WO2024123967A1 - Sarm1 inhibitors, pharmaceutical compositions, and therapeutic applications - Google Patents

Abstract

Provided herein are SARM1 inhibitors, 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 SARM1-mediated disorder, disease, or condition.

Description

Attorney Docket No.156A002WO01 SARM1 INHIBITORS, 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.63/386,643, filed December 8, 2022; the disclosure of which is incorporated herein by reference in its entirety. FIELD [0002] Provided herein are SARM1 inhibitors and pharmaceutical compositions thereof. Also provided herein are methods of their use for treating, preventing, or ameliorating one or more symptoms of a SARM1-mediated disorder, disease, or condition. BACKGROUND [0003] Axons are long, cable-like, cell extensions that connect nerve cells (neurons) and transmit electrical signals critical to a neuronal function. Damage or degeneration of these axons leads to disruption of neuronal signal transmission. Evidence exists indicating that the degeneration of axons precedes clinical symptoms and constitutes an early event in pathological processes in many neurological disorders, including peripheral neuropathies, optic neuropathies, diabetic neuropathy, HIV neuropathy, Charcot-Marie-Tooth disease, traumatic brain injury, glaucoma, multiple sclerosis, Alzheimer’s disease, Parkinson's disease, and amyotrophic lateral sclerosis. Gerdts et al., Neuron 2016, 89, 449-60. While these neurological conditions have unique underlying etiologies, inhibition of axonal degeneration in the conditions’ early stages may slow or prevent their progression by preventing the loss of functional synapses and maintaining neuronal connectivity. [0004] Sterile alpha and TIR motif-containing 1 (SARM1) protein is an essential mediator of axon degeneration through a mechanism triggered via a local destruction program involving rapid breakdown of NAD(+). Gerdts et al., Science 2016, 348, 453-7. Thus, it provides a potential therapeutic target to inhibit axonal degeneration and treat a neurological disorder. Attorney Docket No.156A002WO01 SUMMARY OF THE DISCLOSURE [0005] Provided herein is a compound of Formula (I):

or an enantiomer, a mixture of a a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein: A is a bond, C1-6 alkylene, or C1-6 heteroalkylene; E is a bond, –O–, –S–, –N(R^1a)–, C_1-6 alkylene, or C_1-6 heteroalkylene; U, V, and X are each independently –C(R¹)=, –O–, –S–, –N(R³)–, or –N=; Z is –O–, –S–, –N(R⁴)–, or C1-6 alkylene; each R¹ 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; 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; R² and R⁵ are each independently C3-10 cycloalkyl, C6-14 aryl, heteroaryl, or heterocyclyl; each R³ and R⁴ is independently (i) hydrogen; (ii) C_1-6 alkyl, C_1-6 heteroalkyl, C_2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 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, –S(O)R^1a, –S(O)₂R^1a, –S(O)NR^1bR^1c, or –S(O)₂NR^1bR^1c; and each R^1a, R^1b, R^1c, and R^1d is independently hydrogen, deuterium, C1-6 alkyl, C1-6 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl; wherein each alkyl, alkylene, heteroalkyl, heteroalkylene, alkenyl, alkynyl, Attorney Docket No.156A002WO01 cycloalkyl, aryl, aralkyl, heteroaryl, and heterocyclyl is optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Q, wherein each Q is independently selected from: (a) deuterium, cyano, halo, imino, nitro, and oxo; (b) C_1-6 alkyl, C_1-6 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, and heterocyclyl, each of which is further optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents 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, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Q^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, C7-15 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) C1-6 alkyl, C2-6 alkenyl, C2-6 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. [0006] Also provided herein is a pharmaceutical composition comprising a compound of Attorney Docket No.156A002WO01 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. [0007] Additionally, provided herein is a method of treating, preventing, or ameliorating one or more symptoms of a SARM1-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. [0008] Furthermore, provided herein is a method of treating, preventing, or ameliorating one or more symptoms of a neurological 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. [0009] Provided herein is a method of inhibiting the activity of a SARM1, comprising contacting the SARM1 with an 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 Attorney Docket No.156A002WO01 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. Attorney Docket No.156A002WO01 [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, 2nd ed.; Gibson Ed.; CRC Press, 2009. [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. Attorney Docket No.156A002WO01 [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 (C3-6) carbon atoms. As used herein, linear C1-6 and branched C3-6 alkyl groups are also referred as “lower alkyl.” Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl (including all isomeric forms, e.g., 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 terms “alkylene” and “alkanediyl” are used interchangeably herein in reference to a linear or branched saturated divalent hydrocarbon radical, wherein the alkanediyl is optionally substituted with one or more substituents Q as described herein. For example, C_1-6 alkanediyl refers to a linear saturated divalent hydrocarbon radical of 1 to 6 carbon atoms or a branched saturated divalent hydrocarbon radical of 3 to 6 carbon atoms. In certain embodiments, the alkanediyl is a linear saturated divalent hydrocarbon radical that has 1 to 30 (C_1-30), 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 divalent hydrocarbon radical of 3 to 30 (C3-30), 3 to 20 (C3-20), 3 to 15 (C3-15), 3 to 10 (C3-10), or 3 to 6 (C_3-6) carbon atoms. As used herein, linear C_1-6 and branched C_3-6 alkanediyl groups are also referred as “lower alkanediyl.” Examples of alkanediyl groups include, but are not limited to, methanediyl, ethanediyl (including all isomeric forms, e.g., ethane-1,1-diyl and ethane-1,2- diyl), propanediyl (including all isomeric forms, e.g., propane-1,1-diyl, propane-1,2-diyl, and propane-1,3-diyl), butanediyl (including all isomeric forms, e.g., butane-1,1-diyl, butane-1,2- diyl, butane-1,3-diyl, and butane-1,4-diyl), pentanediyl (including all isomeric forms, e.g., pentane-1,1-diyl, pentane-1,2-diyl, pentane-1,3-diyl, and pentane-1,5-diyl), and hexanediyl (including all isomeric forms, e.g., hexane-1,1-diyl, hexane-1,2-diyl, hexane-1,3-diyl, and hexane-1,6-diyl). Examples of substituted alkanediyl groups include, but are not limited to, –C(O)CH2–, –C(O)(CH2)2–, –C(O)(CH2)3–, –C(O)(CH2)4–, –C(O)(CH2)5–, –C(O)(CH2)6–, Attorney Docket No.156A002WO01 –C(O)(CH2)7–, –C(O)(CH2)8–, –C(O)(CH2)9–, –C(O)(CH2)10–, –C(O)CH2C(O)–, –C(O)(CH2)2C(O)–, –C(O)(CH2)3C(O)–, –C(O)(CH2)4C(O)–, or –C(O)(CH2)5C(O)–. [0023] 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 (C3-20), 3 to 15 (C3-15), 3 to 10 (C3-10), or 3 to 6 (C3-6) carbon atoms. As used herein, linear C1-6 and branched C3-6 heteroalkyl groups are also referred as “lower heteroalkyl.” Examples of heteroalkyl groups include, but are not limited to, –OCH₃, –OCH₂CH₃, –CH₂OCH₃, –NHCH₃, –ONHCH3, –NHOCH3, –SCH3, –CH2NHCH2CH3, and –NHCH2CH2CH3. Examples of substituted heteroalkyl groups include, but are not limited to, –CH2NHC(O)CH3 and –NHC(O)CH₂CH₃. [0024] The terms “heteroalkylene” and “heteroalkanediyl” are used interchangeably herein in reference to a linear or branched saturated divalent hydrocarbon radical that contains one or more heteroatoms in its main chain, each independently selected from O, S, and N. The heteroalkylene is optionally substituted with one or more substituents Q as described herein. For example, C1-6 heteroalkylene refers to a linear saturated divalent hydrocarbon radical of 1 to 6 carbon atoms or a branched saturated divalent hydrocarbon radical of 3 to 6 carbon atoms. In certain embodiments, the heteroalkylene is a linear saturated divalent hydrocarbon radical that has 1 to 20 (C1-20), 1 to 15 (C1-15), 1 to 10 (C1-10), or 1 to 6 (C1-6) carbon atoms, or branched saturated divalent hydrocarbon radical of 3 to 20 (C3-20), 3 to 15 (C3-15), 3 to 10 (C3-10), or 3 to 6 (C_3-6) carbon atoms. As used herein, linear C_1-6 and

C_3-6 heteroalkylene groups are also referred as “lower heteroalkylene.” Examples of heteroalkylene groups include, but are not limited to, –CH2O–, –(CH2)2O–, –(CH2)3O–, –(CH2)4O–, –(CH2)5O–, –(CH2)6O–, –(CH2)7O–, –(CH₂)₈O–, –(CH₂)₉O–, –(CH₂)₁₀O–, –CH₂OCH₂–, –CH₂CH₂O–, –(CH₂CH₂O)₂–, –(CH₂CH₂O)₃–, –(CH₂CH₂O)₄–, –(CH₂CH₂O)₅–, –CH₂NH–, –CH₂NHCH₂–, –CH₂CH₂NH–, Attorney Docket No.156A002WO01 –CH2S–, –CH2SCH2–, and –CH2CH2S–. Examples of substituted heteroalkylene groups include, but are not limited to, –C(O)CH2O–, –C(O)(CH2)2O–, –C(O)(CH2)3O–, –C(O)(CH2)4O–, –C(O)(CH₂)₅O–, –C(O)(CH₂)₆O–, –C(O)(CH₂)₇O–, –C(O)(CH₂)₈O–, –C(O)(CH₂)₉O–, –C(O)(CH2)10O–, –C(O)CH2OCH2CH2O–, –C(O)CH2O(CH2CH2O)2–, –C(O)CH2O(CH2CH2O)3–, –C(O)CH2O(CH2CH2O)4, –C(O)CH2O(CH2CH2O)5–, –CH₂NHC(O)CH₂–, or –CH₂CH₂C(O)NH–. [0025] 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, C2-6 alkenyl refers to a linear unsaturated monovalent hydrocarbon radical of 2 to 6 carbon atoms or a branched unsaturated monovalent hydrocarbon radical of 3 to 6 carbon atoms. In certain embodiments, the alkenyl is a linear monovalent hydrocarbon radical of 2 to 20 (C2-20), 2 to 15 (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). [0026] 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, C2-6 alkynyl refers to a linear unsaturated monovalent hydrocarbon radical of 2 to 6 carbon atoms or a branched unsaturated monovalent hydrocarbon radical of 4 to 6 carbon atoms. In certain embodiments, the alkynyl is a linear monovalent hydrocarbon radical of 2 to 20 (C2-20), 2 to 15 (C2-15), 2 to 10 (C2-10), or 2 to 6 (C2-6) carbon atoms, or a branched monovalent hydrocarbon radical of 4 to 20 (C_4-20), 4 to 15 (C_4-15), 4 to 10 (C_4-10), or 4 to 6 (C_4-6) carbon atoms. Examples of alkynyl groups include, but are not limited to, Attorney Docket No.156A002WO01 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). [0027] The term “cycloalkyl” refers to a cyclic monovalent hydrocarbon radical, which is optionally substituted with one or more substituents Q as described herein. In one embodiment, the cycloalkyl is a saturated or unsaturated but non-aromatic, and/or bridged or non-bridged, and/or fused bicyclic group. In certain embodiments, the cycloalkyl has from 3 to 20 (C3-20), from 3 to 15 (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. [0028] The term “aryl” refers to a monovalent monocyclic aromatic hydrocarbon radical and/or monovalent polycyclic aromatic hydrocarbon radical that contain at least one aromatic carbon ring. In certain embodiments, the aryl has from 6 to 20 (C6-20), from 6 to 15 (C6-15), 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. [0029] The term “aralkyl” or “arylalkyl” refers to a monovalent alkyl group substituted with one or more aryl groups. In certain embodiments, the aralkyl has from 7 to 30 (C7-30), from 7 to 20 (C_7-20), or from 7 to 16 (C_7-16) carbon atoms. Examples of aralkyl groups include, but are Attorney Docket No.156A002WO01 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. [0030] 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), imidazo- pyridinyl (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]- Attorney Docket No.156A002WO01 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-phen- anthrolinyl, 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. [0031] 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, dihydro- benzisoxazinyl (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, dihydro- pyranyl, dihydropyrazolyl, dihydropyrazinyl, dihydropyridinyl, dihydropyrimidinyl, dihydro- pyrrolyl, dioxolanyl, 1,4-dithianyl, furanonyl, imidazolidinyl, imidazolinyl, indolinyl, isochromanyl, isoindolinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, oxazolidinonyl, oxazolidinyl, oxiranyl, piperazinyl, piperidinyl, 4- Attorney Docket No.156A002WO01 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. [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) C1-6 alkyl, C1-6 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, and heterocyclyl, each of which is further optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents 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) C1-6 alkyl, C1-6 heteroalkyl, C2-6 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 Attorney Docket No.156A002WO01 cycloalkyl, C6-14 aryl, C7-15 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) C1-6 alkyl, C2-6 alkenyl, C2-6 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. Attorney Docket No.156A002WO01 [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 , carbon-12 (¹²C), carbon-13 (¹³C), carbon-14 (¹⁴C), nitrogen-13 (¹³N), nitrogen-14 (¹⁴N), 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 Attorney Docket No.156A002WO01 position is substantially greater than its natural abundance. [0039] The term “isotopic enrichment factor” refers to the ratio between the isotopic abundance in an isotopically enriched compound and the natural abundance of a specific isotope. [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, Attorney Docket No.156A002WO01 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. Attorney Docket No.156A002WO01 [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 mixture of two or more

diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein: A is a bond, C1-6 alkylene, or C1-6 heteroalkylene; E is a bond, –O–, –S–, –N(R^1a)–, C_1-6 alkylene, or C_1-6 heteroalkylene; U, V, and X are each independently –C(R¹)=, –O–, –S–, –N(R³)–, or –N=; Z is –O–, –S–, –N(R⁴)–, or C1-6 alkylene; each R¹ is independently (i) hydrogen, deuterium, cyano, halo, or nitro; (ii) C1-6 alkyl, C_1-6 heteroalkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_3-10 cycloalkyl, C_6-14 aryl, C_7-15 aralkyl, heteroaryl, 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, Attorney Docket No.156A002WO01 –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; R² and R⁵ are each independently C_3-10 cycloalkyl, C_6-14 aryl, heteroaryl, or heterocyclyl; each R³ and R⁴ is independently (i) hydrogen; (ii) C1-6 alkyl, C1-6 heteroalkyl, C2-6 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, –S(O)R^1a, –S(O)2R^1a, –S(O)NR^1bR^1c, or –S(O)2NR^1bR^1c; and each R^1a, R^1b, R^1c, and R^1d is independently hydrogen, deuterium, C1-6 alkyl, C1-6 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, alkylene, heteroalkyl, heteroalkylene, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heteroaryl, and heterocyclyl is optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Q, wherein each Q is independently selected from: (a) deuterium, cyano, halo, imino, nitro, and oxo; (b) C1-6 alkyl, C1-6 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) C1-6 alkyl, C1-6 heteroalkyl, C2-6 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 Attorney Docket No.156A002WO01 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) C1-6 alkyl, C1-6 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, and heterocyclyl; and (c) –C(O)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) C1-6 alkyl, C2-6 alkenyl, C2-6 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 another embodiment, provided herein is a compound of Formula (II): or an enantiomer, a mixture of 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 R², R⁵, A, E, U, V, X, and Z are each as defined herein. [0050] In yet another embodiment, provided herein is a compound of Formula (III): or an enantiomer, a mixture of mixture of two or more diastereomers, a tautomer, a

or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R², R⁵, A, U, V, X, and Z are each as defined herein. Attorney Docket No.156A002WO01 [0051] In certain embodiments, in any one of Formulae (I) to (III), A is a bond or C1-6 alkylene optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulae (I) to (III), A is a bond. In certain embodiments, in any one of Formulae (I) to (III), A is C1-6 alkylene, optionally substituted with one, two, or three substituents Q. In certain embodiments, in any one of Formulae (I) to (III), A is methanediyl (–CH2–), optionally substituted with one or two substituents Q. In certain embodiments, in any one of Formulae (I) to (III), A is methanediyl. [0052] In certain embodiments, in any one of Formulae (I) to (III), E is a bond or C1-6 alkylene optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulae (I) to (III), E is a bond. In certain embodiments, in any one of Formulae (I) to (III), E is C1-6 alkylene, optionally substituted with one, two, or three substituents Q. In certain embodiments, in any one of Formulae (I) to (III), E is methanediyl, optionally substituted with one or two substituents Q. In certain embodiments, in any one of Formulae (I) to (III), E is methanediyl. [0053] In yet another embodiment, provided herein is a compound of Formula (IV): or an enantiomer, a mixture of 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 R², R⁵, U, V, X, and Z are each as defined herein. [0054] In one embodiment, provided herein is a compound in an endo configuration, having the structure of Formula (IVa): or an enantiomer, a mixture of mixture of two or more diastereomers, a tautomer, a

or an isotopic variant thereof; or Attorney Docket No.156A002WO01 a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R², R⁵, U, V, X, and Z are each as defined herein. [0055] In another embodiment, provided herein is a compound in an endo configuration, having the structure of Formula (IVb): or an enantiomer, a mixture of

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 R², R⁵, U, V, X, and Z are each as defined herein. [0056] In yet another embodiment, provided herein is a compound in an exo configuration, having the structure of Formula (IVc): or an enantiomer, a mixture of

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 R², R⁵, U, V, X, and Z are each as defined herein. [0057] In still another embodiment, provided herein is a compound in an exo configuration, having the structure of Formula (IVd): R² U N R⁵ _(IVd) or an enantiomer, a mixture of mixture of two or more diastereomers, a tautomer, a

or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R², R⁵, U, V, X, and Z are each as defined herein. Attorney Docket No.156A002WO01 [0058] In yet another embodiment, provided herein is a compound of Formula (V):

or an enantiomer, a mixture of a 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 R², R⁵, U, V, X, and Z are each as defined herein. [0059] In one embodiment, provided herein is a compound in an endo configuration, having of Formula (Va): or an enantiomer, a mixture of

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 R², R⁵, U, V, X, and Z are each as defined herein. [0060] In another embodiment, provided herein is a compound in an endo configuration, having of Formula (Vb): or an enantiomer, a mixture of mixture of two or more diastereomers, a tautomer, a

or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R², R⁵, U, V, X, and Z are each as defined herein. [0061] In yet another embodiment, provided herein is a compound in an exo configuration, having of Formula (Vc): Attorney Docket No.156A002WO01

or an enantiomer, a mixture of 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 R², R⁵, U, V, X, and Z are each as defined herein. [0062] In still another embodiment, provided herein is a compound in an exo configuration, having of Formula (Vd): or an enantiomer, a mixture of

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 R², R⁵, U, V, X, and Z are each as defined herein. [0063] In yet another embodiment, provided herein is a compound of Formula (VI): or an enantiomer, a mixture of mixture of two or more

diastereomers, a tautomer, a or more or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R², R⁵, U, V, X, and Z are each as defined herein. [0064] In yet another embodiment, provided herein is a compound of Formula (VII): or an enantiomer, a mixture of mixture of two or more diastereomers, a tautomer, a

or an isotopic variant thereof; or Attorney Docket No.156A002WO01 a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R², R⁵, U, V, X, and Z are each as defined herein. [0065] In one embodiment, in any one of Formulae (I) to (VII), (IVa) to (IVd), and (Va) to (Vd), R² is heteroaryl, optionally substituted with one, two, or three substituents Q; R⁵ is C_6-14 aryl or heteroaryl, each optionally substituted with one, two, or three substituents Q; and Z is –O–, –N(R^1a)–, or C1-6 alkylene optionally substituted with one, two, or three substituents Q; wherein R^1a is as defined herein. [0066] In another embodiment, in any one of Formulae (I) to (VII), (IVa) to (IVd), and (Va) to (Vd), R² is monocyclic heteroaryl, optionally substituted with one, two, or three substituents Q; R⁵ is phenyl or monocyclic heteroaryl, each optionally substituted with one, two, or three substituents Q; and Z is –O–, –N(H)–, or C_1-6 alkylene optionally substituted with one, two, or three substituents Q. [0067] In yet another embodiment, in any one of Formulae (I) to (VII), (IVa) to (IVd), and (Va) to (Vd), R² is pyridinyl, pyridazinyl, or pyrimidinyl, each optionally substituted with one, two, or three substituents, wherein each substituent is independently cyano, oxo, methyl, trifluoromethyl, hydroxymethyl, cyclopropyl, hydroxyl, or methoxy; R⁵ is phenyl or pyridinyl, each optionally substituted with one, two, or three substituents, wherein each substituent is independently fluoro, chloro, methyl, ethyl, isopropyl, trifluoromethyl, hydroxymethyl, aminomethyl, or cyclopropyl; and Z is –O–, –N(H)–, or methanediyl. [0068] In yet another embodiment, in any one of Formulae (I) to (VII), (IVa) to (IVd), and (Va) to (Vd), R² is pyridinyl, pyridazinyl, or pyrimidinyl, each optionally substituted with one, Attorney Docket No.156A002WO01 two, or three substituents, wherein each substituent is independently cyano, fluoro, chloro, oxo, methyl, hydroxymethyl, cyclopropyl, hydroxyl, methoxy, or amino; R⁵ is phenyl or pyridinyl, each optionally substituted with one, two, or three substituents, wherein each substituent is independently cyano, fluoro, chloro, bromo, methyl, or trifluoromethyl; and Z is –O–, –N(H)–, or methanediyl. [0069] In yet another embodiment, in any one of Formulae (I) to (VII), (IVa) to (IVd), and (Va) to (Vd), R² is pyridin-3-yl, pyridin-4-yl, pyridazin-4-yl, or pyrimidin-4-yl, each optionally substituted with one, two, or three substituents, wherein each substituent is independently cyano, oxo, methyl, trifluoromethyl, hydroxymethyl, cyclopropyl, hydroxyl, or methoxy; R⁵ is phenyl, pyridin-2-yl, or pyridin-3-yl, each optionally substituted with one, two, or three substituents, wherein each substituent is independently fluoro, chloro, methyl, ethyl, isopropyl, trifluoromethyl, hydroxymethyl, aminomethyl, or cyclopropyl; and Z is –O–, –N(H)–, or methanediyl. [0070] In yet another embodiment, in any one of Formulae (I) to (VII), (IVa) to (IVd), and (Va) to (Vd), R² is pyridin-3-yl, pyridin-4-yl, pyridazin-4-yl, or pyrimidin-4-yl, each optionally substituted with one, two, or three substituents, wherein each substituent is independently cyano, fluoro, chloro, oxo, methyl, hydroxymethyl, cyclopropyl, hydroxyl, methoxy, or amino; R⁵ is phenyl or pyridin-3-yl, each optionally substituted with one, two, or three substituents, wherein each substituent is independently cyano, fluoro, chloro, bromo, methyl, or trifluoromethyl; and Z is –O–, –N(H)–, or methanediyl. [0071] In yet another embodiment, in any one of Formulae (I) to (VII), (IVa) to (IVd), and (Va) to (Vd), R² is pyridin-4-yl, 1-oxopyridin-4-yl, 3-cyanopyridin-4-yl, 6-cyanopyridin-3-yl, 3-methylpyridin-4-yl, 6-hydroxylpyridin-3-yl, pyridazin-4-yl, 6-cyanopyridazin-4-yl, 3-methyl- pyridazin-4-yl, 5-methylpyridazin-4-yl, 6-methylpyridazin-4-yl, 5-trifluomethylpyridazin-4-yl, Attorney Docket No.156A002WO01 5-hydroxymethylpyridazin-4-yl, 5-cyclopropylpyridazin-4-yl, 3-hydroxypyridazin-4-yl, 3- methoxypyridazin-4-yl, or pyrimidin-4-yl; R⁵ is 4-fluorophenyl, 4-chlorophenyl, 4-chloro-3-fluoroophenyl, 5-chloropyridin- 2-yl, 6-fluoropyridin-3-yl, 6-chloropyridin-3-yl, 6-methylpyridin-3-yl, 6-trifluoromethylpyridin- 3-yl, 6-isopropylpyridin-3-yl, 6-cyclopropylpyridin-3-yl, 6-chloro-5-fluoropyridin-3-yl, 6-fluoro- 2-methylpyridin-3-yl, 6-chloro-2-methylpyridin-3-yl, 6-chloro-5-methylpyridin-3-yl, 6-chloro-2- ethylpyridin-3-yl, 6-chloro-2-trifluoromethylpyridin-3-yl, 6-chloro-2-hydroxymethylpyridin-3- yl, 2-aminomethyl-6-chloropyridin-3-yl, or 6-chloro-5-cyclopropylpyridin-3-yl; and Z is –O–, –N(H)–, or methanediyl. [0072] In still another embodiment, in any one of Formulae (I) to (VII), (IVa) to (IVd), and (Va) to (Vd), R² is 6-cyanopyridin-3-yl, 6-hydroxylpyridin-3-yl, pyridin-4-yl, 3-cyanopyridin- 4-yl, 1-oxopyridin-4-yl, pyridazin-4-yl, 3-methylpyridazin-4-yl, 5-methylpyridazin-4-yl, 5- hydroxymethylpyridazin-4-yl, 6-cyano-pyridazin-4-yl, 6-methylpyridazin-4-yl, or pyrimidin-4- yl; R⁵ is 4-fluorophenyl, 4-chlorophenyl, 3-fluoro-4-chlorophenyl, 6-chloropyridin-3- yl, or 6-methylpyridin-3-yl; and Z is –O–, –N(H)–, or methanediyl. [0073] In certain embodiments, in any one of the formulae described herein, including Formulae (I) to (VII), (IVa) to (IVd), and (Va) to (Vd), U is –C(R¹)=, wherein R¹ is as defined herein. In certain embodiments, in any one of the formulae described herein, U is –C(H)=, –C(CN)=, –C(F)=, –C(CH₃)=, –C(CF₃)=, or –C(CH₂OH)=. In certain embodiments, in any one of the formulae described herein, U is –C(H)=, –C(CN)=, –C(CH₃)=, or –C(CH₂OH)=. In certain embodiments, in any one of the formulae described herein, U is –C(H)=. In certain embodiments, in any one of the formulae described herein, U is –O–. In certain embodiments, in any one of the formulae described herein, U is –S–. In certain embodiments, in any one of the formulae described herein, U is –N(R³)–, wherein R³ is as defined herein. In certain embodiments, in any one of the formulae described herein, U is –N(H)–. In certain embodiments, in any one of the formulae described herein, U is –N=. Attorney Docket No.156A002WO01 [0074] In certain embodiments, in any one of the formulae described herein, including Formulae (I) to (VII), (IVa) to (IVd), and (Va) to (Vd), V is –C(R¹)=, wherein R¹ is as defined herein. In certain embodiments, in any one of the formulae described herein, V is –C(H)=, –C(CN)=, –C(F)=, –C(CH3)=, –C(CF3)=, or –C(CH2OH)=. In certain embodiments, in any one of the formulae described herein, V is –C(H)=, –C(F)=, –C(CH3)=, or –C(CF3)=. In certain embodiments, in any one of the formulae described herein, V is –O–. In certain embodiments, in any one of the formulae described herein, V is –S–. In certain embodiments, in any one of the formulae described herein, V is –N(R³)–, wherein R³ is as defined herein. In certain embodiments, in any one of the formulae described herein, V is –N(H)–. In certain embodiments, in any one of the formulae described herein, V is –N=. [0075] In certain embodiments, in any one of the formulae described herein, including Formulae (I) to (VII), (IVa) to (IVd), and (Va) to (Vd), X is –C(R¹)=, wherein R¹ is as defined herein. In certain embodiments, in any one of the formulae described herein, X is –C(H)=, –C(CN)=, –C(F)=, –C(CH3)=, –C(CF3)=, or –C(CH2OH)=. In certain embodiments, in any one of the formulae described herein, X is –C(H)= or –C(CH3)=. In certain embodiments, in any one of the formulae described herein, X is –C(H)=. In certain embodiments, in any one of the formulae described herein, X is –O–. In certain embodiments, in any one of the formulae described herein, X is –S–. In certain embodiments, in any one of the formulae described herein, X is –N(R³)–, wherein R³ is as defined herein. In certain embodiments, in any one of the formulae described herein, X is –N(H)–. In certain embodiments, in any one of the formulae described herein, X is –N=. [0076] In certain embodiments, in any one of the formulae described herein, including Formulae (I) to (VII), (IVa) to (IVd), and (Va) to (Vd), U is –C(R¹)=; V is –N(R³)–; and X is –N=; wherein R¹ and R³ are each as defined herein. In certain embodiments, in one of the formulae

, , , U is –C(R¹)=; V is –N(H)–; and X is –N=; wherein R¹ is as defined herein. In certain embodiments, in any one of the formulae described herein, U is –C(R¹)=; V is –N=; and X is –N(R³)–; wherein R¹ and R³ are each as defined herein. In certain embodiments, in any one of the formulae described herein, U is –C(R¹)=; V is –N=; and X is –N(H)–; wherein R¹ is as defined herein. Attorney Docket No.156A002WO01 [0077] In certain embodiments, in any one of the formulae described herein, including Formulae (I) to (VII), (IVa) to (IVd), and (Va) to (Vd), U is –N=; V is –C(R¹)=; and X is –N(R³)–; wherein R¹ and R³ are each as defined herein. In certain embodiments, in any one of the formulae described herein, including Formulae (I) to (VII), (IVa) to (IVd), and (Va) to (Vd), U is –N=; V is –C(R¹)=; and X is –N(H)–; wherein R¹ is as defined herein. In certain embodiments, in any one of the formulae described herein, including Formulae (I) to (VII), (IVa) to (IVd), and (Va) to (Vd), U is –N=; V is –C(H)=, –C(CN)=, –C(F)=, –C(CH₃)=, –C(CF₃)=, or –C(CH2OH)=; and X is –N(H)–. In certain embodiments, in any one of the formulae described herein, including Formulae (I) to (VII), (IVa) to (IVd), and (Va) to (Vd), U is –N=; V is –C(F)=, –C(CH₃)=, or –C(CF₃)=; and X is –N(H)–. In certain embodiments, in any one of the formulae described herein, U is –N(R³)–; V is –C(R¹)=; and X is –N=; wherein R¹ and R³ are each as defined herein. In certain embodiments, in any one of the formulae described herein, U is –N(H)–; V is –C(R¹)=; and X is –N=; wherein R¹ is as defined herein. [0078] In certain embodiments, in any one of the formulae described herein, including Formulae (I) to (VII), (IVa) to (IVd), and (Va) to (Vd), U is –N=; V is –N(R³)–; and X is –C(R¹)=; wherein R¹ and R³ are each as defined herein. In certain embodiments, in any one of the formulae described herein, including Formulae (I) to (VII), (IVa) to (IVd), and (Va) to (Vd), U is –N=; V is –N(H)–; and X is –C(R¹)=; wherein R¹ is as defined herein. In certain embodiments, in any one of the formulae described herein, including Formulae (I) to (VII), (IVa) to (IVd), and (Va) to (Vd), U is –N=; V is –N(H)–; and X is –C(H)=, –C(CN)=, –C(F)=, –C(CH3)=, –C(CF3)=, or –C(CH2OH)=. In certain embodiments, in any one of the formulae described herein, including Formulae (I) to (VII), (IVa) to (IVd), and (Va) to (Vd), U is –N=; V is –N(H)–; and X is –C(CH₃)=. In certain embodiments, in any one of the formulae described herein, including Formulae (I) to (VII), (IVa) to (IVd), and (Va) to (Vd), U is –N(R³)–; V is –N=; and X is –C(R¹)=; wherein R¹ and R³ are each as defined herein. In certain embodiments, in any one of the formulae described herein, including Formulae (I) to (VII), (IVa) to (IVd), and (Va) to (Vd), U is –N(H)–; V is –N=; and X is –C(R¹)=; wherein R¹ is as defined herein. [0079] In certain embodiments, in any one of the formulae described herein, including Formulae (I) to (VII), (IVa) to (IVd), and (Va) to (Vd), U and V are each –N=; and X is –N(R³)–; wherein R³ is as defined herein. In certain embodiments, in any one of the formulae Attorney Docket No.156A002WO01 described herein, including Formulae (I) to (VII), (IVa) to (IVd), and (Va) to (Vd), U and V are each –N=; and X is –N(H)–. In certain embodiments, in any one of the formulae described herein, U and X are each –N=; and V is –N(R³)–; wherein R³ is as defined herein. In certain embodiments, in any one of the formulae described herein, U and X are each –N=; and V is –N(H)–. In certain embodiments, in any one of the formulae described herein, U is –N(R³)–; and V and X are each –N=; wherein R³ is as defined herein. In certain embodiments, in any one of the formulae described herein, U is –N(H)–; and V and X are each –N=. [0080] In yet another embodiment, provided herein is a compound of Formula (VIII): or an enantiomer, a mixture of

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, R³, R⁵, and Z are each as defined herein. [0081] In one embodiment, provided herein is a compound in an endo configuration, having the structure of Formula (VIIIa): or an enantiomer, a mixture of of two or more

diastereomers, a tautomer, a or more or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R¹, R², R³, R⁵, and Z are each as defined herein. [0082] In another embodiment, provided herein is a compound in an endo configuration, having the structure of Formula (VIIIb): Attorney Docket No.156A002WO01

or an enantiomer, a mixture of 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, R³, R⁵, and Z are each as defined herein. [0083] In yet another embodiment, provided herein is a compound in an exo configuration, having the structure of Formula (VIIIc): or an enantiomer, a mixture of

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, R³, R⁵, and Z are each as defined herein. [0084] In still another embodiment, provided herein is a compound in an exo configuration, having the structure of Formula (VIIId): or an enantiomer, a mixture of of two or more diastereomers, a tautomer, a

or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R¹, R², R³, R⁵, and Z are each as defined herein. [0085] In yet another embodiment, provided herein is a compound of Formula (IX): Attorney Docket No.156A002WO01

or an enantiomer, a mixture of 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, R³, R⁵, and Z are each as defined herein. [0086] In one embodiment, provided herein is a compound in an endo configuration, having the structure of Formula (IXa): or an enantiomer, a mixture of

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, R³, R⁵, and Z are each as defined herein. [0087] In another embodiment, provided herein is a compound in an endo configuration, having the structure of Formula (IXb): or an enantiomer, a mixture of mixture of two or more diastereomers, a tautomer, a

or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R¹, R², R³, R⁵, and Z are each as defined herein. [0088] In yet another embodiment, provided herein is a compound in an exo configuration, having the structure of Formula (IXc): Attorney Docket No.156A002WO01

or an enantiomer, a mixture of 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, R³, R⁵, and Z are each as defined herein. [0089] In still another embodiment, provided herein is a compound in an exo configuration, having the structure of Formula (IXd): or an enantiomer, a mixture of

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, R³, R⁵, and Z are each as defined herein. [0090] In yet another embodiment, provided herein is a compound of Formula (X): or an enantiomer, a mixture of mixture of two or more diastereomers, a tautomer, a

or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R¹, R², R³, R⁵, and Z are each as defined herein. [0091] In yet another embodiment, provided herein is a compound of Formula (XI): Attorney Docket No.156A002WO01

or an enantiomer, a mixture of 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, R³, R⁵, and Z are each as defined herein. [0092] In one embodiment, in any one of Formulae (VIII) to (XI), (VIIIa) to (VIIId), and (IXa) to (IXd), R¹ is (i) hydrogen, cyano, or halo; or (ii) C1-6 alkyl or C3-10 cycloalkyl, each optionally substituted with one, two, or three substituents Q; R² is heteroaryl, optionally substituted with one, two, or three substituents Q; R³ is hydrogen or C1-6 alkyl optionally substituted with one, two, or three substituents Q; R⁵ is C_6-14 aryl or heteroaryl, each optionally substituted with one, two, or three substituents Q; and Z is –O–, –N(R^1a)–, or C_1-6 alkylene optionally substituted with one, two, or three substituents Q; wherein R^1a is as defined herein. [0093] In another embodiment, in any one of Formulae (VIII) to (XI), (VIIIa) to (VIIId), and (IXa) to (IXd), R¹ is (i) hydrogen, cyano, or halo; or (ii) C_1-6 alkyl or monocyclic C_3-10 cycloalkyl, each optionally substituted with one, two, or three substituents Q; R² is monocyclic heteroaryl, optionally substituted with one, two, or three substituents Q; R³ is hydrogen or C1-6 alkyl optionally substituted with one, two, or three substituents Q; R⁵ is phenyl or monocyclic heteroaryl, each optionally substituted with one, two, or three substituents Q; and Z is –O–, –N(H)–, or C1-6 alkylene optionally substituted with one, two, or three substituents Q. Attorney Docket No.156A002WO01 [0094] In yet another embodiment, in any one of Formulae (VIII) to (XI), (VIIIa) to (VIIId), and (IXa) to (IXd), R¹ is hydrogen, cyano, fluoro, chloro, bromo, methyl, hydroxymethyl, cyclopropyl, cyclobutyl, or methoxy; R² is pyridinyl, pyridazinyl, or pyrimidinyl, each optionally substituted with one, two, or three substituents, wherein each substituent is independently cyano, oxo, methyl, trifluoromethyl, hydroxymethyl, cyclopropyl, hydroxyl, or methoxy; R³ is hydrogen or methyl; R⁵ is phenyl or pyridinyl, each optionally substituted with one, two, or three substituents, wherein each substituent is independently fluoro, chloro, methyl, ethyl, isopropyl, trifluoromethyl, hydroxymethyl, aminomethyl, or cyclopropyl; and Z is –O–, –N(H)–, or methanediyl. [0095] In yet another embodiment, in any one of Formulae (VIII) to (XI), (VIIIa) to (VIIId), and (IXa) to (IXd), R¹ is hydrogen, cyano, fluoro, chloro, bromo, methyl, hydroxymethyl, cyclopropyl, cyclobutyl, or methoxy; R² is pyridinyl, pyridazinyl, or pyrimidinyl, each optionally substituted with one, two, or three substituents, wherein each substituent is independently cyano, fluoro, chloro, oxo, methyl, hydroxymethyl, cyclopropyl, hydroxyl, methoxy, or amino; R³ is hydrogen or methyl; R⁵ is phenyl or pyridinyl, each optionally substituted with one, two, or three substituents, wherein each substituent is independently cyano, fluoro, chloro, bromo, methyl, or trifluoromethyl; and Z is –O–, –N(H)–, or methanediyl. [0096] In yet another embodiment, in any one of Formulae (VIII) to (XI), (VIIIa) to (VIIId), and (IXa) to (IXd), R¹ is hydrogen, cyano, fluoro, chloro, methyl, hydroxymethyl, cyclopropyl, or cyclobutyl; R² is pyridin-3-yl, pyridin-4-yl, pyridazin-4-yl, or pyrimidin-4-yl, each optionally substituted with one, two, or three substituents, wherein each substituent is independently cyano, Attorney Docket No.156A002WO01 oxo, methyl, trifluoromethyl, hydroxymethyl, cyclopropyl, hydroxyl, or methoxy; R³ is hydrogen or methyl; R⁵ is phenyl, pyridin-2-yl, or pyridin-3-yl, each optionally substituted with one, two, or three substituents, wherein each substituent is independently fluoro, chloro, methyl, ethyl, isopropyl, trifluoromethyl, hydroxymethyl, aminomethyl, or cyclopropyl; and Z is –O–, –N(H)–, or methanediyl. [0097] In yet another embodiment, in any one of Formulae (VIII) to (XI), (VIIIa) to (VIIId), and (IXa) to (IXd), R¹ is hydrogen, cyano, fluoro, chloro, bromo, methyl, hydroxymethyl, cyclopropyl, cyclobutyl, or methoxy; R² is pyridin-3-yl, pyridin-4-yl, pyridazin-4-yl, or pyrimidin-4-yl, each optionally substituted with one, two, or three substituents, wherein each substituent is independently cyano, fluoro, chloro, oxo, methyl, hydroxymethyl, cyclopropyl, hydroxyl, methoxy, or amino; R³ is hydrogen or methyl; R⁵ is phenyl or pyridin-3-yl, each optionally substituted with one, two, or three substituents, wherein each substituent is independently cyano, fluoro, chloro, bromo, methyl, or trifluoromethyl; and Z is –O–, –N(H)–, or methanediyl. [0098] In yet another embodiment, in any one of Formulae (VIII) to (XI), (VIIIa) to (VIIId), and (IXa) to (IXd), R¹ is hydrogen, cyano, fluoro, chloro, methyl, trifluoromethyl, or hydroxymethyl; R² is pyridin-4-yl, 1-oxopyridin-4-yl, 3-cyanopyridin-4-yl, 6-cyanopyridin-3-yl, 3-methylpyridin-4-yl, 6-hydroxylpyridin-3-yl, pyridazin-4-yl, 6-cyanopyridazin-4-yl, 3-methyl- pyridazin-4-yl, 5-methylpyridazin-4-yl, 6-methylpyridazin-4-yl, 5-trifluomethylpyridazin-4-yl, 5-hydroxymethylpyridazin-4-yl, 5-cyclopropylpyridazin-4-yl, 3-hydroxypyridazin-4-yl, 3- methoxypyridazin-4-yl, or pyrimidin-4-yl; R³ is hydrogen; R⁵ is 4-fluorophenyl, 4-chlorophenyl, 4-chloro-3-fluoroophenyl, 5-chloropyridin- 2-yl, 6-fluoropyridin-3-yl, 6-chloropyridin-3-yl, 6-methylpyridin-3-yl, 6-trifluoromethylpyridin- 3-yl, 6-isopropylpyridin-3-yl, 6-cyclopropylpyridin-3-yl, 6-chloro-5-fluoropyridin-3-yl, 6-fluoro- Attorney Docket No.156A002WO01 2-methylpyridin-3-yl, 6-chloro-2-methylpyridin-3-yl, 6-chloro-5-methylpyridin-3-yl, 6-chloro-2- ethylpyridin-3-yl, 6-chloro-2-trifluoromethylpyridin-3-yl, 6-chloro-2-hydroxymethylpyridin-3- yl, 2-aminomethyl-6-chloropyridin-3-yl, or 6-chloro-5-cyclopropylpyridin-3-yl; and Z is –O–, –N(H)–, or methanediyl. [0099] In still another embodiment, in any one of Formulae (VIII) to (XI), (VIIIa) to (VIIId), and (IXa) to (IXd), R¹ is hydrogen, chloro, bromo, methyl, or hydroxymethyl; R² is 6-cyanopyridin-3-yl, 6-hydroxylpyridin-3-yl, pyridin-4-yl, 3-cyanopyridin- 4-yl, 1-oxopyridin-4-yl, pyridazin-4-yl, 3-methylpyridazin-4-yl, 5-methylpyridazin-4-yl, 5- hydroxymethylpyridazin-4-yl, 6-cyano-pyridazin-4-yl, 6-methylpyridazin-4-yl, or pyrimidin-4- yl; R³ is hydrogen; R⁵ is 4-fluorophenyl, 4-chlorophenyl, 3-fluoro-4-chlorophenyl, 6-chloropyridin-3- yl, or 6-methylpyridin-3-yl; and Z is –O–, –N(H)–, or methanediyl. [00100] In certain embodiments, in any one of the formulae described herein, including Formulae (I) to (XI), (IVa) to (IVd), (Va) to (Vd), (VIIIa) to (VIIId), and (IXa) to (IXd), R¹ is (i) hydrogen, deuterium, halo, or hydroxyl; or (ii) C1-6 alkyl or C3-10 cycloalkyl, each optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R¹ is (i) hydrogen, deuterium, halo, or hydroxyl; or (ii) C_1-6 alkyl or monocyclic C3-10 cycloalkyl, each optionally substituted with one, two, or three substituents Q. In certain embodiments, in any one of the formulae described herein, R¹ is (i) hydrogen, deuterium, halo, or hydroxyl; or (ii) C_1-6 alkyl, optionally substituted with one, two, or three substituents Q. In certain embodiments, in any one of the formulae described herein, R¹ is (i) hydrogen or deuterium; or (ii) C1-6 alkyl, optionally substituted with one, two, or three substituents Q. In certain embodiments, in any one of the formulae described herein, R¹ is hydrogen. In certain embodiments, in any one of the formulae described herein, R¹ is halo. In certain embodiments, in any one of the formulae described herein, R¹ is fluoro, chloro, or bromo. In certain embodiments, in any one of the formulae described herein, R¹ is C_1-6 alkyl, optionally substituted with one, two, or three substituents Q. In certain embodiments, in any one of the Attorney Docket No.156A002WO01 formulae described herein, R¹ is monocyclic C3-10 cycloalkyl, optionally substituted with one, two, or three substituents Q. In certain embodiments, in any one of the formulae described herein, R¹ is hydrogen, cyano, fluoro, chloro, bromo, methyl, hydroxymethyl, cyclopropyl, cyclobutyl, or methoxy. In certain embodiments, in any one of the formulae described herein, R¹ is hydrogen, methyl, or hydroxymethyl. [00101] In yet another embodiment, provided herein is a compound of Formula (XII): or an enantiomer, a mixture of

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 R², R³, R⁵, and Z are each as defined herein. [00102] In one embodiment, provided herein is a compound in an endo configuration, having the structure of Formula (XIIa): or an enantiomer, a mixture of of two or more

diastereomers, a tautomer, a two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R², R³, R⁵, and Z are each as defined herein. [00103] In another embodiment, provided herein is a compound in an endo configuration, having the structure of Formula (XIIb): or an enantiomer, a mixture of of two or more diastereomers, a tautomer, a

or an isotopic variant thereof; or Attorney Docket No.156A002WO01 a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R², R³, R⁵, and Z are each as defined herein. [00104] In yet another embodiment, provided herein is a compound in an exo configuration, having the structure of Formula (XIIc): or an enantiomer, a mixture of

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 R², R³, R⁵, and Z are each as defined herein. [00105] In still another embodiment, provided herein is a compound in an exo configuration, having the structure of Formula (XIId): or an enantiomer, a mixture of 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 R², R³, R⁵, and Z are each as defined herein. [00106] In yet another embodiment, provided herein is a compound of Formula (XIII): or an enantiomer, a mixture of mixture of two or more diastereomers, a tautomer, a

or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R², R³, R⁵, and Z are each as defined herein. Attorney Docket No.156A002WO01 [00107] In one embodiment, provided herein is in an endo configuration, having the structure of Formula (XIIIa):

or an enantiomer, a mixture of a a 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 R², R³, R⁵, and Z are each as defined herein. [00108] In another embodiment, provided herein is in an endo configuration, having the structure of Formula (XIIIb): or an enantiomer, a mixture of

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 R², R³, R⁵, and Z are each as defined herein. [00109] In yet another embodiment, provided herein is in an exo configuration, having the structure of Formula (XIIIc): or an enantiomer, a mixture of of two or more diastereomers, a tautomer, a

or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R², R³, R⁵, and Z are each as defined herein. Attorney Docket No.156A002WO01 [00110] In still another embodiment, provided herein is in an endo configuration, having the structure of Formula (XIIId):

or an enantiomer, a mixture of a a 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 R², R³, R⁵, and Z are each as defined herein. [00111] In yet another embodiment, provided herein is a compound of Formula (XIV): or an enantiomer, a mixture of

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 R², R³, R⁵, and Z are each as defined herein. [00112] In still another embodiment, provided herein is a compound of Formula (XV): or an enantiomer, a mixture of mixture of two or more diastereomers, a tautomer, a

or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R², R³, R⁵, and Z are each as defined herein. [00113] In one embodiment, in any one of Formulae (XII) to (XV), (XIIa) to (XIId), and (XIIIa) to (XIIId), R² is heteroaryl, optionally substituted with one, two, or three substituents Q; R³ is hydrogen or C_1-6 alkyl optionally substituted with one, two, or three Attorney Docket No.156A002WO01 substituents Q; R⁵ is C6-14 aryl or heteroaryl, each optionally substituted with one, two, or three substituents Q; and Z is –O–, –N(R^1a)–, or C1-6 alkylene optionally substituted with one, two, or three substituents Q; wherein R^1a is as defined herein. [00114] In another embodiment, in any one of Formulae (XII) to (XV), (XIIa) to (XIId), and (XIIIa) to (XIIId), R² is monocyclic heteroaryl, optionally substituted with one, two, or three substituents Q; R³ is hydrogen or C_1-6 alkyl optionally substituted with one, two, or three substituents Q; R⁵ is phenyl or monocyclic heteroaryl, each optionally substituted with one, two, or three substituents Q; and Z is –O–, –N(H)–, or C1-6 alkylene optionally substituted with one, two, or three substituents Q. [00115] In yet another embodiment, in any one of Formulae (XII) to (XV), (XIIa) to (XIId), and (XIIIa) to (XIIId), R² is pyridinyl, pyridazinyl, or pyrimidinyl, each optionally substituted with one, two, or three substituents, wherein each substituent is independently cyano, oxo, methyl, trifluoromethyl, hydroxymethyl, cyclopropyl, hydroxyl, or methoxy; R³ is hydrogen or methyl; R⁵ is phenyl or pyridinyl, each optionally substituted with one, two, or three substituents, wherein each substituent is independently fluoro, chloro, methyl, ethyl, isopropyl, trifluoromethyl, hydroxymethyl, aminomethyl, or cyclopropyl; and Z is –O–, –N(H)–, or methanediyl. [00116] In yet another embodiment, in any one of Formulae (XII) to (XV), (XIIa) to (XIId), and (XIIIa) to (XIIId), R² is pyridinyl, pyridazinyl, or pyrimidinyl, each optionally substituted with one, two, or three substituents, wherein each substituent is independently cyano, fluoro, chloro, oxo, Attorney Docket No.156A002WO01 methyl, hydroxymethyl, cyclopropyl, hydroxyl, methoxy, or amino; R³ is hydrogen or methyl; R⁵ is phenyl or pyridinyl, each optionally substituted with one, two, or three substituents, wherein each substituent is independently cyano, fluoro, chloro, bromo, methyl, or trifluoromethyl; and Z is –O–, –N(H)–, or methanediyl. [00117] In yet another embodiment, in any one of Formulae (XII) to (XV), (XIIa) to (XIId), and (XIIIa) to (XIIId), R² is pyridin-3-yl, pyridin-4-yl, pyridazin-4-yl, or pyrimidin-4-yl, each optionally substituted with one, two, or three substituents, wherein each substituent is independently cyano, oxo, methyl, trifluoromethyl, hydroxymethyl, cyclopropyl, hydroxyl, or methoxy; R³ is hydrogen or methyl; R⁵ is phenyl, pyridin-2-yl, or pyridin-3-yl, each optionally substituted with one, two, or three substituents, wherein each substituent is independently fluoro, chloro, methyl, ethyl, isopropyl, trifluoromethyl, hydroxymethyl, aminomethyl, or cyclopropyl; and Z is –O–, –N(H)–, or methanediyl. [00118] In yet another embodiment, in any one of Formulae (XII) to (XV), (XIIa) to (XIId), and (XIIIa) to (XIIId), R² is pyridin-3-yl, pyridin-4-yl, pyridazin-4-yl, or pyrimidin-4-yl, each optionally substituted with one, two, or three substituents, wherein each substituent is independently cyano, fluoro, chloro, oxo, methyl, hydroxymethyl, cyclopropyl, hydroxyl, methoxy, or amino; R³ is hydrogen or methyl; R⁵ is phenyl or pyridin-3-yl, each optionally substituted with one, two, or three substituents, wherein each substituent is independently cyano, fluoro, chloro, bromo, methyl, or trifluoromethyl; and Z is –O–, –N(H)–, or methanediyl. [00119] In yet another embodiment, in any one of Formulae (XII) to (XV), (XIIa) to (XIId), and (XIIIa) to (XIIId), R² is pyridin-4-yl, 1-oxopyridin-4-yl, 3-cyanopyridin-4-yl, 6-cyanopyridin-3-yl, Attorney Docket No.156A002WO01 3-methylpyridin-4-yl, 6-hydroxylpyridin-3-yl, pyridazin-4-yl, 6-cyanopyridazin-4-yl, 3-methyl- pyridazin-4-yl, 5-methylpyridazin-4-yl, 6-methylpyridazin-4-yl, 5-trifluomethylpyridazin-4-yl, 5-hydroxymethylpyridazin-4-yl, 5-cyclopropylpyridazin-4-yl, 3-hydroxypyridazin-4-yl, 3- methoxypyridazin-4-yl, or pyrimidin-4-yl; R³ is hydrogen; R⁵ is 4-fluorophenyl, 4-chlorophenyl, 4-chloro-3-fluoroophenyl, 5-chloropyridin- 2-yl, 6-fluoropyridin-3-yl, 6-chloropyridin-3-yl, 6-methylpyridin-3-yl, 6-trifluoromethylpyridin- 3-yl, 6-isopropylpyridin-3-yl, 6-cyclopropylpyridin-3-yl, 6-chloro-5-fluoropyridin-3-yl, 6-fluoro- 2-methylpyridin-3-yl, 6-chloro-2-methylpyridin-3-yl, 6-chloro-5-methylpyridin-3-yl, 6-chloro-2- ethylpyridin-3-yl, 6-chloro-2-trifluoromethylpyridin-3-yl, 6-chloro-2-hydroxymethylpyridin-3- yl, 2-aminomethyl-6-chloropyridin-3-yl, or 6-chloro-5-cyclopropylpyridin-3-yl; and Z is –O–, –N(H)–, or methanediyl. [00120] In still another embodiment, in any one of Formulae (XII) to (XV), (XIIa) to (XIId), and (XIIIa) to (XIIId), R² is 6-cyanopyridin-3-yl, 6-hydroxylpyridin-3-yl, pyridin-4-yl, 3-cyanopyridin- 4-yl, 1-oxopyridin-4-yl, pyridazin-4-yl, 3-methylpyridazin-4-yl, 5-methylpyridazin-4-yl, 5- hydroxymethylpyridazin-4-yl, 6-cyano-pyridazin-4-yl, 6-methylpyridazin-4-yl, or pyrimidin-4- yl; R³ is hydrogen; R⁵ is 4-fluorophenyl, 4-chlorophenyl, 3-fluoro-4-chlorophenyl, 6-chloropyridin-3- yl, or 6-methylpyridin-3-yl; and Z is –O–, –N(H)–, or methanediyl. [00121] In certain embodiments, in any one of the formulae described herein, including Formulae (I) to (XV), (IVa) to (IVd), (Va) to (Vd), (VIIIa) to (VIIId), (IXa) to (IXd), (XIIa) to (XIId), and (XIIIa) to (XIIId), R² is C6-14 aryl or heteroaryl, each optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R² is heteroaryl, optionally substituted with one, two, or three substituents Q. In certain embodiments, in any one of the formulae described herein, R² is monocyclic heteroaryl, optionally substituted with one, two, or three substituents Q. In certain embodiments, in any one of the formulae described herein, R² is 5- or 6-membered heteroaryl, each optionally substituted Attorney Docket No.156A002WO01 with one, two, or three substituents Q. In certain embodiments, in any one of the formulae described herein, R² is 6-membered heteroaryl, optionally substituted with one, two, or three substituents Q. In certain embodiments, in any one of the formulae described herein, R² is pyridinyl, pyridazinyl, or pyrimidinyl, each optionally substituted with one, two, or three substituents Q. In certain embodiments, in any one of the formulae described herein, R² is pyridinyl, pyridazinyl, or pyrimidinyl, each optionally substituted with one, two, or three substituents, wherein each substituent is independently cyano, oxo, methyl, trifluoromethyl, hydroxymethyl, cyclopropyl, hydroxyl, or methoxy. In certain embodiments, in any one of the formulae described herein, R² is pyridinyl, pyridazinyl, or pyrimidinyl, each optionally substituted with one, two, or three substituents, wherein each substituent is independently cyano, oxo, fluoro, chloro, methyl, hydroxymethyl, cyclopropyl, hydroxyl, methoxy, or amino. In certain embodiments, in any one of the formulae described herein, R² is pyridin-3-yl, pyridin-4- yl, pyridazin-4-yl, or pyrimidin-4-yl, each optionally substituted with one, two, or three substituents, wherein each substituent is independently cyano, oxo, methyl, trifluoromethyl, hydroxymethyl, cyclopropyl, hydroxyl, or methoxy. In certain embodiments, in any one of the formulae described herein, R² is pyridin-3-yl, pyridin-4-yl, pyridazin-4-yl, or pyrimidin-4-yl, each optionally substituted with one, two, or three substituents, wherein each substituent is independently cyano, oxo, fluoro, chloro, methyl, hydroxymethyl, cyclopropyl, hydroxyl, methoxy, or amino. [00122] In certain embodiments, in any one of the formulae described herein, R² is pyridin-4-yl, 1-oxopyridin-4-yl, 3-cyanopyridin-4-yl, 6-cyanopyridin-3-yl, 3-methylpyridin-4-yl, 6-hydroxylpyridin-3-yl, pyridazin-4-yl, 6-cyanopyridazin-4-yl, 3-methyl-pyridazin-4-yl, 5- methylpyridazin-4-yl, 6-methylpyridazin-4-yl, 5-trifluomethylpyridazin-4-yl, 5- hydroxymethylpyridazin-4-yl, 5-cyclopropylpyridazin-4-yl, 3-hydroxypyridazin-4-yl, 3- methoxypyridazin-4-yl, or pyrimidin-4-yl. In certain embodiments, in any one of the formulae described herein, R² is 6-cyanopyridin-3-yl, 6-hydroxylpyridin-3-yl, pyridin-4-yl, 3- cyanopyridin-4-yl, 1-oxopyridin-4-yl, pyridazin-4-yl, 3-methylpyridazin-4-yl, 5-methyl- pyridazin-4-yl, 5-hydroxymethylpyridazin-4-yl, 6-cyano-pyridazin-4-yl, 6-methylpyridazin-4-yl, or pyrimidin-4-yl. [00123] In certain embodiments, in any one of the formulae described herein, including Attorney Docket No.156A002WO01 Formulae (I) to (XV), (IVa) to (IVd), (Va) to (Vd), (VIIIa) to (VIIId), (IXa) to (IXd), (XIIa) to (XIId), and (XIIIa) to (XIIId), R³ is hydrogen or C1-6 alkyl optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R³ is C1-6 alkyl, optionally substituted with one, two, or three substituents Q. In certain embodiments, in any one of the formulae described herein, R³ is hydrogen or methyl. In certain embodiments, in any one of the formulae described herein, R³ is hydrogen. [00124] In certain embodiments, in any one of the formulae described herein, including Formulae (I) to (XV), (IVa) to (IVd), (Va) to (Vd), (VIIIa) to (VIIId), (IXa) to (IXd), (XIIa) to (XIId), and (XIIIa) to (XIIId), R⁴ is hydrogen. [00125] In certain embodiments, in any one of the formulae described herein, including Formulae (I) to (XV), (IVa) to (IVd), (Va) to (Vd), (VIIIa) to (VIIId), (IXa) to (IXd), (XIIa) to (XIId), and (XIIIa) to (XIIId), R⁵ is C6-14 aryl or heteroaryl, each optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R⁵ is C6-14 aryl, optionally substituted with one, two, or three substituents Q. In certain embodiments, in any one of the formulae described herein, R⁵ is phenyl, optionally substituted with one, two, or three substituents Q. In certain embodiments, in any one of the formulae described herein, R⁵ is heteroaryl, optionally substituted with one, two, or three substituents Q. In certain embodiments, in any one of the formulae described herein, R⁵ is monocyclic heteroaryl, optionally substituted with one, two, or three substituents Q. In certain embodiments, in any one of the formulae described herein, R⁵ is 5- or 6-membered heteroaryl, each optionally substituted with one, two, or three substituents Q. In certain embodiments, in any one of the formulae described herein, R⁵ is 6-membered heteroaryl, optionally substituted with one, two, or three substituents Q. [00126] In certain embodiments, in any one of the formulae described herein, R⁵ is phenyl or pyridinyl, each optionally substituted with one, two, or three substituents, wherein each substituent is independently fluoro, chloro, methyl, ethyl, isopropyl, trifluoromethyl, hydroxymethyl, aminomethyl, or cyclopropyl. In certain embodiments, in any one of the formulae described herein, R⁵ is phenyl or pyridinyl, each optionally substituted with one, two, or three substituents, wherein each substituent is independently cyano, fluoro, chloro, bromo, Attorney Docket No.156A002WO01 methyl, or trifluoromethyl. In certain embodiments, in any one of the formulae described herein, R⁵ is phenyl, pyridin-2-yl, or pyridin-3-yl, each optionally substituted with one, two, or three substituents, wherein each substituent is independently fluoro, chloro, methyl, ethyl, isopropyl, trifluoromethyl, hydroxymethyl, aminomethyl, or cyclopropyl. In certain embodiments, in any one of the formulae described herein, R⁵ is phenyl or pyridin-3-yl, each optionally substituted with one, two, or three substituents, wherein each substituent is independently cyano, fluoro, chloro, bromo, methyl, or trifluoromethyl. In certain embodiments, in any one of the formulae described herein, R⁵4-fluorophenyl, 4-chlorophenyl, 4-chloro-3-fluoroophenyl, 5-chloropyridin- 2-yl, 6-fluoropyridin-3-yl, 6-chloropyridin-3-yl, 6-methylpyridin-3-yl, 6-trifluoromethylpyridin- 3-yl, 6-isopropylpyridin-3-yl, 6-cyclopropylpyridin-3-yl, 6-chloro-5-fluoropyridin-3-yl, 6-fluoro- 2-methylpyridin-3-yl, 6-chloro-2-methylpyridin-3-yl, 6-chloro-5-methylpyridin-3-yl, 6-chloro-2- ethylpyridin-3-yl, 6-chloro-2-trifluoromethylpyridin-3-yl, 6-chloro-2-hydroxymethylpyridin-3- yl, 2-aminomethyl-6-chloropyridin-3-yl, or 6-chloro-5-cyclopropylpyridin-3-yl. In certain embodiments, in any one of the formulae described herein, R⁵ is 4-fluorophenyl, 4-chlorophenyl, 3-fluoro-4-chlorophenyl, 6-chloropyridin-3-yl, or 6-methylpyridin-3-yl. [00127] In certain embodiments, in any one of the formulae described herein, including Formulae (I) to (XV), (IVa) to (IVd), (Va) to (Vd), (VIIIa) to (VIIId), (IXa) to (IXd), (XIIa) to (XIId), and (XIIIa) to (XIIId), Z is –O–. In certain embodiments, in any one of the formulae described herein, Z is –S–. In certain embodiments, in any one of the formulae described herein, Z is –N(R⁴)–, wherein R⁴ is as defined herein. In certain embodiments, in any one of the formulae described herein, Z is –N(H)–. In certain embodiments, in any one of the formulae described herein, Z is C_1-6 alkylene, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, Z is methanediyl, optionally substituted with one, two, or three substituents Q. In certain embodiments, in any one of the formulae described herein, Z is methanediyl. [00128] The groups, R¹, R², R³, R⁴, R⁵, U, V, X, Y, and Z in the formulae described herein, including Formulae (I) to (XV), (IVa) to (IVd), (Va) to (Vd), (VIIIa) to (VIIId), (IXa) to (IXd), (XIIa) to (XIId), and (XIIIa) to (XIIId), are defined in the embodiments described herein. All combinations of the embodiments provided herein for such groups are within the scope of this disclosure. Attorney Docket No.156A002WO01 [00129] 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 bromo. In certain embodiments, R¹ is nitro. In certain embodiments, R¹ is C1-6 alkyl, optionally substituted with one or more substituents Q. In certain embodiments, R¹ is methyl, optionally substituted with one or more substituents Q. In certain embodiments, R¹ is methyl or hydroxymethyl. In certain embodiments, R¹ is C1-6 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 C3-10 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 C7-15 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. [00130] 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 methoxy. 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 Attorney Docket No.156A002WO01 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. [00131] In certain embodiments, R² is C3-10 cycloalkyl, optionally substituted with one or more substituents Q. In certain embodiments, R² is monocyclic C3-10 cycloalkyl, optionally substituted with one or more substituents Q. In certain embodiments, R² is bicyclic C_4-10 cycloalkyl, optionally substituted with one or more substituents Q. In certain embodiments, R² is bridged, fused, or spiro C4-10 cycloalkyl, each 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 phenyl, optionally substituted with one or more substituents Q. In certain embodiments, R² is bicyclic C8-15 aryl, optionally substituted with one Attorney Docket No.156A002WO01 or more substituents Q. [00132] In certain embodiments, R² is heteroaryl, optionally substituted with one or more substituents Q. In certain embodiments, R² is monocyclic heteroaryl, optionally substituted with one or more substituents Q. In certain embodiments, R² is 5-membered heteroaryl, each optionally substituted with one or more substituents Q. In certain embodiments, R² is 6- membered heteroaryl, each optionally substituted with one or more substituents Q. In certain embodiments, R² is pyridinyl, pyridazinyl, or pyrimidinyl, each optionally substituted with one or more substituents Q. In certain embodiments, R² is pyridin-3-yl, pyridin-4-yl, pyridazin-4-yl, or pyrimidin-4-yl, each optionally substituted with one or more substituents Q. In certain embodiments, R² is pyridin-4-yl, 1-oxopyridin-4-yl, 3-cyanopyridin-4-yl, 6-cyanopyridin-3-yl, 3- methylpyridin-4-yl, 6-hydroxylpyridin-3-yl, pyridazin-4-yl, 6-cyanopyridazin-4-yl, 3---4-yl, 5- methylpyridazin-4-yl, 6-methylpyridazin-4-yl, 5-trifluomethylpyridazin-4-yl, 5-hydroxymethyl- pyridazin-4-yl, 5-cyclopropylpyridazin-4-yl, 3-hydroxypyridazin-4-yl, 3-methoxypyridazin-4-yl, or pyrimidin-4-yl. In certain embodiments, R² is 6-cyanopyridin-3-yl, 6-hydroxylpyridin-3-yl, pyridin-4-yl, 3-cyanopyridin-4-yl, 1-oxopyridin-4-yl, pyridazin-4-yl, 3-methylpyridazin-4-yl, 5- methylpyridazin-4-yl, 5-hydroxymethylpyridazin-4-yl, 6-cyanopyridazin-4-yl, 6-methyl- pyridazin-4-yl, or pyrimidin-4-yl. In certain embodiments, R² is bicyclic heteroaryl, optionally substituted with one or more substituents Q. In certain embodiments, R² is 5,5-, 5,6-, or 6,6- fused heteroaryl, each optionally substituted with one or more substituents Q. In certain embodiments, R² is 5,5-fused heteroaryl, optionally substituted with one or more substituents Q. In certain embodiments, R² is 5,6-fused heteroaryl, optionally substituted with one or more substituents Q. In certain embodiments, R² is 6,6-fused heteroaryl, optionally substituted with one or more substituents Q. [00133] In certain embodiments, R² is heterocyclyl, optionally substituted with one or more substituents Q. In certain embodiments, R² is monocyclic heterocyclyl, optionally substituted with one or more substituents Q. In certain embodiments, R² is 3-, 4-, 5-, 6-, or 7- membered heterocyclyl, each optionally substituted with one or more substituents Q. In certain embodiments, R² is bicyclic heterocyclyl, optionally substituted with one or more substituents Q. In certain embodiments, R² is bridged, fused, or spiro heterocyclyl, each optionally substituted with one or more substituents Q. Attorney Docket No.156A002WO01 [00134] In certain embodiments, R³ is hydrogen. In certain embodiments, R³ is C1-6 alkyl, optionally substituted with one or more substituents Q. In certain embodiments, R³ is methyl. In certain embodiments, R³ is C_1-6 heteroalkyl, optionally substituted with one or more substituents Q. In certain embodiments, R³ is trifluoromethyl. In certain embodiments, R³ is C2-6 alkenyl, optionally substituted with one or more substituents Q. In certain embodiments, R³ is C2-6 alkynyl, optionally substituted with one or more substituents Q. In certain embodiments, R³ is C_3-10 cycloalkyl, optionally substituted with one or more substituents Q. In certain embodiments, R³ is C6-14 aryl, optionally substituted with one or more substituents Q. In certain embodiments, R³ is C_7-15 aralkyl, optionally substituted with one or more substituents Q. In certain embodiments, R³ is heteroaryl, optionally substituted with one or more substituents Q. In certain embodiments, R³ is heterocyclyl, optionally substituted with one or more substituents Q. [00135] In certain embodiments, R³ is –C(O)R^1a, wherein R^1a is as defined herein. In certain embodiments, R³ is –C(O)OR^1a, wherein R^1a is as defined herein. In certain embodiments, R³ is –C(O)NR^1bR^1c, wherein R^1b and R^1c are each as defined herein. In certain embodiments, R³ is –C(O)SR^1a, wherein R^1a is as defined herein. In certain embodiments, R³ is –C(NR^1a)NR^1bR^1c, wherein R^1a, R^1b, and R^1c are each as defined herein. In certain embodiments, R³ is –C(S)R^1a, wherein R^1a is as defined herein. In certain embodiments, R³ is –C(S)OR^1a, wherein R^1a is as defined herein. In certain embodiments, R³ is –C(S)NR^1bR^1c, wherein R^1b and R^1c are each as defined herein. In certain embodiments, R³ is –S(O)R^1a, wherein R^1a is as defined herein. In certain embodiments, R³ is –S(O)₂R^1a, wherein R^1a is as defined herein. In certain embodiments, R³ is –S(O)NR^1bR^1c, wherein R^1b and R^1c are each as defined herein. In certain embodiments, R³ is –S(O)₂NR^1bR^1c, wherein R^1b and R^1c are each as defined herein. [00136] In certain embodiments, R⁴ is hydrogen. 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 C1-6 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 C2-6 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, Attorney Docket No.156A002WO01 R⁴ is C7-15 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. [00137] 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 –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. [00138] In certain embodiments, R⁵ is C3-10 cycloalkyl, optionally substituted with one or more substituents Q. In certain embodiments, R⁵ is monocyclic C_3-10 cycloalkyl, optionally substituted with one or more substituents Q. In certain embodiments, R⁵ is bicyclic C_4-10 cycloalkyl, optionally substituted with one or more substituents Q. In certain embodiments, R⁵ is bridged, fused, or spiro C_4-10 cycloalkyl, each 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 phenyl, optionally substituted with one or more substituents Q. In certain embodiments, R⁵ is 4-fluorophenyl, 4-chlorophenyl, or 3-fluoro-4- chlorophenyl. In certain embodiments, R⁵ is bicyclic C_8-15 aryl, optionally substituted with one or more substituents Q. [00139] In certain embodiments, R⁵ is heteroaryl, optionally substituted with one or more substituents Q. In certain embodiments, R⁵ is monocyclic heteroaryl, optionally substituted with one or more substituents Q. In certain embodiments, R⁵ is 5-membered heteroaryl, each optionally substituted with one or more substituents Q. In certain embodiments, R⁵ is 6- membered heteroaryl, each optionally substituted with one or more substituents Q. In certain Attorney Docket No.156A002WO01 embodiments, R⁵ is pyridinyl, optionally substituted with one or more substituents Q. In certain embodiments, R⁵ is pyridin-2-yl, optionally substituted with one or more substituents Q. In certain embodiments, R⁵ is pyridin-3-yl, optionally substituted with one or more substituents Q. In certain embodiments, R⁵ is 4-fluorophenyl, 4-chlorophenyl, 4-chloro-3-fluoroophenyl, 5- chloropyridin-2-yl, 6-fluoropyridin-3-yl, 6-chloropyridin-3-yl, 6-methylpyridin-3-yl, 6-trifluoro- methylpyridin-3-yl, 6-isopropylpyridin-3-yl, 6-cyclopropylpyridin-3-yl, 6-chloro-5-fluoro- pyridin-3-yl, 6-fluoro-2-methylpyridin-3-yl, 6-chloro-2-methylpyridin-3-yl, 6-chloro-5-methyl- pyridin-3-yl, 6-chloro-2-ethylpyridin-3-yl, 6-chloro-2-trifluoromethylpyridin-3-yl, 6-chloro-2- hydroxymethylpyridin-3-yl, 2-aminomethyl-6-chloropyridin-3-yl, or 6-chloro-5-cyclopropyl- pyridin-3-yl. In certain embodiments, R⁵ is 4-fluorophenyl, 4-chlorophenyl, 3-fluoro-4-chloro- phenyl, 6-chloropyridin-3-yl, or 6-methylpyridin-3-yl. In certain embodiments, R⁵ is bicyclic heteroaryl, optionally substituted with one or more substituents Q. In certain embodiments, R⁵ is 5,5-, 5,6-, or 6,6-fused heteroaryl, each optionally substituted with one or more substituents Q. In certain embodiments, R⁵ is 5,5-fused heteroaryl, optionally substituted with one or more substituents Q. In certain embodiments, R⁵ is 5,6-fused heteroaryl, optionally substituted with one or more substituents Q. In certain embodiments, R⁵ is 6,6-fused heteroaryl, optionally substituted with one or more substituents Q. [00140] In certain embodiments, R⁵ is heterocyclyl, optionally substituted with one or more substituents Q. In certain embodiments, R⁵ is monocyclic heterocyclyl, optionally substituted with one or more substituents Q. In certain embodiments, R⁵ is 3-, 4-, 5-, 6-, or 7- membered heterocyclyl, each optionally substituted with one or more substituents Q. In certain embodiments, R⁵ is bicyclic heterocyclyl, optionally substituted with one or more substituents Q. In certain embodiments, R⁵ is bridged, fused, or spiro heterocyclyl, each optionally substituted with one or more substituents Q. [00141] In certain embodiments, A is a bond. In certain embodiments, A is C1-6 alkylene, optionally substituted with one or more substituents Q. In certain embodiments, A is methanediyl, optionally substituted with one or two substituents Q. In certain embodiments, A is methanediyl. In certain embodiments, A is C1-6 heteroalkylene, optionally substituted with one or more substituents Q. Attorney Docket No.156A002WO01 [00142] In certain embodiments, E is a bond. In certain embodiments, E is –O–. In certain embodiments, E is –S–. In certain embodiments, E is –NR^1a–, wherein R^1a is as defined herein. In certain embodiments, E is –NH–. In certain embodiments, E is C_1-6 alkylene, optionally substituted with one or more substituents Q. In certain embodiments, E is methanediyl, optionally substituted with one or two substituents Q. In certain embodiments, E is methanediyl. In certain embodiments, E is C_1-6 heteroalkylene, optionally substituted with one or more substituents Q. [00143] In certain embodiments, U is –C(R¹)=, wherein R¹ is as defined herein. In certain embodiments, U is –C(H)=, wherein R¹ is as defined herein. In certain embodiments, U is –O–. In certain embodiments, U is –S–. In certain embodiments, U is –N(R³)–, wherein R³ is as defined herein. In certain embodiments, U is –N(H)–. In certain embodiments, U is –N=. [00144] In certain embodiments, V is –C(R¹)=, wherein R¹ is as defined herein. In certain embodiments, V is –C(H)=, wherein R¹ is as defined herein. In certain embodiments, V is –O–. In certain embodiments, V is –S–. In certain embodiments, V is –N(R³)–, wherein R³ is as defined herein. In certain embodiments, V is –N(H)–. In certain embodiments, V is –N=. [00145] In certain embodiments, X is –C(R¹)=, wherein R¹ is as defined herein. In certain embodiments, X is –C(H)=, wherein R¹ is as defined herein. In certain embodiments, X is –O–. In certain embodiments, X is –S–. In certain embodiments, X is –N(R³)–, wherein R³ is as defined herein. In certain embodiments, X is –N(H)–. In certain embodiments, X is –N=. [00146] In certain embodiments, Z is –O–. In certain embodiments, Z is –S–. In certain embodiments, Z is –N(R⁴)–, wherein R⁴ is as defined herein. In certain embodiments, Z is –N(H)–. In certain embodiments, Z is C_1-6 alkylene, optionally substituted with one or more substituents Q. In certain embodiments, Z is methanediyl, optionally substituted with one or two substituents Q. In certain embodiments, Z is methanediyl. [00147] In one embodiment, provided herein is: exo-4-(4-chlorobenzyl)-2-(3-(pyridin-4-yl)-1H-pyrazol-5-yl)-2-azabicyclo[3.1.0]- hexan-3-one A1; endo-4-(4-chlorobenzyl)-2-(3-(pyridin-4-yl)-1H-pyrazol-5-yl)-2-azabicyclo- Attorney Docket No.156A002WO01 [3.1.0]hexan-3-one A2; endo-4-(4-chlorobenzyl)-2-(3-(pyridazin-4-yl)-1H-pyrazol-5-yl)-2-azabicyclo- [3.1.0]hexan-3-one A3; exo-4-(4-chlorobenzyl)-2-(3-(pyridazin-4-yl)-1H-pyrazol-5-yl)-2-azabicyclo- [3.1.0]hexan-3-one A4; endo-4-(4-chlorobenzyl)-2-(3-(5-methylpyridazin-4-yl)-1H-pyrazol-5-yl)-2-aza- bicyclo[3.1.0]hexan-3-one A5; exo-4-(4-chlorobenzyl)-2-(3-(5-methylpyridazin-4-yl)-1H-pyrazol-5-yl)-2-aza- bicyclo[3.1.0]hexan-3-one A6; 4-((6-chloropyridin-3-yl)methyl)-2-(3-(pyridazin-4-yl)-1H-pyrazol-5-yl)-2-aza- bicyclo[3.1.0]hexan-3-one A7; endo-4-((6-chloropyridin-3-yl)methyl)-2-(3-(5-methylpyridazin-4-yl)-1H-pyrazol- 5-yl)-2-azabicyclo[3.1.0]hexan-3-one A8; endo-4-(5-(4-(4-chlorobenzyl)-3-oxo-2-azabicyclo[3.1.0]hexan-2-yl)-1H-pyrazol- 3-yl)pyridine 1-oxide A9; endo-4-(4-chlorobenzyl)-2-(3-(6-methylpyridazin-4-yl)-1H-pyrazol-5-yl)-2-aza- bicyclo[3.1.0]hexan-3-one A10; endo-4-(4-chlorobenzyl)-2-(3-(6-hydroxypyridin-3-yl)-1H-pyrazol-5-yl)-2-aza- bicyclo[3.1.0]hexan-3-one A11; endo-4-(4-chlorobenzyl)-2-(3-(pyrimidin-4-yl)-1H-pyrazol-5-yl)-2-azabicyclo- [3.1.0]hexan-3-one A12; endo-5-(5-(4-(4-chlorobenzyl)-3-oxo-2-azabicyclo[3.1.0]hexan-2-yl)-1H-pyrazol- 3-yl)picolinonitrile A13; endo-5-(5-(4-(4-chlorobenzyl)-3-oxo-2-azabicyclo[3.1.0]hexan-2-yl)-1H-pyrazol- 3-yl)pyridazine-3-carbonitrile A14; endo-4-(5-(4-(4-chlorobenzyl)-3-oxo-2-azabicyclo[3.1.0]hexan-2-yl)-1H-pyrazol- 3-yl)nicotinonitrile A15; endo-4-(4-chlorobenzyl)-2-(3-(5-(hydroxymethyl)pyridazin-4-yl)-1H-pyrazol-5- yl)-2-azabicyclo[3.1.0]hexan-3-one A16; endo-4-(4-chlorobenzyl)-2-(4-methyl-3-(pyridazin-4-yl)-1H-pyrazol-5-yl)-2-aza- bicyclo[3.1.0]hexan-3-one A17; Attorney Docket No.156A002WO01 endo-4-(4-chlorobenzyl)-2-(4-(hydroxymethyl)-3-(pyridazin-4-yl)-1H-pyrazol-5- yl)-2-azabicyclo[3.1.0]hexan-3-one A18; endo-5-(4-(4-chlorobenzyl)-3-oxo-2-azabicyclo[3.1.0]hexan-2-yl)-3-(pyridazin-4- yl)-1H-pyrazole-4-carbonitrile A19; endo-4-(4-chloro-3-fluorobenzyl)-2-(3-(pyridazin-4-yl)-1H-pyrazol-5-yl)-2-aza- bicyclo[3.1.0]hexan-3-one A20; endo-4-(4-fluorobenzyl)-2-(3-(pyridazin-4-yl)-1H-pyrazol-5-yl)-2-azabicyclo- [3.1.0]hexan-3-one A21; endo-4-((6-methylpyridin-3-yl)methyl)-2-(3-(pyridazin-4-yl)-1H-pyrazol-5-yl)-2- azabicyclo[3.1.0]hexan-3-one A22; endo-4-(4-chlorobenzyl)-2-(3-(3-methylpyridazin-4-yl)-1H-pyrazol-5-yl)-2-aza- bicyclo[3.1.0]hexan-3-one A23; endo-4-(4-chlorophenoxy)-2-(3-(pyridazin-4-yl)-1H-pyrazol-5-yl)-2-azabicyclo- [3.1.0]hexan-3-one A24; endo-4-((4-chlorophenyl)amino)-2-(3-(pyridazin-4-yl)-1H-pyrazol-5-yl)-2-aza- bicyclo[3.1.0]hexan-3-one A25; or endo-4-(4-chlorobenzyl)-2-(3-(5-methylpyridazin-4-yl)-1H-1,2,4-triazol-5-yl)-2- azabicyclo[3.1.0]hexan-3-one A26; or an enantiomer, a mixture of 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. [00148] In another embodiment, provided herein is: (1R,4S,5R)-4-((6-chloropyridin-3-yl)methyl)-2-(3-(5-methylpyridazin-4-yl)-1H- pyrazol-5-yl)-2-azabicyclo[3.1.0]hexan-3-one A27; (1S,4R,5S)-4-((6-chloropyridin-3-yl)-methyl)-2-(3-(5-methylpyridazin-4-yl)-1H- pyrazol-5-yl)-2-azabicyclo[3.1.0]hexan-3-one A28; endo-4-((6-chloropyridin-3-yl)methyl)-2-(5-methyl-4-(pyridin-4-yl)-1H-imidazol- 2-yl)-2-azabicyclo[3.1.0]hexan-3-one A29; endo-4-((6-chloropyridin-3-yl)methyl)-2-(5-methyl-2-(pyridin-4-yl)-1H-imidazol- 4-yl)-2-azabicyclo[3.1.0]hexan-3-one A30; endo-4-((6-chloropyridin-3-yl)methyl)-2-(4-(pyridin-4-yl)-5-(trifluoromethyl)- Attorney Docket No.156A002WO01 1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hexan-3-one A31; (1S,4R,5S)-4-((6-chloro-5-methylpyridin-3-yl)methyl)-2-(3-(pyridazin-4-yl)-1H- pyrazol-5-yl)-2-azabicyclo[3.1.0]hexan-3-one A32; endo-4-[(6-chloro-5-cyclopropyl-3-pyridyl)methyl]-2-[3-(4-pyridyl)-1H-pyrazol- 5-yl]-2-azabicyclo[3.1.0]hexan-3-one A33; endo-4-((6-chloro-2-ethylpyridin-3-yl)methyl)-2-(3-(5-methylpyridazin-4-yl)-1H- pyrazol-5-yl)-2-azabicyclo[3.1.0]hexan-3-one A34; endo-4-((6-chloro-2-(trifluoromethyl)pyridin-3-yl)methyl)-2-(3-(5-methyl- pyridazin-4-yl)-1H-pyrazol-5-yl)-2-azabicyclo[3.1.0]hexan-3-one A35; endo-4-((2-(aminomethyl)-6-chloropyridin-3-yl)methyl)-2-(3-(5-methylpyridazin- 4-yl)-1H-pyrazol-5-yl)-2-azabicyclo[3.1.0]hexan-3-one A36; endo-4-((6-cyclopropylpyridin-3-yl)methyl)-2-(3-(pyridin-4-yl)-1H-pyrazol-5-yl)- 2-azabicyclo[3.1.0]hexan-3-one A37; (1S,4R,5S)-4-((6-chloropyridin-3-yl)methyl)-2-(3-(pyridin-4-yl)-1H-pyrazol-5- yl)-2-azabicyclo[3.1.0]hexan-3-one A38; (1S,4R,5S)-4-((6-chloropyridin-3-yl)methyl)-2-(4-methyl-3-(pyridazin-4-yl)-1H- pyrazol-5-yl)-2-azabicyclo[3.1.0]hexan-3-one A39; (1S,4R,5S)-4-((6-chloropyridin-3-yl)methyl)-2-(3-(5-(trifluoromethyl)pyridazin-4- yl)-1H-pyrazol-5-yl)-2-azabicyclo[3.1.0]hexan-3-one A40; (1S,4R,5S)-4-((6-chloropyridin-3-yl)methyl)-2-(4-methyl-3-(pyridin-4-yl)-1H- pyrazol-5-yl)-2-azabicyclo[3.1.0]hexan-3-one A41; (1S,4R,5S)-4-((6-chloropyridin-3-yl)methyl)-2-(3-(3-methylpyridin-4-yl)-1H- pyrazol-5-yl)-2-azabicyclo[3.1.0]hexan-3-one A42; (1S,4R,5S)-4-((6-chloropyridin-3-yl)methyl)-2-(3-(3-methylpyridazin-4-yl)-1H- pyrazol-5-yl)-2-azabicyclo[3.1.0]hexan-3-one A43; endo-4-((6-chloropyridin-3-yl)methyl)-2-(5-fluoro-4-(pyridin-4-yl)-1H-imidazol- 2-yl)-2-azabicyclo[3.1.0]hexan-3-one A44; (1S,4R,5S)-4-((6-chloropyridin-3-yl)methyl)-2-(3-(5-cyclopropylpyridazin-4-yl)- 1H-pyrazol-5-yl)-2-azabicyclo[3.1.0]hexan-3-one A45; (1S,4R,5S)-4-((6-chloropyridin-3-yl)methyl)-2-(3-(pyridin-4-yl)-1H-1,2,4-triazol- 5-yl)-2-azabicyclo[3.1.0]hexan-3-one A46; Attorney Docket No.156A002WO01 (1S,4R,5S)-4-((6-chloropyridin-3-yl)methyl)-2-(3-(3-methoxypyridazin-4-yl)-1H- pyrazol-5-yl)-2-azabicyclo[3.1.0]hexan-3-one A47; (1S,4R,5S)-4-((6-chloropyridin-3-yl)-methyl)-2-(3-(3-oxo-2,3-dihydropyridazin- 4-yl)-1H-pyrazol-5-yl)-2-azabicyclo[3.1.0]hexan-3-one A48; (1S,4R,5S)-4-((6-chloropyridin-3-yl)methyl)-2-(3-(5-cyclopropylpyridazin-4-yl)- 4-methyl-1H-pyrazol-5-yl)-2-azabicyclo[3.1.0]hexan-3-one A49; (1S,4R,5S)-4-((6-fluoropyridin-3-yl)methyl)-2-(3-(pyridazin-4-yl)-1H-pyrazol-5- yl)-2-azabicyclo[3.1.0]hexan-3-one A50; (1S,4R,5S)-2-(3-(Pyridazin-4-yl)-1H-pyrazol-5-yl)-4-((6-(trifluoromethyl)pyridin- 3-yl)methyl)-2-azabicyclo[3.1.0]hexan-3-one A51; (1S,4R,5S)-4-((6-chloro-2-methylpyridin-3-yl)methyl)-2-(3-(pyridazin-4-yl)-1H- pyrazol-5-yl)-2-azabicyclo[3.1.0]hexan-3-one A52; (1S,4R,5S)-4-((6-chloro-2-methylpyridin-3-yl)methyl)-2-(3-(5-methylpyridazin-4- yl)-1H-pyrazol-5-yl)-2-azabicyclo[3.1.0]hexan-3-one A53; (1S,4R,5S)-4-((6-chloro-2-methylpyridin-3-yl)methyl)-2-(4-methyl-3-(5-methyl- pyridazin-4-yl)-1H-pyrazol-5-yl)-2-azabicyclo[3.1.0]hexan-3-one A54; (1S,4R,5S)-4-((5-chloropyridin-2-yl)methyl)-2-(3-(pyridazin-4-yl)-1H-pyrazol-5- yl)-2-azabicyclo[3.1.0]hexan-3-one A55; (1S,4R,5S)-4-((6-isopropylpyridin-3-yl)methyl)-2-(3-(pyridin-4-yl)-1H-pyrazol-5- yl)-2-azabicyclo[3.1.0]hexan-3-one A56; endo-4-((6-chloro-2-(hydroxymethyl)pyridin-3-yl)methyl)-2-(3-(5-methyl- pyridazin-4-yl)-1H-pyrazol-5-yl)-2-azabicyclo[3.1.0]hexan-3-one A57; (1S,4R,5S)-4-(4-chlorobenzyl)-2-(3-(pyridin-4-yl)-1H-1,2,4-triazol-5-yl)-2- azabicyclo[3.1.0]hexan-3-one A58; (1S,4R,5S)-4-(4-chlorobenzyl)-2-(3-(5-methylpyridazin-4-yl)-1H-1,2,4-triazol-5- yl)-2-azabicyclo[3.1.0]hexan-3-one A59; (1S,4R,5S)-4-((6-chloropyridin-3-yl)methyl)-2-(3-(5-methylpyridazin-4-yl)-1H- 1,2,4-triazol-5-yl)-2-azabicyclo[3.1.0]hexan-3-one A60; (1S,4R,5S)-4-((6-chloro-2-methylpyridin-3-yl)methyl)-2-(3-(pyridin-4-yl)-1H- 1,2,4-triazol-5-yl)-2-azabicyclo[3.1.0]hexan-3-one A61; (1S,4R,5S)-4-((6-chloro-5-fluoropyridin-3-yl)methyl)-2-(3-(pyridin-4-yl)-1H- Attorney Docket No.156A002WO01 1,2,4-triazol-5-yl)-2-azabicyclo[3.1.0]hexan-3-one A62; (1S,4R,5S)-4-((6-fluoropyridin-3-yl)methyl)-2-(3-(pyridin-4-yl)-1H-1,2,4-triazol- 5-yl)-2-azabicyclo[3.1.0]hexan-3-one A63; or (1S,4R,5S)-4-((6-fluoro-2-methylpyridin-3-yl)methyl)-2-(3-(pyridin-4-yl)-1H- 1,2,4-triazol-5-yl)-2-azabicyclo[3.1.0]hexan-3-one A64; or an enantiomer, a mixture of 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. [00149] In yet another embodiment, provided herein is 4-(4-chlorobenzyl)-2-(3-(pyridin- 4-yl)-1H-pyrazol-5-yl)-2-azabicyclo[4.1.0]heptan-3-one 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. [00150] In yet another embodiment, provided herein is 4-(4-chlorobenzyl)-2-(3- (pyridazin-4-yl)-1H-pyrazol-5-yl)-2-azabicyclo[2.1.1]-hexan-3-one 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. [00151] In still another embodiment, provided herein is 4-(4-chlorobenzyl)-2-(3- (pyridazin-4-yl)-1H-pyrazol-5-yl)-2-azabicyclo[3.1.1]-heptan-3-one D1; or an enantiomer, a mixture of 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. [00152] 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. Attorney Docket No.156A002WO01 [00153] 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. [00154] 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%. [00155] 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. [00156] The compounds provided herein are intended to encompass all possible Attorney Docket No.156A002WO01 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. [00157] 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. [00158] 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. [00159] 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 Attorney Docket No.156A002WO01 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. [00160] 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. [00161] 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. Attorney Docket No.156A002WO01 Pharmaceutical Compositions [00162] 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. [00163] 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. [00164] 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. [00165] 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 Attorney Docket No.156A002WO01 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. [00166] 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 [00167] 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. [00168] 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 Attorney Docket No.156A002WO01 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. [00169] 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. [00170] 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 Attorney Docket No.156A002WO01 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. [00171] 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. [00172] 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 absorption 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- Attorney Docket No.156A002WO01 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. [00173] It should be understood that many carriers and excipients may serve several functions, even within the same formulation. [00174] 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. [00175] 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. [00176] 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 Attorney Docket No.156A002WO01 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). [00177] 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. [00178] 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 Attorney Docket No.156A002WO01 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. [00179] The pharmaceutical composition provided herein for oral administration can also be 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. [00180] 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. [00181] Coloring and flavoring agents can be used in all of the dosage forms described herein. [00182] 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 [00183] The pharmaceutical composition provided herein can be administered parenterally by injection, infusion, or implantation, for local or systemic administration. Parenteral administration, as used herein, includes intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, intrasternal, intracranial, intramuscular, intrasynovial, intravesical, and subcutaneous administration. [00184] The pharmaceutical composition provided herein for parenteral administration can be formulated in any dosage forms that are suitable for parenteral administration, including, but Attorney Docket No.156A002WO01 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. [00185] 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. [00186] 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. [00187] 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 Attorney Docket No.156A002WO01 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^®). [00188] 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. [00189] 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. [00190] 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. [00191] 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 Attorney Docket No.156A002WO01 diffuse through. [00192] 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. [00193] 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 [00194] 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. [00195] 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. [00196] Pharmaceutically acceptable carriers and excipients suitable for use in the topical Attorney Docket No.156A002WO01 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. [00197] The pharmaceutical composition can also be administered topically by electroporation, iontophoresis, phonophoresis, sonophoresis, or microneedle or needle-free injection, such as POWDERJECT™ and BIOJECT™. [00198] 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. [00199] 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. [00200] 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 Attorney Docket No.156A002WO01 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. [00201] 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. [00202] 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. [00203] 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. [00204] The pharmaceutical composition provided herein can be administered intranasally or by inhalation to the respiratory tract. The pharmaceutical composition can be provided in the Attorney Docket No.156A002WO01 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. [00205] 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. [00206] 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. [00207] 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. [00208] 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. Attorney Docket No.156A002WO01 D. Modified Release [00209] 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 [00210] 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. [00211] 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. [00212] 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 Attorney Docket No.156A002WO01 (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. [00213] 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. [00214] 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 Attorney Docket No.156A002WO01 polymer, and other excipients or carriers in the compositions. [00215] 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 [00216] 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). [00217] 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. [00218] The other class of osmotic agents is osmogens, which are capable of imbibing Attorney Docket No.156A002WO01 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. [00219] 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. [00220] 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. [00221] 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, Attorney Docket No.156A002WO01 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. [00222] 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. [00223] 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. [00224] The total amount of the active ingredient(s) released and the release rate can substantially be 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. [00225] 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. [00226] 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. Attorney Docket No.156A002WO01 [00227] 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. [00228] 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 [00229] 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. [00230] 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 [00231] The pharmaceutical composition provided herein can also be formulated to be Attorney Docket No.156A002WO01 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 [00232] In one embodiment, provided herein is a method of treating, preventing, or ameliorating one or more symptoms of a SARM1-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. [00233] In certain embodiments, the SARM1-mediated disorder, disease, or condition is a neurological disorder. [00234] In another embodiment, provided herein is a method of treating, preventing, or ameliorating one or more symptoms of a neurological disorder 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. [00235] In certain embodiments, the subject is a mammal. In certain embodiments, the subject is a human. [00236] 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 Attorney Docket No.156A002WO01 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. [00237] 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. [00238] 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. [00239] A compound provided herein can be delivered as a single dose such as, e.g., a Attorney Docket No.156A002WO01 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. [00240] 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. [00241] 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. [00242] 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. [00243] 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 Attorney Docket No.156A002WO01 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. [00244] 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. [00245] In one embodiment, provided herein is a method of inhibiting the activity of a SARM1, comprising contacting the SARM1 with an 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. [00246] 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. [00247] In certain embodiments, provided herein is a kit which, when used by a medical Attorney Docket No.156A002WO01 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. [00248] 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. [00249] 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. [00250] The disclosure will be further understood by the following non-limiting examples. EXAMPLES [00251] 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); Boc (tert-butoxycarbonyl); BPin (4,4,5,5-tetramethyl- Attorney Docket No.156A002WO01 1,3,2-dioxaborolan-2-yl); B2Pin2 (4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan- 2-yl)-1,3,2-dioxa-borolane); nBu (butyl); s-BuLi (sec-butyllithium); t-BuONO (tert-butyl nitrite); DCM (dichloromethane); DIAD (diisopropyl azodicarboxylate); DIEA (N,N- diisopropylethylamine); DMAP (4-dimethylaminopyridine); DMEDA (1,2-dimethylethylene- diamine); DMSO (dimethyl sulfoxide); Et (ethyl); EtOAc (ethyl acetate); EtOH (ethanol); LDA (lithium diisopropylamide); LiHMDS (lithium bis(trimethylsilyl)amide); LiTEBH (lithium triethylborohydride); Me (methyl); MeOH (methanol); NBS (N-bromosuccinimide); Pd(PPh3)2Cl2 (bis(triphenylphosphine)palladium chloride); Pd(PPh3)4 (tetrakis(triphenyl- phosphine)palladium); Pd(PtBu₃)₂ (bis(tri-tert-butylphosphine)palladium(0)); Phth (phthaloyl); PMB (p-methoxybenzyl); [Rh(cod)OH]₂ (bis(cyclooctadiene)dihydroxodirhodium); SEM (2- (trimethylsilyl)ethoxy-methyl); SEMCl (2-(trimethylsilyl)ethoxymethyl chloride); SPhos Pd G3 ((2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl) [2-(2′-amino-1,1′-biphenyl)]palladium(II) methanesulfonate); TBS (tert-butyldimethylsilyl); TBSCl (tert-butyldimethylsilyl chloride); TEA (triethylamine); TFA (trifluoroacetic acid); TFAA (trifluoroacetic anhydride); THF (tetrahydro- furan); TMEDA (tetramethylethylenediamine); TMS (trimethylsilyl); XPhos (2-dicyclohexyl- phosphino-2′,4′,6′-triisopropylbiphenyl); LCMS (liquid chromatography-mass spectrometry); MS (mass spectrometry); NMR (nuclear magnetic resonance); prep-HPLC (preparative high performance liquid chromatography); prep-TLC (preparative thin-layer chromatography); and SPC (supercritical fluid chromatography). [00252] 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 exo-4-(4-chlorobenzyl)-2-(3-(pyridin-4-yl)-1H-pyrazol-5-yl)-2- azabicyclo[3.1.0]hexan-3-one A1 and endo-4-(4-chlorobenzyl)-2-(3-(pyridin-4-yl)-1H-pyrazol- Attorney Docket No.156A002WO01 5-yl)-2-azabicyclo[3.1.0]hexan-3-one A2 Cl

[00253] Compounds A1 and A2 were synthesized as shown in Schemes 1A and 1B.

Attorney Docket No.156A002WO01 3,5-dibromo-1H-pyrazole (8 g, 35.4 mmol) in THF (80 mL) was added NaH (2.12 g, 53.1 mmol, 60% purity). After the mixture was stirred at 0 °C for 1 h, SEMCl (8.86 g, 53.1 mmol) in THF (20 mL) was added. The reaction mixture was stirred at 0 °C for 2 h, and then diluted with water (100 mL) and extracted with EtOAc (100 mL x 3). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4, filtered, and concentrated to yield a crude product, which was purified by silica-gel column chromatography to afford compound 1a (7 g). LCMS (ESI) m/z: 297.0, 299.0, 301.0 [M+H-58]⁺; ¹H NMR (400 MHz, CDCl₃) δ 6.38 (s, 1H), 5.44 (s, 2H), 3.66-3.60 (m, 2H), 0.95-0.86 (m, 2H), -0.01 (s, 9H). [00255] 4-(5-Bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-yl)pyridine 1b. A mixture of compound 1a (1 g, 2.81 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)- pyridine (576 mg, 2.81 mmol), Pd(dppf)Cl2 (205 mg, 281 µmol), and K2CO3 (776 mg, 5.62 mmol) in dioxane (10 mL) and H2O (2 mL) was stirred at 60 °C under N2 for 16 h. The reaction mixture was diluted with water (30 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (15 mL), dried over anhydrous Na2SO4, and concentrated to yield a crude product, which was purified by silica-gel column chromatography to afford compound 1b (600 mg) in 60% yield. LCMS (ESI) m/z: 354.0, 356.0 [M+H]⁺. [00256] Tert-butyl 2-azabicyclo[3.1.0]hexane-2-carboxylate 1c. To a mixture of tert-butyl 4-chloropiperidine-1-carboxylate (2 g, 9.1 mmol) in THF (10 mL) at -78 °C were added 1.3M s- BuLi (14.7 mL) and TMEDA (2.22 g, 19.1 mmol) in THF (10 mL) dropwise. After stirring at -78 °C for 4 h, the reaction was quenched with MeOH (1 mL), and the reaction mixture was poured into water (50 mL) and extracted with EtOAc (100 mL x 3). The combined organic layers were dried over anhydrous Na₂SO₄ and concentrated to yield a crude product, which was purified by silica-gel chromatography to afford compound 1c (1.4 g). ¹H NMR (400 MHz, CDCl3) δ 3.63 (br t, J = 10.1 Hz, 1H), 3.39 (br s, 1H), 2.93 (td, J = 8.9, 11.4 Hz, 1H), 2.15-2.04 (m, 1H), 1.97-1.86 (m, 1H), 1.57-1.49 (m, 1H), 1.49-1.33 (m, 9H), 0.73-0.59 (m, 1H), 0.52 (dt, J = 2.4, 5.3 Hz, 1H). [00257] Tert-butyl 3-oxo-2-azabicyclo[3.1.0]hexane-2-carboxylate 1d. To a solution of RuO2 ^H2O (519 mg, 3.44 mmol) and NaIO4 (8.17 g, 38.2 mmol) in H2O (10 mL) was added compound 1c (1.4 g, 7.64 mmol) in EtOAc (13 mL) dropwise. After stirring at 20 °C for 16 h, Attorney Docket No.156A002WO01 the reaction mixture was filtered, and the resulting filtrate was treated with 5% aq. Na2S2O3 (30 mL) and extracted with EtOAc (200 mL x 3). The combined organic layers were dried over anhydrous Na₂SO₄ and concentrated to yield a crude product, which was purified by silica-gel column chromatography to afford compound 1d (1 g). LCMS (ESI) m/z: 142.2 [M+H-56]⁺. [00258] Tert-butyl 4-(4-chlorobenzyl)-3-oxo-2-azabicyclo[3.1.0]hexane-2-carboxylate 1e. To a mixture of compound 1d (610 mg, 3.09 mmol) in THF (6 mL) at -70 °C was added 2M LDA (1.7 mL) dropwise. After the mixture was stirred at -70 °C for 30 min, 1-(bromomethyl)-4- chlorobenzene (636 mg, 3.09 mmol) was added. After stirring at -70 °C for 1 h, the reaction was quenched with sat. aq. NH₄Cl (20 mL) and the reaction mixture was extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (15 mL), dried over anhydrous Na2SO4, and concentrated to yield a crude product, which was purified by silica-gel column chromatography and further purified by reversed-phase column chromatography to afford compound 1e (260 mg). LCMS (ESI) m/z: 266.1 [M+H-56]⁺; ¹H NMR (400 MHz, CDCl₃) δ 7.33-7.27 (m, 2H), 7.23-7.16 (m, 2H), 3.63-3.56 (m, 0.5H), 3.49-3.41 (m, 0.5H), 3.30-3.11 (m, 1.5H), 2.84-2.79 (m, 1H), 2.50 (dd, J = 11.3, 13.4 Hz, 0.5H), 1.58-1.53 (m, 9H), 1.51-1.37 (m, 1H), 1.01-0.90 (m, 1H), 0.50-0.41 (m, 1H). [00259] 4-(4-Chlorobenzyl)-2-azabicyclo[3.1.0]hexan-3-one 1f. To a mixture of compound 1e (50 mg, 155 μmol) in EtOAc (1 mL) was added 4M HCl in EtOAc (2 mL). After stirring at 25 °C for 1 h, the reaction mixture was concentrated to afford compound 1f (35 mg), which was used directly in the next step without further purification. LCMS (ESI) m/z: 222.1 [M+H]⁺. [00260] 4-(4-Methylbenzyl)-2-(3-(pyridin-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H- pyrazol-5-yl)-2-azabicyclo[3.1.0]hexan-3-one 1g. To a mixture of compound 1f (35 mg, 158 μmol), CuI (3 mg, 15.8 μmol), and K3PO4 (84 mg, 395 μmol) in toluene (2 mL) under N2 were added DMEDA (2.8 mg, 31.6 μmol) and compound 1b (56 mg, 158 μmol). After stirring at 100 °C under N₂ for 16 h, the reaction mixture was filtered and concentrated to yield a crude product, which was purified by prep-TLC to afford compound 1g (36 mg). LCMS (ESI) m/z: 495.5 [M+H]⁺; ¹H NMR (400 MHz, CDCl3) δ 8.72 (br d, J = 2.6 Hz, 2H), 7.61 (br d, J = 5.6 Hz, 2H), 7.35-7.28 (m, 3H), 7.24-7.21 (m, 1H), 7.15 (d, J = 1.1 Hz, 1H), 5.44-5.39 (m, 2H), 3.83-3.87 (m, Attorney Docket No.156A002WO01 0.5H), 3.78 (ddd, J = 5.0, 7.7, 8.9 Hz, 2H), 3.65-3.73 (m, 0.5H), 3.32-3.24 (m, 1H), 2.93-2.88 (m, 1H), 1.60-1.53 (m, 1H), 1.52-1.38 (m, 1H), 1.10-1.03 (m, 1H), 1.01-0.95 (m, 2H), 0.61-0.46 (m, 1H), 0.00 (m, 9H). [00261] Exo-4-(4-chlorobenzyl)-2-(3-(pyridin-4-yl)-1H-pyrazol-5-yl)-2-azabicyclo[3.1.0]- hexan-3-one A1 and endo-4-(4-chlorobenzyl)-2-(3-(pyridin-4-yl)-1H-pyrazol-5-yl)-2- azabicyclo[3.1.0]hexan-3-one A2. To a mixture of compound 1g (36 mg, 72.7 µmol) in DCM (1 mL) was added TFA (770 mg, 6.75 mmol). After stirring for 1 h, the reaction mixture was concentrated to yield a crude product, which was purified by reverse-phase prep-HPLC to afford exo-isomer A1 (8.86 mg) and endo-isomer A2 (7.96 mg). Exo-isomer A1: LCMS (ESI) m/z: 365.1 [M+H]⁺; ¹H NMR (400 MHz, CD₃OD) δ 8.77 (br d, J = 6.4 Hz, 1H), 8.28 (br d, J = 6.4 Hz, 2H), 7.30 (s, 4H), 7.22 (s, 1H), 3.56 (br t, J = 5.4 Hz, 1H), 3.23 (dd, J = 2.9, 12.2 Hz, 1H), 3.08-2.91 (m, 2H), 1.60 (dt, J = 5.1, 7.9 Hz, 1H), 1.11 (td, J = 5.7, 8.5 Hz, 1H), 0.62-0.51 (m, 1H). Endo-isomer A2: LCMS (ESI) m/z: 365.1 [M+H]⁺; ¹H NMR (400 MHz, CD₃OD) δ 8.77 (br d, J = 6.0 Hz, 1H), 8.28 (br d, J = 5.7 Hz, 1H), 7.37-7.29 (m, 4H), 7.24 (s, 1H), 3.76 (br t, J = 5.4 Hz, 1H), 3.38 (ddd, J = 4.4, 7.0, 11.2 Hz, 1H), 3.19 (dd, J = 4.2, 13.8 Hz, 1H), 2.62 (dd, J = 11.7, 13.4 Hz, 1H), 1.72-1.58 (m, 1H), 1.13-0.96 (m, 1H), 0.60 (br t, J = 5.6 Hz, 1H). Example 2 Preparation of endo-4-(4-chlorobenzyl)-2-(3-(pyridazin-4-yl)-1H-pyrazol-5-yl)-2- azabicyclo[3.1.0]hexan-3-one A3 and exo-4-(4-chlorobenzyl)-2-(3-(pyridazin-4-yl)-1H-pyrazol- 5-yl)-2-azabicyclo[3.1.0]hexan-3-one A4 N ^en_d ^Cl N o ^{e Cl} x N N _o [00262]

[00263] Tert-butyl exo-4-(4-chlorobenzyl)-3-oxo-2-azabicyclo[3.1.0]hexane-2- carboxylate 1e-exo and tert-butyl endo-4-(4-chlorobenzyl)-3-oxo-2-azabicyclo[3.1.0]hexane-2- carboxylate 1e-endo. Compound 1e as a mixture of endo- and exo-isomers was separated by silica-gel column chromatography and further separated by reverse-phase prep-HPLC to afford Attorney Docket No.156A002WO01 endo-isomer 1e-endo and exo-isomer 1e-exo. Endo-isomer 1e-endo: LCMS (ESI) m/z: 266.1 [M+H-56]⁺; ¹H NMR (400 MHz, CDCl3) δ 7.32-7.26 (m, 2H), 7.22-7.11 (m, 1H), 3.50-3.36 (m, 1H), 3.29-3.17 (m, 1H), 2.88-2.72 (m, 2H), 1.56-1.50 (m, 9H), 1.30-1.21 (m, 1H), 1.00-0.90 (m, 1H), 0.48-0.39 (m, 1H). Exo-isomer 1e-exo: LCMS (ESI) m/z: 266.1 [M+H-56]⁺; ¹H NMR (400 MHz, CDCl3) δ 7.32-7.26 (m, 2H), 7.22-7.11 (m, 2H), 3.50-3.36 (m, 1H), 3.29-3.17 (m, 1H), 2.88-2.72 (m, 2H), 1.56-1.50 (m, 9H), 1.30-1.21 (m, 1H), 1.00-0.90 (m, 1H), 0.48-0.39 (m, 1H).

mixture of compound 1e-endo (70 mg, 218 μmol) in EtOAc (1 mL) was added 4M HCl in EtOAc (2 mL). The reaction mixture was stirred for 1 h and concentrated to afford compound 1f-endo (49 Attorney Docket No.156A002WO01 mg), which was used directly in the next step without further purification. LCMS (ESI) m/z: 222.1 [M+H]⁺. [00265] 2-[(5-Bromo-3-pyridazin-4-yl-pyrazol-1-yl)methoxy]ethyltrimethylsilane 2a. A mixture of 2-[(3,5-dibromopyrazol-1-yl)methoxy]ethyltrimethylsilane 1a (600 mg, 1.68 mmol), tributyl(pyridazin-4-yl)stannane (622 mg, 1.68 mmol), CuI (96 mg, 505 μmol), Pd(PPh3)4 (195 mg, 168 μmol), and CsF (512 mg, 3.37 mmol) in DMF (2 mL) was stirred at 80 °C under N₂ for 16 h. The reaction mixture was then diluted with H₂O (100 mL) and extracted with EtOAc (100 mL x 3). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated to yield a crude product, which was purified by prep-TLC and further purified by reverse-phase prep-HPLC to afford compound 2a (30 mg). LCMS (ESI) m/z: 355.1, 357.1 [M+H]⁺. [00266] Endo-4-(4-chlorobenzyl)-2-(3-(pyridazin-4-yl)-1-((2-(trimethylsilyl)ethoxy)- methyl)-1H-pyrazol-5-yl)-2-azabicyclo[3.1.0]hexan-3-one 2b. To a mixture of compound 1f- endo (16 mg, 72.2 μmol), CuI (1.4 mg, 7.22 μmol), and K3PO4 (38.3 mg, 180 μmol) in toluene (2 mL) under N2 were added DMEDA (1.3 mg, 14 μmol) and compound 2a (25.6 mg, 72.2 μmol). After stirring at 100 °C under N₂ for 16 h, the reaction mixture was poured into H₂O (50 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4, and concentrated to yield a crude product, which was purified by prep-TLC to afford compound 2b (23 mg). LCMS (ESI) m/z: 496.4 [M+H]⁺. [00267] Endo-4-(4-chlorobenzyl)-2-(3-(pyridazin-4-yl)-1H-pyrazol-5-yl)-2-azabicyclo- [3.1.0]hexan-3-one A3. A mixture of compound 2b (23 mg, 46.4 μmol) in DCM (1 mL) and TFA (5.3 mg, 46.4 μmol) was stirred for 1 h. The reaction mixture was then concentrated to yield a crude product, which was purified by reverse-phase prep-HPLC to afford compound A3 as an endo isomer (5 mg). LCMS (ESI) m/z: 366.2 [M+H]⁺; ¹H NMR (400 MHz, CD3OD) δ 9.74-9.45 (m, 1H), 9.35-8.98 (m, 1H), 8.21-7.83 (m, 1H), 7.48-7.13 (m, 5H), 3.91-3.57 (m, 1H), 3.23-3.07 (m, 1H), 2.74-2.46 (m, 1H), 1.70-1.51 (m, 2H), 1.40-1.29 (m, 4H), 0.93-0.83 (m, 2H). [00268] Exo-4-(4-chlorobenzyl)-2-(3-(pyridazin-4-yl)-1H-pyrazol-5-yl)-2-azabicyclo- [3.1.0]hexan-3-one A4. Compound A4 was prepared from compounds 2a and 1f-exo as described for compound A3. LCMS (ESI) m/z: 366.3 [M+H]⁺; ¹H NMR (400 MHz, CD₃OD) δ: Attorney Docket No.156A002WO01 9.58 (br s, 1H), 9.21 (br d, J = 5.0 Hz, 1H), 8.11-7.89 (m, 1H), 7.31 (s, 5H), 3.58 (br s, 1H), 3.23 (dd, J = 3.3, 12.6 Hz, 1H), 3.05-2.89 (m, 2H), 1.58 (br d, J = 5.1 Hz, 1H), 1.17-1.02 (m, 1H), 0.55 (br s, 1H). Example 3 Preparation of endo-4-(4-chlorobenzyl)-2-(3-(5-methylpyridazin-4-yl)-1H-pyrazol-5-yl)-2- azabicyclo[3.1.0]hexan-3-one A5 and exo-4-(4-chlorobenzyl)-2-(3-(5-methylpyridazin-4-yl)-1H- pyrazol-5-yl)-2-azabicyclo[3.1.0]hexan-3-one A6

[00269] Compound A5 was synthesized as shown in Scheme 3.

3a. A mixture of compound 1a (2 g, 5.62 mmol), prop-1-yne (1M, 8.42 mL), CuI (107 mg, 562 µmol), TEA (2.27 g, 22.5 mmol), and Pd(PPh₃)₂Cl₂ (315 mg, 449 µmol) in THF (15 mL) was stirred under N2 for 16 h. The reaction mixture was then poured into H2O (30 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (15 mL), dried over anhydrous Na₂SO₄, and concentrated to yield a crude product, which was purified by silica- gel column chromatography to afford compound 3a (676 mg). LCMS (ESI) m/z: 257.0, 259.0 Attorney Docket No.156A002WO01 [M+H-58]⁺. [00271] 4-(5-Bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-yl)-5-methyl- pyridazine 3b. A mixture of compound 3a (300 mg, 952 μmol) and 1,2,4,5-tetrazine (312 mg, 3.81 mmol) in dioxane (6 mL) was stirred at 130 °C for 16 h. The reaction mixture was then filtered and concentrated to yield a crude product, which was purified by reverse-phase prep- HPLC to afford compound 3b (164 mg). LCMS (ESI) m/z: 368.9, 370.9 [M+H]⁺. [00272] Endo-4-(4-chlorobenzyl)-2-(3-(5-methylpyridazin-4-yl)-1-((2-(trimethylsilyl)- ethoxy)methyl)-1H-pyrazol-5-yl)-2-azabicyclo[3.1.0]hexan-3-one 3c. To a mixture of compound 3b (30 mg, 81.2 μmol), compound 1f-endo (18 mg, 81.2 μmol), DMEDA (1.4 mg, 16.3 μmol), and K₃PO₄ (43 mg, 203 μmol) in toluene (0.6 mL) was added CuI (1.6 mg, 8.12 μmol) in toluene (0.6 mL). After stirring at 100 °C under N2 for 16 h, the reaction mixture was filtered and was concentrated to yield a crude product, which was purified by prep-TLC to afford compound 3c (20 mg). LCMS (ESI) m/z: 510.4 [M+H]⁺. [00273] Endo-4-(4-chlorobenzyl)-2-(3-(5-methylpyridazin-4-yl)-1H-pyrazol-5-yl)-2-aza- bicyclo[3.1.0]hexan-3-one A5. A mixture of compound 3c (20 mg, 39.2 μmol) in DCM (0.5 mL) and TFA (179 mg, 1.57 mmol) was stirred for 1 h. The reaction mixture was then concentrated to yield a crude product, which was purified by reverse-phase prep-HPLC to afford endo isomer A5 (1.8 mg). LCMS (ESI) m/z: 380.3 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d6) δ 13.48-13.07 (m, 1H), 9.32 (s, 1H), 9.19 (s, 1H), =

5.6 Hz, 1H), 3.05 (dd, J = 4.4, 13.8 Hz, 1H), = , s, , 2.47 (m, 3H), 1.52 (br dd, J = 5.3, 7.0 Hz, 1H), 0.92 (td, J = 5.6, 8.4 Hz, 1H), 0.57 (br s, 1H). [00274] Exo-4-(4-chlorobenzyl)-2-(3-(5-methylpyridazin-4-yl)-1H-pyrazol-5-yl)-2-aza- bicyclo[3.1.0]hexan-3-one A6. Compound A6 was prepared from exo-4-(4-chlorobenzyl)-2- azabicyclo[3.1.0]-hexan-3-one 1f-exo and compound 3b as described for compound A5. LCMS (ESI) m/z: 380.3 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d6) δ 13.36-13.00 (m, 1H), 9.31 (s, 1H), 9.19 (s, 1H), 7.39-7.33 (m, 4H), 7.03 (br s, 1H), 3.60 (br d, J = 5.1 Hz, 1H), 3.15 (d, J = 9.4 Hz, 1H), 2.94-2.83 (m, 2H), 2.52-2.52 (m, 1H), 2.48-2.47 (m, 3H), 1.47-1.40 (m, 1H), 1.01 (td, J = 5.5, 8.4 Hz, 1H), 0.50 (br s, 1H). Attorney Docket No.156A002WO01 Example 4 Preparation of endo-4-((6-chloropyridin-3-yl)methyl)-2-(3-(pyridazin-4-yl)-1H-pyrazol-5-yl)-2- azabicyclo[3.1.0]hexan-3-one A7

[00275] Compound A7 was synthesized as shown in Scheme 4.

- - hexane-2-carboxylate 4a. To a mixture of tert-butyl 3-oxo-2-azabicyclo[3.1.0]hexane-2- carboxylate 1d (700 mg, 3.55 mmol) in THF (5 mL) at -70 °C was added 1.3M s-BuLi in THF (4.1 mL). After the mixture was stirred at -70 °C for 30 min, 2-chloro-5-(chloromethyl)pyridine (575 mg, 3.55 mmol) was added. After stirring at -70 °C for 1 h, the reaction was quenched with sat. aq. NH4Cl (20 mL) and the reaction mixture was extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (15 mL), dried over anhydrous Na2SO4, and concentrated to yield a crude product, which was purified by prep-TLC and further purified by reverse-phase prep-HPLC to afford compound 4a (160 mg). LCMS (ESI) m/z: 222.8 [M+H- 100]⁺; ¹H NMR (400 MHz, CDCl3) δ 8.33 (d, J = 2.3 Hz, 1H), 7.59 (dd, J = 2.4, 8.2 Hz, 1H), 7.30 (d, J = 8.3 Hz, 1H), 3.63 (ddd, J = 2.1, 5.4, 7.4 Hz, 1H), 3.29-3.07 (m, 2H), 2.55 (dd, J = 10.9, 13.8 Hz, 1H), 1.47-1.40 (m, 1H), 0.96 (td, J = 6.1, 8.3 Hz, 1H), 0.54-0.38 (m, 1H). Attorney Docket No.156A002WO01 [00277] Endo-4-((6-chloropyridin-3-yl)methyl)-2-azabicyclo[3.1.0]hexan-3-one 4b. To a mixture of compound 4a (80 mg, 155 μmol) in EtOAc (1 mL) was added 4M HCl in EtOAc (0.5 mL). The reaction mixture was stirred for 1 h and then concentrated to afford compound 4b (57 mg), which was used directly in the next step without further purification. LCMS (ESI) m/z: 223.1 [M+H]⁺. [00278] Endo-4-((6-chloropyridin-3-yl)methyl)-2-(3-(pyridazin-4-yl)-1-((2-(trimethyl- silyl)ethoxy)methyl)-1H-pyrazol-5-yl)-2-azabicyclo[3.1.0]hexan-3-one 4c. A mixture of 2-[(5- bromo-3-pyridazin-4-yl-pyrazol-1-yl)methoxy]ethyl-trimethylsilane 2a (33.5 mg, 94.3 μmol), compound 4b (21 mg, 94.3 μmol), CuI (1.8 mg, 9.43 μmol), DMEDA (1.7 mg, 18.9 μmol), and K₃PO₄ (50 mg, 236 μmol) in toluene (2 mL) was stirred at 100 °C under N₂ for 16 h. The reaction mixture was then poured into H2O (20 mL) and extracted with EtOAc (20 ml x 3). The combined organic layers were dried over anhydrous Na2SO4 and concentrated to yield a crude product, which was purified by prep-TLC to afford compound 4c (16 mg). LCMS (ESI) m/z: 497.3 [M+H]⁺. [00279] Endo-4-((6-chloropyridin-3-yl)methyl)-2-(3-(pyridazin-4-yl)-1H-pyrazol-5-yl)-2- azabicyclo[3.1.0]hexan-3-one A7. To a mixture of compound 4c (16 mg, 72.7 µmol) in DCM (1 mL) was added TFA (768 mg, 6.73 mmol). After stirring for 1 h, the reaction mixture was concentrated to yield a crude product, which was purified by reverse-phase prep-HPLC to afford endo-isomer A7 (6.12 mg). LCMS (ESI) m/z: 367.2 [M+H]⁺; ¹H NMR (400 MHz, CD₃OD) δ 9.75 (s, 1H), 9.36 (d, J = 5.6 Hz, 1H), 8.42-8.26 (m, 2H), 7.86 (dd, J = 2.4, 8.3 Hz, 1H), 7.45 (d, J = 8.3 Hz, 1H), 7.26 (s, 1H), 3.78 (dt, J = 2.5, 4.9 Hz, 1H), 3.44 (br d, J = 4.4 Hz, 1H), 3.21 (dd, J = 4.7, 14.1 Hz, 1H), 2.72 (dd, J = 10.8, 13.9 Hz, 1H), 1.70 (br d, J = 2.8 Hz, 1H), 1.11-0.97 (m, 1H), 0.70-0.57 (m, 1H). Example 5 Preparation of endo-4-((6-chloropyridin-3-yl)methyl)-2-(3-(5-methylpyridazin-4-yl)-1H-pyrazol- 5-yl)-2-azabicyclo[3.1.0]hexan-3-one A8 Attorney Docket No.156A002WO01

[00280] Compound A8 was synthesized as shown in Scheme 5.

- - ((2- (trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)-2-azabicyclo[3.1.0]hexan-3-one 5a. A mixture of 4-(5-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-yl)-5-methyl-pyridazine 3b (69.7 mg, 189 μmol), endo-4-((6-chloropyridin-3-yl)methyl)-2-azabicyclo[3.1.0]hexan-3-one 4b (35 mg, 157 μmol), K₃PO₄ (83 mg, 393 μmol), DMEDA (2.8 mg, 31.4 μmol), and CuI (3 mg, 15.7 μmol) in toluene (1 mL) was stirred at 90 °C under N2 for 16 h. The reaction mixture was then concentrated to yield a crude product, which was purified by silica-gel column chromatography to afford compound 5a (40 mg). LCMS (ESI) m/z: 511.3 [M+H]⁺. [00282] Endo-4-((6-chloropyridin-3-yl)methyl)-2-(3-(5-methylpyridazin-4-yl)-1H- pyrazol-5-yl)-2-azabicyclo[3.1.0]hexan-3-one A8. A mixture of compound 5a (40 mg, 78.3 μmol) and TFA (178 mg, 1.57 mmol) in DCM (0.5 mL) was stirred at for 1 h. The reaction mixture was then concentrated to yield a crude product, which was purified by reverse-phase prep-HPLC to afford endo-isomer A8 (8.95 mg). LCMS (ESI) m/z: 381.2 [M+H]⁺; ¹H NMR (400 MHz, CDCl3) δ 9.42 (s, 1H), 9.10 (s, 1H), 8.38 (d, J = 2.3 Hz, 1H), 7.64 (dd, J = 2.5, 8.1 Attorney Docket No.156A002WO01 Hz, 1H), 7.34 (d, J = 8.1 Hz, 1H), 6.57 (br s, 1H), 3.69 (br t, J = 5.1 Hz, 1H), 3.35 (ddd, J = 4.4, 6.8, 10.9 Hz, 1H), 3.27 (dd, J = 4.2, 14.1 Hz, 1H), 2.67-2.62 (m, 4H), 1.71 (td, J = 7.1, 13.7 Hz, 1H), 1.19-1.12 (m, 1H), 0.66-0.61 (m, 1H). Example 6 Preparation of (1R,4S,5R)-4-((6-chloropyridin-3-yl)methyl)-2-(3-(5-methylpyridazin-4-yl)-1H- pyrazol-5-yl)-2-azabicyclo[3.1.0]hexan-3-one A27 and (1S,4R,5S)-4-((6-chloropyridin-3-yl)- methyl)-2-(3-(5-methylpyridazin-4-yl)-1H-pyrazol-5-yl)-2-azabicyclo[3.1.0]hexan-3-one A28

[00283] was NH4OH) under isocratic conditions to afford stereoisomers 6A and 6B, which are assigned to the structures of compounds A27 and A28, respectively.  Stereoisomer 6A: LCMS (ESI) m/z: 381.0 [M+H]⁺; ¹H NMR (400 MHz, CD3OD) δ 9.49 (s, 1H), 9.26 (s, 1H), 8.37 (d, J = 2.4 Hz, 1H), 7.86 (dd, J = 2.5, 8.3 Hz, 1H), 7.44 (d, J = 8.1 Hz, 1H), 7.08 (s, 1H), 3.80 (ddd, J = 2.0, 5.1, 7.2 Hz, 1H), 3.55-3.38 (m, 1H), 3.21 (dd, J = 4.6, 14.0 Hz, 1H), 2.79-2.69 (m, 1H), 2.71 (s, 3H), 1.69 (ddd, J = 1.9, 7.0, 8.4 Hz, 1H), 1.13-1.00 (m, 1H), 0.70-0.59 (m, 1H). Stereoisomer 6B: LCMS (ESI) m/z: 381.0 [M+H]⁺; ¹H NMR (400 MHz, CD3OD) δ 9.46 (s, 1H), 9.25 (s, 1H), 8.37 (d, J = 2.0 Hz, 1H), 7.87 (dd, J = 2.4, 8.3 Hz, 1H), 7.45 (d, J = 8.3 Hz, 1H), 7.08 (s, 1H), 3.81 (ddd, J = 1.9, 5.1, 7.0 Hz, 1H), 3.55-3.39 (m, 1H), 3.21 (dd, J = 4.7, 13.9 Hz, 1H), 2.80-2.71 (m, 1H), 2.69 (s, 3H), 1.78-1.59 (m, 1H), 1.15-0.98 (m, 1H), 0.72-0.56 (m, 1H). Example 7 Preparation of endo-4-((6-chloropyridin-3-yl)methyl)-2-(5-methyl-4-(pyridin-4-yl)-1H-imidazol- 2-yl)-2-azabicyclo[3.1.0]hexan-3-one A29 Attorney Docket No.156A002WO01

[00284] Compound A29 was synthesized as shown in Scheme 6. Scheme 6

solution of NaH (298 mg, 7.45 mmol, 60% purity) in THF (20 mL) was added 4-bromo-5- methyl-1H-imidazole 6a (1 g, 6.21 mmol) at 0 °C under N₂. After the mixture was stirred at 0 °C for 0.5 h, SEMCl (1.35 g, 8.07 mmol) was added. The reaction mixture was stirred at 25 °C for 2.5 h, and then diluted with aq. NH4Cl (100 mL) and extracted with EtOAc (100 mL x 3). The combined organic layers were washed with brine, dried over anhydrous Na₂SO₄, filtered, and concentrated to yield a crude product, which was purified by silica-gel chromatography to afford compound 6b (1.6 g). [00286] Trimethyl[2-[[5-methyl-4-(4-pyridyl)imidazol-1-yl]methoxy]ethyl]silane 6c. A mixture of compound 6b (800 mg, 2.75 mmol), 4-pyridylboronic acid (506 mg, 4.12 mmol), Pd(dppf)Cl2 (201 mg, 275 µmol), and K2CO3 (759 mg, 5.49 mmol) in dioxane (10 mL) and H2O (1 mL) was stirred at 100 °C for 20 h under N2. The reaction mixture was then poured into water Attorney Docket No.156A002WO01 (100 mL) and EtOAc (100 mL x 3). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated to yield a crude product, which was by silica- gel chromatography to afford compound 6c (241 mg). LCMS (ESI) m/z: 290.2 [M+H]⁺. [00287] 4-(5-Methyl-1H-imidazol-4-yl)pyridine 6d. To a solution of compound 6c (320 mg, 1.11 mmol) in EtOAc (2 mL) was added 2M HCl in EtOAc (2 mL). After stirring at 25 °C for 20 h, the reaction mixture was concentrated and purified by reverse-phase prep-HPLC to afford compound 6d (120 mg). [00288] 4-(2-Bromo-5-methyl-1H-imidazol-4-yl)pyridine 6e. To a solution of compound 6d (120 mg, 754 µmol) in DMF (3 mL) was added NBS (268 mg, 1.51 mmol). After stirring at 25 °C for 4 h, the reaction mixture was diluted with sat. aq. Na₂SO₃ (5 mL) and extracted with EtOAc (5 mL). The organic layer was washed with brine (5 mL), dried over anhydrous Na2SO4, filtered, and concentrated to yield a crude product, which was purified by reverse phase prep- HPLC to afford compound 6e (35 mg). [00289] 2-[[2-Bromo-5-methyl-4-(4-pyridyl)imidazol-1-yl]methoxy]ethyltrimethylsilane 6f. To a solution of NaH (6.5 mg, 162 µmol, 60% purity) in THF (2 mL) was added compound 6e (35 mg, 147 µmol) at 0 °C under N₂. After the mixture was stirred at 0 °C for 0.5 h, SEMCl (27 mg, 162 µmol) was added. The reaction mixture was stirred at 25 °C for 2.5 h, and then diluted with sat. aq. NH4Cl (10 mL) and extracted with EtOAc (30 mL x 2). The combined organic layers were washed with brine (10 mL), dried over anhydrous MgSO₄, filtered, and concentrated to yield a crude product, which was purified by reverse-phase prep-TLC to afford compound 6f (33 mg). [00290] Endo-4-[(6-chloro-3-pyridyl)methyl]-2-[5-methyl-4-(4-pyridyl)-1H-imidazol-2- yl]-2-azabicyclo[3.1.0]hexan-3-one A29. Compound A29 was prepared from compounds 4b and 6f according to the synthetic procedures or methodologies exemplified herein. LCMS (ESI) m/z: 380.1 [M+H]⁺; ¹H NMR (400 MHz, CD3OD) δ 8.89 (d, J = 6.8 Hz, 2H), 8.41 (d, J = 2.3 Hz, 1H), 8.33 (d, J = 6.9 Hz, 2H), 7.94 (dd, J = 2.4, 8.3 Hz, 1H), 7.51 (d, J = 8.3 Hz, 1H), 4.02 (ddd, J = 1.7, 5.1, 7.1 Hz, 1H), 3.66-3.60 (m, 1H), 3.24 (dd, J = 5.2, 14.1 Hz, 1H), 2.84 (dd, J = 10.3, 14.1 Hz, 1H), 2.68 (s, 3H), 1.90 (td, J = 7.2, 13.9 Hz, 1H), 1.25-1.18 (m, 1H), 1.00-0.90 (m, 1H). Attorney Docket No.156A002WO01 Example 8 Preparation of (1S,4R,5S)-4-((6-chloro-5-methylpyridin-3-yl)methyl)-2-(3-(pyridazin-4-yl)-1H- pyrazol-5-yl)-2-azabicyclo[3.1.0]hexan-3-one A32

[00291] Compound A32 was synthesized as shown in Scheme 7.

[00292] (1S,5S)-Tert-butyl 4-methylene-3-oxo-2-azabicyclo[3.1.0]hexane-2-carboxylate 7b. To a solution of tert-butyl (1S,5S)-3-oxo-2-azabicyclo[3.1.0]hexane-2-carboxylate 7a (500 mg, 2.54 mmol) in THF (10 mL) was added 1M LiHMDS (4.31 mL) dropwise at -70 °C under N2. After the mixture was stirred for 1 h, dimethyl(methylene)ammonium iodide (703.5 mg, 3.80 mmol) was added. The reaction mixture was stirred at -70 °C for 1 h and then diluted with sat. aq. NH₄Cl (50 mL) and extracted with EtOAc (50 mL). The organic layer was washed with brine (30 mL), dried with anhydrous Na2SO4, filtered, and concentrated. The resulting residue Attorney Docket No.156A002WO01 was dissolved in EtOH (12 mL), followed by addition of 3-bromoprop-1-ene (2.45 g, 20.3 mmol) and Na2CO3 (1.61 g, 15.2 mmol). The resulting mixture was stirred at 20 °C for 16 h, and then diluted with H₂O (100 mL) and extracted with EtOAc (100 mL). The organic layer was washed with brine (30 mL), dried with anhydrous Na2SO4, filtered, and concentrated to yield a crude product, which was purified by silica-gel column chromatography to afford compound 7b (300 mg). ¹H NMR (400 MHz, CDCl₃) δ 6.16 (s, 1H), 5.61 (s, 1H), 3.76 (ddd, J = 2.5, 5.3, 6.8 Hz, 1H), 2.29-2.14 (m, 1H), 1.57 (s, 9H), 1.21 (td, J = 5.7, 8.8 Hz, 1H), 0.79-0.71 (m, 1H). [00293] (1S,4R,5S)-Tert-butyl-4-((6-chloro-5-methylpyridin-3-yl)methyl)-3-oxo-2- azabicyclo[3.1.0]hexane-2-carboxylate 7c. A mixture of compound 7b (200 mg, 956 µmol), (6- chloro-5-methyl-3-pyridyl)boronic acid (327.6 mg, 1.91 mmol), and [Rh(cod)OH]₂ (43.6 mg, 95.6 µmol) in dioxane (2 mL) and H2O (0.2 mL) was stirred at 80 °C for 2 h under N2. The reaction mixture was poured into water (50 mL) and extracted with EtOAc (50 mL). The organic layer was washed with brine (30 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated to yield a crude product, which was purified by prep-TLC and further purified by reverse-phase prep-HPLC to afford compound 7c (61 mg). ¹H NMR (400 MHz, CDCl3) δ 8.16 (d, J = 2.0 Hz, 1H), 7.48 (d, J = 1.9 Hz, 1H), 3.62 (ddd, J = 2.0, 5.4, 7.3 Hz, 1H), 3.21-3.09 (m, 2H), 2.56-2.45 (m, 1H), 2.38 (s, 3H), 1.56 (s, 9H), 1.46-1.39 (m, 1H), 0.96 (td, J = 6.1, 8.3 Hz, 1H), 0.52-0.41 (m, 1H). [00294] (1S,4R,5S)-4-((6-Chloro-5-methylpyridin-3-yl)methyl)-2-azabicyclo[3.1.0]hexan- 3-one 7d. To a solution of compound 7c (61 mg, 181 µmol) in EtOAc (2 mL) was added 4M HCl in EtOAc (2 mL). After stirring at 25 °C for 2 h, the reaction mixture was concentrated to afford compound 7d (42 mg), which was used directly in the next step without further purification. LCMS (ESI) m/z: 237.1 [M+H]⁺. [00295] (1S,4R,5S)-4-((6-Chloro-5-methylpyridin-3-yl)methyl)-2-(3-(pyridazin-4-yl)-1- ((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)-2-azabicyclo[3.1.0]hexan-3-one 7e. Compound 7e was prepared from compounds 2a and 7d similarly according to the synthetic procedures or methodologies exemplified herein. LCMS (ESI) m/z: 511.2 [M+H]⁺. [00296] (1S,4R,5S)-4-((6-Chloro-5-methylpyridin-3-yl)methyl)-2-(3-(pyridazin-4-yl)-1H- pyrazol-5-yl)-2-azabicyclo[3.1.0]hexan-3-one A32. Compound A32 was prepared from Attorney Docket No.156A002WO01 compound 7e similarly according to the synthetic procedures or methodologies exemplified herein. LCMS (ESI) m/z: 381.0 [M+H]⁺; ¹H NMR (400 MHz, CD3OD) δ 9.95 (dd, J = 0.8, 2.3 Hz, 1H), 9.53 (dd, J = 0.9, 6.1 Hz, 1H), 8.75 (dd, J = 2.4, 6.0 Hz, 1H), 8.22 (d, J = 2.1 Hz, 1H), 7.84 (d, J = 2.0 Hz, 1H), 7.31 (s, 1H), 3.77 (ddd, J = 2.0, 5.1, 7.2 Hz, 1H), 3.47 (ddd, J = 4.8, 6.7, 11.0 Hz, 1H), 3.19 (dd, J = 4.9, 14.0 Hz, 1H), 2.71 (dd, J = 10.8, 14.0 Hz, 1H), 2.42 (s, 3H), 1.79-1.67 (m, 1H), 1.09 (ddd, J = 5.1, 6.3, 8.5 Hz, 1H), 0.73-0.64 (m, 1H). Example 9 Preparation of endo-4-((2-(aminomethyl)-6-chloropyridin-3-yl)methyl)-2-(3-(5-methylpyridazin- 4-yl)-1H-pyrazol-5-yl)-2-azabicyclo[3.1.0]hexan-3-one A36 Cl N

[00297] Compound A36 was synthesized as shown in Scheme 8.

of compound 8a (500 mg, 2.25 mmol) in THF (20 mL) were added isoindoline-1,3-dione (331 mg, 2.25 mmol), PPh₃ (884 mg, 3.37 mmol), and DIAD (682 mg, 3.37 mmol) at 0 °C. After stirring at 25 °C for 2 h, the reaction mixture was poured into water (50 mL) and extracted with EtOAc (50 mL). The organic layer was washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated to yield a crude product, which was purified by silica-gel column Attorney Docket No.156A002WO01 chromatography to afford compound 8b (1 g). LCMS (ESI) m/z: 352.9 [M+H]^＋. [00299] 2-[[6-Chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-pyridyl]methyl]- isoindoline-1,3-dione 8c. A mixture of compound 8b (780 mg, 2.22 mmol), B2Pin2 (620 mg, 2.44 mmol), Pd(dppf)Cl2 (162 mg, 222 µmol), and KOAc (544 mg, 5.55 mmol) in dioxane (10 mL) was stirred at 80 °C for 8 h under N₂. The reaction mixture was then poured into water (50 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated to yield a crude product, which was purified by silica-gel column chromatography to afford compound 8c (130 mg). [00300] 2-[[6-Chloro-3-[[2-[3-(5-methylpyridazin-4-yl)-1H-pyrazol-5-yl]-3-oxo-2-aza- bicyclo[3.1.0]hexan-4-yl]methyl]-2-pyridyl]methyl]isoindoline-1,3-dione 8g. Compound 8g was prepared from compound 8c and tert-butyl 4-methylene-3-oxo-2-azabicyclo[3.1.0]hexane-2- carboxylate similarly according to the synthetic procedures or methodologies exemplified herein. [00301] Endo-4-((2-(aminomethyl)-6-chloropyridin-3-yl)methyl)-2-(3-(5-methyl- pyridazin-4-yl)-1H-pyrazol-5-yl)-2-azabicyclo[3.1.0]hexan-3-one A36. To a solution of compound 8g (12 mg, 22.2 µmol) in EtOH (0.5 mL) was added NH₂NH₂ ^H₂O (0.09 g, 1.80 mmol). After stirring at 60 °C for 2 h, the reaction mixture was concentrated to yield a crude product, which was purified by reverse-phase prep-HPLC to afford compound A36 (1.85 mg). LCMS (ESI) m/z: 410.2 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 9.32 (d, J = 0.6 Hz, 1H), 9.19 (s, 1H), 7.78 (d, J = 8.1 Hz, 1H), 7.36 (d, J = 8.0 Hz, 1H), 7.04-7.03 (m, 1H), 3.89 (s, 2H), 3.77 (ddd, J = 1.9, 5.2, 7.2 Hz, 1H), 3.10 (br dd, J = 4.5, 14.4 Hz, 2H), 2.67 (dd, J = 11.1, 14.2 Hz, 1H), 2.48 (s, 3H), 1.62-1.52 (m, 1H), 0.93 (td, J = 5.6, 8.3 Hz, 1H), 0.68-0.59 (m, 1H). Example 10 Preparation of endo-4-((6-cyclopropylpyridin-3-yl)methyl)-2-(3-(pyridin-4-yl)-1H-pyrazol-5-yl)- 2-azabicyclo[3.1.0]hexan-3-one A37 Attorney Docket No.156A002WO01 [00302] Compound A37 was synthesized as shown in Scheme 9.

[00303] Tert-butyl4-[(6-cyclopropyl-3-pyridyl)methyl]-3-oxo-2-azabicyclo[3.1.0]hexane- 2-carboxylate 9a. A mixture of tert-butyl endo-4-((6-chloropyridin-3-yl)methyl)-3-oxo-2- azabicyclo[3.1.0]-hexane-2-carboxylate 4a (35 mg, 108 µmol), potassium cyclopropyl- (trifluoro)borohydride (160 mg, 1.08 mmol), SPhos Pd G3 (8.46 mg, 10.8 µmol), and Cs2CO3 (1.5 M, 145 μL) in toluene (2 mL) and H2O (0.2 mL) was stirred at 90 °C for 2 h under N2. The reaction mixture was diluted with H₂O (50 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated to yield a crude product, which was purified by reverse-phase prep- HPLC to afford compound 9a (13 mg). LCMS (ESI) m/z: 329.3 [M+H]⁺. [00304] Endo-4-((6-cyclopropylpyridin-3-yl)methyl)-2-(3-(pyridin-4-yl)-1H-pyrazol-5- yl)-2-azabicyclo[3.1.0]hexan-3-one A37. Compound A37 was prepared from compounds 1b and 9a similarly according to the synthetic procedures or methodologies exemplified herein. LCMS (ESI) m/z: 372.3 [M+H]⁺; ¹H NMR (400 MHz, CD₃OD) δ 8.83 (d, J = 6.8 Hz, 2H), 8.64 (d, J = 1.5 Hz, 1H), 8.49 (dd, J = 1.8, 8.5 Hz, 1H), 8.41 (d, J = 6.5 Hz, 2H), 7.65 (d, J = 8.5 Hz, 1H), 7.30 (br s, 1H), 3.83 (br t, J = 5.2 Hz, 1H), 3.55 (td, J = 6.3, 9.8 Hz, 1H), 3.30-3.22 (m, 1H), 2.95 (dd, J = 9.9, 14.1 Hz, 1H), 2.46-2.31 (m, 1H), 1.91-1.71 (m, 1H), 1.54-1.42 (m, 2H), 1.29-1.20 (m, 2H), 1.16-1.03 (m, 1H), 0.72 (br t, J = 4.8 Hz, 1H). Example 11 Preparation of (1S,4R,5S)-4-((6-chloropyridin-3-yl)methyl)-2-(3-(pyridin-4-yl)-1H-pyrazol-5- Attorney Docket No.156A002WO01 yl)-2-azabicyclo[3.1.0]hexan-3-one A38 Cl

[00305] Compound A38 was synthesized as shown in Scheme 10.

- - oxo- - hexane-2-carboxylate 10a. To a mixture of (1S,5S)-tert-butyl-3-oxo-2-azabicyclo[3.1.0]hexane- 2-carboxylate 7a (3.7 g, 18.8 mmol) in THF (30 mL) was added s-BuLi (1.3 M, 21.7 mL) dropwise at -70 °C under N₂. After the mixture was stirred for 1 h, 2-chloro-5-(chloromethyl)- pyridine (3.04 g, 18.8 mmol) was added. The resulting mixture was stirred at -70 °C for 0.5 h and -10 °C for 3 h. The reaction was quenched with sat. aq. NH4Cl (50 mL) and the reaction mixture extracted with EtOAc (100 mL x 3). The combined organic layers were washed with brine (50 mL), dried over anhydrous MgSO₄, filtered, and concentrated to yield a crude product, which was purified by reverse-phase prep-HPLC to afford compound 10a (750 mg). LCMS (ESI) m/z: 223.2 [M+H-100]⁺; ¹H NMR (400 MHz, CDCl₃) δ 8.33 (d, J = 2.4 Hz, 1H), 7.59 (dd, J = 2.4, 8.2 Hz, 1H), 7.30 (d, J = 8.3 Hz, 1H), 3.63 (ddd, J = 2.1, 5.4, 7.3 Hz, 1H), 3.24-3.18 (m, 1H), 3.17-3.11 (m, 1H), 2.55 (dd, J = 10.9, 13.8 Hz, 1H), 1.56 (s, 9H), 1.44-1.38 (m, 1H), 0.96 (td, J = 6.0, 8.4 Hz, 1H), 0.47-0.43 (m, 1H). Attorney Docket No.156A002WO01 [00307] (1S,4R,5S)-4-[(6-Chloro-3-pyridyl)methyl]-2-azabicyclo[3.1.0]hexan-3-one 10b. To a mixture of compound 10a (520 mg, 1.61 mmol) in EtOAc (2 mL) was added 4M HCl in EtOAc (2 mL). The reaction mixture was stirred at 25 °C for 1 h and then concentrated to yield compound 10b (360 mg), which was used directly in the next step without further purification. LCMS (ESI) m/z: 223.0 [M+H]⁺. [00308] (1S,4R,5S)-4-((6-Chloropyridin-3-yl)methyl)-2-(3-(pyridin-4-yl)-1H-pyrazol-5- yl)-2-azabicyclo[3.1.0]hexan-3-one A38. Compound A38 was prepared from compounds 1b and 10b similarly according to the synthetic procedures or methodologies exemplified herein. LCMS (ESI) m/z: 366.0 [M+H]⁺; ¹H NMR (400 MHz, CD₃OD) δ 8.82 (d, J = 6.8 Hz, 2H), 8.43 (d, J = 6.8 Hz, 2H), 8.37 (d, J = 2.1 Hz, 1H), 7.87 (dd, J = 2.4, 8.2 Hz, 1H), 7.45 (d, J = 8.3 Hz, 1H), 7.28 (br s, 1H), 3.78 (br t, J = 5.1 Hz, 1H), 3.45 (ddd, J = 4.8, 6.6, 10.9 Hz, 1H), 3.21 (dd, J = 4.8, 14.0 Hz, 1H), 2.73 (dd, J = 10.7, 13.9 Hz, 1H), 1.78-1.65 (m, 1H), 1.14-1.02 (m, 1H), 0.71-0.62 (m, 1H). Example 12 Preparation of (1S,4R,5S)-4-((6-chloropyridin-3-yl)methyl)-2-(3-(5-(trifluoromethyl)pyridazin-4- yl)-1H-pyrazol-5-yl)-2-azabicyclo[3.1.0]hexan-3-one A40 [00309] Compound

11. [00310] 2-[5-Bromo-1-(2-trimethylsilylethoxymethyl)pyrazol-3-yl]ethynyltrimethylsilane 11b. A mixture of 3,5-dibromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole 11a (3 g, 8.42 mmol), ethynyl(trimethyl)silane (1.24 g, 12.6 mmol), Pd(PPh₃)₂Cl₂ (1.18 g, 1.68 mmol), CuI (1.28 g, 6.74 mmol), and TEA (2.56 g, 25.3 mmol) in toluene (30 mL) was stirred at 25 °C for 16 h under N₂. The reaction mixture was partitioned between EtOAc (50 mL) and water (50 mL) for three times. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated to yield a crude product, which was purified by silica-gel Attorney Docket No.156A002WO01 column chromatography to afford compound 11b (1.5 g). ¹H NMR (400 MHz, CDCl3) δ 6.36 (s, 1H), 5.38 (s, 2H), 3.68-3.58 (m, 2H), 0.97-0.86 (m, 2H), 0.04 (s, 9H), 0 (s, 9H).

a solution of compound 11b (1.3 g, 3.48 mmol) in MeOH (5 mL) was added K2CO3 (2.41 g, 17.4 mmol). After stirring at 25 °C for 1 h, the reaction mixture was filtered and concentrated to yield a crude product, which was purified by prep-TLC to afford compound 11c (132 mg). [00312] 2-[[5-Bromo-3-(3,3,3-trifluoroprop-1-ynyl)pyrazol-1-yl]methoxy]ethyltrimethyl- silane 11d. A mixture of compound 11c (150 mg, 498 µmol), 3,3-dimethyl-1-(trifluoromethyl)- 1,2-benziodoxole (362 mg, 1.10 mmol), 1,10-phenanthroline (80.8 mg, 448 µmol), CuI (123 mg, 647 µmol), and NaHCO₃ (54.4 mg, 647 µmol) in DCM (2 mL) was stirred at 20 °C for 16 h under N2. The reaction mixture was then poured into water (20 mL) and extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine, dried over anhydrous Na₂SO₄, filtered, and concentrated to yield a crude product, which was purified by prep-TLC to afford compound 11d (50 mg). ¹H NMR (400 MHz, CDCl3) δ 6.59 (s, 1H), 5.45 (s, 2H), 3.66- 3.58 (m, 2H), 0.92-0.8 (m, 2H), 0.01 (s, 9H).

Attorney Docket No.156A002WO01 [00313] 2-[[5-Bromo-3-[5-(trifluoromethyl)pyridazin-4-yl]pyrazol-1-yl]methoxy]ethyl- trimethylsilane 11e. To a solution of compound 11d (50 mg, 135 µmol) in dioxane (2 mL) was added 1,2,4,5-tetrazine (55.6 mg, 677 µmol). After stirring at 130 °C for 32 h, the reaction mixture was poured into water (10 mL) and extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated to yield a crude product, which was purified by prep-TLC to afford compound 11e (46 mg). ¹H NMR (400 MHz, CDCl₃) δ 9.58 (s, 1H), 9.51-9.41 (m, 1H), 6.52 (s, 1H), 5.21 (s, 2H), 3.74-3.55 (m, 2H), 0.97-0.83 (m, 2H), 0.01 (s, 9H). [00314] (1S,4R,5S)-4-((6-Chloropyridin-3-yl)methyl)-2-(3-(5-(trifluoromethyl)pyridazin- 4-yl)-1H-pyrazol-5-yl)-2-azabicyclo[3.1.0]hexan-3-one A40. Compound A40 was prepared from compounds 10b and 11e similarly according to the synthetic procedures or methodologies exemplified herein. LCMS (ESI) m/z: 435.2 [M+H]⁺; ¹H NMR (400 MHz, CD3OD) δ 9.72 (s, 1H), 9.59 (s, 1H), 8.39 (d, J = 2.4 Hz, 1H), 7.89 (dd, J = 2.5, 8.3 Hz, 1H), 7.47 (d, J = 8.3 Hz, 1H), 7.02 (s, 1H), 3.79 (ddd, J = 2.0, 5.1, 7.2 Hz, 1H), 3.44 (ddd, J = 4.8, 6.7, 11.1 Hz, 1H), 3.21 (dd, J = 4.6, 14.0 Hz, 1H), 2.72 (dd, J = 10.8, 13.9 Hz, 1H), 1.74-1.61 (m, 1H), 1.12-1.01 (m, 1H), 0.71-0.62 (m, 1H). Example 13 Preparation of (1S,4R,5S)-4-((6-chloropyridin-3-yl)methyl)-2-(3-(3-methylpyridazin-4-yl)-1H- pyrazol-5-yl)-2-azabicyclo[3.1.0]hexan-3-one A43 Cl N N N [00315] Compound

12. [00316] 3-(3-Methylpyridazin-4-yl)-3-oxopropanenitrile 12b. To a solution of NaH (144 mg, 3.61 mmol, 60% purity) in dioxane (10 mL) was added ACN (624 mg, 15.2 mmol) at 0 °C. After the mixture was stirred at 20 °C for 0.5 h, ethyl 3-methylpyridazine-4-carboxylate 12a (500 mg, 3.01 mmol) was added. The reaction was stirred at 100 °C for 16 h and the resulting Attorney Docket No.156A002WO01 precipitates were collected by filtration to afford compound 12b (500 mg). LCMS (ESI) m/z: 167.2 [M+H]⁺.

[00317] 1-(4-Methoxybenzyl)-3-(3-methylpyridazin-4-yl)-1H-pyrazol-5-amine 12c. To a solution of compound 12b (180 mg, 1.12 mmol) in EtOH (5 mL) was added 12M HCl (93 μL) and (4-methoxyphenyl)methylhydrazine hydrochloride (211 mg, 1.12 mmol). After stirring at 80 °C for 2 h, the reaction mixture was concentrated and purified by reverse-phase prep-HPLC to afford compound 12c (20 mg). LCMS (ESI) m/z: 296.2 [M+H]⁺. [00318] 4-(5-Bromo-1-(4-methoxybenzyl)-1H-pyrazol-3-yl)-3-methylpyridazine 12d. To a solution of compound 12c (20 mg, 67.7 µmol) and CuBr (9.7 mg, 67.7 µmol) in ACN (2 mL) was added t-BuONO (10.5 mg, 102 µmol) at 50 °C. After stirring at 50 °C for 1 h, the reaction mixture was diluted with sat. aq. Na2SO3 (5 mL) and extracted with EtOAc (5 mL). The organic layer was concentrated and purified by reverse-phase prep-HPLC to yield compound 12d (5 mg). [00319] (1S,4R,5S)-4-((6-Chloropyridin-3-yl)methyl)-2-(3-(3-methylpyridazin-4-yl)-1H- pyrazol-5-yl)-2-azabicyclo[3.1.0]hexan-3-one A43. Compound A43 was prepared from compounds 10b and 12d similarly according to the synthetic procedures or methodologies exemplified herein. LCMS (ESI) m/z: 381.2 [M+H]⁺; ¹H NMR (400 MHz, CD3OD) δ 9.12 (br d, J = 5.1 Hz, 1H), 8.38 (d, J = 2.3 Hz, 1H), 7.87 (dd, J = 2.4, 8.3 Hz, 1H), 7.82 (br s, 1H), 7.45 (d, J = 8.1 Hz, 1H), 7.34-6.72 (m, 1H), 3.91-3.69 (m, 1H), 3.45-3.38 (m, 1H), 3.21 (dd, J = 4.6, 13.9 Attorney Docket No.156A002WO01 Hz, 1H), 2.88 (br s, 3H), 2.71 (dd, J = 10.8, 13.9 Hz, 1H), 1.71-1.62 (m, 1H), 1.10-0.99 (m, 1H), 0.63 (br s, 1H). Example 14 Preparation of (1S,4R,5S)-4-((6-chloropyridin-3-yl)methyl)-2-(3-(pyridin-4-yl)-1H-1,2,4-triazol- 5-yl)-2-azabicyclo[3.1.0]hexan-3-one A46 Cl

[00320] Compound A46 was synthesized as shown in Scheme 13. [00321]

To a solution of 3,5-dibromo-1H-1,2,4-triazole 13a (2 g, 8.82 mmol) in DCM (15 mL) were added TEA (1.32 g, 13.06 mmol) and SEMCl (1.47 g, 8.82 mmol). After stirring at 25 °C for 2 h, the reaction mixture was concentrated and purified by silica-gel column chromatography to afford compound 13b (2.4 g). [00322] 4-(5-Bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-3-yl)pyridine 13c. A mixture of compound 13b (1 g, 2.8 mmol), 4-pyridylboronic acid (344 mg, 2.8 mmol), Pd(dppf)Cl₂ (205 mg, 280 µmol), and K₂CO₃ (774 mg, 5.6 mmol) in dioxane (10 mL) and H₂O (1 mL) was stirred at 80 °C for 16 h under N₂. The reaction mixture was then poured into water Attorney Docket No.156A002WO01 (50 mL) and extracted with EtOAc (50 mL). The organic layer was washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated to yield a crude product, which was purified by silica-gel column chromatography to afford compound 13c (618 mg). [00323] (1S,4R,5S)-4-((6-Chloropyridin-3-yl)methyl)-2-(3-(pyridin-4-yl)-1H-1,2,4-triazol- 5-yl)-2-azabicyclo[3.1.0]hexan-3-one A46. Compound A46 was prepared from compounds 10b and 13c similarly according to the synthetic procedures or methodologies exemplified herein. LCMS (ESI) m/z: 367.0 [M+H]⁺; ¹H NMR (400 MHz, CD₃OD) δ 8.92 (d, J = 6.9 Hz, 2H), 8.67 (d, J = 6.9 Hz, 2H), 8.42 (d, J = 2.3 Hz, 1H), 7.96 (dd, J = 2.5, 8.3 Hz, 1H), 7.52 (d, J = 8.1 Hz, 1H), 4.03 (ddd, J = 1.9, 5.2, 7.1 Hz, 1H), 3.61-3.49 (m, 1H), 3.24 (dd, J = 5.0, 14.0 Hz, 1H), 2.81 (dd, J = 10.5, 14.0 Hz, 1H), 1.86-1.73 (m, 1H), 1.18-1.07 (m, 1H), 0.81-0.72 (m, 1H). Example 15 Preparation of (1S,4R,5S)-4-((6-chloropyridin-3-yl)methyl)-2-(3-(3-methoxypyridazin-4-yl)-1H- pyrazol-5-yl)-2-azabicyclo[3.1.0]hexan-3-one A47 and (1S,4R,5S)-4-((6-chloropyridin-3-yl)- methyl)-2-(3-(3-oxo-2,3-dihydropyridazin-4-yl)-1H-pyrazol-5-yl)-2-azabicyclo[3.1.0]hexan-3- one A48 [00324]

[00325] 3-Methoxy-4-(tributylstannyl)pyridazine 14b. To a mixture of N-isopropyl- propan-2-amine (1.38 g, 13.6 mmol) in THF (20 mL) was added n-BuLi (2.5 M, 5.45 mL) at -78 °C under N₂. The mixture was warmed to 0 °C and stirred for 0.5 h, and then cooled to -78 °C, followed by addition of 3-methoxypyridazine 14a (1 g, 9.08 mmol). After the mixture was stirred for 0.5 h, tributyl(chloro)stannane (4.85 g, 14.9 mmol) was added at -78 °C. The reaction mixture was stirred at 0 °C for 1.5 h, and then diluted with sat. aq. NH4Cl (100 mL) and extracted with EtOAc (300 mL x 3). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4, filtered, and concentrated to yield a crude product, which Attorney Docket No.156A002WO01 was purified by silica-gel column chromatography to afford 14b (1.1 g). ¹H NMR (400 MHz, CDCl3) δ 8.74-8.62 (m, 1H), 7.51-7.36 (m, 1H), 4.10 (s, 3H), 1.59-1.43 (m, 6H), 1.39-1.25 (m, 6H), 1.15-1.08 (m, 6H), 0.92-0.86 (m, 9H).

[00326] 4-(5-Bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-yl)-3-methoxy- pyridazine 14c. A mixture of compound 14b (900 mg, 2.25 mmol), 3,5-dibromo-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-pyrazole (803 mg, 2.25 mmol), CsF (685 mg, 4.51 mmol), and Pd(PtBu3)2 (115 mg, 225 µmol) in dioxane (10 mL) was stirred at 80 °C for 2 h under N2. The reaction mixture was then diluted with H2O (100 mL) and extracted with EtOAc (100mL x 3). The combined organic layers were washed with brine (100mL), dried over anhydrous Na₂SO₄, filtered, and concentrated to yield a crude product, which was purified by silica-gel column chromatography to afford compound 14c (350 mg). [00327] (1S,4R,5S)-4-((6-Chloropyridin-3-yl)methyl)-2-(3-(3-methoxypyridazin-4-yl)-1H- pyrazol-5-yl)-2-azabicyclo[3.1.0]hexan-3-one A47. Compound A47 was prepared from compounds 10b and 14c similarly according to the synthetic procedures or methodologies exemplified herein. LCMS (ESI) m/z: 397.1 [M+H]⁺; ¹H NMR (400 MHz, CD3OD) δ 9.21 (d, J = 5.6 Hz, 1H), 8.61 (d, J = 5.6 Hz, 1H), 8.37 (d, J = 2.3 Hz, 1H), 7.87 (dd, J = 2.5, 8.3 Hz, 1H), 7.54-7.38 (m, 2H), 4.35 (s, 3H), 3.84 (ddd,

7.2 Hz, 1H), 3.44 (ddd, J = 4.8, 6.7, 11.0 Hz, 1H), 3.21 (dd, J = 4.8, 14.0 Hz, 1H), 2.72 (dd, J = 10.8, 14.0 Hz, 1H), 1.76-1.63 (m, 1H), 1.12-1.00 (m, 1H), 0.72-0.56 (m, 1H). Attorney Docket No.156A002WO01 [00328] (1S,4R,5S)-4-((6-Chloropyridin-3-yl)methyl)-2-(3-(3-oxo-2,3-dihydropyridazin-4- yl)-1H-pyrazol-5-yl)-2-azabicyclo[3.1.0]hexan-3-one A48. To a mixture of compound A47 (8 mg, 20.2 µmol) in DCM (1 mL) was added BBr₃ (20.2 mg, 80.6 µmol) at -20 °C. After stirring at 25 °C for 3 h, the reaction was quenched with MeOH (0.1 mL) at 0 °C. The reaction mixture was concentrated to yield a crude product, which was purified by reverse-phase prep-HPLC to afford compound A48 (2.48 mg). LCMS (ESI) m/z: 383.1 [M+H]⁺; ¹H NMR (400 MHz, CDCl₃) δ 11.25-10.98 (m, 1H), 8.39 (d, J = 2.3 Hz, 1H), 7.98 (d, J = 4.3 Hz, 1H), 7.65 (dd, J = 2.4, 8.3 Hz, 1H), 7.61 (d, J = 4.3 Hz, 1H), 7.39-7.30 (m, 2H), 3.92 (br t, J = 5.2 Hz, 1H), 3.73 (q, J = 7.0 Hz, 1H), 3.30-3.26 (m, 1H), 2.68-2.54 (m, 1H), 2.03 (d, J = 10.8 Hz, 1H), 1.09 (br d, J = 7.8 Hz, 1H), 0.55 (br t, J = 4.9 Hz, 1H). Example 16 Preparation of endo-4-((6-chloro-2-(hydroxymethyl)pyridin-3-yl)methyl)-2-(3-(5-methyl- pyridazin-4-yl)-1H-pyrazol-5-yl)-2-azabicyclo[3.1.0]hexan-3-one A57 Cl N [00329] Compound

15.

mixture of (3-bromo-6-chloropyridin-2-yl)methanol 8a (400 mg, 1.8 mmol), imidazole (158 mg, 2.32 mmol), and DMAP (43.9 mg, 360 µmol) in DCM (2 mL) was added tert-butylchloro- dimethylsilane (325 mg, 2.16 mmol). After stirring at 20 °C for 16 h, the reaction mixture was diluted with H₂O (50 mL) and extracted with DCM (50 mL x 3). The combined organic layers Attorney Docket No.156A002WO01 were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated to yield a crude product, which was purified by silica-gel column chromatography to afford compound 15a (580 mg) in 96% yield. LCMS (ESI) m/z: 337.9 [M+H]⁺. [00331] Endo-4-((6-chloro-2-(hydroxymethyl)pyridin-3-yl)methyl)-2-(3-(5-methyl- pyridazin-4-yl)-1H-pyrazol-5-yl)-2-azabicyclo[3.1.0]hexan-3-one A57. Compound A57 was prepared from compounds 3b and 15a similarly according to the synthetic procedures or methodologies exemplified herein. LCMS (ESI) m/z: 411.1 [M+H]⁺; ¹H NMR (400 MHz, CD3OD) δ 9.36-9.21 (m, 1H), 9.13 (s, 1H), 7.84 (d, J = 8.1 Hz, 1H), 7.36 (d, J = 8.1 Hz, 1H), 7.29-6.77 (m, 1H), 4.80 (d, J = 6.9 Hz, 2H), 3.95-3.72 (m, 1H), 3.48 (ddd, J = 4.5, 6.7, 10.8 Hz, 1H), 3.35-3.32 (m, 1H), 2.76 (dd, J = 10.8, 14.2 Hz, 1H), 2.58 (s, 3H), 1.74-1.61 (m, 1H), 1.06 (td, J = 5.8, 8.2 Hz, 1H), 0.65 (br s, 1H). Example 17 Preparation of (1S,4R,5S)-4-(4-chlorobenzyl)-2-(3-(pyridin-4-yl)-1H-1,2,4-triazol-5-yl)-2- azabicyclo[3.1.0]hexan-3-one A58 Cl N

[00332] Compound A58 was synthesized as shown in Scheme 16. Scheme 16 N Cl

Attorney Docket No.156A002WO01 [00333] (1S,4R,5S)-4-(4-Chlorobenzyl)-2-(3-(pyridin-4-yl)-1-((2-(trimethylsilyl)ethoxy)- methyl)-1H-1,2,4-triazol-5-yl)-2-azabicyclo[3.1.0]hexan-3-one 16b. A mixture of 4-(5-bromo- 1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-3-yl)pyridine 13c (40.1 mg, 113 µmol), (1S,4R,5S)-4-(4-chlorobenzyl)-2-azabicyclo[3.1.0]hexan-3-one 16a (25 mg, 113 µmol), CuI (2.15 mg, 11.3 µmol), DMEDA (2 mg, 22.6 µmol), and K3PO4 (59.9 mg, 282 µmol) in toluene (2 mL) was stirred at 90 °C for 16 h under N₂. The reaction mixture was diluted with H₂O (50 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated to yield a crude product, which was purified by prep-TLC to afford compound 16b (40 mg). LCMS (ESI) m/z: 496.2 [M+H]⁺. [00334] (1S,4R,5S)-4-(4-Chlorobenzyl)-2-(3-(pyridin-4-yl)-1H-1,2,4-triazol-5-yl)-2-aza- bicyclo[3.1.0]hexan-3-one A58. Compound A58 was prepared from compound 16b similarly according to the synthetic procedures or methodologies exemplified herein. LCMS (ESI) m/z: 466.1 [M+H]⁺; ¹H NMR (400 MHz, CD3OD) δ 8.66-8.59 (m, 2H), 8.12-7.98 (m, 2H), 7.45-7.26 (m, 4H), 3.97 (ddd, J = 1.9, 5.2, 7.2 Hz, 1H), 3.44 (ddd, J = 4.3, 7.0, 11.2 Hz, 1H), 3.21 (dd, J = 4.3, 13.7 Hz, 1H), 2.67 (dd, J = 11.3, 13.8 Hz, 1H), 1.77-1.63 (m, 1H), 1.08 (ddd, J = 5.3, 6.5, 8.5 Hz, 1H), 0.76-0.63 (m, 1H). Example 18 Preparation of (1S,4R,5S)-4-(4-chlorobenzyl)-2-(3-(5-methylpyridazin-4-yl)-1H-1,2,4-triazol-5- yl)-2-azabicyclo[3.1.0]hexan-3-one A59 Cl N N ^N [00335] Compound

17. [00336] 2-[(5-Bromo-3-prop-1-ynyl-1,2,4-triazol-1-yl)methoxy]ethyltrimethylsilane 17b. A mixture of 2-[(3,5-dibromo-1,2,4-triazol-1-yl)methoxy]ethyltrimethylsilane (1 g, 2.8 mmol), prop-1-yne (1M, 8.4 mL), Pd(CH₃CN)₂Cl₂ (72.7 mg, 280 µmol), XPhos (400 mg, 840 µmol), Attorney Docket No.156A002WO01 TEA (567 mg, 5.6 mmol), and Cs2CO3 (912 mg, 2.8 mmol) in toluene (10 mL) was stirred at 60 °C for 16 h under N2. The reaction mixture was then poured into water (50 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated to yield a crude product, which was purified by silica-gel column chromatography to afford compound 17b (700 mg).

[00337] 2-[[5-Bromo-3-(5-methylpyridazin-4-yl)-1,2,4-triazol-1-yl]methoxy]ethyl- trimethyl-silane 17c. To a solution of 1,2,4,5-tetrazine (843 mg, 10.3 mmol) in dioxane (10 mL) was added compound 17b (650 mg, 2.06 mmol). After stirring at 130 °C for 24 h, the reaction mixture was poured into water (50 mL) and extracted with EtOAc (50 mL). The organic layer was washed with brine, dried over anhydrous Na₂SO₄, filtered, and concentrated to yield a crude product, which was purified by silica-gel column chromatography to afford compound 17c (380 mg). LCMS (ESI) m/z: 370.0 [M+H]⁺. [00338] (1S,4R,5S)-4-(4-Chlorobenzyl)-2-(3-(5-methylpyridazin-4-yl)-1H-1,2,4-triazol-5- yl)-2-azabicyclo[3.1.0]hexan-3-one A59. Compound A59 was prepared from compounds 10b and 17c similarly according to the synthetic procedures or methodologies exemplified herein. LCMS (ESI) m/z: 381.1 [M+H]⁺; ¹H NMR (400 MHz, CD3OD) δ 9.66 (s, 1H), 9.13 (s, 1H), 7.46-7.25 (m, 4H), 4.09-3.90 (m, 1H), 3.45 (ddd, J = 4.4, 6.9, 11.1 Hz, 1H), 3.21 (dd, J = 4.3, 13.8 Hz, 1H), 2.77 (s, 3H), 2.67 (dd, J = 11.3, 13.7 Hz, 1H), 1.70 (td, J = 7.1, 13.8 Hz, 1H), 1.08 (td, J = 6.1, 8.1 Hz, 1H), 0.76-0.60 (m, 1H). Attorney Docket No.156A002WO01 Example 19 Preparation of 4-(4-chlorobenzyl)-2-(3-(pyridin-4-yl)-1H-pyrazol-5-yl)-2-azabicyclo[4.1.0]- heptan-3-one B1

[00339] Compound B1 was synthesized as shown in Scheme 18. Scheme 18 O OMe OMe Br Br OMe

of 1-[(2,4-dimethoxyphenyl)methyl]piperidine-2,6-dione 18a (6.9 g, 26.2 mmol) in toluene (70 mL) was slowly added 1M LiTEBH (31.5 mL) at -78 °C. After the mixture was stirred at -78 °C Attorney Docket No.156A002WO01 for 30 min, DIEA (18.97 g, 147 mmol), DMAP (64 mg, 524 µmol), and TFAA (6.61 g, 31.5 mmol) was added. The reaction mixture was stirred at 25 °C for 16 h, and then diluted with sat. aq. NH₄Cl (30 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated to yield a crude product, which was purified by silica-gel column chromatography to afford compound 18b (2.19 g). LCMS (ESI) m/z: 248.2 [M+H]⁺; ¹H NMR (400 MHz, CDCl₃) δ 7.19-7.13 (m, 1H), 6.47-6.40 (m, 2H), 6.10 (td, J = 1.4, 7.8 Hz, 1H), 5.12-5.05 (m, 1H), 4.62 (s, 2H), 3.80 (d, J = 6.5 Hz, 6H), 2.61-2.42 (m, 2H), 2.38-2.25 (m, 2H). [00341] 7,7-Dibromo-2-[(2,4-dimethoxyphenyl)methyl]-2-azabicyclo[4.1.0]heptan-3-one 18c. A mixture of compound 18b (2.1 g, 8.49 mmol) in CHBr₃ (22 mL) were added methyl(trioctyl)ammonium chloride (68.6 mg, 170 µmol) and NaOH (679 mg, 8.49 mmol) in H2O (8 mL). After stirring at 25 °C for 16 h under N2, the reaction mixture was diluted with sat. aq. NH₄Cl (20 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated to yield a crude product, which was purified by silica-gel column chromatography to afford compound 18c (807 mg). LCMS (ESI) m/z: 418.1, 420.1 [M +H]⁺; ¹H NMR (400 MHz, CDCl₃) δ 7.34-7.30 (m, 1H), 6.51-6.46 (m, 2H), 5.17 (d, J = 14.1 Hz, 1H), 4.19 (d, J = 14.1 Hz, 1H), 3.88 (s, 3H), 3.82 (s, 3H), 3.15 (d, J = 9.9 Hz, 1H), 2.56-2.41 (m, 1H), 2.34-2.25 (m, 2H), 2.15 (dt, J = 5.9, 9.9 Hz, 1H), 1.96-1.79 (m, 1H). [00342] 2-[(2,4-Dimethoxyphenyl)methyl]-2-azabicyclo[4.1.0]heptan-3-one 18d. To a solution of TPGS-750-M (954 µmol) in H₂O (8 mL) were added diacetoxynickel tetrahydrate (23.8 mg, 95.4 µmol) and 3,4,7,8-tetramethyl-1,10-phenanthroline (45.1 mg, 191 µmol) under N₂. After the mixture was stirred at 25 °C for 10 min, pyridine (226 mg, 2.86 mmol), sodium borohydride (361 mg, 9.54 mmol), and compound 18c (800 mg, 1.91 mmol) in THF (1.5 mL) were added under N2. The reaction mixture was stirred at 45 °C for 30 min under N2, and then diluted with sat. aq. NH4Cl (30 mL) and extracted with EtOAc (40 mL x 3). The combined organic layers dried over anhydrous Na₂SO₄, filtered, and concentrated to yield a crude product, which purified by silica-gel column chromatography to afford compound 18d (211 mg). LCMS (ESI) m/z: 262.2 [M+H]⁺; ¹H NMR (400 MHz, CDCl3) δ 7.19-7.15 (m, 1H), 6.45 (qd, J = 2.3, 4.5 Hz, 2H), 4.84 (d, J = 14.6 Hz, 1H), 4.41 (d, J = 14.6 Hz, 1H), 3.81 (d, J = 3.0 Hz, 6H), 2.54 (ddd, J = 3.5, 6.4, 8.3 Hz, 1H), 2.48-2.38 (m, 1H), 2.36-2.27 (m, 1H), 2.25-2.18 (m, 1H), 1.63- Attorney Docket No.156A002WO01 1.54 (m, 1H), 1.32-1.24 (m, 1H), 0.83-0.70 (m, 1H), 0.37 (dt, J = 3.6, 5.6 Hz, 1H). [00343] 4-[(4-Chlorophenyl)methyl]-2-[(2,4-dimethoxyphenyl)methyl]-2-azabicyclo- [4.1.0]heptan-3-one 18e. To a solution of compound 18d (100 mg, 383 µmol) in THF (1 mL) was added 2M LDA (191 μL) under N2. After the mixture was stirred at -78 °C for 30 min, 1- (bromomethyl)-4-chlorobenzene (78.6 mg, 383 µmol) was added. The reaction mixture was stirred at 25 °C for 1 h under N₂, and then diluted with sat. aq. NH₄Cl and H₂O 10 mL, and extracted with EtOAc (20 mL x 3). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated to yield a crude product, which was purified by silica-gel column chromatography to afford compound 18e (97 mg). LCMS (ESI) m/z: 386.1 [M+H]⁺; ¹H NMR (400 MHz, CDCl₃) δ 7.25 (s, 2H), 7.19-7.12 (m, 3H), 6.49-6.45 (m, 2H), 4.91 (d, J = 14.5 Hz, 1H), 4.33 (d, J = 14.5 Hz, 1H), 3.82 (s, 6H), 3.15 (dd, J = 5.1, 13.6 Hz, 1H), 2.85 (dd, J = 10.4, 13.5 Hz, 1H), 2.61 (ddd, J = 3.6, 6.4, 8.1 Hz, 1H), 2.52 (qd, J = 4.6, 9.6 Hz, 1H), 2.05-1.98 (m, 1H), 1.62-1.56 (m, 1H), 1.24-1.15 (m, 1H), 0.87-0.81 (m, 1H), 0.40-0.34 (m, 1H). [00344] 4-[(4-Chlorophenyl)methyl]-2-azabicyclo[4.1.0]heptan-3-one 18f. A mixture of compound 18e (90 mg, 233 µmol) and TFA (798 mg, 7 mmol) in DCM (1 mL) was stirred at 25 °C for 32 h. The reaction mixture was concentrated and purified by prep-TLC to afford compound 18f (16 mg). LCMS (ESI) m/z: 236.1 [M+H]⁺; ¹H NMR (400 MHz, CDCl₃) δ = 7.29 (br s, 2H), 7.17 (br d, J = 6.8 Hz, 2H), 3.63-3.39 (m, 1H), 3.26-3.05 (m, 1H), 2.82-2.74 (m, 1H), 2.52-2.37 (m, 1H), 2.03 (br s, 1H), 1.76-1.66 (m, 1H), 1.26-1.19 (m, 1H), 0.89 (br d, J = 4.1 Hz, 1H), 0.54 (br s, 1H). [00345] 4-[(4-Chlorophenyl) methyl]-2-[5-(4-pyridyl)-2-(2-trimethylsilylethoxymethyl)- pyrazol-3-yl]-2-azabicyclo[4.1.0]heptan-3-one 18g. To a mixture of compound 18f (16 mg, 67.9 µmol) and K₃PO₄ (36 mg, 170 µmol) in toluene (0.5 mL) were added CuI (1.3 mg, 6.79 µmol), DMEDA (1.2 mg, 13.6 µmol), and 2-[[5-bromo-3-(4-pyridyl)pyrazol-1-yl]methoxy]ethyl- trimethylsilane (31.3 mg, 88.2 µmol) under N2. After stirring at 100 °C for 16 h under N2, the reaction mixture was concentrated and purified by prep-TLC to afford compound 18g (11 mg). LCMS (ESI) m/z: 509.3 [M+H]⁺. [00346] 4-(4-Chlorobenzyl)-2-(3-(pyridin-4-yl)-1H-pyrazol-5-yl)-2-azabicyclo[4.1.0]- heptan-3-one B1. To a mixture of compound 18g (11 mg, 21.6 µmol) in DCM (0.5 mL) was Attorney Docket No.156A002WO01 added TFA (98.5 mg, 864 µmol). After stirring at 25 °C for 1 h, the reaction mixture was concentrated and purified by reverse-phase prep-HPLC to afford compound B1 (1.9 mg) as a TFA salt in 17% yield. LCMS (ESI) m/z: 379.3 [M+H]⁺; ¹H NMR (400 MHz, CDCl₃) δ 8.82 (br d, J = 5.9 Hz, 2H), 8.20 (br d, J = 4.5 Hz, 2H), 7.34 (br d, J = 7.8 Hz, 2H), 7.20 (br d, J = 8.2 Hz, 2H), 6.60 (s, 1H), 3.20 (br dd, J = 5.9, 13.6 Hz, 1H), 3.16-3.10 (m, 1H), 3.01 (br dd, J = 10.1, 13.6 Hz, 1H), 2.79 (br d, J = 3.3 Hz, 1H), 2.33-2.30 (m, 1H), 1.60 (br d, J = 14.3 Hz, 1H), 1.48- 1.38 (m, 1H), 1.28-1.22 (m, 1H), 0.80-0.71 (m, 1H). [00347] The following compounds were prepared similarly according to the synthetic procedures or methodologies exemplified herein. [00348] Endo-4-(5-(4-(4-chlorobenzyl)-3-oxo-2-azabicyclo[3.1.0]hexan-2-yl)-1H-pyrazol- 3-yl)pyridine 1-oxide A9. LCMS (ESI) m/z: 381.2 [M+H]⁺. [00349] Endo-4-(4-chlorobenzyl)-2-(3-(6-methylpyridazin-4-yl)-1H-pyrazol-5-yl)-2- azabicyclo[3.1.0]hexan-3-one A10. LCMS (ESI) m/z: 380.1 [M+H]⁺. [00350]

- - yl)-2- azabicyclo[3.1.0]hexan-3-one A11. LCMS (ESI) m/z: 381.1 [M+H]⁺. [00351] Endo-4-(4-chlorobenzyl)-2-(3-(pyrimidin-4-yl)-1H-pyrazol-5-yl)-2- azabicyclo[3.1.0]hexan-3-one A12. LCMS (ESI) m/z: 366.1 [M+H]⁺. [00352]

1H-pyrazol- 3-yl)picolinonitrile A13. LCMS (ESI) m/z: 390.1 [M+H]⁺. Attorney Docket No.156A002WO01 [00353] Endo-5-(5-(4-(4-chlorobenzyl)-3-oxo-2-azabicyclo[3.1.0]hexan-2-yl)-1H-pyrazol- 3-yl)pyridazine-3-carbonitrile A14. LCMS (ESI) m/z: 391.2 [M+H]⁺.

[00354] Endo-4-(5-(4-(4-chlorobenzyl)-3-oxo-2-azabicyclo[3.1.0]hexan-2-yl)-1H-pyrazol- 3-yl)nicotinonitrile A15. LCMS (ESI) m/z: 390.1 [M+H]⁺. [00355] Endo-4-((6-chloropyridin-3-yl)methyl)-2-(5-methyl-2-(pyridin-4-yl)-1H- imidazol-4-yl)-2-azabicyclo[3.1.0]hexan-3-one A30. LCMS (ESI) m/z: 380.0 [M+H]⁺; ¹H NMR (400 MHz, CD₃OD) δ 8.94 (d, J = 6.9 Hz, 2H), 8.52-8.44 (m, 3H), 8.05 (dd, J = 2.3, 8.3 Hz, 1H), 7.60 (d, J = 8.3 Hz, 1H), 3.66 (br t, J = 5.1 Hz, 1H), 3.47 (ddd, J = 5.3, 6.7, 10.5 Hz, 1H), 3.23 (dd, J = 5.0, 14.0 Hz, 1H), 2.84 (dd, J = 10.4, 13.9 Hz, 1H), 2.41 (s, 3H), 1.82-1.69 (m, 1H), 1.11-1.01 (m, 1H), 0.85 (br t, J = 4.9 Hz, 1H). [00356]

- 1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hexan-3-one A31. LCMS (ESI) m/z: 434.0 [M+H]⁺; ¹H NMR (400 MHz, CD₃OD) δ 8.89 (br d, J = 6.9 Hz, 2H), 8.37 (d, J = 2.3 Hz, 1H), 8.22 (br d, J = 6.5 Hz, 2H), 7.90-7.83 (m, 1H), 7.45 (d, J = 8.3 Hz, 1H), 3.98 (ddd, J = 1.9, 5.1, 7.1 Hz, 1H), 3.56-3.48 (m, 1H), 3.22 (dd, J = 4.8, 14.2 Hz, 1H), 2.78 (dd, J = 10.7, 14.1 Hz, 1H), 1.81-1.68 (m, 1H), 1.12 (ddd, J = 5.4, 6.4, 8.5 Hz, 1H), 0.76-0.66 (m, 1H). [00357] Endo-4-[(6-chloro-5-cyclopropyl-3-pyridyl)methyl]-2-[3-(4-pyridyl)-1H-pyrazol- 5-yl]-2-azabicyclo[3.1.0]hexan-3-one A33. LCMS (ESI) m/z: 406.1 [M+H]⁺; ¹H NMR (400 MHz, CD3OD) δ 8.82 (d, J = 6.9 Hz, 2H), 8.42 (d, J = 6.9 Hz, 1H), 8.16 (d, J = 2.3 Hz, 1H), 7.48 (d, J = 2.3 Hz, 1H), 7.27 (s, 1H), 3.77 (br d, J = 2.0 Hz, 1H), 3.44 (s, 1H), 3.16 (dd, J = 4.8, 14.1 Attorney Docket No.156A002WO01 Hz, 1H), 2.69 (dd, J = 10.6, 13.9 Hz, 1H), 2.19 (br d, J = 5.1 Hz, 1H), 1.73-1.63 (m, 1H), 1.17- 1.01 (m, 3H), 0.85-0.72 (m, 2H), 0.62 (s, 1H).

[00358] Endo-4-((6-chloro-2-ethylpyridin-3-yl)methyl)-2-(3-(5-methylpyridazin-4-yl)-1H- pyrazol-5-yl)-2-azabicyclo[3.1.0]hexan-3-one A34. LCMS (ESI) m/z: 409.1 [M+H]⁺; ¹H NMR (400 MHz, CD₃OD) δ 9.26 (br d, J = 2.8 Hz, 1H), 9.13 (br s, 1H), 7.76 (d, J = 8.1 Hz, 1H), 7.28- 6.77 (m, 2H), 3.96-3.69 (m, 1H), 3.41-3.34 (m, 1H), 3.25 (dd, J = 4.1, 14.1 Hz, 1H), 2.97-2.87 (m, 2H), 2.70 (dd, J = 11.1, 14.2 Hz, 1H), 2.58 (br s, 3H), 1.67 (br s, 1H), 1.30 (t, J = 7.5 Hz, 3H), 1.12-1.01 (m, 1H), 0.83-0.52 (m, 1H). [00359] Endo-4-((6-chloro-2-(trifluoromethyl)pyridin-3-yl)methyl)-2-(3-(5-methyl- pyridazin-4-yl)-1H-pyrazol-5-yl)-2-azabicyclo[3.1.0]hexan-3-one A35. LCMS (ESI) m/z: 448.1 [M+H]⁺; ¹H NMR (400 MHz, CD₃OD) δ 9.55 (s, 1H), 9.30 (s, 1H), 8.22-8.03 (m, 1H), 7.78 (d, J = 7.8 Hz, 1H), 7.26-6.92 (m, 1H), 3.82 (ddd, J = 1.9, 5.1, 7.1 Hz, 1H), 3.61 (ddd, J = 5.2, 6.8, 10.5 Hz, 1H), 3.41 (dd, J = 5.0, 14.0 Hz, 1H), 2.93 (dd, J = 10.4, 14.1 Hz, 1H), 2.75 (s, 3H), 1.79-1.66 (m, 1H), 1.10 (ddd, J = 5.3, 6.3, 8.4 Hz, 1H), 0.78-0.64 (m, 1H). Cl N N [00360]

4-yl)-1H- pyrazol-5-yl)-2-azabicyclo[3.1.0]hexan-3-one A39. LCMS (ESI) m/z: 381.2 [M+H]⁺; ¹H NMR (400 MHz, CD3OD) δ 9.88 (s, 1H), 9.52 (d, J = 6.0 Hz, 1H), 8.61 (dd, J = 1.9, 5.9 Hz, 1H), 8.38 (s, 1H), 7.88 (dd, J = 2.2, 8.3 Hz, 1H), 7.46 (d, J = 8.1 Hz, 1H), 3.61-3.52 (m, 1H), 3.48-3.40 (m, 1H), 3.21 (dd, J = 4.6, 14.0 Hz, 1H), 2.77 (dd, J = 10.8, 13.9 Hz, 1H), 2.35 (s, 3H), 1.79-1.68 (m, 1H), 1.04 (td, J = 5.7, 8.4 Hz, 1H), 0.82-0.73 (m, 1H). Attorney Docket No.156A002WO01 [00361] (1S,4R,5S)-4-((6-Chloropyridin-3-yl)methyl)-2-(4-methyl-3-(pyridin-4-yl)-1H- pyrazol-5-yl)-2-azabicyclo[3.1.0]hexan-3-one A41. LCMS (ESI) m/z: 380.0 [M+H]⁺; ¹H NMR (400 MHz, CD₃OD) δ 8.86 (br d, J = 6.0 Hz, 2H), 8.44-8.30 (m, 3H), 7.88 (dd, J = 2.3, 8.2 Hz, 1H), 7.46 (d, J = 8.1 Hz, 1H), 3.56 (ddd, J = 1.7, 5.0, 7.0 Hz, 1H), 3.49-3.36 (m, 1H), 3.21 (dd, J = 4.6, 14.0 Hz, 1H), 2.77 (dd, J = 10.7, 13.9 Hz, 1H), 2.31 (s, 3H), 1.78-1.65 (m, 1H), 1.09-0.98 (m, 1H), 0.83-0.72 (m, 1H). Cl

[00362] (1S,4R,5S)-4-((6-Chloropyridin-3-yl)methyl)-2-(3-(3-methylpyridin-4-yl)-1H- pyrazol-5-yl)-2-azabicyclo[3.1.0]hexan-3-one A42. LCMS (ESI) m/z: 380.2 [M+H]⁺; ¹H NMR (400 MHz, CD3OD) δ 8.90-8.61 (m, 2H), 8.47-8.21 (m, 2H), 7.95-7.78 (m, 1H), 7.54-7.37 (m, 1H), 7.02 (s, 1H), 3.93-3.69 (m, 1H), 3.51-3.39 (m, 1H), 3.25-3.17 (m, 1H), 2.76 (s, 3H), 2.76- 2.61 (m, 1H), 1.80-1.59 (m, 1H), 1.21-0.95 (m, 1H), 0.77-0.54 (m, 1H). [00363] Endo-4-((6-chloropyridin-3-yl)methyl)-2-(5-fluoro-4-(pyridin-4-yl)-1H-imidazol- 2-yl)-2-azabicyclo[3.1.0]hexan-3-one A44. LCMS (ESI) m/z: 365.1 [M+H]⁺; ¹H NMR (400 MHz, CD₃OD) δ 8.62 (br s, 2H), 8.37 (d, J = 2.4 Hz, 1H), 8.03 (br d, J = 6.3 Hz, 2H), 7.86 (dd, J = 2.4, 8.2 Hz, 1H), 7.45 (d, J = 8.3 Hz, 1H), 3.88 (ddd, J = 2.0, 5.2, 7.2 Hz, 1H), 3.58-3.48 (m, 1H), 3.25-3.18 (m, 1H), 2.78 (dd, J = 10.6, 14.1 Hz, 1H), 1.79-1.69 (m, 1H), 1.14-1.05 (m, 1H), 0.78-0.68 (m, 1H). [00364]

4-yl)- 1H-pyrazol-5-yl)-2-azabicyclo[3.1.0]hexan-3-one A45. LCMS (ESI) m/z: 407.1 [M+H]⁺; ¹H NMR (400 MHz, CD3OD) δ 9.70 (s, 1H), 9.16 (s, 1H), 8.40 (d, J = 2.4 Hz, 1H), 7.92 (dd, J = 2.4, 8.3 Hz, 1H), 7.49 (d, J = 8.3 Hz, 1H), 7.20 (s, 1H), 3.80 (ddd, J = 2.0, 5.1, 7.2 Hz, 1H), 3.50- Attorney Docket No.156A002WO01 3.43 (m, 1H), 3.21 (dd, J = 4.9, 14.0 Hz, 1H), 2.95-2.86 (m, 1H), 2.75 (dd, J = 10.6, 14.0 Hz, 1H), 1.74 (ddd, J = 1.7, 6.9, 8.4 Hz, 1H), 1.58-1.49 (m, 2H), 1.39-1.30 (m, 2H), 1.09 (ddd, J = 5.0, 6.3, 8.4 Hz, 1H), 0.74-0.61 (m, 1H). [00365] (1S,4R,5S)-4-((6-Chloropyridin-3-yl)methyl)-2-(3-(5-cyclopropylpyridazin-4-yl)- 4-methyl-1H-pyrazol-5-yl)-2-azabicyclo[3.1.0]hexan-3-one A49. LCMS (ESI) m/z: 421.2 [M+H]⁺; ¹H NMR (400 MHz, CD₃OD) δ 9.40 (s, 1H), 9.09 (s, 1H), 8.38 (d, J = 2.3 Hz, 1H), 7.88 (dd, J = 2.3, 8.2 Hz, 1H), 7.46 (d, J = 8.3 Hz, 1H), 3.59 (ddd, J = 1.9, 5.1, 7.1 Hz, 1H), 3.48-3.39 (m, 1H), 3.21 (dd, J = 4.7, 13.9 Hz, 1H), 2.77 (dd, J = 10.6, 13.9 Hz, 1H), 2.47-2.36 (m, 1H), 2.08 (s, 3H), 1.77-1.68 (m, 1H), 1.58 (br t, J = 8.2 Hz, 2H), 1.03 (ddd, J = 5.1, 6.2, 8.4 Hz, 1H), 0.81-0.69 (m, 1H).

[00366] (1S,4R,5S)-4-((6-Fluoropyridin-3-yl)methyl)-2-(3-(pyridazin-4-yl)-1H-pyrazol-5- yl)-2-azabicyclo[3.1.0]hexan-3-one A50. LCMS (ESI) m/z: 351.1 [M+H]⁺; ¹H NMR (400 MHz, CD3OD) δ 9.75 (d, J = 1.3 Hz, 1H), 9.36 (dd, J = 0.9, 5.7 Hz, 1H), 8.35 (dd, J = 2.1, 5.6 Hz, 1H), 8.19 (d, J = 2.4 Hz, 1H), 7.99 (dt, J = 2.6, 8.1 Hz, 1H), 7.26 (s, 1H), 7.07 (dd, J = 2.4, 8.4 Hz, 1H), 3.78 (ddd, J = 2.0, 5.1, 7.2 Hz, 1H), 3.43 (ddd, J = 4.7, 6.8, 11.0 Hz, 1H), 3.22 (dd, J = 4.6, 14.0 Hz, 1H), 2.72 (dd, J = 10.9, 14.0 Hz, 1H), 1.78-1.57 (m, 1H), 1.16-1.00 (m, 1H), 0.73-0.56 (m, 1H). [00367] (1S,4R,5S)-2-(3-(Pyridazin-4-yl)-1H-pyrazol-5-yl)-4-((6-(trifluoromethyl)pyridin- 3-yl)methyl)-2-azabicyclo[3.1.0]hexan-3-one A51. LCMS (ESI) m/z: 401.1 [M+H]⁺; ¹H NMR (400 MHz, CD3OD) δ 9.59 (br d, J = 2.1 Hz, 1H), 9.22 (br d, J = 4.3 Hz, 1H), 8.73 (d, J = 1.6 Hz, 1H), 8.08 (dd, J = 1.6, 8.1 Hz, 1H), 8.05-7.91 (m, 1H), 7.81 (d, J = 8.0 Hz, 1H), 7.56-6.74 (m, 1H), 3.97-3.69 (m, 1H), 3.57-3.43 (m, 1H), 3.33 (br s, 1H), 2.82 (dd, J = 10.9, 13.8 Hz, 1H), 1.81-1.58 (m, 1H), 1.15-0.99 (m, 1H), 0.80-0.51 (m, 1H). Attorney Docket No.156A002WO01

[00368] (1S,4R,5S)-4-((6-Chloro-2-methylpyridin-3-yl)methyl)-2-(3-(pyridazin-4-yl)-1H- pyrazol-5-yl)-2-azabicyclo[3.1.0]hexan-3-one A52. LCMS (ESI) m/z: 381.2 [M+H]⁺; ¹H NMR (400 MHz, CD3OD) δ 9.89 (s, 1H), 9.47 (d, J = 5.9 Hz, 1H), 8.62 (br d, J = 0.8 Hz, 1H), 7.77 (d, J = 8.1 Hz, 1H), 7.42-7.18 (m, 2H), 3.78 (ddd, J = 1.9, 5.0, 7.2 Hz, 1H), 3.44 (ddd, J = 4.4, 6.8, 10.9 Hz, 1H), 3.24 (dd, J = 4.4, 14.3 Hz, 1H), 2.73 (dd, J = 10.8, 14.3 Hz, 1H), 2.61 (s, 3H), 1.80-1.67 (m, 1H), 1.09 (ddd, J = 5.1, 6.3, 8.4 Hz, 1H), 0.78-0.60 (m, 1H). [00369] (1S,4R,5S)-4-((6-Chloro-2-methylpyridin-3-yl)methyl)-2-(3-(5-methylpyridazin- 4-yl)-1H-pyrazol-5-yl)-2-azabicyclo[3.1.0]hexan-3-one A53. LCMS (ESI) m/z: 395.1 [M+H]⁺; ¹H NMR (400 MHz, CD3OD) δ 9.60 (s, 1H), 9.33 (s, 1H), 7.75 (d, J = 8.1 Hz, 1H), 7.27 (d, J = 8.1 Hz, 1H), 7.11 (s, 1H), 3.81 (br t, J = 2.1 Hz, 1H), 3.48-3.39 (m, 1H), 3.23 (dd, J = 4.4, 14.3 Hz, 1H), 2.80-2.69 (m, 4H), 2.60 (s, 3H), 1.78-1.66 (m, 1H), 1.12-1.03 (m, 1H), 0.71-0.64 (m, 1H). Cl Cl N N [00370]

3-(5-methyl- pyridazin-4-yl)-1H-pyrazol-5-yl)-2-azabicyclo[3.1.0]hexan-3-one A54. LCMS (ESI) m/z: 409.1 [M+H]⁺; ¹H NMR (400 MHz, CD₃OD) δ 9.56 (d, J = 18.1 Hz, 2H), 8.04-7.86 (m, 1H), 7.51-7.34 (m, 1H), 3.62 (ddd, J = 1.9, 5.0, 7.1 Hz, 1H), 3.44 (ddd, J = 4.8, 6.5, 10.9 Hz, 1H), 3.25 (dd, J = 4.6, 14.3 Hz, 1H), 2.82 (dd, J = 10.8, 14.2 Hz, 1H), 2.74 (s, 3H), 2.67 (s, 3H), 2.06 (s, 3H), 1.84- 1.67 (m, 1H), 1.13-1.01 (m, 1H), 0.81 (br t, J = 5.1 Hz, 1H). [00371] (1S,4R,5S)-4-((5-Chloropyridin-2-yl)methyl)-2-(3-(pyridazin-4-yl)-1H-pyrazol-5- yl)-2-azabicyclo[3.1.0]hexan-3-one A55. LCMS (ESI) m/z: 367.1 [M+H]⁺; ¹H NMR (400 MHz, Attorney Docket No.156A002WO01 CD3OD) δ 9.88-9.79 (m, 1H), 9.49-9.40 (m, 1H), 8.69-8.50 (m, 2H), 8.01 (dd, J = 2.5, 8.4 Hz, 1H), 7.92 (dd, J = 2.6, 8.4 Hz, 1H), 7.63-7.56 (m, 1H), 7.54-7.48 (m, 1H), 7.34-7.18 (m, 1H), 3.87-3.73 (m, 1H), 3.72-3.62 (m, 1H), 3.41-3.33 (m, 1H), 3.11-2.84 (m, 1H), 1.86-1.70 (m, 1H), 1.06 (ddd, J = 5.0, 6.4, 8.5 Hz, 1H), 0.65 (s, 1H).

[00372] (1S,4R,5S)-4-((6-Isopropylpyridin-3-yl)methyl)-2-(3-(pyridin-4-yl)-1H-pyrazol-5- yl)-2-azabicyclo[3.1.0]hexan-3-one A56. LCMS (ESI) m/z: 375.1 [M+H]⁺; ¹H NMR (400 MHz, CD₃OD) δ 9.94 (d, J = 1.6 Hz, 1H), 9.55 (d, J = 6.0 Hz, 1H), 8.84-8.72 (m, 2H), 8.63 (dd, J = 1.4, 8.4 Hz, 1H), 8.02 (d, J = 8.3 Hz, 1H), 7.34 (s, 1H), 3.83 (br t, J = 5.1 Hz, 1H), 3.60 (td, J = 6.4, 9.5 Hz, 1H), 3.51-3.32 (m, 2H), 3.02 (dd, J = 9.7, 14.2 Hz, 1H), 1.92-1.78 (m, 1H), 1.47 (d, J = 7.0 Hz, 6H), 1.21-1.08 (m, 1H), 0.77 (br t, J = 4.8 Hz, 1H). [00373] (1S,4R,5S)-4-((6-Chloropyridin-3-yl)methyl)-2-(3-(5-methylpyridazin-4-yl)-1H- 1,2,4-triazol-5-yl)-2-azabicyclo[3.1.0]hexan-3-one A60. LCMS (ESI) m/z: 382.2 [M+H]⁺; ¹H NMR (400 MHz, CD₃OD) δ 9.65 (s, 1H), 9.13 (s, 1H), 8.38 (d, J = 2.3 Hz, 1H), 7.87 (dd, J = 2.4, 8.2 Hz, 1H), 7.45 (d, J = 8.1 Hz, 1H), 4.02 (ddd, J = 2.0, 5.2, 7.2 Hz, 1H), 3.55-3.46 (m, 1H), 3.23 (dd, J = 4.9, 14.0 Hz, 1H), 2.82-2.72 (m, 4H), 1.81-1.69 (m, 1H), 1.16-1.07 (m, 1H), 0.79-0.70 (m, 1H). Cl N

[00374] (1S,4R,5S)-4-((6-Chloro-2-methylpyridin-3-yl)methyl)-2-(3-(pyridin-4-yl)-1H- 1,2,4-triazol-5-yl)-2-azabicyclo[3.1.0]hexan-3-one A61. LCMS (ESI) m/z: 381.1 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 8.68 (dd, J = 1.6, 4.4 Hz, 2H), 7.91 (dd, J = 1.6, 4.4 Hz, 2H), 7.74 (d, J = 8.0 Hz, 1H), 7.32 (d, J = 8.0 Hz, 1H), 3.88 (t, J = 5.2 Hz, 1H), 3.58-3.49 (m, 1H), 3.05 Attorney Docket No.156A002WO01 (dd, J = 4.8, 14.4 Hz, 1H), 2.73 (dd, J = 10.6, 14.5 Hz, 1H), 2.53 (s, 1), 1.70-1.61 (m, 1H), 1.04- 0.95 (m, 1H), 0.87-0.81 (m, 1H). [00375] (1S,4R,5S)-4-((6-Chloro-5-fluoropyridin-3-yl)methyl)-2-(3-(pyridin-4-yl)-1H- 1,2,4-triazol-5-yl)-2-azabicyclo[3.1.0]hexan-3-one A62. LCMS (ESI) m/z: 385.1 [M+H]⁺; ¹H NMR (400 MHz, CD3OD) δ 8.90 (d, J = 6.4 Hz, 2H), 8.65 (d, J = 6.8 Hz, 2H), 8.25 (s, 1H), 7.81 (dd, J = 2.0, 12.1 Hz, 1H), 4.07-4.00 (m, 1H), 3.61-3.52 (m, 1H), 3.25 (dd, J = 5.0, 14.2 Hz, 1H), 2.83 (dd, J = 10.4, 14.0 Hz, 1H), 1.85-1.75 (m, 1H), 1.16-1.08 (m, 1H), 0.81-0.73 (m, 1H).

[00376] (1S,4R,5S)-4-((6-Fluoropyridin-3-yl)methyl)-2-(3-(pyridin-4-yl)-1H-1,2,4-triazol- 5-yl)-2-azabicyclo[3.1.0]hexan-3-one A63. LCMS (ESI) m/z: 351.1 [M+H]⁺. [00377] (1S,4R,5S)-4-((6-Fluoro-2-methylpyridin-3-yl)methyl)-2-(3-(pyridin-4-yl)-1H- 1,2,4-triazol-5-yl)-2-azabicyclo[3.1.0]hexan-3-one A64. LCMS (ESI) m/z: 365.1 [M+H]⁺.

[00378] The following compounds are prepared similarly according to the synthetic procedures or methodologies exemplified herein. [00379] Endo-4-(4-chlorobenzyl)-2-(3-(5-(hydroxymethyl)pyridazin-4-yl)-1H-pyrazol-5- yl)-2-azabicyclo[3.1.0]hexan-3-one A16. [00380] Endo-4-(4-chlorobenzyl)-2-(4-methyl-3-(pyridazin-4-yl)-1H-pyrazol-5-yl)-2- azabicyclo[3.1.0]hexan-3-one A17. Attorney Docket No.156A002WO01

[00381] Endo-4-(4-chlorobenzyl)-2-(4-(hydroxymethyl)-3-(pyridazin-4-yl)-1H-pyrazol-5- yl)-2-azabicyclo[3.1.0]hexan-3-one A18. [00382] Endo-5-(4-(4-chlorobenzyl)-3-oxo-2-azabicyclo[3.1.0]hexan-2-yl)-3-(pyridazin- 4-yl)-1H-pyrazole-4-carbonitrile A19.

[00383] Endo-4-(4-chloro-3-fluorobenzyl)-2-(3-(pyridazin-4-yl)-1H-pyrazol-5-yl)-2- azabicyclo[3.1.0]hexan-3-one A20. [00384] Endo-4-(4-fluorobenzyl)-2-(3-(pyridazin-4-yl)-1H-pyrazol-5-yl)-2- azabicyclo[3.1.0]hexan-3-one A21. eⁿ _do [00385]

5-yl)-2- azabicyclo[3.1.0]hexan-3-one A22. [00386] Endo-4-(4-chlorobenzyl)-2-(3-(3-methylpyridazin-4-yl)-1H-pyrazol-5-yl)-2- azabicyclo[3.1.0]hexan-3-one A23. Attorney Docket No.156A002WO01

[00387] Endo-4-(4-chlorophenoxy)-2-(3-(pyridazin-4-yl)-1H-pyrazol-5-yl)-2- azabicyclo[3.1.0]hexan-3-one A24. [00388] Endo-4-((4-chlorophenyl)amino)-2-(3-(pyridazin-4-yl)-1H-pyrazol-5-yl)-2- azabicyclo[3.1.0]hexan-3-one A25.

[00389] Endo-4-(4-chlorobenzyl)-2-(3-(5-methylpyridazin-4-yl)-1H-1,2,4-triazol-5-yl)-2- azabicyclo[3.1.0]hexan-3-one A26. [00390] 4-(4-Chlorobenzyl)-2-(3-(pyridazin-4-yl)-1H-pyrazol-5-yl)-2-azabicyclo[2.1.1]- hexan-3-one C1. [00391]

[3.1.1]- heptan-3-one D1.

Attorney Docket No.156A002WO01 Example B1 SARM1 Hydrolase Inhibition Assay [00392] For an exemplary compound, a SARM1 fluorogenic assay kit (BPS Bioscience) was used to determine its inhibitory activity (IC50) against a SARM1 hydrolase. The hydrolase activity of a recombinant human SARM1 enzyme was determined using etheno-NAD as a fluorogenic substrate. The exemplary compound in DMSO was diluted in a 10-point 3-fold series in duplicates using a SARM1 hydrolase buffer and then added in a black 96-well plate (a final concentration of DMSO was attained at 1% for the assay). To each well was added 300 ng of the SARM1 enzyme. After the 96-well plate was preincubated 60 min at room temperature with slow shaking, a diluted etheno-NAD (1 mM) was added to each well to initiate an enzyme reaction. After incubation for 120 min at room temperature in dark, the fluorescence signals were measured on a plate reader with excitation at 300 nm and emission readout at 410 nm. The emission readouts (less blank emission readout without enzyme) were used to calculate an IC₅₀ value using GraphPad Prism (GraphPad Software). The results are summarized in Table 1, where “A” represents an IC50 value of less than 500 nM, “B” represents an IC50 value of no less than 500 nM and less than 1,000 nM, and “C” represents an IC₅₀ value of no less than 1,000 nM and less than 10 µM.

Attorney Docket No.156A002WO01 Table 1. SARM1 Inhibition Activity

[00393] The examples set forth

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

Attorney Docket No.156A002WO01 What is claimed is: 1. A compound of Formula (I):

or an enantiomer, a mixture of a a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein: A is a bond, C1-6 alkylene, or C1-6 heteroalkylene; E is a bond, –O–, –S–, –N(R^1a)–, C_1-6 alkylene, or C_1-6 heteroalkylene; U is –C(R¹)=, –O–, –S–, –N(R³)–, or –N=; V is –N=, –N(R³)–, –C(R¹)=, –O–, or –S–;

Z is C_1-6 alkylene, –O–, –S–, or –N(R⁴)–; each R¹ is independently (i) hydrogen, deuterium, cyano, halo, or nitro; (ii) C1-6 alkyl, C1-6 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) –C(O)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; R² and R⁵ are each independently heteroaryl, heterocyclyl, C_6-14 aryl, or C_3-10 cycloalkyl; each R³ and R⁴ is independently (i) hydrogen; (ii) C1-6 alkyl, C1-6 heteroalkyl, C2-6 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, –S(O)R^1a, –S(O)2R^1a, –S(O)NR^1bR^1c, or –S(O)2NR^1bR^1c; 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 Attorney Docket No.156A002WO01 heterocyclyl; wherein each alkyl, alkylene, heteroalkyl, heteroalkylene, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heteroaryl, and heterocyclyl is optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Q, wherein each Q is independently selected from: (a) deuterium, cyano, halo, imino, nitro, and oxo; (b) C1-6 alkyl, C1-6 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) C1-6 alkyl, C1-6 heteroalkyl, C2-6 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, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) R^f and R^g Attorney Docket No.156A002WO01 together with the N atom to which they are attached form heterocyclyl. of Formula (II):

or an enantiomer, a mixture of a 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. 3. The compound of claim 1, having the structure of Formula (III): or an enantiomer, a mixture of

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. 4. The compound of any one of claims 1 to 3, wherein A is a bond or C_1-6 alkylene optionally substituted with one or more substituents Q. 5. The compound of any one of claims 1 to 4, wherein A is a bond. 6. The compound of any one of claims 1 to 4, wherein A is C1-6 alkylene, optionally substituted with one or more substituents Q. 7. The compound of any one of claims 1 to 4 and 6, wherein A is methanediyl, optionally substituted with one or two substituents Q. 8. The compound of any one of claims 1 to 7, wherein E is a bond or C_1-6 alkylene optionally substituted with one or more substituents Q. 9. The compound of any one of claims 1 to 8, wherein E is a bond. 10. The compound of any one of claims 1 to 7, wherein E is C_1-6 alkylene, optionally Attorney Docket No.156A002WO01 substituted with one or more substituents Q. 11. The compound of any one of claims 1 to 7 and 10, wherein E is methanediyl, optionally substituted with one or two substituents Q. 12. The compound of claim 1 or 2, having the structure of Formula (IV): or an enantiomer, a mixture of

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. 13. The compound of claim 1 or 2, having the structure of Formula (V): or an enantiomer, a mixture of

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. 14. The compound of claim 1 or 2, having the structure of Formula (VI): or an enantiomer, a mixture of mixture of two or more diastereomers, a tautomer, a

or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof. 15. The compound of claim 1 or 3, having the structure of Formula (VII): or an enantiomer, a mixture of mixture of two or more Attorney Docket No.156A002WO01 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. 16. The compound of any one of claims 1 to 15, wherein U is –C(R¹)=, –N(R³)–, or –N=. 17. The compound of any one of claims 1 to 16, wherein U is –C(R¹)=. 18. The compound of any one of claims 1 to 16, wherein U is –N(R³)–. 19. The compound of any one of claims 1 to 16 and 18, wherein U is –N(H)–. 20. The compound of any one of claims 1 to 16, wherein U is –N=. 21. The compound of any one of claims 1 to 15, wherein U is –O–. 22. The compound of any one of claims 1 to 15, wherein U is –S–. 23. The compound of any one of claims 1 to 22, wherein V is –C(R¹)=, –N(R³)–, or –N=. 24. The compound of any one of claims 1 to 23, wherein V is –C(R¹)=. 25. The compound of any one of claims 1 to 23, wherein V is –N(R³)–. 26. The compound of any one of claims 1 to 23 and 25, wherein V is –N(H)–. 27. The compound of any one of claims 1 to 23, wherein V is –N=. 28. The compound of any one of claims 1 to 22, wherein V is –O–. 29. The compound of any one of claims 1 to 22, wherein V is –S–. 30. The compound of any one of claims 1 to 29, wherein X is –C(R¹)=, –N(R³)–, or –N=. 31. The compound of any one of claims 1 to 30, wherein X is –C(R¹)=. Attorney Docket No.156A002WO01 32. The compound of any one of claims 1 to 30, wherein X is –N(R³)–. 33. The compound of any one of claims 1 to 30 and 32, wherein X is –N(H)–. 34. The compound of any one of claims 1 to 30, wherein X is –N=. 35. The compound of any one of claims 1 to 29, wherein X is –O–. 36. The compound of any one of claims 1 to 29, wherein X is –S–. 37. The compound of any one of claims 1, 2, and 12, wherein the compound is a compound of Formula (VIII): or an enantiomer, a mixture of

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. 38. The compound of any one of claims 1, 2, and 13, wherein the compound is a compound of Formula (IX): or an enantiomer, a mixture of mixture of two or more diastereomers, a tautomer, a

or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof. 39. The compound of any one of claims 1, 2, and 14, wherein the compound is a compound of Formula (X): Attorney Docket No.156A002WO01 or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof. 40. The compound of any one of claims 1, 3, and 15, wherein the compound is a compound of Formula (XI): or an enantiomer, a mixture of

mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof. 41. The compound of any one of claims 1 to 40, wherein R¹ is (i) hydrogen, deuterium, or halo; or (ii) C1-6 alkyl, optionally substituted with one or more substituents Q. 42. The compound of any one of claims 1 to 41, wherein R¹ is hydrogen. 43. The compound of any one of claims 1 to 41, wherein R¹ is halo. 44. The compound of any one of claims 1 to 41, wherein R¹ is C1-6 alkyl, optionally substituted with one or more substituents Q. 45. The compound of any one of claims 1 to 40, wherein R¹ is hydrogen, cyano, fluoro, chloro, bromo, methyl, hydroxymethyl, cyclopropyl, cyclobutyl, or methoxy. 46. The compound of any one of claims 1 to 41 and 45, wherein R¹ is hydrogen, methyl, or hydroxymethyl. 47. The compound of any one of claims 1, 2, and 12, wherein the compound is a compound of Formula (XII): R² N N R⁵ Z _(XII) Attorney Docket No.156A002WO01 or an enantiomer, a mixture of 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. 48. The compound of any one of claims 1, 2, and 13, wherein the compound is a compound of Formula (XIII): or an enantiomer, a mixture of

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. 49. The compound of any one of claims 1, 2, and 14, wherein the compound is a compound of Formula (XIV): or an enantiomer, a mixture of 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. 50. The compound of any one of claims 1, 2, and 15, wherein the compound is a compound of Formula (XV): or an enantiomer, a mixture of mixture of two or more diastereomers, a tautomer, a

or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof. 51. The compound of any one of claims 1 to 50, wherein R² is C_6-14 aryl or heteroaryl, Attorney Docket No.156A002WO01 each optionally substituted with one or more substituents Q. 52. The compound of any one of claims 1 to 51, wherein R² is heteroaryl, optionally substituted with one or more substituents Q. 53. The compound of any one of claims 1 to 52, wherein R² is monocyclic heteroaryl, optionally substituted with one or more substituents Q. 54. The compound of any one of claims 1 to 53, wherein R² is 5- or 6-membered heteroaryl, each optionally substituted with one or more substituents Q. 55. The compound of any one of claims 1 to 54, wherein R² is 6-membered heteroaryl, each optionally substituted with one or more substituents Q. 56. The compound of any one of claims 1 to 55, wherein R² is pyridinyl, pyridazinyl, or pyrimidinyl, each optionally substituted with one or more substituents Q. 57. The compound of any one of claims 1 to 56, wherein R² is pyridin-3-yl, pyridin-4- yl, pyridazin-4-yl, or pyrimidin-4-yl, each optionally substituted with one, two, or three substituents, each of which is independently cyano, oxo, methyl, trifluoromethyl, hydroxy- methyl, cyclopropyl, hydroxyl, or methoxy. 58. The compound of any one of claims 1 to 57, wherein R² is pyridin-4-yl, 1-oxo- pyridin-4-yl, 3-cyanopyridin-4-yl, 6-cyanopyridin-3-yl, 3-methylpyridin-4-yl, 6-hydroxyl- pyridin-3-yl, pyridazin-4-yl, 6-cyanopyridazin-4-yl, 3-methylpyridazin-4-yl, 5-methylpyridazin- 4-yl, 6-methylpyridazin-4-yl, 5-trifluomethylpyridazin-4-yl, 5-hydroxymethylpyridazin-4-yl, 5- cyclopropylpyridazin-4-yl, 3-hydroxypyridazin-4-yl, 3-methoxypyridazin-4-yl, or pyrimidin-4- yl. 59. The compound of any one of claims 1 to 58, wherein R³ is hydrogen. 60. The compound of any one of claims 1 to 59, wherein R⁵ is C_6-14 aryl or heteroaryl, each optionally substituted with one or more substituents Q. 61. The compound of any one of claims 1 to 60, wherein R⁵ is C6-14 aryl, optionally Attorney Docket No.156A002WO01 substituted with one or more substituents Q. 62. The compound of any one of claims 1 to 61, wherein R⁵ is phenyl, optionally substituted with one or more substituents Q. 63. The compound of any one of claims 1 to 60, wherein R⁵ is heteroaryl, optionally substituted with one or more substituents Q. 64. The compound of any one of claims 1 to 60 and 63, wherein R⁵ is monocyclic heteroaryl, optionally substituted with one or more substituents Q. 65. The compound of any one of claims 1 to 60, 63, and 64, wherein R⁵ is 5- or 6- membered heteroaryl, each optionally substituted with one or more substituents Q. 66. The compound of any one of claims 1 to 60 and 63 to 65, wherein R⁵ is 6- membered heteroaryl, each optionally substituted with one or more substituents Q. 67. The compound of any one of claims 1 to 60 and 63 to 66, wherein R⁵ is pyridinyl, optionally substituted with one or more substituents Q. 68. The compound of any one of claims 1 to 60, wherein R⁵ is phenyl, pyridin-2-yl, or pyridin-3-yl, each optionally substituted with one, two, or three substituents, each of which is independently fluoro, chloro, methyl, ethyl, isopropyl, trifluoromethyl, hydroxymethyl, amino- methyl, or cyclopropyl. 69. The compound of any one of claims 1 to 60 or 68, wherein R⁵ is 4-fluorophenyl, 4-chlorophenyl, 4-chloro-3-fluoroophenyl, 5-chloropyridin-2-yl, 6-fluoropyridin-3-yl, 6-chloro- pyridin-3-yl, 6-methylpyridin-3-yl, 6-trifluoromethylpyridin-3-yl, 6-isopropylpyridin-3-yl, 6- cyclopropylpyridin-3-yl, 6-chloro-5-fluoropyridin-3-yl, 6-fluoro-2-methylpyridin-3-yl, 6-chloro- 2-methylpyridin-3-yl, 6-chloro-5-methylpyridin-3-yl, 6-chloro-2-ethylpyridin-3-yl, 6-chloro-2- trifluoromethylpyridin-3-yl, 6-chloro-2-hydroxymethylpyridin-3-yl, 2-aminomethyl-6-chloro- pyridin-3-yl, or 6-chloro-5-cyclopropylpyridin-3-yl. 70. The compound of any one of claims 1 to 69, wherein Z is –O–, –N(R⁴)–, or C1-6 alkylene, optionally substituted with one or more substituents Q. Attorney Docket No.156A002WO01 71. The compound of any one of claims 1 to 70, wherein Z is –O–. 72. The compound of any one of claims 1 to 70, wherein Z is –N(R⁴)–. 73. The compound of any one of claims 1 to 70 and 72, wherein Z is –N(H)–. 74. The compound of any one of claims 1 to 70, wherein Z is C1-6 alkylene, optionally substituted with one or more substituents Q. 75. The compound of any one of claims 1 to 70 and 74, wherein Z is methanediyl, optionally substituted with one or two substituents Q. 76. The compound of any one of claims 1 to 70, 74, and 75, wherein Z is methanediyl. 77. A compound of: exo-4-(4-chlorobenzyl)-2-(3-(pyridin-4-yl)-1H-pyrazol-5-yl)-2-azabicyclo[3.1.0]- hexan-3-one A1; endo-4-(4-chlorobenzyl)-2-(3-(pyridin-4-yl)-1H-pyrazol-5-yl)-2- azabicyclo[3.1.0]hexan-3-one A2; endo-4-(4-chlorobenzyl)-2-(3-(pyridazin-4-yl)-1H-pyrazol-5-yl)-2- azabicyclo[3.1.0]hexan-3-one A3; exo-4-(4-chlorobenzyl)-2-(3-(pyridazin-4-yl)-1H-pyrazol-5-yl)-2- azabicyclo[3.1.0]hexan-3-one A4; endo-4-(4-chlorobenzyl)-2-(3-(5-methylpyridazin-4-yl)-1H-pyrazol-5-yl)-2- azabicyclo[3.1.0]hexan-3-one A5; exo-4-(4-chlorobenzyl)-2-(3-(5-methylpyridazin-4-yl)-1H-pyrazol-5-yl)-2- azabicyclo[3.1.0]hexan-3-one A6; 4-((6-chloropyridin-3-yl)methyl)-2-(3-(pyridazin-4-yl)-1H-pyrazol-5-yl)-2- azabicyclo[3.1.0]hexan-3-one A7; endo-4-((6-chloropyridin-3-yl)methyl)-2-(3-(5-methylpyridazin-4-yl)-1H-pyrazol- 5-yl)-2-azabicyclo[3.1.0]hexan-3-one A8; endo-4-(5-(4-(4-chlorobenzyl)-3-oxo-2-azabicyclo[3.1.0]hexan-2-yl)-1H-pyrazol- 3-yl)pyridine 1-oxide A9; Attorney Docket No.156A002WO01 endo-4-(4-chlorobenzyl)-2-(3-(6-methylpyridazin-4-yl)-1H-pyrazol-5-yl)-2-aza- bicyclo[3.1.0]hexan-3-one A10; endo-4-(4-chlorobenzyl)-2-(3-(6-hydroxypyridin-3-yl)-1H-pyrazol-5-yl)-2-aza- bicyclo[3.1.0]hexan-3-one A11; endo-4-(4-chlorobenzyl)-2-(3-(pyrimidin-4-yl)-1H-pyrazol-5-yl)-2-azabicyclo- [3.1.0]hexan-3-one A12; endo-5-(5-(4-(4-chlorobenzyl)-3-oxo-2-azabicyclo[3.1.0]hexan-2-yl)-1H-pyrazol- 3-yl)picolinonitrile A13; endo-5-(5-(4-(4-chlorobenzyl)-3-oxo-2-azabicyclo[3.1.0]hexan-2-yl)-1H-pyrazol- 3-yl)pyridazine-3-carbonitrile A14; endo-4-(5-(4-(4-chlorobenzyl)-3-oxo-2-azabicyclo[3.1.0]hexan-2-yl)-1H-pyrazol- 3-yl)nicotinonitrile A15; endo-4-(4-chlorobenzyl)-2-(3-(5-(hydroxymethyl)pyridazin-4-yl)-1H-pyrazol-5- yl)-2-azabicyclo[3.1.0]hexan-3-one A16; endo-4-(4-chlorobenzyl)-2-(4-methyl-3-(pyridazin-4-yl)-1H-pyrazol-5-yl)-2-aza- bicyclo[3.1.0]hexan-3-one A17; endo-4-(4-chlorobenzyl)-2-(4-(hydroxymethyl)-3-(pyridazin-4-yl)-1H-pyrazol-5- yl)-2-azabicyclo[3.1.0]hexan-3-one A18; endo-5-(4-(4-chlorobenzyl)-3-oxo-2-azabicyclo[3.1.0]hexan-2-yl)-3-(pyridazin-4- yl)-1H-pyrazole-4-carbonitrile A19; endo-4-(4-chloro-3-fluorobenzyl)-2-(3-(pyridazin-4-yl)-1H-pyrazol-5-yl)-2-aza- bicyclo[3.1.0]hexan-3-one A20; endo-4-(4-fluorobenzyl)-2-(3-(pyridazin-4-yl)-1H-pyrazol-5-yl)-2-azabicyclo- [3.1.0]hexan-3-one A21; endo-4-((6-methylpyridin-3-yl)methyl)-2-(3-(pyridazin-4-yl)-1H-pyrazol-5-yl)-2- azabicyclo[3.1.0]hexan-3-one A22; endo-4-(4-chlorobenzyl)-2-(3-(3-methylpyridazin-4-yl)-1H-pyrazol-5-yl)-2-aza- bicyclo[3.1.0]hexan-3-one A23; endo-4-(4-chlorophenoxy)-2-(3-(pyridazin-4-yl)-1H-pyrazol-5-yl)-2-aza- bicyclo[3.1.0]hexan-3-one A24; endo-4-((4-chlorophenyl)amino)-2-(3-(pyridazin-4-yl)-1H-pyrazol-5-yl)-2-aza- Attorney Docket No.156A002WO01 bicyclo[3.1.0]hexan-3-one A25; endo-4-(4-chlorobenzyl)-2-(3-(5-methylpyridazin-4-yl)-1H-1,2,4-triazol-5-yl)-2- azabicyclo[3.1.0]hexan-3-one A26; (1R,4S,5R)-4-((6-chloropyridin-3-yl)methyl)-2-(3-(5-methylpyridazin-4-yl)-1H- pyrazol-5-yl)-2-azabicyclo[3.1.0]hexan-3-one A27; (1S,4R,5S)-4-((6-chloropyridin-3-yl)-methyl)-2-(3-(5-methylpyridazin-4-yl)-1H- pyrazol-5-yl)-2-azabicyclo[3.1.0]hexan-3-one A28; endo-4-((6-chloropyridin-3-yl)methyl)-2-(5-methyl-4-(pyridin-4-yl)-1H-imidazol- 2-yl)-2-azabicyclo[3.1.0]hexan-3-one A29; endo-4-((6-chloropyridin-3-yl)methyl)-2-(5-methyl-2-(pyridin-4-yl)-1H-imidazol- 4-yl)-2-azabicyclo[3.1.0]hexan-3-one A30; endo-4-((6-chloropyridin-3-yl)methyl)-2-(4-(pyridin-4-yl)-5-(trifluoromethyl)- 1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hexan-3-one A31; (1S,4R,5S)-4-((6-chloro-5-methylpyridin-3-yl)methyl)-2-(3-(pyridazin-4-yl)-1H- pyrazol-5-yl)-2-azabicyclo[3.1.0]hexan-3-one A32; endo-4-[(6-chloro-5-cyclopropyl-3-pyridyl)methyl]-2-[3-(4-pyridyl)-1H-pyrazol- 5-yl]-2-azabicyclo[3.1.0]hexan-3-one A33; endo-4-((6-chloro-2-ethylpyridin-3-yl)methyl)-2-(3-(5-methylpyridazin-4-yl)-1H- pyrazol-5-yl)-2-azabicyclo[3.1.0]hexan-3-one A34; endo-4-((6-chloro-2-(trifluoromethyl)pyridin-3-yl)methyl)-2-(3-(5-methyl- pyridazin-4-yl)-1H-pyrazol-5-yl)-2-azabicyclo[3.1.0]hexan-3-one A35; endo-4-((2-(aminomethyl)-6-chloropyridin-3-yl)methyl)-2-(3-(5-methylpyridazin- 4-yl)-1H-pyrazol-5-yl)-2-azabicyclo[3.1.0]hexan-3-one A36; endo-4-((6-cyclopropylpyridin-3-yl)methyl)-2-(3-(pyridin-4-yl)-1H-pyrazol-5-yl)- 2-azabicyclo[3.1.0]hexan-3-one A37; (1S,4R,5S)-4-((6-chloropyridin-3-yl)methyl)-2-(3-(pyridin-4-yl)-1H-pyrazol-5- yl)-2-azabicyclo[3.1.0]hexan-3-one A38; (1S,4R,5S)-4-((6-chloropyridin-3-yl)methyl)-2-(4-methyl-3-(pyridazin-4-yl)-1H- pyrazol-5-yl)-2-azabicyclo[3.1.0]hexan-3-one A39; (1S,4R,5S)-4-((6-chloropyridin-3-yl)methyl)-2-(3-(5-(trifluoromethyl)pyridazin-4- yl)-1H-pyrazol-5-yl)-2-azabicyclo[3.1.0]hexan-3-one A40; Attorney Docket No.156A002WO01 (1S,4R,5S)-4-((6-chloropyridin-3-yl)methyl)-2-(4-methyl-3-(pyridin-4-yl)-1H- pyrazol-5-yl)-2-azabicyclo[3.1.0]hexan-3-one A41; (1S,4R,5S)-4-((6-chloropyridin-3-yl)methyl)-2-(3-(3-methylpyridin-4-yl)-1H- pyrazol-5-yl)-2-azabicyclo[3.1.0]hexan-3-one A42; (1S,4R,5S)-4-((6-chloropyridin-3-yl)methyl)-2-(3-(3-methylpyridazin-4-yl)-1H- pyrazol-5-yl)-2-azabicyclo[3.1.0]hexan-3-one A43; endo-4-((6-chloropyridin-3-yl)methyl)-2-(5-fluoro-4-(pyridin-4-yl)-1H-imidazol- 2-yl)-2-azabicyclo[3.1.0]hexan-3-one A44; (1S,4R,5S)-4-((6-chloropyridin-3-yl)methyl)-2-(3-(5-cyclopropylpyridazin-4-yl)- 1H-pyrazol-5-yl)-2-azabicyclo[3.1.0]hexan-3-one A45; (1S,4R,5S)-4-((6-chloropyridin-3-yl)methyl)-2-(3-(pyridin-4-yl)-1H-1,2,4-triazol- 5-yl)-2-azabicyclo[3.1.0]hexan-3-one A46; (1S,4R,5S)-4-((6-chloropyridin-3-yl)methyl)-2-(3-(3-methoxypyridazin-4-yl)-1H- pyrazol-5-yl)-2-azabicyclo[3.1.0]hexan-3-one A47; (1S,4R,5S)-4-((6-chloropyridin-3-yl)-methyl)-2-(3-(3-oxo-2,3-dihydropyridazin- 4-yl)-1H-pyrazol-5-yl)-2-azabicyclo[3.1.0]hexan-3-one A48; (1S,4R,5S)-4-((6-chloropyridin-3-yl)methyl)-2-(3-(5-cyclopropylpyridazin-4-yl)- 4-methyl-1H-pyrazol-5-yl)-2-azabicyclo[3.1.0]hexan-3-one A49; (1S,4R,5S)-4-((6-fluoropyridin-3-yl)methyl)-2-(3-(pyridazin-4-yl)-1H-pyrazol-5- yl)-2-azabicyclo[3.1.0]hexan-3-one A50; (1S,4R,5S)-2-(3-(Pyridazin-4-yl)-1H-pyrazol-5-yl)-4-((6-(trifluoromethyl)pyridin- 3-yl)methyl)-2-azabicyclo[3.1.0]hexan-3-one A51; (1S,4R,5S)-4-((6-chloro-2-methylpyridin-3-yl)methyl)-2-(3-(pyridazin-4-yl)-1H- pyrazol-5-yl)-2-azabicyclo[3.1.0]hexan-3-one A52; (1S,4R,5S)-4-((6-chloro-2-methylpyridin-3-yl)methyl)-2-(3-(5-methylpyridazin-4- yl)-1H-pyrazol-5-yl)-2-azabicyclo[3.1.0]hexan-3-one A53; (1S,4R,5S)-4-((6-chloro-2-methylpyridin-3-yl)methyl)-2-(4-methyl-3-(5-methyl- pyridazin-4-yl)-1H-pyrazol-5-yl)-2-azabicyclo[3.1.0]hexan-3-one A54; (1S,4R,5S)-4-((5-chloropyridin-2-yl)methyl)-2-(3-(pyridazin-4-yl)-1H-pyrazol-5- yl)-2-azabicyclo[3.1.0]hexan-3-one A55; (1S,4R,5S)-4-((6-isopropylpyridin-3-yl)methyl)-2-(3-(pyridin-4-yl)-1H-pyrazol-5- Attorney Docket No.156A002WO01 yl)-2-azabicyclo[3.1.0]hexan-3-one A56; endo-4-((6-chloro-2-(hydroxymethyl)pyridin-3-yl)methyl)-2-(3-(5-methyl- pyridazin-4-yl)-1H-pyrazol-5-yl)-2-azabicyclo[3.1.0]hexan-3-one A57; (1S,4R,5S)-4-(4-chlorobenzyl)-2-(3-(pyridin-4-yl)-1H-1,2,4-triazol-5-yl)-2- azabicyclo[3.1.0]hexan-3-one A58; (1S,4R,5S)-4-(4-chlorobenzyl)-2-(3-(5-methylpyridazin-4-yl)-1H-1,2,4-triazol-5- yl)-2-azabicyclo[3.1.0]hexan-3-one A59; (1S,4R,5S)-4-((6-chloropyridin-3-yl)methyl)-2-(3-(5-methylpyridazin-4-yl)-1H- 1,2,4-triazol-5-yl)-2-azabicyclo[3.1.0]hexan-3-one A60; (1S,4R,5S)-4-((6-chloro-2-methylpyridin-3-yl)methyl)-2-(3-(pyridin-4-yl)-1H- 1,2,4-triazol-5-yl)-2-azabicyclo[3.1.0]hexan-3-one A61; (1S,4R,5S)-4-((6-chloro-5-fluoropyridin-3-yl)methyl)-2-(3-(pyridin-4-yl)-1H- 1,2,4-triazol-5-yl)-2-azabicyclo[3.1.0]hexan-3-one A62; (1S,4R,5S)-4-((6-fluoropyridin-3-yl)methyl)-2-(3-(pyridin-4-yl)-1H-1,2,4-triazol- 5-yl)-2-azabicyclo[3.1.0]hexan-3-one A63; (1S,4R,5S)-4-((6-fluoro-2-methylpyridin-3-yl)methyl)-2-(3-(pyridin-4-yl)-1H- 1,2,4-triazol-5-yl)-2-azabicyclo[3.1.0]hexan-3-one A64; 4-(4-chlorobenzyl)-2-(3-(pyridin-4-yl)-1H-pyrazol-5-yl)-2-azabicyclo[4.1.0]- heptan-3-one B1; 4-(4-chlorobenzyl)-2-(3-(pyridazin-4-yl)-1H-pyrazol-5-yl)-2-azabicyclo[2.1.1]- hexan-3-one C1; or 4-(4-chlorobenzyl)-2-(3-(pyridazin-4-yl)-1H-pyrazol-5-yl)-2-azabicyclo[3.1.1]- heptan-3-one D1; or an enantiomer, a mixture of 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. 78. A pharmaceutical composition comprising the compound of any one of claims 1 to 77, or an enantiomer, a mixture of 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. Attorney Docket No.156A002WO01 79. The pharmaceutical composition of claim 78, wherein the composition is in single dosage form. 80. The pharmaceutical composition of claim 78 or 79, wherein the composition is in an oral, parenteral, or intravenous dosage form. 81. The pharmaceutical composition of claim 80, wherein the composition is formulated in an oral dosage form. 82. The pharmaceutical composition of claim 81, wherein the oral dosage form is a tablet or capsule. 83. A method of treating, preventing, or ameliorating one or more symptoms of SARM1-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 77, or an enantiomer, a mixture of 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; or a pharmaceutical composition of any one of claims 78 to 82. 84. The method of claim 83, wherein the SARM1-mediated disorder, disease, or condition is a neurological disease. 85. A method of treating, preventing, or ameliorating one or more symptoms of a neurological 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 77, or an enantiomer, a mixture of 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; or a pharmaceutical composition of any one of claims 78 to 82. 86. The method of any one of claims 83 to 85, wherein the subject is a human. 87. A method of inhibiting the activity of a SARM1, comprising contacting the SARM1 with an effective amount of a compound of any one of claims 1 to 77, or an enantiomer, Attorney Docket No.156A002WO01 a mixture of 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; or a pharmaceutical composition of any one of claims 78 to 82.