SOS1 protein degraders, pharmaceutical compositions, and therapeutic applications

Abstract

Provided herein are SOS1 protein degraders, e.g., a compound of Formula (I), and pharmaceutical compositions thereof. Also provided herein are methods of their use for treating, preventing, or ameliorating one or more symptoms of an SOS1-mediated disorder, disease, or condition.

Description

SOS1 PROTEIN DEGRADERS, PHARMACEUTICAL COMPOSITIONS , AND THERAPEUTIC APPLICATIONSCROSS REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of the priority of U.S Provisional Application Nos. 63 / 520,067, filed August 16, 2023; and 63 / 578,285, filed August 23, 2023; the disclosure of each of which is incorporated herein by reference in its entirety.FIELD

[0002] Provided herein are SOS1 protein degraders and pharmaceutical compositions thereof. Also provided herein are methods of their use for treating, preventing, or ameliorating one or more symptoms of an SOSl-mediated disorder, disease, or condition.BACKGROUND

[0003] The three RAS oncogenes, KRAS, HRAS, and NRAS, are from the most frequently mutated oncogene family in cancer. Milburn et al., Science 1990, 247, 939-45; Cox et al., Nat. Rev. Drug Discov. 2014, 13, 828-51; Papke and Der, Science 2017, 355, 1158-63. RAS mutations have been detected in up to 30% of all human cancer. Cox et al., Nat. Rev. Drug Discov. 2014, 13, 828-51. RAS mutations are found in about 95% of pancreatic ductal adenocarcinomas (PDACs), about 50% of colorectal adenocarcinomas (CRCs), and about 30% of lung adenocarcinomas (LACs). Papke and Der, Science 2017, 355, 1158-63. Among the three, KRAS mutations are the most common and alone account for about a million death per year worldwide. Cox et al., Nat. Rev. Drug Discov. 2014, 13, 828-51; Simanshu et al., Cell 2017, 170, 17-33.

[0004] A RAS protein is a small GTPase encoded by a RAS oncogene. Papke and Der, Science 2017, 355, 1158-63. The RAS protein functions as a molecular switch cycling between the active guanosine triphosphate (GTP)-bound and inactive guanosine diphosphate (GDP)- bound states. Milburn et al., Science 1990, 247, 939-45. The GTP-bound active RAS activates downstream effector pathways, including rat fibrosarcoma / mitogen-activated protein kinase kinase / extracellular regulated kinase (RAF / MEK / ERK) and phosphoinositide 3-kinase / proteinkinase B / mechanistic target of rapamycin kinase (PI3K / AKT / mTOR). Rebocho and Marais, Cancer 397Discov. 2011, 7, 98-9. Oncogenic mutations in RAS proteins impair their ability for GTP hydrolysis, resulting in the accumulation of GTP-bound active RAS and hyperactivation of downstream signaling cascades that lead to uncontrolled cell proliferation and survival. Uras et al., hit. J. Mol. Set. 2020, 21, 4325.

[0005] The RAS signaling is tightly regulated by guanine nucleotide exchange factor (GEF) proteins, which catalyze the exchange of GDP for GTP, and GTPase-activating proteins (GAPs), which increase the rate of GTP hydrolysis to GDP. Simanshu et al., Cell 2017, 170, 17- 33. In other words, the RAS GTP / GDP cycle is regulated negatively by GAPs and positively by GEFs. Bos, Cell 2007, 129, 865-77. The son of sevenless homolog 1 (S0S1) is a GEF that binds to RAS to promote nucleotide exchange and formation of GTP-bound active RAS. Wang et al., Bioorg. Med. Chem. Lett. 2012, 22, 5766-76. Small molecule S0S1 inhibitors have been shown to be effective in downregulating active RAS in tumor cells with wild-type KRAS as well as tumor cells bearing a KRAS mutation. Hillig et al., Proc. Nat. Acad. Set. 2019, 114, 2551-60. By preventing formation of the KRAS-SOS1 complex, the S0S1 inhibitors block reloading of KRAS with GTP, leading to antiproliferative activity. Id.

[0006] Despite the advances in cancer treatment, cancer remains a major worldwide public health problem. It was estimated that there will be 1,958,310 new cancer cases diagnosed and 609,820 cancer deaths in the US alone in 2023. Cancer Facts & Figures 2023. Therefore, there is a need for an effective therapy for cancer treatment.SUMMARY OF THE DISCLOSURE

[0007] Provided herein is a compound of Formula (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; ora pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein:A is C3-10 cycloalkylene, C6-14 arylene, heteroarylene, or heterocyclylene;L is C1-6 alkylene, C7-15 aralkylene, or a linker;U and V are each independently -C(R4a)= or -N=;X is -N= or -C(R4b)=;R1is hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl;R3is C3-10 cycloalkyl, C6-14 aryl, heteroaryl, or heterocyclyl; each R4is independently (i) deuterium, cyano, halo, or nitro; (ii) C1-6 alkyl, C1-6 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) -C(O)R1a, -C(O)OR1a, -C(O)NR1bR1c, -C(O)SR1a, -C(NR1a)NR1bR1c, -C(S)R1a, -C(S)OR1a, -C(S)NR1bR1c, -OR1a, -OC(O)R1a, -OC(O)OR1a, -OC(O)NR1bR1c, -OC(O)SR1a, -OC(NR1 a)NR1bR1c, -OC(S)R1a, -OC(S)OR1a, -OC(S)NR1bR1c, -OS(O)R1a, -OS(O)2R1a, -OS(O)NR1bR1c, -OS(O)2NR1bR1c, -NR1bR1c, -NR1aC(O)R1d, -NR1aC(O)OR1d, -NR1 aC(O)NR1bR1c, -NR1 aC(O)SR1d, -NR1 aC(NR1d)NR1bR1c, -NR1aC(S)R1d, -NR1 aC(S)OR1d, -NR1 aC(S)NR1bR1c, -NR1aS(O)R1d, -NR1 aS(O)2R1d, -NR1 aS(O)NR1bR1c, -NR1aS(O)2NR1bR1c, -SR1a, -S(O)R1a, -S(O)2R1a, -S(O)NR1bR1c, or -S(O)2NR1bR1c;R2aand R2bare each independently hydrogen, deuterium, halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, heteroaryl, or heterocyclyl; each R4aand R4bis independently hydrogen or R4;Reis an E3 ubiquitin ligase binding moiety; each R1a, Rlb, R1c, and R1dis independently hydrogen, deuterium, C1-6 alkyl, C1-6 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl; and a is an integer of 0, 1, or 2; wherein each alkyl, alkylene, heteroalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylene, aryl, arylene, aralkyl, aralkylene, heteroaryl, heteroarylene, heterocyclyl, and heterocyclylene is optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Q, wherein each Q is independently selected from: (a) deuterium, cyano, halo, imino, nitro, and oxo; (b) C1-6 alkyl, C1-6 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, and heterocyclyl, each of which is furtheroptionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Qa; and (c) -C(O)Ra, -C(O)ORa, -C(O)NRbRc, -C(O)SRa, -C(NRa)NRbRc, -C(S)Ra, -C(S)ORa, -C(S)NRbRc, -ORa, -OC(O)Ra, -OC(O)ORa, -OC(O)NRbRc, -OC(O)SRa, -OC(NRa)NRbRc, -OC(S)Ra, -OC(S)ORa, -OC(S)NRbRc, -OP(O)(ORb)ORc, -OS(O)Ra, -OS(O)2Ra, -OS(O)NRbRc, -OS(O)2NRbRe, -NRbRe, -NRaC(O)Rd, -NRaC(O)ORd, -NRaC(O)NRbRe, -NRaC(O)SRd, -NRaC(NRd)NRbRc, -NRaC(S)Rd, -NRaC(S)ORd, -NRaC(S)NRbRc, -NRaS(O)Rd, -NRaS(O)2Rd, -NRaS(O)NRbRe, -NRaS(O)2NRbRc, -SRa, -S(O)Ra, -S(O)2Ra, -S(O)NRbRc, and -S(O)2NRbRc, wherein each Ra, Rb, Re, and Rdis independently (i) hydrogen or deuterium; (ii) Ci-6 alkyl, Ci-6 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-i4 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Qa; or (iii) Rband Rctogether with the N atom to which they are attached form heterocyclyl, optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Qa; wherein each Qais independently selected from: (a) deuterium, cyano, halo, nitro, imino, and oxo; (b) C1-6 alkyl, C1-6 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, and heterocyclyl; and (c) -C(O)Re, -C(O)ORe, -C(O)NRfRs, -C(O)SRe, -C(NRe)NRfRg, -C(S)Re, -C(S)ORe, -C(S)NRfRg, -ORe, -OC(O)Re, -OC(O)ORe, -OC(O)NRfRg, -OC(O)SRe, -OC(NRe)NRfRg, -OC(S)Re, -OC(S)ORe, -OC(S)NRfRg, -OP(O)(ORf)ORg, -OS(O)Re, -OS(O)2Re, -OS(O)NRfRg, -OS(O)2NRfRs, -NRfRg, -NReC(O)Rh, -NReC(O)ORf, -NReC(O)NRfRg, -NReC(O)SRf, -NReC(NRh)NRfRg, -NReC(S)Rh, -NReC(S)ORf, -NReC(S)NRfRg, -NReS(O)Rb, -NReS(O)2Rh, -NReS(O)NRfRg, -NReS(O)2NRfRg, -SRe, -S(O)Re, -S(O)2Re, -S(O)NRfRg, and -S(O)2NRfRg; wherein each Re, R1, Rg, and Rbis independently (i) hydrogen or deuterium; (ii) C1-6 alkyl, C1-6 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) Rfand Rgtogether with the N atom to which they are attached form heterocyclyl.

[0008] Also provided herein is a pharmaceutical composition comprising a compound of Formula (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; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; and a pharmaceutically acceptable excipient.

[0009] Additionally provided herein is a method of treating, preventing, or ameliorating one or more symptoms of a disorder, disease, or condition mediated by a son of sevenless homolog 1 (S0S1) in a subject, comprising administering to the subject in need thereof a therapeutically effective amount of a compound of Formula (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; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0010] Furthermore, provided herein is a method of treating, preventing, or ameliorating one or more symptoms of a disorder, disease, or condition mediated by a RAS in a subject, comprising administering to the subject in need thereof a therapeutically effective amount of a compound of Formula (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; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0011] Provided herein is a method of treating, preventing, or ameliorating one or more symptoms of a proliferative disease in a subject, comprising administering to the subject in need thereof a therapeutically effective amount of a compound of Formula (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; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0012] Provided herein is a method of inhibiting the growth of a cell, comprising contacting the cell with a compound of Formula (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; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0013] Provided herein is a method of inducing degradation of an S0S1, comprising contacting the S0S1 with a compound of Formula (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; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.DETAILED DESCRIPTION

[0014] To facilitate understanding of the disclosure set forth herein, a number of 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., human), cow, pig, sheep, goat, horse, dog, cat, rabbit, rat, or mouse. The terms “subject” and “patient” are used interchangeably herein in reference, for example, 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 meant to include alleviating or abrogating a disorder, disease, or condition, or one or more of the symptoms associated with the disorder, disease, or condition; or alleviating or eradicating the cause(s) of the disorder, disease, or condition itself.

[0018] The terms “prevent,” “preventing,” and “prevention” are meant to include a method of delaying and / or precluding the onset of a disorder, disease, or condition, and / or its attendant symptoms; barring a subject from acquiring a disorder, disease, or condition; or reducing a subject’s risk of acquiring a disorder, disease, or condition.

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

[0020] The term “contacting” or “contact” is meant to refer to bringing together of a therapeutic agent and a biological molecule (e.g., a protein, enzyme, RNA, or DNA), cell, ortissue such that a physiological and / or chemical effect takes place as a result of such contact. Contacting can take place 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 a cell in cell culture (in vitro) to determine the effect of the therapeutic agent on the cell. In yet another embodiment, the contacting of a therapeutic agent with a biological molecule, cell, or tissue includes the administration of a 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 meant to include the amount of a compound that, when administered, is sufficient to prevent development of, or alleviate to some extent, one or more of the 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 a biological or medical response of a biological molecule (e.g., a protein, enzyme, RNA, or DNA), cell, tissue, system, animal, or human, which is being sought by a researcher, veterinarian, medical doctor, or clinician.

[0022] The term “pharmaceutically acceptable carrier,” “pharmaceutically acceptable excipient,” “physiologically acceptable carrier,” or “physiologically acceptable excipient” refers to a pharmaceutically acceptable material, composition, or vehicle, such as a liquid or solid fdler, diluent, solvent, or encapsulating material. In one embodiment, each component is “pharmaceutically acceptable” in the sense of being compatible with the other ingredients of a pharmaceutical formulation, and suitable for use in contact with the tissue or organ of a subject (e.g., a human) without excessive toxicity, irritation, allergic response, immunogenicity, or other problems or complications, and commensurate with a reasonable benefit / risk ratio. See, e.g., Remington: The Science and Practice of Pharmacy, 23rd ed.; Adejare Ed.; Academic Press, 2020; Handbook of Pharmaceutical Excipients, 9th ed.; Sheskey el al., Eds.; Pharmaceutical Press, 2020; Handbook of Pharmaceutical Additives, 3rd ed.; Ash and Ash Eds.; Synapse Information Resources, 2007; Pharmaceutical Preformulation and Formulation, Ist ed.; Gibson Ed.; CRC Press, 2015.

[0023] The term “about” or “approximately” means an acceptable error for a particularvalue as determined by one of ordinary skill in the art, which depends in part on how the value is measured or determined. In certain embodiments, the term “about” or “approximately” means within 1, 2, or 3 standard deviations. In certain 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.

[0024] The term “alkyl” refers to a linear or branched saturated monovalent hydrocarbon radical, wherein the alkyl is optionally substituted with one or more substituents Q as described herein. For example, Ci-6 alkyl refers to 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, the alkyl is a linear saturated monovalent hydrocarbon radical that has 1 to 20 (C1-20), 1 to 15 (C1-15), 1 to 10 (C1-10), or 1 to 6 (Ci-e) carbon atoms, or branched saturated monovalent hydrocarbon radical of 3 to 20 (C3-20), 3 to 15 (C3-15), 3 to 10 (C3-10), or 3 to 6 (C3-6) carbon atoms. As used herein, linear C1-6 and branched C3-6 alkyl groups are also referred as “lower alkyl.” Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl (including all isomeric forms, e.g., / / -propyl and isopropyl), butyl (including all isomeric forms, e.g., / / -butyl, isobutyl, ec-butyl, and Ebutyl), pentyl (including all isomeric forms, e.g., / / -pentyl, isopentyl, sec-pentyl, neopentyl, and Zc / 7-pentyl), and hexyl (including all isomeric forms, e.g., n-hexyl, isohexyl, and sec-hexyl).

[0025] The terms “alkylene” and “alkanediyl” are used interchangeably herein in reference to a linear or branched saturated divalent hydrocarbon radical, wherein the alkanediyl is optionally substituted with one or more substituents Q as described herein. For example, C1-6 alkanediyl 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, the alkanediyl is a linear saturated divalent hydrocarbon radical that has 1 to 30 (C1-30), 1 to 20 (C1-20), 1 to 15 (C1-15), 1 to 10 (C1-10), or 1 to 6 (Ci-e) carbon atoms, or branched saturated divalent hydrocarbon radical of 3 to 30 (C3-30), 3 to 20 (C3-20), 3 to 15 (C3-15), 3 to 10 (C3-10), or 3 to 6 (C3-6) carbon atoms. As used herein, linear C1-6 and branched C3-6 alkanediyl groups are also referred as “lower alkanediyl.” Examples of alkanediyl groups include, but are not limited to, methanediyl, ethanediyl (including all isomeric forms, e.g., ethane- 1 , 1 -diyl and ethane-1,2- diyl), propanediyl (including all isomeric forms, e.g., propane- 1,1 -diyl, propane- 1,2-diyl, andpropane-l,3-diyl), butanediyl (including all isomeric forms, e.g, butane- 1,1 -diyl, butane-1,2- diyl, butane- 1,3 -diyl, and butane- 1,4-diyl), pentanediyl (including all isomeric forms, e.g., pentane- 1,1 -diyl, pentane- 1,2-diyl, pentane- 1,3 -diyl, and pentane- 1,5 -diyl), and hexanediyl (including all isomeric forms, e.g., hexane- 1,1 -diyl, hexane- 1,2-diyl, hexane- 1,3 -diyl, and hexane- 1,6-diyl). Examples of substituted alkanediyl groups include, but are not limited to, -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-, -C(0)(CH2)IO-, -C(O)CH2C(O)-, -C(O)(CH2)2C(O)-, -C(O)(CH2)3C(O)-, -C(O)(CH2)4C(O)-, or -C(O)(CH2)5C(O)-.

[0026] The term “heteroalkyl” refers to a linear or branched saturated monovalent hydrocarbon radical that contains one or more heteroatoms on its main chain, each independently selected from O, S, and N. The heteroalkyl is optionally substituted with one or more substituents Q as described herein. For example, Ci-6 heteroalkyl refers to 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, the heteroalkyl is a linear saturated monovalent hydrocarbon radical that has 1 to 20 (C1-20), 1 to 15 (Ci-is), 1 to 10 (Ci-io), or 1 to 6 (Ci-6) carbon atoms, or branched saturated monovalent hydrocarbon radical of 3 to 20 (C3-20), 3 to 15 (C3-15), 3 to 10 (C3-10), or 3 to 6 (C3-6) carbon atoms. As used herein, linear C1-6 and branched C3-6 heteroalkyl groups are also referred as “lower heteroalkyl.” Examples of heteroalkyl groups include, but are not limited to, -OCH3, -OCH2CH3, -CH2OCH3, -NHCH3, -ONHCH3, -NHOCH3, -SCH3, -CH2NHCH2CH3, and -NHCH2CH2CH3. Examples of substituted heteroalkyl groups include, but are not limited to, -CH2NHC(O)CH3and -NHC(O)CH2CH3.

[0027] The terms “heteroalkylene” and “heteroalkanediyl” are used interchangeably herein in reference to a linear or branched saturated divalent hydrocarbon radical that contains one or more heteroatoms in its main chain, each independently selected from O, S, and N. The heteroalkylene is optionally substituted with one or more substituents Q as described herein. For example, C1-6 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, the heteroalkylene is a linear saturated divalent hydrocarbon radical that has 1 to 20 (Ci -20), 1 to 15 (C1-15), 1 to 10 (C1-10), or 1 to 6 (Cue) carbon atoms, or branchedsaturated divalent hydrocarbon radical of 3 to 20 (C3-20), 3 to 15 (C3-15), 3 to 10 (C3-10), or 3 to 6 (C3-6) carbon atoms. As used herein, linear C1-6 and branched C3-6 heteroalkylene groups are also referred as “lower heteroalkylene.” Examples of heteroalkylene groups include, but are not limited to, -CH2O-, -(CH2)2O-, -(Cfh^O-, -(CH2)4O- -(CH2)5O-, -(CH2)6O- -(CH2)7O-, -(CH2)SO-, -(CH2)9O-, -(CH2)IOO-, -CH2OCH2-, -CH2CH2O-, -(CH2CH2O)2-, -(CH2CH2O)3-, -(CH2CH2O)4-, -(CH2CH2O)5-, -CH2NH-, -CH2NHCH2-, -CH2CH2NH- -CH2S-, -CH2SCH2-, and -CH2CH2S-. Examples of substituted heteroalkylene groups include, but are not limited to, -C(O)CH2O-, -C(O)(CH2)2O- -C(O)(CH2)3O- -C(O)(CH2)4O- -C(O)(CH2)5O- -C(O)(CH2)6O-, -C(O)(CH2)7O- -C(O)(CH2)SO-, -C(O)(CH2)9O-C(0)(CH2)IOO , C(O)CH2OCH2CH2O , C(O)CH2O(CH2CH2O)2 , -C(O)CH2O(CH2CH2O)3-, -C(O)CH2O(CH2CH2O)4, -C(O)CH2O(CH2CH2O)5-, -CH2NHC(O)CH2-, or -CH2CH2C(O)NH-.

[0028] The term “alkenyl” refers to a linear or branched monovalent hydrocarbon radical, which contains one or more, in one embodiment, one, two, three, or four, in another embodiment, one, carbon-carbon double bond(s). The alkenyl is optionally substituted with one or more substituents Q as described herein. The term “alkenyl” embraces radicals having a “cis” or “trans” configuration or a mixture thereof, or alternatively, a “Z”configuration or a mixture thereof, as appreciated by those of ordinary skill in the art. For example, C2-6 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 certain embodiments, the alkenyl is a linear monovalent hydrocarbon radical of 2 to 20 (C2-20), 2 to 15 (C2-15), 2 to 10 (C2-10), or 2 to 6 (C2-6) carbon atoms, or a branched monovalent hydrocarbon radical of 3 to 20 (C3-20), 3 to 15 (C3-15), 3 to 10 (C3-10), or 3 to 6 (C3-6) carbon atoms. 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-l-yl).

[0029] The terms “alkenylene” and “alkenediyl” are used interchangeably herein in reference to a linear or branched divalent hydrocarbon radical, which contains one or more, in one embodiment, one, two, three, or four, in another embodiment, one, carbon-carbon double bond(s). The alkenediyl is optionally substituted with one or more substituents Q as describedherein. The term “alkenediyl” embraces radicals having a “cis” or “trans” configuration or a mixture thereof, or alternatively, a “Z”configuration or a mixture thereof, as appreciated by those of ordinary skill in the art. For example, C2-6 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, the alkenediyl is a linear divalent hydrocarbon radical of 2 to 30 (C2-30), 2 to 20 (C2-20), 2 to 15 (C2-15), 2 to 10 (C2-10), or 2 to 6 (C2-6) carbon atoms, or a branched divalent hydrocarbon radical of 3 to 30 (C3-30), 3 to 20 (C3-20), 3 to 15 (C3-15), 3 to 10 (C3-10), or 3 to 6 (C3-6) carbon atoms. Examples of alkenediyl groups include, but are not limited to, ethenediyl (including all isomeric forms, e.g., ethene- 1,1- diyl and ethene- 1,2-diyl), propenediyl (including all isomeric forms, e.g., 1 -propene- 1,1 -diyl, 1- propene-l,2-diyl, and 1 -propene- 1,3 -diyl), butenediyl (including all isomeric forms, e.g., 1- butene- 1,1 -diyl, 1 -butene- 1,2-diyl, and 1 -butene- 1,4-diyl), pentenediyl (including all isomeric forms, e.g., 1 -pentene- 1,1 -diyl, l-pentene-l,2-diyl, and 1 -pentene- 1,5 -diyl), and hexenediyl (including all isomeric forms, e.g., 1 -hexene- 1,1 -diyl, 1 -hexene- 1,2-diyl, l-hexene-l,3-diyl, 1- hexene- 1,4-diyl, 1 -hexene- 1,5 -diyl, and 1 -hexene- 1,6-diyl).

[0030] The terms “heteroalkenylene” and “heteroalkenediyl” are used interchangeably herein in reference to a linear or branched divalent hydrocarbon radical, which contains one or more, in one embodiment, one, two, three, or four, in another embodiment, one, carbon-carbon double bond(s), and which contains one or more heteroatoms each independently selected from O, S, and N in the hydrocarbon chain. The heteroalkenylene is optionally substituted with one or more substituents Q as described herein. The term “heteroalkenylene” embraces radicals having a "cis" or "trans ' configuration or a mixture thereof, or alternatively, a “Z” or “£” configuration or a mixture thereof, as appreciated by those of ordinary skill in the art. For example, C2-6 heteroal kenylene 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, the heteroalkenylene is a linear divalent hydrocarbon radical of 2 to 20 (C2-20), 2 to 15 (C2-15), 2 to 10 (C2-10), or 2 to 6 (C2-6) carbon atoms, or a branched divalent hydrocarbon radical of 3 to 20 (C3-20), 3 to 15 (C3-15), 3 to 10 (C3-10), or 3 to 6 (C3-6) carbon atoms. Examples of heteroalkenylene groups include, but are not limited to, -CH=CHO-, -CH=CHOCH2- -CH=CHCH2O- -CH=CHS- -CH=CHSCH2- -CH=CHCH2S- or -CH=CHCH2NH-

[0031] The term “alkynyl” refers to a linear or branched monovalent hydrocarbon radical, which contains one or more, in one embodiment, one, two, three, or four, in another embodiment, one, carbon-carbon triple bond(s). An alkynyl group does not contain a carboncarbon double bond. The alkynyl is optionally substituted with one or more substituents Q as described herein. For example, C2-6 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 certain embodiments, the alkynyl is a linear monovalent hydrocarbon radical of 2 to 20 (C2-20), 2 to 15 (C2-15), 2 to 10 (C2-10), or 2 to 6 (C2-6) carbon atoms, or a branched monovalent hydrocarbon radical of 4 to 20 (C4-20), 4 to 15 (C4-15), 4 to 10 (C4-10), or 4 to 6 (C4-6) carbon atoms. Examples of alkynyl groups include, but are not limited to, ethynyl (-C=CH), propynyl (including all isomeric forms, e.g., 1-propynyl (-OCCH3) and propargyl (-CH2OCH)), butynyl (including all isomeric forms, e.g., 1-butyn-l-yl and 2-butyn- 1-yl), pentynyl (including all isomeric forms, e.g., 1-pentyn-l-yl and l-methyl-2-butyn-l-yl), and hexynyl (including all isomeric forms, e.g., 1-hexyn-l-yl and 2-hexyn-l-yl).

[0032] The terms “alkynylene” and “alkynediyl” are used interchangeably herein in reference to a linear or branched divalent hydrocarbon radical, which contains one or more, in one embodiment, one, two, three, or four, in another embodiment, one, carbon-carbon triple bond(s). An alkynylene group does not contain a carbon-carbon double bond. The alkynediyl is optionally substituted with one or more substituents Q as described herein. For example, C2-6 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, the alkynediyl is a linear divalent hydrocarbon radical of 2 to 30 (C2-30), 2 to 20 (C2-20), 2 to 15 (C2-15), 2 to 10 (C2-10), or 2 to 6 (C2-6) carbon atoms, or a branched divalent hydrocarbon radical of 4 to 30 (C4-30), 4 to 20 (C4-20), 4 to 15 (C4-15), 4 to 10 (C4-10), or 4 to 6 (C4- e) carbon atoms. Examples of alkynediyl groups include, but are not limited to, ethynediyl, propynediyl (including all isomeric forms, e.g., 1 -propyne- 1,3 -diyl and l-propyne-3,3-diyl), butynediyl (including all isomeric forms, e.g., l-butyne-l,3-diyl, 1 -butyne- 1,4-diyl, and 2- butyne- 1,1 -diyl), pentynediyl (including all isomeric forms, e.g., l-pentyne-l,3-diyl, 1-pentyne- 1,4-diyl, and 2-pentyne- 1,1 -diyl), and hexynediyl (including all isomeric forms, e.g., 1-hexyne- 1,3-diyl, 1 -hexyne- 1,4-diyl, and 2-hexyne- 1,1 -diyl).

[0033] The terms “heteroal kynylene” and “heteroalkynediyl” are used interchangeably herein in reference to a linear or branched divalent hydrocarbon radical, which contains one or more, in one embodiment, one, two, three, or four, in another embodiment, one, carbon-carbon triple bond(s), and which contains one or more heteroatoms in its main chain, each independently selected from O, S, and N. A heteroalkynylene group does not contain a carbon-carbon double bond. The heteroalkynylene is optionally substituted with one or more substituents Q as described herein. For example, C2-6 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, the heteroalkynylene is a linear divalent hydrocarbon radical of 2 to 30 (C2-30), 2 to 20 (C2-20), 2 to 15 (C2-15), 2 to 10 (C2-10), or 2 to 6 (C2- 6) carbon atoms, or a branched divalent hydrocarbon radical of 4 to 30 (C4-30), 4 to 20 (C4-20), 4 to 15 (C4-15), 4 to 10 (C4-10), or 4 to 6 (C4-6) carbon atoms. Examples of heteroalkynylene groups include, but are not limited to, -C^CCIEO-, -C^CCFFS-. or OCCH2NH .

[0034] The term “cycloalkyl” refers to a cyclic monovalent hydrocarbon radical, which is optionally substituted with one or more substituents Q as described herein. In one embodiment, the cycloalkyl is a saturated or unsaturated but non-aromatic, and / or bridged or non-bridged, and / or fused bicyclic group. In certain embodiments, the cycloalkyl has from 3 to 20 (C3-20), from 3 to 15 (C3-15), from 3 to 10 (C3-10), or from 3 to 7 (C3-7) carbon atoms. In one embodiment, the cycloalkyl is monocyclic. In another embodiment, the cycloalkyl is bicyclic. In yet another embodiment, the cycloalkyl is tricyclic. In still 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[l. l.l]pentyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, decalinyl, and adamantyl.

[0035] The terms “cycloalkylene” and “cycloalkanediyl” are used interchangeably herein in reference to a cyclic divalent hydrocarbon radical, which may be optionally substituted with one or more substituents Q as described herein. In one embodiment, cycloalkanediyl groups may be saturated or unsaturated but non-aromatic, and / or bridged, and / or non-bridged, and / or fused bicyclic groups. In certain embodiments, the cycloalkanediyl has from 3 to 30 (C3-30), 3 to 20 (C3-20), from 3 to 15 (C3-15), from 3 to 10 (C3-10), or from 3 to 7 (C3-7) carbon atoms. Examplesof cycloalkanediyl groups include, but are not limited to, cyclopropanediyl (including all isomeric forms, e.g., cyclopropane- 1,1 -diyl and cyclopropane- 1,2-diyl), cyclobutanediyl (including all isomeric forms, e.g., cyclobutane- 1, 1 -diyl, cyclobutane- 1,2-diyl, and cyclobutane- 1,3-diyl), cyclopentanediyl (including all isomeric forms, e.g., cyclopentane- 1,1 -diyl, cyclopentane- 1,2-diyl, and cyclopentane- 1,3 -diyl), cyclohexanediyl (including all isomeric forms, e.g., cyclohexane-l,l-diyl, cyclohexane- 1,2-diyl, cyclohexane-l,3-diyl, and cyclohex-1, 4- diyl), cycloheptanediyl (including all isomeric forms, e.g., cycloheptane- 1,1 -diyl, cycloheptane- 1,2-diyl, cycloheptane- 1,3 -diyl, and cycloheptane-l,4-diyl), decalinediyl (including all isomeric forms, e.g., decaline- 1,1 -diyl, decaline-1, 2-diyl, and decaline-1, 8-diyl), and adamantdiyl (including all isomeric forms, e.g., adamant- 1,2-diyl, adamant- 1,3 -diyl, and adamant- 1,8-diyl).

[0036] The term “aryl” refers to a monovalent monocyclic aromatic hydrocarbon radical and / or monovalent polycyclic aromatic hydrocarbon radical that contain at least one aromatic carbon ring. In certain embodiments, the aryl has from 6 to 20 (C6-20), from 6 to 15 (C6-is), or from 6 to 10 (C6-io) ring carbon atoms. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, fluorenyl, azulenyl, anthryl, phenanthryl, pyrenyl, biphenyl, and terphenyl. The aryl also refers to bicyclic or tricyclic carbon rings, where one of the rings is aromatic and the others of which may be saturated, partially unsaturated, or aromatic, for example, dihydronaphthyl, indenyl, indanyl, or tetrahydronaphthyl (tetralinyl). In one embodiment, the aryl is monocyclic. In another embodiment, the aryl is bicyclic. In yet another embodiment, the aryl is tricyclic. In still another embodiment, the aryl is polycyclic. In certain embodiments, the aryl is optionally substituted with one or more substituents Q as described herein.

[0037] The terms “arylene” and “arenediyl” are used interchangeably herein in reference to a divalent monocyclic aromatic hydrocarbon radical or divalent polycyclic aromatic hydrocarbon radical that contains at least one aromatic hydrocarbon ring. In certain embodiments, the arylene has from 6 to 20 (C6-20), from 6 to 15 (C6-is), or from 6 to 10 (C6-io) ring atoms. Examples of arylene groups include, but are not limited to, phenylene (including all isomeric forms, e.g., phen- 1,2-diyl, phen-l,3-diyl, and phen-l,4-diyl), naphthylene (including all isomeric forms, e.g., naphth- 1,2-diyl, naphth- 1,3 -diyl, and naphth- 1,8-diyl), fluorenylene (including all isomeric forms, e.g., fluoren-l,2-diyl, fluoren- 1,3 -diyl, and fluoren- 1,8-diyl), azulenylene (including all isomeric forms, e.g., azulen- 1,2-diyl, azulen- 1,3 -diyl, and azulen-1,8-diyl), anthrylene (including all isomeric forms, e.g., anthr-l,2-diyl, anthr- 1,3 -diyl, and anthr-1,8- diyl), phenanthrylene (including all isomeric forms, e.g., phenanthr-l,2-diyl, phenanthr-l,3-diyl, and phenanthr-l,8-diyl), pyrenylene (including all isomeric forms, e.g., pyren-l,2-diyl, pyren- 1,3-diyl, and pyren-l,8-diyl), biphenylene (including all isomeric forms, e.g., biphen-2,3-diyl, biphen-3,4’-diyl, and biphen-4,4’-diyl), and terphenylene (including all isomeric forms, e.g., terphen-2,3-diyl, terphen-3,4’-diyl, and terphen-4,4’-diyl). Arylene also refers to bicyclic or tricyclic carbon rings, where one of the rings is aromatic and the others of which may be saturated, partially unsaturated, or aromatic, for example, dihydronaphthylene (including all isomeric forms, e.g., dihydronaphth- 1,2-diyl and dihydronaphth- 1 ,8-diyl), indenylene (including all isomeric forms, e.g., inden- 1,2-diyl, inden- 1,5-diyl, and inden-l,7-diyl), indanylene (including all isomeric forms, e.g., indan- 1,2-diyl, indan- 1,5 -diyl, and indan- 1 ,7-diyl), or tetrahydronaphthylene (tetralinyl ene) (including all isomeric forms, e.g., tetrahydronaphth- 1 ,2- diyl, tetrahydronaphth-l,5-diyl, and tetrahydronaphth- 1 ,8-diyl). In certain embodiments, arylene is optionally substituted with one or more substituents Q as described herein.

[0038] The term “aralkyl” or “arylalkyl” refers to a monovalent alkyl group substituted with one or more aryl groups. In certain embodiments, the aralkyl has from 7 to 30 (C7-30), from 7 to 20 (C7-20), or from 7 to 16 (C7-16) carbon atoms. 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 certain embodiments, the aralkyl is optionally substituted with one or more substituents Q as described herein.

[0039] The term “aralkylene” or “arylalkylene” refers to a divalent alkyl group substituted with one or more aryl groups. In certain embodiments, the aralkylene has from 7 to 30 (C7-30), from 7 to 20 (C7-20), or from 7 to 16 (C7-16) carbon atoms. Examples of aralkylene groups include, but are not limited to, benzylene (including all isomeric forms, e.g., phenylmethdiyl), phenylethylene (including all isomeric forms, e.g., 2-phenyl-ethan- 1,1 -diyl and 2-phenyl-ethan-l,2-diyl), and phenyl propylene (including all isomeric forms, e.g., 3-phenyl- propan- 1,1 -diyl, 3-phenyl-propan-l,2-diyl, and 3-phenyl-propan-l,3-diyl). In certain embodiments, the aralkylene is optionally substituted with one or more substituents Q as described herein.

[0040] The term “heteroaryl” refers to a monovalent monocyclic aromatic group or monovalent polycyclic aromatic group that contain at least one aromatic ring, wherein at least one aromatic ring contains one or more heteroatoms, each independently selected from O, S, and N, in the ring. For a heteroaryl group containing a heteroaromatic ring and a nonaromatic heterocyclic ring, the heteroaryl group is not bonded to the rest of a molecule through its nonaromatic heterocyclic ring. Each ring of a 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 certain embodiments, the heteroaryl has from 5 to 20, from 5 to 15, or from 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, but are not limited to, benzofuranyl, benzimidazolyl, benzoisoxazolyl, benzopyranyl, benzothiadiazolyl, benzothiazolyl, benzothienyl, benzotriazolyl, benzoxazolyl, furopyrindyl (including all isomeric forms, e.g., furo[2,3-Z>]pyridinyl, furo[2,3-c]pyridinyl, furo[3,2- / >]pyridinyl, furo[3,2-c]pyridinyl, furo[3,4- / >]pyridinyl, and furo[3,4-c]pyridinyl), imidazopyridinyl (including all isomeric forms, e.g., imidazo[l,2-rz]pyridinyl, imidazo[4,5- Z>]pyridinyl, and imidazo[4,5-c]pyridinyl), imidazothiazolyl (including all isomeric forms, e.g., imidazo[2,l-Z>]thiazolyl and imidazo[4,5- ]thiazolyl), indazolyl, indolizinyl, indolyl, isobenzofuranyl, isobenzothienyl (i.e., benzo[c]thienyl), isoindolyl, isoquinolinyl, naphthyridinyl (including all isomeric forms, e.g., 1,5-naphthyridinyl, 1,6-naphthyridinyl, 1,7-naphthyridinyl, and 1,8-naphthyridinyl), oxazolopyridinyl (including all isomeric forms, e.g., oxazolo[4,5- Z>]pyridinyl, oxazolo[4,5-c]pyridinyl, oxazolo[5,4-Z>]pyridinyl, and oxazolo[5,4-c]pyridinyl), phthalazinyl, pteridinyl, purinyl, pyrrolopyridyl (including all isomeric forms, e.g., pyrrolo[2,3- / >]pyridinyl, pyrrolo[2,3-c]pyridinyl, pyrrolo[3,2-Z>]pyridinyl, and pyrrolo[3,2-c]pyridinyl), quinolinyl, quinoxalinyl, quinazolinyl, thiadiazolopyrimidyl (including all isomeric forms, e.g., [l,2,5]thiadiazolo[3,4-d]pyrimidinyl and [l,2,3]thiadiazolo[4,5- ]pyrimidinyl), and thienopyridyl (including all isomeric forms, e.g., thieno[2,3-6]pyridinyl, thieno[2,3-c]pyridinyl, thieno[3,2-Z>]pyridinyl, and thieno[3,2-c]pyridinyl). In yet another embodiment, the 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 certain embodiments, the heteroaryl is optionally substituted with one or more substituents Q as described herein.

[0041] The terms “heteroarylene” and “heteroarenediyl” are used interchangeably herein in reference to a divalent monocyclic aromatic group or divalent polycyclic aromatic group that contains at least one aromatic ring, wherein at least one aromatic ring contains one or more heteroatoms in the ring, each of which is independently selected from O, S, and N. For a heteroarylene group containing a heteroaromatic ring and a nonaromatic heterocyclic ring, the heteroarylene group is not bonded to the rest of a molecule via its nonaromatic heterocyclic 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, the heteroarylene has from 5 to 20, from 5 to 15, or from 5 to 10 ring atoms. Examples of monocyclic heteroarylene groups include, but are not limited to, furandiyl, imidazoldiyl, isothiazoldiyl, isoxazoldiyl, oxadiazoldiyl, oxazoldiyl, pyrazindiyl, pyrazoldiyl, pyridazindiyl, pyridindiyl, pyrimidindiyl, pyrrol diyl, thiadiazoldiyl, thiazoldiyl, thiendiyl, tetrazol diyl, triazinediyl, and triazol diyl. Examples of bicyclic heteroarylene groups include, but are not limited to, benzofurandiyl, benzimidazoldiyl, benzoisoxazoldiyl, benzopyrandiyl, benzothiadiazoldiyl, benzothiazoldiyl, benzothiendiyl, benzotriazoldiyl, benzoxazoldiyl, furopyridindiyl (including all isomeric forms, e.g., furo[2,3-Z?]pyridindiyl, furo[2,3-c]pyridindiyl, furo[3,2- / >]pyridindiyl, furo[3,2-c]- pyridindiyl, furo[3,4-Z>]pyridindiyl, and furo[3,4-c]pyridindiyl), imidazopyridindiyl (including all isomeric forms, e.g., imidazo[l,2-rz]pyridindiyl, imidazo[4,5- / >]pyridindiyl, and imidazo[4,5-c]- pyridindiyl), imidazothiazoldiyl (including all isomeric forms, e.g., imidazo[2,l-£>]thiazoldiyl and imidazo[4,5- ]thiazoldiyl), indazoldiyl, indolizindiyl, indoldiyl, isobenzofurandiyl, isobenzothiendiyl (i.e., benzo[c]thiendiyl), isoindoldiyl, isoquinolindiyl, naphthyridindiyl (including all isomeric forms, e.g., 1,5-naphthyridindiyl, 1,6-naphthyridindiyl, 1,7- naphthyridindiyl, and 1,8-naphthyridindiyl), oxazolopyridindiyl (including all isomeric forms, e.g., oxazolo[4,5-Z>]pyridindiyl, oxazolo[4,5-c]pyridindiyl, oxazolo[5,4-Z>]pyridindiyl, and oxazolo[5,4-c]pyridindiyl), phthalazindiyl, pteridindiyl, purindiyl, pyrrolopyridindiyl (includingall isomeric forms, e.g., pyrrolo[2,3-Z>]pyridindiyl, pyrrolo[2,3-c]pyridindiyl, pyrrolo[3,2- / >]- pyridindiyl, and pyrrolo[3,2-c]pyridindiyl), quinolindiyl, quinoxalindiyl, quinazolindiyl, thiadiazolopyrimidindiyl (including all isomeric forms, e.g., [l,2,5]thiadiazolo[3,4- ]- pyrimidindiyl and [l,2,3]thiadiazolo[4,5-d]pyrimidindiyl), and thienopyridindiyl (including all isomeric forms, e.g., thieno[2,3-Z>]pyridindiyl, thieno[2,3-c]pyridindiyl, thieno[3,2-Z>]pyridindiyl, and thieno[3,2-c]pyridindiyl). Examples of tricyclic heteroarylene groups include, but are not limited to, acridindiyl, benzindoldiyl, carbazoldiyl, dibenzofurandiyl, perimidindiyl, phenanthrolindiyl (including all isomeric forms, e.g., 1,5-phenanthrolindiyl, 1,6- phenanthrolindiyl, 1,7-phenanthrolindiyl, 1,9-phenanthrolindiyl, and 2,10-phenanthrolindiyl), phenanthridindiyl, phenarsazindiyl, phenazindiyl, phenothiazindiyl, phenoxazindiyl, and xanthendiyl. In certain embodiments, heteroarylene is optionally substituted with one or more substituents Q as described herein.

[0042] The term “heterocyclyl” or “heterocyclic” refers to a monovalent monocyclic non-aromatic ring system or monovalent polycyclic ring system that contains at least one nonaromatic ring, wherein one or more of the non-aromatic ring atoms are heteroatoms, each independently selected from O, S, and N; and the remaining ring atoms are carbon atoms. For a heterocyclyl group containing a heteroaromatic ring and a nonaromatic heterocyclic ring, the heterocyclyl group is not bonded to the rest of a molecule through the heteroaromatic ring. In certain embodiments, the heterocyclyl or heterocyclic group has from 3 to 20, from 3 to 15, from 3 to 10, from 3 to 8, from 4 to 7, or from 5 to 6 ring atoms. In certain embodiments, the heterocyclyl is a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which 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 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 heterocyclyls and heterocyclic groups include, but are not limited to, azepinyl, benzodioxanyl, benzodi oxolyl, benzofuranonyl, chromanyl, decahydroisoquinolinyl, dihydrobenzofuranyl, dihydrobenzisothiazolyl, dihydrobenzisoxazinyl (including all isomeric forms, e.g., l,4-dihydrobenzo[<7][l,3]oxazinyl, 3,4-dihydrobenzo[c][l,2]-oxazinyl, and 3,4-dihydrobenzo[ ][l,2]oxazinyl), dihydrobenzothienyl, dihydroisobenzofuranyl, dihydrobenzo[c]thienyl, dihydrofuryl, dihydroisoindolyl, dihydropyranyl, dihydropyrazolyl, dihydropyrazinyl, dihydropyridinyl,dihydropyrimidinyl, dihydropyrrolyl, 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.

[0043] The term “heterocyclylene” refers to a divalent monocyclic non-aromatic ring system or divalent polycyclic ring system that contains at least one non-aromatic ring, wherein one or more of the non-aromatic ring atoms are heteroatoms independently selected from O, S, and N; and the remaining ring atoms are carbon atoms. For a heterocyclylene group containing a heteroaromatic ring and a nonaromatic heterocyclic ring, the heterocyclylene group has at least one bond to the rest of a molecule via its nonaromatic heterocyclic ring. In certain embodiments, the heterocyclylene group has from 3 to 20, from 3 to 15, from 3 to 10, from 3 to 8, from 4 to 7, or from 5 to 6 ring atoms. In certain embodiments, the heterocyclylene is a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may be fused or bridged, and in which nitrogen or sulfur atoms may be optionally oxidized, nitrogen atoms may be optionally quatemized, 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 which results in the creation of a stable compound. Examples of such heterocyclylene groups include, but are not limited to, azepindiyl, benzodi oxandiyl, benzodioxoldiyl, benzofuranondiyl, chromandiyl, decahydroisoquinolindiyl, dihydrobenzofurandiyl, dihydrobenzisothiazoldiyl, dihydrobenzisoxazindiyl (including all isomeric forms, e. ., l,4-dihydrobenzo

[0006] [l,3]oxazindiyl, 3,4-dihydrobenzo[c][l,2]oxazindiyl, and 3,4-dihydrobenzo[ ][l,2]oxazindiyl), dihydrobenzothiendiyl, dihydroisobenzofurandiyl, dihydrobenzo[c]thiendiyl, dihydrofurdiyl, dihydroisoindoldiyl, dihydropyrandiyl, dihydropyrazoldiyl, dihydropyrazindiyl, dihydropyridindiyl, dihydropyrimidindiyl, dihydropyrrol diyl, dioxolandiyl, 1,4-dithiandiyl, furanondiyl, imidazolidindiyl, imidazolindiyl, indolindiyl, isochromandiyl, isoindolindiyl, isothiazolidindiyl, isoxazolidindiyl, morpholindiyl, octahydroindoldiyl, octahydroisoindoldiyl, oxazolidinondiyl, oxazolidindiyl, oxirandiyl, piperazindiyl, piperidindiyl, 4-piperidondiyl, pyrazolidindiyl, pyrazolindiyl, pyrrolidindiyl, pyrrolindiyl, quinuclidindiyl, tetrahydrofurdiyl, tetrahydroisoquinolindiyl, tetrahydropyrandiyl,tetrahydrothiendiyl, thiamorpholindiyl, thiazolidindiyl, thiochromandiyl, tetrahydroquinolindiyl, and 1,3,5-trithiandiyl. In certain embodiments, the heterocyclylene is optionally substituted with one or more substituents Q as described herein.

[0044] The term “halogen,” “halide,” or “halo” refers to fluoro, chloro, bromo, and / or iodo.

[0045] The term “optionally substituted” is intended to mean that 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, may be substituted with one or more, in one embodiment, one, two, three, or four, substituents Q, each of which is independently selected from, e.g., (a) deuterium (-D), cyano (-CN), halo, imino (=NH), nitro (-NO2), and oxo (=0); (b) C1-6 alkyl, C1-6 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, and heterocyclyl, each of which is further optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Qa; and (c) -C(O)Ra, -C(O)ORa, -C(O)NRbRc, -C(O)SRa, -C(NRa)NRbRc, -C(S)Ra, -C(S)ORa, -C(S)NRbRc, -ORa, -OC(O)Ra, -OC(O)ORa, -OC(O)NRbRc, -OC(O)SRa, -0C(NRa)NRbRc, -OC(S)Ra, -OC(S)ORa, -OC(S)NRbRc, -OP(O)(ORb)ORc, -OS(O)Ra, -OS(O)2Ra, -OS(O)NRbRc, -OS(O)2NRbRc, -NRbRc, -NRaC(O)Rd, -NRaC(O)ORd, -NRaC(O)NRbRc, -NRaC(O)SRd, -NRaC(NRd)NRbRc, -NRaC(S)Rd, -NRaC(S)ORd, -NRaC(S)NRbRc, -NRaS(O)Rd, -NRaS(O)2Rd, -NRaS(O)NRbRc, -NRaS(O)2NRbRc, -SRa, -S(O)Ra, -S(O)2Ra, -S(O)NRbRc, and -S(O)2NRbRc, wherein each Ra, Rb, Rc, and Rdis independently (i) hydrogen or deuterium; (ii) C1-6 alkyl, C1-6 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Qa; or (iii) Rband Rctogether with the N atom to which they are attached form heterocyclyl optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Qa. As used herein, all groups that can be substituted are “optionally substituted.”

[0046] In one embodiment, each Qais independently selected from: (a) deuterium, cyano, halo, imino, nitro, and oxo; (b) C1-6 alkyl, C1-6 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, and heterocyclyl; and (c) -C(O)Re, -C(O)ORe, -C(O)NRfRg, -C(O)SRe, -C(NRe)NRfRg, -C(S)Re, -C(S)ORe, -C(S)NRfRg, -ORe, -OC(O)Re, -OC(O)ORC, -OC(O)NRfRg, -OC(O)SRC, -OC(NRc)NRfRs, -OC(S)RC, -OC(S)ORC, -OC(S)NRfRg, -OP(O)(ORf)ORg, -OS(O)Re, -OS(O)2Re, -OS(O)NRfRg, -OS(O)2NRfRg, -NRfRg, -NReC(O)Rh, -NReC(O)ORf, -NReC(O)NRfRg, -NReC(O)SRf, -NReC(NRh)NRfRg, -NReC(S)Rh, -NReC(S)ORf, -NReC(S)NRfRg, -NReS(O)Rh, -NReS(O)2Rh, -NReS(O)NRfRg, -NReS(O)2NRfRg, -SRe, -S(O)Re, -S(O)2Re, -S(O)NRfRg, and -S(O)2NRfRg; wherein each Re, Rf, Rg, and Rhis independently (i) hydrogen or deuterium; (ii) C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-i4 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) Rfand Rgtogether with the N atom to which they are attached form heterocyclyl.

[0047] In certain embodiments, “optically active” and ’’enantiomerically active” refer to a collection of molecules, which has an enantiomeric excess of no less than about 80%, no less than about 90%, no less than about 91%, no less than about 92%, no less than about 93%, no less than about 94%, no less than about 95%, no less than about 96%, no less than about 97%, no less than about 98%, no less than about 99%, no less than about 99.5%, or no less than about 99.8%. In certain embodiments, an optically active compound comprises 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 certain embodiments, an optically active compound comprises 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 certain embodiments, an optically active compound comprises 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.

[0048] 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(s). The (+) and (-) are used to denote the optical rotation of the compound, that is, the direction in which a plane of polarized light is rotated by the optically active compound. The (-) prefix indicates that the compound is levorotatory, that is, the compound rotates the plane of polarized light to the left or counterclockwise. The (+) prefix indicates that the compound is dextrorotatory, that is, the compound rotates the plane of polarized light to the right or clockwise. However, the sign of optical rotation, (+) and (-), is not related to the absolute configuration of the compound, R and S.

[0049] The term “isotopically enriched” refers to a compound that contains an unnatural proportion of an isotope at one or more of the atoms that constitute such a compound. In certain embodiments, an isotopically enriched compound contains unnatural proportions of one or more isotopes, including, but not limited to, hydrogen (1H), deuterium (2H), tritium (3H), carbon- 11 (UC), carbon-12 (12C), carbon-13 (13C), carbon-14 (14C), nitrogen-13 (13N), nitrogen-14 (14N), nitrogen-15 (15N), oxygen-14 (14O), oxygen-15 (13O), oxygen-16 (16O), oxygen-17 (17O), oxygen-18 (18O), fluorine-17 (17F), fluorine-18 (18F), phosphorus-31 (31P), phosphorus-32 (32P), phosphorus-33 (33P), sulfur-32 (32S), sulfur-33 (33S), sulfur-34 (34S), sulfur-35 (35S), sulfur-36 (36S), chlorine-35 (3?C1), chlorine-36 (36C1), chlorine-37 (37C1), bromine-79 (79Br), bromine-81 (81Br), iodine-123 (123I), iodine-125 (125I), iodine-127 (127I), iodine-129 (129I), and iodine-131 (131I). In certain embodiments, an isotopically enriched compound is in a stable form, that is, non-radioactive. In certain embodiments, an isotopically enriched compound contains unnatural proportions of one or more isotopes, including, but not limited to, hydrogen (1H), deuterium (2H), carbon- 12 (12C), carbon- 13 (13C), nitrogen- 14 (14N), nitrogen- 15 (15N), oxygen- 16 (16O), oxygen-17 (17O), oxygen-18 (18O), fluorine-17 (17F), phosphorus-31 (31P), sulfur-32 (32S), sulfur- 33 (33S), sulfur-34 (34S), sulfur-36 (36S), chlorine-35 (35C1), chlorine-37 (37C1), bromine-79 (79Br), bromine-81 (81Br), and iodine-127 (127I). In certain embodiments, an isotopically enriched compound is in an unstable form, that is, radioactive. In certain embodiments, an isotopically enriched compound contains unnatural proportions of one or more isotopes, including, but not limited to, tritium (3H), carbon-11 (UC), carbon-14 (14C), nitrogen-13 (13N), oxygen-14 (14O), oxygen-15 (15O), fluorine-18 (18F), phosphorus-32 (32P), phosphorus-33 (33P), sulfur-35 (35S), chlorine-36 (36C1), iodine-123 (123I), iodine-125 (125I), iodine-129 (129I), and iodine-131 (131I). It will be understood that, in a compound as provided herein, any hydrogen can be2H, as example, or any carbon can be13C, as example, or any nitrogen can be15N, as example, or any oxygen can be18O, as example, where feasible according to the judgment of one of ordinary skill in the art.

[0050] The term “isotopic enrichment” refers to the percentage of incorporation of a less prevalent isotope (e.g., D for deuterium or hydrogen-2) of an element at a given position in a molecule in the place of a more prevalent isotope e.g.,1H for protium or hydrogen-1) of the element. As used herein, when an atom at a particular position in a molecule is designated as a particular less prevalent isotope, it is understood that the abundance of that isotope at thatposition is substantially greater than its natural abundance.

[0051] The term “isotopic enrichment factor” refers to the ratio between the isotopic abundance in an isotopically enriched compound and the natural abundance of a specific isotope.

[0052] The term “hydrogen” or the symbol “H” refers to the composition of naturally occurring hydrogen isotopes, which include protium (1H), deuterium (2H or D), and tritium (3H), in their natural abundances. Protium is the most common hydrogen isotope having a natural abundance of more than 99.98%. Deuterium is a less prevalent hydrogen isotope having a natural abundance of about 0.0156%.

[0053] The term “deuterium enrichment” refers to the percentage of incorporation of deuterium at a given position in a molecule in the place of hydrogen. For example, deuterium enrichment of 1% at a given position means that 1% of molecules in a given sample contain deuterium at the specified position. Because the naturally occurring distribution of deuterium is about 0.0156% on average, deuterium enrichment at any position in a compound synthesized using non-enriched starting materials 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 greater than its natural abundance (0.0156%).

[0054] The term “carbon” or the symbol “C” refers to the composition of naturally occurring carbon isotopes, which include carbon- 12 (12C) and carbon- 13 (13C) in their natural abundances. Carbon-12 is the most common carbon isotope having a natural abundance of more than 98.89%. Carbon-13 is a less prevalent carbon isotope having a natural abundance of about 1.11%.

[0055] The term “carbon-13 enrichment” or “13C enrichment” refers to the percentage of incorporation of carbon- 13 at a given position in a molecule in the place of carbon. For example, carbon- 13 enrichment of 10% at a given position means that 10% of molecules in a given sample contain carbon- 13 at the specified position. Because the naturally occurring distribution of carbon- 13 is about 1.11% on average, carbon- 13 enrichment at any position in a compound synthesized using non-enriched starting materials is about 1.11% on average. 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 greater than its natural abundance (1.11%).

[0056] The terms “substantially pure” and “substantially homogeneous” mean, when referred to a substance, sufficiently homogeneous to appear free of readily detectable impurities as determined by a standard analytical method used by one of ordinary skill 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 such that further purification would not detectably alter the physical, chemical, biological, and / or pharmacological properties, such as enzymatic and biological activities, of the substance. In certain embodiments, “substantially pure” or “substantially homogeneous” refers to a collection of molecules, wherein 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 prevalent isotope, a molecule that contains other than the designated isotope at the specified position is an impurity with respect to the isotopically enriched compound. Thus, for a deuterated compound that has an atom at a particular position designated as deuterium, a compound that contains a protium at the same position is an impurity.

[0057] The term “solvate” refers to a complex or aggregate formed by one or more molecules of a solute, e.g., a compound provided herein, and one or more molecules of a solvent, which are present in a stoichiometric or non-stoichiometric amount. Suitable solvents include, but are not limited to, water, methanol, ethanol, / / -propanol, isopropanol, and acetic acid. In certain 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 a noncrystalline form. Where the solvent is water, the solvate is a hydrate. Examples of hydrates include, but are not limited to, a hemihydrate, monohydrate, dihydrate, trihydrate, tetrahydrate, and pentahydrate.

[0058] For a divalent group 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)-.

[0059] The phrase “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’ has the same meaning as the phrase “(i) 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 of the compound referenced therein; (ii) a pharmaceutically acceptable salt, solvate, hydrate, or prodrug of the compound referenced therein; or (iii) a pharmaceutically acceptable salt, solvate, hydrate, or prodrug of 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 of the compound referenced therein.”Compounds

[0060] In one embodiment, provided herein is a compound of Formula (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; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein:A is C3-10 cycloalkylene, C6-14 arylene, heteroarylene, or heterocyclylene;L is C1-6 alkylene, C7-15 aralkylene, or a linker;U and V are each independently -C(R4a)= or -N=;X is -N= or -C(R4b)=;R1is hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl;R3is C3-10 cycloalkyl, C6-14 aryl, heteroaryl, or heterocyclyl;each R4is independently (i) deuterium, cyano, halo, or nitro; (ii) Ci-6 alkyl, Ci-6 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) -C(O)R1a, -C(O)OR1a, -C(O)NR1bR1c, -C(O)SR1a, -C(NR1a)NR1bR1c, -C(S)R1a, -C(S)OR1a, -C(S)NR1bR1c, -OR1a, -OC(O)R1a, -OC(O)OR1a, -OC(O)NR1bR1c, -OC(O)SR1a, -OC(NR1 a)NR1bR1c, -OC(S)R1a, -OC(S)OR1a, -OC(S)NR1bR1c, -OS(O)R1a, -OS(O)2R1a, -OS(O)NR1bR1c, -OS(O)2NR1bR1c, -NR1bR1c, -NR1aC(O)R1d, -NR1aC(O)OR1d, -NR1 aC(O)NR1bR1c, -NR1 aC(O)SR1d, -NR1 aC(NR1d)NR1bR1c, -NR1aC(S)R1d, -NR1 aC(S)OR1d, -NR1 aC(S)NR1bR1c, -NR1aS(O)R1d, -NR1 aS(O)2R1d, -NR1 aS(O)NR1bR1c, -NR1aS(O)2NR1bR1c, -SR1a, -S(O)R1a, -S(O)2R1a, -S(O)NR1bR1c, or -S(O)2NR1bR1c;R2aand R2bare each independently hydrogen, deuterium, halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, heteroaryl, or heterocyclyl; each R4aand R4bis independently hydrogen or R4;Reis an E3 ubiquitin ligase binding moiety; each R1a, Rlb, R1c, and R1dis independently hydrogen, deuterium, C1-6 alkyl, C1-6 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl; and a is an integer of 0, 1, or 2; wherein each alkyl, alkylene, heteroalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylene, aryl, arylene, aralkyl, aralkylene, heteroaryl, heteroarylene, heterocyclyl, and heterocyclylene is optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Q, wherein each Q is independently selected from: (a) deuterium, cyano, halo, imino, nitro, and oxo; (b) C1-6 alkyl, C1-6 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, and heterocyclyl, each of which is further optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Qa; and (c) -C(O)Ra, -C(O)ORa, -C(O)NRbRc, -C(O)SRa, -C(NRa)NRbRc, -C(S)Ra, -C(S)ORa, -C(S)NRbRc, -ORa, -OC(O)Ra, -OC(O)ORa, -OC(O)NRbRc, -OC(O)SRa, -OC(NRa)NRbRc, -OC(S)Ra, -OC(S)ORa, -OC(S)NRbRc, -OP(O)(ORb)ORe, -OS(O)Ra, -OS(O)2Ra, -OS(O)NRbRc, -OS(O)2NRbRc, -NRbRc, -NRaC(O)Rd, -NRaC(O)ORd, -NRaC(O)NRbRc,NRaC(O)SRd, NRaC(NRd)NRbRc, NRaC(S)Rd, NRaC(S)ORd, NRaC(S)NRbRc, -NRaS(O)Rd, -NRaS(O)2Rd, -NRaS(O)NRbRc, -NRaS(O)2NRbRe, -SRa, -S(O)Ra, -S(O)2Ra, -S(O)NRbRc, and -S(O)2NRbRc, wherein each Ra, Rb, Rc, and Rdis independently (i) hydrogenor deuterium; (ii) C1-6 alkyl, C1-6 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Qa; or (iii) Rband Rctogether with the N atom to which they are attached form heterocyclyl, optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Qa; wherein each Qais independently selected from: (a) deuterium, cyano, halo, nitro, imino, and oxo; (b) C1-6 alkyl, C1-6 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, and heterocyclyl; and (c) -C(O)Re, -C(O)ORe, -C(O)NRfRs, -C(O)SRe, -C(NRe)NRfRg, -C(S)Re, -C(S)ORe, -C(S)NRfRg, -ORe, -OC(O)Re, -OC(O)ORe, OC(O)NRfRg, OC(O)SRe, OC(NRe)NRfRg, OC(S)Re, OC(S)ORe, OC(S)NRfRg, -OP(O)(ORf)ORg, -OS(O)Re, -OS(O)2Re, -OS(O)NRfRg, -OS(O)2NRfRg, -NRfRg, -NReC(O)Rh, -NReC(O)ORf, -NReC(O)NRfRg, -NReC(O)SRf, -NReC(NRh)NRfRg, -NReC(S)Rh, -NReC(S)ORf, -NReC(S)NRfRg, -NReS(O)Rh, -NReS(O)2Rh, -NReS(O)NRfRg, -NReS(O)2NRfRg, -SRe, -S(O)Re, -S(O)2Re, -S(O)NRfRg, and -S(O)2NRfRg; wherein each Re, Rf, Rg, and Rhis independently (i) hydrogen or deuterium; (ii) C1-6 alkyl, C1-6 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) R1and R8together with the N atom to which they are attached form heterocyclyl.

[0061] In certain embodiments, in any one of the formulae described herein, A is C3-10 cycloalkylene, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, A is monocyclic C3-10 cycloalkylene, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, A is bicyclic C4-10 cycloalkylene, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, A is bridged, fused, or spiro C4-10 cycloalkylene, each optionally substituted with one or more substituents Q.

[0062] In certain embodiments, in any one of the formulae described herein, A is C6-14 arylene, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, A is phendiyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, A is phendiyl, optionally substituted with one, two, or three substituents Q, wherein each substituentis independently halo, Ci-6 alkyl, or Ci-6 heteroalkyl. In certain embodiments, in any one of the formulae described herein, A is phendiyl, optionally substituted with one, two, or three substituents Q, wherein each substituent is independently fluoro, chloro, or methyl. In certain embodiments, in any one of the formulae described herein, A is phen-l,2-diyl, phen-l,3-diyl, or phen-l,4-diyl, each optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, A is phen- 1,3 -diyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, A is phen-l,3-diyl, optionally substituted with one, two, or three substituents Q, wherein each substituent is independently halo, Ci-6 alkyl, or Ci-6 heteroalkyl. In certain embodiments, in any one of the formulae described herein, A is phen- 1,3 -diyl, optionally substituted with one, two, or three substituents Q, wherein each substituent is independently fluoro, chloro, or methyl. In certain embodiments, in any one of the formulae described herein, A is phen-l,3-diyl, 2-fluorophen- 1,3 -diyl, 4-fluorophen- 1,3 -diyl, 5 -fluorophen- 1,3 -diyl, 2- chlorophen-l,3-diyl, 4-chlorophen-l,3-diyl, 5-chlorophen-l,3-diyl, 2-methylphen- 1,3 -diyl, 4- methylphen- 1,3 -diyl, or 5-methylphen-l,3-diyl.

[0063] In certain embodiments, in any one of the formulae described herein, A is heteroarylene, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, A is monocyclic heteroarylene, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, A is 5- or 6-membered heteroarylene, each optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, A is 5-membered heteroarylene, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, A is 6-membered heteroarylene, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, A is furandiyl, thiendiyl, or pyridindiyl, each optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, A is furan-2,4-diyl, thien-2,4-diyl, pyridin-2,4-diyl, pyridin-2,6-diyl, or pyridin-3,5-diyl, each optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, A is bicyclic heteroarylene, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, A is 5,5-, 5,6-, or 6,6-fused heteroarylene, each optionallysubstituted with one or more substituents Q.

[0064] In certain embodiments, in any one of the formulae described herein, A is heterocyclylene, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, A is monocyclic heterocyclylene, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, A is 3-, 4-, 5-, 6-, or 7-membered heterocyclylene, each optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, A is 6-membered heterocyclylene, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, A is 1,2-dihydro- pyridindiyl, piperidindiyl, morpholindiyl, or piperazindiyl, each optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, A is l,2-dihydropyridin-l,5-diyl, l,2-dihydropyridin-3,5-diyl, piperidin-l,3-diyl, morpholin-2,4- diyl, or piperazin- 1 ,4-diyl, each optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, A is l-methyl-2-oxo-l,2- dihydropyri din-3, 5-diyl, 2-oxo-l,2-dihydropyridin-l,5-diyl, 3-fluoropiperidin-l,3-diyl, morpholin-2,4-diyl, or piperazin- 1 ,4-diyl. In certain embodiments, in any one of the formulae described herein, A is bicyclic heterocyclylene, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, A is bridged, fused, or spiro heterocyclylene, each optionally substituted with one or more substituents Q.

[0065] In certain embodiments, in any one of the formulae described herein, A is C6-14 arylene, heteroarylene, or heterocyclylene, each optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, A is phendiyl, monocyclic heteroarylene, or monocyclic heterocyclylene, each optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, A is phendiyl, furandiyl, thiendiyl, pyridindiyl, 1,2-dihydropyridindiyl, piperidindiyl, morpholindiyl, or piperazindiyl, each optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, A is phen-l,3-diyl, furan-2,4- diyl, thien-2,4-diyl, pyridin-2,4-diyl, pyridin-2,6-diyl, pyridin-3, 5-diyl, l,2-dihydropyridin-3,5- diyl, 1,2-dihydropyridin-l, 5-diyl, morpholin-2,4-diyl, piperazin- 1,4-diyl, or piperi din- 1,3 -diyl,each optionally substituted with one or more substituents Q.

[0066] In certain embodiments, in any one of the formulae described herein, A has the structurewherein:U5, V5, X5, and Z5are each independently -C(R5)= or -N=;U6is -C(R6b)2- or -O-; each R5, R6a, and R6bis independently (i) hydrogen, deuterium, cyano, halo, or nitro; (ii) Ci-6 alkyl, Ci-6 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl, each optionally substituted with one or more substituents Q; or (iii) -C(O)R1a, -C(O)OR1a, -C(O)NR1bR1c, -C(O)SR1a, -C(NR1a)NR1bR1c, -C(S)R1a, -C(S)OR1a, -C(S)NR1bR1c, -OR1a, -OC(O)R1a, -OC(O)OR1a, -OC(O)NR1 bR1c, -OC(O)SR1a, -OC(NR1a)NR1bR1c, -OC(S)R1a, -OC(S)OR1a, -OC(S)NR1bR1c, -OS(O)R1a, -OS(O)2R1a, -OS(O)NR1bR1c, -OS(O)2NR1bR1c, -NR1bR1c, -NR1 aC(O)R1d, -NR1aC(O)OR1d, -NR1 aC(O)NR1bR1c, -NR1 aC(O)SR1d, -NR1 aC(NR1d)NR1bR1c, -NR1aC(S)R1d, -NR1 aC(S)OR1d, -NR1 aC(S)NR1bR1c, -NR1aS(O)R1d, -NR1 aS(O)2R1d, -NR1 aS(O)NR1bR1c, -NR1aS(O)2NR1bR1c, -SR1a, -S(O)R1a, -S(O)2R1a, -S(O)NR1bR1c, or -S(O)2NR1bR1c; each R6is independently (i) deuterium, cyano, halo, or nitro; (ii) C1-6 alkyl, C1-6 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl, each optionally substituted with one or more substituents Q; or (iii) -C(O)R1a, C(O)OR1a, C(O)NR1 bR1c, C(O)SR1a, C(NR1 a)NR1bR1c, C(S)R1a, C(S)OR1a, -C(S)NR1bR1c, -OR1a, -OC(O)R1a, -OC(O)OR1a, -OC(O)NR1bR1c, -OC(O)SR1a, -OC(NR1a)NR1bR1c, -OC(S)R1a, -OC(S)OR1a, -OC(S)NR1 bR1c, -OS(O)R1a, -OS(O)2R1a, -OS(O)NR1 bR1c, -OS(O)2NR1bR1c, -NR1bR1c, -NR1 aC(O)R1d, -NR1aC(O)OR1d, -NR1 aC(O)NR1bR1c, -NR1 aC(O)SR1d, -NR1 aC(NR1d)NR1bR1c, -NR1aC(S)R1d, -NR1 aC(S)OR1d, -NR1 aC(S)NR1bR1c, -NR1aS(O)R1d, -NR1 aS(O)2R1d, -NR1 aS(O)NR1 bR1c, -NR1aS(O)2NR1bR1c, -SR1a, -S(O)R1a, -S(O)2R1a, -S(O)NRlbR1c, or -S(O)2NR1bR1c; b is an integer of 0, 1, 2, 3, 4, 5, or 6; and R1a, Rlb, R1c, and R1dare each as defined herein.

[0067] In one embodiment, provided herein is a compound of Formula (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; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R1, R3, R4, R2a, R2b, Re, L, U, V, X, U3, V5, X5, Z5, and a are each as defined herein.

[0068] In another embodiment, provided herein is a compound of Formula (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; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R1, R3, R4, R6, R2a, R2b, R6a, Re, L, U, V, X, U6, a, and b are each as defined herein.

[0069] In certain embodiments, in any one of the formulae described herein, R3is C3-10 cycloalkyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R3is monocyclic C3-10 cycloalkyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R3is bicyclic C4-10 cycloalkyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R3is bridged, fused, or spiro C4-10 cycloalkyl, each optionally substituted with one or more substituents Q.

[0070] In certain embodiments, in any one of the formulae described herein, R3is C6-14 aryl, optionally substituted with one, two, or three substituents Q. In certain embodiments, in any one of the formulae described herein, R3is C6-14 aryl, substituted with one, two, or three substituents Q. In certain embodiments, in any one of the formulae described herein, R3is C6-14aryl, substituted with one substituent Q. In certain embodiments, in any one of the formulae described herein, R3is C6-14 aryl, substituted with two substituents Q. In certain embodiments, in any one of the formulae described herein, R3is C6-14 aryl, substituted with three substituents Q.

[0071] In certain embodiments, in any one of the formulae described herein, R3is C6-14 aryl, substituted with one, two, or three substituents, wherein each substituent is independently (i) cyano, halo, or nitro; (ii) Ci-6 alkyl or C6-14 aryl, each optionally substituted with one or more substituents Q; or (iii) -OR1a, -NR1bR1c, or -S(O)2R1a, wherein each R1a, Rlb, and R1cis as defined herein. In certain embodiments, in any one of the formulae described herein, R3is C6-14 aryl, substituted with one, two, or three substituents, wherein each substituent is independently cyano, fluoro, chloro, bromo, nitro, methyl, ethyl, fluoromethyl, difluoromethyl, trifluoromethyl, 1 -cyano- 1 , 1 -difluoromethyl, 1 , 1 -difluoro-2-hydroxy ethyl, 1 , 1 -difluoro-2-hydroxy-2-methyl- propyl, methylaminomethyl, 2-aminomethylphenyl, 2-(2-aminoethyl)phenyl, 2-methylamino- methylphenyl, 2-dimethylaminomethylphenyl, hydroxyl, methoxy, amino, or methyl sulfonyl. In certain embodiments, in any one of the formulae described herein, R3is C6-14 aryl, substituted with one, two, or three substituents, wherein each substituent is independently cyano, fluoro, nitro, methyl, difluoromethyl, trifluoromethyl, or amino. In certain embodiments, in any one of the formulae described herein, R3is C6-14 aryl, substituted with one, two, or three substituents, wherein each substituent is independently cyano, fluoro, methyl, difluoromethyl, trifluoromethyl, or amino.

[0072] In certain embodiments, in any one of the formulae described herein, R3is phenyl, optionally substituted with one, two, or three substituents Q. In certain embodiments, in any one of the formulae described herein, R3is phenyl, substituted with one, two, or three substituents Q. In certain embodiments, in any one of the formulae described herein, R3is phenyl, substituted with one substituent Q. In certain embodiments, in any one of the formulae described herein, R3is phenyl, substituted with two substituents Q. In certain embodiments, in any one of the formulae described herein, R3is phenyl, substituted with three substituents Q.

[0073] In certain embodiments, in any one of the formulae described herein, R3is phenyl, substituted with one, two, or three substituents, wherein each substituent is independently (i) cyano, halo, or nitro; (ii) Ci-6 alkyl or C6-14 aryl, each optionally substituted with one or moresubstituents Q; or (iii) -OR1a, -NR1bR1c, or -S(O)2R1a, wherein each R1a, Rlb, and R1cis as defined herein. In certain embodiments, in any one of the formulae described herein, R3is phenyl, substituted with one, two, or three substituents, wherein each substituent is independently cyano, fluoro, chloro, bromo, nitro, methyl, ethyl, fluoromethyl, difluoromethyl, trifluoromethyl, 1 -cyano- 1,1 -difluoromethyl, 1 , 1 -difluoro-2-hydroxy ethyl, 1 , 1 -difluoro-2- hydroxy-2-methylpropyl, methylaminomethyl, 2-aminomethylphenyl, 2-(2-aminoethyl)phenyl, 2-methylaminomethyl-phenyl, 2-dimethylaminomethylphenyl, hydroxyl, methoxy, amino, or methyl sulfonyl. In certain embodiments, in any one of the formulae described herein, R3is phenyl, substituted with one, two, or three substituents, wherein each substituent is independently cyano, fluoro, nitro, methyl, difluoromethyl, trifluoromethyl, or amino. In certain embodiments, in any one of the formulae described herein, R3is phenyl, substituted with one, two, or three substituents, wherein each substituent is independently cyano, fluoro, methyl, difluoromethyl, trifluoromethyl, or amino.

[0074] In certain embodiments, in any one of the formulae described herein, R3is 3- cyanophenyl, 3-bromophenyl, 3 -methylphenyl, 3 -difluorom ethylphenyl, 3 -trifluorom ethylphenyl, 3-(l-cyano-l,l-difhioromethyl)phenyl, 3-(l,l-difhioro-2-hydroxyethyl)phenyl, 3-(2- aminomethylphenyl)phenyl, 3-cyano-5-fluorophenyl, 3-cyano-2-methylphenyl, 3-cyano-5- methylphenyl, 3-cyano-2-trifluoromethylphenyl, 3-cyano-5-hydroxyphenyl, 3 -cyano-2-m ethoxyphenyl, 3-nitro-5-trifluoromethylphenyl, 2,3-difluorophenyl, 2,4-difluorophenyl, 2-chloro-3- fluorophenyl, 2-chloro-4-fluorophenyl, 2-chloro-3 -difluorom ethylphenyl, 2-chl oro-3 -methylphenyl, 3-chloro-2-methylphenyl, 3-difluoromethyl-2-fluorophenyl, 3-difluoromethyl-2-fluoro- methylphenyl, 3 -difluorom ethyl-2-ethylphenyl, 3 -difluorom ethyl-2-methylphenyl, 2-fluoro-3- (1,1 -difl uoro-2-hydroxy-2-methylpropyl)phenyl, 2-fluoro-3 -methylphenyl, 3-fluoro-2-methyl- phenyl, 3 -fluoro-4-m ethylphenyl, 4-fluoro-2-methylphenyl, 2-fluoro-3 -trifluoromethylphenyl, 3- fluoro-5-trifluoromethylphenyl, 2,3-di(difluoromethyl)phenyl, 2-methyl-3 -trifluorom ethylphenyl, 2-methyl-3-methylaminomethylphenyl, 2-methyl-3-methylsulfonylphenyl, 3-methyl-5- trifluoromethylphenyl, 3-hydroxy-5-trifluoromethylphenyl, 3-amino-5-trifluoromethylphenyl, 3- amino-4-fluoro-5-trifluoromethylphenyl, 5-amino-2-fluoro-3 -trifluoromethylphenyl, 5-amino-2- methyl-3 -trifluoromethylphenyl, 3-cyano-2,5-difluorophenyl, 3-cyano-5-fluoro-2-methylphenyl, or 5-fluoro-2-methyl-3-trifluoromethylphenyl. In certain embodiments, in any one of the formulae described herein, R3is 3-difluoromethyl-2-fluorophenyl, 3-difluoromethyl-2-methyl-phenyl, 3-cyano-2-methylphenyl, 3-nitro-5-trifluoromethylphenyl, 3-fluoro-2-methylphenyl, 2- methyl-3 -trifluoromethylphenyl, or 3-amino-5-trifluoromethylphenyl. In certain embodiments, in any one of the formulae described herein, R3is 3-difluoromethyl-2-fluorophenyl, 3-difluoro- methyl-2-methylphenyl, 3-cyano-2-methylphenyl, 3-fluoro-2-methylphenyl, 2-methyl-3- trifluoromethylphenyl, or 3 -amino-5-trifluorom ethylphenyl.

[0075] In certain embodiments, in any one of the formulae described herein, R3is bicyclic Cs-14 aryl, optionally substituted with one, two, or three substituents Q. In certain embodiments, in any one of the formulae described herein, R3is bicyclic Cs-i4 aryl, substituted with one, two, or three substituents Q. In certain embodiments, in any one of the formulae described herein, R3is bicyclic Cs-14 aryl, substituted with one substituent Q. In certain embodiments, in any one of the formulae described herein, R3is bicyclic Cs-14 aryl, substituted with two substituents Q. In certain embodiments, in any one of the formulae described herein, R3is bicyclic Cs-14 aryl, substituted with three substituents Q.

[0076] In certain embodiments, in any one of the formulae described herein, R3is 5,6- or 6,6-fused C9-14 aryl, each optionally substituted with one, two, or three substituents Q. In certain embodiments, in any one of the formulae described herein, R3is 2,3-dihydroindenyl or naphthyl, each optionally substituted with one, two, or three substituents Q. In certain embodiments, in any one of the formulae described herein, R3is 2,3-dihydroindenyl or naphthyl, each optionally substituted with one, two, or three substituents, each of which is independently (i) cyano, halo, or nitro; (ii) C1-6 alkyl or C6-14 aryl, each optionally substituted with one or more substituents Q; or (iii) -OR1a, -NR1 bR1c, or -S(O)2R1a, wherein each R1a, Rlb, and R1cis as defined herein. In certain embodiments, in any one of the formulae described herein, R3is 2,3-dihydroinden-4-yl, 2,3-dihydroinden-5-yl, naphth-l-yl, or naphth-2-yl, each optionally substituted with one, two, or three substituents, each of which is independently cyano, fluoro, chloro, bromo, nitro, methyl, ethyl, fluoromethyl, difluoromethyl, trifluoromethyl, 1 -cyano- 1,1 -difluoromethyl, l,l-difluoro-2- hydroxy ethyl, l,l-difluoro-2-hydroxy-2-m ethylpropyl, methylaminomethyl, 2-aminom ethylphenyl, 2-(2-aminoethyl)phenyl, 2-methylaminomethylphenyl, 2-dimethylaminomethylphenyl, hydroxyl, methoxy, amino, or methyl sulfonyl. In certain embodiments, in any one of the formulae described herein, R3is l,l-difluoro-2,3-dihydroinden-4-yl or naphth-l-yl.

[0077] In certain embodiments, in any one of the formulae described herein, R3is heteroaryl, optionally substituted with one, two, or three substituents Q. In certain embodiments, in any one of the formulae described herein, R3is monocyclic heteroaryl, optionally substituted with one, two, or three substituents Q. In certain embodiments, in any one of the formulae described herein, R3is 5- or 6-membered heteroaryl, each optionally substituted with one, two, or three substituents Q. In certain embodiments, in any one of the formulae described herein, R3is thienyl or pyridinyl, each optionally substituted with one, two, or three substituents Q. In certain embodiments, in any one of the formulae described herein, R3is thien-2-yl or thien-3-yl, each independently substituted with C6-14 aryl or heteroaryl, where the aryl and heteroaryl are each optionally further substituted with one, two, or three substituents Qa. In certain embodiments, in any one of the formulae described herein, R3is thienyl or pyridinyl, each optionally substituted with one, two, or three substituents, each of which is independently (i) cyano, halo, or nitro; (ii) Ci-6 alkyl or C6-14 aryl, each optionally substituted with one or more substituents Q; or (iii) -OR1a, -NR1bR1c, or -S(O)2R1a, wherein each R1a, Rlb, and R1cis as defined herein. In certain embodiments, in any one of the formulae described herein, R3is thien- 2-yl, thien-3-yl, pyridin-2-yl, pyridin-3-yl, or pyridin-4-yl, each optionally substituted with one, two, or three substituents, wherein each substituent is independently cyano, fluoro, chloro, bromo, nitro, methyl, ethyl, fluoromethyl, difluoromethyl, trifluoromethyl, 1 -cyano- 1,1 -difluoro- methyl, 1,1 -difl uoro-2-hydroxy ethyl, l,l-difluoro-2-hydroxy-2-methylpropyl, methylaminomethyl, 2-aminomethylphenyl, 2-(2-aminoethyl)phenyl, 2-methylaminomethylphenyl, 2- dimethylaminomethylphenyl, hydroxyl, methoxy, amino, or methyl sulfonyl. In certain embodiments, in any one of the formulae described herein, R3is thien-2-yl, 5-(2-hydroxy- methylphenyl)thien-2-yl, 5-(2-aminomethylphenyl)thien-2-yl, 4-(2-methylaminomethylphenyl)- thien-2-yl, or 5-(2-(2-aminoethyl)phenyl)thien-2-yl. In certain embodiments, in any one of the formulae described herein, R3is bicyclic heteroaryl, optionally substituted with one, two, or three substituents Q. In certain embodiments, in any one of the formulae described herein, R3is 5,5-, 5,6-, or 6,6-fused heteroaryl, each optionally substituted with one, two, or three substituents Q. In certain embodiments, in any one of the formulae described herein, R3is 5,5-fused heteroaryl, optionally substituted with one, two, or three substituents Q. In certain embodiments, in any one of the formulae described herein, R3is 5,6-fused heteroaryl, optionally substituted with one, two, or three substituents Q. In certain embodiments, in any one of the formulaedescribed herein, R3is 6,6-fused heteroaryl, optionally substituted with one, two, or three substituents Q. In certain embodiments, in any one of the formulae described herein, R3is thien- 2-yl, 5-(2-hydroxymethyl-phenyl)thien-2-yl, 5-(2-amino-methylphenyl)thien-2-yl, 4-(2-methyl- aminomethylphenyl)thien-2-yl, 5-(2-(2-aminoethyl)-phenyl)thien-2-yl, or 5-(6,7-dihydro- py rrol o [ 1 ,2-a] imi dazol -3 -y 1 )thi en-2-y 1.

[0078] In certain embodiments, in any one of the formulae described herein, R3is heterocyclyl, optionally substituted with one, two, or three substituents Q. In certain embodiments, in any one of the formulae described herein, R3is monocyclic heterocyclyl, optionally substituted with one, two, or three substituents Q. In certain embodiments, in any one of the formulae described herein, R3is 3-, 4-, 5-, 6-, or 7-membered heterocyclyl, each optionally substituted with one, two, or three substituents Q. In certain embodiments, in any one of the formulae described herein, R3is bicyclic heterocyclyl, optionally substituted with one, two, or three substituents Q. In certain embodiments, in any one of the formulae described herein, R3is bridged, fused, or spiro heterocyclyl, each optionally substituted with one, two, or three substituents Q. In certain embodiments, in any one of the formulae described herein, R3is 2,3- dihydrobenzofuranyl, optionally substituted with one, two, or three substituents Q.

[0079] In certain embodiments, in any one of the formulae described herein, R3is C6-14 aryl or heteroaryl, each optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R3is phenyl or monocyclic heteroaryl, each optionally substituted with one or more substituents Q.

[0080] In certain embodiments, in any one of the formulae described herein, R3is 3- cyanophenyl, 3 -bromophenyl, 3 -methylphenyl, 3 -difluoromethylphenyl, 3 -trifluorom ethylphenyl, 3-(l,l-difhioroethyl)phenyl, 3-(l-cyano-l-fluoromethyl)phenyl, 3-(l-cyano-l,l-difluoro- methyl)phenyl, 3-(l,l-difluoro-2-hydroxyethyl)phenyl, 3-(2-aminomethylphenyl)phenyl, 3- cyano-5-fluorophenyl, 3-cyano-2-methylphenyl, 3-cyano-5-methylphenyl, 3-cyano-2-trifluoro- methylphenyl, 3-cyano-5-hydroxyphenyl, 3-cyano-2-methoxyphenyl, 3 -nitro-5-trifluorom ethylphenyl, 2,3-difluorophenyl, 2,4-difluorophenyl, 2-chloro-3-fluorophenyl, 2-chloro-4-fluoro- phenyl, 2-chloro-3-difluoromethylphenyl, 2-chl oro-3 -methylphenyl, 3 -chloro-2-m ethylphenyl, 3- difhroromethyl-2-fluorophenyl, 3-difluoromethyl-2-methylphenyl, 2-fluoro-3-(l, l-difluoro-2-hydroxy-2-methylpropyl)phenyl, 2-fluoro-3 -methylphenyl, 3-fluoro-2-methylphenyl, 3-fluoro-4- methylphenyl, 4-fluoro-2-methylphenyl, 2-fluoro-3 -difluoromethylphenyl, 2-fluoro-3 -trifluoromethylphenyl, 3-fluoro-5-trifluoromethylphenyl, 2-fluoromethyl-3-difluoromethylphenyl, 2,3- di(difluoromethyl)phenyl, 2-methyl-3-trifluoromethylphenyl, 2-ethyl-3 -difluoromethylphenyl, 2- methyl-3 -methylaminomethylphenyl, 2-methyl-3 -methylsulfonylphenyl, 3-methyl-5-trifluoro- methylphenyl, 3-hydroxy-5-trifluoromethylphenyl, 3-amino-5-trifluoromethylphenyl, 3-amino-4- fluoro-5-trifluoromethylphenyl, 5 -amino-2-fluoro-3 -trifluoromethylphenyl, 5-amino-2-methyl-3- trifluoromethylphenyl, 3-cyano-2,5-difluorophenyl, 3-cyano-5-fluoro-2-methylphenyl, 5-fluoro- 2-methyl-3-trifluoromethylphenyl, l,l-difluoro-2,3-dihydroinden-4-yl, naphth-l-yl, 5-(2-amino- methylphenyl)thien-2-yl, 5-(2-(2-aminoethyl)phenyl)thien-2-yl, 4-(2-methylaminomethyl- phenyl)thien-2-yl, 4-(2-dimethylaminomethylphenyl)thien-2-yl, 5-(2-methylaminomethyl- phenyl)thien-2-yl, 5-(3-fluoro-2-methylaminomethylphenyl)thien-2-yl, 5-(2-dimethylamino- methylphenyl)thien-2-yl, 2-methyl-pyri din-3 -yl, 4-amino-6-difluoromethylpyridin-2-yl, 4- amino-6-trifluoromethylpyridin-2-yl, or 3,3-difluoro-2,3-dihydrobenzofuran-7-yl.

[0081] In certain embodiments, in any one of the formulae described herein, R2bis hydrogen. In certain embodiments, in any one of the formulae described herein, R2bis deuterium. In certain embodiments, in any one of the formulae described herein, R2bis halo. In certain embodiments, in any one of the formulae described herein, R2bis Ci-6 alkyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R2bis methyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R2bis Ci-6 heteroalkyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R2bis C2-6 alkenyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R2bis C2-6 alkynyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R2bis C3-10 cycloalkyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R2bis C6-14 aryl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R2bis C7-15 aralkyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R2bis heteroaryl, optionally substituted with one or more substituents Q. In certain embodiments, inany one of the formulae described herein, R2bis heterocyclyl, optionally substituted with one or more substituents Q.

[0082] In one embodiment, provided herein is a compound of Formula (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; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein:R3a, R3b, R3C, R3d, and R3eare each independently (i) hydrogen, deuterium, cyano, halo, or nitro; (ii) Ci-6 alkyl, Ci-6 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl, each optionally substituted with one or more substituents Q; or (iii) -C(O)R1a, -C(O)OR1a, -C(O)NR1bR1c, -C(O)SR1a, -C(NR1 a)NR1bR1c, -C(S)R1a, -C(S)OR1a, -C(S)NR1bR1c, -OR1a, -OC(O)R1a, -OC(O)OR1a, -OC(O)NR1bR1c, -OC(O)SR1a, -OC(NR1 a)NR1bR1c, -OC(S)R1a, -OC(S)OR1a, -OC(S)NR1bR1c, -OS(O)R1a, -OS(O)2R1a, -OS(O)NR1bR1c, -OS(O)2NR1bR1c, -NR1bR1c, -NR1 aC(O)R1d, -NR1 aC(O)OR1d, -NR1aC(O)NR1bR1c, -NR1 aC(O)SR1d, -NR1 aC(NR1d)NR1bR1c, -NR1aC(S)R1d, -NR1 aC(S)OR1d, -NR1 aC(S)NR1bR1c, -NR1aS(O)R1d, -NR1 aS(O)2R1d, -NR1 aS(O)NR1bR1c, -NR1aS(O)2NR1bR1c, -SR1a, -S(O)R1a, -S(O)2R1a, -S(O)NR1bR1c, or -S(O)2NR1bR1c; andR1, R4, R1a, Rlb, R1c, R1d, R2a, Re, L, U, V, X, U5, V5, X5, Z5, and a are each as defined herein.

[0083] In another embodiment, provided herein is a compound of Formula (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; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R1, R4, R6, R2a, R3a, R3b, R3C, R3d, R3e, R6a, Re, L, U, V, X, U6, a, and b are each as defined herein.

[0084] In certain embodiments, in any one of the formulae described herein, X is -C(R4b)=, wherein R4bis as defined herein. In certain embodiments, in any one of the formulae described herein, X is -C(H)=. In certain embodiments, in any one of the formulae described herein, X is -N=.

[0085] In certain embodiments, in any one of the formulae described herein, U is -C(R4a)=; V is -N=; and X is -C(R4b)=; wherein R4aand R4bare each as defined herein. In certain embodiments, in any one of the formulae described herein, U is -N=; V is -C(R4a)=; and X is -C(R4b)=; wherein R4aand R4bare each as defined herein.

[0086] In one embodiment, provided herein is a compound of Formula (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; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R1, R4, R2a, R3a,R3b, R3C, R3d, R3e, Re, L, U, V, U5, V5, X5, Z5, and a are each as defined herein.

[0087] In another embodiment, provided herein is a compound of Formula (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; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R1, R4, R6, R2a, R3a, R3b, R3C, R3d, R3e, R6a, Re, L, U, V, U6, a, and b are each as defined herein.

[0088] In certain embodiments, in any one of the formulae described herein, U is -C(R4a)=, wherein R4ais as defined herein. In certain embodiments, in any one of the formulae described herein, U is -C(R4a)=, wherein R4ais Ci-6 alkyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, U is -C(CH3)=. In certain embodiments, in any one of the formulae described herein, U is -N=.

[0089] In certain embodiments, in any one of the formulae described herein, V is -C(R4a)=, wherein R4ais as defined herein. In certain embodiments, in any one of the formulae described herein, V is -C(R4a)=, wherein R4ais Ci-6 alkyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, V is -C(CH3)=. In certain embodiments, in any one of the formulae described herein, V is -N=.

[0090] In one embodiment, provided herein is a compound of Formula (VIIIA):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; wherein R1, R4, R2a, R3a, R3b, R3e, R3d, R3e, R4a, Re, L, U5, V5, X5, Z5, and a are each as defined herein.

[0091] In another embodiment, provided herein is a compound of Formula (VIIIB):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; wherein R1, R4, R2a, R3a, R3b, R3e, R3d, R3e, R4a, Re, L, U5, V5, X5, Z5, and a are each as defined herein.

[0092] In one embodiment, provided herein is a compound of Formula (IXA):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; wherein R1, R4, R6, R2a, R3a, R3b, R3C, R3d, R3e, R4a, R6a, Re, L, U6, a, and b are each as defined herein.

[0093] In another embodiment, provided herein is a compound of Formula (XA):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; wherein R1, R4, R6, R2a, R3a, R3b, R3C, R3d, R3e, R4a, R6a, Re, L, U6, a, and b are each as defined herein.

[0094] In yet another embodiment, provided herein is a compound of Formula (XIA):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; wherein R1, R4, R6, R2a, R3a, R3b, R3C, R3d, R3e, R4a, R6a, Re, L, U6, a, and b are each as defined herein.

[0095] In one embodiment, provided herein is a compound of Formula (IXB):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; wherein R1, R4, R6, R2a, R3a, R3b, R3C, R3d, R3e, R4a, R6a, Re, L, U6, a, and b are each as defined herein.

[0096] In yet another embodiment, provided herein is a compound of Formula (XB):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; wherein R1, R4, R6, R2a, R3a, R3b, R3c, R3d, R3e, R4a, R6a, Re, L, U6, a, and b are each as defined herein.

[0097] In yet another embodiment, provided herein is a compound of Formula (XIB):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; wherein R1, R4, R6, R2a, R3a, R3b, R3C, R3d, R3e, R4a, R6a, Re, L, U6, a, and b are each as defined herein.

[0098] In certain embodiments, in any one of the formulae described herein, Reis a moiety of a cereblon (CRBN) E3 ligand.

[0099] In certain embodiments, in any one of the formulae described herein, Reis a moiety having the structure of Formula (El):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; wherein:Aeis a bond, C3-10 cycloalkylene, C6-14 arylene, heteroarylene, or heterocyclylene; Z is -CH2- or -C(O)-; one of Z1, Z2, Z3, and Z4is C= and the remaining three of Z1, Z2, Z3, and Z4are each independently -C(Re4)=; or Z1is a bond; one of Z2, Z3, and Z4is -C=, and the remaining two of Z2, Z3, and Z4are each independently -C(Re4)= or -S-;Re1is hydrogen, deuterium, halo, or C1-6 alkyl;Re2is hydrogen or C1-6 alkyl; each Re3is independently (i) deuterium, cyano, halo, or nitro; (ii) C1-6 alkyl, C1-6heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) -C(O)R1a, -C(O)OR1a, -C(O)NR1bR1c, -C(O)SR1a, -C(NR1a)NR1bR1c, -C(S)R1a, -C(S)OR1a, -C(S)NR1bR1c, -OR1a, -OC(O)R1a, -OC(O)OR1a, -OC(O)NR1bR1c, -OC(O)SR1a, -OC(NR1 a)NR1bR1c, -OC(S)R1a, -OC(S)OR1a, -OC(S)NR1bR1c, -OS(O)R1a, -OS(O)2R1a, -OS(O)NR1bR1c, -OS(O)2NR1bR1c, -NR1bR1c, -NR1 aC(O)R1d, -NR1 aC(O)OR1d, -NR1aC(O)NR1bR1c, -NR1 aC(O)SR1d, -NR1 aC(NR1d)NR1bR1c, -NR1aC(S)R1d, -NR1 aC(S)OR1d, -NR1 aC(S)NR1bR1c, -NR1aS(O)R1d, -NR1 aS(O)2R1d, -NR1 aS(O)NR1bR1c, -NR1aS(O)2NR1bR1c, -SR1a, -S(O)R1a, -S(O)2R1a, -S(O)NR1bR1c, or -S(O)2NR1bR1c; each Re4is independently hydrogen or Re3; m is an integer of 0, 1, or 2; and R1a, Rlb, R1c, and R1dare each as defined herein; wherein each alkyl, heteroalkyl, cycloalkyl, cycloalkylene, aryl, arylene, aralkyl, heteroaryl, heteroarylene, heterocyclyl, and heterocyclylene is optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Q.

[0100] In certain embodiments, in any one of the formulae described herein, Reis a moiety having the structure of Formula (Eli):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; wherein n is an integer of 0, 1, 2, or 3; and Ae, Re1, Re2, Re3, Z, and m are each as defined herein.

[0101] In certain embodiments, in any one of the formulae described herein, Rcis a moiety having the structure of Formula (EIII):or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or morediastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; wherein Ae, Re1, Re2, Re4, Z, and m are each as defined herein.

[0102] In certain embodiments, in any one of the formulae described herein, Reis a moiety having the structure of Formula (EIV):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; wherein Ae, Re1, Re2, Re4, Z, and m are each as defined herein.

[0103] In certain embodiments, in any one of the formulae described herein, Reis a moiety having the structure of Formula (EV):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; wherein Ae, Re1, Re2, Re4, Z, and m are each as defined herein.

[0104] In certain embodiments, in any one of the formulae described herein, Reis a moiety having the structure of Formula (EVI):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; wherein n is an integer of 0 or 1; and Ae, Re1, Re2, Re3, Z, and m are each as defined herein.

[0105] In certain embodiments, in any one of the formulae described herein, Reis amoiety having the structure of Formula (EVII):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; wherein Ae, Re1, Re2, Re4, Z, and m are each as defined herein.

[0106] In certain embodiments, in any one of the formulae described herein, Reis a moiety having the structure of Formula (EVIII):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; wherein Ae, Re1, Re2, Re4, Z, and m are each as defined herein.

[0107] In certain embodiments, in any one of the formulae described herein, Reis a moiety having the structure of Formula (EIX):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; wherein n is an integer of 0 or 1; and Ae, Re1, Re2, Re3, Z, and m are each as defined herein.

[0108] In certain embodiments, in any one of the formulae described herein, Reis a moiety having the structure of Formula (EX):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; wherein Ae, Re1, Re2, Re4, Z, and m are each as defined herein.

[0109] In certain embodiments, in any one of the formulae described herein, Reis a moiety having the structure of Formula (EXI):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; wherein Ae, Re1, Re2, Re4, Z, and m are each as defined herein.

[0110] In certain embodiments, in any one of the formulae described herein, Reis a moiety having the structure of Formula (EXII):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; wherein n is an integer of 0 or 1; and Ae, Re1, Re2, Re3, Z, and m are each as defined herein.

[0111] In certain embodiments, in any one of the formulae described herein, Reis a moiety having the structure of Formula (EXIII):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; wherein Ae, Re1, Re2, Re4, Z, and m are each as defined herein.

[0112] In certain embodiments, in any one of the formulae described herein, Reis a moiety having the structure of Formula (EXIV):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; wherein Ae, Re1, Re2, Re4, Z, and m are each as defined herein.

[0113] In certain embodiments, in any one of the formulae described herein, Reis a moiety having the structure of Formula (EXV):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; wherein:Xcis C(Rcl) or N;Re5is (i) hydrogen; (ii) Ci-6 alkyl, Ci-6 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Q; or (iii) -C(O)R1a, -C(O)OR1a, -C(O)NR1bR1c, -C(O)SR1a, -C(NR1 a)NR1bR1c, -C(S)R1a, -C(S)OR1a, -C(S)NR1bR1c, -S(O)R1a, -S(O)2R1a, -S(O)NR1bR1c, or -S(O)2NR1bR1c; andAe, R1a, Rlb, R1c, R1d, Re1, Re2, Re3, m, and n are each as defined herein.

[0114] In certain embodiments, in any one of the formulae described herein, Reis a moiety having the structure of Formula (EXVI):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; wherein Ae, Re1, Re2, Re3, Re5, m, and n are each as defined herein.

[0115] In certain embodiments, in any one of the formulae described herein, Reis a moiety having the structure of Formula (EXVII):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; wherein Ae, Re1, Re2, Re3, Re5, m, and n are each as defined herein.

[0116] In certain embodiments, in any one of the formulae described herein, Reis a moiety having the structure of Formula (EXVIII):(EXVIII)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; wherein Ae, Re1, Re2, Re3, Re5, m, and n are each as defined herein.

[0117] In certain embodiments, in any one of the formulae described herein, Reis a moiety having the structure of Formula (EXIX):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; wherein Ae, Re2, Re3, Re5, m, and n are each as defined herein.

[0118] In certain embodiments, in any one of the formulae described herein, Reis a moiety having the structure of Formula (EXX):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; wherein Ae, Re2, Re3, Rw, m, and n are each as defined herein.

[0119] In certain embodiments, in any one of the formulae described herein, Reis a moiety having the structure of Formula (EXXI):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; wherein Ae, Re2, Re3, Re?, m, and n are each as defined herein.

[0120] In certain embodiments, in any one of the formulae described herein, Reis a moiety having the structure of Formula (EXXII):(EXXII)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; wherein Ae, Re2, Re3, Xe, m, and n are each as defined herein.

[0121] In certain embodiments, in any one of the formulae described herein, Reis a moiety having the structure of Formula (EXXIII):(EXXIII)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; wherein Ae, Re1, Re2, Re3, m, and n are each as defined herein.

[0122] In certain embodiments, in any one of the formulae described herein, Reis a moiety having the structure of Formula (EXXIV):(EXXIV)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; wherein Ae, Re1, Re2, Re3, m, and n are each as defined herein.

[0123] In certain embodiments, in any one of the formulae described herein, Reis a moiety having the structure of Formula (EXXV):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; wherein Ac, Rcl, Rc2, Rc3, m, and n are each as defined herein.

[0124] In certain embodiments, in any one of the formulae described herein, Reis a moiety having the structure of Formula (EXXVI):(EXXVI)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; wherein Ae, Re2, Re3, m, and n are each as defined herein.

[0125] In certain embodiments, in any one of the formulae described herein, Reis a moiety having the structure of Formula (EXXVII):(EXXVII)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; wherein Ae, Re2, Re3, m, and n are each as defined herein.

[0126] In certain embodiments, in any one of the formulae described herein, Reis a moiety having the structure of Formula (EXXII):(EXXVIII)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; wherein Ae, Re2, Re3, m, and n are each as defined herein.

[0127] In one embodiment, in any one of the formulae described herein, Reis a moiety having the structure of Formula (El), 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 any one of the formulae described herein, Reis a moiety having the structure of Formula (Eli), 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 any one of the formulae described herein, Reis a moiety having the structure of Formula (EIII), 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 any one of the formulae described herein, Reis a moiety having the structure of Formula (EIV), 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 any one of the formulae described herein, Reis a moiety having the structure of Formula (EV), 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 any one of the formulae described herein, Reis a moiety having the structure of Formula (EVI), 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 any one of the formulae described herein, Reis a moiety having the structure of Formula (EVII), 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 any one of the formulae described herein, Reis a moiety having the structure of Formula (EVIII), 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 any one of the formulae described herein, Reis a moiety having the structure of Formula (EIX), 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 any one of the formulae described herein, Reis a moiety having the structure of Formula (EX), 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 any one of the formulae described herein, Rcis a moiety having the structure of Formula (EXI), 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 any one of the formulae described herein, Reis a moiety having the structure of Formula (EXII), 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 any one of the formulae described herein, Reis a moiety having the structure of Formula (EXIII), 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 still another embodiment, in any one of the formulae described herein, Reis a moiety having the structure of Formula (EXIV), 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.

[0128] In one embodiment, in any one of the formulae described herein, Reis a moiety having the structure of Formula (EXV), 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 any one of the formulae described herein, Reis a moiety having the structure of Formula (EXVI), 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 any one of the formulae described herein, Reis a moiety having the structure of Formula (EXVII), 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 any one of the formulae described herein, Reis a moiety having the structure of Formula (EXVIII), 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 any one of the formulae described herein, Reis a moiety having the structure of Formula (EXIX), or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture oftwo or more tautomers, or an isotopic variant thereof. In yet another embodiment, in any one of the formulae described herein, Reis a moiety having the structure of Formula (EXX), 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 still another embodiment, in any one of the formulae described herein, Reis a moiety having the structure of Formula (EXXI), 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.

[0129] In one embodiment, in any one of the formulae described herein, Reis a moiety having the structure of Formula (EXXII), 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 any one of the formulae described herein, Reis a moiety having the structure of Formula (EXXIII), 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 any one of the formulae described herein, Reis a moiety having the structure of Formula (EXXIV), 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 any one of the formulae described herein, Reis a moiety having the structure of Formula (EXXV), 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 any one of the formulae described herein, Reis a moiety having the structure of Formula (EXXVI), 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 any one of the formulae described herein, Reis a moiety having the structure of Formula (EXXVII), 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 still another embodiment, in any one of the formulae described herein, Reis a moiety having the structure of Formula (EXXVIII), 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 isotopicvariant thereof.

[0130] In certain embodiments, in any one of the formulae described herein, Reis a moiety having the structure of: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; wherein Aeand Re4are each as defined herein.

[0131] In certain embodiments, in any one of the formulae described herein, Reis a moiety having the structure of Formula El, 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 certain embodiments, in any one of the formulae described herein, Reis a moiety having the structure of Formula E2, 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.

[0132] In certain embodiments, in any one of the formulae described herein, Reis a moiety having the structure of:or an enantiomer, a mixture of enantiomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof.

[0133] In certain embodiments, in any one of the formulae described herein, Reis a moiety having the structure of:or an enantiomer, a mixture of enantiomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof.

[0134] In certain embodiments, in any one of the formulae described herein, Reis a moiety having the structure of:or an enantiomer, a mixture of enantiomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; wherein Ae, Re1, and Re4are each as defined herein.

[0135] In one embodiment, in any one of the formulae described herein, Reis a moiety having the structure of Formula E3, 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 any one of the formulae described herein, Reis a moiety having the structure of Formula E4, 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 any one of the formulae described herein, Reis a moiety having the structure of Formula E5, 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 any one of the formulae described herein, Reis a moiety having the structure of Formula E6, 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 any one of the formulae described herein, Reis a moiety having the structure of Formula E7, 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 variantthereof. In still another embodiment, in any one of the formulae described herein, Reis a moiety having the structure of Formula E8, 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.

[0136] In certain embodiments, in any one of the formulae described herein, Reis a moiety having the structure of:or an enantiomer, a mixture of enantiomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof.

[0137] In certain embodiments, in any one of the formulae described herein, Reis a moiety having the structure of:or an enantiomer, a mixture of enantiomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; wherein Ae, Re1, Re3, and n are each as defined herein.

[0138] In one embodiment, in any one of the formulae described herein, Reis a moiety having the structure of Formula E9, 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 any one of the formulae described herein, Reis a moiety having the structure of Formula E10, or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or moretautomers, or an isotopic variant thereof. In yet another embodiment, in any one of the formulae described herein, Reis a moiety having the structure of Formula Ell, 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 any one of the formulae described herein, Reis a moiety having the structure of Formula Ell, 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 any one of the formulae described herein, Reis a moiety having the structure of Formula E13, 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 still another embodiment, in any one of the formulae described herein, Reis a moiety having the structure of Formula E14, 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.

[0139] In certain embodiments, in any one of the formulae described herein, Reis a moiety having the structure of:or an enantiomer, a mixture of enantiomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof.

[0140] In certain embodiments, in any one of the formulae described herein, Reis a moiety having the structure of:or an enantiomer, a mixture of enantiomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof.

[0141] In one embodiment, provided herein is a compound of Formula (XIIA):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; ora pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R1, R4, R2a, R3a, R3b, R3e, R3d, R3e, R4a, Re1, Re2, Re4, Ae, L, U5, V5, X5, Z5, and a are each as defined herein.

[0142] In another embodiment, provided herein is a compound of Formula (XIIIA):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; wherein R1, R4, R2a, R3a, R3b, R3C, R3d, R3e, R4a, Re1, Re2, Re4, Ae, L, U5, V5, X5, Z5, and a are each as defined herein.

[0143] In one embodiment, provided herein is a compound of Formula (XIIB):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; wherein R1, R4, R2a, R3a, R3b, R3C, R3d, R3e, R4a, Re1, Re2, Re4, Ae, L, U5, V5, X5, Z5, and a are each as defined herein.

[0144] In another embodiment, provided herein is a compound of Formula (XIIIB):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; wherein R1, R4, R2a, R3a, R3b, R3C, R3d, R3e, R4a, Re1, Re2, Re4, Ae, L, U5, V5, X5, Z5, and a are each as defined herein.

[0145] In one embodiment, provided herein is a compound of Formula (XIVA):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; wherein R1, R4, R2a, R3a, R3b, R3e, R3d, R3e, R4a, Re2, Re4, Re5, Ae, L, U5, V5, X5, Z5, Xe, and a are each as defined herein.

[0146] In another embodiment, provided herein is a compound of Formula (XV A):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; wherein R1, R4, R2a, R3a, R3b, R3e, R3d, R3e, R4a, Re1, Re2, Re4, Re3, Ae, L, U5, V5, X3, Z3, and a are each as defined herein.

[0147] In yet another embodiment, provided herein is a compound of Formula (XVIA):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; wherein R1, R4, R2a, R3a, R3b, R3e, R3d, R3e, R4a, Re1, Re2, Re4, Re3, Ae, L, U5, V5, X3, Z3, and a are each as defined herein.

[0148] In yet another embodiment, provided herein is a compound of Formula (XVIIA):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; wherein R1, R4, R2a, R3a, R3b, R3c, R3d, R3e, R4a, Re1, Re2, Re4, Re3, Ae, L, U5, V5, X5, Z5, and a are each as defined herein.

[0149] In still another embodiment, provided herein is a compound of Formula(XVIII A):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; wherein R1, R4, R2a, R3a, R3b, R3c, R3d, R3c, R4a, Rc2, Rc4, Rc5, Ac, L, U5, V5, X5, Z5, and a are each as defined herein.

[0150] In one embodiment, provided herein is a compound of Formula (XIVB):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; wherein R1, R4, R2a, R3a, R3b, R3c, R3d, R3c, R4a, Rc2, Rc4, Rc5, Ac, L, U5, V5, X5, Z5, Xc, and a are each as defined herein.

[0151] In another embodiment, provided herein is a compound of Formula (XVB):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; wherein R1, R4, R2a, R3a, R3b, R3C, R3d, R3e, R4a, Re1, Re2, Re4, Re5, Ae, L, U5, V5, X5, Z5, and a are each as defined herein.

[0152] In yet another embodiment, provided herein is a compound of Formula (XVIB):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; wherein R1, R4, R2a, R3a, R3b, R3c, R3d, R3e, R4a, Re1, Re2, Re4, Re5, Ae, L, IF, V2, X5, Z5, and a are each as defined herein.

[0153] In yet another embodiment, provided herein is a compound of Formula (XVIIB):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; wherein R1, R4, R2a, R3a, R3b, R3C, R3d, R3e, R4a, Re1, Re2, Re4, Re5, Ae, L, U5, V5, X5, Z5, and a are each as defined herein.

[0154] In still another embodiment, provided herein is a compound of Formula (XVIIIB):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; wherein R1, R4, R2a, R3a, R3b, R3c, R3d, R3e, R4a, Re2, Re4, Re5, Ae, L, U5, V5, X5, Z5, and a are each as defined herein.

[0155] In one embodiment, provided herein is a compound of Formula (XIXA):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; wherein R1, R4, R2a, R3a, R3b, R3e, R3d, R3e, R4a, Re2, Re4, Re5, Ae, L, U5, V5, X5, Z5, Xe, and a are each as defined herein.

[0156] In another embodiment, provided herein is a compound of Formula (XXA):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; wherein R1, R4, R2a, R3a, R3b, R3e, R3d, R3e, R4a, Re1, Re2, Re4, Re3, Ae, L, U5, V5, X3, Z3, and a are each as defined herein.

[0157] In yet another embodiment, provided herein is a compound of Formula (XXIA):or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or morediastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R1, R4, R2a, R3a, R3b, R3C, R3d, R3C, R4a, Rcl, Rc2, Rc4, Rc5, Ac, L, U5, V5, X5, Z5, and a are each as defined herein.

[0158] In yet another embodiment, provided herein is a compound of Formula (XXIIA):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; wherein R1, R4, R2a, R3a, R3b, R3C, R3d, R3e, R4a, Re1, Re2, Re4, Re3, Ae, L, U5, V5, X3, Z3, and a are each as defined herein.

[0159] In still another embodiment, provided herein is a compound of Formula(XXIII A):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; wherein R1, R4, R2a, R3a, R3b, R3C, R3d, R3e, R4a, Re1, Re2, Re4, Re5, Ae, L, U5, V5, X5, Z5, and a are each as defined herein.

[0160] In one embodiment, provided herein is a compound of Formula (XIXB):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; wherein R1, R4, R2a, R3a, R3b, R3C, R3d, R3e, R4a, Re2, Re4, Re5, Ae, L, U5, V5, X5, Z5, Xe, and a are each as defined herein.

[0161] In another embodiment, provided herein is a compound of Formula (XXB):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; wherein R1, R4, R2a, R3a, R3b, R3C, R3d, R3e, R4a, Re1, Re2, Re4, Re5, Ae, L, U5, V5, X5, Z5, and a are each as defined herein.

[0162] In yet another embodiment, provided herein is a compound of Formula (XXIB):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; wherein R1, R4, R2a, R3a, R3b, R3C, R3d, R3e, R4a, Re1, Re2, Re4, Re5, Ae, L, U5, V5, X5, Z5, and a are each as defined herein.

[0163] In yet another embodiment, provided herein is a compound of Formula (XXIIB):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; wherein R1, R4, R2a, R3a, R3b, R3C, R3d, R3e, R4a, Re1, Re2, Re4, Re5, Ae, L, U5, V5, X5, Z5, and a are each as defined herein.

[0164] In still another embodiment, provided herein is a compound of Formula (XXIIIB):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; wherein R1, R4, R2a, R3a, R3b, R3C, R3d, R3e, R4a, Re2, Re5, Re6, Ae, L, U5, V5, X5, Z5, and a are each as defined herein.

[0165] In one embodiment, provided herein is a compound of Formula (XXIVA):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; wherein R1, R4, R2a, R3a, R3b, R3e, R3d, R3e, R4a, Re2, Re3, Ae, L, U5, V5, X3, Z5, Xe, a, and n are each as defined herein.

[0166] In another embodiment, provided herein is a compound of Formula (XXV A):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; wherein R1, R4, R2a, R3a, R3b, R3C, R3d, R3e, R4a, Re1, Re2, Re3, Ae, L, U3, V5, X5, Z5, a, and n are each as defined herein.

[0167] In yet another embodiment, provided herein is a compound of Formula (XXVIA):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; wherein R1, R4, R2a, R3a, R3b, R3e, R3d, R3e, R4a, Re1, Re2, Re3, Ae, L, U5, V5, X5, Z5, a, and n are each as defined herein.

[0168] In yet another embodiment, provided herein is a compound of Formula(XXVIIA):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; wherein R1, R4, R2a, R3a, R3b, R3C, R3d, R3e, R4a, Re1, Re2, Re3, Ae, L, U3, V3, X5, Z5, a, and n are each as defined herein.

[0169] In still another embodiment, provided herein is a compound of Formula (XXVIII A):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; wherein R1, R4, R2a, R3a, R3b, R3e, R3d, R3e, R4a, Re2, Re3, Ae, L, U5, V5, X3, Z3, a, and n are each as defined herein.

[0170] In one embodiment, provided herein is a compound of Formula (XXIVB):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; wherein R1, R4, R2a, R3a, R3b, R3e, R3d, R3e, R4a, Re2, Re3, Ae, L, U5, V5, X3, Z3, Xe, a, and n are each as defined herein.

[0171] In another embodiment, provided herein is a compound of Formula (XXVB):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; wherein R1, R4, R2a, R3a, R3b, R3C, R3d, R3e, R4a, Re1, Re2, Re3, Ae, L, U5, V5, X5, Z5, a, and n are each as defined herein.

[0172] In yet another embodiment, provided herein is a compound of Formula (XXVIB):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; wherein R1, R4, R2a, R3a, R3b, R3C, R3d, R3e, R4a, Re1, Re2, Re3, Ae, L, U5, V5, X5, Z5, a, and n are each as defined herein.

[0173] In yet another embodiment, provided herein is a compound of Formula(XXVIIB):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; wherein R1, R4, R2a, R3a, R3b, R3C, R3d, R3e, R4a, Re1, Re2, Re3, Ae, L, U5, V5, X5, Z5, a, and n are each as defined herein.

[0174] In still another embodiment, provided herein is a compound of Formula (XXVIIIB):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; wherein R1, R4, R2a, R3a, R3b, R3e, R3d, R3e, R4a, Re2, Re3, Ae, L, U5, V5, X3, Z5, a, and n are each as defined herein.

[0175] In one embodiment, provided herein is a compound of Formula (XXIXA):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; wherein R1, R4, R2a, R3a, R3b, R3C, R3d, R3e, R4a, Re2, Re3, Ae, L, U5, V5, X?, Z5, Xe, a, and n are each as defined herein.

[0176] In another embodiment, provided herein is a compound of Formula (XXXA):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; wherein R1, R4, R2a, R3a, R3b, R3e, R3d, R3e, R4a, Re1, Re2, Re3, Ae, L, U5, V5, X5, Z5, a, and n are each as defined herein.

[0177] In yet another embodiment, provided herein is a compound of Formula (XXXIA):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; wherein R1, R4, R2a, R3a, R3b, R3C, R3d, R3e, R4a, Re1, Re2, Re3, Ae, L, U3, V5, X5, Z5, a, and n are each as defined herein.

[0178] In yet another embodiment, provided herein is a compound of Formula(XXXIIA):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; wherein R1, R4, R2a, R3a, R3b, R3C, R3d, R3e, R4a, Re1, Re2, Re3, Ae, L, U5, V5, X5, Z5, a, and n are each as defined herein.

[0179] In still another embodiment, provided herein is a compound of Formula (XXXIIIA):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; wherein R1, R4, R2a, R3a, R3b, R3e, R3d, R3e, R4a, Re2, Re3, Ae, L, U5, V5, X3, Z3, a, and n are each as defined herein.

[0180] In one embodiment, provided herein is a compound of Formula (XXIXB):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; wherein R1, R4, R2a, R3a, R3b, R3e, R3d, R3e, R4a, Re2, Re3, Ae, L, U5, V5, X3, Z5, Xe, a, and n are each as defined herein.

[0181] In another embodiment, provided herein is a compound of Formula (XXXB):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; wherein R1, R4, R2a, R3a, R3b, R3e, R3d, R3e, R4a, Re1, Re2, Re3, Ae, L, U5, V5, X5, Z5, a, and n are each as defined herein.

[0182] In yet another embodiment, provided herein is a compound of Formula (XXXIB):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; wherein R1, R4, R2a, R3a, R3b, R3C, R3d, R3e, R4a, Re1, Re2, Re3, Ae, L, U5, V5, X5, Z5, a, and n are each as defined herein.

[0183] In yet another embodiment, provided herein is a compound of Formula(XXXIIB):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; wherein R1, R4, R2a, R3a, R3b, R3e, R3d, R3e, R4a, Re1, Re2, Re3, Ae, L, U5, V5, X5, Z5, a, and n are each as defined herein.

[0184] In still another embodiment, provided herein is a compound of Formula (XXXIIIB):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; wherein R1, R4, R2a, R3a, R3b, R3C, R3d, R3e, R4a, Re2, Re3, Ae, L, L , V2, X5, Z5, a, and n are each as defined herein.

[0185] In certain embodiments, in any one of the formulae described herein, R1is hydrogen. In certain embodiments, in any one of the formulae described herein, R1is Ci-6 alkyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R1is methyl. In certain embodiments, in any one of the formulae described herein, R1is Ci-6 heteroalkyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R1is C2-6 alkenyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R1is C2-6 alkynyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R1is C3-10 cycloalkyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R1is C6-14 aryl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R1is C7-15 aralkyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R1is heteroaryl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R1is heterocyclyl, optionally substituted with one or more substituents Q.

[0186] In certain embodiments, in any one of the formulae described herein, R4is deuterium. In certain embodiments, in any one of the formulae described herein, R4is cyano. In certain embodiments, in any one of the formulae described herein, R4is halo. In certainembodiments, in any one of the formulae described herein, each R4is independently fluoro or chloro. In certain embodiments, in any one of the formulae described herein, R4is nitro. In certain embodiments, in any one of the formulae described herein, each R4is independently Ci-6 alkyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R4is methyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, each R4is independently Ci-6 heteroalkyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, each R4is independently C2-6 alkenyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, each R4is independently C2-6 alkynyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, each R4is independently C3-10 cycloalkyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, each R4is independently C6-14 aryl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, each R4is independently C7-15 aralkyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, each R4is independently heteroaryl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, each R4is independently heterocyclyl, optionally substituted with one or more substituents Q.

[0187] In certain embodiments, in any one of the formulae described herein, each R4is independently -C(O)R1a, wherein R1ais independently as defined herein. In certain embodiments, in any one of the formulae described herein, each R4is independently -C(O)OR1a, wherein R1ais independently as defined herein. In certain embodiments, in any one of the formulae described herein, each R4is independently -C(O)NR1bR1c, wherein Rlband R1care each as defined herein. In certain embodiments, in any one of the formulae described herein, each R4is independently -C(O)SR1a, wherein R1ais as defined herein. In certain embodiments, in any one of the formulae described herein, each R4is independently -C(NR1 a)NR1bR1c, wherein R1a, Rlb, and R1care each as defined herein. In certain embodiments, in any one of the formulae described herein, each R4is independently -C(S)R1a, wherein R1ais independently as defined herein. In certain embodiments, in any one of the formulae described herein, each R4isindependently -C(S)OR1a, wherein R1ais independently as defined herein. In certain embodiments, in any one of the formulae described herein, each R4is independently -C(S)NR1bR1c, wherein Rlband R1care each as defined herein. In certain embodiments, in any one of the formulae described herein, each R4is independently -OR1a, wherein R1ais independently as defined herein. In certain embodiments, in any one of the formulae described herein, each R4is independently -OC(O)R1a, wherein R1ais independently as defined herein. In certain embodiments, in any one of the formulae described herein, each R4is independently -OC(O)OR1a, wherein R1ais independently as defined herein. In certain embodiments, in any one of the formulae described herein, each R4is independently -OC(O)NR1bR1c, wherein Rlband R1care each as defined herein. In certain embodiments, in any one of the formulae described herein, each R4is independently -OC(O)SR1a, wherein R1ais independently as defined herein. In certain embodiments, in any one of the formulae described herein, each R4is independently -OC(NR1a)NR1bR1c, wherein R1a, Rlb, and R1care each as defined herein. In certain embodiments, in any one of the formulae described herein, each R4is independently -OC(S)R1a, wherein R1ais independently as defined herein. In certain embodiments, in any one of the formulae described herein, each R4is independently -OC(S)OR1a, wherein R1ais independently as defined herein. In certain embodiments, in any one of the formulae described herein, each R4is independently -OC(S)NR1bR1c, wherein Rlband R1care each as defined herein. In certain embodiments, in any one of the formulae described herein, each R4is independently -OS(O)R1a, wherein R1ais independently as defined herein. In certain embodiments, in any one of the formulae described herein, each R4is independently -OS(O)2R1a, wherein R1ais independently as defined herein. In certain embodiments, in any one of the formulae described herein, each R4is independently -OS(O)NR1bR1c, wherein Rlband R1care each as defined herein. In certain embodiments, in any one of the formulae described herein, each R4is independently -OS(O)2NR1bR1c, wherein Rlband R1care each as defined herein. In certain embodiments, in any one of the formulae described herein, each R4is independently -NR1bR1c, wherein Rlband R1care each as defined herein. In certain embodiments, in any one of the formulae described herein, each R4is independently -NR1aC(O)R1d, wherein R1aand R1dare each as defined herein. In certain embodiments, in any one of the formulae described herein, each R4is independently -NR1 aC(O)OR1d, wherein R1aand R1dare each as defined herein. In certain embodiments, in any one of the formulae described herein, each R4is independently-NR1 aC(O)NR1bR1c, wherein Rlband R1care each as defined herein. In certain embodiments, in any one of the formulae described herein, each R4is independently -NR1aC(O)SR1d, wherein R1aand R1dare each as defined herein. In certain embodiments, in any one of the formulae described herein, each R4is independently -NR1aC(NR1 d)NR1 bR1c, wherein R1a, Rlb, R1c, and R1dare each as defined herein. In certain embodiments, in any one of the formulae described herein, each R4is independently -NR1aC(S)R1d, wherein R1aand R1dare each as defined herein. In certain embodiments, in any one of the formulae described herein, each R4is independently -NR1 aC(S)OR1d, wherein R1aand R1dare each as defined herein. In certain embodiments, in any one of the formulae described herein, each R4is independently -NR1 aC(S)NR1bR1c, wherein R1a, Rlb, and R1care each as defined herein. In certain embodiments, in any one of the formulae described herein, each R4is independently -NR1aS(O)R1d, wherein R1aand R1dare each as defined herein. In certain embodiments, in any one of the formulae described herein, each R4is independently -NR1 aS(O)2R1d, wherein R1aand R1dare each as defined herein. In certain embodiments, in any one of the formulae described herein, each R4is independently -NR1 aS(O)NR1bR1c, wherein R1a, Rlb, and R1care each as defined herein. In certain embodiments, in any one of the formulae described herein, each R4is independently -NR1aS(0)2NR1bR1c, wherein R1a, Rlb, and R1care each as defined herein. In certain embodiments, in any one of the formulae described herein, each R4is independently -SR1a, wherein R1ais independently as defined herein. In certain embodiments, in any one of the formulae described herein, each R4is independently -S(O)R1a, wherein R1ais independently as defined herein. In certain embodiments, in any one of the formulae described herein, each R4is independently -S(O)2R1a, wherein R1ais independently as defined herein. In certain embodiments, in any one of the formulae described herein, each R4is independently -S(O)NR1bR1c, wherein Rlband R1care each as defined herein. In certain embodiments, in any one of the formulae described herein, each R4is independently -S(O)2NR1bR1c, wherein Rlband R1care each as defined herein.

[0188] In certain embodiments, in any one of the formulae described herein, R5is hydrogen. In certain embodiments, in any one of the formulae described herein, R5is deuterium. In certain embodiments, in any one of the formulae described herein, R?is cyano. In certain embodiments, in any one of the formulae described herein, each R is independently halo. In certain embodiments, in any one of the formulae described herein, each R5is independentlyfluoro or chloro. In certain embodiments, in any one of the formulae described herein, R5is fluoro. In certain embodiments, in any one of the formulae described herein, R5is nitro. In certain embodiments, in any one of the formulae described herein, each R5is independently Ci-6 alkyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R5is methyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, each R5is independently Ci-6 heteroalkyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, each R5is independently C2-6 alkenyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, each R5is independently C2-6 alkynyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, each R5is independently C3-10 cycloalkyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, each R5is independently C6-14 aryl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, each R5is independently C7-15 aralkyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, each R5is independently heteroaryl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, each R5is independently heterocyclyl, optionally substituted with one or more substituents Q.

[0189] In certain embodiments, in any one of the formulae described herein, each R5is independently -C(O)R1a, wherein R1ais independently as defined herein. In certain embodiments, in any one of the formulae described herein, each R5is independently -C(O)OR1a, wherein R1ais independently as defined herein. In certain embodiments, in any one of the formulae described herein, each R5is independently -C(O)NR1bR1c, wherein Rlband R1care each as defined herein. In certain embodiments, in any one of the formulae described herein, each R3is independently -C(O)SR1a, wherein R1ais independently as defined herein. In certain embodiments, in any one of the formulae described herein, each R5is independently -C(NR1a)NR1bR1c, wherein R1a, Rlb, and R1care each as defined herein. In certain embodiments, in any one of the formulae described herein, each R3is independently -C(S)R1a, wherein R1ais independently as defined herein. In certain embodiments, in any one of the formulae describedherein, each R5is independently -C(S)OR1a, wherein R1ais independently as defined herein. In certain embodiments, in any one of the formulae described herein, each R5is independently -C(S)NR1bR1c, wherein Rlband R1care each as defined herein. In certain embodiments, in any one of the formulae described herein, each R5is independently -OR1a, wherein R1ais independently as defined herein. In certain embodiments, in any one of the formulae described herein, each R3is independently -OC(O)R1a, wherein R1ais independently as defined herein. In certain embodiments, in any one of the formulae described herein, each R5is independently -OC(O)OR1a, wherein R1ais independently as defined herein. In certain embodiments, in any one of the formulae described herein, each R5is independently -OC(O)NR1bR1c, wherein Rlband R1care each as defined herein. In certain embodiments, in any one of the formulae described herein, each R5is independently -OC(O)SR1a, wherein R1ais independently as defined herein. In certain embodiments, in any one of the formulae described herein, each R5is independently -OC(NR1a)NR1bR1c, wherein R1a, Rlb, and R1care each as defined herein. In certain embodiments, in any one of the formulae described herein, each R5is independently -OC(S)R1a, wherein R1ais independently as defined herein. In certain embodiments, in any one of the formulae described herein, each R5is independently -OC(S)OR1a, wherein R1ais independently as defined herein. In certain embodiments, in any one of the formulae described herein, each R5is independently -OC(S)NR1bR1c, wherein Rlband R1care each as defined herein. In certain embodiments, in any one of the formulae described herein, each R5is independently -OS(O)R1a, wherein R1ais independently as defined herein. In certain embodiments, in any one of the formulae described herein, each R5is independently -OS(O)2R1a, wherein R1ais independently as defined herein. In certain embodiments, in any one of the formulae described herein, each R5is independently -OS(O)NR1bR1c, wherein Rlband R1care each as defined herein. In certain embodiments, in any one of the formulae described herein, each R5is independently -OS(O)2NR1bR1c, wherein Rlband R1care each as defined herein. In certain embodiments, in any one of the formulae described herein, each R5is independently -NR1bR1c, wherein Rlband R1care each as defined herein. In certain embodiments, in any one of the formulae described herein, each R3is independently -NR1 aC(O)R1d, wherein R1aand R1dare each as defined herein. In certain embodiments, in any one of the formulae described herein, each R5is independently -NR1 aC(O)OR1d, wherein R1aand R1dare each as defined herein. In certain embodiments, in any one of the formulae described herein, each R5is independently -NR1 aC(O)NR1bR1c, wherein Rlband R1care each as defined herein. In certain embodiments, in any one of the formulae described herein, each R5is independently -NR1 aC(O)SR1d, wherein R1aand R1dare each as defined herein. In certain embodiments, in any one of the formulae described herein, each R5is independently -NR1 aC(NR1 d)NR1bR1c, wherein R1a, Rlb, R1c, and R1dare each as defined herein. In certain embodiments, in any one of the formulae described herein, each R5is independently -NR1aC(S)R1d, wherein R1aand R1dare each as defined herein. In certain embodiments, in any one of the formulae described herein, each R5is independently -NR1 aC(S)OR1d, wherein R1aand R1dare each as defined herein. In certain embodiments, in any one of the formulae described herein, each R is independently -NR1 aC(S)NR1 bR1c, wherein R1a, Rlb, and R1care each as defined herein. In certain embodiments, in any one of the formulae described herein, each R5is independently -NR1 aS(O)R1d, wherein R1aand R1dare each as defined herein. In certain embodiments, in any one of the formulae described herein, each R?is independently -NR1 aS(0)2R1d, wherein R1aand R1dare each as defined herein. In certain embodiments, in any one of the formulae described herein, each R5is independently -NR1 aS(O)NR1 bR1c, wherein R1a, Rlb, and R1care each as defined herein. In certain embodiments, in any one of the formulae described herein, each R5is independently -NR1aS(O)2NR1bR1c, wherein R1a, Rlb, and R1care each as defined herein. In certain embodiments, in any one of the formulae described herein, each R5is independently -SR1a, wherein R1ais independently as defined herein. In certain embodiments, in any one of the formulae described herein, each R5is independently -S(O)R1a, wherein R1ais independently as defined herein. In certain embodiments, in any one of the formulae described herein, each R5is independently -S(O)2R1a, wherein R1ais independently as defined herein. In certain embodiments, in any one of the formulae described herein, each R5is independently -S(O)NR1bR1c, wherein Rlband R1care each as defined herein. In certain embodiments, in any one of the formulae described herein, each R5is independently -S(O)2NR1bR1c, wherein Rlband R1care each as defined herein.

[0190] In certain embodiments, in any one of the formulae described herein, R6is deuterium. In certain embodiments, in any one of the formulae described herein, R6is cyano. In certain embodiments, in any one of the formulae described herein, each R6is independently halo. In certain embodiments, in any one of the formulae described herein, each R6is independently fluoro or chloro. In certain embodiments, in any one of the formulae described herein, R6is fluoro. In certain embodiments, in any one of the formulae described herein, R6is nitro. Incertain embodiments, in any one of the formulae described herein, each R6is independently Ci-6 alkyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R6is methyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, each R6is independently Ci-6 heteroalkyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, each R6is independently C2-6 alkenyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, each R6is independently C2-6 alkynyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, each R6is independently C3-10 cycloalkyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, each R6is independently C6-14 aryl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, each R6is independently C7-15 aralkyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, each R6is independently heteroaryl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, each R6is independently heterocyclyl, optionally substituted with one or more substituents Q.

[0191] In certain embodiments, in any one of the formulae described herein, each R6is independently -C(O)R1a, wherein R1ais independently as defined herein. In certain embodiments, in any one of the formulae described herein, each R6is independently -C(O)OR1a, wherein R1ais independently as defined herein. In certain embodiments, in any one of the formulae described herein, each R6is independently -C(O)NR1bR1c, wherein Rlband R1care each as defined herein. In certain embodiments, in any one of the formulae described herein, each R6is independently -C(O)SR1a, wherein R1ais independently as defined herein. In certain embodiments, in any one of the formulae described herein, each R6is independently -C(NR1a)NR1bR1c, wherein R1a, Rlb, and R1care each as defined herein. In certain embodiments, in any one of the formulae described herein, each R6is independently -C(S)R1a, wherein R1ais independently as defined herein. In certain embodiments, in any one of the formulae described herein, each R6is independently -C(S)OR1a, wherein R1ais independently as defined herein. In certain embodiments, in any one of the formulae described herein, each R6is independently-C(S)NR1 bR1c, wherein Rlband R1care each as defined herein. In certain embodiments, in any one of the formulae described herein, each R6is independently -OR1a, wherein R1ais independently as defined herein. In certain embodiments, in any one of the formulae described herein, each R6is independently -OC(O)R1a, wherein R1ais independently as defined herein. In certain embodiments, in any one of the formulae described herein, each R6is independently -OC(O)OR1a, wherein R1ais independently as defined herein. In certain embodiments, in any one of the formulae described herein, each R6is independently -OC(O)NR1bR1c, wherein Rlband R1care each as defined herein. In certain embodiments, in any one of the formulae described herein, each R6is independently -OC(O)SR1a, wherein R1ais independently as defined herein. In certain embodiments, in any one of the formulae described herein, each R6is independently -OC(NR1a)NR1bR1c, wherein R1a, Rlb, and R1care each as defined herein. In certain embodiments, in any one of the formulae described herein, each R6is independently -OC(S)R1a, wherein R1ais independently as defined herein. In certain embodiments, in any one of the formulae described herein, each R6is independently -OC(S)OR1a, wherein R1ais independently as defined herein. In certain embodiments, in any one of the formulae described herein, each R6is independently -OC(S)NR1bR1c, wherein Rlband R1care each as defined herein. In certain embodiments, in any one of the formulae described herein, each R6is independently -OS(O)R1a, wherein R1ais independently as defined herein. In certain embodiments, in any one of the formulae described herein, each R6is independently -OS(O)2R1a, wherein R1ais independently as defined herein. In certain embodiments, in any one of the formulae described herein, each R6is independently -OS(O)NR1bR1c, wherein Rlband R1care each as defined herein. In certain embodiments, in any one of the formulae described herein, each R6is independently -OS(O)2NR1bR1c, wherein Rlband R1care each as defined herein. In certain embodiments, in any one of the formulae described herein, each R6is independently -NR1bR1c, wherein Rlband R1care each as defined herein. In certain embodiments, in any one of the formulae described herein, each R6is independently -NR1 aC(O)R1d, wherein R1aand R1dare each as defined herein. In certain embodiments, in any one of the formulae described herein, each R6is independently -NR1aC(O)OR1d, wherein R1aand R1dare each as defined herein. In certain embodiments, in any one of the formulae described herein, each R6is independently -NR1 aC(O)NR1bR1c, wherein Rlband R1care each as defined herein. In certain embodiments, in any one of the formulae described herein, each R6is independently -NR1 aC(O)SR1d, wherein R1aand R1dare each as definedherein. In certain embodiments, in any one of the formulae described herein, each R6is independently -NR1 aC(NR1 d)NR1bR1c, wherein R1a, Rlb, R1c, and R1dare each as defined herein. In certain embodiments, in any one of the formulae described herein, each R6is independently -NR1 aC(S)R1d, wherein R1aand R1dare each as defined herein. In certain embodiments, in any one of the formulae described herein, each R6is independently -NR1 aC(S)OR1d, wherein R1aand R1dare each as defined herein. In certain embodiments, in any one of the formulae described herein, each R6is independently -NR1 aC(S)NR1 bR1c, wherein R1a, Rlb, and R1care each as defined herein. In certain embodiments, in any one of the formulae described herein, each R6is independently -NR1 aS(O)R1d, wherein R1aand R1dare each as defined herein. In certain embodiments, in any one of the formulae described herein, each R6is independently -NR1 aS(0)2R1d, wherein R1aand R1dare each as defined herein. In certain embodiments, in any one of the formulae described herein, each R6is independently -NR1 aS(O)NR1 bR1c, wherein R1a, Rlb, and R1care each as defined herein. In certain embodiments, in any one of the formulae described herein, each R6is independently -NR1aS(O)2NR1bR1c, wherein R1a, Rlb, and R1care each as defined herein. In certain embodiments, in any one of the formulae described herein, each R6is independently -SR1a, wherein R,ais independently as defined herein. In certain embodiments, in any one of the formulae described herein, each R6is independently -S(O)R1a, wherein R1ais independently as defined herein. In certain embodiments, in any one of the formulae described herein, each R6is independently -S(O)2R1a, wherein R1ais independently as defined herein. In certain embodiments, in any one of the formulae described herein, each R6is independently -S(O)NR1bR1c, wherein Rlband R1care each as defined herein. In certain embodiments, in any one of the formulae described herein, each R6is independently -S(O)2NR1bR1c, wherein Rlband R1care each as defined herein.

[0192] In certain embodiments, in any one of the formulae described herein, R2ais hydrogen. In certain embodiments, in any one of the formulae described herein, R2ais deuterium. In certain embodiments, in any one of the formulae described herein, R2ais halo. In certain embodiments, in any one of the formulae described herein, R2ais Ci-6 alkyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R2ais methyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R2ais methyl. In certain embodiments, in any one of the formulae described herein, R2ais Ci-6 heteroalkyl, optionallysubstituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R2ais C2-6 alkenyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R2ais C2-6 alkynyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R2ais C3-10 cycloalkyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R2ais C6-14 aryl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R2ais C7-15 aralkyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R2ais heteroaryl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R2ais heterocyclyl, optionally substituted with one or more substituents Q.

[0193] In certain embodiments, in any one of the formulae described herein, R3ais hydrogen. In certain embodiments, in any one of the formulae described herein, R3ais deuterium. In certain embodiments, in any one of the formulae described herein, R3ais cyano. In certain embodiments, in any one of the formulae described herein, R3ais halo. In certain embodiments, in any one of the formulae described herein, R3ais fluoro or chloro. In certain embodiments, in any one of the formulae described herein, R3ais fluoro. In certain embodiments, in any one of the formulae described herein, R3ais nitro.

[0194] In certain embodiments, in any one of the formulae described herein, R3ais C1-6 alkyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R3ais methyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R3ais methyl. In certain embodiments, in any one of the formulae described herein, R3ais C1-6 heteroalkyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R3ais C2-6 alkenyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R3ais C2-6 alkynyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R3ais C3-10 cycloalkyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R3ais C6-14 aryl, optionally substituted with one or more substituents Q. In certain embodiments, inany one of the formulae described herein, R3ais C7-15 aralkyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R3ais heteroaryl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R3ais heterocyclyl, optionally substituted with one or more substituents Q.

[0195] In certain embodiments, in any one of the formulae described herein, R3ais -C(O)R1a, wherein R1ais as defined herein. In certain embodiments, in any one of the formulae described herein, R3ais -C(O)OR1a, wherein R1ais as defined herein. In certain embodiments, in any one of the formulae described herein, R3ais -C(O)NR1bR1c, wherein Rlband R1care each as defined herein. In certain embodiments, in any one of the formulae described herein, R3ais -C(O)SR1a, wherein R1ais as defined herein. In certain embodiments, in any one of the formulae described herein, R3ais -C(NR1a)NR1bR1c, wherein R1a, Rlb, and R1care each as defined herein. In certain embodiments, in any one of the formulae described herein, R3ais -C(S)R1a, wherein R1ais as defined herein. In certain embodiments, in any one of the formulae described herein, R3ais -C(S)OR1a, wherein R1ais as defined herein. In certain embodiments, in any one of the formulae described herein, R3ais -C(S)NR1bR1c, wherein Rlband R1care each as defined herein. In certain embodiments, in any one of the formulae described herein, R3ais -OR1a, wherein R1ais as defined herein. In certain embodiments, in any one of the formulae described herein, R3ais -OC(O)R1a, wherein R1ais as defined herein. In certain embodiments, in any one of the formulae described herein, R3ais -OC(O)OR1a, wherein R1ais as defined herein. In certain embodiments, in any one of the formulae described herein, R3ais -OC(O)NR1bR1c, wherein Rlband R1care each as defined herein. In certain embodiments, in any one of the formulae described herein, R3ais -OC(O)SR1a, wherein R1ais as defined herein. In certain embodiments, in any one of the formulae described herein, R3ais -OC(NR1a)NR1bR1c, wherein R1a, Rlb, and R1care each as defined herein. In certain embodiments, in any one of the formulae described herein, R3ais -OC(S)R1a, wherein R1ais as defined herein. In certain embodiments, in any one of the formulae described herein, R3ais -OC(S)OR1a, wherein R1ais as defined herein. In certain embodiments, in any one of the formulae described herein, R3ais -OC(S)NR1bR1c, wherein Rlband R1care each as defined herein. In certain embodiments, in any one of the formulae described herein, R3ais -OS(O)R1a, wherein R1ais as defined herein. In certain embodiments, in any one of the formulae described herein, R3ais -OS(O)2R1a, wherein R1ais as defined herein. In certain embodiments,in any one of the formulae described herein, R3ais -OS(O)NR1bR1c, wherein Rlband R1care each as defined herein. In certain embodiments, in any one of the formulae described herein, R3ais -OS(O)2NR1bR1c, wherein Rlband R1care each as defined herein. In certain embodiments, in any one of the formulae described herein, R3ais -NR1 bR1c, wherein Rlband R1care each as defined herein. In certain embodiments, in any one of the formulae described herein, R3ais -NR1aC(O)R1d, wherein R1aand R1dare each as defined herein. In certain embodiments, in any one of the formulae described herein, R3ais -NR1aC(O)OR1d, wherein R1aand R1dare each as defined herein. In certain embodiments, in any one of the formulae described herein, R3ais -NR1 aC(O)NR1bR1c, wherein Rlband R1care each as defined herein. In certain embodiments, in any one of the formulae described herein, R3ais -NR1 aC(O)SR1d, wherein R1aand R1dare each as defined herein. In certain embodiments, in any one of the formulae described herein, R3ais -NR1 aC(NR1 d)NR1 bR1c, wherein R1a, Rlb, R1c, and R1dare each as defined herein. In certain embodiments, in any one of the formulae described herein, R3ais -NR1 aC(S)R1d, wherein R1aand R1dare each as defined herein. In certain embodiments, in any one of the formulae described herein, R3ais -NR1aC(S)OR1d, wherein R1aand R1dare each as defined herein. In certain embodiments, in any one of the formulae described herein, R3ais -NR1 aC(S)NR1bR1c, wherein R1a, Rlb, and R1care each as defined herein. In certain embodiments, in any one of the formulae described herein, R3ais -NR1 aS(O)R1d, wherein R1aand R1dare each as defined herein. In certain embodiments, in any one of the formulae described herein, R3ais -NR1 aS(O)2R1d, wherein R1aand R1dare each as defined herein. In certain embodiments, in any one of the formulae described herein, R3ais -NR1 aS(O)NR1 bR1c, wherein R1a, Rlb, and R1care each as defined herein. In certain embodiments, in any one of the formulae described herein, R3ais -NR1 aS(0)2NR1bR1c, wherein R1a, Rlb, and R1care each as defined herein. In certain embodiments, in any one of the formulae described herein, R3ais -SR1a, wherein R1ais as defined herein. In certain embodiments, in any one of the formulae described herein, R3ais -S(O)R1a, wherein R1ais as defined herein. In certain embodiments, in any one of the formulae described herein, R3ais -S(O)2R1a, wherein R1ais as defined herein. In certain embodiments, in any one of the formulae described herein, R3ais -S(O)NR1bR1c, wherein Rlband R1care each as defined herein. In certain embodiments, in any one of the formulae described herein, R3ais -S(O)2NR1bR1c, wherein Rlband R1care each as defined herein.

[0196] In certain embodiments, in any one of the formulae described herein, R3ais (i)hydrogen, cyano, or halo; (ii) Ci-6 alkyl or C6-14 aryl, each optionally substituted with one or more substituents Q; or (iii) -OR1a, -NR1bR1c, or -S(O)2R1a, wherein each R1a, Rlb, and R1cis as defined herein. In certain embodiments, in any one of the formulae described herein, R3ais hydrogen, cyano, fluoro, chloro, bromo, methyl, ethyl, fluoromethyl, difluoromethyl, trifluoromethyl, 1 -cyano- 1,1 -difluoromethyl, l,l-difluoro-2-hydroxy ethyl, l,l-difluoro-2-hydroxy-2- methylpropyl, methylaminomethyl, 2-aminomethylphenyl, 2-(2-aminoethyl)phenyl, 2-methyl- aminomethylphenyl, 2-dimethylaminomethylphenyl, hydroxyl, methoxy, amino, or methylsulfonyl. In certain embodiments, in any one of the formulae described herein, R3ais hydrogen, fluoro, chloro, methyl, ethyl, fluoromethyl, difluoromethyl, trifluoromethyl, or methoxy. In certain embodiments, in any one of the formulae described herein, R3ais hydrogen, fluoro, or methyl. In certain embodiments, in any one of the formulae described herein, R3ais hydrogen. In certain embodiments, in any one of the formulae described herein, R3ais fluoro. In certain embodiments, in any one of the formulae described herein, R3ais methyl.

[0197] In certain embodiments, in any one of the formulae described herein, R3bis hydrogen. In certain embodiments, in any one of the formulae described herein, R3bis deuterium. In certain embodiments, in any one of the formulae described herein, R3bis cyano. In certain embodiments, in any one of the formulae described herein, R3bis halo. In certain embodiments, in any one of the formulae described herein, R3bis fluoro or chloro. In certain embodiments, in any one of the formulae described herein, R3bis fluoro. In certain embodiments, in any one of the formulae described herein, R3bis nitro.

[0198] In certain embodiments, in any one of the formulae described herein, R3bis Ci-6 alkyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R3bis methyl or ethyl, each optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R3bis difluoromethyl, trifluoromethyl, or 1 , 1 -difluoro-2-hydroxy ethyl. In certain embodiments, in any one of the formulae described herein, R3bis Ci-6 heteroalkyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R3bis C2-6 alkenyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R3bis C2-6 alkynyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulaedescribed herein, R3bis C3-10 cycloalkyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R3bis C6-14 aryl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R3bis C7-15 aralkyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R3bis heteroaryl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R3bis heterocyclyl, optionally substituted with one or more substituents Q.

[0199] In certain embodiments, in any one of the formulae described herein, R3bis -C(O)R1a, wherein R1ais as defined herein. In certain embodiments, in any one of the formulae described herein, R3bis -C(O)OR1a, wherein R1ais as defined herein. In certain embodiments, in any one of the formulae described herein, R3bis -C(O)NR1bR1c, wherein Rlband R1care each as defined herein. In certain embodiments, in any one of the formulae described herein, R3bis -C(O)SR1a, wherein R1ais as defined herein. In certain embodiments, in any one of the formulae described herein, R3bis -C(NR1a)NR1bR1c, wherein R1a, Rlb, and R1care each as defined herein. In certain embodiments, in any one of the formulae described herein, R3bis -C(S)R1a, wherein R1ais as defined herein. In certain embodiments, in any one of the formulae described herein, R3bis -C(S)OR1a, wherein R1ais as defined herein. In certain embodiments, in any one of the formulae described herein, R3bis -C(S)NR1bR1c, wherein Rlband R1care each as defined herein. In certain embodiments, in any one of the formulae described herein, R3bis -OR1a, wherein R1ais as defined herein. In certain embodiments, in any one of the formulae described herein, R3bis -OC(O)R1a, wherein R1ais as defined herein. In certain embodiments, in any one of the formulae described herein, R3bis -OC(O)OR1a, wherein R1ais as defined herein. In certain embodiments, in any one of the formulae described herein, R3bis -OC(O)NR1bR1c, wherein Rlband R1care each as defined herein. In certain embodiments, in any one of the formulae described herein, R3bis -OC(O)SR1a, wherein R1ais as defined herein. In certain embodiments, in any one of the formulae described herein, R3bis -OC(NR1a)NR1bR1c, wherein R1a, Rlb, and R1care each as defined herein. In certain embodiments, in any one of the formulae described herein, R3bis -OC(S)R1a, wherein R1ais as defined herein. In certain embodiments, in any one of the formulae described herein, R3bis -OC(S)OR1a, wherein R1ais as defined herein. In certain embodiments, in any one of the formulae described herein, R3bis -OC(S)NR1bR1c, wherein Rlband R1care each as defined herein. In certain embodiments, in any one of the formulae described herein, R3bis-OS(O)R1a, wherein R1ais as defined herein. In certain embodiments, in any one of the formulae described herein, R3bis -OS(O)2R1a, wherein R1ais as defined herein. In certain embodiments, in any one of the formulae described herein, R3bis -OS(O)NR1bR1c, wherein Rlband R1care each as defined herein. In certain embodiments, in any one of the formulae described herein, R3bis -OS(O)2NR1bR1c, wherein Rlband R1care each as defined herein. In certain embodiments, in any one of the formulae described herein, R3bis -NR1bR1c, wherein Rlband R1care each as defined herein. In certain embodiments, in any one of the formulae described herein, R3bis amino. In certain embodiments, in any one of the formulae described herein, R3bis -NR1 aC(O)R1d, wherein R1aand R1dare each as defined herein. In certain embodiments, in any one of the formulae described herein, R3bis -NR1aC(O)OR1d, wherein R1aand R1dare each as defined herein. In certain embodiments, in any one of the formulae described herein, R3bis -NR1 aC(O)NR1bR1c, wherein Rlband R1care each as defined herein. In certain embodiments, in any one of the formulae described herein, R3bis -NR1aC(O)SR1d, wherein R1aand R1dare each as defined herein. In certain embodiments, in any one of the formulae described herein, R3bis -NR1 aC(NR1 d)NR1 bR1c, wherein R1a, Rlb, R1c, and R1dare each as defined herein. In certain embodiments, in any one of the formulae described herein, R3bis -NR1 aC(S)R1d, wherein R1aand R1dare each as defined herein. In certain embodiments, in any one of the formulae described herein, R3bis -NR1 aC(S)OR1d, wherein R1aand R1dare each as defined herein. In certain embodiments, in any one of the formulae described herein, R3bis -NR1 aC(S)NR1bR1c, wherein R1a, Rlb, and R1care each as defined herein. In certain embodiments, in any one of the formulae described herein, R3bis -NR1aS(O)R1d, wherein R1aand R1dare each as defined herein. In certain embodiments, in any one of the formulae described herein, R3bis -NR1 aS(O)2R1d, wherein R1aand R1dare each as defined herein. In certain embodiments, in any one of the formulae described herein, R3bis -NR1aS(O)NR1 bR1c, wherein R1a, Rlb, and R1care each as defined herein. In certain embodiments, in any one of the formulae described herein, R3bis -NR1 aS(O)2NR1bR1c, wherein R1a, Rlb, and R1care each as defined herein. In certain embodiments, in any one of the formulae described herein, R3bis -SR1a, wherein R1ais as defined herein. In certain embodiments, in any one of the formulae described herein, R3bis -S(O)R1a, wherein R1ais as defined herein. In certain embodiments, in any one of the formulae described herein, R3bis -S(O)2R1a, wherein R1ais as defined herein. In certain embodiments, in any one of the formulae described herein, R3bis -S(O)NR1 bR1c, wherein Rlband R1care each asdefined herein. In certain embodiments, in any one of the formulae described herein, R3bis -S(O)2NR1bR1c, wherein Rlband R1care each as defined herein.

[0200] In certain embodiments, in any one of the formulae described herein, R3bis (i) hydrogen, cyano, or halo; (ii) Ci-6 alkyl or C6-14 aryl, each optionally substituted with one or more substituents Q; or (iii) -OR1a, -NR1bR1c, or -S(O)2R1a, wherein each R1a, Rlb, and R1cis as defined herein. In certain embodiments, in any one of the formulae described herein, R3bis hydrogen, cyano, fluoro, chloro, bromo, methyl, ethyl, fluoromethyl, difluoromethyl, trifluoro- methyl, 1 -cyano- 1,1 -difluoromethyl, 1 , 1 -difluoro-2-hydroxy ethyl, l,l-difluoro-2-hydroxy-2- methylpropyl, methylaminomethyl, 2-aminomethylphenyl, 2-(2-aminoethyl)phenyl, 2-methyl- aminomethylphenyl, 2-dimethylaminomethylphenyl, hydroxyl, methoxy, amino, or methylsulfonyl. In certain embodiments, in any one of the formulae described herein, R3bis hydrogen, cyano, fluoro, chloro, bromo, methyl, difluoromethyl, trifluoromethyl, 1 -cyano- 1,1 -difluoro- methyl, l,l-difluoro-2-hydroxy ethyl, l,l-difluoro-2-hydroxy-2-methylpropyl, methylaminomethyl, hydroxyl, amino, or methylsulfonyl. In certain embodiments, in any one of the formulae described herein, R3bis cyano, fluoro, nitro, difluoromethyl, trifluoromethyl, or amino. In certain embodiments, in any one of the formulae described herein, R3bis cyano, fluoro, difluoromethyl, trifluoromethyl, or amino. In certain embodiments, in any one of the formulae described herein, R3bis cyano. In certain embodiments, in any one of the formulae described herein, R3bis fluoro. In certain embodiments, in any one of the formulae described herein, R3bis difluoromethyl. In certain embodiments, in any one of the formulae described herein, R3bis trifluoromethyl. In certain embodiments, in any one of the formulae described herein, R3bis amino.

[0201] In certain embodiments, in any one of the formulae described herein, R3cis hydrogen. In certain embodiments, in any one of the formulae described herein, R3cis deuterium. In certain embodiments, in any one of the formulae described herein, R3cis cyano. In certain embodiments, in any one of the formulae described herein, R3cis halo. In certain embodiments, in any one of the formulae described herein, R3cis fluoro or chloro. In certain embodiments, in any one of the formulae described herein, R3cis fluoro. In certain embodiments, in any one of the formulae described herein, R3cis nitro.

[0202] In certain embodiments, in any one of the formulae described herein, R3cis Ci-6 alkyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R3eis Ci-6 heteroalkyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R3cis C2-6 alkenyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R3cis C2-6 alkynyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R3cis C3-10 cycloalkyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R3cis C6-i4 aryl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R3cis C7-15 aralkyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R3cis heteroaryl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R3cis heterocyclyl, optionally substituted with one or more substituents Q.

[0203] In certain embodiments, in any one of the formulae described herein, R3eis -C(O)R1a, wherein R1ais as defined herein. In certain embodiments, in any one of the formulae described herein, R3cis -C(O)OR1a, wherein R1ais as defined herein. In certain embodiments, in any one of the formulae described herein, R3cis -C(O)NR1bR1c, wherein Rlband R1care each as defined herein. In certain embodiments, in any one of the formulae described herein, R3cis -C(O)SR1a, wherein R1ais as defined herein. In certain embodiments, in any one of the formulae described herein, R3cis -C(NR1a)NR1bR1c, wherein R1a, Rlb, and R1care each as defined herein. In certain embodiments, in any one of the formulae described herein, R3cis -C(S)R1a, wherein R1ais as defined herein. In certain embodiments, in any one of the formulae described herein, R3Cis -C(S)OR1a, wherein R1ais as defined herein. In certain embodiments, in any one of the formulae described herein, R3cis -C(S)NR1bR1c, wherein Rlband R1care each as defined herein. In certain embodiments, in any one of the formulae described herein, R3cis -OR1a, wherein R1ais as defined herein. In certain embodiments, in any one of the formulae described herein, R3cis -OC(O)R1a, wherein R1ais as defined herein. In certain embodiments, in any one of the formulae described herein, R3cis -OC(O)OR1a, wherein R1ais as defined herein. In certain embodiments, in any one of the formulae described herein, R3cis -OC(O)NR1bR1c, wherein Rlband R1care each as defined herein. In certain embodiments, in any one of the formulae describedherein, R3cis -OC(O)SR1a, wherein R1ais as defined herein. In certain embodiments, in any one of the formulae described herein, R3eis -OC(NR1a)NR1bR1c, wherein R1a, Rlb, and R1care each as defined herein. In certain embodiments, in any one of the formulae described herein, R3cis -OC(S)R1a, wherein R1ais as defined herein. In certain embodiments, in any one of the formulae described herein, R3cis -OC(S)OR1a, wherein R1ais as defined herein. In certain embodiments, in any one of the formulae described herein, R3cis -OC(S)NR1bR1c, wherein Rlband R1care each as defined herein. In certain embodiments, in any one of the formulae described herein, R3cis -OS(O)R1a, wherein R1ais as defined herein. In certain embodiments, in any one of the formulae described herein, R3cis -OS(O)2R1a, wherein R1ais as defined herein. In certain embodiments, in any one of the formulae described herein, R3cis -OS(O)NR1bR1c, wherein Rlband R1care each as defined herein. In certain embodiments, in any one of the formulae described herein, R3cis -OS(O)2NR1bR1c, wherein Rlband R1care each as defined herein. In certain embodiments, in any one of the formulae described herein, R3cis -NR1bR1c, wherein Rlband R1care each as defined herein. In certain embodiments, in any one of the formulae described herein, R3cis -NR1 aC(O)R1d, wherein R1aand R1dare each as defined herein. In certain embodiments, in any one of the formulae described herein, R3cis -NR1aC(O)OR1d, wherein R1aand R1dare each as defined herein. In certain embodiments, in any one of the formulae described herein, R3cis -NR1 aC(O)NR1bR1c, wherein Rlband R1care each as defined herein. In certain embodiments, in any one of the formulae described herein, R3eis -NR1 aC(O)SR1d, wherein R1aand R1dare each as defined herein. In certain embodiments, in any one of the formulae described herein, R3cis -NR1 aC(NR1 d)NR1bR1c, wherein R1a, Rlb, R1c, and R1dare each as defined herein. In certain embodiments, in any one of the formulae described herein, R3cis -NR1 aC(S)R1d, wherein R1aand R1dare each as defined herein. In certain embodiments, in any one of the formulae described herein, R3cis -NR1aC(S)OR1d, wherein R1aand R1dare each as defined herein. In certain embodiments, in any one of the formulae described herein, R3cis -NR1 aC(S)NR1bR1c, wherein R1a, Rlb, and R1care each as defined herein. In certain embodiments, in any one of the formulae described herein, R3cis -NR1 aS(O)R1d, wherein R1aand R1dare each as defined herein. In certain embodiments, in any one of the formulae described herein, R3cis -NR1 aS(O)2R1d, wherein R1aand R1dare each as defined herein. In certain embodiments, in any one of the formulae described herein, R3cis -NR1 aS(O)NR1 bR1c, wherein R1a, Rlb, and R1care each as defined herein. In certain embodiments, in any one of the formulae described herein, R3cis-NR1 aS(O)2NR1bR1c, wherein R1a, Rlb, and R1care each as defined herein. In certain embodiments, in any one of the formulae described herein, R3cis -SR1a, wherein R1ais as defined herein. In certain embodiments, in any one of the formulae described herein, R3cis -S(O)R1a, wherein R1ais as defined herein. In certain embodiments, in any one of the formulae described herein, R3cis -S(O)2R1a, wherein R1ais as defined herein. In certain embodiments, in any one of the formulae described herein, R3cis -S(O)NR1bR1c, wherein Rlband R1care each as defined herein. In certain embodiments, in any one of the formulae described herein, R3cis -S(O)2NR1bR1c, wherein Rlband R1care each as defined herein.

[0204] In certain embodiments, in any one of the formulae described herein, R3eis (i) hydrogen, cyano, or halo; (ii) Ci-6 alkyl or C6-14 aryl, each optionally substituted with one or more substituents Q; or (iii) -OR1a, -NR1bR1c, or -S(O)2R1a, wherein each R1a, Rlb, and R1cis as defined herein. In certain embodiments, in any one of the formulae described herein, R3cis hydrogen, cyano, fluoro, chloro, bromo, methyl, ethyl, fluoromethyl, difluoromethyl, trifluoromethyl, 1 -cyano- 1,1 -difluoromethyl, 1 , 1 -difluoro-2-hydroxy ethyl, 1 , 1 -difluoro-2-hydroxy-2- methylpropyl, methylaminomethyl, 2-aminomethylphenyl, 2-(2-aminoethyl)phenyl, 2-methyl- aminomethyl-phenyl, 2-dimethylaminomethylphenyl, hydroxyl, methoxy, amino, or methylsulfonyl. In certain embodiments, in any one of the formulae described herein, R3cis hydrogen, fluoro, or methyl. In certain embodiments, in any one of the formulae described herein, R3cis hydrogen.

[0205] In certain embodiments, in any one of the formulae described herein, R3dis hydrogen. In certain embodiments, in any one of the formulae described herein, R3dis deuterium. In certain embodiments, in any one of the formulae described herein, R3dis cyano. In certain embodiments, in any one of the formulae described herein, R3dis halo. In certain embodiments, in any one of the formulae described herein, R3dis fluoro or chloro. In certain embodiments, in any one of the formulae described herein, R3dis fluoro. In certain embodiments, in any one of the formulae described herein, R3dis nitro.

[0206] In certain embodiments, in any one of the formulae described herein, R3dis Ci-6 alkyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R3dis methyl or ethyl, each optionally substituted with oneor more substituents Q. In certain embodiments, in any one of the formulae described herein, R3dis difluoromethyl, trifluoromethyl, or 1 , 1 -difluoro-2-hydroxy ethyl. In certain embodiments, in any one of the formulae described herein, R3dis Ci-6 heteroalkyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R3dis C2-6 alkenyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R3dis C2-6 alkynyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R3dis C3-10 cycloalkyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R3dis C6-i4 aryl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R3dis C7-15 aralkyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R3dis heteroaryl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R3dis heterocyclyl, optionally substituted with one or more substituents Q.

[0207] In certain embodiments, in any one of the formulae described herein, R3dis -C(O)R1a, wherein R1ais as defined herein. In certain embodiments, in any one of the formulae described herein, R3dis -C(O)OR1a, wherein R1ais as defined herein. In certain embodiments, in any one of the formulae described herein, R3dis -C(O)NR1bR1c, wherein Rlband R1care each as defined herein. In certain embodiments, in any one of the formulae described herein, R3dis -C(O)SR1a, wherein R1ais as defined herein. In certain embodiments, in any one of the formulae described herein, R3dis -C(NR1a)NR1bR1c, wherein R1a, Rlb, and R1care each as defined herein. In certain embodiments, in any one of the formulae described herein, R3dis -C(S)R1a, wherein R1ais as defined herein. In certain embodiments, in any one of the formulae described herein, R3dis -C(S)OR1a, wherein R1ais as defined herein. In certain embodiments, in any one of the formulae described herein, R3dis -C(S)NR1bR1c, wherein Rlband R1care each as defined herein. In certain embodiments, in any one of the formulae described herein, R3dis -OR1a, wherein R1ais as defined herein. In certain embodiments, in any one of the formulae described herein, R3dis -OC(O)R1a, wherein R1ais as defined herein. In certain embodiments, in any one of the formulae described herein, R3dis -OC(O)OR1a, wherein R1ais as defined herein. In certain embodiments, in any one of the formulae described herein, R3dis -OC(O)NR1bR1c, wherein Rlband R1care each as defined herein. In certain embodiments, in any one of the formulae describedherein, R3dis -OC(O)SR1a, wherein R1ais as defined herein. In certain embodiments, in any one of the formulae described herein, R3dis -OC(NR1a)NR1bR1c, wherein R1a, Rlb, and R1care each as defined herein. In certain embodiments, in any one of the formulae described herein, R3dis -OC(S)R1a, wherein R1ais as defined herein. In certain embodiments, in any one of the formulae described herein, R3dis -OC(S)OR1a, wherein R1ais as defined herein. In certain embodiments, in any one of the formulae described herein, R3dis -OC(S)NR1bR1c, wherein Rlband R1care each as defined herein. In certain embodiments, in any one of the formulae described herein, R3dis -OS(O)R1a, wherein R1ais as defined herein. In certain embodiments, in any one of the formulae described herein, R3dis -OS(O)2R1a, wherein R1ais as defined herein. In certain embodiments, in any one of the formulae described herein, R3dis -OS(O)NR1bR1c, wherein Rlband R1care each as defined herein. In certain embodiments, in any one of the formulae described herein, R3dis -OS(O)2NR1bR1c, wherein Rlband R1care each as defined herein. In certain embodiments, in any one of the formulae described herein, R3dis -NR1bR1c, wherein Rlband R1care each as defined herein. In certain embodiments, in any one of the formulae described herein, R3dis amino. In certain embodiments, in any one of the formulae described herein, R3dis -NR1 aC(O)R1d, wherein R1aand R1dare each as defined herein. In certain embodiments, in any one of the formulae described herein, R3dis -NR1aC(O)OR1d, wherein R1aand R1dare each as defined herein. In certain embodiments, in any one of the formulae described herein, R3dis -NR1 aC(O)NR1bR1c, wherein Rlband R1care each as defined herein. In certain embodiments, in any one of the formulae described herein, R3dis -NR1aC(O)SR1d, wherein R1aand R1dare each as defined herein. In certain embodiments, in any one of the formulae described herein, R3dis -NR1 aC(NR1 d)NR1bR1c, wherein R1a, Rlb, R1c, and R1dare each as defined herein. In certain embodiments, in any one of the formulae described herein, R3dis -NR1 aC(S)R1d, wherein R1aand R1dare each as defined herein. In certain embodiments, in any one of the formulae described herein, R3dis -NR1 aC(S)OR1d, wherein R1aand R1dare each as defined herein. In certain embodiments, in any one of the formulae described herein, R3dis -NR1 aC(S)NR1bR1c, wherein R1a, Rlb, and R1care each as defined herein. In certain embodiments, in any one of the formulae described herein, R3dis -NR1aS(O)R1d, wherein R1aand R1dare each as defined herein. In certain embodiments, in any one of the formulae described herein, R3dis -NR1 aS(O)2R1d, wherein R1aand R1dare each as defined herein. In certain embodiments, in any one of the formulae described herein, R3dis -NR1aS(O)NR1bR1c, wherein R1a, Rlb, and R1care each asdefined herein. In certain embodiments, in any one of the formulae described herein, R3dis -NR1 aS(O)2NR1bR1c, wherein R1a, Rlb, and R1care each as defined herein. In certain embodiments, in any one of the formulae described herein, R3dis -SR1a, wherein R1ais as defined herein. In certain embodiments, in any one of the formulae described herein, R3dis -S(O)R1a, wherein R1ais as defined herein. In certain embodiments, in any one of the formulae described herein, R3dis -S(O)2R1a, wherein R1ais as defined herein. In certain embodiments, in any one of the formulae described herein, R3dis -S(O)NR1 bR1c, wherein Rlband R1care each as defined herein. In certain embodiments, in any one of the formulae described herein, R3dis -S(O)2NR1bR1c, wherein Rlband R1care each as defined herein.

[0208] In certain embodiments, in any one of the formulae described herein, R3dis (i) hydrogen, cyano, or halo; (ii) Ci-6 alkyl or C6-14 aryl, each optionally substituted with one or more substituents Q; or (iii) -OR1a, -NR1bR1c, or -S(O)2R1a, wherein each R1a, Rlb, and R1cis as defined herein. In certain embodiments, in any one of the formulae described herein, R3dis hydrogen, cyano, fluoro, chloro, bromo, methyl, ethyl, fluoromethyl, difluoromethyl, trifluoromethyl, 1 -cyano- 1,1 -difluoromethyl, l,l-difluoro-2-hydroxy ethyl, l,l-difluoro-2-hydroxy-2- methylpropyl, methylaminomethyl, 2-aminomethylphenyl, 2-(2-aminoethyl)phenyl, 2-methyl- aminomethylphenyl, 2-dimethylaminomethylphenyl, hydroxyl, methoxy, amino, or methylsulfonyl. In certain embodiments, in any one of the formulae described herein, R3dis hydrogen, cyano, fluoro, chloro, bromo, methyl, di fluoromethyl, trifluoromethyl, l-cyano-1,1 -difluoro- methyl, 1 , 1 -difluoro-2-hydroxy ethyl, l,l-difluoro-2-hydroxy-2-methylpropyl, methylaminomethyl, hydroxyl, amino, or methyl sulfonyl. In certain embodiments, in any one of the formulae described herein, R3dis cyano, fluoro, nitro, difluoromethyl, trifluoromethyl, or amino. In certain embodiments, in any one of the formulae described herein, R3dis cyano, fluoro, difluoromethyl, tri fluoromethyl, or amino. In certain embodiments, in any one of the formulae described herein, R3dis cyano. In certain embodiments, in any one of the formulae described herein, R3dis fluoro. In certain embodiments, in any one of the formulae described herein, R3dis difluoromethyl. In certain embodiments, in any one of the formulae described herein, R3dis trifluoromethyl. In certain embodiments, in any one of the formulae described herein, R3dis amino.

[0209] In certain embodiments, in any one of the formulae described herein, R3eishydrogen. In certain embodiments, in any one of the formulae described herein, R3eis deuterium. In certain embodiments, in any one of the formulae described herein, R3eis cyano. In certain embodiments, in any one of the formulae described herein, R3cis halo. In certain embodiments, in any one of the formulae described herein, R3eis fluoro or chloro. In certain embodiments, in any one of the formulae described herein, R3eis fluoro. In certain embodiments, in any one of the formulae described herein, R3eis nitro.

[0210] In certain embodiments, in any one of the formulae described herein, R3eis Ci-6 alkyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R3eis methyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R3eis methyl. In certain embodiments, in any one of the formulae described herein, R3eis Ci-6 heteroalkyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R3eis C2-6 alkenyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R3eis C2-6 alkynyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R3eis C3-10 cycloalkyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R3eis C6-14 aryl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R3eis C7-15 aralkyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R3eis heteroaryl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R3eis heterocyclyl, optionally substituted with one or more substituents Q.

[0211] In certain embodiments, in any one of the formulae described herein, R3eis -C(O)R1a, wherein R1ais as defined herein. In certain embodiments, in any one of the formulae described herein, R3eis -C(O)OR1a, wherein R1ais as defined herein. In certain embodiments, in any one of the formulae described herein, R3eis -C(O)NR1bR1c, wherein Rlband R1care each as defined herein. In certain embodiments, in any one of the formulae described herein, R3eis -C(O)SR1a, wherein R1ais as defined herein. In certain embodiments, in any one of the formulae described herein, R3eis -C(NR1a)NR1bR1c, wherein R1a, Rlb, and R1care each as defined herein.In certain embodiments, in any one of the formulae described herein, R3eis -C(S)R1a, wherein R1ais as defined herein. In certain embodiments, in any one of the formulae described herein, R3cis -C(S)OR1a, wherein R1ais as defined herein. In certain embodiments, in any one of the formulae described herein, R3eis -C(S)NR1bR1c, wherein Rlband R1care each as defined herein. In certain embodiments, in any one of the formulae described herein, R3eis -OR1a, wherein R1ais as defined herein. In certain embodiments, in any one of the formulae described herein, R3eis -OC(O)R1a, wherein R1ais as defined herein. In certain embodiments, in any one of the formulae described herein, R3eis -OC(O)OR1a, wherein R1ais as defined herein. In certain embodiments, in any one of the formulae described herein, R3eis -OC(O)NR1bR1c, wherein Rlband R1care each as defined herein. In certain embodiments, in any one of the formulae described herein, R3eis -OC(O)SR1a, wherein R1ais as defined herein. In certain embodiments, in any one of the formulae described herein, R3eis -OC(NR1a)NR1 bR1c, wherein R1a, Rlb, and R1care each as defined herein. In certain embodiments, in any one of the formulae described herein, R3eis -OC(S)R1a, wherein R1ais as defined herein. In certain embodiments, in any one of the formulae described herein, R3eis -OC(S)OR1a, wherein R1ais as defined herein. In certain embodiments, in any one of the formulae described herein, R3eis -OC(S)NR1bR1c, wherein R1band R1care each as defined herein. In certain embodiments, in any one of the formulae described herein, R3eis -OS(O)R1a, wherein R1ais as defined herein. In certain embodiments, in any one of the formulae described herein, R3eis -OS(O)2R1a, wherein R1ais as defined herein. In certain embodiments, in any one of the formulae described herein, R3eis -OS(O)NR1bR1c, wherein Rlband R1care each as defined herein. In certain embodiments, in any one of the formulae described herein, R3eis -OS(O)2NR1bR1c, wherein Rlband R1care each as defined herein. In certain embodiments, in any one of the formulae described herein, R3eis -NR1 bR1c, wherein Rlband R1care each as defined herein. In certain embodiments, in any one of the formulae described herein, R3eis -NR1aC(O)R1d, wherein R1aand R1dare each as defined herein. In certain embodiments, in any one of the formulae described herein, R3eis -NR1aC(O)OR1d, wherein R1aand R1dare each as defined herein. In certain embodiments, in any one of the formulae described herein, R3eis -NR1aC(O)NR1bR1c, wherein Rlband R1care each as defined herein. In certain embodiments, in any one of the formulae described herein, R3eis -NR1 aC(O)SR1d, wherein R1aand R1dare each as defined herein. In certain embodiments, in any one of the formulae described herein, R3eis -NR1 aC(NR1 d)NR1 bR1c, wherein R1a, Rlb, R1c, and R1dare each as defined herein. In certainembodiments, in any one of the formulae described herein, R3eis -NR1 aC(S)R1d, wherein R1aand R1dare each as defined herein. In certain embodiments, in any one of the formulae described herein, R3cis -NR1aC(S)OR1d, wherein R1aand R1dare each as defined herein. In certain embodiments, in any one of the formulae described herein, R3eis -NR1 aC(S)NR1bR1c, wherein R1a, Rlb, and R1care each as defined herein. In certain embodiments, in any one of the formulae described herein, R3eis -NR1 aS(O)R1d, wherein R1aand R1dare each as defined herein. In certain embodiments, in any one of the formulae described herein, R3eis -NR1 aS(O)2R1d, wherein R1aand R1dare each as defined herein. In certain embodiments, in any one of the formulae described herein, R3eis -NR1 aS(O)NR1bR1c, wherein R1a, Rlb, and R1care each as defined herein. In certain embodiments, in any one of the formulae described herein, R3eis -NR1 aS(O)2NR1bR1c, wherein R1a, Rlb, and R1care each as defined herein. In certain embodiments, in any one of the formulae described herein, R3eis -SR1a, wherein R1ais as defined herein. In certain embodiments, in any one of the formulae described herein, R3eis -S(O)R1a, wherein R1ais as defined herein. In certain embodiments, in any one of the formulae described herein, R3eis -S(O)2R1a, wherein R1ais as defined herein. In certain embodiments, in any one of the formulae described herein, R3eis -S(O)NR1bR1c, wherein Rlband R1care each as defined herein. In certain embodiments, in any one of the formulae described herein, R3eis -S(O)2NR1bR1c, wherein Rlband R1care each as defined herein.

[0212] In certain embodiments, in any one of the formulae described herein, R3eis (i) hydrogen, cyano, or halo; (ii) Ci-6 alkyl or C6-14 aryl, each optionally substituted with one or more substituents Q; or (iii) -OR1a, -NR1bR1c, or -S(O)2R1a, wherein each R1a, Rlb, and R1cis as defined herein. In certain embodiments, in any one of the formulae described herein, R3eis hydrogen, cyano, fluoro, chloro, bromo, methyl, ethyl, fluoromethyl, difluoromethyl, trifluoromethyl, 1 -cyano- 1,1 -difluoromethyl, l,l-difluoro-2-hydroxy ethyl, l,l-difluoro-2-hydroxy-2- methylpropyl, methylaminomethyl, 2-aminomethylphenyl, 2-(2-aminoethyl)phenyl, 2-methyl- aminomethylphenyl, 2-dimethylaminomethylphenyl, hydroxyl, methoxy, amino, or methylsulfonyl. In certain embodiments, in any one of the formulae described herein, R3eis hydrogen, fluoro, chloro, methyl, ethyl, fluoromethyl, difluoromethyl, trifluoromethyl, or methoxy. In certain embodiments, in any one of the formulae described herein, R3eis hydrogen, fluoro, or methyl. In certain embodiments, in any one of the formulae described herein, R3eis hydrogen. In certain embodiments, in any one of the formulae described herein, R3eis fluoro. In certainembodiments, in any one of the formulae described herein, R3eis methyl.

[0213] In certain embodiments, in any one of the formulae described herein, R4ais hydrogen. In certain embodiments, in any one of the formulae described herein, R4ais deuterium. In certain embodiments, in any one of the formulae described herein, R4ais cyano. In certain embodiments, in any one of the formulae described herein, R4ais halo. In certain embodiments, in any one of the formulae described herein, R4ais fluoro or chloro. In certain embodiments, in any one of the formulae described herein, R4ais nitro. In certain embodiments, in any one of the formulae described herein, R4ais Ci-6 alkyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R4ais methyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R4ais Ci-6 heteroalkyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R4ais C2-6 alkenyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R4ais C2-6 alkynyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R4ais C3-10 cycloalkyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R4ais C6-14 aryl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R4ais C7-15 aralkyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R4ais heteroaryl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R4ais heterocyclyl, optionally substituted with one or more substituents Q.

[0214] In certain embodiments, in any one of the formulae described herein, R4ais -C(O)R1a, wherein R1ais as defined herein. In certain embodiments, in any one of the formulae described herein, R4ais -C(O)OR1a, wherein R1ais as defined herein. In certain embodiments, in any one of the formulae described herein, R4ais -C(O)NR1bR1c, wherein Rlband R1care each as defined herein. In certain embodiments, in any one of the formulae described herein, R4ais -C(O)SR1a, wherein R1ais as defined herein. In certain embodiments, in any one of the formulae described herein, R4ais -C(NR1a)NR1bR1c, wherein R1a, Rlb, and R1care each as defined herein. In certain embodiments, in any one of the formulae described herein, R4ais -C(S)R1a, wherein- I l l -R1ais as defined herein. In certain embodiments, in any one of the formulae described herein, R4ais -C(S)OR1a, wherein R1ais as defined herein. In certain embodiments, in any one of the formulae described herein, R4ais -C(S)NR1bR1c, wherein Rlband R1care each as defined herein. In certain embodiments, in any one of the formulae described herein, R4ais -OR1a, wherein R1ais as defined herein. In certain embodiments, in any one of the formulae described herein, R4ais -OC(O)R1a, wherein R1ais as defined herein. In certain embodiments, in any one of the formulae described herein, R4ais -OC(O)OR1a, wherein R1ais as defined herein. In certain embodiments, in any one of the formulae described herein, R4ais -OC(O)NR1bR1c, wherein Rlband R1care each as defined herein. In certain embodiments, in any one of the formulae described herein, R4ais -OC(O)SR1a, wherein R1ais as defined herein. In certain embodiments, in any one of the formulae described herein, R4ais -OC(NR1a)NR1bR1c, wherein R1a, Rlb, and R1care each as defined herein. In certain embodiments, in any one of the formulae described herein, R4ais -OC(S)R1a, wherein R1ais as defined herein. In certain embodiments, in any one of the formulae described herein, R4ais -OC(S)OR1a, wherein R1ais as defined herein. In certain embodiments, in any one of the formulae described herein, R4ais -OC(S)NR1bR1c, wherein Rlband R1care each as defined herein. In certain embodiments, in any one of the formulae described herein, R4ais -OS(O)R1a, wherein R1ais as defined herein. In certain embodiments, in any one of the formulae described herein, R4ais -OS(O)2R1a, wherein R1ais as defined herein. In certain embodiments, in any one of the formulae described herein, R4ais -OS(O)NR1bR1c, wherein Rlband R1care each as defined herein. In certain embodiments, in any one of the formulae described herein, R4ais -OS(O)2NR1bR1c, wherein Rlband R1care each as defined herein. In certain embodiments, in any one of the formulae described herein, R4ais -NR1bR1c, wherein Rlband R1care each as defined herein. In certain embodiments, in any one of the formulae described herein, R4ais -NR1 aC(O)R1d, wherein R1aand R1dare each as defined herein. In certain embodiments, in any one of the formulae described herein, R4ais -NR1aC(O)OR1d, wherein R1aand R1dare each as defined herein. In certain embodiments, in any one of the formulae described herein, R4ais -NR1 aC(O)NR1bR1c, wherein Rlband R1care each as defined herein. In certain embodiments, in any one of the formulae described herein, R4ais -NR1 aC(O)SR1d, wherein R1aand R1dare each as defined herein. In certain embodiments, in any one of the formulae described herein, R4ais -NR1 aC(NR1 d)NR1bR1c, wherein R1a, Rlb, R1c, and R1dare each as defined herein. In certain embodiments, in any one of the formulae described herein, R4ais -NR1 aC(S)R1d, wherein R1aandR1dare each as defined herein. In certain embodiments, in any one of the formulae described herein, R4ais -NR1aC(S)OR1d, wherein R1aand R1dare each as defined herein. In certain embodiments, in any one of the formulae described herein, R4ais -NR1 aC(S)NR1bR1c, wherein R1a, Rlb, and R1care each as defined herein. In certain embodiments, in any one of the formulae described herein, R4ais -NR1 aS(O)R1d, wherein R1aand R1dare each as defined herein. In certain embodiments, in any one of the formulae described herein, R4ais -NR1 aS(0)2R1d, wherein R1aand R1dare each as defined herein. In certain embodiments, in any one of the formulae described herein, R4ais -NR1 aS(O)NR1 bR1c, wherein R1a, Rlb, and R1care each as defined herein. In certain embodiments, in any one of the formulae described herein, R4ais -NR1 aS(0)2NR1bR1c, wherein R1a, Rlb, and R1care each as defined herein. In certain embodiments, in any one of the formulae described herein, R4ais -SR1a, wherein R1ais as defined herein. In certain embodiments, in any one of the formulae described herein, R4ais -S(O)R1a, wherein R1ais as defined herein. In certain embodiments, in any one of the formulae described herein, R4ais -S(O)2R1a, wherein R1ais as defined herein. In certain embodiments, in any one of the formulae described herein, R4ais -S(O)NR1bR1c, wherein Rlband R1care each as defined herein. In certain embodiments, in any one of the formulae described herein, R4ais -S(O)2NR1bR1c, wherein Rlband R1care each as defined herein.

[0215] In certain embodiments, in any one of the formulae described herein, R4bis hydrogen. In certain embodiments, in any one of the formulae described herein, R4bis deuterium. In certain embodiments, in any one of the formulae described herein, R4bis cyano. In certain embodiments, in any one of the formulae described herein, R4bis halo. In certain embodiments, in any one of the formulae described herein, R4bis fluoro or chloro. In certain embodiments, in any one of the formulae described herein, R4bis nitro. In certain embodiments, in any one of the formulae described herein, R4bis Ci-6 alkyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R4bis methyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R4bis Ci-6 heteroalkyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R4bis C2-6 alkenyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R4bis C2-6 alkynyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R4bisC3-10 cycloalkyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R4bis C6-14 aryl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R4bis C7-15 aralkyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R4bis heteroaryl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R4bis heterocyclyl, optionally substituted with one or more substituents Q.

[0216] In certain embodiments, in any one of the formulae described herein, R4bis -C(O)R1a, wherein R1ais as defined herein. In certain embodiments, in any one of the formulae described herein, R4bis -C(O)OR1a, wherein R1ais as defined herein. In certain embodiments, in any one of the formulae described herein, R4bis -C(O)NR1bR1c, wherein Rlband R1care each as defined herein. In certain embodiments, in any one of the formulae described herein, R4bis -C(O)SR1a, wherein R1ais as defined herein. In certain embodiments, in any one of the formulae described herein, R4bis -C(NR1a)NR1bR1c, wherein R1a, Rlb, and R1care each as defined herein. In certain embodiments, in any one of the formulae described herein, R4bis -C(S)R1a, wherein R1ais as defined herein. In certain embodiments, in any one of the formulae described herein, R4bis -C(S)OR1a, wherein R1ais as defined herein. In certain embodiments, in any one of the formulae described herein, R4bis -C(S)NR1bR1c, wherein Rlband R1care each as defined herein. In certain embodiments, in any one of the formulae described herein, R4bis -OR1a, wherein R1ais as defined herein. In certain embodiments, in any one of the formulae described herein, R4bis -OC(O)R1a, wherein R1ais as defined herein. In certain embodiments, in any one of the formulae described herein, R4bis -OC(O)OR1a, wherein R1ais as defined herein. In certain embodiments, in any one of the formulae described herein, R4bis -OC(O)NR1bR1c, wherein Rlband R1care each as defined herein. In certain embodiments, in any one of the formulae described herein, R4bis -OC(O)SR1a, wherein R1ais as defined herein. In certain embodiments, in any one of the formulae described herein, R4bis -OC(NR1a)NR1bR1c, wherein R1a, Rlb, and R1care each as defined herein. In certain embodiments, in any one of the formulae described herein, R4bis -OC(S)R1a, wherein R1ais as defined herein. In certain embodiments, in any one of the formulae described herein, R4bis -OC(S)OR1a, wherein R1ais as defined herein. In certain embodiments, in any one of the formulae described herein, R4bis -OC(S)NR1bR1c, wherein Rlband R1care each as defined herein. In certain embodiments, in any one of the formulae described herein, R4bis-OS(O)R1a, wherein R1ais as defined herein. In certain embodiments, in any one of the formulae described herein, R4bis -OS(O)2R1a, wherein R1ais as defined herein. In certain embodiments, in any one of the formulae described herein, R4bis -OS(O)NR1bR1c, wherein Rlband R1care each as defined herein. In certain embodiments, in any one of the formulae described herein, R4bis -OS(O)2NR1bR1c, wherein Rlband R1care each as defined herein. In certain embodiments, in any one of the formulae described herein, R4bis -NR1bR1c, wherein Rlband R1care each as defined herein. In certain embodiments, in any one of the formulae described herein, R4bis -NR1 aC(O)R1d, wherein R1aand R1dare each as defined herein. In certain embodiments, in any one of the formulae described herein, R4bis -NR1aC(O)OR1d, wherein R1aand R1dare each as defined herein. In certain embodiments, in any one of the formulae described herein, R4bis -NR1 aC(O)NR1bR1c, wherein Rlband R1care each as defined herein. In certain embodiments, in any one of the formulae described herein, R4bis -NR1aC(O)SR1d, wherein R1aand R1dare each as defined herein. In certain embodiments, in any one of the formulae described herein, R4bis -NR1 aC(NR1 d)NR1bR1c, wherein R1a, Rlb, R1c, and R1dare each as defined herein. In certain embodiments, in any one of the formulae described herein, R4bis -NR1 aC(S)R1d, wherein R1aand R1dare each as defined herein. In certain embodiments, in any one of the formulae described herein, R4bis -NR1 aC(S)OR1d, wherein R1aand R1dare each as defined herein. In certain embodiments, in any one of the formulae described herein, R4bis -NR1 aC(S)NR1bR1c, wherein R1a, Rlb, and R1care each as defined herein. In certain embodiments, in any one of the formulae described herein, R4bis -NR1aS(O)R1d, wherein R1aand R1dare each as defined herein. In certain embodiments, in any one of the formulae described herein, R4bis -NR1 aS(O)2R1d, wherein R1aand R1dare each as defined herein. In certain embodiments, in any one of the formulae described herein, R4bis -NR1aS(O)NR1 bR1c, wherein R1a, Rlb, and R1care each as defined herein. In certain embodiments, in any one of the formulae described herein, R4bis -NR1aS(0)2NR1bR1c, wherein R1a, Rlb, and R1care each as defined herein. In certain embodiments, in any one of the formulae described herein, R4bis -SR1a, wherein R1ais as defined herein. In certain embodiments, in any one of the formulae described herein, R4bis -S(O)R1a, wherein R1ais as defined herein. In certain embodiments, in any one of the formulae described herein, R4bis -S(O)2R1a, wherein R1ais as defined herein. In certain embodiments, in any one of the formulae described herein, R4bis -S(O)NR1bR1c, wherein Rlband R1care each as defined herein. In certain embodiments, in any one of the formulae described herein, R4bis-S(O)2NR1bR1c, wherein Rlband R1care each as defined herein.

[0217] In certain embodiments, in any one of the formulae described herein, R6ais hydrogen. In certain embodiments, in any one of the formulae described herein, R6ais deuterium. In certain embodiments, in any one of the formulae described herein, R6ais cyano. In certain embodiments, in any one of the formulae described herein, R6ais halo. In certain embodiments, in any one of the formulae described herein, R6ais fluoro or chloro. In certain embodiments, in any one of the formulae described herein, R6ais fluoro. In certain embodiments, in any one of the formulae described herein, R6ais nitro. In certain embodiments, in any one of the formulae described herein, R6ais Ci-6 alkyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R6ais methyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R6ais Ci-6 heteroalkyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R6ais C2-6 alkenyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R6ais C2-6 alkynyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R6ais C3-10 cycloalkyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R6ais C6-14 aryl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R6ais C7-15 aralkyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R6ais heteroaryl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R6ais heterocyclyl, optionally substituted with one or more substituents Q.

[0218] In certain embodiments, in any one of the formulae described herein, R6ais -C(O)R1a, wherein R1ais as defined herein. In certain embodiments, in any one of the formulae described herein, R6ais -C(O)OR1a, wherein R1ais as defined herein. In certain embodiments, in any one of the formulae described herein, R6ais -C(O)NR1bR1c, wherein Rlband R1care each as defined herein. In certain embodiments, in any one of the formulae described herein, R6ais -C(O)SR1a, wherein R1ais as defined herein. In certain embodiments, in any one of the formulae described herein, R6ais -C(NR1a)NR1bR1c, wherein R1a, Rlb, and R1care each as defined herein.In certain embodiments, in any one of the formulae described herein, R6ais -C(S)R1a, wherein R1ais as defined herein. In certain embodiments, in any one of the formulae described herein, R6ais -C(S)OR1a, wherein R1ais as defined herein. In certain embodiments, in any one of the formulae described herein, R6ais -C(S)NR1bR1c, wherein Rlband R1care each as defined herein. In certain embodiments, in any one of the formulae described herein, R6ais -OR1a, wherein R1ais as defined herein. In certain embodiments, in any one of the formulae described herein, R6ais -OC(O)R1a, wherein R1ais as defined herein. In certain embodiments, in any one of the formulae described herein, R6ais -OC(O)OR1a, wherein R1ais as defined herein. In certain embodiments, in any one of the formulae described herein, R6ais -OC(O)NR1bR1c, wherein Rlband R1care each as defined herein. In certain embodiments, in any one of the formulae described herein, R6ais -OC(O)SR1a, wherein R1ais as defined herein. In certain embodiments, in any one of the formulae described herein, R6ais -OC(NR1a)NR1 bR1c, wherein R1a, Rlb, and R1care each as defined herein. In certain embodiments, in any one of the formulae described herein, R6ais -OC(S)R1a, wherein R1ais as defined herein. In certain embodiments, in any one of the formulae described herein, R6ais -OC(S)OR1a, wherein R1ais as defined herein. In certain embodiments, in any one of the formulae described herein, R6ais -OC(S)NR1bR1c, wherein R1band R1care each as defined herein. In certain embodiments, in any one of the formulae described herein, R6ais -OS(O)R1a, wherein R1ais as defined herein. In certain embodiments, in any one of the formulae described herein, R6ais -OS(O)2R1a, wherein R1ais as defined herein. In certain embodiments, in any one of the formulae described herein, R6ais -OS(O)NR1bR1c, wherein Rlband R1care each as defined herein. In certain embodiments, in any one of the formulae described herein, R6ais -OS(O)2NR1bR1c, wherein Rlband R1care each as defined herein. In certain embodiments, in any one of the formulae described herein, R6ais -NR1 bR1c, wherein Rlband R1care each as defined herein. In certain embodiments, in any one of the formulae described herein, R6ais -NR1aC(O)R1d, wherein R1aand R1dare each as defined herein. In certain embodiments, in any one of the formulae described herein, R6ais -NR1aC(O)OR1d, wherein R1aand R1dare each as defined herein. In certain embodiments, in any one of the formulae described herein, R6ais -NR1aC(O)NR1bR1c, wherein Rlband R1care each as defined herein. In certain embodiments, in any one of the formulae described herein, R6ais -NR1 aC(O)SR1d, wherein R1aand R1dare each as defined herein. In certain embodiments, in any one of the formulae described herein, R6ais -NR1 aC(NR1 d)NR1 bR1c, wherein R1a, Rlb, R1c, and R1dare each as defined herein. In certainembodiments, in any one of the formulae described herein, R6ais -NR1 aC(S)R1d, wherein R1aand R1dare each as defined herein. In certain embodiments, in any one of the formulae described herein, R6ais -NR1aC(S)OR1d, wherein R1aand R1dare each as defined herein. In certain embodiments, in any one of the formulae described herein, R6ais -NR1 aC(S)NR1bR1c, wherein R1a, Rlb, and R1care each as defined herein. In certain embodiments, in any one of the formulae described herein, R6ais -NR1 aS(O)R1d, wherein R1aand R1dare each as defined herein. In certain embodiments, in any one of the formulae described herein, R6ais -NR1 aS(0)2R1d, wherein R1aand R1dare each as defined herein. In certain embodiments, in any one of the formulae described herein, R6ais -NR1 aS(O)NR1bR1c, wherein R1a, Rlb, and R1care each as defined herein. In certain embodiments, in any one of the formulae described herein, R6ais -NR1 aS(0)2NR1bR1c, wherein R1a, Rlb, and R1care each as defined herein. In certain embodiments, in any one of the formulae described herein, R6ais -SR1a, wherein R1ais as defined herein. In certain embodiments, in any one of the formulae described herein, R6ais -S(O)R1a, wherein R1ais as defined herein. In certain embodiments, in any one of the formulae described herein, R6ais -S(O)2R1a, wherein R1ais as defined herein. In certain embodiments, in any one of the formulae described herein, R6ais -S(O)NR1bR1c, wherein Rlband R1care each as defined herein. In certain embodiments, in any one of the formulae described herein, R6ais -S(O)2NR1bR1c, wherein Rlband R1care each as defined herein.

[0219] In certain embodiments, in any one of the formulae described herein, R6bis hydrogen. In certain embodiments, in any one of the formulae described herein, R6bis deuterium. In certain embodiments, in any one of the formulae described herein, R6bis cyano. In certain embodiments, in any one of the formulae described herein, R6bis halo. In certain embodiments, in any one of the formulae described herein, R6bis fluoro or chloro. In certain embodiments, in any one of the formulae described herein, R6bis fluoro. In certain embodiments, in any one of the formulae described herein, R6bis nitro. In certain embodiments, in any one of the formulae described herein, R6bis Ci-6 alkyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R6bis methyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R6bis Ci-6 heteroalkyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R6bis C2-6 alkenyl, optionally substituted with one or more substituents Q. In certain embodiments, inany one of the formulae described herein, R6bis C2-6 alkynyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R6bis C3-10 cycloalkyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R6bis C6-14 aryl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R6bis C7-15 aralkyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R6bis heteroaryl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R6bis heterocyclyl, optionally substituted with one or more substituents Q.

[0220] In certain embodiments, in any one of the formulae described herein, R6bis -C(O)R1a, wherein R1ais as defined herein. In certain embodiments, in any one of the formulae described herein, R6bis -C(O)OR1a, wherein R1ais as defined herein. In certain embodiments, in any one of the formulae described herein, R6bis -C(O)NR1bR1c, wherein Rlband R1care each as defined herein. In certain embodiments, in any one of the formulae described herein, R6bis -C(O)SR1a, wherein R1ais as defined herein. In certain embodiments, in any one of the formulae described herein, R6bis -C(NR1a)NR1bR1c, wherein R1a, Rlb, and R1care each as defined herein. In certain embodiments, in any one of the formulae described herein, R6bis -C(S)R1a, wherein R1ais as defined herein. In certain embodiments, in any one of the formulae described herein, R6bis -C(S)OR1a, wherein R1ais as defined herein. In certain embodiments, in any one of the formulae described herein, R6bis -C(S)NR1bR1c, wherein Rlband R1care each as defined herein. In certain embodiments, in any one of the formulae described herein, R6bis -OR1a, wherein R1ais as defined herein. In certain embodiments, in any one of the formulae described herein, R6bis -OC(O)R1a, wherein R1ais as defined herein. In certain embodiments, in any one of the formulae described herein, R6bis -OC(O)OR1a, wherein R1ais as defined herein. In certain embodiments, in any one of the formulae described herein, R6bis -OC(O)NR1bR1c, wherein Rlband R1care each as defined herein. In certain embodiments, in any one of the formulae described herein, R6bis -OC(O)SR1a, wherein R1ais as defined herein. In certain embodiments, in any one of the formulae described herein, R6bis -OC(NR1a)NR1bR1c, wherein R1a, Rlb, and R1care each as defined herein. In certain embodiments, in any one of the formulae described herein, R6bis -OC(S)R1a, wherein R1ais as defined herein. In certain embodiments, in any one of the formulae described herein, R6bis -OC(S)OR1a, wherein R1ais as defined herein. In certain embodiments,in any one of the formulae described herein, R6bis -OC(S)NR1bR1c, wherein Rlband R1care each as defined herein. In certain embodiments, in any one of the formulae described herein, R6bis -OS(O)R1a, wherein R1ais as defined herein. In certain embodiments, in any one of the formulae described herein, R6bis -OS(O)2R1a, wherein R1ais as defined herein. In certain embodiments, in any one of the formulae described herein, R6bis -OS(O)NR1bR1c, wherein Rlband R1care each as defined herein. In certain embodiments, in any one of the formulae described herein, R6bis -OS(O)2NR1bR1c, wherein Rlband R1care each as defined herein. In certain embodiments, in any one of the formulae described herein, R6bis -NR1bR1c, wherein Rlband R1care each as defined herein. In certain embodiments, in any one of the formulae described herein, R6bis -NR1 aC(O)R1d, wherein R1aand R1dare each as defined herein. In certain embodiments, in any one of the formulae described herein, R6bis -NR1aC(O)OR1d, wherein R1aand R1dare each as defined herein. In certain embodiments, in any one of the formulae described herein, R6bis -NR1 aC(O)NR1bR1c, wherein Rlband R1care each as defined herein. In certain embodiments, in any one of the formulae described herein, R6bis -NR1aC(O)SR1d, wherein R1aand R1dare each as defined herein. In certain embodiments, in any one of the formulae described herein, R6bis -NR1 aC(NR1 d)NR1bR1c, wherein R1a, R1b, R1c, and R1dare each as defined herein. In certain embodiments, in any one of the formulae described herein, R6bis -NR1 aC(S)R1d, wherein R1aand R1dare each as defined herein. In certain embodiments, in any one of the formulae described herein, R6bis -NR1 aC(S)OR1d, wherein R1aand R1dare each as defined herein. In certain embodiments, in any one of the formulae described herein, R6bis -NR1 aC(S)NR1bR1c, wherein R1a, Rlb, and R1care each as defined herein. In certain embodiments, in any one of the formulae described herein, R6bis -NR1aS(O)R1d, wherein R1aand R1dare each as defined herein. In certain embodiments, in any one of the formulae described herein, R6bis -NR1 aS(O)2R1d, wherein R1aand R1dare each as defined herein. In certain embodiments, in any one of the formulae described herein, R6bis -NR1aS(O)NR1bR1c, wherein R1a, Rlb, and R1care each as defined herein. In certain embodiments, in any one of the formulae described herein, R6bis -NR1 aS(O)2NR1bR1c, wherein R1a, Rlb, and R1care each as defined herein. In certain embodiments, in any one of the formulae described herein, R6bis -SR1a, wherein R1ais as defined herein. In certain embodiments, in any one of the formulae described herein, R6bis -S(O)R1a, wherein R1ais as defined herein. In certain embodiments, in any one of the formulae described herein, R6bis -S(O)2R1a, wherein R1ais as defined herein. In certain embodiments, inany one of the formulae described herein, R6bis -S(O)NR1 bR1c, wherein Rlband R1care each as defined herein. In certain embodiments, in any one of the formulae described herein, R6bis -S(O)2NR1bR1c, wherein Rlband R1care each as defined herein.

[0221] In certain embodiments, in any one of the formulae described herein, Re1is hydrogen. In certain embodiments, in any one of the formulae described herein, Re1is deuterium. In certain embodiments, in any one of the formulae described herein, Re1is halo. In certain embodiments, in any one of the formulae described herein, Re1is fluoro. In certain embodiments, in any one of the formulae described herein, Re1is Ci-6 alkyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, Re1is methyl.

[0222] In certain embodiments, in any one of the formulae described herein, Re2is hydrogen. In certain embodiments, in any one of the formulae described herein, Re2is Ci-6 alkyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, Re2is (pivaloyloxy )methyl, valyloxymethyl, or ((di-tert- butoxyphosphoryl)oxy)methyl.

[0223] In certain embodiments, in any one of the formulae described herein, Re3is deuterium. In certain embodiments, in any one of the formulae described herein, Re3is cyano. In certain embodiments, in any one of the formulae described herein, Re3is independently halo. In certain embodiments, in any one of the formulae described herein, each Re3is independently fluoro or chloro. In certain embodiments, in any one of the formulae described herein, Re3is nitro. In certain embodiments, in any one of the formulae described herein, each Re3is independently Ci-6 alkyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, Re3is methyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, each Re3is independently Ci-6 heteroalkyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, each Re3is independently C2-6 alkenyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, each Re3is independently C2-6 alkynyl, optionally substituted with one or more substituents Q. In certain embodiments, in anyone of the formulae described herein, each Re3is independently C3-10 cycloalkyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, each Rc3is independently C6-14 aryl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, each Re3is independently C7-15 aralkyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, each Re3is independently heteroaryl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, each Re3is independently heterocyclyl, optionally substituted with one or more substituents Q.

[0224] In certain embodiments, in any one of the formulae described herein, each Re3is independently -C(O)R1a, wherein R1ais independently as defined herein. In certain embodiments, in any one of the formulae described herein, each Re3is independently -C(O)OR1a, wherein R1ais independently as defined herein. In certain embodiments, in any one of the formulae described herein, each Re3is independently -C(O)NR1bR1c, wherein Rlband R1care each as defined herein. In certain embodiments, in any one of the formulae described herein, each Re3is independently -C(O)SR1a, wherein R1ais independently as defined herein. In certain embodiments, in any one of the formulae described herein, each Re3is independently -C(NR1a)NR1bR1c, wherein R1a, Rlb, and R1care each as defined herein. In certain embodiments, in any one of the formulae described herein, each Re3is independently -C(S)R1a, wherein R1ais independently as defined herein. In certain embodiments, in any one of the formulae described herein, each Re3is independently -C(S)OR1a, wherein R1ais independently as defined herein. In certain embodiments, in any one of the formulae described herein, each Re3is independently -C(S)NR1bR1c, wherein Rlband R1care each as defined herein. In certain embodiments, in any one of the formulae described herein, each Re3is independently -OR1a, wherein R1ais independently as defined herein. In certain embodiments, in any one of the formulae described herein, each Re3is independently -OC(O)R1a, wherein R1ais independently as defined herein. In certain embodiments, in any one of the formulae described herein, each Re3is independently -OC(O)OR1a, wherein R1ais independently as defined herein. In certain embodiments, in any one of the formulae described herein, each Re3is independently -OC(O)NR1bR1c, wherein Rlband R1care each as defined herein. In certain embodiments, in any one of the formulae described herein, each Re3is independently -OC(O)SR1a, wherein R1ais independently as defined herein.In certain embodiments, in any one of the formulae described herein, each Re3is independently -OC(NR1a)NR1bR1c, wherein R1a, Rlb, and R1care each as defined herein. In certain embodiments, in any one of the formulae described herein, each Rc3is independently -OC(S)R1a, wherein R1ais independently as defined herein. In certain embodiments, in any one of the formulae described herein, each Re3is independently -OC(S)OR1a, wherein R1ais independently as defined herein. In certain embodiments, in any one of the formulae described herein, each Re3is independently -OC(S)NR1bR1c, wherein Rlband R1care each as defined herein. In certain embodiments, in any one of the formulae described herein, each Re3is independently -OS(O)R1a, wherein R1ais independently as defined herein. In certain embodiments, in any one of the formulae described herein, each Re3is independently -OS(O)2R1a, wherein R1ais independently as defined herein. In certain embodiments, in any one of the formulae described herein, each Re3is independently -OS(O)NR1bR1c, wherein Rlband R1care each as defined herein. In certain embodiments, in any one of the formulae described herein, each Re3is independently -OS(O)2NR1bR1c, wherein Rlband R1care each as defined herein. In certain embodiments, in any one of the formulae described herein, each Re3is independently -NR1bR1c, wherein Rlband R1care each as defined herein. In certain embodiments, in any one of the formulae described herein, each Re3is independently -NR1aC(O)R1d, wherein R1aand R1dare each as defined herein. In certain embodiments, in any one of the formulae described herein, each Re3is independently -NR1 aC(O)OR1d, wherein R1aand R1dare each as defined herein. In certain embodiments, in any one of the formulae described herein, each Re3is independently -NR1 aC(O)NR1bR1c, wherein Rlband R1care each as defined herein. In certain embodiments, in any one of the formulae described herein, each Re3is independently -NR1aC(O)SR1d, wherein R1aand R1dare each as defined herein. In certain embodiments, in any one of the formulae described herein, each Re3is independently -NR1 aC(iNR1d)NR1bR1c, wherein R1a, Rlb, R1c, and R1dare each as defined herein. In certain embodiments, in any one of the formulae described herein, each Re3is independently -NR1 aC(S)R1d, wherein R1aand R1dare each as defined herein. In certain embodiments, in any one of the formulae described herein, each Re3is independently -NR1 aC(S)OR1d, wherein R1aand R1dare each as defined herein. In certain embodiments, in any one of the formulae described herein, each Re3is independently -NR1 aC(S)NR1bR1c, wherein R1a, Rlb, and R1care each as defined herein. In certain embodiments, in any one of the formulae described herein, each Re3is independently -NR1 aS(O)R1d, wherein R1aand R1dare each as defined herein. Incertain embodiments, in any one of the formulae described herein, each Re3is independently -NR1 aS(O)2R1d, wherein R1aand R1dare each as defined herein. In certain embodiments, in any one of the formulae described herein, each Rc3is independently -NR1 aS(O)NR1bR1c, wherein R1a, Rlb, and R1care each as defined herein. In certain embodiments, in any one of the formulae described herein, each Re3is independently -NR1 aS(O)2NR1bR1c, wherein R1a, Rlb, and R1care each as defined herein. In certain embodiments, in any one of the formulae described herein, each Re3is independently -SR1a, wherein R1ais independently as defined herein. In certain embodiments, in any one of the formulae described herein, each Re3is independently -S(O)R1a, wherein R1ais independently as defined herein. In certain embodiments, in any one of the formulae described herein, each Re3is independently -S(O)2R1a, wherein R1ais independently as defined herein. In certain embodiments, in any one of the formulae described herein, each Re3is independently -S(O)NR1bR1c, wherein Rlband R1care each as defined herein. In certain embodiments, in any one of the formulae described herein, each Re3is independently -S(O)2NR1bR1c, wherein Rlband R1care each as defined herein.

[0225] In certain embodiments, in any one of the formulae described herein, Re4is hydrogen. In certain embodiments, in any one of the formulae described herein, Re4is deuterium. In certain embodiments, in any one of the formulae described herein, Re4is cyano. In certain embodiments, in any one of the formulae described herein, Re4is halo. In certain embodiments, in any one of the formulae described herein, Re4is fluoro or chloro. In certain embodiments, in any one of the formulae described herein, Re4is nitro. In certain embodiments, in any one of the formulae described herein, Re4is Ci-6 alkyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, Re4is methyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, Re4is Ci-6 heteroalkyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, Re4is C2-6 alkenyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, Re4is C2-6 alkynyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, Re4is C3-10 cycloalkyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, Re4is C6-14 aryl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, Re4isC?-i5 aralkyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, Re4is heteroaryl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, Re4is heterocyclyl, optionally substituted with one or more substituents Q.

[0226] In certain embodiments, in any one of the formulae described herein, Re4is -C(O)R1a, wherein R1ais as defined herein. In certain embodiments, in any one of the formulae described herein, Re4is -C(O)OR1a, wherein R1ais as defined herein. In certain embodiments, in any one of the formulae described herein, Re4is -C(O)NR1bR1c, wherein Rlband R1care each as defined herein. In certain embodiments, in any one of the formulae described herein, Re4is -C(O)SR1a, wherein R1ais as defined herein. In certain embodiments, in any one of the formulae described herein, Re4is -C(NR1a)NR1bR1c, wherein R1a, Rlb, and R1care each as defined herein. In certain embodiments, in any one of the formulae described herein, Re4is -C(S)R1a, wherein R1ais as defined herein. In certain embodiments, in any one of the formulae described herein, Re4is -C(S)OR1a, wherein R1ais as defined herein. In certain embodiments, in any one of the formulae described herein, Re4is -C(S)NR1bR1c, wherein Rlband R1care each as defined herein. In certain embodiments, in any one of the formulae described herein, Re4is -OR1a, wherein R1ais as defined herein. In certain embodiments, in any one of the formulae described herein, Re4is -OC(O)R1a, wherein R1ais as defined herein. In certain embodiments, in any one of the formulae described herein, Re4is -OC(O)OR1a, wherein R1ais as defined herein. In certain embodiments, in any one of the formulae described herein, Re4is -OC(O)NR1bR1c, wherein Rlband R1care each as defined herein. In certain embodiments, in any one of the formulae described herein, Re4is -OC(O)SR1a, wherein R1ais as defined herein. In certain embodiments, in any one of the formulae described herein, Re4is -OC(NR1a)NR1bR1c, wherein R1a, Rlb, and R1care each as defined herein. In certain embodiments, in any one of the formulae described herein, Re4is -OC(S)R1a, wherein R1ais as defined herein. In certain embodiments, in any one of the formulae described herein, Re4is -OC(S)OR1a, wherein R1ais as defined herein. In certain embodiments, in any one of the formulae described herein, Re4is -OC(S)NR1bR1c, wherein Rlband R1care each as defined herein. In certain embodiments, in any one of the formulae described herein, Re4is -OS(O)R1a, wherein R1ais as defined herein. In certain embodiments, in any one of the formulae described herein, Re4is -OS(O)2R1a, wherein R1ais as defined herein. In certain embodiments, in any one of the formulae described herein, Re4is -OS(O)NR1bR1c, wherein Rlband R1care eachas defined herein. In certain embodiments, in any one of the formulae described herein, Re4is -0S(0)2NR1bR1c, wherein Rlband R1care each as defined herein. In certain embodiments, in any one of the formulae described herein, Rc4is -NR1bR1c, wherein Rlband R1care each as defined herein. In certain embodiments, in any one of the formulae described herein, Re4is -NR1 aC(O)R1d, wherein R1aand R1dare each as defined herein. In certain embodiments, in any one of the formulae described herein, Re4is -NR1aC(O)OR1d, wherein R1aand R1dare each as defined herein. In certain embodiments, in any one of the formulae described herein, Re4is -NR1 aC(O)NR1bR1c, wherein Rlband R1care each as defined herein. In certain embodiments, in any one of the formulae described herein, Re4is -NR1 aC(O)SR1d, wherein R1aand R1dare each as defined herein. In certain embodiments, in any one of the formulae described herein, Re4is -NR1 aC(NR1 d)NR1bR1c, wherein R1a, Rlb, R1c, and R1dare each as defined herein. In certain embodiments, in any one of the formulae described herein, Re4is -NR1 aC(S)R1d, wherein R1aand R1dare each as defined herein. In certain embodiments, in any one of the formulae described herein, Re4is -NR1aC(S)OR1d, wherein R1aand R1dare each as defined herein. In certain embodiments, in any one of the formulae described herein, Re4is -NR1 aC(S)NR1bR1c, wherein R1a, R1b, and R1care each as defined herein. In certain embodiments, in any one of the formulae described herein, Re4is -NR1aS(O)R1d, wherein R1aand R1dare each as defined herein. In certain embodiments, in any one of the formulae described herein, Re4is -NR1 aS(0)2R1d, wherein R1aand R1dare each as defined herein. In certain embodiments, in any one of the formulae described herein, Re4is -NR1 aS(O)NR1bR1c, wherein R1a, Rlb, and R1care each as defined herein. In certain embodiments, in any one of the formulae described herein, Re4is -NR1 aS(0)2NR1bR1c, wherein R1a, Rlb, and R1care each as defined herein. In certain embodiments, in any one of the formulae described herein, Re4is -SR1a, wherein R1ais as defined herein. In certain embodiments, in any one of the formulae described herein, Re4is -S(O)R1a, wherein R1ais as defined herein. In certain embodiments, in any one of the formulae described herein, Re4is -S(O)2R1a, wherein R1ais as defined herein. In certain embodiments, in any one of the formulae described herein, Re4is -S(O)NR1bR1c, wherein Rlband R1care each as defined herein. In certain embodiments, in any one of the formulae described herein, Re4is -S(O)2NR1bR1c, wherein Rlband R1care each as defined herein.

[0227] In certain embodiments, in any one of the formulae described herein, Re5is hydrogen. In certain embodiments, in any one of the formulae described herein, Re5is Ci-6 alkyl,optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, Re5is methyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, Re5is Ci-6 heteroalkyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, Re5is C2-6 alkenyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, Re5is C2-6 alkynyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, Re5is C3-10 cycloalkyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, Re5is C6-14 aryl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, Re5is C7-15 aralkyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, Re3is heteroaryl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, Re5is heterocyclyl, optionally substituted with one or more substituents Q.

[0228] In certain embodiments, in any one of the formulae described herein, Re5is -C(O)R1a, wherein R1ais as defined herein. In certain embodiments, in any one of the formulae described herein, Re5is -C(O)OR1a, wherein R1ais as defined herein. In certain embodiments, in any one of the formulae described herein, Re5is -C(O)NR1bR1c, wherein Rlband R1care each as defined herein. In certain embodiments, in any one of the formulae described herein, Re5is -C(O)SR1a, wherein R1ais as defined herein. In certain embodiments, in any one of the formulae described herein, Re5is -C(NR1a)NR1bR1c, wherein R1a, Rlb, and R1care each as defined herein. In certain embodiments, in any one of the formulae described herein, Re5is -C(S)R1a, wherein R1ais as defined herein. In certain embodiments, in any one of the formulae described herein, Re?is -C(S)OR1a, wherein R1ais as defined herein. In certain embodiments, in any one of the formulae described herein, Re5is -C(S)NR1bR1c, wherein Rlband R1care each as defined herein. In certain embodiments, in any one of the formulae described herein, Re5is -S(O)R1a, wherein R1ais as defined herein. In certain embodiments, in any one of the formulae described herein, Re5is -S(O)2R1a, wherein R1ais as defined herein. In certain embodiments, in any one of the formulae described herein, Re?is -S(O)NR1 bR1c, wherein Rlband R1care each as defined herein. In certain embodiments, in any one of the formulae described herein, Re5is -S(O)2NR1bR1c,wherein Rlband R1care each as defined herein.

[0229] In certain embodiments, in any one of the formulae described herein, Aeis a bond. In certain embodiments, in any one of the formulae described herein, Aeis C3-10 cycloalkylene, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, Aeis monocyclic C3-10 cycloalkylene, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, Aeis bicyclic C4-10 cycloalkylene, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, Aeis bridged, fused, or spiro C4-10 cycloalkylene, each optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, Aeis C6-14 arylene, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, Aeis heteroarylene, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, Aeis heterocyclylene, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, Aeis monocyclic heterocyclylene, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, Aeis 3-, 4-, 5-, 6-, or 7-membered heterocyclylene, each optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, Aeis 6- membered heterocyclylene, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, Aeis bicyclic heterocyclylene, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, Aeis bridged, fused, or spiro heterocyclylene, each optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, Aeis bridged heterocyclylene, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, Aeis fused heterocyclylene, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, Aeis spiro heterocyclylene, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, Aeis piperidindiyl, piperazindiyl, or 8-azabicyclo[3.2.1]octandiyl, each optionally substituted with one or more substituents Q. In yet another embodiment, in any one of the formulae described herein, Aeis piperidin-l,4-diyl, piperazin- 1,4-diyl, or 8-azabicyclo-[3.2.1 ]octan-3,8-diyl, each optionally substituted with one or more substituents Q.

[0230] In certain embodiments, in any one of the formulae described herein, L is Ci-6 alkylene or C7-14 arylene, each optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, L is C1-6 alkylene, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, L is methanediyl, ethanediyl, propanediyl, or butanediyl, each optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, L is methanediyl, ethanediyl, propanediyl, or butanediyl, each optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, L is methanediyl or ethane- 1 ,2-diyl, each optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, L is methanediyl. In certain embodiments, in any one of the formulae described herein, L is ethane- 1 ,2-diyl. In certain embodiments, in any one of the formulae described herein, L is C7-14 arylene, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, L is monocyclic C7-14 arylene, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, L is phendiylmethandiyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, L is phen-l,3-diylmethandiyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, L is -C(O)-.

[0231] In certain embodiments, in any one of the formulae described herein, L is a linker having the structure of -Zk-(Rk-Zk)z- wherein: each Rkis independently C1-6 alkylene, C2-6 alkenylene, C2-6 alkynylene, C3-10 cycloalkylene, C6-14 arylene, heteroarylene, or heterocyclylene, each of which is optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Q; each Zkis independently a bond, -C(O)-, -C(O)O- -C(O)NR1 b-, -C(O)S- C(NR1a)NR1b, C(S) , -C(S)O , C(S)NR1b, O , OC(O)O , OC(O)NR1b, OC(O)S , -OC(NR1a)NR1b-, -OC(S)O-, -OC(S)NR1b- -OS(O)-, -OS(O)2-, -OS(O)NR1 b- -OS(O)2NR1b- -NR1b-, -NR1 aC(O)NR1b- -NR1aC(O)S-, -NR1 aC(NR1d)NR1b- -NR1 aC(S)NR1b-, -NR1aS(O)NR1b-, -NR1aS(O)2NR1b-, -S-, -S(O)-, -S(O)2-, -S(O)NR1b-, or-S(O)2NR1b-; where each R1a, Rlb, and R1dis as defined herein; and z is an integer of 0, 1, 2, 3, 4, or 5.

[0232] In certain embodiments, in any one of the formulae described herein, each Rkis independently Ci-6 alkylene, C2-6 alkynylene, C3-10 cycloalkylene, C6-14 arylene, heteroarylene, or heterocyclylene, each optionally substituted with one or more substituents Q; each Zkis independently a bond, -C(O)-, -C(O)NR1b-, -C(NR1 a)NR1b-, -O-, -OC(O)NR1b-, -NR1 b- -NR1 aC(O)NR1b-, -NR1 aC(NR1 d)NR1b-, -NR1 aS(O)NR1b-, -NR1 aS(O)2NR1b-, -S-, -S(O)- -S(O)2-, -S(O)NR1b-, or -S(O)2NR1b-; and z is an integer of 0, 1, 2, or 3; where each R1a, Rlb, and R1dis as defined herein.

[0233] In certain embodiments, in any one of the formulae described herein, each Rkis independently C1-6 alkylene, C2-6 alkynylene, C3-10 cycloalkylene, C6-14 arylene, heteroarylene, or heterocyclylene, each optionally substituted with one or more substituents Q; each Zkis independently a bond, -C(O)-, -C(O)NR1b-, -O-, -OC(O)NR1 b-, -NR1 b-, -NR1aC(O)NR1b- -NR1 aC(NR1 d)NR1b-, or -S-; and z is an integer of 0, 1, 2, or 3; where each R1a, R1b, and R1dis as defined herein.

[0234] In certain embodiments, in any one of the formulae described herein, each Rkis independently methanediyl, ethanediyl, propanediyl, butanediyl, pentanediyl, hexanediyl, ethynediyl, cyclobutanediyl, cyclopentanediyl, cyclohexanediyl, phendiyl, pyrazoldiyl, imidazoldiyl, tetrazoldiyl, pyrimidindiyl, azetidindiyl, 1,3-dioxandiyl, piperazindiyl, piperidindiyl, or 3,9-diazaspiro[5.5]undecanediyl, each optionally substituted with one or more substituents Q; each Zkis independently a bond, -C(O)-, -C(O)O-, -C(O)NH-, -OC(O)NH- -O-, -NH-, -N(CH3)-, -NHC(O)NH-, or -S-; and z is an integer of 0, 1, 2, or 3.

[0235] In certain embodiments, in any one of the formulae described herein, each Rkis independently methanediyl, ethane- 1,2-diyl, propane- 1,3 -diyl, butane- 1,4-diyl, pentane- 1,5-diyl, hexane-l,6-diyl, ethyne- 1,2-diyl, cyclobutane- 1,1 -diyl, cyclobutane-l,3-diyl, cyclopentane- 1,3- diyl, cyclohexane-l,3-diyl, cyclohexane- 1,4-diyl, phen-l,3-diyl, phen- 1,4-diyl, pyrazol- 1,3 -diyl, pyrazol- 1,4-diyl, imidazol-l,4-diyl, 1,2, 3 -triazol- 1,4-diyl, pyrimidin-2,4-diyl, pyrimidin-2,5-diyl, pyrazolidin-l,3-diyl, pyrazolidin- 1,4-diyl, azetidin-l,3-diyl, l,3-dioxan-2,5-diyl, piperazin- 1,4- diyl, piperi din- 1,3 -diyl, or piperi din- 1,4-diyl, each optionally substituted with one or more, inone embodiment, one, two, three, or four, substituents Q; each Zkis independently a bond, -C(O)-, -C(O)O- -C(0)NH-, -OC(O)NH-, -O-, -NH-, -N(CH3)-, -NHC(0)NH- or -S-; and z is an integer of 0, 1, 2, or 3.

[0236] In certain embodiments, in any one of the formulae described herein, L is:wherein each Akis independently a bond, -O-, -NH-, or -N(CHs)-.

[0237] In certain embodiments, in any one of the formulae described herein, L is:wherein each Akis independently a bond, -O-, -NH-, or -N(CHs)-.

[0238] In certain embodiments, in any one of the formulae described herein, L is:wherein each Akis independently a bond, -O-, -NH-, or -N(CH3)-.

[0239] In certain embodiments, in any one of the formulae described herein, L is:wherein each Akis independently a bond, -O-, -NH-, or -N(CH?)-; and wherein each amino (NH) group is optionally substituted with methyl.

[0240] In certain embodiments, in any one of the formulae described herein, L is:wherein each Akis independently a bond, -O-, -NH-, or -N(CHs)-; and wherein each amino(NH) group is optionally substituted with methyl.

[0241] In certain embodiments, in any one of the formulae described herein, L is:wherein each Akis independently a bond, -O-, -NH-, or -N(CHa)-; and wherein each amino group (NH) is optionally substituted with methyl.

[0242] In certain embodiments, in any one of the formulae described herein, L is:wherein each Akis independently a bond, -O-, -NH- or -N(CHs)-.

[0243] In certain embodiments, in any one of the formulae described herein, L is:wherein each Akis independently a bond, -O-, -NH-, or -N(CHs)-; and wherein each amino group (NH) is optionally substituted with methyl.

[0244] In certain embodiments, in any one of the formulae described herein, L is:wherein each Akis independently a bond, -O-, -NH-, or -N(CH3)-; and wherein each amino group (NH) is optionally substituted with methyl.

[0245] In certain embodiments, in any one of the formulae described herein, L is:wherein each Akis independently a bond, -O-, -NH-, or -N(CH3)-.

[0246] In certain embodiments, in any one of the formulae described herein, L is:wherein each Akis independently a bond, -O-, -NH-, or -N(CHa)-; and wherein each amino group (NH) is optionally substituted with methyl.

[0247] In certain embodiments, in any one of the formulae described herein, L is:wherein each Akis independently a bond, -O-, -NH-, or -N(CHs)-.

[0248] In certain embodiments, in any one of the formulae described herein, U5is -C(R5)=, wherein R5is as defined herein. In certain embodiments, in any one of the formulae described herein, U5is -C(R5)=, wherein R5is (i) hydrogen or halo; or (ii) Ci-6 alkyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, U5is C(R5)=, wherein R5is hydrogen, fluoro, chloro, or methyl. In certain embodiments, in any one of the formulae described herein, U5is -N=.

[0249] In certain embodiments, in any one of the formulae described herein, V5is -C(R3)=, wherein R?is as defined herein. In certain embodiments, in any one of the formulae described herein, V5is -C(R5)=, wherein R5is (i) hydrogen or halo; or (ii) Ci-6 alkyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, V5is -C(R5)=, wherein R5is hydrogen, fluoro, chloro, or methyl. In certainembodiments, in any one of the formulae described herein, V5is -N=.

[0250] In certain embodiments, in any one of the formulae described herein, X5is -C(R5)=, wherein R5is as defined herein. In certain embodiments, in any one of the formulae described herein, X5is -C(R5)=, wherein R5is (i) hydrogen or halo; or (ii) Ci-6 alkyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, X5is -C(R5)=, wherein R5is hydrogen, fluoro, chloro, or methyl. In certain embodiments, in any one of the formulae described herein, X5is -N=.

[0251] In certain embodiments, in any one of the formulae described herein, Z5is -C(R5)=, wherein R3is as defined herein. In certain embodiments, in any one of the formulae described herein, Z5is -C(R5)=, wherein R5is (i) hydrogen or halo; or (ii) Ci-6 alkyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, Z5is -C(R5)=, wherein R5is hydrogen, fluoro, chloro, or methyl. In certain embodiments, in any one of the formulae described herein, Z5is -N=.

[0252] In one embodiment, in any one of the formulae described herein, U5, V5, X5, and Z5are each independently -C(R5)=, wherein R5is as defined herein. In another embodiment, in any one of the formulae described herein, U5is -N=; and V5, X5, and Z5are each independently -C(R5)=, wherein R5is as defined herein. In yet another embodiment, in any one of the formulae described herein, U5, X5, and Z3are each independently -C(R5)=, wherein R5is as defined herein; and V5is -N=. In yet another embodiment, in any one of the formulae described herein, U5, V5, and Z3are each independently -C(R3)=, wherein R3is as defined herein; and X5is -N=. In still another embodiment, in any one of the formulae described herein, U5, V5, and X5are each independently -C(R3)=, wherein R5is as defined herein; and Z5is -N=.

[0253] In one embodiment, in any one of the formulae described herein, U5, V5, X5, and Z3are each independently -C(R5)=, wherein each R5is independently (i) hydrogen or halo; or (ii) Ci-6 alkyl, optionally substituted with one or more substituents Q. In another embodiment, in any one of the formulae described herein, U5is -N=; and V5, X5, and Z5are each independently -C(R5)=, wherein each R5is independently (i) hydrogen or halo; or (ii) Ci-6 alkyl, optionally substituted with one or more substituents Q. In yet another embodiment, in any one of the formulae described herein, U3, X5, and Z5are each independently -C(R5)=, wherein each R3isindependently (i) hydrogen or halo; or (ii) Ci-6 alkyl, optionally substituted with one or more substituents Q; and V5is -N=. In yet another embodiment, in any one of the formulae described herein, L , V5, and Z5are each independently -C(R5)=, wherein each R5is independently (i) hydrogen or halo; or (ii) Ci-6 alkyl, optionally substituted with one or more substituents Q. In still another embodiment, in any one of the formulae described herein, U5, V5, and X5are each independently -C(R3)=, wherein each R3is independently (i) hydrogen or halo; or (ii) Ci-6 alkyl, optionally substituted with one or more substituents Q; and Z5is -N=.

[0254] In one embodiment, in any one of the formulae described herein, U5, V5, X5, and Z5are each independently -C(R5)=, wherein each R5is independently hydrogen, fluoro, chloro, or methyl. In another embodiment, in any one of the formulae described herein, U5is -N=; and V5, X5, and Z3are each independently -C(R3)=, wherein each R5is independently hydrogen, fluoro, chloro, or methyl. In yet another embodiment, in any one of the formulae described herein, U3, X5, and Z5are each independently -C(R5)=, wherein each R5is independently hydrogen, fluoro, chloro, or methyl; and V5is -N=. In yet another embodiment, in any one of the formulae described herein, U5, V5, and Z5are each independently -C(R5)=, wherein each R5is independently hydrogen, fluoro, chloro, or methyl. In still another embodiment, in any one of the formulae described herein, U5, V3, and X5are each independently -C(R5)=, wherein each R3is independently hydrogen, fluoro, chloro, or methyl; and Z5is -N=.

[0255] In certain embodiments, in any one of the formulae described herein, U6is -C(Rb)2-, wherein each R6bis as defined herein. In certain embodiments, in any one of the formulae described herein, U6is -C(H)(R6b)-, wherein R6bis as defined herein. In certain embodiments, in any one of the formulae described herein, U6is -C(H2)-. In certain embodiments, in any one of the formulae described herein, U6is -O-.

[0256] In certain embodiments, in any one of the formulae described herein, Xeis C(Re1), wherein Re1is as defined herein. In certain embodiments, in any one of the formulae described herein, Xeis N.

[0257] In certain embodiments, in any one of the formulae described herein, Z is -Chhin certain embodiments, in any one of the formulae described herein, Z is -C(O)-.

[0258] In certain embodiments, in any one of the formulae described herein, a is an integer of 0. In certain embodiments, in any one of the formulae described herein, a is an integer of 1. In certain embodiments, in any one of the formulae described herein, a is an integer of 2.

[0259] In certain embodiments, in any one of the formulae described herein, b is an integer of 0. In certain embodiments, in any one of the formulae described herein, b is an integer of 1. In certain embodiments, in any one of the formulae described herein, b is an integer of 2. In certain embodiments, in any one of the formulae described herein, b is an integer of 3. In certain embodiments, in any one of the formulae described herein, b is an integer of 4. In certain embodiments, in any one of the formulae described herein, b is an integer of 5. In certain embodiments, in any one of the formulae described herein, b is an integer of 6.

[0260] In certain embodiments, in any one of the formulae described herein, m is an integer of 0. In certain embodiments, in any one of the formulae described herein, m is an integer of 1. In certain embodiments, in any one of the formulae described herein, m is an integer of 2.

[0261] In certain embodiments, in any one of the formulae described herein, n is an integer of 0. In certain embodiments, in any one of the formulae described herein, n is an integer of 1 . In certain embodiments, in any one of the formulae described herein, n is an integer of 2. In certain embodiments, in any one of the formulae described herein, n is an integer of 3.

[0262] In certain embodiments, in any one of the formulae described herein, n is an integer of 1; and Re3is (i) halo; or (ii) Ci-6 alkyl or C3-10 cycloalkyl, each optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, n is an integer of 1; and Re3is (i) halo; or (ii) C1-6 alkyl or monocyclic C3-10 cycloalkyl, each optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, n is an integer of 1; and Re3is fluoro, chloro, methyl, difluoromethyl, trifluorom ethyl, or cyclopropyl. In certain embodiments, in any one of the formulae described herein, n is an integer of 2; and each Re3is independently (i) halo; or (ii) C1-6 alkyl or C3-10 cycloalkyl, each optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, n is an integer of 2; and each Re3is independently (i) halo; or (ii) C1-6 alkyl or monocyclic C3-10 cycloalkyl, each optionallysubstituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, n is an integer of 2; and each Re3is independently fluoro, chloro, methyl, difluoromethyl, trifluoromethyl, or cyclopropyl.

[0263] All combinations of the embodiments provided herein for the groups in the formulae described herein, including, e.g., R1, R3, R4, R5, R6, R2a, R2b, R3a, R3b, R3c, R3d, R3e, R4a, R4b, R6a, R6b, Re, Re1, Re2, Re3, Re4, Re5, A, Ae, L, U, V, X, Xe, Z, U5, V5, X5, Z5, U6, a, b, m, and n, are within the scope of this disclosure.

[0264] In one embodiment, provided herein is a compound of:3-(5-(1-(5-(4-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methyl- pyrido[3,4-d ]pyrimidin-6-yl)-2-fluorobenzyl)piperidin-4-yl)-l-oxoisoindolin-2-yl)piperidine-2,6- dione A001;3-(5-(1-(3-(4-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methyl- pyrido[3,4-d ]pyrimidin-6-yl)benzyl)piperidin-4-yl)-l -ox oisoindolin-2-yl)piperidine-2, 6-dione A002;3 -(5 -( 1 -(3 -(4-(((R)- 1 -(3 -(difluorom ethyl )-2-methylphenyl)ethyl)amino)-2- methylpyrido[3,4-d]pyrimidin-6-yl)benzyl)piperidin-4-yl)-l-oxoisoindolin-2-yl)piperidine-2,6- dione A003;3-(5-(1-(5-(4-(((R)-1-(3-(difluoromethyl)-2-methylphenyl)ethyl)amino)-2- methylpyrido[3,4-d]pyrimidin-6-yl)-2-fluorobenzyl)piperidin-4-yl)-l-oxoisoindolin-2-yl)- piperidine-2, 6-dione A004; or3 -(5 -( 1 -((5 -(4-(((R)- 1 -(3 -(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2- methylpyrido[3,4-d]pyrimidin-6-yl)pyri din-3 -yl)methyl)piperidin-4-yl)-6-fluoro- 1-oxo- isoindolin-2-yl)piperidine-2, 6-dione A005; or an enantiomer, a mixture of enantiomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0265] In another embodiment, provided herein is (R)-3-(6-(1-(3-(4-(((R)-1-(3-(difluoro- methyl)-2-fluorophenyl)ethyl)amino)-2-methylpyrido[3,4-d ]pyrimidin-6-yl)benzyl)piperidin-4- yl)-5-fluoro-l-methyl-1H-indazol-3-yl)-3-methylpiperidine-2, 6-dione A051; or an enantiomer, amixture of enantiomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0266] In yet another embodiment, provided herein is a compound of(R)- 1 -(6-( 1 -(5 -( 1 -(( 1 -(3 -(difluoromethyl)-2-fluorophenyl)ethyl)amino)-4-methy 1- pyrido[3,4-d]pyridazin-7-yl)-2-fluorobenzyl)piperidin-4-yl)-l-methyl-l / 7-indazol-3-yl)dihydro- pyrimidine-2, 4(1H,3H)-dione A061; (R)-1-(6-(1-(5-(4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methyl- pyrido[3,4-d]pyrimidin-6-yl)-2-fluorophenethyl)piperidin-4-yl)-l -methyl- l / 7-indazol-3-yl)- dihydropyrimidine-2,4((1H,3H)-)dione A062;(R)- 1 -(6-( 1 -(5-(4-(( 1 -(3 -(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methyl- pyrido[3,4-d]pyrimidin-6-yl)-2-fluorobenzyl)piperidin-4-yl)-5-fluoro-l -methyl- 1 / 7-indazol -3- yl)dihydropyrimidine-2, 4(1H,3H)-dione A063; or (R)-1-(6-(1-(3-(4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methyl- pyrido[3,4-d]pyrimidin-6-yl)benzyl)piperidin-4-yl)-5-fluoro-l-m ethyl- 1H-indazol-3-yl)dihydro- pyrimidine-2, 4(1H,3H)-dione A064; or an enantiomer, a mixture of enantiomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0267] In yet another embodiment, provided herein is a compound of: (R)-3-(4-(1-(5-(4-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2- methylpyrido[3,4-d]pyrimidin-6-yl)-2-fluorobenzyl)piperidin-4-yl)phenyl)-3-methylpiperidine- 2, 6-dione A101;3 -(4-( 1 -( 5 -(4-(((R)- 1 -(3 -(difluorom ethyl )-2-fluorophenyl )ethyl)amino)-2-methyl- pyrido[3,4-d]pyrimidin-6-yl)-2-fluorobenzyl)piperidin-4-yl)-3-methylphenyl)piperidine-2,6- dione A102; (R)-3-(4-(1-(5-(4-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2- methylpyrido[3,4-d]pyrimidin-6-yl)-2-fluorobenzyl)piperidin-4-yl)-3-methylphenyl)-3 -methyl- piperidine-2, 6-dione A103;(R)-3 -(4-( 1 -(3 -(4-(((R)- 1 -(3 -(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2- methylpyrido[3,4-d]pyrimidin-6-yl)benzyl)piperidin-4-yl)-3-methylphenyl)-3 -methylpiperidine-2,6-dione A104;(R)-3 -(4-( 1 -(5 -(4-(((R)- 1 -(3 -(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2- methylpyrido[3,4-d]pyrimidin-6-yl)-2-fluorobenzyl)piperidin-4-yl)-3-(trifluoromethyl)phenyl)- 3-methylpiperidine-2, 6-dione A105;(R)-3 -(4-( 1 -(3 -(4-(((R)- 1 -(3 -(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2- methylpyrido[3,4-d]pyrimidin-6-yl)benzyl)piperidin-4-yl)-3-(trifluoromethyl)phenyl)-3-methyl- piperidine-2, 6-dione A106;(R)-3 -(4-( 1 -(3 -(4-(((R)- 1 -(3 -(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2- methylpyrido[3,4-d ]pyrimidin-6-yl)benzyl)piperidin-4-yl)-3-fluoro-5-methylphenyl)-3-methyl- piperidine-2, 6-dione A107;(R)-3 -(4-( 1 -(5 -(4-(((R)- 1 -(3 -(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2- methylpyrido[3,4-< ]pyrimidin-6-yl)-2-fluorobenzyl)piperidin-4-yl)-3-fluoro-5-methylphenyl)-3- methylpiperidine-2, 6-dione A108;(R)-3 -(3 -cyclopropyl-4-(l -(5-(4-(((R)- 1 -(3 -(difluoromethyl)-2-fluorophenyl)- ethyl)amino)-2-methylpyrido[3,4-d]pyrimidin-6-yl)-2-fluorobenzyl)piperidin-4-yl)phenyl)-3- methylpiperidine-2, 6-dione A109; (R)-3-(4-(1-(5-(4-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2- methylpyrido[3,4-fi?]pyrimidin-6-yl)-2-fluorobenzyl)piperidin-4-yl)-3-fluorophenyl)-3 -methyl- piperidine-2, 6-dione A110;(R)-3 -(3 -cy clopropy l-4-( 1 -(3 -(4-(((R)- 1 -(3 -(diflu oromethy l)-2-fluoropheny 1)- ethyl)amino)-2-methylpyrido[3,4-d]pyrimidin-6-yl)benzyl)piperidin-4-yl)phenyl)-3-methyl- piperidine-2, 6-dione A1li;3-(4-(1-(3-(4-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methyl- pyrido[3,4-d ]pyrimidin-6-yl)benzyl)piperidin-4-yl)-3-methylphenyl)piperidine-2, 6-dione A112; (R)-3-(3-chloro-4-(1-(5-(4-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)- amino)-2-methylpyrido[3,4-d ]pyrimidin-6-yl)-2-fluorobenzyl)piperidin-4-yl)phenyl)-3-methyl- piperidine-2, 6-dione A113;(R)-3 -(3 -chloro-4-( 1 -(3 -(4-(((R)- 1 -(3 -(difluoromethy l)-2-fluoropheny 1 )ethy 1 ) - amino)-2-methylpyrido[3,4-d ]pyrimidin-6-yl)benzyl)piperidin-4-yl)phenyl)-3-methylpiperidine- 2,6-dione A114; R)-3 -(4-( 1 -((51 -(3 -(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methylpyrido[3,4-d]pyrimidin-6-yl)-l -methyl -2-oxo-l,2-dihydropyridin-3-yl)methyl)piperidin- 4-yl)phenyl)-3 -methylpiperidine-2, 6-dione A115;(R)-3 -(3 -(difluoromethyl)-4-( 1 -(3 -(4-( ((R)- 1 -(3 -(difluoromethyl )-2-fluoro- phenyl)ethyl)amino)-2-methylpyrido[3,4-d]pyrimidin-6-yl)benzyl)piperidin-4-yl)phenyl)-3- methylpiperidine-2, 6-dione A116; (R)-3-(3-(difluoromethyl)-4-(1-(5-(4-(((R)-1-(3-(difluoromethyl)-2-fluoro- phenyl)ethyl)amino)-2-methylpyrido[3,4-d]pyrimidin-6-yl)-2-fluorobenzyl)piperidin-4-yl)- phenyl)-3 -methylpiperidine-2, 6-dione A117; (R) - 3 -(4 - ( 1 - (3 -(4-(((R)- 1 -(3 -(difluoromethyl)-2-fluoropheny l)ethy l)amino)-2- methylpyrido[3,4-d]pyrimidin-6-yl)benzyl)piperidin-4-yl)-3,5-difluorophenyl)-3-methyl- piperidine-2, 6-dione A118;3-(4-(1-(3-(4-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methyl- pyrido[3,4-d]pyrimidin-6-yl)benzyl)piperidin-4-yl)-3-fluoro-5-methylphenyl)piperidine-2,6- di one A119;3-(4-(1-(5-(4-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methyl- pyrido[3,4-d]pyrimidin-6-yl)-2-fluorobenzyl)piperidin-4-yl)-3-fluoro-5-methylphenyl)- piperidine-2, 6-dione A120;(R)-3 -(4-( 1 -(3 -(4-(((R)- 1 -(3 -(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2- methylpyrido[3,4-d]pyrimidin-6-yl)benzyl)piperidin-4-yl)-2,3-difluorophenyl)-3-methyl- piperidine-2, 6-dione A121;(R)-3 -(4-( 1 -(5 -(4-(((R)- 1 -(3 -(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2- methylpyrido[3,4-d]pyrimidin-6-yl)-2-fluorobenzyl)piperidin-4-yl)-3,5-difluorophenyl)-3- methyl-piperidine-2, 6-dione A122;(R)-3 -(4-( 1 -(((S)- 1 -(4-(((R)- 1 -(3 -(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2- methylpyrido[3,4-d]pyrimidin-6-yl)-3-fluoropiperidin-3-yl)methyl)piperidin-4-yl)-3-methyl- phenyl)-3-methylpiperidine-2, 6-dione A123; or(R)-3 -(4-( 1 -(3 -(4-(((R)- 1 -(3 -(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2- methylpyrido[3,4-t / ]pyrimidin-6-yl)benzyl)piperidin-4-yl)-2-fluoro-3-methylphenyl)-3-methyl- piperidine-2, 6-dione A124; or an enantiomer, a mixture of enantiomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrugthereof.

[0268] In yet another embodiment, provided herein is a compound of:3 -(5-(4-(3 -(1 -(((R)- 1 -(3 -(difluoromethyl)-2-fluorophenyl)ethyl)amino)-4-methyl- pyrido[3,4-d ]pyridazin-7-yl)benzyl)piperazin-l-yl)-l-oxoisoindolin-2-yl)piperidine-2, 6-dione B001;3 -(6-fluoro-5 -( 1 -(3 -(4-m ethyl- 1 -(((R)- 1 -(2-methyl-3 -(trifluoromethyl)phenyl)- ethyl)amino)pyrido[3,4--d]pyridazin-7-yl)benzyl)piperidin-4-yl)-l-oxoisoindolin-2-yl)piperidine- 2,6-dione B002;3-(5-(4-(3-(1-(((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-4-methyl- pyrido[3,4-d ]pyridazin-7-yl)benzyl)piperazin-l-yl)-l-oxoisoindolin-2-yl)piperidine-2, 6-dione B003;3 -(5-( 1 -(5-(l -(((R)- 1 -(3 -(difluoromethyl)-2-fluorophenyl)ethyl)amino)-4-methyl- pyrido[3,4-d]pyridazin-7-yl)-2-fluorobenzyl)piperidin-4-yl)-6-fluoro-l-oxoisoindolin-2-yl)- piperidine-2, 6-dione B004;3-(5-(1-(5-(1-(((R)-1-(3-(difluoromethyl)-2-methylphenyl)ethyl)amino)-4- methylpyrido[3,4- ]pyridazin-7-yl)-2-fluorobenzyl)piperidin-4-yl)-l-oxoisoindolin-2-yl)- piperidine-2, 6-dione B005;3-(5-(1-(5-(l -(((R)- 1 -(3 -(difluoromethyl)-2-methylphenyl)ethyl)amino)-4- methylpyri do[3,4-d ]pyridazin-7-yl)-2 -fluorobenzyl )piperidin-4-yl)-6-fluoro-l-oxoisoindolin-2- yl)piperidine-2, 6-dione B006; or3-(5-(1-(3-(l -(((R)- 1 -(3 -(difluoromethyl)-2-fluorophenyl)ethyl)amino)-4-methyl- pyrido[3,4--d]pyridazin-7-yl)benzyl)piperidin-4-yl)-l-oxoisoindolin-2-yl)piperidine-2, 6-dione B007; or an enantiomer, a mixture of enantiomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0269] In yet another embodiment, provided herein is a compound of:3 -( 1 -methyl-6-(4-(3 -(4-methyl- 1 -(((R)- 1 -(2-methyl-3 -(trifluoromethyl)phenyl)- ethyl)amino)pyrido[3,4-d ]pyridazin-7-yl)benzyl)piperazin-l-yl)-17 / -indazol-3-yl)piperidine-2,6- dione B051;3-((17?)-1-((7-(4-(3-((4-(3-(2,6-dioxopiperidin-3-yl)-l-methyl-1H-indazol-6-yl)- piperidin-l-yl)methyl)phenyl)piperazin-l-yl)-4-methylpyrido[3,4-d]pyridazin-l-yl)amino)ethyl)- 2-methylbenzonitrile B052;3 -(( 17?)- 1 -((7-(3 -((4-(3 -(2,6-dioxopiperidin-3 -yl)- 1 -methyl- 1H-indazol-6-yl)- piperi din- l-yl)methyl)phenyl)-4-methylpyrido[3,4-d ]pyridazin-l-yl)amino)ethyl)-2 -methylbenzonitrile B053;3 -( 1 -methyl-7 -( 1 -(3 -(4-methyl- 1 -(((R)- 1 -(2-methyl-3 -(trifluoromethyl)phenyl)- ethyl)amino)pyrido[3,4--d]pyridazin-7-yl)benzyl)piperidin-4-yl)-1H-indazol-3-yl)piperidine-2,6- dione B054;3-(6-(1-(3-(l -(((R)- 1 -(3 -(difluoromethyl)-2-fluorophenyl)ethyl)amino)-4-methyl- pyrido[3,4-d]pyridazin-7-yl)benzyl)piperidin-4-yl)-l-methyl-1H-indazol-3-yl)piperidine-2,6- dione B055;3 -((17?)- 1 -((7-(3 -((4-(3 -(2,6-dioxopiperidin-3 -yl)- 1 -methyl- 1H-indazol-7-yl)- piperidin-l-yl)methyl)phenyl)-4-methylpyrido[3,4-d]pyridazin-l-yl)amino)ethyl)-2-methyl- benzonitrile B056;3-(7-(1-(5-(l -(((R)- 1 -(3 -(difluoromethy l)-2-fluoropheny l)ethyl)amino)-4-methy 1- pyrido[3,4-d]pyridazin-7-yl)-2-fluorobenzyl)piperidin-4-yl)-l-methyl-17 / -indazol-3-yl)- piperidine-2, 6-dione B057; or (R) - 3 -(6 - ( 1 - ( 5 -( 1 -(((R)- 1 -(3 -(difluoromethyl)-2-fluorophenyl)ethyl)amino)-4- methylpyrido[3,4-d ]pyridazin-7-yl)-2-fluorobenzyl)piperidin-4-yl)-l-methyl-1H-indazol-3-yl)-3- methylpiperidine-2, 6-dione B058; or an enantiomer, a mixture of enantiomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0270] In yet another embodiment, provided her...

Claims

What is claimed is:

1. A compound of Formula (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; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein:A is C3-10 cycloalkylene, C6-14 arylene, heteroarylene, or heterocyclylene;L is C1-6 alkylene, C7-15 aralkylene, or a linker;U and V are each independently -C(R4a)= or -N=;X is -N= or -C(R4b)=;R1is hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl;R3is C3-10 cycloalkyl, C6-14 aryl, heteroaryl, or heterocyclyl; each R4is independently (i) deuterium, cyano, halo, or nitro; (ii) C1-6 alkyl, C1-6 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) -C(O)R1a, -C(O)OR1a, -C(O)NR1bR1c, -C(O)SR1a, -C(NR1a)NR1 bR1c, -C(S)R1a, -C(S)OR1a, -C(S)NR1bR1c, -OR1a, -OC(O)R1a, -OC(O)OR1a, -OC(O)NR1bR1c, -OC(O)SR1a, -OC(NR1 a)NR1bR1c, -OC(S)R1a, -OC(S)OR1a, -OC(S)NR1bR1c, -OS(O)R1a, -OS(O)2R1a, -OS(O)NR1bR1c, -OS(O)2NR1bR1c, -NR1bR1c, -NR1 aC(O)R1d, -NR1aC(O)OR1d, -NR1 aC(O)NR1bR1c, -NR1 aC(O)SR1 d, -NR1 aC(NR1d)NR1bR1c, -NR1aC(S)R1d, -NR1 aC(S)OR1d, -NR1aC(S)NR1bR1c, -NR1aS(O)R1d, -NR1aS(O)2R1d, -NR1aS(O)NR1bR1c, -NR1aS(O)2NR1bR1c, -SR1a, -S(O)R1a, -S(O)2R1a, -S(O)NR1bR1c, or -S(O)2NR1bR1c;R2aand R2bare each independently hydrogen, deuterium, halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, heteroaryl, or heterocyclyl; each R4aand R4bis independently hydrogen or R4;Reis an E3 ubiquitin ligase binding moiety; each R1a, Rlb, R1c, and R1dis independently hydrogen, deuterium, C1-6 alkyl, C1-6heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl; and a is an integer of 0, 1, or 2; wherein each alkyl, alkylene, heteroalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylene, aryl, arylene, aralkyl, aralkylene, heteroaryl, heteroarylene, heterocyclyl, and heterocyclylene is optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Q, wherein each Q is independently selected from: (a) deuterium, cyano, halo, imino, nitro, and oxo; (b) C1-6 alkyl, C1-6 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, and heterocyclyl, each of which is further optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Qa; and (c) -C(O)Ra, -C(O)ORa, -C(O)NRbRc, -C(O)SRa, -C(NRa)NRbRc, -C(S)Ra, -C(S)ORa, -C(S)NRbRc, -ORa, -OC(O)Ra, -OC(O)ORa, -OC(O)NRbRc, -OC(O)SRa, -OC(NRa)NRbRc, -OC(S)Ra, -OC(S)ORa, -OC(S)NRbRc, -OP(O)(ORb)ORc, -OS(O)Ra, -OS(O)2Ra, -OS(O)NRbRc, -OS(O)2NRbRc, -NRbRc, -NRaC(O)Rd, -NRaC(O)ORd, -NRaC(O)NRbRc, -NRaC(O)SRd, -NRaC(NRd)NRbRc, -NRaC(S)Rd, -NRaC(S)ORd, -NRaC(S)NRbRc, -NRaS(O)Rd, -NRaS(O)2Rd, -NRaS(O)NRbRe, -NRaS(O)2NRbRc, -SRa, -S(O)Ra, -S(O)2Ra, -S(O)NRbRc, and -S(O)2NRbRc, wherein each Ra, Rb, Rc, and Rdis independently (i) hydrogen or deuterium; (ii) C1-6 alkyl, C1-6 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Qa; or (iii) Rband Rctogether with the N atom to which they are attached form heterocyclyl, optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Qa; wherein each Qais independently selected from: (a) deuterium, cyano, halo, nitro, imino, and oxo; (b) C1-6 alkyl, C1-6 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, and heterocyclyl; and (c) -C(O)Re, -C(O)ORe, -C(O)NR‘Rg, -C(O)SRe, -C(NRe)NRfRg, -C(S)Re, -C(S)ORe, -C(S)NRfRg, -ORe, -OC(O)Re, -OC(O)ORe, -OC(O)NRfRg, -OC(O)SRe, -OC(NRe)NRfRg, -OC(S)Re, -OC(S)ORe, -OC(S)NRfRg, -OP(O)(ORf)ORg, -OS(O)Re, -OS(O)2Re, -OS(O)NRfRg, -OS(O)2NRfRg, -NRfRg, NReC(O)Rh, NReC(O)ORf, NReC(O)NRfRg, NReC(O)SRf, NReC(NRh)NRfRg, -NReC(S)Rh, -NReC(S)ORf, -NReC(S)NRfRg, -NReS(O)Rb, -NReS(O)2Rb, -NReS(O)NRfR8, -NReS(O)2NRfRg, -SRe, -S(O)Re, -S(O)2Re, -S(O)NRfRg, and -S(O)2NRfRg; wherein each Re,R1, Rg, and Rhis independently (i) hydrogen or deuterium; (ii) Ci-6 alkyl, Ci-6 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) Rfand Rgtogether with the N atom to which they are attached form heterocyclyl.

2. The compound of claim 1, wherein A is C6-14 arylene, heteroarylene, or heterocyclylene, each optionally substituted with one or more substituents Q.

3. The compound of claim 1 or 2, wherein A is phendiyl, monocyclic heteroarylene, or monocyclic heterocyclylene, each optionally substituted with one or more substituents Q.

4. The compound of any one of claims 1 to 3, wherein A is phendiyl, furandiyl, thiendiyl, pyridindiyl, 1,2-dihydropyridindiyl, piperidindiyl, morpholindiyl, or piperazindiyl, each optionally substituted with one or more substituents Q.

5. The compound of any one of claims 1 to 4, wherein A is phen-l,3-diyl, furan-2,4- diyl, thien-2,4-diyl, pyridin-2,4-diyl, pyridin-2,6-diyl, pyridin-3,5-diyl, l,2-dihydropyridin-3,5- diyl, l,2-dihydropyridin-l,5-diyl, morpholin-2,4-diyl, piperazin- 1,4-diyl, or piperidin- 1 ,3-diyl, each optionally substituted with one or more substituents Q.

6. The compound of any one of claims 1 to 5, wherein A is phen-l,3-diyl, 2- fluorophen- 1,3 -diyl, 4-fluorophen- 1,3 -diyl, 5 -fluorophen- 1,3 -diyl, 2-chlorophen-l,3-diyl, 4- chlorophen-l,3-diyl, 5-chlorophen-l,3-diyl, 2-methylphen-l,3-diyl, 4-methylphen-l,3-diyl, 5- m ethylphen- 1,3 -diyl, furan-2,4-diyl, thien-2,4-diyl, pyridin-2,4-diyl, pyridin-2,6-diyl, pyridin- 3,5-diyl, l-methyl-2-oxo-l,2-dihydropyridin-3,5-diyl, 2-oxo-l,2-dihydropyridin-l,5-diyl, 3- fluoropiperidin-l,3-diyl, morpholin-2,4-diyl, or piperazin- 1,4-diyl.

7. The compound of any one of claims 1 to 6, wherein R3is C6-14 aryl or heteroaryl, each optionally substituted with one or more substituents Q.

8. The compound of any one of claims 1 to 7, wherein R3is phenyl or monocyclic heteroaryl, each optionally substituted with one or more substituents Q.

9. The compound of any one of claims 1 to 8, wherein R2bis hydrogen.

10. The compound of any one of claims 1 to 9, wherein X is -C(R4b)=.1 1 . The compound of any one of claims 1 to 9, wherein X is -N=.

12. The compound of claim 10, wherein U is -C(R4a)=; and V is -N=.

13. The compound of claim 10, wherein U is -N=; and V is -C(R4a)=.

14. The compound of any one of claims 1 to 3, having the structure of Formula (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; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein:U5, V5, X5, and Z5are each independently -C(R5)= or -N=; and each R3a, R3b, R3c, R3d, R3e, and R5is each independently (i) hydrogen, deuterium, cyano, halo, or nitro; (ii) Ci-6 alkyl, Ci-6 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl, each optionally substituted with one or more substituents Q; or (iii) -C(O)R1a, -C(O)OR1a, -C(O)NR1bR1c, -C(O)SR1a, -C(NR1 a)NR1bR1c,C(S)R1a, C(S)OR1a, C(S)NR1bR1c, OR1a, OC(O)R1a, OC(O)OR1a, OC(O)NR1bR1c, -OC(O)SR1a, -OC(NR1 a)NR1bR1c, -OC(S)R1a, -OC(S)OR1a, -OC(S)NR1bR1c, -OS(O)R1a, -OS(O)2R1a, -OS(O)NR1bR1c, -OS(O)2NR1bR1c, -NR1bR1c, -NR1 aC(O)R1d, -NR1aC(O)OR1d, -NR1 aC(O)NR1bR1c, -NR1 aC(O)SR1d, -NR1 aC(NR1d)NR1bR1c, -NR1aC(S)R1d, -NR1 aC(S)OR1d, -NR1 aC(S)NR1bR1c, -NR1aS(O)R1d, -NR1 aS(O)2R1d, -NR1 aS(O)NR1bR1c, -NR1aS(O)2NR1bR1c, -SR1a, -S(O)R1a, -S(O)2R1a, -S(O)NR1bR1c, or -S(O)2NR1bR1c.

15. The compound of any one of claims 1 to 3, having the structure of Formula (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; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein:U6is -C(R6b)2- or -O-; each R3a, R3b, R3c, R3d, R3e, R6a, and R6bis independently (i) hydrogen, deuterium, cyano, halo, or nitro; (ii) Ci-6 alkyl, Ci-6 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl, each optionally substituted with one or more substituents Q; or (iii) C(O)R1a, C(O)OR1a, C(O)NR1bR1c, C(O)SR1a, C(NR1 a)NR1bR1c, -C(S)R1a, -C(S)OR1a, -C(S)NR1bR1c, -OR1a, -OC(O)R1a, -OC(O)OR1a, -OC(O)NR1bR1c, -OC(O)SR1a, -OC(NR1 a)NR1bR1c, -OC(S)R1a, -OC(S)OR1a, -OC(S)NR1bR1c, -OS(O)R1a, -OS(O)2R1a, -OS(O)NR1bR1c, -OS(O)2NR1bR1c, -NR1bR1c, -NR1 aC(O)R1d, -NR1 aC(O)OR1d, -NR1 aC(O)NR1bR1c, -NR1 aC(O)SR1d, -NR1 aC(NR1d)NR1bR1c, -NR1aC(S)R1d, -NR1 aC(S)OR1d, -NR1 aC(S)NR1bR1c, -NR1aS(O)R1d, -NR1 aS(O)2R1d, -NR1 aS(O)NR1 bR1c, -NR1aS(O)2NR1bR1c, -SR1a, -S(O)R1a, -S(O)2R1a, -S(O)NR1bR1c, or -S(O)2NR1bR1c; each R6is independently (i) deuterium, cyano, halo, or nitro; (ii) C1-6 alkyl, C1-6 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl, each optionally substituted with one or more substituents Q; or (iii) -C(O)R1a, -C(O)OR1a, -C(O)NR1bR1c, -C(O)SR1a, -C(NR1a)NR1bR1c, -C(S)R1a, -C(S)OR1a, -C(S)NR1bR1c, -OR1a, -OC(O)R1a, -OC(O)OR1a, -OC(O)NR1bR1c, -OC(O)SR1a, -OC(NR1a)NR1bR1c, -OC(S)R1a, -OC(S)OR1a, -OC(S)NR1bR1c, -OS(O)R1a, -OS(O)2R1a, -OS(O)NR1bR1c, -OS(O)2NR1bR1c, -NR1bR1c, -NR1 aC(O)R1d, -NR1aC(O)OR1d, -NR1 aC(O)NR1bR1c, -NR1 aC(O)SR1d, -NR1 aC(NR1d)NR1bR1c, -NR1aC(S)R1d, -NR1 aC(S)OR1d, -NR1aC(S)NR1bR1c, -NR1aS(O)R1d, -NR1aS(O)2R1d, -NR1 aS(O)NR1bR1c, -NR1aS(O)2NR1bR1c, -SR1a, -S(O)R1a, -S(O)2R1a, -S(O)NR1bR1c, or -S(O)2NR1bR1c; andb is an integer of 0, 1, 2, 3, 4, 5, or 6.

16. The compound of any one of claims 1 to 15, wherein U is -C(R4a)=.

17. The compound of any one of claims 1 to 15, wherein U is -N=.

18. The compound of any one of claims 1 to 17, wherein V is -C(R4a)=.

19. The compound of any one of claims 1 to 17, wherein V is -N=.

20. The compound of claim 14, having the structure of Formula (VIIIA):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.

21. The compound of claim 14, having the structure of Formula (VIIIB):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.

22. The compound of claim 15, having the structure of Formula (IXA):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.

23. The compound of claim 15 or 22, having the structure of Formula (XA):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.

24. The compound of claim 15 or 22, having the structure of Formula (XIA):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.

25. The compound of claim 15, having the structure of Formula (IXB):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.

26. The compound of claim 15 or 25, having the structure of Formula (XB):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.

27. The compound of claim 15 or 25, having the structure of Formula (XIB):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.

28. The compound of any one of claims 15 to 19 and 22 to 27, wherein R6ais hydrogen or halo.

29. The compound of any one of claims 15 to 19 and 22 to 28, wherein R6ais hydrogen or fluoro.

30. The compound of any one of claims 15 to 19 and 22 to 29, wherein U6is-C(H2)- or -O-.

31. The compound of any one of claims 15 to 19 and 22 to 30, wherein b is an integer of 0.

32. The compound of any one of claims 1 to 31, wherein Reis a moiety of a cereblon (CRBN) E3 ligand.

33. The compound of any one of claims 1 to 32, wherein Reis a moiety having the structure of Formula (El):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; wherein:Aeis a bond, C3-10 cycloalkylene, C6-14 arylene, heteroarylene, or heterocyclylene;Z is -CH2- or -C(O)-; one of Z1, Z2, Z3, and Z4is -C= and the remaining three of Z1, Z2, Z3, and Z4are each independently -C(Re4)=; or Z1is a bond; one of Z2, Z3, and Z4is -C=, and the remaining two of Z2, Z3, and Z4are each independently -C(Re4)= or -S-;Re1is hydrogen, deuterium, halo, or Ci-6 alkyl;Re2is hydrogen or Ci-6 alkyl; each Rc3is independently (i) deuterium, cyano, halo, or nitro; (ii) Ci-6 alkyl, Ci-6 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) -C(O)R1a, -C(O)OR1a, -C(O)NR1bR1c, -C(O)SR1a, -C(NR1a)NR1bR1c, -C(S)R1a, -C(S)OR1a, -C(S)NR1bR1c, -OR1a, -OC(O)R1a, -OC(O)OR1a, -OC(O)NR1bR1c, -OC(O)SR1a, -OC(NR1 a)NR1bR1c, -OC(S)R1a, -OC(S)OR1a, -OC(S)NR1bR1c, -OS(O)R1a, -OS(O)2R1a, -OS(O)NR1bR1c, -OS(O)2NR1bR1c, -NR1bR1c, -NR1 aC(O)R1d, -NR1aC(O)OR1d, -NR1 aC(O)NR1bR1c, -NR1 aC(O)SR1d, -NR1 aC(NR1d)NR1bR1c, -NR1aC(S)R1d, -NR1 aC(S)OR1d, NR1 aC(S)NR1bR1c, NR1aS(O)R1d, NR1 aS(O)2R1d, NR1 aS(O)NR1bR1c, NR1aS(O)2NR1bR1c, -SR1a, -S(O)R1a, -S(O)2R1a, -S(O)NR1bR1c, or -S(O)2NR1bR1c; each Re4is independently hydrogen or Re3; and m is an integer of 0, 1, or 2; wherein each alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylene, aryl, arylene, aralkyl, heteroaryl, heteroarylene, heterocyclyl, and heterocyclyl ene is optionally substituted with one or more substituents Q.

34. The compound of claim 33, wherein Reis a moiety having the structure of Formula (EIV):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.

35. The compound of claim 33, wherein Reis a moiety having the structure of Formula (EV):or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or morediastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof.

36. The compound of any one of claims 33 to 35, wherein Z is -CH2-.

37. The compound of any one of claims 33 to 35, wherein Z is -C(O)-.

38. The compound of any one of claims 33 to 37, wherein m is an integer of 1.

39. The compound of claim 33, having the structure of Formula (XIIA):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.

40. The compound of claim 33, having the structure of Formula (XIIIA):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.

41. The compound of claim 33, having the structure of Formula (XIIB):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.

42. The compound of claim 33, having the structure of Formula (XIIIB):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.

43. The compound of any one of claims 1 to 32, wherein Reis a moiety having the structure of Formula (EXV):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; wherein:Aeis a bond, C3-10 cycloalkylene, C6-14 arylene, heteroarylene, or heterocyclylene;Xeis C(Re1) or N;Re1is hydrogen, deuterium, halo, or C1-6 alkyl;Re2is hydrogen or C1-6 alkyl; each Re3is independently (i) deuterium, cyano, halo, or nitro; (ii) C1-6 alkyl, C1-6 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) -C(O)R1a, -C(O)OR1a, -C(O)NR1bR1c, -C(O)SR1a, -C(NR1a)NR1 bR1c, -C(S)R1a, -C(S)OR1a, -C(S)NR1bR1c, -OR1a, -OC(O)R1a, -OC(O)OR1a, -OC(O)NR1bR1c, -OC(O)SR1a, -OC(NR1 a)NR1bR1c, -OC(S)R1a, -OC(S)OR1a, -OC(S)NR1bR1c, -OS(O)R1a,OS(O)2R1a, OS(O)NR1bR1c, OS(O)2NR1bR1c, NR1bR1c, NR1 aC(O)R1d, NR1 aC(O)OR1d, -NR1 aC(O)NR1bR1c, -NR1 aC(O)SR1d, -NR1 aC(NR1d)NR1bR1c, -NR1aC(S)R1d, -NR1 aC(S)OR1d, -NR1 aC(S)NR1bR1c, -NR1aS(O)R1d, -NR1 aS(O)2R1d, -NR1 aS(O)NR1 bR1c, -NR1aS(O)2NR1bR1c, -SR1a, -S(O)R1a, -S(O)2R1a, -S(O)NR1bR1c, or -S(O)2NR1bR1c;Re5is (i) hydrogen; (ii) C1-6 alkyl, C1-6 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) -C(O)R1a, -C(O)OR1a, -C(O)NR1bR1c, -C(O)SR’a, -C(NR1 a)NR1bR1 c, -C(S)R1a, -C(S)OR1a, -C(S)NR1bR1 c, -S(O)R1a, -S(O)2R1a, -S(O)NR1bR1c, or -S(O)2NR1bR1c; m is an integer of 0, 1, or 2; and n is an integer of 0, 1, 2, or 3; wherein each alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylene, aryl, arylene, aralkyl, heteroaryl, heteroarylene, heterocyclyl, and heterocyclylene is optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Q.

44. The compound of claim 43, wherein Reis a moiety having the structure of Formula (EXVII):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.

45. The compound of claim 43, wherein Reis a moiety having the structure of Formula (EXVIII):(EXVIII)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.

46. The compound of claim 43, wherein Reis a moiety having the structure of Formula (EXX):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.

47. The compound of claim 43, wherein Reis a moiety having the structure of Formula (EXXI):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.

48. The compound of any one of claims 43 to 47, wherein m is an integer of 1.

49. The compound of any one of claims 43 to 48, wherein n is an integer of 0 or 1.

50. The compound of any one of claims 43 to 49, wherein Re3is halo.

51. The compound of any one of claims 43 to 50, wherein Re3is fluoro or chloro.

52. The compound of claim 43, wherein the compound is a compound of Formula(XIV A):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; wherein Re4is hydrogen or Re3.

53. The compound of claim 43, wherein the compound is a compound of Formula(XIVB):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; wherein Re4is hydrogen or Re3.

54. The compound of any one of claims 43, 52, and 53, wherein Xeis C(Re1).

55. The compound of claim 52, wherein the compound is a compound of Formula(XVIA):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.

56. The compound of claim 52, wherein the compound is a compound of Formula (XVII A):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.

57. The compound of claim 52, wherein the compound is a compound of Formula (XVIII A):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.

58. The compound of claim 53, wherein the compound is a compound of Formula(XVIB):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.

59. The compound of claim 53, wherein the compound is a compound of Formula (XVIIB):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.

60. The compound of claim 53, wherein the compound is a compound of Formula (XVIIIB):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.

61. The compound of claim 43, wherein the compound is a compound of Formula(XIX A):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; wherein Re4is hydrogen or Re3.

62. The compound of claim 43, wherein the compound is a compound of Formula(XIXB):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; wherein Re4is hydrogen or Re3.

63. The compound of claim 61 or 62, wherein Xeis C(Re1).

64. The compound of claim 61, wherein the compound is a compound of Formula(XXIA):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.

65. The compound of claim 61, wherein the compound is a compound of Formula (XXII A):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.

66. The compound of claim 61, wherein the compound is a compound of Formula (XXIIIA):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.

67. The compound of claim 62, wherein the compound is a compound of Formula(XXIB):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.

68. The compound of claim 62, wherein the compound is a compound of Formula(XXIIB):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.

69. The compound of claim 62, wherein the compound is a compound of Formula (XXIIIB):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.

70. The compound of any one of claims 43 to 69, wherein Re5is Ci-6 alkyl, optionally substituted with one or more substituents Q.71 . The compound of any one of claims 43 to 70, wherein Re5is methyl.

72. The compound of any one of claims 1 to 32, wherein Reis a moiety having the structure of Formula (EXXII):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; wherein:Aeis a bond, C3-10 cycloalkylene, C6-14 arylene, heteroarylene, or heterocyclylene;Xeis C(Re1) or N;Re1is hydrogen, deuterium, halo, or C1-6 alkyl;Re2is hydrogen or C1-6 alkyl; each Re3is independently (i) deuterium, cyano, halo, or nitro; (ii) C1-6 alkyl, C1-6 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) -C(O)R1a, -C(O)OR1a, -C(O)NR1bR1c, -C(O)SR1a, -C(NR1a)NR1bR1c, -C(S)R1a, -C(S)OR1a, -C(S)NR1bR1c, -OR1a, -OC(O)R1a, -OC(O)OR1a, -OC(O)NR1hR1c, -OC(O)SR1a, -OC(NR1 a)NR1bR1c, -OC(S)R1a, -OC(S)OR1a, -OC(S)NR1bR1c, -OS(O)R1a, -OS(O)2R1a, -OS(O)NR1bR1c, -OS(O)2NR1bR1c, -NR1bR1c, -NR1 aC(O)R1d, -NR1aC(O)OR1d, -NR1 aC(O)NR1bR1c, -NR1 aC(O)SR1d, -NR1 aC(NR1d)NR1bR1c, -NR1aC(S)R1d, -NR1 aC(S)OR1d, -NR1 aC(S)NR’bR1c, -NR1aS(O)R1d, -NR1 aS(O)2R1 d, -NR1 aS(O)NR1bR1c, -NR1aS(O)2NR1bR1c, -SR1a, -S(O)R1a, -S(O)2R1a, -S(O)NR1bR1c, or -S(O)2NR1bR1c; m is an integer of 0, 1, or 2; and n is an integer of 0, 1, 2, 3, or 4; wherein each alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylene, aryl, arylene, aralkyl, heteroaryl, heteroarylene, heterocyclyl, and heterocyclylene is optionally substituted with one or more substituents Q.

73. The compound of claim 72, wherein Reis a moiety having the structure of Formula (EXXIV):(EXXIV)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.

74. The compound of claim 72, wherein Reis a moiety having the structure ofFormula (EXXV):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.

75. The compound of claim 72, wherein Reis a moiety having the structure of Formula (EXXVII):(EXXVII)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.

76. The compound of claim 72, wherein Reis a moiety having the structure of Formula (EXXVIII):(EXXVIII)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.

77. The compound of any one of claims 72 to 76, wherein m is an integer of 1 .

78. The compound of claim 72, having the structure of Formula (XXIVA):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.

79. The compound of claim 72, having the structure of Formula (XXIVB):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.

80. The compound of any one of claims 72, 78, and 79, wherein Xeis C(Re1).81 . The compound of claim 78, having the structure of Formula (XXVIA):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.

82. The compound of claim 78, having the structure of Formula (XXVIIA):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.

83. The compound of claim 78, having the structure of Formula (XXVIIIA):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.

84. The compound of claim 79, having the structure of Formula (XXVIB):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.

85. The compound of claim 79, having the structure of Formula (XXVIIB):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.

86. The compound of claim 79, having the structure of Formula (XXVIIIB):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.

87. The compound of claim 72, having the structure of Formula (XXIXA):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.

88. The compound of claim 72, having the structure of Formula (XXIXB):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.

89. The compound of claim 87 or 88, wherein Xeis C(Re1).

90. The compound of claim 87, having the structure of Formula (XXXIA):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.

91. The compound of claim 87, having the structure of Formula (XXXIIA):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.

92. The compound of claim 87, having the structure of Formula (XXXIIIA):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; ora pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

93. The compound of claim 88, having the structure of Formula (XXXIB):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.

94. The compound of claim 88, having the structure of Formula (XXXIIB):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.

95. The compound of claim 88, having the structure of Formula (XXXIIIB):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.

96. The compound of any one of claims 72 to 95, wherein n is an integer of 0, 1, or 3.

97. The compound of any one of claims 72 to 96, wherein each Re3is independently (i) halo; or (ii) Ci-6 alkyl, Ci-6 heteroalkyl, or C3-7 cycloalkyl, each optionally substituted with one or more substituents Q.

98. The compound of any one of claims 72 to 97, wherein each Re3is independently fluoro, chloro, methyl, difluoromethyl, trifluoromethyl, or cyclopropyl.

99. The compound of any one of claims 1 to 98, wherein R1is hydrogen.

100. The compound of any one of claims 1 to 99, wherein R2ais C1-6 alkyl, optionally substituted with one or more substituents Q.

101. The compound of any one of claims 1 to 100, wherein R2ais methyl.

102. The compound of any one of claims 14 to 101, wherein R3ais (i) hydrogen, cyano, halo, or nitro; (ii) C1-6 alkyl or C6-14 aryl, each optionally substituted with one or more substituents Q; or (iii) -OR1a, -NR1bR1c, or -S(O)2R1a.

103. The compound of any one of claims 14 to 102, wherein R3ais hydrogen, cyano, fluoro, chloro, bromo, nitro, methyl, ethyl, fluoromethyl, difluoromethyl, tri fluoromethyl, 1- cyano- 1 , 1 -difluoromethyl, 1 , 1 -difluoro-2-hydroxy ethyl, 1 , 1 -difluoro-2-hydroxy-2-methylpropyl,methylaminomethyl, 2-aminomethylphenyl, 2-(2-aminoethyl)phenyl, 2-methylaminomethyl- phenyl, 2-dimethylaminomethylphenyl, hydroxyl, methoxy, amino, or methyl sulfonyl.

104. The compound of any one of claims 14 to 103, wherein R3ais hydrogen, fluoro, or methyl.

105. The compound of any one of claims 14 to 104, wherein R3bis (i) hydrogen, cyano, halo, or nitro; (ii) Ci-6 alkyl or C6-14 aryl, each optionally substituted with one or more substituents Q; or (iii) -OR1a, -NR1bR1c, or -S(O)2R1a.

106. The compound of any one of claims 14 to 105, wherein R3bis hydrogen, cyano, fluoro, chloro, bromo, nitro, methyl, ethyl, fluoromethyl, difluoromethyl, trifluorom ethyl, 1- cyano- 1 , 1 -difluoromethyl, 1 , 1 -difluoro-2-hydroxy ethyl, 1 , 1 -difluoro-2-hydroxy-2-methylpropyl, methylaminomethyl, 2-aminomethylphenyl, 2-(2-aminoethyl)phenyl, 2-methylaminomethyl- phenyl, 2-dimethylaminomethylphenyl, hydroxyl, methoxy, amino, or methylsulfonyl.

107. The compound of any one of claims 14 to 106, wherein R3bis hydrogen, cyano, fluoro, difluoromethyl, trifluoromethyl, or amino.

108. The compound of any one of claims 14 to 107, wherein R3cis (i) hydrogen, cyano, halo, or nitro; (ii) Ci-6 alkyl or C6-14 aryl, each optionally substituted with one or more substituents Q; or (iii) -OR1a, -NR1bR1c, or -S(O)2R1a.

109. The compound of any one of claims 14 to 108, wherein R3cis hydrogen, cyano, fluoro, chloro, bromo, nitro, methyl, ethyl, fluoromethyl, difluoromethyl, trifluorom ethyl, 1- cyano- 1 , 1 -difluoromethyl, 1 , 1 -difluoro-2-hydroxy ethyl, 1 , 1 -difluoro-2-hydroxy-2-methylpropyl, methylaminomethyl, 2-aminomethylphenyl, 2-(2-aminoethyl)phenyl, 2-methylaminomethyl- phenyl, 2-dimethylaminomethylphenyl, hydroxyl, methoxy, amino, or methylsulfonyl.

110. The compound of any one of claims 14 to 109, wherein R3cis hydrogen.

111. The compound of any one of claims 14 to 110, wherein R3dis (i) hydrogen, cyano, halo, or nitro; (ii) Ci-6 alkyl or C6-14 aryl, each optionally substituted with one or more substituents Q; or (iii) -OR1a, -NR1bR1c, or -S(O)2R1a.

112. The compound of any one of claims 14 to 1 11 , wherein R3dis hydrogen, cyano, fluoro, chloro, bromo, nitro, methyl, ethyl, fluoromethyl, difluorom ethyl, trifluorom ethyl, 1- cyano- 1 , 1 -difluoromethyl, 1 , 1 -difluoro-2-hydroxy ethyl, 1 , 1 -difluoro-2-hydroxy-2-methylpropyl, methylaminomethyl, 2-aminomethylphenyl, 2-(2-aminoethyl)phenyl, 2-methylaminomethyl- phenyl, 2-dimethylaminomethylphenyl, hydroxyl, methoxy, amino, or methyl sulfonyl.

113. The compound of any one of claims 14 to 112, wherein R3dis hydrogen.

114. The compound of any one of claims 14 to 113, wherein R3eis (i) hydrogen, cyano, halo, or nitro; (ii) Ci-6 alkyl or C6-14 aryl, each optionally substituted with one or more substituents Q; or (iii) -OR1a, -NR1bR1c, or -S(O)2R1a.

115. The compound of any one of claims 14 to 114, wherein R3eis hydrogen, cyano, fluoro, chloro, bromo, nitro, methyl, ethyl, fluoromethyl, difluoromethyl, trifluoromethyl, 1- cyano- 1 , 1 -difluoromethyl, 1 , 1 -difluoro-2-hydroxy ethyl, 1 , 1 -difluoro-2-hydroxy-2-methylpropyl, methylaminomethyl, 2-aminomethylphenyl, 2-(2-aminoethyl)phenyl, 2-methylaminomethyl- phenyl, 2-dimethylaminomethylphenyl, hydroxyl, methoxy, amino, or methylsulfonyl.

116. The compound of any one of claims 14 to 115, wherein R3eis hydrogen.

117. The compound of any one of claims 1 to 116, wherein R4ais Ci-6 alkyl, optionally substituted with one or more substituents Q.

118. The compound of any one of claims 1 to 117, wherein R4ais methyl.

119. The compound of any one of claims 33 to 118, wherein Aeis heterocyclylene, optionally substituted with one or more substituents Q.

120. The compound of any one of claims 33 to 119, wherein Aeis monocyclic heterocyclylene, optionally substituted with one or more substituents Q.

121. The compound of any one of claims 33 to 119, wherein Aeis bicyclic heterocyclylene, optionally substituted with one or more substituents Q.

122. The compound of any one of claims 33 to 119, wherein Aeis piperidindiyl,piperazindiyl, or 8-azabicyclo[3.2.1]octandiyl, each optionally substituted with one or more substituents Q.

123. The compound of any one of claims 33 to 119 and 122, wherein Aeis piperidin- 1,4-diyl, piperazin- 1,4-diyl, or 8-azabicyclo[3.2.1]octan-3,8-diyl, each optionally substituted with one or more substituents Q.

124. The compound of any one of claims 33 to 118, wherein Aeis a bond,125. The compound of any one of claims 33 to 45, 48 to 56, 58, 59, 61 to 65, 67, 68, 70 to 74, 77 to 82, 84, 85, 87 to 91, 93, 94, and 96 to 124, wherein Re1is Ci-6 alkyl, optionally substituted with one or more substituents Q.

126. The compound of any one of claims 33 to 45, 48 to 56, 58, 59, 61 to 65, 67, 68, 70 to 74, 77 to 82, 84, 85, 87 to 91, 93, 94, and 96 to 125, wherein Re1is methyl.

127. The compound of any one of claims 33 to 45, 48 to 56, 58, 59, 61 to 65, 67, 68, 70 to 74, 77 to 82, 84, 85, 87 to 91, 93, 94, and 96 to 124, wherein Re1is hydrogen.

128. The compound of any one of claims 33 to 127, wherein Re2is Ci-6 alkyl, optionally substituted with one or more substituents Q.

129. The compound of any one of claims 33 to 128, wherein Re2is (pivaloyloxy)- methyl, valyloxymethyl, or ((di- / er / -butoxyphosphoryl)oxy)methyl.

130. The compound of any one of claims 33 to 127, wherein Re2is hydrogen.

131. The compound of any one of claims 34 to 42, 52 to 71, and 99 to 130, wherein Re4is halo.

132. The compound of any one of claims 34 to 42, 52 to 71, and 99 to 131, wherein Re4is fluoro or chloro.

133. The compound of any one of claims 34 to 42, 52 to 71, and 99 to 132, wherein Re4is fluoro.

134. The compound of any one of claims 34 to 42, 52 to 71 , and 99 to 130, wherein Re4is hydrogen.

135. The compound of any one of claims 20, 21, and 32 to 134, wherein U5is -C(R5)=.

136. The compound of any one of claims 20, 21, and 32 to 134, wherein U5is -N=.

137. The compound of any one of claims 20, 21, and 32 to 136, wherein V5is -C(R .

138. The compound of any one of claims 20, 21, and 32 to 136, whereinis -N=.

139. The compound of any one of claims 20, 21, and 32 to 138, wherein X5is-C(R5)=.

140. The compound of any one of claims 20, 21, and 32 to 138, wherein X5is -N=.

141. The compound of any one of claims 20, 21, and 32 to 140, wherein Z5is -C(R5)=.

142. The compound of any one of claims 20, 21, and 32 to 140, wherein Z5is -N=.

143. The compound of any one of claims 20, 21, and 32 to 134, wherein U5, V5, X5, and Z’ are each independently -C(R5)=.

144. The compound of any one of claims 20, 21, and 32 to 134, wherein U5is -N=; and V5, X5, and Z5are each independently -C(R5)=.

145. The compound of any one of claims 20, 21, and 32 to 134, wherein U5, X5, and Z5are each independently -C(R5)=; and V5is -N=.

146. The compound of any one of claims 20, 21, and 32 to 134, wherein U5, V5, and Z5are each independently -C(R’)=; and X5is -N=.

147. The compound of any one of claims 20, 21, and 32 to 134, wherein U5, V5, and X5are each independently -C(R3)=; and Z5is -N=.

148. The compound of any one of claims 135 and 137 to 147, wherein each R? is independently (i) hydrogen or halo; or (ii) Ci-6 alkyl, optionally substituted with one or more substituents Q.

149. The compound of any one of claims 135 and 137 to 148, wherein each R5is independently hydrogen, fluoro, chloro, or methyl.

150. The compound of any one of claims 1 to 149, wherein L has the structure of:-Zk-(Rk-Zk)z-; wherein: each Rkis independently Ci-6 alkylene, C2-6 alkenylene, C2-6 alkynylene, C3-10 cycloalkylene, C6-14 arylene, heteroarylene, or heterocyclylene, each of which is optionally substituted with one or more substituents Q; each Zkis independently a bond, -C(O)-, -C(O)O- -C(O)NR1 b- -C(O)S- -C(NR1a)NR1b-, -C(S)-, -C(S)O- -C(S)NR1b-, -O-, -OC(O)O-, -OC(O)NR1b- -OC(O)S- -OC(NR1a)NR1b-, -OC(S)O-, -OC(S)NR1b-, -OS(O)-, -OS(O)2- -OS(O)NR1 b- -OS(O)2NR1b- -NR1b- -NR1aC(O)NR1b-, -NR1aC(O)S-, -NR1aC(NR1d)NR1b- -NR1 aC(S)NR1b-, -NR1aS(O)NR1b-, -NR1aS(O)2NR1b-, -S-, -S(O)-, -S(O)2-, -S(O)NR1b-, or -S(O)2NR1b-; where each R1a, Rlb, and R1dis as defined herein; and z is an integer of 0, 1, 2, 3, 4, or 5.

151. The compound of any one of claims 1 to 150, wherein L is C1-6 alkylene or C7-14 arylene, each optionally substituted with one or more substituents Q.

152. The compound of any one of claims 1 to 151, wherein L is methanediyl, ethane- 1,2-diyl, phen-l,3-diylmethandiyl, or -C(O)-.

153. The compound of any one of claims 1 to 152, wherein L is methanediyl.

154. The compound of any one of claims 1 to 153, wherein a is an integer of 0.

155. A compound of :3 -(5 -( 1 -( 5 - (4- ( ((R)- 1 -(3 -(difluorom ethyl )-2-fluorophenyl )ethyl)amino)-2-methyl- pyrido[3,4-d ]pyrimidin-6-yl)-2-fluorobenzyl)piperidin-4-yl)-l-oxoisoindolin-2-yl)piperidine-2,6-dione A001;3 - (5 - ( 1 -(3 -(4-(((R)- 1 -(3 -(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methyl- pyrido[3, 4- J]pyrimidin-6-yl)benzyl)piperidin-4-yl)-l-oxoisoindolin-2-yl)piperidine-2, 6-dione A002;3 -(5 -( 1 -(3 -(4-(((R)- 1 -(3 -(difluoromethyl)-2-methylphenyl)ethyl)amino)-2- methylpyrido[3,4-d]pyrimidin-6-yl)benzyl)piperidin-4-yl)-l-oxoisoindolin-2-yl)piperidine-2,6- dione A003;3 -(5-( 1 -(5-(4-(( (R)- 1 -(3 -(difluoromethyl)-2-methylphenyl)ethyl)amino)-2- methylpyrido[3,4-d]pyrimidin-6-yl)-2-fluorobenzyl)piperidin-4-yl)-l-oxoisoindolin-2-yl)- piperidine-2, 6-dione A004;3 -(5-( 1 -((5-(4-(((R)- 1 -(3 -(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2- methylpyrido[3,4-d]pyrimidin-6-yl)pyridin-3-yl)methyl)piperidin-4-yl)-6-fluoro-l-oxo- isoindolin-2-yl)piperidine-2, 6-dione A005;(R)-3 -(6-( 1 -(3 -(4 - (((R) - 1 -(3 -(difluoro-methyl)-2-fluorophenyl)ethyl )amino)-2- methylpyrido[3,4-d]pyrimidin-6-yl)benzyl)piperidin-4-yl)-5-fluoro-l -methyl- 1H-indazol-3-yl)- 3 -methylpiperidine-2, 6-dione A051 ; (R)-1-(6-(1-(5-(1-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-4-methyl- pyrido[3,4-d]pyridazin-7-yl)-2-fluorobenzyl)piperidin-4-yl)-l-methyl-1H-indazol-3-yl)dihydro- pyrimidine-2, 4(1H, 3H)-dione A061; (R)-1-(6-(1-(5-(4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methyl- pyrido[3,4-d]pyrimidin-6-yl)-2-fluorophenethyl)piperidin-4-yl)-l -methyl- 1H-indazol-3-yl)- dihydropyrimidine-2,4( 1H,3H)-dione A062; (R)-1-(6-(1-(5-(4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methyl- pyrido[3,4-d]pyrimidin-6-yl)-2-fluorobenzyl)piperidin-4-yl)-5-fluoro-l -methyl- 1H-indazol-3- yl)dihydropyrimidine-2,4(1H, 3H)-dione A063; (R)-1-(6-(1-(3-(4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methyl- pyrido[3,4-d]pyrimidin-6-yl)benzyl)piperidin-4-yl)-5-fluoro-l-m ethyl- 1H-indazol-3-yl)dihydro- pyrimidine-2,4(1H,3H)-dione A064; (R)-3-(4-(1-(5-(4-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2- methylpyrido[3,4-d]pyrimidin-6-yl)-2-fluorobenzyl)piperidin-4-yl)phenyl)-3-methylpiperidine- 2,6-dione A101;3-(4-(1-(5-(4-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methyl- pyrido[3,4-d ]pyrimidin-6-yl)-2-fluorobenzyl)piperidin-4-yl)-3-methylphenyl)piperidine-2,6- dione A102; (R)-3-(4-(1-(5-(4-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2- methylpyrido[3,4- ]pyrimidin-6-yl)-2-fluorobenzyl)piperidin-4-yl)-3-methylphenyl)-3 -methyl- piperidine-2, 6-dione A103; (R)-3 -(4-( 1 -(3 -(4-(((R)- 1 -(3 -(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2- methylpyrido[3,4-d]pyrimidin-6-yl)benzyl)piperidin-4-yl)-3-methylphenyl)-3-ni ethylpiperidine- 2,6-dione A104; (R)-3-(4-(1-(5-(4-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2- methylpyrido[3,4-d]pyrimidin-6-yl)-2-fluorobenzyl)piperidin-4-yl)-3-(trifluoromethyl)phenyl)- 3-methylpiperidine-2, 6-dione A105;(R)-3 -(4-( 1 -(3 -(4-(((R)- 1 -(3 -(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2- methylpyrido[3,4-d]pyrimidin-6-yl)benzyl)piperidin-4-yl)-3-(trifluoromethyl)phenyl)-3-methyl- piperidine-2, 6-dione A106;(R)-3 -(4-( 1 -(3 -(4-(((R)- 1 -(3 -(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2- methylpyrido[3,4-d]pyrimidin-6-yl)benzyl)piperidin-4-yl)-3-fluoro-5-methylphenyl)-3-methyl- piperidine-2, 6-dione A107; R)-3 -(4-( 1 -(5 -(4-(((R)- 1 -(3 -(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2- methylpyrido[3,4-r / ]pyrimidin-6-yl)-2-fluorobenzyl)piperidin-4-yl)-3-fluoro-5-methylphenyl)-3- methylpiperidine-2, 6-dione A108;(R)-3 -(3 -cy clopropy l-4-( 1 - ( 5 -(4 - (((R) - 1 -(3 -(difluoromethy l)-2-fluorophenyl)- ethyl)amino)-2-methylpyrido[3,4-7]pyrimidin-6-yl)-2-fluorobenzyl)piperidin-4-yl)phenyl)-3- methylpiperidine-2, 6-dione A109; (R)-3-(4-(1-(5-(4-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2- methylpyrido[3,4-7]pyrimidin-6-yl)-2-fluorobenzyl)piperidin-4-yl)-3-fluorophenyl)-3 -methyl- piperidine-2, 6-dione A110;(R)-3 -(3 -cy clopropy l-4-( 1 -(3 -(4-(((R)- 1 -(3 -(difluoromethy l)-2-fluoropheny 1)- ethyl)amino)-2-methylpyrido[3,4-7]pyrimidin-6-yl)benzyl)piperidin-4-yl)phenyl)-3-methyl- piperidine-2, 6-dione A1li;3-(4-(1-(3-(4-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methyl-pyrido[3,4-r / ]pyrimidin-6-yl)benzyl)piperidin-4-yl)-3-methylphenyl)piperidine-2, 6-dione A112; (R)-3-(3-chloro-4-(1-(5-(4-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)- amino)-2-methylpyrido[3,4-d]pyrimidin-6-yl)-2-fluorobenzyl)piperidin-4-yl)phenyl)-3-methyl- piperidine-2, 6-dione A113;(R)-3 -(3 -chloro-4-( 1 -(3 -(4-(((R)- 1 -(3 -(difluorom ethyl)-2-fluorophenyl)ethyl)- amino)-2-methylpyrido[3,4--d]pyrimidin-6-yl)benzyl)piperidin-4-yl)phenyl)-3-methylpiperidine- 2,6-dione A114;(R)-3 -(4-( 1 -((5 -(4-(((R)- 1 -(3 -(difluoromethyl)-2-fluorophenyl)ethy l)amino)-2- methylpyrido[3,4-d]pyrimidin-6-yl)-l -methyl -2-oxo- 1,2-dihydropyri din-3 -yl)m ethyl)piperidin- 4-yl)phenyl)-3-methylpiperidine-2, 6-dione A115;(R)-3 -(3 -(difluoromethyl)-4-( 1 -(3 -(4-(((R)- 1 -(3 -(difluorom ethyl)-2-fluoro- phenyl)ethyl)amino)-2-methylpyrido[3,4-d]pyrimidin-6-yl)benzyl)piperidin-4-yl)phenyl)-3- methylpiperidine-2, 6-dione A116;(R)-3 -(3 -(difluoromethyl)-4-( 1 -(5 -(4-( ((R)- 1 -(3 -(difluorom ethyl )-2-fluoro- phenyl)ethyl)amino)-2-methylpyrido[3,4-d]pyrimidin-6-yl)-2-fluorobenzyl)piperidin-4-yl)- phenyl)-3 -methylpiperidine-2, 6-dione A117;(R)-3 -(4-( 1 -(3 -(4-(((R)- 1 -(3 -(difluorom ethyl)-2-flu oropheny l)ethy l)amino)-2- methylpyrido[3,4-fi?]pyrimidin-6-yl)benzyl)piperidin-4-yl)-3,5-difluorophenyl)-3-methyl- piperidine-2, 6-dione A118;3-(4-(1-(3-(4-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methyl- pyrido[3,4-d]pyrimidin-6-yl)benzyl)piperidin-4-yl)-3-fluoro-5-methylphenyl)piperidine-2,6- di one A119;3-(4-(1-(5-(4-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methyl- pyrido[3,4-d]pyrimidin-6-yl)-2-fluorobenzyl)piperidin-4-yl)-3-fluoro-5-methylphenyl)- piperidine-2, 6-dione A120;(R)-3 -(4-( 1 -(3 -(4-(((R)- 1 -(3 -(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2- methylpyrido[3,4-d]pyrimidin-6-yl)benzyl)piperidin-4-yl)-2,3-difluorophenyl)-3-methyl- piperidine-2, 6-dione A121; (R)-3-(4-(l -(5 -(4-(((R)-l -(3 -(difluorom ethyl)-2-fluorophenyl)ethyl)amino)-2- methylpyrido[3,4-d]pyrimidin-6-yl)-2-fluorobenzyl)piperidin-4-yl)-3,5-difluorophenyl)-3- methyl-piperidine-2, 6-dione A122;(R)-3-(4-(l -(((5)-1-(4-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2- methylpyrido[3,4-d]pyrimidin-6-yl)-3-fluoropiperidin-3-yl)methyl)piperidin-4-yl)-3-methyl- phenyl)-3-methylpiperidine-2, 6-dione A123; (R)-3 -(4-( 1 -(3 -(4-(((R)- 1 -(3 -(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2- methylpyrido[3,4--d]pyrimidin-6-yl)benzyl)piperidin-4-yl)-2-fluoro-3-methylphenyl)-3-methyl- piperidine-2, 6-dione A124;3-(5-(4-(3-(1-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-4-methyl- pyrido[3,4-d ]pyridazin-7-yl)benzyl)piperazin-l-yl)-l-oxoisoindolin-2-yl)piperidine-2, 6-dione B001;3-(6-fluoro-5-(1-(3-(4-methyl-1-(((R)-1-(2-methyl-3-(trifluoromethyl)phenyl)- ethyl)amino)pyrido[3,4-d]pyridazin-7-yl)benzyl)piperidin-4-yl)-l-oxoisoindolin-2-yl)piperidine- 2,6-dione B002;3-(5-(4-(3-(1-(((R)-1-(3-arnino-5-(trifluoromethyl)phenyl)ethyl)amino)-4-methyl- pyrido[3,4-d]pyridazin-7-yl)benzyl)piperazin-l-yl)-l-oxoisoindolin-2-yl)piperidine-2, 6-dione B003;3 -(5-( 1 -(5-(l -(((R)- 1 -(3 -(difluoromethyl)-2-fluorophenyl)ethyl)amino)-4-methyl- pyrido[3, 4-d]pyridazin-7-yl)-2 -fluorobenzyl )piperi din-4-yl)-6-fluoro- 1 -oxoisoindolin-2-yl)- piperidine-2, 6-dione B004;3 -(5 -( 1 -(5 -( 1 -(((R)- 1 -(3 -(difluoromethyl)-2-methylphenyl)ethyl)amino)-4- methylpyrido[3,4-d ]pyridazin-7-yl)-2-fluorobenzyl)piperidin-4-yl)-l-oxoisoindolin-2-yl)- piperidine-2, 6-dione B005;3 -(5 -( 1 -(5 -( 1 -(((R)- 1 -(3 -(difluoromethyl )-2-methylphenyl)ethyl)amino)-4- methylpyrido[3,4-d ]pyridazin-7-yl)-2-fluorobenzyl)piperidin-4-yl)-6-fluoro-l-oxoisoindolin-2- yl)piperidine-2, 6-dione B006;3-(5-(1-(3-(1-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-4-methyl- pyrido[3,4-d ]pyridazin-7-yl)benzyl)piperidin-4-yl)-l-oxoisoindolin-2-yl)piperidine-2, 6-dione B007;3-(l-methyl-6-(4-(3-(4-methyl-1-(((R)-1-(2-methyl-3-(trifluoromethyl)phenyl)- ethyl)amino)pyrido[3,4-d]pyridazin-7-yl)benzyl)piperazin-l-yl)-17 / -indazol-3-yl)piperidine-2,6- dione B051;3-((17?)-1-((7-(4-(3-((4-(3-(2,6-dioxopiperidin-3-yl)-l-methyl-17 / -indazol-6-yl)-piperidin-l -yl)methyl)phenyl)piperazin-l-yl)-4-methylpyrido[3,4-d ]pyridazin-l-yl)amino)ethyl)- 2-methylbenzonitrile B052;3 -(( 1R)- 1 -((7-(3 -((4-(3 -(2,6-dioxopiperidin-3 -yl)- 1 -methyl- 1H-indazol-6-yl)- piperidin-l-yl)methyl)phenyl)-4-methylpyrido[3,4-d ]pyridazin-l-yl)amino)ethyl)-2-methyl- benzonitrile B053;3 -( 1 -methy l-7-( 1 -(3 -(4-methyl- 1 - ( ((R)- 1 -(2-methyl-3 -(trifluoromethyl)phenyl)- ethyl)amino)pyrido[3,4-d]pyridazin-7-yl)benzyl)piperidin-4-yl)-1H-indazol-3-yl)piperidine-2,6- dione B054;3-(6-(1-(3-(1-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-4-methyl- pyrido[3,4-d ]pyridazin-7-yl)benzyl)piperidin-4-yl)-l -methyl- 1H-indazol-3-yl)piperidine-2, 6- dione B055;3-((17?)-1-((7-(3-((4-(3-(2,6-dioxopiperidin-3-yl)-l-methyl-17 / -indazol-7-yl)- piperi din- l-yl)methyl)phenyl)-4-methylpyrido[3,4-7]pyridazin-l-yl)amino)ethyl)-2 -methylbenzonitrile B056;3 -(7-( 1 -(5 -( 1 -(((R)- 1 -(3 -(difluoromethyl)-2-fluorophenyl)ethyl)amino)-4-methyl- pyrido[3,4-d ]pyridazin-7-yl)-2-fluorobenzyl)piperidin-4-yl)-l-methyl-17 / -indazol-3-yl)- piperidine-2, 6-dione B057; (R)-3 -(6-( 1 -(5 -( 1 -(((R)- 1 -(3 -(difluoromethyl)-2-fluorophenyl)ethyl)amino)-4- methylpyrido[3,4--d]pyridazin-7-yl)-2-fluorobenzyl)piperidin-4-yl)-l-methyl-17 / -indazol-3-yl)-3- methylpiperidine-2, 6-dione B058;(R)- 1 -(6-( 1 -(5 -( 1 -(( 1 -(3 -(difluoromethyl)-2-fluorophenyl)ethyl)amino)-4- methylpyrido[3,4--d]pyridazin-7-yl)-2-fluorobenzyl)piperidin-4-yl)-l -methyl- 1H-indazol-3- yl)dihydropyrimidine-2, 4(1H, 3H)-di one B091;(R)- 1 -(6-( 1 -(5 -( 1 -(( 1 -(3 -(difluoromethyl)-2-fluorophenyl)ethyl)-amino)-4- methylpyrido[3,4--d]pyridazin-7-yl)-2-fluorophenethyl)piperidin-4-yl)-l-methyl-1H-indazol-3- yl)-dihydropyrimidine-2,4(17f,3H)-dione B092;3 -(4-( 1 -(((R)-4-( 1 -(((R)- 1 -(3 -amino-5-(trifluoromethyl)phenyl)ethyl)amino)-4- methylpyrido[3,4--d]pyridazin-7-yl)morpholin-2-yl)methyl)piperidin-4-yl)phenyl)piperidine-2,6- dione B101;3-(4-(1-(3-(l -(((R)- 1 -(3 -amino-5-(trifluoromethyl)phenyl)ethyl)amino)-4-methyl- pyrido[3,4-d ]pyridazin-7-yl)benzyl)piperidin-4-yl)phenyl)piperidine-2, 6-dione B102;3-(4-(1-(3-(1-(((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-4-methyl- pyrido[3,4-d ]pyridazin-7-yl)phenethyl)piperidin-4-yl)phenyl)piperidine-2, 6-dione B103;3 -(4-(4-(3 -( 1 -(((R)- 1 -(3 -amino-5-(trifluoromethyl)phenyl)ethyl)amino)-4-methyl- pyrido[3,4--d]pyridazin-7-yl)phenethyl)piperazin-l-yl)phenyl)piperidine-2, 6-dione B104;3 -(4-(4-(3 -( 1 -(((R)- 1 -(3 -amino-5-(trifluoromethyl)phenyl)ethyl)amino)-4-methyl- pyrido[3,4- ]pyridazin-7-yl)benzyl)piperazin-l-yl)phenyl)piperidine-2, 6-dione B105;3 -(4-( 1 -(((R)-4-( 1 -(((R)- 1 -(3 -amino-5 -(trifluoromethyl)phenyl)ethyl)amino)-4- methylpyrido[3,4--d]pyridazin-7-yl)morpholin-2-yl)methyl)piperidin-4-yl)-3-methylphenyl)- piperidine-2, 6-dione B106;3-(4-(2-(5-(1-(((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-4-methyl- pyrido[3,4-d]pyridazin-7-yl)-2-oxopyridin-l(27 / )-yl)ethyl)phenyl)piperidine-2, 6-dione B107;3-(4-(1-(3-(1-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-4-methyl- pyrido[3,4-d ]pyridazin-7-yl)benzyl)piperidin-4-yl)phenyl)piperidine-2, 6-dione B108;3-((17?)-1-((7-(3-((4-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-l-yl)methyl)- phenyl)-4-methylpyrido[3,4-t / ]pyridazin-l-yl)amino)ethyl)-2-methylbenzonitrile B109;3 -(4-( 1 -(3 -(4-m ethyl- 1 -(((R)- 1 -(2-methyl-3 -(trifluoromethy l)pheny 1 ) ethyl ) - amino)pyrido[3,4- ]pyridazin-7-yl)benzyl)piperidin-4-yl)phenyl)piperidine-2, 6-dione Bl 10;3 -(4-( 1 -(2-(5-(l -(((R)- 1 -(3 -amino-5 -(trifluorom ethyl)phenyl)ethyl)amino)-4- methylpyrido[3,4--d]pyridazin-7-yl)-2-oxopyridin-l(2H)-yl)ethyl)piperidin-4-yl)phenyl)- piperidine-2, 6-dione Bill;3 -(4-( 1 -(3 -( 1 -(((R)- 1 -(3 -(difluoromethyl)-2-fluorophenyl)ethyl)amino)-4-methyl- pyrido[3,4-d]pyridazin-7-yl)-5-fluorobenzyl)piperidin-4-yl)phenyl)piperidine-2, 6-dione B112;3-(4-(1-(3-(1-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-4-methyl- pyrido[3,4-d ]pyridazin-7-yl)-4-fluorobenzyl)piperidin-4-yl)phenyl)piperidine-2, 6-dione Bl 13;3 - (4 - ( 1 -( 5 - ( 1 -(((R)- 1 -(3 -(difluorom ethyl )-2-fluorophenyl )ethyl)amino)-4-methyl- pyrido[3,4-d ]pyridazin-7-yl)-2-fluorobenzyl)piperidin-4-yl)phenyl)piperidine-2, 6-dione Bl 14;3 -(4-( 1 -(3 -( 1 -(((R)- 1 -(3 -(difluoromethyl)-2-fluorophenyl)ethyl)amino)-4-methyl- pyrido[3,4-d]pyridazin-7-yl)-2-fluorobenzyl)piperidin-4-yl)phenyl)piperidine-2, 6-dione Bl 15;3 -(4-( 1 -(3 -(1 -(((R)- 1 -(3 -(difluorom ethyl)-2-fluorophenyl)ethyl)amino)-4-methyl- pyrido[3,4-d]pyridazin-7-yl)-5-methylbenzyl)piperidin-4-yl)phenyl)piperidine-2, 6-dione B116;3-(4-(1-(5-(1-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-4-methyl-pyrido[3,4-d]pyridazin-7-yl)-2-methylbenzyl)piperidin-4-yl)phenyl)piperidine-2, 6-dione Bl 17;3 -(4-( 1 -(3 -( 1 -(((R)- 1 -(3 -(difluoromethyl)-2-fluorophenyl)ethyl)amino)-4-methyl- pyrido[3, 4- J]pyridazin-7-yl)-4-methylbenzyl)piperidin-4-yl)phenyl)piperidine-2, 6-dione Bl 18;3-(4-(1-(3-(1-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-4-methyl- pyrido[3,4-d]pyridazin-7-yl)-2-methylbenzyl)piperidin-4-yl)phenyl)piperidine-2, 6-dione Bl 19;3 -(4-( 1 -(3 -(1 -(((R)- 1 -(3 -(difluoromethyl)-2-fluorophenyl)ethyl)amino)-4-methyl- pyrido[3,4-d]pyridazin-7-yl)phenethyl)piperidin-4-yl)phenyl)piperidine-2, 6-dione B120;3 -(4-( 1 -(2-chl oro-5 -( 1 -(((R)- 1 -(3 -(difluoromethy l)-2-fluoropheny l)ethyl)amino)- 4-methylpyrido[3,4-d]pyridazin-7-yl)benzyl)piperidin-4-yl)phenyl)piperidine-2, 6-dione B121;2-methyl-3-((R)-1-((4-methyl-7-(3-((4-(4-((R)-3-methyl-2,6-dioxopiperidin-3-yl)- phenyl)piperidin-l-yl)methyl)phenyl)pyrido[3,4-d]pyridazin-l-yl)amino)ethyl)benzonitrile B122; (R)-3 -methyl-3 -(4-( 1 -(3-(4-methyl- 1 -(((R)- 1 -(2-methy 1-3 -(trifluoromethyl)- phenyl)ethyl)amino)pyrido[3,4-d]pyridazin-7-yl)benzyl)piperidin-4-yl)phenyl)piperidine-2,6- dione B123;2-methyl-3-((R)-1-((4-methyl-7-(3-((4-(4-((R)-3-methyl-2,6-dioxopiperidin-3-yl)- phenyl)piperidin-l-yl)methyl)phenyl)pyrido[3,4-d]pyridazin-l-yl)amino)ethyl)benzonitrile B124; (R)-3 -(4-( 1 -(3 -( 1 -(((R)- 1 -(3 -(difluoromethyl)-2-fluorophenyl)ethyl)amino)-4- methylpyrido[3,4-d]pyridazin-7-yl)benzyl)piperidin-4-yl)phenyl)-3-methylpiperidine-2, 6-dione B125; (R) - 3 -(4 - ( 1 - ( 5 -( 1 - (((R) - 1 -(3 -(difluoromethy l)-2-fluoropheny l)ethyl)amino)-4- methylpyrido[3,4-d]pyridazin-7-yl)-2-fluorobenzyl)piperidin-4-yl)phenyl)-3-methylpiperidine- 2,6-dione B126; (R)-3 -(4-(l -(5-( 1 - (((R) - 1 -(3 -(difluoromethyl)-2-fluoropheny l)ethyl)amino)-4- methylpyrido[3,4-d]pyridazin-7-yl)-2-fluorobenzyl)piperidin-4-yl)phenyl)-3-methylpiperidine- 2,6-dione B127; (R)-3-(4-(1-(5-(1-(((R)-1-(3-(difluoromethyl)-2-methylphenyl)ethyl)amino)-4- methylpyrido[3,4--d]pyridazin-7-yl)-2-fluorobenzyl)piperidin-4-yl)phenyl)-3-methylpiperidine- 2, 6-dione B128; (R)-3-(4-(1-(2-fluoro-5-(1-(((R)-1-(3-fluoro-2-methylphenyl)ethyl)amino)-4-methylpyrido[3,4-d ]pyridazin-7-yl)benzyl)pi peri din-4-yl)phenyl)-3-methylpiperidine-2, 6-dione B129;3-(4-(1-(5-(l - ( ((R)- 1 -(3 -(difluoromethyl)-2-fluorophenyl)ethyl)amino)-4-methyl- pyrido[3,4-d ]pyridazin-7-yl)-2-fluorobenzyl)piperidin-4-yl)-3-methylphenyl)piperidine-2,6- dione B130;3 -(4-( 1 -( 5 -( 1 -(((R)- 1 -(3 -(difluorom ethyl )-2-fluorophenyl )ethyl)amino)-4-methyl- pyrido[3,4-d ]pyridazin-7-yl)-2-fluorobenzyl)piperidin-4-yl)-3-fluorophenyl)piperidine-2, 6-dione B131;3 -(4-( 1 -(((R)-4-( 1 -(((R)- 1 -(3 -(difluoromethyl)-2-fluorophenyl)ethyl)amino)-4- methylpyrido[3,4--d]pyridazin-7-yl)morpholin-2-yl)methyl)piperidin-4-yl)-3-methylphenyl)- piperidine-2, 6-dione B132; (R)-3 -(4-( 1 -(3 -( 1 -(((R)- 1 -(3 -(difluorom ethyl)-2-flu orophenyl)ethyl)amino)-4- methylpyrido[3,4-d ]pyridazin-7-yl)-2-fluorobenzyl)piperidin-4-yl)phenyl)-3-methylpiperidine- 2,6-dione B133; (R)-3 -(4-( 1 -(3 -( 1 -(((R)- 1 -(3 -(difluorom ethyl)-2-flu oropheny l)ethyl)amino)-4- methylpyrido[3,4--d]pyridazin-7-yl)-5-fluorobenzyl)piperidin-4-yl)phenyl)-3-methylpiperidine- 2, 6-dione B134; (R)-3 -(4-( 1 -(3 -( 1 -(((R)- 1 -(3 -(difluorom ethyl)-2-flu orophenyl)ethyl)amino)-4- methylpyrido[3,4--d]pyridazin-7-yl)-4-fluorobenzyl)piperidin-4-yl)phenyl)-3-methylpiperidine- 2, 6-dione B135; (R)-3 -(4-( 1 -(((R)-4-( 1 -(((R)- 1 -(3 -(difluorom ethyl)-2-fluorophenyl)ethy l)amino)-4- methylpyrido[3,4--d]pyridazin-7-yl)morpholin-2-yl)methyl)piperidin-4-yl)phenyl)-3-methyl- piperidine-2, 6-dione B136; (R)-3 -(4-( 1 -(3 -( 1 -(((R)- 1 -(3 -(difluoromethyl)-2-fluorophenyl)ethyl)amino)-4- methylpyrido[3,4--d]pyridazin-7-yl)benzyl)piperidin-4-yl)-3-methylphenyl)-3-mefhylpiperidine- 2, 6-dione B137; (R)-3 -(4-( 1 -(5 -( 1 -(((R)- 1 -(3 -(difluoromethyl)-2-methylphenyl)ethyl)amino)-4- methylpyrido[3,4--d]pyridazin-7-yl)-2-fluorobenzyl)piperidin-4-yl)-3-methylphenyl)-3-mefhyl- piperidine-2, 6-dione B138; (R) - 3 -(4 - ( 1 - ( 5 -( 1 - (((R) - 1 -(3 -(difluorom ethy l)-2-fluoropheny l)ethyl)amino)-4- methylpyrido[3,4-d ]pyridazin-7-yl)-2-fluorobenzyl)piperidin-4-yl)-3-methylphenyl)-3-methyl-piperidine-2, 6-dione B139;(R)-3 -(4-( 1 -(5 -( 1 -(((R)- 1 -(3 -(difluoromethyl)-2-fluorophenyl)ethyl)amino)-4- methylpyrido[3,4-d]pyridazin-7-yl)-2-fluorobenzyl)-l,2,3,6-tetrahydropyridin-4-yl)-3-methyl- phenyl)-3-methylpiperidine-2, 6-dione B140;(R)-3 -(4-( 1 -((4-( 1 -(((R)- 1 -(3 -(difluoromethyl)-2-fluorophenyl)ethyl)amino)-4- methylpyrido[3,4--d]pyridazin-7-yl)furan-2-yl)methyl)piperidin-4-yl)-3-methylphenyl)-3-methyl- piperidine-2, 6-dione B141;(37?) - 3 -(4-(8-(((R)-4-( 1 -(((R)- 1 -(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)- 4-methylpyrido[3,4-d ]pyridazin-7-yl)morpholin-2-yl)methyl)-8-azabicyclo[3.2.1]octan-3-yl)-3- methylphenyl)-3-methylpiperidine-2, 6-dione B142;(37?) - 3 -(4 - (8 - (5 - ( 1 -(((R) - 1 - (3 -(difluoromethyl)-2-fluorophenyl)ethyl)amino)-4- methylpyrido[3,4-d ]pyridazin-7-yl)-2-fluorobenzyl)-8-azabicyclo[3.2.1]octan-3-yl)-3-methyl- phenyl)-3-methylpiperidine-2, 6-dione B143; (R) - 3 -( 4 - ( 1 - ( (5 - ( 1 - (((R)- 1 -(3 -(difluoromethyl)-2-fluorophenyl)ethyl )amino)-4- methylpyrido[3,4-d ]pyridazin-7-yl)pyridin-3-yl)methyl)piperidin-4-yl)-3-methylphenyl)-3- methylpiperidine-2, 6-dione B144; (R) - 3 -(4 - ( 1 - ( 5 -( 1 - (((R) - 1 -(3 -(difluoromethyl)-2-fhiorophenyl)ethyl)amino)-4- methylpyrido[3,4-d ]pyridazin-7-yl)-2-fluorobenzyl)piperidin-4-yl)-3-(trifluorornethyl)phenyl)-3- methylpiperidine-2, 6-dione B145;(R)-3 -(4-( 1 -(3 -( 1 - (((R) - 1 -(3 -(difluoromethyl)-2-fluorophenyl)ethyl)amino)-4- methylpyrido[3,4--d]pyridazin-7-yl)benzyl)piperidin-4-yl)-3-(trifluoromethyl)phenyl)-3-methyl- piperidine-2, 6-dione B146; (R)-3 -(4-( 1 -(3 -( 1 -(((R)- 1 -(3 -(difluoromethyl)-2-fluorophenyl)ethyl)amino)-4- methylpyrido[3,4-d ]pyridazin-7-yl)benzyl)piperidin-4-yl)-3-fluoro-5-methylphenyl)-3-methyl- piperidine-2, 6-dione B147; (R)-3 -(4-( 1 -(5 -( 1 -(((R)- 1 -(3 -(difluoromethyl)-2-fluoropheny l)ethyl)amino)-4- methylpyrido[3,4--d]pyridazin-7-yl)-2-fluorobenzyl)piperidin-4-yl)-3-fluoro-5-methylphenyl)-3- methylpiperidine-2, 6-dione B148; (R)-3 -(4-( 1 -((4-( 1 -(((R)- 1 -(3 -(difluoromethyl)-2-fluorophenyl)ethyl)amino)-4- methylpyrido[3,4--d]pyridazin-7-yl)thiophen-2-yl)methyl)piperidin-4-yl)-3-methylphenyl)-3- methylpiperidine-2, 6-dione B149;(R)-3-(4-(l -(5-(1-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)arnino)-4- methylpyrido[3,4--d]pyridazin-7-yl)-2-fluorobenzyl)piperidin-4-yl)-3-fluorophenyl)-3-methyl- piperidine-2, 6-dione B150;(R)-3 -(4-( 1 -(3 -( 1 -(((R)- 1 -(3 -(difluoromethyl)-2-fluorophenyl)ethyl)amino)-4- methylpyrido[3,4-d]pyridazin-7-yl)benzyl)piperidin-4-yl)-3-fluorophenyl)-3-methylpiperidine- 2,6-dione B151; (R)-3 -(4-( 1 -(5 -( 1 -(((R)- 1 -(3 -(difluoromethyl)-2-fluorophenyl)ethyl)amino)-4- methylpyrido[3,4--d]pyridazin-7-yl)-2-fluorobenzoyl)piperidin-4-yl)phenyl)-3-methylpiperidine-2.6-dione B152;((R)-3 -(4-( 1 -(5 -( 1 -(((R)- 1 -(3 -(difluorornethyl)-2-fluorophenyl)ethyl)amino)-4- methylpyrido[3,4--d]pyridazin-7-yl)-2-fluorobenzyl)piperidin-4-yl)-3-methylphenyl)-3-methyl-2.6-dioxopiperidin-l-yl)methyl pivalate B153;3 -(4-( 1 -(3 -( 1 -(((R)- 1 -(3 -(difluoromethyl)-2-fluorophenyl)ethyl)amino)-4-methyl- pyrido[3,4-d]pyridazin-7-yl)benzyl)piperidin-4-yl)-3-methylphenyl)piperidine-2, 6-dione B154; (R)-3 -(4-( 1 -((4-( 1 -(((R)- 1 -(3 -(difluoromethyl)-2-fluorophenyl)ethyl)amino)-4- methylpyrido[3,4--d]pyridazin-7-yl)pyridin-2-yl)methyl)piperidin-4-yl)-3-methylphenyl)-3- methylpiperidine-2, 6-dione B155; (R)-3 -(3 -chloro-4-( 1 -(5-( 1 -(((R)- 1 -(3 -(difluoromethy l)-2-fluorophenyl)ethyl)- amino)-4-methylpyrido[3,4-d]pyridazin-7-yl)-2-fluorobenzyl)piperidin-4-yl)phenyl)-3-methyl- piperidine-2, 6-dione B156; (R)-3-(3-chloro-4-(1-(3-(1-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)- amino)-4-methylpyrido[3,4-d]pyridazin-7-yl)benzyl)piperidin-4-yl)phenyl)-3-methylpiperidine-2.6-dione B157; (R)-3 -(3 -cy clopropyl-4-( 1 -(5 -( 1 -(((R)- 1 -(3 -(difluoromethyl)-2-fluorophenyl)- ethyl)amino)-4-methylpyrido[3,4-d]pyridazin-7-yl)-2-fluorobenzyl)piperidin-4-yl)phenyl)-3- methylpiperidine-2, 6-dione B158;(R)-3 -(3 -cy clopropyl-4-( 1 -(3 -( 1 -(((R)- 1 -(3 -(difluoromethyl)-2-fluorophenyl)- ethyl)amino)-4-methylpyrido[3,4-d]pyridazin-7-yl)benzyl)piperidin-4-yl)phenyl)-3-methyl- piperidine-2, 6-dione B159;(R)-3 -(4-( 1 -(( (S)- 1 -( 1 -(((R)- 1 -(3 -(difluoromethyl)-2-fluorophenyl)ethyl)amino)-4- methylpyrido[3,4-d]pyridazin-7-yl)-3-fluoropiperidin-3-yl)methyl)piperidin-4-yl)-3-methyl-phenyl)-3-methylpiperidine-2, 6-dione B160;(R)-3 -(4-( 1 -(5 -( 1 -(((R)- 1 -(3 -(difluoromethy l)-2-fluorophenyl)ethyl)amino)-4- methylpyrido[3,4--d]pyridazin-7-yl)-2-fluorobenzyl)piperidin-4-yl)-3,5-difluorophenyl)-3- methylpiperidine-2, 6-dione B161;(R)-3 -(4-( 1 -(3 -( 1 - (((R) - 1 -(3 -(difluoromethy l)-2-fluorophenyl)ethyl)amino)-4- methylpyrido[3,4--d]pyridazin-7-yl)benzyl)piperidin-4-yl)-3-fluoro-2-methylphenyl)-3-methyl- piperidine-2, 6-dione B162;(R)-3 -(3 -(difluoromethyl)-4-( 1 -(5 -( 1 -(((R)- 1 -(3 -(difluoromethy l)-2-fluoro- phenyl)ethyl)amino)-4-methylpyrido[3,4-d]pyridazin-7-yl)-2-fluorobenzyl)piperidin-4-yl)- phenyl)-3-methylpiperidine-2, 6-dione B163;(R)-3 -(3 -(difluoromethyl)-4-( 1 -(3 -( 1 -(((R)- 1 -(3 -(difluoromethyl)-2-fluoro- phenyl)ethyl)amino)-4-methylpyrido[3,4-d]pyridazin-7-yl)benzyl)piperidin-4-yl)phenyl)-3- methylpiperidine-2, 6-dione B164;(R)-3 -(4-( 1 -(3 -( 1 -(((R)- 1 -(3 -(difluoromethyl)-2-fluorophenyl)ethyl)amino)-4- methylpyrido[3,4-d]pyridazin-7-yl)benzyl)piperidin-4-yl)-3,5-difluorophenyl)-3-methyl- piperidine-2, 6-dione B165;3-(4-(1-(3-(1-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-4-methyl- pyrido[3,4-d]pyridazin-7-yl)benzyl)piperidin-4-yl)-3-fluoro-5-methylphenyl)piperidine-2,6- dione B166;3-(4-(1-(5-(1-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-4-methyl- pyrido[3,4-d]pyridazin-7-yl)-2-fluorobenzyl)piperidin-4-yl)-3-fluoro-5-methylphenyl)piperidine- 2,6-dione B167; (R)-1-(4-(1-(5-(1-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-4-methyl- pyrido[3,4-d]pyridazin-7-yl)-2-fluorobenzyl)piperidin-4-yl)phenyl)dihydropyrimidine- 2, 4( 1H,370-dione B201; (R)-3 -(4-( 1 -((6-(4-(((R)- 1 -(3 -(difluoromethyl)-2-fluorophenyl)ethyl)amino)- 1 - methylphthalazin-6-yl)pyri din-2 -yl)methyl)piperidin-4-yl)-3-methylphenyl)-3-methylpiperidine- 2, 6-dione C001; (R)-3 -(4-( 1 -((2-(4-(((R)- 1 -(3 -(difluoromethyl)-2-fluorophenyl)ethyl)amino)- 1 - methylphthal azin-6-yl)pyri din-4-yl)methyl)piperidin-4-yl)-3-methylphenyl)-3-methylpiperidine- 2, 6-dione C002; or(R)-3-(4-(l -((4-(4-(((R)-l -(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-l - methylphthalazin-6-yl)pyri din-2 -yl)methyl)piperidin-4-yl)-3-methylphenyl)-3-methylpiperidine- 2,6-dione C003; or an enantiomer, a mixture of enantiomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

156. A pharmaceutical composition comprising the compound of any one of claims 1 to 155, 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, or hydrate thereof; and a pharmaceutically acceptable excipient.

157. The pharmaceutical composition of claim 156, wherein the composition is in single dosage form.

158. The pharmaceutical composition of claim 156 or 157, wherein the composition is in an oral, parenteral, or intravenous dosage form.

159. The pharmaceutical composition of claim 158, wherein the composition is formulated in an oral dosage form.

160. The pharmaceutical composition of claim 159, wherein the oral dosage form is a tablet or capsule.

161. A method of treating, preventing, or ameliorating one or more symptoms of a disorder, disease, or condition mediated by a son of sevenless homolog 1 (S0S1) in a subject, comprising administering to the subject in need thereof a therapeutically effective amount of a compound of a compound of any one of claims 1 to 155 or a pharmaceutical composition of any one of claims 156 to 160.

162. The method of claim 161, wherein the disorder, disease, or condition mediated by the S0S1 is a proliferative disease.

163. A method of treating, preventing, or ameliorating one or more symptoms of adisorder, disease, or condition mediated by a RAS in a subject, comprising administering to the subject in need thereof a therapeutically effective amount of a compound of any one of claims 1 to 155 or a pharmaceutical composition of any one of claims 156 to 160.

164. The method of claim 163, wherein the disorder, disease, or condition mediated by the RAS is a proliferative disease.

165. A method of treating, preventing, or ameliorating one or more symptoms of a proliferative disease in a subject, comprising administering to the subject in need thereof a therapeutically effective amount of a compound of any one of claims 1 to 155 or a pharmaceutical composition of any one of claims 156 to 160.

166. The method of claim 163, 164, or 165, wherein the proliferative disease is cancer.

167. The method of claim 166, wherein the cancer is colon cancer, colorectal cancer, lung cancer, or pancreatic cancer.

168. The method of claim 166 or 167, wherein the cancer is relapsed or refractory.

169. The method of any one of claims 166 to 168, wherein the cancer is metastatic.

170. The method of any one of claims 166 to 169, wherein the cancer is drug-resistant.

171. The method of any one of claims 161 to 170, wherein the subject is a human.

172. A method of inhibiting the growth of a cell, comprising contacting the cell with an effective amount of a compound of any one of claims 1 to 155 or a pharmaceutical composition of any one of claims 156 to 160.

173. The method of claim 172, wherein the cell is a cancerous cell.

174. A method of inducing degradation of an S0S1, comprising contacting the S0S1 with an effective amount of a compound of any one of claims 1 to 155 or a pharmaceutical composition of any one of claims 156 to 160.

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