PDE4 degraders, pharmaceutical compositions, and therapeutic applications

Abstract

Provided herein are phosphodiesterase 4 (PDE4) degraders, such as compounds of Formula (I) or Formula (IA), and pharmaceutical compositions thereof. Also provided herein are methods of their use to treat, prevent, or ameliorate one or more symptoms of a PDE4-mediated disease, disorder, or condition. [Formula 1] TIFF2024500377000464.tif34170

Description

[Technical Field]

[0001] (CROSS-REFERENCE TO RELATED APPLICATIONS) This application claims the benefit of priority to U.S. Provisional Patent Application No. 63 / 124,877, filed December 14, 2020; the disclosure of which is incorporated herein by reference in its entirety.

[0002] (Field) Provided herein are phosphodiesterase 4 (PDE4) degraders and pharmaceutical compositions thereof, as well as methods of their use to treat, prevent, or ameliorate one or more symptoms of a PDE4-mediated disease, disorder, or condition. [Background technology]

[0003] (background) Abnormal protein function or protein imbalance is a hallmark of many disease states. For example, immune system function is precisely balanced by the activity of pro- and anti-inflammatory mediators or cytokines. Some cytokines promote inflammation (pro-inflammatory cytokines), while others suppress the activity of the pro-inflammatory cytokines (anti-inflammatory cytokines). For example, interleukin-4 (IL-4), interleukin-10 (IL-10), and interleukin-13 (IL-13) are potent activators of B lymphocytes and also act as anti-inflammatory agents. These are anti-inflammatory cytokines due to their ability to suppress the genes of pro-inflammatory cytokines such as interleukin-1 (IL-1), tumor necrosis factor (TNF), and chemokines.

[0004] Unregulated activity of these mediators can lead to the development of severe inflammatory conditions. For example, autoimmune diseases occur when immune system cells (lymphocytes and macrophages) become sensitized to "self." Lymphocytes and macrophages are normally under control in this system. However, the system can become misdirected against the body's own tissues in response to an unknown trigger. One hypothesis is that lymphocytes recognize antigens that mimic "self," resulting in a cascade of activation of various components of the immune system, ultimately leading to tissue destruction. Genetic predisposition is also postulated to play a role in autoimmune disorders.

[0005] For example, phosphodiesterase 4 (PDE4) is involved in cytokine production, angiogenesis, and the functional properties of other cell types, such as keratinocytes, in part through the degradation of cyclic adenosine monophosphate (cAMP). cAMP is an important second messenger that regulates inflammatory responses. Therefore, PDE4 inhibitors can block the synthesis of several pro-inflammatory cytokines and chemokines, such as tumor necrosis factor-α (TNF-α), interleukin-23 (IL-23), chemokine ligand 9 (CXCL9, also known as interferon-γ-inducible monokine (MIG)), and chemokine ligand 10 (CXCL10, also known as interferon-γ-inducible protein 10 (IP-10)), in multiple cell types, and can interfere with the production of leukotriene B4, inducible nitric oxide synthase, and matrix metalloproteinases. This interference reduces certain inflammatory processes such as dendritic cell infiltration, epidermal skin thickening, and joint destruction, such as those in psoriasis and other inflammatory and / or autoimmune diseases such as arthritis, ankylosing spondylitis, osteoarthritis, rheumatoid arthritis, Behcet's disease, inflammatory bowel disease (e.g., Crohn's disease and ulcerative colitis), psoriasis, atopic dermatitis, and contact dermatitis.

[0006] Psoriasis is an autoimmune skin disease caused by the pro-inflammatory cytokines interferon-γ (IFN-γ) and TNF-α. The immune response in psoriasis involves the involvement of monocytes, dendritic cells, neutrophils, and T cells, all of which contribute to abnormal keratinocyte proliferation. PDE4 inhibition can reduce the production of multiple mediators from PBMCs, such as TNF-α, IFN-γ, CXCL9, CXCL10, interleukin-2 (IL-2), interleukin-12 (IL-12), interleukin-23 (IL-23), macrophage inflammatory protein-1-α (MIP-1α), monocyte chemotactic protein-1 (MCP1), and granulocyte-macrophage colony-stimulating factor (GM-CSF). Therefore, there is a continuing need for small molecule PDE4 modulators as an effective therapy for treating inflammatory diseases. Summary of the Invention

[0007] (Disclosure Summary) Provided herein are compounds of formula (I): [ka] (In the formula, L is a linker; X is —CH— or —C(O)—; Y is C 1-6 Alkylene or C 3-10 is cycloalkylene; R E is the E3 ubiquitin ligase binding moiety; R 1 is (i)C 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 aralkyl, heteroaryl, or heterocyclyl; or (ii) —OR 1a or -NR 1b R 1c and; R 2is hydrogen or deuterium; R 3a , R 3d , and R 3e are each independently (i) hydrogen, deuterium, cyano, halo, or nitro; (ii) C 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) —C(O)R 1a , -C(O)OR 1a , -C(O)NR 1b R 1c , -C(O)SR 1a , -C(NR 1a )NR 1b R 1c , -C(S)R 1a , -C(S)OR 1a , -C(S)NR 1b R 1c , -OR 1a , -OC(O)R 1a , -OC(O)OR 1a , -OC(O)NR 1b R 1c , -OC(O)SR 1a , -OC(NR 1a )NR 1b R 1c , -OC(S)R 1a , -OC(S)OR 1a , -OC(S)NR 1b R 1c , -OS(O)R 1a , -OS(O)2R 1a , -OS(O)NR 1b R 1c , -OS(O)2NR 1b R 1c , -NR 1b R 1c , -NR 1a C(O)R 1d , -NR 1a C(O)OR 1d , -NR 1a C(O)NR 1bR 1c , -NR 1a C(O)SR 1d , -NR 1a C(NR 1d )NR 1b R 1c , -NR 1a C(S)R 1d , -NR 1a C(S)OR 1d , -NR 1a C(S)NR 1b R 1c , -NR 1a S(O)R 1d , -NR 1a S(O)2R 1d , -NR 1a S(O)NR 1b R 1c , -NR 1a S(O)NR 1b R 1c , -SR 1a , -S(O)R 1a , -S(O)2R 1a , -S(O)NR 1b R 1c , or -S(O)NR 1b R 1c and; R 3b and R 3c are each independently, C 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 aralkyl, heteroaryl, or heterocyclyl; Each R 4a are independently (i) deuterium, cyano, halo, or nitro; (ii) C 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) —C(O)R1a 、-C(O)OR 1a 、-C(O)NR 1b R 1c 、-C(O)SR 1a 、-C(NR 1a )NR 1b R 1c 、-C(S)R 1a 、-C(S)OR 1a 、-C(S)NR 1b R 1c 、-OR 1a 、-OC(O)R 1a 、-OC(O)OR 1a 、-OC(O)NR 1b R 1c 、-OC(O)SR 1a 、-OC(NR 1a )NR 1b R 1c 、-OC(S)R 1a 、-OC(S)OR 1a 、-OC(S)NR 1b R 1c 、-OS(O)R 1a 、-OS(O)2R 1a 、-OS(O)NR 1b R 1c 、-OS(O)2NR 1b R 1c 、-NR 1b R 1c 、-NR 1a C(O)R 1d 、-NR 1a C(O)OR 1d 、-NR 1a C(O)NR 1b R 1c 、-NR 1a C(O)SR 1d 、-NR 1a C(NR 1d )NR 1b R 1c 、-NR 1a C(S)R 1d 、-NR 1a C(S)OR 1d 、-NR 1a C(S)NR 1b R 1c 、-NR 1a S(O)R 1d 、-NR 1aS(O)2R 1d , -NR 1a S(O)NR 1b R 1c , -NR 1a S(O)NR 1b R 1c , -SR 1a , -S(O)R 1a , -S(O)2R 1a , -S(O)NR 1b R 1c , or -S(O)NR 1b R 1c and; Each R 1a , R 1b , R 1c , and R 1d are independently hydrogen, deuterium, and C 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 aralkyl, heteroaryl, or heterocyclyl; and a is an integer of 0, 1, 2, 3, or 4; wherein each alkyl, alkylene, heteroalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylene, aryl, aralkyl, heteroaryl, and heterocyclyl is optionally substituted with one or more, and in one embodiment one, two, three, or four, substituents Q, wherein each Q is independently: (a) deuterium, cyano, halo, imino, nitro, and oxo; (b) each is one or more, and in one embodiment one, two, three, or four, substituents Q. a optionally further substituted with C 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 aralkyl, heteroaryl, and heterocyclyl; and (c) —C(O)R a , -C(O)OR a、-C(O)NR b R c 、-C(O)SR a 、-C(NR a )NR b R c 、-C(S)R a 、-C(S)OR a 、-C(S)NR b R c 、-OR a 、-OC(O)R a 、-OC(O)OR a 、-OC(O)NR b R c 、-OC(O)SR a 、-OC(NR a )NR b R c 、-OC(S)R a 、-OC(S)OR a 、-OC(S)NR b R c 、-OP(O)(OR a )OR d 、-OS(O)R a 、-OS(O)2R a 、-OS(O)NR b R c 、-OS(O)2NR b R c 、-NR b R c 、-NR a C(O)R d 、-NR a C(O)OR d 、-NR a C(O)NR b R c 、-NR a C(O)SR d 、-NR a C(NR d )NR b R c 、-NR a C(S)R d 、-NR a C(S)OR d 、-NR a C(S)NR b R c 、-NR a S(O)R d 、-NRa S(O)2R d , -NR a S(O)NR b R c , -NR a S(O)NR b R c , -SR a , -S(O)R a , -S(O)2R a , -S(O)NR b R c , and -S(O)NR b R c where each R a , R b , R c , and R d are independently (i) hydrogen or deuterium; (ii) each one or more, in one embodiment one, two, three, or four, substituents Q a optionally substituted with, C 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) R b and R c together with the N atom to which they are attached, one or more, in one embodiment one, two, three or four, substituents Q a forming an optionally substituted heterocyclyl; Here, each Q a are independently: (a) deuterium, cyano, halo, nitro, imino, and oxo; (b) C 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 aralkyl, heteroaryl, and heterocyclyl; and (c) —C(O)R e , -C(O)OR e , -C(O)NRf R g 、-C(O)SR e 、-C(NR e )NR f R g 、-C(S)R e 、-C(S)OR e 、-C(S)NR f R g 、-OR e 、-OC(O)R e 、-OC(O)OR e 、-OC(O)NR f R g 、-OC(O)SR e 、-OC(NR e )NR f R g 、-OC(S)R e 、-OC(S)OR e 、-OC(S)NR f R g 、-OP(O)(OR f )OR g 、-OS(O)R e 、-OS(O)2R e 、-OS(O)NR f R g 、-OS(O)2NR f R g 、-NR f R g 、-NR e C(O)R h 、-NR e C(O)OR f 、-NR e C(O)NR f R g 、-NR e C(O)SR f 、-NR e C(NR h )NR f R g 、-NR e C(S)R h 、-NR e C(S)OR f 、-NR e C(S)NR f R g 、-NR e S(O)R h 、-NR eS(O)2R h , -NR e S(O)NR f R g , -NR e S(O)NR f R g , -SR e , -S(O)R e , -S(O)2R e , -S(O)NR f R g , and -S(O)NR f R g where each R e , R f , R g , and R h are independently (i) hydrogen or deuterium; (ii) C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) R f and R g together with the N atom to which they are attached form a heterocyclyl) or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0008] Also provided herein is a compound of formula (IA): [ka] (In the formula, L is a linker; R E is the E3 ubiquitin ligase binding moiety; Each R 5a are independently (i) deuterium, cyano, halo, or nitro; (ii) C 1-6 Alkyl, C 1-6Heteroalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) —C(O)R 1a , -C(O)OR 1a , -C(O)NR 1b R 1c , -C(O)SR 1a , -C(NR 1a )NR 1b R 1c , -C(S)R 1a , -C(S)OR 1a , -C(S)NR 1b R 1c , -OR 1a , -OC(O)R 1a , -OC(O)OR 1a , -OC(O)NR 1b R 1c , -OC(O)SR 1a , -OC(NR 1a )NR 1b R 1c , -OC(S)R 1a , -OC(S)OR 1a , -OC(S)NR 1b R 1c , -OS(O)R 1a , -OS(O)2R 1a , -OS(O)NR 1b R 1c , -OS(O)2NR 1b R 1c , -NR 1b R 1c , -NR 1a C(O)R 1d , -NR 1a C(O)OR 1d , -NR 1a C(O)NR 1b R 1c , -NR 1a C(O)SR 1d , -NR 1a C(NR 1d )NR 1b R 1c , -NR 1a C(S)R1d , -NR 1a C(S)OR 1d , -NR 1a C(S)NR 1b R 1c , -NR 1a S(O)R 1d , -NR 1a S(O)2R 1d , -NR 1a S(O)NR 1b R 1c , -NR 1a S(O)NR 1b R 1c , -SR 1a , -S(O)R 1a , -S(O)2R 1a , -S(O)NR 1b R 1c , or -S(O)NR 1b R 1c and; R 6 is hydrogen, C 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 aralkyl, heteroaryl, or heterocyclyl; R 7a , R 7b , R 7c , and R 7d are each independently (i) hydrogen, deuterium, cyano, halo, or nitro; (ii) C 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) —C(O)R 1a , -C(O)OR 1a , -C(O)NR 1b R 1c , -C(O)SR 1a , -C(NR 1a )NR1b R 1c 、-C(S)R 1a 、-C(S)OR 1a 、-C(S)NR 1b R 1c 、-OR 1a 、-OC(O)R 1a 、-OC(O)OR 1a 、-OC(O)NR 1b R 1c 、-OC(O)SR 1a 、-OC(NR 1a )NR 1b R 1c 、-OC(S)R 1a 、-OC(S)OR 1a 、-OC(S)NR 1b R 1c 、-OS(O)R 1a 、-OS(O)2R 1a 、-OS(O)NR 1b R 1c 、-OS(O)2NR 1b R 1c 、-NR 1b R 1c 、-NR 1a C(O)R 1d 、-NR 1a C(O)OR 1d 、-NR 1a C(O)NR 1b R 1c 、-NR 1a C(O)SR 1d 、-NR 1a C(NR 1d )NR 1b R 1c 、-NR 1a C(S)R 1d 、-NR 1a C(S)OR 1d 、-NR 1a C(S)NR 1b R 1c 、-NR 1a S(O)R 1d 、-NR 1a S(O)2R 1d 、-NR 1a S(O)NR 1b R 1c 、-NR 1a S(O)2NR 1b R1c , -SR 1a , -S(O)R 1a , -S(O)2R 1a , -S(O)NR 1b R 1c , or -S(O)NR 1b R 1c and; Each R 1a , R 1b , R 1c , and R 1d are independently hydrogen, deuterium, and C 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 aralkyl, heteroaryl, or heterocyclyl; and b is an integer of 0, 1, 2, 3, or 4; wherein each alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heteroaryl, and heterocyclyl is optionally substituted with one or more, and in one embodiment one, two, three, or four, substituents Q, wherein each Q is independently: (a) deuterium, cyano, halo, imino, nitro, and oxo; (b) each is one or more, and in one embodiment one, two, three, or four, substituents Q. a optionally further substituted with C 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 aralkyl, heteroaryl, and heterocyclyl; and (c) —C(O)R a , -C(O)OR a , -C(O)NR b R c , -C(O)SR a , -C(NR a )NR b R c , -C(S)R a、-C(S)OR a 、-C(S)NR b R c 、-OR a 、-OC(O)R a 、-OC(O)OR a 、-OC(O)NR b R c 、-OC(O)SR a 、-OC(NR a )NR b R c 、-OC(S)R a 、-OC(S)OR a 、-OC(S)NR b R c 、-OP(O)(OR a )OR d 、-OS(O)R a 、-OS(O)2R a 、-OS(O)NR b R c 、-OS(O)2NR b R c 、-NR b R c 、-NR a C(O)R d 、-NR a C(O)OR d 、-NR a C(O)NR b R c 、-NR a C(O)SR d 、-NR a C(NR d )NR b R c 、-NR a C(S)R d 、-NR a C(S)OR d 、-NR a C(S)NR b R c 、-NR a S(O)R d 、-NR a S(O)2R d 、-NR a S(O)NR b R c 、-NR a S(O)2NR b R c, -SR a , -S(O)R a , -S(O)2R a , -S(O)NR b R c , and -S(O)NR b R c where each R a , R b , R c , and R d are independently (i) hydrogen or deuterium; (ii) each one or more, in one embodiment one, two, three, or four, substituents Q a optionally substituted with, C 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) R b and R c together with the N atom to which they are attached, one or more, in one embodiment one, two, three or four, substituents Q a forming an optionally substituted heterocyclyl; Here, each Q a are independently: (a) deuterium, cyano, halo, nitro, imino, and oxo; (b) C 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 aralkyl, heteroaryl, and heterocyclyl; and (c) —C(O)R e , -C(O)OR e , -C(O)NR f R g , -C(O)SR e , -C(NR e )NR f R g , -C(S)R e , -C(S)OR e、-C(S)NR f R g 、-OR e 、-OC(O)R e 、-OC(O)OR e 、-OC(O)NR f R g 、-OC(O)SR e 、-OC(NR e )NR f R g 、-OC(S)R e 、-OC(S)OR e 、-OC(S)NR f R g 、-OP(O)(OR f )OR g 、-OS(O)R e 、-OS(O)2R e 、-OS(O)NR f R g 、-OS(O)2NR f R g 、-NR f R g 、-NR e C(O)R h 、-NR e C(O)OR f 、-NR e C(O)NR f R g 、-NR e C(O)SR f 、-NR e C(NR h )NR f R g 、-NR e C(S)R h 、-NR e C(S)OR f 、-NR e C(S)NR f R g 、-NR e S(O)R h 、-NR e S(O)2R h 、-NR e S(O)NR f R g 、-NR e S(O)2NR f R g 、-SR e, -S(O)R e , -S(O)2R e , -S(O)NR f R g , and -S(O)NR f R g where each R e , R f , R g , and R h are independently (i) hydrogen or deuterium; (ii) C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) R f and R g together with the N atom to which they are attached form a heterocyclyl) or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0009] Further provided herein is a pharmaceutical composition comprising a compound of Formula (I) or Formula (IA), or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; and a pharmaceutically acceptable excipient.

[0010] Further provided herein is a method for treating, preventing, or ameliorating one or more symptoms of a disorder, disease, or condition mediated by phosphodiesterase 4 (PDE4) in a subject, comprising administering to the subject in need thereof a therapeutically effective amount of a compound of Formula (I) or Formula (IA), or an enantiomer, mixture of enantiomers, diastereomer, mixture of two or more diastereomers, tautomer, mixture of two or more tautomers, or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0011] Provided herein are methods for treating, preventing, or ameliorating one or more symptoms of an inflammatory disease in a subject, comprising administering to the subject in need thereof a therapeutically effective amount of a compound of Formula (I) or Formula (IA), or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0012] Provided herein is a method for inhibiting the activity of PDE4, comprising contacting the PDE4 with an effective amount of a compound of Formula (I) or Formula (IA), or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0013] Provided herein is a method for inducing the degradation of PDE4, comprising contacting the PDE4 with an effective amount of a compound of Formula (I) or Formula (IA), or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof. DETAILED DESCRIPTION OF THE INVENTION

[0014] (Detailed explanation) To facilitate understanding of the disclosure set forth herein, several terms are defined below.

[0015] Generally, the nomenclature used herein and the laboratory procedures in organic chemistry, medicinal chemistry, biochemistry, biology, and pharmacology described herein are those well known and commonly employed in the art. Unless defined otherwise, all technical and scientific terms used herein generally have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs.

[0016] The term "subject" refers to an animal, including, but not limited to, a primate (e.g., a human), cow, pig, sheep, goat, horse, dog, cat, rabbit, rat, or mouse. The terms "subject" and "patient" are used interchangeably herein to refer to a mammalian subject, such as a human subject. In one embodiment, the subject is a human.

[0017] The terms "treat," "treating," and "treatment" are intended to include alleviating or arresting a disorder, disease, or condition, or one or more symptoms associated with a disorder, disease, or condition; or alleviating or eradicating the cause of the disorder, disease, or condition itself.

[0018] The terms "prevent," "preventing," and "prevention" are intended to include methods of delaying and / or preventing the onset of a disorder, disease, or condition, and / or its attendant symptoms; methods of barring a subject from acquiring a disorder, disease, or condition; or methods of reducing a subject's risk of acquiring a disorder, disease, or condition.

[0019] The terms "alleviate" and "alleviating" mean to relieve or reduce one or more symptoms (e.g., pain) of a disorder, disease, or condition. The terms can also mean to reduce adverse effects associated with an active ingredient. Sometimes, the beneficial effects a subject derives from a prophylactic or therapeutic agent do not result in a cure of the disorder, disease, or condition.

[0020] The terms "contacting" or "contacting" refer to bringing together a therapeutic agent and a biological molecule (e.g., a protein, enzyme, RNA, or DNA), cell, or tissue such that a physiological and / or chemical effect occurs as a result of such contact. Contacting can occur in vitro, ex vivo, or in vivo. In one embodiment, a therapeutic agent is contacted with a biological molecule in vitro to determine the effect of the therapeutic agent on the biological molecule. In another embodiment, a therapeutic agent is contacted with cells in cell culture (in vitro) to determine the effect of the therapeutic agent on the cells. In yet another embodiment, contacting a therapeutic agent with a biological molecule, cell, or tissue comprises administering the therapeutic agent to a subject having the biological molecule, cell, or tissue to be contacted.

[0021] The term "therapeutically effective amount" or "effective amount" is intended to include the amount of a compound that, when administered, is sufficient to prevent the onset of, or alleviate to some extent, one or more symptoms of the disorder, disease, or condition being treated. The term "therapeutically effective amount" or "effective amount" also refers to the amount of a compound that is sufficient to elicit the biological or medical response in a biological molecule (e.g., protein, enzyme, RNA, or DNA), cell, tissue, system, animal, or human that is being sought by a researcher, veterinarian, medical doctor, or clinician.

[0022] The term “IC 50 " or "EC 50 " means the amount, concentration, or dosage of a compound required for 50% inhibition of a maximal response in an assay that measures such response.

[0023] The terms "pharmaceutically acceptable carrier," "pharmaceutically acceptable excipient," "physiologically acceptable carrier," or "physiologically acceptable excipient" refer to a pharmaceutically acceptable substance, composition, or vehicle, such as a liquid or solid filler, diluent, solvent, or encapsulating material. In one embodiment, each component is "pharmaceutically acceptable" in the sense of being compatible with the other components of the pharmaceutical formulation and suitable for use in contact with the tissues or organs of a subject (e.g., a human or animal) without excessive toxicity, irritation, allergic response, immunogenicity, or other problem or complication, and commensurate with a reasonable benefit / risk ratio. See, e.g., Remington: The Science and Practice of Pharmacy, 22nd ed.; Allen, ed.: Pharmaceutical Press: London, 2012; Handbook of Pharmaceutical Excipients, 8th ed.; Sheskey et al., eds.; Pharmaceutical Press: London, 2017; Handbook of Pharmaceutical Additives, 3rd ed.; Ash and Ash, eds.; Synapse Information Resources: 2007; Pharmaceutical Preformulation and Formulation, 2nd ed.; Gibson, ed.; Drugs and the Pharmaceutical Sciences 199; Informa Healthcare: New York, NY, 2009.

[0024] The term "about" or "approximately" refers to a tolerance for error associated with a particular value as determined by one of ordinary skill in the art, which will depend in part on how the value is measured or determined. In some embodiments, the term "about" or "approximately" means within 1, 2, or 3 standard deviations. In some embodiments, the term "about" or "approximately" means within 25%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, or 0.05% of a given value or range.

[0025] The term "alkyl" refers to a straight or branched chain saturated monovalent hydrocarbon radical, where alkyl is optionally substituted with one or more substituents Q as described herein. For example, C 1-6 Alkyl refers to a straight-chain saturated monovalent hydrocarbon radical of 1 to 6 carbon atoms or a branched-chain saturated monovalent hydrocarbon radical of 3 to 6 carbon atoms. In some embodiments, alkyl refers to a group having 1 to 20 carbon atoms (C 1-20 ), 1~15 pieces (C 1-15 ), 1~10 pieces (C 1-10 ), or 1 to 6 (C 1-6 ) or a linear saturated monovalent hydrocarbon radical having 3 to 20 carbon atoms (C 3-20 ), 3~15 pieces (C 3-15 ), 3~10 pieces (C 3-10 ), or 3 to 6 (C 3-6 ) is a branched, saturated, monovalent hydrocarbon radical. 1-6 and branched chain C 3-6 An alkyl group is also referred to as a “lower alkyl.” Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl (including all isomeric forms, e.g., n-propyl and isopropyl), butyl (including all isomeric forms, e.g., n-butyl, isobutyl, sec-butyl, and t-butyl), pentyl (including all isomeric forms, e.g., n-pentyl, isopentyl, sec-pentyl, neopentyl, and tert-pentyl), and hexyl (including all isomeric forms, e.g., n-hexyl, isohexyl, and sec-hexyl).

[0026] The term "heteroalkyl" refers to a straight or branched chain saturated monovalent hydrocarbon radical containing in its backbone one or more heteroatoms independently selected from O, S, and N. Heteroalkyl is optionally substituted with one or more substituents Q as described herein. For example, C 1-6 Heteroalkyl means a linear saturated monovalent hydrocarbon radical of 1 to 6 carbon atoms or a branched saturated monovalent hydrocarbon radical of 3 to 6 carbon atoms. In certain embodiments, heteroalkyl is a heterocyclic group having 1 to 20 carbon atoms (C 1-20 ), 1~15 pieces (C 1-15 ), 1~10 pieces (C 1-10 ), or 1 to 6 (C 1-6 ) or a linear saturated monovalent hydrocarbon radical having 3 to 20 carbon atoms (C 3-20 ), 3~15 pieces (C 3-15 ), 3~10 pieces (C 3-10 ), or 3 to 6 (C 3-6 ) is a branched, saturated, monovalent hydrocarbon radical. As used herein, linear C 1-6 and branched chain C 3-6 Heteroalkyl groups are also referred to as "lower heteroalkyl." Examples of heteroalkyl groups include, but are not limited to, -OCH, -OCHCH, -CHOCH, -NHCH, -ONHCH, -NHOCH, -SCH, -CHNHCHCH, and -NHCHCHCH. Examples of substituted heteroalkyl groups include, but are not limited to, -CHNHC(O)CH and -NHC(O)CHCH.

[0027] The terms "alkylene" and "alkanediyl" are used interchangeably herein, where alkanediyl refers to a straight or branched chain saturated divalent hydrocarbon radical, optionally substituted with one or more substituents Q as described herein. For example, C 1-6Alkanediyl refers to a linear saturated divalent hydrocarbon radical of 1 to 6 carbon atoms or a branched saturated divalent hydrocarbon radical of 3 to 6 carbon atoms. In certain embodiments, alkanediyl refers to a hydrocarbon radical having 1 to 30 carbon atoms (C 1-30 ), 1~20 pieces (C 1-20 ), 1~15 pieces (C 1-15 ), 1~10 pieces (C 1-10 ), or 1 to 6 (C 1-6 ) or a linear saturated divalent hydrocarbon radical having 3 to 30 carbon atoms (C 3-30 ), 3~20 pieces (C 3-20 ), 3~15 pieces (C 3-15 ), 3~10 pieces (C 3-10 ), or 3 to 6 (C 3-6 ) is a branched, saturated, divalent hydrocarbon radical. As used herein, linear C 1-6 and branched chain C 3-6 Alkanediyl groups are also referred to as “lower alkanediyl.” Examples of alkanediyl groups include methanediyl, ethanediyl (including all isomeric forms, for example, ethane-1,1-diyl and ethane-1,2-diyl), propanediyl (including all isomeric forms, for example, propane-1,1-diyl, propane-1,2-diyl, and propane-1,3-diyl), butanediyl (including all isomeric forms, for example, butane-1,1-diyl, butane-1,2-diyl, butane-1,3-diyl, and butane-1,4-diyl), pentanediyl (including all isomeric forms, for example, pentane-1,1-diyl, pentane-1,2-diyl, pentane-1,3-diyl, and pentane-1,5-diyl), and hexanediyl (including all isomeric forms, for example, hexane-1,1-diyl, hexane-1,2-diyl, hexane-1,3-diyl, and hexane-1,6-diyl). Examples of substituted alkanediyl groups include -C(O)CH2-, -C(O)(CH2)2-, -C(O)(CH2)3-, -C(O)(CH2)4-, -C(O)(CH2)5-, -C(O)(CH2)6-, -C(O)(CH2)7-, -C(O)(CH2)8-, -C(O)(CH2)9-, and -C(O)(CH2) 10Examples include, but are not limited to, -, -C(O)CHC(O)-, -C(O)-(CH)C(O)-, -C(O)(CH)C(O)-, -C(O)(CH)C(O)-, or -C(O)(CH)C(O)-.

[0028] The terms "heteroalkylene" and "heteroalkanediyl" are used interchangeably herein to refer to a straight or branched chain saturated divalent hydrocarbon radical containing in its backbone one or more heteroatoms independently selected from O, S, and N. The heteroalkylene is optionally substituted with one or more substituents Q as described herein. For example, C 1-6 Heteroalkylene refers to a linear saturated divalent hydrocarbon radical of 1 to 6 carbon atoms or a branched saturated divalent hydrocarbon radical of 3 to 6 carbon atoms. In certain embodiments, heteroalkylene refers to a hydrocarbon radical having 1 to 20 carbon atoms (C 1-20 ), 1~15 pieces (C 1-15 ), 1~10 pieces (C 1-10 ), or 1 to 6 (C 1-6 ) or a linear saturated divalent hydrocarbon radical having 3 to 20 carbon atoms (C 3-20 ), 3~15 pieces (C 3-15 ), 3~10 pieces (C 3-10 ), or 3 to 6 (C 3-6 ) is a branched, saturated, divalent hydrocarbon radical. As used herein, linear C 1-6 and branched chain C 3-6 Heteroalkylene groups are also referred to as "lower heteroalkylene." Examples of heteroalkylene groups include -CHO-, -(CH)O-, -(CH)O-, -(CH)O-, -(CH)O-, -(CH)O-, -(CH)O-, -(CH)O-, -(CH)O-, -(CH)O-, -(CH) 10These include, but are not limited to, O-, -CH2OCH2-, -CH2CH2O-, -(CH2CH2O)2-, -(CH2-CH2O)3-, -(CH2CH2O)4-, -(CH2CH2O)5-, -CH2NH-, -CH2NHCH2-, -CH2CH2NH-, -CH2S-, -CH2SCH2-, and -CH2CH2S-. Examples of substituted heteroalkylene groups include -C(O)CHO-, -C(O)(CH)O-, -C(O)(CH)O-, -C(O)(CH)O-, -C(O)(CH)O-, -C(O)(CH)O-, -C(O)(CH)O-, -C(O)(CH)O-, -C(O)(CH)O-, -C(O)(CH)O-, -C(O)(CH) 10 Examples include, but are not limited to, O-, -C(O)CHOCHCHO-, -C(O)CHO(CHCHO)-, -C(O)CHO(CHCHO)-, -C(O)CHO(CHCHO)-, -C(O)CHO-(CHCHO)-, -C(O)CHO(CHCHO)-, -CHNHC(O)CH-, or -CHCHC(O)NH-.

[0029] The term "alkenyl" refers to a straight- or branched-chain monovalent hydrocarbon radical containing one or more, in one embodiment 1, 2, 3, or 4, and in another embodiment 1, carbon-carbon double bonds. The alkenyl is optionally substituted with one or more substituents Q as described herein. The term "alkenyl" embraces radicals having the "cis" or "trans" configuration, or a mixture thereof, or the "Z" or "E" configuration, or a mixture thereof, as will be apparent to one of ordinary skill in the art. For example, C 2-6 Alkenyl refers to a linear unsaturated monovalent hydrocarbon radical of 2 to 6 carbon atoms or a branched unsaturated monovalent hydrocarbon radical of 3 to 6 carbon atoms. In some embodiments, alkenyl refers to a hydrocarbon radical of 2 to 20 carbon atoms (C 2-20 ), 2~15 pieces (C 2-15 ), 2~10 pieces (C 2-10 ), or 2 to 6 (C 2-6 ) or a linear monovalent hydrocarbon radical of 3 to 20 carbon atoms (C 3-20 ), 3~15 pieces (C3-15 ), 3~10 pieces (C 3-10 ), or 3 to 6 (C 3-6 ) is a branched-chain monovalent hydrocarbon radical. Examples of alkenyl groups include, but are not limited to, ethenyl, propenyl (including all isomeric forms, e.g., propen-1-yl, propen-2-yl, and allyl), and butenyl (including all isomeric forms, e.g., buten-1-yl, buten-2-yl, buten-3-yl, and 2-buten-1-yl).

[0030] The terms "alkenylene" and "alkenediyl" are used interchangeably herein to refer to a straight- or branched-chain divalent hydrocarbon radical containing one or more, in one embodiment one, two, three, or four, and in another embodiment one, carbon-carbon double bonds. The alkenediyl is optionally substituted with one or more substituents Q as described herein. The term "alkenediyl" encompasses radicals having a "cis" or "trans" configuration, or a mixture thereof, or a "Z" or "E" configuration, or a mixture thereof, as recognized by those skilled in the art. For example, C 2-6 Alkenediyl refers to a linear unsaturated divalent hydrocarbon radical of 2 to 6 carbon atoms or a branched unsaturated divalent hydrocarbon radical of 3 to 6 carbon atoms. In certain embodiments, alkenediyl refers to a hydrocarbon radical of 2 to 30 carbon atoms (C 2-30 ), 2~20 pieces (C 2-20 ), 2~15 pieces (C 2-15 ), 2~10 pieces (C 2-10 ), or 2 to 6 (C 2-6 ) or a linear divalent hydrocarbon radical having 3 to 30 carbon atoms (C 3-30 ), 3~20 pieces (C 3-20 ), 3~15 pieces (C 3-15 ), 3~10 pieces (C 3-10 ), or 3 to 6 (C 3-6Examples of alkenediyl groups include ethenediyl (including all isomeric forms, for example, ethene-1,1-diyl and ethene-1,2-diyl), propenediyl (including all isomeric forms, for example, 1-propene-1,1-diyl, 1-propene-1,2-diyl, and 1-propene-1,3-diyl), butenediyl (including all isomeric forms, for example, 1-butene-1,1-diyl, 1-butene-1,2-diyl, and 1-butene-1,4-diyl), pentaerythritol, benzophenone, benzophenone, benzophenone-1,1-diyl, benzophenone-1,2-diyl, and benzophenone-1,4-diyl). Examples include, but are not limited to, enediyl (including all isomeric forms, for example, 1-pentene-1,1-diyl, 1-pentene-1,2-diyl, and 1-pentene-1,5-diyl), and hexenediyl (including all isomeric forms, for example, 1-hexene-1,1-diyl, 1-hexene-1,2-diyl, 1-hexene-1,3-diyl, 1-hexene-1,4-diyl, 1-hexene-1,5-diyl, and 1-hexene-1,6-diyl).

[0031] The terms "heteroalkenylene" and "heteroalkenediyl" are used interchangeably herein to refer to a straight-chain or branched-chain divalent hydrocarbon radical containing one or more, in one embodiment one, two, three, or four, and in another embodiment one, carbon-carbon double bonds and containing one or more heteroatoms independently selected from O, S, and N within the hydrocarbon chain. The heteroalkenylene is optionally substituted with one or more substituents Q as described herein. The term "heteroalkenylene" encompasses radicals having a "cis" or "trans" configuration or a mixture thereof, or a "Z" or "E" configuration or a mixture thereof, as recognized by those of skill in the art. For example, C 2-6 Heteroalkenylene means a linear unsaturated divalent hydrocarbon radical of 2 to 6 carbon atoms or a branched unsaturated divalent hydrocarbon radical of 3 to 6 carbon atoms. In certain embodiments, heteroalkenylene is a heteroalkenylene having 2 to 20 carbon atoms (C 2-20 ), 2~15 pieces (C 2-15 ), 2~10 pieces (C 2-10 ), or 2 to 6 (C2-6 ) or a straight-chain divalent hydrocarbon radical having 3 to 20 carbon atoms (C 3-20 ), 3~15 pieces (C 3-15 ), 3~10 pieces (C 3-10 ), or 3 to 6 (C 3-6 Examples of heteroalkenylene groups include, but are not limited to, -CH=CHO-, -CH=CHOCH2-, -CH=CHCHO-, -CH=CHS-, -CH=CHSCH2-, -CH=CHCH2S-, or -CH=CHCH2NH-.

[0032] The term "alkynyl" refers to a straight or branched chain monovalent hydrocarbon radical containing one or more, in one embodiment 1, 2, 3, or 4, and in another embodiment 1, carbon-carbon triple bonds. Alkynyl is optionally substituted with one or more substituents Q as described herein. For example, C 2-6 Alkynyl refers to a linear unsaturated monovalent hydrocarbon radical of 2 to 6 carbon atoms or a branched unsaturated monovalent hydrocarbon radical of 4 to 6 carbon atoms. In some embodiments, alkynyl refers to a hydrocarbon radical of 2 to 20 carbon atoms (C 2-20 ), 2~15 pieces (C 2-15 ), 2~10 pieces (C 2-10 ), or 2 to 6 (C 2-6 ) or a linear monovalent hydrocarbon radical of 4 to 20 carbon atoms (C 4-20 ), 4~15 pieces (C 4-15 ), 4~10 pieces (C 4-10 ), or 4 to 6 (C 4-6) is a branched-chain monovalent hydrocarbon radical. Examples of alkynyl groups include, but are not limited to, ethynyl (-C≡CH), propynyl (including all isomeric forms, e.g., 1-propynyl (-C≡CCH) and propargyl (-CHC≡CH)), butynyl (including all isomeric forms, e.g., 1-butyn-1-yl and 2-butyn-1-yl), pentynyl (including all isomeric forms, e.g., 1-pentyn-1-yl and 1-methyl-2-butyn-1-yl), and hexynyl (including all isomeric forms, e.g., 1-hexyn-1-yl and 2-hexyn-1-yl).

[0033] The terms "alkynylene" and "alkynediyl" are used interchangeably herein to refer to a straight or branched chain divalent hydrocarbon radical containing one or more, in one embodiment one, two, three, or four, and in another embodiment one, carbon-carbon triple bonds. An alkynediyl is optionally substituted with one or more substituents Q as described herein. For example, C 2-6 Alkynediyl refers to a linear unsaturated divalent hydrocarbon radical of 2 to 6 carbon atoms or a branched unsaturated divalent hydrocarbon radical of 4 to 6 carbon atoms. In certain embodiments, alkynediyl refers to a hydrocarbon radical of 2 to 30 carbon atoms (C 2-30 ), 2~20 pieces (C 2-20 ), 2~15 pieces (C 2-15 ), 2~10 pieces (C 2-10 ), or 2 to 6 (C 2-6 ) or a linear divalent hydrocarbon radical having 4 to 30 carbon atoms (C 4-30 ), 4~20 pieces (C 4-20 ), 4~15 pieces (C 4-15 ), 4~10 pieces (C 4-10 ), or 4 to 6 (C 4-6) is a branched-chain divalent hydrocarbon radical. Examples of alkynediyl groups include, but are not limited to, ethynediyl, propynediyl (including all isomeric forms, for example, 1-propyne-1,3-diyl and 1-propyne-3,3-diyl), butynediyl (including all isomeric forms, for example, 1-butyne-1,3-diyl, 1-butyne-1,4-diyl, and 2-butyne-1,1-diyl), pentynediyl (including all isomeric forms, for example, 1-pentyne-1,3-diyl, 1-pentyne-1,4-diyl, and 2-pentyne-1,1-diyl), and hexynediyl (including all isomeric forms, for example, 1-hexyne-1,3-diyl, 1-hexyne-1,4-diyl, and 2-hexyne-1,1-diyl).

[0034] The terms "heteroalkynylene" and "heteroalkynediyl" are used interchangeably herein to refer to a straight or branched chain divalent hydrocarbon radical containing one or more, in one embodiment one, two, three, or four, and in another embodiment one, carbon-carbon triple bonds and containing in its backbone one or more heteroatoms independently selected from O, S, and N. Heteroalkynylene is optionally substituted with one or more substituents Q as described herein. For example, C 2-6 Heteroalkynylene refers to a linear unsaturated divalent hydrocarbon radical of 2 to 6 carbon atoms or a branched unsaturated divalent hydrocarbon radical of 4 to 6 carbon atoms. In certain embodiments, heteroalkynylene refers to a hydrocarbon radical of 2 to 30 carbon atoms (C 2-30 ), 2~20 pieces (C 2-20 ), 2~15 pieces (C 2-15 ), 2~10 pieces (C 2-10 ), or 2 to 6 (C 2-6 ) or a linear divalent hydrocarbon radical having 4 to 30 carbon atoms (C 4-30 ), 4~20 pieces (C 4-20 ), 4~15 pieces (C 4-15 ), 4~10 pieces (C 4-10 ), or 4 to 6 (C 4-6Examples of heteroalkynylene groups include, but are not limited to, -C≡CCH2O-, -C≡CCH2S-, or -C≡CCH2NH-.

[0035] The term "cycloalkyl" refers to a cyclic monovalent hydrocarbon radical, optionally substituted with one or more substituents Q as described herein. In one embodiment, a cycloalkyl is a saturated or unsaturated but non-aromatic, and / or bridged or unbridged, and / or fused bicyclic group. In some embodiments, a cycloalkyl is a cyclic group having 3 to 20 carbon atoms (C 3-20 ), 3~15 pieces (C 3-15 ), 3~10 pieces (C 3-10 ), or 3 to 7 (C 3-7 ) In one embodiment, the cycloalkyl is monocyclic. In another embodiment, the cycloalkyl is bicyclic. In yet another embodiment, the cycloalkyl is tricyclic. In yet another embodiment, the cycloalkyl is polycyclic. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptenyl, bicyclo[1.1.1]pentyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, decalinyl, and adamantyl.

[0036] The terms "cycloalkylene" and "cycloalkanediyl" are used interchangeably herein to refer to a cyclic divalent hydrocarbon radical, optionally substituted with one or more substituents Q as described herein. In one embodiment, a cycloalkanediyl group can be a saturated or unsaturated but non-aromatic, and / or bridged and / or unbridged, and / or fused bicyclic group. In certain embodiments, a cycloalkanediyl is a cycloalkanediyl having from 3 to 30 carbon atoms (C 3-30 ), 3~20 pieces (C 3-20 ), 3~15 pieces (C 3-15 ), 3~10 pieces (C3-10 ), or 3 to 7 (C 3-7 Examples of cycloalkanediyl groups include cyclopropanediyl (including all isomeric forms, for example, cyclopropane-1,1-diyl and cyclopropane-1,2-diyl), cyclobutanediyl (including all isomeric forms, for example, cyclobutane-1,1-diyl, cyclobutane-1,2-diyl, and cyclobutane-1,3-diyl), cyclopentanediyl (including all isomeric forms, for example, cyclopentane-1,1-diyl, cyclopentane-1,2-diyl, and cyclopentane-1,3-diyl), cyclohexanediyl (including all isomeric forms, for example, cyclohexane-1,1-diyl, cyclohexane-1,2-diyl), , cyclohexane-1,3-diyl, and cyclohexa-1,4-diyl), cycloheptanediyl (including all isomeric forms, for example, cycloheptane-1,1-diyl, cycloheptane-1,2-diyl, cycloheptane-1,3-diyl, and cycloheptane-1,4-diyl), decalindiyl (including all isomeric forms, for example, decalin-1,1-diyl, decalin-1,2-diyl, and decalin-1,8-diyl), and adamantodiyl (including all isomeric forms, for example, adamant-1,2-diyl, adamant-1,3-diyl, and adamant-1,8-diyl).

[0037] The term "aryl" refers to a monovalent monocyclic aromatic hydrocarbon radical and / or a monovalent polycyclic aromatic hydrocarbon radical containing at least one aromatic carbocyclic ring. In some embodiments, an aryl has 6 to 20 ring carbon atoms (C 6-20 ), 6~15 pieces (C 6-15 ), or 6 to 10 (C 6-10) Examples of aryl groups include, but are not limited to, phenyl, naphthyl, fluorenyl, azulenyl, anthryl, phenanthryl, pyrenyl, biphenyl, and terphenyl. Aryl also refers to a bicyclic or tricyclic carbocycle, where one ring is aromatic and the other ring can be saturated, partially unsaturated, or aromatic, such as dihydro-naphthyl, indenyl, indanyl, or tetrahydronaphthyl (tetralinyl). In one embodiment, an aryl is monocyclic. In another embodiment, an aryl is bicyclic. In yet another embodiment, an aryl is tricyclic. In yet another embodiment, an aryl is polycyclic. In some embodiments, an aryl is optionally substituted with one or more substituents Q as described herein.

[0038] The terms "arylene" and "arenediyl" are used interchangeably herein to refer to a divalent monocyclic aromatic hydrocarbon radical or a divalent polycyclic aromatic hydrocarbon radical containing at least one aromatic hydrocarbon ring. In certain embodiments, an arylene has 6 to 20 ring atoms (C 6-20 ), 6~15 pieces (C 6-15 ), or 6 to 10 (C 6-10Examples of arylene groups include phenylene (including all isomeric forms, for example, phen-1,2-diyl, phen-1,3-diyl, and phen-1,4-diyl), naphthylene (including all isomeric forms, for example, naphth-1,2-diyl, naphth-1,3-diyl, and naphth-1,8-diyl), fluorenylene (including all isomeric forms, for example, fluorene-1,2-diyl, fluorene-1,4-diyl), and the like. azulenylene (including all isomeric forms, for example, azulen-1,2-diyl, azulen-1,3-diyl, and azulen-1,8-diyl), anthrylene (including all isomeric forms, for example, anthr-1,2-diyl, anthra-1,3-diyl, and anthra-1,8-diyl), , phenanthrylene (including all isomeric forms, for example, phenanthra-1,2-diyl, phenanthra-1,3-diyl, and phenanthra-1,8-diyl), pyrenylene (including all isomeric forms, for example, pyrene-1,2-diyl, pyrene-1,3-diyl, and pyrene-1,8-diyl), biphenylene (including all isomeric forms, for example, biphen-2,3-diyl, biphen-3,4'-diyl, and biphen-4,4'-diyl), and terphenylene (including all isomeric forms, for example, terphen-2,3-diyl, terphen-3,4'-diyl, and terphen-4,4'-diyl).Arylene also refers to a bicyclic or tricyclic carbocycle in which one of the rings is aromatic and the other rings can be saturated, partially unsaturated, or aromatic, such as dihydronaphthylene (including all isomeric forms, e.g., dihydronaphth-1,2-diyl and dihydronaphth-1,8-diyl), indenylene (including all isomeric forms, e.g., indene-1,2-diyl, indene-1,5-diyl, and indene-1,7-diyl), indanylene (including all isomeric forms, e.g., indan-1,2-diyl, indan-1,5-diyl, and indan-1,7-diyl), or tetrahydronaphthylene (tetralinylene) (including all isomeric forms, e.g., tetrahydronaphth-1,2-diyl, tetrahydronaphth-1,5-diyl, and tetrahydronaphth-1,8-diyl). In certain embodiments, the arylene is optionally substituted with one or more substituents Q as described herein.

[0039] The terms "aralkyl" or "arylalkyl" refer to a monovalent alkyl group substituted with one or more aryl groups. In some embodiments, an aralkyl is an alkyl group having 7 to 30 carbon atoms (C 7-30 ), 7~20 pieces (C 7-20 ), or 7 to 16 (C 7-16 ) Examples of aralkyl groups include, but are not limited to, benzyl, phenylethyl (including all isomeric forms, e.g., 1-phenylethyl and 2-phenylethyl), and phenylpropyl (including all isomeric forms, e.g., 1-phenylpropyl, 2-phenylpropyl, and 3-phenylpropyl). In some embodiments, the aralkyl is optionally substituted with one or more substituents Q as described herein.

[0040] The terms "aralkylene" or "arylalkylene" refer to a divalent alkyl group substituted with one or more aryl groups. In certain embodiments, the aralkylene is an alkyl group having 7 to 30 carbon atoms (C 7-30 ), 7~20 pieces (C 7-20 ), or 7 to 16 (C 7-16) Examples of aralkylene groups include, but are not limited to, benzylene (including all isomeric forms, e.g., phenyl-methdiyl), phenylethylene (including all isomeric forms, e.g., 2-phenyl-ethane-1,1-diyl and 2-phenyl-ethane-1,2-diyl), and phenylpropylene (including all isomeric forms, e.g., 3-phenyl-propane-1,1-diyl, 3-phenyl-propane-1,2-diyl, and 3-phenyl-propane-1,3-diyl). In certain embodiments, the aralkylene is optionally substituted with one or more substituents Q as described herein.

[0041] The term "heteroaryl" refers to a monovalent monocyclic aromatic group or a monovalent polycyclic aromatic group containing at least one aromatic ring, at least one of which contains one or more heteroatoms independently selected from O, S, and N. The heteroaryl is linked to the rest of the molecule via the aromatic ring. Each ring of the heteroaryl group can contain one or two O atoms, one or two S atoms, and / or one to four N atoms, provided that the total number of heteroatoms in each ring is four or less and each ring contains at least one carbon atom. In some embodiments, the heteroaryl has 5 to 20, 5 to 15, or 5 to 10 ring atoms. In one embodiment, the heteroaryl is monocyclic. Examples of monocyclic heteroaryl groups include, but are not limited to, furanyl, imidazolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl, thiadiazolyl, thiazolyl, thienyl, tetrazolyl, triazinyl, and triazolyl. In another embodiment, the heteroaryl is bicyclic.Examples of bicyclic heteroaryl groups include benzofuranyl, benzimidazolyl, benzisoxazolyl, benzopyranyl, benzothiadiazolyl, benzothiazolyl, benzothienyl, benzotriazolyl, benzoxazolyl, furopyrindyl (including all isomeric forms, e.g., furo[2,3-b]pyridinyl, furo[2,3-c]pyridinyl, furo[3,2-b]pyridinyl, furo[3,2-c]pyridinyl, furo[3,4-b]pyridinyl, and furo[3,4-c]pyridinyl), imidazolyl, pyridinyl (including all isomeric forms, for example, imidazo[1,2-a]pyridinyl, imidazo[4,5-b]pyridinyl, and imidazo[4,5-c]pyridinyl), imidazothiazolyl (including all isomeric forms, for example, imidazo[2,1-b]-thiazolyl and imidazo[4,5-d]thiazolyl), indazolyl, indolizinyl, indolyl, isobenzofuranyl, isobenzo-thienyl (i.e., benzo[c]thienyl), isoindolyl, isoquinolinyl, naphthyridinyl (including all isomeric forms, for example, 1,5-naphthalene-2-yl, phthalazinyl, pteridinyl, purinyl, pyrrolopyridyl (including all isomeric forms, for example, pyrrolo[2,3-b]pyridinyl, pyrrolo[2,3-c]pyridinyl, pyrrolo[3,2-b]pyridinyl, and pyrrolo[3,2-c]pyridinyl), quinolinyl, quinoxalinyl, quinazolinyl, thiadiazolopyrimidyl (including all isomeric forms, e.g., [1,2,5]thiadiazolo[3,4-d]pyrimidinyl and [1,2,3]thiadiazolo[4,5-d]pyrimidinyl), and thienopyridyl (including all isomeric forms, e.g., thieno[2,3-b]pyridinyl, thieno[2,3-c]pyridinyl, thieno[3,2-b]pyridinyl, and thieno[3,2-c]pyridinyl). In yet another embodiment, heteroaryl is tricyclic.Examples of tricyclic heteroaryl groups include, but are not limited to, acridinyl, benzindolyl, carbazolyl, dibenzofuranyl, perimidinyl, phenanthrolinyl, phenanthridinyl (including all isomeric forms, e.g., 1,5-phenanthrolinyl, 1,6-phenanthrolinyl, 1,7-phenanthrolinyl, 1,9-phenanthrolinyl, and 2,10-phenanthrolinyl), phenarsazinyl, phenazinyl, phenothiazinyl, phenoxazinyl, and xanthenyl. In some embodiments, heteroaryl is optionally substituted with one or more substituents Q as described herein.

[0042] The terms "heteroarylene" and "heteroarenediyl" are used interchangeably herein to refer to a divalent monocyclic aromatic group or a divalent polycyclic aromatic group comprising at least one aromatic ring, wherein at least one aromatic ring comprises one or more heteroatoms, each independently selected from O, S, and N, within the ring. A heteroarylene group has at least one bond to the rest of the molecule through its aromatic ring. Each ring of a heteroarylene group can contain one or two O atoms, one or two S atoms, and / or one to four N atoms, provided that the total number of heteroatoms in each ring is four or less and each ring contains at least one carbon atom. In certain embodiments, a heteroarylene has 5 to 20, 5 to 15, or 5 to 10 ring atoms. Examples of monocyclic heteroarylene groups include, but are not limited to, furandiyl, imidazolediyl, isothiazolediyl, isoxazolediyl, oxadiazolediyl, oxazolediyl, pyrazinediyl, pyrazolediyl, pyridazinediyl, pyridinediyl, pyrimidinediyl, pyrrolediyl, thiadiazolediyl, thiazolediyl, thiendiyl, tetrazolediyl, triazinediyl, and triazolediyl. Examples of bicyclic heteroarylene groups include benzofurandiyl, benzimidazolediyl, benzoisoxazolediyl, benzopyrandiyl, benzothiadiazolediyl, benzothienediyl, benzotriazolediyl, benzoxazolediyl, furopyridinediyl (all isomeric forms, e.g., furo[2,3-b]pyridinediyl, furo[2,3-c]pyridinediyl, furo[3,2-b]pyridinediyl). , furo[3,2-c]pyridinediyl, furo[3,4-b]pyridinediyl, and furo[3,4-c]pyridinediyl), imidazopyridinediyl (including all isomeric forms, for example, imidazo[1,2-a]pyridinediyl, imidazo[4,5-b]pyridinediyl, and imidazo[4,5-c]pyridinediyl), imidazothiazoldiyl (including all isomeric forms, for example, imidazo[2,1-b]thiazoldiyl and imidazo[4,5-d]thiazolediyl), indazolediyl, indolizinediyl, indolediyl, isobenzofurandiyl, isobenzothienediyl (i.e., including benzo[c]thienediyl), isoindolediyl, isoquinolinediyl, naphthyridinediyl (including all isomeric forms, for example, 1,5-naphthyridinediyl, 1,6-naphthyridinediyl, 1,7-naphthyridinediyl, and 1,8-naphthyridinediyl), oxazolopyridinediyl (including all isomeric forms, for example, oxazolo[4,5-b]pyridinediyl, oxazolo[4,5-c]pyridinediyl, oxazolo[5,4-b]pyridinediyl, and oxazolo[5,4-c]pyridinediyl), phthalazinediyl, pteridinediyl, purinediyl, pyrrolopyridinediyl benzol (including all isomeric forms, for example, pyrrolo[2,3-b]pyridinediyl, pyrrolo[2,3-c]pyridinediyl, pyrrolo[3,2-b]pyridinediyl, and pyrrolo[3,2-c]pyridinediyl), quinolinediyl, quinoxalinediyl, quinazolinediyl, thiadiazolopyrimidinediyl (including all isomeric forms, for example, [1,2,5]thiadiazolo[3,4 [1,2,3]thiadiazolo[4,5-d]pyrimidinediyl and [1,2,3]thiadiazolo[4,5-d]pyrimidinediyl), and thienopyridinediyl (including all isomeric forms, for example, thieno[2,3-b]pyridinediyl, thieno[2,3-c]pyridinediyl, thieno[3,2-b]pyridinediyl, and thieno[3,2-c]pyridinediyl). Examples of tricyclic heteroarylene groups include, but are not limited to, acridinediyl, benzindolediyl, carbazolediyl, dibenzofurandiyl, perimidinediyl, phenanthrolinediyl (including all isomeric forms, e.g., 1,5-phenanthrolinediyl, 1,6-phenanthrolinediyl, 1,7-phenanthrolinediyl, 1,9-phenanthrolinediyl, and 2,10-phenanthrolinediyl), phenanthridinediyl, phenarsazinediyl, phenazinediyl, phenothiazinediyl, phenoxazinediyl, and xanthenediyl. In certain embodiments, heteroarylene is optionally substituted with one or more substituents Q as described herein.

[0043] The term "heterocyclyl" or "heterocyclic" refers to a monovalent, monocyclic, non-aromatic ring system or a monovalent polycyclic ring system containing at least one non-aromatic ring, wherein one or more of the non-aromatic ring atoms is a heteroatom independently selected from O, S, and N; and the remaining ring atoms are carbon atoms. In some embodiments, the heterocyclyl or heterocyclic group has 3 to 20, 3 to 15, 3 to 10, 3 to 8, 4 to 7, or 5 to 6 ring atoms. The heterocyclyl is attached to the remainder of the molecule via a non-aromatic ring. In some embodiments, the heterocyclyl is a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may be fused or bridged, and in which the nitrogen or sulfur atoms may be optionally oxidized, the nitrogen atoms may be optionally quaternized, and some rings may be partially or fully saturated or aromatic. The heterocyclyl may be attached to the main structure at any heteroatom or carbon atom which results in the creation of a stable compound.Examples of heterocyclyl and heterocyclic groups include azepinyl, benzodioxanyl, benzodioxolyl, benzofuranonyl, chromanyl, decahydroisoquinolinyl, dihydrobenzofuranyl, dihydrobenzisothiazolyl, dihydrobenzisoxazinyl (including all isomeric forms, e.g., 1,4-dihydrobenzo[d][1,3]oxazinyl, 3,4-dihydrobenzo[c][1,2]oxazinyl, and 3,4-dihydrobenzo[d][1,2]oxazinyl), dihydrobenzothienyl, dihydroisobenzofuranyl, dihydrobenzo[c]thienyl, dihydrofuryl, dihydroisoindolyl, dihydropyranyl, dihydropyrazolyl, dihydropyrazinyl, dihydropyridinyl, dihydropyrimidinyl, dihydrobenzothien ...isoindolyl, dihydropyranyl, dihydroisoindolyl, dihydroisoindolyl, dihydroisoindolyl, dihydroisoindolyl, dihydroisoindolyl, dihydroisoindolyl, dihydroisoindolyl, dihydroisoindolyl, dihydroisoindolyl, dihydroisoindolyl, dihydroisoindolyl, dihydroisoindolyl, dihydroisoindolyl, dihydroisoindolyl, dihydro Examples of heterocyclyl include, but are not limited to, hydropyrrolyl, dioxolanyl, 1,4-dithianyl, furanonyl, imidazolidinyl, imidazolinyl, indolinyl, isochromanyl, isoindolinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, oxazolidinonyl, oxazolidinyl, oxiranyl, piperazinyl, piperidinyl, 4-piperidonyl, pyrazolidinyl, pyrazolinyl, pyrrolidinyl, pyrrolinyl, quinuclidinyl, tetrahydrofuryl, tetrahydroisoquinolinyl, tetrahydropyranyl, tetrahydrothienyl, thiamorpholinyl, thiazolidinyl, thiochromanyl, tetrahydroquinolinyl, and 1,3,5-trithianyl. In certain embodiments, the heterocyclyl is optionally substituted with one or more substituents Q as described herein.

[0044] The term "heterocyclylene" refers to a divalent monocyclic non-aromatic ring system or a divalent polycyclic ring system containing at least one non-aromatic ring, wherein one or more of the non-aromatic ring atoms is a heteroatom independently selected from O, S, and N; and the remaining ring atoms are carbon atoms. The heterocyclylene group is attached to the remainder of the molecule via the non-aromatic ring. In certain embodiments, the heterocyclylene group has 3 to 20, 3 to 15, 3 to 10, 3 to 8, 4 to 7, or 5 to 6 ring atoms. In certain embodiments, the heterocyclylene is a monocyclic, bicyclic, tricyclic, or tetracyclic ring system that may be fused or bridged, and in which nitrogen or sulfur atoms may be optionally oxidized, nitrogen atoms may be optionally quaternized, and some rings may be partially or fully saturated or aromatic. The heterocyclylene may be attached to the main structure at any heteroatom or carbon atom that results in the creation of a stable compound.Examples of such heterocyclylene groups are azepinediyl, benzodioxanediyl, benzodioxolediyl, benzofuranonediyl, chromandiyl, decahydroisoquinolinediyl, dihydrobenzofurandiyl, dihydrobenzisothiazolediyl, dihydrobenzisoxazinediyl (including all isomeric forms, e.g., 1,4-dihydrobenzo[d][1,3]oxazinediyl, 3,4-dihydrobenzo[c][1,2]oxazinediyl, and 3,4-dihydrobenzo[d][1,2]oxazinediyl), dihydrobenzothienediyl, dihydroisobenzofurandiyl, dihydrobenzo[c]thienediyl, dihydrofuldiyl, dihydroisoindolediyl, dihydropyrandiyl, dihydro-pyrazolediyl, dihydropyrazinediyl, dihydropyridinediyl, dihydropyrimidinediyl, dihydropyrrolediyl, dihydrobenzothienediyl, dihydroisobenzofurandiyl, dihydrobenzo[c]thienediyl, dihydrofurandiyl, dihydroisoindolediyl, dihydropyrandiyl, dihydro-pyrazolediyl, dihydropyrazinediyl, dihydropyridinediyl, dihydropyrimidinediyl, dihydropyrrolediyl, dihydrobenzothienedi ...rrolediyl, dihydrobenzothienediyl, dihydroisoindolediyl, dihydrobenzothienediyl, dihydroisoindolediyl These include, but are not limited to, oxolanediyl, 1,4-dithianediyl, furanonediyl, imidazolidinediyl, imidazolinediyl, indolinediyl, isochromanediyl, isoindolinediyl, isothiazolidinediyl, isoxazolidinediyl, morpholinediyl, octahydroindolediyl, octahydroisoindolediyl, oxazolidineonediyl, oxazolidinediyl, oxiranediyl, piperazinediyl, piperidinediyl, 4-piperidonediyl, pyrazolidinediyl, pyrazolinediyl, pyrrolidinediyl, pyrrolinediyl, quinuclidinediyl, tetrahydrofuldiyl, tetrahydroisoquinolinediyl, tetrahydropyrandiyl, tetrahydrothienediyl, thiamorpholinediyl, thiazolidinediyl, thiochromanediyl, tetrahydroquinolinediyl, and 1,3,5-trithianediyl. In certain embodiments, the heterocyclylene is optionally substituted with one or more substituents Q as described herein.

[0045] The terms "halogen," "halide," or "halo" refer to fluoro, chloro, bromo, and / or iodo.

[0046] The term "optionally substituted" refers to a group or substituent, such as an alkyl, alkylene, heteroalkyl, heteroalkylene, alkenyl, alkenylene, heteroalkenylene, alkynyl, alkynylene, heteroalkynylene, cycloalkyl, cycloalkylene, aryl, arylene, aralkyl, aralkylene, heteroaryl, heteroarylene, heterocyclyl, or heterocyclylene group, that is optionally substituted with, for example, (a) deuterium (-D), cyano (-CN), halo, imino (=NH), nitro (-NO), and oxo (=O); (b) each of which is one or more, and in one embodiment, one, two, three, or four, substituents Q a optionally further substituted with C 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 aralkyl, heteroaryl, and heterocyclyl; and (c) —C(O)R a , -C(O)OR a , -C(O)NR b R c , -C(O)SR a , -C(NR a )NR b R c , -C(S)R a , -C(S)OR a , -C(S)NR b R c , -OR a , -OC(O)R a , -OC(O)OR a , -OC(O)NR b R c , -OC(O)SR a , -OC(NR a )NR b R c , -OC(S)R a , -OC(S)OR a , -OC(S)NR b R c , -OP(O)(OR a ) OR d , -OS(O)R a, -OS(O)2R a , -OS(O)NR b R c , -OS(O)2NR b R c , -NR b R c , -NR a C(O)R d , -NR a C(O)OR d , -NR a C(O)NR b R c , -NR a C(O)SR d , -NR a C(NR d )NR b R c , -NR a C(S)R d , -NR a C(S)OR d , -NR a C(S)NR b R c , -NR a S(O)R d , -NR a S(O)2R d , -NR a S(O)NR b R c , -NR a S(O)NR b R c , -SR a , -S(O)R a , -S(O)2R a , -S(O)NR b R c , and -S(O)NR b R c (where each R a , R b , R c , and R d are independently (i) hydrogen or deuterium; (ii) each one or more, in one embodiment one, two, three, or four, substituents Q a optionally substituted with, C 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 Alkenyl, C 2-6Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) R b and R c together with the N atom to which they are attached, one or more, in one embodiment one, two, three or four, substituents Q a and R is 0 or 1; R is 1 or 2; and R is 2 or 3; R is 3 or 4; and R is 4 or 5; R is 5 or 6; and R is 6 or 7; R is 7 or 8; R is 8 or 9; R is 9 or 10; R is 10 or 11; R is 10 or 11; R is 11 or 12; R is 12 or 13; R is 13 or 14; R is 14 or 15; R is 15 or 16; R is 16 or 17; R is 18 or 19; R is 20 or 21; R is 22 or 23; R is 24 or 25; R is 25 or 26; R is 26 or 27; R is 28 or 29; R is 30 or 30; R is 31 or 32; R is 33 or 34; R is 35 or 36; R is 37 or 38; R is 39 or 40; R is 30 or 31; R is 32 or 33; R is 34 or 35; R is 35 or 36; R is 37 or 38; R is 39 or 40; R is 30 or 41; R is 32 or 33; R is 34 or 34; R is 35 or 42; R is 35 or 43; R is 35 or 44; R is 35 or 45; R is 36 or 37; R is 38 or 45; R is 39 or 46; R is 39 or 47; R is 39 or 48; R is 39 or 49; R is 40 or 41; R is 30 or 42; R is 30 or

[0047] In one embodiment, each Q a are: (a) deuterium, cyano, halo, imino, nitro, and oxo; (b) C 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 aralkyl, heteroaryl, and heterocyclyl; and (c) —C(O)R e , -C(O)OR e , -C(O)NR f R g , -C(O)SR e , -C(NR e )NR f R g , -C(S)R e , -C(S)OR e , -C(S)NR f R g , -OR e , -OC(O)R e , -OC(O)OR e , -OC(O)NR f R g , -OC(O)SR e , -OC(NR e )NR f R g , -OC(S)R e, -OC(S)OR e , -OC(S)NR f R g , -OP(O)(OR f ) OR g , -OS(O)R e , -OS(O)2R e , -OS(O)NR f R g , -OS(O)2NR f R g , -NR f R g , -NR e C(O)R h , -NR e C(O)OR f , -NR e C(O)NR f R g , -NR e C(O)SR f , -NR e C(NR h )NR f R g , -NR e C(S)R h , -NR e C(S)OR f , -NR e C(S)NR f R g , -NR e S(O)R h , -NR e S(O)2R h , -NR e S(O)NR f R g , -NR e S(O)NR f R g , -SR e , -S(O)R e , -S(O)2R e , -S(O)NR f R g , and -S(O)NR f R g where each R e , R f , R g , and R h are independently (i) hydrogen or deuterium; (ii) C 1-6Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) R f and R g together with the N atom to which they are attached form a heterocyclyl.

[0048] In some embodiments, "optically active" and "enantiomerically active" refer to a collection of molecules having an enantiomeric excess of about 80% or more, about 90% or more, about 91% or more, about 92% or more, about 93% or more, about 94% or more, about 95% or more, about 96% or more, about 97% or more, about 98% or more, about 99% or more, about 99.5% or more, or about 99.8% or more. In some embodiments, an optically active compound contains about 95% or more of one enantiomer and about 5% or less of the other enantiomer, based on the total weight of the enantiomeric mixture in question. In some embodiments, an optically active compound contains about 98% or more of one enantiomer and about 2% or less of the other enantiomer, based on the total weight of the enantiomeric mixture in question. In some embodiments, an optically active compound contains about 99% or more of one enantiomer and about 1% or less of the other enantiomer, based on the total weight of the enantiomeric mixture in question.

[0049] In describing an optically active compound, the prefixes R and S are used to denote the absolute configuration of the compound about its chiral center. The prefixes (+) and (-) are used to denote the optical rotation of the compound, i.e., the direction in which a plane of polarized light is rotated by the optically active compound. The prefix (-) means that the compound is levorotatory, i.e., the compound rotates the plane of polarized light to the left or counterclockwise. The prefix (+) means that the compound is dextrorotatory, i.e., the compound rotates the plane of polarized light to the right or clockwise. However, the symbols of optical rotation (+) and (-) are independent of the absolute configuration R and S of the compound.

[0050] The term "isotopically enriched" refers to a compound that contains an unnatural proportion of isotopes at one or more atoms that constitute such a compound. In some embodiments, isotopically enriched compounds include, but are not limited to, hydrogen ( 1 H), deuterium ( 2 H), tritium ( 3 H), carbon-11( 11 C), carbon-12( 12 C), carbon-13( 13 C), carbon-14( 14 C), nitrogen-13( 13 N), nitrogen-14( 14 N), nitrogen-15( 15 N), oxygen-14( 14 O), oxygen-15( 15 O), oxygen-16( 16 O), oxygen-17( 17 O), oxygen-18( 18 O), fluorine-17( 17 F), fluorine-18( 18 F), Phosphorus-31( 31 P), phosphorus-32( 32 P), phosphorus-33( 33 P), sulfur-32( 32 S), sulfur-33( 33 S), sulfur-34( 34 S), sulfur-35( 35 S), sulfur-36( 36 S), chlorine-35( 35 Cl), chlorine-36( 36 Cl), chlorine-37( 37 Cl), Bromine-79( 79 Br), Bromine-81( 81 Br), iodine-123( 123 I), iodine-125( 125 I), iodine-127( 127 I), iodine-129( 129 I), and iodine-131( 131 In some embodiments, the isotopically enriched compound is in a stable form, i.e., is non-radioactive. ... 1H), deuterium ( 2 H), carbon-12( 12 C), carbon-13( 13 C), nitrogen-14( 14 N), nitrogen-15( 15 N), oxygen-16( 16 O), oxygen-17( 17 O), oxygen-18( 18 O), fluorine-17( 17 F), Phosphorus-31( 31 P), sulfur-32( 32 S), sulfur-33( 33 S), sulfur-34( 34 S), sulfur-36( 36 S), chlorine-35( 35 Cl), chlorine-37( 37 Cl), Bromine-79( 79 Br), Bromine-81( 81 Br), and iodine-127( 127 In some embodiments, the isotopically enriched compound is in an unstable form, i.e., radioactive. ... 3 H), carbon-11( 11 C), carbon-14( 14 C), nitrogen-13( 13 N), oxygen-14( 14 O), oxygen-15( 15 O), fluorine-18( 18 F), phosphorus-32( 32 P), phosphorus-33( 33 P), sulfur-35( 35 S), chlorine-36( 36 Cl), iodine-123( 123 I), iodine-125( 125 I), iodine-129( 129 I), and iodine-131( 131 In the compounds provided herein, any hydrogen atom may be used as an example, if feasible according to the judgment of a person skilled in the art. 2 H or any carbon, e.g. 13C or any nitrogen, for example 15 It can be N or any oxygen, for example 18 It will be understood that the number of

[0051] The term "isotopically enriched" refers to the presence of a more common isotope of an element (e.g., protium or hydrogen-1) at a given position in a molecule. 1 "H" refers to the incorporation rate of a less common isotope of that element (e.g., D, representing deuterium or hydrogen-2) in place of the less common isotope of that element. As used herein, when an atom at a particular location within a molecule is designated as a particular less common isotope, it is understood that the abundance of that isotope at that location is substantially greater than its natural abundance.

[0052] The term "isotopic enrichment factor" refers to the ratio between the abundance of an isotope in an isotopically enriched compound and the natural abundance of the specified isotope.

[0053] The term "hydrogen" or the symbol "H" refers to protium ( 1 H), deuterium ( 2 H or D), and tritium ( 3 H) at their natural abundance. Protium is the most common hydrogen isotope, with a natural abundance greater than 99.98%. Deuterium is the less common hydrogen isotope, with a natural abundance of approximately 0.0156%.

[0054] The term "deuterium enrichment" refers to the rate at which deuterium is incorporated in place of hydrogen at a given position in a molecule. For example, 1% deuterium enrichment at a given position means that 1% of the molecules in a given sample contain deuterium at that particular position. Since the natural distribution of deuterium is about 0.0156% on average, the deuterium enrichment at any position in a compound synthesized using a non-enriched starting material is about 0.0156% on average. As used herein, when a particular position in an isotopically enriched compound is designated as having deuterium, it is understood that the abundance of deuterium at that position in the compound is substantially higher than its natural abundance (0.0156%).

[0055] The term "carbon" or the symbol "C" refers to carbon-12 ( 12 C) and carbon-13 ( 13 Carbon-12 refers to the composition of naturally occurring carbon isotopes, including carbon-12, carbon-13, and carbon-14, carbon-15, carbon-16, carbon-17, carbon-18, carbon-19, carbon-20, carbon-21, carbon-22, carbon-23, carbon-24, carbon-25, carbon-26, carbon-27, carbon-28, carbon-29, carbon-30, carbon-31, carbon-32, carbon-33, carbon-34, carbon-35, carbon-36, carbon-37, carbon-38, carbon-39, carbon-40, carbon-41, carbon-42, carbon-43, carbon-44, carbon-45, carbon-46, carbon-47, carbon-48, carbon-49, carbon-50, carbon-51, carbon-52, carbon-53, carbon-54, carbon-55, carbon-56, carbon-57, carbon-58, carbon-

[0056] The term "carbon-13 enriched" or " 13 "C enrichment" refers to the rate of incorporation of carbon-13 in place of carbon at a given position in a molecule. For example, 10% carbon-13 enrichment at a given position means that 10% of the molecules in a given sample contain carbon-13 at that particular position. Because the natural distribution of carbon-13 averages about 1.11%, the carbon-13 enrichment at any position in a compound synthesized using non-enriched starting materials will average about 1.11%. As used herein, when a particular position in an isotopically enriched compound is designated as having carbon-13, it is understood that the abundance of carbon-13 at that position in the compound is substantially higher than its natural abundance (1.11%).

[0057] The terms "substantially pure" and "substantially homogeneous," when applied to a substance, mean sufficiently homogeneous to appear free of readily detectable impurities as determined by standard analytical methods used by those skilled in the art, including, but not limited to, thin layer chromatography (TLC), gel electrophoresis, high performance liquid chromatography (HPLC), gas chromatography (GC), nuclear magnetic resonance (NMR), and mass spectrometry (MS); or sufficiently pure that further purification would not detectably alter the physical, chemical, biological, and / or pharmaceutical properties, such as enzymatic activity and biological activity, of the substance. In some embodiments, "substantially pure" or "substantially homogeneous" refers to a collection of molecules in which at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or at least about 99.5% by weight of the molecules are a single compound, including a single enantiomer, a racemic mixture, or a mixture of enantiomers, as determined by standard analytical methods. As used herein, when an atom at a particular position in an isotopically enriched molecule is designated as a particular less common isotope, molecules containing an isotope other than the designated isotope at that particular position are impurities with respect to the isotopically enriched compound. Thus, with respect to a deuterated compound having an atom designated as deuterium at a particular position, a compound containing protium at the same position is an impurity.

[0058] The term "solvate" refers to a complex or aggregate formed by one or more molecules of a solute, such as one or more molecules of a compound provided herein, and one or more molecules of a solvent present in a stoichiometric or non-stoichiometric amount. Suitable solvents include, but are not limited to, water, methanol, ethanol, n-propanol, isopropanol, and acetic acid. In some embodiments, the solvent is pharmaceutically acceptable. In one embodiment, the complex or aggregate is in a crystalline form. In another embodiment, the complex or aggregate is in an amorphous form. When the solvent is water, the solvate is a hydrate. Examples of hydrates include, but are not limited to, hemihydrate, monohydrate, dihydrate, trihydrate, tetrahydrate, and pentahydrate.

[0059] For divalent groups described herein, no orientation is implied by the direction in which the divalent group is presented. For example, unless a particular orientation is specified, the formula -C(O)NH- represents both -C(O)NH- and -NHC(O)-.

[0060] The phrase "an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof" has the same meaning as the phrase "(i) an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant of a compound referred to therein; (ii) a pharmaceutically acceptable salt, solvate, hydrate, or prodrug of a compound referred to therein, or (iii) a pharmaceutically acceptable salt, solvate, hydrate, or prodrug of an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant of a compound referred to therein."

[0061] In one embodiment, provided herein is a compound of formula (I): [ka] (In the formula, L is a linker; X is —CH— or —C(O)—; Y is C 1-6 Alkylene or C 3-10 is cycloalkylene; R E is the E3 ubiquitin ligase binding moiety; R 1 is (i)C 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10Cycloalkyl, C 6-14 Aryl, C 7-15 aralkyl, heteroaryl, or heterocyclyl; or (ii) —OR 1a or -NR 1b R 1c and; R 2 is hydrogen or deuterium; R 3a , R 3d , and R 3e are each independently (i) hydrogen, deuterium, cyano, halo, or nitro; (ii) C 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) —C(O)R 1a , -C(O)OR 1a , -C(O)NR 1b R 1c , -C(O)SR 1a , -C(NR 1a )NR 1b R 1c , -C(S)R 1a , -C(S)OR 1a , -C(S)NR 1b R 1c , -OR 1a , -OC(O)R 1a , -OC(O)OR 1a , -OC(O)NR 1b R 1c , -OC(O)SR 1a , -OC(NR 1a )NR 1b R 1c , -OC(S)R 1a , -OC(S)OR 1a , -OC(S)NR 1b R 1c , -OS(O)R 1a , -OS(O)2R 1a , -OS(O)NR 1b R 1c , -OS(O)2NR 1bR 1c , -NR 1b R 1c , -NR 1a C(O)R 1d , -NR 1a C(O)OR 1d , -NR 1a C(O)NR 1b R 1c , -NR 1a C(O)SR 1d , -NR 1a C(NR 1d )NR 1b R 1c , -NR 1a C(S)R 1d , -NR 1a C(S)OR 1d , -NR 1a C(S)NR 1b R 1c , -NR 1a S(O)R 1d , -NR 1a S(O)2R 1d , -NR 1a S(O)NR 1b R 1c , -NR 1a S(O)NR 1b R 1c , -SR 1a , -S(O)R 1a , -S(O)2R 1a , -S(O)NR 1b R 1c , or -S(O)NR 1b R 1c and; R 3b and R 3c are each independently, C 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 aralkyl, heteroaryl, or heterocyclyl; Each R 4a are independently (i) deuterium, cyano, halo, or nitro; (ii) C 1-6 Alkyl, C 1-6Heteroalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) —C(O)R 1a , -C(O)OR 1a , -C(O)NR 1b R 1c , -C(O)SR 1a , -C(NR 1a )NR 1b R 1c , -C(S)R 1a , -C(S)OR 1a , -C(S)NR 1b R 1c , -OR 1a , -OC(O)R 1a , -OC(O)OR 1a , -OC(O)NR 1b R 1c , -OC(O)SR 1a , -OC(NR 1a )NR 1b R 1c , -OC(S)R 1a , -OC(S)OR 1a , -OC(S)NR 1b R 1c , -OS(O)R 1a , -OS(O)2R 1a , -OS(O)NR 1b R 1c , -OS(O)2NR 1b R 1c , -NR 1b R 1c , -NR 1a C(O)R 1d , -NR 1a C(O)OR 1d , -NR 1a C(O)NR 1b R 1c , -NR 1a C(O)SR 1d , -NR 1a C(NR 1d )NR 1b R 1c , -NR 1a C(S)R1d , -NR 1a C(S)OR 1d , -NR 1a C(S)NR 1b R 1c , -NR 1a S(O)R 1d , -NR 1a S(O)2R 1d , -NR 1a S(O)NR 1b R 1c , -NR 1a S(O)NR 1b R 1c , -SR 1a , -S(O)R 1a , -S(O)2R 1a , -S(O)NR 1b R 1c , or -S(O)NR 1b R 1c and R 4 is hydrogen or R 4a and; Each R 1a , R 1b , R 1c , and R 1d are independently hydrogen, deuterium, and C 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 aralkyl, heteroaryl, or heterocyclyl; and a is an integer of 0, 1, 2, 3, or 4; wherein each alkyl, alkylene, heteroalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylene, aryl, aralkyl, heteroaryl, and heterocyclyl is optionally substituted with one or more, in one embodiment one, two, three, or four, substituents Q, wherein each Q is: (a) deuterium, cyano, halo, imino, nitro, and oxo; (b) each is one or more, in one embodiment one, two, three, or four, substituents Q a optionally further substituted with C 1-6Alkyl, C 1-6 Heteroalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 aralkyl, heteroaryl, and heterocyclyl; and (c) —C(O)R a , -C(O)OR a , -C(O)NR b R c , -C(O)SR a , -C(NR a )NR b R c , -C(S)R a , -C(S)OR a , -C(S)NR b R c , -OR a , -OC(O)R a , -OC(O)OR a , -OC(O)NR b R c , -OC(O)SR a , -OC(NR a )NR b R c , -OC(S)R a , -OC(S)OR a , -OC(S)NR b R c , -OP(O)(OR a ) OR d , -OS(O)R a , -OS(O)2R a , -OS(O)NR b R c , -OS(O)2NR b R c , -NR b R c , -NR a C(O)R d , -NR a C(O)OR d , -NR a C(O)NR b R c , -NR a C(O)SR d , -NR a C(NR d )NRb R c , -NR a C(S)R d , -NR a C(S)OR d , -NR a C(S)NR b R c , -NR a S(O)R d , -NR a S(O)2R d , -NR a S(O)NR b R c , -NR a S(O)NR b R c , -SR a , -S(O)R a , -S(O)2R a , -S(O)NR b R c , and -S(O)NR b R c where each R a , R b , R c , and R d are independently (i) hydrogen or deuterium; (ii) each one or more, in one embodiment one, two, three, or four, substituents Q a optionally substituted with, C 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) R b and R c together with the N atom to which they are attached, one or more, in one embodiment one, two, three or four, substituents Q a forming an optionally substituted heterocyclyl; Here, each Q a are: (a) deuterium, cyano, halo, nitro, imino, and oxo; (b) C 1-6 Alkyl, C 1-6Heteroalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 aralkyl, heteroaryl, and heterocyclyl; and (c) —C(O)R e , -C(O)OR e , -C(O)NR f R g , -C(O)SR e , -C(NR e )NR f R g , -C(S)R e , -C(S)OR e , -C(S)NR f R g , -OR e , -OC(O)R e , -OC(O)OR e , -OC(O)NR f R g , -OC(O)SR e , -OC(NR e )NR f R g , -OC(S)R e , -OC(S)OR e , -OC(S)NR f R g , -OP(O)(OR f ) OR g , -OS(O)R e , -OS(O)2R e , -OS(O)NR f R g , -OS(O)2NR f R g , -NR f R g , -NR e C(O)R h , -NR e C(O)OR f , -NR e C(O)NR f R g , -NR e C(O)SR f , -NR e C(NR h )NR f Rg , -NR e C(S)R h , -NR e C(S)OR f , -NR e C(S)NR f R g , -NR e S(O)R h , -NR e S(O)2R h , -NR e S(O)NR f R g , -NR e S(O)NR f R g , -SR e , -S(O)R e , -S(O)2R e , -S(O)NR f R g , and -S(O)NR f R g where each R e , R f , R g , and R h are independently (i) hydrogen or deuterium; (ii) C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) R f and R g together with the N atom to which they are attached form a heterocyclyl) or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0062] In certain embodiments, in Formula (I), Y is C optionally substituted with one or more substituents Q. 1-6In some embodiments, in Formula (I), Y is methylene optionally substituted with one or more substituents Q. In some embodiments, in Formula (I), Y is -CH2- or -CD2-. In some embodiments, in Formula (I), Y is C optionally substituted with one or more substituents Q. 3-10 In certain embodiments, in Formula (I), Y is cyclopropane-1,1-diyl.

[0063] In certain embodiments, in Formula (I), R 3a is hydrogen or deuterium. In certain embodiments, in formula (I), R 3d is hydrogen or deuterium. In certain embodiments, in formula (I), R 3e is hydrogen or deuterium. In certain embodiments, in formula (I), R 3a , R 3d , and R 3e are hydrogen atoms.

[0064] In another embodiment, provided herein is a compound of formula (II): [ka] (In the formula, R 1 , R 2 , R 3b , R 3c , R 4a , R E , L, X, and a are each as defined herein. or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0065] In certain embodiments, in Formula (I) or (II), a is an integer of 0, 1, or 2. In certain embodiments, in Formula (I) or (II), a is an integer of 0. In certain embodiments, in Formula (I) or (II), a is an integer of 1. In certain embodiments, in Formula (I) or (II), a is an integer of 2.

[0066] In yet another embodiment, provided herein is a compound of formula (III): [ka] (In the formula, R 1 , R 2 , R 3b , R 3c , R E , L, and X are each as defined herein. or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0067] In yet another embodiment, provided herein is a compound of formula (IV): [ka] (In the formula, R 1 , R 2 , R 3b , R 3c , R E , L, and X are each as defined herein. or a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0068] In yet another embodiment, provided herein is a compound of formula (V): [ka] (In the formula, R 1 , R 2 , R 4 , R 3b , R 3c , R E , L, and X are each as defined herein. or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0069] In yet another embodiment, provided herein is a compound of formula (VI): [ka] (In the formula, R 1 , R 2 , R 4 , R 3b , R 3c , R E , L, and X are each as defined herein. or a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0070] In certain embodiments, in any one of Formulas (I) to (VI), R 1 (i) C, each of which is optionally substituted with one or more substituents Q 1-6 Alkyl, C 3-10 cycloalkyl, heteroaryl, or heterocyclyl; or (ii) —OR 1a or -NR 1b R 1c (In the formula, R 1a , R 1b , and R 1cand each are as defined herein. In certain embodiments, in any one of Formulas (I) to (VI), R 1 each of which is optionally substituted with one or more substituents Q 1-6 Alkyl or C 3-10 In certain embodiments, in any one of Formulas (I) to (VI), R 1 is C optionally substituted with one or more substituents Q 1-6 In certain embodiments, in any one of Formulas (I) to (VI), R 1 is methyl or cyclopropylmethyl. In certain embodiments, in any one of Formulas (I) to (VI), R 1 is methyl. In certain embodiments, in any one of Formulas (I) to (VI), R 1 is C optionally substituted with one or more substituents Q 3-10 In certain embodiments, in any one of Formulas (I) to (VI), R 1 is cyclopropyl.

[0071] In certain embodiments, in any one of Formulas (I) to (VI), R 2 is hydrogen. In certain embodiments, in any one of Formulas (I) to (VI), R 2 is deuterium.

[0072] In certain embodiments, in any one of Formulas (I) to (VI), R 3b each optionally substituted with one or more substituents Q; 1-6 Alkyl, C 1-6 Heteroalkyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 In certain embodiments, in any one of Formulas (I) to (VI), R 3b each optionally substituted with one or more substituents Q; 1-6 Alkyl, C1-6 Heteroalkyl, or C 3-10 In certain embodiments, in any one of Formulas (I) to (VI), R 3b is C optionally substituted with one or more substituents Q 1-6 In certain embodiments, in any one of Formulas (I) to (VI), R 3b is methyl, ethyl, or cyclopropylmethyl. In certain embodiments, in any one of Formulas (I) to (VI), R 3b is ethyl. In certain embodiments, in any one of Formulas (I) to (VI), R 3b is C optionally substituted with one or more substituents Q 3-10 In certain embodiments, in any one of Formulas (I) to (VI), R 3b is cyclopropyl.

[0073] In certain embodiments, in any one of Formulas (I) to (VI), R 3c each optionally substituted with one or more substituents Q; 1-6 Alkyl, C 1-6 Heteroalkyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 In certain embodiments, in any one of Formulas (I) to (VI), R 3c each optionally substituted with one or more substituents Q; 1-6 Alkyl, C 1-6 Heteroalkyl, or C 3-10 In certain embodiments, in any one of Formulas (I) to (VI), R 3c is C optionally substituted with one or more substituents Q 1-6 In certain embodiments, in any one of Formulas (I) to (VI), R 3c is methyl, ethyl, or cyclopropylmethyl. In certain embodiments, in any one of Formulas (I) to (VI), R3c is methyl. In certain embodiments, in any one of Formulas (I) to (VI), R 3c is C optionally substituted with one or more substituents Q 3-10 In certain embodiments, in any one of Formulas (I) to (VI), R 3c is cyclopropyl.

[0074] In certain embodiments, in any one of Formulas (I) to (VI), R 3b and R 3c each independently represents C optionally substituted with one or more substituents Q; 1-6 In certain embodiments, in any one of Formulas (I) to (VI), R 3b and R 3c are each independently methyl or ethyl. In certain embodiments, in any one of Formulas (I) to (VI), R 3b is methyl and R 3c is ethyl. In certain embodiments, in any one of Formulas (I) to (VI), R 3b is ethyl and R 3c is methyl.

[0075] In certain embodiments, in Formula (V) or Formula (VI), R 4 -NR 1b R 1c , or -NR 1a C(O)R 1d where R 1a , R 1b , R 1c , and R 1d and R are each as defined herein. In certain embodiments, in Formula (V) or Formula (VI), R 4 is hydrogen. In certain embodiments, in Formula (V) or Formula (VI), R 4 is deuterium. In certain embodiments, in Formula (V) or Formula (VI), R 4 is halo. In certain embodiments, in Formula (V) or Formula (VI), R4 is -NR 1b R 1c where R 1b and R 1c and R are each as defined herein. In certain embodiments, in Formula (V) or Formula (VI), R 4 is —NH. In certain embodiments, in Formula (V) or Formula (VI), R 4 is -NR 1a C(O)R 1d where R 1a and R 1d and R are each as defined herein. In certain embodiments, in Formula (V) or Formula (VI), R 4 is -NHC(O)R 1d where R 1d is C optionally substituted with one or more substituents Q 1-6 In some embodiments, in Formula (V) or Formula (VI), R 4 is -NHC(O)CH3.

[0076] In certain embodiments, in any one of Formulas (I) to (VI), X is -CH2-. In certain embodiments, in any one of Formulas (I) to (VI), X is -C(O)-.

[0077] In one embodiment, in any one of Formulas (I) to (VI), R 1 is C 1-6 Alkyl or C 3-10 is cycloalkyl; R 2 is hydrogen or deuterium; R 3b and R 3c are each independently, C 1-6 is alkyl; R 4 When present, is hydrogen or -NHC(O)R 1d (In the formula, R 1d is C 1-6 alkyl); and X is —CH— or —C(O)—; wherein each alkyl and cycloalkyl is optionally substituted with one or more substituents Q.

[0078] In another embodiment, in any one of Formulas (I) to (VI), R 1 is methyl or cyclopropylmethyl; R 2 is hydrogen or deuterium; R 3b and R 3c are each independently methyl or ethyl; R 4 is, if present, hydrogen or —NHC(O)CH; and X is —CH— or —C(O)—.

[0079] In one embodiment, provided herein is a compound of formula (VII): [ka] (In the formula, R E and L are each as defined herein. or a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0080] In another embodiment, provided herein is a compound of formula (VIII): [ka] (In the formula, R E and L are each as defined herein. or a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0081] In one embodiment, provided herein is a compound of formula (IA): [ka] (In the formula, L is a linker; R E is the E3 ubiquitin ligase binding moiety; Each R 5a are independently (i) deuterium, cyano, halo, or nitro; (ii) C 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) —C(O)R 1a , -C(O)OR 1a , -C(O)NR 1b R 1c , -C(O)SR 1a , -C(NR 1a )NR 1b R 1c , -C(S)R 1a , -C(S)OR 1a , -C(S)NR 1b R 1c , -OR 1a , -OC(O)R 1a , -OC(O)OR 1a , -OC(O)NR 1b R 1c , -OC(O)SR 1a , -OC(NR 1a )NR 1b R 1c , -OC(S)R 1a , -OC(S)OR 1a , -OC(S)NR 1b R 1c , -OS(O)R 1a , -OS(O)2R 1a , -OS(O)NR 1b R 1c , -OS(O)2NR 1b R1c , -NR 1b R 1c , -NR 1a C(O)R 1d , -NR 1a C(O)OR 1d , -NR 1a C(O)NR 1b R 1c , -NR 1a C(O)SR 1d , -NR 1a C(NR 1d )NR 1b R 1c , -NR 1a C(S)R 1d , -NR 1a C(S)OR 1d , -NR 1a C(S)NR 1b R 1c , -NR 1a S(O)R 1d , -NR 1a S(O)2R 1d , -NR 1a S(O)NR 1b R 1c , -NR 1a S(O)NR 1b R 1c , -SR 1a , -S(O)R 1a , -S(O)2R 1a , -S(O)NR 1b R 1c , or -S(O)NR 1b R 1c and R 5 is hydrogen or R 5a and; R 6 is hydrogen, C 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 aralkyl, heteroaryl, or heterocyclyl; R 7a , R 7b , R 7c , and R 7dare each independently (i) hydrogen, deuterium, cyano, halo, or nitro; (ii) C 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) —C(O)R 1a , -C(O)OR 1a , -C(O)NR 1b R 1c , -C(O)SR 1a , -C(NR 1a )NR 1b R 1c , -C(S)R 1a , -C(S)OR 1a , -C(S)NR 1b R 1c , -OR 1a , -OC(O)R 1a , -OC(O)OR 1a , -OC(O)NR 1b R 1c , -OC(O)SR 1a , -OC(NR 1a )NR 1b R 1c , -OC(S)R 1a , -OC(S)OR 1a , -OC(S)NR 1b R 1c , -OS(O)R 1a , -OS(O)2R 1a , -OS(O)NR 1b R 1c , -OS(O)2NR 1b R 1c , -NR 1b R 1c , -NR 1a C(O)R 1d , -NR 1a C(O)OR 1d , -NR 1a C(O)NR 1b R 1c , -NR 1a C(O)SR 1d , -NR 1a C(NR1d )NR 1b R 1c , -NR 1a C(S)R 1d , -NR 1a C(S)OR 1d , -NR 1a C(S)NR 1b R 1c , -NR 1a S(O)R 1d , -NR 1a S(O)2R 1d , -NR 1a S(O)NR 1b R 1c , -NR 1a S(O)NR 1b R 1c , -SR 1a , -S(O)R 1a , -S(O)2R 1a , -S(O)NR 1b R 1c , or -S(O)NR 1b R 1c and; Each R 1a , R 1b , R 1c , and R 1d are independently hydrogen, deuterium, and C 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 aralkyl, heteroaryl, or heterocyclyl; and b is an integer of 0, 1, 2, 3, or 4; wherein each alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heteroaryl, and heterocyclyl is optionally substituted with one or more, in one embodiment one, two, three, or four, substituents Q, wherein each Q is: (a) deuterium, cyano, halo, imino, nitro, and oxo; (b) each is one or more, in one embodiment one, two, three, or four, substituents Q a optionally further substituted with C1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 aralkyl, heteroaryl, and heterocyclyl; and (c) —C(O)R a , -C(O)OR a , -C(O)NR b R c , -C(O)SR a , -C(NR a )NR b R c , -C(S)R a , -C(S)OR a , -C(S)NR b R c , -OR a , -OC(O)R a , -OC(O)OR a , -OC(O)NR b R c , -OC(O)SR a , -OC(NR a )NR b R c , -OC(S)R a , -OC(S)OR a , -OC(S)NR b R c , -OP(O)(OR a ) OR d , -OS(O)R a , -OS(O)2R a , -OS(O)NR b R c , -OS(O)2NR b R c , -NR b R c , -NR a C(O)R d , -NR a C(O)OR d , -NR a C(O)NR b R c , -NR a C(O)SR d , -NR a C(NRd )NR b R c , -NR a C(S)R d , -NR a C(S)OR d , -NR a C(S)NR b R c , -NR a S(O)R d , -NR a S(O)2R d , -NR a S(O)NR b R c , -NR a S(O)NR b R c , -SR a , -S(O)R a , -S(O)2R a , -S(O)NR b R c , and -S(O)NR b R c where each R a , R b , R c , and R d are independently (i) hydrogen or deuterium; (ii) each one or more, in one embodiment one, two, three, or four, substituents Q a optionally substituted with, C 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) R b and R c together with the N atom to which they are attached, one or more, in one embodiment one, two, three or four, substituents Q a forming an optionally substituted heterocyclyl; Here, each Q a are: (a) deuterium, cyano, halo, nitro, imino, and oxo; (b) C 1-6Alkyl, C 1-6 Heteroalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 aralkyl, heteroaryl, and heterocyclyl; and (c) —C(O)R e , -C(O)OR e , -C(O)NR f R g , -C(O)SR e , -C(NR e )NR f R g , -C(S)R e , -C(S)OR e , -C(S)NR f R g , -OR e , -OC(O)R e , -OC(O)OR e , -OC(O)NR f R g , -OC(O)SR e , -OC(NR e )NR f R g , -OC(S)R e , -OC(S)OR e , -OC(S)NR f R g , -OP(O)(OR f ) OR g , -OS(O)R e , -OS(O)2R e , -OS(O)NR f R g , -OS(O)2NR f R g , -NR f R g , -NR e C(O)R h , -NR e C(O)OR f , -NR e C(O)NR f R g , -NR e C(O)SR f , -NR e C(NR h )NRf R g , -NR e C(S)R h , -NR e C(S)OR f , -NR e C(S)NR f R g , -NR e S(O)R h , -NR e S(O)2R h , -NR e S(O)NR f R g , -NR e S(O)NR f R g , -SR e , -S(O)R e , -S(O)2R e , -S(O)NR f R g , and -S(O)NR f R g where each R e , R f , R g , and R h are independently (i) hydrogen or deuterium; (ii) C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) R f and R g together with the N atom to which they are attached form a heterocyclyl) or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0082] In certain embodiments, in Formula (IA), each R 5aare independently (i) deuterium; (ii) C optionally substituted with one or more substituents Q; 1-6 alkyl; or (iii) -OR 1a (In the formula, R 1a is as defined herein. In certain embodiments, in Formula (IA), each R 5a is deuterium. In certain embodiments, in Formula (IA), each R 5a are independently C optionally substituted with one or more substituents Q 1-6 In certain embodiments, in Formula (IA), each R 5a are independently, -OR 1a (In the formula, R 1a is as defined herein. In certain embodiments, in Formula (IA), each R 5a are independently, -OR 1a (In the formula, R 1a is C optionally substituted with one or more substituents Q 1-6 In certain embodiments, in Formula (IA), each R 5a is independently methoxy, difluoromethoxy, trifluoromethoxy, ethoxy, or cyclopropylmethoxy. In certain embodiments, in Formula (IA), each R 5a is independently difluoromethoxy or cyclopropylmethoxy.

[0083] In certain embodiments, in Formula (IA), b is an integer of 0, 1, or 2. In certain embodiments, in Formula (IA), b is an integer of 0. In certain embodiments, in Formula (IA), b is an integer of 1. In certain embodiments, in Formula (IA), b is an integer of 2.

[0084] In another embodiment, provided herein is a compound of formula (IIA): [ka] (In the formula, R 5 , R 6 , R 7a , R 7b , R7c , R 7d , R E , and L are each as defined herein. or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0085] In yet another embodiment, provided herein is a compound of formula (IIIA): [ka] (In the formula, R 5 , R 6 , R 7a , R 7b , R 7c , R 7d , R E , and L are each as defined herein. or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0086] In certain embodiments, in Formula (IIA) or Formula (IIIA), R 5 is (i) hydrogen or deuterium; (ii) C optionally substituted with one or more substituents Q 1-6 alkyl; or (iii) -OR 1a (In the formula, R 1a is as defined herein. In certain embodiments, in Formula (IIA) or Formula (IIIA), R 5 is hydrogen or deuterium. In certain embodiments, in Formula (IIA) or Formula (IIIA), R 5 is C optionally substituted with one or more substituents Q 1-6In certain embodiments, in Formula (IIA) or Formula (IIIA), R 5 -OR 1a (In the formula, R 1a is as defined herein. In certain embodiments, in Formula (IIA) or Formula (IIIA), R 5 -OR 1a (In the formula, R 1a is C optionally substituted with one or more substituents Q 1-6 In some embodiments, in Formula (IIA) or Formula (IIIA), R 5 is methoxy, difluoromethoxy, trifluoromethoxy, ethoxy, or cyclopropylmethoxy. In certain embodiments, in Formula (IIA) or Formula (IIIA), R 5 is difluoromethoxy or cyclopropylmethoxy. In certain embodiments, in Formula (IIA), R 5 In certain embodiments, in Formula (IIIA), R 5 is cyclopropylmethoxy.

[0087] In certain embodiments, in Formula (IA), Formula (IIA), or Formula (IIIA), R 6 is hydrogen or C optionally substituted with one or more substituents Q 1-6 In certain embodiments, in Formula (IA), Formula (IIA), or Formula (IIIA), R 6 is hydrogen.

[0088] In certain embodiments, in Formula (IA), Formula (IIA), or Formula (IIIA), R 7a is hydrogen, deuterium, halo, or C optionally substituted with one or more substituents Q 1-6 In certain embodiments, in Formula (IA), Formula (IIA), or Formula (IIIA), R 7a is hydrogen, halo, or C optionally substituted with one or more substituents Q 1-6In certain embodiments, in Formula (IA), Formula (IIA), or Formula (IIIA), R 7a is hydrogen. In certain embodiments, in Formula (IA), Formula (IIA), or Formula (IIIA), R 7a is deuterium. In certain embodiments, in Formula (IA), Formula (IIA), or Formula (IIIA), R 7a In certain embodiments, in Formula (IA), Formula (IIA), or Formula (IIIA), R 7a In certain embodiments, in Formula (IA), Formula (IIA), or Formula (IIIA), R 7a is C optionally substituted with one or more substituents Q 1-6 In certain embodiments, in Formula (IA), Formula (IIA), or Formula (IIIA), R 7a is methyl optionally substituted with one or more substituents Q. In certain embodiments, in Formula (IA), Formula (IIA), or Formula (IIIA), R 7a is trifluoromethyl.

[0089] In certain embodiments, in Formula (IA), Formula (IIA), or Formula (IIIA), R 7b is hydrogen, deuterium, or C optionally substituted with one or more substituents Q 1-6 In certain embodiments, in Formula (IA), Formula (IIA), or Formula (IIIA), R 7b is hydrogen. In certain embodiments, in Formula (IA), Formula (IIA), or Formula (IIIA), R 7b is deuterium.

[0090] In certain embodiments, in Formula (IA), Formula (IIA), or Formula (IIIA), R 7c is hydrogen, deuterium, or C optionally substituted with one or more substituents Q 1-6 In certain embodiments, in Formula (IA), Formula (IIA), or Formula (IIIA), R 7cis hydrogen. In certain embodiments, in Formula (IA), Formula (IIA), or Formula (IIIA), R 7c is deuterium.

[0091] In certain embodiments, in Formula (IA), Formula (IIA), or Formula (IIIA), R 7d is hydrogen, deuterium, halo, or C optionally substituted with one or more substituents Q 1-6 In certain embodiments, in Formula (IA), Formula (IIA), or Formula (IIIA), R 7d is hydrogen, halo, or C optionally substituted with one or more substituents Q 1-6 In certain embodiments, in Formula (IA), Formula (IIA), or Formula (IIIA), R 7d is hydrogen. In certain embodiments, in Formula (IA), Formula (IIA), or Formula (IIIA), R 7d is deuterium. In certain embodiments, in Formula (IA), Formula (IIA), or Formula (IIIA), R 7d In certain embodiments, in Formula (IA), Formula (IIA), or Formula (IIIA), R 7d In certain embodiments, in Formula (IA), Formula (IIA), or Formula (IIIA), R 7d is C optionally substituted with one or more substituents Q 1-6 In certain embodiments, in Formula (IA), Formula (IIA), or Formula (IIIA), R 7d is methyl optionally substituted with one or more substituents Q. In certain embodiments, in Formula (IA), Formula (IIA), or Formula (IIIA), R 7d is trifluoromethyl.

[0092] In one embodiment, provided herein is a compound of formula (IVA): [ka] (In the formula, R E and L are each as defined herein. or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0093] In another embodiment, provided herein is a compound of formula (VA): [ka] (In the formula, R E and L are each as defined herein. or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0094] In some embodiments, R E is part of the cereblon (CRBN) E3 ligand, inhibitor of apoptosis protein (IAP) E3 ligand, mouse double minute 2 homolog (MDM2) E3 ligand, or von Hippel-Lindau (VHL) E3 ligand.

[0095] In some embodiments, R E is a portion of the CRBN E3 ligand.

[0096] In some embodiments, R E is represented by formula (EC-I): [ka] (In the formula, A E is a bond, -O-, -N(R 1b )-, -S-, C 1-6 Alkylene, C 1-6 Heteroalkylene, C 2-6 Alkenylene, C 2-6 Heteroalkenylene, C2-6 Alkynylene, C 2-6 Heteroalkynylene, C 3-10 Cycloalkylene, C 6-14 Arylene, C 7-15 Aralkylene, heteroarylene, heterocyclylene, C 1-6 Heteroalkylene-C 6-14 Arylene or C 2-6 alkynylene-heterocyclylene; Z is —CH— or —C(O)—; Z 1 , Z 2 , Z 3 , and Z 4 One of the groups is -C= and Z 1 , Z 2 , Z 3 , and Z 4 The remaining three of the groups are each independently -C(R E5 ) = or Z 1 is a bond, and Z 2 , Z 3 , and Z 4 One of the groups is -C= and Z 2 , Z 3 , and Z 4 The remaining two of the groups independently represent -C(R E5 ) = or -S-; m is an integer of 0, 1, or 2; R E1 is hydrogen, deuterium, halo, or C 1-6 is alkyl; R E2 is hydrogen or C 1-6 is alkyl; Each R E4 are independently (i) deuterium, cyano, halo, or nitro; (ii) C 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) —C(O)R 1a、-C(O)OR 1a 、-C(O)NR 1b R 1c 、-C(O)SR 1a 、-C(NR 1a )NR 1b R 1c 、-C(S)R 1a 、-C(S)OR 1a 、-C(S)NR 1b R 1c 、-OR 1a 、-OC(O)R 1a 、-OC(O)OR 1a 、-OC(O)NR 1b R 1c 、-OC(O)SR 1a 、-OC(NR 1a )NR 1b R 1c 、-OC(S)R 1a 、-OC(S)OR 1a 、-OC(S)NR 1b R 1c 、-OS(O)R 1a 、-OS(O)2R 1a 、-OS(O)NR 1b R 1c 、-OS(O)2NR 1b R 1c 、-NR 1b R 1c 、-NR 1a C(O)R 1d 、-NR 1a C(O)OR 1d 、-NR 1a C(O)NR 1b R 1c 、-NR 1a C(O)SR 1d 、-NR 1a C(NR 1d )NR 1b R 1c 、-NR 1a C(S)R 1d 、-NR 1a C(S)OR 1d 、-NR 1a C(S)NR 1b R 1c 、-NR 1a S(O)R 1d 、-NR 1a S(O)2R1d , -NR 1a S(O)NR 1b R 1c , -NR 1a S(O)NR 1b R 1c , -SR 1a , -S(O)R 1a , -S(O)2R 1a , -S(O)NR 1b R 1c , or -S(O)NR 1b R 1c and; Each R E5 are independently hydrogen or R E4 and R 1a , R 1b , R 1c , and R 1d are each as defined herein; wherein each alkyl, alkylene, heteroalkyl, heteroalkylene, alkenyl, alkenylene, heteroalkenylene, alkynyl, alkynylene, heteroalkynylene, cycloalkyl, cycloalkylene, aryl, arylene, aralkyl, aralkylene, heteroaryl, heteroarylene, heterocyclyl, and heterocyclylene is optionally substituted with one or more, and in one embodiment, one, two, three, or four, substituents Q. or an enantiomer, mixture of enantiomers, diastereomer, mixture of two or more diastereomers, tautomer, mixture of two or more tautomers, or isotopic variant thereof.

[0097] In some embodiments, R E is represented by formula (EC-II): [ka] wherein n is an integer of 0, 1, 2, or 3; and A E , R E1 , R E2 , R E4 , Z, and m are each as defined herein. or an enantiomer, mixture of enantiomers, diastereomer, mixture of two or more diastereomers, tautomer, mixture of two or more tautomers, or isotopic variant thereof.

[0098] In some embodiments, R E is represented by formula (EC-III): [ka] (In the formula, A E , R E1 , R E2 , R E5 , Z, and m are each as defined herein. or an enantiomer, mixture of enantiomers, diastereomer, mixture of two or more diastereomers, tautomer, mixture of two or more tautomers, or isotopic variant thereof. E5 is hydrogen or fluoro.

[0099] In some embodiments, R E is represented by formula (EC-IV): [ka] (In the formula, A E , R E1 , R E2 , R E5 , Z, and m are each as defined herein. or an enantiomer, mixture of enantiomers, diastereomer, mixture of two or more diastereomers, tautomer, mixture of two or more tautomers, or isotopic variant thereof. E5 is hydrogen or fluoro.

[0100] In some embodiments, R E is expressed by the formula (EC-V): [ka] (In the formula, A E , R E1 , R E2 , R E5 , Z, and m are each as defined herein. or an enantiomer, mixture of enantiomers, diastereomer, mixture of two or more diastereomers, tautomer, mixture of two or more tautomers, or isotopic variant thereof. E5 is hydrogen or fluoro.

[0101] In some embodiments, R E is represented by formula (EC-VI): [ka] (wherein n is an integer of 0 or 1; and A E , R E1 , R E2 , R E4 , Z, and m are each as defined herein. or an enantiomer, mixture of enantiomers, diastereomer, mixture of two or more diastereomers, tautomer, mixture of two or more tautomers, or isotopic variant thereof.

[0102] In some embodiments, R E is represented by formula (EC-VII): [ka] (In the formula, A E , R E1 , R E2 , R E5 , Z, and m are each as defined herein. or an enantiomer, mixture of enantiomers, diastereomer, mixture of two or more diastereomers, tautomer, mixture of two or more tautomers, or isotopic variant thereof. E5 is hydrogen or fluoro.

[0103] In some embodiments, R E is represented by formula (EC-VIII): [ka] (In the formula, A E , R E1 , R E2 , R E5 , Z, and m are each as defined herein. or an enantiomer, mixture of enantiomers, diastereomer, mixture of two or more diastereomers, tautomer, mixture of two or more tautomers, or isotopic variant thereof. E5 is hydrogen or fluoro.

[0104] In some embodiments, R E is expressed by the formula (EC-IX): [ka] (wherein n is an integer of 0 or 1; and A E , R E1 , R E2 , R E4 , Z, and m are each as defined herein. or an enantiomer, mixture of enantiomers, diastereomer, mixture of two or more diastereomers, tautomer, mixture of two or more tautomers, or isotopic variant thereof.

[0105] In some embodiments, R E is the formula (EC-X): [ka] (In the formula, A E , R E1 , R E2 , R E5 , Z, and m are each as defined herein. or an enantiomer, mixture of enantiomers, diastereomer, mixture of two or more diastereomers, tautomer, mixture of two or more tautomers, or isotopic variant thereof. E5 is hydrogen or fluoro.

[0106] In some embodiments, R E is the formula (EC-XI): [ka] (In the formula, A E , R E1 , R E2 , R E5 , Z, and m are each as defined herein. or an enantiomer, mixture of enantiomers, diastereomer, mixture of two or more diastereomers, tautomer, mixture of two or more tautomers, or isotopic variant thereof. E5 is hydrogen or fluoro.

[0107] In some embodiments, R E is represented by formula (EC-XII): [ka] (wherein n is an integer of 0 or 1; and A E , R E1 , R E2 , R E4 , Z, and m are each as defined herein. or an enantiomer, mixture of enantiomers, diastereomer, mixture of two or more diastereomers, tautomer, mixture of two or more tautomers, or isotopic variant thereof.

[0108] In some embodiments, R E is represented by formula (EC-XIII): [ka] (In the formula, A E , R E1 , R E2 , R E5 , Z, and m are each as defined herein. or an enantiomer, mixture of enantiomers, diastereomer, mixture of two or more diastereomers, tautomer, mixture of two or more tautomers, or isotopic variant thereof. E5 is hydrogen or fluoro.

[0109] In some embodiments, R E is represented by formula (EC-XIV): [ka] (In the formula, A E , R E1 , R E2 , R E5 , Z, and m are each as defined herein. or an enantiomer, mixture of enantiomers, diastereomer, mixture of two or more diastereomers, tautomer, mixture of two or more tautomers, or isotopic variant thereof. E5 is hydrogen or fluoro.

[0110] In some embodiments, R E is expressed by the formula (EC-XV): [ka] (In the formula, R E3 is optionally substituted with hydrogen, deuterium, halo, or one or more, in one embodiment one, two, three, or four, substituents Q; 1-6 alkyl; and A E , R E1 , R E2 , Z 1 , Z 2 , Z 3 , Z 4, and m are each as defined herein. or an enantiomer, mixture of enantiomers, diastereomer, mixture of two or more diastereomers, tautomer, mixture of two or more tautomers, or isotopic variant thereof.

[0111] In some embodiments, R E is represented by formula (EC-XVI): [ka] wherein n is an integer of 0, 1, 2, or 3; and A E , R E1 , R E2 , R E3 , R E4 , and m are each as defined herein. or an enantiomer, mixture of enantiomers, diastereomer, mixture of two or more diastereomers, tautomer, mixture of two or more tautomers, or isotopic variant thereof.

[0112] In some embodiments, R E is represented by formula (EC-XVII): [ka] (In the formula, A E , R E1 , R E2 , R E3 , R E5 , and m are each as defined herein. or an enantiomer, mixture of enantiomers, diastereomer, mixture of two or more diastereomers, tautomer, mixture of two or more tautomers, or isotopic variant thereof. E5 is hydrogen or fluoro.

[0113] In some embodiments, R E is represented by formula (EC-XVIII): [ka] (In the formula, A E , R E1 , R E2 , R E3 , R E5 , and m are each as defined herein. or an enantiomer, mixture of enantiomers, diastereomer, mixture of two or more diastereomers, tautomer, mixture of two or more tautomers, or isotopic variant thereof. E5 is hydrogen or fluoro.

[0114] In some embodiments, R E is expressed by the formula (EC-XIX): [ka] (wherein n is an integer of 0 or 1; and A E , R E1 , R E2 , R E3 , R E4 , and m are each as defined herein. or an enantiomer, mixture of enantiomers, diastereomer, mixture of two or more diastereomers, tautomer, mixture of two or more tautomers, or isotopic variant thereof.

[0115] In some embodiments, R E is the formula (EC-XX): [ka] (In the formula, A E , R E1 , R E2 , R E3 , R E5 , and m are each as defined herein. or an enantiomer, mixture of enantiomers, diastereomer, mixture of two or more diastereomers, tautomer, mixture of two or more tautomers, or isotopic variant thereof. E5 is hydrogen or fluoro.

[0116] In some embodiments, R E is the formula (EC-XXI): [ka] (In the formula, A E , R E1 , R E2 , R E3 , R E5 , and m are each as defined herein. or an enantiomer, mixture of enantiomers, diastereomer, mixture of two or more diastereomers, tautomer, mixture of two or more tautomers, or isotopic variant thereof. E5 is hydrogen or fluoro.

[0117] In some embodiments, R E is represented by formula (EC-XXII): [ka] (wherein n is an integer of 0 or 1; and A E , R E1 , R E2 , R E3 , R E4 , and m are each as defined herein. or an enantiomer, mixture of enantiomers, diastereomer, mixture of two or more diastereomers, tautomer, mixture of two or more tautomers, or isotopic variant thereof.

[0118] In some embodiments, R E is represented by formula (EC-XXIII): [ka] (In the formula, A E , R E1 , R E2 , R E3 , R E5 , and m are each as defined herein. or an enantiomer, mixture of enantiomers, diastereomer, mixture of two or more diastereomers, tautomer, mixture of two or more tautomers, or isotopic variant thereof. E5 is hydrogen or fluoro.

[0119] In some embodiments, R E is represented by formula (EC-XXIV): [ka] (In the formula, A E , R E1 , R E2 , R E3 , R E5 , and m are each as defined herein. or an enantiomer, mixture of enantiomers, diastereomer, mixture of two or more diastereomers, tautomer, mixture of two or more tautomers, or isotopic variant thereof. E5 is hydrogen or fluoro.

[0120] In some embodiments, R E is the formula (EC-XXV): [ka] (wherein n is an integer of 0 or 1; and A E , R E1 , R E2 , R E3 , R E4 , and m are each as defined herein. or an enantiomer, mixture of enantiomers, diastereomer, mixture of two or more diastereomers, tautomer, mixture of two or more tautomers, or isotopic variant thereof.

[0121] In some embodiments, R E is represented by formula (EC-XXVI): [ka] (In the formula, A E , R E1 , R E2 , R E3 , R E5 , and m are each as defined herein. or an enantiomer, mixture of enantiomers, diastereomer, mixture of two or more diastereomers, tautomer, mixture of two or more tautomers, or isotopic variant thereof. E5 is hydrogen or fluoro.

[0122] In some embodiments, R E is represented by formula (EC-XXVII): [ka] (In the formula, A E , R E1 , R E2 , R E3 , R E5 , and m are each as defined herein. or an enantiomer, mixture of enantiomers, diastereomer, mixture of two or more diastereomers, tautomer, mixture of two or more tautomers, or isotopic variant thereof. E5 is hydrogen or fluoro.

[0123] In some embodiments, R E is represented by formula (EC-XXVIII): [ka] (In the formula, R E6 is (i) hydrogen; (ii) C, each optionally substituted with one or more, in one embodiment, one, two, or three, substituents Q; 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) —C(O)R 1a , -C(O)OR 1a , -C(O)NR 1b R 1c , -C(O)SR 1a , -C(NR 1a )NR 1b R 1c , -C(S)R 1a , -C(S)OR 1a , -C(S)NR 1b R 1c , -OR 1a , -OC(O)R 1a , -OC(O)OR 1a , -OC(O)NR 1b R 1c , -OC(O)SR 1a , -OC(NR 1a )NR 1b R 1c , -OC(S)R 1a , -OC(S)OR 1a , -OC(S)NR 1b R 1c , -OS(O)R 1a , -OS(O)2R 1a , -OS(O)NR 1b R 1c , -OS(O)2NR 1b R 1c , -NR 1b R 1c , -NR 1a C(O)R 1d , -NR 1a C(O)OR 1d , -NR 1aC(O)NR 1b R 1c , -NR 1a C(O)SR 1d , -NR 1a C(NR 1d )NR 1b R 1c , -NR 1a C(S)R 1d , -NR 1a C(S)OR 1d , -NR 1a C(S)NR 1b R 1c , -NR 1a S(O)R 1d , -NR 1a S(O)2R 1d , -NR 1a S(O)NR 1b R 1c , -NR 1a S(O)NR 1b R 1c , -S(O)R 1a , -S(O)2R 1a , -S(O)NR 1b R 1c , or -S(O)NR 1b R 1c and; X E is C(R E1 ) or N; and A E , R E1 , R E2 , R E4 , m, and n are each as defined herein. or an enantiomer, mixture of enantiomers, diastereomer, mixture of two or more diastereomers, tautomer, mixture of two or more tautomers, or isotopic variant thereof.

[0124] In some embodiments, R E is the formula (EC-XXIX): [ka] (In the formula, A E , R E1 , R E2, R E4 , R E6 , m, and n are each as defined herein. or an enantiomer, mixture of enantiomers, diastereomer, mixture of two or more diastereomers, tautomer, mixture of two or more tautomers, or isotopic variant thereof.

[0125] In some embodiments, R E is the formula (EC-XXX): [ka] (In the formula, A E , R E1 , R E2 , R E4 , R E6 , m, and n are each as defined herein. A moiety having the structure

[0126] or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof.

[0127] In some embodiments, R E is represented by formula (EC-XXXI): [ka] (In the formula, A E , R E1 , R E2 , R E4 , R E6 , m, and n are each as defined herein. or an enantiomer, mixture of enantiomers, diastereomer, mixture of two or more diastereomers, tautomer, mixture of two or more tautomers, or isotopic variant thereof.

[0128] In some embodiments, R E is represented by formula (EC-XXXII): [ka] (In the formula, A E , R E2 , R E4 , R E6 , m, and n are each as defined herein. or an enantiomer, mixture of enantiomers, diastereomer, mixture of two or more diastereomers, tautomer, mixture of two or more tautomers, or isotopic variant thereof.

[0129] In some embodiments, R E is represented by formula (EC-XXXIII): [ka] (In the formula, A E , R E2 , R E4 , R E6 , m, and n are each as defined herein. or an enantiomer, mixture of enantiomers, diastereomer, mixture of two or more diastereomers, tautomer, mixture of two or more tautomers, or isotopic variant thereof.

[0130] In some embodiments, R E is represented by formula (EC-XXXIV): [ka] (In the formula, A E , R E2 , R E4 , R E6 , m, and n are each as defined herein. or an enantiomer, mixture of enantiomers, diastereomer, mixture of two or more diastereomers, tautomer, mixture of two or more tautomers, or isotopic variant thereof.

[0131] In some embodiments, R E is the formula (EC-XXXV): [ka] (In the formula, Y E is a bond, C 1-6 Alkylene, -O-, -S-, -S(O)-, -S(O2)-, or -N(R E7 )-and; R E7 is hydrogen or C 1-6 is alkyl; and A E , R E2 , R E4 , X E , m, and n are each as defined herein. or an enantiomer, mixture of enantiomers, diastereomer, mixture of two or more diastereomers, tautomer, mixture of two or more tautomers, or isotopic variant thereof.

[0132] In some embodiments, R E is represented by formula (EC-XXXVI): [ka] (In the formula, A E , R E2 , R E4 , X E , m, and n are each as defined herein. or an enantiomer, mixture of enantiomers, diastereomer, mixture of two or more diastereomers, tautomer, mixture of two or more tautomers, or isotopic variant thereof.

[0133] In some embodiments, R E is represented by formula (EC-XXXVII): [ka] (In the formula, A E , R E1, R E2 , R E4 , m, and n are each as defined herein. or an enantiomer, mixture of enantiomers, diastereomer, mixture of two or more diastereomers, tautomer, mixture of two or more tautomers, or isotopic variant thereof.

[0134] In some embodiments, R E is represented by formula (EC-XXXVIII): [ka] (In the formula, A E , R E1 , R E2 , R E4 , m, and n are each as defined herein. or an enantiomer, mixture of enantiomers, diastereomer, mixture of two or more diastereomers, tautomer, mixture of two or more tautomers, or isotopic variant thereof.

[0135] In some embodiments, R E is represented by formula (EC-XXXIX): [ka] (In the formula, A E , R E1 , R E2 , R E4 , m, and n are each as defined herein. or an enantiomer, mixture of enantiomers, diastereomer, mixture of two or more diastereomers, tautomer, mixture of two or more tautomers, or isotopic variant thereof.

[0136] In some embodiments, R E is the formula (EC-XL): [ka] (In the formula, A E , R E2 , R E4 , m, and n are each as defined herein. or an enantiomer, mixture of enantiomers, diastereomer, mixture of two or more diastereomers, tautomer, mixture of two or more tautomers, or isotopic variant thereof.

[0137] In some embodiments, R E is the formula (EC-XLI): [ka] (In the formula, A E , R E2 , R E4 , m, and n are each as defined herein. or an enantiomer, mixture of enantiomers, diastereomer, mixture of two or more diastereomers, tautomer, mixture of two or more tautomers, or isotopic variant thereof.

[0138] In some embodiments, R E is represented by formula (EC-XLII): [ka] (In the formula, A E , R E2 , R E4 , m, and n are each as defined herein. or an enantiomer, mixture of enantiomers, diastereomer, mixture of two or more diastereomers, tautomer, mixture of two or more tautomers, or isotopic variant thereof.

[0139] In some embodiments, R E is represented by formula (EC-XLIII): [ka] (In the formula, AE , R E1 , R E2 , R E4 , R E7 , m, and n are each as defined herein. or an enantiomer, mixture of enantiomers, diastereomer, mixture of two or more diastereomers, tautomer, mixture of two or more tautomers, or isotopic variant thereof.

[0140] In some embodiments, R E is represented by formula (EC-XLIV): [ka] (In the formula, A E , R E1 , R E2 , R E4 , R E7 , m, and n are each as defined herein. or an enantiomer, mixture of enantiomers, diastereomer, mixture of two or more diastereomers, tautomer, mixture of two or more tautomers, or isotopic variant thereof.

[0141] In some embodiments, R E is the formula (EC-XLV): [ka] (In the formula, A E , R E1 , R E2 , R E4 , R E7 , m, and n are each as defined herein. or an enantiomer, mixture of enantiomers, diastereomer, mixture of two or more diastereomers, tautomer, mixture of two or more tautomers, or isotopic variant thereof.

[0142] In some embodiments, R Eis a portion of an E3 ubiquitin ligase binding agent disclosed in US 9,938,302 B2; US 10,336,771 B2; US 10,406,165 B2; US 10,513,515 B2; US 2019 / 0322682 A1; US ​​2020 / 0000814 A1; US ​​2020 / 0148663 A1; US ​​2020 / 0369679 A1; and WO 2019 / 173224 A1, the disclosures of each of which are incorporated herein by reference in their entireties. In certain embodiments, R E is a moiety among the E3 ubiquitin ligase binders disclosed in U.S. Pat. No. 9,938,302 B2, the entirety of which is incorporated herein by reference, and in one embodiment, is a moiety among compounds 1-57 disclosed therein in columns 108-137. In certain embodiments, R E is a moiety of an E3 ubiquitin ligase binder disclosed in US 10,336,771 B2, which is incorporated herein by reference in its entirety, and in one embodiment is a moiety of one of compounds 1-57 and 64-66 disclosed therein in columns 113-161 and 169-172. E is a moiety of an E3 ubiquitin ligase binder disclosed in U.S. Pat. No. 10,406,165 B2, the entirety of which is incorporated herein by reference, and in one embodiment is a moiety of one of compounds 1-27 disclosed therein in columns 40-64. In certain embodiments, R E is a moiety of an E3 ubiquitin ligase binder disclosed in U.S. Pat. No. 10,513,515 B2, which is incorporated herein by reference in its entirety, and in one embodiment is a moiety of one of compounds 1-5, 7-12, 14-16, 19, 23, and 27 disclosed therein in columns 97-104, 106-112, 114-117, 122, 126, and 132. In certain embodiments, R Eis a moiety of an E3 ubiquitin ligase binder disclosed in US 2019 / 0322682 A1, which is incorporated herein by reference in its entirety, and in one embodiment, is a moiety of one of compounds 1-15 disclosed therein on pages 31-36. In certain embodiments, R E is a moiety of an E3 ubiquitin ligase binder disclosed in US 2020 / 0000814 A1, which is incorporated herein by reference in its entirety, and in one embodiment, is a moiety of one of compounds 1-21 disclosed therein on pages 26-41. In certain embodiments, R E is a moiety of an E3 ubiquitin ligase binder disclosed in US 2020 / 0148663 A1, which is incorporated herein by reference in its entirety, and in one embodiment, is a moiety of one of compounds 1-21 disclosed therein on pages 18-34. In certain embodiments, R E is a moiety of an E3 ubiquitin ligase binder disclosed in US 2020 / 0369679 A1, which is incorporated herein by reference in its entirety, and in one embodiment is a moiety of one of compounds I-1 to I-106 and II-1 to II-164 disclosed therein on pages 50 to 101. In certain embodiments, R E is a moiety of an E3 ubiquitin ligase binder disclosed in WO 2019 / 173224 A1, the entirety of which is incorporated herein by reference, and in one embodiment is a moiety of compounds 1-3 disclosed on pages 62-65 thereof and one of the compounds disclosed on page 78 thereof.

[0143] In some embodiments, R E is a portion of an E3 ubiquitin ligase binding agent disclosed in US 2020 / 0199073 A1, the disclosure of which is incorporated herein by reference in its entirety. In certain embodiments, R Eis a portion of an E3 ubiquitin ligase binder disclosed in U.S. Patent Application No. US 2020 / 0199073 A1, which is incorporated herein by reference in its entirety, and in one embodiment is a portion of one of compounds 1-291 disclosed therein on pages 118-193.

[0144] In one embodiment, in any one of Formulas (EC-I) to (EC-XXVII), A E is a bond, -O-, -N(R 1b )-, C 2-6 Alkynylene, heterocyclylene, C 1-6 Heteroalkylene-C 6-14 Arylene or C 2-6 alkynylene-heterocyclylene, where each heteroalkylene, alkynylene, arylene, and heterocyclylene is optionally substituted with one or more, and in one embodiment one, two, three, or four, substituents Q; Z, if present, is —CH— or —C(O)—; m is an integer of 0, 1, or 2; R E1 and R E2 are each hydrogen; and R E5 When present, is independently hydrogen or fluoro.

[0145] In one embodiment, in any one of Formulas (EC-I) to (EC-XXVII), A E is a bond, —O—, —NH—, ethynediyl, piperidinediyl, piperazinediyl, (phendiyl)oxymethanediyl, or (piperidinediyl)ethynediyl; Z, if present, is —CH— or —C(O)—; m is an integer of 0, 1, or 2; R E1 and R E2 are each hydrogen; and R E5When present, is independently hydrogen or fluoro.

[0146] In one embodiment, in any one of Formulas (EC-I) to (EC-XXVII), A E is a bond, —NH—, piperidine-1,3-diyl, piperidine-1,4-diyl, piperaz-1,4-diyl, (phen-1,4-diyl)oxymethanediyl, or (piperidine-1,4-diyl)ethynediyl; Z, if present, is —CH— or —C(O)—; m is an integer of 0, 1, or 2; R E1 and R E2 are each hydrogen; and R E5 When present, is independently hydrogen or fluoro.

[0147] In one embodiment, in a compound of any one of Formulas (I) to (VIII) and Formulas (IA) to (VA), R E is a moiety having the structure of Formula (EC-I), or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof. In another embodiment, in a compound of any one of Formulas (I) through (VIII) and Formulas (IA) through (VA), R E is a moiety having the structure of Formula (EC-II), or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof. In yet another embodiment, in a compound of any one of Formulas (I) through (VIII) and Formulas (IA) through (VA), R Eis a moiety having the structure of Formula (EC-III), or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof. In yet another embodiment, in a compound of any one of Formulas (I) through (VIII) and Formulas (IA) through (VA), R E is a moiety having the structure of Formula (EC-IV), or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof. In yet another embodiment, in a compound of any one of Formulas (I) through (VIII) and Formulas (IA) through (VA), R E is a moiety having the structure of Formula (EC-V), or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof. In yet another embodiment, in a compound of any one of Formulas (I) through (VIII) and Formulas (IA) through (VA), R E is a moiety having the structure of Formula (EC-VI), or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof. In yet another embodiment, in a compound of any one of Formulas (I) through (VIII) and Formulas (IA) through (VA), R E is a moiety having the structure of Formula (EC-VII), or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof. In yet another embodiment, in a compound of any one of Formulas (I) through (VIII) and Formulas (IA) through (VA), R Eis a moiety having the structure of Formula (EC-VIII), or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof. In yet another embodiment, in a compound of any one of Formulas (I) through (VIII) and Formulas (IA) through (VA), R E is a moiety having the structure of Formula (EC-IX), or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof. In yet another embodiment, in a compound of any one of Formulas (I) through (VIII) and Formulas (IA) through (VA), R E is a moiety having the structure of formula (EC-X), or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof. In yet another embodiment, in a compound of any one of Formulas (I) through (VIII) and Formulas (IA) through (VA), R E is a moiety having the structure of Formula (EC-XI), or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof. In yet another embodiment, in a compound of any one of Formulas (I) through (VIII) and Formulas (IA) through (VA), R E is a moiety having the structure of Formula (EC-XII), or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof. In yet another embodiment, in a compound of any one of Formulas (I) through (VIII) and Formulas (IA) through (VA), R Eis a moiety having the structure of Formula (EC-XIII), or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof. In yet another embodiment, in a compound of any one of Formulas (I) through (VIII) and Formulas (IA) through (VA), R E is a moiety having the structure of formula (EC-XIV), or an enantiomer, mixture of enantiomers, diastereomer, mixture of two or more diastereomers, tautomer, mixture of two or more tautomers, or isotopic variant thereof.

[0148] In one embodiment, in a compound of any one of Formulas (I) to (VIII) and Formulas (IA) to (VA), R E is a moiety having the structure of Formula (EC-XV), or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof. In another embodiment, in a compound of any one of Formulas (I) through (VIII) and Formulas (IA) through (VA), R E is a moiety having the structure of Formula (EC-XVI), or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof. In yet another embodiment, in a compound of any one of Formulas (I) through (VIII) and Formulas (IA) through (VA), R E is a moiety having the structure of Formula (EC-XVII), or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof. In yet another embodiment, in a compound of any one of Formulas (I) through (VIII) and Formulas (IA) through (VA), R Eis a moiety having the structure of Formula (EC-XVIII), or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof. In yet another embodiment, in a compound of any one of Formulas (I) through (VIII) and Formulas (IA) through (VA), R E is a moiety having the structure of Formula (EC-XIX), or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof. In yet another embodiment, in a compound of any one of Formulas (I) through (VIII) and Formulas (IA) through (VA), R E is a moiety having the structure of Formula (EC-XX), or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof. In yet another embodiment, in a compound of any one of Formulas (I) through (VIII) and Formulas (IA) through (VA), R E is a moiety having the structure of formula (EC-XXI), or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof. In yet another embodiment, in a compound of any one of Formulas (I) through (VIII) and Formulas (IA) through (VA), R E is a moiety having the structure of Formula (EC-XXII), or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof. In yet another embodiment, in a compound of any one of Formulas (I) through (VIII) and Formulas (IA) through (VA), R Eis a moiety having the structure of Formula (EC-XXIII), or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof. In yet another embodiment, in a compound of any one of Formulas (I) through (VIII) and Formulas (IA) through (VA), R E is a moiety having the structure of formula (EC-XXIV), or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof. In yet another embodiment, in a compound of any one of Formulas (I) through (VIII) and Formulas (IA) through (VA), R E is a moiety having the structure of Formula (EC-XXV), or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof. In yet another embodiment, in a compound of any one of Formulas (I) through (VIII) and Formulas (IA) through (VA), R E is a moiety having the structure of Formula (EC-XXVI), or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof. In yet another embodiment, in a compound of any one of Formulas (I) through (VIII) and Formulas (IA) through (VA), R E is a moiety having the structure of formula (EC-XXVII), or an enantiomer, mixture of enantiomers, diastereomer, mixture of two or more diastereomers, tautomer, mixture of two or more tautomers, or isotopic variant thereof.

[0149] In one embodiment, in a compound of any one of Formulas (I) to (VIII) and Formulas (IA) to (VA), R Eis a moiety having the structure of Formula (EC-XXVIII), or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof. In another embodiment, in a compound of any one of Formulas (I) through (VIII) and Formulas (IA) through (VA), R E is a moiety having the structure of formula (EC-XXIX), or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof. In yet another embodiment, in a compound of any one of Formulas (I) through (VIII) and Formulas (IA) through (VA), R E is a moiety having the structure of formula (EC-XXX), or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof. In yet another embodiment, in a compound of any one of Formulas (I) through (VIII) and Formulas (IA) through (VA), R E is a moiety having the structure of Formula (EC-XXXI), or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof. In yet another embodiment, in a compound of any one of Formulas (I) through (VIII) and Formulas (IA) through (VA), R E is a moiety having the structure of Formula (EC-XXXII), or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof. In yet another embodiment, in a compound of any one of Formulas (I) through (VIII) and Formulas (IA) through (VA), R Eis a moiety having the structure of Formula (EC-XXXIII), or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof. In yet another embodiment, in a compound of any one of Formulas (I) through (VIII) and Formulas (IA) through (VA), R E is a moiety having the structure of formula (EC-XXXIV), or an enantiomer, mixture of enantiomers, diastereomer, mixture of two or more diastereomers, tautomer, mixture of two or more tautomers, or isotopic variant thereof.

[0150] In one embodiment, in a compound of any one of Formulas (I) to (VIII) and Formulas (IA) to (VA), R E is a moiety having the structure of Formula (EC-XXXV), or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof. In another embodiment, in a compound of any one of Formulas (I) through (VIII) and (IA) through (VA), R E is a moiety having the structure of Formula (EC-XXXVI), or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof. In yet another embodiment, in a compound of any one of Formulas (I) through (VIII) and Formulas (IA) through (VA), R E is a moiety having the structure of Formula (EC-XXXVII), or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof. In yet another embodiment, in a compound of any one of Formulas (I) through (VIII) and Formulas (IA) through (VA), R Eis a moiety having the structure of Formula (EC-XXXVIII), or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof. In yet another embodiment, in a compound of any one of Formulas (I) through (VIII) and Formulas (IA) through (VA), R E is a moiety having the structure of Formula (EC-XXXIX), or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof. In yet another embodiment, in a compound of any one of Formulas (I) through (VIII) and Formulas (IA) through (VA), R E is a moiety having the structure of formula (EC-XL), or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof. In yet another embodiment, in a compound of any one of Formulas (I) through (VIII) and Formulas (IA) through (VA), R E is a moiety having the structure of Formula (EC-XLI), or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof. In yet another embodiment, in a compound of any one of Formulas (I) through (VIII) and Formulas (IA) through (VA), R E is a moiety having the structure of Formula (EC-XLII), or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof. In yet another embodiment, in a compound of any one of Formulas (I) through (VIII) and Formulas (IA) through (VA), R Eis a moiety having the structure of Formula (EC-XLIII), or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof. In yet another embodiment, in a compound of any one of Formulas (I) through (VIII) and Formulas (IA) through (VA), R E is a moiety having the structure of Formula (EC-XLIV), or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof. In yet another embodiment, in a compound of any one of Formulas (I) through (VIII) and Formulas (IA) through (VA), R E is a moiety having the structure of formula (EC-XLV), or an enantiomer, mixture of enantiomers, diastereomer, mixture of two or more diastereomers, tautomer, mixture of two or more tautomers, or isotopic variant thereof.

[0151] In some embodiments, R E teeth: [ka] (In the formula, A E is as defined herein) or an enantiomer, mixture of enantiomers, diastereomer, mixture of two or more diastereomers, tautomer, mixture of two or more tautomers, or isotopic variant thereof.

[0152] In one embodiment, in any one of Formulas EC-1 to EC-6, A E is a bond, -O-, -NH-, ethynediyl, piperidinediyl, piperazinediyl, (phendiyl)oxymethanediyl, or (piperidinediyl)-ethynediyl. E is a bond. In still another embodiment, in any one of Formulas EC-1 to EC-6, AE is —O—. In still another embodiment, in any one of Formulas EC-1 to EC-6, A E In still another embodiment, in any one of Formulas EC-1 to EC-6, A E is ethynediyl. In still another embodiment, in any one of Formulas EC-1 to EC-6, A E is piperidinediyl. In still another embodiment, in any one of Formulas EC-1 to EC-6, A E is piperazinediyl. In still another embodiment, in any one of Formulas EC-1 to EC-6, A E is (phendiyl)oxymethanediyl. In still another embodiment, in any one of Formulas EC-1 to EC-6, A E is (piperidinediyl)ethynediyl.

[0153] In one embodiment, in any one of Formulas EC-1 to EC-6, A E is a bond, -O-, -NH-, ethynediyl, piperidine-1,3-diyl, piperidine-1,4-diyl, piperazine-1,4-diyl, (phen-1,4-diyl)-oxymethanediyl, or (piperidine-1,4-diyl)ethynediyl. E is piperidine-1,3-diyl. In still another embodiment, in any one of Formulas EC-1 to EC-6, A E is piperidine-1,4-diyl. In still another embodiment, in any one of Formulas EC-1 to EC-6, A E is piperazine-1,4-diyl. In still another embodiment, in any one of Formulas EC-1 to EC-6, A E is (phen-1,4-diyl)oxymethanediyl. In still another embodiment, in any one of Formulas EC-1 to EC-6, A Eis (piperidine-1,4-diyl)ethynediyl. In still another embodiment, in any one of Formulas EC-1 to EC-6, A E is 1-(piperidine-1,4-diyl)ethynediyl.

[0154] In one embodiment, in a compound of any one of Formulas (I) to (VIII) and Formulas (IA) to (VA), R E is a moiety having the structure of Formula EC-1, or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof. In another embodiment, in a compound of any one of Formulas (I) through (VIII) and Formulas (IA) through (VA), R E is a moiety having the structure of formula EC-2, or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof. In yet another embodiment, in a compound of any one of Formulas (I) through (VIII) and Formulas (IA) through (VA), R E is a moiety having the structure of formula EC-3, or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof. In yet another embodiment, in a compound of any one of Formulas (I) through (VIII) and Formulas (IA) through (VA), R E is a moiety having the structure of formula EC-4, or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof. In yet another embodiment, in a compound of any one of Formulas (I) through (VIII) and Formulas (IA) through (VA), R Eis a moiety having the structure of formula EC-5, or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof. In yet another embodiment, in a compound of any one of Formulas (I) through (VIII) and Formulas (IA) through (VA), R E is a moiety having the structure of formula EC-6, or an enantiomer, mixture of enantiomers, diastereomer, mixture of two or more diastereomers, tautomer, mixture of two or more tautomers, or isotopic variant thereof.

[0155] In some embodiments, R E teeth: [ka] TIFF2024500377000064.tif87170, or an enantiomer, mixture of enantiomers, tautomer, mixture of two or more tautomers, or isotopic variant thereof.

[0156] In one embodiment, in a compound of any one of Formulas (I) to (VIII) and Formulas (IA) to (VA), R E is a moiety having the structure of formula EC-7, or an enantiomer, mixture of enantiomers, tautomer, mixture of two or more tautomers, or isotopic variant thereof. In another embodiment, in a compound of any one of Formulas (I) through (VIII) and Formulas (IA) through (VA), R E is a moiety having the structure of formula EC-8, or an enantiomer, mixture of enantiomers, tautomer, mixture of two or more tautomers, or isotopic variant thereof. In yet another embodiment, in a compound of any one of Formulas (I) through (VIII) and Formulas (IA) through (VA), R Eis a moiety having the structure of formula EC-9, or an enantiomer, mixture of enantiomers, tautomer, mixture of two or more tautomers, or isotopic variant thereof. In yet another embodiment, in a compound of any one of Formulas (I) through (VIII) and Formulas (IA) through (VA), R E is a moiety having the structure of formula EC-10, or an enantiomer, mixture of enantiomers, tautomer, mixture of two or more tautomers, or isotopic variant thereof. In yet another embodiment, in a compound of any one of Formulas (I) through (VIII) and Formulas (IA) through (VA), R E is a moiety having the structure of formula EC-11, or an enantiomer, mixture of enantiomers, tautomer, mixture of two or more tautomers, or isotopic variant thereof. In yet another embodiment, in a compound of any one of Formulas (I) through (VIII) and Formulas (IA) through (VA), R E is a moiety having the structure of formula EC-12, or an enantiomer, mixture of enantiomers, tautomer, mixture of two or more tautomers, or isotopic variant thereof. In yet another embodiment, in a compound of any one of Formulas (I) through (VIII) and Formulas (IA) through (VA), R E is a moiety having the structure of formula EC-13, or an enantiomer, mixture of enantiomers, tautomer, mixture of two or more tautomers, or isotopic variant thereof. In yet another embodiment, in a compound of any one of Formulas (I) through (VIII) and Formulas (IA) through (VA), R E is a moiety having the structure of formula EC-14, or an enantiomer, mixture of enantiomers, tautomer, mixture of two or more tautomers, or isotopic variant thereof. In yet another embodiment, in a compound of any one of Formulas (I) through (VIII) and Formulas (IA) through (VA), R E is a moiety having the structure of formula EC-15, or an enantiomer, mixture of enantiomers, tautomer, mixture of two or more tautomers, or isotopic variant thereof. In yet another embodiment, in a compound of any one of Formulas (I) through (VIII) and Formulas (IA) through (VA), RE is a moiety having the structure of formula EC-16, or an enantiomer, mixture of enantiomers, tautomer, mixture of two or more tautomers, or isotopic variant thereof. In yet another embodiment, in a compound of any one of Formulas (I) through (VIII) and Formulas (IA) through (VA), R E is a moiety having the structure of formula EC-17, or an enantiomer, mixture of enantiomers, tautomer, mixture of two or more tautomers, or isotopic variant thereof. In yet another embodiment, in a compound of any one of Formulas (I) through (VIII) and Formulas (IA) through (VA), R E is a moiety having the structure of formula EC-18, or an enantiomer, mixture of enantiomers, tautomer, mixture of two or more tautomers, or isotopic variant thereof. In yet another embodiment, in a compound of any one of Formulas (I) through (VIII) and Formulas (IA) through (VA), R E is a moiety having the structure of formula EC-19, or an enantiomer, mixture of enantiomers, tautomer, mixture of two or more tautomers, or isotopic variant thereof. In yet another embodiment, in a compound of any one of Formulas (I) through (VIII) and Formulas (IA) through (VA), R E is a moiety having the structure of formula EC-20, or an enantiomer, mixture of enantiomers, tautomer, mixture of two or more tautomers, or isotopic variant thereof. In yet another embodiment, in a compound of any one of Formulas (I) through (VIII) and Formulas (IA) through (VA), R E is a moiety having the structure of formula EC-21, or an enantiomer, mixture of enantiomers, tautomer, mixture of two or more tautomers, or isotopic variant thereof.

[0157] In some embodiments, R E teeth: [ka] (In the formula, A E is as defined herein) or an enantiomer, mixture of enantiomers, diastereomer, mixture of two or more diastereomers, tautomer, mixture of two or more tautomers, or isotopic variant thereof.

[0158] In one embodiment, in Formula EC-22 or Formula EC-23, A E is a bond, -O-, -NH-, ethynediyl, piperidinediyl, piperazinediyl, (phendiyl)oxymethanediyl, or (piperidinediyl)ethynediyl. E is a bond. In yet another embodiment, in Formula EC-22 or Formula EC-23, A E is —O—. In yet another embodiment, in Formula EC-22 or Formula EC-23, A E In yet another embodiment, in Formula EC-22 or Formula EC-23, A E is ethynediyl. In yet another embodiment, in Formula EC-22 or Formula EC-23, A E is piperidinediyl. In yet another embodiment, in Formula EC-22 or Formula EC-23, A E is piperazinediyl. In yet another embodiment, in Formula EC-22 or Formula EC-23, A E is (phendiyl)oxymethanediyl. In yet another embodiment, in Formula EC-22 or Formula EC-23, A E is (piperidinediyl)ethynyl.

[0159] In one embodiment, in Formula EC-22 or Formula EC-23, A E is a bond, -O-, -NH-, ethynediyl, piperidine-1,3-diyl, piperidine-1,4-diyl, piperazine-1,4-diyl, (phen-1,4-diyl)oxy-methanediyl, or (piperidine-1,4-diyl)ethynediyl. Eis piperidine-1,3-diyl. In yet another embodiment, in Formula EC-22 or Formula EC-23, A E is piperidine-1,4-diyl. In yet another embodiment, in Formula EC-22 or Formula EC-23, A E is piperazine-1,4-diyl. In yet another embodiment, in Formula EC-22 or Formula EC-23, A E is (phen-1,4-diyl)oxy-methanediyl. In yet another embodiment, in Formula EC-22 or Formula EC-23, A E is (piperidine-1,4-diyl)ethynediyl.

[0160] In one embodiment, in a compound of any one of Formulas (I) to (VIII) and Formulas (IA) to (VA), R E is a moiety having the structure of formula EC-22, or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof. In another embodiment, in a compound of any one of Formulas (I) through (VIII) and Formulas (IA) through (VA), R E is a moiety having the structure of formula EC-23, or an enantiomer, mixture of enantiomers, diastereomer, mixture of two or more diastereomers, tautomer, mixture of two or more tautomers, or isotopic variant thereof.

[0161] In some embodiments, R E teeth: [ka] or an enantiomer, mixture of enantiomers, tautomer, mixture of two or more tautomers, or isotopic variant thereof.

[0162] In one embodiment, in a compound of any one of Formulas (I) to (VIII) and Formulas (IA) to (VA), R Eis a moiety having the structure of formula EC-24, or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof. In another embodiment, in a compound of any one of Formulas (I) through (VIII) and Formulas (IA) through (VA), R E is a moiety having the structure of formula EC-25, or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof. In yet another embodiment, in a compound of any one of Formulas (I) through (VIII) and Formulas (IA) through (VA), R E is a moiety having the structure of formula EC-26, or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof. In yet another embodiment, in a compound of any one of Formulas (I) through (VIII) and Formulas (IA) through (VA), R E is a moiety having the structure of formula EC-27, or an enantiomer, mixture of enantiomers, diastereomer, mixture of two or more diastereomers, tautomer, mixture of two or more tautomers, or isotopic variant thereof.

[0163] In some embodiments, R E teeth: [ka] (In the formula, A E is as defined herein) or an enantiomer, mixture of enantiomers, tautomer, mixture of two or more tautomers, or isotopic variant thereof.

[0164] In one embodiment, in a compound of any one of Formulas (I) to (VIII) and Formulas (IA) to (VA), R Eis a moiety having the structure of formula EC-28, or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof. In another embodiment, in a compound of any one of Formulas (I) through (VIII) and Formulas (IA) through (VA), R E is a moiety having the structure of formula EC-29, or an enantiomer, mixture of enantiomers, diastereomer, mixture of two or more diastereomers, tautomer, mixture of two or more tautomers, or isotopic variant thereof.

[0165] In some embodiments, R E teeth: [ka] or an enantiomer, mixture of enantiomers, tautomer, mixture of two or more tautomers, or isotopic variant thereof.

[0166] In one embodiment, in a compound of any one of Formulas (I) to (VIII) and Formulas (IA) to (VA), R E is a moiety having the structure of formula EC-30, or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof. In another embodiment, in a compound of any one of Formulas (I) through (VIII) and Formulas (IA) through (VA), R E is a moiety having the structure of formula EC-31, or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof. In yet another embodiment, in a compound of any one of Formulas (I) through (VIII) and Formulas (IA) through (VA), R Eis a moiety having the structure of formula EC-32, or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof. In yet another embodiment, in a compound of any one of Formulas (I) through (VIII) and Formulas (IA) through (VA), R E is a moiety having the structure of formula EC-33, or an enantiomer, mixture of enantiomers, diastereomer, mixture of two or more diastereomers, tautomer, mixture of two or more tautomers, or isotopic variant thereof.

[0167] In some embodiments, R E teeth: [ka] (In the formula, A E is as defined herein) or an enantiomer, mixture of enantiomers, tautomer, mixture of two or more tautomers, or isotopic variant thereof.

[0168] In one embodiment, in a compound of any one of Formulas (I) to (VIII) and Formulas (IA) to (VA), R E is a moiety having the structure of formula EC-34, or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof. In another embodiment, in a compound of any one of Formulas (I) through (VIII) and Formulas (IA) through (VA), R E is a moiety having the structure of formula EC-35, or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof. In yet another embodiment, in a compound of any one of Formulas (I) through (VIII) and Formulas (IA) through (VA), R Eis a moiety having the structure of formula EC-36, or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof. In yet another embodiment, in a compound of any one of Formulas (I) through (VIII) and Formulas (IA) through (VA), R E is a moiety having the structure of formula EC-37, or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof. In yet another embodiment, in a compound of any one of Formulas (I) through (VIII) and Formulas (IA) through (VA), R E is a moiety having the structure of formula EC-38, or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof. In yet another embodiment, in a compound of any one of Formulas (I) through (VIII) and Formulas (IA) through (VA), R E is a moiety having the structure of formula EC-39, or an enantiomer, mixture of enantiomers, diastereomer, mixture of two or more diastereomers, tautomer, mixture of two or more tautomers, or isotopic variant thereof.

[0169] In some embodiments, R E teeth: [ka] or an enantiomer, mixture of enantiomers, tautomer, mixture of two or more tautomers, or isotopic variant thereof.

[0170] In one embodiment, in a compound of any one of Formulas (I) to (VIII) and Formulas (IA) to (VA), R Eis a moiety having the structure of formula EC-40, or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof. In another embodiment, in a compound of any one of Formulas (I) through (VIII) and Formulas (IA) through (VA), R E is a moiety having the structure of formula EC-41, or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof. In yet another embodiment, in a compound of any one of Formulas (I) through (VIII) and Formulas (IA) through (VA), R E is a moiety having the structure of formula EC-42, or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof. In yet another embodiment, in a compound of any one of Formulas (I) through (VIII) and Formulas (IA) through (VA), R E is a moiety having the structure of formula EC-43, or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof. In yet another embodiment, in a compound of any one of Formulas (I) through (VIII) and Formulas (IA) through (VA), R E is a moiety having the structure of formula EC-44, or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof. In yet another embodiment, in a compound of any one of Formulas (I) through (VIII) and Formulas (IA) through (VA), R Eis a moiety having the structure of formula EC-45, or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof. In yet another embodiment, in a compound of any one of Formulas (I) through (VIII) and Formulas (IA) through (VA), R E is a moiety having the structure of formula EC-46, or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof. In yet another embodiment, in a compound of any one of Formulas (I) through (VIII) and Formulas (IA) through (VA), R E is a moiety having the structure of formula EC-47, or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof. In yet another embodiment, in a compound of any one of Formulas (I) through (VIII) and Formulas (IA) through (VA), R E is a moiety having the structure of formula EC-48, or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof. In yet another embodiment, in a compound of any one of Formulas (I) through (VIII) and Formulas (IA) through (VA), R E is a moiety having the structure of formula EC-48, or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof. In yet another embodiment, in a compound of any one of Formulas (I) through (VIII) and Formulas (IA) through (VA), R Eis a moiety having the structure of formula EC-50, or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof. In yet another embodiment, in a compound of any one of Formulas (I) through (VIII) and Formulas (IA) through (VA), R E is a moiety having the structure of formula EC-51, or an enantiomer, mixture of enantiomers, diastereomer, mixture of two or more diastereomers, tautomer, mixture of two or more tautomers, or isotopic variant thereof.

[0171] In one embodiment, provided herein is a compound of formula (IX): [ka] (In the formula, R 1 , R 2 , R 3a , R 3b , R 3c , R 3d , R 3e , R 4a , R E1 , R E2 , A E , L, X, Y, Z, Z 1 , Z 2 , Z 3 , Z 4 , a, and m are each as defined herein. or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0172] In another embodiment, provided herein is a compound of formula (X): [ka] (In the formula, R 1 , R 2 , R 3a , R3b , R 3c , R 3d , R 3e , R 4a , R E1 , R E2 , A E , L, X, Z, and a are each as defined herein. or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0173] In yet another embodiment, provided herein is a compound of formula (XI): [ka] (In the formula, R 1 , R 3b , R 3c , A E , and L are each as defined herein. or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0174] In yet another embodiment, provided herein is a compound of formula (XII): [ka] (In the formula, R 1 , R 3b , R 3c , A E , and L are each as defined herein. or a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0175] In yet another embodiment, provided herein is a compound of formula (XIII): [ka] (In the formula, R 1 , R 3b , R 3c , and L are each as defined herein. or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0176] In yet another embodiment, provided herein is a compound of formula (XIV): [ka] (In the formula, R 1 , R 3b , R 3c , and L are each as defined herein. or a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0177] In one embodiment, provided herein is a compound of formula (XV): [ka] (In the formula, R 1 , R 2 , R 4 , R 3a , R3b , R 3c , R 3d , R 3e , R E1 , R E2 , A E , L, X, Y, Z, Z 1 , Z 2 , Z 3 , Z 4 , and m are each as defined herein. or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0178] In another embodiment, provided herein is a compound of formula (XVI): [ka] (In the formula, R 1 , R 2 , R 4 , R 3a , R 3b , R 3c , R 3d , R 3e , R E1 , R E2 , A E , L, X, and Z are each as defined herein. or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0179] In yet another embodiment, provided herein is a compound of formula (XVII): [ka] (In the formula, R 1 , R 4 , R 3b , R3c , A E , and L are each as defined herein. or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0180] In yet another embodiment, provided herein is a compound of formula (XVIII): [ka] (In the formula, R 1 , R 4 , R 3b , R 3c , A E , and L are each as defined herein. or a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0181] In yet another embodiment, provided herein is a compound of formula (XIX): [ka] (In the formula, R 1 , R 4 , R 3b , R 3c , and L are each as defined herein. or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0182] In yet another embodiment, provided herein is a compound of formula (XX): [ka] (In the formula, R 1 , R 4 , R 3b , R 3c , and L are each as defined herein. or a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0183] In one embodiment, provided herein is a compound of formula (XXI): [ka] (In the formula, R 1 , R 2 , R 3a , R 3b , R 3c , R 3d , R 3e , R 4a , R E1 , R E2 , R E4 , A E , L, X, Y, Z, a, m, and n are each as defined herein. or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0184] In another embodiment, provided herein is a compound of formula (XXII): [ka] (In the formula, R 1 , R 2 , R 3a , R3b , R 3c , R 3d , R 3e , R 4a , R E1 , R E2 , R E5 , A E , L, X, Z, and a are each as defined herein. or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof. E5 is hydrogen or fluoro.

[0185] In yet another embodiment, provided herein is a compound of formula (XXIII): [ka] (In the formula, R 1 , R 3b , R 3c , R E5 , A E , and L are each as defined herein. or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof. E5 is hydrogen or fluoro.

[0186] In yet another embodiment, provided herein is a compound of formula (XXIV): [ka] (In the formula, R 1 , R 3b , R 3c , R E5 , A E, and L are each as defined herein. or a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof. In one embodiment, R E5 is hydrogen or fluoro.

[0187] In yet another embodiment, provided herein is a compound of formula (XXV): [ka] (In the formula, R 1 , R 3b , R 3c , R E5 , and L are each as defined herein. or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof. E5 is hydrogen or fluoro.

[0188] In yet another embodiment, provided herein is a compound of formula (XXVI): [ka] (In the formula, R 1 , R 3b , R 3c , R E5 , and L are each as defined herein. or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof. E5 is hydrogen or fluoro.

[0189] In one embodiment, provided herein is a compound of formula (XXVII): [ka] (In the formula, R 1 , R 2 , R 3a , R 3b , R 3c , R 3d , R 3e , R 4a , R E1 , R E2 , R E5 , A E , L, X, Z, and a are each as defined herein. or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0190] In another embodiment, provided herein is a compound of formula (XXVIII): [ka] (In the formula, R 1 , R 3b , R 3c , R E5 , A E , and L are each as defined herein. or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof. E5 is hydrogen or fluoro.

[0191] In yet another embodiment, provided herein is a compound of formula (XXIX): [ka] (In the formula, R 1 , R 3b , R 3c , R E5 , A E , and L are each as defined herein. or a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof. In one embodiment, R E5 is hydrogen or fluoro.

[0192] In yet another embodiment, provided herein is a compound of formula (XXX): [ka] (In the formula, R 1 , R 3b , R 3c , R E5 , and L are each as defined herein. or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof. E5 is hydrogen or fluoro.

[0193] In yet another embodiment, provided herein is a compound of formula (XXXI): [ka] (In the formula, R 1 , R 3b , R 3c , R E5 , and L are each as defined herein. or a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof. In one embodiment, R E5 is hydrogen or fluoro.

[0194] In one embodiment, provided herein is a compound of formula (XXXII): [ka] (In the formula, R 1 , R 2 , R 4 , R 3a , R 3b , R 3c , R 3d , R 3e , R E1 , R E2 , R E4 , A E , L, X, Y, Z, m, and n are each as defined herein. or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0195] In another embodiment, provided herein is a compound of formula (XXXIII): [ka] (In the formula, R 1 , R 2 , R 4 , R 3a , R 3b , R 3c , R 3d , R 3e , R E1 , R E2 , R E5 , A E , L, X, and Z are each as defined herein. or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof. E5 is hydrogen or fluoro.

[0196] In yet another embodiment, provided herein is a compound of formula (XXXIV): [ka] (In the formula, R 1 , R 4 , R 3b , R 3c , R E5 , A E , and L are each as defined herein. or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof. E5 is hydrogen or fluoro.

[0197] In yet another embodiment, provided herein is a compound of formula (XXXV): [ka] (In the formula, R 1 , R 4 , R 3b , R 3c , R E5 , A E , and L are each as defined herein. or a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof. In one embodiment, R E5 is hydrogen or fluoro.

[0198] In yet another embodiment, provided herein is a compound of formula (XXXVI): [ka] (In the formula, R 1 , R 4 , R 3b , R 3c , R E5 , and L are each as defined herein. or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof. E5 is hydrogen or fluoro.

[0199] In yet another embodiment, provided herein is a compound of formula (XXXVII): [ka] (In the formula, R 1 , R 4 , R 3b , R 3c , R E5 , and L are each as defined herein. or a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof. In one embodiment, R E5 is hydrogen or fluoro.

[0200] In one embodiment, provided herein is a compound of formula (XXXVIII): [ka] (In the formula, R 1 , R 2 , R 4 , R 3a , R 3b , R 3c , R 3d , R 3e , R E1 , R E2 , R E5 , A E , L, X, and Z are each as defined herein. or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof. E5 is hydrogen or fluoro.

[0201] In another embodiment, provided herein is a compound of formula (XXXIX): [ka] (In the formula, R 1 , R 4 , R 3b , R 3c , R E5 , A E , and L are each as defined herein. or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof. E5 is hydrogen or fluoro.

[0202] In yet another embodiment, provided herein is a compound of formula (XL): [ka] (In the formula, R 1 , R 4 , R 3b , R 3c , R E5 , A E , and L are each as defined herein. or a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0203] In yet another embodiment, provided herein is a compound of formula (XLI): [ka] (In the formula, R 1 , R 4 , R 3b , R 3c , R E5 , and L are each as defined herein. or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0204] In yet another embodiment, provided herein is a compound of formula (XLII): [ka] (In the formula, R 1 , R 4 , R 3b , R 3c , R E5 , and L are each as defined herein. or a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0205] In certain embodiments, in any one of Formulas (IX) to (XLII), R 1 (i) C, each optionally substituted with one or more substituents Q; 1-6 Alkyl, C 3-10 cycloalkyl, heteroaryl, or heterocyclyl; or (ii) —OR 1a or -NR 1b R 1c (In the formula, R 1a , R 1b , and R 1c and each are as defined herein. In certain embodiments, in any one of Formulas (IX) to (XLII), R 1 each optionally substituted with one or more substituents Q; 1-6 Alkyl or C 3-10 In certain embodiments, in any one of Formulas (IX) to (XLII), R 1 is C optionally substituted with one or more substituents Q 1-6 In certain embodiments, in any one of Formulas (IX) to (XLII), R 1 is methyl or cyclopropylmethyl. In certain embodiments, in any one of Formulas (IX) to (XLII), R 1 is methyl. In certain embodiments, in any one of Formulas (IX) to (XLII), R 1 is C optionally substituted with one or more substituents Q 3-10 In certain embodiments, in any one of Formulas (IX) to (XLII), R 1 is cyclopropyl.

[0206] In certain embodiments, in any one of Formulas (IX) to (XLII), R 3b each optionally substituted with one or more substituents Q; 1-6 Alkyl, C 1-6 Heteroalkyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 In certain embodiments, in any one of Formulas (IX) to (XLII), R 3b each optionally substituted with one or more substituents Q; 1-6 Alkyl, C 1-6 Heteroalkyl, or C 3-10 In certain embodiments, in any one of Formulas (IX) to (XLII), R 3b is C optionally substituted with one or more substituents Q 1-6 In certain embodiments, in any one of Formulas (IX) to (XLII), R 3b is methyl, ethyl, or cyclopropylmethyl. In certain embodiments, in any one of Formulas (IX) to (XLII), R 3b is ethyl. In certain embodiments, in any one of Formulas (IX) to (XLII), R 3b is C optionally substituted with one or more substituents Q 3-10 In certain embodiments, in any one of Formulas (IX) to (XLII), R 3b is cyclopropyl.

[0207] In certain embodiments, in any one of Formulas (IX) to (XLII), R 3c each optionally substituted with one or more substituents Q; 1-6 Alkyl, C 1-6 Heteroalkyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15In certain embodiments, in any one of Formulas (IX) to (XLII), R 3c each optionally substituted with one or more substituents Q; 1-6 Alkyl, C 1-6 Heteroalkyl, or C 3-10 In certain embodiments, in any one of Formulas (IX) to (XLII), R 3c is C optionally substituted with one or more substituents Q 1-6 In certain embodiments, in any one of Formulas (IX) to (XLII), R 3c is methyl, ethyl, or cyclopropylmethyl. In certain embodiments, in any one of Formulas (IX) to (XLII), R 3c is methyl. In certain embodiments, in any one of Formulas (IX) to (XLII), R 3c is C optionally substituted with one or more substituents Q 3-10 In certain embodiments, in any one of Formulas (IX) to (XLII), R 3c is cyclopropyl.

[0208] In certain embodiments, in any one of Formulas (IX) to (XLII), R 3b and R 3c each independently represents C optionally substituted with one or more substituents Q; 1-6 In certain embodiments, in any one of Formulas (IX) to (XLII), R 3b and R 3c are each independently methyl or ethyl. In certain embodiments, in any one of Formulas (IX) to (XLII), R 3b is methyl and R 3c is ethyl. In certain embodiments, in any one of Formulas (IX) to (XLII), R 3b is ethyl and R 3c is methyl.

[0209] In one embodiment, in any one of Formulas (XV) to (XX) and Formulas (XXXII) to (XLII), R 4 -NR 1b R 1c , or -NR 1a C(O)R 1d where R 1a , R 1b , R 1c , and R 1d and R are each as defined herein. In certain embodiments, in any one of Formulas (XV) to (XX) and Formulas (XXXII) to (XLII), R 4 is hydrogen. In one embodiment, in any one of Formulas (XV) to (XX) and Formulas (XXXII) to (XLII), R 4 is deuterium. In certain embodiments, in any one of Formulas (XV) to (XX) and Formulas (XXXII) to (XLII), R 4 In certain embodiments, in any one of Formulas (XV) to (XX) and Formulas (XXXII) to (XLII), R 4 is -NR 1b R 1c where R 1b and R 1c and R are each as defined herein. In certain embodiments, in any one of Formulas (XV) to (XX) and Formulas (XXXII) to (XLII), R 4 In one embodiment, in any one of Formulas (XV) to (XX) and Formulas (XXXII) to (XLII), R 4 is -NR 1a C(O)R 1d where R 1a and R 1d and R are each as defined herein. In certain embodiments, in any one of Formulas (XV) to (XX) and Formulas (XXXII) to (XLII), R 4 is -NHC(O)R 1d where R 1d is C optionally substituted with one or more substituents Q1-6 In some embodiments, in any one of Formulas (XV) to (XX) and Formulas (XXXII) to (XLII), R 4 is -NHC(O)CH3.

[0210] In one embodiment, in any one of Formulas (XXII) to (XVIV), Formulas (XXVII) to (XXXI), and Formulas (XXXIII) to (XLII), R E5 is hydrogen. In one embodiment, in any one of Formulas (XXII) to (XVIV), Formulas (XXVII) to (XXXI), and Formulas (XXXIII) to (XLII), R E5 is fluoro.

[0211] In one embodiment, in any one of Formulas (IX) to (XLII), R 1 is methyl or cyclopropylmethyl; R 2 is, if present, hydrogen or deuterium; R 3b and R 3c are each independently methyl or ethyl; R 4 is, when present, hydrogen or —NHC(O)CH; R E5 is, if present, hydrogen or fluoro; and X, if present, is —CH 2 — or —C(O)—.

[0212] In one embodiment, provided herein is a compound of formula (VIA): [ka] (In the formula, R 5 , R 6 , R 7a , R 7b , R 7c , R 7d , R E1 , R E2 , A E , L, Z, Z1 , Z 2 , Z 3 , Z 4 , and m are each as defined herein. or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0213] In another embodiment, provided herein is a compound of formula (VIIA): [ka] (In the formula, R 5 , R 6 , R 7a , R 7b , R 7c , R 7d , R E1 , R E2 , A E , L, and Z are each as defined herein. or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0214] In yet another embodiment, provided herein is a compound of formula (VIIIA): [ka] (In the formula, R 5 , R 7a , R 7d , A E , and L are each as defined herein. or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0215] In yet another embodiment, provided herein is a compound of formula (IXA): [ka] (In the formula, R 5 , R 7a , R 7d , and L are each as defined herein. or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0216] In one embodiment, provided herein is a compound of formula (XA): [ka] (In the formula, R 5 , R 6 , R 7a , R 7b , R 7c , R 7d , R E1 , R E2 , R E5 , A E , L, and Z are each as defined herein. or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof. E5 is hydrogen or fluoro.

[0217] In another embodiment, provided herein is a compound of formula (XIA): [ka] (In the formula, R 5 , R 7a , R 7d , R E5 , A E , and L are each as defined herein. or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0218] In yet another embodiment, provided herein is a compound of formula (XIIA): [ka] (In the formula, R 5 , R 7a , R 7d , R E5 , and L are each as defined herein. or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof. E5 is hydrogen or fluoro.

[0219] In one embodiment, provided herein is a compound of formula (XIIIA): [ka] (In the formula, R 5 , R 6 , R 7a , R 7b , R 7c , R 7d , RE1 , R E2 , R E5 , A E , L, and Z are each as defined herein. or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof. E5 is hydrogen or fluoro.

[0220] In another embodiment, provided herein is a compound of formula (XIVA): [ka] (In the formula, R 5 , R 7a , R 7d , R E5 , A E , and L are each as defined herein. or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof. E5 is hydrogen or fluoro.

[0221] In yet another embodiment, provided herein is a compound of formula (XVA): [ka] (In the formula, R 5 , R 7a , R 7d , R E5 , and L are each as defined herein. or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof. E5 is hydrogen or fluoro.

[0222] In one embodiment, provided herein is a compound of formula (XVIA): [ka] (In the formula, R 5 , R 6 , R 7a , R 7b , R 7c , R 7d , R E1 , R E2 , A E , L, Z, Z 1 , Z 2 , Z 3 , Z 4 , and m are each as defined herein. or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0223] In another embodiment, provided herein is a compound of formula (XVIIA): [ka] (In the formula, R 5 , R 6 , R 7a , R 7b , R 7c , R 7d , R E1 , R E2 , A E , L, and Z are each as defined herein. or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0224] In yet another embodiment, provided herein is a compound of formula (XVIIIA): [ka] (In the formula, R 5 , R 7a , R 7d , A E , and L are each as defined herein. or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0225] In yet another embodiment, provided herein is a compound of formula (XIXA): [ka] (In the formula, R 5 , R 7a , R 7d , and L are each as defined herein. or a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0226] In one embodiment, provided herein is a compound of formula (XXA): [ka]

[0227] (In the formula, R 5 , R 6 , R 7a , R 7b , R 7c , R 7d , R E1 , R E2 , R E5 , A E , L, and Z are each as defined herein. or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof. E5 is hydrogen or fluoro.

[0228] In another embodiment, provided herein is a compound of formula (XXIA): [ka] (In the formula, R 5 , R 7a , R 7d , R E5 , A E , and L are each as defined herein. or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof. E5 is hydrogen or fluoro.

[0229] In yet another embodiment, provided herein is a compound of formula (XXIIA): [ka] (In the formula, R 5 , R 7a , R 7d , R E5, and L are each as defined herein. or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof. E5 is hydrogen or fluoro.

[0230] In one embodiment, provided herein is a compound of formula (XXIIIA): [ka] (In the formula, R 5 , R 6 , R 7a , R 7b , R 7c , R 7d , R E1 , R E2 , R E5 , A E , L, and Z are each as defined herein. or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof. E5 is hydrogen or fluoro.

[0231] In another embodiment, provided herein is a compound of formula (XXIVA): [ka] (In the formula, R 5 , R 7a , R 7d , R E5 , A E , and L are each as defined herein. or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof. E5 is hydrogen or fluoro.

[0232] In yet another embodiment, provided herein is a compound of formula (XXVA): [ka] (In the formula, R 5 , R 7a , R 7d , R E5 , and L are each as defined herein. or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof. E5 is hydrogen or fluoro.

[0233] In certain embodiments, in either one of Formula (VIA) or Formula (XXVA), R 5 is (i) hydrogen or deuterium; (ii) C optionally substituted with one or more substituents Q 1-6 alkyl; or (iii) -OR 1a (In the formula, R 1a is as defined herein. In certain embodiments, in either one of Formula (VIA) or Formula (XXVA), R 5 is hydrogen or deuterium. In certain embodiments, in either Formula (VIA) or Formula (XXVA), R 5 is C optionally substituted with one or more substituents Q 1-6 In certain embodiments, in either Formula (VIA) or Formula (XXVA), R 5-OR 1a (In the formula, R 1a is as defined herein. In certain embodiments, in either one of Formula (VIA) or Formula (XXVA), R 5 -OR 1a (In the formula, R 1a is C optionally substituted with one or more substituents Q 1-6 In certain embodiments, in either Formula (VIA) or Formula (XXVA), R 5 is methoxy, difluoromethoxy, trifluoromethoxy, ethoxy, or cyclopropylmethoxy. In certain embodiments, in either Formula (VIA) or Formula (XXVA), R 5 is difluoromethoxy or cyclopropylmethoxy.

[0234] In certain embodiments, in either one of Formula (VIA) or Formula (XXVA), R 7a is hydrogen, deuterium, halo, or C optionally substituted with one or more substituents Q 1-6 In certain embodiments, in either Formula (VIA) or Formula (XXVA), R 7a is hydrogen, halo, or C optionally substituted with one or more substituents Q 1-6 In certain embodiments, in either Formula (VIA) or Formula (XXVA), R 7a is hydrogen. In certain embodiments, in either Formula (VIA) or Formula (XXVA), R 7a is deuterium. In certain embodiments, in either Formula (VIA) or Formula (XXVA), R 7a In certain embodiments, in either Formula (VIA) or Formula (XXVA), R 7a In certain embodiments, in either Formula (VIA) or Formula (XXVA), R 7a is C optionally substituted with one or more substituents Q 1-6In certain embodiments, in either Formula (VIA) or Formula (XXVA), R 7a is methyl optionally substituted with one or more substituents Q. In certain embodiments, in either one of Formula (VIA) or Formula (XXVA), R 7a is trifluoromethyl.

[0235] In certain embodiments, in either one of Formula (VIA) or Formula (XXVA), R 7d is hydrogen, deuterium, halo, or C optionally substituted with one or more substituents Q 1-6 In certain embodiments, in either Formula (VIA) or Formula (XXVA), R 7d is hydrogen, halo, or C optionally substituted with one or more substituents Q 1-6 In certain embodiments, in either Formula (VIA) or Formula (XXVA), R 7d is hydrogen. In certain embodiments, in either Formula (VIA) or Formula (XXVA), R 7d is deuterium. In certain embodiments, in either Formula (VIA) or Formula (XXVA), R 7d In certain embodiments, in either Formula (VIA) or Formula (XXVA), R 7d In certain embodiments, in either Formula (VIA) or Formula (XXVA), R 7d is C optionally substituted with one or more substituents Q 1-6 In certain embodiments, in either Formula (VIA) or Formula (XXVA), R 7d is methyl optionally substituted with one or more substituents Q. In certain embodiments, in either one of Formula (VIA) or Formula (XXVA), R 7d is trifluoromethyl.

[0236] In one embodiment, in any one of Formulas (XA) to (XVA) and Formulas (XXA) to (XXVA), R E5is hydrogen. In certain embodiments, in any one of Formulas (XA) to (XVA) and Formulas (XXA) to (XXVA), R E5 is fluoro.

[0237] In some embodiments, R E is a portion of an IAP E3 ligand. E teeth: [ka] or a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof.

[0238] In some embodiments, R E teeth: [ka] or a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof.

[0239] In one embodiment, in a compound of any one of Formulas (I) to (VIII) and Formulas (IA) to (VA), R E is a moiety of compound EI-1, or a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof. In another embodiment, in a compound of any one of Formulas (I) through (VIII) and Formulas (IA) through (VA), R E is a moiety of compound EI-2, or a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof.

[0240] In one embodiment, in a compound of any one of Formulas (I) to (VIII) and Formulas (IA) to (VA), R Eis a moiety having the structure of formula EI-3, or a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof.

[0241] In some embodiments, R E is a portion of the MDM2 E3 ligand. E teeth: [ka] or a portion of an MDM2 E3 ligand having the structure of a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof.

[0242] In one embodiment, in a compound of any one of Formulas (I) to (VIII) and Formulas (IA) to (VA), R E is part of the compound EM-1, or a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof.

[0243] In some embodiments, R E is a portion of the VHL E3 ligand.

[0244] In some embodiments, R E is represented by formula (EV-I): [ka] (In the formula, R E6 , R E8 , and R E9 are independently hydrogen, deuterium, and C 1-6 Alkyl or C 3-10 is cycloalkyl; and R E7 is hydrogen, deuterium, halo, hydroxyl, -OC 1-6 Alkyl or -OC 3-10 is cycloalkyl; wherein each alkyl and cycloalkyl is optionally substituted with one or more, in one embodiment one, two, three, or four, substituents Q. or the structure of a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof.

[0245] In some embodiments, R E is represented by formula (EV-II): [ka] (In the formula, R E10 is -NHC(O)C 1-6 Alkyl, -NHC(O)C 3-10 cycloalkyl, or heterocyclyl, wherein the alkyl, cycloalkyl, and heterocyclyl are each optionally substituted with one or more, in one embodiment one, two, three, or four, substituents Q; and R E6 , R E7 , and R E8 are each as defined herein) or the structure of a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof.

[0246] In some embodiments, R E is represented by formula (EV-III): [ka] (In the formula, R E6 , R E8 , R E9 , and R E10 are each as defined herein) or the structure of a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof.

[0247] In one embodiment, in any one of Formulas (EV-I) to (EV-III), R E6 is methyl; R E7 is hydrogen, if present; R E8 is hydrogen; R E9 is, when present, propyl, butyl, or cyclopropyl; and R E10 is, when present, acetamido, cyclopropamido, or isoindolinyl; wherein the propyl, butyl, cyclopropyl, acetamido, cyclopropamido, and isoindolinyl are each optionally substituted with cyano, fluoro, or trifluoromethyl.

[0248] In one embodiment, in any one of Formulas (EV-I) to (EV-III), R E6 is methyl; R E7 is hydrogen, if present; R E8 is hydrogen; R E9 when present, is isopropyl, tert-butyl, cyclopropyl, 1-fluorocyclopropyl, or 1-trifluoromethylcyclopropyl; and R E10 When present, is acetamide, cyclopropamide, 1-cyanocyclopropamide, 1-fluorocyclopropamide, or 1-oxoisoindolin-2-yl.

[0249] In one embodiment, in a compound of any one of Formulas (I) to (VIII) and Formulas (IA) to (VA), R Eis a moiety having the structure of formula (EV-I), or a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof. In another embodiment, in a compound of any one of Formulas (I) through (VIII) and Formulas (IA) through (VA), R E is a moiety having the structure of formula (EV-II), or a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof. In yet another embodiment, in a compound of any one of Formulas (I) through (VIII) and Formulas (IA) through (VA), R E is a moiety having the structure of formula (EV-III), or a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof.

[0250] In some embodiments, R E is the following: [ka] or a portion of a VHL E3 ligand having the structure of a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof.

[0251] In one embodiment, in a compound of any one of Formulas (I) to (VIII) and Formulas (IA) to (VA), R E is a moiety of compound EV-1, or a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof. In another embodiment, in a compound of any one of Formulas (I) through (VIII) and Formulas (IA) through (VA), R E is part of compound EV-2, or a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof. In yet another embodiment, in a compound of any one of Formulas (I) through (VIII) and Formulas (IA) through (VA), RE is part of compound EV-3, or a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof. In yet another embodiment, in a compound of any one of Formulas (I) through (VIII) and Formulas (IA) through (VA), R E is part of compound EV-4, or a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof. In yet another embodiment, in a compound of any one of Formulas (I) through (VIII) and Formulas (IA) through (VA), R E is part of compound EV-5, or a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof. In yet another embodiment, in a compound of any one of Formulas (I) through (VIII) and Formulas (IA) through (VA), R E is part of compound EV-6, or a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof. In yet another embodiment, in a compound of any one of Formulas (I) through (VIII) and Formulas (IA) through (VA), R E is part of the compound EV-7, or a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof.

[0252] In some embodiments, R E teeth: [ka] or a moiety having the structure of a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof.

[0253] In some embodiments, R E teeth: [ka] or a moiety having the structure of a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof.

[0254] In one embodiment, in a compound of any one of Formulas (I) to (VIII) and Formulas (IA) to (VA), R E is a moiety having a structure of formula EV-8, or a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof. In another embodiment, in a compound of any one of Formulas (I) through (VIII) and Formulas (IA) through (VA), R E is a moiety having a structure of formula EV-9, or a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof. In yet another embodiment, in a compound of any one of Formulas (I) through (VIII) and Formulas (IA) through (VA), R E is a moiety having a structure of formula EV-10, or a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof. In yet another embodiment, in a compound of any one of Formulas (I) through (VIII) and Formulas (IA) through (VA), R E is a moiety having a structure of formula EV-11, or a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof. In yet another embodiment, in a compound of any one of Formulas (I) through (VIII) and Formulas (IA) through (VA), R E is a moiety having a structure of formula EV-12, or a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof. In yet another embodiment, in a compound of any one of Formulas (I) through (VIII) and Formulas (IA) through (VA), R Eis a moiety having a structure of formula EV-13, or a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof. In yet another embodiment, in a compound of any one of Formulas (I) through (VIII) and Formulas (IA) through (VA), R E is a moiety having a structure of formula EV-14, or a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof. In yet another embodiment, in a compound of any one of Formulas (I) through (VIII) and Formulas (IA) through (VA), R E is a moiety having the structure of formula EV-15, or a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof.

[0255] In one embodiment, provided herein is a compound of formula (XLIII): [ka] (In the formula, R 1 , R 2 , R 3a , R 3b , R 3c , R 3d , R 3e , R 4a , R E6 , R E7 , R E8 , R E9 , L, X, Y, and a are each as defined herein. or a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0256] In another embodiment, provided herein is a compound of formula (XLIV): [ka] (In the formula, R 1 , R 3b , R 3c , and L are each as defined herein. or a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0257] In one embodiment, provided herein is a compound of formula (XLV): [ka] (In the formula, R 1 , R 2 , R 4 , R 3a , R 3b , R 3c , R 3d , R 3e , R E6 , R E7 , R E8 , R E9 , L, X, and Y are each as defined herein. or a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0258] In another embodiment, provided herein is a compound of formula (XLVI): [ka] (In the formula, R 1 , R 4 , R 3b , R 3c , and L are each as defined herein. or a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0259] In one embodiment, provided herein is a compound of formula (XXVIA): [ka] (In the formula, R 5 , R 6 , R 7a , R 7b , R 7c , R 7d , R E6 , R E7 , R E8 , R E9 , and L are each as defined herein. or a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0260] In another embodiment, provided herein is a compound of formula (XXVIIA): [ka] (In the formula, R 5 , R 7a , R 7d , and L are each as defined herein. or a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0261] In one embodiment, provided herein is a compound of formula (XXVIIIA): [ka] (In the formula, R 5 , R 6 , R 7a , R 7b , R 7c , R 7d , R E6 , R E7 , R E8 , R E9 , and L are each as defined herein. or a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0262] In another embodiment, provided herein is a compound of formula (XXIXA): [ka] (In the formula, R 5 , R 7a , R 7d , and L are each as defined herein. or a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0263] In certain embodiments, L is C, each of which is optionally substituted with one or more, in one embodiment one, two, three, or four, substituents Q. 1-20 Alkylene, C 1-20 Heteroalkylene, C 2-20 Alkenylene, C 2-20 Heteroalkenylene, C 2-20 Alkynylene, C 2-20 Heteroalkynylene, C 3-10 Cycloalkylene, C 6-14In certain embodiments, L is arylene, heteroarylene, or heterocyclylene, each of which is optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Q. 1-20 Alkylene, C 1-20 Heteroalkylene, C 2-20 Alkenylene, C 2-20 Heteroalkenylene, C 2-20 Alkynylene, or C 2-20 In certain embodiments, L is heteroalkynylene, each of which is optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Q. 1-20 Alkylene or C 1-20 It is heteroalkylene.

[0264] In certain embodiments, L is C optionally substituted with one, two, or three substituents Q. 1-20 In some embodiments, L is C optionally substituted with 1, 2, or 3 substituents Q. 4-16 In some embodiments, L is C optionally substituted with 1, 2, or 3 substituents Q. 4-12 In some embodiments, L is C optionally substituted with one or two oxo groups. 1-20 In some embodiments, L is C optionally substituted with one or two oxo groups. 4-16 In some embodiments, L is C optionally substituted with one or two oxo groups. 4-12 In some embodiments, L is -(CH) optionally substituted with one or two oxo groups. p where p is an integer of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16. In certain embodiments, L is —(CH) optionally substituted with one or two oxo. p where p is an integer of 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12. In certain embodiments, L is —(CH) optionally substituted with one or two oxo.p where p is an integer of 5, 6, 7, 8, or 9.

[0265] In certain embodiments, L is C optionally substituted with one, two, or three substituents Q. 1-20 In some embodiments, L is a C optionally substituted with one, two, or three substituents Q. 4-16 In some embodiments, L is a C optionally substituted with one, two, or three substituents Q. 4-12 In some embodiments, L is C optionally substituted with 1, 2, or 3 oxo. 1-20 In some embodiments, L is C optionally substituted with 1, 2, or 3 oxo. 4-16 In some embodiments, L is C optionally substituted with 1, 2, or 3 oxo. 4-12 It is heteroalkylene.

[0266] In certain embodiments, L is a C 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 30 36 37 38 40 45 50 55 60 65 2 containing an ethyleneoxy (—CH2CH2O—) group, optionally substituted with one or more substituents Q. 2-20 In some embodiments, L is a C 1 -containing ethyleneoxy group, optionally substituted with one or more substituents Q. 2-14 In some embodiments, L is a C 1 -containing ethyleneoxy group, optionally substituted with one or more substituents Q. 2-10 In some embodiments, L is a C 1 -C 2 -C ... 3-20 In some embodiments, L is a C 10 alkylene group containing a propyleneoxy group, optionally substituted with one or more substituents Q. 3-14 In some embodiments, L is a C 10 alkylene group containing a propyleneoxy group, optionally substituted with one or more substituents Q. 3-10 It is heteroalkylene.

[0267] In certain embodiments, L is C 1-20 Alkylene, C 1-20 Heteroalkylene, C 2-20 Alkenylene, C 2-20 Heteroalkenylene, C 2-20 Alkynylene, or C 2-20 heteroalkynylene, wherein one or more methylene groups are each independently replaced by a divalent radical, and each divalent radical is independently selected from the group consisting of C 3-10 Cycloalkylene, C 6-14 and wherein the alkylene, heteroalkylene, alkenylene, heteroalkenylene, alkynylene, heteroalkynylene, cycloalkylene, arylene, heteroarylene, and heterocyclylene are each optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Q. In certain embodiments, L is C 1-20 Alkylene or C 1-20 heteroalkylene, wherein one or more methylene groups are each independently replaced by a divalent radical, and each divalent radical is independently selected from the group consisting of C 3-10 Cycloalkylene, C 6-14 and wherein the alkylene, heteroalkylene, cycloalkylene, arylene, heteroarylene, and heterocyclylene are each optionally substituted with one or more, and in one embodiment, one, two, three, or four, substituents Q.

[0268] In certain embodiments, L is C 1-20 alkylene, wherein one or more methylene groups are each independently replaced by a divalent radical, and each divalent radical is independently selected from the group consisting of: C 3-10 Cycloalkylene, C 6-14and wherein the alkylene, cycloalkylene, arylene, heteroarylene, and heterocyclylene are each optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Q. In certain embodiments, L is C 1-20 alkylene, wherein one or two methylene groups are each independently selected from C 3-10 and wherein the alkylene and cycloalkylene are each optionally substituted with one or more, in one embodiment 1, 2, 3, or 4, substituents Q. In certain embodiments, L is C 1-20 alkylene, wherein one or two methylene groups are each independently selected from C 6-14 and wherein the alkylene and arylene are each optionally substituted with one or more, in one embodiment 1, 2, 3, or 4, substituents Q. In certain embodiments, L is C 1-20 In certain embodiments, L is alkylene, wherein one or two methylene groups are each independently replaced by heteroarylene; and wherein the alkylene and heteroarylene are each optionally substituted with one or more, in one embodiment one, two, three, or four, substituents Q. In certain embodiments, L is C 1-20 In certain embodiments, L is alkylene, wherein one or two methylene groups are each independently replaced by heterocyclylene; and wherein the alkylene and heterocyclylene are each optionally substituted with one or more, in one embodiment one, two, three, or four, substituents Q. In certain embodiments, L is C 1-20 alkylene, wherein one, two, or three methylene groups are each independently replaced by a divalent group; and wherein each divalent group is independently cyclohexane-1,4-diyl, phen-1,3-diyl, phen-1,4-diyl, 1,2,3-triazole-1,4-diyl, or 2,5-dioxopyrrolidine-1,3-diyl.

[0269] In certain embodiments, L is C 1-20 alkylene, wherein one or two methylene groups are each independently replaced by a divalent radical; and wherein each divalent radical is independently selected from the group consisting of C 3-10 Cycloalkylene, C 6-14 and wherein the alkylene, cycloalkylene, arylene, heteroarylene, and heterocyclylene are each optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Q. In certain embodiments, L is C 1-20 In some embodiments, L is alkylene, wherein one or two methylene groups are each independently replaced by a divalent group; and wherein each divalent group is independently cyclohexanediyl, phendiyl, triazoldiyl, or 2,5-dioxopyrrolidinediyl. 1-20 alkylene, wherein one or two methylene groups are each independently replaced by a divalent group; and wherein each divalent group is independently cyclohexane-1,4-diyl, phen-1,3-diyl, phen-1,4-diyl, 1,2,3-triazole-1,4-diyl, or 2,5-dioxopyrrolidine-1,3-diyl.

[0270] In certain embodiments, L is C 1-20 alkylene, wherein a methylene group is replaced by a divalent radical; and wherein the divalent radical is C 3-10 Cycloalkylene, C 6-14 and wherein the alkylene, cycloalkylene, arylene, heteroarylene, and heterocyclylene are each optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Q. In certain embodiments, L is C 1-20In certain embodiments, L is alkylene, wherein a methylene group is replaced by a divalent group; and wherein the divalent group is cyclohexanediyl, phendiyl, triazoldiyl, or 2,5-dioxopyrrolidinediyl. 1-20 alkylene, wherein a methylene group is replaced by a divalent group; and wherein each divalent group is independently cyclohexane-1,4-diyl, phen-1,3-diyl, phen-1,4-diyl, 1,2,3-triazole-1,4-diyl, or 2,5-dioxopyrrolidine-1,3-diyl.

[0271] In certain embodiments, L is C 1-20 heteroalkylene, wherein one or more methylene groups are each independently replaced by a divalent radical; and wherein each divalent radical is independently selected from the group consisting of C 3-10 Cycloalkylene, C 6-14 and wherein the heteroalkylene, cycloalkylene, arylene, heteroarylene, and heterocyclylene are each optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Q. In certain embodiments, L is C 1-20 heteroalkylene, wherein one, two, or three methylene groups are each independently replaced by a divalent radical; and wherein each divalent radical is independently selected from the group consisting of C 3-10 Cycloalkylene, C 6-14 and wherein the heteroalkylene, cycloalkylene, arylene, heteroarylene, and heterocyclylene are each optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Q. In certain embodiments, L is C 1-20In some embodiments, L is heteroalkylene, wherein one, two, or three methylene groups are each independently replaced by a divalent group; and wherein each divalent group is independently cyclohexanediyl, phendiyl, triazoldiyl, or 2,5-dioxopyrrolidinediyl. 1-20 alkylene, wherein one, two, or three methylene groups are each independently replaced by a divalent group; and wherein each divalent group is independently cyclohexane-1,4-diyl, phen-1,3-diyl, phen-1,4-diyl, 1,2,3-triazole-1,4-diyl, or 2,5-dioxopyrrolidine-1,3-diyl.

[0272] In certain embodiments, L is C 1-20 heteroalkylene, wherein one or two methylene groups are each independently replaced by a divalent radical; and wherein each divalent radical is independently selected from the group consisting of C 3-10 Cycloalkylene, C 6-14 and wherein the heteroalkylene, cycloalkylene, arylene, heteroarylene, and heterocyclylene are each optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Q. In certain embodiments, L is C 1-20 In some embodiments, L is heteroalkylene, wherein one or two methylene groups are each independently replaced by a divalent group; and wherein each divalent group is independently cyclohexanediyl, phendiyl, triazoldiyl, or 2,5-dioxopyrrolidinediyl. 1-20 Heteroalkylene, wherein one or two methylene groups are each independently replaced by a divalent group; and wherein each divalent group is independently cyclohexane-1,4-diyl, phen-1,3-diyl, phen-1,4-diyl, 1,2,3-triazole-1,4-diyl, or 2,5-dioxopyrrolidine-1,3-diyl.

[0273] In certain embodiments, L is C1-20 heteroalkylene, wherein a methylene group is replaced by a divalent radical; and wherein the divalent radical is C 3-10 Cycloalkylene, C 6-14 and wherein the heteroalkylene, cycloalkylene, arylene, heteroarylene, and heterocyclylene are each optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Q. In certain embodiments, L is C 1-20 In certain embodiments, L is heteroalkylene, wherein a methylene group is replaced by a divalent group; and wherein the divalent group is cyclohexanediyl, phendiyl, triazoldiyl, or 2,5-dioxopyrrolidinediyl. 1-20 Heteroalkylene in which a methylene group is replaced by a divalent group; and in which each divalent group is independently cyclohexane-1,4-diyl, phen-1,3-diyl, phen-1,4-diyl, 1,2,3-triazole-1,4-diyl, or 2,5-dioxopyrrolidine-1,3-diyl.

[0274] In certain embodiments, L is C 1-15 Alkylene-C 3-10 Cycloalkylene, C 1-15 Heteroalkylene-C 3-10 Cycloalkylene, C 1-15 Alkylene-C 6-14 Arylene, C 1-15 Heteroalkylene-C 6-14 Arylene, C 1-15 Alkylene-heteroarylene, C 1-15 Heteroalkylene-heteroarylene, C 1-15 Alkylene-heterocyclylene, C 1-15In certain embodiments, L is a heteroalkylene-heterocyclylene or heteroarylene-heterocyclylene, where each alkylene, heteroalkylene, cycloalkylene, arylene, heteroarylene, and heterocyclylene is optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Q. In certain embodiments, L is C 1-15 Alkylene-C 3-10 In certain embodiments, L is cycloalkylene, wherein the alkylene and cycloalkylene are each optionally substituted with one or more, in one embodiment one, two, three, or four, substituents Q. In certain embodiments, L is C 1-15 Heteroalkylene-C 3-10 In certain embodiments, L is a cycloalkylene, wherein the heteroalkylene and cycloalkylene are each optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Q. In certain embodiments, L is C 1-15 Alkylene-C 6-14 In certain embodiments, L is an arylene, wherein the alkylene and arylene are each optionally substituted with one or more, in one embodiment one, two, three, or four, substituents Q. In certain embodiments, L is C 1-15 Heteroalkylene-C 6-14 In certain embodiments, L is an arylene, wherein the heteroalkylene and arylene are each optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Q. In certain embodiments, L is C 1-15 In certain embodiments, L is an alkylene-heteroarylene, wherein the alkylene and heteroarylene are each optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Q. In certain embodiments, L is C 1-15 In certain embodiments, L is a heteroalkylene-heteroarylene, wherein the heteroalkylene and heteroarylene are each optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Q. In certain embodiments, L is C 1-15In certain embodiments, L is an alkylene-heterocyclylene, wherein the alkylene and heterocyclylene are each optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Q. In certain embodiments, L is C 1-15 In certain embodiments, L is a heteroalkylene-heterocyclylene, wherein the heteroalkylene and heterocyclylene are each optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Q. In certain embodiments, L is C 1-15 heteroarylene-heterocyclylene, wherein the heteroarylene and heterocyclylene are each optionally substituted with one or more, and in one embodiment one, two, three, or four, substituents Q.

[0275] In certain embodiments, L is L 1 -L 2 -L 3 (In the formula, L 1 is a bond, C 1-10 Alkylene, C 1-10 heteroalkylene or heterocyclylene; L 2 is C 3-10 Cycloalkylene, C 6-14 arylene, heteroarylene, or heterocyclylene; and L 3 is C 1-10 Alkylene, C 1-10 heteroalkylene, heteroarylene, or heterocyclylene; wherein each alkylene, heteroalkylene, cycloalkylene, arylene, heteroarylene, and heterocyclylene is optionally substituted with one or more, and in one embodiment, one, two, three, or four, substituents Q. It has the following structure.

[0276] In one embodiment, L 2 is optionally substituted with one or more, in one embodiment one, two, three or four, substituents Q; 3-10In certain embodiments, L is cycloalkylene. 2 is a monocyclic C optionally substituted with one or more, in one embodiment one, two, three or four, substituents Q; 3-10 In certain embodiments, L is cycloalkylene. 2 is cyclopentanediyl or cyclohexanediyl, each optionally substituted with one or more, in one embodiment one, two, three, or four, substituents Q. In certain embodiments, L 2 is cyclopentane-1,3-diyl or cyclohexane-1,4-diyl, each optionally substituted with one or more, in one embodiment one, two, three, or four, substituents Q.

[0277] In one embodiment, L 2 is optionally substituted with one or more, in one embodiment one, two, three or four, substituents Q; 6-14 In certain embodiments, L 2 is phendiyl optionally substituted with one or more, in one embodiment one, two, three, or four, substituents Q. In certain embodiments, L 2 is phen-1,4-diyl optionally substituted with one or more, in one embodiment one, two, three or four, substituents Q.

[0278] In one embodiment, L 2 is heteroarylene optionally substituted with one or more, in one embodiment 1, 2, 3, or 4, substituents Q. In certain embodiments, L 2 is a monocyclic heteroarylene optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Q. In certain embodiments, L 2 is a 5- or 6-membered heteroarylene, each optionally substituted with one or more, in one embodiment 1, 2, 3, or 4, substituents Q. In certain embodiments, L 2is triazolediyl optionally substituted with one or more, in one embodiment one, two, three, or four, substituents Q. In certain embodiments, L 2 is 1,2,3-triazole-1,4-diyl optionally substituted with one or more, in one embodiment one, two, three or four, substituents Q.

[0279] In one embodiment, L 2 is heterocyclylene optionally substituted with one or more, in one embodiment 1, 2, 3, or 4, substituents Q. In certain embodiments, L 2 is a monocyclic heterocyclylene optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Q. In certain embodiments, L 2 is a 5- or 6-membered heterocyclylene, each optionally substituted with one or more, in one embodiment 1, 2, 3, or 4, substituents Q. In certain embodiments, L 2 is piperidinediyl or piperazinediyl, each optionally substituted with one or more, in one embodiment one, two, three, or four, substituents Q. In certain embodiments, L 2 is piperidine-1,3-diyl, piperidine-1,4-diyl, or piperazine-1,4-diyl, each optionally substituted with one or more, in one embodiment one, two, three, or four, substituents Q.

[0280] In certain embodiments, L is -Z L -(R L -Z L ) z - (In the formula: Each R L are independently selected from the group consisting of C, ... 1-10 Alkylene, C 2-10 Alkenylene, C 2-10 Alkynylene, C 3-10 Cycloalkylene, C 6-14arylene, heteroarylene, or heterocyclylene; each Z L are independently a bond, -C(O)-, -C(O)O-, or -C(O)NR 1b -, -C(O)S-, -C(NR 1a )NR 1b -, -C(S)-, -C(S)O-, -C(S)NR 1b -, -O-, -OC(O)O-, -OC(O)NR 1b -, -OC(O)S-, -OC(NR 1a )NR 1b -, -OC(S)O-, -OC(S)NR 1b -, -OS(O)-, -OS(O)2-, -OS(O)NR 1b -,-OS(O)2NR 1b -, -NR 1b -, -NR 1a C(O)NR 1b -, -NR 1a C(O)S-, -NR 1a C(NR 1d )NR 1b -, -NR 1a C(S)NR 1b -, -NR 1a S(O)NR 1b -, -NR 1a S(O)NR 1b -, -S-, -S(O)-, -S(O)2-, -S(O)NR 1b - or -S(O)NR 1b - where each R 1a and R 1b is as defined herein; and z is an integer of 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. It is a linker having the structure:

[0281] In certain embodiments, each R L are independently selected from the group consisting of C, ... 1-10 Alkylene, C 2-10 Alkynylene, C 3-10 Cycloalkylene, C 6-14arylene, heteroarylene, or heterocyclylene; each Z L are independently a bond, -C(O)-, or -C(O)NR 1b -, -C(NR 1a )NR 1b -, -O-, -OC(O)NR 1b -, -NR 1b -, -NR 1a C(O)NR 1b -, -NR 1a C(NR 1d )NR 1b -, -NR 1a S(O)NR 1b -, -NR 1a S(O)NR 1b -, -S-, -S(O)-, -S(O)2-, -S(O)NR 1b - or -S(O)NR 1b and z is an integer of 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; where each R 1a , R 1b , and R 1d is as defined herein.

[0282] In certain embodiments, each R L are independently selected from the group consisting of C, ... 1-10 Alkylene, C 2-10 Alkynylene, C 3-10 Cycloalkylene, C 6-14 arylene, heteroarylene, or heterocyclylene; each Z L are independently a bond, -C(O)-, or -C(O)NR 1b -, -O-, -OC(O)NR 1b -, -NR 1b -, -NR 1a C(O)NR 1b - or -NR 1a C(NR 1d )NR 1b and z is an integer of 1, 2, 3, 4, 5, 6, 7, or 8; where each R 1a and R 1b is as defined herein.

[0283] In certain embodiments, each R L is independently methanediyl, ethanediyl, propanediyl, butanediyl, pentanediyl, hexanediyl, heptanediyl, octanediyl, nonanediyl, decanediyl, undecanediyl, dodecanediyl, tridecanediyl, ethynediyl, cyclobutanediyl, cyclopentanediyl, cyclohexanediyl, cycloheptanediyl, bicyclo[2.2.2]octanediyl, phendiyl, pyrazolediyl, imidazolediyl, tetrazolediyl, pyrimidinediyl, 5,6,7,8,9,10-hexahydrocycloocta[d]-pyridazinediyl, 1,3-dioxanediyl, piperazinediyl, piperidinediyl, or 3,9-diazaspiro[5.5]undecanediyl, each optionally substituted with one or more substituents Q; L is independently a bond, —C(O)—, —C(O)O—, —C(O)NH—, —OC(O)NH—, —O—, —NH—, —N(CH)—, or —NHC(O)NH—; and z is an integer of 1, 2, 3, 4, 5, 6, 7, or 8.

[0284] In certain embodiments, each R Lare independently selected from methanediyl, ethane-1,2-diyl, propane-1,3-diyl, butane-1,4-diyl, pentane-1,5-diyl, hexane-1,6-diyl, heptane-1,7-diyl, octane-1,8-diyl, nonane-1,9-diyl, decane-1,10-diyl, undecane-1,11-diyl, dodecane-1,12-diyl, tridecane-1,13-diyl, ethyne-1,2-diyl, cyclobutane-1,3-diyl, cyclopentane-1,3-diyl, cyclohexane-1,3-diyl, cyclohexane-1,4-diyl, cycloheptane-1,3-diyl, cycloheptane-1,4-diyl, and bicyclohexyl, each of which is optionally substituted with one or more substituents Q. Z is 2,4-dimethyl-1,4-diyl, 2,4-dimethyl-1,4-dimethylphenyl ... L is independently a bond, —C(O)—, —C(O)O—, —C(O)NH—, —OC(O)NH—, —O—, —NH—, —N(CH)—, or —NHC(O)NH—; and z is an integer of 1, 2, 3, 4, 5, 6, 7, or 8.

[0285] In some embodiments, L is: [ka] is.

[0286] In some embodiments, L is: [ka] is.

[0287] In some embodiments, L is: [ka] TIFF2024500377000145.tif233170TIFF2024500377000146.tif218170TIFF2024500377000147.tif40170.

[0288] In some embodiments, L is: [ka] TIFF2024500377000149.tif222170TIFF2024500377000150.tif18170.

[0289] In some embodiments, L is: [ka] is.

[0290] In some embodiments, L is: [ka] [ka] TIFF2024500377000154.tif216170TIFF2024500377000155.tif219170TIFF2024500377000156.tif138170 [ka] TIFF2024500377000158.tif223170TIFF2024500377000159.tif24170 (in the formula, each R L are independently hydrogen or C optionally substituted with one or more substituents Q 1-6 alkyl) is.

[0291] In certain embodiments, L is selected from the group consisting of pentane-1,5-diyl, hexa-1,6-diyl, heptane-1,7-diyl, octane-1,8-diyl, nonane-1,9-diyl, decane-1,10-diyl, undecane-1,11-diyl, piperazine-1,4-diyl, [ka] is.

[0292] In certain embodiments, L is pentane-1,5-diyl, heptane-1,7-diyl, nonane-1,9-diyl, [ka] is.

[0293] In some embodiments, L is: [ka] The file is TIFF2024500377000163.tif232170.

[0294] In one embodiment, provided herein is: N-(6-(7-(4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1-oxoisoindolin-4-yl)piperidin-1-yl)heptyl)-2-((S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)-1,3-dioxoisoindolin-4-yl)acetamide A1; N-(6-(7-(4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1-oxoisoindolin-4-yl)piperidin-1-yl)hept-1-yn-1-yl)-2-((S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)-1,3-dioxo-isoindolin-4-yl)acetamide A2; N-(6-(5-(4-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)ethynyl)piperidin-1-yl)-5-oxopentyl)-2-((S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)-1,3-dioxo-isoindolin-4-yl)acetamide A3; 14-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)-N-(2-((S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)-1,3-dioxoisoindolin-4-yl)-3,6,9,12-tetraoxa-tetradecan-1-amide A4; N-(6-(3-(4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1-oxoisoindolin-4-yl)piperidin-1-yl)propyl)-2-((S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)-1,3-dioxo-isoindolin-4-yl)acetamide A5; 12-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)-N-(2-((S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)-1,3-dioxoisoindolin-4-yl)dodecanamide A6; 9-(4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1-oxoisoindolin-5-yl)piperidin-1-yl)-N-(2-((S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)-1,3-dioxoisoindolin-4-yl)-nonanamide A7; N-(6-(7-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)piperidin-4-yl)-heptyl)-2-((S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)-1,3-dioxoisoindolin-4-yl)acetamide A8; 3-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethoxy)-ethoxy)-N-(2-((S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)-1,3-dioxoisoindolin-4-yl)propanamide A9; 3-(2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethoxy)-ethoxy)ethoxy)-N-(2-((S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)-1,3-dioxo-isoindolin-4-yl)propanamide A10; 3-((4-((2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethoxy)-methyl)benzyl)oxy)-N-(2-((S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)-1,3-dioxoisoindolin-4-yl)propanamide A11; 9-((4-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methoxy)benzyl)amino)-N-(2-((S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)-1,3-dioxoisoindolin-4-yl)nonanamide A12; 9-(4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1-oxoisoindolin-4-yl)piperidin-1-yl)-N-(2-((S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)-1,3-dioxoisoindolin-4-yl)-nonanamide A13; N-(6-(12-(4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1-oxoisoindolin-4-yl)piperidin-1-yl)dodecyl)-2-((S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)-1,3-dioxo-isoindolin-4-yl)acetamide A14; 9-{1-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]-piperidin-4-yl}-N-{2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-methanesulfonylethyl]-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl}nonanamide A15; 9-({[4-({[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-yl]oxy}-methyl)phenyl]methyl}amino)-N-{2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-methanesulfonyl-ethyl]-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl}nonanamide A16; N-[7-(12-{4-[2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1-oxo-2,3-dihydro-1H-isoindol-4-yl]piperidin-1-yl}dodecyl)-2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-methane-sulfonylethyl]-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]acetamide A17; 4-Amino-7-(12-{4-[2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1-oxo-2,3-dihydro-1H-isoindol-4-yl]piperidin-1-yl}dodecyl)-2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-methane-sulfonylethyl]-2,3-dihydro-1H-isoindole-1,3-dione A18; 10-{4-[2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1-oxo-2,3-dihydro-1H-isoindol-5-yl]piperidin-1-yl}-N-{2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-methanesulfonylethyl]-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl}decanamide A19; 9-(4-{2-[2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1-oxo-2,3-dihydro-1H-isoindol-5-yl]ethynyl}piperidin-1-yl)-N-{2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-methanesulfonylethyl]-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl}nonanamide A20; 9-{4-[2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1-oxo-2,3-dihydro-1H-isoindol-5-yl]piperidin-1-yl}-N-{2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-methanesulfonylethyl]-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl}nonanamide A21; 8-{4-[2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1-oxo-2,3-dihydro-1H-isoindol-5-yl]piperidin-1-yl}-N-{2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-methanesulfonylethyl]-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl}octanamide A22; 9-{4-[2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1-oxo-2,3-dihydro-1H-isoindol-5-yl]-1H-1,2,3-triazol-1-yl}-N-{2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-methanesulfonylethyl]-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl}nonanamide A23; 4-[1-(2-{4-[2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1-oxo-2,3-dihydro-1H-isoindol-5-yl]piperidin-1-yl}ethyl)-1H-1,2,3-triazol-4-yl]-N-{2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-methanesulfonylethyl]-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl}butanamide A24; 4-[(9-{4-[2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1-oxo-2,3-dihydro-1H-isoindol-5-yl]piperidin-1-yl}nonyl)amino]-2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-methanesulfonyl-ethyl]-2,3-dihydro-1H-isoindole-1,3-dione A25; 9-{4-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]piperidin-1-yl}-N-{2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-methanesulfonylethyl]-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl}nonanamide A26; 4-(10-{4-[2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1-oxo-2,3-dihydro-1H-isoindol-5-yl]piperidin-1-yl}decyl)-2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-methanesulfonylethyl]-2,3-dihydro-1H-isoindole-1,3-dione A27; 2-[4-(4-{4-[2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1-oxo-2,3-dihydro-1H-isoindol-5-yl]piperidin-1-yl}butyl)piperazin-1-yl]-N-{2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-methane-sulfonylethyl]-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl}acetamide A28; 6-{4-[2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1-oxo-2,3-dihydro-1H-isoindol-5-yl]-[1,4'-bipiperidin]-1'-yl}-N-{2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-methanesulfonylethyl]-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl}hexanamide A29; 5-{4-[2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1-oxo-2,3-dihydro-1H-isoindol-5-yl]-[1,4'-bipiperidin]-1'-yl}-N-{2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-methanesulfonylethyl]-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl}pentanamide A30; 3-[4-(3-{4-[2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1-oxo-2,3-dihydro-1H-isoindol-5-yl]piperidin-1-yl}propyl)piperazin-1-yl]-N-{2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-methanesulfonylethyl]-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl}propanamide A31; 8-(4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1-oxoisoindolin-4-yl)piperidin-1-yl)-N-(2-((S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)-1,3-dioxoisoindolin-4-yl)-octanamide A32; 3-(2-(2-(3-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)amino)propoxy)-ethoxy)ethoxy)-N-(2-((S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)-1,3-dioxo-isoindolin-4-yl)propanamide A33; N-(6-(2-(2-(2-(3-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)amino)-propoxy)-ethoxy)ethoxy)ethyl)-2-((S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)-1,3-dioxoisoindolin-4-yl)acetamide A34; 6-(4-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)ethynyl)piperidin-1-yl)-N-(2-((S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)-1,3-dioxoisoindolin-4-yl)-6-oxohexanamide A35; 8-(4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)piperidin-1-yl)-N-(2-((S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)-1,3-dioxoisoindolin-4-yl)octanamide A36; N-(6-(7-(4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)piperidin-1-yl)-heptyl)-2-((S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)-1,3-dioxoisoindolin-4-yl)acetamide A37; 7-((4-((5-((S)-2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)-methoxy)benzyl)amino)-N-(2-((S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)-ethyl)-1,3-dioxoisoindolin-4-yl)heptanamide A38; 5-((4-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methoxy)benzyl)amino)-N-(2-((S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)-1,3-dioxoisoindolin-4-yl)pentanamide A39; 2-{4-[(4-{[5-(2,6-dioxopiperidin-3-yl)-4-oxo-4H,5H,6H-thieno[3,4-c]pyrrol-1-yl]methoxy}phenyl)methyl]morpholin-2-yl}-N-{2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-methanesulfonylethyl]-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl}acetamide A40; 3-[2-(2-{[(4-{[5-(2,6-dioxopiperidin-3-yl)-4-oxo-4H,5H,6H-thieno[3,4-c]pyrrol-1-yl]methoxy}phenyl)methyl]amino}ethoxy)ethoxy]-N-{2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-methanesulfonylethyl]-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl}propanamide A41; 4-[4-(2-{[(4-{[5-(2,6-dioxopiperidin-3-yl)-4-oxo-4H,5H,6H-thieno[3,4-c]pyrrol-1-yl]methoxy}phenyl)methyl]amino}ethyl)phenyl]-N-{2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-methanesulfonylethyl]-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl}butanamide A42; 11-{[(4-{[5-(2,6-dioxopiperidin-3-yl)-4-oxo-4H,5H,6H-thieno[3,4-c]pyrrol-1-yl]methoxy}phenyl)methyl]amino}-N-{2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-methane-sulfonylethyl]-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl}undecanamide A43; 4-[(9-{[(4-{[5-(2,6-dioxopiperidin-3-yl)-4-oxo-4H,5H,6H-thieno[3,4-c]pyrrol-1-yl]methoxy}phenyl)methyl]amino}nonyl)amino]-2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-methanesulfonylethyl]-2,3-dihydro-1H-isoindole-1,3-dione A44; 4-[4-(2-{[(4-{[5-(2,6-dioxopiperidin-3-yl)-4-oxo-4H,5H,6H-thieno[3,4-c]pyrrol-1-yl]methoxy}phenyl)methyl]amino}ethyl)piperazin-1-yl]-N-{2-[(1S)-1-(3-ethoxy-4-methoxy-phenyl)-2-methanesulfonylethyl]-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl}butanamide A45; 11-{[(4-{[5-(2,6-dioxopiperidin-3-yl)-4-oxo-4H,5H,6H-thieno[3,4-c]pyrrol-1-yl]-methoxy}phenyl)methyl](methyl)amino}-N-{2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-methanesulfonylethyl]-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl}undecanamide A46; 8-(4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1-oxoisoindolin-4-yl)piperidin-1-yl)-N-(2-((S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)-1,3-dioxoisoindolin-4-yl)octanamide A47; 4-[1-(2-{[(4-{[5-(2,6-dioxopiperidin-3-yl)-4-oxo-4H,5H,6H-thieno[3,4-c]pyrrol-1-yl]methoxy}phenyl)methyl]amino}ethyl)-1H-1,2,3-triazol-4-yl]-N-{2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-methanesulfonylethyl]-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl}butanamide A48; 4-(10-{[(4-{[5-(2,6-dioxopiperidin-3-yl)-4-oxo-4H,5H,6H-thieno[3,4-c]pyrrol-1-yl]methoxy}phenyl)methyl]amino}decyl)-2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-methane-sulfonylethyl]-2,3-dihydro-1H-isoindole-1,3-dione A49; 4-[(9-{[(4-{[5-(2,6-dioxopiperidin-3-yl)-4-oxo-4H,5H,6H-thieno[3,4-c]pyrrol-1-yl]methoxy}phenyl)methyl]amino}nonyl)oxy]-2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-methanesulfonylethyl]-2,3-dihydro-1H-isoindole-1,3-dione A50; 4-({2-[4-(4-{[(4-{[5-(2,6-dioxopiperidin-3-yl)-4-oxo-4H,5H,6H-thieno[3,4-c]-pyrrol-1-yl]methoxy}phenyl)methyl]amino}butyl)phenyl]ethyl}amino)-2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-methanesulfonylethyl]-2,3-dihydro-1H-isoindole-1,3-dione A51; 4-[(11-{[(4-{[5-(2,6-dioxopiperidin-3-yl)-4-oxo-4H,5H,6H-thieno[3,4-c]pyrrol-1-yl]methoxy}phenyl)methyl]amino}undecyl)amino]-2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-methanesulfonylethyl]-2,3-dihydro-1H-isoindole-1,3-dione A52; 4-({4-[4-(2-{[(4-{[5-(2,6-dioxopiperidin-3-yl)-4-oxo-4H,5H,6H-thieno[3,4-c]-pyrrol-1-yl]methoxy}phenyl)methyl]amino}ethyl)phenyl]butyl}amino)-2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-methanesulfonylethyl]-2,3-dihydro-1H-isoindole-1,3-dione A53; 9-[4-(2-{[5-(2,6-dioxopiperidin-3-yl)-4-oxo-4H,5H,6H-thieno[3,4-c]pyrrol-1-yl]methoxy}acetyl)piperazin-1-yl]-N-{2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-methane-sulfonylethyl]-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl}nonanamide A54; 4-[4-(2-{[(4-{[5-(2,6-dioxopiperidin-3-yl)-4-oxo-4H,5H,6H-thieno[3,4-c]pyrrol-1-yl]methoxy}phenyl)methyl](methyl)amino}ethyl)phenyl]-N-{2-[(1S)-1-(3-ethoxy-4-methoxy-phenyl)-2-methanesulfonylethyl]-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl}butanamide A55; 11-(4-{[5-(2,6-dioxopiperidin-3-yl)-4-oxo-4H,5H,6H-thieno[3,4-c]pyrrol-1-yl]methoxy}phenyl)-N-{2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-methanesulfonylethyl]-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl}undecanamide A56; 11-(4-{[5-(2,6-dioxopiperidin-3-yl)-4-oxo-4H,5H,6H-thieno[3,4-c]pyrrol-1-yl]methoxy}phenyl)-N-{2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-methanesulfonylethyl]-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl}undecanamide A57; 8-(4-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methoxy)phenyl)-N-(2-((S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)-1,3-dioxoisoindolin-4-yl)octanamide A58; or N-(6-(7-(4-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methoxy)phenyl)heptyl)-2-((S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)-1,3-dioxoisoindolin-4-yl)acetamide A59; or a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0295] In another embodiment, provided herein is: N 1 -(2-((S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)-1,3-dioxo-isoindolin-4-yl)-N 10 -((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)-pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)decanediamide A60; (2S,4R)-1-[(2S)-2-(13-{7-acetamido-2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-methanesulfonylethyl]-1,3-dioxo-2,3-dihydro-1H-isoindol-5-yl}tridecanamido)-3,3-dimethyl-butanoyl]-4-hydroxy-N-{[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl}pyrrolidine-2-carboxamide A61; (2S,4R)-1-[(2S)-2-(11-{2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-methane-sulfonylethyl]-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl}undecanamido)-3,3-dimethylbutanoyl]-4-hydroxy-N-{[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl}pyrrolidine-2-carboxamide A62; (2S,4R)-1-[(2S)-2-(2-{4-[4-({2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-methane-sulfonylethyl]-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl}carbamoyl)butyl]piperazin-1-yl}acetamido)-3,3-dimethylbutanoyl]-4-hydroxy-N-{[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl}-pyrrolidine-2-carboxamide A63; N-{2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-methanesulfonylethyl]-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl}-N'-[(2S)-1-[(2S,4R)-4-hydroxy-2-({[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl}carbamoyl)pyrrolidin-1-yl]-3,3-dimethyl-1-oxobutan-2-yl]dodecanediamide A64; (2S,4R)-1-[(2S)-2-{[9-({2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-methane-sulfonylethyl]-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl}carbamoyl)nonyl]amino}-3,3-dimethyl-butanoyl]-4-hydroxy-N-{[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl}pyrrolidine-2-carboxamide A65; (2S,4R)-1-[(2S)-2-(5-{4-[2-({2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-methane-sulfonylethyl]-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl}amino)acetyl]piperazin-1-yl}pentan-amido)-3,3-dimethylbutanoyl]-4-hydroxy-N-{[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl}-pyrrolidine-2-carboxamide A66; N-{2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-methanesulfonylethyl]-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl}-N'-[(2S)-1-[(2S,4R)-4-hydroxy-2-({[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl}carbamoyl)pyrrolidin-1-yl]-3,3-dimethyl-1-oxobutan-2-yl]octanediamide A67; (2S,4R)-1-[(2S)-2-(2-{4-[4-({2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-methane-sulfonylethyl]-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl}carbamoyl)butyl]piperidin-1-yl}acetamido)-3,3-dimethylbutanoyl]-4-hydroxy-N-{[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl}-pyrrolidine-2-carboxamide A68; (2S,4R)-1-[(2S)-2-{[10-({2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-methane-sulfonylethyl]-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl}amino)decyl]amino}-3,3-dimethyl-butanoyl]-4-hydroxy-N-{[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl}pyrrolidine-2-carboxamide A69; (2S,4R)-1-[(2S)-2-{6-[4-(2-{2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-methane-sulfonylethyl]-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl}ethyl)piperidin-1-yl]hexanamido}-3,3-dimethylbutanoyl]-4-hydroxy-N-{[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl}pyrrolidine-2-carboxamide A70; (2S,4R)-1-[(2S)-2-(5-{1-[2-({2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-methane-sulfonylethyl]-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl}amino)acetyl]piperidin-4-yl}pentan-amido)-3,3-dimethylbutanoyl]-4-hydroxy-N-{[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl}-pyrrolidine-2-carboxamide A71; (2S,4R)-1-((S)-2-((8-((2-((S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)-ethyl)-1,3-dioxoisoindolin-4-yl)amino)-8-oxooctyl)amino)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide A72; (2S,4R)-1-((S)-2-((7-(7-acetamido-2-((S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)-1,3-dioxoisoindolin-5-yl)heptyl)amino)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide A73; (2S,4R)-1-[(2S)-2-acetamido-3,3-dimethylbutanoyl]-N-[(2-{[8-({2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-methanesulfonylethyl]-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl}-carbamoyl)octyl]oxy}-4-(4-methyl-1,3-thiazol-5-yl)phenyl)methyl]-4-hydroxypyrrolidine-2-carboxamide A74; (2S,4R)-1-[(2S)-2-acetamido-3,3-dimethylbutanoyl]-N-[(2-{[10-({2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-methanesulfonylethyl]-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl}-carbamoyl)decyl]oxy}-4-(4-methyl-1,3-thiazol-5-yl)phenyl)methyl]-4-hydroxypyrrolidine-2-carboxamide A75; or (2S,4R)-1-[(2S)-2-acetamido-3,3-dimethylbutanoyl]-N-[(2-{[6-({2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-methanesulfonylethyl]-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl}-carbamoyl)hexyl]oxy}-4-(4-methyl-1,3-thiazol-5-yl)phenyl)methyl]-4-hydroxypyrrolidine-2-carboxamide A76; or a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0296] In yet another embodiment, provided herein is: 8-[4-({[3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-6-yl]carbamoyl}-methyl)piperazin-1-yl]-N-{2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-methanesulfonylethyl]-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl}octanamide A77; 6-[4-({[3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-6-yl]carbamoyl}-methyl)piperazin-1-yl]-N-{2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-methanesulfonylethyl]-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl}hexanamide A78; 10-[4-({[3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-6-yl]carbamoyl}-methyl)piperazin-1-yl]-N-{2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-methanesulfonylethyl]-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl}decanamide A79; 8-[4-({[3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-7-yl]carbamoyl}-methyl)piperazin-1-yl]-N-{2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-methanesulfonylethyl]-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl}octanamide A80; 10-[4-({[3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-7-yl]carbamoyl}-methyl)piperazin-1-yl]-N-{2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-methanesulfonylethyl]-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl}decanamide A81; or 6-[4-({[3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-7-yl]carbamoyl}-methyl)piperazin-1-yl]-N-{2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-methanesulfonylethyl]-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl}hexanamide A82; or a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0297] In yet another embodiment, provided herein is: 6-[4-({[4-(2,6-dioxopiperidin-3-yl)phenyl]carbamoyl}methyl)piperazin-1-yl]-N-{2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-methanesulfonylethyl]-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl}hexanamide A83; 8-[4-({[4-(2,6-dioxopiperidin-3-yl)phenyl]carbamoyl}methyl)piperazin-1-yl]-N-{2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-methanesulfonylethyl]-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl}octanamide A84; 8-[4-({[3-(2,6-dioxopiperidin-3-yl)phenyl]carbamoyl}methyl)piperazin-1-yl]-N-{2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-methanesulfonylethyl]-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl}octanamide A85; 10-[4-({[4-(2,6-dioxopiperidin-3-yl)phenyl]carbamoyl}methyl)piperazin-1-yl]-N-{2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-methanesulfonylethyl]-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl}decanamide A86; 6-[4-({[3-(2,6-dioxopiperidin-3-yl)phenyl]carbamoyl}methyl)piperazin-1-yl]-N-{2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-methanesulfonylethyl]-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl}hexanamide A87; or 10-[4-({[3-(2,6-dioxopiperidin-3-yl)phenyl]carbamoyl}methyl)piperazin-1-yl]-N-{2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-methanesulfonylethyl]-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl}decanamide A88; or a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0298] In yet another embodiment, provided herein is: N-{6-[12-({3-[(2,6-dioxopiperidin-3-yl)amino]phenyl}amino)dodecyl]-2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-methanesulfonylethyl]-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl}acetamide A89; 4-amino-6-[12-({3-[(2,6-dioxopiperidin-3-yl)amino]phenyl}amino)dodecyl]-2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-methanesulfonylethyl]-2,3-dihydro-1H-isoindole-1,3-dione A90; 9-({3-[(2,6-dioxopiperidin-3-yl)amino]phenyl}amino)-N-{2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-methanesulfonylethyl]-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl}nonanamide A91; or 6-{4-[({3-[(2,6-dioxopiperidin-3-yl)amino]phenyl}carbamoyl)methyl]piperazin-1-yl}-N-{2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-methanesulfonylethyl]-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl}hexanamide A92; or a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0299] In yet another embodiment, provided herein is: N-(3,5-dichloropyridin-4-yl)-4-(difluoromethoxy)-3-((7-(4-(2-(2,6-dioxo-piperidin-3-yl)-6-fluoro-1-oxoisoindolin-4-yl)piperidin-1-yl)heptyl)oxy)benzamide B1; N-(3,5-dichloropyridin-4-yl)-4-(difluoromethoxy)-3-((5-(4-((2-(2,6-dioxo-piperidin-3-yl)-1-oxoisoindolin-4-yl)ethynyl)piperidin-1-yl)-5-oxopentyl)oxy)benzamide B2; N-(3,5-dichloropyridin-4-yl)-4-(difluoromethoxy)-3-((7-(4-(2-(2,6-dioxo-piperidin-3-yl)-6-fluoro-1-oxoisoindolin-5-yl)piperidin-1-yl)heptyl)oxy)benzamide B3; N-(3,5-dichloropyridin-4-yl)-4-(difluoromethoxy)-3-((9-(4-(2-(2,6-dioxo-piperidin-3-yl)-6-fluoro-1-oxoisoindolin-4-yl)piperidin-1-yl)nonyl)oxy)benzamide B4; N-(3,5-dichloropyridin-4-yl)-4-(difluoromethoxy)-3-((5-(4-(2-(2,6-dioxo-piperidin-3-yl)-6-fluoro-1-oxoisoindolin-4-yl)piperidin-1-yl)pentyl)oxy)benzamide B5; N-(3,5-dichloropyridin-4-yl)-4-(difluoromethoxy)-3-((7-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)heptyl)oxy)benzamide B6; N-(3,5-dichloropyridin-4-yl)-4-(difluoromethoxy)-3-((12-(4-(2-(2,6-dioxo-piperidin-3-yl)-6-fluoro-1-oxoisoindolin-4-yl)piperidin-1-yl)dodecyl)oxy)benzamide B7; N-(3,5-dichloropyridin-4-yl)-3-(difluoromethoxy)-4-(2-(2-(2-(2-((2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethoxy)ethoxy)ethoxy)ethoxy)benzamide B8; 3-(cyclopropylmethoxy)-N-(3,5-dichloropyridin-4-yl)-4-(2-(2-(2-(3-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)amino)propoxy)ethoxy)ethoxy)ethoxy)benzamide B9; 3-(cyclopropylmethoxy)-N-(3,5-dichloropyridin-4-yl)-4-((7-(4-(2-(2,6-dioxo-piperidin-3-yl)-6-fluoro-1-oxoisoindolin-4-yl)piperidin-1-yl)heptyl)oxy)benzamide B10; N-(3,5-dichloropyridin-4-yl)-4-(difluoromethoxy)-3-(3-(4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1-oxoisoindolin-4-yl)piperidin-1-yl)propoxy)benzamide B11; 3-(cyclopropylmethoxy)-N-(3,5-dichloropyridin-4-yl)-4-((9-(4-(2-(2,6-dioxo-piperidin-3-yl)-6-fluoro-1-oxoisoindolin-4-yl)piperidin-1-yl)nonyl)oxy)benzamide B12; 3-((9-(4-(2-(1-acetamido-1-oxopropan-2-yl)-6-fluoro-1-oxoisoindolin-4-yl)-piperidin-1-yl)nonyl)oxy)-N-(3,5-dichloropyridin-4-yl)-4-(difluoromethoxy)benzamide B13; N-(3,5-dichloropyridin-4-yl)-4-(difluoromethoxy)-3-((7-(1-(2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxoisoindolin-4-yl)piperidin-4-yl)heptyl)oxy)benzamide B14; N-(3,5-dichloropyridin-4-yl)-4-(difluoromethoxy)-3-(2-{4-[2-(2,6-dioxo-piperidin-3-yl)-6-fluoro-1-oxo-2,3-dihydro-1H-isoindol-5-yl]piperidin-1-yl}ethoxy)benzamide B15; N-(3,5-dichloropyridin-4-yl)-4-(difluoromethoxy)-3-(2-(2-(2-(3-((2-(2,6-dioxo-piperidin-3-yl)-1-oxoisoindolin-4-yl)amino)propoxy)ethoxy)ethoxy)ethoxy)benzamide B16; N-(3,5-dichloropyridin-4-yl)-4-(difluoromethoxy)-3-((7-(4-(2-(2,6-dioxo-piperidin-3-yl)-1-oxoisoindolin-4-yl)piperidin-1-yl)heptyl)oxy)benzamide B17; N-(3,5-dichloropyridin-4-yl)-4-(difluoromethoxy)-3-((7-((4-((5-(2,6-dioxo-piperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methoxy)benzyl)amino)heptyl)-oxy)benzamide B18; or N-(3,5-dichloropyridin-4-yl)-4-(difluoromethoxy)-3-((7-(4-((5-(2,6-dioxo-piperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methoxy)phenyl)heptyl)oxy)-benzamide B19; or a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0300] In yet another embodiment, provided herein is: (2S,4R)-1-((S)-2-(9-(5-((3,5-dichloropyridin-4-yl)carbamoyl)-2-(difluoro-methoxy)phenoxy)nonanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide B20; (2S,4R)-1-((S)-2-(11-(5-((3,5-dichloropyridin-4-yl)carbamoyl)-2-(difluoro-methoxy)phenoxy)undecanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide B21; (2S,4R)-1-((S)-2-(9-(2-(cyclopropylmethoxy)-5-((3,5-dichloropyridin-4-yl)-carbamoyl)phenoxy)nonanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide B22; or (2S,4R)-1-((S)-2-((7-(5-((3,5-dichloropyridin-4-yl)carbamoyl)-2-(difluoro-methoxy)-phenoxy)heptyl)amino)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)-pyrrolidine-2-carboxamide B23; or a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0301] In yet another embodiment, provided herein is: N-(3,5-dichloropyridin-4-yl)-4-(difluoromethoxy)-3-(2-(4-(2-((3-((2,6-dioxo-piperidin-3-yl)amino)phenyl)amino)-2-oxoethyl)piperazin-1-yl)ethoxy)benzamide B24; or N-(3,5-dichloropyridin-4-yl)-4-(difluoromethoxy)-3-(4-(4-(2-((3-((2,6-dioxo-piperidin-3-yl)amino)phenyl)amino)-2-oxoethyl)piperazin-1-yl)butoxy)benzamide B25; or a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0302] In certain embodiments, compounds provided herein are 8-(4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1-oxoisoindolin-4-yl)piperidin-1-yl)-N-(2-((S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)-1,3-dioxoisoindolin-4-yl)octanamide; N-(6-(7-(4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1-oxoisoindolin-4-yl)piperidin-1-yl)heptyl)-2-((S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)-1,3-dioxoisoindolin-4-yl)acetamide; 3-(2-(2-(3-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)amino)propoxy)ethoxy)ethoxy)-N-(2-((S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)-1,3-dioxoisoindolin-4-yl)propenamide; N-(6-(2-(2-(2-(3-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)amino)propoxy)ethoxy)-ethoxy)ethyl)-2-((S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)-1,3-dioxo-isoindolin-4-yl)acetamide; 6-(4-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)ethynyl)-piperidin-1-yl)-N-(2-((S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)-1,3-dioxo-isoindolin-4-yl)-6-oxohexanamide; N-(6-(5-(4-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)ethynyl)piperidin-1-yl)-5-oxopentyl)-2-((S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)-1,3-dioxoisoindolin-4-yl)acetamide;8-(4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)piperidin-1-yl)-N-(2-((S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)-ethyl)-1,3-dioxoisoindolin-4-yl)octanamide; N-(6-(7-(4-(2-(2,6-dioxopiperidin-3-yl)-1-oxo-isoindolin-4-yl)piperidin-1-yl)heptyl)-2-((S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)-ethyl)-1,3-dioxoisoindolin-4-yl)acetamide; 8-(4-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methoxy)phenyl)-N-(2-((S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)-1,3-dioxoisoindolin-4-yl)octanamide; N-(6-(7-(4-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methoxy)phenyl)heptyl)-2-((S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)-1,3-dioxoisoindolin-4-yl)acetamide; (2S,4R)-1-((S)-2-((8-((2-((S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)-1,3-dioxo-isoindolin-4-yl)amino)-8-oxooctyl)amino)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methyl-thiazol-5-yl)benzyl)pyrrolidine-2-carboxamide; and 2S,4R)-1-((S)-2-((7-(7-acetamido-2-((S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)-1,3-dioxoisoindolin-5-yl)heptyl)amino)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;

[0303] In certain embodiments, compounds provided herein are 3-(cyclopropylmethoxy)-N-(3,5-dichloropyridin-4-yl)-4-(difluoromethoxy)-N-(7-(4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1-oxoisoindolin-4-yl)piperidin-1-yl)heptyl)benzamide; N-(3,5-dichloropyridin-4-yl)-4-(difluoromethoxy)-3-((7-(4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1-oxoisoindolin-4-yl)piperidin-1-yl)heptyl)oxy)benzamide; 3-(cyclopropylmethoxy)-N-(3,5-dichloropyridin-4-yl)-4-(difluoromethoxy)-N-(2-(2-(2-(3-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)amino)propoxy)ethoxy)ethoxy)ethyl)benzamide; N-(3,5-dichloropyridin-4-yl)-4-(difluoromethoxy)-3-(2-(2-(2-(3-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)-amino)propoxy)ethoxy)ethoxy)ethoxy)benzamide; 3-(cyclopropylmethoxy)-N-(3,5-dichloro-pyridin-4-yl)-4-(difluoromethoxy)-N-(5-(4-((2-(2,6-dioxopiperidin-3-yl)-1-oxo-isoindolin-4-yl)-ethynyl)piperidin-1-yl)-5-oxopentyl)benzamide; N-(3,5-dichloropyridin-4-yl)-4-(difluoro-methoxy)-3-((5-(4-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)ethynyl)-piperidin-1-yl)-5-oxopentyl)oxy)benzamide; 3-(cyclopropylmethoxy)-N-(3,5-dichloropyridin-4-yl)-4-(difluoro-methoxy)-N-(7-(4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)piperidin-1-yl)heptyl)-benzamide;N-(3,5-dichloropyridin-4-yl)-4-(difluoromethoxy)-3-((7-(4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)piperidin-1-yl)heptyl)oxy)benzamide; 3-(cyclopropylmethoxy)-N-(3,5-dichloropyridin-4-yl)-4-(difluoromethoxy)-N-(7-(4-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methoxy)phenyl)heptyl)benzamide; N-(3,5-dichloropyridin-4-yl)-4-(difluoromethoxy)-3-((7-(4-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methoxy)phenyl)heptyl)oxy)benzamide; Neither (2S,4R)-1-((S)-2-((7-(3-(cyclopropylmethoxy)-N-(3,5-dichloropyridin-4-yl)-4-(difluoromethoxy)benzamido)heptyl)-amino)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide; nor (2S,4R)-1-((S)-2-((7-(5-((3,5-dichloropyridin-4-yl)carbamoyl)-2-(difluoromethoxy)phenoxy)heptyl)amino)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;

[0304] In some embodiments, the compounds provided herein are deuterium enriched. In some embodiments, the compounds provided herein are carbon-13 enriched. In some embodiments, the compounds provided herein are carbon-14 enriched. In some embodiments, the compounds provided herein are nitrogen enriched. 15 N; for oxygen 17 O or 18 O and sulfur 34 S, 35 S, or36 Contains one or more uncommon isotopes of other elements, including but not limited to S.

[0305] In some embodiments, the compounds provided herein have an isotopic enrichment factor of about 5 or more, about 10 or more, about 20 or more, about 50 or more, about 100 or more, about 200 or more, about 500 or more, about 1,000 or more, about 2,000 or more, about 5,000 or more, or about 10,000 or more. However, in any case, the isotopic enrichment factor of a specified isotope does not exceed the maximum isotopic enrichment factor of the specified isotope, which is the isotopic enrichment factor when the compound is 100% enriched with the specified isotope at a given position. Therefore, the maximum isotopic enrichment factor for different isotopes is different. The maximum isotopic enrichment factor is 6,410 for deuterium and 90 for carbon-13.

[0306] In certain embodiments, the compounds provided herein have an RI of about 64 (about 1% deuterium enriched) or greater, about 130 (about 2% deuterium enriched) or greater, about 320 (about 5% deuterium enriched) or greater, about 640 (about 10% deuterium enriched) or greater, about 1,300 (about 20% deuterium enriched) or greater, about 3,200 (about 50% deuterium enriched) or greater, about 4,800 (about 75% deuterium enriched) or greater, about 5,130 (about 80% deuterium enriched) or greater. The deuterium enrichment factor may be greater than or equal to about 5,450 (about 85% deuterium enriched), greater than or equal to about 5,770 (about 90% deuterium enriched), greater than or equal to about 6,090 (about 95% deuterium enriched), greater than or equal to about 6,220 (about 97% deuterium enriched), greater than or equal to about 6,280 (about 98% deuterium enriched), greater than or equal to about 6,350 (about 99% deuterium enriched), or greater than or equal to about 6,380 (about 99.5% deuterium enriched). Deuterium enrichment can be determined using routine analytical methods known to those skilled in the art, including mass spectrometry and nuclear magnetic resonance spectroscopy. In certain embodiments, at least one atom of a compound provided herein that is specified as being deuterium enriched has a deuterium enrichment of greater than or equal to about 50%, greater than or equal to about 70%, greater than or equal to about 80%, greater than or equal to about 90%, or greater than or equal to about 98%.

[0307] In certain embodiments, the compounds provided herein are isolated or purified, ie, at least about 90%, at least about 95%, at least about 98%, at least about 99%, or at least about 99.5% pure by weight.

[0308] The compounds provided herein are intended to encompass all possible stereoisomers unless a specific stereochemistry is specified. When a compound provided herein contains an alkenyl group, the compound can exist as one or a mixture of cis / trans (or Z / E) geometric isomers. Where structural isomers are interchangeable, the compound can exist as a single tautomer or a mixture of tautomers. This can take the form of proton tautomerism in compounds containing imino, keto, or oxime groups; or so-called valence tautomerism in compounds containing aromatic moieties. A single compound may exhibit more than one type of isomerism.

[0309] The compounds provided herein can be enantiomerically pure, such as a single enantiomer or a single diastereomer, or can be a stereoisomeric mixture, such as a mixture of enantiomers, e.g., a racemic mixture of two enantiomers; or a mixture of two or more diastereomers. Thus, those skilled in the art will recognize that, for compounds that undergo epimerization in vivo, administration of a compound in its (R) form is equivalent to administration of the compound in its (S) form. Conventional techniques for the preparation / isolation of individual enantiomers include synthesis from appropriate optically pure precursors, asymmetric synthesis from achiral starting materials, or resolution of enantiomeric mixtures, e.g., chiral chromatography, recrystallization, resolution, formation of diastereomeric salts, or derivatization to diastereomeric adducts followed by separation.

[0310] When the compounds provided herein contain an acidic or basic moiety, they can also be provided as pharmaceutically acceptable salts.See Berge et al., J. Pharm. Sci. 1977, 66, 1-19; "Handbook of Pharmaceutical Salts: Properties, Selection, and Use", 2nd Edition; Stahl and Wermuth, eds.; John Wiley & Sons, 2011.In some embodiments, the pharmaceutically acceptable salts of the compounds provided herein are solvates.In some embodiments, the pharmaceutically acceptable salts of the compounds provided herein are hydrates.

[0311] Suitable acids for use in preparing the pharmaceutically acceptable salts of the compounds provided herein include acetic acid, 2,2-dichloroacetic acid, acylated amino acids, adipic acid, alginic acid, ascorbic acid, L-aspartic acid, benzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, boric acid, (+)-camphoric acid, camphorsulfonic acid, (+)-(1S)-camphor-10-sulfonic acid, capric acid, caproic acid, caprylic acid, cinnamic acid, citric acid, cyclamic acid, cyclohexanesulfamic acid, dodecyl sulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, 2-hydroxy-ethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid, D-gluconic acid, D-glucuronic acid, L-glutamic acid, α- These include, but are not limited to, oxoglutaric acid, glycolic acid, hippuric acid, hydrobromic acid, hydrochloric acid, hydroiodic acid, (+)-L-lactic acid, (±)-DL-lactic acid, lactobionic acid, lauric acid, maleic acid, (-)-L-malic acid, malonic acid, (±)-DL-mandelic acid, methanesulfonic acid, naphthalene-2-sulfonic acid, naphthalene-1,5-disulfonic acid, 1-hydroxy-2-naphthoic acid, nicotinic acid, nitric acid, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid, perchloric acid, phosphoric acid, L-pyroglutamic acid, saccharic acid, salicylic acid, 4-amino-salicylic acid, sebacic acid, stearic acid, succinic acid, sulfuric acid, tannic acid, (+)-L-tartaric acid, thiocyanic acid, p-toluenesulfonic acid, undecylenic acid, and valeric acid.

[0312] Bases suitable for use in preparing the pharmaceutically acceptable salts of the compounds provided herein include inorganic bases such as magnesium hydroxide, calcium hydroxide, potassium hydroxide, zinc hydroxide, or sodium hydroxide; as well as L-arginine, benethamine, benzathine, choline, deanol, diethanolamine, diethylamine, dimethylamine, dipropylamine, diisopropylamine, 2-(diethylamino)-ethanol, ethanolamine, ethylamine, ethylenediamine, isopropylamine, N-methyl-glucamine, hydrabamine, 1H-imidazole, L- These include, but are not limited to, organic bases such as primary, secondary, tertiary, and quaternary aliphatic and aromatic amines, including, but not limited to, lysine, morpholine, 4-(2-hydroxyethyl)-morpholine, methylamine, piperidine, piperazine, propylamine, pyrrolidine, 1-(2-hydroxyethyl)-pyrrolidine, pyridine, quinuclidine, quinoline, isoquinoline, triethanolamine, trimethylamine, triethylamine, N-methyl-D-glucamine, 2-amino-2-(hydroxymethyl)-1,3-propanediol, and tromethamine.

[0313] The compounds provided herein may also be provided as prodrugs, which are functional derivatives of the compounds and can be easily converted into the parent compounds in vivo. In some situations, prodrugs are often useful because they can be administered more easily than the parent compounds. For example, prodrugs may be bioavailable by oral administration, whereas the parent compounds may not. Prodrugs may also have increased solubility in pharmaceutical compositions over the parent compounds. Prodrugs can be converted into the parent drugs by various mechanisms, including enzymatic processing and metabolic hydrolysis.

[0314] (Pharmaceutical composition) In one embodiment, provided herein is a pharmaceutical composition comprising a compound provided herein, e.g., a compound of Formula (I) or Formula (IA), or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; and a pharmaceutically acceptable excipient.

[0315] The pharmaceutical compositions provided herein can be formulated into various dosage forms, including, but not limited to, dosage forms for oral, parenteral, and topical administration. The pharmaceutical compositions can also be formulated as modified-release dosage forms, such as delayed-release, extended-release, prolonged-release, sustained-release, pulsed-release, controlled-release, accelerated-release, fast-release, targeted-release, programmed-release, and gastric retention dosage forms. These dosage forms can be prepared according to conventional methods and techniques known to those skilled in the art. See, for example, "Remington: The Science and Practice of Pharmacy," supra; "Modified-Release Drug Delivery Technology," 2nd ed., edited by Rathbone et al.; Drugs and the Pharmaceutical Sciences 184; CRC Press: Boca Raton, FL, 2008.

[0316] In one embodiment, the pharmaceutical compositions provided herein are formulated into a dosage form for oral administration.In another embodiment, the pharmaceutical compositions provided herein are formulated into a dosage form for parenteral administration.In yet another embodiment, the pharmaceutical compositions provided herein are formulated into a dosage form for intravenous administration.In yet another embodiment, the pharmaceutical compositions provided herein are formulated into a dosage form for intramuscular administration.In yet another embodiment, the pharmaceutical compositions provided herein are formulated into a dosage form for subcutaneous administration.In yet another embodiment, the pharmaceutical compositions provided herein are formulated into a dosage form for topical administration.

[0317] The pharmaceutical compositions provided herein can be provided in unit-dosage form or multiple-dosage form. Unit-dosage form, as used herein, refers to a physically discrete unit suitable for administration to a subject and packaged individually as known in the art. Each unit dose contains a predetermined amount of active ingredient (e.g., a compound provided herein) sufficient to produce the desired therapeutic effect, in association with the required pharmaceutical excipients. Examples of unit-dosage forms include, but are not limited to, ampoules, syringes, and individually packaged tablets and capsules. Unit-dosage forms may be administered in fractions or multiples thereof. A multiple-dosage form is a plurality of identical unit-dosage forms packaged in a single container to be administered in segregated unit-dosage form. Examples of multiple-dosage forms include, but are not limited to, vials, bottles of tablets or capsules, or bottles of pints or gallons.

[0318] The pharmaceutical compositions provided herein can be administered once or multiple times at time intervals.It is understood that the exact dosage and duration of treatment can vary depending on the age, weight, and condition of the subject being treated, and can be determined empirically using known testing protocols or by extrapolation from in vivo or in vitro tests or diagnostic data.It is further understood that for any particular individual, the specific dosage regimen must be adjusted over time according to the needs of the subject and the professional judgment of the person administering or supervising the administration of the pharmaceutical composition.

[0319] (A. Oral Administration) The pharmaceutical compositions for oral administration provided herein can be provided in solid, semi-solid, or liquid dosage forms for oral administration. As used herein, oral administration also includes buccal, lingual, and sublingual administration. Suitable oral dosage forms include, but are not limited to, tablets, fastmelts, chewable tablets, capsules, pills, strips, lozenges, lozenges, pastilles, cachets, pellets, medicated chewing gum, bulk powders, effervescent or non-effervescent powders or granules, oral mists, solutions, emulsions, suspensions, wafers, sprinkles, elixirs, and syrups. The pharmaceutical compositions may contain, in addition to the active ingredient, one or more pharmaceutically acceptable carriers or excipients including, but not limited to, binders, fillers, diluents, disintegrants, wetting agents, lubricants, glidants, colorants, color transfer inhibitors, sweeteners, flavoring agents, emulsifiers, suspending and dispersing agents, preservatives, solvents, non-aqueous liquids, organic acids, and a carbon dioxide source.

[0320] Binders or granulating agents impart cohesive properties to the tablet and ensure that the tablet remains intact after compression. Suitable binders or granulating agents include starches such as corn starch, potato starch, and pregelatinized starch (e.g., STARCH 1500®); gelatin; sugars such as sucrose, glucose, dextrose, molasses, and lactose; natural and synthetic gums such as gum arabic, alginic acid, alginates, Chorizoides extract, panwar gum, ghatti gum, isagol husk mucilage, carboxymethylcellulose, methylcellulose, polyvinylpyrrolidone (PVP), Veegum®, larch arabinogalactan, powdered tragacanth, and guar gum; celluloses such as ethylcellulose, cellulose acetate, calcium carboxymethylcellulose, sodium carboxymethylcellulose, methylcellulose, hydroxyethylcellulose (HEC), hydroxypropylcellulose (HPC), hydroxypropylmethylcellulose (HPMC); and AVICEL® PH-101, AVICEL® PH-103, AVICEL® Suitable fillers include, but are not limited to, microcrystalline cellulose such as PH-105 and AVICEL® RC-581. Suitable fillers include, but are not limited to, talc, calcium carbonate, microcrystalline cellulose, powdered cellulose, dextrates, kaolin, mannitol, silicic acid, sorbitol, starch, and pregelatinized starch. The amount of binder or filler in the pharmaceutical compositions provided herein varies depending on the type of formulation and is readily discernible to one of ordinary skill in the art. The binder or filler may be present in the pharmaceutical compositions provided herein in an amount of about 50 to about 99% by weight.

[0321] Suitable diluents include, but are not limited to, dicalcium phosphate, calcium sulfate, lactose, sorbitol, sucrose, inositol, cellulose, kaolin, mannitol, sodium chloride, dry starch, and powdered sugar. Some diluents, such as mannitol, lactose, sorbitol, sucrose, and inositol, when present in sufficient amounts, can impart properties to some compressed tablets that allow them to disintegrate in the mouth by chewing. Such compressed tablets can be used as chewable tablets. The amount of diluent in the pharmaceutical compositions provided herein varies depending on the type of formulation and can be easily determined by those skilled in the art.

[0322] Suitable disintegrants include, but are not limited to, agar; bentonite; celluloses such as methylcellulose and carboxymethylcellulose; wood products; natural sponge; cation exchange resins; alginic acid; gums such as guar gum and Veegum® HV; citrus pulp; cross-linked celluloses such as croscarmellose; cross-linked polymers such as crospovidone; cross-linked starch; calcium carbonate; microcrystalline celluloses such as sodium starch glycolate; polacrilin potassium; starches such as corn starch, potato starch, tapioca starch, and pregelatinized starch; clay; and algin. The amount of disintegrant in the pharmaceutical compositions provided herein varies depending on the type of formulation and is readily discernible to those skilled in the art. The pharmaceutical compositions provided herein may contain about 0.5 to about 15% or about 1 to about 5% by weight of disintegrant.

[0323] Suitable lubricants include calcium stearate; magnesium stearate; mineral oil; light mineral oil; glycerin; sorbitol; mannitol; glycols such as glycerol behenate and polyethylene glycol (PEG); stearic acid; sodium lauryl sulfate; talc; hydrogenated vegetable oils such as peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, and soybean oil; zinc stearate; ethyl oleate; ethyl laurate; agar; starch; Examples of lubricants include, but are not limited to, lycopodium; and silica or silica gels such as AEROSIL® 200 and CAB-O-SIL®. The amount of lubricant in the pharmaceutical compositions provided herein varies depending on the type of formulation and is readily discernible to one of ordinary skill in the art. The pharmaceutical compositions provided herein may contain about 0.1 to about 5% by weight of lubricant.

[0324] Suitable glidants include, but are not limited to, colloidal silicon dioxide, CAB-O-SIL®, and asbestos-free talc. Suitable coloring agents include, but are not limited to, any of the approved, certified, water-soluble FD&C dyes, water-insoluble FD&C dyes suspended on alumina hydrate, and color lakes. Color lakes are the combination of a water-soluble dye by adsorption to a hydrous oxide of a heavy metal, rendering the dye insoluble. Suitable flavoring agents include, but are not limited to, natural flavors extracted from plants such as fruits, and synthetic blends of compounds that produce a pleasant taste, such as peppermint and methyl salicylate. Suitable sweetening agents include, but are not limited to, sucrose, lactose, mannitol, syrup, glycerin, and artificial sweeteners such as saccharin and aspartame. Suitable emulsifying agents include, but are not limited to, gelatin, gum arabic, tragacanth, bentonite, and surfactants such as polyoxyethylene sorbitan monooleate (TWEEN® 20), polyoxyethylene sorbitan monooleate 80 (TWEEN® 80), and triethanolamine oleate. Suitable suspending and dispersing agents include, but are not limited to, sodium carboxymethylcellulose, pectin, tragacanth, Veegum®, gum arabic, sodium carbomethylcellulose, hydroxypropyl methylcellulose, and polyvinylpyrrolidone. Suitable preservatives include, but are not limited to, glycerin, methyl and propylparaben, benzoic acid, sodium benzoate, and alcohol. Suitable wetting agents include, but are not limited to, propylene glycol monostearate, sorbitan monooleate, diethylene glycol monolaurate, and polyoxyethylene lauryl ether. Suitable solvents include, but are not limited to, glycerin, sorbitol, ethyl alcohol, and syrup. Suitable non-aqueous liquids utilized in emulsions include, but are not limited to, mineral oil and cottonseed oil. Suitable organic acids include, but are not limited to, citric acid and tartaric acid.Suitable sources of carbon dioxide include, but are not limited to, sodium bicarbonate and sodium carbonate.

[0325] It should be understood that many carriers and excipients may serve several functions, even within the same formulation.

[0326] The pharmaceutical compositions for oral administration provided herein can be provided as compressed tablets, molded tablets, chewable lozenges, quick-dissolving tablets, multi-layer compressed tablets, or enteric-coated tablets, sugar-coated tablets, or film-coated tablets. Enteric-coated tablets are compressed tablets coated with a substance that resists the action of stomach acid but dissolves or disintegrates in the intestine, thereby protecting the active ingredients from the acidic environment of the stomach. Enteric coatings include, but are not limited to, fatty acids, fats, phenyl salicylate, waxes, shellac, ammoniated shellac, and cellulose acetate phthalate. Sugar-coated tablets are compressed tablets surrounded by a sugar coating, which can be beneficial in masking objectionable tastes or odors and protecting the tablets from oxidation. Film-coated tablets are compressed tablets coated with a thin layer or film of a water-soluble substance. Film coatings include, but are not limited to, hydroxyethylcellulose, sodium carboxymethylcellulose, polyethylene glycol 4000, and cellulose acetate phthalate. Film coatings exhibit the same general characteristics as sugar coatings. Multilayer compressed tablets are compressed tablets made by more than one compression cycle, including layered tablets and press-coated or dry-coated tablets.

[0327] Tablet dosage forms can be prepared from the active ingredient in powdered, crystalline, or granular form, alone or in combination with one or more carriers or excipients described herein, such as binders, disintegrants, release-controlling polymers, lubricants, diluents, and / or coloring agents. Flavoring and sweetening agents are particularly useful in the production of chewable tablets and lozenges.

[0328] The pharmaceutical compositions for oral administration provided herein can be provided as soft or hard capsules, which can be made from gelatin, methylcellulose, starch, or calcium alginate. Hard gelatin capsules, also known as dry-fill capsules (DFCs), consist of two sections, one sliding over the other, completely enclosing the active ingredient. Soft elastic capsules (SECs) are soft, spherical shells, such as gelatin shells, plasticized by the addition of glycerin, sorbitol, or similar polyols. Soft gelatin shells may contain preservatives to prevent microbial growth. Suitable preservatives are those described herein, including methylparaben, propylparaben, and sorbic acid. The liquid, semisolid, and solid dosage forms provided herein may be encapsulated. Suitable liquid and semisolid dosage forms include solutions and suspensions in propylene carbonate, vegetable oils, or triglycerides. Capsules containing such solutions can be prepared as described in U.S. Patent Nos. 4,328,245; 4,409,239; and 4,410,545. The capsules may also be coated as known to those skilled in the art to modify or maintain dissolution of the active ingredient.

[0329] The pharmaceutical compositions for oral administration provided herein can be provided in liquid and semisolid dosage forms, including emulsions, solutions, suspensions, elixirs, and syrups. Emulsions are two-phase systems in which one liquid is dispersed in the form of small globules throughout another liquid and can be oil-in-water or water-in-oil. Emulsions may contain a pharmaceutically acceptable non-aqueous liquid or solvent, an emulsifier, and a preservative. Suspensions may contain a pharmaceutically acceptable suspending agent and a preservative. Hydroalcoholic solutions may contain a pharmaceutically acceptable acetal, such as a di(lower alkyl)acetal of a lower alkyl aldehyde, e.g., acetaldehyde diethyl acetal; and a water-miscible solvent having one or more hydroxyl groups, such as propylene glycol and ethanol. Elixirs are clear, sweetened hydroalcoholic solutions. Syrups are concentrated aqueous solutions of a sugar, e.g., sucrose, and may also contain a preservative. For a liquid dosage form, the solution, for example, in a polyethylene glycol solvent, may be diluted with a sufficient quantity of a pharmaceutically acceptable liquid carrier, e.g., water, to be conveniently measured for administration.

[0330] Other useful liquid and semisolid dosage forms include, but are not limited to, those containing an active ingredient and dialkylated mono- or poly-alkylene glycols, including 1,2-dimethoxymethane, diglyme, triglyme, tetraglyme, polyethylene glycol-350-dimethyl ether, polyethylene glycol-550-dimethyl ether, polyethylene glycol-750-dimethyl ether (where 350, 550, and 750 refer to the approximate average molecular weights of the polyethylene glycol). These dosage forms may further contain one or more antioxidants, such as butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), propyl gallate, vitamin E, hydroquinone, hydroxycoumarin, ethanolamine, lecithin, cephalin, ascorbic acid, malic acid, sorbitol, phosphoric acid, bisulfite, sodium metabisulfite, thiodipropionic acid and its esters, and dithiocarbamates.

[0331] The pharmaceutical compositions for oral administration provided herein can also be provided in the form of liposomes, micelles, microspheres, or nanosystems. Micelle dosage forms can be prepared as described in U.S. Patent No. 6,350,458.

[0332] The pharmaceutical compositions for oral administration provided herein can be provided as non-effervescent or effervescent granules and powders for reconstitution into a liquid dosage form. Pharmaceutically acceptable carriers and excipients used in non-effervescent granules or powders may include diluents, sweeteners, and wetting agents. Pharmaceutically acceptable carriers and excipients used in effervescent granules or powders may include organic acids and a carbon dioxide source.

[0333] Coloring and flavoring agents can be used in all of the dosage forms described herein.

[0334] The pharmaceutical compositions for oral administration provided herein can be formulated as immediate or modified release dosage forms, including delayed-, sustained-, pulsed-, controlled-, targeted-, and programmed-release forms.

[0335] (B. Parenteral Administration) The pharmaceutical compositions provided herein can be administered parenterally by injection, infusion, or implantation for local or systemic administration. Parenteral administration as used herein includes intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraureteral, intrasternal, intracranial, intramuscular, intrasynovial, intravesical, and subcutaneous administration.

[0336] The pharmaceutical compositions for parenteral administration provided herein can be formulated in any dosage form suitable for parenteral administration, including, but not limited to, solutions, suspensions, emulsions, micelles, liposomes, microspheres, nanosystems, and the like, as well as solid forms suitable for solution or suspension in liquid prior to injection. Such dosage forms can be prepared according to conventional methods known to those skilled in the art of pharmaceutical sciences. See, e.g., Remington: The Science and Practice of Pharmacy, supra.

[0337] Pharmaceutical compositions for parenteral administration provided herein can comprise one or more pharmaceutically acceptable carriers and excipients, including, but not limited to, aqueous vehicles, water-miscible vehicles, non-aqueous vehicles, antimicrobial agents or preservatives to prevent the growth of microorganisms, stabilizers, solubility enhancers, isotonicity agents, buffers, antioxidants, local anesthetics, suspending and dispersing agents, wetting or emulsifying agents, complexing agents, sequestering or chelating agents, cryoprotectants, lyoprotectants, thickening agents, pH adjusting agents, and inert gases.

[0338] Suitable aqueous vehicles include, but are not limited to, water, saline, normal saline or phosphate-buffered saline (PBS), sodium chloride injection, Ringer's injection, isotonic dextrose injection, sterile water injection, dextrose and lactated Ringer's injection. Suitable non-aqueous vehicles include, but are not limited to, fixed oils of vegetable origin, castor oil, corn oil, cottonseed oil, olive oil, peanut oil, peppermint oil, safflower oil, sesame oil, soybean oil, hydrogenated vegetable oil, hydrogenated soybean oil, and coconut oil, medium-chain triglycerides, and palm kernel oil. Suitable water-miscible vehicles include, but are not limited to, ethanol, 1,3-butanediol, liquid polyethylene glycols (e.g., polyethylene glycol 300 and polyethylene glycol 400), propylene glycol, glycerin, N-methyl-2-pyrrolidone, N,N-dimethylacetamide, and dimethyl sulfoxide.

[0339] Suitable antimicrobial agents or preservatives include, but are not limited to, phenol, cresol, mercurials, benzyl alcohol, chlorobutanol, methyl and propyl p-hydroxybenzoate, thimerosal, benzalkonium chloride (e.g., benzethonium chloride), methyl- and propyl-paraben, and sorbic acid. Suitable isotonicity agents include, but are not limited to, sodium chloride, glycerin, and dextrose. Suitable buffering agents include, but are not limited to, phosphates and citrates. Suitable antioxidants include those described herein, such as bisulfites and sodium metabisulfite. Suitable local anesthetics include, but are not limited to, procaine hydrochloride. Suitable suspending and dispersing agents include those described herein, such as sodium carboxymethylcellulose, hydroxypropyl methylcellulose, and polyvinylpyrrolidone. Suitable emulsifying agents include those described herein, such as polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbitan monooleate 80, and triethanolamine oleate. Suitable sequestering or chelating agents include, but are not limited to, EDTA. Suitable pH adjusting agents include, but are not limited to, sodium hydroxide, hydrochloric acid, citric acid, and lactic acid. Suitable complexing agents include, but are not limited to, cyclodextrins such as α-cyclodextrin, β-cyclodextrin, hydroxypropyl-β-cyclodextrin, sulfobutylether-β-cyclodextrin, and sulfobutylether 7-β-cyclodextrin (CAPTISOL®).

[0340] When the pharmaceutical compositions provided herein are formulated for multiple dose administration, the multiple dose parenteral formulation must contain the antibacterial agent in a bacteriostatic or fungistatic concentration. All parenteral formulations must be sterile, as known and practiced in the art.

[0341] In one embodiment, the pharmaceutical composition for parenteral administration is provided as a ready-to-use sterile solution.In another embodiment, the pharmaceutical composition is provided as a sterile dry soluble product, such as a freeze-dried powder and a hypodermic tablet, which must be reconstituted with a vehicle before use.In yet another embodiment, the pharmaceutical composition is provided as a ready-to-use sterile suspension.In yet another embodiment, the pharmaceutical composition is provided as a sterile dry insoluble product, which must be reconstituted with a vehicle before use.In yet another embodiment, the pharmaceutical composition is provided as a ready-to-use sterile emulsion.

[0342] The pharmaceutical compositions provided herein for parenteral administration can be formulated as immediate or modified release dosage forms, including delayed-, sustained-, pulsed-, controlled-, targeted-, and programmed-release forms.

[0343] The pharmaceutical compositions provided herein for parenteral administration can be formulated as a suspension, solid, semi-solid, or thixotropic liquid for administration as an implanted depot. In one embodiment, the pharmaceutical compositions provided herein are dispersed in a solid inner matrix surrounded by an outer polymeric membrane that is insoluble in body fluids but allows the active ingredient in the pharmaceutical composition to diffuse through it.

[0344] Suitable inner matrices include, but are not limited to, polymethyl methacrylate, polybutyl methacrylate, plasticized or unplasticized polyvinyl chloride, plasticized nylon, plasticized polyethylene terephthalate, natural rubber, polyisoprene, polyisobutylene, polybutadiene, polyethylene, ethylene-vinyl acetate copolymer, silicone rubber, polydimethylsiloxane, silicone carbonate copolymer, hydrophilic polymers (such as hydrogels of esters of acrylic and methacrylic acid), collagen, cross-linked polyvinyl alcohol, and cross-linked partially hydrolyzed polyvinyl acetate.

[0345] Suitable polymeric outer membranes include, but are not limited to, polyethylene, polypropylene, ethylene / propylene copolymers, ethylene / ethyl acrylate copolymers, ethylene / vinyl acetate copolymers, silicone rubber, polydimethylsiloxane, neoprene rubber, chlorinated polyethylene, polyvinyl chloride, vinyl acetate, vinylidene chloride, vinyl chloride copolymers with ethylene and propylene, ionomeric polyethylene terephthalate, butyl rubber, epichlorohydrin rubber, ethylene / vinyl alcohol copolymers, ethylene / vinyl acetate / vinyl alcohol terpolymers, and ethylene / vinyloxyethanol copolymers.

[0346] (C. Topical Administration) The pharmaceutical compositions provided herein can be administered topically to the skin, orifices, or mucosa. As used herein, topical administration includes (intracutaneous), conjunctival, intracorneal, intraocular, intraocular, intraaural, transdermal, nasal, vaginal, urethral, ​​respiratory, and rectal administration.

[0347] The pharmaceutical compositions provided herein can be formulated in any dosage form suitable for topical administration for local or systemic effect, including, but not limited to, emulsions, solutions, suspensions, creams, gels, hydrogels, ointments, dusting powders, bandages, elixirs, lotions, suspensions, tinctures, pastes, foams, films, aerosols, douches, sprays, suppositories, bandages, and skin patches. Topical formulations of the pharmaceutical compositions provided herein can also include liposomes, micelles, microspheres, and nanosystems.

[0348] Pharmaceutically acceptable carriers and excipients suitable for use in topical formulations include, but are not limited to, aqueous vehicles, water-miscible vehicles, non-aqueous vehicles, antimicrobial agents or preservatives to prevent the growth of microorganisms, stabilizers, solubility enhancers, isotonicity agents, buffers, antioxidants, local anesthetics, suspending and dispersing agents, wetting or emulsifying agents, complexing agents, sequestering or chelating agents, penetration enhancers, cryoprotectants, lyoprotectants, thickening agents, and inert gases.

[0349] The pharmaceutical compositions may also be administered locally b...

Claims

1. Formula (I): 【Chemistry 1】 (In the formula, L is a linker; X is -CH 2 - or -C(O)-; Y is C 1-6 Alkylene or C 3-10 is cycloalkylene; R E teeth, 【Chemistry 2】 and; R 1 (i) C 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 aralkyl, heteroaryl, or heterocyclyl; or (ii) -OR 1a or -NR 1b R 1c and; R 2 is hydrogen or deuterium; R 3a , R 3d , and R 3e are each independently: (i) hydrogen, deuterium, cyano, halo, or nitro; 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) —C(O)R 1a , -C(O)OR 1a , -C(O)NR 1b R 1c , -C(O)SR 1a , -C(NR 1a )NR 1b R 1c , -C(S)R 1a , -C(S)OR 1a , -C(S)NR 1b R 1c , -OR 1a , -OC(O)R 1a , -OC(O)OR 1a , -OC(O)NR 1b R 1c , -OC(O)SR 1a , -OC(NR 1a )NR 1b R 1c , -OC(S)R 1a , -OC(S)OR 1a , -OC(S)NR 1b R 1c , -OS(O)R 1a , -OS(O) 2 R 1a , -OS(O)NR 1b R 1c , -OS(O) 2 NR 1b R 1c , -NR 1b R 1c , -NR 1a C(O)R 1d , -NR 1a C(O)OR 1d , -NR 1a C(O)NR 1b R 1c , -NR 1a C(O)SR 1d , -NR 1a C(NR 1d )NR 1b R 1c , -NR 1a C(S)R 1d , -NR 1a C(S)OR 1d , -NR 1a C(S)NR 1b R 1c , -NR 1a S(O)R 1d , -NR 1a S(O) 2 R 1d , -NR 1a S(O)NR 1b R 1c , -NR 1a S(O) 2 NR 1b R 1c , -SR 1a , -S(O)R 1a , -S(O) 2 R 1a , -S(O)NR 1b R 1c , or -S(O) 2 NR 1b R 1c and; R 3b and R 3c are each independently, C 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 aralkyl, heteroaryl, or heterocyclyl; Each R 4a are independently: (i) deuterium, cyano, halo, or nitro; (ii) C 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) —C(O)R 1a , -C(O)OR 1a , -C(O)NR 1b R 1c , -C(O)SR 1a , -C(NR 1a )NR 1b R 1c , -C(S)R 1a , -C(S)OR 1a , -C(S)NR 1b R 1c , -OR 1a , -OC(O)R 1a , -OC(O)OR 1a , -OC(O)NR 1b R 1c , -OC(O)SR 1a , -OC(NR 1a )NR 1b R 1c , -OC(S)R 1a , -OC(S)OR 1a , -OC(S)NR 1b R 1c , -OS(O)R 1a , -OS(O) 2 R 1a , -OS(O)NR 1b R 1c , -OS(O) 2 NR 1b R 1c , -NR 1b R 1c , -NR 1a C(O)R 1d , -NR 1a C(O)OR 1d , -NR 1a C(O)NR 1b R 1c , -NR 1a C(O)SR 1d , -NR 1a C(NR 1d )NR 1b R 1c , -NR 1a C(S)R 1d , -NR 1a C(S)OR 1d , -NR 1a C(S)NR 1b R 1c , -NR 1a S(O)R 1d , -NR 1a S(O) 2 R 1d , -NR 1a S(O)NR 1b R 1c , -NR 1a S(O) 2 NR 1b R 1c , -SR 1a , -S(O)R 1a , -S(O) 2 R 1a , -S(O)NR 1b R 1c , or -S(O) 2 NR 1b R 1c and R 4 is hydrogen or R 4a and; Each A E are independently a bond, -O-, -N(R 1b )-, -S-, C 1-6 Alkylene, C 1-6 Heteroalkylene, C 2-6 Alkenylene, C 2-6 Heteroalkenylene, C 2-6 Alkynylene, C 2-6 Heteroalkynylene, C 3-10 Cycloalkylene, C 6-14 Arylene, C 7-15 Aralkylene, Heteroarylene, Heterocyclylene, C 1-6 Heteroalkylene-C 6-14 Arylene or C 2-6 alkynylene-heterocyclylene; each X E are independently E1 ) or N; Y E is a bond, C 1-6 Alkylene, -O-, -S-, -S(O)-, -S(O 2 )- or -N(R E7 )-and; Z is -CH 2 - or -C(O)-; Z 1 , Z 2 , Z 3 , and Z 4 One of the groups is -C= and Z 1 , Z 2 , Z 3 , and Z 4 The remaining three of each independently represent -C(R E5 ) = or Z 1 is a bond, and Z 2 , Z 3 , and Z 4 One of the groups is -C= and Z 2 , Z 3 , and Z 4 The remaining two of each independently represent -C(R E5 )=or -S-; Each R E1 are independently hydrogen, deuterium, halo, or C 1-6 is alkyl; Each R E2 are independently hydrogen or C 1-6 is alkyl; and Each R E4 are independently: (i) deuterium, cyano, halo, or nitro; (ii) C 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) —C(O)R 1a , -C(O)OR 1a , -C(O)NR 1b R 1c , -C(O)SR 1a , -C(NR 1a )NR 1b R 1c , -C(S)R 1a , -C(S)OR 1a , -C(S)NR 1b R 1c , -OR 1a , -OC(O)R 1a , -OC(O)OR 1a , -OC(O)NR 1b R 1c , -OC(O)SR 1a , -OC(NR 1a )NR 1b R 1c , -OC(S)R 1a , -OC(S)OR 1a , -OC(S)NR 1b R 1c , -OS(O)R 1a , -OS(O) 2 R 1a , -OS(O)NR 1b R 1c , -OS(O) 2 NR 1b R 1c , -NR 1b R 1c , -NR 1a C(O)R 1d , -NR 1a C(O)OR 1d , -NR 1a C(O)NR 1b R 1c , -NR 1a C(O)SR 1d , -NR 1a C(NR 1d )NR 1b R 1c , -NR 1a C(S)R 1d , -NR 1a C(S)OR 1d , -NR 1a C(S)NR 1b R 1c , -NR 1a S(O)R 1d , -NR 1a S(O) 2 R 1d , -NR 1a S(O)NR 1b R 1c , -NR 1a S(O) 2 NR 1b R 1c , -SR 1a , -S(O)R 1a , -S(O) 2 R 1a , -S(O)NR 1b R 1c , or -S(O) 2 NR 1b R 1c and; Each R E5 are independently hydrogen or R E4 and; R E6 is (i) hydrogen; (ii) C 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) —C(O)R 1a , -C(O)OR 1a , -C(O)NR 1b R 1c , -C(O)SR 1a , -C(NR 1a )NR 1b R 1c , -C(S)R 1a , -C(S)OR 1a , -C(S)NR 1b R 1c , -OR 1a , -OC(O)R 1a , -OC(O)OR 1a , -OC(O)NR 1b R 1c , -OC(O)SR 1a , -OC(NR 1a )NR 1b R 1c , -OC(S)R 1a , -OC(S)OR 1a , -OC(S)NR 1b R 1c , -OS(O)R 1a , -OS(O) 2 R 1a , -OS(O)NR 1b R 1c , -OS(O) 2 NR 1b R 1c , -NR 1b R 1c , -NR 1a C(O)R 1d , -NR 1a C(O)OR 1d , -NR 1a C(O)NR 1b R 1c , -NR 1a C(O)SR 1d , -NR 1a C(NR 1d )NR 1b R 1c , -NR 1a C(S)R 1d , -NR 1a C(S)OR 1d , -NR 1a C(S)NR 1b R 1c , -NR 1a S(O)R 1d , -NR 1a S(O) 2 R 1d , -NR 1a S(O)NR 1b R 1c , -NR 1a S(O) 2 NR 1b R 1c , -S(O)R 1a , -S(O) 2 R 1a , -S(O)NR 1b R 1c , or -S(O) 2 NR 1b R 1c and; R E7 is hydrogen or C 1-6 is alkyl; Each R 1a , R 1b , R 1c , and R 1d are independently hydrogen, deuterium, and C 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 aralkyl, heteroaryl, or heterocyclyl; a is an integer of 0, 1, 2, 3, or 4; each m is independently an integer of 0, 1, or 2; and each n is independently an integer of 0, 1, 2, or 3; wherein each alkyl, alkylene, heteroalkyl, heteroalkylene, alkenyl, alkenylene, heteroalkenylene, alkynyl, alkynylene, heteroalkynylene, cycloalkyl, cycloalkylene, aryl, arylene, aralkyl, aralkylene, heteroaryl, heteroarylene, heterocyclyl, and heterocyclylene is optionally substituted with one or more substituents Q, where each Q is independently selected from: (a) deuterium, cyano, halo, imino, nitro, and oxo; (b) each is selected from one or more substituents Q a Optionally further substituted with C 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 aralkyl, heteroaryl, and heterocyclyl; and (c) -C(O)R a , -C(O)OR a , -C(O)NR b R c , -C(O)SR a , -C(NR a )NR b R c , -C(S)R a , -C(S)OR a , -C(S)NR b R c , -OR a , -OC(O)R a , -OC(O)OR a , -OC(O)NR b R c , -OC(O)SR a , -OC(NR a )NR b R c , -OC(S)R a , -OC(S)OR a , -OC(S)NR b R c , -OP(O)(OR a ) OR d , -OS(O)R a , -OS(O) 2 R a , -OS(O)NR b R c , -OS(O) 2 NR b R c , -NR b R c , -NR a C(O)R d , -NR a C(O)OR d , -NR a C(O)NR b R c , -NR a C(O)SR d , -NR a C(NR d )NR b R c , -NR a C(S)R d , -NR a C(S)OR d , -NR a C(S)NR b R c , -NR a S(O)R d , -NR a S(O) 2 R d , -NR a S(O)NR b R c , -NR a S(O) 2 NR b R c , -SR a , -S(O)R a , -S(O) 2 R a , -S(O)NR b R c , and -S(O) 2 NR b R c where each R a , R b , R c , and R d are independently: (i) hydrogen or deuterium; (ii) each represents one or more substituents Q a C optionally substituted with 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) R b and R c together with the N atom to which they are attached, one or more substituents Q a forming an optionally substituted heterocyclyl; Here, each Q a are: (a) deuterium, cyano, halo, nitro, imino, and oxo; (b) C 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 aralkyl, heteroaryl, and heterocyclyl; and (c) -C(O)R e , -C(O)OR e , -C(O)NR f R g , -C(O)SR e , -C(NR e )NR f R g , -C(S)R e , -C(S)OR e , -C(S)NR f R g , -OR e , -OC(O)R e , -OC(O)OR e , -OC(O)NR f R g , -OC(O)SR e , -OC(NR e )NR f R g , -OC(S)R e , -OC(S)OR e , -OC(S)NR f R g , -OP(O)(OR f ) OR g , -OS(O)R e , -OS(O) 2 R e , -OS(O)NR f R g , -OS(O) 2 NR f R g , -NR f R g , -NR e C(O)R h , -NR e C(O)OR f , -NR e C(O)NR f R g , -NR e C(O)SR f , -NR e C(NR h )NR f R g , -NR e C(S)R h , -NR e C(S)OR f , -NR e C(S)NR f R g , -NR e S(O)R h , -NR e S(O) 2 R h , -NR e S(O)NR f R g , -NR e S(O) 2 NR f R g , -SR e , -S(O)R e , -S(O) 2 R e , -S(O)NR f R g , and -S(O) 2 NR f R g where each R e , R f , R g , and R h are independently: (i) hydrogen or deuterium; (ii) C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) R f and R g together with the N atom to which they are attached form a heterocyclyl) or an enantiomer, mixture of enantiomers, diastereomer, mixture of two or more diastereomers, tautomer, mixture of two or more tautomers, or isotopic variant thereof; or a pharma- ceutically acceptable salt, solvate, hydrate, or prodrug thereof.

2. Y is optionally substituted with one or more substituents Q 1-6 is alkylene; and / or R 3a is hydrogen; and / or R 3d is hydrogen; and / or R 3e The compound of claim 1, wherein is hydrogen.

3. Formula (IV): 【Chemistry 3】 or a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharma- ceutically acceptable salt, solvate, hydrate, or prodrug thereof; or Formula (VI): 【Chemistry 4】 3. The compound of claim 1 or 2, having the structure:

4. R E But formula (EC-I): 【Chemistry 5】 or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof.

5. Formula (IX): 【Chemistry 6】 or an enantiomer, mixture of enantiomers, diastereomer, mixture of two or more diastereomers, tautomer, mixture of two or more tautomers, or isotopic variant thereof; or a pharma- ceutically acceptable salt, solvate, hydrate, or prodrug thereof; or Formula (XV): 【Chemistry 7】 5. The compound of claim 4 having the structure: or an enantiomer, mixture of enantiomers, diastereomer, mixture of two or more diastereomers, tautomer, mixture of two or more tautomers, or isotopic variant thereof; or a pharma- ceutically acceptable salt, solvate, hydrate, or prodrug thereof.

6. m is an integer equal to 1; and / or Z 1 is a bond; and / or Z 2 is S; or Z 3 is S; or Z 4 The compound according to claim 4 or 5, wherein is S.

7. Formula (X): 【Chemistry 8】 or an enantiomer, mixture of enantiomers, diastereomer, mixture of two or more diastereomers, tautomer, mixture of two or more tautomers, or isotopic variant thereof; or a pharma- ceutically acceptable salt, solvate, hydrate, or prodrug thereof; or Formula (XXI): 【Chemistry 9】 or an enantiomer, mixture of enantiomers, diastereomer, mixture of two or more diastereomers, tautomer, mixture of two or more tautomers, or isotopic variant thereof; or a pharma- ceutically acceptable salt, solvate, hydrate, or prodrug thereof; or Formula (XXII): 【Chemistry 10】 or an enantiomer, mixture of enantiomers, diastereomer, mixture of two or more diastereomers, tautomer, mixture of two or more tautomers, or isotopic variant thereof; or a pharma- ceutically acceptable salt, solvate, hydrate, or prodrug thereof, optionally comprising: E5 is hydrogen, halo, or fluoro; or Formula (XXVII): 【Chemistry 11】 or an enantiomer, mixture of enantiomers, diastereomer, mixture of two or more diastereomers, tautomer, mixture of two or more tautomers, or isotopic variant thereof; or a pharma- ceutically acceptable salt, solvate, hydrate, or prodrug thereof, optionally comprising: E5 is hydrogen, halo, or fluoro; or Formula (XVI): 【Chemistry 12】 or an enantiomer, mixture of enantiomers, diastereomer, mixture of two or more diastereomers, tautomer, mixture of two or more tautomers, or isotopic variant thereof; or a pharma- ceutically acceptable salt, solvate, hydrate, or prodrug thereof; or Formula (XXXII): 【Chemistry 13】 or an enantiomer, mixture of enantiomers, diastereomer, mixture of two or more diastereomers, tautomer, mixture of two or more tautomers, or isotopic variant thereof; or a pharma- ceutically acceptable salt, solvate, hydrate, or prodrug thereof; or Formula (XXXIII): 【Chemistry 14】 or an enantiomer, mixture of enantiomers, diastereomer, mixture of two or more diastereomers, tautomer, mixture of two or more tautomers, or isotopic variant thereof; or a pharma- ceutically acceptable salt, solvate, hydrate, or prodrug thereof, optionally comprising: E5 is hydrogen, halo, or fluoro; or Formula (XXXVIII): 【Chemistry 15】 or an enantiomer, mixture of enantiomers, diastereomer, mixture of two or more diastereomers, tautomer, mixture of two or more tautomers, or isotopic variant thereof; or a pharma- ceutically acceptable salt, solvate, hydrate, or prodrug thereof, optionally comprising: E5 is hydrogen, halo, or fluoro).

8. X is -CH 2 -; or X is -C(O)-; and / or R 2 is hydrogen; and / or Z is -CH 2 -; or Z is -C(O)-.

9. Formula (XI): 【Chemistry 16】 or an enantiomer, mixture of enantiomers, diastereomer, mixture of two or more diastereomers, tautomer, mixture of two or more tautomers, or isotopic variant thereof; or a pharma- ceutically acceptable salt, solvate, hydrate, or prodrug thereof; or Formula (XIII): 【Chemistry 17】 or an enantiomer, mixture of enantiomers, diastereomer, mixture of two or more diastereomers, tautomer, mixture of two or more tautomers, or isotopic variant thereof; or a pharma- ceutically acceptable salt, solvate, hydrate, or prodrug thereof; or Formula (XXIII): 【Chemistry 18】 or an enantiomer, mixture of enantiomers, diastereomer, mixture of two or more diastereomers, tautomer, mixture of two or more tautomers, or isotopic variant thereof; or a pharma- ceutically acceptable salt, solvate, hydrate, or prodrug thereof, optionally comprising R E5 is hydrogen, halo, or fluoro; or Formula (XXV): 【Chemistry 19】 or an enantiomer, mixture of enantiomers, diastereomer, mixture of two or more diastereomers, tautomer, mixture of two or more tautomers, or isotopic variant thereof; or a pharma- ceutically acceptable salt, solvate, hydrate, or prodrug thereof, optionally comprising R E5 is hydrogen, halo, or fluoro; or Formula (XXVIII): 【Chemistry 20】 or an enantiomer, mixture of enantiomers, diastereomer, mixture of two or more diastereomers, tautomer, mixture of two or more tautomers, or isotopic variant thereof; or a pharma- ceutically acceptable salt, solvate, hydrate, or prodrug thereof, optionally comprising R E5 is hydrogen, halo, or fluoro; Formula (XXX): 【Chemistry 21】 or an enantiomer, mixture of enantiomers, diastereomer, mixture of two or more diastereomers, tautomer, mixture of two or more tautomers, or isotopic variant thereof; or a pharma- ceutically acceptable salt, solvate, hydrate, or prodrug thereof, optionally comprising R E5 is hydrogen, halo, or fluoro; or Formula (XVII): 【Chemical 22】 or an enantiomer, mixture of enantiomers, diastereomer, mixture of two or more diastereomers, tautomer, mixture of two or more tautomers, or isotopic variant thereof; or a pharma- ceutically acceptable salt, solvate, hydrate, or prodrug thereof; or Formula (XIX): 【Chemistry 23】 or an enantiomer, mixture of enantiomers, diastereomer, mixture of two or more diastereomers, tautomer, mixture of two or more tautomers, or isotopic variant thereof; or a pharma- ceutically acceptable salt, solvate, hydrate, or prodrug thereof; or Formula (XXXIV): 【Chemistry 24】 or an enantiomer, mixture of enantiomers, diastereomer, mixture of two or more diastereomers, tautomer, mixture of two or more tautomers, or isotopic variant thereof; or a pharma- ceutically acceptable salt, solvate, hydrate, or prodrug thereof, optionally comprising R E5 is hydrogen, halo, or fluoro; or Formula (XXXVI): 【Chemistry 25】 or an enantiomer, mixture of enantiomers, diastereomer, mixture of two or more diastereomers, tautomer, mixture of two or more tautomers, or isotopic variant thereof; or a pharma- ceutically acceptable salt, solvate, hydrate, or prodrug thereof, optionally comprising R E5 is hydrogen, halo, or fluoro; or Formula(XXXIX): 【Chemistry 26】 or an enantiomer, mixture of enantiomers, diastereomer, mixture of two or more diastereomers, tautomer, mixture of two or more tautomers, or isotopic variant thereof; or a pharma- ceutically acceptable salt, solvate, hydrate, or prodrug thereof, optionally comprising R E5 is hydrogen, halo, or fluoro; or Formula (XLI): 【Chemical 27】 or an enantiomer, mixture of enantiomers, diastereomer, mixture of two or more diastereomers, tautomer, mixture of two or more tautomers, or isotopic variant thereof; or a pharma- ceutically acceptable salt, solvate, hydrate, or prodrug thereof, optionally comprising R E5 is hydrogen, halo, or fluoro).

10. R E But formula (EC-XXVIII): 【Chemistry 28】 or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or R E but: 【Chemical 29】 or an enantiomer, a mixture of enantiomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or R E but: 【Chemistry 30】 or an enantiomer, a mixture of enantiomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof.

11. R E But, formula (EC-XXXV): 【Chemistry 31】 or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or R E but: 【Chemistry 32】 or an enantiomer, mixture of enantiomers, tautomer, mixture of two or more tautomers, or isotopic variant thereof; or R E but: 【Chemical Formula 33】 or an enantiomer, a mixture of enantiomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof.

12. R 1 each of which is optionally substituted with one or more substituents Q 1-6 Alkyl or C 3 - 7 is cycloalkyl; or R 1 C optionally substituted with one or more substituents Q 1-6 is alkyl; or R 1 is methyl; and / or R 3b each of which is optionally substituted with one or more substituents Q 1-6 Alkyl or C 3 - 7 is cycloalkyl; or R 3b C optionally substituted with one or more substituents Q 1-6 is alkyl; or R 3b is ethyl; and / or R 3c each of which is optionally substituted with one or more substituents Q 1-6 Alkyl or C 3 - 7 is cycloalkyl; or R 3c C optionally substituted with one or more substituents Q 1-6 is alkyl; or R 3c The compound according to any one of claims 1 to 11, wherein is methyl.

13. R 4 is hydrogen or -NR 1a C(O)R 1d is; or R 4 But -NHC(O)-C 1-6 is alkyl; or R 4 But -NHC(O)CH 3 and / or A E is a bond, -O-, -NH-, ethynediyl, piperidinediyl, piperazinediyl, (phendiyl)oxymethanediyl, or (piperidinediyl)ethynediyl; or A E 13. The compound of any one of claims 5 to 12, wherein is a bond, -NH-, piperidine-1,4-diyl, piperadi-1,4-diyl, (phen-1,4-diyl)oxymethanediyl, or (piperidine-1,4-diyl)ethynediyl.

14. L is optionally substituted with one or more substituents Q; 1-20 Alkylene, C 1-20 Heteroalkylene, C 2-20 Alkenylene, C 2-20 Heteroalkenylene, C 2-20 Alkynylene, C 2-20 Heteroalkynylene, C 3-10 Cycloalkylene, C 6-14 arylene, heteroarylene, or heterocyclylene; or L is optionally substituted with one or more substituents Q; 1-20 Alkylene, C 1-20 Heteroalkylene, C 2-20 Alkynylene or C 2-20 is heteroalkynylene; or L is C 1-20 Alkylene, C 1-20 Heteroalkylene, C 2-20 Alkenylene, C 2-20 Heteroalkenylene, C 2-20 Alkynylene or C 2-20 heteroalkynylene, where one or more methylene groups are each independently replaced by a divalent radical, and each divalent radical is independently selected from the group consisting of C 3-10 Cycloalkylene, C 6-14 arylene, heteroarylene, or heterocyclylene; and wherein the alkylene, heteroalkylene, alkenylene, heteroalkenylene, alkynylene, heteroalkynylene, cycloalkylene, arylene, heteroarylene, and heterocyclylene are each optionally substituted with one or more substituents Q; or L is C 1-20 Alkylene or C 1-20 heteroalkylene, where one or more methylene groups are each independently replaced by a divalent radical, and each divalent radical is independently selected from the group consisting of C 3-10 Cycloalkylene, C 6-14 arylene, heteroarylene, or heterocyclylene; and wherein the alkylene, cycloalkylene, arylene, heteroarylene, and heterocyclylene are each optionally substituted with one or more substituents Q; or L: 【Chemical 34】 【change】 【change】 The compound according to any one of claims 1 to 13, wherein

15. N-(6-(7-(4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1-oxoisoindolin-4-yl)piperidin-1-yl)heptyl)-2-((S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)-1,3-dioxoisoindolin-4-yl)acetamide A1; N-(6-(7-(4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1-oxoisoindolin-4-yl)piperidin-1-yl)hept-1-yn-1-yl)-2-((S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)-1,3-dioxo-isoindolin-4-yl)acetamide A2; N-(6-(5-(4-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)ethynyl)piperidin-1-yl)-5-oxopentyl)-2-((S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)-1,3-dioxo-isoindolin-4-yl)acetamide A3; 14-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)-N-(2-((S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)-1,3-dioxoisoindolin-4-yl)-3,6,9,12-tetraoxa-tetradecane-1-amide A4; N-(6-(3-(4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1-oxoisoindolin-4-yl)piperidin-1-yl)propyl)-2-((S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)-1,3-dioxo-isoindolin-4-yl)acetamide A5; 12-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)-N-(2-((S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)-1,3-dioxoisoindolin-4-yl)dodecanamide A6; 9-(4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1-oxoisoindolin-5-yl)piperidin-1-yl)-N-(2-((S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)-1,3-dioxoisoindolin-4-yl)-nonanamide A7; N-(6-(7-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)piperidin-4-yl)-heptyl)-2-((S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)-1,3-dioxoisoindolin-4-yl)acetamide A8; 3-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethoxy)-ethoxy)-N-(2-((S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)-1,3-dioxoisoindolin-4-yl)propanamide A9; 3-(2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethoxy)-ethoxy)ethoxy)-N-(2-((S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)-1,3-dioxo-isoindolin-4-yl)propanamide A10; 3-((4-((2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethoxy)-methyl)benzyl)oxy)-N-(2-((S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)-1,3-dioxoisoindolin-4-yl)propanamide A11; 9-((4-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methoxy)benzyl)amino)-N-(2-((S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)-1,3-dioxoisoindolin-4-yl)nonanamide A12; 9-(4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1-oxoisoindolin-4-yl)piperidin-1-yl)-N-(2-((S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)-1,3-dioxoisoindolin-4-yl)-nonanamide A13; N-(6-(12-(4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1-oxoisoindolin-4-yl)piperidin-1-yl)dodecyl)-2-((S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)-1,3-dioxo-isoindolin-4-yl)acetamide A14; 9-{1-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]-piperidin-4-yl}-N-{2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-methanesulfonylethyl]-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl}nonanamide A15; 9-({[4-({[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-yl]oxy}-methyl)phenyl]methyl}amino)-N-{2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-methanesulfonyl-ethyl]-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl}nonanamide A16; N-[7-(12-{4-[2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1-oxo-2,3-dihydro-1H-isoindol-4-yl]piperidin-1-yl}dodecyl)-2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-methane-sulfonylethyl]-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]acetamide A17; 4-Amino-7-(12-{4-[2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1-oxo-2,3-dihydro-1H-isoindol-4-yl]piperidin-1-yl}dodecyl)-2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-methane-sulfonylethyl]-2,3-dihydro-1H-isoindole-1,3-dione A18; 10-{4-[2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1-oxo-2,3-dihydro-1H-isoindol-5-yl]piperidin-1-yl}-N-{2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-methanesulfonylethyl]-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl}decanamide A19; 9-(4-{2-[2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1-oxo-2,3-dihydro-1H-isoindol-5-yl]ethynyl}piperidin-1-yl)-N-{2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-methanesulfonylethyl]-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl}nonanamide A20; 9-{4-[2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1-oxo-2,3-dihydro-1H-isoindol-5-yl]piperidin-1-yl}-N-{2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-methanesulfonylethyl]-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl}nonanamide A21; 8-{4-[2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1-oxo-2,3-dihydro-1H-isoindol-5-yl]piperidin-1-yl}-N-{2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-methanesulfonylethyl]-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl}octanamide A22; 9-{4-[2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1-oxo-2,3-dihydro-1H-isoindol-5-yl]-1H-1,2,3-triazol-1-yl}-N-{2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-methanesulfonylethyl]-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl}nonanamide A23; 4-[1-(2-{4-[2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1-oxo-2,3-dihydro-1H-isoindol-5-yl]piperidin-1-yl}ethyl)-1H-1,2,3-triazol-4-yl]-N-{2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-methanesulfonylethyl]-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl}butanamide A24; 4-[(9-{4-[2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1-oxo-2,3-dihydro-1H-isoindol-5-yl]piperidin-1-yl}nonyl)amino]-2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-methanesulfonyl-ethyl]-2,3-dihydro-1H-isoindole-1,3-dione A25; 9-{4-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]piperidin-1-yl}-N-{2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-methanesulfonylethyl]-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl}nonanamide A26; 4-(10-{4-[2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1-oxo-2,3-dihydro-1H-isoindol-5-yl]piperidin-1-yl}decyl)-2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-methanesulfonylethyl]-2,3-dihydro-1H-isoindole-1,3-dione A27; 2-[4-(4-{4-[2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1-oxo-2,3-dihydro-1H-isoindol-5-yl]piperidin-1-yl}butyl)piperazin-1-yl]-N-{2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-methane-sulfonylethyl]-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl}acetamide A28; 6-{4-[2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1-oxo-2,3-dihydro-1H-isoindol-5-yl]-[1,4'-bipiperidine]-1'-yl}-N-{2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-methanesulfonylethyl]-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl}hexanamide A29; 5-{4-[2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1-oxo-2,3-dihydro-1H-isoindol-5-yl]-[1,4'-bipiperidine]-1'-yl}-N-{2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-methanesulfonylethyl]-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl}pentanamide A30; 3-[4-(3-{4-[2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1-oxo-2,3-dihydro-1H-isoindol-5-yl]piperidin-1-yl}propyl)piperazin-1-yl]-N-{2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-methanesulfonylethyl]-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl}propanamide A31; 8-(4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1-oxoisoindolin-4-yl)piperidin-1-yl)-N-(2-((S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)-1,3-dioxoisoindolin-4-yl)-octanamide A32; 3-(2-(2-(3-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)amino)propoxy)-ethoxy)ethoxy)-N-(2-((S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)-1,3-dioxo-isoindolin-4-yl)propanamide A33; N-(6-(2-(2-(2-(3-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)amino)-propoxy)-ethoxy)ethoxy)ethyl)-2-((S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)-1,3-dioxoisoindolin-4-yl)acetamide A34; 6-(4-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)ethynyl)piperidin-1-yl)-N-(2-((S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)-1,3-dioxoisoindolin-4-yl)-6-oxohexanamide A35; 8-(4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)piperidin-1-yl)-N-(2-((S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)-1,3-dioxoisoindolin-4-yl)octanamide A36; N-(6-(7-(4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)piperidin-1-yl)-heptyl)-2-((S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)-1,3-dioxoisoindolin-4-yl)acetamide A37; 7-((4-((5-((S)-2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)-methoxy)benzyl)amino)-N-(2-((S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)-ethyl)-1,3-dioxoisoindolin-4-yl)heptanamide A38; 5-((4-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methoxy)benzyl)amino)-N-(2-((S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)-1,3-dioxoisoindolin-4-yl)pentanamide A39; 2-{4-[(4-{[5-(2,6-dioxopiperidin-3-yl)-4-oxo-4H,5H,6H-thieno[3,4-c]pyrrol-1-yl]methoxy}phenyl)methyl]morpholin-2-yl}-N-{2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-methanesulfonylethyl]-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl}acetamide A40; 3-[2-(2-{[(4-{[5-(2,6-dioxopiperidin-3-yl)-4-oxo-4H,5H,6H-thieno[3,4-c]pyrrol-1-yl]methoxy}phenyl)methyl]amino}ethoxy)ethoxy]-N-{2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-methanesulfonylethyl]-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl}propanamide A41; 4-[4-(2-{[(4-{[5-(2,6-dioxopiperidin-3-yl)-4-oxo-4H,5H,6H-thieno[3,4-c]pyrrol-1-yl]methoxy}phenyl)methyl]amino}ethyl)phenyl]-N-{2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-methanesulfonylethyl]-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl}butanamide A42; 11-{[(4-{[5-(2,6-dioxopiperidin-3-yl)-4-oxo-4H,5H,6H-thieno[3,4-c]pyrrol-1-yl]methoxy}phenyl)methyl]amino}-N-{2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-methane-sulfonylethyl]-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl}undecanamide A43; 4-[(9-{[(4-{[5-(2,6-dioxopiperidin-3-yl)-4-oxo-4H,5H,6H-thieno[3,4-c]pyrrol-1-yl]methoxy}phenyl)methyl]amino}nonyl)amino]-2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-methanesulfonylethyl]-2,3-dihydro-1H-isoindole-1,3-dione A44; 4-[4-(2-{[(4-{[5-(2,6-dioxopiperidin-3-yl)-4-oxo-4H,5H,6H-thieno[3,4-c]pyrrol-1-yl]methoxy}phenyl)methyl]amino}ethyl)piperazin-1-yl]-N-{2-[(1S)-1-(3-ethoxy-4-methoxy-phenyl)-2-methanesulfonylethyl]-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl}butanamide A45; 11-{[(4-{[5-(2,6-dioxopiperidin-3-yl)-4-oxo-4H,5H,6H-thieno[3,4-c]pyrrol-1-yl]-methoxy}phenyl)methyl](methyl)amino}-N-{2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-methanesulfonylethyl]-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl}undecanamide A46; 8-(4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1-oxoisoindolin-4-yl)piperidin-1-yl)-N-(2-((S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)-1,3-dioxoisoindolin-4-yl)octanamide A47; 4-[1-(2-{[(4-{[5-(2,6-dioxopiperidin-3-yl)-4-oxo-4H,5H,6H-thieno[3,4-c]pyrrol-1-yl]methoxy}phenyl)methyl]amino}ethyl)-1H-1,2,3-triazol-4-yl]-N-{2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-methanesulfonylethyl]-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl}butanamide A48; 4-(10-{[(4-{[5-(2,6-dioxopiperidin-3-yl)-4-oxo-4H,5H,6H-thieno[3,4-c]pyrrol-1-yl]methoxy}phenyl)methyl]amino}decyl)-2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-methane-sulfonylethyl]-2,3-dihydro-1H-isoindole-1,3-dione A49; 4-[(9-{[(4-{[5-(2,6-dioxopiperidin-3-yl)-4-oxo-4H,5H,6H-thieno[3,4-c]pyrrol-1-yl]methoxy}phenyl)methyl]amino}nonyl)oxy]-2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-methanesulfonylethyl]-2,3-dihydro-1H-isoindole-1,3-dione A50; 4-({2-[4-(4-{[(4-{[5-(2,6-dioxopiperidin-3-yl)-4-oxo-4H,5H,6H-thieno[3,4-c]-pyrrol-1-yl]methoxy}phenyl)methyl]amino}butyl)phenyl]ethyl}amino)-2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-methanesulfonylethyl]-2,3-dihydro-1H-isoindole-1,3-dione A51; 4-[(11-{[(4-{[5-(2,6-dioxopiperidin-3-yl)-4-oxo-4H,5H,6H-thieno[3,4-c]pyrrol-1-yl]methoxy}phenyl)methyl]amino}undecyl)amino]-2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-methanesulfonylethyl]-2,3-dihydro-1H-isoindole-1,3-dione A52; 4-({4-[4-(2-{[(4-{[5-(2,6-dioxopiperidin-3-yl)-4-oxo-4H,5H,6H-thieno[3,4-c]-pyrrol-1-yl]methoxy}phenyl)methyl]amino}ethyl)phenyl]butyl}amino)-2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-methanesulfonylethyl]-2,3-dihydro-1H-isoindole-1,3-dione A53; 9-[4-(2-{[5-(2,6-dioxopiperidin-3-yl)-4-oxo-4H,5H,6H-thieno[3,4-c]pyrrol-1-yl]methoxy}acetyl)piperazin-1-yl]-N-{2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-methane-sulfonylethyl]-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl}nonanamide A54; 4-[4-(2-{[(4-{[5-(2,6-dioxopiperidin-3-yl)-4-oxo-4H,5H,6H-thieno[3,4-c]pyrrol-1-yl]methoxy}phenyl)methyl](methyl)amino}ethyl)phenyl]-N-{2-[(1S)-1-(3-ethoxy-4-methoxy-phenyl)-2-methanesulfonylethyl]-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl}butanamide A55; 11-(4-{[5-(2,6-dioxopiperidin-3-yl)-4-oxo-4H,5H,6H-thieno[3,4-c]pyrrol-1-yl]methoxy}phenyl)-N-{2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-methanesulfonylethyl]-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl}undecanamide A56; 11-(4-{[5-(2,6-dioxopiperidin-3-yl)-4-oxo-4H,5H,6H-thieno[3,4-c]pyrrol-1-yl]methoxy}phenyl)-N-{2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-methanesulfonylethyl]-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl}undecanamide A57; 8-(4-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methoxy)phenyl)-N-(2-((S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)-1,3-dioxoisoindolin-4-yl)octanamide A58; N-(6-(7-(4-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methoxy)phenyl)heptyl)-2-((S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)-1,3-dioxoisoindolin-4-yl)acetamide A59; 8-[4-({[3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-6-yl]carbamoyl}-methyl)piperazin-1-yl]-N-{2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-methanesulfonylethyl]-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl}octanamide A77; 6-[4-({[3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-6-yl]carbamoyl}-methyl)piperazin-1-yl]-N-{2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-methanesulfonylethyl]-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl}hexanamide A78; 10-[4-({[3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-6-yl]carbamoyl}-methyl)piperazin-1-yl]-N-{2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-methanesulfonylethyl]-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl}decanamide A79; 8-[4-({[3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-7-yl]carbamoyl}-methyl)piperazin-1-yl]-N-{2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-methanesulfonylethyl]-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl}octanamide A80; 10-[4-({[3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-7-yl]carbamoyl}-methyl)piperazin-1-yl]-N-{2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-methanesulfonylethyl]-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl}decanamide A81; 6-[4-({[3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-7-yl]carbamoyl}-methyl)piperazin-1-yl]-N-{2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-methanesulfonylethyl]-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl}hexanamide A82; 6-[4-({[4-(2,6-dioxopiperidin-3-yl)phenyl]carbamoyl}methyl)piperazin-1-yl]-N-{2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-methanesulfonylethyl]-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl}hexanamide A83; 8-[4-({[4-(2,6-dioxopiperidin-3-yl)phenyl]carbamoyl}methyl)piperazin-1-yl]-N-{2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-methanesulfonylethyl]-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl}octanamide A84; 8-[4-({[3-(2,6-dioxopiperidin-3-yl)phenyl]carbamoyl}methyl)piperazin-1-yl]-N-{2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-methanesulfonylethyl]-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl}octanamide A85; 10-[4-({[4-(2,6-dioxopiperidin-3-yl)phenyl]carbamoyl}methyl)piperazin-1-yl]-N-{2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-methanesulfonylethyl]-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl}decanamide A86; 6-[4-({[3-(2,6-dioxopiperidin-3-yl)phenyl]carbamoyl}methyl)piperazin-1-yl]-N-{2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-methanesulfonylethyl]-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl}hexanamide A87; 10-[4-({[3-(2,6-dioxopiperidin-3-yl)phenyl]carbamoyl}methyl)piperazin-1-yl]-N-{2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-methanesulfonylethyl]-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl}decanamide A88; N-{6-[12-({3-[(2,6-dioxopiperidin-3-yl)amino]phenyl}amino)dodecyl]-2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-methanesulfonylethyl]-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl}acetamide A89; 4-Amino-6-[12-({3-[(2,6-dioxopiperidin-3-yl)amino]phenyl}amino)dodecyl]-2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-methanesulfonylethyl]-2,3-dihydro-1H-isoindole-1,3-dione A90; 9-({3-[(2,6-dioxopiperidin-3-yl)amino]phenyl}amino)-N-{2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-methanesulfonylethyl]-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl}nonanamide A91; or 6-{4-[({3-[(2,6-dioxopiperidin-3-yl)amino]phenyl}carbamoyl)methyl]piperazin-1-yl}-N-{2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-methanesulfonylethyl]-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl}hexanamide A92 or a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharma- ceutically acceptable salt, solvate, hydrate, or prodrug thereof.

16. A pharmaceutical composition comprising a compound according to any one of claims 1 to 15 or a pharma- ceutical acceptable salt thereof.

17. 16. A pharmaceutical composition comprising a compound according to any one of claims 1 to 15 for use in a method for treating, preventing or ameliorating one or more symptoms of an inflammatory disease, optionally wherein the inflammatory disease is arthritis, ankylosing spondylitis, osteoarthritis, rheumatoid arthritis, Behcet's disease, inflammatory bowel disease, psoriasis, psoriatic arthritis, atopic dermatitis or contact dermatitis, chronic or obstructive pulmonary disease (COPD).

Images