WO2023023474A1 - Tr-beta modulators, pharmaceutical compositions, and therapeutic applications - Google Patents

Abstract

Provided herein are TRβ modulators, for example, 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 a TRβ-mediated disorder, disease, or condition.

Description

TR-BETA MODULATORS, PHARMACEUTICAL COMPOSITIONS, AND THERAPEUTIC APPLICATIONS CROSS REFERENCE TO RELATED APPLICATION [0001] This application claims the benefit of the priority of U.S. Provisional Application No.63/233,358, filed August 16, 2021; the disclosure of which is incorporated herein by reference in its entirety. FIELD [0002] Provided herein are TRβ modulators and pharmaceutical compositions thereof. Also provided herein are methods of their use for treating, preventing, or ameliorating one or more symptoms of a TRβ-mediated disorder, disease, or condition. BACKGROUND [0003] Thyroid hormones (THs) are indispensable for normal development and metabolism of virtually all human cells. Yen, Physiol. Rev.2001, 81, 1097-142; Mullur et al., Physiol. Rev.2014, 94, 355-82. Thyroxine (T4), the parental form of the THs, and triiodothyronine (T3), the major active form of the THs, are produced and released from the thyroid gland in response to the thyroid-stimulating hormone (TSH). Souza et al., Mol. Endocrinol.2014, 28, 534-45. Canonical TH signaling is based on their interactions with nuclear TH receptors (TRs), leading to activation or repression of the transcription of a large number of genes. There are two subtypes of TH receptors, TH receptor α (TRα) and TH receptor β (TRβ). Ortiga-Carvalho et al., Nat. Rev. Endocrinol.2014, 10, 582-91. TRα1 is the major TR isoform in the heart, also expressed in other tissues, including skeletal muscle, brain, cartilage, and bone. TRα2 lacks part of the TH binding domain, so it is unable to bind TH and thought to mediate constitutive repression of transcription. TRβ1 is found in the liver, kidney, and skeletal muscle, while TRβ2 is mainly expressed in the brain and anterior pituitary, where it regulates the negative feedback mechanism of the TH in the hypothalamic-pituitary-thyroid axis. TRβ plays an important role in lipid metabolism and thyroid-stimulating hormone (TSH) suppression, whereas TRα plays an important role in regulating the heart rate. Wikström et al., EMBO J. 1998, 17, 455-61; Forrest & Vennström, Thyroid 2000, 10, 41-52; O’Shea & Williams, J. Endocrinol.2002, 175, 553-70; Flamant & Samarut, Trends Endocrinol. Metab.2003, 14, 85-90. [0004] Thyroid hormone mimetics are compounds that are structurally similar to the THs and designed to interact with their molecular targets - nuclear TRs. Studies have shown that thyroid hormone mimetics affect organ-specific fat deposition and reduce body fat by increasing the basal metabolic rate. They reduce serum cholesterol, reverse hepatic steatosis, increase mitochondrial activity, and exhibit beneficial effects on apolipoprotein(a) (LpA), an atherogenic lipoprotein particle. [0005] The functional consequence of TR subtype distribution suggests that TRβ- selective agonists can be advantageous in asserting some of these beneficial effects without cardiac thyrotoxicosis. Selective TRβ agonists (e.g., sobetirome and eprotirome) aimed at dyslipidemia, particularly hypercholesterolemia, have been studied clinically. Both sobetirome and eprotirome were reported to produce a significant reduction in total and LDL cholesterol after 2-3 weeks of treatment in small groups of hypercholesterolemia patients. Despite the recognition of their therapeutical potentials, no selective TRβ agonists have yet been approved for clinical use. Therefore, there is a need for an effective and safe selective TRβ agonist as a therapeutic agent. SUMMARY OF THE DISCLOSURE [0006] Provided herein is a compound of Formula (I): or an enantiomer, a mixture o

enant omers, a d astereomer, a m xture 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, R², R⁴, and R⁵ are each independently (i) hydrogen, deuterium, cyano, halo, or nitro; (ii) C_1-6 alkyl, C_1-6 heteroalkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_3-10 cycloalkyl, C_6-14 aryl, C_7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) –C(O)R^1a, –C(O)OR^1a, –C(O)NR^1bR^1c, –C(O)SR^1a, –C(NR^1a)NR^1bR^1c, –C(S)R^1a, –C(S)OR^1a, –C(S)NR^1bR^1c, –OR^1a, –OC(O)R^1a, –OC(O)OR^1a, –OC(O)NR^1bR^1c, –OC(O)SR^1a, –OC(NR^1a)NR^1bR^1c, –OC(S)R^1a, –OC(S)OR^1a, –OC(S)NR^1bR^1c, –OS(O)R^1a, –OS(O)₂R^1a, –OS(O)NR^1bR^1c, –OS(O)₂NR^1bR^1c, –NR^1bR^1c, –NR^1aC(O)R^1d, –NR^1aC(O)OR^1d, –NR^1aC(O)NR^1bR^1c, –NR^1aC(O)SR^1d, –NR^1aC(NR^1d)NR^1bR^1c, –NR^1aC(S)R^1d, –NR^1aC(S)OR^1d, –NR^1aC(S)NR^1bR^1c, –NR^1aS(O)R^1d, –NR^1aS(O)₂R^1d, –NR^1aS(O)NR^1bR^1c, –NR^1aS(O)₂NR^1bR^1c, –SR^1a, –S(O)R^1a, –S(O)₂R^1a, –S(O)NR^1bR^1c, or –S(O)₂NR^1bR^1c; R³ is heteroaryl; R⁶ is (i) hydrogen; (ii) C_1-6 alkyl, C_1-6 heteroalkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_3-10 cycloalkyl, C_6-14 aryl, C_7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) –C(O)R^1a, –C(O)OR^1a, –C(O)NR^1bR^1c, –C(O)SR^1a, –C(NR^1a)NR^1bR^1c, –C(S)R^1a, –C(S)OR^1a, –C(S)NR^1bR^1c, –OR^1a, –OC(O)R^1a, –OC(O)OR^1a, –OC(O)NR^1bR^1c, –OC(O)SR^1a, –OC(NR^1a)NR^1bR^1c, –OC(S)R^1a, –OC(S)OR^1a, –OC(S)NR^1bR^1c, –OS(O)R^1a, –OS(O)₂R^1a, –OS(O)NR^1bR^1c, –OS(O)₂NR^1bR^1c, –NR^1bR^1c, –NR^1aC(O)R^1d, –NR^1aC(O)OR^1d, –NR^1aC(O)NR^1bR^1c, –NR^1aC(O)SR^1d, –NR^1aC(NR^1d)NR^1bR^1c, –NR^1aC(S)R^1d, –NR^1aC(S)OR^1d, –NR^1aC(S)NR^1bR^1c, –NR^1aS(O)R^1d, –NR^1aS(O)₂R^1d, –NR^1aS(O)NR^1bR^1c, –NR^1aS(O)₂NR^1bR^1c, –S(O)R^1a, –S(O)₂R^1a, –S(O)NR^1bR^1c, or –S(O)₂NR^1bR^1c; R^7a and R^7b are each independently (i) hydrogen, deuterium, cyano, halo, or nitro; (ii) C_1-6 alkyl, C_1-6 heteroalkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_3-10 cycloalkyl, C_6-14 aryl, C_7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) –C(O)R^1a, –C(O)OR^1a, –C(O)NR^1bR^1c, –C(O)SR^1a, –C(NR^1a)NR^1bR^1c, –C(S)R^1a, –C(S)OR^1a, –C(S)NR^1bR^1c, –OR^1a, –OC(O)R^1a, –OC(O)OR^1a, –OC(O)NR^1bR^1c, –OC(O)SR^1a, –OC(NR^1a)NR^1bR^1c, –OC(S)R^1a, –OC(S)OR^1a, –OC(S)NR^1bR^1c, –OS(O)R^1a, –OS(O)₂R^1a, –OS(O)NR^1bR^1c, –OS(O)₂NR^1bR^1c, –NR^1bR^1c, –NR^1aC(O)R^1d, –NR^1aC(O)OR^1d, –NR^1aC(O)NR^1bR^1c, –NR^1aC(O)SR^1d, –NR^1aC(NR^1d)NR^1bR^1c, –NR^1aC(S)R^1d, –NR^1aC(S)OR^1d, –NR^1aC(S)NR^1bR^1c, –NR^1aS(O)R^1d, –NR^1aS(O)₂R^1d, –NR^1aS(O)NR^1bR^1c, –NR^1aS(O)₂NR^1bR^1c, –SR^1a, –S(O)R^1a, –S(O)₂R^1a, –S(O)NR^1bR^1c, or –S(O)₂NR^1bR^1c; or R^7a and R^7b together with the carbon atom to which they are attached form C(O), C_3-10 cycloalkylene, or heterocyclylene; R^8a and R^8b are each independently (i) hydrogen, deuterium, cyano, halo, or nitro; (ii) C_1-6 alkyl, C_1-6 heteroalkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_3-10 cycloalkyl, C_6-14 aryl, C_7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) –C(O)R^1a, –C(O)OR^1a, –C(O)NR^1bR^1c, –C(O)SR^1a, –C(NR^1a)NR^1bR^1c, –C(S)R^1a, –C(S)OR^1a, –C(S)NR^1bR^1c, –OR^1a, –OC(O)R^1a, –OC(O)OR^1a, –OC(O)NR^1bR^1c, –OC(O)SR^1a, –OC(NR^1a)NR^1bR^1c, –OC(S)R^1a, –OC(S)OR^1a, –OC(S)NR^1bR^1c, –OS(O)R^1a, –OS(O)₂R^1a, –OS(O)NR^1bR^1c, –OS(O)₂NR^1bR^1c, –NR^1bR^1c, –NR^1aC(O)R^1d, –NR^1aC(O)OR^1d, –NR^1aC(O)NR^1bR^1c, –NR^1aC(O)SR^1d, –NR^1aC(NR^1d)NR^1bR^1c, –NR^1aC(S)R^1d, –NR^1aC(S)OR^1d, –NR^1aC(S)NR^1bR^1c, –NR^1aS(O)R^1d, –NR^1aS(O)₂R^1d, –NR^1aS(O)NR^1bR^1c, –NR^1aS(O)₂NR^1bR^1c, –SR^1a, –S(O)R^1a, –S(O)₂R^1a, –S(O)NR^1bR^1c, or –S(O)₂NR^1bR^1c; or R^8a and R^8b together with the carbon atom to which they are attached form C(O), C_3-10 cycloalkylene, or heterocyclylene; A is –O–, –S–, –NR^A1–, or –C(R^A2R^A3)–; L is a bond, –O–, –S–, –NR^1a–, or –C(O)N(R^1a)–; U, V, and W are each independently CR^U or N; X and Y are each independently a bond, –O–, –S–, –NR^X1–, or –C(R^X2R^X3)–; Z is –O–, –S–, –NR^Z1–, or –C(R^Z2R^Z3)–; each R^A1, R^X1 and R^Z1 is independently (i) hydrogen; (ii) C_1-6 alkyl, C_1-6 heteroalkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_3-10 cycloalkyl, C_6-14 aryl, C_7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) –C(O)R^1a, –C(O)OR^1a, –C(O)NR^1bR^1c, –C(O)SR^1a, –C(NR^1a)NR^1bR^1c, –C(S)R^1a, –C(S)OR^1a, –C(S)NR^1bR^1c, –OR^1a, –OC(O)R^1a, –OC(O)OR^1a, –OC(O)NR^1bR^1c, –OC(O)SR^1a, –OC(NR^1a)NR^1bR^1c, –OC(S)R^1a, –OC(S)OR^1a, –OC(S)NR^1bR^1c, –OS(O)R^1a, –OS(O)₂R^1a, –OS(O)NR^1bR^1c, –OS(O)₂NR^1bR^1c, –NR^1bR^1c, –NR^1aC(O)R^1d, –NR^1aC(O)OR^1d, –NR^1aC(O)NR^1bR^1c, –NR^1aC(O)SR^1d, –NR^1aC(NR^1d)NR^1bR^1c, –NR^1aC(S)R^1d, –NR^1aC(S)OR^1d, –NR^1aC(S)NR^1bR^1c, –NR^1aS(O)R^1d, –NR^1aS(O)₂R^1d, –NR^1aS(O)NR^1bR^1c, –NR^1aS(O)₂NR^1bR^1c, –S(O)R^1a, –S(O)₂R^1a, –S(O)NR^1bR^1c, or –S(O)₂NR^1bR^1c; each R^A2, R^A3, R^U, R^X2, R^X3, R^Z2, and R^Z3 is independently (i) hydrogen, deuterium, cyano, halo, or nitro; (ii) C_1-6 alkyl, C_1-6 heteroalkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_3-10 cycloalkyl, C_6-14 aryl, C_7-15 aralkyl, heteroaryl, or heterocyclyl; (iii) –C(O)R^1a, –C(O)OR^1a, –C(O)NR^1bR^1c, –C(O)SR^1a, –C(NR^1a)NR^1bR^1c, –C(S)R^1a, –C(S)OR^1a, –C(S)NR^1bR^1c, –OR^1a, –OC(O)R^1a, –OC(O)OR^1a, –OC(O)NR^1bR^1c, –OC(O)SR^1a, –OC(NR^1a)NR^1bR^1c, –OC(S)R^1a, –OC(S)OR^1a, –OC(S)NR^1bR^1c, –OS(O)R^1a, –OS(O)₂R^1a, –OS(O)NR^1bR^1c, –OS(O)₂NR^1bR^1c, –NR^1bR^1c, –NR^1aC(O)R^1d, –NR^1aC(O)OR^1d, –NR^1aC(O)NR^1bR^1c, –NR^1aC(O)SR^1d, –NR^1aC(NR^1d)NR^1bR^1c, –NR^1aC(S)R^1d, –NR^1aC(S)OR^1d, –NR^1aC(S)NR^1bR^1c, –NR^1aS(O)R^1d, –NR^1aS(O)₂R^1d, –NR^1aS(O)NR^1bR^1c, –NR^1aS(O)₂NR^1bR^1c, –SR^1a, –S(O)R^1a, –S(O)₂R^1a, –S(O)NR^1bR^1c, or –S(O)₂NR^1bR^1c; or R^A2 and R^A3 together with the C atom to which they are attached form C_3-10 cycloalkylene or heterocyclylene; or R^X2 and R^X3 together with the C atom to which they are attached form C_3-10 cycloalkylene or heterocyclylene; or R^Z2 and R^Z3 together with the C atom to which they are attached form C_3-10 cycloalkylene or heterocyclylene; and each R^1a, R^1b, R^1c, and R^1d is independently hydrogen, deuterium, C_1-6 alkyl, C_1-6 heteroalkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_3-10 cycloalkyl, C_6-14 aryl, C_7-15 aralkyl, heteroaryl, or heterocyclyl; wherein each alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylene, aryl, aralkyl, heteroaryl, 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) C_1-6 alkyl, C_1-6 heteroalkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_3-10 cycloalkyl, C_6-14 aryl, C_7-15 aralkyl, heteroaryl, and heterocyclyl, each of which is further optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Q^a; and (c) –C(O)R^a, –C(O)OR^a, –C(O)NR^bR^c, –C(O)SR^a, –C(NR^a)NR^bR^c, –C(S)R^a, –C(S)OR^a, –C(S)NR^bR^c, –OR^a, –OC(O)R^a, –OC(O)OR^a, –OC(O)NR^bR^c, –OC(O)SR^a, –OC(NR^a)NR^bR^c, –OC(S)R^a, –OC(S)OR^a, –OC(S)NR^bR^c, –OP(O)(OR^b)OR^c, –OS(O)R^a, –OS(O)₂R^a, –OS(O)NR^bR^c, –OS(O)₂NR^bR^c, –NR^bR^c, –NR^aC(O)R^d, –NR^aC(O)OR^d, –NR^aC(O)NR^bR^c, –NR^aC(O)SR^d, –NR^aC(NR^d)NR^bR^c, –NR^aC(S)R^d, –NR^aC(S)OR^d, –NR^aC(S)NR^bR^c, –NR^aS(O)R^d, –NR^aS(O)₂R^d, –NR^aS(O)NR^bR^c, –NR^aS(O)₂NR^bR^c, –SR^a, –S(O)R^a, –S(O)₂R^a, –S(O)NR^bR^c, and –S(O)₂NR^bR^c, wherein each R^a, R^b, R^c, and R^d is independently (i) hydrogen or deuterium; (ii) C_1-6 alkyl, C_1-6 heteroalkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_3-10 cycloalkyl, C_6-14 aryl, C_7-15 aralkyl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Q^a; or (iii) R^b and R^c together 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 Q^a; wherein each Q^a is independently selected from: (a) deuterium, cyano, halo, nitro, imino, and oxo; (b) C_1-6 alkyl, C_1-6 heteroalkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_3-10 cycloalkyl, C_6-14 aryl, C_7-15 aralkyl, heteroaryl, and heterocyclyl; and (c) –C(O)R^e, –C(O)OR^e, –C(O)NR^fR^g, –C(O)SR^e, –C(NR^e)NR^fR^g, –C(S)R^e, –C(S)OR^e, –C(S)NR^fR^g, –OR^e, –OC(O)R^e, –OC(O)OR^e, –OC(O)NR^fR^g, –OC(O)SR^e, –OC(NR^e)NR^fR^g, –OC(S)R^e, –OC(S)OR^e, –OC(S)NR^fR^g, –OP(O)(OR^f)OR^g, –OS(O)R^e, –OS(O)₂R^e, –OS(O)NR^fR^g, –OS(O)₂NR^fR^g, –NR^fR^g, –NR^eC(O)R^h, –NR^eC(O)OR^f, –NR^eC(O)NR^fR^g, –NR^eC(O)SR^f, –NR^eC(NR^h)NR^fR^g, –NR^eC(S)R^h, –NR^eC(S)OR^f, –NR^eC(S)NR^fR^g, –NR^eS(O)R^h, –NR^eS(O)₂R^h, –NR^eS(O)NR^fR^g, –NR^eS(O)₂NR^fR^g, –SR^e, –S(O)R^e, –S(O)₂R^e, –S(O)NR^fR^g, and –S(O)₂NR^fR^g; wherein each R^e, R^f, R^g, and R^h is independently (i) hydrogen or deuterium; (ii) C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_3-10 cycloalkyl, C_6-14 aryl, C_7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) R^f and R^g together with the N atom to which they are attached form heterocyclyl. [0007] 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. [0008] Additionally, provided herein is a method of treating, preventing, or ameliorating one or more symptoms of a TRβ-mediated disorder, disease, or condition 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. [0009] Furthermore, provided herein is a method of treating, preventing, or ameliorating one or more symptoms of a liver 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. DETAILED DESCRIPTION [0010] To facilitate understanding of the disclosure set forth herein, a number of terms are defined below. [0011] 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. [0012] 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. [0013] 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. [0014] 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. [0015] 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. [0016] 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, or tissue 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. [0017] 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. [0018] The term “IC50” or “EC₅₀” refers to an amount, concentration, or dosage of a compound that is required for 50% inhibition of a maximal response in an assay that measures such a response. [0019] 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 filler, 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 et al., Eds.; Pharmaceutical Press, 2020; Handbook of Pharmaceutical Additives, 3rd ed.; Ash and Ash Eds.; Synapse Information Resources, 2007; Pharmaceutical Preformulation and Formulation, 1st ed.; Gibson Ed.; CRC Press, 2015. [0020] The term “about” or “approximately” means an acceptable error for a particular value 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. [0021] 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, C_1-6 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 (C_1-20), 1 to 15 (C_1-15), 1 to 10 (C_1-10), or 1 to 6 (C_1-6) carbon atoms, or branched saturated monovalent hydrocarbon radical of 3 to 20 (C_3-20), 3 to 15 (C_3-15), 3 to 10 (C_3-10), or 3 to 6 (C_3-6) carbon atoms. As used herein, linear C_1-6 and branched C_3-6 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., n-propyl and isopropyl), butyl (including all isomeric forms, e.g., n-butyl, isobutyl, sec-butyl, and t-butyl), pentyl (including all isomeric forms, e.g., n-pentyl, isopentyl, sec-pentyl, neopentyl, and tert-pentyl), and hexyl (including all isomeric forms, e.g., n-hexyl, isohexyl, and sec-hexyl). [0022] 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, C_1-6 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 (C_1-20), 1 to 15 (C_1-15), 1 to 10 (C_1-10), or 1 to 6 (C_1-6) carbon atoms, or branched saturated monovalent hydrocarbon radical of 3 to 20 (C_3-20), 3 to 15 (C_3-15), 3 to 10 (C_3-10), or 3 to 6 (C_3-6) carbon atoms. As used herein, linear C_1-6 and branched C_3-6 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)CH₃ and –NHC(O)CH₂CH₃. [0023] 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” or “E” configuration or a mixture thereof, as appreciated by those of ordinary skill in the art. For example, C_2-6 alkenyl refers to a linear unsaturated monovalent hydrocarbon radical of 2 to 6 carbon atoms or a branched unsaturated monovalent hydrocarbon radical of 3 to 6 carbon atoms. In certain embodiments, the alkenyl is a linear monovalent hydrocarbon radical of 2 to 20 (C_2-20), 2 to 15 (C_2-15), 2 to 10 (C_2-10), or 2 to 6 (C_2-6) carbon atoms, or a branched monovalent hydrocarbon radical of 3 to 20 (C_3-20), 3 to 15 (C_3-15), 3 to 10 (C_3-10), or 3 to 6 (C_3-6) 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-1-yl). [0024] 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 carbon- carbon double bond. The alkynyl is optionally substituted with one or more substituents Q as described herein. For example, C_2-6 alkynyl refers to a linear unsaturated monovalent hydrocarbon radical of 2 to 6 carbon atoms or a branched unsaturated monovalent hydrocarbon radical of 4 to 6 carbon atoms. In certain embodiments, the alkynyl is a linear monovalent hydrocarbon radical of 2 to 20 (C_2-20), 2 to 15 (C_2-15), 2 to 10 (C_2-10), or 2 to 6 (C_2-6) carbon atoms, or a branched monovalent hydrocarbon radical of 4 to 20 (C_4-20), 4 to 15 (C_4-15), 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 (–C≡CCH₃) and propargyl (–CH₂C≡CH)), butynyl (including all isomeric forms, e.g., 1-butyn-1-yl and 2-butyn- 1-yl), pentynyl (including all isomeric forms, e.g., 1-pentyn-1-yl and 1-methyl-2-butyn-1-yl), and hexynyl (including all isomeric forms, e.g., 1-hexyn-1-yl and 2-hexyn-1-yl). [0025] 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 (C_3-20), from 3 to 15 (C_3-15), from 3 to 10 (C_3-10), or from 3 to 7 (C_3-7) 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[1.1.1]pentyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, decalinyl, and adamantyl. [0026] 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 (C_3-30), 3 to 20 (C_3-20), from 3 to 15 (C_3-15), from 3 to 10 (C_3-10), or from 3 to 7 (C_3-7) carbon atoms. Examples of 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-1,1-diyl, cyclohexane-1,2-diyl, cyclohexane-1,3-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-1,4-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). [0027] 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 (C_6-20), from 6 to 15 (C_6-15), or from 6 to 10 (C_6-10) 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. [0028] 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 (C_7-30), from 7 to 20 (C_7-20), or from 7 to 16 (C_7-16) 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. [0029] 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-b]pyridinyl, furo[2,3-c]pyridinyl, furo[3,2-b]-pyridinyl, furo[3,2-c]pyridinyl, furo[3,4-b]pyridinyl, and furo[3,4-c]pyridinyl), imidazopyridinyl (including all isomeric forms, e.g., imidazo[1,2-a]pyridinyl, imidazo[4,5- b]pyridinyl, and imidazo[4,5-c]pyridinyl), imidazothiazolyl (including all isomeric forms, e.g., imidazo[2,1-b]-thiazolyl and imidazo[4,5-d]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- b]pyridinyl, oxazolo[4,5-c]-pyridinyl, oxazolo[5,4-b]pyridinyl, and oxazolo[5,4-c]pyridinyl), phthalazinyl, pteridinyl, purinyl, pyrrolopyridyl (including all isomeric forms, e.g., pyrrolo[2,3- b]pyridinyl, pyrrolo[2,3-c]pyridinyl, pyrrolo[3,2-b]pyridinyl, and pyrrolo[3,2-c]pyridinyl), quinolinyl, quinoxalinyl, quinazolinyl, thiadiazolopyrimidyl (including all isomeric forms, e.g., [1,2,5]thiadiazolo[3,4-d]-pyrimidinyl and [1,2,3]thiadiazolo[4,5-d]pyrimidinyl), and thienopyridyl (including all isomeric forms, e.g., thieno[2,3-b]pyridinyl, thieno[2,3-c]pyridinyl, thieno[3,2-b]pyridinyl, and thieno-[3,2-c]pyridinyl). In yet another embodiment, the heteroaryl is tricyclic. Examples of tricyclic heteroaryl groups include, but are not limited to, acridinyl, benzindolyl, carbazolyl, dibenzo-furanyl, 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. [0030] The term “heterocyclyl” or “heterocyclic” refers to a monovalent monocyclic non-aromatic ring system or monovalent polycyclic ring system that contains at least one non- aromatic 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, benzodioxolyl, benzofuranonyl, chromanyl, decahydroisoquinolinyl, dihydrobenzofuranyl, dihydrobenzisothiazolyl, dihydrobenzisoxazinyl (including all isomeric forms, e.g., 1,4-dihydrobenzo[d][1,3]oxazinyl, 3,4-dihydrobenzo[c][1,2]-oxazinyl, and 3,4-dihydrobenzo[d][1,2]oxazinyl), dihydrobenzothienyl, dihydroisobenzofuranyl, dihydrobenzo[c]thienyl, dihydrofuryl, dihydroisoindolyl, dihydropyranyl, dihydropyrazolyl, dihydropyrazinyl, dihydropyridinyl, dihydropyrimidinyl, 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. [0031] 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. If a heterocyclylene group containing a nonaromatic heterocyclic ring also contains a heteroaromatic ring, the heterocyclylene group does not have a linkage to the rest of a molecule via its heteroaromatic 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 quaternized, and some rings may be partially or fully saturated, or aromatic. The heterocyclylene may be attached to the main structure at any heteroatom or carbon atom which results in the creation of a stable compound. Examples of such heterocyclylene groups include, but are not limited to, azepindiyl, benzodioxandiyl, benzodioxoldiyl, benzofuranondiyl, chromandiyl, decahydroisoquinolindiyl, dihydrobenzofurandiyl, dihydrobenzisothiazoldiyl, dihydrobenzisoxazindiyl (including all isomeric forms, e.g., 1,4-dihydrobenzo[d][1,3]oxazindiyl, 3,4-dihydrobenzo[c][1,2]oxazindiyl, and 3,4-dihydrobenzo[d][1,2]oxazindiyl), dihydrobenzothiendiyl, dihydroisobenzofurandiyl, dihydrobenzo[c]thiendiyl, dihydrofurdiyl, dihydroisoindoldiyl, dihydropyrandiyl, dihydropyrazoldiyl, dihydropyrazindiyl, dihydropyridindiyl, dihydropyrimidindiyl, dihydropyrroldiyl, 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. [0032] The term “halogen”, “halide,” or “halo” refers to fluoro, chloro, bromo, and/or iodo. [0033] The term “optionally substituted” is intended to mean that a group or substituent, such as an alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylene, aryl, aralkyl, heteroaryl, 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 (=O); (b) C_1-6 alkyl, C_1-6 heteroalkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_3-10 cycloalkyl, C_6-14 aryl, C_7-15 aralkyl, heteroaryl, and heterocyclyl, each of which is further optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Q^a; and (c) –C(O)R^a, –C(O)OR^a, –C(O)NR^bR^c, –C(O)SR^a, –C(NR^a)NR^bR^c, –C(S)R^a, –C(S)OR^a, –C(S)NR^bR^c, –OR^a, –OC(O)R^a, –OC(O)OR^a, –OC(O)NR^bR^c, –OC(O)SR^a, –OC(NR^a)NR^bR^c, –OC(S)R^a, –OC(S)OR^a, –OC(S)NR^bR^c, –OP(O)(OR^b)OR^c, –OS(O)R^a, –OS(O)₂R^a, –OS(O)NR^bR^c, –OS(O)₂NR^bR^c, –NR^bR^c, –NR^aC(O)R^d, –NR^aC(O)OR^d, –NR^aC(O)NR^bR^c, –NR^aC(O)SR^d, –NR^aC(NR^d)NR^bR^c, –NR^aC(S)R^d, –NR^aC(S)OR^d, –NR^aC(S)NR^bR^c, –NR^aS(O)R^d, –NR^aS(O)₂R^d, –NR^aS(O)NR^bR^c, –NR^aS(O)₂NR^bR^c, –SR^a, –S(O)R^a, –S(O)₂R^a, –S(O)NR^bR^c, and –S(O)₂NR^bR^c, wherein each R^a, R^b, R^c, and R^d is independently (i) hydrogen or deuterium; (ii) C_1-6 alkyl, C_1-6 heteroalkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_3-10 cycloalkyl, C_6-14 aryl, C_7-15 aralkyl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Q^a; or (iii) R^b and R^c together 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 Q^a. As used herein, all groups that can be substituted are “optionally substituted.” [0034] In one embodiment, each Q^a is independently selected from: (a) deuterium, cyano, halo, imino, nitro, and oxo; (b) C_1-6 alkyl, C_1-6 heteroalkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_3-10 cycloalkyl, C_6-14 aryl, C_7-15 aralkyl, heteroaryl, and heterocyclyl; and (c) –C(O)R^e, –C(O)OR^e, –C(O)NR^fR^g, –C(O)SR^e, –C(NR^e)NR^fR^g, –C(S)R^e, –C(S)OR^e, –C(S)NR^fR^g, –OR^e, –OC(O)R^e, –OC(O)OR^e, –OC(O)NR^fR^g, –OC(O)SR^e, –OC(NR^e)NR^fR^g, –OC(S)R^e, –OC(S)OR^e, –OC(S)NR^fR^g, –OP(O)(OR^f)OR^g, –OS(O)R^e, –OS(O)₂R^e, –OS(O)NR^fR^g, –OS(O)₂NR^fR^g, –NR^fR^g, –NR^eC(O)R^h, –NR^eC(O)OR^f, –NR^eC(O)NR^fR^g, –NR^eC(O)SR^f, –NR^eC(NR^h)NR^fR^g, –NR^eC(S)R^h, –NR^eC(S)OR^f, –NR^eC(S)NR^fR^g, –NR^eS(O)R^h, –NR^eS(O)₂R^h, –NR^eS(O)NR^fR^g, –NR^eS(O)₂NR^fR^g, –SR^e, –S(O)R^e, –S(O)₂R^e, –S(O)NR^fR^g, and –S(O)₂NR^fR^g; wherein each R^e, R^f, R^g, and R^h is independently (i) hydrogen or deuterium; (ii) C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_3-10 cycloalkyl, C_6-14 aryl, C_7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) R^f and R^g together with the N atom to which they are attached form heterocyclyl. [0035] 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. [0036] 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. [0037] 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 (¹¹C), carbon-12 (¹²C), carbon-13 (¹³C), carbon-14 (¹⁴C), nitrogen-13 (¹³N), nitrogen-14 (¹⁴N), nitrogen-15 (¹⁵N), oxygen-14 (¹⁴O), oxygen-15 (¹⁵O), 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 (³⁵Cl), chlorine-36 (³⁶Cl), chlorine-37 (³⁷Cl), 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 (³⁵Cl), chlorine-37 (³⁷Cl), 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 (¹¹C), 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 (³⁶Cl), 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 be ²H, as example, or any carbon can be ¹³C, as example, or any nitrogen can be ¹⁵N, as example, or any oxygen can be ¹⁸O, as example, where feasible according to the judgment of one of ordinary skill in the art. [0038] 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 that position is substantially greater than its natural abundance. [0039] The term “isotopic enrichment factor” refers the ratio between the isotopic abundance in an isotopically enriched compound and the natural abundance of a specific isotope. [0040] 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%. [0041] 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%). [0042] 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%. [0043] 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%). [0044] 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. [0045] 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, n-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. [0046] 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)–. [0047] 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 [0048] 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: R¹, R², R⁴, and R⁵ are each independently (i) hydrogen, deuterium, cyano, halo, or nitro; (ii) C_1-6 alkyl, C_1-6 heteroalkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_3-10 cycloalkyl, C_6-14 aryl, C_7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) –C(O)R^1a, –C(O)OR^1a, –C(O)NR^1bR^1c, –C(O)SR^1a, –C(NR^1a)NR^1bR^1c, –C(S)R^1a, –C(S)OR^1a, –C(S)NR^1bR^1c, –OR^1a, –OC(O)R^1a, –OC(O)OR^1a, –OC(O)NR^1bR^1c, –OC(O)SR^1a, –OC(NR^1a)NR^1bR^1c, –OC(S)R^1a, –OC(S)OR^1a, –OC(S)NR^1bR^1c, –OS(O)R^1a, –OS(O)₂R^1a, –OS(O)NR^1bR^1c, –OS(O)₂NR^1bR^1c, –NR^1bR^1c, –NR^1aC(O)R^1d, –NR^1aC(O)OR^1d, –NR^1aC(O)NR^1bR^1c, –NR^1aC(O)SR^1d, –NR^1aC(NR^1d)NR^1bR^1c, –NR^1aC(S)R^1d, –NR^1aC(S)OR^1d, –NR^1aC(S)NR^1bR^1c, –NR^1aS(O)R^1d, –NR^1aS(O)₂R^1d, –NR^1aS(O)NR^1bR^1c, –NR^1aS(O)₂NR^1bR^1c, –SR^1a, –S(O)R^1a, –S(O)₂R^1a, –S(O)NR^1bR^1c, or –S(O)₂NR^1bR^1c; R³ is heteroaryl; R⁶ is (i) hydrogen; (ii) C_1-6 alkyl, C_1-6 heteroalkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_3-10 cycloalkyl, C_6-14 aryl, C_7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) –C(O)R^1a, –C(O)OR^1a, –C(O)NR^1bR^1c, –C(O)SR^1a, –C(NR^1a)NR^1bR^1c, –C(S)R^1a, –C(S)OR^1a, –C(S)NR^1bR^1c, –OR^1a, –OC(O)R^1a, –OC(O)OR^1a, –OC(O)NR^1bR^1c, –OC(O)SR^1a, –OC(NR^1a)NR^1bR^1c, –OC(S)R^1a, –OC(S)OR^1a, –OC(S)NR^1bR^1c, –OS(O)R^1a, –OS(O)₂R^1a, –OS(O)NR^1bR^1c, –OS(O)₂NR^1bR^1c, –NR^1bR^1c, –NR^1aC(O)R^1d, –NR^1aC(O)OR^1d, –NR^1aC(O)NR^1bR^1c, –NR^1aC(O)SR^1d, –NR^1aC(NR^1d)NR^1bR^1c, –NR^1aC(S)R^1d, –NR^1aC(S)OR^1d, –NR^1aC(S)NR^1bR^1c, –NR^1aS(O)R^1d, –NR^1aS(O)₂R^1d, –NR^1aS(O)NR^1bR^1c, –NR^1aS(O)₂NR^1bR^1c, –S(O)R^1a, –S(O)₂R^1a, –S(O)NR^1bR^1c, or –S(O)₂NR^1bR^1c; R^7a and R^7b are each independently (i) hydrogen, deuterium, cyano, halo, or nitro; (ii) C_1-6 alkyl, C_1-6 heteroalkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_3-10 cycloalkyl, C_6-14 aryl, C_7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) –C(O)R^1a, –C(O)OR^1a, –C(O)NR^1bR^1c, –C(O)SR^1a, –C(NR^1a)NR^1bR^1c, –C(S)R^1a, –C(S)OR^1a, –C(S)NR^1bR^1c, –OR^1a, –OC(O)R^1a, –OC(O)OR^1a, –OC(O)NR^1bR^1c, –OC(O)SR^1a, –OC(NR^1a)NR^1bR^1c, –OC(S)R^1a, –OC(S)OR^1a, –OC(S)NR^1bR^1c, –OS(O)R^1a, –OS(O)₂R^1a, –OS(O)NR^1bR^1c, –OS(O)₂NR^1bR^1c, –NR^1bR^1c, –NR^1aC(O)R^1d, –NR^1aC(O)OR^1d, –NR^1aC(O)NR^1bR^1c, –NR^1aC(O)SR^1d, –NR^1aC(NR^1d)NR^1bR^1c, –NR^1aC(S)R^1d, –NR^1aC(S)OR^1d, –NR^1aC(S)NR^1bR^1c, –NR^1aS(O)R^1d, –NR^1aS(O)₂R^1d, –NR^1aS(O)NR^1bR^1c, –NR^1aS(O)₂NR^1bR^1c, –SR^1a, –S(O)R^1a, –S(O)₂R^1a, –S(O)NR^1bR^1c, or –S(O)₂NR^1bR^1c; or R^7a and R^7b together with the carbon atom to which they are attached form C(O), C_3-10 cycloalkylene, or heterocyclylene; R^8a and R^8b are each independently (i) hydrogen, deuterium, cyano, halo, or nitro; (ii) C_1-6 alkyl, C_1-6 heteroalkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_3-10 cycloalkyl, C_6-14 aryl, C_7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) –C(O)R^1a, –C(O)OR^1a, –C(O)NR^1bR^1c, –C(O)SR^1a, –C(NR^1a)NR^1bR^1c, –C(S)R^1a, –C(S)OR^1a, –C(S)NR^1bR^1c, –OR^1a, –OC(O)R^1a, –OC(O)OR^1a, –OC(O)NR^1bR^1c, –OC(O)SR^1a, –OC(NR^1a)NR^1bR^1c, –OC(S)R^1a, –OC(S)OR^1a, –OC(S)NR^1bR^1c, –OS(O)R^1a, –OS(O)₂R^1a, –OS(O)NR^1bR^1c, –OS(O)₂NR^1bR^1c, –NR^1bR^1c, –NR^1aC(O)R^1d, –NR^1aC(O)OR^1d, –NR^1aC(O)NR^1bR^1c, –NR^1aC(O)SR^1d, –NR^1aC(NR^1d)NR^1bR^1c, –NR^1aC(S)R^1d, –NR^1aC(S)OR^1d, –NR^1aC(S)NR^1bR^1c, –NR^1aS(O)R^1d, –NR^1aS(O)₂R^1d, –NR^1aS(O)NR^1bR^1c, –NR^1aS(O)₂NR^1bR^1c, –SR^1a, –S(O)R^1a, –S(O)₂R^1a, –S(O)NR^1bR^1c, or –S(O)₂NR^1bR^1c; or R^8a and R^8b together with the carbon atom to which they are attached form C(O), C_3-10 cycloalkylene, or heterocyclylene; A is –O–, –S–, –NR^A1–, or –C(R^A2R^A3)–; L is a bond, –O–, –S–, –NR^1a–, or –C(O)N(R^1a)–; U, V, and W are each independently CR^U or N; X and Y are each independently a bond, –O–, –S–, –NR^X1–, or –C(R^X2R^X3)–; Z is –O–, –S–, –NR^Z1–, or –C(R^Z2R^Z3)–; each R^A1, R^X1 and R^Z1 is independently (i) hydrogen; (ii) C_1-6 alkyl, C_1-6 heteroalkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_3-10 cycloalkyl, C_6-14 aryl, C_7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) –C(O)R^1a, –C(O)OR^1a, –C(O)NR^1bR^1c, –C(O)SR^1a, –C(NR^1a)NR^1bR^1c, –C(S)R^1a, –C(S)OR^1a, –C(S)NR^1bR^1c, –OR^1a, –OC(O)R^1a, –OC(O)OR^1a, –OC(O)NR^1bR^1c, –OC(O)SR^1a, –OC(NR^1a)NR^1bR^1c, –OC(S)R^1a, –OC(S)OR^1a, –OC(S)NR^1bR^1c, –OS(O)R^1a, –OS(O)₂R^1a, –OS(O)NR^1bR^1c, –OS(O)₂NR^1bR^1c, –NR^1bR^1c, –NR^1aC(O)R^1d, –NR^1aC(O)OR^1d, –NR^1aC(O)NR^1bR^1c, –NR^1aC(O)SR^1d, –NR^1aC(NR^1d)NR^1bR^1c, –NR^1aC(S)R^1d, –NR^1aC(S)OR^1d, –NR^1aC(S)NR^1bR^1c, –NR^1aS(O)R^1d, –NR^1aS(O)₂R^1d, –NR^1aS(O)NR^1bR^1c, –NR^1aS(O)₂NR^1bR^1c, –S(O)R^1a, –S(O)₂R^1a, –S(O)NR^1bR^1c, or –S(O)₂NR^1bR^1c; each R^A2, R^A3, R^U, R^X2, R^X3, R^Z2, and R^Z3 is independently (i) hydrogen, deuterium, cyano, halo, or nitro; (ii) C_1-6 alkyl, C_1-6 heteroalkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_3-10 cycloalkyl, C_6-14 aryl, C_7-15 aralkyl, heteroaryl, or heterocyclyl; (iii) –C(O)R^1a, –C(O)OR^1a, –C(O)NR^1bR^1c, –C(O)SR^1a, –C(NR^1a)NR^1bR^1c, –C(S)R^1a, –C(S)OR^1a, –C(S)NR^1bR^1c, –OR^1a, –OC(O)R^1a, –OC(O)OR^1a, –OC(O)NR^1bR^1c, –OC(O)SR^1a, –OC(NR^1a)NR^1bR^1c, –OC(S)R^1a, –OC(S)OR^1a, –OC(S)NR^1bR^1c, –OS(O)R^1a, –OS(O)₂R^1a, –OS(O)NR^1bR^1c, –OS(O)₂NR^1bR^1c, –NR^1bR^1c, –NR^1aC(O)R^1d, –NR^1aC(O)OR^1d, –NR^1aC(O)NR^1bR^1c, –NR^1aC(O)SR^1d, –NR^1aC(NR^1d)NR^1bR^1c, –NR^1aC(S)R^1d, –NR^1aC(S)OR^1d, –NR^1aC(S)NR^1bR^1c, –NR^1aS(O)R^1d, –NR^1aS(O)₂R^1d, –NR^1aS(O)NR^1bR^1c, –NR^1aS(O)₂NR^1bR^1c, –SR^1a, –S(O)R^1a, –S(O)₂R^1a, –S(O)NR^1bR^1c, or –S(O)₂NR^1bR^1c; or R^A2 and R^A3 together with the C atom to which they are attached form C_3-10 cycloalkylene or heterocyclylene; or R^X2 and R^X3 together with the C atom to which they are attached form C_3-10 cycloalkylene or heterocyclylene; or R^Z2 and R^Z3 together with the C atom to which they are attached form C_3-10 cycloalkylene or heterocyclylene; and each R^1a, R^1b, R^1c, and R^1d is independently hydrogen, deuterium, C_1-6 alkyl, C_1-6 heteroalkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_3-10 cycloalkyl, C_6-14 aryl, C_7-15 aralkyl, heteroaryl, or heterocyclyl; wherein each alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylene, aryl, aralkyl, heteroaryl, 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) C_1-6 alkyl, C_1-6 heteroalkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_3-10 cycloalkyl, C_6-14 aryl, C_7-15 aralkyl, heteroaryl, and heterocyclyl, each of which is further optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Q^a; and (c) –C(O)R^a, –C(O)OR^a, –C(O)NR^bR^c, –C(O)SR^a, –C(NR^a)NR^bR^c, –C(S)R^a, –C(S)OR^a, –C(S)NR^bR^c, –OR^a, –OC(O)R^a, –OC(O)OR^a, –OC(O)NR^bR^c, –OC(O)SR^a, –OC(NR^a)NR^bR^c, –OC(S)R^a, –OC(S)OR^a, –OC(S)NR^bR^c, –OP(O)(OR^b)OR^c, –OS(O)R^a, –OS(O)₂R^a, –OS(O)NR^bR^c, –OS(O)₂NR^bR^c, –NR^bR^c, –NR^aC(O)R^d, –NR^aC(O)OR^d, –NR^aC(O)NR^bR^c, –NR^aC(O)SR^d, –NR^aC(NR^d)NR^bR^c, –NR^aC(S)R^d, –NR^aC(S)OR^d, –NR^aC(S)NR^bR^c, –NR^aS(O)R^d, –NR^aS(O)₂R^d, –NR^aS(O)NR^bR^c, –NR^aS(O)₂NR^bR^c, –SR^a, –S(O)R^a, –S(O)₂R^a, –S(O)NR^bR^c, and –S(O)₂NR^bR^c, wherein each R^a, R^b, R^c, and R^d is independently (i) hydrogen or deuterium; (ii) C_1-6 alkyl, C_1-6 heteroalkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_3-10 cycloalkyl, C_6-14 aryl, C_7-15 aralkyl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Q^a; or (iii) R^b and R^c together 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 Q^a; wherein each Q^a is independently selected from: (a) deuterium, cyano, halo, nitro, imino, and oxo; (b) C_1-6 alkyl, C_1-6 heteroalkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_3-10 cycloalkyl, C_6-14 aryl, C_7-15 aralkyl, heteroaryl, and heterocyclyl; and (c) –C(O)R^e, –C(O)OR^e, –C(O)NR^fR^g, –C(O)SR^e, –C(NR^e)NR^fR^g, –C(S)R^e, –C(S)OR^e, –C(S)NR^fR^g, –OR^e, –OC(O)R^e, –OC(O)OR^e, –OC(O)NR^fR^g, –OC(O)SR^e, –OC(NR^e)NR^fR^g, –OC(S)R^e, –OC(S)OR^e, –OC(S)NR^fR^g, –OP(O)(OR^f)OR^g, –OS(O)R^e, –OS(O)₂R^e, –OS(O)NR^fR^g, –OS(O)₂NR^fR^g, –NR^fR^g, –NR^eC(O)R^h, –NR^eC(O)OR^f, –NR^eC(O)NR^fR^g, –NR^eC(O)SR^f, –NR^eC(NR^h)NR^fR^g, –NR^eC(S)R^h, –NR^eC(S)OR^f, –NR^eC(S)NR^fR^g, –NR^eS(O)R^h, –NR^eS(O)₂R^h, –NR^eS(O)NR^fR^g, –NR^eS(O)₂NR^fR^g, –SR^e, –S(O)R^e, –S(O)₂R^e, –S(O)NR^fR^g, and –S(O)₂NR^fR^g; wherein each R^e, R^f, R^g, and R^h is independently (i) hydrogen or deuterium; (ii) C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_3-10 cycloalkyl, C_6-14 aryl, C_7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) R^f and R^g together with the N atom to which they are attached form heterocyclyl. [0049] In certain embodiments, in Formula (I), R³ is monocyclic heteroaryl, optionally substituted with one or more substituents Q. In certain embodiments, in Formula (I), R³ is 5- or 6-membered heteroaryl, each optionally substituted with one or more substituents Q. In certain embodiments, in Formula (I), R³ is 5-membered heteroaryl, optionally substituted with one or more substituents Q. In certain embodiments, in Formula (I), R³ is oxadiazolyl, optionally substituted with one or more substituents Q. In certain embodiments, in Formula (I), R³ is 1,2,4- oxadiazolyl, optionally substituted with one or more substituents Q. In certain embodiments, in Formula (I), R³ is 1,2,4-oxadiazol-3-yl, optionally substituted with one or more substituents Q. In certain embodiments, in Formula (I), R³ is 5-hydroxyl-1,2,4-oxadiazol-3-yl. [0050] In certain embodiments, in Formula (I), R³ is 6-membered heteroaryl, optionally substituted with one or more substituents Q. In certain embodiments, in Formula (I), R³ is triazinyl, optionally substituted with one or more substituents Q. In certain embodiments, in Formula (I), R³ is 1,2,4-triazinyl, optionally substituted with one or more substituents Q. In certain embodiments, in Formula (I), R³ is 1,2,4-triazinyl, optionally substituted with one, two, or three substituents Q, each of which is independently cyano, oxo, C_1-6 alkyl, C_1-6 heteroalkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_3-10 cycloalkyl, –C(O)OR^a, –C(O)NR^bR^c, or –NR^bR^c, where each R^a, R^b, and R^c are as defined herein. In certain embodiments, in Formula (I), R³ is 1,2,4-triazinyl, optionally substituted with one, two, or three substituents Q, each of which is independently cyano, oxo, methyl, ethyl, isopropyl, ethynyl, cyclopropyl, amino, methylamino, dimethylamino, –COOH, or –CONH₂. In certain embodiments, in Formula (I), R³ is 1,2,4-triazin-2-yl, optionally substituted with one or more substituents Q. In certain embodiments, in Formula (I), R³ is 1,2,4- triazin-2-yl, optionally substituted with one, two, or three substituents Q, each of which is independently cyano, oxo, C_1-6 alkyl, C_1-6 heteroalkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_3-10 cycloalkyl, –C(O)OR^a, –C(O)NR^bR^c, or –NR^bR^c, where each R^a, R^b, and R^c are as defined herein. In certain embodiments, in Formula (I), R³ is 1,2,4-triazin-2-yl, optionally substituted with one, two, or three substituents Q, each of which is independently cyano, oxo, methyl, ethyl, isopropyl, ethynyl, cyclopropyl, amino, methylamino, dimethylamino, –COOH, or –CONH₂. In certain embodiments, in Formula (I), R³ is 1,2,4-triazin-6-yl, optionally substituted with one or more substituents Q. In certain embodiments, in Formula (I), R³ is 1,2,4-triazin-6-yl, optionally substituted with one, two, or three substituents Q, each of which is independently cyano, oxo, C_{1- 6} alkyl, C_1-6 heteroalkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_3-10 cycloalkyl, –C(O)OR^a, –C(O)NR^bR^c, or –NR^bR^c, where each R^a, R^b, and R^c are as defined herein. In certain embodiments, in Formula (I), R³ is 1,2,4-triazin-6-yl, optionally substituted with one, two, or three substituents Q, each of which is independently cyano, oxo, methyl, ethyl, isopropyl, ethynyl, cyclopropyl, amino, methylamino, dimethylamino, –COOH, or –CONH₂. [0051] In another 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: R^3a is (i) hydrogen, deuterium, cyano, halo, or nitro; (ii) C_1-6 alkyl, C_1-6 heteroalkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_3-10 cycloalkyl, C_6-14 aryl, C_7-15 aralkyl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one or more substituents Q; or (iii) –C(O)R^1a, –C(O)OR^1a, –C(O)NR^1bR^1c, –C(O)SR^1a, –C(NR^1a)NR^1bR^1c, –C(S)R^1a, –C(S)OR^1a, –C(S)NR^1bR^1c, –OR^1a, –OC(O)R^1a, –OC(O)OR^1a, –OC(O)NR^1bR^1c, –OC(O)SR^1a, –OC(NR^1a)NR^1bR^1c, –OC(S)R^1a, –OC(S)OR^1a, –OC(S)NR^1bR^1c, –OS(O)R^1a, –OS(O)₂R^1a, –OS(O)NR^1bR^1c, –OS(O)₂NR^1bR^1c, –NR^1bR^1c, –NR^1aC(O)R^1d, –NR^1aC(O)OR^1d, –NR^1aC(O)NR^1bR^1c, –NR^1aC(O)SR^1d, –NR^1aC(NR^1d)NR^1bR^1c, –NR^1aC(S)R^1d, –NR^1aC(S)OR^1d, –NR^1aC(S)NR^1bR^1c, –NR^1aS(O)R^1d, –NR^1aS(O)₂R^1d, –NR^1aS(O)NR^1bR^1c, –NR^1aS(O)₂NR^1bR^1c, –SR^1a, –S(O)R^1a, –S(O)₂R^1a, –S(O)NR^1bR^1c, or –S(O)₂NR^1bR^1c; and R¹, R², R⁴, R⁵, R⁶, R^1a, R^1b, R^1c, R^1d, R^7a, R^7b, R^8a, R^8b, A, L, U, V, W, X, Y, and Z are each as defined herein. [0052] In yet 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: R^3b is (i) hydrogen; (ii) C_1-6 alkyl, C_1-6 heteroalkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_{3- 10} cycloalkyl, C_6-14 aryl, C_7-15 aralkyl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one or more substituents Q; or (iii) –C(O)R^1a, –C(O)OR^1a, –C(O)NR^1bR^1c, –C(O)SR^1a, –C(NR^1a)NR^1bR^1c, –C(S)R^1a, –C(S)OR^1a, –C(S)NR^1bR^1c, –OR^1a, –OC(O)R^1a, –OC(O)OR^1a, –OC(O)NR^1bR^1c, –OC(O)SR^1a, –OC(NR^1a)NR^1bR^1c, –OC(S)R^1a, –OC(S)OR^1a, –OC(S)NR^1bR^1c, –OS(O)R^1a, –OS(O)₂R^1a, –OS(O)NR^1bR^1c, –OS(O)₂NR^1bR^1c, –NR^1bR^1c, –NR^1aC(O)R^1d, –NR^1aC(O)OR^1d, –NR^1aC(O)NR^1bR^1c, –NR^1aC(O)SR^1d, –NR^1aC(NR^1d)NR^1bR^1c, –NR^1aC(S)R^1d, –NR^1aC(S)OR^1d, –NR^1aC(S)NR^1bR^1c, –NR^1aS(O)R^1d, –NR^1aS(O)₂R^1d, –NR^1aS(O)NR^1bR^1c, –NR^1aS(O)₂NR^1bR^1c, –S(O)R^1a, –S(O)₂R^1a, –S(O)NR^1bR^1c, or –S(O)₂NR^1bR^1c; and R¹, R², R⁴, R⁵, R⁶, R^1a, R^1b, R^1c, R^1d, R^7a, R^7b, R^8a, R^8b, A, L, U, V, W, X, Y, and Z are each as defined herein. [0053] In yet another 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 R¹, R², R⁴, R⁵, R⁶, R^7a, R^7b, R^8a, R^8b, A, L, U, V, W, X, Y, and Z are each as defined herein. [0054] In one embodiment, in Formula (II), (III), or (IV), R¹ and R⁵ are each independently halo, C_1-6 alkyl, or C_1-6 heteroalkyl; R² and R⁴ are hydrogen or deuterium; R⁶ is hydrogen; R^3a, if present, is cyano, C_1-6 alkyl, C_1-6 heteroalkyl, or –NH₂; R^3b, if present, is C_1-6 alkyl or C_1-6 heteroalkyl; R^7a and R^7b are each independently hydrogen, deuterium, C_1-6 alkyl, or C_1-6 heteroalkyl, or –C(O)NH₂; or R^7a and R^7b together with the carbon atom to which they are attached form C(O), C_3-10 cycloalkylene, or heterocyclylene; R^8a is hydrogen, deuterium, C_1-6 alkyl, or C_1-6 heteroalkyl; and R^8b is C_1-6 alkyl or C_1-6 heteroalkyl; or R^8a and R^8b together with the carbon atom to which they are attached form C_3-10 cycloalkylene or heterocyclylene; A is –O– or –CH₂–; L is a bond or –C(O)N(H)–; U and V are each independently CR^U; and W is CR^U or N; where each R^U is independently hydrogen, deuterium, cyano, halo, C_1-6 alkyl, or C_1-6 heteroalkyl; X is a bond or –CH₂–; Y is a bond, –O–, –N(H)–, –N(C(O)OCH₃)–, or –CH₂–; and Z is –O– or –CH₂–; wherein each alkyl, heteroalkyl, cycloalkylene, and heterocyclylene is optionally substituted with one or more substituents Q. [0055] In another embodiment, in Formula (II), (III), or (IV), R¹ and R⁵ are each independently chloro or trifluoromethyl; R² and R⁴ are hydrogen; R⁶ is hydrogen; R^3a, if present, is cyano, amino, methyl, trifluoromethyl, or hydroxylmethyl; R^3b, if present, is methyl; R^7a and R^7b are each independently hydrogen, methyl, trifluoromethyl, hydroxylmethyl, 2-hydroxylethyl, or –CONH₂; or R^7a and R^7b together with the carbon atom to which they are attached form C(O) or tetrahydrofur-3,3-diyl; R^8a is hydrogen or methyl; and R^8b is methyl; or R^8a and R^8b together with the carbon atom to which they are attached form cyclobutane-1,1-diyl, 3-cyanocyclobutane-1,1-diyl, 3-hydroxylcyclobutane-1,1-diyl, or 3,3-difluorocyclobutane-1,1-diyl; A is –O– or –CH₂–; L is a bond or –C(O)N(H)–; U is C(H), C(CN), C(F), C(CH₃), C(CHF₂), or C(CF₃); V is C(H) or C(F); W is C(H), C(F), or N; X is a bond or –CH₂–; Y is a bond, –O–, –N(H)–, –N(C(O)OCH₃)–, or –CH₂–; and Z is –O– or –CH₂–. [0056] In yet another embodiment, in Formula (II), (III), or (IV), R¹ and R⁵ are each independently chloro or trifluoromethyl; R² and R⁴ are hydrogen; R⁶ is hydrogen; R^3a, if present, is cyano or amino; R^3b, if present, is methyl; R^7a and R^7b are each independently hydrogen, methyl, trifluoromethyl, hydroxylmethyl, 2-hydroxylethyl, or –CONH₂; or R^7a and R^7b together with the carbon atom to which they are attached form C(O) or tetrahydrofur-3,3-diyl; R^8a is hydrogen or methyl; and R^8b is methyl; or R^8a and R^8b together with the carbon atom to which they are attached form cyclobutane-1,1-diyl, 3-cyanocyclobutane-1,1-diyl, 3-hydroxylcyclobutane-1,1-diyl, or 3,3-difluorocyclobutane-1,1-diyl; A is –O– or –CH₂–; L is a bond or –C(O)N(H)–; U is C(H), C(CN), C(F), C(CH₃), C(CHF₂), or C(CF₃); V is C(H) or C(F); W is C(H), C(F), or N; X is a bond or –CH₂–; Y is a bond, –O–, –N(H)–, –N(C(O)OCH₃)–, or –CH₂–; and Z is –O– or –CH₂–. [0057] In one embodiment, in Formula (II), (III), or (IV), R¹ and R⁵ are each independently halo, C_1-6 alkyl, or C_1-6 heteroalkyl; R² and R⁴ are hydrogen or deuterium; R⁶ is hydrogen; R^3a, if present, is cyano, aminocarbonyl, C_1-6 alkyl, C_1-6 heteroalkyl, or –NH₂; R^3b, if present, is C_1-6 alkyl or C_1-6 heteroalkyl; R^7a and R^7b are each independently hydrogen, deuterium, C_1-6 alkyl, or C_1-6 heteroalkyl, or –C(O)NH₂; or R^7a and R^7b together with the carbon atom to which they are attached form C(O), C_3-10 cycloalkylene, or heterocyclylene; R^8a is hydrogen, deuterium, C_1-6 alkyl, or C_1-6 heteroalkyl; and R^8b is C_1-6 alkyl or C_1-6 heteroalkyl; or R^8a and R^8b together with the carbon atom to which they are attached form C_3-10 cycloalkylene or heterocyclylene; A is –O– or –CH₂–; L is a bond or –C(O)N(H)–; U and V are each independently CR^U; and W is CR^U or N; where each R^U is independently hydrogen, deuterium, cyano, halo, C_1-6 alkyl, or C_1-6 heteroalkyl; X is a bond or –CH₂–; Y is a bond, –O–, –N(H)–, –N(C(O)OCH₃)–, or –CH₂–; and Z is –O– or –CH₂–; wherein each alkyl, heteroalkyl, cycloalkylene, and heterocyclylene is optionally substituted with one or more substituents Q. [0058] In another embodiment, in Formula (II), (III), or (IV), R¹ and R⁵ are each independently fluoro, chloro, or trifluoromethyl; R² and R⁴ are hydrogen; R⁶ is hydrogen; R^3a, if present, is cyano, aminocarbonyl, amino, methyl, trifluoromethyl, or hydroxylmethyl; R^3b, if present, is methyl; R^7a and R^7b are each independently hydrogen, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, hydroxylmethyl, 2-hydroxylethyl, or –CONH₂; or R^7a and R^7b together with the carbon atom to which they are attached form C(O) or tetrahydrofur-3,3-diyl; R^8a is hydrogen or methyl; and R^8b is methyl; or R^8a and R^8b together with the carbon atom to which they are attached form cyclobutane-1,1-diyl, 3-cyanocyclobutane-1,1-diyl, 3-hydroxylcyclobutane-1,1-diyl, or 3,3-difluorocyclobutane-1,1-diyl; A is –O– or –CH₂–; L is a bond or –C(O)N(H)–; U is C(H), C(CN), C(F), C(CH₃), C(CHF₂), or C(CF₃); V is C(H) or C(F); W is C(H), C(F), or N; X is a bond or –CH₂–; Y is a bond, –O–, –N(H)–, –N(C(O)OCH₃)–, or –CH₂–; and Z is –O– or –CH₂–. [0059] In yet another embodiment, in Formula (II), (III), or (IV), R¹ and R⁵ are each independently fluoro, chloro, or trifluoromethyl; R² and R⁴ are hydrogen; R⁶ is hydrogen; R^3a, if present, is cyano, aminocarbonyl, or amino; R^3b, if present, is methyl; R^7a and R^7b are each independently hydrogen, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, hydroxylmethyl, 2-hydroxylethyl, or –CONH₂; or R^7a and R^7b together with the carbon atom to which they are attached form C(O) or tetrahydrofur-3,3-diyl; R^8a is hydrogen or methyl; and R^8b is methyl; or R^8a and R^8b together with the carbon atom to which they are attached form cyclobutane-1,1-diyl, 3-cyanocyclobutane-1,1-diyl, 3-hydroxylcyclobutane-1,1-diyl, or 3,3-difluorocyclobutane-1,1-diyl; A is –O– or –CH₂–; L is a bond or –C(O)N(H)–; U is C(H), C(CN), C(F), C(CH₃), C(CHF₂), or C(CF₃); V is C(H) or C(F); W is C(H), C(F), or N; X is a bond or –CH₂–; Y is a bond, –O–, –N(H)–, –N(C(O)OCH₃)–, or –CH₂–; and Z is –O– or –CH₂–. [0060] In certain embodiments, in Formula (I), (II), (III), or (IV), L is a bond or –C(O)N(R^1a)–, wherein R^1a is as defined herein. In certain embodiments, in Formula (I), (II), (III), or (IV), L is a bond. In certain embodiments, in Formula (I), (II), (III), or (IV), L is –C(O)N(R^1a)–, wherein R^1a is as defined herein. In certain embodiments, in Formula (I), (II), (III), or (IV), L is –C(O)N(H)–. [0061] In yet another embodiment, provided herein is a compound of Formula (V): or an enantiomer, a mixtur

e of 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, R², R⁴, R⁵, R⁶, R^3a, R^7a, R^7b, R^8a, R^8b, A, U, V, W, X, Y, and Z are each as defined herein. [0062] In yet another 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, R², R⁴, R⁵, R⁶, R^3b, R^7a, R^7b, R^8a, R^8b, A, U, V, W, X, Y, and Z are each as defined herein. [0063] In yet 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, R², R⁴, R⁵, R⁶, R^7a, R^7b, R^8a, R^8b, A, U, V, W, X, Y, and Z are each as defined herein. [0064] In one embodiment, in Formula (V), (VI), or (VII), R¹ and R⁵ are each independently halo, C_1-6 alkyl, or C_1-6 heteroalkyl; R² and R⁴ are hydrogen or deuterium; R⁶ is hydrogen; R^3a, if present, is cyano, C_1-6 alkyl, C_1-6 heteroalkyl, or –NH₂; R^3b, if present, is C_1-6 alkyl or C_1-6 heteroalkyl; R^7a and R^7b are each independently hydrogen, deuterium, C_1-6 alkyl, or C_1-6 heteroalkyl, or –C(O)NH₂; or R^7a and R^7b together with the carbon atom to which they are attached form C(O), C_3-10 cycloalkylene, or heterocyclylene; R^8a is hydrogen, deuterium, C_1-6 alkyl, or C_1-6 heteroalkyl; and R^8b is C_1-6 alkyl or C_1-6 heteroalkyl; or R^8a and R^8b together with the carbon atom to which they are attached form C_3-10 cycloalkylene or heterocyclylene; A is –O– or –CH₂–; U and V are each independently CR^U; and W is CR^U or N; where each R^U is independently hydrogen, deuterium, cyano, halo, C_1-6 alkyl, or C_1-6 heteroalkyl; X is a bond or –CH₂–; Y is a bond, –O–, –N(H)–, –N(C(O)OCH₃)–, or –CH₂–; and Z is –O– or –CH₂–; wherein each alkyl, heteroalkyl, cycloalkylene, and heterocyclylene is optionally substituted with one or more substituents Q. [0065] In another embodiment, in Formula (V), (VI), or (VII), R¹ and R⁵ are each independently chloro or trifluoromethyl; R² and R⁴ are hydrogen; R⁶ is hydrogen; R^3a, if present, is cyano, amino, methyl, trifluoromethyl, or hydroxylmethyl; R^3b, if present, is methyl; R^7a and R^7b are each independently hydrogen, methyl, trifluoromethyl, hydroxylmethyl, 2-hydroxylethyl, or –CONH₂; or R^7a and R^7b together with the carbon atom to which they are attached form C(O) or tetrahydrofur-3,3-diyl; R^8a is hydrogen or methyl; and R^8b is methyl; or R^8a and R^8b together with the carbon atom to which they are attached form cyclobutane-1,1-diyl, 3-cyanocyclobutane-1,1-diyl, 3-hydroxylcyclobutane-1,1-diyl, or 3,3-difluorocyclobutane-1,1-diyl; A is –O– or –CH₂–; U is C(H), C(CN), C(F), C(CH₃), C(CHF₂), or C(CF₃); V is C(H) or C(F); W is C(H), C(F), or N; X is a bond or –CH₂–; Y is a bond, –O–, –N(H)–, –N(C(O)OCH₃)–, or –CH₂–; and Z is –O– or –CH₂–. [0066] In yet another embodiment, in Formula (V), (VI), or (VII), R¹ and R⁵ are each independently chloro or trifluoromethyl; R² and R⁴ are hydrogen; R⁶ is hydrogen; R^3a, if present, is cyano or amino; R^3b, if present, is methyl; R^7a and R^7b are each independently hydrogen, methyl, trifluoromethyl, hydroxylmethyl, 2-hydroxylethyl, or –CONH₂; or R^7a and R^7b together with the carbon atom to which they are attached form C(O) or tetrahydrofur-3,3-diyl; R^8a is hydrogen or methyl; and R^8b is methyl; or R^8a and R^8b together with the carbon atom to which they are attached form cyclobutane-1,1-diyl, 3-cyanocyclobutane-1,1-diyl, 3-hydroxylcyclobutane-1,1-diyl, or 3,3-difluorocyclobutane-1,1-diyl; A is –O– or –CH₂–; U is C(H), C(CN), C(F), C(CH₃), C(CHF₂), or C(CF₃); V is C(H) or C(F); W is C(H), C(F), or N; X is a bond or –CH₂–; Y is a bond, –O–, –N(H)–, –N(C(O)OCH₃)–, or –CH₂–; and Z is –O– or –CH₂–. [0067] In one embodiment, in Formula (V), (VI), or (VII), R¹ and R⁵ are each independently halo, C_1-6 alkyl, or C_1-6 heteroalkyl; R² and R⁴ are hydrogen or deuterium; R⁶ is hydrogen; R^3a, if present, is cyano, aminocarbonyl, C_1-6 alkyl, C_1-6 heteroalkyl, or –NH₂; R^3b, if present, is C_1-6 alkyl or C_1-6 heteroalkyl; R^7a and R^7b are each independently hydrogen, deuterium, C_1-6 alkyl, or C_1-6 heteroalkyl, or –C(O)NH₂; or R^7a and R^7b together with the carbon atom to which they are attached form C(O), C_3-10 cycloalkylene, or heterocyclylene; R^8a is hydrogen, deuterium, C_1-6 alkyl, or C_1-6 heteroalkyl; and R^8b is C_1-6 alkyl or C_1-6 heteroalkyl; or R^8a and R^8b together with the carbon atom to which they are attached form C_3-10 cycloalkylene or heterocyclylene; A is –O– or –CH₂–; U and V are each independently CR^U; and W is CR^U or N; where each R^U is independently hydrogen, deuterium, cyano, halo, C_1-6 alkyl, or C_1-6 heteroalkyl; X is a bond or –CH₂–; Y is a bond, –O–, –N(H)–, –N(C(O)OCH₃)–, or –CH₂–; and Z is –O– or –CH₂–; wherein each alkyl, heteroalkyl, cycloalkylene, and heterocyclylene is optionally substituted with one or more substituents Q. [0068] In another embodiment, in Formula (V), (VI), or (VII), R¹ and R⁵ are each independently fluoro, chloro, or trifluoromethyl; R² and R⁴ are hydrogen; R⁶ is hydrogen; R^3a, if present, is cyano, aminocarbonyl, amino, methyl, trifluoromethyl, or hydroxylmethyl; R^3b, if present, is methyl; R^7a and R^7b are each independently hydrogen, methyl, , fluoromethyl, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, hydroxylmethyl, 2-hydroxylethyl, or –CONH₂; or R^7a and R^7b together with the carbon atom to which they are attached form C(O) or tetrahydrofur-3,3-diyl; R^8a is hydrogen or methyl; and R^8b is methyl; or R^8a and R^8b together with the carbon atom to which they are attached form cyclobutane-1,1-diyl, 3-cyanocyclobutane-1,1-diyl, 3-hydroxylcyclobutane-1,1-diyl, or 3,3-difluorocyclobutane-1,1-diyl; A is –O– or –CH₂–; U is C(H), C(CN), C(F), C(CH₃), C(CHF₂), or C(CF₃); V is C(H) or C(F); W is C(H), C(F), or N; X is a bond or –CH₂–; Y is a bond, –O–, –N(H)–, –N(C(O)OCH₃)–, or –CH₂–; and Z is –O– or –CH₂–. [0069] In yet another embodiment, in Formula (V), (VI), or (VII), R¹ and R⁵ are each independently fluoro, chloro, or trifluoromethyl; R² and R⁴ are hydrogen; R⁶ is hydrogen; R^3a, if present, is cyano, aminocarbonyl, or amino; R^3b, if present, is methyl; R^7a and R^7b are each independently hydrogen, methyl, , fluoromethyl, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, hydroxylmethyl, 2-hydroxylethyl, or –CONH₂; or R^7a and R^7b together with the carbon atom to which they are attached form C(O) or tetrahydrofur-3,3-diyl; R^8a is hydrogen or methyl; and R^8b is methyl; or R^8a and R^8b together with the carbon atom to which they are attached form cyclobutane-1,1-diyl, 3-cyanocyclobutane-1,1-diyl, 3-hydroxylcyclobutane-1,1-diyl, or 3,3-difluorocyclobutane-1,1-diyl; A is –O– or –CH₂–; U is C(H), C(CN), C(F), C(CH₃), C(CHF₂), or C(CF₃); V is C(H) or C(F); W is C(H), C(F), or N; X is a bond or –CH₂–; Y is a bond, –O–, –N(H)–, –N(C(O)OCH₃)–, or –CH₂–; and Z is –O– or –CH₂–. [0070] In yet another embodiment, provided herein is a compound of Formula (VIII): or an enantiomer, a mixtu

re of 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, R², R⁴, R⁵, R⁶, R^3a, R^7a, R^7b, R^8a, R^8b, A, U, V, W, Y, and Z are each as defined herein. [0071] In yet another embodiment, provided herein is a compound of Formula (IX):

or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R¹, R², R⁴, R⁵, R⁶, R^3b, R^7a, R^7b, R^8a, R^8b, A, U, V, W, Y, and Z are each as defined herein. [0072] In still another embodiment, provided herein is a compound of Formula (X):

or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R¹, R², R⁴, R⁵, R⁶, R^7a, R^7b, R^8a, R^8b, A, U, V, W, Y, and Z are each as defined herein. [0073] In one embodiment, in Formula (VIII), (IX), or (X), R¹ and R⁵ are each independently halo, C_1-6 alkyl, or C_1-6 heteroalkyl; R² and R⁴ are hydrogen or deuterium; R⁶ is hydrogen; R^3a, if present, is cyano, C_1-6 alkyl, C_1-6 heteroalkyl, or –NH₂; R^3b, if present, is C_1-6 alkyl or C_1-6 heteroalkyl; R^7a and R^7b are each independently hydrogen, deuterium, C_1-6 alkyl, or C_1-6 heteroalkyl, or –C(O)NH₂; or R^7a and R^7b together with the carbon atom to which they are attached form C(O), C_3-10 cycloalkylene, or heterocyclylene; R^8a is hydrogen, deuterium, C_1-6 alkyl, or C_1-6 heteroalkyl; and R^8b is C_1-6 alkyl or C_1-6 heteroalkyl; or R^8a and R^8b together with the carbon atom to which they are attached form C_3-10 cycloalkylene or heterocyclylene; A is –O– or –CH₂–; U and V are each independently CR^U; and W is CR^U or N; where each R^U is independently hydrogen, deuterium, cyano, halo, C_1-6 alkyl, or C_1-6 heteroalkyl; Y is a bond, –O–, –N(H)–, –N(C(O)OCH₃)–, or –CH₂–; and Z is –O– or –CH₂–; wherein each alkyl, heteroalkyl, cycloalkylene, and heterocyclylene is optionally substituted with one or more substituents Q. [0074] In another embodiment, in Formula (VIII), (IX), or (X), R¹ and R⁵ are each independently chloro or trifluoromethyl; R² and R⁴ are hydrogen; R⁶ is hydrogen; R^3a, if present, is cyano, amino, methyl, trifluoromethyl, or hydroxylmethyl; R^3b, if present, is methyl; R^7a and R^7b are each independently hydrogen, methyl, trifluoromethyl, hydroxylmethyl, 2-hydroxylethyl, or –CONH₂; or R^7a and R^7b together with the carbon atom to which they are attached form C(O) or tetrahydrofur-3,3-diyl; R^8a is hydrogen or methyl; and R^8b is methyl; or R^8a and R^8b together with the carbon atom to which they are attached form cyclobutane-1,1-diyl, 3-cyanocyclobutane-1,1-diyl, 3-hydroxylcyclobutane-1,1-diyl, or 3,3-difluorocyclobutane-1,1-diyl; A is –O– or –CH₂–; U is C(H), C(CN), C(F), C(CH₃), C(CHF₂), or C(CF₃); V is C(H) or C(F); W is C(H), C(F), or N; Y is a bond, –O–, –N(H)–, –N(C(O)OCH₃)–, or –CH₂–; and Z is –O– or –CH₂–. [0075] In yet another embodiment, in Formula (VIII), (IX), or (X), R¹ and R⁵ are each independently chloro or trifluoromethyl; R² and R⁴ are hydrogen; R⁶ is hydrogen; R^3a, if present, is cyano or amino; R^3b, if present, is methyl; R^7a and R^7b are each independently hydrogen, methyl, trifluoromethyl, hydroxylmethyl, 2-hydroxylethyl, or –CONH₂; or R^7a and R^7b together with the carbon atom to which they are attached form C(O) or tetrahydrofur-3,3-diyl; R^8a is hydrogen or methyl; and R^8b is methyl; or R^8a and R^8b together with the carbon atom to which they are attached form cyclobutane-1,1-diyl, 3-cyanocyclobutane-1,1-diyl, 3-hydroxylcyclobutane-1,1-diyl, or 3,3-difluorocyclobutane-1,1-diyl; A is –O– or –CH₂–; U is C(H), C(CN), C(F), C(CH₃), C(CHF₂), or C(CF₃); V is C(H) or C(F); W is C(H), C(F), or N; Y is a bond, –O–, –N(H)–, –N(C(O)OCH₃)–, or –CH₂–; and Z is –O– or –CH₂–. [0076] In one embodiment, in Formula (VIII), (IX), or (X), R¹ and R⁵ are each independently halo, C_1-6 alkyl, or C_1-6 heteroalkyl; R² and R⁴ are hydrogen or deuterium; R⁶ is hydrogen; R^3a, if present, is cyano, aminocarbonyl, C_1-6 alkyl, C_1-6 heteroalkyl, or –NH₂; R^3b, if present, is C_1-6 alkyl or C_1-6 heteroalkyl; R^7a and R^7b are each independently hydrogen, deuterium, C_1-6 alkyl, or C_1-6 heteroalkyl, or –C(O)NH₂; or R^7a and R^7b together with the carbon atom to which they are attached form C(O), C_3-10 cycloalkylene, or heterocyclylene; R^8a is hydrogen, deuterium, C_1-6 alkyl, or C_1-6 heteroalkyl; and R^8b is C_1-6 alkyl or C_1-6 heteroalkyl; or R^8a and R^8b together with the carbon atom to which they are attached form C_3-10 cycloalkylene or heterocyclylene; A is –O– or –CH₂–; U and V are each independently CR^U; and W is CR^U or N; where each R^U is independently hydrogen, deuterium, cyano, halo, C_1-6 alkyl, or C_1-6 heteroalkyl; Y is a bond, –O–, –N(H)–, –N(C(O)OCH₃)–, or –CH₂–; and Z is –O– or –CH₂–; wherein each alkyl, heteroalkyl, cycloalkylene, and heterocyclylene is optionally substituted with one or more substituents Q. [0077] In another embodiment, in Formula (VIII), (IX), or (X), R¹ and R⁵ are each independently fluoro, chloro, or trifluoromethyl; R² and R⁴ are hydrogen; R⁶ is hydrogen; R^3a, if present, is cyano, aminocarbonyl, amino, methyl, trifluoromethyl, or hydroxylmethyl; R^3b, if present, is methyl; R^7a and R^7b are each independently hydrogen, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, hydroxylmethyl, 2-hydroxylethyl, or –CONH₂; or R^7a and R^7b together with the carbon atom to which they are attached form C(O) or tetrahydrofur-3,3-diyl; R^8a is hydrogen or methyl; and R^8b is methyl; or R^8a and R^8b together with the carbon atom to which they are attached form cyclobutane-1,1-diyl, 3-cyanocyclobutane-1,1-diyl, 3-hydroxylcyclobutane-1,1-diyl, or 3,3-difluorocyclobutane-1,1-diyl; A is –O– or –CH₂–; U is C(H), C(CN), C(F), C(CH₃), C(CHF₂), or C(CF₃); V is C(H) or C(F); W is C(H), C(F), or N; Y is a bond, –O–, –N(H)–, –N(C(O)OCH₃)–, or –CH₂–; and Z is –O– or –CH₂–. [0078] In yet another embodiment, in Formula (VIII), (IX), or (X), R¹ and R⁵ are each independently fluoro, chloro, or trifluoromethyl; R² and R⁴ are hydrogen; R⁶ is hydrogen; R^3a, if present, is cyano, aminocarbonyl, or amino; R^3b, if present, is methyl; R^7a and R^7b are each independently hydrogen, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, hydroxylmethyl, 2-hydroxylethyl, or –CONH₂; or R^7a and R^7b together with the carbon atom to which they are attached form C(O) or tetrahydrofur-3,3-diyl; R^8a is hydrogen or methyl; and R^8b is methyl; or R^8a and R^8b together with the carbon atom to which they are attached form cyclobutane-1,1-diyl, 3-cyanocyclobutane-1,1-diyl, 3-hydroxylcyclobutane-1,1-diyl, or 3,3-difluorocyclobutane-1,1-diyl; A is –O– or –CH₂–; U is C(H), C(CN), C(F), C(CH₃), C(CHF₂), or C(CF₃); V is C(H) or C(F); W is C(H), C(F), or N; Y is a bond, –O–, –N(H)–, –N(C(O)OCH₃)–, or –CH₂–; and Z is –O– or –CH₂–. [0079] The groups, R¹, R², R⁴, R⁵, R⁶, R^3a, R^3b, R^7a, R^7b, R^8a, R^8b, A, L, U, V, W, X, Y, and Z in the formulae described herein, including Formulae (I) to (X), are defined in the embodiments described herein. All combinations of the embodiments provided herein for the groups described in the formulae described herein, including Formulae (I) to (X), are within the scope of this disclosure. [0080] In certain embodiments, R¹ is hydrogen. In certain embodiments, R¹ is deuterium. In certain embodiments, R¹ is cyano. In certain embodiments, R¹ is halo. In certain embodiments, R¹ is fluoro, chloro, or bromo. In certain embodiments, R¹ is fluoro. In certain embodiments, R¹ is chloro. In certain embodiments, R¹ is nitro. In certain embodiments, R¹ is C_1-6 alkyl, optionally substituted with one or more substituents Q. In certain embodiments, R¹ is methyl. In certain embodiments, R¹ is C_1-6 heteroalkyl, optionally substituted with one or more substituents Q. In certain embodiments, R¹ is trifluoromethyl. In certain embodiments, R¹ is C_2- 6 alkenyl, optionally substituted with one or more substituents Q. In certain embodiments, R¹ is C_2-6 alkynyl, optionally substituted with one or more substituents Q. In certain embodiments, R¹ is C_3-10 cycloalkyl, optionally substituted with one or more substituents Q. In certain embodiments, R¹ is C_6-14 aryl, optionally substituted with one or more substituents Q. In certain embodiments, R¹ is C_7-15 aralkyl, optionally substituted with one or more substituents Q. In certain embodiments, R¹ is heteroaryl, optionally substituted with one or more substituents Q. In certain embodiments, R¹ is heterocyclyl, optionally substituted with one or more substituents Q. [0081] In certain embodiments, R¹ is –C(O)R^1a, wherein R^1a is as defined herein. In certain embodiments, R¹ is –C(O)OR^1a, wherein R^1a is as defined herein. In certain embodiments, R¹ is –C(O)NR^1bR^1c, wherein R^1b and R^1c are each as defined herein. In certain embodiments, R¹ is –C(O)SR^1a, wherein R^1a is as defined herein. In certain embodiments, R¹ is –C(NR^1a)NR^1bR^1c, wherein R^1a, R^1b, and R^1c are each as defined herein. In certain embodiments, R¹ is –C(S)R^1a, wherein R^1a is as defined herein. In certain embodiments, R¹ is –C(S)OR^1a, wherein R^1a is as defined herein. In certain embodiments, R¹ is –C(S)NR^1bR^1c, wherein R^1b and R^1c are each as defined herein. In certain embodiments, R¹ is –OR^1a, wherein R^1a is as defined herein. In certain embodiments, R¹ is –OC(O)R^1a, wherein R^1a is as defined herein. In certain embodiments, R¹ is –OC(O)OR^1a, wherein R^1a is as defined herein. In certain embodiments, R¹ is –OC(O)NR^1bR^1c, wherein R^1b and R^1c are each as defined herein. In certain embodiments, R¹ is –OC(O)SR^1a, wherein R^1a is as defined herein. In certain embodiments, R¹ is –OC(NR^1a)NR^1bR^1c, wherein R^1a, R^1b, and R^1c are each as defined herein. In certain embodiments, R¹ is –OC(S)R^1a, wherein R^1a is as defined herein. In certain embodiments, R¹ is –OC(S)OR^1a, wherein R^1a is as defined herein. In certain embodiments, R¹ is –OC(S)NR^1bR^1c, wherein R^1b and R^1c are each as defined herein. In certain embodiments, R¹ is –OS(O)R^1a, wherein R^1a is as defined herein. In certain embodiments, R¹ is –OS(O)₂R^1a, wherein R^1a is as defined herein. In certain embodiments, R¹ is –OS(O)NR^1bR^1c, wherein R^1b and R^1c are each as defined herein. In certain embodiments, R¹ is –OS(O)₂NR^1bR^1c, wherein R^1b and R^1c are each as defined herein. In certain embodiments, R¹ is –NR^1bR^1c, wherein R^1b and R^1c are each as defined herein. In certain embodiments, R¹ is –NR^1aC(O)R^1d, wherein R^1a and R^1d are each as defined herein. In certain embodiments, R¹ is –NR^1aC(O)OR^1d, wherein R^1a and R^1d are each as defined herein. In certain embodiments, R¹ is –NR^1aC(O)NR^1bR^1c, wherein R^1a, R^1b, and R^1c are each as defined herein. In certain embodiments, R¹ is –NR^1aC(O)SR^1d, wherein R^1a and R^1d are each as defined herein. In certain embodiments, R¹ is –NR^1aC(NR^1d)NR^1bR^1c, wherein R^1a, R^1b, R^1c, and R^1d are each as defined herein. In certain embodiments, R¹ is –NR^1aC(S)R^1d, wherein R^1a and R^1d are each as defined herein. In certain embodiments, R¹ is –NR^1aC(S)OR^1d, wherein R^1a and R^1d are each as defined herein. In certain embodiments, R¹ is –NR^1aC(S)NR^1bR^1c, wherein R^1a, R^1b, and R^1c are each as defined herein. In certain embodiments, R¹ is –NR^1aS(O)R^1d, wherein R^1a and R^1d are each as defined herein. In certain embodiments, R¹ is –NR^1aS(O)₂R^1d, wherein R^1a and R^1d are each as defined herein. In certain embodiments, R¹ is –NR^1aS(O)NR^1bR^1c, wherein R^1a, R^1b, and R^1c are each as defined herein. In certain embodiments, R¹ is –NR^1aS(O)₂NR^1bR^1c, wherein R^1a, R^1b, and R^1c are each as defined herein. In certain embodiments, R¹ is –SR^1a, wherein R^1a is as defined herein. In certain embodiments, R¹ is –S(O)R^1a, wherein R^1a is as defined herein. In certain embodiments, R¹ is –S(O)₂R^1a, wherein R^1a is as defined herein. In certain embodiments, R¹ is –S(O)NR^1bR^1c, wherein R^1b and R^1c are each as defined herein. In certain embodiments, R¹ is –S(O)₂NR^1bR^1c, wherein R^1b and R^1c are each as defined herein. [0082] In certain embodiments, R² is hydrogen. In certain embodiments, R² is deuterium. In certain embodiments, R² is cyano. In certain embodiments, R² is halo. In certain embodiments, R² is fluoro, chloro, or bromo. In certain embodiments, R² is chloro. In certain embodiments, R² is nitro. In certain embodiments, R² is C_1-6 alkyl, optionally substituted with one or more substituents Q. In certain embodiments, R² is methyl. In certain embodiments, R² is C_1-6 heteroalkyl, optionally substituted with one or more substituents Q. In certain embodiments, R² is trifluoromethyl. In certain embodiments, R² is C_2-6 alkenyl, optionally substituted with one or more substituents Q. In certain embodiments, R² is C_2-6 alkynyl, optionally substituted with one or more substituents Q. In certain embodiments, R² is C_3-10 cycloalkyl, optionally substituted with one or more substituents Q. In certain embodiments, R² is C_6-14 aryl, optionally substituted with one or more substituents Q. In certain embodiments, R² is C_7-15 aralkyl, optionally substituted with one or more substituents Q. In certain embodiments, R² is heteroaryl, optionally substituted with one or more substituents Q. In certain embodiments, R² is heterocyclyl, optionally substituted with one or more substituents Q. [0083] In certain embodiments, R² is –C(O)R^1a, wherein R^1a is as defined herein. In certain embodiments, R² is –C(O)OR^1a, wherein R^1a is as defined herein. In certain embodiments, R² is –C(O)NR^1bR^1c, wherein R^1b and R^1c are each as defined herein. In certain embodiments, R² is –C(O)SR^1a, wherein R^1a is as defined herein. In certain embodiments, R² is –C(NR^1a)NR^1bR^1c, wherein R^1a, R^1b, and R^1c are each as defined herein. In certain embodiments, R² is –C(S)R^1a, wherein R^1a is as defined herein. In certain embodiments, R² is –C(S)OR^1a, wherein R^1a is as defined herein. In certain embodiments, R² is –C(S)NR^1bR^1c, wherein R^1b and R^1c are each as defined herein. In certain embodiments, R² is –OR^1a, wherein R^1a is as defined herein. In certain embodiments, R² is –OC(O)R^1a, wherein R^1a is as defined herein. In certain embodiments, R² is –OC(O)OR^1a, wherein R^1a is as defined herein. In certain embodiments, R² is –OC(O)NR^1bR^1c, wherein R^1b and R^1c are each as defined herein. In certain embodiments, R² is –OC(O)SR^1a, wherein R^1a is as defined herein. In certain embodiments, R² is –OC(NR^1a)NR^1bR^1c, wherein R^1a, R^1b, and R^1c are each as defined herein. In certain embodiments, R² is –OC(S)R^1a, wherein R^1a is as defined herein. In certain embodiments, R² is –OC(S)OR^1a, wherein R^1a is as defined herein. In certain embodiments, R² is –OC(S)NR^1bR^1c, wherein R^1b and R^1c are each as defined herein. In certain embodiments, R² is –OS(O)R^1a, wherein R^1a is as defined herein. In certain embodiments, R² is –OS(O)₂R^1a, wherein R^1a is as defined herein. In certain embodiments, R² is –OS(O)NR^1bR^1c, wherein R^1b and R^1c are each as defined herein. In certain embodiments, R² is –OS(O)₂NR^1bR^1c, wherein R^1b and R^1c are each as defined herein. In certain embodiments, R² is –NR^1bR^1c, wherein R^1b and R^1c are each as defined herein. In certain embodiments, R² is –NR^1aC(O)R^1d, wherein R^1a and R^1d are each as defined herein. In certain embodiments, R² is –NR^1aC(O)OR^1d, wherein R^1a and R^1d are each as defined herein. In certain embodiments, R² is –NR^1aC(O)NR^1bR^1c, wherein R^1a, R^1b, and R^1c are each as defined herein. In certain embodiments, R² is –NR^1aC(O)SR^1d, wherein R^1a and R^1d are each as defined herein. In certain embodiments, R² is –NR^1aC(NR^1d)NR^1bR^1c, wherein R^1a, R^1b, R^1c, and R^1d are each as defined herein. In certain embodiments, R² is –NR^1aC(S)R^1d, wherein R^1a and R^1d are each as defined herein. In certain embodiments, R² is –NR^1aC(S)OR^1d, wherein R^1a and R^1d are each as defined herein. In certain embodiments, R² is –NR^1aC(S)NR^1bR^1c, wherein R^1a, R^1b, and R^1c are each as defined herein. In certain embodiments, R² is –NR^1aS(O)R^1d, wherein R^1a and R^1d are each as defined herein. In certain embodiments, R² is –NR^1aS(O)₂R^1d, wherein R^1a and R^1d are each as defined herein. In certain embodiments, R² is –NR^1aS(O)NR^1bR^1c, wherein R^1a, R^1b, and R^1c are each as defined herein. In certain embodiments, R² is –NR^1aS(O)₂NR^1bR^1c, wherein R^1a, R^1b, and R^1c are each as defined herein. In certain embodiments, R² is –SR^1a, wherein R^1a is as defined herein. In certain embodiments, R² is –S(O)R^1a, wherein R^1a is as defined herein. In certain embodiments, R² is –S(O)₂R^1a, wherein R^1a is as defined herein. In certain embodiments, R² is –S(O)NR^1bR^1c, wherein R^1b and R^1c are each as defined herein. In certain embodiments, R² is –S(O)₂NR^1bR^1c, wherein R^1b and R^1c are each as defined herein. [0084] In certain embodiments, R⁴ is hydrogen. In certain embodiments, R⁴ is deuterium. In certain embodiments, R⁴ is cyano. In certain embodiments, R⁴ is halo. In certain embodiments, R⁴ is fluoro, chloro, or bromo. In certain embodiments, R⁴ is chloro. In certain embodiments, R⁴ is nitro. In certain embodiments, R⁴ is C_1-6 alkyl, optionally substituted with one or more substituents Q. In certain embodiments, R⁴ is methyl. In certain embodiments, R⁴ is C_1-6 heteroalkyl, optionally substituted with one or more substituents Q. In certain embodiments, R⁴ is trifluoromethyl. In certain embodiments, R⁴ is C_2-6 alkenyl, optionally substituted with one or more substituents Q. In certain embodiments, R⁴ is C_2-6 alkynyl, optionally substituted with one or more substituents Q. In certain embodiments, R⁴ is C_3-10 cycloalkyl, optionally substituted with one or more substituents Q. In certain embodiments, R⁴ is C_6-14 aryl, optionally substituted with one or more substituents Q. In certain embodiments, R⁴ is C_7-15 aralkyl, optionally substituted with one or more substituents Q. In certain embodiments, R⁴ is heteroaryl, optionally substituted with one or more substituents Q. In certain embodiments, R⁴ is heterocyclyl, optionally substituted with one or more substituents Q. [0085] In certain embodiments, R⁴ is –C(O)R^1a, wherein R^1a is as defined herein. In certain embodiments, R⁴ is –C(O)OR^1a, wherein R^1a is as defined herein. In certain embodiments, R⁴ is –C(O)NR^1bR^1c, wherein R^1b and R^1c are each as defined herein. In certain embodiments, R⁴ is –C(O)SR^1a, wherein R^1a is as defined herein. In certain embodiments, R⁴ is –C(NR^1a)NR^1bR^1c, wherein R^1a, R^1b, and R^1c are each as defined herein. In certain embodiments, R⁴ is –C(S)R^1a, wherein R^1a is as defined herein. In certain embodiments, R⁴ is –C(S)OR^1a, wherein R^1a is as defined herein. In certain embodiments, R⁴ is –C(S)NR^1bR^1c, wherein R^1b and R^1c are each as defined herein. In certain embodiments, R⁴ is –OR^1a, wherein R^1a is as defined herein. In certain embodiments, R⁴ is –OC(O)R^1a, wherein R^1a is as defined herein. In certain embodiments, R⁴ is –OC(O)OR^1a, wherein R^1a is as defined herein. In certain embodiments, R⁴ is –OC(O)NR^1bR^1c, wherein R^1b and R^1c are each as defined herein. In certain embodiments, R⁴ is –OC(O)SR^1a, wherein R^1a is as defined herein. In certain embodiments, R⁴ is –OC(NR^1a)NR^1bR^1c, wherein R^1a, R^1b, and R^1c are each as defined herein. In certain embodiments, R⁴ is –OC(S)R^1a, wherein R^1a is as defined herein. In certain embodiments, R⁴ is –OC(S)OR^1a, wherein R^1a is as defined herein. In certain embodiments, R⁴ is –OC(S)NR^1bR^1c, wherein R^1b and R^1c are each as defined herein. In certain embodiments, R⁴ is –OS(O)R^1a, wherein R^1a is as defined herein. In certain embodiments, R⁴ is –OS(O)₂R^1a, wherein R^1a is as defined herein. In certain embodiments, R⁴ is –OS(O)NR^1bR^1c, wherein R^1b and R^1c are each as defined herein. In certain embodiments, R⁴ is –OS(O)₂NR^1bR^1c, wherein R^1b and R^1c are each as defined herein. In certain embodiments, R⁴ is –NR^1bR^1c, wherein R^1b and R^1c are each as defined herein. In certain embodiments, R⁴ is –NR^1aC(O)R^1d, wherein R^1a and R^1d are each as defined herein. In certain embodiments, R⁴ is –NR^1aC(O)OR^1d, wherein R^1a and R^1d are each as defined herein. In certain embodiments, R⁴ is –NR^1aC(O)NR^1bR^1c, wherein R^1a, R^1b, and R^1c are each as defined herein. In certain embodiments, R⁴ is –NR^1aC(O)SR^1d, wherein R^1a and R^1d are each as defined herein. In certain embodiments, R⁴ is –NR^1aC(NR^1d)NR^1bR^1c, wherein R^1a, R^1b, R^1c, and R^1d are each as defined herein. In certain embodiments, R⁴ is –NR^1aC(S)R^1d, wherein R^1a and R^1d are each as defined herein. In certain embodiments, R⁴ is –NR^1aC(S)OR^1d, wherein R^1a and R^1d are each as defined herein. In certain embodiments, R⁴ is –NR^1aC(S)NR^1bR^1c, wherein R^1a, R^1b, and R^1c are each as defined herein. In certain embodiments, R⁴ is –NR^1aS(O)R^1d, wherein R^1a and R^1d are each as defined herein. In certain embodiments, R⁴ is –NR^1aS(O)₂R^1d, wherein R^1a and R^1d are each as defined herein. In certain embodiments, R⁴ is –NR^1aS(O)NR^1bR^1c, wherein R^1a, R^1b, and R^1c are each as defined herein. In certain embodiments, R⁴ is –NR^1aS(O)₂NR^1bR^1c, wherein R^1a, R^1b, and R^1c are each as defined herein. In certain embodiments, R⁴ is –SR^1a, wherein R^1a is as defined herein. In certain embodiments, R⁴ is –S(O)R^1a, wherein R^1a is as defined herein. In certain embodiments, R⁴ is –S(O)₂R^1a, wherein R^1a is as defined herein. In certain embodiments, R⁴ is –S(O)NR^1bR^1c, wherein R^1b and R^1c are each as defined herein. In certain embodiments, R⁴ is –S(O)₂NR^1bR^1c, wherein R^1b and R^1c are each as defined herein. [0086] In certain embodiments, R⁵ is hydrogen. In certain embodiments, R⁵ is deuterium. In certain embodiments, R⁵ is cyano. In certain embodiments, R⁵ is halo. In certain embodiments, R⁵ is fluoro, chloro, or bromo. In certain embodiments, R⁵ is fluoro. In certain embodiments, R⁵ is chloro. In certain embodiments, R⁵ is nitro. In certain embodiments, R⁵ is C_1-6 alkyl, optionally substituted with one or more substituents Q. In certain embodiments, R⁵ is methyl. In certain embodiments, R⁵ is C_1-6 heteroalkyl, optionally substituted with one or more substituents Q. In certain embodiments, R⁵ is trifluoromethyl. In certain embodiments, R⁵ is C_2- 6 alkenyl, optionally substituted with one or more substituents Q. In certain embodiments, R⁵ is C_2-6 alkynyl, optionally substituted with one or more substituents Q. In certain embodiments, R⁵ is C_3-10 cycloalkyl, optionally substituted with one or more substituents Q. In certain embodiments, R⁵ is C_6-14 aryl, optionally substituted with one or more substituents Q. In certain embodiments, R⁵ is C_7-15 aralkyl, optionally substituted with one or more substituents Q. In certain embodiments, R⁵ is heteroaryl, optionally substituted with one or more substituents Q. In certain embodiments, R⁵ is heterocyclyl, optionally substituted with one or more substituents Q. [0087] In certain embodiments, R⁵ is –C(O)R^1a, wherein R^1a is as defined herein. In certain embodiments, R⁵ is –C(O)OR^1a, wherein R^1a is as defined herein. In certain embodiments, R⁵ is –C(O)NR^1bR^1c, wherein R^1b and R^1c are each as defined herein. In certain embodiments, R⁵ is –C(O)SR^1a, wherein R^1a is as defined herein. In certain embodiments, R⁵ is –C(NR^1a)NR^1bR^1c, wherein R^1a, R^1b, and R^1c are each as defined herein. In certain embodiments, R⁵ is –C(S)R^1a, wherein R^1a is as defined herein. In certain embodiments, R⁵ is –C(S)OR^1a, wherein R^1a is as defined herein. In certain embodiments, R⁵ is –C(S)NR^1bR^1c, wherein R^1b and R^1c are each as defined herein. In certain embodiments, R⁵ is –OR^1a, wherein R^1a is as defined herein. In certain embodiments, R⁵ is –OC(O)R^1a, wherein R^1a is as defined herein. In certain embodiments, R⁵ is –OC(O)OR^1a, wherein R^1a is as defined herein. In certain embodiments, R⁵ is –OC(O)NR^1bR^1c, wherein R^1b and R^1c are each as defined herein. In certain embodiments, R⁵ is –OC(O)SR^1a, wherein R^1a is as defined herein. In certain embodiments, R⁵ is –OC(NR^1a)NR^1bR^1c, wherein R^1a, R^1b, and R^1c are each as defined herein. In certain embodiments, R⁵ is –OC(S)R^1a, wherein R^1a is as defined herein. In certain embodiments, R⁵ is –OC(S)OR^1a, wherein R^1a is as defined herein. In certain embodiments, R⁵ is –OC(S)NR^1bR^1c, wherein R^1b and R^1c are each as defined herein. In certain embodiments, R⁵ is –OS(O)R^1a, wherein R^1a is as defined herein. In certain embodiments, R⁵ is –OS(O)₂R^1a, wherein R^1a is as defined herein. In certain embodiments, R⁵ is –OS(O)NR^1bR^1c, wherein R^1b and R^1c are each as defined herein. In certain embodiments, R⁵ is –OS(O)₂NR^1bR^1c, wherein R^1b and R^1c are each as defined herein. In certain embodiments, R⁵ is –NR^1bR^1c, wherein R^1b and R^1c are each as defined herein. In certain embodiments, R⁵ is –NR^1aC(O)R^1d, wherein R^1a and R^1d are each as defined herein. In certain embodiments, R⁵ is –NR^1aC(O)OR^1d, wherein R^1a and R^1d are each as defined herein. In certain embodiments, R⁵ is –NR^1aC(O)NR^1bR^1c, wherein R^1a, R^1b, and R^1c are each as defined herein. In certain embodiments, R⁵ is –NR^1aC(O)SR^1d, wherein R^1a and R^1d are each as defined herein. In certain embodiments, R⁵ is –NR^1aC(NR^1d)NR^1bR^1c, wherein R^1a, R^1b, R^1c, and R^1d are each as defined herein. In certain embodiments, R⁵ is –NR^1aC(S)R^1d, wherein R^1a and R^1d are each as defined herein. In certain embodiments, R⁵ is –NR^1aC(S)OR^1d, wherein R^1a and R^1d are each as defined herein. In certain embodiments, R⁵ is –NR^1aC(S)NR^1bR^1c, wherein R^1a, R^1b, and R^1c are each as defined herein. In certain embodiments, R⁵ is –NR^1aS(O)R^1d, wherein R^1a and R^1d are each as defined herein. In certain embodiments, R⁵ is –NR^1aS(O)₂R^1d, wherein R^1a and R^1d are each as defined herein. In certain embodiments, R⁵ is –NR^1aS(O)NR^1bR^1c, wherein R^1a, R^1b, and R^1c are each as defined herein. In certain embodiments, R⁵ is –NR^1aS(O)₂NR^1bR^1c, wherein R^1a, R^1b, and R^1c are each as defined herein. In certain embodiments, R⁵ is –SR^1a, wherein R^1a is as defined herein. In certain embodiments, R⁵ is –S(O)R^1a, wherein R^1a is as defined herein. In certain embodiments, R⁵ is –S(O)₂R^1a, wherein R^1a is as defined herein. In certain embodiments, R⁵ is –S(O)NR^1bR^1c, wherein R^1b and R^1c are each as defined herein. In certain embodiments, R⁵ is –S(O)₂NR^1bR^1c, wherein R^1b and R^1c are each as defined herein. [0088] In certain embodiments, R^3a is hydrogen. In certain embodiments, R^3a is deuterium. In certain embodiments, R^3a is cyano. In certain embodiments, R^3a is halo. In certain embodiments, R^3a is fluoro, chloro, or bromo. In certain embodiments, R^3a is chloro. In certain embodiments, R^3a is nitro. In certain embodiments, R^3a is C_1-6 alkyl, optionally substituted with one or more substituents Q. In certain embodiments, R^3a is methyl, trifluoromethyl, or hydroxylmethyl. In certain embodiments, R^3a is C_1-6 heteroalkyl, optionally substituted with one or more substituents Q. In certain embodiments, R^3a is trifluoromethyl. In certain embodiments, R^3a is C_2-6 alkenyl, optionally substituted with one or more substituents Q. In certain embodiments, R^3a is C_2-6 alkynyl, optionally substituted with one or more substituents Q. In certain embodiments, R^3a is C_3-10 cycloalkyl, optionally substituted with one or more substituents Q. In certain embodiments, R^3a is C_6-14 aryl, optionally substituted with one or more substituents Q. In certain embodiments, R^3a is C_7-15 aralkyl, optionally substituted with one or more substituents Q. In certain embodiments, R^3a is heteroaryl, optionally substituted with one or more substituents Q. In certain embodiments, R^3a is heterocyclyl, optionally substituted with one or more substituents Q. [0089] In certain embodiments, R^3a is –C(O)R^1a, wherein R^1a is as defined herein. In certain embodiments, R^3a is –C(O)OR^1a, wherein R^1a is as defined herein. In certain embodiments, R^3a is –C(O)NR^1bR^1c, wherein R^1b and R^1c are each as defined herein. In certain embodiments, R^3a is –C(O)NH₂. In certain embodiments, R^3a is –C(O)SR^1a, wherein R^1a is as defined herein. In certain embodiments, R^3a is –C(NR^1a)NR^1bR^1c, wherein R^1a, R^1b, and R^1c are each as defined herein. In certain embodiments, R^3a is –C(S)R^1a, wherein R^1a is as defined herein. In certain embodiments, R^3a is –C(S)OR^1a, wherein R^1a is as defined herein. In certain embodiments, R^3a is –C(S)NR^1bR^1c, wherein R^1b and R^1c are each as defined herein. In certain embodiments, R^3a is –OR^1a, wherein R^1a is as defined herein. In certain embodiments, R^3a is –OC(O)R^1a, wherein R^1a is as defined herein. In certain embodiments, R^3a is –OC(O)OR^1a, wherein R^1a is as defined herein. In certain embodiments, R^3a is –OC(O)NR^1bR^1c, wherein R^1b and R^1c are each as defined herein. In certain embodiments, R^3a is –OC(O)SR^1a, wherein R^1a is as defined herein. In certain embodiments, R^3a is –OC(NR^1a)NR^1bR^1c, wherein R^1a, R^1b, and R^1c are each as defined herein. In certain embodiments, R^3a is –OC(S)R^1a, wherein R^1a is as defined herein. In certain embodiments, R^3a is –OC(S)OR^1a, wherein R^1a is as defined herein. In certain embodiments, R^3a is –OC(S)NR^1bR^1c, wherein R^1b and R^1c are each as defined herein. In certain embodiments, R^3a is –OS(O)R^1a, wherein R^1a is as defined herein. In certain embodiments, R^3a is –OS(O)₂R^1a, wherein R^1a is as defined herein. In certain embodiments, R^3a is –OS(O)NR^1bR^1c, wherein R^1b and R^1c are each as defined herein. In certain embodiments, R^3a is –OS(O)₂NR^1bR^1c, wherein R^1b and R^1c are each as defined herein. In certain embodiments, R^3a is –NR^1bR^1c, wherein R^1b and R^1c are each as defined herein. In certain embodiments, R^3a is –NH₂. In certain embodiments, R^3a is –NR^1aC(O)R^1d, wherein R^1a and R^1d are each as defined herein. In certain embodiments, R^3a is –NR^1aC(O)OR^1d, wherein R^1a and R^1d are each as defined herein. In certain embodiments, R^3a is –NR^1aC(O)NR^1bR^1c, wherein R^1a, R^1b, and R^1c are each as defined herein. In certain embodiments, R^3a is –NR^1aC(O)SR^1d, wherein R^1a and R^1d are each as defined herein. In certain embodiments, R^3a is –NR^1aC(NR^1d)NR^1bR^1c, wherein R^1a, R^1b, R^1c, and R^1d are each as defined herein. In certain embodiments, R^3a is –NR^1aC(S)R^1d, wherein R^1a and R^1d are each as defined herein. In certain embodiments, R^3a is –NR^1aC(S)OR^1d, wherein R^1a and R^1d are each as defined herein. In certain embodiments, R^3a is –NR^1aC(S)NR^1bR^1c, wherein R^1a, R^1b, and R^1c are each as defined herein. In certain embodiments, R^3a is –NR^1aS(O)R^1d, wherein R^1a and R^1d are each as defined herein. In certain embodiments, R^3a is –NR^1aS(O)₂R^1d, wherein R^1a and R^1d are each as defined herein. In certain embodiments, R^3a is –NR^1aS(O)NR^1bR^1c, wherein R^1a, R^1b, and R^1c are each as defined herein. In certain embodiments, R^3a is –NR^1aS(O)₂NR^1bR^1c, wherein R^1a, R^1b, and R^1c are each as defined herein. In certain embodiments, R^3a is –SR^1a, wherein R^1a is as defined herein. In certain embodiments, R^3a is –S(O)R^1a, wherein R^1a is as defined herein. In certain embodiments, R^3a is –S(O)₂R^1a, wherein R^1a is as defined herein. In certain embodiments, R^3a is –S(O)NR^1bR^1c, wherein R^1b and R^1c are each as defined herein. In certain embodiments, R^3a is –S(O)₂NR^1bR^1c, wherein R^1b and R^1c are each as defined herein. [0090] In certain embodiments, R^3b is hydrogen. In certain embodiments, R^3b is C_1-6 alkyl, optionally substituted with one or more substituents Q. In certain embodiments, R^3b is methyl. In certain embodiments, R^3b is C_1-6 heteroalkyl, optionally substituted with one or more substituents Q. In certain embodiments, R^3b is trifluoromethyl. In certain embodiments, R^3b is C_2-6 alkenyl, optionally substituted with one or more substituents Q. In certain embodiments, R^3b is C_2-6 alkynyl, optionally substituted with one or more substituents Q. In certain embodiments, R^3b is C_3-10 cycloalkyl, optionally substituted with one or more substituents Q. In certain embodiments, R^3b is C_6-14 aryl, optionally substituted with one or more substituents Q. In certain embodiments, R^3b is C_7-15 aralkyl, optionally substituted with one or more substituents Q. In certain embodiments, R^3b is heteroaryl, optionally substituted with one or more substituents Q. In certain embodiments, R^3b is heterocyclyl, optionally substituted with one or more substituents Q. [0091] In certain embodiments, R^3b is –C(O)R^1a, wherein R^1a is as defined herein. In certain embodiments, R^3b is –C(O)OR^1a, wherein R^1a is as defined herein. In certain embodiments, R^3b is –C(O)NR^1bR^1c, wherein R^1b and R^1c are each as defined herein. In certain embodiments, R^3b is –C(O)SR^1a, wherein R^1a is as defined herein. In certain embodiments, R^3b is –C(NR^1a)NR^1bR^1c, wherein R^1a, R^1b, and R^1c are each as defined herein. In certain embodiments, R^3b is –C(S)R^1a, wherein R^1a is as defined herein. In certain embodiments, R^3b is –C(S)OR^1a, wherein R^1a is as defined herein. In certain embodiments, R^3b is –C(S)NR^1bR^1c, wherein R^1b and R^1c are each as defined herein. In certain embodiments, R^3b is –OR^1a, wherein R^1a is as defined herein. In certain embodiments, R^3b is –OC(O)R^1a, wherein R^1a is as defined herein. In certain embodiments, R^3b is –OC(O)OR^1a, wherein R^1a is as defined herein. In certain embodiments, R^3b is –OC(O)NR^1bR^1c, wherein R^1b and R^1c are each as defined herein. In certain embodiments, R^3b is –OC(O)SR^1a, wherein R^1a is as defined herein. In certain embodiments, R^3b is –OC(NR^1a)NR^1bR^1c, wherein R^1a, R^1b, and R^1c are each as defined herein. In certain embodiments, R^3b is –OC(S)R^1a, wherein R^1a is as defined herein. In certain embodiments, R^3b is –OC(S)OR^1a, wherein R^1a is as defined herein. In certain embodiments, R^3b is –OC(S)NR^1bR^1c, wherein R^1b and R^1c are each as defined herein. In certain embodiments, R^3b is –OS(O)R^1a, wherein R^1a is as defined herein. In certain embodiments, R^3b is –OS(O)₂R^1a, wherein R^1a is as defined herein. In certain embodiments, R^3b is –OS(O)NR^1bR^1c, wherein R^1b and R^1c are each as defined herein. In certain embodiments, R^3b is –OS(O)₂NR^1bR^1c, wherein R^1b and R^1c are each as defined herein. In certain embodiments, R^3b is –NR^1bR^1c, wherein R^1b and R^1c are each as defined herein. In certain embodiments, R^3b is –NH₂. In certain embodiments, R^3b is –NR^1aC(O)R^1d, wherein R^1a and R^1d are each as defined herein. In certain embodiments, R^3b is –NR^1aC(O)OR^1d, wherein R^1a and R^1d are each as defined herein. In certain embodiments, R^3b is –NR^1aC(O)NR^1bR^1c, wherein R^1a, R^1b, and R^1c are each as defined herein. In certain embodiments, R^3b is –NR^1aC(O)SR^1d, wherein R^1a and R^1d are each as defined herein. In certain embodiments, R^3b is –NR^1aC(NR^1d)NR^1bR^1c, wherein R^1a, R^1b, R^1c, and R^1d are each as defined herein. In certain embodiments, R^3b is –NR^1aC(S)R^1d, wherein R^1a and R^1d are each as defined herein. In certain embodiments, R^3b is –NR^1aC(S)OR^1d, wherein R^1a and R^1d are each as defined herein. In certain embodiments, R^3b is –NR^1aC(S)NR^1bR^1c, wherein R^1a, R^1b, and R^1c are each as defined herein. In certain embodiments, R^3b is –NR^1aS(O)R^1d, wherein R^1a and R^1d are each as defined herein. In certain embodiments, R^3b is –NR^1aS(O)₂R^1d, wherein R^1a and R^1d are each as defined herein. In certain embodiments, R^3b is –NR^1aS(O)NR^1bR^1c, wherein R^1a, R^1b, and R^1c are each as defined herein. In certain embodiments, R^3b is –NR^1aS(O)₂NR^1bR^1c, wherein R^1a, R^1b, and R^1c are each as defined herein. In certain embodiments, R^3b is –S(O)R^1a, wherein R^1a is as defined herein. In certain embodiments, R^3b is –S(O)₂R^1a, wherein R^1a is as defined herein. In certain embodiments, R^3b is –S(O)NR^1bR^1c, wherein R^1b and R^1c are each as defined herein. In certain embodiments, R^3b is –S(O)₂NR^1bR^1c, wherein R^1b and R^1c are each as defined herein. [0092] In certain embodiments, R^7a is hydrogen. In certain embodiments, R^7a is deuterium. In certain embodiments, R^7a is cyano. In certain embodiments, R^7a is halo. In certain embodiments, R^7a is fluoro, chloro, or bromo. In certain embodiments, R^7a is chloro. In certain embodiments, R^7a is nitro. In certain embodiments, R^7a is C_1-6 alkyl, optionally substituted with one or more substituents Q. In certain embodiments, R^7a is methyl, trifluoromethyl, hydroxylmethyl, or 2-hydroxylethyl. In certain embodiments, R^7a is methyl, fluoromethyl, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, hydroxylmethyl, or 2- hydroxylethyl. In certain embodiments, R^7a is C_1-6 heteroalkyl, optionally substituted with one or more substituents Q. In certain embodiments, R^7a is trifluoromethyl. In certain embodiments, R^7a is C_2-6 alkenyl, optionally substituted with one or more substituents Q. In certain embodiments, R^7a is C_2-6 alkynyl, optionally substituted with one or more substituents Q. In certain embodiments, R^7a is C_3-10 cycloalkyl, optionally substituted with one or more substituents Q. In certain embodiments, R^7a is C_6-14 aryl, optionally substituted with one or more substituents Q. In certain embodiments, R^7a is C_7-15 aralkyl, optionally substituted with one or more substituents Q. In certain embodiments, R^7a is heteroaryl, optionally substituted with one or more substituents Q. In certain embodiments, R^7a is heterocyclyl, optionally substituted with one or more substituents Q. [0093] In certain embodiments, R^7a is –C(O)R^1a, wherein R^1a is as defined herein. In certain embodiments, R^7a is –C(O)OR^1a, wherein R^1a is as defined herein. In certain embodiments, R^7a is –C(O)NR^1bR^1c, wherein R^1b and R^1c are each as defined herein. In certain embodiments, R^7a is –C(O)NH₂. In certain embodiments, R^7a is –C(O)SR^1a, wherein R^1a is as defined herein. In certain embodiments, R^7a is –C(NR^1a)NR^1bR^1c, wherein R^1a, R^1b, and R^1c are each as defined herein. In certain embodiments, R^7a is –C(S)R^1a, wherein R^1a is as defined herein. In certain embodiments, R^7a is –C(S)OR^1a, wherein R^1a is as defined herein. In certain embodiments, R^7a is –C(S)NR^1bR^1c, wherein R^1b and R^1c are each as defined herein. In certain embodiments, R^7a is –OR^1a, wherein R^1a is as defined herein. In certain embodiments, R^7a is –OC(O)R^1a, wherein R^1a is as defined herein. In certain embodiments, R^7a is –OC(O)OR^1a, wherein R^1a is as defined herein. In certain embodiments, R^7a is –OC(O)NR^1bR^1c, wherein R^1b and R^1c are each as defined herein. In certain embodiments, R^7a is –OC(O)SR^1a, wherein R^1a is as defined herein. In certain embodiments, R^7a is –OC(NR^1a)NR^1bR^1c, wherein R^1a, R^1b, and R^1c are each as defined herein. In certain embodiments, R^7a is –OC(S)R^1a, wherein R^1a is as defined herein. In certain embodiments, R^7a is –OC(S)OR^1a, wherein R^1a is as defined herein. In certain embodiments, R^7a is –OC(S)NR^1bR^1c, wherein R^1b and R^1c are each as defined herein. In certain embodiments, R^7a is –OS(O)R^1a, wherein R^1a is as defined herein. In certain embodiments, R^7a is –OS(O)₂R^1a, wherein R^1a is as defined herein. In certain embodiments, R^7a is –OS(O)NR^1bR^1c, wherein R^1b and R^1c are each as defined herein. In certain embodiments, R^7a is –OS(O)₂NR^1bR^1c, wherein R^1b and R^1c are each as defined herein. In certain embodiments, R^7a is –NR^1bR^1c, wherein R^1b and R^1c are each as defined herein. In certain embodiments, R^7a is –NH₂. In certain embodiments, R^7a is –NR^1aC(O)R^1d, wherein R^1a and R^1d are each as defined herein. In certain embodiments, R^7a is –NR^1aC(O)OR^1d, wherein R^1a and R^1d are each as defined herein. In certain embodiments, R^7a is –NR^1aC(O)NR^1bR^1c, wherein R^1a, R^1b, and R^1c are each as defined herein. In certain embodiments, R^7a is –NR^1aC(O)SR^1d, wherein R^1a and R^1d are each as defined herein. In certain embodiments, R^7a is –NR^1aC(NR^1d)NR^1bR^1c, wherein R^1a, R^1b, R^1c, and R^1d are each as defined herein. In certain embodiments, R^7a is –NR^1aC(S)R^1d, wherein R^1a and R^1d are each as defined herein. In certain embodiments, R^7a is –NR^1aC(S)OR^1d, wherein R^1a and R^1d are each as defined herein. In certain embodiments, R^7a is –NR^1aC(S)NR^1bR^1c, wherein R^1a, R^1b, and R^1c are each as defined herein. In certain embodiments, R^7a is –NR^1aS(O)R^1d, wherein R^1a and R^1d are each as defined herein. In certain embodiments, R^7a is –NR^1aS(O)₂R^1d, wherein R^1a and R^1d are each as defined herein. In certain embodiments, R^7a is –NR^1aS(O)NR^1bR^1c, wherein R^1a, R^1b, and R^1c are each as defined herein. In certain embodiments, R^7a is –NR^1aS(O)₂NR^1bR^1c, wherein R^1a, R^1b, and R^1c are each as defined herein. In certain embodiments, R^7a is –SR^1a, wherein R^1a is as defined herein. In certain embodiments, R^7a is –S(O)R^1a, wherein R^1a is as defined herein. In certain embodiments, R^7a is –S(O)₂R^1a, wherein R^1a is as defined herein. In certain embodiments, R^7a is –S(O)NR^1bR^1c, wherein R^1b and R^1c are each as defined herein. In certain embodiments, R^7a is –S(O)₂NR^1bR^1c, wherein R^1b and R^1c are each as defined herein. [0094] In certain embodiments, R^7b is hydrogen. In certain embodiments, R^7b is deuterium. In certain embodiments, R^7b is cyano. In certain embodiments, R^7b is halo. In certain embodiments, R^7b is fluoro, chloro, or bromo. In certain embodiments, R^7b is chloro. In certain embodiments, R^7b is nitro. In certain embodiments, R^7b is C_1-6 alkyl, optionally substituted with one or more substituents Q. In certain embodiments, R^7b is methyl, trifluoromethyl, hydroxylmethyl, or 2-hydroxylethyl. In certain embodiments, R^7b is methyl, fluoromethyl, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, hydroxylmethyl, or 2- hydroxylethyl. In certain embodiments, R^7b is C_1-6 heteroalkyl, optionally substituted with one or more substituents Q. In certain embodiments, R^7b is trifluoromethyl. In certain embodiments, R^7b is C_2-6 alkenyl, optionally substituted with one or more substituents Q. In certain embodiments, R^7b is C_2-6 alkynyl, optionally substituted with one or more substituents Q. In certain embodiments, R^7b is C_3-10 cycloalkyl, optionally substituted with one or more substituents Q. In certain embodiments, R^7b is C_6-14 aryl, optionally substituted with one or more substituents Q. In certain embodiments, R^7b is C_7-15 aralkyl, optionally substituted with one or more substituents Q. In certain embodiments, R^7b is heteroaryl, optionally substituted with one or more substituents Q. In certain embodiments, R^7b is heterocyclyl, optionally substituted with one or more substituents Q. [0095] In certain embodiments, R^7b is –C(O)R^1a, wherein R^1a is as defined herein. In certain embodiments, R^7b is –C(O)OR^1a, wherein R^1a is as defined herein. In certain embodiments, R^7b is –C(O)NR^1bR^1c, wherein R^1b and R^1c are each as defined herein. In certain embodiments, R^7b is –C(O)NH₂. In certain embodiments, R^7b is –C(O)SR^1a, wherein R^1a is as defined herein. In certain embodiments, R^7b is –C(NR^1a)NR^1bR^1c, wherein R^1a, R^1b, and R^1c are each as defined herein. In certain embodiments, R^7b is –C(S)R^1a, wherein R^1a is as defined herein. In certain embodiments, R^7b is –C(S)OR^1a, wherein R^1a is as defined herein. In certain embodiments, R^7b is –C(S)NR^1bR^1c, wherein R^1b and R^1c are each as defined herein. In certain embodiments, R^7b is –OR^1a, wherein R^1a is as defined herein. In certain embodiments, R^7b is –OC(O)R^1a, wherein R^1a is as defined herein. In certain embodiments, R^7b is –OC(O)OR^1a, wherein R^1a is as defined herein. In certain embodiments, R^7b is –OC(O)NR^1bR^1c, wherein R^1b and R^1c are each as defined herein. In certain embodiments, R^7b is –OC(O)SR^1a, wherein R^1a is as defined herein. In certain embodiments, R^7b is –OC(NR^1a)NR^1bR^1c, wherein R^1a, R^1b, and R^1c are each as defined herein. In certain embodiments, R^7b is –OC(S)R^1a, wherein R^1a is as defined herein. In certain embodiments, R^7b is –OC(S)OR^1a, wherein R^1a is as defined herein. In certain embodiments, R^7b is –OC(S)NR^1bR^1c, wherein R^1b and R^1c are each as defined herein. In certain embodiments, R^7b is –OS(O)R^1a, wherein R^1a is as defined herein. In certain embodiments, R^7b is –OS(O)₂R^1a, wherein R^1a is as defined herein. In certain embodiments, R^7b is –OS(O)NR^1bR^1c, wherein R^1b and R^1c are each as defined herein. In certain embodiments, R^7b is –OS(O)₂NR^1bR^1c, wherein R^1b and R^1c are each as defined herein. In certain embodiments, R^7b is –NR^1bR^1c, wherein R^1b and R^1c are each as defined herein. In certain embodiments, R^7b is –NH₂. In certain embodiments, R^7b is –NR^1aC(O)R^1d, wherein R^1a and R^1d are each as defined herein. In certain embodiments, R^7b is –NR^1aC(O)OR^1d, wherein R^1a and R^1d are each as defined herein. In certain embodiments, R^7b is –NR^1aC(O)NR^1bR^1c, wherein R^1a, R^1b, and R^1c are each as defined herein. In certain embodiments, R^7b is –NR^1aC(O)SR^1d, wherein R^1a and R^1d are each as defined herein. In certain embodiments, R^7b is –NR^1aC(NR^1d)NR^1bR^1c, wherein R^1a, R^1b, R^1c, and R^1d are each as defined herein. In certain embodiments, R^7b is –NR^1aC(S)R^1d, wherein R^1a and R^1d are each as defined herein. In certain embodiments, R^7b is –NR^1aC(S)OR^1d, wherein R^1a and R^1d are each as defined herein. In certain embodiments, R^7b is –NR^1aC(S)NR^1bR^1c, wherein R^1a, R^1b, and R^1c are each as defined herein. In certain embodiments, R^7b is –NR^1aS(O)R^1d, wherein R^1a and R^1d are each as defined herein. In certain embodiments, R^7b is –NR^1aS(O)₂R^1d, wherein R^1a and R^1d are each as defined herein. In certain embodiments, R^7b is –NR^1aS(O)NR^1bR^1c, wherein R^1a, R^1b, and R^1c are each as defined herein. In certain embodiments, R^7b is –NR^1aS(O)₂NR^1bR^1c, wherein R^1a, R^1b, and R^1c are each as defined herein. In certain embodiments, R^7b is –SR^1a, wherein R^1a is as defined herein. In certain embodiments, R^7b is –S(O)R^1a, wherein R^1a is as defined herein. In certain embodiments, R^7b is –S(O)₂R^1a, wherein R^1a is as defined herein. In certain embodiments, R^7b is –S(O)NR^1bR^1c, wherein R^1b and R^1c are each as defined herein. In certain embodiments, R^7b is –S(O)₂NR^1bR^1c, wherein R^1b and R^1c are each as defined herein. [0096] In certain embodiments, R^7a and R^7b together with the carbon atom to which they are attached form C(O). In certain embodiments, R^7a and R^7b together with the carbon atom to which they are attached form C_3-10 cycloalkylene, optionally substituted with one or more substituents Q. In certain embodiments, R^7a and R^7b together with the carbon atom to which they are attached form monocyclic C_3-10 cycloalkylene, optionally substituted with one or more substituents Q. In certain embodiments, R^7a and R^7b together with the carbon atom to which they are attached form cyclopropane-1,1-diyl, cyclobutane-1,1-yl, cyclopentane-1,1-diyl, cyclohexane-1,1-diyl, or cycloheptane-1,1-diyl, each optionally substituted with one or more substituents Q. In certain embodiments, R^7a and R^7b together with the carbon atom to which they are attached form heterocyclylene, optionally substituted with one or more substituents Q. In certain embodiments, R^7a and R^7b together with the carbon atom to which they are attached form monocyclic heterocyclylene, optionally substituted with one or more substituents Q. In certain embodiments, R^7a and R^7b together with the carbon atom to which they are attached form 5- membered heterocyclylene, optionally substituted with one or more substituents Q. In certain embodiments, R^7a and R^7b together with the carbon atom to which they are attached form tetrahydrofurdiyl, optionally substituted with one or more substituents Q. In certain embodiments, R^7a and R^7b together with the carbon atom to which they are attached form tetrahydrofur-3,3-diyl, optionally substituted with one or more substituents Q. In certain embodiments, R^7a and R^7b together with the carbon atom to which they are attached form 6- membered heterocyclylene, optionally substituted with one or more substituents Q. [0097] In certain embodiments, R^8a is hydrogen. In certain embodiments, R^8a is deuterium. In certain embodiments, R^8a is cyano. In certain embodiments, R^8a is halo. In certain embodiments, R^8a is fluoro, chloro, or bromo. In certain embodiments, R^8a is chloro. In certain embodiments, R^8a is nitro. In certain embodiments, R^8a is C_1-6 alkyl, optionally substituted with one or more substituents Q. In certain embodiments, R^8a is methyl, trifluoromethyl, hydroxylmethyl, or 2-hydroxylethyl. In certain embodiments, R^8a is C_1-6 heteroalkyl, optionally substituted with one or more substituents Q. In certain embodiments, R^8a is trifluoromethyl. In certain embodiments, R^8a is C_2-6 alkenyl, optionally substituted with one or more substituents Q. In certain embodiments, R^8a is C_2-6 alkynyl, optionally substituted with one or more substituents Q. In certain embodiments, R^8a is C_3-10 cycloalkyl, optionally substituted with one or more substituents Q. In certain embodiments, R^8a is C_6-14 aryl, optionally substituted with one or more substituents Q. In certain embodiments, R^8a is C_7-15 aralkyl, optionally substituted with one or more substituents Q. In certain embodiments, R^8a is heteroaryl, optionally substituted with one or more substituents Q. In certain embodiments, R^8a is heterocyclyl, optionally substituted with one or more substituents Q. [0098] In certain embodiments, R^8a is –C(O)R^1a, wherein R^1a is as defined herein. In certain embodiments, R^8a is –C(O)OR^1a, wherein R^1a is as defined herein. In certain embodiments, R^8a is –C(O)NR^1bR^1c, wherein R^1b and R^1c are each as defined herein. In certain embodiments, R^8a is –C(O)NH₂. In certain embodiments, R^8a is –C(O)SR^1a, wherein R^1a is as defined herein. In certain embodiments, R^8a is –C(NR^1a)NR^1bR^1c, wherein R^1a, R^1b, and R^1c are each as defined herein. In certain embodiments, R^8a is –C(S)R^1a, wherein R^1a is as defined herein. In certain embodiments, R^8a is –C(S)OR^1a, wherein R^1a is as defined herein. In certain embodiments, R^8a is –C(S)NR^1bR^1c, wherein R^1b and R^1c are each as defined herein. In certain embodiments, R^8a is –OR^1a, wherein R^1a is as defined herein. In certain embodiments, R^8a is –OC(O)R^1a, wherein R^1a is as defined herein. In certain embodiments, R^8a is –OC(O)OR^1a, wherein R^1a is as defined herein. In certain embodiments, R^8a is –OC(O)NR^1bR^1c, wherein R^1b and R^1c are each as defined herein. In certain embodiments, R^8a is –OC(O)SR^1a, wherein R^1a is as defined herein. In certain embodiments, R^8a is –OC(NR^1a)NR^1bR^1c, wherein R^1a, R^1b, and R^1c are each as defined herein. In certain embodiments, R^8a is –OC(S)R^1a, wherein R^1a is as defined herein. In certain embodiments, R^8a is –OC(S)OR^1a, wherein R^1a is as defined herein. In certain embodiments, R^8a is –OC(S)NR^1bR^1c, wherein R^1b and R^1c are each as defined herein. In certain embodiments, R^8a is –OS(O)R^1a, wherein R^1a is as defined herein. In certain embodiments, R^8a is –OS(O)₂R^1a, wherein R^1a is as defined herein. In certain embodiments, R^8a is –OS(O)NR^1bR^1c, wherein R^1b and R^1c are each as defined herein. In certain embodiments, R^8a is –OS(O)₂NR^1bR^1c, wherein R^1b and R^1c are each as defined herein. In certain embodiments, R^8a is –NR^1bR^1c, wherein R^1b and R^1c are each as defined herein. In certain embodiments, R^8a is –NH₂. In certain embodiments, R^8a is –NR^1aC(O)R^1d, wherein R^1a and R^1d are each as defined herein. In certain embodiments, R^8a is –NR^1aC(O)OR^1d, wherein R^1a and R^1d are each as defined herein. In certain embodiments, R^8a is –NR^1aC(O)NR^1bR^1c, wherein R^1a, R^1b, and R^1c are each as defined herein. In certain embodiments, R^8a is –NR^1aC(O)SR^1d, wherein R^1a and R^1d are each as defined herein. In certain embodiments, R^8a is –NR^1aC(NR^1d)NR^1bR^1c, wherein R^1a, R^1b, R^1c, and R^1d are each as defined herein. In certain embodiments, R^8a is –NR^1aC(S)R^1d, wherein R^1a and R^1d are each as defined herein. In certain embodiments, R^8a is –NR^1aC(S)OR^1d, wherein R^1a and R^1d are each as defined herein. In certain embodiments, R^8a is –NR^1aC(S)NR^1bR^1c, wherein R^1a, R^1b, and R^1c are each as defined herein. In certain embodiments, R^8a is –NR^1aS(O)R^1d, wherein R^1a and R^1d are each as defined herein. In certain embodiments, R^8a is –NR^1aS(O)₂R^1d, wherein R^1a and R^1d are each as defined herein. In certain embodiments, R^8a is –NR^1aS(O)NR^1bR^1c, wherein R^1a, R^1b, and R^1c are each as defined herein. In certain embodiments, R^8a is –NR^1aS(O)₂NR^1bR^1c, wherein R^1a, R^1b, and R^1c are each as defined herein. In certain embodiments, R^8a is –SR^1a, wherein R^1a is as defined herein. In certain embodiments, R^8a is –S(O)R^1a, wherein R^1a is as defined herein. In certain embodiments, R^8a is –S(O)₂R^1a, wherein R^1a is as defined herein. In certain embodiments, R^8a is –S(O)NR^1bR^1c, wherein R^1b and R^1c are each as defined herein. In certain embodiments, R^8a is –S(O)₂NR^1bR^1c, wherein R^1b and R^1c are each as defined herein. [0099] In certain embodiments, R^8b is hydrogen. In certain embodiments, R^8b is deuterium. In certain embodiments, R^8b is cyano. In certain embodiments, R^8b is halo. In certain embodiments, R^8b is fluoro, chloro, or bromo. In certain embodiments, R^8b is chloro. In certain embodiments, R^8b is nitro. In certain embodiments, R^8b is C_1-6 alkyl, optionally substituted with one or more substituents Q. In certain embodiments, R^8b is methyl, trifluoromethyl, hydroxylmethyl, or 2-hydroxylethyl. In certain embodiments, R^8b is C_1-6 heteroalkyl, optionally substituted with one or more substituents Q. In certain embodiments, R^8b is trifluoromethyl. In certain embodiments, R^8b is C_2-6 alkenyl, optionally substituted with one or more substituents Q. In certain embodiments, R^8b is C_2-6 alkynyl, optionally substituted with one or more substituents Q. In certain embodiments, R^8b is C_3-10 cycloalkyl, optionally substituted with one or more substituents Q. In certain embodiments, R^8b is C_6-14 aryl, optionally substituted with one or more substituents Q. In certain embodiments, R^8b is C_7-15 aralkyl, optionally substituted with one or more substituents Q. In certain embodiments, R^8b is heteroaryl, optionally substituted with one or more substituents Q. In certain embodiments, R^8b is heterocyclyl, optionally substituted with one or more substituents Q. [00100] In certain embodiments, R^8b is –C(O)R^1a, wherein R^1a is as defined herein. In certain embodiments, R^8b is –C(O)OR^1a, wherein R^1a is as defined herein. In certain embodiments, R^8b is –C(O)NR^1bR^1c, wherein R^1b and R^1c are each as defined herein. In certain embodiments, R^8b is –C(O)NH₂. In certain embodiments, R^8b is –C(O)SR^1a, wherein R^1a is as defined herein. In certain embodiments, R^8b is –C(NR^1a)NR^1bR^1c, wherein R^1a, R^1b, and R^1c are each as defined herein. In certain embodiments, R^8b is –C(S)R^1a, wherein R^1a is as defined herein. In certain embodiments, R^8b is –C(S)OR^1a, wherein R^1a is as defined herein. In certain embodiments, R^8b is –C(S)NR^1bR^1c, wherein R^1b and R^1c are each as defined herein. In certain embodiments, R^8b is –OR^1a, wherein R^1a is as defined herein. In certain embodiments, R^8b is –OC(O)R^1a, wherein R^1a is as defined herein. In certain embodiments, R^8b is –OC(O)OR^1a, wherein R^1a is as defined herein. In certain embodiments, R^8b is –OC(O)NR^1bR^1c, wherein R^1b and R^1c are each as defined herein. In certain embodiments, R^8b is –OC(O)SR^1a, wherein R^1a is as defined herein. In certain embodiments, R^8b is –OC(NR^1a)NR^1bR^1c, wherein R^1a, R^1b, and R^1c are each as defined herein. In certain embodiments, R^8b is –OC(S)R^1a, wherein R^1a is as defined herein. In certain embodiments, R^8b is –OC(S)OR^1a, wherein R^1a is as defined herein. In certain embodiments, R^8b is –OC(S)NR^1bR^1c, wherein R^1b and R^1c are each as defined herein. In certain embodiments, R^8b is –OS(O)R^1a, wherein R^1a is as defined herein. In certain embodiments, R^8b is –OS(O)₂R^1a, wherein R^1a is as defined herein. In certain embodiments, R^8b is –OS(O)NR^1bR^1c, wherein R^1b and R^1c are each as defined herein. In certain embodiments, R^8b is –OS(O)₂NR^1bR^1c, wherein R^1b and R^1c are each as defined herein. In certain embodiments, R^8b is –NR^1bR^1c, wherein R^1b and R^1c are each as defined herein. In certain embodiments, R^8b is –NH₂. In certain embodiments, R^8b is –NR^1aC(O)R^1d, wherein R^1a and R^1d are each as defined herein. In certain embodiments, R^8b is –NR^1aC(O)OR^1d, wherein R^1a and R^1d are each as defined herein. In certain embodiments, R^8b is –NR^1aC(O)NR^1bR^1c, wherein R^1a, R^1b, and R^1c are each as defined herein. In certain embodiments, R^8b is –NR^1aC(O)SR^1d, wherein R^1a and R^1d are each as defined herein. In certain embodiments, R^8b is –NR^1aC(NR^1d)NR^1bR^1c, wherein R^1a, R^1b, R^1c, and R^1d are each as defined herein. In certain embodiments, R^8b is –NR^1aC(S)R^1d, wherein R^1a and R^1d are each as defined herein. In certain embodiments, R^8b is –NR^1aC(S)OR^1d, wherein R^1a and R^1d are each as defined herein. In certain embodiments, R^8b is –NR^1aC(S)NR^1bR^1c, wherein R^1a, R^1b, and R^1c are each as defined herein. In certain embodiments, R^8b is –NR^1aS(O)R^1d, wherein R^1a and R^1d are each as defined herein. In certain embodiments, R^8b is –NR^1aS(O)₂R^1d, wherein R^1a and R^1d are each as defined herein. In certain embodiments, R^8b is –NR^1aS(O)NR^1bR^1c, wherein R^1a, R^1b, and R^1c are each as defined herein. In certain embodiments, R^8b is –NR^1aS(O)₂NR^1bR^1c, wherein R^1a, R^1b, and R^1c are each as defined herein. In certain embodiments, R^8b is –SR^1a, wherein R^1a is as defined herein. In certain embodiments, R^8b is –S(O)R^1a, wherein R^1a is as defined herein. In certain embodiments, R^8b is –S(O)₂R^1a, wherein R^1a is as defined herein. In certain embodiments, R^8b is –S(O)NR^1bR^1c, wherein R^1b and R^1c are each as defined herein. In certain embodiments, R^8b is –S(O)₂NR^1bR^1c, wherein R^1b and R^1c are each as defined herein. [00101] In certain embodiments, R^8a and R^8b together with the carbon atom to which they are attached form C(O). In certain embodiments, R^8a and R^8b together with the carbon atom to which they are attached form C_3-10 cycloalkylene, optionally substituted with one or more substituents Q. In certain embodiments, R^8a and R^8b together with the carbon atom to which they are attached form monocyclic C_3-10 cycloalkylene, optionally substituted with one or more substituents Q. In certain embodiments, R^8a and R^8b together with the carbon atom to which they are attached form cyclopropane-1,1-diyl, cyclobutane-1,1-yl, cyclopentane-1,1-diyl, cyclohexane-1,1-diyl, or cycloheptane-1,1-diyl, each optionally substituted with one or more substituents Q. In certain embodiments, R^8a and R^8b together with the carbon atom to which they are attached form cyclobutane-1,1-diyl, 3-cyanocyclobutane-1,1-diyl, 3-hydroxylcyclobutane- 1,1-diyl, or 3,3-difluoro-cyclobutane-1,1-diyl. In certain embodiments, R^8a and R^8b together with the carbon atom to which they are attached form heterocyclylene, optionally substituted with one or more substituents Q. In certain embodiments, R^8a and R^8b together with the carbon atom to which they are attached form monocyclic heterocyclylene, optionally substituted with one or more substituents Q. In certain embodiments, R^8a and R^8b together with the carbon atom to which they are attached form 5-membered heterocyclylene, optionally substituted with one or more substituents Q. In certain embodiments, R^8a and R^8b together with the carbon atom to which they are attached form tetrahydrofurdiyl, optionally substituted with one or more substituents Q. In certain embodiments, R^8a and R^8b together with the carbon atom to which they are attached form tetrahydrofur-3,3-diyl, optionally substituted with one or more substituents Q. In certain embodiments, R^8a and R^8b together with the carbon atom to which they are attached form 6-membered heterocyclylene, optionally substituted with one or more substituents Q. [00102] In certain embodiments, A is –O–. In certain embodiments, A is –S–. In certain embodiments, A is –NR^A1–, wherein R^A1 is as defined herein. In certain embodiments, A is –NH–. In certain embodiments, A is –C(R^A2R^A3)–, wherein R^A2 and R^A3 are each as defined herein. In certain embodiments, A is –CH₂–. [00103] In certain embodiments, L is a bond. In certain embodiments, L is –O–. In certain embodiments, L is –S–. In certain embodiments, L is –NR^1a–, wherein R^1a is as defined herein. In certain embodiments, L is –NH–. In certain embodiments, L is –C(O)N(R^1a)–, wherein R^1a is as defined herein. In certain embodiments, L is –C(O)N(H)–. [00104] In certain embodiments, U is CR^U, wherein R^U is as defined herein. In certain embodiments, U is CR^U, wherein R^U is (i) hydrogen, deuterium, cyano, or halo; or (ii) C_1-6 alkyl or C_1-6 heteroalkyl, each optionally substituted with one or more substituents Q. In certain embodiments, U is CR^U, wherein R^U is hydrogen, deuterium, cyano, fluoro, methyl, difluoromethyl, or trifluoromethyl. In certain embodiments, U is N. [00105] In certain embodiments, V is CR^U, wherein R^U is as defined herein. In certain embodiments, V is CR^U, wherein R^U is (i) hydrogen, deuterium, cyano, or halo; or (ii) C_1-6 alkyl or C_1-6 heteroalkyl, each optionally substituted with one or more substituents Q. In certain embodiments, V is CR^U, wherein R^U is hydrogen, deuterium, cyano, fluoro, methyl, difluoromethyl, or trifluoromethyl. In certain embodiments, V is CR^U, wherein R^U is hydrogen, deuterium, or fluoro. In certain embodiments, V is N. [00106] In certain embodiments, W is CR^U, wherein R^U is as defined herein. In certain embodiments, W is CR^U, wherein R^U is (i) hydrogen, deuterium, cyano, or halo; or (ii) C_1-6 alkyl or C_1-6 heteroalkyl, each optionally substituted with one or more substituents Q. In certain embodiments, W is CR^U, wherein R^U is hydrogen, deuterium, cyano, fluoro, methyl, difluoromethyl, or trifluoromethyl. In certain embodiments, W is CR^U, wherein R^U is hydrogen, deuterium, or fluoro. In certain embodiments, W is N. [00107] In certain embodiments, L is a bond. In certain embodiments, L is –O–. In certain embodiments, L is –S–. In certain embodiments, L is –NR^1a–, wherein R^1a is as defined herein. In certain embodiments, L is –NH–. In certain embodiments, L is –C(O)N(R^1a)–, wherein R^1a is as defined herein. In certain embodiments, L is –C(O)N(H)–. [00108] In certain embodiments, X is a bond. In certain embodiments, X is –O–. In certain embodiments, X is –S–. In certain embodiments, X is –NR^X1–, wherein R^X1 is as defined herein. In certain embodiments, X is –NH–. In certain embodiments, X is –C(R^X2R^X3)–, wherein R^X2 and R^X3 are each as defined herein. In certain embodiments, X is –CH₂–. [00109] In certain embodiments, Y is a bond. In certain embodiments, Y is –O–. In certain embodiments, Y is –S–. In certain embodiments, Y is –NR^X1–, wherein R^X1 is as defined herein. In certain embodiments, Y is –NH–. In certain embodiments, Y is –C(R^X2R^X3)–, wherein R^X2 and R^X3 are each as defined herein. In certain embodiments, Y is –CH₂–. [00110] In certain embodiments, Z is –O–. In certain embodiments, Z is –S–. In certain embodiments, Z is –NR^Z1–, wherein R^Z1 is as defined herein. In certain embodiments, Z is –NH–. In certain embodiments, Z is –C(R^Z2R^Z3)–, wherein R^Z2 and R^Z3 are each as defined herein. In certain embodiments, Z is –CH₂–. [00111] In one embodiment, provided herein is: 2-(3,5-dichloro-4-((4-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-6-yl)oxy)- phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile A1; 2-(3,5-dichloro-4-((1,1,4,4-tetramethyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-6- yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile A2; 2-(3,5-dichloro-4-((4,4-dimethyl-1-oxo-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol- 6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile A3; 2-(3,5-dichloro-4-((6,9-difluoro-1,1-dimethyl-1,3,4,5-tetrahydropyrano[4,3-b]- indol-8-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile A4; 2-(3,5-dichloro-4-((4',4'-dimethyl-2',3',4,4',5,9'-hexahydro-2H-spiro[furan-3,1'- pyrido[3,4-b]indol]-6'-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile A5; methyl 6-(2,6-dichloro-4-(6-cyano-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)- phenoxy)-4,4-dimethyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indole-2-carboxylate A6; 6-(2,6-dichloro-4-(6-cyano-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)- phenoxy)-4,4-dimethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-1-carboxamide A7; 2-(3,5-dichloro-4-((4,4-dimethyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-6-yl)oxy)- phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile A8; 2-(3,5-dichloro-4-((4,4-dimethyl-1-(trifluoromethyl)-2,3,4,9-tetrahydro-1H- pyrido[3,4-b]indol-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile A9; 2-(3,5-dichloro-4-((4,4-dimethyl-1-(trifluoromethyl)-2,3,4,9-tetrahydro-1H- pyrido[3,4-b]indol-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile A10; 2-(3,5-dichloro-4-((6,7-difluoro-1,1-dimethyl-1,3,4,5-tetrahydropyrano[4,3-b]- indol-8-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile A11; 2-(3,5-dichloro-4-((5,8-difluoro-1-methyl-1,2,3,4-tetrahydrocyclopenta[b]indol-7- yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile A12; 2-(3,5-dichloro-4-((4,4-dimethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-6- yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile A13; 2-(3,5-dichloro-4-((1,1,4,4-tetramethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol- 6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile A14; 2-(3,5-dichloro-4-((1,4,4-trimethyl-1-(trifluoromethyl)-2,3,4,9-tetrahydro-1H- pyrido[3,4-b]indol-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile A15; 2-(3,5-dichloro-4-((5,8-difluoro-4,4-dimethyl-1,3,4,9-tetrahydropyrano[3,4-b]- indol-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile A16; 2-(3,5-dichloro-4-((5,8-difluoro-1-methyl-3,4-dihydro-1H-furo[3,4-b]indol-7-yl)- oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile A17; 2-(3,5-dichloro-4-((5,5-dimethyl-8-(trifluoromethyl)-6,7,8,9-tetrahydro-5H- pyrrolo[2,3-b:5,4-c']dipyridin-3-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6- carbonitrile A18; 2-(3,5-dichloro-4-((1',9'-dihydro-3'H-spiro[cyclobutane-1,4'-pyrano[3,4-b]indol]- 6'-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile A19; 2-(3,5-dichloro-4-((7,8-difluoro-4,4-dimethyl-1,3,4,9-tetrahydropyrano[3,4-b]- indol-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile A20; 2-(3,5-dichloro-4-((1,1-dimethyl-1,4,5,6-tetrahydro-2H-oxepino[4,5-b]indol-9- yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile A21; 2-(3,5-dichloro-4-((8-fluoro-4,5-dimethyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-6- yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile A22; 2-(3,5-dichloro-4-((1-(hydroxymethyl)-4,4-dimethyl-1,3,4,9-tetrahydro- pyrano[3,4-b]indol-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile A23; 2-(3,5-dichloro-4-((1-(2-hydroxyethyl)-4,4-dimethyl-1,3,4,9-tetrahydro- pyrano[3,4-b]indol-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile A24; 2-(3,5-dichloro-4-((5,5-dimethyl-5,6,8,9-tetrahydropyrano[4',3':4,5]pyrrolo[2,3- b]pyridin-3-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile A25; 6-(2,6-dichloro-4-(6-cyano-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)- phenoxy)-4,4-dimethyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-5-carbonitrile A26; 2-(3,5-dichloro-4-((5-(difluoromethyl)-8-fluoro-4,4-dimethyl-1,3,4,9-tetrahydro- pyrano[3,4-b]indol-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile A27; 2-(3-chloro-4-((4,4-dimethyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-6-yl)methyl)- 5-(trifluoromethyl)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile A28; 6-amino-2-(3,5-dichloro-4-((4,4-dimethyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-6- yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione A29; 2-(3,5-dichloro-4-((8-fluoro-4,4-dimethyl-5-(trifluoromethyl)-1,3,4,9-tetrahydro- pyrano[3,4-b]indol-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile A30; 2-(3,5-dichloro-4-((3,3-difluoro-1',9'-dihydro-3'H-spiro[cyclobutane-1,4'- pyrano[3,4-b]indol]-6'-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile A31; 6'-(2,6-dichloro-4-(6-cyano-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)- phenoxy)-1',9'-dihydro-3'H-spiro[cyclobutane-1,4'-pyrano[3,4-b]indole]-3-carbonitrile A32; or 2-(3,5-dichloro-4-((3-hydroxy-1',9'-dihydro-3'H-spiro[cyclobutane-1,4'- pyrano[3,4-b]indol]-6'-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile A33; or an enantiomer, a mixture of 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. [00112] In another embodiment, provided herein is: 2-(3,5-dichloro-4-((5,8-difluoro-4,4-dimethyl-1,3,4,9-tetrahydropyrano[3,4-b]- indol-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile A34; 2-(3,5-dichloro-4-((4,4-dimethyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-6-yl)oxy)- phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxamide A35; 2-(3,5-dichloro-4-((5,8-difluoro-1,1,4,4-tetramethyl-1,3,4,9-tetrahydro- pyrano[3,4-b]indol-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile A36; 2-(4-((4,4-dimethyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-6-yl)oxy)-3,5-difluoro- phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile A37; 6-(2,6-dichloro-4-(6-cyano-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)- phenoxy)-8-fluoro-4,4-dimethyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-5-carbonitrile A38; 2-(3,5-dichloro-4-((4,4-dimethyl-1-(2,2,2-trifluoroethyl)-1,3,4,9-tetrahydro- pyrano[3,4-b]indol-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile A39; 2-(4-((7,8-difluoro-4,4-dimethyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-6-yl)oxy)- 3,5-difluorophenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile A40; 2-(3,5-dichloro-4-((1-(difluoromethyl)-4,4-dimethyl-1,3,4,9-tetrahydro- pyrano[3,4-b]indol-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile A41; 2-(3,5-dichloro-4-((1-(fluoromethyl)-4,4-dimethyl-1,3,4,9-tetrahydropyrano[3,4- b]indol-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile A42; or 2-(3,5-dichloro-4-((5,5,8,8-tetramethyl-5,6,8,9-tetrahydropyrano[4',3':4,5]- pyrrolo[2,3-b]pyridin-3-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile A43; or an enantiomer, a mixture of 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. [00113] In yet another embodiment, provided herein is 6-(3,5-dichloro-4-((4,4-dimethyl-1- (trifluoromethyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-6-yl)oxy)phenyl)-2-methyl-1,2,4- triazine-3,5(2H,4H)-dione B1; or an enantiomer, a mixture of 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. [00114] In yet another embodiment, provided herein is N-(3,5-dichloro-4-((4,4-dimethyl- 1-(trifluoromethyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-6-yl)oxy)phenyl)-5-oxo-4,5- dihydro-1,2,4-oxadiazole-3-carboxamide C1; or an enantiomer, a mixture of 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. [00115] In still another embodiment, provided herein is N-(3,5-dichloro-4-((5-cyano-4,4- dimethyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-6-yl)oxy)phenyl)-5-oxo-4,5-dihydro-1,2,4- oxadiazole-3-carboxamide C2; or an enantiomer, a mixture of 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. [00116] In certain embodiments, a compound provided herein is deuterium-enriched. In certain embodiments, a compound provided herein is carbon-13 enriched. In certain embodiments, a compound provided herein is carbon-14 enriched. In certain embodiments, a compound provided herein contains one or more less prevalent isotopes for other elements, including, but not limited to, ¹⁵N for nitrogen; ¹⁷O or ¹⁸O for oxygen, and ³⁴S, ³⁵S, or ³⁶S for sulfur. [00117] In certain embodiments, a compound provided herein has an isotopic enrichment factor of no less than about 5, no less than about 10, no less than about 20, no less than about 50, no less than about 100, no less than about 200, no less than about 500, no less than about 1,000, no less than about 2,000, no less than about 5,000, or no less than about 10,000. In any events, however, an isotopic enrichment factor for a specified isotope is no greater than the maximum isotopic enrichment factor for the specified isotope, which is the isotopic enrichment factor when a compound at a given position is 100% enriched with the specified isotope. Thus, the maximum isotopic enrichment factor is different for different isotopes. The maximum isotopic enrichment factor is 6,410 for deuterium and 90 for carbon-13. [00118] In certain embodiments, a compound provided herein has a deuterium enrichment factor of no less than about 64 (about 1% deuterium enrichment), no less than about 130 (about 2% deuterium enrichment), no less than about 320 (about 5% deuterium enrichment), no less than about 640 (about 10% deuterium enrichment), no less than about 1,300 (about 20% deuterium enrichment), no less than about 3,200 (about 50% deuterium enrichment), no less than about 4,800 (about 75% deuterium enrichment), no less than about 5,130 (about 80% deuterium enrichment), no less than about 5,450 (about 85% deuterium enrichment), no less than about 5,770 (about 90% deuterium enrichment), no less than about 6,090 (about 95% deuterium enrichment), no less than about 6,220 (about 97% deuterium enrichment), no less than about 6,280 (about 98% deuterium enrichment), no less than about 6,350 (about 99% deuterium enrichment), or no less than about 6,380 (about 99.5% deuterium enrichment). The deuterium enrichment can be determined using conventional analytical methods known to one of ordinary skill in the art, including mass spectrometry and nuclear magnetic resonance spectroscopy. In certain embodiments, at least one of the atoms of a compound provided herein, as specified as deuterium-enriched, has deuterium enrichment of no less than about 50%, no less than about 70%, no less than about 80%, no less than about 90%, or no less than about 98%. [00119] In certain embodiments, a compound provided herein is isolated or purified. In certain embodiments, a compound provided herein has a purity of at least about 90%, at least about 95%, at least about 98%, at least about 99%, or at least about 99.5% by weight. [00120] The compounds provided herein are intended to encompass all possible stereoisomers unless a particular stereochemistry is specified. Where a compound provided herein contains an alkenyl group, the compound may exist as one or mixture of geometric cis/trans (or Z/E) isomers. Where structural isomers are interconvertible, the compound may exist as a single tautomer or a mixture of tautomers. This can take the form of proton tautomerism in the compound that contains, for example, an imino, keto, or oxime group; or so- called valence tautomerism in the compound that contains an aromatic moiety. It follows that a single compound may exhibit more than one type of isomerism. [00121] A compound provided herein can be enantiomerically pure, such as a single enantiomer or a single diastereomer, or be stereoisomeric mixtures, such as a mixture of enantiomers, e.g., a racemic mixture of two enantiomers; or a mixture of two or more diastereomers. As such, one of ordinary skill in the art will recognize that administration of a compound in its (R) form is equivalent, for the compound that undergoes epimerization in vivo, to administration of the compound in its (S) form. Conventional techniques for the preparation/isolation of individual enantiomers include synthesis from a suitable optically pure precursor, asymmetric synthesis from achiral starting materials, or resolution of an enantiomeric mixture, for example, chiral chromatography, recrystallization, resolution, diastereomeric salt formation, or derivatization into diastereomeric adducts followed by separation. [00122] When a compound provided herein contains an acidic or basic moiety, it can also be provided as a pharmaceutically acceptable salt. See, Berge et al., J. Pharm. Sci.1977, 66, 1- 19; Handbook of Pharmaceutical Salts: Properties, Selection, and Use, 2nd ed.; Stahl and Wermuth Eds.; John Wiley & Sons, 2011. In certain embodiments, a pharmaceutically acceptable salt of a compound provided herein is a solvate. In certain embodiments, a pharmaceutically acceptable salt of a compound provided herein is a hydrate. [00123] Suitable acids for use in the preparation of pharmaceutically acceptable salts of a compound provided herein include, but are not limited to, acetic acid, 2,2-dichloroacetic acid, acylated amino acids, adipic acid, alginic acid, ascorbic acid, L-aspartic acid, benzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, boric acid, (+)-camphoric acid, camphorsulfonic acid, (+)-(1S)-camphor-10-sulfonic acid, capric acid, caproic acid, caprylic acid, cinnamic acid, citric acid, cyclamic acid, cyclohexanesulfamic acid, dodecylsulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, 2-hydroxy-ethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid, D-gluconic acid, D-glucuronic acid, L-glutamic acid, α- oxoglutaric acid, glycolic acid, hippuric acid, hydrobromic acid, hydrochloric acid, hydroiodic acid, (+)-L-lactic acid, (±)-DL-lactic acid, lactobionic acid, lauric acid, maleic acid, (-)-L-malic acid, malonic acid, (±)-DL-mandelic acid, methanesulfonic acid, naphthalene-2-sulfonic acid, naphthalene-1,5-disulfonic acid, 1-hydroxy-2-naphthoic acid, nicotinic acid, nitric acid, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid, perchloric acid, phosphoric acid, L- pyroglutamic acid, saccharic acid, salicylic acid, 4-amino-salicylic acid, sebacic acid, stearic acid, succinic acid, sulfuric acid, tannic acid, (+)-L-tartaric acid, thiocyanic acid, p- toluenesulfonic acid, undecylenic acid, and valeric acid. [00124] Suitable bases for use in the preparation of pharmaceutically acceptable salts of a compound provided herein include, but are not limited to, inorganic bases, such as magnesium hydroxide, calcium hydroxide, potassium hydroxide, zinc hydroxide, or sodium hydroxide; and organic bases, such as primary, secondary, tertiary, and quaternary, aliphatic and aromatic amines, including, but not limited to, L-arginine, benethamine, benzathine, choline, deanol, diethanolamine, diethylamine, dimethylamine, dipropylamine, diisopropylamine, 2- (diethylamino)-ethanol, ethanolamine, ethylamine, ethylenediamine, isopropylamine, N-methyl- glucamine, hydrabamine, 1H-imidazole, L-lysine, morpholine, 4-(2-hydroxyethyl)-morpholine, methylamine, piperidine, piperazine, propylamine, pyrrolidine, 1-(2-hydroxyethyl)-pyrrolidine, pyridine, quinuclidine, quinoline, isoquinoline, triethanolamine, trimethylamine, triethylamine, N-methyl-D-glucamine, 2-amino-2-(hydroxymethyl)-1,3-propanediol, and tromethamine. [00125] A compound provided herein may also be provided as a prodrug, which is a functional derivative of the compound and is readily convertible into the parent compound in vivo. Prodrugs are often useful because, in some situations, they may be easier to administer than the parent compound. They may, for instance, be bioavailable by oral administration whereas the parent compound is not. The prodrug may also have enhanced solubility in pharmaceutical compositions over the parent compound. A prodrug may be converted into the parent drug by various mechanisms, including enzymatic processes and metabolic hydrolysis. Pharmaceutical Compositions [00126] In one embodiment, provided herein is a pharmaceutical composition, comprising a compound provided herein, e.g., 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. [00127] The pharmaceutical composition provided herein can be formulated in various dosage forms, including, but not limited to, dosage forms for oral, parenteral, and topical administration. The pharmaceutical composition can also be formulated as modified release dosage forms, including delayed-, extended-, prolonged-, sustained-, pulsatile-, controlled-, accelerated-, fast-, targeted-, programmed-release, and gastric retention dosage forms. These dosage forms can be prepared according to conventional methods and techniques known to those skilled in the art. See, e.g., Remington: The Science and Practice of Pharmacy, supra; Modified- Release Drug Delivery Technology, 2nd ed.; Rathbone et al., Eds.; Drugs and the Pharmaceutical Sciences 184; CRC Press: Boca Raton, FL, 2008. [00128] In one embodiment, the pharmaceutical composition provided herein is formulated in a dosage form for oral administration. In another embodiment, the pharmaceutical composition provided herein is formulated in a dosage form for parenteral administration. In yet another embodiment, the pharmaceutical composition provided herein is formulated in a dosage form for intravenous administration. In yet another embodiment, the pharmaceutical composition provided herein is formulated in a dosage form for intramuscular administration. In yet another embodiment, the pharmaceutical composition provided herein is formulated in a dosage form for subcutaneous administration. In still another embodiment, the pharmaceutical composition provided herein is formulated in a dosage form for topical administration. [00129] The pharmaceutical composition provided herein can be provided in a unit-dosage form or multiple-dosage form. A unit-dosage form, as used herein, refers to physically discrete a unit suitable for administration to a subject, and packaged individually as is known in the art. Each unit-dose contains a predetermined quantity of an active ingredient(s) (e.g., a compound provided herein) sufficient to produce the desired therapeutic effect, in association with the required pharmaceutical excipient(s). Examples of a unit-dosage form include, but are not limited to, an ampoule, syringe, and individually packaged tablet and capsule. A unit-dosage form may be administered in fractions or multiples thereof. A multiple-dosage form is a plurality of identical unit-dosage forms packaged in a single container to be administered in a segregated unit-dosage form. Examples of a multiple-dosage form include, are not limited to, a vial, bottle of tablets or capsules, or bottle of pints or gallons. [00130] The pharmaceutical composition provided herein can be administered at once or multiple times at intervals of time. It is understood that the precise dosage and duration of treatment may vary with the age, weight, and condition of the subject being treated, and may be determined empirically using known testing protocols or by extrapolation from in vivo or in vitro test or diagnostic data. It is further understood that for any particular individual, specific dosage regimens should be adjusted over time according to the subject’s need and the professional judgment of the person administering or supervising the administration of the pharmaceutical composition. A. Oral Administration [00131] The pharmaceutical composition provided herein for oral administration can be provided in solid, semisolid, or liquid dosage forms for oral administration. As used herein, oral administration also includes buccal, lingual, and sublingual administration. Suitable oral dosage forms include, but are not limited to, tablets, fastmelts, chewable tablets, capsules, pills, strips, troches, lozenges, pastilles, cachets, pellets, medicated chewing gum, bulk powders, effervescent or non-effervescent powders or granules, oral mists, solutions, emulsions, suspensions, wafers, sprinkles, elixirs, and syrups. In addition to the active ingredient(s), the pharmaceutical composition can contain one or more pharmaceutically acceptable carriers or excipients, including, but not limited to, binders, fillers, diluents, disintegrants, wetting agents, lubricants, glidants, coloring agents, dye-migration inhibitors, sweetening agents, flavoring agents, emulsifying agents, suspending and dispersing agents, preservatives, solvents, non-aqueous liquids, organic acids, and sources of carbon dioxide. [00132] Binders or granulators impart cohesiveness to a tablet to ensure the tablet remaining intact after compression. Suitable binders or granulators include, but are not limited to, starches, such as corn starch, potato starch, and pre-gelatinized starch (e.g., STARCH 1500®); gelatin; sugars, such as sucrose, glucose, dextrose, molasses, and lactose; natural and synthetic gums, such as acacia, alginic acid, alginates, extract of Irish moss, Panwar gum, Ghatti gum, mucilage of isabgol husks, carboxymethylcellulose, methylcellulose, polyvinylpyrrolidone (PVP), VEEGUM®, larch arabinogalactan, powdered tragacanth, and guar gum; celluloses, such as ethyl cellulose, cellulose acetate, carboxymethyl cellulose calcium, sodium carboxymethyl cellulose, methyl cellulose, hydroxyethylcellulose (HEC), hydroxypropylcellulose (HPC), hydroxypropyl methyl cellulose (HPMC); and microcrystalline celluloses, such as AVICEL® PH-101, AVICEL® PH-103, AVICEL® PH-105, and AVICEL® RC-581. Suitable fillers include, but are not limited to, talc, calcium carbonate, microcrystalline cellulose, powdered cellulose, dextrates, kaolin, mannitol, silicic acid, sorbitol, starch, and pre-gelatinized starch. The amount of a binder or filler in the pharmaceutical composition provided herein varies upon the type of formulation, and is readily discernible to those of ordinary skill in the art. The binder or filler may be present from about 50 to about 99% by weight in the pharmaceutical composition provided herein. [00133] Suitable diluents include, but are not limited to, dicalcium phosphate, calcium sulfate, lactose, sorbitol, sucrose, inositol, cellulose, kaolin, mannitol, sodium chloride, dry starch, and powdered sugar. Certain diluents, such as mannitol, lactose, sorbitol, sucrose, and inositol, when present in sufficient quantity, can impart properties to some compressed tablets that permit disintegration in the mouth by chewing. Such compressed tablets can be used as chewable tablets. The amount of a diluent in the pharmaceutical composition provided herein varies upon the type of formulation, and is readily discernible to those of ordinary skill in the art. [00134] Suitable disintegrants include, but are not limited to, agar; bentonite; celluloses, such as methylcellulose and carboxymethylcellulose; wood products; natural sponge; cation- exchange resins; alginic acid; gums, such as guar gum and VEEGUM® HV; citrus pulp; cross- linked celluloses, such as croscarmellose; cross-linked polymers, such as crospovidone; cross- linked starches; calcium carbonate; microcrystalline cellulose, such as sodium starch glycolate; polacrilin potassium; starches, such as corn starch, potato starch, tapioca starch, and pre- gelatinized starch; clays; and algins. The amount of a disintegrant in the pharmaceutical composition provided herein varies upon the type of formulation, and is readily discernible to those of ordinary skill in the art. The pharmaceutical composition provided herein may contain from about 0.5 to about 15% or from about 1 to about 5% by weight of a disintegrant. [00135] Suitable lubricants include, but are not limited to, calcium stearate; magnesium stearate; mineral oil; light mineral oil; glycerin; sorbitol; mannitol; glycols, such as glycerol behenate and polyethylene glycol (PEG); stearic acid; sodium lauryl sulfate; talc; hydrogenated vegetable oil, such as peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, and soybean oil; zinc stearate; ethyl oleate; ethyl laureate; agar; starch; lycopodium; and silica or silica gels, such as AEROSIL^® 200 and CAB-O-SIL^®. The amount of a lubricant in the pharmaceutical composition provided herein varies upon the type of formulation, and is readily discernible to those of ordinary skill in the art. The pharmaceutical compositions provided herein may contain about 0.1 to about 5% by weight of a lubricant. [00136] Suitable glidants include, but are not limited to, colloidal silicon dioxide, CAB-O- SIL^®, and asbestos-free talc. Suitable coloring agents include, but are not limited to, any of the approved, certified, water soluble FD&C dyes, and water insoluble FD&C dyes suspended on alumina hydrate, and color lakes. A color lake is a combination by adsorption of a water-soluble dye to a hydrous oxide of a heavy metal, resulting in an insoluble form of the dye. Suitable flavoring agents include, but are not limited to, natural flavors extracted from plants, such as fruits, and synthetic blends of compounds which produce a pleasant taste sensation, such as peppermint and methyl salicylate. Suitable sweetening agents include, but are not limited to, sucrose, lactose, mannitol, syrups, glycerin, and artificial sweeteners, such as saccharin and aspartame. Suitable emulsifying agents include, but are not limited to, gelatin, acacia, tragacanth, bentonite, and surfactants, such as polyoxyethylene sorbitan monooleate (TWEEN^® 20), polyoxyethylene sorbitan monooleate 80 (TWEEN^® 80), and triethanolamine oleate. Suitable suspending and dispersing agents include, but are not limited to, sodium carboxy- methylcellulose, pectin, tragacanth, VEEGUM®, acacia, sodium carboxymethylcellulose, hydroxypropyl methylcellulose, and polyvinylpyrrolidone. Suitable preservatives include, but are not limited to, glycerin, methyl and propylparaben, benzoic add, and sodium benzoate and alcohol. Suitable wetting agents include, but are not limited to, propylene glycol monostearate, sorbitan monooleate, diethylene glycol monolaurate, and polyoxyethylene lauryl ether. Suitable solvents include, but are not limited to, glycerin, sorbitol, ethyl alcohol, and syrup. Suitable non- aqueous liquids utilized in emulsions include, but are not limited to, mineral oil and cottonseed oil. Suitable organic acids include, but are not limited to, citric and tartaric acid. Suitable sources of carbon dioxide include, but are not limited to, sodium bicarbonate and sodium carbonate. [00137] It should be understood that many carriers and excipients may serve several functions, even within the same formulation. [00138] The pharmaceutical composition provided herein for oral administration can be provided as compressed tablets, tablet triturates, chewable lozenges, rapidly dissolving tablets, multiple compressed tablets, or enteric-coating tablets, sugar-coated, or film-coated tablets. Enteric-coated tablets are compressed tablets coated with substances that resist the action of stomach acid but dissolve or disintegrate in the intestine, thus protecting the active ingredient(s) from the acidic environment of the stomach. Enteric-coatings include, but are not limited to, fatty acids, fats, phenyl salicylate, waxes, shellac, ammoniated shellac, and cellulose acetate phthalates. Sugar-coated tablets are compressed tablets surrounded by a sugar coating, which may be beneficial in covering up objectionable tastes or odors and in protecting the tablets from oxidation. Film-coated tablets are compressed tablets that are covered with a thin layer or film of a water-soluble material. Film coatings include, but are not limited to, hydroxyethylcellulose, sodium carboxymethylcellulose, polyethylene glycol 4000, and cellulose acetate phthalate. Film coating imparts the same general characteristics as sugar coating. Multiple compressed tablets are compressed tablets made by more than one compression cycle, including layered tablets, and press-coated or dry-coated tablets. [00139] The tablet dosage forms can be prepared from an active ingredient(s) in powdered, crystalline, or granular forms, alone or in combination with one or more carriers or excipients described herein, including binders, disintegrants, controlled-release polymers, lubricants, diluents, and/or colorants. Flavoring and sweetening agents are especially useful in the formation of chewable tablets and lozenges. [00140] The pharmaceutical composition provided herein for oral administration can be provided as soft or hard capsules, which can be made from gelatin, methylcellulose, starch, or calcium alginate. The hard gelatin capsule, also known as the dry-filled capsule (DFC), consists of two sections, one slipping over the other, thus completely enclosing the active ingredient(s). The soft elastic capsule (SEC) is a soft, globular shell, such as a gelatin shell, which is plasticized by the addition of glycerin, sorbitol, or a similar polyol. The soft gelatin shells may contain a preservative to prevent the growth of microorganisms. Suitable preservatives are those as described herein, including methyl- and propyl-parabens, and sorbic acid. The liquid, semisolid, and solid dosage forms provided herein may be encapsulated in a capsule. Suitable liquid and semisolid dosage forms include solutions and suspensions in propylene carbonate, vegetable oils, or triglycerides. Capsules containing such solutions can be prepared as described in U.S. Pat. Nos.4,328,245; 4,409,239; and 4,410,545. The capsules may also be coated as known by those of skill in the art in order to modify or sustain dissolution of the active ingredient(s). [00141] The pharmaceutical composition provided herein for oral administration can be provided in liquid and semisolid dosage forms, including emulsions, solutions, suspensions, elixirs, and syrups. An emulsion is a two-phase system, in which one liquid is dispersed in the form of small globules throughout another liquid, which can be oil-in-water or water-in-oil. Emulsions may include a pharmaceutically acceptable non-aqueous liquid or solvent, emulsifying agent, and preservative. Suspensions may include a pharmaceutically acceptable suspending agent and preservative. Aqueous alcoholic solutions may include a pharmaceutically acceptable acetal, such as a di(lower alkyl) acetal of a lower alkyl aldehyde, e.g., acetaldehyde diethyl acetal; and a water-miscible solvent having one or more hydroxyl groups, such as propylene glycol and ethanol. Elixirs are clear, sweetened, and hydroalcoholic solutions. Syrups are concentrated aqueous solutions of a sugar, for example, sucrose, and may also contain a preservative. For a liquid dosage form, for example, a solution in a polyethylene glycol may be diluted with a sufficient quantity of a pharmaceutically acceptable liquid carrier, e.g., water, to be measured conveniently for administration. [00142] Other useful liquid and semisolid dosage forms include, but are not limited to, those containing an active ingredient(s), and a dialkylated mono- or poly-alkylene glycol, including, 1,2-dimethoxymethane, diglyme, triglyme, tetraglyme, polyethylene glycol-350- dimethyl ether, polyethylene glycol-550-dimethyl ether, polyethylene glycol-750-dimethyl ether, wherein 350, 550, and 750 refer to the approximate average molecular weight of the polyethylene glycol. These dosage forms can further comprise one or more antioxidants, such as butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), propyl gallate, vitamin E, hydroquinone, hydroxycoumarins, ethanolamine, lecithin, cephalin, ascorbic acid, malic acid, sorbitol, phosphoric acid, bisulfite, sodium metabisulfite, thiodipropionic acid and its esters, and dithiocarbamates. [00143] The pharmaceutical composition provided herein for oral administration can be also provided in the forms of liposomes, micelles, microspheres, or nanosystems. Micellar dosage forms can be prepared as described in U.S. Pat. No.6,350,458. [00144] The pharmaceutical composition provided herein for oral administration can be provided as non-effervescent or effervescent, granules and powders, to be reconstituted into a liquid dosage form. Pharmaceutically acceptable carriers and excipients used in the non- effervescent granules or powders may include diluents, sweeteners, and wetting agents. Pharmaceutically acceptable carriers and excipients used in the effervescent granules or powders may include organic acids and a source of carbon dioxide. [00145] Coloring and flavoring agents can be used in all of the dosage forms described herein. [00146] The pharmaceutical composition provided herein for oral administration can be formulated as immediate or modified release dosage forms, including delayed-, sustained, pulsed-, controlled, targeted-, and programmed-release forms. B. Parenteral Administration [00147] The pharmaceutical composition provided herein can be administered parenterally by injection, infusion, or implantation, for local or systemic administration. Parenteral administration, as used herein, include intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, intrasternal, intracranial, intramuscular, intrasynovial, intravesical, and subcutaneous administration. [00148] The pharmaceutical composition provided herein for parenteral administration can be formulated in any dosage forms that are suitable for parenteral administration, including, but not limited to, solutions, suspensions, emulsions, micelles, liposomes, microspheres, nanosystems, and solid forms suitable for solutions or suspensions in liquid prior to injection. Such dosage forms can be prepared according to conventional methods known to those skilled in the art of pharmaceutical science. See, e.g., Remington: The Science and Practice of Pharmacy, supra. [00149] The pharmaceutical composition provided herein for parenteral administration can include one or more pharmaceutically acceptable carriers and excipients, including, but not limited to, aqueous vehicles, water-miscible vehicles, non-aqueous vehicles, antimicrobial agents or preservatives against the growth of microorganisms, stabilizers, solubility enhancers, isotonic agents, buffering agents, antioxidants, local anesthetics, suspending and dispersing agents, wetting or emulsifying agents, complexing agents, sequestering or chelating agents, cryoprotectants, lyoprotectants, thickening agents, pH adjusting agents, and inert gases. [00150] Suitable aqueous vehicles include, but are not limited to, water, saline, physiological saline or phosphate buffered saline (PBS), sodium chloride injection, Ringer’s injection, isotonic dextrose injection, sterile water injection, dextrose and lactated Ringer’s injection. Suitable non-aqueous vehicles include, but are not limited to, fixed oils of vegetable origin, castor oil, corn oil, cottonseed oil, olive oil, peanut oil, peppermint oil, safflower oil, sesame oil, soybean oil, hydrogenated vegetable oils, hydrogenated soybean oil, and medium- chain triglycerides of coconut oil, and palm seed oil. Suitable water-miscible vehicles include, but are not limited to, ethanol, 1,3-butanediol, liquid polyethylene glycol (e.g., polyethylene glycol 300 and polyethylene glycol 400), propylene glycol, glycerin, N-methyl-2-pyrrolidone, N,N-dimethylacetamide, and dimethyl sulfoxide. [00151] Suitable antimicrobial agents or preservatives include, but are not limited to, phenols, cresols, mercurials, benzyl alcohol, chlorobutanol, methyl and propyl p- hydroxybenzoates, thimerosal, benzalkonium chloride (e.g., benzethonium chloride), methyl- and propyl-parabens, and sorbic acid. Suitable isotonic agents include, but are not limited to, sodium chloride, glycerin, and dextrose. Suitable buffering agents include, but are not limited to, phosphate and citrate. Suitable antioxidants include those described herein, such as bisulfite and sodium metabisulfite. Suitable local anesthetics include, but are not limited to, procaine hydrochloride. Suitable suspending and dispersing agents include those described herein, such as sodium carboxymethylcellulose, hydroxypropyl methylcellulose, and polyvinylpyrrolidone. Suitable emulsifying agents include those described herein, such as polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbitan monooleate 80, and triethanolamine oleate. Suitable sequestering or chelating agents include, but are not limited to, EDTA. Suitable pH adjusting agents include, but are not limited to, sodium hydroxide, hydrochloric acid, citric acid, and lactic acid. Suitable complexing agents include, but are not limited to, cyclodextrins, including ^- cyclodextrin, ^-cyclodextrin, hydroxypropyl- ^-cyclodextrin, sulfobutylether- ^-cyclodextrin, and sulfobutylether 7- ^-cyclodextrin (CAPTISOL^®). [00152] When the pharmaceutical composition provided herein is formulated for multiple dosage administration, multiple dosage parenteral formulations must contain an antimicrobial agent at bacteriostatic or fungistatic concentrations. All parenteral formulations must be sterile, as known and practiced in the art. [00153] In one embodiment, the pharmaceutical composition for parenteral administration is provided as a ready-to-use sterile solution. In another embodiment, the pharmaceutical composition is provided as a sterile dry soluble product, including a lyophilized powder and hypodermic tablet, to be reconstituted with a vehicle prior to use. In yet another embodiment, the pharmaceutical composition is provided as a ready-to-use sterile suspension. In yet another embodiment, the pharmaceutical composition is provided as a sterile dry insoluble product to be reconstituted with a vehicle prior to use. In still another embodiment, the pharmaceutical composition is provided as a ready-to-use sterile emulsion. [00154] The pharmaceutical composition provided herein for parenteral administration can be formulated as immediate or modified release dosage forms, including delayed-, sustained, pulsed-, controlled, targeted-, and programmed-release forms. [00155] The pharmaceutical composition provided herein for parenteral administration can be formulated as a suspension, solid, semi-solid, or thixotropic liquid, for administration as an implanted depot. In one embodiment, the pharmaceutical composition provided herein are dispersed in a solid inner matrix, which is surrounded by an outer polymeric membrane that is insoluble in body fluids but allows the active ingredient(s) in the pharmaceutical composition to diffuse through. [00156] Suitable inner matrixes include, but are not limited to, polymethylmethacrylate, polybutylmethacrylate, plasticized or unplasticized polyvinylchloride, plasticized nylon, plasticized polyethylene terephthalate, natural rubber, polyisoprene, polyisobutylene, polybutadiene, polyethylene, ethylene-vinyl acetate copolymers, silicone rubbers, polydimethylsiloxanes, silicone carbonate copolymers, hydrophilic polymers (such as hydrogels of esters of acrylic and methacrylic acid), collagen, cross-linked polyvinyl alcohol, and cross- linked partially hydrolyzed polyvinyl acetate. [00157] Suitable outer polymeric membranes include, but are not limited to, polyethylene, polypropylene, ethylene/propylene copolymers, ethylene/ethyl acrylate copolymers, ethylene/vinyl acetate copolymers, silicone rubbers, polydimethylsiloxanes, neoprene rubber, chlorinated polyethylene, polyvinylchloride, vinyl chloride copolymers with vinyl acetate, vinylidene chloride, ethylene and propylene, ionomer polyethylene terephthalate, butyl rubber epichlorohydrin rubbers, ethylene/vinyl alcohol copolymer, ethylene/vinyl acetate/vinyl alcohol terpolymer, and ethylene/vinyloxyethanol copolymer. C. Topical Administration [00158] The pharmaceutical composition provided herein can be administered topically to the skin, orifices, or mucosa. The topical administration, as used herein, includes (intra)dermal, conjunctival, intracorneal, intraocular, ophthalmic, auricular, transdermal, nasal, vaginal, urethral, respiratory, and rectal administration. [00159] The pharmaceutical composition provided herein can be formulated in any dosage forms that are suitable for topical administration for local or systemic effect, including, but not limited to, emulsions, solutions, suspensions, creams, gels, hydrogels, ointments, dusting powders, dressings, elixirs, lotions, suspensions, tinctures, pastes, foams, films, aerosols, irrigations, sprays, suppositories, bandages, and dermal patches. The topical formulations of the pharmaceutical composition provided herein can also comprise liposomes, micelles, microspheres, and nanosystems. [00160] Pharmaceutically acceptable carriers and excipients suitable for use in the topical formulations include, but are not limited to, aqueous vehicles, water-miscible vehicles, non- aqueous vehicles, antimicrobial agents or preservatives against the growth of microorganisms, stabilizers, solubility enhancers, isotonic agents, buffering agents, antioxidants, local anesthetics, suspending and dispersing agents, wetting or emulsifying agents, complexing agents, sequestering or chelating agents, penetration enhancers, cryoprotectants, lyoprotectants, thickening agents, and inert gases. [00161] The pharmaceutical composition can also be administered topically by electroporation, iontophoresis, phonophoresis, sonophoresis, or microneedle or needle-free injection, such as POWDERJECT™ and BIOJECT™. [00162] The pharmaceutical composition provided herein can be provided in the forms of ointments, creams, and gels. Suitable ointment vehicles include oleaginous or hydrocarbon vehicles, including lard, benzoinated lard, olive oil, cottonseed oil, and other oils, white petrolatum; emulsifiable or absorption vehicles, such as hydrophilic petrolatum, hydroxystearin sulfate, and anhydrous lanolin; water-removable vehicles, such as hydrophilic ointment; water- soluble ointment vehicles, including polyethylene glycols of varying molecular weight; emulsion vehicles, either water-in-oil (W/O) emulsions or oil-in-water (O/W) emulsions, including cetyl alcohol, glyceryl monostearate, lanolin, and stearic acid. See, e.g., Remington: The Science and Practice of Pharmacy, supra. These vehicles are emollient but generally require addition of antioxidants and preservatives. [00163] Suitable cream base can be oil-in-water or water-in-oil. Suitable cream vehicles may be water-washable, and contain an oil phase, an emulsifier, and an aqueous phase. The oil phase is also called the “internal” phase, which is generally comprised of petrolatum and a fatty alcohol such as cetyl or stearyl alcohol. The aqueous phase usually, although not necessarily, exceeds the oil phase in volume, and generally contains a humectant. The emulsifier in a cream formulation may be a nonionic, anionic, cationic, or amphoteric surfactant. [00164] Gels are semisolid, suspension-type systems. Single-phase gels contain organic macromolecules distributed substantially uniformly throughout the liquid carrier. Suitable gelling agents include, but are not limited to, crosslinked acrylic acid polymers, such as carbomers, carboxypolyalkylenes, and CARBOPOL^®; hydrophilic polymers, such as polyethylene oxides, polyoxyethylene-polyoxypropylene copolymers, and polyvinylalcohol; cellulosic polymers, such as hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropyl methylcellulose, hydroxypropyl methylcellulose phthalate, and methylcellulose; gums, such as tragacanth and xanthan gum; sodium alginate; and gelatin. In order to prepare a uniform gel, dispersing agents such as alcohol or glycerin can be added, or the gelling agent can be dispersed by trituration, mechanical mixing, and/or stirring. [00165] The pharmaceutical composition provided herein can be administered rectally, urethrally, vaginally, or perivaginally in the forms of suppositories, pessaries, bougies, poultices or cataplasm, pastes, powders, dressings, creams, plasters, contraceptives, ointments, solutions, emulsions, suspensions, tampons, gels, foams, sprays, or enemas. These dosage forms can be manufactured using conventional processes as described in Remington: The Science and Practice of Pharmacy, supra. [00166] Rectal, urethral, and vaginal suppositories are solid bodies for insertion into body orifices, which are solid at ordinary temperatures but melt or soften at body temperature to release the active ingredient(s) inside the orifices. Pharmaceutically acceptable carriers utilized in rectal and vaginal suppositories include bases or vehicles, such as stiffening agents, which produce a melting point in the proximity of body temperature, when formulated with an active ingredient(s); and antioxidants as described herein, including bisulfite and sodium metabisulfite. Suitable vehicles include, but are not limited to, cocoa butter (theobroma oil), glycerin-gelatin, carbowax (polyoxyethylene glycol), spermaceti, paraffin, white and yellow wax, and appropriate mixtures of mono-, di- and triglycerides of fatty acids, and hydrogels, such as polyvinyl alcohol, hydroxyethyl methacrylate, and polyacrylic acid. Combinations of the various vehicles can also be used. Rectal and vaginal suppositories may be prepared by compressing or molding. The typical weight of a rectal and vaginal suppository is about 2 to about 3 g. [00167] The pharmaceutical composition provided herein can be administered ophthalmically in the forms of solutions, suspensions, ointments, emulsions, gel-forming solutions, powders for solutions, gels, ocular inserts, and implants. [00168] The pharmaceutical composition provided herein can be administered intranasally or by inhalation to the respiratory tract. The pharmaceutical composition can be provided in the form of an aerosol or solution for delivery using a pressurized container, pump, spray, atomizer, such as an atomizer using electrohydrodynamics to produce a fine mist, or nebulizer, alone or in combination with a suitable propellant, such as 1,1,1,2-tetrafluoroethane or 1,1,1,2,3,3,3-hepta- fluoropropane. The pharmaceutical composition can also be provided as a dry powder for insufflation, alone or in combination with an inert carrier such as lactose or phospholipids; and nasal drops. For intranasal use, the powder can comprise a bioadhesive agent, including chitosan or cyclodextrin. [00169] Solutions or suspensions for use in a pressurized container, pump, spray, atomizer, or nebulizer can be formulated to contain ethanol, aqueous ethanol, or a suitable alternative agent for dispersing, solubilizing, or extending release of an active ingredient(s); a propellant as solvent; and/or a surfactant, such as sorbitan trioleate, oleic acid, or an oligolactic acid. [00170] The pharmaceutical composition provided herein can be micronized to a size suitable for delivery by inhalation, such as about 50 micrometers or less, or about 10 micrometers or less. Particles of such sizes can be prepared using a comminuting method known to those skilled in the art, such as spiral jet milling, fluid bed jet milling, supercritical fluid processing to form nanoparticles, high pressure homogenization, or spray drying. [00171] Capsules, blisters, and cartridges for use in an inhaler or insufflator can be formulated to contain a powder mix of the pharmaceutical composition provided herein; a suitable powder base, such as lactose or starch; and a performance modifier, such as l-leucine, mannitol, or magnesium stearate. The lactose may be anhydrous or in the form of the monohydrate. Other suitable excipients or carriers include, but are not limited to, dextran, glucose, maltose, sorbitol, xylitol, fructose, sucrose, and trehalose. The pharmaceutical composition provided herein for inhaled/intranasal administration can further comprise a suitable flavor, such as menthol and levomenthol; and/or sweeteners, such as saccharin and saccharin sodium. [00172] The pharmaceutical composition provided herein for topical administration can be formulated to be immediate release or modified release, including delayed-, sustained-, pulsed-, controlled-, targeted, and programmed release. D. Modified Release [00173] The pharmaceutical composition provided herein can be formulated as a modified release dosage form. As used herein, the term “modified release” refers to a dosage form in which the rate or place of release of an active ingredient(s) is different from that of an immediate dosage form when administered by the same route. Modified release dosage forms include, but are not limited to, delayed-, extended-, prolonged-, sustained-, pulsatile-, controlled-, accelerated- and fast-, targeted-, programmed-release, and gastric retention dosage forms. The pharmaceutical composition in modified release dosage forms can be prepared using a variety of modified release devices and methods known to those skilled in the art, including, but not limited to, matrix-controlled release devices, osmotic controlled release devices, multiparticulate controlled release devices, ion-exchange resins, enteric coatings, multilayered coatings, microspheres, liposomes, and combinations thereof. The release rate of the active ingredient(s) can also be modified by varying the particle sizes and polymorphism of the active ingredient(s). 1. Matrix Controlled Release Devices [00174] The pharmaceutical composition provided herein in a modified release dosage form can be fabricated using a matrix-controlled release device known to those skilled in the art. See, e.g., Takada et al. in Encyclopedia of Controlled Drug Delivery, Mathiowitz Ed.; Wiley, 1999; Vol.2. [00175] In certain embodiments, the pharmaceutical composition provided herein in a modified release dosage form is formulated using an erodible matrix device, which is water- swellable, erodible, or soluble polymers, including, but not limited to, synthetic polymers, and naturally occurring polymers and derivatives, such as polysaccharides and proteins. [00176] Materials useful in forming an erodible matrix include, but are not limited to, chitin, chitosan, dextran, and pullulan; gum agar, gum arabic, gum karaya, locust bean gum, gum tragacanth, carrageenans, gum Ghatti, guar gum, xanthan gum, and scleroglucan; starches, such as dextrin and maltodextrin; hydrophilic colloids, such as pectin; phosphatides, such as lecithin; alginates; propylene glycol alginate; gelatin; collagen; cellulosics, such as ethyl cellulose (EC), methylethyl cellulose (MEC), carboxymethyl cellulose (CMC), CMEC, hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC), cellulose acetate (CA), cellulose propionate (CP), cellulose butyrate (CB), cellulose acetate butyrate (CAB), CAP, CAT, hydroxypropyl methyl cellulose (HPMC), HPMCP, HPMCAS, hydroxypropyl methyl cellulose acetate trimellitate (HPMCAT), and ethyl hydroxyethyl cellulose (EHEC); polyvinyl pyrrolidone; polyvinyl alcohol; polyvinyl acetate; glycerol fatty acid esters; polyacrylamide; polyacrylic acid; copolymers of ethacrylic acid or methacrylic acid (EUDRAGIT®); poly(2-hydroxyethyl- methacrylate); polylactides; copolymers of L-glutamic acid and ethyl-L-glutamate; degradable lactic acid-glycolic acid copolymers; poly-D-(-)-3-hydroxybutyric acid; and other acrylic acid derivatives, such as homopolymers and copolymers of butylmethacrylate, methyl methacrylate, ethyl methacrylate, ethylacrylate, (2-dimethylaminoethyl)methacrylate, and (trimethylaminoethyl)methacrylate chloride. [00177] In certain embodiments, the pharmaceutical composition provided herein is formulated with a non-erodible matrix device. The active ingredient(s) is dissolved or dispersed in an inert matrix and is released primarily by diffusion through the inert matrix once administered. Materials suitable for use as a non-erodible matrix device include, but are not limited to, insoluble plastics, such as polyethylene, polypropylene, polyisoprene, polyisobutylene, polybutadiene, polymethylmethacrylate, polybutylmethacrylate, chlorinated polyethylene, polyvinylchloride, methyl acrylate-methyl methacrylate copolymers, ethylene- vinyl acetate copolymers, ethylene/propylene copolymers, ethylene/ethyl acrylate copolymers, vinyl chloride copolymers with vinyl acetate, vinylidene chloride, ethylene and propylene, ionomer polyethylene terephthalate, butyl rubbers, epichlorohydrin rubbers, ethylene/vinyl alcohol copolymer, ethylene/vinyl acetate/vinyl alcohol terpolymer, ethylene/vinyloxyethanol copolymer, polyvinyl chloride, plasticized nylon, plasticized polyethylene terephthalate, natural rubber, silicone rubbers, polydimethylsiloxanes, and silicone carbonate copolymers; hydrophilic polymers, such as ethyl cellulose, cellulose acetate, crospovidone, and cross-linked partially hydrolyzed polyvinyl acetate; and fatty compounds, such as carnauba wax, microcrystalline wax, and triglycerides. [00178] In a matrix-controlled release system, the desired release kinetics can be controlled, for example, via the polymer type employed, the polymer viscosity, the particle sizes of the polymer and/or the active ingredient(s), the ratio of the active ingredient(s) versus the polymer, and other excipients or carriers in the compositions. [00179] The pharmaceutical composition provided herein in a modified release dosage form can be prepared by methods known to those skilled in the art, including direct compression, dry or wet granulation followed by compression, and melt-granulation followed by compression. 2. Osmotic Controlled Release Devices [00180] The pharmaceutical composition provided herein in a modified release dosage form can be fabricated using an osmotic controlled release device, including, but not limited to, one-chamber system, two-chamber system, asymmetric membrane technology (AMT), and extruding core system (ECS). In general, such devices have at least two components: (a) a core which contains an active ingredient; and (b) a semipermeable membrane with at least one delivery port, which encapsulates the core. The semipermeable membrane controls the influx of water to the core from an aqueous environment of use so as to cause drug release by extrusion through the delivery port(s). [00181] In addition to the active ingredient(s), the core of the osmotic device optionally includes an osmotic agent, which creates a driving force for transport of water from the environment of use into the core of the device. One class of osmotic agents is water-swellable hydrophilic polymers, which are also referred to as “osmopolymers” and “hydrogels.” Suitable water-swellable hydrophilic polymers as osmotic agents include, but are not limited to, hydrophilic vinyl and acrylic polymers, polysaccharides such as calcium alginate, polyethylene oxide (PEO), polyethylene glycol (PEG), polypropylene glycol (PPG), poly(2-hydroxyethyl methacrylate), poly(acrylic) acid, poly(methacrylic) acid, polyvinylpyrrolidone (PVP), crosslinked PVP, polyvinyl alcohol (PVA), PVA/PVP copolymers, PVA/PVP copolymers with hydrophobic monomers such as methyl methacrylate and vinyl acetate, hydrophilic polyurethanes containing large PEO blocks, sodium croscarmellose, carrageenan, hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC), hydroxypropyl methyl cellulose (HPMC), carboxymethyl cellulose (CMC) and carboxyethyl, cellulose (CEC), sodium alginate, polycarbophil, gelatin, xanthan gum, and sodium starch glycolate. [00182] The other class of osmotic agents is osmogens, which are capable of imbibing water to affect an osmotic pressure gradient across the barrier of the surrounding coating. Suitable osmogens include, but are not limited to, inorganic salts, such as magnesium sulfate, magnesium chloride, calcium chloride, sodium chloride, lithium chloride, potassium sulfate, potassium phosphates, sodium carbonate, sodium sulfite, lithium sulfate, potassium chloride, and sodium sulfate; sugars, such as dextrose, fructose, glucose, inositol, lactose, maltose, mannitol, raffinose, sorbitol, sucrose, trehalose, and xylitol; organic acids, such as ascorbic acid, benzoic acid, fumaric acid, citric acid, maleic acid, sebacic acid, sorbic acid, adipic acid, edetic acid, glutamic acid, p-toluenesulfonic acid, succinic acid, and tartaric acid; urea; and mixtures thereof. [00183] Osmotic agents of different dissolution rates can be employed to influence how rapidly the active ingredient(s) is initially delivered from the dosage form. For example, amorphous sugars, such as MANNOGEM^™ EZ can be used to provide faster delivery during the first couple of hours to promptly produce the desired therapeutic effect, and gradually and continually release of the remaining amount to maintain the desired level of therapeutic or prophylactic effect over an extended period of time. In this case, the active ingredient(s) is released at such a rate to replace the amount of the active ingredient metabolized and excreted. [00184] The core can also include a wide variety of other excipients and carriers as described herein to enhance the performance of the dosage form or to promote stability or processing. [00185] Materials useful in forming the semipermeable membrane include various grades of acrylics, vinyls, ethers, polyamides, polyesters, and cellulosic derivatives that are water- permeable and water-insoluble at physiologically relevant pHs or are susceptible to being rendered water-insoluble by chemical alteration, such as crosslinking. Examples of suitable polymers useful in forming the coating, include plasticized, unplasticized, and reinforced cellulose acetate (CA), cellulose diacetate, cellulose triacetate, CA propionate, cellulose nitrate, cellulose acetate butyrate (CAB), CA ethyl carbamate, CAP, CA methyl carbamate, CA succinate, cellulose acetate trimellitate (CAT), CA dimethylaminoacetate, CA ethyl carbonate, CA chloroacetate, CA ethyl oxalate, CA methyl sulfonate, CA butyl sulfonate, CA p-toluene sulfonate, agar acetate, amylose triacetate, beta glucan acetate, beta glucan triacetate, acetaldehyde dimethyl acetate, triacetate of locust bean gum, hydroxylated ethylene-vinylacetate, EC, PEG, PPG, PEG/PPG copolymers, PVP, HEC, HPC, CMC, CMEC, HPMC, HPMCP, HPMCAS, HPMCAT, poly(acrylic) acids and esters and poly-(methacrylic) acids and esters and copolymers thereof, starch, dextran, dextrin, chitosan, collagen, gelatin, polyalkenes, polyethers, polysulfones, polyethersulfones, polystyrenes, polyvinyl halides, polyvinyl esters and ethers, natural waxes, and synthetic waxes. [00186] Semipermeable membrane can also be a hydrophobic microporous membrane, wherein the pores are substantially filled with a gas and are not wetted by the aqueous medium but are permeable to water vapor, as disclosed in U.S. Pat. No.5,798,119. Such hydrophobic but water-vapor permeable membrane are typically composed of hydrophobic polymers such as polyalkenes, polyethylene, polypropylene, polytetrafluoroethylene, polyacrylic acid derivatives, polyethers, polysulfones, polyethersulfones, polystyrenes, polyvinyl halides, polyvinylidene fluoride, polyvinyl esters and ethers, natural waxes, and synthetic waxes. [00187] The delivery port(s) on the semipermeable membrane can be formed post-coating by mechanical or laser drilling. Delivery port(s) can also be formed in situ by erosion of a plug of water-soluble material or by rupture of a thinner portion of the membrane over an indentation in the core. In addition, delivery ports can be formed during coating process, as in the case of asymmetric membrane coatings of the type disclosed in U.S. Pat. Nos.5,612,059 and 5,698,220. [00188] The total amount of the active ingredient(s) released and the release rate can substantially by modulated via the thickness and porosity of the semipermeable membrane, the composition of the core, and the number, size, and position of the delivery ports. [00189] The pharmaceutical composition in an osmotic controlled-release dosage form can further comprise additional conventional excipients or carriers as described herein to promote performance or processing of the formulation. [00190] The osmotic controlled-release dosage forms can be prepared according to conventional methods and techniques known to those skilled in the art. See, e.g., Remington: The Science and Practice of Pharmacy, supra; Santus and Baker, J. Controlled Release, 1995, 35, 1-21; Verma et al., Drug Dev. Ind. Pharm., 2000, 26, 695-708; Verma et al., J. Controlled Release, 2002, 79, 7-27. [00191] In certain embodiments, the pharmaceutical composition provided herein is formulated as an AMT controlled-release dosage form, which comprises an asymmetric osmotic membrane that coats a core comprising the active ingredient(s) and other pharmaceutically acceptable excipients or carriers. See, e.g., U.S. Pat. No.5,612,059 and WO 2002/17918. The AMT controlled-release dosage forms can be prepared according to conventional methods and techniques known to those skilled in the art, including direct compression, dry granulation, wet granulation, and a dip-coating method. [00192] In certain embodiments, the pharmaceutical composition provided herein is formulated as an ESC controlled-release dosage form, which comprises an osmotic membrane that coats a core comprising the active ingredient(s), a hydroxyethyl cellulose, and other pharmaceutically acceptable excipients or carriers. 3. Multiparticulate Controlled Release Devices [00193] The pharmaceutical composition provided herein in a modified release dosage form can be fabricated as a multiparticulate controlled release device, which comprises a multiplicity of particles, granules, or pellets, ranging from about 10 µm to about 3 mm, about 50 µm to about 2.5 mm, or from about 100 µm to about 1 mm in diameter. Such multiparticulates can be made by the processes known to those skilled in the art, including wet-and dry- granulation, extrusion/spheronization, roller-compaction, melt-congealing, and by spray-coating seed cores. See, e.g., Multiparticulate Oral Drug Delivery; Ghebre-Sellassie Eds.; Drugs and the Pharmaceutical Sciences 65; CRC Press: 1994; and Pharmaceutical Palletization Technology; Ghebre-Sellassie Eds.; Drugs and the Pharmaceutical Sciences 37; CRC Press: 1989. [00194] Other excipients or carriers as described herein can be blended with the pharmaceutical composition to aid in processing and forming the multiparticulates. The resulting particles can themselves constitute the multiparticulate device or can be coated by various film-forming materials, such as enteric polymers, water-swellable, and water-soluble polymers. The multiparticulates can be further processed as a capsule or a tablet. 4. Targeted Delivery [00195] The pharmaceutical composition provided herein can also be formulated to be targeted to a particular tissue, receptor, or other area of the body of the subject to be treated, including liposome-, resealed erythrocyte-, and antibody-based delivery systems. Examples include, but are not limited to, those disclosed in U.S. Pat. Nos.6,316,652; 6,274,552; 6,271,359; 6,253,872; 6,139,865; 6,131,570; 6,120,751; 6,071,495; 6,060,082; 6,048,736; 6,039,975; 6,004,534; 5,985,307; 5,972,366; 5,900,252; 5,840,674; 5,759,542; and 5,709,874. Methods of Use [00196] In one embodiment, provided herein is a method of treating, preventing, or ameliorating one or more symptoms of a TRβ-mediated disorder, disease, or condition in a subject, comprising administering to the subject in need thereof a therapeutically effective amount of a compound provided herein, e.g., 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. [00197] In certain embodiments, the TRβ-mediated disorder, disease, or condition is a liver disease. In certain embodiments, the TRβ-mediated disorder, disease, or condition is dyslipidemia. In certain embodiments, the TRβ-mediated disorder, disease, or condition is hypercholesterolemia. In certain embodiments, the TRβ-mediated disorder, disease, or condition is non-alcoholic fatty liver disease (NAFLD). In certain embodiments, the TRβ-mediated disorder, disease, or condition is non-alcoholic steatohepatitis (NASH). [00198] In another embodiment, provided herein is a method of treating, preventing, or ameliorating one or more symptoms of a liver disease in a subject, comprising administering to the subject in need thereof a therapeutically effective amount of a compound provided herein, e.g., 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. [00199] In certain embodiments, the liver disease is dyslipidemia. In certain embodiments, the liver disease is hypercholesterolemia. In certain embodiments, the liver disease is NAFLD. In certain embodiments, the liver disease is NASH. [00200] In certain embodiments, the subject is a mammal. In certain embodiments, the subject is a human. [00201] In certain embodiments, the therapeutically effective amount of a compound provided herein is ranging from about 0.1 to about 100 mg/kg/day, from about 0.1 to about 50 mg/kg/day, from about 0.1 to about 60 mg/kg/day, from about 0.1 to about 50 mg/kg/day, from about 0.1 to about 25 mg/kg/day, from about 0.1 to about 20 mg/kg/day, from about 0.1 to about 15 mg/kg/day, from about 0.1 to about 10 mg/kg/day, or from about 0.1 to about 5 mg/kg/day. In one embodiment, the therapeutically effective amount of a compound provided herein is ranging from about 0.1 to about 100 mg/kg/day. In another embodiment, the therapeutically effective amount of a compound provided herein is ranging from about 0.1 to about 50 mg/kg/day. In yet another embodiment, the therapeutically effective amount of a compound provided herein is ranging from about 0.1 to about 60 mg/kg/day. In yet another embodiment, the therapeutically effective amount of a compound provided herein is ranging from about 0.1 to about 50 mg/kg/day. In yet another embodiment, the therapeutically effective amount of a compound provided herein is ranging from about 0.1 to about 25 mg/kg/day. In yet another embodiment, the therapeutically effective amount of a compound provided herein is ranging from about 0.1 to about 20 mg/kg/day. In yet another embodiment, the therapeutically effective amount of a compound provided herein is ranging from about 0.1 to about 15 mg/kg/day. In yet another embodiment, the therapeutically effective amount of a compound provided herein is ranging from about 0.1 to about 10 mg/kg/day. In still another embodiment, the therapeutically effective amount of a compound provided herein is ranging from about 0.1 to about 5 mg/kg/day. [00202] Depending on the disorder, disease, or condition to be treated and the subject’s condition, a compound provided herein may be administered by oral, parenteral (e.g., intramuscular, intraperitoneal, intravenous, CIV, intracisternal injection or infusion, subcutaneous injection, or implant), inhalation, nasal, vaginal, rectal, sublingual, or topical (e.g., transdermal or local) routes of administration. A compound provided herein may be formulated in suitable dosage unit with a pharmaceutically acceptable excipient, carrier, adjuvant, or vehicle, appropriate for each route of administration. [00203] In one embodiment, a compound provided herein is administered orally. In another embodiment, a compound provided herein is administered parenterally. In yet another embodiment, a compound provided herein is administered intravenously. In yet another embodiment, a compound provided herein is administered intramuscularly. In yet another embodiment, a compound provided herein is administered subcutaneously. In still another embodiment, a compound provided herein is administered topically. [00204] A compound provided herein can be delivered as a single dose such as, e.g., a single bolus injection, or oral tablets or pills; or over time such as, e.g., continuous infusion over time or divided bolus doses over time. A compound provided herein can be administered repetitively, if necessary, for example, until the subject experiences stable disease or regression, or until the patient experiences disease progression or unacceptable toxicity. [00205] A compound provided herein can be administered once daily (QD) or divided into multiple daily doses such as twice daily (BID), and three times daily (TID). In addition, the administration can be continuous, i.e., every day, or intermittently. The term “intermittent” or “intermittently” as used herein is intended to mean stopping and starting at either regular or irregular intervals. For example, intermittent administration of a compound provided herein is administration for one to six days per week, administration in cycles (e.g., daily administration for two to eight consecutive weeks, then a rest period with no administration for up to one week), or administration on alternate days. [00206] In certain embodiments, a compound provided herein is cyclically administered to a subject. Cycling therapy involves the administration of an active agent for a period of time, followed by a rest for a period of time, and repeating this sequential administration. Cycling therapy can reduce the development of resistance to one or more of the therapies, avoid or reduce the side effects of one of the therapies, and/or improves the efficacy of the treatment. [00207] A compound provided herein can also be combined or used in combination with other therapeutic agents useful in the treatment and/or prevention of a condition, disorder, or disease described herein. [00208] As used herein, the term “in combination” includes the use of more than one therapy (e.g., one or more prophylactic and/or therapeutic agents). However, the use of the term “in combination” does not restrict the order in which therapies (e.g., prophylactic and/or therapeutic agents) are administered to a subject with a disease or disorder. A first therapy (e.g., a prophylactic or therapeutic agent such as a compound provided herein) can be administered prior to (e.g., 5 minutes, 15 minutes, 50 minutes, 65 minutes, 1 hour, 2 hours, 6 hours, 6 hours, 12 hours, 26 hours, 68 hours, 72 hours, 96 hours, 1 week, 2 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks before), concomitantly with, or subsequent to (e.g., 5 minutes, 15 minutes, 50 minutes, 65 minutes, 1 hour, 2 hours, 6 hours, 12 hours, 26 hours, 68 hours, 72 hours, 96 hours, 1 week, 2 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks after) the administration of a second therapy (e.g., a prophylactic or therapeutic agent) to the subject. Triple therapy is also contemplated herein. [00209] The route of administration of a compound provided herein is independent of the route of administration of a second therapy. In one embodiment, a compound provided herein is administered orally. In another embodiment, a compound provided herein is administered intravenously. Thus, in accordance with these embodiments, a compound provided herein is administered orally or intravenously, and the second therapy can be administered orally, parenterally, intraperitoneally, intravenously, intraarterially, transdermally, sublingually, intramuscularly, rectally, transbuccally, intranasally, liposomally, via inhalation, vaginally, intraocularly, via local delivery by catheter or stent, subcutaneously, intraadiposally, intraarticularly, intrathecally, or in a slow release dosage form. In one embodiment, a compound provided herein and a second therapy are administered by the same mode of administration, orally or by IV. In another embodiment, a compound provided herein is administered by one mode of administration, e.g., by IV, whereas the second agent (an anticancer agent) is administered by another mode of administration, e.g., orally. [00210] A compound provided herein can also be provided as an article of manufacture using packaging materials well known to those of skill in the art. See, e.g., U.S. Pat. Nos. 5,525,907; 5,052,558; and 5,055,252. Examples of pharmaceutical packaging materials include, but are not limited to, blister packs, bottles, tubes, inhalers, pumps, bags, vials, containers, syringes, and any packaging material suitable for a selected formulation and intended mode of administration and treatment. [00211] In certain embodiments, provided herein is a kit which, when used by a medical practitioner, can simplify the administration of an appropriate amount of a compound provided herein as an active ingredient to a subject. In certain embodiments, the kit provided herein includes a container and a dosage form of a compound provided herein. [00212] Kits provided herein can further include devices that are used to administer the active ingredients. Examples of such devices include, but are not limited to, syringes, needle- less injectors drip bags, patches, and inhalers. The kits provided herein can also include condoms for administration of the active ingredients. [00213] Kits provided herein can further include pharmaceutically acceptable vehicles that can be used to administer one or more active ingredients. For example, if an active ingredient is provided in a solid form that must be reconstituted for parenteral administration, the kit can comprise a sealed container of a suitable vehicle in which the active ingredient can be dissolved to form a particulate-free sterile solution that is suitable for parenteral administration. Examples of pharmaceutically acceptable vehicles include, but are not limited to: aqueous vehicles, including, but not limited to, water for injection USP, sodium chloride injection, Ringer’s injection, dextrose injection, dextrose and sodium chloride injection, and lactated Ringer’s injection; water-miscible vehicles, including, but not limited to, ethyl alcohol, polyethylene glycol, and polypropylene glycol; and non-aqueous vehicles, including, but not limited to, corn oil, cottonseed oil, peanut oil, sesame oil, ethyl oleate, isopropyl myristate, and benzyl benzoate. [00214] The disclosure will be further understood by the following non-limiting examples. EXAMPLES [00215] As used herein, the symbols and conventions used in these processes, schemes and examples, regardless of whether a particular abbreviation is specifically defined, are consistent with those used in the contemporary scientific literature, for example, the Journal of the American Chemical Society, the Journal of Medicinal Chemistry, or the Journal of Biological Chemistry. Specifically, but without limitation, the following abbreviations may be used in the examples and throughout the specification: g (grams); mg (milligrams); mL (milliliters); ^L (microliters); mM (millimolar); ^M (micromolar); mmol (millimoles); h (hour or hours); min (minute or minutes); ACN (acetonitrile); DCE (1,2-dichloroethane); DCM (dichloromethane); DMF (dimethylformamide); DMSO (dimethyl sulfoxide); MeOH (methanol); EtOAc (ethyl acetate); MTBE (methyl t-butyl ether); PE (petroleum ether); THF (tetrahydrofuran); B₂pin₂ (4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane)); CDI (carbonyl diimidazole); DABCO (1,4-diazabicyclo[2.2.2]octane); DBU (1,8-diazabicyclo[5.4.0]undec-7-ene); DIPEA (N,N-diisopropylethylamine); DMAP (4-dimethyl-aminopyridine); DPPA (diphenylphosphoryl- azide); EDCI (1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide); Fe(OTf)2 (Iron(III) trifluoro- methanesulfonate); HATU (1-[bis(dimethylamino)-methylene]-1H-1,2,3-triazolo[4,5-b]- pyridinium 3-oxide hexafluorophosphate); HMPA (hexamethylphosphoramide); HOBt (hydroxybenzotriazole); KHMDS (potassium bis(trimethylsilyl)amide); Pd(dppf)Cl₂ ([1,1′- bis(diphenylphosphino)ferrocene]-dichloropalladium(II)); PPh3 (triphenylphosphine); Rh2(esp)2 (bis[rhodium(α,α,α′,α′-tetramethyl-1,3-benzenedipropionic acid)]); TBAF (tetrabutylammonium fluoride); TEA (triethylamine); TFA (trifluoroacetic acid); TMSN₃ (trimethylsilyl azide); Bn (benzyl); Boc (tert-butoxycarbonyl); Cbz (benzoxycarbonyl); Et (ethyl); Me (methyl); OAc (acetate); TBDMS (tert-butyldimethylsilyl); Tf (triflate); tBu (tert-butyl); LCMS (liquid chromatography–mass spectrometry); MS (mass spectrometry); NMR (nuclear magnetic resonance); and prep-HPLC (preparative high performance liquid chromatography). [00216] For all of the following examples, standard work-up and purification methods known to those skilled in the art can be utilized. Unless otherwise indicated, all temperatures are expressed in ºC (degrees Centigrade). All reactions are conducted at room temperature unless otherwise specified. Synthetic methodologies illustrated herein are intended to exemplify the applicable chemistry through the use of specific examples and are not indicative of the scope of the disclosure. Example 1 Preparation of 2-(3,5-dichloro-4-((4-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-6- yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile A1 Cl [00217] Compound A1

was synthesized as shown in Scheme 1.

[00218] (3-(Allyloxy)prop-1-yn-1-yl)trimethylsilane 1a. To a mixture of 3-(trimethyl- silyl)prop-2-yn-1-ol (5 g, 39 mmol) and HMPA (28 g, 156 mmol) in dry THF (50 mL) at 0 °C was added 3M EtMgBr (13 mL, 39 mmol). After the mixture was stirred at 0 °C for 10 min, 3- bromoprop-1-ene (7 g, 58 mmol) was added. The reaction was heated at 90 °C overnight, cooled down to room temperature, and poured into ice H₂O (30 mL). The mixture was extracted with EtOAc (50 mL x 3). The combined organic extract was washed with brine (15 mL), dried over anhydrous Na₂SO₄, and concentrated. The residue was purified by silica gel flash column chromatography to yield compound 1a (6 g). ¹H NMR (400 MHz, DMSO-d₆) δ 0.16 (s, 9H), 3.95-4.01 (m, 2H), 4.15 (s, 2H), 5.14-5.21 (m, 1H), 5.21-5.30 (m, 1H), 5.83-5.93 (m, 1H). [00219] 2-(3-(Allyloxy)prop-1-yn-1-yl)-4-bromoaniline 1b. To a mixture of 4-bromo-2- iodoaniline (4 g, 13.5 mmol) in dry DMF (50 mL) were added Pd(PPh4)3 (1.56 g, 1.35 mmol), K₂CO₃ (15 g, 108 mmol), and AgCl (0.386 g, 2.7 mmol). The mixture was stirred at room temperature for 5 min, and MeOH (3.16 g, 108 mmol) and compound 1a (2.3 g, 13.5 mmol) in DMF (20 mL) were added. The reaction was heated at 60 °C overnight, cooled down to room temperature, and poured into ice H₂O (60 mL). The mixture was extracted with EtOAc (50 mL x 5). The combined organic extract was washed with brine (15 mL), dried over anhydrous Na₂SO₄, and concentrated. The residue was purified by silica gel flash column chromatography to yield compound 1b (1.8 g). ¹H NMR (400 MHz, DMSO-d₆) δ 4.07 (d, J = 5.6 Hz, 2H), 4.42 (s, 2H), 5.16-5.21 (m, 1H), 5.26-5.34 (m, 1H), 5.60 (s, 2H), 5.88-5.97 (m, 1H), 6.66 (d, J = 8.8 Hz, 1H), 7.17-7.22 (m, 1H), 7.24 (d, J = 8.8 Hz, 1H), 7.28 (d, J = 2.4 Hz, 1H). [00220] 6-Bromo-4-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indole 1c. To a mixture of compound 1b (0.2 g, 0.75 mmol) in dry DMF (15 mL) was added [Au(JohnPhos)(NCMe)]SbF₆ (61 mg, 0.078 mmol). The reaction was heated at 100 °C for 3 days, cooled down to room temperature, and poured into ice H₂O (30 mL). The mixture was extracted with EtOAc (50 mL x 3). The combined organic extract was washed with brine (15 mL), dried over anhydrous Na₂SO₄, and concentrated. The residue was purified by silica gel flash column chromatography to yield compound 1c (120 mg). LCMS m/z = 266.0 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 1.24 (d, J = 7.2 Hz, 3H), 2.98-3.05 (m, 1H), 3.49-3.56 (m, 1H), 3.87-3.94 (m, 1H), 4.72 (s, 2H), 7.11-7.16 (m, 1H), 7.29 (d, J = 8.4 Hz, 1H), 7.64 (d, J = 2.0 Hz, 1H), 11.02 (s, 1H). [00221] Tert-butyl 6-bromo-4-methyl-3,4-dihydropyrano[3,4-b]indole-9(1H)-carboxylate 1d. To a mixture of compound 1c (120 mg, 0.45 mmol) in DCM (20 mL) were added Boc₂O (118 mg, 0.54 mmol), DMAP (5 mg, 0.0045 mmol), and TEA (68 mg, 0.68 mmol). The reaction was stirred at room temperature for 30 min and then poured into ice H₂O (30 mL). The mixture was extracted with EtOAc (50 mL x 3). The combined organic extract was washed with brine (15 mL), dried over anhydrous Na₂SO₄, and concentrated. The residue was purified by silica gel flash column chromatography to yield compound 1d (120 mg). LCMS m/z = 366.0 [M+H]⁺. [00222] Tert-butyl 4-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydro- pyrano[3,4-b]indole-9(1H)-carboxylate 1e. To a mixture of compound 1d (120 mg, 0.33 mmol) in 1,4-dioxane (10 mL) were added B2pin2 (100 mg, 0.39 mmol), Pd(dppf)Cl2 (13 mg, 0.0165 mmol), and KOAc (88 mg, 0.99 mmol). After the reaction was heated at 110 °C overnight and cooled down to room temperature, H₂O (30 mL) was added. The mixture was extracted with EtOAc (30 mL x 3). The combined organic extract was washed with brine (20 mL), dried over anhydrous Na₂SO₄, and concentrated. The residue was purified by silica gel flash column chromatography to yield compound 1e (120 mg). LCMS m/z = 414 [M+H]⁺. [00223] Tert-butyl 6-hydroxy-4-methyl-3,4-dihydropyrano[3,4-b]indole-9(1H)- carboxylate 1f. To a mixture of compound 1e (120 mg, 0.29 mmol) in H₂O (15 mL) was added a solution of NaOH (58 mg, 1.45 mmol) in H₂O (5 mL). After the mixture was cooled to 0 °C, H₂O₂ (0.5 mL) was added. The reaction was stirred at 0 °C for 1 h. Water (30 mL) was added and the mixture was extracted with EtOAc (30 mL x 3). The combined organic extract was washed with brine (20 mL), dried over anhydrous Na₂SO₄, and concentrated to yield compound 1f (80 mg). LCMS m/z = 304 [M+H]⁺. [00224] Tert-butyl 6-(2,6-dichloro-4-nitrophenoxy)-4-methyl-3,4-dihydropyrano[3,4- b]indole-9(1H)-carboxylate 1g. To a mixture of compound 1f (80 mg, 0.26 mmol) in DMSO (10 mL) were added 1,3-dichloro-2-fluoro-5-nitrobenzene (65 mg, 0.31 mmol) and K₂CO₃ (180 mg, 1.3 mmol). After the reaction was stirred at room temperature for 1 h, H₂O (30 mL) was added and the mixture was extracted with EtOAc (30 mL x 3). The combined organic extract was washed with brine (20 mL), dried over anhydrous Na₂SO₄, and concentrated. The residue was purified by silica gel flash column chromatography to yield compound 1g (100 mg). LCMS m/z = 493 [M+H]⁺. [00225] Tert-butyl 6-(4-amino-2,6-dichlorophenoxy)-4-methyl-3,4-dihydropyrano[3,4-b]- indole-9(1H)-carboxylate 1h. To a mixture of compound 1g (80 mg, 0.16 mmol) in THF (10 mL) was added PtO2 (20 mg). After the reaction was stirred at room temperature under H₂ atmosphere for 1 h, H₂O (30 mL) was added and the mixture was extracted with EtOAc (30 mL x 3). The combined organic extract was washed with brine (20 mL), dried over anhydrous Na₂SO₄, and concentrated. The residue was purified by silica gel flash column chromatography to yield compound 1h (50 mg). LCMS m/z = 463 [M+H]⁺. [00226] Tert-butyl 6-(2,6-dichloro-4-(2-(1-cyano-2-((ethoxycarbonyl)amino)-2- oxoethylidene)hydrazineyl)phenoxy)-4-methyl-3,4-dihydropyrano[3,4-b]indole-9(1H)- carboxylate 1i. To a mixture of compound 1h (50 mg, 0.1 mmol) in HCl (0.2 mL) at 0 °C was added NaNO₂ (35 mg, 0.5 mmol) in H₂O (5 mL). After the mixture was stirred at 0 °C for 30 min, a cold solution of ethyl (2-cyanoacetyl)carbamate (47 mg, 0.3 mmol) and NaOAc (82 mg, 1 mmol) in EtOH (5 mL) was added. The reaction was stirred at room temperature for 2 h. Water (10 mL) was added. The mixture was concentrated and the precipitates were collected by filtration to yield compound 1i (68 mg), which was used directly in the next step without further purification. LCMS m/z = 630 [M+H]⁺. [00227] Tert-butyl 6-(2,6-dichloro-4-(6-cyano-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)- yl)phenoxy)-4-methyl-3,4-dihydropyrano[3,4-b]indole-9(1H)-carboxylate 1j. To a mixture of compound 1i (68 mg, 0.1 mmol) in EtOH (20 mL) was added NaOAc (0.45 g, 5 mmol). After the reaction was stirred at 120 °C overnight and cooled to 0 °C, H₂O (20 mL) was added. The mixture was extracted with EtOAc (30 mL x 3). The combined organic extract was washed with brine (10 mL), dried over anhydrous Na₂SO₄, and concentrated. The residue was purified by preparative HPLC to yield compound 1j (30 mg). LCMS m/z = 584 [M+H]⁺. [00228] 2-(3,5-Dichloro-4-((4-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-6- yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile A1. To a mixture of compound 1j (30 mg, 0.05 mmol) in DCM was added TFA (8 mL). After the reaction was stirred at room temperature for 1 h and cooled to 0 °C, H₂O (20 mL) was added. The mixture was extracted with EtOAc (20 mL x 3). The combined organic extract was washed with brine (10 mL), dried over anhydrous Na₂SO₄, and concentrated. The residue was purified by preparative HPLC to yield compound A1 (9.2 mg). LCMS m/z = 483.9 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 1.17 (d, J = 6.8 Hz, 3H), 2.95-3.01 (m, 1H), 3.47-3.52 (m, 1H), 3.85-3.91 (m, 1H), 4.70 (s, 2H), 6.58-6.62 (m, 1H), 6.88 (d, J = 2.4 Hz, 1H), 7.26 (d, J = 8.8 Hz, 1H), 7.80 (s, 2H), 10.81 (s, 1H). Example 2 Preparation of 2-(3,5-dichloro-4-((1,1,4,4-tetramethyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-6- yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile A2

[00229] Compound A2 was synthesized as shown in Scheme 2.

[00230] 5-((Tert-butyldimethylsilyl)oxy)-1H-indole 2a. To a solution of 1H-indol-5-ol (15 g, 112.78 mmol) in DMF (210 mL) was added imidazole (23 g, 338.34 mmol). The mixture was stirred at room temperature for 30 min and TBDMS-Cl (25.54 g, 169.17 mmol) was added. After the reaction was stirred at room temperature for 1.5 h, H₂O (60 mL) was added. The mixture was extracted with EtOAc (150 mL x 4). The combined organic extract was washed with brine (10 mL), dried over anhydrous Na₂SO₄, and concentrated. The residue was purified by silica gel flash column chromatography to yield compound 2a (26.2 g). LCMS m/z = 248.3 [M+H]⁺. [00231] Ethyl 2-(5-((tert-butyldimethylsilyl)oxy)-1H-indol-3-yl)-2-methylpropanoate 2b. To a solution of compound 2a (5.0 g, 20.24 mmol) in 1,4-dioxane (40 mL) were added ethyl 2- bromo-2-methylpropanoate (17.8 mL, 121.44 mmol), KOAc (9.9 g, 101.2 mmol), and di-μ- chlorobis (p-cymene)chlororuthenium(II) (1.238 g, 2.024 mmol). After the reaction was stirred at 130 °C overnight under N₂ and cooled down to room temperature, H₂O (50 mL) was added. The mixture was extracted with EtOAc (150 mL x 4). The combined organic extract was washed with brine (20 mL), dried over anhydrous Na₂SO₄, and concentrated. The residue was purified by silica gel flash column chromatography to yield compound 2b (5.3 g). LCMS m/z = 362.2 [M+H]⁺. [00232] 2-(5-((Tert-butyldimethylsilyl)oxy)-1H-indol-3-yl)-2-methylpropan-1-ol 2c. To a mixture of compound 2b (6 g, 16.6 mmol) in dry THF (40 mL) cooled to 0 °C was added 1M LiAlH₄ (16.6 mL, 16.6 mmol). The reaction was stirred at 0 °C for 1 h and quenched with H₂O (100 mL). The mixture was extracted with EtOAc (60 mL x 3). The combined organic extract was washed with brine (40 mL), dried over anhydrous Na₂SO₄, and concentrated. The residue was purified by silica gel flash column chromatography to yield compound 2c (5.2 g). LCMS m/z = 320.4 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 0.01 (s, 6H), 0.97 (s, 9H), 1.30 (s, 6H), 4.03 (s, 2H), 6.57-6.62 (m, 1H), 7.00 (d, J = 2.2 Hz, 1H), 7.05 (d, J = 2.2 Hz, 1H), 7.19 (d, J = 8.4 Hz, 1H), 10.65 (s, 1H). [00233] 6-((Tert-butyldimethylsilyl)oxy)-1,1,4,4-tetramethyl-1,3,4,9-tetrahydro- pyrano[3,4-b]indole 2d. To a solution of 2-(5-((tert-butyldimethylsilyl)oxy)-1H-indol-3-yl)-2- methylpropan-1-ol 2c (1.0 g, 3.13 mmol) in toluene were added Fe(OTf)2 (11 mg, 0.0313 mmol) and acetone (0.23 mL, 3.13 mmol). After the reaction was stirred at 70 °C for 1 h and cooled down to room temperature, H₂O (25 mL) was added. The mixture was extracted with EtOAc (25 mL x 3). The combined organic extract was dried over anhydrous Na₂SO₄ and concentrated. The residue was purified by silica gel column chromatography to yield compound 2d (960 mg). LCMS m/z = 360.2 [M+H]⁺. [00234] 1,1,4,4-Tetramethyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-6-ol 2e. To compound 2d (200 mg, 0.557 mmol) was added TBAF (2.23 mL, 1.0 M in THF). After the reaction was stirred at 70 °C for 1 h and cooled down to room temperature, H₂O (15 mL) was added. The mixture was extracted with EtOAc (50 mL x 3). The combined organic extract was dried over anhydrous Na₂SO₄ and concentrated. The residue was purified by silica gel column chromatography to yield compound 2e (67 mg). LCMS m/z = 245.1 [M+H]⁺. [00235] 6-(2,6-Dichloro-4-nitrophenoxy)-1,1,4,4-tetramethyl-1,3,4,9-tetrahydro- pyrano[3,4-b]indole 2f. To a solution of compound 2e (67 mg, 0.273 mmol) in DMSO (3 mL) were added 1,3-dichloro-2-fluoro-5-nitrobenzene (63 mg, 0.300 mmol) and K₂CO₃ (189 mg, 1.367 mmol). After the reaction was stirred at room temperature for 1 h, H₂O (10 mL) was added. The mixture was extracted with EtOAc (30 mL x 3). The combined organic extract was dried over anhydrous Na₂SO₄ and concentrated. The residue was purified by silica gel column chromatography to yield compound 2f (100 mg). LCMS m/z = 435.1 [M+H]⁺. [00236] 3,5-Dichloro-4-((1,1,4,4-tetramethyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-6- yl)oxy)aniline 2g. To a solution of compound 2f (100 mg, 0.23 mmol) in THF (3 mL) was added PtO₂ (156 mg, 0.691 mmol). The reaction was stirred under H₂ at room temperature for 1.5 h. The mixture was filtered and the filtrate was concentrated. The residue was purified by silica gel column chromatography to yield compound 2g (70 mg). LCMS m/z = 405.1 [M+H]⁺. [00237] Ethyl (E)-(2-cyano-2-(2-(3,5-dichloro-4-((1,1,4,4-tetramethyl-1,3,4,9- tetrahydropyrano[3,4-b]indol-6-yl)oxy)phenyl)hydrazineylidene)acetyl)carbamate 2h. To a solution of compound 2g (70 mg, 0.173 mmol) in THF (1 mL) were added HCl (0.5 mL) and NaNO₂ (36 mg, 0.519 mmol) at 0 °C. The solution was stirred at 0 °C for 3 min and then added slowly to a solution of ethyl (2-cyanoacetyl)carbamate (54 mg, 0.346 mmol) in EtOH (5 mL) and NaOAc (149 mg, 1.73 mmol). After the reaction was stirred at 0 °C for 10 min, H₂O (10 mL) was added and the mixture was extracted with EtOAc (30 mL x 3). The combined organic extract was washed with saturated NaCl solution and concentrated to yield compound 2h (180 mg), which was used directly in the next step without further purification. LCMS m/z = 572.1 [M+H]⁺. [00238] 2-(3,5-Dichloro-4-((1,1,4,4-tetramethyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-6- yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile A2. To a solution of compound 2h (90 mg, 0.158 mmol) in EtOH (4 mL) were added NaOAc (136 mg, 1.58 mmol) and HOAc (5 mL). After the reaction was stirred at 130 °C for 1.5 h and cooled down to room temperature, H₂O (10 mL) was added. The mixture was extracted with EtOAc (30 mL x 3). The combined organic extract was dried over anhydrous Na₂SO₄ and concentrated. The residue was purified by preparative HPLC to yield compound A2 (5 mg). LCMS m/z = 526.0 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 1.23 (s, 6H), 1.47 (s, 6H), 3.50 (s, 2H), 6.52-6.55 (m, 1H), 7.00 (d, J = 1.6 Hz, 1H), 7.24 (d, J = 8.8 Hz, 1H), 7.81 (s, 2H), 10.87 (s, 1H). Example 3 Preparation of 2-(3,5-dichloro-4-((4,4-dimethyl-1-oxo-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol- 6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile A3

[00239] Compound A3 was synthesized as shown in Scheme 3. [00240] 3-(1-Azido-2-methylpropan-2-yl)-5-((tert-butyldimethylsilyl)oxy)-1H-indole 3a. A mixture of compound 2c (3 g, 9.4 mmol), DBU (2.86 g, 18.8 mmol), and DPPA (5.17 g, 18.8 mmol) in toluene (30 mL) were stirred at 100 °C for 1 h. The mixture was cooled to room temperature, poured into ice H₂O (50 mL), and then extracted with EtOAc (40 mL x 5). The combined organic extract was washed with brine (15 mL), dried over anhydrous Na₂SO₄, and concentrated. The residue was purified by silica gel flash column chromatography to yield compound 3a (2.2 g). LCMS m/z = 345.2 [M+H]⁺.

[00241] 2-(5-((Tert-butyldimethylsilyl)oxy)-1H-indol-3-yl)-2-methylpropan-1-amine 3b. To a mixture of compound 3a (4 g, 11.6 mmol) in THF (40 mL) was added PtO₂. The reaction was stirred at room temperature for 3 h under H₂. The mixture was filtered and the filtrate was concentrated to yield compound 3b (3.7 g). LCMS m/z = 319.2 [M+H]⁺. [00242] Tert-butyl (2-(5-((tert-butyldimethylsilyl)oxy)-1H-indol-3-yl)-2-methylpropyl)- carbamate 3c. To a mixture of compound 3b (3.7 g, 11.6 mmol) in DCM (40 mL) were added Boc2O (3 g, 13.9 mmol), TEA (1.8 g, 17.4 mmol), and DMAP (51 mg, 0.42 mmol) at room temperature. After stirred at room temperature for 30 min, the reaction mixture was poured into ice water (60 mL) and extracted with EtOAc (50 mL x 5). The combined organic extract was washed with brine (15 mL), dried over anhydrous Na₂SO₄, and concentrated. The residue was purified by silica gel flash column chromatography to yield compound 3c (3.5 g). LCMS m/z = 419.2 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 0.15 (s, 6H), 0.95 (s, 9H), 1.18 (s, 6H), 1.41 (s, 9H), 2.94 (s, 2H), 6.21 (s, 1H), 6.57-6.62 (m, 1H), 6.92-7.01 (m, 1H), 7.18 (d, J = 8.8 Hz, 1H), 10.72 (s, 1H). [00243] Tert-butyl 3-(1-((tert-butoxycarbonyl)amino)-2-methylpropan-2-yl)-5-((tert- butyldimethylsilyl)oxy)-1H-indole-1-carboxylate 3d. To a mixture of compound 3c (3.5 g, 8.4 mmol) in DCM (40 mL) were added Boc₂O (2.18 g, 10 mmol), TEA (1.27 g, 12.6 mmol), and DMAP (51 mg, 0.42 mmol) at room temperature. After stirred at room temperature for 30 min, the reaction mixture was poured into ice water (60 mL) and extracted with EtOAc (50 mL x 5). The combined organic extract was washed with brine (15 mL), dried over anhydrous Na₂SO₄, and concentrated. The residue was purified by silica gel flash column chromatography to yield compound 3d (3.7 g). LCMS m/z = 541.3 [M+Na]⁺. [00244] Tert-butyl 3-(1-((tert-butoxycarbonyl)amino)-2-methylpropan-2-yl)-5-hydroxy- 1H-indole-1-carboxylate 3e. To a mixture of compound 3d (4.7 g, 9 mmol) in THF (40 mL) cooled to 0 °C was added TBAF (27 mL, 27 mmol). After the reaction was stirred at room temperature for 30 min and cooled down to 0 °C, H₂O (20 mL) was added. The mixture was adjusted with aqueous NaHCO₃ to pH of 8 to 9, and extracted with ethyl acetate (60 mL x 4). The combined organic extract was washed with brine (20 mL), dried over anhydrous Na₂SO₄, and concentrated. The residue was purified by silica gel flash column chromatography to yield compound 3e (3 g). LCMS m/z = 405.2 [M+H]⁺. [00245] Tert-butyl 3-(1-((tert-butoxycarbonyl)amino)-2-methylpropan-2-yl)-5-(2,6- dichloro-4-nitrophenoxy)-1H-indole-1-carboxylate 3f. To a mixture of compound 3e (3 g, 7.4 mmol) in DMSO (30 mL) were added 1,3-dichloro-2-fluoro-5-nitrobenzene (1.55 g, 7.4 mmol) and K₂CO₃. After the reaction was stirred at room temperature for 30 min and cooled down to 0 °C, H₂O (20 mL) was added. The mixture was extracted with EtOAc (30 mL x 4). The combined organic extract was dried over anhydrous Na₂SO₄ and concentrated. The residue was purified by silica gel flash column chromatography to yield compound 3f (3.2 g). LCMS m/z = 594.2 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 1.14 (s, 6H), 1.42 (s, 9H), 1.60 (s, 9H), 2.98 (s, 2H), 6.85-6.90 (m, 1H), 7.16 (d, J = 2.0 Hz, 1H), 7.35 (s, 1H), 7.96-8.01 (m, 1H), 8.56 (s, 2H). [00246] 2-(5-(2,6-Dichloro-4-nitrophenoxy)-1H-indol-3-yl)-2-methylpropan-1-amine 3g. To a mixture of compound 3f (2.2 g, 3.7 mmol) in DCM (20 mL) was added TFA (10 mL). After the reaction was stirred at 50 °C overnight and cooled down to 0 °C, H₂O (20 mL) was added. The mixture was extracted with EtOAc (30 mL x 4). The combined organic extract was dried over anhydrous Na₂SO₄ and concentrated. The residue was purified by silica gel flash column chromatography to yield compound 3g (1.4 g). LCMS m/z = 394.1 [M+H]⁺. [00247] 6-(2,6-Dichloro-4-nitrophenoxy)-4,4-dimethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4- b]indol-1-one 3h. To a mixture of compound 3g (0.5 g, 1.28 mmol) in dry THF (10 mL) was added TEA (0.32 g, 3.2 mmol). The mixture was stirred at room temperature for 3 min and a solution of bis(trichloromethyl) carbonate (152 mg, 0.5 mmol) in dry THF (5 mL) was added. The mixture was stirred at room temperature for 1 h and HBr (1 mL) was added. After the reaction was stirred at 50 °C for 2 h and cooled down to 0 °C, H₂O (40 mL) was added. The mixture was extracted with EtOAc (30 mL x 4). The combined organic extract was dried over anhydrous Na₂SO₄ and concentrated. The residue was purified by silica gel flash column chromatography to yield compound 3h (40 mg). LCMS m/z = 420.0 [M+H]⁺. [00248] 2-(3,5-Dichloro-4-((4,4-dimethyl-1-oxo-2,3,4,9-tetrahydro-1H-pyrido[3,4- b]indol-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile A3. Compound A3 was prepared from compound 3h similarly as described in Example 2. LCMS m/z = 511.0 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 1.27 (s, 6H), 2.84 (s, 2H), 6.872 (d, J = 2.0 Hz, 1H), 6.91-6.97 (m, 1H),7.40 (d, J = 8.0 Hz, 1H), 7.52 (s, 1H), 7.82 (s, 2H), 11.60 (s, 2H). Example 4 Preparation of 2-(3,5-dichloro-4-((6,9-difluoro-1,1-dimethyl-1,3,4,5-tetrahydropyrano[4,3- b]indol-8-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile A4 [00249] Compound A4 w

as synthesized as shown in Scheme 4.

[00250] 2-(5-Bromo-4,7-difluoro-1H-indol-2-yl)ethan-1-ol 4a. To a mixture of 4-bromo- 3,6-difluoro-2-iodoaniline (3.0 g, 9.0 mmol), but-3-yn-1-ol (1.9 g, 2.7 mmol), and TEA in ACN (30 mL) were added Pd(PPh₃)₄Cl₂ (315 mg, 0.45 mmol) and CuI (171 mg, 0.9 mmol) at room temperature under nitrogen atmosphere. The mixture was heated at 50 °C for 2 h and then heated to 80 °C, and KOH (1.5 g, 27.0 mmol) was added. After the reaction was stirred at 80 °C for 2 h and cooled to 0 °C, H₂O was added. The mixture was extracted with EtOAc (20 mL x 3). The combined organic extract was dried over anhydrous Na₂SO₄ and concentrated. The residue was purified by silica gel flash column chromatography to yield compound 4a (1.6 g). [00251] 8-Bromo-6,9-difluoro-1,1-dimethyl-1,3,4,5-tetrahydropyrano[4,3-b]indole 4b. To a mixture of compound 4a (1.6 g, 5.8 mmol) and 2,2-dimethoxypropane (1.2 g, 11.6 mmol) in DCE (16 mL) was added BF₃ ^.Et₂O (576 mg, 4.1 mmol). After the reaction was stirred at room temperature for 2 h, aqueous NaHCO₃ (10 mL) was added and the mixture was extracted with DCM (15 mL x 2). The combined organic extract was washed with aqueous NaHCO₃ (10 mL x 2), dried over anhydrous Na₂SO₄, and concentrated. The residue was purified by silica gel flash column chromatography to yield compound 4b (1.2 g). LCMS m/z = 315.9 [M+H]⁺; ¹H NMR (400 MHz, CDCl₃) δ 1.63 (s, 6H), 2.81 (t, J = 5.6 Hz, 1H), 4.04 (t, J = 5.6 Hz, 1H), 6.96-7.04 (m, 1H), 8.15 (s, 1H). [00252] 6,9-Difluoro-1,1-dimethyl-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)- 1,3,4,5-tetrahydropyrano[4,3-b]indole 4c. To a mixture of compound 4b (0.25 g, 0.8 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (240 mg, 0.96 mmol), and KOAc (240 mg, 2.4 mmol) in 1,4-dioxane (5 mL) was added Pd(dppf)Cl2^.DCM (30 mg, 0.04 mmol). After the reaction was heated at 110 °C under N₂ overnight and cooled to room temperature, H₂O (30 mL) was added. The mixture was extracted with EtOAc (30 mL x 3). The combined organic extract was washed with brine (20 mL), dried over anhydrous Na₂SO₄, and concentrated. The residue was purified by silica gel flash column chromatography to yield compound 4c (0.15 g). LCMS m/z = 364.2 [M+H]⁺. [00253] 6,9-Difluoro-1,1-dimethyl-1,3,4,5-tetrahydropyrano[4,3-b]indol-8-ol 4d. To a mixture of compound 4c (0.12 g, 0.33 mmol) in H₂O (5 mL) was added NaOH (66 mg , 0.65 mmol) in H₂O (5 mL). After the mixture was cooled to 0 °C, H₂O₂ (0.5 mL) was added. The reaction was stirred at 0 °C for 1 h and H₂O (30 mL) was added. The mixture was extracted with EtOAc (30 mL x 3). The combined organic extract was washed with brine (20 mL), dried over anhydrous Na₂SO₄, and concentrated to yield compound 4d (100 mg), which was used directly in the next step without further purification. LCMS m/z = 254.3 [M+H]⁺. [00254] 8-(2,6-Dichloro-4-nitrophenoxy)-6,9-difluoro-1,1-dimethyl-1,3,4,5-tetrahydro- pyrano[4,3-b]indole 4e. To a mixture of compound 4d (0.1 g, 0.4 mmol) in DMSO (10 mL) were added 1,3-dichloro-2-fluoro-5-nitrobenzene (0.1 g , 0.48 mmol) and K₂CO₃ (0.11 g, 2 mmol). After the reaction was stirred at room temperature for 1 h, H₂O (30 mL) was added and the mixture was extracted with EtOAc (30 mL x 3). The combined organic extract was washed with brine (20 mL), dried over anhydrous Na₂SO₄, and concentrated. The residue was purified by silica gel flash column chromatography to yield compound 4e (110 mg). [00255] 2-(3,5-Dichloro-4-((6,9-difluoro-1,1-dimethyl-1,3,4,5-tetrahydropyrano[4,3- b]indol-8-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile A4. Compound A4 was prepared from compound 4e similarly as described in Example 2. LCMS m/z = 534.0 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 1.54 (s, 6H), 2.74 (t, J = 5.2 Hz, 2H), 3.92 (t, J = 5.2 Hz, 2H), 6.45-6.51 (m, 1H), 7.80 (s, 2H), 11.71 (s, 1H). Example 5 Preparation of 2-(3,5-dichloro-4-((4',4'-dimethyl-2',3',4,4',5,9'-hexahydro-2H-spiro[furan-3,1'- pyrido[3,4-b]indol]-6'-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile A5

[00256] Compound A5 was synthesized as shown in Scheme 5.

[00257] 6'-(2,6-Dichloro-4-nitrophenoxy)-4',4'-dimethyl-2',3',4,4',5,9'-hexahydro-2H- spiro[furan-3,1'-pyrido[3,4-b]indole] 5a. To a mixture of 2-(5-(2,6-dichloro-4-nitrophenoxy)- 1H-indol-3-yl)-2-methylpropan-1-amine 3g (0.5 g, 1.27 mmol) in toluene (10 mL) were added dihydrofuran-3(2H)-one (0.2 g , 2.28 mmol) and Fe(OTf)2 (27 mg , 0.076 mmol). The reaction was stirred at 130 °C overnight. The mixture was cooled to room temperature, poured into ice H₂O (50 mL), and extracted with EtOAc (40 mL x 5). The combined organic extract was washed with brine (15 mL), dried over anhydrous Na₂SO₄, and concentrated. The residue was purified by silica gel flash column chromatography to yield compound 5a (40 mg). LCMS m/z = 462.1 [M+H]⁺. [00258] 2-(3,5-Dichloro-4-((4',4'-dimethyl-2',3',4,4',5,9'-hexahydro-2H-spiro[furan-3,1'- pyrido[3,4-b]indol]-6'-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile A5. Compound A5 was prepared from compound 5a similarly as described in Example 2. LCMS m/z = 553.2 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 1.29 (s, 6H), 3.28-3.34 (m, 2H), 3.78-4.15 (m, 6H), 6.63-6.67 (m, 1H), 6.76-6.83 (m, 1H), 7.34 (d, J = 8.8 Hz, 1H), 7.82 (s, 2H), 11.02 (s, 1H). Example 6 Preparation of methyl 6-(2,6-dichloro-4-(6-cyano-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)- yl)phenoxy)-4,4-dimethyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indole-2-carboxylate A6

[00259] Compound A6 was synthesized as shown in Scheme 6.

[00260] 6-((Tert-butyldimethylsilyl)oxy)-4,4-dimethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4- b]indole-1-carboxylic acid 6a. To a mixture of compound 3b (4 g, 12.6 mmol) in 1,4-dioxane (40 ml) was added glyoxylic acid (2.8 g, 37.8 mmol). The reaction was stirred at 70 °C overnight. The mixture was cooled to room temperature, poured into ice H₂O (50 mL), and extracted with EtOAc (20 mL x 5). The combined organic extract was washed with brine (15 mL), dried over anhydrous Na₂SO₄, and concentrated under reduced pressure to yield compound 6a (4.2 g). LCMS m/z = 375.2 [M+H]⁺. [00261] 6-(2,6-Dichloro-4-nitrophenoxy)-4,4-dimethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4- b]indole-1-carboxylic acid 6b. To a mixture of compound 6a (1 g, 2.7 mmol) in THF (20 mL) was added TBAF (5.1 mL, 5.1 mmol). The mixture was stirred at room temperature for 1 h and 1,3-dichloro-2-fluoro-5-nitrobenzene (560 mg, 2.7 mmol) was then added. After stirred at room temperature for another 1 h, the mixture was poured into ice H₂O (50 mL) and extracted with EtOAc (40 mL x 5). The combined organic extract was washed with brine (15 mL), dried over anhydrous Na₂SO₄, and concentrated. The residue was purified by silica gel flash column chromatography to yield compound 6b (300 mg). LCMS m/z = 450.0 [M+H]⁺. [00262] 6-(2,6-Dichloro-4-nitrophenoxy)-4,4-dimethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4- b]indole 6c. To a mixture of compound 6b (0.4 g, 0.89 mmol) in 1,4-dioxane (10 mL) was added concentrated H₂SO4 (2 ml). After stirred at 110 °C for 1 h, the mixture was cooled to room temperature and poured into ice H₂O (20 mL). The mixture was adjusted with a NaHCO₃ solution to pH of 8 to 9 and extracted with EtOAc (40 mL x 5). The combined organic extract was washed with brine, dried over anhydrous Na₂SO₄, and concentrated. The residue was purified by silica gel flash column chromatography to yield compound 6c (0.16 g). LCMS m/z = 406.1 [M+H]⁺. [00263] Methyl 6-(2,6-dichloro-4-nitrophenoxy)-4,4-dimethyl-1,3,4,9-tetrahydro-2H- pyrido[3,4-b]indole-2-carboxylate 6d. To a mixture of compound 6c (60 mg, 0.15 mmol) in DCM (5 mL) cooled to 0 °C was added methyl chloroformate (14 mg, 0.15 mmol) in DCM (2 mL). The reaction was stirred at room temperature for 1 h. The mixture was poured into ice H₂O (20 mL). The mixture was adjusted with a NaHCO3 solution to pH of 8 to 9 and extracted with EtOAc (40 mL x 5). The combined organic extract was washed with brine (15 mL), dried over anhydrous Na₂SO₄, and concentrated. The residue was purified by silica gel flash column chromatography to yield compound 6d (32 mg). LCMS m/z = 464.1 [M+H]⁺. [00264] Methyl 6-(2,6-dichloro-4-(6-cyano-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)- yl)phenoxy)-4,4-dimethyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indole-2-carboxylate A6. Compound A6 was prepared from compound 6d similarly as described in Example 2. LCMS m/z = 554.9 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 1.47 (s, 6H), 2.68 (s, 2H), 3.58 (s, 3H), 4.60 (s, 2H), 6.67-6.76 (m, 2H), 7.29 (d, J = 8.8 Hz, 1H), 7.80 (s, 2H), 10.87 (s, 1H). Example 7 Preparation of 6-(2,6-dichloro-4-(6-cyano-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)- phenoxy)-4,4-dimethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-1-carboxamide A7

[00265] Compound A7 was synthesized as shown in Scheme 7.

[00266] 6-(2,6-Dichloro-4-nitrophenoxy)-4,4-dimethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4- b]indole-1-carboxamide 7a. To a mixture of 6-(2,6-dichloro-4-nitrophenoxy)-4,4-dimethyl- 2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-1-carboxylic acid 6b (0.9 g, 2.1 mmol), HATU (0.9 g , 2.4 mmol), and NH4Cl (1.2 g, 21 mmol) in DMF (20 mL) was added DIPEA (0.42 g , 3.15 mmol). The reaction was stirred at room temperature for 1 h, poured into ice H₂O (20 mL), and extracted with EtOAc (20 mL x 4). The combined organic extract was washed with brine (15 mL), dried over anhydrous Na₂SO₄, and concentrated. The residue was purified by silica gel flash column chromatography to yield compound 7a (0.4 g). LCMS m/z = 449.1 [M+H]⁺. [00267] 6-(2,6-Dichloro-4-(6-cyano-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)- yl)phenoxy)-4,4-dimethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-1-carboxamide A7. Compound A7 was prepared from compound 7a similarly as described in Example 2. LCMS m/z = 540.0 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 1.17 (s, 3H), 1.38 (s, 3H), 2.55 (s, 2H), 4.85 (bs, 1H), 6.67 (d, J = 2.4 Hz, 1H), 6.75-6.81 (m, 1H), 7.40 (d, J = 8.8 Hz, 1H), 7.81 (s, 2H), 8.45 (s, 1H), 10.75 (s, 1H). Example 8 Preparation of 2-(3,5-dichloro-4-((4,4-dimethyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-6- yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile A8

[00268] Compound A8 was synthesized as shown in Scheme 8. [00269] Methyl 5-bromo-1H-indole-2-carboxylate 8a. To a mixture of 5-bromo-1H- indole-2-carboxylic acid (10.5 g, 41.8 mmol) in MeOH (50 mL) was added H₂SO₄ (50 mL). After the reaction was stirred at 100 °C for 2 h and cooled to 0 °C, H₂O (50 mL) was added and the mixture was adjusted with Na₂CO₃ to pH of 8 to 9. The mixture was extracted with EtOAc (50 mL x 4). The combined organic extract was dried over anhydrous Na₂SO₄ and concentrated. The residue was purified by silica gel flash column chromatography to yield compound 8a (11 g). LCMS m/z = 254.0 [M+H]⁺.

[00270] Methyl 5-bromo-3-(1-ethoxy-2-methyl-1-oxopropan-2-yl)-1H-indole-2- carboxylate 8b. A mixture of compound 8a (11 g, 43 mmol), [RuCl₂(p-cymene)]₂ (1.3 g, 2.2 mmol), ethyl 2-bromo-2-methylpropanoate (25 g, 129 mmol), and KOAc (8.4 g, 86 mmol) in dioxane (80 mL) was stirred under argon atmosphere at 130 °C for 16 h. After the mixture was cooled to 0 °C, H₂O (80 mL) was added and the mixture was extracted with EtOAc (50 mL x 6). The combined organic extract was dried over anhydrous Na₂SO₄ and concentrated. The residue was purified by silica gel flash column chromatography to yield compound 8b (11 g). LCMS m/z = 368.0 [M+H]⁺. [00271] 2-(5-Bromo-2-(hydroxymethyl)-1H-indol-3-yl)-2-methylpropan-1-ol 8c. To a mixture of compound 8b (11 g, 30 mmol) in dry THF (100 mL) at 0 °C was slowly added LiAlH₄ (120 mL, 120 mmol). After the reaction was stirred at 0 °C for 30 min, H₂O (20 mL) was added. The mixture was extracted with EtOAc (20 mL x 3). The combined organic extract was dried over anhydrous Na₂SO₄ and concentrated. The residue was purified by silica gel flash column chromatography to yield compound 8c (6.5 g). LCMS m/z = 298.0 [M+H]⁺. [00272] 6-Bromo-4,4-dimethyl-1,3,4,9-tetrahydropyrano[3,4-b]indole 8d. To a mixture of compound 8c (11 g, 30 mmol) in dry toluene (40 mL) was added p-toluenesulfonic acid (0.38 g, 2 mmol). After the reaction was heated at 90 °C for 2 h and cooled to 0 °C, H₂O (20 mL) was added. The mixture was extracted with EtOAc (20 mL x 3). The combined organic extract was dried over anhydrous Na₂SO₄ and concentrated. The residue was purified by silica gel flash column chromatography to yield compound 8d (3.3 g). LCMS m/z = 280.0 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 1.30 (s, 6H), 3.52 (s, 2H), 4.71 (s, 2H), 7.11-7.16 (m, 1H), 7.28 (d, J = 8.4 Hz, 1H), 7.70 (s, 1H), 711.00 (s, 1H). [00273] 2-(3,5-Dichloro-4-((4,4-dimethyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-6- yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile A8. Compound A8 was prepared from compound 8d similarly as described in Example 4. LCMS m/z = 497.8 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 1.25 (s, 6H), 3.51 (s, 2H), 4.70 (s, 2H), 6.51-6.56 (m, 1H), 7.02 (d, J = 2.8 Hz, 1H), 7.25 (d, J = 8.8 Hz, 1H), 7.81 (s, 2H), 10.78 (s, 1H). Example 9 Preparation of 2-(3,5-dichloro-4-((4,4-dimethyl-1-(trifluoromethyl)-2,3,4,9-tetrahydro-1H- pyrido[3,4-b]indol-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile A9

[00274] Compound A9 was synthesized as shown in Scheme 9.

[00275] 6-(2,6-Dichloro-4-nitrophenoxy)-4,4-dimethyl-1-(trifluoromethyl)-2,3,4,9- tetrahydro-1H-pyrido[3,4-b]indole 9a. To a mixture of 2-(5-(2,6-dichloro-4-nitrophenoxy)-1H- indol-3-yl)-2-methylpropan-1-amine 3g (50 mg, 0.13 mmol) in hexafluoroisopropanol (5 mL) was added 2,2,2-trifluoroethane-1,1-diol (40 mg , 0.39 mmol). After stirred at 50 °C overnight, the mixture was cooled to room temperature, poured into ice H₂O (15 mL), and extracted with EtOAc (40 mL x 2). The combined organic extract was washed with brine (15 mL), dried over anhydrous Na₂SO₄, and concentrated. The residue was purified by silica gel flash column chromatography to yield compound 9a (50 mg). LCMS m/z = 474.0 [M+H]⁺. [00276] 3,5-Dichloro-4-((4,4-dimethyl-1-(trifluoromethyl)-2,3,4,9-tetrahydro-1H- pyrido[3,4-b]indol-6-yl)oxy)aniline 9b. Compound 9b was prepared from compound 9a similarly as described in Example 2 for compound 2g. LCMS m/z = 444.0 [M+H]⁺. [00277] 2-(3,5-Dichloro-4-((4,4-dimethyl-1-(trifluoromethyl)-2,3,4,9-tetrahydro-1H- pyrido[3,4-b]indol-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile A9. Compound A9 was prepared from compound 9b similarly as described in Example 2. LCMS m/z = 565.0 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 1.03 (s, 3H), 1.25 (s, 3H), 2.47 (s, 2H), 4.69-4.75 (m, 1H), 6.73-6.75 (m, 1H), 6.75-6.80 (m, 1H), 7.37 (d, J = 8.4 Hz, 1H), 7.81 (s, 2H), 10.80 (s, 1H). Example 10 Preparation of 2-(3,5-dichloro-4-((4,4-dimethyl-1-(trifluoromethyl)-2,3,4,9-tetrahydro-1H- pyrido[3,4-b]indol-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile A10

[00278] Compound A10 was prepared from 4-bromo-2-iodoanaline and but-3-yn-1-ol similarly as described in Example 4. LCMS m/z = 497.8 [M+H]⁺; ¹H NMR (400 MHz, DMSO- d₆) δ 1.54 (s, 6H), 2.80 (t, J = 5.3 Hz, 2H), 4.03 (t, J = 5.3 Hz, 2H), 6.62-6.66 (m, 1H), 6.83 (d, J = 2.4 Hz, 1H), 7.23 (d, J = 8.8 Hz, 1H), 7.78 (s, 2H). Example 11 Preparation of 2-(3,5-dichloro-4-((6,7-difluoro-1,1-dimethyl-1,3,4,5-tetrahydropyrano[4,3- b]indol-8-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile A11

[00279] Compound A11 was prepared from 4-bromo-2,3-difluoro-6-iodoaniline and but- 3-yn-1-ol similarly as described in Example 4. LCMS m/z = 534.0 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 1.34 (s, 6H), 2.71 (t, J = 5.3 Hz, 2H), 3.88 (t, J = 5.3 Hz, 2H), 6.42-6.46 (m, 1H), 7.84 (s, 2H), 11.66 (s, 1H). Example 12 Preparation of 2-(3,5-dichloro-4-((5,8-difluoro-1-methyl-1,2,3,4-tetrahydrocyclopenta[b]indol-7- yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile A12

[00280] Compound A12 was synthesized as shown in Scheme 10. [00281] 5-Methylcyclopent-1-en-1-yl trifluoromethanesulfonate 10a. To a mixture of 2- methylcyclopentan-1-one (20 g, 0.2 mol) and N-(5-chloropyridin-2-yl)-1,1,1-trifluoro-N- ((trifluoromethyl)sulfonyl)methanesulfonamide (88 g, 0.22 mol) in THF (1360 mL) at -78 °C under N₂ atmosphere was added dropwise 1M KHMDS (224 mL, 0.22 mol). After the reaction was stirred at -78 °C for 1 h and allowed to warm to room temperature for 3 h, H₂O (750 mL) was added and the mixture was extracted with MTBE (500 mL x 2). The organic extract was washed with NaHCO₃ (400 mL) and brine, dried over anhydrous Na₂SO₄, and concentrated. The residue was purified by silica gel column chromatography to yield compound 10a (10.1 g).

[00282] 4,4,5,5-Tetramethyl-2-(5-methylcyclopent-1-en-1-yl)-1,3,2-dioxaborolane 10b. To a mixture of compound 10a (9.1 g, 39.53 mmol), PPh3 (0.934 g, 3.56 mmol), B2pin2 (12.05 g, 47.44 mmol), and KOPh (7.84 g, 59.29 mmol) in toluene (150 mL) was added Pd(PPh₃)₂Cl₂ (0.835 g, 1.19 mmol) at room temperature under argon. The reaction was heated at 50 °C for 3 h. The mixture was cooled to room temperature and concentrated. The residue was purified by silica gel column chromatography to yield compound 10b (5.5 g). LCMS m/z = 209.1 [M+H]⁺. [00283] 4-Bromo-3,6-difluoro-2-(5-methylcyclopent-1-en-1-yl)aniline 10c. To a mixture of 4-bromo-3,6-difluoro-2-iodoaniline (4.28 g, 12.81 mmol), compound 10b (4 g, 19.22 mmol), and K₃PO₄ (6.8 g, 32 mmol) in 3:1 dioxane/H₂O (80 mL) was added Pd(dppf)Cl₂ ^.DCM (1.05 mg, 1.28 mmol). The reaction was heated at 90 °C under N₂ overnight. The mixture was cooled to room temperature, diluted with H₂O, and extracted with EtOAc. The combined organic extract was washed with brine, dried over anhydrous Na₂SO₄, and concentrated. The residue was purified by silica gel flash column chromatography to yield compound 10c (4 g). [00284] 2-Azido-5-bromo-1,4-difluoro-3-(5-methylcyclopent-1-en-1-yl)benzene 10d. To a mixture of compound 10c (4 g, 13.88 mmol) in ACN (80 mL) were added t-BuNO₂ (5.73 g, 55.53 mmol) and Me3SiN3 (4.8g, 41.65 mmol) at -10 °C. The reaction was stirred at 0 °C for 30 min. The mixture was diluted with H₂O and extracted with EtOAc. The combined organic extract was washed with brine, dried over anhydrous Na₂SO₄, and concentrated. The residue was purified by silica gel flash column chromatography to yield compound 10d (2.3 g). [00285] 7-Bromo-5,8-difluoro-1-methyl-1,2,3,4-tetrahydrocyclopenta[b]indole 10e. To a mixture of compound 10d (500 mg, 1.6 mmol) in toluene (20 mL) was added FeBr₂ (34.5 mg, 0.16 mmol). The reaction was heated at 110 °C for 15 h in a sealed tube. The mixture was cooled to room temperature and filtered and the filtrate was concentrated. The residue was purified by silica gel flash column chromatography to yield compound 10e (340 mg). [00286] 2-(3,5-Dichloro-4-((5,8-difluoro-1-methyl-1,2,3,4-tetrahydrocyclopenta[b]indol- 7-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile A12. Compound A12 was prepared from compound 10e similarly as described in Example 4. LCMS m/z = 504.0 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 1.30 (d, J = 6.4 Hz, 3H), 1.96-2.06 (m, 1H), 2.64- 2.77 (m, 1H), 2.77-2.83 (m, 1H), 2.83-2.92 (m, 1H), 3.26-3.34 (m, 1H), 6.37-6.44 (m, 1H), 7.79 (s, 2H), 11.57 (s, 1H). Example 13 Preparation of 2-(3,5-dichloro-4-((4,4-dimethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-6- yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile A13

[00287] Compound A13 was prepared from 6-(2,6-dichloro-4-nitrophenoxy)-4,4- dimethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole 6c similarly as described in Example 2. LCMS m/z = 497.1 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 1.38 (s, 6H), 2.79 (s, 2H), 4.34 (s, 2H), 6.69 (d, J = 2.4 Hz, 1H), 6.80-6.86 (m, 1H), 7.38 (d, J = 8.8 Hz, 1H), 7.82 (s, 2H), 11.09 (s, 1H). Example 14 Preparation of 2-(3,5-dichloro-4-((1,1,4,4-tetramethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol- 6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile A14

[00288] Compound A14 was synthesized as shown in Scheme 11.

[00289] 6-((Tert-butyldimethylsilyl)oxy)-1,1,4,4-tetramethyl-2,3,4,9-tetrahydro-1H- pyrido[3,4-b]indole 11a. To a solution of 2-(5-((tert-butyldimethylsilyl)oxy)-1H-indol-3-yl)-2- methylpropan-1-amine 3b (200 mg, 0.629 mmol) in toluene (3 mL) were added Fe(OTf)₂ (2.2 mg, 0.00629 mmol) and acetone (0.05 mL, 0.629 mmol). After the reaction was stirred at 120 °C for 2 days in a sealed tube and cooled to room temperature, H₂O was added and the mixture was extracted with EtOAc (40 mL x 4). The combined organic extract was washed with NaCl, dried over anhydrous Na₂SO₄, and concentrated to yield compound 11a (960 mg). LCMS m/z = 359.2 [M+H]⁺. [00290] 6-(2,6-Dichloro-4-nitrophenoxy)-1,1,4,4-tetramethyl-2,3,4,9-tetrahydro-1H- pyrido[3,4-b]indole 11b. To a solution of compound 11a (200 mg, 0.558 mmol) in THF was added TBAF (2.23 mL, 1.0 M in THF). The mixture was stirred at room temperature for 1 h and concentrated. 1,3-Dichloro-2-fluoro-5-nitrobenzene (234 mg, 1.117 mmol) and K₂CO₃ (385 mg, 2.793 mmol) and in DMSO was then added. After the reaction was stirred at room temperature for 1 h, H₂O was added and the mixture was extracted with EtOAc (50 mL x 4). The combined organic extract was dried over anhydrous Na₂SO₄ and concentrated. The residue was purified by silica gel column chromatography to yield compound 11b (80 mg). LCMS m/z = 434.1 [M+H]⁺. [00291] Tert-butyl 6-(2,6-dichloro-4-nitrophenoxy)-1,1,4,4-tetramethyl-1,3,4,9- tetrahydro-2H-pyrido[3,4-b]indole-2-carboxylate 11c. To a solution of compound 11b (80 mg, 0.185 mmol) in THF (4 mL) were added Boc₂O (0.05 mL, 0.221 mmol), DMAP (2.7 mg, 0.0185 mmol), and TEA (0.07 mL, 0.555 mmol). After the reaction was stirred at room temperature overnight, H₂O was added and the mixture was extracted with EtOAc (50 mL x 4). The combined organic extract was dried over anhydrous Na₂SO₄ and concentrated. The residue was purified by silica gel column chromatography to yield compound 11c (30 mg). LCMS m/z = 534.1 [M+H]⁺. [00292] Tert-butyl 6-(2,6-dichloro-4-(6-cyano-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)- yl)phenoxy)-1,1,4,4-tetramethyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indole-2-carboxylate 11d. Compound 11d was prepared from compound 11c similarly as described in Example 2. LCMS m/z = 625.2 [M+H]⁺. [00293] 2-(3,5-Dichloro-4-((1,1,4,4-tetramethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol- 6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile A14. To a solution of compound 11d (40 mg, 0.064 mmol) in DCM (4 mL) was added TFA (0.5 mL). The reaction was stirred at room temperature for 2 h and H₂O was then added. After adjusted with aqueous NaHCO₃ to pH of 9 to 10, the mixture was extracted with EtOAc (30 mL x 4) and concentrated. The residue was purified by prep-HPLC to yield compound A14 (3 mg). LCMS m/z = 525.0 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 1.43 (s, 6H), 1.72 (s, 6H), 2.80 (s, 2H), 6.70 (d, J = 2.4 Hz, 1H), 6.82-6.88 (m, 1H), 7.36 (d, J = 8.8 Hz, 1H), 7.37 (d, J = 8.4 Hz, 1H), 7.82 (s, 2H), 11.30 (s, 1H). Example 15 Preparation of 2-(3,5-dichloro-4-((1,4,4-trimethyl-1-(trifluoromethyl)-2,3,4,9-tetrahydro-1H- pyrido[3,4-b]indol-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile A15

[00294] Compound A15 was prepared from 2-(5-(2,6-dichloro-4-nitrophenoxy)-1H-indol- 3-yl)-2-methylpropan-1-amine 3g and 1,1,1-trifluoroacetone similarly as described in Example 9 for compound A9. LCMS m/z = 579.1 [M-H]-; ¹H NMR (400 MHz, DMSO-d₆) δ 1.05 (s, 3H), 1.23 (s, 3H), 1.64 (s, 3H), 2.40-2.47 (m, 1H), 6.74-6.78 (m, 1H), 6.78 (s, 1H), 7.32-7.37 (m, 1H), 7.81 (s, 2H), 11.05 (s, 1H). Example 16 Preparation of 2-(3,5-dichloro-4-((5,8-difluoro-4,4-dimethyl-1,3,4,9-tetrahydropyrano[3,4- b]indol-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile A16

[00295] Compound A16 was synthesized as shown in Scheme 12.

[00296] 2,2-Dimethyl-3-oxobutyl 2,2,2-trifluoroacetate 12a. To a mixture of 3- methylbutan-2-one (300 g, 3.48 mol) in TFA (798 g, 7.0 mol) was added paraformaldehyde (125.5 g, 4.18 mol). After stirred at 90 °C for 12 h and cooled to room temperature, the mixture was neutralized and extracted with EtOAc three times. The combined organic extract was dried over anhydrous Na₂SO₄ and concentrated to yield compound 12a (420 g). [00297] 4-Hydroxy-3,3-dimethylbutan-2-one 12b. To a mixture of compound 12a (420 g, 1.98 mol) in MeOH (2.5 L) was added 2N NaOH (1.09 L, 2.18 mol) at 0 °C. After stirred at room temperature for 1 h, the mixture was concentrated and aqueous NH₄Cl was added. The mixture was extracted with EtOAc. The combined organic extract was washed with brine, dried over anhydrous Na₂SO₄, and concentrated. The residue was distilled at reduced pressure (90 °C, 50 mbar) to yield compound 12b (200 g). [00298] 3,3-Dimethyl-2,3-dihydro-4H-pyran-4-one 12c. To a mixture of triethyl orthoformate (254.9 g, 1.72 mol) in DCM was added 1M SnCl₄ (1.72L, 1.72 mol) dropwise at -40 °C, followed by the addition of a solution of compound 12b (100 g, 0.86 mol) in DCM (800 mL). After stirred at -20 to 0 °C for 2 h, the mixture was washed with NaHCO₃. The organic layer was dried over anhydrous Na₂SO₄ and concentrated to yield compound 12c (110 g). [00299] 3,3-Dimethyltetrahydro-4H-pyran-4-one 12d. To a solution of compound 12c (110 g, 0.87 mol) in EtOAc was added Pd/C (20 g). After stirred at room temperature under H₂ atmosphere for 12 h, the reaction mixture was filtered and the filtrate was concentrated. The residue was purified by silica gel flash column chromatography to yield compound 12d (47 g). [00300] 3,3-Dimethyl-3,6-dihydro-2H-pyran-4-yl trifluoromethanesulfonate 12e. A solution of 1 M KHMDS (171.6 mL, 0.171 mol) was added dropwise to a mixture of compound 12d (20 g, 0.156 mol) and N-(5-chloropyridin-2-yl)-1,1,1-trifluoro-N-((trifluoromethyl)sulfonyl)- methanesulfonamide (67.4 g, 0.171 mol) in THF (600 mL) at -78 °C under N₂ atmosphere. After the reaction was stirred at -78 °C for 1 h and at room temperature for 3 h, H₂O was added and the mixture was extracted three times with EtOAc. The combined organic extract was washed with brine, dried over anhydrous Na₂SO₄, and concentrated. The residue was purified by silica gel flash column chromatography to yield compound 12e (19 g). [00301] 2-(3,3-Dimethyl-3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2- dioxaborolane 12f. To a mixture of compound 12e (16 g, 61.48 mmol), 4,4,4',4',5,5,5',5'- octamethyl-2,2'-bi(1,3,2-dioxaborolane) (23.4 g, 92.22 mmol), PPh₃ (2.41 g, 9.2 mmol), and KOPh (12.19 mg, 92.2 mmol) in toluene (350 mL) was added Pd(PPh₃)Cl₂ (2.15 g, 3.07 mmol). After the reaction was heated at 60 °C under N₂ for 12 h and cooled to room temperature, H₂O was added and the mixture was extracted with EtOAc. The combined organic extract was washed with brine, dried over anhydrous Na₂SO₄, and concentrated. The residue was purified by silica gel flash column chromatography to yield compound 12f (6 g). [00302] 4-Bromo-2-(3,3-dimethyl-3,6-dihydro-2H-pyran-4-yl)-3,6-difluoroaniline 12g. To a mixture of compound 12f (5.0 g, 21 mmol), 4-bromo-3,6-difluoro-2-iodoaniline (10.52 g, 31.5 mmol), and K₃PO₄ (11.1 g, 52.5 mmol) in dioxane (450 mL) and H₂O (15 mL) was added Pd(dppf)Cl₂ ^.DCM (1.71 g, 2.1 mmol). After heated at 85 °C under N₂ for 12 h and cooled to room temperature, the mixture was diluted with H₂O and extracted with EtOAc. The combined organic extract was washed with brine, dried over anhydrous Na₂SO₄, and concentrated. The residue was purified by silica gel flash column chromatography to yield compound 12g (3.4 g). LCMS m/z = 317.8 [M+H]⁺. [00303] 4-(2-Azido-5-bromo-3,6-difluorophenyl)-3,3-dimethyl-3,6-dihydro-2H-pyran 12h. To a mixture of compound 12g (3.4 g, 10.68 mmol) in acetonitrile (60 mL) were added t- butyl nitrite (4.41 g, 42.75 mmol) and TMSN₃ (3.7 g, 32.06 mmol) at -10 °C. After stirred at 0 °C for 30 min, the reaction mixture was diluted with H₂O and extracted with EtOAc. The combined organic extract was washed with brine, dried over anhydrous Na₂SO₄, and concentrated. The residue was purified by silica gel flash column chromatography to yield compound 12h (1.7 g). [00304] 6-Bromo-5,8-difluoro-4,4-dimethyl-1,3,4,9-tetrahydropyrano[3,4-b]indole 12i. To a mixture of compound 12h (1.2 g, 3.49 mmol) in toluene (24 mL) was added Rh₂(esp)₂ (231 mg, 0.35 mmol). After heated at 110 °C for 12 h and cooled down to room temperature, the mixture was filtered and the filtrate was concentrated. The residue was purified by preparative HPLC to yield compound 12i (320 mg). LCMS m/z = 314.0 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 1.26 (s, 6H), 3.56 (s, 2H), 4.70 (s, 2H), 7.18-7.25 (m, 1H), 11.83 (s, 1H). [00305] 2-(3,5-Dichloro-4-((5,8-difluoro-4,4-dimethyl-1,3,4,9-tetrahydropyrano[3,4- b]indol-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile A16. Compound A16 was prepared from compound 12i similarly as described in Example 4. LCMS m/z = 534.0 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 1.30 (s, 6H), 3.59 (s, 2H), 4.70 (s, 2H), 6.46-6.52 (m, 1H), 7.81 (s, 2H), 11.59 (s, 1H). Example 17 Preparation of 2-(3,5-dichloro-4-((5,8-difluoro-1-methyl-3,4-dihydro-1H-furo[3,4-b]indol-7- yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile A17

[00306] 7-Bromo-5,8-difluoro-1-methyl-3,4-dihydro-1H-furo[3,4-b]indole. The compound was prepared from 2-methyldihydrofuran-3(2H)-one similarly as described in Example 16 for compound 12i. LCMS m/z = 285.8 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 1.46 (s, 3H), 4.88-4.96 (m, 1H), 4.97-5.05 (m, 1H), 5.32-5.45 (m, 1H), 7.22-7.28 (m, 1H), 12.12 (s, 1H). [00307] 2-(3,5-Dichloro-4-((5,8-difluoro-1-methyl-3,4-dihydro-1H-furo[3,4-b]indol-7- yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile A17. Compound A17 was prepared from 7-bromo-5,8-difluoro-1-methyl-3,4-dihydro-1H-furo[3,4-b]indole similarly as described in Example 1. LCMS m/z = 505.9 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 1.50 (d, J = 6.4 Hz, 3H), 1.56 (s, 9H), 5.00-5.07 (m, 1H), 5.10-5.17 (m, 1H), 5.41-5.47 (m, 1H), 6.72- 6.80 (m, 1H), 7.84 (s, 2H). Example 18 Preparation of 2-(3,5-dichloro-4-((1',9'-dihydro-3'H-spiro[cyclobutane-1,4'-pyrano[3,4-b]indol]- 6'-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile A19

[00308] Compound A19 was synthesized as shown in Scheme 13. [00309] Methyl 5-bromo-3-(1-(ethoxycarbonyl)cyclobutyl)-1H-indole-2-carboxylate 13a. A mixture of methyl 5-bromo-1H-indole-2-carboxylate (5 g, 19.76 mmol), ethyl 1- bromocyclobutane-1-carboxylate (12.04 g, 59.29 mmol), [RuCl₂(p-cymene)]₂ (1.21 g, 1.98 mmol), and KOAc (9.68 g, 98.81 mmol) in dioxane (50 mL) was heated under argon atmosphere at 130 °C overnight. After the mixture was cooled to 0 °C, H₂O (50 mL) was added. The mixture was extracted with EtOAc (30 mL x 5). The combined organic extract was dried over anhydrous Na₂SO₄ and concentrated. The residue was purified by silica gel flash column chromatography to yield compound 13a (5.6 g). LCMS m/z = 380.0 [M+H]⁺.

[00310] 6'-Bromo-1',9'-dihydro-3'H-spiro[cyclobutane-1,4'-pyrano[3,4-b]indole] 13b. Compound 13b was prepared from compound 13a similarly as described in Example 8 for compound 8d. LCMS m/z = 292.0 [M+H]⁺. [00311] 2-(3,5-Dichloro-4-((1',9'-dihydro-3'H-spiro[cyclobutane-1,4'-pyrano[3,4-b]indol]- 6'-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile A19. Compound A19 was prepared from compound 13b similarly as described in Example 4. LCMS m/z = 510.0 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 1.92-2.02 (m, 4H), 2.42-2.52 (m, 2H), 3.84 (s, 2H), 4.68 (s, 2H), 6.55-6.59 (m, 1H), 7.21-7.24 (m, 1H), 7.28 (d, J = 8.8 Hz, 1H), 7.83 (s, 2H), 8.15 (s, 1H), 10.83 (s, 1H). Example 19 Preparation of 2-(3,5-dichloro-4-((8-fluoro-4,5-dimethyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-6- yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile A22

[00312] Compound A22 was synthesized as shown in Scheme 14.

[00313] 4-Bromo-6-fluoro-2-iodo-3-methylaniline 14a. To a mixture of 4-bromo-2- fluoro-5-methylaniline (20.0 g, 147 mmol) in acetic acid (210 mL) were added N- iodosuccinimide (NIS) (36.4 g, 162 mmol) and TFA (2.1 mL). After stirred at room temperature for 4 h, the reaction mixture was poured into ice water and adjusted to pH of 8 to 9 with NH₃ ^.H₂O. The mixture was filtered, and the filter cake was washed with H₂O and dried to yield compound 14a (45 g). [00314] 5-Bromo-7-fluoro-4-methyl-1H-indole-2-carboxylic acid 14b. To a mixture of compound 14a (20 g, 0.06 mol), DABCO^.6H₂O (26.7 g, 0.12 mol), and pyruvic acid (53.4 g, 0.6 mol) in DMF (200 mL) was added Pd(OAc)₂ (1.4 g, 0.006 mol). After the reaction was heated at 100 °C overnight and cooled to room temperature, H₂O (500 mL) was added and the mixture was extracted with EtOAc (500 mL x 3). The combined organic extract was washed with H₂O and brine, dried over anhydrous Na₂SO₄, and concentrated. The residue was purified by silica gel column chromatography to yield compound 14b (16.0 g). [00315] 6-Bromo-8-fluoro-4,5-dimethyl-1,3,4,9-tetrahydropyrano[3,4-b]indole 14c. Compound 14 c was prepared from compound 14b similarly as described in Example 8 for compound 8d. ¹H NMR (400 MHz, DMSO-d₆) δ 1.30 (s, 3H), 2.57 (s, 3H), 3.10-3.20 (m, 1H), 3.70-3.80 (m, 1H), 3.82-3.86 (m, 1H), 4.66-4.81 (m, 2H), 7.12 (d, J = 10.2 Hz, 1H), 11.45 (s, 1H). [00316] 2-(3,5-Dichloro-4-((8-fluoro-4,5-dimethyl-1,3,4,9-tetrahydropyrano[3,4-b]indol- 6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile A22. Compound A22 was prepared from compound 14b similarly as described in Example 4. Example 20 Preparation of 6-(3,5-dichloro-4-((4,4-dimethyl-1-(trifluoromethyl)-2,3,4,9-tetrahydro-1H- pyrido[3,4-b]indol-6-yl)oxy)phenyl)-2-methyl-1,2,4-triazine-3,5(2H,4H)-dione B1

[00317] Compound B1 was synthesized as shown in Scheme 15. [00318] 6-Bromo-2-methyl-1,2,4-triazine-3,5(2H,4H)-dione 15a. To a mixture of 6- bromo-1,2,4-triazine-3,5(2H,4H)-dione (0.4 g, 2 mmol) in ACN (10 mL) was added bis(trimethylsilyl)acetamide (BSA) (1.06 g, 5.2 mmol). The mixture was stirred at 90 °C for 3 h and methyl iodide (0.45 g, 3.2 mmol) was added. After the reaction was stirred at 90 °C overnight and cooled to room temperature, H₂O (30 mL) was added and the mixture was extracted with EtOAc (30 mL x 3). The combined organic extract was washed with brine (20 mL), dried over anhydrous Na₂SO₄, and concentrated. The residue was purified by silica gel flash column chromatography to yield compound 15a (220 mg). LCMS m/z = 208.0 [M+H]⁺. [00319] 6-(4-Bromo-2,6-dichlorophenoxy)-4,4-dimethyl-1-(trifluoromethyl)-2,3,4,9- tetrahydro-1H-pyrido[3,4-b]indole 15b. To a mixture of t-butyl nitrite (0.17 g, 1.69 mmol) and CuBr₂ (0.38 g, 1.69 mmol) in ACN (10 mL) at 0 °C was added a solution of 3,5-dichloro-4- ((4,4-dimethyl-1-(trifluoromethyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-6-yl)oxy)aniline 9b (0.5 g, 1.13 mmol) in ACN (5 mL). After stirred at 0 °C for 30 min, the mixture was poured into ice water (30 mL) and extracted with EtOAc (20 mL x 4). The combined organic extract was washed with brine (15 mL), dried over anhydrous Na₂SO₄, and concentrated. The residue was purified by silica gel column chromatography to yield compound 15b (100 mg). LCMS m/z = 507.0 [M+H]⁺.

[00320] 6-(2,6-Dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)-4,4- dimethyl-1-(trifluoromethyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole 15c. To a mixture of compound 15b (100 mg, 0.26 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (79 mg, 0.31 mmol), and KOAc (69 mg, 0.78 mmol) in dioxane (15 mL) was added Pd(dppf)Cl₂ ^.DCM (11 mg, 0.013 mmol). After the reaction was heated at 80 °C under N₂ overnight and cooled to room temperature, H₂O (30 mL) was added and the mixture was extracted with EtOAc (20 mL x 5). The combined organic extract was washed with brine (20 mL), dried over anhydrous Na₂SO₄, and concentrated. The residue was purified by silica gel flash column chromatography to yield compound 15c (40 mg). LCMS m/z = 555.2 [M+H]⁺. [00321] 6-(3,5-Dichloro-4-((4,4-dimethyl-1-(trifluoromethyl)-2,3,4,9-tetrahydro-1H- pyrido[3,4-b]indol-6-yl)oxy)phenyl)-2-methyl-1,2,4-triazine-3,5(2H,4H)-dione B1. To a mixture of compound 15a (22 mg, 0.11 mmol), compound 15c (40 mg, 0.07 mmol), and K₂CO₃ (30 mg, 0.22 mmol) in dioxane (15 mL) and H₂O (5 mL) was added Pd(dppf)Cl₂ (5 mg, 0.007 mmol). After the reaction was heated at 80 °C for 2 h and cooled to room temperature, H₂O (30 mL) was added and the mixture was extracted with EtOAc (30 mL x 3). The combined organic extract was washed with brine (20 mL), dried over anhydrous Na₂SO₄, and concentrated. The residue was purified by preparative HPLC to yield compound B1 (20 mg). LCMS m/z = 554.1 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 1.03 (s, 3H), 1.24 (s, 3H), 2.45 (s, 2H), 3.60 (s, 3H), 4.68-4.74 (m, 1H), 6.70 (d, J = 2.4 Hz, 1H), 6.75-6.81 (m, 1H), 7.37 (d, J = 8.4 Hz, 1H), 8.16 (s, 2H), 10.79 (s, 1H). Example 21 Preparation of N-(3,5-dichloro-4-((4,4-dimethyl-1-(trifluoromethyl)-2,3,4,9-tetrahydro-1H- pyrido[3,4-b]indol-6-yl)oxy)phenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxamide C1

[00322] Compound C1 was synthesized as shown in Scheme 16. [00323] Ethyl 5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxylate 16a. To a mixture of ethyl 2-amino-2-(hydroxyimino)acetate (3 g, 22.7 mmol) in dioxane (15 mL) were added DBU (4.5 g, 29.5 mmol) and CDI (4.8 g, 29.5 mmol). The reaction was heated at 100 °C for 2 h. The mixture was cooled to room temperature, poured into ice H₂O (50 mL), and extracted with EtOAc (40 mL x 5). The combined organic extract was washed with brine (15 mL), dried over anhydrous Na₂SO₄, and concentrated. The residue was purified by silica gel column chromatography to yield compound 16a (960 mg). LCMS m/z = 159.0 [M+H]⁺. Scheme 16

[00324] 5-Oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxylic acid 16b. To a mixture of compound 16a (1.58 g, 10 mmol) in MeOH (15 mL) was added NaOH (1.6 g, 40 mmol) in H₂O (16 mL). The reaction was stirred at room temperature overnight. The mixture was concentrated and adjusted with 1N HCl solution to pH of 2 to 3. The mixture was filtered and the filter cake was dried to yield compound 16b (1 g). LCMS m/z = 131.0 [M+H]⁺. [00325] N-(3,5-Dichloro-4-((4,4-dimethyl-1-(trifluoromethyl)-2,3,4,9-tetrahydro-1H- pyrido[3,4-b]indol-6-yl)oxy)phenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxamide C1. To a mixture of compound 16b in DCM (10 mL) at 0 °C was added oxalyl dichloride (342 mg, 2.7 mmol). The mixture was stirred at 0 °C for 30 min and concentrated, and residue was dissolved in DCM (10 mL). The solution was added to a mixture of 3,5-dichloro-4-((4,4-dimethyl-1- (trifluoromethyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-6-yl)oxy)aniline 9b (40 mg, 0.09 mmol) and DIPEA (35 mg, 0.27 mmol) in DCM (10 mL) at 0 °C. After the reaction was stirred at 0 °C for 30 min, H₂O (30 mL) was added and the mixture was extracted with EtOAc (30 mL x 3). The combined organic extract was washed with brine (20 mL), dried over anhydrous Na₂SO₄, and concentrated. The residue was purified by preparative HPLC to yield compound C1 (5 mg). LCMS m/z = 556.1 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 1.33 (s, 3H), 1.25 (s, 3H), 2.48 (s, 2H), 4.72-4.78 (m, 1H), 6.73-6.78 (m, 1H), 7.35 (d, J = 8.8 Hz, 1H), 8.07 (s, 2H), 10.76 (s, 1H), 11.07 (s, 1H). [00326] The following compounds were prepared similarly according to the synthetic procedures or methodologies exemplified herein. [00327] 2-(3,5-Dichloro-4-((7,8-difluoro-4,4-dimethyl-1,3,4,9-tetrahydropyrano[3,4-b]- indol-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile A20. LCMS m/z = 533.8 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 1.12 (s, 6H), 3.46 (s, 2H), 4.67 (s, 2H), 6.54 (d, J = 6.4 Hz, 1H), 7.85 (s, 2H), 11.53 (s, 1H). [00328] 2-(3,5-Dichloro-4-((5,5-dimethyl-5,6,8,9-tetrahydropyrano[4',3':4,5]pyrrolo[2,3- b]pyridin-3-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile A25. LCMS m/z = 499.0 [M+H]⁺; ¹H NMR (400 MHz, CD3OD) δ 1.30 (s, 6H), 3.60 (s, 2H), 4.76 (s, 2H), 7.43 (d, J = 2.8 Hz, 1H), 7.79 (d, J = 2.8 Hz, 1H), 7.81 (s, 2H).

[00329] 6-Amino-2-(3,5-dichloro-4-((4,4-dimethyl-1,3,4,9-tetrahydropyrano[3,4-b]indol- 6-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione A29. LCMS m/z = 487.9 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 1.22 (s, 6H), 3.50 (s, 2H), 4.68 (s, 2H), 6.51-6.66 (m, 1H), 6.94 (d, J = 2.4 Hz, 1H), 7.24 (d, J = 8.8 Hz, 1H), 7.89 (s, 2H), 10.75 (s, 1H), 12.27 (s, 1H). [00330] 2-(3,5-Dichloro-4-((5,8-difluoro-4,4-dimethyl-1,3,4,9-tetrahydropyrano[3,4-b]- indol-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile A34. LCMS m/z = 534.0 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 1.30 (s, 6H), 3.59 (s, 2H), 4.70 (s, 2H), 6.49 (q, J = 5.2 Hz, 1H), 7.81 (s, 2H), 11.59 (s, 1H).

[00331] 2-(3,5-Dichloro-4-((4,4-dimethyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-6-yl)oxy)- phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxamide A35. LCMS m/z = 515.8 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 1.24 (s, 6H), 3.50 (s, 2H), 4.69 (s, 2H), 6.49-6.55 (m, 1H), 7.02 (d, J = 2.0 Hz, 1H), 7.24 (d, J = 8.8 Hz, 1H), 7.87 (s, 2H), 7.94 (s, 1H), 8.13 (s, 1H), 10.77 (s, 1H), 12.78 (s, 1H). [00332] 2-(3,5-Dichloro-4-((5,8-difluoro-1,1,4,4-tetramethyl-1,3,4,9-tetrahydro- pyrano[3,4-b]indol-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile A36. LCMS m/z = 561.8 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 1.29 (s, 6H), 1.51 (s, 6H), 3.57 (s, 2H), 4.70 (s, 2H), 6.46 (q, J = 5.6 Hz, 1H), 7.81 (s, 2H), 11.55 (s, 1H).

[00333] 2-(4-((4,4-Dimethyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-6-yl)oxy)-3,5-difluoro- phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile A37. LCMS m/z = 466.0 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 1.25 (s, 6H), 3.51 (s, 2H), 4.69 (s, 2H), 6.66-6.71 (m, 1H), 7.15-7.18 (m, 1H), 7.26 (d, J = 8.8 Hz, 1H), 7.51 (d, J = 8.8 Hz, 1H), 10.81 (s, 1H). [00334] 6-(2,6-Dichloro-4-(6-cyano-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)- phenoxy)-8-fluoro-4,4-dimethyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-5-carbonitrile A38. LCMS m/z = 540.7 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 1.47 (s, 6H), 3.58 (s, 2H), 4.76 (s, 2H), 6.52 (d, J = 10.8 Hz, 1H), 7.86 (s, 2H), 12.10 (s, 1H).

[00335] 2-(3,5-Dichloro-4-((4,4-dimethyl-1-(2,2,2-trifluoroethyl)-1,3,4,9-tetrahydro- pyrano[3,4-b]indol-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile A39. LCMS m/z = 579.0 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 1.14 (s, 3H), 1.42 (s, 3H), 2.54-2.71 (m, 3H), 3.15-3.24 (m, 1H), 4.52-4.64 (m, 1H), 6.68 (d, J = 2.4 Hz, 1H), 6.79 (d, J = 8.0 Hz, 1H), 7.33 (d, J = 8.8 Hz, 1H), 10.98 (s, 1H). [00336] 2-(4-((7,8-Difluoro-4,4-dimethyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-6-yl)oxy)- 3,5-difluorophenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile A40. LCMS m/z = 501.9 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 1.12 (s, 6H), 3.49 (s, 2H), 4.68 (s, 2H), 7.08 (d, J = 6.4 Hz, 1H), 7.52 (d, J = 9.2 Hz, 1H), 11.55 (s, 1

[00337] 2-(3,5-Dichloro-4-((1-(difluoromethyl)-4,4-dimethyl-1,3,4,9-tetrahydro- pyrano[3,4-b]indol-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile A41. LCMS m/z = 547.0 [M+H]⁺; ¹H NMR (400 MHz, CD₃OD) δ 1.20 (s, 3H), 1.45 (s, 3H), 2.61-2.76 (m, 1H), 4.61-4.69 (m, 2H), 5.97-6.28 (m, 1H), 6.74 (d, J = 2.4 Hz, 1H), 6.84-6.88 (m, 1H), 7.36 (d, J = 8.4 Hz, 1H), 7.77 (s, 1H). [00338] 2-(3,5-Dichloro-4-((1-(fluoromethyl)-4,4-dimethyl-1,3,4,9-tetrahydropyrano[3,4- b]indol-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile A42. LCMS m/z = 528.8 [M+H]⁺; ¹H NMR (400 MHz, CD3OD) δ 1.23 (s, 3H), 1.47 (s, 3H), 2.74 (s, 2H), 4.90-5.15 (m, 3H), 6.70 (d, J = 2.8 Hz, 1H), 6.82-6.87 (m, 1H), 7.38 (d, J = 8.8 Hz, 1H), 11.25 (s, 1H).

[00339] 2-(3,5-Dichloro-4-((5,5,8,8-tetramethyl-5,6,8,9-tetrahydropyrano[4',3':4,5]- pyrrolo[2,3-b]pyridin-3-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile A43. LCMS m/z = 526.9 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 1.23 (s, 6H), 1.48 (s, 6H), 3.51 (s, 2H), 7.09 (s, 1H), 7.46 (d, J = 2.8 Hz, 1H), 7.74 (d, J = 2.8 Hz, 1H), 7.84 (s, 2H), 11.54 (s, 1H). [00340] N-(3,5-Dichloro-4-((5-cyano-4,4-dimethyl-1,3,4,9-tetrahydropyrano[3,4-b]indol- 6-yl)oxy)phenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxamide C2. LCMS m/z = 514.1 [M+H]⁺; ¹H NMR (400 MHz, CD3OD) δ 1.56 (s, 6H), 3.65 (s, 2H), 4.80 (s, 2H), 6.36 (d, J = 9.2 Hz, 1H), 7.47 (d, J = 9.2 Hz, 1H), 8.00 (s, 2H).

[00341] The following compounds were prepared similarly according to the synthetic procedures or methodologies exemplified herein. [00342] 2-(3,5-Dichloro-4-((5,5-dimethyl-8-(trifluoromethyl)-6,7,8,9-tetrahydro-5H- pyrrolo[2,3-b:5,4-c']dipyridin-3-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6- carbonitrile A18. [00343] 2-(3,5-Dichloro-4-((7,8-difluoro-4,4-dimethyl-1,3,4,9-tetrahydropyrano[3,4- b]indol-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile A20.

[00344] 2-(3,5-Dichloro-4-((1,1-dimethyl-1,4,5,6-tetrahydro-2H-oxepino[4,5-b]indol-9- yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile A21. [00345] 2-(3,5-Dichloro-4-((1-(hydroxymethyl)-4,4-dimethyl-1,3,4,9-tetrahydro- pyrano[3,4-b]indol-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile A23.

[00346] 2-(3,5-Dichloro-4-((1-(2-hydroxyethyl)-4,4-dimethyl-1,3,4,9-tetrahydro- pyrano[3,4-b]indol-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile A24. [00347] 6-(2,6-Dichloro-4-(6-cyano-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)- phenoxy)-4,4-dimethyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-5-carbonitrile A26.

[00348] 2-(3,5-Dichloro-4-((5-(difluoromethyl)-8-fluoro-4,4-dimethyl-1,3,4,9-tetrahydro- pyrano[3,4-b]indol-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile A27. [00349] 2-(3-Chloro-4-((4,4-dimethyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-6-yl)methyl)- 5-(trifluoromethyl)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile A28.

[00350] 2-(3,5-Dichloro-4-((8-fluoro-4,4-dimethyl-5-(trifluoromethyl)-1,3,4,9-tetrahydro- pyrano[3,4-b]indol-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile A30. [00351] 2-(3,5-Dichloro-4-((3,3-difluoro-1',9'-dihydro-3'H-spiro[cyclobutane-1,4'- pyrano[3,4-b]indol]-6'-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile A31.

[00352] 6'-(2,6-Dichloro-4-(6-cyano-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)- phenoxy)-1',9'-dihydro-3'H-spiro[cyclobutane-1,4'-pyrano[3,4-b]indole]-3-carbonitrile A32. [00353] 2-(3,5-Dichloro-4-((3-hydroxy-1',9'-dihydro-3'H-spiro[cyclobutane-1,4'- pyrano[3,4-b]indol]-6'-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile A33.

Example B1 Time-resolved Fluorescence Resonance Energy Transfer (TR-FRET) Thyroid Hormone Receptor Coregulator Peptide Recruitment Assay [00354] For an exemplary compound, LANTHASCREEN™ TR-FRET coregulator recruitment assay was performed to determine its agonist EC₅₀ by investigating the conformational changes of the TRα and TRβ ligand binding domains that resulted in the recruitment of a fluorescein-labeled coregulator peptide upon ligand binding. Complete TR- FRET Coregulator Buffer C was prepared by adding 1 M DTT to TR-FRET Coregulator Buffer C for a final concentration of 5 mM DTT. For the “0% activation” controls, DMSO was added to Complete TR-FRET Coregulator Buffer C for a final concentration of 2% DMSO. The exemplary compound and T3 as a control compound were prepared at 100X of the final desired maximum starting concentrations using DMSO. The “100% activation” control was prepared by diluting 100X of the final starting concentration of T3 to 2X working concentration using Complete TR-FRET Coregulator Buffer C. 10-point titrations of 100X dilution series of the exemplary compound and T3 were prepared in a 96-well plate by serially diluting the 100X solutions three-fold using DMSO. The 100X dilution series were then further diluted to a 4X dilution series using Complete TR-FRET Coregulator Buffer C. A 2X working solution of TRβ- LBD and Tb anti-GST antibody mixture was prepared by adding stock solutions of TRβ -LBD, GST, and anti-GST antibody to an appropriate amount of cold Complete TR-FRET Coregulator Buffer C. A solution of 0.4 µM fluorescein-SRC2-2 (4X) was prepare from 100 µM fluorescein- SRC2-2 peptide (Sequence: LKEKHKILHRLLQDSSSPV) in 50 mM HEPES buffer using Complete TR-FRET Coregulator Buffer C at room temperature. To duplicate columns of a 384- well assay plate were added 4 µL each of the 4X agonist serial dilutions and controls. Each of the wells were then added 8 µL of 2X TRβ-LBD/antibody and 4 µL of 4X Coregulator peptide solution. The 384-well plate was gently mixed on a plate shaker and incubated at room temperature in dark. After 2-h incubation, the TR-FRET signal was measured on an ENVISION™ plate reader with excitation at 340 nm and dual emission readout at 495 and 520 nm with the delay time of 100 microsecond and the integration time of 200 microsecond. The TR-FRET ratio was calculated by dividing the fluorescein emission signal at 520 nm by the terbium emission signal at 495 nm. A binding curve was generated by plotting the emission ratio vs. the log [Compound Concentration] to give EC₅₀ using an equation for a sigmoidal dose response. In every batch of a compound screening, T3 (L-3,3’,5-triiodothyronine sodium salt) was used as a reference compound. The results are summarized in Table 1, where “A” represents an EC₅₀ value of less than 20 nM, “B” represents an EC₅₀ value of no less than 20 nM and less than 100 nM, “C” represents an EC₅₀ value of no less than 100 nM and less than 1 µM, and “D” represents an EC₅₀ value of no less than 1 µM; and where “A’” represents a TRβ selectivity value of no less than 40, “B’” represents a TRβ selectivity value of less than 40 and no less than 20, “C’” represents a TRβ selectivity value of less than 20 and no less than 10, and “D’” represents a TRβ selectivity value of on less than 10. Table 1. TR Agonistic Activity (EC₅₀)

Example B2 Cell Reporter Assay [00355] The functional human thyroid hormone receptor beta activity assay was performed using INDIGO's reporter cells having a luciferase reporter gene functionally linked to a TRβ responsive promoter. After a rapid thaw of the reporter cells with a cell recovery medium pre-warmed and equilibrated at 37 °C, 200 µL of a reporter cell suspension is dispensed into wells of an assay plate and pre-incubated (37 °C, ≥ 70% humidity, 5% CO2) for 4-6 h. The culture media were then discarded and 200 µL/well 1x-concentration of 10-point, 3-fold dilution of the control and exemplary compounds in compound screen media were added. The assay plate was incubated 22- 24 h. After the incubation, the treatment media were discarded, and 100 µL luciferase detection reagent (prepared from luciferase detection substrate and detection buffer) was added. The intensity of light emission from each assay well is quantified using a plate-reading luminometer. All EC₅₀ determination was performed using 10-point titrations, 3- fold dilution series of the compounds. The results are summarized in Table 2, where “A” represents an EC₅₀ value of less than 5 µM, “B” represents an EC₅₀ value of no less than 5 µM and less than 20 µM, “C” represents an EC₅₀ value of no less than 20 µM and less than 50 µM, and “D” represents an EC₅₀ value of no less than 50 µM. Table 2. TRβ Agonistic Activity

* * * * * [00356] The examples set forth above are provided to give those of ordinary skill in the art with a complete disclosure and description of how to make and use the claimed embodiments and are not intended to limit the scope of what is disclosed herein. Modifications that are obvious to persons of skill in the art are intended to be within the scope of the following claims. All publications, patents, and patent applications cited in this specification are incorporated herein by reference as if each such publication, patent or patent application were specifically and individually indicated to be incorporated herein by reference.

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: R¹, R², R⁴, and R⁵ are each independently (i) hydrogen, deuterium, cyano, halo, or nitro; (ii) C_1-6 alkyl, C_1-6 heteroalkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_3-10 cycloalkyl, C_6-14 aryl, C_7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) –C(O)R^1a, –C(O)OR^1a, –C(O)NR^1bR^1c, –C(O)SR^1a, –C(NR^1a)NR^1bR^1c, –C(S)R^1a, –C(S)OR^1a, –C(S)NR^1bR^1c, –OR^1a, –OC(O)R^1a, –OC(O)OR^1a, –OC(O)NR^1bR^1c, –OC(O)SR^1a, –OC(NR^1a)NR^1bR^1c, –OC(S)R^1a, –OC(S)OR^1a, –OC(S)NR^1bR^1c, –OS(O)R^1a, –OS(O)₂R^1a, –OS(O)NR^1bR^1c, –OS(O)₂NR^1bR^1c, –NR^1bR^1c, –NR^1aC(O)R^1d, –NR^1aC(O)OR^1d, –NR^1aC(O)NR^1bR^1c, –NR^1aC(O)SR^1d, –NR^1aC(NR^1d)NR^1bR^1c, –NR^1aC(S)R^1d, –NR^1aC(S)OR^1d, –NR^1aC(S)NR^1bR^1c, –NR^1aS(O)R^1d, –NR^1aS(O)₂R^1d, –NR^1aS(O)NR^1bR^1c, –NR^1aS(O)₂NR^1bR^1c, –SR^1a, –S(O)R^1a, –S(O)₂R^1a, –S(O)NR^1bR^1c, or –S(O)₂NR^1bR^1c; R³ is heteroaryl; R⁶ is (i) hydrogen; (ii) C_1-6 alkyl, C_1-6 heteroalkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_3-10 cycloalkyl, C_6-14 aryl, C_7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) –C(O)R^1a, –C(O)OR^1a, –C(O)NR^1bR^1c, –C(O)SR^1a, –C(NR^1a)NR^1bR^1c, –C(S)R^1a, –C(S)OR^1a, –C(S)NR^1bR^1c, –OR^1a, –OC(O)R^1a, –OC(O)OR^1a, –OC(O)NR^1bR^1c, –OC(O)SR^1a, –OC(NR^1a)NR^1bR^1c, –OC(S)R^1a, –OC(S)OR^1a, –OC(S)NR^1bR^1c, –OS(O)R^1a, –OS(O)₂R^1a, –OS(O)NR^1bR^1c, –OS(O)₂NR^1bR^1c, –NR^1bR^1c, –NR^1aC(O)R^1d, –NR^1aC(O)OR^1d, –NR^1aC(O)NR^1bR^1c, –NR^1aC(O)SR^1d, –NR^1aC(NR^1d)NR^1bR^1c, –NR^1aC(S)R^1d, –NR^1aC(S)OR^1d, –NR^1aC(S)NR^1bR^1c, –NR^1aS(O)R^1d, –NR^1aS(O)₂R^1d, –NR^1aS(O)NR^1bR^1c, –NR^1aS(O)₂NR^1bR^1c, –S(O)R^1a, –S(O)₂R^1a, –S(O)NR^1bR^1c, or –S(O)₂NR^1bR^1c; R^7a and R^7b are each independently (i) hydrogen, deuterium, cyano, halo, or nitro; (ii) C_1-6 alkyl, C_1-6 heteroalkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_3-10 cycloalkyl, C_6-14 aryl, C_7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) –C(O)R^1a, –C(O)OR^1a, –C(O)NR^1bR^1c, –C(O)SR^1a, –C(NR^1a)NR^1bR^1c, –C(S)R^1a, –C(S)OR^1a, –C(S)NR^1bR^1c, –OR^1a, –OC(O)R^1a, –OC(O)OR^1a, –OC(O)NR^1bR^1c, –OC(O)SR^1a, –OC(NR^1a)NR^1bR^1c, –OC(S)R^1a, –OC(S)OR^1a, –OC(S)NR^1bR^1c, –OS(O)R^1a, –OS(O)₂R^1a, –OS(O)NR^1bR^1c, –OS(O)₂NR^1bR^1c, –NR^1bR^1c, –NR^1aC(O)R^1d, –NR^1aC(O)OR^1d, –NR^1aC(O)NR^1bR^1c, –NR^1aC(O)SR^1d, –NR^1aC(NR^1d)NR^1bR^1c, –NR^1aC(S)R^1d, –NR^1aC(S)OR^1d, –NR^1aC(S)NR^1bR^1c, –NR^1aS(O)R^1d, –NR^1aS(O)₂R^1d, –NR^1aS(O)NR^1bR^1c, –NR^1aS(O)₂NR^1bR^1c, –SR^1a, –S(O)R^1a, –S(O)₂R^1a, –S(O)NR^1bR^1c, or –S(O)₂NR^1bR^1c; or R^7a and R^7b together with the carbon atom to which they are attached form C(O), C_3-10 cycloalkylene, or heterocyclylene; R^8a and R^8b are each independently (i) hydrogen, deuterium, cyano, halo, or nitro; (ii) C_1-6 alkyl, C_1-6 heteroalkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_3-10 cycloalkyl, C_6-14 aryl, C_7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) –C(O)R^1a, –C(O)OR^1a, –C(O)NR^1bR^1c, –C(O)SR^1a, –C(NR^1a)NR^1bR^1c, –C(S)R^1a, –C(S)OR^1a, –C(S)NR^1bR^1c, –OR^1a, –OC(O)R^1a, –OC(O)OR^1a, –OC(O)NR^1bR^1c, –OC(O)SR^1a, –OC(NR^1a)NR^1bR^1c, –OC(S)R^1a, –OC(S)OR^1a, –OC(S)NR^1bR^1c, –OS(O)R^1a, –OS(O)₂R^1a, –OS(O)NR^1bR^1c, –OS(O)₂NR^1bR^1c, –NR^1bR^1c, –NR^1aC(O)R^1d, –NR^1aC(O)OR^1d, –NR^1aC(O)NR^1bR^1c, –NR^1aC(O)SR^1d, –NR^1aC(NR^1d)NR^1bR^1c, –NR^1aC(S)R^1d, –NR^1aC(S)OR^1d, –NR^1aC(S)NR^1bR^1c, –NR^1aS(O)R^1d, –NR^1aS(O)₂R^1d, –NR^1aS(O)NR^1bR^1c, –NR^1aS(O)₂NR^1bR^1c, –SR^1a, –S(O)R^1a, –S(O)₂R^1a, –S(O)NR^1bR^1c, or –S(O)₂NR^1bR^1c; or R^8a and R^8b together with the carbon atom to which they are attached form C(O), C_3-10 cycloalkylene, or heterocyclylene; A is –O–, –S–, –NR^A1–, or –C(R^A2R^A3)–; L is a bond, –O–, –S–, –NR^1a–, or –C(O)N(R^1a)–; U, V, and W are each independently CR^U or N; X and Y are each independently a bond, –O–, –S–, –NR^X1–, or –C(R^X2R^X3)–; Z is –O–, –S–, –NR^Z1–, or –C(R^Z2R^Z3)–; each R^A1, R^X1 and R^Z1 is independently (i) hydrogen; (ii) C_1-6 alkyl, C_1-6 heteroalkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_3-10 cycloalkyl, C_6-14 aryl, C_7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) –C(O)R^1a, –C(O)OR^1a, –C(O)NR^1bR^1c, –C(O)SR^1a, –C(NR^1a)NR^1bR^1c, –C(S)R^1a, –C(S)OR^1a, –C(S)NR^1bR^1c, –OR^1a, –OC(O)R^1a, –OC(O)OR^1a, –OC(O)NR^1bR^1c, –OC(O)SR^1a, –OC(NR^1a)NR^1bR^1c, –OC(S)R^1a, –OC(S)OR^1a, –OC(S)NR^1bR^1c, –OS(O)R^1a, –OS(O)₂R^1a, –OS(O)NR^1bR^1c, –OS(O)₂NR^1bR^1c, –NR^1bR^1c, –NR^1aC(O)R^1d, –NR^1aC(O)OR^1d, –NR^1aC(O)NR^1bR^1c, –NR^1aC(O)SR^1d, –NR^1aC(NR^1d)NR^1bR^1c, –NR^1aC(S)R^1d, –NR^1aC(S)OR^1d, –NR^1aC(S)NR^1bR^1c, –NR^1aS(O)R^1d, –NR^1aS(O)₂R^1d, –NR^1aS(O)NR^1bR^1c, –NR^1aS(O)₂NR^1bR^1c, –S(O)R^1a, –S(O)₂R^1a, –S(O)NR^1bR^1c, or –S(O)₂NR^1bR^1c; each R^A2, R^A3, R^U, R^X2, R^X3, R^Z2, and R^Z3 is independently (i) hydrogen, deuterium, cyano, halo, or nitro; (ii) C_1-6 alkyl, C_1-6 heteroalkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_3-10 cycloalkyl, C_6-14 aryl, C_7-15 aralkyl, heteroaryl, or heterocyclyl; (iii) –C(O)R^1a, –C(O)OR^1a, –C(O)NR^1bR^1c, –C(O)SR^1a, –C(NR^1a)NR^1bR^1c, –C(S)R^1a, –C(S)OR^1a, –C(S)NR^1bR^1c, –OR^1a, –OC(O)R^1a, –OC(O)OR^1a, –OC(O)NR^1bR^1c, –OC(O)SR^1a, –OC(NR^1a)NR^1bR^1c, –OC(S)R^1a, –OC(S)OR^1a, –OC(S)NR^1bR^1c, –OS(O)R^1a, –OS(O)₂R^1a, –OS(O)NR^1bR^1c, –OS(O)₂NR^1bR^1c, –NR^1bR^1c, –NR^1aC(O)R^1d, –NR^1aC(O)OR^1d, –NR^1aC(O)NR^1bR^1c, –NR^1aC(O)SR^1d, –NR^1aC(NR^1d)NR^1bR^1c, –NR^1aC(S)R^1d, –NR^1aC(S)OR^1d, –NR^1aC(S)NR^1bR^1c, –NR^1aS(O)R^1d, –NR^1aS(O)₂R^1d, –NR^1aS(O)NR^1bR^1c, –NR^1aS(O)₂NR^1bR^1c, –SR^1a, –S(O)R^1a, –S(O)₂R^1a, –S(O)NR^1bR^1c, or –S(O)₂NR^1bR^1c; or R^A2 and R^A3 together with the C atom to which they are attached form C_3-10 cycloalkylene or heterocyclylene; or R^X2 and R^X3 together with the C atom to which they are attached form C_3-10 cycloalkylene or heterocyclylene; or R^Z2 and R^Z3 together with the C atom to which they are attached form C_3-10 cycloalkylene or heterocyclylene; and each R^1a, R^1b, R^1c, and R^1d is independently hydrogen, deuterium, C_1-6 alkyl, C_1-6 heteroalkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_3-10 cycloalkyl, C_6-14 aryl, C_7-15 aralkyl, heteroaryl, or heterocyclyl; wherein each alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylene, aryl, aralkyl, heteroaryl, 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) C_1-6 alkyl, C_1-6 heteroalkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_3-10 cycloalkyl, C_6-14 aryl, C_7-15 aralkyl, heteroaryl, and heterocyclyl, each of which is further optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Q^a; and (c) –C(O)R^a, –C(O)OR^a, –C(O)NR^bR^c, –C(O)SR^a, –C(NR^a)NR^bR^c, –C(S)R^a, –C(S)OR^a, –C(S)NR^bR^c, –OR^a, –OC(O)R^a, –OC(O)OR^a, –OC(O)NR^bR^c, –OC(O)SR^a, –OC(NR^a)NR^bR^c, –OC(S)R^a, –OC(S)OR^a, –OC(S)NR^bR^c, –OP(O)(OR^b)OR^c, –OS(O)R^a, –OS(O)₂R^a, –OS(O)NR^bR^c, –OS(O)₂NR^bR^c, –NR^bR^c, –NR^aC(O)R^d, –NR^aC(O)OR^d, –NR^aC(O)NR^bR^c, –NR^aC(O)SR^d, –NR^aC(NR^d)NR^bR^c, –NR^aC(S)R^d, –NR^aC(S)OR^d, –NR^aC(S)NR^bR^c, –NR^aS(O)R^d, –NR^aS(O)₂R^d, –NR^aS(O)NR^bR^c, –NR^aS(O)₂NR^bR^c, –SR^a, –S(O)R^a, –S(O)₂R^a, –S(O)NR^bR^c, and –S(O)₂NR^bR^c, wherein each R^a, R^b, R^c, and R^d is independently (i) hydrogen or deuterium; (ii) C_1-6 alkyl, C_1-6 heteroalkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_3-10 cycloalkyl, C_6-14 aryl, C_7-15 aralkyl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Q^a; or (iii) R^b and R^c together 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 Q^a; wherein each Q^a is independently selected from: (a) deuterium, cyano, halo, nitro, imino, and oxo; (b) C_1-6 alkyl, C_1-6 heteroalkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_3-10 cycloalkyl, C_6-14 aryl, C_7-15 aralkyl, heteroaryl, and heterocyclyl; and (c) –C(O)R^e, –C(O)OR^e, –C(O)NR^fR^g, –C(O)SR^e, –C(NR^e)NR^fR^g, –C(S)R^e, –C(S)OR^e, –C(S)NR^fR^g, –OR^e, –OC(O)R^e, –OC(O)OR^e, –OC(O)NR^fR^g, –OC(O)SR^e, –OC(NR^e)NR^fR^g, –OC(S)R^e, –OC(S)OR^e, –OC(S)NR^fR^g, –OP(O)(OR^f)OR^g, –OS(O)R^e, –OS(O)₂R^e, –OS(O)NR^fR^g, –OS(O)₂NR^fR^g, –NR^fR^g, –NR^eC(O)R^h, –NR^eC(O)OR^f, –NR^eC(O)NR^fR^g, –NR^eC(O)SR^f, –NR^eC(NR^h)NR^fR^g, –NR^eC(S)R^h, –NR^eC(S)OR^f, –NR^eC(S)NR^fR^g, –NR^eS(O)R^h, –NR^eS(O)₂R^h, –NR^eS(O)NR^fR^g, –NR^eS(O)₂NR^fR^g, –SR^e, –S(O)R^e, –S(O)₂R^e, –S(O)NR^fR^g, and –S(O)₂NR^fR^g; wherein each R^e, R^f, R^g, and R^h is independently (i) hydrogen or deuterium; (ii) C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_3-10 cycloalkyl, C_6-14 aryl, C_7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) R^f and R^g together with the N atom to which they are attached form heterocyclyl.

2. The compound of claim 1, wherein R³ is monocyclic heteroaryl, optionally substituted with one or more substituents Q.

3. The compound of claim 1 or 2, wherein R³ is 5- or 6-membered heteroaryl, each optionally substituted with one or more substituents Q.

4. The compound of any one of claims 1 to 3, wherein R³ is oxadiazolyl or triazinyl, each optionally substituted with one or more substituents Q.

5. The compound of any one of claims 1 to 4, wherein R³ is 1,2,4-oxadiazolyl or 1,2,4-triazinyl, each optionally substituted with one or more substituents Q.

6. The compound of any one of claims 1 to 5, wherein R³ is 1,2,4-oxadiazol-3-yl, 1,2,4-triazin-2-yl, or 1,2,4-triazin-6-yl, each optionally substituted with one or more substituents Q.

7. The compound of any one of claims 1 to 6, wherein the compound 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 R^3a is (i) hydrogen, deuterium, cyano, halo, or nitro; (ii) C_1-6 alkyl, C_1-6 heteroalkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_3-10 cycloalkyl, C_6-14 aryl, C_7-15 aralkyl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one or more substituents Q; or (iii) –C(O)R^1a, –C(O)OR^1a, –C(O)NR^1bR^1c, –C(O)SR^1a, –C(NR^1a)NR^1bR^1c, –C(S)R^1a, –C(S)OR^1a, –C(S)NR^1bR^1c, –OR^1a, –OC(O)R^1a, –OC(O)OR^1a, –OC(O)NR^1bR^1c, –OC(O)SR^1a, –OC(NR^1a)NR^1bR^1c, –OC(S)R^1a, –OC(S)OR^1a, –OC(S)NR^1bR^1c, –OS(O)R^1a, –OS(O)₂R^1a, –OS(O)NR^1bR^1c, –OS(O)₂NR^1bR^1c, –NR^1bR^1c, –NR^1aC(O)R^1d, –NR^1aC(O)OR^1d, –NR^1aC(O)NR^1bR^1c, –NR^1aC(O)SR^1d, –NR^1aC(NR^1d)NR^1bR^1c, –NR^1aC(S)R^1d, –NR^1aC(S)OR^1d, –NR^1aC(S)NR^1bR^1c, –NR^1aS(O)R^1d, –NR^1aS(O)₂R^1d, –NR^1aS(O)NR^1bR^1c, –NR^1aS(O)₂NR^1bR^1c, –SR^1a, –S(O)R^1a, –S(O)₂R^1a, –S(O)NR^1bR^1c, or –S(O)₂NR^1bR^1c.

8. The compound of any one of claims 1 to 6, wherein the compound 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 R^3b is (i) hydrogen; (ii) C_1-6 alkyl, C_1-6 heteroalkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_3-10 cycloalkyl, C_6-14 aryl, C_7-15 aralkyl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one or more substituents Q; or (iii) –C(O)R^1a, –C(O)OR^1a, –C(O)NR^1bR^1c, –C(O)SR^1a, –C(NR^1a)NR^1bR^1c, –C(S)R^1a, –C(S)OR^1a, –C(S)NR^1bR^1c, –OR^1a, –OC(O)R^1a, –OC(O)OR^1a, –OC(O)NR^1bR^1c, –OC(O)SR^1a, –OC(NR^1a)NR^1bR^1c, –OC(S)R^1a, –OC(S)OR^1a, –OC(S)NR^1bR^1c, –OS(O)R^1a, –OS(O)₂R^1a, –OS(O)NR^1bR^1c, –OS(O)₂NR^1bR^1c, –NR^1bR^1c, –NR^1aC(O)R^1d, –NR^1aC(O)OR^1d, –NR^1aC(O)NR^1bR^1c, –NR^1aC(O)SR^1d, –NR^1aC(NR^1d)NR^1bR^1c, –NR^1aC(S)R^1d, –NR^1aC(S)OR^1d, –NR^1aC(S)NR^1bR^1c, –NR^1aS(O)R^1d, –NR^1aS(O)₂R^1d, –NR^1aS(O)NR^1bR^1c, –NR^1aS(O)₂NR^1bR^1c, –S(O)R^1a, –S(O)₂R^1a, –S(O)NR^1bR^1c, or –S(O)₂NR^1bR^1c.

9. The compound of any one of claims 1 to 6, wherein the compound 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.

10. The compound of any one of claims 1 to 9, wherein L is a bond or –C(O)N(R^1a)–.

11. The compound of any one of claims 1 to 10, wherein L is a bond.

12. The compound of any one of claims 1 to 10, wherein L is –C(O)N(H)–.

13. The compound of any one of claims 1 to 12, wherein X is a bond, –O–, –NR^X1–, or –C(R^X2R^X3)–.

14. The compound of any one of claims 1 to 13, wherein X is a bond.

15. The compound of any one of claims 1 to 13, wherein X is –CH₂–.

16. The compound of claim 1 or 7, wherein the compound is a compound of Formula (VIII):

or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

17. The compound of claim 7 or 16, wherein R^3a is (i) cyano or –NR^1bR^1c; or (ii) C_1-6 alkyl, C_1-6 heteroalkyl, each optionally substituted with one or more substituents Q.

18. The compound of claim 7, 16, or 17, wherein R^3a is cyano, aminocarbonyl, amino, methyl, trifluoromethyl, or hydroxylmethyl.

19. The compound of any one of claims 7 and 16 to 18, wherein R^3a is cyano.

20. The compound of claim 1 or 8, wherein the compound is a compound of Formula (IX): or an enantiomer, a mixtu

re o enan omers, a as ereomer, a m x ure 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 8 or 20, wherein R^3b is C_1-6 alkyl or C_1-6 heteroalkyl, each optionally substituted with one or more substituents Q.

22. The compound of claim 8, 20, or 21, wherein R^3b is methyl.

23. The compound of claim 1 or 9, wherein the compound is a compound of Formula (X):

or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

24. The compound of any one of claims 1 to 23, wherein R¹ is (i) hydrogen, deuterium, or halo; or (ii) C_1-6 alkyl or C_1-6 heteroalkyl, each optionally substituted with one or more substituents Q.

25. The compound of any one of claims 1 to 24, wherein R¹ is fluoro, chloro, or trifluoromethyl.

26. The compound of any one of claims 1 to 25, wherein R¹ is chloro.

27. The compound of any one of claims 1 to 26, wherein R² is hydrogen or deuterium.

28. The compound of any one of claims 1 to 27, wherein R⁴ is hydrogen or deuterium.

29. The compound of any one of claims 1 to 28, wherein R⁵ is (i) hydrogen, deuterium, or halo; or (ii) C_1-6 alkyl or C_1-6 heteroalkyl, each optionally substituted with one or more substituents Q.

30. The compound of any one of claims 1 to 29, wherein R⁵ is fluoro, chloro, or trifluoromethyl.

31. The compound of any one of claims 1 to 30, wherein R⁵ is chloro.

32. The compound of any one of claims 1 to 31, wherein R⁶ is hydrogen.

33. The compound of any one of claims 1 to 32, wherein R^7a is (i) hydrogen, deuterium, or –C(O)NR^1bR^1c; or (ii) C_1-6 alkyl or C_1-6 heteroalkyl, each optionally substituted with one or more substituents Q.

34. The compound of any one of claims 1 to 33, wherein R^7a is hydrogen, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, hydroxylmethyl, 2- hydroxylethyl, or –CONH₂.

35. The compound of any one of claims 1 to 34, wherein R^7b is (i) hydrogen, deuterium, or –C(O)NR^1bR^1c; or (ii) C_1-6 alkyl or C_1-6 heteroalkyl, each optionally substituted with one or more substituents Q.

36. The compound of any one of claims 1 to 35, wherein R^7b is hydrogen, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, hydroxylmethyl, 2- hydroxylethyl, or –CONH₂.

37. The compound of any one of claims 1 to 32, wherein R^7a and R^7b together with the carbon atom to which they are attached form (i) C(O); or (ii) C_3-10 cycloalkylene or heterocyclylene, each optionally substituted with one or more substituents Q.

38. The compound of any one of claims 1 to 32 and 37, wherein R^7a and R^7b together with the carbon atom to which they are attached form heterocyclylene, optionally substituted with one or more substituents Q.

39. The compound of any one of claims 1 to 32, 37, and 38, wherein R^7a and R^7b together with the carbon atom to which they are attached form monocyclic heterocyclylene, optionally substituted with one or more substituents Q.

40. The compound of any one of claims 1 to 32 and 37 to 39, wherein R^7a and R^7b together with the carbon atom to which they are attached form tetrahydrofurdiyl, optionally substituted with one or more substituents Q.

41. The compound of any one of claims 1 to 40, wherein R^8a is (i) hydrogen or deuterium; or (ii) C_1-6 alkyl or C_1-6 heteroalkyl, each optionally substituted with one or more substituents Q.

42. The compound of any one of claims 1 to 41, wherein R^8a is hydrogen, deuterium, or methyl.

43. The compound of any one of claims 1 to 42, wherein R^8b is C_1-6 alkyl or C_1-6 heteroalkyl, each optionally substituted with one or more substituents Q.

44. The compound of any one of claims 1 to 43, wherein R^8b is methyl.

45. The compound of any one of claims 1 to 40, wherein R^8a and R^8b together with the carbon atom to which they are attached form (i) C(O); or (ii) C_3-10 cycloalkylene or heterocyclylene, each optionally substituted with one or more substituents Q.

46. The compound of any one of claims 1 to 40 and 45, wherein R^8a and R^8b together with the carbon atom to which they are attached form C_3-10 cycloalkylene, optionally substituted with one or more substituents Q.

47. The compound of any one of claims 1 to 40, 45, and 46, wherein R^8a and R^8b together with the carbon atom to which they are attached form monocyclic C_3-10 cycloalkylene, optionally substituted with one or more substituents Q.

48. The compound of any one of claims 1 to 40 and 45 to 47, wherein R^8a and R^8b together with the carbon atom to which they are attached form cyclopropanediyl, cyclobutanediyl, cyclopentanediyl, cyclohexanediyl, or cycloheptanediyl, each optionally substituted with one or more substituents Q.

49. The compound of any one of claims 1 to 40 and 45 to 48, wherein R^8a and R^8b together with the carbon atom to which they are attached form cyclobutane-1,1-diyl, 3- cyanocyclobutane-1,1-diyl, 3-hydroxylcyclobutane-1,1-diyl, or 3,3-difluorocyclobutane-1,1-diyl.

50. The compound of any one of claims 1 to 49, wherein A is –O–, –S–, or –C(R^A2R^A3)–.

51. The compound of any one of claims 1 to 50, wherein A is –O–.

52. The compound of any one of claims 1 to 50, wherein A is –CH₂–.

53. The compound of any one of claims 1 to 52, wherein U is CR^U.

54. The compound of any one of claims 1 to 53, wherein V is CR^U.

55. The compound of any one of claims 1 to 54, wherein W is CR^U.

56. The compound of any one of claims 1 to 54, wherein W is N.

57. The compound of any one of claim 1 to 56, wherein R^U is (i) hydrogen, deuterium, cyano, or halo; or (ii) C_1-6 alkyl or C_1-6 heteroalkyl, each optionally substituted with one or more substituents Q.

58. The compound of any one of claims 1 to 57, wherein R^U is hydrogen, deuterium, cyano, fluoro, methyl, difluoromethyl, or trifluoromethyl.

59. The compound of any one of claims 1 to 58, wherein U is CH.

60. The compound of any one of claims 1 to 59, wherein V is CH.

61. The compound of any one of claims 1 to 55 and 57 to 60, wherein W is CH.

62. The compound of any one of claims 1 to 61, wherein Y is a bond, –O–, –NR^X1–, or –C(R^X2R^X3)–;

63. The compound of any one of claims 1 to 62, wherein Y is a bond, –O–, –N(H)–, –N(C(O)OCH₃)–, or –CH₂–.

64. The compound of any one of claims 1 to 63, wherein Z is –O– or –C(R^Z2R^Z3)–.

65. The compound of any one of claims 1 to 64, wherein Z is –CH₂–.

66. The compound of any one of claims 1 to 64, wherein Z is –O–.

67. A compound of: 2-(3,5-dichloro-4-((4-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-6-yl)oxy)- phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile A1; 2-(3,5-dichloro-4-((1,1,4,4-tetramethyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-6- yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile A2; 2-(3,5-dichloro-4-((4,4-dimethyl-1-oxo-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol- 6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile A3; 2-(3,5-dichloro-4-((6,9-difluoro-1,1-dimethyl-1,3,4,5-tetrahydropyrano[4,3-b]- indol-8-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile A4; 2-(3,5-dichloro-4-((4',4'-dimethyl-2',3',4,4',5,9'-hexahydro-2H-spiro[furan-3,1'- pyrido[3,4-b]indol]-6'-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile A5; methyl 6-(2,6-dichloro-4-(6-cyano-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)- phenoxy)-4,4-dimethyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indole-2-carboxylate A6; 6-(2,6-dichloro-4-(6-cyano-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)- phenoxy)-4,4-dimethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-1-carboxamide A7; 2-(3,5-dichloro-4-((4,4-dimethyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-6-yl)oxy)- phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile A8; 2-(3,5-dichloro-4-((4,4-dimethyl-1-(trifluoromethyl)-2,3,4,9-tetrahydro-1H- pyrido[3,4-b]indol-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile A9; 2-(3,5-dichloro-4-((4,4-dimethyl-1-(trifluoromethyl)-2,3,4,9-tetrahydro-1H- pyrido[3,4-b]indol-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile A10; 2-(3,5-dichloro-4-((6,7-difluoro-1,1-dimethyl-1,3,4,5-tetrahydropyrano[4,3-b]- indol-8-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile A11; 2-(3,5-dichloro-4-((5,8-difluoro-1-methyl-1,2,3,4-tetrahydrocyclopenta[b]indol-7- yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile A12; 2-(3,5-dichloro-4-((4,4-dimethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-6- yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile A13; 2-(3,5-dichloro-4-((1,1,4,4-tetramethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol- 6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile A14; 2-(3,5-dichloro-4-((1,4,4-trimethyl-1-(trifluoromethyl)-2,3,4,9-tetrahydro-1H- pyrido[3,4-b]indol-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile A15; 2-(3,5-dichloro-4-((5,8-difluoro-4,4-dimethyl-1,3,4,9-tetrahydropyrano[3,4-b]- indol-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile A16; 2-(3,5-dichloro-4-((5,8-difluoro-1-methyl-3,4-dihydro-1H-furo[3,4-b]indol-7-yl)- oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile A17; 2-(3,5-dichloro-4-((5,5-dimethyl-8-(trifluoromethyl)-6,7,8,9-tetrahydro-5H- pyrrolo[2,3-b:5,4-c']dipyridin-3-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6- carbonitrile A18; 2-(3,5-dichloro-4-((1',9'-dihydro-3'H-spiro[cyclobutane-1,4'-pyrano[3,4-b]indol]- 6'-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile A19; 2-(3,5-dichloro-4-((7,8-difluoro-4,4-dimethyl-1,3,4,9-tetrahydropyrano[3,4-b]- indol-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile A20; 2-(3,5-dichloro-4-((1,1-dimethyl-1,4,5,6-tetrahydro-2H-oxepino[4,5-b]indol-9- yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile A21; 2-(3,5-dichloro-4-((8-fluoro-4,5-dimethyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-6- yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile A22; 2-(3,5-dichloro-4-((1-(hydroxymethyl)-4,4-dimethyl-1,3,4,9-tetrahydro- pyrano[3,4-b]indol-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile A23; 2-(3,5-dichloro-4-((1-(2-hydroxyethyl)-4,4-dimethyl-1,3,4,9-tetrahydro- pyrano[3,4-b]indol-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile A24; 2-(3,5-dichloro-4-((5,5-dimethyl-5,6,8,9-tetrahydropyrano[4',3':4,5]pyrrolo[2,3- b]pyridin-3-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile A25; 6-(2,6-dichloro-4-(6-cyano-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)- phenoxy)-4,4-dimethyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-5-carbonitrile A26; 2-(3,5-dichloro-4-((5-(difluoromethyl)-8-fluoro-4,4-dimethyl-1,3,4,9-tetrahydro- pyrano[3,4-b]indol-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile A27; 2-(3-chloro-4-((4,4-dimethyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-6-yl)methyl)- 5-(trifluoromethyl)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile A28; 6-amino-2-(3,5-dichloro-4-((4,4-dimethyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-6- yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione A29; 2-(3,5-dichloro-4-((8-fluoro-4,4-dimethyl-5-(trifluoromethyl)-1,3,4,9-tetrahydro- pyrano[3,4-b]indol-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile A30; 2-(3,5-dichloro-4-((3,3-difluoro-1',9'-dihydro-3'H-spiro[cyclobutane-1,4'- pyrano[3,4-b]indol]-6'-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile A31; 6'-(2,6-dichloro-4-(6-cyano-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)- phenoxy)-1',9'-dihydro-3'H-spiro[cyclobutane-1,4'-pyrano[3,4-b]indole]-3-carbonitrile A32; 2-(3,5-dichloro-4-((3-hydroxy-1',9'-dihydro-3'H-spiro[cyclobutane-1,4'- pyrano[3,4-b]indol]-6'-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile A33; 2-(3,5-dichloro-4-((5,8-difluoro-4,4-dimethyl-1,3,4,9-tetrahydropyrano[3,4-b]- indol-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile A34; 2-(3,5-dichloro-4-((4,4-dimethyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-6-yl)oxy)- phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxamide A35; 2-(3,5-dichloro-4-((5,8-difluoro-1,1,4,4-tetramethyl-1,3,4,9-tetrahydro- pyrano[3,4-b]indol-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile A36; 2-(4-((4,4-dimethyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-6-yl)oxy)-3,5-difluoro- phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile A37; 6-(2,6-dichloro-4-(6-cyano-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)- phenoxy)-8-fluoro-4,4-dimethyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-5-carbonitrile A38; 2-(3,5-dichloro-4-((4,4-dimethyl-1-(2,2,2-trifluoroethyl)-1,3,4,9-tetrahydro- pyrano[3,4-b]indol-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile A39; 2-(4-((7,8-difluoro-4,4-dimethyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-6-yl)oxy)- 3,5-difluorophenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile A40; 2-(3,5-dichloro-4-((1-(difluoromethyl)-4,4-dimethyl-1,3,4,9-tetrahydro- pyrano[3,4-b]indol-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile A41; 2-(3,5-dichloro-4-((1-(fluoromethyl)-4,4-dimethyl-1,3,4,9-tetrahydropyrano[3,4- b]indol-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile A42; 2-(3,5-dichloro-4-((5,5,8,8-tetramethyl-5,6,8,9-tetrahydropyrano[4',3':4,5]- pyrrolo[2,3-b]pyridin-3-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile A43; 6-(3,5-dichloro-4-((4,4-dimethyl-1-(trifluoromethyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-6- yl)oxy)phenyl)-2-methyl-1,2,4-triazine-3,5(2H,4H)-dione B1; N-(3,5-dichloro-4-((4,4-dimethyl-1-(trifluoromethyl)-2,3,4,9-tetrahydro-1H- pyrido[3,4-b]indol-6-yl)oxy)phenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxamide C1; or N-(3,5-dichloro-4-((5-cyano-4,4-dimethyl-1,3,4,9-tetrahydropyrano[3,4-b]indol- 6-yl)oxy)phenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxamide C2; or an enantiomer, a mixture of 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. A pharmaceutical composition comprising the compound of any one of claims 1 to 66, or an enantiomer, a mixture of 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.

69. The pharmaceutical composition of claim 67, wherein the composition is in single dosage form.

70. The pharmaceutical composition of claim 67 or 68, wherein the composition is in an oral, parenteral, or intravenous dosage form.

71. The pharmaceutical composition of claim 69, wherein the composition is formulated in an oral dosage form.

72. The pharmaceutical composition of claim 70, wherein the oral dosage form is a tablet or capsule.

73. A method of treating, preventing, or ameliorating one or more symptoms of a TRβ-mediated disorder, disease, or condition 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 66 or a pharmaceutical composition of any one of claims 67 to 71.

74. The method of claim 72, wherein the TRβ-mediated disorder, disease, or condition is a liver disease.

75. A method of treating, preventing, or ameliorating one or more symptoms of a liver 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 66 or a pharmaceutical composition of any one of claims 67 to 71.

76. The method of any one of claims 73 to 75, wherein the disease is dyslipidemia, hypercholesterolemia, non-alcoholic fatty liver disease (NAFLD), or non-alcoholic steatohepatitis (NASH).

77. The method of any one of claims 72 to 76, wherein the subject is a human.