thereof, wherein each of Ring A, R ¹ , R ² , R ³ , m, n, p, L, and LBM is as defined in embodiments and classes and subclasses herein. [0583] In certain embodiments, the present invention provides a compound of formula I-1, I-1’, of one of formulas VII-g, VII-h, or VII-i, respectively:

or a pharmaceutically acceptable salt thereof, wherein each of Ring A, R ¹ , R ² , R ³ , m, n, p, L, and LBM is as defined in embodiments and classes and subclasses herein. [0584] In certain embodiments, the present invention provides a compound of formula I-1, I-1’, thereby forming a compound of one of formulas VII-j, VII-k, VII-l, VII-m, VII-n, or VII-o, respectively:

or a pharmaceutically acceptable salt thereof, wherein each of Ring A, R ¹ , R ² , R ³ , m, n, p, L, and LBM is as defined in embodiments and classes and subclasses herein. [0585] In certain embodiments, the present invention provides a compound of formula I-1, I-1’, I-2, I-2’, I-3 or I-3’, wherein ERBM is ,

compound of one of formulas VII-p, VII-q, or VII-r, respectively: or a pharmaceutically acceptable salt thereof, wherein each of Ring A, R ¹ , R ² , R ³ , m, n, p, L, and LBM is as defined in embodiments and classes and subclasses herein. [0586] In some embodiments, the compound is a compound of formula VII-a, or a pharmaceutically acceptable salt thereof. [0587] In some embodiments, the compound is a compound of formula VII-b, or a pharmaceutically acceptable salt thereof. [0588] In some embodiments, the compound is a compound of formula VII-c, or a pharmaceutically acceptable salt thereof. [0589] In some embodiments, the compound is a compound of formula VII-d, or a pharmaceutically acceptable salt thereof. [0590] In some embodiments, the compound is a compound of formula VII-e, or a pharmaceutically acceptable salt thereof. [0591] In some embodiments, the compound is a compound of formula VII-f, or a pharmaceutically acceptable salt thereof. [0592] In some embodiments, the compound is a compound of formula VII-g, or a pharmaceutically acceptable salt thereof. [0593] In some embodiments, the compound is a compound of formula VII-h, or a pharmaceutically acceptable salt thereof. [0594] In some embodiments, the compound is a compound of formula VII-i, or a pharmaceutically acceptable salt thereof. [0595] In some embodiments, the compound is a compound of formula VII-j, or a pharmaceutically acceptable salt thereof. [0596] In some embodiments, the compound is a compound of formula VII-k, or a pharmaceutically acceptable salt thereof. [0597] In some embodiments, the compound is a compound of formula VII-l, or a pharmaceutically acceptable salt thereof. [0598] In some embodiments, the compound is a compound of formula VII-m, or a pharmaceutically acceptable salt thereof. [0599] In some embodiments, the compound is a compound of formula VII-n, or a pharmaceutically acceptable salt thereof. [0600] In some embodiments, the compound is a compound of formula VII-o, or a pharmaceutically acceptable salt thereof. [0601] In some embodiments, the compound is a compound of formula VII-p, or a pharmaceutically acceptable salt thereof. [0602] In some embodiments, the compound is a compound of formula VII-q, or a pharmaceutically acceptable salt thereof. [0603] In some embodiments, the compound is a compound of formula VII-r, or a pharmaceutically acceptable salt thereof. [0604] In some embodiments, the compound is a compound of one of formulas VIII-d, VIII-e, and VIII-f: or a pharmaceutically acceptable salt thereof wherein each of X ¹ , X ² , R ¹ , R ³ , m, p, L, and LBM is as defined in embodiments and classes and subclasses herein.In some embodiments, the compound is a compound of formula VIII-d, or a pharmaceutically acceptable salt thereof. [0605] In some embodiments, the compound is a compound of formula VIII-e, or a pharmaceutically acceptable salt thereof. [0606] In some embodiments, the compound is a compound of formula VIII-f, or a pharmaceutically acceptable salt thereof. [0607] In some embodiments, the compound is a compound of one of formulas VIII-g, VIII-h, VIII-i, VIII-j, VIII-k or VIII-l: or a pharmaceutically acceptable salt thereof wherein each of Ring A, R ¹ , R ³ , m, p, L, and LBM is as defined in embodiments and classes and subclasses herein. [0608] In some embodiments, the compound is a compound of formula VIII-g, or a pharmaceutically acceptable salt thereof. [0609] In some embodiments, the compound is a compound of formula VIII-h, or a pharmaceutically acceptable salt thereof. [0610] In some embodiments, the compound is a compound of formula VIII-i, or a pharmaceutically acceptable salt thereof. [0611] In some embodiments, the compound is a compound of formula VIII-j, or a pharmaceutically acceptable salt thereof. [0612] In some embodiments, the compound is a compound of formula VIII-k, or a pharmaceutically acceptable salt thereof. [0613] In some embodiments, the compound is a compound of formula VIII-l, or a pharmaceutically acceptable salt thereof. [0614] In some embodiments, the compound is a compound of one of formulas VIII-m, VIII-n, VIII-o, VIII-p, VIII-q, VIII-r, VIII-s, VIII-t, or VIII-u: or a pharmaceutically acceptable salt thereof wherein each of R ^A1 , R ¹ , R ³ , m, p, L, and LBM is as defined in embodiments and classes and subclasses herein. [0615] In some embodiments, the compound is a compound of formula VIII-m, or a pharmaceutically acceptable salt thereof. [0616] In some embodiments, the compound is a compound of formula VIII-n, or a pharmaceutically acceptable salt thereof. [0617] In some embodiments, the compound is a compound of formula VIII-o, or a pharmaceutically acceptable salt thereof. [0618] In some embodiments, the compound is a compound of formula VIII-p, or a pharmaceutically acceptable salt thereof. [0619] In some embodiments, the compound is a compound of formula VIII-q, or a pharmaceutically acceptable salt thereof. [0620] In some embodiments, the compound is a compound of formula VIII-r, or a pharmaceutically acceptable salt thereof. [0621] In some embodiments, the compound is a compound of formula VIII-s, or a pharmaceutically acceptable salt thereof. [0622] In some embodiments, the compound is a compound of formula VIII-t, or a pharmaceutically acceptable salt thereof. [0623] In some embodiments, the compound is a compound of formula VIII-u, or a pharmaceutically acceptable salt thereof. [0624] In some embodiments, the compound is a compound of one of formulas IX-d, IX-e, IX-f: or a pharmaceutically acceptable salt thereof wherein each of X ¹ , X ² , Ring C, R ¹ , R ³ , R ⁶ , m, p, t, L, and LBM is as defined in embodiments and classes and subclasses herein. [0625] In some embodiments, the compound is a compound of formula IX-d, or a pharmaceutically acceptable salt thereof. [0626] In some embodiments, the compound is a compound of formula IX-e, or a pharmaceutically acceptable salt thereof. [0627] In some embodiments, the compound is a compound of formula IX-f, or a pharmaceutically acceptable salt thereof. [0628] In some embodiments, the compound is a compound of one of formulas IX-g, IX-h, IX-i, IX-j, IX-k, IX-l, IX-m, IX-n, IX-o: or a pharmaceutically acceptable salt thereof, wherein each of X ¹ , X ² , X ³ , Ring A, Ring C, R ¹ , R ³ , R ⁶ , m, p, t, L, and LBM is as defined in embodiments and classes and subclasses herein. [0629] In some embodiments, the compound is a compound of formula IX-g, or a pharmaceutically acceptable salt thereof. [0630] In some embodiments, the compound is a compound of formula IX-h, or a pharmaceutically acceptable salt thereof. [0631] In some embodiments, the compound is a compound of formula IX-i, or a pharmaceutically acceptable salt thereof. [0632] In some embodiments, the compound is a compound of formula IX-j, or a pharmaceutically acceptable salt thereof. [0633] In some embodiments, the compound is a compound of formula IX-k, or a pharmaceutically acceptable salt thereof. [0634] In some embodiments, the compound is a compound of formula IX-l, or a pharmaceutically acceptable salt thereof. [0635] In some embodiments, the compound is a compound of formula IX-m, or a pharmaceutically acceptable salt thereof. [0636] In some embodiments, the compound is a compound of formula IX-n, or a pharmaceutically acceptable salt thereof. [0637] In some embodiments, the compound is a compound of formula IX-o, or a pharmaceutically acceptable salt thereof. [0638] Examples of compounds of the present disclosure include those listed in the Tables and exemplification herein, or a pharmaceutically acceptable salt, stereoisomer, or mixture of stereoisomers thereof. In some embodiments, the present disclosure provides a compound selected from those depicted in Table 1 or Table 2, below, or a pharmaceutically acceptable salt, stereoisomer, or mixture of stereoisomers thereof. In some embodiments, the present disclosure provides a compound set forth in Table 1 or Table 2, below, or a pharmaceutically acceptable salt thereof. In some embodiments, the present disclosure provides a compound set forth in Table 1 or Table 2, below.

Table 1. Representative Compounds of the Disclosure

I-277 I-278

I-300

denotes compounds for which the initial stereochemistry was arbitrarily assigned, as indicated by the previous “or1” designation at the respective stereocenters. Current stereochemistry assignment has been confirmed by independent experiments, as indicated by the “abs” designation at the respective stereocenters. Table 2. Additional Representative Compounds of the Disclosure. II-12 II-13 II-14 II-15

II-86 II-88 II-89 II-90 (*)

II-107 II-108 II-109 stereochemistry assignment has been confirmed by independent experiments, as indicated by the “abs” designation at the respective stereocenters. [0639] In chemical structures in Table 1 or Table 2, above, and the Examples, below, stereogenic centers are described according to the Enhanced Stereo Representation format (MDL/Biovia, e.g. using labels “or1”, “or2”, “abs”, “and1”). [0640] In some embodiments, the present disclosure comprises a compound of formula I-1, I-1’, I-2, I-2’, I-3 or I-3’ selected from those depicted in Table 1 or Table 2, above, or a pharmaceutically acceptable salt, stereoisomer, or mixture of stereoisomers thereof. In some embodiments, the present disclosure comprises a compound of formula I-1 selected from those depicted in Table 1 or Table 2, above, or a pharmaceutically acceptable salt, diastereomer, or mixture of diastereomers thereof. In some embodiments, the present disclosure provides a compound of formula I-1, I-1’, I-2, I-2’, I-3 or I-3’ selected from those depicted in Table 1 or Table 2, above, or a pharmaceutically acceptable salt thereof. In some embodiments, the present disclosure provides a compound of formula I-1, I-1’, I-2, I-2’, I-3 or I-3’ selected from those depicted in Table 1 or Table 2, above. [0641] The compounds in Table 1 or Table 2 were made in accordance with chemical procedures described in the Examples section, or similar procedures that would be readily understood by a person of skill in the art on the basis of the instant disclosure and knowledge present in the art. The compounds marked with (*) in Table 1 or Table 2 are prophetic examples and can be made by methods similar to those included in the Examples section. 4. Uses, Formulation, and Administration Pharmaceutically Acceptable Compositions [0642] According to another embodiment, the disclosure provides a composition comprising a compound of this disclosure, or a pharmaceutically acceptable derivative thereof, and a pharmaceutically acceptable carrier, adjuvant, or vehicle. In some embodiments, the disclosure provides a pharmaceutical composition comprising a compound of this disclosure, and a pharmaceutically acceptable carrier. The amount of compound in compositions of this disclosure is such that is effective to measurably degrade ERα, or a mutant thereof, in a biological sample or in a patient. In certain embodiments, the amount of compound in compositions of this disclosure is such that it is effective to measurably degrade ERα, or a mutant thereof, in a biological sample or in a patient. In certain embodiments, a composition of this disclosure is formulated for administration to a patient in need of such composition. In some embodiments, a composition of this disclosure is formulated for oral administration to a patient. [0643] The terms “subject” and “patient,” as used herein, means an animal (i.e., a member of the kingdom animal), preferably a mammal, and most preferably a human. In some embodiments, the subject is a human, mouse, rat, cat, monkey, dog, horse, or pig. In some embodiments, the subject is a human. In some embodiments, the subject is a mouse, rat, cat, monkey, dog, horse, or pig. [0644] The term “pharmaceutically acceptable carrier, adjuvant, or vehicle” 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 of this disclosure 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. [0645] A “pharmaceutically acceptable derivative” means any non-toxic salt, ester, salt of an ester or other derivative of a compound of this disclosure that, upon administration to a recipient, is capable of providing, either directly or indirectly, a compound of this disclosure or an inhibitorily active metabolite or residue thereof. [0646] As used herein, the term “degratorily active metabolite or residue thereof” means that a metabolite or residue thereof is also a degrader of ERα, or a mutant thereof. [0647] Compositions of the present disclosure 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. Preferably, the compositions are administered orally, intraperitoneally or intravenously. [0648] Sterile injectable forms of the compositions of this disclosure 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. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. [0649] For this purpose, any bland fixed oil may be employed including synthetic mono- or di- glycerides. Fatty acids, such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically-acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions. These oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant, such as carboxymethyl cellulose or similar dispersing agents that are commonly used in the formulation of pharmaceutically acceptable dosage forms including emulsions and suspensions. Other commonly used surfactants, such as Tweens, Spans and other emulsifying agents or bioavailability enhancers which are commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms may also be used for the purposes of formulation. [0650] Pharmaceutically acceptable compositions of this disclosure may be orally administered in any orally acceptable dosage form including, but not limited to, capsules, tablets, aqueous suspensions or solutions. In the case of tablets for oral use, carriers commonly used include lactose and corn starch. Lubricating agents, such as magnesium stearate, are also typically added. For oral administration in a capsule form, useful diluents include lactose and dried cornstarch. When aqueous suspensions are required for oral use, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening, flavoring or coloring agents may also be added. [0651] Alternatively, pharmaceutically acceptable compositions of this disclosure may be administered in the form of suppositories for rectal or vaginal administration. These can be prepared by mixing the agent with a suitable non-irritating excipient that is solid at room temperature but liquid at rectal or vaginal temperature and therefore will melt in the rectum or vagina to release the drug. Such materials include cocoa butter, beeswax and polyethylene glycols. [0652] Pharmaceutically acceptable compositions of this disclosure may also be administered topically, especially when the target of treatment includes areas or organs readily accessible by topical application, including diseases of the eye, the skin, or the lower intestinal tract. Suitable topical formulations are readily prepared for each of these areas or organs. [0653] Topical application for the lower intestinal tract can be effected in a rectal suppository formulation (see above) or in a suitable enema formulation. Topically-transdermal patches may also be used. [0654] For topical applications, provided pharmaceutically acceptable compositions may be formulated in a suitable ointment containing the active component suspended or dissolved in one or more carriers. Carriers for topical administration of compounds of this disclosure include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax and water. Alternatively, provided pharmaceutically acceptable compositions can be formulated in a suitable lotion or cream containing the active components suspended or dissolved in one or more pharmaceutically acceptable carriers. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water. [0655] For ophthalmic use, provided pharmaceutically acceptable compositions may be formulated as micronized suspensions in isotonic, pH adjusted sterile saline, or, preferably, as solutions in isotonic, pH adjusted sterile saline, either with or without a preservative such as benzylalkonium chloride. Alternatively, for ophthalmic uses, the pharmaceutically acceptable compositions may be formulated in an ointment such as petrolatum. [0656] Pharmaceutically acceptable compositions of this disclosure may also be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well-known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other conventional solubilizing or dispersing agents. [0657] Preferably, pharmaceutically acceptable compositions of this disclosure are formulated for oral administration. Such formulations may be administered with or without food. In some embodiments, pharmaceutically acceptable compositions of this disclosure are administered without food. In other embodiments, pharmaceutically acceptable compositions of this disclosure are administered with food. [0658] The amount of compounds of the present disclosure that may be combined with the carrier materials to produce a composition in a single dosage form will vary depending upon the patient treated, the particular mode of administration. Preferably, provided compositions should be formulated so that a dosage of between 0.01 - 100 mg/kg body weight/day of the inhibitor can be administered to a patient receiving these compositions. [0659] It should also be understood that 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 being treated. The amount of a compound of the present disclosure in the composition will also depend upon the particular compound in the composition. [0660] The precise dose to be employed in the compositions will also depend on the route of administration, and should be decided according to the judgment of the practitioner and each subject’s circumstances. In specific embodiments of the disclosure, suitable dose ranges for oral administration of the compounds of the disclosure are generally about 1 mg/day to about 1000 mg/day. In some embodiments, the oral dose is about 1 mg/day to about 800 mg/day. In some embodiments, the oral dose is about 1 mg/day to about 500 mg/day. In some embodiments, the oral dose is about 1 mg/day to about 250 mg/day. In some embodiments, the oral dose is about 1 mg/day to about 100 mg/day. In some embodiments, the oral dose is about 5 mg/day to about 50 mg/day. In some embodiments, the oral dose is about 5 mg/day. In some embodiments, the oral dose is about 10 mg/day. In some embodiments, the oral dose is about 20 mg/day. In some embodiments, the oral dose is about 30 mg/day. In some embodiments, the oral dose is about 40 mg/day. In some embodiments, the oral dose is about 50 mg/day. In some embodiments, the oral dose is about 60 mg/day. In some embodiments, the oral dose is about 70 mg/day. In some embodiments, the oral dose is about 100 mg/day. It will be recognized that any of the dosages listed herein may constitute an upper or lower dosage range, and may be combined with any other dosage to constitute a dosage range comprising an upper and lower limit. [0661] In some embodiments, pharmaceutically acceptable compositions contain a provided compound and/or a pharmaceutically acceptable salt thereof at a concentration ranging from about 0.01 to about 90 wt%, about 0.01 to about 80 wt%, about 0.01 to about 70 wt%, about 0.01 to about 60 wt%, about 0.01 to about 50 wt%, about 0.01 to about 40 wt%, about 0.01 to about 30 wt%, about 0.01 to about 20 wt%, about 0.01 to about 2.0 wt%, about 0.01 to about 1 wt%, about 0.05 to about 0.5 wt%, about 1 to about 30 wt%, or about 1 to about 20 wt%. The composition can be formulated as a solution, suspension, ointment, or a capsule, and the like. The pharmaceutical composition can be prepared as an aqueous solution and can contain additional components, such as preservatives, buffers, tonicity agents, antioxidants, stabilizers, viscosity- modifying ingredients and the like. [0662] Pharmaceutically acceptable carriers are well-known to those skilled in the art, and include, e.g., adjuvants, diluents, excipients, fillers, lubricants and vehicles. In some embodiments, the carrier is a diluent, adjuvant, excipient, or vehicle. In some embodiments, the carrier is a diluent, adjuvant, or excipient. In some embodiments, the carrier is a diluent or adjuvant. In some embodiments, the carrier is an excipient. [0663] Examples of pharmaceutically acceptable carriers may include, e.g., water or saline solution, polymers such as polyethylene glycol, carbohydrates and derivatives thereof, oils, fatty acids, or alcohols. Non-limiting examples of oils as pharmaceutical carriers include oils of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like. The pharmaceutical carriers may also be saline, gum acacia, gelatin, starch paste, talc, keratin, colloidal silica, urea, and the like. In addition, auxiliary, stabilizing, thickening, lubricating and coloring agents may be used. Other examples of suitable pharmaceutical carriers are described in e.g., Remington’s: The Science and Practice of Pharmacy, 22nd Ed. (Allen, Loyd V., Jr ed., Pharmaceutical Press (2012)); Modern Pharmaceutics, 5 ^th Ed. (Alexander T. Florence, Juergen Siepmann, CRC Press (2009)); Handbook of Pharmaceutical Excipients, 7 ^th Ed. (Rowe, Raymond C.; Sheskey, Paul J.; Cook, Walter G.; Fenton, Marian E. eds., Pharmaceutical Press (2012)) (each of which hereby incorporated by reference in its entirety). [0664] The pharmaceutically acceptable carriers employed herein may be selected from various organic or inorganic materials that are used as materials for pharmaceutical formulations and which are incorporated as analgesic agents, buffers, binders, disintegrants, diluents, emulsifiers, excipients, extenders, glidants, solubilizers, stabilizers, suspending agents, tonicity agents, vehicles and viscosity-increasing agents. Pharmaceutical additives, such as antioxidants, aromatics, colorants, flavor-improving agents, preservatives, and sweeteners, may also be added. Examples of acceptable pharmaceutical carriers include carboxymethyl cellulose, crystalline cellulose, glycerin, gum arabic, lactose, magnesium stearate, methyl cellulose, powders, saline, sodium alginate, sucrose, starch, talc and water, among others. In some embodiments, the term “pharmaceutically acceptable” means approved by a regulatory agency of the Federal or a state government or listed in the U.S. Pharmacopeia or other generally recognized pharmacopeia for use in animals, and more particularly in humans. [0665] Surfactants such as, e.g., detergents, are also suitable for use in the formulations. Specific examples of surfactants include polyvinylpyrrolidone, polyvinyl alcohols, copolymers of vinyl acetate and of vinylpyrrolidone, polyethylene glycols, benzyl alcohol, mannitol, glycerol, sorbitol or polyoxyethylenated esters of sorbitan; lecithin or sodium carboxymethylcellulose; or acrylic derivatives, such as methacrylates and others, anionic surfactants, such as alkaline stearates, in particular sodium, potassium or ammonium stearate; calcium stearate or triethanolamine stearate; alkyl sulfates, in particular sodium lauryl sufate and sodium cetyl sulfate; sodium dodecylbenzenesulphonate or sodium dioctyl sulphosuccinate; or fatty acids, in particular those derived from coconut oil, cationic surfactants, such as water-soluble quaternary ammonium salts of formula N ⁺ R'R''R'''R''''Y-, in which the R radicals are identical or different optionally hydroxylated hydrocarbon radicals and Y- is an anion of a strong acid, such as halide, sulfate and sulfonate anions; cetyltrimethylammonium bromide is one of the cationic surfactants which can be used, amine salts of formula N ⁺ R'R''R''', in which the R radicals are identical or different optionally hydroxylated hydrocarbon radicals; octadecylamine hydrochloride is one of the cationic surfactants which can be used, non-ionic surfactants, such as optionally polyoxyethylenated esters of sorbitan, in particular Polysorbate 80, or polyoxyethylenated alkyl ethers; polyethylene glycol stearate, polyoxyethylenated derivatives of castor oil, polyglycerol esters, polyoxyethylenated fatty alcohols, polyoxyethylenated fatty acids or copolymers of ethylene oxide and of propylene oxide, amphoteric surfactants, such as substituted lauryl compounds of betaine. [0666] Suitable pharmaceutical carriers may also include excipients such as starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene, glycol, polyethylene glycol 300, water, ethanol, polysorbate 20, and the like. The present compositions, if desired, may also contain wetting or emulsifying agents, or pH buffering agents. [0667] Tablets and capsule formulations may further contain one or more adjuvants, binders, diluents, disintegrants, excipients, fillers, or lubricants, each of which are known in the art. Examples of such include carbohydrates such as lactose or sucrose, dibasic calcium phosphate anhydrous, corn starch, mannitol, xylitol, cellulose or derivatives thereof, microcrystalline cellulose, gelatin, stearates, silicon dioxide, talc, sodium starch glycolate, acacia, flavoring agents, preservatives, buffering agents, disintegrants, and colorants. Orally administered compositions may contain one or more optional agents such as, e.g., sweetening agents such as fructose, aspartame or saccharin; flavoring agents such as peppermint, oil of wintergreen, or cherry; coloring agents; and preservative agents, to provide a pharmaceutically palatable preparation. Uses of Compounds and Pharmaceutically Acceptable Compositions [0668] Compounds and compositions described herein are generally useful for the degradation of ERα. In some embodiments, the nuclear transcription factor degraded by the compounds and compositions described herein is ERα. [0669] Compounds or compositions of the disclosure can be useful in applications that benefit from the degradation of ERα. For example, ERα degraders of the present disclosure are useful for the treatment of cellular proliferative diseases generally. [0670] The activity of a compound utilized in this disclosure as an degrader of ERα, or a mutant thereof, may be assayed in vitro, in vivo or in a cell line. In vitro assays include assays that determine inhibition of either the signaling activity and/or the subsequent functional consequences, of an activated ERα, or a mutant thereof. Alternative in vitro assays quantitate the ability of the degrader to degrade ERα. Representative in vitro and in vivo assays useful in assaying an ERα degrader include those described and disclosed in the patent and scientific publications described herein. Detailed conditions for assaying a compound utilized in this disclosure as an degrader of ERα, or a mutant thereof, are set forth in the Examples below. Treatment of Disorders [0671] Provided compounds are degraders of ERα and are therefore useful for treating one or more disorders associated with activity of ERα or mutants thereof. Thus, in certain embodiments, the present disclosure provides a method of treating an ERα-mediated disorder in a subject, comprising administering a therapeutically effective amount of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable present disclosure provides a method of treating an ERα-mediated disorder in a subject comprising administering a therapeutically effective amount of a compound of the present disclosure, or a pharmaceutically acceptable composition thereof, to a subject in need thereof. In some embodiments, the subject has a mutant ERα. In some embodiments, the subject has ERα containing a D538G, Y537S, or L536R mutation. [0672] As used herein, the term “ERα-mediated” disorders, diseases, and/or conditions means any disease or other deleterious condition in which ERα or a mutant thereof is known to play a role. Accordingly, another embodiment of the present disclosure relates to treating or lessening the severity of one or more diseases in which ERα, or a mutant thereof, is known to play a role. Such ERα-mediated disorders include, but are not limited to, cellular proliferative disorders (e.g. cancer). In some embodiments, the ERα-mediated disorder is a disorder mediated by a mutant ERα. In some embodiments, the ERα-mediated disorder is a disorder mediated by an ERα containing a D538G, Y537S, or L536R mutation. [0673] In some embodiments, the present disclosure provides a method for treating a cellular proliferative disease, said method comprising administering to a patient in need thereof a therapeutically effective amount of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable composition of either of the foregoing. In some embodiments, the present disclosure provides a method for treating a cellular proliferative disease, said method comprising administering to a patient in need thereof, a therapeutically effective amount of a compound of the present disclosure, or a pharmaceutically acceptable composition thereof. [0674] In some embodiments, the method of treatment comprises the steps of: i) identifying a subject in need of such treatment; (ii) providing a disclosed compound, or a pharmaceutically acceptable salt thereof; and (iii) administering said provided compound in a therapeutically effective amount to treat, suppress and/or prevent the disease state or condition in a subject in need of such treatment. In some embodiments, the subject has a mutant ERα. In some embodiments, the subject has ERα containing a D538G, Y537S, or L536R mutation. [0675] In some embodiments, the method of treatment comprises the steps of: i) identifying a subject in need of such treatment; (ii) providing a composition comprising a disclosed compound, or a pharmaceutically acceptable salt thereof; and (iii) administering said composition in a therapeutically effective amount to treat suppress and/or prevent the disease state or condition in a subject in need of such treatment. In some embodiments, the subject has a mutant ERα. In some embodiments, the subject has ERα containing a D538G, Y537S, or L536R mutation. [0676] Another aspect of the disclosure provides a compound according to the definitions herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of either of the foregoing, for use in the treatment of a disorder described herein. Another aspect of the disclosure provides the use of a compound according to the definitions herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of either of the foregoing, for the treatment of a disorder described herein. Similarly, the disclosure provides the use of a compound according to the definitions herein, or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for the treatment of a disorder described herein. Cellular Proliferative Diseases [0677] In some embodiments, the disorder is a cellular proliferative disease. In some embodiments, the cellular proliferative disease is cancer. In some embodiments, the cancer is a tumor. In some embodiments, the cancer is a hematopoietic cancer. In some embodiments, the cancer is a solid tumor. In some embodiments, the cellular proliferative disease is a tumor and/or cancerous cell growth. In some embodiments, the cellular proliferative disease is a tumor. In some embodiments, the cellular proliferative disease is a solid tumor. In some embodiments, the cellular proliferative disease is a cancerous cell growth. [0678] In some embodiments, the cancer is selected from sarcoma; lung; bronchus; prostate; breast (including sporadic breast cancers and sufferers of Cowden disease); pancreas; gastrointestinal; colon; rectum; carcinoma; colon carcinoma; adenoma; colorectal adenoma; thyroid; liver; intrahepatic bile duct; hepatocellular; adrenal gland; stomach; gastric; glioma; glioblastoma; endometrial; melanoma; kidney; renal pelvis; urinary bladder; uterine corpus; uterine cervix; vagina; ovary (including clear cell ovarian cancer); multiple myeloma; esophagus; a leukemia; acute myelogenous leukemia; chronic myelogenous leukemia; lymphocytic leukemia; myeloid leukemia; brain; a carcinoma of the brain; oral cavity and pharynx; larynx; small intestine; non- Hodgkin lymphoma; villous colon adenoma; a neoplasia; a neoplasia of epithelial character; lymphoma; a mammary carcinoma; basal cell carcinoma; squamous cell carcinoma; actinic keratosis; neck; head; polycythemia vera; essential thrombocythemia; myelofibrosis with myeloid metaplasia; and Waldenstrom macroglobulinemia. [0679] In some embodiments, the cancer is selected from lung; bronchus; prostate; breast (including sporadic breast cancers and Cowden disease); pancreas; gastrointestinal; colon; rectum; thyroid; liver; intrahepatic bile duct; hepatocellular; adrenal gland; stomach; gastric; endometrial; kidney; renal pelvis; urinary bladder; uterine corpus; uterine cervix; vagina; ovary (including clear cell ovarian cancer); esophagus; a leukemia; acute myelogenous leukemia; chronic myelogenous leukemia; lymphocytic leukemia; myeloid leukemia; brain; oral cavity and pharynx; larynx; small intestine; neck; and head. In some embodiments, the cancer is selected from sarcoma; carcinoma; colon carcinoma; adenoma; colorectal adenoma; glioma; glioblastoma; melanoma; multiple myeloma; a carcinoma of the brain; non-Hodgkin lymphoma; villous colon adenoma; a neoplasia; a neoplasia of epithelial character; lymphoma; a mammary carcinoma; basal cell carcinoma; squamous cell carcinoma; actinic keratosis; polycythemia vera; essential thrombocythemia; myelofibrosis with myeloid metaplasia; and Waldenstrom macroglobulinemia. [0680] In some embodiments, the cancer is selected from lung; bronchus; prostate; breast (including sporadic breast cancers and Cowden disease); pancreas; gastrointestinal; colon; rectum; thyroid; liver; intrahepatic bile duct; hepatocellular; adrenal gland; stomach; gastric; endometrial; kidney; renal pelvis; urinary bladder; uterine corpus; uterine cervix; vagina; ovary (including clear cell ovarian cancer); esophagus; brain; oral cavity and pharynx; larynx; small intestine; neck; and head. In some embodiments, the cancer is a leukemia. In some embodiments, the cancer is acute myelogenous leukemia; chronic myelogenous leukemia; lymphocytic leukemia; or myeloid leukemia. [0681] In some embodiments, the cancer is breast cancer (including sporadic breast cancers and Cowden disease). In some embodiments, the cancer is breast cancer. In some embodiments, the cancer is ER+ breast cancer. In some embodiments, the cancer is ER+/HER2- breast cancer. In some embodiments, the cancer is ER+/HER2- breast cancer, and the subject is intolerant to, or ineligible for, treatment with alpelisib. In some embodiments, the cancer is sporadic breast cancer. In some embodiments, the cancer is Cowden disease. In some embodiments, the cancer is ER+ advanced/metastatic breast cancer. In some embodiments, the cancer is ER+/HER2- advanced/metastatic breast cancer. In some embodiments, the breast cancer has mutant ERα. In some embodiments, the breast cancer has ERα containing a D538G, Y537S, or L536R mutation. [0682] In some embodiments, the cancer is uterine cancer. In some embodiments, the uterine cancer has mutant ERα. In some embodiments, the uterine cancer has ERα containing a D538G, Y537S, or L536R mutation. [0683] In some embodiments, the ERα-mediated disorder is endometriosis. In some embodiments, the endometriosis has mutant ERα. In some embodiments, the endometriosis has ERα containing a D538G, Y537S, or L536R mutation. [0684] In some embodiments, the cellular proliferative disease displays overexpression or amplification of ERα, or somatic mutation of ERα. Routes of Administration and Dosage Forms [0685] The compounds and compositions, according to the methods of the present disclosure, may be administered using any amount and any route of administration effective for treating or lessening the severity of the disorder (e.g. a proliferative disorder). The exact amount required will vary from subject to subject, depending on the species, age, and general condition of the subject, the severity of the infection, the particular agent, its mode of administration, and the like. Compounds of the disclosure are preferably formulated in unit dosage form for ease of administration and uniformity of dosage. The expression “unit dosage form” as used herein refers to a physically discrete unit of agent appropriate for the patient to be treated. It will be understood, however, that the total daily usage of the compounds and compositions of the present disclosure will be decided by the attending physician within the scope of sound medical judgment. The specific effective dose level for any particular patient or organism will depend upon a variety of factors including the disorder being treated and the severity of the disorder; the activity of the specific compound employed; the specific composition employed; the age, body weight, general health, sex and diet of the patient; the time of administration, route of administration, and rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidental with the specific compound employed, and like factors well known in the medical arts. [0686] Pharmaceutically acceptable compositions of this disclosure can be administered to humans and other animals orally, rectally, parenterally, intracisternally, intravaginally, intraperitoneally, topically (as by powders, ointments, or drops), bucally, as an oral or nasal spray, or the like. In certain embodiments, the compounds of the disclosure may be administered orally 1 mg/kg to about 25 mg/kg, of subject body weight per day, one or more times a day, to obtain the desired therapeutic effect. [0687] Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof. Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents. [0688] Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution, suspension or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution, U.S.P. and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil can be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid are used in the preparation of injectables. [0689] Injectable formulations can be sterilized, for example, by filtration through a bacterial- retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use. [0690] In order to prolong the effect of a compound of the present disclosure, it is often desirable to slow the absorption of the compound from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the compound then depends upon its rate of dissolution that, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered compound form is accomplished by dissolving or suspending the compound in an oil vehicle Injectable depot forms are made by forming microencapsule matrices of the compound in biodegradable polymers such as polylactide-polyglycolide. Depending upon the ratio of compound to polymer and the nature of the particular polymer employed, the rate of compound release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by entrapping the compound in liposomes or microemulsions that are compatible with body tissues. [0691] Compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing the compounds of this disclosure with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound. [0692] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar--agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite clay, and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also comprise buffering agents. [0693] Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes. Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polethylene glycols and the like. [0694] The active compounds can also be in micro-encapsulated form with one or more excipients as noted above. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings, release controlling coatings and other coatings well known in the pharmaceutical formulating art. In such solid dosage forms the active compound may be admixed with at least one inert diluent such as sucrose, lactose or starch. Such dosage forms may also comprise, as is normal practice, additional substances other than inert diluents, e.g., tableting lubricants and other tableting aids such a magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes. [0695] Dosage forms for topical or transdermal administration of a compound of this disclosure include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches. The active component is admixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives or buffers as may be required. Ophthalmic formulation, ear drops, and eye drops are also contemplated as being within the scope of this disclosure. Additionally, the present disclosure contemplates the use of transdermal patches, which have the added advantage of providing controlled delivery of a compound to the body. Such dosage forms can be made by dissolving or dispensing the compound in the proper medium. Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate can be controlled by either providing a rate controlling membrane or by dispersing the compound in a polymer matrix or gel. Dosage Amounts and Regimens [0696] In accordance with the methods of the present disclosure, the compounds of the disclosure are administered to the subject in a therapeutically effective amount, e.g., to reduce or ameliorate symptoms of the disorder in the subject. This amount is readily determined by the skilled artisan, based upon known procedures, including analysis of titration curves established in vivo and methods and assays disclosed herein. [0697] In some embodiments, the methods comprise administration of a therapeutically effective dosage of the compounds of the disclosure. In some embodiments, the therapeutically effective dosage is at least about 0.0001 mg/kg body weight, at least about 0.001 mg/kg body weight, at least about 0.01 mg/kg body weight, at least about 0.05 mg/kg body weight, at least about 0.1 mg/kg body weight, at least about 0.25 mg/kg body weight, at least about 0.3 mg/kg body weight, at least about 0.5 mg/kg body weight, at least about 0.75 mg/kg body weight, at least about 1 mg/kg body weight, at least about 2 mg/kg body weight, at least about 3 mg/kg body weight, at least about 4 mg/kg body weight, at least about 5 mg/kg body weight, at least about 6 mg/kg body weight, at least about 7 mg/kg body weight, at least about 8 mg/kg body weight, at least about 9 mg/kg body weight, at least about 10 mg/kg body weight, at least about 15 mg/kg body weight, at least about 20 mg/kg body weight, at least about 25 mg/kg body weight, at least about 30 mg/kg body weight, at least about 40 mg/kg body weight, at least about 50 mg/kg body weight, at least about 75 mg/kg body weight, at least about 100 mg/kg body weight, at least about 200 mg/kg body weight, at least about 250 mg/kg body weight, at least about 300 mg/kg body weight, at least about 350 mg/kg body weight, at least about 400 mg/kg body weight, at least about 450 mg/kg body weight, at least about 500 mg/kg body weight, at least about 550 mg/kg body weight, at least about 600 mg/kg body weight, at least about 650 mg/kg body weight, at least about 700 mg/kg body weight, at least about 750 mg/kg body weight, at least about 800 mg/kg body weight, at least about 900 mg/kg body weight, or at least about 1000 mg/kg body weight. It will be recognized that any of the dosages listed herein may constitute an upper or lower dosage range, and may be combined with any other dosage to constitute a dosage range comprising an upper and lower limit. [0698] In some embodiments, the therapeutically effective dosage is in the range of about 0.1 mg to about 10 mg/kg body weight, about 0.1 mg to about 6 mg/kg body weight, about 0.1 mg to about 4 mg /kg body weight, or about 0.1 mg to about 2 mg/kg body weight. [0699] In some embodiments the therapeutically effective dosage is in the range of about 1 to 500 mg, about 2 to 150 mg, about 2 to 120 mg, about 2 to 80 mg, about 2 to 40 mg, about 5 to 150 mg, about 5 to 120 mg, about 5 to 80 mg, about 10 to 150 mg, about 10 to 120 mg, about 10 to 80 mg, about 10 to 40 mg, about 20 to 150 mg, about 20 to 120 mg, about 20 to 80 mg, about 20 to 40 mg, about 40 to 150 mg, about 40 to 120 mg or about 40 to 80 mg. [0700] In some embodiments, the methods comprise a single dosage or administration (e.g., as a single injection or deposition). Alternatively, in some embodiments, the methods comprise administration once daily, twice daily, three times daily or four times daily to a subject in need thereof for a period of from about 2 to about 28 days, or from about 7 to about 10 days, or from about 7 to about 15 days, or longer. In some embodiments, the methods comprise chronic administration. In yet other embodiments, the methods comprise administration over the course of several weeks, months, years or decades. In still other embodiments, the methods comprise administration over the course of several weeks. In still other embodiments, the methods comprise administration over the course of several months. In still other embodiments, the methods comprise administration over the course of several years. In still other embodiments, the methods comprise administration over the course of several decades. [0701] The dosage administered can vary depending upon known factors such as the pharmacodynamic characteristics of the active ingredient and its mode and route of administration; time of administration of active ingredient; age, sex, health and weight of the recipient; nature and extent of symptoms; kind of concurrent treatment, frequency of treatment and the effect desired; and rate of excretion. These are all readily determined and may be used by the skilled artisan to adjust or titrate dosages and/or dosing regimens. Degradation of ERα [0702] According to one embodiment, the disclosure relates to a method of degrading ERα in a biological sample comprising the step of contacting said biological sample with a compound of this disclosure, or a composition comprising said compound. According to another embodiment, the disclosure relates to a method of degrading ERα, or a mutant thereof, in a biological sample comprising the step of contacting said biological sample with a compound of this disclosure, or a composition comprising said compound. According to another embodiment, the disclosure relates to a method of degrading ERα, or a mutant thereof, in a biological sample comprising the step of contacting said biological sample with a compound of this disclosure, or a composition comprising said compound. In some embodiments, the ERα is a mutant ERα. In some embodiments, ERα contains a D538G, Y537S, or L536R mutation. [0703] Without wishing to be bound by any particular theory, it is contemplated that compounds of the present invention catalyze the destruction of ERα. The compounds of the present invention are proteolysis targeting chimeras (PROTACs) A PROTAC is a bifunctional molecule with one portion capable of engaging an E3 ubiquitin ligase, and the other portion having the ability to bind to a target protein meant for degradation by the cellular protein quality control machinery. Recruitment of the target protein to the specific E3 ligase results in its tagging for destruction (i.e., ubiquitination) and subsequent degradation by the proteasome. Any E3 ligase can be used. The portion of the PROTAC that engages the E3 ligase is connected to the portion of the PROTAC that engages the target protein via a linker which consists of a variable chain of atoms. Recruitment of ERα to the E3 ligase will thus result in the destruction of the ERα protein. The variable chain of atoms can include, for example, rings, heteroatoms, and/or repeating polymeric units. It can be rigid or flexible. It can be attached to the two portions described above using standard techniques in the art of organic synthesis. [0704] In some embodiments, the disclosure provides a method of selectively inhibiting a mutant ERα over a wild-type ERα. [0705] The term “biological sample”, as used herein, includes, without limitation, cell cultures or extracts thereof; biopsied material obtained from a mammal or extracts thereof; and blood, saliva, urine, feces, semen, tears, or other body fluids or extracts thereof. [0706] Inhibition of activity of a ERα (for example, ERα, or a mutant thereof) in a biological sample is useful for a variety of purposes that are known to one of skill in the art. Examples of such purposes include, but are not limited to, blood transfusion, organ-transplantation, biological specimen storage, and biological assays. [0707] Another embodiment of the present disclosure relates to a method of inhibiting ERα- mediated transcription regulation in a patient comprising the step of administering to said patient a compound of the present disclosure, or a composition comprising said compound. [0708] According to another embodiment, the disclosure relates to a method of inhibiting activity of a ERα, or a mutant thereof, in a patient comprising the step of administering to said patient a compound of the present disclosure, or a composition comprising said compound. In some embodiments, the disclosure relates to a method of inhibiting activity of ERα, or a mutant thereof, in a patient comprising the step of administering to said patient a compound of the present disclosure, or a composition comprising said compound. In some embodiments, the ERα is a mutant ERα. In some embodiments, the ERα contains a D538G, Y537S, or L536R mutation. [0709] According to another embodiment, the present disclosure provides a method for treating a of administering to said patient a compound according to the present disclosure or pharmaceutically acceptable composition thereof. In some embodiments, the present disclosure provides a method for treating a disorder mediated by ERα, or a mutant thereof, in a patient in need thereof, comprising the step of administering to said patient a compound according to the present disclosure or pharmaceutically acceptable composition thereof. In some embodiments, the ERα is a mutant ERα. In some embodiments, the ERα contains a D538G, Y537S, or L536R mutation. [0710] According to another embodiment, the present disclosure provides a method of inhibiting ERα-mediated transcription regulation, or a mutant thereof, in a subject, comprising administering a therapeutically effective amount of a compound according to the present disclosure, or a pharmaceutically acceptable composition thereof, to a subject in need thereof. In some embodiments, the present disclosure provides a method of inhibiting ERα-mediated transcription regulation in a subject, comprising administering a therapeutically effective amount of a compound according to the present disclosure, or a pharmaceutically acceptable composition thereof, to a subject in need thereof. In some embodiments, the ERα is a mutant ERα. In some embodiments, the ERα contains a D538G, Y537S, or L536R mutation. In some embodiments, the subject has a D538G, Y537S, or L536R mutant ERα. In some embodiments, the subject has ERα containing D538G, Y537S, or L536R mutation. Combination Therapies [0711] Depending upon the particular disorder, condition, or disease, to be treated, additional therapeutic agents, that are normally administered to treat that condition, may be administered in combination with compounds and compositions of this disclosure. As used herein, additional therapeutic agents that are normally administered to treat a particular disease, or condition, are known as “appropriate for the disease, or condition, being treated.” [0712] Accordingly, in certain embodiments, the method of treatment comprises administering the compound or composition of the disclosure in combination with one or more additional therapeutic agents. In certain other embodiments, the methods of treatment comprise administering the compound or composition of the disclosure as the only therapeutic agent. [0713] The structure of the active compounds identified by code numbers, generic or trade names may be taken from the actual edition of the standard compendium "The Merck Index" or from [0714] A compound of the current disclosure may also be used in combination with known therapeutic processes, for example, the administration of hormones or radiation. In certain embodiments, a provided compound is used as a radiosensitizer, especially for the treatment of tumors which exhibit poor sensitivity to radiotherapy. [0715] A compound of the current disclosure can be administered alone or in combination with one or more other therapeutic compounds, possible combination therapy taking the form of fixed combinations or the administration of a compound of the disclosure and one or more other therapeutic compounds being staggered or given independently of one another, or the combined administration of fixed combinations and one or more other therapeutic compounds. A compound of the current disclosure can besides or in addition be administered especially for tumor therapy in combination with chemotherapy, radiotherapy, immunotherapy, phototherapy, surgical intervention, or a combination of these. Long-term therapy is equally possible as is adjuvant therapy in the context of other treatment strategies, as described above. Other possible treatments are therapy to maintain the patient's status after tumor regression, or even chemopreventive therapy, for example in patients at risk. [0716] Those additional agents may be administered separately from an inventive compound- containing composition, as part of a multiple dosage regimen. Alternatively, those agents may be part of a single dosage form, mixed together with a compound of this disclosure in a single composition. If administered as part of a multiple dosage regime, the two active agents may be submitted simultaneously, sequentially or within a period of time from one another normally within five hours from one another. [0717] As used herein, the term “combination,” “combined,” and related terms refers to the simultaneous or sequential administration of therapeutic agents in accordance with this disclosure. For example, a compound of the present disclosure may be administered with another therapeutic agent simultaneously or sequentially in separate unit dosage forms or together in a single unit dosage form. Accordingly, the present disclosure provides a single unit dosage form comprising a compound of the current disclosure, an additional therapeutic agent, and a pharmaceutically acceptable carrier, adjuvant, or vehicle. [0718] The amount of both an inventive compound and additional therapeutic agent (in those compositions which comprise an additional therapeutic agent as described above) that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. Preferably, compositions of this disclosure should be formulated so that a dosage of between 0.01 - 100 mg/kg body weight/day of an inventive compound can be administered. [0719] In those compositions which comprise an additional therapeutic agent, that additional therapeutic agent and the compound of this disclosure may act synergistically. Therefore, the amount of additional therapeutic agent in such compositions will be less than that required in a monotherapy utilizing only that therapeutic agent. In such compositions a dosage of between 0.01 – 1,000 Pg/kg body weight/day of the additional therapeutic agent can be administered. [0720] The amount of additional therapeutic agent present in the compositions of this disclosure will be no more than the amount that would normally be administered in a composition comprising that therapeutic agent as the only active agent. Preferably the amount of additional therapeutic agent in the presently disclosed compositions will range from about 50% to 100% of the amount normally present in a composition comprising that agent as the only therapeutically active agent. [0721] Any of the compounds and/or compositions of the disclosure may be provided in a kit comprising the compounds and/or compositions. Thus, in some embodiments, the compound and/or composition of the disclosure is provided in a kit. [0722] The disclosure is further described by the following non-limiting Examples. Selected Embodiments 1. A compound of formula I-3’: I-3’ or a pharmaceutically acceptable salt thereof, wherein:

the -L-LBM moiety to a modifiable carbon, oxygen, nitrogen, or sulfur atom of the ERBM moiety; X ¹ is N, NH, CH, CH ₂ , CH(R ^A1 ) or C(R ^A1 ) ₂ or C(R ^A1 ) as allowed by the other substituents; X ² is N(R ^A2 ), O, CH ₂ , CH(R ^A3 ), or C(R ^A3 ) ₂ ; X ³ is N(R ^A4 ), O, CH2, CH(R ^A5 ), or C(R ^A5 )2; provided that X ¹ and X ² or X ² and X ³ are not both heteroatoms; each instance of R ¹ , R ² , R ⁴ , R ⁵ , R ⁶ , R ^A1 , R ^A2 , R ^A3 R ^A4 and R ^A5 is independently R ^A or R ^B , and is substituted by 0-4 instances of R ^C ; each instance of R ³ is independently R ^A or R ^B , and is substituted by 0-4 instances of R ^C , or two R ³ groups are optionally taken together to form a 5-8 membered partially unsaturated or aryl fused ring having 0-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each instance of R ^A is independently oxo, deuterium, halogen, –CN, –NO2, –OR, –SF5, –SR, –NR2, –S(O)2R, –S(O)2NR2, –S(O)2F, –S(O)R, –S(O)NR2, –S(O)(NR)R, –S(O)(NCN)R, –S(NCN)R, –C(O)R, –C(O)OR, –C(O)NR ₂ , –C(O)N(R)OR, –OC(O)R, –OC(O)NR ₂ , –N(R)C(O)OR, –N(R)C(O)R, –N(R)C(O)NR ₂ , –N(R)C(NR)NR ₂ , –N(R)S(O) ₂ NR ₂ , –N(R)S(O) ₂ R, –P(O)R ₂ , –P(O)(R)OR, or –B(OR) _2; each instance of R ^B is independently a C _1-6 aliphatic chain; phenyl; naphthyl; cubanyl; adamantyl; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 5-12 membered saturated or partially unsaturated bicyclic carbocyclic ring; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each instance of R ^C is independently oxo, deuterium, halogen, –CN, –NO2, –OR, –SF5, –SR, –NR2, –S(O)2R, –S(O)2NR2, –S(O)2F, –S(O)R, –S(O)NR2, –S(O)(NR)R, –C(O)R, –C(O)OR, – C(O)NR ₂ , –C(O)N(R)OR, –OC(O)R, –OC(O)NR ₂ , –N(R)C(O)OR, –N(R)C(O)R, – N(R)C(O)NR ₂ , –N(R)C(NR)NR ₂ , –N(R)S(O) ₂ NR ₂ , –N(R)S(O) ₂ R, –P(O)R ₂ , –P(O)(R)OR, – B(OR) ₂ ,or an optionally substituted group selected from C _1-6 aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and each instance of R is independently hydrogen, or an optionally substituted group selected from C _{1- 6} aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5- 6 membered monocyclic 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 form an optionally substituted 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; Ring A and Ring B are each independently phenyl; 1,1'-biphenyl; naphthyl; tetrahydronaphthalenyl; dihydroindenyl; benzocyclobutenyl; cubanyl; adamantyl; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 5-12 membered saturated or partially unsaturated bicyclic carbocyclic ring; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Ring C is a spiro-fused 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a spiro-fused 5-12 membered saturated or partially unsaturated bicyclic carbocyclic ring; a spiro-fused 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a spiro-fused 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; L is a covalent bond or a bivalent, saturated or unsaturated, straight or branched C _1-50 hydrocarbon chain, wherein 0-6 methylene units of L are independently replaced by –Cy–, –CH(R)–, –C(R) ₂ –, –O–, –NR–, –S–, –OC(O)–, –C(O)O–, –C(O)–, –S(O)–, –S(O) ₂ –, –NRS(O) ₂ –, –S(O) ₂ NR–, – , 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 5-11 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 5-11 membered saturated or partially 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 6-10 membered bridged 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, or an 8-10 membered bicyclic heteroarylenyl having 1- 5 heteroatoms independently selected from nitrogen, oxygen, or sulfur;

n is 0 1 2 3 or 4; p is 0, 1, 2, 3, or 4; each of q is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; r is 0, 1, 2, 3, or 4; s is 0, 1, 2, 3, or 4; and t is 0, 1, 2, 3, or 4. 2. A compound of formula I-3’: the -L-LBM moiety to a modifiable carbon, oxygen, nitrogen, or sulfur atom of the ERBM moiety; X ¹ is N, NH, CH, CH ₂ , CH(R ^A1 ) or C(R ^A1 ) ₂ or C(R ^A1 ) as allowed by the other substituents; X ² is N(R ^A2 ), O, CH ₂ , CH(R ^A3 ), or C(R ^A3 ) ₂ ; X ³ is N(R ^A4 ), O, CH ₂ , CH(R ^A5 ), or C(R ^A5 ) ₂ ; provided that X ¹ and X ² or X ² and X ³ are not both heteroatoms; each instance of R ¹ , R ² , R ⁴ , R ⁵ , R ⁶ , R ^A1 , R ^A2 , R ^A3 R ^A5 and R ^A5 is independently R ^A or R ^B , and is substituted by 0-4 instances of R ^C ; each instance of R ³ is independently R ^A or R ^B , and is substituted by 0-4 instances of R ^C , or two R ³ groups are optionally taken together to form a 5-8 membered partially unsaturated or aryl fused ring having 0-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each instance of R ^A is independently oxo, deuterium, halogen, –CN, –NO ₂ , –OR, –SF ₅ , –SR, –NR ₂ , –S(O) ₂ R, –S(O) ₂ NR ₂ , –S(O) ₂ F, –S(O)R, –S(O)NR ₂ , –S(O)(NR)R, –S(O)(NCN)R, –S(NCN)R, –C(O)R, –C(O)OR, –C(O)NR ₂ , –C(O)N(R)OR, –OC(O)R, –OC(O)NR ₂ , –N(R)C(O)OR, –N(R)C(O)R, –N(R)C(O)NR ₂ , –N(R)C(NR)NR ₂ , –N(R)S(O) ₂ NR ₂ , –N(R)S(O) ₂ R, –P(O)R ₂ , –P(O)(R)OR, or –B(OR) _2; each instance of R ^B is independently a C _1-6 aliphatic chain; phenyl; naphthyl; cubanyl; adamantyl; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 5-12 membered saturated or partially unsaturated bicyclic carbocyclic ring; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each instance of R ^C is independently oxo, deuterium, halogen, –CN, –NO ₂ , –OR, –SF ₅ , –SR, –NR ₂ , –S(O) ₂ R, –S(O) ₂ NR ₂ , –S(O) ₂ F, –S(O)R, –S(O)NR ₂ , –S(O)(NR)R, –C(O)R, –C(O)OR, – C(O)NR ₂ , –C(O)N(R)OR, –OC(O)R, –OC(O)NR ₂ , –N(R)C(O)OR, –N(R)C(O)R, – N(R)C(O)NR ₂ , –N(R)C(NR)NR ₂ , –N(R)S(O) ₂ NR ₂ , –N(R)S(O) ₂ R, –P(O)R ₂ , –P(O)(R)OR, – saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and each instance of R is independently hydrogen, or an optionally substituted group selected from C _{1- 6} aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5- 6 membered monocyclic 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 form an optionally substituted 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; Ring A and Ring B are each independently phenyl; 1,1'-biphenyl; naphthyl; tetrahydronaphthalenyl; dihydroindenyl; benzocyclobutenyl; cubanyl; adamantyl; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 5-12 membered saturated or partially unsaturated bicyclic carbocyclic ring; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Ring C is a spiro-fused 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a spiro-fused 5-12 membered saturated or partially unsaturated bicyclic carbocyclic ring; a spiro-fused 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a spiro-fused 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; L is a covalent bond or a bivalent, saturated or unsaturated, straight or branched C _1-50 hydrocarbon

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 5-11 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 5-11 membered saturated or partially 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 6-10 membered bridged 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, or an 8-10 membered bicyclic heteroarylenyl having 1- 5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; , , m is 0, 1, 2, 3, or 4; n is 0, 1, 2, 3, or 4; p is 0, 1, 2, 3, or 4; each of q is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; r is 0, 1, 2, 3, or 4; s is 0, 1, 2, 3, or 4; and t is 0, 1, 2, 3, or 4,

wherein X ¹ is CH or N, Ring B is phenyl; Ring A is phenyl or a 6 membered monocyclic heteroaryl ring having 1-3 nitrogen heteroatoms; at least one R ³ is –OH or –OMe; p is 1, 2, or 3; m is 0, 1 or 2; R ¹ is selected from –F and –Cl; n is 0, 1 or 2; and R ² is selected from –OH, –Me, –OMe, –F, –Br, –CF ₃ and – ⁱ Pr; then LBM is not stereoisomer thereof. I-3’ or a pharmaceutically acceptable salt thereof, wherein: the -L-LBM moiety to a modifiable carbon, oxygen, nitrogen, or sulfur atom of the ERBM moiety; X ¹ is N, NH, CH, CH ₂ , CH(R ^A1 ) or C(R ^A1 ) ₂ or C(R ^A1 ) as allowed by the other substituents; X ² is N(R ^A2 ), O, CH ₂ , CH(R ^A3 ), or C(R ^A3 ) ₂ ; X ³ is N(R ^A4 ), O, CH ₂ , CH(R ^A5 ), or C(R ^A5 ) ₂ ; provided that X ¹ and X ² or X ² and X ³ are not both heteroatoms; each instance of R ¹ , R ² , R ⁴ , R ⁵ , R ⁶ , R ^A1 , R ^A2 , R ^A3 R ^A5 and R ^A5 is independently R ^A or R ^B , and is substituted by 0-4 instances of R ^C ; each instance of R ³ is independently R ^A or R ^B , and is substituted by 0-4 instances of R ^C , or two R ³ groups are optionally taken together to form a 5-8 membered partially unsaturated or aryl fused ring having 0-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each instance of R ^A is independently oxo, deuterium, halogen, –CN, –NO ₂ , –OR, –SF ₅ , –SR, –NR ₂ , –S(O) ₂ R, –S(O) ₂ NR ₂ , –S(O) ₂ F, –S(O)R, –S(O)NR ₂ , –S(O)(NR)R, –S(O)(NCN)R, –S(NCN)R, –C(O)R, –C(O)OR, –C(O)NR ₂ , –C(O)N(R)OR, –OC(O)R, –OC(O)NR ₂ , –N(R)C(O)OR, –N(R)C(O)R, –N(R)C(O)NR ₂ , –N(R)C(NR)NR ₂ , –N(R)S(O) ₂ NR ₂ , –N(R)S(O) ₂ R, –P(O)R ₂ , –P(O)(R)OR, or –B(OR) _2; each instance of R ^B is independently a C _1-6 aliphatic chain; phenyl; naphthyl; cubanyl; adamantyl; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 5-12 membered saturated or partially unsaturated bicyclic carbocyclic ring; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each instance of R ^C is independently oxo, deuterium, halogen, –CN, –NO ₂ , –OR, –SF ₅ , –SR, –NR ₂ , –S(O) ₂ R, –S(O) ₂ NR ₂ , –S(O) ₂ F, –S(O)R, –S(O)NR ₂ , –S(O)(NR)R, –C(O)R, –C(O)OR, – C(O)NR ₂ , –C(O)N(R)OR, –OC(O)R, –OC(O)NR ₂ , –N(R)C(O)OR, –N(R)C(O)R, – N(R)C(O)NR ₂ , –N(R)C(NR)NR ₂ , –N(R)S(O) ₂ NR ₂ , –N(R)S(O) ₂ R, –P(O)R ₂ , –P(O)(R)OR, – B(OR) ₂ ,or an optionally substituted group selected from C _1-6 aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and each instance of R is independently hydrogen, or an optionally substituted group selected from C _{1- 6} aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic 6 membered monocyclic 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 form an optionally substituted 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; Ring A and Ring B are each independently phenyl; 1,1'-biphenyl; naphthyl; tetrahydronaphthalenyl; dihydroindenyl; benzocyclobutenyl; cubanyl; adamantyl; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 5-12 membered saturated or partially unsaturated bicyclic carbocyclic ring; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Ring C is a spiro-fused 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a spiro-fused 5-12 membered saturated or partially unsaturated bicyclic carbocyclic ring; a spiro-fused 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a spiro-fused 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; L is a covalent bond or a bivalent, saturated or unsaturated, straight or branched C _1-50 hydrocarbon chain, wherein 0-6 methylene units of L are independently replaced by –Cy–, –CH(R)–, –C(R) ₂ –, –O–, –NR–, –S–, –OC(O)–, –C(O)O–, –C(O)–, –S(O)–, –S(O) ₂ –, –NRS(O) ₂ –, –S(O) ₂ NR–, –

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 5-11 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 5-11 membered saturated or partially 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 6-10 membered bridged 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, or an 8-10 membered bicyclic heteroarylenyl having 1- 5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; , , m is 0, 1, 2, 3, or 4; n is 0, 1, 2, 3, or 4; p is 0, 1, 2, 3, or 4; each of q is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; r is 0, 1, 2, 3, or 4; s is 0, 1, 2, 3, or 4; and t is 0, 1, 2, 3, or 4,

wherein X ¹ is CH or N, Ring B is phenyl; Ring A is phenyl or a 6 membered monocyclic heteroaryl ring having 1-3 nitrogen heteroatoms; then R ³ is not –OH or –OMe. 4. A compound of formula I-3’: or a pharmaceutically acceptable salt thereof, wherein:

the -L-LBM moiety to a modifiable carbon, oxygen, nitrogen, or sulfur atom of the ERBM moiety; X ¹ is N, NH, CH, CH ₂ , CH(R ^A1 ) or C(R ^A1 ) ₂ or C(R ^A1 ) as allowed by the other substituents; X ² is N(R ^A2 ), O, CH ₂ , CH(R ^A3 ), or C(R ^A3 ) ₂ ; X ³ is N(R ^A4 ), O, CH2, CH(R ^A5 ), or C(R ^A5 )2; provided that X ¹ and X ² or X ² and X ³ are not both heteroatoms; each instance of R ¹ , R ² , R ⁴ , R ⁵ , R ⁶ , R ^A1 , R ^A2 , R ^A3 R ^A5 and R ^A5 is independently R ^A or R ^B , and is substituted by 0-4 instances of R ^C ; each instance of R ³ is independently R ^A or R ^B , and is substituted by 0-4 instances of R ^C , or two R ³ groups are optionally taken together to form a 5-8 membered partially unsaturated or aryl fused ring having 0-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each instance of R ^A is independently oxo, deuterium, halogen, –CN, –NO2, –OR, –SF5, –SR, –NR2, –S(O)2R, –S(O)2NR2, –S(O)2F, –S(O)R, –S(O)NR2, –S(O)(NR)R, –S(O)(NCN)R, –S(NCN)R, –C(O)R, –C(O)OR, –C(O)NR ₂ , –C(O)N(R)OR, –OC(O)R, –OC(O)NR ₂ , –N(R)C(O)OR, –N(R)C(O)R, –N(R)C(O)NR ₂ , –N(R)C(NR)NR ₂ , –N(R)S(O) ₂ NR ₂ , –N(R)S(O) ₂ R, –P(O)R ₂ , –P(O)(R)OR, or –B(OR) _2; each instance of R ^B is independently a C _1-6 aliphatic chain; phenyl; naphthyl; cubanyl; adamantyl; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 5-12 membered saturated or partially unsaturated bicyclic carbocyclic ring; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each instance of R ^C is independently oxo, deuterium, halogen, –CN, –NO2, –OR, –SF5, –SR, –NR2, –S(O)2R, –S(O)2NR2, –S(O)2F, –S(O)R, –S(O)NR2, –S(O)(NR)R, –C(O)R, –C(O)OR, – C(O)NR ₂ , –C(O)N(R)OR, –OC(O)R, –OC(O)NR ₂ , –N(R)C(O)OR, –N(R)C(O)R, – N(R)C(O)NR ₂ , –N(R)C(NR)NR ₂ , –N(R)S(O) ₂ NR ₂ , –N(R)S(O) ₂ R, –P(O)R ₂ , –P(O)(R)OR, – B(OR) ₂ ,or an optionally substituted group selected from C _1-6 aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and each instance of R is independently hydrogen, or an optionally substituted group selected from C _{1- 6} aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5- 6 membered monocyclic 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 form an optionally substituted 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; Ring A and Ring B are each independently phenyl; 1,1'-biphenyl; naphthyl; tetrahydronaphthalenyl; dihydroindenyl; benzocyclobutenyl; cubanyl; adamantyl; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 5-12 membered saturated or partially unsaturated bicyclic carbocyclic ring; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Ring C is a spiro-fused 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a spiro-fused 5-12 membered saturated or partially unsaturated bicyclic carbocyclic ring; a spiro-fused 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a spiro-fused 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; L is a covalent bond or a bivalent, saturated or unsaturated, straight or branched C _1-50 hydrocarbon chain, wherein 0-6 methylene units of L are independently replaced by –Cy–, –CH(R)–, –C(R) ₂ –, –O–, –NR–, –S–, –OC(O)–, –C(O)O–, –C(O)–, –S(O)–, –S(O) ₂ –, –NRS(O) ₂ –, –S(O) ₂ NR–, – , 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 5-11 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 5-11 membered saturated or partially 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 6-10 membered bridged 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, or an 8-10 membered bicyclic heteroarylenyl having 1- 5 heteroatoms independently selected from nitrogen, oxygen, or sulfur;

n is 0 1 2 3 or 4; p is 0, 1, 2, 3, or 4; each of q is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; r is 0, 1, 2, 3, or 4; s is 0, 1, 2, 3, or 4; and t is 0, 1, 2, 3, or 4, wherein X ¹ is CH or N; X ² is CH ₂ ; Ring B is phenyl; then Ring A is not phenyl or a 6 membered monocyclic heteroaryl ring having 1-3 nitrogen heteroatoms. 5. A compound of formula I-3’: I-3’ or a pharmaceutically acceptable salt thereof wherein:

the -L-LBM moiety to a modifiable carbon, oxygen, nitrogen, or sulfur atom of the ERBM moiety; X ¹ is N, NH, CH, CH ₂ , CH(R ^A1 ) or C(R ^A1 ) ₂ or C(R ^A1 ) as allowed by the other substituents; X ² is N(R ^A2 ), O, CH ₂ , CH(R ^A3 ), or C(R ^A3 ) ₂ ; X ³ is N(R ^A4 ), O, CH2, CH(R ^A5 ), or C(R ^A5 )2; provided that X ¹ and X ² or X ² and X ³ are not both heteroatoms; each instance of R ¹ , R ² , R ⁴ , R ⁵ , R ⁶ , R ^A1 , R ^A2 , R ^A3 , R ^A4 , and R ^A5 is independently R ^A or R ^B , and is substituted by 0-4 instances of R ^C ; each instance of R ³ is independently R ^A or R ^B , and is substituted by 0-4 instances of R ^C , or two R ³ groups are optionally taken together to form a 5-8 membered partially unsaturated or aryl fused ring having 0-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each instance of R ^A is independently oxo, deuterium, halogen, –CN, –NO2, –OR, –SF5, –SR, –NR2, –S(O)2R, –S(O)2NR2, –S(O)2F, –S(O)R, –S(O)NR2, –S(O)(NR)R, –S(O)(NCN)R, –S(NCN)R, –C(O)R, –C(O)OR, –C(O)NR ₂ , –C(O)N(R)OR, –OC(O)R, –OC(O)NR ₂ , –N(R)C(O)OR, –N(R)C(O)R, –N(R)C(O)NR ₂ , –N(R)C(NR)NR ₂ , –N(R)S(O) ₂ NR ₂ , –N(R)S(O) ₂ R, –P(O)R ₂ , –P(O)(R)OR, or –B(OR) _2; each instance of R ^B is independently a C _1-6 aliphatic chain; phenyl; naphthyl; cubanyl; adamantyl; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 5-12 membered saturated or partially unsaturated bicyclic carbocyclic ring; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each instance of R ^C is independently oxo, deuterium, halogen, –CN, –NO2, –OR, –SF5, –SR, –NR2, –S(O)2R, –S(O)2NR2, –S(O)2F, –S(O)R, –S(O)NR2, –S(O)(NR)R, –C(O)R, –C(O)OR, – C(O)NR ₂ , –C(O)N(R)OR, –OC(O)R, –OC(O)NR ₂ , –N(R)C(O)OR, –N(R)C(O)R, – N(R)C(O)NR ₂ , –N(R)C(NR)NR ₂ , –N(R)S(O) ₂ NR ₂ , –N(R)S(O) ₂ R, –P(O)R ₂ , –P(O)(R)OR, – B(OR) ₂ ,or an optionally substituted group selected from C _1-6 aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and each instance of R is independently hydrogen, or an optionally substituted group selected from C _{1- 6} aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5- 6 membered monocyclic 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 form an optionally substituted 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; Ring A and Ring B are each independently phenyl; 1,1'-biphenyl; naphthyl; tetrahydronaphthalenyl; dihydroindenyl; benzocyclobutenyl; cubanyl; adamantyl; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 5-12 membered saturated or partially unsaturated bicyclic carbocyclic ring; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Ring C is a spiro-fused 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a spiro-fused 5-12 membered saturated or partially unsaturated bicyclic carbocyclic ring; a spiro-fused 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a spiro-fused 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; L is a covalent bond or a bivalent, saturated or unsaturated, straight or branched C _1-50 hydrocarbon chain, wherein 0-6 methylene units of L are independently replaced by –Cy–, –CH(R)–, –C(R) ₂ –, –O–, –NR–, –S–, –OC(O)–, –C(O)O–, –C(O)–, –S(O)–, –S(O) ₂ –, –NRS(O) ₂ –, –S(O) ₂ NR–, – , 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 5-11 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 5-11 membered saturated or partially 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 6-10 membered bridged 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, or an 8-10 membered bicyclic heteroarylenyl having 1- 5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; LBM is selected from , ,

n is 0 1 2 3 or 4; p is 0, 1, 2, 3, or 4; each of q is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; r is 0, 1, 2, 3, or 4; s is 0, 1, 2, 3, or 4; and t is 0, 1, 2, 3, or 4, Ring A is other than phenyl or a 6 membered monocyclic heteroaryl ring having 1-3 nitrogen heteroatoms. 6. A compound of formula I-3: or a pharmaceutically acceptable salt thereof, wherein:

the -L-LBM moiety to a modifiable carbon, oxygen, nitrogen, or sulfur atom of the ERBM moiety; X ¹ is N, CH, or C(R ^A1 ); X ² is N(R ^A2 ), O, CH ₂ , CH(R ^A3 ), or C(R ^A3 ) ₂ ; provided that X ¹ and X ² are not both heteroatoms; each instance of R ¹ , R ² , R ⁴ , R ⁵ , R ^A1 , R ^A2 , and R ^A3 is independently R ^A or R ^B , and is substituted by 0-4 instances of R ^C ; each instance of R ³ is independently R ^A or R ^B , and is substituted by 0-4 instances of R ^C , or two R ³ groups are optionally taken together to form a 5-8 membered partially unsaturated or aryl fused ring having 0-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each instance of R ^A is independently oxo, deuterium, halogen, –CN, –NO ₂ , –OR, –SF ₅ , –SR, –NR ₂ , –S(O) ₂ R, –S(O) ₂ NR ₂ , –S(O) ₂ F, –S(O)R, –S(O)NR ₂ , –S(O)(NR)R, –S(O)(NCN)R, –S(NCN)R, –C(O)R, –C(O)OR, –C(O)NR ₂ , –C(O)N(R)OR, –OC(O)R, –OC(O)NR ₂ , –N(R)C(O)OR, –N(R)C(O)R, –N(R)C(O)NR ₂ , –N(R)C(NR)NR ₂ , –N(R)S(O) ₂ NR ₂ , –N(R)S(O) ₂ R, –P(O)R ₂ , –P(O)(R)OR, or –B(OR) _2; each instance of R ^B is independently a C1-6 aliphatic chain; phenyl; naphthyl; cubanyl; adamantyl; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from independently selected from nitrogen, oxygen, and sulfur; a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 5-12 membered saturated or partially unsaturated bicyclic carbocyclic ring; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each instance of R ^C is independently oxo, deuterium, halogen, –CN, –NO2, –OR, –SF5, –SR, –NR2, –S(O)2R, –S(O)2NR2, –S(O)2F, –S(O)R, –S(O)NR2, –S(O)(NR)R, –C(O)R, –C(O)OR, – C(O)NR ₂ , –C(O)N(R)OR, –OC(O)R, –OC(O)NR ₂ , –N(R)C(O)OR, –N(R)C(O)R, – N(R)C(O)NR ₂ , –N(R)C(NR)NR ₂ , –N(R)S(O) ₂ NR ₂ , –N(R)S(O) ₂ R, –P(O)R ₂ , –P(O)(R)OR, – B(OR) ₂ ,or an optionally substituted group selected from C _1-6 aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and each instance of R is independently hydrogen, or an optionally substituted group selected from C1- 6 aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5- 6 membered monocyclic 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 form an optionally substituted 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; Ring A and Ring B are each independently phenyl; 1,1'-biphenyl; naphthyl; tetrahydronaphthalenyl; dihydroindenyl; benzocyclobutenyl; cubanyl; adamantyl; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 5-12 membered saturated or partially unsaturated bicyclic carbocyclic ring; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; L is a covalent bond or a bivalent, saturated or unsaturated, straight or branched C _1-50 hydrocarbon chain, wherein 0-6 methylene units of L are independently replaced by –Cy–, –CH(R)–, –C(R) ₂ –, 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 5-11 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 5-11 membered saturated or partially 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 6-10 membered bridged 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, or an 8-10 membered bicyclic heteroarylenyl having 1- 5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; , , , , n is 0, 1, 2, 3, or 4; p is 0, 1, 2, 3, or 4; each of q is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; r is 0, 1, 2, 3, or 4; and s is 0, 1, 2, 3, or 4. 7. A compound of formula I-3: or a pharmaceutically acceptable salt thereof, wherein: the -L-LBM moiety to a modifiable carbon, oxygen, nitrogen, or sulfur atom of the ERBM moiety; X ¹ is N, CH, or C(R ^A1 ); X ² is N(R ^A2 ), O, CH2, CH(R ^A3 ), or C(R ^A3 )2; provided that X ¹ and X ² are not both heteroatoms; each instance of R ¹ , R ² , R ⁴ , R ⁵ , R ^A1 , R ^A2 , and R ^A3 is independently R ^A or R ^B , and is substituted by 0-4 instances of R ^C ; each instance of R ³ is independently R ^A or R ^B , and is substituted by 0-4 instances of R ^C , or two R ³ groups are optionally taken together to form a 5-8 membered partially unsaturated or aryl fused ring having 0-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each instance of R ^A is independently oxo, deuterium, halogen, –CN, –NO ₂ , –OR, –SF ₅ , –SR, –NR ₂ , –S(O) ₂ R, –S(O) ₂ NR ₂ , –S(O) ₂ F, –S(O)R, –S(O)NR ₂ , –S(O)(NR)R, –S(O)(NCN)R, –S(NCN)R, –C(O)R, –C(O)OR, –C(O)NR2, –C(O)N(R)OR, –OC(O)R, –OC(O)NR2, –N(R)C(O)OR, –N(R)C(O)R, –N(R)C(O)NR2, –N(R)C(NR)NR2, –N(R)S(O)2NR2, –N(R)S(O) ₂ R, –P(O)R ₂ , –P(O)(R)OR, or –B(OR) _2; each instance of R ^B is independently a C _1-6 aliphatic chain; phenyl; naphthyl; cubanyl; adamantyl; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 5-12 membered saturated or partially unsaturated bicyclic carbocyclic ring; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each instance of R ^C is independently oxo, deuterium, halogen, –CN, –NO ₂ , –OR, –SF ₅ , –SR, –NR ₂ , –S(O) ₂ R, –S(O) ₂ NR ₂ , –S(O) ₂ F, –S(O)R, –S(O)NR ₂ , –S(O)(NR)R, –C(O)R, –C(O)OR, – C(O)NR2, –C(O)N(R)OR, –OC(O)R, –OC(O)NR2, –N(R)C(O)OR, –N(R)C(O)R, – N(R)C(O)NR2, –N(R)C(NR)NR2, –N(R)S(O)2NR2, –N(R)S(O)2R, –P(O)R2, –P(O)(R)OR, – B(OR) ₂ ,or an optionally substituted group selected from C _1-6 aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and each instance of R is independently hydrogen, or an optionally substituted group selected from C _1- 6 aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5- 6 membered monocyclic 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 form an optionally substituted 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; Ring A and Ring B are each independently phenyl; 1,1'-biphenyl; naphthyl; tetrahydronaphthalenyl; dihydroindenyl; benzocyclobutenyl; cubanyl; adamantyl; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 5-12 membered saturated or partially unsaturated bicyclic carbocyclic ring; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; L is a covalent bond or a bivalent, saturated or unsaturated, straight or branched C _1-50 hydrocarbon chain, wherein 0-6 methylene units of L are independently replaced by –Cy–, –CH(R)–, –C(R) ₂ –, 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 5-11 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 5-11 membered saturated or partially 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 6-10 membered bridged bicyclic saturated or partially unsaturated heterocyclylenyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, d lf 56 b d h t l l h i 1 4 h t t i d d tl l t d from nitrogen, oxygen, and sulfur, or an 8-10 membered bicyclic heteroarylenyl having 1- 5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; , , , , n is 0, 1, 2, 3, or 4; p is 0, 1, 2, 3, or 4; each of q is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; r is 0, 1, 2, 3, or 4; and s is 0, 1, 2, 3, or 4,

wherein X ¹ is CH or N, X ² is CH ₂ ; Ring B is phenyl; Ring A is phenyl or a 6 membered monocyclic heteroaryl ring having 1-3 nitrogen heteroatoms; at least one R ³ is –OH or –OMe; p is 1, 2, or 3; m is 0, 1 or 2; R ¹ is selected from –F and –Cl; n is 0, 1 or 2; and R ² is selected from –OH, –Me, –OMe, –F, –Br, –CF ₃ and – ⁱ Pr; then LBM is not stereoisomer thereof. 8. A compound of formula I-3: or a pharmaceutically acceptable salt thereof, wherein: ERBM , indicates the site of attachment of the -L-LBM moiety to a modifiable carbon, oxygen, nitrogen, or sulfur atom of the ERBM moiety; X ¹ is N, CH, or C(R ^A1 ); X ² is N(R ^A2 ), O, CH ₂ , CH(R ^A3 ), or C(R ^A3 ) ₂ ; provided that X ¹ and X ² are not both heteroatoms; each instance of R ¹ , R ² , R ⁴ , R ⁵ , R ^A1 , R ^A2 , and R ^A3 is independently R ^A or R ^B , and is substituted by 0-4 instances of R ^C ; each instance of R ³ is independently R ^A or R ^B , and is substituted by 0-4 instances of R ^C , or two R ³ groups are optionally taken together to form a 5-8 membered partially unsaturated or aryl fused ring having 0-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each instance of R ^A is independently oxo, deuterium, halogen, –CN, –NO2, –OR, –SF5, –SR, –NR2, –S(O)2R, –S(O)2NR2, –S(O)2F, –S(O)R, –S(O)NR2, –S(O)(NR)R, –S(O)(NCN)R, –S(NCN)R, –C(O)R, –C(O)OR, –C(O)NR ₂ , –C(O)N(R)OR, –OC(O)R, –OC(O)NR ₂ , –N(R)C(O)OR, –N(R)C(O)R, –N(R)C(O)NR ₂ , –N(R)C(NR)NR ₂ , –N(R)S(O) ₂ NR ₂ , –N(R)S(O) ₂ R, –P(O)R ₂ , –P(O)(R)OR, or –B(OR) _2; each instance of R ^B is independently a C _1-6 aliphatic chain; phenyl; naphthyl; cubanyl; adamantyl; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 5-12 membered saturated or partially unsaturated bicyclic carbocyclic ring; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each instance of R ^C is independently oxo, deuterium, halogen, –CN, –NO2, –OR, –SF5, –SR, –NR2, –S(O)2R, –S(O)2NR2, –S(O)2F, –S(O)R, –S(O)NR2, –S(O)(NR)R, –C(O)R, –C(O)OR, – C(O)NR ₂ , –C(O)N(R)OR, –OC(O)R, –OC(O)NR ₂ , –N(R)C(O)OR, –N(R)C(O)R, – N(R)C(O)NR ₂ , –N(R)C(NR)NR ₂ , –N(R)S(O) ₂ NR ₂ , –N(R)S(O) ₂ R, –P(O)R ₂ , –P(O)(R)OR, – B(OR) ₂ ,or an optionally substituted group selected from C _1-6 aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and each instance of R is independently hydrogen, or an optionally substituted group selected from C _{1- 6} aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5- 6 membered monocyclic 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 form an optionally substituted 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; Ring A and Ring B are each independently phenyl; 1,1'-biphenyl; naphthyl; tetrahydronaphthalenyl; dihydroindenyl; benzocyclobutenyl; cubanyl; adamantyl; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 5-12 membered saturated or partially unsaturated bicyclic carbocyclic ring; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; L is a covalent bond or a bivalent, saturated or unsaturated, straight or branched C _1-50 hydrocarbon chain, wherein 0-6 methylene units of L are independently replaced by –Cy–, –CH(R)–, –C(R) ₂ –, 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 5-11 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 5-11 membered saturated or partially 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, 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, or an 8-10 membered bicyclic heteroarylenyl having 1- 5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; , , , , , n is 0, 1, 2, 3, or 4; p is 0, 1, 2, 3, or 4; each of q is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; r is 0, 1, 2, 3, or 4; and s is 0, 1, 2, 3, or 4, wherein X ¹ is CH or N, X ² is CH2; Ring B is phenyl; Ring A is phenyl or a 6 membered monocyclic heteroaryl ring having 1-3 nitrogen heteroatoms; then R ³ is not –OH or –OMe. 9. A compound of formula I-3: or a pharmaceutically acceptable salt thereof, wherein:

the -L-LBM moiety to a modifiable carbon, oxygen, nitrogen, or sulfur atom of the ERBM moiety; X ¹ is N, CH, or C(R ^A1 ); X ² is N(R ^A2 ), O, CH ₂ , CH(R ^A3 ), or C(R ^A3 ) ₂ ; provided that X ¹ and X ² are not both heteroatoms; each instance of R ¹ , R ² , R ⁴ , R ⁵ , R ^A1 , R ^A2 , and R ^A3 is independently R ^A or R ^B , and is substituted by 0-4 instances of R ^C ; each instance of R ³ is independently R ^A or R ^B , and is substituted by 0-4 instances of R ^C , or two R ³ groups are optionally taken together to form a 5-8 membered partially unsaturated or aryl fused ring having 0-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each instance of R ^A is independently oxo, deuterium, halogen, –CN, –NO ₂ , –OR, –SF ₅ , –SR, –NR ₂ , –S(O) ₂ R, –S(O) ₂ NR ₂ , –S(O) ₂ F, –S(O)R, –S(O)NR ₂ , –S(O)(NR)R, –S(O)(NCN)R, –S(NCN)R, –C(O)R, –C(O)OR, –C(O)NR ₂ , –C(O)N(R)OR, –OC(O)R, –OC(O)NR ₂ , –N(R)C(O)OR, –N(R)C(O)R, –N(R)C(O)NR ₂ , –N(R)C(NR)NR ₂ , –N(R)S(O) ₂ NR ₂ , –N(R)S(O) ₂ R, –P(O)R ₂ , –P(O)(R)OR, or –B(OR) _2; each instance of R ^B is independently a C1-6 aliphatic chain; phenyl; naphthyl; cubanyl; adamantyl; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from independently selected from nitrogen, oxygen, and sulfur; a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 5-12 membered saturated or partially unsaturated bicyclic carbocyclic ring; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each instance of R ^C is independently oxo, deuterium, halogen, –CN, –NO2, –OR, –SF5, –SR, –NR2, –S(O)2R, –S(O)2NR2, –S(O)2F, –S(O)R, –S(O)NR2, –S(O)(NR)R, –C(O)R, –C(O)OR, – C(O)NR ₂ , –C(O)N(R)OR, –OC(O)R, –OC(O)NR ₂ , –N(R)C(O)OR, –N(R)C(O)R, – N(R)C(O)NR ₂ , –N(R)C(NR)NR ₂ , –N(R)S(O) ₂ NR ₂ , –N(R)S(O) ₂ R, –P(O)R ₂ , –P(O)(R)OR, – B(OR) ₂ ,or an optionally substituted group selected from C _1-6 aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and each instance of R is independently hydrogen, or an optionally substituted group selected from C1- 6 aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5- 6 membered monocyclic 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 form an optionally substituted 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; Ring A and Ring B are each independently phenyl; 1,1'-biphenyl; naphthyl; tetrahydronaphthalenyl; dihydroindenyl; benzocyclobutenyl; cubanyl; adamantyl; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 5-12 membered saturated or partially unsaturated bicyclic carbocyclic ring; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; L is a covalent bond or a bivalent, saturated or unsaturated, straight or branched C _1-50 hydrocarbon chain, wherein 0-6 methylene units of L are independently replaced by –Cy–, –CH(R)–, –C(R) ₂ –, 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 5-11 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 5-11 membered saturated or partially 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 6-10 membered bridged 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, or an 8-10 membered bicyclic heteroarylenyl having 1- 5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; , , , , n is 0, 1, 2, 3, or 4; p is 0, 1, 2, 3, or 4; each of q is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; r is 0, 1, 2, 3, or 4; and s is 0, 1, 2, 3, or 4,

wherein X ¹ is CH or N, Ring B is phenyl; then Ring A is not phenyl or a 6 membered monocyclic heteroaryl ring having 1-3 nitrogen heteroatoms. 10. A compound of formula I-3: or a pharmaceutically acceptable salt thereof, wherein:

the -L-LBM moiety to a modifiable carbon, oxygen, nitrogen, or sulfur atom of the ERBM moiety; X ¹ is N, CH, or C(R ^A1 ); X ² is N(R ^A2 ), O, CH ₂ , CH(R ^A3 ), or C(R ^A3 ) ₂ ; provided that X ¹ and X ² are not both heteroatoms; each instance of R ¹ , R ² , R ⁴ , R ⁵ , R ^A1 , R ^A2 , and R ^A3 is independently R ^A or R ^B , and is substituted by 0-4 instances of R ^C ; each instance of R ³ is independently R ^A or R ^B , and is substituted by 0-4 instances of R ^C , or two R ³ groups are optionally taken together to form a 5-8 membered partially unsaturated or aryl fused ring having 0-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each instance of R ^A is independently oxo, deuterium, halogen, –CN, –NO ₂ , –OR, –SF ₅ , –SR, –NR ₂ , –S(O) ₂ R, –S(O) ₂ NR ₂ , –S(O) ₂ F, –S(O)R, –S(O)NR ₂ , –S(O)(NR)R, –S(O)(NCN)R, –S(NCN)R, –C(O)R, –C(O)OR, –C(O)NR ₂ , –C(O)N(R)OR, –OC(O)R, –OC(O)NR ₂ , –N(R)C(O)OR, –N(R)C(O)R, –N(R)C(O)NR ₂ , –N(R)C(NR)NR ₂ , –N(R)S(O) ₂ NR ₂ , –N(R)S(O) ₂ R, –P(O)R ₂ , –P(O)(R)OR, or –B(OR) _2; each instance of R ^B is independently a C1-6 aliphatic chain; phenyl; naphthyl; cubanyl; adamantyl; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from independently selected from nitrogen, oxygen, and sulfur; a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 5-12 membered saturated or partially unsaturated bicyclic carbocyclic ring; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each instance of R ^C is independently oxo, deuterium, halogen, –CN, –NO2, –OR, –SF5, –SR, –NR2, –S(O)2R, –S(O)2NR2, –S(O)2F, –S(O)R, –S(O)NR2, –S(O)(NR)R, –C(O)R, –C(O)OR, – C(O)NR ₂ , –C(O)N(R)OR, –OC(O)R, –OC(O)NR ₂ , –N(R)C(O)OR, –N(R)C(O)R, – N(R)C(O)NR ₂ , –N(R)C(NR)NR ₂ , –N(R)S(O) ₂ NR ₂ , –N(R)S(O) ₂ R, –P(O)R ₂ , –P(O)(R)OR, – B(OR) ₂ ,or an optionally substituted group selected from C _1-6 aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and each instance of R is independently hydrogen, or an optionally substituted group selected from C1- 6 aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5- 6 membered monocyclic 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 form an optionally substituted 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; Ring A and Ring B are each independently phenyl; 1,1'-biphenyl; naphthyl; tetrahydronaphthalenyl; dihydroindenyl; benzocyclobutenyl; cubanyl; adamantyl; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 5-12 membered saturated or partially unsaturated bicyclic carbocyclic ring; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; L is a covalent bond or a bivalent, saturated or unsaturated, straight or branched C _1-50 hydrocarbon chain, wherein 0-6 methylene units of L are independently replaced by –Cy–, –CH(R)–, –C(R) ₂ –, 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 5-11 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 5-11 membered saturated or partially 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 6-10 membered bridged 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, or an 8-10 membered bicyclic heteroarylenyl having 1- 5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; , , , , n is 0, 1, 2, 3, or 4; p is 0, 1, 2, 3, or 4; each of q is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; r is 0, 1, 2, 3, or 4; and s is 0, 1, 2, 3, or 4, provided that when Ring B is phenyl, X ¹ is CH or N and X ² is CH ₂ ; then Ring A is other than phenyl or a 6 membered monocyclic heteroaryl ring having 1-3 nitrogen heteroatoms. 11. A compound of formula I-3: or a pharmaceutically acceptable salt thereof, wherein: , indicates the site of attachment of the -L-LBM moiety to a modifiable carbon, oxygen, nitrogen, or sulfur atom of the ERBM moiety; X ² is N(R ^A2 ), O, CH2, CH(R ^A3 ), or C(R ^A3 )2; provided that X ¹ and X ² are not both heteroatoms; each instance of R ¹ , R ² , R ⁴ , R ⁵ , R ^A1 , R ^A2 , and R ^A3 is independently R ^A or R ^B , and is substituted by 0-4 instances of R ^C ; each instance of R ³ is independently R ^A or R ^B , and is substituted by 0-4 instances of R ^C , or two R ³ groups are optionally taken together to form a 5-8 membered partially unsaturated or aryl fused ring having 0-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each instance of R ^A is independently oxo, deuterium, halogen, –CN, –NO ₂ , –OR, –SF ₅ , –SR, –NR ₂ , –S(O) ₂ R, –S(O) ₂ NR ₂ , –S(O) ₂ F, –S(O)R, –S(O)NR ₂ , –S(O)(NR)R, –S(O)(NCN)R, –S(NCN)R, –C(O)R, –C(O)OR, –C(O)NR ₂ , –C(O)N(R)OR, –OC(O)R, –OC(O)NR ₂ , –N(R)C(O)OR, –N(R)C(O)R, –N(R)C(O)NR ₂ , –N(R)C(NR)NR ₂ , –N(R)S(O) ₂ NR ₂ , –N(R)S(O) ₂ R, –P(O)R ₂ , –P(O)(R)OR, or –B(OR) _2; each instance of R ^B is independently a C _1-6 aliphatic chain; phenyl; naphthyl; cubanyl; adamantyl; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 5-12 membered saturated or partially unsaturated bicyclic carbocyclic ring; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each instance of R ^C is independently oxo, deuterium, halogen, –CN, –NO ₂ , –OR, –SF ₅ , –SR, –NR ₂ , –S(O) ₂ R, –S(O) ₂ NR ₂ , –S(O) ₂ F, –S(O)R, –S(O)NR ₂ , –S(O)(NR)R, –C(O)R, –C(O)OR, – C(O)NR ₂ , –C(O)N(R)OR, –OC(O)R, –OC(O)NR ₂ , –N(R)C(O)OR, –N(R)C(O)R, – N(R)C(O)NR ₂ , –N(R)C(NR)NR ₂ , –N(R)S(O) ₂ NR ₂ , –N(R)S(O) ₂ R, –P(O)R ₂ , –P(O)(R)OR, – B(OR) ₂ ,or an optionally substituted group selected from C _1-6 aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and each instance of R is independently hydrogen, or an optionally substituted group selected from C1- 6 aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5- 6 membered monocyclic 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 form an optionally substituted 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; Ring A and Ring B are each independently phenyl; naphthyl; tetrahydronaphthalenyl; dihydroindenyl; benzocyclobutenyl; cubanyl; adamantyl; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 5-12 membered saturated or partially unsaturated bicyclic carbocyclic ring; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; L is a covalent bond or a bivalent, saturated or unsaturated, straight or branched C _1-50 hydrocarbon chain, wherein 0-6 methylene units of L are independently replaced by –Cy–, –CH(R)–, –C(R) ₂ –, 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 5-11 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 5-11 membered saturated or partially 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 6-10 membered bridged 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, or an 8-10 membered bicyclic heteroarylenyl having 1- 5 heteroatoms independently selected from nitrogen, oxygen, or sulfur;

m is 0, 1, 2, 3, or 4; n is 0, 1, 2, 3, or 4; p is 0, 1, 2, 3, or 4; each of q is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; r is 0, 1, 2, 3, or 4; and s is 0, 1, 2, 3, or 4. 12. A compound of formula I-3: or a pharmaceutically acceptable salt thereof, wherein: ERBM is selected from , indicates the site of attachment of the -L-LBM moiety to a modifiable carbon, oxygen, nitrogen, or sulfur atom of the ERBM moiety; X ¹ is N, CH, or C(R ^A1 ); provided that X ¹ and X ² are not both heteroatoms; each instance of R ¹ , R ² , R ⁴ , R ⁵ , R ^A1 , R ^A2 , and R ^A3 is independently R ^A or R ^B , and is substituted by 0-4 instances of R ^C ; each instance of R ³ is independently R ^A or R ^B , and is substituted by 0-4 instances of R ^C , or two R ³ groups are optionally taken together to form a 5-8 membered partially unsaturated or aryl fused ring having 0-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each instance of R ^A is independently oxo, deuterium, halogen, –CN, –NO ₂ , –OR, –SF ₅ , –SR, –NR ₂ , –S(O) ₂ R, –S(O) ₂ NR ₂ , –S(O) ₂ F, –S(O)R, –S(O)NR ₂ , –S(O)(NR)R, –S(O)(NCN)R, –S(NCN)R, –C(O)R, –C(O)OR, –C(O)NR ₂ , –C(O)N(R)OR, –OC(O)R, –OC(O)NR ₂ , –N(R)C(O)OR, –N(R)C(O)R, –N(R)C(O)NR ₂ , –N(R)C(NR)NR ₂ , –N(R)S(O) ₂ NR ₂ , –N(R)S(O) ₂ R, –P(O)R ₂ , –P(O)(R)OR, or –B(OR) _2; each instance of R ^B is independently a C _1-6 aliphatic chain; phenyl; naphthyl; cubanyl; adamantyl; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 5-12 membered saturated or partially unsaturated bicyclic carbocyclic ring; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 14 h t t i d d tl l t d f it d lf each instance of R ^C is independently oxo, deuterium, halogen, –CN, –NO2, –OR, –SF5, –SR, –NR2, –S(O)2R, –S(O)2NR2, –S(O)2F, –S(O)R, –S(O)NR2, –S(O)(NR)R, –C(O)R, –C(O)OR, – C(O)NR ₂ , –C(O)N(R)OR, –OC(O)R, –OC(O)NR ₂ , –N(R)C(O)OR, –N(R)C(O)R, – N(R)C(O)NR ₂ , –N(R)C(NR)NR ₂ , –N(R)S(O) ₂ NR ₂ , –N(R)S(O) ₂ R, –P(O)R ₂ , –P(O)(R)OR, – B(OR) ₂ ,or an optionally substituted group selected from C _1-6 aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and each instance of R is independently hydrogen, or an optionally substituted group selected from C _{1- 6} aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5- 6 membered monocyclic 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 form an optionally substituted 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; Ring A and Ring B are each independently phenyl; naphthyl; tetrahydronaphthalenyl; dihydroindenyl; benzocyclobutenyl; cubanyl; adamantyl; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 5-12 membered saturated or partially unsaturated bicyclic carbocyclic ring; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 7- 12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; L is a covalent bond or a bivalent, saturated or unsaturated, straight or branched C1-50 hydrocarbon chain, wherein 0-6 methylene units of L are independently replaced by –Cy–, –CH(R)–, –C(R)2–, –O– –NR– –S– –OC(O)– –C(O)O– –C(O)– –S(O)– –S(O) ₂ – –NRS(O) ₂ – –S(O) ₂ NR– –

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 5-11 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 5-11 membered saturated or partially 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 6-10 membered bridged 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, or an 8-10 membered bicyclic heteroarylenyl having 1- 5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; LBM is selected from , ,

m is 0, 1, 2, 3, or 4; n is 0, 1, 2, 3, or 4; p is 0, 1, 2, 3, or 4; each of q is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; r is 0, 1, 2, 3, or 4; and s is 0, 1, 2, 3, or 4. 13. A compound of formula I-3’: or a pharmaceutically acceptable salt thereof, wherein: ERBM is selected from ,

-L-LBM moiety to a modifiable carbon, oxygen, nitrogen, or sulfur atom of the ERBM moiety; X ¹ is N, NH, CH, CH2, CH(R ^A1 ) or C(R ^A1 )2 or C(R ^A1 ) as allowed by the other substituents; X ² is N(R ^A2 ), O, CH ₂ , CH(R ^A3 ), or C(R ^A3 ) ₂ ; X ³ is N(R ^A4 ), O, CH ₂ , CH(R ^A5 ), or C(R ^A5 ) ₂ ; provided that X ¹ and X ² or X ² and X ³ are not both heteroatoms; each instance of R ¹ , R ² , R ⁴ , R ⁵ , R ⁶ , R ^A1 , R ^A2 , R ^A3 , R ^A4 , and R ^A5 is independently R ^A or R ^B , and is substituted by 0-4 instances of R ^C ; each instance of R ³ is independently R ^A or R ^B , and is substituted by 0-4 instances of R ^C , or two R ³ groups are optionally taken together to form a 5-8 membered partially unsaturated or aryl fused ring having 0-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each instance of R ^A is independently oxo, deuterium, halogen, –CN, –NO ₂ , –OR, –SF ₅ , –SR, –NR ₂ , –S(O) ₂ R, –S(O) ₂ NR ₂ , –S(O) ₂ F, –S(O)R, –S(O)NR ₂ , –S(O)(NR)R, –S(O)(NCN)R, –S(NCN)R, –C(O)R, –C(O)OR, –C(O)NR ₂ , –C(O)N(R)OR, –OC(O)R, –OC(O)NR ₂ , –N(R)C(O)OR, –N(R)C(O)R, –N(R)C(O)NR ₂ , –N(R)C(NR)NR ₂ , –N(R)S(O) ₂ NR ₂ , –N(R)S(O)2R, –P(O)R2, –P(O)(R)OR, or –B(OR)2; each instance of R ^B is independently a C _1-6 aliphatic chain; phenyl; naphthyl; cubanyl; adamantyl; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from independently selected from nitrogen, oxygen, and sulfur; a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 5-12 membered saturated or partially unsaturated bicyclic carbocyclic ring; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each instance of R ^C is independently oxo, deuterium, halogen, –CN, –NO2, –OR, –SF5, –SR, –NR2, –S(O)2R, –S(O)2NR2, –S(O)2F, –S(O)R, –S(O)NR2, –S(O)(NR)R, –C(O)R, –C(O)OR, – C(O)NR ₂ , –C(O)N(R)OR, –OC(O)R, –OC(O)NR ₂ , –N(R)C(O)OR, –N(R)C(O)R, – N(R)C(O)NR ₂ , –N(R)C(NR)NR ₂ , –N(R)S(O) ₂ NR ₂ , –N(R)S(O) ₂ R, –P(O)R ₂ , –P(O)(R)OR, – B(OR) ₂ ,or an optionally substituted group selected from C _1-6 aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and each instance of R is independently hydrogen, or an optionally substituted group selected from C1- 6 aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5- 6 membered monocyclic 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 form an optionally substituted 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; Ring A and Ring B are each independently phenyl; naphthyl; tetrahydronaphthalenyl; dihydroindenyl; benzocyclobutenyl; cubanyl; adamantyl; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 5-12 membered saturated or partially unsaturated bicyclic carbocyclic ring; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Ring C is a spiro-fused 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a spiro-fused 5-12 membered saturated or partially unsaturated bicyclic carbocyclic ring; a spiro-fused 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a spiro-fused 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; L is a covalent bond or a bivalent, saturated or unsaturated, straight or branched C _1-50 hydrocarbon chain, wherein 0-6 methylene units of L are independently replaced by –Cy–, –CH(R)–, –C(R) ₂ –, 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 5-11 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 5-11 membered saturated or partially 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 6-10 membered bridged 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, or an 8-10 membered bicyclic heteroarylenyl having 1- 5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; , , , , m is 0, 1, 2, 3, or 4; n is 0, 1, 2, 3, or 4; p is 0, 1, 2, 3, or 4; h f i i d d tl 1 2 3 4 5 6 7 8 9 10 r is 0, 1, 2, 3, or 4; s is 0, 1, 2, 3, or 4; and t is 0, 1, 2, 3, or 4. 14. A compound of formula I-3’: I-3’ or a pharmaceutically acceptable salt thereof, wherein: L-LBM moiety to a modifiable carbon, oxygen, nitrogen, or sulfur atom of the ERBM moiety; X ¹ is N NH CH CH ₂ CH(R ^A1 ) or C(R ^A1 ) ₂ or C(R ^A1 ) as allowed by the other substituents; X ² is N(R ^A2 ), O, CH2, CH(R ^A3 ), or C(R ^A3 )2; X ³ is N(R ^A4 ), O, CH ₂ , CH(R ^A5 ), or C(R ^A5 ) ₂ ; provided that X ¹ and X ² or X ² and X ³ are not both heteroatoms; each instance of R ¹ , R ² , R ⁴ , R ⁵ , R ⁶ , R ^A1 , R ^A2 , R ^A3 , R ^A4 , and R ^A5 is independently R ^A or R ^B , and is substituted by 0-4 instances of R ^C ; each instance of R ³ is independently R ^A or R ^B , and is substituted by 0-4 instances of R ^C , or two R ³ groups are optionally taken together to form a 5-8 membered partially unsaturated or aryl fused ring having 0-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each instance of R ^A is independently oxo, deuterium, halogen, –CN, –NO ₂ , –OR, –SF ₅ , –SR, –NR ₂ , –S(O) ₂ R, –S(O) ₂ NR ₂ , –S(O) ₂ F, –S(O)R, –S(O)NR ₂ , –S(O)(NR)R, –S(O)(NCN)R, –S(NCN)R, –C(O)R, –C(O)OR, –C(O)NR ₂ , –C(O)N(R)OR, –OC(O)R, –OC(O)NR ₂ , –N(R)C(O)OR, –N(R)C(O)R, –N(R)C(O)NR ₂ , –N(R)C(NR)NR ₂ , –N(R)S(O) ₂ NR ₂ , –N(R)S(O) ₂ R, –P(O)R ₂ , –P(O)(R)OR, or –B(OR) ₂ ; each instance of R ^B is independently a C _1-6 aliphatic chain; phenyl; naphthyl; cubanyl; adamantyl; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 5-12 membered saturated or partially unsaturated bicyclic carbocyclic ring; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each instance of R ^C is independently oxo, deuterium, halogen, –CN, –NO ₂ , –OR, –SF ₅ , –SR, –NR ₂ , –S(O) ₂ R, –S(O) ₂ NR ₂ , –S(O) ₂ F, –S(O)R, –S(O)NR ₂ , –S(O)(NR)R, –C(O)R, –C(O)OR, – C(O)NR ₂ , –C(O)N(R)OR, –OC(O)R, –OC(O)NR ₂ , –N(R)C(O)OR, –N(R)C(O)R, – N(R)C(O)NR ₂ , –N(R)C(NR)NR ₂ , –N(R)S(O) ₂ NR ₂ , –N(R)S(O) ₂ R, –P(O)R ₂ , –P(O)(R)OR, – B(OR) ₂ ,or an optionally substituted group selected from C _1-6 aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and each instance of R is independently hydrogen, or an optionally substituted group selected from C _{1- 6} aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5- 6 membered monocyclic 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 form an optionally substituted 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; Ring A and Ring B are each independently phenyl; naphthyl; tetrahydronaphthalenyl; dihydroindenyl; benzocyclobutenyl; cubanyl; adamantyl; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 5-12 membered saturated or partially unsaturated bicyclic carbocyclic ring; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Ring C is a spiro-fused 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a spiro-fused 5-12 membered saturated or partially unsaturated bicyclic carbocyclic ring; a spiro-fused 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a spiro-fused 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; L is a covalent bond or a bivalent, saturated or unsaturated, straight or branched C _1-50 hydrocarbon chain, wherein 0-6 methylene units of L are independently replaced by –Cy–, –CH(R)–, –C(R) ₂ –,

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 5-11 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 5-11 membered saturated or partially 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 6-10 membered bridged 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, or an 8-10 membered bicyclic heteroarylenyl having 1- 5 heteroatoms independently selected from nitrogen, oxygen, or sulfur;

LBM is selected from m is 0, 1, 2, 3, or 4; n is 0, 1, 2, 3, or 4; p is 0, 1, 2, 3, or 4; each of q is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; r is 0, 1, 2, 3, or 4; s is 0, 1, 2, 3, or 4; and t is 0, 1, 2, 3, or 4. 15. A compound of formula I-3: I-3 or a pharmaceutically acceptable salt thereof, wherein:

the -L-LBM moiety to a modifiable carbon, oxygen, nitrogen, or sulfur atom of the ERBM moiety; X ¹ is N, CH, or C(R ^A1 ); X ² is N(R ^A2 ), O, CH ₂ , CH(R ^A3 ), or C(R ^A3 ) ₂ ; provided that X ¹ and X ² are not both heteroatoms; each instance of R ¹ , R ² , R ⁴ , R ⁵ , R ^A1 , R ^A2 , and R ^A3 is independently R ^A or R ^B , and is substituted by 0-4 instances of R ^C ; each instance of R ³ is independently R ^A or R ^B , and is substituted by 0-4 instances of R ^C , or two R ³ groups are optionally taken together to form a 5-8 membered partially unsaturated or aryl fused ring having 0-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each instance of R ^A is independently oxo, deuterium, halogen, –CN, –NO ₂ , –OR, –SF ₅ , –SR, –NR ₂ , –S(O) ₂ R, –S(O) ₂ NR ₂ , –S(O) ₂ F, –S(O)R, –S(O)NR ₂ , –S(O)(NR)R, –S(O)(NCN)R, –S(NCN)R, –C(O)R, –C(O)OR, –C(O)NR ₂ , –C(O)N(R)OR, –OC(O)R, –OC(O)NR ₂ , –N(R)C(O)OR, –N(R)C(O)R, –N(R)C(O)NR ₂ , –N(R)C(NR)NR ₂ , –N(R)S(O) ₂ NR ₂ , –N(R)S(O) ₂ R, –P(O)R ₂ , –P(O)(R)OR, or –B(OR) _2; each instance of R ^B is independently a C1-6 aliphatic chain; phenyl; naphthyl; cubanyl; adamantyl; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from independently selected from nitrogen, oxygen, and sulfur; a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 5-12 membered saturated or partially unsaturated bicyclic carbocyclic ring; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each instance of R ^C is independently oxo, deuterium, halogen, –CN, –NO2, –OR, –SF5, –SR, –NR2, –S(O)2R, –S(O)2NR2, –S(O)2F, –S(O)R, –S(O)NR2, –S(O)(NR)R, –C(O)R, –C(O)OR, – C(O)NR ₂ , –C(O)N(R)OR, –OC(O)R, –OC(O)NR ₂ , –N(R)C(O)OR, –N(R)C(O)R, – N(R)C(O)NR ₂ , –N(R)C(NR)NR ₂ , –N(R)S(O) ₂ NR ₂ , –N(R)S(O) ₂ R, –P(O)R ₂ , –P(O)(R)OR, – B(OR) ₂ ,or an optionally substituted group selected from C _1-6 aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and each instance of R is independently hydrogen, or an optionally substituted group selected from C1- 6 aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5- 6 membered monocyclic 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 form an optionally substituted 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; Ring A and Ring B are each independently phenyl; naphthyl; tetrahydronaphthalenyl; dihydroindenyl; benzocyclobutenyl; cubanyl; adamantyl; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 5-12 membered saturated or partially unsaturated bicyclic carbocyclic ring; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; L is a covalent bond or a bivalent, saturated or unsaturated, straight or branched C _1-50 hydrocarbon chain, wherein 0-6 methylene units of L are independently replaced by –Cy–, –CH(R)–, –C(R) ₂ –, 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 5-11 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 5-11 membered saturated or partially 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 6-10 membered bridged 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, or an 8-10 membered bicyclic heteroarylenyl having 1- 5 heteroatoms independently selected from nitrogen, oxygen, or sulfur;

m is 0, 1, 2, 3, or 4; n is 0, 1, 2, 3, or 4; p is 0, 1, 2, 3, or 4; each of q is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; r is 0, 1, 2, 3, or 4; and s is 0, 1, 2, 3, or 4; provided that when Ring B is phenyl, X ¹ is CH or N and X ² is CH ₂ ; then Ring A is other than phenyl or a 6 membered monocyclic heteroaryl ring having 1-3 nitrogen heteroatoms. 16. A compound of formula I-3: the -L-LBM moiety to a modifiable carbon, oxygen, nitrogen, or sulfur atom of the ERBM moiety; X ² is N(R ^A2 ), O, CH2, CH(R ^A3 ), or C(R ^A3 )2; provided that X ¹ and X ² are not both heteroatoms; each instance of R ¹ , R ² , R ⁴ , R ⁵ , R ^A1 , R ^A2 , and R ^A3 is independently R ^A or R ^B , and is substituted by 0-4 instances of R ^C ; each instance of R ³ is independently R ^A or R ^B , and is substituted by 0-4 instances of R ^C , or two R ³ groups are optionally taken together to form a 5-8 membered partially unsaturated or aryl fused ring having 0-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each instance of R ^A is independently oxo, deuterium, halogen, –CN, –NO ₂ , –OR, –SF ₅ , –SR, –NR ₂ , –S(O) ₂ R, –S(O) ₂ NR ₂ , –S(O) ₂ F, –S(O)R, –S(O)NR ₂ , –S(O)(NR)R, –S(O)(NCN)R, –S(NCN)R, –C(O)R, –C(O)OR, –C(O)NR ₂ , –C(O)N(R)OR, –OC(O)R, –OC(O)NR ₂ , –N(R)C(O)OR, –N(R)C(O)R, –N(R)C(O)NR ₂ , –N(R)C(NR)NR ₂ , –N(R)S(O) ₂ NR ₂ , –N(R)S(O) ₂ R, –P(O)R ₂ , –P(O)(R)OR, or –B(OR) _2; each instance of R ^B is independently a C _1-6 aliphatic chain; phenyl; naphthyl; cubanyl; adamantyl; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 5-12 membered saturated or partially unsaturated bicyclic carbocyclic ring; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each instance of R ^C is independently oxo, deuterium, halogen, –CN, –NO ₂ , –OR, –SF ₅ , –SR, –NR ₂ , –S(O) ₂ R, –S(O) ₂ NR ₂ , –S(O) ₂ F, –S(O)R, –S(O)NR ₂ , –S(O)(NR)R, –C(O)R, –C(O)OR, – C(O)NR ₂ , –C(O)N(R)OR, –OC(O)R, –OC(O)NR ₂ , –N(R)C(O)OR, –N(R)C(O)R, – N(R)C(O)NR ₂ , –N(R)C(NR)NR ₂ , –N(R)S(O) ₂ NR ₂ , –N(R)S(O) ₂ R, –P(O)R ₂ , –P(O)(R)OR, – B(OR) ₂ ,or an optionally substituted group selected from C _1-6 aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and each instance of R is independently hydrogen, or an optionally substituted group selected from C1-6 aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered monocyclic 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 form an optionally substituted 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; Ring A and Ring B are each independently phenyl; naphthyl; tetrahydronaphthalenyl; dihydroindenyl; benzocyclobutenyl; cubanyl; adamantyl; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 5-12 membered saturated or partially unsaturated bicyclic carbocyclic ring; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 7- 12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; L is a covalent bond or a bivalent, saturated or unsaturated, straight or branched C _1-50 hydrocarbon chain, wherein 0-6 methylene units of L are independently replaced by –Cy–, – 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 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 5-11 membered saturated or partially 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 6-10 membered bridged 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, or an 8-10 membered bicyclic heteroarylenyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; m is 0, 1, 2, 3, or 4; n is 0, 1, 2, 3, or 4; p is 0, 1, 2, 3, or 4; each of q is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; r is 0, 1, 2, 3, or 4; and i 0 1 2 3 4 provided that when Ring B is phenyl, X ¹ is CH or N and X ² is CH ₂ ; then Ring A is other than phenyl or a 6 membered monocyclic heteroaryl ring having 1-3 nitrogen heteroatoms. 17. A compound of formula I-3’: or a pharmaceutically acceptable salt thereof, wherein: ERBM selected , indicates the site of attachment of the - L-LBM moiety to a modifiable carbon, oxygen, nitrogen, or sulfur atom of the ERBM moiety; X ¹ is N, NH, CH, CH ₂ , CH(R ^A1 ), C(R ^A1 ) ₂ or C(R ^A1 ) as allowed by the other substituents; X ² is N(R ^A2 ), O, CH ₂ , CH(R ^A3 ), or C(R ^A3 ) ₂ ; X ³ is N(R ^A4 ), O, CH2, CH(R ^A5 ), or C(R ^A5 )2; provided that X ¹ and X ² or X ² and X ³ are not both heteroatoms; each instance of R ¹ , R ² , R ⁴ , R ⁵ , R ⁶ , R ^A1 , R ^A2 , R ^A3 , R ^A4 , and R ^A5 is independently R ^A or R ^B , and is substituted by 0-4 instances of R ^C ; each instance of R ³ is independently R ^A or R ^B , and is substituted by 0-4 instances of R ^C , or two R ³ groups are optionally taken together to form a 5-8 membered partially unsaturated or aryl fused ring having 0-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each instance of R ^A is independently oxo, deuterium, halogen, –CN, –NO ₂ , –OR, –SF ₅ , –SR, –NR ₂ , –S(O) ₂ R, –S(O) ₂ NR ₂ , –S(O) ₂ F, –S(O)R, –S(O)NR ₂ , –S(O)(NR)R, –S(O)(NCN)R, –S(NCN)R, –C(O)R, –C(O)OR, –C(O)NR ₂ , –C(O)N(R)OR, –OC(O)R, –OC(O)NR ₂ , –N(R)C(O)OR, –N(R)C(O)R, –N(R)C(O)NR ₂ , –N(R)C(NR)NR ₂ , –N(R)S(O) ₂ NR ₂ , –N(R)S(O) ₂ R, –P(O)R ₂ , –P(O)(R)OR, or –B(OR) _2; each instance of R ^B is independently a C _1-6 aliphatic chain; phenyl; naphthyl; cubanyl; adamantyl; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 5-12 membered saturated or partially unsaturated bicyclic carbocyclic ring; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having each instance of R ^C is independently oxo, deuterium, halogen, –CN, –NO2, –OR, –SF5, –SR, –NR2, –S(O)2R, –S(O)2NR2, –S(O)2F, –S(O)R, –S(O)NR2, –S(O)(NR)R, –C(O)R, –C(O)OR, – C(O)NR ₂ , –C(O)N(R)OR, –OC(O)R, –OC(O)NR ₂ , –N(R)C(O)OR, –N(R)C(O)R, – N(R)C(O)NR ₂ , –N(R)C(NR)NR ₂ , –N(R)S(O) ₂ NR ₂ , –N(R)S(O) ₂ R, –P(O)R ₂ , –P(O)(R)OR, – B(OR) ₂ ,or an optionally substituted group selected from C _1-6 aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and each instance of R is independently hydrogen, or an optionally substituted group selected from C _{1- 6} aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5- 6 membered monocyclic 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 form an optionally substituted 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; Ring A and Ring B are each independently phenyl; naphthyl; tetrahydronaphthalenyl; dihydroindenyl; benzocyclobutenyl; cubanyl; adamantyl; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 5-12 membered saturated or partially unsaturated bicyclic carbocyclic ring; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Ring C is a spiro-fused 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a spiro-fused 5-12 membered saturated or partially unsaturated bicyclic carbocyclic ring; a spiro-fused 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a spiro-fused 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; L is a covalent bond or a bivalent, saturated or unsaturated, straight or branched C _1-50 hydrocarbon chain, wherein 0-6 methylene units of L are independently replaced by –Cy–, –CH(R)–, –C(R) ₂ –, 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 5-11 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 5-11 membered saturated or partially 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 6-10 membered bridged 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, or an 8-10 membered bicyclic heteroarylenyl having 1- 5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; , , , , , m is 0, 1, 2, 3, or 4; n is 0, 1, 2, 3, or 4; p is 0, 1, 2, 3, or 4; each of q is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; r is 0, 1, 2, 3, or 4; i 0 1 2 3 4 d t is 0, 1, 2, 3, or 4; provided that when ; and Ring B is phenyl, X ¹ is CH or N and X ² is CH ₂ ; then Ring A is other than phenyl or a 6 membered monocyclic heteroaryl ring having 1-3 nitrogen heteroatoms. 18. A compound of formula I-3’: I-3’ or a pharmaceutically acceptable salt thereof, wherein: indicates the site of attachment of the - L-LBM moiety to a modifiable carbon, oxygen, nitrogen, or sulfur atom of the ERBM moiety; X ¹ is N, NH, CH, CH ₂ , CH(R ^A1 ), C(R ^A1 ) ₂ or C(R ^A1 ) as allowed by the other substituents; X ² is N(R ^A2 ), O, CH ₂ , CH(R ^A3 ), or C(R ^A3 ) ₂ ; X ³ is N(R ^A4 ), O, CH2, CH(R ^A5 ), or C(R ^A5 )2; provided that X ¹ and X ² or X ² and X ³ are not both heteroatoms; each instance of R ¹ , R ² , R ⁴ , R ⁵ , R ⁶ , R ^A1 , R ^A2 , R ^A3 , R ^A4 , and R ^A5 is independently R ^A or R ^B , and is substituted by 0-4 instances of R ^C ; each instance of R ³ is independently R ^A or R ^B , and is substituted by 0-4 instances of R ^C , or two R ³ groups are optionally taken together to form a 5-8 membered partially unsaturated or aryl fused ring having 0-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each instance of R ^A is independently oxo, deuterium, halogen, –CN, –NO ₂ , –OR, –SF ₅ , –SR, –NR ₂ , –S(O) ₂ R, –S(O) ₂ NR ₂ , –S(O) ₂ F, –S(O)R, –S(O)NR ₂ , –S(O)(NR)R, –S(O)(NCN)R, –S(NCN)R, –C(O)R, –C(O)OR, –C(O)NR ₂ , –C(O)N(R)OR, –OC(O)R, –OC(O)NR ₂ , –N(R)C(O)OR, –N(R)C(O)R, –N(R)C(O)NR ₂ , –N(R)C(NR)NR ₂ , –N(R)S(O) ₂ NR ₂ , –N(R)S(O) ₂ R, –P(O)R ₂ , –P(O)(R)OR, or –B(OR) _2; each instance of R ^B is independently a C _1-6 aliphatic chain; phenyl; naphthyl; cubanyl; adamantyl; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 5-12 membered saturated or partially unsaturated bicyclic carbocyclic ring; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having each instance of R ^C is independently oxo, deuterium, halogen, –CN, –NO2, –OR, –SF5, –SR, –NR2, –S(O)2R, –S(O)2NR2, –S(O)2F, –S(O)R, –S(O)NR2, –S(O)(NR)R, –C(O)R, –C(O)OR, – C(O)NR ₂ , –C(O)N(R)OR, –OC(O)R, –OC(O)NR ₂ , –N(R)C(O)OR, –N(R)C(O)R, – N(R)C(O)NR ₂ , –N(R)C(NR)NR ₂ , –N(R)S(O) ₂ NR ₂ , –N(R)S(O) ₂ R, –P(O)R ₂ , –P(O)(R)OR, – B(OR) ₂ ,or an optionally substituted group selected from C _1-6 aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and each instance of R is independently hydrogen, or an optionally substituted group selected from C _{1- 6} aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5- 6 membered monocyclic 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 form an optionally substituted 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; Ring A and Ring B are each independently phenyl; naphthyl; tetrahydronaphthalenyl; dihydroindenyl; benzocyclobutenyl; cubanyl; adamantyl; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 5-12 membered saturated or partially unsaturated bicyclic carbocyclic ring; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Ring C is a spiro-fused 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a spiro-fused 5-12 membered saturated or partially unsaturated bicyclic carbocyclic ring; a spiro-fused 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a spiro-fused 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; L is a covalent bond or a bivalent, saturated or unsaturated, straight or branched C _1-50 hydrocarbon chain, wherein 0-6 methylene units of L are independently replaced by –Cy–, –CH(R)–, –C(R) ₂ –, 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 5-11 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 5-11 membered saturated or partially 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 6-10 membered bridged 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, or an 8-10 membered bicyclic heteroarylenyl having 1- 5 heteroatoms independently selected from nitrogen, oxygen, or sulfur;

m is 0, 1, 2, 3, or 4; n is 0, 1, 2, 3, or 4; p is 0, 1, 2, 3, or 4; each of q is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; r is 0, 1, 2, 3, or 4; s is 0, 1, 2, 3, or 4; and t is 0, 1, 2, 3, or 4; provided that when ; and Ring B is phenyl, X ¹ is CH or N and X ² is CH ₂ ; then Ring A is other than phenyl or a 6 membered monocyclic heteroaryl ring having 1-3 nitrogen heteroatoms. 19. The compound of any one of embodiments 1-18, wherein ERBM is pharmaceutically acceptable salt thereof. 20. The compound of any one of embodiments 1-18, wherein ERBM is . or a pharmaceutically acceptable salt thereof. 21. The compound of any one of embodiments 1-18, wherein ERBM is pharmaceutically acceptable salt thereof. 22. The compound of any one of embodiments 1-18, wherein ERBM is pharmaceutically acceptable salt thereof. 23. The compound of any one of embodiments 1-18, wherein the compound is a compound of formula II-a, II-b, or II-c: or a pharmaceutically acceptable salt thereof. 24. The compound of any one of embodiments 1-18, wherein the compound is a compound of formula II-a-1, II-b-1, or II-c-1: or a pharmaceutically acceptable salt thereof. 25. The compound of embodiment 24, wherein the compound is a compound of formula II- a-1, or a pharmaceutically acceptable salt thereof. 26. The compound of embodiment 24, wherein the compound is a compound of formula II- b-1, or a pharmaceutically acceptable salt thereof. 27. The compound of embodiment 24, wherein the compound is a compound of formula II- c-1, or a pharmaceutically acceptable salt thereof. 28. The compound of any one of embodiments 1-18, wherein the compound is a compound of formula

or a pharmaceutically acceptable salt thereof. 29. The compound of embodiment 28, wherein the compound is a compound of formula VIII-a, or a pharmaceutically acceptable salt thereof. 30. The compound of embodiment 28, wherein the compound is a compound of formula VIII-b, or a pharmaceutically acceptable salt thereof. 31. The compound of embodiment 28, wherein the compound is a compound of formula VIII-c, or a pharmaceutically acceptable salt thereof. 32. The compound of embodiment 28, wherein the compound is a compound of formula IX- a, or a pharmaceutically acceptable salt thereof. 33. The compound of embodiment 28, wherein the compound is a compound of formula IX- b, or a pharmaceutically acceptable salt thereof. 34. The compound of embodiment 28, wherein the compound is a compound of formula IX- c, or a pharmaceutically acceptable salt thereof. 35. The compound of any one of embodiments 1-18, wherein the compound is a compound of formula VIII-a-1, VIII-b-1, or VIII-c-1: or a pharmaceutically acceptable salt thereof. 36. The compound of embodiment 35, wherein the compound is a compound of formula VIII-a-1, or a pharmaceutically acceptable salt thereof. 37. The compound of embodiment 35, wherein the compound is a compound of formula VIII-b-1, or a pharmaceutically acceptable salt thereof. 38. The compound of embodiment 35, wherein the compound is a compound of formula VIII-c-1, or a pharmaceutically acceptable salt thereof. 39. The compound of any one of embodiments 1-18, wherein the compound is a compound of formula IX-a-1, IX-b-1 or IX-c-1

or a pharmaceutically acceptable salt thereof. 40. The compound of embodiment 39, wherein the compound is a compound of formula IX- a-1, or a pharmaceutically acceptable salt thereof. 41. The compound of embodiment 39, wherein the compound is a compound of formula IX- b-1, or a pharmaceutically acceptable salt thereof. 42. The compound of embodiment 39, wherein the compound is a compound of formula IX- c-1, or a pharmaceutically acceptable salt thereof. 43. The compound of any one of embodiments 1-42, wherein X ¹ is N or CH. 44. The compound of any one of embodiments 1-42, wherein X ¹ is N. 45. The compound of any one of embodiments 1-42, wherein X ¹ is CH. 46. The compound of any one of embodiments 1-42, wherein X ¹ is NH or CH2. 47. The compound of any one of embodiments 1-42, wherein X ¹ is CH(R ^A1 ). 48. The compound of any one of embodiments 1-42, wherein X ¹ is C(R ^A1 ). 49 The compound of any one of embodiments 1-42 wherein X ¹ is C(R ^A1 )2 50. The compound of any one of embodiments 1-49, wherein X ² is O or CH2, provided that X ¹ and X ² are not both simultaneously heteroatoms. 51. The compound of any one of embodiments 1-49, wherein X ² is O. 52. The compound of any one of embodiments 1-49, wherein X ² is CH ₂ . 53. The compound of any one of embodiments 1-52, wherein X ³ is O, CH ₂ , CH(R ^A5 ) or C(R ^A5 ). 54. The compound of any one of embodiments 1-52, wherein X ³ is O. 55. The compound of any one of embodiments 1-52, wherein X ³ is CH ₂ . 56. The compound of any one of embodiments 1-52, wherein X ³ is CH(R ^A5 ). 57. The compound of any one of embodiments 1-52, wherein X ³ is C(R ^A5 ). 58. The compound of any one of embodiments 1-18, wherein the compound is a compound of formula

or a pharmaceutically acceptable salt thereof, provided that when the compound is of formula II- d, II-e, II-f, II-j, II-k and II-l and Ring B is phenyl, then Ring A is other than phenyl or a 6 membered monocyclic heteroaryl ring having 1-3 nitrogen heteroatoms. 59. The compound of embodiment 58, wherein the compound is a compound of formula II- d, or a pharmaceutically acceptable salt thereof, provided that when Ring B is phenyl, then Ring A is other than phenyl or a 6 membered monocyclic heteroaryl ring having 1-3 nitrogen heteroatoms. 60. The compound of embodiment 58, wherein the compound is a compound of formula II-e, or a pharmaceutically acceptable salt thereof, provided that when Ring B is phenyl, then Ring A is other than phenyl or a 6 membered monocyclic heteroaryl ring having 1-3 nitrogen heteroatoms. 61. The compound of embodiment 58, wherein the compound is a compound of formula II-f, or a pharmaceutically acceptable salt thereof, provided that when Ring B is phenyl, then Ring A is other than phenyl or a 6 membered monocyclic heteroaryl ring having 1-3 nitrogen heteroatoms. 62. The compound of embodiment 58, wherein the compound is a compound of formula II-g, h i ll bl l h f 63. The compound of embodiment 58, wherein the compound is a compound of formula II- h, or a pharmaceutically acceptable salt thereof. 64. The compound of embodiment 58, wherein the compound is a compound of formula II-i, or a pharmaceutically acceptable salt thereof. 65. The compound of embodiment 58, wherein the compound is a compound of formula II-j, or a pharmaceutically acceptable salt thereof, provided that when Ring B is phenyl, then Ring A is other than phenyl or a 6 membered monocyclic heteroaryl ring having 1-3 nitrogen heteroatoms. 66. The compound of embodiment 58, wherein the compound is a compound of formula II- k, or a pharmaceutically acceptable salt thereof, provided that when Ring B is phenyl, then Ring A is other than phenyl or a 6 membered monocyclic heteroaryl ring having 1-3 nitrogen heteroatoms. 67. The compound of embodiment 58, wherein the compound is a compound of formula II-l, or a pharmaceutically acceptable salt thereof, provided that when Ring B is phenyl, then Ring A is other than phenyl or a 6 membered monocyclic heteroaryl ring having 1-3 nitrogen heteroatoms. 68. The compound of any one of embodiments 1-18, wherein the compound is a compound of formula I II-j-A, II-k-A, or II-l-A:

or a pharmaceutically acceptable salt thereof, provided that when the compound is of formula II- d-A, II-e-A, II-f-A, II-j-A, II-k-A and II-l-A and Ring B is phenyl, then Ring A is other than phenyl or a 6 membered monocyclic heteroaryl ring having 1-3 nitrogen heteroatoms. 69. The compound of embodiment 68, wherein the compound is a compound of formula II- d-A, or a pharmaceutically acceptable salt thereof, provided that when Ring B is phenyl, then Ring A is other than phenyl or a 6 membered monocyclic heteroaryl ring having 1-3 nitrogen heteroatoms. 70. The compound of embodiment 68, wherein the compound is a compound of formula II- e-A, or a pharmaceutically acceptable salt thereof, provided that when Ring B is phenyl, then Ring A is other than phenyl or a 6 membered monocyclic heteroaryl ring having 1-3 nitrogen heteroatoms. 71. The compound of embodiment 68, wherein the compound is a compound of formula II-f- A, or a pharmaceutically acceptable salt thereof, provided that when Ring B is phenyl, then Ring A is other than phenyl or a 6 membered monocyclic heteroaryl ring having 1-3 nitrogen heteroatoms. 72. The compound of embodiment 68, wherein the compound is a compound of formula II- d-B, or a pharmaceutically acceptable salt thereof. 73. The compound of embodiment 68, wherein the compound is a compound of formula II- e-B, or a pharmaceutically acceptable salt thereof. 74. The compound of embodiment 68, wherein the compound is a compound of formula II-f- B, or a pharmaceutically acceptable salt thereof. 75. The compound of embodiment 68, wherein the compound is a compound of formula II- d-C, or a pharmaceutically acceptable salt thereof. 76. The compound of embodiment 68, wherein the compound is a compound of formula II- e-C, or a pharmaceutically acceptable salt thereof. 77. The compound of embodiment 68, wherein the compound is a compound of formula II-f- C, or a pharmaceutically acceptable salt thereof. 78. The compound of embodiment 68, wherein the compound is a compound of formula II-j- A, or a pharmaceutically acceptable salt thereof, provided that when Ring B is phenyl, then Ring A is other than phenyl or a 6 membered monocyclic heteroaryl ring having 1-3 nitrogen heteroatoms. 79. The compound of embodiment 68, wherein the compound is a compound of formula II- k-A, or a pharmaceutically acceptable salt thereof, provided that when Ring B is phenyl, then Ring A is other than phenyl or a 6 membered monocyclic heteroaryl ring having 1-3 nitrogen heteroatoms. 80. The compound of embodiment 68, wherein the compound is a compound of formula II-l- A, or a pharmaceutically acceptable salt thereof, provided that when Ring B is phenyl, then Ring A is other than phenyl or a 6 membered monocyclic heteroaryl ring having 1-3 nitrogen heteroatoms. 81. The compound of any one of embodiments 1-18, wherein the compound is a compound of one of formulas II-n, II-o, II-p, II-q, II-r, II-s, II-t, II-u or II-v:

or a pharmaceutically acceptable salt thereof. 82. The compound of embodiment 81, wherein the compound is a compound of formula II- n, or a pharmaceutically acceptable salt thereof. 83. The compound of embodiment 81, wherein the compound is a compound of formula II-o, or a pharmaceutically acceptable salt thereof. 84. The compound of embodiment 81, wherein the compound is a compound of formula II- p, or a pharmaceutically acceptable salt thereof. 85. The compound of embodiment 81, wherein the compound is a compound of formula II- q, or a pharmaceutically acceptable salt thereof. 86. The compound of embodiment 81, wherein the compound is a compound of formula II-r, or a pharmaceutically acceptable salt thereof. 87. The compound of embodiment 81, wherein the compound is a compound of formula II-s, or a pharmaceutically acceptable salt thereof. 88. The compound of embodiment 81, wherein the compound is a compound of formula II-t, 89. The compound of embodiment 81, wherein the compound is a compound of formula II- u, or a pharmaceutically acceptable salt thereof. 90. The compound of embodiment 81, wherein the compound is a compound of formula II-v, or a pharmaceutically acceptable salt thereof. 91. The compound of any one of embodiments 1-18, wherein the compound is a compound of one of formulas II-w, II-x, II-y, II-z, II-aa, II-bb, II-cc, II-dd or II-ee: or a pharmaceutically acceptable salt thereof. 92. The compound of embodiment 91, wherein the compound is a compound of formula II- w, or a pharmaceutically acceptable salt thereof. 93. The compound of embodiment 91, wherein the compound is a compound of formula II-x, or a pharmaceutically acceptable salt thereof. 94. The compound of embodiment 91, wherein the compound is a compound of formula II-y, or a pharmaceutically acceptable salt thereof. 95. The compound of embodiment 91, wherein the compound is a compound of formula II-z, or a pharmaceutically acceptable salt thereof. 96. The compound of embodiment 91, wherein the compound is a compound of formula II- aa, or a pharmaceutically acceptable salt thereof. 97. The compound of embodiment 91, wherein the compound is a compound of formula II- bb, or a pharmaceutically acceptable salt thereof. 98. The compound of embodiment 91, wherein the compound is a compound of formula II- cc, or a pharmaceutically acceptable salt thereof. 99. The compound of embodiment 91, wherein the compound is a compound of formula II- dd, or a pharmaceutically acceptable salt thereof. 100. The compound of embodiment 91, wherein the compound is a compound of formula II-ee, or a pharmaceutically acceptable salt thereof. 101. The compound of any one of embodiments 1-18, wherein the compound is a compound of one of formulas II-d-1, II-e-1, II-f-1, II-g-1, II-h-1, II-i-1, II-j-1, II-k-1, or II-l-1:

or a pharmaceutically acceptable salt thereof, provided that when the compound is of formula II-d-1, II-e-1, II-f-1, II-j-1, II-k-1 and II-l-1 and Ring B is phenyl, then Ring A is other than phenyl or a 6 membered monocyclic heteroaryl ring having 1-3 nitrogen heteroatoms. 102. The compound of embodiment 101, wherein the compound is a compound of formula II-d-1, or a pharmaceutically acceptable salt thereof, provided that when Ring B is phenyl, then Ring A is other than phenyl or a 6 membered monocyclic heteroaryl ring having 1-3 nitrogen heteroatoms. 103. The compound of embodiment 101, wherein the compound is a compound of formula II-e-1, or a pharmaceutically acceptable salt thereof, provided that when Ring B is phenyl, then Ring A is other than phenyl or a 6 membered monocyclic heteroaryl ring having 1-3 nitrogen heteroatoms. 104. The compound of embodiment 101, wherein the compound is a compound of formula II-f-1, or a pharmaceutically acceptable salt thereof, provided that when Ring B is phenyl, then Ring A is other than phenyl or a 6 membered monocyclic heteroaryl ring having 1-3 nitrogen heteroatoms. 105. The compound of embodiment 101, wherein the compound is a compound of formula II-g-1, or a pharmaceutically acceptable salt thereof. 106. The compound of embodiment 101, wherein the compound is a compound of formula II-h-1, or a pharmaceutically acceptable salt thereof. 107. The compound of embodiment 101, wherein the compound is a compound of formula I or a pharmaceutically acceptable salt thereof. 108. The compound of embodiment 101, wherein the compound is a compound of formula II-j-1, or a pharmaceutically acceptable salt thereof, provided that when Ring B is phenyl, then Ring A is other than phenyl or a 6 membered monocyclic heteroaryl ring having 1-3 nitrogen heteroatoms. 109. The compound of embodiment 101, wherein the compound is a compound of formula II-k-1, or a pharmaceutically acceptable salt thereof, provided that when Ring B is phenyl, then Ring A is other than phenyl or a 6 membered monocyclic heteroaryl ring having 1-3 nitrogen heteroatoms. 110. The compound of embodiment 101, wherein the compound is a compound of formula II-l-1, or a pharmaceutically acceptable salt thereof, provided that when Ring B is phenyl, then Ring A is other than phenyl or a 6 membered monocyclic heteroaryl ring having 1-3 nitrogen heteroatoms. 111. The compound of any one of embodiments 1-18, wherein the compound is a compound of formula II-d-1-A, II-e-1-A, II-f-1-A, II-d-1-B, II-e-1-B, II-f-1-B, II-d-1-C, II-e-

or a pharmaceutically acceptable salt thereof, provided that when the compound is of formula II-d-1-A, II-e-1-A, II-f-1-A, II-j-1-A, II-k-1-A and II-l-1-A and Ring B is phenyl, then Ring A is other than phenyl or a 6 membered monocyclic heteroaryl ring having 1-3 nitrogen heteroatoms. 112. The compound of embodiment 111, wherein the compound is a compound of formula II-d-1-A, or a pharmaceutically acceptable salt thereof, provided that when Ring B is phenyl, then Ring A is other than phenyl or a 6 membered monocyclic heteroaryl ring having 1-3 nitrogen heteroatoms. 113. The compound of embodiment 111, wherein the compound is a compound of formula II-e-1-A, or a pharmaceutically acceptable salt thereof, provided that when Ring B is phenyl, then Ring A is other than phenyl or a 6 membered monocyclic heteroaryl ring having 1-3 nitrogen heteroatoms. 114. The compound of embodiment 111, wherein the compound is a compound of formula II f 1 A or a pharmaceutically acceptable salt thereof provided that when Ring B is phenyl, then Ring A is other than phenyl or a 6 membered monocyclic heteroaryl ring having 1-3 nitrogen heteroatoms. 115. The compound of embodiment 111, wherein the compound is a compound of formula II-d-1-B, or a pharmaceutically acceptable salt thereof. 116. The compound of embodiment 111, wherein the compound is a compound of formula II-e-1-B, or a pharmaceutically acceptable salt thereof. 117. The compound of embodiment 111, wherein the compound is a compound of formula II-f-1-B, or a pharmaceutically acceptable salt thereof. 118. The compound of embodiment 111, wherein the compound is a compound of formula II-d-1-C, or a pharmaceutically acceptable salt thereof. 119. The compound of embodiment 111, wherein the compound is a compound of formula II-e-1-C, or a pharmaceutically acceptable salt thereof. 120. The compound of embodiment 111, wherein the compound is a compound of formula II-f-1-C, or a pharmaceutically acceptable salt thereof. 121. The compound of embodiment 111, wherein the compound is a compound of formula II-j-1-A, or a pharmaceutically acceptable salt thereof, provided that when Ring B is phenyl, then Ring A is other than phenyl or a 6 membered monocyclic heteroaryl ring having 1-3 nitrogen heteroatoms. 122. The compound of embodiment 111, wherein the compound is a compound of formula II-k-1-A, or a pharmaceutically acceptable salt thereof, provided that when Ring B is phenyl, then Ring A is other than phenyl or a 6 membered monocyclic heteroaryl ring having 1-3 nitrogen heteroatoms. 123. The compound of embodiment 111, wherein the compound is a compound of formula II-l-1-A, or a pharmaceutically acceptable salt thereof, provided that when Ring B is phenyl, then Ring A is other than phenyl or a 6 membered monocyclic heteroaryl ring having 1-3 nitrogen heteroatoms. 124. The compound of any one of embodiments 1-18, wherein the compound is a compound of formula II-m-1: or a pharmaceutically acceptable salt thereof. 125. The compound of any one of embodiments 1-18, wherein the compound is a compound of one of formulas or a pharmaceutically acceptable salt thereof. 126. The compound of embodiment 125, wherein the compound is a compound of formula II-n-1, or a pharmaceutically acceptable salt thereof. 127. The compound of embodiment 125, wherein the compound is a compound of formula II-o-1, or a pharmaceutically acceptable salt thereof. 128. The compound of embodiment 125, wherein the compound is a compound of formula II-p-1, or a pharmaceutically acceptable salt thereof. 129. The compound of embodiment 125, wherein the compound is a compound of formula II-q-1, or a pharmaceutically acceptable salt thereof. 130. The compound of embodiment 125, wherein the compound is a compound of formula II-r-1, or a pharmaceutically acceptable salt thereof. 131. The compound of embodiment 125, wherein the compound is a compound of formula II-s-1, or a pharmaceutically acceptable salt thereof. 132. The compound of embodiment 125, wherein the compound is a compound of formula II-t-1, or a pharmaceutically acceptable salt thereof. 133. The compound of embodiment 125, wherein the compound is a compound of formula II-u-1, or a pharmaceutically acceptable salt thereof. 134. The compound of embodiment 125, wherein the compound is a compound of formula II-v-1, or a pharmaceutically acceptable salt thereof. 135. The compound of any one of embodiments 1-18, wherein the compound is a compound of one of formulas II-w-1, II-x-1, II-y-1, II-z-1, II-aa-1, II-bb-1, II-cc-1, II-dd-1 or II-ee-1:

or a pharmaceutically acceptable salt thereof. 136. The compound of embodiment 135, wherein the compound is a compound of formula II-w-1, or a pharmaceutically acceptable salt thereof. 137. The compound of embodiment 135, wherein the compound is a compound of formula II-x-1, or a pharmaceutically acceptable salt thereof. 138. The compound of embodiment 135, wherein the compound is a compound of formula II-y-1, or a pharmaceutically acceptable salt thereof. 139. The compound of embodiment 135, wherein the compound is a compound of formula II-z-1, or a pharmaceutically acceptable salt thereof. 140. The compound of embodiment 135, wherein the compound is a compound of formula II-aa-1, or a pharmaceutically acceptable salt thereof. 141. The compound of embodiment 135, wherein the compound is a compound of formula II-bb-1, or a pharmaceutically acceptable salt thereof. 142. The compound of embodiment 135, wherein the compound is a compound of formula II-cc-1, or a pharmaceutically acceptable salt thereof. 143. The compound of embodiment 135, wherein the compound is a compound of f l II dd 1 h ti ll t bl lt th f 144. The compound of embodiment 135, wherein the compound is a compound of formula II-ee-1 , or a pharmaceutically acceptable salt thereof. 145. The compound of any one of embodiments 1-18, wherein the compound is a compound of one of formulas II-ff-1, II-gg-1, II-hh-1, II-ii-1, II-jj-1, II-kk-1, II-mm-1 or II-nn-1: or a pharmaceutically acceptable salt thereof. 146. The compound of embodiment 145, wherein the compound is a compound of formula II-ff-1, or a pharmaceutically acceptable salt thereof. 147. The compound of embodiment 145, wherein the compound is a compound of formula II-gg-1, or a pharmaceutically acceptable salt thereof. 148. The compound of embodiment 145, wherein the compound is a compound of formula II-hh-1, or a pharmaceutically acceptable salt thereof. 149. The compound of embodiment 145, wherein the compound is a compound of formula II ii 1 or a pharmaceutically acceptable salt thereof 150. The compound of embodiment 145, wherein the compound is a compound of formula I , or a pharmaceutically acceptable salt thereof. 151. The compound of embodiment 145, wherein the compound is a compound of formula II-kk-1, or a pharmaceutically acceptable salt thereof. 152. The compound of embodiment 145, wherein the compound is a compound of formula II-ll-1, or a pharmaceutically acceptable salt thereof. 153. The compound of embodiment 145, wherein the compound is a compound of formula II-mm-1, or a pharmaceutically acceptable salt thereof. 154. The compound of embodiment 145, wherein the compound is a compound of formula II-nn-1 , or a pharmaceutically acceptable salt thereof. 155. The compound of any one of embodiments 1-154, wherein Ring A together with , wherein the top attachment point connects to L and the bottom attachment point connects to the six-member ring of the ERBM moiety. 156. The compound of any one of embodiments 1-154, wherein Ring A together with , wherein the top attachment point connects to L and the bottom attachment point connects to the six-member ring of the ERBM moiety. 157. The compound of any one of embodiments 1-154, wherein Ring A together with its R ¹ substituents , wherein the top attachment point connects to L and the bottom attachment point connects to the six-member ring of the ERBM moiety. 158. The compound of any one of embodiments 1-154, wherein Ring A together with its R ¹ substituents , wherein the top attachment point connects to L and the bottom attachment point connects to the six-member ring of the ERBM moiety. 159. The compound of any one of embodiments 1-154, wherein Ring A together with its R ¹ substituents , wherein the top attachment point connects to L and the bottom attachment point connects to the six-member ring of the ERBM moiety.

160. The compound of any one of embodiments 1-154, wherein Ring A together with its R ¹ substituents , wherein the top attachment point connects to L and the bottom attachment point connects to the six-member ring of the ERBM moiety. 161. The compound of any one of embodiments 1-154, wherein Ring A together with , wherein the top attachment point connects to L and the bottom attachment point connects to the six-member ring of the ERBM moiety. 162. The compound of any one of embodiments 1-154, wherein Ring A together with its R1 substituents i , wherein the top attachment point connects to L and the bottom attachment point connects to the six-member ring of the ERBM moiety. 163. The compound of any one of embodiments 1-154, wherein Ring A together with its R1 substituents , wherein the top attachment point connects to L and the bottom attachment point connects to the six-member ring of the ERBM moiety. The compound of any one of embodiments 1-154, wherein Ring A together with its R1 substituents , wherein the top attachment point connects to L and the bottom attachment point connects to the six-member ring of the ERBM moiety. 165. The compound of any one of embodiments 1-154, wherein Ring A together with its R1 substituents i , wherein the top attachment point connects to L and the bottom attachment point connects to the six-member ring of the ERBM moiety. 166. The compound of any one of embodiments 1-154, wherein Ring A together with its R1 substituents , wherein the top attachment point connects to L and the bottom attachment point connects to the six-member ring of the ERBM moiety. 167. The compound of any one of embodiments 1-154, wherein Ring A together with its R1 substituents , wherein the top attachment point connects to L and the bottom attachment point connects to the six-member ring of the ERBM moiety. 168. The compound of any one of embodiments 1-154, wherein Ring A together with its R1 substituents i wherein the top attachment point connects to L and the bottom attachment point connects to the six-member ring of the ERBM moiety. 169. The compound of any one of embodiments 1-154, wherein Ring A together with its R1 substituents is , wherein the top attachment point connects to L and the bottom attachment point connects to the six-member ring of the ERBM moiety. 170. The compound of any one of embodiments 1-154, wherein Ring A together with its R1 substituents , wherein the top attachment point connects to L and the bottom attachment point connects to the six-member ring of the ERBM moiety. 171. The compound of any one of embodiments 1-154, wherein Ring A together with its R1 substituents , wherein the top attachment point connects to L and the bottom attachment point connects to the six-member ring of the ERBM moiety. 172. The compound of any one of embodiments 1-171, wherein Ring B together with 173. The compound of any one of embodiments 1-171, wherein Ring B together with

. 174. The compound of any one of embodiments 1-171, wherein Ring B together with

175. The compound of any one of embodiments 1-171, wherein Ring B together with its R ² substituents is selected from: , , , ,

. 176. The compound of any one of embodiments 1-171, wherein Ring B together with The compound of any one of embodiments 1-171, wherein Ring B together with its R ² substituents . 178. The compound of any one of embodiments 1-171, wherein Ring B together with its R ² substituents i The compound of any one of embodiments 1-171, wherein Ring B together with its R ² substituents i 180. The compound of any one of embodiments 1-171, wherein Ring B together with its R ² substituents i 181. The compound of any one of embodiments 1-171, wherein Ring B together with its R ² substituents i 182. The compound of any one of embodiments 1-171, wherein Ring B together with its R ² substituents . 183. The compound of any one of embodiments 1-171, wherein Ring B together with its R ² substituents . 184. The compound of any one of embodiments 1-171, wherein Ring B together with its substituents 185. The compound of any one of embodiments 1-171, wherein Ring B together with its R ² substituents i . 186. The compound of any one of embodiments 1-171, wherein Ring B together with its R ² substituents . 187. The compound of any one of embodiments 1-171, wherein Ring B together with its R ² substituents 188. The compound of any one of embodiments 1-171, wherein Ring B together with its R ² substituents i 189. The compound of any one of embodiments 1-171, wherein Ring B together with its R ² substituents 190. The compound of any one of embodiments 1-171, wherein Ring B together with its R ² substituents 191. The compound of any one of embodiments 1-171, wherein Ring B together with its R ² substituents i . 192. The compound of any one of embodiments 1-171, wherein Ring B together with its R ² substituents i . The compound of any one of embodiments 1-171, wherein Ring B together with its R ² substituents i . 194. The compound of any one of embodiments 1-171, wherein Ring B together with its R ² substituents . 195. The compound of any one of embodiments 1-171, wherein Ring B together with its substituents i . 196. The compound of any one of embodiments 1-171, wherein Ring B together with its R ² substituents . 197. The compound of any one of embodiments 1-171, wherein Ring B together with its R ² substituents i . 198. The compound of any one of embodiments 1-171, wherein Ring B together with its R ² substituents . 199. The compound of any one of embodiments 1-171, wherein Ring B together with its R ² substituents i . 200. The compound of any one of embodiments 1-171, wherein Ring B together with its R ² substituents 201. The compound of any one of embodiments 1-171, wherein Ring B together with its R ² substituents . 202. The compound of any one of embodiments 1-171, wherein Ring B together with its R ² substituents i 203. The compound of any one of embodiments 1-171, wherein Ring B together with its R ² substituents . 204. The compound of any one of embodiments 1-171, wherein Ring B together with its R ² substituents i 205. The compound of any one of embodiments 1-171, wherein Ring B together with its R ² substituents i . 206. The compound of any one of embodiments 1-171, wherein Ring B together with its R ² substituents i 207. The compound of any one of embodiments 1-171, wherein Ring B together with its R ² substituents . 208. The compound of any one of embodiments 1-171, wherein Ring B together with its R ² substituents . 209. The compound of any one of embodiments 1-171, wherein Ring B together with its R ² substituents i 210. The compound of any one of embodiments 1-171, wherein Ring B together with its R ² substituents . 211. The compound of any one of embodiments 1-171, wherein Ring B together with its R ² substituents . The compound of any one of embodiments 1-171, wherein Ring B together with 213. The compound of any one of embodiments 1-171, wherein Ring B together with its R ² substituents 214. The compound of any one of embodiments 1-171, wherein Ring B together with its R ² substituents . 215. The compound of any one of embodiments 1-171, wherein Ring B together with its R ² substituents i . 216. The compound of any one of embodiments 1-171, wherein Ring B together with its R ² substituents i . 217. The compound of any one of embodiments 1-171, wherein Ring B together with . 218. The compound of any one of embodiments 1-171, wherein Ring B together with its R ² substituents i . 219. The compound of any one of embodiments 1-171, wherein Ring B together with its R ² substituents 220. The compound of any one of embodiments 1-171, wherein Ring B together with its R ² substituents . 221. The compound of any one of embodiments 1-171, wherein Ring B together with . 222. The compound of any one of embodiments 1-171, wherein Ring B together with its R ² substituents . The compound of any one of embodiments 1-171, wherein Ring B together with its R ² substituents i 224. The compound of any one of embodiments 1-171, wherein Ring B together with its R ² substituents i 225. The compound of any one of embodiments 1-171, wherein Ring B together with its R ² substituents 226. The compound of any one of embodiments 1-171, wherein Ring B together with its R ² substituents i . The compound of any one of embodiments 1-171, wherein Ring B together with its R ² substituents i 228. The compound of any one of embodiments 1-171, wherein Ring B together with its R ² substituents . 229. The compound of any one of embodiments 1-171, wherein Ring B together with its R ² substituents 230. The compound of any one of embodiments 1-171, wherein Ring B together with its R ² substituents i . 231. The compound of any one of embodiments 1-171, wherein Ring B together with its R ² substituents . 232. The compound of any one of embodiments 1-171, wherein Ring B together with its R ² substituents 233. The compound of any one of embodiments 1-171, wherein Ring B together with its R ² substituents i 234. The compound of any one of embodiments 1-171, wherein Ring B together with its R ² substituents . 235. The compound of any one of embodiments 1-171, wherein Ring B together with its R ² substituents i . 236. The compound of any one of embodiments 1-171, wherein Ring B together with its R ² substituents 237. The compound of any one of embodiments 1-171, wherein Ring B together with its R ² substituents . 238. The compound of any one of embodiments 1-171, wherein Ring B together with its R ² substituents 239. The compound of any one of embodiments 1-171, wherein Ring B together with its R ² substituents . 240. The compound of any one of embodiments 1-171, wherein Ring B together with its R ² substituents 241. The compound of any one of embodiments 1-171, wherein Ring B together with its R ² substituents . 242. The compound of any one of embodiments 1-171, wherein Ring B together with its R ² substituents i 243. The compound of any one of embodiments 1-171, wherein Ring B together with 244. The compound of any one of embodiments 1-171, wherein Ring B together with its R ² substituents i . 245. The compound of any one of embodiments 1-171, wherein Ring B together with its R ² substituents i . 246. The compound of any one of embodiments 1-171, wherein Ring B together with its R ² substituents . 247. The compound of any one of embodiments 1-171, wherein Ring B together with its R ² substituents . 248. The compound of any one of embodiments 1-171, wherein Ring B together with its R ² substituents 249. The compound of any one of embodiments 1-171, wherein Ring B together with its R ² substituents i . 250. The compound of any one of embodiments 1-171, wherein Ring B together with 251. The compound of any one of embodiments 1-171, wherein Ring B together with its R ² substituents i . The compound of any one of embodiments 1-171, wherein Ring B together with its R ² substituents i . . The compound of any one of embodiments 1-171, wherein Ring B together with its R ² substituents i . 254. The compound of any one of embodiments 1-171, wherein Ring B together with its R ² substituents i . 255. The compound of any one of embodiments 1-171, wherein Ring B together with 256. The compound of any one of embodiments 1-171, wherein Ring B together with its R ² substituents 257. The compound of any one of embodiments 1-171, wherein Ring B together with 258. The compound of any one of embodiments 1-171, wherein Ring B together with its R ² substituents i . 259. The compound of any one of embodiments 1-171, wherein Ring B together with its R ² substituents i 260. The compound of any one of embodiments 1-171, wherein Ring B together with its R ² substituents i . 261. The compound of any one of embodiments 1-171, wherein Ring B together with its R ² substituents 262. The compound of any one of embodiments 1-171, wherein Ring B together with its R ² substituents i . 263. The compound of any one of embodiments 1-171, wherein Ring B together with its R ² substituents i . 264. The compound of any one of embodiments 1-171, wherein Ring B together with its R ² substituents i . 265. The compound of any one of embodiments 1-171, wherein Ring B together with its R ² substituents i . 266. The compound of any one of embodiments 1-171, wherein Ring B together with its R ² substituents i . 267. The compound of any one of embodiments 1-171, wherein Ring B together with its R ² substituents i . 268. The compound of any one of embodiments 1-171, wherein Ring B together with its R ² substituents . 269. The compound of any one of embodiments 1-171, wherein Ring B together with its R ² substituents i . 270. The compound of any one of embodiments 1-171, wherein Ring B together with its R ² substituents i 271. The compound of any one of embodiments 1-171, wherein Ring B together with its R ² substituents 272. The compound of any one of embodiments 1-171, wherein Ring B together with its R ² substituents . 273. The compound of any one of embodiments 1-171, wherein Ring B together with its R ² substituents . 274. The compound of any one of embodiments 1-171, wherein Ring B together with its R ² substituents . 275. The compound of any one of embodiments 1-171, wherein Ring B together with its R ² substituents i 276. The compound of any one of embodiments 1-171, wherein Ring B together with its R ² substituents . 277. The compound of any one of embodiments 1-171, wherein Ring B together with its R ² substituents i . 278. The compound of any one of embodiments 1-171, wherein Ring B together with its R ² substituents i . 279. The compound of any one of embodiments 1-171, wherein Ring B together with its R ² substituents i 280. The compound of any one of embodiments 1-171, wherein Ring B together with its R ² substituents i 281. The compound of any one of embodiments 1-171, wherein Ring B together with its R ² substituents i 282. The compound of any one of embodiments 1-171, wherein Ring B together with its R ² substituents 283. The compound of any one of embodiments 1-171, wherein Ring B together with its R ² substituents i . 284. The compound of any one of embodiments 1-171, wherein Ring B together with its R ² substituents . 285. The compound of any one of embodiments 1-171, wherein Ring B together with its R ² substituents i 286. The compound of any one of embodiments 1-171, wherein Ring B together with its R ² substituents 287. The compound of any one of embodiments 1-171, wherein Ring B together with its R ² substituents i 288. The compound of any one of embodiments 1-287, wherein the compound is a compound of one of formulas III-a, III-b, or III-c: III-c or a pharmaceutically acceptable salt thereof, provided that when X ¹ is CH or N and X ² is CH ₂ , then Ring B is other than phenyl. 289. The compound of embodiment 288, wherein the compound is a compound of formula III-a, or a pharmaceutically acceptable salt thereof, provided that when X ¹ is CH or N and X ² is CH ₂ , then Ring B is other than phenyl. 290. The compound of embodiment 288, wherein the compound is a compound of formula III-b, or a pharmaceutically acceptable salt thereof, provided that when X ¹ is CH or N and X ² is CH ₂ , then Ring B is other than phenyl. 291. The compound of embodiment 288, wherein the compound is a compound of formula III-c, or a pharmaceutically acceptable salt thereof, provided that when X ¹ is CH or N and X ² is CH ₂ , then Ring B is other than phenyl. 292. The compound of any one of embodiments 1-287, wherein the compound is a compound of one of formulas III-a-A, III-b-A, III-c-A, III-a-B, III-b-B, III-c-B, III-a-C, III- b-C and III-c-C: or a pharmaceutically acceptable salt thereof, provided that for formulae III-a-A, III-b-A and III-c-A when X ¹ is CH or N and X ² is CH2, then Ring B is other than phenyl. 293. The compound of embodiment 292, wherein the compound is a compound of formula III-a-A, or a pharmaceutically acceptable salt thereof, provided that when X ¹ is CH or N and X ² is CH ₂ , then Ring B is other than phenyl. 294. The compound of embodiment 292, wherein the compound is a compound of formula III-b-A, or a pharmaceutically acceptable salt thereof, provided that when X ¹ is CH or N and X ² 295. The compound of embodiment 292, wherein the compound is a compound of formula III-c-A, or a pharmaceutically acceptable salt thereof, provided that when X ¹ is CH or N and X ² is CH ₂ , then Ring B is other than phenyl. 296. The compound of embodiment 292, wherein the compound is a compound of formula III-a-B, or a pharmaceutically acceptable salt thereof. 297. The compound of embodiment 292, wherein the compound is a compound of formula III-b-B, or a pharmaceutically acceptable salt thereof. 298. The compound of embodiment 292, wherein the compound is a compound of formula III-c-B, or a pharmaceutically acceptable salt thereof. 299. The compound of embodiment 292, wherein the compound is a compound of formula III-a-C, or a pharmaceutically acceptable salt thereof. 300. The compound of embodiment 292, wherein the compound is a compound of formula III-b-C, or a pharmaceutically acceptable salt thereof. 301. The compound of embodiment 292, wherein the compound is a compound of formula III-c-C, or a pharmaceutically acceptable salt thereof. 302. The compound of any one of embodiments 1-287, wherein the compound is a compound of one of formulas I : III-d III-e III-f

or a pharmaceutically acceptable salt thereof, provided that when the compound is of formula III- d, III-e, III-f, III-j, III-k or III-l, then Ring B is other than phenyl. 303. The compound of embodiment 302, wherein the compound is a compound of formula I , or a pharmaceutically acceptable salt thereof, provided that Ring B is other than phenyl. 304. The compound of embodiment 302, wherein the compound is a compound of formula III-e, or a pharmaceutically acceptable salt thereof, provided that Ring B is other than phenyl. 305. The compound of embodiment 302, wherein the compound is a compound of formula III-f, or a pharmaceutically acceptable salt thereof, provided that Ring B is other than phenyl. 306. The compound of embodiment 302, wherein the compound is a compound of formula III-g, or a pharmaceutically acceptable salt thereof. 307. The compound of embodiment 302, wherein the compound is a compound of formula III-h, or a pharmaceutically acceptable salt thereof. The compound of embodiment 302, wherein the compound is a compound of formula III-i, or a pharmaceutically acceptable salt thereof. 309. The compound of embodiment 302, wherein the compound is a compound of formula III-j, or a pharmaceutically acceptable salt thereof, provided that Ring B is other than phenyl. 310. The compound of embodiment 302, wherein the compound is a compound of formula III-k, or a pharmaceutically acceptable salt thereof, provided that Ring B is other than phenyl. 311. The compound of embodiment 302, wherein the compound is a compound of formula III-l, or a pharmaceutically acceptable salt thereof, provided that Ring B is other than phenyl. 312. The compound of any one of embodiments 1-287, wherein the compound is a compound of formula III-d-A, III-e-A, III-f-A, III-d-B, III-e-B, III-f-B, III-d-C, III-e-C, III- f-C, III-g, III-h, III-i, III-j-A, III-k-A, or III-l-A: III-d-B III-e-B III-f-B

III-j-A III-k-A III-l-A or a pharmaceutically acceptable salt thereof, provided that when the compound is of formula III- d-A, III-e-A, III-f-A, III-j-A, III-k-A, or III-l-A, then Ring B is other than phenyl. 313. The compound of embodiment 312, wherein the compound is a compound of formula III-d-A, or a pharmaceutically acceptable salt thereof, provided that Ring B is other than phenyl. 314. The compound of embodiment 312, wherein the compound is a compound of formula III-e-A, or a pharmaceutically acceptable salt thereof, provided that Ring B is other than phenyl. 315. The compound of embodiment 312, wherein the compound is a compound of formula III-f-A, or a pharmaceutically acceptable salt thereof, provided that Ring B is other than phenyl. 316. The compound of embodiment 312, wherein the compound is a compound of formula III-d-B, or a pharmaceutically acceptable salt thereof. 317. The compound of embodiment 312, wherein the compound is a compound of formula III-e-B, or a pharmaceutically acceptable salt thereof. 318. The compound of embodiment 312, wherein the compound is a compound of formula III-f-B, or a pharmaceutically acceptable salt thereof. 319. The compound of embodiment 312, wherein the compound is a compound of formula III-d-C, or a pharmaceutically acceptable salt thereof. 320. The compound of embodiment 312, wherein the compound is a compound of formula III-e-C, or a pharmaceutically acceptable salt thereof. 321. The compound of embodiment 312, wherein the compound is a compound of formula I or a pharmaceutically acceptable salt thereof. 322. The compound of embodiment 302, wherein the compound is a compound of formula III-j-A, or a pharmaceutically acceptable salt thereof, provided that Ring B is other than phenyl. 323. The compound of embodiment 302, wherein the compound is a compound of formula III-k-A, or a pharmaceutically acceptable salt thereof, provided that Ring B is other than phenyl. 324. The compound of embodiment 302, wherein the compound is a compound of formula III-l-A, or a pharmaceutically acceptable salt thereof, provided that Ring B is other than phenyl 325. The compound of any one of embodiments 1-287, wherein the compound is a compound of one of formulas III-m, III-n, or III-o:

III-o or a pharmaceutically acceptable salt thereof, provided that when X ¹ is CH or N and X ² is CH ₂ , then Ring A is other than phenyl or a 6 membered monocyclic heteroaryl ring having 1-3 nitrogen heteroatoms. 326. The compound of embodiment 325, wherein the compound is a compound of formula III-m, or a pharmaceutically acceptable salt thereof, provided that when X ¹ is CH or N and X ² is CH ₂ , then Ring A is other than phenyl or a 6 membered monocyclic heteroaryl ring having 1-3 nitrogen heteroatoms. 327. The compound of embodiment 325, wherein the compound is a compound of formula III-n, or a pharmaceutically acceptable salt thereof, provided that when X ¹ is CH or N and X ² is CH ₂ , then Ring A is other than phenyl or a 6 membered monocyclic heteroaryl ring having 1-3 nitrogen heteroatoms. 328. The compound of embodiment 325, wherein the compound is a compound of formula III-o, or a pharmaceutically acceptable salt thereof, provided that when X ¹ is CH or N and X ² is CH ₂ , then Ring A is other than phenyl or a 6 membered monocyclic heteroaryl ring having 1-3 nitrogen heteroatoms. 329. The compound of any one of embodiments 1-287, wherein is a compound of one of formulas III-m-A, III-n-A, or III-o-A, III-m-B, III-n-B, III-o-B, III-m-C, III-n-C, or III-o- or a pharmaceutically acceptable salt thereof, provided that when the compound is of formulae III-m-A, III-n-A or III-o-A and X ¹ is CH or N and X ² is CH ₂ , then Ring A is other than phenyl or a 6 membered monocyclic heteroaryl ring having 1-3 nitrogen heteroatoms. 330. The compound of embodiment 329, wherein the compound is a compound of formula III-m-A, or a pharmaceutically acceptable salt thereof, provided that when X ¹ is CH or N and X ² is CH ₂ , then Ring A is other than phenyl or a 6 membered monocyclic heteroaryl ring having 1-3 nitrogen heteroatoms. 331. The compound of embodiment 329, wherein the compound is a compound of formula III-n-A, or a pharmaceutically acceptable salt thereof, provided that when X ¹ is CH or N and X ² is CH2, then Ring A is other than phenyl or a 6 membered monocyclic heteroaryl ring having 1-3 nitrogen heteroatoms. 332. The compound of embodiment 329, wherein the compound is a compound of formula III-o-A, or a pharmaceutically acceptable salt thereof, provided that when X ¹ is CH or N and X ² is CH ₂ , then Ring A is other than phenyl or a 6 membered monocyclic heteroaryl ring having 1-3 nitrogen heteroatoms. 333. The compound of embodiment 329, wherein the compound is a compound of formula III-m-B. 334. The compound of embodiment 329, wherein the compound is a compound of formula III-n-B. 335. The compound of embodiment 329, wherein the compound is a compound of formula III-o-B. 336. The compound of embodiment 329, wherein the compound is a compound of formula III-m-C. 337. The compound of embodiment 329, wherein the compound is a compound of formula III-n-C. 338. The compound of embodiment 329, wherein the compound is a compound of formula III-o-C. 339. The compound of any one of embodiments 1-287, wherein the compound is a compound of one of formulas III-p, III-q, III-r, III-s, III-t, III-u, III-v, III-w, or III-x: III-p III-q III-r

III-v III-w III-x or a pharmaceutically acceptable salt thereof, provided that when the compound is of formulas III- p, III-q, III-r, III-v, III-w or III-x,then Ring A is other than phenyl or a 6 membered monocyclic heteroaryl ring having 1-3 nitrogen heteroatoms. 340. The compound of embodiment 339, wherein the compound is a compound of formula III-p, or a pharmaceutically acceptable salt thereof, provided that Ring A is other than phenyl or a 6 membered monocyclic heteroaryl ring having 1-3 nitrogen heteroatoms. 341. The compound of embodiment 339, wherein the compound is a compound of formula III-q, or a pharmaceutically acceptable salt thereof, provided that Ring A is other than phenyl or a 6 membered monocyclic heteroaryl ring having 1-3 nitrogen heteroatoms. 342. The compound of embodiment 339, wherein the compound is a compound of formula III-r, or a pharmaceutically acceptable salt thereof, provided that Ring A is other than phenyl or a 6 membered monocyclic heteroaryl ring having 1-3 nitrogen heteroatoms. 343. The compound of embodiment 339, wherein the compound is a compound of formula III-s, or a pharmaceutically acceptable salt thereof. 344. The compound of embodiment 339, wherein the compound is a compound of formula III-t, or a pharmaceutically acceptable salt thereof. 345. The compound of embodiment 339, wherein the compound is a compound of formula III-u, or a pharmaceutically acceptable salt thereof. 346. The compound of embodiment 339, wherein the compound is a compound of formula III-v, or a pharmaceutically acceptable salt thereof, provided that Ring A is other than phenyl or a 6 membered monocyclic heteroaryl ring having 1-3 nitrogen heteroatoms. 347. The compound of embodiment 339, wherein the compound is a compound of formula III-w, or a pharmaceutically acceptable salt thereof, provided that Ring A is other than phenyl or a 6 membered monocyclic heteroaryl ring having 1-3 nitrogen heteroatoms. 348. The compound of embodiment 339, wherein the compound is a compound of formula III-x, or a pharmaceutically acceptable salt thereof, provided that Ring A is other than phenyl or a 6 membered monocyclic heteroaryl ring having 1-3 nitrogen heteroatoms. The compound of any one of embodiments 1-287, wherein the compound is a compound of one of formulas III-p-A, III-q-A, III-r-A, III-p-B, III-q-B, III-r-B, III-p-C, III- q-C, III-r-C, III-s, III-t, III-u, III-v-A, III-w-A, or III-x-A: III-p-A III-q-A III-r-A

or a pharmaceutically acceptable salt thereof, provided that when the compound is of formulas III- p-A, III-q-A, III-r-A, III-v-A, III-w-A or III-x-A,then Ring A is other than phenyl or a 6 membered monocyclic heteroaryl ring having 1-3 nitrogen heteroatoms. 350. The compound of embodiment 349, wherein the compound is a compound of formula III-p-A, or a pharmaceutically acceptable salt thereof, provided that Ring A is other than phenyl or a 6 membered monocyclic heteroaryl ring having 1-3 nitrogen heteroatoms. 351. The compound of embodiment 349, wherein the compound is a compound of formula III-q-A, or a pharmaceutically acceptable salt thereof, provided that Ring A is other than phenyl or a 6 membered monocyclic heteroaryl ring having 1-3 nitrogen heteroatoms. 352. The compound of embodiment 349, wherein the compound is a compound of formula III-r-A, or a pharmaceutically acceptable salt thereof, provided that Ring A is other than phenyl or a 6 membered monocyclic heteroaryl ring having 1-3 nitrogen heteroatoms. 353. The compound of embodiment 349, wherein the compound is a compound of formula III-p-B, or a pharmaceutically acceptable salt thereof. 354. The compound of embodiment 349, wherein the compound is a compound of formula III-q-B, or a pharmaceutically acceptable salt thereof. 355. The compound of embodiment 349, wherein the compound is a compound of formula III-r-B, or a pharmaceutically acceptable salt thereof. 356. The compound of embodiment 349, wherein the compound is a compound of formula III-p-C, or a pharmaceutically acceptable salt thereof. 357. The compound of embodiment 349, wherein the compound is a compound of formula III-q-C, or a pharmaceutically acceptable salt thereof. 358. The compound of embodiment 349, wherein the compound is a compound of formula III-r-C, or a pharmaceutically acceptable salt thereof. 359. The compound of embodiment 349, wherein the compound is a compound of formula III-v-A, or a pharmaceutically acceptable salt thereof, provided that Ring A is other than phenyl or a 6 membered monocyclic heteroaryl ring having 1-3 nitrogen heteroatoms. 360. The compound of embodiment 349, wherein the compound is a compound of formula III-w-A, or a pharmaceutically acceptable salt thereof, provided that Ring A is other than phenyl or a 6 membered monocyclic heteroaryl ring having 1-3 nitrogen heteroatoms. 361. The compound of embodiment 349, wherein the compound is a compound of formula III-x-A, or a pharmaceutically acceptable salt thereof, provided that Ring A is other than phenyl or a 6 membered monocyclic heteroaryl ring having 1-3 nitrogen heteroatoms. 362. The compound of any one of embodiments 1-287, wherein the compound is a compound of one of formulas IV-a, IV-b, or IV-c: or a pharmaceutically acceptable salt thereof, wherein represents a single or double bond. 363. The compound of embodiment 362, wherein the compound is a compound of formula IV-a, or a pharmaceutically acceptable salt thereof. 364. The compound of embodiment 362, wherein the compound is a compound of formula IV-b, or a pharmaceutically acceptable salt thereof. 365. The compound of embodiment 362, wherein the compound is a compound of formula IV-c, or a pharmaceutically acceptable salt thereof. 366. The compound of any one of embodiments 1-287, wherein the compound is a compound of one of formulas IV-d, IV-e, IV-f, IV-g, IV-h, IV-i, IV-j, IV-k, or IV-l: IV-j IV-k IV-l or a pharmaceutically acceptable salt thereof, wherein represents a single or double bond. 367. The compound of embodiment 366, wherein the compound is a compound of formula IV-d, or a pharmaceutically acceptable salt thereof. 368. The compound of embodiment 366, wherein the compound is a compound of formula IV-e, or a pharmaceutically acceptable salt thereof. 369. The compound of embodiment 366, wherein the compound is a compound of formula IV-f, or a pharmaceutically acceptable salt thereof. 370. The compound of embodiment 366, wherein the compound is a compound of formula IV-g, or a pharmaceutically acceptable salt thereof. 371. The compound of embodiment 366, wherein the compound is a compound of formula IV-h, or a pharmaceutically acceptable salt thereof. 372. The compound of embodiment 366, wherein the compound is a compound of formula IV-i, or a pharmaceutically acceptable salt thereof. 373. The compound of embodiment 366, wherein the compound is a compound of formula IV-j, or a pharmaceutically acceptable salt thereof. 374. The compound of embodiment 366, wherein the compound is a compound of formula IV-k, or a pharmaceutically acceptable salt thereof. 375. The compound of embodiment 366, wherein the compound is a compound of formula IV-l, or a pharmaceutically acceptable salt thereof. 376. The compound of any one of embodiments 1-287, wherein the compound is a compound of one of formulas IV-m, IV-n, or IV-o: IV-o or a pharmaceutically acceptable salt thereof, provided that when X ¹ is CH or N then X ² is other than CH ₂ . 377. The compound of embodiment 376, wherein the compound is a compound of formula IV-m, or a pharmaceutically acceptable salt thereof, provided that when X ¹ is CH or N then X ² is other than CH ₂ . 378. The compound of embodiment 376, wherein the compound is a compound of formula IV-n, or a pharmaceutically acceptable salt thereof, provided that when X ¹ is CH or N then X ² is other than CH ₂ . 379. The compound of embodiment 376, wherein the compound is a compound of formula IV-o, or a pharmaceutically acceptable salt thereof, provided that when X ¹ is CH or N then X ² is other than CH ₂ . 380. The compound of any one of embodiments 1-287, wherein the compound is a compound of formula IV-m-A, IV-n-A, IV-o-A, IV-m-B, IV-n-B, IV-o-B, IV-m-C, IV-n-C, or IV-o-C:

IV-o-C or a pharmaceutically acceptable salt thereof, provided that when the compound is of formula IV- m-A, IV-n-A or IV-o-A and X ¹ is CH or N then X ² is other than CH2. 381. The compound of embodiment 380, wherein the compound is a compound of formula IV-m-A, or a pharmaceutically acceptable salt thereof, provided that when X ¹ is CH or N then X ² is other than CH ₂ . 382. The compound of embodiment 380, wherein the compound is a compound of formula IV-n-A, or a pharmaceutically acceptable salt thereof, provided that when X ¹ is CH or N then X ² is other than CH ₂ . 383. The compound of embodiment 380, wherein the compound is a compound of formula IV-o-A, or a pharmaceutically acceptable salt thereof, provided that when X ¹ is CH or N then X ² is other than CH ₂ . 384. The compound of embodiment 380, wherein the compound is a compound of formula IV-m-B, or a pharmaceutically acceptable salt thereof. 385. The compound of embodiment 380, wherein the compound is a compound of formula IV-n-B, or a pharmaceutically acceptable salt thereof. 386. The compound of embodiment 380, wherein the compound is a compound of formula IV-o-B, or a pharmaceutically acceptable salt thereof. 387. The compound of embodiment 380, wherein the compound is a compound of formula IV-m-C, or a pharmaceutically acceptable salt thereof. 388. The compound of embodiment 380, wherein the compound is a compound of formula IV-n-C, or a pharmaceutically acceptable salt thereof. 389. The compound of embodiment 380, wherein the compound is a compound of formula IV-o-C, or a pharmaceutically acceptable salt thereof. 390. The compound of any one of embodiments 1-287, wherein the compound is a compound of one of formulas IV-s, IV-t, IV-u, IV-v, IV-w, or IV-x:

IV-v IV-w IV-x or a pharmaceutically acceptable salt thereof. 391. The compound of embodiment 390, wherein the compound is a compound of formula IV-s, or a pharmaceutically acceptable salt thereof. 392. The compound of embodiment 390, wherein the compound is a compound of formula IV-t, or a pharmaceutically acceptable salt thereof. 393. The compound of embodiment 390, wherein the compound is a compound of formula IV-u, or a pharmaceutically acceptable salt thereof. 394. The compound of embodiment 390, wherein the compound is a compound of formula IV-v, or a pharmaceutically acceptable salt thereof. 395. The compound of embodiment 390, wherein the compound is a compound of formula IV-w, or a pharmaceutically acceptable salt thereof. 396. The compound of embodiment 390, wherein the compound is a compound of formula IV-x, or a pharmaceutically acceptable salt thereof. The compound of any one of embodiments 1-287, wherein the compound is a compound of formula IV-aa, IV-bb, IV-cc, IV-dd, IV-ee, IV-ff, IV-gg, IV-hh, IV-ii, IV-jj, IV- kk, or IV-ll: IV jj IV kk IV ll or a pharmaceutically acceptable salt thereof. 398. The compound of embodiment 397, wherein the compound is a compound of formula IV-aa, or a pharmaceutically acceptable salt thereof. 399. The compound of embodiment 397, wherein the compound is a compound of formula IV-bb, or a pharmaceutically acceptable salt thereof. 400. The compound of embodiment 397, wherein the compound is a compound of formula IV-cc, or a pharmaceutically acceptable salt thereof. 401. The compound of embodiment 397, wherein the compound is a compound of formula IV-dd, or a pharmaceutically acceptable salt thereof. 402. The compound of embodiment 397, wherein the compound is a compound of formula IV-ee, or a pharmaceutically acceptable salt thereof. 403. The compound of embodiment 397, wherein the compound is a compound of formula IV-ff, or a pharmaceutically acceptable salt thereof. 404. The compound of embodiment 397, wherein the compound is a compound of formula IV-gg, or a pharmaceutically acceptable salt thereof. 405. The compound of embodiment 397, wherein the compound is a compound of formula IV-hh, or a pharmaceutically acceptable salt thereof. 406. The compound of embodiment 397, wherein the compound is a compound of formula IV-ii, or a pharmaceutically acceptable salt thereof. 407. The compound of embodiment 397, wherein the compound is a compound of formula IV-jj, or a pharmaceutically acceptable salt thereof. 408. The compound of embodiment 397, wherein the compound is a compound of formula IV-kk, or a pharmaceutically acceptable salt thereof. 409. The compound of embodiment 397, wherein the compound is a compound of formula IV-ll, or a pharmaceutically acceptable salt thereof. 410. The compound of any one of embodiments 1-287, wherein the compound is a compound of one of formulas V-a, V-b, or V-c: V-c or a pharmaceutically acceptable salt thereof, wherein represents a single or double bond. 411. The compound of embodiment 410, wherein the compound is a compound of formula V-a, or a pharmaceutically acceptable salt thereof. 412. The compound of embodiment 410, wherein the compound is a compound of formula V-b, or a pharmaceutically acceptable salt thereof. 413. The compound of embodiment 410, wherein the compound is a compound of formula V-c, or a pharmaceutically acceptable salt thereof. 414. The compound of any one of embodiments 1-287, wherein the compound is a compound of one of formulas V-d, V-e, V-f, V-g, V-h, V-i, V-j, V-k, or V-l:

or a pharmaceutically acceptable salt thereof, wherein represents a single or double bond. 415. The compound of embodiment 414, wherein the compound is a compound of formula V-d, or a pharmaceutically acceptable salt thereof. 416. The compound of embodiment 414, wherein the compound is a compound of formula V-e, or a pharmaceutically acceptable salt thereof. 417. The compound of embodiment 414, wherein the compound is a compound of formula V-f, or a pharmaceutically acceptable salt thereof. 418. The compound of embodiment 414, wherein the compound is a compound of formula V-g, or a pharmaceutically acceptable salt thereof. 419. The compound of embodiment 414, wherein the compound is a compound of formula V-h, or a pharmaceutically acceptable salt thereof. 420. The compound of embodiment 414, wherein the compound is a compound of formula V-i, or a pharmaceutically acceptable salt thereof. 421. The compound of embodiment 414, wherein the compound is a compound of formula V-j, or a pharmaceutically acceptable salt thereof. 422. The compound of embodiment 414, wherein the compound is a compound of formula V-k, or a pharmaceutically acceptable salt thereof. 423. The compound of embodiment 414, wherein the compound is a compound of formula V-l, or a pharmaceutically acceptable salt thereof. 424. The compound of any one of embodiments 1-287, wherein the compound is a compound of one of formulas VI-a, VI-b, or VI-c: VI-c or a pharmaceutically acceptable salt thereof, wherein each of Ring A, R ¹ , R ² , R ³ , m, n, p, L, and LBM is as defined in embodiments and classes and subclasses herein. 425. The compound of embodiment 424, wherein the compound is a compound of formula VI-a, or a pharmaceutically acceptable salt thereof. 426. The compound of embodiment 424, wherein the compound is a compound of formula VI-b, or a pharmaceutically acceptable salt thereof. 427. The compound of embodiment 424, wherein the compound is a compound of formula VI-c, or a pharmaceutically acceptable salt thereof. The compound of any one of embodiments 1-287, wherein the compound is a compound of one of formulas VI-d, VI-e, or VI-f: VI-d VI-e VI-f or a pharmaceutically acceptable salt thereof, wherein each of Ring A, R ¹ , R ² , R ³ , m, n, p, L, and LBM is as defined in embodiments and classes and subclasses herein. 429. The compound of embodiment 428, wherein the compound is a compound of formula VI-d, or a pharmaceutically acceptable salt thereof. 430. The compound of embodiment 428, wherein the compound is a compound of formula VI-e, or a pharmaceutically acceptable salt thereof. 431. The compound of embodiment 428, wherein the compound is a compound of formula VI-f, or a pharmaceutically acceptable salt thereof. 432. The compound of any one of embodiments 1-287, wherein the compound is a compound of one of formulas VI-g, VI-h, VI-i, VI-j, VI-k, or VI-l: VI-g VI-h VI-i

or a pharmaceutically acceptable salt thereof, wherein each of Ring A, R ¹ , R ² , R ³ , m, n, p, L, and LBM is as defined in embodiments and classes and subclasses herein. 433. The compound of embodiment 432, wherein the compound is a compound of formula VI-g, or a pharmaceutically acceptable salt thereof. 434. The compound of embodiment 432, wherein the compound is a compound of formula VI-h, or a pharmaceutically acceptable salt thereof. 435. The compound of embodiment 432, wherein the compound is a compound of formula VI-i, or a pharmaceutically acceptable salt thereof. 436. The compound of embodiment 432, wherein the compound is a compound of formula VI-j, or a pharmaceutically acceptable salt thereof. 437. The compound of embodiment 432, wherein the compound is a compound of formula VI-k, or a pharmaceutically acceptable salt thereof. 438. The compound of embodiment 432, wherein the compound is a compound of formula VI-l, or a pharmaceutically acceptable salt thereof. 439. The compound of any one of embodiments 1-287, wherein the compound is a compound of one of formulas VI-m, VI-n, or VI-o: VI-m VI-n VI-o or a pharmaceutically acceptable salt thereof, wherein each of Ring A, R ¹ , R ² , R ³ , m, n, p, L, and LBM is as defined in embodiments and classes and subclasses herein. 440. The compound of embodiment 439, wherein the compound is a compound of formula VI-m, or a pharmaceutically acceptable salt thereof. 441. The compound of embodiment 439, wherein the compound is a compound of formula VI-n, or a pharmaceutically acceptable salt thereof. 442. The compound of embodiment 439, wherein the compound is a compound of formula VI-o, or a pharmaceutically acceptable salt thereof. 443. The compound of any one of embodiments 1-287, wherein the compound is a compound of one of formulas II-j-2, II-k-2, or II-l-2: or a pharmaceutically acceptable salt thereof, wherein each of Ring A, Ring B, R ¹ , R ² , R ³ , m, n, p, L, and LBM is as defined in embodiments and classes and subclasses herein. 444. The compound of embodiment 443, wherein the compound is a compound of formula II-j-2, or a pharmaceutically acceptable salt thereof. 445. The compound of embodiment 443, wherein the compound is a compound of formula II-k-2, or a pharmaceutically acceptable salt thereof. 446. The compound of embodiment 443, wherein the compound is a compound of formula II-l-2, or a pharmaceutically acceptable salt thereof. 447. The compound of any one of embodiments 1-287, wherein the compound is a compound of one of formulas VII-a, VII-b, VII-c, VII-d, VII-e, or VII-f: or a pharmaceutically acceptable salt thereof, wherein each of Ring A, R ¹ , R ² , R ³ , m, n, p, L, and LBM is as defined in embodiments and classes and subclasses herein. 448. The compound of embodiment 447, wherein the compound is a compound of 449. The compound of embodiment 447, wherein the compound is a compound of formula VII-b, or a pharmaceutically acceptable salt thereof. 450. The compound of embodiment 447, wherein the compound is a compound of formula VII-c, or a pharmaceutically acceptable salt thereof. 451. The compound of embodiment 447, wherein the compound is a compound of formula VII-d, or a pharmaceutically acceptable salt thereof. 452. The compound of embodiment 447, wherein the compound is a compound of formula VII-e, or a pharmaceutically acceptable salt thereof. 453. The compound of embodiment 447, wherein the compound is a compound of formula VII-f, or a pharmaceutically acceptable salt thereof. 454. The compound of any one of embodiments 1-287, wherein the compound is a compound of one of formulas VII-g, VII-h, or VII-i: or a pharmaceutically acceptable salt thereof, wherein each of Ring A, R ¹ , R ² , R ³ , m, n, p, L, and 455. The compound of embodiment 454, wherein the compound is a compound of formula VII-g, or a pharmaceutically acceptable salt thereof. 456. The compound of embodiment 454, wherein the compound is a compound of formula VII-h, or a pharmaceutically acceptable salt thereof. 457. The compound of embodiment 454, wherein the compound is a compound of formula VII-i, or a pharmaceutically acceptable salt thereof. 458. The compound of any one of embodiments 1-287, wherein the compound is a compound of one of formulas VII-j, VII-k, VII-l, VII-m, VII-n, or VII-o: or a pharmaceutically acceptable salt thereof, wherein each of Ring A, R ¹ , R ² , R ³ , m, n, p, L, and LBM is as defined in embodiments and classes and subclasses herein. 459. The compound of embodiment 458, wherein the compound is a compound of formula VII-j, or a pharmaceutically acceptable salt thereof. 460. The compound of embodiment 458, wherein the compound is a compound of formula VII-k, or a pharmaceutically acceptable salt thereof. 461. The compound of embodiment 458, wherein the compound is a compound of formula VII-l, or a pharmaceutically acceptable salt thereof. 462. The compound of embodiment 458, wherein the compound is a compound of formula VII-m, or a pharmaceutically acceptable salt thereof. 463. The compound of embodiment 458, wherein the compound is a compound of formula VII-n, or a pharmaceutically acceptable salt thereof. 464. The compound of embodiment 458, wherein the compound is a compound of formula VII-o, or a pharmaceutically acceptable salt thereof. 465. The compound of any one of embodiments 1-287, wherein the compound is a compound of one of formulas VII-p, VII-q, or VII-r, respectively: VII-p VII-q

or a pharmaceutically acceptable salt thereof, wherein each of Ring A, R ¹ , R ² , R ³ , m, n, p, L, and LBM is as defined in embodiments and classes and subclasses herein. 466. The compound of embodiment 465, wherein the compound is a compound of formula VII-p, or a pharmaceutically acceptable salt thereof. 467. The compound of embodiment 465, wherein the compound is a compound of formula VII-q, or a pharmaceutically acceptable salt thereof. 468. The compound of embodiment 465, wherein the compound is a compound of formula VII-r, or a pharmaceutically acceptable salt thereof. 469. The compound of any one of embodiments 1-287, wherein the compound is a compound of one of formulas VIII-d, VIII-e, and VIII-f: or a pharmaceutically acceptable salt thereof. 470. The compound of embodiment 469, wherein the compound is a compound of formula VIII-d, or a pharmaceutically acceptable salt thereof. 471. The compound of embodiment 469, wherein the compound is a compound of formula VIII-e, or a pharmaceutically acceptable salt thereof. 472. The compound of embodiment 469, wherein the compound is a compound of formula VIII-f, or a pharmaceutically acceptable salt thereof. 473. The compound of any one of embodiments 1-287, wherein the compound is a compound of one of formulas VIII-g, VIII-h, VIII-i, VIII-j, VIII-k or VIII-l: or a pharmaceutically acceptable salt thereof. 474. The compound of embodiment 473, wherein the compound is a compound of formula VIII-g, or a pharmaceutically acceptable salt thereof. 475. The compound of embodiment 473, wherein the compound is a compound of formula VIII-h, or a pharmaceutically acceptable salt thereof. 476. The compound of embodiment 473, wherein the compound is a compound of formula VIII-i, or a pharmaceutically acceptable salt thereof. 477. The compound of embodiment 473, wherein the compound is a compound of formula VIII-j, or a pharmaceutically acceptable salt thereof. 478. The compound of embodiment 473, wherein the compound is a compound of formula VIII-k, or a pharmaceutically acceptable salt thereof. 479. The compound of embodiment 473, wherein the compound is a compound of f l VIII l h ti ll t bl lt th f 480. The compound of any one of embodiments 1-287, wherein the compound is a compound of one of formulas VIII-m, VIII-n, VIII-o, VIII-p, VIII-q, VIII-r, VIII-s, VIII-t, or VIII-u: or a pharmaceutically acceptable salt thereof. 481. The compound of embodiment 480, wherein the compound is a compound of formula VIII-m , or a pharmaceutically acceptable salt thereof. 482. The compound of embodiment 480, wherein the compound is a compound of formula VIII-n, or a pharmaceutically acceptable salt thereof. 483. The compound of embodiment 480, wherein the compound is a compound of formula VIII-o, or a pharmaceutically acceptable salt thereof. 484. The compound of embodiment 480, wherein the compound is a compound of formula VIII-p, or a pharmaceutically acceptable salt thereof. 485. The compound of embodiment 480, wherein the compound is a compound of formula VIII-q, or a pharmaceutically acceptable salt thereof. 486. The compound of embodiment 480, wherein the compound is a compound of formula VIII-r, or a pharmaceutically acceptable salt thereof. 487. The compound of embodiment 480, wherein the compound is a compound of formula VIII-s, or a pharmaceutically acceptable salt thereof. 488. The compound of embodiment 480, wherein the compound is a compound of formula V or a pharmaceutically acceptable salt thereof. 489. The compound of embodiment 480, wherein the compound is a compound of formula VIII-u, or a pharmaceutically acceptable salt thereof. 490. The compound of any one of embodiments 1-287, wherein the compound is a compound of one of formulas IX-d, IX-e, IX-f: or a pharmaceutically acceptable salt thereof. 491. The compound of embodiment 490, wherein the compound is a compound of formula IX-d, or a pharmaceutically acceptable salt thereof. 492. The compound of embodiment 490, wherein the compound is a compound of formula IX-e, or a pharmaceutically acceptable salt thereof. 493. The compound of embodiment 490, wherein the compound is a compound of formula IX-f, or a pharmaceutically acceptable salt thereof. 494. The compound of any one of embodiments 1-287, wherein the compound is a compound of one of formulas IX-g, IX-h, IX-i, IX-j, IX-k, IX-l, IX-m, IX-n, IX-o:

or a pharmaceutically acceptable salt thereof. 495. The compound of embodiment 494, wherein the compound is a compound of formula IX-g, or a pharmaceutically acceptable salt thereof. 496. The compound of embodiment 494, wherein the compound is a compound of formula IX-h, or a pharmaceutically acceptable salt thereof. 497. The compound of embodiment 494, wherein the compound is a compound of formula IX-i, or a pharmaceutically acceptable salt thereof. 498. The compound of embodiment 494, wherein the compound is a compound of formula IX-j, or a pharmaceutically acceptable salt thereof. 499. The compound of embodiment 494, wherein the compound is a compound of formula IX-k, or a pharmaceutically acceptable salt thereof. 500. The compound of embodiment 494, wherein the compound is a compound of formula IX-l, or a pharmaceutically acceptable salt thereof. 501. The compound of embodiment 494, wherein the compound is a compound of formula IX-m, or a pharmaceutically acceptable salt thereof. 502. The compound of embodiment 494, wherein the compound is a compound of formula IX-n, or a pharmaceutically acceptable salt thereof. 503. The compound of embodiment 494, wherein the compound is a compound of formula IX-o, or a pharmaceutically acceptable salt thereof. 504. The compound of any one of embodiments 1-287, wherein Ring C together with its R ⁶ substituents is selected from: 505. The compound of embodiment 504, wherein Ring C together with its R ⁶ substituents 506. The compound of embodiment 504, wherein Ring C together with its R ⁶ substituents i . 507. The compound of embodiment 504, wherein Ring C together with its R ⁶ substituents i . 508. The compound of embodiment 504, wherein Ring C together with its R ⁶ substituents 509. The compound of embodiment 504, wherein Ring C together with its R ⁶ substituents 510. The compound of embodiment 504, wherein Ring C together with its R ⁶ substituents 511. The compound of embodiment 504, wherein Ring C together with its R ⁶ substituents 512. The compound of embodiment 504, wherein Ring C together with its R ⁶ b i d of embodiment 504, wherein Ring C together with its R ⁶ . 514. The compound of embodiment 504, wherein Ring C together with its R ⁶ substituents 515. The compound of embodiment 504, wherein Ring C together with its R ⁶ substituents 516. The compound of embodiment 504, wherein Ring C together with its R ⁶ substituents i 517. The compound of embodiment 504, wherein Ring C together with its R ⁶ substituents i 518. The compound of embodiment 504, wherein Ring C together with its R ⁶ substituents i . The compound of embodiment 504, wherein Ring C together with its R ⁶ substituents 520. The compound of any one of embodiments 1-519, wherein X ¹ is selected from CH and C(R ^A1 ). . The compound of any one of embodiments 1-519, wherein X ² is selected from O, CH ₂ , CH(R ^A3 ), and C(R ^A3 )2, provided that X ¹ and X ² are not both simultaneously heteroatoms. 522. The compound of any one of embodiments 1-521, wherein L is L is a bivalent, saturated or unsaturated, straight or branched C _1-50 hydrocarbon chain, wherein 0-6 methylene units of L are independently replaced by –Cy–, –CH(R)–, –C(R) ₂ –, –O–, –NR–, –S–, –OC(O)–, 523. The compound of any one of embodiments 1-521, wherein L is a bivalent, saturated or unsaturated, straight or branched C _3-5 hydrocarbon chain, wherein 0, 1, 2 or 3 methylene units of L are independently replaced by –Cy–, –CH(R)–, –C(R)2–, –O–, –NR–, –S–, –OC(O)–, –C(O)O–, –C(O)–, –S(O)–, –S(O)2–, –NRS(O)2–, –S(O)2NR–, –NRC(O)–, –

524. The compound of any one of embodiments 1-521, wherein L is a bivalent, saturated or unsaturated, straight or branched C3-5 hydrocarbon chain, wherein 1, 2 or 3 methylene units of L are independently replaced by –Cy–, –CH(R)–, –C(R)2–, –O– or–NR– . 525. The compound of any one of embodiments 1-521, wherein L is a bivalent, saturated or unsaturated, straight or branched C3-5 hydrocarbon chain, wherein 1, 2 or 3 methylene units of L are independently replaced by –Cy– or–NR– . 526. The compound of any one of embodiments 1-521, wherein each –Cy– is independently an optionally substituted bivalent ring selected from a 4-7 membered saturated or partially unsaturated monocyclic carbocyclylenyl, a 5-11 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 monocyclic heterocyclylenyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-11 membered monocyclic saturated or partially 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 and a 6-10 membered bridged bicyclic saturated or partially unsaturated heterocyclylenyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 527. The compound of any one of embodiments 1-521, wherein each –Cy– is independently an optionally substituted bivalent ring selected from a 4-7 membered saturated or partially unsaturated monocyclic carbocyclylenyl, a 5-11 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 monocyclic heterocyclylenyl containing 1-2 nitrogen atoms, a 5-11 membered monocyclic saturated or partially unsaturated spiro heterocyclylenyl containing 1-2 nitrogen atoms, an 8-10 membered bicyclic saturated or partially unsaturated heterocyclylenyl containing 1-2 nitrogen atoms, and a 6-10 membered bridged bicyclic saturated or partially unsaturated heterocyclylenyl containing 1-2 nitrogen atoms. 528. The compound of any one of embodiments 1-527, wherein the bivalent ring of each –Cy– is independently substituted with 0, 1 or 2 substituents independently selected from deuterium, C ₁ -C ₄ alkyl, C ₁ -C ₄ haloalkyl, C ₃ -C ₇ cycloalkyl, –O-C ₁ -C ₄ alkyl, halo, cyano, –OH, – NH ₂ , –N(H)(C ₁ -C ₄ alkyl) and –N(C ₁ -C ₄ alkyl) ₂ . 529. The compound of any one of embodiments 1-527, wherein the bivalent ring of each –Cy– is independently substituted with 0, 1 or 2 substituents independently selected from – C1-C4 alkyl, –C1-C4 haloalkyl, –C3-C7 cycloalkyl, –O-C1-C4 alkyl, halo, cyano, –OH, –NH2, –N(H)(C1-C4 alkyl) and –N(C1-C4 alkyl)2. 530. The compound of any one of embodiments 1-527, wherein the bivalent ring of each –Cy– is independently substituted with 0, 1 or 2 substituents independently selected from – Me, –Et, Pr, iPr, cyclopropyl, –CF3, –OMe, –F, –Cl, –CN, –NH2, –NHMe and –NMe2. 531. The compound of any one of embodiments 1-527, wherein the bivalent ring of each –Cy– is independently substituted with 0, 1 or 2 substituents independently selected from – Me, –OMe and –F. 532. The compound of any one of embodiments 1-527, wherein the bivalent ring of each –Cy– is independently substituted with 0, 1 or 2 instances of –Me. 533. The compound of any one of embodiments 1-527, wherein the bivalent ring of each –Cy– is unsubstituted. 534. The compound of any one of embodiments 1-527, wherein the bivalent ring of each –Cy– is substituted with 1 or 2 substituents. 535. The compound of any one of embodiments 1-527, wherein L is . 536. The compound of any one of embodiments 1-527, wherein L is selected from: , , , , , , , , , 537. The compound of any one of embodiments 1-527, wherein L is selected from: , , , , , , , , , 538. The compound of any one of embodiments 1-527, wherein L is selected from: , , , , , 539. The compound of any one of embodiments 1-527, wherein L is selected from: , . 545. The compound of any one of embodiments 1-527, wherein L is ound of any one of embodiments 1-527, wherein L is ound of any one of embodiments 1-527, wherein L is . 548. The compound of any one of embodiments 1-527, wherein L is . pound of any one of embodiments 1-527, wherein L is pound of any one of embodiments 1-527, wherein L is pound of any one of embodiments 1-527, wherein L is . 552. The compound of any one of embodiments 1-527, wherein L is und of any one of embodiments 1-527, wherein L is und of any one of embodiments 1-527, wherein L is . 555. The compound of any one of embodiments 1-527, wherein L is pound of any one of embodiments 1-527, wherein L is . pound of any one of embodiments 1-527, wherein L is . pound of any one of embodiments 1-527, wherein L is . 559. The compound of any one of embodiments 1-527, wherein L is 560. The compound of any one of embodiments 1-527, wherein L is . 561. The compound of any one of embodiments 1-527, wherein L is . 562. The compound of any one of embodiments 1-527, wherein L is . 563. The compound of any one of embodiments 1-527, wherein L is . 564. The compound of any one of embodiments 1-527, wherein L is . 565. The compound of any one of embodiments 1-527, wherein L is . 566. The compound of any one of embodiments 1-527, wherein L is . 567. The compound of any one of embodiments 1-527, wherein L is . 568. The compound of any one of embodiments 1-527, wherein L is N N N . 569. The compound of any one of embodiments 1-527, wherein L is . 570. The compound of any one of embodiments 1-527, wherein L is . 571. The compound of any one of embodiments 1-527, wherein L is . 572. The compound of any one of embodiments 1-527, wherein L is . 573. The compound of any one of embodiments 1-527, wherein L is . 574. The compound of any one of embodiments 1-527, wherein L is . 575. The compound of any one of embodiments 1-527, wherein L is . 576. The compound of any one of embodiments 1-527, wherein L is . 577. The compound of any one of embodiments 1-527, wherein L is . 578. The compound of any one of embodiments 1-527, wherein L is . 579. The compound of any one of embodiments 1-527, wherein L is . 580. The compound of any one of embodiments 1-527, wherein L is . 581. The compound of any one of embodiments 1-527, wherein L is . 582. The compound of any one of embodiments 1-527, wherein L is . 583. The compound of any one of embodiments 1-527, wherein L is . 584. The compound of any one of embodiments 1-527, wherein L is . 585. The compound of any one of embodiments 1-527, wherein L is . 586. The compound of any one of embodiments 1-585, wherein LBM is selected from: , , , , , ,

587. The compound of any one of embodiments 1-585, wherein LBM is selected from: 588. The compound of any one of embodiments 1-585, wherein LBM is selected from . 589. The compound of any one of embodiments 1-588, wherein each R ⁴ is independently selected from deuterium, C _1-6 aliphatic chain substituted with 0-3 instances of halo, halogen, –CN, –OR, –NR ₂ , –S(O) ₂ R, –S(O) ₂ NR ₂ , –S(O)R, –S(O)NR ₂ , -S(O)(NR)R, – C(O)NR ₂ , –C(O)N(R)OR, –OC(O)NR ₂ , –N(R)C(O)OR, –N(R)C(O)R, -N(R)C(O)NR ₂ , – N(R)S(O) ₂ NR ₂ and –N(R)S(O) ₂ R, wherein R is H or a C _1-6 aliphatic chain. 590. The compound of any one of embodiments 1-588, wherein each R ⁴ is independently selected from –Me, –Et, –F, –Cl, –CF ₃ , –CN, –OH, –OMe, –NH ₂ , –NHMe and – NMe ₂ . 591. The compound of any one of embodiments 1-590, wherein each R ⁵ is independently selected from deuterium, C _1-6 aliphatic chain substituted with 0-3 instances of halo, halogen, –CN, –OR, –NR ₂ , –S(O) ₂ R, –S(O) ₂ NR ₂ , –S(O)R, –S(O)NR ₂ , –S(O)(NR)R, – C(O)NR ₂ , –C(O)N(R)OR, –OC(O)NR ₂ , –N(R)C(O)OR, –N(R)C(O)R, –N(R)C(O)NR ₂ , – N(R)S(O) ₂ NR ₂ and –N(R)S(O) ₂ R, wherein R is H or a C _1-6 aliphatic chain. 592. The compound of any one of embodiments 1-590, wherein each R ⁵ is independently selected from –Me, –Et, –F, –Cl, –CF3, –CN, –OH, –OMe, –NH2, –NHMe and – NMe2. 593. The compound of any one of embodiments 1-590, wherein each R ⁵ is independently selected from –Me and –F. 594. The compound of any one of embodiments 1-593, wherein r is 0, 1 or 2. 595. The compound of any one of embodiments 1-593, wherein r is 0. 596. The compound of any one of embodiments 1-593, wherein r is 1. 597. The compound of any one of embodiments 1-593, wherein r is 2. 598. The compound of any one of embodiments 1-597, wherein s is 0, 1 or 2. 599. The compound of any one of embodiments 1-597, wherein s is 0. 600. The compound of any one of embodiments 1-597, wherein s is 1. 601. The compound of any one of embodiments 1-597, wherein s is 2. 602. The compound of any one of embodiments 1-585, wherein LBM is selected from

. 603. The compound of any one of embodiments 1-585, wherein LBM is selected from:

604. The compound of any one of embodiments 1-585, wherein LBM is selected from 605. The compound of any one of embodiments 1-585, wherein LBM is selected from , and . 606. The compound of any one of embodiments 1-585, wherein LBM is . 607. The compound of any one of embodiments 1-585, wherein LBM is . 608. The compound of any one of embodiments 1-585, wherein LBM is . 609. The compound of any one of embodiments 1-585, wherein LBM is . 610. The compound of any one of embodiments 1-585, wherein LBM is . 611. The compound of any one of embodiments 1-585, wherein LBM is 612. The compound of any one of embodiments 1-585, wherein LBM is O NH O . 613. The compound of any one of embodiments 1-585, wherein LBM is . 614. The compound of any one of embodiments 1-585, wherein LBM is . 615. The compound of any one of embodiments 1-585, wherein LBM is . 616. The compound of any one of embodiments 1-585, wherein LBM is . 617. The compound of any one of embodiments 1-585, wherein LBM is . 618. The compound of any one of embodiments 1-585, wherein LBM is . 619. The compound of any one of embodiments 1-585, wherein LBM is . 620. The compound of any one of embodiments 1-585, wherein LBM is O N O H . 621. The compound of any one of embodiments 1-585, wherein LBM is 622. The compound of any one of embodiments 1-585, wherein LBM is . 623. The compound of any one of embodiments 1-585, wherein LBM is . 624. The compound of any one of embodiments 1-585, wherein LBM is . 625. The compound of any one of embodiments 1-585, wherein LBM is . 626. The compound of any one of embodiments 1-585, wherein LBM is . 627. The compound of any one of embodiments 1-585, wherein LBM is . 628. The compound of any one of embodiments 1-585, wherein LBM is . 629. The compound of any one of embodiments 1-585, wherein LBM is . 630. The compound of any one of embodiments 1-585, wherein LBM is . 631. The compound of any one of embodiments 1-585, wherein LBM is . 632. The compound of any one of embodiments 1-585, wherein LBM is . 633. The compound of any one of embodiments 1-585, wherein LBM is . 634. The compound of any one of embodiments 1-585, wherein LBM is und of any one of embodiments 1-585, wherein LBM is und of any one of embodiments 1-585, wherein LBM is . 637. The compound of any one of embodiments 1-636, wherein each R ¹ is independently selected from deuterium, C _1-6 aliphatic chain substituted with 0-3 instances of halo, halogen, –CN, –SR, –OR, –NR ₂ , –S(O) ₂ R, –S(O) ₂ NR ₂ , –S(O)R, –S(O)NR ₂ , –S(O)(NR)R, –C(O)OR, –C(O)NR ₂ , –C(O)N(R)OR, –OC(O)NR ₂ , –N(R)C(O)OR, –N(R)C(O)R, – N(R)C(O)NR ₂ , –N(R)S(O) ₂ NR ₂ and –N(R)S(O) ₂ R, wherein R is H or a C _1-6 aliphatic chain substituted with 0-3 instances of halo. 638. The compound of any one of embodiments 1-636, wherein each R ¹ is independently selected from –Me, –Et, –F, –Cl, –SCF ₃ , –OCF ₃ , –CF ₃ , –CN, –OH, –OMe, –NH ₂ , –NHMe and –NMe ₂ . 639. The compound of any one of embodiments 1-636, wherein each R ¹ is independently selected from –Me and –F, 640. The compound of any one of embodiments 1-639, wherein each R ² is independently selected from deuterium, C1-6 aliphatic chain substituted with 0-3 instances of halo, halogen, –CN, –OR, –NR ₂ , –S(O) ₂ R, –S(O) ₂ NR ₂ , –S(O)R, –S(O)NR ₂ , –S(O)(NR)R, – C(O)OR, –C(O)NR ₂ , –C(O)N(R)OR, –OC(O)NR ₂ , –N(R)C(O)OR, –N(R)C(O)R, – N(R)C(O)NR ₂ , –N(R)S(O) ₂ NR ₂ and –N(R)S(O) ₂ R, wherein R is H or a C _1-6 aliphatic chain. 641. The compound of any one of embodiments 1-639, wherein each R ² is independently selected from –Me, –Et, –F, –Cl, –CF ₃ , –CN, –OH, –OMe, –NH ₂ , –NHMe and – NMe ₂ . 642. The compound of any one of embodiments 1-639, wherein each R ² is independently selected from –F, –Cl and –CF ₃ . 643. The compound of any one of embodiments 1-642, wherein m is 0, 1 or 2. 644. The compound of any one of embodiments 1-642, wherein m is 0. 645. The compound of any one of embodiments 1-642, wherein m is 1. 646. The compound of any one of embodiments 1-642, wherein m is 2. 647. The compound of any one of embodiments 1-646, wherein n is 0, 1 or 2. 648. The compound of any one of embodiments 1-646, wherein n is 0. 649. The compound of any one of embodiments 1-646, wherein n is 1. 650. The compound of any one of embodiments 1-646, wherein n is 2. 651. The compound of any one of embodiments 1-650, wherein each R ³ is independently selected from deuterium, C _1-6 aliphatic chain substituted with 0-3 instances of halo, halogen, –CN, –OR, –NR ₂ , –S(O) ₂ R, –S(O) ₂ NR ₂ , –S(O)R, –S(O)NR ₂ , –S(O)(NR)R, – C(O)OR, –C(O)NR ₂ , –C(O)N(R)OR, –OC(O)NR ₂ , –N(R)C(O)OR, –N(R)C(O)R, – N(R)C(O)NR ₂ , –N(R)S(O) ₂ NR ₂ and –N(R)S(O) ₂ R, wherein R is H or a C _1-6 aliphatic chain or two R ³ groups are taken together to form . 652. The compound of any one of embodiments 1-650, wherein each R ³ is independently selected from –Me, –Et, –F, –Cl, –CF3,-CO2H, –CN, –OH, –OMe, –NH2, –NHMe and –NMe ₂ or two R ³ groups are taken together to form . 653. The compound of any one of embodiments 1-650, wherein each R ³ is independently selected from –F, –OH, and –CO ₂ H. 654. The compound of any one of embodiments 1-650, wherein each R ³ is independently selected from –Me, –F, –OH, and –CO2H. 655. The compound of any one of embodiments 1-650, wherein each R ³ is independently selected from –F and –OH. 656. The compound of any one of embodiments 1-650, wherein each R ³ is independently selected from –Me and –F. 657. The compound of any one of embodiments 1-650, wherein two R ³ groups are taken together to form . 658. The compound of any one of embodiments 1-657, wherein p is 0, 1 or 2. 659. The compound of any one of embodiments 1-657, wherein p is 0. 660. The compound of any one of embodiments 1-657, wherein p is 1. 661. The compound of any one of embodiments 1-657, wherein p is 2. 662. The compound of any one of embodiments 1-661, wherein each R ⁶ is independently selected from –Me, –Et, –F, –Cl, –CF ₃ , –CO ₂ H, –CN, –OH, –OMe, –NH ₂ , – NHMe and –NMe ₂ 663. The compound of any one of embodiments 1-661, wherein each R ⁶ is independently selected from –Me, and –F. 664. The compound of any one of embodiments 1-663, wherein t is 0, 1 or 2. 665. The compound of any one of embodiments 1-663, wherein t is 0. 666. The compound of any one of embodiments 1-663, wherein t is 1. 667. The compound of any one of embodiments 1-663, wherein t is 2. 668. The compound of any one of embodiments 1-667, wherein the compound is a compound shown in Table 1 or a pharmaceutically acceptable salt thereof. 669. A compound shown in Table 2 or a pharmaceutically acceptable salt thereof. 670. A pharmaceutical composition comprising a compound of any one of embodiments 1-669, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, adjuvant, or diluent. 671. A method of inhibiting ERα signaling in a sample, e.g., in vivo or in vitro, by contacting ERα with a compound of any one of embodiments 1-669, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of embodiment 670. 672. The method of embodiment 671, wherein the inhibiting of ERα signaling comprises reducing the signaling activity of ERα by at least 1%, 2%, 5%, 7.5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, e.g., relative to a reference standard. 673. The method of embodiment 671, wherein the inhibiting of ERα signaling comprises reducing the signaling activity of ERα by at least 1-fold, 1.5-fold, 2-fold, 3-fold, 5- fold, 10-fold, 20-fold, 30-fold, 50-fold, 100-fold, or more, e.g., relative to a reference standard. 674. A method of treating an ERα-mediated disorder in a patient in need thereof, comprising administering to the patient a compound of any one of embodiments 1-669, or a pharmaceutically acceptable salt thereof, or a composition of embodiment 670. 675. The method of embodiment 674, wherein the ERα-mediated disorder is associated with estrogen receptor accumulation and aggregation. 676. The method of any of embodiments 674 or 675, wherein the ERα-mediated disorder is cancer or a neoplasia associated with estrogen receptor accumulation and aggregation. 677. The method of embodiment 676, wherein the ERα-mediated disorder is a disorder mediated by a ERα containing a D544G, Y543S, or L542R mutation. 678. The method of any one of embodiments 674-677, wherein the ERα-mediated disorder is a disorder described herein. 679. The method of any one of embodiments 674-678, wherein the method comprises the steps of: (i) identifying a subject in need of such treatment; (ii) providing a disclosed compound, or a pharmaceutically acceptable salt thereof; and (iii) administering said provided compound in a therapeutically effective amount to treat, suppress and/or prevent the disease state or condition in a subject in need of such treatment. 680. The method of any one of embodiments 674-679, wherein the ERα-mediated disorder is breast cancer or uterine cancer. 681. The method of embodiment 680, wherein the breast cancer is selected from the group consisting of ER+ breast cancer, ER+/HER2- breast cancer, ER+ advanced/metastatic breast cancer, and ER+/HER2- advanced/metastatic breast cancer. 682. The method of any one of embodiments 674-681, wherein the ERα-mediated disorder is endometriosis. 683. A compound or pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, according to any one of embodiments 1-669, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of embodiment 670, for use as a medicament. 684. A compound or pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, according to any one of embodiments 1-669, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of embodiment 670, for use in the treatment of an ERα-mediated disorder. EXAMPLES [0723] Examples are provided herein to facilitate a more complete understanding of the disclosure. The following examples serve to illustrate the exemplary modes of making and practicing the subject matter of the disclosure. However, the scope of the disclosure is not to be construed as limited to specific embodiments disclosed in these examples, which are illustrative only. [0724] As depicted in the Examples below, in certain exemplary embodiments, compounds are prepared according to the following general procedures. It will be appreciated that, although the general methods depict the synthesis of certain compounds of the present disclosure, the following general methods, and other methods known to one of ordinary skill in the art, can be applied to other classes and subclasses and species of each of these compounds, as described herein. Additional compounds of the disclosure were prepared by methods substantially similar to those described herein in the Examples and methods known to one skilled in the art. [0725] In the description of the synthetic methods described below, unless otherwise stated, it is to be understood that all reaction conditions (for example, reaction solvent, atmosphere, temperature, duration, and workup procedures) are selected from the standard conditions for that reaction, unless otherwise indicated. The starting materials for the Examples are either commercially available or are readily prepared by standard methods from known materials. General Methods [0726] The parameters used for the HPLC measurement in the synthesis procedures below are as follows: Mobile Phase: 2.75ML/4LTFA in water (solvent A) and 2.5ML/4LTFA in acetonitrile (solvent B), using the elution gradient 10%-80% (solvent B) over 6 minutes and holding at 80% for 2 minutes at a flow rate of 1.2 ml/min; Column: Ultimate C18 3.0*50mm,3um Wavelength:UV220nm,215nm,254nm; Column temperature: 40^. [0727] The parameters for the LCMS (acidic) measurement in the synthesis procedures below are one of the following: (1) Mobile Phase: 1.5ML/4LTFA in water (solvent A) and 0.75ML/4LTFA in acetonitrile (solvent B), using the elution gradient 5%-95% (solvent B) over0.7 minutes and holding at 95%; for 0.4 minutes at a flow rate of 1.5 ml/min; Column: MerckChromolith®FlashRP-183*25mm,3um; Wavelength:UV 220nm,254nm; Column temperature: 50^; MS ionization: ESI. (2) Mobile Phase: 1.5ML/4LTFA in water (solvent A) and 0.75ML/4LTFA in acetonitrile (solvent B), using the elution gradient 10%-80% (solvent B) over 3 minutes and holding at 80%; for 0.5 minutes at a flow rate of 0.8 ml/min; column: Xtimate C182.1*30mm,3um. [0728] The parameters for the LCMS (basic) measurement in the synthesis procedures below are as follows: Mobile Phase: 0.8mL/4L NH3·H2O in water (solvent A) and acetonitrile (solvent B), using the elution gradient 30%-90% (solvent B) over 2 minutes and holding at 90%; for 0.48minutes at a flow rate of 1.2 ml/min; Column: Xbridge Shield RP-18,5um,2.1*50mm; Wavelength:UV 220nm & 254nm ; Column temperature: 50^; MS ionization:ESI. Wavelength:UV 220nm & 254nm; Column temperature: 50^; MS ionization:ESI. List of Abbreviations aq: aqueous Ac: acetyl ACN or MeCN: acetonitrile AmF: ammonium formate anhyd.: anhydrous BINAP: (±)-2,2ƍ-Bis(diphenylphosphino)-1,1ƍ-binaphthalene Bn: Benzyl conc.: concentrated DBU: 1,8-Diazabicyclo[5.4.0]undec-7-ene DCE: Dichloroethane DCM: Dichloromethane DIPEA: Diisopropylamine DMF: N,N-dimethylformamide DMP: Dess-Martin periodinane DMPU: N,Nƍ-Dimethylpropyleneurea DMSO: dimethylsulfoxide DIPEA: diisopropylethylamine EA or EtOAc: ethyl acetate EDCI, EDC, or EDAC: 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide equiv or eq: molar equivalents Et: ethyl HATU: 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyri dinium 3-oxid Hexafluorophosphate HPLC: high pressure liquid chromatography LCMS or LC-MS: liquid chromatography-mass spectrometry Ms: methanesulfonyl NBS: N-bromosuccinimide NMR: nuclear magnetic resonance PE: petroleum ether PMB: p-methoxybenzyl rt or RT: room temperature sat: saturated TBS: tert-butyldimethylsilyl TEA: triethylamine Tf: trifluoromethanesulfonate TFA: trifluoroacetic acid THF: tetrahydrofuran TLC: thin layer chromatography Tol: toluene UV: ultraviolet General Synthetic Scheme 1 Reagents and conditions: (a) Pd(PPh3)2Cl2, DMF, DIEA, CuI, ethynylbenzene, 120 °C; (b) I2, NaHCO ₃ , CH ₃ CN, r.t. overnight; , Pd(dppf)Cl ₂ , Na ₂ CO ₃ , dioxane:H ₂ O = 4:1, 60 °C, 16 h; (d) Pd/C, H ₂ , MeOH, r.t., 16 h, 15 Psi; (e) SFC (enantiomers processed separately after isolation); (f) or (f’) 10% H2SO4, THF, 70 °C, 3 h; (g) or (g’)

H ₂ , 25 °C, 3h; then SFC (enantiomers processed separately after isolation); (g) or (g’) 10% H ₂ SO ₄ ,

Intermediate 1. Preparation of 7-(benzyloxy)-4-(4-bromophenyl)-4-hydroxyisochroman- Step 1: To a solution of a-1 (300 g, 1.49 mol, 1.00 eq) in DMF (1.50 L) was added K ₂ CO ₃ (412 g, 2.98 mol, 2.00 eq) and BnBr (331 g, 1.94 mol, 230 mL, 1.30 eq) at 25 °C. The mixture was heated to 60 °C and stirred at 60 °C for 8 hrs. The combined mixture was diluted with ethyl acetate (1.50 L) and water (6.00 L), separated. The aqueous phase was extracted with ethyl acetate (1.50 L), then the combined organic layers were washed with brine (3.00 L), dried over Na2SO4. The mixture was triturated with Petroleum ether/Ethyl acetate = 30/1 (3.20 L) at 25 °C for 3 hrs. The mixture was filtered and the filter cake was dried under reduce pressure to get a-2 (800 g, 2.75 mol, 92.0% yield) as an off-white solid. 400 MHz, CDCl ₃ į 10.31 (s, 1H), 7.52 (t, J = 9.2 Hz, 2H), 7.45 - 7.30 (m, 5H), 7.20 - 7.05 (m, 1H), 5.10 (s, 2H) Step 2: To a solution of a-2 (160 g, 549 mmol, 1.00 eq) in EtOH (1.60 L) and THF (160 mL) was added NaBH ₄ (13.5 g, 357 mmol, 0.65 eq) in portions at 10 ~ 20 °C over 30 mins. The mixture was warmed to 25 °C and stirred at 25 °C for 1 hr. The mixture was poured into aqueous NH ₄ Cl (4.50 L) slowly over 5 mins in parallel. Two batches reaction mixture were combined and extracted with ethyl acetate (3.00 L * 2). The organic layers were washed with brine (5.00 L), dried over Na ₂ SO ₄ , filtered and concentrated to get a-3 (320 g, 1.09 mol, 99.3% yield) as a white solid. ¹ H NMR: 400 MHz, CDCl ₃ į 7.55 - 7.30 (m, 6H), 7.16 (d, J = 2.8 Hz, 1H), 6.08 (t, J = 3.2 Hz, 1H), 5.06 (s, 2H), 4.70 (s, 2H), 2.10 (s, 1H). Step 3: To a solution of a-3 (210 g, 716 mmol, 1.00 eq) in THF (1.68 mL) was added DIPEA (138 g, 1.07 mol, 187 mL, 1.50 eq) and MOMCl (128 g, 1.59 mol, 120 mL, 2.22 eq) at 25 °C. The mixture was heated to 80 °C and stirred at 80 °C for 12 hrs. Three batches of reaction were processed in parallel. The reaction was cooled to room temperature, diluted with ethyl acetate (500 mL) , adjusted to pH = 7 by saturated NaHCO3 aqueous solution. The mixture was combined and separated, the aqueous phase was extracted with ethyl acetate (1.00 L * 3). The organic layers was combined and washed with brine (2.00 L), dried over anhydrous Na ₂ SO ₄ , and concentrated under reduced pressure. The residue was purified by column chromatography (SiO ₂ , Petroleum ether/Ethyl acetate=1/0 to 0/1, R _f = 0.40, Petroleum ether/Ethyl acetate = 5/1) to get a (1.40 kg, 4.15 mol, 79.6% yield) as a white solid. 400 MHz, CDCl ₃ į 7.50 - 7.35 (m, 6H), 7.17 (d, J = 3.2 Hz, 1H), 6.80 (t, J = 3.2 Hz, 1H), 5.07 (s, 2H), 4.77 (s, 2H), 4.64 (s, 2H), 3.44 (s, 3H) Step 4: To a solution of a (151 g, 447 mmol, 1.15 eq) in THF (750 mL) was added n-BuLi (2.50 M 171 L 110 ) d i t 78 °C d ti d f 30 i Th CAS 20201267 (100 389 mmol, 1.00 eq) in THF (750 mL) was added the mixture dropwise. The reaction was warmed to 25 °C and stirred for 12 hrs. The reaction was quenched by sat.NH4Cl (1.00 L). The mixture was combined, extracted with ethyl acetate (1.00 L * 3), dried with Na ₂ SO ₄ and concentrated. The residue was purified by column chromatography (SiO ₂ , Petroleum ether/Ethyl acetate=1/0 to 0/1, R _f = 0.50, Petroleum ether/Ethyl acetate = 2/1) to give 1 (380 g, 737 mmol, 63.1% yield) as yellow gum. ¹ H NMR: 400 MHz, CDCl ₃ į 7.50 - 7.48 (m, 2H), 7.45 - 7.38 (m, 7H), 7.22 (d, J = 2.8 Hz, 1H), 6.92 - 6.89 (m, 1H), 6.80 - 6.79 (m, 1H), 5.09 (s, 2H), 4.67 - 4.53 (m, 4H), 4.39 - 4.32 (m, 2H), 3.31 (s, 3H), 1.28 (t, J = 7.2 Hz, 3H) Step 5: To a solution of 1 (110 g, 213 mmol, 1.00 eq) in DCM (2.20 L) was added b (93.2 g, 426 mmol, 2.00 eq) and ZnBr ₂ (96.1 g, 426 mmol, 21.3 mL, 2.00 eq) at 0 °C, then warmed to 25 °C and stirred for 2 hrs. TLC (Petroleum ether/Ethyl acetate = 3/1) showed that 1 (R _f = 0.40) was consumed and one major spot (R _f = 0.41) was formed. Three batches of reaction were processed in parallel. The mixture was concentrated and the residue was purified by column chromatography (SiO ₂ , Petroleum ether/Ethyl acetate=1/0 to 0/1, R _f = 0.41, Petroleum ether/Ethyl acetate = 3/1) to get 7-(benzyloxy)-4-(4-bromophenyl)-4-hydroxyisochroman-3-one (475 g, 1.12 mol, 36.7% yield, 90.7% purity) as a light yellow gum. LCMS: RT = 0.355 mins, product: m/z = 407.0 (M-17)- HPLC: product: RT = 1.402 mins, 90.7% purity under 220 nm ¹ H NMR: 400MHz, CDCl3 į 7.80 (d, J = 8.8 Hz, 1H), 7.55 - 7.40 (m, 7H), 7.15 (d, J = 8.4 Hz, 1H), 7.04 (d, J = 8.8 Hz, 2H), 6.84 (s, 1H), 5.15 - 5.05 (m, 3H), 4.91 (d, J = 13.6 Hz, 1H), 4.28 (s, 1H). Intermediate 2. Preparation of 2-(4-(benzyloxy)-2-(((tert- butyldimethylsilyl)oxy)methyl)phenyl)-2-(4-bromophenyl)-N-me thoxy-N-methylacetamide Step 1: To a solution of 1a (100 g, 226 mmol, 1.00 eq) in Tol. (800 mL) was added cyclopentane;dimethyltitanium (0.90 M, 755 mL, 3.00 eq) at 25 °C under N ₂ . The mixture was heated to 80 °C and stirred at 80 °C for 5 hrs. The crude product was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate = 20/1 to 15/1, petroleum ether/ethyl acetate = 5/1, Rf = 0.60). Compound 1 (442 g, 1.01 mol, 63.1% yield) was obtained as yellow oil and confirmed by ¹ H NMR. 400 MHz, CDCl ₃ į 7.46 - 7.42 (m, 2H), 7.41 - 7.40 (m, 4H), 7.40 - 7.39 (m, 1H), 7.17 - 7.11 (m, 4H), 6.94 - 6.91 (m, 1H), 5.75 (s, 1H), 5.23 (s, 1H), 5.11 (s, 2H), 4.55 (s, 2H), 4.33 (s, 2H), 3.28 (s, 3H). Step 2: To a solution of compound 1 (116 g, 264 mmol, 1.00 eq) in THF (1.16 L) was added BH3•Me2S (10.0 M, 52.8 mL, 2.00 eq) at 25 °C under N2. The mixture was heated to 50 °C and stirred at 50 °C for 0.5 hr. Then the mixture was cooled to 0 °C and MeOH (332 mL) was added to mixture slowly and NaOH (2 M, 396 mL, 3.00 eq) was added to mixture, then H ₂ O ₂ (150 g, 1.33 mol, 127 mL, 30% purity, 5.02 eq) was added to mixture slowly. The mixture was warmed to 25 °C and stirred at 25 °C for 2 hrs. The mixture was poured into 10% Na ₂ S ₂ O ₃ aqueous solution (1.16 L) slowly, stirred for 10 mins and separated, four batches of the organic phase was washed water (4.80 L), brine (4.80 L), dried over Na ₂ SO ₄ , filtered, and concentrated. The crude product was purified by column chromatography (SiO ₂ , Petroleum ether/Ethyl acetate = 20/1 to 15/1, Petroleum ether/Ethyl acetate = 2/1, R _f = 0.30). Compound 2 (360 g, 753 mmol, 95.6% purity, 74.5% yield) was obtained as colorless oil and confirmed by LCMS and ¹ H NMR. LCMS: product: RT = 0.999 min, m/z = 481.2 (M+Na) ⁺ . ¹ H NMR: 400 MHz, CDCl3 į 7.44 - 7.39 (m, 7H), 7.21 - 7.19 (m, 1H), 7.11 - 7.06 (m, 3H), 7.02 - 6.95 (m, 1H), 5.06 (s, 2H), 4.67 - 4.64 (m, 3H), 4.48 - 4.42 (m, 2H), 4.14 - 4.09 (m, 2H), 3.39 (s, 3H). Step 3: To a solution of compound 2 (90.0 g, 197 mmol, 1.00 eq) in ACN (990 mL) was cooled to 0 °C and NaClO ₂ (142 g, 1.57 mol, 8.00 eq) in H ₂ O (180 mL) was added to mixture. Then TEMPO (3.71 g, 23.6 mmol, 0.12 eq), Na ₂ HPO ₄ (0.67 M, 294 mL, 1.00 eq) and NaH ₂ PO ₄ (0.67 M, 294 mL, 1.00 eq) were added to mixture at 0 °C. NaOCl (29.3 g, 23.6 mmol, 24.3 mL, 6% purity, 0.12 eq) in H ₂ O (180 mL) was added to mixture at 0 °C. The mixture was warmed to 25 °C and stirred at 25 °C for 0.5 hr. Then the mixture was heated to 35 °C and stirred at 35 °C for 2 hrs. The mixture was poured into saturated Na2SO3 aqueous solution (1.50 L) slowly and stirred for 0.5 hr. Then extracted with ethyl acetate (800 mL * 2), the organic phase was washed with Na ₂ SO ₃ solution (4.00 L), brine (4.00 L), dried over Na ₂ SO ₄ , filtered, and concentrated. Compound 3 (363 g, crude) was obtained as yellow oil. LCMS: product: RT = 0.994 min, m/z = 493.1 (M+Na) ⁺ . Step 4: To a solution of compound 3 (121 g, 257 mmol, 1.00 eq) in DCM (1.45 L) was added ZnBr ₂ (86.7 g, 385 mmol, 19.3 mL, 1.50 eq) and compound c (123 g, 565 mmol, 2.20 eq) at chromatography (SiO2, Petroleum ether/Ethyl acetate = 20/1 to 15/1, Petroleum ether/Ethyl acetate = 3/1, Rf = 0.70). Compound 4 (220 g, 537 mmol, 69.8% yield over two steps) was obtained as off-white solid and confirmed by ¹ H NMR. ¹ H NMR: 400 MHz, CDCl ₃ į 7.49 - 7.39 (m, 7H), 7.07 - 7.05 (m, 2H), 7.05 - 6.99 (m, 2H), 6.91 (s, 1H), 5.19 (s, 2H), 5.10 (s, 2H), 4.89 (s, 1H). Step 5: To a solution of HN (OCH ₃ ) CH ₃ •HCl (39.3 g, 403 mmol, 1.50 eq) in DCM (220 mL) was added AlMe ₃ (2 M, 201 mL, 1.50 eq) at -10 °C and the mixture was stirred at 0 °C for 30 mins. Then compound 4 (110 g, 269 mmol, 1.00 eq) in DCM (440 mL) was added to reaction mixture at -10 °C and stirred at 0 °C for 1 hr. The mixture poured into saturated NH4Cl aqueous solution (1.50 L) and extracted with DCM (500 mL * 2), two batches of the organic phase was washed with brine (1.00 L), dried over Na ₂ SO ₄ , filtered, and concentrated. Compound 5 (240 g, crude) was obtained as off-white solid. Step 6: To a solution of compound 5 (120 g, 255 mmol, 1.00 eq) in DCM (1.20 L) was added TBSCl (57.7 g, 383 mmol, 47.0 mL, 1.50 eq) and imidazole (34.7 g, 510 mmol, 2.00 eq) at 25 °C. The mixture was stirred at 25 °C for 1 hr. TLC (Petroleum ether/Ethyl acetate = 2/1) showed compound 5 (R _f = 0.10) was consumed and a main spot (R _f = 0.60) was formed. The mixture was poured into H ₂ O (1.20 L) and separated, the aqueous phase was extracted with DCM (500 mL). Two batches of the organic phase was washed with brine (1.00 L), dried over Na ₂ SO ₄ , filtered, and concentrated. The crude product was purified by column chromatography (SiO ₂ , Petroleum ether/Ethyl acetate = 20/1 to 15/1, Petroleum ether/Ethyl acetate = 3/1, R _f = 0.50). 2-(4-(benzyloxy)-2-(((tert-butyldimethylsilyl)oxy)methyl)phe nyl)-2-(4-bromophenyl)-N- methoxy-N-methylacetamide (240 g, 401 mmol, 73.0% yield over two steps, 97.8% purity) was obtained as yellow oil and confirmed by HPLC and ¹ H NMR . LCMS: product: RT = 1.284 mins, m/z = 586.2 (M+H) ⁺ . HPLC: product: RT = 4.546 mins, 97.8% purity under 220 nm. ¹ H NMR: 400 MHz, CDCl ₃ į 7.44 - 7.37 (m, 7H), 7.20 - 7.18 (m, 1H), 7.09 - 7.07 (m, 3H), 6.88 - 6.87 (m, 1H), 5.63 (s, 1H), 5.06 (s, 2H), 4.70 - 4.57 (m, 2H), 3.39 (s, 3H), 3.22 (s, 3H), 0.91 (s, 9H), 0.05 - 0.03 (m, 6H). Intermediate 3. Preparation of 3-(1-methyl-6-(piperazin-1-yl)-1H-indazol-3- yl)piperidine-2,6-dione and 3-(1-methyl-7-(piperazin-1-yl)-1H-indazol-3-yl)piperidine-2, 6- dione

Step 1: To a solution of compound 1_1 (40.0 g, 124 mmol, 1.00 eq) in THF (400 mL) was added t-BuOK (41.7 g, 372 mmol, 3.00 eq). The mixture was stirred for 30 mins at 25 ^o C under N ₂ atmosphere. And then MeI (26.4 g, 186 mmol, 1.50 eq) in THF (50.0 mL) was added dropwise. The resulting mixture was stirred at 0 ~ 25 °C for 12 hrs. TLC (Petroleum ether : EtOAc = 10 : 1, compound 1_1 R _f = 0.40, compound 1_2 R _f = 0.60) indicated compound 1_1 was consumed completely, and one new spot was detected. The resultant mixture was diluted with H ₂ O 500 mL and extracted with EtOAc 600 mL (300 mL * 2), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , Petroleum ether : EtOAc = 40 : 1 to 10 : 1) to give compound 1_2 (26.3 g, 98.5% purity, 63.0% yield) was obtained as a yellow solid. LCMS: product RT = 0.463 min, 98.5% purity, m/z = 337.0[M+H] ^{+ 1} H NMR: (400 MHz, DMSO-d6) į 8.02 (d, J=0.63 Hz, 1 H) 7.29 - 7.38 (m, 2 H) 4.05 (s, 3 H) Step 2: To a solution of compound 1_2 (25.0 g, 74.1 mmol, 1.00 eq), compound 1A (29.7 g, 88.9 mmol, 1.20 eq), K ₃ PO ₄ (49.0 g, 231 mmol, 3.00 eq) and Pd(PPh ₃ ) ₄ (8.50 g, 8.20 mmol, 0.10 eq) in dioxane (280 mL) and H ₂ O (30.0 mL) was degassed and purged with N ₂ for 3 times, and then the mixture was stirred at 100 ^o C for 16 hrs under N ₂ atmosphere. TLC (Petroleum ether : EtOAc = 10 : 1, compound 1_2 Rf = 0.60, compound 1_3 Rf = 0.20) indicated compound 1_2 was consumed completely, and one new spot was detected. The resultant mixture was diluted with H ₂ O (200 mL) at 25 ^o C and extracted with EtOAc (300 mL * 2). The combined organic layers were washed with brine 300 mL, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , Petroleum ether : EtOAc = 40 : 1 to 2 : 1) to give compound 1_3 (28.8 g, 57.5 mmol, 68.5% yield) as a yellow solid. LCMS: product RT = 0.678 min, 97.6% purity, m/z = 502.2[M+H] ⁺ Step 3: A mixture of compound 2_3 (28.0 g, 55.9 mmol, 1.00 eq), compound 2A (15.6 g, 83.9 mmol, 1.50 eq), Pd(dba) ₂ (5.13 g, 5.59 mmol, 0.10 eq), RuPhos (2.61 g, 5.59 mmol, 0.10 eq) and t-BuONa (16.1 g, 168 mmol, 3.00 eq) in dioxane (300 mL) was degassed and purged with N ₂ for 3 times, and then the mixture was stirred at 110 °C for 1 hr under N ₂ atmosphere. LCMS (product: RT = 0.661 min) showed compound 1_3 was consumed completely and 56.7% of compound 1_4 was detected. The reaction was concentrated under reduced pressure to remove solvent. The residue was dissolved in H ₂ O 250 mL, washed with EtOAc 700 mL (350 mL*2). The combined organic layers were washed with brine 400 mL, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , Petroleum ether : EtOAc = 40 : 1 to 5 : 1) to give Compound 1_4 (21.2 g, 35.0 mmol, 62.5% yield) as a yellow solid.. LCMS: product RT = 0.661 min, m/z = 606.5 [M+H] ⁺ Step 4: To a solution of compound 1_4 (21.0 g, 34.6 mmol, 1.00 eq) in EtOH (210 mL) was added Pd/C (20.0 g, 18.8 mmol, 10% purity) and Pd(OH)2 (20.0 g, 28.5 mmol, 10% purity) mixture was stirred under H2 (50 Psi) at 50 ^o C for 4 hrs. LCMS product: RT = 0.444 min) showed compound 1_4 was consumed completely and 76.8% of compound 1_5 was detected. The reaction mixture was filtered and concentrated under reduced pressure to remove solvent. The crude product was triturated with EtOAc 15 mL and Petroleum ether 30 mL at 25 ^o C for 30 mins to give Compound 1_5 (7.78 g, 16.6 mmol, 52.7% yield) was obtained as a pink solid. LCMS: product RT = 0.444 min, m/z = 428.4[M+H] ⁺ LCMS: product RT = 0.414 min, m/z = 428.4[M+H] ⁺ Step 5: To a solution of compound 1_5 (7.35 g, 17.2 mmol, 1.00 eq) in dioxane (75.0 mL) was added HCl/dioxane (4 M, 90.0 mL, 17.1 eq). The mixture was stirred at 25 ^o C for 4 hrs. LCMS (product: RT = 0.267 min) showed compound 1_5 was consumed completely and 96.6% of 3-(1- methyl-7-(piperazin-1-yl)-1H-indazol-3-yl)piperidine-2,6-dio ne was detected. The reaction mixture was filtered and concentrated under reduced pressure to give 3-(1-methyl-6-(piperazin- 1-yl)-1H-indazol-3-yl)piperidine-2,6-dione (5.00 g, 15.3 mmol, 94.3% yield) as a white solid. LCMS: product RT = 0.267 min, m/z = 328.2[M+H] ⁺ LCMS: product RT = 0.773 min, m/z = 328[M+H] ⁺ HPLC: product RT = 1.130 mins, 92.7% purity ¹ H NMR: (400 MHz, DMSO-d ₆ ) į 10.86 (s, 1 H) 9.53 (s, 2 H) 7.56 (d, J=8.88 Hz, 1 H) 6.93 - 7.01 (m, 2 H) 4.28 (dd, J=9.38, 5.13 Hz, 1 H) 3.92 (s, 3 H) 3.45 - 3.51 (m, 4 H) 3.23 (s, 4 H) 2.57 - 2.67 (m, 2 H) 2.25 - 2.38 (m, 1 H) 2.11 - 2.20 (m, 1 H). Step 6: To a solution of compound 2_1 (75.0 g, 232 mmol, 1.00 eq) in THF (400 mL) was added t-BuOK (78.2 g, 696 mmol, 3.00 eq). The mixture was stirred for 30 mins at 25 ^o C under N ₂ atmosphere. And then MeI (49.4 g, 349 mmol, 1.50 eq) in THF (50.0 mL) was added dropwise. The resulting mixture was stirred at 25 ^o C for 12 hrs. TLC (Petroleum ether : EtOAc = 10 : 1, compound 2_1 R _f = 0.40, compound 2_2 R _f = 0.60) indicated compound 2_1 was consumed completely, and one new spot was detected. The resultant mixture was diluted with H ₂ O (200 mL) at 0 ^o C and extracted with EtOAc 100 L (500 mL * 2) The combined organic layers were washed with brine 300 mL, dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether : EtOAc = 40 : 1 to 10 : 1) to give compound 2_2 (55.0 g, 163 mmol, 70.3% yield) as a yellow solid. Step 7: To a solution of compound 2_2 (55.0 g, 163 mmol, 1.00 eq), compound 1A (71.7 g, 214 mmol, 1.20 eq), K ₃ PO ₄ (104 g, 490 mmol, 3.00 eq) and Pd(PPh ₃ ) ₄ (18.9 g, 16.3 mmol, 0.10 eq) in dioxane (550 mL) and H ₂ O (55.0 mL) was degassed and purged with N ₂ for 3 times, and then the mixture was stirred at 100 ^o C for 16 hrs under N ₂ atmosphere. TLC (Petroleum ether : EtOAc = 10 : 1, compound 2_2 R _f = 0.60, compound 2_3 R _f = 0.30) indicated compound 2_2 was consumed completely, and one new spot was detected. The resultant mixture was diluted with H ₂ O (200 mL) at 25 ^o C and extracted with EtOAc (300 mL * 2). The combined organic layers were washed with brine 300 mL, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , Petroleum ether : EtOAc = 40 : 1 to 2 : 1) to give compound 2_3 (50.0 g, 99.9 mmol, 61.2% yield) as a yellow solid. Step 8: A mixture of compound 2_3 (24.0 g, 48.0 mmol, 1.00 eq), compound 2A (17.9 g, 95.9 mmol, 2.00 eq), Pd(dba) ₂ (2.76 g, 4.80 mmol, 0.10 eq), RuPhos (2.24 g, 4.80 mmol, 0.1 eq) and t-BuONa (13.8 g, 144 mmol, 3.00 eq) in dioxane (240 mL) was degassed and purged with N ₂ for 3 times, and then the mixture was stirred at 110 °C for 1 hr under N ₂ atmosphere. The reaction was concentrated under reduced pressure to remove solvent. The residue was dissolved in H ₂ O 250 mL, washed with EtOAc 700 mL (350 mL*2). The combined organic layers were washed with brine 400 mL, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , Petroleum ether : EtOAc = 40 : 1 to 5 : 1) to give Compound 2_4 (47.0 g, 77.6 mmol, 80.9% yield) as a yellow solid.. LCMS: RT = 0.627 min, m/z = 606.8 [M+H] ⁺ Step 9: To a solution of compound 2_4 (20.0 g, 33.0 mmol, 1.00 eq) in EtOH (200 mL) was added Pd/C (20.0 g, 18.8 mmol, 10% purity) and Pd(OH) ₂ (20.0 g, 28.5 mmol, 10% purity) under Ar2 atmosphere. The suspension was degassed and purged with H2 for 3 times. The i t ti d d H (50 P i) t 50 ^o C f 4 h Th ti i t filt d d concentrated under reduced pressure to remove solvent. The crude product was triturated with EtOAc 15 mL and Petroleum ether 30 mL at 25 ^o C for 30 mins to give Compound 2_5 (11.5 g, 24.6 mmol, 74.4% yield) was obtained as a white solid. LCMS: RT = 0.455 min, m/z = 428.5 [M+H] ⁺ LCMS: RT = 0.465 min, m/z = 428.5 [M+H] ⁺ Step 10: To a solution of compound 2_5 (9.00 g, 21.1 mmol, 1.00 eq) in dioxane (90 mL) was added HCl/dioxane (4 M, 90.0 mL, 17.1 eq). The mixture was stirred at 25 ^o C for 4 hrs. The reaction mixture was filtered and concentrated under reduced pressure to give 3-(1-methyl-7- (piperazin-1-yl)-1H-indazol-3-yl)piperidine-2,6-dione (6.50 g, 19.9 mmol, 94.3% yield) as a white solid. LCMS: RT = 0.280 min, m/z = 328.1 [M+H] ⁺ LCMS: RT = 0.841 min, m/z = 328.0 [M+H] ⁺ HPLC: RT = 0.757 min, 97.7% purity į 10.89 (s, 1H), 9.61 (s, 1H), 9.52 (s, 1H), 9.71 - 9.39 (m, 1H), 9.19 (s, 1H), 7.47 (d, J = 6.5 Hz, 1H), 7.12 - 7.01 (m, 2H), 4.36 (dd, J = 5.0, 9.8 Hz, 1H), 4.25 (s, 3H), 3.42 - 3.09 (m, 8H), 2.73 - 2.58 (m, 2H), 2.39 - 2.28 (m, 1H), 2.25 - 2.09 (m, 1H).

Intermediate 4. Preparation of 3-(3-methyl-2-oxo-5-(piperazin-1-yl)-2,3-dihydro-1H- benzo[d]imidazol-1-yl)piperidine-2,6-dione and 3-(3-methyl-2-oxo-4-(piperazin-1-yl)-2,3- dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione Step 1: To the solution of compound 3_1 (19.0 g, 76.2 mmol, 1.00 eq.) in DCM (20.0 mL) and MTBE (40.0 mL) was added Tf ₂ O (28.0 g, 99.1 mmol, 16.4 mL, 1.30 eq.) and DIEA (14.8 g, detected compound 3_1 was consumed completed. The reaction material was diluted with H2O (30.0 mL), and extracted with MTBE (40.0 mL), then the combined organic layers were used to next step. HPLC: RT = 1.778 min Step 2: To the solution of compound 3_5 (9.50 g, 41.8 mmol, 1.00 eq.) in THF (95.0 mL) was added t-BuOK (7.51 g, 66.9 mmol, 1.60 eq.) at 0 ^o C, then the mixture was stirred at 25 ^o C for 0.5 hr, then compound 3_2 (25.5 g, 66.9 mmol, 1.60 eq.) was added to the mixture at 0 ^o C and stirred at 25 ^o C for 12 hrs. HPLC detected compound 3_5 was consumed completed. The reaction mixture was filtered and concentrated under reduced pressure to give the compound 3_3 (16.0 g, 34.3 mmol, 81.9% yield, 98.1% purity) was obtained as a yellow solid , which was confirmed by HPLC. HPLC: RT = 1.761 min HPLC: RT = 1.067 min Step 3: To the solution of compound 3_3 (15.0 g, 32.7 mmol, 1.00 eq.) in Tol. (150 mL) was added AlCl ₃ (17.5 g, 131 mmol, 7.15 mL, 4.00 eq.) at 25 ^o C, then the mixture was stirred at 80 ^o C for 2 hrs. TLC (PE: EA = 3: 1) showed the starting material (R _f = 0.63) was consumed and one new spot (R _f = 0.34) was formed. The reaction mixture was quenched by addition 1 M HCl (20.0 mL) at 5 - 10 ^o C, then stirred at 25 ^o C for 0.5 hrs and concentrated under reduced pressure to give the compound 3_a (10.0 g, 27.6 mmol, 84.4% yield, 93.4% purity) as a gray solid, which was confirmed by HPLC . HPLC: RT = 1.767 min Step 4: To the solution of compound 3_a (10.0 g, 29.6 mmol, 1.00 eq.) and compound 2A (8.26 g, 44.4 mmol, 1.50 eq.) in Tol. (50.0 mL) was added LiHMDS (1.00 M, 177 mL, 6.00 eq.) at 25 ^o C under N ₂ , then stirred for 0.5 hrs. [2-(2-aminophenyl)phenyl]-chloro-palladium;dicyclohexyl- [2-(2,6-diisopropoxyphenyl)phenyl]phosphane (2.30 g, 2.96 mmol, 0.10 eq.) and RuPhos (1.38 g, 2.96 mmol, 0.10 eq.) was added to the reaction at 25 ^o C under N ₂ . The mixture was stirred at 80 ^o C for 2 hrs. TLC (DCM: MeOH = 20: 1) showed the starting material (Rf = 0.62) was consumed and one new spot (Rf = 025) was formed The reaction mixture was quenched by addition HCOOH (40.0 mL) at 0 ^o C, and then diluted with H2O (150 mL) and extracted with DCM (100 mL), the organic phase was separated and the water phase was extracted by DCM (100 mL), combined organic phase, washed by brine (100 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give the compound 3_b (9.00 g, 14.5 mmol, 49.1% yield, 71.5% purity) as a brown oil, which was confirmed by HPLC. HPLC: RT = 1.184 min. Step 5: The solution of compound 3_b (9.00 g, 20.3 mmol, 1.00 eq.) in HCl/EtOAc (100 mL) was stirred at 25 ^o C for 1 hr. TLC (DCM: MeOH = 20: 1) showed compound 3_b (R _f = 0.48) was consumed and one new spot was formed (Product R _f = 0.00). The reaction mixture was filtered and concentrated under reduced pressure to give a crude product. The crude product was purified by Pre- HPLC to give the 3-(3-methyl-2-oxo-5-(piperazin-1-yl)-2,3-dihydro-1H- benzo[d]imidazol-1-yl)piperidine-2,6-dione (5.00 g, 14.2 mmol, 70.1% yield, 97.7% purity) as off-white solid, which was confirmed by ¹ H NMR, LCMS and HPLC. LCMS: RT = 0.348 min, Ms+1 = 344.2 HPLC: RT = 0.553 min 400 MHz, DMSO-d ₆ į ppm 7.05 - 6.95 (m, 1H), 6.94 - 6.85 (m, 1H), 6.81 - 6.72 (m, 1H), 5.18 (br dd, J = 5.6, 12.8 Hz, 1H), 3.62 - 3.53 (m, 2H), 3.36 - 3.28 (m, 3H), 3.26 - 3.20 (m, 4H), 3.14 - 3.02 (m, 2H), 2.87 - 2.75 (m, 1H), 2.72 - 2.54 (m, 2H), 2.09 - 1.99 (m, 1H). Step 6: To the solution of compound 4_1 (19.0 g, 76.2 mmol, 1.00 eq.) in DCM (20.0 mL) and MTBE (40.0 mL) was added Tf ₂ O (28.0 g, 99.1 mmol, 16.4 mL, 1.30 eq.) and DIEA (14.8 g, 114 mmol, 19.9 mL, 1.50 eq.) at 0 ^o C, then the mixture was stirred at 25 ^o C for 1 hr. LCMS detected compound 4_1 was consumed completed. The reaction material was diluted with H ₂ O (100 mL), and extracted with MTBE (100 mL*2), then the combined organic layers were used to next step. LCMS: RT = 0.556 min Step 7: To the solution of compound 4_5 (9.50 g, 41.8 mmol, 1.00 eq.) in THF (100 mL) was added t-BuOK (7.51 g, 66.9 mmol, 1.60 eq.) at 0 ^o C, then the mixture was stirred at 25 ^o C for 0.5 hr, then compound 4_2 (25.5 g, 66.9 mmol, 1.60 eq.) was added to the mixture at 0 ^o C and stirred at 25 ^o C for 16 hrs. HPLC detected compound 4_5 was consumed completed. The reaction mixture was filtered and concentrated under reduced pressure to give the compound 4_3 (17.1 g, 35.1 mmol, 83.9% yield, 94.1% purity) was obtained as a gray solid , which was confirmed by HPLC. HPLC: RT = 1.807 min HPLC: RT = 1.067 min Step 8: To the solution of compound 3_3 (17.0 g, 37.1 mmol, 1.00 eq.) in Tol. (340 mL) was added AlCl ₃ (19.8 g, 148 mmol, 8.11 mL, 4.00 eq.) at 25 ^o C, then the mixture was stirred at 80 ^o C for 2 hrs. TLC (PE: EA = 3: 1) showed the starting material (R _f = 0.60) was consumed and one new spot (R _f = 0.30) was formed. The reaction mixture was quenched by addition HCl (400 mL, 1 N) at 5 - 10 °C, then stirred at 25 ^o C for 0.5 hr and concentrated under reduced pressure to give the compound 4_a (9.60 g, 27.1 mmol, 73.0% yield, 95.4% purity) as a gray solid, which was confirmed by HPLC. HPLC: RT = 1.069 min Step 9: To the solution of compound 4_a (9.60 g, 28.4 mmol, 1.00 eq.) and compound 2A (9.52 g, 51.1 mmol, 1.80 eq.) in Tol. (100 mL) was added LiHMDS (1 M, 369 mL, 13.0 eq.) at 0 ^o C under N ₂ , then stirred at 0 ^o C for 30 mins. [2-(2-aminophenyl)phenyl]-chloro-palladium; dicyclohexyl- [2-(2,6-diisopropoxyphenyl) phenyl]phosphane (2.21 g, 2.84 mmol, 0.10 eq.) and RuPhos (1.32 g, 2.84 mmol, 0.1 eq.) was added to the reaction at 25 ^o C under N ₂ . The mixture was stirred at 80 °C for 2 hrs. TLC (DCM: MeOH = 20: 1) showed the starting material (R _f = 0.70) was consumed and one new spot (R _f = 0.30) was formed. The reaction mixture was adjust pH = 5 - 6 by addition HCOOH (40.0 mL) at 0 ^o C, and then diluted with H ₂ O (150 mL) and extracted with DCM (100 mL), the organic phase was separated and the water phase was extracted by DCM (100 mL), combined organic phase, washed by brine (100 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give the compound 4_b (22.1 g, 21.93 mmol, 77.2% yield, 44.6% purity) as a brown oil, which was confirmed by HPLC. HPLC: RT = 1.474 min. Step 10: The solution of compound 4_b (22.1 g, 21.9 mmol, 1.00 eq.) in HCl/EtOAc (300 mL) was stirred at 25 ^o C for 1 hr. TLC (DCM: MeOH = 20: 1) showed compound 4_b (R _f = 0.40) was consumed and one new spot was formed (Product R _f = 0.00). The reaction mixture was filtered and concentrated under reduced pressure to give a crude product. The crude product was purified by reversed-phase HPLC (0.1% HCl condition) to give 3-(3-methyl-2-oxo-4-(piperazin- 1-yl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-di one (5.50 g, 14.2 mmol, 64.8% yield, 98.1% purity, HCl) as white solid, which was confirmed by ¹ H NMR , LCMS and HPLC. (column: Phenomenex luna C18150*40mm* 15um;mobile phase: [water(HCl)- ACN];gradient:22%-52% B over 15 min). LCMS: RT = 0.326 min, Ms+1 = 344.1 HPLC: RT = 0.670 min ¹ H NMR: 400 MHz, DMSO-d6 į ppm 7.07 – 7.03 (m, 1H), 6.98 - 6.92 (m, 2H), 5.26 – 5.22 (m, 1H), 3.59 (s, 3H), 3.30 - 3.14 (m, 6H), 3.10 - 3.06 (m, 2H), 2.82 – 2.79 (m, 1H), 2.66 – 2.50 (m, 2H), 2.02 – 1.97 (m, 1H).

Intermediate 5. Preparation of (4-(benzyloxy)-2-((methoxymethoxy)methyl)phenyl)(4- bromophenyl)methanone Step 1: To a solution of 1-a (150 g, 511 mmol, 1.00 eq) in THF (1.20 L) was added DIEA (99.2 g, 767 mmol, 133 mL, 1.50 eq) and MOMCl (112 g, 1.39 mol, 105 mL, 2.72 eq) at 25 °C. The mixture heated to 80 °C and stirred at 80 °C for 12 hrs. TLC (petroleum ether: ethyl acetate = 10: 1) showed 1-a (R _f = 0.10) was consumed and a new spot (R _f = 0.60) was formed. Three batches were treated in parallel. The reaction was cooled to room temperature, diluted with 700 mL Ethyl acetate , adjusted to pH = 7 by saturated NaHCO ₃ aqueous solution. The mixture was separated, the aqueous phase was extracted with ethyl acetate (1.00 L) * 3. The organic layers was combined and washed with brine (1.00 L), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was purified by column chromatography (SiO2, petroleum ether: ethyl acetate = 30: 1 to 20: 1, petroleum ether: ethyl acetate = 10: 1, R _f = 0.60). Compound 1 (502 g, 1.49 mol, 87.4% yield) was obtained as white solid. ¹ H NMR: 400 MHz, CDCl ₃ į 7.60 - 7.45 (m, 6H), 7.17 - 7.16 (m, 1H), 6.80 - 6.78 (m, 1H), 5.07 (s, 2H), 4.76 (s, 2H), 4.63 (s, 2H), 3.34 (s, 3H). Step 2: To a solution of compound 1 (187 g, 554 mmol, 1.00 eq) in THF (935 mL) was added n- 70 °C for 0.5 hr. Then compound a (123 g, 665 mmol, 1.20 eq) in THF (374 mL) was added to mixture slowly at -70 °C and stirred at -70 - -60 °C for 2.5 hrs. TLC (Petroleum ether: Ethyl acetate = 5: 1) showed compound 1 (R _f = 0.70) was consumed and a main spot (R _f = 0.30) was formed. Two batches reaction were carried out in parallel. The mixture was poured into saturated NH ₄ Cl aqueous solution (3.00 L). The mixture was extracted with Ethyl acetate (1.50 L * 3). The combined organic phase washed with brine (1.50 L), dried over Na ₂ SO ₄ , filtered, and concentrated. The crude product was purified by column chromatography (SiO ₂ , Petroleum ether: Ethyl acetate = 10: 1 to 5: 1, petroleum ether: ethyl acetate = 5: 1, R _f = 0.30). Compound 2 (296 g, 667 mmol, 65.0% yield) was obtained as colorless oil and confirmed by ¹ H NMR. ¹ H NMR: 400 MHz, CDCl ₃ į 7.48 - 7.39 (m, 7H), 7.27 - 7.25 (m, 2H), 7.11 (d, J = 8.0 Hz, 1H), 7.02 (d, J = 2.8 Hz, 1H), 6.90 - 6.88 (m, 1H), 5.99 (d, J = 2.4 Hz, 1H), 5.07 (s, 2H), 4.69 - 4.65 (m, 3H), 4.48 (d, J = 12.0 Hz, 1H), 3.37 (s, 3H). Step 3: To a solution of compound 2 (190 g, 428 mmol, 1.00 eq) in DCM (1330 mL) was added 4A MS (190 g), NMO (75.3 g, 642 mmol, 67.8 mL, 1.50 eq) and TPAP (15.0 g, 42.8 mmol, 0.100 eq) at 25 °C. The mixture was stirred at 25 °C for 0.5 hr. TLC (petroleum ether: ethyl acetate = 5: 1) showed compound 2 (R _f = 0.30) was consumed and a main new spot (R _f = 0.60) was formed. The reaction was poured into 2.50 L of 10% Na ₂ S ₂ O ₃ aqueous solution. This mixture was stirred for about 15 mins at 25 °C, and then the entire mixture was filtered through a thin pad of celite to remove ruthenium solids and the sieves. The layers were then separated, the organic phase was washed with brine, dried over Na ₂ SO ₄ , filtered, and concentrated. The crude product was triturated with petroleum ether: ethyl acetate = 10: 1 (1.20 L) at 25 °C for 2 hrs. Filtrated and the filter cake was concentrated to give product 1 (175 g, 396 mmol, 90.5% yield) as a white solid. Special LCMS: Product Rt = 2.331min (ELSD), (m/z) = 441.0 (M+H) ⁺ HPLC: product: RT = 3.915 mins, 97.0% purity under 220 nm. 400 MHz, CDCl ₃ 2H), 4.80 (s, 2H), 4.63 (s, 2H), 3.33 (s, 3H). Intermediate 6. Preparation of 1-(4-bromo-2-methylphenyl)dihydropyrimidine- 2,4(1H,3H)-dione Step 1: To the stirred solution of compound 1 (20.0 g, 108 mmol, 1.00 eq) in Tol. (200 mL) was added compound a (15.5 g, 215 mmol, 14.7 mL, 2.00 eq) at 20 °C. The mixture was heated to 90 °C and stirred at 90 °C for 12 hrs under N ₂ . LCMS showed that compound 1 was consumed and desired MS (RT = 0.520 min) was detected. The reaction mixture was concentrated directly to give compound 2 (32.0 g, crude) as brown gum. LCMS: product: RT = 0.520 min, m/z = 332.1 (M+H) ⁺ Step 2: A mixture of compound 2 (32.0 g, 96.9 mmol, 1.00 eq) and compound b (8.73 g, 145 mmol, 7.82 mL, 1.50 eq) in AcOH (160 mL) was stirred at 120 °C for 12 hrs. LCMS showed compound 2 was consumed and desired MS (RT = 0.482 min) was detected. The reaction mixture was cooled down to 20 °C and concentrated directly. The residue was adjusted to pH = 8 ~ 9 with Na ₂ CO ₃ and extracted with ethyl acetate (500 mL * 2). The combined organic phases were washed with brine (500 mL), dried over Na ₂ SO ₄ , concentrated under vacuum. The crude product was triturated with ethyl acetate (100 mL, 5.00 V) at 20 °C for 30 mins to give 1-(4- bromo-2-methylphenyl)dihydropyrimidine-2,4(1H,3H)-dione (15.0 g, 51.3 mmol, 49.2% yield over two steps, 96.9% purity) as off-white solid. LCMS: product: RT = 0.482 min, m/z = 283.1 (M+H) ⁺ MS: m/z = 283.1 (M+H) ⁺ HPLC: product: RT = 2.305 mins, 96.9% purity under 220 nm 400 MHz, DMSO_d6 į 10.4 (s, 1H), 7.52 (d, J = 1.6 Hz, 1H), 7.44 (dd, J = 2.0 Hz, 2.0 Hz, 1H), 7.24 (d, J = 8.8 Hz, 1H), 3.81 - 3.74 (m, 1H), 3.52 - 3.46 (m, 1H), 2.2.78 - 2.50 (m, 2H), 2.18 (s, 3H). Intermediate 7. Preparation of 1-(1-methyl-6-(piperazin-1-yl)-1H-indazol-3- yl)dihydropyrimidine-2,4(1H,3H)-dione Step 1: To the stirred solution of compound 1 (50.0 g, 221 mmol, 1.00 eq) in HCl (2 M, 500 mL, 4.52 eq) (2 M aqueous solution) was added TBAB (7.13 g, 22.1 mmol, 0.10 eq) at 20 °C. The reaction mixture was heated to 50 °C (internal temperature), and compound a (23.9 g, 332 mmol, 22.8 mL, 1.50 eq) was added dropwise. The reaction was then heated to 100 °C (external) for 12 hrs. After the reaction was complete, the reaction mixture was cooled to 20 °C and diluted with ice-cold water (2.00 L). It was neutralized to pH 6.5 to 7 with 2 M NaHCO ₃ solution (2.00 L) with good stirring. The solid precipitation was filtered-off, washed with excess ice-cold water (500 mL), and dried under reduced pressure to give compound 2 (45.0 g, crude) as a yellow solid. LCMS: product: Rt = 0.468 min, m/z = 299.7 (M+H) ⁺ HPLC: product: Rt = 1.591 mins, 81.4% purity under 220 nm ¹ -d ₆ ) į 7.64 - 7.61 (m, 2H), 6.99 - 7.02 (m, 1H), 3.74 (s, 3H), 3.45 - 3.42 (m, 2H), 2.56 - 2.60 (m, 2H) Step 2: To a solution of compound 2 (10.0 g, 33.5 mmol, 1.00 eq) in HOAc (100 mL) was added compound b (4.36 g, 67.1 mmol, 2.00 eq). The mixture was stirred at 60 °C for 14 hrs. Then HCl (2 M, 100 mL, 5.96 eq) (aqueous solution) was added, and the mixture was stirred at 60 °C for another 3 hrs. The reaction mixture was cooled to 20 °C. A white solid was precipitated, which was filtered and washed with water (100 mL) to give compound 3 (11.7 g, crude) as a white solid. LCMS: Rt = 0.414 min, , m/z = 342.8 (M+NH ₄ ) ^{+ 1} H NMR: (400 MHz, DMSO-d ₆ ) į 10.6 (s, 1H), 7.97 (d, J = 1.0 Hz, 1H), 7.62 (d, J = 8.8 Hz, 1H), 7.25 (dd, J = 8.6, 1.6 Hz, 1H), 3.98 (s, 3H), 3.93 (t, J = 6.6 Hz, 2H), 2.76 (t, J = 6.6 Hz, 2H) Step 3: Three batches of reaction were carried out in parallel. To a stirred solution of compound 3 (4.00 g, 12.4 mmol, 1.00 eq) and compound c (3.23 g, 17.3 mmol, 1.40 eq) in dioxane (80.0 mL) was degassed with nitrogen for 3 mins. t-BuONa (3.27 g, 34.0 mmol, 2.75 eq) and bis(tri-t-BuP)Pd (316 mg, 619 ^mol, 0.05 eq) was added to the reaction mixture at 20 °C and further degassed with nitrogen for 3 mins. The reaction vial was heated at 100 °C for 2 hrs under N ₂ . Three batches were combined to work up. The reaction mixture was concentrated under vacuum at 45 °C. The residue was purified by silica gel chromatography (Petroleum ether/Ethyl acetate = 1/1 to 0/1, Petroleum ether/Ethyl acetate = 0/1, R _f = 0.20). The fraction was concentrated under vacuum to give compound 4 (8.60 g, 18.0 mmol, 48.4% yield) ll lid LCMS: Rt = 0.479 min, m/z = 429.2 (M+H) ^{+ 1} -d ₆ ) į 10.5 (s, 1H), 7.48 (d, J = 9.0 Hz, 1H), 6.97 - 6.85 (m, 2H), 3.93 - 3.86 (m, 5H), 3.53 - 3.44 (m, 4H), 3.22 - 3.14 (m, 4H), 2.73 (t, J = 6.6 Hz, 2H), 1.43 (s, 9H) Step 4: To a stirred solution of compound 4 (7.70 g, 18.0 mmol, 1.00 eq) in DCM (140 mL) was added TFA (30.7 g, 270 mmol, 20.0 mL, 15.0 eq) at 25 °C. The mixture was stirred at 25 °C for 2 hrs. The reaction mixture was concentrated under vacuum at 45 °C. The residue was purified by prep-HPLC (TFA condition: column: Phenomenex luna c18250 mm*100mm*10um; mobile phase: [water (TFA) - ACN]; gradient: 0%-30% B over 20 mins). The eluent was concentrated in vacuum to remove acetonitrile and H ₂ O, the residual aqueous was lyophilized to give 1-(1- methyl-6-(piperazin-1-yl)-1H-indazol-3-yl)dihydropyrimidine- 2,4(1H,3H)-dione (7.32 g, 16.5 mmol, 91.9% yield, 99.8% purity, TFA) as an off-white solid. LCMS: Rt = 0.663 min, m/z = 329.2 (M+H) ⁺ HPLC: Rt = 1.331 mins, 99.8% purity under 220 nm ¹ H NMR: (400 MHz, DMSO-d ₆ ) į 10.5 (s, 1H), 8.80 (d, J = 1.2 Hz, 2H), 7.66 - 7.44 (m, 1H), 7.05 - 6.85 (m, 2H), 3.93 - 3.87 (m, 5H), 3.48 - 3.39 (m, 4H), 3.28 (s, 4H), 2.74 (t, J = 6.6 Hz, 2H) ¹⁹ F NMR: (400 MHz, DMSO-d ₆ ) į -74.06.

Synthesis of isochromanes from Weinreb amides General scheme: Grignard addition Intermediate 8.2-(4-(benzyloxy)-2-(((tert-butyldimethylsilyl)oxy)methyl)p henyl)-2-(4- bromophenyl)-1-(4-fluorophenyl)ethan-1-one. To a solution of 2-(4-(benzyloxy)-2-(((tert-butyldimethylsilyl)oxy)methyl)phe nyl)-2-(4- bromophenyl)-N-methoxy-N-methylacetamide (500 mg, 1 Eq, 855 ^mol) in THF (5 mL) was added 4-Fluorophenylmagnesium bromide, 1M in diethyl ether (511 mg, 2.57 mL, 1 molar, 3 Eq, 2.57 mmol) at room temperature and the reaction mixture was allowed to stir at this temperature for 18 hours. The reaction mixture was quenched with ammonium chloride and extracted with ethyl acetate. The organic layer was separated, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography, 24 g column, eluted with 0-50 % ethyl acetate in heptane. The selected fractions were combined and concentrated in vacuo to give 2-(4-(benzyloxy)-2-(((tert-butyldimethylsilyl)oxy)methyl)phe nyl)- 2-(4-bromophenyl)-1-(4-fluorophenyl)ethan-1-one (400 mg, 646 ^mol, 75.5 %) as a colorless oil whose provisionally interpreted spectra are consistent with the assigned structure.1H NMR (500 MHz, CDCl3) į 8.09 – 8.01 (m, 2H), 7.46 – 7.32 (m, 7H), 7.07 – 6.94 (m, 6H), 6.81 (dd, J = 8.5, 2.8 Hz, 1H), 6.31 (s, 1H), 5.02 (s, 2H), 4.70 (d, J = 12.2 Hz, 1H), 4.45 (d, J = 12.2 Hz, 1H), 0.92 (s 9H) 008 (d J = 44 Hz 6H) Intermediate 9.2-(4-(benzyloxy)-2-(((tert-butyldimethylsilyl)oxy)methyl)p henyl)-1-(4- (benzyloxy)phenyl)-2-(4-bromophenyl)ethan-1-one ¹ H NMR (400 MHz, CDCl ₃ ) į 8.06 – 7.91 (m, 2H), 7.58 – 7.30 (m, 12H), 7.12 – 6.97 (m, 4H), 6.97 – 6.85 (m, 2H), 6.81 (dd, J = 8.5, 2.8 Hz, 1H), 6.27 (s, 1H), 5.09 (s, 2H), 5.02 (s, 2H), 4.69 (d, J = 12.3 Hz, 1H), 4.46 (d, J = 12.3 Hz, 1H), 0.91 (s, 9H), 0.07 (d, J = 3.4 Hz, 6H). Intermediate 10.2-(4-(benzyloxy)-2-(((tert-butyldimethylsilyl)oxy)methyl) phenyl)-2-(4- bromophenyl)-1-(5-fluoro-2-methylphenyl)ethan-1-one ¹ H NMR (400 MHz, CDCl ₃ ) į 7.49 – 7.28 (m, 8H), 7.17 (dd, J = 8.5, 5.6 Hz, 1H), 7.08 – 6.98 (m, 5H), 6.84 (dd, J = 8.5, 2.8 Hz, 1H), 6.18 (s, 1H), 5.04 (s, 2H), 4.63 (d, J = 12.6 Hz, 1H), 4.49 (d, J = 12.6 Hz, 1H), 2.45 (s, 3H), 0.89 (s, 9H), 0.04 (s, 6H).

Intermediate 11.2-(4-(benzyloxy)-2-(((tert-butyldimethylsilyl)oxy)methyl) phenyl)-2-(4- bromophenyl)-1-(3-fluoro-4-methylphenyl)ethan-1-one ¹ H NMR (400 MHz, CDCl ₃ ) į 7.73 – 7.61 (m, 2H), 7.47 – 7.28 (m, 7H), 7.17 (td, J = 7.7, 0.9 Hz, 1H), 7.04 – 6.92 (m, 4H), 6.81 (dd, J = 8.6, 2.8 Hz, 1H), 6.28 (s, 1H), 5.02 (s, 2H), 4.69 (d, J = 12.3 Hz, 1H), 4.46 (d, J = 12.3 Hz, 1H), 2.29 (d, J = 1.9 Hz, 3H), 0.92 (s, 9H), 0.08 (d, J = 2.4 Hz, 6H). Intermediate 12.2-(4-(benzyloxy)-2-(((tert-butyldimethylsilyl)oxy)methyl) phenyl)-2-(4- bromophenyl)-1-(3-fluoro-5-methylphenyl)ethan-1-one ¹ H NMR (400 MHz, CDCl ₃ ) į 7.56 (s, 1H), 7.51 – 7.28 (m, 8H), 7.01 (dt, J = 6.1, 3.4 Hz, 4H), 6.94 (d, J = 8.5 Hz, 1H), 6.82 (dd, J = 8.5, 2.8 Hz, 1H), 6.26 (s, 1H), 5.03 (s, 2H), 4.68 (d, J = 12.4 Hz, 1H), 4.48 (d, J = 12.5 Hz, 1H), 2.35 (s, 3H), 0.91 (s, 9H), 0.06 (d, J = 1.7 Hz, 6H). Intermediate 13.2-(4-(benzyloxy)-2-(((tert-butyldimethylsilyl)oxy)methyl) phenyl)-2-(4- bromophenyl)-1-(4-fluoro-3-methylphenyl)ethan-1-one ¹ H NMR (400 MHz, CDCl ₃ ) į 7.89 – 7.80 (m, 2H), 7.46 – 7.31 (m, 7H), 7.04 – 6.90 (m, 5H), 6.81 (dd, J = 8.5, 2.8 Hz, 1H), 6.28 (s, 1H), 5.02 (s, 2H), 4.68 (d, J = 12.3 Hz, 1H), 4.46 (d, J = 12.4 Hz, 1H), 2.26 (d, J = 1.9 Hz, 3H), 0.91 (s, 9H), 0.06 (d, J = 2.0 Hz, 6H). Intermediate 14.2-(4-(benzyloxy)-2-(((tert-butyldimethylsilyl)oxy)methyl) phenyl)-2-(4- bromophenyl)-1-(4-fluoro-2-methylphenyl)ethan-1-one ¹ H NMR (400 MHz, CDCl ₃ ) į 7.84 (dd, J = 8.7, 5.8 Hz, 1H), 7.48 – 7.28 (m, 7H), 7.06 – 6.97 (m, 4H), 6.92 (ddd, J = 9.7, 2.7, 0.8 Hz, 1H), 6.88 – 6.76 (m, 2H), 6.22 (s, 1H), 5.03 (s, 2H), 4.63 (d, J = 12.4 Hz, 1H), 4.46 (d, J = 12.5 Hz, 1H), 2.54 (s, 3H), 0.90 (s, 9H), 0.05 (d, J = 1.1 Hz, 6H). Intermediate 15.2-(4-(benzyloxy)-2-(((tert-butyldimethylsilyl)oxy)methyl) phenyl)-2-(4- bromophenyl)-1-(3-fluoro-2-methylphenyl)ethan-1-one ¹ H NMR (400 MHz, CDCl ₃ ) į 7.56 – 7.47 (m, 1H), 7.47 – 7.29 (m, 7H), 7.17 – 6.97 (m, 6H), 6.85 (dd, J = 8.5, 2.8 Hz, 1H), 6.17 (s, 1H), 5.03 (s, 2H), 4.61 (d, J = 12.6 Hz, 1H), 4.48 (d, J = 12.6 Hz, 1H), 2.35 (d, J = 2.4 Hz, 3H), 0.88 (s, 9H), 0.02 (s, 6H). Intramolecular reductive etherification of TBS-ethers Intermediate 16. Cis-7-(benzyloxy)-4-(4-bromophenyl)-3-(4-fluorophenyl)isochr omane To a solution of 2-(4-(benzyloxy)-2-(((tert-butyldimethylsilyl)oxy)methyl)phe nyl)-2-(4- bromophenyl)-1-(4-fluorophenyl)ethan-1-one (398 mg, 1 Eq, 642 ^mol) in DCM (3 mL) was added triethylsilane (112 mg, 154 ^L, 1.5 Eq, 963 ^mol), the resulting mixture was cooled at - 78 °C and TMS-OTf (214 mg, 174 ^L, 1.5 Eq, 963 ^mol) was added, and the resulting mixture was allowed to stir for 30 min at this temperature a period during which the reaction was judged complete by LCMS. The reaction mixture was quenched with sodium bicarbonate, diluted with DCM and the resulting mixture stirred vigorously for 5 minutes. The organic layer was separated through a phase separator and concentrated in vacuo. The residue was purified by silica gel chromatography, 24 g column, eluted with Ea in Hpt, 0-40%. The selected fractions (4-fluorophenyl)isochromane as a colorless oil whose provisionally interpreted spectra are consistent with the assigned structure. ¹ H NMR (500 MHz, CDCl3) į 7.49 – 7.37 (m, 4H), 7.37 – 7.31 (m, 1H), 7.19 – 7.09 (m, 2H), 6.96 – 6.74 (m, 7H), 6.64 – 6.57 (m, 2H), 5.16 (d, J = 15.3 Hz, 1H), 5.05 (dd, J = 15.1, 3.3 Hz, 4H), 4.00 (d, J = 3.3 Hz, 1H). Intermediate 17.7-(benzyloxy)-4-(4-bromophenyl)-3-(3-fluoro-5-methylpheny l)isochromane ¹ H NMR (500 MHz, CDCl ₃ ) į 7.47 – 7.30 (m, 5H), 7.18 – 7.14 (m, 2H), 6.93 (d, J = 8.5 Hz, 1H), 6.82 (dd, J = 8.5, 2.6 Hz, 1H), 6.75 (d, J = 2.6 Hz, 1H), 6.68 – 6.60 (m, 3H), 6.57 (td, J = 1.5, 0.7 Hz, 1H), 6.51 (dd, J = 9.7, 2.1 Hz, 1H), 5.16 (d, J = 15.3 Hz, 1H), 5.10 – 4.98 (m, 4H), 4.02 (d, J = 3.3 Hz, 1H), 2.22 (s, 3H). General scheme Intermediate 18.7-(benzyloxy)-4-(4-bromophenyl)-3-(4-fluoro-2-methylpheny l)isochromane ¹ H NMR (500 MHz, CDCl3) į 7.49 – 7.28 (m, 6H), 7.17 – 7.11 (m, 2H), 6.82 (td, J = 9.6, 2.6 Hz, 2H), 6.77 (d, J = 2.6 Hz, 1H), 6.62 – 6.49 (m, 4H), 5.20 – 5.02 (m, 5H), 4.03 (d, J = 3.2 Hz, 1H), 2.38 (s, 3H). Intermediate 19.7-(benzyloxy)-4-(4-bromophenyl)-3-(3-fluoro-2-methylpheny l)isochromane ¹ H NMR (500 MHz, CDCl ₃ ) į 7.48 – 7.31 (m, 5H), 7.16 – 7.09 (m, 2H), 6.93 (d, J = 8.5 Hz, 1H), 6.86 – 6.79 (m, 3H), 6.77 (d, J = 2.6 Hz, 1H), 6.56 – 6.51 (m, 2H), 6.50 – 6.43 (m, 1H), 5.20 – 5.12 (m, 2H), 5.12 – 5.03 (m, 3H), 4.05 (d, J = 3.2 Hz, 1H), 2.29 (d, J = 2.1 Hz, 3H). Intermediate 20.7-(benzyloxy)-4-(4-bromophenyl)-3-(5-fluoro-2-methylpheny l)isochromane ¹ H NMR (400 MHz, CDCl ₃ ) į 7.56 – 7.32 (m, 5H), 7.22 – 7.11 (m, 2H), 7.05 (dd, J = 8.4, 5.7 Hz, 1H), 6.93 (d, J = 8.5 Hz, 1H), 6.89 – 6.65 (m, 3H), 6.58 – 6.50 (m, 2H), 6.42 (dd, J = 10.4, 2.9 Hz, 1H), 5.19 (s, 1H), 5.14 – 5.00 (m, 4H), 4.08 (d, J = 3.2 Hz, 1H), 2.36 (s, 3H).

Intermediate 21.7-(benzyloxy)-3-(4-(benzyloxy)phenyl)-4-(4-bromophenyl)is ochromane ¹ H NMR (400 MHz, CDCl ₃ ) į 7.51 – 7.28 (m, 11H), 7.22 – 6.55 (m, 10H), 5.23 – 4.87 (m, 6H), 4.53 (d, J = 9.6 Hz, 1H), 4.16 (d, J = 9.5 Hz, 1H). Intermediate 22.7-(benzyloxy)-4-(4-bromophenyl)-3-(3-fluoro-4-methylpheny l)isochromane ¹ H NMR (400 MHz, CDCl ₃ ) į 7.47 – 7.28 (m, 5H), 7.20 – 7.12 (m, 2H), 7.02 – 6.89 (m, 2H), 6.82 (dd, J = 8.5, 2.7 Hz, 1H), 6.75 (d, J = 2.6 Hz, 1H), 6.70 – 6.57 (m, 4H), 5.15 (d, J = 15.3 Hz, 1H), 5.06 (d, J = 2.0 Hz, 2H), 5.04 – 4.97 (m, 2H), 4.02 (d, J = 3.3 Hz, 1H), 2.19 (d, J = 1.9 Hz, 3H). Intermediate 23.7-(benzyloxy)-4-(4-bromophenyl)-3-(4-fluoro-3-methylpheny l)isochromane ¹ H NMR (500 MHz, CDCl3) į 7.46 – 7.31 (m, 5H), 7.24 – 7.13 (m, 2H), 6.92 (d, J = 8.5 Hz, 1H), 6.84 – 6.71 (m, 5H), 6.63 – 6.58 (m, 2H), 5.15 (d, J = 15.3 Hz, 1H), 5.11 – 4.96 (m, 4H), 3.98 (d, J = 3.3 Hz, 1H), 2.13 (d, J = 1.9 Hz, 3H). Intermediate 24.7-(benzyloxy)-4-(4-bromophenyl)-3-(3-fluoro-2-methylpheny l)isochromane ¹ H NMR (500 MHz, CDCl ₃ ) į 7.48 – 7.31 (m, 5H), 7.16 – 7.09 (m, 2H), 6.93 (d, J = 8.5 Hz, 1H), 6.86 – 6.79 (m, 3H), 6.77 (d, J = 2.6 Hz, 1H), 6.56 – 6.51 (m, 2H), 6.50 – 6.43 (m, 1H), 5.20 – 5.12 (m, 2H), 5.12 – 5.03 (m, 3H), 4.05 (d, J = 3.2 Hz, 1H), 2.29 (d, J = 2.1 Hz, 3H). Synthesis of isochromanes from D-hydroxylactone Grignard addition into D-hydroxylactone Intermediate 25.2-(4-(benzyloxy)-2-(hydroxymethyl)phenyl)-2-(4-bromopheny l)-1-cyclohexyl- 2-hydroxyethan-1-one To a solution of 7-(benzyloxy)-4-(4-bromophenyl)-4-hydroxyisochroman-3-one (220 mg, 1 Eq, 517 ^mol) in THF (2 mL) cooled at 0 °C, on an ice bath, was added Cyclohexylmagnesium chloride solution in THF (296 mg, 2.07 mL, 1 molar, 4 Eq, 2.07 mmol) and the resulting mixture was allowed to warm up to room temperature and stirred 3 hours, at this time TLC, 30 % Ea in Hptn, indicated about 50 % conversion. More Cyclohexylmagnesium chloride solution in THF for 12 hours. At this time the reaction was judged complete by TLC (7:3, Hptn/Ea). The mixture was cooled on ice, and quenched with ammonium chloride, and extracted with Ea. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography, 12 g column, eluted with 0-30 % ethyl acetate in heptane. The selected fractions were combined and concentrated in vacuo to give 2-(4-(benzyloxy)-2- (hydroxymethyl)phenyl)-2-(4-bromophenyl)-1-cyclohexyl-2-hydr oxyethan-1-one (192 mg, 377 ^mol, 72.9 %) as a colorless oil whose provisionally interpreted spectra are consistent with the assigned structure. 1H NMR (500 MHz, CDCl3) į 7.46 – 7.35 (m, 8H), 7.34 – 7.30 (m, 1H), 7.23 (d, J = 8.7 Hz, 1H), 6.81 (dd, J = 8.7, 2.6 Hz, 1H), 6.60 (d, J = 2.6 Hz, 1H), 5.08 (d, J = 15.3 Hz, 1H), 5.01 (d, J = 3.1 Hz, 2H), 4.79 (d, J = 15.4 Hz, 1H), 3.10 (s, 1H), 2.78 (s, 1H), 2.22 (d, J = 12.8 Hz, 1H), 1.91 (d, J = 12.7 Hz, 1H), 1.71 (d, J = 7.8 Hz, 1H), 1.64 (d, J = 12.8 Hz, 1H), 1.57 (d, J = 7.8 Hz, 1H), 1.32 (tt, J = 12.0, 3.0 Hz, 1H), 1.10-0.85 (m, 5H). Intermediate 26. 2-(4-(benzyloxy)-2-(hydroxymethyl)phenyl)-2-(4-bromophenyl)- 2-hydroxy-1- (2-isopropylphenyl)ethan-1-one ¹ H NMR (400 MHz, CDCl ₃ ) į 7.48 – 7.32 (m, 9H), 7.14 – 7.03 (m, 4H), 6.91 (dd, J = 8.8, 3.0 Hz, 1H), 6.74 – 6.70 (m, 2H), 5.26 (d, J = 15.4 Hz, 1H), 5.08 (s, 2H), 5.00 (d, J = 15.4 Hz, 1H), 3.32 (s, 1H), 3.23 (s, 1H), 3.13 (s, 1H), 1.13 (d, J = 6.7 Hz, 3H), 0.65 (d, J = 6.9 Hz, 3H).

Intramolecular reductive etherification & dehydroxylation Intermediate 27.7-(benzyloxy)-4-(4-bromophenyl)-3-cyclohexylisochromane A mixture of 2-(4-(benzyloxy)-2-(hydroxymethyl)phenyl)-2-(4-bromophenyl)- 1-cyclohexyl-2- hydroxyethan-1-one (192 mg, 1 Eq, 377 ^mol) and triethylsilane (219 mg, 301 ^L, 5 Eq, 1.88 mmol) in DCM (2 mL) was cooled on ice and triethylsilane (219 mg, 301 ^L, 5 Eq, 1.88 mmol) was added and the resulting mixture allowed to warm up to room temperature and stirred for 18 hours, a period during which the starting material was fully consumed to form a new slightly more polar compound as judged by TLC (7:3, Hptn/Ea). The reaction mixture was quenched with sodium bicarbonate, and extracted with DCM. The organic layer was separated through a phase separator and concentrated in vacuo. The residue was purified by silica gel chromatography, 12 g column, eluted with 0-30 % ethyl acetate in heptane to give 7-(benzyloxy)-4-(4-bromophenyl)-3-cyclohexylisochromane (145 mg, 304 ^mol, 80.6 %) as a white solid whose provisionally interpreted spectra are consistent with the assigned structure.1H NMR (500 MHz, CDCl3) į 7.45 – 7.29 (m, 7H), 7.20 – 7.15 (m, 2H), 6.89 (d, J = 8.5 Hz, 1H), 6.76 – 6.69 (m, 1H), 6.64 (dd, J = 13.0, 3.1 Hz, 1H), 5.10 – 4.95 (m, 3H), 4.87 – 4.78 (m, 1H), 3.86 (d, J = 2.9 Hz, 1H), 3.51 – 3.41 (m, 1H), 2.12 – 2.00 (m, 1H), 1.82 (d, J = 12.5 Hz, 1H), 1.72 – 1.57 (m, 3H), 1.18 – 1.00 (m, 4H), 0.93 (dt, J = 24.6, 12.8 Hz, 2H).

Intermediate 28.7-(benzyloxy)-4-(4-bromophenyl)-3-(2-isopropylphenyl)isoc hromane ¹ H NMR (500 MHz, CDCl ₃ ) į 7.48 – 7.33 (m, 6H), 7.13 (dq, J = 7.9, 2.0 Hz, 3H), 6.94 (d, J = 8.5 Hz, 1H), 6.85 – 6.81 (m, 2H), 6.78 (d, J = 2.7 Hz, 1H), 6.59 (dd, J = 7.9, 1.4 Hz, 1H), 6.55 – 6.50 (m, 2H), 5.33 – 5.25 (m, 1H), 5.18 (d, J = 15.3 Hz, 1H), 5.11 – 5.04 (m, 3H), 4.01 (d, J = 3.1 Hz, 1H), 3.18 (p, J = 6.9 Hz, 1H), 1.40 (d, J = 6.8 Hz, 3H), 1.22 (d, J = 6.8 Hz, 3H). Intermediate 29.7-(benzyloxy)-4-(4-bromophenyl)-3-(4-fluoro-3-methylpheny l)isochromane ¹ H NMR (500 MHz, CDCl ₃ ) į 7.48 – 7.28 (m, 9H), 7.21 – 7.06 (m, 6H), 6.97 – 6.58 (m, 12H), 6.49 – 6.39 (m, 2H), 5.20 – 5.11 (m, 2H), 5.08 – 5.01 (m, 5H), 4.02 (d, J = 3.3 Hz, 1H), 3.60 (s, 3H).

Buchwald amination Intermediate 30.1-(4-(7-(benzyloxy)-3-(4-fluorophenyl)isochroman-4-yl)phe nyl)-4- (dimethoxymethyl)piperidine A mixture of (3S,4R)-7-(benzyloxy)-4-(4-bromophenyl)-3-(4-fluorophenyl)is ochromane (277 mg, 1 Eq, 566 ^mol), x-phos (54.0 mg, 0.2 Eq, 113 ^mol), PdOAc2 (19.1 mg, 0.15 Eq, 84.9 ^mol), 4-(dimethoxymethyl)piperidine (135 mg, 1.5 Eq, 849 ^mol), and NaOtBu (81.6 mg, 1.5 Eq, 849 ^mol) in Toluene (3 mL) was heated to 90 °C for 16 hours, a period during which the desired product was observed by LCMS. The reaction mixture was allowed to cool to room temperature, diluted with ethyl acetate and filtered through a short pad of celite. The residue was purified by silica gel chromatography, 24 g column, and eluted with 0-50 % Ea, Hptn. The selected fractions were combined and concentrated in vacuo to give 1-(4-(7-(benzyloxy)-3-(4- fluorophenyl)isochroman-4-yl)phenyl)-4-(dimethoxymethyl)pipe ridine (200 mg, 352 ^mol, 62.2 %) as a white solid whose provisionally interpreted spectra are consistent with the assigned structure. ¹ H NMR (500 MHz, CDCl ₃ ) į 7.48 – 7.29 (m, 5H), 6.99 – 6.88 (m, 3H), 6.83 (ddt, J = 11.2, 8.2, 2.7 Hz, 3H), 6.74 (d, J = 2.6 Hz, 1H), 6.60 (q, J = 8.9 Hz, 4H), 5.16 (d, J = 15.2 Hz, 1H), 5.10 – 5.02 (m, 3H), 4.99 (d, J = 3.2 Hz, 1H), 4.05 (d, J = 7.3 Hz, 1H), 3.95 (d, J = 3.2 Hz, 1H), 3.59 – 3.54 (m, 2H), 3.35 (s, 6H), 2.54 (ddd, J = 12.6, 9.8, 5.0 Hz, 2H), 1.79 (d, J = 13.1 Hz, 2H), 1.70 (dtt, J = 11.6, 7.6, 3.7 Hz, 1H), 1.41 (ddt, J = 16.5, 12.2, 6.0 Hz, 2H).

Intermediate 31.1-(4-(7-(benzyloxy)-3-cyclohexylisochroman-4-yl)phenyl)-4 - (dimethoxymethyl)piperidine A mixture of 7-(benzyloxy)-4-(4-bromophenyl)-3-cyclohexylisochromane (145 mg, 1 Eq, 304 ^mol), x-phos (29.0 mg, 0.2 Eq, 60.7 ^mol), PdOAc2 (10.2 mg, 0.15 Eq, 45.6 ^mol), 4- (dimethoxymethyl)piperidine (72.5 mg, 1.5 Eq, 456 ^mol), and NaOtBu (43.8 mg, 1.5 Eq, 456 ^mol) in Toluene (3 mL) was heated to 90 °C for 16 hours, a period during which the desired product was observed by LCMS. The reaction mixture was allowed to cool to room temperature, quenched with water and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered through a short pad of celite and concentrated in vacuo. The residue was purified by silica gel chromatography, 24 g column, dry-loading on celite, and eluted with 0-50 % Ea, Hptn. The selected fractions were combined and concentrated in vacuo to give 1-(4-(7- (benzyloxy)-3-cyclohexylisochroman-4-yl)phenyl)-4-(dimethoxy methyl)piperidine (117 mg, 211 ^mol, 69.3 %) as a sticky solid whose provisionally interpreted spectra are consistent with the assigned structure. 1H NMR (500 MHz, CDCl3) į 7.44 – 7.29 (m, 6H), 7.12 (d, J = 8.1 Hz, 2H), 6.93 (d, J = 8.1 Hz, 1H), 6.81 (d, J = 8.1 Hz, 1H), 6.74 (dd, J = 8.6, 2.6 Hz, 1H), 6.65 (s, 1H), 4.98 (d, J = 2.3 Hz, 4H), 4.82 (t, J = 13.8 Hz, 1H), 4.09 (dd, J = 16.2, 7.4 Hz, 1H), 3.82 (s, 1H), 3.66 (d, J = 12.2 Hz, 2H), 3.43 – 3.33 (m, 8H), 2.60 (s, 2H), 2.06 (d, J = 13.1 Hz, 1H), 1.83 (d, J = 13.2 Hz, 3H), 1.68 – 1.59 (m, 3H), 1.43 (d, J = 12.2 Hz, 2H), 1.17 – 1.04 (m, 5H).

Intermediate 32.1-(4-(7-(benzyloxy)-3-(3-methoxyphenyl)isochroman-4-yl)ph enyl)-4- (dimethoxymethyl)piperidine ¹ H NMR (500 MHz, CDCl3) į 7.46 – 7.31 (m, 6H), 7.16 – 7.03 (m, 2H), 6.84 – 6.56 (m, 8H), 5.16 (d, J = 15.3 Hz, 1H), 5.06 (d, J = 3.1 Hz, 2H), 5.04 (d, J = 5.5 Hz, 1H), 4.99 (s, 1H), 4.07 (dd, J = 15.6, 7.1 Hz, 1H), 3.99 (d, J = 14.3 Hz, 1H), 3.58 (d, J = 3.6 Hz, 5H), 3.36 (dd, J = 8.3, 2.9 Hz, 6H), 2.51 (d, J = 13.8 Hz, 2H), 1.79 (d, J = 13.1 Hz, 2H), 1.69 (s, 1H), 1.39 (d, J = 12.6 Hz, 2H). Bn deprotection Intermediate 33.4-(4-(4-(dimethoxymethyl)piperidin-1-yl)phenyl)-3-(4- fluorophenyl)isochroman-7-ol A solution of 1-(4-(7-(benzyloxy)-3-(4-fluorophenyl)isochroman-4-yl)phenyl )-4- (dimethoxymethyl)piperidine (80 mg 1 Eq 014 mmol) in ethyl acetate was sparged with nitrogen and Pd-C (75 mg, 10% Wt, 0.5 Eq, 70 ^mol) was added, the reaction vessel was capped and evacuated and filled with hydrogen from a balloon a few times, and was allowed to stir at room temperature for 3 hours, a period during which the reaction was judged complete by LCMS. The reaction mixture was sparged with nitrogen, and filtered through a short pad of celite, and concentrated in vacuo. The residue was purified by silica gel chromatography, 24 g column, dry-loaded on silica gel, and eluted with Ea, Hptn, 0-50 %. The selected fractions were combined and concentrated in vacuo to give 4-(4-(4-(dimethoxymethyl)piperidin-1-yl)phenyl)-3- (4-fluorophenyl)isochroman-7-ol (38 mg, 80 ^mol, 56 %) as white solid whose provisionally interpreted spectra re consistent with the assigned structure. NMR (400 MHz, CDCl ₃ ) į 6.95 – 6.78 (m, 5H), 6.74 – 6.47 (m, 6H), 5.13 (d, J = 15.3 Hz, 1H), 5.02 (d, J = 15.3 Hz, 1H), 4.98 (d, J = 3.2 Hz, 1H), 4.66 (s, 1H), 4.05 (d, J = 7.3 Hz, 1H), 3.93 (d, J = 3.2 Hz, 1H), 3.56 (d, J = 12.0 Hz, 2H), 3.35 (s, 6H), 2.54 (t, J = 12.3 Hz, 2H), 1.79 (d, J = 13.1 Hz, 2H), 1.68 (ddd, J = 11.4, 7.6, 3.8 Hz, 1H), 1.50 – 1.34 (m, 2H). Intermediate 34.3-cyclohexyl-4-(4-(4-(dimethoxymethyl)piperidin-1-yl)phen yl)isochroman-7- ol A solution of 1-(4-(7-(benzyloxy)-3-cyclohexylisochroman-4-yl)phenyl)-4- (dimethoxymethyl)piperidine (117 mg, 1 Eq, 211 ^mol) in ethyl acetate was sparged with nitrogen and Pd-C (112 mg, 10% Wt, 0.5 Eq, 105 ^mol) was added, the reaction vessel was capped and evacuated and filled with hydrogen from a balloon a few times, and was allowed to stir at room temperature for 3 hours, a period during which the reaction was judged complete by LCMS. The reaction mixture was sparged with nitrogen, and filtered through a short pad of celite, and concentrated in vacuo. The residue was purified by silica gel chromatography, 24 g column, dry-loaded on silica gel, and eluted with Ea, Hptn, 0-50 %. The selected fractions were bi d d t t d i t i 3 l h l 4 (4 (4 (di th th l) i idi 1-yl)phenyl)isochroman-7-ol (55 mg, 0.12 mmol, 56 %) as white solid whose provisionally interpreted spectra re consistent with the assigned structure. 1H NMR (500 MHz, CDCl3) į 7.16 (d, J = 8.0 Hz, 2H), 6.92 (q, J = 6.3 Hz, 1H), 6.85 (d, J = 8.1 Hz, 2H), 6.61 (d, J = 8.6 Hz, 1H), 6.55 (s, 1H), 5.01 (d, J = 15.2 Hz, 1H), 4.84 (t, J = 13.9 Hz, 1H), 4.64 (s, 1H), 4.13 (dd, J = 15.9, 7.4 Hz, 1H), 3.85 (s, 1H), 3.70 (d, J = 12.3 Hz, 2H), 3.51 – 3.38 (m, 8H), 2.62 (d, J = 31.7 Hz, 2H), 2.21 – 2.04 (m, 1H), 1.88 (d, J = 12.8 Hz, 3H), 1.82 – 1.62 (m, 4H), 1.48 (d, J = 12.6 Hz, 2H), 1.23 – 1.06 (m, 5H). Intermediate 35.4,4-difluoro-6-methoxy-3,4-dihydronaphthalen-1(2H)-one Step 1. To a mixture of compound 1 (280 g, 1.59 mol, 1.00 eq) and compound 1a (157 g, 1.67 mol, 140 mL, 1.05 eq) in DCM (1.40 L) was added BF ₃ .Et ₂ O (960 g, 3.18 mol, 834 mL, 47.0% purity, 2.00 eq) at 20 °C under N ₂ . The mixture was stirred at 20 °C for 3 hrs. The mixture was quenched with saturated NaHCO ₃ aqueous solution (3.00 L). The aqueous was extracted with DCM (1.00 L * 3), the combined organic layer was washed with brine (500 mL * 2), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO ₂ , Petroleum ether: Ethyl acetate = 1 ^ 0 to 10 ^1) and the fraction was concentrated under reduced pressure to compound 2 (380 g, 1.51 mol, 94.7% yield) as a white solid which was confirmed by ¹ H NMR. LCMS: RT = 0.864 min, m/z = 253.0 (M+H) ⁺ . ¹ H NMR: 400 MHz, CDCl ₃ į 7.49 (d, J = 2.8 Hz, 1H), 6.92 (d, J = 8.4 Hz, 1H), 6.73 (dd, J = 8.8, 2.4 Hz, 1H), 3.81 (s, 3H), 3.69 - 3.54 (m, 2H), 3.53 - 3.41 (m, 2H), 2.74 (t, J = 6.4 Hz, 2H), 2.44 - 2.34 (m, 2H), 2.04 - 1.92 (m, 2H). Step 2. To a solution of NIS (285 g, 1.27 mol, 2.00 eq) in DCM (1.60 L) was added Py. HF (359 g, 2.54 mol, 326 mL, 70% purity, 4.00 eq) at -65 °C under N2. The mixture was stirred at -65 °C for 30 mins. A solution of compound 2 (160 g, 634 mmol, 1.00 eq) dissolved in DCM (500 mL) was added to the mixture at -65 °C, then the mixture was stirred at -65 °C for 1.5 hrs. The mixture was poured into saturated NaHCO ₃ aqueous solution (3.00 L) under stirring, the aqueous phase was adjusted pH value to 7 with saturated NaHCO ₃ aqueous solution. The mixture was quenched with saturated Na ₂ SO ₃ aqueous solution (2.00 L). The mixture was extracted with DCM (1.00 L * 3), then combined organic layer was washed with HCl (1M, 500 mL), brine (500 mL * 2), dried with Na ₂ SO ₄ , filtered, and concentrated under reduced pressure to obtain compound 3 (133 g, crude) as yellow oil which was confirmed by ¹ H NMR and F NMR . ¹ H NMR: 400 MHz, CDCl ₃ į 7.17 (d, J = 2.8 Hz, 1H), 7.08 (d, J = 8.8 Hz, 1H), 6.98 - 6.89 (m, 1H), 3.83 (s, 3H), 2.78 - 2.75 (m, 2H), 2.37 - 2.17 (m, 2H), 2.04 - 1.93 (m, 2H). Step 3. To a solution of compound 3 (110 g, 555 mmol, 1.00 eq) in AcOH (600 mL) was added a solution of CrO ₃ (166 g, 1.66 mol, 61.7 mL, 3.00 eq) in H ₂ O (150 mL) at 10 °C. The mixture was warmed to 25 °C and stirred at 25 °C for 12 hrs. The mixture was poured into H2O (2.00 L) under stirring, then the aqueous phase was adjusted pH value to 7 with saturated NaHCO3 aqueous solution. The mixture was extracted with ethyl acetate (1.50 L * 3), then combined organic layer was washed with brine (500 mL * 2), dried with Na ₂ SO ₄ , filtered, concentrated under reduced pressure. The residue was dissolved in Petroleum ether: Ethyl acetate (1: 1, 1.50 L). The mixture was filtered through SiO ₂ and the fraction was concentrated under reduced pressure. The crude product was triturated with Petroleum ether: Ethyl acetate (20: 1, 100 mL) at 20 °C for 30 mins and filtered under reduced pressure to obtain 4,4-difluoro-6-methoxy-3,4- dihydronaphthalen-1(2H)-one (53.0 g, 244 mmol, 44.1% yield, 97.9% purity) as a yellow solid which was confirmed by ¹ H NMR, F NMR, LCMS and HPLC. LCMS: RT = 0.704 min, m/z = 213.0(M+H) ⁺ . ¹ H NMR: 400 MHz, CDCl ₃ į 8.01 (d, J = 8.4 Hz, 1H), 7.19 (d, J = 2.4 Hz, 1H), 7.07 (dd, J = 8.4, 2.4 Hz, 1H), 3.92 (s, 3H), 2.91 - 2.78 (m, 2H), 2.69 - 2.56 (m, 2H). EXAMPLE 1. Preparation of (3S)-3-[5-[4-[[1-[4-[(1S,2S)-2-cyclohexyl-6-hydroxy- tetralin-1-yl]phenyl]-4-piperidyl]methyl]piperazin-1-yl]-1-o xo-isoindolin-2-yl]piperidine- 2,6-dione (I-5) and (3S)-3-[5-[4-[[1-[4-[(1R,2R)-2-cyclohexyl-6-hydroxy-tetralin -1- yl]phenyl]-4-piperidyl]methyl]piperazin-1-yl]-1-oxo-isoindol in-2-yl]piperidine-2,6-dione (I- 6). [0729] Step 1: A mixture of 1.1 (800 mg, 1.46 mmol), 1.2 (334 mg, 1.60 mmol), 1,1'-Bis(di-t- butylphosphino)ferrocene palladium dichloride (95.1 mg, 146 ^mol) and Na ₂ CO ₃ (309 mg, 2.92 mmol) in 1,4-dioxane (10 mL) and H ₂ O (2 mL) was degassed and purged with N ₂ for 3 times, and then the mixture was stirred at 80 °C for 12 h under N ₂ atmosphere. The mixture was diluted with water (20 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic phases were washed with brine (30 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ethyl acetate in petroleum ether = 0% to 25%) to give 1.3 (450 mg, 53.0 % yield) as a yellow solid. LC- MS (ESI ⁺ ) m/z: 550.5 (M+H) ⁺ . [0730] Step 2: To a solution of Pd/C (400 mg, 10.0% purity, 376 ^mol) in MeOH (15 mL) was added 1.3 (450 mg, 794 ^mol) under N ₂ . The suspension was degassed under vacuum and purged with H ₂ several times. The mixture was stirred under H ₂ (15 psi) at 25 °C for 3 h. The reaction mixture was filtered and the filter was concentrated to give a residue which was separated by chiral SFC (column: DAICEL CHIRALCEL OJ (250mm*30mm,10um); mobile phase: [0.1%NH3H2O EtOH]; B%: 30%-30%, Flow Rate (80 ml/min) peak 1: 1.835 min, peak 2: 2.088 min) to yield Peak 1 and Peak 2. Peak 1 was concentrated under reduced pressure to yield 1.4 (120 mg, 29.9 % yield) as a yellow solid. LC-MS (ESI ⁺ ) m/z: 464.4 (M+H) ⁺ . [0731] Peak 2 was concentrated under reduced pressure to yield 1.4A (120 mg, 29.9 % yield) as a yellow solid. LC-MS (ESI ⁺ ) m/z: 464.4 (M+H) ⁺ . [0732] Step 3: To a solution of 1.4 (120 mg, 258.82 ^mol) in THF (3 mL) was added H ₂ SO ₄ (3 mL, 5.63 mmol, 10.0% purity). The mixture was stirred at 70 °C for 3 h. The reaction mixture was quenched by addition of water (10 mL), ajuust pH to 8 by NaHCO ₃ saturated solution, extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (10 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give 1.5 (130 mg, 96.23% yield) as a yellow solid. LC-MS (ESI ⁺ ) m/z: 418.4 (M+H) ⁺ . [0733] Step 3A: To a solution of 1.4A (120 mg, 258.82 ^mol) in THF (3 mL) was added H ₂ SO ₄ (3 mL, 5.63 mmol, 10.0% purity). The mixture was stirred at 70 °C for 3 h. The reaction mixture was quenched by addition of water (10 mL), ajuust pH to 8 by NaHCO ₃ saturated solution, extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (10 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give 1.5A (130 mg, 96.2% yield) as a yellow solid. LC-MS (ESI ⁺ ) m/z: 418.4 (M+H) ⁺ . [0734] Step 4: To a solution of 1.5 (60 mg, 114.95 ^mol) and (3S)-3-(1-oxo-5-piperazin-1-yl- isoindolin-2-yl)piperidine-2,6-dione (37.74 mg, 114.95 ^mol) in DCM (2.5 mL) and MeOH (2.5 mL) after stirred 30 min was added sodium cyanoboranuide (36.12 mg, 574.74 ^mol). The mixture was stirred at 25 °C for 12.5 h. The reaction mixture was concentrated to yield a residue which was purified by preparative HPLC (column: Boston Green ODS 150*30mm*5um; mobile phase: [(1S,2S)-2-cyclohexyl-6-hydroxy-tetralin-1-yl]phenyl]-4-pipe ridyl]methyl]piperazin-1-yl]-1- oxo-isoindolin-2-yl]piperidine-2,6-dione, I-5, (30 mg, 35.0% yield, 0.1FA) as a white solid. [0735] LC-MS (ESI+) m/z: 730.4 (M+H)+. LCMS: calc. for C45H55N5O4: 729.4, found: [M+H]+ 730.4. [0736] HPLC: 100% purity at 254 nm. [0737] 1H NMR (500MHz, MeOD-d4): į 8.10 (s, 1H), 7.70 (d, J = 9.0 Hz, 1H), 7.67 (s, 1H), 7.21 - 7.14 (m, 2H), 6.98 - 6.87 (m, 4H), 6.65 (d, J = 8.4 Hz, 1H), 6.55 (d, J = 2.1 Hz, 1H), 6.45 (dd, J = 2.4, 8.3 Hz, 1H), 5.12 (dd, J = 5.2, 13.4 Hz, 1H), 4.50 - 4.36 (m, 2H), 4.14 (d, J = 4.4 Hz, 1H), 3.81 - 3.51 (m, 4H), 3.41 (s, 5H), 3.10 (d, J = 6.4 Hz, 2H), 2.95 - 2.86 (m, 2H), 2.84 - 2.70 (m, 4H), 2.47 (d, J = 4.5, 13.1 Hz, 1H), 2.18 - 2.09 (m, 2H), 2.05 (s, 1H), 1.92 (d, J = 12.2 Hz, 2H), 1.84 - 1.72 (m, 2H), 1.67 - 1.55 (m, 4H), 1.55 - 1.45 (m, 2H), 1.34 - 0.96 (m, 7H), 0.85 - 0.73 (m, 1H). [0738] Step 4A: To a solution of 1.5A (60 mg, 114.95 ^mol) and (3S)-3-(1-oxo-5-piperazin-1-yl- isoindolin-2-yl)piperidine-2,6-dione (37.74 mg, 114.95 ^mol) in DCM (2.5 mL) and MeOH (2.5 mL) after stirred 30 min was added sodium cyanoboranuide (36.12 mg, 574.74 ^mol). The mixture was stirred at 25 °C for 12.5 h. The reaction mixture was concentrated to yield a residue which was purified by preparative HPLC (column: Boston Green ODS 150*30mm*5um; mobile phase: [water(FA)-ACN]; B%: 27%-47%, 12min), followed by lyophilization to give (3S)-3-[5-[4-[[1- [4-[(1R,2R)-2-cyclohexyl-6-hydroxy-tetralin-1-yl]phenyl]-4-p iperidyl]methyl]piperazin-1-yl]-1- oxo-isoindolin-2-yl]piperidine-2,6-dione, I-6, (30.6 mg, 36.3% yield, 0.06FA) as a white solid. [0739] LC-MS (ESI+) m/z: 730.4 (M+H)+. LCMS: calc. for C45H55N5O4: 729.4, found: [M+H]+ 730.4. [0740] HPLC: 100% purity at 254 nm. [0741] 1H NMR (500MHz, MeOD-d4): į 8.09 (s, 1H), 7.73 - 7.66 (m, 1H), 7.22 - 7.15 (m, 2H), 6.91 (q, J = 8.6 Hz, 4H), 6.65 (d, J = 8.4 Hz, 1H), 6.55 (d, J = 2.1 Hz, 1H), 6.45 (dd, J = 2.4, 8.3 Hz, 1H), 5.12 (dd, J = 5.1, 13.4 Hz, 1H), 4.51-4.36 (m, 2H), 4.14 (d, J = 4.3 Hz, 1H), 3.68 (s, 4H), 3.45 (s, 5H), 3.17 - 3.08 (m, 2H), 2.95 - 2.85 (m, 2H), 2.82 - 2.70 (m, 4H), 2.47 (d, J = 4.5, 13.2 Hz, 1H), 2.27 - 2.11 (m, 2H), 2.05 (d, J = 11.3 Hz, 1H), 1.92 (d, J = 12.5 Hz, 2H), 1.81 - 1.72 (m, 2H), 1.71 - 1.37 (m, 7H), 1.35 - 0.98 (m, 7H), 0.79 (q, J = 10.9 Hz, 1H). EXAMPLE 2. Preparation of (I-13) S)-3-(5-(4-((1-(4-((1S,2R)-4,4-difluoro-6- hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)pi peridin-4- yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2, 6-dione [0742] Step 1: To a solution of 4,4-difluoro-6-methoxy-3,4-dihydronaphthalen-1(2H)-one (5.3 g, 25 mmol) in DMF (100 mL) at r.t. was added EtSNa (8.4 g, 0.1 mol) with N ₂ . After addition, the mixture was stirred at 135 °C for 16 h with N ₂ . The reaction mixture was added H ₂ O (200 mL) and extracted with ethyl acetate (200 mL x 2). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ethyl acetate in petroleum ether = 0% to 20%) to give the product of 4,4-difluoro-6-hydroxy-3,4-dihydronaphthalen-1(2H)-one (4.1 g, 73 % yield) as a yellow solid. LC-MS (ESI ⁺ ) m/z: 199.1 (M+H) ⁺ . [0743] Step 2: To a solution of 4,4-difluoro-6-hydroxy-3,4-dihydronaphthalen-1(2H)-one (4.1 g, 18 mmol) in CH ₃ CN (50 mL) at r.t. was added (bromomethyl)benzene (3.7 g, 22 mmol) and K ₂ CO ₃ (5.0 g, 36 mmol) with N ₂ . After addition, the mixture was stirred at 25 °C for 16 h. The mixture was treated with H ₂ O (150 mL), extracted with EtOAc (150 mL x 2). The combined extracts was dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to dryness in vacuo to give a residue. The residue was subjected to column chromatography over silica gel (petroleum ether/ethyl acetate f 100/0 t 80/20) Th f ti ll t d d t t d t d i t give 6-(benzyloxy)-4,4-difluoro-3,4-dihydronaphthalen-1(2H)-one (5 g, 100 % yield,) as a white solid. LC-MS (ESI ⁺ ) m/z: 289.1 (M+H) ⁺ . [0744] Step 3: To a solution of 1-(4-bromophenyl)-4-(dimethoxymethyl)piperidine (7 g, 0.02 mol) in THF (60 mL) was added dropwise n-BuLi (2 g, 2.5 M, 0.03 mol) at -78 °C with N ₂ . After addition, the mixture was stirred at this temperature for 1 h, then 6-(benzyloxy)-4,4-difluoro-3,4- dihydronaphthalen-1(2H)-one (5 g, 0.02 mol) in THF (20 mL) was added dropwise at -78 °C. The resulting mixture was stirred at -78 °C-r.t. for 16 h. The reaction mixture was quenched into a solution of saturated ammonium chloride solution followed by extraction with EtOAc (100 mL x 2). The combined extracts was dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to dryness in vacuo to give a residue. The residue was subjected to column chromatography over silica gel (petroleum ether/ethyl acetate from 100/0 to 80/20). The pure fractions were collected and concentrated to dryness in vacuo to give 6-(benzyloxy)-1-(4-(4-(dimethoxymethyl)piperidin-1- yl)phenyl)-4,4-difluoro-1,2,3,4-tetrahydronaphthalen-1-ol (6.37 g, 60 % yield) as a white solid. LC-MS (ESI+) m/z: 524.3 (M+H) ⁺ . [0745] Step 4: A mixture of 6-(benzyloxy)-1-(4-(4-(dimethoxymethyl)piperidin-1-yl)phenyl )- 4,4-difluoro-1,2,3,4-tetrahydronaphthalen-1-ol (6.37 g, 10.6 mmol) in Dioxane (80 mL) at r.t., then TsOH (202 mg, 1.06mmol) was added to the mixture and was stirred at 65 °C for 5 h. The mixture was treated with H ₂ O (300 mL), extracted with EtOAc (300 mL x 2). The combined extracts was dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to dryness in vacuo to give a residue. The residue was subjected to column chromatography over silica gel (petroleum ether/ethyl acetate from 100/0 to 70/30). The pure fractions were collected and concentrated to dryness in vacuo to give 1-(4-(6-(benzyloxy)-4,4-difluoro-3,4-dihydronaphthalen-1-yl) phenyl)-4- (dimethoxymethyl)piperidine (4.6 g, 86% yield) as a yellow solid. LC-MS (ESI ⁺ ) m/z: 506.3 (M+H) ⁺ . [0746] Step 5: To a mixture of 1-(4-(6-(benzyloxy)-4,4-difluoro-3,4-dihydronaphthalen-1- yl)phenyl)-4-(dimethoxymethyl)piperidine (1.28 g, 2.30 mmol) and Diisopropylethylamine (446 mg, 3.45 mmol) in DCM (15 mL) at 0 °C, and Pyridinium bromide perbromide (809 mg, 2.53 mmol) was added to the mixture at 0 °C, then the mixture was stirred at 0 °C for 4 h. The mixture was concentrated to dryness in vacuo to give a residue. The residue was subjected to column chromatography over silica gel (petroleum ether/ethyl acetate from 100/0 to 70/30). The pure fractions were collected and concentrated to dryness in vacuo to give 1-(4-(6-(benzyloxy)-2- bromo-4,4-difluoro-3,4-dihydronaphthalen-1-yl)phenyl)-4-(dim ethoxymethyl)piperidine (1.36 g, 47.0% yield) as a yellow solid. LC-MS (ESI+) m/z: 586.1 (M+H) ⁺ . [0747] Step 6: 1,1'-Bis(di-t-butylphosphino)ferrocene palladium dichloride (70.5 mg, 108 ^mol) was added to the mixture of 1-(4-(6-(benzyloxy)-2-bromo-4,4-difluoro-3,4-dihydronaphthal en-1- yl)phenyl)-4-(dimethoxymethyl)piperidine (1.36 g, 1.08 mmol), phenylboronic acid (198 mg, 1.62 mmol) and Sodium carbonate (344 mg, 3.24 mmol) in Dioxane (20 mL) and H ₂ O (5 mL) at r.t.. N2 was bubbled into the mixture for 5 min. The reaction mixture was heated at 50 °C for 12 h. The mixture was treated with H2O (150 mL), extracted with EtOAc (150 mL x 2). The combined extracts was dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to dryness in vacuo to give a residue. The residue was subjected to column chromatography over silica gel (petroleum ether/ethyl acetate from 100/0 to 70/30). The pure fractions were collected and concentrated to dryness in vacuo to give 1-(4-(6-(benzyloxy)-4,4-difluoro-2-phenyl-3,4-dihydronaphtha len-1- yl)phenyl)-4-(dimethoxymethyl)piperidine (1.15 g, 88.6 % yield) as a yellow solid. LC-MS (ESI+) m/z: 582.5 (M+H) ⁺ . [0748] Step 7: A mixture of 1-(4-(6-(benzyloxy)-4,4-difluoro-2-phenyl-3,4-dihydronaphtha len-1- yl)phenyl)-4-(dimethoxymethyl)piperidine (950 mg, 792 ^mol) , Pd/C (500 mg, 470 ^mol,10 % wt), Pd(OH) ₂ (500 mg, 712 ^mol, 20 % wt) in MeOH (15 mL) was degassed and purged with H ₂ for 3 times, and then the mixture was stirred at 25 °C for 16 h under H ₂ atmosphere (15 psi). The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Xtimate C18 150*40mm*5um; mobile phase: [water(FA)-ACN];B% 55%-95%,8min) and was further separated by SFC (condition: column: DAICEL CHIRALPAK AD(250mm*30mm,10um);mobile phase: [Neu-ETOH];B%: 30%-30%, min ) to give (5S, 6R)-5-(4-(4-(dimethoxymethyl)piperidin-1-yl)phenyl)-8,8-difl uoro-6-phenyl- 5,6,7,8-tetrahydronaphthalen-2-ol (100 mg, 25.4 % yield) and (5R, 6S)5-(4-(4- (dimethoxymethyl)piperidin-1-yl)phenyl)-8,8-difluoro-6-pheny l-5,6,7,8-tetrahydronaphthalen-2- ol (110 mg, 27.7 % yield) as yellow solid. LC-MS (ESI+) m/z: 494.3, 494.2 (M+H) ⁺ . [0749] Step 8: A mixture of (5S, 6R)-5-(4-(4-(dimethoxymethyl) piperidin-1-yl)phenyl)-8,8- difluoro-6-phenyl-5,6,7,8-tetrahydronaphthalen-2-ol (50 mg, 0.10 mmol) in THF (3.5 mL) and 10% H ₂ SO ₄ (3.5 mL) was stirred at 70 °C for 1 h. The reaction was adjust to pH=8 with aq.NaHCO ₃ (10 mL). Then the mixture was added water (20 mL) and extracted with ethyl acetate (2 x 20 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to dryness in vacuo to give a yellow solid of 1-(4-((1S,2R)-4,4-difluoro- 6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl) piperidine-4-carbaldehyde (45 mg, 97 % yield). LC-MS (ESI+) m/z: 466.3 (M+H) ⁺ . [0750] Step 9: A mixture of 1-(4-((1S,2R)-4,4-difluoro-6-hydroxy-2-phenyl-1,2,3,4- tetrahydronaphthalen-1-yl)phenyl)piperidine-4-carbaldehyde (45 mg, 98 ^mol) , (S)-3-(1-oxo-5- (piperazin-1-yl)isoindolin-2-yl)piperidine-2,6-dione, TsOH salt (0.12 g, 0.15 mmol) and acetic acid (12 mg, 0.20mmol) and sodium acetate (40 mg, 0.49 mmol) in THF (1 mL) and MeOH (1 mL) at 25 °C for 1 h, then sodium triacetoxyborohydride (41 mg, 0.20 mmol) was added to the mixture and was stirred at 25 °C for 16 h. Then the mixture was added water (10 mL) and extracted with ethyl acetate (2 x 15 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to dryness in vacuo to give a residue. The residue was purified by prep-HPLC (column: O-Welch C18 150*30mm* 5um; mobile phase: [water(FA)-ACN];B% 10%-50%, 10 min) to give (S)-3-(5-(4-((1-(4-((1S,2R)-4,4-difluoro-6- hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)pi peridin-4-yl)methyl)piperazin-1- yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (19.2 mg, 26 % yield). LC-MS (ESI+) m/z: 760.4 (M+H) ⁺ . [0751] LCMS: calc. for C ₄₅ H ₄₇ F ₂ N ₅ O ₄ : 759.36, found: [M+H] ⁺ 760.4. [0752] HPLC: 100% purity at 220 nm. [0753] ¹ HNMR (400MHz, DMSO-d ₆ ) į = 10.95 (s, 1H), 9.73 (s, 1H), 8.14 (s, 1H), 7.61 - 7.47 (m, 1H), 7.26 - 7.17 (m, 3H), 7.09 (br s, 3H), 6.95 - 6.83 (m, 4H), 6.58 (br d, J=8.0 Hz, 2H), 6.14 (br d, J=8.1 Hz, 2H), 5.06 (dd, J=5.1, 13.1 Hz, 1H), 4.38 - 4.28 (m, 2H), 4.27 - 4.17 (m, 1H), 3.67 (br d, J=15.7 Hz, 1H), 3.53 (br s, 3H), 3.31 - 3.30 (m, 4H), 2.96 - 2.84 (m, 1H), 2.61 (br s, 9H), 2.37 (br d, J=8.9 Hz, 2H), 2.01 - 1.93 (m, 1H), 1.77 (br d, J=11.4 Hz, 3H), 1.19 (br s, 2H) [0754] SFC: retention time, 2.682 min; Area, 97.658 %.

EXAMPLE 3. Preparation of (I-51) (S)-3-(5-(4-((1-(4-((1R,2S)-4,4-difluoro-6- hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)pi peridin-4- yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2, 6-dione [0755] Step 1: A mixture of (5R,6S)-5-(4-(4-(dimethoxymethyl)piperidin-1-yl)phenyl)-8,8- difluoro-6-phenyl-5,6,7,8-tetrahydronaphthalen-2-ol (55 mg, 0.11 mmol) in THF (3.5 mL) and 10% H2SO4 (3.5 mL) was stirred at 70 °C for 1 h. The reaction was adjust to pH=8 with aq.NaHCO3 (10 mL). Then the mixture was added water (20 mL) and extracted with ethyl acetate (2 x 20 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to dryness in vacuo to give a yellow solid of 1-(4-((1R,2S)-4,4-difluoro- 6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl) piperidine-4-carbaldehyde (50 mg, 98 % yield). LC-MS (ESI+) m/z: 466.3 (M+H) ⁺ . [0756] Step 2: A mixture of 1-(4-((1R,2S)-4,4-difluoro-6-hydroxy-2-phenyl-1,2,3,4- tetrahydronaphthalen-1-yl)phenyl)piperidine-4-carbaldehyde (50 mg, 0.11 mmol), (S)-3-(1-oxo- 5-(piperazin-1-yl)isoindolin-2-yl)piperidine-2,6-dione, TsOH salt (0.12 g, 0.15 mmol) and Acetic acid (12 mg, 0.20mmol) and sodium acetate (40 mg, 0.49 mmol) in THF (1 mL) and MeOH (1 mL) at 25 °C for 1 h, then sodium triacetoxyborohydride (41 mg, 0.20mmol) was added to the mixture and was stirred at 25 °C for 16 h. Then the mixture was added water (10 mL) and extracted with ethyl acetate (2 x 15 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to dryness in vacuo to give a residue. The residue was purified by prep-HPLC (column: O-Welch C18 150*30mm* 5um; mobile phase: [water(FA)-ACN];B% 10%-50%, 10 min) to give (S)-3-(5-(4-((1-(4-((1R,2S)-4,4-difluoro-6- hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)pi peridin-4-yl)methyl)piperazin-1- yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (27.2 mg, 33 % yield). LC-MS (ESI+) m/z: 760.4 (M+H) ⁺ . [0757] LCMS: calc. for C ₄₅ H ₄₇ F ₂ N ₅ O ₄ : 759.36, found: [M+H] ⁺ 760.4. [0759] ¹ HNMR (400MHz, DMSO-d6) į = 10.96 (s, 1H), 8.19 (s, 1H), 7.52 (d, J=8.7 Hz, 1H), 7.25 - 7.16 (m, 3H), 7.11 - 7.03 (m, 3H), 6.94 - 6.83 (m, 4H), 6.57 (br d, J=8.8 Hz, 2H), 6.13 (d, J=8.6 Hz, 2H), 5.05 (dd, J=4.9, 13.3 Hz, 1H), 4.36 - 4.28 (m, 2H), 4.25 - 4.17 (m, 1H), 3.67 (br d, J=17.4 Hz, 1H), 3.53 (br d, J=8.6 Hz, 3H), 3.28 (br s, 7H), 3.00 - 2.82 (m, 1H), 2.61 (br s, 5H), 2.43 - 2.35 (m, 1H), 2.19 (br d, J=7.2 Hz, 2H), 2.01 - 1.91 (m, 1H), 1.75 (br d, J=11.3 Hz, 2H), 1.64 (br s, 1H), 1.22 - 1.08 (m, 2H). [0760] SFC: retention time, 2.806 min; Area, 94.060%. EXAMPLE 4. Preparation of (I-300) 1-(6-(4-((1-(4-((1R,2S)-4,4-difluoro-6-hydroxy- 2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperidin- 4-yl)methyl)piperazin-1-yl)- 1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione Step 1: A mixture of (5R,6S)-5-(4-(4-(dimethoxymethyl)piperidin-1-yl)phenyl)-8,8- difluoro-6- phenyl-5,6,7,8-tetrahydronaphthalen-2-ol (100 mg, 97.6% purity, 1 Eq, 198 ^mol) in THF (3 mL) and 10% H ₂ SO ₄ (3 mL) was stirred at 70 °C for 0.5 h. The reaction was adjust to pH=8 with saturated aqueous NaHCO ₃ (6 mL) at 0 °C. Then the mixture was added H ₂ O (20 mL) and extracted with ethyl acetate (20 mL * 2). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated to dryness in vacuum to give 1-(4-((1R,2S)-4,4- difluoro-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-y l)phenyl)piperidine-4- carbaldehyde (90 mg, 98 % yield, 96.4% purity) as a yellow solid. LC-MS (ESI+) m/z: 448.1 (M+H) ⁺ . Step 2: A mixture of 1-(1-methyl-6-(piperazin-1-yl)-1H-indazol-3-yl)dihydropyrimi dine- 2,4(1H,3H)-dione (50 mg, 1 Eq, 0.15 mmol), 1-(4-((1R,2S)-4,4-difluoro-6-hydroxy-2-phenyl- 1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperidine-4-carbal dehyde (78 mg, 1.1 Eq, 0.17 mmol) sodium acetate (62 mg 5 Eq 076 mmol) and acetic acid (27 mg 26 ^L 3 Eq 046 mmol) in THF (4 mL) and MeOH (4 mL) was stirred at 25 °C for 1 h, then sodium triacetoxyborohydride (65 mg, 2 Eq, 0.3 mmol) was added to the mixture and stirred at 25 °C for 16 h. Then the mixture was added H ₂ O (50 mL) and extracted with ethyl acetate (50 mL * 2). The combined extracts were dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to dryness in vacuum to give a residue. The residue was purified by prep-HPLC (column: Welch Xtimate C18150*30mm*5um; mobile phase: [water (FA)-ACN]; B% 10%-60%, 8 min) to give 1-(6-(4- ((1-(4-((1R,2S)-4,4-difluoro-6-hydroxy-2-phenyl-1,2,3,4-tetr ahydronaphthalen-1- yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-methyl-1H- indazol-3-yl)dihydropyrimidine- 2,4(1H,3H)-dione (61.5 mg, 53 % yield, 99.5% purity) as a white solid. LC-MS (ESI+) m/z: 760.3 (M+H) ⁺ . LCMS: calc. for C ₄₄ H ₄₇ F ₂ N ₇ O ₃ : 759.37, found: [M+H] ⁺ 760.3. HPLC: 99.517 % purity at 220 nm. ¹ HNMR (400MHz, DMSO-d ₆ ) į = 10.52 (s, 1H), 9.96 - 9.58 (m, 1H), 8.17 (s, 0.409H), 7.45 (d, J=9.1 Hz, 1H), 7.25 - 7.17 (m, 3H), 7.09 (s, 1H), 6.96 - 6.80 (m, 6H), 6.57 (d, J=8.7 Hz, 2H), 6.13 (d, J=8.6 Hz, 2H), 4.31 (br s, 1H), 3.96 - 3.84 (m, 5H), 3.67 (br d, J=14.8 Hz, 1H), 3.54 (br d, J=9.4 Hz, 2H), 3.22 (br s, 3H), 2.74 (t, J=6.7 Hz, 2H), 2.70 - 2.52 (m, 6H), 2.50 - 2.46 (m, 2H), 2.32 (br t, J=15.3 Hz, 1H), 2.20 (br d, J=7.0 Hz, 2H), 1.81 - 1.58 (m, 3H), 1.22 - 1.08 (m, 2H) SFC: retention time, 2.679 min; Area, 100 %.

EXAMPLE 5. Preparation of (I-294) 1-(4-(2-((1-(4-((1R,2S)-4,4-difluoro-6-hydroxy- 2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperidin- 4-yl)methyl)-2,8- diazaspiro[4.5]decan-8-yl)-2-methylphenyl)dihydropyrimidine- 2,4(1H,3H)-dione Step 1: A mixture of 1-(4-bromo-2-methylphenyl)dihydropyrimidine-2,4(1H,3H)-dione (2 g, 1 Eq, 7.1 mmol), tert-butyl2,8-diazaspiro[4.5]decane-2-carboxylate (2 g, 1.2 Eq, 8.5 mmol) , Pd- PEPPSI-IHeptCl (0.69 g, 0.1 Eq, 0.71 mmol) and cesium carbonate (6.9 g, 3 Eq, 21 mmol) in dioxane (30 mL) was stirred at r.t.. N ₂ was bubbled into the mixture for 5 min. The reaction was heated at 100 °C for 3 h. The mixture was added H ₂ O (100 mL) and extracted with ethyl acetate (100 mL x 2). The combined extracts were dried over anhydrous Na ₂ SO ₄ , then filtered and concentrated to dryness in vacuo to give a residue. The residue was subjected to column chromatography over silica gel (petroleum ether/ethyl acetate from 100/0 to 0/100). The pure fractions were collected and concentrated to dryness in vacuo to give tert-butyl 8-(4-(2,4- dioxotetrahydropyrimidin-1(2H)-yl)-3-methylphenyl)-2,8-diaza spiro[4.5]decane-2-carboxylate (1 g, 30 % yield, 85.2% purity) as a white solid. LC-MS (ESI+) m/z: 443.3 (M+H) ⁺ . Step 2: A mixture of tert-butyl 8-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-3-methylphenyl) - 2,8-diazaspiro[4.5]decane-2-carboxylate (1 g, 1 Eq, 2 mmol) in HCl/dioxane (25 mL) was stirred at 25 °C for 16 h. The mixture was concentrated to dryness in vacuo to give 1-(2-methyl-4-(2,8- diazaspiro[4.5]decan-8-yl)phenyl)dihydropyrimidine-2,4(1H,3H )-dione (0.8 g, 100 % yield, 93.3% purity) as a white solid. LC-MS (ESI+) m/z: 343.3 (M+H) ⁺ . Step 3: A mixture of 1-(4-((1R,2S)-4,4-difluoro-6-hydroxy-2-phenyl-1,2,3,4- tetrahydronaphthalen-1-yl)phenyl)piperidine-4-carbaldehyde (110 mg, 1 Eq, 224 ^mol) , 1-(2- methyl-4-(2,8-diazaspiro[4.5]decan-8-yl)phenyl)dihydropyrimi dine-2,4(1H,3H)-dione (98.5 mg, 1.2 Eq, 268 ^mol), sodium acetate (91.7 mg, 5 Eq, 1.12 mmol) and acetic acid (40.3 mg, 38.6 ^L, 3 Eq, 671 ^mol) in DCM (3 mL) and MeOH (3 mL) was stirred at 30 °C for 1 h, then sodium triacetoxyborohydride (94.8 mg, 2 Eq, 447 ^mol) was added to the mixture and stirred at 30 °C for 16 h. Then the mixture was added H ₂ O (30 mL) and extracted with ethyl acetate (30 mL x 2). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to dryness in vacuo to give a residue. The residue was purified by prep-HPLC (column: Welch Xtimate C18150*30mm*5um; mobile phase: [water (FA)- ACN]; B% 8%-48%, 9 min) to give 1-(4-(2-((1-(4-((1R,2S)-4,4-difluoro-6-hydroxy-2-phenyl- 1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperidin-4-yl)meth yl)-2,8-diazaspiro[4.5]decan-8-yl)- 2-methylphenyl)dihydropyrimidine-2,4(1H,3H)-dione (114.7 mg, 63.0 % yield, 95.134% purity) as a white solid. LC-MS (ESI+) m/z: 774.4 (M+H) ⁺ . LCMS: calc. for C47H53F2N5O3: 773.41, found: [M+H] ⁺ 774.4. HPLC: 95.134% purity at 220 nm. ¹ HNMR (400MHz, DMSO-d ₆ ) į = 10.24 (s, 1H), 8.18 (s, 1H), 7.24 - 7.16 (m, 3H), 7.10 - 7.01 (m, 2H), 6.93 - 6.75 (m, 6H), 6.56 (d, J=8.8 Hz, 2H), 6.13 (d, J=8.8 Hz, 2H), 4.30 (br d, J=2.8 Hz, 1H), 3.71 - 3.62 (m, 2H), 3.57 - 3.41 (m, 3H), 3.21 - 3.04 (m, 4H), 2.77 - 2.55 (m, 5H), 2.50 - 2.44 (m, 2H), 2.41 (s, 2H), 2.37 - 2.26 (m, 3H), 2.11 (s, 3H), 1.74 (br d, J=11.8 Hz, 2H), 1.66 - 1.49 (m, 7H), 1.20 - 1.07 (m, 2H) SFC: retention time, 2.893 min; Area, 100 %. EXAMPLE 6. Preparation of (I-290) 1-(4-((S)-7-((1-(4-((1R,2S)-4,4-difluoro-6- hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)pi peridin-4-yl)methyl)-2,7- diazaspiro[4.4]nonan-2-yl)phenyl)dihydropyrimidine-2,4(1H,3H )-dione Step 1: To a solution of (5R,6S)-5-(4-(4-(dimethoxymethyl)piperidin-1-yl)phenyl)-8,8- difluoro- 6- phenyl-5,6,7,8-tetrahydronaphthalen-2-ol (50 mg, 0.10 mmol ^ 1.0 eq.) in THF (3 mL) was added H ₂ SO ₄ (0.09 g, 0.05 mL, 9 eq., 0.9 mmol) and water (0.5 mL). The mixture was stirred at 40 °C for 0.5 h. The reaction mixture was quenched by addition of water (10 mL), adjust pH to 8 by NaHCO ₃ saturated solution, extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (10 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give 1-(4-((1R,2S)-4,4-difluoro-6-hydroxy-2-phenyl -1,2,3,4- tetrahydronaphthalen-1-yl)phenyl)piperidine-4-carbaldehyde (40 mg, 89 ^mol, 88 % yield) as a yellow solid. LC-MS (ESI ⁺ ) m/z: 448.3 (M+H) ⁺ . Step 2: To a solution of 1-(4-((1R,2S)-4,4-difluoro-6-hydroxy-2-phenyl-1,2,3,4- tetrahydronaphthalen e-1-yl)phenyl)piperidine-4-carbaldehyde (40.0 mg, 1 eq., 89.4 ^mol) and (S)-1-(4-(2,7- diazaspiro[4.4]nonan-2-yl)phenyl)dihydropyrimidine-2,4(1H,3H )-dione (33.7 mg, 107 ^mol, 1.2 eq.) in DCE (3 mL) and MeOH (3 mL) was added Sodium triacetoxyborohydride (56.8 mg, 268 ^mol, 3.0 eq.). The mixture was stirred at 20 °C for 2 hour. LCMS showed the reaction was completed. The crude was purified by prep-HPLC together (Boston Green ODS 150*30mm*5um, water(FA)-ACN as a mobile phase, from 18% to 48%, Gradient Time (min): 12, Flow Rate (ml/min): 25) to give 1-(4-((S)-7-((1-(4-((1R,2S)-4,4-difluoro-6- hydroxy-2- phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperidin-4- yl)methyl)-2,7- diazaspiro[4.4]nonan-2-yl)phenyl)dihydropyrimidine-2,4(1H,3H )-dione (13.6 mg, 18.2 ^mol, 20.4 % yield) as a white solid. LC-MS (ESI ⁺ ) m/z: 746.4 (M+H) ⁺ . LCMS: calc. for C45H49F2N5O3:745.92, found: [M+H] ⁺ 746.4 HPLC: 100.00% purity at 220 nm. ¹ H NMR (400 MHz, METHANOL-d ₄ ) į: ppm 8.47 - 8.55 (m, 1 H), 7.08 - 7.20 (m, 6 H), 6.78 - 6.91 (m, 4 H), 6.54 - 6.68 (m, 4 H), 6.25 (d, J=8.40 Hz, 2 H), 4.25 - 4.32 (m, 1 H), 3.74 - 3.81 (m, 2 H), 3.66 - 3.73 (m, 1 H), 3.52 - 3.59 (m, 2 H), 3.37 - 3.42 (m, 2 H), 3.33 - 3.36 (m, 2 H), 3.27 (s, 2 H), 2.98 - 3.19 (m, 3 H), 2.79 (t, J=6.80 Hz, 3 H), 2.65 - 2.73 (m, 1 H), 2.55 - 2.63 (m, 2 H), 2.23 - 2.33 (m, 1 H), 1.99 - 2.16 (m, 4 H), 1.81 - 1.88 (m, 2 H), 1.70 - 1.81 (m, 1 H), 1.31 - 1.39 (m, 2 H). EXAMPLE 7. Preparation of (I-98) (S)-3-(5-(4-((1-(4-((1S,2S)-2-cyclohexyl-4,4- difluoro-6-hydroxy-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl) piperidin-4- yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2, 6-dione Step 1: To a mixture of 1-(4-(6-(benzyloxy)-4,4-difluoro-3,4-dihydronaphthalen-1-yl) phenyl)-4- (dimethoxymethyl)piperidine (1.2 g, 1 Eq, 2.2 mmol) and TEA (0.33 g, 0.45 mL, 1.5 Eq, 3.2 mmol) in DCM (40 mL) at 0 °C, and Pyridinium bromide perbromide (0.76 g, 1.1 Eq, 2.4 mmol) was added to the mixture at 0 °C, then the mixture was stirred at 0 °C for 0.5 hour. TLC (petroleum ether: ethyl acetate=5:1, R _f =0.5, UV) showed one main new spot was observed. The reaction mixture was quenched by addition H ₂ O 50 mL, and then diluted with H ₂ O 50 mL and extracted with DCM (50 mL * 2). The organic layer was washed with brine (50 mL) and dried over Na2SO4 and concentrated in vacuo to give a yellow solid. The residue was subjected to column chromatography over silica gel (gradient elution: 0~30% ethyl acetate in petroleum ether). The pure fractions were collected and concentrated to dryness in vacuo to give 1-(4-(6- (benzyloxy)-2-bromo-4, 4-difluoro-3,4-dihydronaphthalen-1-yl)phenyl)-4- (dimethoxymethyl)piperidine (1.2 g, 0.95 mmol, 44 %, 46.216% purity) as a yellow solid. LC- MS (ESI ⁺ ) m/z: 586.2 (M+H) ⁺ . Step 2: A mixture of 1-(4-(6-(benzyloxy)-2-bromo-4,4-difluoro-3,4-dihydronaphthal en-1- yl)phenyl)-4-(dimethoxymethyl)piperidine (1.18 g, 1 Eq, 2.02 mmol) , Cyclohexen-1- ylboronicacid (254 mg, 1 Eq, 2.02 mmol) , Sodium carbonate (642 mg, 3 Eq, 6.06 mmol) 1,1'- Bis(di-t-butylphosphino)ferrocene palladium dichloride (132 mg, 0.1 Eq, 202 ^mol) in 1,4- Dioxane (20 mL) and H2O (5.0 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 50 °C for 16 hour under N ₂ atmosphere. TLC (petroleum ether: ethyl acetate=5:1, R _f =0.5, UV) showed one main new spot was observed. The reaction was quenched with water (50 mL) and extracted with ethyl acetate (150 mL*2). The organic layer was washed with brine (100 mL) and dried over Na ₂ SO ₄ and concentrated in vacuo to give a white solid. The white solid was subjected to column chromatography over silica gel (gradient elution: 0 – 100% EtOAc). The desired fractions were collected, and concentrated to dryness in vacuo to give 1-(4- (6-(benzyloxy)-2-(cyclohex-1-en-1-yl)-4,4-difluoro-3,4-dihyd ronaphthalen-1-yl)phenyl)-4- (dimethoxymethyl)piperidine (1.1 g, 0.90 mmol, 45 %, 48.181% purity) as a white solid. LC-MS (ESI ⁺ ) m/z: 586.3 (M+H) ⁺ Step 3: A mixture of 1-(4-(6-(benzyloxy)-4,4-difluoro-2-phenyl-3,4-dihydronaphtha len-1- yl)phenyl)-4-(dimethoxymethyl)piperidine (1.1 g, 48.181% Wt, 1 Eq, 0.91 mmol) , Pd/C (300 mg, 10% Wt, 0.31 Eq, 282 ^mol), Pd(OH) ₂ (300 mg, 20% Wt, 0.47 Eq, 427 ^mol) in MeOH (15 mL) and THF (15 mL) was degassed and purged with H2 for 3 times, and then the mixture was stirred at 25 °C for 16 hour under H2 atmosphere (15 psi). The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was concentrated under reduced pressure to give desired compound as a yellow oil, which was further separated by SFC (condition: column: DAICEL CHIRALPAK AD(250mm*30mm,10um); mobile phase: [0.1% NH3.H2O EtOH]; B%: 35%-35%) to give (5S,6S)-6-cyclohexyl-5-(4-(4- (dimethoxymethyl)piperidin-1-yl)phenyl)-8,8-difluoro-5,6,7,8 -tetrahydronaphthalen-2-ol (80 mg, 0.16 mmol, 18 ) and (5R,6R)-6-cyclohexyl-5-(4-(4-(dimethoxymethyl)piperidin-1- yl)phenyl)-8,8-difluoro-5,6,7,8-tetrahydronaphthalen-2-ol (130 mg, 263 ^mol, 29 %) as yellow solid. LC-MS (ESI ⁺ ) m/z: 500.2 (M+H-56) ⁺ . Step 4: To a solution of (5S, 6S)-6-cyclohexyl-5-(4-(4-(dimethoxymethyl)piperidin-1- yl)phenyl)-8,8-difluoro-5,6,7,8-tetrahydronaphthalen-2-ol (80 mg, 1 Eq, 0.16 mmol) in 10% H ₂ SO ₄ (4 mL) and THF (4 mL) was stirred at 70 °C for 1 hour . LCMS showed 100% desired MS. The reaction was adjust to pH=8 with aq.NaHCO ₃ (30 mL).Then the mixture was added water (30 mL ) and extracted with ethyl acetate (2×30 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to dryness in vacuo to give 1-(4-((1S,2S)-2-cyclohexyl-4,4-difluoro-6-hydroxy-1,2,3,4- tetrahydronaphthalen-1-yl)phenyl)piperidine-4-carbaldehyde (80 mg, 0.18 mmol, 100% purity) as a yellow solid. LC-MS (ESI ⁺ ) m/z: 472.3 (M+H2O) ⁺ Step 5: To a solution of 1-(4-((1S,2S)-2-cyclohexyl-4,4-difluoro-6-hydroxy-1,2,3,4- tetrahydronaphthalen-1-yl)phenyl)piperidine-4-carbaldehyde (80 mg, 1 Eq, 0.18 mmol), (R)-3- (1-oxo-5-(piperazin-1-yl)isoindolin-2-yl)piperidine-2,6-dion e, TsOH salt(88 mg, 1 Eq, 0.18 mmol) in DCM (3 mL), MeOH (3 mL) was added Sodium acetate (43 mg, 3 Eq, 0.53 mmol) was stirred at 25 °C for 60 mins, Then Na(OAc) ₃ BH (75 mg, 2 Eq, 0.35 mmol) and acetic acid (32 mg, 30 ^L, 3 Eq, 0.53 mmol) was added .The mixture was stirred at 25 °C for 16 hour. The reaction was quenched with H ₂ O (50 mL) and extracted with ethyl acetate (50 mL*2). The organic layer was washed with brine (30 mL) and dried over Na ₂ SO ₄ and concentrated in vacuo to give a yellow oil. The residue was purified by prep-HPLC (column: Welch Xtimate C18 150*30mm*5um;mobile phase: [water(FA)-ACN];B% 31%-51%,7min) to give (S)-3-(5-(4-((1- (4-((1S,2S)-2-cyclohexyl-4,4-difluoro-6-hydroxy-1,2,3,4-tetr ahydronaphthalen-1- yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindo lin-2-yl)piperidine-2,6-dione (43.4 mg, 56.1 ^mol, 32 %, 98.930% Purity) was obtained as a white solid. LCMS: calc. for C45H53F2N5O4: 765.95, found: [M+H]+ 766.2. HPLC: 98.930% purity at 220 nm. ¹ H NMR (400 MHz, DMSO-d ₆ ) į = 10.95 (s, 1H), 9.63 (br d, J = 1.3 Hz, 1H), 8.21 - 8.18 (m, 0.217H), 7.52 (d, J = 8.5 Hz, 1H), 7.09 - 7.04 (m, 2H), 6.98 (s, 1H), 6.86 - 6.78 (m, 3H), 6.78 - 6.73 (m, 2H), 6.87 - 6.72 (m, 1H), 5.05 (dd, J = 5.1, 13.1 Hz, 1H), 4.38 - 4.29 (m, 1H), 4.26 - 4.17 (m, 2H), 3.68 - 3.58 (m, 2H), 3.39 (br s, 1H), 3.31 - 3.29 (m, 3H), 3.23 (br d, J = 6.2 Hz, 1H), 2.95 - 2.85 (m, 1H), 2.65 - 2.53 (m, 5H), 2.45 - 2.34 (m, 2H), 2.29 - 2.18 (m, 3H), 2.16 - 2.03 (m, 2H), 2.00 - 1.92 (m, 2H), 1.83 - 1.64 (m, 3H), 1.64 (br s, 1H), 1.61 - 1.51 (m, 2H), 1.30 - 1.25 (m, 1H), 1.33 - 1.00 (m, 7H), 0.83 - 0.70 (m, 1H) SFC: retention time, 2.824 min; Area, 93.589%.

EXAMPLE 8. Preparation of (I-99) (S)-3-(5-(4-((1-(4-((1R,2R)-2-cyclohexyl-4,4- difluoro-6-hydroxy-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl) piperidin-4- yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2, 6-dione Step 1: To a solution of (5R, 6R)-6-cyclohexyl-5-(4-(4-(dimethoxymethyl)piperidin-1- yl)phenyl)-8,8-difluoro-5,6,7,8-tetrahydronaphthalen-2-ol (130 mg, 1 Eq, 260 ^mol) in 10% H ₂ SO ₄ (4 mL) and THF (4 mL) was stirred at 70 °C for 1 hour . LCMS showed 77.158% desired MS. The reaction was adjust to pH=8 with aq.NaHCO ₃ (30 mL).Then the mixture was added water (30 mL ) and extracted with ethyl acetate (2×30 mL). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to dryness in vacuo to give 1-(4-((1R,2R)-2-cyclohexyl-4,4-difluoro-6-hydroxy-1,2,3,4- tetrahydronaphthalen-1-yl)phenyl)piperidine-4-carbaldehyde (140 mg, 269 ^mol, 104 %, 77.158% purity) as a yellow solid. LC-MS (ESI ⁺ ) m/z: 472.4 (M+H ₂ O) ⁺ Step 2: To a solution of 1-(4-((1R,2R)-2-cyclohexyl-4,4-difluoro-6-hydroxy-1,2,3,4- tetrahydronaphthalen-1-yl)phenyl)piperidine-4-carbaldehyde (140 mg, 1 Eq, 309 ^mol), (R)-3- (1-oxo-5-(piperazin-1-yl)isoindolin-2-yl)piperidine-2,6-dion e, TsOH salt (154 mg, 1 Eq, 309 ^mol) in DCM (3 mL), MeOH (3 mL) was added Sodium acetate (76.0 mg, 3 Eq, 926 ^mol) was stirred at 25 °C for 60 mins, Then Na(OAc) ₃ BH (131 mg, 2 Eq, 617 ^mol) and acetic acid (55.6 mg, 53.3 ^L, 3 Eq, 926 ^mol) was added .The mixture was stirred at 25 °C for 16 hour. The reaction was quenched with H ₂ O (50 mL) and extracted with ethyl acetate (50 mL*2). The organic layer was washed with brine (30 mL) and dried over Na ₂ SO ₄ and concentrated in vacuo to give a yellow oil. The residue was purified by prep-HPLC (column: Welch Xtimate C18150*30mm*5um;mobile phase: [water(FA)-ACN];B% 30%-50%,7min) to give (S)-3-(5-(4- ((1-(4-((1R,2R)-2-cyclohexyl-4,4-difluoro-6-hydroxy-1,2,3,4- tetrahydronaphthalen-1- yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindo lin-2-yl)piperidine-2,6-dione (62.6 mg, 78.9 ^mol, 25.6 %, 96.547% Purity) was obtained as a white solid. LCMS: calc for C ₄₅ H ₅₃ F ₂ N ₅ O ₄ : 76595 found: [M+H] ⁺ 7662 HPLC: 96.547% purity at 220 nm. ¹ H NMR (400 MHz, DMSO-d6) į = 10.95 (s, 1H), 9.71 - 9.57 (m, 1H), 8.21 - 8.19 (m, 0.171H), 7.52 (d, J = 8.6 Hz, 1H), 7.10 - 7.04 (m, 2H), 6.98 (s, 1H), 6.78 - 6.73 (m, 2H), 6.87 - 6.71 (m, 4H), 5.05 (dd, J = 5.1, 13.2 Hz, 1H), 4.37 - 4.29 (m, 1H), 4.26 - 4.18 (m, 2H), 3.68 - 3.57 (m, 2H), 3.41 (br s, 1H), 3.29 - 3.29 (m, 1H), 3.29 - 3.25 (m, 1H), 2.96 - 2.85 (m, 1H), 2.58 (br d, J = 13.8 Hz, 4H), 2.53 (br s, 3H), 2.46 - 2.25 (m, 3H), 2.21 (br d, J = 7.3 Hz, 2H), 2.14 - 1.90 (m, 4H), 1.79 (br d, J = 11.6 Hz, 2H), 1.75 - 1.61 (m, 2H), 1.60 - 1.52 (m, 2H), 1.30 - 1.26 (m, 1H), 1.32 - 0.98 (m, 7H), 0.85 - 0.70 (m, 1H) SFC: retention time, 2.922 min; Area, 90.839%. EXAMPLE 9. Preparation of (I-311) (S)-3-(5-(4-((1-(4-((1S,2R)-4,4-difluoro-2-(4- fluorophenyl)-6-hydroxy-1,2,3,4-tetrahydronaphthalen-1-yl)ph enyl)piperidin-4- yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2, 6-dione Step 1: 1,1'-Bis(di-t-butylphosphino)ferrocene palladium dichloride (0.10 g, 0.1 Eq, 0.16 mmol) was added to the mixture of 1-(4-(6-(benzyloxy)-2-bromo-4,4-difluoro-3,4-dihydronaphthal en-1- yl)phenyl)-4-(dimethoxymethyl)piperidine (1.0 g, 1 Eq, 1.6 mmol), (4-fluorophenyl)boronic acid (0.33 g, 1.5 Eq, 2.4 mmol) and sodium carbonate (0.50 g, 3 Eq, 4.7 mmol) in dioxane (12 mL) and H ₂ O (3 mL) at r.t.. N ₂ was bubbled into the mixture for 5 min. The reaction mixture was heated at 50 °C for 12 h. The mixture was added with H2O (100 mL) and extracted with EtOAc (100 2) h bi d d i d h d SO fil d d concentrated to dryness in vacuo to give a residue. The residue was subjected to column chromatography over silica gel (petroleum ether/ethyl acetate from 100/0 to 70/30). The pure fractions were collected and concentrated to dryness in vacuo to give 1-(4-(6-(benzyloxy)-4,4- difluoro-2-(4-fluorophenyl)-3,4-dihydronaphthalen-1-yl)pheny l)-4-(dimethoxymethyl)piperidine (920 mg, 87.484% purity) as a yellow solid. LC-MS (ESI+) m/z: 600.2 (M+H) ⁺ . Step 2: A mixture of 1-(4-(6-(benzyloxy)-4,4-difluoro-2-(4-fluorophenyl)-3,4- dihydronaphthalen-1-yl)phenyl)-4-(dimethoxymethyl)piperidine (920 mg, 1 Eq, 1.34 mmol), 10% Pd/C(500 mg, 470 ^mol), 20% Pd(OH) ₂ /C (500 mg, 712 ^mol) in MeOH (10 mL) and THF (10 mL) was degassed and purged with H ₂ for 3 times, then the mixture was stirred at 25 °C for 16 h under H ₂ atmosphere (15 psi). The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by SFC (condition: column: DAICEL CHIRALCEL OJ(250mm*30mm,10um));mobile phase: [CO2- MeOH(0.1%NH3H2O)];B%: 35%-35%, min) to give (5S,6R)-5-(4-(4- (dimethoxymethyl)piperidin-1-yl)phenyl)-8,8-difluoro-6-(4-fl uorophenyl)-5,6,7,8- tetrahydronaphthalen-2-ol (310 mg, 98.821% purity) and(5R,6S)-5-(4-(4- (dimethoxymethyl)piperidin-1-yl)phenyl)-8,8-difluoro-6-(4-fl uorophenyl)-5,6,7,8- tetrahydronaphthalen-2-ol (340 mg, 98.523% purity) as white solids. LC-MS (ESI+) m/z: 512.2 (M+H) ⁺ . Step 3: To a solution of (5S,6R)-5-(4-(4-(dimethoxymethyl)piperidin-1-yl)phenyl)-8,8- difluoro- 6-(4-fluorophenyl)-5,6,7,8-tetrahydronaphthalen-2-ol (310 mg, 1 Eq, 599 ^mol) in THF (4 mL) and 10%H ₂ SO ₄ (4 mL) was stirred at 70 °C for 1 h. The reaction was adjust to pH=8 with aq.NaHCO ₃ . Then the mixture was added H ₂ O (50 mL) and extracted with ethyl acetate (50 mL x 2). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to dryness in vacuo to give 1-(4-((1S,2R)-4,4-difluoro-2-(4- fluorophenyl)-6-hydroxy-1,2,3,4-tetrahydronaphthalen-1-yl)ph enyl)piperidine-4-carbaldehyde (310 mg, 89.142% purity) as a yellow solid. LC-MS (ESI+) m/z: 466.0 (M+H) ⁺ . Step 4: A mixture of 1-(4-((1S,2R)-4,4-difluoro-2-(4-fluorophenyl)-6-hydroxy-1,2, 3,4- tetrahydronaphthalen-1-yl)phenyl)piperidine-4-carbaldehyde (310 mg, 1 Eq, 594 ^mol), (S)-3- (1-oxo-5-(piperazin-1-yl)isoindolin-2-yl)piperidine-2,6-dion e, PhSO3H salt (386 mg, 1.3 Eq, 772 ^mol) and sodium acetate (243 mg, 5 Eq, 2.97 mmol) and acetic acid (107 mg, 3 Eq, 1.78 mmol) 2 Eq, 1.19 mmol) was added to the mixture and was stirred at 25 °C for 16 h. Then the mixture was added H2O (50 mL) and extracted with ethyl acetate (50 mL x 2). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to dryness in vacuo to give a residue. The residue was purified by prep-HPLC (column: Xtimate C18150*40mm*5um; mobile phase: [water (FA)-ACN]; B% 13%-53%, 9 min) to give (S)-3-(5-(4-((1-(4-((1S,2R)-4,4-difluoro-2-(4-fluorophenyl)- 6-hydroxy-1,2,3,4- tetrahydronaphthalen-1-yl)phenyl)piperidin-4-yl)methyl)piper azin-1-yl)-1-oxoisoindolin-2- yl)piperidine-2,6-dione (222.5 mg, 100% purity) as a white solid. LC-MS (ESI+) m/z: 778.1 (M+H) ⁺ . LCMS: calc. for C ₄₅ H ₄₆ F ₃ N ₅ O ₄ : 777.35, found: [M+H] ⁺ 778.1. HPLC: 100% purity at 220 nm. ¹ HNMR (400MHz, DMSO-d ₆ ) į = 10.96 (s, 1H), 9.76 (br s, 1H), 8.15 (s, 1H), 7.52 (d, J=8.6 Hz, 1H), 7.10 - 7.00 (m, 5H), 6.97 - 6.83 (m, 4H), 6.61 (d, J=8.7 Hz, 2H), 6.15 (d, J=8.6 Hz, 2H), 5.05 (dd, J=5.1, 13.3 Hz, 1H), 4.37 - 4.27 (m, 2H), 4.24 - 4.17 (m, 1H), 3.75 - 3.64 (m, 1H), 3.55 (br s, 3H), 3.28 (br s, 7H), 2.96 - 2.85 (m, 1H), 2.71 - 2.54 (m, 3H), 2.49 - 2.47 (m, 1H), 2.43 - 2.26 (m, 2H), 2.20 (br d, J=7.0 Hz, 2H), 2.02 - 1.91 (m, 1H), 1.81 - 1.59 (m, 3H), 1.23 - 1.08 (m, 2H) SFC: retention time, 2.504 min; Area, 96.302 %. EXAMPLE 10. Preparation of (I-192) (S)-3-(5-(4-((1-(4-((1R,2S)-4,4-difluoro-2-(4- fluorophenyl)-6-hydroxy-1,2,3,4-tetrahydronaphthalen-1-yl)ph enyl)piperidin-4- yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2, 6-dione Step 1: To a solution of (5R,6S)-5-(4-(4-(dimethoxymethyl)piperidin-1-yl)phenyl)-8,8- difluoro- 6-(4-fluorophenyl)-5,6,7,8-tetrahydronaphthalen-2-ol (340 mg, 1 Eq, 655 ^mol) in THF (4 mL) and 10% H ₂ SO ₄ (4 mL) was stirred at 70 °C for 1 h. The reaction mixture was quenched by addition NaHCO3 at 0°C, then added H2O (30 mL), extracted with EtOAc (50 mL x 2). The combined organic layers were washed with brine (30 mL) and dried over Na2SO4, filtered and concentrated under reduced pressure to give 1-(4-((1R,2S)-4,4-difluoro-2-(4-fluorophenyl)-6- hydroxy-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperidine- 4-carbaldehyde (300 mg, 90.141% purity) as a yellow solid. LC-MS (ESI+) m/z: 466.1 (M+H) ⁺ . Step 2: A mixture of 1-(4-((1R,2S)-4,4-difluoro-2-(4-fluorophenyl)-6-hydroxy-1,2, 3,4- tetrahydronaphthalen-1-yl)phenyl)piperidine-4-carbaldehyde (300 mg, 1 Eq, 581 ^mol) , (S)-3- (1-oxo-5-(piperazin-1-yl)isoindolin-2-yl)piperidine-2,6-dion e, PhSO ₃ H salt (378 mg, 1.3 Eq, 755 ^mol) and sodium acetate (238 mg, 5 Eq, 2.90 mmol) and acetic acid (105 mg, 3 Eq, 1.74 mmol) in THF (8 mL) and MeOH (8 mL) at 25 °C for 1 h, then sodium triacetoxyborohydride (246 mg, 2 Eq, 1.16 mmol) was added to the mixture and was stirred at 25 °C for 16 h. The mixture was added H ₂ O (20 mL), extracted with ethyl acetate (20 mL x 2). The combined extracts was dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to dryness in vacuo to give a residue. The residue was purified by prep-HPLC (column: Welch Xtimate C18150*30mm*5um ; mobile phase: [water(FA)-ACN];B% 13%-53%,9min) to give (S)-3-(5-(4-((1-(4-((1R,2S)-4,4-difluoro- 2-(4-fluorophenyl)-6-hydroxy-1,2,3,4-tetrahydronaphthalen-1- yl)phenyl)piperidin-4- yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2, 6-dione (195.8 mg, 99.793% purity) as a white solid. LC-MS (ESI+) m/z: 778.2 (M+H) +. LCMS: calc. for C ₄₅ H ₄₆ F ₃ N ₅ O ₄ : 777.35, found: [M+H] ⁺ 778.2. HPLC: 99.793% purity at 220 nm. ¹ HNMR (400MHz, DMSO-d ₆ ) į = 10.96 (s, 1H), 9.75 (br s, 1H), 8.15 (s, 1H), 7.52 (d, J=8.7 Hz, 1H), 7.11 - 6.99 (m, 5H), 6.98 - 6.82 (m, 4H), 6.61 (br d, J=8.7 Hz, 2H), 6.15 (d, J=8.6 Hz, 2H), 5.05 (dd, J=5.1, 13.3 Hz, 1H), 4.37 - 4.26 (m, 2H), 4.25 - 4.17 (m, 1H), 3.70 (br d, J=13.4 Hz, 1H), 3.55 (br s, 3H), 3.28 (br s, 7H), 2.97 - 2.84 (m, 1H), 2.70 - 2.54 (m, 3H), 2.49 - 2.47 (m, 1H), 2.42 - 2.26 (m, 2H), 2.21 (br d, J=6.9 Hz, 2H), 2.02 - 1.91 (m, 1H), 1.82 - 1.59 (m, 3H), 1.22 - 1.07 (m, 2H) SFC: retention time, 2.620 min; Area, 90.272%. EXAMPLE 11. Preparation of (I-196) (3S)-3-[5-[4-[[1-[4-[(1R,2S)-2- (cyclopentylmethyl)-4,4-difluoro-6-hydroxy-tetralin-1-yl]phe nyl]-4- piperidyl]methyl]piperazin-1-yl]-1-oxo-isoindolin-2-yl]piper idine-2,6-dione Step 1: A mixture of 2,2,6,6-tetramethyl piperidine (1.2 g, 1.5 mL, 1.2 Eq, 8.9 mmol) was dissolved in THF (20 mL) and cooled to -30 °C under N ₂ atmosphere. N-butyllithium (3.6 mL, 2.5 molar, 1.2 Eq, 8.9 mmol) was added dropwise, and the reaction mixture was stirred at the same temperature for 30 min. Next, the reaction was cooled to -78 °C, and a solution of bis(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)methane (2 g, 1 Eq, 7.46 mmol) in THF (20 mL) was added dropwise. After stirring for 30 min, a solution of cyclopentanone (753 mg, 1.2 Eq, 8.9 mmol) in THF (13 mL) was added dropwise at -78 °C. The reaction mixture was allowed to slowly warm up to 25 °C, and stirred 16 hour. TLC (PE: EtOAc=2:1, R _F= 0.4) showed three t d t t d Th ti h d b t t d i hl id l ti (30 mL), then stirred for 0.5 h. Water (200 mL) was added then the mixture was extracted with EtOAc (150 mL x 3). The organic layers was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to yield (compound B) (cyclopentylidenemethyl)-4, 4, 5, 5- tetramethyl-1, 3, 2-dioxaborolane (1.5 g, 7.2 mmol, 97% yield) as a yellow oil and used without additional purification. Step 2: A mixture of 1-[4-(6-benzyloxy-2-bromo-4,4-difluoro-3H-naphthalen-1-yl)ph enyl]-4- (dimethoxymethyl)piperidine (270 mg, 461.9 ^mol, 1 eq) , 2-(cyclopentylidenemethyl)-4,4,5,5- tetramethyl-1,3,2-dioxaborolane (288.4 mg, 1.39 mmol, 3 eq) , Na ₂ CO ₃ (147 mg, 1.4 mmol, 3 eq) , 1,1'-Bis(di-t-butylphosphino)ferrocene palladium dichloride (30.11 mg, 46.19 ^mol, 0.1 eq) in dioxane (4 mL) and H ₂ O (1 mL) was degassed and purged with N ₂ for 3 times, and then the mixture was stirred at 50 °C for 16 hr under N ₂ atmosphere. The reaction mixture was diluted with 20 mL H ₂ O and extracted with ethyl acetate (20 mL * 2). The combined organic layers were washed with 20 mL brine, dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether/ethyl acetate= 5/1). Compound 1-[4-[6-benzyloxy-2-(cyclopentylidenemethyl)- 4,4-difluoro-3H-naphthalen-1-yl]phenyl]-4-(dimethoxymethyl)p iperidine (260 mg, 443.9 ^mol, 96.09% yield) was obtained as a yellow solid. LC-MS (ESI+) m/z: 586.3 (M+H) ⁺ . Step 3: To a solution of 1-[4-[6-benzyloxy-2-(cyclopentylidenemethyl)-4,4-difluoro-3H - naphthalen-1-yl]phenyl]-4-(dimethoxymethyl)piperidine (400 mg, 683 ^mol, 1 eq) in THF (4 mL) and MeOH (4 mL) was added Pd/C (0.2 g, 188 ^mol, 10% purity), Pd(OH) ₂ /C (0.1 g, 163 ^mol, 20% purity) under N ₂ atmosphere. The suspension was degassed and purged with H ₂ for 3 times. The mixture was stirred under H ₂ (15 Psi) at 25 °C for 16 hr. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Welch Xtimate C18150*30mm*5um; mobile phase: [water (FA)-ACN]; gradient: 65%-95% B over 7 min) and was further separated by SFC (column: DAICEL CHIRALPAK AD (250mm*30mm, 10um); mobile phase: [CO2-EtOH]; B%:40%, isocratic elution mode). Compound (1R, 2S)-2-(cyclopentylmethyl)-1-[4-[4-(dimethoxymethyl)-1- piperidyl] phenyl]-4, 4-difluoro-tetralin-6-ol (48 mg, 96 ^mol, 14.07% yield) was obtained as a yellow solid. Compound (1S, 2R)-2-(cyclopentylmethyl)-1-[4-[4-(dimethoxymethyl)-1- piperidyl]phenyl]-4,4-difluoro-tetralin-6-ol (46 mg, 92.07 ^mol, 13.48% yield) was obtained as a white solidLC-MS (ESI+) m/z: 5002 (M+H) ⁺ Step 4: To a solution of (1R,2S)-2-(cyclopentylmethyl)-1-[4-[4-(dimethoxymethyl)-1- piperidyl]phenyl]-4,4-difluoro-tetralin-6-ol (48 mg, 96 ^mol, 1 eq) in THF (4 mL) was added 10% H ₂ SO ₄ (4 mL) .The mixture was stirred at 70 °C for 40 min. The reaction mixture was quenched by addition 20 mL saturated aq. NaHCO ₃ solution at 25 °C, and then diluted with 5 mL H ₂ O and extracted with 30 mL ethyl acetate. The combined organic layers were washed with 20 mL brine, dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The crude product 1-[4-[(1R, 2S)-2-(cyclopentylmethyl)-4,4-difluoro-6-hydroxy-tetralin-1- yl] phenyl] piperidine-4-carbaldehyde (85 mg, 90 ^mol, 94% yield, 95% purity) as a yellow oil was used into the next step without further purification. LC-MS (ESI+) m/z: 454.3 (M+H) ⁺ . Step 5: To a solution of 1-[4-[(1R,2S)-2-(cyclopentylmethyl)-4,4-difluoro-6-hydroxy-t etralin-1- yl]phenyl]piperidine-4-carbaldehyde (85 mg, 90 ^mol, 1.0 eq) and (3S)-3-(1-oxo-5-piperazin-1- yl-isoindolin-2-yl)piperidine-2,6-dione (45 mg, 90 ^mol, 1.0 eq, PhSO ₃ H salt) in DCM (4 mL) and MeOH (4 mL) was added sodium acetate (22 mg, 270 ^mol, 3 eq). The mixture was stirred at 30 °C for 0.5 hr. Then the mixture was added NaBH(OAc) ₃ (38 mg, 180 ^mol, 2 eq) and acetic acid (16 mg, 270 ^mol, 15 ^L, 3 eq) .The mixture was stirred at 30 °C for 16 h. The reaction mixture was diluted with 10 mL H2O and extracted with 20 mL DCM. The combined organic layers were washed with 10 mL brine, dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Welch Xtimate C18150*30mm*5um; mobile phase: [water (FA)-ACN]; gradient: 27%-57% B over 7 min). Compound (3S)-3-[5-[4-[[1-[4-[(1R,2S)-2-(cyclopentylmethyl)-4,4-diflu oro-6-hydroxy- tetralin-1-yl]phenyl]-4-piperidyl]methyl]piperazin-1-yl]-1-o xo-isoindolin-2-yl]piperidine-2,6- dione (26.9 mg, 35 ^mol, 39% yield) was obtained as a white solid. LC-MS (ESI ⁺ ) m/z: 766.5 (M+H) ⁺ . HPLC: 98.7%, purity at 220 nm. SFC: Rt: 3.023 min; Area, 94.214%. NMR (400 MHz, DMSO-d ₆ ) į ppm 10.96 (s, 1 H) 9.42 - 9.92 (m, 1 H) 8.16 (s, 0.563 H) 7.48 - 7.56 (m, 1 H) 7.03 - 7.10 (m, 2 H) 7.00 (s, 1 H) 6.78 - 6.85 (m, 4 H) 6.71 (br d, J=8.58 Hz, 2 H) 5.05 (dd, J=13.17, 4.95 Hz, 1 H) 4.30 - 4.37 (m, 1 H) 4.16 - 4.24 (m, 1 H) 4.06 (br d, J=1.67 Hz, 1 H) 3.61 (br d, J=4.77 Hz, 3 H) 3.29 (br s, 8 H) 2.86 - 2.93 (m, 1 H) 2.55 - 2.61 (m, 3 H) 2.32 - 2.40 (m, 1 H) 2.18 - 2.24 (m, 3 H) 1.90 - 2.01 (m, 3 H) 1.76 - 1.83 (m, 2 H) 1.71 (br d, J=5.72 Hz, 3 H) 1.47 - 1.60 (m, 4 H) 1.15 - 1.29 (m, 3 H) 1.02 (br dd, J=7.03, 3.70 Hz, 2 H) 0.82 - 0.92 (m, 1 H) EXAMPLE 12. Preparation of (I-229) (3S)-3-[5-[4-[[1-[4-[(1S,2R)-2- (cyclopentylmethyl)-4,4-difluoro-6-hydroxy-tetralin-1-yl]phe nyl]-4- piperidyl]methyl]piperazin-1-yl]-1-oxo-isoindolin-2-yl]piper idine-2,6-dione Step 1: To a solution of (1S, 2R)-2-(cyclopentylmethyl)-1-[4-[4-(dimethoxymethyl)-1-piperi dyl] phenyl]-4, 4-difluoro-tetralin-6-ol (46.00 mg, 92 ^mol, 1 eq) in THF (4 mL) was added 10% H ₂ SO ₄ (4 mL) .The mixture was stirred at 70 °C for 40 min. The reaction mixture was quenched by addition 20 mL saturated NaHCO ₃ aqueous solution at 25 °C, and then diluted with 5 mL H ₂ O and extracted with 30 mL ethyl acetate. The combined organic layers were washed with brine 20 mL, dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The crude product 1-[4-[(1S,2R)-2-(cyclopentylmethyl)-4,4-difluoro-6-hydroxy-t etralin- 1-yl]phenyl]piperidine-4-carbaldehyde (80 mg, 84.66 ^mol, 91.96% yield) was used in the next step without further purification. Compound 1-[4-[(1S,2R)-2-(cyclopentylmethyl)-4,4-difluoro- 6-hydroxy-tetralin-1-yl]phenyl]piperidine-4-carbaldehyde (80 mg, 84.66 ^mol, 91.96% yield) was obtained as a yellow oil.LC-MS (ESI+) m/z: 454.2 (M+H) ⁺ . Step 2: To a solution of 1-[4-[(1S,2R)-2-(cyclopentylmethyl)-4,4-difluoro-6-hydroxy-t etralin-1- yl]phenyl]piperidine-4-carbaldehyde (80 mg, 84.66 ^mol, 1 eq) and (3S)-3-(1-oxo-5-piperazin- 1-yl-isoindolin-2-yl)piperidine-2,6-dione (42.38 mg, 84.66 ^mol, 1 eq, PhSO ₃ H salt) in DCM (4 mL) and MeOH (4 mL) was added sodium acetate (20.84 mg, 253.99 ^mol, 3 eq) .The mixture was stirred at 30 °C for 0.5 hr. Then the mixture was added NaBH(OAc) ₃ (35 mg, 169 ^mol, 2 eq) and acetic acid (15 mg, 254 ^mol, 14 ^L, 3 eq) .The mixture was stirred at r.t. for 16 hr combined organic layers were washed with 10 mL brine, dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Welch Xtimate C18150*30mm*5um; mobile phase: [water (FA)-ACN]; gradient: 27%-57% B over 7 min). Compound (3S)-3-[5-[4-[[1-[4-[(1S,2R)-2-(cyclopentylmethyl)-4,4- difluoro-6-hydroxy-tetralin-1-yl]phenyl]-4-piperidyl]methyl] piperazin-1-yl]-1-oxo-isoindolin-2- yl]piperidine-2,6-dione (25.8 mg, 33.68 ^mol, 39.79% yield) was obtained as a white solid. LC-MS (ESI ⁺ ) m/z: 766.5 (M+H) ⁺ . HPLC: 98.986%, purity at 220 nm. SFC: Rt: 2.875 min; Area, 94.205%. ¹ H NMR (400 MHz, DMSO-d ₆ ) į ppm 10.96 (s, 1 H) 9.59 - 9.74 (m, 1 H) 8.17 (s, 0.367 H) 7.52 (d, J=8.23 Hz, 1 H) 7.03 - 7.09 (m, 2 H) 6.95 - 7.02 (m, 1 H) 6.78 - 6.85 (m, 4 H) 6.71 (br d, J=8.34 Hz, 2 H) 5.01 - 5.09 (m, 1 H) 4.29 - 4.38 (m, 1 H) 4.16 - 4.24 (m, 1 H) 4.03 - 4.09 (m, 1 H) 3.58 - 3.66 (m, 3 H) 3.29 (br s, 8 H) 2.86 - 2.94 (m, 1 H) 2.56 - 2.62 (m, 3 H) 2.37 (br dd, J=13.47, 4.53 Hz, 1 H) 2.18 - 2.24 (m, 3 H) 1.91 - 2.02 (m, 3 H) 1.80 (br d, J=12.87 Hz, 2 H) 1.65 - 1.74 (m, 3 H) 1.47 - 1.60 (m, 4 H) 1.16 - 1.29 (m, 3 H) 0.98 - 1.06 (m, 2 H) 0.81 - 0.93 (m, 1 H)

EXAMPLE 13. Preparation of (I-234) (S)-3-(5-(4-((1-(4-((1S,2S)-2-cyclopentyl-4,4- difluoro-6-hydroxy-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl) piperidin-4- yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2, 6-dione Step 1: 1,1'-Bis(di-t-butylphosphino)ferrocene palladium dichloride (61.5 mg, 0.1 Eq, 94.4 ^mol) was added to the mixture of 1-(4-(6-(benzyloxy)-2-bromo-4,4-difluoro-3,4- dihydronaphthalen-1-yl)phenyl)-4-(dimethoxymethyl)piperidine (600 mg, 1 Eq, 944 ^mol), cyclopent-1-en-1-ylboronic acid (127 mg, 1.2 Eq, 1.1 mmol) and Na ₂ CO ₃ (300 mg, 3 Eq, 2.8 mmol) in 1,4-dioxane (8 mL) and H ₂ O (2 mL) at r.t..N ₂ was bubbled into the mixture for 5 min. The reaction mixture was heated at 50 °C for 16 hour. Then the reaction was cooled to room temperature. TLC (PE/EtOAc = 2/1, R _f = 0.4) showed a new spot was detected. The mixture was filtered and the filter cake was washed with EtOAc (50 mL). The filtrate was treated with H ₂ O (150 mL), extracted with EtOAc (150 mL * 2). The combined extracts was dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to dryness in vacuo to give a residue. The residue was subjected to column chromatography over silica gel (petroleum ether/ethyl acetate from 100/0 to 70/30). The pure fractions were collected and concentrated to dryness in vacuo to give 1-(4-(6- (benzyloxy)-2-(cyclopent-1-en-1-yl)-4,4-difluoro-3,4-dihydro naphthalen-1-yl)phenyl)-4- (dimethoxymethyl)piperidine (450 mg, 787 ^mol, 83.4 % yield) as a yellow solid. LC-MS (ESI ⁺ ) m/z: 571.2 (M+H) ⁺ . Step 2: A mixture of 1-(4-(6-(benzyloxy)-2-(cyclopent-1-en-1-yl)-4,4-difluoro-3,4 - dihydronaphthalen-1-yl)phenyl)-4-(dimethoxymethyl)piperidine (400 mg, 1 Eq, 700 ^mol) , Pd/C (200 mg, 10% Wt, 0.269 Eq, 188 ^mol), Pd(OH) ₂ /C (200 mg, 20% Wt, 0.407 Eq, 285 ^mol) in MeOH (15 mL) and THF (15 mL)was degassed and purged with H ₂ for 3 times, and then the mixture was stirred at 25 °C for 16 hour under H ₂ atmosphere(15 psi). The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was concentrated under reduced pressure to give desired compound as a yellow oil, which was further separated by SFC (condition: column: DAICEL CHIRALPAK AD (250mm*30mm,10um); mobile phase: [0.1% NH ₃ .H ₂ O EtOH]; B%: 40%-40%) to give (5S,6S)- 6-cyclopentyl-5-(4-(4-(dimethoxymethyl)piperidin-1-yl)phenyl )-8,8-difluoro-5,6,7,8- tetrahydronaphthalen-2-ol (60 mg, 0.11 mmol, 16 %, 92.4% purity) and (5R,6R)-6-cyclopentyl- 5-(4-(4-(dimethoxymethyl)piperidin-1-yl)phenyl)-8,8-difluoro -5,6,7,8-tetrahydronaphthalen-2-ol (80 mg, 0.15 mmol, 21 %, 88.2% purity) as yellow solid. LC-MS (ESI ⁺ ) m/z: 486.2 (M+H) ⁺ . Step 3: To a solution of (5S,6S)-6-cyclopentyl-5-(4-(4-(dimethoxymethyl)piperidin-1- yl)phenyl)-8,8-difluoro-5,6,7,8-tetrahydronaphthalen-2-ol (60 mg, 1 Eq, 0.12 mmol) in 10% H ₂ SO ₄ (2 mL) and THF (2 mL) was stirred at 70 °C for 1 hour .TLC (petroleum ether: ethyl acetate=3:1,R _f =0.4, UV) showed a new spot was desired. The reaction was adjust to pH=~8 with aq.NaHCO ₃ (20 mL).Then the mixture was added water(30 mL) and extracted with ethyl acetate (30×2 mL).The combined organic layers were washed with brine(30 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to dryness in vacuum to give 1-(4-((1S,2S)-2-cyclopentyl-4,4- difluoro-6-hydroxy-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl) piperidine-4-carbaldehyde (70 mg, 0.16 mmol) as a yellow solid. Step 4: To a solution of 1-(4-((1S,2S)-2-cyclopentyl-4,4-difluoro-6-hydroxy-1,2,3,4- tetrahydronaphthalen-1-yl)phenyl)piperidine-4-carbaldehyde (70.0 mg, 1 Eq, 159 ^mol), (S)-3- (1-oxo-5-(piperazin-1-yl)isoindolin-2-yl)piperidine-2,6-dion e, PhSO ₃ H salt (120 mg, 1.5 Eq, 239 ^mol) in DCM (4 mL) and MeOH (4 mL) was added Sodium acetate (39.2 mg, 3 Eq, 478 ^mol) was stirred at 25 °C for 60 mins, Then Sodium triacetoxyborohydride (67.5 mg, 2 Eq, 319 ^mol) and acetic acid (28.7 mg, 27.5 ^L, 3 Eq, 478 ^mol) was added .The mixture was stirred at 25 °C for 16 hour. The reaction was quenched with H2O (50 mL) and extracted with ethyl acetate (50 mL*2) The organic layer was washed with brine (30 mL) and dried over Na ₂ SO ₄ and concentrated in vacuum to give a yellow oil. The residue was purified by prep-HPLC (column: Welch Xtimate C18150*30mm*5um;mobile phase: [water(FA)-ACN];B% 23%-53%,7min) to give (S)-3-(5-(4-((1-(4-((1S,2S)-2-cyclopentyl-4,4-difluoro-6-hyd roxy-1,2,3,4- tetrahydronaphthalen-1-yl)phenyl)piperidin-4-yl)methyl)piper azin-1-yl)-1-oxoisoindolin-2- yl)piperidine-2,6-dione (65.4 mg, 86.4 ^mol, 54.3 %, 99.4% Purity) was obtained as a white solid.LC-MS (ESI ⁺ ) m/z: 752.2 (M+H) ⁺ . LCMS: calc. 751.9, found: [M+H] ⁺ 752.2 HPLC: 99.4% purity at 220 nm. ¹ H NMR (400 MHz, DMSO-d ₆ ) į = 10.96 (s, 1H), 9.65 (br s, 1H), 8.14 (s, 0.474H), 7.53 (d, J = 8.7 Hz, 1H), 7.11 - 7.03 (m, 2H), 6.99 (s, 1H), 6.89 - 6.72(m, 6H), 5.06 (dd, J = 5.0, 13.2 Hz, 1H), 4.39 - 4.29 (m, 1H), 4.26 - 4.17 (m, 1H), 4.12 (br s, 1H), 3.62 (br d, J = 8.6 Hz, 2H), 3.30 (br s, 6H), 2.97 - 2.84 (m,1H), 2.65 - 2.55 (m, 5H), 2.40 - 2.31 (m, 1H), 2.24 (br d, J = 6.3 Hz, 3H), 2.18 - 2.10 (m, 1H), 2.09 - 2.01 (m, 1H), 1.99 - 1.86 (m, 2H), 1.80 (br d, J = 12.0Hz, 2H), 1.74 - 1.64 (m, 1H), 1.63 - 1.47 (m, 4H), 1.44 - 1.26 (m, 3H), 1.26 - 1.13 (m, 2H), 1.09 - 0.95 (m, 1H) SFC: retention time, 2.861 min; Area, 94.6 %. EXAMPLE 14. Preparation of (I-198) (S)-3-(5-(4-((1-(4-((1R,2R)-2-cyclopentyl-4,4- difluoro-6-hydroxy-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl) piperidin-4- yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2, 6-dione Step 1: To a solution of (5R,6R)-6-cyclopentyl-5-(4-(4-(dimethoxymethyl)piperidin-1- yl)phenyl)-8,8-difluoro-5,6,7,8-tetrahydronaphthalen-2-ol (80 mg, 1 Eq, 0.16 mmol) in 10% H ₂ SO ₄ (2 mL) and THF (2 mL) was stirred at 70 °C for 1 hour. TLC (petroleum ether: ethyl acetate=3:1, R _f =0.4, UV) showed a new spot was desired. The reaction was adjust to pH=~8 with aq.NaHCO ₃ (15 mL).Then the mixture was added water (30 mL ) and extracted with ethyl anhydrous Na2SO4, filtered and concentrated to dryness in vacuum to give 1-(4-((1R,2R)-2- cyclopentyl-4,4-difluoro-6-hydroxy-1,2,3,4-tetrahydronaphtha len-1-yl)phenyl)piperidine-4- carbaldehyde (80 mg, 0.18 mmol) as a yellow solid. Step 2: To a solution of 1-(4-((1R,2R)-2-cyclopentyl-4,4-difluoro-6-hydroxy-1,2,3,4- tetrahydronaphthalen-1-yl)phenyl)piperidine-4-carbaldehyde (80.0 mg, 1 Eq, 182 ^mol), (S)-3- (1-oxo-5-(piperazin-1-yl)isoindolin-2-yl)piperidine-2,6-dion e, PhSO ₃ H salt (137 mg, 1.5 Eq, 273 ^mol) in DCM (4 mL) and MeOH (4 mL) was added sodium acetate (44.8 mg, 3 Eq, 546 ^mol) was stirred at 25 °C for 60 mins, Then sodium triacetoxyborohydride (77.1 mg, 2 Eq, 364 ^mol) and acetic acid (32.8 mg, 31.4 ^L, 3 Eq, 546 ^mol) was added .The mixture was stirred at 25 °C for 16 hour. The reaction was quenched with H ₂ O (50 mL) and extracted with ethyl acetate (50 mL*2). The organic layer was washed with brine (30 mL) and dried over Na ₂ SO ₄ and concentrated in vacuo to give a yellow oil. The residue was purified by prep-HPLC (column: Welch Xtimate C18150*30mm*5um;mobile phase: [water(FA)-ACN];B% 23%-53%,7min) to give (S)-3-(5-(4-((1-(4-((1R,2R)-2-cyclopentyl-4,4-difluoro-6-hyd roxy-1,2,3,4- tetrahydronaphthalen-1-yl)phenyl)piperidin-4-yl)methyl)piper azin-1-yl)-1-oxoisoindolin-2- yl)piperidine-2,6-dione (33.6 mg, 44.0 ^mol, 24.2 %, 98.5% purity) was obtained as a white solid. LC-MS (ESI+) m/z: 752.2 (M+H) ⁺ . LCMS: calc. for C ₄₁ H ₅₁ F ₂ N ₅ O ₄ : 751.92, found: [M+H] ⁺ 752.2 HPLC: 98.5% purity at 220 nm. ¹ H NMR (400 MHz, DMSO-d ₆ ) į = 10.96 (s, 1H), 9.67 (br d, J = 5.8 Hz, 1H), 8.17 (s, 0.464H), 7.53 (d, J = 8.6 Hz, 1H), 7.10 - 7.03 (m, 2H), 6.99 (s, 1H),6.88 - 6.75 (m, 6H), 5.05 (dd, J = 5.0, 13.4 Hz, 1H), 4.39 - 4.28 (m, 1H), 4.27 - 4.16 (m, 1H), 4.12 (br d, J = 2.4 Hz, 1H), 3.63 (br dd, J = 3.1, 8.7 Hz, 3H),3.29 (br s, 6H), 2.96 - 2.85 (m, 1H), 2.66 - 2.55 (m, 4H), 2.40 - 2.30 (m, 1H), 2.21 (br d, J = 7.2 Hz, 3H), 2.17 - 2.10 (m, 1H), 2.09 - 2.01 (m, 1H), 1.99 - 1.87(m, 2H), 1.80 (br d, J = 11.7 Hz, 2H), 1.73 - 1.64 (m, 1H), 1.62 - 1.46 (m, 4H), 1.44 - 1.26 (m, 3H), 1.25 - 1.11 (m, 2H), 1.08 - 0.96 (m, 1H) SFC: retention time, 2.952 min; Area, 95.9 %. EXAMPLE 15. Preparation of (I-336) (S)-3-(5-(4-((1-(4-((1S,2R)-4,4-difluoro-6- hydroxy-2-(phenyl-d5)-1,2,3,4-tetrahydronaphthalen-1-yl)phen yl)piperidin-4- yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2, 6-dione Step 1.1,1'-Bis(di-t-butylphosphino)ferrocene palladium dichloride (40.8 mg, 0.1 Eq, 62.6 ^mol) was added to the mixture of 1-(4-(6-(benzyloxy)-2-bromo-4,4-difluoro-3,4-dihydronaphthal en-1- yl)phenyl)-4-(dimethoxymethyl)piperidine (400 mg, 1 Eq, 626 ^mol), B-(Phenyl-2,3,4,5,6- d5)boronic acid (95.3 mg, 1.2 Eq, 751 ^mol) and Sodium carbonate (199 mg, 3 Eq, 1.88 mmol) in Dioxane (8 mL) and H2O (2 mL) at r.t.. N2 was bubbled into the mixture for 5 min. The reaction mixture was heated at 50 °C for 12 h. The mixture was added with H ₂ O (100 mL) and extracted with EtOAc (100 mL x 2). The combined extracts was dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to dryness in vacuo to give a residue. The residue was subjected to column chromatography over silica gel (petroleum ether/ethyl acetate from 100/0 to 70/30). The pure fractions were collected and concentrated to dryness in vacuo to give 1-(4-(6-(benzyloxy)- 4,4-difluoro-2-(phenyl-d5)-3,4-dihydronaphthalen-1-yl)phenyl )-4-(dimethoxymethyl)piperidine (450 mg, 81.2 % Yield) as a yellow solid. LC-MS (ESI+) m/z: 587.0 (M+H) ⁺ . Step 2. A mixture of 1-(4-(6-(benzyloxy)-4,4-difluoro-2-(phenyl-d5)-3,4-dihydrona phthalen-1- yl)phenyl)-4-(dimethoxymethyl)piperidine (450 mg, 508 ^mol) , Pd/C (240 mg, 10% Wt, 226 ^mol), Pd(OH) ₂ /C (240 mg, 20% Wt, 342 ^mol) in MeOH (5 mL) and THF (5 mL) was H2 atmosphere (15 psi). The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by HPLC (condition: column: DAICEL Xtimate C18150*40mm*5um; mobile phase: [water(FA)- ACN];B%: 30%-70%, 9 min), then was purified by SFC (condition: column: DAICEL CHIRALCEL OJ(250mm*30mm,10um);mobile phase: [CO2-MeOH(0.1%NH3H2O)];B%: 35%-35%, min) to give (5S,6R)-5-(4-(4-(dimethoxymethyl)piperidin-1-yl)phenyl)-8,8- difluoro-6-(phenyl-d5)- 5,6,7,8-tetrahydronaphthalen-2-ol (58 mg, 92.265% purity) (5R,6S)-5-(4-(4- (dimethoxymethyl)piperidin-1-yl)phenyl)-8,8-difluoro-6-(phen yl-d5)-5,6,7,8- tetrahydronaphthalen-2-ol (54 mg, 98.992% purity) as white solids. LC-MS (ESI+) m/z: 499.1 (M+H) ⁺ . Step 3. To a solution of (5S,6R)-5-(4-(4-(dimethoxymethyl)piperidin-1-yl)phenyl)-8,8- difluoro- 6-(phenyl-d5)-5,6,7,8-tetrahydronaphthalen-2-ol (58 mg, 0.11 mmol) in THF (2 mL) and 10%H ₂ SO ₄ (2 mL) was stirred at 70 °C for 0.5 h. The reaction was adjust to pH=8 with aq. NaHCO ₃ at 0 °C. Then the mixture was added H ₂ O (10 mL) and extracted with ethyl acetate (20 mL x 2). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered and concentrated to dryness in vacuo to give 1-(4-((1S,2R)-4,4-difluoro-6- hydroxy-2-(phenyl-d5)-1,2,3,4-tetrahydronaphthalen-1-yl)phen yl)piperidine-4-carbaldehyde (50 mg, 97 %, 94.520% Purity) as a yellow solid. LC-MS (ESI+) m/z: 453.2 (M+H) ⁺ . Step 4. A mixture of 1-(4-((1S,2R)-4,4-difluoro-6-hydroxy-2-(phenyl-d5)-1,2,3,4- tetrahydronaphthalen-1-yl)phenyl)piperidine-4-carbaldehyde (50 mg, 0.10 mmol) , (S)-3-(1-oxo- 5-(piperazin-1-yl)isoindolin-2-yl)piperidine-2,6-dione, PhSO ₃ H salt (63 mg, 1.2 Eq, 0.13 mmol) and sodium acetate (43 mg, 5 Eq, 0.52 mmol) and acetic acid (19 mg, 3 Eq, 0.31 mmol) in THF (3 mL) and MeOH (3 mL) at 25 °C for 1 h, then sodium triacetoxyborohydride (44 mg, 2 Eq, 0.21 mmol) was added to the mixture and was stirred at 25 °C for 16 h. Then the mixture was added H ₂ O (20 mL) and extracted with EtOAc (20 mL x 2). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to dryness in vacuo to give a residue. The residue was purified by prep-HPLC (column: Welch Xtimate C18 150*30mm*5um; mobile phase: [water (FA)-ACN]; B% 15%-55%, 9 min) to give (S)-3-(5-(4- ((1-(4-((1S,2R)-4,4-difluoro-6-hydroxy-2-(phenyl-d5)-1,2,3,4 -tetrahydronaphthalen-1- yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindo lin-2-yl)piperidine-2,6-dione (45.6 mg 57 % 99842% purity) as a white solid LC-MS (ESI+) m/z: 7652 (M+H) ⁺ LCMS: calc. for C45H42D5F2N5O4: 764.93, found: [M+H] ⁺ 765.2. HPLC: 99.842% purity at 220 nm. ¹ HNMR (400MHz, DMSO-d ₆ ) į = 10.96 (s, 1H), 9.74 (br s, 1H), 8.16 (s, 1H), 7.52 (d, J=8.6 Hz, 1H), 7.11 - 7.03 (m, 3H), 6.91 - 6.83 (m, 2H), 6.57 (d, J=8.7 Hz, 2H), 6.13 (d, J=8.7 Hz, 2H), 5.05 (dd, J=5.0, 13.2 Hz, 1H), 4.37 - 4.28 (m, 2H), 4.24 - 4.16 (m, 1H), 3.67 (br d, J=15.1 Hz, 1H), 3.53 (br d, J=9.4 Hz, 3H), 3.28 (br s, 5H), 2.96 - 2.85 (m, 1H), 2.75 - 2.54 (m, 3H), 2.49 - 2.45 (m, 3H), 2.40 - 2.30 (m, 2H), 2.19 (br d, J=7.3 Hz, 2H), 2.01 - 1.91 (m, 1H), 1.75 (br d, J=13.1 Hz, 2H), 1.64 (br s, 1H), 1.22 - 1.07 (m, 2H) SFC: retention time, 2.620 min; Area, 97.354 %. EXAMPLE 16. Preparation of (I-335) (S)-3-(5-(4-((1-(4-((1R,2S)-4,4-difluoro-6- hydroxy-2-(phenyl-d5)-1,2,3,4-tetrahydronaphthalen-1-yl)phen yl)piperidin-4- yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2, 6-dione Step 1. To a solution of (5R,6S)-5-(4-(4-(dimethoxymethyl)piperidin-1-yl)phenyl)-8,8- difluoro- 6-(phenyl-d5)-5,6,7,8-tetrahydronaphthalen-2-ol (54 mg, 0.11 mmol) in THF (2 mL) and 10%H ₂ SO ₄ (2 mL) was stirred at 70 °C for 0.5 h. The reaction was adjust to pH=8 with aq. NaHCO ₃ at 0 °C. Then the mixture was added H ₂ O (10 mL) and extracted with ethyl acetate (20 mL x 2). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to dryness in vacuo to give 1-(4-((1R,2S)-4,4-difluoro-6- hydroxy-2-(phenyl-d5)-1,2,3,4-tetrahydronaphthalen-1-yl)phen yl)piperidine-4-carbaldehyde (50 mg, 96 %, 92.771% Purity) as a yellow solid. LC-MS (ESI+) m/z: 453.2 (M+H) ⁺ . Step 2. A mixture of 1-(4-((1R,2S)-4,4-difluoro-6-hydroxy-2-(phenyl-d5)-1,2,3,4- tetrahydronaphthalen-1-yl)phenyl)piperidine-4-carbaldehyde (50 mg, 0.10 mmol) , (S)-3-(1-oxo- 5-(piperazin-1-yl)isoindolin-2-yl)piperidine-2,6-dione, PhSO3H salt (62 mg, 1.2 Eq, 0.12 l) di t t (42 5 E 051 l) d ti id (18 3 E 031 l) i THF (3 mL) and MeOH (3 mL) at 25 °C for 1 h, then sodium triacetoxyborohydride (43 mg, 2 Eq, 0.20 mmol) was added to the mixture and was stirred at 25 °C for 16 h. The mixture was added H ₂ O (20 mL), extracted with EtOAc (20 mL x 2). The combined extracts was dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to dryness in vacuo to give a residue. The residue was purified by prep-HPLC (column: Welch Xtimate C18150*30mm*5um ; mobile phase: [water(FA)-ACN];B% 15%-55%, 9min) to give (S)-3-(5-(4-((1-(4-((1R,2S)-4,4-difluoro-6- hydroxy-2-(phenyl-d5)-1,2,3,4-tetrahydronaphthalen-1-yl)phen yl)piperidin-4- yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2, 6-dione (41.4 mg, 53 %, 99.557% purity) as a white solid. LC-MS (ESI+) m/z: 765.2 (M+H) ⁺ . LCMS: calc. for C ₄₅ H ₄₂ D ₅ F ₂ N ₅ O ₄ : 764.39, found: [M+H] ⁺ 765.2. HPLC: 99.557% purity at 220 nm. ¹ HNMR (400MHz, DMSO-d ₆ ) į = 10.96 (s, 1H), 9.75 (br s, 1H), 8.17 (s, 1H), 7.52 (d, J=8.7 Hz, 1H), 7.11 - 7.03 (m, 3H), 6.91 - 6.83 (m, 2H), 6.57 (d, J=8.7 Hz, 2H), 6.13 (d, J=8.7 Hz, 2H), 5.05 (dd, J=5.1, 13.2 Hz, 1H), 4.37 - 4.28 (m, 2H), 4.25 - 4.16 (m, 1H), 3.67 (br d, J=14.9 Hz, 1H), 3.53 (br d, J=9.5 Hz, 3H), 3.28 (br s, 5H), 2.96 - 2.85 (m, 1H), 2.72 - 2.55 (m, 3H), 2.49 (br s, 3H), 2.40 - 2.30 (m, 2H), 2.19 (br d, J=7.0 Hz, 2H), 2.01 - 1.91 (m, 1H), 1.75 (br d, J=13.4 Hz, 2H), 1.64 (br s, 1H), 1.21 - 1.07 (m, 2H) SFC: retention time, 2.739 min; Area, 97.162%.

EXAMPLE 17. Preparation of (I-338) (3S)-3-[5-[4-[[1-[5-[(1R,2R)-4,4-difluoro-6- hydroxy-2-phenyl-tetralin-1-yl]-2-pyridyl]-4-piperidyl]methy l]piperazin-1-yl]-1-oxo- isoindolin-2-yl]piperidine-2,6-dione Step 1. To a solution of 5-bromo-2-fluoro-pyridine (5 g, 28.4 mmol, 2.9 mL, 1 eq) and 4- (dimethoxymethyl)piperidine (4.5 g, 28.4 mmol, 1 eq) in CH3CN (20 mL) was added K2CO3 (7.8 g, 56.8 mmol, 2 eq) .The mixture was stirred at 80 °C for 12 hr. TLC showed (Petroleum ether/Ethyl acetate= 10/1, R _f =0.3) new spot was formed. The reaction mixture was diluted with 50 mL H ₂ O and extracted with ethyl acetate (40 mL * 2). The combined organic layers were washed with brine 40 mL, dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate= 10/1) Compound 5-bromo-2-[4-(dimethoxymethyl)-1-piperidyl]pyridine (5.1 g, 16.1 mmol, 57% yield) was obtained as a yellow solid. LC-MS (ESI ⁺ ) m/z: 316.7 (M+H) Step 2. To a solution of 5-bromo-2-[4-(dimethoxymethyl)-1-piperidyl]pyridine (1 g, 3.2 mmol, 1 eq) and N-[(E)-(6-benzyloxy-4,4-difluoro-tetralin-1-ylidene)amino]-4 -methyl- benzenesulfonamide (1.4 g, 3.17 mmol, 1 eq) in dioxane (10 mL) was added lithium 2- methylpropan-2-olate (508 mg, 6.3 mmol, 2 eq), Pd(dppf)Cl ₂ (259 mg, 317 ^mol, 0.1 eq) and X- Phos (756 mg, 1.6 mmol, 0.5 eq).The mixture was stirred at 100 °C for 12 hr. TLC showed (Petroleum ether/Ethyl acetate= 5/1, R _f =0.3) new spot was formed. The reaction mixture was diluted with 50 mL H ₂ O and extracted with 50 mL ethyl acetate. The organic layer was washed with brine 50 mL, dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , Petroleum ether/Ethyl acetate= 5/1) .Compound 5-(6-benzyloxy-4,4-difluoro-3H-naphthalen-1-yl)-2-[4- (dimethoxymethyl)-1-piperidyl]pyridine (610 mg, 1.2 mmol, 38% yield) was obtained as a yellow solid.LC-MS (ESI ⁺ ) m/z: 507.1 (M+H) ⁺ . Step 3. A mixture of 5-(6-benzyloxy-4,4-difluoro-3H-naphthalen-1-yl)-2-[4-(dimeth oxymethyl)- 1-piperidyl]pyridine (610 mg, 1.2 mmol, 1 eq), Py.HBr ₃ (385 mg, 1.2 mmol, 1 eq), N,N- diethylethanamine (183 mg, 1.8 mmol, 251 ^L, 1.5 eq) in DCM (10 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 0 °C for 0.5hr under N2 atmosphere. TLC showed (Petroleum ether/Ethyl acetate= 5/1, R _f =0.4) new spot was formed. The residue was purified by column chromatography (SiO ₂ , Petroleum ether/Ethyl acetate=3/1) Compound 5-(6-benzyloxy-2-bromo-4,4-difluoro-3H-naphthalen-1-yl)-2-[4 -(dimethoxymethyl)- 1-piperidyl]pyridine (550 mg, 939 ^mol, 78% yield) was obtained as a yellow oil. LC-MS (ESI ⁺ ) m/z: 587.3 (M+H) ⁺ . Step 4. A mixture of 5-(6-benzyloxy-2-bromo-4,4-difluoro-3H-naphthalen-1-yl)-2-[4 - (dimethoxymethyl)-1-piperidyl]pyridine (500 mg, 854 ^mol, 1 eq), phenylboronic acid (125 mg, 1 mmol, 1.2 eq), Na ₂ CO ₃ (271 mg, 2.5 mmol, 3 eq), Pd-118(56 mg, 85 ^mol, 0.1 eq) in dioxane (4 mL) and H ₂ O (1 mL) was degassed and purged with N ₂ for 3 times, and then the mixture was stirred at 50 °C for 16 hr under N ₂ atmosphere. TLC showed (Petroleum ether/Ethyl acetate= 5/1, R _f =0.3) new spot was formed. The reaction mixture was diluted with 10 mL H ₂ O and extracted with ethyl acetate (10 mL * 2). The combined organic layers were washed with brine 10 mL (5 mL * 2), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , Petroleum ether/Ethyl acetate=3/1). Compound 5-(6-benzyloxy-4,4-difluoro-2-phenyl-3H-naphthalen-1-yl)-2-[ 4- (dimethoxymethyl)-1-piperidyl]pyridine (500 mg, 772 ^mol, 90% yield, 90% purity) was obtained as a yellow solid. LC-MS (ESI ⁺ ) m/z: 583.2 (M+H) ⁺ . Step 5. To a solution of 5-(6-benzyloxy-4,4-difluoro-2-phenyl-3H-naphthalen-1-yl)-2-[ 4- (dimethoxymethyl)-1-piperidyl]pyridine (500 mg, 858 ^mol, 1 eq) in THF (4 mL) and MeOH (4 mL) was added Pd/C (10%, 0.25 g) and Pd(OH) ₂ /C (20%, 0.25 g) under N ₂ atmosphere. The suspension was degassed and purged with H ₂ for 3 times. The mixture was stirred under H ₂ (15 Psi) at 25 °C for 12hr. TLC showed (Petroleum ether/Ethyl acetate= 5/1, R _f =0.3) new spot was formed. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex C1880*40mm*3um; mobile phase: [water(NH ₃ H ₂ O+NH ₄ HCO ₃ )-ACN];gradient:62%-92% B over 7 min). Then the residue was further separated by SFC (column: DAICEL CHIRALPAK AD(250mm*30mm,10um);mobile phase: [CO ₂ -i-PrOH(0.1%NH ₃ H ₂ O)];B%:30%%, isocratic elution mode). Compound (1R,2R)-1-[6-[4-(dimethoxymethyl)-1-piperidyl]-3-pyridyl]-4, 4- difluoro-2-phenyl-tetralin-6-ol (70 mg, 141 ^mol, 16.5% yield) was obtained as a white solid. Compound (1S,2S)-1-[6-[4-(dimethoxymethyl)-1-piperidyl]-3-pyridyl]-4, 4-difluoro-2-phenyl- tetralin-6-ol (60 mg, 121 ^mol, 14% yield) was obtained as a white solid. LC-MS (ESI ⁺ ) m/z: 495.1 (M+H) ⁺ . Step 6. To a solution of (1R,2R)-1-[6-[4-(dimethoxymethyl)-1-piperidyl]-3-pyridyl]-4, 4- difluoro-2-phenyl-tetralin-6-ol (70 mg, 141.54 ^mol, 1 eq) in THF (4 mL) was added H ₂ SO ₄ (4 mL,10%) .The mixture was stirred at 70 °C for 40 min. LCMS showed 88% desired MS. The reaction mixture was quenched by Saturated NaHCO ₃ aqueous solution addition 20 mL at 25 °C, and then diluted with 20 mL H ₂ O and extracted with 30 mL ethyl acetate. The combined organic layers were washed with 20 mL brine, dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The crude product 1-[5-[(1R,2R)-4,4-difluoro-6-hydroxy-2- phenyl-tetralin-1-yl]-2-pyridyl]piperidine-4-carbaldehyde (68 mg, 130.39 ^mol, 92% yield) was used into the next step without further purification. Compound 1-[5-[(1R,2R)-4,4-difluoro-6- hydroxy-2-phenyl-tetralin-1-yl]-2-pyridyl]piperidine-4-carba ldehyde (68 mg, 130 ^mol, 92% yield) was obtained as a yellow oil. LC-MS (ESI ⁺ ) m/z: 449.2 (M+H) ⁺ . Step 7. To a solution of 1-[5-[(1R,2R)-4,4-difluoro-6-hydroxy-2-phenyl-tetralin-1-yl] -2- pyridyl]piperidine-4-carbaldehyde (68 mg, 130.39 ^mol, 1 eq) and(3S)-3-(1-oxo-5-piperazin-1- yl-isoindolin-2-yl)piperidine-2,6-dione (65 mg, 130 ^mol, 1 eq, PhSO3H salt) in DCM (4 mL) and MeOH (4 mL) was added sodium acetate (32 mg, 391 ^mol, 3 eq).The mixture was stirred at 30 °C for 0.5 hr. Then the mixture was added NaBH(OAc)3 (55 mg, 260 ^mol, 2 eq) and acetic acid (23 mg, 391 ^mol, 22 ^L, 3 eq) .The mixture was stirred at 30 °C for 16 hr finally. The reaction mixture was diluted with 20 mL H ₂ O and extracted with 20 mL DCM. The combined organic layers were washed with 20 mL brine, dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Welch Xtimate C18150*30mm*5um;mobile phase: [water(FA)-ACN];gradient:12%-42% B over 7 min) Compound (3S)-3-[5-[4-[[1-[5-[(1R,2R)-4,4-difluoro-6-hydroxy-2-phenyl -tetralin-1- yl]-2-pyridyl]-4-piperidyl]methyl]piperazin-1-yl]-1-oxo-isoi ndolin-2-yl]piperidine-2,6-dione (17 mg, 22.34 ^mol, 17.14% yield) was obtained as a white solid. LC-MS (ESI ⁺ ) m/z: 761.4 (M+H) ⁺ . HPLC: 99.157% purity at 220 nm. SFC: Rt: 2.649 min; Area, 94.975%. ¹ H NMR (400 MHz, DMSO-d ₆ ) į ppm 10.96 (s, 1 H) 9.76 - 9.82 (m, 1 H) 8.14 (s, 0.424 H) 7.52 (d, J=8.46 Hz, 1 H) 7.20 - 7.27 (m, 3 H) 7.04 - 7.11 (m, 3 H) 6.97 - 7.01 (m, 3 H) 6.85 - 6.93 (m, 2 H) 6.47 - 6.55 (m, 1 H) 6.37 - 6.45 (m, 1 H) 5.05 (dd, J=13.23, 5.25 Hz, 1 H) 4.29 - 4.37 (m, 2 H) 4.16 - 4.24 (m, 1 H) 4.06 - 4.14 (m, 2 H) 3.65 - 3.74 (m, 1 H) 3.29 (br d, J=1.43 Hz, 8 H) 2.84 - 2.96 (m, 1 H) 2.60 - 2.69 (m, 4 H) 2.32 - 2.39 (m, 2 H) 2.13 - 2.26 (m, 2 H) 1.91 - 2.00 (m, 1 H) 1.68 - 1.80 (m, 3 H) 0.95 - 1.09 (m, 2 H) EXAMPLE 18. Preparation of (I-202) (3S)-3-[5-[4-[[1-[5-[(1S,2S)-4,4-difluoro-6- hydroxy-2-phenyl-tetralin-1-yl]-2-pyridyl]-4-piperidyl]methy l]piperazin-1-yl]-1-oxo- isoindolin-2-yl]piperidine-2,6-dione Step 1. To a solution of (1S,2S)-1-[6-[4-(dimethoxymethyl)-1-piperidyl]-3-pyridyl]-4, 4-difluoro- 2 h l t t li 6 l (60 121 ^ l 1 ) i THF (4 L) dd d H SO (4 mL,10%) .The mixture was stirred at 70 °C for 40min. LCMS showed 88% desired MS. The reaction mixture was quenched by Saturated NaHCO3 aqueous solution addition 20 mL at 25 °C, and then diluted with 20 mL H ₂ O and extracted with 30 mL ethyl acetate. The combined organic layers were washed with 20 mL brine, dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The crude product 1-[5-[(1S,2S)-4,4-difluoro-6-hydroxy-2- phenyl-tetralin-1-yl]-2-pyridyl]piperidine-4-carbaldehyde (58 mg, 116 ^mol, 95% yield) was used into the next step without further purification. Compound 1-[5-[(1S,2S)-4,4-difluoro-6- hydroxy-2-phenyl-tetralin-1-yl]-2-pyridyl]piperidine-4-carba ldehyde (58 mg, 116 ^mol, 95% yield) was obtained as a yellow oil. LC-MS (ESI ⁺ ) m/z: 449.2 (M+H) ⁺ . Step 2. To a solution of 1-[5-[(1S,2S)-4,4-difluoro-6-hydroxy-2-phenyl-tetralin-1-yl] -2- pyridyl]piperidine-4-carbaldehyde (58 mg, 116 ^mol, 1eq) and (3S)-3-(1-oxo-5-piperazin-1-yl- isoindolin-2-yl)piperidine-2,6-dione (58 mg, 116 ^mol, 1 eq, PhSO ₃ H salt) in DCM (4 mL) and MeOH (4 mL) was added sodium acetate (28 mg, 349 ^mol, 3 eq) .The mixture was stirred at 30 °C for 0.5 hr. Then the mixture was added NaBH(OAc) ₃ (49 mg, 232 ^mol, 2 eq) and acetic acid (21 mg, 349 ^mol, 20 ^L, 3 eq) .The mixture was stirred at 30 °C for 16 hr finally. The reaction mixture was diluted with 20 mL H2O and extracted with 20 mL DCM. The combined organic layers were washed with 20 mL brine, dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Welch Xtimate C18150*30mm*5um;mobile phase: [water(FA)-ACN];gradient:12%-42% B over 7 min) Compound (3S)-3-[5-[4-[[1-[5-[(1S,2S)-4,4-difluoro-6-hydroxy-2-phenyl -tetralin-1- yl]-2-pyridyl]-4-piperidyl]methyl]piperazin-1-yl]-1-oxo-isoi ndolin-2-yl]piperidine-2,6-dione (28.8 mg, 37 ^mol, 32% yield) was obtained as a white solid. LC-MS (ESI ⁺ ) m/z: 761.4 (M+H) ⁺ . HPLC: 99.115% purity at 220 nm. SFC: Rt: 2.778 min; Area, 95.682%. ¹ H NMR (400 MHz, DMSO-d ₆ ) į ppm 10.96 (s, 1 H) 9.79 (s, 1 H) 8.14 (s, 0.376 H) 7.52 (d, J=8.46 Hz, 1 H) 7.21 - 7.28 (m, 3 H) 7.05 - 7.11 (m, 3 H) 6.96 - 7.00 (m, 3 H) 6.85 - 6.92 (m, 2 H) 6.47 - 6.53 (m, 1 H) 6.38 - 6.45 (m, 1 H) 5.05 (dd, J=13.29, 5.07 Hz, 1 H) 4.29 - 4.37 (m, 2 H) 4.17 - 4.24 (m, 1 H) 4.05 - 4.13 (m, 2 H) 3.66 - 3.74 (m, 1 H) 3.25 - 3.34 (m, 8 H) 2.84 - 2.96 (m, 1 H) 2.60 - 2.69 (m, 4 H) 2.32 - 2.39 (m, 2 H) 2.13 - 2.29 (m, 2 H) 1.91 - 2.00 (m, 1 H) 1.67 - 1.80 (m, 3 H) 0.96 - 1.08 (m, 2 H) EXAMPLE 19. Preparation of (I-220) (S)-3-(5-(4-((1-(4-((1S,2R)-4,4-difluoro-6- hydroxy-2-isobutyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl) piperidin-4- yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2, 6-dione Step 1. A mixture of 1,1'-Bis(di-t-butylphosphino)ferrocene palladium dichloride (78 mg, 0.1 Eq, 120 ^mol) , (2-methylprop-1-en-1-yl)boronic acid (120 mg, 1 Eq, 1 mmol), sodium carbonate (381 mg, 3 Eq, 3.6 mmol) 1-(4-(6-(benzyloxy)-2-bromo-4,4-difluoro-3,4-dihydronaphthal en-1- yl)phenyl)-4-(dimethoxymethyl)piperidine (700 mg, 1 Eq, 1.2 mmol) in 1,4-dioxane (8 mL) and H ₂ O (2 mL) was degassed and purged with N ₂ for 3 times, and then the mixture was stirred at 50 °C for 16 hour under N ₂ atmosphere. TLC (petroleum ether: ethyl acetate=5:1, R _f= 0.5 UV) showed one main new spot was observed. The reaction was quenched with water (100 mL) and extracted with ethyl acetate(150 mL*2).The organic layer was washed with brine(100 mL) and dried over Na ₂ SO ₄ and concentrated in vacuum to give a white solid. The white solid was subjected to column chromatography over silica gel (gradient elution: 0 – 100% EtOAc).The desired fractions were collected, and concentrated to dryness in vacuum to give 1-(4-(6- (benzyloxy)-4,4-difluoro-2-(2-methylprop-1-en-1-yl)-3,4-dihy dronaphthalen-1-yl)phenyl)-4- (dimethoxymethyl)piperidine (640 mg, 1.01 mmol, 84.7 %, 88.7% purity) as a white solid. LC-MS (ESI ⁺ ) m/z: 560.29 (M+H) ⁺ . Step 2. A mixture of 1-(4-(6-(benzyloxy)-4,4-difluoro-2-(2-methylprop-1-en-1-yl)- 3,4- dihydronaphthalen-1-yl)phenyl)-4-(dimethoxymethyl)piperidine (640 mg, 1 Eq, 1 mmol), Pd/C (320 mg, 10% Wt, 0.3 Eq, 301 ^mol), Pd(OH) ₂ /C(320 mg, 20% Wt, 0.4 Eq, 456 ^mol) in MeOH (15 mL) and THF (15 mL)was degassed and purged with H ₂ for 3 times, and then the mixture was stirred at 25 °C for 12 hour under H ₂ atmosphere(15 psi). The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was concentrated under reduced pressure to give desired compound as a yellow oil, which was further separated by SFC (condition: column: DAICEL CHIRALPAK AD (250mm*30mm,10um); mobile phase: [CO2-i- PrOH(0.1%NH3H2O)]; B%: 30%-30%) to give (5S,6R)-5-(4-(4-(dimethoxymethyl)piperidin-1- yl)phenyl)-8,8-difluoro-6-isobutyl-5,6,7,8-tetrahydronaphtha len-2-ol (100 mg, 211 ^mol, 18.5 %) and (5R,6S)-5-(4-(4-(dimethoxymethyl)piperidin-1-yl)phenyl)-8,8- difluoro-6-isobutyl- 5,6,7,8-tetrahydronaphthalen-2-ol (130 mg, 274 ^mol, 24.0 %) as yellow solid. LC-MS (ESI ⁺ ) m/z: 474.2 (M+H) ⁺ . Step 3. To a solution of (5S,6R)-5-(4-(4-(dimethoxymethyl)piperidin-1-yl)phenyl)-8,8- difluoro- 6-isobutyl-5,6,7,8-tetrahydronaphthalen-2-ol (100 mg, 1 Eq, 211 ^mol) in 10% H2SO4 (3 mL) and THF (3 mL) was stirred at 70 °C for 40 min .TLC (petroleum ether:ethyl acetate=3:1,Rf=0.4UV) showed a new spot was desired. The reaction was adjust to pH=~8 with aq.NaHCO ₃ (20 mL). Then the mixture was added water(30 mL) and extracted with ethyl acetate (30×2 mL).The combined organic layers were washed with brine(30 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to dryness in vacuo to give 1-(4-((1S,2R)-4,4-difluoro-6- hydroxy-2-isobutyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl) piperidine-4-carbaldehyde (90 mg, 0.21 mmol, 100 %) as a yellow solid. Step 4. To a solution of 1-(4-((1S,2R)-4,4-difluoro-6-hydroxy-2-isobutyl-1,2,3,4- tetrahydronaphthalen-1-yl)phenyl)piperidine-4-carbaldehyde (90 mg, 1 Eq, 211 ^mol), (S)-3-(1- oxo-5-(piperazin-1-yl)isoindolin-2-yl)piperidine-2,6-dione, PhSO ₃ H salt (105 mg, 1 Eq, 211 ^mol) in DCM (4 mL) and MeOH (4 mL) was added sodium acetate (52 mg, 3 Eq, 632 ^mol) was stirred at 25 °C for 60 min. Then sodium triacetoxyborohydride (89 mg, 2 Eq, 421 ^mol) and acetic acid (38 mg, 36 ^L, 3 Eq, 632 ^mol) was added .The mixture was stirred at 25 °C for 16 hour. The reaction was quenched with H2O (50 mL) and extracted with ethyl acetate(50 concentrated in vacuo to give a yellow oil. The residue was purified by prep-HPLC (column: Welch Xtimate C18150*30mm*5um;mobile phase: [water(FA)-ACN];B% 20%-50%,7min) to give (S)-3-(5-(4-((1-(4-((1S,2R)-4,4-difluoro-6-hydroxy-2-isobuty l-1,2,3,4- tetrahydronaphthalen-1-yl)phenyl)piperidin-4-yl)methyl)piper azin-1-yl)-1-oxoisoindolin-2- yl)piperidine-2,6-dione (71.5 mg, 95.1 ^mol, 45.2 %, 98.365% purity) was obtained as a white solid. LC-MS (ESI ⁺ ) m/z: 740.2 (M+H) ⁺ . LCMS: calc. for C ₄₃ H ₅₁ F ₂ N ₅ O ₄ : 739.91, found: [M+H] ⁺ 740.2 HPLC: 98.365% purity at 220 nm. ¹ H NMR (400 MHz, DMSO-d ₆ ) į = 10.96 (s, 1H), 9.66 (br s, 1H), 8.16 (s, 0.168H), 7.52 (d, J = 8.6 Hz, 1H), 7.07 (s, 2H), 7.00 (s, 1H), 6.82 (br d, J = 7.2Hz, 4H), 6.70 (br d, J = 8.6 Hz, 2H), 5.05 (dd, J = 5.0, 13.2 Hz, 1H), 4.39 - 4.28 (m, 1H), 4.26 - 4.16 (m, 1H), 4.03 (br s, 1H), 3.62 (br s, 2H), 3.48 - 3.25 (m,7H), 2.89 (br d, J = 12.8 Hz, 1H), 2.65 - 2.52 (m, 4H), 2.43 - 2.33 (m, 1H), 2.21 (br d, J = 6.9 Hz, 3H), 2.13 - 1.91 (m, 3H), 1.79 (br d, J = 12.3 Hz, 4H), 1.19(br d, J = 9.4 Hz, 3H), 0.85 (dd, J = 3.6, 6.4 Hz, 6H), 0.78 - 0.69 (m, 1H) SFC: retention time, 2.180 min; Area, 96.310 %. EXAMPLE 20. Preparation of (I-197) (S)-3-(5-(4-((1-(4-((1R,2S)-4,4-difluoro-6- hydroxy-2-isobutyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl) piperidin-4- yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2, 6-dione Step 1. To a solution of (5R,6S)-5-(4-(4-(dimethoxymethyl)piperidin-1-yl)phenyl)-8,8- difluoro- 6-isobutyl-5,6,7,8-tetrahydronaphthalen-2-ol (130 mg, 1 Eq, 274 ^mol) in 10% H ₂ SO ₄ (3 mL) and THF (3 mL) was stirred at 70 °C for 40 min TLC (petroleum ether:ethyl acetate=3:1,Rf=0.4UV) showed a new spot was formed. The reaction was adjust to pH=~8 with aq.NaHCO3 (15 mL). Then the mixture was added water(30 mL) and extracted with ethyl acetate (30×2 mL).The combined organic layers were washed with brine(30 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to dryness in vacuum to give 1-(4-((1R,2S)-4,4-difluoro-6- hydroxy-2-isobutyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl) piperidine-4-carbaldehyde (120 mg, 281 ^mol) as a yellow solid. Step 2. To a solution of 1-(4-((1R,2S)-4,4-difluoro-6-hydroxy-2-isobutyl-1,2,3,4- tetrahydronaphthalen-1-yl)phenyl)piperidine-4-carbaldehyde (120 mg, 1 Eq, 281 ^mol), (S)-3- (1-oxo-5-(piperazin-1-yl)isoindolin-2-yl)piperidine-2,6-dion e, PhSO ₃ H salt (141 mg, 1 Eq, 281 ^mol) in DCM (4 mL) and MeOH (4 mL) was added sodium acetate (69 mg, 3 Eq, 842 ^mol) was stirred at 25 °C for 60 mins, Then sodium triacetoxyborohydride (119 mg, 2 Eq, 561 ^mol) and acetic acid (51 mg, 48 ^L, 3 Eq, 842 ^mol) was added .The mixture was stirred at 25 °C for 16 hour. The reaction was quenched with H ₂ O (50 mL) and extracted with ethyl acetate (50 mL*2).The organic layer was washed with brine(30 mL) and dried over Na ₂ SO ₄ and concentrated in vacuum to give a yellow oil. The residue was purified by prep-HPLC (column: Welch Xtimate C18150*30mm*5um;mobile phase: [water(FA)-ACN];B% 20%-50%,7min) to give (S)-3-(5-(4-((1-(4-((1R,2S)-4,4-difluoro-6-hydroxy-2-isobuty l-1,2,3,4- tetrahydronaphthalen-1-yl)phenyl)piperidin-4-yl)methyl)piper azin-1-yl)-1-oxoisoindolin-2- yl)piperidine-2,6-dione (72.4 mg, 93.8 ^mol, 33.4 %, 95.865% purity) was obtained as a white solid.LC-MS (ESI ⁺ ) m/z: 740.2 (M+H) ⁺ . LCMS: calc. for C ₄₃ H ₅₁ F ₂ N ₅ O ₄ : 739.91, found: [M+H] ⁺ 740.2 HPLC: 95.865% purity at 220 nm. NMR (400 MHz, DMSO-d ₆ ) į = 10.96 (s, 1H), 9.66 (br s, 1H), 8.16 (s, 0.165H), 7.52 (d, J = 8.6 Hz, 1H), 7.07 (s, 2H), 7.00 (s, 1H), 6.82 (br d, J = 6.9 Hz,4H), 6.70 (d, J = 8.6 Hz, 2H), 5.05 (dd, J = 5.1, 13.2 Hz, 1H), 4.37 - 4.29 (m, 1H), 4.25 - 4.16 (m, 1H), 4.03 (br d, J = 2.4 Hz, 1H), 3.62 (br d, J = 1.0 Hz, 2H),3.34 (br s, 8H), 2.90 (br s, 1H), 2.60 (br d, J = 1.2 Hz, 3H), 2.37 (br dd, J = 4.7, 13.3 Hz, 1H), 2.21 (br d, J = 7.2 Hz, 3H), 2.14 - 1.92 (m, 3H), 1.80 (br d, J =12.8 Hz, 3H), 1.67 (br d, J = 3.5 Hz, 1H), 1.19 (br d, J = 9.4 Hz, 2H), 1.14 - 1.05 (m, 1H), 0.85 (dd, J = 3.9, 6.4 Hz, 6H), 0.75 (br d, J = 6.4 Hz, 1H) SFC: retention time, 2.173 min; Area, 94.166 %. EXAMPLE 21. Preparation of (I-307) (S)-3-(5-(4-((1-(4-((1R,2R)-4,4-difluoro-6- hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)-3-fluoro phenyl)piperidin-4- yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2, 6-dione Step 1. To a solution of 1-bromo-2-fluoro-4-iodobenzene (5 g, 16.6 mmol, 1eq), 4- (dimethoxymethyl)piperidine (2.65 g, 16.62 mmol, 1 eq), iodocopper (633 mg, 3.32 mmol, 0.2 eq), potassium carbonate (4.59 g, 33.23 mmol, 2 eq), (2S)-pyrrolidine-2-carboxylic acid (765 mg, 6.7 mmol, 0.4 eq) was added in DMF (50 mL) and purged with N ₂ for 3 times, the mixture was stirred at 90 °C for 16 hr under N2. The resulting was treated with 100 mL H2O, The reaction was extracted with ethyl acetate (200 mL*2). The organic layers were dried with anhydrous Na ₂ SO ₄ , filtered, and concentrated to give the crude product. The crude product was subjected to column chromatography over silica gel (gradient elution: 0–20% EtOAc). The desired fractions were collected, and concentrated to dryness in vacuo to give 1-(4-bromo-3- fluorophenyl)-4-(dimethoxymethyl)piperidine (2.5 g, 7.5 mmol, 45% yield) as a yellow oil. LC- MS (ESI ⁺ ) m/z: 332.21 (M+H) ⁺ . Step 2. To a mixture of nBuLi (2.5 M, 180.61 ^L, 1.5 eq) was added into mixture of 1-(4-bromo- 3-fluorophenyl)-4-(dimethoxymethyl)piperidine (2.4 g, 1 Eq, 7.2 mmol) in THF (30 mL) under N ₂ at -68°C, and the mixture was stirred at -68°C for 0.5 h under N ₂ atmosphere, and then 6- (benzyloxy)-4,4-difluoro-3,4-dihydronaphthalen-1(2H)-one (2.9 g, 1.4 Eq, 10 mmol) was added in the mixture at -68°C and was stirred at 25°C for 16hr. TLC (petroleum ether: ethyl acetate=10:1, R _f =0.5, UV) showed one main new spot was observed. The reaction was quenched with sat. NH ₄ Cl aqueous (50 mL) and extracted with ethyl acetate (150 mL*2). The organic layer was washed with brine (50 mL) and dried over Na ₂ SO ₄ and concentrated in vacuo to give a black solid. The black solid was subjected to column chromatography over silica gel (gradient elution: 0 – 10% EtOAc). The desired fractions were collected, and concentrated to dryness in vacuo to give 6-(benzyloxy)-1-(4-(4-(dimethoxymethyl)piperidin-1-yl)-2-flu orophenyl)-4,4-difluoro- 1,2,3,4-tetrahydronaphthalen-1-ol (2.5 g, 4.6 mmol, 64%) as a yellow solid. LC-MS (ESI ⁺ ) m/z: 541.61 (M+H) ⁺ . Step 3. A mixture of 6-(benzyloxy)-1-(4-(4-(dimethoxymethyl)piperidin-1-yl)-2-flu orophenyl)- 4,4-difluoro-1,2,3,4-tetrahydronaphthalen-1-ol (2 g, 1 Eq, 4 mmol) in 4N HCl/MeOH (20 mL) at r.t., and the reaction was stirred at 25°C for 1 hour. TLC (petroleum ether: ethyl acetate=3:1, R _f =0.5 UV) showed a new spot was observed. The reaction was quenched with sat.aq.NaHCO ₃ (100 mL) and extracted with ethyl acetate (150 mL*2). The organic layer was washed with brine (100 mL) and dried over Na ₂ SO ₄ and concentrated in vacuum to give a white solid. The white solid was subjected to column chromatography over silica gel (gradient elution: 0 – 100% EtOAc). The desired fractions were collected, and concentrated to dryness in vacuum to give 1- (4-(6-(benzyloxy)-4,4-difluoro-3,4-dihydronaphthalen-1-yl)-3 -fluorophenyl)-4- (dimethoxymethyl)piperidine (1.1 g, 2.1 mmol, 60 %) as a white solid. LC-MS (ESI ⁺ ) m/z: 523.60 (M+H) ⁺ . Step 4. A mixture of 1-(4-(6-(benzyloxy)-4,4-difluoro-3,4-dihydronaphthalen-1-yl) -3- fluorophenyl)-4-(dimethoxymethyl)piperidine (1.1 g, 1 Eq, 2.1 mmol) and Diisopropylethylamine (0.4 g, 0.5 mL, 1.5 Eq, 3.2 mmol) in DCM (20 mL) at 0 °C, and pyridinium bromide perbromide (0.67 g, 1 Eq, 2.1 mmol) was added to the mixture at 0°C, then showed a new spot was observed. The reaction was treated with water (100 mL) and extracted with ethyl acetate(150 mL*2).The organic layer was washed with brine(100 mL) and dried over Na ₂ SO ₄ and concentrated in vacuo to give a white solid. The white solid was subjected to column chromatography over silica gel (gradient elution: 0 – 100% EtOAc). The desired fractions were collected, and concentrated to dryness in vacuum to give 1-(4-(6-(benzyloxy)-2- bromo-4,4-difluoro-3,4-dihydronaphthalen-1-yl)-3-fluoropheny l)-4- (dimethoxymethyl)piperidine (860 mg, 1.4 mmol, 68 %) as a white solid. LC-MS (ESI ⁺ ) m/z: 602.49 (M+H) ⁺ . Step 5. A mixture of 1,1'-Bis(di-t-butylphosphino)ferrocene palladium dichloride (93 mg, 0.1 Eq, 143 ^mol), phenylboronic acid (174 mg, 1 Eq, 1.43 mmol), sodium carbonate (454 mg, 3 Eq, 4 mmol) 1-(4-(6-(benzyloxy)-2-bromo-4,4-difluoro-3,4-dihydronaphthal en-1-yl)-3-fluorophenyl)- 4-(dimethoxymethyl)piperidine (860 mg, 1 Eq, 1.43 mmol) in 1,4-dioxane (8 mL) and H ₂ O (2 mL) was degassed and purged with N ₂ for 3 times, and then the mixture was stirred at 50 °C for 16 hour under N ₂ atmosphere. TLC (petroleum ether: ethyl acetate=5:1, R _f =0.5 UV) showed one main new spot was observed. The reaction was quenched with water (100 mL) and extracted with ethyl acetate(150 mL*2).The organic layer was washed with brine(100 mL) and dried over Na ₂ SO ₄ and concentrated in vacuum to give a white solid. The white solid was subjected to column chromatography over silica gel (gradient elution: 0 – 100% EtOAc).The desired fractions were collected, and concentrated to dryness in vacuum to give 1-(4-(6-(benzyloxy)-4,4-difluoro- 2-phenyl-3,4-dihydronaphthalen-1-yl)-3-fluorophenyl)-4-(dime thoxymethyl)piperidine (810 mg, 1.35 mmol, 94.6 %) as a white solid. LC-MS (ESI ⁺ ) m/z: 413.3 (M+H) ⁺ . Step 6. A mixture of 1-(4-(6-(benzyloxy)-4,4-difluoro-2-phenyl-3,4-dihydronaphtha len-1-yl)-3- fluorophenyl)-4-(dimethoxymethyl)piperidine (640 mg, 1 Eq, 1 mmol), Pd/C (320 mg, 10% Wt, 0.3 Eq, 301 ^mol), Pd(OH) ₂ /C (320 mg, 20% Wt, 0.427 Eq, 456 ^mol) in MeOH (15 mL) and THF (15 mL)was degassed and purged with H ₂ for 3 times, and then the mixture was stirred at 50 °C for 12 hour under H ₂ atmosphere(15 psi).The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was concentrated under reduced pressure to give desired compound as a yellow oil, which was further separated by SFC (condition: column: DAICEL CHIRALPAK AD (250mm*30mm,10um); mobile phase: [CO2- EtOH(0.1%NH3H2O)]; B%: 30%-30%) to give (5R,6R)-5-(4-(4-(dimethoxymethyl)piperidin-1- yl)-2-fluorophenyl)-88-difluoro-6-phenyl-5678-tetrahydronaph thalen-2-ol (80 mg 016 mmol 15 %) and (5S,6S)-5-(4-(4-(dimethoxymethyl)piperidin-1-yl)-2-fluorophe nyl)-8,8-difluoro-6- phenyl-5,6,7,8-tetrahydronaphthalen-2-ol (80 mg, 0.16 mmol, 15 %) as yellow solid. LC-MS 512.3 (M+H) ⁺ . Step 7. To a solution of (5R,6R)-5-(4-(4-(dimethoxymethyl)piperidin-1-yl)-2-fluorophe nyl)-8,8- difluoro-6-phenyl-5,6,7,8-tetrahydronaphthalen-2-ol (80 mg, 1 Eq, 0.16 mmol) in 10%H ₂ SO ₄ (3 mL) and THF (3 mL) was stirred at 70 °C for 40 min .TLC (petroleum ether : ethyl acetate=3:1,R _f =0.4UV) showed a new spot was desired. The reaction was adjust to pH=~8 with aq.NaHCO ₃ (15 mL).Then the mixture was added water(30 mL) and extracted with ethyl acetate (2×30 mL). The combined organic layers were washed with brine(30 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to dryness in vacuo to give 1-(4-((1R,2R)-4,4-difluoro-6- hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)-3-fluoro phenyl)piperidine-4-carbaldehyde (50 mg, 0.11 mmol, 69 %) as a yellow solid. Step 8. To a solution of 1-(4-((1R,2R)-4,4-difluoro-6-hydroxy-2-phenyl-1,2,3,4- tetrahydronaphthalen-1-yl)-3-fluorophenyl)piperidine-4-carba ldehyde (50 mg, 1 Eq, 107 ^mol), (S)-3-(1-oxo-5-(piperazin-1-yl)isoindolin-2-yl)piperidine-2, 6-dione, PhSO3H salt(54 mg, 1 Eq, 107 ^mol) in DCM (4 mL) and MeOH (4 mL) was added sodium acetate (26 mg, 18 ^L, 3 Eq, 322 ^mol) was stirred at 25 °C for 30 mins, Then Na(OAc) ₃ BH (46 mg, 2 Eq, 215 ^mol) and acetic acid (19.3 mg, 19 ^L, 3 Eq, 322 ^mol) was added .The mixture was stirred at 25 °C for 16 hour. The reaction was quenched with H ₂ O (50 mL) and extracted with ethyl acetate(50 mL*2).The organic layer was washed with brine(30 mL) and dried over Na ₂ SO ₄ and concentrated in vacuum to give a yellow oil. The residue was purified by prep-HPLC (column: Welch Xtimate C18150*30mm*5um;mobile phase: [water(FA)-ACN];B% 25%-55%,7min) to give (S)-3-(5-(4-((1-(4-((1R,2R)-4,4-difluoro-6-hydroxy-2-phenyl- 1,2,3,4-tetrahydronaphthalen- 1-yl)-3-fluorophenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1 -oxoisoindolin-2-yl)piperidine-2,6- dione (40.9 mg, 52.2 ^mol, 48.6 %, 99.282% Purity) was obtained as a white solid. LC-MS (ESI ⁺ ) m/z: 778.2 (M+H) ⁺ . LCMS: calc. for C ₄₅ H ₄₆ F ₃ N ₅ O ₄ : 777.89, found: [M+H]+ 778.2. HPLC: 99.282% purity at 220 nm. ¹ H NMR (400 MHz, DMSO-d6) į = 10.96 (s, 1H), 9.83 (br d, J = 3.5 Hz, 1H), 8.15 (s, 0.582H), 7.52 (d, J = 8.7 Hz, 1H), 7.22 - 7.13 (m, 3H), 7.11 - 7.02(m, 3H), 6.96 - 6.83 (m, 4H), 6.55 (dd, J = 1.9, 8.7 Hz, 1H), 6.38 - 6.27 (m, 2H), 5.05 (dd, J = 5.1, 13.3 Hz, 1H), 4.57 (br d, J = 2.9 Hz, 1H), 4.39 - 4.28 (m,1H), 4.26 - 4.15 (m, 1H), 3.60 (br d, J = 12.2 Hz, 4H), 3.28 (br s, 7H), 2.97 - 2.85 (m, 1H), 2.73 (br s, 1H), 2.57 (br s, 3H), 2.34 (br s, 2H), 2.19 (br d, J = 6.7Hz, 2H), 1.97 (br d, J = 5.2 Hz, 1H), 1.74 (br d, J = 13.0 Hz, 3H), 1.13 (br d, J = 11.3 Hz, 2H) SFC: retention time, 2.485 min; Area, 96.830%. EXAMPLE 22. Preparation of (I-199) (S)-3-(5-(4-((1-(4-((1S,2S)-4,4-difluoro-6- hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)-3-fluoro phenyl)piperidin-4- yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2, 6-dione Step 1. To a solution of (5S,6S)-5-(4-(4-(dimethoxymethyl)piperidin-1-yl)-2-fluorophe nyl)-8,8- difluoro-6-phenyl-5,6,7,8-tetrahydronaphthalen-2-ol (80 mg, 1 Eq, 0.16 mmol) in 10% H ₂ SO ₄ (3 mL) and THF (3 mL) was stirred at 70 °C for 40 min. TLC (petroleum ether: ethyl acetate=3:1,R _f =0.4, UV) showed a new spot was desired. The reaction was adjust to pH=~8 with sat.aq.NaHCO ₃ (15 mL). Then the mixture was added water(30 mL) and extracted with ethyl acetate (2×30 mL).The combined organic layers were washed with brine(30 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to dryness in vacuum to give 1-(4-((1S,2S)-4,4- difluoro-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-y l)-3-fluorophenyl)piperidine-4- carbaldehyde (100 mg, 215 ^mol, crude) as a yellow solid. Step 2. To a solution of 1-(4-((1S,2S)-4,4-difluoro-6-hydroxy-2-phenyl-1,2,3,4- tetrahydronaphthalen-1-yl)-3-fluorophenyl)piperidine-4-carba ldehyde (100 mg, 1 Eq, 215 ^mol), (S)-3-(1-oxo-5-(piperazin-1-yl)isoindolin-2-yl)piperidine-2, 6-dione, PhSO3H salt (108 mg, 1 Eq, 215 ^ l) i DCM (4 L) d M OH (4 L) dd d di t t (53 3 E 644 ^mol) was stirred at 25 °C for 30 mins. Then NaBH(OAc)3 (91mg, 2 Eq, 430 ^mol) and acetic acid (39 mg, 37 ^L, 3 Eq, 644 ^mol) was added. The mixture was stirred at 25 °C for 16 hour. The reaction was quenched with H ₂ O (50 mL) and extracted with ethyl acetate(50 mL*2).The organic layer was washed with brine(30 mL) and dried over Na ₂ SO ₄ and concentrated in vacuum to give a yellow oil. The residue was purified by prep-HPLC (column: Welch Xtimate C18 150*30mm*5um;mobile phase: [water(NH ₃ H ₂ O+NH ₄ HCO ₃ )-ACN];B% 70%-100%,7min) to give (S)-3-(5-(4-((1-(4-((1S,2S)-4,4-difluoro-6-hydroxy-2-phenyl- 1,2,3,4-tetrahydronaphthalen- 1-yl)-3-fluorophenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1 -oxoisoindolin-2-yl)piperidine-2,6- dione (28.1 mg, 35.4 ^mol, 16.5 %, 97.864% purity) was obtained as a white solid.LC-MS (ESI ⁺ ) m/z: 778.2 (M+H) ⁺ . LCMS: calc. for C ₄₅ H ₄₆ F ₃ N ₅ O ₄ : 777.89, found: [M+H] ⁺ 778.6. HPLC: 97.864% purity at 220 nm. ¹ H NMR (400 MHz, DMSO-d ₆ ) į = 10.96 (s, 1H), 9.77 (s, 1H), 7.52 (d, J = 8.6 Hz, 1H), 7.16 (br s, 3H), 7.07 (s, 3H), 6.86 (s, 4H), 6.55 (dd, J = 2.0, 8.7 Hz,1H), 6.37 - 6.27 (m, 2H), 5.05 (dd, J = 4.9, 13.3 Hz, 1H), 4.57 (br d, J = 3.0 Hz, 1H), 4.39 - 4.28 (m, 1H), 4.26 - 4.15 (m, 1H), 3.69 (br d, J = 13.4 Hz, 1H),3.60 (br d, J = 11.9 Hz, 2H), 3.40 - 3.27 (m, 8H), 2.90 (s, 1H), 2.74 (s, 1H), 2.57 (br s, 3H), 2.35 (br d, J = 4.6 Hz, 2H), 2.18 (br d, J = 6.8 Hz, 2H), 2.02 - 1.89(m, 1H), 1.73 (br s, 3H), 1.12 (br d, J = 11.2 Hz, 2H) SFC: retention time, 2.581 min; Area, 95.294%.

EXAMPLE 23. Preparation of (I-405) (S)-3-(5-(4-((1-(5-((R)-4,4-difluoro-6-hydroxy- 1,2,3,4-tetrahydronaphthalen-1-yl)-4-methoxy-[1,1'-biphenyl] -2-yl)piperidin-4- yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2, 6-dione Step 1. To a mixture of 6-(benzyloxy)-4,4-difluoro-3,4-dihydronaphthalen-1(2H)-one (5.00 g, 1 Eq, 17.3 mmol) and 4-methylbenzenesulfonic acid hydrazide (3.88 g, 1.2 Eq, 20.8 mmol) in acetonitrile (60 mL), then the mixture was stirred at 90 °C for 6 hour. LCMS showed 80% d i d MS TLC ( t l th th l tt 51 R 05 UV) h d i t was observed. The reaction was quenched with water (100 mL) and extracted with ethyl acetate (200 mL*2). The organic layer was washed with brine (50 mL) and dried over Na2SO4 and concentrated in vacuum to give a white solid. The white solid was subjected to column chromatography over silica gel (gradient elution: 0–100% EtOAc). The desired fractions were collected, and concentrated to dryness in vacuum to give (E)-N'-(6-(benzyloxy)-4, 4-difluoro- 3,4-dihydronaphthalen-1(2H)-ylidene)-4-methylbenzenesulfonoh ydrazide (7.5 g, 16 mmol, 95 %) as a white solid. LC-MS (ESI+) m/z: 457.2(M+H) ⁺ . Step 2. To a solution of 1-bromo-4-iodo-2-methoxybenzene (5.00 g, 1 Eq, 16.0 mmol) and 4- (dimethoxymethyl)piperdine (2.54 g, 2.52 mL, 1 Eq, 16.0 mmol) in DMSO (50 mL) was added cuprous iodide (609 mg, 0.2 Eq, 3.20 mmol)), (S)-(-)-proline (736 mg, 0.4 Eq, 6.39 mmol) and potassium carbonate (4.42 g, 2 Eq, 32.0 mmol). The mixture was stirred at 80 °C for 12 hour. LCMS showed 52.7% desired MS was detected. TLC (petroleum ether: ethyl acetate=10:1, UV, R _f =0.3) showed one main new spot was observed. The reaction was quenched with water (300 mL) and extracted with ethyl acetate(300 mL*2).The organic layer was washed with brine(50 mL) and dried over Na2SO4 and concentrated in vacuo to give 1-(4-bromo-3-methoxyphenyl)-4- (dimethoxymethyl)piperdine as a brown oil. The brown oil was subjected to column chromatography over silica gel (gradient elution: 0 – 15% EtOAc). The desired fractions were collected, and concentrated to dryness in vacuum to give 1-(4-bromo-3-methoxyphenyl)-4- (dimethoxymethyl) piper dine (3.6 g, 9.4 mmol, 59 % yield, 90% purity) as a white solid. LC- MS (ESI+) m/z: 346.1(M+H) ⁺ . Step 3. To a solution of lithium 2-methyl-2-propanolate (631 mg, 733 ^L, 2 Eq, 7.89 mmol) and 2-(dicyclohexylphosphanyl)-2',4',6'-tris(isopropyl)biphenyl (940 mg, 0.5 Eq, 1.97 mmol) in dioxane (80 mL) was added 1-(4-bromo-3-methoxyphenyl)-4-(dimethoxymethyl)piperidine (1.36 g, 1 Eq, 3.94 mmol), (E)-N'-(6-(benzyloxy)-4,4-difluoro-3,4-dihydronaphthalen-1(2 H)- ylidene)-4-methylbenzenesulfonohydrazide (1.80 g, 1 Eq, 3.94 mmol) and Pd(dppf)Cl ₂ -DCM adduct (322 mg, 0.1 Eq, 394 ^mol).The mixture was stirred at 100 °C for 6 hour. TLC (petroleum ether: ethyl acetate=2:1, UV) showed one main new spot was observed.100 mL water was added, and the mixture was extracted with dichloromethane (150 mL x2). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4, filtered and concentrated to dryness in vacuo to give a yellow oil. The yellow oil was purified by flash column (petroleum ether/ethyl acetate from 100/0 to 0/100) and the organic layer was concentrated in vacuo to give 1-(4-(6-(benzyloxy)-4,4-difluoro-3,4-dihydronaphthalen-1-yl) -3- methoxyphenyl)-4-(dimethoxymethyl)piperidine--1-(4-(6-(benzy loxy)-4-fluoro-3,4- dihydronaphthalen-1-yl)-3-methoxyphenyl)-4-(dimethoxymethyl) piperidine (1.70 g, 1.61 mmol, 40.9 %) as a yellow solid. LC-MS (ESI+) m/z: 536.0(M+H) ⁺ . Step 4. A solution of pyridinium bromide perbromide (0.36 g, 0.7 Eq, 1.1 mmol) was added to 1- (4-(6-(benzyloxy)-4,4-difluoro-3,4-dihydronaphthalen-1-yl)-3 -methoxyphenyl)-4- (dimethoxymethyl)piperidine (1.7 g, 1 Eq, 1.6 mmol) in DCM (20 mL) was stirred at 0 °C for 1 hour. LCMS showed 19% desired MS was detected.50 mL water was added, and the mixture was extracted with dichloromethane (100 mL x2). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to dryness in vacuo to give a yellow oil. The yellow solid was purified by preparative high-performance liquid chromatography. Condition: Column: Xtimate C18150*40mm*5um A: water (FA); B: ACN; Gradient Time (min) 9; 100% B hold Time (min) 2, Flow Rate (ml/min) 30. The pure fractions were collected and the solvent was evaporated under vacuum. The aqueous layer was lyophilized to dryness to give 1-(4-(6-(benzyloxy)-4, 4-difluoro-3, 4-dihydronaphthalen-1-yl)-2-bromo-5- methoxyphenyl)-4-(dimethoxymethyl) piperidine(500 mg, 813.6 ^mol, 50 %) as a yellow solid. Step 5. To a mixture of 1,1'-Bis(di-t-butylphosphino)ferrocene palladium dichloride (53 mg, 0.1 Eq, 81.4 ^mol), Na ₂ CO ₃ (259 mg, 3 Eq, 2.44 mmol) and 1-(4-(6-(benzyloxy)-4,4-difluoro-3,4- dihydronaphthalen-1-yl)-2-bromo-5-methoxyphenyl)-4-(dimethox ymethyl)piperidine (500 mg, 1 Eq, 813.6 ^mol), phenylboronic acid (148.81 mg, 1.5 Eq, 1.2204 mmol) in Dioxane (10 mL) and water (2 mL) was stirred at 80°C for 12h. LCMS showed 77% desired MS was detected. TLC (petroleum ether: ethyl acetate=5:1, UV) showed one main new spot was observed.50 mL water was added, and the mixture was extracted with dichloromethane (100 mL x2). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to dryness in vacuo to give a yellow oil. The yellow oil was purified by flash column (petroleum ether/ethyl acetate from 100/0 to 0/100) and the organic layer was concentrated in vacuo to give 1-(5-(6-(benzyloxy)-4,4-difluoro-3,4-dihydronaphthalen-1-yl) -4- methoxy-[1,1'-biphenyl]-2-yl)-4-(dimethoxymethyl)piperidine (270.0 mg, 0.34 mmol, 42 % yield, 78% purity) as a yellow solid. LC-MS (ESI+) m/z: 612.2(M+H) ⁺ . Step 6. To a solution of 1-(5-(6-(benzyloxy)-4,4-difluoro-3,4-dihydronaphthalen-1-yl) -4- MeOH (5 mL) and THF (5 mL) was added Pd/C(250 mg, 10% Wt.) under N2 atmosphere. The suspension was degassed and purged with dihydrogen for three times. The mixture was stirred under 15 psi dihydrogen (859 ^g, 1 Eq, 425.02 ^mol) at 50 °C for 16 hr. LCMS showed 74.8% desired MS was detected. The mixture was filtered and concentrated under reduced pressure to give the residue as a yellow solid. The residue was concentrated under reduced pressure to give desired compound as a yellow oil, which was further separated by SFC (condition: column: DAICEL CHIRALPAK AD (250mm*30mm, 10um)); mobile phase: CO ₂ -EtOH (0.1%NH ₃ H ₂ O) ; B%: 35%-35%) to give (R)-5-(6-(4-(dimethoxymethyl)piperidin-1-yl)-4-methoxy-[1,1' - biphenyl]-3-yl)-8,8-difluoro-5,6,7,8-tetrahydronaphthalen-2- ol (80.0 mg, 153 ^mol, 35.9 %) and (S)-5-(6-(4-(dimethoxymethyl)piperidin-1-yl)-4-methoxy-[1,1' -biphenyl]-3-yl)-8,8-difluoro- 5,6,7,8-tetrahydronaphthalen-2-ol (72.0 mg, 138 ^mol, 32.4 %) as a white solid LC-MS (ESI+) m/z: 524.3(M+H) ⁺ . Step 7. To a solution of (R)-5-(6-(4-(dimethoxymethyl)piperidin-1-yl)-4-methoxy-[1,1' - biphenyl]-3-yl)-8,8-difluoro-5,6,7,8-tetrahydronaphthalen-2- ol (80.00 mg, 1 Eq, 152.8 ^mol) in THF (4 mL) and 10%H2SO4 (4 mL).The mixture was stirred at 70 °C for 1.5 hour. LCMS showed 80.5% desired MS was detected. The reaction mixture was quenched by addition H2O 50 mL at 25°C, and then diluted with 50 mL H ₂ O and extracted with ethyl acetate (50 mL * 2). The combined organic layers were washed with 50 mL brine and dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give (S)-1-(5-(4,4-difluoro-6-hydroxy-1,2,3,4- tetrahydronaphthalen-1-yl)-4-methoxy-[1,1'-biphenyl]-2-yl)pi peridine-4-carbaldehyde (75 mg, 0.16 mmol, 100 %) as a residue. LC-MS (ESI+) m/z: 456.1(M+H) ⁺ . Step 8. To a solution of (R)-1-(5-(4,4-difluoro-6-hydroxy-1,2,3,4-tetrahydronaphthale n-1-yl)-4- methoxy-[1,1'-biphenyl]-2-yl)piperidine-4-carbaldehyde (70.0 mg, 1 Eq, 147 ^mol), (S)-3-(1- oxo-5-(piperazin-1-yl)isoindolin-2-yl)piperidine-2,6-dione benzenesulfonate (85.6 mg, 1.2 Eq, 176 ^mol) in DCM (2 mL), MeOH (2 mL) was added sodium acetate (36.1 mg, 3 Eq, 440 ^mol) was stirred at 25 °C for 30 mins, Then sodium triacetoxyborohydride (62.1 mg, 2 Eq, 293 ^mol) and acetic acid (26.4 mg, 3 Eq, 440 ^mol) was added. The mixture was stirred at 25 °C for 16 hour. LCMS showed 72.9% desired MS was detected. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was purified by prep-HPLC (column: Welch Xtimate C18150*30mm*5um phase: [water(FA)-ACN];B%: 17%-57%,9 min to methoxy-[1,1'-biphenyl]-2-yl)piperidin-4-yl)methyl)piperazin -1-yl)-1-oxoisoindolin-2- yl)piperidine-2,6-dione (29.3 mg, 35.2 ^mol, 24.0 %, 94.8% purity) was obtained as a white solid. LCMS: calc. for C ₄₆ H ₄₉ F ₂ N ₅ O ₅ : 789.92, found: [M+H] ⁺ 790.4. HPLC: 94.833% purity at 220 nm. NMR (400MHz, DMSO-d ₆ ) į = 10.96 (s, 1 H) 9.13 - 10.22 (m, 1 H) 8.18 (s, 0.510 H) 7.52 (d, J=8.58 Hz, 1 H) 7.40 - 7.44 (m, 2 H) 7.33 (t, J=7.63 Hz, 2 H) 7.17 - 7.24 (m, 1 H) 7.01 - 7.07 (m, 2 H) 6.97 (d, J=1.79 Hz, 1 H) 6.76 - 6.81 (m, 1 H) 6.69 - 6.75 (m, 2 H) 6.34 - 6.45 (m, 1 H) 6.41 (s, 1 H) 5.05 (dd, J=13.29, 5.07 Hz, 1 H) 4.30 - 4.43 (m, 2 H) 4.16 - 4.24 (m, 1 H) 3.85 (s, 3 H) 3.26 (br s, 4 H) 3.07 (br t, J=12.04 Hz, 2 H) 2.84 - 2.96 (m, 1 H) 2.55 - 2.62 (m, 2 H) 2.46 (br s, 4 H) 2.31 - 2.39 (m, 1 H) 1.87 - 2.29 (m, 8 H) 1.53 - 1.67 (m, 3 H) 1.02 (br t, J=12.22 Hz, 2 H) SFC: retention time, 1.996 min; Area, 94.495%. EXAMPLE 24. Preparation of (I-156) (S)-3-(5-(4-((1-(4-((1R,2R)-4,4-difluoro-6- hydroxy-2-isopropyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl )piperidin-4- yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2, 6-dione Step 1: To a solution of (5R,6R)-5-(4-(4-(dimethoxymethyl)piperidin-1-yl)phenyl)-8,8- difluoro- 6-isopropyl-5,6,7,8-tetrahydronaphthalen-2-ol (70 mg, 1 Eq, 0.15 mmol) in 10% H ₂ SO ₄ (2 mL) and THF (2 mL) was stirred at 70 °C for 1 hour. TLC (petroleum ether:ethyl acetate=3:1, R _f =0.4, UV) showed a new spot was desired. The reaction was adjust to pH=~8 with aq. NaHCO ₃ (5 mL).Then the mixture was added water(30 mL ) and extracted with ethyl acetate (2×30 mL). The combined organic layers were washed with brine(30 mL), dried over anhydrous Na2SO4, filtered and concentrated to dryness in vacuo to give 1-(4-((1R,2R)-4,4-difluoro-6-hydroxy-2- isopropyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperidin e-4-carbaldehyde (60 mg, 0.15 mmol, 95 %) as a yellow solid. Step 2: To a solution of 1-(4-((1R,2R)-4,4-difluoro-6-hydroxy-2-isopropyl-1,2,3,4- tetrahydronaphthalen-1-yl)phenyl)piperidine-4-carbaldehyde (60.0 mg, 1 Eq, 145 ^mol), (S)-3- (1-oxo-5-(piperazin-1-yl)isoindolin-2-yl)piperidine-2,6-dion e, PhSO ₃ H salt(109 mg, 1.5 Eq, 218 ^mol) in DCM (4 mL) and MeOH (4 mL) was added sodium acetate (35.7 mg, 3 Eq, 435 ^mol) was stirred at 25 °C for 60 mins. Then sodium triacetoxyborohydride (61.5 mg, 2 Eq, 290 ^mol) and Acetic acid (26.1 mg, 25.0 ^L, 3 Eq, 435 ^mol) was added .The mixture was stirred at 25 °C for 16 hour. The reaction was quenched with H ₂ O (50 mL) and extracted with ethyl acetate(50 mL*2).The organic layer was washed with brine(30 mL) and dried over Na ₂ SO ₄ and concentrated in vacuo to give a yellow oil. The residue was purified by prep-HPLC (column: Welch Xtimate C18150*30mm*5um;mobile phase: [water(FA)-ACN];B% 22%-52%,7min) to give (S)-3-(5-(4-((1-(4-((1R,2R)-4,4-difluoro-6-hydroxy-2-isoprop yl-1,2,3,4- tetrahydronaphthalen-1-yl)phenyl)piperidin-4-yl)methyl)piper azin-1-yl)-1-oxoisoindolin-2- yl)piperidine-2,6-dione (20 mg, 27 ^mol, 19 %, 99.625% Purity) was obtained as a white solid. LC-MS (ESI+) m/z: 726.3 (M+H) ⁺ . LCMS: calc. for C ₄₂ H ₄₉ F ₂ N ₅ O ₄ : 725.88, found: [M+H] ⁺ 726.3 HPLC: 99.625% purity at 220 nm. ¹ H NMR (400 MHz, DMSO-d ₆ ) į = 10.96 (s, 1H), 8.18 (s, 0.672H), 7.52 (d, J = 8.5 Hz, 1H), 7.11 - 7.02 (m, 2H), 6.99 (s, 1H), 6.89 - 6.73 (m, 6H), 5.05 (dd, J = 5.0, 13.2 Hz, 1H), 4.40 - 4.27 (m, 1H), 4.26 - 4.14 (m, 2H), 3.62 (br d, J = 10.5 Hz, 3H), 3.28 (br s, 5H), 2.97 - 2.83 (m, 1H), 2.64 - 2.53 (m, 4H), 2.46 -2.24 (m, 3H), 2.21 (br d, J = 7.0 Hz, 2H), 2.14 - 2.01 (m, 1H), 2.00 - 1.91 (m, 1H), 1.90 - 1.74 (m, 3H), 1.68 (br d, J = 7.2 Hz, 1H), 1.33 (br dd, J = 6.7, 13.4Hz, 1H), 1.25 - 1.12 (m, 2H), 1.06 (d, J = 6.4 Hz, 3H), 0.64 (d, J = 6.7 Hz, 3H).

EXAMPLE 25. Preparation of (I-153) (S)-3-(5-(4-((1-(4-((1S,2S)-4,4-difluoro-6- hydroxy-2-isopropyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl )piperidin-4- yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2, 6-dione

Step 1: To a solution of 4,4-difluoro-6-methoxy-3,4-dihydronaphthalen-1(2H)-one (5.0 g, 1 Eq, N2. After addition, the mixture was stirred at 140 °C for 16 h under N2. The reaction was adjust to pH=6 with HCl (2 M, 50 mL) and added H2O (200 mL) and extracted with ethyl acetate (300 mL x 2). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ethyl acetate in petroleum ether = 0% to 20%) to give the product of 4,4-difluoro-6-hydroxy- 3,4-dihydronaphthalen-1(2H)-one (4 g, 80 % Yield, 90.159% Purity) as a brown solid. LC-MS (ESI ⁺ ) m/z: 199.1 (M+H) ⁺ . Step 2: To a solution of 4,4-difluoro-6-hydroxy-3,4-dihydronaphthalen-1(2H)-one (3.8 g, 1 Eq, 17 mmol) in CH ₃ CN (50 mL) at r.t. was added (bromomethyl)benzene (3.5 g, 1.2 Eq, 21 mmol) and K ₂ CO ₃ (4.8 g, 2 Eq, 35 mmol). After addition, the mixture was stirred at 25 °C for 16 h. The mixture was treated with H ₂ O (200 mL), extracted with EtOAc (200 mL x 2). The combined extracts was dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to dryness in vacuo to give a residue. The residue was subjected to column chromatography over silica gel (petroleum ether/ethyl acetate from 100/0 to 80/20). The pure fractions were collected and concentrated to dryness in vacuo to give 6-(benzyloxy)-4,4-difluoro-3,4-dihydronaphthalen-1(2H)-one (5.0 g, 100 % yield, 100% Purity) as a white solid. LC-MS (ESI ⁺ ) m/z: 289.1 (M+H) ⁺ . Step 3: To a solution of 1-(4-bromophenyl)-4-(dimethoxymethyl)piperidine (6.5 g, 1.2 Eq, 21 mmol) in THF (60 mL) was added dropwise n-BuLi (1.4 g, 1.3 Eq, 23 mmol) at -78 °C under N ₂ . After addition, the mixture was stirred at this temperature for 1 h, and then 6-(benzyloxy)-4, 4- difluoro-3, 4-dihydronaphthalen-1(2H)-one (5.0 g, 1 Eq, 17 mmol) in THF (20 mL) was added dropwise at -78 °C. The resulting mixture was stirred at -78 °C for 16 h. The reaction mixture was quenched with aq.NH ₄ Cl (50 mL) at 0 °C, then added H ₂ O (200 mL) and extraction with EtOAc (300 mL x 2). The combined extracts was dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to dryness in vacuo to give a residue. The residue was subjected to column chromatography over silica gel (petroleum ether/ethyl acetate from 100/0 to 80/20). The pure fractions were collected and concentrated to dryness in vacuo to give 6-(benzyloxy)-1-(4-(4- (dimethoxymethyl)piperidin-1-yl)phenyl)-4,4-difluoro-1,2,3,4 -tetrahydronaphthalen-1-ol (7.3 g, 72 % Yield, 89.103% Purity) as a yellow solid. LC-MS (ESI+) m/z: 524.3 (M+H) ⁺ . Step 4: A mixture of 6-(benzyloxy)-1-(4-(4-(dimethoxymethyl)piperidin-1-yl)phenyl )-4,4- difluoro-1,2,3,4-tetrahydronaphthalen-1-ol (7.3 g, 1 Eq, 12 mmol) in Dioxane (70 mL) at r.t., The mixture was treated with H2O (200 mL), extracted with EtOAc (300 mL x 2). The combined extracts was dried over anhydrous Na2SO4, filtered and concentrated to dryness in vacuo to give a residue. The residue was subjected to column chromatography over silica gel (petroleum ether/ethyl acetate from 100/0 to 70/30). The pure fractions were collected and concentrated to dryness in vacuo to give 11-(4-(6-(benzyloxy)-4,4-difluoro-3,4-dihydronaphthalen-1-yl )phenyl)- 4-(dimethoxymethyl)piperidine (6.1 g, 63 % Yield, 64.465% Purity) as a yellow solid. LC-MS (ESI ⁺ ) m/z: 506.2 (M+H) ⁺ . Step 5: To a mixture of 1-(4-(6-(benzyloxy)-4,4-difluoro-3,4-dihydronaphthalen-1-yl) phenyl)-4- (dimethoxymethyl)piperidine (1.5 g, 1 Eq, 1.9 mmol), DIEA (0.37 g, 1.5 Eq, 2.9 mmol) and Pyridinium bromide perbromide (0.92 g, 1.5 Eq, 2.9 mmol) in DCM (20 mL) at 0 °C, then the mixture was stirred at 0 °C for 1 h. The mixture was treated with H ₂ O (150 mL), extracted with DCM (200 mL x 2). The combined extracts was dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to dryness in vacuo to give a residue. The residue was subjected to column chromatography over silica gel (petroleum ether/ethyl acetate from 100/0 to 70/30). The pure fractions were collected and concentrated to dryness in vacuo to give 1-(4-(6-(benzyloxy)-2- bromo-4,4-difluoro-3,4-dihydronaphthalen-1-yl)phenyl)-4-(dim ethoxymethyl)piperidine (1.1 g, 68 % Yield, 68.965% Purity) as a yellow solid. LC-MS (ESI+) m/z: 586.0 (M+H) ⁺ . Step 6: XPhos Pd G3 (94.9 mg, 0.1 Eq, 112 ^mol) was added to the mixture of 1-(4-(6- (benzyloxy)-2-bromo-4,4-difluoro-3,4-dihydronaphthalen-1-yl) phenyl)-4- (dimethoxymethyl)piperidine (950 mg, 1 Eq, 1.12 mmol), 4,4,5,5-tetramethyl-2-(prop-1-en-2- yl)-1,3,2-dioxaborolane (377 mg, 2 Eq, 2.24 mmol) and Sodium carbonate (356 mg, 3 Eq, 3.36 mmol) in Dioxane (10 mL) and H ₂ O (2.5 mL) at r.t.. N ₂ was bubbled into the mixture for 5 min. Then the reaction mixture was heated at 60 °C for 12 h. The mixture was added H ₂ O (150 mL) and extracted with EtOAc (150 mL x 2). The combined extracts was dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to dryness in vacuo to give a residue. The residue was subjected to column chromatography over silica gel (petroleum ether/ethyl acetate from 100/0 to 70/30). The pure fractions were collected and concentrated to dryness in vacuo to give a yellow solid. Then the yellow solid was purified by prep-HPLC (column: Xtimate C18 150*40mm*10um; mobile phase: [water (FA)-ACN]; B% 70%-100%, 6min) to give 1-(4-(6- (benzyloxy)-4,4-difluoro-2-(prop-1-en-2-yl)-3,4-dihydronapht halen-1-yl)phenyl)-4- (dimethoxymethyl)piperidine (320 mg 523 % Yield) as a white solid TLC (PE:EtOAc=2:1, Rf=0.5) confirmed. Step 7: A mixture of 1-(4-(6-(benzyloxy)-4,4-difluoro-2-(prop-1-en-2-yl)-3,4- dihydronaphthalen-1-yl)phenyl)-4-(dimethoxymethyl)piperidine (300 mg, 1 Eq, 550 ^mol) , palladium (300 mg, 10% Wt, 0.513 Eq, 282 ^mol), PdOH ₂ (300 mg, 20% Wt, 0.777 Eq, 427 ^mol) in MeOH (15 mL) and THF (15 mL)was degassed and purged with H ₂ for 3 times, and then the mixture was stirred at 25 °C for 12 hour under H ₂ atmosphere(15 psi).The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was concentrated under reduced pressure to give (5S,6S)-5-(4-(4-(dimethoxymethyl)piperidin-1- yl)phenyl)-8,8-difluoro-6-isopropyl-5,6,7,8-tetrahydronaphth alen-2-ol as a yellow oil, which was further separated by SFC (condition: column: DAICEL CHIRALPAK AD (250mm*30mm,10um); mobile phase: [0.1% NH ₃ ^. H ₂ O EtOH]; B%: 25%-25%) to give (5S,6S)- 5-(4-(4-(dimethoxymethyl)piperidin-1-yl)phenyl)-8,8-difluoro -6-isopropyl-5,6,7,8- tetrahydronaphthalen-2-ol (50 mg, 0.11 mmol, 19 %, 97.963% Purity) and (5R,6R)-5-(4-(4- (dimethoxymethyl)piperidin-1-yl)phenyl)-8,8-difluoro-6-isopr opyl-5,6,7,8- tetrahydronaphthalen-2-ol (70 mg, 0.15 mmol, 28 %, 100.0% Purity) as yellow solid. Step 8: To a solution of (5S,6S)-5-(4-(4-(dimethoxymethyl)piperidin-1-yl)phenyl)-8,8- difluoro- 6-isopropyl-5,6,7,8-tetrahydronaphthalen-2-ol (50 mg, 1 Eq, 0.11 mmol) in 10%H ₂ SO ₄ (2 mL) and THF (2 mL) was stirred at 70 °C for 1 hour. TLC (petroleum ether: ethyl acetate=3:1, Rf=0.4UV) showed a new spot was desired. The reaction was adjust to PH~=8 with aq.NaHCO ₃ (5 mL).Then the mixture was added water(30 mL ) and extracted with ethyl acetate (2×30 mL). The combined organic layers were washed with brine(30 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to dryness in vacuo to give 1-(4-((1S,2S)-4,4-difluoro-6-hydroxy-2- isopropyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperidin e-4-carbaldehyde (60 mg, 0.15 mmol, 130 %) as a yellow solid. Step 9: To a solution of 1-(4-((1S,2S)-4,4-difluoro-6-hydroxy-2-isopropyl-1,2,3,4- tetrahydronaphthalen-1-yl)phenyl)piperidine-4-carbaldehyde (60.0 mg, 1 Eq, 145 ^mol), (S)-3- (1-oxo-5-(piperazin-1-yl)isoindolin-2-yl)piperidine-2,6-dion e, PhSO ₃ H salt (109 mg, 1.5 Eq, 218 ^mol) in DCM (4 mL) and MeOH (4 mL) was added sodium acetate (35.7 mg, 3 Eq, 435 ^mol) was stirred at 25 °C for 60 mins, Then Sodium triacetoxyborohydride (61.5 mg, 2 Eq, 290 ^mol) and acetic acid (26.1 mg, 25.0 ^L, 3 Eq, 435 ^mol) was added .The mixture was stirred at 25 °C mL*2).The organic layer was washed with brine(30 mL) and dried over Na2SO4 and concentrated in vacuo to give a yellow oil. The residue was purified by prep-HPLC (column: Welch Xtimate C18150*30mm*5um;mobile phase: [water(FA)-ACN];B% 22%-52%,7min) to give (S)-3-(5-(4-((1-(4-((1S,2S)-4,4-difluoro-6-hydroxy-2-isoprop yl-1,2,3,4- tetrahydronaphthalen-1-yl)phenyl)piperidin-4-yl)methyl)piper azin-1-yl)-1-oxoisoindolin-2- yl)piperidine-2,6-dione (24.7 mg, 33.1 ^mol, 22.8 %, 97.332% Purity) was obtained as a white solid. LC-MS (ESI+) m/z: 726.3 (M+H) ⁺ . LCMS: calc. for C ₄₂ H ₄₉ F ₂ N ₅ O ₄ : 725.88, found: [M+H] ⁺ 726.3 HPLC: 97.332% purity at 220 nm. ¹ H NMR (400 MHz, DMSO-d ₆ ) į = 10.96 (s, 1H), 8.19 (s, 0.450H), 7.52 (d, J = 8.6 Hz, 1H), 7.11 - 7.03 (m, 2H), 6.99 (s, 1H), 6.88 - 6.71 (m, 6H), 5.05 (dd, J = 5.1, 13.3 Hz, 1H), 4.37 - 4.29 (m, 1H), 4.25 - 4.16 (m, 2H), 3.62 (br d, J = 11.1 Hz, 3H), 3.29 (br s, 6H), 2.97 - 2.84 (m, 1H), 2.65 - 2.53 (m, 4H), 2.40 -2.25 (m, 2H), 2.21 (br d, J = 7.0 Hz, 2H), 2.17 - 2.02 (m, 1H), 2.01 - 1.92 (m, 1H), 1.90 - 1.74 (m, 3H), 1.66 (br d, J = 6.0 Hz, 1H), 1.33 (dt, J = 6.9, 13.9 Hz,1H), 1.26 - 1.12 (m, 2H), 1.06 (d, J = 6.4 Hz, 3H), 0.64 (d, J = 6.7 Hz, 3H). EXAMPLE 26. Preparation of (I-285) (R)-3-(4-(2-((1-(4-((1R,2S)-4,4-difluoro-6- hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)pi peridin-4-yl)methyl)-2,8- diazaspiro[4.5]decan-8-yl)phenyl)piperidine-2,6-dione and (I-286) (S)-3-(4-(2-((1-(4-

((1R,2S)-4,4-difluoro-6-hydroxy-2-phenyl-1,2,3,4-tetrahyd ronaphthalen-1- yl)phenyl)piperidin-4-yl)methyl)-2,8-diazaspiro[4.5]decan-8- yl)phenyl)piperidine-2,6-dione Step 1: A mixture of 1-bromo-4-iodo-benzene (600 mg, 2.12 mmol, 1 eq.) , tert-butyl 2,8- diazaspiro [4.5]decane-2-carboxylate (611.68 mg, 2.55 mmol, 1.2 eq.) , (2S)-pyrrolidine-2- carboxylic acid (146.50 mg, 1.27 mmol, 0.6 eq.), iodocopper (242.35 mg, 1.27 mmol, 0.6 eq.) and K ₂ CO ₃ (732.79 mg, 5.30 mmol, 2.5 eq.) in DMSO (3 mL) was degassed and purged with N ₂ for 3 times, and then the mixture was stirred at 80 ^o C for 3 hour under N ₂ atmosphere. LCMS showed one main peak with desired mass was detected. The reaction mixture was partitioned between EA (40 mL×2) and water (50 mL).After quenching the reaction, the reaction mixture was poured into separatory funnel and separated. The crude product was purified by silica gel chromatography eluted with PE: EtOAc=3: 1. tert-butyl 8-(4-bromophenyl)-2,8- diazaspiro[4.5]decane-2-carboxylate (260 mg, 657.67 ^mol, 31.01% yield) was obtained as a white solid. LC-MS (ESI ⁺ ) m/z: 397.1 (M+H) ⁺ . Step 2: A mixture of tert-butyl 8-(4-bromophenyl)-2,8-diazaspiro[4.5]decane-2-carboxylate (100 mg, 253 ^mol, 1.0 eq.), (2,6-bis(benzyloxy)pyridin-3-yl)boronic acid (93.3 mg, 278 ^mol, 1.1 eq.), K ₂ CO ₃ (105 mg, 759 ^mol, 3.0 eq.) and PdCl ₂ (dppf) (18.5 mg, 25.3 ^mol, 0.1 eq.)in Dioxane (2 mL) and Water (0.5 mL) was degassed and purged with N ₂ for 3 times, and then the mixture was stirred at 80 °C for 3 hour under N ₂ atmosphere. LCMS showed the reaction was completed. The reaction mixture was quenched by addition EA 10 mL at 20 °C, and then diluted with water 10 mL and extracted with EA 30 mL (10 mL x 3). The combined organic layers were washed with EA 15 mL (5 mL x 3), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The crude material was purified on silica gel column chromatography (from pure PE to PE/EtOAc = 4/1) to give tert-butyl 8-(4-(2,6-bis(benzyloxy)pyridin-3- yl)phenyl)-2,8-diazaspiro[4.5] decane-2-carboxylate (120 mg, 0.16 mmol, 63 % yield, 80% Purity) as a yellow solid. LC-MS (ESI ⁺ ) m/z: 606.3 (M+H) ⁺ . Step 3: To a solution of tert-butyl 8-(4-(2,6-bis(benzyloxy)pyridin-3-yl)phenyl)-2,8- diazaspiro[4.5] decane-2-carboxylate (0.10 g, 0.17 mmol, 1.0 eq.) in EtOH (3 mL), DCM (3 mL) and EtOAc (3 mL) was added Pd/C (5wt%, 0.1 g) under H ₂ atmosphere. The suspension was degassed and purged with H ₂ for 3 times. The mixture was stirred under H ₂ (30 psi) at 30 °C for 16 hour. LCMS showed the reaction was completed. The mixture was filtered and the filtrate was concentrated to give tert-butyl 8-(4-(2,6-dioxopiperidin-3-yl)phenyl)-2,8-diazaspiro[4.5] decane-2-carboxylate (65 mg, 0.15 mmol, 92 %) as a white solid. LC-MS (ESI ⁺ ) m/z: 428.2 (M+H) ⁺ . Step 4: To a solution of tert-butyl 8-(4-(2,6-dioxopiperidin-3-yl)phenyl)-2,8- diazaspiro[4.5]decane-2- carboxylate (60 mg, 0.14 mmol, 1.0 eq.) in HCl/MeOH (3 mL). The mixture was stirred at 20 °C for 1 hour. LCMS showed the reaction was completed. The mixture was concentrated in vacuum to give crude product. No further purification as it is used LC-MS (ESI+) m/z: 328.2 (M+H)+. Step 5: To a solution of 3-(4-(2,8-diazaspiro[4.5]decan-8-yl)phenyl)piperidine-2,6-di one (140.0 mg, 427.6 ^mol, 2.0 eq.) in MeOH (6 mL) and DCE (9 ml) was added 1-(4-((1R,2S)-4,4- difluoro-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-y l)phenyl)piperidine-4- carbaldehyde (95.68 mg, 213.8 ^mol, 1.0 eq.) at 25 °C. After addition, the mixture was stirred at this temperature for 0.5 hr, and then NaBH ₃ (OAc) ₃ (271.9 mg, 190 ^L, 3 Eq, 1.283 mmol)) was added at 25 °C. The resulting mixture was stirred at 25 °C for 3 hr. The reaction mixture was concentrated to yield a residue. The residue was purified by preparative HPLC (column: Boston Green ODS 150 * 30 mm * 5um; mobile phase: [water (FA) - ACN]; B%: 15%-45%,12min) , followed by lyophilization to yield 3-(4-(2-((1-(4-((1R,2S)-4,4-difluoro-6-hydroxy-2-phenyl- 1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperidin-4-yl)meth yl)-2,8-diazaspiro[4.5]decan-8- yl)phenyl)piperidine-2,6-dione (120 mg, 158 ^mol, 37.0 %) was obtained as a white solid. LC- MS (ESI+) m/z: 759.3 [M+H]+. Step 6: 3-(4-(2-((1-(4-((1R,2S)-4,4-difluoro-6-hydroxy-2-phenyl-1,2, 3,4-tetrahydronaphthalen- 1-yl)phenyl)piperidin-4-yl)methyl)-2,8-diazaspiro[4.5]decan- 8-yl)phenyl)piperidine-2,6-dione (120 mg, 158 ^mol, 1.0 eq) was separated by chiral SFC (Column DAICEL CHIRALPAK ID (250mm*30mm,10um), Condition MeOH-ACN Begin B 50% End B 50%) FlowRate (ml/min) : 80) . I-285 (37.1 mg, 48.9 ^mol, 30.9 %). LC-MS (ESI+) m/z: 759.4(M+H) ⁺ . LCMS: calc. for C ₄₇ H ₅₂ F ₂ N ₄ O ₃ : 758.95, found: [M+H] ⁺ 759.4. HPLC: 100 % purity at 220 nm NMR (400 MHz, DMSO-d ₆ ) į ppm 10.77 (s, 1 H) 9.73 (s, 1 H) 7.17 - 7.22 (m, 3 H) 7.08 (s, 1 H) 7.02 (d, J=8.70 Hz, 2 H) 6.88 - 6.91 (m, 3 H) 6.83 (br d, J=0.95 Hz, 3 H) 6.55 (d, J=8.70 Hz, 2 H) 6.12 (d, J=8.58 Hz, 2 H) 4.29 (br d, J=2.74 Hz, 1 H) 3.63 - 3.74 (m, 2 H) 3.47 - 3.54 (m, 2 H) 3.03 - 3.14 (m, 4 H) 2.58 - 2.69 (m, 2 H) 2.42 - 2.48 (m, 4 H) 2.27 - 2.34 (m, 3 H) 2.21 (br d, J=7.03 Hz, 2 H) 2.11 (td, J=11.59, 8.29 Hz, 1 H) 1.96 - 2.03 (m, 1 H) 1.70 - 1.77 (m, 2 H) 1.43 - 1.65 (m, 8 H) 1.06 - 1.16 (m, 2 H). I-286 (39.5 mg, 52.0 ^mol, 32.9 %). LC-MS (ESI+) m/z: 759.4(M+H) ⁺ . HPLC: 100 % purity at 220 nm ¹ H NMR (400 MHz, DMSO-d6) į ppm 10.78 (s, 1 H) 9.74 (s, 1 H) 7.17 - 7.23 (m, 3 H) 7.08 (s, 1 H) 7.03 (d, J=8.70 Hz, 2 H) 6.89 - 6.92 (m, 3 H) 6.83 - 6.88 (m, 3 H) 6.56 (d, J=8.70 Hz, 2 H) 6.12 (d, J=8.70 Hz, 2 H) 4.30 (br d, J=3.10 Hz, 1 H) 3.64 - 3.74 (m, 2 H) 3.49 - 3.56 (m, 2 H) 3.04 - 3.16 (m, 4 H) 2.57 - 2.68 (m, 2 H) 2.41 - 2.49 (m, 4 H) 2.27 - 2.36 (m, 3 H) 2.22 (br d, J=6.32 Hz, 2 H) 2.07 - 2.15 (m, 1 H) 1.97 - 2.04 (m, 1 H) 1.71 - 1.78 (m, 2 H) 1.38 - 1.68 (m, 8 H) 1.07 - 1.17 (m, 2 H). EXAMPLE 27. Preparation of (I-317) (S)-3-(5-(4-((1-(4-((1S,2R)-2-(2,5- difluorophenyl)-4,4-difluoro-6-hydroxy-1,2,3,4-tetrahydronap hthalen-1- yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindo lin-2-yl)piperidine-2,6-dione and (I-316) (S)-3-(5-(4-((1-(4-((1R,2S)-2-(2,5-difluorophenyl)-4,4-diflu oro-6-hydroxy-

1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperidin-4-yl)m ethyl)piperazin-1-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione Step 1: To a mixture of compound 1(604 mg, 1.03 mmol, 1.0 eq) and compound 2 (163.18 mg, 1.03 mmol, 1.0 eq) in 1, 4-Dioxane (8 mL) and water (2 mL) was added Pd(dtbpf)Cl2 (67.35 mg, 103.34 ^mol, 0.1 eq), K2CO3 (285.65 mg, 2.07 mmol, 2.0 eq) in one portion at 25 °C under N2. The mixture was stirred for 0.5 hours. The reaction mixture extracted with EtOAc (20 mL x 3). The combined organic layers were washed with solvent 10 mL saturated NaCl solution, dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Boston Green ODS 150*30mm*5um; mobile phase: water (FA)-ACN; B%: 80%-100%, 12 min) to give product. Compound 3 (200 mg, 323.80 ^mol, 31.33% yield) was obtained as a white solid. LC-MS (ESI ⁺ ) m/z: 618.4(M+H) ⁺ . Step 2: To a solution of compound 3 (250 mg, 404.75 ^mol, 1.0 eq) in THF (4 mL) and MeOH (4 mL) was added Pd/C (215.37 mg, 202.37 ^mol, 10wt%, 0.5 eq). The suspension was degassed under vacuum and purged with H ₂ several times. The mixture was heated to 50 °C (15 psi) and stirred for 6 hours. LCMS showed that the desired compound was detected. The crude product was filtered and the filter was concentrated to give the crude as a yellow solid. The mixture was filtered and concentrated in vacuum. The residue was purified by pre-HPLC (Column Boston Green ODS 150*30mm*5um˗ Condition water(FA)-ACN˗ B%: 10%- 40%,12 min) to afford compound 4 (110.3 mg, 208.28 ^mol, 51.46% yield) as a white solid. LC-MS (ESI ⁺ ) m/z: 530.3 (M+H) ⁺ . Step 3: Compound 4 (100 mg) was separated by chiral SFC (Column DAICEL CHIRALPAK AD (250mm*30mm,10um), Condition CO2-EtOH(0.1%NH3H2O) Begin B 20% End B 20%) FlowRate (ml/min): 60) Compound 5A (52 mg), compound 5B (41 mg). Step 4: Compound 6A: To a solution of compound 5A (52 mg, 98.19 ^mol, 1.0 eq) in DCM (4 mL) was added TFA (11.20 mg, 98.19 ^mol, 1.0 eq.). The mixture was stirred at 25 °C for 0.2 hr. LCMS showed that the starting material was consumed and the desired product was detected. The reaction liquid is dried with N ₂ at 0 °C to give Compound 6A (40.2 mg, 83.14 ^mol, 84.67% yield) was obtained as yellow oil which was used in the next step without further purification.. LC-MS (ESI+) m/z: 484.3 (M+H) ⁺ . Step 5: Compound 6B: To a solution of compound 5B (41 mg, 77.42 ^mol, 1.0 eq) in DCM (4 mL) was added TFA (8.83 mg, 77.42 ^mol, 1.0 eq). The mixture was stirred at 25 °C for 0.2 hr. LCMS showed that the starting material was consumed and the desired product was detected. The reaction liquid is dried with N ₂ at 0 °C to give Compound 6B (35.6 mg, 73.63 ^mol, 95.10% yield) was obtained as yellow oil which was used in the next step without further purification. LC-MS (ESI+) m/z: 484.3(M+H) ⁺ . Step 6: To a solution of compound 6A (40.2 mg, 83.14 ^mol, 1.0 eq) in DCM (4 mL) and MeOH (4 mL) was added compound 034 (27.30 mg, 83.14 ^mol, 1.0 eq) and DIEA (10.75 mg, 83.14 ^mol, 1.0 eq) at 25 °C. After addition, the mixture was stirred at this temperature for 0.5 hr, and then NaBH(OAc) ₃ (35.24 mg, 166.29 ^mol, 2.0 eq) was added at 25 °C. The resulting mixture was stirred at 25 °C for 1 hr. The reaction mixture was concentrated to yield a residue. The residue was purified by preparative HPLC (column: C18-1150*30mm*5um; mobile phase: [water (NH ₄ HCO ₃ ) - ACN]; B%: 52%-80%,11min), followed by lyophilization to yield I-317 (27.7 mg, 34.81 ^mol, 41.86% yield) was obtained as a white solid. LC-MS (ESI+) m/z: 796.5 [M+H] ⁺ . LCMS: calc. for C ₄₅ H ₄₅ F ₄ N ₅ O ₄ : 795.34, found: [M+H] ⁺ 796.5. HPLC: 100% purity at 220 nm. ¹ H NMR (400 MHz, DMSO-d ₆ ) į ppm 10.91 (s, 1 H), 9.74 (s, 1 H), 7.49 (d, J=8.70 Hz, 1 H), 7.23 (dt, J=9.36, 4.74 Hz, 1 H), 7.02 - 7.09 (m, 4 H), 6.86 (br d, J=10.01 Hz, 2 H), 6.61 (d, J=8.70 Hz, 2 H), 6.33 (ddd, J=9.09, 5.87, 3.16 Hz, 1 H), 6.20 (d, J=8.58 Hz, 2 H), 5.02 (dd, J=13.17, 4.95 Hz, 1 H), 4.32 (s, 4 H), 3.77 - 3.84 (m, 1 H), 3.54 (br d, J=12.04 Hz, 2 H), 3.25 - 3.28 (m, 6 H), 2.83 - 2.92 (m, 1 H), 2.56 - 2.67 (m, 2 H), 2.24 - 2.43 (m, 4 H), 2.16 (br d, J=6.79 Hz, 2 H), 1.91 - 1.97 (m, 1 H), 1.54 - 1.85 (m, 4 H), 1.10 - 1.17 (m, 2 H). Step 7: To a solution of compound 6A (30 mg, 62.05 ^mol, 1.0 eq) in DCM (4 mL) and MeOH (4 mL) was added compound 034 (20.37 mg, 62.05 ^mol, 1.0 eq) and DIEA (8.02 mg, 62.05 ^mol, 1.0 eq) at 25 °C. After addition, the mixture was stirred at this temperature for 0.5 hr, and then NaBH(OAc) ₃ (26.30 mg, 124.10 ^mol, 2.0 eq) was added at 25 °C. The resulting mixture was stirred at 25 °C for 1 hr. The reaction mixture was concentrated to yield a residue. The residue was purified by preparative HPLC (column: C18-1150*30mm*5um; mobile phase: [ t (NH HCO ) ACN] B% 52% 80% 11 i ) f ll d b l hili ti t i ld I 316 (38.7 mg, 48.63 ^mol, 78.37% yield) was obtained as a white solid. LC-MS (ESI+) m/z: 796.6 [M+H] ⁺ . LCMS: calc. for C ₄₅ H ₄₅ F ₄ N ₅ O ₄ : 795.34, found: [M+H] ⁺ 796.6. HPLC: 100 % purity at 220 nm ppm 10.94 (s, 1 H), 9.77 (s, 1 H), 7.52 (d, J=8.70 Hz, 1 H), 7.24 - 7.29 (m, 1 H), 7.04 - 7.11 (m, 4 H), 6.89 (br d, J=10.13 Hz, 2 H), 6.64 (d, J=8.70 Hz, 2 H), 6.36 (ddd, J=9.09, 5.75, 3.28 Hz, 1 H), 6.23 (d, J=8.58 Hz, 2 H), 5.05 (dd, J=13.17, 5.07 Hz, 1 H), 4.12 (s, 4 H), 3.81 - 3.87 (m, 1 H), 3.54 - 3.59 (m, 2 H), 3.28 - 3.30 (m, 6 H), 2.85 - 2.92 (m, 1 H), 2.60 - 2.69 (m, 2 H), 2.26 - 2.46 (m, 4 H), 2.19 (br d, J=6.91 Hz, 2 H), 1.94 - 1.99 (m, 1 H), 1.54 - 1.83 (m, 4 H), 1.16 (br d, J=11.09 Hz, 2 H). EXAMPLE 28. Preparation of (I-326) (S)-3-(5-(4-((1-(4-((1R,2S)-4,4-difluoro-2-(4- fluoro-2-methylphenyl)-6-hydroxy-1,2,3,4-tetrahydronaphthale n-1-yl)phenyl)piperidin-4- yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2, 6-dione Step 1: A mixture of (5R,6S)-5-(4-(4-(dimethoxymethyl)piperidin-1-yl)phenyl)-8,8- difluoro-6- (4-fluoro-2-methylphenyl)-5,6,7,8-tetrahydronaphthalen-2-ol (65 mg, 1 Eq, 0.12 mmol) in THF (1.5 mL), then 10%H ₂ SO ₄ (1.5 mL) was added to the mixture and stirred at 70 °C for 0.5 h. The reaction was adjust to pH=8 with aq. NaHCO ₃ at 0 °C. Then the mixture was added H ₂ O (10 mL) and extracted with EtOAc (20 mL x 2). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to dryness in vacuo to give 1-(4- ((1R,2S)-4,4-difluoro-2-(4-fluoro-2-methylphenyl)-6-hydroxy- 1,2,3,4-tetrahydronaphthalen-1- yl)phenyl)piperidine-4-carbaldehyde (65 mg, 100 % yield, 91.7% purity) as a yellow solid. LC- MS (ESI+) m/z: 480.3 (M+H) ⁺ . Step 2: A mixture of 1-(4-((1R,2S)-4,4-difluoro-2-(4-fluoro-2-methylphenyl)-6-hyd roxy-1,2,3,4- tetrahydronaphthalen-1-yl)phenyl)piperidine-4-carbaldehyde (65 mg, 1 Eq, 0.12 mmol), (S)-3- (1-oxo-5-(piperazin-1-yl)isoindolin-2-yl)piperidine-2,6-dion e benzenesulfonate (79 mg, 1.3 Eq, 0.16 mmol), sodium acetate (51 mg, 5 Eq, 0.62 mmol) and acetic acid (22 mg, 21 ^L, 3 Eq, 0.37 mmol) in DCM (3 mL) and MeOH (3 mL) was stirred at 25 °C for 1 h, then NaBH(OAc) ₃ (53 mg, 2 Eq, 0.25 mmol) was added to the mixture and was stirred at 25 °C for 16 h. The mixture was added H2O (20 mL), extracted with EtOAc (20 mL x 2). The combined extracts was dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to dryness in vacuo to give a residue. The residue was purified by prep-HPLC (column: Welch Xtimate C18150*30mm*5um ; mobile phase: [water(FA)-ACN];B% 25%-65%, 9min) to give (S)-3-(5-(4-((1-(4-((1R,2S)-4,4-difluoro- 2-(4-fluoro-2-methylphenyl)-6-hydroxy-1,2,3,4-tetrahydronaph thalen-1-yl)phenyl)piperidin-4- yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2, 6-dione (16.1 mg, 16 % yield, 100% purity) as a white solid. LC-MS (ESI+) m/z: 792.3 (M+H) ⁺ . LCMS: calc. for C ₄₆ H ₄₈ F3N5O4: 791.37, found: [M+H] + 792.3. HPLC: 100% purity at 220 nm. ¹ HNMR (400MHz, DMSO-d ₆ ) į = 10.95 (s, 1H), 9.75 (s, 1H), 8.14 (s, 1H), 7.55 (br s, 1H), 7.21 - 7.03 (m, 4H), 6.95 - 6.83 (m, 2H), 6.73 - 6.57 (m, 3H), 6.20 - 6.10 (m, 3H), 5.06 (br dd, J=4.9, 13.4 Hz, 1H), 4.40 - 4.18 (m, 3H), 3.98 (br s, 1H), 3.72 (br d, J=15.4 Hz, 1H), 3.57 (br s, 3H), 3.31 - 3.24 (m, 3H), 3.11 (br s, 2H), 2.96 - 2.86 (m, 1H), 2.79 - 2.53 (m, 6H), 2.47 (s, 3H), 2.44 - 2.31 (m, 2H), 2.22 (br t, J=14.9 Hz, 2H), 2.02 - 1.92 (m, 1H), 1.80 (br s, 2H), 1.24 (br s, 2H) EXAMPLE 29. Preparation of (I-406) (S)-3-(5-(4-((1-(4-((1R,2R)-4,4-difluoro-6- hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)-3-methox yphenyl)piperidin-4- yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2, 6-dione Step 1: To a solution of (S)-5-(6-(4-(dimethoxymethyl)piperidin-1-yl)-4-methoxy-[1,1' - biphenyl]-3-yl)-8,8-difluoro-5,6,7,8-tetrahydronaphthalen-2- ol (80.00 mg, 1 Eq, 152.8 ^mol) in THF (3 mL)and 10%H2SO4 (3 mL).The mixture was stirred at 70 °C for 2 hour .LCMS showed 93% desired MS was detected. The reaction mixture was quenched by addition 50 mL H ₂ O at 25°C, and then diluted with 50 mL H ₂ O and extracted with ethyl acetate (50 mL * 2). The combined organic layers were washed with 50 mL brine and dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give (S)-1-(5-(4,4-difluoro-6-hydroxy-1,2,3,4- tetrahydronaphthalen-1-yl)-4-methoxy-[1,1'-biphenyl]-2-yl)pi peridine-4-carbaldehyde (70 mg, 0.14 mmol, 89 %, 93% purity) as a residue. LC-MS (ESI+) m/z: 478.1(M+H) ⁺ . Step 2: To a solution of (S)-1-(5-(4,4-difluoro-6-hydroxy-1,2,3,4-tetrahydronaphthale n-1-yl)-4- methoxy-[1,1'-biphenyl]-2-yl)piperidine-4-carbaldehyde (70.00 mg, 1 Eq, 146.6 ^mol), (S)-3-(1- oxo-5-(piperazin-1-yl)isoindolin-2-yl)piperidine-2,6-dione benzenesulfonate (85.58 mg, 1.2 Eq, 1759 ^mol) in DCM (2 mL) MeOH (2 mL) was added sodium acetate (3607 mg 3 Eq 4397 ^mol) was stirred at 25 °C for 30 mins, Then sodium triacetoxyborohydride (62.13 mg, 2 Eq, 293.2 ^mol) and acetic acid (26.41 mg, 25.29 ^L, 3 Eq, 439.7 ^mol) was added .The mixture was stirred at 25 °C for 16 hour. LCMS showed 93% desired MS was detected. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was purified by prep-HPLC (column: Welch Xtimate C18150*30mm*5um phase: [water(FA)-ACN];B%: 17%- 57%,9 min to give (S)-3-(5-(4-((1-(4-((1R,2R)-4,4-difluoro-6-hydroxy-2-phenyl- 1,2,3,4- tetrahydronaphthalen-1-yl)-3-methoxyphenyl)piperidin-4-yl)me thyl)piperazin-1-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione (28.2 mg, 34.8 ^mol, 23.7 %, 97.4% purity) was obtained as a white solid. LCMS: calc. for C ₄₆ H ₄₉ F ₂ N ₅ O ₅ : 789.92, found: [M+H] ⁺ 790.4. HPLC: 97.472% purity at 220 nm. ¹ H NMR (400MHz, DMSO-d ₆ ) į = 10.96 (s, 1 H) 9.20 - 10.38 (m, 1 H) 8.17 (s, 0.586 H) 7.52 (d, J=8.53 Hz, 1 H) 7.39 - 7.45 (m, 2 H) 7.33 (t, J=7.53 Hz, 2 H) 7.17 -7.25 (m, 1 H) 7.01 - 7.08 (m, 2 H) 6.97 (d, J=1.76 Hz, 1 H) 6.75 - 6.81 (m, 1 H) 6.67 - 6.75 (m, 2 H) 6.41 (s, 1 H) 5.05 (dd, J=13.30, 5.02 Hz, 1 H) 4.28 - 4.43(m, 2 H) 4.15 - 4.24 (m, 1 H) 3.85 (s, 3 H) 3.25 (br s, 4 H) 3.07 (br t, J=11.67 Hz, 2 H) 2.84 - 2.97 (m, 1 H) 2.53 - 2.62 (m, 2 H) 2.46 (br s, 4 H) 2.31 - 2.40(m, 1 H) 1.88 - 2.28 (m, 8 H) 1.52 - 1.67 (m, 3 H) 0.96 - 1.10 (m, 2 H)

EXAMPLE 30. Preparation of (I-320) (S)-3-(5-(4-((1-(4-((1*S,2*R)-4,4-difluoro-6- hydroxy-2-(p-tolyl)-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl )piperidin-4- yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2, 6-dione Step 1: A 40mL thread vial equipped with magnetic stirrer. To a mixture of 1-(4-(6-(benzyloxy)- 2-bromo-4,4-difluoro-3,4-dihydronaphthalen-1-yl)phenyl)-4-(d imethoxymethyl)piperidine (600 mg, 1 Eq, 901 ^mol), p-Tolueneboronic acid (147 mg, 1.2 Eq, 1.08 mmol), Sodium carbonate (287 mg, 174 ^L, 3 Eq, 2.70 mmol) and 1,1'-Bis(di-t-butylphosphino)ferrocene palladium dichloride (58.7 mg, 0.1 Eq, 90.1 ^mol) in dioxane (12 mL) and H ₂ O (3 mL) was stirred at 50 °C for 2 hour under N ₂ . TLC (petroleum ether: ethyl acetate=5:1, UV) showed one main new spot was observed. The reaction was quenched with water (100 mL) and extracted with ethyl acetate (200 mL*2). The organic layer was washed with brine(50 mL) and dried over Na ₂ SO ₄ and concentrated in vacuo to give 1-(4-(6-(benzyloxy)-4,4-difluoro-2-(p-tolyl)-3,4- dihydronaphthalen-1-yl)phenyl)-4-(dimethoxymethyl)piperidine as a brown oil. The brown oil was subjected to column chromatography over silica gel (gradient elution: 0 – 20% EtOAc). The desired fractions were collected, and concentrated to dryness in vacuo to give 1-(4-(6- (benzyloxy)-4,4-difluoro-2-(p-tolyl)-3,4-dihydronaphthalen-1 -yl)phenyl)-4- (dimethoxymethyl)piperidine (570 mg, 918 ^mol, 95.97% purity) as a white solid. LC-MS (ESI ⁺ ) m/z: 596.3 (M+H) ⁺ . Step 2: A mixture of 1-(4-(6-(benzyloxy)-4,4-difluoro-2-(p-tolyl)-3,4-dihydronaph thalen-1- yl)phenyl)-4-(dimethoxymethyl)piperidine (570 mg, 95.97% Wt, 1 Eq, 918 ^mol), dihydrogen (1.85 mg, 1 Eq, 918 ^mol), Pd/C (570 mg, 10% Wt, 0.583 Eq, 536 ^mol) and Pd(OH) ₂ /C (570 mg, 20% Wt, 0.884 Eq, 812 ^mol) in THF (10 mL) and MeOH (10 mL) was degassed and purged with H ₂ for 3 times, and then the mixture was stirred at 25 °C for 4 hour under H ₂ atmosphere (15psi). The reaction was filtered and concentrated to dryness in vacuo to give 5-(4- (4-(dimethoxymethyl)piperidin-1-yl)phenyl)-8,8-difluoro-6-(p -tolyl)-5,6,7,8- tetrahydronaphthalen-2-ol (480 mg, 812 ^mol, 88.4 %, 85.89% purity)as a white solid. LC-MS (ESI ⁺ ) m/z: 508.3 (M+H) ⁺ . Step 3: The white solid was purified by SFC. Column: DAICEL CHIRALCEL OJ (250mm*30mm, 10um); Condition: CO ₂ -EtOH(0.1%NH ₃ H ₂ O); At the beginning: B (30%); At the end: B (30%); Flow Rate (ml/min) 80. The aqueous phase was lyophilized to dryness to give (5R,6S)-5-(4-(4-(dimethoxymethyl)piperidin-1-yl)phenyl)-8,8- difluoro-6-(p-tolyl)-5,6,7,8- tetrahydronaphthalen-2-ol (190 mg, 374 ^mol, 46.1 %, 100% purity) as a colorless oil and (5S,6R)-5-(4-(4-(dimethoxymethyl)piperidin-1-yl)phenyl)-8,8- difluoro-6-(p-tolyl)-5,6,7,8- tetrahydronaphthalen-2-ol (200 mg, 382 ^mol, 47.1 %, 97.01% purity) as a colorless oil. LC-MS (ESI ⁺ ) m/z: 508.2 (M+H) ⁺ . Step 4: To a solution of (5R,6S)-5-(4-(4-(dimethoxymethyl)piperidin-1-yl)phenyl)-8,8- difluoro- 6-(p-tolyl)-5,6,7,8-tetrahydronaphthalen-2-ol (190 mg, 1 Eq, 374 ^mol) in THF (10 mL) was added sulfuric acid (367 mg, 10 mL, 10% Wt, 1 Eq, 374 ^mol). The mixture was stirred at 70 °C for 40 min. The mixture was adjusted to pH=8-9 by progressively adding NaHCO ₃ . The reaction mixture was quenched by addition 100 mL EtOAc at 20°C, and then diluted with 50 mL H ₂ O and extracted with EtOAc 50mL (25 mL * 2). The combined organic layers were washed with 10 mL (10 mL * 1), dried over Na ₂ SO ₄ . The reaction was filtered and concentrated under reduced pressure to give 1-(4-((1R,2S)-4,4-difluoro-6-hydroxy-2-(p-tolyl)-1,2,3,4-tet rahydronaphthalen- 1-yl)phenyl)piperidine-4-carbaldehyde (200 mg, 418 ^mol, 96.5% purity) as a yellow oil. LC- MS (ESI+) m/z: 480.2 (M+H) ⁺ . Step 5: A mixture of 1-(4-((1R,2S)-4,4-difluoro-6-hydroxy-2-(p-tolyl)-1,2,3,4- tetrahydronaphthalen-1-yl)phenyl)piperidine-4-carbaldehyde (200 mg, 1 Eq, 418 ^mol), (S)-3- (1-oxo-5-(piperazin-1-yl)isoindolin-2-yl)piperidine-2,6-dion e, PhSO3H salt (137 mg, 1 Eq, 418 ^mol) and sodium acetate (172 mg, 5 Eq, 2.09 mmol) in DCM (8 mL) and MeOH (8 mL) at 20°C for 0.5 hour, pH=8, then acetic acid (75.3 mg, 71.7 ^L, 3 Eq, 1.25 mmol) at 20°C for 1 hour, pH=6, then added Sodium triacetoxyborohydride (177 mg, 124 ^L, 2 Eq, 836 ^mol) the mixture, and then the mixture was stirred at 25 °C for 16 hour. The reaction was quenched with water (50 mL) and extracted with ethyl acetate (50 mL*2). The reaction was concentrated to give (S)-3-(5-(4-((1-(4-((1R,2S)-4,4-difluoro-6-hydroxy-2-(p-toly l)-1,2,3,4-tetrahydronaphthalen-1- yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindo lin-2-yl)piperidine-2,6-dione as a yellow oil. The yellow oil was purified by preparative high-performance liquid chromatography. Condition: water (FA)-ACN. Column: Welch Xtimate C18150*30mm*5um. Begin B: 18%, End B: 48%. Gradient Time (min) 7; 100% B hold Time (min) 3.2, Flow Rate(ml/min) 25. The pure fractions were collected and the solvent was evaporated under vacuum. The aqueous layer was lyophilized to dryness to give (S)-3-(5-(4-((1-(4-((1*R,2*S)-4,4- difluoro-6-hydroxy-2-(p-tolyl)-1,2,3,4-tetrahydronaphthalen- 1-yl)phenyl)piperidin-4- yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2, 6-dione (106.9 mg, 135.6 ^mol, 32.4 %, 98.18% purity) as a white solid. HPLC: 98.18% purity at 220 nm. 10.97 - 10.94 (m, 1H), 9.75 - 9.71 (m, 1H), 8.13 (s, 0.516H), 7.53 - 7.49 (m, 1H), 7.06 (br s, 3H), 7.00 (d, J = 7.9 Hz, 2H), 6.86 (s, 2H), 6.79 - 6.75 (m, 2H), 6.61 - 6.55 (m, 2H), 6.17 - 6.13 (m, 2H), 5.08 - 5.01 (m, 1H), 4.35 - 4.29 (m, 1H), 4.27 (br d, J = 2.7 Hz, 1H), 4.22 (s, 1H), 3.62 - 3.50 (m, 3H), 3.27 (br s, 5H), 2.95 - 2.84 (m, 1H), 2.71 - 2.52 (m, 4H), 2.48 - 2.45 (m, 2H), 2.43 - 2.29 (m, 2H), 2.25 (s, 4H), 2.19 (br d, J = 6.3 Hz, 2H), 1.99 - 1.91 (m, 1H), 1.79 - 1.71 (m, 2H), 1.68 - 1.59 (m, 1H), 1.20 - 1.09 (m, 2H) EXAMPLE 31. Preparation of (I-321) (R)-3-(5-(4-((1-(4-((1S,2R)-4,4-difluoro-6- hydroxy-2-(p-tolyl)-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl )piperidin-4- yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2, 6-dione Step 1: To a solution of (5S,6R)-5-(4-(4-(dimethoxymethyl)piperidin-1-yl)phenyl)-8,8- difluoro- 6-(p-tolyl)-5,6,7,8-tetrahydronaphthalen-2-ol (200 mg, 1 Eq, 776 ^mol) in THF (10 mL) was added sulfuric acid (761 mg, 10 mL, 10% Wt, 1 Eq, 776 ^mol). The mixture was stirred at 70 °C for 40 min The mixture was adjusted to pH=8-9 by progressively adding NaHCO ₃ The reaction mixture was quenched by addition 100 mL EtOAc at 20°C, and then diluted with 50 mL H2O and extracted with EtOAc 50mL (25 mL * 2). The combined organic layers were washed with 10 mL (10 mL * 1), dried over Na ₂ SO ₄ . The reaction was filtered and concentrated under reduced pressure to give 1-(4-((1S,2R)-4,4-difluoro-6-hydroxy-2-(p-tolyl)-1,2,3,4-tet rahydronaphthalen- 1-yl)phenyl)piperidine-4-carbaldehyde (195 mg, 400 ^mol, 51.5 %, 94.6% Purity) as a yellow oil. LC-MS (ESI+) m/z: 480.1(M+H) ⁺ . Step 2: A mixture of 1-(4-((1S,2R)-4,4-difluoro-6-hydroxy-2-(p-tolyl)-1,2,3,4- tetrahydronaphthalen-1-yl)phenyl)piperidine-4-carbaldehyde (195 mg, 1 Eq, 400 ^mol), (S)-3- (1-oxo-5-(piperazin-1-yl)isoindolin-2-yl)piperidine-2,6-dion e, PhSO ₃ H salt (131 mg, 1 Eq, 400 ^mol) and sodium acetate (164 mg, 5 Eq, 2.00 mmol) in DCM (8 mL) and MeOH (8 mL) at 20°C for 0.5 hour, pH=8, then acetic acid (72.0 mg, 68.6 ^L, 3 Eq, 1.20 mmol) at 20°C for 1 hour, pH=6, then added Sodium triacetoxyborohydride (169 mg, 118 ^L, 2 Eq, 799 ^mol) the mixture, and then the mixture was stirred at 25 °C for 16 hour. The reaction was quenched with water (50 mL) and extracted with ethyl acetate (50 mL*2). The reaction was concentrated to give (S)-3-(5-(4-((1-(4-((1S,2R)-4,4-difluoro-6-hydroxy-2-(p-toly l)-1,2,3,4-tetrahydronaphthalen-1- yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindo lin-2-yl)piperidine-2,6-dione as a yellow oil. The yellow oil was purified by preparative high-performance liquid chromatography. Condition: water (FA)-CAN. Column: Welch Xtimate C18150*30mm*5um. Begin B: 26%, End B: 56%), Gradient Time (min) 7; 100% B hold Time(min) 3.2, Flow Rate(ml/min) 25. The pure fractions were collected and the solvent was evaporated under vacuum. The aqueous layer was lyophilized to dryness to give (R)-3-(5-(4-((1-(4-((1S,2R)-4,4-difluoro-6-hydroxy-2-(p- tolyl)-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperidin-4- yl)methyl)piperazin-1-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione (102.8 mg, 129.5 ^mol, 32.4 %, 97.50% Purity) as a white solid. LCMS: calc. for C ₄₆ H ₄₉ F ₂ N ₅ O ₄ : 773.38, found: [M+H] ⁺ 774.3. HPLC: 97.50% purity at 220 nm. NMR (400 MHz, DMSO-d ₆ ) į=10.95 (s, 1H), 9.75 - 9.70 (m, 1H), 8.14 (s, 0.227H), 7.54 - 7.48 (m, 1H), 7.08 - 7.03 (m, 3H), 7.00 (d, J = 8.1 Hz, 2H), 6.89 - 6.82 (m, 2H), 6.80 - 6.75 (m, 2H), 6.58 (d, J = 8.8 Hz, 2H), 6.18 - 6.11 (m, 2H), 5.09 - 5.00 (m, 1H), 4.36 - 4.25 (m, 2H), 4.21 ( 1H) 363 350 ( 3H) 327 (b 5H) 295 284 ( 1H) 268 253 ( 3H) 248 244 (m, 3H), 2.43 - 2.29 (m, 2H), 2.25 (s, 4H), 2.21 - 2.16 (m, 2H), 1.99 - 1.91 (m, 1H), 1.78 - 1.71 (m, 2H), 1.68 - 1.60 (m, 1H), 1.21 - 1.09 (m, 2H) EXAMPLE 32. Preparation of (I-328) (S)-3-(5-(4-((1-(4-((1S,2R)-4,4-difluoro-6- hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)-2-fluoro phenyl)piperidin-4- yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2, 6-dione and (I-194) (S)-3-(5-(4- ((1-(4-((1R,2S)-4,4-difluoro-6-hydroxy-2-phenyl-1,2,3,4-tetr ahydronaphthalen-1-yl)-2-

fluorophenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoi soindolin-2-yl)piperidine-2,6- dione Step 1: To a solution of compound 1 (3.0 g, 18.86 mmol, 1 eq) and 2 (3.60 g, 22.63 mmol, 1.2 eq) in EtOAc (30 mL) was added Et3N (5.72 g, 56.57 mmol, 3 eq). The mixture was stirred at 25 °C for 3 hr. The mixture was concentrated in reduced pressure. The residue was poured into water (30mL). The aqueous phase was extracted with ethyl acetate (60 mL x 3). The combined organic phase was washed with brine (30 mL x 3), dried with anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuum. The residue was purified by silica gel chromatography (column height: 250 mm, diameter: 100 mm, 100-200 mesh silica gel, Petroleum ether/Ethyl acetate=3:1) to afford compound 3 (4.43 g, 14.85 mmol, 78.75% yield) as yellow oil. LC-MS (ESI+) m/z: 299.2 (M+H) ⁺ . Step 2: To a solution of compound 3 (4.43 g, 14.85 mmol, 1.0 eq.) in EtOH (50 mL) and H ₂ O (17 mL) was added Fe (3.32 g, 59.35 mmol, 4 eq) and NH ₄ Cl (1.59 g, 29.67 mmol, 2 eq). The mixture was stirred at 80 °C for 5 hr. LCMS showed that the starting material was consumed and the desired product was detected. The residue was poured into water (55mL). The aqueous phase was extracted with ethyl acetate (100 mL x 3). The combined organic phase was washed with brine (55 mL), dried with anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was purified by silica gel chromatography (column height: 250 mm, diameter: 100 mm, 100-200 mesh silica gel, Petroleum ether/Ethyl acetate=3:1) to afford compound 4 (3.72 g, 13.86 mmol, 93.44% yield) as yellow oil. The reaction mixture was filtered under reduced pressure to give a compound. Compound 4 (3.72 g, 13.86 mmol, 93.44% yield) was obtained as yellow oil. LC-MS (ESI+) m/z: 269.2 (M+H) ⁺ . Step 3: To a solution of compound 4 (3.72 g, 13.86 mmol, 1eq) in MeCN (70 mL) and H ₂ O (70 mL) was added KI (6.90 g, 41.59 mmol, 3eq), HCl (2 M, 6.93 mL, 1eq) and NaNO ₂ (2.87 g, 41.59 mmol, 3eq). The mixture was stirred at 25 °C for 5 hr. LC-MS showed that the starting material was consumed and the desired product was detected. The residue was poured into water (70 mL). The aqueous phase was extracted with ethyl acetate (140 mL x 3). The combined organic phase was washed with brine (70 mL), dried with anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuum. The residue was purified by silica gel chromatography (column height: 250 mm, diameter: 100 mm, 100-200 mesh silica gel, Petroleum ether/Ethyl acetate=3:1) to afford 5 (4.42 g, 11.66 mmol, 84.07% yield) as yellow oil. The reaction mixture was filtered under reduced pressure to give a compound. Compound 5 (4.42 g, 11.66 mmol, 84.07% yield) was obtained as yellow oil . LC-MS (ESI+) m/z: 380.1(M+H) ⁺ . Step 4: To a solution of 5 (3.0 g, 7.91 mmol, 1 eq) in THF (35 mL) was added dropwise n-BuLi (2.5 M, 3.80 mL, 1.2eq) at -78 C. After addition, the mixture was stirred at this temperature for 1 hr, and then compound 6 (2.28 g, 7.91 mmol, 1eq) in THF (35 mL) was added dropwise at - 78 °C. The resulting mixture was stirred at -78 °C for 3 hr. LCMS showed that the starting material was consumed and the desired product was detected. The residue was poured into water (35mL). The aqueous phase was extracted with ethyl acetate (70 mL x 3). The combined organic phase was washed with brine (30 mL), dried with anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuum. The residue was purified by silica gel chromatography (column height: 250 mm, diameter: 100 mm, 100-200 mesh silica gel, Petroleum ether/Ethyl acetate=3:1) to afford 7 (2.12 g, 3.91 mmol, 49.48% yield) as yellow oil. The reaction mixture was filtered under reduced pressure to give a compound. Compound 7 (2.12 g, 3.91 mmol, 49.48% yield) was obtained as yellow oil. LC-MS (ESI+) m/z: 542.3 (M+H) ⁺ . Step 5: To a solution of compound 7 (2.12 g, 3.91 mmol, 1 eq) in HCl/MeOH (25 mL). The mixture was stirred at 25 °C for 3 hr. LCMS showed that the starting material was consumed and the desired product was detected. The reaction mixture was quenched by addition of water (8 mL), adjust pH to 7 by NaHCO ₃ , extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (8 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to yield 8 (1.22 g, 2.33 mmol, 59.53% yield) which was used in the next step without further purification. LC-MS (ESI+) m/z: 524.4(M+H) ⁺ . Step 6: To a solution of compound 8 (1.22 g, 2.33 mmol, 1eq) in DCM (25 mL) was added Py.HBr ₃ (745.21 mg, 2.33 mmol, 1eq). The mixture was stirred at 25 °C for 1 hr. LCMS showed that the starting material was consumed and the desired product was detected. The residue was poured into water (25mL). The aqueous phase was extracted with ethyl acetate (50 Na2SO4, filtered and concentrated in vacuum. The residue was purified by silica gel chromatography (column height: 250 mm, diameter: 100 mm, 100-200 mesh silica gel, Petroleum ether/Ethyl acetate=3:1) to afford 9 (888 mg, 1.47 mmol, 63.26% yield) as yellow oil. The reaction mixture was filtered under reduced pressure to give a compound. Compound 9 (888 mg, 1.47 mmol, 63.26% yield) was obtained as yellow oil. LC-MS (ESI+) m/z: 604.2 (M+H) ⁺ . Step 7: A mixture of compound 9 (888 mg, 1.47 mmol, 1eq), compound 10 (179.71 mg, 1.47 mmol, 1eq), K ₂ CO ₃ (407.40 mg, 2.95 mmol, 2 eq) and Pd(dppf)Cl ₂ (107.85 mg, 147.39 ^mol, 0.1 eq) in dioxane (10 mL) and H ₂ O (3 mL) was degassed and purged with N ₂ for 3 times, and then the mixture was stirred at 80 °C for 3 hr under N ₂ atmosphere. LCMS showed that the starting material was consumed and the desired product was detected. The reaction mixture was filtered under reduced pressure to give a residue. The residue was poured into H ₂ O (13 mL). The aqueous phase was extracted with ethyl acetate (26 mL x 3). The combined organic phase was washed with brine (13 mL), dried with anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuum. The residue was purified by silica gel chromatography (column height: 250 mm, diameter: 100 mm, 100-200 mesh silica gel, Petroleum ether/Ethyl acetate=3:1) to afford 10 (800 mg, 1.33 mmol, 90.51% yield) as yellow oil. LC-MS (ESI+) m/z: 600.4(M+H) ⁺ . Step 8: To a solution of compound 11 (591 mg, 985.52 ^mol, 1eq) in MeOH (10 mL) was added Pd/C (524.40 mg, 492.76 ^mol, 10% purity, 0.5eq). The mixture was stirred under H ₂ at 25 °C and 15 Psi for 16 hr. LCMS showed that the starting material was consumed and the desired product was detected. The reaction mixture was filtered under reduced pressure to give residue. The residue was purified by prep-HPLC (column: Boston Green ODS 150*30mm*5um; mobile phase: [water(TFA)-ACN]; B%: 50%-80%,12min) to give compound 12 (200 mg, 390.95 ^mol, 39.67% yield) was obtained as a white solid. LC-MS (ESI+) m/z: 512.3(M+H) ⁺ . Step 9: Compound 13 and 13A (200 mg) was separated by chiral SFC (Column DAICEL CHIRALPAK AD (250mm*30mm,10um), Condition CO2-EtOH(0.1%NH3H2O) Begin B 25% End B 25%) FlowRate (ml/min):70) Compound 13 (70 mg, 136.83 ^mol, 35.00% yield), compound 13A (120 mg, 234.57 ^mol, 60.00% yield). LC-MS (ESI+) m/z: 512.3(M+H) ⁺ . Step 10: Compound 14: To a solution of compound 13 (70 mg, 136.83 ^mol, 1.0 eq) in DCM (2 mL) was added TFA (15.60 mg, 136.83 ^mol, 10.16 ^L, 1eq). The mixture was stirred at 25 °C for 0.5 hr. LCMS showed that the starting material was consumed and the desired product was detected. The reaction liquid is dried with N ₂ at 0°C to give Compound 14 (42 mg, 90.22 ^mol, 65.94% yield) was obtained as yellow oil which was used in the next step without further purification.. LC-MS (ESI+) m/z: 466.1 (M+H)+. Step 11: Compound 14A: To a solution of compound 13A (70 mg, 136.83 ^mol, 1 eq) in DCM (2 mL) was added TFA (15.60 mg, 136.83 ^mol, 10.16 ^L, 1eq). The mixture was stirred at 25 °C for 0.5 hr. LCMS showed that the starting material was consumed and the desired product was detected. The reaction liquid is dried with N2 at 0 °C to give Compound 14A (40 mg, 85.93 ^mol, 62.80% yield) was obtained as yellow oil which was used in the next step without further purification.. LC-MS (ESI+) m/z: 466.1(M+H) ⁺ . Step 12: To a solution of compound 14 (40 mg, 85.93 ^mol, 1 eq) in DCM (3 mL) and MeOH (3 mL) was added compound 034 (28.22 mg, 85.93 ^mol, 1eq) and DIEA (11.11 mg, 85.93 ^mol, 14.97 ^L, 1eq) at 25 °C. After addition, the mixture was stirred at this temperature for 0.5 hr, and then NaBH ₃ (OAc) ₃ (36.42 mg, 171.86 ^mol, 2 eq) was added at 25 °C. The resulting mixture was stirred at 25 °C for 3 hr. The reaction mixture was concentrated to yield a residue. The residue was purified by preparative HPLC (column: Boston Green ODS 150 * 30 mm * 5um; mobile phase: [water (FA) - ACN]; B%: 18%-48%,14min) , followed by lyophilization to yield I-328 (46.6 mg, 59.91 ^mol, 69.72% yield) was obtained as a white solid. LC-MS (ESI+) m/z: 778.6 [M+H]+. LCMS: calc. for C45H46F3N5O4: 777.35, found: [M+H] ⁺ 778.6. HPLC: 9712% purity at 220 nm NMR (400 MHz, METHANOL-d4) į ppm 8.36 (br s, 1 H) 7.62 (d, J=8.46 Hz, 1 H) 7.16 - 7.20 (m, 3 H) 7.13 (s, 1 H) 7.06 - 7.09 (m, 2 H) 6.83 - 6.88 (m, 4 H) 6.68 (t, J=8.76 Hz, 1 H) 6.05 - 6.10 (m, 1 H) 5.91 - 5.97 (m, 1 H) 5.08 (dd, J=13.35, 5.13 Hz, 1 H) 4.35 - 4.44 (m, 2 H) 4.31 (br d, J=3.81 Hz, 1 H) 3.66 - 3.73 (m, 1 H) 3.39 (br d, J=4.53 Hz, 4 H) 2.82 - 2.90 (m, 1 H) 2.69 - 2.82 (m, 6 H) 2.50 - 2.68 (m, 4 H) 2.41 - 2.49 (m, 3 H) 2.26 - 2.34 (m, 1 H) 2.09 - 2.16 (m, 1 H) 1.74 - 1.87 (m, 3 H) 1.32 - 1.41 (m, 2 H) Step 13: To a solution of compound 14A (40 mg, 85.93 ^mol, 1 eq) in DCM (3 mL) and MeOH (3 mL) was added compound 034 (28.22 mg, 85.93 ^mol, 1 eq) and DIEA (11.11 mg, 85.93 ^mol, 14.97 ^L, 1eq) at 25 °C. After addition, the mixture was stirred at this temperature for 0.5 hr, and then NaBH ₃ (OAc) ₃ (36.42 mg, 171.86 ^mol, 2eq) was added at 25°C. The resulting mixture was stirred at 25 °C for 3 hr. The reaction mixture was concentrated to yield a residue. The residue was purified by preparative HPLC (column: Boston Green ODS 150 * 30 mm * 5um; mobile phase: [water (FA) - ACN]; B%: 18%-48%,14min), followed by lyophilization to yield I-194 (42 mg, 53.99 ^mol, 62.84% yield) was obtained as a white solid. LC-MS (ESI+) m/z: 778.5 [M+H]+. LCMS: calc. for C45H46F3N5O4: 777.35, found: [M+H] ⁺ 778.5. HPLC: 92.14% purity at 220 nm ppm 8.39 (s, 1 H) 7.62 (d, J=8.46 Hz, 1 H) 7.17 - 7.22 (m, 3 H) 7.13 (s, 1 H) 7.06 - 7.10 (m, 2 H) 6.82 - 6.88 (m, 4 H) 6.65 - 6.73 (m, 1 H) 6.06 - 6.11 (m, 1 H) 5.95 (br d, J=13.83 Hz, 1 H) 5.08 (br d, J=8.46 Hz, 1 H) 4.36 - 4.44 (m, 2 H) 4.31 - 4.34 (m, 1 H) 3.68 - 3.73 (m, 1 H) 3.38 (br s, 4 H) 2.84 - 2.90 (m, 1 H) 2.68 - 2.80 (m, 6 H) 2.51 - 2.66 (m, 4 H) 2.38 - 2.46 (m, 3 H) 2.27 - 2.34 (m, 1 H) 2.09 - 2.15 (m, 1 H) 1.72 - 1.87 (m, 3 H) 1.31 - 1.40 (m, 2 H).

EXAMPLE 33. Preparation of (I-313) (S)-3-(5-(4-((1-(4-((1S,2R)-4,4-difluoro-2-(2- fluorophenyl)-6-hydroxy-1,2,3,4-tetrahydronaphthalen-1-yl)ph enyl)piperidin-4- yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2, 6-dione Step 1: To a mixture of 1-(4-(6-(benzyloxy)-4,4-difluoro-3,4-dihydronaphthalen-1-yl) phenyl)-4- (dimethoxymethyl)piperidine (7.8 g, 1 Eq, 15 mmol), DIEA (3.0 g, 4.0 mL, 1.5 Eq, 23 mmol) in DCM (25 mL) at 0 °C, then Pyridinium bromide perbromide (8 g, 2 Eq, 0.03 mol) was added to (500 mL), extracted with EtOAc (600 mL). The combined extracts was dried over anhydrous Na2SO4, filtered and concentrated to dryness in vacuo to give a residue. The residue was subjected to column chromatography over silica gel (gradient elution: 0~30% ethyl acetate in petroleum ether). The pure fractions were collected and concentrated to dryness in vacuo to give 1-(4-(6-(benzyloxy)-2-bromo-4,4-difluoro-3,4-dihydronaphthal en-1-yl)phenyl)-4- (dimethoxymethyl)piperidine (8 g, 0.01 mol, 80 %, 87.8% purity) as a white solid LC-MS (ESI ⁺ ) m/z: 586.2 (M+H) ⁺ . Step 2: 1,1'-Bis(di-t-butylphosphino)ferrocene palladium dichloride (0.1 g, 0.1 Eq, 0.2 mmol) was added to the mixture of 1-(4-(6-(benzyloxy)-2-bromo-4,4-difluoro-3,4-dihydronaphthal en-1- yl)phenyl)-4-(dimethoxymethyl)piperidine (1 g, 1 Eq, 2 mmol), (2-Fluorophenyl)boranediol (0.2 g, 1 Eq, 2 mmol) and Na ₂ CO ₃ (0.5 g, 3 Eq, 5 mmol) in dioxane (8 mL) and H ₂ O (2 mL) at r.t.. N ₂ was bubbled into the mixture for 5 min. The reaction mixture was heated at 50 °C for 4 hour. Then the reaction was cooled to room temperature. The mixture was treated with H ₂ O (100 mL), extracted with EtOAc (100 mL). The combined extracts was dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to dryness in vacuo to give a residue. The residue was subjected to column chromatography over silica gel (gradient elution: 0~30% ethyl acetate in petroleum ether). The pure fractions were collected and concentrated to dryness in vacuo to give 1-(4-(6- (benzyloxy)-4,4-difluoro-2-(2-fluorophenyl)-3,4-dihydronapht halen-1-yl)phenyl)-4- (dimethoxymethyl)piperidine (900 mg, 1.43 mmol, 100 %, 95.6% Purity) as a yellow oil. LC-MS (ESI ⁺ ) m/z: 600.3 (M+H) ⁺ . Step 3: A mixture of 1-(4-(6-(benzyloxy)-4,4-difluoro-2-(2-fluorophenyl)-3,4- dihydronaphthalen-1-yl)phenyl)-4-(dimethoxymethyl)piperidine (700 mg, 1 Eq, 1.12 mmol), Pd/C (350 mg, 10% Wt, 0.295 Eq, 329 ^mol), Pd(OH) ₂ /C(350 mg, 20% Wt, 0.447 Eq, 498 ^mol), dihydrogen (2.25 mg, 1 Eq, 1.12 mmol) in THF (4 mL) and MeOH (4 mL). The suspension was degassed and purged with H ₂ for 3 times. The mixture was stirred under H ₂ (15 psi) at 25 °C for 4 hour. The reaction was filtered and concentrated to dryness in vacuo to give a white solid. The white solid was subjected by SFC: Column: DAICEL CHIRALCEL OJ (250 mm *30 mm, 10 um); Mobile phase: A: Supercritical CO ₂ , B: MeOH (0.1% NH ₃ H ₂ O), A:B = 30:30 at 70 mL/min. The aqueous phase was lyophilized to dryness to give (5R,6S)-5-(4-(4- (di th th l) i idi 1 l) h l) 88 difl 6 (2 fl h l) 5678 tetrahydronaphthalen-2-ol (120 mg, 231 ^mol, 40.4 %, 98.5% Purity) and (5S,6R)-5-(4-(4- (dimethoxymethyl)piperidin-1-yl)phenyl)-8,8-difluoro-6-(2-fl uorophenyl)-5,6,7,8- tetrahydronaphthalen-2-ol (150 mg, 293 ^mol, 51.2 %, 100% Purity) as a yellow solid. LC-MS (ESI ⁺ ) m/z: 512.2 (M+H) ⁺ . Step 4: A mixture of (5S,6R)-5-(4-(4-(dimethoxymethyl)piperidin-1-yl)phenyl)-8,8- difluoro-6- (2-fluorophenyl)-5,6,7,8-tetrahydronaphthalen-2-ol (100 mg, 1 Eq, 193 ^mol) in 10% H ₂ SO ₄ (1.5 mL) and THF (1.5 mL), then the mixture was stirred at 60 °C for 0.5 hour. The solvent was removed under vacum. The aqueous solution was added NaHCO ₃ to adjust pH=6. The residue was dissolved in water (20 mL) and extracted by ethyl acetate (20 mL). The combined organic layer was dried over Na ₂ SO ₄ , filtered and concentrated under vaccum to give 1-(4-((1S,2R)-4,4- difluoro-2-(2-fluorophenyl)-6-hydroxy-1,2,3,4-tetrahydronaph thalen-1-yl)phenyl)piperidine-4- carbaldehyde (80 mg, 0.17 mmol, 89 %) as a yellow oil. LC-MS (ESI+) m/z: 466.1 (M+H)+ Step 5: A mixture of 1-(4-((1S,2R)-4,4-difluoro-2-(2-fluorophenyl)-6-hydroxy-1,2, 3,4- tetrahydronaphthalen-1-yl)phenyl)piperidine-4-carbaldehyde (80 mg, 1 Eq, 0.17 mmol), (S)-3- (1-oxo-5-(piperazin-1-yl)isoindolin-2-yl)piperidine-2,6-dion e benzenesulfonate (0.11 g, 1.3 Eq, 0.22 mmol) and sodium acetate (70 mg, 5 Eq, 0.86 mmol) and Acetic acid (31 mg, 30 ^L, 3 Eq, 0.52 mmol) in DCM (2 mL) and MeOH (2 mL) at 25 °C for 1 hour, then sodium triacetoxyborohydride (73 mg, 2 Eq, 0.34 mmol) was added to the mixture and was stirred at 25 °C for 16 hour. The reaction was treated with H ₂ O (20 mL), extracted with EtOAc (20 mL). The combined extracts was dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to dryness in vacuo to give a residue. The residue was purified by prep.HPLC (column: Welch Xtimate C18 150*30mm*5um; mobile phase: [water (FA)-ACN]; B%: 19%-49%, 7min). The aqueous phase was lyophilized to dryness to give (S)-3-(5-(4-((1-(4-((1S,2R)-4,4-difluoro-2-(2-fluorophenyl)- 6- hydroxy-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperidin-4 -yl)methyl)piperazin-1-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione (99.3 mg, 127 ^mol, 74 %, 99.251% purity) as a white solid. LC-MS (ESI+) m/z: 778.2 (M+H)+ ¹ H NMR (400 MHz, DMSO-d6) į = 10.96 (s, 1H), 9.79 (br s, 1H), 8.14 (s, 0.373H), 7.52 (d, J = 8.6 Hz, 1H), 7.32 - 7.16 (m, 2H), 7.12 - 7.02 (m, 3H), 6.98 - 6.84 (m, 3H), 6.65 - 6.50 (m, 3H), 6.18 (d, J = 8.5 Hz, 2H), 5.05 (dd, J = 5.1, 13.3 Hz, 1H), 4.38 - 4.28 (m, 2H), 4.26 - 4.16 (m, 1H), 3.86 (br d, J = 14.7 Hz, 1H), 3.60 - 3.46 (m, 3H), 3.34 - 3.19 (m, 8H), 2.98 - 2.84 (m, 1H), 2.83 - 2.67 (m, 1H), 2.64 - 2.54 (m, 2H), 2.43 - 2.27 (m, 2H), 2.20 (br d, J = 6.7 Hz, 2H), 2.02 - 1.90 (m, 1H), 1.75 (br d, J = 12.3 Hz, 2H), 1.66 (br d, J = 9.4 Hz, 1H), 1.25 - 1.07 (m, 2H). EXAMPLE 34. Preparation of (I-312) (S)-3-(5-(4-((1-(4-((1R,2S)-4,4-difluoro-2-(2- fluorophenyl)-6-hydroxy-1,2,3,4-tetrahydronaphthalen-1-yl)ph enyl)piperidin-4- yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2, 6-dione Step 1: A mixture of (5R,6S)-5-(4-(4-(dimethoxymethyl)piperidin-1-yl)phenyl)-8,8- difluoro-6- (2-fluorophenyl)-5,6,7,8-tetrahydronaphthalen-2-ol (100 mg, 1 Eq, 195 ^mol) in 10% H ₂ SO ₄ (1.5 mL) and THF (1.5 mL), then the mixture was stirred at 60 °C for 0.5 hour. The solvent was removed under vaccum. The aqueous solution was added NaHCO ₃ to adjust pH=6. The residue was dissolved in water (20 mL) and extracted by ethyl acetate (20 mL). The combined organic l d i d N SO filt d d t t d d t i 1 (4 ((1R2S) 44 difluoro-2-(2-fluorophenyl)-6-hydroxy-1,2,3,4-tetrahydronaph thalen-1-yl)phenyl)piperidine-4- carbaldehyde (80 mg, 0.17 mmol, 88 %) as a yellow oil. LC-MS (ESI+) m/z: 466.1 (M+H)+ Step 2: A mixture of 1-(4-((1R,2S)-4,4-difluoro-2-(2-fluorophenyl)-6-hydroxy-1,2, 3,4- tetrahydronaphthalen-1-yl)phenyl)piperidine-4-carbaldehyde (80 mg, 1 Eq, 0.17 mmol), (R)-3- (1-oxo-5-(piperazin-1-yl)isoindolin-2-yl)piperidine-2,6-dion e benzenesulfonate (0.11 g, 1.3 Eq, 0.22 mmol) and sodium acetate (70 mg, 5 Eq, 0.86 mmol) andacetic acid (31 mg, 30 ^L, 3 Eq, 0.52 mmol) in DCM (2 mL) and MeOH (2 mL) at 25 °C for 1 hour, then sodium triacetoxyborohydride (73 mg, 2 Eq, 0.34 mmol) was added to the mixture and was stirred at 25 °C for 16 hour. The reaction was treated with H ₂ O (20 mL), extracted with EtOAc (20 mL). The combined extracts was dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to dryness in vacuo to give a residue. The residue was purified by prep.HPLC (column: Welch Xtimate C18 150*30mm*5um; mobile phase: [water (FA)-ACN]; B%: 19%-49%, 7min). The aqueous phase was lyophilized to dryness to give (S)-3-(5-(4-((1-(4-((1R,2S)-4,4-difluoro-2-(2-fluorophenyl)- 6- hydroxy-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperidin-4 -yl)methyl)piperazin-1-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione (51 mg, 65 ^mol, 38 %, 99.111% purity) as a white solid. LC-MS (ESI+) m/z: 778.2 (M+H)+ HPLC: 99.111%, purity at 220 nm. ¹ H NMR (400 MHz, DMSO-d ₆ ) į = 10.96 (s, 1H), 9.89 - 9.69 (m, 1H), 8.16 (s, 0.605H), 7.52 (d, J = 8.6 Hz, 1H), 7.32 - 7.17 (m, 2H), 7.11 - 7.03 (m, 3H), 6.98 - 6.83 (m, 3H), 6.59 (d, J = 8.8 Hz, 2H), 6.53 (t, J = 7.3 Hz, 1H), 6.18 (d, J = 8.7 Hz, 2H), 5.05 (dd, J = 5.2, 13.4 Hz, 1H), 4.39 - 4.28 (m, 2H), 4.26 - 4.15 (m, 1H), 3.85 (br dd, J = 3.0, 14.8 Hz, 1H), 3.60 - 3.48 (m, 3H), 3.30 - 3.16 (m, 8H), 2.96 - 2.84 (m, 1H), 2.79 - 2.67 (m, 1H), 2.65 - 2.53 (m, 2H), 2.40 - 2.29 (m, 2H), 2.19 (br d, J = 6.9 Hz, 2H), 2.01 - 1.91 (m, 1H), 1.75 (br d, J = 13.0 Hz, 2H), 1.69 - 1.58 (m, 1H), 1.23 - 1.08 (m, 2H). EXAMPLE 35. Preparation of (I-323) (S)-3-(5-(4-((1-(4-((1S,2R)-4,4-difluoro-6- hydroxy-2-(o-tolyl)-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl )piperidin-4- yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2, 6-dione and (I-322) (S)-3-(5-(4- ((1-(4-((1R,2S)-4,4-difluoro-6-hydroxy-2-(o-tolyl)-1,2,3,4-t etrahydronaphthalen-1- yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindo lin-2-yl)piperidine-2,6-dione Step 1: To a solution of 1 (2.00 g, 3.96 mmol, 1.0 eq.) in DCM (20 mL) was added Pyridinium bromide perbromide (759 mg, 2.37 mmol, 0.6 eq.). The mixture was stirred at 20 °C for 1 hour. water 30 mL at 20 °C, then diluted with water 30 mL and extracted with DCM 90 mL (30 mL x 3). The combined organic layers were washed with DCM 30 mL (10 mL x 3), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The crude material was purified on silica gel column chromatography (from pure PE to PE/EtOAc = 6/1) to give compound 2 (1.50 g, 1.8 mmol, 45 % yield, 70% Purity) as a yellow solid. LC-MS (ESI ⁺ ) m/z: 506.3 (M+H) ⁺ Step 2: A mixture of 2 (400 mg, 684 ^mol, 1.0 eq.), compound 3 (112 mg, 821 ^mol, 1.2 eq.), PdCl ₂ (dppf) (50.1 mg, 68.4 ^mol, 0.1 eq.) and K ₂ CO ₃ (236 mg, 1.71 mmol, 2.5 eq.) in dioxane (16 mL) and water (4 mL) was degassed and purged with N ₂ for 3 times, and then the mixture was stirred at 60 °C for 3 hour under N ₂ atmosphere. LCMS showed the reaction was completed. The reaction mixture was quenched by addition EA 10 mL at 20 °C, and then diluted with water 10 mL and extracted with EA 90 mL (30 mL x 3). The combined organic layers were washed with EA 15 mL (5 mL x 3), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The crude material was purified on silica gel column chromatography (from pure PE to PE/EtOAc = 4/1) to give compound 4 (300 mg, 0.40 mmol, 59 %, 80% Purity) as a yellow solid. LC-MS (ESI ⁺ ) m/z: 596.2(M+H) ⁺ Step 3: To a solution of compound 4(300 mg, 504 ^mol, 1.0 eq.) in THF (3 mL) and MeOH (3 mL) was added Pd/C (10wt%, 0.05 g) and Pd(OH) ₂ /C (10wt%, 0.07 g) under H ₂ atmosphere. The suspension was degassed and purged with H ₂ for 3 times. The mixture was stirred under H ₂ (15 Psi.) at 25 °C for 4 hours. LCMS showed the reaction was completed. The crude was purified by prep.HPLC together (Welch Xtimate C18150*25mm*5um, water (FA)-ACN as a mobile phase, from 33% to 63%, Gradient Time (min): 11, Flow Rate (ml/min): 25) to give compound 5(60 mg, 0.12 mmol, 23 %) as a white solid. LC-MS (ESI ⁺ ) m/z: 508.3 (M+H) ⁺ Step 4: The compound 5 (60 mg, 1 eq., 0.12 mmol) was purified by SFC (Column: DAICEL CHIRALCEL OD-H (250mm*30mm,10um); Mobile phase: 0.1%NH ₃ H ₂ O ETOH; from 25% to 25%; Flow rate: 60 mL/min) to give compound 6 (25 mg, 49 ^mol, 42% yield) and compound compound 6: LC-MS (ESI+) m/z: 508.3(M+H) ⁺ compound 6A: LC-MS (ESI+) m/z: 508.3(M+H) ⁺ Step 5: Compound 7: To a solution of compound 6 (10 mg, 19.70 ^mol, 1.0 eq) in DCM (3 mL) was added TFA 2.25 mg, 19.70 ^mol, 1.0 eq). The mixture was stirred at 25 °C for 0.2 hr. LCMS showed that the starting material was consumed and the desired product was detected. The reaction liquid is dried with N ₂ at 0 °C to give Compound 7 (8.2 mg, 17.77 ^mol, 90.18% yield) was obtained as yellow oil which was used in the next step without further purification.. LC-MS (ESI+) m/z: 462.2 (M+H) ⁺ . Step 6: Compound 7A: To a solution of compound 6A (10 mg, 19.70 ^mol, 1.0 eq) in DCM (2 mL) was added TFA (2.25 mg, 19.70 ^mol, 1.0eq). The mixture was stirred at 25 °C for 0.2 hr. LCMS showed that the starting material was consumed and the desired product was detected. The reaction liquid is dried with N ₂ at 0 °C to give compound 7A (8.5 mg, 18.42 ^mol, 93.48% yield) was obtained as yellow oil which was used in the next step without further purification.. LC-MS (ESI+) m/z: 462.2(M+H) ⁺ . Step 7: To a solution of compound 7 (9.55 mg, 20.68 ^mol, 1.0 eq) in DCM (3 mL) and MeOH (3 mL) was added compound 034 (6.79 mg, 20.68 ^mol, 1.0 eq) and DIEA (2.67 mg, 20.68 ^mol, 1.0 eq) at 25 °C. After addition, the mixture was stirred at this temperature for 0.5 hr, and then NaBH(OAc) ₃ (8.77 mg, 41.37 ^mol, 2.0 eq) was added at 25 °C. The resulting mixture was stirred at 25 °C for 1 hr. The reaction mixture was concentrated to yield a residue. The residue was purified by preparative HPLC (column: Boston Green ODS 150*30mm*5um; mobile phase: [water (FA) - ACN]; B%: 26%-36%, 12min), followed by lyophilization to yield I-323 (6.7 mg, 8.66 ^mol, 41.86% yield) was obtained as a white solid. LC-MS (ESI+) m/z: 774.6 [M+H] ⁺ . LCMS: calc. for C ₄₆ H ₄₉ F ₂ N ₅ O ₄ : 773.38, found: [M+H] ⁺ 774.6. HPLC: 97.34% purity at 220 nm. ¹ H NMR (400 MHz, METHANOL-d4) į ppm 8.32 - 8.36 (m, 1 H), 7.60 - 7.72 (m, 1 H), 7.30 - 7.56 (m, 1 H), 7.20 - 7.25 (m, 1 H), 7.06 - 7.18 (m, 4 H), 6.80 - 6.93 (m, 3 H), 6.66 (d, J=8.63 Hz 2 H) 623 (d J=850 Hz 1 H) 615 (d J=763 Hz 1 H) 512 (dd J=1320 519 Hz 1 H) 4.33 - 4.48 (m, 3 H), 3.84 - 3.94 (m, 1 H), 3.58 (br d, J=10.76 Hz, 2 H), 3.43 - 3.51 (m, 4 H), 2.86 - 2.99 (m, 5 H), 2.70 - 2.84 (m, 2 H), 2.57 - 2.69 (m, 4 H), 2.40 - 2.53 (m, 4 H), 2.13 - 2.27 (m, 2 H), 1.79 - 1.94 (m, 3 H), 1.33 - 1.42 (m, 2 H). Step 8: To a solution of compound 7A (9.91 mg, 21.48 ^mol, 1.0 eq) in DCM (3 mL) and MeOH (3 mL) was added compound 034 (7.05 mg, 21.48 ^mol, 1.0 eq) and DIEA (2.78 mg, 21.48 ^mol, 1.0 eq) at 25 °C. After addition, the mixture was stirred at this temperature for 0.5 hr, and then NaBH(OAc) ₃ (9.11 mg, 42.96 ^mol, 2.0 eq) was added at 25 °C. The resulting mixture was stirred at 25 °C for 1 hr. The reaction mixture was concentrated to yield a residue. The residue was purified by pre-HPLC (column: Boston Green ODS 150*30mm*5um; mobile phase: [water (FA) - ACN]; B%: 26%-36%, 11min), followed by lyophilization to yield I-322 (11.1 mg, 14.34 ^mol, 66.77% yield) was obtained as a white solid. LC-MS (ESI ⁺ ) m/z: 774.6 [M+H] ⁺ . LCMS: calc. for C ₄₆ H ₄₉ F ₂ N ₅ O ₄ : 773.38, found: [M+H] ⁺ 774.6. HPLC: 95.85% purity at 220 nm ppm 8.30 (br s, 1 H), 7.65 (d, J=8.88 Hz, 1 H), 7.39 - 7.44 (m, 1 H), 7.20 (d, J=7.75 Hz, 1 H), 7.04 - 7.14 (m, 4 H), 6.78 - 6.89 (m, 3 H), 6.64 (d, J=8.63 Hz, 2 H), 6.19 - 6.21 (m, 1 H), 6.12 (d, J=7.63 Hz, 1 H), 5.09 (dd, J=13.26, 5.13 Hz, 1 H), 4.30 - 4.41 (m, 3 H), 3.84 - 3.90 (m, 1 H), 3.52 - 3.57 (m, 2 H), 3.44 (br s, 4 H), 2.84 - 2.92 (m, 5 H), 2.71 - 2.80 (m, 2 H), 2.54 - 2.63 (m, 4 H), 2.42 - 2.49 (m, 4 H), 2.12 - 2.22 (m, 2 H), 1.80 - 1.90 (m, 3 H), 1.30 - 1.38 (m, 2 H).

EXAMPLE 36. Preparation of (I-324) (S)-3-(5-(4-((1-(4-((1R,2S)-2-(2,5-difluoro-4- methylphenyl)-4,4-difluoro-6-hydroxy-1,2,3,4-tetrahydronapht halen-1-yl)phenyl)piperidin- 4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine- 2,6-dione Step 1: A mixture of 1,1'-Bis(di-t-butylphosphino)ferrocene palladium dichloride (199 mg, 0.1 carbonate (971 mg, 3 Eq, 9.2 mmol) and 1-(4-(6-(benzyloxy)-2-bromo-4,4-difluoro-3,4- dihydronaphthalen-1-yl)phenyl)-4-(dimethoxymethyl)piperidine (1.8 g, 1.0 Eq, 3 mmol) in 1,4- dioxane (12 mL) and H ₂ O (3 mL) was degassed and purged with N ₂ for 3 times, and then the mixture was stirred at 50 °C for 16 h under N ₂ atmosphere. TLC (petroleum ether: ethyl acetate=3:1, Rf=0.6 UV) showed one main new spot was observed. The resulting solution was treated with 50 mL H ₂ O and was extracted with 100 mL ethyl acetate. The organic layers were dried with anhydrous Na ₂ SO ₄ , filtered, and concentrated to give the crude product. The residue was purified by column chromatography (SiO ₂ , Petroleum ether/Ethyl acetate=10/0 to 8/2). The reaction mixture was filtered and concentrated to dryness in vacuum to give 1-(4-(6-(benzyloxy)- 2-(2,5-difluoro-4-methylphenyl)-4,4-difluoro-3,4-dihydronaph thalen-1-yl)phenyl)-4- (dimethoxymethyl)piperidine (1.88 g, 2.98 mmol, 98% yield) as a white solid. Step 2: A mixture of 1-(4-(6-(benzyloxy)-2-(2,5-difluoro-4-methylphenyl)-4,4-difl uoro-3,4- dihydronaphthalen-1-yl)phenyl)-4-(dimethoxymethyl)piperidine (1.8 g, 1 Eq, 2.8 mmol), palladium on carbon (900 mg, 10% Wt, 0.3 Eq, 846 ^mol), and Pd(OH) ₂ /C (900 mg, 20% Wt, 0.45 Eq, 1.28 mmol) in MeOH (20 mL) and THF (20 mL) was degassed under N2 atmosphere, The suspension was degassed and purged with H2 for 3 times. The mixture was stirred under H2 (15 Psi) at 50 °C for 4 h. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was concentrated under reduced pressure to give (5R,6S)- 6-(2,5-difluoro-4-methylphenyl)-5-(4-(4-(dimethoxymethyl)pip eridin-1-yl)phenyl)-8,8-difluoro- 5,6,7,8-tetrahydronaphthalen-2-ol as a yellow oil, which was further separated by SFC (condition: column: DAICEL CHIRALPAK IG (250mm*30mm,10um); mobile phase: [CO2-i- PrOH(0.1%NH3H2O)]; B%: 30%-30%) to give (5R,6S)-6-(2,5-difluoro-4-methylphenyl)-5-(4- (4-(dimethoxymethyl)piperidin-1-yl)phenyl)-8,8-difluoro-5,6, 7,8-tetrahydronaphthalen-2-ol (300 mg, 531 ^mol, 19 %, 96% Purity) and (5S,6R)-6-(2,5-difluoro-4-methylphenyl)-5-(4-(4- (dimethoxymethyl)piperidin-1-yl)phenyl)-8,8-difluoro-5,6,7,8 -tetrahydronaphthalen-2-ol (250 mg, 444 ^mol, 16 %, 97% Purity) as yellow solid. LC-MS (ESI+) m/z: 544.2 (M+H) + Step 3: A mixture of (1S,2R)-2-(2,5-difluoro-4-methyl-phenyl)-1-[4-[4-(dimethoxym ethyl)-1- piperidyl]phenyl]-4,4-difluoro-tetralin-6-ol (100 mg, 184 ^mol, 1 eq) was added in THF (3 mL) and 10% H2SO4 (3 mL) and then the mixture was stirred at 70 °C for 40 min. The resulting solution was quenched with 10 mL NaHCO3, the mixture was treated with 50 mL H2O and was extracted with ethyl acetate 100 mL The organic layers were dried with anhydrous Na ₂ SO ₄ filtered, and concentrated to give 1-[4-[(1S,2R)-2-(2,5-difluoro-4-methyl-phenyl)-4,4-difluoro- 6- hydroxy-tetralin-1-yl]phenyl]piperidine-4-carbaldehyde (90 mg, 181 ^mol, 98% yield) was obtained as a white solid. LC-MS (ESI+) m/z: 498.1 (M+H) + Step 4: A mixture of (S)-3-(1-oxo-5-(piperazin-1-yl)isoindolin-2-yl)piperidine-2, 6-dione (136 mg, 271.34 ^mol, 1.5 eq, PhSO ₃ H salt), 1-[4-[(1*S,2*R)-2-(2,5-difluoro-4-methyl-phenyl)-4,4- difluoro-6-hydroxy-tetralin-1-yl]phenyl]piperidine-4-carbald ehyde (90 mg, 180.9 ^mol, 1 eq), AcONa (45 mg, 543 ^mol, 3 eq) was added in the DCM (2 mL) and MeOH (2 mL), the mixture was stirred at 30°C for 1 h, and then AcOH (33 mg, 542 ^mol, 31 ^L, 3 eq) and Na(OAc) ₃ BH (77 mg, 362 ^mol, 2 eq) was added to the mixture and stirred at 30 °C for 12 h. The reaction mixture was treated with 30 mL H ₂ O and extracted with 50 mL ethyl acetate. The organic layers were dried with anhydrous Na ₂ SO ₄ , filtered, concentrated to give a residue that was purified by prep. HPLC (column: Xtimate C18150*40mm*10um; mobile phase: [water (FA)-ACN]; gradient: 28%-58% B over 6 min). The aqueous phase was lyophilized to dryness to give (3S)-3- [5-[4-[[1-[4-[(1*S,2*R)-2-(2,5-difluoro-4-methyl-phenyl)-4,4 -difluoro-6-hydroxy-tetralin-1- yl]phenyl]-4-piperidyl]methyl]piperazin-1-yl]-1-oxo-isoindol in-2-yl]piperidine-2,6-dione (51.4 mg, 63.47 ^mol, 35.08% yield). LC-MS (ESI+) m/z: 810.2 (M+H) +. HPLC: 100%, purity at 220nm. ¹ H NMR (400 MHz, DMSO-d ₆ ) į = 11.02 - 10.91 (m, 1H), 9.86 - 9.72 (m, 1H), 8.18 - 8.12 (m, 0.396H), 7.60 - 7.45 (m, 1H), 7.23 - 7.13 (m, 1H), 6.99 (d, J =2.4 Hz, 3H), 6.95 - 6.79 (m, 2H), 6.70 - 6.56 (m, 2H), 6.35 - 6.07 (m, 3H), 5.14 - 4.93 (m, 1H), 4.39 - 4.15 (m, 3H), 3.85 - 3.72 (m, 1H), 3.64 - 3.50 (m, 2H),3.32 - 3.21 (m, 8H), 2.99 - 2.85 (m, 1H), 2.78 - 2.62 (m, 2H), 2.44 - 2.25 (m, 4H), 2.19 (s, 5H), 2.05 - 1.88 (m, 1H), 1.83 - 1.54 (m, 3H), 1.26 - 1.01 (m, 2H).

EXAMPLE 37. Preparation of (I-325) (S)-3-(5-(4-((1-(4-((1S,2R)-2-(2,5-difluoro-4- methylphenyl)-4,4-difluoro-6-hydroxy-1,2,3,4-tetrahydronapht halen-1-yl)phenyl)piperidin- 4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine- 2,6-dione Step 1: A mixture of 1R,2S)-2-(2,5-difluoro-4-methyl-phenyl)-1-[4-[4-(dimethoxyme thyl)-1- piperidyl]phenyl]-4,4-difluoro-tetralin-6-ol (100 mg, 183.9 ^mol, 1 eq) was added in THF (3 mL) and 10% H ₂ SO ₄ in water (3 mL) and then the mixture was stirred at 70 °C for 40 min. The resulting solution was quenched with 10 mL aq. NaHCO3. The mixture was treated with 50 mL H2O and was extracted with 100 mL ethyl acetate. The organic layers were dried with anhydrous Na ₂ SO ₄ , filtered, and concentrated to give 1-[4-[(1R,2S)-2-(2,5-difluoro-4-methyl-phenyl)-4,4- difluoro-6-hydroxy-tetralin-1-yl]phenyl]piperidine-4-carbald ehyde (70 mg, 140.7 ^mol, 76% yield). LC-MS (ESI+) m/z: 498.1(M+H)+ Step 2: A mixture of (S)-3-(1-oxo-5-(piperazin-1-yl)isoindolin-2-yl)piperidine-2, 6-dione (106 mg, 211.05 ^mol, 1.5 eq, PhSO ₃ H salt), 1-[4-[(1R,2S)-2-(2,5-difluoro-4-methyl-phenyl)-4,4- difluoro-6-hydroxy-tetralin-1-yl]phenyl]piperidine-4-carbald ehyde (70 mg, 140.7 ^mol, 1 eq), and AcONa (35 mg, 422 ^mol, 3 eq) was added in the DCM (2 mL) and MeOH (2 mL), the mixture was stirred at 30 °C for 1 h, and then AcOH (25 mg, 422.09 ^mol, 24 ^L, 3 eq), 16 h. The reaction mixture was treated with 30 mL H2O and extracted with 50 mL ethyl acetate. The organic layers were dried with anhydrous Na2SO4, filtered, the residue was purified by prep. HPLC (column: Xtimate C18150*40mm*10um; mobile phase: [water(FA)-ACN];gradient:28%- 58% B over 6 min). The aqueous phase was lyophilized to dryness to give (3S)-3-[5-[4-[[1-[4- [(1*R,2*S)-2-(2,5-difluoro-4-methyl-phenyl)-4,4-difluoro-6-h ydroxy-tetralin-1-yl]phenyl]-4- piperidyl]methyl]piperazin-1-yl]-1-oxo-isoindolin-2-yl]piper idine-2,6-dione (39.3 mg, 48.53 ^mol, 34% yield). LC-MS (ESI+) m/z: 810.3 (M+H) +. HPLC: 100%, purity at 220nm. ¹ H NMR (400 MHz, DMSO-d ₆ ) į = 11.00 - 10.93 (m, 1H), 9.83 - 9.74 (m, 1H), 8.17 - 8.13 (m, 0.334H), 7.55 - 7.47 (m, 1H), 7.22 - 7.13 (m, 1H), 7.12 - 7.01(m, 3H), 6.93 - 6.82 (m, 2H), 6.71 - 6.56 (m, 2H), 6.33 (d, J = 4.1 Hz, 3H), 5.05 (dd, J = 5.1, 13.1 Hz, 1H), 4.38 - 4.16 (m, 3H), 3.83 - 3.73 (m, 1H), 3.64 -3.51 (m, 2H), 3.32 - 3.19 (m, 8H), 2.97 - 2.82 (m, 1H), 2.78 - 2.60 (m, 2H), 2.46 - 2.24 (m, 4H), 2.23 - 2.11 (m, 5H), 2.03 - 1.90 (m, 1H), 1.83 - 1.59 (m, 3H), 1.26 - 1.07 (m, 2H). EXAMPLE 38. Preparation of (I-315) (S)-3-(5-(4-((1-(4-((1S,2R)-2-(3,4- difluorophenyl)-4,4-difluoro-6-hydroxy-1,2,3,4-tetrahydronap hthalen-1- yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindo lin-2-yl)piperidine-2,6-dione and (I-314) (S)-3-(5-(4-((1-(4-((1R,2S)-2-(3,4-difluorophenyl)-4,4-diflu oro-6-hydroxy-

1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperidin-4-yl)m ethyl)piperazin-1-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione Step 1: To a mixture of compound 1 (618 mg, 1.06 mmol, 1.0 eq) and compound 2 (166.96 mg, 1.06 mmol, 1.0 eq) in 1,4-Dioxane (8 mL) and water (2 mL)was added Pd(dtbpf)Cl ₂ (68.91 mg, 105.73 ^mol, 0.1 eq), K ₂ CO ₃ (292.26 mg, 2.11 mmol, 2.0 eq) in one portion at 25 °C under N ₂ . The mixture was stirred for 0.5 hours. The reaction mixture extracted with EtOAc (20 mL x 3). The combined organic layers were washed with solvent 10 mL saturated NaCl solution, dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Boston Green ODS 150*30mm*5um; mobile phase: water (FA)-ACN; B%: 80%-100%, 12 min) to give product. Compound 3 (200 mg, 323.80 ^mol, 3062% i ld) bt i d hit lid LC-MS (ESI ⁺ ) m/z: 618.4(M+H) ⁺ . Step 2: To a solution of compound 3 (230 mg, 372.37 ^mol, 1.0 eq) in THF (4 mL) and MeOH (4 mL) was added Pd/C (198.14 mg, 186.18 ^mol, 10wt% purity, 0.5 eq). The suspension was degassed under vacuum and purged with H ₂ several times. The mixture was heated to 50 °C (15 psi) and stirred for 6 hours. LCMS showed that the desired compound was detected. The crude product was filtered and the filter was concentrated to give the crude as a yellow solid. The mixture was filtered and concentrated in vacuum. The residue was purified by pre-HPLC (Column Boston Green ODS 150*30mm*5um˗ Condition water(FA)-ACN˗ B%: 10%- 40%,12 min) to afford compound 4(130 mg, 245.48 ^mol, 65.93% yield) as a white solid. LC-MS (ESI ⁺ ) m/z: 530.3 (M+H) ⁺ . Step 3: Compound 4 (100 mg) was separated by chiral SFC (Column DAICEL CHIRALPAK AD(250mm*30mm,10um), Condition CO ₂ -EtOH(0.1%NH ₃ H ₂ O) Begin B 25% End B 25%), FlowRate (ml/min): 60) Compound 5A (35 mg), compound 5B (30 mg). Step 4: Compound 6A: To a solution of compound 5A (20 mg, 37.77 ^mol, 1.0 eq) in DCM (2 mL) was added TFA (4.31 mg, 37.77 ^mol, 1.0 eq). The mixture was stirred at 25 °C for 0.2 hr. LCMS showed that the starting material was consumed and the desired product was detected. The reaction liquid was dried with N ₂ at 0°C to give Compound 6A (13.5 mg, 27.92 ^mol, 73.93% yield) was obtained as yellow oil which was used in the next step without further purification.. LC-MS (ESI+) m/z: 484.3 (M+H)+. Step 5: Compound 6B: To a solution of compound 5B (25 mg, 47.21 ^mol, 1.0 eq) in DCM (2 mL) was added TFA (5.38 mg, 47.21 ^mol, 1.0 eq). The mixture was stirred at 25 °C for 0.2 hr. LCMS showed that the starting material was consumed and the desired product was detected. The reaction liquid is dried with N ₂ at 0 °C to give Compound 6B (18 mg, 37.23 ^mol, 78.86% yield) was obtained as yellow oil which was used in the next step without further purification.. LC-MS (ESI+) m/z: 484.3(M+H) ⁺ . Step 6: To a solution of compound 6A (13.5 mg, 27.92 ^mol, 1.0eq) in DCM (3 mL) and MeOH ^mol, 1.0 eq) at 25 °C. After addition, the mixture was stirred at this temperature for 0.5 hr, and then NaBH(OAc)3 (11.84 mg, 55.84 ^mol, 2.0 eq) was added at 25 °C. The resulting mixture was stirred at 25 °C for 1 hr. The reaction mixture was concentrated to yield a residue. The residue was purified by preparative HPLC (column: Boston Green ODS 150 * 30 mm * 5um; mobile phase: [water (FA) - ACN]; B%: 27%-37%, 12min) , followed by lyophilization to yield I-315 (12.4 mg, 15.58 ^mol, 55.80% yield) was obtained as a white solid. LC-MS (ESI+) m/z: 796.5 [M+H] ⁺ . LCMS: calc. for C ₄₅ H ₄₅ F ₄ N ₅ O ₄ : 795.34, found: [M+H] ⁺ 796.5. HPLC: 98.58% purity at 220 nm. ¹ H NMR (400 MHz, METHANOL-d4) į ppm 7.65 (d, J=8.58 Hz, 1 H), 7.04 - 7.16 (m, 4 H), 6.83 - 6.93 (m, 2 H), 6.64 - 6.76 (m, 4 H), 6.33 (d, J=8.70 Hz, 2 H), 5.11 (dd, J=13.29, 5.07 Hz, 1 H), 4.36 - 4.48 (m, 2 H), 4.32 (br d, J=3.46 Hz, 1 H), 3.69 - 3.77 (m, 1 H), 3.57 - 3.63 (m, 2 H), 3.37 - 3.40 (m, 4 H), 2.87 - 2.97 (m, 1 H), 2.67 - 2.84 (m, 2 H), 2.61 - 2.66 (m, 5 H), 2.41 - 2.54 (m, 1 H), 2.31 (d, J=7.03 Hz, 2 H), 2.13 - 2.20 (m, 1 H), 1.89 (br d, J=12.16 Hz, 2 H), 1.62 - 1.75 (m, 1 H), 1.31 - 1.35 (m, 4 H). Step 7: To a solution of compound 6B (10 mg, 20.68 ^mol, 1.0 eq) in DCM (3 mL) and MeOH (3 mL) was added compound 034 (6.79 mg, 20.68 ^mol, 1.0 eq) and DIEA (2.67 mg, 20.68 ^mol, 1.0 eq) at 25 °C. After addition, the mixture was stirred at this temperature for 0.5 hr, and then NaBH(OAc) ₃ (8.77 mg, 41.37 ^mol, 2.0 eq) was added at 25 °C. The resulting mixture was stirred at 25 °C for 1 hr. The reaction mixture was concentrated to yield a residue. The residue was purified by preparative HPLC (column: Boston Green ODS 150 * 30 mm * 5um; mobile phase: [water (FA) - ACN]; B%: 27%-37%,12min) , followed by lyophilization to yield I-314 (6.7 mg, 8.42 ^mol, 40.70% yield) was obtained as a white solid. LC-MS (ESI+) m/z: 796.5 [M+H] ⁺ . LCMS: calc. for C ₄₅ H ₄₅ F ₄ N ₅ O ₄ : 795.34, found: [M+H] ⁺ 796.5. HPLC: 97.25 % purity at 220 nm ¹ H NMR (400 MHz, METHANOL-d4) į ppm 7.63 (d, J=8.46 Hz, 1 H), 7.01 - 7.17 (m, 4 H), 6.80 (s, 2 H), 6.61 - 6.74 (m, 4 H), 6.26 - 6.38 (m, 2 H), 5.09 (dd, J=13.41, 5.30 Hz, 1 H), 4.40 (d, J=6.08 Hz, 2 H), 4.29 (br d, J=2.86 Hz, 1 H), 3.68 - 3.75 (m, 1 H), 3.58 (br d, J=11.92 Hz, 2 H), 3.34 - 3.38 (m, 4 H), 2.84 - 2.94 (m, 1 H), 2.65 - 2.82 (m, 2 H), 2.59 - 2.64 (m, 5 H), 2.40 - (m, 1 H), 1.29 - 1.33 (m, 4 H).

EXAMPLE 39. Preparation of (I-337) (S)-3-(5-(4-((1-(6-((1R,2R)-4,4-difluoro-6- hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)pyridin-3 -yl)piperidin-4- yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2, 6-dione Step 1: A mixture of 4-(dimethoxymethyl)piperidine (2.8 g, 17.6 mmol, 1eq), 2-bromo-5-iodo- pyridine (5 g, 17.6 mmol, 1 eq), iodocopper (671 mg, 3.5 mmol, 0.2 eq), dipotassium carbonate (4.9 g, 35 mmol, 2 eq), (2S)-pyrrolidine-2-carboxylic acid (811 mg, 7.04 mmol, 0.4 eq) was added in DMSO (50 mL) and purged with N ₂ for 3 times, the mixture was stirred at 90 °C for 16h under N ₂ . TLC (petroleum ether: ethyl acetate=5:1, R _f =0.7, UV) showed one main new spot was observed. Then the mixture was treated with H ₂ O (50 mL), extracted with ethyl acetate (100 mL). The combined extracts was dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to dryness in vacuum to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® Silica Flash Column, Eluent of 0~20% Petroleum ether/Ethyl acetate @ 40 mL/min). The pure fractions were collected and concentrated to dryness in vacuum to give 2-bromo-5-(4-(dimethoxymethyl)piperidin-1-yl)pyridine (1.6 g, 5.1 mmol, 29% yield) was obtained as a yellow oil. LC-MS (ESI+) m/z: 317.1 (M+H)+ Step 2: A mixture of butyllithium (2.5 M, 2.4 mL, 1.2 eq) was added into mixture of 6- (benzyloxy)-4,4-difluoro-3,4-dihydronaphthalen-1(2H)-one (2.9 g, 10.2 mmol, 2 eq) in THF (15 mL) under N2 at -78°C, and the mixture was stirred at -68°C for 0.5h under N2 atmosphere, and then 2-bromo-5-(4-(dimethoxymethyl)piperidin-1-yl)pyridine (1.6 g, 5.08 mmol, 1 eq) was added in the mixture at -68°C and was stirred at 25°C for 16 h. TLC (petroleum ether: ethyl acetate=5:1, R _f =0.5 UV) showed one main new spot was observed. Then the mixture was quenched with saturation NH ₄ Cl 20 ml at 0°C under N ₂ and treated with H ₂ O (50 mL), extracted with ethyl acetate (100 mL). The combined organic layers were washed with brine (100 mL) and was dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to dryness in vacuum to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® Silica Flash Column, Eluent of 0~10% Petroleum ether/Ethyl acetate @ 40 mL/min). The pure fractions were collected and concentrated to dryness in vacuum to give 6-(benzyloxy)-1-(5-(4- (dimethoxymethyl)piperidin-1-yl)pyridin-2-yl)-4,4-difluoro-1 ,2,3,4-tetrahydronaphthalen-1-ol (1.8 g, 3.4 mmol, 66.8% yield) was obtained as a yellow oil. LC-MS (ESI+) m/z: 525.2 (M+H)+ Step 3: A mixture of 6-(benzyloxy)-1-(5-(4-(dimethoxymethyl)piperidin-1-yl)pyridi n-2-yl)-4,4- difluoro-1,2,3,4-tetrahydronaphthalen-1-ol (1.7 g, 3.2 mmol, 1 eq) was added in 4 N HCl in MeOH (10 mL), the mixture was stirred at 50 °C for 2 h. The reaction mixture was filtered and concentrated to dryness in vacuo to give 2-(6-(benzyloxy)-4,4-difluoro-3,4-dihydronaphthalen-1- yl)-5-(4-(dimethoxymethyl)piperidin-1-yl)pyridine (910 mg 18 mmol 55% yield) Step 4: A mixture of 2-(6-(benzyloxy)-4,4-difluoro-3,4-dihydronaphthalen-1-yl)-5- (4- (dimethoxymethyl)piperidin-1-yl)pyridine (910 mg, 1.8 mmol, 1 eq), N,N-diethylethanamine (273 mg, 2.7 mmol, 375 ^L, 1.5 eq), Py.HBr ₃ (747 mg, 2.3 mmol, 1.3 eq) in DCM (30 mL) was degassed at 0 °C for 2 h. TLC (petroleum ether: ethyl acetate=5:1, R _f =0.6 UV) showed one main new spot was observed. The resulting solution was diluted with H ₂ O (50 mL) and extracted with DCM (100 mL ×3).The organic layers were dried with anhydrous Na ₂ SO ₄ , filtered, and concentrated to give the crude product. The residue was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® Silica Flash Column, Eluent of 0~30% Petroleum ether/Ethyl acetate @ 30 mL/min). The pure fractions were collected and concentrated to dryness in vacuo to give 2-(6-(benzyloxy)-2-bromo-4,4-difluoro-3,4-dihydronaphthalen- 1-yl)-5-(4- (dimethoxymethyl)piperidin-1-yl)pyridine (920 mg, 1.6 mmol, 87% yield). Step 5: A mixture of 2-(6-(benzyloxy)-2-bromo-4,4-difluoro-3,4-dihydronaphthalen- 1-yl)-5-(4- (dimethoxymethyl)piperidin-1-yl)pyridine (820 mg, 1.4 mmol, 1 eq), phenylboronic acid (205 mg, 1.7 mmol, 1.2 eq), Na ₂ CO ₃ (445 mg, 4.2 mmol, 3 eq), Pd-118 (91 mg, 140 ^mol, 0.1 eq) in dioxane (10 mL) and H2O (2.5 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 50 °C for 2 h under N2 atmosphere. TLC (petroleum ether: ethyl acetate=5:1, R _f =0.5 UV) showed one main new spot was observed. Then the mixture was treated with H ₂ O (50 mL), extracted with ethyl acetate (100 mL). The combined organic layers were washed with saturated salt water (100 mL) and was dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to dryness in vacuum to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® Silica Flash Column, Eluent of 0~10% Petroleum ether/Ethyl acetate @ 20 mL/min). The pure fractions were collected and concentrated to dryness in vacuum to give 2-(6-(benzyloxy)-4,4-difluoro-2-phenyl-3,4- dihydronaphthalen-1-yl)-5-(4-(dimethoxymethyl)piperidin-1-yl )pyridine (800 mg, 1.4 mmol, 98% yield) was obtained as a yellow oil. Step 6: A mixture of 2-(6-(benzyloxy)-4,4-difluoro-2-phenyl-3,4-dihydronaphthalen -1-yl)-5-(4- (dimethoxymethyl)piperidin-1-yl)pyridine (170 mg, 292 ^mol, 1 eq), Pd/C (90 mg, 85 ^mol, 10% purity, 0.29 eq), Pd(OH) ₂ /C (90 mg, 641 ^mol, 2.2 eq) was added in THF (5 mL) and MeOH (5 mL) under N2 atmosphere, the suspension was degassed and purged with H2 for 3 times. The mixture was stirred under H2 (15 psi) at 25°C overnight. The reaction mixture was filtered and concentrated under reduced pressure to give a residue The crude product was purified by reversed-phase SFC (Column: DAICEL CHIRALCEL OJ (250mm*30mm, 10um); Condition: CO2-EtOH (0.1%NH3 in H2O); at the beginning: B (45%); at the end: B (45%); Flow Rate (ml/min) 80. The reaction mixture was filtered and concentrated to dryness in vacuum to give (5R,6R)-5-(5-(4-(dimethoxymethyl)piperidin-1-yl)pyridin-2-yl )-8,8-difluoro-6-phenyl- 5,6,7,8-tetrahydronaphthalen-2-ol (30 mg, 59.9 ^mol), (5S,6S)-5-(5-(4- (dimethoxymethyl)piperidin-1-yl)pyridin-2-yl)-8,8-difluoro-6 -phenyl-5,6,7,8- tetrahydronaphthalen-2-ol (30 mg, 59.9 ^mol) was obtained as a white solid. LC-MS (ESI+) m/z: 494.58(M+H) ⁺ Step 7: A mixture of (5R,6R)-5-(5-(4-(dimethoxymethyl)piperidin-1-yl)pyridin-2-yl )-8,8- difluoro-6-phenyl-5,6,7,8-tetrahydronaphthalen-2-ol (30 mg, 59.9 ^mol, 1 eq) was added THF (2 mL) and 10%H ₂ SO ₄ (2 mL). The mixture was stirred at 70 °C for 40 min. The resulting solution was quenched with 10 mL aq.NaHCO ₃ and was treated with 20 mL H ₂ O and was extracted with ethyl acetate (50 mL ×3).The organic layers were dried with anhydrous Na ₂ SO ₄ , filtered, and concentrated to give the crude product. The reaction mixture was filtered and concentrated to dryness in vacuum to give 1-(6-((1R,2R)-4,4-difluoro-6-hydroxy-2-phenyl-1,2,3,4- tetrahydronaphthalen-1-yl)pyridin-3-yl)piperidine-4-carbalde hyde (25 mg, 55 ^mol, 92% yield). Step 8: A mixture of (S)-3-(1-oxo-5-(piperazin-1-yl)isoindolin-2-yl)piperidine-2, 6-dione (41 mg, 82.50 ^mol, 1.5 eq, PhSO ₃ H salt) , 1-(6-((1R,2R)-4,4-difluoro-6-hydroxy-2-phenyl-1,2,3,4- tetrahydronaphthalen-1-yl)pyridin-3-yl)piperidine-4-carbalde hyde (25 mg, 55 ^mol, 1 eq), AcONa (14 mg, 165 ^mol, 3 eq) was added in the DCM (2 mL) and MeOH (2 mL) , the mixture was stirred at 30 °C for 0.5 h, and then AcOH (10 mg, 165 ^mol, 9 ^L, 3 eq), NaBH(OAc) ₃ (23 mg, 110 ^mol, 2 eq) was added in the mixture and was stirred at 30 °C for 16 h. The reaction mixture was treated with 30 mL H ₂ O and extracted with 50 mL ethyl acetate. The organic layers were dried with anhydrous Na ₂ SO ₄ , filtered, the residue was purified by prep.HPLC (column: Welch Xtimate C18150*30mm*5um; mobile phase: [water (FA)-ACN]; gradient: 12%-42% B over 7 min). The aqueous phase was lyophilized to dryness to give (S)-3-(5-(4-((1-(6-((1R,2R)- 4,4-difluoro-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen -1-yl)pyridin-3-yl)piperidin-4- yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2, 6-dione (9.3 mg, 12.2 ^mol, 22% yield). LC-MS (ESI+) m/z: 761.2 (M+H)+. HPLC: 100 %, purity at 220 nm. ¹ H NMR (400 MHz, DMSO-d6) į = 10.99 - 10.94 (m, 1H), 9.66 - 9.59 (m, 1H), 8.16 (s, 0.295H), 8.09 - 8.00 (m, 1H), 7.57 - 7.46 (m, 1H), 7.22 - 7.00 (m, 6H), 6.97 - 6.75 (m, 5H), 6.47 - 6.33 (m, 1H), 5.10 - 5.00 (m, 1H), 4.39 - 4.28 (m, 2H), 4.25 - 4.16 (m, 1H), 3.75 - 3.46 (m, 4H), 3.32 - 3.21 (m, 5H), 2.99 -2.80 (m, 1H), 2.70 - 2.53 (m, 5H), 2.44 - 2.14 (m, 5H), 2.01 - 1.88 (m, 1H), 1.82 - 1.60 (m, 3H), 1.28 - 1.04 (m, 2H). EXAMPLE 40. Preparation of (I-203) (S)-3-(5-(4-((1-(6-((1S,2S)-4,4-difluoro-6- hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)pyridin-3 -yl)piperidin-4- yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2, 6-dione Step 1: A mixture of (5S,6S)-5-(5-(4-(dimethoxymethyl)piperidin-1-yl)pyridin-2-yl )-8,8- difluoro-6-phenyl-5,6,7,8-tetrahydronaphthalen-2-ol (30 mg, 60 ^mol, 1 eq) was added THF (2 mL) and 10%H ₂ SO ₄ (2 mL). The mixture was stirred at 70 °C for 40 min. The resulting solution was quenched with 10 ml NaHCO ₃ and was treated with 20 mL H ₂ O and was extracted with ethyl acetate (50 mL ×3). The organic layers were dried with anhydrous Na ₂ SO ₄ , filtered, and concentrated to give the crude product. The reaction mixture was filtered and concentrated to dryness in vacuum to give 1-(6-((1S,2S)-4,4-difluoro-6-hydroxy-2-phenyl-1,2,3,4- Step 2: A mixture of (S)-3-(1-oxo-5-(piperazin-1-yl)isoindolin-2-yl)piperidine-2, 6-dione (41 mg, 82.5 ^mol, 1.5 eq, PhSO3H salt), 1-(6-((1S,2S)-4,4-difluoro-6-hydroxy-2-phenyl-1,2,3,4- tetrahydronaphthalen-1-yl)pyridin-3-yl)piperidine-4-carbalde hyde (25 mg, 55 ^mol, 1 eq), AcONa (14 mg, 165 ^mol, 3 eq) was added in the DCM (2 mL) and MeOH (2 mL), the mixture was stirred at 30 °C for 0.5h, and then AcOH (10 mg, 165 ^mol, 9 ^L, 3 eq), NaBH(OAc) ₃ (23 mg, 110 ^mol, 2 eq) was added in the mixture and was stirred at 30 °C for 16 h. The reaction mixture was treated with 30 mL H ₂ O and extracted with 50 mL ethyl acetate. The organic layers were dried with anhydrous Na ₂ SO ₄ , filtered, the residue was purified by prep. HPLC (column: Welch Xtimate C18150*30mm*5um; mobile phase: [water (FA)-ACN]; gradient: 12%-42% B over 7 min). The aqueous phase was lyophilized to dryness to give (3S)-3-[5-[4-[[1-[6-[(1S,2S)- 4,4-difluoro-6-hydroxy-2-phenyl-tetralin-1-yl]-3-pyridyl]-4- piperidyl]methyl]piperazin-1-yl]-1- oxo-isoindolin-2-yl]piperidine-2,6-dione (12.1 mg, 15.9 ^mol, 28% yield). LC-MS (ESI+) m/z: 761.1 (M+H) +. HPLC: 100 %, purity at 220nm. ¹ H NMR (400 MHz, DMSO-d6) į = 10.99 - 10.93 (m, 1H), 9.66 - 9.62 (m, 1H), 8.18 - 8.14 (m, 0.307H), 8.09 - 8.01 (m, 1H), 7.56 - 7.48 (m, 1H), 7.19 - 7.10(m, 3H), 7.09 - 7.02 (m, 3H), 6.96 - 6.89 (m, 3H), 6.87 - 6.75 (m, 2H), 6.44 - 6.36 (m, 1H), 5.10 - 5.01 (m, 1H), 4.39 - 4.29 (m, 2H), 4.25 - 4.16 (m, 1H), 3.75- 3.48 (m, 4H), 3.33 - 3.21 (m, 5H), 3.00 - 2.85 (m, 1H), 2.70 - 2.54 (m, 5H), 2.45 - 2.15 (m, 5H), 2.04 - 1.90 (m, 1H), 1.81 - 1.61 (m, 3H), 1.25 - 1.03 (m, 2H).

EXAMPLE 41. Preparation of (I-330) (S)-3-(5-(4-((1-(4-((1S,2R)-4,4-difluoro-6- hydroxy-2-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydronaph thalen-1- yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindo lin-2-yl)piperidine-2,6-dione Step 1: A mixture of 1-(4-(6-(benzyloxy)-2-bromo-4,4-difluoro-3,4-dihydronaphthal en-1- yl)phenyl)-4-(dimethoxymethyl)piperidine (600 mg, 1 mmol, 1 eq), [4- (trifluoromethyl)phenyl]boronic acid (234 mg, 1.2 mmol, 1.2 eq), Na ₂ CO ₃ (326 mg, 3 mmol, 3 eq), Pd-118 (67 mg, 103 ^mol, 0.1 eq) in dioxane (8 mL) and H ₂ O (2 mL) was degassed and purged with N ₂ for 3 times, and then the mixture was stirred at 50 °C for 2 h under N ₂ h C ( l h h l 1 0 ) h d i was observed. The resulting solution was treated with 50 mL H2O and was extracted with 100 mL ethyl acetate. The organic layers were dried with anhydrous Na2SO4, filtered, and concentrated to give the crude product. The residue was purified by column chromatography (SiO ₂ , Petroleum ether/Ethyl acetate=10/0 to 8/2). The reaction mixture was filtered and concentrated to dryness in vacuum to give 1-(4-(6-(benzyloxy)-4,4-difluoro-2-(4- (trifluoromethyl)phenyl)-3,4-dihydronaphthalen-1-yl)phenyl)- 4-(dimethoxymethyl)piperidine (570 mg, 877 ^mol, 85% yield) was obtained as a yellow oil. Step 2: A mixture of 1-(4-(6-(benzyloxy)-4,4-difluoro-2-(4-(trifluoromethyl)pheny l)-3,4- dihydronaphthalen-1-yl)phenyl)-4-(dimethoxymethyl)piperidine (570 mg, 877 ^mol, 1 eq), Pd/C (519 mg, 488 ^mol, 10% purity), Pd(OH) ₂ /C (519 mg, 3.7 mmol, 10% purity) was added in THF (5 mL) and MeOH (5 mL) under N ₂ atmosphere. The suspension was degassed and purged with H ₂ for 3 times. The mixture was stirred under H ₂ (15 psi) at 25°C for 4 h. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The crude product was purified by reversed-phase SFC (column: DAICEL CHIRALPAK AD (250mm*30mm, 10um); mobile phase: [CO2-i-PrOH (0.1%NH3H2O)]; B%:20%%, isocratic elution mode rentention time 1.373, 1.512). The reaction mixture was filtered and concentrated to dryness in vacuum to give (5S,6R)-5-(4-(4-(dimethoxymethyl)piperidin-1-yl)phenyl)-8,8- difluoro-6-(4- (trifluoromethyl)phenyl)-5,6,7,8-tetrahydronaphthalen-2-ol (110 mg, 196 umol, 22% yield), (5R,6S)-5-(4-(4-(dimethoxymethyl)piperidin-1-yl)phenyl)-8,8- difluoro-6-(4- (trifluoromethyl)phenyl)-5,6,7,8-tetrahydronaphthalen-2-ol (120 mg, 214 ^mol, 24% yield) was obtained as a white solid. LC-MS (ESI+) m/z: 562.1 (M+H) + Step 3: A mixture of (5S,6R)-5-(4-(4-(dimethoxymethyl)piperidin-1-yl)phenyl)-8,8- difluoro-6- (4-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydronaphthalen-2-o l (110 mg, 196 ^mol, 1 eq) was added THF (3 mL) and 10% H ₂ SO ₄ (3 mL) .The mixture was stirred at 70 °C for 40 min. The resulting solution was quenched with 10 mL aq.NaHCO ₃ , the mixture was treated with 50 mL H ₂ O and was extracted with 100 mL ethyl acetate. The organic layers were dried with anhydrous Na ₂ SO ₄ , filtered, and concentrated to give 1-(4-((1S,2R)-4,4-difluoro-6-hydroxy-2-(4- (trifluoromethyl)phenyl)-1,2,3,4-tetrahydronaphthalen-1-yl)p henyl)piperidine-4-carbaldehyde (100 mg, 194 ^mol, 99% yield) was obtained as a white solid. Step 4: A mixture of (S)-3-(1-oxo-5-(piperazin-1-yl)isoindolin-2-yl)piperidine-2, 6-dione (146 (trifluoromethyl)phenyl)-1,2,3,4-tetrahydronaphthalen-1-yl)p henyl)piperidine-4-carbaldehyde (100 mg, 194 ^mol, 1 eq), AcONa (48 mg, 582 ^mol, 3 eq) was added in the DCM (2 mL) and MeOH (2 mL), the mixture was stirred at 30 °C for 1 h, and then AcOH (35 mg, 582 ^mol, 33 ^L, 3 eq), Na(OAc) ₃ BH (82 mg, 388^mol, 2 eq) was added in the mixture and was stirred at 30 °C for 16h. The reaction mixture was treated with 30 mL H ₂ O and extracted with 50 mL ethyl acetate. The organic layers were dried with anhydrous Na ₂ SO ₄ , filtered, the residue was purified by prep. HPLC (column: Welch Xtimate C18150*30mm*5um; mobile phase: [water(FA)- ACN];gradient:26%-56% B over 7 min). The aqueous phase was lyophilized to dryness to give (S)-3-(5-(4-((1-(4-((1S,2R)-4,4-difluoro-6-hydroxy-2-(4-(tri fluoromethyl)phenyl)-1,2,3,4- tetrahydronaphthalen-1-yl)phenyl)piperidin-4-yl)methyl)piper azin-1-yl)-1-oxoisoindolin-2- yl)piperidine-2,6-dione (68.6 mg, 83 ^mol, 43% yield). LC-MS (ESI+) m/z: 828.3 (M+H) +. HPLC: 98.948 %, purity at 220nm. ¹ H NMR (400 MHz, DMSO-d6) į = 11.00 - 10.90 (m, 1H), 9.89 - 9.69 (m, 1H), 8.15˄s, 0.41 H), 7.60 - 7.46 (m, 3H), 7.20 - 7.12 (m, 2H), 7.11 - 7.01 (m, 3H), 6.92 - 6.82 (m, 2H), 6.64 - 6.54 (m, 2H), 6.22 - 6.12 (m, 2H), 5.11 - 5.01 (m, 1H), 4.40 - 4.28 (m, 2H), 4.25 - 4.15 (m, 1H), 3.86 - 3.75 (m, 1H), 3.62 -3.48 (m, 2H), 3.47 - 3.33 (m, 8H), 3.00 - 2.83 (m, 1H), 2.81 - 2.54 (m, 4H), 2.43 - 2.28 (m, 2H), 2.28 - 2.10 (m, 2H), 2.03 - 1.89 (m, 1H), 1.81 - 1.57 (m, 3H), 1.03 (s, 2H).

EXAMPLE 42. Preparation of (I-329) (S)-3-(5-(4-((1-(4-((1R,2S)-4,4-difluoro-6- hydroxy-2-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydronaph thalen-1- yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindo lin-2-yl)piperidine-2,6-dione Step 1: A mixture of (5R,6S)-5-(4-(4-(dimethoxymethyl)piperidin-1-yl)phenyl)-8,8- difluoro-6- (4-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydronaphthalen-2-o l (120 mg, 213 ^mol, 1 eq) was added THF (3 mL) and H ₂ SO ₄ (3 mL). The mixture was stirred at 70 °C for 40min. The resulting solution was quenched with 10 mL aq.NaHCO ₃ , the mixture was treated with 50 mL H ₂ O and was extracted with 50 mL ethyl acetate. The organic layers were dried with anhydrous Na ₂ SO ₄ , filtered, and concentrated to give 1-[4-[(1R,2S)-4,4-difluoro-6-hydroxy-2-[4- (trifluoromethyl)phenyl]tetralin-1-yl]phenyl]piperidine-4-ca rbaldehyde (100 mg, 194 ^mol, 91% yield) was obtained as a white solid. Step 2: A mixture of S-3-(1-oxo-5-(piperazin-1-yl)isoindolin-2-yl)piperidine-2,6- dione (146 mg, 291 ^mol, 1.5 eq, PhSO3H salt), 1-[4-[(1R,2S)-4,4-difluoro-6-hydroxy-2-[4- (trifluoromethyl)phenyl]tetralin-1-yl]phenyl]piperidine-4-ca rbaldehyde (100 mg, 194 ^mol, 1 eq), AcONa (48 mg, 582 ^mol, 3 eq) was added in the DCM (2 mL) and MeOH (2 mL), the mixture was stirred at 30 °C for 1h, and then AcOH (35 mg, 582 ^mol, 33 ^L, 3 eq), Na(OAc) ₃ BH (82 mg, 388 ^mol, 2 eq) was added in the mixture and was stirred at 30 °C for 16 h The reaction mixture was treated with 30 mL H ₂ O and extracted with 50 mL ethyl acetate The organic layers were dried with anhydrous Na2SO4, filtered, the residue was purified by prep. HPLC (column: Welch Xtimate C18150*30mm*5um; mobile phase: [water (FA)-ACN]; gradient: 26%-56% B over 7 min). The aqueous phase was lyophilized to dryness to give (3S)- 3-[5-[4-[[1-[4-[(1R,2S)-4,4-difluoro-6-hydroxy-2-[4-(trifluo romethyl)phenyl]tetralin-1- yl]phenyl]-4-piperidyl]methyl]piperazin-1-yl]-1-oxo-isoindol in-2-yl]piperidine-2,6-dione (82.6 mg, 99 ^mol, 51% yield). LC-MS (ESI+) m/z: 828.2 (M+H) +. HPLC: 100 %, purity at 220nm. ¹ H NMR (400 MHz, DMSO-d ₆ ) į = 11.03 - 10.87 (m, 1H), 9.89 - 9.69 (m, 1H), 8.19 - 8.10 (m, 0.245H), 7.61 - 7.44 (m, 3H), 7.20 - 7.12 (m, 2H), 7.11 - 6.99 (m, 3H), 6.94 - 6.81 (m, 2H), 6.68 - 6.51 (m, 2H), 6.22 - 6.05 (m, 2H), 5.14 - 4.97 (m, 1H), 4.44 - 4.26 (m, 2H), 4.25 - 4.09 (m, 1H), 3.87 - 3.74 (m, 1H), 3.63-3.47 (m, 2H), 3.44 - 3.34 (m, 8H), 2.98 - 2.82 (m, 1H), 2.81 - 2.53 (m, 4H), 2.42 - 2.31 (m, 2H), 2.25 - 2.14 (m, 2H), 2.01 - 1.91 (m, 1H), 1.82 - 1.56 (m, 3H), 1.26 - 1.04 (m, 2H).

EXAMPLE 43. Preparation of (I-308) 3-(4-(2-((1-(4-((1R,2S)-4,4-difluoro-6-hydroxy- 2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperidin- 4-yl)methyl)-2,8- diazaspiro[4.5]decan-8-yl)phenyl)piperidine-2,6-dione Step 1: A mixture of 1-bromo-4-iodo-benzene (600 mg, 2.12 mmol, 1 eq.) , tert-butyl 2,8- diazaspiro [4.5]decane-2-carboxylate (611.68 mg, 2.55 mmol, 1.2 eq.) , (2S)-pyrrolidine-2- carboxylic acid (146.50 mg, 1.27 mmol, 0.6 eq.), copper(I) iodide (242.35 mg, 1.27 mmol, 0.6 eq.) and K ₂ CO ₃ (732.79 mg, 5.30 mmol, 2.5 eq.) in DMSO (3 mL) was degassed and purged with N ₂ for 3 times, and then the mixture was stirred at 80 ^o C for 3 hour under N ₂ atmosphere. LC-MS showed one main peak with desired mass was detected. The reaction mixture was partitioned between ethyl acetate (40 mL×2) and water (50 mL). After quenching the reaction, the reaction mixture was poured into separatory funnel and separated. The crude product was purified by silica gel chromatography eluted with PE: EtOAc=3:1. Tert-butyl 8-(4- bromophenyl)-2,8-diazaspiro[4.5]decane-2-carboxylate (260 mg, 657.67 ^mol, 31.01% yield) was obtained as a white solid. LC-MS (ESI ⁺ ) m/z: 397.1 (M+H) ⁺ . Step 2: A mixture of tert-butyl 8-(4-bromophenyl)-2,8-diazaspiro[4.5]decane-2-carboxylate (100 eq.), K2CO3 (105 mg, 759 ^mol, 3.0 eq.) and PdCl2(dppf) (18.5 mg, 25.3 ^mol, 0.1 eq.) in Dioxane (2 mL) and Water (0.5 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 80 °C for 3 hour under N ₂ atmosphere. LC-MS showed the reaction was completed. The reaction mixture was quenched by addition ethyl acetate (10 mL) at 20 °C, and then diluted with water (10 mL) and extracted with ethyl acetate 30 mL (10 mL x 3). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The crude material was purified on silica gel column chromatography (from 100% PE to PE/EtOAc = 4/1) to give tert-butyl 8-(4-(2,6-bis(benzyloxy)pyridin-3- yl)phenyl)-2,8-diazaspiro[4.5] decane-2-carboxylate (120 mg, 0.16 mmol, 63 % yield, 80% Purity) as a yellow solid. LC-MS (ESI ⁺ ) m/z: 606.3 (M+H) ⁺ . Step 3: To a solution of tert-butyl 8-(4-(2,6-bis(benzyloxy)pyridin-3-yl)phenyl)-2,8- diazaspiro[4.5] decane-2-carboxylate (0.10 g, 0.17 mmol, 1.0 eq.) in EtOH (3 mL), DCM (3 mL) and EtOAc (3 mL) was added Pd/C (5 wt%, 0.1 g) under H ₂ atmosphere. The suspension was degassed and purged 3x with H2. The mixture was stirred under H2 (30 psi) at 30 °C for 16 h. LC-MS showed the reaction was completed. The mixture was filtered and the filtrate was concentrated to give tert-butyl 8-(4-(2,6-dioxopiperidin-3-yl)phenyl)-2,8-diazaspiro[4.5] decane- 2-carboxylate (65 mg, 0.15 mmol, 92 %) as a white solid. LC-MS (ESI ⁺ ) m/z: 428.2 (M+H) ⁺ . Step 4: To a solution of tert-butyl 8-(4-(2,6-dioxopiperidin-3-yl)phenyl)-2,8- diazaspiro[4.5]decane-2- carboxylate (60 mg, 0.14 mmol, 1.0 eq.) in HCl/MeOH (3 mL). The mixture was stirred at 20 °C for 1 hour. LCMS showed the reaction was completed. The mixture was concentrated in vacuum to give crude product. No further purification as it is used for the next step directly. LC-MS (ESI+) m/z: 328.2 (M+H)+ Step 5: To a solution of 1-(4-((1R,2S)-4,4-difluoro-6-hydroxy-2-phenyl-1,2,3,4- tetrahydronaphthalen -1-yl)phenyl)piperidine-4-carbaldehyde (35.0 mg, 78.2 ^mol, 1.0 eq.) and 3-(4-(2,8-diazaspiro [4.5]decan-8-yl)phenyl)piperidine-2,6-dione (28.2 mg, 86.0 ^mol, 1.1 eq.) ^mol, 3.8 eq.). The mixture was stirred at 20 °C for 2 h. LC-MS showed the reaction was complete. The crude was purified by prep-HPLC (Boston Green ODS 150*30mm*5um, water (FA)-ACN as a mobile phase, from 13% to 43%, Gradient Time (min): 12, Flow Rate (ml/min): 25) to give 3-(4-(2-((1-(4-((1R,2S)-4,4-difluoro-6-hydroxy-2-phenyl-1,2, 3,4- tetrahydronaphthalen-1-yl)phenyl)piperidin-4-yl)methyl)-2,8- diazaspiro[4.5]decan-8- yl)phenyl)piperidine-2,6-dione (16.9 mg, 22.3 ^mol, 28.5 % yield) as a white solid. LC-MS (ESI ⁺ ) m/z: 759.5 (M+H) ⁺ . LCMS: calc. for C ₄₇ H ₅₂ F ₂ N ₄ O ₃ :758.95, found: [M+H] ⁺ 759.5 HPLC: 100.00% purity at 220 nm. ¹ H NMR (400 MHz, DMSO-d ₄ ) į: ppm 10.68 - 10.79 (m, 1 H), 9.38 - 10.05 (m, 1 H), 8.20 (s, 1 H), 7.16 - 7.21 (m, 3 H), 7.08 (s, 1 H), 7.02 (d, J=8.58 Hz, 2 H), 6.83 - 6.91 (m, 6 H), 6.55 (d, J=8.70 Hz, 2 H), 6.12 (d, J=8.58 Hz, 2 H), 4.27 - 4.32 (m, 1 H), 3.73 (s, 1 H), 3.63 - 3.68 (m, 1 H), 3.46 - 3.55 (m, 3 H), 3.02 - 3.16 (m, 5 H), 2.56 - 2.68 (m, 4 H), 2.40 - 2.47 (m, 2 H), 2.33 (s, 3 H), 2.23 (d, J=7.15 Hz, 2 H), 2.00 - 2.11 (m, 1 H), 1.73 (d, J=10.97 Hz, 2 H), 1.48 - 1.65 (m, 7 H), 1.07 - 1.17 (m, 2 H). EXAMPLE 44. Preparation of (I-319) (S)-3-(5-(4-((1-(4-((1S,2R)-2-(2,4- difluorophenyl)-4,4-difluoro-6-hydroxy-1,2,3,4-tetrahydronap hthalen-1- yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindo lin-2-yl)piperidine-2,6-dione and (I-318) (S)-3-(5-(4-((1-(4-((1R,2S)-2-(2,4-difluorophenyl)-4,4-diflu oro-6-hydroxy-

1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperidin-4-yl)m ethyl)piperazin-1-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione Step 1: To a mixture of compound 1 (500 mg, 855 ^mol, 1.0 eq.) and compound 2 (205 mg, 855 ^mol, 1.0 eq.) in 1,4-Dioxane (8 mL) and water (2 mL) was added Pd(t-Bu ₃ P) ₂ (87.4 mg, 0.2 eq., 171 ^mol), K ₃ PO ₄ (545 mg, 2.57 mmol, 3.0 eq.) in one portion at 25 °C under N ₂ . The mixture was stirred for 16 hours. The mixture was concentrated and then water (100 mL) was added. The mixture was extracted with EtOAc (80 mL x 3). The combined organic layers were washed with brine (100 mL), dried over Na ₂ SO ₄ , filtered and concentrated. The crude material was purified on silica gel column chromatography (from PE/EtOAc =10/1 to 4/1) to yield compound LC-MS (ESI ⁺ ) m/z: 618.7(M+H) ⁺ . Step 2: To a solution of compound 3(430 mg, 1 eq., 696 ^mol) in THF (5 mL) and MeOH (5 mL) was added Pd(OH) ₂ (196 mg, 10% Wt, 0.2 eq., 139 ^mol) and Pd/C (148 mg, 10% Wt, 0.2 eq., 139 ^mol). The suspension was degassed under vacuum and purged with H ₂ several times. The mixture was heated to 45 °C (50 psi) and stirred for 16 hours. LCMS showed that the desired compound was detected. The crude product was filtered and the filter was concentrated to give the crude as a yellow solid. The mixture was filtered and concentrated in vacuum. The residue was purified by pre-HPLC(Column Boston Green ODS 150*30mm*5um˗ Condition water(FA)-ACN˗ Begin B 60˗End B 90˗ Gradient Time(min) 12˗ 100%B Hold Time(min) 2˗ Flow Rate (ml/min) 25) to afford compound 4(150 mg, 283 ^mol, 40.7 %) as a yellow solid. LC-MS (ESI ⁺ ) m/z: 530.5 (M+H) ⁺ . ¹ H NMR (400 MHz, METHANOL-d ₄ ) į ppm˖ 7.13 (s, 1 H), 6.84 - 6.98 (m, 3 H), 6.62 - 6.70 (m, 3 H), 6.38 - 6.46 (m, 1 H), 6.32 (d, J=8.58 Hz, 2 H), 4.31 (br d, J=3.34 Hz, 1 H), 4.07 (d, J=6.79 Hz, 1 H), 3.89 - 3.98 (m, 1 H), 3.56 (br d, J=11.21 Hz, 2 H), 3.35 (s, 6 H), 3.14 (d, J=7.27 Hz, 4 H), 2.49 - 2.57 (m, 2 H), 2.25 (br t, J=14.96 Hz, 1 H), 1.77 (br d, J=13.11 Hz, 2 H). Step 3: Compound 4 (150 mg, 283 ^mol, 1.0 eq.) was separated by prep-SFC (Column DAICEL CHIRALPAK AD (250mm*30mm,10um) ;Condition CO ₂ -i-PrOH(0.1%NH ₃ H ₂ O); Begin B 25%; End B 25%; FlowRate(ml/min) 70) to give compound 5A(70 mg, 0.13 mmol, 47 %) (Rt =3.908 min) and compound 5B (70 mg, 0.13 mmol, 47 %) (Rt = 4.098 min) as a white solid. Step 4: Compound 6A: To a solution of compound 5A (50.00 mg, 94.42 ^mol, 1.0 eq) in DCM (2 mL) was added TFA (10.77 mg, 94.42 ^mol, 1.0 eq). The mixture was stirred at 25 °C for 0.2 hr. LCMS showed that the starting material was consumed and the desired product was detected. The reaction liquid is dried with N2 at 0°C to give Compound 6A (30 mg, 62.05 ^mol, 65.72% yield) was obtained as yellow oil which was used in the next step without further purification.. LC-MS (ESI+) m/z: 484.21 (M+H)+. Step 5: Compound 6B: To a solution of compound 5B (56.00 mg, 105.75 ^mol, 1.0 eq) in DCM (2 mL) was added TFA (12.06 mg, 105.75 ^mol, 1.0 eq). The mixture was stirred at 25 °C for detected. The reaction liquid is dried with N2 at 0 °C to give Compound 6B (32 mg, 66.18 ^mol, 62.59% yield) was obtained as yellow oil which was used in the next step without further purification.. LC-MS (ESI+) m/z: 484.2(M+H) ⁺ . Step 6: To a solution of compound 6A (30 mg, 62.05 ^mol, 1.0eq) in DCM (3 mL) and MeOH (3 mL) was added compound 034 (20.37 mg, 62.05 ^mol, 1.0 eq) and DIEA (8.02 mg, 62.05 ^mol, 1.0 eq) at 25 °C. After addition, the mixture was stirred at this temperature for 0.5 hr, and then NaBH(OAc) ₃ (26.30 mg, 124.10 ^mol, 2.0eq) was added at 25 °C. The resulting mixture was stirred at 25 °C for 3 hr. The reaction mixture was concentrated to yield a residue. The residue was purified by preparative HPLC (column: Boston Green ODS 150 * 30 mm * 5um; mobile phase: [water (NH ₄ HCO ₃ ) - ACN]; B%: 52%-80%,11min) , followed by lyophilization to yield I-319 (39.7 mg, 49.88 ^mol, 80.39% yield) was obtained as a white solid. LC-MS (ESI+) m/z: 796.5 [M+H] ⁺ . LCMS: calc. for C ₄₅ H ₄₅ F ₄ N ₅ O ₄ : 795.34, found: [M+H] ⁺ 796.5. HPLC: 100% purity at 220 nm. NMR (400 MHz, DMSO-d ₆ ) į ppm 10.94 (br s, 1 H), 9.74 - 9.80 (m, 1 H), 7.51 (d, J=8.58 Hz, 1 H), 7.21 - 7.27 (m, 1 H), 7.04 - 7.08 (m, 3 H), 6.83 - 6.91 (m, 3 H), 6.54 - 6.63 (m, 3 H), 6.20 (d, J=8.46 Hz, 2 H), 5.04 (dd, J=13.29, 5.07 Hz, 1 H), 4.27 - 4.35 (m, 2 H), 4.17 - 4.22 (m, 1 H), 3.81 (br d, J=12.99 Hz, 1 H), 3.55 (br s, 2 H), 3.26 - 3.30 (m, 6 H), 2.86 - 2.93 (m, 1 H), 2.58 - 2.77 (m, 3 H), 2.26 - 2.44 (m, 4 H), 2.18 (br d, J=7.15 Hz, 2 H), 1.93 - 1.98 (m, 1 H), 1.75 (br d, J=12.28 Hz, 4 H), 1.11 - 1.18 (m, 2 H). Step 7: To a solution of compound 6B (32 mg, 66.18 ^mol, 1.0 eq) in DCM (3 mL) and MeOH (3 mL) was added compound 034 (21.73 mg, 66.18 ^mol, 1.0 eq) and DIEA (8.55 mg, 66.18 ^mol, 1.0 eq) at 25 °C. After addition, the mixture was stirred at this temperature for 0.5 hr, and then NaBH(OAc) ₃ (28.05 mg, 132.37 ^mol, 2.0 eq) was added at 25 °C. The resulting mixture was stirred at 25 °C for 3 hr. The reaction mixture was concentrated to yield a residue. The residue was purified by preparative HPLC (column: Boston Green ODS 150 * 30 mm * 5um; mobile phase: [water (NH ₄ HCO ₃ ) - ACN]; B%: 52%-80%,11min) , followed by lyophilization to yield I-318 (33.1 mg, 41.59 ^mol, 62.84% yield) was obtained as a white solid. LC-MS (ESI+) / 7966 [M+H] ⁺ LCMS: calc. for C45H45F4N5O4: 795.34, found: [M+H] ⁺ 796.6. HPLC: 100% purity at 220 nm ¹ H NMR (400 MHz, DMSO-d ₆ ) į ppm 10.95 (br s, 1 H), 9.78 (s, 1 H), 7.52 (d, J=8.70 Hz, 1 H), 7.22 - 7.28 (m, 1 H), 7.04 - 7.09 (m, 3 H), 6.84 - 6.90 (m, 3 H), 6.56 - 6.64 (m, 3 H), 6.21 (d, J=8.70 Hz, 2 H), 5.05 (dd, J=13.23, 5.01 Hz, 1 H), 4.28 - 4.35 (m, 2 H), 4.18 - 4.23 (m, 1 H), 3.80 - 3.85 (m, 1 H), 3.56 (br d, J=2.50 Hz, 2 H), 3.28 - 3.31 (m, 6 H), 2.87 - 2.94 (m, 1 H), 2.60 - 2.76 (m, 3 H), 2.28 - 2.45 (m, 4 H), 2.19 (br d, J=7.03 Hz, 2 H), 1.94 - 1.99 (m, 1 H), 1.59 - 1.81 (m, 4 H), 1.11 - 1.18 (m, 2 H).

EXAMPLE 45. Preparation of (I-327) (S)-3-(5-(4-((1-(4-((1S,2R)-4,4-difluoro-2-(4- fluoro-2-methylphenyl)-6-hydroxy-1,2,3,4-tetrahydronaphthale n-1-yl)phenyl)piperidin-4- yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2, 6-dione Step 1: A mixture of 1-(4-(6-(benzyloxy)-2-bromo-4,4-difluoro-3,4-dihydronaphthal en-1- yl)phenyl)-4-(dimethoxymethyl)piperidine (1.0 g, 1 Eq, 1.5 mmol), (4-fluoro-2- methylphenyl)boronic acid (028 g 12 Eq 18 mmol) Na ₂ CO ₃ (048 g 3 Eq 45 mmol) and Pd- 118 (98 mg, 0.1 Eq, 0.15 mmol) in dioxane (6 mL) and H2O (1.5 mL) at r.t.. N2 was bubbled into the mixture for 5 min. The reaction mixture was heated at 50 °C for 4 h with N2 The mixture was added with H ₂ O (100 mL) and extracted with EtOAc (100 mL x 2). The combined extracts was dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to dryness in vacuo to give a residue. The residue was subjected to column chromatography over silica gel (petroleum ether/ethyl acetate from 100/0 to 70/30). The pure fractions were collected and concentrated to dryness in vacuo to give 1-(4-(6-(benzyloxy)-4,4-difluoro-2-(4-fluoro-2-methylphenyl) -3,4- dihydronaphthalen-1-yl)phenyl)-4-(dimethoxymethyl)piperidine (1 g, 90 %, 80.3% purity) as a yellow solid. LC-MS (ESI+) m/z: 614.3 (M+H) ⁺ . Step 2: A mixture of 1-(4-(6-(benzyloxy)-4,4-difluoro-2-(3-fluoro-5-methylphenyl) -3,4- dihydronaphthalen-1-yl)phenyl)-4-(dimethoxymethyl)piperidine (950 mg, 1 Eq, 1.24 mmol), Pd/C (500 mg, 10% Wt, 0.378 Eq, 470 ^mol), Pd(OH) ₂ /C(500 mg, 20% Wt, 0.573 Eq, 712 ^mol) in MeOH (7 mL) and THF (7 mL) was degassed and purged with H ₂ for 3 times, then the mixture was stirred at 25 °C for 16 h with H ₂ atmosphere (15 psi). The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by HPLC (condition: column: Welch Xtimate C18150*30mm*5um; mobile phase: [water(FA)- ACN];B%: 36%-76%, 9 min), then was purified by SFC (condition: column: DAICEL CHIRALPAK AD(250mm*30mm,10um);mobile phase: [CO2-EtOH];B%: 25%-25%, min) to give (5R,6S)-5-(4-(4-(dimethoxymethyl)piperidin-1-yl)phenyl)-8,8- difluoro-6-(4-fluoro-2- methylphenyl)-5,6,7,8-tetrahydronaphthalen-2-ol (70 mg, 11 %, 100% purity) and (5S,6R)-5-(4- (4-(dimethoxymethyl)piperidin-1-yl)phenyl)-8,8-difluoro-6-(4 -fluoro-2-methylphenyl)-5,6,7,8- tetrahydronaphthalen-2-ol (40 mg, 6.1 %, 100% purity) as white solids. LC-MS (ESI+) m/z: 526.1 (M+H) ⁺ . Step 3: A mixture of (5S,6R)-5-(4-(4-(dimethoxymethyl)piperidin-1-yl)phenyl)-8,8- difluoro-6- (4-fluoro-2-methylphenyl)-5,6,7,8-tetrahydronaphthalen-2-ol (40 mg, 1 Eq, 76 ^mol) in THF (1.5 mL), then 10%H ₂ SO ₄ (1.5 mL) was added to the mixture and stirred at 70 °C for 0.5 h. The reaction was adjusted to pH=8 with aq. NaHCO ₃ at 0 °C. Then the mixture was added H ₂ O (10 mL) and extracted with EtOAc (20 mL x 2). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered and concentrated to dryness in vacuo to give 1-(4-((1S,2R)-4,4-difluoro-2-(4-fluoro-2-methylphenyl)-6-hyd roxy-1,2,3,4- tetrahydronaphthalen-1-yl)phenyl)piperidine-4-carbaldehyde (37 mg 99 % 97206% purity) as a yellow solid. LC-MS (ESI+) m/z: 480.1 (M+H) ⁺ . Step 4: A mixture of 1-(4-((1S,2R)-4,4-difluoro-2-(4-fluoro-2-methylphenyl)-6-hyd roxy-1,2,3,4- tetrahydronaphthalen-1-yl)phenyl)piperidine-4-carbaldehyde (40 mg, 1 Eq, 81 ^mol) , (S)-3-(1- oxo-5-(piperazin-1-yl)isoindolin-2-yl)piperidine-2,6-dione benzenesulfonate (51 mg, 1.3 Eq, 0.11 mmol), sodium acetate (33 mg, 5 Eq, 0.41 mmol) and acetic acid (15 mg, 14 ^L, 3 Eq, 0.24 mmol) in DCM (3 mL) and MeOH (3 mL) was stirred at 25 °C for 1 h, then NaBH(OAc) ₃ (34 mg, 2 Eq, 0.16 mmol) was added to the mixture and was stirred at 25 °C for 16 h. Then the mixture was added H ₂ O (20 mL) and extracted with EtOAc (20 mL x 2). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to dryness in vacuo to give a residue. The residue was purified by prep-HPLC (column: Welch Xtimate C18150*30mm*5um; mobile phase: [water (FA)-ACN]; B% 15%-55%, 9 min) to give (S)-3-(5-(4-((1-(4-((1S,2R)-4,4-difluoro-2-(4-fluoro-2-methy lphenyl)-6-hydroxy-1,2,3,4- tetrahydronaphthalen-1-yl)phenyl)piperidin-4-yl)methyl)piper azin-1-yl)-1-oxoisoindolin-2- yl)piperidine-2,6-dione (21.8 mg, 34 %, 100% purity) as a white solid. LC-MS (ESI+) m/z: 792.4 (M+H) ⁺ . LCMS: calc. for C ₄₆ H ₄₈ F ₃ N ₅ O ₄ : 791.37, found: [M+H] ⁺ 792.4. HPLC: 100% purity at 220 nm. ¹ HNMR (400MHz, DMSO-d ₆ ) į = 10.96 (s, 1H), 9.76 (br s, 1H), 8.15 (s, 1H), 7.52 (d, J=8.5 Hz, 1H), 7.12 - 7.01 (m, 4H), 6.94 - 6.83 (m, 2H), 6.73 - 6.55 (m, 3H), 6.21 - 6.08 (m, 3H), 5.05 (dd, J=5.0, 13.2 Hz, 1H), 4.37 - 4.28 (m, 2H), 4.24 - 4.17 (m, 1H), 3.71 (br d, J=12.6 Hz, 1H), 3.55 (br d, J=9.4 Hz, 2H), 3.28 (br s, 5H), 2.97 - 2.84 (m, 1H), 2.79 - 2.53 (m, 4H), 2.47 (s, 6H), 2.37 (dq, J=4.9, 13.3 Hz, 1H), 2.27 - 2.15 (m, 3H), 2.00 - 1.91 (m, 1H), 1.82 - 1.59 (m, 3H), 1.23 - 1.09 (m, 2H).

EXAMPLE 46. Preparation of (I-305) 3-(5-(4-((1-(4-((1R,2S)-4,4-difluoro-6-hydroxy- 2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperidin- 4-yl)methyl)piperazin-1-yl)- 1-oxoisoindolin-2-yl)piperidine-2,6-dione Step 1: To a solution of (5S,6R)-5-(4-(4-(dimethoxymethyl)piperidin-1-yl)phenyl)-8,8- difluoro- 6-phenyl-5,6,7,8-tetrahydronaphthalen-2-ol (60 mg, 1 Eq, 0.12 mmol) in THF (5 mL) was added sulfuric acid (0.12 g, 5 mL, 10% Wt% in water, 1.0 Eq, 0.12 mmol). The mixture was stirred at 70 °C for 30 min. The mixture was adjusted to pH=8-9 by progressively adding saturated aqueous NaHCO ₃ . The reaction mixture was quenched by addition 100 mL EtOAc at 20°C, and then diluted with 50 mL H ₂ O and extracted with EtOAc (25 mL * 2). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na ₂ SO ₄ . The reaction was filtered and concentrated under reduced pressure to give 1-(4-((1S,2R)-4,4-difluoro-6-hydroxy-2-phenyl- 1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperidine-4-carbal dehyde (42 mg, 80 ^mol, 66 % yield, 84.8% purity) as a colorless oil. LC-MS (ESI+) m/z: 466.1(M+H) ⁺ . Step 2: A mixture of 1-(4-((1S,2R)-4,4-difluoro-6-hydroxy-2-phenyl-1,2,3,4- tetrahydronaphthalen-1-yl)phenyl)piperidine-4-carbaldehyde (42.0 mg, 1 Eq, 79.6 ^mol), 3-(1- oxo-5-(piperazin-1-yl)isoindolin-2-yl)piperidine-2,6-dione (26.1 mg, 1 Eq, 79.6 ^mol, HCl salt) was stirred for 1 h. Acetic acid (14.3 mg, 13.7 ^L, 3 Eq, 239 ^mol) was added at 20°C and stirred for an additional 1 h, then added Na(OAc)3BH (33.7 mg, 2 Eq, 159 ^mol) was added to the mixture and stirred at 25 °C for 16 h. The reaction was quenched with water (50 mL) and extracted with ethyl acetate (50 mL*2). The reaction was concentrated to give 3-(5-(4-((1-(4- ((1R,2S)-4,4-difluoro-6-hydroxy-2-phenyl-1,2,3,4-tetrahydron aphthalen-1-yl)phenyl)piperidin- 4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine- 2,6-dione as a brown oil. The brown oil was purified by preparative high-performance liquid chromatography. Condition: water (FA)- ACN. Column: Welch Xtimate C18150*30mm*5um. Begin B: 21%, End B: 51%. Gradient Time (min) 7; 100% B hold Time(min)2.7, Flow Rate(ml/min) 25. The pure fractions were collected, and the solvent was evaporated under vacuum. The aqueous layer was lyophilized to dryness to give 3-(5-(4-((1-(4-((1R,2S)-4,4-difluoro-6-hydroxy-2-phenyl-1,2, 3,4- tetrahydronaphthalen-1-yl)phenyl)piperidin-4-yl)methyl)piper azin-1-yl)-1-oxoisoindolin-2- yl)piperidine-2,6-dione (27 mg, 35 ^mol, 44 % yield, 99.2% purity) as a white solid. LCMS: calc. for C ₄₅ H ₄₇ F ₂ N ₅ O ₄ : 759.36, found: [M+H] ⁺ 760.3. HPLC: 99.22% purity at 220 nm. 10.99 - 10.92 (m, 1H), 9.79 - 9.69 (m, 1H), 8.16 - 8.14 (m, 0.443H), 7.54 - 7.49 (m, 1H), 7.22 - 7.17 (m, 3H), 7.06 (s, 3H), 6.92 - 6.89 (m, 2H), 6.86 (br d, J = 4.4 Hz, 2H), 6.60 - 6.53 (m, 2H), 6.16 - 6.08 (m, 2H), 5.08 - 5.00 (m, 1H), 4.36 - 4.27 (m, 2H), 4.23 - 4.15 (m, 1H), 3.70 - 3.62 (m, 1H), 3.57 - 3.49 (m, 2H), 3.27 (br s, 5H), 2.95 - 2.84 (m, 1H), 2.71 - 2.52 (m, 4H), 2.48 - 2.45 (m, 3H), 2.38 - 2.27 (m, 2H), 2.21 - 2.15 (m, 2H), 1.99 - 1.91 (m, 1H), 1.78 - 1.70 (m, 2H), 1.67 - 1.58 (m, 1H), 1.20 - 1.08 (m, 2H).

EXAMPLE 47. Preparation of (I-306) (R)-3-(5-(4-((1-(4-((1R,2S)-4,4-difluoro-6- hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)pi peridin-4- yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2, 6-dione Step 1: 1,1'-Bis(di-t-butylphosphino)ferrocene palladium dichloride (97.9 mg, 0.1 Eq, 150 ^mol) was added to the mixture of 1-(4-(6-(benzyloxy)-2-bromo-4,4-difluoro-3,4-dihydronaphthal en-1- yl)phenyl)-4-(dimethoxymethyl)piperidine (1 g, 1 Eq, 1.50 mmol), phenylboronic acid (275 mg, 1.5 Eq, 2.25 mmol) and sodium carbonate (478 mg, 3 Eq, 4.51 mmol) in dioxane (20 mL) and H ₂ O (5 mL) at r.t.N ₂ was bubbled into the mixture for 5 min. The reaction mixture was heated at 50 °C for 16 hour. TLC (PE/EtOAc = 5/1, Rf = 0.3) showed a new spot was detected. The mixture was filtered and the filter cake was washed with EtOAc (150 mL). The filtrate was treated with H ₂ O (150 mL), extracted with EtOAc (150 mL * 2). The combined extracts was dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to dryness in vacuo to give a residue. The residue was subjected to column chromatography over silica gel (petroleum ether/ethyl acetate from 100/0 to 80/20). The pure fractions were collected and concentrated to dryness in vacuo to give 1-(4-(6-(benzyloxy)-4,4-difluoro-2-phenyl-3,4-dihydronaphtha len-1-yl)phenyl)-4- (dimethoxymethyl)piperidine (1.1 g, 1.7 mmol, 88.1% purity) as a brown solid. LC-MS (ESI ⁺ ) m/z: 582.1 (M+H) ⁺ . Step 2: A mixture of 1-(4-(6-(benzyloxy)-4,4-difluoro-2-phenyl-3,4-dihydronaphtha len-1- yl)phenyl)-4-(dimethoxymethyl)piperidine (1.1 g, 1 Eq, 1.7 mmol), dihydrogen (3.4 mg, 1 Eq, 1.7 mmol), Pd/C (550 mg, 10% Wt) and Pd(OH) ₂ /C(550 mg, 20% Wt) in THF (30 mL) and MeOH (30 mL) was degassed and purged with H ₂ for 3 times, and then the mixture was stirred at 25 °C for 16 hour under H ₂ atmosphere (15 psi). The reaction was filtered and concentrated to dryness in vacuo to give 5-(4-(4-(dimethoxymethyl)piperidin-1-yl)phenyl)-8,8-difluoro -6- phenyl-5,6,7,8-tetrahydronaphthalen-2-ol (839 mg, 1.52 mmol, 91 %, 89.50% purity) as a brown solid. LC-MS (ESI ⁺ ) m/z: 494.3(M+H) ⁺ . Step 3: The brown solid was purified by SFC. Column: DAICEL CHIRALPAK AD(250mm*30mm,10um); Condition: CO ₂ -EtOH(0.1%NH ₃ H ₂ O); At the beginning: B (35%); At the end: B (35%); Flow Rate (ml/min) 80. The aqueous phase was lyophilized to dryness to give (5*S,6*R)-5-(4-(4-(dimethoxymethyl)piperidin-1-yl)phenyl)-8, 8-difluoro-6-phenyl-5,6,7,8- tetrahydronaphthalen-2-ol (341 mg, 688 ^mol, 45.2 %, 99.58% purity) as a colorless oil, (5*R,6*S)-5-(4-(4-(dimethoxymethyl)piperidin-1-yl)phenyl)-8, 8-difluoro-6-phenyl-5,6,7,8- tetrahydronaphthalen-2-ol (350 mg, 684 ^mol, 45.0 %, 96.44% purity) as a colorless oil and 5- (4-(4-(dimethoxymethyl)piperidin-1-yl)phenyl)-8-fluoro-6-phe nylnaphthalen-2-ol (52 mg, 0.10 mmol, 6.7 %, 93% purity) as a white solid. LC-MS (ESI ⁺ ) m/z: 494.1 and 472.1 (M+H) ⁺ Step 4: To a solution of (5*S,6*R)-5-(4-(4-(dimethoxymethyl)piperidin-1-yl)phenyl)-8, 8- difluoro-6-phenyl-5,6,7,8-tetrahydronaphthalen-2-ol (90 mg, 1 Eq, 0.18 mmol) in THF (5 mL) was added 10% sulfuric acid (0.17 g, 5 mL). The mixture was stirred at 70 °C for 30 min. The mixture was adjusted to pH 8-9 by progressively adding NaHCO3. The reaction mixture was with EtOAc (25 mL * 2). The combined organic layers were washed with 10 mL (10 mL * 1), dried over Na2SO4. The reaction was filtered and concentrated under reduced pressure to give 1- (4-((1*S,2*R)-4,4-difluoro-6-hydroxy-2-phenyl-1,2,3,4-tetrah ydronaphthalen-1- yl)phenyl)piperidine-4-carbaldehyde (100 mg, 222 ^mol, 99.5% purity) as a colorless oil. LC- MS (ESI+) m/z: 466.0 (M+H) ⁺ . Step 5: A mixture of 1-(4-((1R,2S)-4,4-difluoro-6-hydroxy-2-phenyl-1,2,3,4- tetrahydronaphthalen-1-yl)phenyl)piperidine-4-carbaldehyde (100 mg, 1 Eq, 222 ^mol), (R)-3- (1-oxo-5-(piperazin-1-yl)isoindolin-2-yl)piperidine-2,6-dion e hydrochloride (81.1 mg, 1 Eq, 222 ^mol) and sodium acetate (91.2 mg, 5 Eq, 1.11 mmol) in DCM (4 mL) and MeOH (4 mL) at 20°C for 0.5 hour, then acetic acid is added (40.1 mg, 38.1 ^L, 3 Eq, 667 ^mol) at 20°C for 1 h, then added sodium triacetoxyborohydride (94.2 mg, 2 Eq, 445 ^mol) to the mixture, and then the mixture was stirred at 25 °C for 16 h. The reaction was quenched with water (50 mL) and extracted with ethyl acetate (50 mL*2). The reaction was concentrated to give (R)-3-(5-(4-((1-(4- ((1R,2S)-4,4-difluoro-6-hydroxy-2-phenyl-1,2,3,4-tetrahydron aphthalen-1-yl)phenyl)piperidin- 4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine- 2,6-dione as a brown oil. The brown oil was purified by preparative high-performance liquid chromatography. Condition: water(FA)- ACN. Column: Welch Xtimate C18150*30mm*5um. Begin B:20%, End B: 60%. Gradient Time(min) 9; 100% B hold Time(min)3, Flow Rate(ml/min) 30. The pure fractions were collected, and the solvent was evaporated under vacuum. The aqueous layer was lyophilized to dryness to give (R)-3-(5-(4-((1-(4-((1R,2S)-4,4-difluoro-6-hydroxy-2-phenyl- 1,2,3,4- tetrahydronaphthalen-1-yl)phenyl)piperidin-4-yl)methyl)piper azin-1-yl)-1-oxoisoindolin-2- yl)piperidine-2,6-dione (57.9 mg, 76.2 ^mol, 34.3 %, 100% purity) as a white solid. LCMS: calc. for C ₄₅ H ₄₇ F ₂ N ₅ O ₄ : 759.36, found: [M+H] ⁺ 760.4. HPLC: 100% purity at 220 nm. ¹ H NMR (400 MHz, DMSO-d ₆ ) į 10.98 - 10.90 (m, 1H), 9.78 - 9.67 (m, 1H), 8.14 - 8.12 (m, 0.124H), 7.55 - 7.48 (m, 1H), 7.23 - 7.16 (m, 3H), 7.11 - 7.03 (m, 3H), 6.93 - 6.83 (m, 4H), 6.61 - 6.52 (m, 2H), 6.18 - 6.09 (m, 2H), 5.09 - 5.00 (m, 1H), 4.37 - 4.27 (m, 2H), 4.24 - 4.15 (m, 1H), 3.70 - 3.61 (m, 1H), 3.57 - 3.49 (m, 2H), 3.31 - 3.18 (m, 6H), 2.95 - 2.84 (m, 1H), 2.72 - 2.52 (m, 5H), 2.49 - 2.46 (m, 1H), 2.39 - 2.17 (m, 4H), 2.00 - 1.91 (m, 1H), 1.79 - 1.71 (m, 2H), 170 159 ( 1H) 121 108 ( 2H) EXAMPLE 48. Preparation of (I-309) 3-(5-(4-((1-(4-((1R,2S)-4,4-difluoro-2-(4- fluorophenyl)-6-hydroxy-1,2,3,4-tetrahydronaphthalen-1-yl)ph enyl)piperidin-4- yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2, 6-dione Step 1: A mixture of 1-(4-((1R,2S)-4,4-difluoro-2-(4-fluorophenyl)-6-hydroxy-1,2, 3,4- tetrahydronaphthalen-1-yl)phenyl)piperidine-4-carbaldehyde (80 mg, 1.0 Eq, 0.17 mmol) , 3-(1- oxo-5-(piperazin-1-yl)isoindolin-2-yl)piperidine-2,6-dione, HCl salt (80 mg, 1.3 Eq, 0.22 mmol) and sodium acetate (69 mg, 5 Eq, 0.84 mmol) and acetic acid (30 mg, 29 ^L, 3 Eq, 0.50 mmol) diluted in THF (3 mL) and MeOH (3 mL) at 25 °C and stirred for 1 h. Then sodium triacetoxyborohydride (71 mg, 50 ^L, 2 Eq, 0.34 mmol) was added to the mixture and was stirred at 25 °C for 16 h. The mixture was added H ₂ O (20 mL) and extracted with EtOAc (20 mL x 2). The combined extracts were dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to dryness in vacuo to give a residue. The residue was purified by prep-HPLC (column: Welch Xtimate C18150*30mm*5um; mobile phase: [water(FA)-ACN]; B% 15%-55%, 9 min) to give 3-(5-(4-((1-(4-((1R,2S)-4,4-difluoro-2-(4-fluorophenyl)-6-hy droxy-1,2,3,4- tetrahydronaphthalen-1-yl)phenyl)piperidin-4-yl)methyl)piper azin-1-yl)-1-oxoisoindolin-2- yl)piperidine-2,6-dione (61 mg, 46 %, 99.262% purity) as a white solid. LC-MS (ESI+) m/z: 778.4 (M+H) ⁺ . LCMS: calc. for C ₄₅ H ₄₆ F ₃ N ₅ O ₄ : 777.35, found: [M+H] ⁺ 778.4. HPLC: 99.262% purity at 220 nm. ¹ HNMR (400MHz, DMSO-d6) į = 10.95 (s, 1H), 9.74 (s, 1H), 8.14 (s, 1H), 7.53 (br d, J=8.1 Hz, 1H), 7.10 - 7.00 (m, 5H), 6.97 - 6.91 (m, 2H), 6.90 - 6.83 (m, 2H), 6.61 (br d, J=8.5 Hz, 2H), 6.15 (d, J=8.5 Hz, 2H), 5.05 (dd, J=4.9, 13.4 Hz, 1H), 4.36 - 4.18 (m, 3H), 3.70 (br d, J=11.2 Hz, 1H), 3.56 (br s, 2H), 3.28 (br s, 3H), 2.96 - 2.85 (m, 1H), 2.73 - 2.53 (m, 7H), 2.49 - 2.15 (m, 6H), 2.02 - 1.91 (m, 1H), 1.82 - 1.60 (m, 3H), 1.16 (br d, J=9.8 Hz, 2H). EXAMPLE 49. Preparation of (I-310) (R)-3-(5-(4-((1-(4-((1R,2S)-4,4-difluoro-2-(4- fluorophenyl)-6-hydroxy-1,2,3,4-tetrahydronaphthalen-1-yl)ph enyl)piperidin-4- yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2, 6-dione Step 1: A mixture of 1-(4-((1R,2S)-4,4-difluoro-2-(4-fluorophenyl)-6-hydroxy-1,2, 3,4- tetrahydronaphthalen-1-yl)phenyl)piperidine-4-carbaldehyde (50 mg, 1 Eq, 0.11 mmol) , (R)-3- (1-oxo-5-(piperazin-1-yl)isoindolin-2-yl)piperidine-2,6-dion e, HCl salt (50 mg, 1.3 Eq, 0.14 mmol) and sodium acetate (43 mg, 5 Eq, 0.53 mmol) and acetic acid (19 mg, 18 ^L, 3 Eq, 0.32 mmol) were diluted in THF (3 mL) and MeOH (3 mL) at 25 °C for 1 h, then sodium triacetoxyborohydride (45 mg, 2 Eq, 0.21 mmol) was added to the mixture and was stirred at 25 °C for 16 h. The mixture was added to H ₂ O (20 mL) and extracted with EtOAc (20 mL x 2). The combined extracts were dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to dryness in vacuo to give a residue. The residue was purified by prep-HPLC (column: Welch Xtimate C18 150*30mm*5um; mobile phase: [water(FA)-ACN]; B% 15%-55%, 9 min) to give (R)-3-(5-(4- ((1-(4-((1R,2S)-4,4-difluoro-2-(4-fluorophenyl)-6-hydroxy-1, 2,3,4-tetrahydronaphthalen-1- yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindo lin-2-yl)piperidine-2,6-dione (21.6 mg, 26 %, 100% purity) as a white solid. LC-MS (ESI+) m/z: 778.4 (M+H) ⁺ . LCMS: calc. for C ₄₅ H ₄₆ F ₃ N ₅ O ₄ : 777.35, found: [M+H] ⁺ 778.4. HPLC: 100% purity at 220 nm. ¹ HNMR (400MHz, DMSO-d ₆ ) į = 10.95 (s, 1H), 9.74 (s, 1H), 8.14 (s, 1H), 7.53 (d, J=8.5 Hz, 1H), 7.10 - 7.00 (m, 5H), 6.97 - 6.91 (m, 2H), 6.90 - 6.83 (m, 2H), 6.61 (d, J=8.6 Hz, 2H), 6.15 (d, J=8.6 Hz, 2H), 5.05 (dd, J=5.1, 13.2 Hz, 1H), 4.36 - 4.27 (m, 2H), 4.24 - 4.18 (m, 1H), 3.70 (br d, J=13.2 Hz, 1H), 3.55 (br s, 2H), 3.30 (br s, 4H), 2.97 - 2.84 (m, 1H), 2.73 - 2.52 (m, 8H), 2.50 - 2.49 (m, 1H), 2.44 - 2.18 (m, 3H), 2.01 - 1.92 (m, 1H), 1.80 - 1.62 (m, 3H), 1.24 - 1.09 (m, 2H).

EXAMPLE 50. Preparation of (I-292) 1-(4-(2-((1-(4-((1R,2S)-4,4-difluoro-6-hydroxy- 2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperidin- 4-yl)methyl)-2,8- diazaspiro[4.5]decan-8-yl)phenyl)dihydropyrimidine-2,4(1H,3H )-dione Step 1: To a solution of (5R,6S)-5-(4-(4-(dimethoxymethyl)piperidin-1-yl)phenyl)-8,8- difluoro- 6- phenyl-5,6,7,8-tetrahydronaphthalen-2-ol (50.0 mg, 101 ^molˈ1.0 eq.) in DCM (3 mL) was added TFA (173 mg, 117 ^L, 15 eq., 1.52 mmol). The mixture was stirred at 20 °C for 30 min. LCMS showed the reaction was completed. The mixture was concentrated in vacuum to give crude product. No further purification as it is used for the next step directly. LC-MS (ESI ⁺ ) m/z: 448.3 (M+H) ⁺ . Step 2: To a solution of 1-(4-((1R,2S)-4,4-difluoro-6-hydroxy-2-phenyl-1,2,3,4- tetrahydronaphthalen -1-yl)phenyl)piperidine-4-carbaldehyde (35.0 mg, 78.2 ^mol, 1.0eq.) and 1-(4-(2,8-diazaspiro [4.5]decan-8-yl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione (28.3 mg, 86.0 ^mol, 1.1 eq.) in DCE (3 mL) and MeOH (1 mL) was added Sodium triacetoxyborohydride (497 mg 235 ^mol 30 eq) The mixture was stirred at 20 °C for 2 h LC MS showed the reaction was completed. The crude was purified by prep-HPLC together (Boston Green ODS 150*30mm*5um, water(FA)-ACN as a mobile phase, from 13% to 43%, Gradient Time (min): 14, Flow Rate (ml/min): 25) to give 1-(4-(2-((1-(4-((1R,2S)-4,4-difluoro-6-hydroxy-2- phenyl- 1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperidin-4-yl)meth yl)-2,8-diazaspiro[4.5]decan-8- yl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione (14.9 mg, 19.6 ^mol, 25.1 % yield) as a white solid. LC-MS (ESI ⁺ ) m/z: 760.4 (M+H) ⁺ . LCMS: calc. for C ₄₆ H ₅₁ F ₂ N ₅ O ₃ :759.94, found: [M+H] ⁺ 760.4 HPLC: 100.00% purity at 220 nm. ¹ H NMR (400 MHz, DMSO-d ₄ ) į: ppm 10.25 (s, 1 H), 9.66 - 9.77 (m, 1 H), 8.16 (s, 1 H), 7.15 - 7.23 (m, 3 H), 7.12 (d, J=8.80 Hz, 2 H), 7.08 (s, 1 H), 6.83 - 6.94 (m, 6 H), 6.55 (d, J=8.40 Hz, 2 H), 6.12 (d, J=8.40 Hz, 2 H), 4.79 - 4.79 (m, 1 H), 4.30 (d, J=2.40 Hz, 1 H), 3.63 - 3.71 (m, 3 H), 3.47 - 3.55 (m, 2 H), 3.27 - 3.31 (m, 4 H), 3.04 - 3.17 (m, 4 H), 2.67 (t, J=6.40 Hz, 3 H), 2.34 (d, J=14.40 Hz, 3 H), 2.25 (d, J=7.20 Hz, 2 H), 1.73 (d, J=12.80 Hz, 2 H), 1.45 - 1.67 (m, 7 H), 1.05 - 1.19 (m, 2 H). EXAMPLE 51. Preparation of (I-281) 3-(4-((S)-7-((1-(4-((1R,2S)-4,4-difluoro-6- hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)pi peridin-4-yl)methyl)-2,7- diazaspiro[4.4]nonan-2-yl)phenyl)piperidine-2,6-dione Step 1: To a solution of compound 1 (20.00 mg, 57.17 ^mol, 1.0 eq, HCl) in MeOH (1 mL) and DCM (2 ml) was added compound 2 (12.79 mg, 28.58 ^mol, 0.5 eq.) at 25 °C. After addition, the mixture was stirred at this temperature for 0.5 hr, and then NaBH ₃ (OAc) ₃ (12.12 mg, 57.17 ^mol, 1.0 eq.) was added at 25 °C. The resulting mixture was stirred at 25 °C for 0.5 hr. The reaction mixture was concentrated to yield a residue. The residue was purified by preparative HPLC (column: Boston Green ODS 150 x 30 mm x 5 ^m; mobile phase: [water (FA)-ACN]; B%: 17%-47%, 14min.), followed by lyophilization to yield I-281 (22.8 mg, 30.61 ^mol, 53.54% yield.) was obtained as a white solid. LC-MS (ESI+) m/z: 745.4 [M+H] ⁺ . LCMS: calc. for C ₄₆ H ₅₀ F ₂ N ₄ O ₃ : 744.93, found: [M+H] ⁺ 745.4. HPLC: 100 % purity at 220 nm NMR (400 MHz, DMSO-d6) į ppm 10.74 (s, 1 H), 9.63 - 9.86 (m, 1 H), 8.16 (s, 1 H), 7.17 - 7.23 (m, 3 H), 7.07 (s, 1 H), 6.97 (d, J=8.58 Hz, 2 H), 6.83 - 6.91 (m, 4 H), 6.55 (d, J=8.70 Hz, 2 H), 6.44 (d, J=8.70 Hz, 2 H), 6.12 (d, J=8.58 Hz, 2 H), 4.29 - 4.34 (m, 1 H), 3.67 (br dd, J=10.43, 4.95 Hz, 2 H), 3.51 (br d, J=11.68 Hz, 2 H), 3.44 - 3.47 (m, 1 H), 3.42 (br d, J=7.03 Hz, 2 H), 3.09 - 3.24 (m, 4 H), 2.57 - 2.67 (m, 3 H), 2.38 - 2.45 (m, 2 H), 2.26 (br d, J=6.91 Hz, 2 H), 2.05 - 2.14 (m, 1 H), 1.97 - 2.03 (m, 1 H), 1.85 - 1.96 (m, 2 H), 1.69 - 1.79 (m, 4 H), 1.45 - 1.56 (m, 1 H), 1.01 - 1.16 (m, 4 H).

EXAMPLE 52. Preparation of (I-282) 3-(4-((R*)-7-((1-(4-((1R,2S)-4,4-difluoro-6- hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)pi peridin-4-yl)methyl)-2,7- diazaspiro[4.4]nonan-2-yl)phenyl)piperidine-2,6-dione Step 1: To a solution of (5R,6S)-5-(4-(4-(dimethoxymethyl)piperidin-1-yl)phenyl)-8,8- difluoro- 6- phenyl-5,6,7,8-tetrahydronaphthalen-2-ol (50 mg, 1 eq., 0.10 mmol) in THF (3 mL) was added H ₂ SO ₄ (0.09 g, 0.05 mL, 9 eq., 0.9 mmol) and water (0.5 mL). The mixture was stirred at 40 °C for 0.5 h. The reaction mixture was quenched by addition of water (10 mL), adjust pH to 8 by NaHCO ₃ saturated solution, extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (10 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give 1-(4-((1R,2S)-4,4-difluoro-6-hydroxy-2-phenyl -1,2,3,4- tetrahydronaphthalen-1-yl)phenyl)piperidine-4-carbaldehyde (40 mg, 89 ^mol, 88 % yield) as a yellow solid. LC-MS (ESI ⁺ ) m/z: 448.2 (M+H) ⁺ . Step 2: To a solution of 1-(4-((1R,2S)-4,4-difluoro-6-hydroxy-2-phenyl-1,2,3,4- tetrahydronaphthalen -1-yl)phenyl)piperidine-4-carbaldehyde (40.0 mg, 89.4 ^mol, 1.0 eq.) and 3-(4-((R)-2,7- diazaspiro[4.4]nonan-2-yl)phenyl)piperidine-2,6-dione (33.6 mg, 107 ^mol, 1.2 eq.) in DCE (3 mL) and MeOH (3 mL) was added Sodium triacetoxyborohydride (75.8 mg, 358 ^mol, 4.0 eq.). The mixture was stirred at 20 °C for 2 hour. LCMS showed the reaction was completed. The crude was purified by prep-HPLC together (Phenomenex Gemini NX 150×30mm,5^m, water(water(NH ₄ HCO ₃ )-ACN) as a mobile phase, from 60% to 90%, Gradient Time (min): 11, Flow Rate (ml/min): 25) to give 3-(4-((R)-7-((1-(4-((1R,2S)-4,4- difluoro-6- hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)pi peridin-4-yl)methyl)-2,7- diazaspiro[4.4]nonan-2-yl)phenyl)piperidine-2,6-dione (27.6 mg, 37.1 ^mol, 41.5 %) as a white solid. LC-MS (ESI ⁺ ) m/z: 745.4 (M+H) ⁺ . LCMS: calc. for C ₄₆ H ₅₀ F ₂ N ₄ O ₃ :744.93, found: [M+H] ⁺ 745.4 HPLC: 100.00% purity at 220 nm. ¹ H NMR (400 MHz, METHANOL-d ₄ ) į: ppm 7.11 - 7.19 (m, 4 H), 7.03 (d, J=8.40 Hz, 2 H), 6.80 - 6.89 (m, 4 H), 6.63 (d, J=8.80 Hz, 2 H), 6.52 (d, J=8.40 Hz, 2 H), 6.24 (d, J=8.80 Hz, 2 H), 4.29 (d, J=2.80 Hz, 1 H), 3.64 - 3.75 (m, 2 H), 3.48 - 3.56 (m, 2 H), 3.34 (s, 2 H), 3.27 (d, J=9.40 Hz, 1 H),3.15 - 3.21 (m, 1 H), 2.68 (s, 1 H), 2.61 - 2.67 (m, 3 H), 2.49 - 2.60 (m, 4 H), 2.34 - 2.44 (m, 2 H), 2.23 - 2.32 (m, 1 H), 2.13 - 2.20 (m, 2 H), 1.95 - 2.06 (m, 2 H), 1.80 - 1.91 (m, 4 H), 1.54 - 1.64 (m, 1 H), 1.25 - 1.33 (m, 2 H). EXAMPLE 53. Preparation of (I-277) (S)-3-(5-(4-((1-(4-((1R,2S)-4,4-difluoro-6- hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)pi peridin-4-

yl)methyl)piperazin-1-yl)-3-methyl-2-oxo-2,3-dihydro-1H-b enzo[d]imidazol-1- yl)piperidine-2,6-dione Step 1: To a solution of compound 1 (90.0 mg, 237 ^mol, 1.0 eq.) in MeOH (2 mL) and DCE (3 mL) was added compound 2 (53.0 mg, 118 ^mol, 0.5 eq.) at 25 °C. After addition, the mixture was stirred at this temperature for 0.5 hr, and then NaBH3(OAc)3 (151.00 mg, 105 ^L, 711 ^mol, 3.0 eq.) was added at 25 °C. The resulting mixture was stirred at 25 °C for 1 hr. The reaction mixture was concentrated to yield a residue. The residue was purified by preparative HPLC (column: Boston Green ODS 150 x 30 mm x 5 ^m; mobile phase: [water (FA)-ACN]; B%: 13%- 43%, 11 min.), followed by lyophilization to yield I-277 (46.1 mg, 59.5 ^mol, 25.1 %) was obtained as a white solid. LC-MS (ESI+) m/z: 775.3 [M+H] ⁺ . LCMS: calc. for C ₄₅ H ₄₈ : 774.91, found: [M+H] ⁺ 775.3 HPLC: 100 % purity at 220 nm. ¹ H NMR (400 MHz, DMSO-d ₆ ) į ppm 11.05 (s, 1 H), 9.64 - 9.80 (m, 1 H), 8.15 (s, 1 H), 7.18 - 7.24 (m, 3 H), 7.08 (s, 1 H), 6.83 - 6.94 (m, 6 H), 6.55 - 6.63 (m, 3 H), 6.13 (d, J=8.58 Hz, 2 H), 5.28 (dd, J=12.64, 5.25 Hz, 1 H), 4.31 (br d, J=3.58 Hz, 1 H), 3.46 - 3.71 (m, 4 H), 3.30 (br s, 5 H), 3.08 (br s, 4 H), 2.84 - 2.93 (m, 1 H), 2.52 - 2.74 (m, 6 H), 2.34 (br d, J=13.59 Hz, 1 H), 2.19 (br d, J=7.15 Hz, 2 H), 1.94 - 2.02 (m, 1 H), 1.57 - 1.77 (m, 3 H), 1.09 - 1.20 (m, 2 H). EXAMPLE 54. Preparation of (I-278) (R)-3-(5-(4-((1-(4-((1R,2S)-4,4-difluoro-6- hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)pi peridin-4- yl)methyl)piperazin-1-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benz o[d]imidazol-1- yl)piperidine-2,6-dione Step 1: To a mixture of compound 1 (80 mg, 0.18 mmol, 1 eq) in DCM (3 mL) was added HCl/dioxane (3 mL) at 25 °C. The mixture was stirred at 25 °C for 1 h. LCMS (RLN-NB-2491- 8-R1A1) showed the reaction was completed. The reaction mixture was concentrated to give compound 2 (60 mg, 80% purity, 77% yield) as a yellow solid, which was used to next step directly. LC-MS (ESI ⁺ ) m/z: 344.2 (M+H) ⁺ . Step 2: To a mixture of compound 2 (50 mg, 0.15 mmol, 1 eq) in MeOH (3 mL) and DCE (3 mL) was added compound 3 (46 mg, 0.10 mmol, 0.7 eq) and NaBH(OAc)3 (62 mg, 0.29 mmol, 2 eq) at 25 °C. The mixture was stirred at 25 °C for 1 h. LCMS (RLN-NB-2491-10-R1A) showed the reaction was completed. The reaction mixture was concentrated to give a crude, which was purified by prep-HPLC (Column: Boston Green ODS 150 × 30 mm x 5 ^m; Condition: water(FA)-ACN; Begin B: 13; End B: 43; Gradient Time(min): 12; 100% B Hold Time(min): 2; Flow Rate(mL/min): 25; injections: 8.) to give I-278 (41.0 mg, 36% yield) as a white solid. LC- MS (ESI ⁺ ) m/z: 775.5 (M+H) ⁺ . LCMS: calc. for C ₄₅ H ₄₈ F ₂ N ₆ O ₄ : 774.91, found: [M+H] ⁺ 775.5. HPLC: 100% purity at 220 nm. ¹ H NMR: ¹ H NMR (400 MHz, DMSO-d ₆ ) į = 11.06 (s, 1H), 9.77 - 9.68 (m, 1H), 8.16 (s, 1H), 7.24 - 7.17 (m, 3H), 7.09 (s, 1H), 6.95 - 6.83 (m, 6H), 6.64 - 6.55 (m, 3H), 6.14 (d, J = 8.7 Hz, 2H), 5.34 - 5.24 (m, 1H), 4.31 (br d, J = 3.2 Hz, 1H), 3.70 - 3.63 (m, 1H), 3.57 - 3.50 (m, 2H), 3.30 (br s, 7H), 3.08 (br s, 4H), 2.95 - 2.85 (m, 1H), 2.75 - 2.56 (m, 4H), 2.47 - 2.26 (m, 2H), 2.20 (br d, J = 7.2 Hz, 2H), 2.03 - 1.95 (m, 1H), 1.80 - 1.71 (m, 2H), 1.68 - 1.58 (m, 1H), 1.21 - 1.09 (m, 2H).

EXAMPLE 55. Preparation of (I-289) 1-(4-((R)-7-((1-(4-((1R,2S)-4,4-difluoro-6- hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)pi peridin-4-yl)methyl)-2,7- diazaspiro[4.4]nonan-2-yl)phenyl)dihydropyrimidine-2,4(1H,3H )-dione Step 1: To a mixture of compound 1 (100 mg, 241 ^mol, 1 eq) in DCM (4 mL) was added HCl/dioxane (4 mL) at 25 °C. The mixture was stirred at 25 °C for 1 h. LCMS (RLN-NB-2491- 13-R1B) showed the reaction was completed. The reaction mixture was concentrated to give compound 2 (70 mg, 92% yield) as a yellow solid. LC-MS (ESI ⁺ ) m/z: 315.1 (M+H) ⁺ . Step 2: To a mixture of compound 2 (70 mg, 0.22 mmol, 2 eq) in MeOH (3 mL) and DCE (3 mL) was added compound 3 (50 mg, 0.11 mmol, 1 eq) and NaBH(OAc) ₃ (71 mg, 0.34 mmol, 3 eq) at 25 °C. The mixture was stirred at 25 °C for 1 h. LCMS (RLN-NB-2491-14-R1A) showed the reaction was completed. The reaction mixture was concentrated to give a crude, which was ifi d b HPLC (C l Ph G i i NX 150 30 5 ^ C diti water(NH4HCO3)-ACN; Begin B: 65; End B: 95; Gradient Time(min): 11; 100% B Hold Time(min): 2; Flow Rate(mL/min): 25; injections: 1.) to give I-289 (17.9 mg, 21% yield) as a white solid. LC-MS (ESI ⁺ ) m/z: 746.3 (M+H) ⁺ . LCMS: calc. for C ₄₅ H ₄₉ F ₂ N ₅ O ₃ : 745.92, found: [M+H] ⁺ 746.3. HPLC: 99.33% purity at 220 nm. 7.20 - 7.12 (m, 6H), 6.91 - 6.83 (m, 4H), 6.65 (d, J = 8.7 Hz, 2H), 6.57 (d, J = 8.9 Hz, 2H), 6.26 (d, J = 8.7 Hz, 2H), 4.31 (br d, J = 3.1 Hz, 1H), 3.79 (t, J = 6.8 Hz, 2H), 3.74 - 3.67 (m, 1H), 3.58 - 3.52 (m, 2H), 3.38 - 3.35 (m, 2H), 3.25 - 3.21 (m, 1H), 2.80 (t, J = 6.7 Hz, 3H), 2.75 - 2.63 (m, 3H), 2.61 - 2.53 (m, 3H), 2.46 - 2.27 (m, 3H), 2.09 - 2.00 (m, 2H), 1.92 - 1.84 (m, 4H), 1.67 - 1.58 (m, 1H), 1.41 - 1.24 (m, 3H). EXAMPLE 56. Preparation of (I-227) (S)-3-(5-(4-((1-(4-((1R,2R)-2-((S)-1- cyclopropylethyl)-4,4-difluoro-6-hydroxy-1,2,3,4-tetrahydron aphthalen-1- yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindo lin-2-yl)piperidine-2,6-dione and (I-228) (S)-3-(5-(4-((1-(4-((1R,2R)-2-((R)-1-cyclopropylethyl)-4,4-d ifluoro-6-hydroxy-

1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperidin-4-yl)m ethyl)piperazin-1-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione Step 1: To a solution of 1-(4-bromophenyl)-4-(dimethoxymethyl)piperidine (1.5g, 4.774 mmol, 1.0 eq.) in THF (25 mL) was added dropwise n-butyllithium (2.3 mL, 5.728 mmol.1.2 eq.) at - 70 °C over 1 hour. After addition, the mixture was stirred at this temperature for 1 hour, and then 6-(benzyloxy)-4,4-difluoro-3,4-dihydronaphthalen-1(2H)-one (1.651 g, 5.728 mmol, 1.2 eq.) in THF (25 mL) was added dropwise at 0 °C. The resulting mixture was stirred at 0°C for 12 hour. LCMS showed the reaction was completed. The reaction mixture was quenched by addition NH ₄ Cl at 20 °C, and then diluted with water 30 mL and extracted with EA 90 mL (30 mL x 3). The combined organic layers were washed with EA 30 mL (10 mL x 3), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The crude material was purified on silica gel column chromatography (from pure PE to PE/EtOAc = 5/1) to give Compound 3 (1.5 g, 2.9 mmol, 60 % yield) as a brown solid. LC-MS (ESI ⁺ ) m/z: 524.2 (M+H) ⁺ Step 2: To a solution of 6-(benzyloxy)-1-(4-(4-(dimethoxymethyl)piperidin-1-yl)phenyl )-4,4- difluoro -1,2,3,4-tetrahydronaphthalen-1-ol (1.5 g, 1 eq., 2.9 mmol) in DCM (15 mL) was added into HCl/MeOH (15 mL, 4 M) at room temperature. The mixture was stirred at 20 °C for 1 hour. LCMS showed the reaction was completed. The reaction mixture was quenched by addition NaHCO ₃ at 20 °C, and then diluted with water 30 mL and extracted with EA 90 mL (30 mL x 3). The combined organic layers were washed with EA 30 mL (10 mL x 3), dried over Na2SO4, filtered and concentrated under reduced pressure to give 1-(4-(6-(benzyloxy)-4,4- difluoro-3,4-dihydronaphthalen-1-yl)phenyl)-4-(dimethoxymeth yl)piperidine (1.2 g, 2.1 mmol, 75 % yield, 90% Purity) as a brown solid. LC-MS (ESI ⁺ ) m/z: 506.2 (M+H) ⁺ Step 3: To a solution of 1-(4-(6-(benzyloxy)-4,4-difluoro-3,4-dihydronaphthalen-1-yl) phenyl)-4- (dimethoxymethyl)piperidine (1.20 g, 2.37 mmol, 1.0 eq.) in DCM (20 mL) was added Pyridinium bromide perbromide (0.77 g, 2.37 mmol, 1.0 eq.). The mixture was stirred at 20 °C for 1 hour. LCMS showed the reaction was completed. The reaction mixture was quenched by addition water 30 mL at 20 °C, and then diluted with water 30 mL and extracted with DCM 90 mL (30 mL x 3). The combined organic layers were washed with DCM 30 mL (10 mL x 3), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The crude material was purified on silica gel column chromatography (from pure PE to PE/EtOAc = 5/1) to give Compound 5 (1.06 g, 1.86 mmol, 78 % yield) as a yellow solid. LC-MS (ESI ⁺ ) m/z: 586.2 (M+H) ⁺ Step 4: A mixture of 1-(4-(6-(benzyloxy)-2-bromo-4,4-difluoro-3,4-dihydronaphthal en-1- yl)phenyl)- 4-(dimethoxymethyl)piperidine (1.30 g, 2.22 mmol, 1.0 eq.), 2-(1-cyclopropylvinyl)- 4,4,5,5- tetramethyl-1,3,2-dioxaborolane (475 mg, 2.45 mmol, 1.1 eq.), PdCl ₂ (dppf) (163 mg, 222 ^mol, 0.1 eq.) and K ₂ CO ₃ (922 mg, 6.67 mmol, 3.0 eq.) in Dioxane (16 mL) and water (4 mL) was degassed and purged with N ₂ for 3 times, and then the mixture was stirred at 90 °C for 2 hour under N ₂ atmosphere. LC-MS showed the reaction was completed. The reaction mixture was quenched by addition EA 10 mL at 20 °C, and then diluted with water 10 mL and extracted with EA 90 mL (30 mL x 3). The combined organic layers were washed with EA 15 mL (5 mL x 3), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The crude material was purified on silica gel column chromatography (from pure PE to PE/EtOAc = 4/1) to give 1-(4-(6-(benzyloxy)-2- (1-cyclopropylvinyl)-4,4-difluoro-3,4-dihydronaphthalen-1- yl)phenyl)-4-(dimethoxymethyl)piperidine (300 mg, 0.47 mmol, 21 % yield, 90% Purity) as a red solid. LC-MS (ESI ⁺ ) m/z: 572.4 (M+H) ⁺ Step 5: To a solution of Compound 7 (0.300 g, 525 ^mol, 1.0 eq.) in THF (3 mL) and MeOH (3 mL) was added Pd/C (27.9 mg, 262 ^mol, 0.5 eq.) and Pd(OH)2 (36.8 mg, 0.5 eq., 262 ^mol) under N ₂ atmosphere. The suspension was degassed and purged with H ₂ for 3 times. The mixture was stirred under H ₂ (15 Psi) at 40 °C for 5 hour. LCMS showed the reaction was completed. The crude was purified by prep.HPLC together (Boston Green ODS 150*30mm*5um, water(FA)-ACN as a mobile phase, from 75% to 100%, Gradient Time (min): 11, Flow Rate (ml/min): 25) to give 6-(1-cyclopropylethyl)-5-(4-(4-(dimethoxymethyl) piperidin-1-yl)phenyl)-8,8-difluoro-5,6,7,8-tetrahydronaphth alen-2-ol (60 mg, 0.12 mmol, 23 % yield) as a white solid. LC-MS (ESI ⁺ ) m/z: 486.2 (M+H) ⁺ Step 6: The compound 8 (90 mg, 0.19 mmol, 1.0 eq.) was purified by SFC (Column: DAICEL CHIRALCEL OJ (250mm*30mm,10um); Mobile phase:CO ₂ -EtOH(0.1%NH ₃ H ₂ O); from 20% to 20%; Flow rate: 70 mL/min) to give Compound 9 (45 mg, 93 ^mol, 50 % yield) and Compound 9A (45 mg, 93 ^mol, 50 % yield) both as white solid. Compound 9: LC-MS (ESI+) m/z: 486.2(M+H)+ Compound 9A: LC-MS (ESI+) m/z: 486.2(M+H)+ Step 7: To a solution of Compound 9 (15 mg, 1 eq., 31 ^mol) in THF (3 mL) was added H ₂ SO ₄ (92 mg, 50 ^L, 30 eq., 0.94 mmol) and water (0.5 mL). The mixture was stirred at 40 °C for 20 min. LCMS showed the reaction was completed. The mixture neutralized with 1N NaHCO ₃ to pH = 8. The mixture was extracted with EtOAc (15 mL x 3). The combined organic layers were washed with brine (15 mL), dried over Na ₂ SO ₄ , filtered and concentrated to give Compound 10 (10 mg, 21 ^mol, 67 %) as a white solid. LC-MS (ESI+) m/z: 440.3(M+H)+ Step 8: To a solution of Compound 9A (15 mg, 1 eq., 31 ^mol) in THF (3 mL) was added H ₂ SO ₄ (92 mg, 50 ^L, 30 eq., 0.94 mmol) and water (0.5 mL). The mixture was stirred at 40 °C for 20 min. LCMS showed the reaction was completed. The mixture neutralized with 1N NaHCO3 to pH = 8. The mixture was extracted with EtOAc (15 mL x 3). The combined organic layers were washed with brine (15 mL), dried over Na ₂ SO ₄ , filtered and concentrated to give Compound 10A (10 mg, 21 ^mol, 67 %) as a white solid. LC-MS (ESI+) m/z: 440.3(M+H)+ Step 9: To a solution of Compound 10 (10.00 mg, 22.75 ^mol, 1.0 eq.) and (S)-3-(1-oxo-5- (piperazin-1-yl)isoindolin-2-yl)piperidine-2,6-dione (7.471 mg, 22.75 ^mol, 1.0 eq.) in DCE (3 mL) and MeOH (3 mL) was added Sodium triacetoxyborohydride (14.47 mg, 68.25 ^mol, 3.0 eq.). The mixture was stirred at 20 °C for 2 hour. LCMS showed the reaction was completed. The crude was purified by prep-HPLC together (Phenomenex Gemini NX 150×30mm, 5^m, water (NH ₄ HCO ₃ )-ACN) as a mobile phase, from 60% to 90%, Gradient Time (min): 11, Flow Rate (ml/min): 25) to give I-227 (6.00 mg, 7.98 ^mol, 35.1 %) as a white solid. LC-MS (ESI+) m/z: 752.4(M+H) ⁺ LCMS: calc. for C ₄₄ H ₅₁ F ₂ N ₅ O ₄ :751.92, found: [M+H] ⁺ 752.4 HPLC: 9769% purity at 220 nm ¹ H NMR (400 MHz, METHANOL-d4) į: ppm 7.64 (d, J=8.80 Hz, 1 H), 7.05 - 7.11 (m, 5 H), 7.00 (d, J=9.60 Hz, 2 H), 6.68 (m, 1 H), 6.52 (d, J=8.40 Hz, 1 H), 5.10 (m, 1 H), 4.41 (d, J=6.40 Hz, 2 H), 3.73 - 3.78 (m, 2 H), 3.37 - 3.41 (m, 4 H), 2.81 - 2.95 (m, 2 H), 2.76 - 2.81 (m, 3 H), 2.62 - 2.66 (m, 4 H), 2.41 - 2.56 (m, 2 H), 2.35 (d, J=6.80 Hz, 2 H), 2.13 - 2.19 (m, 1 H), 1.96 (d, J=12.80 Hz, 2 H), 1.76 - 1.84 (m, 1 H), 1.37 - 1.45 (m, 3 H), 1.22 - 1.30 (m, 2 H), 1.09 - 1.16 (m, 1 H), 0.96 - 0.99 (m, 3 H), 0.78 (t, J=7.20 Hz, 4 H). Step 10: To a solution of Compound 10A (10 mg, 23 ^mol, 1.0 eq.) and (S)-3-(1-oxo-5- (piperazin-1 -yl)isoindolin-2-yl)piperidine-2,6-dione (8.2 mg, 25 ^mol, 1.1 eq.) in DCE (3 mL) and MeOH (3 mL) was added Sodium triacetoxyborohydride (14 mg, 68 ^mol, 3.0 eq.). The mixture was stirred at 20 °C for 2 hour. LCMS showed the reaction was completed. The crude was purified by prep-HPLC together (Phenomenex Gemini NX 150×30mm,5^m, water(water( NH ₄ HCO ₃ )-ACN) as a mobile phase, from 60% to 90%, Gradient Time (min): 11, Flow Rate (ml/min): 25) to give I-228 (8.2 mg, 11 ^mol, 48 %) as a white solid. LC-MS (ESI+) m/z: 752.4(M+H) ⁺ LCMS: calc. for C44H51F2N5O4:751.92, found: [M+H] ⁺ 752.4 HPLC: 100.00% purity at 220 nm. ¹ H NMR (400 MHz, METHANOL-d ₄ ) į: ppm 7.66 (d, J=8.40 Hz, 1 H), 7.07 - 7.13 (m, 5 H), 6.98 - 7.03 (m, 2 H), 6.70 (m, 1 H), 6.54 (d, J=8.40 Hz, 1 H), 5.12 (m, 1 H), 4.43 (d, J=6.00 Hz, 2 H), 3.77 (d, J=10.40 Hz, 2 H), 3.39 - 3.43 (m, 4 H), 2.84 - 2.94 (m, 2 H), 2.78 - 2.82 (m, 3 H), 2.67 (s, 1 H), 2.45 - 2.57 (m, 2 H), 2.38 (d, J=6.80 Hz, 2 H), 2.14 - 2.20 (m, 1 H), 1.98 (d, J=12.40 Hz, 2 H), 1.78 - 1.85 (m, 1 H), 1.40 - 1.48 (m, 3 H), 1.21 - 1.28 (m, 2 H), 1.10 - 1.17 (m, 1 H), 0.97 - 1.01 (m, 3 H), 0.74 - 0.94 (m, 4 H). EXAMPLE 57. Preparation of (I-297) 3-(6-(4-((1-(4-((1R,2S)-4,4-difluoro-6-hydroxy- 2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperidin- 4-yl)methyl)piperazin-1-yl)- 1-methyl-1H-indazol-3-yl)piperidine-2,6-dione and (I-298) 3-(6-(4-((1-(4-((1R,2S)-4,4- difluoro-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-y l)phenyl)piperidin-4- yl)methyl)piperazin-1-yl)-1-methyl-1H-indazol-3-yl)piperidin e-2,6-dione Step 1: A mixture of compound 1A (873.00 mg, 1.77 mmol, 1.0 eq.), compound 4C (215.31 mg, 1.77 mmol, 1.0 eq.), K ₂ CO ₃ (488.11 mg, 3.53 mmol, 2.0 eq.) and Pd(dppf)Cl ₂ (115.09 mg, 176.59 ^mol, 0.1 eq.) in dioxane (8 mL) and H2O (2 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 80 °C for 0.5 hr under N ₂ atmosphere. LCMS showed that the starting material was consumed and the desired product was detected. The residue was purified by prep-HPLC (column: Boston Prime C18150 x 30 mm x 5 ^m; mobile phase: water (NH4HCO3)-ACN; B%: 85%-100%, 10 min) to afford compound 1B (600.00 mg, 1.22 mmol, 69.12% yield) as a white solid. LC-MS (ESI+) m/z: 582.2(M+H) ⁺ . Step 2: To a solution of compound 1B (1.5 g, 2.58 mmol, 1.0 eq.) in MeOH (3 ml) and THF (3 ml) was added Pd/C (1.37 g, 1.29 mmol, 10% purity, 0.5 eq.). The mixture was stirred under H ₂ at 25 °C and 15 Psi for 4 hr. LCMS showed that the starting material was consumed and the desired product was detected. The reaction mixture was filtered under reduced pressure to give residue. The residue was purified by prep-HPLC (column: Boston Green ODS 150 x 30 mm x 5 ^m; mobile phase: [water (TFA)-ACN]; B%: 50%-80%, 12 min.) to give compound 1C (1.00 g, 2.03 mmol, 78.57 % yield) was obtained as a white solid. LC-MS (ESI+) m/z: 494.5(M+H) ⁺ . Step 3: Compound 1C (840.00 mg) was separated by chiral SFC (Column: DAICEL CHIRALPAK AD (250 mm x 30 mm, 10 ^m), Condition: CO2-EtOH (0.1% NH3H2O), Begin B 30%, End B 30%, Flow Rate (ml/min): 70.) to give compound 1D (401.00 mg, 547.02 ^mol, 45.00% yield). LC-MS (ESI+) m/z: 494.3(M+H) ⁺ . Step 4: To a solution of compound 1D (80.00 mg, 0.16 mmol, 1.0 eq.) in THF (2 mL) was added H ₂ SO ₄ (0.37 g, 0.20 mL, 10% Wt, 0.37 mmol, 2.3 eq.). The mixture was stirred at 25 °C for 0.5 hr. LCMS showed that the starting material was consumed and the desired product was detected. The reaction liquid is dried with N ₂ at 0 °C to give compound 1 (65.00 mg, 0.15 mmol.) was obtained as yellow oil which was used in the next step without further purification. LC-MS (ESI+) m/z: 448.2 (M+H) ⁺ . Step 5: To a solution of compound 1 (100.00 mg, 275 ^mol, 1.0 eq.) in MeOH (3 mL) and DCE (3 ml) was added compound 2 (61.5 mg, 137 ^mol, 0.5 eq.) at 25 °C. After addition, the mixture was stirred at this temperature for 0.5 hr, and then NaBH ₃ (OAc) ₃ (58.2 mg, 40.7 ^L, 275 ^mol, 1.0 eq.) was added at 25 °C. The resulting mixture was stirred at 25 °C for 3 hr. The reaction mixture was concentrated to yield a residue. The residue was purified by preparative HPLC 45%, 12 min.), followed by lyophilization to yield compound 3 (120.00 mg, 158 ^mol, 57.5 %) was obtained as a white solid. LC-MS (ESI+) m/z: 759.3 [M+H] ⁺ . Step 6: Compound 3 (120.0 mg, 158.0 ^mol, 1.0 eq.) was separated by chiral SFC (Column: DAICEL CHIRALPAK ID (250 mm x 30 mm,10 ^m), Condition: MeOH-ACN Begin B 50% End B 50%, Begin B 25%, End B 25%, Flow Rate (mL/min): 80) to give I-297 (25.1 mg, 33.1 ^mol, 20.9 %) as a white solid and I-298 (23.1 mg, 30.4 ^mol, 19.3 %)as a white sold. I-297: LC-MS (ESI+) m/z: 759.3(M+H) ⁺ . LCMS: calc. for C ₄₅ H ₄₈ F ₂ N ₆ O ₃ : 758.91, found: [M+H] ⁺ 759.3. HPLC: 100 % purity at 220 nm ¹ H NMR (400 MHz, DMSO-d ₆ ) į ppm 10.86 (s, 1 H), 9.73 (s, 1 H), 7.50 (d, J=8.94 Hz, 1 H), 7.18 - 7.24 (m, 3 H), 7.09 (s, 1 H), 6.83 - 6.93 (m, 6 H), 6.57 (d, J=8.70 Hz, 2 H), 6.14 (d, J=8.70 Hz, 2 H), 4.31 (br d, J=2.98 Hz, 1 H), 4.26 (dd, J=9.18, 5.13 Hz, 1 H), 3.89 (s, 3 H), 3.67 (br d, J=13.83 Hz, 1 H), 3.50 - 3.58 (m, 2 H), 3.18 - 3.32 (m, 5 H), 2.52 - 2.70 (m, 6 H), 2.10 - 2.37 (m, 6 H), 1.76 (br d, J=12.52 Hz, 2 H), 1.61 - 1.70 (m, 1 H), 1.07 - 1.28 (m, 3 H). I-298: LC-MS (ESI+) m/z: 759.3(M+H) ⁺ . LCMS: calc. for C ₄₅ H ₄₈ F ₂ N ₆ O ₃ : 758.91, found: [M+H] ⁺ 759.3. HPLC: 100 % purity at 220 nm ¹ H NMR (400 MHz, DMSO-d ₆ ) į ppm 10.85 (s, 1 H), 9.73 (s, 1 H), 7.49 (d, J=8.94 Hz, 1 H), 7.17 - 7.22 (m, 3 H), 7.08 (s, 1 H), 6.83 - 6.92 (m, 6 H), 6.57 (d, J=8.58 Hz, 2 H), 6.13 (d, J=8.58 Hz, 2 H), 4.30 (br d, J=3.93 Hz, 1 H), 4.25 (dd, J=9.18, 5.13 Hz, 1 H), 3.88 (s, 3 H), 3.63 - 3.69 (m, 1 H), 3.50 - 3.56 (m, 2 H), 3.21 (br s, 5 H), 2.53 - 2.69 (m, 6 H), 2.10 - 2.37 (m, 6 H), 1.75 (br d, J=12.52 Hz, 2 H), 1.59 - 1.69 (m, 1 H), 1.09 - 1.26 (m, 3 H).

EXAMPLE 58. Preparation of (I-4) (S)-3-(5-(4-((1-(4-((3R,4S)-7-hydroxy-3- phenylisochroman-4-yl)phenyl)piperidin-4-yl)methyl)piperazin -1-yl)-1-oxoisoindolin-2- yl)piperidine-2,6-dione Step 1: To a solution of 2-bromo-5-hydroxybenzoic acid (1 g, 5 mmol,), K ₂ CO ₃ (1 g, 10 mmol,) in DMF (15 mL) was added BnBr (2 g, 10 mmol,). The mixture was stirred at 25 °C for solvent was removed under vacuum. The residue was dissolved in water (30 mL) and extracted with ethyl acetate (2*15 mL). The combined organic layer was dried over Na2SO4, filtered and concentrated under vacuum to give benzyl 5-(benzyloxy)-2-bromobenzoate ˄1.7 g, 90% yield˅as a yellow oil. TLC: petroleum ether: ethyl acetate=5:1, R _f =0.3 Step 2: To a solution of benzyl 5-(benzyloxy)-2-bromobenzoate (1.7 g, 4.3 mmol) in MeOH (15 mL) was added KOH (1.3 mL, 13 mmol). The mixture was stirred at 50 °C for 4 hr.TLC (petroleum ether: ethyl acetate=3:1, R _f =0.3) indicated a new spot formed. The reaction was clean according to TLC. The mixture was dissolved in water (30 mL) and extracted with ethyl acetate (2*30 mL). The combined organic layer was dried over Na ₂ SO ₄ , filtered and concentrated under vacuum to give the compound as a yellow oil. The reaction was purified by flash column (petroleum ether/ethyl acetate from 100/0 to 60/40) and the organic layer was concentrated in vacuo to give 5-(benzyloxy)-2-bromobenzoic acid (1.2 g, 91% yield) as a yellow solid. TLC: petroleum ether: ethyl acetate=3:1, R _f =0.3 Step 3: To a solution of 5-(benzyloxy)-2-bromobenzoic acid (1.2 g, 3.9 mmol) in THF (25 mL) was added dropwise BH ₃ (1 M in THF, 9.8 mL, 9.8 mmol) at 0°C over 30min. After addition, the mixture was stirred at this temperature refluxed at 70 ^o C for 2hr. TLC (petroleum ether: ethyl acetate=3:1, R _f =0.3) indicated a new spot formed. The reaction was clean according to TLC. The reaction mixture was quenched by addition MeOH at 0 °C, and then extracted with EtoAc 30 mL (10 mL * 3). The combined organic layers were dried over Na ₂ SO ₄ , filtered, and concentrated under reduced pressure to give a yellow solid. The reaction was purified by flash column (petroleum ether/ethyl acetate from 100/0 to 60/40) and the organic layer was concentrated in vacuo to give (5-(benzyloxy)-2-bromophenyl)methanol (900 mg, 75% yield) as a white solid. TLC: petroleum ether: ethyl acetate=3:1, Rf =0.3 Step 4: To a mixture of (5-(benzyloxy)-2-bromophenyl)methanol (3 g, 1.0 eq., 0.01 mol), CuI (0.2 g, 0.03 mL, 0.1 eq., 1 mmol) in DMF (20 mL) was added bis-(triphenylphosphino)- palladous chloride (0.7 g, 0.1 eq., 1 mmol), DIEA (4 g, 5 mL, 3 eq., 0.03 mol) and 12 hours under N2. The mixture was added water (50 mL) and extracted with ethyl acetate (2*50 mL). The combined organic layer was dried over Na2SO4, filtered and concentrated under vacuum to give the compound as a yellow oil. The oil was purified by flash column (petroleum ether/ethyl acetate from 100/0 to 60/40) to give (5-(benzyloxy)-2-(phenylethynyl) phenyl) methanol (1.8 g, 4.5 mmol, 77.8% purity) as a yellow solid. LC-MS (ESI ⁺ ) m/z: 315.1 (M+H) ⁺ . Step 5: To a solution of (5-(benzyloxy)-2-(phenylethynyl)phenyl)methanol (500 mg, 1 eq., 1.24 mmol) in MeCN (24 mL) was added sodium bicarbonate (312 mg, 3 Eq, 3.71 mmol) and iodine (942 mg, 3 eq., 3.71 mmol). The mixture was stirred at 25 °C for 12 hours under N ₂ . The mixture was added water (30 mL) and extracted ethyl acetate (2*30 mL). The combined organic layer was dried over Na ₂ SO ₄ , filtered and concentrated under vacuum to give the compound as a yellow oil. The oil was purified by flash column (petroleum ether/ethyl acetate from 100/0 to 90/10) and concentrated in vacuo to give 7-(benzyloxy)-4-iodo-3-phenyl-1H-isochromene (110 mg, 250 ^mol, 20.2% yield) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d6) į = 7.67 - 7.57 (m, 2H), 7.49 - 7.38 (m, 8H), 7.30 - 7.26 (m, 1H), 7.06 - 7.01 (m, 1H), 6.93 - 6.90 (m, 1H), 5.23 - 5.19 (m, 2H), 5.16 - 5.13 (m, 2H) Step 6: A mixture of 1-(4-(6-(benzyloxy)-2-bromo-3,4-dihydronaphthalen-1-yl)pheny l)-4- (dimethoxymethyl) piperidine (600 mg, 1 eq., 1.09 mmol) ,(4-fluorophenyl)boronic acid (168 mg, 1.1 eq., 1.20 mmol) , sodium carbonate (348 mg, 3 eq., 3.28 mmol) ,1,1'-bis(di-t- butylphosphino)ferrocene palladium dichloride (71.3 mg, 0.1 eq., 109 ^mol) in 1,4-dioxane (8 mL) and H ₂ O (2 mL) was degassed and purged with N ₂ for 3 times, and then the mixture was stirred at 80 °C for 12 hour under N ₂ atmosphere. The reaction mixture was quenched by addition 50 mL H ₂ O at 20°C, and extracted with ethyl acetate 50 mL (50 mL * 2). The combined organic layers were washed with brine 50 mL, dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The reaction was purified by flash column (petroleum ether/ethyl acetate from 100/0 to 60/40) and the organic layer was concentrated in vacuo to give 1-(4-(6-(benzyloxy)-2-(4-fluorophenyl)-3,4-dihydronaphthalen -1-yl)phenyl)-4- (dimethoxymethyl)piperidine (520 mg, 76.3 % purity) as a yellow solid. LC-MS (ESI ⁺ ) m/z: 564.3 (M+H) ⁺ TLC(petroleum ether/ethyl acetate=3/1,Rf=0.4) confirmed Step 7: A mixture of 1-(4-(6-(benzyloxy)-2-(4-fluorophenyl)-3,4-dihydronaphthalen -1- yl)phenyl)-4-(dimethoxymethyl)piperidine (500 mg, 1 eq., 887 ^mol) , Pd/C (472 mg, 10% Wt) in MeOH (10 mL) was degassed and purged with N ₂ for 3 times, and then the mixture was stirred at 25 °C for 12 hour under H ₂ atmosphere (15 psi). The reaction mixture was filtered and concentrated to dryness in vacuo to give a white solid. The white solid was subjected by SFC: Column: DAICEL CHIRALCEL OD(250mm*30mm,10um) Mobile phase: A: Supercritical CO ₂ , B: MEOH (0.1%NH ₃ H ₂ O), A:B =60:40 at 80mL/min; Column Temp: 38 °C; Nozzle Pressure: 100Bar; Nozzle Temp: 60 °C; Evaporator Temp: 20 °C; Trimmer Temp: 25 °C ; Wavelength: 220nm. The aqueous phase was lyophilized to dryness to give (3R,4S)-4-(4-(4- (dimethoxymethyl)piperidin-1-yl)phenyl)-3-phenylisochroman-7 -ol (164 mg, 345 ^mol, 38.9 %) and (3S,4R)-4-(4-(4-(dimethoxymethyl)piperidin-1-yl)phenyl)-3-ph enylisochroman-7-ol (174 mg, 366 ^mol, 41.2 %) as a white solid. LC-MS (ESI ⁺ ) m/z: 476.2 (M+H) ⁺ Step 8: A mixture of (3R,4S)-4-(4-(4-(dimethoxymethyl)piperidin-1-yl)phenyl)-3- phenylisochroman-7-ol (100 mg, 200.18 umol, 92% purity, 1 eq) in 10% H ₂ SO ₄ (1.5 mL)and THF (1.5 mL) , then the mixture was stirred at 60 °C for 12 hr. The reaction mixture was diluted with H ₂ O (15 mL) and extracted with EtOAc (5 mL * 3). The combined organic layers were washed with 15 mL brine , dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give 1-(4-((3R,4S)-7-hydroxy-3-phenylisochroman-4-yl)phenyl)piper idine-4-carbaldehyde (80 mg, 183.79 umol, 91.81% yield, 95% purity)as a white solid. LC-MS (ESI ⁺ ) m/z: 4142 (M+H) ⁺ Step 9: A mixture of 1-(4-((3R,4S)-7-hydroxy-3-phenylisochroman-4-yl)phenyl)piper idine-4- carbaldehyde (50 mg, 114.87 umol, 95% purity, 1 eq) , HOAc (20.69 mg, 344.61 umol, 19.71 uL, 3 eq) , NaOAc (47.12 mg, 574.36 umol, 5 eq) and (3S)-3-(1-oxo-5-piperazin-1-yl-isoindolin- 2-yl)piperidine-2,6-dione (56.58 mg, 172.31 umol, 1.5 eq, p-TSA salt) in DCM (1 mL) and MeOH (1 mL) was stirred at 20 ^o C for 1 h, NaCNBH ₃ (48.69 mg, 229.74 umol, 2 eq) was added to the reaction and then the mixture was stirred at 20 °C for 12 hr. The reaction mixture was diluted with 15 mL H ₂ O and extracted with EtOAc (5 mL * 3). The combined organic layers were washed with 15 mL brine, dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a yellow oil. The residue was purified by prep-HPLC (column: Welch Xtimate C18150*30mm*5um; mobile phase: [water (FA)-ACN]; B%: 18%-48%,7 min). The aqueous phase was lyophilized to dryness to give (S)-3-(5-(4-((1-(4-((3R,4S)-7-hydroxy-3- phenylisochroman-4-yl)phenyl)piperidin-4-yl)methyl)piperazin -1-yl)-1-oxoisoindolin-2- yl)piperidine-2,6-dione (32 mg, 44.08 umol, 38.38% yield, 100% purity) as a white solid. LC-MS (ESI ⁺ ) m/z: 726.4 (M+H) ⁺ HPLC: 100 % purity at 220 nm NMR (400 MHz, DMSO-d ₆ ) į = 10.99 - 10.92 (m, 1H), 9.31 - 9.27 (m, 1H), 8.15 - 8.14 (m, 0.516 H), 7.57 - 7.51 (m, 1H), 7.18 - 7.05 (m, 7H), 6.80 -6.75 (m, 1H), 6.65 - 6.60 (m, 2H), 6.59 - 6.53 (m, 4H), 5.13 - 4.98 (m, 3H), 4.96 - 4.87 (m, 1H), 4.39 - 4.29 (m, 1H), 4.25 - 4.16 (m, 1H), 4.07 - 4.01 (m, 1H),3.56 - 3.44 (m, 3H), 2.96 - 2.85 (m, 1H), 2.53 (br d, J = 2.0 Hz, 9H), 2.44 - 2.22 (m, 4H), 2.01 - 1.91 (m, 1H), 1.81 - 1.61 (m, 3H), 1.25 - 1.08 (m, 2H).

EXAMPLE 59. Preparation of (I-3) (S)-3-(5-(4-((1-(4-((3S,4R)-7-hydroxy-3- phenylisochroman-4-yl)phenyl)piperidin-4-yl)methyl)piperazin -1-yl)-1-oxoisoindolin-2- yl)piperidine-2,6-dione Step 1: A mixture of (3S,4R)-4-(4-(4-(dimethoxymethyl)piperidin-1-yl)phenyl)-3- phenylisochroman-7-ol (90 mg, 182.12 umol, 93% purity, 1 eq) in 10% H ₂ SO ₄ (1.5 mL)and THF (1.5 mL) , then the mixture was stirred at 60 °C for 12 hr. The reaction mixture was diluted with 15 mL H2O and extracted with EtOAc (5 mL * 3). The combined organic layers were washed with brine 15 mL, dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give 1-(4-((3S,4R)-7-hydroxy-3-phenylisochroman-4-yl)phenyl)piper idine-4-carbaldehyde (80 mg, 181.86 umol, 99.85% yield, 94% purity) as a white solid. LC-MS (ESI ⁺ ) m/z: 414.2 (M+H) ⁺ Step 2: A mixture of 1-(4-((3S,4R)-7-hydroxy-3-phenylisochroman-4-yl)phenyl)piper idine-4- carbaldehyde (50 mg, 113.66 umol, 94% purity, 1 eq) , HOAc (20.48 mg, 340.99 umol, 19.50 uL, 3 eq) , NaOAc (46.62 mg, 568.31 umol, 5 eq) and (3S)-3-(1-oxo-5-piperazin-1-yl-isoindolin- 2-yl)piperidine-2,6-dione (55.98 mg, 170.49 umol, 1.5 eq, p-TSA salt) in DCM (1 mL) and MeOH (1 mL) was stirred at 20 ^o C for 1 h, NaCNBH ₃ (48.18 mg, 227.32 umol, 2 eq) was added to the reaction and then the mixture was stirred at 20 °C for 12 hr. The reaction mixture was diluted with H ₂ O 15 mL and extracted with EtOAc (5 mL * 3). The combined organic layers were washed with 15 mL brine, dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a yellow oil. The residue was purified by prep-HPLC (column: Welch Xtimate C18150*30mm*5um;mobile phase: [water(FA)-ACN];B%: 16%-46%,7min).The aqueous phase was lyophilized to dryness to give (S)-3-(5-(4-((1-(4-((3S,4R)-7-hydroxy-3-phenylisochroman-4- yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindo lin-2-yl)piperidine-2,6-dione (29.6 mg, 40.78 umol, 35.88% yield, 100% purity) as a white solid. LC-MS (ESI ⁺ ) m/z: 726.4 (M+H) ⁺ HPLC: 100% purity at 220 nm NMR (400 MHz, DMSO-d ₆ ) į = 10.98 - 10.93 (m, 1H), 9.34 - 9.27 (m, 1H), 8.18 - 8.12 (m, 0.331H), 7.56 - 7.50 (m, 1H), 7.19 - 7.03 (m, 7H), 6.83 - 6.75(m, 1H), 6.66 - 6.59 (m, 2H), 6.59 - 6.51 (m, 4H), 5.12 - 4.98 (m, 3H), 4.95 - 4.87 (m, 1H), 4.39 - 4.28 (m, 1H), 4.24 - 4.17 (m, 1H), 4.09 - 3.99 (m, 1H), 3.63- 3.42 (m, 3H), 2.97 - 2.83 (m, 1H), 2.53 (br d, J = 2.0 Hz, 9H), 2.43 - 2.15 (m, 4H), 2.03 - 1.90 (m, 1H), 1.81 - 1.56 (m, 3H), 1.28 - 1.07 (m, 2H).

EXAMPLE 60. Preparation of (I-122) (S)-3-(5-(4-((1-(4-((S)-7'- hydroxyspiro[cyclohexane-1,3'-isochroman]-4'-yl)phenyl)piper idin-4-yl)methyl)piperazin- 1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione Step 1: A mixture of ethyl 1-hydroxycyclohexane-1-carboxylate (8.00 g, 1 Eq, 46.5 mmol),1- (benzyloxy)-3-(bromomethyl)benzene (19.3 g, 1.5 Eq, 69.7 mmol),Tetra-n- 60% Wt, 2.5 Eq, 116 mmol) in THF (100 mL)and DMF (10 mL) at 25 °C for 16 hour. TLC (petroleum ether: ethyl acetate = 5:1, Rf =0.5 UV) showed one main new spot was observed. The reaction mixture was added 50 mL water at 0°C and extracted with ethyl acetate (100 mL * 3). The combined organic layers were washed with brine (100 mL * 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® Silica Flash Column, Eluent of 0~15% Ethyl acetate/Petroleum ether gradient @ 45 mL/min) to give the product of ethyl 1-((3- (benzyloxy)benzyl)oxy)cyclohexane-1-carboxylate (13 g, 35 mmol, 76 %). Step 2: To a solution of ethyl 1-((3-(benzyloxy)benzyl)oxy)cyclohexane-1-carboxylate (12.00 g, 1 Eq, 32.57 mmol) in THF (50 mL) and MeOH (50 mL) was added NaOH (5.211 g, 32.57 mL, 4 M 4 Eq, 130.3 mmol) .The mixture was stirred at 50 °C for 16 hour. TLC (petroleum ether/ethyl acetate = 5:1, R _f = 0.3) showed a new spot was formed. The mixture was adjusted to pH~4 with 2N HCl.100 mL H ₂ O was added, and the mixture was extracted with ethyl acetate (2×100 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to dryness in vacuo to give 1-((3-(benzyloxy)benzyl)oxy)cyclohexane- 1-carboxylic acid (8 g, 0.02 mol, 70 %) as yellow oil. Step 3: 2,2,2-Trifluoroacetic anhydride (9.25 g, 6.12 mL, 5 Eq, 44.1 mmol) was added to 1-((3- (benzyloxy)benzyl)oxy)cyclohexane-1-carboxylic acid (3.00 g, 1 Eq, 8.81 mmol) in DCM (30 mL) . The reaction was stirred at 0 °C for 30 min. The reaction was stirred at 25 °C for 16 hour. TLC (petroleum ether: ethyl acetate = 10:1, UV) showed one main new spot was observed.100 mL water was added, and the mixture was extracted with ethyl acetate (200 mL *2). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to dryness in vacuo to give a white solid. The white solid was purified by flash column (petroleum ether/ethyl acetate from 100/0 to 0/100) and the organic layer was concentrated in vacuo to give 620 mg of 7'-(benzyloxy)spiro[cyclohexane-1,3'-isochroman]-4'- one as a yellow solid.620 mg of 7'-(benzyloxy)spiro[cyclohexane-1,3'-isochroman]-4'-one was purified by preparative high-performance liquid chromatography. Condition: Column: O-Welch C18150*30mm* 5um A : water (FA) B: ACN˗ at the beginning: A (42%) and B (58%)˗at the end: A: (5%) and B (98%)˗ Gradient Time(min) 10; 100% B hold Time(min) 2, Flow Rate(ml/min) 30. The pure fractions were collected, and the solvent was evaporated under vacuum. The aqueous layer was lyophilized to dryness to give 7'-(benzyloxy)spiro[cyclohexane- 1,3'-isochroman]-4'-one (300 mg, 931 ^mol, 10.6 %) as a white solid. Step 4: 1-(4-bromophenyl)-4-(dimethoxymethyl)piperidine (584.78 mg, 2 Eq, 1.8610 mmol), a stir bar, and THF (10 mL) were added an oven-dried and nitrogen-purged 100 mL three round- bottomed flask, which was subsequently evacuated and refilled with argon (x3), before the reaction vessel was cooled to 25 °C (dry ice/EtOH). The resulting mixture treated with n- Butyllithium (89.41 mg, 558.31 ^L, 2.5 M, 1.5 Eq, 1.3958 mmol), dropwise over 2 min at -68 °C (dry ice/EtOH), while stirring an additional 30 min at -68 °C (dry ice/EtOH). The resulting mixture treated with 7'-(benzyloxy)spiro[cyclohexane-1,3'-isochroman]-4'-one (300.000 mg, 1 Eq, 930.52 ^mol) in THF (2 mL), dropwise over 5 min, and the reaction vessel removed to the r.t., while stirring an additional 2 h at -68 °C. TLC (petroleum ether/ethyl acetate = 5/1, R _f = 0.4) The reaction mixture treated with sat. aq. NH ₄ Cl (20 mL), dropwise over 3 min, extracted with EtOAc (50 mL x 3), and the combined extracts washed with brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated to dryness in vacuo to give a crude product, which was then subjected to silica gel chromatography (0-50% EtOAc/pet ether) to give 7'-(benzyloxy)-4'-(4-(4- (dimethoxymethyl)piperidin-1-yl)phenyl)spiro[cyclohexane-1,3 '-isochroman]-4'-ol (300 mg, 538 ^mol, 46.9 %) as a yellow solid. Step 5: A mixture of 7'-(benzyloxy)-4'-(4-(4-(dimethoxymethyl)piperidin-1- yl)phenyl)spiro[cyclohexane-1,3'-isochroman]-4'-ol (300 mg, 1 Eq, 538 ^mol), Pd/C (286 mg, 10% Wt, 0.5 Eq, 269 ^mol) in MeOH (10 mL) was degassed and purged with H ₂ (15 psi) for 3 times, and then the mixture was stirred at 50 °C for 16 hour under H ₂ atmosphere. LCMS showed desired MS was detected. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was concentrated under reduced pressure to give desired compound (0.5 g, purity ~90%) as a yellow oil, which was further separated by SFC (condition: column: DAICEL CHIRALCELOJ (250mm*30mm,10um);mobile phase: [0.1% NH ₃ -H ₂ O EtOH]; B%: 35%-35%, min ) to give (S)-4'-(4-(4-(dimethoxymethyl)piperidin-1- yl)phenyl)spiro[cyclohexane-1,3'-isochroman]-7'-ol (110 mg, 244 ^mol, 45.3 %) was obtained as a yellow oil and (R)-4'-(4-(4-(dimethoxymethyl)piperidin-1-yl)phenyl)spiro[cy clohexane-1,3'- isochroman]-7'-ol (100 mg, 221 ^mol, 43%). Step 6: To a solution of (S)-4'-(4-(4-(dimethoxymethyl)piperidin-1-yl)phenyl)spiro[cy clohexane- mixture was stirred at 70 °C for 3 hour . TLC (petroleum ether: ethyl acetate=3:1, UV) showed one main new spot was observed. The reaction mixture was quenched by addition 50 mL H2O at 25°C, and then diluted with 50 mL H ₂ O and extracted with Ethyl acetate 100 mL (50 mL * 2). The combined organic layers were washed with 50 mL brine and dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The reaction was no further purification for the next step. Step 7: To a solution of (S)-1-(4-(7'-hydroxyspiro[cyclohexane-1,3'-isochroman]-4'- yl)phenyl)piperidine-4-carbaldehyde (70 mg, 1 Eq, 0.17 mmol), (S)-3-(1-oxo-5-(piperazin-1- yl)isoindolin-2-yl)piperidine-2,6-dione, TsOH salt (86 mg, 1 Eq, 0.17 mmol) in DCM (3 mL), MeOH (3 mL) was added Sodium acetate (42 mg, 3 Eq, 0.52 mmol) was stirred at 25 °C for 30 mins, Then Sodium triacetoxyborohydride (73 mg, 2 Eq, 0.35 mmol) and Acetic acid (31 mg, 30 ^L, 3 Eq, 0.52 mmol) was added. The mixture was stirred at 25 °C for 16 hours. TLC (DCM/MeOH = 10/1, R _f = 0.4) showed new spot was formed. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was purified by prep-HPLC (column: Welch Xtimate C18150*30mm*5um;mobile phase: [water(FA)-ACN]; B% 18%- 48%,7min) to give (S)-3-(5-(4-((1-(4-((S)-7'-hydroxyspiro[cyclohexane-1,3'-iso chroman]-4'- yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindo lin-2-yl)piperidine-2,6-dione (25.1 mg, 35.0 ^mol, 20 %, 100% purity) was obtained as a white solid. LCMS: calc. for C ₄₃ H ₅₁ N ₅ O ₅ : 717.39, found: [M+H]+ 718.2. HPLC: 100.00% purity at 220 nm. NMR (400 MHz, DMSO-d ₆ ) į = 10.95 (s, 1H), 9.17 (br s, 1H), 8.16 (s, 0.29H), 7.52 (d, J=8.6 Hz, 1H), 7.11 - 7.02 (m, 2H), 6.92 (br s, 2H), 6.77 (d, J=8.9 Hz, 2H), 6.68 (d, J=8.3 Hz, 1H), 6.54 - 6.41 (m, 2H), 5.05 (dd, J=5.1, 13.3 Hz, 1H), 4.81 - 4.71 (m, 1H), 4.68 - 4.57 (m, 1H), 4.42 - 4.28 (m, 1H), 4.26 - 4.15 (m, 1H), 3.60 (br d, J=9.2 Hz, 2H), 3.51 (s, 1H), 3.29 (br s, 4H), 2.98 - 2.84 (m, 1H), 2.63 - 2.52 (m, 6H), 2.44 - 2.30 (m, 2H), 2.22 (br d, J=7.0 Hz, 2H), 2.03 - 1.91 (m, 1H), 1.80 (br d, J=11.7 Hz, 3H), 1.67 (br s, 1H), 1.56 - 1.33 (m, 5H), 1.31 - 1.14 (m, 4H), 1.09 (br s, 2H). EXAMPLE 61. Preparation of (I-123) (S)-3-(5-(4-((1-(4-((R)-7'- hydroxyspiro[cyclohexane-1,3'-isochroman]-4'-yl)phenyl)piper idin-4-yl)methyl)piperazin- 1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione Step 1: To a solution of (R)-4'-(4-(4-(dimethoxymethyl)piperidin-1- yl)phenyl)spiro[cyclohexane-1,3'-isochroman]-7'-ol (100 mg, 1 Eq, 221 ^mol) in 10%H ₂ SO ₄ (10 mL)and THF (10 mL).The mixture was stirred at 70 °C for 3 hour. TLC (petroleum ether: ethyl aceatte=3:1, UV) showed one main new spot was observed. The reaction mixture was quenched by addition 50 mL H ₂ O at 25°C, and then diluted with 50 mL H ₂ O and extracted with Ethyl acetate 100 mL (50 mL * 2). The combined organic layers were washed with 50 mL brine and dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The reaction was no further purification for next step. Step 2: To a solution of (R)-1-(4-(7'-hydroxyspiro[cyclohexane-1,3'-isochroman]-4'- yl)phenyl)piperidine-4-carbaldehyde (60 mg, 1 Eq, 0.15 mmol), (S)-3-(1-oxo-5-(piperazin-1- yl)isoindolin-2-yl)piperidine-2,6-dione, TsOH salt (74 mg, 1 Eq, 0.15 mmol) in DCM (3 mL), MeOH (3 mL) was added Sodium acetate (36 mg, 3 Eq, 0.44 mmol) was stirred at 25 °C for 30 mins, Then Sodium triacetoxyborohydride (63 mg, 2 Eq, 0.30 mmol) and Acetic acid (27 mg, 26 ^L, 3 Eq, 0.44 mmol) was added .The mixture was stirred at 25 °C for 16 hour. TLC (DCM/MeOH=10/1, Rf=0.4) showed new spot was formed. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was purified by prep-HPLC (column: Welch Xtimate C18150*30mm*5um;mobile phase: [water(FA)-ACN];B% 18%- 48%,7min) to give (S)-3-(5-(4-((1-(4-((R)-7'-hydroxyspiro[cyclohexane-1,3'-iso chroman]-4'- yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindo lin-2-yl)piperidine-2,6-dione (29.8 mg, 41.5 ^mol, 28 %, 100% Purity) was obtained as a white solid. LCMS: calc. for C ₄₃ H ₅₁ N ₅ O ₅ : 717.39, found: [M+H]+ 718.2. HPLC: 100.00% purity at 220 nm. NMR (400MHz, DMSO-d ₆ ) į = 10.95 (s, 1H), 9.17 (s, 1H), 8.14 (s, 0.49H), 7.53 (d, J=8.7 Hz, 1H), 7.11 - 7.02 (m, 2H), 6.92 (br s, 2H), 6.77 (d, J=8.9 Hz, 2H), 6.68 (d, J=8.3 Hz, 1H), 6.53 - 6.42 (m, 2H), 5.05 (dd, J=5.1, 13.2 Hz, 1H), 4.80 - 4.71 (m, 1H), 4.69 - 4.59 (m, 1H), 4.39 - 4.29 (m, 1H), 4.26 - 4.14 (m, 1H), 3.60 (br d, J=9.7 Hz, 2H), 3.51 (s, 1H), 3.30 - 3.26 (m, 4H), 2.99 - 2.83 (m, 1H), 2.64 - 2.53 (m, 6H), 2.41 - 2.30 (m, 2H), 2.24 (br d, J=6.4 Hz, 2H), 2.02 - 1.91 (m, 1H), 1.80 (br d, J=12.2 Hz, 3H), 1.68 (br s, 1H), 1.56 - 1.35 (m, 5H), 1.31 - 1.14 (m, 4H), 1.09 (br s, 2H).

EXAMPLE 62. Preparation of (I-417) (S)-3-(5-(4-((1-(4-((3*R,4*R)-7-hydroxy-3- methyl-3-phenylisochroman-4-yl)phenyl)piperidin-4-yl)methyl) piperazin-1-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione Step 1: A mixture of methyl 2-hydroxy-2-phenylpropanoate (4.9 g, 1 Eq, 27 mmol), 1- and sodium hydride (2.7 g, 60% Wt., 2.5 Eq, 68 mmol) in THF (50 mL) and DMF (20 mL)at 25 °C for 16 hour. LCMS showed 17.4% and 17.9% desired MS. The reaction mixture was added water 300 mL at 0°C and extracted with ethyl acetate (500 mL * 2). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. TLC (petroleum ether: ethyl acetate=1:1, UV) showed two main new spots was observed. The reaction was quenched with water (300 mL) and extracted with ethyl acetate (200 mL*3). The organic layer was washed with brine (50 mL) and dried over Na ₂ SO ₄ and concentrated in vacuum to give a yellow oil. The yellow oil was subjected to column chromatography over silica gel (gradient elution: 0 – 100% EtOAc). LCMS showed 92.2% and 88.4% desired MS. The aqueous layer was lyophilized to dryness to give 2-((3- (benzyloxy)benzyl)oxy)-2-phenylpropanoic acid (1.9 g, 4.8 mmol, 18 %, 92.199% purity) as a yellow oil. The aqueous layer was lyophilized to dryness to give methyl 2-((3- (benzyloxy)benzyl)oxy)-2-phenylpropanoate (2.65 g, 6.22 mmol, 23 %, 88.4% purity) as a yellow oil. LC-MS (ESI ⁺ ) m/z: 399.1 (M+H) ⁺ . Step 2: A 40 mL thread vial was equipped with magnetic stirrer. A solution of methyl 2-((3- (benzyloxy) benzyl)oxy)-2-phenylpropanoate (2.65 g, 1 Eq, 7.04 mmol) in DMF (40 mL) and added N-Bromosuccinimide (1.50 g, 1.2 Eq, 8.45 mmol). The reaction was stirred at 25 °C for 16 hour. LCMS showed 33.2% desired MS. TLC (petroleum ether: ethyl acetate=10:1, UV) showed one main new spot was observed. The reaction was quenched with water (150 mL) and extracted with ethyl acetate (150 mL*3). The organic layer was washed with brine (50 mL) and dried over Na ₂ SO ₄ and concentrated in vacuo to give methyl 2-((5-(benzyloxy)-2- bromobenzyl)oxy)-2-phenylpropanoate as a yellow oil. The yellow oil was subjected to column chromatography over silica gel (gradient elution: 0 – 10% EtOAc). LCMS showed 76% desired MS. The desired fractions were collected, and concentrated to dryness in vacuo to give methyl 2- ((5-(benzyloxy)-2-bromobenzyl) oxy)-2-phenylpropanoate (3.2 g, 5.3 mmol, 76 %, 76% purity) as a yellow oil. NMR confirmed. LC-MS (ESI ⁺ ) m/z: 479.0(M+H) ⁺ . Step 3: A mixture of methyl 2-((5-(benzyloxy)-2-bromobenzyl)oxy)-2-phenylpropanoate (3.2 g, 76% Wt., 1 Eq, 5.3 mmol) and NaOH (1.1 g, 8.9 mL, 3 molar, 5 Eq, 27 mmol)in THF (10 mL) and MeOH (10 mL) at 50 °C for 16 hour. LCMS showed 71% desired MS. The reaction mixture was added 200 mL 1 N HCl at 0°C and extracted with ethyl acetate (200 mL * 3). The combined organic layers were washed with brine dried over anhydrous sodium sulfate filtered and concentrated under reduced pressure. TLC (petroleum ether: ethyl acetate=10:1, UV) showed two main new spots was observed. The reaction was quenched with water (300 mL) and extracted with ethyl acetate (200 mL*3). The organic layer was washed with brine(50 mL) and dried over Na ₂ SO ₄ and concentrated in vacuo to give 2-((5-(benzyloxy)-2-bromobenzyl)oxy)-2- phenylpropanoic acid as a yellow oil. The yellow oil was subjected to column chromatography over silica gel (gradient elution: 0 – 15% EtOAc). LCMS showed 85.8% desired MS. The aqueous layer was lyophilized to dryness to give 2-((5-(benzyloxy)-2-bromobenzyl) oxy)-2- phenylpropanoic acid (1.65 g, 3.21 mmol, 60 %, 85.8% purity) as a yellow oil. NMR confirmed. LC-MS (ESI+) m/z: 458.0 (M+H) ⁺ Step 4: A 40 mL thread vial was equipped with magnetic stirrer. O,N-dimethyl-hydroxylamine HCl salt(375 mg, 1.2 Eq, 3.85 mmol) was added in to 2-((5-(benzyloxy)-2-bromobenzyl) oxy)-2- phenylpropanoic acid (1.65 g, 1 Eq, 3.21 mmol), DIEA (1.24 g, 1.66 mL, 3 Eq, 9.62 mmol) in DMF (15 mL) at r.t 30 min, and added into HATU (1.83 g, 1.5 Eq, 4.81 mmol). The vial was sealed with a rubber septum. The reaction was stirred at r.t. overnight. LCMS showed 20.08% desired MS. TLC (petroleum ether: ethyl acetate=5:1, UV) showed one main new spot was observed. The reaction was quenched with water (100 mL *2) and extracted with ethyl acetate (100 mL*3). The organic layer was washed with brine(50 mL) and dried over Na ₂ SO ₄ and concentrated in vacuo to give 2-((5-(benzyloxy)-2-bromobenzyl)oxy)-N-methoxy-N-methyl-2- phenylpropanamide as a brown oil. The brown oil was subjected to column chromatography over silica gel (gradient elution: 0 – 20% EtOAc). The desired fractions were collected, and concentrated to dryness in vacuo to give 2-((5-(benzyloxy)-2-bromobenzyl)oxy)-N-methoxy-N- methyl-2-phenylpropanamide (1.9 g, 3.5 mmol, 89% purity) as a yellow oil. LC-MS (ESI+) m/z: 506.1 (M+H) ⁺ Step 5: A three bottle equipped with magnetic stirrer. A solution of 2-((5-(benzyloxy)-2- bromobenzyl)oxy)-N-methoxy-N-methyl-2-phenylpropanamide (1.9 g, 1 Eq, 3.5 mmol) in THF (25 mL) was stirred at -78 °C for 30 min under N ₂ atmosphere, then added tert-butyllithium (5.9 mL, 1.3 molar, 2.2 Eq, 7.7 mmol) at -78 °C. The reaction was stirred at -78 °C to 25 °C for 16 hour under N2 atmosphere. LCMS showed 65.9% desired MS. TLC (petroleum ether: ethyl acetate=5:1, UV) showed one main new spot was observed. The reaction was quenched with water (100 mL) and extracted with ethyl acetate (100 mL*3). The organic layer was washed with brine(50 mL) and dried over Na ₂ SO ₄ and concentrated in vacuo to give 7-(benzyloxy)-3-methyl- 3-phenylisochroman-4-one as a colorless oil. The black oil was subjected to column chromatography over silica gel (gradient elution: 0 – 20% EtOAc). The desired fractions were collected and concentrated to dryness in vacuo to give 7-(benzyloxy)-3-methyl-3- phenylisochroman-4-one (960 mg, 2.72 mmol, 78 %, 97.47% purity) as a yellow solid. LC-MS (ESI+) m/z: 345.0(M+H) ⁺ . Step 6: 1-(4-bromophenyl)-4-(dimethoxymethyl)piperidine (1.71 g, 2 Eq, 5.43 mmol), a stir bar, and THF (15 mL) were added an oven-dried and nitrogen-purged 100 mL three round-bottomed flask, which was subsequently evacuated and refilled with N ₂ (x3), before the reaction vessel was cooled to -70 °C (dry ice/EtOH). The resulting mixture treated with n-Butyl lithium, 2.5 M in hexane (1.74 mL, 2.5 molar, 1.6 Eq, 4.35 mmol), dropwise over 2 min at -70°C (dry ice/EtOH). While stirring an additional 1 hour at -70 °C (dry ice/EtOH). The resulting mixture treated with 7-(benzyloxy)-3-methyl-3-phenylisochroman-4-one (960 mg, 1 Eq, 2.72 mmol) in THF(5 mL), dropwise over 5 min, and the reaction vessel removed to the r.t., while stirring an additional 16 hour at 25 °C. LCMS showed 68.565% desired MS. TLC (petroleum ether: ethyl acetate=5:1, UV) showed one main new spot was observed. The reaction was quenched with water (100 mL) and extracted with ethyl acetate (50 mL*3). The organic layer was washed with brine(50 mL) and dried over Na ₂ SO ₄ and concentrated in vacuo to give 7-(benzyloxy)-4-(4-(4- (dimethoxymethyl)piperidin-1-yl)phenyl)-3-methyl-3-phenyliso chroman-4-ol as a yellow oil. The yellow oil was subjected to column chromatography over silica gel (gradient elution: 0 – 20% EtOAc). The desired fractions were collected, and concentrated to dryness in vacuo to give 7-(benzyloxy)-4-(4-(4-(dimethoxymethyl)piperidin-1-yl)phenyl )-3-methyl-3-phenylisochroman- 4-ol (1.5 g, 2.4 mmol, 87 %, 91.73% purity) as a brown solid. LC-MS (ESI+) m/z: 580.3(M+H) ⁺ . Step 7: An 8 mL thread vial was equipped with magnetic stirrer.2,2,2-trifluoroacetic acid (531.02 mg, 345.9 ^L, 9 Eq, 4.7 mmol) and triethylsilane (0.54 g, 0.85 mL, 10 Eq, 4.7 mmol) was added to a mixture suspension of 7-(benzyloxy)-4-(4-(4-(dimethoxymethyl)piperidin-1- yl)phenyl)-3-methyl-3-phenylisochroman-4-ol (300 mg, 1 Eq, 517.5 ^mol) in DCM (5 mL) at 0 °C. The mixture was stirred at 0 °C for 1 hour. LCMS showed 55.3% desired MS. TLC (petroleum ether: ethyl acetate=5:1, UV) showed one main new spot was observed.50 mL water was added, and the mixture was extracted with dichloromethane (100 mL x2). The reaction was concentrated to dryness in vacuo to give a yellow oil The yellow oil was purified by flash column (petroleum ether/ethyl acetate from 100/0 to 0/100) and the organic layer was concentrated in vacuo to give 1-(4-(7-(benzyloxy)-3-methyl-3-phenylisochroman-4-yl) phenyl)- 4-(dimethoxymethyl) piper dine (100 mg, 155 ^mol, 29.9 %, 87.263% purity) as a yellow solid. LC-MS (ESI+) m/z: 564.3 (M+H) ⁺ . Step 8: To a solution of 1-(4-(7-(benzyloxy)-3-methyl-3-phenylisochroman-4-yl)phenyl) -4- (dimethoxymethyl)piperidine (50 mg, 1 Eq, 77 ^mol) in MeOH (1 mL) and THF (1 mL)was added Pd/C(82 mg, 10% Wt.) under N ₂ atmosphere. The suspension was degassed and purged with H ₂ for 3 mines. The mixture was stirred under 15 Psi H ₂ (0.16 mg, 1 Eq, 77 ^mol) at 50 °C for 16 hr. LCMS showed 58.629% desired MS was detected. The mixture was filtered and concentrated under reduced pressure to give a residue. The residue was concentrated under reduced pressure to give desired compound as a yellow oil, which was further separated by SFC (condition: column: DAICEL CHIRALPAK AD(250mm*30mm,10um) ); mobile phase: [0.1% NH ₃ .H ₂ O EtOH]; B%: 55%-55%) to give (3*R,4*R)-4-(4-(4-(dimethoxymethyl)piperidin-1- yl)phenyl)-3-methyl-3-phenylisochroman-7-ol (10 mg, 21 ^mol, 27 %) and (3*S,4*S)-4-(4-(4- (dimethoxymethyl)piperidin-1-yl)phenyl)-3-methyl-3-phenyliso chroman-7-ol (12 mg, 25 ^mol, 33 %) as a white solid LC-MS (ESI+) m/z: 474.3 (M+H) ⁺ . Step 9: 1-(4-((3*R,4*R)-7-hydroxy-3-methyl-3-phenylisochroman-4-yl)p henyl)piperidine-4- carbaldehyde (30 mg, 69 ^mol) in sulfuric acid ( 3 mL, 10% Wt.,) and THF (3 mL) for stirred at 70 °C for 16 hour. LCMS showed 98.775% desired MS. The reaction was adjust to pH=~7 with NaHCO ₃ , then 50 mL water was added, and the mixture was extracted with dichloromethane (10 mL x2). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to dryness in vacuo to give a yellow oil. The yellow oil was concentrated in vacuo to give 1-(4-((3*R,4*R)-7-hydroxy-3-methyl-3-phenylisochroman-4- yl)phenyl)piperidine-4-carbaldehyde (30 mg, 69 ^mol, 98.775% purity, crude) as a yellow solid. LC-MS (ESI+) m/z: 428.2(M+H) ⁺ . Step 10: To a solution of 1-(4-((3R,4R)-7-hydroxy-3-methyl-3-phenylisochroman-4- yl)phenyl)piperidine-4-carbaldehyde (30 mg, 98.775% Wt., 1 Eq, 69 ^mol), (S)-3-(1-oxo-5- (piperazin-1-yl)isoindolin-2-yl)piperidine-2,6-dione, PhSO ₃ H salt (40 mg, 1.2 Eq, 83 ^mol) in DCM (2 mL), MeOH (2 mL) was added sodium acetate (17 mg, 3 Eq, 0.21 mmol) was stirred at 25 °C for 30 mines, Then sodium triacetoxyborohydride (29 mg, 2 Eq, 0.14 mmol) and acetic LCMS showed 85.2% desired MS was detected. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was purified by prep-HPLC (column: Welch Xtimate C18150*30mm*5um phase: [water(FA)-ACN];B%: 5%-45%,8min to give (S)-3-(5-(4-((1-(4-((3*R,4*R)-7-hydroxy- 3-methyl-3-phenylisochroman-4-yl)phenyl)piperidin-4-yl)methy l)piperazin-1-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione (13.6 mg, 18.4 ^mol, 27 %, 100% purity) was obtained as a white solid. LC-MS (ESI+) m/z: 740.2(M+H) ⁺ . LCMS: calc. for C ₄₅ H ₄₉ N ₅ O ₅ , found: [M+H] ⁺ 740.2. HPLC: 100% purity at 220 nm. ¹ H NMR 1H NMR (400MHz, DMSO-d ₆ ) į = ppm 10.95 (s, 1 H) 8.93 - 9.23 (m, 1 H) 8.18 (s, 0.4H) 7.53 (d, J=8.70 Hz, 1 H) 7.43 (d, J=7.51 Hz, 2 H) 7.28 (t, J=7.63 Hz, 2 H) 7.15 - 7.20 (m, 1 H) 7.06 (br d, J=10.97 Hz, 4 H) 6.83 (dd, J=10.43, 8.76 Hz, 3 H) 6.46 (dd, J=8.46, 2.50 Hz, 1 H) 6.26 (d, J=2.38 Hz, 1 H) 5.05 (dd, J=13.29, 5.07 Hz, 1 H) 4.82 (d, J=16.09 Hz, 1 H) 4.50 (s, 1 H) 4.30 - 4.45 (m, 2 H) 4.18 - 4.25 (m, 1 H) 3.63 (br d, J=11.68 Hz, 2 H) 3.26 - 3.30 (m, 8 H) 2.85 - 2.93 (m, 1 H) 2.58 - 2.65 (m, 3 H) 2.34 - 2.40 (m, 1 H) 2.23 (br d, J=7.39 Hz, 2 H) 1.95 - 2.01 (m, 1 H) 1.81 (br d, J=11.92 Hz, 2 H) 1.69 (br s, 1 H) 1.22 (br d, J=12.99 Hz, 2 H) 1.05 (s, 3 H). The absolute stereochemistry was arbitrarily assigned.

EXAMPLE 63. Preparation of (I-345) (S)-3-(5-(4-((1-(4-((3*S,4*S)-7-hydroxy-3- methyl-3-phenylisochroman-4-yl)phenyl)piperidin-4-yl)methyl) piperazin-1-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione Step 1: 1-(4-((3*S,4*S)-7-hydroxy-3-methyl-3-phenylisochroman-4-yl)p henyl)piperidine-4- carbaldehyde (32 mg, 74 ^mol,) in sulfuric acid (58 mg, 1 mL, 10% Wt., 1 Eq, 59 ^mol) and THF (3 mL) for stirred at 70 °C for 16 hour. LCMS showed 98.625% desired MS. The reaction was adjust to pH=~7 with NaHCO ₃ , then 50 mL water was added, and the mixture was extracted with dichloromethane (100 mL x2). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to dryness in vacuum to give a yellow oil. The yellow oil was concentrated in vacuum to give 1-(4-((3*S, 4*S)-7-hydroxy-3- methyl-3-phenylisochroman-4-yl)phenyl)piperidine-4-carbaldeh yde(32 mg, 74 ^mol, 98.625% purity) as a yellow solid. LC-MS (ESI+) m/z: 428.1(M+H) ⁺ . Step 2: To a solution of 1-(4-((3*S,4*S)-7-hydroxy-3-methyl-3-phenylisochroman-4- yl)phenyl)piperidine-4-carbaldehyde (30 mg, 1 Eq, 69 ^mol), (S)-3-(1-oxo-5-(piperazin-1- yl)isoindolin-2-yl)piperidine-2,6-dione, PhSO ₃ H salt(40 mg, 1.2 Eq, 83 ^mol) in DCM (2 mL), MeOH (2 mL) was added sodium acetate (17 mg, 3 Eq, 0.21 mmol) was stirred at 25 °C for 30 mins, Then sodium triacetoxyborohydride (29 mg, 2 Eq, 0.14 mmol) and acetic acid (12 mg, 12 ^L, 3 Eq, 0.21 mmol) was added .The mixture was stirred at 25 °C for 16 hour. LCMS showed 83.584% desired MS was detected. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was purified by prep-HPLC (column: Welch Xtimate C18150*30mm*5um phase: [water(FA)-ACN];B%: 5%-45%,9 min to give (S)-3-(5-(4-((1-(4-((3*S,4*S)-7-hydroxy- 3-methyl-3-phenylisochroman-4-yl)phenyl)piperidin-4-yl)methy l)piperazin-1-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione (13.2 mg, 17.8 ^mol, 26 %, 100% purity) was obtained as a white solid. LC-MS (ESI+) m/z: 740.2(M+H) ⁺ . LCMS: calc. for C ₄₅ H ₄₉ N ₅ O ₅ , found: [M+H] ⁺ 740.2. HPLC: 100% purity at 220 nm. ¹ H NMR 1H NMR (400MHz, DMSO-d ₆ ) į = ppm 10.95 (s, 1 H) 9.11 (br s, 1 H) 8.18 (s, 0.648 H) 7.53 (d, J=8.70 Hz, 1 H) 7.43 (d, J=7.51 Hz, 2 H) 7.28 (t, J=7.63 Hz, 2 H) 7.14 - 7.22 (m, 1 H) 7.06 (br d, J=10.85 Hz, 4 H) 6.83 (dd, J=10.31, 8.76 Hz, 3 H) 6.46 (dd, J=8.23, 2.50 Hz, 1 H) 6.26 (d, J=2.27 Hz, 1 H) 5.05 (dd, J=13.23, 5.13 Hz, 1 H) 4.82 (d, J=16.09 Hz, 1 H) 4.50 (s, 1 H) 4.30 - 4.43 (m, 2 H) 4.17 - 4.25 (m, 1 H) 3.63 (br d, J=12.28 Hz, 2 H) 3.27 - 3.30 (m, 8 H) 2.88 - 2.96 (m, 1 H) 2.59 (br d, J=13.35 Hz, 3 H) 2.37 (br dd, J=13.11, 4.41 Hz, 1 H) 2.23 (br d, J=7.27 Hz, 2 H) 1.93 - 2.01 (m, 1 H) 1.81 (br d, J=12.40 Hz, 2 H) 1.69 (br s, 1 H) 1.22 (br d, J=13.47 Hz, 2 H) 1.05 (s, 3 H). The absolute stereochemistry was arbitrarily assigned.

EXAMPLE 64. Preparation of (I-34) (S)-3-(5-(4-((1-(4-((3R,4R)-3-cyclohexyl-7- hydroxyisochroman-4-yl)phenyl)piperidin-4-yl)methyl)piperazi n-1-yl)-1-oxoisoindolin-2- yl)piperidine-2,6-dione

Step 1: A mixture of 2-cyclohexyl-2-hydroxyacetic acid (5.0 g, 1 Eq, 32 mmol), Cesium fluoride (7.2 g, 1.5 Eq, 47 mmol) and Methyl iodide (6.7 g, 1.5 Eq, 47 mmol) in DMF (100 mL) was stirred at 20 °C for 16 h. The reaction was quenched with H ₂ O (150 mL) and extracted with EtOAc (150 mL x 2). The organic layer was washed with brine (100 mL) and dried over Na ₂ SO ₄ and concentrated in vacuo to give methyl 2-cyclohexyl-2-hydroxyacetate (5 g, 90 % Yield) as a yellow oil. Step 2: A mixture of methyl 2-cyclohexyl-2-hydroxyacetate (5.00 g, 1 Eq, 29.0 mmol) and1- (benzyloxy)-3-(bromomethyl)benzene (9.66 g, 1.2 Eq, 34.8 mmol) in THF (80 mL) at 0 °C, then Sodium hydride (1.51 g, 1.3 Eq, 37.7 mmol) was added to the mixture at 0 °C and stirred for 5 min, the reaction was warmed to 25 °C and stirred for 12 h. The reaction mixture was added to water (200 mL) at 0°C and extracted with EtOAc (200 mL x 3). The organic layer was washed with brine (50 mL) and dried over Na ₂ SO ₄ and concentrated in vacuo to give a residue. The residue was purified by prep-HPLC (column: Welch Xtimate C18100*40mm*3um; mobile phase: [water (FA)-ACN]; B% 65%-100%, 9min) to give methyl 2-((3-(benzyloxy)benzyl)oxy)- 2-cyclohexylacetate (5.2 g, 46 % yield, 93.8% purity) as a yellow oil. LC-MS (ESI ⁺ ) m/z: 386.0 (M+18) ⁺ . Step 3: A mixture of methyl 2-((3-(benzyloxy)benzyl)oxy)-2-cyclohexylacetate (5.2 g, 1 Eq, 13 mmol) and sodium hydroxide (1.6 g, 3 Eq, 40 mmol) in THF (30 mL) and MeOH (30 mL) was stirred at 25 °C for 16 h. The reaction was adjust to pH=5 with 1M HCl. Then the mixture was added water (150 mL) and extracted with ethyl acetate (200 x 2 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to dryness in vacuo to give 2-((3-(benzyloxy)benzyl)oxy)-2-cyclohexylacetic acid (5.1 g, 100 % Yield, 94.168% Purity) as a yellow oil. Step 4: A mixture of 2-((3-(benzyloxy)benzyl)oxy)-2-cyclohexylacetic acid (5.1 g, 1 Eq, 14 mmol) in DCM (70 mL) was stirred at 0 °C with N ₂ , then Trifluoroaceticanhydride (11 g, 4 Eq, 54 mmol) was added to the mixture and the reaction was stirred at 0 °C for 16 h. The mixture was added H ₂ O (150 mL) and extracted with EtOAc (200 mL x 2). The combined extracts was dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to dryness in vacuo to give a residue. The residue was subjected to column chromatography over silica gel (petroleum ether/ethyl acetate from 100/0 to 80/20). The pure fractions were collected and concentrated to dryness in vacuo to give 7-(benzyloxy)-3-cyclohexylisochroman-4-one (1.4 g, 23 % Yield, 74.584% purity) as a yellow solid. LC-MS (ESI+) m/z: 336.9 (M+H) ⁺ Step 5: To a solution of 1-(4-bromophenyl)-4-(dimethoxymethyl)piperidine (1.4 g, 2 Eq, 4.4 mmol) in THF (15 mL) was added dropwise n-Butyllithium, 2.5M in hexane (1.4 mL, 2.5 M, 1.6 Eq, 3.5 mmol) at -78 °C with N ₂ . After addition, the mixture was stirred at this temperature for 1 hour, and then 7-(benzyloxy)-3-cyclohexylisochroman-4-one (1 g, 1 Eq, 2.217 mmol) in THF (5 mL) was added dropwise at -78 °C. The resulting mixture was stirred at 25 °C for 16 hour. TLC (PE/EtOAc = 5/1, R _f = 0.4). The reaction mixture was quenched into a solution of saturated ammonium chloride solution followed by extraction with EtOAc (100 mL*2). The combined extracts was dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to dryness in vacuo to give 7-(benzyloxy)-3-cyclohexyl-4-(4-(4-(dimethoxymethyl)piperidi n-1-yl)phenyl)isochroman-4-ol as a brown oil. The brown oil was purified by flash silica gel chromatography. The desired fractions were collected, and concentrated to dryness in vacuo to give 7-(benzyloxy)-3- cyclohexyl-4-(4-(4-(dimethoxymethyl)piperidin-1-yl)phenyl)is ochroman-4-ol (960 mg, 1.3 mmol, 59 %, 78% purity) as a yellow solid. LC-MS (ESI+) m/z: 572.3(M+H) ⁺ . Step 6: A mixture of 7-(benzyloxy)-3-cyclohexyl-4-(4-(4-(dimethoxymethyl)piperidi n-1- yl)phenyl)isochroman-4-ol (700 mg, 1 Eq, 955 ^mol), dihydrogen (2.17 mg, 1 Eq, 1.07 mmol), Pd/C (2 g, 10% Wt, 2 Eq, 2 mmol) in THF (10 mL) and MeOH (10 mL) was degassed and purged with H ₂ for 3 times, and then the mixture was stirred at 50 °C for 48 h under H ₂ atmosphere (15 psi). LCMS showed 43.4% desired MS. The reaction was filtered and concentrated to dryness in vacuo to give the mixture as a brown oil. The brown oil was purified by Prep. HPLC. Condition: Column: Boston Green ODS 150*30mm*5um, A: water (FA), B: CAN, at the beginning: A (50%) and B (50%), at the end: A: (20%) and B (80%), Gradient Time (min) 6; 100% B hold Time (min) 1, Flow Rate (ml/min) 30. The pure fractions were collected and the solvent was evaporated under vacuum. The aqueous layer was lyophilized to dryness to give cis-3-cyclohexyl-4-(4-(4-(dimethoxymethyl)piperidin-1-yl)phe nyl)isochroman-7-ol (187 mg, 402 ^mol, 37.5 %, 100% purity) as a brown oil and trans-3-cyclohexyl-4-(4-(4- (dimethoxymethyl)piperidin-1-yl)phenyl)isochroman-7-ol (48 mg, 99 ^mol, 9.2 %, 95.8% purity) as a brown oil.2D NMR confirmed. LC-MS (ESI+) m/z: 466.4(M+H) ⁺ . Step 7: The brown oil was purified by SFC. Condition: CO2-EtOH (0.1%NH3H2O); Column: Time(min): 45, Flow Rate(ml/min): 80. The pure fractions were collected and the solvent was evaporated under vacuum. The aqueous layer was lyophilized to dryness to give (3R,4R)-3- cyclohexyl-4-(4-(4-(dimethoxymethyl)piperidin-1-yl)phenyl)is ochroman-7-ol (38 mg, 80 ^mol, 97.71% purity) as a white solid, (3S,4S)-3-cyclohexyl-4-(4-(4-(dimethoxymethyl)piperidin-1- yl)phenyl)isochroman-7-ol (35 mg, 100% Purity) as a white solid. LC-MS (ESI+) m/z: 466.3(M+H) ⁺ . Step 8: To a solution of (3R,4R)-3-cyclohexyl-4-(4-(4-(dimethoxymethyl)piperidin-1- yl)phenyl)isochroman-7-ol (35 mg, 1 Eq, 73 ^mol) in THF (7 mL) was added sulfuric acid (72 mg, 1 Eq, 73 ^mol). The mixture was stirred at 70 °C for 3 h. LCMS showed 94.7 % desired MS. The mixture was adjusted to pH=8 by progressively adding NaHCO ₃ . The reaction mixture was quenched by addition 100 mL EtOAc at 20°C, and then diluted with 50 mL H ₂ O and extracted with EtOAc 50 mL (25 mL x 2). The combined organic layers were washed with brine (10 mL), dried over Na ₂ SO ₄ . The reaction was filtered and concentrated under reduced pressure to give 1-(4-((3R,4R)-3-cyclohexyl-7-hydroxyisochroman-4-yl)phenyl)p iperidine-4- carbaldehyde (64 mg, 94.7% purity, crude) as a brown solid. LC-MS (ESI+) m/z: 438.3(M+H) ⁺ . Step 9: A mixture of 1-(4-((3R,4R)-3-cyclohexyl-7-hydroxyisochroman-4-yl)phenyl)p iperidine- 4-carbaldehyde (64 mg, 1 Eq, 0.14 mmol), (S)-3-(1-oxo-5-(piperazin-1-yl)isoindolin-2- yl)piperidine-2,6-dione, PhSO ₃ H salt (72 mg, 1 Eq, 0.14 mmol) and sodium acetate (59 mg, 5 Eq, 0.72 mmol) in DCM (2 mL) and MeOH (2 mL) at 20 °C for 0.5 h, pH=8, then acetic acid (26 mg, 3 Eq, 0.43 mmol) at 20°C for 1 h, pH=6, then added sodium triacetoxyhydroborate (61 mg, 2 Eq, 0.29 mmol) the mixture, and then the mixture was stirred at 25 °C for 16 h. LCMS showed 41.4% desired MS. The reaction was concentrated to give (S)-3-(5-(4-((1-(4-((3*R,4*R)-3- cyclohexyl-7-hydroxyisochroman-4-yl)phenyl)piperidin-4-yl)me thyl)piperazin-1-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione as a brown oil. The reaction mixture was diluted with 50 mL H ₂ O and extracted with EtOAc (25 mL * 2). The brown oil was purified by preparative high- performance liquid chromatography. Condition: Column: Welch Xtimate C18150*30mm*5um, A: water (FA), B: CAN, at the beginning: A (73%) and B (27%), at the end: A: (43%) and B (57%), Gradient Time (min) 7; 100% B hold Time(min)0, Flow Rate(ml/min) 25. The pure fractions were collected and the solvent was evaporated under vacuum. The aqueous layer was lyophilized to dryness to give (S)-3-(5-(4-((1-(4-((3R,4R)-3-cyclohexyl-7-hydroxyisochroman -4- yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindo lin-2-yl)piperidine-2,6-dione (21 mg, 28 ^mol, 20 %, 98.76% purity) as a white solid. LCMS: calc. for C ₄₄ H ₅₃ N ₅ O ₅ : 731.4, found: [M+H] ⁺ 732.3. HPLC: 98.76% purity at 220 nm. ¹ H NMR (400 MHz, DMSO-d6) į = 10.95 (s, 1H), 9.19 (s, 1H), 8.14 (s, 0.461H), 7.52 (d, J = 8.6 Hz, 1H), 7.09 - 7.04 (m, 4H), 6.75 (dd, J = 8.6, 11.3 Hz, 3H), 6.48 (dd, J = 2.6, 8.3 Hz, 1H), 6.42 (d, J = 2.1 Hz, 1H), 5.04 (dd, J = 5.1, 13.2 Hz, 1H), 4.87 (d, J = 15.3 Hz, 1H), 4.64 (br d, J = 15.3 Hz, 1H), 4.36 - 4.29 (m, 1H), 4.23 - 4.16 (m, 1H), 3.74 (d, J = 2.4 Hz, 1H), 3.60 (br dd, J = 1.8, 4.2 Hz, 2H), 3.29 (br d, J = 3.7 Hz, 9H), 2.89 (s, 1H), 2.58 (br d, J = 13.8 Hz, 4H), 2.38 - 2.32 (m, 1H), 2.21 (br d, J = 6.6 Hz, 2H), 1.99 - 1.93 (m, 2H), 1.80 (br d, J = 11.0 Hz, 3H), 1.61 (br dd, J = 2.4, 6.9 Hz, 4H), 1.24 - 1.17 (m, 2H), 1.03 - 0.88 (m, 5H). EXAMPLE 65. Preparation of (I-250) (S)-3-(5-(4-((1-(4-((3S,4S)-3-cyclohexyl-7- hydroxyisochroman-4-yl)phenyl)piperidin-4-yl)methyl)piperazi n-1-yl)-1-oxoisoindolin-2- yl)piperidine-2,6-dione Step 1: To a solution of (3S,4S)-3-cyclohexyl-4-(4-(4-(dimethoxymethyl)piperidin-1- yl)phenyl)isochroman-7-ol (35 mg, 100% Wt, 1 Eq, 75 ^mol) in THF (7 mL) was added sulfuric acid (74 mg, 7 mL, 10% Wt, 1 Eq, 75 ^mol). The mixture was stirred at 70 °C for 3 hour. LCMS showed 97 % desired MS. The mixture was adjusted to pH 8-9 by progressively adding NaHCO ₃ . The reaction mixture was quenched by addition 100 mL EtOAc at 20°C, and then diluted with 50 mL H ₂ O and extracted with EtOAc(25 mL * 2). The combined organic layers were washed with 10 mL, dried over Na ₂ SO ₄ . The reaction was filtered and concentrated under reduced pressure to give 1-(4-((3S,4S)-3-cyclohexyl-7-hydroxyisochroman-4- yl)phenyl)piperidine-4-carbaldehyde (50 mg, 0.12 mmol, crude, 97% purity) as a brown solid. LC-MS (ESI+) m/z: 438.3(M+H) ⁺ . Step 2: A mixture of 1-(4-((3S,4S)-3-cyclohexyl-7-hydroxyisochroman-4-yl)phenyl)p iperidine- 4-carbaldehyde (50 mg, 97% Wt, 1 Eq, 0.12 mmol), (S)-3-(1-oxo-5-(piperazin-1-yl)isoindolin-2- yl)piperidine-2,6-dione, PhSO ₃ H salt (58 mg, 1 Eq, 0.12 mmol) and sodium acetate (47 mg, 5 Eq, 0.58 mmol) in DCM (2 mL) and MeOH (2 mL) at 20°C for 0.5 hour, pH=8, then acetic acid (21 mg, 20 ^L, 3 Eq, 0.35 mmol) at 20°C for 1 hour, pH=6, then added sodium triacetoxyhydroborate (49 mg, 2 Eq, 0.23 mmol) the mixture, and then the mixture was stirred at 25 °C for 16 hour. LCMS showed 41.59% desired MS. The reaction was concentrated to give (S)-3-(5-(4-((1-(4-((3S,4S)-3-cyclohexyl-7-hydroxyisochroman -4-yl)phenyl)piperidin-4- yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2, 6-dione as a brown oil. The mixture was added 20 mL water and extracted by EtOAc (50 mL x3). The brown oil was purified by preparative high-performance liquid chromatography. Condition: Column: Welch Xtimate C18 150*30mm*5um, A: water (FA), B: CAN, at the beginning: A (73%) and B (27%), at the end: A: (43%) and B (57%), Gradient Time(min) 7; 100% B hold Time(min) 0, Flow Rate(ml/min) 25. The pure fractions were collected and the solvent was evaporated under vacuum. The aqueous layer was lyophilized to dryness to give (S)-3-(5-(4-((1-(4-((3S,4S)-3-cyclohexyl-7- hydroxyisochroman-4-yl)phenyl)piperidin-4-yl)methyl)piperazi n-1-yl)-1-oxoisoindolin-2- yl)piperidine-2,6-dione (18.8 mg, 25.1 ^mol, 22 %, 97.61% purity) as a white solid. LCMS: calc. C ₄₄ H ₅₃ N ₅ O ₅ : 731.4, found: [M+H] ⁺ 732.3. HPLC: 97.61% purity at 220 nm. NMR (400 MH DMSO d ) į 1095 ( 1H) 928 910 ( 1H) 816 ( 0506H) 752 (d J = 8.6 Hz, 1H), 7.11 - 7.02 (m, 4H), 6.75 (dd, J = 8.7, 11.1 Hz, 3H), 6.48 (dd, J = 2.6, 8.3 Hz, 1H), 6.42 (d, J = 2.3 Hz, 1H), 5.04 (dd, J = 5.0, 13.2 Hz, 1H), 4.87 (d, J = 15.6 Hz, 1H), 4.64 (br d, J = 15.1 Hz, 1H), 4.36 - 4.29 (m, 1H), 4.22 (s, 1H), 3.74 (br d, J = 1.5 Hz, 1H), 3.59 (br d, J = 4.8 Hz, 3H), 3.29 (br d, J = 3.2 Hz, 8H), 2.88 (br d, J = 12.6 Hz, 1H), 2.63 - 2.53 (m, 4H), 2.40 - 2.31 (m, 1H), 2.21 (br d, J = 6.9 Hz, 2H), 1.99 - 1.92 (m, 2H), 1.80 (br d, J = 11.6 Hz, 3H), 1.68 - 1.49 (m, 4H), 1.25 - 1.17 (m, 2H), 1.03 - 0.85 (m, 5H). EXAMPLE 66. Preparation of (I-248) (S)-3-(5-(4-((1-(4-((3R,4S)-3-cyclohexyl-7- hydroxyisochroman-4-yl)phenyl)piperidin-4-yl)methyl)piperazi n-1-yl)-1-oxoisoindolin-2- yl)piperidine-2,6-dione Step 1: The brown oil was purified by SFC. Condition: CO2-EtOH (0.1%NH3H2O); Column: DAICEL CHIRALPAK AD (250mm*30mm, 10um), Begin B: 40%, End B: 40%, FlowRate(ml/min): 80, The pure fractions were collected and the solvent was evaporated under vacuum. The aqueous layer was lyophilized to dryness to give (3R,4S)-3-cyclohexyl-4-(4-(4- (dimethoxymethyl)piperidin-1-yl)phenyl)isochroman-7-ol (15 mg, 30 ^mol, 19 %, 93.7% purity) as a colorless oil, (3S,4R)-3-cyclohexyl-4-(4-(4-(dimethoxymethyl)piperidin-1- yl)phenyl)isochroman-7-ol (15 mg, 30 ^mol, 18 %, 92.61% purity) as a colorless oil. LC-MS (ESI+) m/z: 466.3(M+H) ⁺ . Step 2: To a solution of (3R,4S)-3-cyclohexyl-4-(4-(4-(dimethoxymethyl)piperidin-1- yl)phenyl)isochroman-7-ol (15 mg, 93.7% Wt, 1 Eq, 30 ^mol) in THF (2 mL) was added sulfuric acid (30 mg, 2 mL, 10% Wt, 1 Eq, 30 ^mol). The mixture was stirred at 70 °C for 3 hour. LCMS showed 97.97 % desired MS. The mixture was adjusted to pH 8-9 by progressively adding NaHCO ₃ . The reaction mixture was quenched by addition 100 mL EtOAc at 20°C, and then diluted with 50 mL H ₂ O and extracted with EtOAc (25 mL * 2). The combined organic layers were washed with 10 mL, dried over Na2SO4. The reaction was filtered and concentrated under reduced pressure to give 1-(4-((3R,4S)-3-cyclohexyl-7-hydroxyisochroman-4- yl)phenyl)piperidine-4-carbaldehyde (30 mg, 70 ^mol, crude, 97.97% purity) as a brown oil. LC- MS (ESI+) m/z: 438.0(M+H) ⁺ . Step 3: A mixture of 1-(4-((3R,4S)-3-cyclohexyl-7-hydroxyisochroman-4-yl)phenyl)p iperidine- 4-carbaldehyde (30 mg, 1 Eq, 70 ^mol) , (S)-3-(1-oxo-5-(piperazin-1-yl)isoindolin-2- yl)piperidine-2,6-dione, PhSO3H salt (35 mg, 1 Eq, 70 ^mol) and sodium acetate (29 mg, 5 Eq, 0.35 mmol) in DCM (2 mL) and MeOH (2 mL) at 20°C for 0.5 hour, pH=8, then acetic acid (13 mg, 12 ^L, 3 Eq, 0.21 mmol) at 20°C for 1 hour, pH=6, then added sodium triacetoxyhydroborate (30 mg, 2 Eq, 0.14 mmol) the mixture, and then the mixture was stirred at 25 °C for 16 hour. The reaction was concentrated to give (S)-3-(5-(4-((1-(4-((3R,4S)-3- cyclohexyl-7-hydroxyisochroman-4-yl)phenyl)piperidin-4-yl)me thyl)piperazin-1-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione as a brown oil. The reaction mixture was diluted with 50 mL H ₂ O and extracted with EtOAc (25 mL * 2). The brown oil was purified by preparative high- performance liquid chromatography. Condition: Column: Welch Xtimate C18150*30mm*5um, A: water (FA), B: CAN, at the beginning: A (79%) and B (21%), at the end: A: (49%) and B (51%) Gradient Time (min) 7; 100% B hold Time (min) 05 Flow Rate(ml/min) 25 The pure fractions were collected and the solvent was evaporated under vacuum. The aqueous layer was lyophilized to dryness to give (S)-3-(5-(4-((1-(4-((3R,4S)-3-cyclohexyl-7-hydroxyisochroman -4- yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindo lin-2-yl)piperidine-2,6-dione (8.1 mg, 11 ^mol, 16 %, 98.69% purity) as a white solid. LCMS: calc. C ₄₄ H ₅₃ N ₅ O ₅ : 731.94, found: [M+H] ⁺ 732.4. HPLC: 98.69% purity at 220 nm. 10.95 (s, 1H), 9.17 (s, 1H), 8.13 (s, 0.275H), 7.52 (d, J = 8.6 Hz, 1H), 7.09 - 7.04 (m, 2H), 6.97 - 6.92 (m, 2H), 6.89 - 6.83 (m, 2H), 6.47 - 6.39 (m, 3H), 5.05 (dd, J = 4.7, 13.1 Hz, 1H), 4.72 (s, 2H), 4.33 (d, J = 16.9 Hz, 1H), 4.24 - 4.16 (m, 1H), 3.90 (br d, J = 10.3 Hz, 1H), 3.70 - 3.61 (m, 2H), 3.46 (br d, J = 2.0 Hz, 1H), 2.61 (br d, J = 10.7 Hz, 5H), 2.43 - 2.36 (m, 3H), 2.24 (br dd, J = 1.6, 4.9 Hz, 3H), 2.02 - 1.90 (m, 2H), 1.83 (br d, J = 11.3 Hz, 4H), 1.73 - 1.53 (m, 5H), 1.42 - 1.35 (m, 2H), 1.29 - 1.12 (m, 5H), 1.09 - 1.00 (m, 3H). EXAMPLE 67. Preparation of (I-249) (S)-3-(5-(4-((1-(4-((3S,4R)-3-cyclohexyl-7- hydroxyisochroman-4-yl)phenyl)piperidin-4-yl)methyl)piperazi n-1-yl)-1-oxoisoindolin-2- yl)piperidine-2,6-dione Step 1: To a solution of (3S,4R)-3-cyclohexyl-4-(4-(4-(dimethoxymethyl)piperidin-1- yl)phenyl)isochroman-7-ol (15 mg, 92.61% Wt, 1 Eq, 30 ^mol) in THF (2 mL) was added sulfuric acid (29 mg, 2 mL, 10% Wt, 1 Eq, 30 ^mol). The mixture was stirred at 70 °C for 3 hour. LCMS showed 98.01 % desired MS. The mixture was adjusted to pH 8-9 by progressively adding NaHCO ₃ . The reaction mixture was quenched by addition 100 mL EtOAc at 20°C, and then diluted with 50 mL H ₂ O and extracted with EtOAc (25 mL * 2). The combined organic layers were washed with 10 mL, dried over Na ₂ SO ₄ . The reaction was filtered and concentrated under reduced pressure to give 1-(4-((3S,4R)-3-cyclohexyl-7-hydroxyisochroman-4- yl)phenyl)piperidine-4-carbaldehyde (30 mg, 70 ^mol, crude, 98.01% purity) as a brown oil. LC-MS (ESI+) m/z: 438.0(M+H) ⁺ . Step 2: A mixture of 1-(4-((3S,4R)-3-cyclohexyl-7-hydroxyisochroman-4-yl)phenyl)p iperidine- 4-carbaldehyde (30 mg, 1 Eq, 70 ^mol) , (S)-3-(1-oxo-5-(piperazin-1-yl)isoindolin-2- yl)piperidine-2,6-dione, Tosylic acid (35 mg, 1 Eq, 70 ^mol) and sodium acetate (29 mg, 5 Eq, 0.35 mmol) in DCM (2 mL) and MeOH (2 mL) at 20°C for 0.5 hour, pH=8, then acetic acid (13 mg, 12 ^L, 3 Eq, 0.21 mmol) at 20°C for 1 hour, pH=6, then added sodium triacetoxyhydroborate (30 mg, 2 Eq, 0.14 mmol) the mixture, and then the mixture was stirred at 25 °C for 16 hour . LCMS showed 41.4% desired MS. The reaction was concentrated to give (S)-3-(5-(4-((1-(4-((3S,4R)-3-cyclohexyl-7-hydroxyisochroman -4-yl)phenyl)piperidin-4- yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2, 6-dione. The reaction mixture was diluted with 50 mL H ₂ O and extracted with EtOAc (25 mL * 2). The brown oil was purified by preparative high-performance liquid chromatography. Condition: Column: Welch Xtimate C18 150*30mm*5um, A: water (FA), B: CAN, at the beginning: A (79%) and B (21%), at the end: A: (49%) and B (51%), Gradient Time(min) 7; 100% B hold Time(min)0.5, Flow Rate(ml/min) 25. The pure fractions were collected and the solvent was evaporated under vacuum. The aqueous layer was lyophilized to dryness to give (S)-3-(5-(4-((1-(4-((3S,4R)-3-cyclohexyl-7- hydroxyisochroman-4-yl)phenyl)piperidin-4-yl)methyl)piperazi n-1-yl)-1-oxoisoindolin-2- yl)piperidine-2,6-dione (5.8 mg, 7.9 ^mol, 11 %, 100% Purity) as a white solid. LCMS: calc. C ₄₄ H ₅₃ N ₅ O ₅ : 731.9, found: [M+H] ⁺ 732.4. HPLC: 100% purity at 220 nm. ¹ H NMR (400 MH DMSO d ) į 1095 ( 1H) 918 (b d J 26 H 1H) 818 ( 0286H) 7.52 (br d, J = 8.7 Hz, 1H), 7.10 - 7.04 (m, 2H), 6.98 - 6.91 (m, 2H), 6.86 (br d, J = 8.5 Hz, 2H), 6.48 - 6.37 (m, 3H), 5.10 - 5.01 (m, 1H), 4.72 (s, 2H), 4.38 - 4.28 (m, 1H), 4.23 (s, 1H), 3.90 (br d, J = 9.8 Hz, 1H), 3.69 - 3.61 (m, 2H), 3.45 (br d, J = 11.3 Hz, 2H), 2.98 - 2.80 (m, 2H), 2.61 (br d, J = 10.8 Hz, 5H), 2.39 (br s, 3H), 2.23(br d, J = 6.9 Hz, 2H), 1.99 - 1.93 (m, 1H), 1.87 - 1.80 (m, 3H), 1.75 - 1.51 (m, 5H), 1.42 - 1.34 (m, 2H), 1.30 - 1.12 (m, 5H), 1.04 (br d, J = 1.1 Hz, 3H).

EXAMPLE 68. Preparation of (I-418) (S)-3-(5-(4-((1-(4-((3R,4R)-3-cyclohexyl-7- hydroxy-3-methylisochroman-4-yl)phenyl)piperidin-4-yl)methyl )piperazin-1-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione

Step 1: A mixture of 2-cyclohexyl-2-hydroxyacetic acid (10.0 g, 1 Eq, 63.2 mmol), Cesium fluoride (14.4 g, 3.50 mL, 1.5 Eq, 94.8 mmol) and methyl iodide (13.5 g, 6.13 mL, 1.5 Eq, 94.8 mmol) in DMF (80 mL) was stirred at 20 °C for 16 hour. TLC (PE:EtOAc=5:1, R _f =0.5) showed a new spot was detected. The mixture was added H ₂ O (300 mL) and extracted with EtOAc (200 mL * 2). The combined extracts was dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to dryness in vacuo to give methyl 2-cyclohexyl-2-hydroxyacetate (10.52 g, 61.08 mmol, 96.6 %) as a brown oil. NMR confirmed. Step 2: A mixture of methyl 2-cyclohexyl-2-hydroxyacetate (10.52 g, 1 Eq, 61.08 mmol) and1- (benzyloxy)-3-(bromomethyl)benzene (20.32 g, 1.2 Eq, 73.30 mmol) in THF (200 mL) at 0 °C, then Sodium hydride (3.176 g, 2.6 mL, 60% Wt, 1.3 Eq, 79.41 mmol) was added to the mixture at 0 °C and stirred for 5 min, the reaction was warmed to 25 °C and stirred for 12 hour. The reaction mixture was added to water (300 mL) at 0°C and extracted with ethyl acetate (300 mL * 3). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by Prep.HPLC. Column: Xtimate C18150*40mm*5um, Condition: water (FA)-MeOH, at the beginning: A (35%) and B (65%), at the end: A (0%) and B (100%), Gradient Time(min) 9, 100% B hold Time(min) 2, Flow Rate(ml/min) 30. The pure fractions were collected and the solvent was evaporated under vacuum. The aqueous layer was lyophilized to dryness to give methyl 2-((3-(benzyloxy)benzyl)oxy)-2-cyclohexylacetate (8.79 g, 22.4 mmol, 36.6 %, 93.8% purity) as a yellow oil. LCMS and NMR confirmed. LC-MS (ESI ⁺ ) m/z: 391.1 (M+23) ⁺ . Step 3: A mixture of methyl 2-((3-(benzyloxy)benzyl)oxy)-2-cyclohexylacetate (8.79 g, 93.8% Wt, 1 Eq, 22.4 mmol) and sodium hydroxide (2.69 g, 22.4 mL, 3 molar, 3 Eq, 67.1 mmol) in THF (30 mL) and MeOH (30 mL) was stirred at 25 °C for 16 hour. The reaction was adjust to pH=~5 with 1M HCl (40 mL). Then the mixture was added water (200 mL) and extracted with ethyl acetate (3×150 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to dryness in vacuo to give 2-((3- (benzyloxy)benzyl)oxy)-2-cyclohexylacetic acid (8.836 g, 21 mmol, 94 %, 84% purity) as a yellow oil. NMR confirmed. LC-MS (ESI ⁺ ) m/z: 371.9(M+23) ⁺ . Step 4: A mixture of 2-((3-(benzyloxy)benzyl)oxy)-2-cyclohexylacetic acid (8.836 g, 84% Wt, 1 Eq, 20.94 mmol) in DCM (100 mL) was stirred at 0 °C with N2, then Trifluoroaceticanhydride 0 °C for 16 hour. TLC (PE/EtOAc=10/1, Rf =0.4) showed a new spot was detected. The mixture was added H2O (150 mL) and extracted with EtOAc (200 mL * 2). The combined extracts was dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to dryness in vacuo to give a residue. The residue was subjected to column chromatography over silica gel (petroleum ether/ethyl acetate from 100/0 to 90/10). The pure fractions were collected and concentrated to dryness in vacuo to give 7-(benzyloxy)-3-cyclohexylisochroman-4-one (1.35 g, 3.96 mmol, 18.9 %, 98.75% Purity) as a yellow solid. The yellow solid was purified by Prep.HPLC. Condition: Column: Xtimate C18150*40mm*5um, A: water(FA), B:CAN, at the beginning: A (30%) and B (70%), at the end: A: (0%) and B (100%), Gradient Time(min) 9; 100% B hold Time(min) 5, Flow Rate(ml/min) 30. The pure fractions were collected and the solvent was evaporated under vacuum. The aqueous layer was lyophilized to dryness to give 7-(benzyloxy)-3- cyclohexylisochroman-4-one (1.35 g, 3.96 mmol, 18.9 %, 98.75% Purity) as a yellow solid. LC- MS (ESI+) m/z: 337.1 (M+H) ⁺ Step 5: To a solution of 7-(benzyloxy)-3-cyclohexylisochroman-4-one (1.12 g, 1 Eq, 3.33 mmol) in THF (15 mL) was added LDA (713 mg, 3.33 mL, 2 molar, 2 Eq, 6.66 mmol) at -70 °C under N2. The reaction mixture was stirred at -70 °C for 1 hour. Then methyl iodide (1.42 g, 646 ^L, 3 Eq, 9.99 mmol) was added to the mixture dropwise at -70 °C. The reaction mixrure was warmed to 25 °C and stirred for 16 hour. TLC(PE/EtOAc = 10/1, R _f = 0.4) showed two spots. The reaction mixture was quenched into a solution of saturated ammonium chloride solution followed by extraction with EtOAc (100 mL*2). The combined extracts was dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to dryness in vacuo to give mixture as a yellow solid. The yellow solid was purified by flash silica gel chromatography (from PE/EtOAc = 1/0 to 10/1). The desired fractions were collected, and concentrated to dryness in vacuo to give 7- (benzyloxy)-3-cyclohexyl-3-methylisochroman-4-one (400 mg, 1.13 mmol, 34.0 %, 99.1% purity) as a colorless oil. The colorless oil was purified by preparative high-performance liquid chromatography. Condition: Column: Boston Green ODS 150*30mm*5um, A: water(FA), B:CAN, at the beginning: A (15%) and B (85%), at the end: A: (0%) and B (100%), Gradient Time(min) 6; 100% B hold Time(min) 1, Flow Rate(ml/min) 30. The pure fractions were collected and the solvent was evaporated under vacuum. The aqueous layer was lyophilized to dryness to give7-(benzyloxy)-3-cyclohexyl-3-methylisochroman-4-one (400 mg, 1.13 mmol, 34.0 %, 99.1% Purity) as a white solid. NMR confirmed. LC-MS (ESI+) m/z: 351.1(M+H) ⁺ . Step 6: To a solution of 1-(4-bromophenyl)-4-(dimethoxymethyl)piperidine (880 mg, 3 Eq, 2.80 mmol) in THF (20 mL) was added dropwise n-Butyllithium in hexane (149 mg, 933 ^L, 2.5 M, 2.5 Eq, 2.33 mmol) at -78 °C with N ₂ . After addition, the mixture was stirred at this temperature for 1 hour, and then 7-(benzyloxy)-3-cyclohexyl-3-methylisochroman-4-one (330 mg, 1 Eq, 933 ^mol) in THF (5 mL) was added dropwise at -78 °C. The resulting mixture was stirred at 25 °C for 16 hour. TLC(PE/EtOAc = 5/1, R _f = 0.4) showed three spots. The reaction mixture was quenched into a solution of saturated ammonium chloride solution followed by extraction with EtOAc (100 mL*3). The combined extracts was dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to dryness in vacuo to give mixture as a brown oil. The brown oil was purified by flash silica gel chromatography (from PE/EtOAc = 1/0 to 25/1). The desired fractions were collected, and concentrated to dryness in vacuo to give 7-(benzyloxy)-3-cyclohexyl-4-(4-(4- (dimethoxymethyl)piperidin-1-yl)phenyl)-3-methylisochroman-4 -ol (544 mg, 881 ^mol, 94.4 %, 94.87% purity) as a yellow oil. LC-MS (ESI+) m/z: 586.3(M+H) ⁺ . Step 7: A mixture of 7-(benzyloxy)-3-cyclohexyl-4-(4-(4-(dimethoxymethyl)piperidi n-1- yl)phenyl)-3-methylisochroman-4-ol (524 mg, 94.87% Wt, 1 Eq, 849 ^mol), dihydrogen (1.71 mg, 1 Eq, 849 ^mol), Pd/C(780 mg, 10% Wt, 0.864 Eq, 733 ^mol) in THF (10 mL) and MeOH (10 mL) was degassed and purged with H ₂ for 3 times, and then the mixture was stirred at 55 °C for 16 hour under H ₂ atmosphere (15 psi). The mixture was filtered and the filter cake was washed by EtOAc (100 mL * 3). The brown oil was purified by preparative high-performance liquid chromatography. Condition: water(NH ₃ H ₂ O+NH ₄ HCO ₃ )-CAN, Column: Boston Prime C18150*30mm*5um, at the beginning: A (75%) and B (70%), at the end: A: (45%) and B (100%) Gradient Time(min) 7; 100% B hold Time(min) 2, Flow Rate(ml/min) 25. The pure fractions were collected and the solvent was evaporated under vacuum. The reaction was filtered and concentrated to dryness in vacuo to give cis-3-cyclohexyl-4-(4-(4-(dimethoxymethyl)piperidin- 1-yl)phenyl)-3-methylisochroman-7-ol(110 mg, 108 ^mol, 12.7 %, 94.04% purity) as a white solid and trans-3-cyclohexyl-4-(4-(4-(dimethoxymethyl)piperidin-1-yl)p henyl)-3- methylisochroman-7-ol(243 mg, 253 ^mol, 29.8 %, 100% purity) as a white solid. NMR confirmed.2D NMR confirmed. LC-MS (ESI+) m/z: 480.2(M+H) ⁺ . Step 8: The white solid was purified by SFC. Condition: CO2-EtOH(0.1%NH3H2O); Column: DAICEL CHIRALPAK IG (250mm*30mm10um) Begin B:45% End B:45% FlowRate(ml/min): 80. The pure fractions were collected and the solvent was evaporated under vacuum. The aqueous layer was lyophilized to dryness to give (3R,4R)-3-cyclohexyl-4-(4-(4- (dimethoxymethyl)piperidin-1-yl)phenyl)-3-methylisochroman-7 -ol (66 mg, 0.14 mmol, 27 %, 100% purity) as a white solid and (3S,4S)-3-cyclohexyl-4-(4-(4-(dimethoxymethyl)piperidin-1- yl)phenyl)-3-methylisochroman-7-ol (74 mg, 0.15 mmol, 30 %, 100% purity) as a white solid. LC-MS (ESI+) m/z: 480.2(M+H) ⁺ . Step 9: To a solution of (3R,4R)-3-cyclohexyl-4-(4-(4-(dimethoxymethyl)piperidin-1- yl)phenyl)-3-methylisochroman-7-ol (66 mg, 1 Eq, 0.14 mmol) in THF (7 mL) was added sulfuric acid (0.13 g, 7 mL, 10% Wt, 1 Eq, 0.14 mmol). The mixture was stirred at 70 °C for 2 hour. The mixture was adjusted to pH=8-9 by progressively adding NaHCO ₃ . The reaction mixture was quenched by addition 100 mL EtOAc at 20°C, and then diluted with 50 mL H ₂ O and extracted with EtOAc (25 mL * 2). The combined organic layers were washed with 10 mL, dried over Na ₂ SO ₄ . The reaction was filtered and concentrated under reduced pressure to give 1- (4-((3R,4R)-3-cyclohexyl-7-hydroxy-3-methylisochroman-4-yl)p henyl)piperidine-4- carbaldehyde (70 mg, 0.16 mmol, 110 %, 97.34% purity) as a yellow oil. LC-MS (ESI+) m/z: 452.1(M+18) ⁺ . Step 10: A mixture of 1-(4-((3R,4R)-3-cyclohexyl-7-hydroxy-3-methylisochroman-4- yl)phenyl)piperidine-4-carbaldehyde (70 mg, 97.34% Wt, 1 Eq, 0.16 mmol), (S)-3-(1-oxo-5- (piperazin-1-yl)isoindolin-2-yl)piperidine-2,6-dione PhSO ₃ H salt(52 mg, 1 Eq, 0.16 mmol) and sodium acetate (64 mg, 5 Eq, 0.79 mmol) in DCM (2 mL) and MeOH (2 mL) at 20°C for 0.5 hour, pH=8, then acetic acid (28 mg, 27 ^L, 3 Eq, 0.47 mmol) at 20°C for 1 hour, pH=6, then added sodium triacetoxyborohydride (67 mg, 2 Eq, 0.31 mmol) the mixture, and then the mixture was stirred at 25 °C for 16 hour. The reaction was quenched with water (50 mL) and extracted with ethyl acetate(50 mL*2). The reaction was concentrated to give (S)-3-(5-(4-((1-(4-((3R,4R)- 3-cyclohexyl-7-hydroxy-3-methylisochroman-4-yl)phenyl)piperi din-4-yl)methyl)piperazin-1- yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione as a colorless oil. The colorless oil was purified by preparative high-performance liquid chromatography. Condition: Column: Welch Xtimate C18 150*30mm*5um, A: water (FA), B:CAN, at the beginning: A (87%) and B (13%), at the end: A: (57%) and B (43%), Gradient Time(min) 7; 100% B hold Time(min) 3.5, Flow Rate(ml/min) 25. The pure fractions were collected, and the solvent was evaporated under vacuum. The aqueous layer was lyophilized to dryness to give (S)-3-(5-(4-((1-(4-((3R4R)-3-cyclohexyl-7-hydroxy-3- methylisochroman-4-yl)phenyl)piperidin-4-yl)methyl)piperazin -1-yl)-1-oxoisoindolin-2- yl)piperidine-2,6-dione (36.8 mg, 47.5 ^mol, 30 %, 96.26% purity) as a white solid. LCMS: calc. for C ₄₄ H ₅₅ N ₅ O ₅ : 745.42, found: [M+H] ⁺ 746.3. HPLC: 96.26% purity at 220 nm. ¹ H NMR (400 MHz, DMSO-d6) į = 10.95 (s, 1H), 9.14 (br s, 1H), 8.15 (s, 0.321H), 7.51 (d, J = 8.6 Hz, 1H), 7.10 - 7.01 (m, 4H), 6.74 (dd, J = 6.2, 8.3 Hz, 3H), 6.49 - 6.41 (m, 2H), 5.09 - 5.00 (m, 1H), 4.85 - 4.78 (m, 1H), 4.72 - 4.64 (m, 1H), 4.30 (s, 1H), 4.24 - 4.15 (m, 1H), 3.55 (s, 3H), 3.28 (br s, 5H), 2.94 - 2.85 (m, 1H), 2.55 (br d, J = 6.1 Hz, 6H), 2.36 (br dd, J = 4.8, 13.2 Hz, 1H), 2.21 (br s, 2H), 1.98 - 1.93 (m, 1H), 1.86 (br s, 1H), 1.79 (br d, J = 11.0 Hz, 3H), 1.69 - 1.61 (m, 2H), 1.59 - 1.49 (m, 2H), 1.24 - 1.16 (m, 2H), 1.04 (s, 5H), 0.91 (br d, J = 9.9 Hz, 3H), 0.72 - 0.62 (m, 1H). EXAMPLE 69. Preparation of (I-256) (S)-3-(5-(4-((1-(4-((3S,4S)-3-cyclohexyl-7- hydroxy-3-methylisochroman-4-yl)phenyl)piperidin-4-yl)methyl )piperazin-1-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione Step 1: To a solution of (3S,4S)-3-cyclohexyl-4-(4-(4-(dimethoxymethyl)piperidin-1-yl )phenyl)- 3-methylisochroman-7-ol (74 mg, 100% Wt, 1 Eq, 0.15 mmol) in THF (7 mL) was added sulfuric acid (0.15 g, 7 mL, 10% Wt, 1 Eq, 0.15 mmol). The mixture was stirred at 70 °C for 2 hours. The mixture was adjusted to pH =8-9 by progressively adding NaHCO ₃ . The reaction mixture was quenched by addition100 mL EtOAc at 20°C, and then diluted with H ₂ O 50 mL and extracted with EtOAc 50mL (25 mL * 2). The combined organic layers were washed with, dried over Na ₂ SO ₄ . The reaction was filtered and concentrated under reduced pressure to give 1-(4- ((3S,4S)-3-cyclohexyl-7-hydroxy-3-methylisochroman-4-yl)phen yl)piperidine-4-carbaldehyde (80 mg, 0.18 mmol, 120 %, 98.36% purity) as a brown oil. LC-MS (ESI ⁺ ) m/z: 452.1 (M+18) ⁺ . Step 2: A mixture of 1-(4-((3S,4S)-3-cyclohexyl-7-hydroxy-3-methylisochroman-4- yl)phenyl)piperidine-4-carbaldehyde (80 mg, 98.36% Wt, 1 Eq, 0.18 mmol) , (S)-3-(1-oxo-5- (piperazin-1-yl)isoindolin-2-yl)piperidine-2,6-dione PhSO ₃ H salt (60 mg, 1 Eq, 0.18 mmol) and sodium acetate (74 mg, 5 Eq, 0.91 mmol) in DCM (2 mL) and MeOH (2 mL) at 20°C for 0.5 hr, pH=8, then acetic acid (33 mg, 31 ^L, 3 Eq, 0.54 mmol) at 20°C for 1 hr, pH=6, then added sodium triacetoxyborohydride (77 mg, 2 Eq, 0.36 mmol) the mixture, and then the mixture was stirred at 25 °C for 16 hour .LCMS showed 77.3% desired MS. The reaction was quenched with water (50 mL) and extracted with ethyl acetate (50 mL*2). The reaction was concentrated to give (S)-3-(5-(4-((1-(4-((3S,4S)-3-cyclohexyl-7-hydroxy-3-methyli sochroman-4-yl)phenyl)piperidin- 4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine- 2,6-dione as a colorless oil. The colorless oil was purified by preparative high-performance liquid chromatography. Condition: Column: Boston Green ODS 150*30mm*5um A: water (FA) B:CAN at the beginning: A (75%) and B (25%) at the end: A: (45%) and B (55%) Gradient Time(min) 6; 100% B hold Time(min)1, Flow Rate(ml/min) 30. The pure fractions were collected, and the solvent was evaporated under vacuum. The aqueous layer was lyophilized to dryness to give (S)-3-(5-(4-((1- (4-((3S,4S)-3-cyclohexyl-7-hydroxy-3-methylisochroman-4-yl)p henyl)piperidin-4- yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2, 6-dione (49.5 mg, 65.3 ^mol, 36 %, 98.48% purity) as a white solid. LCMS: calc. for C ₄₄ H ₅₅ N ₅ O ₅ : 745.42, found: [M+H] ⁺ 746.3. HPLC: 98.48% purity at 220 nm. ¹ H NMR (400 MH DMSO d ) į 1095 ( 1H) 914 ( 1H) 814 ( 0387H) 751 (d J 8.5 Hz, 1H), 7.09 - 7.02 (m, 4H), 6.74 (dd, J = 6.1, 8.2 Hz, 3H), 6.49 - 6.40 (m, 2H), 5.05 (dd, J = 4.9, 13.4 Hz, 1H), 4.86 - 4.77 (m, 1H), 4.68 (br d, J = 16.3 Hz, 1H), 4.37 - 4.28 (m, 1H), 4.24 - 4.16 (m, 1H), 3.62 - 3.54 (m, 3H), 3.28 (br s, 5H), 2.95 - 2.84 (m, 1H), 2.62 - 2.51 (m, 6H), 2.39 - 2.32 (m, 1H), 2.21 (br d, J = 6.4 Hz, 2H), 1.99 - 1.92 (m, 1H), 1.90 - 1.84 (m, 1H), 1.79 (br d, J = 10.3 Hz, 3H), 1.65 (br s, 2H), 1.59 - 1.48 (m, 2H), 1.19 (br d, J = 10.0 Hz, 2H), 1.04 (s, 5H), 0.91 (br d, J = 10.6 Hz, 3H), 0.73 - 0.61 (m, 1H). EXAMPLE 70. Preparation of (I-257) (S)-3-(5-(4-((1-(4-((3R,4S)-3-cyclohexyl-7- hydroxy-3-methylisochroman-4-yl)phenyl)piperidin-4-yl)methyl )piperazin-1-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione Step 1: The white solid was purified by SFC. Condition: CO2-EtOH(0.1%NH3H2O); Column: DAICEL CHIRALPAK AD(250mm*30mm,10um), Begin B: 50%, End B: 50%, FlowRate(ml/min): 80. The pure fractions were collected and the solvent was evaporated under vacuum. The aqueous layer was lyophilized to dryness to give (3R,4S)-3-cyclohexyl-4-(4-(4- (dimethoxymethyl)piperidin-1-yl)phenyl)-3-methylisochroman-7 -ol (15 mg, 30 ^mol, 14 %, 96.62% purity) as a colorless oil and ((3S,4R)-3-cyclohexyl-4-(4-(4- (dimethoxymethyl)piperidin-1-yl)phenyl)-3-methylisochroman-7 -ol (11 mg, 23 ^mol, 11 %, 100% purity) as a colorless oil. LC-MS (ESI ⁺ ) m/z: 480.2 (M+H) ⁺ . Step 2: To a solution of (3R,4S)-3-cyclohexyl-4-(4-(4-(dimethoxymethyl)piperidin-1-yl )phenyl)- 3-methylisochroman-7-ol (15 mg, 1 Eq, 30 ^mol) in THF (2 mL) was added sulfuric acid (30 mg, 2 mL, 10% Wt, 1 Eq, 30 ^mol). The mixture was stirred at 70 °C for 1 hour. The mixture was adjusted to pH 8-9 by progressively adding NaHCO ₃ . The reaction mixture was quenched by addition 100 mL EtOAc at 20°C, and then diluted with 50 m H ₂ OL and extracted with EtOAc (25 mL * 2). The combined organic layers were washed with 10 mL, dried over Na2SO4. The reaction was filtered and concentrated under reduced pressure to give 1-(4-((3R,4S)-3- cyclohexyl-7-hydroxy-3-methylisochroman-4-yl)phenyl)piperidi ne-4-carbaldehyde (25 mg, 56 ^mol, 180 %, 96.5% purity) as a colorless oil. LC-MS (ESI ⁺ ) m/z: 452.2 (M+18) ⁺ . Step 3: A mixture of 1-(4-((3R,4S)-3-cyclohexyl-7-hydroxy-3-methylisochroman-4- yl)phenyl)piperidine-4-carbaldehyde (25 mg, 96.5% Wt, 1 Eq, 56 ^mol), (S)-3-(1-oxo-5- (piperazin-1-yl)isoindolin-2-yl)piperidine-2,6-dione PhSO3H salt (18 mg, 1 Eq, 56 ^mol) and sodium acetate (23 mg, 5 Eq, 0.28 mmol) in DCM (2 mL) and MeOH (2 mL) at 20°C for 0.5 hour, pH=8, then acetic acid (10 mg, 9.5 ^L, 3 Eq, 0.17 mmol) at 20°C for 1 hour, pH=6, then added Sodium triacetoxyborohydride (24 mg, 2 Eq, 0.11 mmol) the mixture, and then the mixture was stirred at 25 °C for 16 hour. The reaction was quenched with water (50 mL) and extracted with ethyl acetate (50 mL*2). The reaction was concentrated to give (S)-3-(5-(4-((1-(4- ((3R,4S)-3-cyclohexyl-7-hydroxy-3-methylisochroman-4-yl)phen yl)piperidin-4- yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2, 6-dione as a colorless oil. The colorless oil was purified by preparative high-performance liquid chromatography. Condition: water (FA)-CAN. Column: Boston Green ODS 150*30mm*5um. Begin B (20%), End: B (50%). were collected and the solvent was evaporated under vacuum. The aqueous layer was lyophilized to dryness to give (S)-3-(5-(4-((1-(4-((3R,4S)-3-cyclohexyl-7-hydroxy-3-methyli sochroman-4- yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindo lin-2-yl)piperidine-2,6-dione (15.9 mg, 21.1 ^mol, 38 %, 98.89% Purity) as a white solid. LCMS: calc. for C ₄₄ H ₅₅ N ₅ O ₅ : 745.42, found: [M+H] ⁺ 746.5. HPLC: 98.89% purity at 220 nm. ¹ H NMR (400 MHz, DMSO-d ₆ ) į = 10.95 (s, 1H), 9.25 - 9.12 (m, 1H), 8.19 - 8.10 (m, 0.343H), 7.55 - 7.47 (m, 1H), 7.07 (s, 2H), 6.91 (br d, J = 7.7 Hz, 2H), 6.76 (br d, J = 8.8 Hz, 2H), 6.69 (d, J = 8.5 Hz, 1H), 6.51 - 6.43 (m, 2H), 5.09 - 5.01 (m, 1H), 4.77 - 4.70 (m, 1H), 4.64 - 4.57 (m, 1H), 4.36 - 4.29 (m, 1H), 4.24 - 4.16 (m, 1H), 3.81 (s, 1H), 3.59 (br d, J = 11.0 Hz, 2H), 3.28 (br s, 5H), 2.96 - 2.84 (m, 1H), 2.68 - 2.53 (m, 6H), 2.40 - 2.32 (m, 1H), 2.21 (br d, J = 7.0 Hz, 2H), 1.99 - 1.92 (m, 1H), 1.83 - 1.76 (m, 3H), 1.76 - 1.64 (m, 4H), 1.62 - 1.55 (m, 1H), 1.53 - 1.43 (m, 1H), 1.25 - 1.17 (m, 2H), 1.16 - 1.06 (m, 3H), 1.02 (br s, 2H), 0.68 (s, 3H).

EXAMPLE 71. Preparation of (I-258) (S)-3-(5-(4-((1-(4-((3S,4R)-3-cyclohexyl-7- hydroxy-3-methylisochroman-4-yl)phenyl)piperidin-4-yl)methyl )piperazin-1-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione Step 1: To a solution of (3S,4R)-3-cyclohexyl-4-(4-(4-(dimethoxymethyl)piperidin-1-yl )phenyl)- 3-methylisochroman-7-ol (11 mg, 1 Eq, 23 ^mol) in THF (2 mL) was added sulfuric acid (22 mg, 2 mL, 10% Wt, 1 Eq, 23 ^mol). The mixture was stirred at 70 °C for 1 hour. The mixture was adjusted to pH 8-9 by progressively adding NaHCO ₃ . The reaction mixture was quenched by addition 100 mL EtOAc at 20°C, and then diluted with 50 mL H ₂ O and extracted with EtOAc (25 mL * 2). The combined organic layers were washed with 10 mL, dried over Na2SO4. The reaction was filtered and concentrated under reduced pressure to give 1-(4-((3S,4R)-3- cyclohexyl-7-hydroxy-3-methylisochroman-4-yl)phenyl)piperidi ne-4-carbaldehyde (15 mg, 33 ^mol, 140 %, 94.9% purity) as a colorless oil. LC-MS (ESI ⁺ ) m/z: 452.2 (M+18) ⁺ . Step 2: A mixture of 1-(4-((3S,4R)-3-cyclohexyl-7-hydroxy-3-methylisochroman-4- yl)phenyl)piperidine-4-carbaldehyde (15 mg, 94.9% Wt, 1 Eq, 33 ^mol), (S)-3-(1-oxo-5- (piperazin-1-yl)isoindolin-2-yl)piperidine-2,6-dione PhSO ₃ H salt (11 mg, 1 Eq, 33 ^mol) and sodium acetate (13 mg, 5 Eq, 0.16 mmol) in DCM (2 mL) and MeOH (2 mL) at 20°C for 0.5 hour pH=8 then acetic acid (59 mg 56 ^L 3 Eq 98 ^mol) at 20°C for 1 hour pH=6 then added Sodium triacetoxyborohydride (14 mg, 2 Eq, 66 ^mol) the mixture, and then the mixture was stirred at 25 °C for 16 hour. The reaction was quenched with water (50 mL) and extracted with ethyl acetate (50 mL*2). The reaction was concentrated to give (S)-3-(5-(4-((1-(4-((3S,4R)- 3-cyclohexyl-7-hydroxy-3-methylisochroman-4-yl)phenyl)piperi din-4-yl)methyl)piperazin-1- yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione as a colorless oil. The colorless oil was purified by preparative high-performance liquid chromatography. Condition: water(FA)-CAN. Column: Boston Green ODS 150*30mm*5um. Begin B (25%), End: B (55%), Gradient Time(min) 6; 100% B hold Time(min) 1, Flow Rate(ml/min) 30. The pure fractions were collected, and the solvent was evaporated under vacuum. The aqueous layer was lyophilized to dryness to give (S)-3-(5-(4-((1-(4-((3S,4R)-3-cyclohexyl-7-hydroxy-3- methylisochroman-4-yl)phenyl)piperidin-4-yl)methyl)piperazin -1-yl)-1-oxoisoindolin-2- yl)piperidine-2,6-dione (6.4 mg, 8.5 ^mol, 26 %, 99.03% purity) as a white solid. LCMS: calc. for C ₄₄ H ₅₅ N ₅ O ₅ : 745.42, found: [M+H] ⁺ 746.4. HPLC: 99.03% purity at 220 nm. NMR (400 MHz, DMSO-d6) į = 10.98 - 10.93 (m, 1H), 9.22 - 9.16 (m, 1H), 8.20 - 8.17 (m, 0.413H), 7.54 - 7.49 (m, 1H), 7.06 (s, 2H), 6.94 - 6.86 (m, 2H), 6.79 - 6.74 (m, 2H), 6.71 - 6.66 (m, 1H), 6.51 - 6.43 (m, 2H), 5.08 - 5.01 (m, 1H), 4.78 - 4.69 (m, 1H), 4.64 - 4.56 (m, 1H), 4.36 - 4.29 (m, 1H), 4.24 - 4.16 (m, 1H), 3.83 - 3.78 (m, 1H), 3.62 - 3.56 (m, 2H), 3.30 - 3.25 (m, 6H), 2.93 - 2.84 (m, 1H), 2.69 - 2.55 (m, 6H), 2.36 - 2.32 (m, 1H), 2.24 - 2.18 (m, 2H), 1.99 - 1.91 (m, 1H), 1.83 - 1.76 (m, 3H), 1.74 - 1.67 (m, 3H), 1.61 - 1.55 (m, 1H), 1.53 - 1.44 (m, 1H), 1.24 - 1.17 (m, 2H), 1.15 - 1.06 (m, 3H), 1.05 - 0.96 (m, 2H), 0.68 (s, 3H).

EXAMPLE 72. Preparation of (I-267) (S)-3-(5-(4-((1-(4-((1R,4'S)-7'-hydroxy-2,3- dihydrospiro[indene-1,3'-isochroman]-4'-yl)phenyl)piperidin- 4-yl)methyl)piperazin-1-yl)- 1-oxoisoindolin-2-yl)piperidine-2,6-dione (18.5 mg, 24.6 ^mol, 27% yield) Step 1: A mixture of (5-(benzyloxy)-2-bromophenyl)methanol (30 g, 102 mmol, 1 eq), tert-butyl 2-bromoacetate (24 g, 123 mmol, 18 mL, 1.2 eq), KOH (14 g, 102 mmol, 240 mL, 40% purity, 1 eq), TBAB (3 g, 9.3 mmol, 0.09 eq) was added in toluene (200 mL), the mixture was stirred at 50 °C for 16 h. TLC (petroleum ether: ethyl acetate=10:1, R _f =0.7 UV) showed one main new spot was observed. The resulting solution was diluted with H ₂ O (200 mL) and was extracted with Ethyl acetate (300 mL*2), the organic layers were dried with anhydrous Na ₂ SO ₄ , filtered, and concentrated to give the crude product. The residue was purified by column chromatography (SiO ₂ , Petroleum ether/Ethyl acetate=10/0 to 9/1). Compound tert-butyl 2-((5-(benzyloxy)-2- bromobenzyl)oxy)acetate (34 g, 83 mmol, 82% yield) was obtained as a yellow oil. Step 2: A mixture of tert-butyl 2-((5-(benzyloxy)-2-bromobenzyl)oxy)acetate (34 g, 83 mmol, 1 eq) was added in TFA (150 mL) and DCM (150 mL) the mixture was stirred at 25 °C for 1hr. TLC (petroleum ether: ethyl acetate=10:1, R _f =0.2 UV) showed one main new spot was observed. The resulting solution was quenched with saturated aqueous NaHCO ₃ and adjusted pH to 8 at 0 °C, was treated with 200 mL H ₂ O extracted with ethyl acetate (500 mL*2), The organic layers were dried with anhydrous Na2SO4, filtered, and concentrated to give the crude product. The crude product 2-((5-(benzyloxy)-2-bromobenzyl)oxy)acetic acid (1.6 g, 4.6 mmol, 96% yield) was used into the next step without further purification. Compound 2-((5-(benzyloxy)-2- bromobenzyl)oxy)acetic acid (24 g, 68.3 mmol, 82% yield) was obtained as a red oil. Step 3: A mixture of 2-((5-(benzyloxy)-2-bromobenzyl)oxy)acetic acid (24 g, 68.3 mmol, 1 eq), N,O-dimethylhydroxylamine hydrogen chloride (6.7 g, 68 mmol, 1 eq), HATU (39 g, 102.5 mmol, 1.5 eq), DIEA (26.5 g, 205 mmol, 35.7 mL, 3 eq) in DMF (200 mL) and was stirred at 25 °C for 12 h. TLC (petroleum ether: ethyl acetate=10:1, R _f =0.6 UV) showed one main new spot was observed. The resulting solution was diluted with 300 mL H ₂ O and was extracted with Ethyl acetate (600 mL*2), the organic layers were dried with anhydrous Na ₂ SO ₄ , filtered, and concentrated to give the crude product. The residue was purified by column chromatography (SiO ₂ , Petroleum ether/Ethyl acetate=10/0 to 9/1). Compound 2-((5-(benzyloxy)-2- bromobenzyl)oxy)-N-methoxy-N-methylacetamide (20 g, 50.7 mmol, 74% yield) was obtained as a white solid. Step 4: A solution of 2-((5-(benzyloxy)-2-bromobenzyl)oxy)-N-methoxy-N-methylaceta mide (4 g, 1 Eq, 10.1 mmol) in THF (100 mL) was stirred at -78 °C for 10 min under N2 atmosphere, was stirred at -78 °C to 25 °C for 16 hour under N2 atmosphere. TLC (petroleum ether: ethyl acetate=5:1, UV) showed one main new spot was observed. The reaction was quenched with aq.NH ₄ Cl (100 mL) and extracted with ethyl acetate (100 mL*3). The organic layer was washed with brine (100 mL) and dried over Na ₂ SO ₄ and concentrated in vacuum to give crude product. The black oil was subjected to column chromatography over silica gel (gradient elution: 0 – 20% ethyl acetate). The desired fractions were collected, and concentrated to dryness in vacuum to give 7-(benzyloxy)isochroman-4-one (2.3 g, 9 mmol, 89 % yield) as a yellow solid. Step 5: A mixture of 7-(benzyloxy)isochroman-4-one (1.6 g, 6.3 mmol, 1 eq), 2-(2- bromophenyl)ethanol (1.5 g, 7.6 mmol, 1 mL, 1.2 eq), KOH (353 mg, 6.3 mmol, 1 eq), Ru(PPh ₃ ) ₂ Cl ₂ (575 mg, 629 ^mol, 0.1 eq) was added in toluene (10 mL), the mixture was stirred at 100 °C for 12 h. TLC (petroleum ether: ethyl acetate=10:1, R _f =0.7 UV) showed one main new spot was observed. The resulting solution was diluted with H ₂ O (50 mL) and was extracted with ethyl acetate (100 mL*2), the organic layers were dried with anhydrous Na ₂ SO ₄ , filtered, and concentrated to give the crude product. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate=10/0 to 9/1). Compound 7-(benzyloxy)-3-(2- bromophenethyl)isochroman-4-one (1.2 g, 2.7 mmol, 43% yield) was obtained as a yellow oil. Step 6: A mixture of 7-(benzyloxy)-3-(2-bromophenethyl)isochroman-4-one (1.2 g, 2.7 mmol, 1 eq), dicesium carbonate (1.8 g, 5.4 mmol, 2 eq), Pd(OAc) ₂ (61 mg, 272 ^mol, 0.1 eq), [1-(2- diphenylphosphanyl-1-naphthyl)-2-naphthyl]-diphenyl-phosphan e (254 mg, 408 ^mol, 0.15 eq) was added in toluene (10 mL) and was purged N ₂ 3 times, the mixture was stirred at 100 °C for 12h. TLC (petroleum ether: ethyl acetate=10:1, R _f =0.7 UV) showed one main new spot was observed. The resulting solution was quenched with 50 mL H ₂ O and was extracted with ethyl acetate (100 mL*2), the organic layers were dried with anhydrous Na ₂ SO ₄ , filtered, and concentrated to give the crude product. The residue was purified by column chromatography (SiO ₂ , Petroleum ether/Ethyl acetate=10/0 to 9/1). Compound 7'-(benzyloxy)-2,3- dihydrospiro[indene-1,3'-isochroman]-4'-one (700 mg, 2 mmol, 72% yield) was obtained as a yellow oil. Step 7: n-Butyllithium (2.5 M, 2.4 mL, 3 eq) was added into mixture of 1-(4-bromophenyl)-4- (dimethoxymethyl)piperidine (2 g, 6.4 mmol, 3.2 eq) in THF (10 mL) under N2 at -78 °C, and the mixture was stirred at -78 °C for 0.5 h under N2 atmosphere, and 7'-(benzyloxy)-2,3- at -78 °C and was stirred at 25 °C for 12h. TLC (petroleum ether: ethyl acetate=10:1, Rf =0.7 UV) showed one main new spot was observed. The resulting solution was quenched with saturated aqueous NH ₄ Cl (20 mL) at 0 °C and diluted with H ₂ O (50 mL) and was extracted with ethyl acetate (100 mL), The organic layers were washed with brine (50 mL), dried with anhydrous Na ₂ SO ₄ , filtered, and concentrated to give the crude product. The residue was purified by column chromatography (SiO ₂ , Petroleum ether/Ethyl acetate=10/0 to 9/1). Compound 7'-(benzyloxy)-4'-(4-(4-(dimethoxymethyl)piperidin-1-yl)phen yl)-2,3- dihydrospiro[indene-1,3'- isochroman]-4'-ol (1.1 g, 1.9 mmol, 95% yield) was obtained as a yellow oil. Step 8: A mixture of 7'-(benzyloxy)-4'-(4-(4-(dimethoxymethyl)piperidin-1-yl)phen yl)-2,3- dihydrospiro[indene-1,3'- isochroman]-4'-ol (500 mg, 845 ^mol, 1 eq), Pd/C (500 mg, 470 ^mol, 10% purity,), Pd(OH) ₂ /C (500 mg, 3.6 mmol) was added in THF (10 mL) and MeOH (10 mL), the mixture was stirred at 70 °C for 12 h. TLC (petroleum ether: ethyl acetate=10:1, R _f =0.7, UV) showed one main new spot was observed. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The crude product was purified by reversed-phase SFC(column: DAICEL CHIRALCEL OJ(250mm*30mm,10um);mobile phase: [CO2- MeOH(0.1%NH3H2O)];B%:35%%, isocratic elution mode rentention time 3.213,3.534 ) and by HPLC(column: Xtimate C18150*40mm*5um;mobile phase: [water(FA)- ACN];gradient:25%-65% B over 9 min). Compound (1R,4'S)-4'-(4-(4- (dimethoxymethyl)piperidin-1-yl)phenyl)-2,3-dihydrospiro[ind ene-1,3'-isochroman]-7'-ol (100 mg, 205.9 ^mol, 24% yield) and (1S,4'R)-4'-(4-(4-(dimethoxymethyl)piperidin-1-yl)phenyl)-2, 3- dihydrospiro[indene-1,3'-isochroman]-7'-ol (120 mg, 247.1 ^mol, 29% yield) was obtained as a white solid. LC-MS (ESI+) m/z: 486.2 (M+H) ⁺ . Step 9: To a solution of (1R,4'S)-4'-(4-(4-(dimethoxymethyl)piperidin-1-yl)phenyl)-2, 3- dihydrospiro[indene-1,3'-isochroman]-7'-ol (50 mg, 103 ^mol, 1 eq) in 10%H ₂ SO ₄ (4 mL) and THF (4 mL). The mixture was stirred at 70 °C for 1 h. TLC (petroleum ether: ethyl acetate=2:1, R _f =0.3 UV) showed one main new spot was observed. The reaction mixture was quenched by saturated aqueous NaHCO ₃ (20 mL) at 25 °C, and then diluted with H ₂ O (20 mL) and extracted with ethyl acetate (40 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue. The crude product 1-(4-((1R4'S)-7'-hydroxy-23-dihydrospiro[indene-13'-isochrom an]-4'- yl)phenyl)piperidine-4-carbaldehyde (40 mg, 91 ^mol, 88% yield) was used into the next step without further purification. Compound 1-(4-((1R,4'S)-7'-hydroxy-2,3-dihydrospiro[indene-1,3'- isochroman]-4'-yl)phenyl)piperidine-4-carbaldehyde (40 mg, 91 ^mol, 88% yield) was obtained as a yellow oil. LC-MS (ESI+) m/z: 440.1 (M+H) ⁺ . Step 10: To a solution of 1-(4-((1R,4'S)-7'-hydroxy-2,3-dihydrospiro[indene-1,3'-isoch roman]- 4'-yl)phenyl)piperidine-4-carbaldehyde (40 mg, 91 ^mol, 1 eq) and (3S)-3-(1-oxo-5-piperazin-1- yl-isoindolin-2-yl)piperidine-2,6-dione (46 mg, 91 ^mol, 1 eq, PhSO ₃ H salt) in DCM (4 mL) and MeOH (4 mL) was added sodium acetate (22 mg, 273 ^mol, 3 eq) .The mixture was stirred at 30 °C for 0.5 h. Then the mixture was added NaBH(OAc) ₃ (39 mg, 182 ^mol, 2 eq) and acetic acid (16 mg, 273 ^mol, 16 ^L, 3 eq). The mixture was stirred at 30 °C for 16 h finally. TLC (Dichloromethane: Methanol=10:1, R _f =0.3 UV) showed one main new spot was observed. The reaction mixture was diluted with H ₂ O (20 mL) and extracted with DCM (20 mL). The combined organic layers were washed with brine 20 mL, dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Welch Xtimate C18150*30mm*5um; mobile phase: [water(FA)-ACN];gradient:15%- 45% B over 7 min). (S)-3-(5-(4-((1-(4-((1R,4'S)-7'-hydroxy-2,3-dihydrospiro[ind ene-1,3'- isochroman]-4'-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-y l)-1-oxoisoindolin-2-yl)piperidine- 2,6-dione (18.5 mg, 24.6 ^mol, 27% yield) was obtained as a white solid. LC-MS (ESI ⁺ ) m/z: 752.5 (M+H) ⁺ . HPLC: 97%, purity at 220 nm. ¹ H NMR (400 MHz, DMSO-d ₆ ) į ppm 10.96 (s, 1 H) 9.25 - 9.32 (m, 1 H) 8.14 (s, 0.413 H) 7.53 (d, J=8.34 Hz, 1 H) 7.16 - 7.20 (m, 1 H) 7.05 - 7.13 (m, 3 H) 6.80 (t, J=7.27 Hz, 1 H) 6.72 (br d, J=8.82 Hz, 1 H) 6.65 (br s, 4 H) 6.53 - 6.58 (m, 2 H) 6.18 (d, J=7.75 Hz, 1 H) 5.05 (dd, J=13.11, 5.01 Hz, 1 H) 4.84 - 4.98 (m, 2 H) 4.28 - 4.38 (m, 1 H) 4.16 - 4.25 (m, 1 H) 3.80 (s, 1 H) 3.58 (br d, J=9.78 Hz, 2 H) 3.36 - 3.43 (m, 8 H) 2.84 - 2.93 (m, 3 H) 2.55 - 2.60 (m, 4 H) 2.31 - 2.43 (m, 2 H) 2.19 - 2.24 (m, 1 H) 2.07 - 2.14 (m, 1 H) 1.92 - 2.00 (m, 1 H) 1.66 - 1.81 (m, 3 H) 1.16 - 1.27 (m, 2 H). EXAMPLE 73. Preparation of (I-77) (S)-3-(5-(4-((1-(4-((1S,4'R)-7'-hydroxy-2,3- dihydrospiro[indene-1,3'-isochroman]-4'-yl)phenyl)piperidin- 4-yl)methyl)piperazin-1-yl)- 1-oxoisoindolin-2-yl)piperidine-2,6-dione Step 1: To a solution of (1S,4'R)-4'-(4-(4-(dimethoxymethyl)piperidin-1-yl)phenyl)-2, 3- dihydrospiro[indene-1,3'-isochroman]-7'-ol (60 mg, 123 ^mol, 1 eq) in 10% H2SO4 (4 mL) and THF (4 mL). The mixture was stirred at 70 °C for 1 h. TLC (petroleum ether: ethyl acetate=2:1, R _f =0.3 UV) showed one main new spot was observed. The reaction mixture was quenched by saturated aqueous NaHCO ₃ (20 mL) at 25 °C, and then diluted with 20 mL H ₂ O and extracted with 40 mL ethyl acetate. The combined organic layers were washed with 20 mL brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The crude product 1-(4-((1S,4'R)-7'-hydroxy-2,3-dihydrospiro[indene-1,3'-isoch roman]-4'- yl)phenyl)piperidine-4-carbaldehyde (40 mg, 91 ^mol, 74% yield) was used into the next step without further purification. Compound 1-(4-((1S,4'R)-7'-hydroxy-2,3-dihydrospiro[indene-1,3'- isochroman]-4'-yl)phenyl)piperidine-4-carbaldehyde (40 mg, 91 ^mol, 74% yield) was obtained as a yellow oil. LC-MS (ESI+) m/z: 458.2 (M+H ₂ O) ⁺ . Step 2: To a solution of 1-(4-((1S,4'R)-7'-hydroxy-2,3-dihydrospiro[indene-1,3'-isoch roman]-4'- yl)phenyl)piperidine-4-carbaldehyde (40 mg, 91 ^mol, 1 eq) and (3S)-3-(1-oxo-5-piperazin-1-yl- isoindolin-2-yl)piperidine-2,6-dione (45.6 mg, 91 ^mol, 1 eq, PhSO3H salt) in DCM (4 mL) and 30 °C for 0.5 h. Then the mixture was added NaBH(OAc)3 (39 mg, 182 ^mol, 2 eq) and acetic acid (16 mg, 273 ^mol, 16 ^L, 3 eq). The mixture was stirred at 30 °C for 16 h finally. TLC (DCM: Methanol=10:1, R _f =0.3, UV) showed one main new spot was observed. The reaction mixture was diluted with H ₂ O (10 mL) and extracted with DCM (20 mL * 2). The combined organic layers were washed with brine (10 mL * 2), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Welch Xtimate C18150*30mm*5um; mobile phase: [water(FA)-ACN];gradient:15%-45% B over 7 min). (S)-3-(5-(4-((1-(4-((1S,4'R)-7'-hydroxy-2,3-dihydrospiro[ind ene-1,3'-isochroman]- 4'-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoi ndolin-2-yl)piperidine-2,6-dione (21.4 mg, 28 ^mol, 31% yield) was obtained as a white solid. LC-MS (ESI ⁺ ) m/z: 752.4 (M+H) ⁺ . HPLC: 95%, purity at 220 nm. ¹ H NMR (400 MHz, DMSO-d ₆ ) į ppm 10.96 (s, 1 H) 9.28 (s, 1 H) 8.12 - 8.19 (m, 0.379 H) 7.54 (d, J=8.34 Hz, 1 H) 7.15 - 7.24 (m, 1 H) 7.03 - 7.13 (m, 3 H) 6.77 - 6.87 (m, 1 H) 6.61 - 6.75 (m, 5 H) 6.50 - 6.57 (m, 2 H) 6.13 - 6.23 (m, 1 H) 5.02 - 5.13 (m, 1 H) 4.84 - 4.99 (m, 2 H) 4.16 - 4.39 (m, 2 H) 3.76 - 3.84 (m, 1 H) 3.55 - 3.63 (m, 2 H) 3.35 - 3.40 (m, 8 H) 2.84 - 2.94 (m, 3 H) 2.55 - 2.63 (m, 4 H) 2.30 - 2.44 (m, 2 H) 2.18 - 2.25 (m, 1 H) 2.06 - 2.14 (m, 1 H) 1.92 - 2.01 (m, 1 H) 1.78 (br d, J=11.80 Hz, 3 H) 1.17 - 1.27 (m, 2 H).

EXAMPLE 74. Preparation of (I-346) (S)-3-(5-(4-((1-(4-((3R,4S)-3-(4-fluorophenyl)-7- hydroxyisochroman-4-yl)phenyl)piperidin-4-yl)methyl)piperazi n-1-yl)-1-oxoisoindolin-2- yl)piperidine-2,6-dione Step 1: The white solid was purified by SFC. Column: DAICEL CHIRALCEL OJ (250mm*30mm, 10um); Condition: CO ₂ -EtOH(0.1%NH ₃ H ₂ O); At the beginning: B (30%); At the end: B (30%); Flow Rate (ml/min) 80. The aqueous phase was lyophilized to dryness to give (3R,4S)-4-(4-(4-(dimethoxymethyl)piperidin-1-yl)phenyl)-3-(4 -fluorophenyl)isochroman-7-ol (52 mg, 0.10 mmol, 38 %, 95.5% purity) as a colorless oil and (3S,4R)-4-(4-(4- (dimethoxymethyl)piperidin-1-yl)phenyl)-3-(4-fluorophenyl)is ochroman-7-ol (63 mg, 0.13 mmol, 46 %, 95.1% purity) as a colorless oil. Step 2: To a solution of (3R,4S)-4-(4-(4-(dimethoxymethyl)piperidin-1-yl)phenyl)-3-(4 - fluorophenyl)isochroman-7-ol (52 mg, 1 Eq, 0.10 mmol) in THF (5 mL) was added 10% sulfuric acid (0.10 g, 5 mL). The mixture was stirred at 70 °C for 30 min. The mixture was adjusted to pH 8-9 by progressively adding NaHCO ₃ . The reaction mixture was quenched by addition 100 mL ethyl acetate at 20 °C, and then diluted with 50 mL H ₂ O and extracted with ethyl acetate (25 mL * 2). The combined organic layers were washed with 10 mL brine, dried over Na ₂ SO ₄ . The reaction was filtered and concentrated under reduced pressure to give 1-(4-((3R,4S)-3-(4- fluorophenyl)-7-hydroxyisochroman-4-yl)phenyl)piperidine-4-c arbaldehyde (80 mg, 0.17 mmol, 90.77% purity) as a colorless oil. LC-MS (ESI ⁺ ) m/z: 450.2 (M+18) ⁺ . Step 3: A mixture of 1-(4-((3R,4S)-3-(4-fluorophenyl)-7-hydroxyisochroman-4- yl)phenyl)piperidine-4-carbaldehyde (80 mg, 1 Eq, 0.17 mmol), (S)-3-(1-oxo-5-(piperazin-1- yl)isoindolin-2-yl)piperidine-2,6-dione benzenesulfonate (82 mg, 1 Eq, 0.17 mmol) and sodium acetate (69 mg, 5 Eq, 0.84 mmol) in DCM (2.5 mL) and MeOH (2.5 mL) at 20°C for 0.5 hour, pH=8, then acetic acid (30 mg, 29 ^L, 3 Eq, 0.50 mmol) at 20°C for 1 hour, pH=6, then added sodium triacetoxyborohydride (71 mg, 2 Eq, 0.34 mmol) the mixture, and then the mixture was stirred at 25 °C for 16 hour. The reaction was quenched with water (50 mL) and extracted with ethyl acetate (50 mL*2). The reaction was concentrated to give (S)-3-(5-(4-((1-(4-((3*S,4*R)-3- (4-fluorophenyl)-7-hydroxyisochroman-4-yl)phenyl)piperidin-4 -yl)methyl)piperazin-1-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione as a brown oil. The brown oil was purified by preparative high-performance liquid chromatography. Condition: water(NH ₃ H ₂ O+NH ₄ HCO ₃ )- ACN. Column: Boston Prime C18150*30mm*5um. Begin B:60%, End B: 90%. Gradient Time (min) 7; 100% B hold Time(min)0, Flow Rate(ml/min) 25. The pure fractions were collected and the solvent was evaporated under vacuum. The aqueous layer was lyophilized to dryness to give (S)-3-(5-(4-((1-(4-((3R,4S)-3-(4-fluorophenyl)-7-hydroxyisoc hroman-4-yl)phenyl)piperidin-4- yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2, 6-dione (13.5 mg, 17.8 ^mol, 11 %, 97.95% purity) as a white solid. LCMS: calc. for C ₄₄ H ₅₆ FN ₅ O ₅ : 743.35, found: [M+H] ⁺ 744.4. HPLC: 97.95% purity at 220 nm. NMR (400 MHz, DMSO-d6) į = 10.95 - 10.91 (m, 1H), 9.29 - 9.26 (m, 1H), 7.54 - 7.49 (m, 1H) 709 702 ( 4H) 698 692 ( 2H) 680 675 ( 1H) 660 653 ( 6H) 510 4.99 (m, 3H), 4.94 - 4.87 (m, 1H), 4.37 - 4.28 (m, 1H), 4.25 - 4.15 (m, 1H), 4.04 - 3.97 (m, 1H), 3.54 - 3.47 (m, 2H), 3.29 - 3.23 (m, 5H), 2.91 - 2.84 (m, 1H), 2.74 - 2.66 (m, 1H), 2.63 - 2.53 (m, 5H), 2.36 - 2.30 (m, 1H), 2.22 - 2.14 (m, 2H), 2.00 - 1.91 (m, 1H), 1.79 - 1.70 (m, 2H), 1.68 - 1.58 (m, 1H), 1.24 - 1.11 (m, 2H). EXAMPLE 75. Preparation of (I-35) (S)-3-(5-(4-((1-(4-((3S,4R)-3-(4-fluorophenyl)-7- hydroxyisochroman-4-yl)phenyl)piperidin-4-yl)methyl)piperazi n-1-yl)-1-oxoisoindolin-2- yl)piperidine-2,6-dione Step 1: To a solution of 1 (4 g, 1 Eq, 7 mmol) in THF (2 mL) was added 2 (7 g, 0.04 L, 0.8 molar, 5 Eq, 0.03 mol) at 15 °C. Then the mixture was stirred at 15 °C for 12 hours under N2. TLC showed that the new point was detected. NH ₄ CL (sat.aq.) (50 mL) was dropped into the mixture. Then the mixture was filtered and concentrated under vacuum to give the crude. Then the EtOAc (200 ml) was added into the mixture and extracted with EtOAc (3 x 200 mL). The organics players were dried by Na ₂ SO ₄ . The organics was concentrated under vacuum and purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® Silica Flash Column, Eluent of 0-10% Petroleum/Ethyl acetate ether gradient @ 60 mL/min) to give 3 (3 g, 70% yield) as yellow oil. 1H NMR (500 MHz, CHLOROFORM-d) į = 8.11 - 8.01 (m, 2H), 7.49 - 7.29 (m, 7H), 7.13 - 6.89 (m, 6H), 6.87 - 6.80 (m, 1H), 6.32 (s, 1H), 5.03 (s, 2H), 4.74 - 4.43 (m, 2H), 0.96 - 0.89 (m, 9H), 0.09 (d, J = 4.4 Hz, 6H). Step 2: To a solution of 3 (3.5 g, 1 Eq, 5.6 mmol) and Triethylsilane (3.3 g, 4.5 mL, 5 Eq, 28 mmol) in DCM (2 mL) was added Trimethylsilyl triflate (3.8 g, 3.1 mL, 3 Eq, 17 mmol) at - 78 °C. Then the mixture was warmed to 0 °C and stirred for 10 min. TLC showed that the new point was detected. NaHCO3 (sat.aq.) (50 mL) was added into the mixture. Then the mixture was filtered and concentrated under vacuum to give the crude. Then the EtOAc (150 ml) was added into the mixture and extracted with EtOAc (3 x 150 mL). The organics players were dried by Na ₂ SO ₄ . The organics was concentrated under vacuum and purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® Silica Flash Column, Eluent of 0-10% Petroleum/Ethyl acetate ether gradient @ 60 mL/min) to give 4 (2.1 g, 76% yield) as white solid. 1H NMR (400 MHz, CHLOROFORM-d) į = 7.47 - 7.34 (m, 5H), 7.16 (d, J = 8.3 Hz, 2H), 6.95 - 6.76 (m, 7H), 6.61 (d, J = 8.5 Hz, 2H), 5.19 - 5.04 (m, 5H), 4.01 (d, J = 3.0 Hz, 1H). Step 3: To a solution of 4 (2.5 g, 1 Eq, 5.1 mmol) in 1,4-dioxane (60 mL) was added 5 (1.6 g, 2 Eq, 10 mmol) and Cs ₂ CO ₃ (5.0 g, 3 Eq, 15 mmol) at 20 °C. Then the (2- Dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)[2-(2 '-amino-1,1'- biphenyl)]palladium(II) methanesulfonate (0.64 g, 0.15 Eq, 0.77 mmol) was added into the mixture at 20 °C. The mixture was stirred at 90 °C for 6 hours under N ₂ . LCMS showed that the desired product was detected. The mixture was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® Silica Flash Column, Eluent of 0-30% Petroleum/Ethyl acetate ether gradient @ 60 mL/min) to give 6 (1.5 g, 2.6 mmol, 52% yield) as yellow solid. LC-MS (ESI ⁺ ) m/z: 568.2 (M+H) ⁺ . Step 4: A solution of 6 (1 g, 1 Eq, 2 mmol) and Pd/C (2 g, 10% Wt, 1 Eq, 2 mmol) in Ethyl acetate (50 mL) and then degassed and purged with H ₂ for 3 times, and then the mixture was stirred at 15 °C for 12 hour under H ₂ atmosphere. The reaction mixture was filtered and concentrated under reduced pressure to get the product. LCMS showed that the starting material was consumed, and the desired product was detected. The mixture was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® Silica Flash Column, Eluent of 0-50% Petroleum/Ethyl acetate ethergradient @ 50 mL/min) to give 7 (600 mg, 70% yield) as white solid. LC-MS (ESI ⁺ ) m/z: 478.3 (M+H) ⁺ . 1H NMR (400 MHz, DMSO-d6) į = 9.28 (s, 1H), 7.09 - 7.02 (m, 2H), 6.99 - 6.91 (m, 2H), 6.77 (d, J = 8.1 Hz, 1H), 6.60 - 6.53 (m, 6H), 5.06 (d, J = 15.4 Hz, 1H), 5.00 (d, J = 3.0 Hz, 1H), 4.90 (d, J = 15.4 Hz, 1H), 4.04 - 3.97 (m, 2H), 3.52 (br d, J = 12.2 Hz, 2H), 3.30 (s, 2H), 3.24 (s, 6H), 2.44 - 2.40 (m, 1H), 1.63 (br d, J = 10.3 Hz, 2H), 1.31 - 1.20 (m, 2H)^ Step 5: The 7 (1 g, 1 Eq, 2 mmol) was purified by SFC (condition: CO ₂ -EtOH (0.1%NH ₃ H ₂ O), column: DAICEL CHIRALPAK OJ (250mm x 30 mm, 10 um), Begin B: 30, End B: 30) to give 8 (300 mg, 30% yield) as white solid and 8A (300 mg, 30% yield) as white solid. 8: LC-MS (ESI ⁺ ) m/z: 478.3 (M+H) ⁺ . 8A: LC-MS (ESI ⁺ ) m/z: 478.2 (M+H) ⁺ . Step 6: To a solution of 8A (300 mg, 1 Eq, 628 ^mol) in DCM (30 mL) was added Trifluoroacetic acid (4 g, 3 mL, 6e+1 Eq, 0.04 mol) at 15 °C. Then the mixture was stirred at 15 °C for 2 hours. LCMS showed that the desired product was detected. Then the mixture was filtered and concentrated under vacuum to give the 9A (300 mg, crude) as red oil. LC-MS (ESI ⁺ ) m/z: 450.5 (M+H+18) ⁺ Step 7: To a solution of 9A (300 mg, 1 Eq, 695 ^mol) in DCE (1 mL) and MeOH (1 mL) was added 034 (342 mg, 2 Eq, 1.04 mmol) and Sodium triacetoxyborohydride (737 mg, 5 Eq, 3.48 mmol) at 15 °C. Then the mixture was stirred at 15 °C for 1 hour. LCMS showed that the desired product was detected. The mixture was filtered and concentrated under vacuum to give the crude. The residue was purified by prep-HPLC (FA condition: Column: Phenomenex Gemini NX 150 x 30 mm x 5 um; Condition: water (NH ₄ HCO ₃ )-ACN, Begin B 45, End B 75, Gradient Time (min) 11, 100% B Hold Time (min) 2, Flow Rate (mL/min) 25.) to give I-35 (212.8 mg, 41 % yield) as a white solid. LCMS: calc. for C ₄₄ H ₄₆ FN ₅ O _5: 743.88, found: 744.5. HPLC: 100.00% purity at 220 nm ¹ H NMR (400 MHz, DMSO-d ₆ ) į = 10.93 (br s, 1H), 9.29 (s, 1H), 7.51 (d, J = 8.7 Hz, 1H), 7.10 - 7.01 (m, 4H), 7.00 - 6.92 (m, 2H), 6.77 (d, J = 8.1 Hz, 1H), 6.61 - 6.52 (m, 6H), 5.09 - 4.98 (m, 3H), 4.90 (br d, J = 15.3 Hz, 1H), 4.35 - 4.17 (m, 2H), 4.01 (d, J = 2.5 Hz, 1H), 3.51 (br d, J = 11.9 Hz, 2H), 3.27 (br s, 5H), 2.96 - 2.85 (m, 1H), 2.62 - 2.52 (m, 2H), 2.49 - 2.45 (m, 4H), 2.40 - 2.30 (m, 1H), 2.18 (br d, J = 7.0 Hz, 2H), 2.00 - 1.92 (m, 1H), 1.74 (br d, J = 11.7 Hz, 2H), 1.63 (br d, J = 2.4 Hz, 1H), 1.22 - 1.09 (m, 2H).

EXAMPLE 76. Preparation of (I-226) (S)-3-(5-(4-((1-(4-((3S,4S)-7-hydroxy-3- isopropylisochroman-4-yl)phenyl)piperidin-4-yl)methyl)pipera zin-1-yl)-1-oxoisoindolin-2- yl)piperidine-2,6-dione Step 1: A mixture of (3S,4S)-4-(4-(4-(dimethoxymethyl)piperidin-1-yl)phenyl)-3- isopropylisochroman-7-ol (85 mg, 1 Eq, 0.19 mmol) in THF (2.5 mL), then 10% H ₂ SO ₄ (2.5 mL) was added to the mixture and stirred at 70 °C for 0.5 h. The reaction was adjusted to pH=8 with aq. NaHCO ₃ at 0 °C. Then the mixture was added H ₂ O (20 mL) and extracted with EtOAc (20 mL x 2). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to dryness in vacuo to give 1-(4-((3S,4S)-7- hydroxy-3-isopropylisochroman-4-yl)phenyl)piperidine-4-carba ldehyde (75 mg, 100 %, 98.970% Purity) as a yellow solid. LC-MS (ESI+) m/z: 380.2 (M+H) ⁺ . Step 2: A mixture of 1-(4-((3S,4S)-7-hydroxy-3-isopropylisochroman-4-yl)phenyl)pi peridine-4- carbaldehyde (75 mg, 1 Eq, 0.20 mmol), (S)-3-(1-oxo-5-(piperazin-1-yl)isoindolin-2- yl)piperidine-2,6-dione benzenesulfonate (0.12 g, 1.3 Eq, 0.25 mmol), sodium acetate (80 mg, 5 Eq, 0.98 mmol) and AcOH (35 mg, 34 ^L, 3 Eq, 0.59 mmol) in DCM (3 mL) and MeOH (3 mL) was stirred at 25 °C for 1 h, then sodium triacetoxyborohydride (83 mg, 2 Eq, 0.39 mmol) was added to the mixture and was stirred at 25 °C for 16 h Then the mixture was added H ₂ O (20 mL) and extracted with EtOAc (20 mL x 2). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated to dryness in vacuo to give a residue. The residue was purified by prep-HPLC (column: Welch Xtimate C18150*30mm*5um; mobile phase: [water (FA)-ACN]; B% 10%-50%, 8 min) to give (S)-3-(5-(4-((1-(4-((3S,4S)-7- hydroxy-3-isopropylisochroman-4-yl)phenyl)piperidin-4-yl)met hyl)piperazin-1-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione (59.2 mg, 44 %, 99.519% Purity) as a white solid. LC- MS (ESI+) m/z: 692.4 (M+H) ⁺ . LCMS: calc. for C ₄₁ H ₄₉ N ₅ O ₅ : 691.37, found: [M+H] ⁺ 692.4. HPLC: 99.519% purity at 220 nm. ¹ HNMR (400MHz, DMSO-d ₆ ) į = 10.95 (s, 1H), 9.38 - 9.04 (m, 1H), 8.17 (s, 1H), 7.53 (d, J=8.7 Hz, 1H), 7.13 - 7.04 (m, 4H), 6.77 (dd, J=5.8, 8.4 Hz, 3H), 6.50 (dd, J=2.3, 8.2 Hz, 1H), 6.44 (d, J=2.1 Hz, 1H), 5.05 (dd, J=5.1, 13.3 Hz, 1H), 4.89 (d, J=15.4 Hz, 1H), 4.67 (br d, J=15.0 Hz, 1H), 4.38 - 4.30 (m, 1H), 4.26 - 4.17 (m, 1H), 3.77 (d, J=1.9 Hz, 1H), 3.59 (br d, J=9.9 Hz, 2H), 3.45 - 3.32 (m, 4H), 3.24 (br dd, J=2.7, 9.8 Hz, 2H), 2.96 - 2.85 (m, 1H), 2.64 - 2.52 (m, 4H), 2.50 - 2.47 (m, 2H), 2.43 - 2.30 (m, 1H), 2.22 (br d, J=7.2 Hz, 2H), 2.01 - 1.92 (m, 1H), 1.80 (br d, J=11.2 Hz, 2H), 1.67 (br s, 1H), 1.30 - 1.14 (m, 3H), 0.93 - 0.82 (m, 6H).

EXAMPLE 77. Preparation of (I-268) (S)-3-(5-(4-((1-(4-((1'R,4'S)-7'-hydroxy-1'- methylspiro[cyclohexane-1,3'-isochroman]-4'-yl)phenyl)piperi din-4-yl)methyl)piperazin-1- yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione Step 1: To a mixture of 1-(3-(benzyloxy)phenyl)ethan-1-ol (8 g, 1 Eq, 35 mmol) and 1- bromopyrrolidine-2,5-dione (6.9 g, 1.1 Eq, 39 mmol) in DCM (150 mL) at 0 °C for 1 hour, then the mixture was stirred at 25 °C for 12 h. TLC (petroleum ether: ethyl acetate=5:1, R _f= 0.7, UV) showed one main new spot was observed. The reaction was diluted with water (200 mL) and extracted with ethyl acetate (200 mL*2). The organic layer was washed with brine (200 mL) and dried over Na ₂ SO ₄ and concentrated in vacuo to give a white solid. The white solid was subjected to column chromatography over silica gel (gradient elution: 0 – 15% EtOAc). The desired fractions were collected, and concentrated to dryness in vacuo to give 1-(5-(benzyloxy)- 2-bromophenyl)ethan-1-ol (8.9 g, 29 mmol, 83 % yield) as a white solid which confirmed by HNMR. Step 2: A mixture of tetrabutylammonium bromide (1 g, 0.1 Eq, 3.2 mmol), potassium hydroxide (4.5 g, 40% Wt, 1 Eq, 32 mmol), tert-butyl 2-bromoacetate (7.5 g, 1.2 Eq, 39 mmol) 1-(5- (benzyloxy)-2-bromophenyl)ethan-1-ol (9.9 g, 1 Eq, 32 mmol) in toluene (150 mL) was degassed and purged with N ₂ for 3 times, and then the mixture was stirred at 50 °C for 16 h under N2 atmosphere. TLC (petroleum ether: ethyl acetate=5:1, Rf=0.5 UV) showed one main new spot was observed. The reaction was diluted with water (200 mL) and extracted with ethyl acetate (250 mL*2). The organic layer was washed with brine (200 mL) and dried over anhydrous Na ₂ SO ₄ and concentrated in vacuo to give a white solid. The white solid was subjected to column chromatography over silica gel (gradient elution: 0 – 30% EtOAc). The desired fractions were collected, and concentrated to dryness in vacuo to give tert-butyl 2-(1-(5- (benzyloxy)-2-bromophenyl)ethoxy)acetate (7.4 g, 18 mmol, 54 % yield) as a white solid which confirmed by HNMR. Step 3: To a mixture of tert-butyl 2-(1-(5-(benzyloxy)-2-bromophenyl)ethoxy)acetate (10.4 g, 1 Eq, 24.7 mmol) in DCM (150 mL) and TFA (30 mL), then the mixture was stirred at 25 °C for 2 h. TLC (petroleum ether: ethyl acetate=5:1, R _f =0.3 UV) showed one main new spot was observed. The reaction was quenched with water (200 mL) and extracted with ethyl acetate (250 mL*2). The organic layer was washed with brine (200 mL) and dried over anhydrous Na ₂ SO ₄ and concentrated in vacuo to give a white solid. The white solid was subjected to column chromatography over silica gel (gradient elution: 0 – 50% EtOAc in petroleum ether). The desired fractions were collected, and concentrated to dryness in vacuo to give 2-(1-(5- (benzyloxy)-2-bromophenyl)ethoxy)acetic acid (5 g, 0.01 mol, 60 % yield) as a white solid which confirmed by HNMR. Step 4: To a solution of o,n-dimethyl-hydroxylamine hcl (1.3 g, 1 Eq, 14 mmol) and 2-(1-(5- (benzyloxy)-2-bromophenyl)ethoxy)acetic acid (5 g, 1 Eq, 14 mmol) in DMF (80 mL) was added HATU (7.8 g, 1.5 Eq, 21 mmol) and DIEA (5.3 g, 7.1 mL, 3 Eq, 41 mmol). The mixture was stirred at 25 °C for 16 hour. TLC (petroleum ether: ethyl acetate=5:1, Rf=0.5 UV) showed one main new spot was observed. The reaction was diluted with water (200 mL) and extracted with ethyl acetate (200 mL*2). The organic layer was washed with brine (200 mL) and dried over anhydrous Na ₂ SO ₄ and concentrated in vacuo to give a white solid. The white solid was subjected to column chromatography over silica gel (gradient elution: 0 – 50% EtOAc).The desired fractions were collected, and concentrated to dryness in vacuo to give 2-(1-(5- (benzyloxy)-2-bromophenyl)ethoxy)-N-methoxy-N-methylacetamid e (4 g, 0.01 mol, 70 % yield) as a white solid. Step 5: A solution of 2-((5-(benzyloxy)-2-bromobenzyl)oxy)-N-methoxy-N-methylaceta mide (4 g, 1 Eq, 10.1 mmol) in THF (100 mL) was stirred at -78 °C for 10 min under N2 atmosphere, then added tert-butyllithium (1.5 g, 17.9 mL, 1.3 molar, 2.3 Eq, 23.3 mmol) at -78 °C. The reaction was stirred at -78 °C to 25 °C for 5 min under N ₂ atmosphere. TLC (petroleum ether: ethyl acetate=5:1, UV) showed one main new spot was observed. The reaction was quenched with aq.NH ₄ Cl (100 mL) and extracted with ethyl acetate (100 mL*3). The organic layer was washed with brine (100 mL) and dried over anhydrous Na ₂ SO ₄ and concentrated in vacuo to give crude product. The black oil was subjected to column chromatography over silica gel (gradient elution: 0 – 20% EtOAc). The desired fractions were collected, and concentrated to dryness in vacuo to give 7-(benzyloxy)isochroman-4-one (2.3 g, 9 mmol, 89 % yield) as a yellow solid. Step 6: To a cooled stirred (ice-salt) suspension of sodium hydride (148 mg, 0.12 mL, 60% Wt, 3 Eq, 3.69 mmol) in DMF (8 mL) was added dropwise a solution of 7-(benzyloxy)-1- methylisochroman-4-one (330 mg, 1 Eq, 1.23 mmol), then stirred at 0 °C for 2 hour. After this time, 1,5-dibromo-pentane (424 mg, 251 ^L, 1.5 Eq, 1.84 mmol) was added to the reaction and stirred at 25 °C for 16 hour. TLC (petroleum ether: ethyl acetate=10:1, R _f =0.4) showed new spots was observed. The reaction was quenched with water (100 mL) and extracted with ethyl acetate (150 mL*2). The organic layer was washed with brine (100 mL) and dried over subjected to column chromatography over silica gel (gradient elution: 0 – 50% EtOAc). The desired fractions were collected and concentrated to dryness in vacuo to give 7'-(benzyloxy)-1'- methylspiro[cyclohexane-1,3'-isochroman]-4'-one (90 mg, 0.27 mmol, 22 % yield) as a yellow oil. LC-MS (ESI ⁺ ) m/z: 337.1 (M+H) ⁺ . Step 7: To a mixture of 1-(4-bromophenyl)-4-(dimethoxymethyl)piperidine (294 mg, 3.5 Eq, 936 ^mol) in THF (6 mL) at r.t., and the mixture was degassed and purged with N ₂ for 10 minutes. Then the mixture was stirred until it reached -78 °C. n-Butyllithium (51.4 mg, 321 ^L, 2.5 molar, 3 Eq, 803 ^mol) was added to the mixture and stirred at -78 °C for 1 hour, then 7'-(benzyloxy)- 1'-methylspiro[cyclohexane-1,3'-isochroman]-4'-one (90 mg, 1 Eq, 268 ^mol) was added to the mixture at -78 °C and stirred at 25 °C for 16 hour. TLC (petroleum ether: ethyl acetate=5:1, R _f =0.4 UV) showed one main new spot was observed. The reaction was quenched with NH ₄ Cl (100 mL) and extracted with ethyl acetate (100 mL*2). The organic layer was washed with brine (100 mL) and dried over anhydrous Na ₂ SO ₄ and concentrated in vacuo to give a yellow oil. The yellow oil was subjected to column chromatography over silica gel (gradient elution: 0 – 60% EtOAc). The desired fractions were collected, and concentrated to dryness in vacuo to give 7'- (benzyloxy)-4'-(4-(4-(dimethoxymethyl)piperidin-1-yl)phenyl) -1'-methylspiro[cyclohexane-1,3'- isochroman]-4'-ol (80 mg, 0.14 mmol, 52 % yield) as a yellow oil. Step 8: A mixture of 7'-(benzyloxy)-4'-(4-(4-(dimethoxymethyl)piperidin-1-yl)phen yl)-1'- methylspiro[cyclohexane-1,3'-isochroman]-4'-ol (60 mg, 1 Eq, 0.10 mmol), Pd/C (150 mg, 10% Wt, 1.3 Eq, 141 ^mol) in MeOH (15 mL) and THF (15 mL) was degassed and purged with H ₂ for 3 times, and then the mixture was stirred at 70 °C for 18 h under H ₂ atmosphere(15 psi). TLC (petroleum ether: ethyl acetate=5:1, R _f =0.3 UV) showed one main new spot was observed. The reaction mixture was filtered and concentrated under reduced pressure to give residue. The residue was concentrated under reduced pressure to give 4'-(4-(4-(dimethoxymethyl)piperidin-1- yl)phenyl)-1'-methylspiro[cyclohexane-1,3'-isochroman]-7'-ol (90 mg, 0.11 mmol ) as a yellow oil. Step 9: The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was concentrated under reduced pressure to give desired compound as a yellow oil, which was further separated by SFC (condition: column: DAICEL CHIRALPAK AD (250mm*30mm,10um); mobile phase: [CO2-i-PrOH(0.1%NH3H2O)]; B%: 40%-40%) to give isochroman]-7'-ol, ˄20 mg˅(1'R,4'R)-4'-(4-(4-(dimethoxymethyl)piperidin-1-yl)pheny l)-1'- methylspiro[cyclohexane-1,3'-isochroman]-7'-ol, ˄20 mg˅(1'R,4'S)-4'-(4-(4- (dimethoxymethyl)piperidin-1-yl)phenyl)-1'-methylspiro[cyclo hexane-1,3'-isochroman]-7'-ol ˄20 mg˅ and (1'S,4'R)-4'-(4-(4-(dimethoxymethyl)piperidin-1-yl)phenyl)-1 '- methylspiro[cyclohexane-1,3'-isochroman]-7'-ol˄20 mg˅ as yellow solid. Step 10: To a solution of (1'R,4'S)-4'-(4-(4-(dimethoxymethyl)piperidin-1-yl)phenyl)-1 '- methylspiro[cyclohexane-1,3'-isochroman]-7'-ol (20 mg, 1 Eq, 43 ^mol) in 10% H ₂ SO ₄ (3 mL) and THF (3 mL) was stirred at 70 °C for 40 min. TLC (petroleum ether: ethyl acetate=3:1, R _f =0.4, UV) showed a new spot was desired. The reaction was adjust to pH=~8 with saturated aq.NaHCO3 (15 mL). Then the mixture was added water (30 mL) and extracted with ethyl acetate (2×30 mL). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to dryness in vacuo to give 1-(4-((1'R,4'S)-7'- hydroxy-1'-methylspiro[cyclohexane-1,3'-isochroman]-4'-yl)ph enyl)piperidine-4-carbaldehyde (10 mg) as a yellow solid. LC-MS (ESI ⁺ ) m/z: 420.3 (M+H) ⁺ . Step 11: To a solution of 1-(4-((1'R,4'S)-7'-hydroxy-1'-methylspiro[cyclohexane-1,3'- isochroman]-4'-yl)phenyl)piperidine-4-carbaldehyde (10 mg, 1 Eq), (S)-3-(1-oxo-5-(piperazin-1- yl)isoindolin-2-yl)piperidine-2,6-dione benzenesulfonate (12 mg, 1 Eq, 24 ^mol) in DCM (4 mL) and MeOH (4 mL) was added sodium acetate (6 mg, 3 Eq, 72 ^mol) was stirred at 25 °C for 1 h, Then sodium triacetoxyborohydride (10 mg, 7.1 ^L, 2 Eq, 48 ^mol) and acetic acid (4 mg, 4 ^L, 3 Eq, 72 ^mol) was added. The mixture was stirred at 25 °C for 16 hour. The reaction was diluted with H ₂ O (50 mL) and extracted with ethyl acetate (50 mL*2). The organic layer was washed with brine (30 mL) and dried over anhydrous Na ₂ SO ₄ and concentrated in vacuo to give a yellow oil. The residue was purified by prep-HPLC (column: Welch Xtimate C18 150*30mm;mobile phase: [water(FA)-ACN];B% 20%-50%,6min) to give (S)-3-(5-(4-((1-(4- ((1'R,4'S)-7'-hydroxy-1'-methylspiro[cyclohexane-1,3'-isochr oman]-4'-yl)phenyl)piperidin-4- yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2, 6-dione (3.5 mg, 4.7 ^mol, 10 % yield, 99.27% purity) was obtained as a white solid. LC-MS (ESI ⁺ ) m/z: 732.3 (M+H) ⁺ . LCMS: calc. for C ₄₄ H ₅₃ N ₅ O ₅ : 731.94, found: [M+H]+ 732.3. HPLC: 99.273% purity at 220 nm. NMR (400 MHz, DMSO-d6) į = 10.94 (s, 1H), 9.20 - 9.11 (m, 1H), 8.21 (s, 0.264H), 7.52 (d, J = 8.7 Hz, 1H), 7.07 (s, 2H), 6.96 (br d, J = 6.4 Hz, 2H),6.77 (d, J = 8.8 Hz, 2H), 6.70 (d, J = 8.2 Hz, 1H), 6.56 (s, 1H), 6.51 (dd, J = 2.3, 8.3 Hz, 1H), 5.05 (dd, J = 5.2, 13.3 Hz, 1H), 4.73 (br d, J = 5.8 Hz, 1H), 4.38- 4.29 (m, 1H), 4.26 - 4.16 (m, 1H), 3.65 - 3.54 (m, 2H), 3.48 (s, 1H), 3.40 - 3.33 (m, 8H), 2.97 - 2.84 (m, 1H), 2.58 (br s, 3H), 2.41 - 2.31 (m, 1H), 2.22 (br d,J = 7.2 Hz, 2H), 2.02 - 1.92 (m, 1H), 1.81 (br s, 3H), 1.67 (br s, 1H), 1.53 (d, J = 6.4 Hz, 3H), 1.46 (br d, J = 0.8 Hz, 4H), 1.32 (br s, 2H), 1.21 (br s, 3H), 1.10(br s, 1H), 0.99 (br s, 1H). EXAMPLE 78. Preparation of (I-83) (S)-3-(5-(4-((1-(4-((1'S,4'R)-7'-hydroxy-1'- methylspiro[cyclohexane-1,3'-isochroman]-4'-yl)phenyl)piperi din-4-yl)methyl)piperazin-1- yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione Step 1: To a solution of (1'S,4'R)-4'-(4-(4-(dimethoxymethyl)piperidin-1-yl)phenyl)-1 '- methylspiro[cyclohexane-1,3'-isochroman]-7'-ol (20 mg, 1 Eq) in 10% H2SO4 (3 mL) and THF (3 mL) was stirred at 70 °C for 40 min. TLC (petroleum ether: ethyl acetate=3:1, R _f =0.4, UV) showed a new spot was desired. The reaction was adjust to pH=~8 with saturated aq. NaHCO ₃ (15 mL). Then the mixture was added water (30 mL) and extracted with ethyl acetate (2×30 mL). The combined organic layers were washed with brine (30 mL) dried over anhydrous Na ₂ SO ₄ filtered and concentrated to dryness in vacuo to give 1-(4-((1'S,4'R)-7'-hydroxy-1'- methylspiro[cyclohexane-1,3'-isochroman]-4'-yl)phenyl)piperi dine-4-carbaldehyde (10 mg, 24 ^mol) as a yellow solid. LC-MS (ESI ⁺ ) m/z: 438.2 (M+H ₂ O) ⁺ . Step 2: To a solution of 1-(4-((1'S,4'R)-7'-hydroxy-1'-methylspiro[cyclohexane-1,3'- isochroman]-4'-yl)phenyl)piperidine-4-carbaldehyde (10 mg, 1 Eq, 24 ^mol), (S)-3-(1-oxo-5- (piperazin-1-yl)isoindolin-2-yl)piperidine-2,6-dione benzenesulfonate (12 mg, 1 Eq, 24 ^mol) in DCM (4 mL) and MeOH (4 mL) was added Sodium acetate (6 mg, 3 Eq, 72 ^mol) was stirred at 25 °C for 1 h, Then Sodium triacetoxyborohydride (10 mg, 7.1 ^L, 2 Eq, 48 ^mol) and acetic acid (4 mg, 4 ^L, 3 Eq, 72 ^mol) was added. The mixture was stirred at 25 °C for 16 h. The reaction was quenched with H ₂ O (50 mL) and extracted with ethyl acetate (50 mL*2). The organic layer was washed with brine (30 mL) and dried over anhydrous Na ₂ SO ₄ and concentrated in vacuo to give a yellow oil. The residue was purified by prep-HPLC (column: Welch Xtimate C18150*30mm;mobile phase: [water(FA)-ACN];B% 20%-50%,6min) to give (S)-3-(5-(4-((1-(4-((1'S,4'R)-7'-hydroxy-1'-methylspiro[cycl ohexane-1,3'-isochroman]-4'- yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindo lin-2-yl)piperidine-2,6-dione (3.4 mg, 4.6 ^mol, 19 %, 100% purity) was obtained as a white solid. LC-MS (ESI ⁺ ) m/z: 732.3 (M+H) ⁺ . LCMS: calc. for C ₄₄ H ₅₃ N ₅ O ₅ : 731.94, found: 732.3. HPLC: 100% purity at 220 nm. ¹ H NMR (400 MHz, DMSO-d ₆ ) į = 10.94 (s, 1H), 9.15 (br d, J = 5.0 Hz, 1H), 8.19 (s, 0.267H), 7.52 (d, J = 8.7 Hz, 1H), 7.07 (s, 2H), 6.95 (br s, 2H), 6.77(d, J = 8.8 Hz, 2H), 6.70 (d, J = 8.2 Hz, 1H), 6.56 (s, 1H), 6.51 (dd, J = 2.3, 8.2 Hz, 1H), 5.05 (dd, J = 5.0, 13.1 Hz, 1H), 4.73 (br d, J = 6.4 Hz, 1H), 4.38 -4.29 (m, 1H), 4.26 - 4.15 (m, 1H), 3.64 - 3.54 (m, 2H), 3.48 (s, 1H), 3.33 (br s, 8H), 2.90 (br s, 1H), 2.58 (br s, 3H), 2.37 (br d, J = 12.9 Hz, 1H), 2.22 (br d, J= 7.0 Hz, 2H), 1.97 (br d, J = 5.6 Hz, 1H), 1.79 (br d, J = 11.3 Hz, 3H), 1.66 (br s, 1H), 1.53 (d, J = 6.4 Hz, 3H), 1.47 (br s, 4H), 1.32 (br s, 2H), 1.21 (br s,3H), 1.10 (br s, 1H), 0.99 (br s, 1H). EXAMPLE 79. Preparation of (I-269) (S)-3-(5-(4-((1-(4-((1R,4R)-7'-hydroxy-1'- methylspiro[cyclohexane-1,3'-isochroman]-4'-yl)phenyl)piperi din-4-yl)methyl)piperazin-1- yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione Step 1: To a solution of (1R,4R)-4'-(4-(4-(dimethoxymethyl)piperidin-1-yl)phenyl)-1'- methylspiro[cyclohexane-1,3'-isochroman]-7'-ol (20 mg, 1 Eq, 86 ^mol) in 10% H ₂ SO ₄ (3 mL) and THF (3 mL) was stirred at 70 °C for 40 min. TLC (petroleum ether: ethyl acetate=3:1, Rf=0.4, UV) showed a new spot was desired. The reaction was adjusted to pH=~8 with saturated aq. NaHCO3 (15 mL). Then the mixture was added water (30 mL) and extracted with ethyl acetate (2×30 mL). The combined organic layers were washed with brine(30 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to dryness in vacuo to give 1-(4-((1R,4R)-7'- hydroxy-1'-methylspiro[cyclohexane-1,3'-isochroman]-4'-yl)ph enyl)piperidine-4-carbaldehyde (10 mg) as a yellow solid. LC-MS (ESI ⁺ ) m/z: 438.2 (M+H) ⁺ . Step 2: To a solution of 1-(4-((1R,4R)-7'-hydroxy-1'-methylspiro[cyclohexane-1,3'-iso chroman]- 4'-yl)phenyl)piperidine-4-carbaldehyde (10 mg, 1 Eq), (S)-3-(1-oxo-5-(piperazin-1-yl)isoindolin- 2-yl)piperidine-2,6-dione benzenesulfonate (12 mg, 1 Eq, 24 ^mol) in DCM (4 mL) and MeOH (4 mL) was added Sodium acetate (6 mg, 3 Eq, 72 ^mol) was stirred at 25 °C for 1 h, Then Sodium triacetoxyborohydride (10 mg, 7.1 ^L, 2 Eq, 48 ^mol) and acetic acid (4 mg, 4 ^L, 3 Eq, 72 ^mol) was added. The mixture was stirred at 25 °C for 16 hours. The reaction was quenched with H2O (50 mL) and extracted with ethyl acetate (50 mL*2). The organic layer was washed with brine (30 mL) and dried over anhydrous Na ₂ SO ₄ and concentrated in vacuo to give a yellow oil. The residue was purified by prep-HPLC (column: Welch Xtimate C18150*30mm;mobile phase: [water(FA)-ACN];B% 20%-50%,6min) to give (S)-3-(5-(4-((1-(4-((1R,4R)-7'-hydroxy- 1'-methylspiro[cyclohexane-1,3'-isochroman]-4'-yl)phenyl)pip eridin-4-yl)methyl)piperazin-1- yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (3.7 mg, 5 ^mol, 7.1 %, 99.85% purity) was obtained as a white solid. LC-MS (ESI ⁺ ) m/z: 732.3 (M+H) ⁺ . LCMS: calc. for C ₄₄ H ₅₃ N ₅ O ₅ : 731.94, found: [M+ + 732.3. HPLC: 99.85% purity at 220 nm. ¹ H NMR (400 MHz, DMSO-d ₆ ) į = 10.95 (s, 1H), 9.16 (s, 1H), 8.16 (s, 0.203H), 7.53 (d, J = 8.7 Hz, 1H), 7.08 (s, 2H), 6.92 (br s, 2H), 6.89 - 6.83 (m, 2H),6.55 (s, 1H), 6.50 (s, 2H), 5.05 (dd, J = 5.1, 13.3 Hz, 1H), 4.80 (br d, J = 6.2 Hz, 1H), 4.38 - 4.30 (m, 1H), 4.27 - 4.16 (m, 1H), 3.79 (s, 1H), 3.68 (br d, J =11.2 Hz, 2H), 3.42 - 3.33 (m, 8H), 2.89 (br d, J = 12.0 Hz, 1H), 2.63 (br d, J = 13.2 Hz, 3H), 2.37 (br dd, J = 4.7, 13.3 Hz, 1H), 2.24 (br d, J = 7.0 Hz, 2H),1.97 (br d, J = 5.2 Hz, 1H), 1.84 (br d, J = 10.8 Hz, 2H), 1.71 (br s, 3H), 1.55 (br s, 2H), 1.43 (br d, J = 6.4 Hz, 6H), 1.23 (br d, J = 8.9 Hz, 3H), 1.04 - 0.84 (m,2H).

EXAMPLE 80. Preparation of (I-270) (S)-3-(5-(4-((1-(4-((1'S,4'S)-7'-hydroxy-1'- methylspiro[cyclohexane-1,3'-isochroman]-4'-yl)phenyl)piperi din-4-yl)methyl)piperazin-1- yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione Step 1: To a solution of (1S,4S)-4'-(4-(4-(dimethoxymethyl)piperidin-1-yl)phenyl)-1'- methylspiro[cyclohexane-1,3'-isochroman]-7'-ol (20 mg, 1 Eq, 64 ^mol) in 10% H ₂ SO ₄ (3 mL) and THF (3 mL) was stirred at 70 °C for 40 min. TLC (petroleum ether: ethyl acetate=3:1, R _f =0.4, UV) showed a new spot was desired. The reaction was adjusted to pH=~8 with saturated aq. NaHCO ₃ (15 mL). Then the mixture was added water (30 mL) and extracted with ethyl acetate (2×30 mL). The combined organic layers were washed with brine(30 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to dryness in vacuo to give 1-(4-((1S,4S)-7'- hydroxy-1'-methylspiro[cyclohexane-1,3'-isochroman]-4'-yl)ph enyl)piperidine-4-carbaldehyde (10 mg) as a yellow solid. LC-MS (ESI ⁺ ) m/z: 438.1 (M+H2O) ⁺ . Step 2: To a solution of 1-(4-((1S,4S)-7'-hydroxy-1'-methylspiro[cyclohexane-1,3'-iso chroman]- 4'-yl)phenyl)piperidine-4-carbaldehyde (10 mg, 1 Eq), (S)-3-(1-oxo-5-(piperazin-1-yl)isoindolin- 2-yl)piperidine-2,6-dione benzenesulfonate (12 mg, 1 Eq, 24 ^mol) in DCM (4 mL) and MeOH (4 mL) was added sodium acetate (6 mg, 3 Eq, 72 ^mol) was stirred at 25 °C for 1 h, Then 72 ^mol) was added. The mixture was stirred at 30 °C for 16 hours. The reaction was quenched with H2O (50 mL) and extracted with ethyl acetate (50 mL*2). The organic layer was washed with brine (30 mL) and dried over anhydrous Na ₂ SO ₄ and concentrated in vacuo to give a yellow oil. The residue was purified by prep-HPLC (column: Welch Xtimate C18150*30mm;mobile phase: [water(FA)-ACN];B% 20%-50%,6min) to give (S)-3-(5-(4-((1-(4-((1S,4S)-7'-hydroxy-1'- methylspiro[cyclohexane-1,3'-isochroman]-4'-yl)phenyl)piperi din-4-yl)methyl)piperazin-1-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione (1.5 mg, 2 ^mol, 2.9 % yield, 100% purity) was obtained as a white solid. LC-MS (ESI ⁺ ) m/z: 732.3 (M+H) ⁺ . LCMS: calc. for C ₄₄ H ₅₃ N ₅ O ₅ : 731.94, found: [M+ + 732.3. HPLC: 100% purity at 220 nm. ¹ H NMR (400 MHz, DMSO-d ₆ ) į = 10.95 (s, 1H), 9.16 (br s, 1H), 8.25 (s, 0.204H), 7.53 (d, J = 8.7 Hz, 1H), 7.08 (s, 2H), 6.97 - 6.90 (m, 2H), 6.89 - 6.83(m, 2H), 6.55 (d, J = 1.5 Hz, 1H), 6.49 (s, 2H), 5.05 (dd, J = 5.1, 13.4 Hz, 1H), 4.80 (br d, J = 6.2 Hz, 1H), 4.39 - 4.30 (m, 1H), 4.26 - 4.17 (m, 1H), 3.79 (s,1H), 3.68 (br d, J = 10.8 Hz, 2H), 3.33 (br s, 8H), 2.97 - 2.84 (m, 1H), 2.72 - 2.59 (m, 3H), 2.37 (br dd, J = 4.4, 13.1 Hz, 1H), 2.24 (br d, J = 7.0 Hz, 2H),2.02 - 1.92 (m, 1H), 1.84 (br d, J = 11.3 Hz, 2H), 1.71 (br s, 3H), 1.55 (br s, 2H), 1.43 (br d, J = 6.4 Hz, 6H), 1.31 - 1.15 (m, 3H), 1.04 - 0.83 (m, 2H).

EXAMPLE 81. Preparation of (I-347) (S)-3-(5-(4-((1-(4-((3S,4R)-3-(2-fluorophenyl)-7- hydroxyisochroman-4-yl)phenyl)piperidin-4-yl)methyl)piperazi n-1-yl)-1-oxoisoindolin-2- yl)piperidine-2,6-dione Step 1: A 8 mL thread vial was equipped with magnetic stirrer. (2-fluorophenyl)magnesium M solution in THF) was cooled in an ice bath under N2 atmosphere and 1-bromo-2-fluoro- benzene (2.0 g, 1.2 mL, 1 Eq, 11 mmol) was added dropwise. The reaction mixture was stirred at 0 °C for 1 hour. TLC (petroleum ether: ethyl acetate=1:0, UV) showed one new spot was observed. A 40 mL thread vial was equipped with magnetic stirrer.2-(4-(benzyloxy)-2-(((tert- butyldimethylsilyl)oxy)methyl)phenyl)-2-(4-bromophenyl)-N-me thoxy-N-methylacetamide (1.0 g, 1 Eq, 1.7 mmol) was added in THF (4 mL) under N ₂ atmosphere, then added (2- fluorophenyl)magnesium bromide (1.5 g, 4.5 Eq, 7.7 mmol)(prepared freshly) in the mixture at 0 °C for 10 min. The mixture was stirred at 25°C for 16 hours. TLC (petroleum ether: ethyl acetate=5:1, UV) showed one main new spot was observed. The reaction solution was quenched with aq. NH ₄ Cl (15 mL). Water (100 mL) was added, and the mixture was extracted with dichloromethane(50 mL x 3). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated to dryness in vacuo to give a yellow oil. The yellow oil was purified by flash column (petroleum ether/ethyl acetate from 100/0 to 90/10) and the organic layer were concentrated in vacuo to give 2-(4-(benzyloxy)-2-(((tert- butyldimethylsilyl)oxy)methyl)phenyl)-2-(4-bromophenyl)-1-(2 -fluorophenyl)ethan-1-one (314 mg, 499 ^mol, 29 % yield, 98% purity) as a yellow oil. LC-MS (ESI ⁺ ) m/z: 487.1 (M+H) ⁺ . Step 2: To a solution of 2-(4-(benzyloxy)-2-(((tert-butyldimethylsilyl)oxy)methyl)phe nyl)-2-(4- bromophenyl)-1-(2-fluorophenyl)ethan-1-one (314 mg, 1 Eq, 499 ^mol) and triethylsilane (87.1 mg, 120 ^L, 1.5 Eq, 749 ^mol) in DCM (4 mL)ˈthe resulting mixture was cooled at -78 °C and trimethylsilyl triflate (167 mg, 138 ^L, 1.5 Eq, 749 ^mol) was added, and the resulting mixture was allowed to stir for 30 min at this temperature. The reaction mixture was quenched with saturated aq.NaHCO ₃ (5 mL), diluted with DCM(10 mL) and the resulting mixture stirred vigorously for 5 min. The organic layer was separated through a phase separator and concentrated in vacuo to give 7-(benzyloxy)-4-(4-bromophenyl)-3-(2-fluorophenyl)isochroman e (330 mg, 517 ^mol, crude product, 76% purity) as a yellow oil. LC-MS (ESI ⁺ ) m/z: 488.8 (M+H) ⁺ . Step 3: A mixture of 7-(benzyloxy)-4-(4-bromophenyl)-3-(2-fluorophenyl)isochroman e (300 mg, 76% purity, 1 Eq, 470 ^mol), 2-(Dicyclohexylphosphanyl)-2',4',6'-tris(isopropyl)biphenyl (44.8 mg, 0.2 Eq, 94.0 ^mol), palladium diacetate (15.8 mg, 0.15 Eq, 70.5 ^mol), 4- (dimethoxymethyl)piperidine (112 mg, 118 ^L, 1.5 Eq, 705 ^mol), and sodium 2-methylpropan- 2-olate (67.8 mg, 76.0 ^L, 1.5 Eq, 705 ^mol) in toluene (8 mL) was heated to 90 °C for 16 hours under N ₂ atmosphere. TLC (petroleum ether: ethyl acetate=3:1, UV) showed one main new spot was observed.100 mL water was added, and the mixture was extracted with DCM(150 mL x 2 ). The combined organic layers were washed with brine(10 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to dryness in vacuo to give a yellow oil. The yellow oil was purified by flash column (petroleum ether/ethyl acetate from 100/0 to 30/70) and the fraction was concentrated in vacuo to give 1-(4-(7-(benzyloxy)-3-(2-fluorophenyl)isochroman-4-yl)phenyl )- 4-(dimethoxymethyl)piperidine (180 mg, 287 ^mol, 61.2% yield, 90% purity) as a yellow oil. LC-MS (ESI ⁺ ) m/z: 568.1(M+H) ⁺ Step 4: A mixture of 1-(4-(7-(benzyloxy)-3-(2-fluorophenyl)isochroman-4-yl)phenyl )-4- (dimethoxymethyl)piperidine (180 mg, 90% purity, 1 Eq, 287 ^mol), Pd/C (180 mg, 10 % Wt) in THF (2.5 mL) and MeOH (2.5 mL) was degassed and purged with H ₂ for 3 times, and then the mixture was stirred at 25 °C for 2.5 hour under H ₂ atmosphere (15 psi). The reaction was filtered and concentrated to dryness in vacuo to give 4-(4-(4-(dimethoxymethyl)piperidin-1-yl)phenyl)- 3-(2-fluorophenyl)isochroman-7-ol (120 mg, 183 ^mol, 63.7 % yield, 73% purity) as a white solid. LC-MS (ESI+) m/z: 478.3 (M+H) ⁺ . Step 5: The white solid was purified by SFC. Column: DAICEL CHIRALPAK IG (250mm*30mm, 10um); Condition: CO ₂ -EtOH(0.1%NH ₃ H ₂ O); at the beginning: B (50%); at the end: B (50%); Flow rate (ml/min) 80. The aqueous phase was lyophilized to dryness to give (3S,4R)-4-(4-(4-(dimethoxymethyl)piperidin-1-yl)phenyl)-3-(2 -fluorophenyl)isochroman-7-ol (40 mg, 70 ^mol, 38 % yield, 83% purity) as a colorless oil and (3R,4S)-4-(4-(4- (dimethoxymethyl)piperidin-1-yl)phenyl)-3-(2-fluorophenyl)is ochroman-7-ol (40 mg, 81 ^mol, 44 % yield, 96% purity) as a colorless oil. LC-MS (ESI+) m/z: 478.1 (M+H) ⁺ . Step 6: To a solution of (3*S,4*R)-4-(4-(4-(dimethoxymethyl)piperidin-1-yl)phenyl)-3- (2- fluorophenyl)isochroman-7-ol (40 mg, 83% purity, 1 Eq, 70 ^mol) in THF (5 mL) was added sulfuric acid (69 mg, 5 mL, 10% Wt) at 25°C. Then the mixture was stirred at 70 °C for 40 min. The mixture was adjusted to pH 8-9 by progressively adding saturated aq. NaHCO3(10 mL). The ti i t dil t d ith 50 L H O d t t d ith th l t t (25 L * 2) Th combined organic layers were washed with 10 mL (10 mL * 1), dried over Na2SO4. The organic layers were filtered and concentrated under reduced pressure to give 1-(4-((3*S,4*R)-3-(2- fluorophenyl)-7-hydroxyisochroman-4-yl)phenyl)piperidine-4-c arbaldehyde (40 mg, 72 ^mol, crude product, 77% purity) as a colorless oil. LC-MS (ESI+) m/z: 450.3 (M+18) ⁺ Step 7: A mixture of 1-(4-((3S,4R)-3-(2-fluorophenyl)-7-hydroxyisochroman-4- yl)phenyl)piperidine-4-carbaldehyde (40 mg, 77 % purity, 1 Eq, 72 ^mol), (S)-3-(1-oxo-5- (piperazin-1-yl)isoindolin-2-yl)piperidine-2,6-dione, benzene sulfonate (36 mg, 1 Eq, 72 ^mol) and sodium acetate (29 mg, 5 Eq, 0.36 mmol) in DCM (2 mL) and MeOH (2 mL) at 20°C for 0.5 hour, pH=8, then acetic acid (13 mg, 12 ^L, 3 Eq, 0.22 mmol) at 20°C for 1 hour, pH=6, then added sodium triacetoxyborohydride (30 mg, 2 Eq, 0.14 mmol) to the mixture, and then the mixture was stirred at 25 °C for 16 hour. The reaction was diluted with water (50 mL) and extracted with ethyl acetate (50 mL*2). The organic layers were concentrated to give crude product as a brown oil. The brown oil was purified by preparative high-performance liquid chromatography. Condition: water (FA)-ACN. Column: xtimate C18150*40mm*10um. Begin B: 12%, end B: 42%. Gradient time(min) 2; 100% B hold Time(min)2, Flow rate(ml/min) 25. The pure fractions were collected, and the solvent was evaporated under vacuum. The aqueous layer was lyophilized to dryness to give (S)-3-(5-(4-((1-(4-((3S,4R)-3-(2-fluorophenyl)-7- hydroxyisochroman-4-yl)phenyl)piperidin-4-yl)methyl)piperazi n-1-yl)-1-oxoisoindolin-2- yl)piperidine-2,6-dione (17.2 mg, 22.7 ^mol, 32 % yield, 98 % purity) as a white solid. .35, found: [M+H] ⁺ 744.3. 10.94 (s, 1H), 9.32 (s, 1H), 8.13 (s, 0.377H), 7.51 (d, J = 8.5 Hz, 1H), 7.20 - 7.08 (m, 2H), 7.07 - 7.03 (m, 2H), 6.90 - 6.77 (m, 3H), 6.63 - 6.53 (m, 6H), 5.19 (d, J = 2.7 Hz, 1H), 5.12 - 5.01 (m, 2H), 4.94 (d, J = 15.3 Hz, 1H), 4.37 - 4.28 (m, 1H), 4.23 - 4.15 (m, 1H), 4.01 (br s, 1H), 3.50 (br d, J = 11.2 Hz, 2H), 3.30 - 3.22 (m, 5H), 2.95 - 2.84 (m, 1H), 2.63 - 2.51 (m, 3H), 2.49 - 2.30 (m, 4H), 2.26 - 2.15 (m, 2H), 2.00 - 1.91 (m, 1H), 1.74 (br d, J = 12.4 Hz, 2H), 1.64 (br d, J = 1.9 Hz, 1H), 1.21 - 1.08 (m, 2H). EXAMPLE 82. Preparation of (I-348) (S)-3-(5-(4-((1-(4-((3R,4S)-3-(2-fluorophenyl)-7- hydroxyisochroman-4-yl)phenyl)piperidin-4-yl)methyl)piperazi n-1-yl)-1-oxoisoindolin-2- yl)piperidine-2,6-dione Step 1: To a solution of (3R,4S)-4-(4-(4-(dimethoxymethyl)piperidin-1-yl)phenyl)-3-(2 - fluorophenyl)isochroman-7-ol (40 mg, 96% purity, 1 Eq, 81 ^mol) n THF (5 mL) was added sulfuric acid (79 mg, 5 mL, 10% Wt) at 0 °C. The mixture was stirred at 70 °C for 40 min. The mixture was adjusted to pH 8-9 by progressively adding saturated aq. NaHCO ₃ (10mL). The reaction mixture was diluted with 50 mL H ₂ O and extracted with ethyl acetate (50 mL). The combined organic layers were washed with 10 mL brine, dried over Na ₂ SO ₄ . The organic layers were filtered and concentrated under reduced pressure to give 1-(4-((3*R,4*S)-3-(2- fluorophenyl)-7-hydroxyisochroman-4-yl)phenyl)piperidine-4-c arbaldehyde (33 mg, 74 ^mol, 91% yield, crude product, 97% purity) as a colorless oil. LC-MS (ESI+) m/z: 450.3(M+18) ⁺ . Step 2: A mixture of 1-(4-((3R,4S)-3-(2-fluorophenyl)-7-hydroxyisochroman-4- yl)phenyl)piperidine-4-carbaldehyde (33 mg, 97% purity, 1 Eq, 74 ^mol), (S)-3-(1-oxo-5- (piperazin-1-yl)isoindolin-2-yl)piperidine-2,6-dione, benzene sulfonate(37 mg, 1 Eq, 74 ^mol) and sodium acetate (30 mg, 5 Eq, 0.37 mmol) in DCM (2 mL) and MeOH (2 mL) at 20°C for 0.5 hour, pH=8, then acetic acid (13 mg, 13 ^L, 3 Eq, 0.22 mmol) at 20°C for 1 hour, pH=6, then was stirred at 25°C for 16 hour. The reaction was diluted with water (50 mL) and extracted with ethyl acetate (50 mL*2). The organic layers were concentrated to give crude product as a brown oil. The brown oil was purified by preparative high-performance liquid chromatography. Condition: water (FA)-ACN. Column: xtimate C18150*40mm*10um. Begin B: 12%, end B: 42%. Gradient time(min) 2; 100% B hold time(min)2, Flow rate(ml/min) 25. The pure fractions were collected, and the solvent was evaporated under vacuum. The aqueous layer was lyophilized to dryness to give (S)-3-(5-(4-((1-(4-((3R,4S)-3-(2-fluorophenyl)-7- hydroxyisochroman-4-yl)phenyl)piperidin-4-yl)methyl)piperazi n-1-yl)-1-oxoisoindolin-2- yl)piperidine-2,6-dione (16.2 mg, 21.8 ^mol, 29 % yield, 100% purity) as a white solid. LCMS: calc. for C ₄₄ H ₄₆ FN ₅ O5: 743.35, found: [M+H] ⁺ 744.3. HPLC: 100purity at 220 nm. ¹ H NMR (400 MHz, DMSO-d ₆ ) į=^10.94 (s, 1H), 9.32 (br s, 1H), 8.15 (s, 0.554H), 7.51 (d, J = 8.6 Hz, 1H), 7.21 - 7.08 (m, 2H), 7.07 - 7.02 (m, 2H), 6.79 (br d, J = 8.1 Hz, 3H), 6.62 - 6.54 (m, 6H), 5.19 (d, J = 3.1 Hz, 1H), 5.12 - 5.01 (m, 2H), 4.94 (d, J = 15.1 Hz, 1H), 4.36 - 4.28 (m, 1H), 4.24 - 4.16 (m, 1H), 4.01 (br s, 1H), 3.53 - 3.47 (m, 2H), 3.27 (br s, 5H), 2.95 - 2.83 (m, 1H), 2.62 - 2.54 (m, 1H), 2.41 (br d, J = 4.4 Hz, 5H), 2.39 - 2.30 (m, 1H), 2.18 (br d, J = 6.8 Hz, 2H), 1.99 - 1.91 (m, 1H), 1.74 (br d, J = 12.3 Hz, 2H), 1.68 - 1.56 (m, 1H), 1.13 (br d, J = 11.6 Hz, 2H).

EXAMPLE 83. Preparation of (I-350) (S)-3-(5-(4-((1-(4-((3R,4S)-7-hydroxy-3-(4- (trifluoromethyl)phenyl)isochroman-4-yl)phenyl)piperidin-4-y l)methyl)piperazin-1-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione Step 1: To a solution of (3R, 4S)-4-(4-(4-(dimethoxymethyl) piperidin-1-yl) phenyl)-3-(4- (trifluoromethyl) phenyl) isochroman-7-ol (120.0 mg, 1 Eq, 227.5 ^mol) in THF (1.5 mL) and 10% H ₂ SO ₄ (1.5 mL). The mixture was stirred at 70 °C for 1 hour. LCMS showed 99% of desired MS was detected. The aqueous phase was adjusted to pH~=8 with NaHCO ₃ (aq), and it was discarded. The reaction mixture was quenched by addition 50 mL H ₂ O at 25°C, and then diluted with 50 mL H ₂ O and extracted with ethyl acetate 100 mL (50 mL * 2). The combined organic layers were washed with 10 mL brine and dried over Na2SO4, than was filtered and concentrated under reduced pressure to give 1-(4-((3R,4S)-7-hydroxy-3-(4- (trifluoromethyl)phenyl)isochroman-4-yl)phenyl)piperidine-4- carbaldehyde (110 mg, 228 ^mol) as a residue. LC-MS (ESI+) m/z: 482.1(M+H) ⁺ . Step 2: To a solution of 1-(4-((3R,4S)-7-hydroxy-3-(4-(trifluoromethyl)phenyl)isochro man-4- yl)phenyl)piperidine-4-carbaldehyde (110.0 mg, 1 Eq, 228.4 ^mol) , (S)-3-(1-oxo-5-(piperazin- 1-yl)isoindolin-2-yl)piperidine-2,6-dione benzenesulfonate (133.4 mg, 1.2 Eq, 274.1 ^mol) in DCM (2 mL) and MeOH (2 mL) was added sodium acetate (56.22 mg, 3 Eq, 685.3 ^mol) was stirred at 25 °C for 1 hour, Then sodium triacetoxyhydroborate (96.83 mg, 2 Eq, 456.9 ^mol) and acetic acid (41.15 mg, 39.2 ^L, 3 Eq, 685.3 ^mol) was added .The mixture was stirred at 25 °C for 16 hour. LCMS showed 85% desired MS was detected.20 mL water was added and the mixture was extracted with Ethyl acetate (30 mL x2). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to dryness in vacuo to give a yellow oil. The yellow oil was concentrated under reduced pressure to remove solvent. The residue was purified by prep-HPLC (column: Welch Xtimate C18150*30mm*5um phase: [water(FA)-ACN];B%: 10%-50%,9 min to give (S)-3-(5-(4-((1-(4-((3R,4S)-7-hydroxy-3- (4-(trifluoromethyl)phenyl)isochroman-4-yl)phenyl)piperidin- 4-yl)methyl)piperazin-1-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione (121.2 mg, 150 ^mol, 65.8 %, 98.4% Purity) as a white solid. LCMS: calc. for C ₄₅ H ₄₆ F ₃ N ₅ O ₅ : 793.89, found: [M+H] ⁺ 794.4. HPLC: 98.4% purity at 220 nm. NMR 1H NMR (400MHz, DMSO-d ₆ ) į = 10.94 (s, 1 H) 9.31 (br s, 1 H) 8.15 (s, 0.420 H) 7.52 (br d, J=8.03 Hz, 3 H) 7.32 (br d, J=8.03 Hz, 2 H) 6.99 - 7.09 (m, 2 H) 6.80 (br d, J=8.03 Hz, 1 H) 6.54 - 6.66 (m, 6 H) 5.00 - 5.29 (m, 3 H) 4.94 (br d, J=15.31 Hz, 1 H) 4.26 - 4.40 (m, 1 H) 4.14 - 4.25 (m, 1 H) 4.11 (br s, 1 H) 3.50 (br d, J=11.29 Hz, 2 H) 3.28 (br s, 8 H) 2.82 - 3.00 (m, 1 H) 2.59 (br d, J=17.32 Hz, 1 H) 2.45 - 2.49 (m, 2 H) 2.31 - 2.40 (m, 1 H) 2.19 (br d, J=6.53 Hz, 2 H) 1.89 - 2.01 (m, 1 H) 1.60 - 1.78 (m, 3 H) 1.06 - 1.21 (m, 2 H). EXAMPLE 84. Preparation of (I-351) (S)-3-(5-(4-((1-(4-((3S,4R)-7-hydroxy-3-(2- isopropylphenyl)isochroman-4-yl)phenyl)piperidin-4-yl)methyl )piperazin-1-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione and (I-352) (S)-3-(5-(4-((1-(4-((3R,4S)-7-hydroxy-3-

(2-isopropylphenyl)isochroman-4-yl)phenyl)piperidin-4-yl) methyl)piperazin-1-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione Step 1: A solution of 1 (60 mg, 101.39 ^mol, 1.0 eq.) and Pd/C (107.90 mg, 101.39 ^mol, 10% mixture was stirred at 20 °C for 3hr under H2 atmosphere. LCMS showed that the desired product was detected. The reaction mixture was filtered and concentrated under reduced pressure to get the product. The mixture was purified by Pre-TLC (PE/EA= 1/1) to give 2 (45 mg, 80.76% yield) as colorless oil. LC-MS (ESI ⁺ ) m/z: 502.3 (M+H) ⁺ . Step 2: The 2 (55 mg, 109.64 ^mol, 1.0 eq.) was further separated by SFC (condition: CO ₂ - EtOH (0.1%NH ₃ H ₂ O), column: DAICEL CHIRALPAK AD (250mm x 30 mm, 10 um), Begin B: 30, End B 30) to give 3A (20 mg, 36.36% yield) as white solid and 3B (18 mg, 32.73% yield) as white solid. 502.3 (M+H) ⁺ . 3B: LC-MS (ESI ⁺ ) m/z: 502.3 (M+H) ⁺ . Step 3: To a solution of 3A (18 mg, 35.88 ^mol, 1.0 eq.) in DCM (2 mL) was added TFA (767.50 mg, 6.73 mmol, 187.59 eq.) at 20 °C. Then the mixture was stirred at 20 °C for 1 h. LCMS showed that the starting material was consumed, and the desired product was detected. The mixture was filtered and concentrated under vacuum to give 4A (15 mg, crude) as yellow oil. LC-MS (ESI ⁺ ) m/z: 456.2 (M+H) ⁺ Step 4: To a solution of 3B (15 mg, 29.90 ^mol, 1.0 eq.) in DCM (2 mL) was added TFA (767.50 mg, 6.73 mmol, 225.11 eq.) at 20 °C. Then the mixture was stirred at 20 °C for 1 h. LCMS showed that the starting material was consumed, and the desired product was detected. The mixture was filtered and concentrated under vacuum to give 4B (12 mg, crude) as yellow oil. LC-MS (ESI ⁺ ) m/z: 456.2 (M+H) ⁺ Step 5: To a solution of 1-(4-((3S,4R)-7-hydroxy-3-(2-isopropylphenyl)isochroman-4- yl)phenyl)piperidine-4-carbaldehyde (15 mg, 32.92 ^mol, 1.0 eq.) in DCE (5 mL) and MeOH (5 mL) was added (S)-3-(1-oxo-5-(piperazin-1-yl)isoindolin-2-yl)piperidine-2, 6-dione, TsOH salt (2162 mg 6585 ^mol 20 eq) at 20 °C After 5 minutes the sodium;triacetoxyboranuide (34.89 mg, 164.62 ^mol, 5.0 eq.) was added into the mixture at 20 °C. The mixture was stirred at 20 °C for 0.5 h. LCMS showed that the desired product was detected. The mixture was filtered and concentrated under vacuum to give the crude. The residue was purified by prep- HPLC (FA condition: Column: Boston Green ODS 150 x 30 mm x 5 um; Condition: water (FA)- ACN, Begin B 12, End B 42, Gradient Time (min) 12, 100% B Hold Time (min) 2, Flow Rate (mL/min) 25.) to give (S)-3-(5-(4-((1-(4-((3S,4R)-7-hydroxy-3-(2-isopropylphenyl)i sochroman- 4-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoin dolin-2-yl)piperidine-2,6-dione (11.3 mg, 44.69% yield) as white solid. LC-MS (ESI ⁺ ) m/z: 768.4 (M+H) ⁺ LCMS: calc. for C ₄₇ H ₅₃ N ₅ O ₅ : 767.97, found: [M+H] ⁺ 768.4. HPLC: 100.00% purity at 220 nm ¹ H NMR (400 MHz, DMSO-d ₆ ) į = 10.94 (s, 1H), 9.29 (s, 1H), 8.13 (s, 1H), 7.61 - 7.28 (m, 2H), 7.23 (d, J = 7.2 Hz, 1H), 7.07 (br t, J = 7.0 Hz, 2H), 6.81 - 6.72 (m, 2H), 6.62 - 6.48 (m, 7H), 5.17 (d, J = 2.4 Hz, 1H), 5.10 - 5.01 (m, 2H), 4.97 - 4.90 (m, 1H), 4.37 - 4.17 (m, 2H), 3.90 (d, J = 1.9 Hz, 1H), 3.56 - 3.45 (m, 2H), 3.29 (s, 10H), 3.19 - 2.85 (m, 2H), 2.43 - 2.31 (m, 4H), 2.25 - 2.13 (m, 2H), 1.99 - 1.93 (m, 1H), 1.74 (br d, J = 12.4 Hz, 3H), 1.34 (d, J = 6.7 Hz, 3H), 1.15 (br d, J = 6.7 Hz, 3H). Step 6: To a solution of 1-(4-((3R,4S)-7-hydroxy-3-(2-isopropylphenyl)isochroman-4- yl)phenyl)piperidine-4-carbaldehyde (12 mg, 26.34 ^mol, 1.0 eq.) in DCE (5 mL) and MeOH (5 mL) was added (S)-3-(1-oxo-5-(piperazin-1-yl)isoindolin-2-yl)piperidine-2, 6-dione, TsOH salt (17.30 mg, 52.68 ^mol, 2.0 eq.) at 20 °C. After 5 minutes, the sodium;triacetoxyboranuide (27.91 mg, 131.70 ^mol, 5.0 eq.) was added into the mixture at 20 °C. The mixture was stirred at 20 °C for 0.5 h. LCMS showed that the desired product was detected. The mixture was filtered and concentrated under vacuum to give the crude. The residue was purified by prep- HPLC (FA condition: Column: Boston Green ODS 150 x 30 mm x 5 um; Condition: water (FA)- ACN, Begin B 12, End B 42, Gradient Time (min) 12, 100% B Hold Time (min) 2, Flow Rate (mL/min) 25.) to give (S)-3-(5-(4-((1-(4-((3R,4S)-7-hydroxy-3-(2-isopropylphenyl)i sochroman- 4-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoin dolin-2-yl)piperidine-2,6-dione (11.7 mg, 56.75% yield) as white solid. LC-MS (ESI+) m/z: 768.4 (M+H)+ LCMS: calc. for C47H53N5O5: 767.97, found: [M+H] ⁺ 768.4. HPLC: 98.11% purity at 220 nm ¹ H NMR (400 MHz, DMSO-d ₆ ) į = 10.94 (s, 1H), 9.29 (s, 1H), 8.13 (s, 1H), 7.60 - 7.30 (m, 2H), 7.23 (d, J = 7.7 Hz, 1H), 7.07 (br t, J = 7.0 Hz, 2H), 6.80 - 6.73 (m, 2H), 6.62 - 6.49 (m, 7H), 5.17 (d, J = 2.3 Hz, 1H), 5.09 - 5.01 (m, 2H), 4.97 - 4.90 (m, 1H), 4.36 - 4.18 (m, 2H), 3.90 (br d, J = 0.7 Hz, 1H), 3.51 (br d, J = 9.4 Hz, 2H), 3.29 (br s, 10H), 3.19 - 3.13 (m, 1H), 2.95 - 2.85 (m, 1H), 2.45 - 2.31 (m, 4H), 2.26 - 2.12 (m, 2H), 1.99 - 1.93 (m, 1H), 1.79 - 1.62 (m, 3H), 1.34 (d, J = 6.8 Hz, 3H), 1.15 (br d, J = 6.7 Hz, 3H). EXAMPLE 85. Preparation of (I-393) 3-[6-[4-[[1-[4-[(3S,4R)-7-hydroxy-3-phenyl- isochroman-4-yl]phenyl]-4- piperidyl]methyl]piperazin-1-yl]-1-methyl-indazol-3- yl]piperidine-2,6-dione Step 1: To a solution of (3S,4R)-4-[4-[4-(dimethoxymethyl)-1-piperidyl]phenyl]-3-phen yl- isochroman-7-ol (80 mg, 1 eq, 174.07 ^mol) in DCM (2 mL) was added TFA (921.00 mg, 46.4 eq, 8.08 mmol, 600.00 ^L) and the mixture was stirred at 20 °C for 2 h. The reaction mixture h d i h CO (10 ) d d i h OA (10 3) h combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give 1-[4-[(3S,4R)-7-hydroxy-3-phenyl-isochroman-4- yl]phenyl]piperidine-4-carbaldehyde (71 mg, crude) as a brown oil. LC-MS (ESI ⁺ ) m/z: 414.2 (M+H) ⁺ . Step 2: To a solution of 1-[4-[(3S,4R)-7-hydroxy-3-phenyl-isochroman-4-yl]phenyl]pipe ridine - 4-carbaldehyde (70 mg, 1 eq, 169.28 ^mol) in DCE (10 mL) and MeOH (1 mL) was added 3-(1- methyl-6-piperazin-1-yl-indazol-3-yl)piperidine-2,6-dione (55.42 mg, 1 eq, 169.28 ^mol) and stirred at 20 °C for 0.5 h. Then NaBH(OAc) ₃ (107.63 mg, 3 eq, 507.85 ^mol) was added and stirred at 20 °C for 0.5 h.^The solvent was removed to yield a residue which was purified by preparative HPLC (column: Phenomenex Gemini NX 150×30mm,5^m; mobile phase: [water( NH ₄ HCO ₃ )-ACN]; gradient: 50%-77% B over 11 min), followed by lyophilization to give the product of^3-[6-[4-[[1-[4-[(3S,4R)-7-hydroxy-3-phenyl-isochroman-4-y l]phenyl]-4- piperidyl]methyl]piperazin-1-yl]-1-methyl-indazol-3-yl]piper idine-2,6-dione (31 mg, 24.69% yield) as a white solid. LC-MS (ESI ⁺ ) m/z: 725.3 (M+H) ⁺ . LCMS: calc. for C44H48N6O4: 724.91, found: [M+H] ⁺ 725.3. HPLC: 98.907% purity at 254 nm. ¹ HNMR (400MHz, DMSO-d6): į 10.85 (s, 1H), 9.28 (s, 1H), 7.49 (d, J = 8.9 Hz, 1H), 7.17 - 7.11 (m, 2H), 7.11 - 7.04 (m, 3H), 6.91 (d, J = 9.3 Hz, 1H), 6.83 (s, 1H), 6.78 (d, J = 8.0 Hz, 1H), 6.64 - 6.59 (m, 2H), 6.55 (d, J = 6.1 Hz, 4H), 5.07 (d, J = 15.4 Hz, 1H), 5.00 (d, J = 2.6 Hz, 1H), 4.90 (d, J = 15.4 Hz, 1H), 4.25 (dd, J = 5.1, 8.9 Hz, 1H), 4.03 (d, J = 2.5 Hz, 1H), 3.88 (s, 3H), 3.50 (d, J = 11.9 Hz, 2H), 3.32 (s, 6H), 3.20 (s, 4H), 2.65 - 2.56 (m, 2H), 2.31 - 2.10 (m, 4H), 1.75 (d, J = 12.4 Hz, 2H), 1.63 (s, 1H), 1.15 (d, J = 11.2 Hz, 2H).

EXAMPLE 86. Preparation of (I-271) (S)-3-(5-(4-((1-(4-((3R,4S)-7-hydroxy-3',4'- dihydro-2'H-spiro[isochromane-3,1'-naphthalen]-4-yl)phenyl)p iperidin-4- yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2, 6-dione Step 1: A mixture of 7-(benzyloxy)isochroman-4-one (2.3 g, 9.1 mmol, 1 eq), 3-(2- bromophenyl)propan-1-ol (2.3 g, 10.8 mmol, 1.2 eq), KOH(508 mg, 9.1 mmol, 1 eq) , Ru(PPh ₃ ) ₂ Cl ₂ (826 mg, 904.5 ^mol, 0.1 eq) was added in toluene (25 mL) was purged N ₂ 3 times, the mixture was stirred at 100 °C for 12 h. TLC (petroleum ether: ethyl acetate=10:1, R _f =0.7, UV) showed one main new spot was observed. The resulting solution was diluted with 50 mL H ₂ O and was extracted with ethyl acetate (100 mL*2), the organic layers were dried with anhydrous Na ₂ SO ₄ , filtered, and concentrated to give the crude product. The residue was subjected to column chromatography over silica gel (gradient elution: 0 – 20% EtOAc), The desired fractions were collected, and concentrated to dryness in vacuo to give 7-(benzyloxy)-3- (3-(2-bromophenyl)propyl)isochroman-4-one (3 g, 6.7 mmol, 73.5% yield) was obtained as a yellow oil. Step 2: A mixture of 7-(benzyloxy)-3-(3-(2-bromophenyl)propyl)isochroman-4-one (2 g, 4.4 mmol, 1 eq), Cs ₂ CO ₃ (2.9 g, 8.9 mmol, 2 eq), Pd(OAc) ₂ (100 mg, 443.1 ^mol, 0.1 eq), [1-(2- diphenylphosphanyl-1-naphthyl)-2-naphthyl]-diphenyl-phosphan e (414 mg, 664.7 ^mol, 0.15 eq) was added in toluene (100 mL) and was degassed and purged N2 for 3 times, the mixture was stirred at 100 °C for 12 h. TLC (petroleum ether: ethyl acetate=10:1, Rf =0.7, UV) showed one main new spot was observed. The resulting solution was quenched with saturated aqueous NH ₄ Cl (20 mL) and was treated with 50 mL H ₂ O with extracted with 100 mL ethyl acetate. The organic layers were dried with anhydrous Na ₂ SO ₄ , filtered, and concentrated to give the crude product. The residue was purified by prep-HPLC (column: Welch Xtimate C18 150*30mm*5um; mobile phase: [water(FA)-ACN];gradient:60%-100% B over 9 min). Compound 7-(benzyloxy)-3',4'-dihydro-2'H-spiro[isochromane-3,1'-napht halen]-4-one (190 mg, 512.9 ^mol, 11.6% yield) was obtained as a yellow oil. Step 3: N-butyllithium (2.5 M, 615.49 ^L, 3 eq) was added in the mixture of 1-(4-bromophenyl)- 4-(dimethoxymethyl)piperidine (564 mg, 1.8 mmol, 3.5 eq) in THF (4 mL) at -78 °C under N ₂ , the mixture was stirred at -78 °C for 0.5 h, and then 7-(benzyloxy)-3',4'-dihydro-2'H- spiro[isochromane-3,1'-naphthalen]-4-one (190 mg, 512.9 ^mol, 1 eq) was added in the mixture at -78 °C under N ₂ , and was stirred at 25 °C for 12h. TLC (petroleum ether: ethyl acetate=10:1, Rf =0.5 UV) showed one main new spot was observed. The resulting solution was quenched with saturated aqueous NH4Cl (20 mL) adjust to pH=7 at 0 °C, was diluted with H2O (50 mL) extracted with ethyl acetate 100 mL The organic layers were dried with anhydrous Na ₂ SO ₄ filtered, and concentrated to give the crude product. The residue was subjected to column chromatography over silica gel (gradient elution: 0 – 20% EtOAc), The desired fractions were collected, and concentrated to dryness in vacuo to give 7-(benzyloxy)-4-(4-(4- (dimethoxymethyl)piperidin-1-yl)phenyl)-3',4'-dihydro-2'H-sp iro[isochromane-3,1'-naphthalen]- 4-ol (280 mg, 462.2 ^mol, 90% yield) was obtained as a colorless oil. LC-MS (ESI+) m/z: 606.4 (M+H) ⁺ . Step 4: A mixture of 7-(benzyloxy)-4-(4-(4-(dimethoxymethyl)piperidin-1-yl)phenyl )-3',4'- dihydro-2'H-spiro[isochromane-3,1'-naphthalen]-4-ol (280 mg, 462.2 ^mol, 1 eq), Pd/C (280 mg, 263.1 ^mol, 10% wt), Pd(OH) ₂ /C (280 mg, 20% wt, 2 mmol) was added in THF (4 mL) and MeOH (4 mL) under N ₂ atmosphere, The suspension was degassed and purged with H ₂ for 3 times. The mixture was stirred under H ₂ (15 psi) at 70 °C for 12hr. The reaction mixture was filtered and concentrated under reduced pressure to give the crude product. The crude product was used into the next step without further purification. Compound 4-(4-(4- (dimethoxymethyl)piperidin-1-yl)phenyl)-3',4'-dihydro-2'H-sp iro[isochromane-3,1'-naphthalen]- 7-ol (200 mg, 400.3 ^mol, 86.6% yield) was obtained as a white solid. LC-MS (ESI+) m/z: 500.3 (M+H) ⁺ . Step 5: The residue was purified by prep-HPLC (column: Welch Xtimate C18150*30mm*5um; mobile phase: [water (FA)-ACN]; gradient: 48%-78% B over 7 min) to give two fractions. Fraction one (140 mg) was a red solid and fraction two (60 mg) was a red solid. Fraction one was further separated by SFC (column: ChiralPak IH, 250*30mm, 10um; mobile phase: [CO ₂ -EtOH(0.1%NH3H2O)];B%:30%, isocratic elution mode) to give compound (3R,4S)-4-(4-(4-(dimethoxymethyl)piperidin-1-yl)phenyl)-3',4 '-dihydro-2'H-spiro[isochromane- 3,1'-naphthalen]-7-ol (40 mg, 80.1 ^mol, 14.8% yield) as a white solid and compound (3S,4R)-4- (4-(4-(dimethoxymethyl)piperidin-1-yl)phenyl)-3',4'-dihydro- 2'H-spiro[isochromane-3,1'- naphthalen]-7-ol (50 mg, 100.1 ^mol, 18.5% yield) as a white solid. Fraction two was further separated by SFC (column: REGIS(S,S)WHELK- O1(250mm*25mm,10um);mobile phase: [CO ₂ -EtOH(0.1%NH3H2O)];B%:45%, isocratic elution mode) to give compound (3S,4S)-4-(4-(4-(dimethoxymethyl)piperidin-1-yl)phenyl)-3',4 '- dihydro-2'H-spiro[isochromane-3,1'-naphthalen]-7-ol (20 mg, 40 ^mol, 7.4% yield) as a white lid d d (3R4R) 4 (4 (4 (di th th l) i idi 1 l) h l) 3'4' dih d 2'H-spiro[isochromane-3,1'-naphthalen]-7-ol (10 mg, 20 ^mol, 3.7% yield) as a white solid. LC- MS (ESI+) m/z: 500.3 (M+H) ⁺ . Step 6: To a solution of (3R,4S)-4-(4-(4-(dimethoxymethyl)piperidin-1-yl)phenyl)-3',4 '-dihydro- 2'H-spiro[isochromane-3,1'-naphthalen]-7-ol (40 mg, 80.1 ^mol, 1 eq) in THF (4 mL) was added 10% H ₂ SO ₄ (4 mL). The mixture was stirred at 70 °C for 1 h. The reaction mixture was quenched by saturated NaHCO ₃ aqueous solution addition (20 mL) at 25 °C, and then diluted with 20 mL H ₂ O and extracted with ethyl acetate 40 mL. The combined organic layer was washed with 20 mL brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The crude product 1-(4-((3R,4S)-7-hydroxy-3',4'-dihydro-2'H- spiro[isochromane-3,1'-naphthalen]-4-yl)phenyl)piperidine-4- carbaldehyde (30 mg, 66.1 ^mol, 82.6% yield) as a yellow oil was used into the next step without further purification. LC-MS (ESI+) m/z: 454.2 (M+H) ⁺ . Step 7: To a solution of 1-(4-((3R,4S)-7-hydroxy-3',4'-dihydro-2'H-spiro[isochromane- 3,1'- naphthalen]-4-yl)phenyl)piperidine-4-carbaldehyde (30 mg, 66.1 ^mol, 1 eq) and (3S)-3-(1-oxo- 5-piperazin-1-yl-isoindolin-2-yl)piperidine-2,6-dione (32 mg, 66.1 ^mol, 1 eq, PhSO3H salt) in DCM (4 mL) and MeOH (4 mL) was added sodium acetate (16 mg, 198.4 ^mol, 3 eq). The mixture was stirred at 30 °C for 0.5 h. Then the mixture was added NaBH(OAc) ₃ (28 mg, 132.3 ^mol, 2 eq) and acetic acid (12 mg, 198.4 ^mol, 11 ^L, 3 eq) .The mixture was stirred at 30 °C for 16 h finally. The reaction mixture was diluted with 20 mL H ₂ O and extracted with 40 mL DCM. The combined organic layer was washed with 20 mL brine, dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep- HPLC (column: Welch Xtimate C18150*30mm*5um; mobile phase: [water(FA)- ACN];gradient:15%-45% B over 7 min). (S)-3-(5-(4-((1-(4-((3R,4S)-7-hydroxy-3',4'-dihydro- 2'H-spiro[isochromane-3,1'-naphthalen]-4-yl)phenyl)piperidin -4-yl)methyl)piperazin-1-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione (12 mg, 15.67 ^mol, 23.69% yield) was obtained as a white solid. LC-MS (ESI ⁺ ) m/z: 766.2 (M+H) ⁺ . HPLC: 98.23%, purity at 220 nm. NMR (400 MHz, Methanol-d4) į ppm 8.38 - 8.42 (m, 0.197 H) 7.66 (d, J=8.28 Hz, 1 H) 7.09 - 7.14 (m, 2 H) 6.93 - 7.03 (m, 2 H) 6.79 (d, J=9.29 Hz, 1 H) 6.66 - 6.70 (m, 2 H) 6.58 (s, 3 H) 6.50 - 6.56 (m, 3 H) 5.08 - 5.15 (m, 1 H) 5.02 - 5.08 (m, 2 H) 4.42 (d, J=5.77 Hz, 2 H) 4.10 (s, 1 H) 3.51 - 3.59 (m, 2 H) 3.43 (br s, 4 H) 2.85 (s, 3 H) 2.81 (br dd, J=4.52, 2.51 Hz, 1 H) 2.76 (br s, 4 H) 2.68 (s, 3 H) 2.45 (br d, J=7.03 Hz, 2 H) 2.37 (dt, J=12.23, 3.54 Hz, 1 H) 2.12 - 2.21 (m, 1 H) 1.94 - 2.09 (m, 2 H) 1.75 - 1.91 (m, 4 H) 1.32 - 1.43 (m, 2 H)1.16 - 1.27 (m, 2 H). EXAMPLE 87. Preparation of (I-76) (S)-3-(5-(4-((1-(4-((3S,4R)-7-hydroxy-3',4'- dihydro-2'H-spiro[isochromane-3,1'-naphthalen]-4-yl)phenyl)p iperidin-4- yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2, 6-dione Step 1: To a solution of (3S,4R)-4-(4-(4-(dimethoxymethyl)piperidin-1-yl)phenyl)-3',4 '-dihydro- 2'H-spiro[isochromane-3,1'-naphthalen]-7-ol (50 mg, 100.07 ^mol, 1 eq) in THF (4 mL) was added 10% aq.H ₂ SO ₄ (4 mL).The mixture was stirred at 70 °C for 1 h. The reaction mixture was quenched by saturated NaHCO ₃ aqueous solution addition 20 mL at 25 °C, and then diluted with 20 mL H ₂ O and extracted with 40 mL ethyl acetate. The combined organic layers were washed with 20 mL brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced tetralin]-4-yl]phenyl]piperidine-4-carbaldehyde (40 mg, 88.2 ^mol, 88.1% yield) as a yellow oil was used into the next step without further purification. LC-MS (ESI+) m/z: 472.2 (M+H ₂ O) ⁺ . Step 2: To a solution of 1-(4-((3S,4R)-7-hydroxy-3',4'-dihydro-2'H-spiro[isochromane- 3,1'- naphthalen]-4-yl)phenyl)piperidine-4-carbaldehyde (40 mg, 88.2 ^mol, 1 eq) and (3S)-3-(1-oxo- 5-piperazin-1-yl-isoindolin-2-yl)piperidine-2,6-dione (43 mg, 88.2 ^mol, 1 eq, PhSO ₃ H) in DCM (4 mL) and MeOH (4 mL) was added sodium acetate (22 mg, 264.5 ^mol, 3 eq) .The mixture was stirred at 30 °C for 0.5 h. Then the mixture was added NaBH(OAc) ₃ (37 mg, 176.4 ^mol, 2 eq) and acetic acid (16 mg, 264.6^mol, 15 ^L, 3 eq). The mixture was stirred at 30 °C for 16 h finally. The reaction mixture was diluted with 10 mL H ₂ O and extracted with 40 mL DCM. The combined organic layer was washed with 20 mL brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep- HPLC (column: Welch Xtimate C18150*30mm*5um; mobile phase: [water(FA)- ACN];gradient:18%-48% B over 7 min). (S)-3-(5-(4-((1-(4-((3S,4R)-7-hydroxy-3',4'-dihydro- 2'H-spiro[isochromane-3,1'-naphthalen]-4-yl)phenyl)piperidin -4-yl)methyl)piperazin-1-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione (5.3 mg, 6.9 ^mol, 7.9% yield) was obtained as a white solid. LC-MS (ESI ⁺ ) m/z: 766.2 (M+H) ⁺ . HPLC: 98.738%, purity at 220 nm. ¹ H NMR (400 MHz, Methanol-d ₄ ) į ppm 8.33 - 8.38 (m, 0.277 H) 7.64 - 7.69 (m, 1 H) 7.08 - 7.14 (m, 2 H) 6.99 - 7.03 (m, 1 H) 6.93 - 6.97 (m, 1 H) 6.77 - 6.81 (m, 1 H) 6.66 - 6.70 (m, 2 H) 6.57 - 6.64 (m, 3 H) 6.49 - 6.56 (m, 3 H) 5.08 - 5.15 (m, 1 H) 5.03 - 5.07 (m, 2 H) 4.37 - 4.48 (m, 2 H) 4.10 (s, 1 H) 3.56 (br d, J 11.54 Hz, 2 H) 3.44 (br d, J=4.52 Hz, 4 H) 2.86 - 2.99 (m, 3 H) 2.82 (br d, J=4.77 Hz, 5 H) 2.59 - 2.69 (m, 3 H) 2.51 (br d, J=6.27 Hz, 2 H) 2.37 (dt, J=12.42, 3.95 Hz, 1 H) 2.13 - 2.21 (m, 1 H) 1.95 - 2.09 (m, 2 H) 1.80 - 1.92 (m, 4 H) 1.34 - 1.44 (m, 2 H). EXAMPLE 88. Preparation of (I-272) (S)-3-(5-(4-((1-(4-((3S,4S)-7-hydroxy-3',4'- dihydro-2'H-spiro[isochromane-3,1'-naphthalen]-4-yl)phenyl)p iperidin-4- yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2, 6-dione Step 1: To a solution of (3S,4S)-4-(4-(4-(dimethoxymethyl)piperidin-1-yl)phenyl)-3',4 '-dihydro- 2'H-spiro[isochromane-3,1'-naphthalen]-7-ol (20 mg, 40 ^mol, 1 eq) in THF (4 mL) was added 10% aq.H ₂ SO ₄ (4 mL).The mixture was stirred at 70 °C for 1 h. The reaction mixture was quenched by saturated NaHCO ₃ aqueous solution addition 20 mL at 25 °C, and then diluted with 20 mL H ₂ O and extracted with ethyl acetate. The combined organic layers were washed with 20 mL brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The crude product 1-(4-((3S,4S)-7-hydroxy-3',4'-dihydro-2'H-spiro[isochromane- 3,1'-naphthalen]-4-yl)phenyl)piperidine-4-carbaldehyde (17 mg, 37.5 ^mol, 93.6% yield) as a yellow oil was used into the next step without further purification. LC-MS (ESI+) m/z: 472.1 Step 2: To a solution of 1-(4-((3S,4S)-7-hydroxy-3',4'-dihydro-2'H-spiro[isochromane- 3,1'- naphthalen]-4-yl)phenyl)piperidine-4-carbaldehyde (17 mg, 37.5 ^mol, 1 eq) and (3S)-3-(1-oxo- 5-piperazin-1-yl-isoindolin-2-yl)piperidine-2,6-dione (18.2 mg, 37.5 ^mol, 1 eq, PhSO ₃ H salt) in DCM (4 mL) and MeOH (4 mL) was added sodium acetate (9 mg, 112.4 ^mol, 3 eq). The mixture was stirred at 30 °C for 0.5 h. Then the mixture was added NaBH(OAc) ₃ (16 mg, 75 ^mol, 2 eq) and acetic acid (7 mg, 112.4 ^mol, 7 ^L, 3 eq) .The mixture was stirred at 30 °C for 16 h finally. The reaction mixture was diluted with 20 mL H ₂ O and extracted with 40 mL DCM. The combined organic layers were washed with 20 mL brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Welch Xtimate C18150*30mm*5um; mobile phase: [water(FA)- ACN];gradient:15%-45% B over 7 min). (S)-3-(5-(4-((1-(4-((3S,4S)-7-hydroxy-3',4'-dihydro- 2'H-spiro[isochromane-3,1'-naphthalen]-4-yl)phenyl)piperidin -4-yl)methyl)piperazin-1-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione (1 mg, 1.3 ^mol, 3.5% yield) was obtained as a white solid. LC-MS (ESI ⁺ ) m/z: 766.3 (M+H) ⁺ . HPLC: 98.284%, purity at 220 nm. ¹ H NMR (400 MHz, Methanol-d ₄ ) į ppm 8.40 - 8.49 (m, 0.399 H) 7.66 (d, J=8.28 Hz, 1 H) 7.39 (d, J=7.28 Hz, 1 H) 7.15 - 7.20 (m, 1 H) 7.09 - 7.14 (m, 3 H) 7.03 - 7.08 (m, 1 H) 6.97 (d, J=8.78 Hz, 2 H) 6.87 (br d, J=9.03 Hz, 3 H) 6.60 - 6.65 (m, 1 H) 6.44 - 6.48 (m, 1 H) 5.08 - 5.15 (m, 1 H) 4.76 (br s, 1 H) 4.37 - 4.49 (m, 3 H) 4.27 (s, 1 H) 3.61 - 3.68 (m, 2 H) 3.43 (br d, J=4.77 Hz, 4 H) 2.79 - 2.96 (m, 3 H) 2.65 - 2.77 (m, 7 H) 2.48 - 2.60 (m, 2 H) 2.45 (br d, J=6.53 Hz, 2 H) 2.12 - 2.20 (m, 1 H) 1.90 - 1.95 (m, 2 H) 1.56 - 1.78 (m, 3 H) 1.36 - 1.45 (m, 3 H). Absolute stereochemistry was arbitrarily assigned

EXAMPLE 89. Preparation of (I-273) (S)-3-(5-(4-((1-(4-((3R,4R)-7-hydroxy-3',4'- dihydro-2'H-spiro[isochromane-3,1'-naphthalen]-4-yl)phenyl)p iperidin-4- yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2, 6-dione Step 1: To a solution of (3R,4R)-4-(4-(4-(dimethoxymethyl)piperidin-1-yl)phenyl)-3',4 '-dihydro- 2'H-spiro[isochromane-3,1'-naphthalen]-7-ol (10 mg, 20 ^mol, 1 eq) in THF (4 mL) was added 10% aq.H ₂ SO ₄ (4 mL).The mixture was stirred at 70 °C for 1 h. The reaction mixture was quenched by saturated NaHCO ₃ aqueous solution addition 20 mL at 25 °C, and then diluted with 20 mL H ₂ O and extracted with 40 mL ethyl acetate. The combined organic layers were washed with 20 mL brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The crude product 1-(4-((3R,4R)-7-hydroxy-3',4'-dihydro-2'H- spiro[isochromane-3,1'-naphthalen]-4-yl)phenyl)piperidine-4- carbaldehyde (8 mg, 17.6 ^mol, 88.1% yield) as a yellow oil was used into the next step without further purification. LC-MS (ESI+) m/z: 472.1 (M+H ₂ O) ⁺ . Step 2: To a solution of 1-(4-((3R,4R)-7-hydroxy-3',4'-dihydro-2'H-spiro[isochromane- 3,1'- naphthalen]-4-yl)phenyl)piperidine-4-carbaldehyde (8 mg, 17.6 ^mol, 1 eq) and (3S)-3-(1-oxo- 5-piperazin-1-yl-isoindolin-2-yl)piperidine-2,6-dione (8.6 mg, 17.6 ^mol, 1 eq, PhSO ₃ H salt) in mixture was stirred at 30 °C for 0.5 h. Then the mixture was added NaBH(OAc)3 (8 mg, 35.3 ^mol, 2 eq) and acetic acid (3 mg, 52.9 ^mol, 3 ^L, 3 eq). The mixture was stirred at 30 °C for 16 h finally. The reaction mixture was diluted with 20 mL H ₂ O and extracted with 40 mL DCM. The combined organic layer was washed with 20 mL brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Welch Xtimate C18150*30mm*5um; mobile phase: [water(FA)- ACN];gradient:15%-45% B over 7 min). (S)-3-(5-(4-((1-(4-((3R,4R)-7-hydroxy-3',4'-dihydro- 2'H-spiro[isochromane-3,1'-naphthalen]-4-yl)phenyl)piperidin -4-yl)methyl)piperazin-1-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione (0.5 mg, 6.5e-1 ^mol, 3.7% yield) was obtained as a white solid. LC-MS (ESI ⁺ ) m/z: 766.3 (M+H) ⁺ . HPLC: 95.52%, purity at 220 nm. ¹ H NMR (400 MHz, Methanol-d ₄ ) į ppm 8.37 - 8.51 (m, 0.622 H) 7.67 (d, J=8.28 Hz, 1 H) 7.39 (d, J=7.78 Hz, 1 H) 7.15 - 7.20 (m, 1 H) 7.08 - 7.14 (m, 3 H) 7.03 - 7.08 (m, 1 H) 6.94 - 7.00 (m, 2 H) 6.84 - 6.90 (m, 3 H) 6.60 - 6.64 (m, 1 H) 6.46 (d, J=2.51 Hz, 1 H) 5.08 - 5.15 (m, 1 H) 4.76 (s, 1 H) 4.36 - 4.48 (m, 3 H) 4.28 (d, J=15.31 Hz, 1 H) 3.61 - 3.68 (m, 2 H) 3.42 (br d, J=4.77 Hz, 4 H) 2.79 - 2.95 (m, 3 H) 2.71 - 2.79 (m, 5 H) 2.65 - 2.70 (m, 2 H) 2.48 - 2.64 (m, 2 H) 2.43 - 2.47 (m, 2 H) 2.13 - 2.21 (m, 1 H) 1.89 - 1.96 (m, 2 H) 1.57 - 1.79 (m, 3 H) 1.37 - 1.45 (m, 3 H). Absolute stereochemistry was arbitrarily assigned EXAMPLE 90. Preparation of (I-353) (S)-3-(5-(4-((1-(4-((3R,4S)-7-hydroxy-3-(p- tolyl)isochroman-4-yl)phenyl)piperidin-4-yl)methyl)piperazin -1-yl)-1-oxoisoindolin-2- yl)piperidine-2,6-dione and (I-354) (S)-3-(5-(4-((1-(4-((3S,4R)-7-hydroxy-3-(p-

tolyl)isochroman-4-yl)phenyl)piperidin-4-yl)methyl)pipera zin-1-yl)-1-oxoisoindolin-2- yl)piperidine-2,6-dione Step 1: To a solution of 1 (300 mg, 513.16 ^mol, 1.0 eq.) in THF (4 mL) was added 2 (1 M, 1.54 mL 30 eq) at 0 °C under N Then the mixture was stirred at 20 °C for 12 h under N LCMS showed that the starting material was consumed, and the desired product was detected. MeOH (2 mL) was dropped into the mixture. Then the mixture was filtered and concentrated under vacuum to give the crude. The crude product was purified by Pre-TLC (PE/EA=10/1) to give 3 (220 mg, 55.07% yield) as colorless oil. LC-MS (ESI ⁺ ) m/z: 485.0 (M+H-130) ⁺ . 1H NMR (500 MHz, DMSO-d ₆ ) į = 7.87 (d, J = 8.2 Hz, 2H), 7.51 (d, J = 8.4 Hz, 2H), 7.42 - 7.24 (m, 7H), 7.13 - 7.04 (m, 3H), 6.88 - 6.78 (m, 2H), 6.34 (s, 1H), 5.05 (s, 2H), 4.81 - 4.52 (m, 2H), 2.33 (s, 3H), 0.84 (s, 9H), 0.01 (d, J = 7.3 Hz, 6H). Step 2: To a solution of 3 (220 mg, 357.33 ^mol, 1.0 eq.) in DCM (10 mL) was added triethylsilane (124.65 mg, 1.07 mmol 3.0 eq.) at 20 °C. The mixture was cooled to -78 °C. Then the trimethylsilyl trifluoromethanesulfonate (119.13 mg, 536.00 ^mol, 1.5 eq.) was added into the mixture at -78 °C. The mixture was stirred at -78 °C for 1 h. TLC showed that no desired product was detected. Na2CO3 ˄sat aq.˅(3 mL) was added into the mixture. The mixture was diluted and extracted with DCM mL (50 mL x 3), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The mixture was purified by Pre-TLC (PE/EA= 10/1) to give 4 (160 mg, 92.24% yield) as colorless oil. ¹ H NMR (400 MHz, CHLOROFORM-d) į = 7.46 - 7.38 (m, 5H), 7.15 (d, J = 8.3 Hz, 2H), 6.99 - 6.92 (m, 3H), 6.87 - 6.82 (m, 3H), 6.76 (d, J = 2.3 Hz, 1H), 6.64 (d, J = 8.5 Hz, 2H), 5.19 - 5.14 (m, 1H), 5.08 - 5.01 (m, 4H), 4.02 (d, J = 3.1 Hz, 1H), 2.28 (s, 3H). Step 3: To a solution of 4 (150 mg, 309.02 ^mol, 1.0 eq.) in dioxane (1 mL) was added 5 (98.41 mg, 618.03 ^mol, 2.0 eq.) and K ₂ CO ₃ (128.12 mg, 927.05 ^mol, 3.0 eq.) at 20 °C. Then the [2- (2-aminophenyl)phenyl]-methylsulfonyloxy-palladium;dicyclohe xyl-[2-(2,6- diisopropoxyphenyl)phenyl]phosphane (38.77 mg, 46.35 ^mol, 0.15 eq.) was added into the mixture at 20 °C. The mixture was stirred at 100 °C for 4 h under N ₂ . LCMS showed that the starting material was consumed and the desired product was detected. The mixture was filtered and concentrated under vacuum to give the crude. The crude was purified by Pre-TLC (PE/EA=3/1) to give 6 as yellow solid. LC MS (ESI ⁺ ) m/z: 5643 (M+H) ⁺ 1H NMR (400 MHz, chloroform-d) į = 7.48 - 7.33 (m, 7H), 6.95 (br d, J = 7.7 Hz, 3H), 6.84 (br d, J = 7.6 Hz, 3H), 6.75 (br s, 1H), 6.63 (br s, 2H), 5.19 - 5.14 (m, 1H), 5.07 (s, 2H), 5.01 (br d, J = 16.6 Hz, 1H), 4.19 - 4.09 (m, 1H), 4.09 - 3.92 (m, 2H), 3.60 - 3.54 (m, 2H), 3.37 (s, 6H), 2.58 - 2.46 (m, 2H), 2.27 (s, 3H), 1.85 - 1.65 (m, 4H), 1.45 - 1.39 (m, 1H). Step 4: A solution of 6 (120 mg, 212.87 ^mol, 1.0 eq.) and Pd/C (226.54 mg, 212.87 ^mol, 10% purity, 1.0 eq.) in EA (3 mL) and then degassed and purged with H ₂ for 3 times, and then the mixture was stirred at 15 °C for 3hr under H ₂ atmosphere. LCMS showed that the starting material was consumed, and the desired product was detected. The mixture was filtered and concentrated under vacuum to give the crude. The crude was purified by Pre-TLC (PE/EA=1/1) to give 7 (50 mg, 47.99% yield) as colorless solid. LC-MS (ESI ⁺ ) m/z: 474.1 (M+H) ⁺ . Step 5: The 7 (80 mg, 168.92 ^mol, 1.0 eq.) was further separated by SFC (condition: CO ₂ - EtOH (0.1%NH3H2O), column: DAICEL CHIRALPAK AD (250mm x 30 mm, 10 um), Begin B: 25, End B: 25) to give (3R,4S)-4-(4-(4-(dimethoxymethyl)piperidin-1-yl)phenyl)-3-(p - tolyl)isochroman-7-ol 8 (30 mg, 37.50% yield) as white solid and (3S,4R)-4-(4-(4- (dimethoxymethyl)piperidin-1-yl)phenyl)-3-(p-tolyl)isochroma n-7-ol 8A (30 mg, 37.50% yield) as white solid. 8: LC-MS (ESI ⁺ ) m/z: 474.4 (M+H) ⁺ . 1H NMR (400 MHz, DMSO-d6) į = 10.94 (s, 1H), 9.29 (s, 1H), 8.13 (s, 1H), 7.60 - 7.30 (m, 2H), 7.23 (d, J = 7.7 Hz, 1H), 7.07 (br t, J = 7.0 Hz, 2H), 6.80 - 6.73 (m, 2H), 6.62 - 6.49 (m, 7H), 5.17 (d, J = 2.3 Hz, 1H), 5.09 - 5.01 (m, 2H), 4.97 - 4.90 (m, 1H), 4.36 - 4.18 (m, 2H), 3.90 (br d, J = 0.7 Hz, 1H), 3.51 (br d, J = 9.4 Hz, 2H), 3.29 (br s, 10H), 3.19 - 3.13 (m, 1H), 2.95 - 2.85 (m, 1H), 2.45 - 2.31 (m, 4H), 2.26 - 2.12 (m, 2H), 1.99 - 1.93 (m, 1H), 1.79 - 1.62 (m, 3H), 1.34 (d, J = 6.8 Hz, 3H), 1.15 (br d, J = 6.7 Hz, 3H). 8A: LC-MS (ESI ⁺ ) m/z: 474.4 (M+H) ⁺ . 1H NMR (400 MHz, DMSO-d6) į = 9.26 (s, 1H), 6.94 (s, 4H), 6.77 (d, J = 8.1 Hz, 1H), 6.65 - 6.61 (m, 2H), 6.57 - 6.53 (m, 4H), 5.05 (d, J = 15.5 Hz, 1H), 4.94 (d, J = 3.1 Hz, 1H), 4.88 (d, J = 15.4 Hz, 1H), 4.04 (d, J = 6.6 Hz, 1H), 3.99 (d, J = 2.7 Hz, 1H), 3.51 (br d, J = 11.2 Hz, 2H), 3.29 (s, 2H), 3.24 (s, 6H), 2.19 (s, 3H), 1.67 - 1.60 (m, 3H), 1.23 (br d, J = 9.1 Hz, 2H). Step 6: To a solution of (3R,4S)-4-(4-(4-(dimethoxymethyl)piperidin-1-yl)phenyl)-3-(p - tolyl)isochroman-7-ol 8 (25 mg, 1.0 Eq, 53 ^mol)in DCM (1 mL) was added Trifluoroacetic acid (0.4 g, 0.3 mL, 7e+1 Eq, 4 mmol)at 15 °C. Then the mixture was stirred at 15 °C for 1 hour. LCMS showed that the desired product was detected. Then the mixture was filtered and concentrated under vacuum to give the 1-(4-((3R,4S)-7-hydroxy-3-(p-tolyl)isochroman-4- yl)phenyl)piperidine-4-carbaldehyde 9 (20 mg, crude). LC-MS (ESI ⁺ ) m/z: 446.2 (M+H+18) ⁺ Step 7: To a solution of (3S,4R)-4-(4-(4-(dimethoxymethyl)piperidin-1-yl)phenyl)-3-(p - tolyl)isochroman-7-ol 8A (25 mg, 1.0 Eq, 53 ^mol)in DCM (1 mL) was added Trifluoroacetic acid (0.4 g, 0.3 mL, 7e+1 Eq, 4 mmol)at 15 °C. Then the mixture was stirred at 15 °C for 1 hour. LCMS showed that the desired product was detected. Then the mixture was filtered and concentrated under vacuum to give the 1-(4-((3S,4R)-7-hydroxy-3-(p-tolyl)isochroman-4- yl)phenyl)piperidine-4-carbaldehyde 9A (20 mg, crude). LC-MS (ESI ⁺ ) m/z: 446.2 (M+H+18) ⁺ Step 8: To a solution of 1-(4-((3R,4S)-7-hydroxy-3-(p-tolyl)isochroman-4-yl)phenyl)pi peridine- 4-carbaldehyde 9 (20 mg, 1 Eq, 47 ^mol) in DCE (1 mL) and MeOH (1 mL) was added 10 (31 mg, 2 eq, 94 ^mol) and Sodium triacetoxyborohydride (50 mg, 5 Eq, 0.23 mmol) at 15 °C. Then the mixture was stirred at 15 °C for 1 hour. LCMS showed that the desired product was detected. The mixture was filtered and concentrated under vacuum to give the crude. The residue was purified by prep-HPLC (FA condition: Column: Boston Green ODS 150 x 30 mm x 5 um; Condition: water (FA)-ACN, Begin B 10, End B 40, Gradient Time (min) 12, 100% B Hold Time (min) 2, Flow Rate (mL/min) 25.) to give (S)-3-(5-(4-((1-(4-((3R,4S)-7-hydroxy-3- (p-tolyl)isochroman-4-yl)phenyl)piperidin-4-yl)methyl)pipera zin-1-yl)-1-oxoisoindolin-2- yl)piperidine-2,6-dione (27.7 mg, 79 % yield)as white solid. LC-MS (ESI ⁺ ) m/z: 740.4 (M+H) ⁺ LCMS: calc for C45H49N5O5: 73992 found: [M+H] ⁺ 7404 HPLC: 98.84% purity at 220 nm 1H NMR (400 MHz, DMSO-d6) į = 10.95 (s, 1H), 9.28 (s, 1H), 8.13 (s, 1H), 7.60 - 7.54 (m, 1H), 7.38 - 7.24 (m, 1H), 7.09 (br s, 1H), 6.95 (s, 4H), 6.77 (d, J = 8.1 Hz, 1H), 6.67 - 6.61 (m, 2H), 6.59 - 6.52 (m, 4H), 5.09 - 5.00 (m, 2H), 4.97 - 4.86 (m, 2H), 4.36 - 4.18 (m, 2H), 4.00 (br d, J = 2.1 Hz, 1H), 3.52 (br d, J = 10.5 Hz, 2H), 3.32 - 3.07 (m, 8H), 2.94 - 2.86 (m, 1H), 2.60 (br d, J = 2.1 Hz, 4H), 2.43 - 2.30 (m, 2H), 2.19 (s, 3H), 2.00 - 1.93 (m, 1H), 1.76 (br d, J = 12.0 Hz, 3H), 1.26 - 1.09 (m, 2H). Step 9: To a solution of 1-(4-((3S,4R)-7-hydroxy-3-(p-tolyl)isochroman-4-yl)phenyl)pi peridine- 4-carbaldehyde 9A (25 mg, 1 Eq, 58 ^mol) in DCE (1 mL) and MeOH (1 mL) was added 10 (38 mg, 2 Eq, 0.12 mmol) and Sodium triacetoxyborohydride (62 mg, 5 eq, 0.29 mmol) at 15 °C. Then the mixture was stirred at 15 °C for 1 hour. LCMS showed that the desired product was detected. The mixture was filtered and concentrated under vacuum to give the crude. The residue was purified by prep-HPLC (FA condition: Column: Boston Green ODS 150 x 30 mm x 5 um; Condition: water (FA)-ACN, Begin B 10, End B 40, Gradient Time (min) 12, 100% B Hold Time (min) 2, Flow Rate (mL/min) 25.) to give (S)-3-(5-(4-((1-(4-((3S,4R)-7-hydroxy-3- (p-tolyl)isochroman-4-yl)phenyl)piperidin-4-yl)methyl)pipera zin-1-yl)-1-oxoisoindolin-2- yl)piperidine-2,6-dione (28.2 mg, 65 % yield) as white solid. LC-MS (ESI+) m/z: 740.4 (M+H)+ LCMS: calc. for C ₄₅ H ₄₉ N ₅ O ₅ : 739.92, found: [M+H] ⁺ 740.4. HPLC: 99.38% purity at 220 nm NMR (400 MHz, DMSO-d ₆ ) į = 10.95 (s, 1H), 9.28 (s, 1H), 8.13 (s, 1H), 7.52 (br d, J = 8.5 Hz, 2H), 7.07 - 7.05 (m, 1H), 6.95 (s, 4H), 6.77 (d, J = 8.1 Hz, 1H), 6.66 - 6.62 (m, 2H), 6.58 - 6.52 (m, 4H), 5.08 - 5.02 (m, 2H), 4.96 - 4.86 (m, 2H), 4.35 - 4.18 (m, 2H), 4.00 (br d, J = 2.0 Hz, 1H), 3.51 (br d, J = 11.1 Hz, 2H), 3.33 - 3.20 (m, 8H), 2.94 - 2.85 (m, 1H), 2.60 (br s, 4H), 2.41 - 2.31 (m, 2H), 2.19 (s, 3H), 1.99 - 1.92 (m, 1H), 1.80 - 1.62 (m, 3H), 1.23 - 1.11 (m, 2H). EXAMPLE 91. Preparation of (I-394) (R)-3-(6-(4-((1-(4-((3S,4R)-7-hydroxy-3- phenylisochroman-4-yl)phenyl)piperidin-4-yl)methyl)piperazin -1-yl)-1-methyl-1H-indazol- 3-yl)piperidine-2,6-dione and (I-395) (S)-3-(6-(4-((1-(4-((3S,4R)-7-hydroxy-3- phenylisochroman-4-yl)phenyl)piperidin-4-yl)methyl)piperazin -1-yl)-1-methyl-1H-indazol- 3-yl)piperidine-2,6-dione Step 1: To a solution of 1-[4-[(3S,4R)-7-hydroxy-3-phenyl-isochroman-4-yl]phenyl]pipe ridine - 4-carbaldehyde (220 mg, 1 eq, 532.03 ^mol) in DCM (10 mL) and MeOH (1 mL) was added 3- (1-methyl-6-piperazin-1-yl-indazol-3-yl)piperidine-2,6-dione (193.58 mg, 1 eq, 532.03 ^mol, HCl) and stirred at 20 °C for 0.5 h. Then NaBH(OAc) ₃ (338.28 mg, 3 eq, 1.60 mmol) was added and stirred at 20 °C for 0.5 h. The solvent was removed to yield a residue. The residue was purified by preparative HPLC (column: Phenomenex Gemini NX 150×30mm,5^m; mobile phase: [water( NH4HCO3)-ACN]; gradient: 50%-77% B over 11 min), followed by lyophilization to yield a product which was separated by chiral SFC (column:DAICEL CHIRALPAK ID (250mm*30mm,10um);mobile phase: [MeOH-ACN] B%: 50%%, isocratic elution mode, peak 1: 2.324 min, peak 2: 3.447 min) to yield Peak 1 and Peak 2. Peak 1 was concentrated under reduced pressure to give the product of (R)-3-(6-(4-((1-(4 - ((3S,4R)-7-hydroxy-3-phenylisochroman-4-yl)phenyl)piperidin- 4-yl)methyl)piperazin-1-yl)-1- methyl-1H-indazol-3-yl)piperidine-2,6-dione or (S)-3-(6-(4-((1-(4-((3S,4R)-7-hydroxy-3- phenylisochroman-4-yl)phenyl)piperidin-4-yl)methyl)piperazin -1-yl)-1-methyl-1H-indazol-3- yl)piperidine-2,6-dione (49.8 mg, 41.5% yield, SFC: R _t = 2.324) as a white solid. LC-MS (ESI ⁺ ) m/z: 725.3 (M+H) ⁺ . LCMS: calc. for C ₄₄ H ₄₈ N ₆ O ₄ : 724.91, found: [M+H] ⁺ 725.3. HPLC 1000% it t 254 ¹ HNMR (500MHz, DMSO-d6): į 10.84 (s, 1H), 9.28 (s, 1H), 7.49 (d, J = 9.0 Hz, 1H), 7.17 - 7.03 (m, 5H), 6.91 (dd, J = 1.6, 9.1 Hz, 1H), 6.83 (s, 1H), 6.78 (d, J = 8.2 Hz, 1H), 6.64 - 6.59 (m, 2H), 6.58 - 6.52 (m, 4H), 5.07 (d, J = 15.4 Hz, 1H), 5.00 (d, J = 3.1 Hz, 1H), 4.91 (d, J = 15.3 Hz, 1H), 4.25 (dd, J = 5.1, 9.2 Hz, 1H), 4.03 (d, J = 2.7 Hz, 1H), 3.88 (s, 3H), 3.50 (d, J = 11.9 Hz, 2H), 3.30 (s, 6H), 3.20 (s, 4H), 2.65 - 2.58 (m, 2H), 2.34 - 2.25 (m, 1H), 2.23 - 2.09 (m, 3H), 1.75 (d, J = 11.6 Hz, 2H), 1.63 (s, 1H), 1.22 - 1.08 (m, 2H) Peak 2 was concentrated under reduced pressure to give the product of (R)-3-(6-(4-((1-(4 - ((3S,4R)-7-hydroxy-3-phenylisochroman-4-yl)phenyl)piperidin- 4-yl)methyl)piperazin-1-yl)-1- methyl-1H-indazol-3-yl)piperidine-2,6-dione or (S)-3-(6-(4-((1-(4 -((3S,4R)-7-hydroxy-3- phenylisochroman-4-yl)phenyl)piperidin-4-yl)methyl)piperazin -1-yl)-1-methyl-1H-indazol-3- yl)piperidine-2,6-dione (40.9 mg, 33.7% yield, SFC: R _t = 3.447) as a white solid. LC-MS (ESI ⁺ ) m/z: 725.3 (M+H) ⁺ . LCMS: calc. for C ₄₄ H ₄₈ N ₆ O ₄ : 724.91, found: [M+ ⁺ 725.3. HPLC: 100.0% purity at 254 nm. ¹ HNMR (500MHz, DMSO-d6): į 10.84 (s, 1H), 9.28 (s, 1H), 7.49 (d, J = 9.0 Hz, 1H), 7.18 - 7.02 (m, 5H), 6.91 (dd, J = 1.8, 9.0 Hz, 1H), 6.83 (d, J = 1.4 Hz, 1H), 6.78 (d, J = 8.2 Hz, 1H), 6.63 - 6.59 (m, 2H), 6.58 - 6.50 (m, 4H), 5.07 (d, J = 15.6 Hz, 1H), 5.00 (d, J = 3.1 Hz, 1H), 4.91 (d, J = 15.3 Hz, 1H), 4.25 (dd, J = 5.2, 9.2 Hz, 1H), 4.03 (d, J = 2.9 Hz, 1H), 3.88 (s, 3H), 3.50 (d, J = 11.9 Hz, 2H), 3.29 (s, 6H), 3.20 (s, 4H), 2.64 - 2.57 (m, 2H), 2.34 - 2.24 (m, 1H), 2.23 - 2.10 (m, 3H), 1.75 (d, J = 11.4 Hz, 2H), 1.63 (d, J = 3.5 Hz, 1H), 1.15 (q, J = 12.1 Hz, 2H).

EXAMPLE 92. Preparation of (I-398) 3-(5-(4-((1-(4-((3S,4R)-7-hydroxy-3- phenylisochroman-4-yl)phenyl)piperidin-4-yl)methyl)piperazin -1-yl)-1H-indazol-1- yl)piperidine-2,6-dione Step 1: To a solution of (3S,4R)-4-(4-(4-(dimethoxymethyl)piperidin-1-yl)phenyl)-3- phenylisochroman-7-ol (200 mg, 1 Eq, 435 ^mol) in THF (5 mL) was added sulfuric acid (5 mL, 10%v/v) at 0°C. The mixture was stirred at 70°C for 1 hour. The reaction mixture was adjusted to pH=~ 8 by adding saturated aq. NaHCO ₃ (10 mL). The mixture was diluted with 50 mL H ₂ O and extracted with 50 mL ethyl acetate. The organic layers were washed with brine 10 mL and dried over anhydrous Na ₂ SO ₄ . The organic layers were filtered and concentrated under reduced pressure to give 1-(4-((3S,4R)-7-hydroxy-3-phenylisochroman-4-yl)phenyl)piper idine-4- carbaldehyde (220 mg, 494 ^mol, 93% purity, crude product) as a brown oil. LC-MS (ESI+) m/z: 432.1(M+18) ⁺ . Step 2: A mixture of 1-(4-((3S,4R)-7-hydroxy-3-phenylisochroman-4-yl)phenyl)piper idine-4- carbaldehyde (120 mg, 93% purity, 1 Eq, 269 ^mol), 3-(5-(piperazin-1-yl)-1H-indazol-1- yl)piperidine-2,6-dione, trifluoroacetic acid salt(115 mg, 1 Eq, 269 ^mol) and sodium acetate (110 mg, 5 Eq, 1.35 mmol) were added in DCM (2 mL) and MeOH (2 mL) at 25°C for 0.5 hour, then added acetic acid (48.5 mg, 46.2 ^L, 3 Eq, 808 ^mol) and sodium triacetoxyborohydride (114 mg, 2 Eq, 538 ^mol). The mixture was stirred at r.t. for 16 hours. The reaction was diluted with water (50 mL) and extracted with ethyl acetate (50 mL*2). The combined organic layers were concentrated to give crude product as a brown oil. The brown oil was purified by preparative high-performance liquid chromatography. Condition: water (FA)-ACN. Column: C18150×30mm. Begin B: 20%, End B: 50%. Gradient time (min) 6; 100% B hold time (min) 1, Flow rate (ml/min) 30. The aqueous layer was lyophilized to dryness to give 3-(5-(4-((1-(4- ((3S,4R)-7-hydroxy-3-phenylisochroman-4-yl)phenyl)piperidin- 4-yl)methyl)piperazin-1-yl)-1H- indazol-1-yl)piperidine-2,6-dione (78.2 mg, 110 ^mol, 40.8% yield, 99.78% purity) as a white solid. LCMS: calc. 710.36, found: [M+H] ⁺ 711.2. HPLC: 99.78% purity at 220 nm. ¹ H NMR (400 MHz, DMSO-d ₆ ) į = 11.12 (s, 1H), 9.27 (s, 1H), 8.19 (s, 1H), 8.13 (s, 0.364H), 7.47 (br d, J = 9.3 Hz, 1H), 7.17 - 7.04 (m, 6H), 6.90 (br s, 1H), 6.78 (d, J = 8.0 Hz, 1H), 6.64 - 6.59 (m, 2H), 6.55 (br d, J = 6.8 Hz, 4H), 5.62 (br dd, J = 5.1, 11.3 Hz, 1H), 5.07 (br d, J = 15.7 Hz, 1H), 5.00 (d, J = 2.5 Hz, 1H), 4.91 (br d, J = 15.4 Hz, 1H), 4.03 (br d, J = 1.8 Hz, 1H), 3.50 (br d, J = 11.4 Hz, 2H), 3.08 (br d, J = 1.3 Hz, 3H), 2.86 - 2.78 (m, 1H), 2.74 - 2.55 (m, 6H), 2.48 - 2.41 (m, 3H), 2.35 - 2.20 (m, 3H), 1.80 - 1.71 (m, 2H), 1.69 - 1.59 (m, 1H), 1.22 - 1.09 (m, 2H).

EXAMPLE 93. Preparation of (I-397) 3-(5-(4-((1-(4-((3S,4R)-7-hydroxy-3- phenylisochroman-4-yl)phenyl)piperidin-4-yl)methyl)piperazin -1-yl)-2H-indazol-2- yl)piperidine-2,6-dione Step 1: A mixture of 1-(4-((3S,4R)-7-hydroxy-3-phenylisochroman-4-yl)phenyl)piper idine-4- carbaldehyde (100 mg, 93% purity, 1 Eq, 224 ^mol), 3-(5-(piperazin-1-yl)-2H-indazol-2- yl)piperidine-2,6-dione (70.3 mg, 1 Eq, 224 ^mol) and sodium acetate (92.0 mg, 5 Eq, 1.12 mmol) were added in DCM (2 mL) and MeOH (2 mL) at 25°C for 0.5 hour, then added acetic acid (40.4 mg, 38.5 ^L, 3 Eq, 673 ^mol) and sodium triacetoxyborohydride (95.1 mg, 2 Eq, 449 ^mol), then the mixture was stirred at 25°C for 16 hour. The reaction was diluted with water (50 mL) and extracted with ethyl acetate (50 mL*2). The combined organic layers were concentrated to give crude product as a brown oil. The brown oil was purified by preparative high- performance liquid chromatography. Condition: water (FA)-ACN. Column: Boston Prime C18 150*30mm*5um. Begin B: 60%, End B: 90%. Gradient time (min) 7; 100% B hold time (min) 2, Flow rate (ml/min) 25. The aqueous layer was lyophilized to dryness to give 3-(5-(4-((1-(4- ((3S,4R)-7-hydroxy-3-phenylisochroman-4-yl)phenyl)piperidin- 4-yl)methyl)piperazin-1-yl)-2H- indazol-2-yl)piperidine-2,6-dione (22.3 mg, 29.9 ^mol, 13.3% yield, 95.2% purity) as a white solid. LCMS: calc. for C ₄₃ H ₄₆ N ₆ O ₄ : 710.36, found: [M+H] ⁺ 711.3. HPLC: 95.2%purity at 220 nm. = 11.07 (s, 1H), 9.29 (s, 1H), 7.94 (s, 1H), 7.48 (br d, J = 9.2 Hz, 1H), 7.25 (br d, J = 8.9 Hz, 1H), 7.13 (br d, J = 7.5 Hz, 2H), 7.10 - 7.04 (m, 4H), 6.78 (d, J = 5.07 (br d, J = 15.5 Hz, 1H), 5.00 (d, J = 2.5 Hz, 1H), 4.90 (br d, J = 15.0 Hz, 1H), 4.02 (br s, 1H), 3.50 (br d, J = 11.4 Hz, 2H), 3.43 - 3.34 (m, 3H), 3.08 (br s, 4H), 2.90 - 2.80 (m, 1H), 2.72 (br s, 1H), 2.68 (br d, J = 6.2 Hz, 1H), 2.49 - 2.43 (m, 3H), 2.27 - 2.15 (m, 3H), 1.74 (br d, J = 12.3 Hz, 2H), 1.68 - 1.57 (m, 1H), 1.21 - 1.09 (m, 2H). EXAMPLE 94. Preparation of (I-232) (S)-3-(5-(4-((1-(4-((3R,4R)-3- (cyclopentylmethyl)-7-hydroxyisochroman-4-yl)phenyl)piperidi n-4-yl)methyl)piperazin-1- yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione and (I-233) (S)-3-(5-(4-((1-(4-((3S,4S)-3- (cyclopentylmethyl)-7-hydroxyisochroman-4-yl)phenyl)piperidi n-4-yl)methyl)piperazin-1- yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione Step 1: To a solution of 2-[4-benzyloxy-2-[[tert-butyl(dimethyl)silyl]oxymethyl]pheny l]-2-(4- bromophenyl)-N-methoxy-N-methyl-acetamide (1 g, 1.71 mmol) in THF (3 mL) was added (cyclopentylmethyl)magnesium bromide (0.5 M, 13.68 mL) at 0 °C. The mixture was stirred at 20 °C for 16 h under N ₂ atmosphere. The reaction was quenched with sat. aq, NH ₄ Cl (40 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (50 mL), dried over Na ₂ SO ₄ , filtered, and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ethyl acetate in petroleum ether = 0% to 5%) to give a product of 1-[4-benzyloxy-2-[[tert-butyl(dimethyl)silyl]oxymethyl]pheny l]- 1-(4-bromophenyl)-3-cyclopentyl-propan-2-one (850 mg, 73.6% yield) as a yellow gum. ¹ HNMR (400MHz, CDCl ₃ ): į 7.46 - 7.30 (m, 7H), 7.08 - 6.94 (m, 4H), 6.88 (dd, J = 2.7, 8.5 Hz, 1H), 5.39 (s, 1H), 5.07 (s, 2H), 4.68 (d, J = 12.8 Hz, 1H), 4.50 (d, J = 12.8 Hz, 1H), 2.55 (d, J = 7.0 Hz, 2H), 2.32 - 2.21 (m, 1H), 1.89 - 1.75 (m, 2H), 1.58 - 1.48 (m, 4H), 1.13 - 0.96 (m, 2H), 0.92 (s, 9H), 0.06 (d, J = 8.3 Hz, 6H) Step 2: To a solution of 1-[4-benzyloxy-2-[[tert-butyl(dimethyl)silyl]oxymethyl]pheny l]-1-(4- bromophenyl)-3-cyclopentyl-propan-2-one (700 mg, 1.04 mmol) in DCM (10 mL) was added triethylsilane (180.82 mg, 1.56 mmol, 248.38 ^L), the resulting mixture was cooled at -60 °C and trimethylsilyl trifluoromethanesulfonate (345.63 mg, 1.56 mmol, 281.00 ^L) was added dropwise, and the resulting mixture was stirred at -60 °C for 1 h.^^The reaction mixture was quenched with sat. aq. NaHCO ₃ (30 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (80 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue.^The residue was purified by flashsilica gel chromatography (ethyl acetate in petroleum ether= 0% to 5%) to give the product of 7- benzyloxy-4-(4-bromophenyl)-3-(cyclopentylmethyl)isochromane (500 mg, 60.61% yield) as a yellow gum. LC-MS (ESI ⁺ ) m/z: 477.0 (M+H) ⁺ . Step 3: A mixture of 7-benzyloxy-4-(4-bromophenyl)-3-(cyclopentylmethyl)isochroma ne (500 mg, 628.36 ^mol), 4-(dimethoxymethyl)piperidine (130.07 mg, 816.87 ^mol), t-BuONa (120.77 mg, 1.26 mmol), Pd(OAc) ₂ (14.11 mg, 62.84 ^mol) and XPhos (59.91 mg, 125.67 ^mol) in Tol (8 mL) was degassed and purged with N ₂ for 3 times, and then the mixture was stirred at 90 °C for 16 h under N2 atmosphere.^^The reaction was quenched with water (50 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (80 mL), dried was purified by flashsilica gel chromatography (ethyl acetate in petroleum ether= 0% to 20%) to give the product of 1-[4-[7-benzyloxy-3-(cyclopentylmethyl)isochroman-4-yl]pheny l]-4- (dimethoxymethyl)piperidine (150 mg, 42.1% yield) as a yellow oil. LC-MS (ESI ⁺ ) m/z: 556.4 (M+H) ⁺ . Step 4: To a solution of Pd/C (150 mg, 10% purity) in THF (10 mL) was added 1-(4-(7- (benzyloxy)-3-(cyclopentylmethyl)isochroman-4-yl)phenyl)-4-( dimethoxymethyl)piperidine (150 mg, 270 ^mol) under N ₂ . The suspension was degassed under vacuum and purged with H ₂ several times. The mixture was stirred under H ₂ (15 psi) at 25 °C for 8 h. The reaction mixture was filtered and the filter was concentrated to yield a residue which was purified by flash silica gel chromatography (ethyl acetate in petroleum ether = 0% to 30%) to give a residue. The residue was separated by chiral SFC (column: DAICEL CHIRALPAK ID (250mm*30mm,10um); mobile phase: [MeOH-ACN] B%:50%, isocratic elution mode, peak 1: 0.697min, peak 2: 0.984 min) to yield Peak 1 and Peak 2. Peak 1 was concentrated under reduced pressure to give the product of (3R,4R)-3-(cyclopentylmethyl)-4-(4-(4- (dimethoxymethyl)piperidin-1-yl)phenyl)isochroman-7-ol (40 mg, 32 % yield, SFC: Rt = 0.697) as a white solid. LC-MS (ESI ⁺ ) m/z: 466.3 (M+H) ⁺ . Peak 2 was concentrated under reduced pressure to give the product of (3S,4S)-3-(cyclopentylmethyl)-4-(4-(4- (dimethoxymethyl)piperidin-1-yl)phenyl)isochroman-7-ol (40 mg, 32 % yield, SFC: R _t = 0.984) as a white solid. LC-MS (ESI ⁺ ) m/z: 466.3 (M+H) ⁺ . Step 5: To a solution of (3R,4R)-3-(cyclopentylmethyl)-4-(4-(4-(dimethoxymethyl)piper idin-1- yl)phenyl)isochroman-7-ol (40 mg, 86 ^mol) in DCM (2 mL) was added TFA (0.8 mL, 0.01 mol) at 20 °C. The mixture was stirred at 20 °C for 2 h. The reaction was quenched with sat.aq. NaHCO ₃ (10 mL) and extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine (20 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give 1-(4-((3R,4R)-3-(cyclopentylmethyl)-7-hydroxyisochroman-4-yl )phenyl)piperidine-4- carbaldehyde (36 mg, crude) as a yellow oil. LC-MS (ESI ⁺ ) m/z: 420.3 (M+H) ⁺ . Step 6: To a solution of (3S,4S)-3-(cyclopentylmethyl)-4-(4-(4-(dimethoxymethyl)piper idin-1- yl)phenyl)isochroman-7-ol (40 mg, 86 ^mol) in DCM (2 mL) was added TFA (0.8 mL, 0.01 mol) at 20 °C. The mixture was stirred at 20 °C for 2 h. The reaction was quenched with sat.aq. NaHCO3 (10 mL) and extracted with EtOAc (10 mL x 3). The combined organic layers were to give 1-(4-((3S,4S)-3-(cyclopentylmethyl)-7-hydroxyisochroman-4-yl )phenyl)piperidine-4- carbaldehyde (36 mg, crude) as a yellow oil. LC-MS (ESI ⁺ ) m/z: 420.3 (M+H) ⁺ . Step 7: To a solution of 1-(4-((3R,4R)-3-(cyclopentylmethyl)-7-hydroxyisochroman-4- yl)phenyl)piperidine-4-carbaldehyde (36 mg, 86 ^mol) in DCE (10 mL) and MeOH (1 mL) was added (S)-3-(1-oxo-5-(piperazin-1-yl)isoindolin-2-yl)piperidine-2, 6-dione (28 mg, 86 ^mol) and stirred at 20 °C for 10 min. Then NaBH(OAc) ₃ (55 mg, 0.26 mmol) was added and stirred at 20 °C for 10 min. The solvent was removed to yield a residue. The residue was purified by preparative HPLC (column: Phenomenex Gemini NX 150×30mm,5^m; mobile phase: [water( NH ₄ HCO ₃ )-ACN]; B%: 57%-87%,11min), followed by lyophilization to give the product of (S)-3-(5-(4-((1-(4-((3R,4R)-3-(cyclopentylmethyl)-7-hydroxyi sochroman-4- yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindo lin-2-yl)piperidine-2,6-dione (27 mg, 43% yield) as a white solid. LC-MS (ESI ⁺ ) m/z: 732.4 (M+H) ⁺ . LCMS: calc. for C ₄₄ H ₅₃ N ₅ O ₅ : 731.94, found: [M+ ⁺ 732.4. HPLC: 100.0% purity at 254 nm. ¹ HNMR (400MHz, DMSO-d6): į 10.95 (s, 1H), 9.20 (s, 1H), 7.52 (d, J = 8.6 Hz, 1H), 7.11 - 7.01 (m, 2H), 6.95 (d, J = 8.6 Hz, 2H), 6.77 (d, J = 8.7 Hz, 2H), 6.71 (d, J = 8.3 Hz, 1H), 6.54 - 6.47 (m, 1H), 6.45 (s, 1H), 5.04 (dd, J = 5.2, 13.2 Hz, 1H), 4.88 - 4.62 (m, 2H), 4.38 - 4.14 (m, 2H), 3.79 - 3.70 (m, 1H), 3.65 - 3.54 (m, 3H), 3.32 - 3.24 (m, 8H), 2.98 - 2.83 (m, 1H), 2.65 - 2.53 (m, 4H), 2.21 (d, J = 6.9 Hz, 2H), 2.02 - 1.86 (m, 2H), 1.80 (d, J = 12.5 Hz, 2H), 1.67 (d, J = 4.2 Hz, 3H), 1.58 - 1.37 (m, 4H), 1.28 - 1.12 (m, 3H), 1.11 - 0.92 (m, 3H) Step 8: To a solution of 1-(4-((3S,4S)-3-(cyclopentylmethyl)-7-hydroxyisochroman-4- yl)phenyl)piperidine-4-carbaldehyde (36 mg, 86 ^mol) in DCE (10 mL) and MeOH (1 mL) was added (S)-3-(1-oxo-5-(piperazin-1-yl)isoindolin-2-yl)piperidine-2, 6-dione (28 mg, 86 ^mol) and stirred at 20 °C for 10 min. Then NaBH(OAc) ₃ (55 mg, 0.26 mmol) was added and stirred at 20 °C for 10 min. The solvent was removed to yield a residue. The residue was purified by preparative HPLC (column: Phenomenex Gemini NX 150×30mm,5^m;mobile phase: [water( NH ₄ HCO ₃ )-ACN];B%: 57%-87%,11min), followed by lyophilization to give the product of (S)-3-(5-(4-((1-(4-((3S,4S)-3-(cyclopentylmethyl)-7-hydroxyi sochroman-4- yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindo lin-2-yl)piperidine-2,6-dione (23 mg, 37%, yield) as a white solid. LC-MS (ESI ⁺ ) m/z: 732.5 (M+H) ⁺ . LCMS: calc. for C ₄₄ H ₅₃ N ₅ O ₅ : 731.94, found: [M+H] ⁺ 732.5. HPLC: 100.0% purity at 254 nm. ¹ HNMR (400MHz, DMSO-d6): į 10.95 (s, 1H), 9.20 (s, 1H), 7.52 (d, J = 8.6 Hz, 1H), 7.09 - 7.03 (m, 2H), 6.95 (d, J = 8.6 Hz, 2H), 6.77 (d, J = 8.8 Hz, 2H), 6.71 (d, J = 8.3 Hz, 1H), 6.53 - 6.48 (m, 1H), 6.45 (s, 1H), 5.04 (dd, J = 4.9, 13.2 Hz, 1H), 4.87 - 4.64 (m, 2H), 4.38 - 4.16 (m, 2H), 3.78 - 3.70 (m, 1H), 3.62 (s, 3H), 3.30 - 3.25 (m, 8H), 2.98 - 2.81 (m, 1H), 2.59 (d, J = 10.0 Hz, 4H), 2.21 (d, J = 6.9 Hz, 2H), 2.02 - 1.86 (m, 2H), 1.80 (d, J = 11.2 Hz, 2H), 1.67 (d, J = 3.7 Hz, 3H), 1.56 - 1.39 (m, 4H), 1.26 - 1.12 (m, 3H), 1.10 - 0.89 (m, 3H). EXAMPLE 95. Preparation of (I-355) (S)-3-(5-(4-((1-(4-((3S,4R)-3-(3-fluoro-4- methylphenyl)-7-hydroxyisochroman-4-yl)phenyl)piperidin-4-yl )methyl)piperazin-1-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione and (I-356) (S)-3-(5-(4-((1-(4-((3R,4S)-3-(3-fluoro-4-

methylphenyl)-7-hydroxyisochroman-4-yl)phenyl)piperidin-4 -yl)methyl)piperazin-1-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione Step 1: To a solution of compound 1 (250.00 mg, 496.62 ^mol, 1.0 eq.), compound 2 (158.15 mg, 993.24 ^mol, 2.0 eq.), Cs ₂ CO ₃ (404.52 mg, 1.24 mmol, 2.5 eq.) and RuPhos Pd G3 (41.54 mg, 49.66 ^mol, 0.1 eq.) in dioxane (5 mL) was bubbled with N ₂ for 1 min. Then the mixture was stirred at 90 °C for 5 hours. LCMS showed the starting material was consumed completely and a major peak with desired MS was detected. The reaction mixture was concentrated to get a residue. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate = 1/0 to 3/1) to give compound 3 (300.00 mg, 52.96% yield) as a yellow solid. LC-MS (ESI ⁺ ) m/z: 582.3 (M+H) ⁺ . ¹ H NMR (400 MHz, DMSO-d6) į ppm 7.49 - 7.30 (m, 5H), 7.06 (t, J = 8.0 Hz, 1H), 6.92 - 6.72 (m, 5H), 6.68 - 6.55 (m, 4H), 5.15 - 4.91 (m, 5H), 4.05 (s, 2H), 3.57 - 3.48 (m, 2H), 3.24 (s, 6H), 2.46 - 2.32 (m, 2H), 2.12 (s, 3H), 1.70 - 1.57 (m, 3H), 1.30 - 1.20 (m, 2H). Step 2: To a solution of compound 1 (250.00 mg, 496.62 ^mol, 1.0 eq.), compound 2 (158.15 mg, 993.24 ^mol, 2 eq.), Cs ₂ CO ₃ (404.52 mg, 1.24 mmol, 2.5 eq.) and RuPhos Pd G3 (41.54 mg, 49.66 ^mol, 0.1 eq.) in dioxane (5 mL) was bubbled with N ₂ for 1 min. Then the mixture was stirred at 90 °C for 5 hours. LCMS showed the starting material was consumed completely and a major peak with desired MS was detected. The reaction mixture was concentrated to get a residue. The residue was purified by column chromatography (SiO ₂ , Petroleum ether/Ethyl acetate = 1/0 to 3/1) to give compound 2 (300.00 mg, 72.69% yield) as a yellow solid. LC-MS (ESI ⁺ ) m/z:^582.3 (M+H) ⁺ . NMR (400 MHz, DMSO-d6) į = 7.49 - 7.26 (m, 5H), 7.06 (t, J = 8.0 Hz, 1H), 6.94 - 6.70 (m, 5H), 6.68 - 6.54 (m, 4H), 5.16 - 4.91 (m, 5H), 4.12 - 4.04 (m,2H), 3.61 - 3.45 (m, 2H), 3.28 - 3.20 (m, 6H), 2.47 - 2.39 (m, 2H), 2.16 - 2.08 (m, 3H), 1.71 - 1.58 (m, 3H), 1.31 - 1.20 (m, 2H) Step 3: To a solution of compound 3 (300.00 mg, 515.72 ^mol, 1.0 eq.) in EA (20 mL) was added Pd/C (548.83 mg, 515.72 ^mol, 10% purity, 1.0 eq.) under N ₂ atmosphere. The suspension was degassed and purged with H ₂ for 3 times. The mixture was stirred under H ₂ (15 Psi) at 15 °C for 4hr. LCMS showed that the starting material was consumed and the desired product was detected. The reaction mixture was concentrated to get a residue. The residue was purified by prep-HPLC (column: Boston Green ODS 150 x 30 mm x 5 ^m; mobile phase: [water (FA)-ACN]; gradient: 25%-60% B over 14 min.) to give compound 4 (130.00 mg, 51.28% yield) as a yellow solid. LC-MS (ESI ⁺ ) m/z:^492.2 (M+H) ⁺ . Step 4: To a solution of compound 3 (298.00 mg, 512.28 ^mol, 1.0 eq.) in EA (20 mL) was added Pd/C (545.17 mg, 512.28 ^mol, 10% purity, 1.0 eq.) under N ₂ atmosphere. The suspension was degassed and purged with H2 for 3 times. The mixture was stirred under H2 (15 Psi) at 15 °C for 4hr LCMS showed that the starting material was consumed and the desired product was detected. The reaction mixture was concentrated to get a residue. The residue was purified by prep-HPLC (column: Boston Green ODS 150 x 30 mm x 5 ^m; mobile phase: [water (FA)-ACN]; gradient: 25%-60% B over 14 min.) to give compound 4 (130.00 mg, 50.07% yield) as a yellow solid. LC-MS (ESI ⁺ ) m/z:^492.2 (M+H) ⁺ . Step 5: Compound 4 (200.00 mg, 407 ^mol, 1.0 eq.) was purified by SFC (Column: Chiralpak AD-3150¡Á4.6 mm I.D, 3 ^m Mobile phase: 40% of iso-propanol (0.05% DEA) in CO ₂ , Flow rate: 2.5 mL / min, RT: 1.682, 3.608) to give compound 5 (80.00 mg, 40 % yield) as a white solid and compound 5A (50.00 mg, 25 % yield) as a white solid. Compound 5: LC-MS (ESI ⁺ ) m/z:^492.2 (M+H) ⁺ . Compound 5A: LC-MS (ESI ⁺ ) m/z:^492.3 (M+H) ⁺ . Step 6: To a solution of compound 5 (100.00 mg, 203 ^mol, 1.0 eq.) in DCM (3 mL) was added TFA (1 mL) at 20 °C. The mixture was stirred at 20 °C for 2 hour. LCMS showed the starting material was consumed completely and a major peak with desired MS was detected. Water (10 mL) and aq. NaHCO ₃ (15 x 2 mL) was added and the mixture was extracted with DCM (20 mL x 3). The organics were washed with brine (20 mL), dried over Na ₂ SO ₄ , filtered and concentrated to give compound 6 (80.00 mg, 87 % yield) as a white solid. LC-MS (ESI ⁺ ) m/z:^446.3 (M+H) ⁺ . Step 7: To a solution of compound 5A (50.00 mg, 0.10 mmol, 1.0 eq.) in DCM (1.5 mL) was added TFA (0.5 mL) at 20 °C. The mixture was stirred at 20 °C for 2 hour. LCMS showed the starting material was consumed completely and a major peak with desired MS was detected. Water (10 mL) and aq. NaHCO ₃ (15 x 2 mL) was added and the mixture was extracted with DCM (20 mL x 3). The organics were washed with brine (20 mL), dried over Na ₂ SO ₄ , filtered and concentrated to give compound 6A (42.00 mg, 92 % yield) as a yellow solid. LC-MS (ESI ⁺ ) m/z:^446.3 (M+H) ⁺ . Step 8: To a solution of compound 6 (80.00 mg, 0.18 mmol, 1.0 eq.) and compound 7 (65.00 mg 020 mmol 11 eq) in DCE (3 mL) and MeOH (1 mL) was added NaBH(OAc) (019 g 0.13 mL, 0.90 mmol, 5.0 eq.) at 20 °C. Then the mixture was stirred at 20 °C for 2 hour. LCMS showed the starting material was consumed completely and a major peak with desired MS was detected. The mixture was concentrated to get the crude, which was purified by prep-HPLC (column: Phenomenex Gemini NX 150 × 30 mm, 5 ^m; mobile phase: [water (NH ₄ HCO ₃ )- ACN]; gradient: 53%-83% B over 11 min.) to give (S)-3-(5-(4-((1-(4-((3S,4R)-3-(3-fluoro-4- methylphenyl)-7-hydroxyisochroman-4-yl)phenyl)piperidin-4-yl )methyl)piperazin-1-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione (56.7 mg, 41 % yield) as a white solid. LC-MS (ESI ⁺ ) m/z: 758.4 (M+H) ⁺ . LCMS: calc. for C ₄₅ H ₄₈ FN ₅ O ₅ : 757.91, found [M +H] ⁺ 758.4 HPLC: 99.11% purity at 220 nm ppm 10.94 (s, 1 H) 9.28 (s, 1 H) 7.51 (d, J=8.46 Hz, 1 H) 7.03 - 7.08 (m, 3 H) 6.86 (d, J=8.11 Hz, 1 H) 6.71 - 6.79 (m, 2 H) 6.63 - 6.67 (m, 2 H) 6.52 - 6.60 (m, 4 H) 5.01 - 5.09 (m, 2 H) 4.97 (d, J=2.26 Hz, 1 H) 4.89 (br d, J=15.26 Hz, 1 H) 4.17 - 4.35 (m, 2 H) 3.99 - 4.07 (m, 1 H) 3.52 (br d, J=11.92 Hz, 2 H) 3.27 (br s, 4 H) 2.84 - 2.95 (m, 1 H) 2.51 - 2.69 (m, 4 H) 2.31 - 2.48 (m, 4 H) 2.18 (br d, J=7.03 Hz, 2 H) 2.12 (s, 3 H) 1.92 - 1.99 (m, 1 H) 1.59 - 1.77 (m, 3 H) 1.09 - 1.20 (m, 2 H) Step 9: To a solution of compound 6A (42.00 mg, 94 ^mol, 1.0 eq.) and compound 7 (34.00 mg, 0.10 mmol, 1.1 eq.) in DCE (3 mL) and MeOH (1 mL) was added NaBH(OAc) ₃ (0.10 g, 70 ^L, 0.47 mmol, 5.0 eq.) at 20 °C. Then the mixture was stirred at 20 °C for 2 hour. LCMS showed the starting material was consumed completely and a major peak with desired MS was detected. The mixture was concentrated to get the crude, which was purified by prep-HPLC (column: Phenomenex Gemini NX 150 × 30 mm, 5 ^m; mobile phase: [water (NH ₄ HCO ₃ )- ACN]; gradient: 53%-83% B over 11 min) to give (S)-3-(5-(4-((1-(4-((3R,4S)-3-(3-fluoro-4- methylphenyl)-7-hydroxyisochroman-4-yl)phenyl)piperidin-4-yl )methyl)piperazin-1-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione (47.6 mg, 66 % yield) as a white solid. LC-MS (ESI ⁺ ) m/z: 758.4 (M+H) ⁺ . LCMS: calc. for C45H48FN5O5: 757.91, found [M+H] ⁺ 758.4 NMR (400 MHz, DMSO-d6) į ppm 10.90 - 10.98 (m, 1 H) 9.28 (s, 1 H) 7.51 (d, J=8.46 Hz, 1 H) 7.03 - 7.09 (m, 3 H) 6.86 (d, J=7.39 Hz, 1 H) 6.71 - 6.79 (m, 2 H) 6.63 - 6.67 (m, 2 H) 6.52 - 6.60 (m, 4 H) 5.01 - 5.09 (m, 2 H) 4.97 (d, J=2.74 Hz, 1 H) 4.89 (br d, J=15.14 Hz, 1 H) 4.17 - 4.35 (m, 2 H) 4.03 (d, J=2.86 Hz, 1 H) 3.52 (br d, J=10.37 Hz, 2 H) 3.27 (br s, 4 H) 2.84 - 2.95 (m, 1 H) 2.51 - 2.74 (m, 4 H) 2.25 - 2.48 (m, 4 H) 2.18 (br d, J=7.03 Hz, 2 H) 2.12 (s, 3 H) 1.91 - 1.99 (m, 1 H) 1.60 - 1.78 (m, 3 H) 1.09 - 1.20 (m, 2 H).

EXAMPLE 96. Preparation of (I-363) (S)-3-(5-(4-((1-(4-((3S,4R)-3-(bicyclo[4.2.0]octa- 1(6),2,4-trien-3-yl)-7-hydroxyisochroman-4-yl)phenyl)piperid in-4-yl)methyl)piperazin-1- yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione Step 1: A dried three-neck flask equipped with thermometer and condenser was charged with magnesium (312 mg, 5 Eq, 12.8 mmol) and a catalyst diiodine (651 mg, 1 Eq, 2.57 mmol)). The mixture was refluxed 70 ^ for 30 min under N ₂ , then added by a solution of 3-bromobicyclo [420] octa-1 3 5-triene (24 g 5 Eq 128 mmol) in THF (70 mL) dropwise The above reaction mixture was refluxed at 70^ for 1.5 hour. The above reaction mixture was added into a solution of 2-(4-(benzyloxy)-2-(((tert-butyldimethylsilyl)oxy)methyl)phe nyl)-2-(4-bromophenyl)-N- methoxy-N-methylacetamide (1.5 g, 1 Eq, 2.57 mmol) in THF (30 mL) at 25^ under N ₂ and stirred at 25^ under N ₂ for 16 hour. The reaction solution was quenched by saturated aq NH ₄ Cl (50 mL). Then the mixture was added water (50 mL) and the mixture was extracted with dichloromethane (100 mL×3). The combined organic layers were washed with brine(100 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to dryness in vacuum to give 2-(4- (benzyloxy)-2-(((tert-butyldimethylsilyl)oxy)methyl)phenyl)- 1-(bicyclo[4.2.0]octa-1,3,5-trien-3- yl)-2-(4-bromophenyl)ethan-1-one (1.2 g, 1.7 mmol, 68% yield, 96% purity) as a green oil. LC- MS (ESI ⁺ ) m/z: 497.0 (M-129) ⁺ . Step 2: To a solution of 2-(4-(benzyloxy)-2-(((tert-butyldimethylsilyl)oxy)methyl)phe nyl)-1- (bicyclo[4.2.0]octa-1(6),2,4-trien-3-yl)-2-(4-bromophenyl)et han-1-one (400 mg, 96% purity, 1 Eq, 618 ^mol) and triethylsilane (108 mg, 148 ^L, 1.5 Eq, 927 ^mol) were added in DCM (5 mL), the resulting mixture was cooled at -78 °C and trimethylsilyl triflate (206 mg, 171 ^L, 1.5 Eq, 927 ^mol) was added, and the resulting mixture was allowed to stirred for 30 min at this temperature. The reaction mixture was quenched with saturated aq. NaHCO3 (10 mL). The reaction was diluted with water (50 mL) and extracted with dichloromethane (50 mL *2). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to dryness in vacuum to give a yellow oil. The yellow oil was purified by flash column (ISCO®; 20 g SepaFlash® Silica Flash Column, petroleum ether/ethyl acetate from 100/0 to 90/10ˈ@ 40 mL/min) and the fraction was concentrated in vacuum to give 7- (benzyloxy)-3-(bicyclo[4.2.0]octa-1(6),2,4-trien-3-yl)-4-(4- bromophenyl)isochromane (270 mg, 0.52 mmol, 83 % yield, 89% purity) as a colorless oil. Step 3: A mixture of 7-(benzyloxy)-3-(bicyclo[4.2.0]octa-1(6),2,4-trien-3-yl)-4-( 4- bromophenyl)isochromane (220 mg, 89% purity, 1 Eq, 396 ^mol), 2-(Dicyclohexylphosphanyl)- 2',4',6'-tris(isopropyl)biphenyl (38 mg, 0.2 Eq, 79.1 ^mol), palladium diacetate (13 mg, 0.15 Eq, 59.3 ^mol), 4-(dimethoxymethyl)piperidine (95 mg, 99 ^L, 1.5 Eq, 593 ^mol), and sodium 2- methylpropan-2-olate (57 mg, 64 ^L, 1.5 Eq, 593 ^mol) were added in toluene (5 mL) and heated to 90 °C for 16 hours under N ₂ atmosphere. TLC (petroleum ether/ethyl acetate = 5/1, R _f = 0.4) showed a new spot was formed. The reaction was diluted with H ₂ O (100 mL) and t t d ith th l t t (50 L * 2) Th bi d t t d i d h d Na2SO4, filtered and concentrated to dryness in vacuum to give a residue. The residue was subjected to column chromatography (ISCO®; 20 g SepaFlash® Silica Flash Column, petroleum ether/ethyl acetate from 100/0 to 80/20, @ 40 mL/min). The pure fractions were collected and concentrated to dryness in vacuum to give 1-(4-(7-(benzyloxy)-3-(bicyclo [4.2.0] octa-1(6), 2, 4- trien-3-yl) isochroman-4-yl)phenyl)-4-(dimethoxymethyl)piperidine (130 mg, 226 ^mol, 57.1% yield) as a white solid. LC-MS (ESI+) m/z: 576.1(M+H) ⁺ Step 4: A mixture of 1-(4-(7-(benzyloxy)-3-(bicyclo[4.2.0]octa-1(6), 2,4-trien-3-yl)isochroman- 4-yl)phenyl)-4-(dimethoxymethyl)piperidine (130 mg, 1 Eq, 226 ^mol) and Pd/C (130 mg, 10% Wt) were added in THF (2.5 mL) and MeOH (2.5 mL). Then the reaction was degassed and purged with H ₂ for 3 times, and then the mixture was stirred at 25 °C for 2 hour under H ₂ atmosphere (15 psi). The reaction was filtered and concentrated to dryness in vacuum to give 3- (bicyclo[4.2.0]octa-1(6),2,4-trien-3-yl)-4-(4-(4-(dimethoxym ethyl) piperidin-1-yl)phenyl) isochroman-7-ol (120 mg, 225 ^mol, 99.7 % yield, 91.08% purity) as a white solid. LC-MS (ESI+) m/z: 486.3 (M+H) ⁺ . Step 5: The white solid was purified by SFC. Column: DAICEL CHIRALPAK IG (250mm*30mm, 10um); Condition: CO2-EtOH (0.1%NH3H2O); at the beginning: B (50%); at the end: B (50%); Flow Rate (ml/min) 80. The pure fractions were collected respectively and the solvents were evaporated under vacuum to give (3S,4R)-3-(bicyclo[4.2.0]octa-1(6),2,4-trien-3- yl)-4-(4-(4-(dimethoxymethyl)piperidin-1-yl)phenyl)isochroma n-7-ol (50 mg, 0.10 mmol, 44% yield, 96.7% purity) as a white solid and (3R,4S)-3-(bicyclo[4.2.0]octa-1(6),2,4-trien-3-yl)-4-(4- (4-(dimethoxymethyl)piperidin-1-yl)phenyl)isochroman-7-ol (54 mg, 0.11 mmol, 49% yield, 100% purity) as a white solid. LC-MS (ESI+) m/z: 486.4 (M+H) ⁺ . Step 6: To a solution of (3S,4R)-3-(bicyclo[4.2.0]octa-1(6),2,4-trien-3-yl)-4-(4-(4- (dimethoxymethyl)piperidin-1-yl)phenyl)isochroman-7-ol (50 mg, 96.7% purity, 1 Eq, 0.10 mmol) in THF (5 mL) was added 10% sulfuric acid (5 mL) at 0 ^o C. The mixture was stirred at 70 °C for 40 min. The mixture was adjusted to pH=8 by adding saturated aq. NaHCO ₃ (10 mL) at 0 °C for 10 min. The reaction mixture was diluted with 50 mL H ₂ O and extracted with 50 mL ethyl acetate. The organic layers were washed with 50 mL brine and dried over anhydrous Na2SO4. The organic layers were filtered and concentrated under reduced pressure to give crude 1-(4-((3S,4R)-3-(bicyclo[4.2.0]octa-1(6),2,4-trien-3-yl)-7-h ydroxyisochroman-4-yl) phenyl) piperidine-4-carbaldehyde (40 mg, 90 ^mol, 90 % yield, 98.6% purity) as a brown oil. LC-MS (ESI+) m/z: 458.1 (M+18) ⁺ Step 7: A mixture of 1-(4-((3S,4R)-3-(bicyclo[4.2.0]octa-1(6),2,4-trien-3-yl)-7- hydroxyisochroman-4-yl)phenyl)piperidine-4-carbaldehyde (65 mg, 98.6% purity, 1 Eq, 0.15 mmol), (S)-3-(1-oxo-5-(piperazin-1-yl)isoindolin-2-yl)piperidine-2, 6-dione hydrochloride (53 mg, 1 Eq, 0.15 mmol) and sodium acetate (60 mg, 5 Eq, 0.73 mmol) were added in DCM (2 mL) and MeOH (2 mL) at 25°C for 0.5 hour, then added acetic acid (26 mg, 25 ^L, 3 Eq, 0.44 mmol) and sodium triacetoxyborohydride (62 mg, 2 Eq, 0.29 mmol), and then the mixture was stirred at 25 °C for 16 hour. The reaction was diluted with water (50 mL) and extracted with ethyl acetate (50 mL*2). The combined organic layers were concentrated to give crude product as a brown oil. The brown oil was purified by preparative high-performance liquid chromatography. Condition: water (FA)-ACN. Column: Welch Xtimate C18150*30mm*5um. Begin B: 20%, End B: 50%. Gradient time (min) 7; 100% B hold Time (min) 1.7, Flow rate (ml/min) 25. The pure fractions were collected, and the solvent was evaporated under vacuum. The aqueous layer was lyophilized to dryness to give (S)-3-(5-(4-((1-(4-((3S,4R)-3-(bicyclo[4.2.0]octa-1(6),2,4-t rien-3- yl)-7-hydroxyisochroman-4-yl)phenyl)piperidin-4-yl)methyl)pi perazin-1-yl)-1-oxoisoindolin-2- yl)piperidine-2,6-dione (38.6 mg, 49.9 ^mol, 34 % yield, 97.15% purity) as a white solid. LCMS: calc. for C ₄₆ H ₄₉ N ₅ O ₅ : 751.37, found: [M+H] ⁺ 752.3. HPLC: 97.15% purity at 220 nm. NMR (400 MHz, DMSO-d ₆ ) į= 10.92 (s, 1H), 9.24 (br s, 1H), 8.16 (s, 0.203H), 7.51 (d, J = 8.6 Hz, 1H), 7.07 - 7.03 (m, 2H), 6.92 - 6.88 (m, 1H), 6.86 - 6.81 (m, 1H), 6.79 - 6.73 (m, 2H), 6.67 - 6.62 (m, 2H), 6.60 - 6.52 (m, 4H), 5.09 - 5.00 (m, 2H), 4.95 - 4.85 (m, 2H), 4.36 - 4.28 (m, 1H), 4.24 - 4.16 (m, 1H), 3.98 (br d, J = 2.1 Hz, 1H), 3.52 (br d, J = 11.6 Hz, 2H), 3.29 - 3.24 (m, 5H), 3.05 - 2.85 (m, 5H), 2.68 - 2.52 (m, 4H), 2.48 - 2.44 (m, 2H), 2.39 - 2.31 (m, 1H), 2.19 (br d, J = 6.9 Hz, 2H), 2.00 - 1.91 (m, 1H), 1.79 - 1.71 (m, 2H), 1.68 - 1.57 (m, 1H), 1.21 - 1.10 (m, 2H). EXAMPLE 97. Preparation of (I-384) (S)-3-(5-(4-((1-(3-fluoro-4-((3R,4R)-7-hydroxy- 3-phenylchroman-4-yl)phenyl)piperidin-4-yl)methyl)piperazin- 1-yl)-1-oxoisoindolin-2- yl)piperidine-2,6-dione Step 1: To a solution of (3R,4R)-4-(4-(4-(dimethoxymethyl)piperidin-1-yl)-2-fluorophe nyl)-3- phenylisochroman-7-ol (80 mg, 1 Eq, 0.17 mmol) in THF (4 mL) was added 10% H ₂ SO ₄ (4 mL). The mixture was stirred at 70 °C for 40 mins. The reaction mixture was adjusted to pH=7 by adding saturated aqueous NaHCO ₃ (30 mL) at 0 °C and diluted with H ₂ O (20 mL) and extracted with ethyl acetate 50 mL. The organic layer was washed with brine (10 mL). Dried over Na2SO4, filtered and concentrated under reduced pressure to give crude product 1-(3-fluoro-4-((3R,4R)-7- hydroxy-3-phenylchroman-4-yl)phenyl)piperidine-4-carbaldehyd e (60 mg, 0.14 mmol, 83 % yield) as a light red oil _. LC-MS (ESI+) m/z: 450.1 (M+H ₂ O) ⁺ . Step 2: A mixture of 1-(3-fluoro-4-((3R,4R)-7-hydroxy-3-phenylchroman-4- yl)phenyl)piperidine-4-carbaldehyde (60 mg, 1 Eq, 139 ^mol), (S)-3-(1-oxo-5-(piperazin-1- yl)isoindolin-2-yl)piperidine-2,6-dione hydrochloride (51 mg, 1 Eq, 139 ^mol), Sodium acetate (34 mg, 3 Eq, 417 ^mol) and acetic acid (25 mg, 24 ^L, 3 Eq, 417 ^mol) in DCM (4 mL) and MeOH (4 mL) was stirred at 30 °C for 0.5 h, then sodium triacetoxyborohydride (59 mg, 2 Eq, 278.1 ^mol) was added in the mixture and stirred at 30 °C for 16 h. The mixture was added H ₂ O (20 mL), then extracted with ethyl acetate (20 mL * 2). The combined extracts were dried over anhydrous Na ₂ SO ₄ filtered and concentrated to dryness in vacuum to give a residue The residue was purified by prep-HPLC: Column: Welch Xtimate C18150*30mm*5um Condition: A: water (FA) B: ACN at the beginning: A (79%) and B (21%) at the end: A: (49%) and B (51%) Gradient Time (min) 7; 100%B Hold Time (min) 3; Flow Rate (ml/min) 25. The aqueous phase was lyophilized to dryness to give (S)-3-(5-(4-((1-(3-fluoro-4-((3R,4R)-7-hydroxy-3- phenylchroman-4-yl)phenyl)piperidin-4-yl)methyl)piperazin-1- yl)-1-oxoisoindolin-2- yl)piperidine-2,6-dione (44.1 mg, 57.5 ^mol, 41.4 % yield, 97.01% purity) as a white solid. LCMS, HPLC, SFC and NMR confirmed. LC-MS (ESI ⁺ ) m/z: 744.4 (M+H) ⁺ . HPLC: 97.010%, purity at 220 nm. ¹ H NMR (400 MHz, DMSO-d ₆ ) į ppm 10.96 (s, 1 H) 9.25 - 9.44 (m, 1 H) 8.16 (s, 0.330 H) 7.52 (d, J=8.58 Hz, 1 H) 7.04 - 7.18 (m, 7 H) 6.73 - 6.85 (m, 2 H) 6.48 - 6.62 (m, 3 H) 6.29 (dd, J=13.83, 2.15 Hz, 1 H) 4.99 - 5.13 (m, 3 H) 4.91 (br d, J=15.26 Hz, 1 H) 4.27 - 4.43 (m, 2 H) 4.15 - 4.25 (m, 1 H) 3.52 - 3.59 (m, 2 H) 3.28 (br s, 5 H) 2.85 - 2.96 (m, 1 H) 2.51 - 2.63 (m, 6 H) 2.37 (br dd, J=13.17, 4.59 Hz, 1 H) 2.18 (br d, J=6.79 Hz, 2 H) 1.92 - 2.00 (m, 1 H) 1.60 - 1.78 (m, 3 H) 1.05 - 1.20 (m, 2 H).

EXAMPLE 98. Preparation of (I-245) (S)-3-(5-(4-((1-(4-((3R,4R)-3-cyclobutyl-7- hydroxyisochroman-4-yl)phenyl)piperidin-4-yl)methyl)piperazi n-1-yl)-1-oxoisoindolin-2- yl)piperidine-2,6-dione Step 1: A mixture of (3R,4R)-3-cyclobutyl-4-(4-(4-(dimethoxymethyl)piperidin-1- yl)phenyl)isochroman-7-ol (40 mg, 1 Eq, 91 ^mol) was added in THF (3 mL)and 10% H ₂ SO ₄ (3 mL), the mixture was stirred at 70 °C for 40 min. the reaction was quenched with saturated aqueous NaHCO ₃ (5mL), the mixture was treated with H ₂ O (20 mL) and was extracted with ethyl acetate (50 mL), the organic layer was dried with anhydrous Na ₂ SO ₄ , filtered, and concentrated to give 1-(4-((3R,4R)-3-cyclobutyl-7-hydroxyisochroman-4-yl)phenyl)p iperidine- 4-carbaldehyde (30 mg, 77 ^mol, 93 %) as a white soild. LC-MS (ESI+) m/z: 410.1 (M+H2O) ⁺ Step 2: A mixture of 1-(4-((3R,4R)-3-cyclobutyl-7-hydroxyisochroman-4-yl)phenyl)p iperidine- 4-carbaldehyde (30 mg, 1 Eq, 77 ^mol), (S)-3-(1-oxo-5-(piperazin-1-yl)isoindolin-2- yl)piperidine-2,6-dione hydrochloride (34 mg, 1.2 Eq, 92 ^mol, HCl), AcONa (19 mg, 3 Eq, 0.23 mmol) was added in the DCM (2 mL) and MeOH (2 mL), the mixture was stirred at 30 °C for 1 h, then NaBH(OAc) ₃ (32 mg, 2 Eq, 0.15 mmol) and acetic acid (13 mg, 13 ^L, 3 Eq, 0.23 mmol) was added was stirred at 30 °C for 16 h. the reaction was treated with H ₂ O (50 mL) and was extracted with ethyl acetate (100 mL), the organic layers were dried with anhydrous Na ₂ SO ₄ , filtered, and concentrated to give the crude product. the residue was purified by prep- HPLC (column: Welch Xtimate C18150*30mm*5um;mobile phase: [water(FA)- ACN];gradient:16%-46% B over 7 min) to give (S)-3-(5-(4-((1-(4-((3R,4R)-3-cyclobutyl-7- hydroxyisochroman-4-yl)phenyl)piperidin-4-yl)methyl)piperazi n-1-yl)-1-oxoisoindolin-2- yl)piperidine-2,6-dione (23mg, 32 ^mol) was obtained as a white solid. LC-MS (ESI+) m/z: 704.3 (M+H) + HPLC: 99% purity at 220 nm ¹ H NMR (400 MHz, DMSO-d ₆ ) į = 10.94 (s, 1H), 9.20 (br s, 1H), 8.15 (s, 0.397H), 7.52 (d, J = 8.6 Hz, 1H), 7.12 - 7.00 (m, 2H), 6.88 (d, J = 8.6 Hz, 2H), 6.76 (d, J = 8.6 Hz, 2H), 6.71 (d, J = 8.3 Hz, 1H), 6.51 (dd, J = 2.4, 8.2 Hz, 1H), 6.46 (d, J = 2.0 Hz, 1H), 5.05 (dd, J = 5.1, 13.1 Hz, 1H), 4.85 (d, J = 15.1Hz, 1H), 4.68 (d, J = 15.1 Hz, 1H), 4.38 - 4.29 (m, 1H), 4.25 - 4.14 (m, 1H), 3.69 - 3.64 (m, 2H), 3.63 - 3.55 (m, 2H), 2.97 - 2.84 (m, 1H), 2.64 - 2.52 (m, 9H), 2.42 - 2.30 (m, 2H), 2.22 (br d, J = 7.0 Hz, 2H), 2.03 - 1.76 (m, 7H), 1.75 - 1.65 (m, 4H), 1.28 - 1.12 (m, 2H).

EXAMPLE 99. Preparation of (I-244) (S)-3-(5-(4-((1-(4-((3S,4S)-3-cyclobutyl-7- hydroxyisochroman-4-yl)phenyl)piperidin-4-yl)methyl)piperazi n-1-yl)-1-oxoisoindolin-2- yl)piperidine-2,6-dione Step 1: A mixture of cyclobutylmagnesium bromide (17 mL, 5 Eq, 8.55 mmol) was added 2-(4- (benzyloxy)-2-(tert-butyldimethylsilyl)oxy)methyl)phenyl)-2- (4-bromophenyl)-N-methoxy-N- stirred for 16 h at 25 °C. the reaction was quenched with saturated aqueous NH4Cl (50 mL) at 0 °C under N2, the mixture was treated with H2O (50 mL) and was extracted with ethyl acetate (100 mL), the combined organic layers were washed with brine (100 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® Silica Flash Column, Eluent of 0~10% ethyl acetate/Petroleum ethergradient @ 35 mL/min) to give compound 2-(4- (benzyloxy)-2-(((tert-butyldimethylsilyl)oxy)methyl)phenyl)- 2-(4-bromophenyl)-1- cyclobutylethan-1-one (580 mg, 0.90 mmol). LC-MS (ESI+) m/z: 447 (M-132) +. Step 2: A mixture of 2-(4-(benzyloxy)-2-(((tert-butyldimethylsilyl)oxy)methyl)phe nyl)-2-(4- bromophenyl)-1-cyclobutylethan-1-one (580 mg, 1 Eq, 1.00 mmol) and triethylsilane (175 mg, 240 ^L, 1.5 Eq, 1.5 mmol) in DCM (4 mL) under N ₂ , the resulting mixture was cooled at -78 °C and trimethylsilyl triflate (334 mg, 277 ^L, 1.5 Eq, 1.50 mmol) was added, and the resulting mixture was allowed to stir for 30 min at this temperature, and was stirred at 25 °C for 2 h. the reaction was quenched with saturated aqueous NaHCO ₃ (10 mL) at 25 °C under N ₂ , the mixture was treated with H2O (50 mL) and was extracted with ethyl acetate (100 mL), the combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 0~10% ethyl acetate/Petroleum ether gradient @ 30 mL/min) to give compound 7-(benzyloxy)-4-(4- bromophenyl)-3-cyclobutylisochromane (300 mg, 67 ^mol). Step 3: A mixture of 5% Pd-PEPPSI-IHeptCl (86 mg, 0.2 Eq, 89 ^mol), Cs ₂ CO ₃ (435 mg, 3 Eq, 1.34 mmol), 4-(dimethoxymethyl)piperidine (106 mg, 112 ^L, 1.5 Eq, 668 ^mol), 7- (benzyloxy)-4-(4-bromophenyl)-3-cyclobutylisochromane (200 mg, 1 Eq, 445 ^mol) was added in 1,4-dioxane (5 mL) and purged with N ₂ for 3 times, the mixture was stirred at 90 °C for 12 h under N ₂ atmosphere. the mixture was treated with H ₂ O (50 mL) and was extracted with ethyl acetate (100 mL), the combined organic layers were washed with saturated salt water (100 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 0~10% ethyl acetate/Petroleum ether gradient @ 30 mL/min) to give compound 1-(4-(7-(benzyloxy)-3-cyclobutylisochroman-4-yl)phenyl)-4- (dimethoxymethyl)piperidine (100 mg 189 ^mol) LC-MS (ESI+) m/z: 5283 (M+H) ⁺ Step 4: A mixture of 1-(4-(7-(benzyloxy)-3-cyclobutylisochroman-4-yl)phenyl)-4- (dimethoxymethyl)piperidine (100 mg, 1 Eq, 189 ^mol), Pd/C (101 mg, 10% Wt, 0.5 Eq, 94.7 ^mol) was added in THF (2 mL) and MeOH (2 mL) under N ₂ atmosphere, the suspension was degassed and purged with H ₂ for 3 times. the mixture was stirred under H ₂ (15 Psi) at 50 °C for 2 h. the reaction mixture was filtered and concentrated under reduced pressure to give compound 3-cyclobutyl-4-(4-(4-(dimethoxymethyl)piperidin-1-yl)phenyl) isochroman-7-ol (70 mg, 0.16 mmol). The resident was purified by prep-SFC (column: DAICEL CHIRALCEL OD(250mm*30mm,10um);mobile phase: CO ₂ -EtOH(0.1%NH ₃ H ₂ O);B%:40%%, isocratic elution mode) to give (3S,4S)-3-cyclobutyl-4-(4-(4-(dimethoxymethyl)piperidin-1- yl)phenyl)isochroman-7-ol (30 mg, 69 ^mol) and (3R,4R)-3-cyclobutyl-4-(4-(4- (dimethoxymethyl)piperidin-1-yl)phenyl)isochroman-7-ol (40 mg, 91 ^mol) was obtained as a white solid. 5 of LC-MS (ESI+) m/z: 438.4 (M+H) ⁺ , 5A of LC-MS (ESI+) m/z: 438.3 (M+H) ⁺ Step 5: A mixture of (3S,4S)-3-cyclobutyl-4-(4-(4-(dimethoxymethyl)piperidin-1- yl)phenyl)isochroman-7-ol (30 mg, 1 Eq, 69 ^mol) was added in THF (3 mL) and 10% H ₂ SO ₄ (3 mL), the mixture was stirred at 70 °C for 40 min. the reaction was quenched with saturated aqueous NaHCO ₃ (5mL), the mixture was treated with H ₂ O (20 mL) and was extracted with ethyl acetate (50 mL), the organic layer was dried with anhydrous Na ₂ SO ₄ , filtered, and concentrated to give ^1-(4-((3S,4S)-3-cyclobutyl-7-hydroxyisochroman-4-yl)phenyl) piperidine- 4-carbaldehyde (25 mg, 64 ^mol, 93 %) as a white solid. LC-MS (ESI+) m/z: 410.1 (M+H ₂ O)+ Step 6: A mixture of 1-(4-((3S,4S)-3-cyclobutyl-7-hydroxyisochroman-4-yl)phenyl)p iperidine- 4-carbaldehyde (25 mg, 1 Eq, 64 ^mol), (S)-3-(1-oxo-5-(piperazin-1-yl)isoindolin-2- yl)piperidine-2,6-dione hydrochloride (28 mg, 1.2 Eq, 77 ^mol, HCl), AcONa (16 mg, 3 Eq, 0.19 mmol) was added in the DCM (2 mL) and MeOH (2 mL), the mixture was stirred at 30 °C for 1 h, then NaBH(OAc) ₃ (27 mg, 2 Eq, 0.13 mmol) and acetic acid (12 mg, 11 ^L, 3 Eq, 0.19 mmol) was added was stirred at 30 °C for 16 h. the reaction was treated with H ₂ O (50 mL) and was extracted with ethyl acetate (100 mL), the organic layers were dried with anhydrous Na2SO4, filtered, and concentrated to give the crude product. the residue was purified by prep- HPLC ( l W l h Xti t C18150*30 *5 bil h [ t (FA) ACN];gradient:16%-46% B over 7 min) to give (S)-3-(5-(4-((1-(4-((3S,4S)-3-cyclobutyl-7- hydroxyisochroman-4-yl)phenyl)piperidin-4-yl)methyl)piperazi n-1-yl)-1-oxoisoindolin-2- yl)piperidine-2,6-dione (21 mg, 30.3 ^mol) was obtained as a white solid. LC-MS (ESI+) m/z: 704.2 (M+H) ⁺ HPLC: 99% purity at 220 nm ¹ H NMR (400 MHz, DMSO-d ₆ ) ppm = 10.94 (s, 1H), 9.35 - 9.07 (m, 1H), 8.15 (s, 0.451H), 7.52 (d, J = 8.6 Hz, 1H), 7.10 - 7.01 (m, 2H), 6.88 (d, J = 8.6 Hz,2H), 6.76 (d, J = 8.7 Hz, 2H), 6.71 (d, J = 8.3 Hz, 1H), 6.51 (dd, J = 2.2, 8.4 Hz, 1H), 6.46 (d, J = 2.0 Hz, 1H), 5.05 (dd, J = 5.0, 13.2 Hz, 1H), 4.85 (d, J =15.4 Hz, 1H), 4.68 (d, J = 15.0 Hz, 1H), 4.39 - 4.28 (m, 1H), 4.26 - 4.12 (m, 1H), 3.70 - 3.64 (m, 2H), 3.59 (br d, J = 8.8 Hz, 2H), 2.99 - 2.81 (m, 1H), 2.65 -2.52 (m, 9H), 2.42 - 2.29 (m, 2H), 2.22 (br d, J = 7.2 Hz, 2H), 2.01 - 1.76 (m, 7H), 1.75 - 1.61 (m, 5H), 1.31 - 1.13 (m, 2H).

EXAMPLE 100. Preparation of (I-246) (S)-3-(5-(4-((1-(4-((3R,4R)-3-cyclopentyl-7- hydroxyisochroman-4-yl)phenyl)piperidin-4-yl)methyl)piperazi n-1-yl)-1-oxoisoindolin-2- yl)piperidine-2,6-dione Step 1: A mixture of 7-(benzyloxy)-4-(4-bromophenyl)-4-hydroxyisochroman-3-one (1 g, 1 Eq, 2 mmol) in THF (20 mL) was stirred at -78 °C with N ₂ , then cyclopentylmagnesium bromide (2 g 9 mL 1 molar 4 Eq 9 mmol) was added to the mixture and stirred at 78 °C for 2 hours The reaction was warmed to 25 °C slowly and stirred for 14 hours. The reaction was quenched with saturated aqueous NH4Cl solution (20 mL) and was extracted with ethyl acetate (40 mL * 2). The combined organic layers were dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated to dryness in vacuum to give a residue. The residue was subjected to column chromatography over silica gel (petroleum ether/ethyl acetate from 100/0 to 70/30). The pure fractions were collected and concentrated to dryness in vacuum to give 2-(4-(benzyloxy)-2-(hydroxymethyl)phenyl)-2- (4-bromophenyl)-1-cyclopentyl-2-hydroxyethan-1-one (500 mg, 90.716% purity, 40% yield) as a yellow solid. LC-MS (ESI ⁺ ) m/z: 477.0 (M-OH) ⁺ . Step 2: A mixture of 2-(4-(benzyloxy)-2-(hydroxymethyl)phenyl)-2-(4-bromophenyl)- 1- cyclopentyl-2-hydroxyethan-1-one (410 mg, 1 Eq, 828 ^mol) in DCM (8 mL) was bubbled with N ₂ for 3 min and was stirred at 0 °C, then triethylsilane (481 mg, 659 ^L, 5 Eq, 4.14 mmol) and boron trifluoride etherate (235 mg, 209 ^L, 2 Eq, 1.66 mmol) was added to the mixture at 0 °C. The reaction was stirred at 0 °C for 2 hour. The reaction was quenched with saturated aqueous NaHCO ₃ (20 mL) at ice bath and extracted with DCM (20 mL*2). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated to dryness in vacuum to give a residue. The residue was subjected to column chromatography over silica gel (gradient elution: 0 – 20% ethyl acetate in petroleum ether). The pure fractions were collected and concentrated to dryness in vacuo to give 7-(benzyloxy)-4-(4-bromophenyl)-3-cyclopentylisochromane (390 mg, 84.073% purity, 85.5% yield) as a colorless oil. Step 3: A mixture of Pd-PEPPSI-IHeptCl (164 mg, 0.2 Eq, 168 ^mol), Cs ₂ CO ₃ (823 mg, 3 Eq, 2.52 mmol), 4-(dimethoxymethyl)piperidine (201 mg, 211 ^L, 1.5 Eq, 1.26 mmol) and 7- (benzyloxy)-4-(4-bromophenyl)-3-cyclopentylisochromane (390 mg, 1 Eq, 842 ^mol) in 1,4- Dioxane (16 mL) was heated to 100 °C for 16 hour under N ₂ atmosphere. The mixture was diluted with H ₂ O (20 mL) and extracted with ethyl acetate (30 mL * 2). The combined organic layers were dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to dryness in vacuum to give a residue. The residue was subjected to column chromatography over silica gel (gradient elution: 0 – 30% ethyl acetate in petroleum ether). The pure fractions were collected and concentrated to dryness in vacuum to give 1-(4-(7-(benzyloxy)-3-cyclopentylisochroman-4-yl)phenyl)-4- (dimethoxymethyl)piperidine (336 mg, 100% purity, 73.7% yield) as a light yellow solid. LC- MS (ESI ⁺ ) m/z: 542.0 (M+H) ⁺ . Step 4: A mixture of 1-(4-(7-(benzyloxy)-3-cyclopentylisochroman-4-yl)phenyl)-4- (dimethoxymethyl)piperidine (330 mg, 1 Eq, 609 ^mol) , wet Pd/C (10% wt, 64.8 mg, 1 Eq, 609 ^mol) in THF (10 mL) and MeOH (10 mL) was degassed and purged with H ₂ for 3 times, then the mixture was stirred at 15 psi for 2 hour under H ₂ atmosphere. The reaction was filtered and concentrated to dryness in vacuum to give 3-cyclopentyl-4-(4-(4-(dimethoxymethyl)piperidin-1- yl)phenyl)isochroman-7-ol (250 mg, 100% purity, 90.9% yield) as a yellow solid. LC-MS (ESI ⁺ ) m/z: 452.3 (M+H) ⁺ . Step 5: A mixture of 3-cyclopentyl-4-(4-(4-(dimethoxymethyl)piperidin-1- yl)phenyl)isochroman-7-ol was purified by SFC: (column: DAICEL CHIRALPAK IE 250 mm ^ 30 mm, 10 um); Condition: CO ₂ -i-PrOH(0.1%NH ₃ H ₂ O); B%: 45%-45%; Flow Rate: 80 ml/min; peak 1:2.048 min; peak 2: 2.294 min) to give (3R,4R)-3-cyclopentyl-4-(4-(4- (dimethoxymethyl)piperidin-1-yl)phenyl)isochroman-7-ol (115 mg, 98.715% purity) and (3S,4S)-3-cyclopentyl-4-(4-(4-(dimethoxymethyl)piperidin-1-y l)phenyl)isochroman-7-ol (130 mg, 98.505% purity) as yellow foam. Step 6: A solution of (3R,4R)-3-cyclopentyl-4-(4-(4-(dimethoxymethyl)piperidin-1- yl)phenyl)isochroman-7-ol (115 mg, 1 Eq, 255 ^mol) in THF (1.5 mL) and 10% H2SO4 (3.0 mL) was stirred at 70 °C for 1 hour . The reaction mixture was poured into saturated aqueous NaHCO ₃ (20 mL) solution, then was extracted with ethyl acetate (20 mL * 3). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give 1-(4-((3R,4R)-3-cyclopentyl-7-hydroxyisochroman- 4-yl)phenyl)piperidine-4-carbaldehyde (100 mg, crude) as a yellow oil. LC-MS (ESI ⁺ ) m/z: 424.1 (M+H ₂ O) ⁺ . Step 7: A solution of (3R,4R)-3-cyclopentyl-4-(4-(4-(dimethoxymethyl)piperidin-1- yl)phenyl)isochroman-7-ol (100 mg, 1 Eq, 221 umol)ˈ (S)-3-(1-oxo-5-(piperazin-1- yl)isoindolin-2-yl)piperidine-2,6-dione hydrochloride (89 mg, 1.1 Eq, 244 umol) and sodium acetate (91 mg, 5 Eq, 1.11 mmol) in DCM (3 mL) and MeOH (3 mL) was stirred at 25 °C for 1 h, then acetic acid (27 mg, 25 ^L, 2 Eq, 443 ^mol) and sodium triacetoxyhydroborate (94 mg, 2 Eq, 443 ^mol) was added .The mixture was stirred at 25 °C for 16 hour. The mixture was diluted with H ₂ O (20 ml) and was extracted with dichloromethane (20 ml * 3). The combined organic layers were dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a colorless oil (150 mg, crude). The residue was purified by prep-HPLC (column: Welch Xtimate C18150*30mm; mobile phase: [water(FA)-ACN]; B% 18% - 48%, 7 min) to give (S)- 3-(5-(4-((1-(4-((3R,4R)-3-cyclopentyl-7-hydroxyisochroman-4- yl)phenyl)piperidin-4- yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2, 6-dione (110.5 mg, 72% yield, 97.443% purity) was obtained as a pink solid. LC-MS (ESI ⁺ ) m/z: 718.8 (M+H) ⁺ . LCMS: calc. for C ₄₃ H ₅₁ N ₅ O ₅ : 717.39, found: [M+H] ⁺ 718.8. HPLC: 97.443% purity at 220 nm. ¹ H NMR (400 MHz, DMSO-d ₆ ) į = 10.95 (s, 1H), 9.32 - 9.09 (m, 1H), 8.18 (s, 0.192H), 7.52 (d, J = 8.7 Hz, 1H), 7.09 - 6.98 (m, 4H), 6.76 (br d, J = 8.7 Hz, 2H), 6.72 (d, J = 8.5 Hz, 1H), 6.49 (dd, J = 2.3, 8.3 Hz, 1H), 6.44 (d, J = 2.0 Hz, 1H), 5.05 (dd, J = 5.1, 13.2 Hz, 1H), 4.86 (d, J = 15.4 Hz, 1H), 4.68 (br d, J = 15.3 Hz, 1H), 4.37 - 4.16 (m, 2H), 3.68 (br d, J = 1.5 Hz, 1H), 3.62 - 3.56 (m, 2H), 3.41 - 3.32 (m, 9H), 2.94 - 2.85 (m, 1H), 2.61 - 2.54 (m, 3H), 2.40 - 2.31 (m, 1H), 2.21 (br d, J = 7.0 Hz, 2H), 1.99 - 1.91 (m, 1H), 1.79 (br d, J = 11.4 Hz, 2H), 1.62 (br d, J = 4.5 Hz, 3H), 1.55 - 1.47 (m, 2H), 1.44 - 1.30 (m, 4H), 1.27 - 1.14 (m, 3H).

EXAMPLE 101. Preparation of (I-247) (S)-3-(5-(4-((1-(4-((3S,4S)-3-cyclopentyl-7- hydroxyisochroman-4-yl)phenyl)piperidin-4-yl)methyl)piperazi n-1-yl)-1-oxoisoindolin-2- yl)piperidine-2,6-dione Step 1: A solution of (3S,4S)-3-cyclopentyl-4-(4-(4-(dimethoxymethyl)piperidin-1- yl)phenyl)isochroman-7-ol (130 mg, 1 Eq, 288 ^mol) in THF (1.5 mL) and 10% H ₂ SO ₄ (3 mL) was stirred at 70 °C for 1 hour. The reaction mixture was poured into 10 mL saturated aqueous NaHCO ₃ solution, then was extracted with ethyl acetate (20 mL * 3). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give 1-(4-((3S,4S)-3-cyclopentyl-7-hydroxyisochroman-4- yl)phenyl)piperidine-4-carbaldehyde (110 mg, crude) as a yellow oil. LC-MS (ESI ⁺ ) m/z: 424.1 (M+H2O) ⁺ . Step 2: A solution of 1-(4-((3S,4S)-3-cyclopentyl-7-hydroxyisochroman-4-yl)phenyl) piperidine- 4-carbaldehyde (110 mg, 1 Eq, 271 umol)ˈ (S)-3-(1-oxo-5-(piperazin-1-yl)isoindolin-2- yl)piperidine-2,6-dione (109 mg, 1.1 Eq, 298 umol, HCl salt) and sodium acetate (111 mg, 5 Eq, 1.36 mmol) in DCM (3 mL) and MeOH (3 mL) was stirred at 25 °C for 1 h, then acetic acid (33 mg, 31 ^L, 2 Eq, 542 ^mol) and sodium triacetoxyhydroborate (115 mg, 2 Eq, 542 ^mol) was added The mixture was stirred at 25 °C for 16 hour The mixture was diluted with H2O (20 mL) and was extracted with dichloromethane (20 ml * 3). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a colorless oil (180 mg, crude). The residue was purified by prep-HPLC (column: Welch Xtimate C18 150*30mm; mobile phase: [water(FA)-ACN]; B% 18% - 48%, 7 min) to give (S)-3-(5-(4-((1-(4- ((3S,4S)-3-cyclopentyl-7-hydroxyisochroman-4-yl)phenyl)piper idin-4-yl)methyl)piperazin-1- yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (102.6 mg, 56% yield, 98.936% purity) was obtained as a pink solid. LC-MS (ESI ⁺ ) m/z: 718.4 (M+H) ⁺ . LCMS: calc. for C ₄₃ H ₅₁ N ₅ O ₅ : 717.39, found: [M ⁺ H] ⁺ 718.4. HPLC: 98.936% purity at 220 nm. ¹ H NMR (400 MHz, DMSO-d ₆ ) į = 10.96 (s, 1H), 9.30 - 9.12 (m, 1H), 8.19 (s, 0.167H), 7.52 (d, J = 8.7 Hz, 1H), 7.09 - 7.00 (m, 4H), 6.77 (d, J = 8.7 Hz, 2H), 6.73 (d, J = 8.5 Hz, 1H), 6.50 (dd, J = 2.4, 8.2 Hz, 1H), 6.44 (d, J = 2.3 Hz, 1H), 5.09 - 5.02 (m, 1H), 4.87 (d, J = 15.4 Hz, 1H), 4.69 (d, J = 15.1 Hz, 1H), 4.37 - 4.30 (m, 1H), 4.24 - 4.17 (m, 1H), 3.69 (d, J = 2.1 Hz, 1H), 3.64 - 3.55 (m, 2H), 3.36 (br d, J = 5.7 Hz, 9H), 2.96 - 2.85 (m, 1H), 2.63 - 2.54 (m, 3H), 2.42 - 2.33 (m, 1H), 2.22 (br d, J = 7.2 Hz, 2H), 2.01 - 1.92 (m, 1H), 1.80 (br d, J = 12.0 Hz, 2H), 1.63 (br d, J = 4.5 Hz, 3H), 1.52 (br d, J = 4.5 Hz, 2H), 1.46 - 1.31 (m, 4H), 1.27 - 1.15 (m, 3H). EXAMPLE 102. Preparation of (I-383) (S)-3-(5-(4-((1-(3-fluoro-4-((3S,4S)-7-hydroxy- 3-phenylchroman-4-yl)phenyl)piperidin-4-yl)methyl)piperazin- 1-yl)-1-oxoisoindolin-2- yl)piperidine-2,6-dione

Step 1: To a solution of (5-(benzyloxy)-2-(phenylethynyl)phenyl)methanol (400 mg, 1 Eq, 1.3 mmol) in MeCN (20 mL) was added sodium bicarbonate (321 mg, 3 Eq, 3.8 mmol) and iodine (969 mg, 3 Eq, 3.8 mmol). The mixture was stirred at 25 °C for 16 h. TLC (petroleum ether: ethyl acetate= 10:1, Rf= 0.5) showed one new spot was observed. The reaction mixture was quenched by saturated aqueous Na ₂ SO ₃ (20 mL) and diluted with H ₂ O (20 mL) and extracted with ethyl acetate (60 mL). The organic layer was dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under vacuum to give a yellow oil. The yellow oil was purified by silica gel column chromatography (ISCO®; 20 g SepaFlash® Silica Flash Column, Eluent of 0~20% ethyl acetate/petroleum ether gradient @ 24 mL/min) to give 7-(benzyloxy)-4-iodo-3-phenyl-1H- isochromene (220 mg, 480 ^mol, 37.7 % yield, 96.092% purity) as a black solid. Step 2: To a mixture of 4-(dimethoxymethyl)-1-(3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2 - dioxaborolan-2-yl)phenyl)piperidine (208 mg, 1.1 Eq, 550 ^mol),澳sodium carbonate (132 mg, 2.5 Eq, 1.3 mmol) and 4-(dimethoxymethyl)-1-(3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2 - dioxaborolan-2-yl)phenyl)piperidine (208 mg, 1.1 Eq, 550 ^mol) in 1,4-dioxane (8 mL) and H ₂ O (2 mL) was added Pd(dppf) Cl ₂ (37 mg, 0.1 Eq, 50 ^mol) and stirred at 85 °C under N ₂ atmosphere for 16 h.. TLC (petroleum ether: ethyl acetate= 3:1, R _f = 0.6) showed one new spot was observed. The reaction mixture was diluted with H ₂ O (30 mL) and extracted with ethyl acetate 90 mL. The organic layer was washed with brine (20 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® Silica Flash Column, Eluent of 0~30% ethyl acetate/petroleum ether gradient @ 24 mL/min) and the organic layer was concentrated in vacuum to give 1-(4-(7-(benzyloxy)-3-phenyl-1H-isochromen-4-yl)-3- fluorophenyl)-4-(dimethoxymethyl)piperidine (190 mg, 303 ^mol, 60.7 % yield, 90.242% purity) as a light red oil. LC-MS (ESI+) m/z: 566.2 (M+H) ⁺ . Step 3: A mixture of 1-(4-(7-(benzyloxy)-3-phenyl-1H-isochromen-4-yl)-3-fluorophe nyl)-4- (dimethoxymethyl)piperidine (190 mg, 1 Eq, 336 ^mol), Pd/C(190 mg, 10% purity, 0.5 Eq, 179 ^mol) in THF (6 mL) and MeOH (6 mL) was degassed and purged with H ₂ for 3 times, and then the mixture was stirred at 25 °C for 2 h under H ₂ atmosphere ( 15 psi). The reaction was filtered and concentrated to dryness in vacuum to give 4-(4-(4-(dimethoxymethyl)piperidin-1-yl)-2- fluorophenyl)-3-phenylisochroman-7-ol (190 mg, 398 ^mol, 91% purity) as a light red oil. LC- MS (ESI+) m/z: 478.1 (M+H) ⁺ . Step 4: The light red oil was purified by SFC Column: DAICEL CHIRALPAK AD(250mm*30mm,10um) Condition: A: CO ₂ B: ETOH(0.1%NH ₃ H ₂ O) at the beginning: A (45%) and B (55%) at the end: A: (45%) and B (55%) Gradient Time (min) 45; 100%B Hold Time (min); Flow Rate (ml/min) 80. The fractions were filtered and concentrated under reduced pressure to give (3S,4S)-4-(4-(4-(dimethoxymethyl)piperidin-1-yl)-2-fluorophe nyl)-3- phenylisochroman-7-ol (100 mg, 209 ^mol, 52.6 % yield, 100% purity) and (3R,4R)-4-(4-(4- (dimethoxymethyl)piperidin-1-yl)-2-fluorophenyl)-3-phenyliso chroman-7-ol (80 mg, 0.17 mmol, LC-MS (ESI+) m/z: 478.1 (M+H) ⁺ . Step 5: To a solution of (3S,4S)-4-(4-(4-(dimethoxymethyl)piperidin-1-yl)-2-fluorophe nyl)-3- phenylisochroman-7-ol (100 mg, 1 Eq, 209 ^mol) in THF (4 mL) was added 10% H ₂ SO ₄ (4 mL). The mixture was stirred at 70 °C for 40 mins. The reaction mixture was adjusted to pH=7 by adding saturated aqueous NaHCO ₃ (30 mL) at 0 °C and diluted with H ₂ O (20 mL) and extracted with ethyl acetate 50 mL. The organic layer was washed with brine (10 mL). Dried over anhydrous Na ₂ SO _4, filtered and concentrated under reduced pressure to give crude product 1-(3- fluoro-4-((3S,4S)-7-hydroxy-3-phenylchroman-4-yl)phenyl)pipe ridine-4-carbaldehyde (80 mg, 0.19 mmol, 89 % yield) as a light red oil _. LC-MS (ESI+) m/z: 450.1 Step 6: A mixture of 1-(3-fluoro-4-((3S,4S)-7-hydroxy-3-phenylchroman-4- yl)phenyl)piperidine-4-carbaldehyde (80 mg, 1 Eq, 185.4 ^mol), (S)-3-(1-oxo-5-(piperazin-1- yl)isoindolin-2-yl)piperidine-2,6-dione (68 mg, 1 Eq, 185.4 ^mol, HCl salt), sodium acetate (46 mg, 3 Eq, 557 ^mol) and acetic acid (34 mg, 32 ^L, 3 Eq, 557 ^mol) in DCM (4 mL) and MeOH (4 mL) was stirred at 30 °C for 0.5 h, then sodium triacetoxyborohydride (79 mg, 2 Eq, 371 ^mol) was added in the mixture and stirred at 30 °C for 16 h. TLC (DCM/MeOH= 10/1, Rf= 0.6) showed a new spot was detected. The mixture was added H2O (20 mL), then extracted with ethyl acetate (20 mL * 2). The combined extracts were dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to dryness in vacuum to give a residue. The residue was purified by prep-HPLC: Column: Welch Xtimate C18150*30mm*5um Condition: A: water (FA) B: ACN at the beginning: A (79%) and B (21%) at the end: A: (49%) and B (51%) Gradient Time (min) 7; 100%B Hold Time (min) 3.2; Flow Rate (ml/min) 25. The aqueous phase was lyophilized to dryness to give (S)-3-(5-(4-((1-(3-fluoro-4-((3S,4S)-7-hydroxy-3-phenylchrom an-4- yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindo lin-2-yl)piperidine-2,6-dione (46.1 mg, 61.8 ^mol, 33.3 % yield, 99.694% purity) as a white solid. LCMS, HPLC, SFC and NMR confirmed. LC-MS (ESI ⁺ ) m/z: 744.4 (M+H) ⁺ . HPLC: 99.694%, purity at 220 nm. ¹ H NMR (400 MHz, DMSO-d ₆ ) į ppm 10.96 (s, 1 H) 9.28 - 9.41 (m, 1 H) 8.16 (s, 0.375 H) 7.52 (d, J=8.82 Hz, 1 H) 7.02 - 7.17 (m, 7 H) 6.74 - 6.85 (m, 2 H) 6.49 - 6.61 (m, 3 H) 6.29 (dd, J=13.83, 2.27 Hz, 1 H) 5.00 - 5.12 (m, 3 H) 4.91 (br d, J=15.38 Hz, 1 H) 4.29 - 4.42 (m, 2 H) 4.16 - 4.25 (m, 1 H) 3.50 - 3.61 (m, 2 H) 3.28 (br s, 5 H) 2.84 - 2.97 (m, 1 H) 2.51 - 2.62 (m, 6 H) 2.33 - 2.41 (m, 1 H) 2.14 - 2.22 (m, 2 H) 1.92 - 2.01 (m, 1 H) 1.60 - 1.79 (m, 3 H) 1.05 - 1.19 (m, 2 H).

EXAMPLE 103. Preparation of (I-230) (S)-3-(5-(4-((1-(4-((3R,4R)-3- (cyclopropylmethyl)-7-hydroxyisochroman-4-yl)phenyl)piperidi n-4-yl)methyl)piperazin-1- yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione Step 1: Allylmagnesium bromide (0.75 g, 5.1 mL, 1 molar, 3 Eq, 5.1 mmol) was added in THF (4 ) ih h d i d 8 °C h 2(4(b l )2((( butyldimethylsilyl)oxy)methyl)phenyl)-2-(4-bromophenyl)-N-me thoxy-N-methylacetamide (1.0 g, 1 Eq, 1.7 mmol) in THF (1 mL) was added to the mixture and stirred at -78 °C-r.t. for 16 h with N ₂ atmosphere. The reaction was quenched with aq.NH ₄ Cl (10 mL) at ice bath, then the mixture was added H ₂ O (100 mL) and extracted with ethyl acetate (100 mL x 2). The combined extracts were dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to dryness in vacuo to give a residue. The residue was subjected to column chromatography over silica gel (petroleum ether/ethyl acetate from 100/0 to 90/10). The pure fractions were collected and concentrated to dryness in vacuo to give 1-(4-(benzyloxy)-2-(((tert-butyldimethylsilyl)oxy)methyl)phe nyl)-1-(4- bromophenyl)pent-4-en-2-one (680 mg, 60 % yield, 85.9% purity) as a colorless oil. LC-MS (ESI+) m/z: 434.7 (M-132) ⁺ . Step 2: A mixture of 1-(4-(benzyloxy)-2-(((tert-butyldimethylsilyl)oxy)methyl)phe nyl)-1-(4- bromophenyl)pent-4-en-2-one (680 mg, 1 Eq, 1.03 mmol) and triethylsilane (180 mg, 248 ^L, 1.5 Eq, 1.55 mmol) in DCM (6 mL) was added dropwise trimethylsilyl triflate (345 mg, 286 ^L, 1.5 Eq, 1.55 mmol) at -78°C with N ₂ . Then the reaction was stirred at -78 °C for 0.5 h with N ₂ . The reaction was quenched with aq.NaHCO3 (5 mL) at ice bath, then the mixture was added H2O (100 mL) and extracted with ethyl acetate (100 mL x 2). The combined extracts were dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to dryness in vacuo to give a residue. The residue was purified by HPLC (column: Welch Xtimate C18150*30mm*5um; mobile phase: [water (FA)-ACN]; B% 75%-100%, 9 min). The aqueous phase was collected to dryness to give 3-allyl- 7-(benzyloxy)-4-(4-bromophenyl)isochromane (210 mg, 45.0 % yield, 96.4% purity) as a yellow oil. LC-MS (ESI+) m/z: 436.7 (M+H) ⁺ . Step 3: A mixture of trifluoroacetic acid (75.8 mg, 50.6 ^L, 2 Eq, 665 ^mol) in DCM (4 mL) was stirred at 0 °C with N ₂ , then diethylzinc (123 mg, 997 ^L, 1 molar, 3 Eq, 997 ^mol) was added to the mixture and stirred at 0 °C for 30 min. Then methylene iodide (267 mg, 80.3 ^L, 3 Eq, 997 ^mol) in DCM (1 mL) was added to the mixture and stirred at 0 °C for 30 min. Then 3-allyl-7- (benzyloxy)-4-(4-bromophenyl)isochromane (150 mg, 1 Eq, 332 ^mol) in DCM (1 mL) was added to reaction at 0 °C and stirred at 0 °C-r.t for 15 h. The reaction was quenched with aq.NaHCO ₃ (10 mL) at ice bath. The mixture was added H ₂ O (100 mL) and extracted with ethyl acetate (100 mL x 2). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated to dryness in vacuo to give a residue. The residue was subjected to column chromatography over silica gel (petroleum ether/ethyl acetate from 100/0 to 70/30) The pure fractions were collected and concentrated to dryness in vacuo to give 7-(benzyloxy)-4-(4- bromophenyl)-3-(cyclopropylmethyl)isochromane (150 mg, 92.0 % yield, 91.6% purity) as a yellow solid. LC-MS (ESI+) m/z: 450.8 (M+H) ⁺ . Step 4: A mixture of 7-(benzyloxy)-4-(4-bromophenyl)-3-(cyclopropylmethyl)isochro mane (130 mg, 1 Eq, 265 ^mol), 2-(Dicyclohexylphosphanyl)-2',4',6'-tris(isopropyl)biphenyl (25.3 mg, 0.2 Eq, 53.0 ^mol), palladium diacetate (8.93 mg, 0.15 Eq, 39.8 ^mol), 4- (dimethoxymethyl)piperidine (63.3 mg, 1.5 Eq, 398 ^mol) and sodium 2-methylpropan-2-olate (38.2 mg, 1.5 Eq, 398 ^mol) in toluene (5 mL) was stirred at r.t.. N ₂ was bubbled into the mixture for 5 min. Then the reaction was heated to 90 °C for 16 h. The mixture was added H ₂ O (50 mL) and extracted with ethyl acetate (50 mL x 2). The combined organic layers were dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to dryness in vacuo to give a residue. The residue was subjected to column chromatography over silica gel (petroleum ether/ethyl acetate from 100/0 to 80/20). The pure fractions were collected and concentrated to dryness in vacuo to give 1-(4-((3R,4R)-7-(benzyloxy)-3-(cyclopropylmethyl)isochroman- 4-yl)phenyl)-4- (dimethoxymethyl)piperidine (95 mg, 64 % yield, 94.8% purity) as a white solid. LC-MS (ESI+) m/z: 528.3 (M+H) ⁺ . Step 5: A mixture of 1-(4-(7-(benzyloxy)-3-(cyclopropylmethyl)isochroman-4-yl)phe nyl)-4- (dimethoxymethyl)piperidine (95 mg, 1 Eq, 0.17 mmol), Pd-C (100 mg, 10% wt 5.5 Eq, 940 ^mol) and dihydrogen (0.34 mg, 1 Eq, 0.17 mmol) in MeOH (3 mL) and THF (3 mL) was degassed and purged with H ₂ for 3 times, then the mixture was stirred at 25 °C for 1 h with H ₂ atmosphere (15 psi). The mixture was filtered and concentrated to dryness in vacuo to give a white solid. The white solid was purified by SFC (column: DAICEL CHIRALPAK AD (250mm*30mm, 10um); mobile phase: [CO2- EtOH (0.1%NH3H2O)]; B% 40%-40%, 45 min). The aqueous phase was collected to dryness in vacuo to give (3R,4R)-3-(cyclopropylmethyl)-4- (4-(4-(dimethoxymethyl)piperidin-1-yl)phenyl)isochroman-7-ol (25 mg, 33 % yield, 97.7% purity) and (3S,4S)-3-(cyclopropylmethyl)-4-(4-(4-(dimethoxymethyl)piper idin-1- yl)phenyl)isochroman-7-ol (25 mg, 33 % yield, 100% purity) as white solids. LC-MS (ESI+) m/z: 438.4 (M+H) ⁺ . Step 6: A mixture of (3R,4R)-3-(cyclopropylmethyl)-4-(4-(4-(dimethoxymethyl)piper idin-1- yl)phenyl)isochroman-7-ol (25 mg, 1 Eq, 56 ^mol) in THF (1 mL) and 10%H2SO4 (1 mL) was mixture was added H2O (20 mL) and extracted with ethyl acetate (20 mL x 2). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated to dryness in vacuo to give 1-(4-((3R,4R)-3-(cyclopropylmethyl)-7-hydroxyisochroman-4-yl )phenyl)piperidine-4- carbaldehyde (22 mg, 98 % yield, 97.1% purity) as a yellow solid. LC-MS (ESI+) m/z: 392.1 (M+H) ⁺ . Step 7: A mixture of 1-(4-((3R,4R)-3-(cyclopropylmethyl)-7-hydroxyisochroman-4- yl)phenyl)piperidine-4-carbaldehyde (22 mg, 1 Eq, 55 ^mol) , (S)-3-(1-oxo-5-(piperazin-1- yl)isoindolin-2-yl)piperidine-2,6-dione, HCl salt(24 mg, 1.2 Eq, 65 ^mol), sodium acetate (22 mg, 5 Eq, 0.27 mmol) and acetic acid (9.8 mg, 9.4 ^L, 3 Eq, 0.16 mmol) in DCM (3 mL) and MeOH (3 mL) was stirred at 30 °C for 1 h, then sodium triacetoxyborohydride (23 mg, 2 Eq, 0.11 mmol) was added to the mixture and stirred at 30 °C for 16 h. Then the mixture was added H ₂ O (50 mL) and extracted with ethyl acetate (50 mL x 2). The combined extracts were dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to dryness in vacuo to give a residue. The residue was purified by prep-HPLC (column: Welch Xtimate C18150*30mm*5um; mobile phase: [water(FA)-ACN]; B% 10%-50%, 8 min) to give (S)-3-(5-(4-((1-(4-((3R,4R)-3- (cyclopropylmethyl)-7-hydroxyisochroman-4-yl)phenyl)piperidi n-4-yl)methyl)piperazin-1-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione (25.1 mg, 65 % yield, 99.4% purity) as a white solid. LC-MS (ESI+) m/z: 704.2 (M+H) ⁺ . LCMS: calc. for C ₄₂ H ₄₉ N ₅ O ₅ : 703.37, found: [M+H] ⁺ 704.2. HPLC: 99.426 % purity at 220 nm. ¹ HNMR (400MHz, DMSO-d ₆ ) į = 10.98 (s, 1H), 9.39 - 9.14 (m, 1H), 8.22 (s, 1H), 7.53 (d, J=8.6 Hz, 1H), 7.12 - 7.04 (m, 2H), 6.99 (d, J=8.6 Hz, 2H), 6.83 - 6.72 (m, 3H), 6.56 - 6.45 (m, 2H), 5.07 (dd, J=5.1, 13.4 Hz, 1H), 4.86 (d, J=15.4 Hz, 1H), 4.72 (br d, J=15.4 Hz, 1H), 4.39 - 4.30 (m, 1H), 4.27 - 4.17 (m, 1H), 3.81 (br t, J=8.0 Hz, 1H), 3.69 (br s, 1H), 3.61 (br d, J=10.8 Hz, 2H), 3.30 (br s, 5H), 2.99 - 2.85 (m, 1H), 2.65 - 2.55 (m, 4H), 2.51 - 2.48 (m, 2H), 2.45 - 2.30 (m, 1H), 2.23 (br d, J=7.0 Hz, 2H), 2.03 - 1.92 (m, 1H), 1.87 - 1.76 (m, 2H), 1.68 (br s, 1H), 1.29 - 1.15 (m, 2H), 1.10 - 0.97 (m, 2H), 0.85 - 0.74 (m, 1H), 0.45 - 0.32 (m, 2H), 0.06 - -0.05 (m, 2H). EXAMPLE 104. Preparation of (I-231) (S)-3-(5-(4-((1-(4-((3S,4S)-3- (cyclopropylmethyl)-7-hydroxyisochroman-4-yl)phenyl)piperidi n-4-yl)methyl)piperazin-1- yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione Step 1: A mixture of (3S,4S)-3-(cyclopropylmethyl)-4-(4-(4-(dimethoxymethyl)piper idin-1- yl)phenyl)isochroman-7-ol (20 mg, 1 Eq, 46 ^mol) in THF (1 mL) and 10%H ₂ SO ₄ (1 mL) was stirred at 70 °C for 0.5 h. The reaction was adjust to pH=8 with aq. NaHCO ₃ (5 mL) at 0 °C. Then the mixture was added H ₂ O (20 mL) and extracted with ethyl acetate (20 mL x 2). The combined organic layers were dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to dryness in vacuo to give 1-(4-((3S,4S)-3-(cyclopropylmethyl)-7-hydroxyisochroman-4- yl)phenyl)piperidine-4-carbaldehyde (18 mg, 96 % yield, 95.5% purity) as a yellow solid. LC- MS (ESI+) m/z: 392.1 (M+H) ⁺ . Step 2: A mixture of 1-(4-((3S,4S)-3-(cyclopropylmethyl)-7-hydroxyisochroman-4- yl)phenyl)piperidine-4-carbaldehyde (18 mg, 1 Eq, 44 ^mol) , (S)-3-(1-oxo-5-(piperazin-1- yl)isoindolin-2-yl)piperidine-2,6-dione, HCl salt(19 mg, 1.2 Eq, 53 ^mol), sodium acetate (18 mg, 5 Eq, 0.22 mmol) and acetic acid (7.9 mg, 7.6 ^L, 3 Eq, 0.13 mmol) in DCM (3 mL) and MeOH (3 mL) was stirred at 30 °C for 1 h, then sodium triacetoxyborohydride (19 mg, 13 ^L, 2 added H2O (20 mL) and extracted with ethyl acetate (20 mL x 2). The combined extracts were dried over anhydrous Na2SO4, filtered and concentrated to dryness in vacuo to give a residue. The residue was purified by prep-HPLC (column: Welch Xtimate C18150*30mm*5um; mobile phase: [water(FA)-ACN]; B% 10%-50%, 8 min) to give (S)-3-(5-(4-((1-(4-((3S,4S)-3- (cyclopropylmethyl)-7-hydroxyisochroman-4-yl)phenyl)piperidi n-4-yl)methyl)piperazin-1-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione (19.4 mg, 25.9 ^mol, 59 % yield, 93.9% purity) as a white solid. LC-MS (ESI+) m/z: 704.4 (M+H) ⁺ . LCMS: calc. for C ₄₂ H ₄₉ N ₅ O ₅ : 703.37, found: [M+H] ⁺ 704.4. HPLC: 93.932 % purity at 220 nm. ¹ HNMR (400MHz, DMSO-d ₆ ) į = 10.98 (s, 1H), 9.26 (br s, 1H), 8.22 (s, 1H), 7.53 (d, J=8.5 Hz, 1H), 7.10 - 7.04 (m, 2H), 6.99 (d, J=8.7 Hz, 2H), 6.81 - 6.72 (m, 3H), 6.52 (dd, J=2.4, 8.3 Hz, 1H), 6.47 (d, J=2.3 Hz, 1H), 5.07 (dd, J=5.0, 13.2 Hz, 1H), 4.90 - 4.83 (m, 1H), 4.72 (br d, J=15.1 Hz, 1H), 4.38 - 4.31 (m, 1H), 4.25 - 4.18 (m, 1H), 3.81 (br t, J=8.0 Hz, 1H), 3.69 (br s, 1H), 3.61 (br d, J=10.1 Hz, 2H), 3.30 (br s, 6H), 2.98 - 2.85 (m, 1H), 2.65 - 2.54 (m, 4H), 2.50 - 2.48 (m, 1H), 2.38 (dq, J=4.2, 13.2 Hz, 1H), 2.23 (br d, J=7.0 Hz, 2H), 2.02 - 1.93 (m, 1H), 1.86 - 1.76 (m, 2H), 1.68 (br s, 1H), 1.29 - 1.14 (m, 2H), 1.10 - 0.97 (m, 2H), 0.86 - 0.73 (m, 1H), 0.45 - 0.31 (m, 2H), 0.07 - -0.07 (m, 2H).

EXAMPLE 105. Preparation of (I-391) 1-(4-(2-((1-(4-((3S,4R)-7-hydroxy-3- phenylisochroman-4-yl)phenyl)piperidin-4-yl)methyl)-2,8-diaz aspiro[4.5]decan-8- yl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione Step 1: A mixture of compound 1 (893 mg, 3.72 mmol), Cs ₂ CO ₃ (1.21 g, 3.72 mmol) and RuPhos-Pd-G ₃ (155 mg, 186 ^mol) in 1,4-Dioxane (10 mL) was degassed and purged with N ₂ for 3 times, and then the mixture was stirred at 100 °C for 16 h under N ₂ atmosphere. The reaction was quenched with water (20 mL) and extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (50 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by flashsilica gel chromatography (ethyl acetate in petroleum ether = 0% to 100%) to give the product of compound 3 (200 mg, 15 % yield) as a white solid. LC-MS (ESI ⁺ ) m/z: 429.1 (M+H) ⁺ . Step 2: To a solution of compound 3 (200 mg, 467 ^mol) in DCM (3 mL) was added TFA (1 g, 1 mL, 0.01 mol) at 20 °C. The mixture was stirred at 20 °C for 2 h. The solvent was removed to yield a residue which was purified by preparative HPLC (column: Boston Green ODS 150*30mm*5um;mobile phase: [water(HCl)-ACN];B%: 0%-20%,11min), followed by lyophilization to give the product of compound 4 (130 mg, 84.8 % yield) as a brown solid. LC- MS (ESI ⁺ ) m/z: 329.3 (M+H) ⁺ . Step 3: To a solution of compound 4 (45 mg, 0.11 mmol) in DCE (10 mL) and MeOH (1 mL) was added compound 5 (36 mg, 0.11 mmol) and stirred at 20 °C for 10 min. Then NaBH(OAc) ₃ yield a residue. The residue was purified by preparative HPLC (column: Phenomenex Gemini NX 150×30mm, 5^m; mobile phase: [water( NH4HCO3)-ACN];gradient:52%-82% B over 11 min), followed by lyophilization to give 1-(4-(2-((1-(4-((3S,4R)-7-hydroxy-3-phenylisochroman- 4-yl)phenyl)piperidin-4-yl)methyl)-2,8-diazaspiro[4.5]decan- 8-yl)phenyl)dihydropyrimidine- 2,4(1H,3H)-dione (25 mg, 32% yield) as a yellow solid. LC-MS (ESI ⁺ ) m/z: 726.3 (M+H) ⁺ . LCMS: calc. for C ₄₅ H ₅₁ N ₅ O ₄ : 725.93, found: 726.3. HPLC: 100.0% purity at 254 nm. ¹ HNMR (500MHz, DMSO-d6): į 10.24 (s, 1H), 9.27 (s, 1H), 7.17 - 7.10 (m, 4H), 7.10 - 7.04 (m, 3H), 6.91 (d, J = 9.0 Hz, 2H), 6.78 (d, J = 8.1 Hz, 1H), 6.63 - 6.58 (m, 2H), 6.57 - 6.52 (m, 4H), 5.07 (d, J = 15.4 Hz, 1H), 4.99 (d, J = 2.9 Hz, 1H), 4.90 (d, J = 15.3 Hz, 1H), 4.02 (d, J = 2.7 Hz, 1H), 3.68 (t, J = 6.7 Hz, 2H), 3.54 - 3.43 (m, 2H), 3.19 - 3.01 (m, 4H), 2.67 (t, J=6.6 Hz, 2H), 2.52 (d, J = 1.8 Hz, 2H), 2.47 - 2.41 (m, 2H), 2.32 (s, 2H), 2.21 (d, J = 7.2 Hz, 2H), 1.73 (d, J = 12.1 Hz, 2H), 1.66 - 1.53 (m, 6H), 1.49 (dt, J = 3.6, 7.1 Hz, 1H), 1.12 (q, J = 11.9 Hz, 2H). EXAMPLE 106. Preparation of (I-396) 1-(6-(4-((1-(4-((3S,4R)-7-hydroxy-3- phenylisochroman-4-yl)phenyl)piperidin-4-yl)methyl)piperazin -1-yl)-1-methyl-1H-indazol- 3-yl)dihydropyrimidine-2,4(1H,3H)-dione Step 1: To a solution of 1-(4-((3S,4R)-7-hydroxy-3-phenylisochroman-4-yl)phenyl)piper idine-4- carbaldehyde (40 mg, 1 eq,^97 ^mol) in DCE (10 mL) and MeOH (1 mL) was added 1-(1- methyl-6-(piperazin-1-yl)-1H-indazol-3-yl)dihydropyrimidine- 2,4(1H,3H)-dione (32 mg, 1 eq, 97 ^mol) and stirred at 20 °C for 10 min. Then sodium triacetoxyhydroborate (62 mg, 3 eq, 0.29 mmol) was added and stirred at 20 °C for 10 min. The solvent was removed to yield a residue. The residue was purified by preparative HPLC (column: Phenomenex Gemini NX 150×30mm,5^m;mobile phase: [water( NH ₄ HCO ₃ )-ACN];gradient:48%-78% B over 11 min), followed by lyophilization give 1-(6-(4-((1-(4-((3S,4R)-7-hydroxy-3-phenylisochroman-4- yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-methyl-1H- indazol-3-yl)dihydropyrimidine- 2,4(1H,3H)-dione (32 mg, 46% yield) as a white solid. LC-MS (ESI ⁺ ) m/z: 726.4 (M+H) ⁺ . LCMS: calc. for C ₄₃ H ₄₇ N ₇ O ₄ : 725.89, found: [M+H] ⁺ 726.4. HPLC: 100.0% purity at 254 nm. ¹ HNMR (400MHz, DMSO-d6): į 10.50 (s, 1H), 9.28 (s, 1H), 7.44 (d, J = 9.1 Hz, 1H), 7.18 - 7.03 (m, 5H), 6.90 (d, J = 9.2 Hz, 1H), 6.84 - 6.74 (m, 2H), 6.64 - 6.59 (m, 2H), 6.55 (d, J = 6.4 Hz, 4H), 5.07 (d, J = 15.4 Hz, 1H), 5.00 (d, J = 3.0 Hz, 1H), 4.90 (d, J = 15.3 Hz, 1H), 4.03 (d, J = 2.7 Hz, 1H), 3.94 - 3.80 (m, 5H), 3.50 (d, J = 12.4 Hz, 2H), 3.21 (s, 6H), 2.73 (t, J = 6.6 Hz, 2H), 2.55 (s, 2H), 2.46 (d, J = 3.5 Hz, 2H), 2.19 (d, J = 7.0 Hz, 2H), 1.75 (d, J = 12.0 Hz, 2H), 1.63 (s, 1H), 1.25 - 1.06 (m, 2H).

EXAMPLE 107. Preparation of (I-392) 1-(4-(2-((1-(4-((3S,4R)-7-hydroxy-3- phenylisochroman-4-yl)phenyl)piperidin-4-yl)methyl)-2,8-diaz aspiro[4.5]decan-8-yl)-2- methylphenyl)dihydropyrimidine-2,4(1H,3H)-dione Step 1: To a solution of (3S,4R)-4-(4-(4-(dimethoxymethyl)piperidin-1-yl)phenyl)-3- phenylisochroman-7-ol (100 mg, 1 Eq, 218 ^mol) in 10% H ₂ SO ₄ (5 mL) and THF (3 mL) was stirred at 70 °C for 40 min. The reaction was adjust to pH=~8 with saturated aq.NaHCO3 (20 mL). Then the mixture was added water (30 mL) and extracted with ethyl acetate (2×30 mL). The combined organic layers were washed with brine(30 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to dryness in vacuum to give 1-(4-((3S,4R)-7-hydroxy-3- phenylisochroman-4-yl)phenyl)piperidine-4-carbaldehyde (80 mg, 0.18 mmol, 95.55% purity) as a yellow solid. LC-MS (ESI ⁺ ) m/z: 432.1 (M+H ₂ O) ⁺ . Step 2: To a solution of 1-(4-((3S,4R)-7-hydroxy-3-phenylisochroman-4-yl)phenyl)piper idine-4- carbaldehyde (100 mg, 1 Eq, 231.07 ^mol)ˈ 1-(2-methyl-4-(2,8-diazaspiro[4.5]decan-8- yl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione hydrochloride (88 mg, 1 Eq, 231.07 ^mol) in DCM (3 mL) and MeOH (3 mL) was added sodium acetate (114 mg, 6 Eq, 1.3864 mmol) was stirred at 25 °C for 1 h, Then acetic acid (28 mg, 2 Eq, 462.13 ^mol) and sodium triacetoxyhydroborate (98 mg, 2 Eq, 462.13 ^mol) was added. The mixture was stirred at 30 °C for 16 hour. The reaction was quenched with H ₂ O (50 mL) and extracted with ethyl acetate (50 mL*2). The organic layer was washed with brine (30 mL) and dried over anhydrous Na2SO4 and concentrated in vacuo to give a yellow oil. The residue was purified by prep-HPLC (column: Welch Xtimate C18150*30mm*3um;mobile phase: [water(FA)-ACN];B% 11%-41%,7 min) to give 1-(4-(2-((1-(4-((3S,4R)-7-hydroxy-3-phenylisochroman-4-yl)ph enyl)piperidin-4- yl)methyl)-2,8-diazaspiro[4.5]decan-8-yl)-2-methylphenyl)dih ydropyrimidine-2,4(1H,3H)-dione (97.8 mg, 132 ^mol, 100% purity) as a white solid. LC-MS (ESI ⁺ ) m/z: 740.5 (M+H) ⁺ . LCMS: calc. for C ₄₆ H ₅₃ N ₅ O ₄ : 739.41, found: [M+H]+ 740.5. HPLC: 100% purity at 220 nm. NMR (400 MHz, DMSO-d ₆ ) į = 10.24 (s, 1H), 9.57 - 9.07 (m, 1H), 8.18 (s, 0.491H), 7.15 - 7.02 (m, 6H), 6.83 - 6.74 (m, 3H), 6.62 - 6.58 (m, 2H), 6.58 - 6.52 (m, 4H), 5.09 - 4.88 (m, 3H), 4.02 (br d, J = 2.4 Hz, 1H), 3.68 - 3.62 (m, 1H), 3.45 (br d, J = 5.8 Hz, 2H), 3.20 - 3.04 (m, 5H), 2.76 - 2.58 (m, 3H), 2.47 - 2.40 (m, 2H), 2.35 (s, 2H), 2.24 (br d, J = 7.0 Hz, 2H), 2.10 (s, 3H), 1.73 (br d, J = 12.0 Hz, 2H), 1.66 - 1.42 (m, 8H), 1.19 - 1.07 (m, 2H).

EXAMPLE 108. Preparation of (I-367) (S)-3-(5-(4-((1-(4-((1R,3S,4R)-7-hydroxy-1- methyl-3-phenylisochroman-4-yl)phenyl)piperidin-4-yl)methyl) piperazin-1-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione Step 1: A mixture of 1-(4-(7-(benzyloxy)-1-methyl-3-phenylisochroman-4-yl)phenyl) -4- (dimethoxymethyl)piperidine (130 mg, 1 Eq, 231 ^mol), Pd/C (130 mg, 10% purity, 0.53 Eq, 122 ^mol) was added in THF (3 mL) and MeOH (3 mL). The suspension was degassed and purged with H ₂ for 3 times. The mixture was stirred under H ₂ (15 psi) at 25 °C for 16 hour. The mixture was filtered and concentrated to dryness in vacuum to give a white solid. The white solid was subjected by SFC: Column: DAICEL CHIRALPAK AD (250 mm *30 mm, 10 um); Mobile phase: A: Supercritical CO ₂ , B: MeOH (0.1% NH ₃ H ₂ O), A: B = 50:50 at 80 mL/min. The pure fractions were collected respectively and the solvents were evaporated under vacuum to give (1S,3R,4S)-4-(4-(4-(dimethoxymethyl)piperidin-1-yl)phenyl)-1 -methyl-3-phenylisochroman-7- ol (42 mg, 85 ^mol, 37% yield, 96.08% purity) and (1R,3S,4R)-4-(4-(4- (dimethoxymethyl)piperidin-1-yl)phenyl)-1-methyl-3-phenyliso chroman-7-ol (47 mg, 97 ^mol, 42% yield, 97.83% purity) as a yellow solid. LC-MS (ESI ⁺ ) m/z: 474.1 (M+H) ⁺ . Step 2: A mixture of (1R,3S,4R)-4-(4-(4-(dimethoxymethyl)piperidin-1-yl)phenyl)-1 -methyl-3- phenylisochroman-7-ol (47 mg, 97.831% purity, 1 Eq, 97 ^mol) in THF (1.5 mL) and 10% H ₂ SO ₄ (1.5 mL) was stirred at 70 °C for 1 hour. Then the reaction was cooled to room temperature. The reaction mixture was quenched with saturated aq. NaHCO ₃ (5 mL) and stirred for 10 min at 0 °C. Then the mixture was dissolved in water (50 mL) and extracted by ethyl acetate (50 mL*2). The combined organic layer were dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under vacuum to give 1-(4-((1R,3S,4R)-7-hydroxy-1-methyl-3-phenylisochroman- 4-yl)phenyl)piperidine-4-carbaldehyde (40 mg, 94 ^mol, 96 % yield) as a yellow oil. LC-MS (ESI+) m/z: 428.2 (M+H) + Step 3: A mixture of 1-(4-((1R,3S,4R)-7-hydroxy-1-methyl-3-phenylisochroman-4- yl)phenyl)piperidine-4-carbaldehyde (40 mg, 1 Eq, 94 ^mol), (S)-3-(1-oxo-5-(piperazin-1- yl)isoindolin-2-yl)piperidine-2,6-dione hydrochloride (44 mg, 1.3 Eq, 0.12 mmol), sodium acetate (38 mg, 5 Eq, 0.47 mmol) and acetic acid (17 mg, 16 ^L, 3 Eq, 0.28 mmol) in DCM (2 mL) and MeOH (2 mL) stirred at 25 °C for 1 hour, then sodium triacetoxyborohydride (40 mg, 2 Eq, 0.19 mmol) was added to the mixture and stirred at 25 °C for 16 hour. The reaction was treated with H ₂ O (50 mL), extracted with ethyl acetate (50 mL). The extracts was dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to dryness in vacuum to give a residue. The residue was purified by prep.HPLC (column: Welch Xtimate C18150*30 mm*5 um mobile phase: [water (FA)-ACN]; B%: 18%-48%, 7 min). The aqueous phase was lyophilized to dryness to give (S)-3-(5-(4-((1-(4-((1R,3S,4R)-7-hydroxy-1-methyl-3-phenylis ochroman-4- yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindo lin-2-yl)piperidine-2,6-dione (24.7 mg, 32.7 ^mol, 35% yield, 97.854% purity) as a white solid. LC-MS (ESI+) m/z: 740.2 (M+H) ^{+ 1} H NMR (400 MHz, DMSO-d6) į = 10.96 (s, 1H), 9.49 - 9.11 (m, 1H), 8.20 (s, 0.306H), 7.52 (d, 8.6 Hz, 1H), 7.18 - 7.04 (m, 7H), 6.78 (d, J = 8.1 Hz, 1H), 6.62 - 6.51 (m, 6H), 5.32 (q, J = 6.8 Hz, 1H), 5.25 (d, J = 2.7 Hz, 1H), 5.05 (dd, J = 5.0, 13.2 Hz, 1H), 4.38 - 4.28 (m, 1H), 4.24 - 4.17 (m, 1H), 3.98 (d, J = 3.0 Hz, 1H), 3.55 - 3.47 (m, 3H), 3.27 (br s, 5H), 2.97 - 2.84 (m, 1H), 2.58 (br d, J = 16.1 Hz, 1H), 2.48 (br s, 4H), 2.40 - 2.30 (m, 1H), 2.18 (br d, J = 6.9 Hz, 2H), 2.01 - 1.91 (m, 1H), 1.74 (br d, J = 11.8 Hz, 2H), 1.67 - 1.58 (m, 1H), 1.53 (d, J = 6.7 Hz, 3H), 1.21 - 1.08 (m, 2H). EXAMPLE 109. Preparation of (I-368) (S)-3-(5-(4-((1-(4-((1S,3R,4S)-7-hydroxy-1- methyl-3-phenylisochroman-4-yl)phenyl)piperidin-4-yl)methyl) piperazin-1-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione Step 1: A mixture of (1*S,3*R,4*S)-4-(4-(4-(dimethoxymethyl)piperidin-1-yl)phenyl )-1-methyl- 3-phenylisochroman-7-ol (37 mg, 96.08% purity, 1 Eq, 75 ^mol) in THF (1.5 mL) and 10% H ₂ SO ₄ (1.5 mL) was stirred at 70 °C for 1 hour. Then the reaction was cooled to room temperature. The reaction mixture was quenched with saturated aq. NaHCO ₃ (5 mL) and stirred for 10 min at 0 °C. Then the mixture was dissolved in water (50 mL) and extracted by ethyl acetate (50 mL*2). The combined organic layer were dried over anhydrous Na2SO4, filtered and concentrated under vacuum to give 1-(4-((1*S,3*R,4*S)-7-hydroxy-1-methyl-3- phenylisochroman-4-yl)phenyl)piperidine-4-carbaldehyde (32 mg, 75 ^mol, 100 % yield) as a yellow oil. LC-MS (ESI+) m/z: 428.1 (M+H) ⁺ Step 2: A mixture of 1-(4-((1S,3R,4S)-7-hydroxy-1-methyl-3-phenylisochroman-4- yl)phenyl)piperidine-4-carbaldehyde (32 mg, 1 Eq, 75 ^mol), (S)-3-(1-oxo-5-(piperazin-1- yl)isoindolin-2-yl)piperidine-2,6-dione hydrochloride (35 mg, 1.3 Eq, 0.097 mmol), sodium acetate(31 mg, 5 Eq, 0.37 mmol) and acetic acid (13 mg, 13 ^L, 3 Eq, 0.22 mmol) in DCM (2 mL) and MeOH (2 mL) stirred at 25 °C for 1 hour, then sodium triacetoxyborohydride (32 mg, 2 Eq, 0.15 mmol) was added to the mixture and stirred at 25 °C for 16 hour. The reaction was treated with H ₂ O (50 mL), extracted with ethyl acetate (50 mL). The extracts was dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to dryness in vacuum to give a residue. The residue was purified by prep.HPLC (column: Welch Xtimate C18150*30 mm*5 um mobile phase: [water (FA)-ACN]; B%: 19%-49%, 7 min). The aqueous phase was lyophilized to dryness to give (S)-3-(5-(4-((1-(4-((1S,3R,4S)-7-hydroxy-1-methyl-3-phenylis ochroman-4- yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindo lin-2-yl)piperidine-2,6-dione (19.2 mg, 25.9 ^mol, 35% yield, 99.820% purity) as a white solid. LC-MS (ESI+) m/z: 740.2 (M+H) ⁺ HPLC: 99.8%, purity at 220 nm. ¹ H NMR (400 MHz, DMSO-d ₆ ) į = 10.96 (s, 1H), 9.29 (br s, 1H), 8.19 (s, 0.152H), 7.52 (d, J = 8.5 Hz, 1H), 7.18 - 7.02 (m, 7H), 6.82 - 6.74 (m, 1H), 6.65 - 6.52 (m, 6H), 5.38 - 5.20 (m, 2H), 5.05 (dd, J = 5.1, 13.3 Hz, 1H), 4.40 - 4.27 (m, 1H), 4.26 - 4.13 (m, 1H), 3.98 (d, J = 2.9 Hz, 1H), 3.50 (br d, J = 11.4 Hz, 3H), 3.27 (br s, 5H), 2.99 - 2.81 (m, 1H), 2.58 (br d, J = 16.9 Hz, 1H), 2.48 (br s, 4H), 2.37 (br dd, J = 4.5, 12.9 Hz, 1H), 2.25 - 2.13 (m, 2H), 2.01 - 1.90 (m, 1H), 1.80 - 1.69 (m, 2H), 1.67 - 1.59 (m, 1H), 1.56 - 1.48 (m, 3H), 1.20 - 1.07 (m, 2H).^ EXAMPLE 110. Preparation of (I-205) (S)-3-(5-(4-((1-(4-((1*S,3*R,4*R)-3-cyclohexyl- 7-hydroxy-1-methylisochroman-4-yl)phenyl)piperidin-4-yl)meth yl)piperazin-1-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione

Step 1: A mixture of sodium tetrahydrofolate (8.7 g, 1.04 Eq, 229 mmol) was added in 1-(3- (benzyloxy)phenyl)ethan-1-one (50 g, 1 Eq, 221 mmol) in EtOH (300 mL) with N ₂ at 0 °C and was stirred at 0 °C for 1 hour. TLC (petroleum ether: ethyl acetate=5:1, UV) showed one main new spot was observed. The reaction was quenched with saturated aqueous NH ₄ Cl (80 mL) at 0 °C, then mixture was added to H ₂ O (300 mL) was extracted with ethyl acetate (500 mL * 2). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to dryness in vacuum to give 1-(3-(benzyloxy)phenyl)ethan-1-ol (50 g, 219 mmol, 99.1 %) as a yellow solid. Step 2: A mixture of 1-(3-(benzyloxy)phenyl)ethan-1-ol (20 g, 1 Eq, 87.61 mmol) in THF (50 mL) were added to a 250 mL round-bottomed flask, then cooled to 0°C, NaH (4.2 g, 60% purity, 1.2 Eq, 105.1 mmol) was added. The mixture stirred under N ₂ at 0 °C for 30 min. Then 2, 2, 2- trichloroacetonitrile (13.9 g, 9.7 mL, 1.1 Eq, 96.37 mmol) was added dropwise and the reaction was stirred at 20 °C for 16 hour. TLC (petroleum ether: ethyl acetate=10:1, UV) showed one main new spot was observed.300 mL water was added, and the mixture was extracted with dichloromethane (500 mL *2). The combined organic layers were washed with brine (200 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to dryness in vacuum to give a yellow oil. The yellow oil was purified by flash column (petroleum ether/ethyl acetate from 100/0 to 0/100) and the organic layer was concentrated in vacuum to give 1-(3-(benzyloxy) phenyl) ethyl 2, 2, 2-trichloroacetimidate (9 g, 24 mmol, 28 % yield) as a yellow solid. NMR confirmed. Step 3: A mixture of 2-cyclohexyl-2-hydroxyacetic acid (10 g, 1 Eq, 63.2 mmol), cesium fluoride (14.4 g, 3.5 mL, 1.5 Eq, 94.8 mmol) and methyl iodide (13.5 g, 6 mL, 1.5 Eq, 94.8 mmol) in DMF (80 mL) was stirred at 20 °C for 16 hour. TLC (petroleum ether: ethyl acetate =5:1, R _f =0.5) showed a new spot was formed. The mixture was added H ₂ O (300 mL) and extracted with ethyl acetate (200 mL * 2). The combined extracts was dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to dryness in vacuum to give methyl 2-cyclohexyl-2- hydroxyacetate (8 g, 4 mmol) as a yellow oil. Step 4: To a solution of 1-(3-(benzyloxy) phenyl) ethyl 2, 2, 2-trichloroacetimidate (6.2 g, 1 Eq, 16.6 mmol) in DCM (30 mL) was under N ₂ atmosphere. A freshly prepared solution of methyl 2- cyclohexyl-2-hydroxyacetate (3.5 g, 1.2 Eq, 20 mmol) was added. After cooling at 0 °C boron difluoride etherate (236 mg, 208 ^L, 0.1 Eq, 1.66 mmol) was added stirred at 0 °C, and the solution was allowed to reach 0 °C during 2 h under stirring while developing a white precipitate. TLC (petroleum ether: ethyl acetate=10:1, UV) showed one main new spot was observed.100 mL water was added, and the mixture was extracted with dichloromethane (300 mL *2). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to dryness in vacuum to give a yellow oil. The yellow oil was purified by preparative high-performance liquid chromatography. Condition: Column: Welch Xtimate C18150*30mm*5um A: water (FA); B: ACN; at the beginning: A (30%) and B (70%); at the end: A: (0%) and B (100%) Gradient Time (min) 9; 100% B hold Time (min) 3, Flow Rate (ml/min) 30. The pure fractions were collected and the solvent was evaporated under vacuum. The aqueous layer was lyophilized to dryness to give methyl 2-(1-(3-(benzyloxy) phenyl) ethyl)- 2-cyclohexylacetate (1.1 g, 2.9 mmol, 17 % yield) as a yellow solid. NMR confirmed. Step 5: To a mixture of methyl 2-(1-(3-(benzyloxy)phenyl)ethyl)-2-cyclohexylacetate (1.5 g, 1 Eq, 3.92 mmol) and 1-bromopyrrolidine-2,5-dione (942 mg, 1.35 Eq, 5.29 mmol) in DMF (20 mL) was stirred at 0 °C for 1 hour , then the mixture was stirred at 25 °C for 12 hour. TLC (petroleum ether: ethyl acetate=10:1, UV) showed one main new spot was observed. Water (100 mL) was added and extracted with ethyl acetate (250 mL*2). The organic layers were washed with brine (100 mL) and dried over anhydrous Na ₂ SO ₄ and concentrated in vacuum to give a yellow solid. The yellow solid was subjected to column chromatography over silica gel (gradient elution: 0 – 15% EtOAc). The desired fractions were collected and concentrated to dryness in vacuum to give methyl 2-(1-(5-(benzyloxy)-2-bromophenyl) ethyl)-2-cyclohexylacetate (1.62 g, 3.51 mmol, 89.5 % yield) as a white solid. Step 6: A solution of sodium hydroxide (694 mg, 5.78 mL, 3 molar, 5 Eq, 17.3 mmol) was added to methyl 2-(1-(5-(benzyloxy)-2-bromophenyl)ethyl)-2-cyclohexylacetate (1.6 g, 1 Eq, 3.47 mmol) in MeOH (10 mL) and THF (10 mL) was stirred at 50 °C for 16 hour.100 mL water was added, and the mixture was extracted with dichloromethane (150 mL *2). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4, filtered and concentrated to dryness in vacuum to give a yellow oil. TLC (petroleum ether: ethyl acetate=5:1, UV) showed one main new spot was observed. The yellow oil was purified by flash column (20 g) (petroleum ether/ethyl acetate from 100/0 to 0/100) and the organic layer was concentrated in vacuum to give 2-(1-(5-(benzyloxy)-2-bromophenyl) ethyl)-2-cyclohexylacetic acid (1.2 g, 2.7 mmol, 77 % yield) as a yellow solid. Step 7: To a solution of o,n-dimethyl-hydroxylaminehcl (0.29 g, 1.1 Eq, 3.0 mmol) and 2-(1-(5- (benzyloxy)-2-bromophenyl)ethoxy)-2-cyclohexylacetic acid (1.2 g, 1 Eq, 2.7 mmol) in DCM (15 mL) was added HATU (1.5 g, 1.5 Eq, 4.0 mmol) and Diisopropylethylamine (1 g, 1.4 mL, 3 Eq, 8 mmol). The mixture was stirred at 25 °C for 12 hour. TLC (petroleum ether: ethyl acetate=5:1, R _f =0.5 UV) showed one main new spot was observed. The reaction was quenched with water (100 mL) and extracted with ethyl acetate (150 mL*2). The organic layer was washed with brine (100 mL) and dried over anhydrous Na ₂ SO ₄ and concentrated in vacuum to give a white solid. The white solid was subjected to column chromatography over silica gel (gradient elution: 0 – 30% EtOAc). The desired fractions were collected, and concentrated to dryness in vacuum to give 2-(1-(5-(benzyloxy)-2-bromophenyl)ethoxy)-2-cyclohexyl-N-met hoxy-N- methylacetamide (115 g 234 mmol 87 % yield) as a white solid Step 8: A solution of 2-(1-(5-(benzyloxy)-2-bromophenyl)ethoxy)-2-cyclohexyl-N-met hoxy-N- methylacetamide (1 g, 1 Eq, 2.039 mmol) in THF (15 mL) was stirred at -68 °C for 10 min under N ₂ atmosphere, then added tert-butyllithium (3 mL, 1.3 M, 2 Eq, 4.078 mmol) at -68 °C. The reaction was stirred at -68 °C to 25 °C for 16 hour under N ₂ atmosphere. TLC (petroleum ether: ethyl acetate=5:1, UV) showed one main new spot was observed. The reaction was quenched with saturated aqueous NH ₄ Cl (40 mL) and extracted with ethyl acetate (100 mL*3). The organic layer was washed with brine (100 mL) and dried over anhydrous Na ₂ SO ₄ and concentrated in vacuo to give crude product. The yellow solid was purified by preparative high-performance liquid chromatography. Condition: Column: Welch Xtimate C18150*30mm*5um; A: water (FA); B: ACN; at the beginning: A (20%) and B (80%); at the end: A: (0%) and B (100%); Gradient Time (min) 9; 100% B hold Time (min) 2, Flow Rate (ml/min) 30.The pure fractions were collected and the solvent was evaporated under vacuum. The aqueous layer was lyophilized to dryness to give cis-7-(benzyloxy)-3-cyclohexyl-1-methylisochroman-4-one (300 mg, 856 ^mol, 41.98 % yield) and trans-7-(benzyloxy)-3-cyclohexyl-1-methylisochroman-4-one (170 mg, 485.1 ^mol, 23.79 % yield) as a yellow solid. Step 9: To a solution of 1-bromo-4-iodobenzene (403 mg, 2 Eq, 1.4267 mmol) in THF (8 mL) was added n-butyl lithium (428 ^L, 2.5 M, 1.5 Eq, 1.07 mmol) under -78 °C, after stirred 30 min was added cis-7-(benzyloxy)-3-cyclohexyl-1-methylisochroman-4-one (250 mg, 1 Eq, 713.35 ^mol). The resulting mixture was stirred for -78 °C at 2 hour. Then the mixture was stirred at r.t. for 10 hour. TLC (petroleum ether /ethyl acetate =10/1, R _f =0.4) showed new spot was formed. The reaction mixture was quenched by addition of water (20 mL), extracted with ethyl acetate (40 mL * 2). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (from petroleum ether / ethyl acetate = 1/0 to 3/1, TLC: petroleum ether / ethyl acetate = 10/1, R _f = 0.5) to yield a product.7- (benzyloxy)-4-(4-bromophenyl)-3-cyclohexyl-1-methylisochroma n-4-ol (280 mg, 0.47 mmol, 67 % yield, 86% purity) was obtained as yellow oil. LC-MS (ESI ⁺ ) m/z: 491.2 (M-H ₂ O) ⁺ . Step 10: To a solution of boron trifluorideetherate (105 mg, 93 ^L, 1.5 Eq, 738.96 ^mol) and triethylsilane (115 mg, 157 ^L, 2 Eq, 985.28 ^mol) was added to a mixture suspension of 7- (benzyloxy)-4-(4-bromophenyl)-3-cyclohexyl-1-methylisochroma n-4-ol (250 mg, 1 Eq, 492.64 ^mol) in DCM (5 mL) at 0 °C The mixture was stirred at 0 °C for 2 hour TLC (petroleum ether: ethyl acetate=5:1, UV) showed one main new spot was observed.50 mL water was added, and the mixture was extracted with dichloromethane (100 mL *2). The reaction was concentrated to dryness in vacuum to give a yellow oil. The yellow oil was purified by flash column (petroleum ether/ethyl acetate from 100/0 to 0/100) and the organic layer was concentrated in vacuum to give 7-(benzyloxy)-4-(4-bromophenyl)-3-cyclohexyl-1-methylisochro mane (220 mg, 447.6 ^mol, 90.86 % purity) as a yellow solid. Step 11: A mixture of 7-(benzyloxy)-4-(4-bromophenyl)-3-cyclohexyl-1-methylisochro mane (220 mg, 1 Eq, 447.6 ^mol), 4-(dimethoxymethyl)piperidine (107 mg, 126 ^L, 1.5 Eq, 671.5 ^mol), palladium(II) acetate (15 mg, 0.15 Eq, 67.15 ^mol), dicyclohexyl(2',4',6'-triisopropyl- [1,1'-biphenyl]-2-yl)phosphane (43 mg, 0.2 Eq, 89.53 ^mol), and sodium 2-methylpropan-2- olate (64 mg, 1.5 Eq, 671.5 ^mol) in toluene (5 mL) was heated to 90 °C stirred for 16 hour. TLC (petroleum ether: ethyl acetate=10:1, UV) showed one main new spot was observed.50 mL water was added, and the mixture was extracted with dichloromethane (100 mL *2). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to dryness in vacuum to give a yellow oil. The residue was purified by silica gel chromatography, 24 g column, and eluted with 0-50 % EtOAc. The selected fractions were combined and concentrated in vacuum to give 1-(4-(7-(benzyloxy)-3-cyclohexyl-1- methylisochroman-4-yl)phenyl)-4-(dimethoxymethyl) piper dine (170 mg, 298 ^mol, 66.7 % yield , 100% purity) as a white solid. Step 12: To a solution of 1-(4-(7-(benzyloxy)-3-cyclohexyl-1-methylisochroman-4-yl)phe nyl)-4- (dimethoxymethyl)piperidine (170 mg, 1 Eq, 298.4 ^mol) in MeOH (3 mL) and THF (3 mL)was added Pd/C (170 mg, 10% Wt., 0.535 Eq, 160 ^mol) under N ₂ atmosphere. The suspension was degassed and purged with H ₂ (15psi) for 3 mines. The mixture was stirred under H ₂ (15 Psi) at r.t. for 16 hr. The reaction was filtered and concentrated under reduced pressure to give a residue. The residue was concentrated under reduced pressure to give desired compound as a yellow oil, which was further separated by SFC (condition: column: Welch Xtimate C18 150*25mm*5um ); mobile phase: water( NH ₄ HCO ₃ )-ACN ; B%: 85%-100%) to give (1S,3R,4R)-3-cyclohexyl-4-(4-(4-(dimethoxymethyl)piperidin-1 -yl)phenyl)-1- methylisochroman-7-ol (50.0 mg, 104 ^mol, 34.9 % yield, racemate) and (1S,3R,4S)-3- cyclohexyl-4-(4-(4-(dimethoxymethyl)piperidin-1-yl)phenyl)-1 -methylisochroman-7-ol (30.0 mg 625 ^mol 210 % yield racemate) and (1S 3S 4R)-3-cyclohexyl-4-(4-(4- (dimethoxymethyl)piperidin-1-yl)phenyl)-1-methylisochroman-7 -ol (20 mg, 41.7 ^mol, 14 % yield, racemate) as a white solid. LC-MS (ESI ⁺ ) m/z: 480.3 (M+H) ⁺ . Step 13: The mixture from step 12 was concentrated under reduced pressure to give desired compound as a yellow oil, which was further separated by SFC (condition: column: DAICEL CHIRALPAK AD(250mm*30mm,10um)); mobile phase: CO ₂ -i-PrOH(0.1%NH ₃ H ₂ O ; B%: 40%-40%) to give (1*S,3*R,4*R)-3-cyclohexyl-4-(4-(4-(dimethoxymethyl)piperidi n-1- yl)phenyl)-1-methylisochroman-7-ol (23 mg, 48 ^mol, 46 % yield) and (1*R,3*S,4*S)-3- cyclohexyl-4-(4-(4-(dimethoxymethyl)piperidin-1-yl)phenyl)-1 -methylisochroman-7-ol (22 mg, 45.9 ^mol, 44.0 % yield) and as a white solid. Step 14: 1-(4-((1*S,3*R,4*R)-3-cyclohexyl-7-hydroxy-1-methylisochroma n-4- yl)phenyl)piperidine-4-carbaldehyde (18 mg, 40.4 ^mol, 96.8 % purity) in sulfuric acid (41 mg, 2 mL, 10% V/V, 1 Eq, 41.7 ^mol) and THF (2 mL) was stirred at 70 °C for 2 hour. The reaction was adjust to pH=~7 with NaHCO ₃ , then 20 mL water was added, and the mixture was extracted with dichloromethane (20 mL *2). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4, filtered and concentrated to dryness in vacuum to give a yellow oil. The yellow oil was concentrated in vacuum to give 1-(4-((1*S, 3*R, 4*R)-3- cyclohexyl-7-hydroxy-1-methylisochroman-4-yl) phenyl) piperidine-4-carbaldehyde (17.5 mg, 40.4 ^mol, 96.8 % yield) as a yellow solid. LC-MS (ESI ⁺ ) m/z: 452.4 (M+H ₂ O) Step 15: To a solution of 1-(4-((1*S,3*R,4*R)-3-cyclohexyl-7-hydroxy-1-methylisochroma n-4- yl)phenyl)piperidine-4-carbaldehyde (17 mg, 90% purity, 1 Eq, 35.3 ^mol), (S)-3-(1-oxo-5- (piperazin-1-yl)isoindolin-2-yl)piperidine-2,6-dione (14 mg, 1.1 Eq, 38.8 ^mol, HCl salt) in DCM (2 mL), MeOH (2 mL) was added sodium acetate (9 mg, 3 Eq, 106 ^mol) was stirred at r.t. for 1 h, Then sodium triacetoxyhydroborate (15 mg, 2 Eq, 70.6 ^mol) and acetic acid (6 mg, 6 ^L, 3 Eq, 106 ^mol) was added .The mixture was stirred at 25 °C for 15 hour. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was purified by prep-HPLC (column: Welch Xtimate C18100*40mm*3um phase: [water(FA)-ACN];B%: 20%- 60%,9 min to give (S)-3-(5-(4-((1-(4-((1*S,3*R,4*R)-3-cyclohexyl-7-hydroxy-1- methylisochroman-4-yl)phenyl)piperidin-4-yl)methyl)piperazin -1-yl)-1-oxoisoindolin-2- yl)piperidine-2,6-dione (19.1 mg, 25.6 ^mol, 72.6 % yield, 100% purity) as a white solid. LCMS l f C H N O 74542 f d [M+H] ⁺ 7465 HPLC: 100% purity at 220 nm. ¹ H NMR (400MHz, DMSO-d ₆ ) į 10.94 - 11.00 (m, 1 H) 9.16 - 9.24 (m, 1 H) 8.15 (s, 0.310 H) 7.53 (d, J=8.78 Hz, 1 H) 7.03 - 7.13 (m, 4 H) 6.70 - 6.81 (m, 3 H) 6.47 - 6.56 (m, 2 H) 5.06 (dd, J=13.30, 5.27 Hz, 1 H) 4.72 (q, J=6.19 Hz, 1 H) 4.28 - 4.38 (m, 1 H) 4.18 - 4.25 (m, 1 H) 3.75 (br s, 1 H) 3.56 - 3.66 (m, 2 H) 3.25 - 3.34 (m, 7 H) 2.82 - 3.05 (m, 1 H) 2.54 - 2.63 (m, 4 H) 2.30 - 2.48 (m, 2 H) 2.18 - 2.27 (m, 2 H) 1.95 - 2.06 (m, 2 H) 1.80 (br d, J=11.04 Hz, 3 H) 1.58 - 1.70 (m, 3 H) 1.51 - 1.57 (m, 4 H) 1.15 - 1.22 (m, 2 H) 1.05 - 1.12 (m, 1 H) 0.86 - 1.03 (m, 5 H). EXAMPLE 111. Preparation of (I-255) (S)-3-(5-(4-((1-(4-((1R,3R,4S)-3-cyclohexyl-7- hydroxy-1-methylisochroman-4-yl)phenyl)piperidin-4-yl)methyl )piperazin-1-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione Step 1: A solution of 1-(4-((1R,3R,4S)-3-cyclohexyl-7-hydroxy-1-methylisochroman-4 - yl)phenyl)piperidine-4-carbaldehyde (8 mg, 0.02 mmol, 87% purity) in 10% H ₂ SO ₄ (0.02 g, 1 mL, 1 Eq, 0.02 mmol) and THF (1 mL) was stirred at 70 °C for 2 hour. The reaction was adjust to pH=7 with saturated aqueous NaHCO3, then 50 mL water was added, and the mixture was extracted with dichloromethane (100 mL*2). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to dryness in vacuo to give a yellow oil. The yellow oil was concentrated in vacuo to give 1-(4-((1R, 3R, 4S)-3- cyclohexyl-7-hydroxy-1-methylisochroman-4-yl) phenyl) piperidine-4-carbaldehyde (8 mg, 0.02 mmol, 90 % yield, 87% purity) as a yellow solid. Step 2: To a solution of 1-(4-((1R,3R,4S)-3-cyclohexyl-7-hydroxy-1-methylisochroman-4 - yl)phenyl)piperidine-4-carbaldehyde (8 mg, 87% purity, 1 Eq, 0.02 mmol), (S)-3-(1-oxo-5- (piperazin-1-yl)isoindolin-2-yl)piperidine-2,6-dione (6 mg, 1.1 Eq, 0.02 mmol, HCl salt) in DCM (1 mL), MeOH (1 mL) was added sodium acetate (4 mg, 3 Eq, 0.05 mmol) was stirred at 25 °C for 1h, Then sodium triacetoxyhydroborate (7 mg, 2 Eq, 0.03 mmol) and acetic acid (3 mg, 3 ^L, 3 Eq, 0.05 mmol) was added. The mixture was stirred at 25 °C for 16 hours. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was purified by prep-HPLC (column: Welch Xtimate C18150*30mm*5um phase: [water(FA)- ACN];B%: 10%-50%,9 min to give (S)-3-(5-(4-((1-(4-((1R,3R,4S)-3-cyclohexyl-7-hydroxy-1- methylisochroman-4-yl)phenyl)piperidin-4-yl)methyl)piperazin -1-yl)-1-oxoisoindolin-2- yl)piperidine-2,6-dione (2.7 mg, 3.6 ^mol, 20 % yield , 100% purity) as a white solid. LCMS: calc. for C ₄₅ H ₅₅ N ₅ O ₅ : 745.42, found: [M+H] ⁺ 746.5 HPLC: 100 % purity at 220 nm. NMR (400MHz, DMSO-d ₆ ) į 8.37 - 8.52 (m, 0.298 H) 7.67 (d, J=8.46 Hz, 1 H) 7.09 - 7.15 (m, 2 H) 6.95 - 7.03 (m, 4 H) 6.56 - 6.61 (m, 1 H) 6.49 - 6.54 (m, 2 H) 5.08 - 5.16 (m, 1 H) 4.59 - 4.69 (m, 1 H) 4.36 - 4.49 (m, 2 H) 3.93 (d, J=7.75 Hz, 1 H) 3.65 - 3.73 (m, 3 H) 3.39 - 3.46 (m, 4 H) 2.88 - 2.97 (m, 1 H) 2.70 - 2.79 (m, 6 H) 2.40 - 2.54 (m, 3 H) 2.16 - 2.24 (m, 1 H) 1.91 - 1.99 (m, 3 H) 1.70 - 1.85 (m, 3 H) 1.64 (br d, J=1.07 Hz, 1 H) 1.57 (d, J=6.56 Hz, 3 H) 1.29 - 1.50 (m, 8 H) 1.09 - 1.24 (m, 4 H). The absolute stereochemistry was arbitrarily assigned. EXAMPLE 112. Preparation of (I-364) (S)-3-(5-(4-((1-(4-((3R,4S)-3-(bicyclo[4.2.0]octa- 1(6),2,4-trien-3-yl)-7-hydroxyisochroman-4-yl)phenyl)piperid in-4-yl)methyl)piperazin-1- yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione Step 1: To a solution of (3R,4S)-3-(bicyclo[4.2.0]octa-1(6),2,4-trien-3-yl)-4-(4-(4- (dimethoxymethyl)piperidin-1-yl)phenyl)isochroman-7-ol (54 mg, purity 100%, 1 Eq, 0.11 mmol) in THF (5 mL) was added 10% sulfuric acid (5 mL,) at 0°C. The mixture was stirred at 70 °C for 40 min. The mixture was adjusted to pH=~8 by adding saturated aq.NaHCO ₃ (10 mL) at 0°C for 10 min. The reaction mixture was diluted with 50 mL H ₂ O and extracted with 50 mL ethyl acetate. The organic layers were washed with 30 mL brine and dried over anhydrous Na ₂ SO ₄ . The organic layers were filtered and concentrated under reduced pressure to give crude product 1-(4-((3R,4S)-3-(bicyclo[4.2.0]octa-1(6),2,4-trien-3-yl)-7-h ydroxyisochroman-4- yl)phenyl)piperidine-4-carbaldehyde (44 mg, 99 ^mol, 89 % yield, 99.2% purity) as a brown oil. LC-MS (ESI+) m/z: 440.1. Step 2: A mixture of 1-(4-((3R,4S)-3-(bicyclo[4.2.0]octa-1(6),2,4-trien-3-yl)-7- hydroxyisochroman-4-yl)phenyl)piperidine-4-carbaldehyde (65 mg, 99.2% purity, 1 Eq, 0.15 mmol), (S)-3-(1-oxo-5-(piperazin-1-yl)isoindolin-2-yl)piperidine-2, 6-dione hydrochloride (54 mg, 1 Eq, 0.15 mmol) and sodium acetate (60 mg, 5 Eq, 0.73 mmol) were added in DCM (2 mL) and sodium triacetoxyborohydride (62 mg, 2 Eq, 0.29 mmol, then the mixture was stirred at 25 °C for 16 hour. The reaction was diluted with water (50 mL) and extracted with ethyl acetate (50 mL*2). The combined organic layers were concentrated to give crude product as a brown oil. The brown oil was purified by preparative high-performance liquid chromatography. Condition: water (FA)-ACN. Column: Welch Xtimate C18150*30mm*5um. Begin B: 20%, End B: 50%. Gradient time (min) 7; 100% B hold time (min) 1.7, Flow rate (ml/min) 25. The aqueous layer was lyophilized to dryness to give (S)-3-(5-(4-((1-(4-((3R,4S)-3-(bicyclo[4.2.0]octa-1(6),2,4- trien-3-yl)-7-hydroxyisochroman-4-yl)phenyl)piperidin-4-yl)m ethyl)piperazin-1-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione (23.6 mg, 30.9 ^mol, 21 % yield, 98.45% purity) as a white solid. LCMS: calc. for C ₄₆ H ₄₉ N ₅ O ₅ : 751.37, found: [M+H] ⁺ 752.3. HPLC: 98.46% purity at 220 nm. = 10.92 (s, 1H), 9.24 (s, 1H), 8.13 (s, 0.278H), 7.51 (d, J = 8.3 Hz, 1H), 7.08 - 7.02 (m, 2H), 6.92 - 6.88 (m, 1H), 6.85 - 6.81 (m, 1H), 6.79 - 6.73 (m, 2H), 6.66 - 6.62 (m, 2H), 6.60 - 6.52 (m, 4H), 5.08 - 5.01 (m, 2H), 4.95 - 4.85 (m, 2H), 4.36 - 4.29 (m, 1H), 4.24 - 4.17 (m, 1H), 3.98 (br d, J = 1.9 Hz, 1H), 3.52 (br d, J = 11.6 Hz, 2H), 3.29 - 3.23 (m, 4H), 3.04 - 2.85 (m, 5H), 2.58 (br d, J = 17.6 Hz, 4H), 2.48 - 2.44 (m, 2H), 2.44 - 2.30 (m, 2H), 2.20 (br d, J = 1.1 Hz, 2H), 2.00 - 1.92 (m, 1H), 1.75 (br d, J = 12.3 Hz, 2H), 1.69 - 1.60 (m, 1H), 1.21 - 1.09 (m, 2H).

EXAMPLE 113. Preparation of (I-252) (S)-3-(5-(4-((1-(4-((1S,3R,4S)-3-cyclohexyl-7- hydroxy-1-methylisochroman-4-yl)phenyl)piperidin-4-yl)methyl )piperazin-1-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione Step 1: 17 was further separated by SFC (condition: column: DAICEL CHIRALPAK AD (250mm*30mm, 10um) ); mobile phase: CO ₂ -EtOH (0.1%NH ₃ H ₂ O); B%: 30%-30%) to give (1S,3R,4S)-3-cyclohexyl-4-(4-(4-(dimethoxymethyl)piperidin-1 -yl)phenyl)-1- methylisochroman-7-ol (12 mg, 25 ^mol, 40 % yield) and (1R,3S,4R)-3-cyclohexyl-4-(4-(4- (dimethoxymethyl)piperidin-1-yl)phenyl)-1-methylisochroman-7 -ol (13 mg, 27.1 ^mol, 43.3 % yield) and as a white solid. Step 2: A solution of 1-(4-((1S,3R,4S)-3-cyclohexyl-7-hydroxy-1-methylisochroman-4 - yl)phenyl)piperidine-4-carbaldehyde (9 mg, 0.02 mmol, 100 %) in 10% H ₂ SO ₄ (2 mL) and THF (2 mL) was stirred at 70 °C for 2 hour. The reaction was adjust to pH=7 with saturated aqueous NaHCO3, then 50 mL water was added, and the mixture was extracted with dichloromethane (100 mL*2). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to dryness in vacuo to give a yellow oil. The yellow oil was concentrated in vacuo to give 1-(4-((1S, 3R, 4S)-3-cyclohexyl-7-hydroxy-1- methylisochroman-4-yl) phenyl) piperidine-4-carbaldehyde (9 mg, 0.02 mmol, 100 % yield) as a yellow solid. LC-MS (ESI ⁺ ) m/z: 434.3 (M+H) ⁺ . Step 3: To a solution of 1-(4-((1S,3R,4S)-3-cyclohexyl-7-hydroxy-1-methylisochroman-4 - yl)phenyl)piperidine-4-carbaldehyde (9 mg, 100% purity, 1 Eq, 0.02 mmol), (S)-3-(1-oxo-5- (piperazin-1-yl)isoindolin-2-yl)piperidine-2,6-dione HCl salt (8 mg, 1.1 Eq, 0.02 mmol) in DCM (1 mL), MeOH (1 mL) was added sodium acetate (5 mg, 3 Eq, 0.06 mmol) was stirred at 25 °C for 1h, Then sodium triacetoxyhydroborate (9 mg, 2 Eq, 0.04 mmol) and acetic acid (4 mg, 4 ^L, 3 Eq, 0.06 mmol) was added .The mixture was stirred at 25 °C for 15 hour. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was purified by prep- HPLC (column: Welch Xtimate C18150*30mm*5um phase: [water(FA)-ACN];B%: 15%- 55%,9 min to give (S)-3-(5-(4-((1-(4-((1S,3R,4S)-3-cyclohexyl-7-hydroxy-1-meth ylisochroman- 4-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoin dolin-2-yl)piperidine-2,6-dione (2.1 mg, 2.6 ^mol, 10 % yield, 91.9% purity) as a white solid. LCMS: calc. for C ₄₅ H ₅₅ N ₅ O ₅ : 745.42, found: [M+H] ⁺ 746.5 HPLC: 91.9% purity at 220 nm. ¹ H NMR (400MHz, DMSO-d ₆ ) į 10.94 - 11.00 (m, 1 H) 9.16 - 9.24 (m, 1 H) 8.15 (s, 0.310 H) 7.53 (d, J=8.78 Hz, 1 H) 7.03 - 7.13 (m, 4 H) 6.70 - 6.81 (m, 3 H) 6.47 - 6.56 (m, 2 H) 5.06 (dd, J=13.30, 5.27 Hz, 1 H) 4.72 (q, J=6.19 Hz, 1 H) 4.28 - 4.38 (m, 1 H) 4.18 - 4.25 (m, 1 H) 3.75 (br s, 1 H) 3.56 - 3.66 (m, 2 H) 3.25 - 3.34 (m, 7 H) 2.82 - 3.05 (m, 1 H) 2.54 - 2.63 (m, 4 H) 2.30 - 2.48 (m, 2 H) 2.18 - 2.27 (m, 2 H) 1.95 - 2.06 (m, 2 H) 1.80 (br d, J=11.04 Hz, 3 H) 1.58 - 1.70 (m, 3 H) 1.51 - 1.57 (m, 4 H) 1.15 - 1.22 (m, 2 H) 1.05 - 1.12 (m, 1 H) 0.86 - 1.03 (m, 5 H). The absolute stereochemistry was arbitrarily assigned. EXAMPLE 114. Preparation of (I-389) (R)-3-(4-(2-((1-(4-((3S,4R)-7-hydroxy-3- phenylisochroman-4-yl)phenyl)piperidin-4-yl)methyl)-2,8-diaz aspiro[4.5]decan-8- yl)phenyl)piperidine-2,6-dione and (I-390) (S)-3-(4-(2-((1-(4-((3S,4R)-7-hydroxy-3- phenylisochroman-4-yl)phenyl)piperidin-4-yl)methyl)-2,8-diaz aspiro[4.5]decan-8- yl)phenyl)piperidine-2,6-dione Step 1: To a solution of compound 1 (900.00 mg, 3.74 mmol, 2 eq.) in dioxane (15 mL) was added compound 2 (502 mg, 1.87 mmol, 1 eq.), Cs ₂ CO ₃ (1.22 g, 3.74 mmol, 2 eq) and 5% Pd- PEPPSI-IHeptCl (182.00 mg, 187 ^mol, 0.1 eq). The mixture was stirred at 90°C under N ₂ for 2hr. LCMS showed the desired ms was found. The mixture was concentrated to give a residue, which was purified by flash silica gel chromatography eluting with EtOAc in PE from 0% to 100% to give compound 3 (440.00 mg, 83.80% purity) as a yellow solid. Step 2: To a solution of compound 3 (440.00 mg, 1.03 mmol, 1 eq.) in DCM (20 mL) was added HCl/EA (2.57 mL, 10.3 mmol, 10 eq.). The mixture was stirred at 20 °C for 1 hr. LCMS showed the desired ms was found. After completion, the mixture was concentrated under reduced pressure to give compound 4 (450.00 mg, crude) as a yellow solid without purification. LC-MS (ESI ⁺ ) m/z: 328.1 (M+H) ⁺ . Step 3: To a solution of compound 4 (215.00 mg, 655.00 ^mol, 1 eq.) in DCE (10 mL) and MeOH (5 mL) was added compound 5 (135.00 mg, 327.00 ^mol, 0.5 eq.) and NaBH(OAc) ₃ (1.66 g, 7.86 mmol, 12 eq.). The mixture was stirred at 20 °C for 1 hr. The mixture was purified by Prep-HPLC (Column: Boston Green ODS 150 ^ 30mm ^ 5um; Condition water (FA)-CAN, B%: 10%-40%, 12 min) to give compound 6 (110.00 mg, 20.5% yield, 88.34% purity) as a yellow solid. LC-MS (ESI ⁺ ) m/z: 723.4 (M+H) ⁺ . Step 4: Compound 6 (110.00 mg, 152.00 ^mol, 1 eq.) was separated by chiral SFC (column: DAICEL CHIRALPAK IE 250 mm ^ 30 mm, 10 ^m); mobile phase: [MeOH-ACN]; B%: 50%- 50%; Flow Rate: 80 ml/min; peak 1:2.980 min; peak 2: 6.878 min) to yield peak 1 and peak 2. Peak 1 was concentrated under reduced pressure to yield compound I-389 (34.1 mg, 47.0 ^mol, 31.0 % yield, 100% purity) as a white solid. LC-MS (ESI ⁺ ) m/z: 725.4 (M+H) ⁺ . LCMS: calc. C ₄₆ H ₅₂ N ₄ O ₄ for: 724.95, found: [M+H] ⁺ 725.4. HPLC: 100% purity at 220 nm. ¹ H NMR: 1H NMR (400 MHz, DMSO-d6) į = 10.76 (s, 1H), 9.28 (s, 1H), 7.15 - 7.11 (m, 2H), 7.08 (br d, J = 6.8 Hz, 1H), 7.06 - 7.01 (m, 4H), 6.87 (d, J = 8.8 Hz, 2H), 6.77 (d, J = 8.1 Hz, 1H), 6.61 - 6.58 (m, 2H), 6.56 - 6.52 (m, 4H), 5.09 - 4.99 (m, 2H), 4.90 (br d, J = 15.3 Hz, 1H), 4.02 (d, J = 3.1 Hz, 1H), 3.73 - 3.68 (m, 1H), 3.47 (br d, J = 11.5 Hz, 2H), 3.13 - 3.05 (m, 4H), 2.64 - 2.57 (m, 1H), 2.47 - 2.42 (m, 4H), 2.32 (s, 2H), 2.21 (br d, J = 7.0 Hz, 2H), 2.13 - 2.07 (m, 1H), 2.02 - 1.97 (m, 1H), 1.77 - 1.71 (m, 2H), 1.61 - 1.54 (m, 6H), 1.50 - 1.45 (m, 1H), 1.24 - 1.05 (m, 3H). Peak 2 was concentrated under reduced pressure to yield compound I-390 (41.3 mg, 57.0 ^mol, 37.5 % yield, 100% purity) as a white solid. LC-MS (ESI ⁺ ) m/z: 725.4 (M+H) ⁺ . LCMS: calc. C ₄₆ H ₅₂ N ₄ O ₄ for: 724.95, found: [M+H] ⁺ 725.4. HPLC: 100% purity at 220 nm. ¹ H NMR: 1H NMR (400 MHz, DMSO-d6) į = 10.79 - 10.72 (m, 1H), 9.35 - 9.26 (m, 1H), 7.15 - 7.11 (m, 2H), 7.09 (br d, J = 6.8 Hz, 1H), 7.07 - 7.01 (m, 4H), 6.87 (d, J = 8.7 Hz, 2H), 6.77 (d, J = 7.9 Hz, 1H), 6.62 - 6.58 (m, 2H), 6.57 - 6.52 (m, 4H), 5.09 - 4.99 (m, 2H), 4.90 (br d, J = 15.3 Hz, 1H), 4.02 (d, J = 2.7 Hz, 1H), 3.73 - 3.68 (m, 1H), 3.47 (br d, J = 12.5 Hz, 2H), 3.15 - 3.05 (m, 4H), 2.65 - 2.58 (m, 1H), 2.48 - 2.41 (m, 4H), 2.31 (s, 2H), 2.21 (br d, J = 7.1 Hz, 2H), 2.13 - 2.06 (m, 1H), 2.02 - 1.96 (m, 1H), 1.77 - 1.70 (m, 2H), 1.61 - 1.53 (m, 6H), 1.51 - 1.45 (m, 1H), 1.24 - 0.97 (m, 3H). EXAMPLE 115. Preparation of (I-357) (S)-3-(5-(4-((1-(4-((3S,4R)-3-(5-fluoro-2- methylphenyl)-7-hydroxyisochroman-4-yl)phenyl)piperidin-4-yl )methyl)piperazin-1-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione and (I-358) (S)-3-(5-(4-((1-(4-((3R,4S)-3-(5-fluoro-2-

methylphenyl)-7-hydroxyisochroman-4-yl)phenyl)piperidin-4 -yl)methyl)piperazin-1-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione Step 1: To a solution of compound 1 (90 mg, 178.78 ^mol, 1 eq.), compound 2 (31.31 mg, 196.66 ^mol, 1.1 eq.), Cs ₂ CO ₃ (116.50 mg, 357.57 ^mol, 2 eq.) and RuPhos Pd G3 (14.95 mg, 17.88 ^mol, 0.1 eq.) in Dioxane (2 mL) was bubbled with N ₂ for 1 min. Then the mixture was stirred at 90 °C for 5 hours. LCMS showed the starting material was consumed completely and a major peak with desired MS was detected The reaction mixture was concentrated to get a residue. The residue was purified by prep-TLC (SiO2, Petroleum ether/Ethyl acetate=3/1) to give compound 2 (80 mg, 53.85% yield) as a white solid. LC-MS (ESI ⁺ ) m/z: 582.3 (M+H) ⁺ . ¹ H NMR (400 MHz, DMSO-d6) į = 7.49 - 7.31 (m, 5H), 7.15 - 7.07 (m, 1H), 6.95 - 6.77 (m, 4H), 6.61 - 6.48 (m, 4H), 6.36 - 6.29 (m, 1H), 5.17 - 5.04 (m, 4H), 4.18 - 3.95 (m, 3H), 3.56 - 3.47 (m, 2H), 3.24 (s, 6H), 2.48 - 2.40 (m, 2H), 2.38 - 2.31 (m, 3H), 1.70 - 1.57 (m, 3H), 1.31 - 1.20 (m, 2H) Step 2: To a solution of compound 3 (80 mg, 137.52 ^mol, 1 eq.) in EA (10 mL) was added Pd/C (146.35 mg, 137.52 ^mol, 10% purity, 1 eq.) under N ₂ atmosphere. The suspension was degassed and purged with H ₂ for 3 times. The mixture was stirred under H ₂ (15 Psi) at 20 °C for 3hr. LCMS showed the starting material was consumed completely and a major peak with desired MS was detected. The resulting solution was filtrated and concentrated to give a crude. The residue was purified by prep-HPLC (column: Boston Green ODS 150*30mm*5um; mobile phase: [water (FA)-ACN]; gradient: 17%-47% B over 12 min) to give compound 4 (50 mg, 62.86% yield) as a white solid. LC-MS (ESI ⁺ ) m/z:^492.2 (M+H) ⁺ . Step 3: The compound 4 (50 mg, 101.71 ^mol, 1 eq.) was purified by prep-SFC (column: DAICEL CHIRALPAK AD (250mm*30mm, 10um); mobile phase: [CO ₂ -EtOH (0.1%NH ₃ H ₂ O)]; B%:30%%, isocratic elution mode) to give compound 5 (15 mg, 30.00% yield) as a white solid and compound 5A (13 mg, 26.00% yield) as a white solid. Compound 5: LC-MS (ESI ⁺ ) m/z:^492.2 (M+H) ⁺ . Compound 5A: LC-MS (ESI ⁺ ) m/z:^492.2 (M+H) ⁺ . Step 4: To a solution of compound 5 (15 mg, 31 ^mol, 1 eq.) in DCM (3 mL) was added TFA (1 mL) at 20 °C. The mixture was stirred at 20 °C for 2 hour. LCMS showed the starting material was consumed completely and a major peak with desired MS was detected. Water (10 ml) and aq. NaHCO ₃ (10x 2mL) was added and the mixture was extracted with DCM (15 ml x 3). The organics were washed with brine (15 ml), dried over Na2SO4, filtered and concentrated to LC-MS (ESI ⁺ ) m/z:^446.3 (M+H) ⁺ . Step 5: To a solution of compound 5A (13 mg, 26 ^mol, 1 eq.) in DCM (3 mL) was added TFA (1 mL) at 20 °C. The mixture was stirred at 20 °C for 2 hour. LCMS showed the starting material was consumed completely and a major peak with desired MS was detected. Water (10 ml) and aq. NaHCO ₃ (10x 2mL) was added and the mixture was extracted with DCM (15 ml x 3). The organics were washed with brine (15 ml), dried over Na ₂ SO ₄ , filtered and concentrated to give compound 6A (10 mg, 83 % yield) as a yellow solid. LC-MS (ESI ⁺ ) m/z:^446.3 (M+H) ⁺ . Step 6: To a solution of compound 6 (13 mg, 29 ^mol, 1 eq.) and compound 7 (11 mg, 32 ^mol, 1.1 eq.) in DCE (4 mL) and MeOH (1 mL) was added NaBH(OAc) ₃ (31 mg, 0.15 mmol, 5 eq.) at 20 °C. Then the mixture was stirred at 20 °C for 2 hours. LCMS showed the starting material was consumed completely and a major peak with desired MS was detected. The reaction mixture was concentrated to get the crude, which was purified by prep-HPLC (column: Boston Green ODS 150*30mm*5um; mobile phase: water (FA)-ACN; gradient: 15%-45% B over 12 min) to give (S)-3-(5-(4-((1-(4-((3S,4R)-3-(5-fluoro-2-methylphenyl)-7- hydroxyisochroman-4-yl)phenyl)piperidin-4-yl)methyl)piperazi n-1-yl)-1-oxoisoindolin-2- yl)piperidine-2,6-dione (8.4 mg, 38 % yield) as a white solid. LC-MS (ESI ⁺ ) m/z: 758.4 (M+H) ⁺ . LCMS: calc. for C ₄₅ H ₄₈ FN ₅ O ₅ : 757.36, found: [M+H] ⁺ 758.4. HPLC: 100.00% purity at 220 nm ¹ H NMR (400 MHz, DMSO-d6) į = 10.69 (s, 1H), 9.05 (br s, 1H), 7.64 - 7.57 (m, 1H), 7.38 - 7.21 (m, 1H), 7.13 - 7.09 (m, 2H), 6.82 - 6.76 (m, 2H), 6.62 - 6.54 (m, 6H), 6.42 - 6.34 (m, 1H), 5.09 - 4.93 (m, 4H), 4.39 - 4.25 (m, 2H), 4.04 (d, J = 2.9 Hz, 2H), 3.53 (br d, J = 12.4 Hz, 3H), 3.37 - 3.19 (m, 4H), 2.95 - 2.82 (m, 2H), 2.71 - 2.55 (m, 4H), 2.49 - 2.26 (m, 6H), 2.04 - 1.78 (m, 4H), 1.35 - 1.20 (m, 2H) Step 7: To a solution compound 6A (10 mg, 22 ^mol, 1 eq.) and compound 7A (8.1 mg, 25 ^mol, 1.1 eq.) in DCE (4 mL) and MeOH (1 mL) was added NaBH(OAc)3 (24 mg, 0.11 mmol, 5 material was consumed completely and a major peak with desired MS was detected. The mixture was concentrated to get the crude, which was purified by prep-HPLC (column: Boston Green ODS 150*30mm*5um; mobile phase: water (FA)-ACN; gradient: 15%-45% B over 12 min) to give (S)-3-(5-(4-((1-(4-((3R,4S)-3-(5-fluoro-2-methylphenyl)-7-hy droxyisochroman-4- yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindo lin-2-yl)piperidine-2,6-dione (8.3 mg, 49 % yield) as a white solid. LC-MS (ESI ⁺ ) m/z: 758.4 (M+H) ⁺ . LCMS: calc. for C ₄₅ H ₄₈ FN ₅ O ₅ : 757.36, found: [M+H] ⁺ 758.4. HPLC: 100.00% purity at 220 nm ¹ H NMR (400 MHz, DMSO-d6) į = 10.69 (br s, 1H), 9.05 (br s, 1H), 7.64 - 7.56 (m, 1H), 7.37 - 7.21 (m, 1H), 7.12 - 7.09 (m, 2H), 6.82 - 6.75 (m, 2H), 6.61 - 6.53 (m, 6H), 6.42 - 6.33 (m, 1H), 5.14 - 4.89 (m, 4H), 4.40 - 4.20 (m, 2H), 4.04 (d, J = 2.5 Hz, 2H), 3.60 - 3.46 (m, 3H), 3.37 - 3.15 (m, 4H), 2.97 - 2.82 (m,2H), 2.71 - 2.55 (m, 4H), 2.35 (s, 5H), 2.03 - 1.75 (m, 4H), 1.34 - 1.16 (m, 2H). EXAMPLE 116. Preparation of (I-387) (S)-3-(5-(4-((1-(4-((3S,4R)-7-hydroxy-3- phenylisochroman-4-yl)phenyl)piperidin-4-yl)methyl)piperazin -1-yl)-3-methyl-2-oxo-2,3- dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione and (I-388) (R)-3-(5-(4-((1-(4- ((3S,4R)-7-hydroxy-3-phenylisochroman-4-yl)phenyl)piperidin- 4-yl)methyl)piperazin-1-yl)- 3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidi ne-2,6-dione To a solution of compound 1 (140 mg, 1 eq, 339 ^mol) in DCE (10 mL) and MeOH (1 mL) was added compound 2 (116 mg, 1 eq, 339 ^mol) and stirred at 20 °C for 10 min. Then sodium triacetoxyhydroborate (215 mg, 3 eq, 1.02 mmol) was added and stirred at 20 °C for 10 min. The solvent was removed to yield a residue. The residue was purified by preparative HPLC (column: Phenomenex Gemini NX 150×30mm,5^m;mobile phase: [water( NH ₄ HCO ₃ )-ACN]; gradient: 45%-75% B over 11 min), followed by lyophilization to yield a residue which was separated by chiral SFC (column: DAICEL CHIRALPAK ID (250mm*30mm,10um); mobile phase: [MeOH- ACN] B:50%, isocratic elution mode, peak 1: 2.324 min, peak 2: 3.447 min) to yield Peak 1 and Peak 2. Peak 1 was concentrated under reduced pressure to give the product of I-387 (25.5 mg, 36% yield, SFC: R _t = 2.303) as a white solid. LC-MS (ESI ⁺ ) m/z: 741.3 (M+H) ⁺ . LCMS: calc. for C ₄₄ H ₄₈ N ₆ O ₅ : 740.91, found: [M+H] ⁺ 741.3. HPLC: 100.0% purity at 254 nm. ¹ HNMR (500MHz, DMSO-d6): į 11.05 (s, 1H), 9.28 (s, 1H), 7.20 - 7.01 (m, 5H), 6.93 (d, J = 8.5 Hz, 1H), 6.83 (d, J = 2.1 Hz, 1H), 6.78 (d, J = 8.1 Hz, 1H), 6.66 - 6.58 (m, 3H), 6.58 - 6.50 (m, 4H), 5.28 (dd, J = 5.4, 12.9 Hz, 1H), 5.07 (d, J = 15.6 Hz, 1H), 5.00 (d, J = 3.1 Hz, 1H), 4.90 (d, J = 15.3 Hz, 1H), 4.03 (d, J = 2.7 Hz, 1H), 3.49 (d, J = 11.7 Hz, 2H), 3.30 - 3.28 (m, 3H), 3.07 (s, 4H), 2.93 - 2.81 (m, 1H), 2.76 - 2.56 (m, 2H), 2.51 (s, 2H), 2.46 (d, J = 5.5 Hz, 4H), 2.18 (d, J = 7.2 Hz, 2H), 2.06 - 1.93 (m, 1H), 1.74 (d, J = 11.9 Hz, 2H), 1.61 (dd, J = 3.7, 7.2 Hz, 1H), 1.21 - 1.05 (m, 2H) Peak 2 was concentrated under reduced pressure to yield a product I-388 (27.9 mg, 40% yield, SFC: R _t = 3.270) as a white solid. LC-MS (ESI ⁺ ) m/z: 741.3 (M+H) ⁺ . LCMS: calc. for C ₄₄ H ₄₈ N ₆ O ₅ : 740.91, found: [M+H] ⁺ 741.3. HPLC: 99.53 % purity at 254 nm. ¹ HNMR (500MHz, DMSO-d6): į 10.98 (s, 1H), 9.28 (s, 1H), 7.18 - 7.11 (m, 2H), 7.10 - 7.04 (m, 3H), 6.93 (d, J = 8.5 Hz, 1H), 6.83 (d, J = 2.1 Hz, 1H), 6.78 (d, J = 8.1 Hz, 1H), 6.65 - 6.58 (m, 3H), 6.58 - 6.52 (m, 4H), 5.28 (dd, J = 5.4, 12.9 Hz, 1H), 5.07 (d, J = 15.4 Hz, 1H), 5.00 (d, 3.29 (s, 3H), 3.07 (s, 4H), 2.95 - 2.83 (m, 1H), 2.74 - 2.57 (m, 2H), 2.74 - 2.57 (m, 1H), 2.74 - 2.57 (m, 1H), 2.54 (s, 2H), 2.46 (d, J = 5.5 Hz, 4H), 2.18 (d, J = 7.2 Hz, 2H), 2.02 - 1.91 (m, 1H), 1.74 (d, J = 11.6 Hz, 2H), 1.61 (td, J = 3.5, 7.0 Hz, 1H), 1.14 (q, J = 11.7 Hz, 2H). EXAMPLE 117. Preparation of (I-251) (S)-3-(5-(4-((1-(4-((1R,3S,4S)-3-cyclohexyl-7- hydroxy-1-methylisochroman-4-yl)phenyl)piperidin-4-yl)methyl )piperazin-1-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione Step 1: To a solution of 1-(4-((1R,3S,4S)-3-cyclohexyl-7-hydroxy-1-methylisochroman-4 - yl)phenyl)piperidine-4-carbaldehyde (17 mg, 39.2 ^mol, 94 % purity) in 10% H2SO4 ( 2 mL) and THF (2 mL) was stirred at 70 °C for 2 hour. The reaction was adjusted to pH=~7 with saturated aqueous NaHCO ₃ , then 20 mL water was added, and the mixture was extracted with dichloromethane (20 mL*2). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to dryness in vacuo to give a yellow oil. The yellow oil was concentrated in vacuo to give 1-(4-((1R, 3S, 4S)-3-cyclohexyl-7-hydroxy-1- methylisochroman-4-yl) phenyl) piperidine-4-carbaldehyde (17 mg, 39.2 ^mol, 94 % purity) as a Step 2: To a solution of 1-(4-((1R,3S,4S)-3-cyclohexyl-7-hydroxy-1-methylisochroman-4 - yl)phenyl)piperidine-4-carbaldehyde (17 mg, 1 Eq, 39.2 ^mol), (S)-3-(1-oxo-5-(piperazin-1- yl)isoindolin-2-yl)piperidine-2,6-dione (16 mg, 1.1 Eq, 43.1 ^mol, HCl salt) in DCM (2 mL), MeOH (2 mL) was added sodium acetate (10 mg, 3 Eq, 118 ^mol) was stirred at 25 °C for 1 h, Then sodium triacetoxyhydroborate (17 mg, 3 Eq, 118 ^mol) and acetic acid (7 mg, 7 ^L, 3 Eq, 118 ^mol) was added. The mixture was stirred at 25 °C for 15 hours. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was purified by prep-HPLC (column: Welch Xtimate C18150*30mm*5um phase: [water(FA)-ACN];B%: 20%-60%,9 min to give (S)-3-(5-(4-((1-(4-((1R,3S,4S)-3-cyclohexyl-7-hydroxy-1-meth ylisochroman-4- yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindo lin-2-yl)piperidine-2,6-dione (13.1 mg, 17 ^mol, 44 % yield , 98% purity) as a white solid. LC-MS (ESI ⁺ ) m/z: 746.5 (M+H) ⁺ . LCMS: calc. for C ₄₅ H ₅₅ N ₅ O ₅ : 745.42, found: [M+H] ⁺ 746.5 HPLC: 98.1% purity at 220 nm. ¹ H NMR (400MHz, DMSO-d ₆ ) į 10.92 - 11.05 (m, 1 H) 9.10 - 9.30 (m, 1 H) 8.14 - 8.20 (m, 0.718 H) 7.52 (d, J=8.28 Hz, 1 H) 7.05 - 7.14 (m, 4 H) 6.72 - 6.81 (m, 3 H) 6.47 - 6.55 (m, 2 H) 4.98 - 5.16 (m, 1 H) 4.66 - 4.76 (m, 1 H) 4.29 - 4.40 (m, 1 H) 4.14 - 4.28 (m, 1 H) 3.75 (br s, 1 H) 3.58 - 3.66 (m, 2 H) 3.29 (br s, 7 H) 2.85 - 2.91 (m, 1 H) 2.54 - 2.63 (m, 4 H) 2.29 - 2.45 (m, 2 H) 2.22 (br d, J=6.78 Hz, 2 H) 1.95 - 2.05 (m, 2 H) 1.78 - 1.86 (m, 3 H) 1.59 - 1.69 (m, 3 H) 1.50 - 1.56 (m, 4 H) 1.18 - 1.27 (m, 2 H) 1.08 - 1.13 (m, 1 H) 0.87 - 1.03 (m, 5 H). EXAMPLE 118. Preparation of (I-359) (S)-3-(5-(4-((1-(4-((3R*,4R*)-7-hydroxy-3-(4- hydroxyphenyl)isochroman-4-yl)phenyl)piperidin-4-yl)methyl)p iperazin-1-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione and (I-360) (S)-3-(5-(4-((1-(4-((3R,4S)-7-hydroxy-3-

(4-hydroxyphenyl)isochroman-4-yl)phenyl)piperidin-4-yl)me thyl)piperazin-1-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione Step 1: To a solution of 1 (500 mg, 0.866 mmol, 1.0 eq.) in dioxane (2 mL) was added 2 (165.4 mg, 0.104 mmol, 1.2 eq.) and Cs ₂ CO ₃ (846.3 mg, 0.260 mmol, 3.0 eq.) at 20 °C. Then the [2-(2- aminophenyl)phenyl]-methylsulfonyloxy-palladium;dicyclohexyl -[2-(2,6- diisopropoxyphenyl)phenyl]phosphane (108.6 mg, 0.130 mmol, 0.15 eq.) was added into the mixture at 20 °C. The mixture was stirred at 90 °C for 4 h under N2. LCMS showed that the desired product was detected. The reaction mixture was filtered and concentrated under reduced pressure to get the product. The mixture was purified by Pre-TLC (PE/EA= 3/1) to give 3 (300 mg, 43.78% yield) as yellow oil. LC-MS (ESI ⁺ ) m/z: 656.3 (M+H) ⁺ . 1H NMR (400 MHz, DMSO-d6) į = 7.48 - 7.30 (m, 10H), 7.08 (br d, J = 8.6 Hz, 1H), 6.96 - 6.52 (m, 10H), 5.08 - 4.94 (m, 5H), 4.88 - 4.81 (m, 1H), 4.66 (br d, J = 10.1 Hz, 1H), 4.12 - 4.01 (m, 2H), 3.61 - 3.55 (m, 4H), 3.28 - 3.22 (m, 6H), 1.73 - 1.59 (m, 3H), 1.32 - 1.21 (m, 2H). Step 2: A solution of 3 (280 mg, 426.95 ^mol, 1.0 eq.) and Pd/C (454.36 mg, 426.95 ^mol, 10% purity, 1.0 eq.) in EA (10 mL) and then degassed and purged with H ₂ for 3 times, and then the mixture was stirred at 15 °C for 3hr under H ₂ atmosphere. LCMS showed that the starting material was consumed and the desired product was detected. The mixture was filtered and concentrated under vacuum to give the crude. The crude was purified by Pre-TLC (PE/EA=1/1) to give 4 (140 mg, 66.63% yield) as yellow solid. LC-MS (ESI ⁺ ) m/z: 476.1 (M+H) ⁺ . Step 3: The 4 (152 mg, 319.61 ^mol, 1.0 eq.) was further separated by SFC (condition: CO ₂ - EtOH (0.1%NH ₃ H ₂ O), column: DAICEL CHIRALPAK AD (250mm x 30 mm, 10 um), Begin B: 25, End B: 25).to give 5B (30 mg, 19.74%yield) as white solid and 5C (10 mg, 6.58% yield) as white solid. Only two isomers of 4 possible isomers were able to be isolated: 5B : LC-MS (ESI ⁺ ) m/z: 476.2 (M+H) ⁺ . 1H NMR (500 MHz, DMSO-d6) į = 9.24 (br s, 2H), 6.94 (d, J = 8.5 Hz, 2H), 6.78 - 6.71 (m, 4H), 6.57 (d, J = 8.5 Hz, 2H), 6.50 - 6.45 (m, 3H), 4.95 - 4.74 (m, 2H), 4.54 (d, J = 9.8 Hz, 1H), 4.07 (d, J = 6.7 Hz, 1H), 4.02 (d, J = 9.8 Hz, 1H), 3.59 (br d, J = 12.2 Hz, 2H), 3.32 - 3.27 (m, 2H), 3.26 (s, 6H), 1.71 - 1.63 (m, 3H), 1.28 (br d, J = 12.1 Hz, 2H). 5C: 1H NMR (400 MHz, DMSO-d6) į = 9.26 (s, 1H), 9.09 (s, 1H), 6.82 - 6.73 (m, 3H), 6.62 - 6.48 (m, 8H), 5.03 (d, J = 15.4 Hz, 1H), 4.91 - 4.83 (m, 2H), 4.04 (d, J = 6.7 Hz, 1H), 3.91 (d, J = 2.6 Hz, 1H), 3.52 (br d, J = 11.9 Hz, 2H), 3.30 (s, 2H), 3.24 (s, 6H), 1.68 - 1.59 (m, 3H), 1.30 - 1.20 (m, 2H). Step 4: To a solution of 5B (25 mg, 1.0 Eq, 53 ^mol) in DCM (1 mL) was added TFA (400 mg, 0.3 mL, 2e+1 Eq, 4 mmol) at 15 °C. Then the mixture was stirred at 15 °C for 1 hour. LCMS showed that the desired product was detected. Then the mixture was filtered and concentrated LC-MS (ESI ⁺ ) m/z: 446.2 (M+H+16) ⁺ Step 5: To a solution of 5C (8 mg, 1.0 Eq, 20 ^mol) in DCM (1 mL) was added TFA (400 mg, 0.3 mL, 2e+1 Eq, 4 mmol) at 15 °C. Then the mixture was stirred at 15 °C for 1 hour. LCMS showed that the desired product was detected. Then the mixture was filtered and concentrated under vacuum to give the 6C (5 mg, crude) as red oil. LC-MS (ESI ⁺ ) m/z: 448.2 (M+H+18) ⁺ Step 6: To a solution of 6B (30 mg, 1 Eq, 70 ^mol) in DCE (1 mL) and MeOH (1 mL) was added 034 (46 mg, 2 Eq, 0.14 mmol) and Sodium triacetoxyborohydride (74 mg, 52 ^L, 5 Eq, 0.35 mmol) at 15 °C. Then the mixture was stirred at 15 °C for 1 hour. LCMS showed that the desired product was detected. The mixture was filtered and concentrated under vacuum to give the crude. The residue was purified by prep-HPLC (condition: Column: Phenomenex Gemini NX 150 x 30 mm x 5 um; Condition: water (NH ₄ HCO ₃ )-ACN, Begin B 7, End B 27, Gradient Time (min) 12, 100% B Hold Time (min) 2, Flow Rate (mL/min) 25.) and to give I-359 (7.8 mg, 15 % yield) as a white solid. LCMS: calc. for C ₄₄ H ₄₇ N ₅ O ₆ : 741.89, found: [M+H] ⁺ 742.3. HPLC: 100.00% purity at 220 nm ¹ H NMR (500 MHz, DMSO-d ₆ ) į = 10.93 (br s, 1H), 9.24 (br s, 2H), 7.52 (d, J = 8.5 Hz, 1H), 7.08 - 7.04 (m, 2H), 6.94 (d, J = 8.5 Hz, 2H), 6.80 - 6.71 (m, 4H), 6.57 (d, J = 8.5 Hz, 2H), 6.51 - 6.45 (m, 3H), 5.07 - 5.01 (m, 1H), 4.95 - 4.74 (m, 2H), 4.54 (d, J = 9.8 Hz, 1H), 4.35 - 4.18 (m, 2H), 4.03 (d, J = 9.8 Hz, 1H), 3.59 (br d, J = 12.1 Hz, 2H), 3.28 (br s, 8H), 2.95 - 2.82 (m, 1H), 2.60 - 2.53 (m, 3H), 2.40 - 2.31 (m, 1H), 2.21 (br d, J = 7.2 Hz, 2H), 2.00 - 1.91 (m, 1H), 1.79 (br d, J = 11.9 Hz, 2H), 1.71 - 1.60 (m, 1H), 1.23 - 1.13 (m, 2H). Step 7: To a solution of 6C (5 mg, 1 Eq, 0.01 mmol) in DCE (1 mL) and MeOH (1 mL) was added 034 (8 mg, 2 Eq, 0.02 mmol) and Sodium triacetoxyborohydride (0.01 g, 9 ^L, 5 Eq, 0.06 mmol) at 15 °C. Then the mixture was stirred at 15 °C for 1 hour. LCMS showed that the desired product was detected. The mixture was filtered and concentrated under vacuum to give the crude. The residue was purified by prep-HPLC (condition: Column: Phenomenex Gemini NX 150 x 30 mm x 5 um; Condition: water (NH4HCO3)-ACN Begin B 28 End B 58 Gradient Time (min) 12, 100% B Hold Time (min) 2, Flow Rate (mL/min) 25.) and to give I-360 (5.4 mg, 60 % yield) as a white solid. LCMS: calc. for C ₄₄ H ₄₇ N ₅ O ₆ : 741.89, found: [M+H] ⁺ 742.3. HPLC: 100.00% purity at 220 nm ¹ H NMR (500 MHz, DMSO-d ₆ ) į = 10.93 (br s, 1H), 9.32 - 9.01 (m, 2H), 7.51 (d, J = 8.5 Hz, 1H), 7.09 - 7.01 (m, 2H), 6.82 - 6.72 (m, 3H), 6.63 - 6.48 (m, 8H), 5.07 - 4.98 (m, 2H),4.93 - 4.83 (m, 2H), 4.36 - 4.17 (m, 2H), 3.92 (d, J = 2.6 Hz, 1H), 3.51 (br d, J = 12.1 Hz, 2H), 3.31 - 3.23 (m, 8H), 2.95 - 2.81 (m, 1H), 2.63 - 2.52 (m, 3H), 2.40 - 2.33 (m, 1H),2.19 (br d, J = 7.2 Hz, 2H), 2.00 - 1.91 (m, 1H), 1.75 (br d, J = 11.3 Hz, 2H), 1.67 - 1.58 (m, 1H), 1.23 - 1.12 (m, 2H). EXAMPLE 119. Preparation of (I-361) (S)-3-(5-(4-((1-(4-((3R,4S)-7-hydroxy-3-(3- (trifluoromethoxy)phenyl)isochroman-4-yl)phenyl)piperidin-4- yl)methyl)piperazin-1-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione and (I-362) (S)-3-(5-(4-((1-(4-((3S,4R)-7-hydroxy-3-

(3-(trifluoromethoxy)phenyl)isochroman-4-yl)phenyl)piperi din-4-yl)methyl)piperazin-1- yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione Step 1: To a solution of 1-iodo-3-(trifluoromethoxy)benzene (1.03 g, 3.59 mmol, 2.1 eq.) in THF (10 mL) was added chloro(isopropyl)magnesium (2 M, 1.88 mL, 2.2 eq.) at 0 °C, after stirred 1 h was added 2-[4-benzyloxy-2-[[tert-butyl(dimethyl)silyl]oxymethyl]pheny l]-2-(4- bromophenyl)- N-methoxy-N-methyl-acetamide (1 g, 1.71 mmol, 1 eq.) in THF (10 mL). The mixture was stirred at 25 °C for 12 h. The reaction mixture was quenched by addition of water (5 mL), extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by preparative TLC (PE/EtOAc = 5/1, TLC: PE/EtOAc = 5/1, Rf = 0.79) to (trifluoromethoxy)phenyl]ethanone (690 mg, 945.98 ^mol, 55.30% yield, 94% purity) as colourless oil. LC-MS (ESI ⁺ ) m/z: 687.1 (M+H) ⁺ . ¹ H NMR (400MHz, CDCl ₃ ) į = 7.94 (d, J=7.6 Hz, 1H), 7.84 (s, 1H), 7.47 - 7.35 (m, 9H), 7.06 - 7.00 (m, 3H), 6.96 (d, J=8.5 Hz, 1H), 6.83 (dd, J=2.7, 8.5 Hz, 1H), 6.31 (s, 1H), 5.04 (s, 2H), 4.71 (d, J=12.3 Hz, 1H), 4.48 (d, J=12.4 Hz, 1H), 0.92 (s, 9H), 0.08 (d, J=2.3 Hz, 6H) Step 2: To a solution of 2-[4-benzyloxy-2-[[tert-butyl(dimethyl)silyl]oxymethyl]pheny l]-2- (4- bromophenyl)-1-[3-(trifluoromethoxy)phenyl]ethanone (690 mg, 945.98 ^mol, 1 eq.) and triethylsilane (164.99 mg, 1.42 mmol, 226.64 ^L, 1.5 eq.) in DCM (8 mL) was added trimethylsilyl trifluoromethanesulfonate (315.38 mg, 1.42 mmol, 256.40 ^L, 1.5 eq.) at -78 °C. The mixture was stirred at -78 °C for 30 min. The reaction mixture was quenched by adding saturation solution of NaHCO ₃ (10 mL), extracted with DCM (10 mL x 3). The combined organic layers were washed with brine (10 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by preparative TLC (PE/EtOAc = 10/1, TLC: PE/EtOAc = 10/1, R _f = 0.75) to yield 7-benzyloxy-4-(4- bromophenyl)-3-[3-(trifluoromethoxy)phenyl]isochromane (230 mg, 400.88 ^mol, 42.38% yield, 96.8% purity) as a white solid. LC-MS (ESI+) m/z: 555.0 (M+H)+. NMR (400MHz, CDCl ₃ ) į = 7.48 - 7.33 (m, 5H), 7.25 - 7.19 (m, 1H), 7.15 (d, J=8.3 Hz, 2H), 7.03 - 6.92 (m, 3H), 6.88 - 6.81 (m, 2H), 6.77 (d, J=2.4 Hz, 1H), 6.61 (d, J=8.3 Hz, 2H), 5.23 - 5.15 (m, 1H), 5.10 - 5.03 (m, 4H), 4.05 (d, J=3.0 Hz, 1H) Step 3: To a solution of 7-(benzyloxy)-4-(4-bromophenyl)-3-(3-(trifluoromethoxy)pheny l) isochromane (210 mg, 1 eq., 378 ^mol) and 4-(dimethoxymethyl)piperidine (90.3 mg, 1.5 eq., 567 ^mol) in 1,4-Dioxane (8 mL)was added Cs ₂ CO ₃ (370 mg, 3 eq., 1.13 mmol) and (2- Dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)[2-(2 '-amino-1,1'- biphenyl)]palladium(II) methanesulfonate (31.6 mg, 0.1 eq., 37.8 ^mol). The mixture was stirred under N ₂ at 90 °C for 12 h. The reaction mixture was filtered and concentrated to yield a residue. The residue was purified by flash silica gel chromatography (from PE/EtOAc = 1/0 to 20/1, TLC: PE/EtOAc = 10/1, R _f = 0.72) to yield 1-(4-(7-(benzyloxy)-3-(3- (trifluoromethoxy)phenyl)isochroman-4-yl)phenyl)-4-(dimethox ymethyl)piperidine (30 mg, 46 ^mol, 12 %, 97% Purity) was obtained as a white solid. LC-MS (ESI ⁺ ) m/z: 634.2 (M+H) ⁺ . NMR (400MHz, CDCl3) į = 7.47 - 7.39 (m, 4H), 7.37 - 7.32 (m, 1H), 7.23 - 7.16 (m, 1H), 7.03 - 6.94 (m, 3H), 6.83 (td, J=2.8, 5.4 Hz, 2H), 6.76 (d, J=2.4 Hz, 1H), 6.59 (br s, 4H), 5.20 - 5.14 (m, 1H), 5.09 - 5.00 (m, 4H), 4.06 (br d, J=7.0 Hz, 1H), 4.00 (br s, 1H), 3.55 (br d, J=12.2 Hz, 2H), 3.36 (s, 6H), 2.54 (br s, 2H), 1.92 - 1.65 (m, 3H), 1.39 (br d, J=10.6 Hz, 2H) Step 4: To a solution of 1-(4-(7-(benzyloxy)-3-(3-(trifluoromethoxy)phenyl)isochroman -4- yl)phenyl)-4-(dimethoxymethyl)piperidine (160 mg, 1 eq., 252 ^mol) in EtOAc (5 mL) was added Pd/C (160 mg, 10% Wt, 0.595 eq., 150 ^mol). The mixture was stirred under H ₂ 15 psi at 25 °C for 3 h. The reaction mixture was filtered and concentrated to yield a residue. The residue was separated by chiral SFC(column:DAICEL CHIRALPAK AD(250mm*30mm,10um);mobile phase: [TEA-i-PrOH]; B%: 40%-40%,min), followed by lyophilization to yield 7 (3R,4S)-4-(4- (4-(dimethoxymethyl)piperidin-1-yl)phenyl)-3-(3- (trifluoromethoxy)phenyl)isochroman-7-ol (50 mg, 92 ^mol, 42%) SFC: R _t = 1.136) and 7A (3S,4R)-4-(4-(4-(dimethoxymethyl)piperidin-1- yl)phenyl)-3-(3-(trifluoromethoxy)phenyl)isochroman-7-ol (50 mg, 92 ^mol, 42%) SFC: R _t = 2.085) as a white solid. LC-MS (ESI ⁺ ) m/z: 544.1(M+H) ⁺ . ¹ H NMR of 7 (400MHz, CDCl3) į = 7.23 - 7.16 (m, 1H), 6.97 (br d, J=7.6 Hz, 2H), 6.89 - 6.79 (m, 2H), 6.76 - 6.44 (m, 6H), 5.18 - 5.08 (m, 1H), 5.06 - 4.96 (m, 2H), 4.08 (br d, J=7.3 Hz, 1H), 3.98 (br s, 1H), 3.58 - 3.50 (m, 2H), 3.37 (s, 6H), 2.72 - 2.41 (m, 2H), 1.85 - 1.68 (m, 3H), 1.52 - 1.16 (m, 2H) ¹ H NMR of 7A (400MHz, CDCl ₃ ) į = 7.22 - 7.17 (m, 1H), 6.98 (br d, J=7.6 Hz, 2H), 6.86 (br d, J=8.2 Hz, 1H), 6.81 (br s, 1H), 6.76 - 6.46 (m, 6H), 5.19 - 5.09 (m, 1H), 5.07 - 4.96 (m, 2H), 4.08 (br d, J=6.8 Hz, 1H), 3.98 (br s, 1H), 3.54 (br t, J=10.4 Hz, 2H), 3.37 (s, 6H), 2.77 - 2.39 (m, 2H), 1.86 - 1.64 (m, 3H), 1.44 (br s, 2H) Step 5: To a solution of 7 (3R,4S)-4-(4-(4-(dimethoxymethyl)piperidin-1-yl)phenyl)-3-(3 - (trifluoromethoxy)phenyl)isochroman-7-ol (40 mg, 1 eq., 74 ^mol) in DCM (2 mL) was added TFA (0.7 g, 0.5 mL, 9e+1 eq., 6 mmol). The mixture was stirred at 25 °C for 1 h. The reaction mixture was quenched by add to saturation solution of NaHCO ₃ (20 mL), extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine (10 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to yield 81-(4-((3R,4S)-7-hydroxy-3-(3- (trifluoromethoxy)phenyl)isochroman-4-yl)phenyl)piperidine-4 -carbaldehyde (40 mg, 72 ^mol, 98 %, 90% Purity) as a yellow solid which was used in the next step without further purification. LC-MS (ESI ⁺ ) m/z: 498.1 (M+H) ⁺ . Step 6: To a solution of 7A (3S,4R)-4-(4-(4-(dimethoxymethyl)piperidin-1-yl)phenyl)-3-(3 - (trifluoromethoxy)phenyl)isochroman-7-ol (40 mg, 1 eq., 74 ^mol) in DCM (2 mL) was added TFA (0.7 g, 0.5 mL, 9e+1 eq., 6 mmol). The mixture was stirred at 25 °C for 1 h. The reaction mixture was quenched by add to saturation solution of NaHCO ₃ (20 mL), extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine (10 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to yield 8A 1-(4-((3S,4R)-7-hydroxy-3-(3- (trifluoromethoxy)phenyl)isochroman-4-yl)phenyl)piperidine-4 -carbaldehyde (40 mg, 72 ^mol, 98 %, 90% Purity) as a yellow solid which was used in the next step without further purification. LC-MS (ESI ⁺ ) m/z: 498.1 (M+H) ⁺ . Step 7: To a solution of 8, 1-(4-((3R,4S)-7-hydroxy-3-(3-(trifluoromethoxy)phenyl)isochr oman- 4 -yl)phenyl)piperidine-4-carbaldehyde (40 mg, 1 eq., 80 ^mol) and (S)-3-(1-oxo-5-(piperazin - 1-yl)isoindolin-2- yl)piperidine-2,6-dione (53 mg, 2 eq., 0.16 mmol) in DCM (2 mL) and MeOH (2 mL)ˈ after stirred 30 min was added Sodium triacetoxyborohydride (51 mg, 36 ^L, 3 eq., 0.24 mmol). The mixture was stirred at 25 °C for 12 h. The reaction mixture was filtered and concentrated to yield a residue. The residue was purified by preparative HPLC (column:Boston Green ODS 150*30mm*5um;mobile phase: [water(FA)-CAN];B%: 18%- 38%,12min), followed by lyophilization to yield I-361 (S)-3-(5-(4-((1-(4-((3R,4S)-7-hydroxy -3-(3 - (trifluoromethoxy)phenyl)isochroman-4-yl)phenyl)piperidin-4- yl)methyl)piperazin-1-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione (22.9 mg, 28.3 ^mol, 35 %, 100% Purity) as a white solid.LC-MS (ESI ⁺ ) m/z: 810.3 (M+H) ⁺ . LCMS: calc. for C45H46F3N5O6: 809.34, found: [M+H] ⁺ 810.3. HPLC: 100% purity at 220 nm. 10.95 (s, 1H), 9.31 (s, 1H), 8.13 (s, 1H), 7.51 (d, J=8.6 Hz, 1H), 7.33 - 7.28 (m, 1H), 7.19 (d, J=7.9 Hz, 1H), 7.10 - 7.02 (m, 3H), 6.88 (s, 1H), 6.78 (d, J=8.1 Hz, 1H), 6.60 - 6.52 (m, 6H), 5.15 - 4.99 (m, 3H), 4.92 (br d, J=15.3 Hz, 1H), 4.38 - 4.28 (m, 1H), 4.24 - 4.16 (m, 1H), 4.05 (d, J=2.9 Hz, 1H), 3.49 (br d, J=10.3 Hz, 2H), 3.31 - 3.26 (m, 8H), 2.96 - 2.83 (m, 1H), 2.60 (br s, 2H), 2.43 - 2.32 (m, 2H), 2.18 (br s, 2H), 2.00 - 1.93 (m, 1H), 1.73 (br d, J=12.3 Hz, 2H), 1.63 (br s, 1H), 1.19 - 1.08 (m, 2H) Step 8: To a solution of 8A, 1-(4-((3S,4R)-7-hydroxy-3-(3- (trifluoromethoxy)phenyl)isochroman- 4-yl)phenyl)piperidine-4-carbaldehyde (40 mg, 1 eq., 80 ^mol) and (S)-3-(1-oxo-5-(piperazin -1-yl)isoindolin-2-yl)piperidine-2,6-dione (40 mg, 1.5 eq., 0.12 mmol) in DCM (2 mL) and MeOH (2 mL)ˈ after stirred 30 min was added Sodium triacetoxyborohydride (51 mg, 36 ^L, 3 eq., 0.24 mmol) .The mixture was stirred at 25 °C for 25 h. The reaction mixture was filtered and concentrated to yield a residue.The residue was purified by preparative HPLC (column:Boston Green ODS 150*30mm*5um;mobile phase: [water(FA)- CAN];B%: 18%-38%,12min), followed by lyophilization to yield I-362 (S)-3-(5-(4-((1-(4- ((3S,4R)-7-hydroxy-3 -(3-(trifluoromethoxy)phenyl)isochroman-4-yl)phenyl)piperidi n-4- yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2, 6-dione (22.1 mg, 27.3 ^mol, 34 %, 100% Purity) as a white solid.LC-MS (ESI ⁺ ) m/z: 810.3 (M+H) ⁺ . LCMS: calc. for C45H46F3N5O6: 809.34, found: [M+H] ⁺ 810.3. HPLC: 100% purity at 220 nm. ¹ H NMR (400MHz, DMSO-d6) į = 10.94 (s, 1H), 9.31 (s, 1H), 8.14 (s, 1H), 7.51 (d, J=8.5 Hz, 1H), 7.33 - 7.28 (m, 1H), 7.19 (d, J=7.9 Hz, 1H), 7.11 - 7.02 (m, 3H), 6.88 (s, 1H), 6.78 (d, J=8.1 Hz, 1H), 6.60 - 6.53 (m, 6H), 5.12 - 5.01 (m, 3H), 4.92 (br d, J=15.3 Hz, 1H), 4.37 - 4.28 (m, 1H), 4.24 - 4.15 (m, 1H), 4.05 (d, J=2.7 Hz, 1H), 3.49 (br d, J=11.2 Hz, 2H), 3.31 - 3.27 (m, 8H), 2.95 - 2.84 (m, 1H), 2.58 (br d, J=18.6 Hz, 2H), 2.43 - 2.30 (m, 2H), 2.18 (br d, J=6.2 Hz, 2H), 2.01 - 1.92 (m, 1H), 1.73 (br d, J=12.5 Hz, 2H), 1.63 (br s, 1H), 1.13 (br d, J=11.2 Hz, 2H).

EXAMPLE 120. Preparation of (I-253) (S)-3-(5-(4-((1-(4-((1R,3S,4R)-3-cyclohexyl-7- hydroxy-1-methylisochroman-4-yl)phenyl)piperidin-4-yl)methyl )piperazin-1-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione Step 1: A solution of 1-(4-((1R,3S,4R)-3-cyclohexyl-7-hydroxy-1-methylisochroman-4 - yl)phenyl)piperidine-4-carbaldehyde (8 mg, 0.02 mmol, 82% purity) in 10% H ₂ SO ₄ ( 1 mL) and THF (1 mL) was stirred at 70 °C for 2 hour. The reaction was adjust to pH=7 with saturated aqueous NaHCO ₃ , then 50 mL water was added, and the mixture was extracted with dichloromethane (100 mL*2). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to dryness in vacuo to give a yellow oil. The yellow oil was concentrated in vacuo to give 1-(4-((1R, 3S, 4R)-3-cyclohexyl-7-hydroxy-1- methylisochroman-4-yl) phenyl) piperidine-4-carbaldehyde (8 mg, 0.02 mmol, 82% Purity) as a yellow solid. Step 2: To a solution of 1-(4-((1R,3S,4R)-3-cyclohexyl-7-hydroxy-1-methylisochroman-4 - yl)phenyl)piperidine-4-carbaldehyde (8 mg, 82% purity, 1 Eq, 0.02 mmol), (S)-3-(1-oxo-5- (piperazin-1-yl)isoindolin-2-yl)piperidine-2,6-dione (6 mg, 1.1 Eq, 0.02 mmol, HCl salt) in DCM (1 mL), MeOH (1 mL) was added sodium acetate (4 mg, 3 Eq, 0.05 mmol) was stirred at 25 °C for 60 mins, Then sodium triacetoxyhydroborate (6 mg, 2 Eq, 0.03 mmol) and acetic acid (3 mg, 3 ^L, 3 Eq, 0.05 mmol) was added .The mixture was stirred at 25 °C for 15 hour. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was purified by prep-HPLC (column: Welch Xtimate C18150*30mm*5um phase: [water(FA)- ACN];B%: 15%-55%,9 min to give (S)-3-(5-(4-((1-(4-((1R,3S,4R)-3-cyclohexyl-7-hydroxy-1- methylisochroman-4-yl)phenyl)piperidin-4-yl)methyl)piperazin -1-yl)-1-oxoisoindolin-2- yl)piperidine-2,6-dione (2 mg, 3 ^mol, 20 % yield , 96.6% purity) as a white solid. LCMS: calc. for C ₄₅ H ₅₅ N ₅ O ₅ : 745.42, found: [M+H] ⁺ 746.5 HPLC: 96.6% purity at 220 nm. ¹ H NMR (400MHz, DMSO-d ₆ ) į 8.42 - 8.46 (m, 0.218 H) 7.67 (d, J=8.34 Hz, 1 H) 7.09 - 7.16 (m, 2 H) 6.94 - 7.03 (m, 4 H) 6.58 (d, J=1.79 Hz, 1 H) 6.44 - 6.52 (m, 1 H) 6.44 - 6.52 (m, 1 H) 5.13 (dd, J=13.35, 5.25 Hz, 1 H) 4.82 - 4.91 (m, 2 H) 4.35 - 4.50 (m, 2 H) 4.00 (d, J=10.25 Hz, 1 H) 3.63 - 3.74 (m, 2 H) 3.50 - 3.55 (m, 1 H) 3.40 - 3.48 (m, 4 H) 2.87 - 2.97 (m, 1 H) 2.64 - 2.84 (m, 7 H) 2.39 - 2.55 (m, 3 H) 2.11 - 2.22 (m, 1 H) 1.92 - 2.00 (m, 2 H) 1.62 - 1.91 (m, 5 H) 1.52 (d, J=6.44 Hz, 4 H) 1.33 - 1.46 (m, 3 H) 1.27 (br t, J=10.79 Hz, 2 H) 1.11 - 1.16 (m, 2 H). The absolute stereochemistry was arbitrarily assigned. EXAMPLE 121. Preparation of (I-365) (S)-3-(5-(4-((1-(4-((3S,4R)-3-(2,3-dihydro-1H- inden-5-yl)-7-hydroxyisochroman-4-yl)phenyl)piperidin-4-yl)m ethyl)piperazin-1-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione and (I-366) (S)-3-(5-(4-((1-(4-((3R,4S)-3-(2,3-

dihydro-1H-inden-5-yl)-7-hydroxyisochroman-4-yl)phenyl)pi peridin-4- yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2, 6-dione Step 1: To a solution of 5-iodoindane (860.81 mg, 3.42 mmol, 2 eq.) in THF (10 mL) was added chloro(isopropyl)magnesium (2 M, 1.88 mL, 2.2 eq.) at 0 °C, after stirred 1 h was added 2-[4- benzyloxy-2-[[tert-butyl(dimethyl)silyl]oxymethyl]phenyl]-2- (4-bromophenyl)-N-methoxy-N- methyl-acetamide (1 g, 1.71 mmol, 1 eq.) in THF (10 mL). The mixture was stirred at 25 °C for 12 h. The reaction mixture was quenched by addition of water (30 mL), extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (30 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (from PE/EtOAc = 1/0 to 10/1, TLC: PE/EtOAc = 5/1, R _f = 0.79) to yield 2-[4-benzyloxy-2-[[tert-butyl(dimethyl)silyl] oxymethyl]phenyl]-2-(4- bromophenyl)-1-indan-5-yl-ethanone (750 mg, 1.06 mmol, 62.18% yield, 91% purity) as colourless oil. LC-MS (ESI ⁺ ) m/z: 642.1 (M+H) ⁺ . ¹ H NMR (400MHz, CDCl ₃ ) į = 7.87 - 7.79 (m, 2H), 7.45 - 7.30 (m, 7H), 7.20 (d, J=7.9 Hz, 1H), 7.05 - 6.98 (m, 4H), 6.81 (dd, J=2.8, 8.5 Hz, 1H), 6.31 (s, 1H), 5.03 (s, 2H), 4.70 (d, J=12.5 Hz, 1H), 4.49 (d, J=12.5 Hz, 1H), 2.94 - 2.88 (m, 4H), 2.13 - 2.06 (m, 2H), 0.93 (s, 9H), 0.10 - 0.04 (m, 6H) Step 2: To a solution of 2-[4-benzyloxy-2-[[tert-butyl(dimethyl)silyl]oxymethyl]pheny l]-2-(4- bromophenyl)-1-indan-5-yl-ethanone (750 mg, 1.06 mmol, 1 eq.) and triethylsilane (185.51 mg, 1.60 mmol, 254.82 ^L, 1.5 eq.) in DCM (10 mL)was added trimethylsilyl trifluoromethanesulfonate (354.58 mg, 1.60 mmol, 288.28 ^L, 1.5 eq.) at -78 °C. The mixture was stirred at -78 °C for 30 min. The reaction mixture was quenched by addition to saturation solution of NaHCO ₃ (50 mL), extracted with DCM (30 mL x 3). The combined organic layers were washed with brine (20 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (from PE/EtOAc = 1/0 to 20/1, TLC: PE/EtOAc = 10/1, Rf = 0.70) to afford 7-benzyloxy-4-(4 - bromophenyl)-3-indan-5-yl-isochromane (450 mg, 853.46 ^mol, 80.24% yield, 97% purity) as a yellow solid. LC-MS (ESI+) m/z: 511.1 (M+H)+. ¹ H NMR (400MHz, CDCl ₃ ) į = 7.47 - 7.33 (m, 5H), 7.16 (d, J=8.5 Hz, 2H), 7.02 (d, J=7.7 Hz, 1H), 6.94 (d, J=8.5 Hz, 1H), 6.85 - 6.80 (m, 1H), 6.79 - 6.71 (m, 3H), 6.65 (d, J=8.5 Hz, 2H), 5.20 - 5.13 (m, 1H), 5.09 - 5.01 (m, 4H), 4.03 (d, J=2.9 Hz, 1H), 2.85 - 2.68 (m, 4H), 2.01 (quin, J=7.4 Hz, 2H) Step 3: To a solution of 7-(benzyloxy)-4-(4-bromophenyl)-3-(2,3-dihydro-1H-inden-5- yl)isochromane (510 mg, 1 eq., 997 ^mol) and 4-(dimethoxymethyl)piperidine (238 mg, 1.5 eq., 1.50 mmol) in 1,4-Dioxane (10 mL) was added Cs ₂ CO ₃ (812 mg, 2.5 eq., 2.49 mmol) and (2- Dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)[2-(2 '-amino-1,1'- biphenyl)]palladium(II) methanesulfonate (83.4 mg, 0.1 eq., 99.7 ^mol). The mixture was stirred under N ₂ at 90 °C for 12 h. The reaction mixture was quenched by addition of water (50 mL), filtered and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (from PE/EtOAc = 1/0 to 5/1, TLC: PE/EtOAc = 3/1, R _f = 0.49) to afford 1-(4-(7-(benzyloxy)-3-(2,3-dihydro-1H-inden-5- yl)isochroman-4-yl)phenyl)-4-(dimethoxymethyl)piperidine (450 mg, 0.75 mmol, 75 %, 98% Purity) as a yellow solid. LC-MS (ESI ⁺ ) m/z: 590.0 (M+H) ⁺ . NMR (400MHz, CDCl ₃ ) į = 7.47 - 7.32 (m, 4H), 7.37 - 7.31 (m, 1H), 6.99 (t, J=7.6 Hz, 2H), 6.82 (dd, J=2.6, 8.4 Hz, 1H), 6.79 - 6.59 (m, 7H), 5.19 - 5.13 (m, 1H), 5.10 - 4.97 (m, 4H), 4.07 (br d, J=7.1 Hz, 1H), 3.99 (br s, 1H), 3.60 - 3.53 (m, 1H), 3.57 (br d, J=11.9 Hz, 1H), 3.36 (s, 6H), 2.90 - 2.65 (m, 4H), 2.55 (br s, 2H), 2.00 (quin, J=7.1 Hz, 2H), 1.81 (br d, J=10.8 Hz, 2H), 1.70 (br s, 1H), 1.43 (br s, 2H) Step 4: To a solution of 1-(4-(7-(benzyloxy)-3-(2,3-dihydro-1H-inden-5-yl)isochroman- 4-yl) phenyl)-4-(dimethoxymethyl)piperidine (200 mg, 1 eq., 339 ^mol) in EtOAc (5 mL) was added Pd/C (200 mg, 10% Wt, 0.554 eq., 188 ^mol) .The mixture was stirred under H ₂ (15 psi) at 25 °C for 3 h. The reaction mixture was filtered and concentrated to yield a residue. The residue was separated by chiral SFC(column:DAICEL CHIRALPAK AD (250mm*30mm,10um);mobile phase: [CO2-i-PrOH]; B%: 40%-40%,min), followed by lyophilization to yield (3S,4R)-3-(2,3- dihydro-1H-inden-5-yl)-4-(4-(4-(dimethoxymethyl) piperidin-1-yl)phenyl)isochroman-7-ol (70 mg, 0.14 mmol, SFC: R _t = 1.870) as a white solid and (3R,4S)-3-(2,3-dihydro-1H-inden-5-yl)-4- (4-(4-(dimethoxymethyl)piperidin-1 -yl)phenyl)isochroman-7-ol (70 mg, 0.14 mmol, SFC: R _t = 3.617) as a white solid. 500.1(M ⁺ +H) . ¹ H NMR of 7 (500MHz, CDCl ₃ ) į = 7.00 (d, J=7.6 Hz, 1H), 6.89 (d, J=8.2 Hz, 1H), 6.77 - 6.71 (m, 2H), 6.69 - 6.53 (m, 6H), 5.12 (br d, J=15.4 Hz, 2H), 5.04 - 4.96 (m, 2H), 4.13 - 4.05 (m, 1H), 4.00 - 3.94 (m, 1H), 3.60 - 3.53 (m, 2H), 3.37 (s, 6H), 2.82 (t, J=7.3 Hz, 2H), 2.80 - 2.74 (m, 1H), 2.73 - 2.65 (m, 1H), 2.63 - 2.44 (m, 2H), 1.99 (spt, J=6.9 Hz, 2H), 1.81 (br d, J=9.6 Hz, 2H), 1.71 (br s, 1H), 1.44 (br s, 2H) ¹ H NMR of 7A (500MHz, CDCl3) į = 7.00 (d, J=7.6 Hz, 1H), 6.89 (d, J=8.2 Hz, 1H), 6.77 - 6.71 (m, 2H), 6.70 - 6.52 (m, 6H), 5.12 (br d, J=15.4 Hz, 2H), 5.03 - 4.96 (m, 2H), 4.10 - 4.04 (m, 1H), 4.00 - 3.93 (m, 1H), 3.57 (br dd, J=3.5, 8.7 Hz, 2H), 3.37 (s, 6H), 2.82 (t, J=7.3 Hz, 2H), 2.79 - 2.74 (m, 1H), 2.72 - 2.65 (m, 1H), 2.62 - 2.45 (m, 2H), 2.04 - 1.96 (m, 2H), 1.82 (br d J 102 H 2H) 171 (b d J 37 H 1H) 152 132 ( 2H) Step 5: To a solution of (3S,4R)-3-(2,3-dihydro-1H-inden-5-yl)-4-(4-(4-(dimethoxymeth yl) piperidin-1-yl)phenyl)isochroman-7-ol (40 mg, 1 eq., 80 ^mol) in DCM (2 mL) was added TFA (0.7 g, 0.5 mL, 8e+1 eq., 6 mmol). The mixture was stirred at 25 °C for 1 h. The reaction mixture was quenched by add to saturation solution of NaHCO ₃ (20 mL), extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine (10 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to yield 1-(4-((3S,4R)-3-(2,3-dihydro-1H-inden-5-yl)- 7-hydroxyisochroman-4-yl)phenyl)piperidine-4-carbaldehyde (40 mg, 79 ^mol, 99 %, 90% Purity) as a yellow solid which was used in the next step without further purification. LC-MS (ESI ⁺ ) m/z: 454.1 (M+H) ⁺ . Step 6: To a solution of (3R,4S)-3-(2,3-dihydro-1H-inden-5-yl)-4-(4-(4-(dimethoxymeth yl) piperidin-1-yl)phenyl)isochroman-7-ol (40 mg, 1 eq., 80 ^mol) in DCM (2 mL) was added TFA (0.7 g, 0.5 mL, 8e+1 eq., 6 mmol). The mixture was stirred at 25 °C for 1 h. The reaction mixture was quenched by add to saturation solution of NaHCO ₃ (20 mL), extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine (10 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to yield 1-(4-((3R,4S)-3-(2,3-dihydro-1H-inden-5-yl)-7- hydroxyisochroman-4-yl)phenyl)piperidine-4-carbaldehyde (40 mg, 79 ^mol, 99 %, 90% Purity) as a yellow solid which was used in the next step without further purification. LC-MS (ESI ⁺ ) m/z: 454.1 (M+H) ⁺ . Step 7: To a solution of 1-(4-((3S,4R)-3-(2,3-dihydro-1H-inden-5-yl)-7-hydroxyisochro man -4- yl)phenyl)piperidine-4-carbaldehyde (40 mg, 1 eq., 88 ^mol) and (S)-3-(1-oxo-5-(piperazin -1- yl)isoindolin-2-yl)piperidine-2,6-dione (58 mg, 2 eq., 0.18 mmol) in DCM (2 mL) and MeOH (2 mL), after stirred 30 min was added Sodium triacetoxyborohydride (56 mg, 39 ^L, 3 eq., 0.26 mmol). The mixture was stirred at 25 °C for 12 h. The reaction mixture was filtered and concentrated to yield a residue. The residue was purified by preparative HPLC (column:Boston Green ODS 150*30mm*5um;mobile phase: [water(FA)-CAN];B%: 18%-38%,12min), followed by lyophilization to yield (S)-3-(5-(4-((1-(4-((3S,4R)-3-(2,3- dihydro-1H-inden-5-yl)-7- hydroxyisochroman-4-yl)phenyl)piperidin-4-yl)methyl)piperazi n-1-yl)-1-oxoisoindolin-2- yl)piperidine-2,6-dione (16.3 mg, 21.3 ^mol, 24 %, 100% Purity) as a white solid. LC-MS (ESI ⁺ ) m/z: 766.3 (M+H) ⁺ . LCMS: calc. for C47H51N5O5: 765.39, found: [M+H] ⁺ 766.3. HPLC: 100% purity at 220 nm. ¹ H NMR (400MHz, DMSO-d6) į = 10.94 (s, 1H), 9.27 (s, 1H), 8.16 (s, 1H), 7.51 (d, J=8.6 Hz, 1H), 7.08 - 7.01 (m, 2H), 6.97 (d, J=7.7 Hz, 1H), 6.88 (s, 1H), 6.84 - 6.73 (m, 2H), 6.69 - 6.62 (m, 2H), 6.59 - 6.51 (m, 4H), 5.08 - 5.00 (m, 2H), 4.95 - 4.85 (m, 2H), 4.36 - 4.29 (m, 1H), 4.23 - 4.16 (m, 1H), 3.99 (br s, 1H), 3.51 (br d, J=12.4 Hz, 2H), 3.27 (br s, 6H), 2.96 - 2.84 (m, 1H), 2.81 - 2.54 (m, 8H), 2.40 - 2.29 (m, 2H), 2.18 (br d, J=7.0 Hz, 2H), 2.00 - 1.88 (m, 3H), 1.74 (br d, J=11.6 Hz, 2H), 1.63 (br s, 1H), 1.14 (br d, J=10.8 Hz, 2H) Step 8: To a solution of 1-(4-((3R,4S)-3-(2,3-dihydro-1H-inden-5-yl)-7-hydroxyisochro man-4- yl)phenyl)piperidine-4-carbaldehyde (40 mg, 1 eq., 88 ^mol) and (S)-3-(1-oxo-5-(piperazin- 1- yl)isoindolin-2-yl)piperidine-2,6-dione (58 mg, 2 eq., 0.18 mmol) in DCM (2 mL) and MeOH (2 mL)ˈ after stirred 30 min was added Sodium triacetoxyborohydride (56 mg, 39 ^L, 3 eq., 0.26 mmol).The mixture was stirred at 25 °C for 25 h. The reaction mixture was filtered and concentrated to yield a residue. The residue was purified by preparative HPLC (column:Boston Green ODS 150*30mm*5um;mobile phase: [water(FA)-CAN];B%: 18%-48%,12min), followed by lyophilization to yield (S)-3-(5-(4-((1-(4-((3R,4S)-3-(2,3- dihydro-1H-inden-5-yl)-7- hydroxyisochroman-4-yl)phenyl)piperidin-4-yl)methyl)piperazi n-1-yl)-1-oxoisoindolin-2- yl)piperidine-2,6-dione (13.1 mg, 17.1 ^mol, 19 %, 100% Purity) as a white solid. LC-MS (ESI ⁺ ) m/z: 766.3 (M+H) ⁺ . LCMS: calc. for C47H51N5O5: 765.39, found: [ ⁺ +H] 766.3. HPLC: 100% purity at 220 nm. NMR (400MHz, DMSO-d6) į = 10.94 (s, 1H), 9.27 (br s, 1H), 8.18 (s, 1H), 7.51 (d, J=8.3 Hz, 1H), 7.08 - 7.02 (m, 2H), 6.97 (d, J=7.9 Hz, 1H), 6.88 (s, 1H), 6.84 - 6.76 (m, 2H), 6.68 - 6.63 (m, 2H), 6.60 - 6.52 (m, 4H), 5.09 - 5.01 (m, 2H), 4.95 - 4.85 (m, 2H), 4.36 - 4.28 (m, 1H), 4.23 - 4.16 (m, 1H), 3.99 (d, J=2.9 Hz, 1H), 3.51 (br d, J=11.8 Hz, 2H), 3.27 (br s, 6H), 2.96 - 2.84 (m, 1H), 2.80 - 2.53 (m, 8H), 2.44 - 2.28 (m, 2H), 2.18 (br d, J=7.0 Hz, 2H), 1.99 - 1.89 (m, 3H), 1.74 (br d, J=12.2 Hz, 2H), 1.63 (br s, 1H), 1.14 (br d, J=11.0 Hz, 2H). EXAMPLE 122. Preparation of (I-225) (S)-3-(5-(4-((1-(4-((3R,4R)-7-hydroxy-3- isopropylisochroman-4-yl)phenyl)piperidin-4-yl)methyl)pipera zin-1-yl)-1-oxoisoindolin-2- yl)piperidine-2,6-dione Step 1: A mixture of 7-(benzyloxy)-4-(4-bromophenyl)-4-hydroxyisochroman-3-one (5 g, 1 Eq, 12 mmol) in THF (50 mL) was stirred at -78 °C under N ₂ , then isopropyl magnesium bromide solution (7.6 g, 52 mL, 1 M, 4.4 Eq, 52 mmol) was added to the mixture and stirred at -78 °C for 3 h. Then the reaction was warmed to r.t. and stirred for 13 h. The reaction was quenched with saturated aqueous NH ₄ Cl (50 mL) at ice bath, then the mixture was added H ₂ O (100 mL) and extracted with ethyl acetate (200 mL * 2). The combined extracts were dried over anhydrous Na2SO4, filtered, and concentrated to dryness in vacuum to give a residue. The residue was subjected to column chromatography over silica gel (petroleum ether/ethyl acetate from 100/0 to 70/30) The pure fractions were collected and concentrated to dryness in vacuum to give 1 (4 (benzyloxy)-2-(hydroxymethyl)phenyl)-1-(4-bromophenyl)-1-hyd roxy-3-methylbutan-2-one (1.8 g, 29 % yield, 89.4% purity) as a yellow solid. LCMS (ESI+) m/z: 451.1 (M-18) ⁺ . Step 2: A mixture of 1-(4-(benzyloxy)-2-(hydroxymethyl)phenyl)-1-(4-bromophenyl)- 1- hydroxy-3-methylbutan-2-one (1.7 g, 1 Eq, 3.2 mmol) in DCM (30 mL) was stirred at 0 °C under N ₂ , then triethylsilane (1.9 g, 2.6 mL, 5 Eq, 16 mmol) and boron trifluoride etherate (920 mg, 0.82 mL, 2 Eq, 6.5 mmol) were added to the mixture at 0 °C. Then the reaction was warmed to r.t. and stirred for 16 h. The reaction was quenched with saturated aqueous NaHCO ₃ (30 mL) at ice bath, then the mixture was added H ₂ O (100 mL) and extracted with ethyl acetate (100 mL*2). The combined extracts were dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated to dryness in vacuum to give a residue. The residue was subjected to column chromatography over silica gel (petroleum ether/ethyl acetate from 100/0 to 70/30). The pure fractions were collected and concentrated to dryness in vacuum to give 7-(benzyloxy)-4-(4-bromophenyl)-3- isopropylisochromane (1.4 g, 99 % yield) as a white solid. Step 3: A mixture of 7-(benzyloxy)-4-(4-bromophenyl)-3-isopropylisochromane (1.4 g, 1 Eq, 3.2 mmol), 2-(Dicyclohexylphosphanyl)-2',4',6'-tris(isopropyl)biphenyl (0.31 g, 0.2 Eq, 0.64 mmol), palladium diacetate (0.11 g, 0.15 Eq, 0.48 mmol), 4-(dimethoxymethyl)piperidine (0.76 g, 0.8 mL, 1.5 Eq, 4.8 mmol) and sodium 2-methylpropan-2-olate (0.46 g, 1.5 Eq, 4.8 mmol) in toluene (30 mL) was degassed and purged with N ₂ for 3 times at r.t.. Then the reaction was heated at 90 °C for 16 h. The mixture was added H ₂ O (100 mL) and extracted with ethyl acetate (100 mL * 2). The combined extracts were dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to dryness in vacuum to give a residue. The residue was subjected to column chromatography over silica gel (petroleum ether/ethyl acetate from 100/0 to 80/20). The pure fractions were collected and concentrated to dryness in vacuum to give 1-(4-(7-(benzyloxy)-3-isopropylisochroman-4- yl)phenyl)-4-(dimethoxymethyl)piperidine (720 mg, 43 % yield, 98.3% purity) as a white solid. LC-MS (ESI+) m/z: 516.2 (M+H) ⁺ . Step 4: A mixture of 1-(4-(7-(benzyloxy)-3-isopropylisochroman-4-yl)phenyl)-4- (dimethoxymethyl)piperidine (720 mg, 1 Eq, 1.37 mmol), Pd/C (720 mg, 10% wt, 0.493 Eq, 677 ^mol) and H ₂ (2.77 mg, 1 Eq, 1.37 mmol) in THF (5 mL) and MeOH (5 mL) was degassed and purged with H2 for 3 times at r.t., then the mixture was stirred at 25 °C for 1 h with H2 atmosphere (15 psi). The mixture was filtered and concentrated to dryness in vacuum to give a (250mm*30mm, 10um); mobile phase: [CO2- i-PrOH (0.1%NH3H2O)]; B% 40%-40%, 45 min). The aqueous phase was collected to dryness to give (3R, 4R)-4-(4-(4-(dimethoxymethyl) piperidin-1-yl) phenyl)-3-isopropylisochroman-7-ol (224 mg, 37.4 % yield, 97.5% purity) as a white solid. LC-MS (ESI+) m/z: 426.2 (M+H) ⁺ . Step 5: A mixture of (3R,4R)-4-(4-(4-(dimethoxymethyl)piperidin-1-yl)phenyl)-3- isopropylisochroman-7-ol (224 mg, 1 Eq, 513 ^mol) in THF (3 mL) and 10% H ₂ SO ₄ (3 mL) was stirred at 70 °C for 0.5 h. The reaction was adjust to pH=8 with saturated aqueous NaHCO ₃ (10 mL) at 0 °C. Then the mixture was added H ₂ O (20 mL) and extracted with ethyl acetate (20 mL * 2). The combined organic layers were dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to dryness in vacuum to give 1-(4-((3R,4R)-7-hydroxy-3-isopropylisochroman-4- yl)phenyl)piperidine-4-carbaldehyde (195 mg, 98.8 % yield, 98.7% purity) as a yellow solid. LC-MS (ESI+) m/z: 380.2 (M+H) ⁺ . Step 6: A mixture of 1-(4-((3R,4R)-7-hydroxy-3-isopropylisochroman-4-yl)phenyl)pi peridine-4- carbaldehyde (195 mg, 1 Eq, 507 ^mol), (S)-3-(1-oxo-5-(piperazin-1-yl)isoindolin-2- yl)piperidine-2,6-dione HCl (222 mg, 1.2 Eq, 609 ^mol), sodium acetate (208 mg, 5 Eq, 2.54 mmol) and acetic acid (91 mg, 87 ^L, 3 Eq, 1.52 mmol) in THF (3 mL) and MeOH (3 mL) was stirred at 25 °C for 1 h, then sodium triacetoxyborohydride (215 mg, 2 Eq, 1.01 mmol) was added to the mixture and stirred at 25 °C for 16 h. Then the mixture was added H ₂ O (50 mL) and extracted with ethyl acetate (50 mL * 2). The combined extracts were dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to dryness in vacuum to give a residue. The residue was subjected to column chromatography over silica gel (petroleum ether/ethyl acetate from 100/0 to 0/100 and DCM/MeOH from 100/0 to 90/10). The pure fractions were collected and concentrated to dryness in vacuum and lyophilized to dryness to give (S)-3-(5-(4-((1-(4- ((3R,4R)-7-hydroxy-3-isopropylisochroman-4-yl)phenyl)piperid in-4-yl)methyl)piperazin-1-yl)- 1-oxoisoindolin-2-yl)piperidine-2,6-dione (167.2 mg, 45.7 % yield, 95.9% purity) as a white solid. LC-MS (ESI+) m/z: 692.4 (M+H) ⁺ . LCMS: calc. for C ₄₁ H ₄₉ N ₅ O ₅ : 691.37, found: [M+H] ⁺ 692.4. HPLC: 95.898 % purity at 220 nm. ¹ HNMR (400MHz, DMSO-d6) į = 10.96 (s, 1H), 9.21 (br s, 1H), 7.52 (d, J=8.6 Hz, 1H), 7.12 - 7.04 (m, 4H), 6.77 (dd, J=6.6, 8.4 Hz, 3H), 6.50 (dd, J=2.3, 8.2 Hz, 1H), 6.44 (d, J=2.3 Hz, 1H), 5.05 (dd, J=5.1, 13.3 Hz, 1H), 4.89 (d, J=15.3 Hz, 1H), 4.67 (d, J=15.1 Hz, 1H), 4.37 - 4.29 (m, 1H), 4.24 - 4.17 (m, 1H), 3.76 (br s, 1H), 3.59 (br d, J=9.2 Hz, 2H), 3.31 - 3.22 (m, 5H), 2.91 (br t, J=12.8 Hz, 1H), 2.59 (br d, J=13.9 Hz, 5H), 2.50 - 2.46 (m, 2H), 2.44 - 2.33 (m, 1H), 2.22 (br d, J=7.3 Hz, 2H), 2.01 - 1.92 (m, 1H), 1.80 (br d, J=12.8 Hz, 2H), 1.67 (br s, 1H), 1.28 - 1.14 (m, 3H), 0.90 (d, J=6.4 Hz, 3H), 0.84 (d, J=6.7 Hz, 3H). EXAMPLE 123. Preparation of (I-369) (S)-3-(5-(4-((1-(4-((3S,4R)-3-(2,5-difluoro-4- methylphenyl)-7-hydroxyisochroman-4-yl)phenyl)piperidin-4-yl )methyl)piperazin-1-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione and (I-370) (S)-3-(5-(4-((1-(4-((3R,4S)-3-(2,5-

difluoro-4-methylphenyl)-7-hydroxyisochroman-4-yl)phenyl) piperidin-4- yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2, 6-dione Step 1: To a solution of 1,4-difluoro-2-iodo-5-methylbenzene (521 mg, 4 eq, 2.05 mmol) in THF (3 mL) was added isopropylmagnesiumchloridelithiumchloridecomplex (374 ^L, 1M, 5 eq, 2.57 mmol) dropwise at 20 °C and stirred at 20 °C for 0.5 h. Then a solvent of 2-(4-(benzyloxy)-2- (((tert-butyldimethylsilyl)oxy)methyl)phenyl)-2-(4-bromophen yl)-N-methoxy-N- methylacetamide (300 mg, 1 eq, 513 ^mol) in THF (3 mL) was added dropwise, The mixture was stirred at 50 °C for 16 h. The reaction was quenched with sat.aq. NaHCO ₃ (50 mL) and mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flashsilica gel chromatography (ethyl acetate in petroleum ether= 0% to 5%) to give a product of 2-(4-(benzyloxy)-2-(((tert-butyldimethylsilyl)oxy)methyl)phe nyl)-2-(4- bromophenyl)-1-(2,5-difluoro-4-methylphenyl)ethan-1-one (270 mg, 73 % yield) as a white solid ¹ HNMR (400MHz, CDCl ₃ ): į 7.54 (dd, J = 5.8, 9.7 Hz, 1H), 7.44 - 7.34 (m, 7H), 7.12 (d, J = 2.5 Hz, 1H), 7.03 (d, J = 8.5 Hz, 2H), 6.93 - 6.85 (m, 2H), 6.80 (dd, J = 2.6, 8.5 Hz, 1H), 6.03 (s, 1H), 5.04 (s, 2H), 4.76 (d, J = 13.2 Hz, 1H), 4.56 (d, J = 13.4 Hz, 1H), 2.28 (s, 3H), 0.89 (s, 9H), 0.01 (d, J = 2.6 Hz, 6H) Step 2: To a solution of 2-(4-(benzyloxy)-2-(((tert-butyldimethylsilyl)oxy)methyl)phe nyl)-2- (4- bromophenyl)-1-(2,5-difluoro-4-methylphenyl)ethan-1-one (270 mg, 1 eq, 414 ^mol) in DCM (2 mL) was added triethylsilane (132 ^L, 2 eq, 829 ^mol), the resulting mixture was cooled at - 78 °C and trimethylsilyl triflate (115 ^L, 1.5 eq, 621 ^mol) was added dropwise, and the resulting mixture was stirred at -78 °C for 1 h. The reaction was quenched with sat.aq. NaHCO ₃ (50 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (80 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flashsilica gel chromatography (ethyl acetate in petroleum ether= 0% to 5%) to give the product of 7-(benzyloxy)-4-(4-bromophenyl)-3-(2,5- difluoro-4- methylphenyl)isochromane (120 mg, 50% yield) as a white solid. ¹ HNMR (400MHz, CDCl ₃ ): į 7.50 - 7.34 (m, 5H), 7.19 (d, J = 8.3 Hz, 2H), 6.94 (d, J = 8.6 Hz, 1H), 6.87 - 6.79 (m, 2H), 6.77 - 6.69 (m, 3H), 6.54 (dd, J = 6.0, 10.1 Hz, 1H), 5.23 (d, J = 3.0 Hz, 1H), 5.19 - 5.00 (m, 4H), 4.20 (s, 1H), 2.19 (s, 3H) Step 3: A mixture of 7-(benzyloxy)-4-(4-bromophenyl)-3-(2,5-difluoro-4-methylphen yl) isochromane (120 mg, 1 eq, 230 ^mol), 4-(dimethoxymethyl)piperidine (51.3 mg, 1.4 eq, 322 ^mol), Xphos (21.9 mg, 0.2 eq, 46.0 ^mol), t-BuONa (44.2 mg, 2 eq, 460 ^mol) and PdOAc ₂ (5.17 mg, 0.1 eq, 23.0 ^mol) in Toluene (3 mL) was degassed and purged with N ₂ for 3 times, and then the mixture was stirred at 90 °C for 16 h under N ₂ atmosphere. The reaction was quenched with water (20 mL) and extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (30 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by flashsilica gel chromatography ( th l t t i t l th 0% t 20%) t i th d t f 1 (4 (7 (b l ) 3 (25 difluoro -4-methylphenyl)isochroman-4-yl)phenyl)-4-(dimethoxymethyl)p iperidine (80 mg, 49% yield) as a yellow solid. LC-MS (ESI ⁺ ) m/z: 600.3 (M+H) ⁺ . Step 4: To a solution of Pd/C (100 mg, 0.7 eq, 10% Purity) in THF (10 mL) was added 1-(4-(7- (benzyloxy)-3-(2,5-difluoro-4-methylphenyl)isochroman-4-yl)p henyl)-4- (dimethoxymethyl)piperidine (80 mg, 1 eq, 0.13 mmol) under N ₂ . The suspension was degassed under vacuum and purged with H ₂ several times. The mixture was stirred under H ₂ (30 psi) at 25 °C for 8 h. The reaction mixture was filtered and the filter was concentrated to give a residue which was purified by preparative HPLC (column: Phenomenex Gemini NX 150×30mm,5^m;mobile phase: [water(NH ₄ HCO ₃ )-ACN];gradient:60%-90% B over 11 min), followed by lyophilization to yield a residue. The residue was separated by chiral SFC (column:DAICEL CHIRALPAK ID (250mm*30mm,10um);mobile phase: CO ₂ - EtOH(0.1%NH ₃ H ₂ O) B%:45%, isocratic elution mode, peak 1: 1.269 min, peak 2: 2.190 min) to yield Peak 1 and Peak 2. Peak 1 was concentrated under reduced pressure to give the product of (3S,4R)-3-(2,5-difluoro-4-methylphenyl)-4-(4-(4-(dimethoxyme thyl)piperidin-1- yl)phenyl)isochroman-7-ol (30 mg, 44% yield, SFC: Rt = 1.269) as a white solid. LC-MS (ESI ⁺ ) m/z: 510.3 (M+H) ⁺ . Peak 2 was concentrated under reduced pressure to give the product of (3R,4S)-3-(2,5-difluoro-4-methylphenyl)-4-(4-(4-(dimethoxyme thyl)piperidin-1- yl)phenyl)isochroman-7-ol (30 mg, 44% yield, SFC: R _t = 2.190) as a white solid. LC-MS (ESI ⁺ ) m/z: 510.3 (M+H) ⁺ . Step 5: To a solution of (3S,4R)-3-(2,5-difluoro-4-methylphenyl)-4-(4-(4-(dimethoxyme thyl) piperidin-1-yl)phenyl)isochroman-7-ol (30 mg, 1 eq, 59 ^mol) in DCM (3 mL) was added TFA (1.0 mL, 230 eq, 14 mmol) at 20 °C. The mixture was stirred at 20 °C for 2 h. The reaction was quenched with sat.aq. NaHCO ₃ (10 mL) and extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine (20 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give the product of 1-(4-((3S,4R)-3-(2,5- difluoro-4-methylphenyl)-7- hydroxyisochroman-4-yl)phenyl)piperidine-4-carbaldehyde (20 mg, 73% yield) as a yellow solid. LC-MS (ESI ⁺ ) m/z: 464.2 (M+H) ⁺ . Step 6: To a solution of (3R,4S)-3-(2,5-difluoro-4-methylphenyl)-4-(4-(4-(dimethoxyme thyl) i idi 1 l) h l)i h 7 l (30 1 59 ^ l) i DCM (3 L) dd d TFA (1.0 mL, 230 eq, 14 mmol) at 20 °C. The mixture was stirred at 20 °C for 2 h. The reaction was quenched with sat.aq. NaHCO3 (10 mL) and extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine (20 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give the product of 1-(4-((3R,4S)-3-(2,5- difluoro-4-methylphenyl)-7- hydroxyisochroman-4-yl)phenyl)piperidine-4-carbaldehyde (20 mg, 73% yield) as a yellow solid. LC-MS (ESI ⁺ ) m/z: 464.3 (M+H) ⁺ . Step 7: To a solution of 1-(4-((3S,4R)-3-(2,5-difluoro-4-methylphenyl)-7-hydroxyisoch roman -4- yl)phenyl)piperidine-4-carbaldehyde (30 mg, 1 eq, 65 ^mol) in DCE (10 mL) and MeOH (1 mL) was added (S)-3-(1-oxo-5-(piperazin-1-yl)isoindolin-2-yl)piperidine-2, 6-dione (21 mg, 1 eq, 65 ^mol) and stirred at 20 °C for 10 min. Then sodium triacetoxyhydroborate (41 mg, 3 eq, 0.19 mmol) was added and stirred at 20 °C for 10 min. The solvent was removed to yield a residue. The residue was purified by preparative HPLC (column: Phenomenex Gemini NX 150×30mm,5^m;mobile phase:[water( NH ₄ HCO ₃ )-ACN];gradient:52%-82% B over 11 min), followed by lyophilization to give the product of (S)-3-(5-(4-((1-(4-((3S,4R)-3-(2,5-difluoro -4- methylphenyl)-7-hydroxyisochroman-4-yl)phenyl)piperidin-4-yl )methyl)piperazin-1-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione (11.7 mg, 23% yield) as a white solid. LC-MS (ESI ⁺ ) m/z: 776.3 (M+H) ⁺ . LCMS: calc. for C ₄₅ H ₄₇ F ₂ N ₅ O ₅ : 775.90, found: [M+H] ⁺ 776.3. HPLC: 100.0% purity at 254 nm. ¹ HNMR (400MHz, DMSO-d6): į 10.95 (s, 1H), 9.34 (s, 1H), 7.51 (d, J = 8.9 Hz, 1H), 7.15 - 7.00 (m, 3H), 6.79 (d, J = 8.2 Hz, 1H), 6.67 - 6.51 (m, 6H), 6.43 (dd, J = 5.9, 10.3 Hz, 1H), 5.19 - 5.00 (m, 3H), 4.93 (d, J = 15.1 Hz, 1H), 4.40 - 4.27 (m, 1H), 4.25 - 4.14 (m, 1H), 3.98 (s, 1H), 3.53 (d, J = 11.9 Hz, 2H), 3.27 (s, 6H), 3.00 - 2.83 (m, 1H), 2.65 - 2.52 (m, 2H), 2.48 (s, 3H), 2.36 (dq, J = 4.4, 13.2 Hz, 1H), 2.17 (d, J = 6.9 Hz, 2H), 2.12 (s, 3H), 2.01 - 1.90 (m, 1H), 1.79 - 1.55 (m, 3H), 1.14 (q, J = 11.8 Hz, 2H) Step 8: To a solution of 1-(4-((3R,4S)-3-(2,5-difluoro-4-methylphenyl)-7-hydroxyisoch roman-4- yl)phenyl)piperidine-4-carbaldehyde (20 mg, 1 eq, 43 ^mol) in DCE (10 mL) and MeOH (1 mL) was added (S)-3-(1-oxo-5-(piperazin-1-yl)isoindolin-2-yl)piperidine-2, 6-dione (14 mg, 1 eq, 43 ^mol) and stirred at 20 °C for 10 min. Then sodium triacetoxyhydroborate (27 mg, 3 eq, 0.13 mmol) was added and stirred at 20 °C for 10 min. The solvent was removed to yield a residue. The residue was purified by preparative HPLC (column: Phenomenex Gemini NX 150×30mm,5^m;mobile phase: [water( NH ₄ HCO ₃ )-ACN];gradient:52%-82% B over 11 min), followed by lyophilization to give the product of (S)-3-(5-(4-((1-(4-((3R,4S)-3-(2,5-difluoro- 4- methylphenyl)-7-hydroxyisochroman-4-yl)phenyl)piperidin-4-yl )methyl)piperazin-1-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione (17.3 mg, 51% yield) as a white solid. LC-MS (ESI ⁺ ) m/z: 776.3 (M+H) ⁺ . LCMS: calc. for C ₄₅ H ₄₇ F ₂ N ₅ O ₅ : 775.90, found: [M+H] ⁺ 776.3. HPLC: 100.0% purity at 254 nm. ¹ HNMR (400MHz, DMSO-d6): į 10.95 (s, 1H), 9.34 (s, 1H), 7.51 (d, J = 8.7 Hz, 1H), 7.15 - 7.00 (m, 3H), 6.79 (d, J = 8.2 Hz, 1H), 6.68 - 6.51 (m, 6H), 6.43 (dd, J = 5.8, 10.3 Hz, 1H), 5.14 (d, J = 2.7 Hz, 1H), 5.10 - 5.00 (m, 2H), 4.98 - 4.88 (m, 1H), 4.38 - 4.27 (m, 1H), 4.25 - 4.15 (m, 1H), 3.98 (s, 1H), 3.53 (d, J = 12.0 Hz, 2H), 3.27 (s, 6H), 2.97 - 2.83 (m, 1H), 2.63 - 2.53 (m, 2H), 2.48 (s, 3H), 2.36 (dq, J = 4.6, 13.2 Hz, 1H), 2.17 (d, J = 6.9 Hz, 2H), 2.12 (s, 3H), 2.01 - 1.89 (m, 1H), 1.78 - 1.57 (m, 3H), 1.22 - 1.00 (m, 2H). EXAMPLE 124. Preparation of (I-371) (S)-3-(5-(4-((1-(4-((3S,4R)-3-(4-fluoro-2- methylphenyl)-7-hydroxyisochroman-4-yl)phenyl)piperidin-4-yl )methyl)piperazin-1-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione and (I-372) (S)-3-(5-(4-((1-(4-((3R,4S)-3-(4-fluoro-2-

methylphenyl)-7-hydroxyisochroman-4-yl)phenyl)piperidin-4 -yl)methyl)piperazin-1-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione Step 1: To a solution of compound 1 (150 mg, 298 ^mol, 1 eq.), compound 2 (94.9 mg, 596 ^mol, 2 eq.), Cs ₂ CO ₃ (243 mg, 745 ^mol, 2.5 eq.) and RuPhos Pd G3 (24.9 mg, 29.8 ^mol, 0.1 eq.) in Dioxane (1.5 mL) was bubbled with N ₂ for 1 min. Then the mixture was stirred at 90 °C for 6 hours. LCMS showed the starting material was consumed completely and a major peak with desired MS was detected. The reaction mixture was concentrated to get a residue which was purified by column chromagraphy (SiO ₂ , Petroleum ether/Ethyl acetate=1/0 to 3/1) to give compound 3 (160 mg, 89 % yield) as a yellow solid. LC-MS (ESI ⁺ ) m/z: 582.3 (M+H) ⁺ . ¹ H NMR (400 MHz, DMSO-d6) į = 7.56 - 7.19 (m, 5H), 6.98 - 6.79 (m, 4H), 6.64 - 6.44 (m, 6H), 5.11 - 5.07 (m, 3H), 5.00 - 4.92 (m, 1H), 4.05 (d, J = 2.9 Hz, 1H), 3.52 (br d, J = 11.8 Hz, 2H), 3.27 - 3.21 (m, 6H), 2.48 - 2.40 (m, 4H), 2.40 - 2.34 (m, 3H), 1.70 - 1.57 (m, 3H), 1.32 - 1.21 (m, 2H) Step 2: To a solution of compound 3 (130 mg, 223 ^mol, 1 eq.) in Ethyl acetate (10 mL) was added Pd/C (238 mg, 10% Wt, 223 ^mol, 1 eq.) under N ₂ atmosphere. The suspension was degassed and purged with H ₂ for 3 times. The mixture was stirred under H ₂ (15 Psi) at 20 °C for 4 hours. LCMS showed the starting material was consumed uncompletely and a major peak with desired MS was detected. The resulting solution was filtrated and concentrated to give a crude, which was purified by prep-HPLC (column: Boston Green ODS 150*30mm*5um; mobile phase: [water (TFA)-ACN]; gradient: 22%-52% B over 12 min) to give compound 4 (80 mg, 66 % yield) as a white solid. LC-MS (ESI ⁺ ) m/z: 492.2 (M+H) ⁺ . Step 3: Compound 4 (80 mg, 0.16 mmolˈ1 eq.) was purified by SFC (Column: DAICEL CHIRALPAK AD 250mm*30mm,10um, Mobile phase: CO ₂ -EtOH (0.1%NH ₃ H ₂ O), Begin B 50% End B 50% Gradient Time (min) 45 , Flow Rate (ml/min) 80, RT: 1.606,2.025) to give compound 5 (20 mg, 25 % yield) as a white solid and compound 5A (20 mg, 25 % yield) as a white solid. Compound 5: LC-MS (ESI ⁺ ) m/z: 492.3 (M+H) ⁺ . Compound 492.2 (M+H) ⁺ . Step 4: To a solution of compound 5 (20 mg, 41 ^mol, 1 eq.) in DCM (3 mL) was added TFA (1 mL) at 20 °C. The mixture was stirred at 20 °C for 2 hours. LCMS showed the starting material was consumed completely and a major peak with desired MS was detected. Water (10 mL) and aq. NaHCO ₃ (10x 2mL) was added and the mixture was extracted with DCM (20 mL x 3). The organics were washed with brine (20 mL), dried over Na ₂ SO ₄ , filtered and concentrated to give compound 6 (15 mg, 79 % yield) as a white solid. LC-MS (ESI ⁺ ) m/z: 446.4 (M+H) ⁺ . (1 mL) at 20 °C. The mixture was stirred at 20 °C for 2 hours. LCMS showed the starting material was consumed completely and a major peak with desired MS was detected. Water (10 mL) and aq. NaHCO ₃ (20x 2mL) was added and the mixture was extracted with DCM (20 mL x 3). The organics were washed with brine (20 mL), dried over Na ₂ SO ₄ , filtered and concentrated to give compound 6A (16 mg, 85 % yield) as a white solid. LC-MS (ESI ⁺ ) m/z: 446.4 (M+H) ⁺ . Step 6: To a solution of compound 6 (15 mg, 34 ^mol, 1 eq.) and compound 7 (12 mg, 37 ^mol, 1.1 eq) in DCE (3 mL) and MeOH (1 mL) was added NaBH(OAc) ₃ (36 mg, 25 ^L, 0.17 mmol, 5 eq.) at 20 °C. Then the mixture was stirred at 20 °C for 2 hours. LCMS showed the starting material was consumed completely and a major peak with desired MS was detected. The mixture was concentrated to get the crude, which was purified by prep-HPLC (column: Phenomenex Gemini NX 150×30mm, 5^m; mobile phase: [water (NH ₄ HCO ₃ )-ACN]; gradient: 54%-84% B over 11 min) to give I-371 (13.6 mg, 53 % yield) as a white solid. LC-MS (ESI ⁺ ) m/z: 758.4 (M+H) ⁺ . LCMS: calc. for C ₄₅ H ₄₈ FN ₅ O ₅ : 757.91, found: [M+H] ⁺ 758.4. HPLC: 100.00% purity at 220 nm NMR (400 MHz, DMSO-d6) į = 10.95 (br s, 1H), 9.31 (s, 1H), 7.51 (d, J = 8.6 Hz, 1H), 7.08 - 7.02 (m, 2H), 6.94 (br d, J = 10.4 Hz, 1H), 6.79 - 6.74 (m, 1H), 6.62 - 6.54 (m, 6H), 6.52 -6.48 (m, 2H), 5.08 - 5.01 (m, 3H), 4.91 (br d, J = 15.4 Hz, 1H), 4.35 - 4.17 (m, 2H), 4.00 (br s, 1H), 3.51 (br d, J = 10.8 Hz, 2H), 3.27 (br s, 6H), 2.94 - 2.85 (m, 1H), 2.69 - 2.53 (m, 2H), 2.41 (br d, J = 3.6 Hz, 3H), 2.37 (s, 3H), 2.32 (br s, 1H), 2.21 - 2.14 (m, 2H), 1.99 - 1.91 (m, 1H), 1.77 - 1.60 (m, 3H), 1.15 (br d, J = 13.0 Hz, 2H) Step 7: To a solution of compound 6A (20 mg, 45 ^mol, 1 eq.) and compound 7 (16 mg, 49 ^mol, 1.1 eq.) in DCE (3 mL) and MeOH (1 mL) was added NaBH(OAc) ₃ (48 mg, 33 ^L, 0.22 mmol, 5 eq.) at 20 °C. Then the mixture was stirred at 20 °C for 2 hours. LCMS showed the starting material was consumed completely and a major peak with desired MS was detected. The mixture was concentrated to get the crude, which was purified by prep-HPLC (column: Phenomenex Gemini NX 150×30mm, 5^m; mobile phase: [water (NH4HCO3)-ACN]; gradient: 49%-79% B over 11 min) to give I-372 (15.5 mg, 46 % yield) as a white solid. LC-MS (ESI ⁺ ) m/z: 758.4 (M+H) ⁺ . LCMS: calc. for C ₄₅ H ₄₈ FN ₅ O ₅ : 757.91, found: [M+H] ⁺ 758.4. HPLC: 100.00% purity at 220 nm NMR (400 MHz, DMSO-d6) į = 11.01 - 10.91 (m, 1H), 9.31 (s, 1H), 7.51 (d, J = 8.8 Hz, 1H), 7.08 - 7.02 (m, 2H), 6.94 (br d, J = 9.4 Hz, 1H), 6.77 (br d, J = 7.9 Hz, 1H), 6.62 - 6.54 (m, 6H), 6.53 - 6.47 (m, 2H), 5.09 - 5.01 (m, 3H), 4.95 - 4.87 (m, 1H), 4.34 - 4.17 (m, 2H), 4.00 (br d, J = 2.4 Hz, 1H), 3.51 (br d, J = 11.1 Hz, 2H), 3.27 (br s, 6H), 2.92 - 2.86 (m, 1H), 2.61 - 2.56 (m, 2H), 2.47 - 2.40 (m, 3H), 2.37 (s, 3H), 2.35 - 2.31 (m, 1H), 2.18 (br d, J = 6.8 Hz, 2H), 1.99 - 1.93 (m, 1H), 1.77 - 1.61 (m, 3H), 1.23 - 1.12 (m, 2H). EXAMPLE 125. Preparation of (I-373) (S)-3-(5-(4-((1-(4-((3S,4R)-7-hydroxy-3-(3- methoxyphenyl)isochroman-4-yl)phenyl)piperidin-4-yl)methyl)p iperazin-1-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione and (I-374) (S)-3-(5-(4-((1-(4-((3R,4S)-7-hydroxy-3-

(3-methoxyphenyl)isochroman-4-yl)phenyl)piperidin-4-yl)me thyl)piperazin-1-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione I-373 I-374 Step 1: A solution of 1 (50 mg, 1 Eq, 86 ^mol) and Pd/C (92 mg, 10% Wt, 1 Eq, 86 ^mol) in EtOAc (5 mL) and then degassed and purged with H ₂ for 3 times, and then the mixture was stirred at 15 °C for 3 hours under H ₂ atmosphere. The reaction mixture was filtered and concentrated under reduced pressure to get the product. LCMS showed that the starting material was consumed, and the desired product was detected. The mixture was filtered and concentrated under vacuum to give the product. The product was purified by SFC (condition: CO ₂ -EtOH (0.1%NH3H2O), column: DAICEL CHIRALPAK AD (250mm x 30 mm, 10 um), Begin B: 40, End B: 40) to give 2 (8 mg, 20% yield) as white solid and 2A (9 mg, 20% yield) as white solid. 2: LC-MS (ESI ⁺ ) m/z: 490.2 (M+H) ⁺ . 2A: LC-MS (ESI ⁺ ) m/z: 490.1 (M+H) ⁺ . Step 2: To a solution of 2 (8 mg, 1 Eq, 0.02 mmol) in DCM (1 mL) was added Trifluoroacetic acid (0.4 g, 0.3 mL, 200 Eq, 4 mmol) at 15 °C. Then the mixture was stirred at 15 °C for 20 min. LCMS showed that the desired product was detected. Then the mixture was filtered and concentrated under vacuum to give the 3 (10 mg, crude) as red oil. LC-MS (ESI ⁺ ) m/z: 462.3 (M+H+18) ⁺ Step 3: To a solution of 2A (9 mg, 1 Eq, 0.02 mmol) in DCM (1 mL) was added Trifluoroacetic acid (0.4 g, 0.3 mL, 200 Eq, 4 mmol) at 15 °C. Then the mixture was stirred at 15 °C for 20 min. LCMS showed that the desired product was detected. Then the mixture was filtered and concentrated under vacuum to give the 3 (10 mg, crude) as red oil. LC-MS (ESI ⁺ ) m/z: 462.3 (M+H+18) ⁺ Step 4: To a solution of 3 (10 mg, 1 Eq, 23 ^mol) in DCE (1 mL) and MeOH (1 mL) was added 034 (15 mg, 2 Eq, 45 ^mol) and Sodium triacetoxyborohydride (24 mg, 17 ^L, 5 Eq, 0.11 mmol) at 15 °C. Then the mixture was stirred at 15 °C for 10 min. LCMS showed that the desired product was detected. The mixture was filtered and concentrated under vacuum to give the crude. The residue was purified by prep-HPLC (FA condition: Column: Boston Green ODS 150 x 30 mm x 5 um; Condition: water (FA)-ACN, Begin B 10, End B 40, Gradient Time (min) 18, 100% B Hold Time (min) 2, Flow Rate (mL/min) 25.) to give I-373 (3.5 mg, 21% yield) as white solid. LCMS: calc. for C ₄₅ H ₄₉ N ₅ O _6: 755.92, found: [M+H] ⁺ 756.5. HPLC: 100.00% purity at 220 nm ¹ H NMR (400 MHz, DMSO-d ₆ ) į = 10.94 (s, 1H), 9.29 (s, 1H), 8.17 (s, 1H), 7.51 (d, J = 8.6 Hz, 1H), 7.11 - 6.99 (m, 3H), 6.80 - 6.49 (m, 10H), 5.12 - 4.85 (m, 4H), 4.35 - 4.17 (m, 2H), 4.00 (d, J = 2.0 Hz, 1H), 3.55 (s, 3H), 3.53 - 3.48 (m, 2H), 3.27 (br s, 8H), 2.95 - 2.84 (m, 1H), 2.62 - 2.52 (m, 3H), 2.39 - 2.32 (m, 1H), 2.23 - 2.12 (m, 2H), 2.01 - 1.91 (m, 1H), 1.74 (br d, J = 12.2 Hz, 2H), 1.68 - 1.57 (m, 1H), 1.21 - 1.08 (m, 2H). Step 5: To a solution of 3 (10 mg, 1 Eq, 23 ^mol) in DCE (1 mL) and MeOH (1 mL) was added 034 (15 mg, 2 Eq, 45 ^mol) and Sodium triacetoxyborohydride (24 mg, 17 ^L, 5 Eq, 0.11 mmol) at 15 °C. Then the mixture was stirred at 15 °C for 10 min. LCMS showed that the desired product was detected. The mixture was filtered and concentrated under vacuum to give the crude. The residue was purified by prep-HPLC (FA condition: Column: Boston Green ODS 150 x 30 mm x 5 um; Condition: water (FA)-ACN, Begin B 10, End B 40, Gradient Time (min) 18, 100% B Hold Time (min) 2, Flow Rate (mL/min) 25.) to give I-374 (3.6 mg, 21% yield) as white solid. LCMS: calc. for C ₄₅ H ₄₉ N ₅ O _6: 755.92, found: [M+H] ⁺ 756.5. HPLC: 100.00% purity at 220 nm ¹ H NMR (400 MHz, DMSO-d ₆ ) į = 10.94 (s, 1H), 9.29 (br s, 1H), 8.17 (s, 1H), 7.51 (d, J = 8.7 Hz, 1H), 7.09 - 7.02 (m, 3H), 6.79 - 6.52 (m, 10H), 5.09 - 4.87 (m, 4H), 4.35 - 4.17 (m, 2H), 4.00 (d, J = 3.0 Hz, 1H), 3.55 (s, 3H), 3.53 - 3.48 (m, 2H), 3.27 (br s, 8H), 2.93 - 2.85 (m, 1H), 2.61 - 2.53 (m, 3H), 2.38 - 2.31 (m, 1H), 2.18 (br d, J = 6.7 Hz, 2H), 2.00 - 1.91 (m, 1H), 1.74 (br d, J = 12.4 Hz, 2H), 1.68 - 1.58 (m, 1H), 1.19 - 1.09 (m, 2H). EXAMPLE 126. Preparation of (I-221) (S)-3-(5-(4-((1-(4-((3S,4S)-7-hydroxy-3- isobutylisochroman-4-yl)phenyl)piperidin-4-yl)methyl)piperaz in-1-yl)-1-oxoisoindolin-2- yl)piperidine-2,6-dione and (I-222) (S)-3-(5-(4-((1-(4-((3S,4R)-7-hydroxy-3- isobutylisochroman-4-yl)phenyl)piperidin-4-yl)methyl)piperaz in-1-yl)-1-oxoisoindolin-2- yl)piperidine-2,6-dione and (I-223) (S)-3-(5-(4-((1-(4-((3R,4S)-7-hydroxy-3- isobutylisochroman-4-yl)phenyl)piperidin-4-yl)methyl)piperaz in-1-yl)-1-oxoisoindolin-2- yl)piperidine-2,6-dione and (I-224) (S)-3-(5-(4-((1-(4-((3R,4R)-7-hydroxy-3-

isobutylisochroman-4-yl)phenyl)piperidin-4-yl)methyl)pipe razin-1-yl)-1-oxoisoindolin-2- yl)piperidine-2,6-dione

Step 1: To a solution of 3 (1 g, 1 Eq, 2 mmol) in THF (10 mL) was added 2 (1 g, 9 mL, 1 molar, 5 Eq, 9 mmol) at 0 °C under N ₂ . Then the mixture was stirred at 20 °C for 12 hour under N ₂ . TLC showed that the new point was detected. NH ₄ Cl (sat.aq.) (10 mL) was added into the mixture. Then the mixture was filtered and concentrated under vacuum to give the crude. The crude product was purified by flash silica gel chromatography (PE/EA=1/0 to 10/1) to give 3 (250 mg, 30% yield) as colorless oil. 1H NMR (500 MHz, CHLOROFORM-d) į = 7.45 - 7.32 (m, 7H), 7.08 - 7.02 (m, 2H), 7.01 - 6.95 (m, 2H), 6.91 - 6.86 (m, 1H), 5.36 (s, 1H), 5.07 (s, 2H), 4.71 - 4.48 (m, 2H), 2.41 (d, J = 7.0 Hz, 2H), 2.24 - 2.12 (m, 1H), 0.93 - 0.86 (m, 15H), 0.07 (d, J = 10.4 Hz, 6H). Step 2: To a solution of 3 (230 mg, 1 Eq, 395 ^mol) in DCM (1 mL) was added Triethylsilane (138 mg, 189 ^L, 3 Eq, 1.19 mmol) at 15 °C. Then the mixture was cooled to -78 °C. The Trimethylsilyl triflate (176 mg, 146 ^L, 2 Eq, 791 ^mol) was added into the mixture at -78 °C. Then the mixture was stirred at -78 °C for 1 hour. TLC showed that the new point was detected. NaHCO ₃ (sat.aq.) (5 mL) was added into the mixture. The mixture was purified by Pre-TLC (PE/EA=10/1) give 4 (170 mg, 86% yield) as white solid. ¹ H NMR (400 MHz, CHLOROFORM-d) į = 7.46 - 7.33 (m, 7H), 7.08 - 6.99 (m, 2H), 6.90 - 6.62 (m, 3H), 5.31 (s, 1H), 5.06 - 5.01 (m, 2H), 5.00 - 4.85 (m, 2H), 3.96 - 3.68 (m, 2H), 1.92 - 1.78 (m, 1H), 1.21 - 0.93 (m, 2H), 0.89 - 0.74 (m, 6H). Step 3: To a solution of 4 (170 mg, 1 Eq, 377 ^mol) in 1, 4-dioxane (8 mL) was added 5 (120 mg, 2 Eq, 753 ^mol) and Cs ₂ CO ₃ (368 mg, 3 Eq, 1.13 mmol) at 15 °C. Then the (2- Dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)[2-(2 '-amino-1,1'- biphenyl)]palladium(II) methanesulfonate (47.2 mg, 0.15 Eq, 56.5 ^mol) was added into the mixture at 15 °C. The mixture was stirred at 90 °C for 3 hour under N ₂ . LCMS showed that the starting material was consumed and the desired product was detected. The mixture was filtered and concentrated under vacuum to give the crude. The crude was purified by Pre-TLC (PE/EA=3/1) to give 6 (200 mg, 71.8% yield) as yellow solid. LC-MS (ESI ⁺ ) m/z: 530.2 (M+H) ⁺ . Step 4: A solution of 6 (180 mg, 1 Eq, 340 ^mol) and Pd/C (362 mg, 10% Wt, 1 Eq, 340 ^mol) in EtOAc (5 mL) and then degassed and purged with H ₂ for 3 times, and then the mixture was stirred at 15 °C for 3 hour under H ₂ atmosphere. LCMS showed that the starting material was consumed and the desired product was detected. The mixture was filtered and concentrated under vacuum to give the product The product was purified by SFC (condition: CO2-EtOH (0.1%NH3H2O), column: DAICEL CHIRALPAK IG (250mm x 30 mm, 10 um), Begin B: 45, End B: 45) to give 7 (14.5 mg, 9.63% yield) as white solid, 7A (10 mg, 6.6% yield) as white solid, 7B (10 mg, 6.6% yield) as white solid and 7C (10.5 mg, 6.97% yield) as white solid. 7: LC-MS (ESI ⁺ ) m/z: 440.2 (M+H) ⁺ . 7A: LC-MS (ESI ⁺ ) m/z: 440.1 (M+H) ⁺ . 7B: LC-MS (ESI ⁺ ) m/z: 440.2 (M+H) ⁺ . 7C: LC-MS (ESI ⁺ ) m/z: 440.2 (M+H) ⁺ . Step 5: To a solution of 7 (9.5 mg, 1 Eq, 22 ^mol) in DCM (1 mL) was added Trifluoroacetic acid (0.4 g, 0.3 mL, 2e+2 Eq, 4 mmol) at 15 °C. Then the mixture was stirred at 15 °C for 20 min. LCMS showed that the desired product was detected. Then the mixture was filtered and concentrated under vacuum to give the 8 (10 mg, crude) as red oil. LC-MS (ESI ⁺ ) m/z: 412.1 (M+H+18) ⁺ Step 6: To a solution of 7A (15 mg, 1 Eq, 34 ^mol) in DCM (1 mL) was added Trifluoroacetic acid (0.4 g, 0.3 mL, 2e+2 Eq, 4 mmol) at 15 °C. Then the mixture was stirred at 15 °C for 20 min. LCMS showed that the desired product was detected. Then the mixture was filtered and concentrated under vacuum to give the 8A (15 mg, crude) as red oil. LC-MS (ESI ⁺ ) m/z: 412.3 (M+H+18) ⁺ Step 7: To a solution of 7B (10 mg, 1 Eq, 23 ^mol) in DCM (1 mL) was added Trifluoroacetic acid (0.4 g, 0.3 mL, 2e+2 Eq, 4 mmol) at 15 °C. Then the mixture was stirred at 15 °C for 20 min. LCMS showed that the desired product was detected. Then the mixture was filtered and concentrated under vacuum to give the 8B (10 mg, crude) as red oil. LC-MS (ESI ⁺ ) m/z: 412.2 (M+H+18) ⁺ Step 8: To a solution of 7C (10.5 mg, 1 Eq, 23.9 ^mol) in DCM (1 mL) was added Trifluoroacetic acid (0.4 g, 0.3 mL, 2e+2 Eq, 4 mmol) at 15 °C. Then the mixture was stirred at 15 °C for 20 min. LCMS showed that the desired product was detected. Then the mixture was fil d d d d i h 8C (10 d ) d il LC-MS (ESI ⁺ ) m/z: 412.2 (M+H+18) ⁺ Step 9: To a solution of 8 (10 mg, 1 Eq, 25 ^mol) in DCE (1 mL) and MeOH (1 mL) was added 034 (17 mg, 2 Eq, 51 ^mol) and Sodium triacetoxyborohydride (27 mg, 19 ^L, 5 Eq, 0.13 mmol) at 15 °C. Then the mixture was stirred at 15 °C for 0.5 hour. LCMS showed that the desired product was detected. The mixture was filtered and concentrated under vacuum to give the crude. The residue was purified by prep-HPLC (FA condition: Column: Boston Green ODS 150 x 30 mm x 5 um; Condition: water (FA)-ACN, Begin B 10, End B 40, Gradient Time (min) 18, 100% B Hold Time (min) 2, Flow Rate (mL/min) 25.) to give I-221 (9.8 mg, 55% yield) as a white solid. LC-MS (ESI ⁺ ) m/z: 706.4 (M+H) ⁺ LCMS: calc. for C ₄₂ H ₅₁ N ₅ O ₅ : 705.90, found: [M+H] ⁺ 706.4. HPLC: 100.00% purity at 220 nm ¹ H NMR (400 MHz, DMSO-d ₆ ) į = 10.95 (s, 1H), 9.19 (s, 1H), 8.13 (s, 1H), 7.66 - 7.25 (m, 2H), 7.10 (br s, 1H), 6.97 - 6.82 (m, 4H), 6.50 - 6.35 (m, 3H), 5.13 - 5.00 (m, 1H), 4.82 - 4.66 (m, 2H), 4.37 - 4.18 (m, 2H), 3.68 - 3.55 (m, 4H), 3.32 - 3.20 (m, 8H), 2.95 - 2.87 (m, 1H), 2.67 - 2.58 (m, 3H), 2.44 - 2.11 (m, 3H), 2.00 - 1.92 (m, 1H), 1.90 - 1.67 (m, 4H), 1.43 - 1.35 (m, 1H), 1.31 - 1.16 (m, 2H), 1.12 - 1.02 (m, 1H), 0.84 - 0.68 (m, 6H). Step 10: To a solution of 8 (15 mg, 1 Eq, 38 ^mol) in DCE (1 mL) and MeOH (1 mL) was added 034 (25 mg, 2 Eq, 76 ^mol) and Sodium triacetoxyborohydride (40 mg, 5 Eq, 0.19 mmol) at 15 °C. Then the mixture was stirred at 15 °C for 0.5 hour. LCMS showed that the desired product was detected. The mixture was filtered and concentrated under vacuum to give the crude. The residue was purified by prep-HPLC (FA condition: Column: Boston Green ODS 150 x 30 mm x 5 um; Condition: water (FA)-ACN, Begin B 10, End B 40, Gradient Time (min) 18, 100% B Hold Time (min) 2, Flow Rate (mL/min) 25.) to give I-222 (8.1 mg, 30% yield) as a white solid. LC-MS (ESI+) m/z: 706.4 (M+H) ⁺ LCMS: calc. for C ₄₂ H ₅₁ N ₅ O ₅ : 705.90, found: [M+H] ⁺ 706.4. HPLC: 100.00% purity at 220 nm ¹ H NMR (400 MHz, DMSO-d6) į = 10.95 (s, 1H), 9.19 (s, 1H), 8.13 (s, 1H), 7.65 - 7.18 (m, 4.67 (m, 2H), 4.35 - 4.18 (m, 2H), 3.67 - 3.55 (m, 4H), 3.32 - 3.12 (m, 8H), 2.93 - 2.86 (m, 1H), 2.61 (br d, J = 10.8 Hz, 3H), 2.43 - 2.20 (m, 3H), 1.99 - 1.93 (m, 1H), 1.86 - 1.67 (m, 4H), 1.45 - 1.35 (m, 1H), 1.29 - 1.18 (m, 2H), 1.10 - 1.02 (m, 1H), 0.82 - 0.68 (m, 6H). Step 11: To a solution of 8 (10 mg, 1 Eq, 25 ^mol) in DCE (1 mL) and MeOH (1 mL) was added 034 (17 mg, 2 Eq, 51 ^mol) and Sodium triacetoxyborohydride (27 mg, 19 ^L, 5 Eq, 0.13 mmol) at 15 °C. Then the mixture was stirred at 15 °C for 0.5 hour. LCMS showed that the desired product was detected. The mixture was filtered and concentrated under vacuum to give the crude. The residue was purified by prep-HPLC (FA condition: Column: Boston Green ODS 150 x 30 mm x 5 um; Condition: water (FA)-ACN, Begin B 10, End B 40, Gradient Time (min) 18, 100% B Hold Time (min) 2, Flow Rate (mL/min) 25.) to give I-223 (11.1 mg, 59% yield) as white solid. LC-MS (ESI+) m/z: 706.4 (M+H) ⁺ LCMS: calc. for C ₄₂ H ₅₁ N ₅ O ₅ : 705.90, found: [M+H] ⁺ 706.4. HPLC: 95.27% purity at 220 nm ¹ H NMR (400 MHz, DMSO-d6) į = 10.95 (s, 1H), 9.20 (s, 1H), 8.13 (s, 1H), 7.70 - 7.19 (m, 2H), 7.09 - 7.06 (m, 1H), 6.95 (br d, J = 8.6 Hz, 2H), 6.79 - 6.69 (m, 3H), 6.52 - 6.43 (m, 2H), 5.08 - 5.01 (m, 1H), 4.85 - 4.66 (m, 2H), 4.36 - 4.18 (m, 2H), 3.81 - 3.76 (m, 1H), 3.63 - 3.56 (m, 3H), 3.32 - 3.18 (m, 8H), 2.93 - 2.85 (m, 1H), 2.58 (br d, J = 13.7 Hz, 3H), 2.44 - 2.15 (m, 3H), 1.98 - 1.91 (m, 1H), 1.86 - 1.67 (m, 4H), 1.27 - 1.14 (m, 2H), 1.05 - 0.92 (m, 2H), 0.81 (t, J = 6.1 Hz, 6H) Step 12: To a solution of 8C (10 mg, 1 Eq, 38 ^mol) in DCE (1 mL) and MeOH (1 mL) was added 034 (25 mg, 2 Eq, 76 ^mol) and Sodium triacetoxyborohydride (40 mg, 19 ^L, 5 Eq, 0.19 mmol) at 15 °C. Then the mixture was stirred at 15 °C for 0.5 hour. LCMS showed that the desired product was detected. The mixture was filtered and concentrated under vacuum to give the crude. The residue was purified by prep-HPLC (FA condition: Column: Boston Green ODS 150 x 30 mm x 5 um; Condition: water (FA)-ACN, Begin B 10, End B 40, Gradient Time (min) 18, 100% B Hold Time (min) 2, Flow Rate (mL/min) 25.) to give I-224 (9.2 mg, 50% yield) as a white solid. LC-MS (ESI+) m/z: 706.4 (M+H) ⁺ LCMS: calc. for C42H51N5O5: 705.90, found: [M+H] ⁺ 706.4. HPLC: 97.36% purity at 220 nm ¹ H NMR (400 MHz, DMSO-d ₆ ) į = 10.95 (s, 1H), 9.20 (s, 1H), 8.13 (s, 1H), 7.67 - 7.20 (m, 2H), 7.09 - 7.06 (m, 1H), 6.95 (br d, J = 8.6 Hz, 2H), 6.80 - 6.68 (m, 3H), 6.54 - 6.41 (m, 2H), 5.10 - 5.00 (m, 1H), 4.85 - 4.66 (m, 2H), 4.37 - 4.18 (m, 2H), 3.82 - 3.76 (m, 1H), 3.64 - 3.57 (m, 3H), 3.19 (br d, J = 5.4 Hz, 8H), 2.94 - 2.86 (m, 1H), 2.58 (br d, J = 14.5 Hz, 3H), 2.42 - 2.14 (m, 3H), 1.99 - 1.92 (m, 1H), 1.85 - 1.64 (m, 4H), 1.22 (br d, J = 10.8 Hz, 2H), 1.04 - 0.91 (m, 2H), 0.81 (t, J = 6.1 Hz, 6H). EXAMPLE 127. Preparation of (I-375) (S)-3-(5-(4-((1-(4-((3S,4R)-3-(4-fluoro-3- methylphenyl)-7-hydroxyisochroman-4-yl)phenyl)piperidin-4-yl )methyl)piperazin-1-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione and (I-376) (S)-3-(5-(4-((1-(4-((3R,4S)-3-(4-fluoro-3-

methylphenyl)-7-hydroxyisochroman-4-yl)phenyl)piperidin-4 -yl)methyl)piperazin-1-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione Step 1: A mixture of compound 1 (400.0 mg, 1 eq., 794.6 ^mol), 2 (253.0 mg, 2 eq., 1.589 mmol), (2-Dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)[2 -(2'-amino-1,1'- biphenyl)]palladium(II) methanesulfonate (99.69 mg, 0.15 eq., 119.2 ^mol) and Cs ₂ CO ₃ (776.7 mg, 3 eq., 2.384 mmol) in Dioxane (20 mL) was degassed and purged with N ₂ for 3 times, and then the mixture was stirred at 90 °C for 3 hours under N ₂ atmosphere. LCMS showed that the starting material was consumed and the desired product was detected. The reaction mixture was filtered under reduced pressure to give a residue. The residue was poured into water (20 mL). The aqueous phase was extracted with ethyl acetate (40 mL*3). The combined organic phase was washed with brine (20 mL*3), dried with anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuum. The residue was purified by silica gel chromatography (column height: 250 mm, diameter: 100 mm, 100-200 mesh silica gel, Petroleum ether/Ethyl acetate=3:1) to afford compound 3 (413 mg, 710 ^mol, 89.3 %) as yellow oil. The reaction mixture was filtered under reduced pressure to give a compound. LC-MS (ESI ⁺ ) m/z: 582.4(M+H) ⁺ . Step 2: A mixture of compound 3 (450.0 mg, 1 eq., 773.6 ^mol) and Pd/C (493.9 mg, 10% Wt, 0.6 eq., 464.1 ^mol) was added in EtOAc (6 mL), and then degassed and purged with H ₂ for 3 times, and then the mixture was stirred at 15 psi and 25 °C for 6 hours under H ₂ atmosphere. The reaction mixture was filtered and concentrated under reduced pressure to get the product. The residue was purified by prep-HPLC (column: Boston Green ODS 150*30mm*5um; mobile phase: [water (TFA)-ACN]; gradient: 29%-59% B over 18 min) to give product. Compound 4 (320.5 mg, 652.0 ^mol, 84.28 %) was obtained as a white solid. LC-MS (ESI ⁺ ) m/z: 492.7 (M+H) ⁺ . Step 3: Compound 4 (450 mg, 1 eq., 915 ^mol) was separated by chiral SFC (Column: DAICELCHIRALPAKAD (250mm*30mm*10um), Condition CO ₂ -EtOH (0.1%NH ₃ H ₂ O) Begin B 55% End B 55%) Flow Rate (ml/min): 110) compound 5A (100 mg, 203 ^mol, 22.2 %), compound 5B (90 mg, 0.18 mmol, 20 %). Step 4: To a solution of compound 5A (80 mg, 1 eq., 0.16 mmol) in DCM (5 mL) was added TFA (19 mg, 13 ^L, 1 eq., 0.16 mmol). The mixture was stirred at 25 °C for 0.5 hr. LCMS showed that the starting material was consumed and the desired product was detected. The reaction liquid was dried with N ₂ at 0 °C to give compound 6 (70 mg, 0.16 mmol, 97 %) was obtained as yellow oil which was used in the next step without further purification. LC-MS (ESI+) m/z: 464.3 (M+H) ⁺ . Step 5: To a solution of compound 5B (70 mg, 1 eq., 0.14 mmol) in DCM (4 mL) was added TFA (16 mg, 11 ^L, 1 eq., 0.14 mmol). The mixture was stirred at 25 °C for 0.2 hr. LCMS showed that the starting material was consumed and the desired product was detected. The reaction liquid is dried with N ₂ at 0 °C to give compound 6A (60.5 mg, 136 ^mol, 95 %) was obtained as yellow oil which was used in the next step without further purification. LC-MS (ESI+) m/z: 464.2(M+H) ⁺ . Step 6: To a solution of compound 6 (90 mg, 1 eq., 0.20 mmol) in DCE (3 mL) and MeOH (2 mL) was added compound 7 (66 mg, 1 eq., 0.20 mmol) at 25 °C. After addition, the mixture was stirred at this temperature for 0.5 hr, and then NaBH(OAc) ₃ (86 mg, 60 ^L, 2 eq., 0.40 mmol) was added at 25 °C. The resulting mixture was stirred at 25 °C for 0.5 hr. The reaction mixture was concentrated to yield a residue. The residue was purified by preparative HPLC (column: Boston Green ODS 150 * 30 mm * 5um; mobile phase: [water (FA) - ACN]; B%: 12%-42%, 18min), followed by lyophilization to yield I-375 (78.6 mg, 104 ^mol, 51 %) was obtained as a white solid. LC-MS (ESI+) m/z: 758.4 [M+H] ⁺ . LCMS: calc. for C45H48FN5O5: 757.36, found: [M+H] ⁺ 758.4. HPLC: 100% purity at 220 nm. NMR (400 MHz, DMSO-d ₆ ) į ppm 10.94 (s, 1 H) 9.28 (s, 1 H) 8.12 (s, 1 H) 7.55 (br d, J=14.78 Hz, 1 H) 7.27 - 7.33 (m, 1 H) 7.08 (br s, 1 H) 6.84 - 6.90 (m, 3 H) 6.76 (d, J=8.11 Hz, 1 H) 6.51 - 6.60 (m, 6 H) 5.00 - 5.07 (m, 2 H) 4.86 - 4.96 (m, 2 H) 4.17 - 4.34 (m, 2 H) 3.86 - 4.10 (m, 2 H) 3.41 - 3.64 (m, 7 H) 2.85 - 2.93 (m, 1 H) 2.51 - 2.68 (m, 6 H) 2.29 - 2.43 (m, 2 H) 2.07 (s, 3 H) 1.91 - 1.98 (m, 1 H) 1.63 - 1.83 (m, 3 H) 1.11 - 1.26 (m, 2 H) Step 7: To a solution of compound 6A (80 mg, 1 eq., 0.18 mmol) in DCE (3 mL) and MeOH (2 mL) was added compound 7 (59 mg, 1 eq., 0.18 mmol) at 25 °C. After addition, the mixture was stirred at this temperature for 0.5 hr, and then NaBH(OAc) ₃ (76 mg, 53 ^L, 2 eq., 0.36 mmol) was added at 25 °C. The resulting mixture was stirred at 25 °C for 1 hr. The reaction mixture was concentrated to yield a residue. The residue was purified by preparative HPLC (column: Boston Green ODS 150 * 30 mm * 5um; mobile phase: [water (FA) - ACN]; B%: 12%-42%, 18min), followed by lyophilization to yield I-376 (77 mg, 0.10 mmol, 57 %) was obtained as a white solid. LC-MS (ESI+) m/z: 758.4 [M+H] ⁺ . LCMS: calc. for C45H48FN5O5: 757.91, found: [M+H] ⁺ 758.4. HPLC: 98.57 % purity at 220 nm ¹ H NMR (400 MHz, DMSO-d ₆ ) į ppm 10.94 (s, 1 H) 9.29 (s, 1 H) 8.13 (s, 1 H) 7.52 - 7.60 (m, 1 H) 7.15 - 7.39 (m, 1 H) 7.07 (br s, 1 H) 6.86 - 6.91 (m, 3 H) 6.78 (d, J=7.99 Hz, 1 H) 6.54 - 6.61 (m, 6 H) 5.02 - 5.08 (m, 2 H) 4.87 - 4.96 (m, 2 H) 4.18 - 4.35 (m, 2 H) 3.99 (br s, 1 H) 3.52 (br d, J=10.85 Hz, 2 H) 3.28 (br d, J=2.15 Hz, 6 H) 2.86 - 2.94 (m, 1 H) 2.60 (br s, 4 H) 2.30 - 2.43 (m, 2 H) 2.06 - 2.21 (m, 5 H) 1.93 - 1.99 (m, 1 H) 1.61 - 1.78 (m, 3 H) 1.11 - 1.24 (m, 2 H). EXAMPLE 128. Preparation of (I-377) (S)-3-(5-(4-((1-(4-((3S,4R)-3-(3-fluoro-5- methylphenyl)-7-hydroxyisochroman-4-yl)phenyl)piperidin-4-yl )methyl)piperazin-1-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione and (I-378) (S)-3-(5-(4-((1-(4-((3R,4S)-3-(3-fluoro-5- methylphenyl)-7-hydroxyisochroman-4-yl)phenyl)piperidin-4-yl )methyl)piperazin-1-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione Step 1: A mixture of 7-(benzyloxy)-4-(4-bromophenyl)-3-(3-fluoro-5- methylphenyl)isochromane (240 mg, 477 ^mol), 4-(dimethoxymethyl)piperidine (106 mg, 667 ^mol), 2-methylpropan-2-olate pottasium (134 mg, 1.19 mmol), and XPhos-Pd-G3 (80.7 mg, 95.3 ^mol) in Toluene (5 mL) was degassed and purged with N ₂ for 3 times, and then the mixture was stirred at 90 °C for 16 h under N ₂ atmosphere. The reaction was quenched with water (20 mL) and extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (30 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ethyl acetate in petroleum ether= 0% to 20%) to give the product of 1-(4-(7-(benzyloxy)-3-(3-fluoro-5- methylphenyl)isochroman-4-yl)phenyl)-4-(dimethoxymethyl)pipe ridine (150 mg, 48% yield) as a yellow solid. LC-MS (ESI ⁺ ) m/z: 582.4 (M+H) ⁺ . Step 2: To a solution of Pd/C (150 mg, 10% Purity) in THF (10 mL) was added 1-(4-(7- (benzyloxy)-3-(3-fluoro-5-methylphenyl)isochroman-4-yl)pheny l)-4- (dimethoxymethyl)piperidine (150 mg, 258 ^mol) under N ₂ . The suspension was degassed under vacuum and purged with H2 several times. The mixture was stirred under H2 (30 psi) at 25 °C for 8 h. The reaction mixture was filtered and the filter was concentrated. The residue was purified by flash silica gel chromatography (ethyl acetate in petroleum ether= 0% to 40%) to give a residue which was separated by chiral SFC (column: DAICEL CHIRALPAK ID (250mm*30mm, 10um); mobile phase: CO ₂ -EtOH (0.1%NH ₃ H ₂ O) B%:45%%, isocratic elution mode, peak 1: 1.586 min, peak 2: 2.190 min) to yield Peak 1 and Peak 2. Peak 1 was concentrated under reduced pressure to give the product of (3S,4R)-4-(4-(4- (dimethoxymethyl)piperidin-1-yl)phenyl)-3-(3-fluoro-5-methyl phenyl)isochroman-7-ol (40 mg, 32% yield, SFC: R _t = 1.586) as a white solid. LC-MS (ESI ⁺ ) m/z: 492.3 (M+H) ⁺ . Peak 2 was concentrated under reduced pressure to yield a product. (3R,4S)-4-(4-(4- (dimethoxymethyl)piperidin-1-yl)phenyl)-3-(3-fluoro-5-methyl phenyl)isochroman-7-ol (40 mg, 32% yield, SFC: R _t = 2.190) as a white solid. LC-MS (ESI ⁺ ) m/z: 492.4 (M+H) ⁺ . Step 3: To a solution of (3S,4R)-4-(4-(4-(dimethoxymethyl)piperidin-1-yl)phenyl)-3-(3 -fluoro-5- methylphenyl)isochroman-7-ol (40 mg, 81 ^mol) in DCM (3 mL) was added TFA (1 mL, 0.01 mol) at 20 °C. The mixture was stirred at 20 °C for 2 h. The reaction was quenched with sat.aq. NaHCO3 (10 mL) and extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine (20 mL) dried over Na ₂ SO ₄ filtered and concentrated under reduced pressure to give the product of 1-(4-((3S,4R)-3-(3-fluoro-5-methylphenyl)-7-hydroxyisochroma n-4- yl)phenyl)piperidine-4-carbaldehyde (30 mg, 75% yield) as a yellow solid. LC-MS (ESI ⁺ ) m/z: 446.3 (M+H) ⁺ . Step 4: To a solution of (3R,4S)-4-(4-(4-(dimethoxymethyl)piperidin-1-yl)phenyl)-3-(3 -fluoro-5- methylphenyl)isochroman-7-ol (40 mg, 81 ^mol) in DCM (3 mL) was added TFA (1 mL, 0.01 mol) at 20 °C. The mixture was stirred at 20 °C for 2 h. The reaction was quenched with sat.aq. NaHCO ₃ (10 mL) and extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine (20 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give the product of 1-(4-((3R,4S)-3-(3-fluoro-5-methylphenyl)-7-hydroxyisochroma n-4- yl)phenyl)piperidine-4-carbaldehyde (30 mg, 77% yield) as a yellow solid. LC-MS (ESI ⁺ ) m/z: 446.3 (M+H) ⁺ . Step 5: To a solution of 1-(4-((3S,4R)-3-(3-fluoro-5-methylphenyl)-7-hydroxyisochroma n-4- yl)phenyl)piperidine-4-carbaldehyde (30 mg, 67 ^mol) in DCE (10 mL) and MeOH (1 mL) was added (S)-3-(1-oxo-5-(piperazin-1-yl)isoindolin-2-yl)piperidine-2, 6-dione (22 mg, 67 ^mol) and stirred at 20 °C for 10 min. Then sodium triacetoxyhydroborate (43 mg, 0.20 mmol) was added and stirred at 20 °C for 10 min. The solvent was removed to yield a residue. The residue was purified by preparative HPLC (column: Phenomenex Gemini NX 150×30mm, 5^m; mobile phase: [water( NH ₄ HCO ₃ )-ACN];gradient:48%-78% B over 11 min), followed by lyophilization to give the product of (S)-3-(5-(4-((1-(4-((3S,4R)-3-(3-fluoro-5-methylphenyl)-7- hydroxyisochroman-4-yl)phenyl)piperidin-4-yl)methyl)piperazi n-1-yl)-1-oxoisoindolin-2- yl)piperidine-2,6-dione (26.1 mg, 51% yield) as a white solid. LC-MS (ESI ⁺ ) m/z: 758.4 (M+H) ⁺ . LCMS: calc. for C ₄₅ H ₄₈ FN ₅ O ₅ : 757.91, found: [M+H] ⁺ 758.4. HPLC: 99.81% purity at 254 nm. ¹ HNMR (400MHz, DMSO-d6): į 10.94 (s, 1H), 9.30 (s, 1H), 7.51 (d, J = 8.9 Hz, 1H), 7.09 - 7.00 (m, 2H), 6.81 - 6.69 (m, 3H), 6.66 - 6.51 (m, 7H), 5.11 - 4.99 (m, 2H), 4.96 (d, J = 2.7 Hz, 1H), 4.89 (d, J = 15.3 Hz, 1H), 4.37 - 4.16 (m, 2H), 4.02 (d, J = 2.6 Hz, 1H), 3.51 (d, J = 12.0 Hz, 2H), 3.27 (s, 6H), 3.00 - 2.83 (m, 1H), 2.63 - 2.52 (m, 2H), 2.48 (s, 3H), 2.35 (dq, J = 4.2, 13.2 Hz, 1H), 2.22 - 2.13 (m, 5H), 2.00 - 1.89 (m, 1H), 1.73 (d, J = 12.2 Hz, 2H), 1.63 (s, 1H), 1.23 - 1.06 (m, 2H) Step 6: To a solution of (3R,4S)-4-(4-(4-(dimethoxymethyl)piperidin-1-yl)phenyl)-3-(3 -fluoro-5- methylphenyl)isochroman-7-ol (30 mg, 61 ^mol) in DCE (10 mL) and MeOH (1 mL) was added (S)-3-(1-oxo-5-(piperazin-1-yl)isoindolin-2-yl)piperidine-2, 6-dione (20 mg, 61 ^mol) and stirred at 20 °C for 10 min. Then sodium triacetoxyhydroborate (39 mg, 0.18 mmol) was added and stirred at 20 °C for 10 min. The solvent was removed to yield a residue. The residue was purified by preparative HPLC (column: Phenomenex Gemini NX 150×30mm, 5^m; mobile phase: [water( NH ₄ HCO ₃ )-ACN];gradient:48%-78% B over 11 min), followed by lyophilization to give the product of (S)-3-(5-(4-((1-(4-((3R,4S)-3-(3-fluoro-5-methylphenyl)-7- hydroxyisochroman-4-yl)phenyl)piperidin-4-yl)methyl)piperazi n-1-yl)-1-oxoisoindolin-2- yl)piperidine-2,6-dione (24.9 mg, 54% yield) as a white solid. LC-MS (ESI ⁺ ) m/z: 758.4 (M+H) ⁺ . LCMS: calc. for C ₄₅ H ₄₈ FN ₅ O ₅ : 757.91, found: [M+H] ⁺ 758.4. HPLC: 100.0% purity at 254 nm. ¹ HNMR (400MHz, DMSO-d6): į 10.94 (s, 1H), 9.30 (s, 1H), 7.51 (d, J = 8.8 Hz, 1H), 7.09 - 6.99 (m, 2H), 6.81 - 6.70 (m, 3H), 6.66 - 6.49 (m, 7H), 5.10 - 5.00 (m, 2H), 4.99 - 4.84 (m, 2H), 4.37 - 4.14 (m, 2H), 4.02 (d, J = 2.7 Hz, 1H), 3.51 (d, J = 11.9 Hz, 2H), 3.27 (s, 6H), 2.96 - 2.82 (m, 1H), 2.63 - 2.51 (m, 2H), 2.48 (s, 3H), 2.36 (dq, J = 4.5, 13.3 Hz, 1H), 2.25 - 2.11 (m, 5H), 2.01 - 1.90 (m, 1H), 1.73 (d, J = 11.6 Hz, 2H), 1.63 (s, 1H), 1.14 (q, J = 11.8 Hz, 2H). EXAMPLE 129. Preparation of (I-379) (S)-3-(5-(4-((1-(4-((3S,4R)-3-(3-fluoro-2- methylphenyl)-7-hydroxyisochroman-4-yl)phenyl)piperidin-4-yl )methyl)piperazin-1-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione and (I-380) (S)-3-(5-(4-((1-(4-((3R,4S)-3-(3-fluoro-2- methylphenyl)-7-hydroxyisochroman-4-yl)phenyl)piperidin-4-yl )methyl)piperazin-1-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione Step 1: A mixture of compound 1 (200.0 mg, 397.3 ^mol, 1 eq.), 2 (126.5 mg, 794.6 ^mol, 2 eq.), (2-Dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)[2 -(2'-amino-1,1'- biphenyl)]palladium(II) methanesulfonate (49.84 mg, 59.59 ^mol, 0.15 eq.) and Cs ₂ CO ₃ (388.3 mg, 1.192 mmol, 3 eq.) in Dioxane (20 mL) was degassed and purged with N ₂ for 3 times, and then the mixture was stirred at 90 °C for 3 hour under N ₂ atmosphere. LCMS showed that the starting material was consumed and the desired product was detected. The reaction mixture was filtered under reduced pressure to give a residue. The residue was poured into water (20 mL). The aqueous phase was extracted with ethyl acetate (40mL*3). The combined organic phase was washed with brine (20 mL*3), dried with anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuum. The residue was purified by silica gel chromatography (column height: afford compound 3 (173.2 mg, 297.7 ^mol, 74.94 %) as yellow oil. The reaction mixture was filtered under reduced pressure to give a compound. LC-MS (ESI ⁺ ) m/z: 582.7(M+H) ⁺ . Step 2: A mixture of compound 3 (115.0 mg, 197.7 ^mol, 1 eq.) and Pd/C (126.2 mg, 10% Wt, 118.6 ^mol, 0.6 eq.) was added in EtOAc (4 mL) ,and then degassed and purged with H ₂ for 3 times, and then the mixture was stirred at 15 psi and 25 °C for 6 hour under H ₂ atmosphere. The reaction mixture was filtered and concentrated under reduced pressure to get the product. The residue was purified by prep-HPLC (column: Boston Green ODS 150*30mm*5um; mobile phase: [water (FA)-ACN]; gradient: 25%-55% B over 12 min) to give product. Compound 4 (80 mg, 0.16 mmol, 82 %) was obtained as a white solid. LC-MS (ESI ⁺ ) m/z: 492.3 (M+H) ⁺ . Step 3: Compound 4 (0.1 g, 0.2 mmol, 1 eq.) was separated by chiral SFC (Column DAICELCHIRALPAKAD (250mm*30mm, 10um), Condition CO2-EtOH (0.1%NH3H2O) Begin B 40% End B 40%) Flow Rate (ml/min): 150) Compound 5A (35 mg, 71 ^mol, 40 %), compound 5B (30 mg, 61 ^mol, 30 %). Step 4: To a solution of compound 5A (35 mg, 71 ^mol, 1 eq.) in DCM (1 mL) was added TFA (0.37 g, 0.25 mL, 3.2 mmol, 46 eq.) .The mixture was stirred at 25 °C for 0.5 hr. LCMS showed that the starting material was consumed and the desired product was detected. The reaction liquid is dried with N ₂ at 0 °C to give compound 6 (30 mg, 67 ^mol, 95 %) was obtained as yellow oil which was used in the next step without further purification. LC-MS (ESI+) m/z: 464.2 (M+H)+. Step 5: To a solution of compound 5B (30 mg, 61 ^mol, 1 eq.) in DCM (1 mL) was added TFA (0.32 g, 0.22 mL, 2.8 mmol, 46 eq.). The mixture was stirred at 25 °C for 0.5 hr. LCMS showed that the starting material was consumed and the desired product was detected. The reaction liquid is dried with N ₂ at 0 °C to give Compound 6A (25 mg, 56 ^mol, 92 %) was obtained as yellow oil which was used in the next step without further purification. LC-MS (ESI+) m/z: 464.3(M+H) ⁺ . Step 6: To a solution of compound 6 (30 mg, 67 ^mol, 1 eq.) in DCE (3 mL) and MeOH (2 mL) was added compound 034 (22 mg, 67 ^mol, 1 eq.) at 25 °C. After addition, the mixture was stirred at this temperature for 0.5 hr, and then NaBH(OAc) ₃ (29 mg, 20 ^L, 0.13 mmol, 2 eq.) was added at 25 °C. The resulting mixture was stirred at 25 °C for 0.5 hr. The reaction mixture was concentrated to yield a residue. The residue was purified by preparative HPLC (column: Phenomenex Gemini NX 150×30mm, 5^m; mobile phase: [water (NH ₄ HCO ₃ )-ACN]; gradient: 49%-79% B over 11 min), followed by lyophilization to yield I-379 (24.1 mg, 31.8 ^mol, 47 %) was obtained as a white solid. LC-MS (ESI+) m/z: 758.4 [M+H] ⁺ . LCMS: calc. for C ₄₅ H ₄₈ FN ₅ O ₅ : 757.91, found: [M+H] ⁺ 758.3. HPLC: 100% purity at 220 nm. ¹ H NMR (400 MHz, DMSO-d6) į ppm 10.94 (br s, 1 H) 9.30 (s, 1 H) 7.51 (d, J=8.58 Hz, 1 H) 7.02 - 7.08 (m, 2 H) 6.76 - 6.91 (m, 3 H) 6.49 - 6.58 (m, 7 H) 5.01 - 5.13 (m, 3 H) 4.89 - 4.96 (m, 1 H) 4.16 - 4.35 (m, 2 H) 4.01 (d, J=2.26 Hz, 1 H) 3.50 (br d, J=9.66 Hz, 2 H) 3.27 (br s, 4 H) 2.86 - 2.94 (m, 1 H) 2.60 (br s, 2 H) 2.43 - 2.49 (m, 5 H) 2.31 - 2.39 (m, 1 H) 2.16 - 2.27 (m, 5 H) 1.92 - 1.99 (m, 1 H) 1.60 - 1.78 (m, 3 H) 1.09 - 1.21 (m, 2 H) Step 7: To a solution of compound 6A (25 mg, 56 ^mol, 1 eq.) in DCE (3 mL) and MeOH (2 mL) was added compound 034 (18 mg, 56 ^mol, 1 eq.) at 25 °C. After addition, the mixture was stirred at this temperature for 0.5 hr and then NaBH(OAc) ₃ (24 mg, 17 ^L, 0.11 mmol, 2 eq.) was added at 25 °C. The resulting mixture was stirred at 25 °C for 1 hr. The reaction mixture was concentrated to yield a residue. The residue was purified by preparative HPLC (column: Phenomenex Gemini NX 150×30mm, 5^m; mobile phase: [water (NH ₄ HCO ₃ )-ACN]; gradient: 49%-79% B over 11 min), followed by lyophilization to yield I-380 (21.9 mg, 28.9 ^mol, 51 %) was obtained as a white solid. LC-MS (ESI+) m/z: 758.4 [M+H]+. LCMS: calc. for C ₄₅ H ₄₈ FN ₅ O ₅ : 757.91, found: [M+H] ⁺ 758.4. HPLC: 100 % purity at 220 nm ¹ H NMR (400 MHz, DMSO-d6) į ppm 10.88 - 11.00 (m, 1 H) 9.24 - 9.39 (m, 1 H) 7.52 (d, J=8.58 Hz, 1 H) 7.03 - 7.08 (m, 2 H) 6.77 - 6.91 (m, 3 H) 6.51 - 6.59 (m, 7 H) 5.13 (d, J=2.86 Hz, 1 H) 5.02 - 5.09 (m, 2 H) 4.90 - 4.97 (m, 1 H) 4.29 - 4.36 (m, 1 H) 4.16 - 4.25 (m, 1 H) 4.02 (d, J=2.50 Hz, 1 H) 3.50 (br d, J=10.49 Hz, 2 H) 3.28 (br s, 4 H) 2.86 - 2.95 (m, 1 H) 2.53 - 2.75 (m, 2 H) 2.42 (br s, 5 H) 2.32 - 2.39 (m, 1 H) 2.26 (d, J=1.31 Hz, 3 H) 2.19 (br d, J=6.91 Hz, 2 EXAMPLE 130. Preparation of (I-242) (S)-3-(5-(4-((1-(4-((3S,4S)-3-cyclopropyl-7- hydroxyisochroman-4-yl)phenyl)piperidin-4-yl)methyl)piperazi n-1-yl)-1-oxoisoindolin-2- yl)piperidine-2,6-dione and (I-243) (S)-3-(5-(4-((1-(4-((3R,4R)-3-cyclopropyl-7- hydroxyisochroman-4-yl)phenyl)piperidin-4-yl)methyl)piperazi n-1-yl)-1-oxoisoindolin-2- yl)piperidine-2,6-dione Step 1: To a solution of 2-(4-(benzyloxy)-2-(((tert-butyldimethylsilyl)oxy)methyl)phe nyl)-2-(4- bromophenyl)-N-methoxy-N-methylacetamide (1 g, 2 mmol) in THF (10 mL) was added cyclopropylmagnesium bromide solution (20 mL, 0.5M, 10 mmol) dropwise at 0 °C and stirred at 20 °C for 16 h under N ₂ atmosphere The reaction was quenched with sat aq NaHCO ₃ (50 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (80 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flashsilica gel chromatography (ethyl acetate in petroleum ether = 0% to 5%) to give a product of 2-(4-(benzyloxy)-2-(((tert- butyldimethylsilyl)oxy)methyl)phenyl)-2-(4-bromophenyl)-1-cy clopropylethan-1-one (850 mg, 80% yield) as a white solid ¹ HNMR (400MHz, CDCl ₃ ): į 7.49 - 7.30 (m, 8H), 7.09 (d, J = 2.6 Hz, 1H), 7.02 - 6.98 (m, 2H), 6.89 (dd, J = 2.7, 8.5 Hz, 1H), 5.54 (s, 1H), 5.07 (s, 2H), 4.71 (d, J = 12.8 Hz, 1H), 4.53 (d, J = 12.8 Hz, 1H), 2.02 - 1.94 (m, 1H), 1.16 - 1.03 (m, 2H), 0.92 (s, 9H), 0.89 - 0.82 (m, 2H), 0.07 (d, J = 8.9 Hz, 6H) Step 2: To a solution of 2-(4-(benzyloxy)-2-(((tert-butyldimethylsilyl)oxy)methyl)phe nyl)-2-(4- bromophenyl)-1-cyclopropylethan-1-one (850 mg, 1.50 mmol) in DCM (10 mL) was added triethylsilane (480 ^L, 3.01 mmol), the resulting mixture was cooled at -78 °C and trimethylsilyl triflate (416 ^L, 2.25 mmol) was added dropwise, and the resulting mixture was stirred at -78 °C for 1 h. The reaction was quenched with sat.aq. NaHCO3 (50 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (80 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flashsilica gel chromatography (ethyl acetate in petroleum ether = 0% to 7%) to give the product of 7-(benzyloxy)-4-(4-bromophenyl)-3-cyclopropylisochromane (500 mg, 69% yield) as a white solid. ¹ HNMR (400MHz, CDCl ₃ ): į 7.45 - 7.34 (m, 7H), 7.11 (d, J = 8.3 Hz, 2H), 6.90 (d, J = 8.6 Hz, 1H), 6.79 (dd, J = 2.5, 8.5 Hz, 1H), 6.71 - 6.62 (m, 1H), 5.05 - 4.98 (m, 3H), 4.88 - 4.77 (m, 1H), 3.89 (d, J = 3.1 Hz, 1H), 3.02 (dd, J = 3.3, 8.0 Hz, 1H), 0.56 - 0.39 (m, 4H), 0.30 - 0.22 (m, 1H) Step 3: A mixture of 7-(benzyloxy)-4-(4-bromophenyl)-3-cyclopropylisochromane (500 mg, 1.15 mmol), 4-(dimethoxymethyl)piperidine (256 mg, 1.61 mmol), XPhos-Pd-G3 (97.2 mg, 115 ^mol), and t-BuONa (221 mg, 2.30 mmol) in 1,4-Dioxane (10 mL) was degassed and purged with N ₂ for 3 times, and then the mixture was stirred at 90 °C for 16 h under N ₂ atmosphere. The reaction was quenched with water (20 mL) and extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, filtered and t t d d d d t i id Th id ifi d b fl h ili l chromatography (ethyl acetate in petroleum ether= 0% to 20%) to give the product of 1-(4-(7- (benzyloxy)-3-cyclopropylisochroman-4-yl)phenyl)-4-(dimethox ymethyl)piperidine (250 mg, 39% yield) as a white solid. LC-MS (ESI ⁺ ) m/z: 514.4 (M+H) ⁺ . Step 4: To a solution of Pd/C (200 mg, 10% Purity) in THF (10 mL) was added 1-(4-(7- (benzyloxy)-3-cyclopropylisochroman-4-yl)phenyl)-4-(dimethox ymethyl)piperidine (250 mg, 487 ^mol) under N ₂ . The suspension was degassed under vacuum and purged with H ₂ several times. The mixture was stirred under H ₂ (50 psi) at 25 °C for 6 h. The reaction mixture was filtered and the filter was concentrated to give a residue. The residue was separated by chiral SFC (column: DAICEL CHIRALCEL OD-H (250mm*30mm, 5um); mobile phase:CO ₂ -MeOH (0.1%NH ₃ H ₂ O); B%: 40%, isocratic elution mode, peak 1: 1.830 min, peak 2: 2.433 min) to yield Peak 1 and Peak 2. Peak 1 was concentrated under reduced pressure to give the product of (3S,4S)-3-cyclopropyl-4-(4-(4-(dimethoxymethyl)piperidin-1-y l)phenyl)isochroman-7-ol (60 mg, 29% yield, SFC: R _t =1.825) as a white solid. LC-MS (ESI ⁺ ) m/z: 424.2 (M+H) ⁺ . Peak 2 was concentrated under reduced pressure to give the product of (3R,4R)-3-cyclopropyl-4-(4-(4- (dimethoxymethyl)piperidin-1-yl)phenyl)isochroman-7-ol (60 mg, 29% yield, SFC: Rt =2.418) as a white solid. LC-MS (ESI ⁺ ) m/z: 424.2 (M+H) ⁺ . Step 5: To a solution of (3S,4S)-3-cyclopropyl-4-(4-(4-(dimethoxymethyl)piperidin-1- yl)phenyl)isochroman-7-ol (60 mg, 0.14 mmol) in DCM (3 mL) was added TFA (1 mL, 0.01 mol) at 20 °C. The mixture was stirred at 20 °C for 2 h. The reaction was quenched with sat.aq. NaHCO ₃ (10 mL) and extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine (20 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give the product of 1-(4-((3S,4S)-3-cyclopropyl-7-hydroxyisochroman-4-yl)phenyl) piperidine- 4-carbaldehyde (50 mg, 94% yield) as a yellow solid. LC-MS (ESI ⁺ ) m/z: 378.3 (M+H) ⁺ . Step 6: To a solution of (3R,4R)-3-cyclopropyl-4-(4-(4-(dimethoxymethyl)piperidin-1- yl)phenyl)isochroman-7-ol (60 mg, 0.14 mmol) in DCM (3 mL) was added TFA (1 mL, 0.01 mol) at 20 °C. The mixture was stirred at 20 °C for 2 h. The reaction was quenched with sat.aq. NaHCO ₃ (10 mL) and extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine (20 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give the product of 1-(4-((3R,4R)-3-cyclopropyl-7-hydroxyisochroman-4- yl)phenyl)piperidine-4-carbaldehyde (50 mg, 94% yield) as a yellow solid. LC-MS (ESI ⁺ ) m/z: Step 7: To a solution of 1-(4-((3S,4S)-3-cyclopropyl-7-hydroxyisochroman-4- yl)phenyl)piperidine-4-carbaldehyde (50 mg, 0.13 mmol) in DCE (10 mL) and MeOH (1 mL) was added (S)-3-(1-oxo-5-(piperazin-1-yl)isoindolin-2-yl)piperidine-2, 6-dione (43 mg, 0.13 mmol) and stirred at 20 °C for 10 min. Then sodium triacetoxyhydroborate (84 mg, 0.40 mmol) was added and stirred at 20 °C for 10 min. The solvent was removed to yield a residue. The residue was purified by preparative HPLC (column: Phenomenex Gemini NX 150×30mm,5^m;mobile phase: [water (NH ₄ HCO ₃ )-ACN]; gradient: 43%-73% B over 11 min), followed by lyophilization to give the product of (S)-3-(5-(4-((1-(4-((3S,4S)-3-cyclopropyl-7- hydroxyisochroman-4-yl)phenyl)piperidin-4-yl)methyl)piperazi n-1-yl)-1-oxoisoindolin-2- yl)piperidine-2,6-dione (50.4 mg, 55% yield) as a white solid. LC-MS (ESI ⁺ ) m/z: 690.3 (M+H) ⁺ . LCMS: calc. for C ₄₁ H ₄₇ N ₅ O ₅ : 689.86, found: [M+H] ⁺ 690.3. HPLC: 100.0% purity at 254 nm. ¹ HNMR (500MHz, DMSO-d6): į 10.93 (s, 1H), 9.20 (s, 1H), 7.52 (d, J = 8.4 Hz, 1H), 7.11 - 7.03 (m, 2H), 6.98 (d, J = 8.7 Hz, 2H), 6.78 (d, J = 8.7 Hz, 2H), 6.73 (d, J = 8.4 Hz, 1H), 6.51 (dd, J = 2.4, 8.3 Hz, 1H), 6.45 (d, J = 2.1 Hz, 1H), 5.04 (dd, J = 5.1, 13.4 Hz, 1H), 4.83 (d, J = 15.4 Hz, 1H), 4.63 (d, J = 15.3 Hz, 1H), 4.37 - 4.28 (m, 1H), 4.25 - 4.15 (m, 1H), 3.74 (d, J = 2.7 Hz, 1H), 3.66 - 3.54 (m, 2H), 3.31 - 3.22 (m, 7H), 2.98 - 2.83 (m, 2H), 2.63 - 2.52 (m, 4H), 2.40 - 2.34 (m, 1H), 2.21 (d, J = 7.2 Hz, 2H), 2.00 - 1.91 (m, 1H), 1.79 (d, J = 11.6 Hz, 2H), 1.72 - 1.59 (m, 1H), 1.28 - 1.12 (m, 2H), 0.38 - 0.30 (m, 3H), 0.29 - 0.23 (m, 2H) Step 8: To a solution of 1-(4-((3R,4R)-3-cyclopropyl-7-hydroxyisochroman-4- yl)phenyl)piperidine-4-carbaldehyde (50 mg, 0.13 mmol) in DCE (10 mL) and MeOH (1 mL) was added (S)-3-(1-oxo-5-(piperazin-1-yl)isoindolin-2-yl)piperidine-2, 6-dione (43 mg, 0.13 mmol) and stirred at 20 °C for 10 min. Then sodium triacetoxyhydroborate (84 mg, 0.40 mmol) was added and stirred at 20 °C for 10 min. The solvent was removed to yield a residue. The residue was purified by preparative HPLC (column: Phenomenex Gemini NX 150×30mm,5^m;mobile phase: [water (NH ₄ HCO ₃ )-ACN]; gradient: 43%-73% B over 11 min), followed by lyophilization to give the product of (S)-3-(5-(4-((1-(4-((3R,4R)-3-cyclopropyl-7- hydroxyisochroman-4-yl)phenyl)piperidin-4-yl)methyl)piperazi n-1-yl)-1-oxoisoindolin-2- l) i idi 26 di (45 49% i ld) hit lid LC MS (ESI ⁺ ) / 6903 (M+H) ⁺ LCMS: calc. for C41H47N5O5: 689.86, found: [M+H] ⁺ 690.3. HPLC: 100.0% purity at 254 nm. ¹ HNMR (500MHz, DMSO-d6): į 10.94 (s, 1H), 9.20 (s, 1H), 7.52 (d, J = 8.5 Hz, 1H), 7.12 - 7.02 (m, 2H), 6.98 (d, J = 8.7 Hz, 2H), 6.78 (d, J = 8.9 Hz, 2H), 6.73 (d, J = 8.4 Hz, 1H), 6.51 (dd, J = 2.4, 8.3 Hz, 1H), 6.44 (d, J = 2.1 Hz, 1H), 5.04 (dd, J = 5.2, 13.3 Hz, 1H), 4.83 (d, J = 15.3 Hz, 1H), 4.63 (d, J = 15.3 Hz, 1H), 4.36 - 4.29 (m, 1H), 4.24 - 4.17 (m, 1H), 3.74 (d, J = 2.7 Hz, 1H), 3.65 - 3.55 (m, 2H), 3.30 - 3.26 (m, 7H), 2.97 - 2.84 (m, 2H), 2.62 - 2.54 (m, 4H), 2.39 - 2.34 (m, 1H), 2.21 (d, J = 7.2 Hz, 2H), 2.00 - 1.91 (m, 1H), 1.79 (d, J = 11.7 Hz, 2H), 1.72 - 1.60 (m, 1H), 1.27 - 1.12 (m, 2H), 0.37 - 0.31 (m, 3H), 0.28 - 0.23 (m, 2H). EXAMPLE 131. Preparation of (I-381) (S)-3-(5-(4-((1-(2-fluoro-4-((3S,4R)-7-hydroxy- 3-phenylisochroman-4-yl)phenyl)piperidin-4-yl)methyl)piperaz in-1-yl)-1-oxoisoindolin-2- yl)piperidine-2,6-dione and (I-382) (S)-3-(5-(4-((1-(2-fluoro-4-((3R,4S)-7-hydroxy-3-

phenylisochroman-4-yl)phenyl)piperidin-4-yl)methyl)pipera zin-1-yl)-1-oxoisoindolin-2- yl)piperidine-2,6-dione Step 1: To a solution of (5-(benzyloxy)-2-(phenylethynyl)phenyl)methanol (1 g, 3 mmol, 1 eq.) and Sodium bicarbonate (0.8 g, 0.4 mL, 0.01 mol, 3 eq.) in MeCN (100 mL) was added I ₂ (2 g, 0.01 mol, 3 eq.). The mixture was stirred at 25 °C for 12 h. The reaction mixture was quenched by addition of Na ₂ S ₂ O ₃ (50 mL, 10%), extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (10 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (from PE/EtOAc = 1/0 to 20/1, TLC: PE/EtOAc = 10/1, R _f = 0.49) to yield 7- (benzyloxy)-4-iodo-3-phenyl-1H-isochromene (370 mg, 0.76 mmol, 20 %, 90% Purity) as a yellow solid. LC-MS (ESI+) m/z: 439.8 (M-1) ⁺ 7.65 (dd, J=2.4, 7.3 Hz, 2H), 7.49 - 7.31 (m, 9H), 6.94 (dd, J=2.6, 8.5 Hz, 1H), 6.69 (d, J=2.5 Hz, 1H), 5.19 (s, 2H), 5.11 (s, 2H). Step 2: To a solution of 7-(benzyloxy)-4-iodo-3-phenyl-1H-isochromene (500 mg, 1.14 mmol, 1 eq.) and 4-(dimethoxymethyl)-1-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2 -dioxaborolan-2- yl)phenyl) piperidine (574 mg, 75% Wt, 1.14 mmol, 1 eq.) in 1,4-Dioxane (8 mL) and H ₂ O (2 mL) was added sodium carbonate (301 mg, 2.84 mmol, 2.5 eq.) and Pd(dppf)Cl ₂ (83.1 mg, 114 ^mol, 0.1 eq.). The mixture was stirred under N ₂ at 85 °C for 8 h. The reaction mixture was quenched by addition of water (50 mL), extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (10 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (from PE/EtOAc = 1/0 to 5/1, TLC: PE/EtOAc = 3/1, R _f = 0.49) to yield 1-(4- (7-(benzyloxy)-3-phenyl-1H-isochromen-4-yl)-2-fluorophenyl)- 4-(dimethoxymethyl)piperidine (500 mg, 884 ^mol, 77.8 %, 100% Purity) as a yellow solid. LC-MS (ESI+) m/z: 511.1 (M+H)+. NMR (400MHz, CDCl3) į = 7.45 - 7.31 (m, 5H), 7.24 (dd, J=3.0, 6.7 Hz, 2H), 7.18 - 7.12 (m, 3H), 6.95 - 6.85 (m, 3H), 6.78 (s, 3H), 5.21 (s, 2H), 5.08 (s, 2H), 4.11 (br d, J=3.2 Hz, 1H), 3.53 (d, J=11.7 Hz, 2H), 3.39 (s, 6H), 2.66 (t, J=11.4 Hz, 2H), 1.88 (d, J=13.4 Hz, 2H), 1.82 - 1.71 (m, 1H), 1.62 - 1.55 (m, 2H) Step 3: To a solution of 1-(4-(7-(benzyloxy)-3-phenyl-1H-isochromen-4-yl)-2-fluorophe nyl) -4- (dimethoxymethyl)piperidine (500 mg, 884 ^mol, 1 eq.) in THF (10 mL) and MeOH (10 mL) was added Pd/C (500 mg, 10% Wt, 470 ^mol, 0.532 eq.). The mixture was stirred under H ₂ 20 psi at 60 °C for 24 h. The reaction mixture was filtered and concentrated to yield a residue. The residue were separated by chiral SFC (DAICEL CHIRALPAK AD (250mm*30mm, 10um); mobile phase: CO ₂ -EtOH (0.1% NH ₃ H ₂ O); B%: 35%-35%, min), followed by lyophilization to yield (3S,4R)-4-(4-(4- (dimethoxymethyl)piperidin-1-yl)-3-fluorophenyl)-3-phenyliso chroman- 7-ol (180 mg, 0.36 mmol, 43 %, 95% Purity, SFC: R _t = 1.545) as a white solid and (3R,4S)-4-(4- (4-(dimethoxymethyl)piperidin-1-yl)-3-fluorophenyl)-3-phenyl isochroman-7-ol (180 mg, 0.36 mmol, 43 %, 95% Purity, SFC: R _t = 1.994) as a white solid. LC-MS (ESI ⁺ ) m/z: 478.2 (M+H) ⁺ . NMR of 5 (500MHz, CDCl3) į = 7.19 - 7.11 (m, 3H), 7.00 - 6.95 (m, 2H), 6.91 (d, J=8.2 H 1H) 668 656 ( 3H) 646 (dd J 18 140 H 1H) 640 635 ( 1H) 519 510 ( 1H), 5.06 - 4.98 (m, 2H), 4.07 (d, J=7.5 Hz, 1H), 3.98 (d, J=2.6 Hz, 1H), 3.36 (s, 8H), 2.56 - 2.45 (m, 2H), 1.79 (d, J=12.5 Hz, 2H), 1.69 (dt, J=3.8, 7.7 Hz, 1H), 1.48 (dq, J=3.8, 12.3 Hz, 2H). ¹ H NMR of 5A (500MHz, CDCl ₃ ) į = 7.19 - 7.10 (m, 3H), 7.00 - 6.96 (m, 2H), 6.91 (d, J=8.2 Hz, 1H), 6.67 - 6.57 (m, 3H), 6.46 (dd, J=1.8, 13.9 Hz, 1H), 6.37 (dd, J=1.8, 8.2 Hz, 1H), 5.18 - 5.11 (m, 1H), 5.06 - 5.00 (m, 2H), 4.08 (d, J=7.5 Hz, 1H), 3.98 (d, J=2.9 Hz, 1H), 3.40 - 3.30 (m, 8H), 2.56 - 2.44 (m, 2H), 1.79 (d, J=12.2 Hz, 2H), 1.69 (tdt, J=3.8, 7.6, 11.5 Hz, 1H), 1.54 - 1.43 (m, 2H). Step 4: To a solution of (3S,4R)-4-(4-(4-(dimethoxymethyl)piperidin-1-yl)-3-fluorophe nyl) -3- phenylisochroman-7-ol (80 mg, 0.17 mmol, 1 eq.) in DCM (3 mL) was added 2,2,2- trifluoroacetic acid (19 mg, 0.8 mL, 0.17 mmol, 1 eq.). The mixture was stirred at 25 °C for 1 h. The reaction mixture was quenched by add to saturation solution of NaHCO ₃ (20 mL), extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine (10 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to yield 1-(2-fluoro-4-((3S,4R)-7- hydroxy-3-phenylisochroman-4-yl) phenyl)piperidine-4-carbaldehyde (70 mg, 0.15 mmol, 87 %, 90% Purity) as a yellow solid which was used in the next step without further purification. LC- MS (ESI ⁺ ) m/z: 432.0 (M+H) ⁺ . Step 5: To a solution of (3R,4S)-4-(4-(4-(dimethoxymethyl)piperidin-1-yl)-3-fluorophe nyl) -3- phenylisochroman-7-ol (80 mg, 0.17 mmol, 1 eq.) in DCM (3 mL) was added 2,2,2- trifluoroacetic acid (19 mg, 0.8 mL, 0.17 mmol, 1 eq.). The mixture was stirred at 25 °C for 1 h. The reaction mixture was quenched by add to saturation solution of NaHCO ₃ (20 mL), extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine (10 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to yield 1-(2-fluoro-4-((3R,4S)-7- hydroxy-3-phenylisochroman-4 -yl)phenyl)piperidine-4-carbaldehyde (70 mg, 0.15 mmol, 87 %, 90% Purity) as a yellow solid which was used in the next step without further purification. LC- MS (ESI ⁺ ) m/z: 432.0(M+H) ⁺ . Step 6: To a solution of 1-(2-fluoro-4-((3S,4R)-7-hydroxy-3-phenylisochroman-4-yl)phe nyl) piperidine-4-carbaldehyde (70 mg, 90% Wt, 0.15 mmol, 1 eq.) and (S)-3-(1-oxo-5-(piperazin -1- yl)isoindolin-2-yl)piperidine-2,6-dione (72 mg, 0.22 mmol, 1.5 eq.) in DCM (3 mL) and MeOH (3 L) ft ti d 30 i dd d S di t i t b h d id (015 011 L 073 mmol, 5 eq.). The mixture was stirred at 25 °C for 1 h. The reaction mixture was filtered and concentrated to yield a residue. The residue was purified by preparative HPLC (column: Phenomenex Gemini NX 150×30 mm, 5 ^m; mobile phase: [water (NH ₄ HCO ₃ )-ACN]; B%: 46%-76%, 11 min), followed by lyophilization to yield (S)-3-(5-(4-((1-(2-fluoro-4-((3S,4R)-7- hydroxy-3-phenylisochroman-4-yl)phenyl)piperidin-4-yl)methyl )piperazin-1-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione (72.0 mg, 96.2 ^mol, 66 %, 99.442% Purity) as a white solid. LC-MS (ESI ⁺ ) m/z: 744.3 (M+H) ⁺ . LCMS: calc. for C44H46FN5O5: 743.35, found: [M+H] ⁺ 744.3. HPLC: 99.442% purity at 220 nm. ¹ H NMR (400MHz, DMSO-d6) į = 10.94 (s, 1H), 9.35 (s, 1H), 7.51 (d, J=9.0 Hz, 1H), 7.19 - 7.02 (m, 7H), 6.81 (d, J=8.1 Hz, 1H), 6.69 - 6.61 (m, 1H), 6.60 - 6.54 (m, 2H), 6.52 - 6.45 (m, 2H), 5.13 - 5.00 (m, 3H), 4.91 (d, J=15.3 Hz, 1H), 4.36 - 4.27 (m, 1H), 4.24 - 4.16 (m, 1H), 4.11 (d, J=2.6 Hz, 1H), 3.33 - 3.22 (m, 8H), 3.17 (d, J=10.5 Hz, 2H), 2.96 - 2.84 (m, 1H), 2.58 (d, J=16.5 Hz, 1H), 2.46 - 2.30 (m, 3H), 2.19 (d, J=4.9 Hz, 2H), 2.01 - 1.90 (m, 1H), 1.74 (d, J=11.5 Hz, 2H), 1.61 (s, 1H), 1.25 - 1.14 (m, 2H). Step 7: To a solution of 1-(2-fluoro-4-((3R,4S)-7-hydroxy-3-phenylisochroman-4-yl) phenyl)piperidine-4-carbaldehyde (70 mg, 90% Wt, 0.15 mmol, 1 eq.) and (S)-3-(1-oxo-5- (piperazin-1-yl)isoindolin-2-yl)piperidine-2,6-dione (72 mg, 0.22 mmol, 1.5 eq.) in DCM (3 mL) and MeOH (3 mL), after stirred 30 min was added sodium triacetoxyhydroborate (0.15 g, 0.73 mmol, 5 eq.). The mixture was stirred at 25 °C for 1 h. The reaction mixture was filtered and concentrated to yield a residue. The residue was purified by preparative HPLC (column: Phenomenex Gemini NX 150×30 mm, 5 ^m; mobile phase: [water (NH ₄ HCO ₃ )-ACN]; B%: 46%-76%,11 min), followed by lyophilization to yield (S)-3-(5-(4-((1-(2-fluoro-4-((3R,4S)-7- hydroxy-3-phenylisochroman-4-yl)phenyl)piperidin-4-yl)methyl )piperazin-1-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione (70.2 mg, 94.4 ^mol, 65 %, 100% Purity) as a white solid. LC-MS (ESI ⁺ ) m/z: 744.3 (M+H) ⁺ . LCMS: calc. for C ₄₄ H ₄₆ FN ₅ O ₅ : 743.35, found: [M+H] ⁺ 744.3. HPLC: 100% purity at 220 nm. NMR (400MHz, DMSO-d6) į = 10.94 (s, 1H), 9.34 (s, 1H), 7.51 (d, J=8.8 Hz, 1H), 7.18 - 7.03 (m, 7H), 6.81 (d, J=8.1 Hz, 1H), 6.68 - 6.62 (m, 1H), 6.60 - 6.54 (m, 2H), 6.52 - 6.46 (m, 2H), 5.12 - 5.00 (m, 3H), 4.91 (d, J=15.4 Hz, 1H), 4.36 - 4.28 (m, 1H), 4.24 - 4.16 (m, 1H), 4.11 (d, J=2.6 Hz, 1H), 3.33 - 3.21 (m, 8H), 3.17 (d, J=10.8 Hz, 2H), 2.96 - 2.84 (m, 1H), 2.58 (d, J=17.0 Hz, 1H), 2.46 - 2.27 (m, 3H), 2.19 (d, J=6.9 Hz, 2H), 2.00 - 1.92 (m, 1H), 1.74 (d, J=11.8 Hz, 2H), 1.61 (s, 1H), 1.25 - 1.14 (m, 2H). ^{^} EXAMPLE 132. Preparation of (I-385) (S)-3-(5-(4-((1-(5-((3S,4S)-7-hydroxy-3- phenylisochroman-4-yl)pyridin-2-yl)piperidin-4-yl)methyl)pip erazin-1-yl)-1-oxoisoindolin- 2-yl)piperidine-2,6-dione and (I-386) (S)-3-(5-(4-((1-(5-((3R,4R)-7-hydroxy-3-

phenylisochroman-4-yl)pyridin-2-yl)piperidin-4-yl)methyl) piperazin-1-yl)-1-oxoisoindolin- 2-yl)piperidine-2,6-dione Step 1: To a solution of Compound 1 (2.00 g, 6.36 mmol, 1 eq.) in MeCN (100 mL) was added Sodium bicarbonate (1.60 g, 742 ^L, 19.1 mmol, 3 eq.) and I ₂ (4.84 g, 19.1 mmol, 3 eq.). The mixture was stirred at 20 °C for 12 hour. LCMS showed the reaction was completed. The reaction mixture was quenched by the addition of saturated aqueous Na ₂ S ₂ O ₃ solution (100 mL) at 20 °C. The mixture was extracted with EtOAc (100 mL x 3). The combined organic layers hd ih bi ( 0 ) did SO fil d d d h d material was purified on silica gel column chromatography (from pure PE to PE/EtOAc = 15/1) to give Compound 2 (0.8 g, 2 mmol, 30 %) as a black solid. LC-MS (ESI ⁺ ) m/z: 440.9 (M+H) ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) į: ppm 7.63 - 7.73 (m, 2 H), 7.43 - 7.54 (m, 7 H), 7.37 - 7.42 (m, 1 H), 7.31 - 7.36 (m, 1 H), 7.08 (m, 1 H), 6.96 (d, J=2.40 Hz, 1 H), 5.24 - 5.30 (m, 2 H), 5.20 (s, 2 H). Step 2: A mixture of Compound 2 (200 mg, 454 ^mol, 1 eq.), Compound 3 (76.8 mg, 545 ^mol, 1.2 eq.), PdCl ₂ (dppf) (33.2 mg, 45.4 ^mol, 0.1 eq.) and K ₂ CO ₃ (188 mg, 1.36 mmo, 3 eq.l) in Dioxane (12 mL) and Water (3 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 80 °C for 3 hour under N ₂ atmosphere. LCMS showed the reaction was completed. The reaction mixture was quenched by addition EA 10 mL at 20 °C, and then diluted with water 30 mL and extracted with EA 30 mL (10 mL * 3). The combined organic layers were washed with EA 30 mL (10 mL * 3), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The crude material was purified on silica gel column chromatography (from pure PE to PE/EtOAc = 5/1) to give Compound 4 (140 mg, 342 ^mol, 75.3 %) as a yellow solid. LC-MS (ESI ⁺ ) m/z: 410.2 (M+H) ⁺ . Step 3: To a solution of Compound 4 (140.0 mg, 341.9 ^mol, 1 eq.) and Compound 5 (65.33 mg, 410.3 ^mol, 1.2 eq.) in DMF (10 mL) was added Cs ₂ CO ₃ (334.2 mg, 1.026 mmol, 3 eq.). The mixture was stirred at 16 °C for 16 hour. LCMS showed the reaction was completed. The reaction mixture was quenched by addition EA 10 mL at 20 °C, and then diluted with water 30 mL and extracted with EA 30 mL (10 mL * 3). The combined organic layers were washed with EA 30 mL (10 mL * 3), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The crude material was purified on silica gel column chromatography (from pure PE to PE/EtOAc = 3/1) to give compound 6 (90 mg, 0.16 mmol, 48 %) as a yellow solid. LC-MS (ESI ⁺ ) m/z: 549.8 (M+H) ⁺ . Step 4: To a solution of Compound 6 (100 mg, 182 ^mol, 1 eq.) in MeOH (2 mL) and THF (2 mL) was added Pd/C (10% 003 g) under N2 atmosphere The suspension was degassed and purged with H2 for 3 times. The mixture was stirred under H220 psi at 60 °C for 16 hours. LCMS showed the reaction was completed. The mixture was filtered and the filtrate was concentrated to give Compound 7 (50 mg, 0.11 mmol, 60 %). LC-MS (ESI ⁺ ) m/z: 461.2 (M+H) ⁺ . Step 5: The Compound 7 (50 mg, 0.11 mmol, 1 eq.) was purified by SFC (Column: DAICEL CHIRALCEL OD-H (250mm*30mm, 10um); Mobile phase: 0.1% NH ₃ H ₂ O CO ₂ -ETOH; from 40% to 40%; Flow rate: 80 mL/min) to give Compound 8 (25 mg, 54 ^mol, 50 %) and Compound 8A (20 mg, 43 mmol, 40 %) both as a white solid. Compound 8: LC-MS (ESI ⁺ ) m/z: 461.2 (M+H) ⁺ . Compound 8A: LC-MS (ESI ⁺ ) m/z: 461.2 (M+H) ⁺ . Step 6: To a solution of Compound 8 (25 mg, 54 ^mol, 1 eq.) in DCM (3 mL) and TFA (1 mL). The mixture was stirred at 20 °C for 1 hour. LCMS showed the reaction was completed. The mixture was concentrated in vacuo to give crude product. No further purification as it is used for the next step directly. LC-MS (ESI ⁺ ) m/z: 415.2 (M+H) ⁺ . Step 7: To a solution of Compound 8A (25 mg, 54 ^mol, 1 eq.) in DCM (3 mL) and TFA (1 mL). The mixture was stirred at 20 °C for 1 hour. LCMS showed the reaction was completed. The mixture was concentrated in vacuo to give crude product. No further purification as it is used for the next step directly. LC-MS (ESI ⁺ ) m/z: 415.2 (M+H) ⁺ . Step 8: To a solution of Compound 9 (22 mg, 53 ^mol, 1 eq.) and (S)-3-(1-oxo-5-(piperazin-1- yl) isoindolin-2-yl)piperidine-2,6-dione (21 mg, 64 ^mol, 1.2 eq.) in DCM (3 mL) and MeOH (3 mL) was added sodium triacetoxyborohydride (34 mg, 0.16 mmol, 3 eq.). The mixture was stirred at 20 °C for 12 hour. LCMS showed the reaction was completed. The crude was purified by prep.HPLC together (Phenomenex Gemini NX 150×30mm, 5^m, water (NH ₄ HCO ₃ )-ACN as a mobile phase, from 40% to 70%, Gradient Time (min): 11, Flow Rate (ml/min): 25) to give I- 385 (158 mg 217 ^mol 41 %) LCMS: calc. for C43H46N6O5:726.88, found: [M+H] ⁺ 727.4 HPLC: 100.00% purity at 220 nm. ¹ H NMR (500 MHz, METHANOL-d ₄ ) į: ppm 7.63 - 7.67 (m, 1 H), 7.37 - 7.40 (m, 1 H), 7.16 - 7.20 (m, 2 H), 7.07 - 7.15 (m, 5 H), 7.01 (m, 1 H), 6.83 - 6.88 (m, 1 H), 6.63 - 6.66 (m, 1 H), 6.62 (d, J=2.40 Hz, 1 H), 6.51 - 6.56 (m, 1 H), 5.00 - 5.14 (m, 4 H), 4.41 (d, J=8.40 Hz, 2 H), 4.03 - 4.08 (m, 3 H), 3.36 - 3.39 (m, 4 H), 2.87 - 2.95 (m, 1 H), 2.71 - 2.81 (m, 3 H), 2.59 - 2.63 (m, 4 H), 2.43 - 2.52 (m, 1 H), 2.28 (d, J=6.80 Hz, 2 H), 2.12 - 2.19 (m, 1 H), 1.83 (d, J=13.20 Hz, 3 H), 1.19 (s, 2 H). Step 9: To a solution of Compound 9A (15 mg, 36 ^mol, 1 eq.) and (S)-3-(1-oxo-5-(piperazin- 1-yl) isoindolin-2-yl)piperidine-2,6-dione (18 mg, 54 ^mol, 1.5 eq.) in DCM (3 mL) and MeOH (3 mL) was added sodium triacetoxyborohydride (23 mg, 0.11 mmol, 3 eq.). The mixture was stirred at 20 °C for 12 hour. LCMS showed the reaction was completed. The crude was purified by prep.HPLC together (Phenomenex Gemini NX 150×30mm, 5^m, water (NH ₄ HCO ₃ )-ACN as a mobile phase, from 40% to 70%, Gradient Time (min): 11, Flow Rate (ml/min): 25) to give I- 386 (12.7 mg, 17.5 ^mol, 48 %). LCMS: calc. for C ₄₃ H ₄₆ N ₆ O ₅ :726.88, found: [M+H] ⁺ 727.4 HPLC: 100.00% purity at 220 nm. ¹ H NMR (500 MHz, METHANOL-d ₄ ) į: ppm 7.61 - 7.65 (m, 1 H), 7.34 - 7.39 (m, 1 H), 7.14 - 7.18 (m, 2 H), 7.05 - 7.13 (m, 5 H), 6.96 - 7.01 (m, 1 H), 6.82 - 6.87 (m, 1 H), 6.58 - 6.64 (m, 2 H), 6.49 - 6.54 (m, 1 H), 4.98 - 5.12 (m, 4 H), 4.35 - 4.44 (m, 2 H), 4.00 - 4.06 (m, 3 H), 3.35 (d, J=9.60 Hz, 4 H), 2.86 - 2.93 (m, 1 H), 2.69 - 2.79 (m, 3 H), 2.57 - 2.62 (m, 4 H), 2.41 - 2.50 (m, 1 H), 2.26 (d, J=6.40 Hz, 2 H), 2.15 (m, 1 H), 1.81 (d, J=12.80 Hz, 3 H), 1.17 (s, 2 H). EXAMPLE 133. Preparation of (I-408) (S)-3-(1-oxo-5-(4-((1-(4-((6R,7S)-7-phenyl- 6,7,8,9-tetrahydro-3H-benzo[e]indazol-6-yl)phenyl)piperidin- 4-yl)methyl)piperazin-1- yl)isoindolin-2-yl)piperidine-2,6-dione and (I-44) (S)-3-(1-oxo-5-(4-((1-(4-((6S,7R)-7-phenyl- 6,7,8,9-tetrahydro-3H-benzo[e]indazol-6-yl)phenyl)piperidin- 4-yl)methyl)piperazin-1- yl)isoindolin-2-yl)piperidine-2,6-dione

Step 1: To a solution of 4-bromo-1H-indazole (22 g, 1 Eq, 0.11 mol) in DMF (250 mL) was added Benzyl bromide (22 g, 15 mL, 1.15 Eq, 0.13 mol). The mixture was stirred at 110 °C for 16 hour.^TLC (petroleum ether: ethyl acetate=10:1, R _f =0.3) indicated a new spot formed. The reaction was clean according to TLC. The solvent was removed under vaccum. The residue was dissolved in water (200 mL) and washed by ethyl acetate (2*100 mL). The combined organic layer was dried over Na ₂ SO ₄ , filtered and concentrated under vaccum to give the compound as a yellow oil. The reaction was purified by flash column (petroleum ether/ethyl acetate from 100/0 to 80/20) and the organic layer was concentrated in vacuo to give 1-benzyl-4-bromo-1H-indazole (20 g, 70 mmol, 62 %) as a yellow solid. Step 2: To a mixture of 1-benzyl-4-bromo-1H-indazole (20 g, 1 Eq, 70 mmol), (trans)-1- Ethoxyethene-2-boronic acid pinacol ester (15 g, 16 mL, 1.1 Eq, 77 mmol) and sodium carbonate (22 g, 13 mL, 3 Eq, 0.21 mol) in 1,4-dioxane (200 mL) and H ₂ O (50.0 mL) was added Pd(dppf)Cl ₂ (5.7 g, 0.1 Eq, 7.0 mmol). The mixture was stirred overnight at 90 °C for 16 hour under N ₂ . TLC (petroleum ether: ethyl acetate=5:1, R _f =0.3) indicated a new spot formed. The reaction was clean according to TLC. The solvent was removed under vaccum. The residue was dissolved in water (200 mL) and washed by ethyl acetate (2*100 mL). The combined organic layer was dried over Na ₂ SO ₄ , filtered and concentrated under vaccum to give the compound as a yellow oil. The reaction was purified by flash column (petroleum ether/ethyl acetate from 100/0 to 70/30) and the organic layer was concentrated in vacuo to give (E)-1-benzyl-4-(2- ethoxyvinyl)-1H-indazole (14 g, 28 mmol, 40 %, 55% Purity) as a yellow oil. Step 3: To a solution of (E)-1-benzyl-4-(2-ethoxyvinyl)-1H-indazole (14 g, 55% Wt, 1 Eq, 28 mmol) in HCl/dioxane (40 mL). The mixture was stirred at 25 °C for 16 hr. TLC(PE/EtOAc = 5/1, R _f = 0.3) showed a new spot was detected. The solvent was removed under vacuo. The residue was dissolved in water (30 mL) and washed by ethyl acetate (2*15 mL). The combined organic layer was dried over Na ₂ SO ₄ , filtered and concentrated under vacuo to give the compound as a yellow oil. The reaction was purified by flash column (petroleum ether/ethyl acetate from 100/0 to 80/20) and the organic layer was concentrated in vacuo to give 2-(1- benzyl-1H-indazol-4-yl)acetaldehyde (6.7 g, 27 mmol, 97 %) as a yellow oil. Step 4: To a mixture of Sodium hydride (1.3 g, 60% Wt, 1.2 Eq, 32 mmol), in THF (100 mL) was added ethyl 2-(diethoxyphosphoryl)acetate (9.0 g, 8.0 mL, 1.5 Eq, 40 mmol), the resultant g, 1 Eq, 27 mmol) was added to the reaction. Then the resultant mixture was stirred for 2 hour at 0 °C under N2. TLC (petroleum ether/ethyl acetate=3/1, Rf=0.3) showed a new point. The mixture was warmed to room temperature and treated with the saturation NH ₄ Cl aqueous solution (20 mL). The mixture was extracted with EA (30 mL *3), washed with H ₂ O (30 mL) and brine (30 mL). The combined organic layers were dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give the residue which was purified by flash column (petroleum ether/ethyl acetate from 100/0 to 50/50) and the organic layer was concentrated in vacuo to give ethyl (E)-4-(1-benzyl-1H-indazol-4-yl)but-2-enoate (7 g, 0.02 mol, 60 %, 70% Purity) as a yellow oil. LC-MS (ESI+) m/z: 321.2 (M+H) ⁺ . Step 5: To a solution of ethyl (E)-4-(1-benzylindazol-4-yl)but-2-enoate (6.11 g, 17.17 mmol, 90% purity, 1 eq) in THF (50 mL) was added Pd/C(1.10 g, 1.03 mmol, 10% purity, 6.02e-2 eq) under N ₂ atmosphere. The suspension was degassed and purged with H ₂ for 2 times. The mixture was stirred under H ₂ (15 Psi) at 25 °C for 16 hr. The reaction was filtered and the filter cake was pour into H ₂ O, and recycle to catalyst storage. The filtrate was concentrated. Compound ethyl 4- (1-benzylindazol-4-yl)butanoate (5.4 g, 13.40 mmol, 78.05% yield, 80% purity) was obtained as a yellow oil. LC-MS (ESI+) m/z: 323.2 (M+H) ⁺ . Step 6: To a solution of ethyl 4-(1-benzylindazol-4-yl)butanoate (5.4 g, 13.40 mmol, 80% purity, 1 eq) in THF (20 mL) and EtOH (20 mL) was added NaOH (2 M, 20 mL, 2.99 eq) .The mixture was stirred at 20 °C for 12 hr. The reaction mixture was diluted with H ₂ O 50 mL and extracted with EtOAc 100 mL (50 mL * 2). The combined organic layers were washed with saturatedsaltsolution 30 mL, dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a yellow oil. Compound 4-(1-benzylindazol-4-yl)butanoic acid (3.9 g, 13.25 mmol, 98.88% yield) was obtained as a yellow oil. LC-MS (ESI+) m/z: 295.2 (M+H) ⁺ . Step 7: To a solution of 4-(1-benzylindazol-4-yl)butanoic acid (3.9 g, 13.25 mmol, 1 eq) in PPA (30 mL).The mixture was stirred at 100 °C for 1 hr. TLC (petroleum ether:ethyl acetate=3:1) indicated Reactant 1 was consumed completely and many new spots formed. The reaction was messy according to TLC. The reaction mixture was quenched by addition NaHCO ₃ 300 mL at 0 °C, and then diluted with H ₂ O 200 mL and extracted with EtOAc 200 mL (100 mL * 2). The combined organic layers were washed with saturatedsaltsolution 50 mL, dried over Na2SO4, filtered and concentrated under reduced pressure to give a yellow oil. The residue was purified 0~30% Ethyl acetate/Petroleum ethergradient @ 45 mL/min). Compound 3-benzyl-8,9-dihydro- 7H-benzo[e]indazol-6-one (3.5 g, 11.40 mmol, 86.03% yield, 90% purity) was obtained as a yellow solid. LC-MS (ESI+) m/z: 277.1 (M+H) ⁺ Step 8: To a solution of 3-benzyl-3,7,8,9-tetrahydro-6H-benzo[e]indazol-6-one (800 mg, 1 Eq, 2.89 mmol) in THF (30 mL) cooled at -78° C. under N ₂ , and LDA (465 mg, 2.17 mL, 2 molar, 1.5 Eq, 4.34 mmol) was added dropwise and stirred for 30 min.1,1,1-trifluoro-N-phenyl-N- ((trifluoromethyl)sulfonyl)methanesulfonamide (1.55 g, 1.5 Eq, 4.34 mmol) was added. The reaction mixture was stirred for 16 hours. TLC (petroleum ether/ethyl acetate=5/1, R _f =0.4) showed one new spot was formed. The reaction mixture was cooled to room temperature and diluted with water (200 mL). The solids were filtered out and to the filtrate was added saturated NH ₄ Cl(200 mL). The resulting mixture was extracted with ethyl acetate (200 mL x 2) and the organic layers combined. The organic was washed with brine (200 mL x 2), dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by flash silica gel chromatography (ISCO®; 4 g SepaFlash® Silica Flash Column, Eluent of 0~50% Ethyl acetate/Petroleum ether gradient @ 20 mL/min).The organic layer was concentrated in vacuo to give 3-benzyl-8,9-dihydro-3H-benzo[e]indazol-6-yltrifluoromethane sulfonate (500 mg, 1.22 mmol, 42.3 %) as a yellow oil. Step 9: A mixture of Pd-118(90.9 mg, 0.1 Eq, 142 ^mol), 4-(dimethoxymethyl)-1-(4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperidine (821 mg, 1.2 Eq, 1.70 mmol), 3-benzyl- 8,9-dihydro-3H-benzo[e]indazol-6-yl trifluoromethanesulfonate() and Na ₂ CO ₃ (452 mg, 3 Eq, 4.26 mmol) in dioxane (16 mL) and H ₂ O (4.0 mL) at r.t.. N ₂ was bubbled into the mixture for 5 min. The reaction mixture was heated at 70 °C for 12 hour. Then the reaction was cooled to room temperature. TLC(PE/EtOAc = 2/1, R = 0.4) showed one new spot was formed. The mixture was treated with H ₂ O (50 mL), extracted with EtOAc (50 mL * 2). The combined extracts were dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to dryness in vacuo to give a residue. The residue was subjected to column chromatography over silica gel (gradient elution: 0~20% ethyl acetate in petroleum ether). The pure fractions were collected and concentrated to dryness in vacuo to give 3-benzyl-6-(4-(4-(dimethoxymethyl)piperidin-1-yl)phenyl)-8,9 -dihydro-3H- benzo[e]indazole (400 mg, 810 ^mol, 57.1 %) as a white solid. Step 10: To a solution of 3-benzyl-6-[4-[4-(dimethoxymethyl)-1-piperidyl]phenyl]-8,9- added BLAH;pyridin-1-ium (272.11 mg, 850.83 umol, 1.05 eq) and N-ethyl-N-isopropyl- propan-2-amine (157.09 mg, 1.22 mmol, 211.71 uL, 1.5 eq) .The mixture was stirred at 0 °C for 0.5 hr . The reaction mixture was concentrated under reduced pressure to remove DCM .The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate=1/0 to 3/1).Compound 3-benzyl-7-bromo-6-[4-[4-(dimethoxymethyl)-1-piperidyl]pheny l]-8,9- dihydrobenzo[e]indazole (260 mg, 317.89 umol, 39.23% yield, 70% purity) was obtained as a yellow oil. LC-MS (ESI+) m/z: 572.1 (M+H) ⁺ Step 11: A mixture of 3-benzyl-7-bromo-6-[4-[4-(dimethoxymethyl)-1-piperidyl]pheny l]-8,9- dihydrobenzo[e]indazole (220 mg, 384.26 umol, 1 eq) , phenylboronic acid (56.22 mg, 461.11 umol, 1.2 eq) , cyclopentyl(diphenyl)phosphane;dichloromethane;dichloropalla dium;iron (31.38 mg, 38.43 umol, 0.1 eq) , na2co3 (122.18 mg, 1.15 mmol, 3 eq) in dioxane (2 mL) and H2O (0.2 mL) was degassed and purged with N ₂ for 3 times, and then the mixture was stirred at 100 °C for 16 hr under N ₂ atmosphere. The reaction mixture was quenched by addition 5 mL H2O, and then diluted with 20 mL EA and extracted with EA 40 mL (20 mL * 2). The combined organic layers were washed with saturated salt water 10 mL, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , Petroleum ether/Ethyl acetate=0/1 to 3/1). The crude product 3-benzyl-6-[4-[4-(dimethoxymethyl)-1-piperidyl]phenyl]-7-phe nyl-8,9- dihydrobenzo[e]indazole (196 mg, 344.02 umol, 89.53% yield) as yellow solid was used into the next step without further purification. LC-MS (ESI+) m/z: 570.2 (M+H) ⁺ Step 12: To a solution of 3-benzyl-6-[4-[4-(dimethoxymethyl)-1-piperidyl]phenyl]-7-phe nyl-8,9- dihydrobenzo[e]indazole(190 mg, 333.49 umol, 1 eq) in MeOH (10 mL) was added Pd/C (380.00 mg, 3.57 mmol, 10.71 eq) under N ₂ atmosphere. The suspension was degassed and purged with H2 (13.44 mg, 6.67 mmol, 20 eq) for 3 times. The mixture was stirred under H ₂ (15 Psi) at 50 °C for 12 hr. The reaction mixture was filtered and the filter was concentrated. The crude product 6-[4-[4-(dimethoxymethyl)-1-piperidyl]phenyl]-7-phenyl-6,7,8 ,9-tetrahydro-3H- benzo[e]indazole (100 mg, 207.63 umol, 62.26% yield) as white solid was used into the next step ith t f th ifi ti LC-MS (ESI+) m/z: 482.1 (M+H) ⁺ Step 13: 6-[4-[4-(dimethoxymethyl)-1-piperidyl]phenyl]-7-phenyl-6,7,8 ,9-tetrahydro-3H- benzo[e]indazole (100 mg, 207.63 umol, 1 eq) was added to THF (2 mL) and H2SO4 (2 mL, 10% purity) .The mixture was stirred at 70 °C for 16 hr . The reaction mixture was concentrated under reduced pressure to remove THF and diluted with EA 5 mL .Then the mixture was acidified with Saturated sodium carbonate to PH=5 and extracted with EA 50 mL (25 mL * 2). The combined organic layers were washed with saturated salt water 30 mL, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a yellow solid. The crude product 1-[4-(7-phenyl-6,7,8,9-tetrahydro-3H-benzo[e]indazol-6- yl)phenyl]piperidine-4-carbaldehyde (85 mg, 195.15 umol, 93.99% yield) as yellow solid was used into the next step without further purification. LC-MS (ESI+) m/z: 436.0. (M+H) ⁺ Step 14: To a solution of 1-[4-(7-phenyl-6,7,8,9-tetrahydro-3H-benzo[e]indazol-6- yl)phenyl]piperidine-4-carbaldehyde (85.00 mg, 195.15 umol, 1 eq)in DCM (1 mL) and MEOH (1 mL) was added acetic acid (23.44 mg, 390.30 umol, 22.32 uL, 2 eq) (3S)-3-(1-oxo-5- piperazin-1-yl-isoindolin-2-yl)piperidine-2,6-dione (128.16 mg, 390.30 umol, 2 eq) and sodium acetate (80.05 mg, 975.76 umol, 5 eq) .The mixture was stirred at 20 °C for 1 hr .Then the NaBH(OAc) ₃ (82.72 mg, 390.30 umol, 2 eq) added to the mixture and stirred at 20 °C for 12 hr . The reaction mixture was concentrated under reduced pressure to remove DCM and MeOH. The residue was purified by prep-HPLC (column: Boston Green ODS 150*30mm*5um;mobile phase: [water(FA)-ACN];B%: 26%-56%,7min) to give desired compound (30 mg, yield 20.55%, purity 100%) as a white solid, which was further separated by SFC (column: DAICEL CHIRALCEL OJ(250mm*30mm,10um);mobile phase: [0.1%NH3H2O ETOH];B%: 55%- 55%,min). The crude product(3S)-3-[1-oxo-5-[4-[[1-[4-[(6R,7S)-7-phenyl-6,7,8,9-t etrahydro-3H- benzo[e]indazol-6-yl]phenyl]-4-piperidyl]methyl]piperazin-1- yl]isoindolin-2-yl]piperidine-2,6- dione (13 mg, 17.38 umol, 8.91% yield, N/A purity) was used into the next step without further purification. The crude product (3S)-3-[1-oxo-5-[4-[[1-[4-[(6S,7R)-7-phenyl-6,7,8,9-tetrahyd ro-3H- benzo[e]indazol-6-yl]phenyl]-4-piperidyl]methyl]piperazin-1- yl]isoindolin-2-yl]piperidine-2,6- dione (14 mg, 18.72 umol, 9.59% yield, N/A purity) was used into the next step without further purification.^^^ 068: LC-MS (ESI ⁺ ) m/z: 749.3 (M+H) ⁺ HPLC: 87% purity at 220 nm. ¹ H NMR (400 MHz, DMSO-d ₆ ) į = 8.14 (s, 1H), 7.96 (s, 1H), 7.74 (br d, J = 8.5 Hz, 1H), 7.18 (br d, J = 6.3 Hz, 4H), 6.99 (br d, J = 8.8 Hz, 2H),6.87 (br s, 2H), 6.59 (br d, J = 8.3 Hz, 2H), 6.33 (br d, J = 8.8 Hz, 2H), 5.23 - 5.19 (m, 1H), 4.40 (s, 1H), 4.34 (br d, J = 4.3 Hz, 1H), 4.28 (s, 1H), 3.57 (br d, J= 11.3 Hz, 2H), 3.47 (br d, J = 6.0 Hz, 2H), 3.33 (br s, 5H), 2.59 (br s, 6H), 2.31 (br d, J = 12.5 Hz, 4H), 1.85 (br s, 3H), 1.26 (s, 6H) 068A: LC-MS (ESI ⁺ ) m/z: 749.4 (M+H) ⁺ HPLC: 92.924% purity at 220 nm. ¹ H NMR (400 MHz, DMSO-d ₆ ) į = 8.14 (br s, 1H), 8.02 (br s, 1H), 7.74 (br d, J = 8.0 Hz, 1H), 7.23 - 7.15 (m, 4H), 7.00 (br s, 2H), 6.88 - 6.85 (m,2H), 6.60 (br d, J = 9.3 Hz, 2H), 6.33 (br d, J = 7.8 Hz, 2H), 5.21 (br dd, J = 4.5, 13.1 Hz, 1H), 4.45 - 4.38 (m, 1H), 4.34 (br s, 1H), 4.30 - 4.23 (m, 1H), 3.57(br d, J = 10.3 Hz, 2H), 3.48 (br s, 2H), 3.33 (br s, 6H), 2.58 (br s, 6H), 2.33 - 2.21 (m, 4H), 1.92 - 1.80 (m, 3H), 1.34 - 1.24 (m, 6H).

EXAMPLE 134. Preparation of (I-1) (5S,6R)-5-(4-(4-((4-(2-((S)-2,6-dioxopiperidin-3- yl)-1-oxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-y l)phenyl)-6-phenyl-5,6,7,8- tetrahydronaphthalene-2-carboxylic acid Step 1: To a mixture of compound 1 (110 mg, 220.16 ^mol, 1 eq.) in MeOH (2 mL) and water (2 mL) was added LiOH (52.73 mg, 2.20 mmol, 10 eq.). The mixture was stirred at 25 °C for 16 hours. LCMS showed the reaction was completed. The mixture was diluted with saturated HCl aq. till pH = 7. The mixture was concentrated in vacuo to give the residue which was re- crystallized from water, dried by lyophilization. Compound 2 (100 mg, 85.74% yield) was obtained as a yellow solid. LC-MS (ESI ⁺ ) m/z: 486.3 (M+H) ⁺ . Step 2: To a mixture of compound 2 (100 mg, 205.93 ^mol, 1 eq.) in TFA (1 mL) and DCM (3 mL) was stirred at 25 °C for 30 min. TLC (PE/EtOAc=3/1) showed the reaction was completed. The mixture was filtered and concentrated in vacuum. Compound 4 (90 mg, 99.43% yield) was obtained as a white solid. Step 3: To a mixture of compound 3 (90 mg, 204.76 ^mol, 1 eq.) and 034 (102.49 mg, 204.76 ^mol, 1 eq., TsOH) in DCE (8 mL) was added sodium;triacetoxyboranuide (65.09 mg, 307.14 ^mol, 1.5 eq.) and 4-methylmorpholine (20.71 mg, 204.76 ^mol, 1 eq.) in one portion at 25°C. The mixture was stirred at 25 °C for 16 hours. LCMS (ES22193-4-R1A) showed the reaction was complete. The mixture was poured into water (5 mL). The aqueous phase was extracted with DCM (20 mL*3). The combined organic phase was dried with anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuum. The residue was purified by prep-HPLC (Column: Welch Xtimate C18150*25mm*5um, water (FA)-ACN as a mobile phase, from 22% to 52%, Gradient Time (min): 10, Flow Rate (ml/min): 25). I-1 (27 mg, 17.54% yield, 100% purity) was obtained as a white solid. LC-MS (ESI ⁺ ) m/z: 752.6 (M+H) ⁺ . ¹ H NMR (500 MHz, METHANOL-d ₄ ) į ppm: 7.93 (s, 1H), 7.73-7.64 (m, 2H), 7.20-7.10 (m, 5H), 6.99 (d, J = 8.0 Hz, 1H), 6.86-6.83 (m, 2H), 6.70-6.62 (m, 2H), 6.34 (d, J = 8.5 Hz, 2H), 5.14-5.09 (m, 1H), 4.50-4.38 (m, 2H), 4.36 (d, J=5.0 Hz, 1H), 3.71 (s, 1H), 3.61 (d, J=8.5 Hz, 3H), 3.50-3.43 (m, 2H), 3.41 (s, 1H), 3.40-3.37 (m, 2H), 3.38 (d, J = 4.0 Hz, 1H), 3.21-3.11 (m, 4H), 2.96-2.86 (m, 1H), 2.82-2.73 (m, 1H), 2.73-2.64 (m, 2H), 2.52-2.41 (m, 1H), 2.37-2.25 (m, 1H), 2.19-2.12 (m, 1H), 2.02 (d, J = 8.5 Hz, 1H), 1.89 (d, J = 9.5 Hz, 3H), 1.51-1.41 (m, 2H), 1.38-1.18 (m, 1H). EXAMPLE 135. Preparation of (I-2) (5R,6S)-5-(4-(4-((4-(2-((S)-2,6-dioxopiperidin-3- yl)-1-oxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-y l)phenyl)-6-phenyl-5,6,7,8- tetrahydronaphthalene-2-carboxylic acid Step 1: To a mixture of compound 1 (400 mg, 803.82 ^mol, 1 eq.) in MeOH (4 mL) and THF (2 mL) was added Pd/C (85.54 mg, 80.38 ^mol, 10% purity, 0.1 eq.) in one portion at 25 °C under H ₂ . The mixture was stirred at 25 °C for 36 hours. LCMS (ES21801-14-R1A) showed the reaction was complete. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by SFC (condition: Column: DAICEL CHIRALCEL OJ (250mm*30mm, 10 ^m); Mobile phase: A: CO2 B: ethanol (0.1% NH ₃ H ₂ O); Flow rate: 2.8 mL/min; Column temp.: 35 °C; ABPR: 1500psi). Compound 2 (110 mg, 27.39% yield) and compound 2A (150 mg, 37.35% yield) were obtained as a yellow solid. LC-MS (ESI ⁺ ) m/z: 500.4 (M+H) ⁺ . Step 2: To a mixture of compound 2 (120 mg, 240.17 ^mol, 1 eq.) in MeOH (2 mL) and water (2 mL) was added LiOH (57.52 mg, 2.40 mmol, 10 eq.). The mixture was stirred at 25 °C for 16 hours. LCMS showed the reaction was completed. The mixture was diluted with saturated HCl aq. till pH = 7. The mixture was concentrated in vacuo to give the residue which was re- crystallized from water, dried by lyophilization. Compound 3 (100 mg, 85.74% yield) was obtained as a yellow solid. LC-MS (ESI ⁺ ) m/z: 486.3 (M+H) ⁺ . Step 3: To a mixture of compound 3 (100 mg, 205.93 ^mol, 1 eq.) in TFA (1 mL) and DCM (3 mL) was stirred at 25 °C for 30 min. TLC (PE/EtOAc=3/1) showed the reaction was completed. The mixture was filtered and concentrated in vacuum. Compound 4 (90 mg, 99.43% yield) was obtained as a white solid. Step 4: To a mixture of compound 4 (90 mg, 204.76 ^mol, 1 eq.) and 034 (102.49 mg, 204.76 ^mol, 1 eq., TsOH) in DCE (8 mL) was added sodium;triacetoxyboranuide (65.09 mg, 307.14 ^mol, 1.5 eq.) and 4-methylmorpholine (20.71 mg, 204.76 ^mol, 1 eq.) in one portion at 25°C. The mixture was stirred at 25 °C for 16 hours. LCMS (ES22193-3-R1A) showed the reaction was complete. The mixture was poured into water (5 mL). The aqueous phase was extracted with DCM (20 mL*3). The combined organic phase was dried with anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuum. The residue was purified by prep-HPLC (Column: Welch Xtimate C18150*25mm*5um, water (FA)-ACN as a mobile phase, from 22% to 52%, Gradient Time (min): 10, Flow Rate (ml/min): 25). I-2 (60 mg, 38.97% yield, 100% purity) was obtained as a white solid. LC-MS (ESI ⁺ ) m/z: 752.3 (M+H) ⁺ . ¹ H NMR (500 MHz, METHANOL-d ₄ ) į ppm: 7.93 (s, 1H), 7.70-7.65 (m, 2H), 7.15-7.11 (m, 5H), 6.99 (d, J = 8.0 Hz, 1H), 6.86-6.82 (m, 2H), 6.65 (d, J = 8.5 Hz, 2H), 6.32 (d, J = 9.0 Hz, 2H), 5.13-5.08 (m, 1H), 4.45 - 4.36 (m, 2H), 4.35 (d, J = 4.5 Hz, 1H), 3.58 (s, 2H), 3.49 (s, 3H), 3.42-3.36 (m, 2H), 3.33 (d, J = 1.5 Hz, 1H), 3.24-3.19 (m, 1H), 3.15-3.09 (m, 1H), 2.98 (s, 4H), 2.92-2.85 (m, 1H), 2.81-2.74 (m, 1H), 2.67 (s, 1H), 2.62 (s, 2H), 2.51-2.41 (m, 1H), 2.37-2.29 (m, 1H), 2.18-2.11 (m, 1H), 1.87 (d, J=10.5 Hz, 4H), 1.42-1.35 (m, 2H). EXAMPLE 136. Preparation of (I-7) (S)-5-(4-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-1- oxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)phen yl)-6-phenyl-7,8- dihydronaphthalene-2-carboxylic acid Step 1: To a mixture of compound 1 (3.5 g, 17.14 mmol, 1 eq.) in THF (100 mL) was added LDA (2 M, 12.85 mL, 1.5 eq.) in one portion at -75 °C under N2. The mixture was stirred at -75 °C for 1 hour, then compound 2 (12.25 g, 34.28 mmol, 2 eq.) was added. The mixture was stirred at 25 °C for 12 hours. TLC (PE/EtOAc=3/1) showed the reaction was complete. The reaction mixture was quenched by water (20 mL) and extracted with ethyl acetate 150 mL (50 mL * 3). The combined organic layers were washed with brine 150 mL (50 mL * 3), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , Petroleum ether/Ethyl acetate=3/1 to 1/1) to give compound 3 (8 g, 15.70 mmol, 91.61% yield, 66% purity) as a yellow solid. LC-MS (ESI ⁺ ) m/z: 337.0 (M+H) ^{+ 1} H NMR (500MHz, CHLOROFORM-d) į ppm˖7.95-7.93 (m, 1H), 7.86 (d, J =1.0 Hz, 1H), 7.32-7.30 (m, 1H), 6.19-6.14 (m, 1H), 3.93 (s, 3H), 2.95-2.91 (m, 2H), 2.59-2.54 (m, 2H). Step 2: To a mixture of compound 3 (500 mg, 1.49 mmol, 1 eq.) and compound 4 (537.17 mg, 1.49 mmol, 1 eq.) in dioxane (5 mL) and Water (1 mL) was added pd(dppf)Cl ₂ (108.79 mg, 148.68 ^mol, 0.1 eq.) and K ₂ CO ₃ (616.47 mg, 4.46 mmol, 3 eq.) in one portion at 25 °C under N ₂ . The mixture was stirred at 80 °C for 2 hours. LCMS (ES21801-1-P1A) indicated the reaction was complete. The mixture was added water (10 mL). The aqueous phase was extracted with ethyl acetate (50 mL*3). The combined organic phase was washed with brine (20 mL), dried with anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuum. The residue was purified by silica gel chromatography (Petroleum ether/Ethyl acetate=1/1) to give compound 5 (400 mg, 948.93 umol, 63.82% yield) as a white solid. LC-MS (ESI ⁺ ) m/z: 422.2 (M+H) ⁺ . ¹ H NMR (400 MHz, CHLOROFORM-d) į ppm˖7.86 (d, J=1.2 Hz, 1H), 7.78-7.75 (m, 1H), 7.24 - 7.20 (m, 2H), 7.13 (d, J=8.0 Hz, 1H), 6.98 - 6.93 (m, 2H), 6.19-6.17 (m, 1H), 4.14-4.09 (m, 1H), 3.91 (s, 3H), 3.78-3.75 (m, 2H), 3.39 (s, 6H), 2.90-2.86 (m, 2H), 2.75-2.68 (m, 2H), 2.44-2.38 (m, 2H), 1.91-1.86 (m, 2H), 1.83-1.74 (m, 1H), 1.54-1.43 (m, 2H) Step 3: To a mixture of compound 5 (400 mg, 948.93 ^mol, 1 eq.) in DCM (4 mL) was added PyHBr ₃ (212.44 mg, 664.25 ^mol, 0.7 eq.) in one portion at 0°C under N ₂ . The mixture The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate=3/1 to 1/1). Compound 6 (120 mg, 25.27% yield) was obtained as a white solid. LC-MS (ESI ⁺ ) m/z: 501.8 (M+H) ⁺ . Step 4: To a mixture of compound 6 (120 mg, 239.80 ^mol, 1 eq.) and compound 7 (29.24 mg, 239.80 ^mol, 1 eq.) in dioxane (3 mL) and Water (0.1 mL) was added pd(dppf)Cl ₂ (17.55 mg, 23.98 ^mol, 0.1 eq.) and K ₂ CO ₃ (99.42 mg, 719.39 ^mol, 3 eq.) in one portion at 25 °C under N ₂ . The mixture was stirred at 80 °C for 16 hours. LCMS (ES21801-9-R1A) showed the reaction was complete. The reaction mixture was quenched by addition water 20 mL and extracted with ethyl acetate 150 mL (50 mL * 3). The combined organic layers were washed with brine 150 mL (50 mL * 3), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate=3/1 to 1/1). Compound 8 (100 mg, 83.80% yield) was obtained as a yellow solid. LC-MS (ESI ⁺ ) m/z: 498.3 (M+H) ⁺ . Step 5: To a mixture of compound 8 (100 mg, 201 ^mol, 1 eq.) in Water (3 mL) and MeOH (3 mL) was added LiOH (17.3 mg, 402 ^mol, 2 eq.) in one portion. The mixture was stirred at 25 °C for 16 hours. LCMS showed the reaction was completed. The mixture was diluted with saturated HCl aq. till pH = 7. The mixture was concentrated in vacuo to give the residue which was re-crystallized from water, dried by lyophilization. Compound 9 (60 mg, 62 %) was obtained as a white solid. LC-MS (ESI ⁺ ) m/z: 484.2 (M+H) ⁺ . Step 6: To a mixture of compound 9 (60 mg, 0.12 mmol, 1 eq.) in TFA (1 mL) and DCM (3 mL) was stirred at 25 °C for 30 min. TLC (PE/EtOAc=3/1) showed the reaction was completed. The mixture was filtered and concentrated in vacuum. Compound 10 (50 mg, 92 %) was obtained as a white solid. Step 7: To a mixture of compound 10 (50 mg, 114.28 ^mol, 1 eq.) and 034 (57.20 mg, 114.28 ^mol 1 eq TsOH) in DCE (5 mL) was added sodium;triacetoxyboranuide (4844 mg 22856 ^mol, 2 eq.) and 4-methylmorpholine (1.16 mg, 11.43 ^mol, 0.1 eq.) in one portion at 25 °C. The mixture was stirred at 25 °C for 16 hours. LCMS (ES21801-13-R1A) showed the reaction was complete. The mixture was poured into water (5 mL). The aqueous phase was extracted with DCM (20 mL*3). The combined organic phase was dried with anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuum. The residue was purified by prep-HPLC (Column: Welch Xtimate C18150*25mm*5um, water (FA)-ACN as a mobile phase, from 22% to 52%, Gradient Time (min): 10, Flow Rate (ml/min): 25)). I-7 (9.5 mg, 11.09% yield, 100% purity) was obtained as a white solid. LC-MS (ESI ⁺ ) m/z: 750.3 (M+H) ⁺ . ¹ H NMR (500 MHz, METHANOL-d ₄ ) į ppm: 7.85 (d, J = 1.5 Hz, 1H), 7.70-7.64 (m, 2H), 7.13- 7.04 (m, 7H), 6.90 (s, 4H), 6.82 (d, J = 9.0 Hz, 1H), 5.13-5.08 (m, 1H), 4.46-4.36 (m, 2H), 3.72- 3.66 (m, 2H), 3.44-3.42 (m, 4H), 3.03-2.99 (m, 2H), 2.95-2.85 (m, 1H), 2.82-2.70 (m, 9H), 2.49- 2.40 (m, 3H), 2.18-2.12 (m, 1H), 1.94-1.90 (m, 2H), 1.86-1.77 (m, 1H), 1.44-1.34 (m, 2H). EXAMPLE 137. Preparation of (I-135) (3S)-3-[5-[4-[[1-[4-[(1R,2R)-2-cycloheptyl-6- hydroxy-tetralin-1-yl]phenyl]-4-piperidyl]methyl]piperazin-1 -yl]-1-oxo-isoindolin-2- yl]piperidine-2,6-dione and (I-134) (3S)-3-[5-[4-[[1-[4-[(1S,2S)-2-cycloheptyl-6-hydroxy-

tetralin-1-yl]phenyl]-4-piperidyl]methyl]piperazin-1-yl]- 1-oxo-isoindolin-2-yl]piperidine- 2,6-dione Step 1: To a solution of cycloheptanone (1 g, 8.92 mmol, 1.05 mL, 1 eq) and Na ₂ CO ₃ (1.89 g, 17.83 mmol, 2 eq) in DCM (50 mL) was added Tf ₂ O (4.10 g, 14.55 mmol, 2.4 mL, 1.63 eq) under 0 °C The mixture was stirred at 25 °C for 12 h. The reaction mixture was quenched by addition of water (50 mL), extracted with DCM (30 mL x 3). The combined organic layers were to give a residue. The residue was purified by flash silica gel chromatography (from pure PE to PE/EtOAc = 5/1, TLC: PE/EtOAc = 5/1, Rf = 0.82) to yield cyclohepten-1-yl trifluoromethanesulfonate (1.8 g, 6.6 mmol, 74.4% yield, 90% purity) as yellow oil. ¹ H NMR (500MHz, CDCl ₃ ) į = 5.89 (t, J = 6.4 Hz, 1H), 2.57-2.49 (m, 2H), 2.20-2.11 (m, 2H), 1.76-1.68 (m, 4H), 1.64 (td, J = 5.6, 10.9 Hz, 2H). Step 2: To a solution of cyclohepten-1-yl trifluoromethanesulfonate (800 mg, 2.95 mmol, 1 eq) and Pin ₂ B ₂ (973.20 mg, 3.83 mmol, 1.3 eq) in toluene (10 mL) was added Pd(dppf)Cl ₂ (107.85 mg, 147.40 Pmol, 0.05 eq) potassium phenolate (584.60 mg, 4.42 mmol, 1.5 eq) and KBr (526.23 mg, 4.42 mmol, 191.36 PL, 1.5 eq). The mixture was stirred at 50 °C for 2 h. The reaction mixture was quenched by addition of water (50 mL), extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (10 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (from PE/EtOAc = 1/0 to 5/1, TLC: PE/EtOAc = 5/1, R _f = 0.67) to yield 2- (cyclohept-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolan e (470 mg, 2.01 mmol, 68.18% yield, 95% purity) as yellow oil. ¹ H NMR (400MHz, CDCl ₃ ) į = 6.78 (t, J = 6.4 Hz, 1H), 2.25 (d, J = 5.7, 18.8 Hz, 4H), 1.79- 1.71 (m, 2H), 1.52-1.44 (m, 4H), 1.26 (s, 12H). Step 3: To a solution of 1-(4-(6-(benzyloxy)-2-bromo-3,4-dihydronaphthalen-1-yl)pheny l)-4- (dimethoxymethyl)piperidine (900 mg, 1.64 mmol, 1 eq) and 2-(cyclohept-1-en-1-yl)-4,4,5,5- tetramethyl-1,3,2-dioxaborolane3 (422.02 mg, 1.80 mmol, 95% purity, 1.1 eq) in dioxane (9 mL) and H2O (3 mL) was added Pd(dppf)Cl2 (120.06 mg, 164.08 umol, 0.1 eq) and Na2CO3 (434.77 mg, 4.10 mmol, 2.5 eq). The mixture was stirred at 100 °C for 12 h. The reaction mixture was quenched by addition of water (50 mL), extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (10 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (from PE/EtOAc = 1/0 to 10/1, TLC: PE/EtOAc = 5/1, R _f = 0.68) to yield 1-(4- (6-(benzyloxy)-2-(cyclohept-1-en-1-yl)-3,4-dihydronaphthalen -1-yl)phenyl)-4- (dimethoxymethyl)piperidine (500 mg, 824.81 Pmol, 50.27% yield, 93% purity) as a yellow solid. LC-MS (ESI ⁺ ) m/z 564.4 [M+H] ⁺ . ¹ H NMR (400MHz, CDCl3) į = 7.45-7.29 (m, 5H), 7.03 (br d, J = 8.2 Hz, 2H), 6.90 (br d, J = 8.2 Hz, 2H), 6.80 (d, J = 2.4 Hz, 1H), 6.71-6.65 (m, 1H), 6.64-6.59 (m, 1H), 5.50 (br t, J = 6.4 Hz, 1H), 5.04 (s, 2H), 4.12 (t, J = 7.1 Hz, 1H), 3.73 (br d, J = 12.2 Hz, 2H), 3.39 (s, 6H), 2.82 (t, J = 7.7 Hz, 2H), 2.74-2.62 (m, 2H), 2.44 (dd, J = 6.7, 8.8 Hz, 2H), 2.05 (br d, J = 10.4 Hz, 2H), 2.00-1.84 (m, 4H), 1.82-1.72 (m, 1H), 1.67-1.59 (m, 2H), 1.55-1.44 (m, 2H), 1.39-1.28 (m, 4H). Step 4: To a solution of 1-(4-(6-(benzyloxy)-2-(cyclohept-1-en-1-yl)-3,4-dihydronapht halen-1- yl)phenyl)-4-(dimethoxymethyl)piperidine (500 mg, 824.81 Pmol, 93% purity, 1 eq) in MeOH (10 mL) was added Pd/C (500 mg, 10% purity, 1.00 eq). The mixture was stirred under H ₂ (15Psi) at 25 °C for 1 h. The reaction mixture was filtered concentrated to yield a residue. The residue was purified by Chiral SFC (column: DAICEL CHIRALPAK AD(250mm * 30 mm, 10 um); mobile phase: [0.1%NH ₃ H ₂ O ETOH]; B%: 40%-40%, min), followed by lyophilization to yield (1R,2R)-2-cycloheptyl-1-[4-[4-(dimethoxymethyl)-1-piperidyl] phenyl]tetralin-6-ol (150 mg, 314.02 Pmol, 37.5% yield, 100% purity, SFC: R _t = 2.481) as a white solid and (1S,2S)-2- cycloheptyl-1-[4-[4-(dimethoxymethyl)-1-piperidyl]phenyl]tet ralin-6-ol (160 mg, 324.91 Pmol, 38.8% yield, 97% purity, SFC: Rt = 3.873) as a white solid. LC-MS (ESI+) m/z 478.4 [M+H]+. ¹ H NMR of (1R,2R)-2-cycloheptyl-1-[4-[4-(dimethoxymethyl)-1-piperidyl] phenyl]tetralin-6- ol: (400MHz, CDCl ₃ ) į = 6.88 (d, J = 7.4 Hz, 2H), 6.77 (br d, J = 8.2 Hz, 3H), 6.61 (s, 1H), 6.53-6.45 (m, 1H), 4.76-4.49 (m, 1H), 4.15 (br d, J = 4.3 Hz, 1H), 4.09 (br d, J = 7.0 Hz, 1H), 3.64 (br d, J = 12.3 Hz, 2H), 3.37 (s, 6H), 3.00-2.90 (m, 1H), 2.88-2.74 (m, 1H), 2.61 (br s, 2H), 1.90-1.68 (m, 6H), 1.67-1.60 (m, 2H), 1.53-1.32 (m, 10H), 1.29-1.14 (m, 2H), 1.04-0.91 (m, 1H). NMR of (1S,2S)-2-cycloheptyl-1-[4-[4-(dimethoxymethyl)-1-piperidyl] phenyl]tetralin-6- ol: (400MHz, CDCl ₃ ) į = 6.91-6.85 (m, 2H), 6.83-6.74 (m, 3H), 6.61 (d, J = 2.4 Hz, 1H), 6.52- 6.45 (m, 1H), 4.75 (br s, 1H), 4.14 (d, J = 4.5 Hz, 1H), 4.08 (d, J = 7.4 Hz, 1H), 3.64 (br d, J = 11.8 Hz, 2H), 3.37 (s, 6H), 2.99-2.90 (m, 1H), 2.86-2.75 (m, 1H), 2.61 (t, J = 12.0 Hz, 2H), 1.86- 1.71 (m, 6H), 1.67-1.63 (m, 2H), 1.50-1.34 (m, 10H), 1.28-1.20 (m, 2H), 1.04-0.94 (m, 1H). Step 5: To a solution of (1R,2R)-2-cycloheptyl-1-[4-[4-(dimethoxymethyl)-1- piperidyl]phenyl]tetralin-6-ol (70.00 mg, 146.54 Pmol, 100% purity, 1 eq) in DCM (2.5 mL) was added TFA (898.33 mg, 7.88 mmol, 583.33 PL, 53.76 eq). The mixture was stirred at 25 °C for mL x 3). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to yield 1-[4-[(1R,2R)-2-cycloheptyl-6- hydroxy-tetralin-1-yl]phenyl]piperidine-4-carbaldehyde (50 mg, 115.85 Pmol, 79.05% yield, N/A purity) as a white solid which was used in the next step without further purification. LC- MS (ESI+) m/z 432.4 [M+H]+. Step 6: To a solution of 1-[4-[(1R,2R)-2-cycloheptyl-6-hydroxy-tetralin-1-yl]phenyl]p iperidine- 4-carbaldehyde (50.00 mg, 115.85 Pmol, N/A purity, 1 eq) and (3S)-3-(1-oxo-5-piperazin-1-yl- isoindolin-2-yl)piperidine-2,6-dione (38.04 mg, 115.85 Pmol, 1 eq) in DCM (2 mL) and MeOH (2 mL) after stirred 30 min was added NaBH(OAc)3 (98.21 mg, 463.38 Pmol, 4 eq). The mixture was stirred at 25 °C for 12 h. The reaction mixture was concentrated to yield a residue. The residue was purified by preparative HPLC (column: Welch Xtimate C18 150*25mm*5um;mobile phase: [water( NH ₄ HCO ₃ )-ACN]; B%: 75%-95%, 11 min), followed by lyophilization to yield (3S)-3-[5-[4-[[1-[4-[(1R,2R)-2-cycloheptyl-6-hydroxy-tetrali n-1- yl]phenyl]-4-piperidyl]methyl]piperazin-1-yl]-1-oxo-isoindol in-2-yl]piperidine-2,6-dione (45.5 mg, 61.16 Pmol, 52.79% yield, 100% purity) as a white solid. LC-MS (ESI+) m/z 417.2 [M+H]+. LCMS: calc. for C46H57N5O4: 743.44, found: [M+H] ⁺ 744.5. HPLC: 100% purity at 220 nm. 7.63 (d, J = 8.5 Hz, 1H), 7.10-7.05 (m, 2H), 6.93-6.84 (m, 4H), 6.65 (d, J = 8.2 Hz, 1H), 6.55 (d, J = 2.4 Hz, 1H), 6.45 (dd, J = 2.6, 8.4 Hz, 1H), 5.10 (dd, J = 5.1, 13.4 Hz, 1H), 4.45-4.35 (m, 2H), 4.09 (d, J = 4.6 Hz, 1H), 3.60 (br d, J = 12.1 Hz, 2H), 3.39-3.35 (m, 4H), 2.95-2.86 (m, 2H), 2.81-2.74 (m, 2H), 2.70-2.58 (m, 6H), 2.46 (dq, J = 4.5, 13.2 Hz, 1H), 2.31 (d, J = 7.2 Hz, 2H), 2.18-2.10 (m, 1H), 1.90 (br d, J = 12.5 Hz, 2H), 1.84 (br t, J = 7.5 Hz, 1H), 1.79-1.62 (m, 5H), 1.53-1.42 (m, 6H), 1.40-1.29 (m, 4H), 1.26-1.10 (m, 2H), 1.01-0.92 (m, 1H). Step 7: To a solution of (1S,2S)-2-cycloheptyl-1-[4-[4-(dimethoxymethyl)-1- piperidyl]phenyl]tetralin-6-ol (70 mg, 142.15 umol, 97% purity, 1 eq) in DCM (2.5 mL) was added TFA (871.36 mg, 7.64 mmol, 565.82 PL, 53.76 eq). The mixture was stirred at 25 °C for 1 h. The reaction mixture was quenched by addition of water (50 mL), extracted with EtOAc (30 mL x 3) The combined organic layers were washed with brine (10 mL) dried over Na ₂ SO ₄ filtered and concentrated under reduced pressure to yield 1-[4-[(1S,2S)-2-cycloheptyl-6- hydroxy-tetralin-1-yl]phenyl]piperidine-4-carbaldehyde (50 mg, 115.85 Pmol, 81.5% yield, N/A purity) as a white solid which was used in the next step without further purification. LC-MS (ESI+) m/z 432.4 [M+H]+. Step 8: To a solution of 1-[4-[(1S,2S)-2-cycloheptyl-6-hydroxy-tetralin-1-yl]phenyl]p iperidine- 4-carbaldehyde (50.00 mg, 115.85 Pmol, N/A purity, 1 eq) and (3S)-3-(1-oxo-5-piperazin-1-yl- isoindolin-2-yl)piperidine-2,6-dione (38.04 mg, 115.85 Pmol, 1 eq) in DCM (2 mL) and MeOH (2 mL) after stirred 30 min was added NaBH(OAc) ₃ (98.21 mg, 463.38 Pmol, 4 eq). The mixture was stirred at 25 °C for 12.5 h. The reaction mixture was concentrated to yield a residue. The residue was purified by preparative HPLC (column: Welch Xtimate C18150*25mm*5um; mobile phase: [water( NH ₄ HCO ₃ )-ACN]; B%: 75%-95%, 11 min), followed by lyophilization to yield (3S)-3-[5-[4-[[1-[4-[(1S,2S)-2-cycloheptyl-6-hydroxy-tetrali n-1-yl]phenyl]-4- piperidyl]methyl]piperazin-1-yl]-1-oxo-isoindolin-2-yl]piper idine-2,6-dione (44.8 mg, 60.22 Pmol, 51.98% yield, 100% purity) as a white solid. LC-MS (ESI+) m/z 744.6 [M+H]+. LCMS: calc. for C46H57N5O4: 743.44, found: [M+H] ⁺ 744.6. HPLC: 100% purity at 220 nm. 7.63 (d, J = 8.4 Hz, 1H), 7.11-7.05 (m, 2H), 6.93-6.85 (m, 4H), 6.65 (d, J = 8.4 Hz, 1H), 6.55 (d, J = 2.4 Hz, 1H), 6.45 (dd, J = 2.6, 8.4 Hz, 1H), 5.10 (dd, J = 5.1, 13.4 Hz, 1H), 4.45-4.34 (m, 2H), 4.09 (d, J = 4.7 Hz, 1H), 3.60 (br d, J = 11.9 Hz, 2H), 3.39-3.35 (m, 4H), 2.95-2.85 (m, 2H), 2.82-2.73 (m, 2H), 2.68-2.58 (m, 6H), 2.46 (dq, J = 4.6, 13.2 Hz, 1H), 2.31 (d, J = 7.0 Hz, 2H), 2.19-2.10 (m, 1H), 1.90 (br d, J = 12.5 Hz, 2H), 1.84 (br t, J = 7.9 Hz, 1H), 1.78-1.62 (m, 5H), 1.54-1.42 (m, 5H), 1.40-1.29 (m, 4H), 1.23-1.06 (m, 2H), 1.02-0.93 (m, 1H).

EXAMPLE 138. Preparation of (I-163) (S)-3-(5-(4-((1-(4-((1S,2R)-6-hydroxy-2-methyl- 2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperidin- 4-yl)methyl)piperazin-1-yl)- 1-oxoisoindolin-2-yl)piperidine-2,6-dione Step 1: To a solution of (5S,6R)-5-(4-(4-(dimethoxymethyl)piperidin-1-yl)phenyl)-6-me thyl-6- phenyl-5,6,7,8-tetrahydronaphthalen-2-ol (66 mg, 1 Eq, 0.14 mmol) in THF (8 mL) was added 10% sulfuric acid (0.14 g, 8 mL). The mixture was stirred at 70 °C for 2 hour. LCMS showed 98.828 % desired MS. The mixture was adjusted to pH=8-9 by progressively adding NaHCO ₃ . The reaction mixture was quenched by addition 100 mL EtOAc at 20°C, and then diluted with 50 mL H ₂ O and extracted with EtOAc 50mL (25 mL * 2). The combined organic layers were washed with 10 mL (10 mL * 1), dried over Na ₂ SO ₄ . The reaction was filtered and concentrated under reduced pressure to give 1-(4-((1S, 2R)-6-hydroxy-2-methyl-2-phenyl-1,2,3,4- tetrahydronaphthalen-1-yl)phenyl)piperidine-4-carbaldehyde (80 mg, 0.19 mmol, crude, 98.828% purity) was obtained as a brown oil. LC-MS (ESI+) m/z: 444.2(M+H) ⁺ . Step 2: A mixture of 1-(4-((1S,2R)-6-hydroxy-2-methyl-2-phenyl-1,2,3,4-tetrahydro naphthalen- 1-yl)phenyl)piperidine-4-carbaldehyde (80 mg, 1 Eq, 0.19 mmol), (S)-3-(1-oxo-5-(piperazin-1- yl)isoindolin-2-yl)piperidine-2,6-dione, Tosylic acid (93 mg, 1 Eq, 0.19 mmol) and sodium acetate (76 mg, 5 Eq, 0.93 mmol) in DCM (2 mL) and MeOH (2 mL) at 20°C for 0.5 hour, pH=8, then acetic acid (33 mg, 32 ^L, 3 Eq, 0.56 mmol) at 20°C for 1 hour, pH=6, then added sodium triacetoxyhydroborate (79 mg, 2 Eq, 0.37 mmol) the mixture, and then the mixture was stirred at 25 °C for 16 hour. LCMS showed 60.52% desired MS. The reaction was concentrated to give (S)-3-(5-(4-((1-(4-((1S,2R)-6-hydroxy-2-methyl-2-phenyl-1,2, 3,4-tetrahydronaphthalen- 1-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoin dolin-2-yl)piperidine-2,6-dione as a brown oil. The mixture was filtered and the filter cake was washed by EtOAc (50 mL x 3). The brown oil was purified by preparative high-performance liquid chromatography. Condition: Column: Welch Xtimate C18150*30mm*5um ; A: water(FA) ^ B: ACN at the beginning: A (79%) and B (21%) ^ at the end: A: (49%) and B (51%) ; Gradient Time(min) 7 ; 100% B hold Time(min) 3.2, Flow Rate(ml/min) 25. The pure fractions were collected and the solvent was evaporated under vacuum. The aqueous layer was lyophilized to dryness to give (S)-3-(5-(4-((1-(4-((1S,2R)-6-hydroxy-2-methyl-2- phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperidin-4- yl)methyl)piperazin-1-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione (80.5 mg, 108 ^mol, 58 % yield, 98.66% purity) as a white solid. LCMS: calc. for C46H51N5O4: 737.39, found: [M+H] ⁺ 738.5. HPLC: 98.66% purity at 220 nm. NMR (400 MHz, DMSO-d ₆ ) į= 10.95 (s, 1H), 8.98 (s, 1H), 8.13 (s, 0.344H), 7.52 (d, J = 8.7 Hz, 1H), 7.39 (d, J = 7.7 Hz, 2H), 7.21 (t, J = 7.7 Hz, 2H), 7.12 - 7.03 (m, 3H), 6.77 (s, 4H), 6.67 (d, J = 8.3 Hz, 1H), 6.44 - 6.35 (m, 2H), 5.09 - 5.00 (m, 1H), 4.44 (s, 1H), 4.33 (d, J = 17.0 Hz, 1H), 4.24 - 4.16 (m, 1H), 3.61 (br d, J = 11.7 Hz, 2H), 3.38 - 3.34 (m, 6H), 2.95 - 2.84 (m, 1H), 2.79 - 2.71 (m, 1H), 2.59 (br d, J = 2.4 Hz, 2H), 2.56 (br s, 2H), 2.45 - 2.36 (m, 2H), 2.36 - 2.21 (m, 3H), 2.12 - 2.04 (m, 1H), 2.00 - 1.92 (m, 1H), 1.91 - 1.84 (m, 1H), 1.80 (br d, J = 11.7 Hz, 2H), 1.73 - 1.62 (m, 1H), 1.25 - 1.14 (m, 2H), 0.95 (s, 3H)^ SFC: retention time, 2.434 min; Area, 91.36%;

EXAMPLE 139. Preparation of (I-344) (S)-3-(5-(4-((1-(4-((1R,2S)-6-hydroxy-2-methyl- 2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperidin- 4-yl)methyl)piperazin-1-yl)- 1-oxoisoindolin-2-yl)piperidine-2,6-dione Step 1: To a solution of (5R,6S)-5-(4-(4-(dimethoxymethyl)piperidin-1-yl)phenyl)-6-me thyl-6- phenyl-5,6,7,8-tetrahydronaphthalen-2-ol (62 mg, 1 Eq, 0.13 mmol) in THF (8 mL) was added 10% sulfuric acid (0.13 g, 8 mL). The mixture was stirred at 70 °C for 2 hour. LCMS showed 98.86 % desired MS. The mixture was adjusted to pH=8-9 by progressively adding NaHCO ₃ . The reaction mixture was quenched by addition 100 mL EtOAc at 20°C, and then diluted with 50 mL H ₂ O and extracted with EtOAc (25 mL * 2). The combined organic layers were washed with 10 mL brine, dried over Na ₂ SO ₄ . The reaction was filtered and concentrated under reduced pressure to give 1-(4-((1R,2S)-6-hydroxy-2-methyl-2-phenyl-1,2,3,4-tetrahydro naphthalen-1- yl)phenyl)piperidine-4-carbaldehyde (75 mg, 0.17 mmol, crude, 98.86% purity) was obtained as a brown oil. LC-MS (ESI+) m/z: 444.2(M+H) ⁺ . Step 2: A mixture of 1-(4-((1R,2S)-6-hydroxy-2-methyl-2-phenyl-1,2,3,4-tetrahydro naphthalen- 1-yl)phenyl)piperidine-4-carbaldehyde (75 mg, 1 Eq, 0.17 mmol), (S)-3-(1-oxo-5-(piperazin-1- yl)isoindolin-2-yl)piperidine-2,6-dione, PhSO3H salt (87 mg, 1 Eq, 0.17 mmol) and sodium acetate (71 mg, 5 Eq, 0.87 mmol) in DCM (2 mL) and MeOH (2 mL) at 20°C for 0.5 hour, pH=8, then acetic acid (31 mg, 30 ^L, 3 Eq, 0.52 mmol) at 20°C for 1 hour, pH=6, then added sodium triacetoxyhydroborate (74 mg, 2 Eq, 0.35 mmol) the mixture, and then the mixture was stirred at 25 °C for 16 hour. LCMS showed 62.46% desired MS. The reaction was concentrated to give (S)-3-(5-(4-((1-(4-((1S,2R)-6-hydroxy-2-methyl-2-phenyl-1,2, 3,4-tetrahydronaphthalen- 1-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoin dolin-2-yl)piperidine-2,6-dione as a brown oil. The mixture was filtered and the filter cake was washed by EtOAc (50 mL x 3). The brown oil was purified by preparative high-performance liquid chromatography. Condition: Column: Welch Xtimate C18150*30mm*5um; A: water(FA); B:CAN; at the beginning: A (79%) and B (21%); at the end: A: (49%) and B (51%); Gradient Time(min) 7; 100% B hold Time(min) 3.2, Flow Rate(ml/min) 25. The pure fractions were collected and the solvent was evaporated under vacuum. The aqueous layer was lyophilized to dryness to give (S)-3-(5-(4-((1-(4-((1R,2S)-6-hydroxy-2-methyl-2- phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperidin-4- yl)methyl)piperazin-1-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione (80.5 mg, 108 ^mol, 62 % yield, 99.23% purity) as a white solid. LCMS: calc. for C ₄₆ H ₅₁ N ₅ O ₄ : 737.39, found: [M+H] ⁺ 738.5. HPLC: 99.23% purity at 220 nm. ¹ H NMR (400 MHz, DMSO-d ₆ ) į= 10.95 (s, 1H), 8.98 (s, 1H), 8.13 (s, 0.435H), 7.52 (d, J = 8.6 Hz, 1H), 7.39 (d, J = 7.7 Hz, 2H), 7.21 (t, J = 7.7 Hz, 2H), 7.12 - 7.03 (m, 3H), 6.77 (s, 4H), 6.67 (d, J = 8.3 Hz, 1H), 6.44 - 6.36 (m, 2H), 5.05 (dd, J = 5.1, 13.3 Hz, 1H), 4.44 (s, 1H), 4.33 (d, J = 17.0 Hz, 1H), 4.24 - 4.16 (m, 1H), 3.61 (br d, J = 11.1 Hz, 2H), 3.33 (br s, 6H), 2.90 (br s, 1H), 2.73 (br s, 1H), 2.59 (br d, J = 2.6 Hz, 2H), 2.55 (br s, 3H), 2.37 (br s, 1H), 2.36 - 2.30 (m, 1H), 2.24 (br d, J = 6.2 Hz, 2H), 2.07 (br d, J = 4.6 Hz, 1H), 1.98 - 1.92 (m, 1H), 1.91 - 1.84 (m, 1H), 1.80 (br d, J = 10.8 Hz, 2H), 1.72 - 1.63 (m, 1H), 1.26 - 1.14 (m, 2H), 0.95 (s, 3H) SFC: retention time, 2.246 min; Area, 91.17%; EXAMPLE 140. Preparation of (I-157) (3S)-3-[5-[4-[[1-[4-[(1R,2R)-6-hydroxy-2-(2,2,2- trifluoroethyl)tetralin-1-yl]phenyl]-4-piperidyl]methyl]pipe razin-1-yl]-1-oxo-isoindolin-2- yl]piperidine-2,6-dione Step 1: A mixture of 4-(dimethoxymethyl)-1-(4-((1R,2R)-6-methoxy-2-(2,2,2-trifluo roethyl)- 1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperidine (65 mg, 136.11 ^mol, 1 eq) in DCM (4 mL) was degassed and purged with N ₂ for 3 times, and then BBr ₃ (1 M, 408.33 ^L, 3 eq) was degassed the mixture at 0 °C and was stirred at 25 °C for 16 hr under N ₂ atmosphere, LCMS showed 95% of desired compound was detected. The reaction mixture was quenched with NaHCO ₃ 20 mL, and then was treated with 20 mL H ₂ O and extracted with DCM 50 mL (50 mL * 2). The organic layers were dried with anhydrous Na ₂ SO ₄ , filtered, The reaction mixture was filtered and concentrated to dryness in vacuo to give 1-[4-[(1S,2S)-6-hydroxy-2-(2,2,2- trifluoroethyl)tetralin-1-yl]phenyl]piperidine-4-carbaldehyd e (50 mg, 119.77 ^mol, 88.00% yield) was obtained as a white solid. LC-MS (ESI+) m/z: 416 (M+H) ⁺ . Step 2: A mixture of (3S)-3-(1-oxo-5-piperazin-1-yl-isoindolin-2-yl)piperidine-2, 6-dione (89.93 mg, 179.66 ^mol, 1.5 eq, PhSO ₃ H salt), 1-[4-[(1R,2R)-6-hydroxy-2-(2,2,2-trifluoroethyl)tetralin- 1-yl]phenyl]piperidine-4-carbaldehyde (50 mg, 119.77 ^mol, 1 eq), sodium acetate (29.48 mg, 359.31 ^mol, 3 eq) was added in DCM (4 mL) MeOH (4 mL), and the mixture was stirred at 30 °C for 1h, and then NaBH(OAc)3 (50.77 mg, 239.54 ^mol, 2 eq) and acetic acid (99.21 mg, 359.31 ^mol, 94.49 ^L, 3 eq) was added in the mixture, and then the mixture was stirred at 30°C for 12 hr. LCMS showed 72% of desired compound was detected. The reaction mixture was treated with H ₂ O 30 mL and extracted with DCM(50 mL * 2). The organic layers were dried with anhydrous Na ₂ SO ₄ , filtered, the residue was purified by prep. HPLC (column: Welch Xtimate C18150*30mm*5um; mobile phase: [water (FA)-ACN]; gradient: 18%-48% B over 7 min). The aqueous phase was lyophilized to dryness to give (3S)-3-[5-[4-[[1-[4-[(1R,2R)-6- hydroxy-2-(2,2,2-trifluoroethyl)tetralin-1-yl]phenyl]-4-pipe ridyl]methyl]piperazin-1-yl]-1-oxo- isoindolin-2-yl]piperidine-2,6-dione (12.6 mg, 17.26 ^mol, 14.41% yield) was obtained as a yellow solid. LC-MS (ESI+) m/z: 730.2 (M+H) ⁺ . HPLC: 92.601%, purity at 220nm. ¹ H NMR (400 MHz, DMSO-d ₆ ) į = 10.99 - 10.92 (m, 1H), 9.17 - 9.04 (m, 1H), 8.17 - 8.10 (m, 0.313H), 7.58 - 7.48 (m, 1H), 7.12 - 7.02 (m, 2H), 6.88 - 6.76(m, 4H), 6.65 - 6.60 (m, 1H), 6.56 - 6.50 (m, 1H), 6.48 - 6.41 (m, 1H), 5.10 - 5.00 (m, 1H), 4.40 - 4.28 (m, 1H), 4.25 - 4.17 (m, 1H), 4.03 - 3.94 (m, 1H), 3.69- 3.58 (m, 2H), 3.32 - 3.23 (m, 5H), 2.99 - 2.78 (m, 3H), 2.70 - 2.55 (m, 5H), 2.43 - 2.17 (m, 6H), 2.02 - 1.91 (m, 1H), 1.86 - 1.54 (m, 7H), 1.28 - 1.10 (m, 2H). SFC: retention time, 2.273 min; Area, 93.205%; EXAMPLE 141. Preparation of (I-158) (3S)-3-[5-[4-[[1-[4-[(1S,2S)-6-hydroxy-2-(2,2,2- trifluoroethyl)tetralin-1-yl]phenyl]-4-piperidyl]methyl]pipe razin-1-yl]-1-oxo-isoindolin-2- yl]piperidine-2,6-dione Step 1: Ethyl 2-diethoxyphosphorylacetate (20 g, 89.21 mmol, 17.70 mL, 1 eq) was added into mixture of NaH (7.14 g, 178.42 mmol, 60% purity, 2 eq) in THF (200 mL) under N2 at 0°C, and the mixture was stirred at 0 °C for 0.5 h under N ₂ atmosphere, and then 2,2,2-trifluoroethyl trifluoromethanesulfonate (41.41 g, 178.42 mmol, 24.65 mL, 2 eq) was added in the mixture at 0 °C and was stirred at 25 °C for 16 h. TLC (petroleum ether/ethyl acetate=10:1, R _f =0.4) showed new spot was formed. Then the mixture was quenched with H ₂ O (100 mL), extracted with EtOAc (150 mL). The combined extracts was dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to dryness in vacuo to give a residue. The residue was subjected to column chromatography over silica gel (gradient elution: 0-20% ethyl acetate in petroleum ether). The pure fractions were collected and concentrated to dryness in vacuo to give ethyl 2- diethoxyphosphoryl-4,4,4-trifluoro-butanoate (16 g, 52.25 mmol, 58.57% yield) as a colorless oil. LC-MS (ESI+) m/z: 307 (M+H) ⁺ . Step 2: A mixture of ethyl 2-diethoxyphosphoryl-4,4,4-trifluoro-butanoate (16 g, 52.25 mmol, 1 eq) , DBU (7.95 g, 52.25 mmol, 7.87 mL, 1 eq) and LiCl (2.88 g, 67.92 mmol, 1.3 eq) was degassed in CH3CN (160 mL), and the mixture was stirred at 25°C for 10 min. and then 2-(3- methoxyphenyl)acetaldehyde (9.42 g, 62.69 mmol, 1.2 eq) was degassed in the mixture, the mixture was stirred at 25 °C for 12h , TLC (petroleum ether/ethyl acetate=10:1, R _f =0.5) showed new spot was formed. Then the mixture was quenched with H ₂ O (150 Ml), extracted with EtOAc (200 Ml). The combined extracts was dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to dryness in vacuo to give a residue. The residue was subjected to column chromatography over silica gel (gradient elution: 0~30% ethyl acetate in petroleum ether). The pure fractions were collected and concentrated to dryness in vacuo to give ethyl 4-(3-methoxyphenyl)-2-(2,2,2- trifluoroethyl)but-2-enoate (5.5 g, 17.75 mmol, 33.43% yield) as a white solid. Step 3: A mixture of ethyl 4-(3-methoxyphenyl)-2-(2,2,2-trifluoroethyl)but-2-enoate (5.5 g, 17.75 mmol, 1 eq), Pd/C (5.5 g, 0.2 mmol, 10% purity) in THF (50 mL) and purged with H ₂ for 3 times, and then the mixture was stirred at 30°C for 12 hr under H ₂ atmosphere, and then the mixture was stirred at 50°C for 16 hr under H ₂ atmosphere. TLC (petroleum ether/ethyl acetate=10:1, R _f =0.3). The reaction mixture was filtered and concentrated to dryness in vacuo to give ethyl 4,4,4-trifluoro-2-[2-(3-methoxyphenyl)ethyl]butanoate (5.4 g, 4.93 mmol, 98.18% yield) was obtained as a colorless oil. Step 4: To a solution of ethyl 4,4,4-trifluoro-2-[2-(3-methoxyphenyl)ethyl]butanoate (5.4 g, 17.75 mmol, 1 eq), NaOH (2 M, 35.49 mL, 4 eq) in THF (20 mL) and MeOH (20 mL) and then the mixture was stirred at 25 °C for 2 hr. TLC (petroleum ether/ethyl acetate=3:1, R _f =0.4) showed new spot was formed. The reaction mixture was quenched by addition 70 mL 1 M HCl at 25°C, and then was treated with 20 mL H ₂ O and extracted with Ethyl acetate (100 mL* 3). The combined organic layers were washed with brine (50 mL), dried over Na ₂ SO ₄ , The reaction mixture was filtered and concentrated to dryness in vacuo to give 4,4,4-trifluoro-2-[2-(3- methoxyphenyl)ethyl]butanoic acid (4.6 g, 16.65 mmol, 93.84% yield) as a white oil. LC-MS (ESI ⁺ ) m/z: 277 (M+H ₂ O) ⁺ . Step 5: A mixture of 4,4,4-trifluoro-2-[2-(3-methoxyphenyl)ethyl]butanoic acid (2 g, 7.24 mmol, 1 eq), (2,2,2-trifluoroacetyl) 2,2,2-trifluoroacetate (12.16 g, 57.92 mmol, 8.06 mL, 8 eq) in DCM (10 mL) and then the mixture was stirred at 25 °C for 16 hr. TLC (petroleum ether/ethyl acetate=10:1, R _f =0.4) showed new spot was formed. The reaction mixture was quenched by addition 50 mL H ₂ O, and then was treated with 50 mL H ₂ O and extracted with Ethyl acetate 100 mL (50 mL * 2). The organic layers were dried with anhydrous Na2SO4, filtered, the residue was subjected to column chromatography over silica gel (gradient elution: 0~40% ethyl acetate in petroleum ether). The pure fractions were collected and concentrated to dryness in vacuo to give 6-methoxy-2-(2,2,2-trifluoroethyl)tetralin-1-one (1.3 g, 5.03 mmol, 69.53% yield) as a white oil. LC-MS (ESI+) m/z: 259 (M+H) ⁺ . Step 6: n-BuLi (2.5 M, 3.02 mL, 1.5 eq) was added in the 1-(4-bromophenyl)-4- (dimethoxymethyl)piperidine (2.37 g, 7.55 mmol, 1.5 eq) in THF (15 mL) under N ₂ at -78 °C and was stirred at -78 °C for 1h, and then 6-methoxy-2-(2,2,2-trifluoroethyl)tetralin-1-one (1.3 g, 5.03 mmol, 1 eq) was added in the mixture at -78°C and was stirred at 25°C for 12 h under N ₂ atmosphere. TLC (petroleum ether/ethyl acetate=5:1, R _f =0.4) showed new spot was formed. The reaction mixture was quenched with NH ₄ Cl 50 mL, and then was treated with 50 mL H ₂ O and extracted with ethyl acetate 100 mL (50 mL * 2), The organic layers were dried with anhydrous Na ₂ SO ₄ , filtered, The residue was subjected to column chromatography over silica gel (gradient elution: 0~10% ethyl acetate in petroleum ether). The pure fractions were collected and concentrated to dryness in vacuo to give 1-[4-[4-(dimethoxymethyl)-1-piperidyl]phenyl]-6- methoxy-2-(2,2,2-trifluoroethyl)tetralin-1-ol (1.6 g, 3.24 mmol, 64.40% yield) as a white oil. LC-MS (ESI+) m/z: 494 (M+H) ⁺ Step 7: A mixture of 1-(4-(4-(dimethoxymethyl)piperidin-1-yl)phenyl)-6-methoxy-2- (2,2,2- trifluoroethyl)-1,2,3,4-tetrahydronaphthalen-1-ol (800 mg, 1.62 mmol, 1 eq), 4M MeOH/HCl , and then the mixture was stirred at 40 °C for 12 hr. TLC (petroleum ether/ethyl acetate=5:1, R _f =0.6) showed new spot was formed. The reaction mixture was quenched with 50 mL saturated aqueous NaHCO ₃ , and then was treated with 50 mL H ₂ O and extracted with ethyl acetate 100 mL (50 mL * 2). The organic layers were dried with anhydrous Na ₂ SO ₄ , filtered, The reaction mixture was filtered and concentrated to dryness in vacuo to give 4-(dimethoxymethyl)-1-(4-(6- methoxy-2-(2,2,2-trifluoroethyl)-3,4-dihydronaphthalen-1-yl) phenyl)piperidine (700 mg, 1.47 mmol, 90.81% yield) as a white oil. Step 8: A mixture of 4-(dimethoxymethyl)-1-(4-(6-methoxy-2-(2,2,2-trifluoroethyl) -3,4- dihydronaphthalen-1-yl)phenyl)piperidine (700 mg, 1.47 mmol, 1 eq), Pd/C (700.00 mg, 10% purity) and Pd(OH)2 (700.00 mg, 20% purity) in THF (5 mL) and MeOH (5 mL) and purged with H ₂ for 3 times, and then the mixture was stirred at 60°C for 12hr under H ₂ atmosphere. LCMS showed 99.309% of desired compound was detected. The reaction was filtered and concentrated to dryness in vacuo to give a white solid. The white solid was subjected by SFC: DAICEL CHIRALPAK AD(250mm*30mm,10um);mobile phase: [CO2- EtOH(0.1%NH ₃ H ₂ O)];B%:25%%, isocratic elution mode; The aqueous phase was lyophilized to dryness to give 4-(dimethoxymethyl)-1-(4-((1S,2S)-6-methoxy-2-(2,2,2-trifluo roethyl)-1,2,3,4- tetrahydronaphthalen-1-yl)phenyl)piperidine (120 mg, 251.28 ^mol, 17.07% yield) and 4- (dimethoxymethyl)-1-(4-((1R,2R)-6-methoxy-2-(2,2,2-trifluoro ethyl)-1,2,3,4- tetrahydronaphthalen-1-yl)phenyl)piperidine (130 mg, 272.22 ^mol, 18.49% yield) was obtained as a white oil. LC-MS (ESI+) m/z: 462.2 (M+H) ⁺ . Step 9: A mixture of 4-(dimethoxymethyl)-1-(4-((1S,2S)-6-methoxy-2-(2,2,2-trifluo roethyl)- 1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperidine (60 mg, 125.64 ^mol, 1 eq) in DCM (4 mL) was degassed and puged with N ₂ for 3 times, and then BBr ₃ (1 M, 376.92 ^L, 3 eq) was added in the mixture at 0°C and was stirred at 25 °C for 2 hr under N ₂ atmosphere. LCMS showed 95% of desired compound was detected. The reaction mixture was quenched with saturated aqueous NaHCO ₃ 20 mL, and then was treated with 20 mL H ₂ O and extracted with DCM (25 mL * 2). The organic layers were dried with anhydrous Na2SO4, filtered, The reaction mixture was filtered and concentrated to dryness in vacuo to give 1-[4-[(1S,2S)-6-hydroxy-2-(2,2,2- trifluoroethyl)tetralin-1-yl]phenyl]piperidine-4-carbaldehyd e (50 mg, 119.77 ^mol, 95.33% yield) was obtained as a white solid. LC-MS (ESI+) m/z: 416 (M+H) ⁺ . Step 10: A mixture of (3S)-3-(1-oxo-5-piperazin-1-yl-isoindolin-2-yl)piperidine-2, 6-dione (89.93 mg, 179.66 ^mol, 1.5 eq, PhSO ₃ H salt), 1-[4-[(1R,2R)-6-hydroxy-2-(2,2,2- trifluoroethyl)tetralin-1-yl]phenyl]piperidine-4-carbaldehyd e (50 mg, 119.77 ^mol, 1 eq), sodium acetate (29.48 mg, 359.31 ^mol, 3 eq) was added in DCM (4 mL) MeOH (4 mL), and the mixture was stirred at 30°C for 1h, and then NaBH(OAc) ₃ (50.77 mg, 239.54 ^mol, 2 eq) and acetic acid (99.21 mg, 359.31 ^mol, 94.49 ^L, 3 eq) was added in the mixture, and then the mixture was stirred at 30°C for 12 hr. TLC (petroleum ether/ethyl acetate=0:1, R _f =0.2) showed new spot was formed. The reaction mixture was treated with 30 mL H ₂ O and extracted with DCM (50 mL * 2). The organic layers were dried with anhydrous Na ₂ SO ₄ , filtered, the residue was purified by prep HPLC (column: Welch Xtimate C18150*30mm*5um; mobile phase: [water(FA)-ACN];gradient:18%-48% B over 7 min). The aqueous phase was lyophilized to dryness to give (3S)-3-[5-[4-[[1-[4-[(1R,2R)-6-hydroxy-2-(2,2,2-trifluoroeth yl)tetralin-1- yl]phenyl]-4-piperidyl]methyl]piperazin-1-yl]-1-oxo-isoindol in-2-yl]piperidine-2,6-dione (12.6 mg, 17.26 ^mol, 14.41% yield) as a yellow soild.LC-MS (ESI+) m/z: 730.2 (M+H) ⁺ . HPLC: 94.331%, purity at 220nm. ¹ H NMR (400 MHz, DMSO-d ₆ ) į = 11.02 - 10.90 (m, 1H), 9.17 - 9.03 (m, 1H), 8.18 - 8.15 (m, 0.303H), 7.56 - 7.49 (m, 1H), 7.10 - 7.02 (m, 2H), 6.85 - 6.78(m, 4H), 6.66 - 6.60 (m, 1H), 6.56 - 6.52 (m, 1H), 6.47 - 6.42 (m, 1H), 5.01 (br d, J = 4.2 Hz, 1H), 4.39 - 4.28 (m, 1H), 4.25 - 4.16 (m, 1H), 4.03 - 3.92 (m,1H), 3.71 - 3.57 (m, 2H), 3.31 - 3.22 (m, 5H), 2.95 - 2.78 (m, 3H), 2.70 - 2.57 (m, 3H), 2.41 - 2.17 (m, 7H), 2.01 - 1.92 (m, 1H), 1.85 - 1.51 (m, 7H), 1.27 -1.13 (m, 2H). SFC: retention time, 2.260 min; Area, 93.981%;

EXAMPLE 142. Preparation of (I-50) (S)-3-(5-(4-((1-(4-((1R,2S)-6-methyl-2-phenyl- 1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperidin-4-yl)meth yl)piperazin-1-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione Step 1: To a solution of Pd(dppf)Cl2.CH2Cl2(42 mg, 0.1 Eq, 50.9 ^mol) was added (5R,6S)-5-(4- (4-(dimethoxymethyl)piperidin-1-yl)phenyl)-6-phenyl-5,6,7,8- tetrahydronaphthalen-2-yl trifluoromethanesulfonate (300 mg, 1 Eq, 509 ^mol), 2,4,6-trimethyl-1,3,5,2,4,6- trioxatriborinane (128 mg, 151 ^L, 2 Eq, 1.02 mmol) and potassium carbonate (141 mg, 2 Eq, 1.02 mmol) in dioxane (2 mL) at room temperature under N ₂ atmosphere. The mixture was stirred at 90 °C for16 hours. TLC (petroleum ether: ethyl acetate=10:1, UV) showed one main new spot was observed. The reaction was diluted with water (20 mL) and extracted with ethyl acetate (20 mL*2). The combined organic layer were washed with brine (20 mL), dried over Na ₂ SO ₄ and concentrated in vacuum to give crude product as a black oil. The black oil was subjected by flash column (SiO ₂ , Petroleum ether/Ethyl acetate=100/0 to 85/15). The pure fractions were collected and concentrated in vacuum to give 4-(dimethoxymethyl)-1-(4-((1R, 2S)-6-methyl-2-phenyl-1, 2, 3, 4-tetrahydronaphthalen-1-yl) phenyl)piperidine (162 mg, 255 ^mol, 50.2% yield, 72% purity) as a brown solid. LCMS: calc. for C31H37NO2: 455.28, found: [M+H] ⁺ 456.2. Step 2: To a solution of 4-(dimethoxymethyl)-1-(4-((1R, 2S)-6-methyl-2-phenyl-1, 2, 3, 4- tetrahydronaphthalen-1-yl) phenyl)piperidine (162 mg, 1 Eq, 356 ^mol) in HCl/dioxane (4M, 3 Ml) at 60°C for 16 hour. TLC (petroleum ether: ethyl acetate=10:1, UV) showed one main new spot was observed. The reaction was concentrated to dryness in vacuum to give crude product 1- (4-((1R,2S)-6-methyl-2-phenyl-1, 2, 3, 4-tetrahydronaphthalen-1-yl) phenyl) piperidine-4- carbaldehyde (200 mg, 486 ^mol, 99.6% purity) as a pink solid. LCMS: calc. for C ₂₉ H ₃₁ NO: 409.24, found: [M+H] ⁺ 410.1. Step 3: A mixture of 1-(4-((1R,2S)-6-methyl-2-phenyl-1,2,3,4-tetrahydronaphthalen -1- yl)phenyl)piperidine-4-carbaldehyde (100 mg, 1 Eq, 244 ^mol), (R)-3-(1-oxo-5-(piperazin-1- yl)isoindolin-2-yl)piperidine-2,6-dione, TsOH salt (144 mg, 85% purity, 1 Eq, 244 ^mol) and sodium acetate (100 mg, 5 Eq, 1.22 mmol) were added in DCM (1.5 mL) and MeOH (1.5 mL) at 25°C for 1 hour, then added acetic acid (44 mg, 42 ^L, 3 Eq, 732 ^mol) and sodium cyanoborohydride (31 mg, 29 ^L, 2 Eq, 488 ^mol), then the mixture was stirred at 25 °C for 16 hours. The reaction was diluted with water (50 mL) and extracted with ethyl acetate (50 mL*2). The combined organic layer were washed with brine (50 mL), dried over Na ₂ SO ₄ and concentrated in vacuum to give crude product as a brown solid. The brown solid was purified by preparative high-performance liquid chromatography. Condition: Column: Welch xtimate C18150*30mm*5um; A: water (FA), B: CAN, at the beginning: A (74%) and B (26%), at the end: A: (44%) and B (56%), Gradient time (min) 7; 100% B hold time (min) 5.2, Flow rate (ml/min) 25. The aqueous layer was lyophilized to dryness to give (S)-3-(5-(4-((1-(4-((1R,2S)-6-methyl-2- phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperidin-4- yl)methyl)piperazin-1-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione (32 mg, 43 ^mol, 18 % yield, 97.413% purity) as a white solid. LCMS: calc. for C ₄₆ H ₅₁ N ₅ O ₃ : 721.4, found: [M+H] ⁺ 722.2. HPLC: 97.413% purity at 220 nm. 10.95 (s, 1H), 8.15 (s, 0.278H), 7.52 (d, J = 8.8 Hz, 1H), 7.18 - 7.11 (m, 3H), 7.05 (d, J = 10.1 Hz, 3H), 6.88 - 6.83 (m, 3H), 6.74 (d, J = 7.9 Hz, 1H), 6.54 (d, J = 8.7 Hz, 2H), 6.20 (d, J = 8.7 Hz, 2H), 5.05 (dd, J = 5.1, 13.3 Hz, 1H), 4.36 - 4.30 (m, 1H), 4.23 - 4.17 (m, 2H), 3.51 (br d, J = 9.4 Hz, 3H), 3.28 (br d, J = 4.1 Hz, 6H), 3.09 - 2.83 (m, 4H), 2.69 - 2.53 (m, 3H), 2.39 - 2.33 (m, 1H), 2.27 (s, 3H), 2.20 (br d, J = 7.0 Hz, 2H), 2.14 (br dd, J = 6.4, 12.2 Hz, 1H), 2.00 - 1.92 (m, 1H), 1.75 (br d, J = 11.9 Hz, 3H), 1.64 (br d, J = 3.3 Hz, 1H), 1.20 - 1.10 (m, 2H) SFC: retention time: 3.726 min; Area: 91.718%;

EXAMPLE 143. Preparation of (I-40) 3-(4-(4-(1-(4-((1R,2S)-6-hydroxy-2-phenyl- 1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperidin-4-yl)pipe razin-1-yl)phenyl)piperidine- 2,6-dione Step 1: To a solution of 4-(6-(benzyloxy)-2-phenyl-3,4-dihydronaphthalen-1-yl)phenyl 1,1,2,2,3,3,4,4,4-nonafluorobutane-1-sulfonate (1.5 g, 1 Eq, 2.2 mmol) in Toluene (10 mL) was added palladium(II) acetate (49 mg, 0.1 Eq, 0.22 mmol), dicyclohexyl(2',4',6'-triisopropyl-[1,1'- biphenyl]-2-yl)phosphane (0.21 g, 0.2 Eq, 0.44 mmol), sodium 2-methylpropan-2-olate (0.63 g, 3 Eq, 6.6 mmol) and 8-Aza-1,4-dioxaspiro[4.5]decane (0.33 g, 0.29 mL, 1.05 Eq, 2.3 mmol) under N2 balloon. The mixture was stirred under N2 at 90 °C for 16 h. The reaction mixture was added water 100 mL, and then extracted with ethyl acetate 450 mL (150 mL * 3). The combined organic layers were washed with 100 mL water, dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate=100/0 to 50/50) to give 8-(4-(6-(benzyloxy)-2-phenyl-3, 4- dihydronaphthalen-1-yl) phenyl)-1, 4-dioxa-8-azaspiro [4.5] decane (0.6 g, 1 mmol, 40% yield, 84.06% purity) was obtained as a white solid. LC-MS (ESI ⁺ ) m/z: 530.3 (M+H) ⁺ . Step 2: A solution of Pd/C (1.2 g, 10%Wt, 0.50 Eq, 1.1 mmol), was added to 8-(4-(6- (benzyloxy)-2-phenyl-3,4-dihydronaphthalen-1-yl)phenyl)-1,4- dioxa-8-azaspiro[4.5]decane (1.2 g, 1 Eq, 2.3 mmol) in THF (2 mL) and MeOH (2 mL). The reaction was degassed and purged with H ₂ (4.6 mg, 1 Eq, 2.3 mmol) for 10 mins. The mixture was stirred under H ₂ (15Psi) at 50 °C for 16 h. TLC (petroleum ether: ethyl acetate=1:1,) indicated reactant was consumed completely and one new spots formed. The residue was further separated by SFC (condition: column: DAICEL CHIRALCEL OJ(250mm*30mm,10um); mobile phase: [0.1%NH ₃ H ₂ O ETOH]; B%: 50%-50%) to give desired (5R,6S)-5-(4-(1,4-dioxa-8-azaspiro[4.5]decan-8-yl)phenyl)-6- phenyl- 5,6,7,8-tetrahydronaphthalen-2-ol (200 mg, 453 ^mol, 20%) as a yellow solid and (5S,6R)-5-(4- (1,4-dioxa-8-azaspiro[4.5]decan-8-yl)phenyl)-6-phenyl-5,6,7, 8-tetrahydronaphthalen-2-ol (230 mg, 521 ^mol, 23%) as a yellow solid. Step 3: To a solution of ((5R,6S)-5-(4-(1,4-dioxa-8-azaspiro[4.5]decan-8-yl)phenyl)-6 -phenyl- 5,6,7,8-tetrahydronaphthalen-2-ol (200 mg, 1 Eq, 453 ^mol)) in THF (15 mL) was added Sulfuric acid (25 g, 15 mL, 10%Wt, 56 Eq, 25 mmol). The mixture was stirred at 70 °C for 16 h. The reaction was concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash ® Silica Flash Column, Eluent of 0~100% ethyl acetate/Petroleum ether gradient @ 80 mL/min) to give the product of give 1-(4-((1R,2S)-6- hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)pi peridin-4-one (200 mg, 503 ^mol, 111 %) as a light yellow solid. TLC (petroleum ether: ethyl acetate=1:1,) was confirmed. Step 4: To 1-(4-((1R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthale n-1- yl)phenyl)piperidin-4-one (40 mg, 1 Eq, 0.10 mmol), and 3-(4-(piperazin-1- yl)phenyl)piperidine-2,6-dione (41 mg, 1.5 Eq, 0.15 mmol) and titanium tetraisopropoxide (57 mg, 60 ^L, 2 Eq, 0.20 mmol) in DCM (2 mL) and MeOH (2 mL) at 0 °C. The resulting mixture was stirred for 3 hours at 20 °C. Sodium cyanborohydride (25 mg, 24 ^L, 4 Eq, 0.40 mmol) was added to the mixture at 0 °C. The resulting mixture was stirred for 16 h at 20 °C. The yellow Condition: [water (FA)-ACN]; B%: 20%-60%, 8min) the pure fractions were collected and the solvent was evaporated under vacuum. The aqueous layer was lyophilized to dryness to give 3- (4-(4-(1-(4-((1R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydrona phthalen-1-yl)phenyl)piperidin-4- yl)piperazin-1-yl)phenyl)piperidine-2,6-dione (18.9 mg, 28.44 ^mol, 37.25% yield, 98.5% purity) was obtained as a white solid. LCMS: calc. for C ₄₂ H ₄₆ N ₄ O ₃ : 654.36, found: [M+H] ⁺ 655.3. HPLC: 98.541% purity at 220 nm. ¹ H NMR (400 MHz, DMSO-d ₆ ) į = 10.88 - 10.73 (m, 1H), 9.22 -9.06 (m, 1H), 8.16 - 8.14 (m, 1H), 7.17 (br s, 3H), 7.08 - 7.01 (m, 2H), 6.92 - 6.80 (m, 4H),6.66 - 6.46 (m, 5H), 6.26 - 6.15 (m, 2H), 4.17 - 4.09 (m, 1H), 3.73 (br dd, J = 4.9, 11.0 Hz, 1H), 3.58 (br d, J = 10.6 Hz, 2H), 3.40 - 3.25 (m, 3H), 3.12 (br s,4H), 3.02 - 2.89 (m, 2H), 2.68 (br s, 4H), 2.46 - 2.33 (m, 2H), 2.16 - 1.96 (m, 3H), 1.91 - 1.81 (m, 2H), 1.75 - 1.66 (m, 1H), 1.54 - 1.42 (m, 2H). SFC: retention time, 4.742 min, 7.087 min; Area, 50.28 %, 49.72 %; Stereochemistry was arbitrarily assigned.

EXAMPLE 144. Preparation of (I-42) 3-(4-(4-(2-(1-(4-((1S,2R)-6-hydroxy-2-phenyl- 1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperidin-4-yl)ethy l)piperazin-1- yl)phenyl)piperidine-2,6-dione Step 1: To a solution of (5S,6R)-5-(4-(4-(2,2-dimethoxyethyl)piperidin-1-yl)phenyl)-6 -phenyl- 5,6,7,8-tetrahydronaphthalen-2-ol (300 mg, 1 eq, 636 ^mol) in THF (15 mL) was added H ₂ SO ₄ (25 g, 25 mmol, 15 mL, 10% purity, 4 eq).The mixture was stirred at 70 °C for 5 h . The mixture was adjusted to pH=8-9 by progressively adding NaHCO ₃ . The reaction mixture was quenched by addition 20 mL ethyl acetate at 20°C, and then diluted 20 mL with H ₂ O and extracted with ethyl acetate (25 mL * 2). The combined organic layers were washed with 10 mL brine, dried over Na ₂ SO ₄ . The reaction was filtered and concentrated under reduced pressure to give 2-(1-(4- ((1S,2R)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-y l) phenyl) piperidin-4-yl) acetaldehyde (400 mg, 940 ^mol, crude) was obtained as a yellow solid. LC-MS (ESI+) m/z: 426.3 (M+H) ⁺ . Step 2: A mixture of 2-(1-(4-((1S,2R)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphth alen-1- yl)phenyl)piperidin-4-yl)acetaldehyde (100 mg, 1 Eq, 235 ^mol) , 3-(4-(piperazin-1- yl)phenyl)piperidine-2,6-dione (64.2 mg, 1 Eq, 235 ^mol) and sodium acetate (96.4 mg, 5 Eq, 11 l) i C (2 ) d O (2 ) 20 °C f 0 h h i id (423 40.5 ^L, 3 Eq, 705 ^mol) at 20°C for 1 h, then added sodium triacetoxyborohydride (99.6 mg, 2 Eq, 470 ^mol) the mixture, and then the mixture was stirred at 25 °C for 16 h . The reaction was concentrated and was purified by prep-HPLC (FA condition: column: Welch Xtimate C18 150*30mm*5um;mobile phase: [water(FA)-ACN];B%: 20%-15%,6min) to give 3-(4-(4-(2-(1- (4-((1S,2R)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen- 1-yl)phenyl)piperidin-4- yl)ethyl)piperazin-1-yl)phenyl)piperidine-2,6-dione (29.8 mg, 43.6 ^mol, 18.6 %) was obtained as a white solid. LCMS: calc. for C ₄₄ H ₅₀ N ₄ O ₃ : 682.89, found: [M+H] ⁺ 683.3. HPLC: 100% purity at 220 nm. NMR (400MHz, DMSO-d ₆ ) į ppm = 10.81 - 10.76 (m, 1H), 8.19 - 8.16 (m, 1H), 7.18 - 7.07 (m, 3H), 7.07 - 7.00 (m, 2H), 6.92 - 6.85 (m, 2H), 6.84 - 6.79 (m, 2H), 6.67 - 6.58 (m, 2H), 6.55 - 6.45 (m, 3H), 6.23 - 6.16 (m, 2H), 4.16 - 4.09 (m, 1H), 3.76 - 3.67 (m, 1H), 3.49 (br d, J = 9.7 Hz, 2H), 3.31 - 3.24 (m, 1H), 3.14 - 3.05 (m, 4H), 2.87 (br d, J = 6.6 Hz, 2H), 2.67 - 2.58 (m, 1H), 2.52 - 2.51 (m, 5H), 2.44 - 2.42 (m, 1H), 2.48 - 2.41 (m, 3H), 2.39 - 2.34 (m, 2H), 2.16 - 2.05 (m, 2H), 2.02 - 1.96 (m, 1H), 1.70 (br d, J = 11.6 Hz, 2H), 1.43 - 1.38 (m, 2H), 1.24 - 1.14 (m, 2H). SFC: retention time, 6.964 min; Area, 98.794 %; Stereochemistry was arbitrarily assigned

EXAMPLE 145. Preparation of (I-8) 3-(4-(4-(2-(1-(4-((1R,2S)-6-hydroxy-2-phenyl- 1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperidin-4-yl)ethy l)piperazin-1- yl)phenyl)piperidine-2,6-dione Step 1: A mixture of (6-benzyloxy-3,4-dihydronaphthalen-1-yl) trifluoromethanes^Lfonate (10 g, 26.02 mmol, 1 eq), (4-hydroxyphenyl) boronic acid (4.31 g, 31.22 mmol, 1.2 eq), Na2CO3 (5.51 g, 52.03 mmol, 2 eq), Pd(dppf)Cl ₂ (2.12 g, 2.60 mmol, 0.1 eq) in dioxane (100 mL) and H ₂ O (20 mL) was degassed and purged with N ₂ for 3 times, and then the mixture was stirred at 100 °C for 16 h under N ₂ atmosphere. The reaction mixture was added water 500 mL, and then extracted with Ethyl acetate 600 mL (300 mL * 3). The combined organic layers were washed with water 300 mL (100 mL * 3), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate=100/0 to 80/20) to give 4-(6-benzyloxy-3, 4-dihydronaphthalen-1-yl) phenol (4.5 g, 10.92 mmol, 42.0 % yield, 79.7% purity) was obtained as a white solid. LC-MS (ESI ⁺ ) m/z: 329.0 (M+H) ⁺ . Step 2: To a solution of 4-(6-benzyloxy-3,4-dihydronaphthalen-1-yl)phenol (260.32 mg, 792.68 ^mol, 1 eq) in ACN (5 mL) was added NBS (126.98 mg, 713.42 ^mol, 0.9 eq) .The mixture was stirred at 20 °C for 3 h . The residue was concentrated and purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash ® Silica Flash Column, Eluent of 0~50% Ethyl acetate/Petroleum ether gradient @ 30 mL/min). Compound 4-(6-benzyloxy-2-bromo-3, 4- dihydronaphthalen-1-yl) phenol (130 mg, 319.18 ^mol, 40.27% yield) was obtained as a white solid. LC-MS (ESI ⁺ ) m/z: 407.0 (M+H) ⁺ . Step 3: A mixture of 4-(6-(benzyloxy)-2-bromo-3,4-dihydronaphthalen-1-yl)phenol (5.1 g, 1 Eq, 13 mmol) , phenylboronic acid (1.8 g, 1.2 Eq, 15 mmol) , Sodium carbonate (2.7 g, 1.5 mL, 2 Eq, 25 mmol) , [1,1'-Bis(diphenylphosphino)ferrocene]dichloropalladium(II)C omplex with dichloromethane (1.0 g, 0.1 Eq, 1.3 mmol) in 1,4-Dioxane (60 mL) and H ₂ O (15 mL) was degassed and purged with N ₂ for 3 times, and then the mixture was stirred at 100 °C for 16 h under N ₂ atmosphere. The reaction mixture was added water 300 mL at 0°C and extracted with ethyl acetate (200 mL * 3). The combined organic layers were washed with brine (40 mL * 3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash ® Silica Flash Column, Eluent of 0~100% ethyl acetate/petroleum ether gradient @ 80 mL/min) to give the product of 4-(6-(benzyloxy)-2-phenyl-3, 4-dihydronaphthalen-1-yl) phenol (3.9 g, 9.6mmol, 80 %) as a light yellow solid. LC-MS (ESI ⁺ ) m/z: 405.2 (M+H) ⁺ . Step 4: To a solution of Nonafluorobutanesulfonyl fluoride (1 g, 0.9 mL, 1 Eq, 5 mmol) and 4- (6-(benzyloxy)-2-phenyl-3,4-dihydronaphthalen-1-yl)phenol (2 g, 1 Eq, 5 mmol) in THF (30 mL) and ACN (30 mL) was added potassium carbonate (1 g, 0.4 mL, 1.5 Eq, 7 mmol). The reaction was stirred at r.t. for 16 h. TLC (petroleum ether: ethyl acetate=10:1, Rf=0.5) indicated the starting material was consumed completely and one new spot formed. The reaction mixture was concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®; 24 g SepaFlash® Silica Flash Column, Eluent of 0~10% Ethyl acetate/Petroleum ether gradient @ 45 mL/min). To give the product of 4-(6-(benzyloxy)-2- phenyl-3,4-dihydronaphthalen-1-yl)phenyl 1,1,2,2,3,3,4,4,4-nonafluorobutane-1-s^Lfonate (2.9 g, 4.2mmol, 90 %) was obtained as a colorless oil. LC-MS (ESI ⁺ ) m/z: 687.1 (M+H) ⁺ . Step 5: A mixture of benzyl 4-(2-hydroxyethyl)piperidine-1-carboxylate (500 mg, 1.90 mmol) in DCM (1 mL) was degassed and purged with N ₂ for 3 times, the reaction was added (1,1- diacetoxy-3-oxo-1^5,2-benziodoxol-1-yl) acetate (805.34 mg, 1.90 mmol, 587.84 ^L) at 0°C and then the mixture was stirred at 25 °C for 3 h under N ₂ atmosphere. TLC (Petroleum ether: Ethyl acetate=1:1) indicated reactant was consumed completely and one new spot formed. The reaction was clean according to TLC. The reaction mixture was quenched by addition 5 mL NaHCO3, the reaction mixture was added filtered and filter liquor was extracted with 15 mL (5 mL * 3) DCM. The combined organic layers were washed with dried over [Na ₂ SO ₄ ], filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 0~40% Ethyl acetate/Petroleum ethergradient @ 25 mL/min) to give benzyl 4-(2-oxoethyl)piperidine-1- carboxylate (200 mg, 765.36 umol, 40.31% yield, 100.00% purity) was obtained as a yellow oil. LC-MS (ESI ⁺ ) m/z: 262.2 (M+H) ⁺ . Step 6: A solution of trimethoxymethane (203.05 mg, 1.91 mmol, 209.76 ^L) and benzyl 4-(2- oxoethyl)piperidine-1-carboxylate (100 mg, 382.68 ^mol) in MeOH (2 mL) was added 4- methylbenzenesulfonic acid (1.32 mg, 7.65 ^mol). Then the mixture was stirred at 25° C for 1 h. TLC (petroleum ether: ethyl acetate=5:1) showed the starting material was consumed completely and one new spot was formed. The resulting mixture was poured into sat. NaHCO ₃ (10 mL), extracted with EtOAc (10 mL*3), and the combined organic phase was dried over Na2SO4, filtered and concentrated in vacuu. The residue was purified by flash column silica gel chromatography (ISCO 4 g SepaFlash silica flash column eluent of 0-100% ethyl acetate/petroleum ether gradient, 20 mL/min) to give benzyl 4-(2,2-dimethoxyethyl)piperidine-1- carboxylate (70 mg, 227.73 ^mol, 59.51% yield) as a white solid. Step 7: To a solution of benzyl 4-(2,2-dimethoxyethyl)piperidine-1-carboxylate (1.8 g, 5.9 mmol) in methanol (20 mL) was added Pd/C (0.62 g, 10% Wt, 0.59 mmol). The mixture was stirred at 25 °C for 16 h under H ₂ (0.12 g, 59 mmol). LCMS showed one new peak was detected. The reaction was filtered and concentrated in vacuum to give 4-(2,2-dimethoxyethyl)piperidine(1 g, 6 mmol, 100 % yield). LC-MS (ESI ⁺ ) m/z: 174.1 (M+H) ⁺ . Step 8: 4-(2,2-dimethoxyethyl) piperidine (0.5 g, 1 Eq, 3mmol) was added to a mixture suspension of Ruphos-Pd-G ₃ (0.2 g, 0.1 Eq, 0.3 mmol), Ruphos (0.1 g, 0.1 Eq, 0.3 mmol) and 7- (benzyloxy)-4-(4-((perfluorobutyl)sulfonyl)phenyl)-3-phenyl- 1,2-dihydronaphthalene (2 g, 1 Eq, 3 mmol) and cesium carbonate (3 g, 3 Eq, 9 mmol) in Toluene (30 mL). The mixture was stirred at 100 °C for 16 h. The reaction mixture was added water 300 mL at 0°C and extracted with ethyl acetate (100 mL * 3). The combined organic layers were washed with brine (20 mL * 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® Silica Flash Column, Eluent of 0~100% Ethyl acetate/Petroleum ether gradient @ 45 mL/min) to give the product of 1-(4-(6-(benzyloxy)-2-phenyl-3, 4-dihydronaphthalen-1-yl) phenyl)-4-(2, 2- dimethoxyethyl) piperidine (1 g, 2 mmol, 60 % yield) as a yellow solid. LC-MS (ESI ⁺ ) m/z: 560.4 (M+H) ⁺ . Step 9: Pd/C (300 mg, 4.19 Eq, 2.82 mmol, 10% wt) was added to a mixture suspension of 1-(4- (6-(benzyloxy)-2-phenyl-3,4-dihydronaphthalen-1-yl)phenyl)-4 -(2,2-dimethoxyethyl)piperidine (818 mg, 1 Eq, 672 ^mol) in MeOH (4 mL)and THF ^20 mL). The suspension was degassed and purged with H ₂ (15 psi) for 2 times. The mixture was stirred at 50°C for 16h. The reaction was filtrate was concentrated. The residue was further separated by SFC (condition: column: DAICEL CHIRALPAK IG (250mm*30mm,10um);mobile phase: [0.1%NH ₃ H ₂ O ETOH]; B%: 40%-40%,min) to give desired (5R,6S)-5-(4-(4-(2,2-dimethoxyethyl)piperidin-1-yl)phenyl)-6 - phenyl-5,6,7,8-tetrahydronaphthalen-2-ol (300 mg, 636 ^mol, 43.5 %) as a yellow solid and (5S,6R)-5-(4-(4-(2,2-dimethoxyethyl)piperidin-1-yl)phenyl)-6 -phenyl-5,6,7,8- tetrahydronaphthalen-2-ol (300 mg, 636 ^mol, 43.5 %) as a yellow solid. LC-MS (ESI ⁺ ) m/z: 472.3 (M+H) ⁺ . Step 10: To a solution of (5R,6S)-5-(4-(4-(2,2-dimethoxyethyl)piperidin-1-yl)phenyl)-6 -phenyl- 5,6,7,8-tetrahydronaphthalen-2-ol (300 mg, 636 ^mol, 1 eq) in THF (15 mL) was added H2SO4 (25 g, 25 mmol, 15 mL, 10% purity, 40 eq). The mixture was stirred at 70°C for 16 h. The mixture was adjusted to pH 8-9 by progressively adding NaHCO ₃ . The reaction mixture was quenched by addition 20 mL EtOAc at 20°C, and then diluted with 20 mL H ₂ O and extracted with EtOAc (25 mL * 2). The combined organic layers were washed with (10 mL), dried over Na ₂ SO ₄ . The reaction was filtered and concentrated under reduced pressure to give 2-(1-(4-((1R, 2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl) phenyl) piperidin-4-yl) acetaldehyde (400 mg, 940 ^mol, crude) was obtained as a yellow solid. LC-MS (ESI ⁺ ) m/z: 426.3 (M+H) ⁺ . Step 11: A mixture of 2-(1-(4-((1R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphth alen-1- yl)phenyl)piperidin-4-yl)acetaldehyde (200 mg, 1 Eq, 470 ^mol), 3-(4-(piperazin-1- yl)phenyl)piperidine-2,6-dione (128 mg, 1 Eq, 470 ^mol) and sodium acetate (193 mg, 5 Eq, 2.35 mmol) in DCM (3 mL) and MeOH (3 mL) at 20°C for 0.5 hr, pH=8, then acetic acid (84.7 mg, 81.1 ^L, 3 Eq, 1.41 mmol) at 20°C for 1 hr, pH=6,then added sodium triacetoxyborohydride (199 mg, 2 Eq, 940 ^mol) the mixture, and then the mixture was stirred at 25 °C for 16 hr. The reaction was concentrated and was purified by prep-HPLC (FA condition: column: Welch Xtimate C18150*30mm*5um phase: [water(FA)-ACN]; B%: 16%-46%, 6min) to give 3-(4-(4- (2-(1-(4-((1R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronapht halen-1-yl)phenyl)piperidin-4- yl)ethyl)piperazin-1-yl)phenyl)piperidine-2,6-dione (75.8 mg, 111 ^mol, 23.6 %) was obtained as a white solid. LCMS: calc. for C ₄₄ H ₅₀ N ₄ O ₃ : 682.89, found: [M+H] ⁺ 683.3. HPLC: 99.232% purity at 220 nm. ¹ H NMR (400 MHz, DMSO-d ₆ ) į ppm =10.80 - 10.77 (m, 1H), 8.24 - 8.11 (m, 1H), 7.16 - 7.10 (m, 3H), 7.06 - 7.02 (m, 2H), 6.88 (d, J =8.8 Hz, 2H), 6.82 (br d, J = 6.4 Hz, 2H), 6.65 - 6.59 (m, 2H), 6.53 - 6.47 (m, 3H), 6.19 (d, J =8.6 Hz, 2H), 4.13 - 4.10 (m, 1H), 3.74 - 3.69 (m, 1H), 3.51 - 3.45 (m, 1H), 3.48 (br d, J =10.0 Hz, 1H), 3.30 - 3.24 (m, 1H), 3.10 (br s, 4H), 3.00 - 2.86 (m, 2H), 2.67 - 2.57 (m, 1H), 2.52 (br d, J =1.8 Hz, 4H), 2.48 - 2.41 (m, 4H), 2.39 - 2.35 (m, 2H), 2.18 - 1.94 (m, 4H), 1.69 (br d, J =11.3 Hz, 2H), 1.42 (br s, 2H), 1.23 - 1.15 (m, 2H). SFC: retention time, 2.859 min; 3.503 min; Area, 50.675 %; 49.305%; Stereochemistry was arbitrarily assigned EXAMPLE 146. Preparation of (I-9) (3S)-3-(5-(4-((1-(4-(2-cyclohexyl-6-hydroxy- 1,2,3,4-tetrahydroisoquinolin-1-yl)phenyl)piperidin-4-yl)met hyl)piperazin-1-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione Step 1: To a solution of 2-(3-methoxyphenyl)acetic acid (20.0 g, 120.36 mmol) and cyclohexanamine (14.3 g, 144.43 mmol, 16.5 mL) in DCM (400.0 mL) was added EDC (28.0 g, 180.53 mmol, 32.0 mL), TEA (36.5 g, 361.07 mmol, 50.26 mL) and HOBt (8.1 g, 60.18 mmol) at 25 °C. The mixture was stirred at 25 °C for 2.5 hours. The reaction mixture was concentrated under reduced pressure to give the residue, which was diluted with H2O (200.0 mL) and extracted with DCM (100.0 mL x 3). The combined organic layers were washed with brine (150.0 mL x 2), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue, which was purified by column chromatography (SiO ₂ , Petroleum ether/Ethyl acetate = 20/1 to 1/1) to give N-cyclohexyl-2-(3-methoxyphenyl)acetamide (23.3 g, 78.27% yield) as a white solid. LC-MS (ESI ⁺ ) m/z: 248.2 (M+H) ⁺ . ¹ HNMR (500MHz, DMSO-d ₆ ): į 7.90 (d, J = 7.5Hz, 1H), 7.21 - 7.17 (m, 1H), 7.28 - 7.22 (m, 1H), 6.82 - 6.76 (m, 3H), 3.72 (s, 3H), 3.51 - 3.48 (m, 1H), 3.35 - 3.33 (m, 2H), 1.72 - 1.68 (m, 4H), 1.68 - 1.64 (m, 1H), 1.26 - 1.12 (m, 5H). Step 2: To a solution of BH _3/ Me ₂ S (10.0 M, 16.98 mL) in THF (200.0 mL) was added N- cyclohexyl-2-(3-methoxyphenyl)acetamide (21.0 g, 84.91 mmol) in THF (200.0 mL) at 0 °C under N ₂ . The mixture was stirred at 70 °C for 16 hours under N ₂ . The reaction mixture was quenched by MeOH (300.0 mL) and reflux for 2 hours. Then the mixture was concentrated under vacuum to get the crude, which was diluted with treated with DCM (300.0 mL) and washed with H2O (100.0 mL x 3) and brine (100.0 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , DCM/MeOH = 1/0 to 10/1) to give N-(3- methoxyphenethyl)cyclohexanamine (7.4 g, 37.35% yield) as a yellow oil. LC-MS (ESI ⁺ ) m/z: 234.2 (M+H) ⁺ . ¹ HNMR (400MHz, CHLOROFORM-d): į 7.23 - 7.18 (m, 1H), 6.82 - 6.74 (m, 3H), 3.79 (s, 3H), 2.92 - 2.87 (m, 2H), 2.80 - 2.75 (m, 2H), 2.45 - 2.40 (m, 1H), 1.88 - 1.72 (m, 2H), 1.70 - 1.62 (m, 2H), 1.26 - 1.03 (m, 6H). Step 3: To a solution of N-(3-methoxyphenethyl)cyclohexanamine (1.0 g, 4.29 mmol), 4- iodobenzoyl chloride (1.5 g, 5.57 mmol) and TEA (867.3 mg, 8.57 mmol, 1.19 mL) in DCM (10.0 mL) was stirred at 25 °C for 1.5 hours. LCMS showed the desired MS was detected. The mixture was poured into H ₂ O (20.0 mL), extracted with DCM (20.0 mL x 3). The combined organic phase was washed with brine (10.0 mL x 2), dried over Na ₂ SO ₄ and filtered. The residue was purified by column chromatography (SiO ₂ , Petroleum ether/EtOAc = 20/1 to 5/1) to give N- cyclohexyl-4-iodo-N-(3-methoxyphenethyl)benzamide (1.9 g, 95.69% yield) as colorless oil. LC MS (ESI ⁺ ) / 4641 (M+H) ^{+ 1} HNMR (400MHz, CHLOROFORM-d): į 7.75 (d, J = 8.5 Hz, 2H), 7.23 – 7.20 (m, 1H), 7.10 (d, J = 8.5 Hz, 2H), 6.89 - 6.77 (m, 3H), 3.81 (s, 3H), 3.53 - 3.32 (m, 3H), 2.97 (br s, 2H), 1.72 - 1.70 (m, 2H), 1.60 - 1.54 (m, 4H), 1.47 – 1.45 (m, 2H), 1.04 (br s, 2H). Step 4: To a solution of N-cyclohexyl-4-iodo-N-(3-methoxyphenethyl)benzamide (1.7 g, 3.67 mmol) was added POCl ₃ (11.2 g, 73.38 mmol, 6.82 mL) and the mixture was stirred at 120 °C for 16 hours. The mixture was concentrated to get the crude, which was dissolved in Toluene (30.0 mL) and NaBH ₄ (1.4 g, 36.69 mmol) was added to the mixture. Then the mixture was stirred at 70 °C for 16 hours. LCMS showed that the desired mass was detected. The mixture was poured into H ₂ O (30.0 mL), extracted with EtOAc (30.0 mL x 3). The combined organic phase was washed with brine (20.0 mL x 2), dried over Na ₂ SO ₄ and filtered. The filtrate was concentrated under reduced pressure to get the residue. The residue was purified by column chromatography (SiO ₂ , Petroleum ether/EtOAc = 20/1 to 5/1) to give 2-cyclohexyl-1-(4- iodophenyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline (1.3 g, 79.21% yield) as a yellow solid. LC-MS (ESI ⁺ ) m/z: 448.1 (M+H) ⁺ . ¹ HNMR (500MHz, CHLOROFORM-d): į 7.59 (d, J = 8.0 Hz, 2H), 7.05 (d, J = 8.5 Hz, 2H), 6.62 - 6.54 (m, 3H), 4.82 (s, 1H), 3.75 (s, 3H), 3.13 - 3.10 (m, 1H), 3.02 - 2.96 (m, 1H), 2.76 - 2.67 (m, 2H), 2.36 - 2.31 (m, 1H), 1.93 (d, J = 11.5 Hz, 1H), 1.77 - 1.66 (m, 2H), 1.51 - 1.50 (m, 1H), 1.43 - 1.41 (m, 2H), 1.16 - 1.04 (m, 4H). Step 5: To a solution of 2-cyclohexyl-1-(4-iodophenyl)-6-methoxy-1,2,3,4- tetrahydroisoquinoline (1.0 g, 2.24 mmol) in DMSO (100.0 mL) was added 4- (dimethoxymethyl)piperidine (533.8 mg, 3.35 mmol), CuI (85.15 mg, 0.45 mmol); pyrrolidine-2- carboxylic acid (102.94 mg, 894.15 umol) and K ₂ CO ₃ (926.83 mg, 6.71 mmol). The mixture was stirred at 100°C for 2 hours under N ₂ . LCMS showed that the desired mass was detected. The mixture was poured into H ₂ O (20.0 mL), extracted with EtOAC (20.0 mL x 3). The combined organic phase was washed with brine (10.0 mL x 2), dried over Na ₂ SO ₄ and filtered. The filtrate was concentrated under reduced pressure to get the residue. The residue was purified by column chromatography (SiO2, Petroleum ether/EtOAc = 20/1 to 3/1) to give the product 2- cyclohexyl-1-(4-(4-(dimethoxymethyl)piperidin-1-yl)phenyl)-1 ,2,3,4-tetrahydroisoquinoline (640.0 mg, 56.82% yield) as a white solid. LC-MS (ESI ⁺ ) m/z: 479.3 (M+H) ⁺ . ¹ H NMR (400MHz, CHLOROFORM-d) į 7.12 (d, J = 8.4 Hz, 2 H), 6.85 (d, J = 8.4 Hz, 2 H), 6.65 - 6.59 (m, 2H), 6.57 - 6.52 (m, 1H), 4.79 (s, 1H), 4.09 (d, J = 7.2 Hz, 1H), 3.74 (s, 3H) 3.71 - 3.64 (m, 2 H), 3.37 (s, 6H), 3.17 - 3.08 (m, 1H), 3.03 - 2.94 (m, 1H), 2.77 - 2.60 (m, 4H), 2.47 - 2.36 (m, 1H), 1.98 - 1.92 (m, 1H), 1.89 - 1.81 (m, 2H), 1.78 - 1.70 (m, 2H), 1.68 - 1.63 (m, 1H), 1.57 - 1.51 (m, 2H), 1.48 - 1.32 (m, 3H), 1.17 - 1.04 (m, 4H). Step 6: To a solution of 2-cyclohexyl-1-(4-(4-(dimethoxymethyl)piperidin-1-yl)phenyl) -1,2,3,4- tetrahydroisoquinoline (540.0 mg, 1.13 mmol) in DCM (5.0 mL) was added BBr ₃ (1.4 g, 0.5 mL, 5.64 mmol) at -70 °C under N ₂ . After 10 min, the mixture was stirred at 25 °C for 2 hours. LCMS showed that the desired mass was detected. The mixture was concentrated and purified by prep-TLC (EA) to give the product rac-(R)-1-(4-(2-cyclohexyl-6-hydroxy-1,2,3,4- tetrahydroisoquinolin-1-yl)phenyl)piperidine-4-carbaldehyde (120.0 mg, 25.4% yield). LC-MS (ESI ⁺ ) m/z: 479.3 (M+H) ⁺ . Step 7: To a solution of rac-(R)-1-(4-(2-cyclohexyl-6-hydroxy-1,2,3,4-tetrahydroisoqu inolin-1- yl)phenyl)piperidine-4-carbaldehyde (100.0 mg, 0.24 mmol), (S)-3-(1-oxo-5-(piperazin-1- yl)isoindolin-2-yl)piperidine-2,6-dione (78.4 mg, 0.24 mmol) in DCM (5.0 mL) and MeOH (5.0 mL) was added AcONa (39.2 mg, 0.48 mmol) and stirred at 25 °C for 20 min, Then AcOH (28.7 mg, 0.48 mmol) and NaBH ₃ CN (30.0 mg, 0.48 mmol) was added to the mixture and the reaction was stirred for another 3 hours at 25 °C. LCMS showed that the desired mass was detected. The mixture was purified by prep-HPLC (Column: Welch Xtimate C18 150*25mm*5um ;Condition: water(FA)-ACN; Begin B: 18; End B: 38; Gradient Time (min): 11; 100%B Hold Time (min): 2; Flow Rate (ml/min): 25; Detection The mixture was purified by preparative HPLC (water (FA)-ACN as eluents, acidic condition) to give the compound (10 mg, 10 % yield) as a yellow solid LC-MS (ESI ⁺ ) m/z: 731.4 (M+H) ⁺ . LCMS: calc. for C ₄₄ H ₄₈ N ₆ O ₄ : 731.4. HPLC: 100% purity at 220 nm. NMR (400MHz, CHLOROFORM-d) į 7.74 (d, J = 8.8 Hz, 1H), 7.19 - 7.09 (m, 2H), 7.00 (dd, J = 8.8, 2.0 Hz, 1 H), 6.90 - 6.83 (m, 3H), 6.57 - 6.52 (m, 2H), 6.47 - 6.41 (m, 1H), 5.25 - 5.15 (m, 1H), 4.83 (br s, 1H), 4.45 - 4.39 (m, 1H), 4.29 - 4.23 (m, 1H), 3.69 (br d, J = 12.0 Hz, 2H), 3.37 - 3.29 (m, 4H) 3.22 - 2.56 (m, 10H), 2.54 - 2.09 (m, 6H), 2.05 - 1.50 (m, 8H), 1.47 - 1.31 (m, 4H) ,1.19 - 1.00 (m, 4H). EXAMPLE 147. Preparation of (I-39) 3-[4-[4-[[1-[4-[(1R,2S)-6-hydroxy-2-phenyl- tetralin-1-yl] phenyl]-4-piperidyl] methyl]piperazin-1-yl]phenyl]piperidine-2, 6-dione Step 1: A solution of 1-[4-[(1R,2S)-6-hydroxy-2-phenyl-tetralin-1-yl]phenyl]piperi dine-4- carbaldehyde (50 mg, 121.5^mol) 3-(4-piperazin-1-ylphenyl)piperidine-2,6-dione (70 mg, 170^mol, 3.8 Eq. HCl) and sodium acetate (69.7 mg, 849.8 ^mol) in DCM (1.5 mL) and MeOH (1.5 mL) was stirred at 20 °C for 30 mins. Then acetic acid (93.9 mg, 339.9 ^mol, 89.4 ^L) and NaBH ₃ CN (21.4 mg, 339.9 ^mol) was added .The mixture was stirred at 20 °C for 16 h. LCMS showed 42% desired MS. The reaction was concentrated to dryness in vacuo to give a brown oil. The brown oil was purified by prep-HPLC (column: Boston Green ODS 150*30mm*5um; mobile phase: [water (FA)-ACN]; B%: 20%-50%, 6min).The pure fractions were collected and concentrated in vacuo to remove organic solvent. The aqueous phase was lyophilized to dryness to give the title compound 3-[4-[4-[[1-[4-[(1R,2S)-6-hydroxy-2-phenyl-tetralin-1-yl] phenyl]-4- piperidyl] methyl]piperazin-1-yl]phenyl]piperidine-2, 6-dione (18 mg, 15.5% yield, 0.35 Eq. FA) as a white solid. LCMS: calc. for C ₄₃ H ₄₈ N ₄ O ₃ : 668.4, found: [M+H] ⁺ 669.3. HPLC: 97.1% purity at 220 nm ¹ H NMR (400MHz, DMSO-d ₆ ) į = 10.78 (s, 1H), 9.11 (br s, 1H), 8.15 (s, 1H), 7.19 - 7.09 (m, 3H), 7.04 (d, J=8.5 Hz, 2H), 6.92 - 6.80 (m, 4H), 6.64 (d, J=8.3 Hz, 1H), 6.60 (s, 1H), 6.53 (d, J=8.5 Hz, 2H), 6.48 (dd, J=2.3, 8.0 Hz, 1H), 6.20 (d, J=8.5 Hz, 2H), 4.13 (d, J=4.8 Hz, 1H), 3.72 (dd, J=4.9, 11.2 Hz, 1H), 3.51 (br d, J=10.3 Hz, 2H), 3.41 - 3.22 (m, 5H), 3.10 (br s, 4H), 3.03 - 2.82 (m, 2H), 2.65 - 2.52 (m, 4H), 2.23 - 2.05 (m, 4H), 2.04 - 1.94 (m, 1H), 1.81 - 1.54 (m, 4H), 1.23 - 1.07 (m, 2H) SFC: retention time, 2.630 min and 3.546 min; Area, 50.17% and 49.83%. EXAMPLE 148. Preparation of (I-11) 3-[4-[4-[[1-[4-[(1S,2R)-6-hydroxy-2-phenyl- tetralin-1-yl]phenyl]-4-piperidyl]methyl]piperazin-1-yl]phen yl]piperidine-2,6-dione Step 1: A mixture of methyl 2-(4-bromophenyl)acetate (2 g, 8.7 mmol), tert-butyl piperazine-1- carboxylate (1.95 g, 10.5 mmol), cesium carbonate (5.69 g, 17.5 mmol), X-Phos (416.2 mg, 873.1 ^mol) and (1E,4E)-1,5-diphenylpenta-1,4-dien-3-one;palladium (399.8 mg, 436.6 ^mol) in dioxane (20 mL) was degassed and purged with N ₂ for 3 times, and then the mixture was stirred at 90 °C for 16 h under N ₂ atmosphere. LC-MS showed 70% of desired MS was detected. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was diluted with water 100 mL and extracted with Ethyl acetate (25 mL x 2). The combined organic layers were washed with brine (15 mL x 2), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a yellow oil. The yellow oil was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® Silica Flash Column, Eluent of 0~11% Ethyl acetate/Petroleum ether gradient @ 50 mL/min). The desired fractions were collected and the solvent was concentrated in vacuum to give the product tert-butyl 4-[4-(2-methoxy-2-oxo- ethyl) phenyl] piperazine-1-carboxylate (2.6 g, 7.4 mmol, 84.4% yield, 94.8% purity) as a yellow oil. TLC: petroleum ether: ethyl acetate=5:1, R _f = 0.5. LC-MS (ESI ⁺ ) m/z: 335.2 (M+H) ⁺ . Step 2: A mixture of tert-butyl 4-[4-(2-methoxy-2-oxo-ethyl)phenyl]piperazine-1-carboxylate (1 g, 3 mmol ) in DMF (8 mL)was added potassium 2-methylpropan-2-olate (338.9 mg, 3 mmol) at 0 °C, the mixture was degassed and purged with N ₂ for 3 times, then prop-2-enamide (214.7 mg, 3 mmol) in DMF (2 mL) was added at 0 °C, and then the mixture was stirred at 25 °C for 2 h under N ₂ atmosphere. LC-MS showed 14% desired MS was detected. The reaction mixture was poured into aq. NH ₄ Cl 40 mL at 0 °C, and then extracted with Ethyl acetate (15 mL x 2).The combined organic layers were washed with brine (15 mL x 2), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a green solid. The green solid was purified by flash silica gel chromatography (ISCO®; 25 g SepaFlash® Silica Flash Column, Eluent of 0~38% Ethyl acetate/Petroleum ether gradient @ 30 mL/min). The desired fractions were collected and the solvent was concentrated in vacuum to give the product tert-butyl 4-[4- (2,6-dioxo-3-piperidyl)phenyl]piperazine-1-carboxylate (170 mg, 428.3 ^mol, 14.3% yield, 94.1% purity) as a yellow solid. TLC: petroleum ether: ethyl acetate=2:1, R _f = 0.3. LC-MS (ESI ⁺ ) m/z: 374.2 (M+H) ^{+ 1} H NMR (400 MHz, CDCl ₃ ) į = 8.00 (br s, 1H), 7.04 (d, J=8.6 Hz, 2H), 6.85 (d, J=8.7 Hz, 2H), 3.65 (dd, J=5.2, 9.4 Hz, 1H), 3.50 (br t, J=5.0 Hz, 4H), 3.13 - 3.02 (m, 4H), 2.71 - 2.52 (m, 2H), 2.25 - 2.09 (m, 2H), 1.41 (s, 9H). Step 3: To a solution of tert-butyl 4-[4-(2, 6-dioxo-3-piperidyl) phenyl] piperazine-1-carboxylate (160 mg, 428.4 ^mol) in DCM (2 mL) was added HCl/dioxane (2 mL). The mixture was stirred at 20 °C for 16 h. LC-MS showed 86% of desired MS was detected. The reaction was concentrated to dryness in vacuo to give the product 3-(4-piperazin-1-ylphenyl) piperidine-2, 6- dione (175 mg, crude, 3.8 Eq. HCl) as a yellow solid. LC-MS (ESI ⁺ ) m/z: 2741 (M+H) ⁺ Step 4: A solution of 1-[4-[(1S,2R)-6-hydroxy-2-phenyl-tetralin-1-yl]phenyl]piperi dine-4- carbaldehyde (27 mg, 65.6 ^mol), 3-(4-piperazin-1-ylphenyl)piperidine-2,6-dione (50 mg, 121.4 ^mol, 3.8 Eq. HCl) and sodium acetate (49.8 mg, 607.5 ^mol) in DCM (1.5 mL) and MeOH (1.5 mL) was stirred at 20 °C for 30 mins, Then acetic acid (14.6 mg, 242.8 ^mol, 13.9 ^L) and sodium cyanoborohydride (15.2 mg, 243 ^mol) was added .The mixture was stirred at 20 °C for 16 h. CMS showed 48% desired MS. he reaction was concentrated to dryness in vacuo to give a brown oil. The brown oil was purified by prep-HPLC (column: Boston Green ODS 150*30mm*5um; mobile phase: [water (FA)-ACN]; B%: 20%-50%, 6min). The pure fractions were collected and concentrated in vacuo to remove organic solvent. The aqueous phase was lyophilized to dryness to give the title compound 3-[4-[4-[[1-[4-[(1S,2R)-6-hydroxy-2-phenyl- tetralin-1-yl]phenyl]-4-piperidyl]methyl]piperazin-1-yl]phen yl]piperidine-2,6-dione (13.4 mg, 19.8^mol, 16.3% yield, 100% purity, 0.15 Eq. FA) as a yellow solid. LCMS: calc. for C ₄₃ H ₄₈ N ₄ O ₃ : 668.4, found: [M+H] ⁺ 669.5. HPLC: 99.2% purity at 220 nm NMR (400 MHz, DMSO-d6) į = 10.77 (s, 1H), 9.10 (s, 1H), 8.13 (s, 1H), 7.19 - 7.08 (m, 3H), 7.04 (br d, J=8.6 Hz, 2H), 6.91 - 6.79 (m, 4H), 6.67 - 6.57 (m, 2H), 6.56 - 6.44 (m, 3H), 6.19 (br d, J=8.5 Hz, 2H), 4.12 (br d, J=4.8 Hz, 1H), 3.71 (dd, J=4.9, 10.9 Hz, 1H), 3.50 (br d, J=10.3 Hz, 2H), 3.30 (s, 6H), 3.10 (br s, 4H), 3.03 - 2.83 (m, 3H), 2.62 (br s, 2H), 2.26 - 2.05 (m, 4H), 2.01 (br d, J=4.6 Hz, 1H), 1.81 - 1.54 (m, 4H), 1.14 (br d, J=9.9 Hz, 2H) SFC: retention time, 2.528 min and 3.175 min; Area, 48.42% and 51.58%;

EXAMPLE 149. Preparation of (I-10) (S)-3-(5-(4-((1-(3,5-difluoro-4-(6-hydroxy-2- phenyl-3,4-dihydronaphthalen-1-yl)phenyl)piperidin-4-yl)meth yl)piperazin-1-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione a solution of 4-bromo-3,5-difluoro-phenol (4.0 g, 19.14 mmol) and BnBr (3.9 g, 22.97 mmol, 2.73 mL) in DMF (30 mL) was added K ₂ CO ₃ (7.9 g, 57.42 mmol) at 25 °C. The mixture was stirred at 60 °C for 16 hours. The mixture was diluted with H ₂ O (50 mL) and extracted with EtOAc (30 mL x 3) The combined organic layers were washed with brine (40 mL x 2), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue, which was purified by column chromatography (Petroleum ether/Ethyl acetate=1/0 to 10/1) to give the product of 5-benzyloxy-2-bromo-1,3-difluoro-benzene (5.2 g, 16.52 mmol, 95% purity) as colorless oil. ¹ HNMR: (500MHz, CHLOROFORM-d): į 7.43 - 7.33 (m, 5H), 6.64 - 6.58 (m, 2H), 5.03 (s, 2H). Step 2: To a solution of 6-methoxytetralin-1-one (8.0 g, 45.40 mmol) in MeOH (200 mL) was added 4-methylbenzenesulfonohydrazide (8.5 g, 45.40 mmol) at 25 °C. The mixture was stirred at 25 °C for 16 hours. The mixture was filtered, washed with MeOH (100 mL x 3) to give N- [(Z)-(6-methoxytetralin-1-ylidene)amino]-4-methyl-benzenesul fonamide (14.66 g, 90% purity) as a white solid, which was used directly without further purification. ¹ HNMR: (500MHz, CHLOROFORM-d): į 7.95 - 7.91 (m, 3H), 7.45 - 7.42 (m, 1H), 7.32 (d, J = 8.0 Hz, 2H), 6.77 - 6.74 (m, 1H), 6.59 (d, J = 2.5 Hz, 1H), 3.80 (s, 3H), 2.71 - 2.66 (m, 2H), 2.46 - 2.40 (m, 5H), 1.91 - 1.85 (m, 2H). Step 3: To a solution of 5-benzyloxy-2-bromo-1,3-difluoro-benzene (5.0 g, 16.72 mmol) and N- [(Z)-(6-methoxytetralin-1-ylidene)amino]-4-methyl-benzenesul fonamide (8.6 g, 25.07 mmol) in dioxane (200 mL) was added Pd ₂ (dba) ₃ (765.4 mg, 835.81 umol), XPhos (796.9 mg, 1.67 mmol) and t-BuOLi (2.9 g, 36.78 mmol, 3.32 mL) at 25 °C. The mixture was stirred at 100 °C for 16 hours under N ₂ . The reaction mixture was diluted with H ₂ O (300 mL) and extracted with EtOAc (200 mL x 3). The combined organic layers were washed with brine (500 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue, which was purified by column chromatography (Petroleum ether/Ethyl acetate = 1/0 to 10/1) to give 4-(4-benzyloxy-2,6-difluoro-phenyl)-7-methoxy-1,2-dihydronap hthalene (7.6 g, 70% purity) as a white solid. ¹ HNMR: (500MHz, CHLOROFORM-d): į 7.46 - 7.34 (m, 5H), 6.76 - 6.57 (m, 5H), 5.97 - 5.95 (m, 1H), 5.06 (s, 2H), 3.79 (s, 3H), 2.89 - 2.85 (m, 2H), 2.47 - 2.42 (m, 2H). Step 4: To a solution of 4-(4-benzyloxy-2,6-difluoro-phenyl)-7-methoxy-1,2-dihydronap hthalene (7.0 g, 18.50 mmol) in DCM (100 mL) was added Py.HBr3 (6.5 g, 20.35 mmol) at 25 °C. The extracted with DCM (150 mL x 2). The combined organic layers were washed with brine (200 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue, which was purified by flash silica gel chromatography (Petroleum ether/Ethyl acetate=1/0 to 10/1) to give 4-(4-benzyloxy-2,6-difluoro-phenyl)-3-bromo-7-methoxy-1,2-di hydronaphthalene (2.2 g, 26.01% yield) as a yellow solid. ¹ HNMR: (400MHz, CHLOROFORM-d): į 7.46 - 7.34 (m, 5H), 6.76 - 6.57 (m, 5H), 5.07 (s, 2H), 3.78 (s, 3H), 3.05 - 2.95 (m, 4H). Step 5: To a solution of 4-(4-benzyloxy-2,6-difluoro-phenyl)-3-bromo-7-methoxy-1,2- dihydronaphthalene (2.2 g, 4.81 mmol) and PhB(OH) ₂ (879.9 mg, 7.22 mmol) in dioxane (25 mL) and H ₂ O (5 mL) was added Na ₂ CO ₃ (1.5 g, 14.43 mmol) and Pd(PPh ₃ ) ₄ (555.9 mg, 481.08 umol) at 25 °C. The mixture was stirred at 80 °C for 2 hours under N ₂ . The reaction mixture was diluted with H ₂ O (50 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine 80 (mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue, which was purified by flash silica gel chromatography (Petroleum ether/Ethyl acetate = 1/0 to 10/1) to give 4-(4-benzyloxy-2,6-difluoro-phenyl)-7-methoxy-3- phenyl-1,2-dihydronaphthalene (1.55 g, 70.89% yield) as light yellow gum. ¹ HNMR: (400MHz, CHLOROFORM-d): į 7.45 - 7.39 (m, 5H), 7.19 - 7.09 (m, 5H), 6.78 (d, J = 2.4 Hz, 1H), 6.64 - 6.60 (m, 2H), 6.47 - 6.41 (m, 2H), 4.97 (s, 2H), 3.80 (s, 3H), 3.02 - 2.98 (m, 2H), 2.84 - 2.78 (m, 2H). Step 6: To a solution of 4-(4-benzyloxy-2,6-difluoro-phenyl)-7-methoxy-3-phenyl-1,2- dihydronaphthalene (1.55 g, 3.41 mmol) in MeOH (15 mL) was added Pd/C (1.8 g, 1.71 mmol, 10% purity). The suspension was degassed and purged with H ₂ for 3 times. The mixture was stirred under H ₂ (15 Psi) at 25 °C for 1 hour. The mixture was filtered and concentrated under reduced pressure to give the residue, which was purified by flash silica gel chromatography (Petroleum ether/Ethyl acetate = 1/0 to 3/1) to give 3,5-difluoro-4-(6-methoxy-2-phenyl-3,4- dihydronaphthalen-1-yl)phenol (950.0 mg, 61.16% yield, 80% purity) as a white solid. ¹ HNMR: (500MHz, CHLOROFORM-d): į 7.19-7.10 (m, 5H), 6.79 (s, 1H), 6.69 - 6.62 (m, 2H), 6.30 (d, J=8.0 Hz, 2H), 5.16 (s, 1H), 3.81 (s, 3H), 3.02 - 2.98 (m, 2H), 2.83 - 2.77 (m, 2H). Step 7: To a solution of 3,5-difluoro-4-(6-methoxy-2-phenyl-3,4-dihydronaphthalen-1-y l)phenol (950.0 mg, 2.61 mmol) in DCM (20 mL) was added TEA (2.6 g, 26.07 mmol, 3.6 mL) at 25 °C. Then PhNTf ₂ (1.4 g, 3.91 mmol) in DCM (15 mL) was added at -70 °C. The mixture was stirred at -70 °C for 2 hours. The reaction mixture was diluted with H ₂ O (30 mL) and extracted with DCM (20 mL x 3). The combined organic layers were washed with brine (50 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (Petroleum ether/Ethyl acetate = 1/0 to 3/1) to give [3,5-difluoro-4-(6-methoxy-2-phenyl-3,4-dihydronaphthalen-1- yl)phenyl]trifluoromethanesulfonate (515.0 mg, 39.79% yield) was obtained as colorless oil. ¹ HNMR: (400 MHz, CHLOROFORM-d): į 7.18 - 7.12 (m, 3H), 7.04 (dd, J = 1.7, 7.6 Hz, 2H), 6.83 - 6.75 (m, 3H), 6.66 - 6.55 (m, 2H), 3.81 (s, 3H), 3.06 - 2.99 (m, 2H), 2.86 - 2.79 (m, 2H). Step 8: To a solution of 3,5-difluoro-4-(6-methoxy-2-phenyl-3,4-dihydronaphthalen-1-y l)phenyl trifluoromethanesulfonate (50.0 mg, 0.10 mmol) and 4-(dimethoxymethyl)piperidine (19.0 mg, 0.12 mmol)in Toluene (2 mL) was added Cs ₂ CO ₃ (66.0 mg, 2 Eq, 0.20 mmol), Pd(OAc) ₂ (1.1 mg, 5.0 ^mol) and BINAP (6.3 mg, 10 ^mol) at 25 °C. The mixture was stirred at 100 °C for 16 hours under N2. The mixture was concentrated under reduced pressured to give the residue, which was purified by prep-TLC (Petroleum ether/Ethyl acetate = 3/1) to give 1-(3,5-difluoro-4- (6-methoxy-2-phenyl-3,4-dihydronaphthalen-1-yl)phenyl)-4-(di methoxymethyl)piperidine (30.0 mg, 59 %) as colorless gum. ¹ HNMR: (400MHz, CHLOROFORM-d): į 7.17 - 7.09 (m, 5H), 6.77 (d, J = 2.4 Hz, 1H), 6.71 (d, J = 8.4 Hz, 1H), 6.64 - 6.60 (m, 1H), 6.33 - 6.30 (m, 2H), 4.07 (d, J = 7.2 Hz, 1H), 3.80 (s, 3H), 3.64 (d, J = 12.4 Hz, 2H), 3.37 (s, 6H), 3.01 - 2.96 (m, 2H), 2.82 - 2.77 (m, 2H), 2.73 - 2.63 (m, 2H), 1.85 - 1.81 (m, 2H), 1.80 - 1.71 (m, 1H), 1.41 - 1.38 (m, 2H). Step 9: To a solution of 1-(3,5-difluoro-4-(6-methoxy-2-phenyl-3,4-dihydronaphthalen- 1- yl)phenyl)-4-(dimethoxymethyl)piperidine (50.0 mg, 99 ^mol) in DCM (10 mL)was added BBr ₃ (0.12 g, 47 ^L, 0.49 mmol) at -70 °C under N ₂ . After 10 mins, the reaction was stirred at 25 °C for 1 hour. The mixture was quenched by H ₂ O (15 mL), and adjusted to pH 7~8 with NH ₃ ^. H ₂ O, extracted with DCM (8 mL x 3). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give 1-(3,5-difluoro-4-(6- hydroxy-2-phenyl-3,4-dihydronaphthalen-1-yl)phenyl)piperidin e-4-carbaldehyde (67.6 mg, 87%, 57% Purity) as a light yellow solid. LC-MS (ESI+) m/z: 492.3 (M+H) ⁺ . ¹ HNMR: (400MHz, CHLOROFORM-d): į 9.70 (s, 1H), 7.20 - 7.06 (m, 5H), 6.72 - 6.52 (m, 3H), 6.31 - 6.29 (m, 2H), 4.67 (br s, 1H), 3.72 - 3.52 (m, 2H), 3.01 - 2.72 (m, 6H), 2.50 - 2.37 (m, 1H), 2.06 - 1.94 (m, 2H), 1.81 - 1.67 (m, 2H). Step 10: To a solution of 1-(3,5-difluoro-4-(6-hydroxy-2-phenyl-3,4-dihydronaphthalen- 1- yl)phenyl)piperidine-4-carbaldehyde (67.0 mg, 0.15 mmol) and (S)-3-(1-oxo-5-(piperazin-1- yl)isoindolin-2-yl)piperidine-2,6-dione (49.0 mg, 0.15 mmol) in DCM (3 mL) and MeOH (3 mL) was added AcONa (25.0 mg, 0.30 mmol) at 25 °C. After 30 min, NaBH ₃ CN (19.0 mg, 0.30 mmol) and AcOH (18.0 mg, 0.30 mmol) was added to the mixture. The mixture was stirred at 25 °C for 16 hour. The mixture was concentrated under reduced pressured to give the residue, which was purified by prep-HPLC (Column: Welch Xtimate C18150*25mm*5um ; Condition: water (FA)-ACN; Begin B: 30; End B: 60; Gradient Time (min): 12; 100%B Hold Time (min): 2; Flow Rate (ml/min): 25; Detection wavelength: 220 nm) to give the compound (18.2 mg, 16%, FA salt) as a white solid. LCMS: calc. for C ₄₅ H ₄₅ F ₂ N ₅ O ₄ : 757.87, found: [M+H] ⁺ 758.3. HPLC: 100% purity at 254 nm. SFC: Purity: 100.00%. (400MHz, METHANOL-d ₄ ): į 8.22 (s, 1H), 7.67 - 7.65 (m, 1H), 7.14 - 7.06 (m, 7H), 6.66 (s, 1H), 6.53 - 6.40 (m, 4H), 5.11 (dd, J = 5.2, 13.2Hz, 1H), 4.42 (d, J = 6.0 Hz, 2H), 3.72 (br d, J = 12.4 Hz, 2H), 3.49 (br s, 4H), 2.98 (br s, 3H), 2.94 - 2.89 (m, 3H), 2.80 - 2.77 (m, 1H), 2.77 - 2.71 (m, 4H), 2.66 (s, 2H), 2.50 - 2.42 (m, 1H), 2.18 - 2.12 (m, 1H), 1.89 (br d, J = 12.0 Hz, 3H), 1.43 - 1.26 (m, 3H). EXAMPLE 150. Preparation of (I-283) (R)-3-(4-(2-((1-(4-((1R,2S)-6-hydroxy-2-phenyl- 1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperidin-4-yl)meth yl)-2,8-diazaspiro[4.5]decan- 8-yl)phenyl)piperidine-2,6-dione and (I-284) (S)-3-(4-(2-((1-(4-((1R,2S)-6-hydroxy-2- phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperidin-4- yl)methyl)-2,8- diazaspiro[4.5]decan-8-yl)phenyl)piperidine-2,6-dione Step 1: To a solution of tert-butyl 2,8-diazaspiro[4.5]decane-2-carboxylate (900.00 mg, 3.74 mmol, 2 eq.) in dioxane (15 mL) was added 3-(4-bromophenyl)piperidine-2,6-dione (502 mg, 1.87 mmol, 1 eq.), Cs2CO3 (1.22 g, 3.74 mmol, 2 eq) and 5% Pd-PEPPSI-IHeptCl (182.00 mg, 187 ^mol, 0.1 eq). The mixture was stirred at 90°C under N ₂ for 2hr. LCMS showed the desired ms was found. The mixture was concentrated to give a residue, which was purified by flash silica gel chromatography eluting with EtOAc in PE from 0% to 100% to give tert-butyl 8-(4- (2,6-dioxopiperidin-3-yl)phenyl)-2,8-diazaspiro[4.5]decane-2 -carboxylate (440.00 mg, 83.80% purity) as a yellow solid. LC-MS (ESI ⁺ ) m/z: 428.2 (M+H ⁺ ). Step 2: To a solution of tert-butyl 8-(4-(2,6-dioxopiperidin-3-yl)phenyl)-2,8- diazaspiro[4.5]decane-2-carboxylate (220.00 mg, 515 ^mol, 1 eq.) in DCM (10 mL) was added HCl/EA (1.29 mL, 5.15 mmol, 10 eq.). The mixture was stirred at 20 °C for 1 hr. LCMS showed the desired ms was found. After completion, the mixture was concentrated under reduced pressure to give 3-(4-(2,8-diazaspiro[4.5]decan-8-yl)phenyl)piperidine-2,6-di one hydrochloride (200.00 mg, crude) as a yellow solid without purification. Step 3: To a solution of 3-(4-(2,8-diazaspiro[4.5]decan-8-yl)phenyl)piperidine-2,6-di one hydrochloride (200.00 mg, 611.00 ^mol, 1 eq.) in DCE (10 mL) and MeOH (5 mL) was added 1- (4-((1R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen- 1-yl)phenyl)piperidine-4- carbaldehyde (126.00 mg, 305.00 ^mol, 0.5 eq.) and NaBH(OAc) ₃ (1.55 g, 7.33 mmol, 12 eq.). The mixture was stirred at 20 °C for 1 hr. The mixture was purified by Prep-HPLC (Column: Boston Green ODS 150 ^ 30mm ^ 5um; Condition water (FA)-CAN, B%: 13%-43%, 14 min) to give 3-(4-(2-((1-(4-((1R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydr onaphthalen-1- yl)phenyl)piperidin-4-yl)methyl)-2,8-diazaspiro[4.5]decan-8- yl)phenyl)piperidine-2,6-dione (130.00 mg, 180 ^mol, 29.4% yield, 100% purity) as a yellow solid. LC-MS (ESI ⁺ ) m/z: 723.4 (M+H) ⁺ . Step 4: 3-(4-(2-((1-(4-((1R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydr onaphthalen-1- yl)phenyl)piperidin-4-yl)methyl)-2,8-diazaspiro[4.5]decan-8- yl)phenyl)piperidine-2,6-dione (130.00 mg, 180.00 ^mol, 1 eq.) was separated by chiral SFC (column: DAICEL CHIRALPAK IE 250 mm ^ 30 mm, 10 ^m); mobile phase: [MeOH-ACN]; B%: 50%-50%; Flow Rate: 80 ml/min; peak 1:3.484 min; peak 2: 4.629 min) to yield peak 1 and peak 2. Peak 1 was concentrated under reduced pressure to yield compound (R)-3-(4-(2-((1-(4-((1R,2S)- 6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl) piperidin-4-yl)methyl)-2,8- diazaspiro[4.5]decan-8-yl)phenyl)piperidine-2,6-dione (4.0 mg, 6 ^mol, 3% yield, 100% purity) as a white solid. LC-MS (ESI ⁺ ) m/z: 723.4 (M+H) ⁺ . LCMS: calc. for C ₄₇ H ₅₄ N ₄ O ₃ : 722.97, found: [M+H] ⁺ 723.4. HPLC: 100% purity at 220 nm. ¹ H NMR: ¹ H NMR (500 MHz, DMSO-d6) į = 10.76 (s, 1H), 9.09 (s, 1H), 8.25 (br d, J = 1.4 Hz, 2H), 6.64 (d, J = 8.4 Hz, 1H), 6.59 (s, 1H), 6.52 (d, J = 8.7 Hz, 2H), 6.48 - 6.46 (m, 1H), 6.19 (d, J = 8.7 Hz, 2H), 4.12 (d, J = 5.0 Hz, 1H), 3.72 - 3.69 (m, 1H), 3.51 - 3.48 (m, 2H), 3.13 - 3.03 (m, 5H), 2.97 - 2.90 (m, 2H), 2.43 (br d, J = 0.6 Hz, 1H), 2.33 (s, 2H), 2.22 (br d, J = 7.5 Hz, 2H), 2.13 - 1.98 (m, 4H), 1.76 - 1.67 (m, 4H), 1.63 - 1.54 (m, 8H), 1.51 - 1.47 (m, 1H), 1.19 - 1.08 (m, 3H). Peak 2 was concentrated under reduced pressure to yield compound (S)-3-(4-(2-((1-(4-((1R,2S)- 6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl) piperidin-4-yl)methyl)-2,8- diazaspiro[4.5]decan-8-yl)phenyl)piperidine-2,6-dione (6.3 mg, 8.7 ^mol, 4.8% yield, 100% purity) as a white solid. LC-MS (ESI ⁺ ) m/z: 723.4 (M+H) ⁺ . LCMS: calc. for C ₄₇ H ₅₄ N ₄ O ₃ : 722.97, found: [M+H] ⁺ 723.4. HPLC: 100% purity at 220 nm. 10.76 (s, 1H), 9.09 (s, 1H), 8.15 (s, 1H), 7.15 - 7.11 (m, 3H), 7.03 (d, J = 8.5 Hz, 2H), 6.89 (d, J = 8.7 Hz, 2H), 6.83 (br d, J = 6.9 Hz, 2H), 6.65 (d, J = 8.2 Hz, 1H), 6.60 (s, 1H), 6.53 (d, J = 8.7 Hz, 2H), 6.49 - 6.47 (m, 1H), 6.20 (d, J = 8.7 Hz, 2H), 4.13 (d, J = 4.7 Hz, 1H), 3.74 - 3.70 (m, 1H), 3.52 - 3.48 (m, 2H), 3.16 - 3.05 (m, 5H), 2.98 - 2.88 (m, 2H), 2.60 (br d, J = 5.2 Hz, 1H), 2.46 - 2.44 (m, 2H), 2.31 (br s, 2H), 2.14 - 1.99 (m, 4H), 1.79 - 1.69 (m, 4H), 1.61 (br s, 8H), 1.55 - 1.51 (m, 1H), 1.24 - 1.10 (m, 3H).

EXAMPLE 151. Preparation of (I-288) 1-(4-((R)-7-((1-(4-((1R,2S)-6-hydroxy-2-phenyl- 1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperidin-4-yl)meth yl)-2,7-diazaspiro[4.4]nonan- 2-yl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione Step 1: To a solution of tert-butyl (R)-2,7-diazaspiro[4.4]nonane-2-carboxylate (500 mg, 2.21 mmol, 2.0 eq), 1-(4-bromophenyl)dihydropyrimidine-2,4(1H,3H)-dione (297.26 mg, 1.10 mmol, 1.0 eq), Cs ₂ CO ₃ (719.84 mg, 2.21 mmol, 2.0 eq) and RuPhos Pd G3 (92.39 mg, 110.47 ^mol, 0.1 eq) in dioxane (10 mL) was bubbled with N ₂ for 1 min. Then the mixture was stirred at 90 °C for 16 hours. LCMS showed the starting material was consumed completely and a major peak with desired MS was detected. The reaction mixture was concentrated to get a residue. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate=1/0 to 0/1) to give tert-butyl (R)-7-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)-2,7- diazaspiro[4.4]nonane-2-carboxylate (300 mg, 665.87 ^mol, 60.28% yield) as a white solid. LC- MS (ESI ⁺ ) m/z: 415.2 (M+H) ⁺ . ¹ H NMR (400 MHz, DMSO-d6) į ppm 10.20 (s, 1 H), 7.09 (d, J=8.82 Hz, 2 H), 6.50 (d, J=8.82 Hz, 2 H), 3.62 - 3.70 (m, 2 H), 3.32 - 3.39 (m, 3 H), 3.28 - 3.31 (m, 1 H), 3.15 - 3.27 (m, 4 H), 2.67 (t, J=6.74 Hz, 2 H), 1.80 - 1.98 (m, 4 H), 1.40 (br d, J=5.60 Hz, 9 H). Step 2: A solution of tert-butyl (R)-7-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)-2,7- added dropwise into a solution HCl/Dioxane (4 M, 5 mL, 69.08 eq) at 20 °C for 2 h. LCMS showed that the starting material was consumed and the desired product was detected. The reaction mixture was concentrated to get (R)-1-(4-(2,7-diazaspiro[4.4]nonan-2- yl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione (90 mg, crude) was obtained as a white solid. LC-MS (ESI ⁺ ) m/z: 315.2 (M+H) ⁺ . Step 3: To a solution of (R)-1-(4-(2,7-diazaspiro[4.4]nonan-2-yl)phenyl)dihydropyrimi dine- 2,4(1H,3H)-dione (90 mg, 256.53 ^mol, 1.0 eq, HCl) in DCE (15 mL) and MeOH (3 mL) was added 1-(4-((1R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthale n-1-yl)phenyl)piperidine-4- carbaldehyde (63.34 mg, 153.92 ^mol, 0.6 eq) and NaBH(OAc) ₃ (271.84 mg, 1.28 mmol, 5.0 eq) at 20 °C. Then the mixture was stirred at 20 °C for 2 hours. LCMS showed a major peak with desired MS was detected. The reaction mixture was concentrated to get a residue. The residue was purified by prep-HPLC (column: C18150×30mm; mobile phase: [water (NH ₄ HCO ₃ )-ACN]; gradient: 80%-100% B over 11 min) to give 1-(4-((R)-7-((1-(4-((1R,2S)-6-hydroxy-2-phenyl- 1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperidin-4-yl)meth yl)-2,7-diazaspiro[4.4]nonan-2- yl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione (12.5 mg, 17.61 ^mol, 6.86% yield) as a white solid. LC-MS (ESI ⁺ ) m/z: 710.4 (M+H) ⁺ . LCMS: calc. for C45H51N5O3:709.94, found: [M+H] ⁺ 710.4. HPLC: 100.00% purity at 220 nm NMR (400 MHz, DMSO-d ₆ ) į ppm 10.20 (s, 1 H), 9.09 (s, 1 H), 7.06 - 7.16 (m, 5 H), 6.82 (br d, J=6.56 Hz, 2 H), 6.58 - 6.65 (m, 2 H), 6.45 - 6.53 (m, 5 H), 6.14 - 6.24 (m, 2 H), 4.12 (d, J=5.13 Hz, 1 H), 3.65 (t, J=6.68 Hz, 2 H), 3.45 - 3.52 (m, 2 H), 3.20 - 3.28 (m, 4 H), 3.09 - 3.15 (m, 1 H), 2.88 - 2.98 (m, 2 H), 2.54 - 2.75 (m, 4 H), 2.23 - 2.41 (m, 4 H), 1.85 - 2.20 (m, 4 H), 1.67 - 1.78 (m, 5 H), 1.45 - 1.53 (m, 1 H), 1.07 - 1.27 (m, 3 H).

EXAMPLE 152. Preparation of (I-280) 3-(4-((R)-7-((1-(4-((1R,2S)-6-hydroxy-2-phenyl- 1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperidin-4-yl)meth yl)-2,7-diazaspiro[4.4]nonan- 2-yl)phenyl)piperidine-2,6-dione Step 1: To a solution of tert-butyl (R)-2,7-diazaspiro[4.4]nonane-2-carboxylate (300 mg, 1.33 mmol, 2.0 eq), 3-(4-bromophenyl)piperidine-2,6-dione (177.70 mg, 662.79 ^mol, 1.0 eq), Cs ₂ CO ₃ (431.90 mg, 1.33 mmol, 2.0 eq) and 5% Pd-PEPPSI-IHeptCl (64.47 mg, 66.28 ^mol, 0.1 eq) in dioxane (1.5 mL) was bubbled with N2 for 1 min. Then the mixture was stirred at 90 °C for 3 hours. LCMS showed the starting material was consumed completely and a major peak with desired MS was detected. The reaction mixture was concentrated to get a residue. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate=1/0 to 0/1) to give tert-butyl (5R)-7-(4-(2,6-dioxopiperidin-3-yl)phenyl)-2,7-diazaspiro[4. 4]nonane-2- carboxylate (210 mg, 492.61 ^mol, 74.32% yield) as a white solid. LC-MS (ESI ⁺ ) m/z: 414.2 (M+H) ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) į ppm 10.74 (s, 1 H) 6.95 - 7.04 (m, 2 H) 6.48 (d, J=8.70 Hz, 2 H) 3.68 (dd, J=10.61, 4.89 Hz, 1 H) 3.35 (br d, J=4.53 Hz, 2 H) 3.27 - 3.31 (m, 2 H) 3.13 - 3.26 (m, 4 H) 2.57 - 2.69 (m, 1 H) 2.39 - 2.48 (m, 1 H) 1.78 - 2.17 (m, 6 H) 1.40 (br d, J=6.08 Hz, 9 H). Step 2: A solution of tert-butyl (5R)-7-(4-(2,6-dioxopiperidin-3-yl)phenyl)-2,7- diazaspiro[4.4]nonane-2-carboxylate (100.00 mg, 241.83 ^mol, 1.0 eq) in DCM (10 mL) was added dropwise into a solution HCl/Dioxane (4 M, 5 mL, 82.70 eq) at 15 °C for 2 h. LCMS showed that the starting material was consumed and the desired product was detected. The reaction mixture was concentrated to get 3-(4-((R)-2,7-diazaspiro[4.4]nonan-2- yl)phenyl)piperidine-2,6-dione (80 mg, crude) was obtained as a white solid. LC-MS (ESI ⁺ ) m/z: 314.0 (M+H) ⁺ . Step 3: To a solution of 3-(4-((R)-2,7-diazaspiro[4.4]nonan-2-yl)phenyl)piperidine-2, 6-dione (80 mg, 228.67 ^mol, 1.0 eq, HCl) in DCE (15 mL) and MeOH (3 mL) was added 1-(4-((1R,2S)-6- hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)pi peridine-4-carbaldehyde (56.46 mg, 137.20 ^mol, 0.6 eq) and NaBH(OAc) ₃ (242.32 mg, 1.14 mmol, 5.0eq) at 20 °C. Then the mixture was stirred at 20 °C for 2 hours. LCMS showed a major peak with desired MS was detected. The reaction mixture was concentrated to get a residue. The residue was purified by prep-HPLC (column: C18150×30mm; mobile phase: [water (NH4HCO3)-ACN]; gradient: 85%- 100% B over 11 min) to give 3-(4-((R)-7-((1-(4-((1R,2S)-6-hydroxy-2-phenyl-1,2,3,4- tetrahydronaphthalen-1-yl)phenyl)piperidin-4-yl)methyl)-2,7- diazaspiro[4.4]nonan-2- yl)phenyl)piperidine-2,6-dione (16.8 mg, 23.70 ^mol, 10.36% yield) as a white solid. LC-MS (ESI ⁺ ) m/z: 709.4 (M+H) ⁺ .

EXAMPLE 153. Preparation of (I-291) 1-(4-(2-((1-(4-((1R,2S)-6-hydroxy-2-phenyl- 1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperidin-4-yl)meth yl)-2,8-diazaspiro[4.5]decan- 8-yl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione Step 1: To a solution of tert-butyl 2,8-diazaspiro[4.5]decane-2-carboxylate (100.03 mg, 416.21 ^mol, 2 eq.) in dioxane (1 mL) was added 1-(4-bromophenyl)dihydropyrimidine-2,4(1H,3H)- dione (56 mg, 208.11 ^mol, 1 eq.), Cs ₂ CO ₃ (135.61 mg, 416.21 ^mol, 2 eq) and RuPhos Pd G3 (17.41 mg, 20.81 ^mol, 0.1 eq). The mixture was stirred at 90°C under N ₂ for 2hr. LCMS showed the desired ms was found. The mixture was purified by prep-HPLC (Column Boston Green ODS 150*30mm*5^m; Condition: water(FA)-CAN; Begin B 18, End B 48, Gradient Time(min) 14, 100%B Hold Time(min) 2, FlowRate(ml/min) 25, Injections 6, HPLC 90) to give tert-butyl 8-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)-2,8-diaz aspiro[4.5]decane-2- carboxylate (20 mg, 46.67 ^mol, 22.43% yield) as a white solid. Step 2: To a solution of tert-butyl 8-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)-2,8- diazaspiro[4.5]decane-2-carboxylate (20 mg, 46.67 ^mol, 1 eq.) in DCM (2 mL) was added HCl/EA (4 M, 116.68 ^L, 10 eq.). The reaction was stirred at 20 °C for 1hr. LCMS showed the desired mass was found. The reaction mixture was concentrated to dryness. The crude product ^mol, 97.86% yield) as a white solid was used into the next step without further purification. LC-MS (ESI ⁺ ) m/z: 329.1 (M+H) ⁺ . Step 3: To a solution of 1-(4-(2,8-diazaspiro[4.5]decan-8-yl)phenyl)dihydropyrimidine - 2,4(1H,3H)-dione (15 mg, 45.67 ^mol, 1 eq.) in DCE (3 mL) and MeOH (5 mL) was added 1-(4- ((1R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-y l)phenyl)piperidine-4- carbaldehyde (75.19 mg, 182.70 ^mol, 4 eq.) and Na(OAc) ₃ BH (116.16 mg, 548.10 ^mol, 12 eq.). The reaction was stirred at 20°C for 1hr. LCMS showed the desired ms was found. The mixture was purified by Prep-HPLC (C18-1150*30mm*5^m; Condition: water(NH ₄ HCO ₃ )- ACN, Begin B 48, End B 78; Gradient Time(min): 11; 100% B Hold Time(min): 2; Flow Rate (ml/min): 25, Injections 1, HPLC 95) to give compound 1-(4-(2-((1-(4-((1R,2S)-6-hydroxy-2- phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperidin-4- yl)methyl)-2,8- diazaspiro[4.5]decan-8-yl)phenyl)dihydropyrimidine-2,4(1H,3H )-dione (8.2 mg, 11.02 ^mol, 24.13% yield, 97.32% purity) as a white solid. LC-MS (ESI ⁺ ) m/z: 724.4 (M+H) ⁺ . LCMS: calc. for C ₄₆ H ₅₃ N ₅ O ₃ : 723.96, found: [M+H] ⁺ 724.4. HPLC: 97.32% purity at 220 nm. ¹ H NMR: ¹ H NMR (400 MHz, DMSO-d ₆ ) į = 10.33 - 10.13 (m, 1H), 9.15 - 9.03 (m, 1H), 7.16 - 7.10 (m, 5H), 6.92 (d, J = 9.1 Hz, 2H), 6.83 (br d, J = 6.7 Hz, 2H), 6.64 (d, J = 8.3 Hz, 1H), 6.61 - 6.59 (m, 1H), 6.52 (d, J = 8.7 Hz, 2H), 6.49 - 6.46 (m, 1H), 6.19 (br d, J = 8.6 Hz, 2H), 4.13 - 4.11 (m, 1H), 3.68 (t, J = 6.7 Hz, 2H), 3.52 - 3.44 (m, 2H), 3.26 (br s,2H), 3.17 - 3.03 (m, 4H), 2.99 - 2.89 (m, 2H), 2.77 - 2.60 (m, 4H), 2.34 - 2.32 (m, 2H), 2.27 - 2.06 (m, 4H), 1.77 - 1.68 (m, 3H), 1.64 - 1.55 (m, 6H), 1.27 - 1.20 (m, 1H), 1.18 -1.09 (m, 2H). EXAMPLE 154. Preparation of (I-275) (S)-3-(5-(4-((1-(4-((1R,2S)-6-hydroxy-2-phenyl- 1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperidin-4-yl)meth yl)piperazin-1-yl)-3-methyl- 2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-di one and (I-276) (R)-3-(5-(4- ((1-(4-((1R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphtha len-1-yl)phenyl)piperidin-4- yl)methyl)piperazin-1-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benz o[d]imidazol-1- yl)piperidine-2,6-dione Step 1: To a solution of 3-(3-methyl-2-oxo-5-(piperazin-1-yl)-2,3-dihydro-1H-benzo[d] imidazol- 1-yl)piperidine-2,6-dione hydrochloride (1.20 g, 3.16 mmol, 1.0 eq.,HCl) in DCM (10 mL) were added Boc ₂ O (1.09 mL, 4.74 mmol, 1.5 eq.) and DIEA (440.21 ^L,2.53 mmol, 0.8 eq) at 20°C. The mixture was stirred at 20 °C for 16 hr. LCMS showed the desired MS was detected. The mixture was concentrated to give a residue, which was purified by flash silica gel chromatography eluting with EtOAc in PE from 0% to 100% to give tert-butyl 4-(1-(2,6- dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]i midazol-5-yl)piperazine-1- carboxylate (1.1 g, 87.04% purity) as a white solid. LC-MS (ESI ⁺ ) m/z: 444.3 (M+H ⁺ ). Step 2: tert-butyl 4-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H - benzo[d]imidazol-5-yl)piperazine-1-carboxylate (1.1 g, 2.48 mmol, 1 eq.) was separated by chiral SFC (column: DAICEL CHIRALPAK IG 250 mm ^ 30 mm, 10 ^m); mobile phase: [CO ₂ - EtOH (0.1% NH ₃ H ₂ O)]; B%: 60%-60%; Flow Rate: 80 ml/min; peak 1:2.643 min; peak 2: 3.950 min) to yield peak 1 and peak 2. Peak 1 was concentrated under reduced pressure to yield tert-butyl (S)-4-(1-(2,6-dioxopiperidin- 3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)pi perazine-1-carboxylate (265.2 mg, 24.11 % yield) as a white solid. LC-MS (ESI ⁺ ) m/z: 444.2 (M+H) ⁺ . Peak 2 was concentrated under reduced pressure to yield tert-butyl (R)-4-(1-(2,6-dioxopiperidin- 3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)pi perazine-1-carboxylate (251.3 mg, 22.85% yield) as a white solid. LC-MS (ESI ⁺ ) m/z: 444.2 (M+H) ⁺ . Step 3: To a solution of tert-butyl (S)-4-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3- dihydro-1H-benzo[d]imidazol-5-yl)piperazine-1-carboxylate (80.00 mg, 180.39 ^mol, 1 eq.) in DCM (10 mL) was added HCl/EtOAc (450.96 ^L, 1.80 mmol, 208.51 eq.). The mixture was stirred at 20 °C for 1 hr. LCMS showed the desired ms was found. After completion, the mixture was concentrated under reduced pressure to give (S)-3-(3-methyl-2-oxo-5-(piperazin-1- yl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dion e (50.00 mg, crude) as a yellow solid without purification. LC-MS (ESI ⁺ ) m/z: 344.0 (M+H) ⁺ . Step 4: To a solution of tert-butyl (R)-4-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3- dihydro-1H-benzo[d]imidazol-5-yl)piperazine-1-carboxylate (80.00 mg, 172.18 ^mol, 1 eq.) in DCM (10 mL) was added HCl/EtOAc (450.96 ^L, 1.80 mmol, 208.51 eq.). The mixture was stirred at 20 °C for 1 hr. LCMS showed the desired ms was found. After completion, the mixture was concentrated under reduced pressure to give (R)-3-(3-methyl-2-oxo-5-(piperazin-1- yl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dion e (50.00 mg, crude) as a yellow solid without purification. LC-MS (ESI ⁺ ) m/z: 344.0 (M+H) ⁺ . Step 5: To a solution of (S)-3-(3-methyl-2-oxo-5-(piperazin-1-yl)-2,3-dihydro-1H- benzo[d]imidazol-1-yl)piperidine-2,6-dione (50 mg, 145.61 ^mol, 1 eq.) in DCE (5 mL) and MeOH (7 mL) was added 1-(4-((1R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthale n-1- yl)phenyl)piperidine-4-carbaldehyde (239.70 mg, 582.45 ^mol, 4 eq.) and NaBH(OAc) ₃ (370.33 mg, 1.75 mmol, 12 eq.). The mixture was stirred at 20 °C for 1 hr. The mixture was purified by Prep-HPLC (Column: C18-1150 ^ 30mm ^ 5um; Condition water (NH ₄ HCO ₃ )-CAN, B%: 48%- 78%, 11 min) to give (S)-3-(5-(4-((1-(4-((1R,2S)-6-hydroxy-2-phenyl-1,2,3,4- tetrahydronaphthalen-1-yl)phenyl)piperidin-4-yl)methyl)piper azin-1-yl)-3-methyl-2-oxo-2,3- dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (24.3 mg, 32.31 ^mol, 22.19% yield, 98.25% purity) as a white solid. LC-MS (ESI ⁺ ) m/z: 739.4 (M+H) ⁺ . LCMS: calc. for C ₄₅ H ₅₀ N ₆ O ₄ : 738.93, found: [M+ ⁺ 739.4. HPLC: 98.25% purity at 220 nm. NMR: ¹ H NMR (400 MHz, DMSO-d ₆ ) į ppm 11.24 - 10.90 (m, 1H), 9.10 (s, 1H), 7.17 - 7.09 (m, 5H), 6.93 (d, J = 8.7 Hz, 1H), 6.84 - 6.83 (m, 2H), 6.65 - 6.63 (m, 1H), 6.60 (br s, 1H), 6.54 (s, 1H), 6.52 (s, 1H), 6.48 (d, J = 5.8 Hz, 1H), 6.20 (br d, J = 8.7 Hz, 2H), 5.31 - 5.26 (m, 1H), 4.12 (br d, J = 4.6 Hz, 1H), 3.53 - 3.49 (m, 2H), 3.30 (d, J = 2.7 Hz, 6H), 3.07 (br s, 3H), 2.97 - 2.87 (m, 4H), 2.73 - 2.66 (m, 2H), 2.19 (br d, J = 7.2 Hz, 2H), 2.12 - 2.07 (m, 1H), 2.00 - 1.96 (m, 1H), 1.77 - 1.61 (m, 6H), 1.28 - 1.11 (m, 4H). Step 6: To a solution of (R)-3-(3-methyl-2-oxo-5-(piperazin-1-yl)-2,3-dihydro-1H- benzo[d]imidazol-1-yl)piperidine-2,6-dione (50 mg, 145.61 ^mol, 1 eq.) in DCE (5 mL) and MeOH (7 mL) was added 1-(4-((1R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthale n-1- yl)phenyl)piperidine-4-carbaldehyde (239.70 mg, 582.45 ^mol, 4 eq.) and NaBH(OAc)3 (370.33 mg, 1.75 mmol, 12 eq.). The mixture was stirred at 20 °C for 1 hr. The mixture was purified by Prep-HPLC (Column: C18-1150 ^ 30mm ^ 5um; Condition water (NH4HCO3)-CAN, B%: 48%-78%, 11 min) to give (R)-3-(5-(4-((1-(4-((1R,2S)-6-hydroxy-2-phenyl-1,2,3,4- tetrahydronaphthalen-1-yl)phenyl)piperidin-4-yl)methyl)piper azin-1-yl)-3-methyl-2-oxo-2,3- dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (34.1 mg, 45.52 ^mol, 31.26% yield, 98.63% purity) as a white solid. LC-MS (ESI ⁺ ) m/z: 739.4 (M+H) ⁺ . LCMS: calc. for C : 738.93, found: [M+H] ⁺ 739.4. HPLC: 98.63% purity at 220 nm. ¹ H NMR: ¹ H NMR (400 MHz, DMSO-d ₆ ) į ppm 11.15 - 10.99 (m, 1H), 9.10 (s, 1H), 7.17 - 7.09 (m, 5H), 6.93 (d, J = 8.7 Hz, 1H), 6.84 - 6.83 (m, 2H), 6.65 - 6.63 (m, 1H), 6.60 (br s, 1H), 6.54 (s, 1H), 6.52 (s, 1H), 6.48 (d, J = 6.0 Hz, 1H), 6.20 (d, J = 8.6 Hz, 2H), 5.31 - 5.26 (m, 1H), 4.12 (br d, J = 4.9 Hz, 1H), 3.53 - 3.49 (m, 2H), 3.30 (d, J = 2.6 Hz, 6H), 3.08 (br s, 3H), 2.98 - 2.88 (m, 4H), 2.74 - 2.66 (m, 2H), 2.19 (br d, J = 7.0 Hz, 2H), 2.12 - 2.07 (m, 1H), 1.99 - 1.96 (m, 1H), 1.76 - 1.60 (m, 6H), 1.24 - 1.09 (m, 4H). EXAMPLE 155. Preparation of (I-295) (R)-3-(6-(4-((1-(4-((1R,2S)-6-hydroxy-2-phenyl- 1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperidin-4-yl)meth yl)piperazin-1-yl)-1-methyl- 1H-indazol-3-yl)piperidine-2,6-dione and (I-296) (S)-3-(6-(4-((1-(4-((1R,2S)-6-hydroxy-2-

phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperidin -4-yl)methyl)piperazin-1-yl)-1- methyl-1H-indazol-3-yl)piperidine-2,6-dione Step 1: A solution of tert-butyl (R)-4-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-6- into a solution HCl/Dioxane (4 M, 4 mL) at 15 °C for 2 h. LCMS showed that the starting material was consumed and the desired product was detected. The reaction mixture was concentrated to get (R)-3-(1-methyl-6-(piperazin-1-yl)-1H-indazol-3-yl)piperidin e-2,6-dione (50 mg, crude) was obtained as a white solid. LC-MS (ESI ⁺ ) m/z: 328.2 (M+H) ⁺ . Step 2: To a solution of (R)-3-(1-methyl-6-(piperazin-1-yl)-1H-indazol-3-yl)piperidin e-2,6-dione (55.00 mg, 151.16 ^mol, 1.0 eq., HCl) in DCE (5 mL) and MeOH (5 mL) was added 1-(4- ((1R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-y l)phenyl)piperidine-4- carbaldehyde (93.31 mg, 226.75 ^mol, 1.5 eq.) at 20 °C. After 5 minutes, the NaBH(OAc) ₃ (192.23 mg, 906.99 ^mol, 6.0 eq.) was added into the mixture at 20 °C. The mixture was stirred at 20 °C for 0.5 h. LCMS showed that the desired product was detected. The mixture was filtered and concentrated under vacuum to give the crude. The residue was purified by prep- HPLC (condition: Column: Boston Green ODS 150*30mm*5um; Condition: water (FA)-ACN, Begin B 55, End B 75, Gradient Time (min) 12, 100% B Hold Time (min) 2, Flow Rate (mL/min) 25.) to give (R)-3-(6-(4-((1-(4-((1R,2S)-6-hydroxy-2-phenyl-1,2,3,4- tetrahydronaphthalen-1-yl)phenyl)piperidin-4-yl)methyl)piper azin-1-yl)-1-methyl-1H-indazol-3- yl)piperidine-2,6-dione (28 mg, 24.67% yield) as white solid. LC-MS (ESI ⁺ ) m/z: 723.4 (M+H) ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) į = 10.85 (s, 1H), 9.10 (s, 1H), 8.13 (s, 1H), 7.51 (br d, J = 7.2 Hz, 1H), 7.18 - 7.10 (m, 3H), 6.97 - 6.81 (m, 4H), 6.65 - 6.47 (m, 5H), 6.21 (br d, J = 8.3 Hz, 2H), 4.30 - 4.22 (m, 1H), 4.13 (br d, J = 4.8 Hz, 1H), 3.89 (s, 3H), 3.56 - 3.49 (m, 2H), 3.32 (s, 8H), 3.20 (br d, J = 3.3 Hz, 2H), 3.02 - 2.91 (m, 2H), 2.69 - 2.56 (m, 4H), 2.34 - 2.11 (m, 4H), 1.84 - 1.60 (m, 4H), 1.27 - 1.11 (m, 2H). Step 3: A solution of tert-butyl (S)-4-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-6- yl)piperazine-1-carboxylate (69 mg, 161.41 ^mol, 1 eq.) in DCM (10 mL) was added dropwise into a solution HCl/Dioxane (4 M, 1.20 mL) at 15 °C for 2 h. LCMS showed that the starting material was consumed and the desired product was detected. The reaction mixture was concentrated to get (S)-3-(1-methyl-6-(piperazin-1-yl)-1H-indazol-3-yl)piperidin e-2,6-dione (55 mg, crude) as a white solid. LC-MS (ESI ⁺ ) m/z: 328.2 (M+H) ⁺ . Step 4: To a solution of (S)-3-(1-methyl-6-(piperazin-1-yl)-1H-indazol-3-yl)piperidin e-2,6-dione (55 mg, 151.16 ^mol, 1.0 eq., HCl) in DCE (5 mL) and MeOH (5 mL) was added 1-(4-((1R,2S)- 6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl) piperidine-4-carbaldehyde (93.31 mg, 226.75 ^mol, 1.5 eq.) at 20 °C. After 5 minutes, the NaBH(OAc) ₃ (192.23 mg, 906.99 ^mol, 6.0 eq.) was added into the mixture at 20 °C. The mixture was stirred at 20 °C for 12 h. LCMS showed that the desired product was detected. The mixture was filtered and concentrated under vacuum to give the crude. The residue was purified by prep-HPLC (condition: Column: Boston Green ODS 150*30mm*5um; Condition: water (FA)-ACN, Begin B 55, End B 75, Gradient Time (min) 12, 100% B Hold Time (min) 2, Flow Rate (mL/min) 25.) to give (S)-3- (6-(4-((1-(4-((1R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydron aphthalen-1-yl)phenyl)piperidin-4- yl)methyl)piperazin-1-yl)-1-methyl-1H-indazol-3-yl)piperidin e-2,6-dione (25 mg, 22.57% yield) as white solid. LC-MS (ESI ⁺ ) m/z: 723.4 (M+H) ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) į = 10.85 (s, 1H), 9.10 (s, 1H), 8.13 (s, 1H), 7.51 (br d, J = 9.1 Hz, 1H), 7.18 - 7.09 (m, 3H), 6.95 - 6.80 (m, 4H), 6.66 - 6.46 (m, 5H), 6.20 (d, J = 8.6 Hz, 2H), 4.32 - 4.19 (m, 1H), 4.13 (d, J = 4.9 Hz, 1H), 3.89 (s, 3H), 3.56 - 3.49 (m, 2H), 3.32 (s, 8H), 3.24 - 3.16 (m, 2H), 2.99 - 2.88 (m, 2H), 2.69 - 2.57 (m, 4H), 2.33 - 2.11 (m, 4H), 1.82 - 1.63 (m, 4H), 1.18 (br d, J = 9.1 Hz, 2H). Step 5: The (R)-3-(6-(4-((1-(4-((1R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetra hydronaphthalen-1- yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-methyl-1H- indazol-3-yl)piperidine-2,6-dione and (S)-3-(6-(4-((1-(4-((1R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetra hydronaphthalen-1- yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-methyl-1H- indazol-3-yl)piperidine-2,6-dione (53 mg, 73.31 ^mol, 1.0 eq.) was further separated by SFC (condition: CO2-EtOH, column: DAICEL CHIRALPAK ID (250mm*30 mm*10 um).to give (R)-3-(6-(4-((1-(4-((1R,2S)-6- hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)pi peridin-4-yl)methyl)piperazin-1- yl)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione (13.0 mg, 24.53% yield) as white solid and (S)-3-(6-(4-((1-(4-((1R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetra hydronaphthalen-1- yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-methyl-1H- indazol-3-yl)piperidine-2,6-dione (13.0 mg, 24.53% yield) to give solid. (R)-3-(6-(4-((1-(4-((1R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetra hydronaphthalen-1- yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-methyl-1H- indazol-3-yl)piperidine-2,6- dione: LCMS: calc. for C ₄₅ H ₅₀ N ₆ O ₃ : 722.93, found: [M+H] ⁺ 723.4. HPLC: 100.00% purity at 220 nm NMR (400 MHz, DMSO-d ₆ ) į = 10.85 (s, 1H), 9.10 (s, 1H), 7.49 (d, J = 8.9 Hz, 1H), 7.17 - 7.08 (m, 3H), 6.93 - 6.81 (m, 4H), 6.66 - 6.47 (m, 5H), 6.20 (d, J = 8.6 Hz, 2H), 4.31 - 4.20 (m, 1H), 4.13 (d, J = 4.6 Hz, 1H), 3.88 (s, 3H), 3.56 - 3.47 (m, 2H), 3.32 (s, 8H), 3.21 (br s, 2H), 3.02 - 2.85 (m, 2H), 2.69 - 2.54 (m, 3H), 2.33 - 2.13 (m, 5H), 1.79 - 1.62 (m, 4H), 1.22 - 1.12 (m, 2H). (S)-3-(6-(4-((1-(4-((1R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetra hydronaphthalen-1- yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-methyl-1H- indazol-3-yl)piperidine-2,6- dione: LCMS: calc. for C45H50N6O3: 722.93, found: 723.4. HPLC: 100.00% purity at 220 nm ¹ H NMR (400 MHz, DMSO-d ₆ ) į = 10.85 (s, 1H), 9.10 (s, 1H), 7.49 (d, J = 9.1 Hz, 1H), 7.18 - 7.09 (m, 3H), 6.93 - 6.80 (m, 4H), 6.66 - 6.46 (m, 5H), 6.20 (d, J = 8.6 Hz, 2H), 4.33 - 4.21 (m, 1H), 4.13 (d, J = 4.6 Hz, 1H), 3.88 (s, 3H), 3.57 - 3.46 (m, 2H), 3.32 (s, 8H), 3.21 (br s, 2H), 3.01 - 2.86 (m, 2H), 2.70 - 2.56 (m, 3H), 2.33 - 2.10 (m, 5H), 1.80 - 1.60 (m, 4H), 1.23 - 1.12 (m, 2H).

EXAMPLE 156. Preparation of (I-189) 3-(7-(4-((1-(4-((1R,2S)-6-hydroxy-2-phenyl- 1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperidin-4-yl)meth yl)piperazin-1-yl)-1-methyl- 1H-indazol-3-yl)piperidine-2,6-dione Step 1: To a solution of 1-(4-((1R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthale n-1- yl)phenyl)piperidine-4-carbaldehyde (90 mg, 1 Eq, 0.22 mmol) in DCE (10 mL) was added 3-(1- methyl-7-(piperazin-1-yl)-1H-indazol-3-yl)piperidine-2,6-dio ne hydrochloride (95 mg, 1.2 Eq, 0.26 mmol) and NaBH(OAc) ₃ (93 mg, 2 Eq, 0.44 mmol). The mixture was adjusted to pH 5-6 with DIEA (28 mg, 38 ^L, 1 Eq, 0.22 mmol). The mixture was stirred at 25 °C for 3 hours. LCMS showed the reaction was completed. The mixture was concentrated and then water (30 mL) was added. The mixture was extracted with DCM (20 mL x 3). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by HPLC (Column Boston Green ODS 150*30mm*5um ; Condition water(FA)-ACN ;Begin B 20 ;End B 50 ;Gradient Time(min) 12 ;100%B Hold Time(min) 2 ;FlowRate (ml/min) 25 ) to give 3-(7-(4- ((1-(4-((1R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphtha len-1-yl)phenyl)piperidin-4- yl)methyl)piperazin-1-yl)-1-methyl-1H-indazol-3-yl)piperidin e-2,6-dion (20 mg, 28 ^mol, 13 %) as an off-white solid. LC-MS (ESI ⁺ ) m/z: 723.4 (M+H) ⁺ . LCMS: calc. for C ₄₅ H ₅₀ N ₆ O ₄ : 722.93, found: [M+H] ⁺ 723.4. HPLC: 99.78% purity at 220 nm. ¹ H NMR (400 MHz, METHANOL-d ₄ ) į ppm ^8.41 - 8.48 (m, 1 H), 7.44 (d, J=7.51 Hz, 1 H), 7.06 - 7.14 (m, 5 H), 6.78 - 6.83 (m, 2 H), 6.61 - 6.71 (m, 4 H), 6.52 (dd, J=8.40, 2.32 Hz, 1 H), 631 (d J=858 H 2 H) 430 437 ( 4 H) 419 (d J=453 H 1 H) 355 (b dd J=966 2.26 Hz, 2 H), 3.12 - 3.26 (m, 4 H), 2.96 - 3.09 (m, 4 H), 2.72 - 2.80 (m, 2 H), 2.62 - 2.69 (m, 2 H), 2.56 (br d, J=11.92 Hz, 3 H), 2.44 (td, J=9.15, 4.23 Hz, 1 H), 2.20 - 2.34 (m, 2 H), 1.86 - 1.93 (m, 2 H), 1.74 - 1.83 (m, 2 H), 1.25 - 1.45 (m, 4 H). EXAMPLE 157. Preparation of (I-188) 3-(6-(4-((1-(4-((1R,2S)-6-hydroxy-2-phenyl- 1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperidin-4-yl)meth yl)piperazin-1-yl)-1-methyl- 1H-indazol-3-yl)piperidine-2,6-dione Step 1: To a solution of 1-(4-((1R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthale n-1- yl)phenyl) piperidine-4-carbaldehyde (50 mg, 0.12 mmol ^1.0 eq.) and 3-(1-methyl-6- (piperazin-1-yl)-1H- indazol-3-yl)piperidine-2,6-dione (48 mg, 1.2 eq., 0.15 mmol) in DCE (3 mL) and MeOH (3 mL) was added Sodium triacetoxyborohydride (77 mg, 0.36 mmol, 3.0 eq.). The mixture was stirred at 20 °C for 2 hour. LCMS showed the reaction was completed. The crude was purified by prep-HPLC together (Welch Xtimate C18150*25mm*5um, water (FA)- ACN as a mobile phase, from 20% to 55%, Gradient Time (min): 11, Flow Rate (ml/min): 25) to give 3-(6-(4-((1-(4-((1R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydr onaphthalen-1- yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-methyl-1H- indazol-3-yl)piperidine-2,6-dione (15.5 mg, 21.4 ^mol, 18 %) as a white solid. LC-MS (ESI ⁺ ) m/z: 723.6 (M+H) ⁺ . LCMS: calc. for C ₄₅ H ₅₀ N ₆ O ₃ , 722.93 found: [M+H] ⁺ 723.6 HPLC: 100.00% purity at 220 nm. ¹ H NMR (400 MHz, METHANOL-d4) į: ppm 8.21 - 8.68 (m, 1 H), 7.56 (d, J=9.20 Hz, 1 H), 7.08 - 7.13 (m, 3 H), 6.94 - 7.01 (m, 1 H), 6.78 - 6.85 (m, 3 H), 6.69 (d, J=8.40 Hz, 1 H), 6.63 (d, J=8.40 Hz, 3 H), 6.52 (m, 1 H), 6.31 (d, J=8.40 Hz, 2 H), 4.29 (m, 1 H), 4.18 (d, J=5.20 Hz, 1 H), 3.95 (s, 3 H), 3.50 - 3.57 (m, 2 H), 3.36 (s, 4 H), 2.96 - 3.05 (m, 2 H), 2.79 - 2.91 (m, 4 H), 2.69 - 2.79 (m, 2 H), 2.60 (t, J=11.20 Hz, 2 H), 2.49 - 2.56 (m, 2 H), 2.43 (m, 1 H), 2.19 - 2.32 (m, 2 H), 1.88 (d, J=13.60 Hz, 2 H), 1.72 - 1.82 (m, 2 H), 1.27 - 1.46 (m, 3 H). EXAMPLE 158. Preparation of (I-274) 3-(5-(4-((1-(4-((1R,2S)-6-hydroxy-2-phenyl- 1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperidin-4-yl)meth yl)piperazin-1-yl)-1- oxoisoindolin-2-yl)pyrrolidine-2,5-dione Step 1: To a solution of ((benzyloxy)carbonyl)asparagine (1.5 g, 5.63 mmol, 1 eq.) in THF (20 mL) was added DMAP (137.66 mg, 1.13 mmol, 0.2 eq.) and CDI (913.52 mg, 5.63 mmol, 1 eq.). The mixture was stirred at 60 °C for 10hr. LC-MS showed one main peak with desired mass was detected. The reaction mixture was partitioned between EA (50 mL×2) and water (50 mL). separated. The residue was purified by prep-HPLC (Column Boston Green ODS 150*30mm*5^m; Condition: water(FA)-CAN; Begin B 22, End B 32, Gradient Time(min) 12, 100%B Hold Time(min) 2, FlowRate(ml/min) 25, Injections 4, HPLC 90). Compound benzyl N-(2,5-dioxopyrrolidin-3-yl)carbamate (1 g, 4.03 mmol, 71.50% yield) was obtained as a brown liquid. LC-MS (ESI ⁺ ) m/z: 249.3 (M+H) ⁺ . Step 2: The mixture of benzyl N-(2,5-dioxopyrrolidin-3-yl)carbamate (1 g, 4.03 mmol, 1 eq.), Pd/C (8.57 g, 8.06 mmol, 10% purity, 2 eq.) in MeOH (10 mL) was degassed and the mixture was degassed and refilled with H ₂ twice. The reaction mixture was stirred at 25 °C on 15 psi with H ₂ for 24hr. LC-MS showed one main peak with desired mass was detected. The reaction mixture or solution was concentrated to dryness. The crude product 3-aminopyrrolidine-2,5- dione (300 mg, 2.63 mmol, 65.27% yield) as yellow liquid was used into the next step without further purification. LC-MS (ESI ⁺ ) m/z: 115.2 (M+H) ⁺ . Step 3: To a solution of 3-aminopyrrolidine-2,5-dione (50 mg, 438.20 ^mol, 1 eq.) and tert-butyl 4-(3-(bromomethyl)-4-(methoxycarbonyl)phenyl)piperazine-1-ca rboxylate (181.11 mg, 438.20 ^mol, 1 eq.) in CH3CN (3 mL) was added DIPEA (283.17 mg, 2.19 mmol, 381.63 ^L, 5 eq.). The mixture was stirred at 80 °C for 3hr. LC-MS showed one peak with desired mass was detected. The reaction mixture or solution was concentrated to dryness. The residue was purified by prep-HPLC (Column Boston Green ODS 150*30mm*5^m; Condition water(FA)- CAN; Begin B 33, End B 63, Gradient Time(min) 12, 100%B Hold Time(min) 2, FlowRate(ml/min) 25, Injections 6, HPLC 90). tert-butyl 4-(2-(2,5-dioxopyrrolidin-3-yl)-1- oxoisoindolin-5-yl)piperazine-1-carboxylate (12 mg, 28.95 ^mol, 6.61% yield) was obtained as a white solid. LC-MS (ESI ⁺ ) m/z: 415.3 (M+H) ⁺ . Step 4: To a solution of tert-butyl 4-(2-(2,5-dioxopyrrolidin-3-yl)-1-oxoisoindolin-5- yl)piperazine-1-carboxylate (12 mg, 28.95 ^mol, 1 eq) in DCM (5 mL) was added HCl/EA (72.38 ^L, 289.54 ^mol, 10 eq). The reaction was stirred at 20°C for 1hr. LC-MS showed the desired mass was found. The mixture was used for the next step directly. The crude product is about 9 mg. LC-MS (ESI ⁺ ) m/z: 315.2 (M+H) ⁺ . Step 5: To a solution of 3-(1-oxo-5-(piperazin-1-yl)isoindolin-2-yl)pyrrolidine-2,5-d ione (9 mg, 28.63 ^mol, 1 eq) in DCM (3 mL) and MeOH (5 mL) was added 1-(4-((1R,2S)-6-hydroxy-2- h l 1234 t t h d hth l 1 l) h l) i idi 4 b ld h d (4713 11453 ^mol, 4 eq) and Na(OAc)3BH (72.82 mg, 343.58 ^mol, 12 eq). The reaction was stirred at 20°C for 6hr. LC-MS showed the desired ms was found. The mixture was purified by Prep-HPLC (Boston Green ODS 150*30mm*5um; Condition: water(HCl)-ACN, Begin B 20, End B 40; Gradient Time(min): 10.5; 100% B Hold Time(min): 1.5; Flow Rate (ml/min): 25) to give 3-(5- (4-((1-(4-((1R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaph thalen-1-yl)phenyl)piperidin-4- yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)pyrrolidine-2 ,5-dione (4 mg, 5.63 ^mol, 19.68% yield, 100% purity) as a white solid. LC-MS (ESI ⁺ ) m/z: 710.3 (M+H) ⁺ . LCMS: calc. for C ₄₄ H ₄₇ N ₅ O ₄ : 709.89, found: [M+H] ⁺ 710.3. HPLC: 100% purity at 220 nm. NMR: ¹ H NMR (400 MHz, DMSO-d ₆ ) į = 11.54 - 11.47 (m, 1H), 9.32 - 9.05 (m, 1H), 7.58 (d, J = 8.3 Hz, 1H), 7.20 - 7.10 (m, 6H), 6.84 (br d, J = 6.6 Hz, 2H), 6.72 - 6.59 (m, 3H), 6.55 - 6.42 (m, 2H), 6.40 - 6.08 (m, 2H), 5.19 (dd, J = 6.7, 8.9 Hz, 1H), 4.53 (d, J = 17.2 Hz, 1H), 4.27 (d, J = 17.3 Hz, 1H), 4.00 (br d, J = 13.4 Hz, 2H), 3.64 - 3.52 (m, 6H), 3.37 - 3.25 (m, 4H), 3.18 - 3.09 (m, 4H), 3.01 - 2.89 (m, 4H), 2.14 - 1.89 (m, 5H), 1.79 - 1.66 (m, 2H). EXAMPLE 159. Preparation of (I-340) (3S)-3-[5-[4-[[1-[4-[(1R,2S)-6-hydroxy-2- (2,3,4,5,6-pentadeuteriophenyl)tetralin-1-yl]phenyl]-4-piper idyl]methyl]piperazin-1-yl]-1- oxo-isoindolin-2-yl]piperidine-2,6-dione Step 1: To a solution of (1R,2S)-1-[4-[4-(dimethoxymethyl)-1-piperidyl]phenyl]-2-(2,3 ,4,5,6- pentadeuteriophenyl)tetralin-6-ol (100 mg, 216.15 ^mol, 1 eq) in 10% H ₂ SO ₄ (2 mL) and THF (2 mL) .The mixture was stirred at 70 °C for 2 hr . The mixture was alkalied with NaHCO ₃ to pH=7-8. The reaction mixture was diluted with 50 mL H2O and extracted with ethyl acetate (50 ^{mL * 2). The combined organic layers were washed with 50 mL brine, dried over Na} _2SO4, filtered and concentrated under reduced pressure to give a residue. The crude product 1-[4- [(1R,2S)-6-hydroxy-2-(2,3,4,5,6-pentadeuteriophenyl)tetralin -1-yl]phenyl]piperidine-4- carbaldehyde (87 mg, 208.85 ^mol, 96.62% yield) as yellow oil was used into the next step without further purification. LC-MS (ESI ⁺ ) m/z: 417.3 (M+H) ⁺ . Step 2: A mixture of 1-[4-[(1R,2S)-6-hydroxy-2-(2,3,4,5,6-pentadeuteriophenyl)tet ralin-1- yl]phenyl]piperidine-4-carbaldehyde (87 mg, 208.9 ^mol, 1 eq), (S)-3-(1-oxo-5-(piperazin-1- yl)isoindolin-2-yl)piperidine-2,6-dione benzenesulfonate (152.4 mg, 313.3 ^mol, 1.5 eq) and sodium acetate (51.4 mg, 626.6 ^mol, 3 eq) and acetic acid (25.1 mg, 417.7 ^mol, 23.9 ^L, 2 eq) in MeOH (2 mL) and DCM (2 mL) at 30 °C for 1 hour, then NaBH(OAc) ₃ (88.53 mg, 417.70 ^mol, 2 eq) was added to the mixture and was stirred at 30 °C for 16 hr. The reaction mixture was quenched by addition 20 mL H ₂ O at 25 °C, and then diluted with 20 mL ethyl acetate and extracted with ethyl acetate (20 mL * 3). The combined organic layers were washed with brine 20 mL, dried over drying Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Welch Xtimate C18150*30mm*5um;mobile phase: [water(FA)-ACN];gradient:15%-55% B over 9 min). Compound (3S)-3-[5-[4-[[1-[4-[(1R,2S)-6-hydroxy-2-(2,3,4,5,6-pentadeu teriophenyl)tetralin-1- yl]phenyl]-4-piperidyl]methyl]piperazin-1-yl]-1-oxo-isoindol in-2-yl]piperidine-2,6-dione (56.4 mg, 77.4 ^mol, 37.% yield, 100% purity) was obtained as a white solid. LC-MS (ESI ⁺ ) m/z: 729.4 (M+H) ⁺ HPLC: 95.902% purity at 220 nm. ), , 2.83 - 2.74 (m, 2H), 2.58 (br s, 3H), 2.51 (br d, J = 1.5 Hz, 2H), 2.30 - 2.22 (m, 4H),2.15 - 2.10 (m, 3H), 1.78 (br d, J = 13.4 Hz, 2H), 1.28 (br d, J = 11.8 Hz, 2H). SFC: retention time, 2.728 min; Area, 94.252%; EXAMPLE 160. Preparation of (I-341) (3S)-3-[5-[4-[[1-[4-[(1S,2R)-6-hydroxy-2- (2,3,4,5,6-pentadeuteriophenyl)tetralin-1-yl]phenyl]-4-piper idyl]methyl]piperazin-1-yl]-1- oxo-isoindolin-2-yl]piperidine-2,6-dione Step 1: A mixture of 1-(4-(6-(benzyloxy)-2-bromo-3,4-dihydronaphthalen-1-yl)pheny l)-4- (dimethoxymethyl)piperidine (400 mg, 729.2 ^mol, 1 eq) , (2,3,4,5,6- pentadeuteriophenyl)boronic acid (111.1 mg, 875.1 ^mol, 1.2 eq), Pd-118 (47.5 mg, 72.9 ^mol, 0.1 eq) , Na ₂ CO ₃ (231.9 mg, 2.19 mmol, 3 eq) in dioxane (2 mL) and H ₂ O (0.5 mL) was degassed and purged with N ₂ for 3 times, and then the mixture was stirred at 50 °C for 16 hr under N ₂ atmosphere. The reaction mixture was quenched by addition 50 mL H ₂ O at 20 °C, and then diluted with 50 mL ethyl acetate and extracted with ethyl acetate (50 mL* 3). The combined organic layers were washed with brine 50 mL, dried over drying Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 0~15% Ethyl acetate/Petroleum ethergradient @ 20 mL/min). Compound 1-[4-[6-benzyloxy-2- (dimethoxymethyl)piperidine (330 mg, 599.2 ^mol, 82.17% yield) was obtained as a yellow solid. LC-MS (ESI ⁺ ) m/z: 551.2 (M+H) ⁺ . Step 2: To a solution of 1-[4-[6-benzyloxy-2-(2,3,4,5,6-pentadeuteriophenyl)-3,4- dihydronaphthalen-1-yl]phenyl]-4-(dimethoxymethyl)piperidine (330 mg, 599.19 ^mol, 1 eq) in THF (3 mL) and MeOH (3 mL) was added Pd/C (10% wt, 330 mg) under N ₂ atmosphere. The suspension was degassed and purged with H ₂ for 3 times. The mixture was stirred under H ₂ (15 psi) at 30 °C for 16 hr . The reaction mixture was filtered and the filter was concentrated. The residue was purified by SFC (column: DAICEL CHIRALCEL OJ(250mm*30mm,10um);mobile phase: [CO2-EtOH(0.1%NH3H2O)];B%:40%%, isocratic elution mode) Rt=3.532 /4.309 min. Compound (1R,2S)-1-[4-[4-(dimethoxymethyl)-1- piperidyl]phenyl]-2-(2,3,4,5,6-pentadeuteriophenyl)tetralin- 6-ol (103 mg, 211.00 ^mol, 35.21% yield, 94.774% purity) and (1S,2R)-1-[4-[4-(dimethoxymethyl)-1-piperidyl]phenyl]-2-(2,3 ,4,5,6- pentadeuteriophenyl)tetralin-6-ol (100 mg, 207.60 ^mol, 34.65% yield, 96.041% purity) were obtained as yellow oil. LC-MS (ESI ⁺ ) m/z: 463.3 (M+H) ⁺ SFC of (5S,6R)-5-(4-(4-(dimethoxymethyl)piperidin-1-yl)phenyl)-6-(p henyl-d5)-5,6,7,8- tetrahydronaphthalen-2-ol: retention time, 3.524 min; Area, 100%; SFC of (5R,6S)-5-(4-(4-(dimethoxymethyl)piperidin-1-yl)phenyl)-6-(p henyl-d5)-5,6,7,8- tetrahydronaphthalen-2-ol: retention time, 4.290 min; Area, 99.80%; Step 3: To a solution of (1S,2R)-1-[4-[4-(dimethoxymethyl)-1-piperidyl]phenyl]-2-(2,3 ,4,5,6- pentadeuteriophenyl)tetralin-6-ol (103 mg, 222.64 ^mol, 1 eq) in H ₂ SO ₄ (2 mL) and THF (2 mL) .The mixture was stirred at 70 °C for 2 hr . The mixture was alkalied with NaHCO ₃ to pH=7~8.The reaction mixture was diluted with 50 mL H ₂ O and extracted with ethyl acetate (50 mL * 2). The combined organic layers were washed with 50 mL brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The crude product 1- [4-[(1S,2R)-6-hydroxy-2-(2,3,4,5,6-pentadeuteriophenyl)tetra lin-1-yl]phenyl]piperidine-4- carbaldehyde (88 mg, 211.25 ^mol, 94.89% yield) as yellow oil was used into the next step LC-MS (ESI ⁺ ) m/z: 417.3 (M+H) ⁺ . Step 4: A mixture of 1-[4-[(1S,2R)-6-hydroxy-2-(2,3,4,5,6-pentadeuteriophenyl)tet ralin-1- yl]phenyl]piperidine-4-carbaldehyde (88 mg, 211.2 ^mol, 1 eq), (S)-3-(1-oxo-5-(piperazin-1- yl)isoindolin-2-yl)piperidine-2,6-dione benzenesulfonate (154.2 mg, 316.9 ^mol, 1.5 eq) and sodium acetate (52 mg, 633.8 ^mol, 3 eq) and acetic acid (25.4 mg, 422.5 ^mol, 24.2 ^L, 2 eq) in MeOH (2 mL) and DCM (2 mL) at 30 °C for 1 hour, then NaBH(OAc) ₃ (89.6 mg, 422.5 ^mol, 2 eq) was added to the mixture and was stirred at 30 °C for 16 hr . The reaction mixture was quenched by addition 20 mL H ₂ O at 25 °C, and then diluted with 20 mL ethyl acetate and extracted with ethyl acetate (20 mL * 3). The combined organic layers were washed with 20 mL brine, dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Welch Xtimate C18150*30mm*5um; mobile phase: [water(FA)-ACN];gradient:15%-55% B over 9 min). Compound (3S)-3-[5-[4-[[1- [4-[(1S,2R)-6-hydroxy-2-(2,3,4,5,6-pentadeuteriophenyl)tetra lin-1-yl]phenyl]-4- piperidyl]methyl]piperazin-1-yl]-1-oxo-isoindolin-2-yl]piper idine-2,6-dione (61 mg, 83.13 ^mol, 39.35% yield, 99.343% purity) was obtained as a white solid. LC-MS (ESI ⁺ ) m/z: 729.4 (M+H) ⁺ HPLC: 96.695% purity at 220 nm. ¹ H NMR (400 MHz, DMSO-d ₆ ) į = 8.08 (s, 0.185H), 7.91 (s, 1H), 7.67 (d, J = 8.6 Hz, 1H), 6.94 - 6.90 (m, 1H), 6.80 (s, 1H), 6.75 (d, J = 8.5 Hz,1H), 6.63 (d, J = 2.5 Hz, 1H), 6.53 - 6.49 (m, 3H), 6.21 (d, J = 8.6 Hz, 2H), 5.13 (dd, J = 5.1, 13.2 Hz, 1H), 4.37 - 4.31 (m, 1H), 4.21 - 4.16 (m, 1H), 4.13(d, J = 4.8 Hz, 1H), 3.52 - 3.46 (m, 2H), 3.27 (br d, J = 5.2 Hz, 6H), 2.97 (br d, J = 4.2 Hz, 2H), 2.84 - 2.74 (m, 2H), 2.56 (br s, 3H), 2.51 (br s, 2H), 2.25(br d, J = 7.3 Hz, 4H), 2.15 - 2.10 (m, 3H), 1.78 (br d, J = 13.6 Hz, 2H), 1.27 (br d, J = 12.5 Hz, 2H) SFC: retention time, 2.719 min; Area, 93.987%.

EXAMPLE 161. Preparation of (I-174) (S)-3-(5-(4-((1-(4-((1R,2S,3S)-6-hydroxy-3- methyl-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)pip eridin-4- yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2, 6-dione Step 1: To a solution of 4-(dimethoxymethyl)-1-(4-((1R,2S,3S)-6-methoxy-3-methyl-2-ph enyl- 1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperidine (100 mg, 100% Wt, 1 Eq, 206 ^mol) in DCM (2 mL) at 0 °C was added tribromoborane (155 mg, 618 ^L, 1 molar, 3 Eq, 618 ^mol) with N ₂ . After addition, the mixture was stirred at 0 °C for 4 hour and then the reaction was warmed to 25 °C and was stirred at this temperature for 12 hour. The reaction mixture was quenched with saturated NaHCO ₃ 10 mL and stirred for 10 min at 0°C. Then the mixture was dissolved in water (30 mL) and extracted by ethyl acetate (40 mL). The combined organic layer was dried over Na ₂ SO ₄ , filtered and concentrated under vaccum to give 1-(4-((1R,2S,3S)-6-hydroxy-3-methyl- 2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperidine -4-carbaldehyde (85 mg, 0.20 mmol, 97 %) as a yellow solid. LC-MS (ESI+) m/z: 426.2 (M+H) ⁺ . Step 2: A mixture of 1-(4-((1R,2S,3S)-6-hydroxy-3-methyl-2-phenyl-1,2,3,4- tetrahydronaphthalen-1-yl)phenyl)piperidine-4-carbaldehyde (85 mg, 1 Eq, 0.20 mmol), (S)-3- (1-oxo-5-(piperazin-1-yl)isoindolin-2-yl)piperidine-2,6-dion e benzenesulfonate (0.13 g, 1.3 Eq, 0.26 mmol) and sodium acetate (82 mg, 5 Eq, 1.0 mmol) and acetic acid (36 mg, 34 ^L, 3 Eq, 0.60 mmol) in DCM (2 mL) and MeOH (2 mL) at 25 °C for 1 hour, then sodium triacetoxyborohydride (85 mg, 2 Eq, 0.40 mmol) was added to the mixture and was stirred at 25 rC for 16 hour. The reaction was treated with H ₂ O (50 mL), extracted with EtOAc (50 mL). The combined extracts was dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to dryness in vacuo to give a residue. The residue was purified by prep.HPLC (column: Welch Xtimate C18 150*30 mm*3 um mobile phase: [water (FA)-ACN]; B%: 21%-51%, 7 min). The aqueous phase was lyophilized to dryness to give (S)-3-(5-(4-((1-(4-((1R,2S,3S)-6-hydroxy-3-methyl-2-phenyl- 1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperidin-4-yl)meth yl)piperazin-1-yl)-1-oxoisoindolin- 2-yl)piperidine-2,6-dione (60 mg, 81 ^mol, 41 %, 99.509% Purity) as a white solid. LC-MS (ESI+) m/z: 738.3 (M+H) ⁺ . HPLC: 99.509%, purity at 220 nm. SFC: retention time, 2.561 min; Area, 91.502%; NMR (400 MHz, DMSO-d ₆ ) į = 10.96 (s, 1H), 9.24 - 9.09 (m, 1H), 8.14 (s, 0.368H), 7.52 (d, J = 8.7 Hz, 1H), 7.12 - 7.02 (m, 5H), 6.90 - 6.73 (m, 4H), 6.66 - 6.56 (m, 4H), 6.49 (dd, J = 2.4, 8.4 Hz, 1H), 5.05 (dd, J = 5.1, 13.2 Hz, 1H), 4.45 (br d, J = 5.0 Hz, 1H), 4.38 - 4.27 (m, 1H), 4.25 - 4.16 (m, 1H), 3.61 - 3.44 (m, 3H), 3.28 (br s, 5H), 3.11 (br d, J = 4.5 Hz, 1H), 2.98 - 2.83 (m, 1H), 2.71 (br d, J = 12.4 Hz, 1H), 2.63 - 2.51 (m, 4H), 2.42 (br d, J = 3.0 Hz, 3H), 2.40 - 2.28 (m, 1H), 2.20 (br d, J = 6.9 Hz, 2H), 2.01 - 1.91 (m, 1H), 1.76 (br d, J = 11.6 Hz, 2H), 1.69 - 1.57 (m, 1H), 1.25 - 1.08 (m, 2H), 0.72 (br d, J = 6.1 Hz, 3H). EXAMPLE 162. Preparation of (I-334) (S)-3-(5-(4-((1-(4-((1S,2R,3S)-6-hydroxy-3- methyl-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)pip eridin-4- yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2, 6-dione Step 1: To a solution of 4-(dimethoxymethyl)-1-[4-[(3S)-6-methoxy-3-methyl-2-phenyl-3 ,4- dihydronaphthalen-1-yl]phenyl]piperidine (520 mg, 1.08 mmol, 1 eq) in THF (10 mL) and MeOH (10 mL) was added Pd/C (10%, 500 mg) under N ₂ atmosphere. The suspension was degassed and purged with H ₂ for 3 times. The mixture was stirred under H ₂ (15 Psi) at 30 °C for 16 hr. The reaction mixture was filtered and the filter was concentrated. to give 4- (dimethoxymethyl)-1-[4-[(3S)-6-methoxy-3-methyl-2-phenyl-tet ralin-1-yl]phenyl]piperidine (490 mg, 1.01 mmol, 93.84% yield) as a white solid. LC-MS (ESI ⁺ ) m/z: 486.2 (M+H) ⁺ . Step 2: The white solid was subjected by SFC: Column: DAICEL CHIRALPAK AD (250 mm *30 mm, 10 um); Mobile phase: A: Supercritical CO ₂ , B: MeOH (0.1% NH3 H2O), A:B = 35:35 at 80 mL/min. The pure fractions were collected respectively and the solvents were evaporated under vacuum to give the product 4-(dimethoxymethyl)-1-(4-((1R,2S,3S)-6-methoxy-3-methyl- 2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperidine (250 mg, 515 ^mol, 75.8 %, 100% Purity) and 4-(dimethoxymethyl)-1-(4-((1S,2R,3S)-6-methoxy-3-methyl-2-ph enyl-1,2,3,4- tetrahydronaphthalen-1-yl)phenyl)piperidine (30 mg, 60 ^mol, 8.9 %, 97.504% purity) as a white solid. LC-MS (ESI ⁺ ) m/z: 486.2 (M+H) ⁺ . Step 3: To a solution of 4-(dimethoxymethyl)-1-(4-((1S,2R,3S)-6-methoxy-3-methyl-2-ph enyl- 1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperidine (30 mg, 1 Eq, 60 ^mol) in DCM (2 mL) at 0 °C was added tribromoborane (45 mg, 0.18 mL, 1 molar, 3 Eq, 0.18 mmol) with N ₂ . After addition, the mixture was stirred at 0 °C for 4 hour and then the reaction was warmed to 25 °C and was stirred at this temperature for 12 hour. The reaction mixture was quenched with saturated NaHCO ₃ (10 mL) and stirred for 10 min at 0°C. Then the mixture was dissolved in water (30 mL) and extracted by ethyl acetate (40 mL). The combined organic layer was dried over Na ₂ SO ₄ , filtered and concentrated under vaccum to give 1-(4-((1S,2R,3S)-6-hydroxy-3- methyl-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)pip eridine-4-carbaldehyde (25 mg, 59 ^mol, 98 %) as a yellow solid. LC-MS (ESI+) m/z: 426.2 (M+H) ⁺ . Step 4: A mixture of 1-(4-((1S,2R,3S)-6-hydroxy-3-methyl-2-phenyl-1,2,3,4- tetrahydronaphthalen-1-yl)phenyl)piperidine-4-carbaldehyde (25 mg, 1 Eq, 59 ^mol), (S)-3-(1- oxo-5-(piperazin-1-yl)isoindolin-2-yl)piperidine-2,6-dione benzenesulfonate (37 mg, 1.3 Eq, 76 ^mol) and sodium acetate (24 mg, 5 Eq, 0.29 mmol) and acetic acid (11 mg, 10 ^L, 3 Eq, 0.18 mmol) in DCM (2 mL) and MeOH (2 mL) at 25 °C for 1 hour, then sodium 25 °C for 16 hour. The reaction was treated with H2O (50 mL), extracted with EtOAc (50 mL). The combined extracts was dried over anhydrous Na2SO4, filtered and concentrated to dryness in vacuo to give a residue. The residue was purified by prep.HPLC (column: Welch Xtimate C18 150*30 mm*3 um mobile phase: [water (FA)-ACN]; B%: 22%-52%, 7 min). The aqueous phase was lyophilized to dryness to give (S)-3-(5-(4-((1-(4-((1S,2R,3S)-6-hydroxy-3-methyl-2-phenyl- 1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperidin-4-yl)meth yl)piperazin-1-yl)-1-oxoisoindolin- 2-yl)piperidine-2,6-dione (5.9 mg, 8.0 ^mol, 14 %, 99.983% Purity) as a pink solid. LC-MS (ESI+) m/z: 738.3 (M+H)+ HPLC: 99.983%, purity at 220 nm. SFC: retention time, 3.165 min; Area, 93.965%; ¹ H NMR (400 MHz, DMSO-d ₆ ) į = 10.96 (s, 1H), 9.11 (br s, 1H), 8.17 (s, 0.182H), 7.51 (d, J = 8.5 Hz, 1H), 7.15 - 6.97 (m, 5H), 6.70 - 6.52 (m, 6H), 6.45 (dd, J = 2.1, 8.2 Hz, 1H), 6.23 (br d, J = 8.6 Hz, 2H), 5.05 (dd, J = 5.1, 13.2 Hz, 1H), 4.37 - 4.28 (m, 1H), 4.25 - 4.15 (m, 1H), 3.95 (d, J = 5.0 Hz, 1H), 3.60 - 3.48 (m, 2H), 3.28 (br s, 6H), 3.08 (br dd, J = 5.4, 17.4 Hz, 1H), 3.00 - 2.84 (m, 2H), 2.64 - 2.51 (m, 6H), 2.43 - 2.30 (m, 2H), 2.20 (br d, J = 7.0 Hz, 2H), 2.02 - 1.90 (m, 1H), 1.76 (br d, J = 11.9 Hz, 2H), 1.65 (br d, J = 3.3 Hz, 1H), 1.27 - 1.10 (m, 2H), 0.73 (d, J = 6.2 Hz, 3H). EXAMPLE 163. Preparation of (I-175) (S)-3-(5-(4-((1-(4-((1R,2S,3R)-6-hydroxy-3- methyl-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)pip eridin-4- yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2, 6-dione Step 1: To a solution of 4-(dimethoxymethyl)-1-(4-((1R,2S,3R)-6-methoxy-3-methyl-2-ph enyl- 1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperidine (35 mg, 94.264% Wt, 1 Eq, 68 ^mol) in DCM (2 mL) at 0 °C was added tribromoborane (51 mg, 0.20 mL, 1 molar, 3 Eq, 0.20 mmol) with N ₂ . After addition, the mixture was stirred at 0 °C for 4 hour and then the reaction was warmed to 25 °C and was stirred at this temperature for 12 hour. The reaction mixture was quenched with saturated NaHCO ₃ 10 mL and stirred for 10 min at 0°C. Then the mixture was dissolved in water (30 mL) and extracted by ethyl acetate (40 mL). The combined organic layer was dried over Na ₂ SO ₄ , filtered and concentrated under vaccum to give 1-(4-((1R,2S,3R)-6- hydroxy-3-methyl-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl) phenyl)piperidine-4-carbaldehyde (25 mg, 59 ^mol, 86 %) as a yellow solid. LC-MS (ESI+) m/z: 426.2 (M+H) ⁺ . Step 2: A mixture of 1-(4-((1R,2S,3R)-6-hydroxy-3-methyl-2-phenyl-1,2,3,4- tetrahydronaphthalen-1-yl)phenyl)piperidine-4-carbaldehyde (25 mg, 1 Eq, 59 ^mol), (S)-3-(1- oxo-5-(piperazin-1-yl)isoindolin-2-yl)piperidine-2,6-dione benzenesulfonate (37 mg, 1.3 Eq, 76 ^mol) and sodium acetate (24 mg, 5 Eq, 0.29 mmol) and acetic acid (11 mg, 10 ^L, 3 Eq, 0.18 mmol) in DCM (2 mL) and MeOH (2 mL) at 25 °C for 1 hour, then sodium triacetoxyborohydride (25 mg, 2 Eq, 0.12 mmol) was added to the mixture and was stirred at 25 °C for 16 hour. The reaction was treated with H ₂ O (50 mL), extracted with EtOAc (50 mL). The combined extracts was dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to dryness in vacuo to give a residue. The residue was purified by prep.HPLC (column: Welch Xtimate C18 150*30 mm*3 um mobile phase: [water (FA)-ACN]; B%: 20%-50%, 7 min). The aqueous phase was lyophilized to dryness to give (S)-3-(5-(4-((1-(4-((1R,2S,3R)-6-hydroxy-3-methyl-2-phenyl- 1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperidin-4-yl)meth yl)piperazin-1-yl)-1-oxoisoindolin- 2-yl)piperidine-2,6-dione (18.4 mg, 24.8 ^mol, 42 %, 99.513% purity) as a pink solid. LC-MS (ESI+) m/z: 738.3 (M+H) ⁺ HPLC: 99.513%, purity at 220 nm. SFC: retention time, 2.731 min; Area, 94.767%; ¹ H NMR (400 MHz, DMSO-d ₆ ) į = 10.96 (s, 1H), 9.11 (br d, J = 0.7 Hz, 1H), 8.15 (s, 0.608H), 7.52 (d, J = 8.6 Hz, 1H), 7.15 - 7.01 (m, 5H), 6.71 - 6.55 (m, 6H), 6.46 (dd, J = 2.4, 8.2 Hz, 1H), 6.24 (d, J = 8.6 Hz, 2H), 5.05 (dd, J = 4.9, 13.3 Hz, 1H), 4.40 - 4.29 (m, 1H), 4.25 - 4.14 (m, 1H), 3.96 (d, J = 4.9 Hz, 1H), 3.63 - 3.45 (m, 3H), 3.32 - 3.20 (m, 8H), 3.09 (br dd, J = 5.4, 17.5 Hz 1H) 300 - 285 (m 2H) 270 - 254 (m 3H) 242 - 229 (m 2H) 226 - 217 (m2H) 204 - 1.90 (m, 1H), 1.77 (br d, J = 11.8 Hz, 2H), 1.71 - 1.60 (m, 1H), 1.26 - 1.09 (m, 2H), 0.74 (d, J = 6.2 Hz, 3H).

EXAMPLE 164. Preparation of (I-333) (S)-3-(5-(4-((1-(4-((1S,2R,3R)-6-hydroxy-3- methyl-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)pip eridin-4- yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2, 6-dione Step 1: To a solution of NaH (3.65 g, 91.35 mmol, 60% purity, 1.5 eq) in THF (300 mL) degassed and purged with N2 for 3 times then the mixture was added ethyl 2- (diethoxyphosphoryl)acetate (16.38 g, 73.08 mmol, 14.50 mL, 1.2 eq) stirred at 0°C for 0.5 h under N ₂ atmosphere. Then the 1-(3-methoxyphenyl)propan-2-one (10 g, 60.90 mmol, 1 eq) was added to the mixture. The mixture was stirred at 0~75 °C for 13 hr under N ₂ atmosphere. Then the mixture was cooled to room temperature. The reaction was quenched with H ₂ O (200 mL) under N ₂ at ice bath, the mixture was extracted with EtOAc (300 mL). The combined extracts was dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to dryness in vacuo to give a yellow oil. The yellow oil was purified by flash column (petroleum ether/ethyl acetate from 100/0 to 85/15) and the organic layer was concentrated in vacuo to give ethyl (E)-4-(3-methoxyphenyl)-3- methylbut-2-enoate (9.35 g, 37.11 mmol, 60.94% yield, 93% purity) as a colorless oil. LC-MS (ESI ⁺ ) m/z: 235.2 (M+H) ⁺ . Step 2: To a solution of ethyl (E)-4-(3-methoxyphenyl)-3-methyl-but-2-enoate (9.35 g, 37.11 mmol, 1 eq) in MeOH (100 mL) was added Pd/C (10%, 8.7 g) under N ₂ atmosphere. The suspension was degassed and purged with H2 for 3 times. The mixture was stirred under H2 (15 Psi) at 25 °C for 16 hr. The reaction mixture was filtered and the filter was concentrated. The crude product ethyl 4-(3-methoxyphenyl)-3-methylbutanoate (8.5 g, 35.97 mmol, 96.92% yield) as a colorless oil was used into the next step without further purification. Step 3: To a solution of ethyl 4-(3-methoxyphenyl)-3-methyl-butanoate (8.5 g, 35.97 mmol, 1 eq) in MeOH (25 mL) and THF (25 mL) was added NaOH (3 M, 47.96 mL, 4 eq) .The mixture was stirred at 20 °C for 1 hr. The mixture was acidified with HCl (1M) to PH=5~6. To the mixture was added water (100 mL), then was extracted with ethyl acetate 100 mL (50 mL* 2). The combined organic layers were washed with brine (50 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give the crude product 4-(3-methoxyphenyl)-3- methylbutanoic acid (7.4 g, 35.53 mmol, 98.79% yield) as colorless oil was used into the next step without further purification. Step 4: To a solution of 4-(3-methoxyphenyl)-3-methyl-butanoic acid (7.4 g, 35.53 mmol, 1 eq) in DCM (100 mL) was added (2,2,2-trifluoroacetyl) 2,2,2-trifluoroacetate (37.32 g, 177.67 mmol, 24.70 mL, 5 eq) at 0°C under N2 atmosphere, and then the mixture was stirred at 0~20 °C for 16 hr. The reaction mixture was partitioned between H2O 100 mL and DCM 100 mL. The filtered and concentrated under reduced pressure to give a residue. The residue was subjected to column chromatography over silica gel (gradient elution:0~15% ethyl acetate in petroleum ether). The pure fractions were collected and concentrated to dryness in vacuo to give 6- methoxy-3-methyl-3,4-dihydronaphthalen-1(2H)-one (3.7 g, 18.67 mmol, 52.55% yield, 96% purity) as a yellow oil. LC-MS (ESI ⁺ ) m/z: 190.8 (M+H) ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) į = 8.03 (d, J = 8.8 Hz, 1H), 6.85 (dd, J = 2.3, 8.8 Hz, 1H), 6.73 (s, 1H), 3.89 (s, 3H), 2.99 - 2.93 (m, 1H), 2.85 - 2.63 (m, 2H), 2.42 - 2.30 (m, 2H), 1.15 (d, J = 6.0 Hz, 3H). Step 5: To a solution of 1-(4-bromophenyl)-4-(dimethoxymethyl)piperidine (5.95 g, 18.92 mmol, 1.8 eq) in THF (70 mL) was added dropwise n-BuLi (2.5 M, 6.73 mL, 1.6 eq) at -78 °C for 1h and then 6-methoxy-3-methyl-tetralin-1-one (2 g, 10.51 mmol, 1 eq) in THF (70 mL) was added dropwise at -78 °C. The resulting mixture was stirred at -78~25 °C for 16h. The reaction mixture was quenched by addition 200 mL H ₂ O at 25 °C and then extracted with ethyl acetate (100 mL * 3). The combined organic layers were washed with brine 100 mL, dried over drying Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was subjected to column chromatography over silica gel (gradient elution:0~25% ethyl acetate in petroleum ether). The pure fractions were collected and concentrated to dryness in vacuo to give 1-(4-(4-(dimethoxymethyl)piperidin-1-yl)phenyl)-6-methoxy-3- methyl-1,2,3,4- tetrahydronaphthalen-1-ol (2.3 g, 5.40 mmol, 51.41% yield) as a yellow oil. LC-MS (ESI ⁺ ) m/z: 426.3 (M+H) ⁺ . Step 6: To a solution of 1-[4-[4-(dimethoxymethyl)-1-piperidyl]phenyl]-6-methoxy-3-me thyl- tetralin-1-ol (2 g, 4.70 mmol, 1 eq) in HCl/MeOH (20 mL).The mixture was stirred at 30 °C for 1 hr. The mixture was adjusted with NaHCO ₃ to pH=7~8. The reaction mixture was diluted with 50 mL H ₂ O and extracted with ethyl acetate (50 mL * 2). The combined organic layers were washed with brine 50 mL, dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was subjected to column chromatography over silica gel (gradient elution:0~15% ethyl acetate in petroleum ether). The pure fractions were collected and concentrated to dryness in vacuo to give 4-(dimethoxymethyl)-1-[4-(6-methoxy-3-methyl-3,4- dihydronaphthalen-1-yl)phenyl]piperidine (1.8 g, 4.42 mmol, 93.98% yield) as a yellow solid. LC-MS (ESI ⁺ ) m/z: 408.3 (M+H) ⁺ . Step 7: A mixture of 4-(dimethoxymethyl)-1-[4-(6-methoxy-3-methyl-3,4-dihydronaph thalen-1- yl)phenyl]piperidine (1.8 g, 4.42 mmol, 1 eq), BLAH;pyridin-1-ium (1.41 g, 4.42 mmol, 1 eq), TEA (670.38 mg, 6.63 mmol, 922.12 ^L, 1.5 eq) in DCM (30 mL) was degassed and purged with N ₂ for 3 times and then the mixture was stirred at 0 °C for 1 hr under N ₂ atmosphere. The reaction mixture was quenched by addition 100 mL H ₂ O at 25 °C and then extracted with ethyl acetate (100 mL * 3). The combined organic layers were washed with 100 mL brine, dried over drying Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was subjected to column chromatography over silica gel (gradient elution:0~20% ethyl acetate in petroleum ether). The pure fractions were collected and concentrated to dryness in vacuo to give 1-[4-(2-bromo-6-methoxy-3-methyl-3,4-dihydronaphthalen-1-yl) phenyl]-4- (dimethoxymethyl)piperidine (1.7 g, 3.49 mmol, 79.13% yield) as a yellow oil. LC-MS (ESI ⁺ ) m/z: 488.2 (M+H) ⁺ . Step 8: A mixture of 1-[4-(2-bromo-6-methoxy-3-methyl-3,4-dihydronaphthalen-1-yl) phenyl]-4- (dimethoxymethyl)piperidine (1.7 g, 3.49 mmol, 1 eq), phenylboronic acid (511.34 mg, 4.19 mmol, 1.2 eq), disodium;carbonate (1.11 g, 10.48 mmol, 3 eq), cyclopentyl(diphenyl)phosphane;dichloromethane;dichloropalla dium;iron (285.40 mg, 349.48 ^mol, 0.1 eq) in dioxane (20 mL) and H ₂ O (5 mL) was degassed and purged with N ₂ for 3 times and then the mixture was stirred at 80 °C for 16 hr under N ₂ atmosphere. The reaction mixture was diluted with H ₂ O 100 mL and extracted with ethyl acetate (100 mL * 2). The combined organic layers were washed with brine 100 mL, dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® Silica Flash Column, Eluent of 0~20% Ethyl acetate/Petroleum ethergradient @ 40 mL/min) to give desired compound (1.2 g, yield 68.53%, purity 93.6 %) as a yellow gum, which was further separated by SFC (column: DAICEL CHIRALPAK AD (250mm*30mm,10um); mobile phase: [CO ₂ -EtOH(0.1% NH ₃ H ₂ O)]; B%:25%, isocratic elution mode). RT= 4.869 /5.243 min. The pure fractions were collected and concentrated to dryness in vacuo to give 4-(dimethoxymethyl)-1-[4-[(3R)-6-methoxy-3-methyl- 2-phenyl-3,4-dihydronaphthalen-1-yl]phenyl]piperidine (490 mg, 1.01 mmol, 28.79% yield, 99304% purity) and 4-(dimethoxymethyl)-1-[4-[(3S)-6-methoxy-3-methyl-2-phenyl-3 4- dihydronaphthalen-1-yl]phenyl]piperidine (520 mg, 1.04 mmol, 29.70% yield, 96.528% purity) were obtained as white solid. LC-MS (ESI ⁺ ) m/z: 484.2 (M+H) ⁺ . Step 9: To a solution of 4-(dimethoxymethyl)-1-[4-[(3R)-6-methoxy-3-methyl-2-phenyl-3 ,4- dihydronaphthalen-1-yl]phenyl]piperidine (490 mg, 1.01 mmol, 1 eq) in THF (10 mL) and MeOH (10 mL) was added Pd/C (10 %, 500 mg) under N ₂ atmosphere. The suspension was degassed and purged with H ₂ for 3 times. The mixture was stirred under H ₂ (15 Psi) at 30 °C for 16 hr. The reaction mixture was filtered and the filter was concentrated. to give 4- (dimethoxymethyl)-1-[4-[(3R)-6-methoxy-3-methyl-2-phenyl-tet ralin-1-yl]phenyl]piperidine (480 mg, 988.36 ^mol, 97.55% yield) as a white solid. LC-MS (ESI ⁺ ) m/z: 486.2 (M+H) ⁺ . Step 10: The white solid was subjected by SFC: Column: DAICEL CHIRALPAK OJ (250 mm *30 mm, 10 um); Mobile phase: A: Supercritical CO ₂ , B: MeOH (0.1% NH3 H2O), A:B = 35:35 at 80 mL/min. The pure fractions were collected respectively and the solvents were evaporated under vacuum to give the product 4-(dimethoxymethyl)-1-(4-((1S,2R,3R)-6-methoxy-3-methyl- 2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperidine (250 mg, 506 ^mol, 70.3 %, 98.394% Purity) and 4-(dimethoxymethyl)-1-(4-((1R,2S,3R)-6-methoxy-3-methyl-2-ph enyl- 1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperidine (35 mg, 68 ^mol, 9.4 %, 94.264% Purity) as a white solid. LC-MS (ESI ⁺ ) m/z: 486.2 (M+H) ⁺ . Step 11: To a solution of 4-(dimethoxymethyl)-1-(4-((1S,2R,3R)-6-methoxy-3-methyl-2-ph enyl- 1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperidine (100 mg, 1 Eq, 203 ^mol) in DCM (2 mL) at 0 °C was added tribromoborane (152 mg, 608 ^L, 1 molar, 3 Eq, 608 ^mol) with N ₂ . After addition, the mixture was stirred at 0 °C for 4 hour and then the reaction was warmed to 25 °C and was stirred at this temperature for 12 hour. The reaction mixture was quenched with saturated 10 mL NaHCO ₃ and stirred for 10 min at 0°C. Then the mixture was dissolved in water (30 mL) and extracted by ethyl acetate (40 mL). The combined organic layer was dried over Na ₂ SO ₄ , filtered and concentrated under vaccum to give 1-(4-((1S,2R,3R)-6-hydroxy-3-methyl- 2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperidine -4-carbaldehyde (85 mg, 0.20 mmol, 99 %) as a yellow solid. LC-MS (ESI+) m/z: 426.2 (M+H) ⁺ . Step 12: A mixture of 1-(4-((1S,2R,3R)-6-hydroxy-3-methyl-2-phenyl-1,2,3,4- tetrahydronaphthalen-1-yl)phenyl)piperidine-4-carbaldehyde (85 mg, 1 Eq, 0.20 mmol), (S)-3- (1 5 ( i i 1 l)i i d li 2 l) i idi 26 di b lf t (013 13 E 0.26 mmol) and sodium acetate (82 mg, 5 Eq, 1.0 mmol) and acetic acid (36 mg, 34 ^L, 3 Eq, 0.60 mmol) in DCM (2 mL) and MeOH (2 mL) at 25 °C for 1 hour, then sodium triacetoxyborohydride (85 mg, 2 Eq, 0.40 mmol) was added to the mixture and was stirred at 25 ^o C for 16 hour. The reaction was treated with H ₂ O (50 mL), extracted with EtOAc (50 mL). The combined extracts was dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to dryness in vacuo to give a residue. The residue was purified by prep.HPLC (column: Welch Xtimate C18 150*30 mm*3 um mobile phase: [water (FA)-ACN]; B%: 21%-51%, 7 min). The aqueous phase was lyophilized to dryness to give (S)-3-(5-(4-((1-(4-((1S,2R,3R)-6-hydroxy-3-methyl-2-phenyl- 1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperidin-4-yl)meth yl)piperazin-1-yl)-1-oxoisoindolin- 2-yl)piperidine-2,6-dione (69.6 mg, 93.9 ^mol, 47 %, 99.551% purity) as a pink solid. LC-MS (ESI+) m/z: 738.3 (M+H)+ HPLC: 99.551%, purity at 220 nm. SFC: retention time, 3.123 min; Area, 90.089%; NMR (400 MHz, DMSO-d6) į = 11.02 (s, 1H), 9.31 - 9.14 (m, 1H), 8.20 (s, 0.315H), 7.58 (d, J = 8.9 Hz, 1H), 7.17 - 7.08 (m, 5H), 6.97 - 6.79 (m, 4H), 6.72 - 6.62 (m, 4H), 6.55 (dd, J = 2.4, 8.4 Hz, 1H), 5.11 (dd, J = 5.1, 13.3 Hz, 1H), 4.51 (br d, J = 5.0 Hz, 1H), 4.42 - 4.34 (m, 1H), 4.30 - 4.21 (m, 1H), 3.66 - 3.51 (m, 3H), 3.34 (br s, 5H), 3.17 (br d, J = 4.4 Hz, 1H), 3.03 - 2.89 (m, 1H), 2.77 (br d, J = 12.4 Hz, 1H), 2.68 - 2.57 (m, 4H), 2.47 (br d, J = 4.4 Hz, 3H), 2.42 (br dd, J = 4.5, 13.3 Hz, 1H), 2.26 (br d, J = 6.8 Hz, 2H), 2.07 - 1.96 (m, 1H), 1.82 (br d, J = 11.6 Hz, 2H), 1.75 - 1.62 (m, 1H), 1.31 - 1.14 (m, 2H), 0.78 (br d, J = 6.1 Hz, 3H). EXAMPLE 165. Preparation of (I-422) 3-((S)-7-(4-((1-(4-((1R,2S) -6-hydroxy-2-phenyl- 1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperidin-4-yl)meth yl)piperazin-1-yl)-5,6,7,8- tetrahydronaphthalen-2-yl)piperidine-2,6-dione and (I-423) 3-((R)-7-(4-((1-(4-((1R,2S)-6-

hydroxy-2-phenyl-1,2,3,4- tetrahydronaphthalen-1-yl)phenyl)piperidin-4- yl)methyl)piperazin-1-yl)-5,6,7,8-tetrahydronaphthalen-2-yl) piperidine-2,6-dione Step 1: A mixture of 2,6-bis(benzyloxy)-3-bromopyridine (4.00 g, 10.8 mmol, 1.0 eq.), Potassium acetate (3.18 g, 2.03 mL, 3 eq., 32.4 mmol), Bis(pinacolato)diborane (5.49 g, 21.6 mmol, 2.0 eq.) and PdCl ₂ (dppf) (791 mg, 1.08 mmol, 0.1 eq.) in Dioxane (100 mL)was degassed and purged with N ₂ for 3 times, and then the mixture was stirred at 90 °C for 12 hour under N ₂ atmosphere. LCMS showed the reaction was completed. The reaction mixture was quenched by addition EA 10 mL at 20 °C, and then diluted with water 10 mL and extracted with EA 90 mL (30 mL x 3). The combined organic layers were washed with EA 15 mL (5 mL x 3), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The crude material was purified on silica gel column chromatography .(from pure PE to PE/EtOAc = 1/0) to give 2,6-bis(benzyloxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan -2-yl)pyridine (1.8 g, 4.3 mmol, 40 %) as a yellow solid. LC-MS (ESI ⁺ ) m/z: 418.2 (M+H) ⁺ . Step 2: A mixture of 7-bromo-3,4-dihydronaphthalen-2(1H)-one (0.9 g, 4.00 mmol, 1.0 eq.), 2,6- bis(benzyloxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-y l)pyridine (2.10 g, 5.03 mmol, 1.26 eq.), PdCl ₂ (dppf) (293 mg, 400 ^mol, 0.1 eq.) and K ₂ CO ₃ (1.66 g, 12.0 mmol, 3.0 eq.) in Dioxane (20 mL) and water (5 mL) was degassed and purged with N ₂ for 3 times, and then the mixture was stirred at 80 °C for 12 hour under N ₂ atmosphere. LCMS showed the reaction was completed. The reaction mixture was quenched by addition EA 10 mL at 20 °C, and then diluted with water 10 mL and extracted with EA 60 mL (20 mL x 3). The combined organic layers were washed with EA 15 mL (5 mL x 3), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The crude material was purified on silica gel column chromatography (from pure PE to PE/EtOAc = 4/1) to give 7-(2,6-bis(benzyloxy)pyridin-3-yl)-3,4- dihydronaphthalen-2(1H)-one (300 mg, 689 ^mol, 17.2 %) as a yellow solid. LC-MS (ESI+) m/z: 436.1 (M+H) ⁺ . Step 3: To a solution of 7-(2,6-bis(benzyloxy)pyridin-3-yl)-3,4-dihydronaphthalen-2(1 H)-one (300 mg, 689 ^mol, 1.0 eq.) and tert-butyl piperazine-1-carboxylate (154 mg, 1.2 eq., 827 ^mol) in MeOH (4 mL) and DCE (4 mL) was added Sodium triacetoxyborohydride (146 mg, 102 ^L, 1 eq., 689 ^mol). The mixture was stirred at 20 °C for 12 hour. LCMS showed the reaction was completed. The crude material was purified on silica gel column chromatography (from pure PE to PE/EtOAc = 2/3) to give the product as brown oil. LC-MS (ESI+) m/z: 606.4 (M+H) ⁺ . NMR (400 MHz, CHLOROFORM-d) į ppm 7.58 (d, J=8.11 Hz, 1 H), 7.41 - 7.46 (m, 2 H), 7.29 - 7.40 (m, 10 H), 7.13 (d, J=7.99 Hz, 1 H), 6.48 (d, J=8.11 Hz, 1 H), 5.43 (s, 2 H), 5.36 (s, 2 H), 3.63 - 3.90 (m, 4 H), 3.23 - 3.37 (m, 1 H), 3.05 - 3.17 (m, 2 H), 2.92 - 3.15 (m, 6 H), 2.88 - 2.89 (m, 1 H), 2.31 - 2.37 (m, 1 H), 1.85 (m, 1 H), 1.49 (s, 9 H). Step 4: The tert-butyl 4-(7-(2,6-bis(benzyloxy)pyridin-3-yl)-1,2,3,4-tetrahydronaph thalen-2- yl)piperazine-1-carboxylate (600 mg, 990 ^mol, 1.0 eq.) was purified by SFC (Column: DAICEL CHIRALPAK AD (250mm*30mm,10um); Mobile phase: CO ₂ -EtOH(0.1%NH ₃ H ₂ O); from 50% to 50%; Flow rate: 80 mL/min) to give tert-butyl (R)-4-(7-(2,6-bis(benzyloxy)pyridin- 3-yl)-1,2,3,4-tetrahydronaphthalen-2-yl)piperazine-1-carboxy late (220 mg, 363 ^mol, 36.7 %) and tert-butyl (S)-4-(7-(2,6-bis(benzyloxy)pyridin-3-yl)-1,2,3,4-tetrahydro naphthalen-2- yl)piperazine-1-carboxylate (210 mg, 347 ^mol, 35.0 %) both as white solid. tert-butyl (R)-4-(7-(2,6-bis(benzyloxy)pyridin-3-yl)-1,2,3,4-tetrahydro naphthalen-2- yl)piperazine-1-carboxylate: LC-MS (ESI+) m/z: 606.5 (M+H) ⁺ . tert-butyl (S)-4-(7-(2,6-bis(benzyloxy)pyridin-3-yl)-1,2,3,4-tetrahydro naphthalen-2- yl)piperazine-1-carboxylate: LC-MS (ESI+) m/z: 606.5 (M+H) ⁺ . Step 5: To a solution of tert-butyl (S)-4-(7-(2,6-bis(benzyloxy)pyridin-3-yl)-1,2,3,4- tetrahydronaphthalen-2-yl)piperazine-1-carboxylate (200 mg, 330 ^mol, 1.0 eq.) in EtOH (3 mL), DCM (3 mL) and EtOAc (3 mL) was added Pd/C (5wt%, 0.05 g) under N ₂ atmosphere. The suspension was degassed and purged with H2 for 3 times. The mixture was stirred under H2 (15 Psi) at 30 °C for 16 hour. LCMS showed the reaction was completed. The mixture was filtered and the filtrate was concentrated to give tert-butyl 4-((2S)-7-(2,6-dioxopiperidin-3-yl)- 1,2,3,4- tetrahydronaphthalen-2-yl)piperazine-1-carboxylate (120 mg, 0.17 mmol, 51 %, 60% Purity). LC-MS (ESI+) m/z: 428.2 (M+H) ⁺ . To a solution of tert-butyl (R)-4-(7-(2,6-bis(benzyloxy)pyridin-3-yl)-1,2,3,4- tetrahydronaphthalen-2-yl)piperazine-1-carboxylate (200 mg, 330 ^mol, 1.0 eq.) in EtOH (3 mL), DCM (3 mL) and EtOAc (3 mL) was added Pd/C (5%, 0.05 g) under N ₂ atmosphere. The suspension was degassed and purged with H ₂ for 3 times. The mixture was stirred under H ₂ (15 Psi) at 30 °C for 16 hour. LCMS showed the reaction was completed. The mixture was filtered and the filtrate was concentrated to give tert-butyl 4-((2R)-7-(2,6-dioxopiperidin -3-yl)-1,2,3,4- tetrahydronaphthalen-2-yl)piperazine-1-carboxylate (120 mg, 0.17 mmol, 51 %, 60% Purity) as a white solid. LC-MS (ESI+) m/z: 428.2 (M+H) ⁺ . Step 6: To a solution of tert-butyl 4-((2S)-7-(2,6-dioxopiperidin-3-yl)-1,2,3,4- tetrahydronaphthalen- 2-yl)piperazine-1-carboxylate (130 mg, 304 ^mol, 1.0 eq.) in HCl/Dioxane (3 mL) The mixture was stirred at 20 °C for 2 hour LCMS showed the reaction was completed. The mixture was concentrated in vacuum to give crude product. No further purification as it is used for the next step directly. LC-MS (ESI+) m/z: 328.0 (M+H) ⁺ . To a solution of tert-butyl 4-((2R)-7-(2,6-dioxopiperidin-3-yl)-1,2,3,4-tetrahydronaphth alen- 2- yl)piperazine-1-carboxylate (130 mg, 304 ^mol, 1.0 eq.) in HCl/Dioxane (3 mL). The mixture was stirred at 20 °C for 2 hour. LCMS showed the reaction was completed. The mixture was concentrated in vacuum to give crude product. No further purification as it is used for the next step directly. LC-MS (ESI+) m/z: 328.0 (M+H) ⁺ . Step 7: 3-((S)-7-(4-((1-(4-((1R,2S) -6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1- yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-5,6,7,8-tetr ahydronaphthalen-2- yl)piperidine-2,6-dione: To a solution of 1-(4-((1R,2S)-6-hydroxy-2-phenyl-1,2,3,4- tetrahydronaphthalen-1- yl)phenyl)piperidine-4-carbaldehyde (90 mg, 1.1 eq., 0.22 mmol) and 3-((S)-7-(piperazin-1 -yl)-5,6,7,8-tetrahydronaphthalen-2-yl)piperidine-2,6-dione (65 mg, 1 eq., 0.20 mmol) in DCE (3 mL) and MeOH (3 mL) was added Sodium triacetoxyborohydride (0.13 g, 88 ^L, 3 eq., 0.60 mmol). The mixture was stirred at 20 °C for 2 hour. LCMS showed the reaction was completed. The crude was purified by prep-HPLC together (C18-1 150*30mm*5um, water (NH3H2O+NH4HCO3)-ACN as a mobile phase, from 58% to 88%, Gradient Time (min): 11, Flow Rate (ml/min): 25) to give 3-((S)-7-(4-((1-(4-((1R,2S) -6- hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)pi peridin-4-yl)methyl)piperazin-1- yl)-5,6,7,8-tetrahydronaphthalen-2-yl)piperidine-2,6-dione (36.7 mg, 50.8 ^mol, 26 %) as a white solid. LC-MS (ESI+) m/z: 723.4 (M+H) ⁺ . LCMS: calc. for C ₄₇ H ₅₄ N ₄ O ₃ :722.42, found: [M+H] ⁺ 723.4 HPLC: 100.00% purity at 220 nm. ¹ H NMR (400 MHz, METHANOL-d ₄ ) į: ppm 7.04 - 7.12 (m, 4 H), 6.95 - 7.00 (m, 2 H), 6.78 - 6.82 (m, 2 H), 6.69 (d, J=8.40 Hz, 1 H), 6.60 - 6.65 (m, 3 H), 6.51 (m, 1 H), 6.30 (d, J=8.40 Hz, 2 H), 4.18 (d, J=5.20 Hz, 1 H), 3.78 (m, 1 H), 3.51 (m, 2 H), 2.85 - 3.07 (m, 5 H), 2.69 - 2.84 (m, 7 H), 2.61 - 2.68 (m, 2 H), 2.49 - 2.60 (m, 5 H), 2.16 - 2.28 (m, 6 H), 1.83 (d, J=11.20 Hz, 2 H), 1.73 - 1.79 (m, 1 H), 1.59 - 1.69 (m, 2 H), 1.26 - 1.35 (m, 3 H). 3-((R)-7-(4-((1-(4-((1R,2S) -6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1- yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-5,6,7,8-tetr ahydronaphthalen-2- l) i idi 26 di To a solution of 1-(4-((1R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthale n-1-yl)phenyl) piperidine-4-carbaldehyde (90 mg, 1.1 eq., 0.22 mmol) and 3-((R)-7-(piperazin-1-yl)-5,6,7,8- tetrahydronaphthalen-2-yl)piperidine-2,6-dione (65 mg, 1 eq., 0.20 mmol) in DCE (3 mL) and MeOH (3 mL) was added Sodium triacetoxyborohydride (0.13 g, 88 ^L, 3 eq., 0.60 mmol). The mixture was stirred at 20 °C for 2 hour. LCMS showed the reaction was completed. The crude was purified by prep-HPLC together (C18-1150*30mm*5um, water (NH ₃ H ₂ O+NH ₄ HCO ₃ )- ACN as a mobile phase, from 58% to 88%, Gradient Time (min): 11, Flow Rate (ml/min): 25) to give 3-((R)-7-(4-((1-(4-((1R,2S)-6-hydroxy-2-phenyl-1,2,3,4- tetrahydronaphthalen-1- yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-5,6,7,8-tetr ahydronaphthalen-2-yl)piperidine- 2,6-dione (22.4 mg, 31.0 ^mol, 16 %) as a white solid. LC-MS (ESI+) m/z: 723.3 (M+H) ⁺ . LCMS: calc. for C ₄₇ H ₅₄ N ₄ O ₃ :722.42, found: [M+H] ⁺ 723.3 HPLC: 93.69% purity at 220 nm. NMR (400 MHz, METHANOL-d ₄ ) į: ppm 7.05 - 7.12 (m, 4 H), 6.87 - 7.03 (m, 2 H), 6.78 - 6.82 (m, 2 H), 6.69 (d, J=8.40 Hz, 1 H), 6.60 - 6.65 (m, 3 H), 6.52 (m, 1 H), 6.31 (d, J=8.40 Hz, 2 H), 4.18 (d, J=4.80 Hz, 1 H), 3.79 (d, J=4.00 Hz, 1 H), 3.48 - 3.54 (m, 2 H), 2.87 - 3.11 (m, 5 H), 2.69 - 2.85 (m, 7 H), 2.49 - 2.67 (m, 7 H), 2.16 - 2.29 (m, 6 H), 1.84 (d, J=12.40 Hz, 2 H), 1.72 - 1.78 (m, 1 H), 1.59 - 1.69 (m, 2 H), 1.27 - 1.34 (m, 3 H).

EXAMPLE 166. Preparation of (I-185) 3-(2-(1-((1-(4-((1S,2R)-6-hydroxy-2-phenyl- 1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperidin-4-yl)meth yl)piperidin-4-yl)-1,2,3,4- tetrahydroisoquinolin-7-yl)piperidine-2,6-dione Step 1: A mixture of 2,6-bis(benzyloxy)-3-bromopyridine (3.0 g, 1 eq 8.10 mmol), Pin ₂ B ₂ (2.26 g, 8.91 mmol, 1.1 eq.) , Potassium acetate (1.59 g, 16.2 mmol, 2.0 eq.) and PdCl ₂ (dppf) (593 mg, 810 ^mol, 0.1 eq.) in Dioxane (20 ml) was degassed and purged with N ₂ for 3 times, and then the mixture was stirred at 90 ^o C for 6 hours under N ₂ atmosphere. LCMS showed Reactant 1 was consumed completely and one main peak with desired MS was found. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was diluted with brine 20 mL and extracted with ethyl acetate 20 ml (20 ml x 2). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , Petroleum ether/Ethyl acetate=5/1) to give compound 2 (1.25 g, 1.40 mmol, 17.3 % yield, 46.724% Purity). LC-MS (ESI ⁺ ) m/z: 418.2(M+H) ⁺ . Step 2: A mixture of 2,6-bis(benzyloxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan -2-yl)pyridine (900 mg, 2.16 mmol, 1.0 eq.), tert-butyl 7-bromo-3,4-dihydroisoquinoline-2(1H)-carboxylate (741 mg, 2.37 mmol, 1.1 eq.), K ₂ CO ₃ (596 mg, 4.31 mmol, 2.0 eq.), PdCl ₂ (dppf) (158 mg, 216 ^mol, 0.1 eq.) in Dioxane (20 ml) and H ₂ O (0.2 ml) was degassed and purged with N ₂ for 3 times, and then the mixture was stirred at 90 ^o C for 12 hours under N ₂ atmosphere The reaction was clean according to LCMS showed reactant was consumed completely and one main peak with desired MS was detected The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was diluted with brine 100 ml and extracted with ethyl acetate 100 ml (100 ml x 2). The combined organic layers were dried with Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue The residue was purified by column chromatography (SiO ₂ , Petroleum ether/Ethyl acetate=7/1 ) to offer tert-butyl 7-(2,6- bis(benzyloxy)pyridin-3-yl)-3,4-dihydroisoquinoline-2(1H)-ca rboxylate (550 mg, 1.02 mmol, 47.5 %, 97.36% Purity). LC-MS (ESI ⁺ ) m/z: 523.2(M+H) ⁺ . Step 3: To a solution of compound 4 (500 mg, 957 ^mol, 1.0 eq.) in CH ₂ Cl ₂ (10 ml) was added 2,2,2-trifluoroacetaldehyde (469 mg, 4.78 mmol, 5.0 eq.). The mixture was stirred at 25 ^o C for 6 hours. LC-MS showed 86% of desired compound was detected. The reaction mixture was quenched by addition NaHCO ₃ 20 ml at 25 °C, and then diluted with brine 220 ml and extracted with ethyl acetate 20 ml (20 ml x 2). The combined organic layers were dried with Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , Petroleum ether/Ethyl acetate=5/1) to offer 7-(2,6- bis(benzyloxy)pyridin-3-yl)-1,2,3,4-tetrahydroisoquinoline (382 mg, 783 ^mol, 81.8 % yield, 86.58% Purity). LC-MS (ESI ⁺ ) m/z: 423.2(M+H) ⁺ . Step 4: To a solution of 7-(2,6-bis(benzyloxy)pyridin-3-yl)-1,2,3,4-tetrahydroisoquin oline (400 mg, 947 ^mol, 1.0 eq.) (The raw material contains trifluoroacetic acid) in CH ₂ Cl ₂ (10 ml) was added Triethylamine (192 mg, 264 ^L, 2 eq, 1.89 mmol), Adjust the reaction solution to a weak base with triethylamine. The mixture was stirred at 20 ^o C for 10 min. And put tert-butyl 4- oxopiperidine-1-carboxylate (226 mg, 1.14 mmol, 1.2 eq.) into the reaction solution, Stir until completely dissolved in the reaction solution. Sodium triacetoxyborohydride (401 mg, 1.89 mmol, 2.0 eq.) was added into the reaction solution and stirred for 6 hours. LCMS showed Reactant 5 was consumed completely and one main peak with desired MS was detected. The reaction mixture was diluted with water 50 ml and extracted with CH ₂ Cl ₂ 50 ml (20 ml x 2) The combined organic layers were dried with Na2SO4, filtered and concentrated under reduced pressure to give a residue The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate=5/1) to offer tert-butyl 4-(7-(2,6-bis(benzyloxy)pyridin-3-yl)-3,4- dihydroisoquinolin-2(1H)-yl)piperidine-1-carboxylate (100 mg, 142 ^mol, 15.0 % yield, 85.97% Purity). LC-MS (ESI+) m/z: 606.3(M+H) ⁺ . Step 5: A mixture of tert-butyl 4-(7-(2,6-bis(benzyloxy)pyridin-3-yl)-3,4-dihydroisoquinolin - 2(1H)-yl)piperidine-1-carboxylate (220 mg, 1 eq, 363 ^mol) and Pd/C (19.3 mg, 182 ^mol, 0.5 eq.) in MeOH (1 ml),ethyl acetate (1 ml)and CH ₂ Cl ₂ (1 ml) was degassed and purged with H ₂ for 3 times, and then the mixture was stirred at 30 ^o C for 12 hours under H ₂ atmosphere. LCMS showed reactant 7 was consumed completely and no desired MS was detected. The catalyst and solid impurities of the reaction solution are filtered. The reaction mixture was concentrated under reduced pressure to remove solvent to offer tert-butyl 4-(7-(2,6-dioxopiperidin-3-yl)-3,4- dihydroisoquinolin-2(1H)-yl)piperidine-1-carboxylate (122 mg, 80.2 ^mol, 22.1 % yield, 28.12% Purity). LC-MS (ESI ⁺ ) m/z: 428.2(M+H) ⁺ . Step 6: To a solution of tert-butyl 4-(7-(2,6-dioxopiperidin-3-yl)-3,4-dihydroisoquinolin-2(1H)- yl)piperidine-1-carboxylate (60 mg, 1 eq, 0.14 mmol) in CH2Cl2 (0.2 ml) was added TFA (0.16 g, 0.11 mL, 10 eq, 1.4 mmol) .The mixture was stirred at 20 ^o C for 4 hours.LC-MS showed Reactant 8 was consumed completely and one main peak with desired MS was detected The reaction mixture was concentrated under reduced pressure to remove solvent to offer 3-(2- (piperidin-4-yl)-1,2,3,4-tetrahydroisoquinolin-7-yl)piperidi ne-2,6-dione (45 mg, 69 ^mol, 49 %, 50% Purity). LC-MS (ESI ⁺ ) m/z: 328.2(M+H). Step 7: A mixture of 3-(2-(piperidin-4-yl)-1,2,3,4-tetrahydroisoquinolin-7-yl)pip eridine-2,6- dione (70 mg, 0.17 mmol, 1.0 eq.) and 3-(2-(piperidin-4-yl)-1,2,3,4-tetrahydroisoquinolin-7- yl)piperidine-2,6-dione (56 mg, 0.17 mmol, 1.0 eq.) in CH ₂ Cl ₂ (1 ml) and MeOH (1 ml) was stirred for 5 minutes at 20 ^o C, and then the mixture was added Diisopropylethylamine (44 mg, 0.34 mmol, 2.0 eq.) to adjust PH to about 6. Ten minutes later, Sodium triacetoxyborohydride (72 mg, 0.34 mmol, 2.0 eq.) was slowly added to the solution, stirred at 20 ^o C for 4 hour. LCMS showed reactant was remained. Several new peaks were shown on LC-MS and desired compound was detected. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was purified by prep-HPLC (neutral condition) to give desired yl)phenyl)piperidin-4-yl)methyl)piperidin-4-yl)-1,2,3,4-tetr ahydroisoquinolin-7-yl)piperidine- 2,6-dione (12.5 mg, 17.3 ^mol, 10 % yield, 100% Purity) as a white solid. LC-MS (ESI ⁺ ) m/z: 723.6(M+H) ⁺ . LCMS: calc. found: [M+H] ⁺ 723.6 HPLC: 100% purity at 220 nm. NMR (400 MHz, METHANOL-d4) į ppm 7.07 - 7.16 (m, 4 H), 6.95 - 7.05 (m, 2 H), 6.76 - 6.83 (m, 2 H), 6.69 (d, J=8.34 Hz, 1 H), 6.58 - 6.66 (m, 3H), 6.49 - 6.54 (m, 1 H), 6.26 - 6.34 (m, 2 H), 4.15 - 4.21 (m, 1 H), 3.76 - 3.83 (m, 3 H), 3.50 (br d, J=10.37 Hz, 2 H), 2.96 - 3.08 (m, 4 H), 2.83 - 2.93 (m, 4H), 2.43 - 2.72 (m, 6 H), 2.14 - 2.29 (m, 5 H), 1.91 - 2.07 (m, 4 H), 1.80 - 1.87 (m, 2 H), 1.60 - 1.79 (m, 4 H), 1.24 - 1.36 (m, 3 H).

EXAMPLE 167. Preparation of (I-184) 3-(4-((1-((1-(4-((1R,2S)-6-hydroxy-2-phenyl- 1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperidin-4-yl)meth yl)piperidin-4- yl)amino)phenyl)piperidine-2,6-dione Step 1: A mixture of 1-bromo-4-iodobenzene (407 mg, 1.2 Eq, 1.44 mmol) , 2,6-bis(benzyloxy)- 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (500 mg, 1 Eq, 1.20 mmol) ,1,1'- Bis(diphenylphosphino)ferrocene-palladium(II) dichloride (87.7 mg, 0.1 Eq, 120 ^mol), potassium carbonate (331 mg, 140 ^L, 2 Eq, 2.40 mmol) in 1,4-Dioxane (10 mL) and H ₂ O (2.0 mL) was degassed and purged with N ₂ for 3 times, and then the mixture was stirred at 80 °C for 16 hour under N ₂ atmosphere. TLC (petroleum ether: ethyl acetate=5:1, R _f =0.5 UV) showed one main new spot was observed. The reaction was quenched with water (50 mL) and extracted with ethyl acetate (150 mL*2). The organic layer was washed with brine (100 mL) and dried over Na ₂ SO ₄ and concentrated in vacuo to give a white solid. The white solid was subjected to column chromatography over silica gel (gradient elution: 0 – 100% EtOAc).The desired fractions were collected, and concentrated to dryness in vacuo to give 2,6-bis(benzyloxy)-3-(4- bromophenyl)pyridine (340 mg, 762 ^mol, 63.6 %) as a white solid. Step 2: A mixture of 1-T-Butoxycarbonyl-4-Aminopiperidine (169.2 mg, 1.3 Eq, 844.6 ^mol) , 2,6-bis(benzyloxy)-3-(4-bromophenyl)pyridine (290 mg, 1 Eq, 649.7 ^mol), Pd-PEPPSI-IHeptCl (63.2 mg, 0.1 Eq, 65 ^mol), cesium carbonate (635.1 mg, 3 Eq, 1.949 mmol) in dioxane (8 mL) was degassed and purged with N ₂ for 3 times, and then the mixture was stirred at 100 °C for 12 hour under N ₂ atmosphere. TLC (petroleum ether: ethyl acetate=5:1, R _f =0.5 UV) showed one main new spot was observed. The reaction was quenched with water (100 mL) and extracted with ethyl acetate(150 mL*2).The organic layer was washed with brine(100 mL) and dried over Na ₂ SO ₄ and concentrated in vacuo to give a white solid. The white solid was subjected to column chromatography over silica gel (gradient elution: 0–100% EtOAc).The desired fractions were collected, and concentrated to dryness in vacuo to give tert-butyl 4-((4-(2,6- bis(benzyloxy)pyridin-3-yl)phenyl)amino)piperidine-1-carboxy late (280 mg, 495 ^mol, 76.2 %) as a white solid. Step 3: A mixture of tert-butyl 4-((4-(2,6-bis(benzyloxy)pyridin-3-yl)phenyl)amino)piperidin e- 1-carboxylate (280 mg, 1 Eq, 495 ^mol), Pd/C(280 mg, 10% Wt, 0.532 Eq, 263 ^mol), hydrogen (1.00 mg, 1 Eq, 495 ^mol) in DCM (10 mL), ethyl acetate (10 mL)and ethyl alcohol (10 mL) was degassed and purged with H ₂ for 3 times, and then the mixture was stirred at 25 °C for 12 hour under H ₂ atmosphere(15 psi).The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was concentrated under reduced pressure to give tert-butyl 4-((4-(2,6-dioxopiperidin-3-yl)phenyl)amino)piperidine-1-car boxylate (200 mg, 516 ^mol, crude) as a yellow oil. Step 4: To a mixture of tert-butyl 4-((4-(2,6-dioxopiperidin-3-yl)phenyl)amino)piperidine-1- carboxylate (200 mg, 1 Eq, 516 ^mol) in DCM (5 mL) and TFA (1 mL) , then the mixture was stirred at 25 °C for 16 hour. TLC (petroleum ether: ethyl acetate=5:1, R _f =0.5 UV) showed one main new spot was observed. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was concentrated under reduced pressure to give 3-(4- (piperidin-4-ylamino)phenyl)piperidine-2,6-dione, as TFA salt (150 mg, 291 ^mol, 56.4 %) as a yellow oil. Step 5: To a solution of 3-(4-(piperidin-4-ylamino)phenyl)piperidine-2,6-dione (150 mg, 1 Eq, 522 ^mol), 1-(4-((1R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthale n-1- yl)phenyl)piperidine-4-carbaldehyde (215 mg, 1 Eq, 522 ^mol) in DCM (4 mL) and MeOH (4 mL) was added sodium acetate (257 mg, 6 Eq, 3.13 mmol) was stirred at 25 °C for 60 mins, Then NaBH ₃ CN (443 mg, 309 ^L, 4 Eq, 2.09 mmol) and Acetic acid (188 mg, 180 ^L, 6 Eq, 3.13 mmol) was added .The mixture was stirred at 25 °C for 16 hour. The reaction was quenched with H ₂ O (50 mL) and extracted with ethyl acetate (50 mL*2). The organic layer was washed with brine (30 mL) and dried over Na ₂ SO ₄ and concentrated in vacuo to give a yellow oil. The residue was purified by prep-HPLC (column: Welch Xtimate C18150*30mm*5um;mobile phase: [water(FA)-ACN];B% 21%-51%,7min) to give 3-(4-((1-((1-(4-((1R,2S)-6-hydroxy-2- phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperidin-4- yl)methyl)piperidin-4- yl)amino)phenyl)piperidine-2,6-dione (62.5 mg, 85.0 ^mol, 16.3 %, 92.822% purity) was obtained as a white solid. LCMS: calc. for C ₄₄ H ₅₀ N ₄ O ₃ : 682.91, found: [M+H]+ 683.3. HPLC: 92.822% purity at 220 nm. ¹ H NMR (400 MHz, Methanol-d ₄ ) į = 8.52 (br s, 0.737H), 7.11 (br d, J = 1.3 Hz, 3H), 7.03 (d, J = 8.6 Hz, 2H), 6.82 (dd, J = 2.0, 7.2 Hz, 2H), 6.74 -6.58 (m, 6H), 6.53 (dd, J = 2.5, 8.2 Hz, 1H), 6.33 (d, J = 8.6 Hz, 2H), 4.20 (br d, J = 4.9 Hz, 1H), 3.73 (s, 1H), 3.57 (br d, J = 10.0 Hz, 3H), 3.48 (br d, J =12.0 Hz, 2H), 3.35 (br s, 1H), 3.03 (br d, J = 5.6 Hz, 4H), 2.95 (br d, J = 6.6 Hz, 2H), 2.64 (br s, 4H), 2.30 - 2.12 (m, 5H), 1.94 (br d, J = 3.2 Hz, 1H), 1.86 (brd, J = 13.4 Hz, 2H), 1.82 - 1.64 (m, 3H), 1.49 - 1.31 (m, 2H). SFC: retention time, 3.470/4.192 min; Area, 50.102%/49.898%;

EXAMPLE 168. Preparation of (I-183) 3-(3-(9-((1-(4-((1R,2S)-6-hydroxy-2-phenyl- 1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperidin-4-yl)meth yl)-3,9- diazaspiro[5.5]undecan-3-yl)phenyl)piperidine-2,6-dione Step 1: To a stirred mixture of 2,6-bis(benzyloxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan -2- yl)pyridine (1 g, 1 Eq, 2 mmol) and 1-bromo-3-iodobenzene (0.8 g, 1.2 Eq, 3 mmol) in Dioxane (16 mL) and H2O (4 mL) were added 1,1'-Bis(di-t-butylphosphino)ferrocene palladium dichloride (0.2 g, 0.1 Eq, 0.2 mmol) and potassium carbonate (0.7 g, 2 Eq, 5 mmol) at room temperature under nitrogen atmosphere(3 times). The resulting mixture was stirred at 50 °C for 1 hour under nitrogen atmosphere. TLC(PE/EtOAc=10/1, R _f = 0.5) showed two spots. The reaction mixture was quenched into a solution of saturated ammonium chloride solution followed by extraction with EtOAc (100 mL*2). The combined extracts was dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to dryness in vacuo to give mixture as a brown oil. The brown oil was purified by flash silica gel chromatography (from PE/EtOAc = 1/0 to 10/1). The desired fractions were collected, and concentrated to dryness in vacuo to give 2,6-bis(benzyloxy)-3-(3- bromophenyl)pyridine (439 mg, 301 ^mol, 10 %, 30.59% purity) as a colorless oil. LC-MS (ESI ⁺ ) m/z: 448.0(M+H) ⁺ . Step 2: A mixture of tert-butyl 3,9-diazaspiro[5.5]undecane-3-carboxylate (65.0 mg, 1.1 Eq, 256 ^mol), 2,6-bis(benzyloxy)-3-(3-bromophenyl)pyridine (339 mg, 30.59% Wt, 1 Eq, 232 ^mol), Pd-PEPPSI-IHeptCl (22.6 mg, 0.1 Eq, 23.2 ^mol) cesium carbonate (227 mg, 3 Eq, 697 ^mol) in Dioxane (4 mL) was degassed and purged with N ₂ for 3 times, and then the mixture was stirred at 100 °C for 16 hour under N ₂ atmosphere. TLC(PE/EtOAc = 10/1, R _f = 0.5). The reaction mixture was quenched into a solution of saturated ammonium chloride solution followed by extraction with EtOAc (100 mL*2). The combined extracts was dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to dryness in vacuo to give tert-butyl 9-(3-(2,6-bis(benzyloxy)pyridin- 3-yl)phenyl)-3,9-diazaspiro[5.5]undecane-3-carboxylate as a green oil. The green oil was purified by flash silica gel chromatography (from PE/EtOAc = 1/0 to 10/1). The desired fractions were collected, and concentrated to dryness in vacuo to give tert-butyl 9-(3-(2,6- bis(benzyloxy)pyridin-3-yl)phenyl)-3,9-diazaspiro[5.5]undeca ne-3-carboxylate (123 mg, 194 ^mol, 83.5 %, 97.79% Purity) as a green oil. LC-MS (ESI ⁺ ) m/z: 620.2 (M+H) ⁺ . Step 3: A mixture of tert-butyl 9-(3-(2,6-bis(benzyloxy)pyridin-3-yl)phenyl)-3,9- diazaspiro[5.5]undecane-3-carboxylate (123 mg, 97.791% Wt, 1 Eq, 194 ^mol), dihydrogen (392 ^g, 1 Eq, 194 ^mol), Pd/C (124 mg, 10% Wt, 0.6 Eq) in DCM (2 mL), EtOAc (2 mL) and EtOH (2 mL) was degassed and purged with H ₂ for 3 times, and then the mixture was stirred at 25 °C for 16 hour under H ₂ atmosphere (15 psi). The reaction was filtered and concentrated to dryness in vacuo to give tert-butyl 9-(3-(2,6-dioxopiperidin-3-yl)phenyl)-3,9-diazaspiro[5.5]und ecane-3- carboxylate (95 mg, 56 ^mol, 29 %, 26.07% purity) as a green oil. LC-MS (ESI+) m/z: 442.3 (M+H) ⁺ . Step 4: A mixture of tert-butyl 9-(3-(2,6-dioxopiperidin-3-yl)phenyl)-3,9- diazaspiro[5.5]undecane-3-carboxylate (95 mg, 26.07% Wt, 1 Eq, 56 ^mol) in DCM (2.5 mL) and TFA (0.5 mL), then the mixture was stirred at 25 °C for 1 hour. The reaction was concentrated to dryness in vacuo to give 3-(3-(3,9-diazaspiro[5.5]undecan-3- yl)phenyl)piperidine-2,6-dione (45 mg, 59 ^mol, 45% purity) as a yellow oil. LC-MS (ESI+) m/z: 342.1 (M+H) ⁺ . Step 5: A mixture of 1-(4-((1R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthale n-1- yl)phenyl)piperidine-4-carbaldehyde (27 mg, 90% Wt, 1 Eq, 59 ^mol), 3-(3-(3,9- diazaspiro[5.5]undecan-3-yl)phenyl)piperidine-2,6-dione (45 mg, 45% Wt, 1 Eq, 59 ^mol) and sodium acetate (24 mg, 5 Eq, 0.30 mmol) in DCM (2 mL) and MeOH (2 mL) at 20°C for 0.5 hour, pH=8, then acetic acid (11 mg, 10 ^L, 3 Eq, 0.18 mmol) at 20°C for 1 hour, pH=6, then added sodium cyanoborohydride (7.5 mg, 2 Eq, 0.12 mmol) the mixture, and then the mixture was stirred at 25 °C for 16 hour. The reaction was quenched with water (10 mL) and extracted with ethyl acetate (20 mL*2). The organic layer was washed with brine(10 mL) and dried over Na ₂ SO ₄ and concentrated in vacuo to give 3-(3-(9-((1-(4-((1R,2S)-6-hydroxy-2-phenyl-1,2,3,4- tetrahydronaphthalen-1-yl)phenyl)piperidin-4-yl)methyl)-3,9- diazaspiro[5.5]undecan-3- yl)phenyl)piperidine-2,6-dione as a brown oil. The brown oil was purified by preparative high- performance liquid chromatography. Condition: Column: Xtimate C18150*40mm*10um, A: water(FA), B:CAN, at the beginning: A (75%) and B (25%), at the end: A: (45%) and B (55%), Gradient Time(min) 6; 100% B hold Time(min)2, Flow Rate(ml/min) 25. The pure fractions were collected and the solvent was evaporated under vacuum. The aqueous layer was lyophilized to dryness to give 3-(3-(9-((1-(4-((1R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydr onaphthalen-1- yl)phenyl)piperidin-4-yl)methyl)-3,9-diazaspiro[5.5]undecan- 3-yl)phenyl)piperidine-2,6-dione (38.3 mg, 50.9 ^mol, 86 %, 97.99% purity) as a white solid. LCMS: calc. for C ₄₈ H ₅₆ N ₄ O ₃ : 736.44, found: [M+H] + 737.5. HPLC: 97.99% purity at 220 nm. ¹ H NMR (400 MHz, DMSO-d ₆ ) į= 10.80 (s, 1H), 9.11 (br s, 1H), 8.15 (s, 0.731H), 7.18 - 7.07 (m, 4H), 6.86 - 6.75 (m, 4H), 6.66 - 6.44 (m, 6H), 6.19 (d, J = 8.7 Hz, 2H), 4.12 (d, J = 4.8 Hz, 1H), 3.74 (dd, J = 4.9, 11.1 Hz, 1H), 3.54 - 3.45 (m, 3H), 3.27 (br s, 2H), 3.10 (br s, 4H), 3.01 - 2.87 (m, 2H), 2.61 (br d, J = 11.8 Hz, 1H), 2.48 - 2.42 (m, 3H), 2.38 (br s, 3H), 2.24 - 1.97 (m, 5H), 1.70 (br d, J = 11.9 Hz, 3H), 1.59 (br s, 1H), 1.50 (br d, J = 19.0 Hz, 7H), 1.11 (br dd, J = 1.8, 11.2 Hz, 2H) SFC: retention time, 2.028 min, 3.493 min; Area, 50.13%, 49.87%; EXAMPLE 169. Preparation of (I-182) 3-(4-(2-((1-(4-((1R,2S)-6-hydroxy-2-phenyl- 1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperidin-4-yl)meth yl)-2-azaspiro[3.3]heptan-6- yl)phenyl)piperidine-2,6-dione Step 1: A mixture of tert-butyl 6-oxo-2-azaspiro[3.3]heptane-2-carboxylate (2 g, 9.47 mmol, 1 eq), 4-methylbenzenesulfonohydrazide (2.12 g, 11.36 mmol, 1.2 eq) was added in the ACN (20 mL), the mixture was stirred at 90 °C for 16 hr. Then the mixture was treated with H ₂ O (100 mL), extracted with EtOAc (150 mL). The combined extracts was dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to dryness in vacuo to give a residue. The residue was subjected to column chromatography over silica gel (gradient elution: 0~10% ethyl acetate in petroleum ether). The pure fractions were collected and concentrated to dryness in vacuo to give tert-butyl 6-(2-tosylhydrazineylidene)-2-azaspiro[3.3]heptane-2-carboxy late (1.67 g, 4.40 mmol, 46.49% yield) as a yellow oil. LC-MS (ESI+) m/z: 380 (M+H) ⁺ . Step 2: A mixture of tert-butyl 6-(2-tosylhydrazineylidene)-2-azaspiro[3.3]heptane-2- carboxylate (1 g, 2.64 mmol, 1 eq), (4-bromophenyl)boronic acid (740.9 mg, 3.7 mmol, 1.4 eq), Cs ₂ CO ₃ (1.7 g, 5.3 mmol, 2 eq) was added in dioxane (10 mL), the mixture was stirred at 110 °C for 12 hr. Then the mixture was treated with H ₂ O (50 mL), extracted with EtOAc (100 mL). The combined extracts was dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to dryness in vacuo to give a residue. The residue was subjected to column chromatography over silica gel (gradient elution: 0~30% ethyl acetate in petroleum ether). The pure fractions were collected and concentrated to dryness in vacuo to give tert-butyl 6-(4-bromophenyl)-2-azaspiro[3.3]heptane-2- carboxylate (330 mg, 936.8 ^mol, 35.6% yield) as a yellow oil. LC-MS (ESI+) m/z: 352 (M+H) ⁺ . Step 3: A mixture of tert-butyl 6-(4-bromophenyl)-2-azaspiro[3.3]heptane-2-carboxylate (300 mg, 851.63 ^mol, 1 eq) , 2,6-bis(benzyloxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan -2- yl)pyridine (426.47 mg, 1.02 mmol, 1.2 eq), disodium carbonate (270.8 mg, 2.55 mmol, 3 eq), Pd(dppf)Cl ₂ (69.55 mg, 85.16 ^mol, 0.1 eq) in dioxane (4 mL) and H ₂ O (1 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 80 °C for 16hr under N2 atmosphere. Then the mixture was treated with H2O (50 mL), extracted with EtOAc (100 mL). The combined extracts was dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to dryness in vacuo to give a residue. The residue was subjected to column chromatography over silica gel (gradient elution: 0~50% ethyl acetate in petroleum ether). The pure fractions were collected and concentrated to dryness in vacuo to give tert-butyl 6-(4-(2,6-bis(benzyloxy)pyridin-3-yl)phenyl)- 2-azaspiro[3.3]heptane-2-carboxylate (450 mg, 799.72 ^mol, 93.90% yield) was obtained as a white solid. LC-MS (ESI+) m/z: 563.2 (M+H) ⁺ . Step 4: To a solution of tert-butyl 6-(4-(2,6-bis(benzyloxy)pyridin-3-yl)phenyl)-2- azaspiro[3.3]heptane-2-carboxylate (350 mg, 622 ^mol, 1 eq) and Pd/C (662 mg, 622.01 ^mol, 10% purity, 1 eq) in DCM (2 mL) ,EtOAc (2 mL) and EtOH (2 mL) and purged with H ₂ for 3 times, the mixture was stirred at 25°C for 12 hr. The reaction mixture was filtered and concentrated to dryness in vacuo to give tert-butyl 6-(4-(2,6-dioxopiperidin-3-yl)phenyl)-2- azaspiro[3.3]heptane-2-carboxylate (230 mg, 598.23 ^mol, 96.18% yield). LC-MS (ESI ⁺ ) m/z: 385(M+H) ⁺ . Step 5: A mixture of tert-butyl 6-(4-(2,6-dioxopiperidin-3-yl)phenyl)-2-azaspiro[3.3]heptane -2- mixture was stirred at 25 °C for 1 hr. LCMS showed 95% of desired compound was detected. The reaction mixture was filtered and concentrated to dryness in vacuo to give 3-(4-(2- azaspiro[3.3]heptan-6-yl)phenyl)piperidine-2,6-dione (96 mg, 337.6 ^mol, 86.53% yield). LC- MS (ESI ⁺ ) m/z: 285(M+H) ⁺ . Step 6: A mixture of 3-(4-(2-azaspiro[3.3]heptan-6-yl)phenyl)piperidine-2,6-dione (96 mg, 337.61 ^mol,1eq) ,1-(4-((1R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthal en-1- yl)phenyl)piperidine-4-carbaldehyde (139 mg, 337.6 ^mol, 1 eq), sodium acetate (166.2 mg, 2 mmol, 6 eq) was added in DCM (4 mL) and MeOH (4 mL) , the mixture was stirred at 25 °C for 0.5 h, and then sodium;triacetoxyboranuide (286.2 mg, 1.35 mmol, 4 eq), acetic acid (559.3 mg, 2 mmol, 532.7 ^L, 6 eq) was added in the mixture, the mixture was stirred at 25 °C for 16 hr. LCMS showed 49% of desired compound was detected. The reaction mixture was treated with H ₂ O 30 mL and extracted with EtOAc 50 mL (50 mL * 2). The organic layers were dried with anhydrous Na ₂ SO ₄ , filtered, the residue was purified by prep. HPLC (column: Welch Xtimate C18150*30mm*5um; mobile phase: [water(FA)-ACN];gradient:24%-54% B over 7 min). The aqueous phase was lyophilized to dryness to give 3-(4-(2-((1-(4-((1R,2S)-6-hydroxy-2-phenyl- 1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperidin-4-yl)meth yl)-2-azaspiro[3.3]heptan-6- yl)phenyl)piperidine-2,6-dione (29 mg, 42.65 ^mol, 12.63% yield) as a yellow soild. LC-MS (ESI+) m/z: 679 (M+H) ⁺ . HPLC: 97.341%, purity at 220 nm. SFC: retention time, 2.360, 3.019 min; Area, 49.908%, 50.092%; ¹ H NMR (400 MHz, DMSO-d ₆ ) į = 10.85 - 10.76 (m, 1H), 8.17 (s, 0.707H), 7.26 - 7.06 (m, 7H), 6.86 - 6.77 (m, 2H), 6.67 - 6.56 (m, 2H), 6.55 - 6.43 (m,3H), 6.22 - 6.13 (m, 2H), 4.17 - 4.06 (m, 1H), 3.84 - 3.75 (m, 1H), 3.53 - 3.41 (m, 6H), 3.37 - 3.32 (m, 3H), 3.10 - 2.83 (m, 3H), 2.71 - 2.53 (m, 2H), 2.45 -2.39 (m, 4H), 2.22 - 1.91 (m, 5H), 1.67 (br d, J = 12.2 Hz, 3H), 1.45 - 1.30 (m, 1H), 1.21 - 1.05 (m, 2H). EXAMPLE 170. Preparation of (I-421) 3-(4-(2-((1-(4-((1R,2S)-6-hydroxy-2-phenyl- 1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperidin-4-yl)meth yl)-2,8-diazaspiro[4.5]decan- 8-yl)phenyl)piperidine-2,6-dione Step 1: A mixture of 3-(4-bromophenyl)piperidine-2,6-dione (150 mg, 559.5 ^mol, 1 eq) , tert- butyl 2,8-diazaspiro[4.5]decane-2-carboxylate (174.8 mg, 727.3 ^mol, 1.3 eq) , dicesium;carbonate (546.9 mg, 1.68 mmol, 3 eq) , Pd-PEPPSI-IHeptCl (54.4 mg, 56 ^mol, 0.1 eq) in dioxane (5 mL) was degassed and purged with N ₂ for 3 times, and then the mixture was stirred at 100 °C for 3.5 hr under N ₂ atmosphere. The reaction mixture was quenched by addition 50 mL H ₂ O at 20 °C, and then diluted with 50 mL ethyl acetate and extracted with ethyl acetate (50 mL * 3). The combined organic layers were washed with 50 mL brine, dried over drying Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 4 g SepaFlash®Silica Flash Column, Eluent of 0~20%DCM/MeOH @ 30mL/min).Compound tert-butyl-8-(4-(2,6-dioxopiperidin-3-yl)phenyl)-2,8- diazaspiro[4.5]decane-2-carboxylate (137 mg, 320.44 ^mol, 57.27% yield) was obtained as a brown oil. LC-MS (ESI ⁺ ) m/z: 428.2 (M+H) ⁺ . Step 2: To a solution of tert-butyl 8-[4-(2,6-dioxo-3-piperidyl)phenyl]-2,8- diazaspiro[4.5]decane-2-carboxylate (137 mg, 320.4 ^mol, 1 eq) in HCl/dioxane (8 mL).The mixture was stirred at 20 °C for 0.5 hr . TLC indicated no start material was remained, and one major new spot with larger polarity was detected (PE:EA=0:1 R _f =0.1). The reaction mixture was concentrated under reduced pressure to remove HCl/dioxane and give a white solid. The crude product 3-[4-(2,8-diazaspiro[4.5]decan-8-yl)phenyl]piperidine-2,6-di one (166 mg, crude) as white solid was used into the next step without further purification. Step 3: A mixture of 3-[4-(2,8-diazaspiro[4.5]decan-8-yl)phenyl]piperidine-2,6-di one (166 mg, 507 ^mol, 1 eq), 1-(4-((1R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthale n-1- yl)phenyl)piperidine-4-carbaldehyde (313 mg, 760.5 ^mol, 1.5 eq) and sodium;acetate (249.5 mg, 3 mmol, 6 eq) and acetic acid (121.8 mg, 2 mmol, 116.1 ^L, 4 eq) in DCM (2 mL) and MeOH (2 mL) at 30 °C for 1 hour, then NaBH(OAc) ₃ (429.81 mg, 2.03 mmol, 4 eq) was added to the mixture and was stirred at 30 °C for 16 hr The reaction mixture was quenched by addition H2O 20 mL at 25 °C, and then diluted with 20 mL ethyl acetate and extracted with ethyl acetate (20 mL * 3). The combined organic layers were washed with brine 20 mL, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Welch Xtimate C18 150*30mm*5um;mobile phase: [water(FA)-ACN];gradient:17%-47% B over 7 min) Compound 3-(4-(2-((1-(4-((1R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydr onaphthalen-1- yl)phenyl)piperidin-4-yl)methyl)-2,8-diazaspiro[4.5]decan-8- yl)phenyl)piperidine-2,6-dione (16.4 mg, 21.72 ^mol, 4.28% yield, 95.744% purity) was obtained as a white solid. LC-MS (ESI ⁺ ) m/z: 723.4 (M+H) ⁺ . HPLC: 95.744% purity at 220 nm. NMR (400 MHz, DMSO-d ₆ ) į= 12.70 - 12.25 (m, 1H), 7.94 (s, 1H), 7.16 (br d, J = 1.8 Hz, 3H), 7.11 (d, J = 8.5 Hz, 2H), 6.93 (d, J = 8.8 Hz, 2H), 6.82 (s, 3H), 6.73 (d, J = 2.3 Hz, 1H), 6.64 - 6.59 (m, 1H), 6.56 (d, J = 8.5 Hz, 2H), 6.30 (d, J = 8.5 Hz, 2H), 4.21 (d, J = 4.8 Hz, 1H), 3.74 (dd, J = 5.1, 9.4 Hz, 1H), 3.65 - 3.52 (m, 2H), 3.40 - 3.32 (m, 1H), 3.24 - 3.14 (m, 4H), 3.05 (br s, 5H), 2.62 (br s, 5H), 2.25 (s, 3H), 2.11 (s, 6H), 1.87 - 1.75 (m, 4H), 1.53 - 1.39 (m, 4H) SFC: retention time, 3.550/ 4.818 min; Area, 50.274/ 49.726%; EXAMPLE 171. Preparation of (I-180) 3-[4-[9-[[1-[4-[(1R,2S)-6-hydroxy-2-phenyl- tetralin-1-yl]phenyl]-4-piperidyl]methyl]-3,9-diazaspiro[5.5 ]undecan-3- yl]phenyl]piperidine-2,6-dione Step 1: A mixture of tert-butyl 3,9-diazaspiro[5.5]undecane-3-carboxylate (113.9 mg, 447.6 ^mol, 1.2 eq), 3-(4-bromophenyl)piperidine-2,6-dione (100 mg, 373 ^mol, 1 eq), Cs ₂ CO ₃ (364.6 mg, 1.12 mmol, 3 eq), Pd-PEPPSI-IHeptCl (36.3 mg, 37.3 ^mol, 0.1 eq) in dioxane (4 mL) was degassed and purged with N ₂ for 3 times, and then the mixture was stirred at 100 °C for 4hr under N ₂ atmosphere. TLC (DCM/MeOH=10:1, R _f =0.4) showed new spot was formed. The reaction mixture was diluted with 10 mL H2O and extracted with 20 mL EA (10 mL * 2). The combined organic layers were washed with brine (5 mL * 2), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ DCM: MeOH =10:1) Compound tert-butyl 9-[4-(26-dioxo-3- piperidyl)phenyl]-3,9-diazaspiro[5.5]undecane-3-carboxylate (100 mg, 226.5 ^mol, 60.7% yield) was obtained as a yellow solid. LC-MS (ESI+) m/z: 442.3 (M+H) ⁺ . Step 2: To a solution of tert-butyl 9-[4-(2,6-dioxo-3-piperidyl)phenyl]-3,9- diazaspiro[5.5]undecane-3-carboxylate (100 mg, 226.47 ^mol, 1 eq) in 4 M HCl/dioxane (8 mL) was stirred at 25 °C for 1 hr . TLC (petroleum ether/ethyl acetate=5:1, R _f =0.4) showed new spot was formed. The reaction mixture was concentrated under reduced pressure to give a residue. The crude product 3-[4-(3,9-diazaspiro[5.5]undecan-3-yl)phenyl]piperidine-2,6- dione (70 mg, 205.01 ^mol, 90.52% yield) was used into the next step without further purification. Compound 3-[4-(3,9-diazaspiro[5.5]undecan-3-yl)phenyl]piperidine-2,6- dione (70 mg, 205.01 ^mol, 90.52% yield) was obtained as a yellow solid. LC-MS (ESI+) m/z: 342.2 (M+H) ⁺ . Step 3: To a solution of 1-[4-[(1R,2S)-6-hydroxy-2-phenyl-tetralin-1-yl]phenyl]piperi dine-4- carbaldehyde (67.50 mg, 164.01 ^mol, 1 eq) and 3-[4-(3,9-diazaspiro[5.5]undecan-3- yl)phenyl]piperidine-2,6-dione (70 mg, 164.01 ^mol, 1 eq, 2HCL) in DCM (4 mL) and MeOH (4 mL) was added sodium acetate (80.73 mg, 984.05 ^mol, 6 eq) .The mixture was stirred at 30 °C for 1 hr. Then the mixture was added acetic acid (59.09 mg, 984.05 ^mol, 56.33 ^L, 6 eq) , NaH3BCN, (41.23 mg, 656.03 ^mol, 4 eq) .The mixture was stirred at 30 °C for 12 hr finally. The reaction mixture was diluted with 10 mL H ₂ O and extracted with DCM (10 mL * 2). The combined organic layers were washed with brine 10 mL (5 mL * 2), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Welch Xtimate C18150*30mm*5um; mobile phase: [water(FA)- ACN];gradient:18%-48% B over 7 min).Then the residue was further purified by prep- HPLC(column: Welch Xtimate C18150*30mm*5um;mobile phase: [water(FA)- ACN];gradient:21%-41% B over 7 min). Compound 3-[4-[9-[[1-[4-[(1R,2S)-6-hydroxy-2- phenyl-tetralin-1-yl]phenyl]-4-piperidyl]methyl]-3,9-diazasp iro[5.5]undecan-3- yl]phenyl]piperidine-2,6-dione (10.8 mg, 14.65 ^mol, 8.94% yield) was obtained as a white solid. LC-MS (ESI ⁺ ) m/z: 737.5 (M+H) ⁺ . HPLC: 97.978%, purity at 220 nm. b: Rt: 3.999 min; Area, 50.204%, Rt: 7.448 min; Area, 49.796%; NMR (400 MHz, METHANOL-d4) į ppm 8.52 - 8.60 (m, 0.641 H) 7.09 - 7.18 (m, 5 H) 7.00 (d, J=8.70 Hz, 2 H) 6.79 - 6.86 (m, 2 H) 6.70 (d, J=8.46 Hz, 1 H) 6.60 - 6.67 (m, 3 H) 6.50 - 6.56 (m, 1 H) 6.29 - 6.37 (m, 2 H) 4.20 (br d, J=5.25 Hz, 1 H) 3.76 - 3.83 (m, 1 H) 3.52 - 3.60 (m, 2 H) 3.31 - 3.33 (m, 4 H) 3.15 - 3.23 (m, 4 H) 3.07 (br s, 1 H) 2.96 - 3.05 (m, 4 H) 2.80 (br d, J=4.41 Hz, 1 H) 2.56 - 2.71 (m, 4 H) 2.16 - 2.29 (m, 3 H) 1.85 (br d, J=11.92 Hz, 3 H) 1.75 (br d, J=16.33 Hz, 8 H) 1.33 - 1.46 (m, 2 H). EXAMPLE 172. Preparation of (I-179) 3-(3-((3aS,6aS)-4-((1-(4-((1R,2S)-6-hydroxy-2- phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperidin-4- yl)methyl)hexahydropyrrolo[3,2-b]pyrrol-1(2H)-yl)phenyl)pipe ridine-2,6-dione Step 1: A mixture of tert-butyl (3aS,6aS)-hexahydropyrrolo[3,2-b]pyrrole-1(2H)-carboxylate (20.0 mg, 1 Eq, 94.2 ^mol), 2,6-bis(benzyloxy)-3-(3-bromophenyl)pyridine (46.7 mg, 1.1 Eq, 104 ^mol), Pd-PEPPSI-IHeptCl (4.58 mg, 0.05 Eq, 4.71 ^mol) and cesium carbonate (92.1 mg, 3 Eq, 283 ^mol) added in Dioxane (1 mL) was degassed and purged with N ₂ for 3 times, and then the mixture was stirred at 85 °C for 16 hour under N2 atmosphere. TLC(PE/EtOAc = 10/1, Rf= 0.4) showed one new spot. The reaction mixture was quenched into a solution of saturated ammonium chloride(20 mL) solution followed by extraction with EtOAc (50 mL*3). The combined extracts was dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to dryness in chromatography (from PE/EtOAc = 1/0 to 10/1). The desired fractions were collected, and concentrated to dryness in vacuo to give tert-butyl (3aS,6aS)-4-(3-(2,6-bis(benzyloxy)pyridin-3- yl)phenyl)hexahydropyrrolo[3,2-b]pyrrole-1(2H)-carboxylate (50 mg, 84 ^mol, 89 %, 97% purity) as a colorless oil. LC-MS (ESI ⁺ ) m/z: 578.1(M+H) ⁺ . Step 2: A mixture of tert-butyl (3aS,6aS)-4-(3-(2,6-bis(benzyloxy)pyridin-3- yl)phenyl)hexahydropyrrolo[3,2-b]pyrrole-1(2H)-carboxylate (50 mg, 1 Eq, 84 ^mol), dihydrogen (0.17 mg, 1 Eq, 84 ^mol), palladium on carbon(25 mg, 10% Wt, 0.28 Eq, 23 ^mol) in DCM (2 mL), EtOAc (2 mL) and EtOH (2 mL) was degassed and purged with H ₂ for 3 times, and then the mixture was stirred at 25 °C for 16 hour under H ₂ atmosphere (15 psi). The reaction was filtered and concentrated to dryness in vacuo to give tert-butyl (3aS,6aS)-4-(3-(2,6- dioxopiperidin-3-yl)phenyl)hexahydropyrrolo[3,2-b]pyrrole-1( 2H)-carboxylate (49 mg, 58 ^mol, 69 %, 47% purity) as a colorless oil. LC-MS (ESI ⁺ ) m/z: 399.9 (M+H) ⁺ . Step 3: A mixture of tert-butyl (3aS,6aS)-4-(3-(2,6-dioxopiperidin-3- yl)phenyl)hexahydropyrrolo[3,2-b]pyrrole-1(2H)-carboxylate (49 mg, 47% Wt, 1 Eq, 58 ^mol) in DCM (2.5 mL) and TFA (0.5 mL), then the mixture was stirred at 25 °C for 1 hour. The reaction was concentrated to dryness in vacuo to give 3-(3-((3aS,6aS)-hexahydropyrrolo[3,2- b]pyrrol-1(2H)-yl)phenyl)piperidine-2,6-dione (40 mg, 74 ^mol, 130 %, 55.6% purity) as a brown oil. LC-MS (ESI+) m/z: 300.2 (M+H) ⁺ . Step 4: A mixture of 1-(4-((1R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthale n-1- yl)phenyl)piperidine-4-carbaldehyde (61 mg, 90% Wt, 1 Eq, 0.13 mmol), 3-(3-((3aS,6aS)- hexahydropyrrolo[3,2-b]pyrrol-1(2H)-yl)phenyl)piperidine-2,6 -dione (40 mg, 1 Eq, 0.13 mmol) and sodium acetate (55 mg, 5 Eq, 0.67 mmol) in DCM (2 mL) and MeOH (2 mL) at 20°C for 0.5 hour, pH=8, then acetic acid (24 mg, 23 ^L, 3 Eq, 0.40 mmol) at 20°C for 1 hour, pH=6, then added Sodium triacetoxyborohydride (57 mg, 40 ^L, 2 Eq, 0.27 mmol) the mixture, and then the mixture was stirred at 25 °C for 16 hour. The reaction was quenched with water (50 mL) and extracted with ethyl acetate(50 mL*3). The organic layer was washed with brine(50 mL) and dried over Na ₂ SO ₄ and concentrated in vacuo to give 3-(3-((3aS,6aS)-4-((1-(4-((1R,2S)-6- hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)pi peridin-4- yl)methyl)hexahydropyrrolo[3,2-b]pyrrol-1(2H)-yl)phenyl)pipe ridine-2,6-dione as a brown oil. The brown oil was purified by preparative high-performance liquid chromatography. Condition: beginning: A (15%) and B (85%), at the end: A: (0%) and B (100%), Gradient Time(min) 7; 100% B hold Time(min) 2, Flow Rate(ml/min) 25. The pure fractions were collected and the solvent was evaporated under vacuum. The aqueous layer was lyophilized to dryness to give 3- (3-((3aS,6aS)-4-((1-(4-((1R,2S)-6-hydroxy-2-phenyl-1,2,3,4-t etrahydronaphthalen-1- yl)phenyl)piperidin-4-yl)methyl)hexahydropyrrolo[3,2-b]pyrro l-1(2H)-yl)phenyl)piperidine-2,6- dione (8.2 mg, 12 ^mol, 8.8 %, 99.48% Purity) as a white solid. LCMS: calc. for C ₄₅ H ₅₀ N ₄ O ₃ : 694.39, found: [M+H] ⁺ 695.3. HPLC: 99.48% purity at 220 nm. ¹ H NMR (400 MHz, DMSO-d6) į= 10.80 (d, J = 2.6 Hz, 1H), 9.10 (s, 1H), 7.14 (br d, J = 7.4 Hz, 4H), 6.83 (br d, J = 6.8 Hz, 2H), 6.64 (d, J = 8.2 Hz, 1H), 6.59 (d, J = 2.1 Hz, 1H), 6.52 (d, J = 8.7 Hz, 2H), 6.49 (s, 1H), 6.42 (s, 2H), 6.39 - 6.34 (m, 1H), 6.19 (d, J = 8.6 Hz, 2H), 4.17 - 4.09 (m, 2H), 3.76 - 3.69 (m, 1H), 3.50 (br d, J = 11.3 Hz, 2H), 3.30 - 3.20 (m, 3H), 3.10 - 3.06 (m, 1H), 3.00 - 2.88 (m, 3H), 2.68 - 2.56 (m, 2H), 2.47 (br s, 3H), 2.20 - 2.02 (m, 6H), 1.89 - 1.81 (m, 2H), 1.80 - 1.73 (m, 1H), 1.68 (br d, J = 2.9 Hz, 2H), 1.57 - 1.45 (m, 1H), 1.39 - 1.29 (m, 1H), 1.24 - 1.10 (m, 2H) SFC: retention time, 2.265 min, 2.459 min; Area, 45.93%, 54.07%;

EXAMPLE 173. Preparation of (I-178) 3-(3-((3aS,6aS)-4-((1-(4-((1R,2S)-6-hydroxy-2- phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperidin-4- yl)methyl)hexahydropyrrolo[3,2-b]pyrrol-1(2H)-yl)phenyl)pipe ridine-2,6-dione Step 1: A mixture of 2,6-bis(benzyloxy)-3-(3-bromophenyl)pyridine (161.9 mg, 362.7 ^mol, 1.1 eq), tert-butyl (3aR,6aR)-2,3,3a,5,6,6a-hexahydro-1H-pyrrolo[3,2-b]pyrrole-4 -carboxylate (70 mg, 329.7 ^mol, 1 eq), cesium carbonate(322.3 mg, 989.2 ^mol, 3 eq) , 1,3-bis[2,6-bis(1- propylbutyl)phenyl]-4,5-dichloro-2H-imidazol-1-ium-2-ide;3-c hloropyridine;dichloropalladium (32.1 mg, 33 ^mol, 0.1 eq) in dioxane (5 mL) was degassed and purged with N ₂ for 3 times, and then the mixture was stirred at 100 °C for 3.5 hr under N ₂ atmosphere. LCMS showed ~50% desired MS was detected. Then the mixture was treated with H ₂ O (20 mL), extracted with EtOAc (50 mL). The combined extracts was dried over anhydrous Na2SO4, filtered and concentrated to dryness in vacuo to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 4 g SepaFlash® Silica Flash Column, Eluent of 0~20% DCM/MeOH @ 30 mL/min). The pure fractions were collected and concentrated to dryness in vacuo to give tert- butyl(3aR,6aR)-4-(3-(2,6-bis(benzyloxy)pyridin-3-yl)phenyl)h exahydropyrrolo[3,2-b]pyrrole- 1(2H)-carboxylate (90 mg, 155.8 ^mol, 47.25% yield, 100% purity) was obtained as a yellow oil. LC-MS (ESI+) m/z: 578.4 (M+H) ⁺ . Step 2: A mixture of tert-butyl(3aR,6aR)-1-[3-(2,6-dibenzyloxy-3-pyridyl)phenyl]- 2,3,3a,5,6,6a- hexahydropyrrolo[3,2-b]pyrrole-4-carboxylate (90 mg, 155.79 ^mol, 1eq) in DCM (2 mL) ethyl acetate (2 mL) was added Pd/C (10%, 100 mg) under N ₂ atmosphere. The suspension was degassed and purged with H ₂ for 3 times. The mixture was stirred under H ₂ (15 Psi) at 30 °C for 5hr .LCMS showed 70% desired MS was detected. The reaction mixture was filtered and concentrated to dryness in vacuo to give tert-butyl(3aR,6aR)-1-[3-(2,6-dioxo-3- piperidyl)phenyl]-2,3,3a,5,6,6a-hexahydropyrrolo[3,2-b]pyrro le-4-carboxylate (77 mg, crude) as yellow oil. LC-MS (ESI+) m/z: 400.1 (M+H)+. Step 3: A mixture of tert-butyl(3aR,6aR)-1-[3-(2,6-dioxo-3-piperidyl)phenyl]-2,3, 3a,5,6,6a- hexahydropyrrolo[3,2-b]pyrrole-4-carboxylate (77 mg, 192.75 ^mol, 1 eq) in DCM (5 mL) and TFA (1 mL) .The mixture was stirred at 30°C for 1 hr. LCMS showed 64% desired MS was detected. The reaction mixture was filtered and concentrated to dryness in vacuo to give 3-[3- [(3aR,6aR)-2,3,3a,5,6,6a-hexahydro-1H-pyrrolo[3,2-b]pyrrol-4 -yl]phenyl]piperidine-2,6-dione (50 mg, 167.02 ^mol, 86.65% yield) as yellow oil. LC-MS (ESI+) m/z: 299.9 (M+H)+. Step 4: A mixture of 3-[3-[(3aR,6aR)-2,3,3a,5,6,6a-hexahydro-1H-pyrrolo[3,2-b]pyr rol-4- yl]phenyl]piperidine-2,6-dione (50 mg, 167 ^mol, 1 eq), 1-(4-((1R,2S)-6-hydroxy-2-phenyl- 1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperidine-4-carbal dehyde (103.1 mg, 250.5 ^mol, 1.5 eq) and sodium acetate (82.21 mg, 1.00 mmol, 6 eq) and acetic acid (40.1 mg, 668.1 ^mol, 38.3 ^L, 4 eq) in DCM (2 mL) and MeOH (2 mL) at 30 °C for 1 hour, then NaB(OAc) ₃ H (141.6 mg, 668.1 ^mol, 4 eq) was added to the mixture and was stirred at 30 °C for 16 hr. LCMS showed 93% desired MS was detected. The reaction mixture was treated with 30 mL H ₂ O and extracted with EtOAc 50 mL (50 mL * 2). The organic layers were dried with anhydrous Na2SO4, filtered. The residue was purified by prep. HPLC (column: Welch Xtimate C18150*30mm*5um; mobile to dryness to give 3-(3-((3aS,6aS)-4-((1-(4-((1R,2S)-6-hydroxy-2-phenyl-1,2,3,4 - tetrahydronaphthalen-1-yl)phenyl)piperidin-4-yl)methyl)hexah ydropyrrolo[3,2-b]pyrrol-1(2H)- yl)phenyl)piperidine-2,6-dione (40 mg, 39.14 umol, 23.44% yield, 68%purity) was obtained as a white solid. LC-MS (ESI+) m/z: 695.5 (M+H)+. HPLC: 99.109 %, purity at 220nm. SFC: retention time, 2.292, 2.491 min; Area, 41.824%, 58.176 %; NMR (400 MHz, DMSO-d ₆ ) į = 10.85 - 10.76 (m, 1H), 9.16 - 9.05 (m, 1H), 7.21 - 7.05 (m, 4H), 6.88 - 6.80 (m, 2H), 6.70 - 6.57 (m, 2H), 6.57 - 6.35 (m,6H), 6.20 (d, J = 8.6 Hz, 2H), 4.23 - 4.08 (m, 2H), 3.81 - 3.66 (m, 1H), 3.59 - 3.43 (m, 2H), 3.32 - 3.17 (m, 3H), 3.14 - 3.06 (m, 1H), 3.03 - 2.85 (m, 3H), 2.71- 2.54 (m, 2H), 2.49 - 2.40 (m, 3H), 2.26 - 1.98 (m, 6H), 1.93 - 1.60 (m, 5H), 1.59 - 1.44 (m, 1H), 1.35 (br d, J = 3.3 Hz, 1H), 1.26 - 1.09 (m, 2H).

EXAMPLE 174. Preparation of (I-177) 3-(4-((3aS,6aS)-4-((1-(4-((1R,2S)-6-hydroxy-2- phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperidin-4- yl)methyl)hexahydropyrrolo[3,2-b]pyrrol-1(2H)-yl)phenyl)pipe ridine-2,6-dione Step 1: A mixture oftert-butyl (3aS,6aS)-hexahydropyrrolo[3,2-b]pyrrole-1(2H)-carboxylate (100.0 mg, 1 Eq, 471.1 ^mol) , 3-(4-bromophenyl)piperidine-2,6-dione (138.9 mg, 1.1 Eq, 518.2 ^mol) ,Pd-PEPPSI-IHeptCl (45.82 mg, 0.1 Eq, 47.11 ^mol) cesium carbonate (460.4 mg, 3 Eq, 1.413 mmol) in dioxane (2 mL) was degassed and purged with N ₂ for 3 times, and then the mixture was stirred at 80 °C for 12 hour under N2 atmosphere. LCMS showed 25.5% desired MS. TLC (petroleum ether: ethyl acetate=5:1, UV) showed one main new spot was observed.50 mL water was added, and the mixture was extracted with dichloromethane (10 mL x2). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to dryness in vacuo to give a yellow oil. The aqueous phase was adjust to pH=~7 with 1N HCl, and it was discarded. The yellow oil was purified by flash column (petroleum ether/ethyl acetate from 100/0 to 0/100) and the organic layer was concentrated in vacuo to give tert-butyl tert-butyl (3aS,6aS)-4-(4-(2,6-dioxopiperidin-3- yl)phenyl)hexahydropyrrolo[3,2-b]pyrrole-1(2H)-carboxylate as a yellow solid(100 mg, 250 ^mol). LC-MS (ESI+) m/z: 400.3(M+H) ⁺ . Step 2: A solution of tert-butyl (3aS,6aS)-4-(4-(2,6-dioxopiperidin-3- yl)phenyl)hexahydropyrrolo[3,2-b]pyrrole-1(2H)-carboxylate (100 mg, 1 Eq, 250 ^mol) in DCM (2.5 mL) was added TFA (0.7 g, 0.5 mL, 6 mmol) at 0 °C for 5 min. The reaction was stirred at 20 °C for 3 hour. LCMS showed 31.522% desired MS. The reaction was concentrated in vacuo to give 3-(4-((3aS, 6aS)-hexahydropyrrolo [3,2-b] pyrrol-1(2H)-yl) phenyl) piperidine-2, 6- dione, TFA salt(96 mg, 72 ^mol, 29 %, 31% purity) as a yellow oil. LC-MS (ESI+) m/z: 300.3(M+H) ⁺ . Step 3: To a solution of 1-(4-((1R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthale n-1- yl)phenyl)piperidine-4-carbaldehyde (137 mg, 1 Eq, 334 ^mol), 3-(4-((3aS,6aS)- hexahydropyrrolo[3,2-b]pyrrol-1(2H)-yl)phenyl)piperidine-2,6 -dione, TFA salt(96 mg, 72 ^mol, 29 %, 31% purity) in DCM (2 mL), MeOH (2 mL) was added sodium acetate (82.2 mg, 3 Eq, 1.00 mmol) was stirred at 25 °C for 30 mins, Then sodium triacetoxyborohydride (142 mg, 2 Eq, 668 ^mol) and acetic acid (60.2 mg, 57.6 ^L, 3 Eq, 1.00 mmol) was added .The mixture was stirred at 25 °C for 16 hour. LCMS showed 92% desired MS. The reaction was purified by preparative high-performance liquid chromatography. Condition: Column: Welch Xtimate C18 150*30mm*5um; B: ACN; at the beginning: B (14%); at the end: B (54%); Gradient Time (min) 9; 100% B hold Time (min) 2, Flow Rate (ml/min) 30. The pure fractions were collected and the solvent was evaporated under vacuum. The aqueous layer was lyophilized to dryness to give 3- (4-((3aS,6aS)-4-((1-(4-((1R,2S)-6-hydroxy-2-phenyl-1,2,3,4-t etrahydronaphthalen-1- yl)phenyl)piperidin-4-yl)methyl)hexahydropyrrolo[3,2-b]pyrro l-1(2H)-yl)phenyl)piperidine-2,6- dione (72.7 mg, 105 ^mol, 31.3 %, 99.9% purity) as a pink solid. LCMS: calc. for C ₄₅ H ₅₀ N ₄ O ₃ : 694.92, found: [M+H] ⁺ 695.4. HPLC: 99.855% purity at 220 nm. ¹ H NMR (400MHz, DMSO-d6) į = 10.76 (s, 1 H) 9.12 (s, 1 H) 8.14 (s, 0.959 H) 7.09 - 7.20 (m, 3 H) 6.99 (br d, J=8.23 Hz, 2 H) 6.84 (br d, J=6.56 Hz, 2 H) 6.58 - 6.66 (m, 2 H) 6.46 - 6.56 (m, 5 H) 6.20 (br d, J=8.82 Hz, 2 H) 4.13 (br d, J=5.01 Hz, 2 H) 3.68 (br dd, J=10.43, 4.83 Hz, 1 H) 3.51 (br d, J=8.23 Hz, 2 H) 3.26 (br s, 6 H) 2.89 - 3.03 (m, 3 H) 2.58 - 2.69 (m, 1 H) 2.43 - 2.49 (m, 3 H) 2.03 - 2.28 (m, 5 H) 1.85 (br d, J=12.28 Hz, 3 H) 1.69 (br s, 2 H) 1.54 (br s, 1 H) 1.38 (br SFC: retention time, 3.019/7.507 min; Area, 50.911/49.089%; EXAMPLE 175. Preparation of (I-176) 3-(4-((3aR,6aR)-4-((1-(4-((1R,2S)-6-hydroxy-2- phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperidin-4- yl)methyl)hexahydropyrrolo[3,2-b]pyrrol-1(2H)-yl)phenyl)pipe ridine-2,6-dione Step 1: A mixture of tert-butyl (3aS,6aS)-2,3,3a,5,6,6a-hexahydro-1H-pyrrolo[3,2-b]pyrrole-4 - carboxylate (100 mg, 471.1 ^mol, 1 eq) , 3-(4-bromophenyl)piperidine-2,6-dione (151.6 mg, 565.3 ^mol, 1.2 eq), Pd-PEPPSI-IHeptCl (45.8 mg, 47.1 ^mol, 0.1 eq) ,Cs ₂ CO ₃ (460.4 mg, 1.4 mmol, 3 eq) was added in dioxane (3 mL) ,the mixture was stirred at 100 °C for 4 hr. LCMS showed ~38% desired MS was detected. Then the mixture was treated with H ₂ O (20 mL), extracted with EtOAc (50 mL). The combined extracts was dried over anhydrous Na2SO4, filtered and concentrated to dryness in vacuo to give a residue. The residue was subjected to column chromatography over silica gel (gradient elution: 0~10% ethyl acetate in petroleum ether). The pure fractions were collected and concentrated to dryness in vacuo to give tert-butyl (3aR,6aR)-4-(4-(2,6-dioxopiperidin-3-yl)phenyl)hexahydropyrr olo[3,2-b]pyrrole-1(2H)- carboxylate (120 mg, 300.39 ^mol, 63.77% yield) was obtained as a white solid. LC-MS (ESI+) m/z: 400.01 (M+H)+. Step 2: A mixture of tert-butyl (3aR,6aR)-4-(4-(2,6-dioxopiperidin-3- yl)phenyl)hexahydropyrrolo[3,2-b]pyrrole-1(2H)-carboxylate (120 mg, 300.4 ^mol, 1 eq) was added in DCM (5 mL) and TFA (1 mL) ,the mixture was stirred at 25°C for 0.5 hr, LCMS showed 95% desired MS was detected. The reaction mixture was filtered and concentrated to dryness in vacuo to give 3-(4-((3aR,6aR)-hexahydropyrrolo[3,2-b]pyrrol-1(2H)- yl)phenyl)piperidine-2,6-dione (85 mg, 283.93 ^mol, 94.52% yield). LC-MS (ESI+) m/z: 300 (M+H)+. Step 3: A mixture of 1-(4-((1R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthale n-1- yl)phenyl)piperidine-4-carbaldehyde (123.7 mg, 300.6 ^mol, 1 eq), 3-(4-((3aR,6aR)- hexahydropyrrolo[3,2-b]pyrrol-1(2H)-yl)phenyl)piperidine-2,6 -dione (85 mg, 283.9 ^mol, 0.95 eq), sodium acetate (147.97 mg, 1.80 mmol, 6 eq) was added in DCM (4 mL) and MeOH (4 mL), the mixture was stirred at 25 °C for 0.5 h, and then sodium;triacetoxyboranuide (254.87 mg, 1.20 mmol, 4 eq), acetic acid (498.1 mg, 1.8 mmol, 474.4 ^L, 6 eq) was added in mixture, and was stirred at 25 °C for 12 h. LCMS showed 66% desired MS was detected. The reaction mixture was treated with 30 mL H ₂ O and extracted with EtOAc (50 mL * 2). The organic layers were dried with anhydrous Na ₂ SO ₄ , filtered. The residue was purified by prep. HPLC (column: Welch Xtimate C18150*30mm*5um; mobile phase: [water (FA)-ACN];gradient:21%-51% B over 7 min). The aqueous phase was lyophilized to dryness to give 3-(4-((3aR,6aR)-4-((1-(4- ((1R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-y l)phenyl)piperidin-4- yl)methyl)hexahydropyrrolo[3,2-b]pyrrol-1(2H)-yl)phenyl)pipe ridine-2,6-dione (18.6 mg, 43.17 ^mol, 14.36% yield) was obtained as a white solid. LC-MS (ESI+) m/z: 695.3 (M+H)+. HPLC 100% it t 220 SFC: retention time, 3.208, 6.543 min; Area, 50.482%, 49.518%; ¹ H NMR (400 MHz, DMSO-d ₆ ) į = 10.84 - 10.65 (m, 1H), 9.17 - 9.03 (m, 1H), 8.15 (s, 0.339H), 7.21 - 7.08 (m, 3H), 7.02 - 6.94 (m, 2H), 6.88 - 6.79 (m,2H), 6.69 - 6.58 (m, 2H), 6.57 - 6.43 (m, 5H), 6.25 - 6.16 (m, 2H), 4.22 - 4.09 (m, 2H), 3.73 - 3.63 (m, 1H), 3.56 - 3.45 (m, 2H), 3.31 - 3.18 (m, 4H), 3.16 -3.04 (m, 1H), 3.04 - 2.83 (m, 3H), 2.71 - 2.56 (m, 1H), 2.49 - 2.39 (m, 3H), 2.33 - 1.95 (m, 6H), 1.94 - 1.61 (m, 5H), 1.60 - 1.29 (m, 2H), 1.28 - 1.06 (m, 2H). EXAMPLE 176. Preparation of (I-266) (S)-3-(5-(4-((1-(4-((1S,1'R)-6'-hydroxy-3,3',4,4'- tetrahydro-1'H,2H-1,2'-spirobi[naphthalen]-1'-yl)phenyl)pipe ridin-4-yl)methyl)piperazin- 1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione Step 1: To a solution of (1S,1'R)-1'-(4-(4-(dimethoxymethyl)piperidin-1-yl)phenyl)-3, 3',4,4'- tetrahydro-1'H,2H-1,2'-spirobi[naphthalen]-6'-ol (25.0 mg, 1 Eq, 50.2 ^mol) in THF (1.5 mL)and 10% H ₂ SO ₄ (1.5 mL).The mixture was stirred at 70 °C for 1.5 hour. LCMS showed 95% desired MS was detected. The reaction mixture was quenched by addition H ₂ O 50 mL at 25°C, and then diluted with 50 mL H ₂ O and extracted with Ethyl acetate 30 mL (50 mL * 2). The combined organic layers were washed with brine 10 mL. dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give 1-(4-((1S,1'R)-6'-hydroxy-3,3',4,4'-tetrahydro-1'H,2H-1,2'- spirobi[naphthalen]-1'-yl)phenyl)piperidine-4-carbaldehyde (25.0 mg, 53 ^mol, 100 %, 95% purity) as a white oil. LC-MS (ESI+) m/z: 452.2(M+H) ⁺ . Step 2: To a solution of 1-(4-((1S,1'R)-6'-hydroxy-3,3',4,4'-tetrahydro-1'H,2H-1,2'- spirobi[naphthalen]-1'-yl)phenyl)piperidine-4-carbaldehyde (25 mg, 1 Eq, 55.4 ^mol), (S)-3-(1- oxo-5-(piperazin-1-yl)isoindolin-2-yl)piperidine-2,6-dione, Benzene sulfonic acid (32.3 mg, 1.2 ^mol) was stirred at 25 °C for 60 min, Then sodium triacetoxyhydroborate (23.5 mg, 2 Eq, 110.7 ^mol) and acetic acid (10 mg, 3 Eq, 166.1 ^mol) was added .The mixture was stirred at 25 °C for 16 hour. LCMS showed 96% desired MS was detected. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was purified by prep-HPLC (column: Welch Xtimate C18150*30mm*5um phase: [water(FA)-ACN];B%: 15%-55%,9 min to give (S)-3-(5-(4-((1-(4-((1S,1'R)-6'-hydroxy-3,3',4,4'-tetrahydro -1'H,2H-1,2'-spirobi[naphthalen]-1'- yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindo lin-2-yl)piperidine-2,6-dione (10.4 mg, 13.4 ^mol, 24.2 %, 98.4% purity) as a white solid. LCMS: calc. for C ₄₈ H ₅₃ N ₅ O ₄ : 763.98, found: [M+H] ⁺ 764.4. HPLC: 98.398% purity at 220 nm. ¹ H NMR 1H NMR (400MHz, DMSO-d ₆ ) į = 10.96 (s, 1 H) 9.12 (br s, 0.492 H) 8.21 (s, 1 H) 7.54 (dd, J=17.32, 8.03 Hz, 2 H) 7.10 - 7.16 (m, 1 H) 7.01 - 7.08 (m, 3 H) 6.93 (d, J=7.28 Hz, 1 H) 6.68 (s, 4 H) 6.54 - 6.60 (m, 2 H) 6.43 - 6.49 (m, 1 H) 5.05 (dd, J=13.30, 5.02 Hz, 1 H) 4.52 (s, 1 H) 4.28 - 4.37 (m, 1 H) 4.16 - 4.24 (m, 1 H) 3.50 - 3.63 (m, 2 H) 3.28 (br s, 8 H) 2.91 (br t, J=13.05 Hz, 2 H) 2.54 - 2.62 (m, 4 H) 2.29 - 2.45 (m, 3 H) 2.21 (br d, J=7.28 Hz, 2 H) 1.95 - 2.09 (m, 2 H) 1.65 - 1.82 (m, 5 H) 1.43 - 1.57 (m, 2 H) 1.17 (br d, J=10.04 Hz, 3 H). SFC: retention time, 3.011 min; Area, 96.476%;

EXAMPLE 177. Preparation of (I-265) (S)-3-(5-(4-((1-(4-((1R,1'S)-6'-hydroxy-3,3',4,4'- tetrahydro-1'H,2H-1,2'-spirobi[naphthalen]-1'-yl)phenyl)pipe ridin-4-yl)methyl)piperazin- 1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione Step 1: The starting material was concentrated under reduced pressure to give desired compound as a yellow oil, which was further separated by SFC (condition: column: DAICEL CHIRALPAK AD(250mm*30mm,10um) ); mobile phase: CO ₂ -EtOH(0.1%NH ₃ H ₂ O); B%: 30%-30%) to give (1R,1'S)-1'-(4-(4-(dimethoxymethyl)piperidin-1-yl)phenyl)-3, 3',4,4'-tetrahydro-1'H,2H-1,2'- spirobi[naphthalen]-6'-ol (28.0 mg, 56.3 ^mol, 93.3 %) as a white solid. Step 2: To a solution of (1R,1'S)-1'-(4-(4-(dimethoxymethyl)piperidin-1-yl)phenyl)-3, 3',4,4'- tetrahydro-1'H,2H-1,2'-spirobi[naphthalen]-6'-ol (28.00 mg, 1 Eq, 56.26 ^mol) in THF (1.5 mL)and 10%H ₂ SO ₄ (1.5 mL).The mixture was stirred at 70 °C for 1.5 hour .LCMS showed 94% desired MS was detected. The reaction mixture was quenched by addition H ₂ O 50 mL at 25°C, and then diluted with 50 mL H2O and extracted with Ethyl acetate 30 mL (50 mL * 2). The combined organic layers were washed with brine 10 mL. dried over Na2SO4, filtered and concentrated under reduced pressure to give 1-(4-((1R,1'S)-6'-hydroxy-3,3',4,4'-tetrahydro- 1'H,2H-1,2'-spirobi[naphthalen]-1'-yl)phenyl)piperidine-4-ca rbaldehyde (22.0 mg, 46 ^mol, 81 %, 94% purity) as a residue. LC-MS (ESI+) m/z: 452.2(M+H) ⁺ . Step 3: To a solution of 1-(4-((1R,1'S)-6'-hydroxy-3,3',4,4'-tetrahydro-1'H,2H-1,2'- spirobi[naphthalen]-1'-yl)phenyl)piperidine-4-carbaldehyde (22. mg, 1 Eq, 48.7 ^mol), (S)-3-(1- oxo-5-(piperazin-1-yl)isoindolin-2-yl)piperidine-2,6-dione Benzene sulfonic acid (19.2 mg, 1.2 Eq, 58.5 ^mol) in DCM (2 mL), MeOH (2 mL) was added sodium acetate (12 mg, 3 Eq, 146.1 ^mol) was stirred at 25 °C for 60 min, Then sodium triacetoxyhydroborate (20.7 mg, 2 Eq, 97.4 ^mol) and acetic acid (8.8 mg, 8.4 ^L, 3 Eq, 146.1 ^mol) was added .The mixture was stirred at 25 °C for 16 hour. LCMS showed 85% desired MS was detected. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was purified by prep-HPLC (column: Welch Xtimate C18150*30mm*5um phase: [water(FA)-ACN];B%: 10%-50%,9 min to give (S)-3-(5-(4-((1-(4-((1R,1'S)-6'-hydroxy-3,3',4,4'-tetrahydro -1'H,2H-1,2'- spirobi[naphthalen]-1'-yl)phenyl)piperidin-4-yl)methyl)piper azin-1-yl)-1-oxoisoindolin-2- yl)piperidine-2,6-dione (12.9 mg, 16.6 ^mol, 34.2 %, 98.6% purity) as a white solid. LCMS: calc. for C ₄₈ H ₅₃ N ₅ O ₄ : 763.98, found: [M+H] ⁺ 764.5. HPLC: 98.641% purity at 220 nm. ¹ H NMR 1H NMR (400MHz, DMSO-d ₆ ) į = 10.96 (s, 1 H) 9.11 (br s, 1 H) 8.19 (s, 0.539H) 7.54 (dd, J=17.07, 8.28 Hz, 2 H) 7.13 (t, J=7.40 Hz, 1 H) 7.00 - 7.08 (m, 3 H) 6.93 (d, J=7.03 Hz, 1 H) 6.65 - 6.73 (m, 4 H) 6.53 - 6.59 (m, 2 H) 6.46 (dd, J=8.53, 2.51 Hz, 1 H) 5.05 (dd, J=13.43, 4.89 Hz, 1 H) 4.52 (s, 1 H) 4.28 - 4.37 (m, 1H) 4.15 - 4.24 (m, 1 H) 3.58 (br d, J=10.29 Hz, 2 H) 3.28 (br s, 8 H) 2.86 - 2.97 (m, 2 H) 2.54 - 2.62 (m, 4 H) 2.29 - 2.47 (m, 3 H) 2.21 (br d, J=7.03 Hz, 2 H)1.94 - 2.08 (m, 2 H) 1.59 - 1.82 (m, 5 H) 1.41 - 1.58 (m, 2 H) 1.17 (br d, J=10.54 Hz, 3 H). SFC: retention time, 2.985 min; Area, 94.619%; EXAMPLE 178. Preparation of (I-264) (S)-3-(5-(4-((1-(4-((1S,1'S)-6'-hydroxy-3,3',4,4'- tetrahydro-1'H,2H-1,2'-spirobi[naphthalen]'-yl)phenyl)piperi din-4-yl)methyl)piperazin-1- yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione Step 1: To a solution of (1S,1'S)-1'-(4-(4-(dimethoxymethyl)piperidin-1-yl)phenyl)-3, 3',4,4'- tetrahydro-1'H,2H-1,2'-spirobi[naphthalen]-6'-ol (100. mg, 1 Eq, 200.9 ^mol) in THF (5 mL)and 10% H2SO4 (5 mL).The mixture was stirred at 70 °C for 1.5 hour .LCMS showed 100% desired MS was detected. The reaction mixture was quenched by addition H2O 50 mL at 25°C, and then diluted with 50 mL H ₂ O and extracted with Ethyl acetate 30 mL (50 mL * 2). The combined organic layers were washed with brine 10 mL. dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give 1-(4-((1S,1'S)-6'-hydroxy-3,3',4,4'-tetrahydro-1'H,2H-1,2'- spirobi[naphthalen]-1'-yl)phenyl)piperidine-4-carbaldehyde (98.0 mg, 217 ^mol, 108 %, 100% purity) as a residue. LC-MS (ESI+) m/z: 470.1(M+H) ⁺ . Step 2: To a solution of 1-(4-((1S,1'S)-6'-hydroxy-3,3',4,4'-tetrahydro-1'H,2H-1,2'- spirobi[naphthalen]-1'-yl)phenyl)piperidine-4-carbaldehyde (100 mg, 1 Eq, 221.43 ^mol), (S)-3- (1-oxo-5-(piperazin-1-yl)isoindolin-2-yl)piperidine-2,6-dion e, Benzene sulfonic acid (87.3 mg, 1.2 Eq, 265.7 ^mol) in DCM (2 mL), MeOH (2 mL) was added sodium acetate (54.5 mg, 3 Eq, 664.3 ^mol) was stirred at 25 °C for 60 min, Then sodium triacetoxyhydroborate (93.9 mg, 2 Eq, 442.9 ^mol) and acetic acid (39.9 mg, 3 Eq, 664.3 ^mol) was added .The mixture was stirred at 25 °C for 16 hour. LCMS showed 95% desired MS was detected. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was purified by prep-HPLC (column: Welch Xtimate C18150*30mm*5um phase: [water(FA)-ACN];B%: 18%-58%,9 min to give (S)-3-(5-(4-((1-(4-((1S,1'S)-6'-hydroxy-3,3',4,4'-tetrahydro -1'H,2H-1,2'- yl)piperidine-2,6-dione (64.3 mg, 83.7 ^mol, 37.8 %, 99.5% purity) was obtained as a white solid. LCMS: calc. for C ₄₈ H ₅₃ N ₅ O ₄ : 763.98, found: [M+H] ⁺ 764.4. HPLC: 99.457% purity at 220 nm. ¹ H NMR 1H NMR (400MHz, DMSO-d ₆ ) į = 10.96 (s, 1 H) 9.09 (br s, 1 H) 8.14 (s, 0.498 H) 7.53 (d, J=8.58 Hz, 1 H) 7.00 - 7.10 (m, 3 H) 6.91 - 6.98 (m, 1 H) 6.54 - 6.63 (m, 5 H) 6.46 (dd, J=8.23, 2.38 Hz, 1 H) 6.27 (br d, J=8.23 Hz, 2 H) 6.04 (d, J=7.87 Hz, 1 H) 5.06 (dd, J=13.29, 5.07 Hz, 1 H) 4.28 - 4.37 (m, 1 H) 4.16 - 4.25 (m, 1 H) 4.01 (s, 1 H) 3.54 (br d, J=11.44 Hz, 2 H) 3.30 (br s, 6 H) 2.85 - 2.97 (m, 4 H) 2.73 - 2.82 (m, 1 H) 2.61 (br s, 6 H) 2.34 - 2.43 (m, 1 H) 2.23 (br s, 2 H) 1.90 - 2.02 (m, 3 H) 1.76 (br d, J=10.37 Hz, 3 H) 1.67 (br s, 1 H) 1.43 - 1.53 (m, 1 H) 1.33 (br d, J=8.70 Hz, 1 H) 1.14 - 1.25 (m, 2 H) SFC: retention time, 2.640 min; Area, 96.850%.

EXAMPLE 179. Preparation of (I-263) (S)-3-(5-(4-((1-(4-((1R,1'R)-6'-hydroxy-3,3',4,4'- tetrahydro-1'H,2H-1,2'-spirobi[naphthalen]-1'-yl)phenyl)pipe ridin-4-yl)methyl)piperazin- 1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione Step 1: A 100 mL thread vial equipped with magnetic stirrer. Tris(triphenylphosphine)ruthenium(II)Dichloride (760 mg, 0.1 Eq, 793 ^mol),potassium hydroxide (445 mg, 1 Eq, 7.93 mmol),3-(2-bromophenyl)propan-1-ol (2.05 g, 1.2 Eq, 9.51 mmol) and 6-(benzyloxy)-3,4-dihydronaphthalen-1(2H)-one (2.00 g, 1 Eq, 7.93 mmol) was added in toluene (20 mL) at 100 °C for 16 hour under N ₂ atmosphere. TLC (petroleum ether: ethyl acetate=10:1, UV) showed one main new spot was observed.50 mL water was added, and the mixture was extracted with dichloromethane (100 mL x2). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to dryness in vacuum to give a yellow oil. The yellow oil was purified by flash column (petroleum ether/ethyl acetate from 100/0 to 0/100) and the organic layer was concentrated in vacuo to give 6-(benzyloxy)-2-(3-(2-bromophenyl) propyl)-3, 4-dihydronaphthalen-1(2H)-one (1.9 g, 3.4 mmol, 42 %, 79.4% purity) as a yellow solid. LC-MS (ESI+) m/z: 451.2(M+H) ⁺ . Step 2: To a mixture of 6-(benzyloxy)-2-(3-(2-bromophenyl)propyl)-3,4-dihydronaphtha len- 1(2H)-one (1 g, 1 Eq, 2.23 mmol), Pd(OAc) ₂ (50. mg, 0.1 Eq, 223 ^mol) and 2,2'- bis(diphenylphosphaneyl)-1,1'-binaphthalene (139 mg, 0.1 Eq, 223 ^mol) and cesium carbonate (2.18 g, 3 Eq, 6.68 mmol) in 1,4-Dioxane (10 mL) was stirred at 100 °C for 12 hour under N2. TLC (petroleum ether: ethyl acetate=5:1, UV) showed one main new spot was observed.100 mL water was added, and the mixture was extracted with dichloromethane (200 mL x2). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to dryness in vacuo to give a yellow oil. The yellow oil was purified by preparative high-performance liquid chromatography. Condition: Column: Xtimate C18 150*40mm*5um A: water (FA) B: ACN; at the beginning: A (45%) and B (55%); at the end: A: (5%) and B (95%); Gradient Time (min) 9; 100% B hold Time (min) 2, Flow Rate (ml/min) 30. The pure fractions were collected and the solvent was evaporated under vacuum. The aqueous layer was lyophilized to dryness to give 6'-(benzyloxy)-3,3',4,4'-tetrahydro-1'H,2H-1,2'- spirobi[naphthalen]-1'-one (450 mg, 1.22 mmol, 54.9 %) as a yellow solid. Step 3: To a solution of 1-(4-bromophenyl)-4-(dimethoxymethyl) piper dine (1.1g, 3 Eq, 3.5 mmol) in THF (20 mL) was added n-Butyl lithium, 2.5 M in hexane (186.9 mg, 1.167 mL, 2.5 molar, 2.5 Eq, 2.9174 mmol) at -68 °C over 5 min. After addition, the mixture was stirred at - 68 °C for 1 hour, and then 6'-(benzyloxy)-3,3',4,4'-tetrahydro-1'H,2H-1,2'-spirobi[naph thalen]-1'- one (430 mg 1 Eq 11670 mmol)was added dropwise at -68°C The resulting mixture was stirred at 25 °C for 16 hour. TLC (petroleum ether: ethyl acetate=5:1, UV) showed one main new spot was observed. The reaction was quenched with water (200 mL) and extracted with ethyl acetate (200 mL*2). The organic layer was washed with brine (100 mL) and dried over Na ₂ SO ₄ and concentrated in vacuo to give a yellow oil. The white solid was subjected to column chromatography over silica gel (20 g gradient elution: 0 – 30% EtOAc). The desired fractions were collected, and concentrated to dryness in vacuo to give 6'-(benzyloxy)-1'-(4-(4- (dimethoxymethyl)piperidin-1-yl)phenyl)-3,3',4,4'-tetrahydro -1'H,2H-1,2'-spirobi[naphthalen]- 1'-ol (500 mg, 828 ^mol, 71.0 %) as a yellow solid. LC-MS (ESI+) m/z: 606.4(M+H) ⁺ . Step 4: To a solution of 6'-(benzyloxy)-1'-(4-(4-(dimethoxymethyl)piperidin-1-yl)phen yl)- 3,3',4,4'-tetrahydro-1'H,2H-1,2'-spirobi[naphthalen]-1'-ol (500 mg, 1 Eq, 828.09 ^mol) in MeOH (5 mL) and THF (5 mL)was added palladium on carbon (500 mg, 10% Wt., 0.567 Eq, 470 ^mol) under N ₂ atmosphere. The suspension was degassed and purged with dihydrogen for 3 mines. The mixture was stirred under 15 Psi dihydrogen (1.67 mg, 1 Eq, 828.09 ^mol) at 50 °C for 16 hr. LCMS showed 74.512% desired MS was detected. The mixture was filtered and concentrated under reduced pressure to give a residue. The residue was concentrated under reduced pressure to give desired compound as a yellow oil, which was further separated by SFC (condition: column: DAICEL CHIRALPAK AD (250mm*30mm, 10um)); mobile phase: CO ₂ -EtOH (0.1%NH ₃ H ₂ O) ; B%: 35%-35%) to give (1R,1'R)-1'-(4-(4-(dimethoxymethyl)piperidin-1- yl)phenyl)-3,3',4,4'-tetrahydro-1'H,2H-1,2'-spirobi[naphthal en]-6'-ol (160.0 mg, 321.5 ^mol, 38.82 %) and (1S,1'S)-1'-(4-(4-(dimethoxymethyl)piperidin-1-yl)phenyl)-3, 3',4,4'-tetrahydro- 1'H,2H-1,2'-spirobi[naphthalen]-6'-ol (150.0 mg, 301.4 ^mol, 36.40 %) and (1S,1'R)-1'-(4-(4- (dimethoxymethyl)piperidin-1-yl)phenyl)-3,3',4,4'-tetrahydro -1'H,2H-1,2'-spirobi[naphthalen]- 6'-ol (35.0 mg, 70.3 ^mol, 8.49 %) and (1R,1'S)-1'-(4-(4-(dimethoxymethyl)piperidin-1- yl)phenyl)-3,3',4,4'-tetrahydro-1'H,2H-1,2'-spirobi[naphthal en]-6'-ol (25.0 mg, 50.2 ^mol, 6.07 %) as a white solid. Step 5: To a solution of (1R,1'R)-1'-(4-(4-(dimethoxymethyl)piperidin-1-yl)phenyl)-3, 3',4,4'- tetrahydro-1'H,2H-1,2'-spirobi[naphthalen]-6'-ol (100.0 mg, 1 Eq, 200.9 ^mol) in THF (5 mL) and 10%H ₂ SO ₄ (5 mL).The mixture was stirred at 70 °C for 1.5 hour .LCMS showed 100% desired MS was detected. The reaction mixture was quenched by addition H2O 50 mL at 25°C, and then diluted with 50 mL H2O and extracted with Ethyl acetate 30 mL (50 mL * 2). The combined organic layers were washed with brine 10 mL. dried over Na ₂ SO ₄ , filtered and 1'H,2H-1,2'-spirobi[naphthalen]-1'-yl)phenyl)piperidine-4-ca rbaldehyde (102 mg, 226 ^mol, 112 %, 100% purity) as a residue. LC-MS (ESI+) m/z: 470.2(M+H) ⁺ . Step 6: To a solution of 1-(4-((1R,1'R)-6'-hydroxy-3,3',4,4'-tetrahydro-1'H,2H-1,2'- spirobi[naphthalen]-1'-yl)phenyl)piperidine-4-carbaldehyde (100 mg, 1 Eq, 221.4 ^mol), (S)-3- (1-oxo-5-(piperazin-1-yl)isoindolin-2-yl)piperidine-2,6-dion e, Benzene sulfonic acid (129.3 mg, 1.2 Eq, 265.7 ^mol) in DCM (2 mL), MeOH (2 mL) was added sodium acetate (54.5 mg, 3 Eq, 664.3 ^mol) was stirred at 25 °C for 60 min, Then sodium triacetoxyborohydride (93.9 mg, 2 Eq, 442.86 ^mol) and acetic acid (39.9 mg, 38.2 ^L, 3 Eq, 664.29 ^mol) was added .The mixture was stirred at 25 °C for 16 hour. LCMS showed 92% desired MS was detected. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was purified by prep-HPLC (column: Welch Xtimate C18150*30mm*5um phase: [water(FA)-ACN];B%: 12%- 52%,9 min to give (S)-3-(5-(4-((1-(4-((1R,1'R)-6'-hydroxy-3,3',4,4'-tetrahydro -1'H,2H-1,2'- spirobi[naphthalen]-1'-yl)phenyl)piperidin-4-yl)methyl)piper azin-1-yl)-1-oxoisoindolin-2- yl)piperidine-2,6-dione (142.6 mg, 185 ^mol, 83.5 %, 99.1% purity) was obtained as a white solid. LCMS: calc. for C48H53N5O4: 763.98, found: [M+H] ⁺ 764.4. HPLC: 99.123% purity at 220 nm. ¹ H NMR 1H NMR (400MHz, DMSO-d ₆ ) į = 10.96 (s, 1 H) 9.09 (br s, 1 H) 8.14 (s, 0.648 H) 7.52 (d, J=8.46 Hz, 1 H) 7.00 - 7.10 (m, 3 H) 6.91 - 6.98 (m, 1 H) 6.54 - 6.65 (m, 5 H) 6.46 (dd, J=8.23, 2.38 Hz, 1 H) 6.27 (br d, J=7.99 Hz, 2 H) 6.04 (d, J=7.99 Hz, 1 H) 5.05 (dd, J=13.23, 5.13 Hz, 1 H) 4.33 (br d, J=16.81 Hz, 1 H) 4.16 - 4.27 (m, 1 H) 4.01 (s, 1 H) 3.54 (br d, J=10.85 Hz, 2 H) 3.29 (br s, 8 H) 2.91 (br s, 3 H) 2.84 - 2.96 (m, 1 H) 2.78 (br dd, J=16.81, 6.56 Hz, 1 H) 2.54 - 2.59 (m, 4 H) 2.34 - 2.42 (m, 1 H) 2.23 (br d, J=5.96 Hz, 2 H) 1.96 (br d, J=10.37 Hz, 3 H) 1.76 (br d, J=10.37 Hz, 3 H) 1.66 (br s, 1 H) 1.42 - 1.53 (m, 1 H) 1.33 (br d, J=8.94 Hz, 1 H) 1.14 - 1.25 (m, 2 H) SFC: retention time, 2.511 min; Area, 96.141%; EXAMPLE 180. Preparation of (I-262) (S)-3-(5-(4-((1-(4-((1R,1'S)-6'-hydroxy-2,3,3',4'- tetrahydro-1'H-spiro[indene-1,2'-naphthalen]-1'-yl)phenyl)pi peridin-4- yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2, 6-dione Step 1: 1-(4-((1R,1'S)-6'-hydroxy-2,3,3',4'-tetrahydro-1'H-spiro[ind ene-1,2'-naphthalen]-1'- yl)phenyl)piperidine-4-carbaldehyde (90 mg, 0.20 mmol, 100 %, 95.363% purity) in sulfuric acid (187 mg, 3 mL, 10% Wt, 1 Eq, 190 ^mol) and THF (3 mL) for stirred at 70 °C for 16 hour. LCMS showed 95.363% desired MS. The reaction was adjust to pH=~7 with NaHCO3, then 50 mL water was added, and the mixture was extracted with dichloromethane (100 mL x2). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to dryness in vacuum to give a yellow oil. The yellow oil was concentrated in vacuum to give 1-(4-((1R, 1’S)-6'-hydroxy-2, 3, 3’, 4’-tetrahydro-1'H-spiro [indene-1, 2’-naphthalen]-1'-yl)phenyl)piperidine-4-carbaldehyde (90 mg, 0.20 mmol, 100 %, 95.363% purity) as a yellow solid. LC-MS (ESI+) m/z: 438.1(M+H) ⁺ . Step 2: To a solution of 1-(4-((1R,1'S)-6'-hydroxy-2,3,3',4'-tetrahydro-1'H-spiro[ind ene-1,2'- naphthalen]-1'-yl)phenyl)piperidine-4-carbaldehyde (90.0 mg, 1 Eq, 206 ^mol), (S)-3-(1-oxo-5- (piperazin-1-yl)isoindolin-2-yl)piperidine-2,6-dione, Benzenesulfonic acid salt (123 mg, 1.2 Eq, 247 ^mol) in DCM (2 mL), MeOH (2 mL) was added sodium acetate (50.6 mg, 3 Eq, 617 ^mol) was stirred at 25 °C for 60 mines, Then sodium triacetoxyborohydride (87.2 mg, 2 Eq, 411 ^mol) and acetic acid (37.1 mg, 35.5 ^L, 3 Eq, 617 ^mol) was added .The mixture was stirred at 25 °C for 16 hour. LCMS showed 87.956% desired MS was detected. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was purified by prep-HPLC (column: Welch Xtimate C18150*30mm*5um phase: [water(FA)-ACN];B%: 10%-50%,9min to naphthalen]-1'-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-y l)-1-oxoisoindolin-2-yl)piperidine- 2,6-dione (51.2 mg, 68.3 ^mol, 33.2 %, 100% purity) was obtained as a white solid. LC-MS (ESI+) m/z: 750.4(M+H) ⁺ . LCMS: calc. for C ₄₇ H ₅₁ N ₅ O ₄ , found: [M+H] ⁺ 750.2. HPLC: 100% purity at 220 nm. NMR (400MHz, DMSO-d ₆ ) į = 10.96 (s, 1 H) 9.14 (br s, 1 H) 8.16 (s, 0.382 H) 7.53 (d, J=8.70 Hz, 1 H) 7.05 - 7.11 (m, 5 H) 6.93 - 7.00 (m, 1 H) 6.69 (s, 4 H) 6.62 (d, J=8.58 Hz, 1 H) 6.58 (d, J=2.26 Hz, 1 H) 6.49 (dd, J=8.34, 2.50 Hz, 1 H) 5.05 (dd, J=13.41, 5.07 Hz, 1 H) 4.29 - 4.37 (m, 1 H) 4.17 - 4.25 (m, 1 H) 3.96 (s, 1 H) 3.59 (br d, J=10.37 Hz, 2 H) 3.29 (br s, 5 H) 2.86 - 2.95 (m, 2 H) 2.52 - 2.68 (m, 7 H) 2.27 - 2.48 (m, 2 H) 2.22 (br d, J=7.03 Hz, 2 H) 2.03 - 2.16 (m, 2 H) 1.89 - 1.99 (m, 2 H) 1.77 - 1.87 (m, 3 H) 1.67 (br s, 1 H) 1.32 - 1.43 (m, 1 H) 1.16 - 1.26 (m, 2 H) SFC: retention time, 2.834 min; Area, 93.878%; EXAMPLE 181. Preparation of (I-261) (S)-3-(5-(4-((1-(4-((1S*,1'R*)-6'-hydroxy- 2,3,3',4'-tetrahydro-1'H-spiro[indene-1,2'-naphthalen]-1'-yl )phenyl)piperidin-4- yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2, 6-dione Step 1: 1-(4-((1S,1'R)-6'-hydroxy-2,3,3',4'-tetrahydro-1'H-spiro[ind ene-1,2'-naphthalen]-1'- yl)phenyl)piperidine-4-carbaldehyde (105 mg, 236 ^mol, 114 %, 98.453% purity) in sulfuric acid (202.8 mg, 3 mL, 10% Wt, 1 Eq, 206.8 ^mol) and THF (3 mL) for stirred at 70 °C for 16 hour. LCMS showed 98.453% desired MS. The reaction was adjust to pH=~7 with NaHCO ₃ , The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4, filtered and concentrated to dryness in vacuo to give a yellow oil. The yellow oil was concentrated in vacuo to give 1-(4-((1S,1’R)-6'-hydroxy-2, 3, 3’, 4’-tetrahydro-1'H-spiro [indene-1, 2’-naphthalen]-1'-yl)phenyl)piperidine-4-carbaldehyde (105 mg, 236 ^mol, 114 %, 98.453% purity) as a yellow solid. LC-MS (ESI+) m/z: 438.1(M+H) ⁺ . Step 2: To a solution of 1-(4-((1S,1'R)-6'-hydroxy-2,3,3',4'-tetrahydro-1'H-spiro[ind ene-1,2'- naphthalen]-1'-yl)phenyl)piperidine-4-carbaldehyde (100.0 mg, 1 Eq, 228.5 ^mol), (S)-3-(1-oxo- 5-(piperazin-1-yl)isoindolin-2-yl)piperidine-2,6-dione, Benzenesulfonic acid salt (137.2 mg, 1.2 Eq, 274.2 ^mol) in DCM (2 mL), MeOH (2 mL) was added sodium acetate (56.24 mg, 3 Eq, 685.6 ^mol) was stirred at 25 °C for 60 mins, Then sodium triacetoxyborohydride (96.87 mg, 2 Eq, 457.1 ^mol) and acetic acid (41.17 mg, 39.43 ^L, 3 Eq, 685.6 ^mol) was added .The mixture was stirred at 25 °C for 16 hour. LCMS showed 86.788% desired MS was detected. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was purified by prep-HPLC (column: Welch Xtimate C18150*30mm*5um phase: [water(FA)-ACN];B%: 10%- 50%,9min to give (S)-3-(5-(4-((1-(4-((1S,1'R)-6'-hydroxy-2,3,3',4'-tetrahydro -1'H-spiro[indene- 1,2'-naphthalen]-1'-yl)phenyl)piperidin-4-yl)methyl)piperazi n-1-yl)-1-oxoisoindolin-2- yl)piperidine-2,6-dione (46.6 mg, 62.0 ^mol, 27.1 %, 99.8% purity) was obtained as a white solid. LC-MS (ESI+) m/z: 750.4(M+H) ⁺ . LCMS: calc. for C ₄₇ H ₅₁ N ₅ O ₄ , found: [M+H] ⁺ 750.2. HPLC: 99.8% purity at 220 nm. ¹ H NMR (400MHz, DMSO-d ₆ ) į = 10.96 (s, 1 H) 9.11 (br s, 1 H) 8.16 (s, 0.530H) 7.53 (d, J=8.70 Hz, 1 H) 7.04 - 7.11 (m, 5 H) 6.94 - 6.99 (m, 1 H) 6.69 (s, 4 H) 6.62 (d, J=8.46 Hz, 1 H) 6.58 (d, J=2.27 Hz, 1 H) 6.50 (dd, J=8.34, 2.38 Hz, 1 H) 5.06 (dd, J=13.17, 5.07 Hz, 1 H) 4.30 - 4.38 (m, 1 H) 4.16 - 4.25 (m, 1 H) 3.95 (s, 1 H) 3.51 - 3.75 (m, 2 H) 3.29 (br s, 6 H) 2.86 - 2.95 (m, 2 H) 2.55 - 2.66 (m, 5 H) 2.52 - 2.54 (m, 2 H) 2.37 (td, J=13.20, 8.52 Hz, 1 H) 2.22 (br d, J=7.03 Hz, 2 H) 2.04 - 2.18 (m, 2 H) 1.89 - 1.99 (m, 2 H) 1.76 - 1.87 (m, 3 H) 1.67 (br s, 1 H) 1.34 - 1.42 (m, 1 H) 1.15 - 1.26 (m, 2 H). SFC: retention time, 2.892 min; Area, 93.884%; EXAMPLE 182. Preparation of (I-260) (S)-3-(5-(4-((1-(4-((1S,1'S)-6'-hydroxy-2,3,3',4'- tetrahydro-1'H-spiro[indene-1,2'-naphthalen]-1'-yl)phenyl)pi peridin-4- yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2, 6-dione Step 1: 1-(4-((1S,1'S)-6'-hydroxy-2,3,3',4'-tetrahydro-1'H-spiro[ind ene-1,2'-naphthalen]-1'- yl)phenyl)piperidine-4-carbaldehyde (130 mg, 293 ^mol, 94.4 %, 98.506% purity) in sulfuric acid (304.2 mg, 3 mL, 10% Wt, 1 Eq, 310.1 ^mol) and THF (3 mL) was stirred at 70 °C for 16 hour. LCMS showed 84.729% desired MS. The reaction was adjust to pH=~7 with NaHCO ₃ , then 50 mL water was added, and the mixture was extracted with dichloromethane (100 mL x2). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to dryness in vacuum to give a yellow oil. The yellow oil was concentrated in vacuum to give 1-(4-((1S,1’S)-6'-hydroxy-2, 3, 3’, 4’-tetrahydro-1'H- spiro[indene-1, 2’-naphthalen]-1'-yl)phenyl)piperidine-4-carbaldehyde (130 mg, 293 ^mol, 94.4 %, 98.506% purity) as a yellow solid. LC-MS (ESI+) m/z: 456.3(M+H) ⁺ . Step 2: To a solution of 1-(4-((1S,1'S)-6'-hydroxy-2,3,3',4'-tetrahydro-1'H-spiro[ind ene-1,2'- naphthalen]-1'-yl)phenyl)piperidine-4-carbaldehyde (130.0 mg, 1 Eq, 297.1 ^mol), (S)-3-(1-oxo- 5-(piperazin-1-yl)isoindolin-2-yl)piperidine-2,6-dione, Benzenesulfonic acid salt (178.4 mg, 1.2 Eq, 356.5 ^mol) in DCM (2 mL), MeOH (2 mL) was added sodium acetate (73.11 mg, 3 Eq, 891.3 ^mol) was stirred at 25 °C for 60 mines, Then sodium triacetoxyborohydride (125.9 mg, 2 Eq, 594.2 ^mol) and acetic acid (53.52 mg, 51.26 ^L, 3 Eq, 891.3 ^mol) was added .The mixture was stirred at 25 °C for 16 hour. LCMS showed 99% desired MS was detected. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was purified by prep-HPLC (column: Xtimate C18150*40mm*5um phase: [water(FA)-ACN];B%: 15%- 1,2'-naphthalen]-1'-yl)phenyl)piperidin-4-yl)methyl)piperazi n-1-yl)-1-oxoisoindolin-2- yl)piperidine-2,6-dione (71.8 mg, 94.2 ^mol, 31.7 %, 98.4% purity) was obtained as a white solid. LC-MS (ESI+) m/z: 750.4(M+H) ⁺ . LCMS: calc. for C ₄₇ H ₅₁ N ₅ O ₄ , found: [M+H] ⁺ 750.2. HPLC: 98.356% purity at 220 nm. NMR (400MHz, DMSO-d ₆ ) į = 10.96 (s, 1 H) 9.11 (s, 1 H) 8.14 (s, 0.201 H) 7.53 (d, J=8.82 Hz, 1 H) 7.18 (d, J=7.39 Hz, 1 H) 7.03 - 7.10 (m, 3 H) 6.77 (t, J=7.51 Hz, 1 H) 6.57 - 6.62 (m, 4 H) 6.46 (dd, J=8.34, 2.38 Hz, 1 H) 6.29 (br d, J=7.87 Hz, 2 H) 5.92 (d, J=7.63 Hz, 1 H) 5.05 (dd, J=13.29, 5.07 Hz, 1 H) 4.33 (d, J=17.05 Hz, 1 H) 4.17 - 4.26 (m, 1 H) 3.80 (s, 1 H) 3.56 (br d, J=11.80 Hz, 2 H) 3.30 (br s, 6 H) 3.00 - 3.07 (m, 1 H) 2.86 - 2.95 (m, 3 H) 2.74 - 2.81 (m, 1 H) 2.53 - 2.63 (m, 5 H) 2.31 - 2.39 (m, 2 H) 2.24 (br d, J=5.13 Hz, 2 H) 1.89 - 2.00 (m, 3 H) 1.78 (br d, J=11.56 Hz, 2 H) 1.67 (br s, 1 H) 1.40 - 1.48 (m, 1 H) 1.16 - 1.26 (m, 2 H) SFC: retention time, 2.86 min; Area, 91.472%;

EXAMPLE 183. Preparation of (I-259) (S)-3-(5-(4-((1-(4-((1R,1'R)-6'-hydroxy-2,3,3',4'- tetrahydro-1'H-spiro[indene-1,2'-naphthalen]-1'-yl)phenyl)pi peridin-4- yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2, 6-dione Step 1: To a stirred solution of 6-(benzyloxy)-3,4-dihydronaphthalen-1(2H)-one (41.4 g, 3 Eq, 164 mmol) in DMSO (50 mL) were added sodium 2-methylpropan-2-olate (2.10 g, 2.36 mL, 0.4 Eq, 21.9 mmol) and 1-bromo-2-vinylbenzene (10.0 g, 6.85 mL, 1 Eq, 54.6 mmol).The reaction mixture was vigorously stirred for 15 h at 40 °C. LCMS showed 23.435% desired MS.TLC (petroleum ether: ethyl acetate=5:1, UV) showed one main new spot was observed.500 mL combined organic layers were washed with brine(10 mL), dried over anhydrous Na2SO4, filtered and concentrated to dryness in vacuum to give a yellow oil. The yellow oil was purified by flash column (petroleum ether/ethyl acetate from 100/0 to 0/100) and the organic layer was concentrated in vacuum to give 6-(benzyloxy)-2-(2-bromophenethyl)-3, 4-dihydronaphthalen- 1(2H)-one (2 g, 5 mmol, 8 %) as a yellow solid. The yellow solid was purified by preparative high-performance liquid chromatography. Condition: Column: Welch Xtimate C18 150*30mm*5um A: water (FA) B: ACN at the beginning: A (80%) and B (20%) at the end: A: (0%) and B (100%) Gradient Time (min) 9; 100% B hold Time (min) 2, Flow Rate (ml/min) 30. The pure fractions were collected and the solvent was evaporated under vacuum. The aqueous layer was lyophilized to dryness to give 6-(benzyloxy)-2-(2-bromophenethyl)-3, 4- dihydronaphthalen-1(2H)-one (2 g, 5 mmol, 8 %) as a yellow solid. Step 2: To a mixture of(RS)-4-(Anthracen-9-yl)-3-(Tert-Butyl)-2,3- Dihydrobenzo[d][1,3]Oxaphosphole (204 mg, 0.12 Eq, 551 ^mol), sodium 2-methylpropan-2- olate (1.10 g, 2.5 Eq, 11.5 mmol) and Tris(dibezylideneacetone)dipalladium (421 mg, 0.1 Eq, 459 ^mol) and 6-(benzyloxy)-2-(2-bromophenethyl)-3,4-dihydronaphthalen-1(2 H)-one (2.00 g, 1 Eq, 4.59 mmol) in THF (30 mL)and water (6 mL) was stirred at 70 °C for 16 hour under N2. LCMS showed 57.487% desired MS. TLC (petroleum ether: ethyl acetate=5:1, UV) showed one main new spot was observed.100 mL water was added, and the mixture was extracted with dichloromethane (200 mL x2). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to dryness in vacuum to give a yellow oil. The yellow oil was purified by flash column (petroleum ether/ethyl acetate from 100/0 to 0/100) and the organic layer was concentrated in vacuum to give 6'-(benzyloxy)-2,3,3',4'- tetrahydro-1'H-spiro[indene-1,2'-naphthalen]-1'-one (1.5 g, 3.0 mmol, 66 %, 71.352% purity) as a yellow solid. LC-MS (ESI+) m/z: 335.2(M+H) ⁺ . Step 3: To a solution of 1-(4-bromophenyl)-4-(dimethoxymethyl) piperidine (2.00 g, 1 Eq, 6.36 mmol) in THF (50 mL) was added n-Butyl lithium, 2.5M in hexane (408 mg, 2.55 mL, 2.5 molar, 1 Eq, 6.36 mmol) at -68 °C under N ₂ over 5 min. After addition, the mixture was stirred at -68 °C for 1 hour and then 6'-(benzyloxy)-2, 3, 3’, 4’-tetrahydro-1'H-spiro [indene-1, 2’- naphthalen]-1'-one (1.42 g, 0.45 Eq, 2.86 mmol) was added dropwise at -68°C. The resulting mixture was stirred at 25 °C for 16 hour. LCMS showed 48.689% desired MS. The reaction was quenched with water (200 mL) and extracted with ethyl acetate(200 mL*2) The organic layer was washed with brine(100 mL) and dried over Na2SO4 and concentrated in vacuum to give a yellow oil. The white solid was subjected to column chromatography over silica gel (20 g gradient elution: 0 – 30% EtOAc).The desired fractions were collected, and concentrated to dryness in vacuum to give 6'-(benzyloxy)-1'-(4-(4-(dimethoxymethyl)piperidin-1-yl)phen yl)- 2,3,3',4'-tetrahydro-1'H-spiro[indene-1,2'-naphthalen]-1'-ol (400 mg, 0.66 mmol, 10 %, 97% purity) and 6'-(benzyloxy)-2,3,3',4'-tetrahydro-1'H-spiro[indene-1,2'-na phthalen]-1'-one (800 mg, 2.26 mmol, 35.5 %)as a yellow solid. LC-MS (ESI+) m/z: 572.3(M+H) ⁺ . Step 4: To a solution of 6'-(benzyloxy)-1'-(4-(4-(dimethoxymethyl)piperidin-1-yl)phen yl)- 2,3,3',4'-tetrahydro-1'H-spiro[indene-1,2'-naphthalen]-1'-ol (1.00 g, 1 Eq, 1.39 mmol) in MeOH (20 mL) and THF (20 mL) was added Pd/C (1.48 g, 10% Wt, 1 Eq, 1.39 mmol) under N ₂ atmosphere. The suspension was degassed and purged with dihydrogen for 3 mins. The mixture was stirred under 15 psi dihydrogen (2.81 mg, 1 Eq, 1.39 mmol) at 50 °C for 16 hr. LCMS showed 74.8% desired MS was detected. The mixture was filtered and concentrated under reduced pressure to give 1'-(4-(4-(dimethoxymethyl)piperidin-1-yl)phenyl)-2,3,3',4'-t etrahydro- 1'H-spiro[indene-1,2'-naphthalen]-6'-ol (0.8 g, 2 mmol, 100 %) as a yellow solid. The compounds were concentrated under reduced pressure to give desired compound as a yellow oil, which was further separated by SFC (condition: column : DAICEL CHIRALCEL OJ(250mm*30mm,10um)); mobile phase: [0.1% NH3.H2O EtOH]; B%: 35%-35%) to give (1R,1'R)-1'-(4-(4-(dimethoxymethyl)piperidin-1-yl)phenyl)-2, 3,3',4'-tetrahydro-1'H- spiro[indene-1,2'-naphthalen]-6'-ol (0.3 g, 0.6 mmol,) and (1S,1'S)-1'-(4-(4- (dimethoxymethyl)piperidin-1-yl)phenyl)-2,3,3',4'-tetrahydro -1'H-spiro[indene-1,2'-naphthalen]- 6'-ol (0.3 g, 0.6 mmol,) and (1S,1'R)-1'-(4-(4-(dimethoxymethyl)piperidin-1-yl)phenyl)-2, 3,3',4'- tetrahydro-1'H-spiro[indene-1,2'-naphthalen]-6'-ol (0.145 g, 300 ^mol,) and (1R,1'S)-1'-(4-(4- (dimethoxymethyl)piperidin-1-yl)phenyl)-2,3,3',4'-tetrahydro -1'H-spiro[indene-1,2'-naphthalen]- 6'-ol (0.14 g, 0.29 mmol, 21 %)as a white solid. LC-MS (ESI+) m/z: 484.3(M+H) ⁺ . Step 5: (1R, 1’R)-1'-(4-(4-(dimethoxymethyl)piperidin-1-yl)phenyl)-2,3, 3',4'-tetrahydro-1'H- spiro[indene-1,2'-naphthalen]-6'-ol (150.0 mg, 1 Eq, 310.1 ^mol) in sulfuric acid (304.2 mg, 3 mL, 10% Wt, 1 Eq, 310.1 ^mol) and THF (3 mL) for stirred at 70 °C for 16 hour. LCMS showed 96.995% desired MS. The reaction was adjust to pH=~7 with NaHCO3, then 50 mL water was added, and the mixture was extracted with dichloromethane (100 mL x2). The combined organic layers were washed with brine (100 mL) dried over anhydrous Na ₂ SO ₄ filtered and concentrated to dryness in vacuo to give a yellow oil. The yellow oil was concentrated in vacuo to give 1-(4-((1R, 1’R)-6'-hydroxy-2, 3, 3’, 4’-tetrahydro-1'H-spiro[indene-1, 2’-naphthalen]-1'- yl)phenyl)piperidine-4-carbaldehyde (110 mg, 244 ^mol, 78.6 %, 96.995% purity) as a yellow solid. LC-MS (ESI+) m/z: 456.3(M+H) ⁺ . Step 6: To a solution of 1-(4-((1R,1'R)-6'-hydroxy-2,3,3',4'-tetrahydro-1'H-spiro[ind ene-1,2'- naphthalen]-1'-yl)phenyl)piperidine-4-carbaldehyde (180.0 mg, 1 Eq, 411.4 ^mol), (S)-3-(1-oxo- 5-(piperazin-1-yl)isoindolin-2-yl)piperidine-2,6-dione, Benzenesulfonic acid salt (247.0 mg, 1.2 Eq, 493.6 ^mol) in DCM (2 mL), MeOH (2 mL) was added sodium acetate (101.2 mg , 3 Eq, 1.234 mmol) was stirred at 25 °C for 60 mins, Then sodium triacetoxyborohydride (174.4 mg, 2 Eq, 822.7 ^mol) and acetic acid (74.11 mg, 70.98 ^L, 3 Eq, 1.234 mmol) was added .The mixture was stirred at 25 °C for 16 hour. LCMS showed 85.6% desired MS was detected. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was purified by prep-HPLC (column: Welch Xtimate C18150*30mm*5um phase: [water(FA)- ACN];B%: 15%-55%,9min to give (S)-3-(5-(4-((1-(4-((1R,1'R)-6'-hydroxy-2,3,3',4'-tetrahydro - 1'H-spiro[indene-1,2'-naphthalen]-1'-yl)phenyl)piperidin-4-y l)methyl)piperazin-1-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione (54.3 mg, 70.9 ^mol, 17.2 %, 97.9% purity) was obtained as a white solid. LC-MS (ESI+) m/z: 750.4(M+H) ⁺ . LCMS: calc. for C ₄₇ H ₅₁ N ₅ O ₄ , found: [M+H] ⁺ 750.2. HPLC: 97.9% purity at 220 nm. NMR (400MHz, DMSO-d ₆ ) į = 10.96 (s, 1 H) 9.11 (s, 1 H) 8.14 (s, 0.214 H) 7.53 (d, J=8.46 Hz, 1 H) 7.18 (d, J=7.51 Hz, 1 H) 7.03 - 7.09 (m, 3 H) 6.77 (t, J=7.51 Hz, 1 H) 6.57 - 6.62 (m, 4 H) 6.46 (dd, J=8.34, 2.38 Hz, 1 H) 6.29 (br d, J=7.87 Hz, 2 H) 5.92 (d, J=7.51 Hz, 1 H) 5.05 (dd, J=13.23, 5.13 Hz, 1 H) 4.33 (d, J=17.05 Hz, 1 H) 4.17 - 4.25 (m, 1 H) 3.80 (s, 1 H) 3.51 - 3.63 (m, 2 H) 3.23 - 3.32 (m, 6 H) 2.84 - 3.08 (m, 5 H) 2.75 - 2.81 (m, 1 H) 2.55 - 2.62 (m, 4 H) 2.37 (br dd, J=13.29, 4.59 Hz, 2 H) 2.26 (br s, 2 H) 1.90 - 2.00 (m, 3 H) 1.78 (br d, J=12.04 Hz, 2 H) 1.68 (br s, 1 H) 1.44 (br d, J=12.76 Hz, 1 H) 1.16 - 1.26 (m, 2 H). SFC: retention time, 2.842 min; Area, 92.049%; EXAMPLE 184. Preparation of (I-240) (S)-3-(5-(4-((1-(4-((1R,2S)-2-cyclohexyl-6- hydroxy-2-methyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)pi peridin-4- yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2, 6-dione Step 1: To a solution of 1-(4-((1R,2S)-2-cyclohexyl-6-methoxy-2-methyl-1,2,3,4- tetrahydronaphthalen-1-yl)phenyl)-4-(dimethoxymethyl)piperid ine (80 mg, 1 Eq, 0.16 mmol) in DCM (2 mL) at 0 °C was added tribromoborane (0.12 g, 0.48 mL, 1 M, 3 Eq, 0.48 mmol) with N ₂ . After addition, the mixture was stirred at 0 °C for 4 hour, and then the reaction was warmed to 25 °C and was stirred at this temperature for 12 hour. The reaction mixture was quenched with saturated 10 mL NaHCO ₃ and stirred for 10 min at 0°C. Then the mixture was dissolved in water (30 mL) and extracted by ethyl acetate (40 mL). The combined organic layer was dried over Na ₂ SO ₄ , filtered and concentrated under vaccum to give the compound 1-(4-((1R,2S)-2- cyclohexyl-6-hydroxy-2-methyl-1,2,3,4-tetrahydronaphthalen-1 -yl)phenyl)piperidine-4- carbaldehyde (70 mg, 0.16 mmol, 100 %) as a yellow solid. LC-MS (ESI+) m/z: 432.1 (M+H)+. Step 2: A mixture of 1-(4-((1R,2S)-2-cyclohexyl-6-hydroxy-2-methyl-1,2,3,4- tetrahydronaphthalen-1-yl)phenyl)piperidine-4-carbaldehyde (60 mg, 1 Eq, 0.14 mmol), (S)-3- (1-oxo-5-(piperazin-1-yl)isoindolin-2-yl)piperidine-2,6-dion e benzenesulfonate (88 mg, 1.3 Eq, 0.18 mmol) and sodium acetate (57 mg, 5 Eq, 0.70 mmol) and acetic acid (25 mg, 24 ^L, 3 Eq, 0.42 mmol) in DCM (2 mL) and MeOH (2 mL) at 25 °C for 1 hour, then sodium triacetoxyborohydride (59 mg, 2 Eq, 0.28 mmol) was added to the mixture and was stirred at 25 °C for 16 hour. The reaction was treated with H2O (50 mL), extracted with EtOAc (50 mL). The combined extracts was dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to dryness in vacuo to give a residue. The residue was purified by prep.HPLC (column: Welch Xtimate C18 150*40 mm*5 um mobile phase: [water (FA) ACN]; B%: 20% 60% 9 min) The pure fractions were collected respectively and the solvents were evaporated under vacuum to give the product (S)-3-(5-(4-((1-(4-((1R,2S)-2-cyclohexyl-6-hydroxy-2-methyl- 1,2,3,4-tetrahydronaphthalen-1- yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindo lin-2-yl)piperidine-2,6-dione (34 mg, 46 ^mol, 33 %, 99.674% purity)as a white solid. LC-MS (ESI+) m/z: 744.5 (M+H) ⁺ . HPLC: 99.674%, purity at 220 nm. SFC: retention time, 3.017 min; Area, 81.989%; NMR (400 MHz, DMSO-d ₆ ) į = 10.96 (s, 1H), 9.17 - 8.90 (m, 1H), 8.17 (s, 0.420H), 7.53 (d, J = 8.6 Hz, 1H), 7.11 - 7.02 (m, 2H), 6.76 (s, 4H), 6.60 - 6.48 (m, 2H), 6.41 (dd, J = 2.3, 8.3 Hz, 1H), 5.06 (dd, J = 5.0, 13.2 Hz, 1H), 4.40 - 4.29 (m, 1H), 4.26 - 4.15 (m, 1H), 3.89 (s, 1H), 3.65 - 3.57 (m, 2H), 3.29 (br s, 5H), 2.98 - 2.84 (m, 1H), 2.73 - 2.56 (m, 6H), 2.40 - 2.29 (m, 1H), 2.22 (br d, J = 6.9 Hz, 2H), 2.01 - 1.92 (m, 1H), 1.89 - 1.40 (m, 11H), 1.36 - 0.84 (m, 9H), 0.49 (s, 3H). EXAMPLE 185. Preparation of (I-239) (S)-3-(5-(4-((1-(4-((1S,2R)-2-cyclohexyl-6- hydroxy-2-methyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)pi peridin-4- yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2, 6-dione Step 1: To a solution of 1-(4-((1S,2R)-2-cyclohexyl-6-methoxy-2-methyl-1,2,3,4- tetrahydronaphthalen-1-yl)phenyl)-4-(dimethoxymethyl)piperid ine (80 mg, 1 Eq, 0.16 mmol) in DCM (2 mL) at 0 °C was added tribromoborane (0.12 g, 0.49 mL, 1 M, 3 Eq, 0.49 mmol) with N ₂ . After addition, the mixture was stirred at 0 °C for 4 hour, and then the reaction was warmed saturated 10 mL NaHCO3 and stirred for 10 min at 0 °C. Then the mixture was dissolved in water (30 mL) and extracted by ethyl acetate (40 mL). The combined organic layer was dried over Na ₂ SO ₄ , filtered and concentrated under vaccum to give the compound 1-(4-((1S,2R)-2- cyclohexyl-6-hydroxy-2-methyl-1,2,3,4-tetrahydronaphthalen-1 -yl)phenyl)piperidine-4- carbaldehyde (70 mg, 0.16 mmol, 100 %) as a yellow solid. LC-MS (ESI+) m/z: 432.2 (M+H)+. Step 2: A mixture of 1-(4-((1S,2R)-2-cyclohexyl-6-hydroxy-2-methyl-1,2,3,4- tetrahydronaphthalen-1-yl)phenyl)piperidine-4-carbaldehyde (60 mg, 1 Eq, 0.14 mmol), (S)-3- (1-oxo-5-(piperazin-1-yl)isoindolin-2-yl)piperidine-2,6-dion e benzenesulfonate (88 mg, 1.3 Eq, 0.18 mmol) and sodium acetate (57 mg, 5 Eq, 0.70 mmol) and acetic acid (25 mg, 24 ^L, 3 Eq, 0.42 mmol) in DCM (2 mL) and MeOH (2 mL) at 25 °C for 1 hour, then sodium triacetoxyborohydride (59 mg, 2 Eq, 0.28 mmol) was added to the mixture and was stirred at 25 °C for 16 hour. The reaction was treated with H ₂ O (50 mL), extracted with EtOAc (50 mL). The combined extracts was dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to dryness in vacuo to give a residue. The residue was purified by prep.HPLC (column: Welch Xtimate C18 150*40 mm*3 um mobile phase: [water (FA)-ACN]; B%: 20%-60%, 9 min). The aqueous phase was lyophilized to dryness to give (S)-3-(5-(4-((1-(4-((1S,2R)-2-cyclohexyl-6-hydroxy-2- methyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperidin-4- yl)methyl)piperazin-1-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione (43.4 mg, 58.1 ^mol, 42 %, 99.547% Purity) as a pink solid. LC-MS (ESI+) m/z: 744.5 (M+H)+. HPLC: 99.547%, purity at 220 nm. SFC: retention time, 2.974 min; Area, 87.861%; ¹ H NMR (400 MHz, DMSO-d6) į = 10.96 (s, 1H), 9.19 - 8.88 (m, 1H), 8.16 (s, 0.611H), 7.53 (d, J = 8.6 Hz, 1H), 7.11 - 7.03 (m, 2H), 6.82 - 6.72 (m, 4H), 6.58 - 6.49 (m, 2H), 6.41 (dd, J = 2.4, 8.3 Hz, 1H), 5.06 (dd, J = 5.1, 13.2 Hz, 1H), 4.39 - 4.29 (m, 1H), 4.26 - 4.16 (m, 1H), 3.89 (s, 1H), 3.65 - 3.57 (m, 2H), 3.29 (br s, 5H), 2.99 - 2.84 (m, 1H), 2.72 - 2.56 (m, 6H), 2.39 - 2.33 (m, 1H), 2.22 (br d, J = 7.2 Hz, 2H), 2.01 - 1.92 (m, 1H), 1.90 - 1.41 (m, 11H), 1.29 - 0.86 (m, 9H), 0.49 (s, 3H). EXAMPLE 186. Preparation of (I-238) (S)-3-(5-(4-((1-(4-((1R,2R)-2-cyclohexyl-6- hydroxy-2-methyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)pi peridin-4- yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2, 6-dione Step 1: To a solution of 1-(4-((1R,2R)-2-cyclohexyl-6-methoxy-2-methyl-1,2,3,4- tetrahydronaphthalen-1-yl)phenyl)-4-(dimethoxymethyl)piperid ine (150 mg, 1 Eq, 305 ^mol) in DCM (2 mL) at 0 °C was added tribromoborane (229 mg, 915 ^L, 1 M, 3 Eq, 915 ^mol) with N2. After addition, the mixture was stirred at 0 °C for 4 hour, then the reaction was warmed to 25 °C and was stirred at this temperature for 12 hour. The reaction mixture was quenched with saturated 10 mL NaHCO ₃ and stirred for 10 min at 0°C. Then the mixture was dissolved in water (30 mL) and extracted by ethyl acetate (40 mL). The combined organic layer was dried over Na ₂ SO ₄ , filtered and concentrated under vaccum to give the compound 1-(4-((1R,2R)-2- cyclohexyl-6-hydroxy-2-methyl-1,2,3,4-tetrahydronaphthalen-1 -yl)phenyl)piperidine-4- carbaldehyde (125 mg, 290 ^mol, 94.9 %) as a yellow solid. LC-MS (ESI+) m/z: 432.2 (M+H)+. Step 2: A mixture of 1-(4-((1R,2R)-2-cyclohexyl-6-hydroxy-2-methyl-1,2,3,4- tetrahydronaphthalen-1-yl)phenyl)piperidine-4-carbaldehyde (125 mg, 1 Eq, 290 ^mol), (S)-3- (1-oxo-5-(piperazin-1-yl)isoindolin-2-yl)piperidine-2,6-dion e benzenesulfonate (183 mg, 1.3 Eq, 376 ^mol) and sodium acetate (119 mg, 5 Eq, 1.45 mmol) and acetic acid (52.2 mg, 50.0 ^L, 3 Eq, 869 ^mol) in DCM (2 mL) and MeOH (2 mL) at 25 °C for 1 hour, then sodium triacetoxyborohydride (123 mg, 2 Eq, 579 ^mol) was added to the mixture and stirred at 25 °C for 16 hour. The reaction was treated with H2O (50 mL), extracted with EtOAc (50 mL). The combined extracts was dried over anhydrous Na2SO4, filtered and concentrated to dryness in vacuo to give a residue. The residue was purified by prep.HPLC (column: Welch Xtimate C18 150*30 mm*5 um mobile phase: [water (FA)-ACN]; B%: 20%-60% 9 min) The aqueous phase was lyophilized to dryness to give (S)-3-(5-(4-((1-(4-((1R,2R)-2-cyclohexyl-6-hydroxy-2- methyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperidin-4- yl)methyl)piperazin-1-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione (40.7 mg, 54.3 ^mol, 18.7 %, 99.209% Purity) as a white solid. LC-MS (ESI+) m/z: 744.5 (M+H)+. HPLC: 99.209%, purity at 220 nm. SFC: retention time, 3.053 min; Area, 75.875%; NMR (400 MHz, DMSO-d ₆ ) į = 10.96 (s, 1H), 9.04 - 8.92 (m, 1H), 8.17 (s, 0.275H), 7.52 (d, J = 8.6 Hz, 1H), 7.10 - 7.03 (m, 2H), 6.84 - 6.78 (m, 2H), 6.77 - 6.72 (m, 2H), 6.62 (d, J = 8.3 Hz, 1H), 6.51 (d, J = 2.3 Hz, 1H), 6.39 (dd, J = 2.4, 8.2 Hz, 1H), 5.05 (dd, J = 5.1, 13.2 Hz, 1H), 4.38 - 4.29 (m, 1H), 4.27 - 4.17 (m, 1H), 3.73 (s, 1H), 3.66 - 3.56 (m, 2H), 3.31 - 3.18 (m, 6H), 2.97 - 2.83 (m, 2H), 2.82 - 2.71 (m, 1H), 2.65 - 2.54 (m, 5H), 2.39 - 2.32 (m, 1H), 2.21 (br d, J = 7.2 Hz, 2H), 2.13 (br d, J = 11.1 Hz, 1H), 2.01 - 1.92 (m, 1H), 1.80 (br d, J = 11.1 Hz, 2H), 1.74 - 1.63 (m, 3H), 1.62 - 1.52 (m, 4H), 1.26 - 1.15 (m, 2H), 1.09 - 0.87 (m, 5H), 0.76 (s, 4H).

EXAMPLE 187. Preparation of (I-237) (S)-3-(5-(4-((1-(4-((1S,2S)-2-cyclohexyl-6- hydroxy-2-methyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)pi peridin-4- yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2, 6-dione Step 1: To a solution of methyl 2-cyclohexylacetate (100 mg, 105 ^L, 1 Eq, 640 ^mol) in THF (2 mL) cooled at -78 °C under N2, lithium diisopropylamide (137 mg, 640 ^L, 2 M, 2 Eq, 1.28 mmol) was added to the reaction, stirred at -78 °C for 1 hour, was added dropwise 2-(3- methoxyphenyl)acetaldehyde (144 mg, 0.14 mL, 1.5 Eq, 960 ^mol) over 10 min. The reaction mixture was stirred at 25 °C for 12 hour. Then the mixture was cooled to room temperature. The reaction was quenched with NH ₄ Cl (20 mL), the mixture was treated with H ₂ O (30 mL), extracted with EtOAc (40 mL). The combined extracts was dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to dryness in vacuo to give a yellow oil. The yellow oil was purified by flash column (petroleum ether/ethyl acetate from 100/0 to 90/10) and the organic layer was concentrated in vacuo to give methyl 2-cyclohexyl-3-hydroxy-4-(3-methoxyphenyl)butanoate (100 mg, 326 ^mol, 51.0%) as a yellow oil. ¹ H NMR (400 MHz, CD ₃ Cl) į = 7.19 - 7.12 (m, 1H), 6.76 - 6.67 (m, 3H), 4.13 - 3.93 (m, 1H), 3.78 - 3.63 (m, 6H), 2.83 - 2.68 (m, 1H), 2.64 - 2.54 (m, 1H), 2.47 - 2.36 (m, 1H), 1.90 - 1.75 (m, 2H), 1.73 - 1.50 (m, 5H), 1.29 - 0.83 (m, 5H). Step 2: A mixture of Triethylamine (1 g, 1 mL, 3 Eq, 0.01 mol), methanesulfonic anhydride (1 g, 2 Eq, 7 mmol), methyl 2-cyclohexyl-3-hydroxy-4-(3-methoxyphenyl)butanoate (1 g, 1 Eq, 3 mmol) in DCM (10 mL) under N ₂ . Then the reaction was stirred at 25 °C for 12 hour. The mixture was treated with H ₂ O (100 mL), extracted with EtOAc (100 mL). The combined extracts was dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to dryness in vacuo to give a residue. The residue was subjected to column chromatography over silica gel (gradient elution: 0~10% ethyl acetate in petroleum ether). The pure fractions were collected and concentrated to dryness in vacuo to methyl 2-cyclohexyl-4-(3-methoxyphenyl)-3- ((methylsulfonyl)oxy)butanoate(700 mg, 1.6 mmol, 50 %, 88% purity) as a yellow oil. ¹ H NMR (400 MHz, CD ₃ Cl) į = 7.23 (d, J = 8.3 Hz, 1H), 6.85 - 6.79 (m, 3H), 5.07 (ddd, J = 3.8, 6.3, 9.5 Hz, 1H), 3.81 (s, 3H), 3.76 (s, 3H), 3.12 - 2.98 (m, 2H), 2.83 (dd, J = 6.8, 8.0 Hz, 1H), 2.35 (s, 3H), 1.85 - 1.63 (m, 8H), 1.27 - 1.18 (m, 3H). Step 3: A mixture of methyl 2-cyclohexyl-4-(3-methoxyphenyl)-3- ((methylsulfonyl)oxy)butanoate (700 mg, 1 Eq, 1.60 mmol), DBU (732 mg, 724 ^L, 3 Eq, 4.81 mmol) in toulene (10 mL) under N2. Then the reaction was stirred at 65 °C for 16 hour. Then the ti l d t t t T th i t dd d t (100 L) th extracted with ethyl acetate 100 mL (50 mL* 2). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give the crude product. The desired product was purified by flash column (petroleum ether/ethyl acetate from 100/0 to 90/10) and the organic layer was concentrated in vacuo to give methyl 2- cyclohexyl-4-(3-methoxyphenyl)but-3-enoate (400 mg, 1.39 mmol, 86.6 %, 100% purity) as a yellow oil. LC-MS (ESI ⁺ ) m/z: 289.1 (M+H) ⁺ . Step 4: A mixture of methyl 2-cyclohexyl-4-(3-methoxyphenyl)but-3-enoate (400 mg, 1 Eq, 1.39 mmol), Pd/C (600 mg, 10% Wt, 0.406 Eq, 564 ^mol), H ₂ (2.80 mg, 1 Eq, 1.39 mmol) in MeOH (20 mL). The suspension was degassed and purged with H ₂ for 3 times. The mixture was stirred under H ₂ (15 psi) at 25 °C for 16 hour. Then the reaction was cooled to room temperature. The mixture was filtered and concentrated to dryness in vacuo to give methyl 2-cyclohexyl-4-(3- methoxyphenyl)butanoate (350 mg, 1.21 mmol, 86.9 %, 100% Purity) as a yellow oil. LC-MS (ESI ⁺ ) m/z: 308.1 (M+H ₂ O) ⁺ . Step 5: A 100 mL thread vial equipped with magnetic stirrer, sodium hydroxide (3.6 g, 30 mL, 3 molar, 8.2 Eq, 90 mmol) was added to the solution of methyl 2-cyclohexyl-4-(3- methoxyphenyl)butanoate (3.2 g, 100% Wt, 1 Eq, 11 mmol) in MeOH (15 mL). The mixture was stirred at 80 °C for 16 hour. The reaction was treated with 1 N HCl (100 mL), extracted with EtOAC (100 mL). The combined extracts was dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to dryness in vacuo to give 2-cyclohexyl-4-(3-methoxyphenyl)butanoic acid (3 g, 0.01 mol, 100 %) as a white solid. Step 6: A 100 mL thread vial was equipped with magnetic stirrer. Triflic acid (28 g, 17 mL, 20 Eq, 0.19 mol) was added to the solution of 2-cyclohexyl-4-(3-methoxyphenyl)butanoic acid (2.6 g, 1 Eq, 9.4 mmol) in DCM (30 mL). The mixture was stirred at 0 °C for 2.5 hour. The mixture was treated with H ₂ O (100 mL), extracted with DCM (50 mL * 2). The combined extracts was dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to dryness in vacuo to give a residue. The residue was subjected to column chromatography over silica gel (gradient elution: 0~30% ethyl acetate in petroleum ether). The pure fractions were collected and concentrated to dryness in vacuo to give 2-cyclohexyl-6-methoxy-3,4-dihydronaphthalen-1(2H)-one (2.1 g, 8.1 mmol, 86 %, 100% purity) as a yellow solid. LC-MS (ESI ⁺ ) m/z: 259.1 (M+H) ⁺ . Step 7: To a solution of 2-cyclohexyl-6-methoxy-3,4-dihydronaphthalen-1(2H)-one (2 g, 1 Eq, 8 mmol) in THF (15 Ml) was added LDA solution (2 g, 0.01 L, 2 M, 3 Eq, 0.02 mol) at -78 °C. The reaction mixture was stirred at -78 °C for 1 hour. Then Methyl iodide (7 g, 3 Ml, 6 Eq, 0.05 mol) was added to the mixture dropwise at -78 °C. The reaction mixrure was warmed to 25 °C and stirred for 12 hour. The mixture was quenched by the addition of 25 Ml of saturated aqueous NH ₄ Cl. The mixture was treated with H ₂ O (100 Ml), extracted with EtOAc (50 Ml * 2). The combined extracts was dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to dryness in vacuo to give 2-cyclohexyl-6-methoxy-2-methyl-3,4-dihydronaphthalen-1(2H)- one (2.1 g, 7.7 mmol, 100 %) as a yellow oil. LC-MS (ESI ⁺ ) m/z: 273.2 (M+H) ⁺ . Step 8: To a mixture of 1-(4-bromophenyl)-4-(dimethoxymethyl)piperidine (2 g, 2 Eq, 7 mmol) in THF (15 mL) at r.t. and the mixture was degassed and purged with N ₂ for 10 minutes. Then the mixture was stirred until it reached -78 °C. n-Butyllithium, 2.5 M in hexane (0.4 g, 3 mL, 2.5 M, 1.8 Eq, 7 mmol) was added to the mixture and stirred at -78 °C for 1 hour, then 2-cyclohexyl- 6-methoxy-2-methyl-3,4-dihydronaphthalen-1(2H)-one (1 g, 1 Eq, 4 mmol) was added to the mixture and stirred at 25 °C for 16 hour. TLC (PE/EtOAc=5/1, Rf=0.3) showed a new spot was formed. The reaction was quenched with water (100 mL) and extracted with ethyl acetate (100 mL). The organic layer was washed with brine (50 mL) and dried over Na ₂ SO ₄ and concentrated in vacuo to give a yellow oil. The yellow oil was subjected to column chromatography over silica gel (gradient elution: 0 - 40% EtOAc). The desired fractions were collected, and concentrated to dryness in vacuo to give 2-cyclohexyl-1-(4-(4-(dimethoxymethyl)piperidin-1- yl)phenyl)-6-methoxy-2-methyl-1,2,3,4-tetrahydronaphthalen-1 -ol (1.68 g, 3.19 mmol, 90 %, 96.4% purity) as a white solid. LC-MS (ESI ⁺ ) m/z: 508.3 (M+H) ⁺ . Step 9: To a mixture of 2-cyclohexyl-1-(4-(4-(dimethoxymethyl)piperidin-1-yl)phenyl) -6- methoxy-2-methyl-1,2,3,4-tetrahydronaphthalen-1-ol (1.68 g, 1 Eq, 3.19 mmol), Pd/C (2 g, 10% Wt, 0.6 Eq, 2 mmol), H ₂ (6.44 mg, 1 Eq, 3.19 mmol) in MeOH (25 mL) at r.t. and the mixture was degassed and purged with H ₂ for 3 times. Then the mixture was stirred at 50 °C for 16 hour (15 psi). The mixture was filtered and concentrated to dryness in vacuo to give a white solid. The white solid was subjected by SFC: Column: DAICEL CHIRALPAK IG (250 mm *30 mm, 10 um); Mobile phase: A: Supercritical CO2, B: MeOH (0.1% NH3 H2O), A:B = 40:40 at 300 mL/min. The pure fractions were collected respectively and the solvents were evaporated under vacuum to give the product 1-(4-((1S 2S)-2-cyclohexyl-6-methoxy-2-methyl-1234- tetrahydronaphthalen-1-yl)phenyl)-4-(dimethoxymethyl)piperid ine (400 mg, 787 ^mol, 24.7 %, 96.702% purity), 1-(4-((1R,2R)-2-cyclohexyl-6-methoxy-2-methyl-1,2,3,4- tetrahydronaphthalen-1-yl)phenyl)-4-(dimethoxymethyl)piperid ine (330 mg, 671 ^mol, 21.1 %, 100% purity) 1-(4-((1S,2R)-2-cyclohexyl-6-methoxy-2-methyl-1,2,3,4-tetrah ydronaphthalen-1- yl)phenyl)-4-(dimethoxymethyl)piperidine (80 mg, 0.16 mmol, 5.1 %, 100% purity) and 1-(4- ((1R,2S)-2-cyclohexyl-6-methoxy-2-methyl-1,2,3,4-tetrahydron aphthalen-1-yl)phenyl)-4- (dimethoxymethyl)piperidine (150 mg, 96.702% Wt, 1 Eq, 295 ^mol) in DCM (2 mL) at 0 °C was added tribromoborane (222 mg, 885 ^L, 1 M in DCM, 3 Eq, 885 ^mol) with N ₂ . After addition, the mixture was stirred at 0 °C for 4 hour, and then the reaction was warmed to 25 °C and was stirred at this temperature for 12 hour. The reaction mixture was quenched with saturated NaHCO ₃ 10 mL and stirred for 10 min at 0°C. Then the mixture was dissolved in water (30 mL) and extracted by ethyl acetate (40 mL). The combined organic layer was dried over Na ₂ SO ₄ , filtered and concentrated under vaccum to give the compound 1-(4-((1S,2S)-2- cyclohexyl-6-hydroxy-2-methyl-1,2,3,4-tetrahydronaphthalen-1 -yl)phenyl)piperidine-4- carbaldehyde (125 mg, 290 ^mol, 98.2 %) as a yellow solid. LC-MS (ESI+) m/z: 432.2 (M+H)+. Step 11: A mixture of 1-(4-((1S,2S)-2-cyclohexyl-6-hydroxy-2-methyl-1,2,3,4- tetrahydronaphthalen-1-yl)phenyl)piperidine-4-carbaldehyde (125 mg, 1 Eq, 290 ^mol), (S)-3- (1-oxo-5-(piperazin-1-yl)isoindolin-2-yl)piperidine-2,6-dion e benzenesulfonate (183 mg, 1.3 Eq, 376 ^mol) and sodium acetate (119 mg, 5 Eq, 1.45 mmol) and acetic acid (52.2 mg, 50.0 ^L, 3 Eq, 869 ^mol) in DCM (2 mL) and MeOH (2 mL) at 25 °C for 1 hour, then sodium triacetoxyborohydride (123 mg, 2 Eq, 579 ^mol) was added to the mixture and was stirred at 25 °C for 16 hour. The reaction was treated with H ₂ O (50 mL), extracted with EtOAc (50 mL). The combined extracts was dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to dryness in vacuo to give a residue. The residue was purified by prep.HPLC (column: Welch Xtimate C18 150*30 mm*3 um mobile phase: [water (FA)-ACN]; B%: 20%-60%, 9 min). The aqueous phase was lyophilized to dryness to give (S)-3-(5-(4-((1-(4-((1S,2S)-2-cyclohexyl-6-hydroxy-2-methyl- 1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperidin-4-yl)meth yl)piperazin-1-yl)-1-oxoisoindolin- 2-yl)piperidine-2,6-dione (70.7 mg, 93.5 ^mol, 32.3 %, 98.415% purity) as a pink solid. LC-MS (ESI+) m/z: 744.5 (M+H)+. HPLC: 98.415%, purity at 220 nm. b: retention time 2985 min; Area 81252%; ¹ H NMR (400 MHz, DMSO-d6) į = 10.96 (s, 1H), 9.13 - 8.84 (m, 1H), 8.17 (s, 0.390H), 7.52 (d, J = 8.7 Hz, 1H), 7.10 - 7.04 (m, 2H), 6.84 - 6.78 (m, 2H), 6.77 - 6.71 (m, 2H), 6.62 (d, J = 8.3 Hz, 1H), 6.51 (d, J = 2.3 Hz, 1H), 6.39 (dd, J = 2.4, 8.2 Hz, 1H), 5.06 (dd, J = 5.1, 13.3 Hz, 1H), 4.39 - 4.28 (m, 1H), 4.26 - 4.16 (m, 1H), 3.73 (s, 1H), 3.65 - 3.57 (m, 2H), 3.29 (br s, 6H), 2.96 - 2.83 (m, 2H), 2.81 - 2.71 (m, 1H), 2.65 - 2.53 (m, 5H), 2.40 - 2.31 (m, 1H), 2.21 (br d, J = 7.0 Hz, 2H), 2.13 (br d, J = 11.1 Hz, 1H), 2.01 - 1.92 (m, 1H), 1.79 (br d, J = 12.2 Hz, 2H), 1.74 - 1.63 (m, 3H), 1.62 - 1.51 (m, 4H), 1.26 - 1.15 (m, 2H), 1.06 (br dd, J = 6.7, 12.0 Hz, 1H), 1.00 - 0.83 (m, 4H), 0.76 (s, 4H). EXAMPLE 188. Preparation of (I-147) (S)-3-(5-(4-((1-(4-((1S,2S)-6-hydroxy-2-methyl- 2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperidin- 4-yl)methyl)piperazin-1-yl)- 1-oxoisoindolin-2-yl)piperidine-2,6-dione Step 1: To a solution of (5S,6S)-5-(4-(4-(dimethoxymethyl)piperidin-1-yl)phenyl)-6-me thyl-6- phenyl-5,6,7,8-tetrahydronaphthalen-2-ol (85 mg, 1 Eq, 0.18 mmol) in THF (10 mL) was added sulfuric acid (0.18 g, 10 mL, 10% Wt, 1 Eq, 0.18 mmol). The mixture was stirred at 70 °C for 3 hour. LCMS showed 98.99 % desired MS. The mixture was adjusted to pH=8-9 by progressively adding NaHCO ₃ . The reaction mixture was quenched by addition 100 mL EtOAc at 20°C, and then diluted with 50 mL H ₂ O and extracted with EtOAc 50mL (25 mL * 2). The combined organic layers were washed with 10 mL (10 mL * 1), dried over Na ₂ SO ₄ . The reaction was filtered and concentrated under reduced pressure to give 1-(4-((1S,2S)-6-hydroxy-2-methyl-2- phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperidine-4 -carbaldehyde (89 mg, 0.21 mmol, 98.986% purity) was obtained as a brown oil. LC-MS (ESI+) m/z: 444.3(M+H) ⁺ . Step 2: A mixture of 1-(4-((1S,2S)-6-hydroxy-2-methyl-2-phenyl-1,2,3,4-tetrahydro naphthalen- 1-yl)phenyl)piperidine-4-carbaldehyde (89 mg, 98.986% Wt, 1 Eq, 0.21 mmol), (R)-3-(1-oxo-5- (piperazin-1-yl)isoindolin-2-yl)piperidine-2,6-dione, PhSO ₃ H salt (0.10 g, 1 Eq, 0.21 mmol) and sodium acetate (85 mg, 5 Eq, 1.0 mmol) in DCM (2 mL) and MeOH (2 mL) at 20°C for 0.5 hour, pH=8, then acetic acid (37 mg, 36 ^L, 3 Eq, 0.62 mmol) at 20°C for 1 hour, pH=6, then added sodium triacetoxyhydroborate (88 mg, 2 Eq, 0.41 mmol) the mixture, and then the mixture was stirred at 25 °C for 16 hour. LCMS showed 86% desired MS. The reaction was concentrated to give (S)-3-(5-(4-((1-(4-((1R,2R)-6-hydroxy-2-methyl-2-phenyl-1,2, 3,4-tetrahydronaphthalen- 1-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoin dolin-2-yl)piperidine-2,6-dione as a brown oil. The mixture was filtered and the filter cake was washed by EtOAc (50 mL x3). The brown oil was purified by preparative high-performance liquid chromatography. Condition: Column: Welch Xtimate C18150*30mm*5um, A: water(FA), B:CAN, at the beginning: A (82%) and B (18%), at the end: A: (52%) and B (48%), Gradient Time(min) 7; 100% B hold Time(min) 1.7,Flow Rate(ml/min) 25. The pure fractions were collected and the solvent was evaporated under vacuum. The aqueous layer was lyophilized to dryness to give (S)-3-(5-(4-((1- (4-((1S,2S)-6-hydroxy-2-methyl-2-phenyl-1,2,3,4-tetrahydrona phthalen-1-yl)phenyl)piperidin-4- yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2, 6-dione (80.5 mg, 102 ^mol, 49 % yield, 93.16% purity) as a white solid. LCMS: calc. for C ₄₆ H ₅₁ N ₅ O ₄ : 737.39, found: [M+H] ⁺ 738.5. HPLC: 93.16% purity at 220 nm. ¹ H NMR (400 MHz, DMSO-d ₆ ) į= 10.95 (s, 1H), 9.08 (s, 1H), 8.13 (s, 0.262H), 7.51 (d, J = 8.6 Hz, 1H), 7.23 - 7.12 (m, 4H), 7.09 - 7.02 (m, 3H), 6.67 - 6.59 (m, 2H), 6.48 - 6.38 (m, 3H), 6.29 (d, J = 8.8 Hz, 2H), 5.04 (dd, J = 5.1, 13.3 Hz, 1H), 4.32 (d, J = 16.9 Hz, 1H), 4.23 - 4.16 (m, 1H), 4.02 (s, 1H), 3.51 - 3.40 (m, 4H), 3.28 (br s, 4H), 3.02 (br d, J = 6.7 Hz, 1H), 2.97 - 2.85 (m, 2H), 2.62 - 2.53 (m, 3H), 2.45 - 2.32 (m, 4H), 2.22 (br s, 2H), 1.99 - 1.90 (m, 1H), 1.71 (br d, J = 13.6 Hz, 4H), 1.31 (s, 3H), 1.17 - 1.04 (m, 2H) SFC: retention time, 3.267 min; Area, 96.04%; EXAMPLE 189. Preparation of (I-148) (S)-3-(5-(4-((1-(4-((1R,2R)-6-hydroxy-2-methyl- 2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperidin- 4-yl)methyl)piperazin-1-yl)- 1-oxoisoindolin-2-yl)piperidine-2,6-dione Step 1: To a solution of 6-(benzyloxy)-2-phenyl-3,4-dihydronaphthalen-1(2H)-one (3 g, 1 Eq, 9 mmol) in THF (50 mL) was added LDA (1 g, 7 mL, 2 M, 1.5 Eq, 0.01 mol) at -68 °C. The reaction mixture was stirred at -68 °C for1 hour. A solution of Methyl iodide (4 g, 2 mL, 3 Eq, 0.03 mol) ^ was added to the mixture dropwise at -68 °C. The reaction mixture was gradually d t 25 °C d ti d f 12 h LCMS h d 2006% d i d MS TLC ( t l ether: ethyl acetate=10:1, UV) showed one main new spot was observed. The reaction was quenched with water (150 mL) and extracted with ethyl acetate (150 mL*3). The organic layer was washed with brine(100 mL) and dried over Na ₂ SO ₄ and concentrated in vacuo to give 6- (benzyloxy)-2-methyl-2-phenyl-3,4-dihydronaphthalen-1(2H)-on e as a brown oil. The brown oil was subjected to column chromatography over silica gel (gradient elution: 0 – 10% EtOAc). LCMS showed 81.5% desired MS. The desired fractions were collected, and concentrated to dryness in vacuo to give 6-(benzyloxy)-2-methyl-2-phenyl-3,4-dihydronaphthalen-1(2H)- one (810 mg, 1.93 mmol, 20 % yield, 81.5% purity) as a yellow oil. LC-MS (ESI ⁺ ) m/z: 343.1 (M+H) ⁺ . Step 2: 1-(4-bromophenyl)-4-(dimethoxymethyl)piperidine (796 mg, 1.5 Eq, 2.53 mmol), a stir bar, and THF(30 mL) were added an oven-dried and nitrogen-purged three round-bottomed flask(100 mL), which was subsequently evacuated and refilled with argon (x3), before the reaction vessel was cooled to -70°C (dry ice/EtOH). The resulting mixture treated with n- Butyllithium, 2.5M in hexane (152 mg, 946 ^L, 2.5 M, 1.4 Eq, 2.37 mmol), dropwise over 2 min at -70°C (dry ice/EtOH), while stirring an additional 30 min at -70 °C (dry ice/EtOH). The resulting mixture treated with 6-(benzyloxy)-2-methyl-2-phenyl-3,4-dihydronaphthalen-1(2H)- one (710 mg, 81.5% Wt, 1 Eq, 1.69 mmol) in THF(5mL) , dropwise over 5 min, and the reaction vessel removed to the r.t., while stirring an additional 16 hour at 25 °C. LCMS showed 28.61% desired MS. TLC (petroleum ether: ethyl acetate=10:1, UV) showed one main new spot was observed. The reaction was quenched with water (150 mL) and extracted with ethyl acetate (150 mL*3). The organic layer was washed with brine(50 mL) and dried over Na ₂ SO ₄ and concentrated in vacuo to give 6-(benzyloxy)-1-(4-(4-(dimethoxymethyl)piperidin-1-yl)phenyl )- 2-methyl-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-ol as a brown oil. The brown oil was subjected to column chromatography over silica gel (gradient elution: 0 – 10% EtOAc). The desired fractions were collected, and concentrated to dryness in vacuo to give 6-(benzyloxy)-1- (4-(4-(dimethoxymethyl)piperidin-1-yl)phenyl)-2-methyl-2-phe nyl-1,2,3,4- tetrahydronaphthalen-1-ol (600 mg, 1.04 mmol, 61.5 % yield, 100% purity) as a yellow oil. LC- MS (ESI ⁺ ) m/z: 578.3(M+H) ⁺ . Step 3: A mixture of 6-(benzyloxy)-1-(4-(4-(dimethoxymethyl)piperidin-1-yl)phenyl )-2-methyl- 2-phenyl-1,2,3,4-tetrahydronaphthalen-1-ol (660 mg, 1 Eq, 1.14 mmol), Pd/C (700 mg, 10% Wt, 0576 Eq 658 ^mol) in THF (8 mL) and MeOH (8 mL) was degassed and purged with H ₂ for 3 times, and then the mixture was stirred at 55 °C for 16 hour under H2 atmosphere(15 psi). LCMS showed 97.53% desired. The reaction was filtered and concentrated to dryness in vacuo to give 5-(4-(4-(dimethoxymethyl)piperidin-1-yl)phenyl)-6-methyl-6-p henyl-5,6,7,8- tetrahydronaphthalen-2-ol (500 mg, 1.03 mmol, 90.5 % yield, 97.53% purity) as a brown oil. LC-MS (ESI+) m/z: 472.2 (M+H) ⁺ . Step 4: The brown oil was purified by SFC. Condition: 0.1%NH ₃ H ₂ O ETOH. Column: DAICEL CHIRALCEL OJ(250mm*30mm,10um), at the beginning: A (60%) and B (40%),at the end: A: (60%) and B (40%), Flow Rate(ml/min) 80. The pure fractions were collected and the solvent was evaporated under vacuum. The aqueous layer was lyophilized to dryness to give (5R,6R)-5- (4-(4-(dimethoxymethyl)piperidin-1-yl)phenyl)-6-methyl-6-phe nyl-5,6,7,8- tetrahydronaphthalen-2-ol (177 mg, 373 ^mol, 99.4% purity) as a purple solid ^(5S,6S)-5-(4-(4- (dimethoxymethyl)piperidin-1-yl)phenyl)-6-methyl-6-phenyl-5, 6,7,8-tetrahydronaphthalen-2-ol (175 mg, 371 ^mol, 100% purity) as a purple solid ^(5R,6S)-5-(4-(4- (dimethoxymethyl)piperidin-1-yl)phenyl)-6-methyl-6-phenyl-5, 6,7,8-tetrahydronaphthalen-2-ol (62 mg, 0.13 mmol, 100% purity) as a purple solid ^(5S,6R)-5-(4-(4- (dimethoxymethyl)piperidin-1-yl)phenyl)-6-methyl-6-phenyl-5, 6,7,8-tetrahydronaphthalen-2-ol (66 mg, 0.14 mmol, 100% purity) as a purple solid. LC-MS (ESI+) m/z: 472.1 Step 5: To a solution of (5R,6R)-5-(4-(4-(dimethoxymethyl)piperidin-1-yl)phenyl)-6-me thyl-6- phenyl-5,6,7,8-tetrahydronaphthalen-2-ol (85 mg, 1 Eq, 0.18 mmol) in THF (10 mL) was added sulfuric acid (0.18 g, 10 mL, 10% Wt, 1 Eq, 0.18 mmol). The mixture was stirred at 70 °C for 3 hour. LCMS showed 97.47 % desired MS. The mixture was adjusted to pH=8-9 by progressively adding NaHCO ₃ . The reaction mixture was quenched by addition 100 mL EtOAc at 20°C, and then diluted with H ₂ O(50 mL) and extracted with EtOAc 50mL (25 mL * 2). The combined organic layers were washed with 10 mL (10 mL * 1), dried over Na ₂ SO ₄ . The reaction was filtered and concentrated under reduced pressure to give 1-(4-((1R,2R)-6-hydroxy-2-methyl-2- phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperidine-4 -carbaldehyde (89 mg, 0.20 mmol, 97.47% purity) was obtained as a brown oil. LC-MS (ESI+) m/z: 444.3(M+H) ⁺ . Step 6: A mixture of 1-(4-((1R,2R)-6-hydroxy-2-methyl-2-phenyl-1,2,3,4-tetrahydro naphthalen- 1-yl)phenyl)piperidine-4-carbaldehyde (89 mg, 1 Eq, 0.21 mmol), (S)-3-(1-oxo-5-(piperazin-1- yl)isoindolin-2-yl)piperidine-26-dione PhSO ₃ H salt (010 g 1 Eq 021 mmol) and sodium acetate (86 mg, 5 Eq, 1.0 mmol) in DCM (2 mL) and MeOH (2 mL) at 20 °C for 0.5 hour, pH=8, then acetic acid (38 mg, 36 ^L, 3 Eq, 0.63 mmol) at 20°C for 1 hour, pH=6, then added sodium triacetoxyhydroborate (89 mg, 2 Eq, 0.42 mmol) the mixture, and then the mixture was stirred at 25 °C for 16 hour. LCMS showed 78% desired MS. The reaction was concentrated to give (S)-3- (5-(4-((1-(4-((1R,2R)-6-hydroxy-2-methyl-2-phenyl-1,2,3,4-te trahydronaphthalen-1- yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindo lin-2-yl)piperidine-2,6-dione as a yellow oil. The mixture was filtered and the filter cake was washed by EtOAc (50 mL x3). The yellow oil was purified by preparative high-performance liquid chromatography. Condition: Column: Welch Xtimate C18150*30mm*5um, A: water(FA), B:CAN, at the beginning: A (82%) and B (18%), at the end: A: (52%) and B (48%), Gradient Time(min) 7; 100% B hold Time(min) 2.5, Flow Rate(ml/min) 25. The pure fractions were collected and the solvent was evaporated under vacuum. The aqueous layer was lyophilized to dryness to give (S)-3-(5-(4-((1- (4-((1R,2R)-6-hydroxy-2-methyl-2-phenyl-1,2,3,4-tetrahydrona phthalen-1-yl)phenyl)piperidin- 4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine- 2,6-dione (79.4 mg, 101 ^mol, 48 % yield, 93.93% purity) as a white solid. LCMS: calc. for C46H51N5O4: 737.39, found: [M+H] + 738.5. HPLC: 93.93% purity at 220 nm. ¹ H NMR (400 MHz, DMSO-d ₆ ) į= 10.95 (s, 1H), 9.08 (s, 1H), 8.13 (s, 0.260H), 7.52 (d, J = 8.5 Hz, 1H), 7.23 - 7.13 (m, 4H), 7.06 (s, 3H), 6.66 - 6.60 (m, 2H), 6.48 - 6.39 (m, 3H), 6.29 (d, J = 8.7 Hz, 2H), 5.04 (dd, J = 5.1, 13.2 Hz, 1H), 4.32 (d, J = 17.0 Hz, 1H), 4.23 - 4.15 (m, 1H), 4.02 (s, 1H), 3.51 - 3.41 (m, 4H), 3.29 - 3.19 (m, 4H), 3.02 (br d, J = 6.6 Hz, 1H), 2.97 - 2.85 (m, 2H), 2.61 - 2.54 (m, 3H), 2.48 - 2.33 (m, 5H), 2.26 - 2.19 (m, 1H), 1.99 - 1.91 (m, 1H), 1.76 - 1.57 (m, 4H), 1.31 (s, 3H), 1.11 (br d, J = 9.4 Hz, 2H) SFC: retention time, 3.074 min; Area, 96%;

EXAMPLE 190. Preparation of (I-85) (S)-3-(5-(4-((1-(4-((R)-6'-hydroxy-3',4'-dihydro- 1'H-spiro[cyclohexane-1,2'-naphthalen]-1'-yl)phenyl)piperidi n-4-yl)methyl)piperazin-1-yl)- 1-oxoisoindolin-2-yl)piperidine-2,6-dione Step 1: A mixture of (R)-1'-(4-(4-(dimethoxymethyl)piperidin-1-yl)phenyl)-3',4'-d ihydro-1'H- spiro[cyclohexane-1,2'-naphthalen]-6'-ol (100 mg, 100% Wt, 1 Eq, 222 ^mol) in 10% H ₂ SO ₄ (1.5 mL) and THF (1.5 mL), then the mixture was stirred at 60 °C for 16 hour. The solvent was removed under vaccum. The aqueous solution was added NaHCO ₃ to adjust pH=6. The residue was dissolved in water (20 mL) and extracted by ethyl acetate (20 mL). The combined organic layer was dried over Na ₂ SO ₄ , filtered and concentrated under vaccum to give (R)-1-(4-(6'- hydroxy-3',4'-dihydro-1'H-spiro[cyclohexane-1,2'-naphthalen] -1'-yl)phenyl)piperidine-4- carbaldehyde (90 mg, 0.22 mmol, 100% yield) as a yellow oil. LC-MS (ESI+) m/z: 404.2 (M+H)+. Step 2: A mixture of (R)-1-(4-(6'-hydroxy-3',4'-dihydro-1'H-spiro[cyclohexane-1,2 '-naphthalen]- 1'-yl)phenyl)piperidine-4-carbaldehyde (90 mg, 1 Eq, 0.22 mmol), (S)-3-(1-oxo-5-(piperazin-1- yl)isoindolin-2-yl)piperidine-2,6-dione benzenesulfonate (0.14 g, 1.3 Eq, 0.29 mmol) and Sodium acetate (91 mg, 5 Eq, 1.1 mmol) and Acetic acid (40 mg, 38 ^L, 3 Eq, 0.67 mmol) in DCM (2 mL) and MeOH (2 mL) at 25 °C for 1 hour, then Sodium triacetoxyborohydride (95 mg, 2 Eq, 0.45 mmol) was added to the mixture and was stirred at 25 °C for 16 hour. The reaction was treated with H ₂ O (20 mL), extracted with EtOAc (20 mL). The combined extracts was dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to dryness in vacuo to give a residue. The residue was purified by prep.HPLC (column: Welch Xtimate C18150*30mm*5um mobile phase: [water (FA)-ACN]; B%: 21%-51%, 7 min). The aqueous phase was lyophilized to naphthalen]-1'-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-y l)-1-oxoisoindolin-2-yl)piperidine- 2,6-dione (53 mg, 73 ^mol, 33% yield, 98.7% purity) as a white solid. LC-MS (ESI+) m/z: 716.3 (M+H)+ HPLC: 98.709%, purity at 220 nm. SFC: retention time, 3.011 min; Area, 81.517%; NMR (400 MHz, DMSO-d6) į = 10.99 - 10.93 (m, 1H), 9.07 - 8.94 (m, 1H), 8.17 - 8.12 (m, 0.428H), 7.58 - 7.48 (m, 1H), 7.11 - 7.02 (m, 2H), 6.82 - 6.71 (m, 4H), 6.60 - 6.54 (m, 1H), 6.53 - 6.49 (m, 1H), 6.44 - 6.38 (m, 1H), 5.09 - 5.01 (m, 1H), 4.37 - 4.29 (m, 1H), 4.25 - 4.17 (m, 1H), 3.64 - 3.54 (m, 4H), 3.32 - 3.25 (m, 7H), 2.96 - 2.84 (m, 1H), 2.81 - 2.66 (m, 2H), 2.64 - 2.56 (m, 3H), 2.40 - 2.31 (m, 1H), 2.27 - 2.18 (m, 2H), 2.02 - 1.90 (m, 1H), 1.85 - 1.75 (m, 2H), 1.72 - 1.54 (m, 3H), 1.52 - 1.41 (m, 4H), 1.40 - 1.28 (m, 2H), 1.26 - 1.06 (m, 5H), 0.84 - 0.73 (m, 1H).

EXAMPLE 191. Preparation of (I-142) (S)-3-(5-(4-((1-(4-((S)-6'-hydroxy-3',4'-dihydro- 1'H-spiro[cyclohexane-1,2'-naphthalen]-1'-yl)phenyl)piperidi n-4-yl)methyl)piperazin-1-yl)- 1-oxoisoindolin-2-yl)piperidine-2,6-dione Step 1: To a cooled stirred (ice-salt) suspension of sodium hydride (1 g, 0.8 mL, 60% Wt, 2 Eq, 0.02 mol) in DMF (20 mL) was added dropwise a solution of 6-(benzyloxy)-3,4- dihydronaphthalen-1(2H)-one (3 g, 1 Eq, 0.01 mol), then stirred at 0 °C for 2 hour. After this time, 1,5-dibromo-pentane (4 g, 2 mL, 1.5 Eq, 0.02 mol) was added to the reaction and stirred at 25 °C for 16 hour. Then the mixture was cooled to room temperature. The mixture was treated with H ₂ O (100 mL), extracted with EtOAc (150 mL). The combined extracts was dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to dryness in vacuo to give a yellow oil. The yellow oil was purified by flash column (petroleum ether/ethyl acetate from 100/0 to 90/10) and the organic layer was concentrated in vacuo to give 6'-(benzyloxy)-3',4'-dihydro-1'H- spiro[cyclohexane-1,2'-naphthalen]-1'-one (2.1 g, 5.9 mmol, 50 %, 90% Purity) as a yellow oil. LC-MS (ESI+) m/z: 321.2 (M+H)+. Step 2: To a mixture of 1-(4-bromophenyl)-4-(dimethoxymethyl)piperidine (3.7 g, 2 Eq, 12 mmol) in THF (20 mL) at r.t. and the mixture was degassed and purged with N ₂ for 10 minutes. Then the mixture was stirred until it reached -60 °C. n-Butyllithium, 2.5M in hexane (1.1 g, 7.1 mL, 2.5 molar, 3 Eq, 18 mmol) was added to the mixture and stirred at -78 °C for 1 hour, then 6'- (benzyloxy)-3',4'-dihydro-1'H-spiro[cyclohexane-1,2'-naphtha len]-1'-one (2.1 g, 90% Wt, 1 Eq, 5.9 mmol) was added to the mixture at -78 °C and stirred at 25 °C for 16 hour. Then the reaction was cooled to room temperature. The mixture was treated with H ₂ O (100 mL), extracted with EtOAc (100 mL). The combined extracts was dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to dryness in vacuo to give a residue. The residue was subjected to column chromatography over silica gel (gradient elution: 0~50% ethyl acetate in petroleum ether). The pure fractions were collected and concentrated to dryness in vacuo to give 6'-(benzyloxy)-1'-(4- (4-(dimethoxymethyl)piperidin-1-yl)phenyl)-3',4'-dihydro-1'H -spiro[cyclohexane-1,2'- naphthalen]-1'-ol (2.9 g, 5.2 mmol, 88 %, 100% purity) as a yellow solid. LC-MS (ESI+) m/z: 556.2 (M+H)+. Step 3: A mixture of 6'-(benzyloxy)-1'-(4-(4-(dimethoxymethyl)piperidin-1-yl)phen yl)-3',4'- dihydro-1'H-spiro[cyclohexane-1,2'-naphthalen]-1'-ol (1 g, 1 Eq, 2 mmol), Pd/C (1 g, 10 Wt%, 0.5 Eq, 0.9 mmol), H ₂ (4 mg, 1 Eq, 2 mmol) in MeOH (10 mL). The suspension was degassed and purged with H ₂ for 3 times. The mixture was stirred under H ₂ (15 psi) at 50 °C for 24 hour. Then the reaction was cooled to room temperature. The mixture was filtered and concentrated to dryness in vacuo to give a yellow oil. The white solid was subjected by SFC: Column: DAICEL CHIRALPAK IG (250 mm *30 mm, 10 um); Mobile phase: A: Supercritical CO ₂ , B: MeOH (0.1% NH ₃ H ₂ O), A:B = 60:60 at 80 mL/min. The aqueous phase was lyophilized to dryness to give (R)-1'-(4-(4-(dimethoxymethyl)piperidin-1-yl)phenyl)-3',4'-d ihydro-1'H-spiro[cyclohexane- 1,2'-naphthalen]-6'-ol (150 mg, 334 ^mol, 20%, 100% Purity) and (S)-1'-(4-(4- (dimethoxymethyl)piperidin-1-yl)phenyl)-3',4'-dihydro-1'H-sp iro[cyclohexane-1,2'-naphthalen]- 6'-ol (150 mg, 334 ^mol, 20%, 100% Purity) as a yellow solid. LC-MS (ESI ⁺ ) m/z: 450.2 (M+H) ⁺ . Step 4: A mixture of (S)-1'-(4-(4-(dimethoxymethyl)piperidin-1-yl)phenyl)-3',4'-d ihydro-1'H- mL) and THF (1.5 mL) , then the mixture was stirred at 60 °C for 16 hour. The solvent was removed under vaccum. The aqueous solution was added NaHCO3 to adjust pH=7. The residue was dissolved in water (20 mL) and extracted by ethyl acetate (20 mL). The combined organic layer was dried over Na ₂ SO ₄ , filtered and concentrated under vaccum to give (S)-1-(4-(6'-hydroxy- 3',4'-dihydro-1'H-spiro[cyclohexane-1,2'-naphthalen]-1'-yl)p henyl)piperidine-4-carbaldehyde (90 mg, 0.22 mmol, 100 % yield) as a yellow oil. LC-MS (ESI+) m/z: 404.2 (M+H)+. Step 5: A mixture of (S)-1-(4-(6'-hydroxy-3',4'-dihydro-1'H-spiro[cyclohexane-1,2 '-naphthalen]- 1'-yl)phenyl)piperidine-4-carbaldehyde (90 mg, 1 Eq, 0.22 mmol), (S)-3-(1-oxo-5-(piperazin-1- yl)isoindolin-2-yl)piperidine-2,6-dione benzenesulfonate (0.14 g, 1.3 Eq, 0.29 mmol) and Sodium acetate (91 mg, 5 Eq, 1.1 mmol) and Acetic acid (40 mg, 38 ^L, 3 Eq, 0.67 mmol) in DCM (2 mL) and MeOH (2 mL) at 25 °C for 1 hour, then sodium triacetoxyborohydride (95 mg, 2 Eq, 0.45 mmol) was added to the mixture and was stirred at 25 °C for 16 hour. The reaction was treated with H ₂ O (20 mL), extracted with EtOAc (20 mL). The combined extracts was dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to dryness in vacuo to give a residue. The residue was purified by prep.HPLC (column: Welch Xtimate C18150*30mm*5um mobile phase: [water (FA)-ACN]; B%: 21%-51%, 7min). The aqueous phase was lyophilized to dryness to give (S)-3-(5-(4-((1-(4-((S)-6'-hydroxy-3',4'-dihydro-1'H-spiro[c yclohexane-1,2'-naphthalen]- 1'-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoi ndolin-2-yl)piperidine-2,6-dione (81.1 mg, 112 ^mol, 50% yield, 98.783% purity) as a white solid. LC-MS (ESI+) m/z: 716.3 (M+H) ⁺ HPLC: 98.783%, purity at 220 nm. SFC: retention time, 2.998 min; Area, 82.319%; ¹ H NMR (400 MHz, DMSO-d ₆ ) į = 11.00 - 10.93 (m, 1H), 9.06 - 8.95 (m, 1H), 8.17 - 8.12 (m, 0.392H), 7.57 - 7.50 (m, 1H), 7.10 - 7.02 (m, 2H), 6.83 - 6.71 (m, 4H), 6.61 - 6.54 (m, 1H), 6.53 - 6.48 (m, 1H), 6.45 - 6.37 (m, 1H), 5.10 - 5.01 (m, 1H), 4.37 - 4.30 (m, 1H), 4.25 - 4.17 (m, 1H), 3.62 - 3.54 (m, 4H), 3.30 (br s, 7H), 2.96 - 2.85 (m, 1H), 2.80 - 2.65 (m, 2H), 2.63 - 2.56 (m, 3H), 2.42 - 2.32 (m, 1H), 2.29 - 2.22 (m, 2H), 2.01 - 1.92 (m, 1H), 1.85 - 1.75 (m, 2H), 1.73 - 1.54 (m, 3H), 1.50 - 1.41 (m, 4H), 1.40 - 1.28 (m, 2H), 1.26 - 1.08 (m, 5H), 0.84 - 0.73 (m, 1H) EXAMPLE 192. Preparation of (I-151) (S)-3-(5-(4-((1-(4-((1R,2S)-2-cyclohexyl-6- hydroxy-1,2,3,4-tetrahydronaphthalen-1-yl)-3-methoxyphenyl)p iperidin-4- yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2, 6-dione and (I-152) (S)-3-(5-(4- ((1-(4-((1S,2R)-2-cyclohexyl-6-hydroxy-1,2,3,4-tetrahydronap hthalen-1-yl)-3-

methoxyphenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxo isoindolin-2-yl)piperidine-2,6- dione Step 1: A mixture of 1-bromo-4-iodo-2-methoxybenzene (1.5 g, 4.79 mmol, 1.0 eq), 4- (dimethoxymethyl)piperidine (915.88 mg, 5.75 mmol, 1.2 eq), CuI (456.45 mg, 2.40 mmol, 0.5 eq), L-proline (275.93 mg, 2.40 mmol, 0.5 eq) and K ₂ CO ₃ (1.32 g, 9.59 mmol, 2.0 eq) in DMSO (15 mL) was degassed and purged with N ₂ for 3 times, and then the mixture was stirred at 90 °C for 2 hr under N ₂ atmosphere. The mixture was concentrated in reduced pressure. The residue was poured into water (15 mL). The aqueous phase was extracted with ethyl acetate (30 mL x 3). The combined organic phase was washed with brine (15 mL), dried with Na ₂ SO ₄ , filtered and concentrated in vacuum. The residue was purified by silica gel chromatography (Petroleum ether/Ethyl acetate=3/1) . LCMS indicated no desired compound. 1-(4-bromo-3- methoxyphenyl)-4-(dimethoxymethyl)piperidine (1 g, 2.90 mmol, 60.60% yield) was obtained as oil. LC-MS (ESI+) m/z: 345.7 (M+H ⁺ ). Step 2: A mixture of 1-(4-bromo-3-methoxyphenyl)-4-(dimethoxymethyl)piperidine (1.0 g, 2.90 mmol, 1.0 eq), (E)-N'-(6-(benzyloxy)-3,4-dihydronaphthalen-1(2H)-ylidene)-4 - methylbenzenesulfonohydrazide (1.34 g, 3.20 mmol, 1.1 eq), Pd(dppf)Cl ₂ (212.55 mg, 290.49 umol, 0.1 eq), t-BuOLi (697.66 mg, 8.71 mmol, 785.65 uL, 3 eq) and XantPhos-Pd-G3 (245.89 mg, 290.49 umol, 0.1 eq) in dioxane (15 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 100 °C for 16 hr under N ₂ atmosphere. LCMS showed that the starting material was consumed and the desired product was detected. The residue was poured into water (15mL). The aqueous phase was extracted with ethyl acetate (30 mL x 3). The combined organic phase was washed with brine (15 mL), dried with anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuum. The residue was purified by silica gel chromatography (column height: 250 mm, diameter: 100 mm, 100-200 mesh silica gel, Petroleum ether/Ethyl acetate=3/1) to afford 5 (1.02 g, 2.04 mmol, 70.28% yield) as yellow oil. The reaction mixture was filtered under reduced pressure to give a compound.1-(4-(6-(benzyloxy)-3,4-dihydronaphthalen-1-yl)-3- methoxyphenyl)-4-(dimethoxymethyl)piperidine (1.02 g, 2.04 mmol, 70.28% yield) was obtained as oil. LC-MS (ESI+) m/z: 500.3 (M+H ⁺ ). Step 3: To a solution of 1-(4-(6-(benzyloxy)-3,4-dihydronaphthalen-1-yl)-3-methoxyphe nyl)-4- (dimethoxymethyl)piperidine (1.25 g, 2.50 mmol, 1.0 eq) in DCM (15 mL) was added Py.HBr ₃ (800.13 mg, 2.50 mmol, 1.0 eq). The mixture was stirred at 25 °C for 1 hr. LCMS showed that the starting material was consumed and the desired product was detected. The residue was poured into water (15mL) The aqueous phase was extracted with ethyl acetate (30 mL*3) The combined organic phase was washed with brine (15 mL), dried with anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was purified by silica gel chromatography (column height: 250 mm, diameter: 100 mm, 100-200 mesh silica gel, Petroleum ether/Ethyl acetate=3:1) to afford 6 (1 g, 1.73 mmol, 69.09% yield) as yellow oil. The reaction mixture was filtered under reduced pressure to give a compound. 1-(4-(6-(benzyloxy)-2-bromo-3,4-dihydronaphthalen-1- yl)-3-methoxyphenyl)-4-(dimethoxymethyl)piperidine (1 g, 1.73 mmol, 69.09% yield) was obtained as oil. Step 4: A mixture of 1-(4-(6-(benzyloxy)-2-bromo-3,4-dihydronaphthalen-1-yl)-3- methoxyphenyl)-4-(dimethoxymethyl)piperidine (800 mg, 1.38 mmol, 1.0 eq), cyclohex-1-en-1- ylboronic acid (174.18 mg, 1.38 mmol, 1 eq), Pd(dppf)Cl ₂ (101.18 mg, 138.28 ^mol, 0.1 eq), K ₂ CO ₃ (382.22 mg, 2.77 mmol, 2.0 eq) in dioxane (10 mL) and H ₂ O (2.5 mL) was degassed and purged with N ₂ for 3 times, and then the mixture was stirred at 80 °C for 16 hr under N ₂ atmosphere. LCMS showed that the starting material was consumed and the desired product was detected. The reaction mixture was filtered under reduced pressure to give a residue. The residue was poured into H2O (15 mL). The aqueous phase was extracted with ethyl acetate (30 mL*3). The combined organic phase was washed with brine (15 mL), dried with anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuum. The residue was purified by silica gel chromatography (column height: 250 mm, diameter: 100 mm, 100-200 mesh silica gel, Petroleum ether/Ethyl acetate=1:1) to afford 1-(4-(6-(benzyloxy)-2-(cyclohex-1-en-1-yl)-3,4- dihydronaphthalen-1-yl)-3-methoxyphenyl)-4-(dimethoxymethyl) piperidine (756 mg, 1.30 mmol, 94.30% yield) as yellow oil. LC-MS (ESI+) m/z: 580.6(M+H)+. Step 5: To a solution of 1-(4-(6-(benzyloxy)-2-(cyclohex-1-en-1-yl)-3,4-dihydronaphth alen-1- yl)-3-methoxyphenyl)-4-(dimethoxymethyl)piperidine (730 mg, 1.26 mmol, 1.0 eq) in MeOH (4 mL) was added Pd/C (803.98 mg, 755.48 ^mol, 10% purity, 0.6 eq). The mixture was stirred under H ₂ at 50 °C and 50 Psi for 16 hr. LCMS showed that the starting material was consumed and the desired product was detected. The reaction mixture was filtered under reduced pressure to give (5S,6R)-6-cyclohexyl-5-(4-(4-(dimethoxymethyl)piperidin-1-yl )-2-methoxyphenyl)- 5,6,7,8-tetrahydronaphthalen-2-ol. (5R,6S)-6-cyclohexyl-5-(4-(4-(dimethoxymethyl)piperidin-1- yl)-2-methoxyphenyl)-5,6,7,8-tetrahydronaphthalen-2-ol (360 mg, 729.22 ^mol, 57.91% yield) was obtained as oil. LC-MS (ESI+) m/z: 494.4(M+H ⁺ ). Step 6: (5R,6S)-6-cyclohexyl-5-(4-(4-(dimethoxymethyl)piperidin-1-yl )-2-methoxyphenyl)- 5,6,7,8-tetrahydronaphthalen-2-ol and (5S,6R)-6-cyclohexyl-5-(4-(4- (dimethoxymethyl)piperidin-1-yl)-2-methoxyphenyl)-5,6,7,8-te trahydronaphthalen-2-ol (360 mg) was separated by chiral SFC (Column DAICEL CHIRALPAK AS (250mm*30mm,10um) Condition CO ₂ -EtOH (0.1%NH ₃ H ₂ O) Begin B 30% End B 30%) FlowRate (ml/min): 70) (5R,6S)-6-cyclohexyl-5-(4-(4-(dimethoxymethyl)piperidin-1-yl )-2-methoxyphenyl)-5,6,7,8- tetrahydronaphthalen-2-ol (110 mg), (5S,6R)-6-cyclohexyl-5-(4-(4-(dimethoxymethyl)piperidin- 1-yl)-2-methoxyphenyl)-5,6,7,8-tetrahydronaphthalen-2-ol (128.6mg). Step 7: 1-(4-((1R,2S)-2-cyclohexyl-6-hydroxy-1,2,3,4-tetrahydronapht halen-1-yl)-3- methoxyphenyl)piperidine-4-carbaldehyde: To a solution of (5S,6R)-6-cyclohexyl-5-(4-(4- (dimethoxymethyl)piperidin-1-yl)-2-methoxyphenyl)-5,6,7,8-te trahydronaphthalen-2-ol (110 mg, 222.82 ^mol, 1.0 eq) in DCM (10 mL) was added TFA (25.41 mg, 222.82 ^mol, 16.55 ^L, 1.0 eq). The mixture was stirred at 25 °C for 2 hr. LCMS showed that the starting material was consumed and the desired product was detected. The reaction mixture was filtered under reduced pressure to give a residue.1-(4-((1R,2S)-2-cyclohexyl-6-hydroxy-1,2,3,4- tetrahydronaphthalen-1-yl)-3-methoxyphenyl)piperidine-4-carb aldehyde (80 mg, 178.73 ^mol, 80.21% yield) was obtained as a solid. LC-MS (ESI+) m/z: 448.4 (M+H ⁺ ). 1-(4-((1S,2R)-2-cyclohexyl-6-hydroxy-1,2,3,4-tetrahydronapht halen-1-yl)-3- methoxyphenyl)piperidine-4-carbaldehyde: To a solution of (5R,6S)-6-cyclohexyl-5-(4-(4- (dimethoxymethyl)piperidin-1-yl)-2-methoxyphenyl)-5,6,7,8-te trahydronaphthalen-2-ol (128.6 mg, 260.49 ^mol, 1.0 eq) in DCM (12 mL) was added TFA (148.51 mg, 1.30 mmol, 96.75 ^L, 5.0 eq). The mixture was stirred at 25 °C for 2 hr. LCMS showed that the starting material was consumed and the desired product was detected. The reaction mixture was filtered under reduced pressure to give a residue.1-(4-((1S,2R)-2-cyclohexyl-6-hydroxy-1,2,3,4- tetrahydronaphthalen-1-yl)-3-methoxyphenyl)piperidine-4-carb aldehyde (85 mg, 189.90 ^mol, 72.90% yield) was obtained as a solid. LC-MS (ESI+) m/z: 466.4(M+H ⁺ ). Step 8: To a solution of 1-(4-((1R,2S)-2-cyclohexyl-6-hydroxy-1,2,3,4-tetrahydronapht halen-1- yl)-3-methoxyphenyl)piperidine-4-carbaldehyde (60 mg, 134.05 ^mol, 1.0 eq) in DCM (1 mL) and MeOH (1 mL) was added (S)-3-(1-oxo-5-(piperazin-1-yl)isoindolin-2-yl)piperidine-2, 6- dione (44.02 mg, 134.05 ^mol, 1.0 eq) ^C ₆ H ₁₀ BO ₆ Na (56.82 mg, 268.09 ^mol, 2.0 eq) and NMM (1.36 mg, 13.40 ^mol, 1.47 ^L, 0.1 eq). The mixture was stirred at 25 °C for 16 hr. LCMS showed that the starting material was consumed and the desired product was detected. The reaction mixture was filtered under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Boston Green ODS 150*30mm*5um; mobile phase: [water (FA)-ACN];B%: 10%-40%,12min) to give (S)-3-(5-(4-((1-(4-((1R,2S)-2-cyclohexyl-6-hydroxy- 1,2,3,4-tetrahydronaphthalen-1-yl)-3-methoxyphenyl)piperidin -4-yl)methyl)piperazin-1-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione (32.8 mg, 43.16 ^mol, 32.20% yield) as a white solid. LC-MS (ESI ⁺ ) m/z: 760.6 (M+H) ⁺ . LCMS: calc. for C ₄₆ H ₅₅ N ₅ O ₄ : 759.99, found: [M+H] ⁺ 760.6. HPLC: 100% purity at 220 nm. ¹ H NMR (400 MHz, METHANOL-d ₄ ) & = 8.38 (s, 1H), 7.64 (d, J = 8.5 Hz, 1H), 7.12 - 7.07 (m, 2H), 6.59 - 6.56 (m, 2H), 6.53 - 6.48 (m, 2H), 6.41 (dt, J = 2.3, 8.6 Hz, 2H), 5.09 (dd, J = 5.1, 13.4 Hz, 1H), 4.45 - 4.35 (m, 2H), 3.86 (s, 3H), 3.64 (br t, J = 10.5 Hz, 2H), 3.41 (br s, 4H), 2.94 - 2.85 (m, 2H), 2.79 - 2.65 (m, 8H), 2.50 - 2.40 (m, 3H), 2.17 - 2.03 (m, 2H), 1.90 (br d, J = 13.0 Hz, 2H), 1.83 - 1.49 (m, 8H), 1.44 - 1.34 (m, 2H), 1.25 - 0.97 (m, 6H), 0.79 - 0.67 (m, 1H). Step 9: To a solution of 1-(4-((1S,2R)-2-cyclohexyl-6-hydroxy-1,2,3,4-tetrahydronapht halen-1- yl)-3-methoxyphenyl)piperidine-4-carbaldehyde (75 mg, 167.56 ^mol, 1.0 eq) in DCM (2 mL) and MeOH (2 mL) was added (S)-3-(1-oxo-5-(piperazin-1-yl)isoindolin-2-yl)piperidine-2, 6- dione (55.02 mg, 167.56 ^mol, 1.0 eq) ^C ₆ H ₁₀ BO ₆ Na (71.02 mg, 335.12 ^mol, 2.0 eq) and NMM (1.36 mg, 13.40 ^mol, 1.47 ^L, 0.1 eq). The mixture was stirred at 25 °C for 16 hr. LCMS showed that the starting material was consumed and the desired product was detected. The reaction mixture was filtered under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Boston Green ODS 150*30mm*5um; mobile phase: [water (FA)-ACN];B%: 10%-40%,12min) to give (S)-3-(5-(4-((1-(4-((1S,2R)-2-cyclohexyl-6-hydroxy- 1,2,3,4-tetrahydronaphthalen-1-yl)-3-methoxyphenyl)piperidin -4-yl)methyl)piperazin-1-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione (30.5 mg, 40.13 ^mol, 23.95% yield) was obtained as a white solid. LC-MS (ESI ⁺ ) m/z: 76.6 (M+H) ⁺ . LCMS: calc. for C ₄₆ H ₅₅ N ₅ O ₄ : 759.99, found: [M+H] ⁺ 760.6. NMR (400 MHz, METHANOL-d4) & = 8.39 (br s, 1H), 7.64 (d, J = 8.5 Hz, 1H), 7.13 - 7.07 (m, 2H), 6.60 - 6.56 (m, 2H), 6.52 - 6.47 (m, 2H), 6.40 (dt, J = 2.4, 8.9 Hz, 2H), 5.09 (dd, J = 5.1, 13.2 Hz, 1H), 4.46 - 4.35 (m, 2H), 3.86 (s, 3H), 3.68 - 3.60 (m, 2H), 3.40 (br d, J = 4.8 Hz, 4H), 2.94 - 2.85 (m, 2H), 2.79 - 2.65 (m, 8H), 2.51 - 2.40 (m, 3H), 2.16 - 2.03 (m, 2H), 1.90 (br d, J = 12.8 Hz, 2H), 1.84 - 1.46 (m, 8H), 1.43 - 1.33 (m, 2H), 1.26 - 0.97 (m, 6H), 0.79 - 0.68 (m, 1H). EXAMPLE 193. Preparation of (I-144) (S)-3-(5-(4-((1-(4-((1S,2S)-6-hydroxy-2-phenyl- 1,2,3,4-tetrahydronaphthalen-1-yl)-3-methoxyphenyl)piperidin -4-yl)methyl)piperazin-1- yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione Step 1: To a solution of (5S,6S)-5-(4-(4-(dimethoxymethyl)piperidin-1-yl)-2-methoxyph enyl)-6- phenyl-5,6,7,8-tetrahydronaphthalen-2-ol (0.17 g, 5 mL, 1 Eq, 0.35 mmol) in THF (5 mL) was added sulfuric acid (34 mg, 1 Eq, 0.35 mmol). The mixture was stirred at 70 °C for 16 hour. LCMS showed 100 % desired MS. The mixture was adjusted to pH 8-9 by progressively adding NaHCO ₃ . The reaction mixture was quenched by addition 100 mL EtOAc at 20°C, and then diluted with 50 mL H2O and extracted with EtOAc 50mL (25 mL * 2). The combined organic layers were washed with 10 mL (10 mL * 1), dried over Na ₂ SO ₄ . The reaction was filtered and concentrated under reduced pressure to give 1-(4-((1S,2S)-6-hydroxy-2-phenyl-1,2,3,4- tetrahydronaphthalen-1-yl)-3-methoxyphenyl)piperidine-4-carb aldehyde (35 mg, 79 ^mol, 23 %, 100% purity) was obtained as a brown oil. LC-MS (ESI+) m/z: 460.3(M+H) ⁺ . Step 2: A mixture of 1-(4-((1S,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthale n-1-yl)-3- methoxyphenyl)piperidine-4-carbaldehyde (35 mg, 1 Eq, 79 ^mol), (S)-3-(1-oxo-5-(piperazin-1- yl)isoindolin-2-yl)piperidine-2,6-dione, PhSO3H salt (40 mg, 1 Eq, 79 ^mol) and sodium acetate (33 mg, 5 Eq, 0.40 mmol) in DCM (1 mL) and MeOH (1 mL) at 20°C for 0.5 hour, pH=8, then acetic acid (14 mg, 14 ^L, 3 Eq, 0.24 mmol) at 20°C for 1 hour, pH=6, then added sodium triacetoxyhydroborate (34 mg, 2 Eq, 0.16 mmol) the mixture, and then the mixture was stirred at 25 °C for 16 hour. LCMS showed 89.04% desired MS. The reaction was concentrated to give (S)-3-(5-(4-((1-(4-((1S,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetra hydronaphthalen-1-yl)-3- methoxyphenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoiso indolin-2-yl)piperidine-2,6-dione as a brown oil. The mixture was filtered and the filter cake was washed by EtOAc (50 mL x3). The brown oil was purified by preparative high-performance liquid chromatography. Condition: Column: Xtimate C18100*30mm*3um, A: water(FA), B:CAN, at the beginning: A (85%) and B (15%), at the end: A: (45%) and B (55%), Gradient Time(min) 8; 100% B hold Time(min) 2.5, Flow Rate(ml/min) 30. The pure fractions were collected and the solvent was evaporated under vacuum. The aqueous layer was lyophilized to dryness to give (S)-3-(5-(4-((1- (4-((1S,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen- 1-yl)-3-methoxyphenyl)piperidin- 4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine- 2,6-dione (17.5 mg, 23.1 ^mol, 29 %, 99.58% Purity) as a white solid. LCMS: calc. for C46H51N5O5: 753.39, found: [M+H] ⁺ 754.4. HPLC: 99.6% purity at 220 nm. ppm 10.95 (s, 1 H) 9.07 (s, 1 H) 8.15 (s, 0.092 H) 7.52 (d, J=8.70 Hz, 1 H) 7.04 - 7.10 (m, 5 H) 6.71 - 6.76 (m, 2 H) 6.56 (d, J=8.58 Hz, 2 H) 6.46 (dd, J=8.34, 2.27 Hz, 1 H) 6.34 - 6.39 (m, 1 H) 6.28 - 6.33 (m, 1 H) 6.12 (d, J=1.67 Hz, 1 H) 5.05 (dd, J=13.35, 5.01 Hz, 1 H) 4.65 (d, J=5.01 Hz, 1 H) 4.31 - 4.37 (m, 1 H) 4.18 - 4.24 (m, 1 H) 3.56 (br d, J=5.84 Hz, 2 H) 3.29 (br s, 6 H) 3.22 (br d, J=15.38 Hz, 2 H) 2.95 (s, 4 H) 2.86 - 2.92 (m, 2 H) 2.55 - 2.63 (m, 3 H) 2.53 (br s, 2 H) 2.21 (br d, J=7.15 Hz, 3 H) 1.94 - 2.01 (m, 1 H) 1.77 (br d, J=13.11 Hz, 2 H) 1.56 - 1.70 (m, 2 H) 1.19 (br d, J=11.44 Hz, 2 H). SFC: retention time, 2.628 min; Area, 92.65%; EXAMPLE 194. Preparation of (I-143) (S)-3-(5-(4-((1-(4-((1R,2R)-6-hydroxy-2-phenyl- 1,2,3,4-tetrahydronaphthalen-1-yl)-3-methoxyphenyl)piperidin -4-yl)methyl)piperazin-1- yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione Step 1: To a solution of 1-bromo-4-iodo-2-methoxybenzene (3 g, 1 Eq, 0.01 mol) and 4- (dimethoxymethyl)piperidine (2 g, 2 mL, 1 Eq, 0.01 mol) in DMSO (150 mL) was added and potassium carbonate (3 g, 1 mL, 2 Eq, 0.02 mol). The mixture was stirred at 80 °C for 12 hour. LCMS 75.8% desired MS was detected. TLC (petroleum ether: ethyl acetate=10:1, UV, R _f =0.3) showed one main new spot was observed. The reaction was quenched with water (50 mL) and extracted with ethyl acetate (50 mL*2). The organic layer was washed with brine(50 mL) and dried over Na ₂ SO ₄ and concentrated in vacuo to give 1-(4-bromo-3-methoxyphenyl)-4- (dimethoxymethyl)piperidine as a brown oil. The brown oil was subjected to column chromatography over silica gel (gradient elution: 0 – 15% EtOAc). LCMS 100% desired MS was detected. The desired fractions were collected, and concentrated to dryness in vacuo to give 1-(4- bromo-3-methoxyphenyl)-4-(dimethoxymethyl)piperidine(1.6 g, 4.2 mmol, 40 %, 90% purity) as a white solid. LC-MS (ESI ⁺ ) m/z: 344.1 (M+H) ⁺ . Step 2: To a solution of 1-(4-bromo-3-methoxyphenyl)-4-(dimethoxymethyl)piperidine (1.6 g, 1 Eq, 4.6 mmol) in THF (100 mL) was added n-Butyllithium, 2.5 M in hexane (0.33 g, 2.0 mL, 2.5 molar, 1.1 Eq, 5.1 mmol) at -68 °C over 5 min. After addition, the mixture was stirred at this temperature for 1.5 hour, and then isopropoxyboronic acid pinacol ester (1.1 g, 1.2 mL, 1.3 Eq, 6.0 mmol) was added dropwise at -68 °C. The resulting mixture was stirred at 25 °C for 16 hour. LCMS showed 14.27% desired MS. TLC (petroleum ether: ethyl acetate=5:1, UV) showed one main new spot was observed. The reaction was quenched with water (100 mL) and extracted with ethyl acetate (200 mL*2). The organic layer was washed with brine(50 mL) and dried over Na ₂ SO ₄ and concentrated in vacuo to give 4-(dimethoxymethyl)-1-(3-methoxy-4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperidine as a yellow oil. The yellow oil was subjected to column chromatography over silica gel (gradient elution: 0 – 20% EtOAc). LCMS showed 81.5% desired MS. The desired fractions were collected, and concentrated to dryness in vacuo to give 4-(dimethoxymethyl)-1-(3-methoxy-4-(4,4,5,5-tetramethyl-1,3, 2-dioxaborolan-2- yl)phenyl)piperidine (378 mg, 787 ^mol, 17 %, 81.5% purity) as a colorless oil. LC-MS (ESI ⁺ ) m/z: 392.3 (M+H) ⁺ . Step 3: A 8 mL thread vial equipped with magnetic stirrer.6-(benzyloxy)-2-phenyl-3,4- dihydronaphthalen-1-yl trifluoromethanesulfonate (534 mg, 1.2 Eq, 1.16 mmol) was added to a mixture suspension of [1,1'-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) Complex With Dichloromethane (78.9 mg, 0.1 Eq, 96.6 ^mol) and 4-(dimethoxymethyl)-1-(3-methoxy-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperidi ne (378 mg, 1 Eq, 966 ^mol) and sodium carbonate (307 mg 186 ^L 3 Eq 290 mmol) in 14-Dioxane (8 mL) and H ₂ O (2 mL) The mixture was stirred at 90 °C for 16 hour. LCMS showed 41% desired MS. TLC (petroleum ether: ethyl acetate=10:1, UV) showed one main new spot was observed. The reaction was quenched with water (100 mL) and extracted with ethyl acetate (200 mL*2). The organic layer was washed with brine(50 mL) and dried over Na ₂ SO ₄ and concentrated in vacuo to give 1-(4-(6- (benzyloxy)-2-phenyl-3,4-dihydronaphthalen-1-yl)-3-methoxyph enyl)-4- (dimethoxymethyl)piperidine as a black oil. The black oil was subjected to column chromatography over silica gel (gradient elution: 0 – 15% EtOAc). LCMS showed 97.7% desired MS. The desired fractions were collected, and concentrated to dryness in vacuo to give 1- (4-(6-(benzyloxy)-2-phenyl-3,4-dihydronaphthalen-1-yl)-3-met hoxyphenyl)-4- (dimethoxymethyl)piperidine (233 mg, 395 ^mol, 40.9 %, 97.7% Purity) as a red oil. LC-MS (ESI ⁺ ) m/z: 576.3 (M+H) ⁺ . Step 4: A mixture of 1-(4-(6-(benzyloxy)-2-phenyl-3,4-dihydronaphthalen-1-yl)-3- methoxyphenyl)-4-(dimethoxymethyl)piperidine (183 mg, 1 Eq, 318 ^mol), Pd/C(200 mg, 5.91 Eq, 1.88 mmol, 10% purity) in MeOH (5 mL) and THF (5 mL) was degassed and purged with H ₂ for 3 times, and then the mixture was stirred at 50 °C for 16 hour under H2 atmosphere(15 psi). LCMS showed 77.8% desired. TLC (petroleum ether: ethyl acetate=5:1, UV) showed one main new spot was observed. The reaction was filtered and concentrated to dryness in vacuo to give a brown oil. The brown oil was subjected to column chromatography over silica gel (gradient elution: 0 – 20% EtOAc). LCMS showed 95% desired. The desired fractions were collected, and concentrated to dryness in vacuo to give a brown oil (140 mg, 0.27 mmol, 86 % yield, 95% purity). Step 5: The brown oil was purified by SFC. Condition:0.1%NH ₃ H ₂ O EtOH; Column: DAICEL CHIRALCEL OJ(250mm*30mm,10um), at the beginning: A (60%) and B (40%), at the end: A: (60%) and B (40%), Flow Rate(ml/min) 80. The pure fractions were collected and the solvent was evaporated under vacuum to give (5R,6R)-5-(4-(4-(dimethoxymethyl)piperidin-1-yl)-2- methoxyphenyl)-6-phenyl-5,6,7,8-tetrahydronaphthalen-2-ol (41 mg, 84 ^mol, 51 %, 100% purity) as a brown oil and (5S,6S)-5-(4-(4-(dimethoxymethyl)piperidin-1-yl)-2-methoxyph enyl)- 6-phenyl-5,6,7,8-tetrahydronaphthalen-2-ol (34 mg, 70 ^mol, 42 %, 100% Purity) as a brown oil. LC-MS (ESI+) m/z: 488.3(M+H) ⁺ . Step 6: To a solution of (5R,6R)-5-(4-(4-(dimethoxymethyl)piperidin-1-yl)-2-methoxyph enyl)-6- added sulfuric acid (31 mg, 1 Eq, 0.32 mmol). The mixture was stirred at 70 °C for 16 hour. LCMS showed 84.5 % desired MS. The mixture was adjusted to pH 8-9 by progressively adding NaHCO ₃ . The reaction mixture was quenched by addition EtOAc(100 mL) at 20 °C, and then diluted with H ₂ O(50 mL) and extracted with EtOAc 50mL (25 mL * 2). The combined organic layers were washed with 10 mL (10 mL * 1), dried over Na ₂ SO ₄ . The reaction was filtered and concentrated under reduced pressure to give 1-(4-((1R,2R)-6-hydroxy-2-phenyl-1,2,3,4- tetrahydronaphthalen-1-yl)-3-methoxyphenyl)piperidine-4-carb aldehyde (45 mg, 86 ^mol, 27 %, 84.5% purity) was obtained as a brown oil. LC-MS (ESI+) m/z: 460.3(M+H) ⁺ . Step 7: A mixture of 1-(4-((1R,2R)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthale n-1-yl)-3- methoxyphenyl)piperidine-4-carbaldehyde (35 mg, 1 Eq, 79 ^mol), (S)-3-(1-oxo-5-(piperazin-1- yl)isoindolin-2-yl)piperidine-2,6-dione, PhSO ₃ H salt (40 mg, 1 Eq, 79 ^mol) and sodium acetate (33 mg, 5 Eq, 0.40 mmol) in DCM (1 mL) and MeOH (1 mL) at 20°C for 0.5 hour, pH=8, then acetic acid (14 mg, 14 ^L, 3 Eq, 0.24 mmol) at 20°C for 1 hour, pH=6, then added sodium triacetoxyhydroborate (34 mg, 2 Eq, 0.16 mmol) the mixture, and then the mixture was stirred at 25 °C for 16 hour. LCMS showed 91.16% desired MS. The reaction was concentrated to give (S)-3-(5-(4-((1-(4-((1R,2R)-6-hydroxy-2-phenyl-1,2,3,4-tetra hydronaphthalen-1-yl)-3- methoxyphenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoiso indolin-2-yl)piperidine-2,6-dione as a brown oil. The mixture was filtered and the filter cake was washed by EtOAc (50 mL x3). The brown oil was purified by preparative high-performance liquid chromatography. Condition: Column: Xtimate C18100*30mm*3um, A: water(FA), B: CAN, at the beginning: A (85%) and B (15%), at the end: A: (45%) and B (55%), Gradient Time(min) 8; 100% B hold Time(min) 2.5, Flow Rate(ml/min) 30. The pure fractions were collected and the solvent was evaporated under vacuum. The aqueous layer was lyophilized to dryness to give (S)-3-(5-(4-((1-(4-((1R,2R)-6- hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)-3-methox yphenyl)piperidin-4- yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2, 6-dione (24.1 mg, 31.9 ^mol, 40 %, 99.81% purity) as a white solid. LCMS: calc. for C ₄₆ H ₅₁ N ₅ O ₅ : 753.39, found: [M+H] ⁺ 754.4. HPLC: 99.8% purity at 220 nm. ppm 10.95 (s, 1 H) 9.07 (s, 1 H) 8.16 (s, 0.172 H) 7.52 (d, J 846 H 1 H) 704 711 ( 5 H) 672 677 ( 2 H) 656 (d J 858 H 2 H) 646 (dd J=8.34, 2.38 Hz, 1 H) 6.35 - 6.39 (m, 1 H) 6.28 - 6.33 (m, 1 H) 6.12 (d, J=1.79 Hz, 1 H) 5.05 (dd, J=13.29, 5.19 Hz, 1 H) 4.65 (d, J=5.36 Hz, 1 H) 4.30 - 4.37 (m, 1 H) 4.16 - 4.24 (m, 1 H) 3.57 (br s, 2 H) 3.29 (br s, 6 H) 3.22 (br d, J=14.54 Hz, 2 H) 2.92 - 2.96 (m, 4 H) 2.76 - 2.91 (m, 2 H) 2.54 - 2.62 (m, 3 H) 2.27 - 2.39 (m, 2 H) 2.16 - 2.24 (m, 3 H) 1.93 - 2.00 (m, 1 H) 1.77 (br d, J=12.16 Hz, 2 H) 1.49 - 1.68 (m, 2 H) 1.17 - 1.27 (m, 2 H) SFC: retention time, 2.625 min; Area, 91.181%; EXAMPLE 195. Preparation of (I-159) (R)-3-(5-(4-((1-(4-((1R,2R)-2-cyclohexyl-6- hydroxy-1,2,3,4-tetrahydronaphthalen-1-yl)-2,6-difluoropheny l)piperidin-4- yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2, 6-dione Step 1: 6-cyclohexyl-5-(4-(4-(dimethoxymethyl)piperidin-1-yl)-3,5-di fluorophenyl)-5,6,7,8- tetrahydronaphthalen-2-ol (100 mg, 200 ^mol, 1.0 eq.) was purified by SFC (Column: DAICEL CHIRALCEL OD-H (250mm x 30mm, 10um); Mobile phase:CO2-EtOH(0.1%NH3H2O); from 35% to 35%; Flow rate: 100 mL/min) to give (5R,6R)-6-cyclohexyl-5-(4-(4- (dimethoxymethyl)piperidin-1-yl)-3,5-difluorophenyl)-5,6,7,8 -tetrahydronaphthalen-2-ol (40 mg, 80 ^mol, 40 %) as a white solid. LC-MS (ESI ⁺ ) m/z: 500.4 (M+H) ⁺ . Step 2: To a solution of (5R,6R)-6-cyclohexyl-5-(4-(4-(dimethoxymethyl)piperidin-1-yl )-3,5- difluorophenyl)-5,6,7,8-tetrahydronaphthalen-2-ol (40 mg, 80 ^mol, 1.0 eq.) in DCM (3 mL) was added TFA (27 mg, 0.24 mmol, 3.0 eq.). The mixture was stirred at 20 °C for 12 hour. LCMS showed the reaction was completed. The mixture was concentrated in vacuo to give crude product. No further purification as it is used for the next step directly. LC-MS (ESI ⁺ ) m/z: 454.2 (M+H) ⁺ . Step 3: To a solution of 1-(4-((1R,2R)-2-cyclohexyl-6-hydroxy-1,2,3,4-tetrahydronapht halen-1- yl)- 2,6-difluorophenyl)piperidine-4-carbaldehyde (25 mg, 55 ^mol, 1.0 eq.) and (R)-3-(1-oxo- 5-(piperazin-1-yl)isoindolin-2-yl)piperidine-2,6-dione (22 mg, 66 ^mol, 1.2 eq.) in DCE (3 ml) was added Sodium triacetoxyborohydride (35 mg, 0.17 mmol, 3.0 eq.). The mixture was stirred at 20 °C for 2 hour. LCMS showed the reaction was completed. The crude was purified by prep.HPLC together (Boston Green ODS 150*30mm*5um, water(FA)-ACN as a mobile phase, from 20% to 30%, Gradient Time (min): 12, Flow Rate (ml/min): 25) to give (R)-3-(5-(4-((1-(4- ((1R,2R)-2-cyclohexyl-6-hydroxy-1,2,3,4-tetrahydronaphthalen -1-yl)-2,6- difluorophenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxois oindolin-2-yl)piperidine-2,6-dione (20.6 mg, 26.9 ^mol, 49 %) as a white solid. LC-MS (ESI ⁺ ) m/z: 766.5 (M+H) ⁺ . LCMS: calc. for C ₄₅ H ₅₃ F ₂ N ₅ O ₄ :765.95, found: [M+H] ⁺ 766.5. HPLC: 98.84% purity at 220 nm. ¹ H NMR (500 MHz, METHANOL- d ₄ ) į: ppm 7.63 (d, J=8.54 Hz, 1 H), 7.05 - 7.10 (m, 2 H), 6.67 (d, J=8.50 Hz, 1 H), 6.58 (d, J=2.50 Hz, 1 H), 6.48 - 6.55 (m, 3 H), 5.09 (dd, J=13.50, 5.04 Hz, 1 H), 4.35 - 4.44 (m, 2 H), 4.15 (d, J=4.50 Hz, 1 H), 3.35 - 3.39 (m, 4 H), 3.15 - 3.19 (m, 2 H), 3.03 - 3.11 (m, 2H), 2.85 - 2.95 (m, 2 H), 2.74 - 2.82 (m, 2 H), 2.59 - 2.64 (m, 4 H), 2.42 - 2.50 (m, 1 H), 2.31 (d, J=7.00 Hz, 2 H), 2.09 - 2.18 (m, 2 H), 1.71 - 1.87 (m, 5 H), 1.60 - 1.69 (m, 3 H), 1.51 (dq, J=12.50, 6.50 Hz, 1 H), 1.28 - 1.40 (m, 4 H), 1.13 - 1.20 (m, 1 H), 1.04 - 1.12 (m, 3 H), 0.79 - 0.87 (m, 1 H). EXAMPLE 196. Preparation of (I-160) (R)-3-(5-(4-((1-(4-((1S,2S)-2-cyclohexyl-6- hydroxy-1,2,3,4-tetrahydronaphthalen-1-yl)-2,6-difluoropheny l)piperidin-4- yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2, 6-dione Step 1: To a mixture of 1,2,3-trifluoro-5-nitrobenzene (5.00 g, 28.2 mmol, 1.0 eq.), 4- (dimethoxymethyl)piperidine (4.50 g, 28.2 mmol, 1.0 eq.) and K2CO3 (7.80 g, 56.5 mmol, 2.0 eq. ) in DMF (20 mL) was added in one portion . The mixture was stirred at 25 °C for 5 min, then heated to 100°C and stirred for 3 hours. LCMS showed the reaction was completed. The mixture was cooled to 25 °C and concentrated in reduced pressure at 40 °C. The residue was poured into ice-water (w/w = 1/1) (100 mL) and stirred for 5 min. The aqueous phase was extracted with ethyl acetate (100 mL*2). The combined organic phase was washed with brine (50 mL*2), dried with anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuum. The residue was purified by silica gel chromatography (column height: 250 mm, diameter: 100 mm, 100-200 mesh silica gel, Petroleum ether/Ethyl acetate=3/1) to afford 1-(2,6-difluoro-4-nitrophenyl)-4- (dimethoxymethyl)piperidine (4.52 g, 13.0 mmol, 46.2 %, 91.235% Purity) as yellow solid. LC- MS (ESI ⁺ ) m/z: 317.1 (M+H) ⁺ . Step 2: To a mixture of 1-(2,6-difluoro-4-nitrophenyl)-4-(dimethoxymethyl)piperidine (2.00 g, 6.32 mmol, 1.0 eq.), iron (1.06 g, 19.0 mmol, 3.0 eq.) and NH ₄ Cl (1.01 g, 19.0 mmol, 3.0 eq.) in EtOH (5 mL) and H2O (5 mL) was added in one portion. The mixture was stirred at 0 °C for 5 min, then heated to 80°C and stirred for 16 hours. LCMS showed the reaction was completed. The mixture was filter and cooled to 25 °C and concentrated in reduced pressure at 25 °C. The residue was poured into ice-water (w/w = 1/1) (100 mL) and stirred for 5 min. The aqueous phase was extracted with ethyl acetate (100 mL x 2). The combined organic phase was washed with brine (50 mL*1), dried with anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuum. The residue was purified by silica gel chromatography (column height: 250 mm, diameter: 100 mm, 100-200 mesh silica gel, Petroleum ether/Ethyl acetate=10/1) to afford 4-(4- (dimethoxymethyl)piperidin-1-yl)-3,5-difluoroaniline (1.93 g, 5.14 mmol, 81.3 %, 76.287% Purity)} as yellow oil. LC-MS (ESI ⁺ ) m/z: 287.1 (M+H) ⁺ . Step 3: To a mixture of 4-(4-(dimethoxymethyl) piperidin-1-yl)-3,5-difluoroaniline (2.00 g, 6.99 mmol, 1.0 eq.), potassium iodide (3.48 g, 21.0 mmol, 3.0 eq.) and sodium nitrite (964 mg, 14.0 mmol, 2.0 eq.) in HCl (5 mL) and H ₂ O (5 mL) was added in one portion. The mixture was added H ₂ SO ₄ (1.37 g, 745 ^L, 2 eq., 14.0 mmol) to adjust pH to about 5 and stirred at 0 °C for 1 hour, then heated to 25°C and stirred for 3 hours. LCMS showed the reaction was completed. The mixture was cooled to 25 °C and concentrated in reduced pressure at 25 °C. The residue was poured into ice-water (w/w = 1/1) (100 mL) and stirred for 5 min The aqueous phase was extracted with ethyl acetate (1000 mL*2). The combined organic phase was washed with brine (50 mL*2), dried with anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was purified by silica gel chromatography (column height: 250 mm, diameter: 100 mm, 100-200 mesh silica gel, Petroleum ether/Ethyl acetate=10/1) to afford1-(2,6-difluoro-4-iodophenyl)-4- (dimethoxymethyl)piperidine (1.85 g, 4.11 mmol, 58.8 %, 88.192% Purity) as yellow oil. LC- MS (ESI ⁺ ) m/z: 398.0 (M+H) ⁺ . Step 4: A mixture of 1-(2,6-difluoro-4-iodophenyl)-4-(dimethoxymethyl)piperidine (1.50 g, 1 eq., 3.78 mmol, 1.0 eq.), Compound 6 (1.91 g, 4.53 mmol, 1.2 eq.),1,1'- Bis(diphenylphosphino)ferrocene -palladium(II) dichloride (276 mg, 378 ^mol, 0.1 eq.), Lithium 2-methyl-2-propanolate (756 mg, 9.44 mmol, 2.5 eq.) and XPhos Pd G3 (160 mg, 0.05 eq., 189 ^mol) in Dioxane (40 mL) was degassed and purged with N ₂ for 3 times, and then the mixture was stirred at 100 °C for 12 hour under N ₂ atmosphere. LCMS showed the reaction was completed. The reaction mixture was quenched by addition EA 10 mL at 20 °C, and then diluted with water 30 mL and extracted with EA 30 mL (10 mL * 3). The combined organic layers were washed with EA 30 mL (10 mL x 3), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The crude material was purified on silica gel column chromatography (from pure PE to PE/EtOAc = 20/1) to give 1-(4-(6-(benzyloxy)-3,4-dihydronaphthalen-1- yl)phenyl)-4-(dimethoxymethyl)-3,5-difluoropiperidine (0.9 g, 2 mmol, 50 %) as a yellow solid. LC-MS (ESI ⁺ ) m/z: 506.2 (M+H) ⁺ . Step 5: To a solution of 1-(4-(6-(benzyloxy)-3,4-dihydronaphthalen-1-yl)-2,6-difluoro phenyl)-4- (dimethoxymethyl)piperidine (1.00 g, 1.98 mmol, 1.0 eq.) in DCM (20 mL) was added Pyridinium bromide perbromide (443 mg, 1.38 mmol, 0.7 eq.). The mixture was stirred at 20 °C for 1 hour. LCMS showed the reaction was completed. The reaction mixture was quenched by addition water 60 mL at 20 °C, and then diluted with EA 30 mL and extracted with EA 150 mL (50 mL x 3). The combined organic layers were washed with EA 60 mL (20 mL x 3), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The crude material was purified on silica gel column chromatography (from pure PE to PE/EtOAc = 30/1) to give 1- (4-(6-(benzyloxy)-2-bromo-3,4-dihydronaphthalen-1-yl)-2,6-di fluorophenyl) -4- (dimethoxymethyl)piperidine (0.6 g, 0.5 mmol, 30 %, 50% Purity) as a yellow solid. LC-MS (ESI ⁺ ) m/z: 584.2 (M+H) ⁺ . Step 6: A mixture of 1-(4-(6-(benzyloxy)-2-bromo-3,4-dihydronaphthalen-1-yl)-2,6- difluorophenyl) -4-(dimethoxymethyl)piperidine (600 mg, 1.03 mmol, 1.0 eq.), cyclohex-1-en-1- ylboronic acid (154 mg, 1.213mol, 1.2 eq.), PdCl ₂ (dppf) (75.2 mg, 102.1 ^mol, 0.1 eq.) and sodium carbonate (327 mg, 3.08 mmol, 3.0 eq.) in Dioxane (12 mL) and water (3 mL) was degassed and purged with N ₂ for 3 times, and then the mixture was stirred at 80 °C for 3 hour under N ₂ atmosphere. LCMS showed the reaction was completed. The reaction mixture was quenched by addition EA 30 mL at 20 °C, and then diluted with water 30 mL and extracted with EA 90 mL (30 mL x 3). The combined organic layers were washed with EA 30 mL (10 mL x 3), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The crude material was purified on silica gel column chromatography (from pure PE to PE/EtOAc = 3/1) to give compound 10 (600 mg, 0.31 mmol, 45 % yield, 60% Purity) as a yellow solid. LC- MS (ESI ⁺ ) m/z: 586.4 (M+H) ⁺ . Step 7: To a solution of 1-(4-(6-(benzyloxy)-2-(cyclohex-1-en-1-yl)-3,4-dihydronaphth alen-1- yl)-2,6- difluorophenyl)-4-(dimethoxymethyl)piperidine (0.400 g, 683 ^mol, 1.0 eq.) in MeOH (10 mL) was added Pd/C (10wt%, 0.2 g) under N2 atmosphere. The suspension was degassed and purged with H2 for 3 times. The mixture was stirred under H2(50 Psi) at 50 °C for 12 hour. LCMS showed the reaction was completed. The crude was purified by prep.HPLC together (Welch Xtimate C18150*25mm*5um, water(FA)-ACN as a mobile phase, from 85% to 100%, Gradient Time (min): 11, Flow Rate (ml/min): 25) to give 6-cyclohexyl-5-(4-(4- (dimethoxymethyl)piperidin-1-yl)-3,5-difluorophenyl)-5,6,7,8 -tetrahydronaphthalen-2-ol (100 mg, 200 ^mol, 29.3 %) as a white solid. LC-MS (ESI ⁺ ) m/z: 500.4 (M+H) ⁺ . Step 8: 6-cyclohexyl-5-(4-(4-(dimethoxymethyl)piperidin-1-yl)-3,5-di fluorophenyl)-5,6,7,8- tetrahydronaphthalen-2-ol (100 mg, 200 ^mol, 1.0 eq.) was purified by SFC (Column: DAICEL CHIRALCEL OD-H(250mm*30mm,10um); Mobile phase:CO ₂ -EtOH(0.1%NH ₃ H ₂ O); from 35% to 35%; Flow rate: 100 mL/min) to give (5S,6S)-6-cyclohexyl-5-(4-(4- (dimethoxymethyl)piperidin-1-yl)-3,5-difluorophenyl)-5,6,7,8 -tetrahydronaphthalen-2-ol (40 mg, 80 ^mol, 40 % yield) as a white solid. LC-MS (ESI ⁺ ) m/z: 500.4 (M+H) ⁺ . Step 9: To a solution of (5S,6S)-6-cyclohexyl-5-(4-(4-(dimethoxymethyl)piperidin-1-yl )-3,5- difluorophenyl)-5,6,7,8-tetrahydronaphthalen-2-ol (50 mg, 0.10 mmol, 1.0 eq.) in DCM (3 mL) was added TFA (34 mg, 23 ^L, 3 eq., 0.30 mmol). The mixture was stirred at 20 °C for 12 hour. crude product. No further purification as it is used for the next step directly. LC-MS (ESI ⁺ ) m/z: 454.2 (M+H) ⁺ . Step 10: To a solution of 1-(4-((1S,2S)-2-cyclohexyl-6-hydroxy-1,2,3,4-tetrahydronapht halen-1- yl)-2, 6-difluorophenyl)piperidine-4-carbaldehyde (30 mg, 66 ^mol, 1.0 eq.) and (R)-3-(1-oxo-5- (piperazin-1-yl)isoindolin-2-yl)piperidine-2,6-dione (26 mg, 79 ^mol, 1.2 eq.) in DCE (3 mL) was added sodium triacetoxyhydroborate (42 mg, 0.20 mmol, 3.0 eq.). The mixture was stirred at 20 °C for 2 hour. LCMS showed the reaction was completed. The crude was purified by prep.HPLC together (Boston Green ODS 150*30mm*5um, water(FA)-ACN as a mobile phase, from 20% to 30%, Gradient Time (min): 12, Flow Rate (ml/min): 25) to give (R)-3-(5-(4-((1-(4- ((1S,2S)-2-cyclohexyl-6-hydroxy-1,2,3,4-tetrahydronaphthalen -1-yl)-2,6- difluorophenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxois oindolin-2-yl)piperidine-2,6-dione (23.3 mg, 30.4 ^mol, 46 %) as a white solid. LC-MS (ESI ⁺ ) m/z: 766.7 (M+H) ⁺ . LCMS: calc. found: [M+H] ⁺ 766.7 HPLC: 94.59% purity at 220 nm. ¹ H NMR (400 MHz, METHANOL-d ₄ ) į: ppm 8.44 - 8.50 (m, 1 H), 7.66 (d, J=8.40 Hz, 1 H), 7.07 - 7.14 (m, 2 H), 6.69 (d, J=8.40 Hz, 1 H), 6.50 - 6.61(m, 4 H), 5.12 (dd, J=13.20, 5.07 Hz, 1 H), 4.37 - 4.47 (m, 2 H), 4.18 (d, J=4.40 Hz, 1 H), 3.41 (br d, J=4.80 Hz, 4 H), 3.16 - 3.22 (m, 2 H), 3.05 - 3.14 (m,2 H), 2.87 - 2.98 (m, 2 H), 2.77 - 2.85 (m, 2 H), 2.70 - 2.76 (m, 4 H), 2.43 (br d, J=6.20 Hz, 3 H), 2.10 - 2.20 (m, 2 H), 1.75 - 1.88 (m, 5 H), 1.60 - 1.71 (m,3 H), 1.52 (dq, J=12.80, 6.54 Hz, 1 H), 1.26 - 1.44 (m, 4 H), 1.15 - 1.23 (m, 1 H), 1.05 - 1.14 (m, 3 H), 0.79 - 0.91 (m, 1 H). EXAMPLE 197. Preparation of (I-236) (S)-3-(5-(4-((1-(4-((1S,2S)-2-cyclohexyl-6- hydroxy-1,2,3,4-tetrahydronaphthalen-1-yl)-2-fluorophenyl)pi peridin-4- yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2, 6-dione and (I-162) (S)-3-(5-(4- ((1-(4-((1R,2R)-2-cyclohexyl-6-hydroxy-1,2,3,4-tetrahydronap hthalen-1-yl)-2- fluorophenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoi ndolin-2-yl)piperidine-2,6- dione Step 1: To a solution of 1,2-difluoro-4-nitrobenzene (3.0 g, 18.86 mmol, 2.08 mL, 1 eq, 1) and 4- (dimethoxymethyl)piperidine (3.60 g, 22.63 mmol, 1.2 eq) in EtOAc (30 mL) was added Et3N (572 g 5657 mmol 787 mL 3 eq) The mixture was stirred at 25 °C for 3 hr The mixture was concentrated in reduced pressure. The residue was poured into water (30mL). The aqueous phase was extracted with ethyl acetate (60 mL*3). The combined organic phase was washed with brine (30 mL*3), dried with anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was purified by silica gel chromatography (column height: 250 mm, diameter: 100 mm, 100-200 mesh silica gel, Petroleum ether/Ethyl acetate=3:1) to afford 4-(dimethoxymethyl)-1-(2-fluoro-4- nitrophenyl)piperidine (4.77 g, 15.99 mmol, 84.80% yield) as yellow oil. LC-MS (ESI+) m/z: 299.2 (M+H) ⁺ . Step 2: To a solution of 4-(dimethoxymethyl)-1-(2-fluoro-4-nitrophenyl)piperidine (3.5 g, 11.73 mmol, 1 eq) in EtOH (40 mL) and H ₂ O (15 mL) was added Fe (2.62 g, 46.93 mmol, 4 eq) and NH ₄ Cl (1.26 g, 23.47 mmol, 2eq). The mixture was stirred at 80 °C for 5 hr. LCMS showed that the starting material was consumed and the desired product was detected. The residue was poured into water (55mL). The aqueous phase was extracted with ethyl acetate (100 mL*3). The combined organic phase was washed with brine (55 mL), dried with anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuum. The residue was purified by silica gel chromatography (column height: 250 mm, diameter: 100 mm, 100-200 mesh silica gel, Petroleum ether/Ethyl acetate=3:1) to afford 4-(4-(dimethoxymethyl)piperidin-1-yl)-3-fluoroaniline (2.96 g, 11.03 mmol, 94.02% yield) as yellow oil. The reaction mixture was filtered under reduced pressure to give a compound. 4-(4-(dimethoxymethyl)piperidin-1-yl)-3-fluoroaniline (2.96 g, 11.03 mmol, 94.02% yield) was obtained as yellow oil. LC-MS (ESI+) m/z: 269.2 (M+H) ⁺ . Step 3: To a solution of 4-(4-(dimethoxymethyl)piperidin-1-yl)-3-fluoroaniline (2.96 g, 11.03 mmol, 1eq) in MeCN (35 mL) and H ₂ O (35 mL) was added KI (5.49 g, 33.09 mmol, 3eq), NaNO ₂ (2.28 g, 33.09 mmol, 3eq) and HCl (1 M, 11.03 mL, 1eq). The mixture was stirred at 25 °C for 5 hr. LC-MS showed that the starting material was consumed and the desired product was detected. The residue was poured into water (35mL). The aqueous phase was extracted with ethyl acetate (70 mL*3). The combined organic phase was washed with brine (35 mL*3), dried with anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuum. The residue was purified by silica gel chromatography (column height: 250 mm, diameter: 100 mm, 100-200 mesh silica gel, Petroleum ether/Ethyl acetate=1:1) to afford 5 (1.5 g, 3.96 mmol, 35.86% yield) as yellow oil. The reaction mixture was filtered under reduced pressure to give a compound. 4- (dimethoxymethyl)-1-(2-fluoro-4-iodophenyl)piperidine (1.5 g, 3.96 mmol, 35.86% yield) was obtained as yellow oil. LC-MS (ESI+) m/z: 380.1(M+H) ⁺ . Step 4: A mixture of 4-(dimethoxymethyl)-1-(2-fluoro-4-iodophenyl)piperidine (1.6 g, 4.22 mmol, 1 eq), (E)-N'-(6-(benzyloxy)-3,4-dihydronaphthalen-1(2H)-ylidene)-4 - methylbenzenesulfonohydrazide (1.95 g, 4.64 mmol, 1.1 eq), t-BuOLi (1.01 g, 12.66 mmol, 1.14 mL, 3 eq) and XantPhos-Pd-G3 (705.78 mg, 843.86 ^mol, 0.2 eq) in dioxane (30 mL) was degassed and purged with N ₂ for 3 times, and then the mixture was stirred at 100 °C for 16 hr under N ₂ atmosphere. LCMS showed that the starting material was consumed and the desired product was detected. The residue was poured into water (30mL). The aqueous phase was extracted with ethyl acetate (60 mL*3). The combined organic phase was washed with brine (30 mL), dried with anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuum. The residue was purified by silica gel chromatography (column height: 250 mm, diameter: 100 mm, 100-200 mesh silica gel, Petroleum ether/Ethyl acetate=3:1) to afford 1-(4-(6-(benzyloxy)-3,4- dihydronaphthalen-1-yl)-2-fluorophenyl)-4-(dimethoxymethyl)p iperidine (1.2 g, 2.46 mmol, 58.33% yield) as yellow oil. The reaction mixture was filtered under reduced pressure to give a compound.1-(4-(6-(benzyloxy)-3,4-dihydronaphthalen-1-yl)-2-f luorophenyl)-4- (dimethoxymethyl)piperidine (1.2 g, 2.46 mmol, 58.33% yield) was obtained as yellow oil. LC-MS (ESI+) m/z: 488.3 (M+H) ⁺ . Step 5: To a solution of 1-(4-(6-(benzyloxy)-3,4-dihydronaphthalen-1-yl)-2-fluorophen yl)-4- (dimethoxymethyl)piperidine (500 mg, 1.03 mmol, 1 eq) in DCM (35 mL) was added Py.HBr ₃ (327.95 mg, 1.03 mmol, 1 eq). The mixture was stirred at 25 °C for 1 hr. LCMS showed that the starting material was consumed and the desired product was detected. The residue was poured into water (35mL). The aqueous phase was extracted with ethyl acetate (70 mL*3). The combined organic phase was washed with brine (35 mL), dried with anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuum. The residue was purified by silica gel chromatography (column height: 250 mm, diameter: 100 mm, 100-200 mesh silica gel, Petroleum ether/Ethyl acetate=3:1) to afford 8 (400 mg, 706.09 ^mol, 68.86% yield) as yellow oil. The reaction mixture was filtered under reduced pressure to give a compound.1-(4-(6-(benzyloxy)-2-bromo-3,4- dihydronaphthalen-1-yl)-2-fluorophenyl)-4-(dimethoxymethyl)p iperidine (400 mg, 706.09 ^mol, 68.86% yield) was obtained as yellow oil. LC-MS (ESI+) m/z: 568.3(M+H) ⁺ . Step 6: A mixture of 1-(4-(6-(benzyloxy)-2-bromo-3,4-dihydronaphthalen-1-yl)-2- fluorophenyl)-4-(dimethoxymethyl)piperidine (952 mg, 1.68 mmol, 1 eq), cyclohex-1-en-1- ylboronic acid (211.68 mg, 1.68 mmol, 1eq), Pd(dppf)Cl ₂ (122.96 mg, 168.05 ^mol, 0.1eq), K ₂ CO ₃ (464.51 mg, 3.36 mmol, 2eq) in dioxane (20 mL) and H ₂ O (7 mL) was degassed and purged with N ₂ for 3 times, and then the mixture was stirred at 80 °C for 16 hr under N ₂ atmosphere. LCMS showed that the starting material was consumed and the desired product was detected. The reaction mixture was filtered under reduced pressure to give a residue. The residue was poured into H ₂ O (30 mL). The aqueous phase was extracted with ethyl acetate (60 mL*3). The combined organic phase was washed with brine (30 mL), dried with anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuum. The residue was purified by silica gel chromatography (column height: 250 mm, diameter: 100 mm, 100-200 mesh silica gel, Petroleum ether/Ethyl acetate=3:1) to afford 1-(4-(6-(benzyloxy)-2-(cyclohex-1-en-1-yl)-3,4-dihydronaphth alen-1-yl)- 2-fluorophenyl)-4-(dimethoxymethyl)piperidine (701 mg, 1.23 mmol, 73.47% yield) as yellow oil. LC-MS (ESI+) m/z: 568.4(M+H) ⁺ . Step 7: To a solution of 1-(4-(6-(benzyloxy)-2-(cyclohex-1-en-1-yl)-3,4-dihydronaphth alen-1- yl)-2-fluorophenyl)-4-(dimethoxymethyl)piperidine (792 mg, 1.40 mmol, 1 eq) in THF (10 mL) was added Pd/C 742.29 mg, 697.51 ^mol, 10% purity, 0.5eq). The mixture was stirred under H ₂ at 50 °C and 50 Psi for 16 hr. LCMS showed that the starting material was consumed and the desired product was detected. The reaction mixture was filtered under reduced pressure to give racemic (5R,6R)-6-cyclohexyl-5-(4-(4-(dimethoxymethyl)piperidin-1-yl )-3-fluorophenyl)- 5,6,7,8-tetrahydronaphthalen-2-ol. (5R,6R)-6-cyclohexyl-5-(4-(4-(dimethoxymethyl)piperidin- 1-yl)-3-fluorophenyl)-5,6,7,8-tetrahydronaphthalen-2-ol (500 mg, 1.04 mmol, 74.42% yield) was obtained as oil. LC-MS (ESI+) m/z: 482.3(M+H) ⁺ . Step 8: (5R,6S)-6-cyclohexyl-5-(4-(4-(dimethoxymethyl)piperidin-1-yl )-3-fluorophenyl)- 5,6,7,8-tetrahydronaphthalen-2-ol and (5R,6R)-6-cyclohexyl-5-(4-(4- (dimethoxymethyl)piperidin-1-yl)-3-fluorophenyl)-5,6,7,8-tet rahydronaphthalen-2-ol (500 mg) was separated by chiral SFC (Column DAICEL CHIRALPAK OD(250mm*30mm,10um), Condition CO ₂ -EtOH(0.1%NH ₃ H ₂ O) Begin B 35% End B 35%) FlowRate (ml/min): 80) (5S,6S)-6-cyclohexyl-5-(4-(4-(dimethoxymethyl)piperidin-1-yl )-3-fluorophenyl)-5,6,7,8- tetrahydronaphthalen-2-ol (160 mg, 332.20 ^mol, 32.00% yield), (5R,6R)-6-cyclohexyl-5-(4-(4- (dimethoxymethyl)piperidin-1-yl)-3-fluorophenyl)-5,6,7,8-tet rahydronaphthalen-2-ol (160 mg, 332.20 ^mol, 32.00% yield). Step 9: 1-(4-((1S,2S)-2-cyclohexyl-6-hydroxy-1,2,3,4-tetrahydronapht halen-1-yl)-2- fluorophenyl)piperidine-4-carbaldehyde: To a solution of (5R,6R)-6-cyclohexyl-5-(4-(4- (dimethoxymethyl)piperidin-1-yl)-3-fluorophenyl)-5,6,7,8-tet rahydronaphthalen-2-ol (273 mg, 566.81 ^mol, 1eq) in DCM (9 mL) was added TFA (64.63 mg, 566.81 ^mol, 42.10 ^L, 1eq). The mixture was stirred at 25 °C for 2 hr. LCMS showed that the starting material was consumed and the desired product was detected. The reaction mixture was filtered under reduced pressure to give a residue. 1-(4-((1S,2S)-2-cyclohexyl-6-hydroxy-1,2,3,4- tetrahydronaphthalen-1-yl)-2-fluorophenyl)piperidine-4-carba ldehyde (160 mg, 367.33 ^mol, 64.81% yield) was obtained as a solid. LC-MS (ESI+) m/z: 436.3 (M+H)+. 1-(4-((1R,2R)-2-cyclohexyl-6-hydroxy-1,2,3,4-tetrahydronapht halen-1-yl)-2- fluorophenyl)piperidine-4-carbaldehyde: To a solution of (5S,6S)-6-cyclohexyl-5-(4-(4- (dimethoxymethyl)piperidin-1-yl)-3-fluorophenyl)-5,6,7,8-tet rahydronaphthalen-2-ol (165 mg, 342.58 ^mol, 1eq) in DCM (6 mL) was added TFA 39.06 mg, 342.58 ^mol, 25.45 ^L, 1eq). The mixture was stirred at 25 °C for 2 hr. LCMS showed that the starting material was consumed and the desired product was detected. The reaction mixture was filtered under reduced pressure to give a residue. 1-(4-((1R,2R)-2-cyclohexyl-6-hydroxy-1,2,3,4-tetrahydronapht halen-1-yl)-2- fluorophenyl)piperidine-4-carbaldehyde (101.2 mg, 232.34 ^mol, 67.82% yield) was obtained as a solid. LC-MS (ESI+) m/z: 436.4(M+H) ⁺ . Step 10: To a solution of 1-(4-((1S,2S)-2-cyclohexyl-6-hydroxy-1,2,3,4-tetrahydronapht halen-1- yl)-2-fluorophenyl)piperidine-4-carbaldehyde (80 mg, 183.67 ^mol, 1eq) in DCM (8 mL) and MeOH (8 mL) was added (S)-3-(1-oxo-5-(piperazin-1-yl)isoindolin-2-yl)piperidine-2, 6-dione (60.31 mg, 183.67 ^mol, 1eq) ^NaBH ₃ (OAc) ₃ (77.85 mg, 367.33 ^mol, 2 eq) and DIPEA (2.37 mg, 18.37 ^mol, 3.20 ^L, 0.1eq). The mixture was stirred at 25 °C for 5 hr. LCMS showed that the starting material was consumed and the desired product was detected. The reaction mixture was filtered under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Boston Green ODS 150*30mm*5um; mobile phase: [water(FA)-ACN];B%: 23%- 53%,12min) to give (S)-3-(5-(4-((1-(4-((1S,2S)-2-cyclohexyl-6-hydroxy-1,2,3,4- tetrahydronaphthalen-1-yl)-2-fluorophenyl)piperidin-4-yl)met hyl)piperazin-1-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione (66 mg, 88.24 ^mol, 48.05% yield) as a white solid. LC-MS (ESI+) m/z: 748.6 (M+H) ⁺ . LCMS: calc. for C ₄₅ H ₅₄ FN ₅ O ₄ : 747.42, found: [M+H] ⁺ 748.6. HPLC: 100% purity at 220 nm. ¹ H NMR (400 MHz, METHANOL-d ₄ ) į ppm 8.43 (s, 1 H) 7.64 (d, J=8.58 Hz, 1 H) 7.07 - 7.12 (m, 2 H) 6.89 - 6.95 (m, 1 H) 6.77 (dd, J=8.29, 1.49 Hz, 1 H) 6.62 - 6.68 (m, 2 H) 6.56 (d, J=2.50 Hz, 1 H) 6.47 (dd, J=8.34, 2.50 Hz, 1 H) 5.10 (dd, J=13.23, 5.13 Hz, 1 H) 4.35 - 4.45 (m, 2 H) 4.15 (d, J=4.65 Hz, 1 H) 3.39 (br d, J=4.65 Hz, 6 H) 2.85 - 2.96 (m, 2 H) 2.64 - 2.81 (m, 8 H) 2.40 - 2.52 (m, 3 H) 2.10 - 2.19 (m, 2 H) 1.86 - 1.93 (m, 2 H) 1.74 - 1.83 (m, 3 H) 1.51 - 1.67 (m, 4 H) 1.37 - 1.47 (m, 2 H) 1.23 - 1.32 (m, 2 H) 1.03 - 1.19 (m, 4 H) 0.74 - 0.86 (m, 1 H). Step 11: To a solution of 1-(4-((1R,2R)-2-cyclohexyl-6-hydroxy-1,2,3,4-tetrahydronapht halen-1- yl)-2-fluorophenyl)piperidine-4-carbaldehyde (85 mg, 195.15 ^mol, 1eq) in DCM (8 mL) and MeOH (8 mL) was added (S)-3-(1-oxo-5-(piperazin-1-yl)isoindolin-2-yl)piperidine-2, 6-dione (64.08 mg, 195.15 ^mol, 1eq) ^NaBH ₃ (OAc) ₃ (82.72 mg, 390.29 ^mol, 2eq) and DIPEA (2.52 mg, 19.51 ^mol, 3.40 ^L, 0.1eq). The mixture was stirred at 25 °C for 5 hr. LCMS showed that the starting material was consumed and the desired product was detected. The reaction mixture was filtered under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Boston Green ODS 150*30mm*5um; mobile phase: [water (FA)-ACN]; B%: 23%- 53%, 12min) to give (S)-3-(5-(4-((1-(4-((1R,2R)-2-cyclohexyl-6-hydroxy-1,2,3,4- tetrahydronaphthalen-1-yl)-2-fluorophenyl)piperidin-4-yl)met hyl)piperazin-1-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione (67 mg, 89.58 ^mol, 45.90% yield) was obtained as a white solid. LC-MS (ESI+) m/z: 748.6(M+H)+. LCMS: calc. for C ₄₅ H ₅₄ FN ₅ O ₄ : 747.42, found: [M+H] ⁺ 748.6. HPLC: 96.14% purity at 220 nm ¹ H NMR (400 MHz, METHANOL-d ₄ ) į ppm 8.46 (s, 1 H) 7.66 (d, J=8.46 Hz, 1 H) 7.09 - 7.13 (m, 2 H) 6.94 (t, J=8.76 Hz, 1 H) 6.77 - 6.82 (m, 1 H) 6.64 - 6.69 (m, 2 H) 6.58 (d, J=2.50 Hz, 1 H) 6.47 - 6.51 (m, 1 H) 5.12 (dd, J=13.29, 5.19 Hz, 1 H) 4.37 - 4.50 (m, 2 H) 4.15 (s, 1 H) 3.42 (br d J=429 Hz 6 H) 287 298 (m 2 H) 267 284 (m 8 H) 239 252 (m 3 H) 213 222 (m, 2 H) 1.88 - 1.94 (m, 2 H) 1.75 - 1.85 (m, 3 H) 1.54 - 1.69 (m, 4 H) 1.40 - 1.50 (m, 2 H) 1.24 - 1.33 (m, 2 H) 1.03 - 1.19 (m, 4 H) 0.89 (br d, J=2.74 Hz, 1 H). EXAMPLE 198. Preparation of (I-235) (S)-3-(5-(4-((1-(4-((1R, 2S)-2-cyclohexyl-6- hydroxy-1,2,3,4-tetrahydronaphthalen-1-yl)-3-fluoro-5-methyl phenyl)piperidin-4- yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2, 6-dione Step 1: To a solution of (5R,6S)-6-cyclohexyl-5-(4-(4-(dimethoxymethyl)piperidin-1-yl )-2- fluoro-6-methylphenyl)-5,6,7,8-tetrahydronaphthalen-2-ol (150 mg, 302.62 ^mol, 1 eq.) in DCM (9 mL) was added TFA (3.45 g, 30.29 mmol, 2.25 mL, 100.09 eq.). The mixture was stirred at 20 °C for 2 hour. LCMS showed the reaction was completed. The mixture was concentrated in vacuum to give crude product. No further purification as it was used for the next step directly. LC-MS (ESI+) m/z: 450.4 (M+H) ⁺ . Step 2: A mixture of 1-(4-((1R,2S)-2-cyclohexyl-6-hydroxy-1,2,3,4-tetrahydronapht halen-1-yl)- 3-fluoro-5-methylphenyl)piperidine-4-carbaldehyde (150 mg, 333.63 ^mol, 1 eq.), (S)-3-(1-oxo- 5-(piperazin-1-yl)isoindolin-2-yl)piperidine-2,6-dione (120.51 mg, 366.99 ^mol, 1.1 eq.) and DIEA (86.24 mg, 667.26 ^mol, 116.22 ^L, 2 eq.) were added in DCE (10 mL). After addition, the mixture was stirred at 25°C for 30 min, and then NaBH(OAc) ₃ (212.13 mg, 1.00 mmol, 3 eq.) was added in the mixture. The reaction mixture was stirred at 25 °C for 16 hour. LCMS showed the reaction was completed. The crude was purified by preparative HPLC (C18-1150 ^ 30 mm ^ 5 um, Condition water (NH ₄ HCO ₃ )-CAN as a mobile phase, B%: 60%-90%, 11 min) to give (S)-3-(5-(4-((1-(4-((1R,2S)-2-cyclohexyl-6-hydroxy-1,2,3,4-t etrahydronaphthalen-1-yl)-3- fluoro-5-methylphenyl)piperidin-4-yl)methyl)piperazin-1-yl)- 1-oxoisoindolin-2-yl)piperidine- 2,6-dione (47.8 mg, 62.73 ^mol, 18.80% yield, 100% purity) as a white solid. LC-MS (ESI+) m/z: 762.6 (M+H) ⁺ . LCMS: calc. for C : 761.98, found: [M+H] ⁺ 762.6. HPLC: 100% purity at 220 nm. ¹ H NMR: ¹ H NMR (400 MHz, METHANOL-d4) į ppm 7.65 (1 H, d, J=8.46 Hz), 7.03 - 7.15 (5 H, m), 6.76 (1 H, s), 6.62 (1 H, dd, J=12.34, 1.61 Hz), 5.09 (1 H, br s), 4.40 (2 H, d, J=5.84 Hz), 3.93 - 3.98 (1 H, m), 3.76 (2 H, br d, J=12.28 Hz), 3.38 (4 H, br d, J=4.77 Hz), 3.01 - 3.06 (1 H, m), 2.84 - 2.95 (2 H, m), 2.73 - 2.80 (4 H, m), 2.64 (4 H, br d, J=4.29 Hz), 2.42 - 2.51 (2 H, m), 2.39 (1 H, br t, J=5.07 Hz), 2.34 (2 H, br d, J=6.91 Hz), 2.10 - 2.19 (3 H, m), 1.94 (3 H, br d, J=13.47 Hz), 1.86 (3 H, s), 1.73 (1 H, br d, J=13.11 Hz), 1.60 - 1.66 (4 H, m), 1.49 (1 H, br dd, J=12.16, 2.98 Hz), 1.36 - 1.43 (2 H, m), 1.23 (2 H, br dd, J=13.17, 12.10 Hz), 1.04 - 1.09 (1 H, m).

EXAMPLE 199. Preparation of (I-304) (1S,2R)-2-cyclohexyl-1-[4-[4- (dimethoxymethyl)-1-piperidyl]-2-fluoro-6-methyl-phenyl]tetr alin-6-ol Step 1: To a solution of 4-bromo-3-fluoro-5-methyl-aniline (9 g, 43.23 mmol) in ACN (130 mL) was added a solution of H ₂ SO ₄ (10.59 g, 107.96 mmol, 5.75 mL) in H ₂ O (7 mL) at 0 °C. After stirring for 5 minutes, a solution of NaNO ₂ (5.96 g, 86.39 mmol) in H ₂ O (7 mL) was added dropwise and the reaction mixture was stirred for an additional 15 minutes at 0 °C. KI (28.71 g, 172.97 mmol) in H ₂ O (14 mL) was then added, and the ice-bath was removed. After warming to 20 °C, the reaction was stirred at 20 °C for 20 minutes. The reaction was quenched with sat.aq. Na ₂ S ₂ O ₃ (100 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ethyl acetate in petroleum ether = 0% to 10%) to give the product of 2-bromo-1-fluoro-5-iodo-3- methyl-benzene (12 g, 83.74% yield) as a yellow liquid. 7.39 (s, 1H), 7.30 (dd, J = 1.5, 7.5 Hz, 1H), 2.39 (s, 3H). Step 2: A mixture of 2-bromo-1-fluoro-5-iodo-3-methyl-benzene (4.5 g, 13.57 mmol), 4- (dimethoxymethyl)piperidine (2.16 g, 13.57 mmol), CuI (517.07 mg, 2.71 mmol), L-PROLINE (625.15 mg, 5.43 mmol) and K ₂ CO ₃ (3.75 g, 27.15 mmol) in DMSO (40 mL) was degassed and purged with N ₂ for 3 times, and then the mixture was stirred at 80 °C for 16 h under N ₂ atmosphere. The reaction was quenched with sat.aq. Na ₂ S ₂ O ₃ (50 mL) and extracted with EtOAc (80 mL x 3). The combined organic layers were washed with brine (80 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ethyl acetate in petroleum ether= 0% to 10%) to give the product of 1-(4-bromo-3-fluoro-5-methyl-phenyl)-4-(dimethoxymethyl)pipe ridine (2.7 g, 55.7% yield) as a white solid. LC-MS (ESI ⁺ ) m/z: 348.1 (M+H) ⁺ . Step 3: A mixture of 1-(4-bromo-3-fluoro-5-methyl-phenyl)-4-(dimethoxymethyl)pipe ridine (2.6 g, 7.28 mmol), N-[(E)-(6-benzyloxytetralin-1-ylidene)amino]-4-methyl-benzen esulfonamide (3.37 g, 8.01 mmol), t-BuOLi (1.17 g, 14.57 mmol), RuPhos Pd G3 (609.22 mg, 728.41 ^mol) in dioxane (30 mL) was degassed and purged with N ₂ for 3 times, and then the mixture was stirred at 110 °C for 16 h under N ₂ atmosphere. The reaction was quenched with water (60 mL) and extracted with EtOAc (80 mL x 3). The combined organic layers were washed with brine (80 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ethyl acetate in petroleum ether= 0% to 10%) to give the product of 1-[4-(6-benzyloxy-3,4-dihydronaphthalen-1-yl)-3-fluoro-5-met hyl- phenyl]-4-(dimethoxymethyl)piperidine (3 g, 73.9% yield) as a yellow solid. LC-MS (ESI ⁺ ) m/z: 502.4 (M+H) ⁺ . Step 4: To a solution of 1-[4-(6-benzyloxy-3,4-dihydronaphthalen-1-yl)-3-fluoro-5-met hyl- phenyl]-4-(dimethoxymethyl)piperidine (3 g, 5.38 mmol) in DCM (30 mL) was added BLAH;pyridin-1-ium (1.69 g, 5.27 mmol) at 0 °C. The mixture was stirred at 0 °C for 0.5 h. The reaction was quenched with water (50 mL) and extracted with EtOAc (60 mL x 3). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered and t t d d d d t i id Th id ifi d b fl h ili gel chromatography (ethyl acetate in petroleum ether= 0% to 10%) to give the product of 1-[4- (6-benzyloxy-2-bromo-3,4-dihydronaphthalen-1-yl)-3-fluoro-5- methyl-phenyl]-4- (dimethoxymethyl)piperidine (3 g, 89.3% yield) as a yellow solid. LC-MS (ESI ⁺ ) m/z: 580.3 (M+H) ⁺ . Step 5: A mixture of 1-[4-(6-benzyloxy-2-bromo-3,4-dihydronaphthalen-1-yl)-3-fluo ro-5- methyl-phenyl]-4-(dimethoxymethyl)piperidine (3 g, 4.81 mmol), 2-(cyclohexen-1-yl)-4,4,5,5- tetramethyl-1,3,2-dioxaborolane (1.30 g, 6.25 mmol, 1.34 mL), Pd(dppf)Cl ₂ (351.66 mg, 480.60 ^mol), Na ₂ CO ₃ (1.02 g, 9.61 mmol, 2 eq) in dioxane (30 mL) and H ₂ O (6 mL) was degassed and purged with N ₂ for 3 times, and then the mixture was stirred at 100 °C for 16 h under N ₂ atmosphere. The reaction was quenched with water (60 mL) and extracted with EtOAc (60 mL x 3). The combined organic layers were washed with brine (100 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ethyl acetate in petroleum ether= 0% to 9%) to give the product of 1- [4-[6-benzyloxy-2-(cyclohexen-1-yl)-3,4-dihydronaphthalen-1- yl]-3-fluoro-5-methyl-phenyl]-4- (dimethoxymethyl)piperidine (1.4 g, 49.5% yield) as a white solid. LC-MS (ESI ⁺ ) m/z: 582.5 (M+H) ⁺ . Step 6: To a solution of Pd(OH) ₂ /C (2 g, 20% purity) in MeOH (20 mL) was added 1-[4-[6- benzyloxy-2-(cyclohexen-1-yl)-3,4-dihydronaphthalen-1-yl]-3- fluoro-5-methyl-phenyl]-4- (dimethoxymethyl)piperidine (1 g, 1.70 mmol) under N ₂ . The suspension was degassed under vacuum and purged with H ₂ several times. The mixture was stirred under H ₂ (50 psi) at 80 °C for 16 h. The reaction mixture was filtered and the filter was concentrated. The residue was purified by preparative HPLC (column: Boston Uni C1840*150*5 um; mobile phase: [water (TFA)-ACN]; gradient: 61% - 81% B over 10 min), followed by lyophilization to yield a product which was separated by chiral SFC (column: DAICEL CHIRALCEL OJ (250 mm * 30 mm, 10 um); mobile phase: [CO ₂ -EtOH (0.1%NH ₃ H ₂ O)]; B%: 20%%, isocratic elution mode, peak 1: 2.851 min, peak 2: 3.037 min) to yield Peak 1 and Peak 2. Peak 1 was concentrated under reduced pressure to give the product of (1S,2R)-2-cyclohexyl-1-[4-[4-(dimethoxymethyl)-1- piperidyl]-2-fluoro-6-methyl-phenyl]tetralin-6-ol (150 mg, 17.8% yield, SFC: R _t = 2.851) as a white solid. LC-MS (ESI ⁺ ) m/z: 496.5 (M+H) ⁺ . EXAMPLE 200. Preparation of (I-141) (S)-3-(5-(4-((1-(4-((1R,2R)-2-cyclohexyl-6- hydroxy-1,2,3,4-tetrahydronaphthalen-1-yl)-3-methylphenyl)pi peridin-4- yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2, 6-dione Step 1: 6-cyclohexyl-5-(4-(4-(dimethoxymethyl)piperidin-1-yl)-2-meth ylphenyl)-5,6,7,8- tetrahydronaphthalen-2-ol (100 mg, 1 eq., 209 ^mol) was purified by SFC (Column: DAICEL CHIRALCEL OJ (250 mm ^ 30 mm, 10 um); Mobile phase: 0.1% NH ₃ H ₂ O EtOH; from 30% to 30%; Flow rate: 70 mL/min) to give (5R,6R)-6-cyclohexyl-5-(4-(4-(dimethoxymethyl)piperidin- 1-yl)-2-methylphenyl)-5,6,7,8-tetrahydronaphthalen-2-ol (40 mg, 84 ^mol, 40 %) as a white solid. LC-MS (ESI ⁺ ) m/z: 478.4 (M+H) ⁺ . Step 2: To a solution of (5R,6R)-6-cyclohexyl-5-(4-(4-(dimethoxymethyl)piperidin-1-yl )-2- methylphenyl)-5,6,7,8-tetrahydronaphthalen-2-ol (40 mg, 1 eq., 84 ^mol) in DCM (3 mL) was added TFA (57 mg, 39 ^L, 6 eq., 0.50 mmol). The mixture was stirred at 20 °C for 4 hour. LCMS showed the reaction was completed. The mixture was concentrated in vacuum to give crude product. No further purification as it is used for the next step directly. LC-MS (ESI+) m/z: 432.3(M+H) ⁺ . Step 3: A mixture of 1-(4-((1R,2R)-2-cyclohexyl-6-hydroxy-1,2,3,4-tetrahydronapht halen-1-yl)- 3-methylphenyl)piperidine-4-carbaldehyde (40 mg, 92.68 ^mol, 1 eq.), (S)-3-(1-oxo-5- (piperazin-1-yl)isoindolin-2-yl)piperidine-2,6-dione (36.52 mg, 111.21 ^mol, 1.2 eq.) and NMM (9.37 mg, 92.68 ^mol, 10.19 ^L, 1 eq.) were added in DCE (3 mL). After addition, the mixture was stirred at 25°C for 30 min, and then NaBH(OAc) ₃ (49.10 mg, 231.69 ^mol, 2.5 eq.) was added in the mixture. The reaction mixture was stirred at 25 °C for 16 hr. LCMS showed the ti l t d Th d ifi d b ti HPLC (W l h Xti t C18150 ^ 25 mm ^ 5 um, Condition water (FA)-CAN as a mobile phase, B%: 35%-65%, 11 min) to give (S)-3-(5-(4-((1-(4-((1R,2R)-2-cyclohexyl-6-hydroxy-1,2,3,4-t etrahydronaphthalen-1-yl)-3- methylphenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoi ndolin-2-yl)piperidine-2,6-dione (5.5 mg, 7.25 ^mol, 7.83% yield, 98.11% purity) as a white solid. LCMS: calc. for C ₄₆ H ₅₇ N ₅ O ₄ : 743.44, found: [M+H] ⁺ 744.5 HPLC: 100% purity at 220 nm. ppm 8.41 - 8.50 (1 H, m), 7.64 (1 H, d, J=8.39 Hz), 7.09 (2 H, s), 6.83 (1 H, d, J=2.14 Hz), 6.61 - 6.68 (2 H, m), 6.57 (1 H, d, J=8.24 Hz), 6.53 (1 H, d, J=2.59 Hz), 6.42 (1 H, dd, J=8.54, 2.59 Hz), 5.10 (1 H, br d, J=8.24 Hz), 4.35 - 4.46 (3 H, m), 3.57 - 3.66 (2 H, m), 3.40 (4 H, br s), 2.86 - 2.95 (2 H, m), 2.76 - 2.81 (2 H, m), 2.67 - 2.74 (4 H, m), 2.60 - 2.66 (2 H, m), 2.54 (3 H, s), 2.46 (1 H, dd, J=13.05, 4.65 Hz), 2.36 - 2.43 (2 H, m), 2.11 - 2.18 (1 H, m), 1.90 (2 H, br d, J=12.05 Hz), 1.84 (2 H, br d, J=2.90 Hz), 1.69 - 1.77 (4 H, m), 1.55 - 1.59 (1 H, m), 1.43 - 1.48 (1 H, m), 1.33 - 1.39 (3 H, m), 1.21 (2 H, br d, J=13.12 Hz), 1.03 - 1.10 (1 H, m), 0.89 - 0.95 (1 H, m), 0.82 - 0.87 (1 H, m), 0.64 - 0.71 (1 H, m).

EXAMPLE 201. Preparation of (I-140) (S)-3-(5-(4-((1-(4-((1S,2S)-2-cyclohexyl-6- hydroxy-1,2,3,4-tetrahydronaphthalen-1-yl)-3-methylphenyl)pi peridin-4- yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2, 6-dione Step 1: To a mixture of 1-bromo-4-iodo-2-methylbenzene (600 mg, 1 eq, 2.02 mmol),4- (dimethoxymethyl)piperidine (386 mg, 1.2 eq., 2.42 mmol), (S)-(-)-Proline (116 mg, 86.2 ^L, 0.5 eq., 1.01 mmol), K ₂ CO ₃ (838 mg, 3 eq., 6.06 mmol) and, CuI (192 mg, 0.5 eq., 1.01 mmol) in DMSO (2 mL) was added in one portion at 25 °C under N ₂ . The mixture was stirred at 25 °C f 5 i th h t d t 80 °C d ti d f 12 h LCMS h d th ti completed. The mixture was cooled to 25 °C and concentrated in reduced pressure at 40 °C. The residue was poured into ice-water (50 mL) and stirred for 5 min. The aqueous phase was extracted with ethyl acetate (100 mL x 2). The combined organic phase was washed with brine (50 mL*2), dried with anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuum. The residue was purified by silica gel chromatography (column height: 250 mm, diameter: 100 mm, 100-200 mesh silica gel, Petroleum ether/Ethyl acetate=5/1) to afford 1-(4-bromo-3-methylphenyl)-4- (dimethoxymethyl)piperidine (423 mg, 1.24 mmol, 61.5 %, 96.408% Purity) as yellow solid. Step 2: A mixture of compound 3 (1.2 g, 1 eq., 3.7 mmol), compound 4 (1.7 g, 1.1 eq., 4.0 mmol), PdCl ₂ (dppf) (0.27 g, 0.1 eq., 0.37 mmol), X-Phos Pd G3 (85 mg, 0.05 eq., 0.18 mmol) and Lithium 2-methyl-2-propanolate (0.88 g, 1.0 mL, 3 eq., 11 mmol) in Dioxane (100 mL) was degassed and purged with N ₂ for 3 times, and then the mixture was stirred at 100 °C for 12 hour under N2 atmosphere. LCMS showed the reaction was completed. The reaction mixture was quenched by addition EA 30 mL at 20 °C, and then diluted with water 30 mL and extracted with EA 90 mL (30 mL x 3). The combined organic layers were washed with EA 60 mL (20 mL * 3), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The crude material was purified on silica gel column chromatography (from pure PE to PE/EA = 9/1) to as give 1-(4-(6-(benzyloxy)-3,4-dihydronaphthalen-1-yl)-3- methylphenyl)-4- (dimethoxymethyl)piperidine (1.5 g, 3.1 mmol, 85 %) a yellow oil. LC-MS (ESI+) m/z: 484.2(M+H ⁺ ). ¹ H NMR (400 MHz, DMSO-d ₆ ) į: ppm 7.27 - 7.46 (m, 5 H), 6.86 - 6.95 (m, 2 H), 6.73 - 6.82 (m, 2 H), 6.69 (dd, J = 8.46, 2.62 Hz, 1 H), 6.43 (d, J = 8.46 Hz, 1 H), 5.70 (t, J = 4.47 Hz, 1 H), 5.05 (s, 2 H), 4.09 (d, J = 6.56 Hz, 1 H), 4.03 (d, J = 7.15 Hz, 1 H), 3.70 (d, J = 12.16 Hz, 2 H), 3.28 (s, 6 H), 2.73 - 2.84 (m, 2 H), 2.55 - 2.66 (m, 2 H), 2.22 - 2.40 (m, 2 H), 1.96 (s, 3 H), 1.65 - 1.77 (m, 3 H), 1.27 - 1.39 (m, 2 H). Step 3: To a solution of 1-(4-(6-(benzyloxy)-3,4-dihydronaphthalen-1-yl)-3-methylphen yl)-4- (dimethoxymethyl)piperidine (1.50 g, 1 eq., 3.10 mmol) in DCM (30 mL) was added Pyridinium bromide perbromide (7964 mg, 0.8 eq., 2.48 mmol). The mixture was stirred at 20 °C for 1 hour. LCMS showed the reaction was completed. The reaction mixture was quenched by addition EA 30 mL at 20 °C, and then diluted with water 30 mL and extracted with EA 90 mL (30 L 3) Th bi d i l h d ith EA 30 L (10 L 3) d i d Na2SO4, filtered and concentrated under reduced pressure to give a residue. The crude material was purified on silica gel column chromatography (from pure PE to PE/EtOAc = 5/1) to give 1- (4-(6-(benzyloxy)-2-bromo -3,4-dihydronaphthalen-1-yl)-3-methylphenyl)-4- (dimethoxymethyl)piperidine (1.3 g, 2.3 mmol, 75 %) as a yellow solid. LC-MS (ESI+) m/z: 562.4.2(M+H ⁺ ) Step 4: A mixture of 1-(4-(6-(benzyloxy)-2-bromo-3,4-dihydronaphthalen-1-yl)-3- methylphenyl)-4-(dimethoxymethyl)piperidine (1.300 g, 1 eq., 2.311 mmol), cyclohex-1-en-1- ylboronic acid (320.2 mg, 1.1 eq., 2.542 mmol), potassium carbonate (958.1 mg, 3 eq., 6.933 mmol) and PdCl ₂ (dppf) (169.1 mg, 0.1 eq., 231.1 ^mol) in water (4 mL) and Dioxane (20 mL) was degassed and purged with N ₂ for 3 times, and then the mixture was stirred at 80 °C for 12h under N ₂ atmosphere. LCMS showed the reaction was completed. The reaction mixture was quenched by addition EA 30 mL at 20 °C, and then diluted with water 30 mL and extracted with EA 90 mL (30 mL x 3). The combined organic layers were washed with EA 30 mL (10 mL x 3), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The crude material was purified on silica gel column chromatography (from pure PE to PE/EtOAc = 3/1) to give 1-(4-(6-(benzyloxy) -2-(cyclohex-1-en-1-yl)-3,4-dihydronaphthalen-1-yl)-3- methylphenyl)-4-(dimethoxymethyl)piperidine (1.1 g, 1.8 mmol, 76 %, 90% Purity) as a yellow solid. LC-MS (ESI+) m/z: 564.5(M+H ⁺ ) ¹ H NMR (500 MHz, DMSO-d ₆ ) į: ppm 7.66 (dd, J = 9.84, 2.37 Hz, 1 H), 7.49 - 7.55 (m, 1 H), 7.44 (dd, J = 8.54, 2.29 Hz, 1 H), 7.27 (dd, J = 8.54, 2.14 Hz, 1 H), 7.04 (t, J = 8.62 Hz, 1 H), 6.84 (d, J = 2.44 Hz, 1 H), 6.68 (dd, J = 8.47, 2.67 Hz, 1 H), 6.53 (dd, J = 8.39, 1.22 Hz, 1 H), 6.02 (t, J = 4.50 Hz, 1 H), 3.73 (s, 3 H), 2.80 (t, J = 8.09 Hz, 2 H), 2.37 (td, J = 7.82, 4.81 Hz, 2 H). Step 5: To a solution of 1-(4-(6-(benzyloxy) -2-(cyclohex-1-en-1-yl)-3,4-dihydronaphthalen-1- yl)-3-methylphenyl)-4-(dimethoxymethyl)piperidine (1.10 g, 1 eq., 1.95 mmol) in Pd/C (0.60 g, 2.9 eq., 5.6 mmol) was added Pd/C (10%, 0.6 g) under N ₂ atmosphere. The suspension was degassed and purged with H ₂ for 3 times. The mixture was stirred under H ₂ (50 Psi) at 70 °C for 24 hour. LCMS showed the reaction was completed. The crude was purified by prep-HPLC t th (B t G ODS 150*30 *5 t (FA) ACN bil h f 65% t 95%, Gradient Time (min): 12, Flow Rate (ml/min): 25) to give 6-cyclohexyl-5-(4-(4- (dimethoxymethyl)piperidin-1-yl)-2-methylphenyl)-5,6,7,8-tet rahydronaphthalen-2-ol (100 mg, 209 ^mol, 10.7 %). LC-MS (ESI+) m/z: 478.2(M+H ⁺ ). Step 6: 6-cyclohexyl-5-(4-(4-(dimethoxymethyl)piperidin-1-yl)-2-meth ylphenyl)-5,6,7,8- tetrahydronaphthalen-2-ol (100 mg, 1 eq., 209 ^mol) was purified by SFC (Column: DAICEL CHIRALCEL OJ (250mm*30mm, 10um); Mobile phase: 0.1%NH ₃ H ₂ O ETOH; from 30% to 30%; Flow rate: 70 mL/min) to give (5S,6S)-6-cyclohexyl-5-(4-(4-(dimethoxymethyl)piperidin- 1-yl)-2-methylphenyl)-5,6,7,8-tetrahydronaphthalen-2-ol (40 mg, 84 ^mol, 40 %) as white solid. LC-MS (ESI+) m/z: 478.4(M+H ⁺ ). Step 7: To a solution of (5S,6S)-6-cyclohexyl-5-(4-(4-(dimethoxymethyl)piperidin-1-yl )-2- methylphenyl)-5,6,7,8-tetrahydronaphthalen-2-ol (50 mg, 1 eq., 0.10 mmol) in DCM (3 mL) was added TFA (36 mg, 24 ^L, 3 eq., 0.31 mmol). The mixture was stirred at 20 °C for 4 hour. LCMS showed the reaction was completed. The mixture was concentrated in vacuo to give crude product. No further purification as it is used for the next step directly. LC-MS (ESI+) m/z: 432.3(M+H ⁺ ). Step 8: To a solution of 1-(4-((1S,2S)-2-cyclohexyl-6-hydroxy-1,2,3,4-tetrahydronapht halen-1- yl)-3-methylphenyl)piperidine-4-carbaldehyde (25.00 mg, 1 eq., 57.92 ^mol) and (S)-3-(1-oxo- 5- (piperazin-1-yl)isoindolin-2-yl)piperidine-2,6-dione (22.82 mg, 1.2 eq., 69.51 ^mol) in DCE (3 mL) was added dropwise 4-methylmorfolin (5.859 mg, 6.4 ^L, 1 eq., 57.92 ^mol) to pH = 7 at 20 °C. After addition, the mixture was stirred at this temperature for 0.5 hour, and then Sodium triacetoxyborohydride (36.83 mg, 25.8 ^L, 3 eq., 173.8 ^mol) was added dropwise at 20°C. The resulting mixture was stirred at 20 °C for 1.5 hour. LCMS showed the reaction was completed. The crude was purified by prep-HPLC together (Welch Xtimate C18150*25mm*5um, water (FA)-ACN as a mobile phase, from 22% to 52%, Gradient Time (min): 11, Flow Rate (ml/min): 25) to give (S)-3-(5-(4-((1-(4-((1S,2S)-2-cyclohexyl-6-hydroxy-1,2,3,4-t etrahydronaphthalen-1- yl)-3-methylphenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-o xoisoindolin-2-yl)piperidine-2,6- dione (5.4 mg, 7.3 ^mol, 13 %) as a white solid. HPLC: 100.00% purity at 220 nm. ¹ H NMR (400 MHz, METHANOL-d ₄ ) į: ppm 8.38 - 8.48 (m, 1 H), 7.65 (d, J = 8.46 Hz, 1 H), 7.08 - 7.13 (m, 2 H), 6.83 (d, J = 2.15 Hz, 1 H), 6.60 - 6.69 (m, 2 H), 6.51 - 6.59 (m, 2 H), 6.38 - 6.45 (m, 1 H), 5.10 (dd, J = 13.17, 5.07 Hz, 1 H), 4.35 - 4.46 (m, 3 H), 3.57 - 3.64 (m, 2 H), 3.41 (s, 4 H), 2.85 - 2.96 (m, 2 H), 2.76 - 2.82 (m, 2 H), 2.74 (d, J = 4.29 Hz, 4 H), 2.61 - 2.69 (m, 2 H), 2.54 (s, 3 H), 2.40 - 2.50 (m, 3 H), 2.11 - 2.18 (m, 1 H), 1.82 - 1.93 (m, 4 H), 1.67 - 1.78 (m, 4 H), 1.54 - 1.60 (m, 1 H), 1.43 - 1.47 (m, 1 H), 1.30 - 1.39 (m, 3 H), 1.21 (d, J=9.42 Hz, 2 H), 1.02 - 1.11 (m, 1 H), 0.80 - 0.96 (m, 2 H), 0.60 - 0.77 (m, 1 H). EXAMPLE 202. Preparation of (I-139) (S)-3-(5-(4-((1-(4-((1R,2S)-6-hydroxy-2-phenyl- 1,2,3,4-tetrahydronaphthalen-1-yl)-3-methylphenyl)piperidin- 4-yl)methyl)piperazin-1-yl)- 1-oxoisoindolin-2-yl)piperidine-2,6-dione Step 1: To a solution of (5R, 6S)-5-(4-(4-(dimethoxymethyl)piperidin-1-yl)-2-methylphenyl) -6- phenyl-5,6,7,8-tetrahydronaphthalen-2-ol (65 mg, 0.14 mmol) in THF (1 mL) and 10% H ₂ SO ₄ (1 mL) was stirred at 70 °C for 1 h. The reaction mixture was quenched by addition sat. aq. NaHCO ₃ (10 mL) at 0°C, then extracted with ethyl acetate (20 mL x 2). The combined organic layers were washed with 20 mL brine dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give 1-(4-((1R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthale n-1-yl)- 3-methylphenyl)piperidine-4-carbaldehyde (60 mg, 95 % Yield) as a yellow solid. LC-MS (ESI+) m/z: 426.2 (M+H) ⁺ . Step 2: A mixture of 1-(4-((1R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthale n-1-yl)-3- methylphenyl)piperidine-4-carbaldehyde (55 mg, 0.12 mmol), (S)-3-(1-oxo-5-(piperazin-1- (49 mg, 0.60 mmol) and acetic acid (14 mg, 0.24 mmol) in THF (2 mL) and MeOH (2 mL) at 25°C for 1 h, then sodium triacetoxyborohydride (51 mg, 0.24 mmol) was added to the mixture and was stirred at 25 °C for 16 h. The mixture was added H ₂ O (20 mL), extracted with ethyl acetate (20 mL x 2). The combined extracts was dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to dryness in vacuo to give a residue. The residue was purified by prep-HPLC (column: Xtimate C18100*30mm*3um ; mobile phase: [water(FA)-ACN];B% 12%-52%,9min) to give (S)-3-(5-(4-((1-(4-((1R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetra hydronaphthalen-1-yl)-3- methylphenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoi ndolin-2-yl)piperidine-2,6-dione (22.2 mg, 24 % Yield ) as a white solid. LC-MS (ESI+) m/z: 738.2 (M+H) +. LCMS: calc. for C ₄₆ H ₅₁ N ₅ O ₄ : 737.95, found: [M+H] ⁺ 738.2. HPLC: 94.568% purity at 220 nm. ¹ HNMR (400 MHz, DMSO-d ₆ ) į ppm 10.91 - 10.98 (m, 1 H) 9.01 - 9.17 (m, 1 H) 8.15 (s, 0.567 H) 7.52 (d, J=8.70 Hz, 1 H) 7.03 - 7.14 (m, 5 H) 6.72 (br d, J=6.79 Hz, 2 H) 6.55 - 6.63 (m, 3 H) 6.37 - 6.50 (m, 3 H) 5.05 (dd, J=13.29, 5.19 Hz, 1 H) 4.31 - 4.40 (m, 2 H) 4.15 - 4.25 (m, 1 H) 3.54 - 3.59 (m, 2 H) 3.29 (br s, 8 H) 2.87 - 3.04 (m, 4 H) 2.59 - 2.71 (m, 3 H) 2.28 - 2.39 (m, 2 H) 2.21 (br d, J=7.03 Hz, 2 H) 1.92 - 2.01 (m, 1 H) 1.77 (br d, J=12.16 Hz, 2 H) 1.56 - 1.71 (m, 2 H) 1.40 (s, 3 H) 1.11 - 1.24 (m, 2 H) SFC: retention time, 3.211 min; Area, 95.847%;

EXAMPLE 203. Preparation of (I-138) (S)-3-(5-(4-((1-(4-((1S,2R)-6-hydroxy-2-phenyl- 1,2,3,4-tetrahydronaphthalen-1-yl)-3-methylphenyl)piperidin- 4-yl)methyl)piperazin-1-yl)- 1-oxoisoindolin-2-yl)piperidine-2,6-dione Step 1: A mixture of 1-bromo-4-iodo-2-methylbenzene (3.0 g, 10 mmol), 4- (dimethoxymethyl)piperidine (1.6 g, 10 mmol), cuprous iodide (0.38 g, 2.0 mmol), potassium carbonate (2.8 g, 20 mmol) and (S)-(-)-proline (0.47 g, 4.0 mmol) in DMSO (30 mL) at r.t., then the mixture was stirred at 80 °C for 16 h under N2. The reaction mixture was added H2O (100 mL) and extracted with ethyl acetate (100 mL x 2). Then organic phase was washed with H2O (100 mL x 2) and the combined organic layers was dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ethyl acetate in petroleum ether = 0% to 30%) to give the product of 1-(4- bromo-3-methylphenyl)-4-(dimethoxymethyl)piperidine (1.9 g, 56% Yield) as a yellow solid. Step 2: A mixture of 1-(4-bromo-3-methylphenyl)-4-(dimethoxymethyl)piperidine (1.8 g, 5.3 mmol) in THF (50 mL) at -68 °C was added to n-Butyllithium (2.5 M in hexane) (0.37 g, 5.8 mmol) and was stirred for 1 hour, then isopropoxyboronic acid pinacol ester (1.3 g, 6.9 mmol) was added to the reaction and was warmed to 25 °C and stirred for 16 h. The reaction mixture was quenched with aq.NH ₄ Cl (30 mL), then added H ₂ O (100 mL) and extracted with ethyl acetate (100 mL x 2) and the combined organic layers was dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ethyl acetate in petroleum ether = 0% to 25%) to give the product of 4- (dimethoxymethyl)-1-(3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-d ioxaborolan-2- yl)phenyl)piperidine (400 mg, 12 % Yield) as a yellow solid. LC-MS (ESI ⁺ ) m/z: 376.5 (M+H) ⁺ . Step 3: 6-(benzyloxy)-2-phenyl-3,4-dihydronaphthalen-1-yl trifluoromethanesulfonate (348 mg, 756 ^mol) was added to a mixture suspension of [1,1’- Bis(diphenylphosphino)ferrocene]dichloropalladium(II)Complex With Dichloromethane (51.4 mg, 63.0 ^mol) and 4-(dimethoxymethyl)-1-(3-methyl-4-(4,4,5,5-tetramethyl-1,3,2 - dioxaborolan-2-yl)phenyl)piperidine (380 mg, 630 ^mol) and sodium carbonate (200 mg, 1.89 mmol) in 1,4-Dioxane (6 mL) and H2O (1.5 mL). N2 was bubbled into the mixture for 5 min. The reaction mixture was heated at 90 °C for 16 h. The reaction mixture was added H ₂ O (100 mL) and extracted with ethyl acetate (100 mL x 2) and the combined organic layers was dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ethyl acetate in petroleum ether = 0% to 25%) to give the product of 1-(4-(6-(benzyloxy)-2-phenyl-3,4-dihydronaphthalen-1-yl)-3- methylphenyl)-4-(dimethoxymethyl)piperidine (340 mg, 92.9 % Yield) as a yellow solid. LC- MS (ESI ⁺ ) m/z: 560.2 (M+H) ⁺ . Step 4: A mixture of 1-(4-(6-(benzyloxy)-2-phenyl-3,4-dihydronaphthalen-1-yl)-3- methylphenyl)-4-(dimethoxymethyl)piperidine (320 mg, 551 ^mol), H ₂ (1.11 mg, 551 ^mol), Pd/C (500 mg, 470 ^mol, 10 wt% ) in MeOH (10 mL) was degassed and purged with H ₂ for 3 times, and then the mixture was stirred at 50 °C for 16 h under H ₂ atmosphere (15 psi). The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was further separated by SFC (condition: column: DAICEL CHIRALPAK AD(250mm*30mm,10um); mobile phase: [0.1% NH3 ^. H2O-IPA];B%: 45%-45%, min ) to give (5S 6R)-5-(4-(4-(dimethoxymethyl)piperidin-1-yl)-2-methylphenyl) -6-phenyl-5678- tetrahydronaphthalen-2-ol (65 mg, 25 % Yield) was obtained as a white solid. LC-MS (ESI+) m/z: 472.2 (M+H) ⁺ and (5R,6S)-5-(4-(4-(dimethoxymethyl)piperidin-1-yl)-2-methylphe nyl)-6- phenyl-5,6,7,8-tetrahydronaphthalen-2-ol (65 mg, 25 % Yield) was obtained as a white solid. LC-MS (ESI ⁺ ) m/z: 472.1 (M+H) ⁺ . Step 5: To a solution of (5S,6R)-5-(4-(4-(dimethoxymethyl)piperidin-1-yl)-2-methylphe nyl)-6- phenyl-5,6,7,8-tetrahydronaphthalen-2-ol (65 mg, 0.14 mmol) in THF (1 mL) and 10% H ₂ SO ₄ (1 mL) was stirred at 70 °C for 1 h. The reaction mixture was quenched by addition sta. aq. NaHCO ₃ (10 mL) at 0°C, then extracted with ethyl acetate (20 mL x 2). The combined organic layers were washed with 20 mL brine dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give 1-(4-((1S,2R)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthale n-1-yl)- 3-methylphenyl)piperidine-4-carbaldehyde (60 mg, 99 % Yield) as a yellow solid. LC-MS (ESI ⁺ ) m/z: 426.1 (M+H) ⁺ . Step 6: A mixture of 1-(4-((1S,2R)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthale n-1-yl)-3- methylphenyl)piperidine-4-carbaldehyde (50 mg, 0.11 mmol) , (S)-3-(1-oxo-5-(piperazin-1- yl)isoindolin-2-yl)piperidine-2,6-dione benzenesulfonate (83 mg, 0.17 mmol) and Sodium acetate (47 mg, 0.57 mmol) and Acetic acid (14 mg, 0.23 mmol) in THF (2 mL) and MeOH (2 mL) at 25 °C for 1 h, then Sodium triacetoxyborohydride (48 mg, 0.23 mmol) was added to the mixture and stirred at 25 °C for 16 h. The mixture was added H ₂ O (20 mL), extracted with ethyl acetate (20 mL x 2). The combined extracts was dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to dryness in vacuo to give a residue. The residue was purified by prep-HPLC (column: Xtimate C18100*30mm*3um; mobile phase: [water(FA)-ACN];B% 12%-52%,8min) to give (S)-3-(5-(4-((1-(4-((1S,2R)-6-hydroxy-2-phenyl-1,2,3,4-tetra hydronaphthalen-1-yl)-3- methylphenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoi ndolin-2-yl)piperidine-2,6-dione (15.4 mg, 18 % Yield) as a white solid. LC-MS (ESI ⁺ ) m/z: 738.3 (M+H) ⁺ . LCMS: calc. for C ₄ : 737.95, found: [M+H] ⁺ 738.3. HPLC: 96.133% purity at 220 nm. ¹ HNMR (400 MHz, DMSO-d ₆ ) į ppm 10.96 (s, 1 H) 9.01 - 9.15 (m, 1 H) 8.17 (s, 0.404 H) 7.52 (d, J=8.70 Hz, 1 H) 7.01 - 7.15 (m, 5 H) 6.72 (br d, J=6.68 Hz, 2 H) 6.54 - 6.65 (m, 3 H) 6.37 - 6.51 (m, 3 H) 4.99 - 5.10 (m, 1 H) 4.30 - 4.42 (m, 2 H) 4.16 - 4.26 (m, 1 H) 3.57 (br d, J=8.94 Hz, 2 H) 3.29 (br d, J=3.46 Hz, 8 H) 2.85 - 3.05 (m, 4 H) 2.56 - 2.62 (m, 3 H) 2.30- 2.40 (m, 2 H) 2.21 (br d, J=7.15 Hz, 2 H) 1.90 - 2.01 (m, 1 H) 1.77 (br d, J=11.92 Hz, 2 H) 1.56 -1.68 (m, 2 H) 1.40 (s, 3 H) 1.12 - 1.23 (m, 2 H) SFC: retention time, 3.030 min; Area, 96.011 %; EXAMPLE 204. Preparation of (I-137) (S)-3-(5-(4-((1-(4-((1S,2R)-2-cyclohexyl-6- hydroxy-1,2,3,4-tetrahydronaphthalen-1-yl)-3-fluorophenyl)pi peridin-4- yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2, 6-dione Step 1: 1-(4-(2-cyclohexyl-6-methoxy-1,2,3,4-tetrahydronaphthalen-1- yl)-3-fluorophenyl)-4- (dimethoxymethyl)piperidine (200 mg, 1 eq., 403 ^mol) was purified by SFC (Column: DAICEL CHIRALPAK AD (250 mm * 30 mm, 10 um); Mobile phase: 0.1%NH ₃ H ₂ O EtOH; from 25% to 25%; Flow rate: 70 mL/min) to give 1-(4-((1S,2R)-2-cyclohexyl-6-methoxy- 1,2,3,4-tetrahydronaphthalen-1-yl)-3-fluorophenyl)-4-(dimeth oxymethyl)piperidine (60 mg, 0.12 mmol, 30 %) as a white solid. LC-MS (ESI ⁺ ) m/z: 496.3 (M+H) ⁺ . Step 2: To a solution of 1-(4-((1S,2R)-2-cyclohexyl-6-methoxy-1,2,3,4-tetrahydronapht halen-1- yl)-3-fluorophenyl)-4-(dimethoxymethyl)piperidine (60 mg, 1 eq., 0.12 mmol) in DCM (3 mL) was added BBr ₃ (0.15 g, 5 eq., 0.61 mmol). The mixture was stirred at 20 °C for 0.5 hour and then water (0.5 mL) in DCM (3 mL) was added dropwise at 20 °C. The resulting mixture was stirred at 20 °C for 2 hour. LCMS showed the reaction was completed. The mixture was concentrated and then water (10 mL) was added. The mixture was extracted with DCM (10 mL x 3). The combined organic layers were washed with brine (10 mL), dried over Na ₂ SO ₄ , filtered and concentrated. The mixture was concentrated in vacuum to give crude product. No further purification as it was used for the next step directly. Step 3: A mixture of 1-(4-((1S,2R)-2-cyclohexyl-6-hydroxy-1,2,3,4-tetrahydronapht halen-1-yl)- 3-fluorophenyl)piperidine-4-carbaldehyde (60 mg, 137.75 ^mol, 1 eq.), (S)-3-(1-oxo-5- (piperazin-1-yl)isoindolin-2-yl)piperidine-2,6-dione (54.28 mg, 165.30 ^mol, 1.2 eq.) and NMM (13.93 mg, 137.75 ^mol, 15.14 ^L, 1 eq.) were added in DCE (3 mL). After addition, the mixture was stirred at 25°C for 30 min, and then NaBH(OAc) ₃ (72.99 mg, 344.37 ^mol, 2.5 eq.) was added in the mixture. The reaction mixture was stirred at 25 °C for 16 h. LCMS showed the reaction was completed. The residue was purified by preparative HPLC (Column: Boston Green ODS 150 ^ 30 mm ^ 5 um; Condition water (FA)-CAN, B%: 25%-55%, 12 min) followed by lyophilization to yield (S)-3-(5-(4-((1-(4-((1S,2R)-2-cyclohexyl-6-hydroxy-1,2,3,4- tetrahydronaphthalen-1-yl)-3-fluorophenyl)piperidin-4-yl)met hyl)piperazin-1-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione (25 mg, 32.09 ^mol, 23.29% yield, 96% purity) as a white solid. LC-MS (ESI+) m/z: 748.5 (M+H) ⁺ . LCMS: calc. for C ₄₅ H ₅₄ FN ₅ O ₄ : 747.42, found: [M+H] ⁺ 748.5 HPLC: 95.5% purity at 220 nm. ¹ H NMR: ¹ H NMR (400 MHz, METHANOL-d4) į ppm 8.28 - 8.45 (1 H, m), 7.65 (1 H, d, J=8.34 Hz), 7.07 - 7.12 (2 H, m), 6.63 - 6.67 (1 H, m), 6.58 - 6.62 (3 H, m), 6.54 (1 H, d, J=2.15 Hz), 6.45 (1 H, dd, J=8.34, 2.38 Hz), 5.10 (1 H, dd, J=13.29, 5.19 Hz), 4.46 (1 H, d, J=4.53 Hz), 4.40 (2 H, d, J=5.84 Hz), 3.66 - 3.74 (2 H, m), 3.40 (4 H, br d, J=4.65 Hz), 2.86 - 2.95 (2 H, m), 2.78 (2 H, br s), 2.71 - 2.76 (4 H, m), 2.69 (1 H, br s), 2.56 - 2.66 (1 H, m), 2.41 - 2.52 (3 H, m), 2.10 - 2.18 (1 H, m), 2.02 - 2.07 (1 H, m), 1.89 (2 H, br d, J=13.47 Hz), 1.76 - 1.82 (2 H, m), 1.72 (2 H, br d, J=13.23 Hz), 1.56 - 1.65 (3 H, m), 1.32 - 1.40 (2 H, m), 1.25 (2 H, br d, J=12.52 Hz), 1.19 (2 H, br d, J=1.79 Hz), 1.02 - 1.10 (2 H, m), 0.80 (1 H, br d, J=11.32 Hz).

EXAMPLE 205. Preparation of (I-136) (S)-3-(5-(4-((1-(4-((1R,2S)-2-cyclohexyl-6- hydroxy-1,2,3,4-tetrahydronaphthalen-1-yl)-3-fluorophenyl)pi peridin-4- yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2, 6-dione Step 1: To a solution of 4-bromo-3-fluorophenol (2.00 g, 1 eq., 10.5 mmol) and (bromomethyl) benzene (1.97 g, 1.1 eq., 11.5 mmol) in MeCN (30 mL) was added K2CO3 (3.62 g, 2.5 eq., 26.2 mmol). The mixture was stirred at 70 °C for 3 hour. TLC showed the reaction was completed. The crude material was purified on silica gel column chromatography (from pure PE to PE/EtOAc = 1/0) to give 4-(benzyloxy)-1-bromo-2-fluorobenzene (2.3 g, 8.2 mmol, 78 %) as transparent oil. ¹ H NMR (400 MHz, DMSO-d ₆ ) į: ppm: 7.55 (t, J = 8.58 Hz, 1 H), 7.24 - 7.50 (m, 5 H), 7.11 (dd, J = 11.03, 2.44 Hz, 1 H), 6.85 (dd, J = 8.82, 2.15 Hz, 1 H), 5.12 (s, 2 H). Step 2: A mixture of 4-(benzyloxy)-1-bromo-2-fluorobenzene (2.30 g, 1 eq., 8.18 mmol), (E)-N'- (6 -methoxy-3,4-dihydronaphthalen-1(2H)-ylidene)-4-methylbenzen esulfonohydrazide (3.10 g, 1.1 eq., 9.00 mmol), XPhos Pd G3 (346 mg, 0.05 eq., 409 ^mol), Lithium 2-methyl -2- propanolate (1.96 g, 2.28 mL, 3 eq., 24.5 mmol) and PdCl ₂ (dppf) (599 mg, 0.1 eq., 818 ^mol) in Dioxane (100 mL) was degassed and purged with N ₂ for 3 times, and then the mixture was stirred at 100 °C for 12 hour under N ₂ atmosphere. LCMS showed the reaction was completed. The reaction mixture was quenched by addition EA 30 mL at 20 °C, and then diluted with water 50 mL and extracted with EA 90 mL (30 mL x 3). The combined organic layers were washed with EA 30 mL (10 mL x 3), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The crude material was purified on silica gel column chromatography (from pure PE to PE/EtOAc = 20/1) to give 4-(4-(benzyloxy)-2-fluorophenyl)-7-methoxy-1,2- dihydronaphthalene (2.8 g, 7.8 mmol, 95 %) as a yellow solid. LC-MS (ESI+) m/z: 360.9 (M+H ⁺ ) ¹ H NMR (400 MHz, DMSO-d ₆ ) į: ppm 7.29 - 7.53 (m, 5 H), 7.21 (t, J = 8.58 Hz, 1 H), 6.85 - 6.99 (m, 2 H), 6.81 (d, J = 2.38 Hz, 1 H), 6.63 - 6.69 (m, 1 H), 6.55 - 6.62 (m, 1 H), 5.89 (t, J = 4.59 Hz, 1 H), 5.15 (s, 2 H), 3.73 (s, 3 H), 2.77 (t, J = 7.99 Hz, 2 H), 2.32 (td, J = 7.87, 4.77 Hz, 2 H). Step 3: To a solution of 4-(4-(benzyloxy)-2-fluorophenyl)-7-methoxy-1,2-dihydronaphth alene (2.1 g, 1 eq., 5.8 mmol) in Ethyl acetate (30 mL) was added Pd/C (10%, 0.5 g) under N ₂ atmosphere. The suspension was degassed and purged with H ₂ for 3 times. The mixture was stirred under H ₂ (15 psi.) at 20 °C for 12 hour. LCMS showed the reaction was completed. After filtration, the filtrate was concentrated. The crude material was purified on silica gel column chromatography (from pure PE to PE/EtOAc = 2/1) to give 3-fluoro-4-(6-methoxy-3,4- dihydronaphthalen-1-yl)phenol (1.0 g, 3.7 mmol, 63 %) as a yellow solid. LC-MS (ESI+) m/z: 271.2(M+H ⁺ ). ¹ H NMR (400 MHz, DMSO-d6) į: ppm 7.47 - 7.52 (m, 2 H), 7.40 - 7.46 (m, 2 H), 7.35 - 7.40 (m, 1 H), 6.95 (d, J = 9.42 Hz, 2 H), 6.84 (d, J = 2.62 Hz, 1 H), 6.67 (dd, J = 8.52, 2.68 Hz, 1 H), 6.48 (d, J = 8.58 Hz, 1 H), 5.17 (s, 2 H), 3.73 (s, 3 H), 2.96 - 3.02 (m, 2 H), 2.88 - 2.95 (m, 2 H). Step 4: To a solution of 3-fluoro-4-(6-methoxy-3,4-dihydronaphthalen-1-yl)phenol (1.00 g, 1 eq., 3.70 mmol) and TEA (1.12 g, 1.55 mL, 3 eq., 11.1 mmol) in DCM (20 mL) was added Tf2O (1.25 g, 750 ^L, 1.2 eq., 4.44 mmol). The mixture was stirred at 0 °C for 1 hour. LCMS showed the reaction was completed. The reaction mixture was quenched by addition water 10 mL at 20 °C, and then diluted with water 10 mL and extracted with DCM 30 mL (10 mL x 3). The combined organic layers were washed with DCM 15 mL (5 mL x 3), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The crude material was purified on silica gel column chromatography (from PE/EtOAc = 1/0 to 20/1) to yield 3-fluoro-4-(6- methoxy-3,4-dihydronaphthalen-1-yl)phenyl trifluoromethanesulfonate (0.80 g, 2.0 mmol, 54 %) as a colourless oil. LC-MS (ESI+) m/z: 403.6 (M+H ⁺ ) ¹ H NMR (500 MHz, DMSO-d ₆ ) į: ppm 7.66 (dd, J = 9.84, 2.37 Hz, 1 H), 7.49 - 7.55 (m, 1 H), 7.44 (dd, J = 8.54, 2.29 Hz, 1 H), 7.27 (dd, J = 8.54, 2.14 Hz, 1 H), 7.04 (t, J = 8.62 Hz, 1 H), 6.84 (d, J = 2.44 Hz, 1 H), 6.68 (dd, J = 8.47, 2.67 Hz, 1 H), 6.53 (dd, J = 8.39, 1.22 Hz, 1 H), 6.02 (t, J = 4.50 Hz, 1 H), 3.73 (s, 3 H), 2.80 (t, J = 8.09 Hz, 2 H), 2.37 (td, J = 7.82, 4.81 Hz, 2 H). Step 5: A mixture of 3-fluoro-4-(6-methoxy-3,4-dihydronaphthalen-1-yl)phenyl trifluoromethanesulfonate (800 mg, 1 eq., 1.99 mmol), 4-(dimethoxymethyl)piperidine (348 mg, 1.1 eq., 2.19 mmol), (2-Dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl) [2-(2'-amino- 1,1'-biphenyl)]palladium(II) methanesulfonate (166 mg, 0.1 eq., 199 ^mol) and K ₂ CO ₃ (824 mg, 3 eq., 5.96 mmol) in Dioxane (20 mL) was degassed and purged with N ₂ for 3 times, and then the mixture was stirred at 100 °C for 12 hour under N ₂ atmosphere. LCMS showed the reaction was completed. The reaction mixture was quenched by addition EA 10 mL at 20 °C, and then diluted with water 30 mL and extracted with EA 30 mL (10 mL x 3). The combined organic layers were washed with EA 30 mL (10 mL * 3), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The crude material was purified on silica gel column chromatography (from pure PE to PE/EA = 9/1) to as give4-(dimethoxymethyl)-1-(3-fluoro-4- (6-methoxy-3,4- dihydronaphthalen-1-yl) phenyl) piperidine (700 mg, 1.3 mmol, 64 %, 75% Purity) a yellow oil. LC-MS (ESI+) m/z: 412.1 (M+H ⁺ ). Step 6: To a solution of 4-(dimethoxymethyl)-1-(3-fluoro-4-(6-methoxy-3,4-dihydronaph thalen- 1-yl)phenyl)piperidine (800 mg, 1.0 eq., 1.94 mol) in DCM (20 mL) was added Pyridinium bromide perbromide (373 mg, 0.6 eq., 1.17 mol). The mixture was stirred at 20 °C for 1 hour. LCMS showed the reaction was completed. The reaction mixture was quenched by addition water 30 mL at 20 °C, and then diluted with extracted with EA 60 mL (20 mL x 3). The combined organic layers were washed with EA 60 mL (20 mL x 3), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The crude material was purified on silica gel column chromatography (from pure PE to PE/EtOAc = 5/1) to give 1-(4-(2-bromo-6- methoxy-3,4-dihydronaphthalen-1-yl)-3-fluorophenyl)-4-(dimet hoxymethyl)piperidine (550 mg, 1.12 mmol, 57.7 %, 70% Purity) as a yellow solid. LC-MS (ESI+) m/z: 490.1 (M+H ⁺ ). Step 7: A mixture of 1-(4-(2-bromo-6-methoxy-3,4-dihydronaphthalen-1-yl)-3-fluoro phenyl)-4- (dimethoxymethyl)piperidine (550 mg, 1 eq., 1.12 mmol), cyclohex-1-en-1-ylboronic acid (155 mg, 1.1 eq., 1.23 mmol), Cs ₂ CO ₃ (1.10 g, 3 eq., 3.36 mmol) and PdCl ₂ (dppf) (82.1 mg, 0.1 eq., 112 ^mol) in water (2 mL) and Dioxane (10 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 80 °C for 12 hour under N2 atmosphere. LCMS showed the reaction was completed. The reaction mixture was quenched by addition EA 30 mL at 20 °C, and then diluted with water 30 mL and extracted with EA 90 mL (30 mL x 3). The combined organic layers were washed with EA 30 mL (10 mL x 3), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The crude material was purified on silica gel column chromatography (from pure PE to PE/EtOAc = 3/1) to give 1-(4-(2-(cyclohex-1-en- 1-yl)-6-methoxy-3,4-dihydronaphthalen-1-yl)-3-fluorophenyl) -4-(dimethoxymethyl)piperidine (450 mg, 0.67 mmol, 60 %, 73% Purity) as a yellow solid. LC-MS (ESI+) m/z: 492.2(M+H ⁺ ). Step 8: To a solution of 1-(4-(2-(cyclohex-1-en-1-yl)-6-methoxy-3,4-dihydronaphthalen -1-yl)-3- fluorophenyl)-4-(dimethoxymethyl)piperidine (400 mg, 1 eq., 814 ^mol) in Ethyl acetate (15 mL) was added Pd/C (10%, 0.2 g) under N ₂ atmosphere. The suspension was degassed and purged with H ₂ for 3 times. The mixture was stirred under H ₂ (50 Psi) at 70 °C for 72 hour. LCMS showed the reaction was completed. The crude was purified by prep-HPLC together (Welch Xtimate C18150*25mm*5um, water(FA)-ACN as a mobile phase, from 90% to 100%, Gradient Time (min): 11, Flow Rate (ml/min): 25) to give 1-(4-(2-cyclohexyl-6-methoxy- 1,2,3,4-tetrahydronaphthalen-1-yl)-3-fluorophenyl)-4-(dimeth oxymethyl)piperidine (200 mg, 403 ^mol, 49.6 %). LC-MS (ESI+) m/z: 496.4(M+H ⁺ ). Step 9: 1-(4-(2-cyclohexyl-6-methoxy-1,2,3,4-tetrahydronaphthalen-1- yl)-3-fluorophenyl)-4- (dimethoxymethyl)piperidine (200 mg, 1 eq., 403 ^mol) was separated by SFC (Column: DAICEL CHIRALPAK AD (250mm*30mm,10um); Mobile phase: 0.1%NH ₃ H ₂ O ETOH; from 25% to 25%; Flow rate: 70 mL/min) to give 1-(4-((1R,2S)-2-cyclohexyl-6-methoxy-1,2,3,4 - tetrahydronaphthalen-1-yl)-3-fluorophenyl)-4-(dimethoxymethy l) piperidine (60 mg, 0.12 mmol, 30 %) as white solid. LC-MS (ESI+) m/z: 496.4(M+H ⁺ ). Step 10: To a solution of 1-(4-((1R,2S)-2-cyclohexyl-6-methoxy-1,2,3,4 -tetrahydronaphthalen- 1-yl)-3-fluorophenyl)-4-(dimethoxymethyl) piperidine (60 mg, 1 eq., 0.12 mmol) in DCM (3 mL) was added BBr ₃ (0.15 g, 57 ^L, 5 eq., 0.61 mmol). The mixture was stirred at 20 °C for 1 hour and then water (0.5 mL) in DCM (3 mL) was added dropwise at 20 °C, the resulting mixture was stirred at 20 °C for 2 hour. LCMS showed the reaction was completed. The mixture was concentrated and then water (10 mL) was added. The mixture was extracted with DCM (10 mL x 3). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered and concentrated. The mixture was concentrated in vacuo to give crude product. No further purification as it is used for the next step directly. LC-MS (ESI+) m/z: 496.4(M+H ⁺ ). Step 11: To a solution of 1-(4-((1R,2S)-2-cyclohexyl-6-hydroxy-1,2,3,4-tetrahydronapht halen-1- yl)-3-fluorophenyl)piperidine-4-carbaldehyde (30 mg, 1 eq., 69 ^mol) and (S)-3-(1-oxo- 5- (piperazin-1-yl)isoindolin-2-yl)piperidine-2,6-dione (25 mg, 1.1 eq., 76 ^mol) in DCE (3 mL) was added dropwise 4-methylmorfolin (7.0 mg, 7.6 ^L, 1 eq., 69 ^mol) to pH=7 at 0.5 hour. After addition, the mixture was stirred at this temperature for 20 °C, and then Sodium triacetoxyborohydride (15 mg, 10 ^L, 1 eq., 69 ^mol) was added dropwise at 20 °C. The resulting mixture was stirred at 20 °C for 2 hour. LCMS showed the reaction was completed. The crude was purified by prep-HPLC together (Boston Green ODS 150*30mm*5um, water (FA)-ACN as a mobile phase, from 20% to 30%, Gradient Time (min): 12, Flow Rate (ml/min): 25) to give (S)-3-(5-(4-((1-(4-((1R,2S)-2-cyclohexyl-6-hydroxy-1,2,3,4-t etrahydronaphthalen-1- yl)-3-fluorophenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-o xoisoindolin-2-yl)piperidine-2,6- dione (11.6 mg, 15.5 ^mol, 23 %) as a white solid. LCMS: calc. for C45H54FN5O4:747.72, found: [M+H] ⁺ 748.5 HPLC: 95.74% purity at 220 nm. ¹ H NMR (400 MHz, METHANOL-d ₄ ) į: ppm 8.11 - 8.31 (m, 1 H), 7.63 - 7.72 (m, 1 H) ,7.08 - 7.23 (m, 2 H), 6.62 - 6.69 (m, 2 H), 6.61 (d, J=2.74 Hz, 2 H), 6.54 (d, J=2.26 Hz, 1 H), 6.42 - 6.48 (m, 1 H), 5.11 (dd, J=13.29, 4.95 Hz, 1 H), 4.38 - 4.50 (m, 3 H), 3.68 - 3.74 (m, 2 H), 3.46 - 3.66 (m, 4 H), 3.17 (d, J=2.50 Hz, 4 H), 2.89 - 2.96 (m, 2 H) 2.87 (s, 2 H), 2.69 - 2.81 (m, 4 H), 2.41 - 2.52 (m, 1 H), 2.12 - 2.19 (m, 1 H), 2.02 - 2.07 (m, 1 H), 1.92 - 2.01 (m, 1 H), 1.89 (d, J=13.47 Hz, 2 H), 1.79 (dd, J=12.22, 6.85 Hz, 1 H), 1.67 - 1.74 (m, 2 H), 1.56 - 1.66 (m, 3 H), 1.38 - 1.48 (m, 2 H), 1.23 - 1.30 (m, 2 H), 1.13 - 1.22 (m, 2 H), 1.01 - 1.09 (m, 2 H), 0.75 - 0.88 (m, 1 H). EXAMPLE 206. Preparation of (I-110) (S)-3-(5-(4-((1-(4-((1S,2R)-6-hydroxy-2-(3- (trifluoromethoxy)phenyl)-1,2,3,4-tetrahydronaphthalen-1-yl) phenyl)piperidin-4- yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2, 6-dione Step 1: To a solution of (1S,2R)-1-[4-[4-(dimethoxymethyl)-1-piperidyl]phenyl]-2-[3- (trifluoromethoxy)phenyl]tetralin-6-ol (130 mg, 240.03 umol, 1 eq) in THF (4 mL) was added H ₂ SO ₄ (4 mL, 10% purity). The mixture was stirred at 60 °C for 16 hr. LCMS showed desired MS was detected. The reaction was adjust to pH=7 with aq.NaHCO ₃ , then the residue was diluted with 40 mL H ₂ O and extracted with 100 mL EtOAc (50 mL*2). The combined organic layers dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. Compound 1-[4-[(1S,2R)-6-hydroxy-2-[3-(trifluoromethoxy)phenyl]tetral in-1- yl]phenyl]piperidine-4-carbaldehyde (85 mg, 171.53 umol, 71.46% yield) was obtained as a Step 2: To a solution of 1-(4-((1S,2R)-6-hydroxy-2-(3-(trifluoromethoxy)phenyl)-1,2,3 ,4- tetrahydronaphthalen-1-yl)phenyl)piperidine-4-carbaldehyde (85 mg, 171.53 umol, 1 eq) and (3S)-3-(1-oxo-5-piperazin-1-yl-isoindolin-2-yl)piperidine-2, 6-dione (85.86 mg, 171.53 umol, 1 eq, p-TSA) in DCM (4 mL) and MeOH (4 mL) was added sodium acetate (42.21 mg, 514.60 umol, 3 eq). The mixture was stirred at 25 °C for 0.5 hr. Then the mixture was added sodium triacetoxyboranuide (72.71 mg, 343.07 umol, 2 eq) and acetic acid (30.90 mg, 514.60 umol, 29.43 uL, 3 eq).The mixture was stirred at 25 °C overnight. LCMS showed desired MS was detected. The reaction mixture was diluted with H ₂ O 20 mL and extracted with DCM 100 mL (50 mL * 2). The combined organic layers were washed with brine 40 mL (20 mL * 2), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep.HPLC (column: Welch Xtimate C18150*30mm*5um; mobile phase: [water(FA)-ACN];B%: 28%-48%,7min). Compound C ₄₆ H ₄₈ O ₅ N ₅ F ₃ (87 mg, 107.69 umol, 62.78% yield) was obtained as a white solid. LC-MS (ESI+) m/z: 808.2 (M+H) ⁺ HPLC: 100%, purity at 220 nm. SFC: Rt: 2.347 min; Area, 87.568%; NMR (400 MHz, DMSO-d ₆ ) į ppm 10.91 - 11.00 (m, 1 H) 9.06 - 9.23 (m, 1 H) 8.18 - 8.30 (m, 0.400 H) 7.52 (d, J=8.53 Hz, 1 H) 7.27 - 7.33 (m, 1 H) 7.03 - 7.13 (m, 3 H) 6.95 - 7.01 (m, 1 H) 6.62 - 6.68 (m, 2 H) 6.59 - 6.62 (m, 1 H) 6.53 - 6.57 (m, 2 H) 6.47 - 6.51 (m, 1 H) 6.19 - 6.25 (m, 2 H) 5.01 - 5.09 (m, 1 H) 4.29 - 4.42 (m, 1 H) 4.12 - 4.24 (m, 2 H) 3.52 (br d, J=7.53 Hz, 3 H) 3.28 (br s, 6 H) 2.86 - 3.01 (m, 3 H) 2.30 - 2.44 (m, 4 H) 2.16 - 2.23 (m, 2 H) 2.11 (br d, J=6.27 Hz, 2 H) 1.93 - 2.00 (m, 1 H) 1.58 - 1.85 (m, 5 H) 1.09 - 1.20 (m, 2 H). Stereochemistry was arbitrarily assigned

EXAMPLE 207. Preparation of (I-109) (3S)-3-[5-[4-[[1-[4-[(1R,2S)-6-hydroxy-2-[3- (trifluoromethoxy)phenyl]tetralin-1-yl]phenyl]-4-piperidyl]m ethyl]piperazin-1-yl]-1-oxo- isoindolin-2-yl]piperidine-2,6-dione Step 1: A mixture of sodium carbonate (232 mg, 3 Eq, 2.19 mmol) , Pd(dppf)Cl ₂ (59.6 mg, 0.1 Eq, 72.9 ^mol) , 4,4,5,5-tetramethyl-2-(3-(trifluoromethoxy)phenyl)-1,3,2-dio xaborolane (252 mg, 1.2 Eq, 875 ^mol) , 1-(4-(6-(benzyloxy)-2-bromo-3,4-dihydronaphthalen-1-yl)pheny l)-4- (dimethoxymethyl)piperidine (400 mg, 1 Eq, 729 ^mol) in 1,4-Dioxane (8 mL) and H2O (2 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 100 °C for 16 hr under N ₂ atmosphere. LCMS showed 54.862% desired MS. The reaction was quenched with water (50 mL) and extracted with ethyl acetate (100 mL*2). The organic layer was washed with brine (20 mL) and dried over Na ₂ SO ₄ and concentrated in vacuo to give a white solid. The white solid was subjected to column chromatography over silica gel (gradient elution: 0 – 100% EtOAc). The desired fractions were collected, and concentrated to dryness in vacuo to give 1-(4- (6-(benzyloxy)-2-(3-(trifluoromethoxy)phenyl)-3,4-dihydronap hthalen-1-yl)phenyl)-4- (dimethoxymethyl)piperidine (398 mg, 632.04 ^mol, 99.5% yield) as a white solid. LC-MS (ESI ⁺ ) m/z: 605.0 (M+H) ⁺ . Step 2: A mixture of 1-[4-[6-benzyloxy-2-[3-(trifluoromethoxy)phenyl]-3,4-dihydro naphthalen- 1-yl]phenyl]-4- (dimethoxymethyl)piperidine (400 mg, 635.22 umol, 1 eq) , Pd/C (540.80 mg, 508.17 umol, 10% purity, 0.8 eq) in THF (5mL) and MeOH (5 mL) was degassed and purged with H ₂ for 3 times, and then the mixture was stirred at 50 °C for 12 hr under H ₂ atmosphere. The suspension was degassed and purged with dihydrogen (1.08 mg, 1 Eq, 534 ^mol) for 10 mins. The mixture was stirred under 15 psi H ₂ (1.08 mg, 1 Eq, 534 ^mol) at 50 °C for 12 hr. LCMS showed 84.236% desired MS. The reaction was filtrate and concentrated. The residue was further separated by prep-HPLC (TFA condition; or neutral condition; or basic condition) to give desired 1-[4-[4-(dimethoxymethyl)-1-piperidyl]phenyl]-2-[3- (trifluoromethoxy)phenyl]tetralin-6-ol (400 mg, 508.17umol, 80% yield, purity 95%) as a white oil. LC-MS (ESI ⁺ ) m/z: 542.1 (M+H)+. Step 3: 540.8 mg of 1-[4-[4-(dimethoxymethyl)-1-piperidyl]phenyl]-2-[3- (trifluoromethoxy)phenyl]tetralin-6-ol was further separated by SFC (column: DAICEL CHIRALCEL ODH(250mm*30mm,5um);mobile phase: [0.1%NH3H2O ETOH];B%: 35%- 35%,45min) to give desired (1R,2S)-1-[4-[4-(dimethoxymethyl)-1-piperidyl]phenyl]-2-[3- (trifluoromethoxy)phenyl]tetralin-6-ol (70 mg, 129.25 mmol, 20.35 % yield) as a white oil and desired (1S,2R)-1-[4-[4-(dimethoxymethyl)-1-piperidyl]phenyl]-2-[3- (trifluoromethoxy)phenyl]tetralin-6-ol (120 mg, 221.57 mmol, 34.88 % yield) as a white oil. LC-MS (ESI ⁺ ) m/z: 542.1 (M+H) ⁺ . Step 4: To a solution of (1R,2S)-1-[4-[4-(dimethoxymethyl)-1-piperidyl]phenyl]-2-[3- (trifluoromethoxy)phenyl]tetralin-6-ol (112.00 mg, 206.79 umol, 1 eq) in THF (4 mL) was added H ₂ SO ₄ (4 mL, 10% purity) .The mixture was stirred at 70 °C for 16 hr . LCMS showed desired MS was detected. The reaction was adjust to pH=7 with NaHCO ₃ , Then the residue was diluted with 40 mL H ₂ O and extracted with EtOAc 100 mL (50 mL * 2). The combined organic layers dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. Compound 1-[4-[(1R,2S)-6-hydroxy-2-[3-(trifluoromethoxy)phenyl]tetral in-1- yl]phenyl]piperidine-4-carbaldehyde (95 mg, 191.71 umol, 92.71% yield) was obtained as a yellow oil. LC-MS (ESI ⁺ ) m/z: 514.3 (M+H2O) ⁺ . Step 5: To a solution of 1-[4-[(1R,2S)-6-hydroxy-2-[3-(trifluoromethoxy)phenyl]tetral in-1- yl]phenyl]piperidine-4-carbaldehyde (95.00 mg, 191.71 umol, 1 eq) and (3S)-3-(1-oxo-5- piperazin-1-yl-isoindolin-2-yl)piperidine-2,6-dione (95.97 mg, 191.71 umol, 1 eq, p-TSA) in DCM (4 mL) and MeOH (4 mL) was added sodium acetate (47.18 mg, 575.14 umol, 3 eq) .The mixture was stirred at 25 °C for 0.5 hr .Then the mixture was added sodium triacetoxyboranuide (81.26 mg, 383.43 umol, 2 eq) and acetic acid (158.81 mg, 575.14 umol, 151.25 uL, 3 eq) .The mixture was stirred at 25 °C overnight . LCMS showed desired MS was detected. The reaction mixture was diluted with 20 mL H ₂ O and extracted with DCM (50 mL * 2). The combined organic layers were washed with brine (20 mL * 2), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep.HPLC (column: Welch Xtimate C18150*30mm*5um; mobile phase: [water(FA)-ACN];B%: 28%-48%,7min). Compound (3S)-3-[5-[4-[[1-[4-[(1R,2S)-6-hydroxy-2-[3-(trifluoromethox y)phenyl]tetralin-1- yl]phenyl]-4-piperidyl]methyl]piperazin-1-yl]-1-oxo-isoindol in-2-yl]piperidine-2,6-dione (92 mg, 113.88 umol, 59.40% yield) was obtained as a white solid. LCMS (ESI+) m/z: 808.2 (M+H) ⁺ HPLC: 100%, purity at 220 nm. SFC: Rt: 2.321 min; Area, 82.355%; method: Ic_MeOH_DEA_MeCN_50_1ML_10MIN_10CM. NMR (400 MHz, DMSO-d ₆ ) į ppm 10.92 -10.99 (m, 1 H) 9.06 - 9.21 (m, 1 H) 8.20 - 8.26 (m, 1 H) 7.45 - 7.56 (m, 1 H) 7.23 - 7.35 (m, 1 H) 7.03 - 7.16 (m, 3 H) 6.93 - 7.01 (m, 1 H) 6.63 - 6.71 (m, 2 H) 6.59 - 6.61 (m, 1 H) 6.53 - 6.57 (m, 2 H) 6.47 - 6.51 (m, 1 H) 6.15 - 6.27 (m, 2 H) 4.98 - 5.11 (m, 1 H) 4.27 - 4.38 (m, 1 H) 4.08 - 4.25 (m, 2 H) 3.47 - 3.57 (m, 4 H) 3.29 (br s, 5 H) 2.83 - 3.06 (m, 4 H) 2.31 - 2.42 (m, 3 H) 2.13 - 2.23 (m, 3 H) 1.89 - 2.08 (m, 2 H) 1.59 - 1.80 (m, 5 H) 1.07 - 1.23 (m, 2 H). Stereochemistry was arbitrarily assigned EXAMPLE 208. Preparation of (I-130) (3S)-3-[5-[4-[[1-[4-[(1S,2R)-6-hydroxy-2-(4- hydroxyphenyl)tetralin-1-yl]phenyl]-4-piperidyl]methyl]piper azin-1-yl]-1-oxo-isoindolin-2- hydroxyphenyl) tetralin-1-yl]phenyl]-4-piperidyl]methyl]piperazin-1-yl]-1-o xo-isoindolin- 2-yl]piperidine-2,6-dione Step 1: To a solution of 1-[4-(6-benzyloxy-2-bromo-3,4-dihydronaphthalen-1-yl)phenyl] -4- (dimethoxymethyl)piperidine (1 g, 1.8 mmol, 1 eq) and (4-hydroxyphenyl)boronic acid (377.19 mg, 2.73 mmol, 1.5 eq) in dioxane (10 mL) and H ₂ O (2.5 mL) was added Pd(dppf)Cl ₂ (133.40 mg, 182.31 Pmol, 0.1 eq) and Na ₂ CO ₃ (386.46 mg, 3.65 mmol, 2 eq). The mixture was stirred at 100 °C for 12 h. The reaction mixture was quenched by addition of water (50 mL), extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (10 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (from pure PE to PE/EtOAc = 3/1, TLC: PE/EtOAc = 3/1, R _f = 0.21) to yield 4-[6-benzyloxy-1-[4-[4-(dimethoxymethyl)-1-piperidyl]phenyl] -3,4- dihydronaphthalen-2-yl]phenol (960 mg, 1.67 mmol, 91.87% yield, 98% purity) as a brown solid. LC-MS (ESI ⁺ ) m/z 562.4 [M+H] ⁺ . 7.42 (m, 2H), 7.41-7.36 (m, 2H), 7.35-7.30 (m, 1H), 6.95- 6.87 (m, 4H), 6.86-6.78 (m, 3H), 6.75 (d, J = 8.5 Hz, 1H), 6.65 (dd, J = 2.6, 8.5 Hz, 1H), 6.57 (d, J = 8.7 Hz, 2H), 5.06 (s, 2H), 4.11-4.09 (m, 1H), 3.70 (br d, J = 12.2 Hz, 2H), 3.39 (s, 5H), 3.44- 3.35 (m, 1H), 2.92 (br t, J = 7.7 Hz, 2H), 2.78-2.71 (m, 2H), 2.65 (t, J = 11.7 Hz, 2H), 1.87 (br d, J = 12.7 Hz, 2H), 1.80-1.71 (m, 1H), 1.53-1.42 (m, 2H). Step 2: To a solution of 4-[6-benzyloxy-1-[4-[4-(dimethoxymethyl)-1-piperidyl]phenyl] -3,4- dihydronaphthalen-2-yl]phenol (800 mg, 1.40 mmol, 98% purity, 1 eq) in MeOH (10 mL) was added Pd/C (800 mg, 10% purity) .The mixture was stirred at 25 °C for 5 h. The reaction mixture was filtered and concentrated to yield a residue. The residue was separated by chiral SFC(column: DAICEL CHIRALCEL OD-H(250mm*30mm,5um);mobile phase: [0.1%NH ₃ H ₂ O MEOH];B%: 45^%-45%, 45 min), followed by lyophilization to yield (1S,2R)-1-[4-[4- (dimethoxymethyl)-1-piperidyl]phenyl]-2-(4-hydroxyphenyl)tet ralin-6-ol (240 mg, 486.48 Pmol, 44.14% yield, 96% purity) as a white solid and (1R,2S)-1-[4-[4-(dimethoxymethyl)-1- piperidyl]phenyl]-2-(4-hydroxyphenyl)tetralin-6-ol (290 mg, 606.21 Pmol, 55.0% yield, 99% purity) as a white solid. LC-MS (ESI ⁺ ) m/z 474.3 [M+H] ^{+ 1} H NMR of (1S,2R)-1-[4-[4-(dimethoxymethyl)-1-piperidyl]phenyl]-2-(4- hydroxyphenyl)tetralin-6-ol: (400MHz, CDCl ₃ ) į = 6.82 (d, J=8.3 Hz, 1H), 6.71-6.54 (m, 8H), 6.33 (d, J = 8.6 Hz, 2H), 4.16 (d, J = 4.8 Hz, 1H), 4.10 (d, J = 7.3 Hz, 1H), 3.59 (t, J = 10.8 Hz, 2H), 3.38 (s, 5H), 3.39-3.37 (m, 1H), 3.34-3.24 (m, 1H), 3.09-2.97 (m, 2H), 2.66-2.52 (m, 2H), 2.20-2.04 (m, 1H), 1.84 (br d, J = 13.1 Hz, 2H), 1.79-1.66 (m, 4H), 1.49 (br s, 2H) ¹ H NMR of (1R,2S)-1-[4-[4-(dimethoxymethyl)-1-piperidyl]phenyl]-2-(4- hydroxyphenyl)tetralin-6-ol: (400MHz, CDCl ₃ ) į = 6.84 (d, J = 8.3 Hz, 1H), 6.72-6.56 (m, 8H), 6.32 (d, J = 8.7 Hz, 2H), 4.16 (d, J = 4.6 Hz, 1H), 4.09 (d, J = 7.4 Hz, 1H), 3.59 (t, J = 10.1 Hz, 2H), 3.38 (s, 6H), 3.33-3.25 (m, 1H), 3.10-2.95 (m, 2H), 2.57 (t, J = 12.2 Hz, 2H), 2.21-2.05 (m, 1H), 1.83 (br d, J = 12.3 Hz, 2H), 1.79-1.62 (m, 4H), 1.51-1.37 (m, 2H) Step 3 : To a solution of (1S,2R)-1-[4-[4-(dimethoxymethyl)-1-piperidyl]phenyl]-2- (4- hydroxyphenyl)tetralin-6-ol (100 mg 2027 Pmol 96% purity 1 eq) in DCM (25 mL) was added TFA (770.00 mg, 6.75 mmol, 0.5 mL, 33.32 eq). The mixture was stirred at 25 °C for 1 h. The reaction mixture was quenched by addition of water (30 mL), extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (10 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to yield 1-[4-[(1S,2R)-6-hydroxy-2-(4- hydroxyphenyl)tetralin-1-yl]phenyl]piperidine-4-carbaldehyde (80 mg, 187.12 Pmol, 92.3% yield, N/A purity) as a brown solid which was used in the next step without further purification. LC-MS (ESI ⁺ ) m/z 428.3 [M+H] ⁺ . Step 4: To a solution of 1-[4-[(1S,2R)-6-hydroxy-2-(4-hydroxyphenyl)tetralin-1-yl]phe nyl] piperidine-4-carbaldehyde (80 mg, 187.12 Pmol, N/A purity, 1 eq) and (3S)-3-(1-oxo-5- piperazin-1-yl-isoindolin-2-yl)piperidine-2,6-dione (103.03 mg, 205.83 Pmol, 1.1 eq, TsOH) in DCM (2.5 mL) and MeOH (2.5 mL), after stirred 30 min was added NaBH(OAc)3 (118.98 mg, 561.36 Pmol, 3 eq). The mixture was stirred at 25 °C for 12 h. The reaction mixture was concentrated to yield a residue. The residue was purified by preparative HPLC (column: Welch Xtimate C18150*25mm*5um; mobile phase: [water( NH4HCO3) - ACN];B%: 43%-63%, 11 min), followed by lyophilization to yield (3S)-3-[5-[4-[[1-[4-[(1S,2R)-6-hydroxy-2-(4- hydroxyphenyl)tetralin-1-yl]phenyl]-4-piperidyl]methyl]piper azin-1-yl]-1-oxo-isoindolin-2- yl]piperidine-2,6-dione (65.4 mg, 86.34 Pmol, 46.14% yield, 97.684% purity) as a white solid. LC-MS (ESI ⁺ ) m/z 725.5 [M+H] ⁺ . LCMS: calc. for C45H49N5O5: 739.37, found: [M+H] ⁺ 740.5. HPLC: 97.684% purity at 220 nm. ¹ H NMR (400MHz, CD ₃ OD) į = 7.63 (d, J = 8.5 Hz, 1H), 7.12-7.04 (m, 2H), 6.71-6.58 (m, 6H), 6.57-6.48 (m, 3H), 6.33 (d, J = 8.6 Hz, 2H), 5.09 (dd, J = 5.1, 13.4 Hz, 1H), 4.47-4.33 (m, 2H), 4.12 (d, J = 5.1 Hz, 1H), 3.57-3.48 (m, 2H), 3.40-3.34 (m, 4H), 3.25-3.19 (m, 1H), 3.01- 2.84 (m, 3H), 2.81-2.73 (m, 1H), 2.67-2.54 (m, 6H), 2.46 (dq, J = 4.5, 13.2 Hz, 1H), 2.31 (d, J = 7.0 Hz, 2H), 2.14 (ddd, J = 2.7, 5.2, 7.6 Hz, 2H), 1.87 (br d, J = 12.8 Hz, 2H), 1.70 (br d, J = 6.9 Hz, 2H), 1.38-1.28 (m, 2H) Step 5: To a solution of (1R,2S)-1-[4-[4-(dimethoxymethyl)-1-piperidyl]phenyl]-2- (4- hydroxyphenyl)tetralin-6-ol (100 mg, 209.04 Pmol, 99% purity, 1 eq) in DCM (2.5 mL) was dd d TFA (77000 675 l 05 L 3231 ) Th i t ti d t 25 °C f 1 h The reaction mixture was quenched by addition of water (30 mL), extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to yield 1-[4-[(1R,2S)-6-hydroxy-2-(4- hydroxyphenyl)tetralin-1-yl]phenyl]piperidine-4-carbaldehyde (80 mg, 187.12 Pmol, 89.5% yield, N/A purity) as a brown solid which was used in the next step without further purification. LC-MS (ESI ⁺ ) m/z 428.3 [M+H] ⁺ . Step 6: To a solution of 1-[4-[(1R,2S)-6-hydroxy-2-(4-hydroxyphenyl)tetralin-1- yl]phenyl]piperidine -4-carbaldehyde (80.00 mg, 187.12 Pmol, N/A purity, 1 eq) and (3S)-3-(1- oxo-5-piperazin-1-yl-isoindolin-2-yl)piperidine-2,6-dione (103.03 mg, 205.83 Pmol, 1.1 eq, TsOH) in DCM (2.5 mL) and MeOH (2.5 mL), after stirred 30 min was added NaBH(OAc) ₃ (118.98 mg, 561.36 umol, 3 eq). The mixture was stirred at 25 °C for 12 h. The residue was filtered and purified by preparative HPLC (column: Welch Xtimate C18150 * 25 mm * 5 um; mobile phase: [water( NH ₄ HCO ₃ )-ACN]; B%: 43%-63%, 11 min), followed by lyophilization to yield (3S)-3-[5-[4-[[1-[4-[(1R,2S)-6-hydroxy-2-(4-hydroxyphenyl) tetralin-1-yl]phenyl]-4- piperidyl]methyl]piperazin-1-yl]-1-oxo-isoindolin-2-yl]piper idine-2,6-dione (61.6 mg, 83.07 Pmol, 44.39% yield, 99.779% purity) as a white solid. LC-MS (ESI ⁺ ) m/z 740.5 [M+H] ⁺ . LCMS: calc. for C45H49N5O5: 739.37, found: [M+H] ⁺ 740.5. HPLC: 99.779% purity at 220 nm. ¹ H NMR (400MHz, CD ₃ OD) į = 7.63 (d, J = 8.3 Hz, 1H), 7.11-7.05 (m, 2H), 6.70-6.59 (m, 6H), 6.57-6.49 (m, 3H), 6.34 (d, J = 8.6 Hz, 2H), 5.09 (dd, J = 5.0, 13.4 Hz, 1H), 4.46-4.33 (m, 2H), 4.12 (d, J = 5.2 Hz, 1H), 3.53 (br d, J = 10.4 Hz, 2H), 3.39-3.35 (m, 4H), 3.23 (br d, J = 11.1 Hz, 1H), 3.01-2.85 (m, 3H), 2.82-2.73 (m, 1H), 2.64-2.54 (m, 6H), 2.46 (dq, J = 4.5, 13.2 Hz, 1H), 2.31 (d, J = 6.9 Hz, 2H), 2.20-2.09 (m, 2H), 1.87 (br d, J = 13.7 Hz, 2H), 1.70 (br d, J = 7.2 Hz, 2H), 1.38-1.29 (m, 2H), 1.40-1.27 (m, 1H).

EXAMPLE 209. Preparation of (I-127) (3S)-3-[5-[4-[[1-[4-[(1S,2R)-6-hydroxy-2-(3- hydroxyphenyl)tetralin-1-yl]phenyl]-4-piperidyl]methyl]piper azin-1-yl]-1-oxo-isoindolin-2- yl]piperidine-2,6-dione Step 1: To a solution of ((5S,6R)-5-(4-(4-(dimethoxymethyl)piperidin-1-yl)phenyl)-6-( 3- hydroxyphenyl)-5,6,7,8-tetrahydronaphthalen-2-ol (90 mg, 1 Eq, 0.19 mmol)) in THF (3 mL) was added sulfuric acid (0.19 g, 3 mL, 10% Wt, 1 Eq, 0.19 mmol).The mixture was stirred at 70 °C for 6 hr . LCMS showed 77.035% desired MS. The reaction was adjust to pH=7 with NaHCO ₃ , then 50 mL water was added, and the mixture was extracted with dichloromethane (100 mL x 2). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to dryness in vacuo to give a yellow oil. The yellow oil was concentrated in vacuo to give 1-(4-((1S,2R)-6-hydroxy-2-(3-hydroxyphenyl)-1,2,3,4- tetrahydronaphthalen-1-yl)phenyl)piperidine-4-carbaldehyde (80 mg, 0.17 mmol) as a yellow solid. LC-MS (ESI ⁺ ) m/z: 446.3 (M+H ₂ O) ⁺ Step 2: To a solution of 1-[4-[(1S,2R)-6-hydroxy-2-(3-hydroxyphenyl)tetralin-1- yl]phenyl]piperidine-4-carbaldehyde (80 mg, 187.12 umol, 1 eq) and (3S)-3-(1-oxo-5-piperazin- 1-yl-isoindolin-2-yl)piperidine-2,6-dione (93.67 mg, 187.12 umol, 1eq, p-TSA) in DCM (4 mL) and MeOH (4 mL) was added sodium acetate (46.05 mg, 561.36 umol, 3 eq) .The mixture was stirred at 25 °C for 1 h. Then the mixture was added sodium triacetoxyboranuide (79.32 mg, 374.24 umol, 2 eq) and acetic acid (33.71 mg, 561.36 umol, 32.1uL, 3eq)The mixture was stirred at 25 °C for 16 hr . The reaction mixture was diluted with 15 mL H ₂ O and extracted with DCM (50 mL * 2). The combined organic layers were washed with brine 50 mL (25 mL * 2), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The mobile phase: [water(FA)-ACN];B%:17 %-37%,7min). Compound (3S)-3-[5-[4-[[1-[4-[(1S,2R)- 6-hydroxy-2-(3-hydroxyphenyl)tetralin-1-yl]phenyl]-4-piperid yl]methyl]piperazin-1-yl]-1-oxo- isoindolin-2-yl]piperidine-2,6-dione (28 mg, 37.84 umol, 20.22% yield) was obtained as a white solid. LC-MS (ESI+) m/z: 740.5 (M+H)+ HPLC: 97.915%, purity at 220 nm. SFC Rt: 2.605 min; Area, 76.253%; method:ID_MeOH_DEA_MeCN_50_1ML_10MIN_10CM. NMR (400 MHz, DMSO-d ₆ ) į ppm 10.92 - 10.96 (m, 1 H) 8.92 - 9.16 (m, 1 H) 8.16 - 8.21 (m, 0.777 H) 7.45 - 7.58 (m, 1 H) 7.03 - 7.12 (m, 2 H) 6.88 - 6.99 (m, 1 H) 6.62 - 6.68 (m, 1 H) 6.45 - 6.60 (m, 5 H) 6.30 - 6.37 (m, 1 H) 6.20 - 6.28 (m, 3 H) 5.00 - 5.09 (m, 1 H) 4.30 - 4.38 (m, 1 H) 4.17 - 4.25 (m, 1 H) 4.07 - 4.14 (m, 1 H) 3.49 - 3.56 (m, 2 H) 3.29 (br d, J=3.93 Hz, 6 H) 3.14 - 3.23 (m, 2 H) 2.84 - 2.96 (m, 3 H) 2.66 - 2.71 (m, 1 H) 2.55 - 2.64 (m, 2 H) 2.31 - 2.40 (m, 2 H) 2.17 - 2.24 (m, 2 H) 1.92 - 2.09 (m, 2 H) 1.58 - 1.81 (m, 4 H) 1.09 - 1.24 (m, 2 H)

EXAMPLE 210. Preparation of (I-126) (3S)-3-[5-[4-[[1-[4-[(1R,2S)-6-hydroxy-2-(3- hydroxyphenyl)tetralin-1-yl]phenyl]-4-piperidyl]methyl]piper azin-1-yl]-1-oxo-isoindolin-2- yl]piperidine-2,6-dione Step 1: A mixture of sodium carbonate (232 mg, 3 Eq, 2.19 mmol) , Pd(dppf)Cl ₂ (59.6 mg, 0.1 Eq, 72.9 ^mol) , 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (193 mg, 1.2 Eq, 875 ^mol) , 1-(4-(6-(benzyloxy)-2-bromo-3,4-dihydronaphthalen-1-yl)pheny l)-4- (dimethoxymethyl)piperidine (400 mg, 1 Eq, 729 ^mol) in 1,4-Dioxane (8 mL) and H ₂ O (2 mL) was degassed and purged with N ₂ for 3 times, and then the mixture was stirred at 100 °C for 16 hr under N ₂ atmosphere. LCMS showed 38.6% desired MS. TLC (petroleum ether: ethyl acetate=5:1, R _f =0.5 UV) showed one main new spot was observed. The reaction was quenched with water (50 mL) and extracted with ethyl acetate (150 mL*2). The organic layer was washed with brine (20 mL) and dried over Na ₂ SO ₄ and concentrated in vacuo to give a black soild. The EtOAc). The desired fractions were collected, and concentrated to dryness in vacuo to give 3-(6- (benzyloxy)-1-(4-(4-(dimethoxymethyl)piperidin-1-yl)phenyl)- 3,4-dihydronaphthalen-2- yl)phenol (300 mg, 509 ^mol, 69.8 %, 95.323% Purity) as a yellow solid. LC-MS (ESI ⁺ ) m/z: 562.4 (M+H) ⁺ . Step 2: To a solution of 3-(6-(benzyloxy)-1-(4-(4-(dimethoxymethyl)piperidin-1-yl)phe nyl)-3,4- dihydronaphthalen-2-yl)phenol (300 mg, 1 Eq, 534 ^mol) in MeOH (6 mL) was added Pd/C (300 mg, 10% Wt, 0.528 Eq, 282 ^mol) under N ₂ atmosphere. The suspension was degassed and purged with dihydrogen (1.08 mg, 1 Eq, 534 ^mol) for 10mins. The mixture was stirred under 15 Psi dihydrogen (1.08 mg, 1 Eq, 534 ^mol) at 50 °C for 16 hr .LCMS showed 90% desired MS. The reaction was filtrate and concentrated. The residue was further separated by HPLC (condition: column: DAICEL CHIRALPAK IG (250mm*30mm,10um);mobile phase:0.1%NH ₃ HO ₂ ETOH;B%: 40%-40%,min) to give desired 5-(4-(4- (dimethoxymethyl)piperidin-1-yl)phenyl)-6-(3-hydroxyphenyl)- 5,6,7,8-tetrahydronaphthalen-2- ol (220 mg, 465 ^mol, 87.0 %) as a yellow solid. LC-MS (ESI ⁺ ) m/z: 474.3 (M+H) ⁺ . Step 3: 220 mg of 5-(4-(4-(dimethoxymethyl)piperidin-1-yl)phenyl)-6-(3-hydroxy phenyl)- 5,6,7,8-tetrahydronaphthalen-2-ol was further separated by SFC (condition: column: DAICEL CHIRALPAK IG (250mm*30mm,10um) ;mobile phase: 0.1%NH ₃ .H ₂ O ETOH ;B%: 40%- 40%,80 ml/min) to give desired (5R,6S)-5-(4-(4-(dimethoxymethyl)piperidin-1-yl)phenyl)-6-(3 - hydroxyphenyl)-5,6,7,8-tetrahydronaphthalen-2-ol (70 mg, 0.15 mmol) as a yellow solid. LC- MS (ESI ⁺ ) m/z: 474.3 (M+H) ⁺ and (5S,6R)-5-(4-(4-(dimethoxymethyl)piperidin-1-yl)phenyl)-6- (3-hydroxyphenyl)-5,6,7,8-tetrahydronaphthalen-2-ol (90 mg, 0.19 mmol) as a yellow solid. LC- MS (ESI ⁺ ) m/z: 474.3 (M+H) ⁺ . Step 4: To a solution of ((5R,6S)-5-(4-(4-(dimethoxymethyl)piperidin-1-yl)phenyl)-6-( 3- hydroxyphenyl)-5,6,7,8-tetrahydronaphthalen-2-ol (70 mg, 1 Eq, 0.15 mmol)) in THF (3 mL) was added sulfuric acid (0.14 g, 3 mL, 10% Wt, 1 Eq, 0.15 mmol).The mixture was stirred at 70 °C for 6 hr . LCMS showed 91.9% desired MS. The reaction was adjust to pH~=7 with NaHCO ₃ , then 50 mL water was added, and the mixture was extracted with DCM (100 mL x 2). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to dryness in vacuo to give a yellow oil. The yellow oil was concentrated in vacuo to give 1-(4-((1R, 2S)-6-hydroxy-2-(3-hydroxyphenyl)-1,2,3,4- tetrahydronaphthalen-1-yl)phenyl)piperidine-4-carbaldehyde (65 mg, 0.15 mmol, 100 %) as a yellow solid. LC-MS (ESI ⁺ ) m/z: 405.2 (M+H) ⁺ Step 5: To a solution of 1-[4-[(1R,2S)-6-hydroxy-2-(3-hydroxyphenyl)tetralin-1- yl]phenyl]piperidine-4-carbaldehyde (70 mg, 163.73 umol, 1 eq) and (3S)-3-(1-oxo-5-piperazin- 1-yl-isoindolin-2-yl)piperidine-2,6-dione (81.96 mg, 163.73 umol, 1 eq, p-TSA) in DCM (4 mL) and MeOH (4 mL) was added sodium; acetate (40.29 mg, 491.19 umol, 3 eq) .The mixture was stirred at 25 °C for 1 hr .Then the mixture was added sodium triacetoxyboranuide (69.40 mg, 327.46 umol, 2 eq) and acetic aci d (29.50 mg, 491.19 umol, 28.09 uL, 3 eq) The mixture was stirred at 25 °C overnight. LCMS showed desired MS was detected. The reaction mixture was diluted with 20 mL H ₂ O and extracted with DCM (50 mL * 2). The combined organic layers were washed with brine 40 mL (20 mL * 2), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep.HPLC (column: 2_Phenomenex Gemini C1875*40mm*3um; mobile phase: [water(FA)-ACN];B%: 15%- 45%,7min). Compound (3S)-3-[5-[4-[[1-[4-[(1R,2S)-6-hydroxy-2-(3-hydroxyphenyl)te tralin-1- yl]phenyl]-4-piperidyl]methyl]piperazin-1-yl]-1-oxo-isoindol in-2-yl]piperidine-2,6-dione (70 mg, 94.61 umol, 57.78% yield) was obtained as a white solid. LC-MS (ESI+) m/z: 740.4 (M+H) ⁺ . HPLC: 98.082%, purity at 220 nm. SFC: Rt: 2.639 min; Area, 71.130%; method: ID_MeOH_DEA_MeCN_50_1ML_10MIN_10CM. NMR (400 MHz, DMSO-d ₆ ) į ppm 10.92 - 10.97 (m, 1 H) 8.99 - 9.15 (m, 1 H) 8.19 - 8.25 (m, 0.366 H) 7.45 - 7.56 (m, 1 H) 7.02 - 7.10 (m, 2 H) 6.91 (s, 1 H) 6.62 - 6.68 (m, 1 H) 6.45 - 6.60 (m, 5 H) 6.31 - 6.36 (m, 1 H) 6.20 - 6.28 (m, 3 H) 5.01 - 5.09 (m, 1 H) 4.30 - 4.38 (m, 1 H) 4.16 - 4.26 (m, 1 H) 4.07 - 4.14 (m, 1 H) 3.49 - 3.58 (m, 2 H) 3.29 (br d, J=3.46 Hz, 6 H) 3.21 (br s, 2 H) 2.83 - 3.02 (m, 3 H) 2.65 - 2.71 (m, 1 H) 2.55 - 2.63 (m, 2 H) 2.30 - 2.39 (m, 2 H) 2.15 - 2.23 (m, 2 H) 1.91 - 2.10 (m, 2 H) 1.59 - 1.83 (m, 4 H) 1.10 - 1.27 (m, 2 H). EXAMPLE 211. Preparation of (I-121) (S)-3-(5-(4-((1-(4-((1R,2R)-2- (cyclopentylmethyl)-6-hydroxy-1,2,3,4-tetrahydronaphthalen-1 -yl)phenyl)piperidin-4- yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2, 6-dione Step 1: To a solution of (5R,6R)-6-(cyclopentylmethyl)-5-(4-(4-(dimethoxymethyl)piper idin-1- yl)phenyl)-5,6,7,8-tetrahydronaphthalen-2-ol (65 mg, 0.14 mmol) in THF (1 mL) and 10% H ₂ SO ₄ (1 mL) was stirred at 70 °C for 1 h. The reaction mixture was quenched by addition 10 mL NaHCO3 at 0°C, then extracted with ethyl acetate (20 mL x 2). The combined organic layers were washed with 20 mL brine dried over Na2SO4, filtered and concentrated under reduced pressure to give 1-(4-((1R,2R)-2-(cyclopentylmethyl)-6-hydroxy-1,2,3,4-tetrah ydronaphthalen- 1-yl)phenyl)piperidine-4-carbaldehyde (60 mg, 100 % Yield) as a yellow solid. LC-MS (ESI+) m/z: 436.2 (M+18) ⁺ . Step 2: A mixture of 1-(4-((1R,2R)-2-(cyclopentylmethyl)-6-hydroxy-1,2,3,4- tetrahydronaphthalen-1-yl)phenyl)piperidine-4-carbaldehyde (60 mg, 0.14 mmol) , (S)-3-(1-oxo- 5-(piperazin-1-yl)isoindolin-2-yl)piperidine-2,6-dione benzenesulfonate (0.10 g, 0.22 mmol) and Sodium acetate (59 mg, 0.72 mmol) and Acetic acid (17 mg, 0.29 mmol) in THF (2 mL) and MeOH (2 mL) at 25 °C for 1 h, then Sodium triacetoxyborohydride (61 mg, 0.29 mmol) was added to the mixture and was stirred at 25 °C for 16 h. The mixture was added H ₂ O (20 mL), extracted with ethyl acetate (20 mL x 2). The combined extracts was dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to dryness in vacuo to give a residue. The residue was purified by prep-HPLC (column: O-Welch C18150*30mm* 5um; mobile phase: [water(FA)-ACN];B% 20%-60%,10min) to give (S)-3-(5-(4-((1-(4-((1R,2R)-2- (cyclopentylmethyl)-6-hydroxy-1,2,3,4-tetrahydronaphthalen-1 -yl)phenyl)piperidin-4- yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2, 6-dione (46.2 mg, 44 % Yield) as a white solid. LC-MS (ESI+) m/z: 730.3 (M+H) +. LCMS: calc. for C45H55N5O4: 729.97, found: [M+H] ⁺ 730.3. HPLC: 100% purity at 220 nm. ¹ HNMR (400MHz, DMSO-d ₆ ) į = 10.95 (s, 1H), 9.02 (br s, 1H), 8.14 (s, 1H), 7.53 (d, J=8.6 Hz, 1H), 7.10 - 7.03 (m, 2H), 6.77 (s, 4H), 6.61 (d, J=8.3 Hz, 1H), 6.52 (d, J=2.3 Hz, 1H), 6.43 (dd, J=2.4, 8.3 Hz, 1H), 5.05 (dd, J=5.0, 13.4 Hz, 1H), 4.33 (d, J=17.2 Hz, 1H), 4.26 - 4.17 (m, 1H), 3.89 (d, J=4.8 Hz, 1H), 3.60 (br s, 2H), 3.30 (br d, J=3.7 Hz, 6H), 2.96 - 2.71 (m, 4H), 2.60 (br d, J=11.1 Hz, 5H), 2.44 - 2.35 (m, 1H), 2.24 (br d, J=6.6 Hz, 2H), 2.00 - 1.91 (m, 2H), 1.80 (br d, J=11.8 Hz, 3H), 1.70 (br d, J=5.6 Hz, 3H), 1.61 - 1.44 (m, 5H), 1.27 - 1.14 (m, 3H), 0.99 (br s, 2H), 0.86 - 0.75 (m, 1H) SFC: retention time, 2.873 min; Area, 77.429%;

EXAMPLE 212. Preparation of (I-120) (S)-3-(5-(4-((1-(4-((1S,2S)-2- (cyclopentylmethyl)-6-hydroxy-1,2,3,4-tetrahydronaphthalen-1 -yl)phenyl)piperidin-4- yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2, 6-dione Step 1: A mixture of 2,2,6,6 TetraMethyl Piperidine (1.27 g, 1.52 mL, 8.96 mmol) was dissolved in THF (20 mL) and cooled to -30 °C under N ₂ atmosphere. n-butyllithium (574 mg, 3.58 mL, 8.96 mmol) was added dropwise, and the reaction mixture was stirred at the same temperature for 30 min. Next, the reaction was cooled to -78 °C, and a solution of bis (4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)methane (2 g, 7.46 mmol) in THF (20 mL) was added dropwise. After stirring for 30 min, a solution of cyclopentanone (753 mg, 8.96 mmol) in THF (13 mL) was added dropwise at -78 °C. The reaction mixture was allowed to slowly warm up to 25 °C, and stirred 12 h. The reaction was quenched by Saturate the ammonium chloride solution (30 mL), then stirred for 0.5 h. water (100 mL) was added before the mixture extracted with ethyl acetate (100 mL x 3). The organic layers was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to get a yellow oil for next step without purification. Step 2: [1,1'-Bis(diphenylphosphino)ferrocene]dichloropalladium(II)C omplex (52.1 mg, 63.8 ^mol) was added to the mixture of 1-(4-(6-(benzyloxy)-2-bromo-3,4-dihydronaphthalen-1- yl)phenyl)-4-(dimethoxymethyl)piperidine (350 mg, 638 ^mol), 2-(cyclopentylidenemethyl)- 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (700 mg, 3.36 mmol) and Potassium carbonate (265 mg, 112 ^L, 1.91 mmol) in Dioxane (10 mL) and H ₂ O (2 mL) at r.t.. N ₂ was bubbled into the mixture for 5 min. The reaction mixture was heated at 100 °C for 16 h. The mixture was added H ₂ O (100 mL), extracted with ethyl acetate (100 mL x 2). The combined extracts was dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to dryness in vacuo to give a residue. The residue was subjected to column chromatography over silica gel (petroleum ether/ethyl acetate from 100/0 to 80/20). The pure fractions were collected and concentrated to dryness in vacuo to give 1-(4-(6- (benzyloxy)-2-(cyclopentylidenemethyl)-3,4-dihydronaphthalen -1-yl)phenyl)-4- (dimethoxymethyl)piperidine (350 mg, 94.4 % Yield) as a yellow solid. LC-MS (ESI ⁺ ) m/z: 550.3 (M+H) ⁺ . Step 3: A mixture of 1-(4-(6-(benzyloxy)-2-(cyclopentylidenemethyl)-3,4-dihydrona phthalen-1- yl)phenyl)-4-(dimethoxymethyl)piperidine (330 mg, 568 ^mol), dihydrogen (1.15 mg, 568 ^mol), Pd/C(330 mg, 10% Wt, 310 ^mol) in MeOH (5 mL) was degassed and purged with H ₂ for 3 times, and then the mixture was stirred at 50 °C for 16 h under H ₂ atmosphere(15 psi). The mixture was concentrated to dryness in vacuo to give a residue. The residue was subjected to column chromatography over silica gel (petroleum ether/ethyl acetate from 100/0 to 80/20). The pure fractions were collected and concentrated to dryness in vacuo to give a white solid.The white solid was purified by SFC (column: DAICEL CHIRALCEL OJ(250mm*30mm,10um); mobile phase: [0.1%NH3H2O(ETOH)];B% 30%-30%) to give The aqueous phase was lyophilized to dryness to give 1-(4-((1R,2R)-6-(benzyloxy)-2-(cyclopentylmethyl)-1,2,3,4- tetrahydronaphthalen-1-yl)phenyl)-4-(dimethoxymethyl)piperid ine (65 mg, 21 % Yield) and 1- (4-((1S,2S)-6-(benzyloxy)-2-(cyclopentylmethyl)-1,2,3,4-tetr ahydronaphthalen-1-yl)phenyl)-4- (dimethoxymethyl)piperidine (65 mg, 21 % Yield) as white solids. LC-MS (ESI ⁺ ) m/z: 464.2 (M+H) ⁺ . Step 4: To a solution of (5S,6S)-6-(cyclopentylmethyl)-5-(4-(4-(dimethoxymethyl)piper idin-1- H2SO4 (1 mL) was stirred at 70 °C for 1 h. The reaction was adjust to pH~=8 with aq.NaHCO3 (5 mL). Then the mixture was added water (15 mL) and extracted with ethyl acetate (20×2 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to dryness in vacuo to give 1-(4-((1S,2S)-2-(cyclopentylmethyl)-6- hydroxy-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperidine- 4-carbaldehyde (60 mg, 100 % Yield) as a yellow solid. LC-MS (ESI ⁺ ) m/z: 418.1 (M+H) ⁺ . Step 5: A mixture of 1-(4-((1S,2S)-2-(cyclopentylmethyl)-6-hydroxy-1,2,3,4- tetrahydronaphthalen-1-yl)phenyl)piperidine-4-carbaldehyde (60 mg, 0.14 mmol), (S)-3-(1-oxo- 5-(piperazin-1-yl)isoindolin-2-yl)piperidine-2,6-dione benzenesulfonate (0.10 g, 0.21 mmol) and Sodium acetate (57 mg, 0.70 mmol) and Acetic acid (17 mg, 0.28 mmol) in THF (2 mL) and MeOH (2 mL) at 25 °C for 1 h, then Sodium triacetoxyborohydride (59 mg, 0.28 mmol) was added to the mixture and was stirred at 25 °C for 16 h. The mixture was added H ₂ O (10 mL), extracted with ethyl acetate (10 mL x 2). The combined extracts was dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to dryness in vacuo to give a residue. The residue was purified by prep-HPLC (column: O-Welch C18150*30mm* 5um; mobile phase: [water(FA)-ACN];B% 20%-60%,8min) to give (S)-3-(5-(4-((1-(4-((1S,2S)-2-(cyclopentylmethyl)-6-hydroxy- 1,2,3,4- tetrahydronaphthalen-1-yl)phenyl)piperidin-4-yl)methyl)piper azin-1-yl)-1-oxoisoindolin-2- yl)piperidine-2,6-dione (48.4 mg, 47 % Yield) as a white solid. LC-MS (ESI+) m/z: 730.2 (M+H) ⁺ . LCMS: calc. for C ₄₅ H ₅₅ N ₅ O ₄ : 729.97, found: [M+H] + 730.2. HPLC: 100% purity at 220 nm. ¹ HNMR (400MHz, DMSO-d ₆ ) į = 10.95 (s, 1H), 9.02 (s, 1H), 8.14 (s, 1H), 7.53 (d, J=8.6 Hz, 1H), 7.10 - 7.04 (m, 2H), 6.77 (s, 4H), 6.61 (d, J=8.3 Hz, 1H), 6.52 (d, J=2.0 Hz, 1H), 6.43 (dd, J=2.4, 8.2 Hz, 1H), 5.05 (dd, J=4.9, 13.3 Hz, 1H), 4.34 (d, J=17.0 Hz, 1H), 4.25 - 4.17 (m, 1H), 3.89 (d, J=4.8 Hz, 1H), 3.61 (br d, J=5.1 Hz, 2H), 3.32 - 3.27 (m, 6H), 2.98 - 2.69 (m, 3H), 2.63 - 2.54 (m, 6H), 2.43 - 2.35 (m, 1H), 2.25 (br s, 2H), 2.01 - 1.91 (m, 2H), 1.80 (br d, J=12.5 Hz, 3H), 1.70 (br d, J=5.0 Hz, 3H), 1.56 (br s, 3H), 1.48 (br dd, J=4.4, 7.3 Hz, 2H), 1.25 - 1.15 (m, 3H), 0.99 (br s, 2H), 0.85 - 0.77 (m, 1H) SFC: retention time, 2.612 min; Area, 79.202 %; EXAMPLE 213. Preparation of (I-129) (R)-3-(5-(4-((1-(4- ((1S,2S)-6-hydroxy-2- isopropyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperidin -4-yl)methyl)piperazin-1-yl)- 1-oxoisoindolin-2-yl)piperidine-2,6-dione Step 1: The 5-(4-(4-(dimethoxymethyl)piperidin-1-yl)phenyl)-6-isopropyl- 5,6,7,8- tetrahydronaphthalen-2-ol (400 mg, 1 eq., 944 ^mol) was purified by SFC(Column: DAICEL CHIRALCEL OD-H(250mm*30mm,10um); Mobile phase: 0.1%NH3H2O ETOH; from 35% to 35%; Flow rate: 70 mL/min) to give (5S,6S)-5-(4-(4-(dimethoxymethyl)piperidin-1-yl)phenyl)- 6- isopropyl-5,6,7,8-tetrahydronaphthalen-2-ol (130 mg, 307 ^mol, 32.5 %) as white solid. LC-MS (ESI ⁺ ) m/z: 424.4 (M+H) ⁺ . Step 2: To a solution of (5S,6S)-5-(4-(4-(dimethoxymethyl)piperidin-1-yl)phenyl)-6-is opropyl- 5,6,7,8-tetrahydronaphthalen-2-ol (130 mg, 1 eq., 307 ^mol) in DCM (4 mL) was added TFA (105 mg, 70.9 ^L, 3 eq., 921 ^mol). The mixture was strried at 20 °C for 4 hour. The mixture was concentrated in vacuo to give crude product. No further purification as it is used for the next step directly. LC-MS (ESI+) m/z: 378.2(M+H)+ Step 3: To a solution of 1-(4-((1S,2S)-6-hydroxy-2-isopropyl-1,2,3,4-tetrahydronaphth alen-1- yl)phenyl)piperidine-4-carbaldehyde (100 mg, 1 eq., 265 ^mol) and (R)-3-(1-oxo-5- (piperazin- 1-yl)isoindolin-2-yl)piperidine-2,6-dione (113 mg, 1.3 eq., 344 ^mol) in DCE (10 mL) was added dropwise 4-methylmorpholine (26.8 mg, 1 eq., 265 ^mol) to pH=8 at 20 °C. After addition, the mixture was stirred at this temperature for 30 min, and then sodium triacetoxyhydroborate (140 mg, 2.5 eq., 662 ^mol) was added dropwise at 20 °C. The resulting mixture was stirred at 20 °C for 3 hour. The crude was purified by prep.HPLC together (Boston Green ODS 150*30mm*5um, water(FA)-ACN as a mobile phase, from 20% to 30%, Gradient Time (min): 12, Flow Rate (ml/min): 25) to give (R)-3-(5-(4-((1-(4- ((1S,2S)-6-hydroxy-2- isopropyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperidin -4-yl)methyl)piperazin-1-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione (9.3 mg, 13 ^mol, 5.1 %) as a white solid. LC-MS (ESI+) m/z: 690.3(M+H)+ ¹ H NMR (500 MHz, METHANOL-d4) į: ppm 8.26 - 8.41 (m, 1 H), 7.65 (d, J=8.54 Hz, 1 H), 7.09 - 7.13 (m, 2 H), 6.91 - 6.94 (m, 2 H), 6.85 - 6.89 (m, 2 H), 6.66 (d, J=8.39 Hz, 1 H), 6.56 (d, J=2.29 Hz, 1 H), 6.45 (dd, J=8.32, 2.67 Hz, 1 H), 5.10 (br d, J=8.24 Hz, 1 H), 4.32 - 4.46 (m, 2 H), 4.12 (d, J=3.97 Hz, 1 H), 3.62 (br d, J=11.90 Hz, 2 H), 3.44 (br s, 4 H), 2.88 - 2.96 (m, 2 H), 2.83 (br s, 4 H), 2.74 - 2.78 (m, 1 H), 2.67 (br t, J=11.98 Hz, 2 H), 2.49 - 2.55 (m, 2 H), 2.46 (dd, J=13.28, 4.58 Hz, 1 H), 2.12 - 2.18 (m, 1 H), 1.91 (br d, J=12.36 Hz, 2 H), 1.79 (br d, J=12.21 Hz, 2 H), 1.57 - 1.65 (m, 2 H), 1.32 - 1.41 (m, 3 H), 1.08 (d, J=6.56 Hz, 3 H), 0.64 (d, J=6.71 Hz, 3 H). EXAMPLE 214. Preparation of (I-128) (R)-3-(5-(4-((1-(4-((1R,2R)-6-hydroxy-2- isopropyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperidin -4-yl)methyl)piperazin-1-yl)- 1-oxoisoindolin-2-yl)piperidine-2,6-dione Step 1: A mixture of Isopropenylboronicacidpinacolester (0.4 g, 0.4 mL, 1.3 eq., 2 mmol) ^1-(4- (6-(benzyloxy)-2-bromo-3,4-dihydronaphthalen-1-yl)phenyl)-4- (dimethoxymethyl)piperidine (1 g, 1 eq., 2 mmol) ^ Na ₂ CO ₃ (0.6 g, 3 eq., 5 mmol) and dppf (0.1 g, 0.1 eq., 0.2 mmol) in Dioxane (15 mL) and water (3 mL) was degassed and purged with N ₂ for 3 times, and then the mixture was stirred at 80 °C for 8 hour under N ₂ atmosphere. The reaction mixture was quenched by addition EA 10 mL at 20 °C, and then diluted with water 30 mL and extracted with EA 30 mL (10 mL * 3). The combined organic layers were washed with EA 30 mL (10 mL * 3), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The crude material was purified on silica gel column chromatography (from PE/EtOAc = 1/0 to 3/2) to give 1-(4-(6-(benzyloxy)-2-(prop-1-en-2- yl)-3,4-dihydronaphthalen-1-yl)phenyl)-4- (dimethoxymethyl)piperidine (0.6 g, 1 mmol, 60 %) as yellow oil. LC-MS (ESI ⁺ ) m/z: 510.3 (M+H) ⁺ . ¹ H NMR (400 MHz, DMSO-d6) į: ppm 7.28 - 7.47 (m, 5 H), 6.84 - 7.00 (m, 5 H), 6.82 - 6.84 (m, 1 H), 6.68 (dd, J=8.52, 2.56 Hz, 1 H), 6.39 - 6.53 (m, 1 H), 5.06 (s, 2 H), 4.59 - 4.78 (m, 2 H), 4.10 (d, J=6.44 Hz, 1 H), 3.71 (br d, J=12.04 Hz, 2 H), 3.28 (s, 6 H), 2.71 - 2.82 (m, 2 H), 2.60 (br t, J=11.50 Hz, 2 H), 2.31 - 2.48 (m, 2 H), 1.70 - 1.77 (m, 3 H), 1.56 (s, 2 H), 1.37 - 1.41 (m, 1 H), 1.15 - 1.23 (m, 2 H). Step 2: To a solution of 1-(4-(6-(benzyloxy)-2-(prop-1-en-2-yl)-3,4-dihydronaphthalen -1- yl)phenyl)- 4-(dimethoxymethyl)piperidine (600 mg, 1 eq., 1.18 mmol) in MeOH (10 mL) was added Pd/C (10%, 0.5 g) under N ₂ atmosphere. The suspension was degassed and purged with H ₂ for 3 times. The mixture was stirred under H ₂ (1 atm.) at 20 °C for 12 hour. The mixture was filtered and the filtrate was concentrated. The crude material was purified on silica gel column chromatography ^from pure PE to PE/EtOAc = 5/1) to give 5-(4-(4- (dimethoxymethyl)piperidin-1-yl)phenyl)-6-isopropyl-5,6,7,8- tetrahydronaphthalen-2-ol (400 mg, 944 ^mol, 80.2 %) as a yellow solid. LC-MS (ESI ⁺ ) m/z: 424.3 (M+H) ⁺ . Step 3: The 5-(4-(4-(dimethoxymethyl)piperidin-1-yl)phenyl)-6-isopropyl- 5,6,7,8- tetrahydronaphthalen-2-ol (400 mg, 1 eq., 944 ^mol) was purified by SFC(Column: DAICEL CHIRALCEL OD H(250 *30 10 ) M bil h 01%NH3H2O ETOH f 35% t 35%; Flow rate: 70 mL/min) to give (5R,6R)-5-(4-(4-(dimethoxymethyl)piperidin-1-yl)phenyl)- 6- isopropyl-5,6,7,8-tetrahydronaphthalen-2-ol (130 mg, 307 ^mol, 32.5 %) as white solid. LC-MS (ESI ⁺ ) m/z: 424.3 (M+H) ⁺ . Step 4: To a solution of (5R,6R)-5-(4-(4-(dimethoxymethyl)piperidin-1-yl)phenyl)-6-is opropyl- 5,6,7,8-tetrahydronaphthalen-2-ol (140 mg, 1 eq., 331 ^mol) in DCM (4 mL) was added TFA (113 mg, 76.4 ^L, 3 eq., 992 ^mol).The mixture was strried at 20 °C for 4 hour. The mixture was concentrated in vacuo to give crude product. No further purification as it is used for the next step directly. LC-MS (ESI+) m/z: 378.2(M+H)+ Step 5: To a solution of 1-(4-((1R,2R)-6-hydroxy-2-isopropyl-1,2,3,4-tetrahydronaphth alen-1- yl)phenyl)piperidine-4-carbaldehyde (100 mg, 1 eq., 265 ^mol) and (R)-3-(1-oxo-5- (piperazin- 1-yl)isoindolin-2-yl)piperidine-2,6-dione (113 mg, 1.3 eq., 344 ^mol) in DCE (5 mL) was added dropwise 4-methylmorpholine (26.8 mg, 1 eq., 265 ^mol) to pH=8 at 20 °C. After addition, the mixture was stirred at this temperature for 0.5 hour, and then sodium triacetoxyhydroborate (140 mg, 2.5 eq., 662 ^mol) was added dropwise at 20 °C. The resulting mixture was stirred at 20 °C for 2 hour. The crude was purified by prep.HPLC together (Welch Xtimate C18 150*25mm*5um, water(NH ₃ H ₂ O+NH ₄ HCO ₃ )-ACN as a mobile phase, from 35% to 65%, Gradient Time (min): 11, Flow Rate (ml/min): 25) to give (R)-3-(5-(4-((1-(4-((1R,2R)-6- hydroxy-2-isopropyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl )piperidin-4-yl)methyl)piperazin- 1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (70.5 mg, 102 ^mol, 38.6 %) as a white soild. LC-MS (ESI+) m/z: 690.3(M+H),+ ¹ H NMR (500 MHz, METHANOL-d4) į: ppm: 8.34 (s, 1 H), 7.67 (d, J=8.54 Hz, 1 H), 7.09 - 7.15 (m, 2 H), 6.92 - 6.96 (m, 2 H), 6.86 - 6.91 (m, 2 H), 6.68 (d, J=8.39 Hz, 1 H), 6.58 (d, J=2.29 Hz, 1 H), 6.47 (dd, J=8.32, 2.52 Hz, 1 H), 5.12 (dd, J=13.35, 5.11 Hz, 1 H), 4.34 - 4.50 (m, 2 H), 4.14 (d, J=3.81 Hz, 1 H), 3.63 (br d, J=11.44 Hz, 2 H), 3.46 (br s, 4 H), 2.89 - 2.98 (m, 2 H), 2.83 - 2.88 (m, 4 H), 2.76 - 2.81 (m, 1 H), 2.69 (br t, J=12.13 Hz, 2 H), 2.52 - 2.59 (m, 2 H), 2.48 (dd, J=13.20, 4.65 Hz, 1 H), 2.12 - 2.21 (m, 1 H), 1.92 (br d, J=12.97 Hz, 2 H), 1.75 - 1.86 (m, 2 H), 1.57 - 1.68 (m, 2 H), 1.36 - 1.46 (m, 3 H), 1.09 (d, J=6.56 Hz, 3 H), 0.66 (d, EXAMPLE 215. Preparation of (I-112) (S)-3-(5-(4-((1-(4-((1S,2R)-2-ethyl-6-hydroxy- 1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperidin-4-yl)meth yl)piperazin-1-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione Step 1: To a solution of (5S,6R)-5-(4-(4-(dimethoxymethyl)piperidin-1-yl)phenyl)-6-et hyl- 5,6,7,8-tetrahydronaphthalen-2-ol (40 mg, 95 ^mol) in THF (1 mL) and 10% H ₂ SO ₄ (1 mL) was stirred at 70 °C for 1 h. The reaction mixture was quenched by addition 20 mL NaHCO3 at 0°C, then extracted with ethyl acetate (20 mL x 2). The combined organic layers were washed with 20 mL brine dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give 1-(4- ((1R,2S)-2-ethyl-6-hydroxy-1,2,3,4-tetrahydronaphthalen-1-yl )phenyl)piperidine-4-carbaldehyde (35 mg, 98 % Yield) as a yellow solid. LC-MS (ESI+) m/z: 364.3 (M+H) ⁺ . Step 2: A mixture of 1-(4-((1S,2R)-2-ethyl-6-hydroxy-1,2,3,4-tetrahydronaphthalen -1- yl)phenyl)piperidine-4-carbaldehyde (35 mg, 93 ^mol) , (S)-3-(1-oxo-5-(piperazin-1- yl)isoindolin-2-yl)piperidine-2,6-dione benzenesulfonate (68 mg, 0.14 mmol) and Sodium acetate (38 mg, 0.46 mmol) and Acetic acid (11 mg, 0.19 mmol) in THF (1 mL) and MeOH (1 mL) at 25 °C for 1 h, then Sodium triacetoxyborohydride (39 mg, 0.19 mmol) was added to the mixture and was stirred at 25 °C for 16 h. The mixture was added H ₂ O (20 mL), extracted with ethyl acetate (20 mL x 2). The combined extracts was dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to dryness in vacuo to give a residue. The residue was purified by prep-HPLC (column: O-Welch C18150*30mm* 5um; mobile phase: [water(FA)-ACN];B% 10%- 50%,8min) to give (S)-3-(5-(4-((1-(4-((1S,2R)-2-ethyl-6-hydroxy-1,2,3,4-tetrah ydronaphthalen- 1-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoin dolin-2-yl)piperidine-2,6-dione (31.3 mg, 50 % Yield) as a white solid.LC-MS (ESI+) m/z: 676.2 (M+H) +. LCMS: calc. for C ₄₁ H ₄₉ N ₅ O ₄ : 675.87, found: [M+H] ⁺ 676.2. ¹ HNMR (400MHz, DMSO-d6) į = 10.96 (s, 1H), 9.03 (br s, 1H), 8.15 (s, 1H), 7.52 (d, J=8.3 Hz, 1H), 7.11 - 7.02 (m, 2H), 6.77 (s, 4H), 6.62 (d, J=8.5 Hz, 1H), 6.51 (s, 1H), 6.43 (dd, J=2.2, 8.3 Hz, 1H), 5.05 (dd, J=5.0, 13.4 Hz, 1H), 4.38 - 4.29 (m, 1H), 4.25 - 4.17 (m, 1H), 3.93 (br d, J=4.9 Hz, 1H), 3.59 (br d, J=11.6 Hz, 2H), 3.29 (br s, 5H), 2.96 - 2.72 (m, 4H), 2.59 (br d, J=10.4 Hz, 4H), 2.44 - 2.34 (m, 2H), 2.22 (br d, J=6.8 Hz, 2H), 2.00 - 1.93 (m, 1H), 1.80 (br d, J=11.4 Hz, 2H), 1.73 - 1.56 (m, 3H), 1.54 - 1.43 (m, 1H), 1.26 - 1.14 (m, 3H), 0.91 (t, J=7.2 Hz, 3H), 0.77 (td, J=7.3, 14.3 Hz, 1H) SFC: retention time, 2.691 min; Area, 93.989%; Stereochemistry was arbitrarily assigned. EXAMPLE 216. Preparation of (I-111) (S)-3-(5-(4-((1-(4-((1R,2S)-2-ethyl-6-hydroxy- 1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperidin-4-yl)meth yl)piperazin-1-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione Step 1: To a mixture of [1,1'-Bis(diphenylphosphino)ferrocene]dichloropalladium(II)C omplex (74.44 mg, 91.15 ^mol) was added to the mixture of 1-(4-(6-(benzyloxy)-2-bromo-3,4- dihydronaphthalen-1-yl)phenyl)-4-(dimethoxymethyl)piperidine (500 mg, 911.5 ^mol), Vinylboronic Acid Pinacol Ester (168.5 mg, 186 ^L, 1.094 mmol) and K ₂ CO ₃ (377.9 mg, 2.735 mmol) in Dioxane (8 mL) and H ₂ O (2 mL) at r.t.. N ₂ was bubbled into the mixture for 5 min. H2O and extracted with ethyl acetate (100 mL x 2). The combined organic layers was dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ethyl acetate in petroleum ether = 0% to 30%) to give the product of 1-(4-(6-(benzyloxy)-2-vinyl-3,4-dihydronaphthalen-1-yl)pheny l)-4- (dimethoxymethyl)piperidine (230 mg, 36.3 % Yield) as a yellow solid. LC-MS (ESI ⁺ ) m/z: 496.1 (M+H) ⁺ . Step 2: A mixture of 1-(4-(6-(benzyloxy)-2-vinyl-3,4-dihydronaphthalen-1-yl)pheny l)-4- (dimethoxymethyl)piperidine (230 mg, 331 ^mol) , dihydrogen (669 ^g, 331 ^mol), Pd/C (230 mg, 10% Wt, 216 ^mol) in MeOH (5 mL) was degassed and purged with H ₂ for 3 times, and then the mixture was stirred at 25 °C for 16 h under H ₂ atmosphere (15 psi). The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was further separated by SFC (condition: column: DAICEL CHIRALPAK IG (250mm*30mm,10um); mobile phase: [0.1%NH3H2O-MEOH];B%: 60%-60%, min ) to give (5R,6S)-5-(4-(4-(dimethoxymethyl)piperidin-1-yl)phenyl)-6-et hyl-5,6,7,8-tetrahydronaphthalen- 2-ol (40 mg, 27 % Yield) was obtained as a white solid. LC-MS (ESI+) m/z: 410.1 (M+H) ⁺ and (5S,6R)-5-(4-(4-(dimethoxymethyl)piperidin-1-yl)phenyl)-6-et hyl-5,6,7,8-tetrahydronaphthalen- 2-ol (40 mg, 29 % Yield) was obtained as a white solid. LC-MS (ESI ⁺ ) m/z: 410.2 (M+H) ⁺ . Step 3: To a solution of (5R,6S)-5-(4-(4-(dimethoxymethyl)piperidin-1-yl)phenyl)-6-et hyl- 5,6,7,8-tetrahydronaphthalen-2-ol (40 mg, 89 ^mol) in THF (1 mL) and 10% H ₂ SO ₄ (1 mL) was stirred at 70 °C for 1 h. The reaction mixture was quenched by addition 20 mL NaHCO ₃ at 0°C, then extracted with ethyl acetate (20 mL x 2). The combined organic layers were washed with 20 mL brine dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give 1-(4- ((1R,2S)-2-ethyl-6-hydroxy-1,2,3,4-tetrahydronaphthalen-1-yl )phenyl)piperidine-4-carbaldehyde (35 mg, 100 % Yield) as a yellow solid. LC-MS (ESI ⁺ ) m/z: 364.3 (M+H) ⁺ . Step 4: A mixture of 1-(4-((1R,2S)-2-ethyl-6-hydroxy-1,2,3,4-tetrahydronaphthalen -1- yl)phenyl)piperidine-4-carbaldehyde (35 mg, 89 ^mol) , (S)-3-(1-oxo-5-(piperazin-1- yl)isoindolin-2-yl)piperidine-2,6-dione benzenesulfonate (65 mg, 0.13 mmol) and Sodium acetate (37 mg, 0.45 mmol) and Acetic acid (11 mg, 10 ^L, 0.18 mmol) in THF (1 mL) and MeOH (1 mL) at 25 °C for 1 h, then Sodium triacetoxyborohydride (38 mg, 0.18 mmol) was added to the mixture and was stirred at 25 °C for 16 h. The mixture was added H2O (20 mL), Na2SO4, filtered and concentrated to dryness in vacuo to give a residue. The residue was purified by prep-HPLC (column: O-Welch Xtimate C18150*30mm* 5um; mobile phase: [water(FA)- ACN];B% 15%-55%,8min) to give (S)-3-(5-(4-((1-(4-((1R,2S)-2-ethyl-6-hydroxy-1,2,3,4- tetrahydronaphthalen-1-yl)phenyl)piperidin-4-yl)methyl)piper azin-1-yl)-1-oxoisoindolin-2- yl)piperidine-2,6-dione (30.6 mg, 51 % Yield) as a white solid. LC-MS (ESI ⁺ ) m/z: 676.2 (M+H) ⁺ . LCMS: calc. for C ₄₁ H ₄₉ N ₅ O ₄ : 675.87, found: [M+H] + 676.2. HPLC: 100% purity at 220 nm. ¹ HNMR (400MHz, DMSO-d ₆ ) į = 10.96 (s, 1H), 9.03 (s, 1H), 8.14 (s, 1H), 7.52 (d, J=8.6 Hz, 1H), 7.10 - 7.03 (m, 2H), 6.77 (s, 4H), 6.62 (d, J=8.5 Hz, 1H), 6.51 (s, 1H), 6.43 (dd, J=2.4, 8.2 Hz, 1H), 5.05 (dd, J=5.0, 13.2 Hz, 1H), 4.38 - 4.29 (m, 1H), 4.25 - 4.17 (m, 1H), 3.93 (d, J=5.0 Hz, 1H), 3.60 (br d, J=12.5 Hz, 2H), 3.29 (br s, 5H), 2.96 - 2.73 (m, 3H), 2.59 (br d, J=12.2 Hz, 5H), 2.38 (br d, J=4.6 Hz, 2H), 2.22 (br d, J=6.7 Hz, 2H), 2.00 - 1.92 (m, 1H), 1.80 (br d, J=11.6 Hz, 2H), 1.73 - 1.56 (m, 3H), 1.49 (dt, J=6.2, 12.3 Hz, 1H), 1.26 - 1.14 (m, 3H), 0.91 (t, J=7.2 Hz, 3H), 0.78 (qd, J=6.9, 13.7 Hz, 1H) SFC: retention time, 2.656 min; Area, 93.493 %; Stereochemistry was arbitrarily assigned EXAMPLE 217. Preparation of (I-124) (S)-3-(5-(4-((1-(4-((1R,2S)-6-hydroxy-2-methyl- 1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperidin-4-yl)meth yl)piperazin-1-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione and (I-125) (S)-3-(5-(4-((1-(4-((1S,2R)-6-hydroxy-2-

methyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperidin -4-yl)methyl)piperazin-1-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione Step 1: A mixture of 1-(4-(6-(benzyloxy)-2-bromo-3,4-dihydronaphthalen-1-yl)pheny l)-4- (dimethoxymethyl)piperidine (1.0 g, 1.82 mmol, 1 eq), 2,4,6-trimethyl-1,3,5,2,4,6- trioxatriborinane (457.73 mg, 1.82 mmol, 509.72 uL, 50% purity, 1 eq), Pd(dppf)Cl ₂ (133.40 mg, 182.31 umol, 0.1 eq) and K ₂ CO ₃ (503.93 mg, 3.65 mmol, 2 eq) in dioxane (15 mL)and H ₂ O (4 at 80 °C for 16 hr under N2 atmosphere. The mixture was concentrated in reduced pressure. The residue was poured into water (20 mL). The aqueous phase was extracted with ethyl acetate (40 mL*3). The combined organic phase was washed with brine (20 mL), dried with Na ₂ SO ₄ , filtered and concentrated in vacuum. The residue was purified by silica gel chromatography (Petroleum ether/Ethyl acetate=3/1).1-(4-(6-(benzyloxy)-2-methyl-3,4-dihydronaphtha len-1- yl)phenyl)-4-(dimethoxymethyl)piperidine (450 mg, 930.44 umol, 51.04% yield) was obtained as oil. LC-MS (ESI+) m/z: 484.3 (M+H)+. Step 2: A mixture of 1-(4-(6-(benzyloxy)-2-methyl-3,4-dihydronaphthalen-1-yl)phen yl)-4- (dimethoxymethyl)piperidine (280 mg, 578.94 umol, 1 eq) and Pd/C (123.22 mg, 115.79 umol, 10% purity, 0.2 eq) in MeOH (3 mL) was degassed and purged with H2 for 3 times, and then the mixture was stirred at 25 °C for 2 hr under H2 atmosphere. LCMS showed that the starting material was consumed and the desired product was detected. The reaction mixture was filtered under reduced pressure to give 5-(4-(4-(dimethoxymethyl)piperidin-1-yl)phenyl)-6-methyl- 5,6,7,8-tetrahydronaphthalen-2-ol. Then 5-(4-(4-(dimethoxymethyl)piperidin-1-yl)phenyl)-6- methyl-5,6,7,8-tetrahydronaphthalen-2-ol (200 mg, 505.65 umol, 87.34% yield) was obtained as a white solid. LC-MS (ESI+) m/z: 396.2 (M+H)+. Step 3: 5-(4-(4-(dimethoxymethyl)piperidin-1-yl)phenyl)-6-methyl-5,6 ,7,8- tetrahydronaphthalen-2-ol (500 mg) was separated by chiral SFC (Column DAICEL CHIRALPAK AS(250mm*30mm,10um) Condition 0.1% NH ₃ H ₂ O EtOH Begin B 55% End B 55%), 0.1% NH ₃ H ₂ O EtOH ) (5R,6S)-5-(4-(4-(dimethoxymethyl)piperidin-1-yl)phenyl)-6- methyl-5,6,7,8-tetrahydronaphthalen-2-ol (200 mg), (5S,6R)-5-(4-(4- (dimethoxymethyl)piperidin-1-yl)phenyl)-6-methyl-5,6,7,8-tet rahydronaphthalen-2-ol (200 mg ). LC-MS (ESI+) m/z: 396.0(M+H)+. Step 4: 1-(4-((1R,2S)-6-hydroxy-2-methyl-1,2,3,4-tetrahydronaphthale n-1-yl)phenyl)piperidine- 4-carbaldehyde: To a solution of (5R,6S)-5-(4-(4-(dimethoxymethyl)piperidin-1-yl)phenyl)-6- methyl-5,6,7,8-tetrahydronaphthalen-2-ol (100 mg, 252.82 umol, 1 eq) in DCM (8 mL) was LCMS showed that the starting material was consumed and the desired product was detected. The reaction mixture was filtered under reduced pressure to give a residue.1-(4-((1R,2S)-6- hydroxy-2-methyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)pi peridine-4-carbaldehyde (70 mg, 200.31 umol, 79.23% yield) was obtained as oil. 1-(4-((1S,2R)-6-hydroxy-2-methyl-1,2,3,4-tetrahydronaphthale n-1-yl)phenyl)piperidine-4- carbaldehyde: To a solution of (5S,6R)-5-(4-(4-(dimethoxymethyl)piperidin-1-yl)phenyl)-6- methyl-5,6,7,8-tetrahydronaphthalen-2-ol (150 mg, 379.24 umol, 1 eq) in DCM (8 mL) (150 mg, 379.24 umol, 1 eq) in DCM (8 mL) was added TFA (43.24 mg, 379.24 umol, 28.08 uL, 1 eq). The mixture was stirred at 25 °C for 2 hr. LCMS showed that the starting material was consumed and the desired product was detected. The reaction mixture was filtered under reduced pressure to give a residue.1-(4-((1S,2R)-6-hydroxy-2-methyl-1,2,3,4-tetrahydron aphthalen-1- yl)phenyl)piperidine-4-carbaldehyde (100 mg, 286.15 umol, 75.45% yield) was obtained as oil. LC-MS (ESI+) m/z: 368.2(M+H)+. Step 5: To a solution of 1-(4-((1R,2S)-6-hydroxy-2-methyl-1,2,3,4-tetrahydronaphthale n-1- yl)phenyl)piperidine-4-carbaldehyde (126.68 mg, 362.50 umol, 1 eq) and (S)-3-(1-oxo-5- (piperazin-1-yl)isoindolin-2-yl)piperidine-2,6-dione (119.03 mg, 362.50 umol, 1 eq) in MeOH (2 mL) and DCM (3 mL) was added NMM (3.67 mg, 36.25 umol, 3.99 uL, 0.1 eq) and C6H10BO6Na (153.66 mg, 724.99 umol, 2 eq) .The mixture was stirred at 25 °C for 2 hr . LCMS showed that the starting material was consumed and the desired product was detected. The reaction mixture was filtered under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Boston Green ODS 150*30mm*5um; mobile phase: [water(FA)-ACN];B%: 10%-40%,10min) to give (S)-3-(5-(4-((1-(4-((1R,2S)-6-hydroxy- 2-methyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperidin- 4-yl)methyl)piperazin-1-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione (50 mg, 75.55 umol, 20.84% yield) was obtained as white solid. LC-MS (ESI+) m/z: 662.5(M+H) +. HPLC: 100% purity at 220 nm. ¹ H NMR (400 MHz, METHANOL-d4) į = 7.63 (d, J = 8.9 Hz, 1H), 7.11 - 7.06 (m, 2H), 6.87 - 6.80 (m, 4H), 6.63 (d, J = 8.3 Hz, 1H), 6.54 (d, J = 2.0 Hz, 1H), 6.49 - 6.39 (m,1H), 5.10 - 5.05 (m, 1H), 4.43 - 4.35 (m, 2H), 3.89 (d, J = 5.1 Hz, 1H), 3.60 (br d, J = 11.4 Hz, 2H), 3.44 (br s, 4H), 2.91 - 2.75 (m, 8H), 2.70 - 2.56 (m, 4H), 2.49 - 2.39 (m,1H), 2.14 - 2.00 (m, 2H), 1.88 (br d, J = 12.6 Hz, 2H), 1.85 - 1.78 (m, 1H), 1.61 (br s, 1H), 1.53 - 1.47 (m, 1H), 1.35 (br s, 2H), 0.73 (d, J = 6.8 Hz, 3H). Step 6: To a solution of 1-(4-((1S,2R)-6-hydroxy-2-methyl-1,2,3,4-tetrahydronaphthale n-1- yl)phenyl)piperidine-4-carbaldehyde (180 mg, 515.07 umol, 1 eq) and (S)-3-(1-oxo-5-(piperazin- 1-yl)isoindolin-2-yl)piperidine-2,6-dione (169.13 mg, 515.07 umol, 1 eq) in DCE (3 mL) and MeOH (2 mL) was added NMM (5.21 mg, 51.51 umol, 5.66 uL, 0.1 eq) and C6H10BO6Na (218.33 mg, 1.03 mmol, 2 eq) The mixture was stirred at 25 °C for 2 hr . LCMS showed that the starting material was consumed and the desired product was detected. The reaction mixture was filtered under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Boston Green ODS 150*30mm*5um; mobile phase: [water(FA)-ACN];B%: 10%- 40%,10min) to give (S)-3-(5-(4-((1-(4-((1S,2R)-6-hydroxy-2-methyl-1,2,3,4- tetrahydronaphthalen-1-yl)phenyl)piperidin-4-yl)methyl)piper azin-1-yl)-1-oxoisoindolin-2- yl)piperidine-2,6-dione (34 mg, 51.37 umol, 9.97% yield) was obtained as a white solid. LC-MS (ESI+) m/z: 662.5(M+H) ⁺ . HPLC: 100% purity at 220 nm. ¹ H NMR (400 MHz, METHANOL-d4) į = 8.43 - 8.34 (m, 1H), 7.65 (br d, J = 8.5 Hz, 1H), 7.16 - 7.06 (m, 2H), 6.90 - 6.82 (m, 4H), 6.67 (br d, J = 8.1 Hz, 1H), 6.57 (br s, 1H),6.47 (br d, J = 7.9 Hz, 1H), 5.13 - 5.07 (m, 1H), 4.41 (br d, J = 6.1 Hz, 2H), 3.94 - 3.89 (m, 1H), 3.62 (br d, J = 11.9 Hz, 2H), 3.43 (br s, 4H), 2.92 - 2.76 (m, 8H), 2.72 - 2.65(m, 2H), 2.54 - 2.43 (m, 3H), 2.17 - 2.03 (m, 2H), 1.91 (br d, J = 12.4 Hz, 2H), 1.84 - 1.75 (m, 1H), 1.62 - 1.47 (m, 2H), 1.47 - 1.36 (m, 2H), 0.77 (br d, J = 6.8 Hz, 3H).

EXAMPLE 218. Preparation of (I-103) (S)-3-(5-(4-((1-(4-((S)-6-hydroxy-1,2,3,4- tetrahydronaphthalen-1-yl)phenyl)piperidin-4-yl)methyl)piper azin-1-yl)-1-oxoisoindolin-2- yl)piperidine-2,6-dione Step 1: To a solution of (S)-5-(4-(4-(dimethoxymethyl)piperidin-1-yl)phenyl)-5,6,7,8- tetrahydronaphthalen-2-ol (59 mg, 1 Eq, 0.15 mmol) in THF (10 mL) was added sulfuric acid (15 mg, 10 mL, 1 Eq, 0.15 mmol). The mixture was stirred at 70°C for 4 hour. LCMS showed 97.08% desired MS. The mixture was adjusted to pH 8-9 by progressively adding NaHCO ₃ . The reaction mixture was quenched by addition 20 mL EtOAc at 20°C, and then diluted with 20 mL H ₂ O and extracted with 50mL (25 mL * 2) EtOAc. The combined organic layers were washed with 10 mL (10 mL * 1), dried over Na ₂ SO ₄ . The reaction was filtered and concentrated under reduced pressure to give (S)-1-(4-(6-hydroxy-1,2,3,4-tetrahydronaphthalen-1- yl)phenyl)piperidine-4-carbaldehyde (70 mg, 0.21 mmol, 130%, 100% Purity) was obtained as a colorless oil. LC-MS (ESI ⁺ ) m/z: 354.2 (M+H) ⁺ . Step 2: A mixture of (S)-1-(4-(6-hydroxy-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl )piperidine- 4-carbaldehyde (70 mg, 1 Eq, 0.21 mmol), (S)-3-(1-oxo-5-(piperazin-1-yl)isoindolin-2- yl)piperidine-2,6-dione (69 mg, 1 Eq, 0.21 mmol) and Sodium acetate (86 mg, 5 Eq, 1.0 mmol) in DCM (1 mL) and MeOH (1 mL) at 20°C for 0.5 hour, pH=8, then acetic acid (38 mg, 3 Eq, 0.63 mmol) at 20°C for 1 hour, pH=6, then added Sodium triacetoxyborohydride (88 mg, 2 Eq, 0.42 mmol) the mixture, and then the mixture was stirred at 25 °C for 16 hour. LCMS showed 86.85% desired MS. The reaction was concentrated to give (S)-3-(5-(4-((1-(4-((S)-6-hydroxy- 1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperidin-4-yl)meth yl)piperazin-1-yl)-1-oxoisoindolin- 2-yl)piperidine-2,6-dione as a light yellow oil. The light yellow oil was purified by preparative high-performance liquid chromatography. Condition: Column: O-Welch C18150*30mm* 5um ^ A: water(FA) ^ B:CAN ^at the beginning: A (100%) and B (0%) ^ at the end: A: (60%) and B (40%) ^ Gradient Time(min) 10; 100% B hold Time(min) 2, Flow Rate(ml/min) 30. LCMS showed 100% desired MS. The pure fractions were collected and the solvent was evaporated under vacuum. The aqueous layer was lyophilized to dryness to give (S)-3-(5-(4-((1- (4-((S)-6-hydroxy-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)p iperidin-4-yl)methyl)piperazin-1- yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (28.3 mg, 43.7 ^mol, 21%, 100% Purity) as a white solid. LC-MS (ESI+) m/z: 648.2 (M+H) ⁺ . LCMS: calc. for C ₃₉ H ₄₅ N ₅ O ₄ : 647.35, found: [M+H] ⁺ 648.2. HPLC: 100% purity at 220 nm. NMR (400 MHz, DMSO-d6) į= 10.99 - 10.88 (m, 1H), 9.16 - 8.97 (m, 1H), 8.20 - 8.14 (m, 0.481H), 7.55 - 7.48 (m, 1H), 7.09 - 7.03 (m, 2H), 6.91 - 6.82 (m, 4H), 6.54 - 6.47 (m, 2H), 6.46 - 6.40 (m, 1H), 5.15 - 4.97 (m, 1H), 4.37 - 4.30 (m, 1H), 4.25 - 4.15 (m, 1H), 3.91 - 3.82 (m, 1H), 3.65 - 3.58 (m, 2H), 3.31 - 3.29 (m, 6H), 2.96 - 2.84 (m, 1H), 2.73 - 2.59 (m, 4H), 2.39 (br s, 3H), 2.26 - 2.20 (m, 2H), 2.00 - 1.93 (m, 2H), 1.90 - 1.56 (m, 7H), 1.29 - 1.19 (m, 2H) SFC: retention time, 2.759 min; Area, 92.821%; Stereochemistry was arbitrarily assigned

EXAMPLE 219. Preparation of (I-102) (S)-3-(5-(4-((1-(4-((R)-6-hydroxy-1,2,3,4- tetrahydronaphthalen-1-yl)phenyl)piperidin-4-yl)methyl)piper azin-1-yl)-1-oxoisoindolin-2- yl)piperidine-2,6-dione Step 1: A mixture of 1-(4-(6-(benzyloxy)-3,4-dihydronaphthalen-1-yl)phenyl)-4- (dimethoxymethyl)piperidine (400 mg, 1 Eq, 852 ^mol), Pd/C (453 mg, 5 Eq, 4.26 mmol) in MeOH (6 mL) and THF (6 mL)was degassed and purged with H ₂ for 3 times, and then the mixture was stirred at 50°C for 16 hour under H ₂ atmosphere(15 psi). LCMS showed 78% desired. TLC (petroleum ether: ethyl aceatte=3:1, UV, R _f =0.5) showed one main new spot was observed. The reaction was filtered and concentrated to dryness in vacuo to give a blue solid. The blue solid was subjected to column chromatography over silica gel (gradient elution: 0 – 100% EtOAc). LCMS showed 83% desired. The desired fractions were collected, and concentrated to dryness in vacuo to give 5-(4-(4-(dimethoxymethyl)piperidin-1-yl)phenyl)- 5,6,7,8-tetrahydronaphthalen-2-ol (275 mg, 0.60 mmol, 70 %, 83% Purity) as a white solid. LC- MS (ESI ⁺ ) m/z: 382.2 (M+H) ⁺ . Step 2: The white solid was purified by SFC. Column: DAICEL CHIRALCEL OJ (250mm*30mm, 10um); Condition: 0.1%NH3H2O ETOH; At the beginning: A (55%) and B (45%); At the end: A: (55%) and B (45%); Flow Rate (ml/min) 80. The aqueous phase was lyophilized to dryness to give (R)-5-(4-(4-(dimethoxymethyl)piperidin-1-yl)phenyl)-5,6,7,8- tetrahydronaphthalen-2-ol (57 mg, 0.14 mmol, 19%, 91.19% Purity) as a yellow solid and (S)-5- (4-(4-(dimethoxymethyl)piperidin-1-yl)phenyl)-5,6,7,8-tetrah ydronaphthalen-2-ol (59 mg, 0.14 mmol, 20%, 91.52% Purity) as a colorless oil. LC-MS (ESI ⁺ ) m/z: 382.1 (M+H) ⁺ . Step 3: To a solution of (R)-5-(4-(4-(dimethoxymethyl)piperidin-1-yl)phenyl)-5,6,7,8- tetrahydronaphthalen-2-ol (52 mg, 1 Eq, 0.14 mmol) in THF (15 mL) was added 10% sulfuric acid (13 mg, 15 mL, 1 Eq, 0.14 mmol). The mixture was stirred at 70°C for 4 hour. LCMS showed 97.88 % desired MS. The mixture was adjusted to Ph= 8-9 by progressively adding NaHCO ₃ . The reaction mixture was quenched by addition 20 mL EtOAc at 20°C, and then diluted with 20 mL H ₂ O and extracted with 50mL (25 mL * 2) EtOAc. The combined organic layers were washed with 10 mL, dried over Na ₂ SO ₄ . The reaction was filtered and concentrated under reduced pressure to give (R)-1-(4-(6-hydroxy-1,2,3,4-tetrahydronaphthalen-1- yl)phenyl)piperidine-4-carbaldehyde (49 mg, 0.14 mmol, 100%, 97.87% Purity) was obtained as a colorless oil. LC-MS (ESI ⁺ ) m/z: 354.2 (M+H) ⁺ Step 4: A mixture of (R)-1-(4-(6-hydroxy-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl )piperidine- 4-carbaldehyde (49 mg, 1 Eq, 0.15 mmol), (S)-3-(1-oxo-5-(piperazin-1-yl)isoindolin-2- yl)piperidine-2,6-dione (48 mg, 1 Eq, 0.15 mmol) and sodium acetate (60 mg, 5 Eq, 0.73 mmol) in DCM (1 mL) and MeOH (1 mL) at 20°C for 0.5 hour, pH=8, then acetic acid (26 mg, 25 ^L, 3 Eq, 0.44 mmol) at 20°C for 1 hour, pH=6, then added sodium triacetoxyhydroborate (62 mg , 2 Eq, 0.29 mmol) the mixture, and then the mixture was stirred at 25°C for 16 hour. LCMS showed 83.9% desired MS. The reaction was concentrated to give (S)-3-(5-(4-((1-(4-((R)-6- hydroxy-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperidin-4 -yl)methyl)piperazin-1-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione as a light yellow oil. The light yellow oil was purified by preparative high-performance liquid chromatography. Condition: Column: O-Welch C18 150*30mm* 5um; A: water(FA); B:CAN; At the beginning: A (100%) and B (0%); At the end: A: (60%) and B (40%); Gradient Time(min) 10; 100% B hold Time(min) 2,Flow Rate(ml/min) 30. LCMS showed 98.30% desired MS. The pure fractions were collected and the solvent was evaporated under vacuum The aqueous layer was lyophilized to dryness to give (S)-3-(5-(4-((1- (4-((R)-6-hydroxy-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)p iperidin-4-yl)methyl)piperazin-1- yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (21.7 mg, 33.5 ^mol, 23%, 100% Purity) as a white solid. LC-MS (ESI+) m/z: 648.2 (M+H) ⁺ . LCMS: calc. for C ₃₉ H ₄₅ N ₅ O ₄ : 647.35, found: [M+H] ⁺ 648.2. HPLC: 100% purity at 220 nm. ¹ H NMR (400 MHz, DMSO-d ₆ ) į= 10.98 - 10.91 (m, 1H), 9.08 - 9.00 (m, 1H), 8.18 - 8.14 (m, 1H), 7.55 - 7.48 (m, 1H), 7.09 - 7.03 (m, 2H), 6.89 - 6.80 (m, 4H), 6.53 - 6.47 (m, 2H), 6.45 - 6.40 (m, 1H), 5.10 - 4.99 (m, 1H), 4.38 - 4.28 (m, 1H), 4.25 - 4.15 (m, 1H), 3.89 - 3.84 (m, 1H), 3.65 - 3.56 (m, 3H), 2.93 - 2.85 (m, 1H), 2.79 - 2.53 (m, 8H), 2.33 (br s, 4H), 2.24 - 2.20 (m, 2H), 2.00 - 1.92 (m, 2H), 1.80 (br d, J = 11.2 Hz, 7H), 1.26 - 1.18 (m, 2H) SFC: retention time, 2.354 min; Area, 93.433%; Stereochemistry was arbitrarily assigned EXAMPLE 220. Preparation of (I-119) (S)-3-(5-(4-((1- (4-((1S,2R)-2-cyclohexyl-6- hydroxy-1,2,3,4-tetrahydronaphthalen-1-yl)-3,5-difluoropheny l)piperidin-4- yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2, 6-dione Step 1: The 1-(4-(2-cyclohexyl-6-methoxy-1,2,3,4-tetrahydronaphthalen-1- yl)-3,5- difluorophenyl)-4-(dimethoxymethyl)piperidine (600 mg, 1 eq., 1.17 mmol) was purified by SFC(Column: DAICEL CHIRALCEL OD-H(250mm*30mm,10um); Mobile phase: 0.1%NH ₃ H ₂ O ETOH; from 25% to 25%; Flow rate: 70 mL/min) to give 1-(4-((1S,2R)-2- cyclohexyl-6-methoxy -1,2,3,4-tetrahydronaphthalen-1-yl)-3,5-difluorophenyl)-4- (dimethoxymethyl)piperidine (240 mg, 467 ^mol, 40.0 %) both as white solid. LC-MS (ESI ⁺ ) m/z: 514.4 (M+H) ⁺ . Step 2: To a solution of 1-(4-((1S,2R)-2-cyclohexyl-6-methoxy-1,2,3,4-tetrahydronapht halen-1- yl)- 3,5-difluorophenyl)-4-(dimethoxymethyl)piperidine (200 mg, 1 eq., 389 ^mol) in DCM (10 mL) was added BBr ₃ (488 mg, 184 ^L, 5 eq., 1.95 mmol). The mixture was strried at 20 °C for 2 hour and then water (1 mL) in DCM (10 mL) was added dropwise at 20 °C, The resulting mixture was stirred at 20 °C for 30 min. The mixture was concentrated and then water (20 mL) was added. The mixture was extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine (20 mL), dried over Na ₂ SO ₄ , filtered and concentrated. The mixture was concentrated in vacuo to give crude product. No further purification as it is used for the next step directly. LC-MS (ESI+) m/z:454.2 (M+H)+. Step 3: To a solution of 1-(4-((1S,2R)-2-cyclohexyl-6-hydroxy-1,2,3,4-tetrahydronapht halen-1- yl)- 3,5-difluorophenyl)piperidine-4-carbaldehyde (80.0 mg, 1 eq., 176 ^mol) and (R)-3-(1-oxo- 5- (piperazin-1-yl)isoindolin-2-yl)piperidine-2,6-dione (81.1 mg, 1.4 eq., 247 ^mol) in DCE (10 mL) was added dropwise 4-methylmorpholine (17.8 mg, 1 eq., 176 ^mol) to pH=8 at 20 °C. After addition, the mixture was stirred at this temperature for 30 min, and then sodium triacetoxyhydroborate (93.5 mg, 2.5 eq., 441 ^mol) was added dropwise at 20 °C. The resulting mixture was stirred at 20 °C for 3 hour. The crude was purified by prep.HPLC together (YMC- Triart Prep C18150*40mm*7um, water(FA)-ACN as a mobile phase, from 40% to 70%, Gradient Time (min): 15, Flow Rate (ml/min): 25) to give (S)-3-(5-(4-((1- (4-((1S,2R)-2- cyclohexyl-6-hydroxy-1,2,3,4-tetrahydronaphthalen-1-yl)-3,5- difluorophenyl)piperidin-4- yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2, 6-dione (53.6 mg, 70.0 ^mol, 39.7 %) as a white solid. LC-MS (ESI+) m/z: 766.3(M+H)+. ¹ H NMR (400 MHz, DMSO-d6) į: ppm 10.95 (s, 1 H), 9.00 (s, 1 H), 8.13 (s, 1 H), 7.54 - 7.59 (m, 1 H), 7.23 - 7.39 (m, 1 H), 7.02 - 7.19 (m, 2 H), 6.59 (d, J=8.34 Hz, 1 H), 6.45 (br d, J=2.03 Hz, 2 H), 6.40 (dd, J=8.23, 2.38 Hz, 1 H), 5.06 (dd, J=13.23, 5.01 Hz, 1 H), 4.30 - 4.39 (m, 2 H), 4.18 - 4.27 (m, 1 H), 3.72 (br d, J=11.56 Hz, 2 H), 3.51 (br s, 4 H), 2.99 - 3.30 (m, 4 H), 2.82 - 2.95 (m, 2 H), 2.65 - 2.79 (m, 3 H), 2.65 - 2.65 (m, 1 H), 2.59 (br d, J=16.81 Hz, 2 H), 2.37 (br dd, J=13.05, 4.47 Hz, 1 H), 1.92 - 1.99 (m, 1 H), 1.69 - 1.89 (m, 6 H), 1.66 (br d, J=10.01 Hz, 1 H), 1.55 (br d, J=6.79 Hz, 3 H), 1.19 - 1.26 (m, 2 H), 1.05 - 1.19 (m, 4 H), 0.92 - 1.04 (m, 2 H), 0.75 - 0.89 (m, 1 H). EXAMPLE 221. Preparation of (I-118) (S)-3-(5-(4-((1-(4-((1R,2S)-2-cyclohexyl-6- hydroxy-1,2,3,4- tetrahydronaphthalen-1-yl)-3,5-difluorophenyl)piperidin-4- yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2, 6-dione Step 1: To a solution of 4-bromo-3,5-difluorophenol (10 g, 1 eq., 48 mmol) and K ₂ CO ₃ (20 g, 3 eq., 0.14 mol) in MECN (120 mL) was added (bromomethyl)benzene (9.0 g, 1.1 eq., 53 mmol).The mixture was strried at 70 °C for 3 hour. TLC ( PE/EtOAc = 10/1, Rf = 0.8) showed the recation was completed. The reaction mixture was quenched by addition EA 60 mL at 20 °C, and then diluted with water 30 mL and extracted with EA 150 mL (50 mL * 3). The combined organic layers were washed with EA 60 mL (20 mL * 3), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The crude material was purified on silica gel column chromatography (from PE/EtOAc = 1/0 to 1/0, TLC: PE/EtOAc = 10/1, Rf = 0.8) to yield 5-(benzyloxy)-2-bromo-1,3-difluorobenzene (12 g, 40 mmol, 84 %) as a transparent oil. ¹ H NMR (400 MHz, METHANOL-d4) į: ppm 7.23 - 7.53 (m, 5 H), 6.70 - 6.81 (m, 2 H), 5.06 (s, 2 H). Step 2: A mixture of 5-(benzyloxy)-2-bromo-1,3-difluorobenzene (5.00 g, 1 eq., 16.7 mmol),(E)- N' -(6-methoxy-3,4-dihydronaphthalen-1(2H),-ylidene)-4-methylbe nzenesulfonohydrazide (6.91 g, 1.2 eq., 20.1 mmol), XPhos Pd G3 (707 mg, 0.05 eq., 836 ^mol), PdCl ₂ (dppf) adduct (683 mg, 0.05 eq., 836 ^mol) and Lithium 2-methyl-2-propanolate (3.35 g, 3.89 mL, 2.5 eq., 41.8 mmol) in Dioxane (300 mL) was degassed and purged with N ₂ for 3 times, and then the mixture was stirred at 100 °C for 12 hour under N ₂ atmosphere. LCMS showed the reaction was completed. The reaction mixture was quenched by addition EA 100 mL at 20 °C, and then diluted with water 100 mL and extracted with EA 300 mL (100 mL * 3). The combined organic layers were washed with EA 150 mL (50 mL * 3), dried over Na2So4, filtered and concentrated under reduced pressure to give a residue. The crude material was purified on silica gel column chromatography (from PE/EtOAc = 1/0 to 1/0, TLC: PE/EtOAc = 10/1, Rf = 0.8) to yield 4-(4- (benzyloxy)-2,6-difluorophenyl)-7-methoxy-1,2-dihydronaphtha lene (5.0 g, 13 mmol, 79 %) as a yellow solid. LC-MS (ESI+) m/z: 379.2(M+H)+ ¹ H NMR (500 MHz, DMSO-d6) į: ppm 7.46 - 7.50 (m, 2 H), 7.40 - 7.45 (m, 2 H), 7.33 - 7.39 (m, 1 H), 6.86 - 6.93 (m, 2 H), 6.82 (d, J=2.59 Hz, 1 H), 6.66 (dd, J=8.47, 2.67 Hz, 1 H), 6.53 (d, J=8.54 Hz, 1 H), 5.94 (t, J=4.58 Hz, 1 H), 5.16 (s, 2 H), 3.73 (s, 3 H), 2.80 (t, J=8.09 Hz, 2 H), 2.31 - 2.41 (m, 2 H). Step 3: To a solution of 4-(4-(benzyloxy)-2,6-difluorophenyl)-7-methoxy-1,2- dihydronaphthalene (3.2 g, 1 eq., 8.5 mmol) in DCM (40 mL) was added Pyridinium bromide perbromide (3.0 g, 1.1 eq., 9.3 mmol).The mixture was stirred at 20 °C for 1.5 hour. LCMS showed the reaction was completed. The reaction mixture was quenched by addition water 30 mL at 20 °C, and then diluted with water 30 mL and extracted with DCM 90 mL (30 mL * 3). The combined organic layers were washed with DCM 30 mL (10 mL * 3), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The crude material was purified on silica gel column chromatography (from PE/EtOAc = 1/0 to 20/1) to yield 4-(4-(benzyloxy)-2,6-difluorophenyl)-3-bromo-7-methoxy-1,2-d ihydronaphthalene (2.6 g, 5.8 mmol, 69 %) as a yellow solid. LC-MS (ESI+) m/z: 457.1(M+H)+. ¹ H NMR (400 MHz, DMSO-d6) į: ppm 7.47 - 7.52 (m, 2 H), 7.40 - 7.46 (m, 2 H), 7.35 - 7.40 (m, 1 H), 6.95 (d, J=9.42 Hz, 2 H), 6.84 (d, J=2.62 Hz, 1 H), 6.67 (dd, J=8.52, 2.68 Hz, 1 H), 6.48 (d, J=8.58 Hz, 1 H), 5.17 (s, 2 H), 3.73 (s, 3 H), 2.96 - 3.02 (m, 2 H), 2.88 - 2.95 (m, 2 H). Step 4: A mixture of 4-(4-(benzyloxy)-2,6-difluorophenyl)-3-bromo-7-methoxy-1,2- dihydronaphthalene (3.6 g, 1 eq., 7.9 mmol), cyclohex-1-en-1-ylboronic acid (1.1 g, 1.1 eq., 8.7 mmol), PdCl ₂ (dppf) (0.58 g, 0.1 eq., 0.79 mmol) and sodium carbonate (2.5 g, 3 eq., 24 mmol) in Dioxane (20 mL) and water (4 mL) was degassed and purged with N ₂ for 3 times, and then the mixture was stirred at 80 °C for 8 hour under N2 atmosphere. LCMS showed the recation was completed. The reaction mixture was quenched by addition EA 30 mL at 20 °C, and then diluted with water 30 mL and extracted with EA 90 mL (30 mL * 3). The combined organic layers were washed with EA 30 mL (10 mL * 3), dried over Na2So4, filtered and concentrated under reduced pressure to give a residue. The crude material was purified on silica gel column chromatography (from PE/EtOAc = 1/0 to 1/0) to yield 4-(4-(benzyloxy)-2,6- difluorophenyl)-3-(cyclohex-1-en-1-yl)-7-methoxy-1,2-dihydro naphthalene (3.2 g, 7.0 mmol, 89 %) as a yellow solid. LC-MS (ESI+) m/z: 459.2(M+H)+ ¹ H NMR (400 MHz, DMSO-d6) į: ppm 7.44 - 7.50 (m, 2 H), 7.41 (t, J=7.21 Hz, 2 H), 7.32 - 7.38 (m, 1 H), 6.75 - 6.88 (m, 3 H), 6.63 (dd, J=8.46, 2.62 Hz, 1 H), 6.45 (d, J=8.46 Hz, 1 H), 5.24 (br s, 1 H), 5.11 - 5.12 (m, 1 H), 5.15 (s, 1 H), 3.71 (s, 3 H), 2.79 (t, J=7.93 Hz, 2 H), 2.39 (t, J=7.93 Hz, 2 H), 1.91 (br s, 2 H), 1.76 (br d, J=3.58 Hz, 2 H), 1.44 - 1.50 (m, 2 H), 1.20 - 1.29 (m, 2 H). Step 5: To a solution of 4-(4-(benzyloxy)-2,6-difluorophenyl)-3-(cyclohex-1-en-1-yl)- 7- methoxy-1,2- dihydronaphthalene (4.0 g, 1 eq., 8.7 mmol) in MeOH (30 mL) was added Pd/C (10%, 2 g) under N ₂ atmosphere. The suspension was degassed and purged with H ₂ for 3 times. The mixture was stirred under H ₂ (50 Psi) at 50 °C for 24 hour. LCMS showed the recatiom was completed. After filtration, the filtrate was concentrated give crude product. The crude was purified by prep.HPLC together (Boston Uni C1840*150*5um, water(FA)-ACN as a mobile phase, from 70% to 100%, Gradient Time (min): 10, Flow Rate (ml/min): 60) to give 4-(2-cyclohexyl-6-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl) -3,5-difluorophenol (750 mg, 2.01 mmol, 23 %) as a white solid. LC-MS (ESI+) m/z: 373.3(M+H)+ ¹ H NMR (400 MHz, DMSO-d6) į: ppm 9.96 - 10.39 (m, 1 H), 6.29 - 6.74 (m, 5 H), 4.09 - 4.45 (m, 1 H), 2.68 - 2.95 (m, 2 H), 1.47 - 1.92 (m, 7 H), 0.76 - 1.23 (m, 7 H). Step 6: To a solution of 4-(2-cyclohexyl-6-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl) -3,5- difluorophenol (720 mg, 1 eq., 1.93 mmol) and TEA (587 mg, 808 ^L, 3 eq., 5.80 mmol) in DCM (10 mL) was added trifluoromethanesulfonic anhydride (818 mg, 1.5 eq., 2.90 mmol).The mixture was stirred at 0 °C for 2 hour. LCMS showed the reaction was completed. The reaction mixture was quenched by addition water 20 mL at 20 °C, and then diluted with water 10 mL and extracted with DCM 30 mL (10 mL * 3). The combined organic layers were washed with DCM 15 mL (5 mL * 3), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The crude material was purified on silica gel column chromatography (from PE/EtOAc = 1/0 to 40/1) to yield 4-(2-cyclohexyl -6-methoxy-1,2,3,4- tetrahydronaphthalen-1-yl)-3,5-difluorophenyl trifluoromethanesulfonate (460 mg, 912 ^mol, 47.2 %) as a colourless oil. LC-MS (ESI+) m/z: 505.2(M+H)+ ¹ H NMR (400 MHz, DMSO-d6) į: ppm 7.08 - 7.90 (m, 2 H), 6.49 - 6.80 (m, 3 H), 4.56 (d, J=5.84 Hz, 1 H), 3.66 - 3.72 (m, 3 H), 2.75 - 2.98 (m, 2 H), 1.48 - 1.97 (m, 7 H), 0.81 - 1.14 (m, 7 H), -2.64 - -2.62 (m, 1 H). Step 7: A mixture of 4-(2-cyclohexyl -6-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)-3,5- (dimethoxymethyl)piperidine (218 mg, 1.5 eq., 1.37 mmol),potassium carbonate (378 mg, 3 eq., 2.74 mmol) and (2- Dicyclohexylphosphino-2’,6’-diisopropoxy-1,1’-biphenyl )[2-(2’-amino-1,1’- biphenyl)]palladium(II) methanesulfonate (153 mg, 0.2 eq., 182 ^mol) in was degassed and purged with N ₂ for 3 times, and then the mixture was stirred at 100 °C for 12 hour under N ₂ atmosphere. LCMS showed the reaction was completed. The reaction mixture was quenched by addition EA 10 Ml at 20 °C, and then diluted with water 30 Ml and extracted with EA 30 Ml (10 Ml * 3). The combined organic layers were washed with EA 30 Ml (10 Ml * 3), dried over Na2So4, filtered and concentrated under reduced pressure to give a residue. The crude material was purified on silica gel column chromatography (from pure PE to PE/EA = 9/1) to as give 1-(4-(2-cyclohexyl-6-methoxy-1,2,3,4-tetrahydronaphthalen-1- yl)-3,5-difluorophenyl)-4- (dimethoxymethyl)piperidine (400 mg, 779 ^mol, 85.4 %) a yellow oil. LC-MS (ESI+) m/z: 514.4(M+H)+ ¹ H NMR (400 MHz, DMSO-d6) į: ppm 7.08 – 7.90 (m, 2 H), 6.49 – 6.80 (m, 3 H), 4.56 (d, J=5.84 Hz, 1 H), 3.66 – 3.72 (m, 3 H), 2.75 – 2.98 (m, 2 H), 1.48 – 1.97 (m, 7 H), 0.81 – 1.14 (m, 7 H), -2.64 - -2.62 (m, 1 H). Step 8: The 1-(4-(2-cyclohexyl-6-methoxy-1,2,3,4-tetrahydronaphthalen-1- yl)-3,5- difluorophenyl)-4-(dimethoxymethyl)piperidine (600 mg, 1 eq., 1.17 mmol) was purified by SFC(Column: DAICEL CHIRALCEL OD-H(250mm*30mm,10um); Mobile phase: 0.1%NH ₃ H ₂ O ETOH; from 25% to 25%; Flow rate: 70 mL/min) to give 1-(4-((1R,2S)-2- cyclohexyl-6-methoxy- 1,2,3,4-tetrahydronaphthalen-1-yl)-3,5-difluorophenyl)-4- (dimethoxymethyl)piperidine (230 mg, 448 ^mol, 38.3 %) as white solid. LC-MS (ESI+) m/z: 514.4(M+H)+. Step 9: To a solution of 1-(4-((1R,2S)-2-cyclohexyl-6-methoxy-1,2,3,4-tetrahydronapht halen-1- yl) -3,5-difluorophenyl)-4-(dimethoxymethyl)piperidine (200 mg, 1 eq., 389 ^mol) in DCM (10 mL) was added BBr ₃ (488 mg, 184 ^L, 5 eq., 1.95 mmol). The mixture was strried at 20 °C for 2 hour and then water (2 mL) in DCM (10 mL) was added dropwise at 20 °C, The resulting mixture was stirred at 20 °C for 30 min. LCMS showed the recation was completed. The mixture was concentrated and then water (20 mL) was added. The mixture was extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered and concentrated. The mixture was concentrated in vacuo to give crude product. No further purification as it is used for the next step directly. LC-MS (ESI+) m/z: 454.2(M+H)+. Step 10: To a solution of 1-(4-((1R,2S)-2-cyclohexyl-6-hydroxy-1,2,3,4-tetrahydronapht halen-1- yl)- 3,5-difluorophenyl)piperidine-4-carbaldehyde (80 mg, 1 eq., 0.18 mmol) and (R)-3-(1-oxo- 5- (piperazin-1-yl)isoindolin-2-yl)piperidine-2,6-dione (81 mg, 1.4 eq., 0.25 mmol) in DCE (10 mL) was added dropwise 4-methylmorpholine (18 mg, 1 eq., 0.18 mmol) to pH=8 at 20 °C. After addition, the mixture was stirred at this temperature for 0.5 hour, and then sodium triacetoxyhydroborate (93 mg, 2.5 eq., 0.44 mmol) was added dropwise at 20 °C. The resulting mixture was stirred at 20 °C for 3 hour. LCMS showed the recation was completed. The crude was purified by prep.HPLC together (YMC-Triart Prep C18150*40mm*7um, water(FA)-ACN as a mobile phase, from 40% to 70%, Gradient Time (min): 15, Flow Rate (ml/min): 25) to give (S)-3-(5-(4-((1-(4-((1R,2S)-2-cyclohexyl-6-hydroxy-1,2,3,4- tetrahydronaphthalen-1-yl)- 3,5-difluorophenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-o xoisoindolin-2-yl)piperidine-2,6- dione (50.8 mg, 66.3 ^mol, 38 %) as a white solid. LC-MS (ESI+) m/z:766.3(M+H)+ ¹ H NMR (400 MHz, METHANOL-d4) į: ppm 8.11 - 8.16 (m, 1 H), 7.65 - 7.72 (m, 1 H), 7.36 - 7.46 (m, 1 H), 7.13 - 7.19 (m, 2 H), 6.64 (d, J=8.34 Hz, 1 H), 6.50 (d, J=2.50 Hz, 1 H), 6.41 - 6.45 (m, 2 H), 5.11 (dd, J=13.35, 5.13 Hz, 1 H), 4.37 - 4.48 (m, 3 H), 3.74 (br d, J=12.52 Hz, 2 H), 3.61 (br s, 4 H), 3.32 - 3.44 (m, 4 H), 2.98 - 3.07 (m, 2 H), 2.84 - 2.96 (m, 2 H), 2.73 - 2.84 (m, 4 H), 2.46 (qd, J=13.13, 4.59 Hz, 1 H), 2.12 - 2.20 (m, 1 H), 2.01 - 2.09 (m, 1 H), 1.88 (br d, J=10.37 Hz, 3 H), 1.75 - 1.84 (m, 2 H), 1.71 (br d, J=9.30 Hz, 2 H), 1.60 (br d, J=10.01 Hz, 2 H), 1.36 - 1.46 (m, 2 H), 1.19 - 1.32 (m, 3 H), 1.00 - 1.16 (m, 3 H), 0.82 - 0.95 (m, 1 H).

EXAMPLE 222. Preparation of (I-108) (R)-3-(5-(4-((1-(4-((1S,2R)-6-hydroxy-2- (pyridin-3-yl)-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)pipe ridin-4-yl)methyl)piperazin-1- yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione Step 1: The starting material was purified by SFC(Column: DAICEL CHIRALPAK AS(250mm*30mm,10um)); Mobile phase: 0.1%NH ₃ H ₂ O ETOH; from 30% to 30%; Flow rate: 90 mL/min) to give (5S,6R)-5-(4-(4-(dimethoxymethyl)piperidin-1-yl)phenyl)-6-(p yridin-3-yl)- 5,6,7,8-tetrahydronaphthalen-2-ol (76 mg, 0.17 mmol, 36 %) as white solid. LC-MS (ESI ⁺ ) m/z: 459.3 (M+H) ⁺ . Step 2: To a solution of (5S,6R)-5-(4-(4-(dimethoxymethyl)piperidin-1-yl)phenyl)-6-(p yridin-3- yl) -5,6,7,8-tetrahydronaphthalen-2-ol (60 mg, 1 Eq., 0.13 mmol) in DCM (3 mL) was added TFA (45 mg, 30 ^L, 3 Eq., 0.39 mmol) .The mixture was stirred at 25 °C for 4 hour . LCMS showed the reaction was completed. The mixture was concentrated in vacuo to give crude product. No further purification as it is used for the next step directly. LC-MS (ESI+) m/z: 413.2(M+H)+. Step 3: To a solution of 1-(4-((1S,2R)-6-hydroxy-2-(pyridin-3-yl)-1,2,3,4-tetrahydron aphthalen- 1- yl)phenyl)piperidine-4-carbaldehyde (30 mg, 1 Eq., 73 ^mol) and (R)-3-(1-oxo-5-(piperazin- 1-yl)isoindolin-2-yl)piperidine-2,6-dione (36 mg, 1.5 Eq., 0.11 mmol) in DCE (3 mL) was added dropwise 4-methylmorpholine (7.4 mg, 1 Eq., 73 ^mol) to pH=8 at 20 °C. After addition, the mixture was stirred at this temperature for 0.5 hour, and then sodium triacetoxyhydroborate (31 mg, 2 Eq., 0.15 mmol) was added dropwise at 20 °C. The resulting mixture was stirred at 20 °C for 3 hour. LCMS showed the recation was completed. The crude was purified by C h ( l h i C181 0*2 * ( O CO ) AC as a mobile phase, from 35% to 65%, Gradient Time (min): 11, Flow Rate (ml/min): 25) to give (R)-3-(5-(4-((1-(4-((1S,2R)-6-hydroxy-2- (pyridin-3-yl)-1,2,3,4-tetrahydronaphthalen-1- yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindo lin-2-yl)piperidine-2,6-dione (27.4 mg, 37.8 ^mol, 52 %) as a white solid. LC-MS (ESI+) m/z: 725.3(M+H)+ ¹ H NMR (500 MHz, METHANOL-d4) į: ppm 11.80 - 11.84 (m, 1 H), 8.30 (br s, 1 H), 8.01 (br s, 1 H), 7.65 (d, J=8.54 Hz, 1 H), 7.22 (br s, 2 H), 6.94 - 7.17 (m, 2 H), 6.65 - 6.74 (m, 4 H), 6.55 (dd, J=8.39, 2.44 Hz, 1 H), 6.38 (d, J=8.54 Hz, 2 H), 5.11 (dd, J=13.28, 5.19 Hz, 1 H), 4.58 (s, 1 H), 4.28 - 4.54 (m, 2 H), 4.21 (d, J=5.19 Hz, 1 H), 3.52 - 3.59 (m, 2 H), 3.35 - 3.45 (m, 5 H), 3.00 - 3.11 (m, 2 H), 2.84 - 2.96 (m, 1 H), 2.74 - 2.84 (m, 1 H), 2.52 - 2.72 (m, 6 H), 2.47 (qd, J=13.25, 4.81 Hz, 1 H), 2.31 (br d, J=7.02 Hz, 2 H), 2.12 - 2.20 (m, 1 H), 1.88 (br d, J=12.51 Hz, 2 H), 1.66 - 1.82 (m, 2 H), 1.11 - 1.49 (m, 3 H). Stereochemistry was arbitrarily assigned EXAMPLE 223. Preparation of (I-133) (S)-3-(5-(4-((1-(4-((1R,2S)-6- hydroxy-2- (pyridine-4-yl)-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)pip eridin-4-yl)methyl)piperazin- 1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione Step 1: To a mixture of 1-(4-(6-(benzyloxy)-2-bromo-3,4-dihydronaphthalen -1-yl)phenyl)-4- (dimethoxymethyl)piperidine (3.00 g, 1 Eq, 5.47 mmol), 4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)pyridine (1.12 g, 1 Eq, 5.47 mmol), PdCl2(dppf) (800 mg, 0.2 Eq, 1.09 mmol) and K ₂ CO ₃ (2.27 g, 3 Eq, 16.4 mmol) in Dioxane (100 mL) and H ₂ O (2 mL) was added reagent in one portion at 25°C under N ₂ . The mixture was suction air for 3 times under N ₂ , then heated to 85 °C and stirred for 8 hours. TLC showed the reaction was completed. The mixture was cooled to 20°C, solid was filtered and concentrated in reduced pressure at 25 °C. The residue was poured into ice-water (w/w = 1/1) (200 mL) and stirred for 5 min. The aqueous phase was extracted with ethyl acetate (100 mL*2). The combined organic phase was washed with brine (50mL*2), dried with anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was purified by silica gel chromatography (column height: 250 mm, diameter: 100 mm, 100-200 mesh silica gel, Petroleum ether/Ethyl acetate=5/1, N/1) to afford 5-(6-(benzyloxy)-2- (1392yridine-4-yl)-3,4-dihydronaphthalen-1-yl)-2-(4-(dimetho xymethyl)piperidin-1-yl)benzene- 1-ylium (2.54 g, 4.6 mmol, 84 %, 99% Purity) as yellow solid. Step 2: To a mixture of 4-(6-(benzyloxy)-1-(4-(4-(dimethoxymethyl)piperidin -1-yl)phenyl)-3,4- dihydronaphthalen-2-yl)pyridine (2.25 g, 1 Eq, 4.12 mmol) and Pd-C (438 mg, 1 Eq, 4.12 mmol) in Ethyl acetate (100 mL) was added reagent in one portion at 25°C under H ₂ . The mixture was stirred at 25 °C for 5 min, then heated to 80°C and stirred for 24 hours at 50 psi. TLC showed the reaction was completed. The mixture was cooled to 20 °C, add 200 ml solution (DCM and MeOH = 1 : 1) to the mixture and filer solid and concentrated in reduced pressure at 30 °C to afford 5-(4-(4-(dimethoxymethyl)piperidin-1-yl)phenyl)-6-(pyridin-4 -yl)-5,6,7,8- tetrahydronaphthalen-2-ol (1.68 g, 3.88 mmol, 94.26 %) as yellow solid. Step 3: To a mixture of 5-(4-(4-(dimethoxymethyl)piperidin-1-yl)phenyl) -6-(pyridin-4-yl)- 5,6,7,8-tetrahydronaphthalen-2-ol (1.00 g, 1 Eq, 2.18 mmol) in 5-(4-(4- (dimethoxymethyl)piperidin-1-yl)phenyl)-6-(pyridin-4-yl)-5,6 ,7,8-tetrahydronaphthalen-2-ol (1.00 g, 1 Eq, 2.18 mmol). SFC to give (5R,6S)-5-(4-(4- (dimethoxymethyl)piperidin-1- yl)phenyl)-6-(pyridin-4-yl)-5,6,7,8-tetrahydronaphthalen-2-o l (350 mg, 763 ^mol, 70.0 %) and as yellow solid. Step 4: To a mixture To a mixture of To a mixture of (5S,6R)-5-(4-(4- (dimethoxymethyl)piperidin-1-yl)phenyl)-6-(1392etrahyd-4-yl) -5,6,7,8-tetrahydronaphthalen-2- added reagent in one portion. The mixture was stirred at 25°C for 1 hour. LCMS showed the reaction was completed. The mixture was cooled to 25 °C and concentrated in reduced to afford 1-(4-((1S, 2R)-6-hydroxy-2-(pyridin-4-yl)-1,2,3,4- tetrahydronaphthalen-1-yl)phenyl)piperidine- 4-carbaldehyde (104 mg, 153 ^mol, 70.0 %, 60.543% Purity) as yellow solid. Directly to next step. Step 5: To a mixture of 1-(4-((1R,2S)-6-hydroxy-2-(1393yridine-4-yl)-1,2,3,4 - tetrahydronaphthalen-1-yl)phenyl)piperidine-4-carbaldehyde (100 mg, 1 Eq, 242 ^mol), (S)-3- (1-oxo-5-(piperazin-1-yl)isoindolin-2-yl)piperidine- 2,6-dione (159 mg, 2 Eq, 485 ^mol) in DCM (15 mL) was added reagent in one portion at 25°C. The mixture was stirred at 25 °C for 5 min, then add 4-methylmorfolin (49.0 mg, 53 ^L, 2 Eq, 485 ^mol) and Sodium triacetoxyborohydride (154 mg, 108 ^L, 3 Eq, 727 ^mol) to adjust PH to about 6 and stirred for 3 hours. TLC showed the reaction was completed. The mixture was reduced pressure at 25 °C. The residue was further purification by pre-HPLC to afford (S)-3-(5-(4-((1-(4-((1R,2S)- 6- hydroxy-2-(1393yridine-4-yl)-1,2,3,4-tetrahydronaphthalen-1- yl)phenyl)piperidin-4- yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2, 6-dione (10.4 mg, 14.34 ^mol, 5.92 %, 100% Purity) as white solid. The white solid was re-crystallized from water, dried by lyophilization to give a white solid.

EXAMPLE 224. Preparation of (I-60) (3S)-3-[5-[4-[[1-[4-[(1S,2R)-6-hydroxy-2-tetralin- 6-yl-tetralin-1-yl]phenyl]-4-piperidyl]methyl]piperazin-1-yl ]-1-oxo-isoindolin-2- yl]piperidine-2,6-dione Step 1: A mixture of 6-bromotetralin (500 mg, 2.37 mmol, 1 eq), 4,4,5,5-tetramethyl-2-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (902.20 mg, 3.55 mmol, 1.5 eq), potassium acetate (464.91 mg, 4.74 mmol, 2 eq), cyclopentyl(diphenyl)phosphane;dichloromethane;dichloropalla dium;iron (193.43 mg, 236.86 umol, 0.1 eq) in dioxane (15 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 80 °C for 16 hr under N2 atmosphere. TLC (Petroleum ether/Ethyl acetate=5/1, R _f =0.4) showed new spot was formed. The reaction mixture was quenched by addition H ₂ O 50 mL, and then diluted with 50 mL H ₂ O and extracted with Ethyl acetate(50 mL * 2). The combined organic layer was dried over Na ₂ SO ₄ , filtered and concentrated give the crude product, The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate=0% to 20%), Compound 4,4,5,5-tetramethyl-2-tetralin-6-yl-1,3,2-dioxaborolane (350 mg, 1.36 mmol, 57.24% yield) was obtained as a white oil. LC-MS (ESI ⁺ ) m/z: 259.1 (M+H) ⁺ . Step 2: A mixture of 1-[4-(6-benzyloxy-2-bromo-3,4-dihydronaphthalen-1-yl)phenyl] -4- (dimethoxymethyl)piperidine (600 mg, 1.09 mmol, 1 eq), 4,4,5,5-tetramethyl-2-tetralin-6-yl- 1,3,2-dioxaborolane (282.40 mg, 1.09 mmol, 1 eq), cyclopentyl(diphenyl)phosphane;dichloromethane;dichloropalla dium;iron (89.33 mg, 109.39 umol, 0.1 eq), Na ₂ CO ₃ (347.82 mg, 3.28 mmol, 3 eq) in dioxane (10 mL) and H ₂ O (2.5 mL) was degassed and purged with N ₂ for 3 times, and then the mixture was stirred at 100 °C for 12 hr under N ₂ atmosphere. LCMS showed 81% of desired compound was detected. The reaction mixture was quenched by addition 50 mL H ₂ O, and then diluted with 50 mL H ₂ O and extracted with Ethyl acetate (50 mL * 2. The combined organic layer was dried over Na ₂ SO ₄ , filtered and concentrated give the crude product, The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate=0% to 20%), Compound 1-[4-(6-benzyloxy-2-tetralin-6-yl-3,4- dihydronaphthalen-1-yl)phenyl]-4-(dimethoxymethyl)piperidine (620 mg, 1.03 mmol, 94.50% yield) was obtained as a yellow oil. LC-MS (ESI ⁺ ) m/z: 600.2 (M+H) ⁺ . Step 3: A mixture of 1-[4-[4-(dimethoxymethyl)-1-piperidyl]phenyl]-2-tetralin-6-y l-tetralin-6-ol (527.15 mg, 1.03 mmol, 1 eq) , Pd/C (500 mg, 4.71 mmol, 10% purity) ,in MeOH (5 mL) and THF (5 mL) was degassed and purged with H ₂ for 3 times, and then the mixture was stirred at 50 °C for 12 hr under H ₂ atmosphere. LCMS showed 84.236% of desired compound was detected. The reaction mixture was filtered and concentrated to dryness in vacuo to give a white solid. The white solid was subjected by SFC: Column: DAICEL CHIRALCEL OD(250mm*30mm,10um) Mobile phase: [0.1%NH3H2O ETOH];B%: 35%-35%,min Column Temp: 38 °C; Nozzle Pressure: 100Bar; Nozzle Temp: 60 °C; Evaporator Temp: 20 °C; Trimmer Temp: 25 °C ; Wavelength: 220nm. The aqueous phase was lyophilized to dryness to give Compound (1R,2S)-1-[4-[4-(dimethoxymethyl)-1-piperidyl]phenyl]-2-tetr alin-6-yl-tetralin-6-ol (202 mg, 394.77 umol, 38.32% yield) was obtained as a yellow solid. (1S,2R)-1-(4-(4-(dimethoxymethyl)piperidin-1-yl)phenyl)-1,2, 3,4,5',6',7',8'-octahydro-[2,2'- binaphthalen]-6-ol (160 mg, 312.69 umol, 30.35% yield) was obtained as a yellow solid. LC-MS (ESI ⁺ ) m/z: 512.2 (M+H) ⁺ . Step 4: To a solution of (1S,2R)-1-[4-[4-(dimethoxymethyl)-1-piperidyl]phenyl]-2-tetr alin-6-yl- tetralin-6-ol (160 mg, 312.69 umol, 1 eq) was added H2SO4 (10 mL) and THF (10 mL) .The mixture was stirred at 70 °C for 12 hr. LCMS showed 92% of desired compound was detected. The reaction mixture was quenched by addition NaHCO ₃ 30 mL at 25°C, and then diluted with H ₂ O 20 mL and extracted with Ethyl acetate (50 mL * 3). The combined organic layers were washed with brine (50 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give the compound as a yellow oil. The crude product 1-[4-[(1S,2R)-6-hydroxy-2-tetralin-6- yl-tetralin-1-yl]phenyl]piperidine-4-carbaldehyde (130 mg, 279.19 umol, 89.29% yield) was used into the next step without further purification. LC-MS (ESI ⁺ ) m/z: 484.1 (M+H ₂ O) ⁺ . Step 5: A mixture of 1-[4-[(1S,2R)-6-hydroxy-2-tetralin-6-yl-tetralin-1-yl]phenyl ]piperidine-4- carbaldehyde (130.00 mg, 279.19 umol, 1 eq), HOAc (69.64 mg, 1.16 mmol, 66.33 uL, 3 eq), NaOAc (231.27 mg, 837.58 umol, 3 eq) and (3S)-3-(1-oxo-5-piperazin-1-yl-isoindolin-2- yl)piperidine-2,6-dione (139.76 mg, 279.19 umol, 1 eq, p-TSA salt) in DCM (4 mL) and MeOH (4 mL) was stirred at 20 ^o C for 1 h, sodium acetate (68.71 mg, 837.58 umol, 3 eq), Na(OAc) ₃ BH (118.35 mg, 558.39 umol, 2 eq) was added to the reaction and then the mixture was stirred at r.t. for 12 hr. The reaction mixture was quenched by addition 50 mL H2O, and then diluted with 50 mL H ₂ O and extracted with Ethyl acetate 50 mL (50 mL * 2). The organic layers were dried with anhydrous Na ₂ SO ₄ , filtered, and concentrated to give the crude product. The residue was purified by prep-HPLC (column: Welch Xtimate C18150*30mm*5um; mobile phase: [water (FA)- ACN];B%:32%-62%,7min). Compound (3S)-3-[5-[4-[[1-[4-[(1S,2R)-6-hydroxy-2-tetralin-6-yl- tetralin-1-yl]phenyl]-4-piperidyl]methyl]piperazin-1-yl]-1-o xo-isoindolin-2-yl]piperidine-2,6- dione (34.4 mg, 44.22 umol, 15.84% yield) was obtained as a yellow soild. LC-MS (ESI ⁺ ) m/z: 778.2 (M+H) ⁺ HPLC: 99.203 % purity at 220 nm SFC: R _t : 3.280 min; Area: 85.353%; method: IC_MeOH_DEA_MeCN_50_1ML_15MIN_10CM.lcm ¹ H NMR (400 MHz, DMSO-d ₆ ) į = 10.98 - 10.93 (m, 1H), 9.35 - 8.92 (m, 1H), 8.20 - 8.14 (m, 0.590H), 7.55 - 7.49 (m, 1H), 7.09 - 7.03 (m, 2H), 6.84 - 6.77 (m, 1H), 6.67 - 6.62 (m, 1H), 6.61 - 6.54 (m, 3H), 6.53 - 6.46 (m, 2H), 6.42 - 6.35 (m, 1H), 6.27 - 6.21 (m, 2H), 5.09 - 5.01 (m, 1H), 4.36 - 4.29 (m, 1H), 4.25 - 4.17 (m, 1H), 4.06 (br d, J = 4.5 Hz, 1H), 3.59 - 3.49 (m, 4H), 3.46 - 3.35 (m, 6H), 3.15 (br dd, J = 2.5, 12.8 Hz, 2H), 2.97 - 2.83 (m, 3H), 2.69 - 2.55 (m, 5H), 2.45 - 2.33 (m, 2H), 2.23 - 2.16 (m, 2H), 2.13 - 1.90 (m, 2H), 1.80 - 1.59 (m, 8H), 1.26 - 1.09 (m, 2H). Stereochemistry war arbitrarily assigned EXAMPLE 225. Preparation of (I-61) (R)-3-(5-(4-((1-(4-((1S,2R)-6'-hydroxy- 1',2',3',4',5,6,7,8-octahydro-[1,2'-binaphthalen]-1'-yl)phen yl)piperidin-4- yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2, 6-dione Step 1: A mixture of (1S,2R)-1'-(4-(4-(dimethoxymethyl)piperidin-1-yl)phenyl)- 1',2',3',4',5,6,7,8-octahydro-[1,2'-binaphthalen]-6'-ol (150 mg, 1 Eq, 293 ^mol) in 10% H2SO4 (1.5 mL) and THF (1.5 mL), then the mixture was stirred at 60 °C for 16 hour. The solvent was removed under vaccum. The residue was dissolved in water (20 mL), the aqueous solution was added NaHCO ₃ to adjust pH=6.and washed by ethyl acetate (20 mL*2). The combined organic layer was dried over Na ₂ SO ₄ , filtered and concentrated under vaccum to give 1-(4-((1S,2R)-6'- hydroxy-1',2',3',4',5,6,7,8-octahydro-[1,2'-binaphthalen]-1' -yl)phenyl)piperidine-4-carbaldehyde (100 mg, 215 ^mol, 73.3%) as a yellow oil. LC-MS (ESI+) m/z: 466.1 (M+H)+. Step 2: A mixture of 1-(4-((1S,2R)-6'-hydroxy-1',2',3',4',5,6,7,8-octahydro-[1,2' -binaphthalen]- 1'-yl)phenyl)piperidine-4-carbaldehyde (100 mg, 1 Eq, 215 ^mol), (R)-3-(1-oxo-5-(piperazin-1- yl)isoindolin-2-yl)piperidine-2,6-dione, TsOH salt (140 mg, 1.3 Eq, 279 ^mol) and Sodium acetate (88.1 mg, 5 Eq, 1.07 mmol) and Acetic acid (38.7 mg, 37.1 ^L, 3 Eq, 644 ^mol) in DCM (2 mL) and MeOH (2 mL) at 25 °C for 1 hour, then Sodium triacetoxyborohydride (91.0 mg, 2 Eq, 430 ^mol) was added to the mixture and was stirred at 25 °C for 16 hour. The reaction was treated with H ₂ O (20 mL), extracted with EtOAc (20 mL*2). The combined extracts was dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to dryness in vacuo to give a residue. The residue was purified by prep.HPLC (column: Welch Xtimate C18150*30mm*5um; mobile phase: [water (FA)-ACN]; B%: 27%-57%, 7min). The aqueous phase was lyophilized to dryness to give (R)-3-(5-(4-((1-(4-((1S,2R)-6'-hydroxy-1',2',3',4',5,6,7,8-o ctahydro-[1,2'-binaphthalen]- 1'-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoi ndolin-2-yl)piperidine-2,6-dione (100.5 mg, 124.0 ^mol, 57.7%, 95.974% Purity) as a white solid. LC-MS (ESI+) m/z: 778.2 (M+H) ⁺ HPLC: 95.974%, purity at 220 nm. SFC: retention time, 3.095 min; Area, 89.696%; ¹ H NMR (400 MHz, DMSO-d ₆ ) į = 11.01 - 10.92 (m, 1H), 9.21 - 9.01 (m, 1H), 8.19 - 8.12 (m, 0.383H), 7.56 - 7.48 (m, 1H), 7.11 - 7.00 (m, 2H), 6.86 - 6.78 (m, 1H), 6.73 - 6.62 (m, 2H), 6.61 - 6.57 (m, 1H), 6.56 - 6.50 (m, 2H), 6.50 - 6.45 (m, 1H), 6.19 - 6.12 (m, 2H), 6.00 - 5.93 (m, 1H), 5.09 - 5.01 (m, 1H), 4.37 - 4.29 (m, 1H), 4.25 - 4.17 (m, 1H), 4.16 - 4.10 (m, 1H), 3.55 - 3.48 (m, 2H), 3.48 - 3.27 (m, 11H), 2.98 - 2.83 (m, 5H), 2.81 - 2.66 (m, 2H), 2.57 (br s, 1H), 2.40 - 2.32 (m, 1H), 2.24 - 2.06 (m, 3H), 2.02 - 1.91 (m, 1H), 1.90 - 1.82 (m, 1H), 1.80 - 1.69 (m, 5H), 1.68 - 1.50 (m, 2H), 1.25 - 1.08 (m, 2H). Stereochemistry was arbitrarily assigned

EXAMPLE 226. Preparation of (I-58) (S)-3-(5-(4-((1-(4-((1S,2R)-2-(bicyclo[4.2.0]octa- 1(6),2,4-trien-3-yl)-6-hydroxy-1,2,3,4-tetrahydronaphthalen- 1-yl)phenyl)piperidin-4- yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2, 6-dione Step 1: A solution (5S,6R)-6-(bicyclo[4.2.0]octa-1,3,5-trien-3-yl)-5-(4-(4- (dimethoxymethyl)piperidin-1-yl)phenyl)-5,6,7,8-tetrahydrona phthalen-2-ol (98 mg, 1 Eq, 0.20 mmol) in 10% H2SO4 (7 mL) and THF (7 mL) was stirred at 70 °C for 16 hour to give a yellow suspension. The solvent was removed under vaccum. The aqueous solution was added NaHCO ₃ to adjust pH=6. The residue was dissolved in water (20 mL) and extracted by ethyl acetate (50 mL). The combined organic layer was dried over Na ₂ SO ₄ , filtered and concentrated under vaccum to give 1-(4-((1S,2R)-2-(bicyclo[4.2.0]octa-1,3,5-trien-3-yl)-6-hydr oxy-1,2,3,4- tetrahydronaphthalen-1-yl)phenyl)piperidine-4-carbaldehyde (80 mg, 0.18 mmol, 88%, 97.073% Purity) as a yellow oil. LC-MS (ESI ⁺ ) m/z: 438.2 (M+H) ⁺ . Step 2: To a solution of 1-(4-((1S,2R)-2-(bicyclo[4.2.0]octa-1,3,5-trien-3-yl)-6-hydr oxy-1,2,3,4- tetrahydronaphthalen-1-yl)phenyl)piperidine-4-carbaldehyde (80 mg, 1 Eq, 0.18 mmol), (R)-3- (1-oxo-5-(piperazin-1-yl)isoindolin-2-yl)piperidine-2,6-dion e, TsOH (91 mg, 1 Eq, 0.18 mmol) in DCM (3 mL), MeOH (3 mL) was added Sodium acetate (45 mg, 30 ^L, 3 Eq, 0.55 mmol) was stirred at 25 °C for 60 mins, Then Sodium triacetoxyborohydride (77 mg, 54 ^L, 2 Eq, 0.37 mmol) and acetic acid (33 mg, 32 ^L, 3 Eq, 0.55 mmol) was added .The mixture was stirred at 25 °C for 16 hour. The reaction mixture was concentrated under reduced pressure to remove solvent. The reaction was treated with H ₂ O (20 mL), extracted with EtOAc (20 mL). The combined extracts was dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to dryness in vacuo to give a residue. The residue was purified by prep-HPLC (column: Welch Xtimate C18 150*30mm*5um;mobile phase: [water(FA)-ACN];B% 25%-55%,7min) to give (S)-3-(5-(4-((1- (4-((1S,2R)-2-(bicyclo[4.2.0]octa-1(6),2,4-trien-3-yl)-6-hyd roxy-1,2,3,4-tetrahydronaphthalen-1- yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindo lin-2-yl)piperidine-2,6-dione was obtained as a white solid. LC-MS (ESI ⁺ ) m/z: 750.2 (M+H) ⁺ . LCMS: calc. for C47H51N5O4: 749.94, found: [M+H]+ 750.2. HPLC: 99.850% purity at 220 nm. NMR (400 MHz, DMSO-d ₆ ) į = 10.99 - 10.92 (m, 1H), 8.20 - 8.15 (m, 0.551H), 7.55 - 7.49 (m, 1H), 7.10 - 7.02 (m, 2H), 6.88 - 6.82 (m, 1H), 6.69 - 6.62 (m, 2H), 6.61 - 6.54 (m, 3H), 6.51 - 6.46 (m, 2H), 6.27 - 6.19 (m, 2H), 5.11 - 5.01 (m, 1H), 4.38 - 4.28 (m, 1H), 4.26 - 4.15 (m, 1H), 4.12 - 4.05 (m, 1H), 3.59 - 3.48 (m, 3H), 3.46 - 3.34 (m, 6H), 3.11 - 2.84 (m, 8H), 2.71 - 2.58 (m, 1H), 2.46 - 2.43 (m, 2H), 2.41 - 2.29 (m, 2H), 2.23 - 2.17 (m, 2H), 2.14 - 1.89 (m, 3H), 1.81 - 1.73 (m, 2H), 1.69 - 1.60 (m, 2H), 1.25 - 1.11 (m, 2H) SFC: retention time, 3.832 min; Area, 94.215%; Stereochemistry was arbitrarily assigned.

EXAMPLE 227. Preparation of (I-101) (R)-3-(5-(4-((1-(4-((1S,2R)-2- (bicyclo[4.2.0]octa-1,3,5-trien-2-yl)-6-hydroxy-1,2,3,4-tetr ahydronaphthalen-1- yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindo lin-2-yl)piperidine-2,6-dione Step 1: A mixture of (5S,6R)-6-(bicyclo[4.2.0]octa-1,3,5-trien-2-yl)-5-(4-(4- (dimethoxymethyl)piperidin-1-yl)phenyl)-5,6,7,8-tetrahydrona phthalen-2-ol (55 mg, 1 Eq, 0.11 mmol) in 10% H ₂ SO ₄ (1.5 mL) and THF (1.5 mL), then the mixture was stirred at 60 °C for 16 hour. The solvent was removed under vaccum. The residue was dissolved in water (20 mL), the aqueous solution was added NaHCO ₃ to adjust pH=6.and extracted by ethyl acetate (20 mL*2). The combined organic layer was dried over Na ₂ SO ₄ , filtered and concentrated under vaccum to give 1-(4-((1S,2R)-2-(bicyclo[4.2.0]octa-1,3,5-trien-2-yl)-6-hydr oxy-1,2,3,4- tetrahydronaphthalen-1-yl)phenyl)piperidine-4-carbaldehyde (50 mg, 0.11 mmol, 100%) as a yellow oil. LC-MS (ESI+) m/z: 438.1 (M+H)+. Step 2: A mixture of 1-(4-((1S,2R)-2-(bicyclo[4.2.0]octa-1,3,5-trien-2-yl)-6-hydr oxy-1,2,3,4- tetrahydronaphthalen-1-yl)phenyl)piperidine-4-carbaldehyde (50 mg, 1 Eq, 0.11 mmol), (R)-3- (1-oxo-5-(piperazin-1-yl)isoindolin-2-yl)piperidine-2,6-dion e, TsOH salt (74 mg, 1.3 Eq, 0.15 mmol) and Sodium acetate (47 mg, 5 Eq, 0.57 mmol) and Acetic acid (21 mg, 20 ^L, 3 Eq, 0.34 mmol) in DCM (2 mL) and MeOH (2 mL) at 25 °C for 1 hour, then Sodium 25 °C for 16 hour. The reaction was treated with H2O (20 mL), extracted with EtOAc (20 mL*2). The combined extracts was dried over anhydrous Na2SO4, filtered and concentrated to dryness in vacuo to give a residue. The residue was purified by prep.HPLC (column: Welch Xtimate C18150*30mm*5um; mobile phase: [water (FA)-ACN]; B%: 26%-46%, 7min). The aqueous phase was lyophilized to dryness to give (R)-3-(5-(4-((1-(4-((1S,2R)-2- (bicyclo[4.2.0]octa-1,3,5-trien-2-yl)-6-hydroxy-1,2,3,4-tetr ahydronaphthalen-1- yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindo lin-2-yl)piperidine-2,6-dione (35.3 mg, 46.2 ^mol, 40% yield, 98.192% Purity) as a white solid. LC-MS (ESI+) m/z: 750.2 (M+H) ⁺ HPLC: 98.192%, purity at 220 nm. SFC: retention time, 3.045 min; Area, 88.894%; Stereochemistry was arbitrarily assigned. ¹ H NMR (400 MHz, DMSO-d ₆ ) į = 11.04 - 10.82 (m, 1H), 8.23 - 8.18 (m, 0.584H), 7.56 - 7.47 (m, 1H), 7.11 - 7.01 (m, 3H), 6.95 - 6.88 (m, 1H), 6.86 - 6.80 (m, 1H), 6.71 - 6.63 (m, 1H), 6.62 - 6.54 (m, 3H), 6.52 - 6.46 (m, 1H), 6.22 - 6.13 (m, 2H), 5.10 - 5.01 (m, 1H), 4.38 - 4.29 (m, 1H), 4.25 - 4.16 (m, 1H), 4.08 - 4.01 (m, 1H), 3.61 - 3.49 (m, 4H), 3.28 (br s, 5H), 3.23 - 3.14 (m, 2H), 2.97 - 2.84 (m, 4H), 2.74 - 2.66 (m, 2H), 2.63 - 2.53 (m, 3H), 2.37 - 2.31 (m, 1H), 2.23 - 2.15 (m, 2H), 2.08 - 1.92 (m, 2H), 1.79 - 1.62 (m, 5H), 1.26 - 1.10 (m, 2H). EXAMPLE 228. Preparation of (I-114) (3S)-3-[5-[4-[[1-[4-[(1S,2R)-6-hydroxy-2-(2- pyridyl)tetralin-1-yl]phenyl]-4-piperidyl]methyl]piperazin-1 -yl]-1-oxo-isoindolin-2- yl]piperidine-2,6-dione and (I-115) (3S)-3-[5-[4-[[1-[4-[(1R,2S)-6-hydroxy-2-(2-

pyridyl)tetralin-1-yl]phenyl]-4-piperidyl]methyl]piperazi n-1-yl]-1-oxo-isoindolin-2- yl]piperidine-2,6-dione Step 1: To a solution of 1-[4-(6-benzyloxy-2-bromo-3,4-dihydronaphthalen-1-yl)phenyl] -4- (dimethoxymethyl)piperidine (1 g, 1.82 mmol, N/A purity, 1 eq) and tributyl(2-pyridyl)stannane (671.17 mg, 1.82 mmol, 1 eq) in toluene (10 mL) was added [2-(2- aminophenyl)phenyl]palladium(1+);bis(1-adamantyl)-butyl-phos phane;methanesulfonate (132.77 mg, 182.31 Pmol, 0.1 eq) ,CuI (34.72 mg, 182.3 Pmol, 0.1 eq) and CsF (553.88 mg, 3.65 mmol, 134.44 PL, 2 eq). The mixture was stirred at 95 °C for 12 h. The reaction mixture was quenched by addition of water (50 mL), extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (10 mL), dried over Na ₂ SO ₄ , filtered and concentrated chromatography (from pure PE to PE/EtOAc = 3/1, TLC: PE/EtOAc = 3/1, Rf = 0.49) to yield 2- [6-benzyloxy-1-[4-[4-(dimethoxymethyl)-1-piperidyl]phenyl]-3 ,4-dihydronaphthalen-2- yl]pyridine (800 mg, 1.26 mmol, 69.0% yield, 86.0% purity) as green oil. LC-MS (ESI ⁺ ) m/z 547.4 [M+H] ⁺ . 8.55 (s, 1H), 7.46-7.32 (m, 6H), 6.96 (d, J = 8.2 Hz, 3H), 6.89- 6.73 (m, 5H), 6.68 (dd, J = 2.6, 8.6 Hz, 1H), 5.08 (s, 2H), 4.10 (t, J = 3.6 Hz, 1H), 3.72 (br d, J = 12.2 Hz, 2H), 3.39 (s, 6H), 2.95 (s, 4H), 2.68 (br t, J = 11.4 Hz, 2H), 1.88 (d, J = 12.5 Hz, 2H), 1.76 (s, 1H), 1.51-1.40 (m, 2H) Step 2: To a solution of 2-[6-benzyloxy-1-[4-[4-(dimethoxymethyl)-1-piperidyl]phenyl] -3,4- dihydronaphthalen-2-yl]pyridine (750 mg, 1.18 mmol, 86% purity, 1 eq) in MeOH (3 mL) was added Pd/C (600 mg, 10% purity).The mixture was stirred under H ₂ (15 Psi) at 25 °C for 1 h. The reaction mixture was filtered and concentrated to yield a residue. The residue was separated by chiral SFC(column: DAICEL CHIRALCEL OJ(250mm*30mm,10um);mobile phase: [0.1%NH ₃ H ₂ O ETOH]; B%: 25% - 25%, min), followed by lyophilization to yield (1S,2R)-1-[4- [4-(dimethoxymethyl)-1-piperidyl]phenyl]-2-(2-pyridyl)tetral in-6-ol (220 mg, 470.14 Pmol, 39.8% yield, 98.0% purity, SFC: R _t = 2.638) as a red solid and (1R,2S)-1-[4-[4- (dimethoxymethyl)-1-piperidyl]phenyl]-2-(2-pyridyl)tetralin- 6-ol (250 mg, 534.25 Pmol, 45.3% yield, 98.0% purity, SFC: R _t = 2.986) as a red solid. LC-MS (ESI ⁺ ) m/z 459.4 [M+H] ⁺ NMR of (1S,2R)-1-[4-[4-(dimethoxymethyl)-1-piperidyl]phenyl]-2-(2-p yridyl)tetralin-6- ol: (500MHz, CDCl ₃ ) į = 8.57 (d, J = 4.4 Hz, 1H), 7.39 (dt, J = 1.7, 7.6 Hz, 1H), 7.09 (dd, J = 5.1, 7.1 Hz, 1H), 6.78 (d, J = 8.2 Hz, 1H), 6.71 (d, J = 2.3 Hz, 1H), 6.61-6.54 (m, 3H), 6.50 (d, J = 7.9 Hz, 1H), 6.27 (d, J = 8.7 Hz, 2H), 4.45 (d, J = 5.0 Hz, 1H), 4.06 (d, J = 7.5 Hz, 1H), 3.57- 3.50 (m, 3H), 3.35 (s, 6H), 3.09-2.93 (m, 2H), 2.52 (br t, J = 11.4 Hz, 2H), 2.18 (dq, J = 6.0, 12.8 Hz, 1H), 1.88 (dd, J = 5.4, 12.4 Hz, 1H), 1.80 (br d, J = 11.1 Hz, 2H), 1.73 - 1.65 (m, 2H), 1.40 (br d, J = 11.9 Hz, 2H) ¹ H NMR of (1R,2S)-1-[4-[4-(dimethoxymethyl)-1-piperidyl]phenyl]-2-(2-p yridyl)tetralin-6- ol: (500MHz, CDCl ₃ ) į = 8.57 (d, J = 4.1 Hz, 1H), 7.41 (t, J = 7.6 Hz, 1H), 7.13-7.08 (m, 1H), 6.76 (d, J = 8.4 Hz, 1H), 6.71 (d, J = 2.3 Hz, 1H), 6.59 (dd, J = 2.6, 8.2 Hz, 3H), 6.51 (d, J = 7.9 Hz, 1H), 6.28 (d, J = 8.5 Hz, 2H), 4.46 (br d, J = 5.0 Hz, 1H), 4.06 (d, J = 7.3 Hz, 1H), 3.54 (br = 6.0, 12.7 Hz, 1H), 1.87 (dd, J = 5.6, 12.4 Hz, 1H), 1.81 (d, J = 12.2 Hz, 2H), 1.69 (dt, J = 3.9, 7.6 Hz, 2H), 1.43 (s, 2H) Step 3: To a solution of (1S,2R)-1-[4-[4-(dimethoxymethyl)-1-piperidyl]phenyl]-2-(2- pyridyl)tetralin-6-ol (60 mg, 128.22 Pmol, 98% purity, 1 eq) in DCM (2.5 mL) was added TFA (770.00 mg, 6.75 mmol, 0.5 mL, 52.67 eq).The mixture was stirred at 25 °C for 1 h. The reaction mixture was quenched by addition of water (30 mL), extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (10 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to yield 1-[4-[(1S,2R)-6-hydroxy-2-(2-pyridyl)tetralin-1- yl]phenyl]piperidine-4-carbaldehyde (60 mg, 116.36 Pmol, 90.7% yield, 80.0% purity) as a brown solid which was used in the next step without further purification. LC-MS (ESI ⁺ ) m/z 413.3 [M+H] ⁺ . Step 4: To a solution of 1-[4-[(1S,2R)-6-hydroxy-2-(2-pyridyl)tetralin-1-yl]phenyl]pi peridine-4- carbaldehyde (60 mg, 116.36 Pmol, 80% purity, 1 eq) and (3S)-3-(1-oxo-5-piperazin-1-yl- isoindolin-2-yl)piperidine-2,6-dione (87.37 mg, 174.54 Pmol, 1.5 eq, TsOH) in DCM (2.5 mL) and MeOH (2.5 mL), after stirred 30 min was added NaBH(OAc) ₃ (80.00 mg, 377.46 umol, 3.24 eq). The mixture was stirred at 25 °C for 12 h. The reaction mixture was concentrated to yield a residue. The residue was purified by preparative HPLC (column: Welch Xtimate C18 150*25mm*5um;mobile phase: [water( NH4HCO3)-ACN];B%: 40%-55%,13min), followed by lyophilization to yield (3S)-3-[5-[4-[[1-[4-[(1S,2R)-6-hydroxy-2-(2-pyridyl)tetralin -1-yl]phenyl]- 4-piperidyl]methyl]piperazin-1-yl]-1-oxo-isoindolin-2-yl]pip eridine-2,6-dione (25.7 mg, 35.45 Pmol, 30.47% yield, 100% purity) as a white solid. LC-MS (ESI ⁺ ) m/z 725.5 [M+H] ⁺ . LCMS: calc. for C44H48N6O4: 724.37, found: [M+H] ⁺ 725.5. HPLC: 100% purity at 220 nm. ¹ H NMR (500MHz, CD ₃ OD) į = 8.45 (d, J = 4.9 Hz, 1H), 7.63 (d, J = 8.4 Hz, 1H), 7.51 (dt, J = 1.8, 7.7 Hz, 1H), 7.20 (dd, J=5.4, 7.1 Hz, 1H), 7.12-7.04 (m, 2H), 6.72 (d, J = 8.4 Hz, 1H), 6.68- 6.64 (m, 2H), 6.61 (d, J = 8.7 Hz, 2H), 6.53 (dd, J=2.5, 8.3 Hz, 1H), 6.28 (d, J = 8.5 Hz, 2H), 5.09 (dd, J = 5.2, 13.3 Hz, 1H), 4.43-4.35 (m, 2H), 3.54-3.47 (m, 3H), 3.40-3.33 (m, 5H), 3.10- 2.95 (m, 2H), 2.94-2.84 (m, 1H), 2.81-2.74 (m, 1H), 2.64-2.52 (m, 6H), 2.46 (dq, J = 4.8, 13.2 Hz, 1H), 2.32-2.22 (m, 3H), 2.18-2.11 (m, 1H), 1.91-1.83 (m, 3H), 1.75-1.64 (m, 1H), 1.34-1.27 (m, 2H). Step 5: To a solution of (1R,2S)-1-[4-[4-(dimethoxymethyl)-1-piperidyl]phenyl]-2-(2- pyridyl)tetralin-6-ol (60 mg, 128.22 Pmol, 98% purity, 1 eq) in DCM (2.5 mL) was added TFA (770.00 mg, 6.75 mmol, 0.5 mL, 52.67 eq).The mixture was stirred at 25 °C for 1 h. The reaction mixture was quenched by addition of water (30 mL), extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (10 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to yield 1-[4-[(1R,2S)-6-hydroxy-2-(2-pyridyl)tetralin-1- yl]phenyl]piperidine-4-carbaldehyde (60 mg, 116.36 Pmol, 90.75% yield, 80% purity) as a brown solid which was used in the next step without further purification. LC-MS (ESI ⁺ ) m/z 413.3 [M+H] ⁺ . Step 6: To a solution of 1-[4-[(1R,2S)-6-hydroxy-2-(2-pyridyl)tetralin-1-yl]phenyl]pi peridine-4- carbaldehyde (60 mg, 116.36 Pmol, 80% purity, 1 eq) and (3S)-3-(1-oxo-5-piperazin-1-yl- isoindolin-2-yl)piperidine-2,6-dione (87.37 mg, 174.54 Pmol, 1.5 eq, TsOH) in DCM (2.5 mL) and MeOH (2.5 mL), after stirred 30 min was added NaBH(OAc) ₃ (80.00 mg, 377.46 Pmol, 3.24 eq).The mixture was stirred at 25 °C for 12 h. The residue was filtered and purified by preparative HPLC (column: Welch Xtimate C18150*25mm*5um;mobile phase: [water( NH4HCO3)-ACN];B%: 40%-55%, 13 min), followed by lyophilization to yield (3S)-3- [5-[4-[[1-[4-[(1R,2S)-6-hydroxy-2-(2-pyridyl)tetralin-1-yl]p henyl]-4-piperidyl]methyl]piperazin- 1-yl]-1-oxo-isoindolin-2-yl]piperidine-2,6-dione (40.2 mg, 55.46 Pmol, 47.66% yield, 100% purity) as a white solid. LC-MS (ESI ⁺ ) m/z 713.5 [M+H] ⁺ . LCMS: calc. for C44H48N4O5: 712.36, found: [M+H] ⁺ 713.5. HPLC: 100% purity at 220 nm. ¹ H NMR (500MHz, CD ₃ OD) į = 8.45 (d, J = 4.1 Hz, 1H), 7.63 (d, J = 8.5 Hz, 1H), 7.51 (dt, J = 1.8, 7.7 Hz, 1H), 7.20 (dd, J = 5.2, 6.7 Hz, 1H), 7.11-7.04 (m, 2H), 6.71 (d, J = 8.4 Hz, 1H), 6.68 - 6.63 (m, 2H), 6.61 (d, J = 8.7 Hz, 2H), 6.53 (dd, J = 2.5, 8.3 Hz, 1H), 6.28 (d, J = 8.7 Hz, 2H), 5.09 (dd, J = 5.2, 13.4 Hz, 1H), 4.43-4.32 (m, 2H), 3.55-3.46 (m, 3H), 3.40-3.32 (m, 5H), 3.10- 2.95 (m, 2H), 2.95-2.84 (m, 1H), 2.81-2.74 (m, 1H), 2.65-2.51 (m, 6H), 2.46 (dq, J = 4.7, 13.2 Hz, 1H), 2.33-2.21 (m, 3H), 2.18-2.11 (m, 1H), 1.93-1.80 (m, 3H), 1.69 (br s, 1H), 1.30 (q, J = 11.8 Hz, 2H) EXAMPLE 229. Preparation of (I-107) (R)-3-(5-(4-((1-(4-((1R,2S)-6-hydroxy-2- (pyridine -3-yl)-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperidin-4- yl)methyl)piperazin- 1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione Step 1: A mixture of starting aryl bromide (1.50 g, 1 eq., 2.73 mmol), pyridin-3-ylboronic acid (336 mg, 1 eq., 2.73 mmol), sodium carbonate (290 mg, 1 eq., 2.73 mmol) and Reactant IV (2.00 g, 1 eq., 2.73 mmol) in Dioxane (15 mL) and water (3 mL) was degassed and purged with N ₂ for 3 times, and then the mixture was stirred at 80 °C for 4 hour under N ₂ atmosphere. LCMS showed the recationwas completed. The reaction mixture was quenched by addition EA 30 mL at 20 °C, and then diluted with water 30 mL and extracted with EA 90 mL (30 mL * 3). The combined organic layers were washed with EA 30 mL (10 mL * 3), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The crude material was purified on silica gel column chromatography (from PE/EtOAc = 1/0 to 1/1) to yield 3-(6-(benzyloxy)-1-(4- (4-(dimethoxymethyl)piperidin-1-yl)phenyl)-3,4- dihydronaphthalen-2-yl)pyridine (1.3 g, 2.4 mmol, 87 %) as a yellow solid ¹ H NMR (500 MHz, DMSO-d6) į: ppm 8.21 (dd, J=4.88, 1.53 Hz, 1 H), 8.16 (d, J=1.68 Hz, 1 H), 7.36 - 7.47 (m, 5 H), 7.30 - 7.35 (m, 1 H), 7.17 (dd, J=7.93, 4.73 Hz, 1 H), 6.94 (d, J=2.59 Hz, 1 H), 6.81 (s, 4 H), 6.74 (dd, J=8.62, 2.67 Hz, 1 H), 6.60 (d, J=8.70 Hz, 1 H), 5.09 (s, 2 H), 4.08 (d, J=6.56 Hz, 1 H), 3.68 (br d, J=12.21 Hz, 2 H), 3.27 (s, 6 H), 2.87 - 2.94 (m, 2 H), 2.66 - 2.74 (m, 2 H), 2.54 - 2.62 (m, 2 H), 1.65 - 1.74 (m, 3 H), 1.23 - 1.35 (m, 2 H). Step 2: To a solution of 3-(6-(benzyloxy)-1-(4-(4-(dimethoxymethyl)piperidin-1-yl)phe nyl)-3,4- dihydronaphthalen-2-yl)pyridine (0.50 g, 1 eq., 0.91 mmol) in EA (15 mL) was added Pd/C (10%, 0.5 g) under N ₂ atmosphere. The suspension was degassed and purged with H2 for 3 times. The mixture was stirred under H ₂ at 60^ for 24h. LCMS showed the recation was completed. The crude was purified by prep.HPLC together (Waters Xbridge BEH C18 100*30mm*10um, water(NH ₃ H ₂ O+NH ₄ HCO ₃ )-CAN as a mobile phase, from 40% to 70%, Gradient Time (min): 11, Flow Rate (ml/min): 50) to give 5-(4-(4- (dimethoxymethyl)piperidin- 1-yl)phenyl)-6-(pyridine-3-yl)-5,6,7,8-tetrahydronaphthalen- 2-ol (210 mg, 458 ^mol, 50 %) as a white solid. LC-MS (ESI ⁺ ) m/z: 459.2 (M+H) ⁺ . Step 3: 5-(4-(4- (dimethoxymethyl)piperidin-1-yl)phenyl)-6-(pyridine-3-yl)-5, 6,7,8- tetrahydronaphthalen-2-ol was purified by SFC(Column: DAICEL CHIRALPAK AS(250mm*30mm,10um)); Mobile phase: 0.1%NH ₃ H ₂ O ETOH; from 30% to 30%; Flow rate: 90 mL/min) to give (5R,6S)-5-(4-(4-(dimethoxymethyl)piperidin-1-yl)phenyl)-6-(p yridin-3-yl)- 5,6,7,8-tetrahydronaphthalen-2-ol (75 mg, 0.16 mmol, 36 %) as white solid. LC-MS (ESI ⁺ ) m/z: 459.3 (M+H) ⁺ . Step 4: To a solution of (5R,6S)-5-(4-(4-(dimethoxymethyl)piperidin-1-yl)phenyl)-6-(p yridin-3- yl)- 5,6,7,8-tetrahydronaphthalen-2-ol (70 mg, 1 eq., 0.15 mmol) in DCM (2 mL) was added TFA (52 mg, 35 ^L, 3 eq., 0.46 mmol).The mixture was stirred at 20 °C for 4 hour. LCMS showed the reaction was completed. The mixture was concentrated in vacuo to give crude product. No further purification as it is used for the next step directly. LC-MS (ESI+) m/z: 413.2(M+H)+. Step 5: To a solution of 1-(4-((1R,2S)-6-hydroxy-2-(pyridin-3-yl)-1,2,3,4-tetrahydron aphthalen- 1- yl)phenyl)piperidine-4-carbaldehyde (30.0 mg, 1 eq., 72.7 ^mol) and (R)-3-(1-oxo-5- (piperazin-1-yl)isoindolin-2-yl)piperidine-2,6-dione (35.8 mg, 1.5 eq., 109 ^mol) in DCE (3 L) dd d d i 4 th l h li (736 1 727 ^ l) t H 8 t 20 °C After addition, the mixture was stirred at this temperature for 0.5 hour, and then sodium triacetoxyhydroborate (30.8 mg, 2 eq., 145 ^mol) was added dropwise at 20 °C. The resulting mixture was stirred at 20 °C for 3 hour. LCMS showed the recation was completed. The crude was purified by prep.HPLC together (Welch Xtimate C18150*25mm*5um, water(NH ₃ H ₂ O+NH ₄ HCO ₃ )-ACN as a mobile phase, from 35% to 65%, Gradient Time (min): 11, Flow Rate (ml/min): 25) to give (R)-3-(5-(4-((1-(4-((1R,2S)-6-hydroxy-2-(pyridine -3-yl)- 1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperidin-4-yl)meth yl)piperazin-1-yl)-1-oxoisoindolin- 2-yl)piperidine-2,6-dione (27.4 mg, 37.8 ^mol, 52.0 %) as a white solid. LC-MS (ESI+) m/z: 725.3(M+H)+ ¹ H NMR (500 MHz, METHANOL-d4) į: ppm 8.15 - 8.48 (m, 1 H), 7.78 - 8.11 (m, 1 H), 7.64 (d, J=8.39 Hz, 1 H), 7.21 (br s, 2 H), 7.04 - 7.13 (m, 2 H), 6.62 - 6.74 (m, 4 H), 6.53 (dd, J=8.39, 2.59 Hz, 1 H), 6.36 (d, J=8.70 Hz, 2 H), 5.09 (dd, J=13.35, 5.11 Hz, 1 H), 4.33 - 4.53 (m, 2 H), 4.20 (d, J=5.19 Hz, 1 H), 3.51 - 3.57 (m, 2 H), 3.37 - 3.44 (m, 5 H), 2.99 - 3.09 (m, 2 H), 2.85 - 2.93 (m, 1 H), 2.66 - 2.81 (m, 5 H), 2.56 - 2.63 (m, 2 H), 2.43 - 2.52 (m, 1 H), 2.40 (br d, J=6.87 Hz, 2 H), 2.10 - 2.19 (m, 1 H), 1.87 (br d, J=12.97 Hz, 2 H), 1.70 - 1.81 (m, 2 H), 1.23 - 1.41 (m, 3 H). Stereochemistry was arbitrarily assigned

EXAMPLE 230. Preparation of (I-132) (S)-3-(5-(4-((1-(4-((1R,2S)-6- hydroxy-2- (pyridin-4-yl)-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)pipe ridin-4-yl)methyl)piperazin-1- yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione Step 1: To a mixture of 1-(4-(6-(benzyloxy)-2-bromo-3,4-dihydronaphthalen -1-yl)phenyl)-4- (dimethoxymethyl)piperidine (3.00 g, 1 Eq, 5.47 mmol), 4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)pyridine (1.12 g, 1 Eq, 5.47 mmol), PdCl2(dppf) (800 mg, 0.2 Eq, 1.09 mmol) and K ₂ CO ₃ (2.27 g, 3 Eq, 16.4 mmol) in Dioxane (100 mL) and H ₂ O (2 mL) was added reagent in one portion at 25°C under N2.The mixture was Suction air for 3 times under N ₂ , then heated to 85°C and stirred for 8 hours. TLC showed the reaction was completed. The mixture was cooled to 20°C, solid was filtered and concentrated in reduced pressure at 25 °C. The residue was poured into ice-water (w/w = 1/1) (200 mL) and stirred for 5 min. The aqueous phase was extracted with ethyl acetate (100 mL*2). The combined organic phase was washed with brine (50 mL*2), dried with anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuum. The residue was purified by silica gel chromatography (column height: 250 mm, diameter: 100 mm, 100-200 mesh silica gel, Petroleum ether/Ethyl acetate=5/1, N/1) to afford 5-(6-(benzyloxy)-2-(pyridin-4- yl)-3,4-dihydronaphthalen-1-yl)-2-(4-(dimethoxymethyl)piperi din-1-yl)benzene-1-ylium (2.54 g, 46 l 84 % 99% P it ) ll lid Step 2: To a mixture of 4-(6-(benzyloxy)-1-(4-(4-(dimethoxymethyl)piperidin -1-yl)phenyl)-3,4- dihydronaphthalen-2-yl)pyridine (2.25 g, 1 Eq, 4.12 mmol) and P d/C (438 mg, 1 Eq, 4.12 mmol) in Ethyl acetate (100 mL) was added reagent in one portion at 25°C under H ₂ .The mixture was stirred at 25 °C for 5 min, then heated to 80°C and stirred for 24 hours at 50 psi. TLC showed the reaction was completed. The mixture was cooled to 20°C, add 200 ml solution (DCM and MeOH1:1) to the mixture and filer solid and concentrated in reduced pressure at 30 °C to afford 5-(4-(4- (dimethoxymethyl)piperidin-1-yl)phenyl)-6-(pyridine-4-yl)-5, 6,7,8- tetrahydronaphthalen-2-ol (1.68 g, 3.88 mmol, 94.26 %) as yellow solid. Step 3: To a mixture of 5-(4-(4-(dimethoxymethyl)piperidin-1-yl)phenyl)-6-(pyridin-4 -yl)- 5,6,7,8-tetrahydronaphthalen-2-ol (1.00 g, 1 Eq, 2.18 mmol) in 5-(4-(4- (dimethoxymethyl)piperidin-1-yl)phenyl)-6-(pyridin-4-yl)-5,6 ,7,8-tetrahydronaphthalen-2-ol (1.00 g, 1 Eq, 2.18 mmol). SFC to give (5R,6S)-5-(4-(4-(dimethoxymethyl)piperidin-1- yl)phenyl)-6-(pyridin-4-yl)-5,6,7,8-tetrahydronaphthalen-2-o l (350 mg, 763 ^mol, 70.0 %) and as yellow solid. Step 4: To a mixture of (5R,6S)-5-(4-(4-(dimethoxymethyl)piperidin-1-yl) phenyl)-6-(pyridine- 4-yl)-5,6,7,8-tetrahydronaphthalen-2-ol (350 mg, 1 Eq, 763 ^mol) and TFA (435 mg, 294 ^L, 5 Eq, 3.82 mmol) in DCM (20 mL) was added reagent in one portion at 25°C .The mixture was stirred at 25 °C for 2 hours. TLC showed the reaction was completed. The mixture was concentrated in reduced pressure at 25 °C to provide 1-(4-((1R,2S)-6- hydroxy-2-(pyridine-4-yl)- 1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperidine-4-carbal dehyde (298 mg, 0.48 mmol, 62 %, 66% Purity) The residue was used to next step. Step 5: To a mixture of 1-(4-((1R,2S)-6-hydroxy-2-(pyridine-4-yl)-1,2,3,4- 1411yridine1411onaphthalene-1-yl)phenyl)piperidine-4-carbald ehyde (100 mg, 1 Eq, 242 ^mol), (S)-3-(1-oxo-5-(piperazin-1-yl)isoindolin-2-yl)piperidine-2, 6 -dione (159 mg, 2 Eq, 485 ^mol) in DCM (15 mL) was added reagent in one portion at 25°C. The mixture was stirred at 25 °C for 5 min, then add 4-methylmorfolin (49.0 mg, 53 ^L, 2 Eq, 485 ^mol) and Sodium triacetoxyborohydride (154 mg, 108 ^L, 3 Eq, 727 ^mol) to adjust PH to about 6 and stirred for 3 hours. TLC showed the reaction was completed. The mixture was reduced pressure at 25 °C. The residue was further purified by pre-HPLC to provide (S)-3-(5-(4-((1-(4-((1R,2S)-6- hydroxy-2-(pyridine-4-yl)-1,2,3,4-tetrahydronaphthalen-1-yl) phenyl)piperidin-4- 31.2 %, 100% Purity) as white solid. The white solid was re-crystallized from water, dried by lyophilization to give a white solid. EXAMPLE 231. Preparation of (I-59) (3S)-3-[5-[4-[[1-[4-[(1R,2S)-6-hydroxy-2-tetralin- 6-yl-tetralin-1-yl]phenyl]-4-piperidyl]methyl]piperazin-1-yl ]-1-oxo-isoindolin-2- yl]piperidine-2,6-dione Step 1: To a solution of (1R,2S)-1-[4-[4-(dimethoxymethyl)-1-piperidyl]phenyl]-2-tetr alin-6-yl- tetralin-6-ol (202 mg, 394.77 mmol, 1 eq) was added H ₂ SO ₄ (10 mL, 10% purity) and THF (10 mL). The mixture was stirred at 70 °C for 12h. LCMS showed 78% of desired compound was detected. The reaction mixture was quenched by addition NaHCO ₃ 30 mL at 25°C, and then diluted with H2O 20 mL and extracted with Ethyl acetate (50 mL * 3). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give the compound as a yellow oil. The crude product 1-[4-[(1R, 2S)-6- hydroxy-2-tetralin-6-yl-tetralin-1-yl]phenyl]piperidine-4-ca rbaldehyde (180 mg, 386.58 umol, 90% yield) was used into the next step without further purification. LC-MS (ESI ⁺ ) m/z: 484.2 (M+H O) ⁺ Step 2: A mixture of 1-[4-[(1R,2S)-6-hydroxy-2-tetralin-6-yl-tetralin-1-yl]phenyl ]piperidine-4- carbaldehyde (180 mg, 386.58 umol, 1 eq), HOAc (69.64 mg, 1.16 mmol, 66.33 uL, 3 eq), NaOAc (95.14 mg, 1.16 mmol, 3 eq) and (3S)-3-(1-oxo-5-piperazin-1-yl-isoindolin-2- yl)piperidine-2,6-dione (193.51 mg, 386.58 umol, 1 eq, p-TSA salt) in DCM (4 mL) and MeOH (4 mL) was stirred at 25 ^o C for 1 h, Na(OAc) ₃ BH (163.86 mg, 773.16 umol, 2 eq) was added to the reaction and then the mixture was stirred at 25°C for 16 hr. The reaction mixture was quenched by addition 50 mL H ₂ O, and then diluted with 50 mL H ₂ O and extracted with Ethyl acetate(50 mL * 2).The organic layers were dried with anhydrous Na ₂ SO ₄ , filtered, and concentrated to give the crude product. The residue was purified by prep-HPLC (column: Welch Xtimate C18150*30mm*5um; mobile phase: [water (FA)-ACN];B%:32%-62%,7min). Compound (3S)-3-[5-[4-[[1-[4-[(1R,2S)-6-hydroxy-2-tetralin-6-yl-tetra lin-1-yl]phenyl]-4- piperidyl]methyl]piperazin-1-yl]-1-oxo-isoindolin-2-yl]piper idine-2,6-dione (37 mg, 47.56 umol, 12.30% yield) was obtained as a yellow soild. LC-MS (ESI+) m/z: 778.2 (M+H)+ HPLC: 98.731 % purity at 220 nm. SFC: R _t : 3.206 min; Area, 91.573 %; Stereochemistry was arbitrarily assigned. ¹ H NMR (400 MHz, DMSO-d ₆ ) į = 10.99 - 10.92 (m, 1H), 9.14 - 9.06 (m, 1H), 8.18 - 8.09 (m, 0.497H), 7.57 - 7.50 (m, 1H), 7.13 - 7.02 (m, 2H), 6.85 - 6.77(m, 1H), 6.67 - 6.62 (m, 1H), 6.62 - 6.55 (m, 3H), 6.53 - 6.45 (m, 2H), 6.39 (s, 1H), 6.25 (br d, J = 8.5 Hz, 2H), 5.05 (dd, J = 5.0, 13.3 Hz, 1H), 4.37 - 4.30(m, 1H), 4.25 - 4.18 (m, 1H), 4.08 - 4.03 (m, 1H), 3.60 - 3.46 (m, 3H), 3.22 - 3.11 (m, 2H), 3.02 - 2.81 (m, 4H), 2.57 (br s, 9H), 2.43 - 2.28 (m, 4H), 2.15 - 1.91 (m, 3H), 1.80 - 1.60 (m, 9H), 1.25 - 1.11 (m, 2H).

EXAMPLE 232. Preparation of (I-62) (R)-3-(5-(4-((1-(4-((1R,2S)-6'-hydroxy- 1',2',3',4',5,6,7,8-octahydro-[1,2'-binaphthalen]-1'-yl)phen yl)piperidin-4- yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2, 6-dione Step 1: A mixture of 1-(4-(6-(benzyloxy)-2-bromo-3,4-dihydronaphthalen-1-yl)pheny l)-4- (dimethoxymethyl)piperidine (500 mg, 1 Eq, 912 ^mol), 5,6,7,8-Tetrahydronaphthalen-1- ylboronicacid (193 mg, 1.2 Eq, 1.09 mmol), Na ₂ CO ₃ (290 mg, 3 Eq, 2.73 mmol) and [1,1'- Bis(diphenylphosphino)ferrocene]dichloropalladium(II)Complex With Dichloromethane (74.4 mg, 0.1 Eq, 91.2 ^mol) in Dioxane (8 mL) and H ₂ O (2 mL) at r.t.. N ₂ was bubbled into the mixture for 5 min. The reaction mixture was heated at 100 °C for 16 hour. Then the reaction was cooled to room temperature. The mixture was treated with H ₂ O (100 mL), extracted with EtOAc (100 mL*2). The combined extracts was dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to dryness in vacuo to give a residue. The residue was subjected to column chromatography over silica gel (gradient elution: 0~20% ethyl acetate in petroleum ether). The pure fractions were collected and concentrated to dryness in vacuo to give 1-(4-(6'-(benzyloxy)-3',4',5,6,7,8- hexahydro-[1,2'-binaphthalen]-1'-yl)phenyl)-4-(dimethoxymeth yl)piperidine (520 mg, 867 ^mol, 95.1%) as a yellow oil. LC-MS (ESI ⁺ ) m/z: 600.2 (M+H) ⁺ . Step 2: A mixture of 1-(4-(6'-(benzyloxy)-3',4',5,6,7,8-hexahydro-[1,2'-binaphtha len]-1'- yl)phenyl)-4-(dimethoxymethyl)piperidine (500 mg, 1 Eq, 834 ^mol), Pd/C (500 mg, 10% Wt, 0.564 Eq, 470 ^mol), H2 (1.68 mg, 1 Eq, 834 ^mol) in THF (3 Ml) and MeOH (3 Ml). The suspension was degassed and purged with H ₂ for 3 times. The mixture was stirred under H ₂ (15 psi ) at 50 °C for 24 hour. The reaction was filtered and concentrated to dryness in vacuo to give a white solid. The white solid was subjected by SFC: Column: DAICEL CHIRALCEL OD (250 mm *30 mm,10 um); Mobile phase: A: Supercritical CO ₂ , B: MeOH (0.1% NH ₃ H ₂ O), A:B = 45:45 at 100 Ml/min. The aqueous phase was lyophilized to dryness to give (1R,2S)-1'-(4-(4- (dimethoxymethyl)piperidin-1-yl)phenyl)-1',2',3',4',5,6,7,8- octahydro-[1,2'-binaphthalen]-6'-ol (150 mg, 293 ^mol, 35.2%, 100% Purity) and (1S,2R)-1'-(4-(4-(dimethoxymethyl)piperidin-1- yl)phenyl)-1',2',3',4',5,6,7,8-octahydro-[1,2'-binaphthalen] -6'-ol (150 mg, 0.29 mmol, 35%, 99% Purity) as a yellow solid. LC-MS (ESI ⁺ ) m/z: 512.2 (M+H) ⁺ . Step 3: A mixture of (1R,2S)-1'-(4-(4-(dimethoxymethyl)piperidin-1-yl)phenyl)- 1',2',3',4',5,6,7,8-octahydro-[1,2'-binaphthalen]-6'-ol (150 mg, 1 Eq, 293 ^mol) in 10% H ₂ SO ₄ (1.5 mL) and THF (1.5 mL) , then the mixture was stirred at 60 °C for 16 hour. The solvent was removed under vaccum. The residue was dissolved in water (20 mL), the aqueous solution was added NaHCO3 to adjust pH=6.and washed by ethyl acetate (20 mL*2). The combined organic layer was dried over Na ₂ SO ₄ filtered and concentrated under vaccum to give 1-(4-((1R2S)-6'- hydroxy-1',2',3',4',5,6,7,8-octahydro-[1,2'-binaphthalen]-1' -yl)phenyl)piperidine-4-carbaldehyde (100 mg, 215 ^mol, 73.3%) as a yellow oil. LC-MS (ESI+) m/z: 466.1 (M+H)+ Step 4: A mixture of 1-(4-((1R,2S)-6'-hydroxy-1',2',3',4',5,6,7,8-octahydro-[1,2' -binaphthalen]- 1'-yl)phenyl)piperidine-4-carbaldehyde (100 mg, 1 Eq, 215 ^mol), (R)-3-(1-oxo-5-(piperazin-1- yl)isoindolin-2-yl)piperidine-2,6-dione, TsOH salt(140 mg, 1.3 Eq, 279 ^mol) and Sodium acetate (88.1 mg, 5 Eq, 1.07 mmol) and Acetic acid (38.7 mg, 37.1 ^L, 3 Eq, 644 ^mol) in DCM (2 mL) and MeOH (2 mL) at 25 °C for 1 hour, then Sodium triacetoxyborohydride (91.0 mg, 2 Eq, 430 ^mol) was added to the mixture and was stirred at 25 °C for 16 hour. The reaction was treated with H ₂ O (20 mL), extracted with EtOAc (20 mL*2). The combined extracts was dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to dryness in vacuo to give a residue. The residue was purified by prep.HPLC (column: Welch Xtimate C18150*30mm*5um; mobile phase: [water (FA)-ACN]; B%: 31%-51%, 7min). The aqueous phase was lyophilized to dryness to give (R)-3-(5-(4-((1-(4-((1R,2S)-6'-hydroxy-1',2',3',4',5,6,7,8-o ctahydro-[1,2'-binaphthalen]- 1'-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoi ndolin-2-yl)piperidine-2,6-dione (80.4 mg, 101 ^mol, 47.3%, 98.196% Purity) as a white solid. LC-MS (ESI+) m/z: 778.2 (M+H) ⁺ HPLC: 96.196%, purity at 220 nm. SFC: retention time, 3.939 min; Area, 90.044%; Stereochemistry was arbitrarily assigned NMR (400 MHz, DMSO-d ₆ ) į = 10.96 (s, 1H), 9.15 - 9.08 (m, 1H), 8.16 - 8.12 (m, 0.255H), 7.55 - 7.49 (m, 1H), 7.10 - 7.03 (m, 2H), 6.85 - 6.80 (m, 1H), 6.73 - 6.62 (m, 2H), 6.62 - 6.58 (m, 1H), 6.57 - 6.50 (m, 2H), 6.50 - 6.45 (m, 1H), 6.19 - 6.12 (m, 2H), 6.00 - 5.93 (m, 1H), 5.09 - 5.02 (m, 1H), 4.37 - 4.29 (m, 1H), 4.25 - 4.17 (m, 1H), 4.16 - 4.11 (m, 1H), 3.55 - 3.48 (m, 2H), 3.41 - 3.32 (m, 11H), 2.98 - 2.83 (m, 5H), 2.81 - 2.69 (m, 2H), 2.56 (br s, 1H), 2.38 (br d, J = 4.6 Hz, 1H), 2.25 - 2.17 (m, 2H), 2.17 - 2.07 (m, 1H), 2.01 - 1.91 (m, 1H), 1.90 - 1.81 (m, 1H), 1.81 - 1.70 (m, 5H), 1.69 - 1.59 (m, 1H), 1.59 - 1.49 (m, 1H), 1.23 - 1.10 (m, 2H). EXAMPLE 233. Preparation of (I-57) (S)-3-(5-(4-((1-(4-((1R,2S)-2-(bicyclo[4.2.0]octa- 1(6),2,4-trien-3-yl)-6-hydroxy-1,2,3,4-tetrahydronaphthalen- 1-yl)phenyl)piperidin-4- yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2, 6-dione Step 1: A mixture of Bicyclo[4.2.0]octa-1,3,5-trien-3-ylboronic acid (135 mg, 1 Eq, 912 ^mol) ,1-(4-(6-(benzyloxy)-2-bromo-3,4-dihydronaphthalen-1-yl)phen yl)-4- (dimethoxymethyl)piperidine (500 mg, 1 Eq, 912 ^mol), 1,1'-Bis(diphenylphosphino)ferrocene- palladium(II) dichloride (66.7 mg, 0.1 Eq, 91.2 ^mol), sodium carbonate (290 mg, 3 Eq, 2.73 mmol) in 1,4-Dioxane (10 mL) and H ₂ O (2.5 mL) was degassed and purged with N ₂ for 3 times, and then the mixture was stirred at 100 °C for 16 hour under N ₂ atmosphere. TLC (petroleum ether/ethyl acetate=5/1,R _f =0.4) The reaction mixture was quenched by addition H ₂ O 50 mL, and then diluted with H ₂ O 50 mL and extracted with Ethyl acetate 50 mL (50 mL * 2). The combined organic layers were washed with brine 50 mL, dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® Silica Flash Column, Eluent of 50~50% Ethylacetate/Petroleum ethergradient @ 20 mL/min) and the organic layer was concentrated in vacuo to give 1-(4-(6-(benzyloxy)-2-(bicyclo[4.2.0]octa-1,3,5-trien-3-yl)- 3,4-dihydronaphthalen- 1-yl)phenyl)-4-(dimethoxymethyl)piperidine (500 mg, 856 ^mol, 93.9 %, 97.911% purity) as a yellow solid. LC-MS (ESI ⁺ ) m/z: 572.1 (M+H) ⁺ . Step 2: A mixture of 1-(4-(6-(benzyloxy)-2-(bicyclo[4.2.0]octa-1(6),2,4-trien-3-y l)-3,4- dihydronaphthalen-1-yl)phenyl)-4-(dimethoxymethyl)piperidine (500 mg, 1 Eq, 874 ^mol), Pd/C (500 mg, 10% Wt, 0.537 Eq, 470 ^mol) in MeOH (10 mL) and THF (10 mL) was degassed and purged with H ₂ (15 psi) for 3 times, and then the mixture was stirred at 50 °C for 12hr under H ₂ atmosphere. The reaction mixture was filtered and concentrated to dryness in vacuo to give a white solid. The white solid was subjected by SFC: Column: DAICEL CHIRALCEL OD (250 mm *30 mm, 10 um); Mobile phase: A: Supercritical CO ₂ , B: EtOH (0.1% NH ₃ H ₂ O), A:B = 65:35 at 100 mL/min. The aqueous phase was lyophilized to dryness to give (5R,6S)-6- (bicyclo[4.2.0]octa-1(6),2,4-trien-3-yl)-5-(4-(4-(dimethoxym ethyl)piperidin-1-yl)phenyl)- 5,6,7,8-tetrahydronaphthalen-2-ol (110 mg, 227 ^mol, 26.0 %) and (5S,6R)-6- (bicyclo[4.2.0]octa-1,3,5-trien-3-yl)-5-(4-(4-(dimethoxymeth yl)piperidin-1-yl)phenyl)-5,6,7,8- tetrahydronaphthalen-2-ol (98 mg, 0.20 mmol, 23 %) was obtained as a yellow oil. LC-MS (ESI ⁺ ) m/z: 484.3 (M+H) ⁺ Step 3: A solution (5R,6S)-6-(bicyclo[4.2.0]octa-1,3,5-trien-3-yl)-5-(4-(4- (dimethoxymethyl)piperidin-1-yl)phenyl)-5,6,7,8-tetrahydrona phthalen-2-ol (110 mg, 1 Eq, 227 ^mol) in 10%H2SO4 (7 mL) and THF (7 mL) was stirred at 70 °C for 16 hour to give a yellow suspension. The solvent was removed under vaccum. The aqueous solution was added NaHCO ₃ to adjust pH=6. The residue was dissolved in water (20 mL) and extracted by ethyl acetate (50 mL). The combined organic layer was dried over Na ₂ SO ₄ , filtered and concentrated under vaccum to give 1-(4-((1R,2S)-2-(bicyclo[4.2.0]octa-1,3,5-trien-3-yl)-6-hydr oxy-1,2,3,4- tetrahydronaphthalen-1-yl)phenyl)piperidine-4-carbaldehyde (100 mg, 224 ^mol, 98.7 %, 98.227% Purity) as a yellow oil. LC-MS (ESI ⁺ ) m/z: 438.1 (M+H) ⁺ Step 4: To a solution of 1-(4-((1R,2S)-2-(bicyclo[4.2.0]octa-1,3,5-trien-3-yl)-6-hydr oxy-1,2,3,4- tetrahydronaphthalen-1-yl)phenyl)piperidine-4-carbaldehyde (100 mg, 1 Eq, 229 ^mol), (S)-3- (1-oxo-5-(piperazin-1-yl)isoindolin-2-yl)piperidine-2,6-dion e, TsOH salt(114 mg, 1 Eq, 229 ^mol) in DCM (3 mL) and MeOH (3 mL) was added Sodium acetate (56.2 mg, 3 Eq, 686 ^mol) was stirred at 25 °C for 60 mins, Then Sodium triacetoxyborohydride (96.9 mg, 2 Eq, 457 ^mol) and Acetic acid (41.2 mg, 39.4 ^L, 3 Eq, 686 ^mol) was added. The mixture was stirred at 25 °C for 16 hour. The reaction was treated with H2O (20 mL), extracted with EtOAc (30 mL). The combined extracts was dried over anhydrous Na2SO4, filtered and concentrated to pressure to remove solvent. The residue was purified by prep-HPLC (column: Welch Xtimate C18150*30mm*5um;mobile phase: [water(FA)-ACN];B% 26%-56%,7min) to give (S)-3-(5-(4- ((1-(4-((1R,2S)-2-(bicyclo[4.2.0]octa-1(6),2,4-trien-3-yl)-6 -hydroxy-1,2,3,4- tetrahydronaphthalen-1-yl)phenyl)piperidin-4-yl)methyl)piper azin-1-yl)-1-oxoisoindolin-2- yl)piperidine-2,6-dione (48.9 mg, 65.0 ^mol, 28.4 %, 99.660% Purity) was obtained as a white solid. LC-MS (ESI ⁺ ) m/z: 750.2 (M+H) ⁺ . LCMS: calc. for C ₄₇ H ₅₁ N ₅ O ₄ : 749.94, found: [M+H]+ 750.2. HPLC: 99.660% purity at 220 nm. NMR (400 MHz, DMSO-d ₆ ) į = 10.98 - 10.92 (m, 1H), 8.23 - 8.17 (m, 0.377H), 7.56 - 7.48 (m, 1H), 7.11 - 7.01 (m, 2H), 6.90 - 6.80 (m, 1H), 6.69 - 6.62 (m, 2H), 6.61 - 6.53 (m, 3H), 6.51 - 6.43 (m, 2H), 6.28 - 6.19 (m, 2H), 5.10 - 5.00 (m, 1H), 4.38 - 4.28 (m, 1H), 4.26 - 4.15 (m, 1H), 4.11 - 4.05 (m, 1H), 3.59 - 3.49 (m, 3H), 3.47 - 3.36 (m, 6H), 3.10 - 2.81 (m, 8H), 2.70 - 2.58 (m, 2H), 2.47 - 2.27 (m, 4H), 2.24 - 2.16 (m, 2H), 2.11 - 1.91 (m, 2H), 1.81 - 1.72 (m, 2H), 1.70 - 1.59 (m, 2H), 1.26 - 1.10 (m, 2H) SFC: retention time, 3.665 min; Area, 94.697%; Stereochemistry was arbitrarily assigned

EXAMPLE 234. Preparation of (I-100) (R)-3-(5-(4-((1-(4-((1R,2S)-2- (bicyclo[4.2.0]octa-1,3,5-trien-2-yl)-6-hydroxy-1,2,3,4-tetr ahydronaphthalen-1- yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindo lin-2-yl)piperidine-2,6-dione Step 1: To solution of 2-(2,6-dibromophenyl)acetic acid (3 g, 1 Eq, 0.01 mol) in THF (30 mL) was added dropwise over 30 min. BH ₃ .THF (1.3 g, 15 mL, 1 Eq, 15 mmol) at 0 °C, after 10 min, the reaction mixture was warmed to 80 °C, refluxed at 80 °C for 1 hour. The mixture was treated with H ₂ O (200 mL), extracted with EtOAc (150 mL). The organic lay was dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to dryness in vacuo to give 2-(2,6-dibromophenyl)ethan-1-ol (2.4 g, 8.6 mmol, 80%) as a yellow solid. LC-MS (ESI+) m/z: 262.9 (M+H) ⁺ . Step 2: To solution of 2-(2,6-dibromophenyl)ethan-1-ol (2.4 g, 1 Eq, 8.6 mmol), N- Bromosuccinimide (1.7 g, 0.80 mL, 1.1 Eq, 9.4 mmol) in DCM (20 mL) was added dropwise over 10 min. Triphenylphosphine (2.5 g, 2.1 mL, 1.1 Eq, 9.4 mmol) at 0 °C. The reaction mixture was stirred at 25 °C for 16 hour. TLC (PE/EtOAc=20/1) showed a new spot. The mixture was treated with H O (100 mL) extracted with EtOAc (100 mL) The combined extracts was dried over anhydrous Na2SO4, filtered and concentrated to dryness in vacuo to give a residue. The residue was subjected to column chromatography over silica gel (gradient elution: 0~5% ethyl acetate in petroleum ether). The pure fractions were collected and concentrated to dryness in vacuo to give 1,3-dibromo-2-(2-bromoethyl)benzene (2.2 g, 6.4 mmol, 75 %) as a yellow oil. ¹ H NMR (400 MHz, CHLOROFORM-d ₃ ) į = 7.50 - 7.40 (m, 2H), 6.96 - 6.85 (m, 1H), 3.54 - 3.38 (m, 4H) Step 3: 1,3-dibromo-2-(2-bromoethyl)benzene (1 g, 1 Eq, 3 mmol), a stir bar and THF (10 mL) were add to a 50 mL three necked bottle. The resultant mixture was sparged with N ₂ for three times and was subsequently cooled to -68 °C, n-butyllithium (0.18 g, 1.1 mL, 2.5 molar, 0.9 Eq, 2.8 mmol) was added to the reaction over 10 min. The resulting mixture was stirred for 2 hour at -68 °C. The mixture was treated with Saturated aqueous ammonium chloride (10 mL), then was added H ₂ O (100 mL), extracted with EtOAc (100 mL). The combined extracts was dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to dryness in vacuo to give a residue. The residue was subjected to column chromatography over silica gel (gradient elution: 0~10% ethyl acetate in petroleum ether). The pure fractions were collected and concentrated to dryness in vacuo to give 2-bromobicyclo[4.2.0]octa-1,3,5-triene (400 mg, 2.19 mmol, 70 %) was obtained as yellow oil. Step 4: To a solution of 2-bromobicyclo[4.2.0]octa-1,3,5-triene (700 mg, 1 Eq, 3.82 mmol), Bis(pinacolato)diborane (1.46 g, 1.5 Eq, 5.74 mmol), Potassium acetate (751 mg, 478 ^L, 2 Eq, 7.65 mmol) in Dioxane (5 mL). [1,1'- bis(diphenylphosphino)ferrocene]dichloropalladium(II)Complex With Dichloromethane (312 mg, 0.1 Eq, 382 ^mol) was added to the reaction. Then the resultant mixture was stirred for 16 hour at 90 °C under N ₂ . The reaction mixture was quenched by addition of water (100 mL), extracted with EtOAc (100 mL). The combined organic layers were washed with brine (50 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (from PE/EtOAc = 20/1 to 10/1) to yield a product.2-(bicyclo[4.2.0]octa-1,3,5-trien-2-yl)-4,4,5,5-tetr amethyl-1,3,2-dioxaborolane (500 mg, 1.7 mmol, 45% yield, 80% purity) was obtained as yellow oil. LC-MS (ESI+) m/z: 231.1 (M+H)+. Step 5: A mixture of 1-(4-(6-(benzyloxy)-2-bromo-3,4-dihydronaphthalen-1-yl)pheny l)-4- (dimethoxymethyl)piperidine (800 mg, 1 Eq, 1.46 mmol), 2-(bicyclo[4.2.0]octa-1,3,5-trien-2-yl)- 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (500 mg 1.19 Eq, 1.74 mmol), Na ₂ CO ₃ (464 mg, 3 Eq, 4.38 mmol) and [1,1'- bis(diphenylphosphino)ferrocene]dichloropalladium(II)Complex WithDichloromethane (119 mg, 0.1 Eq, 146 ^mol) in Dioxane (4 mL) and H ₂ O (1 mL) at r.t.. N ₂ was bubbled into the mixture for 5 min. The reaction mixture was heated at 100 °C for 16 hour. Then the reaction was cooled to room temperature. The mixture was treated with H ₂ O (100 mL), extracted with EtOAc (100 mL). The combined extracts was dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to dryness in vacuo to give a residue. The residue was subjected to column chromatography over silica gel (gradient elution: 0~20% ethyl acetate in petroleum ether). The pure fractions were collected and concentrated to dryness in vacuo to give 1-(4-(6-(benzyloxy)-2- (bicyclo[4.2.0]octa-1,3,5-trien-2-yl)-3,4-dihydronaphthalen- 1-yl)phenyl)-4- (dimethoxymethyl)piperidine (400 mg, 0.52 mmol, 36% yield, 75% purity) as a yellow solid. LC-MS (ESI ⁺ ) m/z: 572.2 (M+H) ⁺ . Step 6: A mixture of 1-(4-(6-(benzyloxy)-2-(bicyclo[4.2.0]octa-1(6),2,4-trien-2-y l)-3,4- dihydronaphthalen-1-yl)phenyl)-4-(dimethoxymethyl)piperidine (400 mg, 1 Eq, 525 ^mol), Pd/C(300 mg, 10% Wt, 0.537 Eq, 282 ^mol), H ₂ (1.06 mg, 1 Eq, 525 ^mol) in THF (2 mL) and MeOH (2 mL). The suspension was degassed and purged with H ₂ for 3 times. The mixture was stirred under H ₂ (15 psi) at 50 °C for 12 hour. Then the reaction was cooled to room temperature. The reaction was filtered and concentrated to dryness in vacuo to give a white solid. The white solid was subjected by SFC: Column: DAICEL CHIRALCEL OD (250 mm *30 mm,10 um); Mobile phase: A: Supercritical CO ₂ , B: MeOH (0.1% NH ₃ H ₂ O), A:B = 35:35 at 80 mL/min. The aqueous phase was lyophilized to dryness to give (5S,6R)-6-(bicyclo[4.2.0]octa-1(6),2,4- trien-2-yl)-5-(4-(4-(dimethoxymethyl)piperidin-1-yl)phenyl)- 5,6,7,8-tetrahydronaphthalen-2-ol (55 mg, 0.11 mmol, 21% yiled, 98% purity) and (5R,6S)-6-(bicyclo[4.2.0]octa-1(6),2,4-trien-2- yl)-5-(4-(4-(dimethoxymethyl)piperidin-1-yl)phenyl)-5,6,7,8- tetrahydronaphthalen-2-ol (55 mg, 0.11 mmol, 21% yield, 99% purity) as a yellow solid. LC-MS (ESI ⁺ ) m/z: 484.2 (M+H) ⁺ . Step 7: A mixture of (5R,6S)-6-(bicyclo[4.2.0]octa-1,3,5-trien-2-yl)-5-(4-(4- (dimethoxymethyl)piperidin-1-yl)phenyl)-5,6,7,8-tetrahydrona phthalen-2-ol (55 mg, 1 Eq, 0.11 mmol) in 10% H ₂ SO ₄ (15 mL) and THF (15 mL) then the mixture was stirred at 60 °C for 16 hour. The solvent was removed under vaccum. The residue was dissolved in water (20 mL), the aqueous solution was added NaHCO3 to adjust pH=6. and extracted by ethyl acetate (20 mL*2). The combined organic layer was dried over Na ₂ SO ₄ , filtered and concentrated under vaccum to give 1-(4-((1R,2S)-2-(bicyclo[4.2.0]octa-1,3,5-trien-2-yl)-6-hydr oxy-1,2,3,4- tetrahydronaphthalen-1-yl)phenyl)piperidine-4-carbaldehyde (50 mg, 0.11 mmol, 100%) as a yellow oil. LC-MS (ESI+) m/z: 438.1 (M+H)+. Step 8: A mixture of 1-(4-((1R,2S)-2-(bicyclo[4.2.0]octa-1,3,5-trien-2-yl)-6-hydr oxy-1,2,3,4- tetrahydronaphthalen-1-yl)phenyl)piperidine-4-carbaldehyde (50 mg, 1 Eq, 0.11 mmol), (R)-3- (1-oxo-5-(piperazin-1-yl)isoindolin-2-yl)piperidine-2,6-dion e, TsOH salt (74 mg, 1.3 Eq, 0.15 mmol) and Sodium acetate (47 mg, 5 Eq, 0.57 mmol) and Acetic acid (21 mg, 20 ^L, 3 Eq, 0.34 mmol) in DCM (2 mL) and MeOH (2 mL) at 25 °C for 1 hour, then Sodium triacetoxyborohydride (48 mg, 2 Eq, 0.23 mmol) was added to the mixture and was stirred at 25 °C for 16 hour. The reaction was treated with H ₂ O (20 mL), extracted with EtOAc (20 mL). The combined extracts was dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to dryness in vacuo to give a residue. The residue was purified by prep.HPLC (column: Welch Xtimate C18 150*30mm*5um; mobile phase: [water (FA)-ACN]; B%: 26%-46%, 7min). The aqueous phase was lyophilized to dryness to give (R)-3-(5-(4-((1-(4-((1R,2S)-2-(bicyclo[4.2.0]octa-1,3,5-trie n- 2-yl)-6-hydroxy-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)pip eridin-4-yl)methyl)piperazin-1- yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (28.1 mg, 36.8 ^mol, 32%, 98.336% Purity) as a white solid. LC-MS (ESI+) m/z: 750.2 (M+H)+ HPLC: 98.336%, purity at 220 nm. SFC: retention time, 3.096 min; Area, 88.165%; Stereochemistry was arbitrarily assigned. NMR (400 MHz, DMSO-d ₆ ) į = 10.99 - 10.92 (m, 1H), 9.16 - 9.08 (m, 1H), 8.15 - 8.13 (m, 0.260H), 7.59 - 7.49 (m, 1H), 7.14 - 7.02 (m, 3H), 6.95 - 6.89 (m, 1H), 6.86 - 6.80 (m, 1H), 6.70 - 6.64 (m, 1H), 6.62 - 6.55 (m, 3H), 6.53 - 6.46 (m, 1H), 6.22 - 6.14 (m, 2H), 5.12 - 5.00 (m, 1H), 4.38 - 4.29 (m, 1H), 4.27 - 4.17 (m, 1H), 4.08 - 4.01 (m, 1H), 3.67 - 3.42 (m, 4H), 3.28 - 3.14 (m, 3H), 3.05 - 2.80 (m, 5H), 2.79 - 2.64 (m, 4H), 2.63 - 2.54 (m, 4H), 2.45 - 2.22 (m, 3H), 2.11 - 1.92 (m, 2H), 1.84 - 1.65 (m, 5H), 1.30 - 1.12 (m, 2H). EXAMPLE 235. Preparation of (I-161 ) (S)-3-(5-(4-((1-(4-((1R,2S)-2-((3R,5R,7R)- adamantan-1-yl)-6-hydroxy-1,2,3,4-tetrahydronaphthalen-1-yl) phenyl)piperidin-4- yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2, 6-dione Step 1: A mixture of 1-(4-((1R,2S)-2-((3R,5R,7R)-adamantan-1-yl)-6-methoxy-1,2,3, 4- tetrahydronaphthalen-1-yl)phenyl)-4-(dimethoxymethyl)piperid ine (30 mg, 1 Eq, 57 ^mol) in DCM (2 mL) at 0 °C was added tribromoborane (0.17 mL, 1 M, 3 Eq, 0.17 mmol) with N ₂ . After addition, the mixture was stirred at 0 °C for 4 hour, and then the reaction was warmed to 25 °C and was stirred at this temperature for 4 hour. The reaction was treated with aq.NaHCO ₃ (10 mL), extracted with EtOAc (20 mL * 2). The combined extracts was dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to dryness in vacuo to give 1-(4-((1R,2S)-2-((3R,5R,7R)- adamantan-1-yl)-6-hydroxy-1,2,3,4-tetrahydronaphthalen-1-yl) phenyl)piperidine-4-carbaldehyde (25 mg, 53 ^mol, 94 % yield) as yellow oil. Step 2: A mixture of 1-(4-((1R,2S)-2-((3R,5R,7R)-adamantan-1-yl)-6-hydroxy-1,2,3, 4- tetrahydronaphthalen-1-yl)phenyl)piperidine-4-carbaldehyde (22 mg, 1 Eq, 47 ^mol), (S)-3-(1- 5 ( i i 1 l)i i d li 2 l) i idi 26 di PhSO H lt (23 1 E 47 ^ l) in DCM (1.5 mL), MeOH (1.5 mL) was added sodium acetate (12 mg, 3 Eq, 0.14 mmol) was stirred at 25 °C for 30 mins, Then sodium triacetoxyborohydride (20 mg, 2 Eq, 94 ^mol) and acetic acid (8.4 mg, 8.1 ^L, 3 Eq, 0.14 mmol) was added. The mixture was stirred at 25 °C for 16 hour. TLC (DCM/MeOH=10/1, R _f =0.4) showed new spot was formed. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was purified by prep-HPLC (column: Welch Xtimate C18150*30mm*5um;mobile phase: [water(FA)-ACN];B% 18%- 48%,7min) to give (S)-3-(5-(4-((1-(4-((1R,2S)-2-((3R,5R,7R)-adamantan-1-yl)-6- hydroxy- 1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperidin-4-yl)meth yl)piperazin-1-yl)-1-oxoisoindolin- 2-yl)piperidine-2,6-dione (13.2 mg, 16.9 ^mol, 36 % yield) was obtained as a white solid. LC-MS (ESI+) m/z: 782.3 (M+H) ⁺ HPLC: 99.429%, purity at 220 nm. SFC: retention time, 3.564 min; Area, 96.797%; ¹ H NMR (400MHz, DMSO-d6) į = 10.96 (s, 1H), 8.98 (br s, 1H), 8.22 (s, 1H), 7.52 (d, J=8.6 Hz, 1H), 7.14 - 6.90 (m, 4H), 6.76 (br d, J=8.5 Hz, 2H), 6.58 (d, J=8.5 Hz, 1H), 6.48 (d, J=1.9 Hz, 1H), 6.37 (dd, J=2.2, 8.2 Hz, 1H), 5.05 (dd, J=5.0, 13.2 Hz, 1H), 4.43 - 4.28 (m, 1H), 4.25 - 4.15 (m, 1H), 4.11 (br d, J=3.8 Hz, 1H), 3.61 (br t, J=13.2 Hz, 2H), 3.29 (br s, 6H), 3.01 - 2.83 (m, 3H), 2.81 - 2.64 (m, 2H), 2.58 (br d, J=17.0 Hz, 4H), 2.37 (br dd, J=4.9, 12.8 Hz, 1H), 2.20 (br d, J=6.8 Hz, 2H), 1.99 - 1.87 (m, 2H), 1.85 - 1.76 (m, 6H), 1.63 - 1.45 (m, 10H), 1.35 (br d, J=11.8 Hz, 3H), 1.22 (br d, J=12.9 Hz, 2H)

EXAMPLE 236. Preparation of (I-241) (S)-3-(5-(4-((1-(4-((1S,2R)-2-((3S,5S,7S)- adamantan-1-yl)-6-hydroxy-1,2,3,4-tetrahydronaphthalen-1-yl) phenyl)piperidin-4- yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2, 6-dione Step 1: To a mixture of methyl 2-((3r, 5r, 7r)-adamantan-1-yl) acetate (10 g, 1 Eq, 48 mmol) in THF (100 mL) at r.t., and the mixture was degassed and purged with N ₂ for 10 mintues. Then the mixture was stirred until it reached -78 °C. Lithium diisopropylamide solution (6.7 g, 31.2 mL, 2 M, 1.3 Eq, 62.4 mmol) was added to the mixture and stirred at -78 °C for1 hour, then 2-(3- methoxyphenyl)acetaldehyde (7.2 g, 1 Eq, 48 mmol) was added to the mixture at -78 °C and stirred at 25 °C for 12 hour. TLC (petroleum ether: ethyl acetate=10:1, Rf=0.5 UV) showed one main new spot was observed. The reaction was quenched with aqueous NH ₄ Cl (50 mL) and dried over Na2SO4 and concentrated in vacuo to give a black solid. The black solid was subjected to column chromatography over silica gel (gradient elution: 0 – 20% EtOAc). The desired fractions were collected, and concentrated to dryness in vacuo to give methyl 2-((3r,5r,7r)- adamantan-1-yl)-3-hydroxy-4-(3-methoxyphenyl)butanoate (11 g, 31 mmol, 64 % yield) as a yellow oil. Step 2: A mixture of methyl 2-((3r, 5r, 7r)-adamantan-1-yl)-3-hydroxy-4-(3-methoxyphenyl) butanoate (2.6 g, 1 Eq, 7.2 mmol), methanesulfonic anhydride (2.5 g, 2 Eq, 14.4 mmol), triethylamine (2.2 g, 3.0 mL, 3 Eq, 21.6 mmol) and a stir bar were added into DCM (50 mL). Then the mixture was stirred at 25 °C for 2 hour. TLC (petroleum ether: ethyl acetate=10:1, R _f =0.4 UV) showed one main new spot was observed. To the mixture was added water (50 mL), then was extracted with DCM (50 mL* 2). The combined organic layers were washed with brine (50 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give the crude product. The residue was purified by flash silica gel chromatography (petroleum ether/ethyl acetate from 100/0 to 90/10) to obtained the desired product methyl 2-((3r, 5r, 7r)-adamantan-1- yl)-4-(3-methoxyphenyl)-3-((methylsulfonyl)oxy) butanoate (2.6 g, 6.0 mmol, 83 % yield) as brown oil. Step 3: A mixture of methyl 2-((3r, 5r, 7r)-adamantan-1-yl)-4-(3-methoxyphenyl)-3-(tosyloxy) butanoate (2.5 g, 1 Eq, 4.9 mmol), DBU (2.2 g, 2.2 mL, 3 Eq, 15 mmol) in Toulene (20 mL). The suspension was degassed and purged with N ₂ for 3 times. The mixture was stirred under N ₂ at 25 °C for 12 hour. TLC (PE/EtOAc=10/1, R _f =0.4) showed a new spot was formed. To the mixture was added water (100 mL), then was extracted with ethyl acetate (50 mL* 2). The combined organic layers were washed with brine (50 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give the crude product. The desired product was purified by flash column (petroleum ether/ethyl acetate from 100/0 to 90/10) and the organic layer was concentrated in vacuo to give methyl 2-((3r, 5r, 7r)-adamantan-1-yl)-4-(3-methoxyphenyl) but-3- enoate (1.1 g, 3.2 mmol, 66 % yield) as a yellow oil. Step 4: A mixture of methyl 2-((3r,5r,7r)-adamantan-1-yl)-4-(3-methoxyphenyl)but-3-enoat e (1 g, 1 Eq, 2.9 mmol) in MeOH (10 mL) was added Pd/C (1.6 g, 10% Wt, 0.5 Eq, 1.5 mmol) under N2 atmosphere. The suspension was degassed and purged with H2 for 10 mins. The mixture was stirred under 15 psi H2 (5.9 mg, 1 Eq, 2.9 mmol) at 50 °C for 16 hr. TLC (petroleum ether: ethyl concentrated to obtained methyl 2-((3r, 5r, 7r)-adamantan-1-yl)-4-(3-methoxyphenyl) butanoate (600 mg, 1.75 mmol, 59.6 % yield) as yellow oil. Step 5: A mixture of methyl 2-((3r,5r,7r)-adamantan-1-yl)-4-(3-methoxyphenyl)butanoate (600 mg, 1 Eq, 1.75 mmol) in DMSO (6 mL) was added sodium ethane thiolate (295 mg, 2 Eq, 3.5 mmol). The mixture was stirred at 100 °C for 16 hour. TLC (petroleum ether/ethyl acetate=3:1, R _f =0.3) showed new spot was formed. The mixture was adjusted to pH=~4 with 2N HCl.50 mL water was added, and the mixture was extracted with ethyl acetate (2×50 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to dryness in vacuo to give 2-((3r,5r,7r)-adamantan-1-yl)-4-(3- methoxyphenyl)butanoic acid (400 mg, 1.22 mmol, 69.5 % yield) as yellow oil. Step 6: A mixture of 2, 2, 2-trifluoroacetic anhydride (959 mg, 635 ^L, 5 Eq, 4.57 mmol) was added to 2-((3r, 5r, 7r)-adamantan-1-yl)-4-(3-methoxyphenyl) butanoic acid (300 mg, 1 Eq, 913 ^mol) in DCM (10 mL). The reaction was stirred at 0 °C for 30 min. The reaction was stirred at 30 °C for 16 hour. TLC (petroleum ether: ethyl aceatte=10:1, UV) showed one main new spot was observed.50 mL water was added, and the mixture was extracted with ethyl acetate (50 mL x 2). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to dryness in vacuo to give 2-((3r,5r,7r)-adamantan-1-yl)-6- methoxy-3,4-dihydronaphthalen-1(2H)-one (200 mg, 644 ^mol, 70.5 % yield) as a yellow oil. Step 7: A mixture of 1-(4-bromophenyl)-4-(dimethoxymethyl)piperidine (395 mg, 3 Eq, 1.26 mmol), a stir bar, and THF (6 mL) were added an oven-dried and nitrogen-purged 20 mL three round-bottomed flask, which was subsequently evacuated and refilled with argon (x3), before the reaction vessel was cooled to -68°C (dry ice/EtOH). The resulting mixture treated with n-Butyl lithium, 2.5 M in hexane (419 ^L, 2.5 M, 2.5 Eq, 1.05 mmol), dropwise over 2 min at -68 °C (dry ice/EtOH). While stirring an additional 30 min at -68 °C (dry ice/EtOH). The resulting mixture treated with 2-((3r,5r,7r)-adamantan-1-yl)-6-methoxy-3,4-dihydronaphthale n-1(2H)-one (130 mg, 1 Eq, 419 ^mol) in THF (2 mL), dropwise over 5 min, and the reaction vessel removed to the r.t., while stirring an additional 15 h at r.t. TLC(petroleum ether/ethyl acetate=5/1, R _f =0.4). The reaction mixture treated with sat. aq. NH ₄ Cl (20 mL), dropwise over 3 min, extracted with EtOAc (50 mL x 3), and the combined extracts washed with brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated to dryness in vacuo to give a crude product, which was then 1-yl)-1-(4-(4-(dimethoxymethyl)piperidin-1-yl)phenyl)-6-meth oxy-1,2,3,4- tetrahydronaphthalen-1-ol (180 mg, 330 ^mol, 78.8 % yield) as a yellow solid. Step 8: A mixture of 2-((3r,5r,7r)-adamantan-1-yl)-1-(4-(4-(dimethoxymethyl)piper idin-1- yl)phenyl)-6-methoxy-1,2,3,4-tetrahydronaphthalen-1-ol (140 mg, 1 Eq, 257 ^mol) in 4 N HCl/MeOH (5 mL) at r.t., and the reaction was stirred at 25 °C for 5 hour. TLC (petroleum ether/ethyl acetate = 5/1, R _f = 0.3). The mixture was filtered and the filter cake was washed with EtOAc (50 mL). The filtrate was treated with H ₂ O (30 mL), extracted with EtOAc (50 mL * 2). The combined extracts was dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to dryness in vacuo to give a residue. The residue was subjected to column chromatography over silica gel (petroleum ether/ethyl acetate from 100/0 to 70/30).The pure fractions were collected and concentrated to dryness in vacuo to give 1-(4-(2-((3r, 5r, 7r)-adamantan-1-yl)-6-methoxy-3, 4- dihydronaphthalen-1-yl) phenyl)-4-(dimethoxymethyl) piperidine (100 mg, 189 ^mol, 73.9 % yield) as a yellow solid. Step 9: A mixture of Pd/C (80 mg, 10% Wt, 0.50 Eq, 75 ^mol), Pd(OH) ₂ /C(106.4 mg, 20% Wt, 1 Eq, 151.6 ^mol) and 1-(4-(2-((3r,5r,7r)-adamantan-1-yl)-6-methoxy-3,4-dihydronap hthalen-1- yl)phenyl)-4-(dimethoxymethyl)piperidine (80 mg, 1 Eq, 151.6 ^mol) in EtOH (2 mL) and EtOAc (2 mL) was degassed and purged with H ₂ (15 psi) for 3 times, and then the mixture was stirred at 30 °C for 16 hour under H ₂ atmosphere. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was concentrated under reduced pressure to give desired compound (0.1 g, purity ~90%) as a yellow oil, which was further separated by SFC (condition: column: DAICEL CHIRALCELOJ(250mm*30mm,10um);mobile phase: [0.1% NH ₃ ^. H ₂ O EtOH];B%: 35%-35%, min ) to give 1-(4-((1S,2R)-2-((3S,5S,7S)-adamantan-1-yl)-6-methoxy-1,2,3, 4- tetrahydronaphthalen-1-yl)phenyl)-4-(dimethoxymethyl)piperid ine (33 mg, 62 ^mol, 41 % yield) was obtained as a yellow oil and 1-(4-((1R,2S)-2-((3R,5R,7R)-adamantan-1-yl)-6-methoxy- 1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)-4-(dimethoxymethyl )piperidine (30 mg, 57 ^mol, 37 % yield) was obtained as a yellow oil. Step 10: A mixture of 1-(4-((1S, 2R)-2-((3R, 5R, 7R)-adamantan-1-yl)-6-methoxy-1, 2, 3, 4- tetrahydronaphthalen-1-yl) phenyl)-4-(dimethoxymethyl) piperidine (30 mg, 1 Eq, 57 ^mol) in DCM (2 mL) at 0 °C was added tribromoborane (43 mg, 0.17 mL, 1 molar, 3 Eq, 0.17 mmol) acetate =3/1, Rf=0.3) showed new spot was formed. The reaction was treated with aq.NaHCO3 (10 mL), extracted with EtOAc (20mL * 2). The combined extracts was dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to dryness in vacuo to give 1-(4-((1S,2R)-2-((3R,5R,7R)- adamantan-1-yl)-6-hydroxy-1,2,3,4-tetrahydronaphthalen-1-yl) phenyl)piperidine-4-carbaldehyde (25 mg, 53 ^mol, 94 %) as a yellow oil. Step 11: A mixture of 1-(4-((1S,2R)-2-((3S,5S,7S)-adamantan-1-yl)-6-methoxy-1,2,3, 4- tetrahydronaphthalen-1-yl)phenyl)-4-(dimethoxymethyl)piperid ine (25 mg, 1 Eq, 47 ^mol), (S)- 3-(1-oxo-5-(piperazin-1-yl)isoindolin-2-yl)piperidine-2,6-di one, PhSO ₃ H salt (24 mg, 1 Eq, 47 ^mol) in DCM (1.5 mL), MeOH (1.5 mL) was added sodium acetate (12 mg, 3 Eq, 0.14 mmol) was stirred at 25 °C for 30 mins, Then sodium triacetoxyborohydride (20 mg, 2 Eq, 94 ^mol) and acetic acid (8.5 mg, 8.1 ^L, 3 Eq, 0.14 mmol) was added. The mixture was stirred at 25 °C for 16 hour. TLC(DCM/MeOH=10/1, R _f =0.4) showed new spot was formed. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was purified by prep-HPLC (column: Welch Xtimate C18150*30mm*5um; mobile phase: [water(FA)- ACN];B% 18%-48%,7min) to give (S)-3-(5-(4-((1-(4-((1S,2R)-2-((3S,5S,7S)-adamantan-1-yl)- 6-hydroxy-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperidin -4-yl)methyl)piperazin-1-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione (19 mg, 24 ^mol, 51 % yield, 100% purity) was obtained as a white solid. LC-MS (ESI+) m/z: 782.3 (M+H) ⁺ HPLC: 100%, purity at 220 nm. SFC: retention time, 3.564 min; Area, 96.797%. ¹ H NMR (400 MHz, DMSO-d ₆ ) į = 10.96 (s, 1H), 8.98 (br s, 1H), 8.22 (br s, 1H), 7.52 (d, J=8.2 Hz, 1H), 7.10 - 7.02 (m, 2H), 6.98 (br d, J=8.0 Hz, 2H), 6.76 (br d, J=8.3 Hz, 2H), 6.58 (d, J=8.2 Hz, 1H), 6.48 (s, 1H), 6.38 (br d, J=8.1 Hz, 1H), 5.05 (dd, J=4.8, 13.3 Hz, 1H), 4.39 - 4.28 (m, 1H), 4.25 - 4.14 (m, 1H), 4.10 (br s, 1H), 3.59 (br d, J=11.6 Hz, 2H), 3.29 (br s, 6H), 3.03 - 2.65 (m, 4H), 2.58 (br d, J=15.3 Hz, 3H), 2.37 (br dd, J=4.0, 13.4 Hz, 1H), 2.20 (br d, J=6.7 Hz, 2H), 1.95 (br d, J=6.1 Hz, 2H), 1.86 - 1.73 (m, 6H), 1.72 - 1.40 (m, 12H), 1.35 (br d, J=11.3 Hz, 3H), 1.22 (br d, J=12.4 Hz, 2H). EXAMPLE 237. Preparation of (I-116) (3S)-3-[5-[4-[[1-[4-[(1S,2S)-6-hydroxy-2- (3,3,5,5-tetramethylcyclohexyl)tetralin-1-yl]phenyl]-4-piper idyl]methyl]piperazin-1-yl]-1- oxo-isoindolin-2-yl]piperidine-2,6-dione and (I-117) (3S)-3-[5-[4-[[1-[4-[(1R,2R)-6-hydroxy- 2-(3,3,5,5-tetramethylcyclohexyl)tetralin-1-yl]phenyl]-4-pip eridyl]methyl]piperazin-1-yl]-1- oxo-isoindolin-2-yl]piperidine-2,6-dione Step 1: A mixture of 1-[4-(6-benzyloxy-2-bromo-3,4-dihydronaphthalen-1-yl)phenyl] -4- (dimethoxymethyl)piperidine (1 g, 1.55 mmol), 4,4,5,5-tetramethyl-2-(3,3,5,5- tetramethylcyclohexen-1-yl)-1,3,2-dioxaborolane (532.26 mg, 2.01 mmol), RuPhos Pd G3 (129.61 mg, 154.97 ^mol), Cs ₂ CO ₃ (1.01 g, 3.10 mmol) in dioxane (10 mL) was degassed and purged with N ₂ for 3 times, and then the mixture was stirred at 100 °C for 16 h under N ₂ atmosphere. The reaction mixture was quenched by water (50 mL) and extracted with EtOAc (60 mL x 3). The combined organic layers were washed with brine (100 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ethyl acetate in petroleum ether = 0% to 10%) to give 1-[4-[6- benzyloxy-2-(3,3,5,5-tetramethylcyclohexen-1-yl)-3,4-dihydro naphthalen-1-yl]phenyl]-4- (dimethoxymethyl)piperidine (500 mg, 48.5% yield) as a yellow solid. LC-MS (ESI ⁺ ) m/z: 606.5 (M+H) ⁺ . Step 2: To a solution of Pd(OH) ₂ /C (3 g, 20% purity) in MeOH (20 mL) and THF (10 mL) was yl]phenyl]-4-(dimethoxymethyl)piperidine (400 mg, 600.81 ^mol) under N2. The suspension was degassed under vacuum and purged with H2 several times. The mixture was stirred under H2 (50 psi) at 70 °C for 24 h. The reaction mixture was filtered and the filter was concentrated. The residue was purified by flash silica gel chromatography (ethyl acetate in petroleum ether = 0% to 30%) to give 1-[4-[4-(dimethoxymethyl)-1-piperidyl]phenyl]-2-(3,3,5,5- tetramethylcyclohexyl)tetralin-6-ol (50 mg, 14.4% yield) as a white solid. LC-MS (ESI ⁺ ) m/z: 520.5 (M+H) ⁺ . Step 3: 1-[4-[4-(Dimethoxymethyl)-1-piperidyl]phenyl]-2-(3,3,5,5- tetramethylcyclohexyl)tetralin-6-ol (50 mg, 86.58 ^mol) was separated by chiral SFC (column: DAICEL CHIRALCEL OJ(250mm*30mm,10um);mobile phase: [0.1%NH ₃ H ₂ O IPA];B%: 20%- 20%,min, peak 1: 2.748min, peak 2: 3.019min) to yield Peak 1 and Peak 2. Peak 1 was concentrated under reduced pressure to yield (1S,2S)-1-[4-[4-(dimethoxymethyl)-1- piperidyl]phenyl]-2-(3,3,5,5-tetramethylcyclohexyl)tetralin- 6-ol (10 mg, 21.1% yield, SFC: Rt = 2.748) as a white solid. LC-MS (ESI ⁺ ) m/z: 520.5 (M+H) ⁺ . Peak 2 was concentrated under reduced pressure to yield (1R,2R)-1-[4-[4-(dimethoxymethyl)-1-piperidyl]phenyl]-2-(3,3 ,5,5- tetramethylcyclohexyl)tetralin-6-ol (10 mg, 21.1% yield, SFC: Rt = 3.019) as a white solid. LC- MS (ESI ⁺ ) m/z: 520.5 (M+H) ⁺ . Step 4: To a solution of (1R,2R)-1-[4-[4-(dimethoxymethyl)-1-piperidyl]phenyl]-2-(3,3 ,5,5- tetramethylcyclohexyl)tetralin-6-ol (10 mg, 18.66 ^mol) in DCM (2 mL) was added TFA (924.00 mg, 8.10 mmol, 0.6 mL). The mixture was stirred at 25 °C for 1 h, followed by lyophilization to give 1-[4-[(1R,2R)-6-hydroxy-2-(3,3,5,5-tetramethylcyclohexyl)tet ralin-1- yl]phenyl]piperidine-4-carbaldehyde (10 mg, crude) as a yellow solid LC-MS (ESI ⁺ ) m/z: 474.3 (M+H) ⁺ . Step 5: To a solution of (1S,2S)-1-[4-[4-(dimethoxymethyl)-1-piperidyl]phenyl]-2-(3,3 ,5,5- tetramethylcyclohexyl)tetralin-6-ol (10 mg, 18.28 ^mol) in DCM (2 mL) was added TFA (924.00 mg, 8.10 mmol, 0.6 mL). The mixture was stirred at 25 °C for 1 h, followed by lyophilization to give 1-[4-[(1S,2S)-6-hydroxy-2-(3,3,5,5-tetramethylcyclohexyl)tet ralin-1- yl]phenyl]piperidine-4-carbaldehyde (10 mg, crude) as a yellow solid LC-MS (ESI ⁺ ) m/z: 474.3 (M+H) ⁺ . Step 6: To a solution of 1-[4-[(1S,2S)-6-hydroxy-2-(3,3,5,5-tetramethylcyclohexyl)tet ralin-1- yl]phenyl]piperidine-4-carbaldehyde (10 mg, 21.11 ^mol) in MeOH (1 mL) and DCM (1 mL) was added (3S)-3-(1-oxo-5-piperazin-1-yl-isoindolin-2-yl)piperidine-2, 6-dione (10.54 mg, 27.70 ^mol, TSOH) and stirred at 25 °C for 0.5 h. Then NaBH(OAc) ₃ (4.47 mg, 21.11 ^mol) was added and stirred at 25 °C for 0.5 h. The solvent was removed to yield a residue. The residue was purified by preparative HPLC (column: Boston Green ODS 150*30mm*5um;mobile phase: [water(FA)-ACN];B%: 22%-52%,10min), followed by lyophilization to yield (3S)-3-[5-[4-[[1- [4-[(1S,2S)-6-hydroxy-2-(3,3,5,5-tetramethylcyclohexyl)tetra lin-1-yl]phenyl]-4- piperidyl]methyl]piperazin-1-yl]-1-oxo-isoindolin-2-yl]piper idine-2,6-dione (1 mg, 6.0% yield) as a white solid. LC-MS (ESI ⁺ ) m/z: 786.6 (M+H) ⁺ LCMS: calc. for C ₄₉ H ₆₃ N ₅ O ₄ : 785.49, found: [M+H] ⁺ 786.6. HPLC: 97.71% purity at 254 nm. ¹ HNMR (500MHz, MeOD-d4): į 7.67 (d, J = 8.4 Hz, 1H), 7.15 - 7.09 (m, 5H), 7.08 - 7.05 (m, 1H), 7.04 - 6.95 (m, 3H), 5.12 (dd, J = 5.2, 13.3 Hz, 1H), 4.49 - 4.38 (m, 2H), 4.02 (s, 1H), 3.75 (d, J = 12.4 Hz, 2H), 3.44 (s, 4H), 3.09 - 3.03 (m, 1H), 2.97 - 2.87 (m, 1H), 2.80 - 2.73 (m, 8H), 2.53 - 2.43 (m, 4H), 2.17 (d, J = 13.1 Hz, 1H), 1.96 (d, J = 13.0 Hz, 3H), 1.86 (s, 1H), 1.65 (s, 1H), 1.49 - 1.43 (m, 2H), 1.33 - 1.29 (m, 3H), 1.19 - 1.13 (m, 3H), 1.07 (s, 1H), 0.85 (d, J = 4.9 Hz, 6H), 0.69 (s, 3H), 0.66 (s, 3H). Step 7: To a solution of 1-[4-[(1R,2R)-6-hydroxy-2-(3,3,5,5-tetramethylcyclohexyl)tet ralin-1- yl]phenyl]piperidine-4-carbaldehyde (10 mg, 21.11 ^mol) in MeOH (1 mL) and DCM (1 mL) was added (3S)-3-(1-oxo-5-piperazin-1-yl-isoindolin-2-yl)piperidine-2, 6-dione (10.54 mg, 27.70 ^mol, TSOH) and stirred at 25 °C for 0.5 h. Then NaBH(OAc) ₃ (4.47 mg, 21.11 ^mol) was added and stirred at 25 °C for 0.5 h. The solvent was removed to yield a residue. The residue was purified by preparative HPLC (column: Boston Green ODS 150*30mm*5um;mobile phase: [water(FA)-ACN];B%: 22%-52%,10min), followed by lyophilization to yield (3S)-3-[5-[4-[[1- [4-[(1R,2R)-6-hydroxy-2-(3,3,5,5-tetramethylcyclohexyl)tetra lin-1-yl]phenyl]-4- piperidyl]methyl]piperazin-1-yl]-1-oxo-isoindolin-2-yl]piper idine-2,6-dione (1 mg, 6.0% yield) as a white solid. LC-MS (ESI ⁺ ) m/z: 786.6 (M+H) ⁺ LCMS: calc. for C49H63N5O4: 785.49, found: [M+H] ⁺ 786.6. HPLC: 95.70% purity at 254 nm. ¹ HNMR (500MHz, MeOD-d4): į 7.65 (d, J = 8.5 Hz, 1H), 7.13 - 7.07 (m, 5H), 7.06 - 7.03 (m, 1H), 7.02 - 6.95 (m, 3H), 5.10 (dd, J = 5.3, 13.4 Hz, 1H), 4.47 - 4.35 (m, 2H), 4.06 - 3.93 (m, 1H), 3.73 (d, J = 12.7 Hz, 2H), 3.42 (br s, 4H), 3.04 (dd, J = 4.8, 16.3 Hz, 1H), 2.96 - 2.84 (m, 1H), 2.77 - 2.70 (m, 8H), 2.48 - 2.41 (m, 1H), 2.52 - 2.41 (m, 4H), 2.20 - 2.10 (m, 1H), 1.98 - 1.85 (m, 4H), 1.69 - 1.57 (m, 1H), 1.48 - 1.41 (m, 2H), 1.30 (t, J = 12.7 Hz, 3H), 1.18 - 1.11 (m, 3H), 1.06 - 1.01 (m, 1H), 0.83 (d, J = 4.9 Hz, 6H), 0.67 (s, 3H), 0.65 (s, 3H). EXAMPLE 238. Preparation of (I-105) (S)-3-(5-(4-((1-(4-((1R,2R)-2-(4,4- dimethylcyclohexyl)-6-hydroxy-1,2,3,4-tetrahydronaphthalen-1 -yl)phenyl)piperidin-4- yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2, 6-dione and (I-106) (S)-3-(5-(4- ((1-(4-((1S,2S)-2-(4,4-dimethylcyclohexyl)-6-hydroxy-1,2,3,4 -tetrahydronaphthalen-1- yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindo lin-2-yl)piperidine-2,6-dione Step 1: A mixture of 1-(4-(6-(benzyloxy)-2-bromo-3,4-dihydronaphthalen-1-yl)pheny l)-4- (dimethoxymethyl)piperidine (1.5 g, 2.32 mmol, 1.0 eq.), 2-(4,4-dimethylcyclohex-1-en-1-yl)- 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (658.73 mg, 2.79 mmol, 1.2 eq.), RuPhos Pd G ₃ (194.41 mg, 232.45 ^mol, 0.1 eq.), Cs2CO3 (1.51 g, 4.65 mmol, 2.0 eq.) and in dioxane (20 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 100 °C for 16 h EtOAc (60 mL x 3). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (column: Welch Ultimate XB-NH ₂ 250*50*10um;mobile phase: [Heptane-EtOH(0.1%NH ₃ H ₂ O)];B%: 0%-15%,9min) to yield 1-(4-(6-(benzyloxy)-2-(4,4- dimethylcyclohex-1-en-1-yl)-3,4-dihydronaphthalen-1-yl)pheny l)-4- (dimethoxymethyl)piperidine (700 mg, 46.4% yield) as a yellow solid. LC-MS (ESI ⁺ ) m/z: 578.4 (M+H) ⁺ . Step 2: To a suspension of Pd(OH) ₂ /C (1.60 g, 20% purity) in MeOH (30 mL) and THF (10 mL) was added 1-(4-(6-(benzyloxy)-2-(4,4-dimethylcyclohex-1-en-1-yl)-3,4-d ihydronaphthalen-1- yl)phenyl)-4-(dimethoxymethyl)piperidine (600 mg, 924.21 ^mol, 1.0 eq.) under N ₂ . The suspension was degassed under vacuum and purged with H ₂ several times. The mixture was stirred under H ₂ (50 psi) at 70 °C for 24 h. The reaction mixture was filtered and the filter was concentrated. The residue was purified by flash silica gel chromatography (ethyl acetate in petroleum ether= 0% to 40%) to give a product which was separated by chiral SFC (column: DAICEL CHIRALPAK AD (250mm*30mm,10um); mobile phase: [0.1%NH3H2O MEOH];B%: 40%-40%,min, peak 1: 1.528min, peak 2: 2.046 min) to yield Peak 1 and Peak 2. Peak 1 was concentrated under reduced pressure to yield (5R,6R)-5-(4-(4-(dimethoxymethyl)piperidin-1- yl)phenyl)-6-(4,4-dimethylcyclohexyl)-5,6,7,8-tetrahydronaph thalen-2-ol (100 mg, 28.3% yield, SFC: Rt = 1.528 min) as a white solid. LC-MS (ESI ⁺ ) m/z: 492.4 (M+H) ⁺ . Peak 2 was concentrated under reduced pressure to yield (5S,6S)-5-(4-(4-(dimethoxymethyl)piperidin-1- yl)phenyl)-6-(4,4-dimethylcyclohexyl)-5,6,7,8-tetrahydronaph thalen-2-ol (100 mg, 29.5% yield, SFC: Rt = 2.046 min) as a white solid. LC-MS (ESI ⁺ ) m/z: 492.4 (M+H) ⁺ . Step 3: To a solution of (5R,6R)-5-(4-(4-(dimethoxymethyl)piperidin-1-yl)phenyl)-6-(4 ,4- dimethylcyclohexyl)-5,6,7,8-tetrahydronaphthalen-2-ol (50 mg, 95.59 ^mol, 1.0 eq.) in DCM (2 mL) was added TFA (924.00 mg, 8.10 mmol, 0.6 mL). The mixture was stirred at 25 °C for 3 h, followed by lyophilization to give 1-(4-((1R,2R)-2-(4,4-dimethylcyclohexyl)-6-hydroxy-1,2,3,4- tetrahydronaphthalen-1-yl)phenyl)piperidine-4-carbaldehyde (42 mg, crude) as a yellow solid. LC-MS (ESI ⁺ ) m/z: 446.3 (M+H) ⁺ . Step 4: To a solution of (5S,6S)-5-(4-(4-(dimethoxymethyl)piperidin-1-yl)phenyl)-6-(4 ,4- dimethylcyclohexyl)-5,6,7,8-tetrahydronaphthalen-2-ol (50 mg, 95.65 ^mol, 1.0 eq.) in DCM (2 followed by lyophilization to give 1-(4-((1S,2S)-2-(4,4-dimethylcyclohexyl)-6-hydroxy-1,2,3,4- tetrahydronaphthalen-1-yl)phenyl)piperidine-4-carbaldehyde (40 mg, crude) as a yellow solid. LC-MS (ESI ⁺ ) m/z: 446.3 (M+H) ⁺ . Step 5: To a solution of (S)-3-(1-oxo-5-(piperazin-1-yl)isoindolin-2-yl)piperidine-2, 6-dione (30.95 mg, 94.25 ^mol, benzenesulfonic acid, 1.0 eq.) in DCM (1 mL) and MeOH (1 mL) was added 1-(4-((1R,2R)-2-(4,4-dimethylcyclohexyl)-6-hydroxy-1,2,3,4-t etrahydronaphthalen-1- yl)phenyl)piperidine-4-carbaldehyde (42 mg, 94.25 ^mol, 1.0 eq.) and stirred at 25 °C for 0.5 h. Then NaBH(OAc) ₃ (19.97 mg, 94.25 ^mol, 1.0 eq.) was added and stirred at 25 °C for 0.5 h. The solvent was removed to yield a residue. The residue was purified by preparative HPLC (column: Welch Xtimate C18150*25mm*5um; mobile phase: [water (FA)-ACN];B%: 23%- 53%,11min), followed by lyophilization to yield (S)-3-(5-(4-((1-(4-((1R,2R)-2-(4,4- dimethylcyclohexyl)-6-hydroxy-1,2,3,4-tetrahydronaphthalen-1 -yl)phenyl)piperidin-4- yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2, 6-dione (17.8 mg, 23.48 ^mol, 24.9% yield) as a white solid. LC-MS (ESI ⁺ ) m/z: 758.5 (M+H) ⁺ LCMS: calc. for C47H59N5O4: 757.46, found: [M+H] ⁺ 758.5. HPLC: 100.00% purity at 254 nm. ¹ HNMR (500MHz, MeOD-d4): į 7.65 (d, J = 8.4 Hz, 1H), 7.16 - 7.05 (m, 6H), 7.01 (d, J = 8.1 Hz, 1H), 6.98 - 6.92 (m, 1H), 6.95 (dt, J = 2.7, 10.4 Hz, 1H), 5.10 (dd, J = 5.2, 13.3 Hz, 1H), 4.48 - 4.35 (m, 2H), 4.01 - 3.95 (m, 1H), 3.76 (d, J = 12.2 Hz, 2H), 3.44 - 3.39 (m, 4H), 3.03 (dd, 4.7, 15.5 Hz, 1H), 2.95 - 2.86 (m, 1H), 2.82 - 2.67 (m, 9H), 2.49 - 2.39 (m, 4H), 2.36 - 2.26 (m, 1H), 2.23 - 2.11 (m, 2H), 1.97 (d, J = 12.2 Hz, 2H), 1.91 - 1.78 (m, 2H), 1.65 - 1.55 (m, 3H), 1.47 - 1.39 (m, 4H), 1.36 - 1.31 (m, 2H), 0.96 (s, 3H), 0.82 (s, 3H). Step 6: To a solution of (S)-3-(1-oxo-5-(piperazin-1-yl)isoindolin-2-yl)piperidine-2, 6-dione (40 mg, 121.82 ^mol, benzenesulfonic acid, 1.35 eq.) in DCM (1 mL) and MeOH (1 mL) was added 1-(4-((1S,2S)-2-(4,4-dimethylcyclohexyl)-6-hydroxy-1,2,3,4-t etrahydronaphthalen-1- yl)phenyl)piperidine-4-carbaldehyde (40 mg, 89.76 ^mol, 1.0 eq.) and stirred at 25 °C for 0.5 h. Then NaBH(OAc) ₃ (19.02 mg, 89.76 ^mol, 1.0 eq.) and stirred at 25 °C for 0.5 h. The solvent was removed to yield a residue. The residue was purified by preparative HPLC (column: Welch Xtimate C18150*25mm*5um; mobile phase: [water (FA)-ACN];B%: 23%-53%,11min), followed by lyophilization to yield (S)-3-(5-(4-((1-(4-((1S,2S)-2-(4,4-dimethylcyclohexyl)-6- hydroxy-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperidin-4 -yl)methyl)piperazin-1-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione (12.5 mg, 15.99 ^mol, 17.8% yield) as a white solid. LC-MS (ESI ⁺ ) m/z: 758.6 (M+H) ⁺ LCMS: calc. for C ₄₇ H ₅₉ N ₅ O ₄ : 757.46, found: [M+H] ⁺ 758.6. HPLC: 96.95% purity at 254 nm. ¹ HNMR (500MHz, MeOD-d4): į 7.65 (d, J = 8.4 Hz, 1H), 7.16 - 7.05 (m, 6H), 7.01 (d, J = 8.1 Hz, 1H), 6.95 (dt, J = 2.7, 10.4 Hz, 2H), 5.11 (dd, J = 5.0, 13.3 Hz, 1H), 4.47 - 4.35 (m, 2H), 4.02 - 3.94 (m, 1H), 3.76 (d, J = 12.2 Hz, 2H), 3.42 (s, 4H), 3.03 (dd, J = 4.6, 15.9 Hz, 1H), 2.96 - 2.86 (m, 1H), 2.81 - 2.67 (m, 9H), 2.49 - 2.40 (m, 4H), 2.35 - 2.26 (m, 1H), 2.22 - 2.12 (m, 2H), 1.97 (d, J = 12.8 Hz, 2H), 1.85 (d, J = 15.1 Hz, 2H), 1.64 - 1.55 (m, 3H), 1.44 (d, J = 12.4 Hz, 4H), 1.35 - 1.31 (m, 2H), 0.96 (s, 3H), 0.82 (s, 3H). Stereochemistry of the two compounds was arbitrarily assigned

EXAMPLE 239. Preparation of (I-55) (S)-3-(5-(4-((1-(4-((1S,2S)-2-(4,4- difluorocyclohexyl)-6-hydroxy-1,2,3,4-tetrahydronaphthalen-1 -yl)phenyl)piperidin-4- yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2, 6-dione Step 1: A mixture of (5S,6S)-6-(4,4-difluorocyclohexyl)-5-(4-(4-(dimethoxymethyl) piperidin-1- yl)phenyl)-5,6,7,8-tetrahydronaphthalen-2-ol (90 mg, 1 Eq, 0.17 mmol) in 10% H ₂ SO ₄ (1.5 mL) and THF (1.5 mL), then the mixture was stirred at 60 °C for 16 hour. The solvent was removed under vaccum. The residue was dissolved in water (20 mL) and washed by ethyl acetate (20 mL). The aqueous solution was added NaHCO ₃ to adjust pH=6. The combined organic layer was dried over Na ₂ SO ₄ , filtered and concentrated under vaccum to give 1-(4-((1S,2S)-2-(4,4- difluorocyclohexyl)-6-hydroxy-1,2,3,4-tetrahydronaphthalen-1 -yl)phenyl)piperidine-4- carbaldehyde (80 mg, 0.18 mmol, 100%) as a yellow oil. LC-MS (ESI+) m/z: 454.1 (M+H)+. Step 2: A mixture of 1-(4-((1S,2S)-2-(4,4-difluorocyclohexyl)-6-hydroxy-1,2,3,4- tetrahydronaphthalen-1-yl)phenyl)piperidine-4-carbaldehyde (80 mg, 1 Eq, 0.18 mmol), (R)-3- (1-oxo-5-(piperazin-1-yl)isoindolin-2-yl)piperidine-2,6-dion e, Tosylic acid (0.11 g, 1.3 Eq, 0.23 mmol) and Sodium acetate (72 mg, 5 Eq, 0.88 mmol) and Acetic acid (32 mg, 30 ^L, 3 Eq, 0.53 mmol) in DCM (2 mL) and MeOH (2 mL) at 25 °C for 1 hour, then Sodium 25 °C for 16 hour. The reaction was treated with H2O (20 mL), extracted with EtOAc (20 mL). The combined extracts was dried over anhydrous Na2SO4, filtered and concentrated to dryness in vacuo to give a residue. The residue was purified by prep.HPLC (column: Welch Xtimate C18 150*30mm*5um; mobile phase: [water (FA)-ACN]; B%: 21%-51%, 7min). The aqueous phase was lyophilized to dryness to give (S)-3-(5-(4-((1-(4-((1S,2S)-2-(4,4-difluorocyclohexyl)-6- hydroxy-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperidin-4 -yl)methyl)piperazin-1-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione (54.7 mg, 68.5 ^mol, 39%, 95.85% Purity) as a white solid. LC-MS (ESI+) m/z: 766.2 (M+H)+ HPLC: 95.850%, purity at 220 nm. SFC: retention time, 2.655 min; Area, 85.695%; Stereochemistry was arbitrarily assigned ¹ H NMR (400 MHz, DMSO-d ₆ ) į = 11.00 - 10.90 (m, 1H), 9.10 - 8.96 (m, 1H), 8.18 - 8.14 (m, 0.401H), 7.58 - 7.45 (m, 1H), 7.11 - 7.01 (m, 2H), 6.87 - 6.72 (m, 4H), 6.67 - 6.57 (m, 1H), 6.54 - 6.47 (m, 1H), 6.46 - 6.38 (m, 1H), 5.11 - 5.01 (m, 1H), 4.39 - 4.28 (m, 1H), 4.26 - 4.16 (m, 1H), 4.11 - 4.02 (m, 1H), 3.67 - 3.54 (m, 2H), 3.43 - 3.31 (m, 6H), 2.99 - 2.82 (m, 2H), 2.80 - 2.69 (m, 1H), 2.64 - 2.52 (m, 5H), 2.37 - 2.30 (m, 1H), 2.26 - 2.18 (m, 2H), 2.17 - 2.07 (m, 1H), 2.06 - 1.92 (m, 2H), 1.90 - 1.76 (m, 3H), 1.74 - 1.61 (m, 4H), 1.59 - 1.43 (m, 2H), 1.36 - 1.12 (m, 5H), 1.08 - 0.96 (m, 1H).

EXAMPLE 240. Preparation of (I-54) (R)-3-(5-(4-((1-(4-((1R,2R)-2-(4,4- difluorocyclohexyl)-6-hydroxy-1,2,3,4-tetrahydronaphthalen-1 -yl)phenyl)piperidin-4- yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2, 6-dione Step 1: A mixture of 1-(4-(6-(benzyloxy)-2-bromo-3,4-dihydronaphthalen-1-yl)pheny l)-4- (dimethoxymethyl)piperidine (1 g, 1 Eq, 2 mmol), 2-(4,4-difluorocyclohex-1-enyl)-4,4,5,5- tetramethyl-1,3,2-dioxaborolane (0.5 g, 1.2 Eq, 2 mmol), Na ₂ CO ₃ (0.6 g, 3 Eq, 5 mmol) and [1,1'-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex With Dichloromethane (0.1 g, 0.1 Eq, 0.2 mmol) in Dioxane (12 mL) and H2O (3.0 mL) at r.t.. N2 was bubbled into the mixture for 5 min. The reaction mixture was heated at 100 °C for 16 hour. Then the reaction was cooled to room temperature. The mixture was treated with H ₂ O (50 mL), extracted with EtOAc (50 mL). The combined extracts was dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to dryness in vacuo to give a residue. The residue was subjected to column chromatography over silica gel (gradient elution: 0~20% ethyl acetate in petroleum ether). The pure fractions were collected and concentrated to dryness in vacuo to give 1-(4-(6-(benzyloxy)-2-(4,4- difluorocyclohex-1-en-1-yl)-3,4-dihydronaphthalen-1-yl)pheny l)-4-(dimethoxymethyl)piperidine (850 mg, 1.4 mmol, 80 %, 97% Purity) as a white solid. LC-MS (ESI ⁺ ) m/z: 586.2 (M+H) ⁺ . Step 2: A mixture of 1-(4-(6-(benzyloxy)-2-(4,4-difluorocyclohex-1-en-1-yl)-3,4- dihydronaphthalen-1-yl)phenyl)-4-(dimethoxymethyl)piperidine (750 mg, 1 Eq, 1.24 mmol), Pd/C (800 mg, 10% Wt, 0.605 Eq, 752 ^mol), H ₂ (2.51 mg, 1 Eq, 1.24 mmol) in MeOH (3 mL) and THF (3 mL). The suspension was degassed and purged with H ₂ for 3 times. The mixture was stirred under H ₂ (50 psi ) at 50 °C for 24 hour. Then the reaction was cooled to room temperature. The reaction was filtered and concentrated to dryness in vacuo to give a white solid. The white solid was subjected by SFC: Column: DAICEL CHIRALCEL OD (250 mm *30 mm,10 um); Mobile phase: A: Supercritical CO ₂ , B: MeOH (0.1% NH ₃ H ₂ O), A:B = 65:35 at 80 mL/min. The aqueous phase was lyophilized to dryness to give the product (5S,6S)-6-(4,4- difluorocyclohexyl)-5-(4-(4-(dimethoxymethyl)piperidin-1-yl) phenyl)-5,6,7,8- tetrahydronaphthalen-2-ol (90 mg, 0.18 mmol, 15%, 100% Purity) and (5R,6R)-6-(4,4- difluorocyclohexyl)-5-(4-(4-(dimethoxymethyl)piperidin-1-yl) phenyl)-5,6,7,8- tetrahydronaphthalen-2-ol (90 mg, 0.17 mmol, 14%, 95% Purity) as a yellow solid. LC-MS (ESI ⁺ ) m/z: 500.1 (M+H) ⁺ . Step 3: A mixture of (5R,6R)-6-(4,4-difluorocyclohexyl)-5-(4-(4-(dimethoxymethyl) piperidin-1- yl)phenyl)-5,6,7,8-tetrahydronaphthalen-2-ol (90 mg, 1 Eq, 0.18 mmol) in 10% H ₂ SO ₄ (1.5 mL) and THF (1.5 mL), then the mixture was stirred at 60 °C for 16 hour. The solvent was removed under vaccum. The residue was dissolved in water (20 mL) and washed by ethyl acetate (20 mL). The aqueous solution was added NaHCO ₃ to adjust pH=6. The combined organic layer was dried over Na ₂ SO ₄ , filtered and concentrated under vaccum to give 1-(4-((1R,2R)-2-(4,4- difluorocyclohexyl)-6-hydroxy-1,2,3,4-tetrahydronaphthalen-1 -yl)phenyl)piperidine-4- carbaldehyde (80 mg, 0.18 mmol, 98%) as a yellow oil. LC-MS (ESI+) m/z: 454.2 (M+H)+ Step 4: A mixture of 1-(4-((1R,2R)-2-(4,4-difluorocyclohexyl)-6-hydroxy-1,2,3,4- tetrahydronaphthalen-1-yl)phenyl)piperidine-4-carbaldehyde (80 mg, 1 Eq, 0.18 mmol), (R)-3- (1-oxo-5-(piperazin-1-yl)isoindolin-2-yl)piperidine-2,6-dion e, Tosylic acid (0.11 g, 1.3 Eq, 0.23 mmol) and Sodium acetate (72 mg, 5 Eq, 0.88 mmol) and Acetic acid (32 mg, 30 ^L, 3 Eq, 0.53 triacetoxyborohydride (75 mg, 2 Eq, 0.35 mmol) was added to the mixture and was stirred at 25 °C for 16 hour. The reaction was treated with H2O (20 mL), extracted with EtOAc (20 mL). The combined extracts was dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to dryness in vacuo to give a residue. The residue was purified by prep.HPLC (column: Welch Xtimate C18 150*30mm*5um; mobile phase: [water (FA)-ACN]; B%: 21%-51%, 7min). The aqueous phase was lyophilized to dryness to give (R)-3-(5-(4-((1-(4-((1R,2R)-2-(4,4-difluorocyclohexyl)-6- hydroxy-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperidin-4 -yl)methyl)piperazin-1-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione (66.8 mg, 83.8 ^mol, 48 % yield, 96.078% purity) as a white solid. LC-MS (ESI+) m/z: 766.2 (M+H) ⁺ HPLC: 96.078%, purity at 220 nm. SFC: retention time, 3.063 min; Area, 87.591%; Stereochemistry was arbitrarily assigned. NMR (400 MHz, DMSO-d6) į = 11.00 - 10.91 (m, 1H), 9.07 - 8.97 (m, 1H), 8.19 - 8.08 (m, 0.583H), 7.57 - 7.50 (m, 1H), 7.10 - 7.01 (m, 2H), 6.86 - 6.73 (m, 4H), 6.65 - 6.59 (m, 1H), 6.54 - 6.48 (m, 1H), 6.45 - 6.39 (m, 1H), 5.10 - 5.01 (m, 1H), 4.39 - 4.28 (m, 1H), 4.26 - 4.16 (m, 1H), 4.09 - 4.02 (m, 1H), 3.66 - 3.56 (m, 2H), 3.47 - 3.31 (m, 6H), 2.97 - 2.82 (m, 2H), 2.79 - 2.69 (m, 1H), 2.63 - 2.53 (m, 5H), 2.38 - 2.30 (m, 1H), 2.27 - 2.18 (m, 2H), 2.17 - 2.07 (m, 1H), 2.06 - 1.92 (m, 2H), 1.90 - 1.75 (m, 3H), 1.75 - 1.61 (m, 4H), 1.60 - 1.43 (m, 2H), 1.35 - 1.11 (m, 5H), 1.09 - 0.96 (m, 1H)

EXAMPLE 241. Preparation of (I-53) (R)-3-(5-(4-((1-(4-((1S,2S)-2-cyclopentyl-6- hydroxy-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperidin-4 -yl)methyl)piperazin-1-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione Step 1: A mixture of (5S,6S)-6-cyclopentyl-5-(4-(4-(dimethoxymethyl)piperidin-1-y l)phenyl)- 5,6,7,8-tetrahydronaphthalen-2-ol (120 mg, 1 Eq, 265 ^mol) in 10% H ₂ SO ₄ (1.5 mL) and THF (1.5 mL), then the mixture was stirred at 60 °C for 16 hour. The solvent was removed under vaccum. The residue was dissolved in water (20 mL) and washed by ethyl acetate (20 mL). The aqueous solution was added NaHCO ₃ to adjust pH=6. The combined organic layer was dried over Na ₂ SO ₄ , filtered and concentrated under vaccum to give 1-(4-((1S,2S)-2-cyclopentyl-6- hydroxy-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperidine- 4-carbaldehyde (100 mg, 0.248 mmol, 93.4 %) as a yellow oil. LC-MS (ESI+) m/z: 422.1 (M+H)+. Step 2: A mixture of 1-(4-((1S,2S)-2-cyclopentyl-6-hydroxy-1,2,3,4-tetrahydronaph thalen-1- yl)phenyl)piperidine-4-carbaldehyde (100 mg, 1 Eq, 248 ^mol), (R)-3-(1-oxo-5-(piperazin-1- yl)isoindolin-2-yl)piperidine-2,6-dione, TsOH acid (161 mg, 1.3 Eq, 322 ^mol) and Sodium acetate (102 mg, 5 Eq, 1.24 mmol) and Acetic acid (44.6 mg, 42.8 ^L, 3 Eq, 743 ^mol) in DCM (2 mL) and MeOH (2 mL) at 25 °C for 1 hour, then Sodium triacetoxyborohydride (105 mg, 2 Eq, 496 ^mol) was added to the mixture and was stirred at 25 °C for 16 hour. The reaction was anhydrous Na2SO4, filtered and concentrated to dryness in vacuo to give a residue. The residue was purified by prep.HPLC (column: Welch Xtimate C18150*30mm*5um; mobile phase: [water (FA)-ACN]; B%: 31%-61%, 7min). The aqueous phase was lyophilized to dryness to give (R)-3-(5-(4-((1-(4-((1S,2S)-2-cyclopentyl-6-hydroxy-1,2,3,4- tetrahydronaphthalen-1- yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindo lin-2-yl)piperidine-2,6-dione (59.4 mg, 77.8 ^mol, 31.4%, 93.724% Purity) as a pink solid. LC-MS (ESI+) m/z: 716.3 (M+H)+ HPLC: 93.724%, purity at 220 nm. SFC: retention time, 3.024 min; Area, 87.334%; Stereochemistry was arbitrarily assigned ¹ H NMR (400 MHz, DMSO-d ₆ ) į = 10.99 - 10.91 (m, 1H), 9.16 - 8.86 (m, 1H), 8.18 - 8.13 (m, 0.504H), 7.49 (s, 1H), 7.12 - 7.01 (m, 2H), 6.85 - 6.74 (m, 4H), 6.65 - 6.58 (m, 1H), 6.53 - 6.48 (m, 1H), 6.45 - 6.39 (m, 1H), 5.11 - 5.00 (m, 1H), 4.39 - 4.28 (m, 1H), 4.26 - 4.12 (m, 1H), 3.98 - 3.90 (m, 1H), 3.63 - 3.55 (m, 2H), 3.42 - 3.24 (m, 10H), 2.96 - 2.66 (m, 4H), 2.27 - 2.17 (m, 2H), 2.08 - 1.91 (m, 2H), 1.86 - 1.74 (m, 2H), 1.74 - 1.42 (m, 9H), 1.36 - 1.16 (m, 5H), 1.12 - 0.98 (m, 1H).

EXAMPLE 242. Preparation of (I-52) (R)-3-(5-(4-((1-(4-((1R,2R)-2-cyclopentyl-6- hydroxy-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperidin-4 -yl)methyl)piperazin-1-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione Step 1: A mixture of 1-(4-(6-(benzyloxy)-2-bromo-3,4-dihydronaphthalen-1-yl)pheny l)-4- (dimethoxymethyl)piperidine (1 g, 1 Eq, 2 mmol), cyclopent-1-en-1-ylboronic acid (0.2 g, 1.2 Eq, 2 mmol), N ₃ (0.6 g, 3 Eq, 5 mmol) and Pd(dppf)Cl ₂ (0.1 g, 0.1 Eq, 0.2 mmol) in dioxane (12 mL) and H ₂ O (3.0 mL) at r.t.. N ₂ was bubbled into the mixture for 5 min. The reaction mixture was heated at 100 °C for 16 hour. Then the reaction was cooled to room temperature. The mixture was treated with H2O (50 mL), extracted with EtOAc (50 mL). The combined extracts was dried over anhydrous Na2SO4, filtered and concentrated to dryness in vacuo to give a residue. The residue was subjected to column chromatography over silica gel (gradient elution: 0~20% ethyl acetate in petroleum ether). The pure fractions were collected and concentrated to yl)phenyl)-4-(dimethoxymethyl)piperidine (760 mg, 1.3 mmol, 70%, 93% Purity) as a yellow oil. LC-MS (ESI ⁺ ) m/z: 536.1 (M+H) ⁺ . Step 2: A mixture of 1-(4-(6-(benzyloxy)-2-(cyclopent-1-en-1-yl)-3,4-dihydronapht halen-1- yl)phenyl)-4-(dimethoxymethyl)piperidine (650 mg, 93% Wt, 1 Eq, 1.13 mmol), Pd/C(650 mg, 10% Wt, 0.541 Eq, 611 ^mol), H ₂ (2.28 mg, 1 Eq, 1.13 mmol) in THF (3 mL) and MeOH (3 mL) was degassed and purged with H ₂ for 3 times and then the mixture was stirred at at 50 °C for 12 hour under H ₂ (50 psi)atmosphere. The reaction was filtered and concentrated to dryness in vacuo to give a white solid. The white solid was subjected by SFC: Column: DAICEL CHIRALCEL OD (250 mm *30 mm,10 um); Mobile phase: A: Supercritical CO ₂ , B: MeOH (0.1% NH ₃ H ₂ O), A:B = 70:30 at 80 mL/min. The aqueous phase was lyophilized to dryness to give (5S,6S)-6-cyclopentyl-5-(4-(4-(dimethoxymethyl)piperidin-1-y l)phenyl)-5,6,7,8- tetrahydronaphthalen-2-ol (120 mg, 261 ^mol, 23.1%, 97.781% purity) and (5R,6R)-6- cyclopentyl-5-(4-(4-(dimethoxymethyl)piperidin-1-yl)phenyl)- 5,6,7,8-tetrahydronaphthalen-2-ol (120 mg, 265 ^mol, 23.5%, 99.370% purity) as a yellow oil. LC-MS (ESI ⁺ ) m/z: 450.2 (M+H) ⁺ . Step 3: A mixture of (5R,6R)-6-cyclopentyl-5-(4-(4-(dimethoxymethyl)piperidin-1-y l)phenyl)- 5,6,7,8-tetrahydronaphthalen-2-ol (120 mg, 1 Eq, 261 ^mol) in 10% H2SO4 (1.5 mL) and THF (1.5 mL), then the mixture was stirred at 60 °C for 16 hour. The solvent was removed under vaccum. The residue was dissolved in water (20 mL) and washed by ethyl acetate (20 mL). The aqueous solution was added NaHCO ₃ to adjust pH=6. The combined organic layer was dried over Na ₂ SO ₄ , filtered and concentrated under vaccum to give 1-(4-((1R,2R)-6-hydroxy-2-(1- methyl-1H-pyrazol-5-yl)-1,2,3,4-tetrahydronaphthalen-1-yl)ph enyl)piperidine-4-carbaldehyde (100 mg, 0.248 mmol, 93.4%) as a yellow oil. LC-MS (ESI+) m/z: 422.1 (M+H)+ Step 4: A mixture of 1-(4-((1R,2R)-2-cyclopentyl-6-hydroxy-1,2,3,4-tetrahydronaph thalen-1- yl)phenyl)piperidine-4-carbaldehyde (100 mg, 1 Eq, 248 ^mol), (R)-3-(1-oxo-5-(piperazin-1- yl)isoindolin-2-yl)piperidine-2,6-dione, TsOH acid (161 mg, 1.3 Eq, 322 ^mol) and Sodium acetate (102 mg, 5 Eq, 1.24 mmol) and Acetic acid (44.6 mg, 42.8 ^L, 3 Eq, 743 ^mol) in DCM (2 mL) and MeOH (2 mL) at 25 °C for 1 hour, then Sodium triacetoxyborohydride (105 mg, 2 Eq, 496 ^mol) was added to the mixture and was stirred at 25 °C for 16 hour. The reaction was treated with H2O (20 mL), extracted with EtOAc (20 mL). The combined extracts was dried over anhydrous Na2SO4, filtered and concentrated to dryness in vacuo to give a residue. The residue [water (FA)-ACN]; B%: 26%-56%, 7min). The aqueous phase was lyophilized to dryness to give (R)-3-(5-(4-((1-(4-((1R,2R)-2-cyclopentyl-6-hydroxy-1,2,3,4- tetrahydronaphthalen-1- yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindo lin-2-yl)piperidine-2,6-dione (80.8 mg, 109 ^mol, 44.2%, 96.954% Purity) as a pink solid. LC-MS (ESI+) m/z: 716.3 (M+H)+ HPLC: 96.954%, purity at 220 nm. SFC: retention time, 3.039 min; Area, 89.199%; Stereochemistry was arbitrarily assigned. NMR (400 MHz, DMSO-d ₆ ) į = 10.98 - 10.91 (m, 1H), 9.06 - 8.96 (m, 1H), 8.18 - 8.13 (m, 0.230H), 7.55 - 7.50 (m, 1H), 7.10 - 7.02 (m, 2H), 6.88 - 6.73(m, 4H), 6.66 - 6.58 (m, 1H), 6.53 - 6.48 (m, 1H), 6.45 - 6.39 (m, 1H), 5.11 - 5.00 (m, 1H), 4.38 - 4.27 (m, 1H), 4.26 - 4.16 (m, 1H), 3.98 - 3.90 (m, 1H), 3.66 - 3.54 (m, 2H), 3.42 - 3.22 (m, 11H), 2.95 - 2.69 (m, 3H), 2.27 - 2.18 (m, 2H), 2.07 - 1.91 (m, 2H), 1.85 - 1.75 (m, 2H), 1.74 - 1.42 (m, 9H), 1.35 - 1.15 (m, 5H), 1.10 - 0.97 (m, 1H)

EXAMPLE 243. Preparation of (I-49) (5R,6S)-5-(4-(4-((4-(2-((S)-2,6-dioxopiperidin-3- yl)-1-oxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-y l)phenyl)-6-phenyl-5,6,7,8- tetrahydronaphthalene-2-carbonitrile Step 1: A 40 mL thread was vial equipped with magnetic stirrer. (5R,6S)-5-(4-(4- (dimethoxymethyl)piperidin-1-yl)phenyl)-6-phenyl-5,6,7,8-tet rahydronaphthalen-2-yl trifluoromethanesulfonate (500 mg, 848 ^mol), Potassium acetate (83.2 mg, 848 ^mol), and Potassium ferrocyanide (358 mg, 848 ^mol) in 1,4-Dioxane (2.5 mL) and H ₂ O (2.5 mL) was sparged with N ₂ atmosphere for 5 min, and then tBuXPhos (18 mg, 42.4^mol) and tBuXPhos Pd G ₃ (33.7 mg, 42.4 mol) was added. The vial was sealed with a rubber septum. The mixture was stirred at 100 °C for 16 h. LCMS showed 15% desired MS. 50 mL H ₂ O was added, and the mixture was extracted with DCM (2×20 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to dryness in vacuo to give a yellow solid (500 mg). The yellow solid was subjected to column chromatography over ili l ( di l i 0 9% OA i l h ) h d i d f i collected, and concentrated to dryness in vacuo to give a white solid (237 mg, 420 ^mol, 49.5% yield, 82.7% purity). TLC: petroleum ether/ethyl acetate=5:1, R _f =0.3 LC-MS (ESI ⁺ ) m/z: 467.3 (M+H) ⁺ . Step 2: A 40 mL thread vial was equipped with magnetic stirrer. (5R, 6S)-5-(4-(4- (dimethoxymethyl)piperidin-1-yl)phenyl)-6-phenyl-5,6,7,8-tet rahydronaphthalene-2-carbonitrile (220 mg, 390 ^mol) was added into HCl/dioxane (3 mL) at 20 °C. The vial was sealed with a rubber septum. The reaction was stirred at 50 °C for 16 h. LCMS showed 55% desired MS. The reaction was concentrated to dryness in vacuo to give (5R, 6S)-5-(4-(4-formylpiperidin-1- yl)phenyl)-6-phenyl-5,6,7,8-tetrahydronaphthalene-2-carbonit rile (280 mg, 368 ^mol, 94.3 % yield, 55.3% purity) as a yellow solid. LC-MS (ESI ⁺ ) m/z: 421.0 (M+H) ⁺ . Step 3: A solution of (S)-3-(1-oxo-5-(piperazin-1-yl)isoindolin-2-yl)piperidine-2, 6-dione, TsOH salt(302 mg, 358 ^mol) ^(5R,6S)-5-(4-(4-formylpiperidin-1-yl)phenyl)-6-phenyl-5,6,7 ,8- tetrahydronaphthalene-2-carbonitrile (140 mg, 239 ^mol) and Sodium acetate (97.9 mg, 1.19 mmol) in DCM (2 mL) and MeOH (2 mL) was stirred at 50 °C for 3 h, Then acetic acid (28.7 mg, 477 ^mol) and sodium triacetoxyborohydride (101 mg, 477 ^mol) was added. The mixture was stirred at 25 °C for 16 h. The mixture was treated with H ₂ O (20 mL), extracted with EtOAc (20 mL * 2). The combined extracts was dried over anhydrous Na2SO4, filtered and concentrated to dryness in vacuo to give a residue. The residue was purified by prep-HPLC (column: Phenomenex C1880*30mm*3um; mobile phase: [water(FA)-ACN];B% 11%-51%, 8 min) to give (5R,6S)-5-(4-(4-((4-(2-((S)-2,6-dioxopiperidin-3-yl)-1-oxois oindolin-5-yl)piperazin-1- yl)methyl)piperidin-1-yl)phenyl)-6-phenyl-5,6,7,8-tetrahydro naphthalene-2-carbonitrile (20.4 mg, 11.6 % yield). LC-MS (ESI ⁺ ) m/z: 733.4 (M+H) ⁺ . LCMS: calc. for C ₄₆ H ₄₈ N ₆ O ₃ : 732.38, found: [M+H] ⁺ 733.4. HPLC: 99.415% purity at 220 nm. ¹ HNMR (400MHz, DMSO-d ₆ ) į= 10.95 (s, 1H), 8.16 (s, 1H), 7.75 (s, 1H), 7.55 -7.47 (m, 2H), (d, J=8.6 Hz, 2H), 5.05 (dd, J=5.0, 13.1 Hz, 1H), 4.37 - 4.30 (m, 2H), 4.24 - 4.17 (m, 1H), 3.53 (br d, J=12.4 Hz, 2H), 3.28 (br d, J=3.6 Hz, 6H), 3.18 (br dd, J=5.7, 18.2 Hz, 2H), 3.09 - 2.97 (m, 2H), 2.96 - 2.84 (m, 2H), 2.60 (br s, 4H), 2.43 - 2.37 (m, 1H), 2.23 - 2.12 (m, 3H), 2.00 - 1.92 (m, 1H), 1.84 - 1.72 (m, 3H), 1.64 (br s, 1H), 1.20 - 1.10 (m, 2H) SFC: retention time, 4.051 min; Area, 83.101 %; EXAMPLE 244. Preparation of (I-104) (S)-3-(5-(4-((1-(4-((1R,2S)-6-amino-2-phenyl- 1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperidin-4-yl)meth yl)piperazin-1-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione Step 1: (5R,6S)-5-(4-(4-(dimethoxymethyl)piperidin-1-yl)phenyl)-6-ph enyl-5,6,7,8- tetrahydronaphthalen-2-yl trifluoromethanesulfonate (480 mg, 1 Eq, 814 ^mol) and 4,5- Bis(diphenylphosphino)-9,9-dimethyl xanthene (94.2 mg, 0.2 Eq, 163 ^mol) were combined in a nitrogen-purged flask. Diacetoxypalladium (18.3 mg, 0.1 Eq, 81.4 ^mol), tert-butyl carbamate (143 mg, 1.5 Eq, 1.22 mmol) and Cesium carbonate (530 mg, 130 ^L, 2 Eq, 1.63 mmol) were added to the reaction flask in 1,4-dioxane (2 mL) under N ₂ atmosphere. The reaction mixture was stirred under dry nitrogen at 100 °C for 16 hour. TLC (petroleum ether: ethyl aceatte=5:1, UV, Rf = 0.4) showed one main new spot was observed. LCMS showed 48.86% desired MS. The reaction was quenched with water (100 mL) and extracted with ethyl acetate (200 mL*2). The organic layer was washed with brine (50 mL) and dried over Na ₂ SO ₄ and concentrated in vacuo to give the residue as a black oil. The black oil was subjected to column chromatography over silica gel (gradient elution: 0 – 20% EtOAc). LCMS showed 100% desired MS. The desired fractions were collected, and concentrated to dryness in vacuo to give tert-butyl ((5R,6S)-5-(4- (4-(dimethoxymethyl)piperidin-1-yl)phenyl)-6-phenyl-5,6,7,8- tetrahydronaphthalen-2- yl)carbamate (198 mg, 356 ^mol, 43.7 %, 100% Purity) as a colorless oil. LC-MS (ESI ⁺ ) m/z: 557.4 (M+H) ⁺ . Step 2: To a solution of tert-butyl ((5R,6S)-5-(4-(4-(dimethoxymethyl)piperidin-1-yl)phenyl)-6- phenyl-5,6,7,8-tetrahydronaphthalen-2-yl)carbamate (100 mg, 1 Eq, 180 ^mol) in acetone (5 mL) was added 42 ^L of H ₂ O (5 ^L) and amberlyst15ion-exchangeresin (141 mg, 2.5 Eq, 449 ^mol). The reaction mixture was stirred at 25 °C for 16 hour. LCMS showed 90.95% desired MS. The reaction solution filter and spin dry to give tert-butyl ((5R,6S)-5-(4-(4-formylpiperidin- 1-yl)phenyl)-6-phenyl-5,6,7,8-tetrahydronaphthalen-2-yl)carb amate (50 mg, 89 ^mol, 50 %, 90.95% purity) as a colorless solid. LC-MS (ESI ⁺ ) m/z: 529.2 (M+H) ⁺ . Step 3: A mixture of tert-butyl ((5R,6S)-5-(4-(4-formylpiperidin-1-yl)phenyl)-6-phenyl-5,6,7 ,8- tetrahydronaphthalen-2-yl)carbamate (30 mg, 1 Eq, 59 ^mol), (R)-3-(1-oxo-5-(piperazin-1- yl)isoindolin-2-yl)piperidine-2,6-dione, Tosylic acid (29 mg, 1 Eq, 59 ^mol) and Sodium acetate (24 mg, 5 Eq, 0.29 mmol) in DCM (1.5 mL) and MeOH (1.5 mL) at 20°C for 0.5 hour, then acetic acid (11 mg, 10 ^L, 3 Eq, 0.18 mmol) at 20°C for 1 hour, then added Na(OAc) ₃ BH(25 mg, 2 Eq, 0.12 mmol) to the mixture, and the mixture was stirred at 25°C for 16 hour. LCMS showed 70.47% desired MS. The reaction was quenched with water (50 mL) and extracted with ethyl acetate (50 mL*2). The organic layer was washed with brine (50 mL) and dried over Na ₂ SO ₄ and concentrated in vacuo to give tert-butyl ((5R,6S)-5-(4-(4-((4-(2-((S)-2,6- dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperazin-1-yl)met hyl)piperidin-1-yl)phenyl)-6- phenyl-5,6,7,8-tetrahydronaphthalen-2-yl)carbamate (30 mg, 36 ^mol, 62 %) as a brown oil. LC- MS (ESI ⁺ ) m/z: 823.5 (M+H) ⁺ Step 4: A 50 mL thread vial equipped with magnetic stirrer. A solution of tert-butyl ((5R,6S)-5- (4-(4-((4-(2-((S)-2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5 -yl)piperazin-1-yl)methyl)piperidin- 1-yl)phenyl)-6-phenyl-5,6,7,8-tetrahydronaphthalen-2-yl)carb amate (30 mg, 1 Eq, 36 ^mol) in HCL/dioxane (5 mL) was stirred at 25 °C for 16 hour. LCMS showed 36.78% desired MS. The reaction was concentrated and purified by preparative high-performance liquid chromatography. Condition: water(HCl)-CAN; Column: Phenomenex C18150*40mm*5um; A: water (HCl); B:CAN; At the beginning: A (99%) and B (1%); At the end: A: (70%) and B (30%); Gradient Time(min) 10; 100% B hold Time(min) 2, Flow Rate(ml/min) 60. The pure fractions were collected and the solvent was evaporated under vacuum. The aqueous layer was lyophilized to dryness to give (S)-3-(5-(4-((1-(4-((1R,2S)-6-amino-2-phenyl-1,2,3,4-tetrahy dronaphthalen-1- yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindo lin-2-yl)piperidine-2,6-dione (7 mg, 9 ^mol, 30 %, 95.05% Purity) as a white soild. LC-MS (ESI+) m/z: 723.2 (M+H) +. LCMS: calc. for C ₄₅ H ₅₀ N ₆ O ₃ : 722.39, found: [M+H] ⁺ 723.2. HPLC: 95.056% purity at 220 nm. NMR (400 MHz, DMSO-d6) į= 11.00 - 10.95 (m, 1H), 7.62 - 7.58 (m, 1H), 7.23 - 7.12 (m, 8H), 7.03 - 6.99 (m, 1H), 6.97 - 6.94 (m, 1H), 6.87 - 6.85 (m,2H), 6.40 - 6.22 (m, 2H), 5.10 - 5.03 (m, 1H), 4.39 - 4.32 (m, 2H), 4.27 - 4.21 (m, 1H), 4.02 - 3.94 (m, 2H), 3.67 - 3.50 (m, 7H), 3.20 - 3.03 (m, 9H), 2.94 -2.85 (m, 1H), 2.70 - 2.65 (m, 1H), 2.34 - 2.32 (m, 1H), 2.19 - 2.07 (m, 2H), 2.02 - 1.89 (m, 4H), 1.82 - 1.77 (m, 1H). SFC: retention time, 4.276 min; Area, 87.795%;

EXAMPLE 245. Preparation of (I-46) (S)-3-(1-oxo-5-(4-((1-(4-((1R,2S)-2-phenyl-6- (trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)p iperidin-4- yl)methyl)piperazin-1-yl)isoindolin-2-yl)piperidine-2,6-dion e Step 1: A solution of 4-(dimethoxymethyl)-1-(4-((1R,2S)-2-phenyl-6-(4,4,5,5-tetram ethyl-1,3,2- dioxaborolan-2-yl)-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl) piperidine (150 mg, 1 Eq, 264 ^mol) and Reactant II (124 mg, 1.5 Eq, 396 ^mol) in DMF (4 mL) was stirred at 50°C for 16 hour, The mixture was stirred at 50 °C for 16h. LCMS showed 36.093% desired MS. TLC (petroleum ether: ethyl aceatte=5:1, UV) showed one main new spot was observed. The reaction was purified by flash column (petroleum ether/ethyl acetate from 100/0 to 0/100) and the organic layer was concentrated in vacuo to give 4-(dimethoxymethyl)-1-(4-((1R,2S)-2-phenyl-6- (trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)p iperidine (110 mg, 216 ^mol, 81.7 % yield, 100% purity) as a yellow solid. LC-MS (ESI+) m/z: 510.1 (M+H) ⁺ Step 2: To a solution of (4-(dimethoxymethyl)-1-(4-((1R,2S)-2-phenyl-6-(trifluorometh yl)- 1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperidine (110 mg, 1 Eq, 216 ^mol)) in 4 M HCl in dioxane (4 mL) . The mixture was stirred at 60 °C for 6 hour. LCMS showed 100% desired MS. tetrahydronaphthalen-1-yl)phenyl)piperidine-4-carbaldehyde (100 mg, 216 ^mol, 99.9 %yield, 100% purity) as a white yellow. LC-MS (ESI+) m/z: 464.2 (M+H) ⁺ Step 3: A solution of 1-(4-((1R,2S)-2-phenyl-6-(trifluoromethyl)-1,2,3,4-tetrahydr onaphthalen- 1-yl)phenyl)piperidine-4-carbaldehyde (100 mg, 1 Eq, 216 ^mol) and (S)-3-(1-oxo-5-(piperazin- 1-yl)isoindolin-2-yl)piperidine-2,6-dione, 3Tosylic acid (180 mg, 0.987 Eq, 213 ^mol) and AcONa (108 mg, 5 Eq, 1.08 mmol) in DCM (2 mL) and MeOH (2 mL) was stirred at 20°C for 30 mins, Then NaBH(OAc) ₃ (40.7 mg, 3 Eq, 647 ^mol) and Acetic acid (51.8 mg, 49.6 ^L, 4 Eq, 863 ^mol) was added. The mixture was stirred at 20°C for 16h. LCMS showed 89.038% desired MS. The reaction was concentrated to give a brown solid. The brown solid was purified by preparative high-performance liquid chromatography. Condition: Column: 2_Phenomenex Gemini C1875*40mm*3um A: water(FA); B:CAN; at the beginning: A (65%) and B ^35%); at the end: A: (35%) and B ^65%); Gradient Time (min) 7; 100% B hold Time (min) 2, Flow Rate (ml/min) 25. The pure fractions were collected and the solvent was evaporated under vacuum. The aqueous layer was lyophilized to dryness to give (S)-3-(1-oxo-5-(4-((1-(4- ((1R,2S)-2-phenyl-6-(trifluoromethyl)-1,2,3,4-tetrahydronaph thalen-1-yl)phenyl)piperidin-4- yl)methyl)piperazin-1-yl)isoindolin-2-yl)piperidine-2,6-dion e (40.8 mg, 52.6 ^mol, 24.4 % yield, 100% purity) as a white solid. LC-MS (ESI ⁺ ) m/z: 708.4 (M+H) ⁺ LCMS: calc. for C ₄₆ H ₄₈ F ₃ N ₅ O ₃ , found: [M+H] ⁺ 776.3. HPLC: 96.737 % purity at 220 nm. ¹ H NMR (400 MHz, DMSO-d ₆ ) į = 10.95 (s, 1H), 8.21 (s, 1H), 7.62 (s, 1H), 7.52 (d, J=8.5 Hz, 1H), 7.40 (br d, J=7.8 Hz, 1H), 7.20 - 7.04 (m, 6H), 6.87 (br d, J=6.5 Hz, 2H), 6.57 (d, J=8.8 Hz, 2H), 6.22 (d, J=8.8 Hz, 2H), 5.05 (dd, J=5.0, 13.3 Hz, 1H), 4.33 (br d, J=16.6 Hz, 2H), 4.24 - 4.16 (m, 1H), 3.53 (br d, J=10.0 Hz, 2H), 3.35 (br d, J=10.5 Hz, 6H), 3.20 (br d, J=5.3 Hz, 1H), 3.12 - 3.00 (m, 1H), 2.96 - 2.84 (m, 1H), 2.63 - 2.52 (m, 6H), 2.40 - 2.32 (m, 1H), 2.19 (br d, J=7.0 Hz, 3H), 2.00 - 1.93 (m, 1H), 1.85 - 1.70 (m, 3H), 1.64 (br s, 1H), 1.40 - 1.03 (m, 3H) SFC: retention time, 2.612; Area, 91.907 %; EXAMPLE 246. Preparation of (I-45) ((5R,6S)-5-(4-(4-((4-(2-((S)-2,6-dioxopiperidin-3- yl)-1-oxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-y l)phenyl)-6-phenyl-5,6,7,8- tetrahydronaphthalen-2-yl)boronic acid Step 1: (5R,6S)-5-(4-(4-(dimethoxymethyl)piperidin-1-yl)phenyl)-6-ph enyl-5,6,7,8- tetrahydronaphthalen-2-yl trifluoromethanesulfonate (400 mg, 1 Eq, 678 ^mol),4,4,4',4',5,5,5',5'- octamethyl-2,2'-bi(1,3,2-dioxaborolane) (258 mg, 1.5 Eq, 1.02 mmol), potassium acetate (133 mg, 2 Eq, 1.36 mmol) and 1,4-Dioxane (5 mL) were added to a 100 mL round-bottomed flask. The resulting mixture was sparged with N ₂ for 5 min, followed by Pd(dppf)Cl ₂ (55.4 mg, 0.1 Eq, 67.8 ^mol) were added. The resultant mixture was sparged with N ₂ for 5 min and stirred under argon for 12 h at 90 °C. After this time, the mixture was cooled to room temperature. LCMS showed 61.35% desired MS. The mixtrue was discarded without purification. TLC (petroleum ether: ethyl aceatte=5:1, UV) showed one main new spot was observed.50 mL water was added, and the mixture was extracted with dichloromethane (30 mL x 2 ).The combined organic layers were washed with brine(20 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to dryness in vacuo to give a yellow oil. The yellow oil was purified by flash column (petroleum th / th l t t f 100/0 t 0/100) d th i l t t d i t i 4-(dimethoxymethyl)-1-(4-((1R,2S)-2-phenyl-6-(4,4,5,5-tetram ethyl-1,3,2-dioxaborolan-2-yl)- 1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperidine (270 mg, 476 ^mol, 70.1 % yield)as a yellow solid. LC-MS (ESI+) m/z: 568.3 (M+H) ⁺ Step 2: To a solution of (4-(dimethoxymethyl)-1-(4-((1R,2S)-2-phenyl-6-(4,4,5,5-tetra methyl- 1,3,2-dioxaborolan-2-yl)-1,2,3,4-tetrahydronaphthalen-1-yl)p henyl)piperidine (100 mg, 1 Eq, 176 ^mol) in H ₂ O (0.75 mL) was added 2 M hydrogen chloride (5 mL).The mixture was stirred at 80 °C for 16 hr . LCMS showed 69.231% desired MS. The reaction was concentrated in vacuo to give ((5R, 6S)-5-(4-(4-formylpiperidin-1-yl)phenyl)-6-phenyl-5,6,7,8-te trahydronaphthalen-2- yl)boronic acid (100 mg, 158 ^mol, 89.4 %, 69.2% purity) as a yellow solid. LC-MS (ESI+) m/z: 442.3 (M+H) ⁺ Step 3: A solution of AcONa(68 mg, 5 Eq, 0.68 mmol) and (S)-3-(1-oxo-5-(piperazin-1- yl)isoindolin-2-yl)piperidine-2,6-dione, TsOH acid (100 mg, 0.87 Eq, 118 ^mol) and ((5R,6S)-5- (4-(4-formylpiperidin-1-yl)phenyl)-6-phenyl-5,6,7,8-tetrahyd ronaphthalen-2-yl)boronic acid (60 mg, 1 Eq, 0.14 mmol) in DCM (2 mL) and MeOH (2 mL) was stirred at 20°C for 30 mins, Then NaBH(OAc) ₃ (26 mg, 3 Eq, 0.41 mmol) and Acetic acid (33 mg, 31 ^L, 4 Eq, 0.55 mmol) was added. The mixture was stirred at 20 °C for 16h. LCMS showed 40.930% desired MS. The reaction was concentrated to give a brown solid. The brown solid was purified by preparative high-performance liquid chromatography. Condition: Column: Boston Green ODS 150*30mm*5um A: water(FA) B:CAN ^at the beginning: A (80%) and B (20%); at the end: A: (50%) and B (50%); Gradient Time(min) 6; 100% B hold Time(min) 1,Flow Rate(ml/min) 30. The pure fractions were collected and the solvent was evaporated under vacuum. The aqueous layer was lyophilized to dryness to give ((5R,6S)-5-(4-(4-((4-(2-((S)-2,6-dioxopiperidin-3-yl)-1- oxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)phen yl)-6-phenyl-5,6,7,8- tetrahydronaphthalen-2-yl)boronic acid (16.3 mg, 21.6 ^mol, 16 %, 99.5% purity) as a white solid.LC-MS (ESI ⁺ ) m/z: 708.4 (M+H) ⁺ LCMS: calc. for C ₄₅ H ₅₀ BN ₅ O ₅ , found: [M+H] ⁺ 752.0. HPLC: 99.5% purity at 220 nm. NMR (400 MHz, DMSO-d6) į= 10.95 (s, 1H), 8.14 (s, 1H), 7.93 (s, 2H), 7.67 (s, 1H), 7.53 (br d, J=7.8 Hz, 1H), 7.46 (d, J=7.8 Hz, 1H), 7.16 (br d, J=7.5 Hz, 3H), 7.11 - 7.05 (m, 2H), 6.84 (dd, J=7.4, 17.7 Hz, 3H), 6.56 - 6.53 (m, 2H), 6.21 (br d, J=8.8 Hz, 2H), 5.05 (dd, J=5.0, 13.8 Hz, 1H), 4.37 - 4.19 (m, 3H), 3.52 (br d, J=11.3 Hz, 2H), 3.21 - 2.83 (m, 7H), 2.61 (br s, 8H), 2.19 (br s, 2H), 1.97 (br d, J=7.0 Hz, 1H), 1.76 (br d, J=11.8 Hz, 3H), 1.68 (br s, 1H), 1.30 - 1.13 (m, 3H) SFC: retention time, 9.777; Area, 99.213%; EXAMPLE 247. Preparation of (I-47) (S)-3-(1-oxo-5-(4-((1-(4-((1R,2S)-2-phenyl- 1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperidin-4-yl)meth yl)piperazin-1-yl)isoindolin- 2-yl)piperidine-2,6-dione Step 1: To a stirred solution of (5R,6S)-5-(4-(4-(dimethoxymethyl)piperidin-1-yl)phenyl)-6- phenyl-5,6,7,8-tetrahydronaphthalen-2-ol (3 g, 1 Eq, 7 mmol)and Phenyl triflimide (4 g, 1.5 Eq, 0.01 mol) in DCM (30 mL) at 20 °C was added triethylamine (0.8 g, 1 mL, 1.2 Eq, 8 mmol) and a catalytic amount of DMAP(0.2 g, 0.2 Eq, 1 mmol) was then added to the mixture and stirring was continued at 20°C for 6 hours. LCMS showed 84.014% desired MS. TLC (petroleum ether: ethyl aceatte=10:1, UV) showed one main new spot was observed. The reaction was chromatography over silica gel (gradient elution: 0 – 10% EtOAc in petroleum ether). The desired fractions were collected, and concentrated to dryness in vacuo to give (5R,6S)-5-(4-(4- (dimethoxymethyl)piperidin-1-yl)phenyl)-6-phenyl-5,6,7,8-tet rahydronaphthalen-2-yl trifluoromethanesulfonate (3.9 g, 6.6 mmol, 100 %) as a yellow oil. LC-MS (ESI+) m/z: 590.2 (M+H) ⁺ Step 2: Triethylamine (257 mg, 355 ^l, 5 Eq, 2.54 mmol) and Palladium diacetate (11.4 mg, 0.1 Eq, 50.9 ^mol) were added to a stirred mixture of (5R,6S)-5-(4-(4-(dimethoxymethyl)piperidin- 1-yl)phenyl)-6-phenyl-5,6,7,8-tetrahydronaphthalen-2-yl trifluoromethanesulfonate (300 mg, 1 Eq, 509 ^mol), 1,1'-Ferrocendiylbis(diphenylphosphine) (56.4 mg, 0.2 Eq, 102 ^mol) and Formaldehyde (76.4 mg, 70.1 ^L, 5 Eq, 2.54 mmol)) in DMF (5 mL) at 20°C, under nitrogen. The mixture was stirred under nitrogen for 5 hours at 60°C. LCMS showed 87.974% desired MS. TLC (petroleum ether: ethyl aceatte=2:1, UV) showed one main new spot was observed.50 mL water was added, and the mixture was extracted with DCM (100 mL x 2). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to dryness in vacuo to give a yellow oil. The yellow oil was purified by flash column (petroleum ether/ethyl acetate from 100/0 to 0/100) and the organic layer was concentrated in vacuo to give 4-(dimethoxymethyl)-1-(4-((1R,2S)-2-phenyl-1,2,3,4- tetrahydronaphthalen-1-yl)phenyl)piperidine (200 mg, 453 ^mol, 89.0 %) as a yellow solid. LC- MS (ESI+) m/z: 442.3 (M+H) ⁺ Step 3: To a solution of (4-(dimethoxymethyl)-1-(4-((1R,2S)-2-phenyl-1,2,3,4- tetrahydronaphthalen-1-yl)phenyl)piperidine (100 mg, 1 Eq, 226 ^mol)) in HCl in dioxane (4 mL) .The mixture was stirred at 55 °C for 16 hour. LCMS showed 85.493% desired MS. The reaction was concentrated to give 1-(4-((1R,2S)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1- yl)phenyl)piperidine-4-carbaldehyde (85 mg, 0.18 mmol, 81 %, 85.493% purity) as a white yellow. LC-MS (ESI ⁺ ) m/z: 396.2 (M+H) ⁺ . Step 4: A solution of 1-(4-((1R,2S)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1- yl)phenyl)piperidine-4-carbaldehyde (100 mg, 1 Eq, 25 ^mol) and (S)-3-(1-oxo-5-(piperazin-1- yl)isoindolin-2-yl)piperidine-2,6-dione, TsOH acid (140 mg, 0.655 Eq, 166 ^mol) and NaOAc(126 mg, 5 Eq, 1.26 mmol) in DCM (0.5 mL) and MeOH (0.5 mL) was stirred at 20°C f 60 i Th N BH(OA ) (477 447 ^L 3 E 758 ^ l) d A ti id (607 58.2 ^L, 4 Eq, 1.01 mmol) was added .The mixture was stirred at 20°C for 16h. LCMS showed 80.174% desired MS. The reaction was concentrated to a brown solid. The brown solid was purified by preparative high-performance liquid chromatography. Condition: Column: Welch Xtimate C18150*30mm*5um A: water (FA) B: ACN at the beginning: A (72%) and B (28%) at the end: A: (42%) and B (58%) Gradient Time (min) 7; 100% B hold Time (min) 1.7, Flow Rate (ml/min) 25. The pure fractions were collected and the solvent was evaporated under vacuum. The aqueous layer was lyophilized to dryness to give (S)-3-(1-oxo-5-(4-((1-(4-((1R,2S)-2- phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperidin-4- yl)methyl)piperazin-1- yl)isoindolin-2-yl)piperidine-2,6-dione (20.7 mg, 28.1 ^mol, 11.1 % yield, 96.1% purity) as a white solid. LC-MS (ESI ⁺ ) m/z: 708.4 (M+H) ⁺ LCMS: calc. for C ₄₅ H ₄₉ N ₅ O ₃ , found: [M+H] ⁺ 708.4. HPLC: 96.1% purity at 220 nm. ¹ H NMR (400 MHz, DMSO-d ₆ ) į= 10.95 (s, 1H), 8.15 (s, 0.439H), 7.52 (d, J=8.5 Hz, 1H), 7.25 - 7.21 (m, 1H), 7.17 - 7.13 (m, 4H), 7.08 - 7.04 (m, 3H), 6.86 (d, J=6.8 Hz, 4H), 6.55 (d, J=8.8 Hz, 2H), 6.21 (d, J=8.5 Hz, 2H), 5.04 (dd, J=5.1, 13.2 Hz, 1H), 4.39 - 4.11 (m, 4H), 3.52 (br d, J=10.0 Hz, 2H), 3.29 (br s, 8H), 3.12 - 2.85 (m, 3H), 2.19 (br d, J=7.5 Hz, 3H), 1.99 - 1.93 (m, 1H), 1.76 (br d, J=11.3 Hz, 4H), 1.64 (br s, 1H), 1.32 - 0.97 (m, 3H) SFC: retention time, 3.274; Area, 93.534%;

EXAMPLE 248. Preparation of (I-299) 1-(6-(4-((1-(4-((1R,2S)-6-hydroxy-2-phenyl- 1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperidin-4-yl)meth yl)piperazin-1-yl)-1-methyl- 1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione Step 1: To a solution of 1-(1-methyl-6-(piperazin-1-yl)-1H-indazol-3-yl)dihydropyrimi dine- 2,4(1H,3H)-dione hydrochloride (20 mg, 54.82 ^mol, 1 eq.) in DCE (2 mL) and MeOH (3 mL) was added 1-(4-((1R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthale n-1- yl)phenyl)piperidine-4-carbaldehyde (22.56 mg, 54.82 ^mol, 1 eq.) and NaBH(OAc) ₃ (58.09 mg, 274.10 ^mol, 5 eq.). The reaction was stirred at 20°C for 1hr. LCMS showed the desired ms was found. The mixture was purified by Prep-HPLC (Phenomenex Gemini NX 150*30mm*5^m; Condition: water(NH ₄ HCO ₃ )-ACN; Begin B 56, End B 86, Gradient Time(min) 11, 100%B Hold Time(min) 2, FlowRate(ml/min) 25, Injections 1, HPLC 95) to give 1-(6-(4-((1-(4-((1R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydr onaphthalen-1-yl)phenyl)piperidin- 4-yl)methyl)piperazin-1-yl)-1-methyl-1H-indazol-3-yl)dihydro pyrimidine-2,4(1H,3H)-dione (11 mg, 14.84 ^mol, 27.07% yield, 97.66% purity) as a white solid. LC-MS (ESI ⁺ ) m/z: 724.4 (M+H) ⁺ . EXAMPLE 249. Preparation of (I-191) 3-(4-(4-((1-(4-((1R,2S)-6-hydroxy-2-phenyl- 1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperidin-4-yl)meth yl)piperazin-1-yl)-3-methyl- 2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-di one Step 1: To a solution of 1-(4-((1R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthale n-1- yl)phenyl)piperidine-4-carbaldehyde (50 mg, 121.50 ^mol, 1 eq.) and 3-(3-methyl-2-oxo-4- (piperazin-1-yl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperi dine-2,6-dione hydrochloride (50.06 mg, 145.80 ^mol, 1.2 eq.) in DCE (3 mL) was added sodium;triacetoxyboranuide (77.25 mg, 364.49 ^mol, 3 eq.). The mixture was stirred at 25 °C for 2hr. LC-MS showed one main peak with desired mass was detected. The reaction mixture or solution was concentrated to dryness. The residue was purified by prep-HPLC(Column Boston Green ODS 150*30mm*5um, Condition water(HCl)-CAN, Begin B 20, End B 40, Gradient Time(min) 10.5, 100%B Hold Time(min) 1.5, FlowRate(ml/min) 25, Injections 4, HPLC 96). 3-(4-(4-((1-(4-((1R,2S)-6- hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)pi peridin-4-yl)methyl)piperazin-1- yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)pipe ridine-2,6-dione (13 mg, 17.59 ^mol, 14.48% yield) was obtained as a white solid. LC-MS (ESI ⁺ ) m/z: 739.6 (M+H) ⁺ . LCMS: calc. for C ₄₅ H ₅₀ N ₆ O ₄ : 738.39, found: [M+H] ⁺ 739.6. HPLC: 100% purity at 220 nm. NMR: ¹ H NMR (400 MHz, METHANOL-d ₄ ) į ppm 7.07 - 7.28 (m, 7 H) 7.01 (br d, J = 8.46 (m, 1 H) 3.52 - 3.82 (m, 8 H) 3.33 - 3.50 (m, 9 H) 3.25 - 3.29 (m, 1 H) 3.00 - 3.14 (m, 2 H) 2.76 - 2.98 (m, 3 H) 2.28 - 2.43 (m, 1 H) 2.10 - 2.25 (m, 4 H) 1.72 - 1.93 (m, 3 H) EXAMPLE 250. Preparation of (I-190) 3-(5-(4-((1-(4-((1R,2S)-6-hydroxy-2-phenyl- 1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperidin-4-yl)meth yl)piperazin-1-yl)-3-methyl- 2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-di one Step 1: To a solution of 1-(4-((1R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthale n-1- yl)phenyl)piperidine-4-carbaldehyde (50 mg, 121.50 ^mol, 1 eq.) and 3-(3-methyl-2-oxo-5- (piperazin-1-yl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperi dine-2,6-dione hydrochloride (50.06 mg, 145.80 ^mol, 1.2 eq.) in DCE (3 mL) was added sodium;triacetoxyboranuide (77.25 mg, 364.49 ^mol, 3 eq.). The mixture was stirred at 25 °C for 2hr. LC-MS showed one main peak with desired mass was detected. The reaction mixture or solution was concentrated to dryness. The residue was purified by prep-HPLC(Column Boston Green ODS 150*30mm*5um, Condition water(HCl)-CAN, Begin B 20, End B 40, Gradient Time(min) 10.5, 100%B Hold Time(min) 1.5, FlowRate(ml/min) 25, Injections 4, HPLC 96). 3-(5-(4-((1-(4-((1R,2S)-6- hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)pi peridin-4-yl)methyl)piperazin-1- yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)pipe ridine-2,6-dione (14.5 mg, 19.62 ^mol, 16.15% yield) was obtained as a white solid. LC-MS (ESI ⁺ ) m/z: 739.6 (M+H) ⁺ . LCMS: calc. for C ₄₅ H ₅₀ N ₆ O ₄ : 738.39, found: [M+H] ⁺ 739.6. ppm 7.32 (d, J = 8.70 Hz, 2 H) 7.11 - 7.17 (m, 3 H) 7.02 - 7.07 (m, 1 H) 6.93 - 6.98 (m, 1 H) 6.80 - 6.88 (m, 3 H) 6.64 - 6.71 (m, 4 H) 6.48 - 6.58 (m, 1 H) 5.31 (dd, J = 12.70, 5.30 Hz, 1 H) 4.41 (d, J = 5.36 Hz, 1 H) 3.61 - 3.82 (m, 7 H) 3.41 (s, 5 H) 3.20 - 3.29 (m, 3 H) 3.01 - 3.14 (m, 2 H) 2.87 - 2.97 (m, 1 H) 2.69 - 2.85 (m, 2 H) 2.37 - 2.54 (m, 1 H) 2.11 - 2.30 (m, 4 H) 1.80 - 1.99 (m, 3 H) EXAMPLE 251. Preparation of (I-419) (S)-3-(5-(4-((1-(4-((1R,2S,4R)-6-hydroxy-4- methyl-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)pip eridin-4- yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2, 6-dione, (I-332) (S)-3-(5-(4-((1- (4-((1R,2S,4S)-6-hydroxy-4-methyl-2-phenyl-1,2,3,4-tetrahydr onaphthalen-1- yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindo lin-2-yl)piperidine-2,6-dione, (I-420) (S)-3-(5-(4-((1-(4-((1S,2R,4R)-6-hydroxy-4-methyl-2-phenyl-1 ,2,3,4- tetrahydronaphthalen-1-yl)phenyl)piperidin-4-yl)methyl)piper azin-1-yl)-1-oxoisoindolin-2- yl)piperidine-2,6-dione, and (I-331) (S)-3-(5-(4-((1-(4-((1S,2R,4S)-6-hydroxy-4-methyl-2-

phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperidin -4-yl)methyl)piperazin-1-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione Step 1: To a solution of methyl 4-oxopentanoate (23.61 g, 126.79 mmol, 1.1 eq.) in MeOH (100 mL) was added 4-methylbenzenesulfonohydrazide (15 g, 115.26 mmol, 14.27 mL, 1 eq.). The mixture was stirred at 25 °C for 24 hour. LCMS showed the desired MS was detected. The mixture was filtered and solid was collected, washed with MeOH (10 mL x 2), treated under vacuum to yield methyl (E)-4-(2-tosylhydrazineylidene)pentanoate (30 g, 98% purity, 87.24% yield) as a white solid. LC-MS (ESI ⁺ ) m/z: 298.8 (M+H) ⁺ . Step 2: A mixture of (3-methoxyphenyl)boronic acid (10 g, 65.81 mmol, 1 eq.) , methyl (E)-4- (2-tosylhydrazineylidene)pentanoate (21.60 g, 72.39 mmol, 1.1 eq.) and K ₂ CO ₃ (22.74 g, 164.52 mmol, 2.5 eq.) in dioxane (150 mL) was degassed and purged with N ₂ for 3 times, and then the mixture was stirred at 100 °C for 16 hour under N ₂ atmosphere. TLC (PE/EtOAc = 10:1) showed new spot was observed. The reaction mixture was concentrated under reduced pressure to remove dioxane to get the crude product, which was purified by silica gel column chromatography (from PE/EtOAc = 10/1 to 5/1, TLC: PE/EtOAc = 10/1, R _f = 0.63) to yield desired methyl 4-(3-methoxyphenyl)pentanoate (12 g, 82.03% yield) as colorless liquid. Step 3: To a solution of methyl 4-(3-methoxyphenyl)pentanoate (10 g, 44.99 mmol, 0.1 mL, 1 eq.) was added TfOH (169.60 g, 1.13 mol, 100.00 mL, 25.12 eq.). The mixture was stirred at 20 °C for 1 hour. LCMS showed the desired MS was detected. The mixture was adjusted to pH 5-6 with NaHCO ₃ (10%, 50 mL), which was extracted with EA (50 mL x 3). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated to afford the crude product. The crude product was purified by silica gel chromatography (from PE/EtOAc = 3/1 to 2/1, TLC: PE/EtOAc = 3/1, R _f = 0.60) to give the 6-methoxy-4-methyl-3,4-dihydronaphthalen-1(2H)- one (2.7 g, 90% purity, 31.55% yield) as a white solid. LC-MS (ESI ⁺ ) m/z: 191.2 (M+H) ⁺ . Step 4: To a solution of 1-(4-bromophenyl)-4-(dimethoxymethyl)piperidine (5.45 g, 17.35 mmol, 1.1 eq.) in THF (50 mL) was added dropwise n-BuLi (2.5 M, 9.46 mL, 1.5 eq.) at -50 °C. After addition, the mixture was stirred at this temperature for 0.5 hour, and then 6-methoxy-4- methyl-3,4-dihydronaphthalen-1(2H)-one (3 g, 15.77 mmol, 1 eq.) was added dropwise at - 40 °C. The resulting mixture was stirred at 0 °C for 2 hour. LCMS showed desired compound was detected. The mixture was quenched by addition of 10 mL of water, and then the mixture was extracted with EA (50 mL x 3). The combined organic layer was dried over Na ₂ SO ₄ , filtered and concentrated to afford the crude product., which was purified on silica gel column chromatography (from PE/EtOAc = 3/1 to 2/1, TLC: PE/EtOAc = 3/1, Rf = 0.49 ) to yield 1-(4- (4-(dimethoxymethyl)piperidin-1-yl)phenyl)-6-methoxy-4-methy l-1,2,3,4-tetrahydronaphthalen- 1-ol (3 g, 95% purity, 53.64% yield) as a yellow solid. LC-MS (ESI ⁺ ) m/z: 426.3 (M+H) ⁺ . Step 5: To a solution of 1-(4-(4-(dimethoxymethyl)piperidin-1-yl)phenyl)-6-methoxy-4- methyl- 1,2,3,4-tetrahydronaphthalen-1-ol (3 g, 7.05 mmol, 1 eq.) in HCl/MeOH (50 mL) was added. The mixture was stirred at 20 °C for 1 hour. LCMS showed desired compound was detected. The mixture was adjusted to pH 6-7 with NaHCO ₃ . And then water (80 mL) was added into the mixture, which was extracted with EtOAc (50 mL x 3). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated to yield 4-(dimethoxymethyl)-1-(4-(6-methoxy-4-methyl- 3,4-dihydronaphthalen-1-yl)phenyl)piperidine (2.5 g, 90% purity, 87.02% yield) used for the next step directly. LC-MS (ESI ⁺ ) m/z: 408.3 (M+H) ⁺ . Step 6: To a solution of 4-(dimethoxymethyl)-1-(4-(6-methoxy-4-methyl-3,4-dihydronaph thalen- 1-yl)phenyl)piperidine (2.5 g, 6.13 mmol, 1 eq.) in DCM (25 mL) was added Py·HBr ₃ (1.77 g, 5.52 mmol, 0.9 eq.). The mixture was stirred at 20 °C for 0.2 hour. LCMS showed desired compound was detected. The reaction mixture was extracted with DCM (50 mL x 3) and concentrated to get crude product, which was purified on silica gel column chromatography (from PE/EtOAc = 3/1 to 2/1, TLC: PE/EtOAc = 3/1, Rf = 0.58 ) to yield 1-(4-(2-bromo-6- methoxy-4-methyl-3,4-dihydronaphthalen-1-yl)phenyl)-4-(dimet hoxymethyl)piperidine (1.7 g, 87% purity, 56.97% yield) as a white solid. LC-MS (ESI ⁺ ) m/z: 488.2 (M+H ⁺ +2). Step 7: A mixture of 1-(4-(2-bromo-6-methoxy-4-methyl-3,4-dihydronaphthalen-1-yl) phenyl)-4- (dimethoxymethyl)piperidine (1.5 g, 3.08 mmol, 1 eq.), phenylboronic acid (451.18 mg, 3.70 mmol, 1.2 eq.), Pd(dtbpf)Cl ₂ (200.97 mg, 308.36 ^mol, 0.1 eq.) and Na ₂ CO ₃ (980.49 mg, 9.25 mmol, 3 eq.) in dioxane (40 mL) and H ₂ O (8 mL) was degassed and purged with N ₂ for 3 times, and then the mixture was stirred at 90 °C for 3 hour under N ₂ atmosphere. LCMS showed desired compound was detected. The mixture was extracted with EtOAc (50 mL x 3), dried over chromatography (from PE/EtOAc = 3/1 to 2/1, TLC: PE/EtOAc = 3/1, Rf =0.54 ) to yield 4- (dimethoxymethyl)-1-(4-(6-methoxy-4-methyl-2-phenyl-3,4-dihy dronaphthalen-1- yl)phenyl)piperidine (1.2 g, 97% purity, 80.46% yield) as a pink solid. LC-MS (ESI ⁺ ) m/z: 484.3 (M+H) ⁺ . Step 8: To a solution of 4-(dimethoxymethyl)-1-(4-(6-methoxy-4-methyl-2-phenyl-3,4- dihydronaphthalen-1-yl)phenyl)piperidine (1.2 g, 2.48 mmol, 1 eq.) in EtOAc (30 mL) was added Pd/C (2.64 g, 2.48 mmol, 10% purity, 1 eq.) under H ₂ (10.00 mg, 4.96 mmol, 2 eq.) atmosphere. The mixture was stirred under H ₂ atmosphere (15 psi) at 25 °C for 16 hour. LCMS showed desired compound was detected. The mixture was filtered and the filtrate was concentrated to yield 4-(dimethoxymethyl)-1-(4-(6-methoxy-4-methyl-2-phenyl-1,2,3, 4- tetrahydronaphthalen-1-yl)phenyl)piperidine (1.04 g, crude) as a yellow solid used for the next step directly. LC-MS (ESI ⁺ ) m/z: 486.5 (M+H) ⁺ . Step 9: 4-(dimethoxymethyl)-1-(4-(6-methoxy-4-methyl-2-phenyl-1,2,3, 4-tetrahydronaphthalen- 1-yl)phenyl)piperidine (1 g, 2.06 mmol, 1 eq.) was separated by chiral SFC (column: DAICEL CHIRALPAK OJ 250 mm ^ 30 mm, 10 um); mobile phase: [CO ₂ -EtOH (0.1% NH ₃ H ₂ O)]; B%: 30%-30%; Flow Rate: 80 ml/min; peak 1:2.944min; peak 2: 3.156 min; peak 3: 3.244 min; peak 2:3.756 min) to yield peak 1, peak 2, peak 3 and peak 4. Peak 1 was concentrated under reduced pressure to yield 4-(dimethoxymethyl)-1-(4- ((1R,2S,4R)-6-methoxy-4-methyl-2-phenyl-1,2,3,4-tetrahydrona phthalen-1-yl)phenyl)piperidine (250 mg, 25.00 % yield) as a yellow solid. LC-MS (ESI ⁺ ) m/z: 486.4 (M+H) ⁺ . Peak 2 was concentrated under reduced pressure to yield 4-(dimethoxymethyl)-1-(4- ((1S,2R,4R)-6-methoxy-4-methyl-2-phenyl-1,2,3,4-tetrahydrona phthalen-1-yl)phenyl)piperidine (30 mg, 3.00 % yield) as a yellow solid. LC-MS (ESI ⁺ ) m/z: 486.4 (M+H) ⁺ . Peak 3 was concentrated under reduced pressure to yield 4-(dimethoxymethyl)-1-(4-((1R,2S,4S)- 6-methoxy-4-methyl-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-y l)phenyl)piperidine (20 mg, 2.00 % yield) as a yellow solid. LC-MS (ESI ⁺ ) m/z: 486.4 (M+H) ⁺ . Peak 4 was concentrated under reduced pressure to yield 4-(dimethoxymethyl)-1-(4-((1S,2R,4S)- 6-methoxy-4-methyl-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-y l)phenyl)piperidine (150 mg, 15.00 % yield) as a yellow solid. LC-MS (ESI ⁺ ) m/z: 486.4 (M+H) ⁺ . Step 10: 4-(dimethoxymethyl)-1-(4-((1R,2S,4R)-6-methoxy-4-methyl-2-ph enyl-1,2,3,4- tetrahydronaphthalen-1-yl)phenyl)piperidine (100 mg, 205.91 ^mol, 1 eq.) was added in DCM (10 mL), then BBr ₃ (154.75 mg, 617.72 ^mol, 59.52 ^L, 3 eq.) was added in the mixture with stirring at 0 °C. After 30 min, the reaction mixture was quenched by the addition of water (10 mL) at 0 °C. The mixture was stirred at 20 °C for 2 hour. After completion, the mixture was concentrated under reduced pressure to give 1-(4-((1R,2S,4R)-6-hydroxy-4-methyl-2-phenyl- 1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperidine-4-carbal dehyde (80 mg, crude) as a yellow solid without purification. LC-MS (ESI ⁺ ) m/z: 426.3 (M+H) ⁺ . Step 11: 4-(dimethoxymethyl)-1-(4-((1S,2R,4R)-6-methoxy-4-methyl-2-ph enyl-1,2,3,4- tetrahydronaphthalen-1-yl)phenyl)piperidine (30.00 mg, 61.77 ^mol, 1 eq.) was added in DCM (5 mL), then BBr3 (46.43 mg, 185.32 ^mol, 17.86 ^L, 3 eq.) was added in the mixture with stirring at 0 °C. After 30 min, the reaction mixture was quenched by the addition of water (10 mL) at 0 °C. The mixture was stirred at 20 °C for 2 hour. After completion, the mixture was concentrated under reduced pressure to give 1-(4-((1S,2R,4R)-6-hydroxy-4-methyl-2-phenyl- 1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperidine-4-carbal dehyde (30 mg, crude) as a yellow solid without purification. LC-MS (ESI+) m/z: 426.3 (M+H) ⁺ . Step 12: 4-(dimethoxymethyl)-1-(4-((1R,2S,4S)-6-methoxy-4-methyl-2-ph enyl-1,2,3,4- tetrahydronaphthalen-1-yl)phenyl)piperidine (20.00 mg, 41.18 ^mol, 1 eq.) was added in DCM (5 mL), then BBr ₃ (30.95 mg, 123.54 ^mol, 11.90 ^L, 3 eq.) was added in the mixture with stirring at 0 °C. After 30 min, the reaction mixture was quenched by the addition of water (10 mL) at 0 °C. The mixture was stirred at 20 °C for 2 hour. After completion, the mixture was concentrated under reduced pressure to give 1-(4-((1R,2S,4S)-6-hydroxy-4-methyl-2-phenyl- 1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperidine-4-carbal dehyde (20 mg, crude) as a yellow solid without purification. LC-MS (ESI+) m/z: 426.3 (M+H) ⁺ . Step 13: 4-(dimethoxymethyl)-1-(4-((1S,2R,4S)-6-methoxy-4-methyl-2-ph enyl-1,2,3,4- tetrahydronaphthalen-1-yl)phenyl)piperidine (100.00 mg, 205.91 ^mol, 1 eq.) was added in DCM (10 mL), then BBr ₃ (154.75 mg, 617.72 ^mol, 59.52 ^L, 3 eq.) was added in the mixture with stirring at 0 °C. After 30 min, the reaction mixture was quenched by the addition of water (10 mL) at 0 °C. The mixture was stirred at 20 °C for 2 hour. After completion, the mixture was concentrated under reduced pressure to give 1-(4-((1S,2R,4S)-6-hydroxy-4-methyl-2-phenyl- 1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperidine-4-carbal dehyde (100 mg, crude) as a yellow solid without purification. LC-MS (ESI+) m/z: 426.3 (M+H) ⁺ . Step 14: To a solution of 1-(4-((1R,2S,4R)-6-hydroxy-4-methyl-2-phenyl-1,2,3,4- tetrahydronaphthalen-1-yl)phenyl)piperidine-4-carbaldehyde (80 mg, 187.99 ^mol, 1 eq.) and (S)-3-(1-oxo-5-(piperazin-1-yl)isoindolin-2-yl)piperidine-2, 6-dione (61.73 mg, 187.99 ^mol, 1 eq.) in DCE (5 mL) was added DIEA (24.30 mg, 187.99 ^mol, 32.74 ^L, 1 eq.). After addition, the mixture was stirred at 25°C for 30 min, and then NaBH(OAc)3 (119.53 mg, 563.96 ^mol, 3 eq.) was added. The mixture was stirred at 25 °C for 3 hour. After completion, the reaction mixture was concentrated and purified by preparative HPLC (Column: C18-1150 ^ 30mm ^ 5um; Condition water(NH ₄ HCO ₃ )-CAN, B%: 58%-88%, 11 min) followed by lyophilization to yield (S)-3-(5-(4-((1-(4-((1R,2S,4R)-6-hydroxy-4-methyl-2-phenyl-1 ,2,3,4- tetrahydronaphthalen-1-yl)phenyl)piperidin-4-yl)methyl)piper azin-1-yl)-1-oxoisoindolin-2- yl)piperidine-2,6-dione (23.7 mg, 32.12 ^mol, 17.08% yield, 97.76% purity) as a white solid. LC-MS (ESI ⁺ ) m/z: 738.6 (M+H) ⁺ . LCMS: calc. for C ₄₆ H ₅₁ N ₅ O ₄ : 737.95, found: [M+H] ⁺ 738.6. HPLC: 97.76% purity at 220 nm. ¹ H NMR: ¹ H NMR (400 MHz, CHLOROFORM-d) į ppm 7.87 - 7.91 (1 H, m), 7.72 - 7.78 (1 H, m), 7.17 (2 H, s), 7.01 (1 H, dd, J=8.34, 1.79 Hz), 6.89 - 6.94 (2 H, m), 6.83 - 6.87 (3 H, m), 6.60 - 6.63 (3 H, m), 6.29 (2 H, d, J=8.58 Hz), 5.19 - 5.26 (1 H, m), 4.59 - 4.89 (1 H, m), 4.26 - 446 (2 H m) 421 - 424 (1 H m) 356 - 362 (2 H m) 338 - 343 (1 H m) 332 - 336 (4 H m), 3.08 - 3.15 (1 H, m), 2.79 - 2.99 (3 H, m), 2.61 - 2.64 (1 H, m), 2.57 - 2.60 (5 H, m), 2.35 (1 H, dd, J=13.11, 5.01 Hz), 2.28 (2 H, br d, J=7.39 Hz), 2.17 - 2.24 (1 H, m), 1.90 - 1.95 (1 H, m), 1.83 - 1.89 (3 H, m), 1.49 - 1.52 (3 H, m), 1.31 - 1.38 (2 H, m). Step 15: To a solution of 1-(4-((1S,2R,4R)-6-hydroxy-4-methyl-2-phenyl-1,2,3,4- tetrahydronaphthalen-1-yl)phenyl)piperidine-4-carbaldehyde (30.00 mg, 70.50 ^mol, 1 eq.) and (S)-3-(1-oxo-5-(piperazin-1-yl)isoindolin-2-yl)piperidine-2, 6-dione (23.15 mg, 70.50 ^mol, 1 eq.) in DCE (5 mL) was added DIEA (9.11 mg, 70.50 ^mol, 12.28 ^L, 1 eq.). After addition, the mixture was stirred at 25°C for 30 min, and then NaBH(OAc) ₃ (44.82 mg, 211.49 ^mol, 3 eq.) was added. The mixture was stirred at 25 °C for 3 hour. After completion, the reaction mixture was concentrated and purified by preparative HPLC (Column: C18-1150 ^ 30mm ^ 5um; Condition water(NH ₄ HCO ₃ )-CAN, B%: 58%-88%, 11 min) followed by lyophilization to yield (S)-3-(5-(4-((1-(4-((1S,2R,4R)-6-hydroxy-4-methyl-2-phenyl-1 ,2,3,4-tetrahydronaphthalen-1- yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindo lin-2-yl)piperidine-2,6-dione (14.7 mg, 19.92 ^mol, 28.26% yield, 93.06% purity) as a white solid. LC-MS (ESI ⁺ ) m/z: 738.6 (M+H) ⁺ . LCMS: calc. for C ₄₆ H ₅₁ N ₅ O ₄ : 737.95, found: [M+H] ⁺ 738.6. HPLC: 93.06% purity at 220 nm. ¹ H NMR: ¹ H NMR (400 MHz, CHLOROFORM-d) į ppm 7.90 - 7.98 (1 H, m), 7.71 - 7.80 (1 H, m), 7.17 (2 H, s), 6.99 - 7.04 (1 H, m), 6.85 - 6.90 (2 H, m), 6.76 - 6.84 (3 H, m), 6.56 - 6.61 (3 H, m), 6.24 - 6.29 (2 H, m), 5.17 - 5.26 (1 H, m), 4.25 - 4.46 (2 H, m), 4.18 - 4.23 (1 H, m), 3.52 - 3.60 (3 H, m), 3.35 (4 H, br s), 3.24 - 3.29 (1 H, m), 2.82 - 2.94 (2 H, m), 2.60 (5 H, br d, J=8.58 Hz), 2.56 (1 H, br s), 2.35 - 2.47 (2 H, m), 2.28 - 2.32 (2 H, m), 2.21 - 2.25 (1 H, m), 1.86 (2 H, br d, J=13.11 Hz), 1.62 - 1.69 (1 H, m), 1.56 - 1.60 (1 H, m), 1.39 - 1.43 (3 H, m), 1.35 (2 H, br d, J=11.92 Hz). Step 16: To a solution of 1-(4-((1R,2S,4S)-6-hydroxy-4-methyl-2-phenyl-1,2,3,4- tetrahydronaphthalen-1-yl)phenyl)piperidine-4-carbaldehyde (20.00 mg, 47.00 ^mol, 1 eq.) and (S)-3-(1-oxo-5-(piperazin-1-yl)isoindolin-2-yl)piperidine-2, 6-dione (15.43 mg, 47.00 ^mol, 1 eq.) in DCE (5 mL) was added DIEA (6.07 mg, 47.00 ^mol, 8.19 ^L, 1 eq.). After addition, the was added. The mixture was stirred at 25 °C for 3 hour. After completion, the reaction mixture was concentrated and purified by preparative HPLC (Column: C18-1150 ^ 30mm ^ 5um; Condition water(NH ₄ HCO ₃ )-CAN, B%: 60%-90%, 11 min) followed by lyophilization to yield (S)-3-(5-(4-((1-(4-((1R,2S,4S)-6-hydroxy-4-methyl-2-phenyl-1 ,2,3,4-tetrahydronaphthalen-1- yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindo lin-2-yl)piperidine-2,6-dione (8.1 mg, 10.98 ^mol, 23.36% yield, 98.91% purity) as a white solid. LC-MS (ESI ⁺ ) m/z: 738.6 (M+H) ⁺ . LCMS: calc. for C ₄₆ H ₅₁ N ₅ O ₄ : 737.95, found: [M+H] ⁺ 738.6. HPLC: 98.91% purity at 220 nm. ¹ H NMR: ¹ H NMR (400 MHz, CHLOROFORM-d) į ppm 7.80 - 7.86 (1 H, m), 7.60 - 7.70 (1 H, m), 7.07 - 7.09 (2 H, m), 6.90 - 6.96 (1 H, m), 6.76 - 6.81 (2 H, m), 6.75 (2 H, s), 6.67 - 6.69 (1 H, m), 6.47 - 6.52 (3 H, m), 6.15 - 6.19 (2 H, m), 5.04 - 5.21 (1 H, m), 4.36 (2 H, s), 4.09 - 4.13 (1 H, m), 3.44 - 3.52 (3 H, m), 3.22 - 3.29 (4 H, m), 3.16 (1 H, br s), 2.71 - 2.86 (2 H, m), 2.45 - 2.54 (6 H, m), 2.26 (2 H, s), 2.19 - 2.23 (2 H, m), 2.10 - 2.16 (1 H, m), 1.75 - 1.80 (2 H, m), 1.53 - 1.59 (1 H, m), 1.47 (1 H, s), 1.30 - 1.33 (3 H, m), 1.20 - 1.29 (2 H, m). Step 17: To a solution of 1-(4-((1S,2R,4S)-6-hydroxy-4-methyl-2-phenyl-1,2,3,4- tetrahydronaphthalen-1-yl)phenyl)piperidine-4-carbaldehyde (80.00 mg, 187.99 ^mol, 1 eq.) and (S)-3-(1-oxo-5-(piperazin-1-yl)isoindolin-2-yl)piperidine-2, 6-dione (61.73 mg, 187.99 ^mol, 1 eq.) in DCE (5 mL) was added DIEA (24.30 mg, 187.99 ^mol, 32.74 ^L, 1 eq.). After addition, the mixture was stirred at 25°C for 30 min, and then NaBH(OAc) ₃ (119.53 mg, 563.96 ^mol, 3 eq.) was added. The mixture was stirred at 25 °C for 3 hour. After completion, the reaction mixture was concentrated and purified by preparative HPLC (Column: C18-1150 ^ 30mm ^ 5um; Condition water(NH ₄ HCO ₃ )-CAN, B%: 60%-90%, 11 min) followed by lyophilization to yield (S)-3-(5-(4-((1-(4-((1S,2R,4S)-6-hydroxy-4-methyl-2-phenyl-1 ,2,3,4- tetrahydronaphthalen-1-yl)phenyl)piperidin-4-yl)methyl)piper azin-1-yl)-1-oxoisoindolin-2- yl)piperidine-2,6-dione (29.2 mg, 39.57 ^mol, 21.05% yield, 96.74% purity) as a white solid. LC-MS (ESI ⁺ ) m/z: 738.6 (M+H) ⁺ . LCMS: calc for C46H51N5O4: 73795 found: [M+H] ⁺ 7386 HPLC: 96.74% purity at 220 nm. ¹ H NMR: ¹ H NMR (400 MHz, CHLOROFORM-d) į ppm 7.88 - 7.99 (1 H, m), 7.74 (1 H, d, J = 8.46 Hz), 7.16 - 7.18 (2 H, m), 6.98 - 7.02 (1 H, m), 6.87 - 6.92 (2 H, m), 6.83 (3 H, dd, J = 5.30, 2.80 Hz), 6.55 - 6.62 (3 H, m), 6.27 (2 H, d, J=8.46 Hz), 5.21 (1 H, dd, J = 13.17, 5.07 Hz), 4.78 (1 H, s), 4.24 - 4.44 (2 H, m), 4.19 - 4.23 (1 H, m), 3.54 - 3.61 (2 H, m), 3.36 - 3.41 (1 H, m), 3.32 (4 H, br s), 3.05 - 3.13 (1 H, m), 2.89 - 2.96 (1 H, m), 2.78 - 2.88 (1 H, m), 2.60 - 2.63 (1 H, m), 2.54 - 2.60 (5 H, m), 2.33 (1 H, br dd, J=13.35, 4.89 Hz), 2.27 (2 H, br d, J=6.32 Hz), 2.17 - 2.24 (1 H, m), 1.91 (1 H, br d, J=12.04 Hz), 1.86 (3 H, br d, J=8.58 Hz), 1.48 (3 H, d, J=6.79 Hz), 1.29 - 1.37 (2 H, m). The stereochemistry of the ERBM moieties for all four molecules was arbitrarily assigned EXAMPLE 252. Preparation of (I-204) 3-(5-(4-((1-(4-((1R,2S)-6-hydroxy-2-phenyl- 1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperidin-4-yl)meth yl)piperazin-1-yl)-3-methyl- 2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-di one Step 1: 5-(4-(4-(dimethoxymethyl)piperidin-1-yl)phenyl)-6-(2-hydroxy propan-2-yl)-5,6,7,8- tetrahydronaphthalen-2-ol (400 mg, 758.02 ^mol, 1 eq.) was separated by SFC. LCMS showed desired compound was detected. The crude product was purified on silica gel column chromatography (from PE/EtOAc = 1/1 to 2/1, TLC: PE/EtOAc = 3/1, Rf =0.45 ) to yield desired compound as brown oil, which was separated by chiral SFC (column: DAICEL CHIRALPAK AD(250mm*30mm,10um); mobile phase: [0.1%NH ₃ H ₂ O IPA]; B%: 55%-55%, 45min, SFC: Rt = 1.967, 2.372) to yield (5R,6S)-5-(4-(4-(dimethoxymethyl)piperidin-1- yl)phenyl)-6-(2-hydroxypropan-2-yl)-5,6,7,8-tetrahydronaphth alen-2-ol (100 mg, 227.49 ^mol, 30.01% yield) as white solid. LC-MS (ESI ⁺ ) m/z: 440.3 (M+H) ⁺ . Step 2: To a solution of (5R,6S)-5-(4-(4-(dimethoxymethyl)piperidin-1-yl)phenyl)-6-(2 - hydroxypropan-2-yl)-5,6,7,8-tetrahydronaphthalen-2-ol (100.00 mg, 227.49 ^mol, 1 eq.) in DCM (6 mL) was added TFA (259.38 mg, 2.27 mmol, 168.98 ^L, 10 eq.). The mixture was stirred at 25 °C for 2 hr. LC-MS showed one main peak with desired mass was detected. The reaction mixture or solution was concentrated to dryness. 1-(4-((1R,2S)-6-hydroxy-2-(2- hydroxypropan-2-yl)-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl )piperidine-4-carbaldehyde (80 mg, 203.29 ^mol, 89.37% yield) as yellow liquid was used into the next step without further purification. LC-MS (ESI ⁺ ) m/z: 394.2 (M+H) ⁺ . Step 3: To a solution of 1-(4-((1R,2S)-6-hydroxy-2-(2-hydroxypropan-2-yl)-1,2,3,4- tetrahydronaphthalen-1-yl)phenyl)piperidine-4-carbaldehyde (80 mg, 203.29 ^mol, 1 eq.) and (S)-3-(1-oxo-5-(piperazin-1-yl)isoindolin-2-yl)piperidine-2, 6-dione (80.11 mg, 243.95 ^mol, 1.2 eq.) in DCE (20 mL) was added sodium; triacetoxyboranuide (129.26 mg, 609.88 ^mol, 3 eq.) and DIPEA (52.55 mg, 406.59 ^mol, 70.82 ^L, 2 eq.). The mixture was stirred at 25 °C for 5 hr. LC-MS showed one main peak with desired mass was detected. After quenching the reaction, the reaction mixture was poured into separatory funnel and separated. The reaction mixture was partitioned between DCM (100 mL×2) and water (100 mL). The residue was purified by prep- HPLC(Column C18-1150*30mm*5um, Condition water( NH ₄ HCO ₃ )-CAN, Begin B 40, End B 70, Gradient Time(min) 11, 100%B Hold Time(min) 2, FlowRate(ml/min) 25, Injections 5, HPLC 95). (S)-3-(5-(4-((1-(4-((1R,2S)-6-hydroxy-2-(2-hydroxypropan-2-y l)-1,2,3,4- tetrahydronaphthalen-1-yl)phenyl)piperidin-4-yl)methyl)piper azin-1-yl)-1-oxoisoindolin-2- yl)piperidine-2,6-dione (10.6 mg, 15.02 ^mol, 7.39% yield) was obtained as a white solid. LC-MS (ESI ⁺ ) m/z: 706.4 (M+H) ⁺ . LCMS: calc. for C ₄₂ H ₅₁ N ₅ O ₅ : 705.39, found: [M+H] ⁺ 706.4. HPLC: 100.00% purity at 220 nm. ¹ H NMR: ¹ H NMR (400 MHz, METHANOL-d4) į ppm 7.61 - 7.72 (m, 1 H) 7.08 - 7.15 (m, 2 H) 699 - 708 (m 2 H) 685 - 693 (m 2 H) 663 - 670 (m 1 H) 655 - 660 (m 1 H) 642 - 649 (m, 1 H) 5.08 - 5.17 (m, 1 H) 4.36 - 4.47 (m, 2 H) 4.22 - 4.29 (m, 1 H) 3.58 - 3.68 (m, 2 H) 3.41 (br s, 4 H) 2.99 - 3.05 (m, 1 H) 2.86 - 2.90 (m, 1 H) 2.81 (d, J = 2.62 Hz, 1 H) 2.67 - 2.72 (m, 4 H) 2.38 - 2.41 (m, 1 H) 2.14 - 2.20 (m, 1 H) 2.05 (br d, J = 3.46 Hz, 6 H) 1.63 - 1.77 (m, 1 H) 1.31 (br s, 6 H) 1.05 - 1.13 (m, 3 H) 0.87 - 0.96 (m, 1 H) 0.73 - 0.82 (m, 3 H).

EXAMPLE 253. Preparation of (I-219) (S)-3-(5-(4-((1-(4-((1S,2R)-6-hydroxy-2-(2- hydroxypropan-2-yl)-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl )piperidin-4- yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2, 6-dione Step 1: To a solution of 1-(4-(6-(benzyloxy)-2-bromo-3,4-dihydronaphthalen-1-yl)pheny l)-4- (dimethoxymethyl)piperidine (1.5 g, 2.73 mmol, 1 eq.) and phenyl formate (667.93 mg, 5.47 mmol, 596.36 ^L, 2 eq.) in MeCN (10 mL) was added Xantphos (395.59 mg, 683.67 ^mol, 0.25 eq.), TEA (830.17 mg, 8.20 mmol, 1.14 mL, 3 eq.) and Pd(OAc)2 (92.09 mg, 410.20 ^mol, 0.15 eq.). The mixture was stirred at 80 °C for 6 hr. LC-MS showed one main peak with desired mass was detected. The reaction mixture was partitioned between EA (50 mL×2) and water (50 mL). After quenching the reaction, the reaction mixture was poured into separatory funnel and separated. The crude product was purified by silica gel chromatography eluted with PE: EtOAc=2:1~1:1. phenyl 6-(benzyloxy)-1-(4-(4-(dimethoxymethyl)piperidin-1-yl)phenyl )-3,4- dihydronaphthalene-2-carboxylate (1.5 g, 2.54 mmol, 93.01% yield) was obtained as a white solid. LC-MS (ESI ⁺ ) m/z: 590.3(M+H) ⁺ . Step 2: To a solution of phenyl 6-(benzyloxy)-1-(4-(4-(dimethoxymethyl)piperidin-1-yl)phenyl )- 3,4-dihydronaphthalene-2-carboxylate (1 g, 1.70 mmol, 1 eq.) in THF (20 mL) was added bromo(methyl)magnesium (3 M, 5.65 mL, 10 eq.). The mixture was stirred at 0 °C for 5 hr. LC-MS showed one main peak with desired mass was detected. The reaction mixture or solution was concentrated to dryness. The crude product was purified by silica gel chromatography eluted with PE: EtOAc=2:1~1:1. 2-(6-(benzyloxy)-1-(4-(4-(dimethoxymethyl)piperidin-1- yl)phenyl)-3,4-dihydronaphthalen-2-yl)propan-2-ol (400 mg, 758.02 ^mol, 44.70% yield) as brown solid was used into the next step without further purification. LC-MS (ESI ⁺ ) m/z: 528.4 (M+H) ⁺ . Step 3: The mixture of 2-(6-(benzyloxy)-1-(4-(4-(dimethoxymethyl)piperidin-1-yl)phe nyl)-3,4- dihydronaphthalen-2-yl)propan-2-ol (300 mg, 568.51 ^mol, 1 eq.), Palladium (60.50 mg, 56.85 ^mol, 10% purity, 0.1 eq.) in EtOAc (20 mL) was degassed and the mixture was degassed and refilled with H ₂ twice. The reaction mixture was stirred at 50 °C on 50 psi with H ₂ for 10 hours. LC-MS showed one main peak with desired mass was detected. The reaction mixture or solution was concentrated to dryness. The crude product was purified by silica gel chromatography eluted with PE: EtOAc=2:1~1:1. 5-(4-(4-(dimethoxymethyl)piperidin-1-yl)phenyl)-6-(2- hydroxypropan-2-yl)-5,6,7,8-tetrahydronaphthalen-2-ol (120 mg, 272.98 ^mol, 48.02% yield) was obtained as a white solid. LC-MS (ESI ⁺ ) m/z: 440.3 (M+H) ⁺ . Step 4: 5-(4-(4-(dimethoxymethyl)piperidin-1-yl)phenyl)-6-(2-hydroxy propan-2-yl)-5,6,7,8- tetrahydronaphthalen-2-ol (400 mg, 758.02 ^mol, 1 eq.) was seperated by SFC. LCMS showed desired compound was detected. The crude product was purified on silica gel column chromatography (from PE/EtOAc = 1/1 to 2/1, TLC: PE/EtOAc = 3/1, Rf =0.45 ) to yield desired compound as brown oil, which was separated by chiral SFC (column: DAICEL CHIRALPAK AD(250mm*30mm,10um); mobile phase: [0.1%NH3H2O IPA]; B%: 55%-55%, 45min, SFC: Rt = 1.967, 2.372) to yield (5R,6S)-5-(4-(4-(dimethoxymethyl)piperidin-1- yl)phenyl)-6-(2-hydroxypropan-2-yl)-5,6,7,8-tetrahydronaphth alen-2-ol (100 mg, 227.49 ^mol, 30.01% yield) as white solid and (5S,6R)-5-(4-(4-(dimethoxymethyl)piperidin-1-yl)phenyl)-6- (2-hydroxypropan-2-yl)-5,6,7,8-tetrahydronaphthalen-2-ol (110 mg, 250.24 ^mol, 33.01% yield) as white solid. LC-MS (ESI ⁺ ) m/z: 440.3 (M+H) ⁺ . Step 5: To a solution of (5S,6R)-5-(4-(4-(dimethoxymethyl)piperidin-1-yl)phenyl)-6-(2 - hydroxypropan-2-yl)-5,6,7,8-tetrahydronaphthalen-2-ol (110 mg, 250.24 ^mol, 1 eq) in DCM (6 mL) was added TFA (285.32 mg, 2.50 mmol, 185.88 ^L, 10 eq.). The mixture was stirred at 25 °C for 2 hr. LC-MS showed one main peak with desired mass was detected. The reaction mixture or solution was concentrated to dryness. The crude product 1-(4-((1S,2R)-6-hydroxy-2- (2-hydroxypropan-2-yl)-1,2,3,4-tetrahydronaphthalen-1-yl)phe nyl)piperidine-4-carbaldehyde (80 mg, 203.29 ^mol, 81.24% yield) as yellow liquid was used into the next step without further purification. LC-MS (ESI ⁺ ) m/z: 394.2 (M+H) ⁺ . Step 6: To a solution of 1-(4-((1S,2R)-6-hydroxy-2-(2-hydroxypropan-2-yl)-1,2,3,4- tetrahydronaphthalen-1-yl)phenyl)piperidine-4-carbaldehyde (80 mg, 203.29 ^mol, 1 eq.) and (S)-3-(1-oxo-5-(piperazin-1-yl)isoindolin-2-yl)piperidine-2, 6-dione (80.11 mg, 243.95 ^mol, 1.2 eq.) in DCE (20 mL) was added sodium; triacetoxyboranuide (129.26 mg, 609.88 ^mol, 3 eq.) and DIPEA (52.55 mg, 406.59 ^mol, 70.82 ^L, 2 eq.). The mixture was stirred at 25 °C for 5 hr. LC-MS showed one main peak with desired mass was detected. After quenching the reaction, the reaction mixture was poured into separatory funnel and separated. The reaction mixture was partitioned between DCM (100 mL×2) and water (100 mL). The residue was purified by prep- HPLC(C l C181150*30 *5^ C diti t ( NH HCO ) CAN B i B 40 E d B 70, Gradient Time(min) 11, 100%B Hold Time(min) 2, FlowRate(ml/min) 25, Injections 5, HPLC 95). (S)-3-(5-(4-((1-(4-((1S,2R)-6-hydroxy-2-(2-hydroxypropan-2-y l)-1,2,3,4- tetrahydronaphthalen-1-yl)phenyl)piperidin-4-yl)methyl)piper azin-1-yl)-1-oxoisoindolin-2- yl)piperidine-2,6-dione (6.7 mg, 9.49 ^mol, 4.67% yield) was obtained as a white solid. LC-MS (ESI ⁺ ) m/z: 706.4 (M+H) ⁺ . 706.4. pm 7.64 (d, J=8.34 Hz, 1 H) 7.06 - 7.12 (m, 2 H) 7.03 (d, J=8.58 Hz, 2 H) 6.86 (d, J=8.70 Hz, 2 H) 6.65 (d, J=8.34 Hz, 1 H) 6.53 - 6.58 (m, 1 H) 6.41 - 6.47 (m, 1 H) 5.10 (dd, J=13.35, 5.13 Hz, 1 H) 4.35 - 4.45 (m, 2 H) 4.24 (br d, J=3.46 Hz, 1 H) 3.58 - 3.65 (m, 2 H) 3.36 - 3.40 (m, 4 H) 2.96 - 3.03 (m, 1 H) 2.85 - 2.89 (m, 1 H) 2.66 (br d, J=5.84 Hz, 4 H) 2.36 (br d, J=7.03 Hz, 1 H) 2.17 - 2.22 (m, 1 H) 1.86 - 2.05 (m, 6 H) 1.61 - 1.74 (m, 1 H) 1.29 - 1.37 (m, 7 H) 1.07 (s, 3 H) 0.88 - 0.93 (m, 1 H) 0.76 (s, 3 H). EXAMPLE 254. Preparation of (I-154) (S)-3-(5-(4-((1-(5-((1S,2R)-2-cyclohexyl-6- hydroxy-1,2,3,4-tetrahydronaphthalen-1-yl)pyridin-2-yl)piper idin-4-yl)methyl)piperazin-1- yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione and (I-155) (S)-3-(5-(4-((1-(5-((1R,2S)-2-

cyclohexyl-6-hydroxy-1,2,3,4-tetrahydronaphthalen-1-yl)py ridin-2-yl)piperidin-4- yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2, 6-dione Step 1: To a solution of 5-bromo-2-fluoropyridine (1.30 g, 8.18 mmol, 1.2 eq.) and 4- (dimethoxymethyl)piperidine (1.2 g, 6.82 mmol, 701.75 ^L, 1 eq.) in CH ₃ CN (50 mL) were added K ₂ CO ₃ (1.88 g, 13.64 mmol, 2 eq.). The mixture was stirred at 80 °C for 16 hr. The mixture was stirred at 80 °C for 16 hr. LCMS showed the ~93% desired MS was detected. The reaction mixture was extracted with EtOAc (40 mL x 3) and concentrated to get crude product. The crude product was purified on silica gel column chromatography (from PE/EtOAc = 3/1 to 2/1, TLC: PE/EtOAc = 3/1, Rf =0.7) to yield desired 5-bromo-2-(4-(dimethoxymethyl)piperidin- LC-MS (ESI ⁺ ) m/z: 316.8 (M+H ⁺ +2). Step 2: A mixture of v (1.2 g, 3.81 mmol, 1 eq.), (E)-N'-(6-(benzyloxy)-3,4-dihydronaphthalen- 1(2H)-ylidene)-4-methylbenzenesulfonohydrazide (1.76 g, 4.19 mmol, 1.1 eq.), Pd(dppf)Cl ₂ (278.56 mg, 380.70 ^mol, 0.1 eq.), X-Phos (90.74 mg, 190.35 ^mol, 0.05 eq.) and t-BuOLi (914.31 mg, 11.42 mmol, 1.03 mL, 3 eq.) in dioxane (80 mL) was degassed and purged with N ₂ for 3 times, and then the mixture was stirred at 100 °C for 16 h under N ₂ atmosphere. LCMS showed the desired MS was detected. The reaction mixture was concentrated under reduced pressure to remove dioxane to get the crude product, which was purified by silica gel column chromatography (from PE/EtOAc = 3/1 to 2/1, TLC: PE/EtOAc = 3/1, Rf =0.51) to yield desired 5-(6-(benzyloxy)-3,4-dihydronaphthalen-1-yl)-2-(4-(dimethoxy methyl)piperidin-1-yl)pyridine (0.9 g, 90 % purity) as a yellow solid. LC-MS (ESI ⁺ ) m/z: 471.0 (M+H) ⁺ . Step 3: To a solution of v (1 g, 2.12 mmol, 1 eq.) in DCM (20 mL) was added Py·HBr ₃ (407.76 mg, 1.27 mmol, 0.6 eq.). The mixture was stirred at 25 °C for 0.1 hr. LCMS showed the desired MS was detected. The reaction mixture was concentrated in vacuum, which was extracted with DCM (80 mL x 3) and concentrated to get crude product. The crude product was purified by silica gel chromatography (from PE/EtOAc = 3/1 to 2/1, TLC: PE/EtOAc = 3/1, Rf =0.38) to give 5-(6-(benzyloxy)-2-bromo-3,4-dihydronaphthalen-1-yl)-2-(4-(d imethoxymethyl)piperidin- 1-yl)pyridine (0.83 g, 90% purity) as yellow oil. LC-MS (ESI ⁺ ) m/z: 551.2 (M+H ⁺ +2). Step 4: A mixture of 5-(6-(benzyloxy)-2-bromo-3,4-dihydronaphthalen-1-yl)-2-(4- (dimethoxymethyl)piperidin-1-yl)pyridine (830.00 mg, 1.51 mmol, 1 eq.), cyclohex-1-en-1- ylboronic acid (228.31 mg, 1.81 mmol, 1.2 eq.), Pd(dppf)Cl ₂ (110.52 mg, 151.05 ^mol, 0.1 eq.) and K ₂ CO ₃ (626.29 mg, 4.53 mmol, 3 eq.) in dioxane/H ₂ O (15 mL) was degassed and purged with N ₂ for 3 times, and then the mixture was stirred at 80 °C for 3 hr under N ₂ atmosphere. LCMS showed desired compound was detected. The mixture was extracted with EtOAc (30 mL x 3), dried over Na ₂ SO ₄ , filtered and concentrated to get crude product, which was purified on silica gel column chromatography (from PE/EtOAc = 3/1 to 2/1, TLC: PE/EtOAc = 2/1, Rf =0.4 ) to yield 5-(6-(benzyloxy)-2-(cyclohex-1-en-1-yl)-3,4-dihydronaphthale n-1-yl)-2-(4- (dimethoxymethyl)piperidin-1-yl)pyridine (0.7g, 95% purity) as yellow oil. LC-MS (ESI ⁺ ) m/z: 551.3 (M+H) ⁺ . Step 5: To a solution of 5-(6-(benzyloxy)-2-(cyclohex-1-en-1-yl)-3,4-dihydronaphthale n-1-yl)-2- (4-(dimethoxymethyl)piperidin-1-yl)pyridine (500 mg, 907.89 ^mol, 1 eq.) in MeOH (15 mL) was added Pd/C (50wt%, 428.58 mg, 2.52 mmol, 2.78 eq.) under H ₂ atmosphere. The suspension was degassed and purged with H ₂ (32.96 mg, 16.32 mmol, 35.95 eq.) for 3 times. The mixture was stirred under H ₂ (50 psi) at 50 °C for 12 h. LCMS showed desired compound was detected. The mixture was filtered and the filtrate was concentrated to yield 6-cyclohexyl-5- (6-(4-(dimethoxymethyl)piperidin-1-yl)pyridin-3-yl)-5,6,7,8- tetrahydronaphthalen-2-ol (0.34 g, crude) as a white solid used for the next step directly. LC-MS (ESI ⁺ ) m/z: 465.4 (M+H) ⁺ . Step 6: 6-cyclohexyl-5-(6-(4-(dimethoxymethyl)piperidin-1-yl)pyridin -3-yl)-5,6,7,8- tetrahydronaphthalen-2-ol (340 mg, 731.75 ^mol, 1 eq.) was separated by chiral SFC (column: DAICEL CHIRALPAK AD 250 mm ^ 30 mm, 10 um); mobile phase: [CO ₂ -EtOH (0.1% NH ₃ H ₂ O)]; B%: 30%-30%; Flow Rate: 80 ml/min; peak 1:1.685 min; peak 2: 2.036 min) to yield peak 1 and peak 2. Peak 1 was concentrated under reduced pressure to yield (5R,6S)-6-cyclohexyl-5-(6-(4- (dimethoxymethyl)piperidin-1-yl)pyridin-3-yl)-5,6,7,8-tetrah ydronaphthalen-2-ol (120 mg, 35.29 % yield) as yellow oil. LC-MS (ESI ⁺ ) m/z: 465.4 (M+H) ⁺ . Peak 2 was concentrated under reduced pressure to yield (5S,6R)-6-cyclohexyl-5-(6-(4- (dimethoxymethyl)piperidin-1-yl)pyridin-3-yl)-5,6,7,8-tetrah ydronaphthalen-2-ol (80 mg, 23.53% yield) as yellow oil. LC-MS (ESI ⁺ ) m/z: 465.4 (M+H) ⁺ . Step 7: To a solution of (5R,6S)-6-cyclohexyl-5-(6-(4-(dimethoxymethyl)piperidin-1-yl )pyridin- 3-yl)-5,6,7,8-tetrahydronaphthalen-2-ol (120.00 mg, 258.27 ^mol, 1 eq.) in DCM (12 mL) was added TFA (6.14 g, 53.85 mmol, 4.00 mL, 208.51 eq.). The mixture was stirred at 25 °C for 12 hr. LCMS showed desired compound was detected. After completion, the mixture was concentrated under reduced pressure to give 1-(5-((1R2S)-2-cyclohexyl-6-hydroxy-1234- tetrahydronaphthalen-1-yl)pyridin-2-yl)piperidine-4-carbalde hyde (80 mg, crude) as a white solid without purification. LC-MS (ESI ⁺ ) m/z: 419.4 (M+H) ⁺ . Step 8: To a solution of (5S,6R)-6-cyclohexyl-5-(6-(4-(dimethoxymethyl)piperidin-1-yl )pyridin- 3-yl)-5,6,7,8-tetrahydronaphthalen-2-ol (80.00 mg, 172.18 ^mol, 1 eq.) in DCM (6 mL) was added TFA (4.09 g, 35.90 mmol, 2.67 mL, 208.51 eq.). The mixture was stirred at 25 °C for 12 hr. LCMS showed desired compound was detected. After completion, the mixture was concentrated under reduced pressure to give 1-(5-((1S,2R)-2-cyclohexyl-6-hydroxy-1,2,3,4- tetrahydronaphthalen-1-yl)pyridin-2-yl)piperidine-4-carbalde hyde (80 mg, crude) as a white solid without purification. LC-MS (ESI ⁺ ) m/z: 419.4 (M+H) ⁺ . Step 9: To a solution of 1-(5-((1R,2S)-2-cyclohexyl-6-hydroxy-1,2,3,4-tetrahydronapht halen-1- yl)pyridin-2-yl)piperidine-4-carbaldehyde (80 mg, 191.13 ^mol, 1 eq.) and (S)-3-(1-oxo-5- (piperazin-1-yl)isoindolin-2-yl)piperidine-2,6-dione (75.31 mg, 229.35 ^mol, 1.2 eq.) in DCE (10 mL) was added DIEA (49.40 mg, 382.25 ^mol, 66.58 ^L, 2 eq.). After addition, the mixture was stirred at 25°C for 30 min, and then NaBH(OAc) ₃ (121.52 mg, 573.38 ^mol, 3 eq.) was added. The mixture was stirred at 25 °C for 3 hr. After completion, the reaction mixture was concentrated and purified by preparative HPLC (Column: C18-1150 ^ 30mm ^ 5um; Condition water (NH ₄ HCO ₃ )-CAN, B%: 58%-88%, 11 min) followed by lyophilization to yield (S)-3-(5- (4-((1-(5-((1R,2S)-2-cyclohexyl-6-hydroxy-1,2,3,4-tetrahydro naphthalen-1-yl)pyridin-2- yl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-y l)piperidine-2,6-dione (45.4 mg, 62.11 ^mol, 32.50% yield, 100% purity) as a white solid. LC-MS (ESI ⁺ ) m/z: 731.6 (M+H) ⁺ . LCMS: calc. for C ₄₄ H ₅₄ N ₆ O ₄ : 730.42, found: [M+H] ⁺ 731.6. HPLC: 100% purity at 220 nm. ¹ H NMR: ¹ H NMR (400 MHz, METHANOL-d4) į ppm 7.77 - 7.79 (1 H, m), 7.62 - 7.65 (1 H, m), 7.12 - 7.16 (1 H, m), 7.06 - 7.10 (2 H, m), 6.69 (2 H, dd, J=8.46, 6.79Hz), 6.54 - 6.57 (1 H, m), 6.46 - 6.50 (1 H, m), 5.10 (1 H, dd, J=13.29, 5.07 Hz), 4.40 (2 H, d, J=6.08 Hz), 4.10 - 4.18 (3 H m) 335 - 338 (4 H m) 286 - 294 (2H m) 281 - 283 (1 H m) 277 - 281 (2 H m) 2.59 - 2.63 (4 H, m), 2.43 - 2.52 (1 H, m), 2.27 - 2.31 (2 H, m), 2.12 - 2.19 (2 H, m), 1.89 (4 H, br s), 1.74 - 1.79 (1H, m), 1.60 - 1.68 (3 H, m), 1.46 - 1.54 (1 H, m), 1.38 - 1.44 (1 H, m), 1.20 (4 H, br s), 1.12 - 1.17 (1 H, m), 1.01 - 1.11 (3 H, m), 0.81 - 0.91 (1 H, m). Step 10: To a solution of 1-(5-((1S,2R)-2-cyclohexyl-6-hydroxy-1,2,3,4-tetrahydronapht halen-1- yl)pyridin-2-yl)piperidine-4-carbaldehyde (80 mg, 191.13 ^mol, 1 eq.) and (S)-3-(1-oxo-5- (piperazin-1-yl)isoindolin-2-yl)piperidine-2,6-dione (69.04 mg, 210.24 ^mol, 1.1 eq.) in DCE (15 mL) was added DIEA (49.40 mg, 382.25 ^mol, 66.58 ^L, 2 eq.). After addition, the mixture was stirred at 25°C for 30 min, and then NaBH(OAc) ₃ (81.02 mg, 382.25 ^mol, 2 eq.) was added. The mixture was stirred at 25 °C for 3 h. After completion, the reaction mixture was concentrated and purified by preparative HPLC (Column: C18-1150 ^ 30mm ^ 5um; Condition water (NH ₄ HCO ₃ )-CAN, B%: 58%-88%, 11 min) followed by lyophilization to yield (S)-3-(5- (4-((1-(5-((1S,2R)-2-cyclohexyl-6-hydroxy-1,2,3,4-tetrahydro naphthalen-1-yl)pyridin-2- yl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-y l)piperidine-2,6-dione (67 mg, 91.66 ^mol, 47.96% yield, 100% purity) as a white solid. LC-MS (ESI ⁺ ) m/z 731.6 (M+H) ⁺ . LCMS: calc. for C44H54N6O4: 730.42, found: [M+H] ⁺ 731.6. HPLC: 100% purity at 220 nm. ¹ H NMR: ¹ H NMR (400 MHz, METHANOL-d4) į ppm 7.78 (1 H, d, J=2.27 Hz), 7.63 (1 H, d, J=8.58 Hz), 7.14 (1 H, dd, J=8.94, 2.38 Hz), 7.05 - 7.10 (2 H, m), 6.69 (2H, dd, J=8.58, 5.84 Hz), 6.56 (1 H, d, J=2.26 Hz), 6.46 - 6.50 (1 H, m), 5.10 (1 H, br d, J=8.11 Hz), 4.40 (2 H, d, J=5.72 Hz), 4.11 - 4.18 (3 H, m), 3.35 - 3.38 (4H, m), 2.89 - 2.96 (2 H, m), 2.86 (1 H, br d, J=5.25 Hz), 2.80 (2 H, br dd, J=9.06, 2.62 Hz), 2.59 - 2.64 (4 H, m), 2.43 - 2.49 (1 H, m), 2.29 (2 H, br d, J=6.56 Hz), 2.13 - 2.18 (2 H, m), 1.83 - 1.89 (4 H, m), 1.75 - 1.80 (1 H, m), 1.60 - 1.67 (3 H, m), 1.49 (1 H, br dd, J=12.58, 5.78 Hz), 1.41 (1 H, br d, J=12.99 Hz), 1.25 (4 H, br dd, J=11.68, 10.25 Hz), 1.11 - 1.16 (1 H, m), 1.02 - 1.11 (3 H, m), 0.82 - 0.90 (1 H, m). EXAMPLE 255. Preparation of (I-150) (S)-3-(5-(4-((1-(6-((1R,2S)-2-cyclohexyl-6- hydroxy-1,2,3,4-tetrahydronaphthalen-1-yl)pyridin-3-yl)piper idin-4-yl)methyl)piperazin-1- yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione and (I-149) (S)-3-(5-(4-((1-(6-((1S,2R)-2- cyclohexyl-6-hydroxy-1,2,3,4-tetrahydronaphthalen-1-yl)pyrid in-3-yl)piperidin-4- yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2, 6-dione Step 1: A mixture of 2-bromo-5-iodopyridine (5 g, 17.61 mmol, 1 eq.), 4- (dimethoxymethyl)piperidine (3.37 g, 21.13 mmol, 1.2 eq.) , CuI (2.01 g, 10.57 mmol, 0.6 eq.) , L-proline (1.22 g, 10.57 mmol, 0.6 eq.) and K ₂ CO ₃ (4.87 g, 35.22 mmol, 2 eq.) in DMSO (15 mL) was degassed and purged with N ₂ , and then the mixture was stirred at 90 °C for 3 hr under N ₂ atmosphere. LCMS showed the ~46% desired MS was detected. The reaction mixture was extracted with EtOAc (40 mL x 3) and concentrated to get crude product. The crude product was purified on silica gel column chromatography (from PE/EtOAc = 3/1 to 2/1, TLC: PE/EtOAc = 3/1, Rf = 0.57) to yield desired 2-bromo-5-(4-(dimethoxymethyl)piperidin-1- yl)pyridine (1.2g, 90%) as a white solid. LC-MS (ESI ⁺ ) m/z: 316.9 (M+H ⁺ +2). Step 2: A mixture of 2-bromo-5-(4-(dimethoxymethyl)piperidin-1-yl)pyridine (1.1 g, 3.49 mmol, 1 eq.), (E)-N'-(6-(benzyloxy)-3,4-dihydronaphthalen-1(2H)-ylidene)-4 - methylbenzenesulfonohydrazide (1.61 g, 3.84 mmol, 1.1 eq.), Pd(dppf)Cl ₂ .CH ₂ Cl ₂ (284.99 mg, 348.98 ^mol, 0.1 eq.), t-BuOLi (838.12 mg, 10.47 mmol, 943.83 ^L, 3 eq.) and X-Phos (147.70 mg, 174.49 ^mol, 0.05 eq.) in dioxane (20 mL) was degassed and purged with N ₂ for 3 times, and then the mixture was stirred at 100 °C for 16 hr under N ₂ atmosphere. LCMS showed the desired MS was detected. The reaction mixture was concentrated under reduced pressure to remove dioxane to get the crude product, which was purified by silica gel column chromatography (from PE/EtOAc = 3/1 to 2/1, TLC: PE/EtOAc = 3/1, Rf =0.51) to yield desired 2-(6-(benzyloxy)-3,4-dihydronaphthalen-1-yl)-5-(4-(dimethoxy methyl)piperidin-1-yl)pyridine (0.5 g, 85 %) as yellow solid. LC-MS (ESI ⁺ ) m/z: 471.2 (M+H) ⁺ . Step 3: To a solution of 5-(6-(benzyloxy)-3,4-dihydronaphthalen-1-yl)-2-(4- (dimethoxymethyl)piperidin-1-yl)pyridine (500 mg, 1.06 mmol, 1 eq.) in DCM (20 mL) was added Py·HBr3 (271.84 mg, 849.98 ^mol, 0.8 eq.). The mixture was stirred at 25 °C for 0.1 hr. LCMS showed the desired MS was detected. The reaction mixture was concentrated in vacuum, which was extracted with DCM (50 mL x 3) and concentrated to get crude product. The crude product was purified by silica gel chromatography (from PE/EtOAc = 3/1 to 2/1, TLC: PE/EtOAc = 3/1, Rf =0.38) to give 5-(6-(benzyloxy)-2-bromo-3,4-dihydronaphthalen-1-yl)-2-(4- (dimethoxymethyl)piperidin-1-yl)pyridine (0.36 g, 94%) as yellow oil. LC-MS (ESI ⁺ ) m/z: 551.2 (M+H ⁺ +2). Step 4: A mixture of 2-(6-(benzyloxy)-2-bromo-3,4-dihydronaphthalen-1-yl)-5-(4- (dimethoxymethyl)piperidin-1-yl)pyridine (350 mg, 636.95 ^mol, 1 eq.), cyclohex-1-en-1- ylboronic acid (96.28 mg, 764.33 ^mol, 1.2 eq.), Pd(dppf)Cl ₂ (46.61 mg, 63.69 ^mol, 0.1 eq.) and K ₂ CO ₃ (264.10 mg, 1.91 mmol, 3 eq.) in Dioxane/H ₂ O (15 mL) was degassed and purged with N ₂ for 3 times, and then the mixture was stirred at 80 °C for 3 hr under N ₂ atmosphere. LCMS showed desired compound was detected. The crude product was purified on silica gel column chromatography (from PE/EtOAc = 3/1 to 2/1, TLC: PE/EtOAc = 2/1, Rf =0.4) to yield 2-(6-(benzyloxy)-2-(cyclohex-1-en-1-yl)-3,4-dihydronaphthale n-1-yl)-5-(4- (dimethoxymethyl)piperidin-1-yl)pyridine (0.19 g, 84%) as yellow oil. LC-MS (ESI ⁺ ) m/z: 551.3 (M+H) ⁺ . Step 5: To a solution of 2-(6-(benzyloxy)-2-(cyclohex-1-en-1-yl)-3,4-dihydronaphthale n-1-yl)-5- (4-(dimethoxymethyl)piperidin-1-yl)pyridine (250.00 mg, 453.94 ^mol, 1 eq.) in MeOH (15 mL) was added Pd/C (200 mg, 1.18 mmol, 2.59 eq.) under H ₂ atmosphere. The suspension was degassed and purged with H ₂ (32.96 mg, 16.32 mmol, 35.95 eq.) for 3 times. The mixture was stirred under H ₂ (50 psi) at 50 °C for 12 hr. LCMS showed desired compound was detected. The mixture was filtered and the filtrate was concentrated to yield 6-cyclohexyl-5-(5-(4- (dimethoxymethyl)piperidin-1-yl)pyridin-2-yl)-5,6,7,8-tetrah ydronaphthalen-2-ol (0.12 g, 84%) as yellow solid used for the next step directly. LC-MS (ESI ⁺ ) m/z: 465.1 (M+H) ⁺ . Step 6: 6-cyclohexyl-5-(5-(4-(dimethoxymethyl)piperidin-1-yl)pyridin -2-yl)-5,6,7,8- tetrahydronaphthalen-2-ol (120.00 mg, 258.27 ^mol, 1 eq.) was separated by chiral SFC (column: DAICEL CHIRALPAK AD 250 mm ^ 30 mm, 10 um); mobile phase: [CO ₂ - ACN/MeOH (0.1% NH ₃ H ₂ O)]; B%: 45%-45%; Flow Rate: 80 ml/min; peak 1:1.730 min; peak 2: 2.256 min) to yield peak 1 and peak 2. Peak 1 was concentrated under reduced pressure to yield (5R,6S)-6-cyclohexyl-5-(5-(4- (dimethoxymethyl)piperidin-1-yl)pyridin-2-yl)-5,6,7,8-tetrah ydronaphthalen-2-ol (40 mg, 33.33 % yield) as yellow oil. LC-MS (ESI ⁺ ) m/z: 465.3 (M+H) ⁺ . Peak 2 was concentrated under reduced pressure to yield (5S,6R)-6-cyclohexyl-5-(5-(4- (dimethoxymethyl)piperidin-1-yl)pyridin-2-yl)-5,6,7,8-tetrah ydronaphthalen-2-ol (20 mg, 16.67% yield) as yellow oil. LC-MS (ESI ⁺ ) m/z: 465.3 (M+H) ⁺ . Step 7: To a solution of (5R,6S)-6-cyclohexyl-5-(5-(4-(dimethoxymethyl)piperidin-1-yl )pyridin- 2-yl)-5,6,7,8-tetrahydronaphthalen-2-ol (40.00 mg, 86.09 ^mol, 1 eq.) in DCM (6 mL) was added TFA (2.05 g, 17.95 mmol, 1.33 mL, 208.51 eq.). The mixture was stirred at 25 °C for 12 hr. LCMS showed desired compound was detected. After completion, the mixture was concentrated under reduced pressure to give 1-(6-((1R,2S)-2-cyclohexyl-6-hydroxy-1,2,3,4- tetrahydronaphthalen-1-yl)pyridin-3-yl)piperidine-4-carbalde hyde (40 mg, crude) as yellow oil without purification. LC-MS (ESI ⁺ ) m/z: 419.3 [M+H] ⁺ Step 8: To a solution of (5S,6R)-6-cyclohexyl-5-(5-(4-(dimethoxymethyl)piperidin-1-yl )pyridin- 2-yl)-5,6,7,8-tetrahydronaphthalen-2-ol (20.00 mg, 43.04 ^mol, 1 eq.) in DCM (6 mL) was added TFA (1.02 g, 8.98 mmol, 1.33 mL, 208.51 eq.). The mixture was stirred at 25 °C for 12 hr. LCMS showed desired compound was detected. After completion, the mixture was concentrated under reduced pressure to give 1-(6-((1S,2R)-2-cyclohexyl-6-hydroxy-1,2,3,4- tetrahydronaphthalen-1-yl)pyridin-3-yl)piperidine-4-carbalde hyde (40mg, crude) as yellow oil without purification. LC-MS (ESI ⁺ ) m/z: 419.3 [M+H] ⁺ Step 9: To a solution of 1-(6-((1R,2S)-2-cyclohexyl-6-hydroxy-1,2,3,4-tetrahydronapht halen-1- yl)pyridin-3-yl)piperidine-4-carbaldehyde (40 mg, 95.56 ^mol, 1 eq.) and (S)-3-(1-oxo-5- (piperazin-1-yl)isoindolin-2-yl)piperidine-2,6-dione (34.52 mg, 105.12 ^mol, 1.1 eq.) in DCE (10 mL) was added TEA (19.34 mg, 191.13 ^mol, 26.60 ^L, 2 eq.). After addition, the mixture was stirred at 25 °C for 30min, and then NaBH(OAc) ₃ (40.51 mg, 191.13 ^mol, 2 eq.) was added. The mixture was stirred at 25 °C for 3 hr. After completion, the reaction mixture was concentrated and purified by preparative HPLC (Column: Boston Green ODS 150 ^ 30mm ^ 5um; Condition water(NH4HCO3)-CAN, B%: 52%-82%, 11 min) followed by lyophilization to yield (S)-3-(5-(4-((1-(6-((1R,2S)-2-cyclohexyl-6-hydroxy-1,2,3,4-t etrahydronaphthalen-1- yl)pyridin-3-yl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoi soindolin-2-yl)piperidine-2,6-dione (4.6 mg, 6.21 ^mol, 6.50% yield, 98.71% purity) as a white solid. LC-MS (ESI ⁺ ) m/z: 731.6 [M+H] ⁺ . LCMS: calc. for C ₄₄ H ₅₄ N ₆ O ₄ : 730.42, found: [M+H] ⁺ 731.6. HPLC: 98.71% purity at 220 nm. ¹ H NMR: ¹ H NMR (400 MHz, METHANOL-d4) į ppm 8.08 (1 H, s), 7.62 - 7.70 (1 H, m), 7.25 - 7.31 (1 H, m), 7.08 - 7.13 (2 H, m), 6.82 - 6.87 (1 H, m), 6.66 - 6.71 (1 H, m), 6.57 - 6.62 (1 H, m), 6.44 - 6.51 (1 H, m), 5.12 (1 H, br s), 4.42 (2 H, br d, J = 6.08 Hz), 4.29 (1 H, br s), 3.70 - 3.74 (2 H, m), 3.39 (4 H, br s), 2.93 - 2.99 (2 H, m), 2.76 - 2.82 (3 H, m), 2.62 - 2.67 (4 H, m), 2.46 - 2.51 (1 H, m), 2.33 (2 H, br d, J = 6.91 Hz), 2.16 - 2.21 (1 H, m), 2.07 - 2.11 (1 H, m), 1.94 (2 H, br d, J = 12.99 Hz), 1.76 - 1.83 (4 H, m), 1.72 (1 H, br dd, J = 7.81, 1.85 Hz), 1.56 - 1.62 (2 H, m), 1.33 - 1.42 (3 H, m), 1.13 - 1.23 (3 H, m), 1.10 (1 H, br dd, J = 6.91, 2.38 Hz), 0.98 - 1.04 (2 H, m), 0.74 - 0.87 (1 H, m). Step 10: To a solution of 1-(6-((1S,2R)-2-cyclohexyl-6-hydroxy-1,2,3,4-tetrahydronapht halen-1- yl)pyridin-3-yl)piperidine-4-carbaldehyde (40 mg, 95.56 ^mol, 1 eq.) and (S)-3-(1-oxo-5- (piperazin-1-yl)isoindolin-2-yl)piperidine-2,6-dione (34.52 mg, 105.12 ^mol, 1.1 eq.) in DCE (10 mL) was added TEA (19.34 mg, 191.13 ^mol, 26.60 ^L, 2 eq.). After addition, the mixture was stirred at 25°C for 30 min, and then NaBH(OAc) ₃ (40.51 mg, 191.13 ^mol, 2 eq.) was added. The mixture was stirred at 25 °C for 3 hr. After completion, the reaction mixture was concentrated and purified by preparative HPLC (Column: Boston Green ODS 150 ^ 30mm ^ 5um; Condition water(NH ₄ HCO ₃ )-CAN, B%: 52%-82%, 11 min) followed by lyophilization to yield (S)-3-(5-(4-((1-(6-((1S,2R)-2-cyclohexyl-6-hydroxy-1,2,3,4-t etrahydronaphthalen-1- yl)pyridin-3-yl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoi soindolin-2-yl)piperidine-2,6-dione (9.1 mg, 12.45 ^mol, 13.03% yield, 100% purity) as a white solid. LC-MS (ESI ⁺ ) m/z 731.6 [M+H] ⁺ . LCMS: calc. for C ₄₄ H ₅₄ N ₆ O ₄ : 730.42, found: [M+H] ⁺ 731.6. HPLC: 100% purity at 220 nm. ¹ H NMR: ¹ H NMR (400 MHz, METHANOL-d ₄ ) į ppm 8.10 (1 H, d, J = 2.74 Hz), 7.66 (1 H, d, J = 8.46 Hz), 7.24 - 7.30 (1 H, m), 7.07 - 7.13 (2 H, m), 6.81 - 6.86 (1 H, m), 6.69 (1 H, d, J = 8.23 Hz), 6.57 - 6.61 (1 H, m), 6.45 - 6.50 (1 H, m), 5.08 - 5.15 (1 H, m), 4.36 - 4.47 (2 H, m), 4.29 (1 H, br d, J = 3.34 Hz), 3.68 - 3.77 (2 H, m), 3.37 - 3.41 (4 H, m), 2.88 - 3.01 (2 H, m), 2.80 - 2.83 (1 H, m), 2.74 - 2.79 (2 H, m), 2.60 - 2.66 (4 H, m), 2.42 - 2.54 (1 H, m), 2.30 - 2.35 (2 H, m), 2.14 - 2.20 (1 H, m), 2.08 (1 H, br d, J = 12.16 Hz), 1.91 - 1.97 (2 H, m), 1.83 (4 H, br s), 1.74 (1 H, br s), 1.54 - 1.63 (2 H, m), 1.30 - 1.43 (3 H, m), 1.10 - 1.24 (3 H, m), 1.04 - 1.09 (1 H, m), 0.97 - 1.04 (2 H, m), 0.75 - 0.85 (1 H, m). EXAMPLE 256. Preparation of (I-5) (3S)-3-[5-[4-[[1-[4-[(1S,2S)-2-cyclohexyl-6- hydroxy-tetralin-1-yl]phenyl]-4-piperidyl]methyl]piperazin-1 -yl]-1-oxo-isoindolin-2- yl]piperidine-2,6-dione and (I-6) (3S)-3-[5-[4-[[1-[4-[(1R,2R)-2-cyclohexyl-6-hydroxy- tetralin-1-yl]phenyl]-4-piperidyl]methyl]piperazin-1-yl]-1-o xo-isoindolin-2-yl]piperidine- 2,6-dione Step 1: A mixture of 1-(4-(6-(benzyloxy)-2-bromo-3,4-dihydronaphthalen-1-yl)pheny l) -4- (dimethoxymethyl)piperidine (800 mg, 1.46 mmol), 2-(cyclohex-1-en-1-yl)-4,4,5,5- tetramethyl- 1,3,2-dioxaborolane (334 mg, 1.60 mmol), 1,1’-Bis(di-t-butylphosphino)ferrocene palladium dichloride (95.1 mg, 146 ^mol) and Na ₂ CO ₃ (309 mg, 2.92 mmol) in 1,4-dioxane (10 mL) and H ₂ O (2 mL) was degassed and purged with N ₂ for 3 times, and then the mixture was stirred at 80 °C for 12 h under N ₂ atmosphere. The mixture was diluted with water (20 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic phases were washed with brine (30 mL), dried over anhydrous N , filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ethyl acetate in petroleum ether = 0% to 25%) to give the product of 1-(4-(6-(benzyloxy)-2-(cyclohex-1-en-1-yl)-3,4- dihydronaphthalen-1-yl)phenyl)-4-(dimethoxymethyl)piperidine (450 mg, 53.0 % yield) as a yellow solid. LC-MS (ESI ⁺ ) m/z: 550.5 (M+H) ⁺ . Step 2: To a solution of Pd/C (400 mg, 10.0% purity, 376 ^mol) in MeOH (15 mL) was added methyl 1-(4-(6-(benzyloxy)-2-(cyclohex-1-en-1-yl)-3,4-dihydronaphth alen-1-yl)phenyl)-4- (dimethoxymethyl)piperidine (450 mg, 794 ^mol) under N ₂ . The suspension was degassed under vacuum and purged with H ₂ several times. The mixture was stirred under H ₂ (15 psi) at 25 °C for 3 h. The reaction mixture was filtered and the filter was concentrated to give a residue which was separated by chiral SFC (column: DAICEL CHIRALCEL OJ (250mm*30mm,10um); mobile phase: [0.1%NH ₃ H ₂ O EtOH]; B%: 30%-30%, FlowRate(80 ml/min) peak 1: 1.835 min, peak 2: 2.088 min) to yield Peak 1 and Peak 2. Peak 1 was concentrated under reduced pressure to yield (5S,6S)-6-cyclohexyl-5-(4-(4-(dimethoxymethyl) piperidin-1-yl)phenyl)-5,6,7,8- tetrahydronaphthalen-2-ol (120 mg, 29.9 % yield) as a yellow solid. LC-MS (ESI ⁺ ) m/z: 464.4 (M+H) ⁺ . Peak 2 was concentrated under reduced pressure to yield (5R,6R)-6-cyclohexyl-5-(4- (4- (dimethoxymethyl)piperidin-1-yl)phenyl)-5,6,7,8-tetrahydrona phthalen-2-ol (120 mg, 29.9 % yield) as a yellow solid. LC-MS (ESI ⁺ ) m/z: 464.4 (M+H) ⁺ . Step 3: To a solution of (1S,2S)-2-cyclohexyl-1-[4-[4-(dimethoxymethyl)-1-piperidyl]p henyl] tetralin-6-ol (120 mg, 258.82 ^mol) in THF (3 mL) was added H ₂ SO ₄ (3 mL, 5.63 mmol, 10.0% purity). The mixture was stirred at 70 °C for 3 h. The reaction mixture was quenched by addition of water (10 mL), ajuust pH to 8 by NaHCO ₃ saturated solution, extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (10 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give 1-[4-[(1R,2R)-2-cyclohexyl-6-hydroxy-tetralin- 1-yl]phenyl]piperidine-4-carbaldehyde (130 mg, 96.23% yield) as a yellow solid. LC-MS (ESI ⁺ ) m/z: 418.4 (M+H) ⁺ . Step 4: To a solution of (1R,2R)-2-cyclohexyl-1-[4-[4-(dimethoxymethyl)-1-piperidyl]p henyl] tetralin-6-ol (120 mg, 258.82 ^mol) in THF (3 mL) was added H ₂ SO ₄ (3 mL, 5.63 mmol, 10.0% purity). The mixture was stirred at 70 °C for 3 h. The reaction mixture was quenched by addition of water (10 mL), ajuust pH to 8 by NaHCO3 saturated solution, extracted with EtOAc (20 mL x 3) Th bi d i l h d ith b i (10 L) d i d N SO filt d and concentrated under reduced pressure to give 1-[4-[(1R,2R)-2-cyclohexyl-6-hydroxy-tetralin- 1-yl]phenyl]piperidine-4-carbaldehyde (130 mg, 96.2% yield) as a yellow solid. LC-MS (ESI ⁺ ) m/z: 418.4 (M+H) ⁺ . Step 5: To a solution of 1-[4-[(1S,2S)-2-cyclohexyl-6-hydroxy-tetralin-1-yl]phenyl]pi peridine-4- carbaldehyde (60 mg, 114.95 ^mol) and (3S)-3-(1-oxo-5-piperazin-1-yl-isoindolin-2- yl)piperidine-2,6-dione (37.74 mg, 114.95 ^mol) in DCM (2.5 mL) and MeOH (2.5 mL) after stirred 30 min was added sodium;cyanoboranuide (36.12 mg, 574.74 ^mol). The mixture was stirred at 25 °C for 12.5 h. The reaction mixture was concentrated to yield a residue which was purified by preparative HPLC (column: Boston Green ODS 150*30mm*5um; mobile phase: [water(FA)-ACN];B%: 27%-47%,12min), followed by lyophilization to give (3S)-3-[5-[4-[[1-[4- [(1S,2S)-2-cyclohexyl-6-hydroxy-tetralin-1-yl]phenyl]-4-pipe ridyl]methyl]piperazin-1-yl]-1- oxo-isoindolin-2-yl]piperidine-2,6-dione (30 mg, 35.0% yield, 0.1FA) as a white solid. LC-MS (ESI ⁺ ) m/z: 730.4 (M+H) ⁺ LCMS: calc. for C ₄₅ H ₅₅ N ₅ O ₄ : 729.4, found: [M+H] ⁺ 730.4. HPLC: 100% purity at 254 nm. ¹ H NMR (500MHz, MeOD-d4): į 8.10 (s, 1H), 7.70 (d, J = 9.0 Hz, 1H), 7.67 (s, 1H), 7.21 - 7.14 (m, 2H), 6.98 - 6.87 (m, 4H), 6.65 (d, J = 8.4 Hz, 1H), 6.55 (d, J = 2.1 Hz, 1H), 6.45 (dd, J = 2.4, 8.3 Hz, 1H), 5.12 (dd, J = 5.2, 13.4 Hz, 1H), 4.50 - 4.36 (m, 2H), 4.14 (d, J = 4.4 Hz, 1H), 3.81 - 3.51 (m, 4H), 3.41 (s, 5H), 3.10 (d, J = 6.4 Hz, 2H), 2.95 - 2.86 (m, 2H), 2.84 - 2.70 (m, 4H), 2.47 (d, J = 4.5, 13.1 Hz, 1H), 2.18 - 2.09 (m, 2H), 2.05 (s, 1H), 1.92 (d, J = 12.2 Hz, 2H), 1.84 - 1.72 (m, 2H), 1.67 - 1.55 (m, 4H), 1.55 - 1.45 (m, 2H), 1.34 - 0.96 (m, 7H), 0.85 - 0.73 (m, 1H). Step 6: To a solution of 1-[4-[(1R,2R)-2-cyclohexyl-6-hydroxy-tetralin-1-yl]phenyl]pi peridine-4- carbaldehyde (60 mg, 114.95 ^mol) and (3S)-3-(1-oxo-5-piperazin-1-yl-isoindolin-2- yl)piperidine-2,6-dione (37.74 mg, 114.95 ^mol) in DCM (2.5 mL) and MeOH (2.5 mL) after stirred 30 min was added sodium;cyanoboranuide (36.12 mg, 574.74 ^mol). The mixture was stirred at 25 °C for 12.5 h. The reaction mixture was concentrated to yield a residue which was purified by preparative HPLC (column: Boston Green ODS 150*30mm*5um; mobile phase: [water(FA)-ACN];B%: 27%-47%,12min), followed by lyophilization to give (3S)-3-[5-[4-[[1-[4- [(1R,2R)-2-cyclohexyl-6-hydroxy-tetralin-1-yl]phenyl]-4-pipe ridyl]methyl]piperazin-1-yl]-1- oxo-isoindolin-2-yl]piperidine-2,6-dione (30.6 mg, 36.3% yield, 0.06FA) as a white solid. LC- MS (ESI ⁺ ) m/z: 730.4 (M+H) ⁺ LCMS: calc. for C ₄₅ H ₅₅ N ₅ O ₄ : 729.4, found: [M+H] ⁺ 730.4. HPLC: 100% purity at 254 nm. NMR (500MHz, MeOD-d4): į 8.09 (s, 1H), 7.73 - 7.66 (m, 1H), 7.22 - 7.15 (m, 2H), 6.91 (q, J = 8.6 Hz, 4H), 6.65 (d, J = 8.4 Hz, 1H), 6.55 (d, J = 2.1 Hz, 1H), 6.45 (dd, J = 2.4, 8.3 Hz, 1H), 5.12 (dd, J = 5.1, 13.4 Hz, 1H), 4.51-4.36 (m, 2H), 4.14 (d, J = 4.3 Hz, 1H), 3.68 (s, 4H), 3.45 (s, 5H), 3.17 - 3.08 (m, 2H), 2.95 - 2.85 (m, 2H), 2.82 - 2.70 (m, 4H), 2.47 (d, J = 4.5, 13.2 Hz, 1H), 2.27 - 2.11 (m, 2H), 2.05 (d, J = 11.3 Hz, 1H), 1.92 (d, J = 12.5 Hz, 2H), 1.81 - 1.72 (m, 2H), 1.71 - 1.37 (m, 7H), 1.35 - 0.98 (m, 7H), 0.79 (q, J = 10.9 Hz, 1H). EXAMPLE 257. Preparation of (I-407) (3S)-3-[5-[4-[[1-[4-[(1R,2S)-2-(cyclohexen-1-yl)- 6-hydroxy-tetralin-1-yl]phenyl]-4-piperidyl]methyl]piperazin -1-yl]-1-oxo-isoindolin-2- yl]piperidine-2,6-dione and (I-416) (3S)-3-[5-[4-[[1-[4-[(1S,2R)-2-(cyclohexen-1-yl)-6-

hydroxy-tetralin-1-yl]phenyl]-4-piperidyl]methyl]piperazi n-1-yl]-1-oxo-isoindolin-2- yl]piperidine-2,6-dione Step 1: A mixture of 1-[4-(6-benzyloxy-2-bromo-3,4-dihydronaphthalen-1-yl)phenyl] -4- (dimethoxymethyl)piperidine (2.8 g, 4.34 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (1.54 g, 6.07 mmol), Pd(dppf)Cl ₂ (317.49 mg, 433.90 ^mol), Na ₂ CO ₃ (919.78 mg, 8.68 mmol) in dioxane (30 mL) and H ₂ O (6 mL) was degassed and purged with N ₂ for 3 times, and then the mixture was stirred at 90 °C for 16 h under N ₂ atmosphere. The reaction mixture was quenched with water (200 mL) and extracted with EtOAc (300 mL x 3). The combined organic layers were washed with brine (300 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ethyl acetate in petroleum ether= 0% to 20%) to give 1-[4-[6-benzyloxy-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan- 2-yl)-3,4-dihydronaphthalen- 1-yl]phenyl]-4-(dimethoxymethyl)piperidine (2.2 g, 83.4% yield) as a yellow solid. LC-MS (ESI ⁺ ) m/z: 596.1 (M+H) ⁺ . Step 2: To a solution of Pd/C (300 mg, 10% purity) in MeOH (10 mL) was added 1-[4-[6- benzyloxy-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3, 4-dihydronaphthalen-1-yl]phenyl]- 4-(dimethoxymethyl)piperidine (2.2 g, 3.62 mmol) under N ₂ . The suspension was degassed under vacuum and purged with H ₂ several times. The mixture was stirred under H ₂ (15 psi) at 25 °C for 16 h. The reaction mixture was filtered and the filter was concentrated. The residue was purified by preparative HPLC (column: Phenomenex C18150*40mm*5um; mobile phase: [water(NH ₃ H ₂ O+NH ₄ HCO ₃ )-CAN]; B%: 50%-70%, 10min), followed by lyophilization to give 1-[4-[4-(dimethoxymethyl)-1-piperidyl]phenyl]-2-(4,4,5,5-tet ramethyl-1,3,2-dioxaborolan-2- yl)tetralin-6-ol (700 mg, 33.5% yield) as a white solid. LC-MS (ESI ⁺ ) m/z: 508.3 (M+H) ⁺ . Step 3: A stirred solution of 1-bromocyclohexene (55.85 mg, 346.82 ^mol) in THF (1 mL) was cooled to -78 °C and t-BuLi (1.3 M, 533.57 ^L) was added dropwise. The resulting solution was stirred at -78 °C for 30 min and then a solution of 1-[4-[4-(dimethoxymethyl)-1- piperidyl]phenyl]-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan- 2-yl)tetralin-6-ol (100 mg, 173.41 ^mol) in THF (1 mL) was added dropwise. The resulting solution was stirred at -78 °C for 15 min and then warmed to 0 °C and stirred for a further 15 min. After this time, the solution was cooled to -78 °C and a suspension of NaOMe (3 M, 1.16 mL) was added in a single portion followed by dropwise addition of a solution of I ₂ (0.5 M, 416.18 ^L). The resulting mixture was warmed to 0 °C and stirred for 30 min and then warmed to 25 °C and stirred at 25 °C for 16 h. The reaction was quenched with sat.aq. Na ₂ O ₃ S ₂ (10 mL) and diluted with water (20 mL) and extracted with DCM (30 mL x 3). The combined organic layers were washed with brine (40 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (column: Phenomenex C18150*40mm*5um;mobile phase: [water(NH ₃ H ₂ O+NH ₄ HCO ₃ )-CAN]; B%: 60%-90%, 10min,), followed by lyophilization to yield a product which was separated by chiral SFC (column: DAICEL CHIRALPAK IG (250mm*30mm,10um); mobile phase: [0.1%NH ₃ H ₂ O ETOH]; B%: 40%-40%,min, peak 1: 2.039 min, peak 2: 2.291 min) to yield Peak 1 and Peak 2. Peak 1 was concentrated under reduced pressure to yield (1R,2S)-2-(cyclohexen-1-yl)-1-[4-[4-(dimethoxymethyl)-1- piperidyl]phenyl]tetralin-6-ol (40 mg, 9.7% yield) (SFC: Rt = 2.039) s a white solid. LC-MS (ESI ⁺ ) m/z: 4624 (M+H) ⁺ Peak 2 was concentrated under reduced pressure to yield (1S2R)-2- (cyclohexen-1-yl)-1-[4-[4-(dimethoxymethyl)-1-piperidyl]phen yl]tetralin-6-ol (40 mg, 9.79% yield) (SFC: Rt = 2.291) as a white solid. LC-MS (ESI ⁺ ) m/z: 462.4 (M+H) ⁺ . Step 4: To a solution of (1R,2S)-2-(cyclohexen-1-yl)-1-[4-[4-(dimethoxymethyl)-1- piperidyl]phenyl]tetralin-6-ol (40 mg, 84.05 ^mol) in DCM (3 mL) was added TFA (9.58 mg, 84.05 ^mol, 6.22 ^L). The mixture was stirred at 25 °C for 10 min. The solvent was removed to yield a residue which was added H ₂ O (3 mL) and CAN (5 mL), followed by lyophilization to give 1-[4-[(1R,2S)-2-(cyclohexen-1-yl)-6-hydroxy-tetralin-1-yl]ph enyl]piperidine-4- carbaldehyde (30 mg, crude) as a brown solid. LC-MS (ESI ⁺ ) m/z: 416.2 (M+H) ⁺ . Step 5: To a solution of (1S,2R)-2-(cyclohexen-1-yl)-1-[4-[4-(dimethoxymethyl)-1- piperidyl]phenyl]tetralin-6-ol (40 mg, 84.92 ^mol) in DCM (3 mL) was added TFA (9.68 mg, 84.92 ^mol, 6.29 ^L). The mixture was stirred at 25 °C for 10 min. The solvent was removed to yield a residue which was added H ₂ O (3 mL) and ACN (5 mL), followed by lyophilization to give 1-[4-[(1S,2R)-2-(cyclohexen-1-yl)-6-hydroxy-tetralin-1-yl]ph enyl]piperidine-4- carbaldehyde (30 mg, crude) as a brown solid. LC-MS (ESI ⁺ ) m/z: 416.2 (M+H) ⁺ . Step 6: To a solution of 1-[4-[(1R,2S)-2-(cyclohexen-1-yl)-6-hydroxy-tetralin-1- yl]phenyl]piperidine-4-carbaldehyde (40 mg, 96.25 ^mol) in MeOH (3 mL) and DCM (3 mL) was added NaOAc (15.79 mg, 192.51 ^mol), and (3S)-3-(1-oxo-5-piperazin-1-yl-isoindolin-2- yl)piperidine-2,6-dione (48.18 mg, 96.25 ^mol, TsOH) and stirred at 25 °C for 1 h. Then NaBH ₃ CN (30.24 mg, 481.27 ^mol) was added and stirred at 25 °C for 3 h. The solvent was removed to yield a residue. The residue was purified by preparative HPLC (column: Boston Green ODS 150*30mm*5um; mobile phase: [water(FA)-ACN]; B%: 16%-46%,10min), followed by lyophilization to yield (3S)-3-[5-[4-[[1-[4-[(1R,2S)-2-(cyclohexen-1-yl)-6-hydroxy- tetralin-1-yl]phenyl]-4-piperidyl]methyl]piperazin-1-yl]-1-o xo-isoindolin-2-yl]piperidine-2,6- dione (13.0 mg, 18.2% yield, 0.3FA) as a white solid. LC-MS (ESI ⁺ ) m/z: 728.6 (M+H) ⁺ LCMS: calc. for C ₄₅ H ₅₃ N ₅ O ₄ : 727.9, found: [M+H] ⁺ 728.6. HPLC: 100.00% purity at 254 nm. ¹ HNMR (400MHz, MeOD-d4): į 8.40 (s, 1H), 7.65 (d, J = 8.7 Hz, 1H), 7.17 - 7.05 (m, 2H), 6.85 - 6.80 (m, 2H), 6.76 - 6.71 (m, 2H), 6.68 (d, J = 8.3 Hz, 1H), 6.57 (d, J = 2.4 Hz, 1H), 6.48 (d, J = 5.0 Hz, 1H), 3.60 (d, J = 9.1 Hz, 2H), 3.47 - 3.37 (m, 4H), 2.96 - 2.72 (m, 8H), 2.65 (br t, J = 12.0 Hz, 2H), 2.54 - 2.39 (m, 4H), 2.20 - 2.06 (m, 2H), 2.00 - 1.75 (m, 6H), 1.58 - 1.34 (m, 8H). Step 7: To a solution of 1-[4-[(1S,2R)-2-(cyclohexen-1-yl)-6-hydroxy-tetralin-1- yl]phenyl]piperidine-4-carbaldehyde (40 mg, 96.25 ^mol) in MeOH (3 mL) and DCM (3 mL) was added NaOAc (15.79 mg, 192.51 ^mol) and (3S)-3-(1-oxo-5-piperazin-1-yl-isoindolin-2- yl)piperidine-2,6-dione (48.18 mg, 96.25 ^mol, TsOH) and stirred at 25 °C for 1 h. Then NaBH ₃ CN (30.24 mg, 481.27 ^mol) was added and stirred at 25 °C for 3 h. The solvent was removed to yield a residue. The residue was purified by preparative HPLC (column: Boston Green ODS 150*30mm*5um; mobile phase: [water(FA)-CAN]; B%: 16%-46%,10min), followed by lyophilization to yield (3S)-3-[5-[4-[[1-[4-[(1S,2R)-2-(cyclohexen-1-yl)-6- hydroxy-tetralin-1-yl]phenyl]-4-piperidyl]methyl]piperazin-1 -yl]-1-oxo-isoindolin-2- yl]piperidine-2,6-dione (14.3 mg, 19.9% yield, 0.35FA) as a white solid. LC-MS (ESI ⁺ ) m/z: 728.6 (M+H) ⁺ LCMS: calc. for C45H53N5O4: 727.9, found: [M+H] ⁺ 728.6. HPLC: 100.00% purity at 254 nm. ¹ HNMR (400MHz, MeOD-d4): į 8.38 (s, 1H), 7.65 (d, J = 8.7 Hz, 1H), 7.15 - 7.04 (m, 2H), 6.86 - 6.80 (m, 2H), 6.76 - 6.72 (m, 2H), 6.68 (d, J = 8.3 Hz, 1H), 6.57 (d, J = 2.5 Hz, 1H), 6.48 (dd, J = 2.6, 8.3 Hz, 1H), 5.10 (dd, J = 5.2, 13.3 Hz, 1H), 4.97 (s, 1H), 4.47 - 4.33 (m, 2H), 4.09 (d, J = 5.0 Hz, 1H), 3.60 (d, J = 8.9 Hz, 2H), 3.47 - 3.37 (m, 4H), 2.96 - 2.73 (m, 8H), 2.66 (t, J = 12.0 Hz, 2H), 2.54 - 2.38 (m, 4H), 2.20 - 2.08 (m, 2H), 1.99 - 1.72 (m, 6H), 1.58 - 1.33 (m, 8H).

EXAMPLE 258. Preparation of (I-32) (3S)-3-[5-[4-[[1-[4-[(1R,2R)-6-hydroxy-2- tetrahydropyran-4-yl-tetralin-1-yl]phenyl]-4-piperidyl]methy l]piperazin-1-yl]-1-oxo- isoindolin-2-yl]piperidine-2,6-dione Step 1: To a solution of (1R,2R)-1-[4-[4-(dimethoxymethyl)-1-piperidyl]phenyl]-2- tetrahydropyran-4-yl-tetralin-6-ol (30.00 mg, 64.43 umol, 1 eq) in HCl/dioxane (1 mL). The mixture was stirred at 60 °C for 5 hr. This reaction mixture was concentrated under reduced pressure to give a residue as a brown solid Compound 1-[4-[(1R,2R)-6-hydroxy-2- tetrahydropyran-4-yl-tetralin-1-yl]phenyl]piperidine-4-carba ldehyde (30 mg, crude) was obtained as a brown solid. This reaction was used to next step without purification. LC-MS (ESI ⁺ ) m/z: 420.1 (M+H) ^{+ 1} H NMR (400 MHz, DMSO-d6) į ppm 9.61 - 9.72 (m, 1 H) 7.12 - 7.32 (m, 2 H) 6.97 - 7.08 (m, 2 H) 6.62 (d, J=8.25 Hz, 1 H) 6.53 (d, J=2.38 Hz, 1 H) 6.43(dd, J=8.19, 2.44 Hz, 1 H) 4.14 - 4.20 (m, 1 H) 3.80 - 3.91 (m, 2 H) 3.69 - 3.77 (m, 2 H) 3.01 - 3.08 (m, 2 H) 2.86 - 2.96(m, 2 H) 2.69 - 2.82 (m, 2 H) 2.30 -2.35 (m, 1 H) 2.02 - 2.14 (m, 3 H) 1.71 - 1.86 (m, 4 H) 1.60 - 1.70 (m, 2 H) 1.41 - 1.55 (m, 2 H) 1.20 - 1.28 (m, 2 H) Step 2: To a solution of 1-[4-[(1R,2R)-6-hydroxy-2-tetrahydropyran-4-yl-tetralin-1- yl]phenyl]piperidine-4-carbaldehyde (25 mg, 59.59 umol, 1 eq) in mixture of DCM (1 mL) and MeOH (1 mL) was added (3S)-3-(1-oxo-5-piperazin-1-yl-isoindolin-2-yl)piperidine-2, 6-dione (29.35 mg, 89.38 umol, 1.5 eq), HOAc (4.20 mg, 69.94 umol, 4 uL, 1.17 eq) and NaOAc (15 mg, 182.85 umol, 3.07 eq) at 25°C. After addition, the mixture was stirred at this temperature for 1 hr, and then NaBH(OAc) ₃ (20 mg, 94.37 umol, 1.58 eq) was added at 25 °C. The resulting i t ti d t 25 °C f 15 h Th ti i t t t d d d d to give a residue as a yellow solid The residue was purified by prep-HPLC (column: Phenomenex luna C18150*25mm* 10um;mobile phase: [water(FA)-ACN];B%: 13%- 43%,58min).Compound (3S)-3-[5-[4-[[1-[4-[(1R,2R)-6-hydroxy-2-tetrahydropyran-4-y l-tetralin- 1-yl]phenyl]-4-piperidyl]methyl]piperazin-1-yl]-1-oxo-isoind olin-2-yl]piperidine-2,6-dione (4 mg, 5.35 umol, 9.0% yield, 98.0% purity) was obtained as a white solid. LC-MS (ESI ⁺ ) m/z: 732.3 (M+H) ⁺ HPLC: 98.0 % purity at 220 nm SFC: Rt: 1.060 min; Area, 88.684 %; method: OJ-3-IPA+ACN(DEA)-40-3ML-35T. ¹ H NMR (400 MHz, DMSO-d ₆ ) į ppm 10.99 (s, 1 H) 8.91 - 9.08 (m, 1 H) 8.15 - 8.19 (m, 0.573 H) 7.49 - 7.54 (m, 1 H) 7.01 - 7.08 (m, 2 H) 6.73 - 6.85 (m, 4H) 6.58 - 6.63 (m, 1 H) 6.48 - 6.52 (m, 1 H) 6.38 - 6.44 (m, 1 H) 4.98 - 5.08 (m, 1 H) 4.29 - 4.36 (m, 1 H) 4.15 - 4.23 (m, 1 H) 4.05 (br d, J=3.88 Hz, 1 H)3.82 - 3.88 (m, 1 H) 3.70 - 3.75 (m, 1 H) 3.57 - 3.63 (m, 2 H) 3.19 (br d, J=11.63 Hz, 3 H) 3.02 - 3.10 (m, 2 H) 2.88 (br dd, J=17.64, 5.13 Hz, 2 H) 2.70 - 2.78(m, 1 H) 2.54 - 2.61 (m, 3 H) 2.31 - 2.43 (m, 5 H) 2.27 - 2.30 (m, 1 H) 2.18 - 2.23 (m, 2 H) 1.92 - 2.04 (m, 2 H) 1.76 - 1.83 (m, 2 H) 1.64 - 1.74 (m, 2 H) 1.54- 1.59 (m, 1 H) 1.46 - 1.53 (m, 1 H) 1.12 - 1.25 (m, 5 H) 1.03 - 1.09 (m, 1 H)

EXAMPLE 259. Preparation of (I-33) (3S)-3-[5-[4-[[1-[4-[(1S,2S)-6-hydroxy-2- tetrahydropyran-4-yl-tetralin-1-yl]phenyl]-4-piperidyl]methy l]piperazin-1-yl]-1-oxo- isoindolin-2-yl]piperidine-2,6-dione Step 1: A mixture of 1-[4-(6-benzyloxy-2-bromo-3,4-dihydronaphthalen-1-yl)phenyl] -4- (dimethoxymethyl)piperidine (500 mg, 911.5 umol, 1 eq) , 2-(3,6-dihydro-2H-pyran-4-yl)- 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (250 mg, 1.19 mmol, 1.3 eq), Pd(dppf)Cl ₂ ^. CH ₂ Cl ₂ (372 mg, 455.78 umol, 0.5 eq), Na ₂ CO ₃ (290 mg, 2.73 mmol, 3 eq) in dioxane (4mL) and Water (1 mL) was degassed and purged with N ₂ for 3 times, and then the mixture was stirred at 100 °C for 16 hr under N2 atmosphere. The reaction mixture was concentrated under reduced pressure to remove dioxane and water. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 0~30% Ethyl acetate/Petroleum ether @ 40 mL/min). Compound 1-[4-[6-benzyloxy-2-(3,6-dihydro-2H-pyran-4-yl)-3,4-dihydron aphthalen- 1-yl]phenyl]-4-(dimethoxymethyl)piperidine (300 mg, 518.23 umol, 56.8% yield, 95.3% purity) was obtained as a yellow solid. LC-MS (ESI+) m/z: 552.4 (M+H) ⁺ Step 2: A mixture of 1-[4-[6-benzyloxy-2-(3,6-dihydro-2H-pyran-4-yl)-3,4-dihydron aphthalen- 1-yl]phenyl]-4- (dimethoxymethyl)piperidine (300.00 mg, 543.76 umol, 1 eq) , Pd/C (200 mg, 2.72 mmol, 10% purity, 5 eq) in MeOH (2mL) and THF (2 mL) was degassed and purged with H ₂ for 3 times, and then the mixture was stirred at 50 °C for 12 hr under H ₂ (15 psi) atmosphere. The reaction mixture was filtered and the filter cake was rinsed with 50 mL of MeOH, The filter was collected, dried in vacuo to give a colorless oil. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 0~50% Ethyl acetate/Petroleum ether @ 40 mL/min) to give desired a colorless oil. Which was further separated by SFC (condition: column: Welch Ultimate C18 150*25mm*5um;mobile phase: [water(FA)-ACN];B%: 20%-50%,10min) and condition (column: Welch Ultimate C18150*25mm*5um;mobile phase: [water(FA)-ACN];B%: 18%- 48%,10min). Compound (1S,2S)-1-[4-[4-(dimethoxymethyl)-1-piperidyl]phenyl]-2- tetrahydropyran-4-yl-tetralin-6-ol (95 mg, 197.50 umol, 36.32% yield, 96.8% purity) was obtained as a colorless oil. Compound (1R,2R)-1-[4-[4-(dimethoxymethyl)-1-piperidyl]phenyl]-2-tetr ahydropyran-4-yl-tetralin-6-ol (96 mg, 197.93 umol, 36.40% yield, 96% purity) was obtained as a colorless oil. LC-MS (ESI ⁺ ) m/z: 466.2 (M+H) ⁺ SFC for (1S,2S)-1-[4-[4-(dimethoxymethyl)-1-piperidyl]phenyl]-2-tetr ahydropyran-4-yl-tetralin- 6-ol: Rt: 2.055 min; Area, 99.885 %; SFC for (1R,2R)-1-[4-[4-(dimethoxymethyl)-1-piperidyl]phenyl]-2-tetr ahydropyran-4-yl- tetralin-6-ol: Rt: 2.165 min; Area, 98.111 %; Step 3: To a solution of (1S,2S)-1-[4-[4-(dimethoxymethyl)-1-piperidyl]phenyl]-2- tetrahydropyran-4-yl-tetralin-6-ol (30 mg, 64.43 umol, 1 eq) in HCl/dioxane (1 mL). The mixture was stirred at 60 °C for 5 hr. This reaction mixture was concentrated under reduced pressure to give a residue as a brown solid. Compound 1-[4-[(1S,2S)-6-hydroxy-2- tetrahydropyran-4-yl-tetralin-1-yl]phenyl]piperidine-4-carba ldehyde (30 mg, crude) was obtained as a brown solid. This reaction was used to next step without purification. LC-MS (ESI ⁺ ) m/z: 420.0 (M+H) ^{+ 1} H NMR (400 MHz, DMSO-d ₆ ) į ppm 9.57 - 9.72 (m, 1 H) 7.33 - 7.58 (m, 2 H) 7.07 - 7.18 (m, 2 H) 6.62 (d, J=8.25 Hz, 1 H) 6.54 (d, J=2.38 Hz, 1 H) 6.43(dd, J=8.32, 2.44 Hz, 1 H) 3.80 - 3.88 (m, 2 H) 3.69 - 3.76 (m, 2 H) 3.13 - 3.23 (m, 4 H) 2.98 - 3.08 (m, 2 H) 2.63 - 2.78 (m, 3 H) 2.07 - 2.19 (m, 2 H) 1.84 -1.99 (m, 3 H) 1.71 - 1.72 (m, 1 H) 1.61 - 1.71 (m, 2 H) 1.39 - 1.54 (m, 2 H) 1.15 - 1.17 (m, 1 H) Step 4: To a solution of 1-[4-[(1S,2S)-6-hydroxy-2-tetrahydropyran-4-yl-tetralin-1- yl]phenyl]piperidine-4-carbaldehyde (30.00 mg, 71.50 umol, 1 eq) in mixture of DCM (0.5 mL) and MeOH (0.5 mL) was added (3S)-3-(1-oxo-5-piperazin-1-yl-isoindolin-2-yl)piperidine- 2,6-dione (50.11 mg, 100.11 umol, 1.40 eq, p-TSA salt) , HOAc (4.20 mg, 69.94 umol, 4.00 uL, 1 eq) and NaOAc (18.00 mg, 219.43 umol, 3.07 eq) at 25°C. After addition, the mixture was stirred at this temperature for 1 hr, and then NaBH(OAc) ₃ (23.00 mg, 108.52 umol, 1.52 eq) was added at 25°C. The resulting mixture was stirred at 25°C for 15 hr. The reaction mixture concentrated under reduced pressure to give a residue as a yellow solid. The residue was purified by prep-HPLC (column: Phenomenex luna C18150*25mm* 10um;mobile phase: [water(FA)- ACN];B%: 13%-43%,58min). Compound (3S)-3-[5-[4-[[1-[4-[(1S,2S)-6-hydroxy-2- tetrahydropyran-4-yl-tetralin-1-yl]phenyl]-4-piperidyl]methy l]piperazin-1-yl]-1-oxo-isoindolin- 2-yl]piperidine-2,6-dione (8 mg, 10.77 umol, 15.07% yield, 98.560% purity) was obtained as a white solid. LC-MS (ESI+) m/z: 732.3 (M+H) ⁺ SFC: Rt: 0.864 min; Area, 92.143 %; ¹ H NMR (400 MHz, DMSO-d ₆ ) į ppm 10.89 - 10.98 (m, 1 H) 8.98 - 9.05 (m, 1 H) 8.13 - 8.15 (m, 0.332 H) 7.49 - 7.54 (m, 1 H) 7.04 - 7.09 (m, 2 H) 6.74 -6.85 (m, 4 H) 6.62 (d, J=8.38 Hz, 1 H) 6.49 - 6.51 (m, 1 H) 6.38 - 6.43 (m, 1 H) 5.01 - 5.08 (m, 1 H) 4.29 - 4.36 (m, 1 H) 4.16 - 4.23 (m, 1 H) 4.04 (br d, J=4.13 Hz, 1 H) 3.82 - 3.88 (m, 1 H) 3.70 - 3.76 (m, 1 H) 3.55 - 3.64 (m, 2 H) 3.29 (br d, J=3.75 Hz, 5 H) 3.14 - 3.21 (m, 1 H) 3.01 - 3.10 (m, 1 H) 2.82 - 2.92(m, 2 H) 2.64 - 2.79 (m, 2 H) 2.56 - 2.62 (m, 3 H) 2.28 - 2.43 (m, 2 H) 2.18 - 2.24 (m, 2 H) 1.92 - 2.04 (m, 2 H) 1.76 - 1.82 (m, 2 H) 1.63 - 1.75 (m, 2 H) 1.31- 1.62 (m, 3 H) 1.13 - 1.27 (m, 5 H) 1.02 - 1.11 (m, 1 H) EXAMPLE 260. Preparation of (I-29) (S)-3-(5-(4-((1-(4-((1S,2R)-6-hydroxy-2-(1- methyl-1H-pyrazol-3-yl)-1,2,3,4-tetrahydronaphthalen-1-yl)ph enyl)piperidin-4- yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2, 6-dione Step 1: To a solution of (5S,6R)-5-(4-(4-(dimethoxymethyl)piperidin-1-yl)phenyl)-6-(1 -methyl- 1H-pyrazol-3-yl)-5,6,7,8-tetrahydronaphthalen-2-ol (100 mg, 1 Eq, 217 ^mol) in THF (15 mL) was added sulfuric acid (212 mg, 15 mL, 10% Wt., 1 Eq, 217 ^mol).The mixture was stirred at 70 °C for 4 hour. LCMS showed 100 % desired MS. The mixture was adjusted to pH 8-9 by progressively adding NaHCO ₃ . The reaction mixture was quenched by addition 20 mL EtOAc at 20°C, and then diluted with 20 mL H ₂ O and extracted with 50mL (25 mL * 2) EtOAc. The combined organic layers were washed with 10 mL (10 mL * 1) and dried over Na ₂ SO ₄ . The reaction was filtered and concentrated under reduced pressure to give 1-(4-((1S, 2R)-6-hydroxy- 2-(1-methyl-1H-pyrazol-3-yl)-1, 2, 3, 4-tetrahydronaphthalen-1-yl) phenyl) piperidine-4- carbaldehyde (100 mg, 241 ^mol, 111 %, 100% Purity) was obtained as a brown solid. LC-MS (ESI ⁺ ) m/z: 434.0 (M+H) ⁺ . Step 2: A mixture of 1-(4-((1S,2R)-6-hydroxy-2-(1-methyl-1H-pyrazol-3-yl)-1,2,3,4 - tetrahydronaphthalen-1-yl)phenyl)piperidine-4-carbaldehyde (100 mg, 1 Eq, 241 ^mol), (R)-3- (1-oxo-5-(piperazin-1-yl)isoindolin-2-yl)piperidine-2,6-dion e, TsOH salt(142 mg, 84.8% Wt., 1 Eq, 241 ^mol) and sodium acetate (98.7 mg, 5 Eq, 1.20 mmol) in DCM (1.5 mL) and MeOH (1.5 mL) at 20 °C for 0.5 h, pH=8, then Acetic acid (43.4 mg, 41.5 ^L, 3 Eq, 722 ^mol) at 20 °C for 1 h, pH=6, then added NaBH(OAc) ₃ (30.2 mg, 2 Eq, 481 ^mol) in the mixture, and then the mixture was stirred at 25 °C for 16 h. LCMS showed 72.41% desired MS. The reaction was concentrated to give (S)-3-(5-(4-((1-(4-((1S,2R)-6-hydroxy-2-(1-methyl-1H-pyrazol -3-yl)- 1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperidin-4-yl)meth yl)piperazin-1-yl)-1-oxoisoindolin- 2-yl)piperidine-2,6-dione (49.3 g, 62.6 mmol, 26000%, 92.4% Purity) as a brown solid. LCMS: calc. for C ₄₃ H ₄₉ N ₇ O ₄ : 727.89, found: [M+H] ⁺ 728.2. HPLC: 92.4% purity at 220 nm. NMR (400 MHz, DMSO-d ₆ ) į = 11.00 - 10.89 (m, 1H), 9.12 - 9.02 (m, 1H), 8.17 - 8.12 (m, 0.525H), 7.55 - 7.50 (m, 1H), 7.49 - 7.46 (m, 1H), 7.42 - 7.36(m, 1H), 7.13 - 7.05 (m, 2H), 6.68 - 6.56 (m, 4H), 6.48 - 6.36 (m, 3H), 5.52 - 5.46 (m, 1H), 5.10 - 5.00 (m, 1H), 4.38 - 4.29 (m, 1H), 4.25 - 4.18 (m, 2H), 3.77- 3.72 (m, 3H), 3.60 - 3.48 (m, 3H), 3.28 - 3.17 (m, 4H), 2.95 - 2.85 (m, 3H), 2.68 - 2.53 (m, 6H), 2.43 - 2.27 (m, 4H), 2.01 - 1.90 (m, 2H), 1.84 - 1.65 (m,4H), 1.23 - 1.12 (m, 2H) SFC: retention time, 2.599 min; Area, 94.885%; Stereochemistry at the ERBM core is arbitrarily assigned.

EXAMPLE 261. Preparation of (I-28) (S)-3-(5-(4-((1-(4-((1R,2S)-6-hydroxy-2-(1- methyl-1H-pyrazol-3-yl)-1,2,3,4-tetrahydronaphthalen-1-yl)ph enyl)piperidin-4- yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2, 6-dione Step 1: A mixture of 1-[4-(6-benzyloxy-2-bromo-3,4-dihydronaphthalen-1-yl)phenyl] -4- (dimethoxymethyl)piperidine (500 mg, 911.56 ^mol, 1 eq), 1-methyl-3-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl) pyrazole (246 mg, 1.19 mmol, 1.3 eq), Pd(dppf)Cl ₂ .CH ₂ Cl ₂ (372 mg, 455.78 ^mol, 0.5 eq), Na ₂ CO ₃ (290 mg, 2.73 mmol, 3 eq) in dioxane (4 mL) and Water (1 mL) was degassed and purged with N ₂ for 3 times, and then the mixture was stirred at 100 °C for 16 h under N ₂ atmosphere. The reaction mixture was concentrated under reduced pressure to remove dioxane and H ₂ O, The residue was purified by flash silica gel chromatography (ISCO® 12 g SepaFlash® Silica Flash Column Eluent of 0~30% Ethyl acetate/Petroleum ether @ 40 mL/min). Compound 1-[4-[6-benzyloxy-2-(1-methylpyrazol-3-yl)-3, 4-dihydronaphthalen-1-yl] phenyl]-4-(dimethoxymethyl) piperidine (300 mg, 438.64 ^mol, 48.12% yield, 80.37% purity) was obtained as a yellow solid. LC-MS (ESI+) m/z: 550.5 (M+H) ⁺ Step 2: A mixture of 1-[4-[6-benzyloxy-2-(1-methylpyrazol-3-yl)-3,4-dihydronaphth alen-1- yl]phenyl]-4-(dimethoxymethyl)piperidine (800 mg, 1.46 mmol, 1 eq), Pd/C (1 g, 7.28 mmol, 10% purity, 5 eq) in MeOH (2 mL) and THF (2 mL) was degassed and purged with H ₂ for 3 times, and then the mixture was stirred at 60 °C for 48 h under H ₂ (50 psi) atmosphere, The reaction mixture was filtered and the filter cake was rinsed with 50 mL of DCM, The filter was concentrated to dryness in vacuo .The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 0~70% Ethyl acetate/Petroleum ether @ 50 mL/min) to give desired compound (400 mg, purity 96.808%) as a colorless oil, which was further separated by SFC (column: DAICEL CHIRALCEL OJ(250mm*30mm,10um); mobile phase: [0.1%NH ₃ H ₂ O MEOH]; B%:25%-25%, C7.5; 120min). LC-MS (ESI+) m/z: 462.3 (M+H) ⁺ Compound (1R, 2S)-1-[4-[4-(dimethoxymethyl)-1-piperidyl] phenyl]-2-(1-methylpyrazol-3-yl) tetralin-6-ol (190 mg, 370.46 ^mol, 25.45% yield, 90% purity) was obtained as a colorless oil. Compound (1S, 2R)-1-[4-[4-(dimethoxymethyl)-1-piperidyl] phenyl]-2-(1-methylpyrazol-3-yl) tetralin-6-ol (190 mg, 370.46 ^mol, 25.45% yield, 90% purity) was obtained as a colorless oil. Step 3: To a solution of (5R,6S)-5-(4-(4-(dimethoxymethyl)piperidin-1-yl)phenyl)-6-(1 -methyl- 1H-pyrazol-3-yl)-5,6,7,8-tetrahydronaphthalen-2-ol (100 mg, 1 Eq, 217 ^mol) in THF (15 mL) was added sulfuric acid (212 mg, 15 mL, 10% Wt., 1 Eq, 217 ^mol). The mixture was stirred at 70 °C for 16 hour. LCMS showed 97.9 % desired MS. The mixture was adjusted to pH 8-9 by progressively adding NaHCO ₃ . The reaction mixture was quenched by addition 20 mL EtOAc at 20 °C, and then diluted with 20 mL H ₂ O and extracted with 50mL (25 mL * 2) EtOAc. The combined organic layers were washed with 10 mL (10 mL * 1) and dried over Na ₂ SO ₄ . The reaction was filtered and concentrated under reduced pressure to give 1-(4-((1R, 2S)-6-hydroxy- 2-(1-methyl-1H-pyrazol-3-yl)-1, 2, 3, 4-tetrahydronaphthalen-1-yl) phenyl) piperidine-4- carbaldehyde (103 mg, 243 ^mol, 112 %, 97.9% Purity) was obtained as a brown solid. LC-MS (ESI ⁺ ) m/z: 434.0 (M+H) ⁺ . Step 4: A mixture of 1-(4-((1R,2S)-6-hydroxy-2-(1-methyl-1H-pyrazol-3-yl)-1,2,3,4 - tetrahydronaphthalen-1-yl)phenyl)piperidine-4-carbaldehyde, (R)-3-(1-oxo-5-(piperazin-1- yl)isoindolin-2-yl)piperidine-2,6-dione, TsOH acid (142 mg, 84.8% Wt., 1 Eq, 241 ^mol) and Sodium acetate (98.7 mg, 5 Eq, 1.20 mmol) in DCM (1.5 mL) and MeOH (1.5 mL) at 20 °C for 0.5 h, then Acetic acid (43.4 mg, 41.5 ^L, 3 Eq, 722 ^mol) at 20 °C for 1 h, then added NaBH(OAc) ₃ (30.2 mg, 2 Eq, 481 ^mol) the mixture, and then the mixture was stirred at 25 °C for 16 h. LCMS showed 96.2% desired MS. The reaction was concentrated to give (S)-3-(5-(4- ((1-(4-((1R,2S)-6-hydroxy-2-(1-methyl-1H-pyrazol-3-yl)-1,2,3 ,4-tetrahydronaphthalen-1- yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindo lin-2-yl)piperidine-2,6-dione (59.6 mg, 78.2 ^mol, 32.5 %, 95.5% Purity) as a brown solid. LCMS: calc. for C ₄₃ H ₄₉ N ₇ O ₄ : 727.89, found: [M+H] ⁺ 728.2. HPLC: 95.517% purity at 220 nm. 11.01 - 10.87 (m, 1H), 9.17 - 9.04 (m, 1H), 8.16 - 8.13 (m, 0.446H), 7.55 - 7.47 (m, 1H), 7.39 (d, J = 2.0 Hz, 1H), 7.14 -7.05 (m, 1H), 6.69 - 6.55 (m, 3H), 6.50 - 6.38 (m, 3H), 5.53 - 5.45 (m, 1H), 5.11 - 5.00 (m, 1H), 4.37 - 4.30 (m, 1H), 4.26 - 4.17 (m, 2H), 3.76 - 3.72 (m, 3H),3.53 (br d, J = 5.4 Hz, 3H), 3.29 - 3.18 (m, 4H), 2.96 - 2.85 (m, 3H), 2.70 - 2.52 (m, 8H), 2.47 - 2.24 (m, 4H), 2.01 - 1.89 (m, 2H), 1.86 - 1.62 (m, 3H), 1.18 (brd, J = 9.8 Hz, 2H) SFC: retention time, 3.129 min; Area, 95.074%; Stereochemistry at the ERBM core is arbitrarily assigned.

EXAMPLE 262. Preparation of (I-25) (S)-3-(5-(4-((1-(4-((1S,2R)-6-hydroxy-2-(1- methyl-1H-pyrazol-5-yl)-1,2,3,4-tetrahydronaphthalen-1-yl)ph enyl)piperidin-4- yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2, 6-dione Step 1: A mixture of (5S,6R)-5-(4-(4-(dimethoxymethyl)piperidin-1-yl)phenyl)-6-(1 -methyl-1H- pyrazol-5-yl)-5,6,7,8-tetrahydronaphthalen-2-ol (100 mg, 97% Wt, 1 Eq, 217 ^mol) in 10% H ₂ SO ₄ (1.5 mL) and THF (1.5 mL), then the mixture was stirred at 60 °C for 16 hour. The solvent was removed under vaccum. The residue was dissolved in water (20 mL) and washed by ethyl acetate (20 mL). The aqueous solution was added NaHCO ₃ to adjust pH=6. The combined organic layer was dried over Na ₂ SO ₄ , filtered and concentrated under vaccum to give 1-(4- ((1S,2R)-6-hydroxy-2-(1-methyl-1H-pyrazol-5-yl)-1,2,3,4-tetr ahydronaphthalen-1- yl)phenyl)piperidine-4-carbaldehyde (70 mg, 0.17 mmol, 80%) as a yellow oil. LC-MS (ESI+) m/z: 416.3 (M+H)+ Step 2: A mixture of 1-(4-((1S,2R)-6-hydroxy-2-(1-methyl-1H-pyrazol-5-yl)-1,2,3,4 - tetrahydronaphthalen-1-yl)phenyl)piperidine-4-carbaldehyde (70 mg, 1 Eq, 0.17 mmol), (R)-3- (1-oxo-5-(piperazin-1-yl)isoindolin-2-yl)piperidine-2,6-dion e, Tosylic acid (110 mg, 1.3 Eq, 0.22 mmol) and Sodium acetate (69 mg, 5 Eq, 0.84 mmol) and Acetic acid (30 mg, 29 ^L, 3 Eq, 0.50 mmol) in DCM (2 mL) and MeOH (2 mL) at 25 °C for 1 hour, then Sodium triacetoxyborohydride (71 mg, 2 Eq, 0.34 mmol) was added to the mixture and was stirred at 25 °C for 16 hour. The reaction was treated with H2O (20 mL), extracted with EtOAc (20 mL). The combined extracts was dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to dryness in vacuo to give a residue. The residue was purified by prep.HPLC (column: Welch Xtimate C18 150*30mm*5um; mobile phase: [water (FA)-ACN]; B%: 10%-40%, 7min). The aqueous phase was lyophilized to dryness to give (S)-3-(5-(4-((1-(4-((1S,2R)-6-hydroxy-2-(1-methyl-1H- pyrazol-5-yl)-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piper idin-4-yl)methyl)piperazin-1-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione (58.9 mg, 62.4 ^mol, 52% yield, 97.521% purity) as a white solid. LC-MS (ESI+) m/z: 728.4 (M+H)+ HPLC: 97.521%, purity at 220 nm. SFC: retention time, 3.311 min; Area, 87.483%; Stereochemistry at the ERBM core is arbitrarily assigned. ¹ H NMR (400 MHz, DMSO-d ₆ ) į = 11.01 - 10.89 (m, 1H), 9.25 - 9.02 (m, 1H), 8.20 - 8.14 (m, 0.279H), 7.58 - 7.47 (m, 1H), 7.13 - 7.01 (m, 3H), 6.69 - 6.66 (m, 1H), 6.63 - 6.55 (m, 3H), 6.52 - 6.48 (m, 1H), 6.33 - 6.22 (m, 2H), 5.29 - 5.24 (m, 1H), 5.09 - 5.01 (m, 1H), 4.37 - 4.29 (m, 1H), 4.28 - 4.17 (m, 2H), 3.91 - 3.84 (m, 3H), 3.58 - 3.49 (m, 2H), 3.29 (br d, J = 3.7 Hz, 13H), 2.98 - 2.84 (m, 3H), 2.27 - 2.16 (m, 2H), 2.05 - 1.92 (m, 2H), 1.81 - 1.59 (m, 4H), 1.27 - 1.07 (m, 2H)

EXAMPLE 263. Preparation of (I-24) (S)-3-(5-(4-((1-(4-((1R,2S)-6-hydroxy-2-(1- methyl-1H-pyrazol-5-yl)-1,2,3,4-tetrahydronaphthalen-1-yl)ph enyl)piperidin-4- yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2, 6-dione Step 1: A mixture of 1-(4-(6-(benzyloxy)-2-bromo-3,4-dihydronaphthalen-1-yl)pheny l)-4- (dimethoxymethyl)piperidine (1.5 g, 1 Eq, 2.7 mmol), 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-1H-pyrazole (0.63 g, 1.1 Eq, 3.0 mmol), Na2CO3 (0.87 g, 3 Eq, 8.2 mmol) and [1,1'-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (0.22 g, 0.1 Eq, 0.27 mmol) in Dioxane (16 mL) and H ₂ O (4.0 mL) at r.t.. N ₂ was bubbled into the mixture for 5 min. The reaction mixture was heated at 100 °C for 16 hour. Then the reaction was cooled to room temperature. The mixture was treated with H ₂ O (50 mL), extracted with EtOA (50 L) Th bi d t t d i d h d N SO filt d d concentrated to dryness in vacuo to give a residue. The residue was subjected to column chromatography over silica gel (gradient elution: 0~20% ethyl acetate in petroleum ether). The pure fractions were collected and concentrated to dryness in vacuo to give 1-(4-(6-(benzyloxy)- 2-(1-methyl-1H-pyrazol-5-yl)-3,4-dihydronaphthalen-1-yl)phen yl)-4- (dimethoxymethyl)piperidine (600 mg, 1.0 mmol, 38%, 96% Purity) as a white solid. LC-MS (ESI ⁺ ) m/z: 550.3 (M+H) ⁺ . Step 2: A mixture of 1-(4-(6-(benzyloxy)-2-(1-methyl-1H-pyrazol-5-yl)-3,4-dihydro naphthalen- 1-yl)phenyl)-4-(dimethoxymethyl)piperidine (600 mg, 96% Wt, 1 Eq, 1.05 mmol), H ₂ (2.12 mg, 1 Eq, 1.05 mmol), Pd/C (600 mg, 10% Wt, 0.538 Eq, 564 ^mol) in MeOH (1.5 mL), THF (1.5 mL) was degassed and purged with H ₂ for 3 times and then the mixture was stirred at 50 psi, 50 °C for 12 hour under H ₂ atmosphere. The reaction was filtered and concentrated to dryness in vacuo to give a white solid. The white solid was subjected by SFC: Column: DAICEL CHIRALCEL OD (250 mm *30 mm,10 um); Mobile phase: A: Supercritical CO ₂ , B: MeOH (0.1% NH ₃ H ₂ O), A:B = 60:40 at 80 mL/min; The aqueous phase was lyophilized to dryness to give (5R,6S)-5-(4-(4-(dimethoxymethyl)piperidin-1-yl)phenyl)-6-(1 -methyl-1H-pyrazol-5-yl)- 5,6,7,8-tetrahydronaphthalen-2-ol (130 mg, 282 ^mol, 26.9%, 100% Purity) and (5S,6R)-5-(4- (4-(dimethoxymethyl)piperidin-1-yl)phenyl)-6-(1-methyl-1H-py razol-5-yl)-5,6,7,8- tetrahydronaphthalen-2-ol (130 mg, 0.27 mmol, 26%, 97% Purity) as a yellow oil. LC-MS (ESI ⁺ ) m/z: 462.2 (M+H) ⁺ . Step 3: A mixture of (5R,6S)-5-(4-(4-(dimethoxymethyl)piperidin-1-yl)phenyl)-6-(1 -methyl-1H- pyrazol-5-yl)-5,6,7,8-tetrahydronaphthalen-2-ol (100 mg, 100% Wt, 1 Eq, 217 ^mol) in 10% H ₂ SO ₄ (1.5 mL) and THF (1.5 mL), then the mixture was stirred at 60 °C for 16 hour. The solvent was removed under vaccum. The residue was dissolved in water (20 mL) and washed by ethyl acetate (20 mL). The aqueous solution was added NaHCO ₃ to adjust pH=6. The combined organic layer was dried over Na ₂ SO ₄ , filtered and concentrated under vaccum to give 1-(4- ((1R,2S)-6-hydroxy-2-(1-methyl-1H-pyrazol-5-yl)-1,2,3,4-tetr ahydronaphthalen-1- yl)phenyl)piperidine-4-carbaldehyde (70 mg, 0.17 mmol, 78%) as a yellow oil. LC-MS (ESI+) m/z: 416.2 (M+H)+ Step 4: A mixture of 1-(4-((1R,2S)-6-hydroxy-2-(1-methyl-1H-pyrazol-5-yl)-1,2,3,4 - tetrahydronaphthalen-1-yl)phenyl)piperidine-4-carbaldehyde (70 mg, 1 Eq, 0.17 mmol), (R)-3- 0.22 mmol) and Sodium acetate (69 mg, 5 Eq, 0.84 mmol) and Acetic acid (30 mg, 29 ^L, 3 Eq, 0.5 mmol) in DCM (2 mL) and MeOH (2 mL) at 25 °C for 1 hour, then Sodium triacetoxyborohydride (71 mg, 2 Eq, 0.34 mmol) was added to the mixture. Then the reaction was stirred at 25 °C for 16 hour. The reaction was treated with H ₂ O (20 mL), extracted with EtOAc (20 mL). The combined extracts was dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to dryness in vacuo to give a residue. The residue was purified by prep.HPLC (column: Welch Xtimate C18150*30mm*5um; mobile phase: [water (FA)-ACN]; B%: 9%- 39%, 7min). The aqueous phase was lyophilized to dryness to give (S)-3-(5-(4-((1-(4-((1R,2S)- 6-hydroxy-2-(1-methyl-1H-pyrazol-5-yl)-1,2,3,4-tetrahydronap hthalen-1-yl)phenyl)piperidin-4- yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2, 6-dione (46.6 mg, 62.4 ^mol, 41% yield, 97.536% purity) as a white solid. LC-MS (ESI+) m/z: 728.4 (M+H)+ HPLC: 97.536%, purity at 220 nm. SFC: retention time, 3.287 min; Area, 91.314%; Stereochemistry at the ERBM core is arbitrarily assigned. ¹ H NMR (400 MHz, DMSO-d6) į = 10.99 - 10.92 (m, 1H), 9.41 - 8.86 (m, 1H), 8.29 - 8.02 (m, 0.290H), 7.58 - 7.48 (m, 1H), 7.13 - 6.99 (m, 3H), 6.70 - 6.64 (m, 1H), 6.62 - 6.55 (m, 3H), 6.53 - 6.47 (m, 1H), 6.32 - 6.24 (m, 2H), 5.28 - 5.24 (m, 1H), 5.11 - 4.99 (m, 1H), 4.39 - 4.28 (m, 1H), 4.28 - 4.17 (m, 2H), 3.90 - 3.84 (m, 3H), 3.59 - 3.48 (m, 3H), 3.43 - 3.22 (m, 12H), 2.97 - 2.84 (m, 3H), 2.25 - 2.15 (m, 2H), 2.07 - 1.91 (m, 2H), 1.82 - 1.58 (m, 4H), 1.25 - 1.10 (m, 2H).

EXAMPLE 264. Preparation of (I-413) (3S)-3-[5-[4-[[1-[4-[(1S,2R)-6-hydroxy-2-indan- 5-yl-tetralin-1-yl]phenyl]-4-piperidyl]methyl]piperazin-1-yl ]-1-oxo-isoindolin-2- yl]piperidine-2,6-dione Step 1: To a solution of (1S,2R)-1-[4-[4-(dimethoxymethyl)-1-piperidyl]phenyl]-2-inda n-5-yl- tetralin-6-ol (70.00 mg, 140.66 ^mol, 100% purity, 1 eq) in DCM (4 mL) was added TFA (1.54 g, 13.51 mmol, 1 mL, 96.0 eq) .The mixture was stirred at 25 °C for 2 h. The reaction mixture was quenched by addition of saturation solution of NaHCO ₃ (15 mL), extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine (10 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to yield 1-[4-[(1S,2R)-6-hydroxy-2-indan-5-yl- tetralin-1-yl]phenyl]piperidine-4-carbaldehyde (50 mg, 99.65 ^mol, 70.8% yield, 90.0% purity) as a yellow solid which was used in the next step without further purification.LC-MS (ESI ⁺ ) m/z 452.4 [M+H] ⁺ . Step 2: To a solution of 1-[4-[(1S,2R)-6-hydroxy-2-indan-5-yl-tetralin-1-yl]phenyl]pi peridine-4- carbaldehyde (50 mg, 99.6 ^mol, 90% purity, 1 eq) and (3S)-3-(1-oxo-5-piperazin-1-yl- isoindolin-2-yl)piperidine-2,6-dione (49.8 mg, 99.65 ^mol, 1 eq, TsOH) in DCM (2 mL) and MeOH (2 mL) after stirred 30 min was added sodium;cyanoboranuide (31.3 mg, 498.2 ^mol, 5 eq) .The mixture was stirred at 25 °C for 12 h. The residue was filtered and purified by preparative HPLC (column: Boston Green ODS 150 * 30 mm * 5 um; mobile phase: [water(FA) - ACN]; B%: 24% - 54%,12 min), followed by lyophilization to yield (3S)-3-[5-[4-[[1-[4- [(1S,2R)-6-hydroxy-2-indan-5-yl-tetralin-1-yl]phenyl]-4-pipe ridyl]methyl]piperazin-1-yl]-1-oxo- isoindolin-2-yl]piperidine-2,6-dione (25.3 mg, 32.69 ^mol, 32.81% yield, 100% purity) as a white solid. LC-MS (ESI ⁺ ) m/z 764.3 [M+H] ⁺ . HPLC: 100% purity at 220 nm. ¹ H NMR (400MHz, CD ₃ OD) į 8.28 (s, 1H), 7.66 (d, J=9.2 Hz, 1H), 7.15 - 7.08 (m, 2H), 6.95 (d, J=8.2 Hz, 1H), 6.71 - 6.62 (m, 4H), 6.60 - 6.55 (m, 2H), 6.51 (dd, J=2.4, 8.3 Hz, 1H), 6.32 (d, J=8.6 Hz, 2H), 5.10 (dd, J=5.2, 13.4 Hz, 1H), 4.64 (s, 4H), 4.48 - 4.34 (m, 2H), 4.14 (d, J=5.2 Hz, 1H), 3.57 - 3.46 (m, 5H), 3.25 (s, 2H), 2.97 (d, J=11.2 Hz, 4H), 2.87 - 2.76 (m, 4H), 2.69 - 2.60 (m, 4H), 2.52 - 2.41 (m, 1H), 2.23 - 2.10 (m, 2H), 2.01 (quin, J=7.2 Hz, 2H), 1.88 (d, J=12.8 Hz, 3H), 1.72 (d, J=8.2 Hz, 1H), 1.39 (d, J=11.2 Hz, 2H). Stereochemistry at the ERBM core is arbitrarily assigned.

EXAMPLE 265. Preparation of (I-412) (3S)-3-[5-[4-[[1-[4-[(1R,2S)-6-hydroxy-2-indan- 5-yl-tetralin-1-yl]phenyl]-4-piperidyl]methyl]piperazin-1-yl ]-1-oxo-isoindolin-2- yl]piperidine-2,6-dione Step 1: To a solution of 5-bromoindane (700 mg, 3.5 mmol, 1 eq) and bis(pinacolato)diboron (1.8 g, 7.10 mmol, 2 eq) in DMF (30 mL) was added Pd(PPh ₃ ) ₂ Cl ₂ (747.9 mg, 1.07 mmol, 0.3 eq) and KOAc (1.7 g, 17.7 mmol, 5 eq). The mixture was stirred under N2 at 100 °C for 12 h. The reaction mixture was quenched by addition of water (30 mL), extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (20 mL x 3), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (from pure PE to PE/EtOAc = 5/1, TLC: PE/EtOAc = 5/1, Rf = 0.71) to yield 2-indan-5-yl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (400 mg, 1.39 mmol, 39.2% yield, 85% purity) as colourless oil. Step 2: To a solution of 1-[4-(6-benzyloxy-2-bromo-3,4-dihydronaphthalen-1-yl)phenyl] -4- (dimethoxymethyl)piperidine (1.5 g, 2.71 mmol, 99% purity, 1 eq) and 2-indan-5-yl-4,4,5,5- tetramethyl-1,3,2-dioxaborolane (660.96 mg, 2.71 mmol, 1 eq) in dioxane (20 mL) and H ₂ O (5 mL) was added Pd(dppf)Cl ₂ (198.1 mg, 270.7 ^mol, 0.1 eq) and Na ₂ CO ₃ (573.90 mg, 5.4 mmol, 2 eq) .The mixture was stirred under N ₂ at 100 °C for 12 h. The reaction mixture was quenched by addition of water (50 mL), extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (10 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (from pure PE to PE/EtOAc = 5/1, TLC: PE/EtOAc = 5/1, R _f = 0.54) to yield 1-[4-(6-benzyloxy-2- indan-5-yl-3,4-dihydronaphthalen-1-yl)phenyl]-4-(dimethoxyme thyl)piperidine (1.4 g, 1.5 mmol, 55.6% yield, 63% purity) as yellow oil. LC-MS (ESI ⁺ ) m/z 586.8[M+H] ⁺ . Step 3: To a solution of 1-[4-(6-benzyloxy-2-indan-5-yl-3,4-dihydronaphthalen-1-yl)ph enyl]-4- (dimethoxymethyl)piperidine (1.3 g, 1.44 mmol, 65% purity, 1 eq) in MeOH (6 mL) and THF (9 mL) was added Pd/C (500 mg, 10% purity). The mixture was stirred under H ₂ (15Psi) at 25 °C for 1 h. The residue was filtered and purified by preparative HPLC (column: Welch Xtimate C18 150 * 25 mm * 5 um; mobile phase: [water (NH ₄ HCO ₃ ) - ACN]; B%: 70%-95%,11 min), followed by lyophilization to yield a residue. The residue was purified by preparative SFC (column: DAICEL CHIRALCEL OD-H (250 mm * 30 mm, 5 um); mobile phase: [0.1% NH ₃ H ₂ O MEOH]; B%: 50%-50%, min), followed by lyophilization to yield (1R,2S)-1-[4-[4- (dimethoxymethyl)-1-piperidyl]phenyl]-2-indan-5-yl-tetralin- 6-ol (150 mg, 301.41 ^mol, 30.00% yield, 100% purity) as a white solid. LC-MS (ESI ⁺ ) m/z 498.3 [M+H] ⁺ . Step 4: To a solution of (1R,2S)-1-[4-[4-(dimethoxymethyl)-1-piperidyl]phenyl]-2-inda n-5-yl- tetralin-6-ol (60 mg, 120.56 ^mol, 100% purity, 1 eq) in DCM (4 mL) was added TFA (1.32 g, 11.5 mmol, 857.12 ^L, 96.0 eq) .The mixture was stirred at 25 °C for 2 h. The reaction mixture was quenched by addition of saturation solution of NaHCO3 (15 mL), extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, tetralin-1-yl]phenyl]piperidine-4-carbaldehyde (50 mg, 99.6 ^mol, 82.6% yield, 90% purity) as a yellow solid which was used in the next step without further purification.LC-MS (ESI ⁺ ) m/z 452.4 [M+H] ⁺ . Step 5: To a solution of 1-[4-[(1R,2S)-6-hydroxy-2-indan-5-yl-tetralin-1-yl]phenyl]pi peridine-4- carbaldehyde (50 mg, 99.65 ^mol, 90.0% purity, 1 eq) and (3S)-3-(1-oxo-5-piperazin-1-yl- isoindolin-2-yl)piperidine-2,6-dione (49.8 mg, 99.65 ^mol, 1 eq, TsOH) in DCM (2 mL) and MeOH (2 mL) after stirred 30 min was added sodium;cyanoboranuide (31.31 mg, 498.23 ^mol, 5 eq) .The mixture was stirred at 25 °C for 12 h. The residue was filtered and purified by preparative HPLC (column: Boston Green ODS 150 * 30 mm * 5 um; mobile phase: [water(FA) – CAN]; B%: 24% - 54%,12 min), followed by lyophilization to yield (3S)-3-[5-[4-[[1-[4- [(1R,2S)-6-hydroxy-2-indan-5-yl-tetralin-1-yl]phenyl]-4-pipe ridyl]methyl]piperazin-1-yl]-1-oxo- isoindolin-2-yl]piperidine-2,6-dione (25.4 mg, 32.8 ^mol, 32.9% yield, 100.0% purity) as a white solid. LC-MS (ESI ⁺ ) m/z 764.3 [M+H] ⁺ . LCMS: calc. for C48H53N5O4: 763.4, found: [M+H] ⁺ 764.3. HPLC: 100% purity at 220 nm. ¹ H NMR (400MHz, CD ₃ OD) į 8.24 (s, 1H), 7.67 (d, J=9.2 Hz, 1H), 7.15 - 7.09 (m, 2H), 6.96 (d, J=8.2 Hz, 1H), 6.71 - 6.63 (m, 4H), 6.60 - 6.55 (m, 2H), 6.51 (dd, J=2.2, 8.3 Hz, 1H), 6.33 (d, J=8.8 Hz, 2H), 5.10 (br dd, J=5.2, 13.4 Hz, 1H), 4.62 (s, 4H), 4.49 - 4.34 (m, 2H), 4.15 (br d, J=4.8 Hz, 1H), 3.59 - 3.50 (m, 5H), 3.25 (d, J=4.6 Hz, 2H), 3.06 - 2.99 (m, 4H), 2.88 - 2.77 (m, 4H), 2.75 - 2.64 (m, 4H), 2.46 (dq, J=4.6, 13.2 Hz, 1H), 2.24 - 2.11 (m, 2H), 2.07 - 1.99 (m, 2H), 1.88 (d, J=10.4 Hz, 3H), 1.72 (br d, J=8.0 Hz, 1H), 1.40 (q, J=11.2 Hz, 2H). Stereochemistry at the ERBM core is arbitrarily assigned.

EXAMPLE 266. Preparation of (I-411) (3S)-3-[5-[4-[[1-[4-[(1S,2R)-6-hydroxy-2-indan- 4-yl-tetralin-1-yl]phenyl]-4-piperidyl]methyl]piperazin-1-yl ]-1-oxo-isoindolin-2- yl]piperidine-2,6-dione Step 1: To a solution of (1S,2R)-1-[4-[4-(dimethoxymethyl)-1-piperidyl]phenyl]-2-inda n-4-yl- tetralin-6-ol (30 mg, 60.28 umol, 1 eq) in HCl/dioxane (5 mL) .The mixture was stirred at 25 °C for 12 hr .The reaction mixture was concentrated under reduced pressure to remove HCl/dioxane, The crude product was used into the next step without further purification, Compound 1-[4-[(1S,2R)-6-hydroxy-2-indan-4-yl-tetralin-1-yl]phenyl]pi peridine-4- carbaldehyde (30 mg, crude) was obtained as a white solid, LC-MS (ESI ⁺ ) m/z: 452.4 (M+H) ⁺ Step 2: To a solution of 1-[4-[(1S,2R)-6-hydroxy-2-indan-4-yl-tetralin-1-yl]phenyl]pi peridine-4- carbaldehyde (30 mg, 66.43 umol, 1 eq) and (3S)-3-(1-oxo-5-piperazin-1-yl-isoindolin-2- yl)piperidine-2,6-dione (33 mg, 99.65 umol, 1.5 eq) in DCM (2 mL) and MeOH (2 mL) was added acetic acid (18 mg, 66.43 umol, 17.47 uL, 1 eq) , sodium acetate (16 mg, 199.3 umol, 3 eq). The mixture was stirred at 25 °C for 1 hr, and then was added NaBH(OAc) ₃ (21 mg, 99.65 umol, 1.5 eq). The mixture was stirred at 25 °C for 15 hr .The reaction mixture was concentrated under reduced pressure to remove DCM and MeOH. The residue was purified by prep-HPLC (column: Welch Ultimate C18150*25mm*5um; mobile phase: [water (FA)-ACN]; B%: 26%- 56%, 10min). Compound (3S)-3-[5-[4-[[1-[4-[(1S,2R)-6-hydroxy-2-indan-4-yl-tetralin -1- yl]phenyl]-4-piperidyl]methyl]piperazin-1-yl]-1-oxo-isoindol in-2-yl]piperidine-2,6-dione (14 mg, 17.46 umol, 26.28% yield, 95.25% purity) was obtained as a white solid. LC-MS (ESI+) m/z: 7642 (M+H) ⁺ HPLC: 94.910% purity at 220 nm SFC: R _t : 3.058 min; Area, 94.997 %; Stereochemistry at the ERBM core is arbitrarily assigned. NMR (400 MHz, CHLOROFORM-d) į = 7.95 - 7.88 (m, 1H), 7.78 - 7.70 (m, 1H), 7.07 - 6.95 (m, 2H), 6.90 - 6.77 (m, 3H), 6.74 - 6.70 (m, 1H), 6.63 -6.53 (m, 3H), 6.29 - 6.23 (m, 2H), 6.18 - 6.11 (m, 1H), 5.20 (dd, J = 4.9, 13.1 Hz, 1H), 4.45 - 4.40 (m, 1H), 4.30 - 4.21 (m, 2H), 3.61 - 3.51 (m, 2H), 3.44 -3.32 (m, 4H), 3.06 - 2.82 (m, 9H), 2.68 - 2.56 (m, 5H), 2.34 (br dd, J = 5.0, 12.4 Hz, 2H), 2.26 - 1.96 (m, 6H), 1.94 - 1.81 (m, 3H), 1.42 - 1.31 (m, 3H). EXAMPLE 267. Preparation of (I-410) (3S)-3-[5-[4-[[1-[4-[(1R,2S)-6-hydroxy-2-indan- 4-yl-tetralin-1-yl]phenyl]-4-piperidyl]methyl]piperazin-1-yl ]-1-oxo-isoindolin-2- yl]piperidine-2,6-dione _{_} Step 1: A mixture of 1-[4-(6-benzyloxy-2-bromo-3,4-dihydronaphthalen-1-yl)phenyl] -4- (dimethoxymethyl)piperidine (500 mg, 911.56 umol, 1 eq) , 2-indan-4-yl-4,4,5,5-tetramethyl- 1,3,2-dioxaborolane (289 mg, 1.19 mmol, 1.3 eq) , Pd(dppf)Cl ₂ ^. DCM (372 mg, 455.78 umol, 0.5 eq) , Na ₂ CO ₃ (290 mg, 2.73 mmol, 3 eq) in dioxane (4 mL) and H ₂ O (1 mL) was degassed and purged with N ₂ for 3 times, and then the mixture was stirred at 100 °C for 16 hr under N ₂ atmosphere. The reaction mixture was concentrated under reduced pressure to remove dioxane and H ₂ O, The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 0~30% Ethyl acetate/Petroleum ether @ 40 mL/min). Compound 1-[4-(6-benzyloxy-2-indan-4-yl-3,4-dihydronaphthalen-1-yl)ph enyl]-4- (dimethoxymethyl)piperidine (300 mg, 394.7 umol, 43.3% yield, 77.1% purity) was obtained as a yellow solid. LC-MS (ESI ⁺ ) m/z: 586.3 (M+H) ⁺ Step 2: A mixture of 1-[4-(6-benzyloxy-2-indan-4-yl-3,4-dihydronaphthalen-1-yl)ph enyl]-4- (dimethoxymethyl)piperidine (300.00 mg, 512.14 umol, 1 eq) , Pd/C (200 mg, 2.56 mmol, 10% purity, 5 eq) in MeOH (2 mL) and THF (2 mL) was degassed and purged with H2 for 3 times, and then the mixture was stirred at 50 °C for 12 hr under H2 atmosphere. The reation mixture was filtered and the filter cake was rinsed with 50 mL of MeOH, The filter was collected, dried in vacuo to give a white solid, The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 0~30% Ethyl acetate/Petroleum ether @ 40 mL/min) to give desired compound as a colorless oil, which was further separated by SFC (column: Welch Ultimate C18150*25mm*5um;mobile phase: [water(FA)-ACN];B%: 40%- 70%,10min ) and (column: Welch Ultimate C18150*25mm*5um;mobile phase: [water(FA)- ACN];B%:38%-68%,10min). Compound (1R,2S)-1-[4-[4-(dimethoxymethyl)-1-piperidyl]phenyl]-2-inda n-4-yl-tetralin-6-ol (73 mg, 140.9 umol, 27.5% yield, 96.0% purity) was obtained as a white solid. LC-MS (ESI+) m/z: 498.5 (M+H) ⁺ HPLC: 95.454 % purity at 220 nm SFC: Rt: 1.760 min; Area, 100 %; NMR (400 MHz, CHLOROFORM-d) į = 7.06 - 7.02 (m, 1H), 6.87 - 6.79 (m, 2H), 6.73 - 6.69 (m, 1H), 6.62 - 6.54 (m, 3H), 6.29 - 6.21 (m, 2H), 6.17 - 6.12 (m, 1H), 4.25 - 4.19 (m, 1H), 4.09 - 4.02 (m, 1H), 3.63 (s, 2H), 3.40 - 3.34 (m, 6H), 3.06 - 2.79 (m, 6H), 2.62 - 2.46 (m, 2H), 2.24 - 2.00 (m, 3H), 1.84 -1.73 (m, 4H), 1.49 - 1.28 (m, 4H) Compound (1S,2R)-1-[4-[4-(dimethoxymethyl)-1-piperidyl]phenyl]-2-inda n-4-yl-tetralin-6-ol (80 mg, 112.09 umol, 21.89% yield, 69.730% purity) was obtained as a white solid. LC-MS (ESI+) m/z: 498.5 (M+H) ⁺ HPLC: 97.288 % purity at 220 nm SFC: R _t : 2.045 min; Area, 99.894 %; method: OJ-3-MeOH(DEA)-5-40-3mL-35T. NMR (400 MHz, CHLOROFORM-d) į = 7.07 - 7.01 (m, 1H), 6.87 - 6.78 (m, 2H), 6.73 - 6.69 (m, 1H), 6.64 - 6.54 (m, 3H), 6.29 - 6.22 (m, 2H), 6.17 -6.12 (m, 1H), 4.26 - 4.21 (m, 1H), 4.09 - 4.04 (m, 1H), 3.61 - 3.51 (m, 2H), 3.38 - 3.34 (m, 6H), 2.85 (br d, J = 6.9 Hz, 6H), 2.65 - 2.46 (m, 2H), 2.23 - 2.01(m, 3H), 1.86 - 1.68 (m, 6H), 1.49 - 1.25 (m, 5H). Step 3: To a solution of (1R,2S)-1-[4-[4-(dimethoxymethyl)-1-piperidyl]phenyl]-2-inda n-4-yl- tetralin-6-ol (30 mg, 60.28 umol, 1 eq) in HCl/dioxane (5 mL) .The mixture was stirred at 25 °C for 16 hr .The reaction mixture was concentrated under reduced pressure to remove HCl/dioxane , The crude product was used into the next step without further purification, Compound 1-[4-[(1R,2S)-6-hydroxy-2-indan-4-yl-tetralin-1-yl]phenyl]pi peridine-4- carbaldehyde (30 mg, crude) was obtained as a white solid. LC-MS (ESI ⁺ ) m/z: 452.5 (M+H) ⁺ . Step 4: To a solution of 1-[4-[(1R,2S)-6-hydroxy-2-indan-4-yl-tetralin-1-yl]phenyl]pi peridine-4- carbaldehyde (30 mg, 66.43 umol, 1 eq) and (3S)-3-(1-oxo-5-piperazin-1-yl-isoindolin-2- yl)piperidine-2,6-dione (33 mg, 99.65 umol, 1.5 eq) in DCM (2 mL) and MeOH (2 mL) was added acetic acid (18 mg, 66.43 umol, 17.47 uL, 1 eq) and sodium acetate (16, 199.29 umol, 3 eq),The mixture was stirred at 25°C for 1 hr .and then was added NaBH(OAc) ₃ (21 mg, 99.65 umol, 1.5 eq) , The mixture was stirred at 25 °C for 15 hr .The reaction mixture was concentrated under reduced pressure to remove DCM and MeOH. The residue was purified by prep-HPLC 24%-54%, 8min). Compound (3S)-3-[5-[4-[[1-[4-[(1R,2S)-6-hydroxy-2-indan-4-yl-tetralin -1- yl]phenyl]-4-piperidyl]methyl]piperazin-1-yl]-1-oxo-isoindol in-2-yl]piperidine-2,6-dione (7.5 mg, 9.66 umol, 14.54% yield, 98.42% purity) was obtained as a white solid. LC-MS (ESI+) m/z: 764.2 (M+H) ⁺ HPLC: 98.375% purity at 220 nm SFC: R _t : 1.297 min; Area, 96.154 %; Stereochemistry at the ERBM core is arbitrarily assigned NMR (400 MHz, CHLOROFORM-d) į = 7.86 - 7.80 (m, 1H), 7.69 - 7.63 (m, 1H), 6.98 - 6.89 (m, 2H), 6.82 - 6.71 (m, 3H), 6.63 (d, J = 2.4 Hz, 1H), 6.55- 6.46 (m, 3H), 6.21 - 6.15 (m, 2H), 6.09 - 6.04 (m, 1H), 5.16 - 5.09 (m, 1H), 4.37 - 4.30 (m, 1H), 4.23 - 4.13 (m, 2H), 3.52 - 3.44 (m, 2H), 3.36 - 3.25 (m, 4H), 2.97 - 2.71 (m, 9H), 2.60 - 2.47 (m, 5H), 2.25 (br dd, J = 5.1, 12.6 Hz, 2H), 2.17 - 1.91 (m, 6H), 1.82 - 1.75 (m, 3H), 1.36 - 1.24 (m, 3H). EXAMPLE 268. Preparation of (I-409) (S)-3-(5-(4-((4-(4-((1S,2S)-6-hydroxy-2-phenyl- 1,2,3,4-tetrahydronaphthalen-1-yl)-1H-pyrazol-1-yl)piperidin -1-yl)methyl)piperidin-1-yl)- 1-oxoisoindolin-2-yl)piperidine-2,6-dione and (I-48) (R)-3-(5-(4-((4-(4-((1S,2S)-6-hydroxy-2-

phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)-1H-pyrazol-1-yl )piperidin-1- yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2, 6-dione Step 1: A mixture of 4-(dimethoxymethyl)piperidine (2.0 g, 1 Eq, 9.4 mmol), 5- bromoisobenzofuran-1(3H)-one (1.5 g, 1 Eq, 9.4 mmol), Ruphos-Pd-G3 (0.55 g, 0.07 Eq, 0.66 mmol) and Cs ₂ CO ₃ (6.1 g, 1.5 mL, 2 Eq, 19 mmol) in 1,4-Dioxane (40 mL) .The mixture was stirred at 100 °C for 16 hour . The mixture was concentrated in reduced pressure. The residue was poured into water (40 mL). The aqueous phase was extracted with ethyl acetate (80 mL*3). The combined organic phase was washed with brine (20 mL), dried with Na ₂ SO ₄ , filtered and concentrated in vacuum The residue was purified by silica gel chromatography (Petroleum ether/Ethyl acetate=10/1 to 3/1) .LCMS indicated no desired compound.5-(4- (dimethoxymethyl)piperidin-1-yl)isobenzofuran-1(3H)-one (1.5g, 5.1 ^mol, 55%) was obtained as oil. LC-MS (ESI+) m/z: 292.2 (M+H)+. Step 2: To a solution of 5-(4-(dimethoxymethyl)piperidin-1-yl)isobenzofuran-1(3H)-one (1.81 g, 1 Eq, 6.21 mmol), NaOH (1.8 g, 7.1 Eq, 44.1 mmol) in MeOH (9.05 mL) ,H ₂ O(9.05 mL) and THF (18 mL) .The mixture was stirred at 25 °C for 1 hour. LCMS showed that the starting material was consumed and the desired product was detected. Concentrated aqueous HCl was added to the mixture until a precipitate formed, which was collected by filtration to give the 4-(4-(dimethoxymethyl)piperidin-1-yl)-2-(hydroxymethyl)benzo ic acid (1.5 g, 4.8 mmol, 78 %). Step 3: To a solution of 4-(4-(dimethoxymethyl)piperidin-1-yl)-2-(hydroxymethyl)benzo ic acid (2.0 g, 1.0 Eq, 6.5 mmol) and TMSCH ₂ N ₂ (2.8 g, 12 mL, 2 molar, 3.8 Eq, 25 mmol) in MeOH (12.5 mL) and EtOAc (12.5 mL) .The mixture was stirred at -10 °C for 0.25 hour. LCMS showed that the starting material was consumed and the desired product was detected. The residue was poured into water (25 mL). The aqueous phase was extracted with EtOAc (50 mL*3). The combined organic phase was washed with brine (10 mL*3), dried with anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuum to give a residue. The reaction mixture was filtered under reduced pressure to give a compound. methyl 4-(4- (dimethoxymethyl)piperidin-1-yl)-2-(hydroxymethyl)benzoate (1.8 g, 5.6 mmol, 86 %) was obtained as a solid. LC-MS (ESI+) m/z: 324.2(M+H)+. Step 4: A mixture of methyl 4-(4-(dimethoxymethyl)piperidin-1-yl)-2-(hydroxymethyl)benzo ate (765.0 mg, 1 Eq, 2.366 mmol), CBr ₄ (1.177 g, 372 ^L, 1.5 Eq, 3.548 mmol) and PPh3 (930.7 mg, 792.1 ^L, 1.5 Eq, 3.548 mmol) in THF (9 mL) . The mixture was stirred at 25 °C for 1 hour. LCMS showed that the starting material was consumed and the desired product was detected. The reaction mixture was filtered under reduced pressure to give a residue. The residue was poured into H ₂ O (10 mL). The aqueous phase was extracted with ethyl acetate (20 mL*3). The combined organic phase was washed with brine (10 mL*3), dried with anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuum. The residue was purified by silica gel chromatography (column height: 250 mm, diameter: 100 mm, 100-200 mesh silica gel, Petroleum ether/Ethyl acetate=3:1) to afford methyl 2-(bromomethyl)-4-(4-(dimethoxymethyl)piperidin-1-yl)benzoat e (603 mg, 1.56 mmol, 66.0 %) as white solid. LC-MS (ESI+) m/z: 387.9(M+H)+. Step 5: A mixture of (S)-3-aminopiperidine-2,6-dione hydrochloride (144.7 mg, 1.2 Eq, 879.1 ^mol), methyl 2-(bromomethyl)-4-(4-(dimethoxymethyl)piperidin-1-yl)benzoat e (283 mg, 1 Eq, 732.6 ^mol) and DIEA (30 mg, 41 ^L, 3 Eq, 0.23 mmol) in MeCN (8.5 mL) .The mixture was stirred at 75 °C for 48 hour . LCMS showed that the starting material was consumed and the desired product was detected. The residue was poured into water (10 mL). The aqueous phase was extracted with DCM (10 mL*3). The combined organic phase was washed with brine (5 mL*3), dried with anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuum. The residue was purified by silica gel chromatography (column height: 250 mm, diameter: 100 mm, 100-200 mesh silica gel, DCM/MeOH=10:1) to afford (S)-3-(5-(4-(dimethoxymethyl)piperidin-1-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione (200 mg, 498 ^mol, 68.0 %) as solid. LC-MS (ESI+) m/z: 402.3(M+H)+. Step 6: (S)-3-(5-(4-(dimethoxymethyl)piperidin-1-yl)-1-oxoisoindolin -2-yl)piperidine-2,6-dione (369 mg) was separated by chiral SFC (Column DAICEL CHIRALPAK AS(250mm*30mm,10um) Condition 0.1%NH3H2O ETOH Begin B 30% End B 30%) , 0.1%NH ₃ H ₂ O ETOH ) (S)-3-(5-(4-(dimethoxymethyl)piperidin-1-yl)-1-oxoisoindolin -2- yl)piperidine-2,6-dione (100 mg, 235.3 ^mol, 49%), (R)-3-(5-(4-(dimethoxymethyl)piperidin-1- yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (100 mg, 225.9 ^mol, 48 %). Step 7: (S)-1-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)pipe ridine-4-carbaldehyde: A mixture of (S)-3-(5-(4-(dimethoxymethyl)piperidin-1-yl)-1-oxoisoindolin -2-yl)piperidine-2,6- dione (85 mg, 1 Eq, 0.21 mmol), and TFA (0.37 g, 0.25 mL, 15 Eq, 3.2 mmol) in DCM (1 mL) in DCM (1 mL) and then the mixture was stirred at 25 °C for1 hour. LCMS showed that the starting material was consumed and the desired product was detected. The reaction mixture was filtered under reduced pressure to give a residue. (S)-1-(2-(2,6-dioxopiperidin-3-yl)-1- oxoisoindolin-5-yl)piperidine-4-carbaldehyde (50 mg, 0.14 mmol, 66 %) was obtained as solid. (R)-1-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)pipe ridine-4-carbaldehyde: A mixture of (R)-3-(5-(4-(dimethoxymethyl)piperidin-1-yl)-1-oxoisoindolin -2-yl)piperidine-2,6-dione (100 mg, 1 Eq, 272 ^mol), and TFA (1 g, 1 mL, 5e+1 Eq, 0.01 mol) (935 mg, 841 ^L, 20 Eq, 5.43 l) i DCM (4 L) d th th i t ti d t 25 °C f 1 h LCMS h d th t the starting material was consumed and the desired product was detected. The reaction mixture was filtered under reduced pressure to give a residue. (R)-1-(2-(2,6-dioxopiperidin-3-yl)-1- oxoisoindolin-5-yl)piperidine-4-carbaldehyde (90 mg, 0.25 mmol, 93 %) was obtained as solid. Step 8: A mixture of (5S,6S)-6-phenyl-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-5,6, 7,8- tetrahydronaphthalen-2-ol (89.3 mg, 1 Eq, 239 ^mol), (S)-1-(2-(2,6-dioxopiperidin-3-yl)-1- oxoisoindolin-5-yl)piperidine-4-carbaldehyde (85.0 mg, 1 Eq, 239 ^mol) and NaBH ₃ CN (105 mg, 7 Eq, 1.67 mmol) in DCM (1 mL) and MeOH (1 mL). The mixture was stirred at 25 °C for 1 hour . LCMS showed that the starting material was consumed and the desired product was detected. The reaction mixture was filtered under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Boston Green ODS 150*30mm*5um;mobile phase: [water(FA)-ACN];B%: 21%-41%,10min) to give (S)-3-(5-(4-((4-(4-((1S,2S)-6-hydroxy- 2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)-1H-pyrazol-1-yl) piperidin-1-yl)methyl)piperidin-1- yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (20 mg, 28 ^mol, 12 %) as white solid. LC-MS (ESI+) m/z: 713.4(M+H)+. HPLC: 98.097% purity at 220 nm. 10.95 (s, 1H), 9.11 (s, 1H), 7.49 (d, J = 8.8 Hz, 1H), 7.25 - 7.15 (m, 3H), 7.06 - 7.01 (m, 2H), 6.94 (br d, J = 7.2 Hz, 2H), 6.76 (d, J = 8.3 Hz, 1H), 6.56 (s, 1H), 6.52 - 6.45 (m, 2H), 6.33 (s, 1H), 5.07 - 5.01 (m, 1H), 4.34 - 4.28 (m, 1H), 4.22 - 4.16 (m, 1H), 4.12 (br d, J = 4.5 Hz, 1H), 3.89 - 3.87 (m, 1H), 3.25 - 3.16 (m, 2H), 2.96 - 2.75 (m, 8H), 2.04 - 1.90 (m, 3H), 1.82 - 1.70 (m, 8H), 1.26 - 1.08 (m, 3H), 0.05 - -0.25 (m, 4H). Step 9: A mixture of (5S,6S)-6-phenyl-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-5,6, 7,8- tetrahydronaphthalen-2-ol (105.1 mg, 1 Eq, 281.4 ^mol), (R)-1-(2-(2,6-dioxopiperidin-3-yl)-1- oxoisoindolin-5-yl)piperidine-4-carbaldehyde (100.0 mg, 1 Eq, 281.4 ^mol) and NaBH ₃ CN (123.8 mg, 7 Eq, 1.970 mmol) in DCM (1 mL) and MeOH (1 mL) .The mixture was stirred at 25 °C for 1 hour . LCMS showed that the starting material was consumed and the desired product was detected. The reaction mixture was filtered under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Boston Green ODS 150*30mm*5um; mobile phase: [water(FA)-ACN];B%: 21%-41%,10min) to give (R)-3-(5-(4-((4-(4-((1S,2S)-6-hydroxy- 2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)-1H-pyrazol-1-yl) piperidin-1-yl)methyl)piperidin-1- yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (34.2 mg, 48 ^mol, 17 %) as white solid. LC-MS (ESI+) m/z: 713.4(M+H) ⁺ . HPLC: 96.59% purity at 220 nm. ¹ H NMR (400 MHz, DMSO-d6) į = 10.95 (s, 1H), 9.11 (s, 1H), 8.13 (s, 1H), 7.51 (d, J = 8.9 Hz, 1H), 7.24 - 7.15 (m, 3H), 7.09 - 7.04 (m, 2H), 6.95 (br d, J = 7.2 Hz, 2H), 6.76 (d, J = 8.5 Hz, 1H), 6.58 - 6.49 (m, 3H), 6.34 (s, 1H), 5.04 (dd, J = 5.1, 13.3 Hz, 1H), 4.34 - 4.29 (m, 1H), 4.21 - 4.13 (m, 2H), 3.91 - 3.86 (m, 2H), 3.21 (br d, J = 4.9 Hz, 2H), 2.95 - 2.79 (m, 9H), 2.41 - 2.29 (m, 5H), 2.02 - 1.91 (m, 5H), 1.78 (br d, J = 12.0 Hz, 4H), 1.28 - 1.18 (m, 2H). The LBM stereochemistry was arbitrarily assigned. EXAMPLE 269. Preparation of (I-41) 3-[4-[4-[1-[4-[(1S, 2R)-6-hydroxy-2-phenyl- tetralin-1-yl] phenyl]-4-piperidyl] piperazin-1-yl] phenyl] piperidine-2, 6-dione Step 1: To a solution of ((5S,6R)-5-(4-(1,4-dioxa-8-azaspiro[4.5]decan-8-yl)phenyl)-6 -phenyl- 5,6,7,8-tetrahydronaphthalen-2-ol (200 mg, 1 Eq, 453 ^mol)) in THF (15 mL) was added S lf i id (25 15 L 10%Wt 56 E 25 l) Th i t ti d t 70 °C f 6h TLC (petroleum ether: ethyl acetate=1:1,) indicated Reactant 1 was consumed completely and one new spots formed. The reaction was concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash ® Silica Flash Column, Eluent of 0~100% Ethyl acetate/Petroleum ether gradient @ 80 mL/min) to give the product of give 1-(4-((1S,2R)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthale n-1-yl)phenyl)piperidin-4- one (200 mg, 503 ^mol, ) as a light yellow solid. Step 2: To 1-(4-((1S,2R)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthale n-1- yl)phenyl)piperidin-4-one (40 mg, 1 Eq, 0.10 mmol),and 3-(4-(piperazin-1-yl)phenyl)piperidine- 2,6-dione (41 mg, 1.5 Eq, 0.15 mmol) and Titanium tetraisopropoxide (57 mg, 60 ^L, 2 Eq, 0.20 mmol)in DCM (1 mL) and MeOH (1 mL) at 0 °C. The resulting mixture was stirred for 3 hours at 20 °C. Sodium cyanborohydride (25 mg, 24 ^L, 4 Eq, 0.40 mmol) was added to the mixture at 0 °C. The resulting mixture was stirred for 16 h at 20 °C. The yellow solid was purified by Prep.HPLC (column: Column Phenomenex C1875*30mm*3um Condition: [water (FA)-ACN]; B%: 20%-60%, 8 min) the pure fractions were collected and the solvent was evaporated under vacuum. The aqueous layer was lyophilized to dryness to give 3-[4-[4-[1-[4-[(1S, 2R)-6- hydroxy-2-phenyl-tetralin-1-yl] phenyl]-4-piperidyl] piperazin-1-yl] phenyl] piperidine-2, 6- dione (13.1 mg, 19.78 ^mol, 32.37 % yield, 98.85% purity) was obtained as a white solid. LCMS: calc. for C ₄₂ H ₄₆ N ₄ O ₃ : 654.36, found: [M+H] ⁺ 655.2. HPLC: 98.853% purity at 220 nm. NMR (400 MHz, DMSO-d ₆ ) į = 10.79 (s, 1H), 9.13 (br s, 1H), 8.15 (s, 1H), 7.21 - 7.02 (m, 5H), 6.95 - 6.79 (m, 4H), 6.67 - 6.46 (m, 5H), 6.29 - 6.15 (m, J = 8.3 Hz, 2H), 4.14 (br d, J = 4.3 Hz, 1H), 3.77 - 3.59 (m, 3H), 3.32 - 3.17 (m, 5H), 3.03 - 2.76 (m, 6H), 2.71 - 2.57 (m, 3H), 2.17 - 1.90 (m, 5H), 1.75 - 1.49(m, 3H), 1.33 - 1.21 (m, 1H) SFC: retention time, 5.081 min, 7.092 min; Area, 50.26%, 49.74 %; Stereochemistry was arbitrarily assigned. EXAMPLE 270. Preparation of Additional Compounds from Table 2 [0761] The following compounds were synthesized using similar synthetic schemes described in the Examples described herein. II II II II

II II II

II II

Example A1 – Nano Glo HiBiT Lytic Degradation Assay [0762] Selected compounds of the present disclosure were tested in a Nano Glo HiBiT Lytic Degradation Assay to measure the level of ERα protein degradation in MCF7 cells. Table 3. Materials Used.

Table 4. Instruments Used. Table 5. Cell Line Information. [0763] Cell culture: ESR1_HiBiT KI MCF7 cells were maintained in growth media without antibiotics. Cells were maintained in exponential growth phase, between 40% and 90% confluency. [0764] Cell seeding: Cells were counted using a Vi-Cell and seeded in a 384-well flat-bottom microplate (cell culture-treated) at 4000 cells/well in in 25 ^L of growth medium using a BioTek MultiFlo Multimode Dispenser. Plates were incubated for 24h at 37°C, 5% CO2, >95% relative humidity. [0765] Compound preparation: Compounds were screened as 14-point dose response curves 1:3 dilutions. DMSO is used as the vehicle control and all wells were normalized to the same final DMSO concentration (0.1% v/v). Compounds were dosed using an Echo Acoustic Liquid Handler, 25 nL of 1000X (10mM top concentration) DMSO stock/well. Cells were incubated with compounds for 6 hours at 37°C, 5% CO2, >95% relative humidity. Each compound was run in duplicate. [0766] Nano Glo HiBiT Lytic Degradation Assay: HiBiT-tagged ERα protein levels were quantified using a Nano Glo HiBiT Lytic Degradation Assay following the manufacturer’s protocol. Briefly, the Nano-Glo® HiBiT Lytic Reagent was prepared by diluting the LgBiT Protein Buffer at room temperature. The 384-well microplate were equilibrated to room temperature and 25 ^L of Nano-Glo® HiBiT Lytic Reagent was added to each well. Samples were mixed by placing the 384-well microplate on an orbital shaker for 10 minutes. Luminescence was measured using an EnVision 2105 Multimode Plate Reader. [0767] Data processing and analysis: Background signal (wells containing growth medium without cells) was subtracted from individual relative light units (RLU) values and the resulting values were normalized to the DMSO control well values. Dose responses were analyzed with Genedata Screener® using a bell-shape curve fit and the concentrations corresponding to the half- maximal effect of the first Hill model were used as DC ₅₀ values. [0768] Results of the Nano Glo HiBiT Lytic Degradation Assay are presented in Table 6. Table 6. HiBit assay results. INCORPORATION BY REFERENCE [0769] All publications and patents mentioned herein are hereby incorporated by reference in their entirety for all purposes as if each individual publication or patent was specifically and individually incorporated by reference. In case of conflict, the present application, including any definitions herein, will control. EQUIVALENTS [0770] While specific embodiments of the subject disclosure have been discussed, the above specification is illustrative and not restrictive. Many variations of the present disclosure will become apparent to those skilled in the art upon review of this specification. The full scope of the disclosure should be determined by reference to the claims, along with their full scope of equivalents, and the specification, along with such variations. [0771] Unless otherwise indicated, all numbers expressing quantities of ingredients, reaction conditions, and so forth used in the specification and claims are to be understood as being modified in all instances by the term “about.” Accordingly, unless indicated to the contrary, the numerical parameters set forth in this specification and attached claims are approximations that may vary depending upon the desired properties sought to be obtained by the present disclosure.