Estrogen receptor alpha degrading agent and its use

Abstract

This application relates to a bifunctional compound of general formula I-3’ that acts as a degrader of estrogen receptor alpha (ERα) and is useful for the treatment of disorders associated with ERα-mediated transcriptional regulation such as endometriosis and cancer. The compound is a bifunctional molecule that binds to ERα and contains a cereblon-binding moiety LBM linked to a ligand ERBM that includes a benzo-fused partially saturated 6-membered carbon or heterocyclic ring. [I-3’] In the formula, ERBM is selected from the following TIFF2025521686002005.tif120165This application further relates to the targeted degradation of ERα by the use of a bifunctional molecule that includes a bifunctional molecule having a cereblon-binding moiety linked to a ligand that binds to ERα.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS 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.

[0002] The present invention relates to compounds and methods useful for modulating estrogen receptor alpha ("ERα") via ubiquitination and / or degradation by compounds according to the invention. The invention also provides pharmaceutically acceptable compositions comprising the compounds of the invention, and methods of using such compositions in the treatment of various disorders. [Background technology]

[0003] Estrogen receptors (ERs) are members of the nuclear hormone receptor superfamily. There are two classes of ERs: estrogen receptor alpha (ERα) and estrogen receptor beta (ERβ), encoded by the ESR1 and ESR2 genes, respectively. ERα and ERβ are ligand-activated transcriptional regulators activated by the hormone estrogen (e.g., 17β-estradiol). Estrogen, the ligand for ER, is synthesized by the enzyme aromatase.

[0004] In the absence of estrogen, ER is largely inactive and located in the cytoplasm of cells. Upon estrogen binding, ER translocates to the nucleus, dimerizes, and binds to specific genomic sequences called estrogen response elements (EREs). ER further recruits coregulators to form multiprotein complexes that regulate the transcription of multiple target genes involved in cell proliferation and differentiation in target tissues.

[0005] Under physiological conditions, ERα expression is primarily restricted to reproductive tissues such as the uterus, ovaries, breast, as well as bone and white adipose tissue. ERα is expressed in over 70% of breast cancers and is a major contributor to the pathophysiology of breast cancer. Tumors with high levels of ERα are classified as ER-positive breast cancer. The pathogenetic roles of estrogen and ERα in breast cancer are well established, and modulation of the ERα signaling pathway by endocrine therapy is the basis for the treatment of ER+ breast cancer.

[0006] Currently, there are several strategies to inhibit the estrogen / ERα signaling pathway in breast cancer: 1. Aromatase inhibitors (AIs) act upstream of the ERα signaling pathway by blocking estrogen production and reducing circulating estrogen levels through inhibition of the aromatase enzyme; 2. Selective estrogen receptor modulators (SERMs) bind directly to ERα and competitively inhibit estrogen binding, thus antagonizing ERα activity; 3. Selective estrogen receptor downregulators or degraders (SERDs) antagonize ERα and degrade it (this process is mediated by inducible conformational change and ERα proteolysis via the proteasome pathway); 4. Proteolysis-targeted chimeras (PROTACs), which are heterobifunctional molecules, selectively recruit E3 ubiquitin ligase to ERα protein by inducible proximity, mediating ERα ubiquitination and proteasomal degradation.

[0007] The ubiquitin-proteasome pathway (UPP) is a critical pathway that regulates key regulatory proteins and degrades misfolded or abnormal proteins. The UPP is central to multiple cellular processes, and when defective or imbalanced, contributes to the pathogenesis of various diseases. 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 that promote the ubiquitination of different proteins in vivo, which can be divided into four families: HECT domain E3s, U-box E3s, monomeric RING E3s, and multisubunit E3s. 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," Bendsen 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," and 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) entitled "Roles of F-box proteins in cancer."

[0009] The UPP plays a key role in the degradation of short-lived regulatory proteins that are important in various fundamental cellular processes, including cell cycle regulation, cell surface receptor and ion channel regulation, and antigen presentation. This pathway is involved in the pathogenesis of several forms of malignancy, several genetic disorders (including cystic fibrosis, Angelman syndrome, and Liddle syndrome), immune surveillance / viral pathogenesis, and muscle wasting. Many diseases are associated with abnormal UPP, adversely affecting cell cycle and division, cellular responses to stress and extracellular modulators, neuronal network morphogenesis, regulation of cell surface receptors, ion channels, secretory pathways, DNA repair, and organelle biogenesis.

[0010] Recently, abnormalities in this process have been implicated in the pathogenesis of several diseases, both inherited and acquired, which fall into two major groups: (a) diseases resulting from loss of function due to the consequent stabilization of certain proteins, and (b) diseases resulting from gain of function, i.e., abnormal or accelerated degradation of protein targets.

[0011] UPP is used to induce selective protein degradation, including the 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 by recruiting them to E3 ubiquitin ligases and subsequent ubiquitination. These drug-like molecules offer the possibility of transiently controlling protein expression. Such compounds can induce the inactivation of target proteins upon addition to cells or administration to animals or humans, making them useful as biochemical reagents and potentially providing a new paradigm for disease treatment by removing pathogenic or oncogenic proteins (Crews C, Chemistry & Biology, 2010, 17(6):551-555; Schnnekloth JS Jr., Chembiochem, 2005, 6(1):40-46).

[0012] De novo acquired resistance to endocrine therapy can arise through distinct mechanisms, such as overexpression of ERα coregulators or post-translational modifications of ERα and its coregulators upon activation of intercellular signaling pathways. All contribute to the hypersensitivity of ERα to low circulating estrogen levels. Additionally, genomic alterations, such as point mutations or chromosomal translocations in the ESR1 gene, can confer the ability to bind DNA in the absence of ligand and confer hormone independence to ERα-mutant cancer cells. Because most of the identified endocrine therapy resistance mechanisms rely on ERα-dependent mechanisms, strategies aimed at downregulating ERα (both wild-type and mutant forms) through targeted proteolysis may overcome resistance and provide better treatment options. In the art, there is a continuing need for effective treatment of diseases, particularly cancers such as hyperplasia and breast cancer.However, non-specific effects and the inability to target and completely regulate a certain class of proteins, such as transcription factors, remain obstacles to the development of effective anti-cancer drugs.Therefore, small molecule therapeutics that utilize E3 ligase-mediated proteolysis to target cancer-related proteins, such as estrogen receptor alpha ("ERα"), are promising therapeutic drugs.Therefore, there is still a need to find bifunctional compounds that are useful therapeutic agents and are ERα degraders. [Prior art documents] [Non-patent literature]

[0013] [Non-Patent Document 1] Li et al. (PLOS One, 2008, 3, 1487) [Non-patent document 2] Bemdsen et al. (Nat. Struct. Mol. Biol., 2014, 21, 301-307) [Non-patent document 3] Deshaies et al. (Ann.Rev.Biochem.,2009,78,399-434) [Non-patent document 4] Spratt et al. (Biochem. 2014, 458, 421-437) [Non-Patent Document 5] Wang et al. (Nat. Rev. Cancer., 2014, 14, 233-347) [Non-patent document 6] Crews C,Chemistry&Biology,2010,l7(6):551-555 [Non-Patent Document 7] Schnnekloth JS Jr.,Chembiochem,2005,6(l):40-46 Summary of the Invention [Means for solving the problem]

[0014] The present application relates to novel bifunctional compounds that function to recruit ERα to E3 ubiquitin ligase for degradation, as well as methods for preparing and using the same. Specifically, the present disclosure provides bifunctional compounds that find utility as modulators of targeted ubiquitination of ERα, which is then degraded and / or otherwise inhibited by the bifunctional compounds described herein. An advantage of the compounds provided herein is that they are capable of a wide range of pharmacological activity consistent with the degradation / inhibition of ERα. Additionally, the present disclosure provides methods of using an effective amount of the compounds described herein for the treatment or amelioration of conditions 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 linking a cereblon-binding moiety to a ligand that binds to ERα.

[0016] It has now been found that compounds of the present invention, and pharmaceutically acceptable compositions thereof, are effective as degraders of ERα. Such compounds have the general formula I-1: [ka] or a pharmaceutically acceptable salt thereof, wherein each variable is as defined and described herein.

[0017] In one embodiment, a compound of formula I-3': [ka] A compound of the formula: ERBM, [ka] is selected from, where: [ka] indicates the attachment site of the -L-LBM moiety to a modifiable carbon, oxygen, nitrogen, or sulfur atom of the ERBM moiety; X 1 may be N, NH, CH, CH2, CH(R A1 ) or C(R A1 )2, or C(R A1 ) and X 2 But N(R A2 ), O, CH2, CH(R A3 ), or C(R A3 )2, X 3 But N(R A4 ), O, CH2, CH(R A5 ), or C(R A5 )2, but However, X 1 and X 2 Both or X 2 and X 3 and R 1 , R 2 , R 4 , R 5 , R 6 , R A1 , R A2 , R A3 , R A4 , and R A5 Each instance of R A or R B and R C is replaced by 0 to 4 instances of R 3 Each instance of R A Or R B and R C or two R 3 the groups optionally taken together form a 5-8 membered partially unsaturated or aryl fused ring having 0-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; R AEach instance of 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 )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, R B Each instance of C 1-6 an aliphatic chain; phenyl; naphthyl; cubanyl; adamantyl; a 5-6 membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3-7 membered saturated or partially unsaturated monocyclic carbocycle; a 5-12 membered saturated or partially unsaturated bicyclic carbocycle; a 3-7 membered saturated or partially unsaturated monocyclic heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 7-12 membered saturated or partially unsaturated bicyclic heterocycle having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, R C each instance of 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)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 C 1-6an optionally substituted group selected from a 3- to 7-membered saturated or partially unsaturated monocyclic heterocycle having 1 to 2 heteroatoms independently selected from aliphatic, phenyl, nitrogen, oxygen, and sulfur, and a 5- to 6-membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Each instance of R is independently hydrogen or C 1-6 an optionally substituted group selected from aliphatic, phenyl, a 3- to 7-membered saturated or partially unsaturated monocyclic heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5- to 6-membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or two R groups on the same nitrogen optionally taken together with their intervening atoms form an optionally substituted 4- to 7-membered saturated, partially unsaturated, or heteroaryl ring having, in addition to the nitrogen, 0-3 heteroatoms 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- to 6-membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8- to 10-membered bicyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3- to 7-membered saturated or partially unsaturated monocyclic carbocycle; a 5- to 12-membered saturated or partially unsaturated bicyclic carbocycle; a 3- to 7-membered saturated or partially unsaturated monocyclic heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 7- to 12-membered saturated or partially unsaturated bicyclic heterocycle having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Ring C is a spiro-fused 3- to 7-membered saturated or partially unsaturated monocyclic carbocycle; a spiro-fused 5- to 12-membered saturated or partially unsaturated bicyclic carbocycle; a spiro-fused 3- to 7-membered saturated or partially unsaturated monocyclic heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a spiro-fused 7- to 12-membered saturated or partially unsaturated bicyclic heterocycle having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; L is a covalent bond or a divalent, saturated or unsaturated, linear or branched C 1-50 a hydrocarbon chain, wherein 0 to 6 methylene units of L are independently -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)-, -C(O)NR-, -OC(O)NR-, -NRC(O)O-, [ka] is replaced by wherein each -Cy- is independently selected from phenylenyl, 8- to 10-membered bicyclic arylenyl, 4- to 7-membered saturated or partially unsaturated carbocyclylenyl, 5- to 11-membered saturated or partially unsaturated spirocarbocyclylenyl, 8- to 10-membered bicyclic saturated or partially unsaturated carbocyclylenyl, 4- to 7-membered saturated or partially unsaturated heterocyclylenyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 5- to 11-membered saturated or partially unsaturated spiroheterocyclylenyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, nitrogen, oxygen, and an optionally substituted bivalent ring selected from an 8- to 10-membered bicyclic saturated or partially unsaturated heterocyclyl having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 6- to 10-membered bridged bicyclic saturated or partially unsaturated heterocyclyl having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5- to 6-membered heteroarylenyl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or an 8- to 10-membered bicyclic heteroarylenyl having 1 to 5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; LBM, [ka] [ka] 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 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; Compounds of formula I-3', or a pharmaceutically acceptable salt thereof, are provided wherein t is 0, 1, 2, 3, or 4.

[0018] In one embodiment, a compound of formula I-3': [ka] A compound of the formula: ERBM, [ka] is selected from, where: [ka] indicates the attachment site of the -L-LBM moiety to a modifiable carbon, oxygen, nitrogen, or sulfur atom of the ERBM moiety; X 1 may be N, NH, CH, CH2, CH(R A1 ) or C(R A1 )2, or C(R A1 ) and X 2 But N(R A2 ), O, CH2, CH(R A3 ), or C(R A3 )2, X 3 But N(R A4 ), O, CH2, CH(R A5 ), or C(R A5 )2, but However, X 1 and X 2 Both or X 2 and X 3 and R 1 , R 2 , R 4 , R 5 , R 6 , R A1 , R A2 , R A3 , R A5 , and R A5 Each instance of R A or R B and R C is replaced by 0 to 4 instances of R 3 Each instance of R A Or R Band R C or two R 3 the groups optionally taken together form a 5-8 membered partially unsaturated or aryl fused ring having 0-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; R A Each instance of 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 )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, R B Each instance of C 1-6 an aliphatic chain; phenyl; naphthyl; cubanyl; adamantyl; a 5-6 membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3-7 membered saturated or partially unsaturated monocyclic carbocycle; a 5-12 membered saturated or partially unsaturated bicyclic carbocycle; a 3-7 membered saturated or partially unsaturated monocyclic heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 7-12 membered saturated or partially unsaturated bicyclic heterocycle having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, R Ceach instance of 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)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 C 1-6 an optionally substituted group selected from a 3- to 7-membered saturated or partially unsaturated monocyclic heterocycle having 1 to 2 heteroatoms independently selected from aliphatic, phenyl, nitrogen, oxygen, and sulfur, and a 5- to 6-membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Each instance of R is independently hydrogen or C 1-6 an optionally substituted group selected from aliphatic, phenyl, a 3- to 7-membered saturated or partially unsaturated monocyclic heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5- to 6-membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or two R groups on the same nitrogen optionally taken together with their intervening atoms form an optionally substituted 4- to 7-membered saturated, partially unsaturated, or heteroaryl ring having, in addition to the nitrogen, 0-3 heteroatoms 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- to 6-membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8- to 10-membered bicyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3- to 7-membered saturated or partially unsaturated monocyclic carbocycle; a 5- to 12-membered saturated or partially unsaturated bicyclic carbocycle; a 3- to 7-membered saturated or partially unsaturated monocyclic heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 7- to 12-membered saturated or partially unsaturated bicyclic heterocycle having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Ring C is a spiro-fused 3- to 7-membered saturated or partially unsaturated monocyclic carbocycle; a spiro-fused 5- to 12-membered saturated or partially unsaturated bicyclic carbocycle; a spiro-fused 3- to 7-membered saturated or partially unsaturated monocyclic heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a spiro-fused 7- to 12-membered saturated or partially unsaturated bicyclic heterocycle having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; L is a covalent bond or a divalent, saturated or unsaturated, linear or branched C 1-50 a hydrocarbon chain, wherein 0 to 6 methylene units of L are independently -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)-, -C(O)NR-, -OC(O)NR-, -NRC(O)O-, [ka] is replaced by wherein each -Cy- is independently selected from phenylenyl, 8- to 10-membered bicyclic arylenyl, 4- to 7-membered saturated or partially unsaturated carbocyclylenyl, 5- to 11-membered saturated or partially unsaturated spirocarbocyclylenyl, 8- to 10-membered bicyclic saturated or partially unsaturated carbocyclylenyl, 4- to 7-membered saturated or partially unsaturated heterocyclylenyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 5- to 11-membered saturated or partially unsaturated spiroheterocyclylenyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, nitrogen, oxygen, and an optionally substituted bivalent ring selected from an 8- to 10-membered bicyclic saturated or partially unsaturated heterocyclyl having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 6- to 10-membered bridged bicyclic saturated or partially unsaturated heterocyclyl having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5- to 6-membered heteroarylenyl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or an 8- to 10-membered bicyclic heteroarylenyl having 1 to 5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; LBM, [ka] [ka] 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 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; t is 0, 1, 2, 3, or 4, but However, ERBM, [ka] (In the formula, X 1is CH or N, X 2 is CH2, Ring B is phenyl, Ring A is phenyl or a 6-membered monocyclic heteroaryl ring having 1 to 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; R 2 -OH, -Me, -OMe, -F, -Br, -CF3, and - i Pr), LBM, [ka] or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

[0019] The compounds of the present invention, and pharmaceutically acceptable compositions thereof, are useful for treating a variety of diseases, disorders, or conditions associated with modulation of signaling pathways involving ERα, including those described herein.

[0020] The compounds provided by the present invention are also useful for studying the ERα enzyme in biological and pathological phenomena, for studying intracellular signaling pathways occurring in body tissues, and for 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, Formula I-1', Formula I-2, Formula I-2', Formula I-3, or Formula I-3', or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, adjuvant, or diluent.

[0022] In some embodiments, the disclosure provides a method of treating an ERa-mediated disorder, comprising administering to a patient in need thereof a compound of Formula I-1, Formula I-1', Formula I-2, Formula I-2', Formula I-3, or Formula I-3', or a composition comprising such a compound.

[0023] In some embodiments, the present disclosure provides a process for providing a compound of Formula I-1, Formula I-1′, Formula I-2, Formula I-2′, Formula I-3, or Formula I-3′, or a synthetic intermediate thereof.

[0024] In some embodiments, the present disclosure provides a process for providing a pharmaceutical composition comprising a compound of Formula I-1, Formula I-1′, Formula I-2, Formula I-2′, Formula I-3, or Formula I-3′. DETAILED DESCRIPTION OF THE INVENTION

[0025] 1. General Description of Certain Embodiments of the Present Disclosure The compounds of the present disclosure, and pharmaceutical compositions thereof, are useful as degraders of Erα.

[0026] In some embodiments, the present disclosure provides compounds of formula I-1: [ka] A compound of the formula: ERBM, [ka] is selected from, where: [ka] indicates the attachment site 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 ) and X 2 But N(R A2 ), O, CH2, CH(R A3 ), or C(R A3 )2, but However, X 1 and X 2 and R 1 , R 2 , R A1 , R A2 , and R A3 Each instance of R A or R B and R C is replaced by 0 to 4 instances of R 3 Each instance of R A Or R B and R C or two R 3 the groups optionally taken together form a 5-8 membered partially unsaturated or aryl fused ring having 0-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; R A Each instance of 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 )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, R B Each instance of C1-6 an aliphatic chain; phenyl; naphthyl; cubanyl; adamantyl; a 5-6 membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3-7 membered saturated or partially unsaturated monocyclic carbocycle; a 5-12 membered saturated or partially unsaturated bicyclic carbocycle; a 3-7 membered saturated or partially unsaturated monocyclic heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 7-12 membered saturated or partially unsaturated bicyclic heterocycle having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, R C each instance of 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)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 C 1-6 an optionally substituted group selected from a 3- to 7-membered saturated or partially unsaturated monocyclic heterocycle having 1 to 2 heteroatoms independently selected from aliphatic, phenyl, nitrogen, oxygen, and sulfur, and a 5- to 6-membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Each instance of R is independently hydrogen or C 1-6 an optionally substituted group selected from aliphatic, phenyl, a 3- to 7-membered saturated or partially unsaturated monocyclic heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5- to 6-membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or two R groups on the same nitrogen optionally taken together with their intervening atoms form an optionally substituted 4- to 7-membered saturated, partially unsaturated, or heteroaryl ring having, in addition to the nitrogen, 0-3 heteroatoms 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- to 6-membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8- to 10-membered bicyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3- to 7-membered saturated or partially unsaturated monocyclic carbocycle; a 5- to 12-membered saturated or partially unsaturated bicyclic carbocycle; a 3- to 7-membered saturated or partially unsaturated monocyclic heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 7- to 12-membered saturated or partially unsaturated bicyclic heterocycle having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; L is a bivalent moiety connecting the ERBM to the LBM; LBM is a ligase binding moiety; m is 0, 1, 2, 3, or 4; n is 0, 1, 2, 3, or 4; Compounds of formula I-1, or pharmaceutically acceptable salts thereof, are provided wherein p is 0, 1, 2, 3, or 4.

[0027] In some embodiments, the present disclosure provides compounds of formula I-2: [ka] A compound of the formula: ERBM, [ka] is selected from, where: [ka] indicates the attachment site 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 ) and X 2 But N(R A2 ), O, CH2, CH(R A3 ), or C(R A3 )2, but However, X 1 and X 2 and R 1 , R 2 , R 4 , R 5 , R A1 , R A2 , and R A3 Each instance of R A or R B and R C is replaced by 0 to 4 instances of R 3 Each instance of R A Or R B and R C or two R 3 the groups optionally taken together form a 5-8 membered partially unsaturated or aryl fused ring having 0-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; R A Each instance of 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 )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, RB Each instance of C 1-6 an aliphatic chain; phenyl; naphthyl; cubanyl; adamantyl; a 5-6 membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3-7 membered saturated or partially unsaturated monocyclic carbocycle; a 5-12 membered saturated or partially unsaturated bicyclic carbocycle; a 3-7 membered saturated or partially unsaturated monocyclic heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 7-12 membered saturated or partially unsaturated bicyclic heterocycle having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, R C each instance of 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)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 C 1-6 an optionally substituted group selected from a 3- to 7-membered saturated or partially unsaturated monocyclic heterocycle having 1 to 2 heteroatoms independently selected from aliphatic, phenyl, nitrogen, oxygen, and sulfur, and a 5- to 6-membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Each instance of R is independently hydrogen or C 1-6 an optionally substituted group selected from aliphatic, phenyl, a 3- to 7-membered saturated or partially unsaturated monocyclic heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5- to 6-membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or two R groups on the same nitrogen optionally taken together with their intervening atoms form an optionally substituted 4- to 7-membered saturated, partially unsaturated, or heteroaryl ring having, in addition to the nitrogen, 0-3 heteroatoms 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- to 6-membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8- to 10-membered bicyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3- to 7-membered saturated or partially unsaturated monocyclic carbocycle; a 5- to 12-membered saturated or partially unsaturated bicyclic carbocycle; a 3- to 7-membered saturated or partially unsaturated monocyclic heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 7- to 12-membered saturated or partially unsaturated bicyclic heterocycle having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; L is a bivalent moiety connecting the ERBM to the LBM; LBM, [ka] [ka] 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; Compounds of formula I-2, or pharmaceutically acceptable salts thereof, are provided, wherein s is 0, 1, 2, 3, or 4.

[0028] In some embodiments, the compound of formula I-3: [ka] A compound of the formula: ERBM, [ka] is selected from, where: [ka] indicates the attachment site 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 ) and X 2 But N(R A2 ), O, CH2, CH(R A3 ), or C(R A3 )2, but However, X 1 and X 2 and R 1 , R 2 , R 4 , R 5 , R A1 , R A2 , and R A3 Each instance of R A or R B and R C is replaced by 0 to 4 instances of R 3 Each instance of R A Or R B and R C or two R 3 the groups optionally taken together form a 5-8 membered partially unsaturated or aryl fused ring having 0-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; R AEach instance of 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 )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, R B Each instance of C 1-6 an aliphatic chain; phenyl; naphthyl; cubanyl; adamantyl; a 5-6 membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3-7 membered saturated or partially unsaturated monocyclic carbocycle; a 5-12 membered saturated or partially unsaturated bicyclic carbocycle; a 3-7 membered saturated or partially unsaturated monocyclic heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 7-12 membered saturated or partially unsaturated bicyclic heterocycle having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, R C each instance of 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)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 C 1-6an optionally substituted group selected from a 3- to 7-membered saturated or partially unsaturated monocyclic heterocycle having 1 to 2 heteroatoms independently selected from aliphatic, phenyl, nitrogen, oxygen, and sulfur, and a 5- to 6-membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Each instance of R is independently hydrogen or C 1-6 an optionally substituted group selected from aliphatic, phenyl, a 3- to 7-membered saturated or partially unsaturated monocyclic heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5- to 6-membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or two R groups on the same nitrogen optionally taken together with their intervening atoms form an optionally substituted 4- to 7-membered saturated, partially unsaturated, or heteroaryl ring having, in addition to the nitrogen, 0-3 heteroatoms 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- to 6-membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8- to 10-membered bicyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3- to 7-membered saturated or partially unsaturated monocyclic carbocycle; a 5- to 12-membered saturated or partially unsaturated bicyclic carbocycle; a 3- to 7-membered saturated or partially unsaturated monocyclic heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 7- to 12-membered saturated or partially unsaturated bicyclic heterocycle having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; L is a covalent bond or a divalent, saturated or unsaturated, linear or branched C 1-50 a hydrocarbon chain, wherein 0 to 6 methylene units of L are independently -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)-, -C(O)NR-, -OC(O)NR-, -NRC(O)O-, [ka] is replaced by wherein each -Cy- is independently selected from phenylenyl, 8- to 10-membered bicyclic arylenyl, 4- to 7-membered saturated or partially unsaturated carbocyclylenyl, 5- to 11-membered saturated or partially unsaturated spirocarbocyclylenyl, 8- to 10-membered bicyclic saturated or partially unsaturated carbocyclylenyl, 4- to 7-membered saturated or partially unsaturated heterocyclylenyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 5- to 11-membered saturated or partially unsaturated spiroheterocyclylenyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, nitrogen, oxygen, and an optionally substituted bivalent ring selected from an 8- to 10-membered bicyclic saturated or partially unsaturated heterocyclyl having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 6- to 10-membered bridged bicyclic saturated or partially unsaturated heterocyclyl having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5- to 6-membered heteroarylenyl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or an 8- to 10-membered bicyclic heteroarylenyl having 1 to 5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; LBM, [ka] [ka] 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 q is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; r is 0, 1, 2, 3, or 4; Compounds of formula I-3, or a pharmaceutically acceptable salt thereof, are provided, wherein s is 0, 1, 2, 3, or 4.

[0029] In one embodiment, a compound of formula I-3': [ka] A compound of the formula: ERBM, [ka] is selected from, where: [ka] indicates the attachment site of the -L-LBM moiety to a modifiable carbon, oxygen, nitrogen, or sulfur atom of the ERBM moiety; X 1 may be N, NH, CH, CH2, CH(R A1 ) or C(R A1 )2, or C(R A1 ) and X 2 But N(R A2 ), O, CH2, CH(R A3 ), or C(R A3 )2, X 3 But N(R A4 ), O, CH2, CH(R A5 ), or C(R A5 )2, but However, X 1 and X 2 Both or X 2 and X 3 and R 1 , R 2 , R 4 , R 5 , R 6 , R A1 , R A2 , R A3 , R A4 , and R A5Each instance of R A or R B and R C is replaced by 0 to 4 instances of R 3 Each instance of R A Or R B and R C or two R 3 the groups optionally taken together form a 5-8 membered partially unsaturated or aryl fused ring having 0-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; R A Each instance of 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 )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, R B Each instance of C 1-6 an aliphatic chain; phenyl; naphthyl; cubanyl; adamantyl; a 5-6 membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3-7 membered saturated or partially unsaturated monocyclic carbocycle; a 5-12 membered saturated or partially unsaturated bicyclic carbocycle; a 3-7 membered saturated or partially unsaturated monocyclic heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 7-12 membered saturated or partially unsaturated bicyclic heterocycle having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, R CEach instance of 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)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 C 1-6 an optionally substituted group selected from a 3- to 7-membered saturated or partially unsaturated monocyclic heterocycle having 1 to 2 heteroatoms independently selected from aliphatic, phenyl, nitrogen, oxygen, and sulfur, and a 5- to 6-membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Each instance of R is independently hydrogen or C 1-6 an optionally substituted group selected from aliphatic, phenyl, a 3- to 7-membered saturated or partially unsaturated monocyclic heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5- to 6-membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or two R groups on the same nitrogen optionally taken together with their intervening atoms form an optionally substituted 4- to 7-membered saturated, partially unsaturated, or heteroaryl ring having, in addition to the nitrogen, 0-3 heteroatoms 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- to 6-membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8- to 10-membered bicyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3- to 7-membered saturated or partially unsaturated monocyclic carbocycle; a 5- to 12-membered saturated or partially unsaturated bicyclic carbocycle; a 3- to 7-membered saturated or partially unsaturated monocyclic heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 7- to 12-membered saturated or partially unsaturated bicyclic heterocycle having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Ring C is a spiro-fused 3- to 7-membered saturated or partially unsaturated monocyclic carbocycle; a spiro-fused 5- to 12-membered saturated or partially unsaturated bicyclic carbocycle; a spiro-fused 3- to 7-membered saturated or partially unsaturated monocyclic heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a spiro-fused 7- to 12-membered saturated or partially unsaturated bicyclic heterocycle having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; L is a covalent bond or a divalent, saturated or unsaturated, linear or branched C 1-50 a hydrocarbon chain, wherein 0 to 6 methylene units of L are independently -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)-, -C(O)NR-, -OC(O)NR-, -NRC(O)O-, [ka] is replaced by wherein each -Cy- is independently selected from phenylenyl, 8- to 10-membered bicyclic arylenyl, 4- to 7-membered saturated or partially unsaturated carbocyclylenyl, 5- to 11-membered saturated or partially unsaturated spirocarbocyclylenyl, 8- to 10-membered bicyclic saturated or partially unsaturated carbocyclylenyl, 4- to 7-membered saturated or partially unsaturated heterocyclylenyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 5- to 11-membered saturated or partially unsaturated spiroheterocyclylenyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, nitrogen, oxygen, and an optionally substituted bivalent ring selected from an 8- to 10-membered bicyclic saturated or partially unsaturated heterocyclyl having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 6- to 10-membered bridged bicyclic saturated or partially unsaturated heterocyclyl having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5- to 6-membered heteroarylenyl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or an 8- to 10-membered bicyclic heteroarylenyl having 1 to 5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; LBM, [ka] [ka] 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 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; Compounds of formula I-3', or a pharmaceutically acceptable salt thereof, are provided wherein t is 0, 1, 2, 3, or 4.

[0030] 2. Compounds and Definitions Compounds of the present disclosure generally include those described 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, chemical elements shall be defined as defined in the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75 th Additionally, general principles of organic chemistry are identified in "Organic Chemistry," Thomas Sorrell, University Science Books, Sausalito: 1999, and "March's Advanced Organic Chemistry," 5 th Ed., Ed.: Smith, MB and March, J., John Wiley & Sons, New York: 2001, the entire contents of which are incorporated herein by reference.

[0031] As used herein, the term "aliphatic" or "aliphatic group" refers to a straight-chain (i.e., unbranched) or branched, substituted or unsubstituted hydrocarbon chain that is fully saturated or contains one or more units of unsaturation, or a monocyclic or bicyclic hydrocarbon (also referred to herein as "carbocyclic" or "alicyclic") that is fully saturated or contains one or more units of unsaturation, but is not aromatic and has a single point of attachment to the rest of the molecule. Unless otherwise specified, an aliphatic group contains 1-6 aliphatic carbon atoms. In some embodiments, an aliphatic group contains 1-5 aliphatic carbon atoms. In other embodiments, an aliphatic group contains 1-4 aliphatic carbon atoms. In still other embodiments, an aliphatic group contains 1-3 aliphatic carbon atoms, and in still other embodiments, an aliphatic group contains 1-2 aliphatic carbon atoms. In some embodiments, "alicyclic" (or "carbocyclic") refers to a monocyclic C3-C6 hydrocarbon that is fully saturated or contains one or more units of unsaturation, but is not aromatic and 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 groups, alkenyl groups, alkynyl groups, and hybrids thereof, such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl, or (cycloalkyl)alkenyl.

[0032] The term "carbocyclyl" or "carbocyclic group," unless otherwise defined, refers to a saturated or partially unsaturated, but not aromatic, 3- to 10-membered monocyclic or 5- to 14-membered polycyclic ring system, including bridged, spiro, or fused rings, which ring system contains exclusively carbon atoms.

[0033] The term "alkyl," as used herein, unless otherwise indicated, refers to a monovalent aliphatic hydrocarbon radical having straight-chain, branched-chain, monocyclic, or polycyclic moieties, or combinations thereof, which radical is optionally substituted on one or more carbons of the straight-chain, branched-chain, monocyclic, or polycyclic moiety, or combinations thereof, with one or more substituents on each carbon, wherein the one or more substituents are independently selected from the group consisting of C1-C10 Examples of "alkyl" groups include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, norbornyl, and the like.

[0034] The term "lower alkyl" refers to C 1-4 It refers to a straight-chain 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 C alkyl group substituted with one or more halogen atoms. 1-4 It refers to a straight-chain or branched alkyl group.

[0036] The term "heteroatom" refers to oxygen, sulfur, nitrogen, phosphorus, or silicon (any oxidized form of nitrogen, sulfur, phosphorus, or silicon, the quaternized form of any basic nitrogen, or a substitutable nitrogen of a heterocycle, e.g., N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl), or NR + (as in N-substituted pyrrolidinyl).

[0037] As used herein, the term "unsaturated" means that a moiety has one or more units of unsaturation.

[0038] As used herein, "C 1-8 (or C 1-6 Or C 1-4 The term "divalent saturated or unsaturated, straight or branched hydrocarbon chain" refers to divalent straight or branched alkylene, alkenylene, and alkynylene chains as defined herein.

[0039] The term "alkylene" refers to a divalent alkyl group. An "alkylene chain" is a polymethylene group, i.e., -(CH2)n- where n is a positive integer, preferably 1 to 6, 1 to 4, 1 to 3, 1 to 2, or 2 to 3. A substituted alkylene chain is a polymethylene group in which one or more methylene hydrogen atoms have been replaced with a substituent. Suitable substituents include those described below for substituted aliphatic groups.

[0040] The term "alkenylene" refers to a divalent 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 substituted aliphatic groups.

[0041] The term "halogen" means F, Cl, Br, or I.

[0042] The term "aryl," used alone or as part of a larger moiety, such as in "aralkyl," "aralkoxy," or "aryloxyalkyl," refers to a monocyclic or bicyclic ring system having a total of 5 to 14 ring members, where at least one ring in the system is aromatic and 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, including, but not limited to, phenyl, biphenyl, naphthyl, anthracyl, and the like, which may bear one or more substituents.

[0043] As used herein, the term "heteroaryl" or "heteroaromatic," unless otherwise defined, refers to a monocyclic aromatic 5- or 6-membered ring containing one or more heteroatoms, e.g., 1 to 3 heteroatoms such as nitrogen, oxygen, and sulfur, or an 8- to 10-membered polycyclic ring system containing one or more heteroatoms, where 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 the aromatic ring. Heteroaryl rings may be linked to adjacent radicals through 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, and the like. For example, unless otherwise defined, 1,2,3,4-tetrahydroquinoline is a heteroaryl ring, e.g., when its point of attachment is through the benzo ring: [ka]

[0044] The terms "heterocyclyl" or "heterocyclic group," unless otherwise defined, refer to a saturated or partially unsaturated 3- to 10-membered monocyclic or 7- to 14-membered polycyclic ring system, including bridged or fused rings, which ring system contains 1 to 4 heteroatoms, such as nitrogen, oxygen, and sulfur. A heterocyclyl ring may be linked to an adjacent radical through a carbon or nitrogen.

[0045] The term "partially unsaturated" in reference to a ring, unless otherwise defined, refers to a monocyclic ring or a component ring within a polycyclic (e.g., bicyclic, tricyclic, etc.) ring system, where the component ring contains at least one degree of unsaturation in addition to that 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, and the like. When a partially unsaturated ring is part of a polycyclic ring system, the other component rings of the polycyclic ring system may be saturated, partially unsaturated, or aromatic, but the point of attachment of the polycyclic ring system is on the partially unsaturated component ring. For example, unless otherwise defined, 1,2,3,4-tetrahydroquinoline is a partially unsaturated ring when its point of attachment is through the piperidino ring, such as: [ka]

[0046] The term "saturated" in the context of a ring, unless otherwise defined, refers to a 3- to 10-membered monocyclic ring or a 7- to 14-membered polycyclic (e.g., bicyclic, tricyclic, etc.) ring system, where the monocyclic ring or component ring that is the point of attachment of the polycyclic ring system does not contain any additional degree of unsaturation beyond that provided by the ring itself. Examples of monocyclic saturated rings include, but are not limited to, azetidine, oxetane, cyclohexane, etc. When a saturated ring is part of a polycyclic ring system, the other component rings of the polycyclic ring system may be saturated, partially unsaturated, or aromatic, but the point of attachment of the polycyclic ring system is on the saturated component ring. For example, unless otherwise defined, 2-azaspiro[3.4]oct-6-ene is a saturated ring, such as the following, when its point of attachment is through the azetidino ring: [ka]

[0047] As used herein, "alkylene," "arylene," "cycloalkylene," "heteroarylene," "heterocycloalkylene," and other similar terms with the suffix "-ylene" refer to a divalent linked version of the group that the suffix modifies. For example, "alkylene" is a divalent alkyl group that connects 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 valence bonds connecting two bridgeheads, and a "bridgehead" is any skeletal atom of the ring system connected to three or more skeletal atoms (excluding hydrogen). In some embodiments, bridged bicyclic groups have 7 to 12 ring members and 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Such bridged bicyclic groups are well known in the art and include the groups described below, in which each group is attached to the remainder of the molecule at any substitutable carbon or nitrogen atom. Unless otherwise specified, bridged bicyclic groups are optionally substituted with one or more substituents as described for aliphatic groups. Additionally or alternatively, any substitutable nitrogen of a bridged bicyclic group is optionally substituted. Exemplary bridged bicyclic groups include: [ka]

[0049] The suffix "yrenyl," as used herein, refers to a divalent radical (i.e., a radical having two points of attachment) of the moiety to which it is attached. For example, the term "heterocyclylenyl," as used herein, refers to a heterocycle having two points of attachment to the rest of the molecule. One or both points of attachment can be through a carbon atom or a heteroatom. As another example, the term "phenylenyl," as used herein, refers to a divalent form of an optionally substituted phenyl group, either alone or as part of another group, and the term "cycloalkylenyl," as used herein, refers to a divalent form of an optionally substituted cycloalkyl group, either alone or as part of another group.

[0050] As described herein, compounds of the present disclosure may contain "optionally substituted" moieties. In general, the term "substituted," whether preceded by the term "optionally," means that one or more hydrogens of the specified moiety have been 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 if more than one position in any given structure may be substituted with more than one substituent selected from a specified group, these substituents may be the same or different at all positions. Combinations of substituents envisioned by the present disclosure are preferably those that result in the formation of stable or chemically feasible compounds. As used herein, the term "stable" refers to compounds that are substantially unchanged when subjected to conditions that 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; -(CH) 0-4 R°;-(CH2) 0-4 OR°;-O(CH2) 0-4 R o ;-O-(CH2) 0-4 C(O)OR°;-(CH2) 0-4CH(OR°)2;-(CH2) 0-4 SR°; R° may be substituted -(CH2) 0-4 Ph; R° may be substituted with -(CH2) 0-4 O(CH2) 0-1 Ph; may be substituted with R° -CH=CHPh; may be substituted with R° -(CH 0-4 O(CH2) 0-1 -pyridyl; -NO2; -CN; -N3; ​​-(CH2) 0-4 N(R°)2;-(CH2) 0-4 N(R°)C(O)R°;-N(R°)C(S)R°;-(CH2) 0-4 N(R°)C(O)NR°2;-N(R°)C(S)NR°2;-(CH2) 0-4 N(R°)C(O)OR°;-N(R°)N(R°)C(O)R°;-N(R°)N(R°)C(O)NR°2;-N(R°)N(R°)C(O)OR°;-(CH2) 0-4 C(O)R°;-C(S)R°;-(CH2) 0-4 C(O)OR°;-(CH2) 0-4 C(O)SR°;-(CH2) 0-4 C(O)OSiR°3;-(CH2) 0-4 OC(O)R°;-OC(O)(CH2) 0-4 SR°;-SC(S)SR°;-(CH2) 0-4 SC(O)R°;-(CH2) 0-4 C(O)NR°2;-C(S)NR°2;-C(S)SR°;-SC(S)SR°;-(CH2) 0-4 OC(O)NR°2;-C(O)N(OR°)R°;-C(O)C(O)R°;-C(O)CH2C(O)R°;-C(NOR°)R°;-(CH2) 0-4 SSR°;-(CH2) 0-4 S(O)2R°;-(CH2) 0-4 S(O)2OR°;-(CH2) 0-4 OS(O)2R°;-S(O)2NR°2;-(CH2) 0-4S(O)R°;-N(R°)S(O)2NR°2;-N(R°)S(O)2R°;-N(OR°)R°;-C(NH)NR°2;-P(O)(OR°)R°;-P(O)R°2;-OP(O)R°2;-OP(O)(OR°)2;-SiR°3;-(C 1-4 linear or branched alkylene)ON(R°)2; or -(C 1-4 linear or branched alkylene)C(O)ON(R°)2, where each R° is optionally substituted as defined below and independently represents hydrogen, C 1-6 Aliphatic, -CH2Ph, -O(CH2) 0-1 Ph, -CH2- (a 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 above definitions, two independent occurrences of R° taken together with their intervening atom(s) form a 3-12 membered saturated, partially unsaturated, or aryl monocyclic 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 R° (or the ring formed by two independent occurrences of R° together with their intervening atoms) are independently halogen, —(CH) 0-2 R ● ,-(Halo R ● ), -(CH2) 0-2 OH, -(CH2) 0-2 OR ● , -(CH2) 0-2 CH(OR ● )2, -O(HaloR ● ), -CN, -N3, -(CH2) 0-2 C(O)R ● , -(CH2) 0-2 C(O)OH, -(CH2) 0-2 C(O)OR ● , -(CH2) 0-2 SR ● , -(CH2) 0-2 SH, -(CH2) 0-2 NH2, -(CH2)0-2 NHR ● , -(CH2) 0-2 NR ● 2, -NO2, -SiR ● 3. -OSiR ● 3. -C(O)SR ● , -(C 1-4 Linear or branched alkylene)C(O)OR ● , or -SSR ● where each R ● is unsubstituted or, if preceded by "halo", is substituted only with one or more halogens, and independently, C 1-4 Aliphatic, -CH2Ph, -O(CH2) 0-1 or a 5-6 membered saturated, partially saturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents on a saturated carbon atom of R° include =0 and =S.

[0053] Suitable divalent substituents on a saturated carbon atom of an "optionally substituted" group include ═O, ═S, ═NNR * 2, =NNHC(O)R * , =NNHC(O)OR * , =NNHS(O)2R * , =NR * , =NOR * , -O(C(R * 2)) 2-3 O-, or -S(C(R * 2)) 2-3 S-, where R * Each independent occurrence of is hydrogen, which may be substituted as defined below, C 1-6 and optionally substituted groups are selected from aliphatic or unsubstituted 5-6 membered saturated, partially unsaturated, or aryl rings having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Preferred divalent substituents attached to adjacent substitutable carbon atoms of an "optionally substituted" group include -O(CR * 2) 2-3 O-, where R * Each independent occurrence of is hydrogen, which may be substituted as defined below, C1-6 It is selected from aliphatic or unsubstituted 5-6 membered saturated, partially unsaturated, or aryl rings having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0054] R * Suitable substituents on the aliphatic group include halogen, -R ● ,-(Halo R ● ), -OH, -OR ● , -O(HaloR ● ), -CN, -C(O)OH, -C(O)OR ● , -NH2, -NHR ● , -NR ● 2, or -NO2, where each R ● is unsubstituted or, if preceded by "halo", is substituted only with one or more halogens, and independently, C 1-4 Aliphatic, -CH2Ph, -O(CH2) 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)CHC(O)R † , -S(O)2R † , -S(O)NR † 2. -C(S)NR † 2. -C(NH)NR † 2, or -N(R † )S(O)2R † where each R † are independently hydrogen, C which may be substituted as defined below 1-6an aliphatic, unsubstituted -OPh, or unsubstituted 5-6 membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, regardless of the above definitions, R † two independent occurrences of, taken together with their intervening atom(s), form an unsubstituted 3-12 membered saturated, partially unsaturated, or aryl monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0056] R † Suitable substituents on the aliphatic group are independently halogen, —R ● ,-(Halo R ● ), -OH, -OR ● , -O(HaloR ● ), -CN, -C(O)OH, -C(O)OR ● , -NH2, -NHR ● , -NR ● 2, or -NO2, where each R ● is unsubstituted or, if preceded by "halo", is substituted only with one or more halogens, and independently, C 1-4 Aliphatic, -CH2Ph, -O(CH2) 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] As used herein, the term "isomer" refers to compounds having the same chemical formula but different structural or optical configurations. As used herein, the term "stereoisomer" refers to and includes isomeric molecules having the same molecular formula but differing in the location of atoms and / or functional groups in space. All stereoisomers of the present compounds, including enantiomeric and diastereomeric forms (e.g., those that may exist due to asymmetric carbons on various substituents), are contemplated within the scope of the present disclosure. Thus, unless otherwise specified, single stereochemical isomers of the present compounds as well as mixtures of enantiomeric, diastereomeric, and geometric (or conformational) isomers are within the scope of the present disclosure.

[0058] The term "tautomer," as used herein, refers to one of two or more structural isomers that exist in equilibrium and 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 via reorganization of some of the bonding electrons. Proton tautomers include interconversions via migration of a proton, such as keto-enol isomerization and imine-enamine isomerization. Unless otherwise specified, all tautomers of the disclosed compounds are within the scope of the disclosure.

[0059] The term "isotopic substitution" as used herein refers to replacing an atom with its isotope. The term "isotope" as used herein refers to an atom that has the same atomic number as the atomic number of the atom that is predominant in nature, but has a mass number (number of neutrons) that is different from the mass number of the atom that is predominant in nature. It is understood that a compound with isotopic substitution refers to a compound in which at least one atom contained therein is replaced with its isotope. Atoms that can be replaced with isotopes of an atom include, but are not limited to, hydrogen, carbon, and oxygen. Examples of isotopes of a hydrogen atom include: 2 H (also represented as D) and 3 H. Examples of carbon isotopes include: 13 C and 14 C. Examples of isotopes of the oxygen atom include: 18 O. Unless otherwise specified, all isotopic substitutions of the compounds of the present disclosure are within the scope of the present disclosure. Such compounds are useful, for example, as analytical tools, as probes in biological assays, or as therapeutic agents according to the present disclosure. In certain embodiments, for example, the warhead moiety R of the provided compounds W contains one or more deuterium atoms.

[0060] As used herein, the term "pharmaceutically acceptable salt" refers to salts that 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 that are commensurate with a reasonable benefit / risk ratio. Exemplary pharmaceutically acceptable salts can be found, for example, in Berge et al. (J. Pharm. Sci. 1977, 66(1), 1, and Gould, PL, Int. J. Pharmaceutics 1986, 33, 201-217, each of which is incorporated herein by reference in its entirety.

[0061] Pharmaceutically acceptable salts of the compounds of the present disclosure include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable non-toxic acid addition salts are salts of amino groups 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, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, Examples of the salts include phosphate, 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, and valerate.

[0062] Salts derived from appropriate bases include alkali metal salts, alkaline earth metal salts, ammonium salts, and N + (C 1-4 Representative alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include non-toxic ammonium, quaternary ammonium, and amine cations formed, where appropriate, using counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfonates, and aryl sulfonates.

[0063] Pharmaceutically acceptable salts are intended to include hemi-salts, in which the ratio of compound to acid is 2:1, respectively. Exemplary hemi-salts are salts derived from acids containing 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 salts derived from diprotic mineral acids, such as sulfuric acid. Exemplary preferred hemi-salts include, but are not limited to, hemi-maleate, hemifumarate, and hemi-succinate.

[0064] As used herein, the term "about" is used herein to mean approximately, roughly, roughly, or approximately. When the term "about" is used in conjunction with a numerical range, it modifies the range by extending the boundaries above and below the stated numerical values. Generally, the term "about" is used herein to modify numerical values ​​above and below the stated value by a variance of 20 percent (higher or lower).

[0065] As used herein, an "effective amount," "sufficient amount," or "therapeutically effective amount" is an amount of a compound sufficient to achieve a beneficial or desired result, including a clinical result. Thus, an effective amount may be sufficient, for example, to reduce or ameliorate the severity and / or duration of an affliction associated with ERα signaling or one or more symptoms thereof, prevent the progression of a condition or symptom associated with an affliction associated with ERα signaling, or enhance or otherwise improve the prophylactic or therapeutic effect(s) of another therapy. An effective amount also includes an amount of a compound that avoids or substantially attenuates undesirable side effects.

[0066] As used herein and understood in the art, "treatment" refers to an approach for obtaining beneficial or desired results, including clinical results. Beneficial or desired clinical results can include, but are not limited to, alleviation or amelioration of one or more symptoms or conditions, whether detectable or undetectable, reduction in the severity of the disease or affliction, stabilization (i.e., not worsening) of the disease or affliction, prevention of the spread of the disease or affliction, delay or slowing of the progression of the disease or affliction, improvement or palliation of the disease or affliction, and remission (whether partial or complete). "Treatment" can also mean prolonging survival compared to expected survival in the absence of treatment. In some embodiments, treatment can be administered after the onset of one or more symptoms. In other embodiments, treatment can be administered in the absence of symptoms. For example, treatment can 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 can also be continued after symptoms have resolved, e.g., to prevent or delay the recurrence of symptoms.

[0067] The term "in need thereof" refers to the need for symptomatic or asymptomatic relief from a condition associated with ERα signaling or otherwise that can be alleviated by the compounds and / or compositions of the present disclosure.

[0068] 3. Description of Exemplary Embodiments As noted above, in some embodiments, the present disclosure provides compounds of formula I-1: [ka] A compound of the formula: ERBM, [ka] is selected from, where: [ka] indicates the attachment site 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 ) and X 2 But N(R A2 ), O, CH2, CH(R A3 ), or C(R A3 )2, but However, X 1 and X 2 and R 1 , R 2 , R A1 , R A2 , and R A3 Each instance of R A or R B and R C is replaced by 0 to 4 instances of R 3 Each instance of R A Or R B and R C or two R 3 the groups optionally taken together form a 5-8 membered partially unsaturated or aryl fused ring having 0-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; R AEach instance of 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 )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, R B Each instance of C 1-6 an aliphatic chain; phenyl; naphthyl; cubanyl; adamantyl; a 5-6 membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3-7 membered saturated or partially unsaturated monocyclic carbocycle; a 5-12 membered saturated or partially unsaturated bicyclic carbocycle; a 3-7 membered saturated or partially unsaturated monocyclic heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 7-12 membered saturated or partially unsaturated bicyclic heterocycle having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, R C each instance of 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)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 C 1-6an optionally substituted group selected from a 3- to 7-membered saturated or partially unsaturated monocyclic heterocycle having 1 to 2 heteroatoms independently selected from aliphatic, phenyl, nitrogen, oxygen, and sulfur, and a 5- to 6-membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Each instance of R is independently hydrogen or C 1-6 an optionally substituted group selected from aliphatic, phenyl, a 3- to 7-membered saturated or partially unsaturated monocyclic heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5- to 6-membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or two R groups on the same nitrogen optionally taken together with their intervening atoms form an optionally substituted 4- to 7-membered saturated, partially unsaturated, or heteroaryl ring having, in addition to the nitrogen, 0-3 heteroatoms 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- to 6-membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8- to 10-membered bicyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3- to 7-membered saturated or partially unsaturated monocyclic carbocycle; a 5- to 12-membered saturated or partially unsaturated bicyclic carbocycle; a 3- to 7-membered saturated or partially unsaturated monocyclic heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 7- to 12-membered saturated or partially unsaturated bicyclic heterocycle having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; L is a bivalent moiety connecting the ERBM to the LBM; LBM is a ligase binding moiety; m is 0, 1, 2, 3, or 4; n is 0, 1, 2, 3, or 4; Compounds of formula I-1, or pharmaceutically acceptable salts thereof, are provided wherein p is 0, 1, 2, 3, or 4.

[0069] As noted above, in some embodiments, the present disclosure provides a compound of formula I-1': [ka] A compound of the formula: ERBM, [ka] is selected from, where: [ka] indicates the attachment site of the -L-LBM moiety to a modifiable carbon, oxygen, nitrogen, or sulfur atom of the ERBM moiety; X 1 may be N, NH, CH, CH2, CH(R A1 ) or C(R A1 )2, or C(R A1 ) and X 2 But N(R A2 ), O, CH2, CH(R A3 ), or C(R A3 )2, X 3 But N(R A4 ), O, CH2, CH(R A5 ), or C(R A5 )2, but However, X 1 and X 2 Both or X 2 and X 3 and R 1 , R 2 , R 6 , R A1 , R A2 , R A3 , R A4 , and R A5 Each instance of R A or RB and R C is replaced by 0 to 4 instances of R 3 Each instance of R A Or R B and R C or two R 3 the groups optionally taken together form a 5-8 membered partially unsaturated or aryl fused ring having 0-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; R A Each instance of 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 )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, R B Each instance of C 1-6 an aliphatic chain; phenyl; naphthyl; cubanyl; adamantyl; a 5-6 membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3-7 membered saturated or partially unsaturated monocyclic carbocycle; a 5-12 membered saturated or partially unsaturated bicyclic carbocycle; a 3-7 membered saturated or partially unsaturated monocyclic heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 7-12 membered saturated or partially unsaturated bicyclic heterocycle having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, R Ceach instance of 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)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 C 1-6 an optionally substituted group selected from a 3- to 7-membered saturated or partially unsaturated monocyclic heterocycle having 1 to 2 heteroatoms independently selected from aliphatic, phenyl, nitrogen, oxygen, and sulfur, and a 5- to 6-membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Each instance of R is independently hydrogen or C 1-6 an optionally substituted group selected from aliphatic, phenyl, a 3- to 7-membered saturated or partially unsaturated monocyclic heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5- to 6-membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or two R groups on the same nitrogen optionally taken together with their intervening atoms form an optionally substituted 4- to 7-membered saturated, partially unsaturated, or heteroaryl ring having, in addition to the nitrogen, 0-3 heteroatoms 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- to 6-membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8- to 10-membered bicyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3- to 7-membered saturated or partially unsaturated monocyclic carbocycle; a 5- to 12-membered saturated or partially unsaturated bicyclic carbocycle; a 3- to 7-membered saturated or partially unsaturated monocyclic heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 7- to 12-membered saturated or partially unsaturated bicyclic heterocycle having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Ring C is a spiro-fused 3- to 7-membered saturated or partially unsaturated monocyclic carbocycle; a spiro-fused 5- to 12-membered saturated or partially unsaturated bicyclic carbocycle; a spiro-fused 3- to 7-membered saturated or partially unsaturated monocyclic heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a spiro-fused 7- to 12-membered saturated or partially unsaturated bicyclic heterocycle having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; L is a bivalent moiety connecting the ERBM to the 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; Compounds of formula I-1', or a pharmaceutically acceptable salt thereof, are provided, wherein t is 0, 1, 2, 3, or 4.

[0070] In some embodiments, the LBM is an E3 ligase ligand. Such E3 ligase ligands are well known to those skilled in the art and are described in M. Toure, C. M. Crews, Angew. Chem. Int. Ed. 2016, 55, 1966; T. Uehara et al. Nature Chemical Biology 2017,13,675; WO2017 / 176708, US2017 / 0281784 (LBM corresponds to the cereblon-binding warhead); WO2017 / 161119, US2021 / 0177825 (LBM corresponds to the cereblon E3 ubiquitin ligase-binding moiety CLM); WO2017 / 176957, WO2017 / 176958, WO2017 / 180417, US2019 / 0119289, US2019 / 0169195, US2019 / 0127387 , US2021 / 0002289 (LBM corresponds to B); WO2015 / 160845, WO2016 / 197032, WO2019 / 199816, US2015 / 0291562, US2016 / 0058872, US2018 / 0228907, US2020 / 0155689, US2020 / 0155690, US2022 / 0089570 (LBM corresponds to ULM); WO2016 / 105518, US2018 / 0009779, WO2017 / 0 WO2013 / 106643, US2014 / 0356322 (LBM corresponds to degron); WO2002 / 020740, US2002 / 0068063 (LBM corresponds to A); WO2016 / 118666, US2016 / 0214972 (LBM corresponds to ULM); WO2016 / 149668, US2016 / 0272639 (LBM corresponds to ULM); WO2016 / 169989, US2018 / 0118733 (LBM corresponds to IAP binder); WO2016 / 197114, US2018 / 0147202 (LBM corresponds to ULM); WO2017 / 011371, US2017 / 0008904 (LBM corresponds to ULM); WO2017 / 011590, US2017 / 0037004 (LBM corresponds to ULM); WO2017 / 079267, US2017 / 0121321 (LBM corresponds to ULM);WO2017 / 117473, US2020 / 0216454 (LBM corresponds to degron); WO2017 / 117474, US2019 / 0016703 (LBM corresponds to degron); WO2017 / 197036, US2019 / 0076540 (LBM corresponds to degron); WO2017 / 197046, US2019 / 0076542 (LBM corresponds to degron); WO2017 / 197051, US2019 / 0076539 (LBM corresponds to degron); WO2017 / 197055, US2019 / 0076541 (LBM corresponds to degron); WO2017 / 1970 56 (LBM corresponds to degron), WO2022 / 081928 (LBM corresponds to degron); WO2019 / 060742, US2021 / 0238193 (LBM corresponds to UBM); WO2019 / 140380, US2021 / 0002296 (LBM corresponds to UBM); WO2020 / 010177, US2020 / 0010468 (LBM corresponds to CRBN ligand); WO2020 / 010227 (LBM corresponds to UBM); and WO2021 / 011634 (LBM corresponds to UBM), each of which is incorporated herein by reference in its entirety.

[0071] In some embodiments, L is a bivalent moiety that connects the ERBM to the LBM. Such L moieties are well known to those skilled in the art and are described in detail in M. Toure, C. M. Crews, Angew. Chem. Int. Ed. 2016, 55, 1966; T. Uehara et al. Nature Chemical Biology 2017,13,675; WO2017 / 176708, US2017 / 0281784 (L corresponds to connector C); WO2017 / 161119, US2021 / 0177825 (L corresponds to linker L); WO2017 / 176957, WO2017 / 176958, WO2017 / 180417, US2019 / 0119289, US2019 / 0169195, US2019 / 0127387, US2021 / 0002289 (L corresponds to L WO2015 / 160845, WO2016 / 197032, WO2019 / 199816, US2015 / 0291562, US2016 / 0058872, US2018 / 0228907, US2020 / 0155689, US2020 / 0155690, US2022 / 0089570 (where L corresponds to the chemical linker L); W2016 / 105518, US2018 / 0009779, W2017 / 007612, 2018 / 0134684 (where L corresponds to a linker); WO2013 / 106643, US2014 / 0356322 (L corresponds to a linker group L); WO2016 / 118666, US2016 / 0214972 (L corresponds to L); WO2016 / 149668, US2016 / 0272639 (L corresponds to a linker); WO2016 / 169989, US2018 / 0118733 (L corresponds to L); W2016 / 197114, US2018 / 0147202 (L corresponds to L WO2017 / 011371, US2017 / 0008904 (L corresponds to L); WO2017 / 011590, US2017 / 0037004 (L corresponds to L); WO2017 / 079267, US2017 / 0121321 (L corresponds to L); WO2017 / 117473, US2020 / 0216454 (L corresponds to linker); WO2017 / 117474, US2019 / 0016703 (L corresponds to linker);WO2017 / 197036, US2019 / 0076540 (L corresponds to linker); WO2017 / 197046, US2019 / 0076542 (L corresponds to linker); WO2017 / 197051, US2019 / 0076539 (L corresponds to linker); WO2017 / 197055, US2019 / 0076541 (L corresponds to linker); WO2017 / 197056 (LBM corresponds to degron); WO WO2022 / 081928 (where L corresponds to a linker and / or spacer); WO2019 / 060742, US2021 / 0238193 (where L corresponds to L); WO2019 / 140380, US2021 / 0002296 (where L corresponds to L); WO2020 / 010227 (where L corresponds to L); and WO2021 / 011634 (where L corresponds to L), each of which is incorporated herein by reference in its entirety.

[0072] In some embodiments, the present disclosure provides compounds of formula I-2: [ka] A compound of the formula: ERBM, [ka] is selected from, where: [ka] indicates the attachment site 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 ) and X 2 But N(R A2 ), O, CH2, CH(R A3 ), or C(R A3 )2, but However, X 1 and X 2 and R1 , R 2 , R 4 , R 5 , R A1 , R A2 , and R A3 Each instance of R A or R B and R C is replaced by 0 to 4 instances of R 3 Each instance of R A Or R B and R C or two R 3 the groups optionally taken together form a 5-8 membered partially unsaturated or aryl fused ring having 0-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; R A Each instance of 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 )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, R B Each instance of C 1-6an aliphatic chain; phenyl; naphthyl; cubanyl; adamantyl; a 5-6 membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3-7 membered saturated or partially unsaturated monocyclic carbocycle; a 5-12 membered saturated or partially unsaturated bicyclic carbocycle; a 3-7 membered saturated or partially unsaturated monocyclic heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 7-12 membered saturated or partially unsaturated bicyclic heterocycle having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, R C each instance of 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)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 C 1-6 an optionally substituted group selected from a 3- to 7-membered saturated or partially unsaturated monocyclic heterocycle having 1 to 2 heteroatoms independently selected from aliphatic, phenyl, nitrogen, oxygen, and sulfur, and a 5- to 6-membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Each instance of R is independently hydrogen or C 1-6 an optionally substituted group selected from aliphatic, phenyl, a 3- to 7-membered saturated or partially unsaturated monocyclic heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5- to 6-membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or two R groups on the same nitrogen optionally taken together with their intervening atoms form an optionally substituted 4- to 7-membered saturated, partially unsaturated, or heteroaryl ring having, in addition to the nitrogen, 0-3 heteroatoms 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- to 6-membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8- to 10-membered bicyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3- to 7-membered saturated or partially unsaturated monocyclic carbocycle; a 5- to 12-membered saturated or partially unsaturated bicyclic carbocycle; a 3- to 7-membered saturated or partially unsaturated monocyclic heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 7- to 12-membered saturated or partially unsaturated bicyclic heterocycle having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; L is a bivalent moiety connecting the ERBM to the LBM; LBM, [ka] [ka] 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; Compounds of formula I-2, or pharmaceutically acceptable salts thereof, are provided, wherein s is 0, 1, 2, 3, or 4.

[0073] In some embodiments, the present disclosure provides compounds of formula I-2': [ka] A compound of the formula: ERBM, [ka] is selected from, where: [ka] indicates the attachment site of the -L-LBM moiety to a modifiable carbon, oxygen, nitrogen, or sulfur atom of the ERBM moiety; X 1 may be N, NH, CH, CH2, CH(R A1 ) or C(R A1 )2, or C(R A1 ) and X 2 But N(R A2 ), O, CH2, CH(R A3 ), or C(R A3 )2, X 3 But N(R A4 ), O, CH2, CH(R A5 ), or C(R A5 )2, but However, X 1 and X 2 Both or X 2 and X 3 and R 1 , R 2 , R 4 , R 5 , R 6 , R A1 , R A2 , R A3 .R A4 , and R A5 Each instance of R A or R B and R C is replaced by 0 to 4 instances of R 3 Each instance of R A Or R B and R C or two R 3the groups optionally taken together form a 5-8 membered partially unsaturated or aryl fused ring having 0-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; R A Each instance of 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 )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, R B Each instance of C 1-6 an aliphatic chain; phenyl; naphthyl; cubanyl; adamantyl; a 5-6 membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3-7 membered saturated or partially unsaturated monocyclic carbocycle; a 5-12 membered saturated or partially unsaturated bicyclic carbocycle; a 3-7 membered saturated or partially unsaturated monocyclic heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 7-12 membered saturated or partially unsaturated bicyclic heterocycle having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, R Ceach instance of 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)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 C 1-6 an optionally substituted group selected from a 3- to 7-membered saturated or partially unsaturated monocyclic heterocycle having 1 to 2 heteroatoms independently selected from aliphatic, phenyl, nitrogen, oxygen, and sulfur, and a 5- to 6-membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Each instance of R is independently hydrogen or C 1-6 an optionally substituted group selected from aliphatic, phenyl, a 3- to 7-membered saturated or partially unsaturated monocyclic heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5- to 6-membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or two R groups on the same nitrogen optionally taken together with their intervening atoms form an optionally substituted 4- to 7-membered saturated, partially unsaturated, or heteroaryl ring having, in addition to the nitrogen, 0-3 heteroatoms 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- to 6-membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8- to 10-membered bicyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3- to 7-membered saturated or partially unsaturated monocyclic carbocycle; a 5- to 12-membered saturated or partially unsaturated bicyclic carbocycle; a 3- to 7-membered saturated or partially unsaturated monocyclic heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 7- to 12-membered saturated or partially unsaturated bicyclic heterocycle having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Ring C is a spiro-fused 3- to 7-membered saturated or partially unsaturated monocyclic carbocycle; a spiro-fused 5- to 12-membered saturated or partially unsaturated bicyclic carbocycle; a spiro-fused 3- to 7-membered saturated or partially unsaturated monocyclic heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a spiro-fused 7- to 12-membered saturated or partially unsaturated bicyclic heterocycle having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; L is a bivalent moiety connecting the ERBM to the LBM; LBM, [ka] [ka] 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; Compounds of formula I-2', or a pharmaceutically acceptable salt thereof, are provided, wherein t is 0, 1, 2, 3, or 4.

[0074] In some embodiments, the present disclosure provides compounds of formula I-3: [ka] A compound of the formula: ERBM, [ka] is selected from, where: [ka] indicates the attachment site 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 ) and X 2 But N(R A2 ), O, CH2, CH(R A3 ), or C(R A3 )2, but However, X 1 and X 2 and R 1 , R 2 , R 4 , R 5 , R A1 , R A2 , and R A3 Each instance of R A or R B and R C is replaced by 0 to 4 instances of R 3 Each instance of R A Or R B and R C or two R 3 the groups optionally taken together form a 5-8 membered partially unsaturated or aryl fused ring having 0-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; R AEach instance of 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 )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, R B Each instance of C 1-6 an aliphatic chain; phenyl; naphthyl; cubanyl; adamantyl; a 5-6 membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3-7 membered saturated or partially unsaturated monocyclic carbocycle; a 5-12 membered saturated or partially unsaturated bicyclic carbocycle; a 3-7 membered saturated or partially unsaturated monocyclic heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 7-12 membered saturated or partially unsaturated bicyclic heterocycle having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, R C each instance of 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)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 C 1-6an optionally substituted group selected from a 3- to 7-membered saturated or partially unsaturated monocyclic heterocycle having 1 to 2 heteroatoms independently selected from aliphatic, phenyl, nitrogen, oxygen, and sulfur, and a 5- to 6-membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Each instance of R is independently hydrogen or C 1-6 an optionally substituted group selected from aliphatic, phenyl, a 3- to 7-membered saturated or partially unsaturated monocyclic heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5- to 6-membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or two R groups on the same nitrogen optionally taken together with their intervening atoms form an optionally substituted 4- to 7-membered saturated, partially unsaturated, or heteroaryl ring having, in addition to the nitrogen, 0-3 heteroatoms 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- to 6-membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8- to 10-membered bicyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3- to 7-membered saturated or partially unsaturated monocyclic carbocycle; a 5- to 12-membered saturated or partially unsaturated bicyclic carbocycle; a 3- to 7-membered saturated or partially unsaturated monocyclic heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 7- to 12-membered saturated or partially unsaturated bicyclic heterocycle having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; L is a covalent bond or a divalent, saturated or unsaturated, linear or branched C 1-50 a hydrocarbon chain, wherein 0 to 6 methylene units of L are independently -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)-, -C(O)NR-, -OC(O)NR-, -NRC(O)O-, [ka] is replaced by wherein each -Cy- is independently selected from phenylenyl, 8- to 10-membered bicyclic arylenyl, 4- to 7-membered saturated or partially unsaturated carbocyclylenyl, 5- to 11-membered saturated or partially unsaturated spirocarbocyclylenyl, 8- to 10-membered bicyclic saturated or partially unsaturated carbocyclylenyl, 4- to 7-membered saturated or partially unsaturated heterocyclylenyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 5- to 11-membered saturated or partially unsaturated spiroheterocyclylenyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, nitrogen, oxygen, and an optionally substituted bivalent ring selected from an 8- to 10-membered bicyclic saturated or partially unsaturated heterocyclyl having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 6- to 10-membered bridged bicyclic saturated or partially unsaturated heterocyclyl having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5- to 6-membered heteroarylenyl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or an 8- to 10-membered bicyclic heteroarylenyl having 1 to 5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; LBM, [ka] [ka] 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 q is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; r is 0, 1, 2, 3, or 4; Compounds of formula I-3, or pharmaceutically acceptable salts thereof, are provided, wherein s is 0, 1, 2, 3, or 4.

[0075] In one embodiment, a compound of formula I-3': [ka] A compound of the formula: ERBM, [ka] is selected from, where: [ka] indicates the attachment site of the -L-LBM moiety to a modifiable carbon, oxygen, nitrogen, or sulfur atom of the ERBM moiety; X 1 may be N, NH, CH, CH2, CH(R A1 ) or C(R A1 )2, or C(R A1 ) and X 2 But N(R A2 ), O, CH2, CH(R A3 ), or C(R A3 )2, X 3 But N(R A4 ), O, CH2, CH(R A5 ), or C(R A5 )2, but However, X 1 and X 2 Both or X 2 and X 3 and R 1 , R 2 , R 4 , R 5 , R 6 , R A1 , R A2 , R A3 , R A4 , and R A5Each instance of R A or R B and R C is replaced by 0 to 4 instances of R 3 Each instance of R A Or R B and R C or two R 3 the groups optionally taken together form a 5-8 membered partially unsaturated or aryl fused ring having 0-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; R A Each instance of 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 )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, R B Each instance of C 1-6 an aliphatic chain; phenyl; naphthyl; cubanyl; adamantyl; a 5-6 membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3-7 membered saturated or partially unsaturated monocyclic carbocycle; a 5-12 membered saturated or partially unsaturated bicyclic carbocycle; a 3-7 membered saturated or partially unsaturated monocyclic heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 7-12 membered saturated or partially unsaturated bicyclic heterocycle having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, R Ceach instance of 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)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 C 1-6 an optionally substituted group selected from a 3- to 7-membered saturated or partially unsaturated monocyclic heterocycle having 1 to 2 heteroatoms independently selected from aliphatic, phenyl, nitrogen, oxygen, and sulfur, and a 5- to 6-membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Each instance of R is independently hydrogen or C 1-6 an optionally substituted group selected from aliphatic, phenyl, a 3- to 7-membered saturated or partially unsaturated monocyclic heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5- to 6-membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or two R groups on the same nitrogen optionally taken together with their intervening atoms form an optionally substituted 4- to 7-membered saturated, partially unsaturated, or heteroaryl ring having, in addition to the nitrogen, 0-3 heteroatoms 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- to 6-membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8- to 10-membered bicyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3- to 7-membered saturated or partially unsaturated monocyclic carbocycle; a 5- to 12-membered saturated or partially unsaturated bicyclic carbocycle; a 3- to 7-membered saturated or partially unsaturated monocyclic heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 7- to 12-membered saturated or partially unsaturated bicyclic heterocycle having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Ring C is a spiro-fused 3- to 7-membered saturated or partially unsaturated monocyclic carbocycle; a spiro-fused 5- to 12-membered saturated or partially unsaturated bicyclic carbocycle; a spiro-fused 3- to 7-membered saturated or partially unsaturated monocyclic heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a spiro-fused 7- to 12-membered saturated or partially unsaturated bicyclic heterocycle having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; L is a covalent bond or a divalent, saturated or unsaturated, linear or branched C 1-50 a hydrocarbon chain, wherein 0 to 6 methylene units of L are independently -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)-, -C(O)NR-, -OC(O)NR-, -NRC(O)O-, [ka] is replaced by wherein each -Cy- is independently selected from phenylenyl, 8- to 10-membered bicyclic arylenyl, 4- to 7-membered saturated or partially unsaturated carbocyclylenyl, 5- to 11-membered saturated or partially unsaturated spirocarbocyclylenyl, 8- to 10-membered bicyclic saturated or partially unsaturated carbocyclylenyl, 4- to 7-membered saturated or partially unsaturated heterocyclylenyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 5- to 11-membered saturated or partially unsaturated spiroheterocyclylenyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, nitrogen, oxygen, and an optionally substituted bivalent ring selected from an 8- to 10-membered bicyclic saturated or partially unsaturated heterocyclyl having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 6- to 10-membered bridged bicyclic saturated or partially unsaturated heterocyclyl having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5- to 6-membered heteroarylenyl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or an 8- to 10-membered bicyclic heteroarylenyl having 1 to 5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; LBM, [ka] [ka] 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 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; Compounds of formula I-3', or a pharmaceutically acceptable salt thereof, are provided wherein t is 0, 1, 2, 3, or 4.

[0076] In some embodiments, the disclosure provides a compound of Formula I-1, Formula I-1′, Formula I-2, Formula I-2′, Formula I-3, or Formula I-3′, or any subgenus thereof, with the proviso that the ERBM is: [ka] (In the formula, 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 to 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; R 2 -OH, -Me, -OMe, -F, -Br, -CF3, and - i Pr), LBM, [ka] or a stereoisomer thereof.

[0077] In some embodiments, the disclosure provides a compound of Formula I-1, Formula I-1′, Formula I-2, Formula I-2′, Formula I-3, or Formula I-3′, or any subgenus thereof, with the proviso that the ERBM is: [ka] (In the formula, X 1 is CH or N, X 2 is CH2, Ring B is phenyl, When Ring A is phenyl or a 6-membered monocyclic heteroaryl ring having 1 to 3 nitrogen heteroatoms, R 3 is not -OH or -OMe.

[0078] In some embodiments, the disclosure provides a compound of Formula I-1, Formula I-1′, Formula I-2, Formula I-2′, Formula I-3, or Formula I-3′, or any subgenus thereof, with the proviso that the ERBM is: [ka] (In the formula, X 1 is CH or N, X 2 is CH2, Ring B is phenyl, provided that ring A is not phenyl or a 6-membered monocyclic heteroaryl ring having 1 to 3 nitrogen heteroatoms.

[0079] In some embodiments, the disclosure provides a compound of Formula I-1, Formula I-1′, Formula I-2, Formula I-2′, Formula I-3, or Formula I-3′, provided that the ERBM is [ka] and X 1 is CH or N, and X 2 is CH2 and ring B is phenyl, provided that ring A is other than phenyl or a 6-membered monocyclic heteroaryl ring having 1-3 nitrogen heteroatoms.

[0080] As generally defined above, an ERBM is an ERα binding moiety that is capable of binding to ERα.

[0081] As broadly defined above, ERBM is: [ka] is selected, where [ka] indicates the attachment site of the -L-LBM moiety to a modifiable carbon, oxygen, nitrogen, or sulfur atom of the ERBM moiety, where X1, X2, X3, 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.

[0082] In some embodiments, the ERBM is [ka] is.

[0083] In some embodiments, the ERBM is [ka] is.

[0084] In some embodiments, the ERBM is [ka] In some embodiments, the ERBM is [ka] In some embodiments, the ERBM is [ka] In some embodiments, the ERBM is [ka] is.

[0085] In some embodiments, the ERBM is [ka]

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some embodiments, the ERBM is [ka] In some embodiments, the ERBM is [ka] In some embodiments, the ERBM is [ka] In some embodiments, the ERBM is [ka] In some embodiments, the ERBM is [ka] In some embodiments, the ERBM is [ka] In some embodiments, the ERBM is [ka] In some embodiments, the ERBM is [ka] In some embodiments, the ERBM is [ka] In some embodiments, the ERBM is [ka] In some embodiments, the ERBM is [ka] In some embodiments, the ERBM is [ka] In some embodiments, the ERBM is [ka] In some embodiments, the ERBM is [ka] In some embodiments, the ERBM is [ka] In some embodiments, the ERBM is [ka] In some embodiments, the ERBM is [ka] In some embodiments, the ERBM is [ka] In some embodiments, the ERBM is [ka] In some embodiments, the ERBM is [ka] In some embodiments, the ERBM is [ka] In some embodiments, the ERBM is [ka] In some embodiments, the ERBM is [ka] In some embodiments, the ERBM is [ka] In some embodiments, the ERBM is [ka] In some embodiments, the ERBM is [ka] In some 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[ka] In some embodiments, the ERBM is [ka] In some embodiments, the ERBM is [ka] In some embodiments, the ERBM is [ka] In some embodiments, the ERBM is [ka] In some embodiments, the ERBM is [ka] In some embodiments, the ERBM is [ka] In some embodiments, the ERBM is [ka] In some embodiments, the ERBM is [ka] In some embodiments, the ERBM is [ka] In some embodiments, the ERBM is [ka] In some embodiments, the ERBM is [ka] In some embodiments, the ERBM is [ka] In some embodiments, the ERBM is [ka] In some embodiments, the ERBM is [ka] In some embodiments, the ERBM is [ka] In some embodiments, the ERBM is [ka] In some embodiments, the ERBM is [ka] In some embodiments, the ERBM is [ka] In some embodiments, the ERBM is [ka] In some embodiments, the ERBM is [ka] In some embodiments, the ERBM is [ka] In some embodiments, the ERBM is [ka] In some embodiments, the ERBM is [ka] In some embodiments, the ERBM is [ka] In some embodiments, the ERBM is [ka] In some embodiments, the ERBM is [ka] In some embodiments, the ERBM is [ka] In some embodiments, the ERBM is [ka] In some embodiments, the ERBM is [ka] In some embodiments, the ERBM is [ka] In some embodiments, the ERBM is [ka] In some embodiments, the ERBM is [ka] In some embodiments, the ERBM is [ka] In some embodiments, the ERBM is [ka] In some embodiments, the ERBM is [ka] In some embodiments, the ERBM is [ka] In some embodiments, the ERBM is [ka] In some embodiments, the ERBM is [ka] In some embodiments, the ERBM is [ka] In some embodiments, the ERBM is [ka] In some embodiments, the ERBM is [ka] In some embodiments, the ERBM is [ka] In some embodiments, the ERBM is [ka] In some embodiments, the ERBM is [ka] In some embodiments, the ERBM is [ka] In some embodiments, the ERBM is [ka] In some embodiments, the ERBM is [ka] In some embodiments, the ERBM is [ka] In some embodiments, the ERBM is [ka] In some embodiments, the ERBM is [ka] In some embodiments, the ERBM is [ka] In some embodiments, the ERBM is [ka] In some embodiments, the ERBM is [ka] In some embodiments, the ERBM is [ka] In some embodiments, the ERBM is [ka] In some embodiments, the ERBM is [ka] In some embodiments, the ERBM is [ka] In some embodiments, the ERBM is [ka] In some embodiments, the ERBM is [ka] In some embodiments, the ERBM is [ka] In some embodiments, the ERBM is [ka] In some embodiments, the ERBM is [ka] In some embodiments, the ERBM is [ka] In some embodiments, the ERBM is [ka] In some embodiments, the ERBM is [ka] In some embodiments, the ERBM is [ka] In some embodiments, the ERBM is [ka] In some embodiments, the ERBM is [ka] In some embodiments, the ERBM is [ka] In some embodiments, the ERBM is [ka] In some embodiments, the ERBM is [ka] In some embodiments, the ERBM is [ka] In some embodiments, the ERBM is [ka] In some embodiments, the ERBM is [ka] In some embodiments, the ERBM is [ka] In some embodiments, the ERBM is [ka] In some embodiments, the ERBM is [ka] In some embodiments, the ERBM is [ka] In some embodiments, the ERBM is [ka] In some embodiments, the ERBM is [ka] In some embodiments, the ERBM is [ka] In some embodiments, the ERBM is [ka] In some embodiments, the ERBM is [ka] In some embodiments, the ERBM is [ka] In some embodiments, the ERBM is [ka] In some embodiments, the ERBM is [ka] In some embodiments, the ERBM is [ka] In some embodiments, the ERBM is [ka] In some embodiments, the ERBM is [ka] In some embodiments, the ERBM is [ka] In some embodiments, the ERBM is [ka] In some embodiments, the ERBM is [ka] In some embodiments, the ERBM is [ka] In some embodiments, the ERBM is [ka] In some embodiments, the ERBM is [ka] In some embodiments, the ERBM is [ka] In some embodiments, the ERBM is [ka] In some embodiments, the ERBM is [ka] In some embodiments, the ERBM is [ka] In some embodiments, the ERBM is [ka] In some embodiments, the ERBM is [ka] In some embodiments, the ERBM is [ka] In some embodiments, the ERBM is [ka] In some embodiments, the ERBM is [ka] In some embodiments, the ERBM is [ka] In some embodiments, the ERBM is [ka] In some embodiments, the ERBM is [ka] In some embodiments, the ERBM is [ka] In some embodiments, the ERBM is [ka] In some embodiments, the ERBM is [ka] In some embodiments, the ERBM is [ka] In some embodiments, the ERBM is [ka] In some embodiments, the ERBM is [ka] In some embodiments, the ERBM is [ka] In some embodiments, the ERBM is [ka] In some embodiments, the ERBM is [ka] In some embodiments, the ERBM is [ka] In some embodiments, the ERBM is [ka] In some embodiments, the ERBM is [ka] In some embodiments, the ERBM is [ka] In some embodiments, the ERBM is [ka] In some embodiments, the ERBM is [ka] In some embodiments, the ERBM is [ka] In some embodiments, the ERBM is [ka] In some embodiments, the ERBM is [ka] In some embodiments, the ERBM is [ka] In some embodiments, the ERBM is [ka] In some embodiments, the ERBM is [ka] In some embodiments, the ERBM is [ka] In some embodiments, the ERBM is [ka] In some embodiments, the ERBM is [ka] In some embodiments, the ERBM is [ka] In some embodiments, the ERBM is [ka] In some embodiments, the ERBM is [ka] In some embodiments, the ERBM is [ka] In some embodiments, the ERBM is [ka] In some embodiments, the ERBM is [ka] In some embodiments, the ERBM is [ka] In some embodiments, the ERBM is [ka] In some embodiments, the ERBM is [ka] In some embodiments, the ERBM is [ka] In some embodiments, the ERBM is [ka] In some embodiments, the ERBM is [ka] In some embodiments, the ERBM is [ka] In some embodiments, the ERBM is [ka] In some embodiments, the ERBM is [ka] In some embodiments, the ERBM is [ka] In some embodiments, the ERBM is [ka] In some embodiments, the ERBM is [ka] In some embodiments, the ERBM is [ka] In some embodiments, the ERBM is [ka] In some embodiments, the ERBM is [ka] In some embodiments, the ERBM is [ka] In some embodiments, the ERBM is [ka] In some embodiments, the ERBM is [ka] In some embodiments, the ERBM is [ka] In some embodiments, the ERBM is [ka] In some embodiments, the ERBM is [ka] In some embodiments, the ERBM is [ka] In some embodiments, the ERBM is [ka] In some embodiments, the ERBM is [ka] In some embodiments, the ERBM is [ka] In some embodiments, the ERBM is [ka] In some embodiments, the ERBM is [ka] In some embodiments, the ERBM is [ka] In some embodiments, the ERBM is [ka] In some embodiments, the ERBM is [ka] In some embodiments, the ERBM is [ka] In some embodiments, the ERBM is [ka] In some embodiments, the ERBM is [ka] In some embodiments, the ERBM is [ka] In some embodiments, the ERBM is [ka] In some embodiments, the ERBM is [ka] In some embodiments, the ERBM is [ka] In some embodiments, the ERBM is [ka] In some embodiments, the ERBM is [ka] is.

[0087] In some embodiments, the ERBM is selected from the group shown in Table 1 or Table 2 compounds.

[0088] Generally, as defined above, X 1 is N, NH, CH, CH2, CH(R A1 ), C(R A1 )2, or C(R A1 In some embodiments, X 1 is CH2.

[0089] In some embodiments, X 1 is CH(R A1 )

[0090] In some embodiments, X 1 is C(R A1 )

[0091] In some embodiments, 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 group shown in the compounds of Table 1 or Table 2.

[0095] Generally, as defined 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. 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 group shown in the compounds of Table 1 or Table 2.

[0098] Generally as defined herein, X 3 is N(R A4 ), O, CH2, CH(R A5 ), or C(R A5 )2.

[0099] In some embodiments, X 3 are O, CH2, CH(R A5 ), or C(R A5)2.

[0100] In some embodiments, X 3 is O.

[0101] In some embodiments, X 3 is CH2.

[0102] In some embodiments, X 3 is CH(R A5 )

[0103] In some embodiments, X 3 is C(R A5 )2.

[0104] Generally, as defined above, R 1 , R 2 , R 4 , R 5 , R 6 , R A1 , R A2 , R A3 , R A4 , and R A5 Each instance of R A or R B and R C is replaced by 0 to 4 instances of

[0105] In some embodiments, R 1 is R C R replaced by 0 to 4 instances of A In some embodiments, R 1 is R C R replaced by 0 to 4 instances of B is.

[0106] In some embodiments, each R 1 are independently substituted with 0 to 3 instances of deuterium, halo, 1-6and -N(R)S(O)R, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR, -N(R)S(O)NR, and -N(R)S(O)R, where R is selected from an aliphatic chain, halogen, -CN, -SR, -OR, -NR, -S(O)R, -S(O)NR, -S(O)R, -S(O)NR, -S(O)(NR)R, -C(O)OR, -C(O)NR, -C(O)N(R)OR, -OC(O)NR, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR, -N(R)S(O)NR, and -N(R)S(O)R, where R is C substituted with 0-3 instances of H or halo. 1-6 It is an aliphatic chain.

[0107] In some embodiments, each R 1 are independently selected from -Me, -Et, -F, -Cl, -SCF3, -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 group shown in the compounds of Table 1 or Table 2.

[0111] In some embodiments, R 2 is R C R replaced by 0 to 4 instances of A In some embodiments, R 2 is R C R replaced by 0 to 4 instances of B is.

[0112] In some embodiments, each R 2 are independently substituted with 0 to 3 instances of deuterium, halo, 1-6selected from an aliphatic chain, halogen, —CN, —OR, —NR2, —S(O)2R, —S(O)2NR2, —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, where R is H or C 1-6 It is an aliphatic chain.

[0113] In some embodiments, each R 2 are independently selected from -Me, -Et, -F, -Cl, -CF3, -CN, -OH, -OMe, -NH2, -NHMe, and -NMe2.

[0114] In some embodiments, each R 2 is independently selected from -Me, -F, and -CF3.

[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 group shown in the compounds of Table 1 or Table 2.

[0117] In some embodiments, R 4 is R C R replaced by 0 to 4 instances of A In some embodiments, R 4 is R C R replaced by 0 to 4 instances of B is.

[0118] In some embodiments, each R 4 are independently substituted with 0 to 3 instances of deuterium, halo, 1-6and -N(R)S(O)R, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR, -N(R)S(O)NR, and -N(R)S(O)R, wherein R is H or C. 1-6 It is an aliphatic chain.

[0119] In some embodiments, each R 4 are independently selected from -Me, -Et, -F, -Cl, -CF3, -CN, -OH, -OMe, -NH2, -NHMe, and -NMe2.

[0120] In some embodiments, R 4 is -F.

[0121] In some embodiments, R 4 is selected from the group shown in the compounds of Table 1 or Table 2.

[0122] In some embodiments, R 5 is R C R replaced by 0 to 4 instances of A In some embodiments, R 5 is R C R replaced by 0 to 4 instances of B is.

[0123] In some embodiments, each R 5 are independently substituted with 0 to 3 instances of deuterium, halo, 1-6 and -N(R)S(O)R, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR, -N(R)S(O)NR, and -N(R)S(O)R, wherein R is H or C. 1-6 It is an aliphatic chain.

[0124] In some embodiments, each R 5 are independently selected from -Me, -Et, -F, -Cl, -CF3, -CN, -OH, -OMe, -NH2, -NHMe, and -NMe2.

[0125] In some embodiments, each R 5 is independently selected from -Me and -F.

[0126] In some embodiments, R 5 is selected from the group shown in the compounds of Table 1 or Table 2.

[0127] In some embodiments, each R 6 are independently selected from -Me, -Et, -F, -Cl, -CF, -COH, -CN, -OH, -OMe, -NH, -NHMe, and -NMe.

[0128] In some embodiments, each R 6 is independently selected from -Me and -F.

[0129] In some embodiments, R 6 is selected from the group shown in the compounds of Table 1 or Table 2.

[0130] In some embodiments, R A1 is R C R replaced by 0 to 4 instances of A In some embodiments, R A1 is R C R replaced by 0 to 4 instances of B is.

[0131] In some embodiments, each R A1 is independently substituted with 0-3 instances of deuterium, halo, or hydroxy; 1-6and -N(R)S(O)R, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR, -N(R)S(O)NR, and -N(R)S(O)R, wherein R is H or C. 1-6 It is an aliphatic chain.

[0132] In some embodiments, each R A1 is independently substituted with 0-3 instances of deuterium, halo, or hydroxy; 1-6 It is selected from an aliphatic chain and a halogen.

[0133] In some embodiments, each R A1 C substituted with 0-3 instances of halo or hydroxy 1-6 It is selected from an aliphatic chain and a halogen.

[0134] In some embodiments, each R A1 C substituted with 0-3 instances of halo or hydroxy 1-6 It is an aliphatic chain.

[0135] In some embodiments, each R A1 -F, -Me, -Et, - i Pr, -CH=CH-C(CH3)3, -CH 2- CH(CH3)2, -CH 2- C(CH3)3, -CH2CH 2- C(CH3)3, -C(CH3)3, -CH 2- CH(CH3)2, -C(CH3)2OH, -CH2CH 2- It is selected from C(CH3)2OH, -CH2CF3, -CH2-cyclopropyl, -CH(CH3)-cyclopropyl, and -CH2-cyclopentyl.

[0136] In some embodiments, each R A1 -F, -Me, -Et, - iPr, -CH=CH-C(CH3)3, -CH 2- C(CH3)3, -CH2CH 2- C(CH3)3, -C(CH3)3, -CH 2- CH(CH3)2, -CH2CH 2- C(CH3)2OH, and -CH2-cyclopentyl.

[0137] In some embodiments, each R A1 -Me, -Et, - i Pr, -CH=CH-C(CH3)3, -CH 2- C(CH3)3, -CH2CH 2- C(CH3)3, -C(CH3)3, -CH 2- CH(CH3)2, -CH2CH 2- C(CH3)2OH, and -CH2-cyclopentyl.

[0138] In some embodiments, each R A1 are independently selected from -Me, -Et, -F, -Cl, -CF3, -CN, -OH, -OMe, -NH2, -NHMe, and -NMe2.

[0139] In some embodiments, each R A1 is independently selected from -Me, -F, -OH, and -OMe. 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 group shown in the compounds of Table 1 or Table 2.

[0141] In some embodiments, R A2 is R C R replaced by 0 to 4 instances of A In some embodiments, R A2 is R CR replaced by 0 to 4 instances of B is.

[0142] In some embodiments, R A2 is selected from the group shown in the compounds of Table 1 or Table 2.

[0143] In some embodiments, each R A2 are independently substituted with 0 to 3 instances of deuterium, halo, 1-6 an aliphatic chain selected from -S(O)R, -S(O)NR, -S(O)R, -S(O)NR, -S(O)(NR)R, -C(O)NR, -C(O)OR, and -C(O)R, where R is H or C 1-6 It is an aliphatic chain.

[0144] In some embodiments, each R A2 are independently selected from -Me, -Et, -CHCF, -S(O)Me, -S(O)NMe, -S(O)Me, -S(O)NMe, -C(O)NMe, -C(O)NR, -C(O)OMe, and -C(O)Me.

[0145] In some embodiments, each R A2 is independently selected from -Me, -CHCF, 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 C R replaced by 0 to 4 instances of A In some embodiments, R A3 is R C R replaced by 0 to 4 instances of B is.

[0147] In some embodiments, each R A3 are independently substituted with 0 to 3 instances of deuterium, halo, 1-6 and -N(R)S(O)R, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR, -N(R)S(O)NR, and -N(R)S(O)R, wherein R is H or C. 1-6 It is an aliphatic chain.

[0148] In some embodiments, each R A3 are independently selected from -Me, -Et, -F, -Cl, -CF3, -CN, -OH, -OMe, -NH2, -NHMe, and -NMe2.

[0149] In some embodiments, each R A3 is independently selected from -Me, -F, -OH, and -OMe. 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 group shown in the compounds of Table 1 or Table 2.

[0151] Generally, as defined above, R 3 are independent, R A Or R B and R C or two R 3 The groups optionally join together to form a 5-8 membered partially unsaturated or aryl fused ring having 0-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0152] In some embodiments, R 3 is R C R replaced by 0 to 4 instances of A In some embodiments, R 3 is R C R replaced by 0 to 4 instances of B In some embodiments, two R 3 The groups optionally join 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 are independently substituted with 0 to 3 instances of deuterium, halo, 1-6 selected from an aliphatic chain, halogen, —CN, —OR, —NR2, —S(O)2R, —S(O)2NR2, —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, where R is H or C 1-6 It is an aliphatic chain.

[0154] In some embodiments, each R 3 are independently selected from -Me, -Et, -F, -Br, -B(OH), -Cl, -CF, -COH, -CN, -OH, -OMe, -NH, -NHMe, and -NMe.

[0155] In some embodiments, each R 3 are independently selected from -Me, -Br, -B(OH), -Cl, -CF, -COH, -CN, -OH, -OMe, and -NH.

[0156] In some embodiments, R 3 is selected from —F, —OH, and —COH.

[0157] In some embodiments, R3 is selected from —F and —OH.

[0158] In some embodiments, R 3 is —OH. In some embodiments, R 3 is —COH. In some embodiments, R 3 is fluoro. In some embodiments, two R 3 The foundation comes together, [ka] In some embodiments, R 3 is selected from -Me, -F, -OH, and -COH. In some embodiments, R 3 is selected from -Me, -CF, 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 group shown in the compounds of Table 1 or Table 2.

[0159] Generally, as defined above, R A each instance of independently represents 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 )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.

[0160] In some embodiments, R Ameans 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)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.

[0161] In some embodiments, R A is independently selected from deuterium, halogen, —CN, —OR, —NR2, —S(O)2R, —S(O)2NR2, —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, where R is H or C 1-6 It is an aliphatic chain.

[0162] In some embodiments, R A is -F. In some embodiments, R A is —OH. In some embodiments, R A is -CO2H.

[0163] In some embodiments, R A is selected from the group shown in the compounds of Table 1 or Table 2.

[0164] Generally, as defined above, R B Each instance of C is independent. 1-6an aliphatic chain; phenyl; naphthyl; cubanyl; adamantyl; a 5- to 6-membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8- to 10-membered bicyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3- to 7-membered saturated or partially unsaturated monocyclic carbocycle; a 5- to 12-membered saturated or partially unsaturated bicyclic carbocycle; a 3- to 7-membered saturated or partially unsaturated monocyclic heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 7- to 12-membered saturated or partially unsaturated bicyclic heterocycle having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0165] In some embodiments, R B is C 1-6 an aliphatic chain; phenyl; naphthyl; cubanyl; adamantyl; a 5- to 6-membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8- to 10-membered bicyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3- to 7-membered saturated or partially unsaturated monocyclic carbocycle; a 5- to 12-membered saturated or partially unsaturated bicyclic carbocycle; a 3- to 7-membered saturated or partially unsaturated monocyclic heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 7- to 12-membered saturated or partially unsaturated bicyclic heterocycle having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0166] In some embodiments, each R B is C substituted with 0 to 3 instances of halo 1-6 It is an aliphatic chain.

[0167] In some embodiments, R B is methyl. In some embodiments, R B That R C Together with the substituents it is trifluoromethyl.

[0168] In some embodiments, R Bis selected from the group shown in the compounds of Table 1 or Table 2.

[0169] Generally, as defined above, R C each instance of 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)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 C 1-6 An optionally substituted group selected from aliphatic, phenyl, 3- to 7-membered saturated or partially unsaturated monocyclic heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0170] In some embodiments, R C is 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)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 C 1-6 An optionally substituted group selected from aliphatic, phenyl, 3- to 7-membered saturated or partially unsaturated monocyclic heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered monocyclic heteroaryl ring having 1 to 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 group shown in the compounds of Table 1 or Table 2.

[0173] As generally defined above, each instance of R is independently hydrogen, or C 1-6 an optionally substituted group selected from a 3- to 7-membered saturated or partially unsaturated monocyclic heterocycle having 1-2 heteroatoms independently selected from aliphatic, phenyl, nitrogen, oxygen, and sulfur, and a 5- to 6-membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or two R groups on the same nitrogen optionally joined with their intervening atoms to form an optionally substituted 4- to 7-membered saturated, partially unsaturated, or heteroaryl ring having, in addition to the nitrogen, 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0174] In some embodiments, R is hydrogen or C 1-6 an optionally substituted group selected from a 3- to 7-membered saturated or partially unsaturated monocyclic heterocycle having 1-2 heteroatoms independently selected from aliphatic, phenyl, nitrogen, oxygen, and sulfur, and a 5- to 6-membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or two R groups on the same nitrogen optionally joined with their intervening atoms to form an optionally substituted 4- to 7-membered saturated, partially unsaturated, or heteroaryl ring having, in addition to the nitrogen, 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0175] In some embodiments, R is H or C 1-6 In some embodiments, R is selected from the group consisting of C 1-6It is an aliphatic chain.

[0176] In some embodiments, R is H, -Me, -Et, -Pr, - i Pr, and - t In some embodiments, R is selected from -Bu. In some embodiments, R is selected from H or -Me. In some embodiments, R is -Me. In some embodiments, R is H.

[0177] In some embodiments, R is selected from the group shown in the compounds of Table 1 or Table 2.

[0178] As generally defined above, ring A and ring B are each independently phenyl; 1,1'-biphenyl; naphthyl; tetrahydronaphthalenyl; dihydroindenyl; benzocyclobutenyl; cubanyl; adamantyl; a 5- to 6-membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8- to 10-membered bicyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3- to 7-membered saturated or partially unsaturated monocyclic carbocycle; a 5- to 12-membered saturated or partially unsaturated bicyclic carbocycle; a 3- to 7-membered saturated or partially unsaturated monocyclic heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 7- to 12-membered saturated or partially unsaturated bicyclic heterocycle having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0179] As generally defined above, ring A and ring B are each independently phenyl; naphthyl; tetrahydronaphthalenyl; dihydroindenyl; benzocyclobutenyl; cubanyl; adamantyl; a 5- to 6-membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8- to 10-membered bicyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3- to 7-membered saturated or partially unsaturated monocyclic carbocycle; a 5- to 12-membered saturated or partially unsaturated bicyclic carbocycle; a 3- to 7-membered saturated or partially unsaturated monocyclic heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 7- to 12-membered saturated or partially unsaturated bicyclic heterocycle having 1 to 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 carbocycle; a 5-12 membered saturated or partially unsaturated bicyclic carbocycle; a 3-7 membered saturated or partially unsaturated monocyclic heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 7-12 membered saturated or partially unsaturated bicyclic heterocycle 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; or 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; or 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, oxadiazolyl).

[0184] In some embodiments, ring A is a 5-membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur (e.g., furanyl, thiophenyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, oxadiazolyl, oxadiazolyl).

[0185] In some embodiments, Ring A is phenyl, furanyl, thiophenyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, oxadiazolyl, and oxadiazolyl.

[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 is 1 Together with the substituents, [ka] where the top attachment point is attached to L and the bottom attachment point is attached to the 6-membered ring of the ERBM moiety.

[0189] In some embodiments, ring A is 1 Together with the substituents, [ka] where the top attachment point is attached to L and the bottom attachment point is attached to the 6-membered ring of the ERBM moiety.

[0190] In some embodiments, ring A is 1 Together with the substituents, [ka] where the top attachment point is attached to L and the bottom attachment point is attached to the 6-membered ring of the ERBM moiety.

[0191] In some embodiments, ring A is 1 Together with the substituents, [ka] where the top attachment point is attached to L and the bottom attachment point is attached to the 6-membered ring of the ERBM moiety.

[0192] In some embodiments, ring A is 1 Together with the substituents, [ka] where the top attachment point is attached to L and the bottom attachment point is attached to the 6-membered ring of the ERBM moiety.

[0193] In some embodiments, ring A is 1 Together with the substituents, [ka] where the top attachment point is attached to L and the bottom attachment point is attached to the 6-membered ring of the ERBM moiety.

[0194] In some embodiments, ring A is 1 Together with the substituents, [ka] wherein the top attachment point is attached to L and the bottom attachment point is attached to the 6-membered ring of the ERBM moiety. In some embodiments, ring A is attached to the R 1 Together with the substituents, [ka] wherein the top attachment point is attached to L and the bottom attachment point is attached to the 6-membered ring of the ERBM moiety. In some embodiments, ring A is attached to the R 1 Together with the substituents, [ka] wherein the top attachment point is attached to L and the bottom attachment point is attached to the 6-membered ring of the ERBM moiety. In some embodiments, ring A is attached to the R 1 Together with the substituents, [ka] wherein the top attachment point is attached to L and the bottom attachment point is attached to the 6-membered ring of the ERBM moiety. In some embodiments, ring A is attached to the R 1 Together with the substituents, [ka] wherein the top attachment point is attached to L and the bottom attachment point is attached to the 6-membered ring of the ERBM moiety. In some embodiments, ring A is attached to the R 1 Together with the substituents, [ka] wherein the top attachment point is attached to L and the bottom attachment point is attached to the 6-membered ring of the ERBM moiety. In some embodiments, ring A is attached to the R1 Together with the substituents, [ka] wherein the top attachment point is attached to L and the bottom attachment point is attached to the 6-membered ring of the ERBM moiety. In some embodiments, ring A is attached to the R 1 Together with the substituents, [ka] wherein the top attachment point is attached to L and the bottom attachment point is attached to the 6-membered ring of the ERBM moiety. In some embodiments, ring A is attached to the R 1 Together with the substituents, [ka] wherein the top attachment point is attached to L and the bottom attachment point is attached to the 6-membered ring of the ERBM moiety. In some embodiments, ring A is attached to the R 1 Together with the substituents, [ka] wherein the top attachment point is attached to L and the bottom attachment point is attached to the 6-membered ring of the ERBM moiety. In some embodiments, ring A is attached to the R 1 Together with the substituents, [ka] wherein the top attachment point is attached to L and the bottom attachment point is attached to the 6-membered ring of the ERBM moiety. In some embodiments, ring A is attached to the R 1 Together with the substituents, [ka] wherein the top attachment point is attached to L and the bottom attachment point is attached to the 6-membered ring of the ERBM moiety. In some embodiments, ring A is attached to the R 1 Together with the substituents, [ka] wherein the top attachment point is attached to L and the bottom attachment point is attached to the 6-membered ring of the ERBM moiety. In some embodiments, ring A is attached to the R 1 Together with the substituents, [ka] wherein the top attachment point is attached to L and the bottom attachment point is attached to the 6-membered ring of the ERBM moiety. In some embodiments, ring A is attached to the R 1 Together with the substituents, [ka] where the top attachment point is attached to L and the bottom attachment point is attached to the 6-membered ring of the ERBM moiety.

[0195] In some embodiments, ring A is selected from the group shown in the compounds of 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 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3-7 membered saturated or partially unsaturated monocyclic carbocycle; a 5-12 membered saturated or partially unsaturated bicyclic carbocycle; a 3-7 membered saturated or partially unsaturated monocyclic heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 7-12 membered saturated or partially unsaturated bicyclic heterocycle having 1 to 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 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3-7 membered saturated or partially unsaturated monocyclic carbocycle; a 5-12 membered saturated or partially unsaturated bicyclic carbocycle; a 3-7 membered saturated or partially unsaturated monocyclic heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 7-12 membered saturated or partially unsaturated bicyclic heterocycle having 1 to 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 ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3-7 membered saturated or partially unsaturated monocyclic carbocycle; a 5-12 membered saturated or partially unsaturated bicyclic carbocycle; or a 3-7 membered saturated or partially unsaturated monocyclic heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0199] In some embodiments, Ring B is phenyl; tetrahydronaphthalenyl; dihydroindenyl; benzocyclobutenyl; a 3- to 7-membered saturated or partially unsaturated monocyclic heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3- to 7-membered saturated or partially unsaturated monocyclic carbocycle; or a 5- to 12-membered saturated or partially unsaturated bicyclic carbocycle.

[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, oxadiazolyl).

[0203] In some embodiments, Ring B is 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 (eg, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cycloheptenyl).

[0205] In some embodiments, Ring B is a 5- to 12-membered saturated or partially unsaturated bicyclic carbocycle (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 heterocycle 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 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-dihydroindenyl). hydroxybenzoyl, benzothiazolyl, benzothiophenyl, dihydrobenzofuranyl, dihydroisobenzofuranyl, indolinyl, isoindolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, furanyl, thiophenyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, oxatanyl, 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 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.

[0212] In some embodiments, ring B is the R 2 Together with the substituents, [ka] [ka] [ka] is selected from.

[0213] In some embodiments, ring B is the R 2 Together with the substituents, [ka] In some embodiments, ring B is 2 Together with the substituents, [ka] In some embodiments, ring B is 2 Together with the substituents, [ka] In some embodiments, ring B is 2 Together with the substituents, [ka] In some embodiments, ring B is 2 Together with the substituents, [ka] In some embodiments, ring B is 2 Together with the substituents, [ka] In some embodiments, ring B is 2 Together with the substituents, [ka] In some embodiments, ring B is 2 Together with the substituents, [ka] In some embodiments, ring B is 2 Together with the substituents, [ka] In some embodiments, ring B is 2 Together with the substituents, [ka] In some embodiments, ring B is 2 Together with the substituents, [ka] In some embodiments, ring B is 2 Together with the substituents, [ka] In some embodiments, ring B is 2 Together with the substituents, [ka] In some embodiments, ring B is 2 Together with the substituents, [ka] In some embodiments, ring B is 2 Together with the substituents, [ka] In some embodiments, ring B is 2 Together with the substituents, [ka] In some embodiments, ring B is 2 Together with the substituents, [ka] In some embodiments, ring B is 2 Together with the substituents, [ka] In some embodiments, ring B is 2 Together with the substituents, [ka] In some embodiments, ring B is 2 Together with the substituents, [ka] In some embodiments, ring B is 2 Together with the substituents, [ka] In some embodiments, ring B is 2 Together with the substituents, [ka] In some embodiments, ring B is 2 Together with the substituents, [ka] In some embodiments, ring B is 2 Together with the substituents, [ka] In some embodiments, ring B is 2 Together with the substituents, [ka] In some embodiments, ring B is 2 Together with the substituents, [ka] In some embodiments, ring B is 2 Together with the substituents, [ka] In some embodiments, ring B is 2 Together with the substituents, [ka] In some embodiments, ring B is 2 Together with the substituents, [ka] In some embodiments, ring B is 2 Together with the substituents, [ka] In some embodiments, ring B is 2 Together with the substituents, [ka] In some embodiments, ring B is 2 Together with the substituents, [ka] In some embodiments, ring B is 2 Together with the substituents, [ka] In some embodiments, ring B is 2 Together with the substituents, [ka] In some embodiments, ring B is 2 Together with the substituents, [ka] In some embodiments, ring B is 2 Together with the substituents, [ka] In some embodiments, ring B is 2 Together with the substituents, [ka] In some embodiments, ring B is 2 Together with the substituents, [ka] In some embodiments, ring B is 2 Together with the substituents, [ka] In some embodiments, ring B is 2 Together with the substituents, [ka] In some embodiments, ring B is 2 Together with the substituents, [ka] In some embodiments, ring B is 2 Together with the substituents, [ka] In some embodiments, ring B is 2 Together with the substituents, [ka] In some embodiments, ring B is 2 Together with the substituents, [ka] In some embodiments, ring B is 2 Together with the substituents, [ka] In some embodiments, ring B is 2 Together with the substituents, [ka] In some embodiments, ring B is 2 Together with the substituents, [ka] In some embodiments, ring B is 2 Together with the substituents, [ka] In some embodiments, ring B is 2 Together with the substituents, [ka] In some embodiments, ring B is 2 Together with the substituents, [ka] In some embodiments, ring B is 2 Together with the substituents, [ka] In some embodiments, ring B is 2 Together with the substituents, [ka] In some embodiments, ring B is 2 Together with the substituents, [ka] is.

[0214] In some embodiments, ring B is the R 2 Together with the substituents, [ka] In some embodiments, ring B is 2 Together with the substituents, [ka] In some embodiments, ring B is 2 Together with the substituents, [ka] is.

[0215] In some embodiments, ring B is the R 2 Together with the substituents, [ka] In some embodiments, ring B is 2 Together with the substituents, [ka] In some embodiments, ring B is2 Together with the substituents, [ka] In some embodiments, ring B is 2 Together with the substituents, [ka] In some embodiments, ring B is 2 Together with the substituents, [ka] In some embodiments, ring B is 2 Together with the substituents, [ka] In some embodiments, ring B is 2 Together with the substituents, [ka] In some embodiments, ring B is 2 Together with the substituents, [ka] In some embodiments, ring B is 2 Together with the substituents, [ka] In some embodiments, ring B is 2 Together with the substituents, [ka] In some embodiments, ring B is 2 Together with the substituents, [ka] In some embodiments, ring B is2 Together with the substituents, [ka] In some embodiments, ring B is 2 Together with the substituents, [ka] In some embodiments, ring B is 2 Together with the substituents, [ka] In some embodiments, ring B is 2 Together with the substituents, [ka] In some embodiments, ring B is 2 Together with the substituents, [ka] In some embodiments, ring B is 2 Together with the substituents, [ka] In some embodiments, ring B is 2 Together with the substituents, [ka] In some embodiments, ring B is 2 Together with the substituents, [ka] In some embodiments, ring B is 2 Together with the substituents, [ka] In some embodiments, ring B is2 Together with the substituents, [ka] In some embodiments, ring B is 2 Together with the substituents, [ka] In some embodiments, ring B is 2 Together with the substituents, [ka] In some embodiments, ring B is 2 Together with the substituents, [ka] In some embodiments, ring B is 2 Together with the substituents, [ka] In some embodiments, ring B is 2 Together with the substituents, [ka] In some embodiments, ring B is 2 Together with the substituents, [ka] In some embodiments, ring B is 2 Together with the substituents, [ka] In some embodiments, ring B is 2 Together with the substituents, [ka] In some embodiments, ring B is2 Together with the substituents, [ka] In some embodiments, ring B is 2 Together with the substituents, [ka] In some embodiments, ring B is 2 Together with the substituents, [ka] In some embodiments, ring B is 2 Together with the substituents, [ka] In some embodiments, ring B is 2 Together with the substituents, [ka] In some embodiments, ring B is 2 Together with the substituents, [ka] In some embodiments, ring B is 2 Together with the substituents, [ka] In some embodiments, ring B is 2 Together with the substituents, [ka] In some embodiments, ring B is 2 Together with the substituents, [ka] In some embodiments, ring B is2 Together with the substituents, [ka] In some embodiments, ring B is 2 Together with the substituents, [ka] In some embodiments, ring B is 2 Together with the substituents, [ka] In some embodiments, ring B is 2 Together with the substituents, [ka] In some embodiments, ring B is 2 Together with the substituents, [ka] In some embodiments, ring B is 2 Together with the substituents, [ka] In some embodiments, ring B is 2 Together with the substituents, [ka] In some embodiments, ring B is 2 Together with the substituents, [ka] In some embodiments, ring B is 2 Together with the substituents, [ka] In some embodiments, ring B is2 Together with the substituents, [ka] In some embodiments, ring B is 2 Together with the substituents, [ka] In some embodiments, ring B is 2 Together with the substituents, [ka] In some embodiments, ring B is 2 Together with the substituents, [ka] In some embodiments, ring B is 2 Together with the substituents, [ka] In some embodiments, ring B is 2 Together with the substituents, [ka] In some embodiments, ring B is 2 Together with the substituents, [ka] In some embodiments, ring B is 2 Together with the substituents, [ka] In some embodiments, ring B is 2 Together with the substituents, [ka] In some embodiments, ring B is2 Together with the substituents, [ka] is.

[0216] In some embodiments, ring B is the R 2 Together with the substituents, [ka] In some embodiments, ring B is 2 Together with the substituents, [ka] In some embodiments, ring B is 2 Together with the substituents, [ka] is.

[0217] In some embodiments, Ring B is selected from the group shown in the compounds of Table 1 or Table 2.

[0218] As generally defined herein, Ring C is a spiro-fused 3- to 7-membered saturated or partially unsaturated monocyclic carbocycle; a spiro-fused 5- to 12-membered saturated or partially unsaturated bicyclic carbocycle; a spiro-fused 3- to 7-membered saturated or partially unsaturated monocyclic heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a spiro-fused 7- to 12-membered saturated or partially unsaturated bicyclic heterocycle having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0219] In some embodiments, ring C is 6 Together with the substituents, [ka] is selected from.

[0220] In some embodiments, ring C is6 Together with the substituents, [ka] In some embodiments, ring C is 6 Together with the substituents, [ka] In some embodiments, ring C is 6 Together with the substituents, [ka] In some embodiments, ring C is 6 Together with the substituents, [ka] In some embodiments, ring C is 6 Together with the substituents, [ka] In some embodiments, ring C is 6 Together with the substituents, [ka] In some embodiments, ring C is 6 Together with the substituents, [ka] In some embodiments, ring C is 6 Together with the substituents, [ka] In some embodiments, ring C is 6 Together with the substituents, [ka] In some embodiments, ring C is6 Together with the substituents, [ka] In some embodiments, ring C is 6 Together with the substituents, [ka] In some embodiments, ring C is 6 Together with the substituents, [ka] In some embodiments, ring C is 6 Together with the substituents, [ka] In some embodiments, ring C is 6 Together with the substituents, [ka] In some embodiments, ring C is 6 Together with the substituents, [ka] is.

[0221] As generally defined above, L is a bivalent moiety that connects the ERBM to the LBM.

[0222] As generally defined above, L is a covalent bond or a divalent, saturated or unsaturated, linear or branched C 1-50 a hydrocarbon chain, wherein 0 to 6 methylene units of L are independently -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)-, -C(O)NR-, -OC(O)NR-, -NRC(O)O-, [ka] wherein each -Cy- is independently selected from phenylenyl, 8- to 10-membered bicyclic arylenyl, 4- to 7-membered saturated or partially unsaturated carbocyclylenyl, 5- to 11-membered saturated or partially unsaturated spirocarbocyclylenyl, 8- to 10-membered bicyclic saturated or partially unsaturated carbocyclylenyl, 4- to 7-membered saturated or partially unsaturated heterocyclylenyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 5- to 11-membered saturated or partially unsaturated spiroheterocyclylenyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, nitrogen , oxygen, and sulfur; 6- to 10-membered bridged bicyclic saturated or partially unsaturated heterocyclyl having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; 5- to 6-membered heteroarylenyl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or 8- to 10-membered bicyclic heteroarylenyl having 1 to 5 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0223] In some embodiments, L is a covalent bond. In some embodiments, L is a divalent, saturated or unsaturated, linear or branched C 1-50 a hydrocarbon chain, wherein 0 to 6 methylene units of L are independently -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)-, -C(O)NR-, -OC(O)NR-, -NRC(O)O-, [ka] wherein each -Cy- is independently selected from phenylenyl, 8- to 10-membered bicyclic arylenyl, 4- to 7-membered saturated or partially unsaturated carbocyclylenyl, 5- to 11-membered saturated or partially unsaturated spirocarbocyclylenyl, 8- to 10-membered bicyclic saturated or partially unsaturated carbocyclylenyl, 4- to 7-membered saturated or partially unsaturated heterocyclylenyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 5- to 11-membered saturated or partially unsaturated spiroheterocyclylenyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, nitrogen , oxygen, and sulfur; 6- to 10-membered bridged bicyclic saturated or partially unsaturated heterocyclyl having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; 5- to 6-membered heteroarylenyl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or 8- to 10-membered bicyclic heteroarylenyl having 1 to 5 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0224] In some embodiments, L is a divalent, saturated or unsaturated, linear or branched C 3-5 a hydrocarbon chain, wherein 0, 1, 2, or 3 methylene units of L are independently selected from -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)-, -C(O)NR-, -OC(O)NR-, -NRC(O)O-, [ka] is replaced by

[0225] In some embodiments, L is a divalent, saturated or unsaturated, linear or branched C 3-5A hydrocarbon chain wherein one, two, or three methylene units of L are independently replaced by -Cy-, -CH(R)-, -C(R)2-, -O-, or -NR-.

[0226] In some embodiments, L is a divalent, saturated or unsaturated, linear or branched C 3-5 A hydrocarbon chain in which 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- to 7-membered saturated or partially unsaturated monocyclic carbocyclylenyl, a 5- to 11-membered saturated or partially unsaturated spirocarbocyclylenyl, an 8- to 10-membered bicyclic saturated or partially unsaturated carbocyclylenyl, a 4- to 7-membered saturated or partially unsaturated monocyclic heterocyclylenyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5- to 11-membered monocyclic saturated or partially unsaturated spiroheterocyclylenyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, an 8- to 10-membered bicyclic saturated or partially unsaturated heterocyclylenyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 6- to 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- to 7-membered saturated or partially unsaturated monocyclic carbocyclylenyl, a 5- to 11-membered saturated or partially unsaturated spirocarbocyclylenyl, an 8- to 10-membered bicyclic saturated or partially unsaturated carbocyclylenyl, a 4- to 7-membered saturated or partially unsaturated monocyclic heterocyclylenyl containing 1 to 2 nitrogen atoms, a 5- to 11-membered monocyclic saturated or partially unsaturated spiroheterocyclylenyl containing 1 to 2 nitrogen atoms, an 8- to 10-membered bicyclic saturated or partially unsaturated heterocyclylenyl containing 1 to 2 nitrogen atoms, and a 6- to 10-membered bridged bicyclic saturated or partially unsaturated heterocyclylenyl containing 1 to 2 nitrogen atoms.

[0229] In some embodiments, the divalent ring of each -Cy- is independently substituted with 0, 1, or 2 substituents independently selected from deuterium, 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.

[0230] In some embodiments, the divalent 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.

[0231] In some embodiments, the divalent ring of each -Cy- is independently substituted with 0, 1, or 2 substituents independently selected from deuterium, -Me, -Et, Pr, iPr, cyclopropyl, -CF, -OMe, -F, -Cl, -CN, -NH, -NHMe, and -NMe.

[0232] In some embodiments, the divalent ring of each -Cy- is independently substituted with 0, 1, or 2 substituents independently selected from -Me, -Et, Pr, iPr, cyclopropyl, -CF, -OMe, -F, -Cl, -CN, -NH, -NHMe, and -NMe.

[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, L is [ka] is.

[0237] In some embodiments, L is [ka] is selected from.

[0238] In some embodiments, L is [ka] [ka] is selected from.

[0239] In some embodiments, L is [ka] [ka] is selected from.

[0240] In some embodiments, L is [ka] [ka] is selected from.

[0241] In some embodiments, L is [ka] In some embodiments, L is [ka] In some embodiments, L is [ka] In some embodiments, L is [ka] In some embodiments, L is [ka] In some embodiments, L is [ka] In some embodiments, L is [ka] In some embodiments, L is [ka] In some embodiments, L is [ka] In some embodiments, L is [ka] In some embodiments, L is [ka] In some embodiments, L is [ka] In some embodiments, L is [ka] In some embodiments, L is [ka] In some embodiments, L is [ka] In some embodiments, L is [ka] In some embodiments, L is [ka] In some embodiments, L is [ka] In some embodiments, L is [ka] In some embodiments, L is [ka] In some embodiments, L is [ka] In some embodiments, L is [ka] In some embodiments, L is [ka] is.

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

[0243] In some embodiments, L is [ka] In some embodiments, L is [ka] In some embodiments, L is [ka] In some embodiments, L is [ka] In some embodiments, L is [ka] In some embodiments, L is [ka] In some embodiments, L is [ka] In some embodiments, L is [ka] In some embodiments, L is [ka] In some embodiments, L is [ka] In some embodiments, L is [ka] In some embodiments, L is [ka] In some embodiments, L is [ka] is.

[0244] In some embodiments, L is selected from the group shown in the compounds of Table 1 or Table 2.

[0245] As generally defined above, an LBM is a ligase binding moiety.

[0246] As broadly defined above, LBM is: [ka] [ka] is selected from.

[0247] In some embodiments, the LBM comprises: [ka] is selected from.

[0248] In some embodiments, the LBM comprises: [ka] is selected from.

[0249] In some embodiments, the LBM comprises: [ka] is selected from.

[0250] In some embodiments, the LBM comprises: [ka] is selected from.

[0251] In some embodiments, the LBM comprises: [ka] is selected from.

[0252] In some embodiments, the LBM comprises: [ka] is selected from.

[0253] In some embodiments, the LBM comprises: [ka] is selected from.

[0254] In some embodiments, the LBM comprises: [ka] is selected from.

[0255] In some embodiments, the LBM comprises: [ka] is selected from.

[0256] In some embodiments, the LBM comprises: [ka] is selected from.

[0257] In some embodiments, the LBM comprises: [ka] [ka] is selected from.

[0258] In some embodiments, the LBM comprises: [ka] is selected from.

[0259] In some embodiments, the LBM comprises: [ka] is selected from.

[0260] In some embodiments, the LBM comprises: [ka] is selected from.

[0261] In some embodiments, the LBM comprises: [ka] In some embodiments, the LBM is [ka] In some embodiments, the LBM is [ka] In some embodiments, the LBM is [ka] is. In some embodiments, the LBM comprises: [ka] is. In some embodiments, the LBM comprises: [ka] is. In some embodiments, the LBM comprises: [ka] is. In some embodiments, the LBM comprises: [ka] is. In some embodiments, the LBM comprises: [ka] is. In some embodiments, the LBM comprises: [ka] is. In some embodiments, the LBM comprises: [ka] is. In some embodiments, the LBM comprises: [ka] is. In some embodiments, the LBM comprises: [ka] is. In some embodiments, the LBM comprises: [ka] is. In some embodiments, the LBM comprises: [ka] is. In some embodiments, the LBM comprises: [ka] is. In some embodiments, the LBM comprises: [ka] is. In some embodiments, the LBM comprises: [ka] is. In some embodiments, the LBM comprises: [ka] is. In some embodiments, the LBM comprises: [ka] is. In some embodiments, the LBM comprises: [ka] is. In some embodiments, the LBM comprises: [ka] is. In some embodiments, the LBM comprises: [ka] is. In some embodiments, the LBM comprises: [ka] is. In some embodiments, the LBM comprises: [ka] is. In some embodiments, the LBM comprises: [ka] is. In some embodiments, the LBM comprises: [ka] is. In some embodiments, the LBM comprises: [ka] is. In some embodiments, the LBM comprises: [ka] is. In some embodiments, the LBM comprises: [ka] is. In some embodiments, the LBM comprises: [ka] is.

[0262] In some embodiments, the LBM is selected from the group shown in Table 1 or Table 2 compounds.

[0263] As generally defined 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 group shown in the compounds of Table 1 or Table 2.

[0266] As generally defined 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 group shown in the compounds of Table 1 or Table 2.

[0269] As generally defined 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. Notably, R 3 When the number of groups is specified as "p-1" or "p-2," only 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 group shown in the compounds of Table 1 or Table 2.

[0272] Each q is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, as generally defined above.

[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 group shown in the compounds of Table 1 or Table 2.

[0275] As generally defined 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 group shown in the compounds of Table 1 or Table 2.

[0278] As generally defined 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 group shown in the compounds of Table 1 or Table 2.

[0281] In certain embodiments, the present invention provides a compound of Formula I-1, Formula I-1′, Formula I-2, Formula I-2′, Formula I-3, or Formula I-3′, wherein the ERBM is: [ka] and thereby forming a compound of formula II-a, II-b, or II-c, respectively: [ka] and a compound of formula I-1, I-1′, I-2, I-2′, I-3, or I-3′, or a pharmaceutically acceptable salt thereof, wherein ring A, ring B, R 1 , R 2 , R 3 , X 1 , X 2 , m, n, p, L, and LBM are each as defined in the embodiments and classes and subclasses herein.

[0282] In some embodiments, X 1 is CH or N, and 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 to 3 nitrogen heteroatoms.

[0283] In some embodiments, the compound has formula II-a-1, formula II-b-1, or formula II-c-1: [ka] or a pharmaceutically acceptable salt thereof, wherein ring A, ring B, R 1 , R 2 , R 3 , X 1 , X 2 , m, n, p, L, and LBM are each as defined in the embodiments and classes and subclasses herein. 1 is CH or N, and 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 to 3 nitrogen heteroatoms.

[0284] In some embodiments, the compound is a compound of formula II-a-1, or a pharmaceutically acceptable salt thereof. 1 is CH or N, and 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 to 3 nitrogen heteroatoms.

[0285] In some embodiments, the compound is a compound of formula II-b-1, or a pharmaceutically acceptable salt thereof. 1 is CH or N, and 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 to 3 nitrogen heteroatoms.

[0286] In some embodiments, the compound is a compound of formula II-c-1, or a pharmaceutically acceptable salt thereof. 1 is CH or N, and 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 to 3 nitrogen heteroatoms.

[0287] In certain embodiments, the present invention provides a compound of Formula I-1, Formula I-1′, Formula I-2, Formula I-2′, Formula I-3, or Formula I-3′, wherein the ERBM is: [ka] and thereby forming a compound of formula VIII-a, VIII-b, VIII-c, IX-a, IX-b, or IX-c, respectively: [ka] [ka] or a pharmaceutically acceptable salt thereof, wherein X 1 , X 2 , X 3 , ring A, ring C, R 1 , R 3 , R 6 , m, p, t, L, and LBM are each as defined in the 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 has formula VIII-a-1, formula VIII-b-1, or formula VIII-c-1: [ka] or a pharmaceutically acceptable salt thereof, wherein X 1 , X 2 , ring A, R 1 , R 3 , m, p, L, and LBM are each as defined in the 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 has formula IX-a-1, formula IX-b-1, or formula IX-c-1: [ka] or a pharmaceutically acceptable salt thereof, wherein X 2 , X 3 , ring A, ring C, R 1 , R 3 , R 6 , m, p, t, L, and LBM are each as defined in the 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, Formula I-1′, Formula I-2, Formula I-2′, Formula I-3, or Formula I-3′, wherein the ERBM is: [ka] [ka] and thereby forming, respectively, formula II-d, formula II-e, formula II-f, formula II-g, formula II-h, formula II-i, formula II-j, formula II-k, or formula II-l: [ka] [ka] [ka] and a compound of formula I-1, I-1′, I-2, I-2′, I-3, or I-3′, or a pharmaceutically acceptable salt thereof, wherein ring A, ring B, R 1 , R 2 , R 3 , m, n, p, L, and LBM are each as defined in the 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, 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, ring A is other than phenyl or a 6-membered monocyclic heteroaryl ring having 1 to 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, ring A is other than phenyl or a 6-membered monocyclic heteroaryl ring having 1 to 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, ring A is other than phenyl or a 6-membered monocyclic heteroaryl ring having 1 to 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, ring A is other than phenyl or a 6-membered monocyclic heteroaryl ring having 1 to 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, ring A is other than phenyl or a 6-membered monocyclic heteroaryl ring having 1 to 3 nitrogen heteroatoms.

[0312] In some embodiments, the compound is a compound of Formula II-1, or a pharmaceutically acceptable salt thereof. In some embodiments, when ring B is phenyl, ring A is other than phenyl or a 6-membered monocyclic heteroaryl ring having 1 to 3 nitrogen heteroatoms.

[0313] In certain embodiments, the present invention provides a compound of Formula I-1, Formula I-1′, Formula I-2, Formula I-2′, Formula I-3, or Formula I-3′, wherein the ERBM is: [ka] [ka] and thereby forming, respectively, Formula II-dA, Formula II-eA, Formula II-fA, Formula II-dB, Formula II-eB, Formula II-fB, Formula II-dC, Formula II-eC, Formula II-fC, Formula II-g, Formula II-h, Formula II-I, Formula II-jA, Formula II-kA, or Formula II-lA: [ka] [ka] [ka] [ka] and a compound of formula I-1, I-1′, I-2, I-2′, I-3, or I-3′, or a pharmaceutically acceptable salt thereof, wherein ring A, ring B, R 1 , R 2 , R 3, m, n, p, L, and LBM are each as defined in the embodiments and classes and subclasses herein.

[0314] In some embodiments, the compound is of Formula II-dA, Formula II-eA, Formula II-fA, Formula II-jA, Formula II-kA, and Formula II-lA, and when Ring B is phenyl, 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-dA, or a pharmaceutically acceptable salt thereof. In some embodiments, when ring B is phenyl, ring A is other than phenyl or a 6-membered monocyclic heteroaryl ring having 1 to 3 nitrogen heteroatoms.

[0316] In some embodiments, the compound is of Formula II-eA, or a pharmaceutically acceptable salt thereof. In some embodiments, when ring B is phenyl, ring A is other than phenyl or a 6-membered monocyclic heteroaryl ring having 1 to 3 nitrogen heteroatoms.

[0317] In some embodiments, the compound is a compound of Formula II-fA, or a pharmaceutically acceptable salt thereof. In some embodiments, when ring B is phenyl, ring A is other than phenyl or a 6-membered monocyclic heteroaryl ring having 1 to 3 nitrogen heteroatoms.

[0318] In some embodiments, the compound is of formula II-dB, or a pharmaceutically acceptable salt thereof.

[0319] In some embodiments, the compound is of formula II-eB, or a pharmaceutically acceptable salt thereof.

[0320] In some embodiments, the compound is a compound of formula II-fB, or a pharmaceutically acceptable salt thereof.

[0321] In some embodiments, the compound is of formula II-dC, or a pharmaceutically acceptable salt thereof.

[0322] In some embodiments, the compound is of formula II-eC, or a pharmaceutically acceptable salt thereof.

[0323] In some embodiments, the compound is a compound of formula II-fC, or a pharmaceutically acceptable salt thereof.

[0324] In some embodiments, the compound is a compound of Formula II-jA, or a pharmaceutically acceptable salt thereof. In some embodiments, when ring B is phenyl, ring A is other than phenyl or a 6-membered monocyclic heteroaryl ring having 1 to 3 nitrogen heteroatoms.

[0325] In some embodiments, the compound is a compound of Formula II-kA, or a pharmaceutically acceptable salt thereof. In some embodiments, when ring B is phenyl, ring A is other than phenyl or a 6-membered monocyclic heteroaryl ring having 1 to 3 nitrogen heteroatoms.

[0326] In some embodiments, the compound is a compound of Formula II-1A, or a pharmaceutically acceptable salt thereof. In some embodiments, when ring B is phenyl, ring A is other than phenyl or a 6-membered monocyclic heteroaryl ring having 1 to 3 nitrogen heteroatoms.

[0327] In some embodiments, the compound is of formula II-jA, or a pharmaceutically acceptable salt thereof.

[0328] In some embodiments, the compound is of formula II-kA, or a pharmaceutically acceptable salt thereof.

[0329] In some embodiments, the compound is of formula II-1A, or a pharmaceutically acceptable salt thereof.

[0330] In some embodiments, the compound is of formula II-jA, or a pharmaceutically acceptable salt thereof.

[0331] In some embodiments, the compound is of formula II-kA, or a pharmaceutically acceptable salt thereof.

[0332] In some embodiments, the compound is of formula II-1A, or a pharmaceutically acceptable salt thereof.

[0333] In some embodiments, the compound has formula II-d-1, formula II-e-1, formula II-f-1, formula II-g-1, formula II-h-1, formula II-i-1, formula II-j-1, formula II-k-1, or formula II-l-1: [ka] or a pharmaceutically acceptable salt thereof, wherein ring A, ring B, R 1 , R 2 , R 3 , m, n, p, L, and LBM are each as defined in the embodiments and classes and subclasses herein.

[0334] In some embodiments, when the compound is of Formula II-d-1, Formula II-e-1, Formula II-f-1, Formula II-j-1, Formula II-k-1, or Formula II-l-1, and Ring B is phenyl, then Ring A is other than phenyl or a 6-membered monocyclic heteroaryl ring having 1 to 3 nitrogen heteroatoms.

[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, ring A is other than phenyl or a 6-membered monocyclic heteroaryl ring having 1 to 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, ring A is other than phenyl or a 6-membered monocyclic heteroaryl ring having 1 to 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, ring A is other than phenyl or a 6-membered monocyclic heteroaryl ring having 1 to 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 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, ring A is other than phenyl or a 6-membered monocyclic heteroaryl ring having 1 to 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, ring A is other than phenyl or a 6-membered monocyclic heteroaryl ring having 1 to 3 nitrogen heteroatoms.

[0343] In some embodiments, the compound is a compound of Formula II-1-1, or a pharmaceutically acceptable salt thereof. In some embodiments, when ring B is phenyl, ring A is other than phenyl or a 6-membered monocyclic heteroaryl ring having 1 to 3 nitrogen heteroatoms.

[0344] In some embodiments, the compound has formula II-d-1-A, formula II-e-1-A, formula II-f-1-A, formula II-d-1-B, formula II-e-1-B, formula II-f-1-B, formula II-d-1-C, formula II-e-1-C, formula II-f-1-C, formula II-j-1-A, formula II-k-1-A, or formula II-l-1-A: [ka] [ka] or a pharmaceutically acceptable salt thereof, wherein ring A, ring B, R 1 , R 2 , R 3 , m, n, p, L, and LBM are each as defined in the embodiments and classes and subclasses herein.

[0345] In some embodiments, 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 when Ring B is phenyl, Ring A is other than phenyl or a 6-membered monocyclic heteroaryl ring having 1 to 3 nitrogen heteroatoms.

[0346] In some embodiments, the compound is a compound of Formula II-dA, or a pharmaceutically acceptable salt thereof. In some embodiments, when ring B is phenyl, ring A is other than phenyl or a 6-membered monocyclic heteroaryl ring having 1 to 3 nitrogen heteroatoms.

[0347] In some embodiments, the compound is of Formula II-eA, or a pharmaceutically acceptable salt thereof. In some embodiments, when ring B is phenyl, ring A is other than phenyl or a 6-membered monocyclic heteroaryl ring having 1 to 3 nitrogen heteroatoms.

[0348] In some embodiments, the compound is a compound of Formula II-fA, or a pharmaceutically acceptable salt thereof. In some embodiments, when ring B is phenyl, ring A is other than phenyl or a 6-membered monocyclic heteroaryl ring having 1 to 3 nitrogen heteroatoms.

[0349] In some embodiments, the compound is of formula II-dB, or a pharmaceutically acceptable salt thereof.

[0350] In some embodiments, the compound is of formula II-eB, or a pharmaceutically acceptable salt thereof.

[0351] In some embodiments, the compound is a compound of formula II-fB, or a pharmaceutically acceptable salt thereof.

[0352] In some embodiments, the compound is of formula II-dC, or a pharmaceutically acceptable salt thereof.

[0353] In some embodiments, the compound is of formula II-eC, or a pharmaceutically acceptable salt thereof.

[0354] In some embodiments, the compound is a compound of formula II-fC, or a pharmaceutically acceptable salt thereof.

[0355] In some embodiments, the compound is a compound of Formula II-jA, or a pharmaceutically acceptable salt thereof. In some embodiments, when ring B is phenyl, ring A is other than phenyl or a 6-membered monocyclic heteroaryl ring having 1 to 3 nitrogen heteroatoms.

[0356] In some embodiments, the compound is a compound of Formula II-kA, or a pharmaceutically acceptable salt thereof. In some embodiments, when ring B is phenyl, ring A is other than phenyl or a 6-membered monocyclic heteroaryl ring having 1 to 3 nitrogen heteroatoms.

[0357] In some embodiments, the compound is a compound of Formula II-1A, or a pharmaceutically acceptable salt thereof. In some embodiments, when ring B is phenyl, ring A is other than phenyl or a 6-membered monocyclic heteroaryl ring having 1 to 3 nitrogen heteroatoms.

[0358] In some embodiments, the compound is of formula II-jA, or a pharmaceutically acceptable salt thereof.

[0359] In some embodiments, the compound is of formula II-kA, or a pharmaceutically acceptable salt thereof.

[0360] In some embodiments, the compound is of formula II-1A, or a pharmaceutically acceptable salt thereof.

[0361] In some embodiments, the compound is of formula II-jA, or a pharmaceutically acceptable salt thereof.

[0362] In some embodiments, the compound is of formula II-kA, or a pharmaceutically acceptable salt thereof.

[0363] In some embodiments, the compound is of formula II-1A, or a pharmaceutically acceptable salt thereof.

[0364] In some embodiments, the compound has formula II-m-1: [ka] or a pharmaceutically acceptable salt thereof.

[0365] In certain embodiments, the present invention provides a compound of Formula I-1, Formula I-1′, Formula I-2, Formula I-2′, Formula I-3, or Formula I-3′, wherein the ERBM is: [ka] [ka] and thereby forming a compound of formula II-n, II-o, II-p, II-q, II-r, II-s, II-t, II-u, or II-v, respectively: [ka] [ka] [ka] or a pharmaceutically acceptable salt thereof, wherein the rings A, R 1 , R 3 , m, p, L, and LBM are each as defined in the 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 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, Formula I-1′, Formula I-2, Formula I-2′, Formula I-3, or Formula I-3′, wherein the ERBM is: [ka] [ka] and thereby forming, respectively, formula II-w, formula II-x, formula II-y, formula II-z, formula II-aa, formula II-bb, formula II-cc, formula II-dd, or formula II-ee: [ka] [ka] [ka] and a compound of formula I-1, I-1′, I-2, I-2′, I-3, or I-3′, or a pharmaceutically acceptable salt thereof, wherein ring A, ring C, R 1 , R 3 , R6 , m, p, t, L, and LBM are each as defined in the 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 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 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 has formula II-n-1, formula II-o-1, formula II-p-1, formula II-q-1, formula II-r-1, formula II-s-1, formula II-t-1, formula II-u-1, or formula II-v-1: [ka] or a pharmaceutically acceptable salt thereof, wherein ring A, R 1 , R 3 , m, p, L, and LBM are each as defined in the 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 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 has formula II-w-1, formula II-x-1, formula II-y-1, formula II-z-1, formula II-aa-1, formula II-bb-1, formula II-cc-1, formula II-dd-1, or formula II-ee-1: [ka] or a pharmaceutically acceptable salt thereof, wherein ring A, ring C, R 1 , R 3 , R 6 , m, p, t, L, and LBM are each as defined in the 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 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 of formula II-aa-1, or a pharmaceutically acceptable salt thereof.

[0401] In some embodiments, the compound is of formula II-bb-1, or a pharmaceutically acceptable salt thereof.

[0402] In some embodiments, the compound is of formula II-cc-1, or a pharmaceutically acceptable salt thereof.

[0403] In some embodiments, the compound is of formula II-dd-1, or a pharmaceutically acceptable salt thereof.

[0404] In some embodiments, the compound is of formula II-ee-1, or a pharmaceutically acceptable salt thereof.

[0405] In some embodiments, the compound has formula II-ff-1, formula II-gg-1, formula II-hh-1, formula II-ii-1, formula II-jj-1, formula II-kk-1, formula II-ll-1, formula II-mm-1, or formula II-nn-1: [ka] or a pharmaceutically acceptable salt thereof, wherein ring A, R A1 , R 1 , R 3 , m, p, L, and LBM are each as defined in the 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 of formula II-gg-1, or a pharmaceutically acceptable salt thereof.

[0408] In some embodiments, the compound is 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 of formula II-jj-1, or a pharmaceutically acceptable salt thereof.

[0411] In some embodiments, the compound is of formula II-kk-1, or a pharmaceutically acceptable salt thereof.

[0412] In some embodiments, the compound is of formula II-ll-1, or a pharmaceutically acceptable salt thereof.

[0413] In some embodiments, the compound is 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, Formula I-1′, Formula I-2, Formula I-2′, Formula I-3, or Formula I-3′, wherein the ERBM is: [ka] and thereby forming a compound of formula III-a, III-b, or III-c, respectively: [ka] or a pharmaceutically acceptable salt thereof, wherein ring B, R 1 , R 2 , R 3 , X 1 , X 2 , m, n, p, L, and LBM are each as defined in the embodiments and classes and subclasses herein.

[0416] In some embodiments of Formula III-a, Formula III-b, and Formula III-c, X 1 is CH or N, and X 2 When is CH2, 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. 1 is CH or N, and X 2 When 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. 1 is CH or N, and X 2 When is CH2, 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. 1 is CH or N, and X 2 When is CH2, then ring B is other than phenyl.

[0420] In certain embodiments, the present invention provides a compound of Formula I-1, Formula I-1′, Formula I-2, Formula I-2′, Formula I-3, or Formula I-3′, wherein the ERBM is: [ka] and thereby giving formula III-aA, III-bA, III-cA, III-aB, III-bB, III-cB, III-aC, III-bC, and III-cC, respectively: [ka] or a pharmaceutically acceptable salt thereof, wherein ring B, R 1 , R 2 , R 3 , X 1 , X 2, m, n, p, L, and LBM are each as defined in the embodiments and classes and subclasses herein.

[0421] In some embodiments of Formula III-aA, Formula III-bA, and Formula III-cA, X 1 is CH or N, and X 2 When is CH2, then ring B is other than phenyl.

[0422] In some embodiments, the compound is of formula III-aA, or a pharmaceutically acceptable salt thereof. 1 is CH or N, and X 2 When is CH2, then ring B is other than phenyl.

[0423] In some embodiments, the compound is of formula III-bA, or a pharmaceutically acceptable salt thereof. 1 is CH or N, and X 2 When is CH2, then ring B is other than phenyl.

[0424] In some embodiments, the compound is of formula III-cA, or a pharmaceutically acceptable salt thereof. 1 is CH or N, and X 2 When is CH2, then ring B is other than phenyl.

[0425] In some embodiments, the compound is of formula III-aB, or a pharmaceutically acceptable salt thereof.

[0426] In some embodiments, the compound is of formula III-bB, or a pharmaceutically acceptable salt thereof.

[0427] In some embodiments, the compound is a compound of formula III-cB, or a pharmaceutically acceptable salt thereof.

[0428] In some embodiments, the compound is of formula III-aC, or a pharmaceutically acceptable salt thereof.

[0429] In some embodiments, the compound is of formula III-bC, or a pharmaceutically acceptable salt thereof.

[0430] In some embodiments, the compound is of formula III-cC, or a pharmaceutically acceptable salt thereof.

[0431] In certain embodiments, the present invention provides a compound of Formula I-1, Formula I-1′, Formula I-2, Formula I-2′, Formula I-3, or Formula I-3′, wherein the ERBM is: [ka] and thereby forming, respectively, formula III-d, formula III-e, formula III-f, formula III-g, formula III-h, formula III-i, formula III-j, formula III-k, or formula III-l: [ka] or a pharmaceutically acceptable salt thereof, wherein ring B, R 1 , R 2 , R 3 , m, n, p, L, and LBM are each as defined in the 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, 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-1, 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, Formula I-1′, Formula I-2, Formula I-2′, Formula I-3, or Formula I-3′, wherein the ERBM is: [ka] and thereby yielding, respectively, formula III-dA, formula III-eA, formula III-fA, formula III-dB, formula III-eB, formula III-fB, formula III-dC, formula III-eC, formula III-fC, formula III-g, formula III-h, formula III-i, formula III-jA, formula III-kA, or formula III-lA: [ka] [ka] or a pharmaceutically acceptable salt thereof, wherein ring B, R 1 , R 2 , R 3 , m, n, p, L, and LBM are each as defined in the embodiments and classes and subclasses herein.

[0442] In some embodiments, when the compound is of formula III-dA, III-eA, III-fA, III-jA, III-kA, or III-lA, ring B is other than phenyl.

[0443] In some embodiments, the compound is of formula III-dA, or a pharmaceutically acceptable salt thereof: In some embodiments, Ring B is other than phenyl.

[0444] In some embodiments, the compound is of formula III-eA, or a pharmaceutically acceptable salt thereof: In some embodiments, Ring B is other than phenyl.

[0445] In some embodiments, the compound is of formula III-fA, or a pharmaceutically acceptable salt thereof: In some embodiments, Ring B is other than phenyl.

[0446] In some embodiments, the compound is of formula III-dB, or a pharmaceutically acceptable salt thereof.

[0447] In some embodiments, the compound is of formula III-eB, or a pharmaceutically acceptable salt thereof.

[0448] In some embodiments, the compound is a compound of formula III-fB, or a pharmaceutically acceptable salt thereof.

[0449] In some embodiments, the compound is a compound of formula III-dC, or a pharmaceutically acceptable salt thereof.

[0450] In some embodiments, the compound is of formula III-eC, or a pharmaceutically acceptable salt thereof.

[0451] In some embodiments, the compound is a compound of formula III-fC, 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 of formula III-jA, or a pharmaceutically acceptable salt thereof: In some embodiments, Ring B is other than phenyl.

[0456] In some embodiments, the compound is of formula III-kA, 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-1A, 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, Formula I-1′, Formula I-2, Formula I-2′, Formula I-3, or Formula I-3′, wherein the ERBM is: [ka] and thereby forming a compound of formula III-m, III-n, or III-o, respectively: [ka] or a pharmaceutically acceptable salt thereof, wherein the rings A, R 1 , R 2 , R 3 , X 1 , X 2 , m, n, p, L, and LBM are each as defined in the embodiments and classes and subclasses herein.

[0459] In some embodiments, 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 to 3 nitrogen heteroatoms.

[0460] In some embodiments, the compound is a compound of formula III-m, or a pharmaceutically acceptable salt thereof. 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 to 3 nitrogen heteroatoms.

[0461] In some embodiments, the compound is a compound of formula III-n, or a pharmaceutically acceptable salt thereof. 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 to 3 nitrogen heteroatoms.

[0462] In some embodiments, the compound is of formula III-o, or a pharmaceutically acceptable salt thereof. 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 to 3 nitrogen heteroatoms. In certain embodiments, the present invention provides a compound of Formula I-1, Formula I-1′, Formula I-2, Formula I-2′, Formula I-3, or Formula I-3′, wherein the ERBM is: [ka] and thereby forming a compound of formula III-mA, III-nA, or III-oA, III-mB, III-nB, III-oB, III-mC, III-nC, or III-oC, respectively: [ka] or a pharmaceutically acceptable salt thereof, wherein ring B, R 1 , R 2 , R 3 , m, n, p, L, and LBM are each as defined in the embodiments and classes and subclasses herein.

[0463] In some embodiments, the compound is of formula III-mA, formula III-nA, or formula III-oA, and X 1 is CH or N, and X 2is CH2, then ring A is other than phenyl or a 6-membered monocyclic heteroaryl ring having 1 to 3 nitrogen heteroatoms.

[0464] In some embodiments, the compound is of formula III-mA, or a pharmaceutically acceptable salt thereof. 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 to 3 nitrogen heteroatoms.

[0465] In some embodiments, the compound is of formula III-nA, or a pharmaceutically acceptable salt thereof. 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 to 3 nitrogen heteroatoms.

[0466] In some embodiments, the compound is of formula III-oA, or a pharmaceutically acceptable salt thereof. 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 to 3 nitrogen heteroatoms.

[0467] In some embodiments, the compound is of formula III-mB, or a pharmaceutically acceptable salt thereof.

[0468] In some embodiments, the compound is a compound of formula III-nB, or a pharmaceutically acceptable salt thereof.

[0469] In some embodiments, the compound is of formula III-oB, or a pharmaceutically acceptable salt thereof.

[0470] In some embodiments, the compound is of formula III-mC, or a pharmaceutically acceptable salt thereof.

[0471] In some embodiments, the compound is a compound of formula III-nC, or a pharmaceutically acceptable salt thereof.

[0472] In some embodiments, the compound is of formula III-oC, or a pharmaceutically acceptable salt thereof.

[0473] In certain embodiments, the present invention provides a compound of Formula I-1, Formula I-1′, Formula I-2, Formula I-2′, Formula I-3, or Formula I-3′, wherein the ERBM is: [ka] and thereby forming a compound of formula III-p, III-q, III-r, III-s, III-t, III-u, III-v, III-w, or III-x, respectively: [ka] or a pharmaceutically acceptable salt thereof, wherein the rings A, R 1 , R 2 , R 3 , m, n, p, L, and LBM are each as defined in the embodiments and classes and subclasses herein. In some embodiments, when the compound is of Formula III-p, Formula III-q, Formula III-r, Formula III-v, Formula III-w, or Formula III-x, ring A is other than phenyl or a 6-membered monocyclic heteroaryl ring having 1 to 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 to 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 to 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 to 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 III-t, 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 to 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 to 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 to 3 nitrogen heteroatoms. In certain embodiments, the present invention provides a compound of Formula I-1, Formula I-1′, Formula I-2, Formula I-2′, Formula I-3, or Formula I-3′, wherein the ERBM is: [ka] and thereby forming a compound of formula III-pA, III-qA, III-rA, III-pB, III-qB, III-rB, III-pC, III-qC, III-rC, III-s, III-t, III-u, III-vA, III-wA, or III-xA, respectively: [ka] [ka] or a pharmaceutically acceptable salt thereof, wherein the rings A, R 1 , R 2 , R 3 , m, n, p, L, and LBM are each as defined in the embodiments and classes and subclasses herein.

[0483] In some embodiments, when the compound is of formula III-pA, III-qA, III-rA, III-vA, III-wA, or III-xA, 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 of Formula III-pA, or a pharmaceutically acceptable salt thereof. In some embodiments, ring A is other than phenyl or a 6-membered monocyclic heteroaryl ring having 1 to 3 nitrogen heteroatoms.

[0485] In some embodiments, the compound is of Formula III-qA, or a pharmaceutically acceptable salt thereof. In some embodiments, ring A is other than phenyl or a 6-membered monocyclic heteroaryl ring having 1 to 3 nitrogen heteroatoms.

[0486] In some embodiments, the compound is of Formula III-rA, or a pharmaceutically acceptable salt thereof. In some embodiments, ring A is other than phenyl or a 6-membered monocyclic heteroaryl ring having 1 to 3 nitrogen heteroatoms.

[0487] In some embodiments, the compound is of formula III-pB, or a pharmaceutically acceptable salt thereof.

[0488] In some embodiments, the compound is of formula III-qB, or a pharmaceutically acceptable salt thereof.

[0489] In some embodiments, the compound is of formula III-rB, or a pharmaceutically acceptable salt thereof.

[0490] In some embodiments, the compound is of formula III-pC, or a pharmaceutically acceptable salt thereof.

[0491] In some embodiments, the compound is a compound of formula III-qC, or a pharmaceutically acceptable salt thereof.

[0492] In some embodiments, the compound is of formula III-rC, or a pharmaceutically acceptable salt thereof.

[0493] In some embodiments, the compound is of Formula III-vA, 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 of Formula III-wA, 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 of Formula III-xA, 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, Formula I-1′, Formula I-2, Formula I-2′, Formula I-3, or Formula I-3′, wherein the ERBM is: [ka] and thereby forming a compound of formula IV-a, IV-b, or IV-c, respectively: [ka] or a pharmaceutically acceptable salt thereof, wherein: [ka] represents a single bond or a double bond, and rings A and R 1 , R 2 , R 3 , X 1 , X 2 , m, n, p, L, and LBM are each as defined in the 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, Formula I-1′, Formula I-2, Formula I-2′, Formula I-3, or Formula I-3′, wherein the ERBM is: [ka] and thereby forming a compound of formula IV-d, IV-e, IV-f, IV-g, IV-h, IV-i, IV-j, IV-k, or IV-l, respectively: [ka] or a pharmaceutically acceptable salt thereof, wherein: [ka] represents a single bond or a double bond, and rings A and R 1 , R 2 , R 3 , m, n, p, L, and LBM are each as defined in the 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 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 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 of formula IV-1, or a pharmaceutically acceptable salt thereof.

[0510] In certain embodiments, the present invention provides a compound of Formula I-1, Formula I-1′, Formula I-2, Formula I-2′, Formula I-3, or Formula I-3′, wherein the ERBM is: [ka] and thereby forming a compound of formula IV-m, formula IV-n, or formula IV-o, respectively: [ka] or a pharmaceutically acceptable salt thereof, wherein R 1 , R 2 , R 3 , X 1 , X 2 , m, n, p, L, and LBM are each as defined in the embodiments and classes and subclasses herein.1 If is CH or N, X 2 is other than CH2.

[0511] In some embodiments, the compound is of formula IV-m, or a pharmaceutically acceptable salt thereof. 1 If is CH or N, X 2 is other than CH2.

[0512] In some embodiments, the compound is a compound of formula IV-n, or a pharmaceutically acceptable salt thereof. 1 If is CH or N, X 2 is other than CH2.

[0513] In some embodiments, the compound is of formula IV-o, or a pharmaceutically acceptable salt thereof. 1 If is CH or N, X 2 is other than CH2.

[0514] In certain embodiments, the present invention provides a compound of Formula I-1, Formula I-1′, Formula I-2, Formula I-2′, Formula I-3, or Formula I-3′, wherein the ERBM is: [ka] and thereby forming a compound of formula IV-mA, formula IV-nA, formula IV-oA, formula IV-mB, formula IV-nB, formula IV-oB, formula IV-mC, formula IV-nC, or formula IV-oC, respectively: [ka] [ka] or a pharmaceutically acceptable salt thereof, wherein R 1 , R 2 , R3 , X 1 , X 2 , m, n, p, L, and LBM are each as defined in the embodiments and classes and subclasses herein.

[0515] In some embodiments, the compound is of formula IV-mA, formula IV-nA, or formula IV-oA, and X 1 If is CH or N, X 2 is other than CH2.

[0516] In some embodiments, the compound is of formula IV-mA, or a pharmaceutically acceptable salt thereof. 1 If is CH or N, X 2 is other than CH2.

[0517] In some embodiments, the compound is of formula IV-nA, or a pharmaceutically acceptable salt thereof. 1 If is CH or N, X 2 is other than CH2.

[0518] In some embodiments, the compound is of formula IV-oA, or a pharmaceutically acceptable salt thereof. 1 If is CH or N, X 2 is other than CH2.

[0519] In some embodiments, the compound is of formula IV-mB, or a pharmaceutically acceptable salt thereof.

[0520] In some embodiments, the compound is of formula IV-nB, or a pharmaceutically acceptable salt thereof.

[0521] In some embodiments, the compound is of formula IV-oB, or a pharmaceutically acceptable salt thereof.

[0522] In some embodiments, the compound is of formula IV-mC, or a pharmaceutically acceptable salt thereof.

[0523] In some embodiments, the compound is a compound of formula IV-nC, or a pharmaceutically acceptable salt thereof.

[0524] In some embodiments, the compound is of formula IV-oC, or a pharmaceutically acceptable salt thereof.

[0525] In certain embodiments, the present invention provides a compound of Formula I-1, Formula I-1′, Formula I-2, Formula I-2′, Formula I-3, or Formula I-3′, wherein the ERBM is: [ka] and thereby forming a compound of formula IV-p, IV-q, IV-r, IV-s, IV-t, IV-u, IV-v, IV-w, or IV-x, respectively: [ka] or a pharmaceutically acceptable salt thereof, wherein R 1 , R 2 , R 3 , m, n, p, L, and LBM are each as defined in the embodiments and classes and subclasses herein.

[0526] In some embodiments, the compound is 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 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 of formula IV-t, or a pharmaceutically acceptable salt thereof.

[0531] In some embodiments, the compound is 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 of formula IV-x, or a pharmaceutically acceptable salt thereof.

[0535] In certain embodiments, the present invention provides a compound of Formula I-1, Formula I-1′, Formula I-2, Formula I-2′, Formula I-3, or Formula I-3′, wherein the ERBM is: [ka] and thereby forming, respectively, formula IV-aa, formula IV-bb, formula IV-cc, formula IV-dd, formula IV-ee, formula IV-ff, formula IV-gg, formula IV-hh, formula IV-ii, formula IV-jj, formula IV-kk, or formula IV-ll: [ka] [ka] or a pharmaceutically acceptable salt thereof, wherein R 1 , R2 , R 3 , m, n, p, L, and LBM are each as defined in the embodiments and classes and subclasses herein.

[0536] In some embodiments, the compound is of formula IV-aa, or a pharmaceutically acceptable salt thereof.

[0537] In some embodiments, the compound is of formula IV-bb, or a pharmaceutically acceptable salt thereof.

[0538] In some embodiments, the compound is of formula IV-cc, or a pharmaceutically acceptable salt thereof.

[0539] In some embodiments, the compound is of formula IV-dd, or a pharmaceutically acceptable salt thereof.

[0540] In some embodiments, the compound is of formula IV-ee, or a pharmaceutically acceptable salt thereof.

[0541] In some embodiments, the compound is of formula IV-ff, or a pharmaceutically acceptable salt thereof.

[0542] In some embodiments, the compound is of formula IV-gg, or a pharmaceutically acceptable salt thereof.

[0543] In some embodiments, the compound is 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 of formula IV-kk, or a pharmaceutically acceptable salt thereof.

[0547] In some embodiments, the compound is of formula IV-11, or a pharmaceutically acceptable salt thereof.

[0548] In certain embodiments, the present invention provides a compound of Formula I-1, Formula I-1′, Formula I-2, Formula I-2′, Formula I-3, or Formula I-3′, wherein the ERBM is: [ka] and thereby formula Va, formula Vb, or formula Vc, respectively: [ka] or a pharmaceutically acceptable salt thereof, wherein: [ka] represents a single or double bond, and R 1 , R 2 , R 3 , X 1 , X 2 , m, n, p, L, and LBM are each as defined in the embodiments and classes and subclasses herein.

[0549] In some embodiments, the compound is a compound of Formula Va, or a pharmaceutically acceptable salt thereof.

[0550] In some embodiments, the compound is a compound of Formula Vb, or a pharmaceutically acceptable salt thereof.

[0551] In some embodiments, the compound is of formula Vc, or a pharmaceutically acceptable salt thereof.

[0552] In certain embodiments, the present invention provides a compound of Formula I-1, Formula I-1′, Formula I-2, Formula I-2′, Formula I-3, or Formula I-3′, wherein the ERBM is: [ka] and thereby, respectively, formula Vd, formula Ve, formula Vf, formula Vg, formula Vh, formula Vi, formula Vj, formula Vk, or formula Vl: [ka] or a pharmaceutically acceptable salt thereof, wherein: [ka] represents a single or double bond, and R 1 , R 2 , R 3 , m, n, p, L, and LBM are each as defined in the embodiments and classes and subclasses herein.

[0553] In some embodiments, the compound is a compound of formula Vd, or a pharmaceutically acceptable salt thereof.

[0554] In some embodiments, the compound is a compound of formula Ve, or a pharmaceutically acceptable salt thereof.

[0555] In some embodiments, the compound is a compound of formula Vf, or a pharmaceutically acceptable salt thereof.

[0556] In some embodiments, the compound is of formula Vg, or a pharmaceutically acceptable salt thereof.

[0557] In some embodiments, the compound is a compound of formula Vh, or a pharmaceutically acceptable salt thereof.

[0558] In some embodiments, the compound is a compound of formula Vi, or a pharmaceutically acceptable salt thereof.

[0559] In some embodiments, the compound is a compound of formula Vj, or a pharmaceutically acceptable salt thereof.

[0560] In some embodiments, the compound is of formula Vk, or a pharmaceutically acceptable salt thereof.

[0561] In some embodiments, the compound is of formula Vl, or a pharmaceutically acceptable salt thereof.

[0562] In certain embodiments, the present invention provides a compound of Formula I-1, Formula I-1′, Formula I-2, Formula I-2′, Formula I-3, or Formula I-3′, wherein the ERBM is: [ka] and thereby forming a compound of formula VI-a, VI-b, or VI-c, respectively: [ka] or a pharmaceutically acceptable salt thereof, wherein the rings A, R 1 , R 2 , R 3 , m, n, p, L, and LBM are each as defined in the embodiments and classes and subclasses herein.

[0563] In certain embodiments, the present invention provides a compound of Formula I-1, Formula I-1′, Formula I-2, Formula I-2′, Formula I-3, or Formula I-3′, wherein the ERBM is: [ka] and thereby forming, respectively, formula VI-d, formula VI-e, or formula VI-f: [ka] or a pharmaceutically acceptable salt thereof, wherein the rings A, R 1 , R 2 , R 3 , m, n, p, L, and LBM are each as defined in the embodiments and classes and subclasses herein.

[0564] In certain embodiments, the present invention provides a compound of Formula I-1, Formula I-1′, Formula I-2, Formula I-2′, Formula I-3, or Formula I-3′, wherein the ERBM is: [ka] and thereby forming, respectively, formula VI-g, formula VI-h, formula VI-i, formula VI-j, formula VI-k, or formula VI-l: [ka] or a pharmaceutically acceptable salt thereof, wherein the rings A, R 1 , R 2 , R 3 , m, n, p, L, and LBM are each as defined in the embodiments and classes and subclasses herein.

[0565] In certain embodiments, the present invention provides a compound of Formula I-1, Formula I-1′, Formula I-2, Formula I-2′, Formula I-3, or Formula I-3′, wherein the ERBM is: [ka] and thereby forming a compound of formula VI-m, VI-n, or VI-o, respectively: [ka] or a pharmaceutically acceptable salt thereof, wherein the rings A, R 1 , R 2 , R 3 , m, n, p, L, and LBM are each as defined in the 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 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 of formula VI-1, or a pharmaceutically acceptable salt thereof.

[0578] In some embodiments, the compound is 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 of formula VI-o, or a pharmaceutically acceptable salt thereof.

[0581] In certain embodiments, the present invention provides a compound of Formula I-1, Formula I-1′, Formula I-2, Formula I-2′, Formula I-3, or Formula I-3′, wherein the ERBM is: [ka] and thereby forming a compound of formula II-j-2, II-k-2, or II-l-2, respectively: [ka] and a compound of formula I-1, I-1′, I-2, I-2′, I-3, or I-3′, or a pharmaceutically acceptable salt thereof, wherein ring A, ring B, R 1 , R 2 , R 3 , m, n, p, L, and LBM are each as defined in the embodiments and classes and subclasses herein.

[0582] In certain embodiments, the present invention provides a compound of Formula I-1, Formula I-1′, Formula I-2, Formula I-2′, Formula I-3, or Formula I-3′, wherein the ERBM is: [ka] and thereby forming a compound of formula VII-a, VII-b, VII-c, VII-d, VII-e, or VII-f, respectively: [ka] or a pharmaceutically acceptable salt thereof, wherein the rings A, R 1 , R 2 , R 3 , m, n, p, L, and LBM are each as defined in the embodiments and classes and subclasses herein.

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

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

[0585] In certain embodiments, the present invention provides a compound of Formula I-1, Formula I-1′, Formula I-2, Formula I-2′, Formula I-3, or Formula I-3′, wherein the ERBM is: [ka] and thereby forming a compound of formula VII-p, formula VII-q, or formula VII-r, respectively: [ka] or a pharmaceutically acceptable salt thereof, wherein the rings A, R 1 , R 2 , R 3 , m, n, p, L, and LBM are each as defined in the 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 of formula VII-1, 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 of formula VII-o, or a pharmaceutically acceptable salt thereof.

[0601] In some embodiments, the compound is 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 of formula VII-r, or a pharmaceutically acceptable salt thereof.

[0604] In some embodiments, the compound has formula VIII-d, formula VIII-e, or formula VIII-f: [ka] or a pharmaceutically acceptable salt thereof, wherein X 1 , X 2 , R 1 , R 3 , m, p, L, and LBM are each as defined in the 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 has formula VIII-g, formula VIII-h, formula VIII-i, formula VIII-j, formula VIII-k, or formula VIII-l: [ka] or a pharmaceutically acceptable salt thereof, wherein ring A, R 1 , R 3 , m, p, L, and LBM are each as defined in the 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-1, or a pharmaceutically acceptable salt thereof.

[0614] In some embodiments, the compound has formula VIII-m, formula VIII-n, formula VIII-o, formula VIII-p, formula VIII-q, formula VIII-r, formula VIII-s, formula VIII-t, or formula VIII-u: [ka] [ka] or a pharmaceutically acceptable salt thereof, wherein R A1 , R 1 , R 3 , m, p, L, and LBM are each as defined in the 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 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 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 has formula IX-d, formula IX-e, formula IX-f: [ka] or a pharmaceutically acceptable salt thereof, wherein X 1 , X 2 , ring C, R 1 , R 3 , R 6 , m, p, t, L, and LBM are each as defined in the 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 of formula IX-g, formula IX-h, formula IX-i, formula IX-j, formula IX-k, formula IX-l, formula IX-m, formula IX-n, formula IX-o: [ka] or a pharmaceutically acceptable salt thereof, wherein X 1 , X 2 , X 3 , ring A, ring C, R 1 , R 3 , R6 , m, p, t, L, and LBM are each as defined in the 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 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 of formula IX-1, or a pharmaceutically acceptable salt thereof.

[0635] In some embodiments, the compound is 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 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 examples herein, or pharmaceutically acceptable salts, stereoisomers, or mixtures of stereoisomers thereof. In some embodiments, the present disclosure provides a compound selected from the compounds set forth in Table 1 or Table 2 below, or a pharmaceutically acceptable salt, stereoisomer, or mixtures 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 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6] [Table 1-7] [Table 1-8] [Table 1-9] [Table 1-10] [Table 1-11] [Table 1-12] [Table 1-13]

Table 1-14

Table 1-15

Table 1-16

Table 1-17

Table 1-18

Table 1-19

Table 1-20

Table 1-21

Table 1-22

Table 1-23

Table 1-24

Table 1-25

Table 1-26

Table 1-27

Table 1-28

Table 1-29

Table 1-30

Table 1-31

Table 1-32

Table 1-33

Table 1-34

Table 1-35

Table 1-36

Table 1-37

Table 1-38

Table 1-39

Table 1-40

Table 1-41

Table 1-42

Table 1-43

Table 1-44

Table 1-45

Table 1-46

Table 1-47

Table 1-48

Table 1-49

Table 1-50

Table 1-51

Table 1-52

Table 1-53

Table 1-54

Table 1-55

Table 1-56

Table 1-57

Table 1-58

Table 1-59

Table 1-60

Table 1-61

Table 1-62

Table 1-63

Table 1-64

Table 1-65

Table 1-66

Table 1-67

Table 1-68

Table 1-69

Table 1-70

Table 1-71

Table 1-72

Table 1-73

Table 1-74

Table 1-75

Table 1-76

Table 1-77

Table 1-79

Table 1-80

Table 1-81

Table 1-82

Table 1-83

Table 1-84

Table 1-85

Table 1-86

Table 1-87

Table 1-88

Table 1-89

Table 1-90

Table 1-91

Table 1-92

Table 1-93

Table 1-94

Table 1-95

Table 1-96

Table 1-97

Table 1-98

Table 1-99

Table 1-100

Table 1-101

Table 1-103

Table 1-104

Table 1-105

Table 1-106

Table 1-108

Table 1-109

Table 1-110

Table 1-111

Table 1-112

Table 1-113

Table 1-114

Table 1-115

Table 1-116

Table 1-117

Table 1-118

Table 1-119

Table 1-120

Table 1-121

Table 1-122

Table 1-123

Table 1-124

Table 1-125

Table 1-126

Table 1-127

Table 1-129

Table 1-131

Table 1-133

Table 1-136

Table 1-137

Table 1-138

Table 1-139

Table 1-141

Table 2-1

Table 2-2

Table 2-3

Table 2-4

Table 2-5

Table 2-6

Table 2-7

Table 2-8

Table 2-9

Table 2-10

Table 2-11

Table 2-12

Table 2-13

Table 2-14

Table 2-15

Table 2-16

Table 2-17

Table 2-18

Table 2-19

Table 2-20

Table 2-21

Table 2-22

Table 2-23

Table 2-24

[0639] In the chemical structures in Table 1 or Table 2 above, and in the Examples below, stereocenters are described according to enhanced stereo-representation format (MDL / Biovia, e.g., using the labels "or1", "or2", "abs", "and1").

[0640] In some embodiments, the present disclosure includes a compound of Formula I-1, Formula I-1', Formula I-2, Formula I-2', Formula I-3, or Formula I-3', or a pharmaceutically acceptable salt, stereoisomer, or mixture of stereoisomers thereof, selected from the compounds shown in Table 1 or Table 2 above. In some embodiments, the present disclosure includes a compound of Formula I-1, or a pharmaceutically acceptable salt, diastereomer, or mixture of diastereomers thereof, selected from the compounds shown in Table 1 or Table 2 above. In some embodiments, the present disclosure provides a compound of Formula I-1, Formula I-1', Formula I-2, Formula I-2', Formula I-3, or Formula I-3', or a pharmaceutically acceptable salt thereof, selected from the compounds shown in Table 1 or Table 2 above. In some embodiments, the present disclosure provides a compound of Formula I-1, Formula I-1', Formula I-2, Formula I-2', Formula I-3, or Formula I-3', selected from the compounds shown in Table 1 or Table 2 above.

[0641] The compounds in Table 1 or Table 2 were made according to the chemical procedures described in the Examples section or according to similar procedures that would be readily apparent to one of skill in the art based on this disclosure and knowledge existing in the art. Compounds marked with an (*) in Table 1 or Table 2 are prophetic examples and can be made by methods similar to those included in the Examples section.

[0642] 4. Use, Formulation, and Administration Pharmaceutically acceptable compositions According to another embodiment, the present disclosure provides a composition comprising a compound of the present disclosure, or a pharmaceutically acceptable derivative thereof, and a pharmaceutically acceptable carrier, adjuvant, or vehicle. In some embodiments, the present disclosure provides a pharmaceutical composition comprising a compound of the present disclosure and a pharmaceutically acceptable carrier. The amount of the compound in the composition of the present disclosure is an amount effective to measurably degrade ERα or a variant thereof in a biological sample or a patient. In certain embodiments, the amount of the compound in the composition of the present disclosure is an amount effective to measurably degrade ERα or a variant thereof in a biological sample or a patient. In certain embodiments, the composition of the present disclosure is formulated for administration to a patient in need of such a composition. In some embodiments, the composition of the present disclosure is formulated for oral administration to a patient.

[0643] As used herein, the terms "subject" and "patient" refer to an animal (i.e., a member of the animal kingdom), preferably a mammal, and most preferably a human. In some embodiments, the subject is a human, a mouse, a rat, a cat, a monkey, a dog, a horse, or a pig. In some embodiments, the subject is a human. In some embodiments, the subject is a mouse, a rat, a cat, a monkey, a dog, a horse, or a 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 being formulated. Pharmaceutically acceptable carriers, adjuvants, or vehicles that can be used in the compositions of the present 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, polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol, and wool fat.

[0645] "Pharmaceutically acceptable derivative" means any non-toxic salt, ester, salt of an ester, or other derivative of a compound of the present disclosure that, upon administration to a recipient, is capable of providing, either directly or indirectly, a compound of the present disclosure or an inhibitory active metabolite or residue thereof.

[0646] As used herein, the term "degradatively active metabolite or residue thereof" means that the metabolite or residue thereof is also a degradant of ERα or a mutant thereof.

[0647] The compositions of the present disclosure can be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, bucally, vaginally, or via an implanted reservoir. As used herein, the term "parenteral" 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] The sterile injectable form of the composition of the present disclosure may be an aqueous or oily 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. Acceptable vehicles and solvents that can be used include water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile fixed oils are commonly used as solvents or suspending media.

[0649] For this purpose, any bland fixed oil may be used, including synthetic mono- or diglycerides. Fatty acids such as oleic acid and its glyceride derivatives are useful for preparing 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 long-chain alcohol diluents or dispersants such as carboxymethylcellulose, or similar dispersants commonly used in formulating pharmaceutically acceptable dosage forms, including emulsions and suspensions. Other commonly used surfactants, such as Tween®, Span®, and other emulsifiers or bioavailability enhancers, commonly used in producing pharmaceutically acceptable solid, liquid, or other dosage forms, may also be used for formulation purposes.

[0650] The pharmaceutically acceptable compositions of the present disclosure can be orally administered in any orally acceptable dosage form, including but not limited to capsules, tablets, aqueous suspensions or solutions.For tablets for oral use, commonly used carriers include lactose and corn starch.Lubricants such as magnesium stearate are also typically added.For oral administration in capsule form, useful diluents include lactose and dried corn starch.When aqueous suspensions are required for oral use, the active ingredient is combined with emulsifying and suspending agents.If desired, certain sweeteners, flavorings, or coloring agents can also be added.

[0651] Alternatively, the pharmaceutically acceptable compositions of the present disclosure can be administered in the form of suppositories for rectal or vaginal administration. These can be prepared by mixing the drug with a suitable non-irritating excipient that is solid at room temperature but liquid at rectal or vaginal temperature and therefore melts in the rectum or vagina to release the drug. Such materials include cocoa butter, beeswax, and polyethylene glycol.

[0652] The pharmaceutically acceptable compositions of the present disclosure may also be administered topically, particularly when the target of treatment includes areas or organs readily accessible by topical application, including diseases of the eye, skin, or 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. Topical-transdermal patches may also be used.

[0654] For topical application, provided pharmaceutically acceptable compositions can be formulated in a suitable ointment containing the active ingredient suspended or dissolved in one or more carriers.Carriers for topical administration of the compounds of the present disclosure include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compounds, emulsifying wax, and water.Alternatively, provided pharmaceutically acceptable compositions can be formulated in a suitable lotion or cream containing the active ingredient 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 ester wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol, and water.

[0655] For ophthalmic use, the provided pharmaceutically acceptable compositions can be formulated as a micronized suspension in isotonic, pH-adjusted sterile saline, with or without preservatives such as benzylalkonium chloride, or preferably as a solution in isotonic, pH-adjusted sterile saline. Alternatively, for ophthalmic use, the pharmaceutically acceptable compositions can be formulated in an ointment such as petrolatum.

[0656] Pharmaceutically acceptable compositions of the present 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, using benzyl alcohol or other suitable preservatives, absorption enhancers to enhance bioavailability, fluorocarbons, and / or other conventional solubilizing or dispersing agents.

[0657] Preferably, the pharmaceutically acceptable compositions of the present disclosure are formulated for oral administration. Such formulations can be administered with or without food. In some embodiments, the pharmaceutically acceptable compositions of the present disclosure are administered without food. In other embodiments, the pharmaceutically acceptable compositions of the present disclosure are administered with food.

[0658] The amount of the compounds of the present disclosure that can be combined with a carrier material to produce a composition in a single dosage form will vary depending on the patient being treated and the particular mode of administration. Preferably, provided compositions should be formulated so that a dosage of 0.01 to 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 the specific dosage and treatment regimen for any particular patient will depend on a variety of factors, including the activity of the specific compound employed, the patient's age, body weight, general health, sex, diet, time of administration, rate of excretion, concomitant medications, and the judgment of the treating physician, as well as the severity of the particular disease being treated. The amount of a compound of the present disclosure in the composition will also depend on the specific 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 certain embodiments of the present disclosure, suitable dose ranges for oral administration of the compounds of the present disclosure are generally from about 1 mg / day to about 1000 mg / day. In some embodiments, the oral dose is from about 1 mg / day to about 800 mg / day. In some embodiments, the oral dose is from about 1 mg / day to about 500 mg / day. In some embodiments, the oral dose is from about 1 mg / day to about 250 mg / day. In some embodiments, the oral dose is from about 1 mg / day to about 100 mg / day. In some embodiments, the oral dose is from 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 dosage amount listed herein may constitute an upper or lower dosage range, or may be combined with any other dosage amount to constitute upper and lower dosage ranges.

[0661] In some embodiments, the pharmaceutically acceptable composition comprises a provided compound and / or a pharmaceutically acceptable salt thereof at a concentration ranging from about 0.01 to about 90% by weight, about 0.01 to about 80% by weight, about 0.01 to about 70% by weight, about 0.01 to about 60% by weight, about 0.01 to about 50% by weight, about 0.01 to about 40% by weight, about 0.01 to about 30% by weight, about 0.01 to about 20% by weight, about 0.01 to about 2.0% by weight, about 0.01 to about 1% by weight, about 0.05 to about 0.5% by weight, about 1 to about 30% by weight, or about 1 to about 20% by weight. The composition can be formulated as a solution, suspension, ointment, capsule, or the like. The pharmaceutical composition can be prepared as an aqueous solution and can contain additional ingredients such as preservatives, buffers, tonicity agents, antioxidants, stabilizers, and viscosity-adjusting ingredients.

[0662] Pharmaceutically acceptable carriers are well known to those skilled in the art and include, for example, 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, for example, water or saline solution, polymers such as polyethylene glycol, carbohydrates and their derivatives, oils, fatty acids, or alcohols. Non-limiting examples of oils as pharmaceutical carriers include petroleum, animal, vegetable, or synthetic oils, such as peanut oil, soybean oil, mineral oil, and sesame oil. Pharmaceutical carriers may also be saline, acacia gum, gelatin, starch paste, talc, keratin, colloidal silica, urea, and the like. In addition, auxiliary agents, stabilizers, thickeners, lubricants, and colorants may be used. Other examples of suitable pharmaceutical carriers can be found, for example, in 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 is incorporated herein by reference in its entirety.

[0664] As used herein, pharmaceutically acceptable carriers can be selected from a variety of organic or inorganic materials used as pharmaceutical formulation materials and incorporated as analgesics, buffers, binders, disintegrants, diluents, emulsifiers, excipients, bulking agents, glidants, solubilizers, stabilizers, suspending agents, isotonicity agents, vehicles, and viscosity enhancers. Pharmaceutical additives such as antioxidants, flavoring agents, coloring agents, flavor enhancers, preservatives, and sweeteners can also be added. Examples of acceptable pharmaceutical carriers include, among others, carboxymethylcellulose, crystalline cellulose, glycerin, gum arabic, lactose, magnesium stearate, methylcellulose, powder, saline, sodium alginate, sucrose, starch, talc, and water. In some embodiments, the term "pharmaceutically acceptable" means approved by federal or state regulatory authorities for use in animals, more specifically in humans, or listed in the United States Pharmacopoeia or other commonly recognized pharmacopeia.

[0665] Surfactants, such as detergents, are also suitable for use in the formulations. Specific examples of surfactants include polyvinylpyrrolidone, polyvinyl alcohol, copolymers of vinyl acetate and vinylpyrrolidone, polyethylene glycol, benzyl alcohol, polyoxyethylenated esters of mannitol, glycerol, sorbitol, or sorbitan; lecithin or sodium carboxymethylcellulose; or acrylic derivatives, such as methacrylates; anionic surfactants, such as alkaline stearates, particularly sodium, potassium, or ammonium stearate; calcium stearate or triethanolamine stearate; alkyl sulfates, particularly sodium lauryl sulfate and sodium cetyl sulfate; sodium dodecylbenzenesulfonate or sodium dioctyl sulfosuccinate; or fatty acids, particularly those derived from coconut oil; cationic surfactants, such as those of the formula N+R'R''R'''R''''Y-, where the R radicals are the same or different, optionally hydroxylated hydrocarbon radicals. and Y is an anion of a strong acid such as a halide, sulfate, or sulfonate (cetyltrimethylammonium bromide is one example of a cationic surfactant that can be used); amine salts of the formula N+R'R''R''' (where the R radicals are the same or different, optionally hydroxylated hydrocarbon radicals) (octadecylamine hydrochloride is one example of a cationic surfactant that can be used); nonionic surfactants, such as optionally polyoxyethylated esters of sorbitan, in particular polysorbate 80, or polyoxyethylated alkyl ethers; polyethylene glycol stearate, polyoxyethylated derivatives of castor oil, polyglycerol esters, polyoxyethylated fatty alcohols, polyoxyethylated fatty acids, or copolymers of ethylene oxide and 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, nonfat dry milk, glycerol, propylene glycol, polyethylene glycol 300, water, ethanol, polysorbate 20, and the like. The composition, if desired, can also contain wetting or emulsifying agents, or pH buffering agents.

[0667] Tablet and capsule formulations may further comprise one or more adjuvants, binders, diluents, disintegrants, excipients, fillers, or lubricants, each of which is known in the art. Examples of such include carbohydrates, such as lactose or sucrose, anhydrous dibasic calcium phosphate, corn starch, mannitol, xylitol, cellulose or its derivatives, microcrystalline cellulose, gelatin, stearates, silicon dioxide, talc, sodium starch glycolate, acacia, flavoring agents, preservatives, buffers, disintegrants, and coloring agents. Orally administered compositions may comprise one or more optional agents, such as sweeteners, such as fructose, aspartame, or saccharin; flavoring agents, such as peppermint, wintergreen oil, or cherry; coloring agents; and preservatives, to provide a pharmaceutically acceptable preparation.

[0668] Uses of the Compounds and Pharmaceutically Acceptable Compositions The compounds and compositions described herein are generally useful for degrading ERα. In some embodiments, the nuclear transcription factor degraded by the compounds and compositions described herein is ERα.

[0669] The disclosed compounds or compositions can be useful in applications that benefit from degradation of ERα. For example, the disclosed ERα degraders are generally useful in treating cell proliferative disorders.

[0670] The activity of the compounds utilized in the present disclosure as degraders of ERα or its mutants can be assayed in vitro, in vivo, or in cell lines. In vitro assays include assays that determine the inhibition of either the signaling activity of activated ERα or its mutants and / or the subsequent functional consequences. An alternative in vitro assay quantifies the ability of a degrader to degrade ERα. Representative in vitro and in vivo assays useful in assaying ERα degraders include those described and disclosed in the patents and scientific publications referenced herein. Detailed conditions for assaying the compounds utilized in the present disclosure as degraders of ERα or its mutants are described in the Examples below.

[0671] Treatment of the disorder The provided compounds are degraders of ERα and are therefore useful for treating one or more disorders associated with the activity of ERα or its mutant forms. Thus, in certain embodiments, the present disclosure provides a method for treating an ERα-mediated disorder in a subject, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of the present disclosure, a pharmaceutically acceptable salt thereof, or any of the aforementioned pharmaceutically acceptable compositions. In certain embodiments, the present disclosure provides a method for treating an ERα-mediated disorder in a subject, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of the present disclosure, or a pharmaceutically acceptable composition thereof. In some embodiments, the subject has a mutant ERα. In some embodiments, the subject has an ERα comprising a D538G, Y537S, or L536R mutation.

[0672] As used herein, the term "ERα-mediated" disorder, disease, and / or condition refers to any disease or other deleterious condition in which ERα or a mutant form thereof is known to play a role. Accordingly, another embodiment of the present disclosure relates to treating or reducing the severity of one or more diseases in which ERα or a mutant form thereof is known to play a role. Such ERα-mediated disorders include, but are not limited to, cell proliferative disorders (e.g., cancer). In some embodiments, the ERα-mediated disorder is a disorder mediated by mutant ERα. In some embodiments, the ERα-mediated disorder is a disorder mediated by ERα comprising a D538G, Y537S, or L536R mutation.

[0673] In some embodiments, the present disclosure provides a method for treating a cell proliferative disorder, the method comprising administering to a patient in need thereof a therapeutically effective amount of a compound of the present disclosure, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable composition of any of the foregoing. In some embodiments, the present disclosure provides a method for treating a cell proliferative disorder, the 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 methods of treatment include: (i) identifying a subject in need of such treatment; (ii) providing a disclosed compound, or a pharmaceutically acceptable salt thereof; and (iii) administering a therapeutically effective amount of the provided compound to treat, inhibit, and / or prevent a disease state or condition in the subject in need of such treatment. In some embodiments, the subject has a mutant ERα. In some embodiments, the subject has an ERα comprising a D538G, Y537S, or L536R mutation.

[0675] In some embodiments, the method of treatment includes: (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 the composition in a therapeutically effective amount to treat, inhibit, and / or prevent a disease state or condition in the subject in need of such treatment. In some embodiments, the subject has a mutant ERα. In some embodiments, the subject has an ERα comprising a D538G, Y537S, or L536R mutation.

[0676] Another aspect of the present disclosure provides a compound as defined herein, or a pharmaceutically acceptable salt thereof, or any of the aforementioned pharmaceutical compositions, for use in treating a disorder described herein. Another aspect of the present disclosure provides the use of a compound as defined herein, or a pharmaceutically acceptable salt thereof, or any of the aforementioned pharmaceutical compositions, for treating a disorder described herein. Similarly, the present disclosure provides the use of a compound as defined herein, or a pharmaceutically acceptable salt thereof, for preparing a medicament for treating a disorder described herein.

[0677] Cell proliferative disorders In some embodiments, the disorder is a cell proliferative disorder. In some embodiments, the cell proliferative disorder 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 cell proliferative disorder is tumor and / or cancerous cell proliferation. In some embodiments, the cell proliferative disorder is a tumor. In some embodiments, the cell proliferative disorder is a solid tumor. In some embodiments, the cell proliferative disorder is cancerous cell proliferation.

[0678] In some embodiments, the cancer is sarcoma, lung cancer, bronchial cancer, prostate cancer, breast cancer (including sporadic breast cancer and Cowden's disease), pancreatic cancer, gastrointestinal cancer, colon cancer, rectal cancer, carcinoma, colon carcinoma, adenoma, colorectal adenoma, thyroid cancer, liver cancer, intrahepatic cholangiocarcinoma, hepatocellular carcinoma, adrenal gland cancer, stomach cancer, gastric cancer, glioma, neuroblastoma, endometrial cancer, melanoma, kidney cancer, renal pelvis cancer, bladder cancer, uterine cancer, cervical cancer, vaginal cancer, ovarian cancer (including clear cell ovarian cancer), multiple myeloma, esophageal cancer, leukemia, acute myeloid leukemia, chronic myeloid leukemia, lymphocytic leukemia, myeloid leukemia, brain cancer, carcinoma of the brain), oral and pharyngeal cancer, laryngeal cancer, small intestine cancer, non-Hodgkin's lymphoma, villous colon adenoma, neoplasm, neoplasia of epithelial character, lymphoma, mammary carcinoma, basal cell carcinoma, squamous cell carcinoma, actinic keratosis, cervical cancer, head cancer, polycythemia vera, essential thrombocythemia, myelofibrosis with myeloid metaplasia, and Waldenstrom's macroglobulinemia.

[0679] In some embodiments, the cancer is selected from lung cancer, bronchial cancer, prostate cancer, breast cancer (including sporadic breast cancer and Cowden's disease), pancreatic cancer, gastrointestinal cancer, colon cancer, rectal cancer, thyroid cancer, liver cancer, intrahepatic bile duct cancer, hepatocellular carcinoma, adrenal gland cancer, stomach cancer, gastric cancer, endometrial cancer, kidney cancer, renal pelvis cancer, bladder cancer, uterine cancer, cervical cancer, vaginal cancer, ovarian cancer (including clear cell ovarian cancer), esophageal cancer, leukemia, acute myeloid leukemia, chronic myeloid leukemia, lymphocytic leukemia, myeloid leukemia, brain cancer, oral and pharyngeal cancer, laryngeal cancer, small intestine cancer, cervical cancer, and head cancer. In some embodiments, the cancer is selected from sarcoma, carcinoma, colon cancer, adenoma, colorectal adenoma, glioma, neuroblastoma, melanoma, multiple myeloma, brain cancer, non-Hodgkin's lymphoma, villous colon adenoma, neoplasia, neoplasia of epithelial character, lymphoma, breast cancer, basal cell carcinoma, squamous cell carcinoma, actinic keratosis, polycythemia vera, essential thrombocythemia, myelofibrosis with myeloid metaplasia, and Waldenstrom's macroglobulinemia.

[0680] In some embodiments, the cancer is selected from lung cancer, bronchial cancer, prostate cancer, breast cancer (including sporadic breast cancer and Cowden's disease), pancreatic cancer, gastrointestinal cancer, colon cancer, rectal cancer, thyroid cancer, liver cancer, intrahepatic bile duct cancer, hepatocellular carcinoma, adrenal gland cancer, stomach cancer, gastric cancer, endometrial cancer, kidney cancer, renal pelvis cancer, bladder cancer, uterine cancer, cervical cancer, vaginal cancer, ovarian cancer (including clear cell ovarian cancer), esophageal cancer, brain cancer, oral and pharyngeal cancer, laryngeal cancer, small intestine cancer, cervical cancer, and head cancer. In some embodiments, the cancer is leukemia. In some embodiments, the cancer is acute myeloid leukemia, chronic myeloid leukemia, lymphocytic leukemia, or myeloid leukemia.

[0681] In some embodiments, the cancer is breast cancer (including sporadic breast cancer and Cowden's disease). In some embodiments, the cancer is breast cancer. In some embodim...

Claims

1. Compound of formula I-3': 【Chemical 1604】 wherein, ERBM is 【Chemical 1605】 selected from, where 【Chemical 1606】 represents the binding site to a modifiable carbon, oxygen, nitrogen, or sulfur atom of the ERBM moiety of the -L-LBM moiety, X １ is N, NH, CH, CH ２ , CH(R Ａ１ ), or C(R Ａ１ ), ２ or C(R Ａ１ ), as permitted by other substituents, X ２ is N(R Ａ２ ), O, CH ２ (R Ａ３ ), or C(R Ａ３ ) ２ and X ３ is N(R Ａ４ ), O, CH ２ , CH(R Ａ５ ), or C(R Ａ５ ), ２ but However, X １ and X ２ both or X ２ and X ３ are not heteroatoms, provided that R １ 、R ２ 、R ４ 、R ５ 、R ６ 、R Ａ１ 、R Ａ２ 、R Ａ３ 、R Ａ４ 、and R Ａ５ Each case of, R Ａ or R Ｂ is, and R Ｃ is replaced by 0 to 4 cases of, R ３ In each case independently, R Ａ or R Ｂ is, and R Ｃ is replaced by 0 to 4 cases of R, or two R ３ groups optionally combine together to form a 5- to 8-membered partially unsaturated or aryl-fused ring having 0 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. R Ａ For each case 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 and R Ｂ In each case independently, C １－６ an aliphatic chain; phenyl; naphthyl; cubanyl; adamantyl; a 5- or 6-membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8- to 10-membered bicyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclic ring; a 5- to 12-membered saturated or partially unsaturated bicyclic carbocyclic ring; a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 7- to 12-membered saturated or partially unsaturated bicyclic heterocyclic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and R Ｃ In each case 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 C １－６ An optionally substituted group selected from a 3- to 7-membered saturated or partially unsaturated monocyclic heterocycle having 1 to 2 heteroatoms independently selected from aliphatic, phenyl, nitrogen, oxygen, and sulfur, and a 5- to 6-membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur For each instance of R, independently, hydrogen, or C １－６ Optionally substituted group selected from a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from aliphatic, phenyl, nitrogen, oxygen, and sulfur, and a 5- to 6-membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or two R groups on the same nitrogen optionally combine together with their intervening atoms to form an optionally substituted 4- to 7-membered saturated, partially unsaturated, or heteroaryl ring having 0 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur in addition to nitrogen, ring A and ring B are each independently phenyl; naphthyl; tetrahydronaphthalenyl; dihydroindenyl; benzocyclobutenyl; cubanyl; adamantyl; a 5- to 6-membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8- to 10-membered bicyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclic ring; a 5- to 12-membered saturated or partially unsaturated bicyclic carbocyclic ring; a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 7- to 12-membered saturated or partially unsaturated bicyclic heterocyclic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, ring C is a spiro-fused 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclic ring; a spiro-fused 5- to 12-membered saturated or partially unsaturated bicyclic carbocyclic ring; a spiro-fused 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a spiro-fused 7- to 12-membered saturated or partially unsaturated bicyclic heterocyclic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, L is a covalent bond, or a divalent, saturated or unsaturated, linear or branched C １－５０ hydrocarbon chain, wherein 0 to 6 methylene units of L are independently -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-, -NRC(O)-, -C(O)NR-, -OC(O)NR-, -NRC(O)O-, 【Chemical 1607】 is replaced by, Here, each -Cy- is independently an optionally substituted divalent ring selected from phenylenyl, 8- to 10-membered bicyclic arylenyl, 4- to 7-membered saturated or partially unsaturated carbocyclirenyl, 5- to 11-membered saturated or partially unsaturated spirocarbocyclirenyl, 8- to 10-membered bicyclic saturated or partially unsaturated carbocyclirenyl, 4- to 7-membered saturated or partially unsaturated heterocyclirenyl having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 5- to 11-membered saturated or partially unsaturated spiroheterocyclirenyl having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 8- to 10-membered bicyclic saturated or partially unsaturated heterocyclirenyl having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 6- to 10-membered bridged bicyclic saturated or partially unsaturated heterocyclirenyl having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 5- to 6-membered heteroarylenyl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or 8- to 10-membered bicyclic heteroarylenyl having 1 to 5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein LBM is 【Chemical 1608】 【Chemical 1609】 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, 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, t is 0, 1, 2, 3, or 4, for the compound of formula I-3' or a pharmaceutically acceptable salt thereof. **Claim 2** A compound of formula I-3': 【Chemical 1610】 wherein, in the formula, ERBM is 【Chemical 1611】 selected from, where 【Chemical 1612】 represents the binding site to a modifiable carbon, oxygen, nitrogen, or sulfur atom of the ERBM moiety of the -L-LBM moiety, X １ is N, NH, CH, CH ２ , CH(R Ａ１ ), or C(R Ａ１ ), ２ or C(R Ａ１ ), where X ２ is N(R Ａ２ ), O, CH ２ ), CH(R Ａ３ ), or C(R Ａ３ ), ２ and X ３ is N(R Ａ４ ), O, CH ２ , CH(R Ａ５ ), or C(R Ａ５ ), ２ but However, X １ and X ２ both or X ２ and X ３ are not heteroatoms, provided that R １ 、R ２ 、R ４ 、R ５ 、R ６ 、R Ａ１ 、R Ａ２ 、R Ａ３ 、R Ａ４ 、and R Ａ５ In each case, R Ａ or R Ｂ is, and R Ｃ is replaced by 0 to 4 cases of, R ３ In each case, R Ａ or R Ｂ is, and R Ｃ is replaced by 0 to 4 cases of R, or two R ３ groups optionally combine together to form a 5- to 8-membered partially unsaturated or aryl-fused ring having 0 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. R Ａ in each case 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 and R Ｂ For each case of, C １－６ an aliphatic chain; phenyl; naphthyl; cubanyl; adamantyl; a 5- to 6-membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8- to 10-membered bicyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclic ring; a 5- to 12-membered saturated or partially unsaturated bicyclic carbocyclic ring; a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 7- to 12-membered saturated or partially unsaturated bicyclic heterocyclic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and R Ｃ For each case of, 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 C １－６ is an optionally substituted group selected from a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from aliphatic, phenyl, nitrogen, oxygen, and sulfur, and a 5- to 6-membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, For each instance of R, independently, hydrogen, or C １－６ Optionally substituted group selected from a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from aliphatic, phenyl, nitrogen, oxygen, and sulfur, and a 5- to 6-membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or two R groups on the same nitrogen optionally come together with their intervening atoms to form an optionally substituted 4- to 7-membered saturated, partially unsaturated, or heteroaryl ring having 0 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur in addition to nitrogen, Ring A and Ring B are each independently phenyl; naphthyl; tetrahydronaphthalenyl; dihydroindenyl; benzocyclobutenyl; cubanyl; adamantyl; a 5- to 6-membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8- to 10-membered bicyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclic ring; a 5- to 12-membered saturated or partially unsaturated bicyclic carbocyclic ring; a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 7- to 12-membered saturated or partially unsaturated bicyclic heterocyclic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, Ring C is a spiro-fused 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclic ring; a spiro-fused 5- to 12-membered saturated or partially unsaturated bicyclic carbocyclic ring; a spiro-fused 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a spiro-fused 7- to 12-membered saturated or partially unsaturated bicyclic heterocyclic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, L is a covalent bond or a divalent, saturated or unsaturated, straight-chain or branched C １－５０ hydrocarbon chain, where 0 to 6 methylene units of L are independently -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-, -NRC(O)-, -C(O)NR-, -OC(O)NR-, -NRC(O)O-, 【Chemical 1613】 is replaced by, Here, each -Cy- is independently a divalent ring optionally substituted and selected from phenylenyl, 8- to 10-membered bicyclic arylenyl, 4- to 7-membered saturated or partially unsaturated carbocyclirenyl, 5- to 11-membered saturated or partially unsaturated spirocarbocyclirenyl, 8- to 10-membered bicyclic saturated or partially unsaturated carbocyclirenyl, 4- to 7-membered saturated or partially unsaturated heterocyclirenyl having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 5- to 11-membered saturated or partially unsaturated spiroheterocyclirenyl having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 8- to 10-membered bicyclic saturated or partially unsaturated heterocyclirenyl having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 6- to 10-membered bridged bicyclic saturated or partially unsaturated heterocyclirenyl having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 5- to 6-membered heteroarylenyl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or 8- to 10-membered bicyclic heteroarylenyl having 1 to 5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein LBM is 【Chemical 1614】 【Chemical 1615】 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, q is each 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, t is 0, 1, 2, 3, or 4, provided that ERBM is 【Chemical 1616】 (wherein X １ is CH or N, X ２ is CH ２ and ring B is phenyl, ring A is phenyl or a 6-membered monocyclic heteroaryl ring having 1 to 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, wherein LBM is R ２ is, -OH, -Me, -OMe, -F, -Br, -CF ３ , and - ｉ Pr selected), in the case where or a stereoisomer thereof, the compound of formula I-3', or a pharmaceutically acceptable salt thereof. 【Chemical 1617】

3. ERBM is the compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein ERBM is 【Chemical 1618】

4. ERBM is the compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein ERBM is 【Chemical 1619】 the compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof.

5. ERBM is the compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein ERBM is 【Chemical 1620】

6. ERBM is ​ 【Chemical 1621】 The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof.

7. The compound according to claim 1 or 2, wherein the compound is a compound of formula II-a, formula II-b, or formula II-c: 【Chemical 1622】 or a pharmaceutically acceptable salt thereof.

8. The compound according to claim 1 or 2, wherein the compound is a compound of formula II-a-1, formula II-b-1, or formula II-c-1: 【Chemical 1623】 or a pharmaceutically acceptable salt thereof.

9. The compound according to claim 1 or 2, wherein the compound is a compound of formula VIII-a, formula VIII-b, formula VIII-c, formula IX-a, formula IX-b, or formula IX-c: 【Chemical 1624】 【Chemical 1625】 or a pharmaceutically acceptable salt thereof.

10. The compound according to claim 1 or 2, wherein the compound is a compound of formula VIII-a-1, formula VIII-b-1, or formula VIII-c-1: 【Chemical 1626】 or a pharmaceutically acceptable salt thereof.

11. The compound according to claim 1 or 2, wherein the compound is a compound of formula IX-a-1, formula IX-b-1, or formula IX-c-1 【Chemical 1627】 or a pharmaceutically acceptable salt thereof.

12. X １ The compound according to any one of claims 1 to 11, wherein X is N or CH.

13. X １ The compound according to any one of claims 1 to 11, wherein X is N.

14. X １ The compound according to any one of claims 1 to 11, wherein X is CH.

15. X １ The compound according to any one of claims 1 to 11, wherein X is NH or CH2.

16. X １ is CH(R Ａ１ ), the compound according to any one of claims 1 to 11.

17. X １ is C(R Ａ１ ), the compound according to any one of claims 1 to 11.

18. X １ is C(R Ａ１ )2, the compound according to any one of claims 1 to 11.

19. X ２ is O or CH ２ although, provided that X １ and X ２ are not both heteroatoms at the same time, the compound according to any one of claims 1 to 11.

20. X ２ The compound according to any one of claims 1 to 11, wherein X is O.

21. X ２ is CH ２ The compound according to any one of claims 1 to 11, wherein

22. X ３ is O, CH ２ , CH(R Ａ５ ), or C(R Ａ５ ), and the compound according to any one of claims 1 to 11.

23. X ３ The compound according to any one of claims 1 to 11, wherein X is O.

24. X ３ is CH ２ The compound according to any one of claims 1 to 11, wherein

25. X ３ is CH(R Ａ５ ), a compound according to any one of claims 1 to 11.

26. X ３ is C(R Ａ５ ) and is a compound according to any one of claims 1 to 11.

27. The compound according to claim 1 or 2, wherein the compound is a compound of formula II-d-A, formula II-e-A, formula II-f-A, formula II-d-B, formula II-e-B, formula II-f-B, formula II-d-C, formula II-e-C, formula II-f-C, formula II-g, formula II-h, formula II-i, formula II-j-A, formula II-k-A, or formula II-l-A: 【Chemical 1628】 【Chemical 1629】 【Chemical 1630】 【Chemical 1631】 or a pharmaceutically acceptable salt thereof, provided that when the compound is of formula II-d-A, formula II-e-A, formula II-f-A, formula II-j-A, formula II-k-A, and formula II-l-A and ring B is phenyl, ring A is other than phenyl or a 6-membered monocyclic heteroaryl ring having 1 to 3 nitrogen heteroatoms.

28. The compound according to claim 1 or 2, wherein the compound is one of the compounds of formula II-n, formula II-o, formula II-p, formula II-q, formula II-r, formula II-s, formula II-t, formula II-u, or formula II-v: 【Chemical 1632】 【Chemical 1633】 or a pharmaceutically acceptable salt thereof.

29. wherein the compound is a compound of formula II-w, formula II-x, formula II-y, formula II-z, formula II-aa, formula II-bb, formula II-cc, formula II-dd, or formula II-ee: 【Chemical 1634】 【Chemical 1635】 The compound according to claim 1 or 2, which is one of the compounds or a pharmaceutically acceptable salt thereof.

30. wherein the compound is a compound of formula II-d-1, formula II-e-1, formula II-f-1, formula II-g-1, formula II-h-1, formula II-i-1, formula II-j-1, formula II-k-1, or formula II-l-1: 【Chemical 1636】 which is one of the compounds or a pharmaceutically acceptable salt thereof, provided that when the compound is a compound of formula II-d-1, formula II-e-1, formula II-f-1, formula II-j-1, formula II-k-1, and formula II-l-1 and ring B is phenyl, ring A is other than phenyl or a 6-membered monocyclic heteroaryl ring having 1 to 3 nitrogen heteroatoms, the compound according to claim 1 or 2.

31. wherein the compound is a compound of formula II-d-1-A, formula II-e-1-A, formula II-f-1-A, formula II-d-1-B, formula II-e-1-B, formula II-f-1-B, formula II-d-1-C, formula II-e-1-C, formula II-f-1-C, formula II-j-1-A, formula II-k-1-A, or formula II-l-1-A: 【Chemical 1637】 【Chemical 1638】 which is a compound or a pharmaceutically acceptable salt thereof, provided that when the compound is a compound of formula II-d-1-A, formula II-e-1-A, formula II-f-1-A, formula II-j-1-A, formula II-k-1-A, and formula II-l-1-A and ring B is phenyl, ring A is other than phenyl or a 6-membered monocyclic heteroaryl ring having 1 to 3 nitrogen heteroatoms, the compound according to claim 1 or 2.

32. wherein the compound is a compound of formula II-m-1: 【Chemical 1639】 The compound according to claim 1 or 2, which is a compound or a pharmaceutically acceptable salt thereof.

33. wherein the compound is a compound of formula II-n-1, formula II-o-1, formula II-p-1, formula II-q-1, formula II-r-1, formula II-s-1, formula II-t-1, formula II-u-1, or formula II-v-1: 【Chemical 1640】 The compound according to claim 1 or 2, which is one of the compounds or a pharmaceutically acceptable salt thereof.

34. wherein the compound is of formula II-w-1, formula II-x-1, formula II-y-1, formula II-z-1, formula II-aa-1, formula II-bb-1, formula II-cc-1, formula II-dd-1, or formula II-ee-1: 【Chemical 1641】 The compound according to claim 1 or 2, which is one of the compounds of the formulae, or a pharmaceutically acceptable salt thereof.

35. wherein the compound is of formula II-ff-1, formula II-gg-1, formula II-hh-1, formula II-ii-1, formula II-jj-1, formula II-kk-1, formula II-ll-1, formula II-mm-1, or formula II-nn-1: 【Chemical 1642】 The compound according to claim 1 or 2, which is one of the compounds of the formulae, or a pharmaceutically acceptable salt thereof.

36. Ring A together with its R １ substituents 【Chemical 1643】 selected from the group consisting of, wherein the upper bond is attached to L and the lower bond is attached to the 6-membered ring of the ERBM moiety, the compound according to any one of claims 1 to 35.

37. Ring A together with its R １ substituent 【Chemical 1644】 selected from the group consisting of, wherein the upper bond is attached to L and the lower bond is attached to the 6-membered ring of the ERBM moiety, the compound according to any one of claims 1 to 35.

38. Ring B together with its R ２ substituent 【Chemical 1645】 【Chemical 1646】 【Chemical 1647】 selected from the group consisting of, the compound according to any one of claims 1 to 37.

39. wherein the compound is of formula III-a-A, formula III-b-A, formula III-c-A, formula III-a-B, formula III-b-B, formula III-c-B, formula III-a-C, formula III-b-C, and formula III-c-C: 【Chemical 1648】 One of the compounds, or a pharmaceutically acceptable salt thereof, provided that for formula III-a-A, formula III-b-A, and formula III-c-A, X １ is CH or N, and X ２ is CH ２ The compound according to claim 1 or 2, provided that when is, ring B is other than phenyl.

40. wherein the compound is of formula III-d, formula III-e, formula III-f, formula III-g, formula III-h, formula III-i, formula III-j, formula III-k, or formula III-l: 【Chemical 1649】 The compound according to claim 1 or 2, which is one of the compounds of the formulae, or a pharmaceutically acceptable salt thereof, provided that when the compound is of formula III-d, formula III-e, formula III-f, formula III-j, formula III-k, or formula III-l, ring B is other than phenyl.

41. wherein the compound is of formula III-d-A, formula III-e-A, formula III-f-A, formula III-d-B, formula III-e-B, formula III-f-B, formula III-d-C, formula III-e-C, formula III-f-C, formula III-g, formula III-h, formula III-i, formula III-j-A, formula III-k-A, or formula III-l-A: 【Chemical 1650】 【Chemical 1651】 The compound, or a pharmaceutically acceptable salt thereof, provided that when the compound is of formula III-d-A, formula III-e-A, formula III-f-A, formula III-j-A, formula III-k-A, or formula III-l-A, ring B is other than phenyl, the compound according to claim 1 or 2.

42. The compound is of formula III-m, formula III-n, or formula III-o: 【Chemical 1652】 One of the compounds, or a pharmaceutically acceptable salt thereof, provided that X １ is CH or N, and X ２ is CH ２ is a compound according to claim 1 or 2, provided that ring A is other than phenyl or a 6-membered monocyclic heteroaryl ring having 1 to 3 nitrogen heteroatoms.

43. Formula III-m-A, formula III-n-A, or formula III-o-A, formula III-m-B, formula III-n-B, formula III-o-B, formula III-m-C, formula III-n-C, or formula III-o-C: 【Chemical 1653】 One of the compounds, or a pharmaceutically acceptable salt thereof, provided that the compound is of formula III-m-A, formula III-n-A, or formula III-o-A, X １ is CH or N, and X ２ is CH ２ The compound according to claim 1 or 2, provided that when is, ring A is other than phenyl or a 6-membered monocyclic heteroaryl ring having 1 to 3 nitrogen heteroatoms.

44. The compound is of formula III-p, formula III-q, formula III-r, formula III-s, formula III-t, formula III-u, formula III-v, formula III-w, or formula III-x: 【Chemical 1654】 One of the compounds, or a pharmaceutically acceptable salt thereof, provided that when the compound is of formula III-p, formula III-q, formula III-r, formula III-v, formula III-w, or formula III-x, ring A is other than phenyl or a 6-membered monocyclic heteroaryl ring having 1 to 3 nitrogen heteroatoms, the compound according to claim 1 or 2.

45. The compound is of formula III-p-A, formula III-q-A, formula III-r-A, formula III-p-B, formula III-q-B, formula III-r-B, formula III-p-C, formula III-q-C, formula III-r-C, formula III-s, formula III-t, formula III-u, formula III-v-A, formula III-w-A, or formula III-x-A: 【Chemical 1655】 【Chemical 1656】 One of the compounds, or a pharmaceutically acceptable salt thereof, provided that when the compound is of formula III-p-A, formula III-q-A, formula III-r-A, formula III-v-A, formula III-w-A, or formula III-x-A, ring A is other than phenyl or a 6-membered monocyclic heteroaryl ring having 1 to 3 nitrogen heteroatoms, the compound according to claim 1 or 2.

46. The compound is of formula IV-a, formula IV-b, or formula IV-c: 【Chemical 1657】 One of the compounds, or a pharmaceutically acceptable salt thereof, wherein 【Chemical 1658】 represents a single bond or a double bond, the compound according to claim 1 or 2.

47. The compound is one of the compounds of formula IV-d, formula IV-e, formula IV-f, formula IV-g, formula IV-h, formula IV-i, formula IV-j, formula IV-k, or formula IV-l: 【Chemical 1659】 or a pharmaceutically acceptable salt thereof, wherein 【Chemical 1660】 represents a single bond or a double bond, the compound according to claim 1 or 2.

48. The compound is of formula IV-m, formula IV-n, or formula IV-o: 【Chemical 1661】 One of the compounds, or a pharmaceutically acceptable salt thereof, provided that X １ When is CH or N, X ２ Is CH ２ The compound according to claim 1 or 2, provided that it is other than.

49. The compound is of formula IV-m-A, formula IV-n-A, formula IV-o-A, formula IV-m-B, formula IV-n-B, formula IV-o-B, formula IV-m-C, formula IV-n-C, or formula IV-o-C: 【Chemical 1662】 【Chemical 1663】 The compound, or a pharmaceutically acceptable salt thereof, provided that the compound is of formula IV-m-A, formula IV-n-A, or formula IV-o-A, and X １ is CH or N, X ２ is CH ２ The compound according to claim 1 or 2, provided that X is other than CH.

50. The compound is one of the compounds of formula IV-s, formula IV-t, formula IV-u, formula IV-v, formula IV-w, or formula IV-x: 【Chemical 1664】 or a pharmaceutically acceptable salt thereof, the compound according to claim 1 or 2.

51. The compound is of formula IV-aa, formula IV-bb, formula IV-cc, formula IV-dd, formula IV-ee, formula IV-ff, formula IV-gg, formula IV-hh, formula IV-ii, formula IV-jj, formula IV-kk, or formula IV-ll: 【Chemical 1665】 【Chemical 1666】 or a pharmaceutically acceptable salt thereof, the compound according to claim 1 or 2.

52. The compound is one of the compounds of formula V-a, formula V-b, or formula V-c: 【Chemical 1667】 or a pharmaceutically acceptable salt thereof, wherein 【Chemical 1668】 represents a single bond or a double bond, the compound according to claim 1 or 2.

53. The compound is one of the compounds of formula V-d, formula V-e, formula V-f, formula V-g, formula V-h, formula V-i, formula V-j, formula V-k, or formula V-l: 【Chemical 1669】 or a pharmaceutically acceptable salt thereof, wherein 【Chemical 1670】 represents a single bond or a double bond, the compound according to claim 1 or 2.

54. The compound is of formula VI-a, formula VI-b, or formula VI-c: 【Chemical 1671】 One of the compounds, or a pharmaceutically acceptable salt thereof, wherein ring A, R １ , R ２ , R ３ , m, n, p, L, and LBM are each as defined in the claims and the classes and subclasses of this specification, the compound according to claim 1 or 2.

55. The compound is of formula VI-d, formula VI-e, or formula VI-f: 【Chemical 1672】 One of the compounds, or a pharmaceutically acceptable salt thereof, wherein ring A, R １ R ２ R ３ , m, n, p, L, and LBM are each as defined in the claims and the classes and subclasses of this specification, a compound according to claim 1 or 2.

56. The compound is of formula VI-g, formula VI-h, formula VI-i, formula VI-j, formula VI-k, or formula VI-l: 【Chemical 1673】 One of the compounds, or a pharmaceutically acceptable salt thereof, wherein ring A, R １ , R ２ , R ３ , m, n, p, L, and LBM are each as defined in the claims and the classes and subclasses of this specification, the compound according to claim 1 or 2.

57. The compound is of formula VI-m, formula VI-n, or formula VI-o: 【Chemical 1674】 One of the compounds, or a pharmaceutically acceptable salt thereof, wherein ring A, R １ , R ２ , R ３ , m, n, p, L, and LBM are each as defined in the claims and the classes and subclasses of this specification, a compound according to claim 1 or 2.

58. The compound is of formula II-j-2, formula II-k-2, or formula II-l-2: 【Chemical 1675】 One of the compounds, or a pharmaceutically acceptable salt thereof, wherein ring A, ring B, R １ , R ２ , R ３ , m, n, p, L, and LBM are each as defined in the claims and the classes and subclasses of this specification, a compound according to claim 1 or 2.

59. The compound is of formula VII-a, formula VII-b, formula VII-c, formula VII-d, formula VII-e, or formula VII-f: 【Chemical 1676】 One of the compounds, or a pharmaceutically acceptable salt thereof, wherein ring A, R １ , R ２ , R ３ , m, n, p, L, and LBM are each as defined in the claims and the classes and subclasses of this specification, a compound according to claim 1 or 2.

60. wherein the compound is of formula VII-g, formula VII-h, or formula VII-i: 【Chemical 1677】 One of the compounds, or a pharmaceutically acceptable salt thereof, wherein ring A, R １ , R ２ , R ３ , m, n, p, L, and LBM are each as defined in the claims and the classes and subclasses of this specification, a compound according to claim 1 or 2.

61. wherein the compound is of formula VII-j, formula VII-k, formula VII-l, formula VII-m, formula VII-n, or formula VII-o: 【Chemical 1678】 One of the compounds, or a pharmaceutically acceptable salt thereof, wherein ring A, R １ , R ２ , R ３ , m, n, p, L, and LBM are each as defined in the claims and the classes and subclasses of this specification, a compound according to claim 1 or 2.

62. wherein the compound is of formula VII-p, formula VII-q, or formula VII-r, respectively: 【Chemical 1679】 One of the compounds, or a pharmaceutically acceptable salt thereof, wherein ring A, R １ , R ２ , R ３ , m, n, p, L, and LBM are each as defined in the claims and the classes and subclasses of this specification, a compound according to claim 1 or 2.

63. wherein the compound is of formula VIII-d, formula VIII-e, and formula VIII-f: 【Chemical 1680】 The compound according to claim 1 or 2, which is one of the compounds of the following, or a pharmaceutically acceptable salt thereof.

64. wherein the compound is of formula VIII-g, formula VIII-h, formula VIII-i, formula VIII-j, formula VIII-k, or formula VIII-l: 【Chemical 1681】 The compound according to claim 1 or 2, which is one of the compounds of the following, or a pharmaceutically acceptable salt thereof.

65. wherein the compound is of formula VIII-m, formula VIII-n, formula VIII-o, formula VIII-p, formula VIII-q, formula VIII-r, formula VIII-s, formula VIII-t, or formula VIII-u: 【Chemical 1682】 The compound according to claim 1 or 2, which is one of the compounds of the following, or a pharmaceutically acceptable salt thereof.

66. wherein the compound is of formula IX-d, formula IX-e, formula IX-f: 【Chemical 1683】 The compound according to claim 1 or 2, which is one of the compounds of the following, or a pharmaceutically acceptable salt thereof.

67. wherein the compound is of formula IX-g, formula IX-h, formula IX-i, formula IX-j, formula IX-k, formula IX-l, formula IX-m, formula IX-n, formula IX-o: 【Chemical 1684】 The compound according to claim 1 or 2, which is one of the compounds of the following, or a pharmaceutically acceptable salt thereof.

68. Ring C together with its R ６ substituent 【Chemical 1685】 The compound according to any one of claims 1 to 67, which is selected from:

69. X １ wherein X is selected from CH and C(R Ａ１ ), and the compound according to any one of claims 1 to 68.

70. X ２ is selected from O, CH ２ , CH(R Ａ３ ), and C(R Ａ３ ), provided that neither both X ２ nor both X １ and X ２ are heteroatoms simultaneously, the compound according to any one of claims 1 to 69.

71. L is a divalent, saturated or unsaturated, straight-chain or branched C １－５０ hydrocarbon chain, wherein 0 to 6 methylene units of L are independently, -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-, -NRC(O)-, -C(O)NR-, -OC(O)NR-, -NRC(O)O-, 【Chemical 1686】 The compound according to any one of claims 1 to 70, which is replaced by:

72. L is a divalent, saturated or unsaturated, straight-chain or branched C ３－５ hydrocarbon chain, where 0, 1, 2, or 3 methylene units of L are independently -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-, -NRC(O)-, -C(O)NR-, -OC(O)NR-, -NRC(O)O-, 【Chemical 1687】 The compound according to any one of claims 1 to 70, which is replaced by:

73. L is a divalent, saturated or unsaturated, straight-chain 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-, the compound according to any one of claims 1 to 70.

74. L is a divalent, saturated or unsaturated, straight-chain or branched C ３－５ hydrocarbon chain, wherein 1, 2, or 3 methylene units of L are independently replaced by -Cy- or -NR-, a compound according to any one of claims 1 to 70.

75. Each -Cy- is independently an optionally substituted divalent ring selected from a 4- to 7-membered saturated or partially unsaturated monocyclic carbocyclirenyl, a 5- to 11-membered saturated or partially unsaturated spirocarbocyclirenyl, an 8- to 10-membered bicyclic saturated or partially unsaturated carbocyclirenyl, a 4- to 7-membered saturated or partially unsaturated monocyclic heterocyclirenyl having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5- to 11-membered monocyclic saturated or partially unsaturated spiroheterocyclirenyl having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, an 8- to 10-membered bicyclic saturated or partially unsaturated heterocyclirenyl having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 6- to 10-membered bridged bicyclic saturated or partially unsaturated heterocyclirenyl having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, the compound according to any one of claims 1 to 70.

76. Each -Cy- is independently an optionally substituted divalent ring selected from a 4- to 7-membered saturated or partially unsaturated monocyclic carbocyclirenyl, a 5- to 11-membered saturated or partially unsaturated spirocarbocyclirenyl, an 8- to 10-membered bicyclic saturated or partially unsaturated carbocyclirenyl, a 4- to 7-membered saturated or partially unsaturated monocyclic heterocyclirenyl containing 1 to 2 nitrogen atoms, a 5- to 11-membered monocyclic saturated or partially unsaturated spiroheterocyclirenyl containing 1 to 2 nitrogen atoms, an 8- to 10-membered bicyclic saturated or partially unsaturated heterocyclirenyl containing 1 to 2 nitrogen atoms, and a 6- to 10-membered bridged bicyclic saturated or partially unsaturated heterocyclirenyl containing 1 to 2 nitrogen atoms, the compound according to any one of claims 1 to 70.

77. Each divalent ring of -Cy- is independently 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 The compound according to any one of claims 1 to 70, which is substituted with 0, 1, or 2 substituents independently selected from

78. Each divalent ring of -Cy- is independently -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 The compound according to any one of claims 1 to 70, which is substituted with 0, 1, or 2 substituents independently selected from

79. Each of said divalent rings of -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 The compound according to any one of claims 1 to 70, which is substituted with 0, 1, or 2 substituents independently selected from

80. The divalent ring of each -Cy- is independently substituted with 0, 1, or 2 substituents independently selected from -Me, -OMe, and -F, the compound according to any one of claims 1 to 70.

81. The divalent ring of each -Cy- is independently substituted in 0, 1, or 2 instances of -Me, the compound according to any one of claims 1 to 70.

82. The divalent ring of each -Cy- is unsubstituted, the compound according to any one of claims 1 to 70.

83. The compound according to any one of claims 1 to 70, wherein the divalent ring of each -Cy- is substituted with one or two substituents.

84. L is 【Chemical 1688】 The compound according to any one of claims 1 to 70.

85. L is 【Chemical 1689】 【Chemical 1690】 selected from the group consisting of

86. LBM is 【Chemical 1691】 【Chemical 1692】 selected from the group consisting of

87. LBM is 【Chemical 1693】 selected from the group consisting of

88. LBM is 【Chemical 1694】 selected from the group consisting of

89. Each R ４ is independently C substituted with 0 to 3 instances of deuterium, halo １－６ aliphatic chain, halogen, -CN, -OR, -NR ２ , -S(O) ２ , -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, where R is H or C １－６ aliphatic chain, the compound according to any one of claims 1 to 88.

90. Each R ４ independently is selected from -Me, -Et, -F, -Cl, -CF ３ , -CN, -OH, -OMe, -NH ２ , -NHMe, and -NMe ２ and is a compound according to any one of claims 1 to 88

91. Each R ５ is independently C substituted in 0 to 3 instances with deuterium, halo １－６ aliphatic chain, 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, where R is H or C １－６ aliphatic chain, a compound according to any one of claims 1 to 88.

92. Each R ５ is independently selected from -Me, -Et, -F, -Cl, -CF3, -CN, -OH, -OMe, -NH2, -NHMe, and -NMe2, and the compound according to any one of claims 1 to 88.

93. Each R ５ is independently selected from -Me and -F, and the compound according to any one of claims 1 to 92.

94. r is 0, 1, or 2. The compound according to any one of claims 1 to 93.

95. s is 0, 1, or 2. The compound according to any one of claims 1 to 94.

96. LBM is 【Chemical 1695】 【Chemical 1696】 selected from the group consisting of

97. LBM is 【Chemical 1697】 selected from the group consisting of

98. LBM is 【Chemical 1698】 selected from the group consisting of

99. LBM is 【Chemical 1699】 selected from the group consisting of

100. LBM is 【Chemical 1700】 The compound according to any one of claims 1 to 85.

101. Each R １ is independently C substituted with 0 to 3 instances of deuterium, halo １－６ aliphatic chain, 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, where R is C substituted with 0 to 3 instances of H or halo １－６ aliphatic chain, the compound according to any one of claims 1 to 100.

102. 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 and is a compound according to any one of claims 1 to 100.

103. Each R １ which is independently selected from -Me and -F, the compound according to any one of claims 1 to 100.

104. Each R ２ is independently C substituted with 0 to 3 instances of deuterium, halo １－６ aliphatic chain, 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, and wherein R is H or C １－６ aliphatic chain, the compound according to any one of claims 1 to 103.

105. Each R ２ is independently, -Me, -Et, -F, -Cl, -CF ３ , -CN, -OH, -OMe, -NH ２ , -NHMe, and -NMe ２ selected from, the compound according to any one of claims 1 to 103.

106. Each R ２ is independently selected from -F, -Cl, and -CF ３ and is a compound according to any one of claims 1 to 103.

107. m is 0, 1, or 2. The compound according to any one of claims 1 to 106.

108. n is 0, 1, or 2. The compound according to any one of claims 1 to 107.

109. Each R ３ is independently C substituted with 0 to 3 instances of deuterium, halo １－６ aliphatic chain, 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 (where R is H or C １－６ aliphatic chain), or two R ３ groups together form 【Chemical 1701】 forming the compound according to any one of claims 1 to 108.

110. Each R ３ is independently selected from -Me, -Et, -F, -Cl, -CF ３ , -CO ２ H, -CN, -OH, -OMe, -NH ２ , -NHMe, and -NMe ２ or two R ３ groups together form 【Chemical 1702】 forming the compound according to any one of claims 1 to 108.

111. Each R ３ is independently selected from -F, -OH, and -CO ２ H, and the compound according to any one of claims 1 to 108.

112. Each R ３ independently, is selected from -Me, -F, -OH, and -CO ２ H, and is a compound according to any one of claims 1 to 108.

113. Each R ３ independently selected from -F and -OH, the compound according to any one of claims 1 to 108.

114. Each R ３ independently selected from -Me and -F, the compound according to any one of claims 1 to 108.

115. Two Rs ３ groups are combined together 【Chemical 1703】 forming the compound according to any one of claims 1 to 108.

116. p is 0, 1, or 2. The compound according to any one of claims 1 to 115.

117. 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 and is a compound according to any one of claims 1 to 116

118. Each R ６ is independently selected from -Me and -F, and the compound according to any one of claims 1 to 116.

119. t is 0, 1, or 2. The compound according to any one of claims 1 to 118.

120. The compound is 【Chemical 1704】 【Chemical 1705】 【Chemical 1706】 【Chemical 1707】 【Chemical 1708】 【Chemical 1709】 【Chemical 1710】 【Chemical 1711】 【Chemical 1712】 【Chemical 1713】 【Chemical 1714】 【Chemical 1715】 【Chemical 1716】 【Chemical 1717】 【Chemical 1718】 【Chemical 1719】 【Chemical 1720】 【Chemical 1721】 【Chemical 1722】 【Chemical 1723】 【Chemical 1724】 【Chemical 1725】 【Chemical 1726】 【Chemical 1727】 【Chemical 1728】 【Chemical 1729】 【Chemical 1730】 【Chemical 1731】 【Chemical 1732】 【Chemical 1733】 【Chemical 1734】 【Chemical 1735】 【Chemical 1736】 【Chemical 1737】 【Chemical 1738】 【Chemical 1739】 【Chemical 1740】 【Chemical 1741】 【Chemical 1742】 【Chemical 1743】 【Chemical 1744】 【Chemical 1745】 【Chemical 1746】 【Chemical 1747】 【Chemical 1748】 【Chemical 1749】 【Chemical 1750】 【Chemical 1751】 【Chemical 1752】 【Chemical 1753】 【Chemical 1754】 【Chemical 1755】 【Chemical 1756】 【Chemical 1757】 【Chemical 1758】 【Chemical 1759】 【Chemical 1760】 【Chemical 1761】 【Chemical 1762】 【Chemical 1763】 【Chemical 1764】 【Chemical 1765】 【Chemical 1766】 【Chemical 1767】 【Chemical 1768】 【Chemical 1769】 【Chemical 1770】 【Chemical 1771】 【Chemical 1772】 【Chemical 1773】 【Chemical 1774】 【Chemical 1775】 【Chemical 1776】 【Chemical 1777】 【Chemical 1778】 【Chemical 1779】 A compound selected from The compound according to any one of claims 1 to 119, or a pharmaceutically acceptable salt thereof.

121. 【Fig. 1780】 【Chemical 1781】 【Chemical 1782】 【Chemical 1783】 【Chemical 1784】 【Chemical 1785】 【Chemical 1786】 【Chemical 1787】 【Chemical 1788】 【Chemical 1789】 【Chemical 1790】 【Chemical 1791】 【Chemical 1792】 【Chemical 1793】 【Chemical 1794】 【Chemical 1795】 【Chemical 1796】 【Chemical 1797】 【Chemical 1798】 【Chemical 1799】 【Chemical 1800】 A compound selected from Or a pharmaceutically acceptable salt thereof.

122. A pharmaceutical composition comprising the compound according to any one of claims 1 to 121, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, adjuvant, or diluent.

123. A method for inhibiting ERα signaling in a sample, for example, in vivo or in vitro, by contacting ERα with the compound according to any one of claims 1 to 121, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 122.

124. The method according to claim 123, wherein said inhibition 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% as compared to a reference standard, for example.

125. The method according to claim 123, wherein said inhibition 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 as compared to a reference standard, for example.

126. A method for treating an ERα-mediated disorder in a patient in need thereof, comprising administering to said patient the compound according to any one of claims 1 to 121, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 122.

127. The method according to claim 126, wherein said ERα-mediated disorder is related to the accumulation and aggregation of estrogen receptors.

128. The method according to claim 126 or 127, wherein said ERα-mediated disorder is a cancer or neoplasm related to the accumulation and aggregation of estrogen receptors.

129. The method according to claim 128, wherein said ERα-mediated disorder is a disorder mediated by ERα containing the D544G, Y543S, or L542R mutation.

130. The method according to any one of claims 123 to 129, wherein said ERα-mediated disorder is cancer.

131. Said method is (i)identifying a subject in need of such treatment; (ii)providing the disclosed compound, or a pharmaceutically acceptable salt thereof; (iii)administering the disclosed compound in a therapeutically effective amount to treat, suppress, and / or prevent a condition or disorder in a subject in need of such treatment, the method according to any one of claims 123 to 129.

132. The method according to any one of claims 123 to 129, wherein the ERα-mediated disorder is breast cancer or uterine cancer.

133. The method according to claim 132, 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.

134. The method according to any one of claims 123 to 129, wherein the ERα-mediated disorder is endometriosis.

135. The compound according to any one of claims 1 to 121, or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 122, for use as a medicament.

136. The compound according to any one of claims 1 to 121, or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 122, for use in the treatment of ERα-mediated disorders.

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