Oxadiazolone inhibitors of NLRP3 and uses thereof

Abstract

The present disclosure relates to compounds of Formula (I) and (II): and pharmaceutically acceptable salts and tautomers thereof, wherein Ring A, Ring B, R1, R2a, R2b, R3, R4, G1, G2, G3, G4, m, n, and p are described herein, and wherein Ring C is an oxadiazolone of Formula (i-O) or (i-N): Further provided are methods of preparation, methods and use for treating and preventing diseases or disorders, methods of modulating (e.g., inhibiting) NLRP3, and pharmaceutical compositions comprising the same.

Description

OXADIAZOLONE INHIBITORS OF NLRP3 AND USES THEREOFRELATED APPLICATIONS

[0001] This application claims the benefit of U.S. Provisional Patent Application No. 63 / 696,232, filed on September 18, 2024, the entire contents of which is incorporated herein by reference in its entirety.BACKGROUND

[0002] Innate immune responses are mediated by different types of receptors termed patternrecognition receptors (PRRs). PRRs recognize the presence of pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs). Once engaged, these receptors trigger the activation of downstream inflammatory pathways that will help resolve injury. However, in many instances this activation can be uncontrolled and leads to disease.

[0003] The inflammasomes represent a class of PRRs that are crucial components of the innate immune response. Activation of the inflammasomes trigger a cascade of events that releases IL- 1 (3, IL- 18, and promotes an inflammatory form of cell death called pyroptosis induced by the activation of Gasdermin. Pyroptosis is a unique form of inflammatory cell death that leads to the release of not only cytokines but also other intracellular components that promote a broader immune response, both of the innate and acquired immune system. Thus, inflammasome activation is a major regulatory of the inflammatory cascade.

[0004] NLRP3 is the most characterized inflammasome and has been shown to be critical in innate immunity and inflammatory responses. While several other NLR complexes, such as NLRC4, are activated under very specific circumstances, NLRP3 can be activated by numerous stimuli and should be seen as a sensor of intracellular homeostatic imbalance. Therefore, its precise functioning is essential. In addition to playing a role in host immune defense, dysregulation of NLRP3 has been linked to the pathogenesis of many inflammatory disorders. These include genetic diseases, such as cryopyrin-associated periodic syndromes (CAPS), which are caused by gain-of-fimction mutations in the NLRP3 gene, as well as many prevalent neurologic and systemic diseases. Importantly, NLRP3 hyperactivation has been demonstrated pre-clinically to play a critical role in a plethora of inflammatory and degenerative diseases including, NASH, atherosclerosis and other cardiovascular diseases, Alzheimer’s disease, Parkinson’s disease, diabetes, gout, and numerous other autoinflammatory diseases. See, e.g., Li et al., European Journal of Pharmacology (2022)928: 175091; Nguyen et al., Journal of Parkinson s’ Disease (2022) 12:2117 -2133; Su et al., Current Medicinal Chemistry (2021) 25:569-582; Zahid et al., Frontiers in Immunology (2019) 10:2538. Thus, there is an unmet need in the field to develop small molecules for modulating NLRP3 activity to treat various diseases and disorders.SUMMARY

[0005] Provided herein are compounds of Formula (I) and (II): and pharmaceuticallyacceptable salts and tautomers thereof, wherein Ring A, Ring B, R1, R2a, R2b, R3, R4, G1, G2, G3, G4, m, n, and p are described herein, and Ring C is an oxadiazolone of Formula (i- O) or (i-N):

[0006] Compounds of Formula (I) and (II), and pharmaceutically acceptable salts and tautomers thereof, have been found useful as inhibitors of NLRP3.

[0007] Further provided are methods of preparation, methods and use for treating and preventing diseases or disorders, methods of modulating (e.g., inhibiting) NLRP3, and pharmaceutical compositions comprising same. DEFINITIONS

[0008] Definitions of specific functional groups and chemical terms are described in more detail below. The chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75thEd., inside cover, and specific functional groups are generally defined as described therein. Additionally, general principles of organic chemistry, as well as specific functional moieties and reactivity, are described in Organic Chemistry, Thomas Sorrell, University Science Books, Sausalito, 1999; Smith and March March’s Advanced Organic Chemistry, 5thEdition, John Wiley & Sons, Inc., New York, 2001; Larock, Comprehensive Organic Transformations, VCH Publishers, Inc., New York, 1989; and Carruthers, Some Modern Methods of Organic Synthesis, 3rdEdition, Cambridge University Press, Cambridge, 1987.

[0009] Compounds described herein can comprise one or more asymmetric centers, and thus can exist in various stereoisomeric forms, e.g., enantiomers and / or diastereomers. For example, the compounds described herein can be in the form of an individual enantiomer, diastereomer or geometric isomer, or can be in the form of a mixture of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomer. Isomers can be isolated from mixtures by methods known to those skilled in the art, including chiral high pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts; or preferred isomers can be prepared by asymmetric syntheses. See, for example, Jacques et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen et al., Tetrahedron 33:2725 (1977); Eliel, E.L. Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); and Wilen, S.H. Tables of Resolving Agents and Optical Resolutions p.268 (E.L. Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, IN 1972). Compounds described herein can additionally encompass individual isomers substantially free of other isomers, and alternatively, as mixtures of various isomers.

[0010] For example, compounds described herein may be referred to as “Rac-X”, which, for purposes of the Examples, including the data provided in the Assay Methods section, signifies a mixture of 2 or more stereoisomers. For purposes of claiming a “Rac-X” molecule, the claim may encompass a racemic composition of matter, but also may encompass an enantiomerically enriched composition of matter, e.g., enriched in one stereoisomer over others that may have been generated. For example, a claim may encompass a pharmaceutical composition comprising a “Rac-X” compound, or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient, wherein the “Rac-X” compound is >80%, >85%, >90%, >95%, or >99% enantiomerically enriched.

[0011] Unless otherwise stated, compounds described herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms (“isotopically labeled derivative”(s)). For example, compounds having the present structures except for the replacement of hydrogen by deuterium or tritium, replacement of19F with18F, or the replacement of a carbon by a13C- or14C-enriched carbon are within the scope of the disclosure. Such compounds are useful, for example, as a therapeutic or prophylactic agent, as analytical tools or probes in biological assays.

[0012] When a range of values is listed, it is intended to encompass each value and sub-range within the range. For example, “C1-6alkyl” is intended to encompass C1, C2, C3, C4, C5, C6, C1-6, C1-5, C1-4, C1-3, C1-2, C2-6, C2-5, C2-4, C2-3, C3-6, C3-5, C3-4, C4-6, C4-5, and C5-6alkyl.

[0013] “Alkyl” refers to a radical of a straight-chain or branched saturated hydrocarbon group having from 1 to 6 carbon atoms (“C1-6alkyl”). In some embodiments, an alkyl group has 1 to 5 carbon atoms (“C1-5alkyl”). In some embodiments, an alkyl group has 1 to 4 carbon atoms (“C1-4alkyl”). In some embodiments, an alkyl group has 1 to 3 carbon atoms (“C1-3alkyl”). In some embodiments, an alkyl group has 1 to 2 carbon atoms (“C1-2alkyl”). In some embodiments, an alkyl group has 1 carbon atom (“C1alkyl”). In some embodiments, an alkyl group has 2 to 6 carbon atoms (“C2-6alkyl”). Examples of C1-6alkyl groups include methyl (-CH3, C1), ethyl (-CH2CH3, C2), n-propyl(C3), isopropyl (C3), n-butyl (C4), tert-butyl (C4), sec-butyl (C4), iso-butyl (C4), n-pentyl (C5), 3- pentanyl (C5), amyl (C5), neopentyl (C5), 3-methyl-2-butanyl (C5), tertiary amyl (C5), and n-hexyl (C6).

[0014] “Haloalkyl” refers to a substituted alkyl group, as defined herein, wherein one or more of the hydrogen atoms are independently replaced by a halogen, e.g., fluoro, bromo, chloro, or iodo. “Perhaloalkyl” is a subset of haloalkyl, and refers to an alkyl group wherein all of the hydrogen atoms are independently replaced by a halogen, e.g., fluoro, bromo, chloro, or iodo. In some embodiments, the haloalkyl group has 1 to 6 carbon atoms (“C1-6haloalkyl”). In some embodiments, the haloalkyl group has 1 to 5 carbon atoms (“C1-5haloalkyl”). In some embodiments, the haloalkyl group has 1 to 4 carbon atoms (“C1-4haloalkyl”). In some embodiments, the haloalkyl group has 1 to 3 carbon atoms (“C1-3haloalkyl”). In some embodiments, the haloalkyl group has 1 to 2 carbon atoms (“C1-2haloalkyl”). In some embodiments, all of the haloalkyl hydrogen atoms are replaced with fluoro to provide a perfluoroalkyl group. In some embodiments, all of the haloalkyl hydrogen atoms are replaced with chloro to provide a “perchloroalkyl” group. Examples of haloalkyl groups include -CF3, -CF2CF3, -CF2CF2CF3, -CCl3, -CFCl2, -CF2Cl, and the like.

[0015] “Carbocyclyl” or “carbocyclic” refers to a radical of a non-aromatic cyclic hydrocarbon group having from 3 to 4 ring carbon atoms (“C3-4carbocyclyl”) and zero heteroatoms in the non- aromatic ring system. In some embodiments, a carbocyclyl group has 3 ring carbon atoms (“C3carbocyclyl”). In some embodiments, a carbocyclyl group has 4 ring carbon atoms (“C4carbocyclyl”). Exemplary C3-4carbocyclyl groups include, without limitation, cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), and cyclobutenyl (C4).

[0016] “Heterocyclyl” or “heterocyclic” refers to a radical of a 3- to 4-membered non-aromatic ring system having ring carbon atoms and 1 ring heteroatom, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“3-4 membered heterocyclyl”). In heterocyclyl groups that contain one nitrogen atom, the point of attachment can be a carbon or nitrogen atom, as valency permits. Exemplary 3-membered heterocyclyl groups containing 1 heteroatom include, without limitation, azirdinyl, oxiranyl, and thiiranyl. Exemplary 4-membered heterocyclyl groups containing 1 heteroatom include, without limitation, azetidinyl, oxetanyl and thietanyl.

[0017] “Heteroaryl” refers to a radical of a 5-membered monocyclic aromatic ring system having ring carbon atoms and 1-2 ring heteroatoms provided in the aromatic ring system, wherein each ring heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-membered heteroaryl”). In heteroaryl groups that contain one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valency permits. Exemplary 5-membered heteroaryl groups containing 1 heteroatom include, without limitation, pyrrolyl, furanyl and thiophenyl. Exemplary 5-membered heteroaryl groups containing 2 heteroatoms include, without limitation, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl.

[0018] “Halo” or “halogen” refers to fluorine (fluoro, -F), chlorine (chloro, -Cl), bromine (bromo, -Br), or iodine (iodo, -I) radicals.

[0019] Affixing the suffix “-ene” to a group indicates the group is a divalent moiety, e.g., alkylene is the divalent moiety of alkyl, and haloalkylene is the divalent moiety of haloalkyl. By way of example, a C1-3alkylene, which may be linear or branched, include, but are not limited to, -CH2-, -CH(CH3)-, - C(CH3)2-, -CH2CH2-, -CH2CH(CH3)-, -CH2C(CH3)2-, and -CH2CH2CH2-.

[0020] An alkylene or haloalkylene “bridging group” refers to a group where the two ends of the divalent moiety are attached to different carbon atoms which are not vicinal (not next to) each other. Exemplary bridging groups include methylene (-CH2-), ethylene (-CH2CH2-), propylene (- CH2CH2CH2-), and their corresponding halogenated (haloalkylene) groups.

[0021] It is understood herein that compounds of Formula (I) and (II) and pharmaceutically acceptable salts thereof, each of which contain a terminal Ring C oxadiazolone group, may exist as a mixture of tautomeric isomers, e.g.: of Formula (i-O): and of Formula (i-N):

[0022] Amino and oxygen protecting groups are described in detail in Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts, 3rdedition, John Wiley & Sons, 1999.

[0023] Exemplary oxygen (hydroxyl) protecting groups include, but are not limited to, methyl, methoxymethyl (MOM), methylthiomethyl (MTM), t-butylthiomethyl, (phenyldimethylsilyl)methoxymethyl (SMOM), benzyloxymethyl (BOM), p- methoxybenzyloxymethyl (PMBM), (4-methoxyphenoxy)methyl (p-AOM), guaiacolmethyl (GUM), t-butoxymethyl, 4-pentenyloxymethyl (POM), siloxymethyl, 2-methoxyethoxymethyl (MEM), 2,2,2- trichloroethoxymethyl, bis(2-chloroethoxy)methyl, 2-(trimethylsilyl)ethoxymethyl (SEMOR), tetrahydropyranyl (THP), 3-bromotetrahydropyranyl, tetrahydrothiopyranyl, 1-methoxycyclohexyl, 4- methoxytetrahydropyranyl (MTHP), 4-methoxytetrahydrothiopyranyl, 4- methoxytetrahydrothiopyranyl S,S-dioxide, 1-[(2-chloro-4-methyl)phenyl]-4-methoxypiperidin-4-yl (CTMP), tetrahydrofuranyl, benzyl (Bn), trimethylsilyl (TMS), triethylsilyl (TES), triisopropylsilyl (TIPS), t-butyldimethylsilyl (TBDMS), benzoylformate, acetate, chloroacetate, dichloroacetate, trichloroacetate, trifluoroacetate, methyl carbonate, 9-fluorenylmethyl carbonate (Fmoc), ethylcarbonate, 2,2,2-trichloroethyl carbonate (Troc), 2-(trimethylsilyl)ethyl carbonate (TMSEC), allyl carbonate, t-butyl carbonate (BOC), methanesulfonate (mesylate), benzylsulfonate, and tosylate (Ts).

[0024] Exemplary amino protecting groups include, but are not limited to, those that protect the amine as an amide, such as formamide, acetamide, chloroacetamide, trichloroacetamide, trifluoroacetamide, and phenylacetamide; protect the amine as a carbamate, such as methyl carbamate, ethyl carbamate, 9-fluorenylmethyl carbamate (Fmoc), t-butyl carbamate (BOC), 1-adamantyl carbamate (Adoc), and benzyl carbamate (Cbz); and protect the amine as a sulfonamide such as p- toluenesulfonamide (Ts), benzenesulfonamide, methanesulfonamide (Ms), and benzylsulfonamide.

[0025] Salts, pharmaceutically acceptable salts, and free bases of compounds of Formula (I) and (II) are contemplated herein.

[0026] “Salt” refers to any and all salts.

[0027] “Pharmaceutically acceptable salt” refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit / risk ratio. Examples of pharmaceutically acceptable acid addition salts include, but are not limited to, salts formed from inorganic acids, such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid salts, or salts formed from organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and the like. Pharmaceutically acceptable salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N+(C1-4alkyl)4salts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate, and aryl sulfonate.

[0028] A “free base” refers to a neutral non-ionized form of a compound which is not a salt or pharmaceutically acceptable salt.

[0029] A “patient” or “subject” is used interchangeably herein, and refers to a mammal, e.g., a human, mouse, rat, guinea pig, dog, cat, horse, cow, pig, or non-human primate, such as a monkey, chimpanzee, baboon, or rhesus. In some embodiments, the patient or subject is human.

[0030] ‘ ‘Effective amount” or “therapeutically effective amount” are used interchangeably herein, and refer to an amount of a compound, or a pharmaceutically acceptable salt or tautomer thereof, sufficient to provide a therapeutic benefit in the treatment of a disease or disorder, or to delay or minimize one or more symptoms associated with the disease or disorder in a subject in need thereof. An effective amount can encompass an amount that improves overall therapy, reduces or avoids symptoms or causes of disease or disorder, or enhances the therapeutic efficacy of another therapeutic agent. The effective amount of a compound, or a pharmaceutically acceptable salt or tautomer thereof, may vary depending on such factors as the desired biological endpoint, the pharmacokinetics of the compound, the disease being treated, the mode of administration, and the age, health, and condition of the subject.

[0031] ‘ ‘Disease” or “disorder” are used interchangeably herein.

[0032] “Treating,” “treat,” or “treatment” describes the management and care of a subject in need thereof, for the purpose of combating a disease or disorder in the subject that is experiencing or displaying (or has experienced or displayed) symptoms or complications of a disease or disorder, and includes the administration of a compound, or a pharmaceutically acceptable salt or tautomer thereof, as described herein, to alleviate the symptoms or complications of a disease or disorder, or to eliminate the disease or disorder. The term “treat” can also include treatment of a cell in vitro or treatment of an animal model (in vivo). It is to be appreciated that references to “treating” or “treatment” include the alleviation of established symptoms of a disease or disorder in a subject in need thereof, and therefore includes: (1) delaying the appearance of at least one clinical or subclinical symptom of the disease or disorder developing in a subject that is afflicted with the disease or disorder, (2) arresting, reducing or delaying the continued development of the disease or a relapse thereof in a subject (e.g., in case of maintenance treatment) or at least one clinical or subclinical symptom thereof, or (3) relieving or attenuating the disease in a subject, i.e., causing regression of the disease or disorder or at least one of its clinical or subclinical symptoms.

[0033] As used herein, the term “preventing,” “prevent,” or “protecting against” describes the management and care of a subject in need thereof that may have or has a predisposition for the disease or disorder but has not yet experienced or displayed symptoms or complications of a disease or disorder (e.g., clinical or subclinical symptoms of the disease or disorder), for the purpose of preventing the appearance of said symptoms or complications of the disease or disorder in the subject, and includes the administration of a compound, or a pharmaceutically acceptable salt or tautomer thereof, as described herein.

[0034] ‘ ‘Modulation,” “modulating,” “modulate,” and “modulator” refer to the ability of a compound, or a pharmaceutically acceptable salt or tautomer thereof, to change the activity of a particular biological process (e.g., NLRP3 activity) in a cell relative to vehicle. Likewise, “inhibition,” “inhibiting,” “inhibit,” and “inhibitor,” refer to the ability of a compound, or a pharmaceutically acceptable salt or tautomer thereof, to reduce, slow, halt or prevent activity of a particular biologicalprocess (e.g., NLRP3 activity) in a cell relative to vehicle.

[0035] The phrase “at least one” refers to one instance or more than one instance.

[0036] The articles “a” and “an” are used in this disclosure to refer to one or more than one (i.e., to at least one) of the grammatical object of the article.

[0037] The term “and / or” is used in this disclosure to mean either “and” or “or” unless indicated otherwise. DETAILED DESCRIPTION OF SOME EMBODIMENTS (i) Compounds

[0038] Provided herein are compounds of Formula (I) and (II): and pharmaceuticallyacceptable salts and tautomers thereof, wherein: Ring A is a ring system wherein: G1is CRG1or N; G2is CRG2or N; G3is CRG3or N; and G4is CRG4or N; provided no more than two of G1, G2, G3, and G4are N; R1is halo, C1-6alkyl, C1-6haloalkyl, -ORG5, -SRG5, -N(RG5)2, C3-4carbocyclyl, or 3-4 membered heterocyclyl, wherein the carbocyclyl and heterocyclyl are independently substituted with 0, 1, 2, or 3 halo, C1-6alkyl, C1-6haloalkyl, -ORG5, -SRG5, or -N(RG5)2, or R1and G2, together with the atoms to which they are attached, are joined to form a 5- membered heteroaryl ring independently substituted with 0, 1, 2, or 3 RG7; RG1, RG2, RG3, and RG4are each independently selected from the group consisting of hydrogen, halo, C1-6alkyl, C1-6haloalkyl, and -ORG6; RG5and RG6are each independently hydrogen, C1-6alkyl, or C1-6haloalkyl; and each instance of RG7is independently halo, C1-6alkyl, C1-6haloalkyl, -ORG5, -SRG5, or -N(RG5)2; Ring B is a ring system wherein: n is 0 or 1; p is 1 or 2;m is 0, 1, 2, or 3; each instance of R2aand R2bis independently hydrogen, halo, C1-6alkyl, C1-6haloalkyl, C3-4carbocyclyl, or 3-4 membered heterocyclyl, wherein the carbocyclyl or heterocyclyl are each independently substituted with 0, 1, 2, or 3 halo, or R2aand R2bare joined to form a C3carbocyclyl independently substituted with 0, 1, 2, or 3 halo; and each instance of R3is independently halo, C1-6alkyl, or C1-6haloalkyl, or two R3groups are joined to form a C1-3alkylene bridging group or C1-3haloalkylene bridging group; R4is hydrogen, C1-3alkyl, C3-4carbocyclyl, or C3-4carbocyclyl-C1-3alkyl-, wherein the alkyl and carbocyclyl are each independently substituted with 0, 1, 2, 3, 4, 5, or 6 halo, and wherein the carbocyclyl is further independently substituted with 0, 1, or 2 C1-3alkyl or C1-3haloalkyl; and Ring C is an oxadiazolone of Formula (i-O) or (i-N):

[0039] In some embodiments of Formula (I), the compound is of Formula (I-i-O) or (I-i-N): or a pharmaceutically acceptable salt or tautomer thereof. In some embodiments, the compound is of Formula (I-i-O). In some embodiments, the compound is of Formula (I-i-N).

[0040] In some embodiments of Formula (I-i-O), the compound is of Formula (I-i-O′) or (I-i-O′′):or a pharmaceutically acceptable salt or tautomer thereof. In some embodiments, the compound is of Formula (I-i-O′). In some embodiments, the compound is of Formula (I-i-O′′).

[0041] In some embodiments of Formula (I-i-O), the compound is of Formula (I-i-O′-a), (I-i-O′-b), (I-i-O′′-a), or (I-i-O′′-b): or a pharmaceutically acceptable salt or tautomer thereof. In some embodiments, the compound is ofFormula (I-i-O′-a). In some embodiments, the compound is of Formula (I-i-O′-b). In some embodiments, the compound is of Formula (I-i-O′′-a). In some embodiments, the compound is of Formula (I-i-O′′-b).

[0042] In some embodiments of Formula (I-i-N), the compound is of Formula (I-i-N′) or (I-i-N′′): or a pharmaceutically acceptable salt or tautomer thereof. In some embodiments, the compound is of Formula (I-i-N′). In some embodiments, the compound is of Formula (I-i-N′′).

[0043] In some embodiments of Formula (I-i-N), the compound is of Formula (I-i-N′-a), (I-i-N′-b), (I-i-N′′-a), or (I-i-N′′-b):or a pharmaceutically acceptable salt or tautomer thereof. In some embodiments, the compound is of Formula (I-i-N′-a). In some embodiments, the compound is of Formula (I-i-N′-b). In some embodiments, the compound is of Formula (I-i-N′′-a). In some embodiments, the compound is of Formula (I-i-N′′-b).

[0044] In some embodiments of Formula (I), the compound is of Formula (I-i-O′-a) or (I-i-N′-a), or a pharmaceutically acceptable salt or tautomer thereof.

[0045] In some embodiments of Formula (I), the compound is of Formula (I-i-O′-b) or (I-i-N′-b), or a pharmaceutically acceptable salt or tautomer thereof.

[0046] In some embodiments of Formula (I), the compound is of Formula (I-i-O′′-a) or (I-i-N′′-a), or a pharmaceutically acceptable salt or tautomer thereof.

[0047] In some embodiments of Formula (I), the compound is of Formula (I-i-O′′-b) or (I-i-N′′-b), or a pharmaceutically acceptable salt or tautomer thereof.

[0048] In some embodiments of Formula (I-i-O), the compound is of Formula (I-i-O-Bridge): or a pharmaceutically acceptable salt or tautomer thereof, wherein L is a C1-3alkylene bridging group. In some embodiments, L is -CH2CH2-.

[0049] In some embodiments of Formula (I-i-O-Bridge), the compound is of Formula (I-i-O′- Bridge), (I-i-O′′-Bridge), (I-i-O′′′-Bridge), or (I-i-O′′′′-Bridge): or a pharmaceutically acceptable salt or tautomer thereof, wherein L is a C1-3alkylene bridging group. In some embodiments, L is -CH2CH2-. In some embodiments, the compound is of Formula (I-i-O′- Bridge). In some embodiments, the compound is of Formula (I-i-O′′-Bridge). In some embodiments, the compound is of Formula (I-i-O′′′-Bridge). In some embodiments, the compound is of Formula (I- i-O′′′′-Bridge).

[0050] In some embodiments of Formula (I-i-O-Bridge), the compound is of Formula (I-i-O- Bridge-a), (I-i-O-Bridge-b), (I-i-O-Bridge-c), (I-i-O-Bridge-d), (I-i-O-Bridge-e), (I-i-O-Bridge-f), (I-i-O-Bridge-g), or (I-i-O-Bridge-h):or a pharmaceutically acceptable salt or tautomer thereof. In some embodiments, the compound is of Formula (I-i-O-Bridge-a). In some embodiments, the compound is of Formula (I-i-O-Bridge-b). In some embodiments, the compound is of Formula (I-i-O-Bridge-c). In some embodiments, the compound is of Formula (I-i-O-Bridge-d). In some embodiments, the compound is of Formula (I-i-O- Bridge-e). In some embodiments, the compound is of Formula (I-i-O-Bridge-f). In some embodiments, the compound is of Formula (I-i-O-Bridge-g). In some embodiments, the compound is of Formula (I- i-O-Bridge-h).

[0051] In some embodiments of Formula (I-i-N), the compound is of Formula (I-i-N-Bridge): or a pharmaceutically acceptable salt or tautomer thereof, wherein L is a C1-3alkylene bridging group. In some embodiments, L is -CH2CH2-.

[0052] In some embodiments of Formula (I-i-N-Bridge), the compound is of Formula (I-i-N′- Bridge), (I-i-N′′-Bridge), (I-i-N′′′-Bridge), or (I-i-N′′′′-Bridge):or a pharmaceutically acceptable salt or tautomer thereof, wherein L is a C1-3alkylene bridging group. In some embodiments, L is -CH2CH2-. In some embodiments, the compound is of Formula (I-i-N′- Bridge). In some embodiments, the compound is of Formula (I-i-N′′-Bridge). In some embodiments, the compound is of Formula (I-i-N′′′-Bridge). In some embodiments, the compound is of Formula (I- i-N′′′′-Bridge).

[0053] In some embodiments of Formula (I-i-N-Bridge), the compound is of Formula (I-i-N- Bridge-a), (I-i-N-Bridge-b), (I-i-N-Bridge-c), (I-i-N-Bridge-d), (I-i-N-Bridge-e), (I-i-N-Bridge-f), (I-i-N-Bridge-g), or (I-i-N-Bridge-h):or a pharmaceutically acceptable salt or tautomer thereof. In some embodiments, the compound is of Formula (I-i-N-Bridge-a). In some embodiments, the compound is of Formula (I-i-N-Bridge-b). In some embodiments, the compound is of Formula (I-i-N-Bridge-c). In some embodiments, the compound is of Formula (I-i-N-Bridge-d). In some embodiments, the compound is of Formula (I-i-N- Bridge-e). In some embodiments, the compound is of Formula (I-i-N-Bridge-f). In some embodiments, the compound is of Formula (I-i-N-Bridge-g). In some embodiments, the compound is of Formula (I- i-N-Bridge-h).

[0054] In some embodiments of Formula (II), the compound is of Formula (II-i-O) or (II-i-N): or a pharmaceutically acceptable salt or tautomer thereof. In some embodiments, the compound is of Formula (II-i-O). In some embodiments, the compound is of Formula (II-i-N).

[0055] In some embodiments of Formula (II-i-O), the compound is of Formula (II-i-O′) or (II-i- O′′):or a pharmaceutically acceptable salt or tautomer thereof. In some embodiments, the compound is of Formula (II-i-O′). In some embodiments, the compound is of Formula (II-i-O′′).

[0056] In some embodiments of Formula (II-i-O), the compound is of Formula (II-i-O′-a), (II-i-O′- b), (II-i-O′′-a), or (II-i-O′′-b): or a pharmaceutically acceptable salt or tautomer thereof. In some embodiments, the compound is ofFormula (II-i-O′-a). In some embodiments, the compound is of Formula (II-i-O′-b). In some embodiments, the compound is of Formula (II-i-O′′-a). In some embodiments, the compound is of Formula (II-i-O′′-b).

[0057] In some embodiments of Formula (II-i-N), the compound is of Formula (II-i-N′) or (II-i-N′′): or a pharmaceutically acceptable salt or tautomer thereof. In some embodiments, the compound is of Formula (II-i-N′). In some embodiments, the compound is of Formula (II-i-N′′).

[0058] In some embodiments of Formula (II-i-N), the compound is of Formula (II-i-N′-a), (II-i-N′- b), (II-i-N′′-a), or (II-i-N′′-b):or a pharmaceutically acceptable salt or tautomer thereof. In some embodiments, the compound is of Formula (II-i-N′-a). In some embodiments, the compound is of Formula (II-i-N′-b). In some embodiments, the compound is of Formula (II-i-N′′-a). In some embodiments, the compound is of Formula (II-i-N′′-b).

[0059] In some embodiments of Formula (II), the compound is of Formula (II-i-O′-a) or (II-i-N′-a), or a pharmaceutically acceptable salt or tautomer thereof.

[0060] In some embodiments of Formula (II), the compound is of Formula (II-i-O′-b) or (II-i-N′-b), or a pharmaceutically acceptable salt or tautomer thereof.

[0061] In some embodiments of Formula (II), the compound is of Formula (II-i-O′′-a) or (II-i-N′′- a), or a pharmaceutically acceptable salt or tautomer thereof.

[0062] In some embodiments of Formula (II), the compound is of Formula (II-i-O′′-b) or (II-i-N′′- b), or a pharmaceutically acceptable salt or tautomer thereof.

[0063] In some embodiments of Formula (II-i-O), the compound is of Formula (II-i-O-Bridge): or a pharmaceutically acceptablesalt or tautomer thereof, wherein L is a C1-3alkylene bridging group. In some embodiments, L is -CH2CH2-.

[0064] In some embodiments of Formula (II-i-O-Bridge), the compound is of Formula (II-i-O′- Bridge), (II-i-O′′-Bridge), (II-i-O′′′-Bridge), or (II-i-O′′′′-Bridge): or a pharmaceutically acceptable salt or tautomer thereof, wherein L is a C1-3alkylene bridging group. In some embodiments, L is -CH2CH2-. In some embodiments, the compound is of Formula (II-i-O′- Bridge). In some embodiments, the compound is of Formula (II-i-O′′-Bridge). In some embodiments, the compound is of Formula (II-i-O′′′-Bridge). In some embodiments, the compound is of Formula (II-i-O′′′′-Bridge).

[0065] In some embodiments of Formula (II-i-O-Bridge), the compound is of Formula (II-i-O- Bridge-a), (II-i-O-Bridge-b), (II-i-O-Bridge-c), (II-i-O-Bridge-d), (II-i-O-Bridge-e), (II-i-O- Bridge-f), (II-i-O-Bridge-g), or (II-i-O-Bridge-h):or a pharmaceutically acceptable salt or tautomer thereof. In some embodiments, the compound is of Formula (II-i-O-Bridge-a). In some embodiments, the compound is of Formula (II-i-O-Bridge-b). In some embodiments, the compound is of Formula (II-i-O-Bridge-c). In some embodiments, the compound is of Formula (II-i-O-Bridge-d). In some embodiments, the compound is of Formula (II-i- O-Bridge-e). In some embodiments, the compound is of Formula (II-i-O-Bridge-f). In some embodiments, the compound is of Formula (II-i-O-Bridge-g). In some embodiments, the compound is of Formula (II-i-O-Bridge-h).

[0066] In some embodiments of Formula (II-i-N), the compound is of Formula (II-i-N-Bridge): or a pharmaceutically acceptablesalt or tautomer thereof, wherein L is a C1-3alkylene bridging group. In some embodiments, L is -CH2CH2-.

[0067] In some embodiments of Formula (II-i-N-Bridge), the compound is of Formula (II-i-N′- Bridge), (II-i-N′′-Bridge), (II-i-N′′′-Bridge), or (II-i-N′′′′-Bridge):

[0068] or a pharmaceutically acceptable salt or tautomer thereof, wherein L is a C1-3alkylene bridging group. In some embodiments, L is -CH2CH2-. In some embodiments, the compound is of Formula (II-i-N′-Bridge). In some embodiments, the compound is of Formula (II-i-N′′-Bridge). In some embodiments, the compound is of Formula (II-i-N′′′-Bridge). In some embodiments, the compound is of Formula (II-i-N′′′′-Bridge).

[0069] In some embodiments of Formula (II-i-N-Bridge), the compound is of Formula (II-i-N- Bridge-a), (II-i-N-Bridge-b), (II-i-N-Bridge-c), (II-i-N-Bridge-d), (II-i-N-Bridge-e), (II-i-N- Bridge-f), (II-i-N-Bridge-g), or (II-i-N-Bridge-h):or a pharmaceutically acceptable salt or tautomer thereof. In some embodiments, the compound is of Formula (II-i-N′-Bridge-a). In some embodiments, the compound is of Formula (II-i-N′-Bridge-b). In some embodiments, the compound is of Formula (II-i-N′-Bridge-c). In some embodiments, the compound is of Formula (II-i-N′-Bridge-d). In some embodiments, the compound is of Formula (II-i- N′-Bridge-e). In some embodiments, the compound is of Formula (II-i-N′-Bridge-f). In some embodiments, the compound is of Formula (II-i-N′-Bridge-g). In some embodiments, the compound is of Formula (II-i-N-Bridge-h).

[0070] Additional embodiments are further described below and herein. (a) Ring A, R4, G1, G2, G3, G4, R1, RG1, RG2, RG3, RG4, RG5, RG6, and RG7

[0071] As generally described herein, G1is CRG1or N; G2is CRG2or N; G3is CRG3or N; and G4is CRG4or N; provided no more than two of G1, G2, G3, and G4are N.

[0072] In some embodiments, G1is CRG1. In some embodiments, G1is N.

[0073] In some embodiments, G2is CRG2. In some embodiments, G2is N.

[0074] In some embodiments, G3is CRG3. In some embodiments, G3is N.

[0075] In some embodiments, G4is CRG4. In some embodiments, G4is N.

[0076] In some embodiments, G1is CRG1; G2is CRG2; G3is CRG3; and G4is CRG4.

[0077] In some embodiments, at least one of G1, G2, G3, and G4is N.

[0078] In some embodiments, one of G1, G2, G3, and G4is N.

[0079] In some embodiments, G1is CRG1; G2is CRG2; G3is CRG3; and G4is N. In some embodiments, G1is CRG1; G2is CRG2; G3is N; and G4is CRG4. In some embodiments, G1is CRG1; G2is N; G3is CRG3; and G4is CRG4. In some embodiments, G1is N; G2is CRG2; G3is CRG3; and G4is CRG4.

[0080] In some embodiments, two of G1, G2, G3, and G4are N.

[0081] In some embodiments, G1is CRG1; G2is CRG2; G3is N; and G4is N. In some embodiments,G1is CRG1; G2is N; G3is CRG3; and G4is N. In some embodiments, G1is N; G2is CRG2; G3is CRG3; and G4is N. In some embodiments, G1is N; G2is N; G3is CRG3; and G4is CRG4. In some embodiments, G1is N; G2is CRG2; G3is N; and G4is CRG4. In some embodiments, G1is CRG1; G2is N; G3is N; and G4is CRG4.

[0082] In some embodiments, G1is CRG1, G2is CRG2, G3is CRG3, and G4is CRG4; G1is CRG1, G2is CH, G3is CH, and G4is CH; G1is CRG1, G2is CRG2, G3is CH, and G4is CH; G1is CRG1, G2is CH, G3is CRG3, and G4is CH; G1is CRG1, G2is N, G3is CRG3, and G4is CRG4; G1is CRG1, G2is N, G3is CH, and G4is CH; G1is CRG1, G2is CRG2, G3is N, and G4is CRG4; G1is CRG1, G2is CH, G3is N, and G4is CH; G1is CRG1, G2is CH, G3is N, and G4is CH; G1is CRG1, G2is CRG2, G3is CRG3, and G4is N; or G1is CRG1, G2is CH, G3is CH, and G4is N.

[0083] In some embodiments, G1is CH, G2is CH, G3is CH, and G4is CH; or G1is CH, G2is CRG2, G3is CH, and G4is CH.

[0084] As generally described herein, R1is halo, C1-6alkyl, C1-6haloalkyl, -ORG5, -SRG5, -N(RG5)2, C3-4carbocyclyl, or 3-4 membered heterocyclyl, wherein the carbocyclyl and heterocyclyl are independently substituted with 0, 1, 2, or 3 halo, C1-6alkyl, C1-6haloalkyl, -ORG5, -SRG5, or -N(RG5)2, or R1and G2, together with the atoms to which they are attached, are joined to form a 5-membered heteroaryl ring independently substituted with 0, 1, 2, or 3 RG7groups selected from the group consisting of halo, C1-6alkyl, C1-6haloalkyl, -ORG5, -SRG5, and -N(RG5)2.

[0085] In some embodiments, R1is halo.

[0086] In some embodiments, R1is F, Cl, Br, or I. In some embodiments, R1is F, Cl, or Br. In some embodiments, R1is F or Cl.

[0087] In some embodiments, R1is F. In some embodiments, R1is Cl. In some embodiments, R1is Br. In some embodiments, R1is I.

[0088] In some embodiments, R1is C1-6alkyl independently substituted with 0, 1, 2, or 3 halo, C1-6alkyl, C1-6haloalkyl, -ORG5, -SRG5, or -N(RG5)2.

[0089] In some embodiments, R1is C1-6alkyl independently substituted with 1, 2, or 3 halo, C1-6alkyl, C1-6haloalkyl, -ORG5, -SRG5, or -N(RG5)2.

[0090] In some embodiments, R1is unsubstituted C1-6alkyl.

[0091] In some embodiments, R1is methyl. In some embodiments, R1is ethyl. In some embodiments, R1is propyl. In some embodiments, R1is butyl. In some embodiments, R1is pentyl. In some embodiments, R1is hexyl. In some embodiments, R1is isopropyl. In some embodiments, R1is isobutyl. In some embodiments, R1is isopentyl. In some embodiments, R1is isohexyl. In some embodiments, R1is secbutyl. In some embodiments, R1is secpentyl. In some embodiments, R1is sechexyl. In some embodiments, R1is tertbutyl.

[0092] In some embodiments, R1is C1-6haloalkyl.

[0093] In some embodiments, R1is halomethyl. In some embodiments, R1is haloethyl. In some embodiments, R1is halopropyl. In some embodiments, R1is halobutyl. In some embodiments, R1ishalopentyl. In some embodiments, R1is halohexyl.

[0094] In some embodiments, R1is -ORG5.

[0095] In some embodiments, R1is -SRG5.

[0096] In some embodiments, R1is -N(RG5)2.

[0097] In some embodiments, R1is C3-4carbocyclyl or 3-4 membered heterocyclyl, wherein the carbocyclyl or heterocyclyl are independently substituted with 0, 1, 2, or 3 halo, C1-6alkyl, C1-6haloalkyl, -ORG5, -SRG5, or -N(RG5)2.

[0098] In some embodiments, R1is C3-4carbocyclyl independently substituted with 0, 1, 2, or 3 halo, C1-6alkyl, C1-6haloalkyl, -ORG5, -SRG5, or -N(RG5)2.

[0099] In some embodiments, R1is C3carbocyclyl independently substituted with 0, 1, 2, or 3 halo, C1-6alkyl, C1-6haloalkyl, -ORG5, -SRG5, or -N(RG5)2.

[0100] In some embodiments, R1is C4carbocyclyl independently substituted with 0, 1, 2, or 3 halo, C1-6alkyl, C1-6haloalkyl, -ORG5, -SRG5, or -N(RG5)2.

[0101] In some embodiments, R1is C3-4carbocyclyl independently substituted with 1, 2, or 3 halo, C1-6alkyl, C1-6haloalkyl, -ORG5, -SRG5, or -N(RG5)2.

[0102] In some embodiments, R1is C3carbocyclyl independently substituted with 1, 2, or 3 halo, C1-6alkyl, C1-6haloalkyl, -ORG5, -SRG5, or -N(RG5)2.

[0103] In some embodiments, R1is C4carbocyclyl independently substituted with 1, 2, or 3 halo, C1-6alkyl, C1-6haloalkyl, -ORG5, -SRG5, or -N(RG5)2.

[0104] In some embodiments, R1is unsubstituted C3-4carbocyclyl.

[0105] In some embodiments, R1is unsubstituted C3carbocyclyl. In some embodiments, R1is unsubstituted C4carbocyclyl.

[0106] In some embodiments, R1is C3-4carbocyclyl substituted with 1 halo, C1-6alkyl, C1-6haloalkyl, -ORG5, -SRG5, or -N(RG5)2.

[0107] In some embodiments, R1is C3carbocyclyl substituted with 1 halo, C1-6alkyl, C1-6haloalkyl, - ORG5, -SRG5, or -N(RG5)2. In some embodiments, R1is C4carbocyclyl substituted with 1 halo, C1-6alkyl, C1-6haloalkyl, -ORG5, -SRG5, or -N(RG5)2.

[0108] In some embodiments, R1is C3-4carbocyclyl independently substituted with 2 halo, C1-6alkyl, C1-6haloalkyl, -ORG5, -SRG5, or -N(RG5)2.

[0109] In some embodiments, R1is C3carbocyclyl independently substituted with 2 halo, C1-6alkyl, C1-6haloalkyl, -ORG5, -SRG5, or -N(RG5)2. In some embodiments, R1is C4carbocyclyl independently substituted with 2 halo, C1-6alkyl, C1-6haloalkyl, -ORG5, -SRG5, or -N(RG5)2.

[0110] In some embodiments, R1is C3-4carbocyclyl independently substituted with 3 halo, C1-6alkyl, C1-6haloalkyl, -ORG5, -SRG5, or -N(RG5)2.

[0111] In some embodiments, R1is C3carbocyclyl independently substituted with 3 halo, C1-6alkyl, C1-6haloalkyl, -ORG5, -SRG5, or -N(RG5)2. In some embodiments, R1is C4carbocyclyl independently substituted with 3 halo, C1-6alkyl, C1-6haloalkyl, -ORG5, -SRG5, or -N(RG5)2.

[0112] In some embodiments, R1is C3-4carbocyclyl independently substituted with 1, 2, or 3 halo, C1-6alkyl, C1-6haloalkyl, -ORG5, -SRG5, or -N(RG5)2, provided at least one substituent is halo.

[0113] In some embodiments, R1is C3carbocyclyl substituted with at least one halo. In some embodiments, R1is C4carbocyclyl substituted with at least one halo.

[0114] In some embodiments, R1is C3-4carbocyclyl substituted with at least one of F, Cl, Br, or I. In some embodiments, R1is C3-4carbocyclyl substituted with at least one of F, Cl, or Br. In some embodiments, R1is C3-4carbocyclyl substituted with at least one of F or Cl.

[0115] In some embodiments, R1is C3carbocyclyl substituted with at least one of F, Cl, Br, or I. In some embodiments, R1is C3carbocyclyl substituted with at least one of F, Cl, or Br. In some embodiments, R1is C3carbocyclyl substituted with at least one of F or Cl.

[0116] In some embodiments, R1is C4carbocyclyl substituted with at least one of F, Cl, Br, or I. In some embodiments, R1is C4carbocyclyl substituted with at least one of F, Cl, or Br. In some embodiments, R1is C4carbocyclyl substituted with at least one of F or Cl.

[0117] In some embodiments, R1is C3-4carbocyclyl substituted with at least one F. In some embodiments, R1is C3-4carbocyclyl substituted with at least one Cl. In some embodiments, R1is C3-4carbocyclyl substituted with at least one Br. In some embodiments, R1is C3-4carbocyclyl substituted with at least one I.

[0118] In some embodiments, R1is C3carbocyclyl substituted with at least one F. In some embodiments, R1is C3carbocyclyl substituted with at least one Cl. In some embodiments, R1is C3carbocyclyl substituted with at least one Br. In some embodiments, R1is C3carbocyclyl substituted with at least one I.

[0119] In some embodiments, R1is C4carbocyclyl substituted with at least one F. In some embodiments, R1is C4carbocyclyl substituted with at least one Cl. In some embodiments, R1is C4carbocyclyl substituted with at least one Br. In some embodiments, R1is C4carbocyclyl substituted with at least one I.

[0120] In some embodiments, R1is C3-4carbocyclyl substituted with at least one C1-6alkyl.

[0121] In some embodiments, R1is C3-4carbocyclyl independently substituted with 1, 2, or 3 halo, C1-6alkyl, C1-6haloalkyl, -ORG5, -SRG5, or -N(RG5)2, provided at least one substituent is C1-6alkyl.

[0122] In some embodiments, R1is C3-4carbocyclyl substituted with at least one methyl. In some embodiments, R1is C3-4carbocyclyl substituted with at least one ethyl. In some embodiments, R1is C3-4carbocyclyl substituted with at least one propyl. In some embodiments, R1is C3-4carbocyclyl substituted with at least one butyl. In some embodiments, R1is C3-4carbocyclyl substituted with at least one pentyl. In some embodiments, R1is C3-4carbocyclyl substituted with at least one hexyl. In some embodiments, R1is C3-4carbocyclyl substituted with at least one isopropyl. In some embodiments, R1is C3-4carbocyclyl substituted with at least one isobutyl. In some embodiments, R1is C3-4carbocyclyl substituted with at least one isopentyl. In some embodiments, R1is C3-4carbocyclyl substituted with at least one isohexyl. In some embodiments, R1is C3-4carbocyclylsubstituted with at least one secbutyl. In some embodiments, R1is C3-4carbocyclyl substituted with at least one secpentyl. In some embodiments, R1is C3-4carbocyclyl substituted with at least one sechexyl. In some embodiments, R1is C3-4carbocyclyl substituted with at least one tertbutyl.

[0123] In some embodiments, R1is C3carbocyclyl substituted with at least one methyl. In some embodiments, R1is C3carbocyclyl substituted with at least one ethyl. In some embodiments, R1is C3carbocyclyl substituted with at least one propyl. In some embodiments, R1is C3carbocyclyl substituted with at least one butyl. In some embodiments, R1is C3carbocyclyl substituted with at least one pentyl. In some embodiments, R1is C3carbocyclyl substituted with at least one hexyl. In some embodiments, R1is C3carbocyclyl substituted with at least one isopropyl. In some embodiments, R1is C3carbocyclyl substituted with at least one isobutyl. In some embodiments, R1is C3carbocyclyl substituted with at least one isopentyl. In some embodiments, R1is C3carbocyclyl substituted with at least one isohexyl. In some embodiments, R1is C3carbocyclyl substituted with at least one secbutyl. In some embodiments, R1is C3carbocyclyl substituted with at least one secpentyl. In some embodiments, R1is C3carbocyclyl substituted with at least one sechexyl. In some embodiments, R1is C3carbocyclyl substituted with at least one tertbutyl.

[0124] In some embodiments, R1is C4carbocyclyl substituted with at least one methyl. In some embodiments, R1is C4carbocyclyl substituted with at least one ethyl. In some embodiments, R1is C4carbocyclyl substituted with at least one propyl. In some embodiments, R1is C4carbocyclyl substituted with at least one butyl. In some embodiments, R1is C4carbocyclyl substituted with at least one pentyl. In some embodiments, R1is C4carbocyclyl substituted with at least one hexyl. In some embodiments, R1is C4carbocyclyl substituted with at least one isopropyl. In some embodiments, R1is C4carbocyclyl substituted with at least one isobutyl. In some embodiments, R1is C4carbocyclyl substituted with at least one isopentyl. In some embodiments, R1is C4carbocyclyl substituted with at least one isohexyl. In some embodiments, R1is C4carbocyclyl substituted with at least one secbutyl. In some embodiments, R1is C4carbocyclyl substituted with at least one secpentyl. In some embodiments, R1is C4carbocyclyl substituted with at least one sechexyl. In some embodiments, R1is C4carbocyclyl substituted with at least one tertbutyl.

[0125] In some embodiments, R1is C3-4carbocyclyl independently substituted with 1, 2, or 3 halo, C1-6alkyl, C1-6haloalkyl, -ORG5, -SRG5, or -N(RG5)2, provided at least one substituent is C1-6haloalkyl.

[0126] In some embodiments, R1is C3carbocyclyl substituted with at least one C1-6haloalkyl. In some embodiments, R1is C4carbocyclyl substituted with at least one C1-6haloalkyl.

[0127] In some embodiments, R1is C3-4carbocyclyl substituted with at least one halomethyl. In some embodiments, R1is C3-4carbocyclyl substituted with at least one haloethyl. In some embodiments, R1is C3-4carbocyclyl substituted with at least one halopropyl. In some embodiments, R1is C3-4carbocyclyl substituted with at least one halobutyl. In some embodiments, R1is C3-4carbocyclyl substituted with at least one halopentyl. In some embodiments, R1is C3-4carbocyclyl substituted with at least one halohexyl.

[0128] In some embodiments, R1is C3carbocyclyl substituted with at least one halomethyl. In some embodiments, R1is C3carbocyclyl substituted with at least one haloethyl. In some embodiments, R1is C3carbocyclyl substituted with at least one halopropyl. In some embodiments, R1is C3carbocyclyl substituted with at least one halobutyl. In some embodiments, R1is C3carbocyclyl substituted with at least one halopentyl. In some embodiments, R1is C3carbocyclyl substituted with at least one halohexyl.

[0129] In some embodiments, R1is C4carbocyclyl substituted with at least one halomethyl. In some embodiments, R1is C4carbocyclyl substituted with at least one haloethyl. In some embodiments, R1is C4carbocyclyl substituted with at least one halopropyl. In some embodiments, R1is C4carbocyclyl substituted with at least one halobutyl. In some embodiments, R1is C4carbocyclyl substituted with at least one halopentyl. In some embodiments, R1is C4carbocyclyl substituted with at least one halohexyl.

[0130] In some embodiments, R1is C3-4carbocyclyl independently substituted with 1, 2, or 3 halo, C1-6alkyl, C1-6haloalkyl, -ORG5, -SRG5, or -N(RG5)2, provided at least one substituent is -ORG5.

[0131] In some embodiments, R1is C3carbocyclyl substituted with at least one -ORG5. In some embodiments, R1is C4carbocyclyl substituted with at least one -ORG5.

[0132] In some embodiments, R1is C3-4carbocyclyl independently substituted with 1, 2, or 3 halo, C1-6alkyl, C1-6haloalkyl, -ORG5, -SRG5, or -N(RG5)2, provided at least one substituent is -SRG5.

[0133] In some embodiments, R1is C3carbocyclyl substituted with at least one -SRG5. In some embodiments, R1is C4carbocyclyl substituted with at least one -SRG5.

[0134] In some embodiments, R1is C3-4carbocyclyl independently substituted with 1, 2, or 3 halo, C1-6alkyl, C1-6haloalkyl, -ORG5, -SRG5, or -N(RG5)2, provided at least one substituent is -N(RG5)2.

[0135] In some embodiments, R1is C3carbocyclyl substituted with at least one -N(RG5)2. In some embodiments, R1is C4carbocyclyl substituted with at least one -N(RG5)2.

[0136] In some embodiments, R1is 3-4 membered heterocyclyl independently substituted with 0, 1, 2, or 3 halo, C1-6alkyl, C1-6haloalkyl, -ORG5, -SRG5, or -N(RG5)2.

[0137] In some embodiments, R1is 3-membered heterocyclyl independently substituted with 0, 1, 2, or 3 halo, C1-6alkyl, C1-6haloalkyl, -ORG5, -SRG5, or -N(RG5)2. In some embodiments, R1is 4- membered heterocyclyl independently substituted with 0, 1, 2, or 3 halo, C1-6alkyl, C1-6haloalkyl, - ORG5, -SRG5, or -N(RG5)2.

[0138] In some embodiments, R1is 3-4 membered heterocyclyl independently substituted with 1, 2, or 3 halo, C1-6alkyl, C1-6haloalkyl, -ORG5, -SRG5, or -N(RG5)2.

[0139] In some embodiments, R1is 3-membered heterocyclyl independently substituted with 1, 2, or 3 halo, C1-6alkyl, C1-6haloalkyl, -ORG5, -SRG5, or -N(RG5)2. In some embodiments, R1is 4-membered heterocyclyl independently substituted with 1, 2, or 3 halo, C1-6alkyl, C1-6haloalkyl, -ORG5, -SRG5, or -N(RG5)2.

[0140] In some embodiments, R1is unsubstituted 3-4 membered heterocyclyl.

[0141] In some embodiments, R1is unsubstituted 3-membered heterocyclyl. In some embodiments, R1is unsubstituted 4-membered heterocyclyl.

[0142] In some embodiments, R1is 3-4 membered heterocyclyl independently substituted with 1 halo, C1-6alkyl, C1-6haloalkyl, -ORG5, -SRG5, or -N(RG5)2.

[0143] In some embodiments, R1is 3-membered heterocyclyl substituted with 1 halo, C1-6alkyl, C1-6haloalkyl, -ORG5, -SRG5, or -N(RG5)2. In some embodiments, R1is 4-membered heterocyclyl substituted with 1 halo, C1-6alkyl, C1-6haloalkyl, -ORG5, -SRG5, or -N(RG5)2.

[0144] In some embodiments, R1is 3-4 membered heterocyclyl independently substituted with 2 halo, C1-6alkyl, C1-6haloalkyl, -ORG5, -SRG5, or -N(RG5)2.

[0145] In some embodiments, R1is 3-membered heterocyclyl independently substituted with 2 halo, C1-6alkyl, C1-6haloalkyl, -ORG5, -SRG5, or -N(RG5)2. In some embodiments, R1is 4-membered heterocyclyl independently substituted with 2 halo, C1-6alkyl, C1-6haloalkyl, -ORG5, -SRG5, or - N(RG5)2.

[0146] In some embodiments, R1is 3-4 membered heterocyclyl independently substituted with 3 halo, C1-6alkyl, C1-6haloalkyl, -ORG5, -SRG5, or -N(RG5)2.

[0147] In some embodiments, R1is 3-membered heterocyclyl independently substituted with 3 halo, C1-6alkyl, C1-6haloalkyl, -ORG5, -SRG5, or -N(RG5)2. In some embodiments, R1is 4-membered heterocyclyl independently substituted with 3 halo, C1-6alkyl, C1-6haloalkyl, -ORG5, -SRG5, or - N(RG5)2.

[0148] In some embodiments, R1is 3-4 membered heterocyclyl independently substituted with 1, 2, or 3 halo, C1-6alkyl, C1-6haloalkyl, -ORG5, -SRG5, or -N(RG5)2, provided at least one substituent is halo.

[0149] In some embodiments, R1is 3-membered heterocyclyl substituted with at least one halo. In some embodiments, R1is 4-membered heterocyclyl substituted with at least one halo.

[0150] In some embodiments, R1is 3-4 membered heterocyclyl substituted with at least one of F, Cl, Br, or I. In some embodiments, R1is 3-4 membered heterocyclyl substituted with at least one of F, Cl, or Br. In some embodiments, R1is 3-4 membered heterocyclyl substituted with at least one of F or Cl.

[0151] In some embodiments, R1is 3-membered heterocyclyl substituted with at least one of F, Cl, Br, or I. In some embodiments, R1is 3-membered heterocyclyl substituted with at least one of F, Cl, or Br. In some embodiments, R1is 3-membered heterocyclyl substituted with at least one of F or Cl.

[0152] In some embodiments, R1is 4-membered heterocyclyl substituted with at least one of F, Cl, Br, or I. In some embodiments, R1is 4-membered heterocyclyl substituted with at least one of F, Cl, or Br. In some embodiments, R1is 4-membered heterocyclyl substituted with at least one of F or Cl.

[0153] In some embodiments, R1is 3-4 membered heterocyclyl substituted with at least one F. In some embodiments, R1is 3-4 membered heterocyclyl substituted with at least one Cl. In some embodiments, R1is 3-4 membered heterocyclyl substituted with at least one Br. In some embodiments, R1is 3-4 membered heterocyclyl substituted with at least one I.

[0154] In some embodiments, R1is 3-membered heterocyclyl substituted with at least one F. In some embodiments, R1is 3-membered heterocyclyl substituted with at least one Cl. In some embodiments, R1is 3-membered heterocyclyl substituted with at least one Br. In some embodiments, R1is 3- membered heterocyclyl substituted with at least one I.

[0155] In some embodiments, R1is 4-membered heterocyclyl substituted with at least one F. In some embodiments, R1is 4-membered heterocyclyl substituted with at least one Cl. In some embodiments, R1is 4-membered heterocyclyl substituted with at least one Br. In some embodiments, R1is 4- membered heterocyclyl substituted with at least one I.

[0156] In some embodiments, R1is 3-4 membered heterocyclyl independently substituted with 1, 2, or 3 halo, C1-6alkyl, C1-6haloalkyl, -ORG5, -SRG5, or -N(RG5)2, provided at least one substituent is C1-6alkyl.

[0157] In some embodiments, R1is 3-membered heterocyclyl substituted with at least one C1-6alkyl. In some embodiments, R1is 4-membered heterocyclyl substituted with at least one C1-6alkyl.

[0158] In some embodiments, R1is 3-4 membered heterocyclyl substituted with at least one methyl. In some embodiments, R1is 3-4 membered heterocyclyl substituted with at least one ethyl. In some embodiments, R1is 3-4 membered heterocyclyl substituted with at least one propyl. In some embodiments, R1is 3-4 membered heterocyclyl substituted with at least one butyl. In some embodiments, R1is 3-4 membered heterocyclyl substituted with at least one pentyl. In some embodiments, R1is 3-4 membered heterocyclyl substituted with at least one hexyl. In some embodiments, R1is 3-4 membered heterocyclyl substituted with at least one isopropyl. In some embodiments, R1is 3-4 membered heterocyclyl substituted with at least one isobutyl. In some embodiments, R1is 3-4 membered heterocyclyl substituted with at least one isopentyl. In some embodiments, R1is 3-4 membered heterocyclyl substituted with at least one isohexyl. In some embodiments, R1is 3-4 membered heterocyclyl substituted with at least one secbutyl. In some embodiments, R1is 3-4 membered heterocyclyl substituted with at least one secpentyl. In some embodiments, R1is 3-4 membered heterocyclyl substituted with at least one sechexyl. In some embodiments, R1is 3-4 membered heterocyclyl substituted with at least one tertbutyl.

[0159] In some embodiments, R1is 3-membered heterocyclyl substituted with at least one methyl. In some embodiments, R1is 3-membered heterocyclyl substituted with at least one ethyl. In some embodiments, R1is 3-membered heterocyclyl substituted with at least one propyl. In some embodiments, R1is 3-membered heterocyclyl substituted with at least one butyl. In some embodiments, R1is 3-membered heterocyclyl substituted with at least one pentyl. In some embodiments, R1is 3-membered heterocyclyl substituted with at least one hexyl. In some embodiments, R1is 3-membered heterocyclyl substituted with at least one isopropyl. In some embodiments, R1is 3-membered heterocyclyl substituted with at least one isobutyl. In some embodiments, R1is 3-membered heterocyclyl substituted with at least one isopentyl. In some embodiments, R1is 3-membered heterocyclyl substituted with at least one isohexyl. In someembodiments, R1is 3-membered heterocyclyl substituted with at least one secbutyl. In some embodiments, R1is 3-membered heterocyclyl substituted with at least one secpentyl. In some embodiments, R1is 3-membered heterocyclyl substituted with at least one sechexyl. In some embodiments, R1is 3-membered heterocyclyl substituted with at least one tertbutyl.

[0160] In some embodiments, R1is 4-membered heterocyclyl substituted with at least one methyl. In some embodiments, R1is 4-membered heterocyclyl substituted with at least one ethyl. In some embodiments, R1is 4-membered heterocyclyl substituted with at least one propyl. In some embodiments, R1is 4-membered heterocyclyl substituted with at least one butyl. In some embodiments, R1is 4-membered heterocyclyl substituted with at least one pentyl. In some embodiments, R1is 4-membered heterocyclyl substituted with at least one hexyl. In some embodiments, R1is 4-membered heterocyclyl substituted with at least one isopropyl. In some embodiments, R1is 4-membered heterocyclyl substituted with at least one isobutyl. In some embodiments, R1is 4-membered heterocyclyl substituted with at least one isopentyl. In some embodiments, R1is 4-membered heterocyclyl substituted with at least one isohexyl. In some embodiments, R1is 4-membered heterocyclyl substituted with at least one secbutyl. In some embodiments, R1is 4-membered heterocyclyl substituted with at least one secpentyl. In some embodiments, R1is 4-membered heterocyclyl substituted with at least one sechexyl. In some embodiments, R1is 4-membered heterocyclyl substituted with at least one tertbutyl.

[0161] In some embodiments, R1is 3-4 membered heterocyclyl independently substituted with 1, 2, or 3 halo, C1-6alkyl, C1-6haloalkyl, -ORG5, -SRG5, or -N(RG5)2, provided at least one substituent is C1-6haloalkyl.

[0162] In some embodiments, R1is 3-membered heterocyclyl substituted with at least one C1-6haloalkyl. In some embodiments, R1is 4-membered heterocyclyl substituted with at least one C1-6haloalkyl.

[0163] In some embodiments, R1is 3-4 membered heterocyclyl substituted with at least one halomethyl. In some embodiments, R1is 3-4 membered heterocyclyl substituted with at least one haloethyl. In some embodiments, R1is 3-4 membered heterocyclyl substituted with at least one halopropyl. In some embodiments, R1is 3-4 membered heterocyclyl substituted with at least one halobutyl. In some embodiments, R1is 3-4 membered heterocyclyl substituted with at least one halopentyl. In some embodiments, R1is 3-4 membered heterocyclyl substituted with at least one halohexyl.

[0164] In some embodiments, R1is 3-membered heterocyclyl substituted with at least one halomethyl. In some embodiments, R1is 3-membered heterocyclyl substituted with at least one haloethyl. In some embodiments, R1is 3-membered heterocyclyl substituted with at least one halopropyl. In some embodiments, R1is 3-membered heterocyclyl substituted with at least one halobutyl. In some embodiments, R1is 3-membered heterocyclyl substituted with at least one halopentyl. In some embodiments, R1is 3-membered heterocyclyl substituted with at least onehalohexyl.

[0165] In some embodiments, R1is 4-membered heterocyclyl substituted with at least one halomethyl. In some embodiments, R1is 4-membered heterocyclyl substituted with at least one haloethyl. In some embodiments, R1is 4-membered heterocyclyl substituted with at least one halopropyl. In some embodiments, R1is 4-membered heterocyclyl substituted with at least one halobutyl. In some embodiments, R1is 4-membered heterocyclyl substituted with at least one halopentyl. In some embodiments, R1is 4-membered heterocyclyl substituted with at least one halohexyl.

[0166] In some embodiments, R1is 3-4 membered heterocyclyl independently substituted with 1, 2, or 3 halo, C1-6alkyl, C1-6haloalkyl, -ORG5, -SRG5, or -N(RG5)2, provided at least one substituent is - ORG5.

[0167] In some embodiments, R1is 3-membered heterocyclyl substituted with at least one -ORG5. In some embodiments, R1is 4-membered heterocyclyl substituted with at least one -ORG5.

[0168] In some embodiments, R1is 3-4 membered heterocyclyl independently substituted with 1, 2, or 3 halo, C1-6alkyl, C1-6haloalkyl, -ORG5, -SRG5, or -N(RG5)2, provided at least one substituent is - SRG5.

[0169] In some embodiments, R1is 3-membered heterocyclyl substituted with at least one -SRG5. In some embodiments, R1is 4-membered heterocyclyl substituted with at least one -SRG5.

[0170] In some embodiments, R1is 3-4 membered heterocyclyl independently substituted with 1, 2, or 3 halo, C1-6alkyl, C1-6haloalkyl, -ORG5, -SRG5, or -N(RG5)2, provided at least one substituent is - N(RG5)2.

[0171] In some embodiments, R1is 3-membered heterocyclyl substituted with at least one -N(RG5)2. In some embodiments, R1is 4-membered heterocyclyl substituted with at least one -N(RG5)2.

[0172] In some embodiments, R1and G2, together with the atoms to which they are attached, are joined to form a 5-membered heteroaryl ring independently substituted with 0, 1, 2, or 3 RG7selected from the group consisting of halo, C1-6alkyl, C1-6haloalkyl, -ORG5, -SRG5, and -N(RG5)2.

[0173] In some embodiments, R1and G2, together with the atoms to which they are attached, are joined to form an unsubstituted 5-membered heteroaryl ring.

[0174] In some embodiments, R1and G2, together with the atoms to which they are attached, are joined to form a 5-membered heteroaryl ring substituted with 1 RG7selected from the group consisting of halo, C1-6alkyl, C1-6haloalkyl, -ORG5, -SRG5, and -N(RG5)2.

[0175] In some embodiments, R1and G2, together with the atoms to which they are attached, are joined to form a 5-membered heteroaryl ring independently substituted with 2 RG7selected from the group consisting of halo, C1-6alkyl, C1-6haloalkyl, -ORG5, -SRG5, and -N(RG5)2.

[0176] In some embodiments, R1and G2, together with the atoms to which they are attached, are joined to form a 5-membered heteroaryl ring independently substituted with 3 RG7selected from the group consisting of halo, C1-6alkyl, C1-6haloalkyl, -ORG5, -SRG5, and -N(RG5)2.

[0177] In some embodiments, R1and G2, together with the atoms to which they are attached, are joined to form a 5-membered heteroaryl ring independently substituted with 0, 1, 2, or 3 RG7selected from the group consisting of halo, C1-6alkyl, C1-6haloalkyl, -ORG5, -SRG5, and -N(RG5)2, provided at least one substituent is halo.

[0178] In some embodiments, R1and G2, together with the atoms to which they are attached, are joined to form a 5-membered heteroaryl ring substituted with at least one of F, Cl, Br, or I. In some embodiments, R1and G2, together with the atoms to which they are attached, are joined to form a 5- membered heteroaryl ring substituted with at least one of F, Cl, or Br. In some embodiments, R1and G2, together with the atoms to which they are attached, are joined to form a 5-membered heteroaryl ring substituted with at least one of F or Cl.

[0179] In some embodiments, R1and G2, together with the atoms to which they are attached, are joined to form a 5-membered heteroaryl ring substituted with at least one F. In some embodiments, R1and G2, together with the atoms to which they are attached, are joined to form a 5-membered heteroaryl ring substituted with at least one Cl. In some embodiments, R1and G2, together with the atoms to which they are attached, are joined to form a 5-membered heteroaryl ring substituted with at least one Br. In some embodiments, R1and G2, together with the atoms to which they are attached, are joined to form a 5-membered heteroaryl ring substituted with at least one I.

[0180] In some embodiments, R1and G2, together with the atoms to which they are attached, are joined to form a 5-membered heteroaryl ring independently substituted with 0, 1, 2, or 3 RG7selected from the group consisting of halo, C1-6alkyl, C1-6haloalkyl, -ORG5, -SRG5, and -N(RG5)2, provided at least one substituent is C1-6alkyl.

[0181] In some embodiments, R1and G2, together with the atoms to which they are attached, are joined to form a 5-membered heteroaryl ring substituted with at least one methyl. In some embodiments, R1and G2, together with the atoms to which they are attached, are joined to form a 5- membered heteroaryl ring substituted with at least one ethyl. In some embodiments, R1and G2, together with the atoms to which they are attached, are joined to form a 5-membered heteroaryl ring substituted with at least one propyl. In some embodiments, R1and G2, together with the atoms to which they are attached, are joined to form a 5-membered heteroaryl ring substituted with at least one butyl. In some embodiments, R1and G2, together with the atoms to which they are attached, are joined to form a 5-membered heteroaryl ring substituted with at least one pentyl. In some embodiments, R1and G2, together with the atoms to which they are attached, are joined to form a 5-membered heteroaryl ring substituted with at least one hexyl. In some embodiments, R1and G2, together with the atoms to which they are attached, are joined to form a 5-membered heteroaryl ring substituted with at least one isopropyl. In some embodiments, R1and G2, together with the atoms to which they are attached, are joined to form a 5-membered heteroaryl ring substituted with at least one isobutyl. In some embodiments, R1and G2, together with the atoms to which they are attached, are joined to form a 5-membered heteroaryl ring substituted with at least one isopentyl. In some embodiments, R1andG2, together with the atoms to which they are attached, are joined to form a 5-membered heteroaryl ring substituted with at least one isohexyl. In some embodiments, R1and G2, together with the atoms to which they are attached, are joined to form a 5-membered heteroaryl ring substituted with at least one secbutyl. In some embodiments, R1and G2, together with the atoms to which they are attached, are joined to form a 5-membered heteroaryl ring substituted with at least one secpentyl. In some embodiments, R1and G2, together with the atoms to which they are attached, are joined to form a 5- membered heteroaryl ring substituted with at least one sechexyl. In some embodiments, R1and G2, together with the atoms to which they are attached, are joined to form a 5-membered heteroaryl ring substituted with at least one tertbutyl.

[0182] In some embodiments, R1and G2, together with the atoms to which they are attached, are joined to form a 5-membered heteroaryl ring independently substituted with 0, 1, 2, or 3 RG7selected from the group consisting of halo, C1-6alkyl, C1-6haloalkyl, -ORG5, -SRG5, and -N(RG5)2, provided at least one substituent is C1-6haloalkyl.

[0183] In some embodiments, R1and G2, together with the atoms to which they are attached, are joined to form a 5-membered heteroaryl ring substituted with at least one halomethyl. In some embodiments, R1and G2, together with the atoms to which they are attached, are joined to form a 5- membered heteroaryl ring substituted with at least one haloethyl. In some embodiments, R1and G2, together with the atoms to which they are attached, are joined to form a 5-membered heteroaryl ring substituted with at least one halopropyl. In some embodiments, R1and G2, together with the atoms to which they are attached, are joined to form a 5-membered heteroaryl ring substituted with at least one halobutyl. In some embodiments, R1and G2, together with the atoms to which they are attached, are joined to form a 5-membered heteroaryl ring substituted with at least one halopentyl. In some embodiments, R1and G2, together with the atoms to which they are attached, are joined to form a 5- membered heteroaryl ring substituted with at least one halohexyl.

[0184] In some embodiments, R1and G2, together with the atoms to which they are attached, are joined to form a 5-membered heteroaryl ring independently substituted with 0, 1, 2, or 3 RG7groups selected from the group consisting of halo, C1-6alkyl, C1-6haloalkyl, -ORG5, -SRG5, and -N(RG5)2, provided at least one substituent is -ORG5.

[0185] In some embodiments, R1and G2, together with the atoms to which they are attached, are joined to form a 5-membered heteroaryl ring independently substituted with 0, 1, 2, or 3 RG7groups selected from the group consisting of halo, C1-6alkyl, C1-6haloalkyl, -ORG5, -SRG5, and -N(RG5)2, provided at least one substituent is -SRG5.

[0186] In some embodiments, R1and G2, together with the atoms to which they are attached, are joined to form a 5-membered heteroaryl ring independently substituted with 0, 1, 2, or 3 RG7groups selected from the group consisting of halo, C1-6alkyl, C1-6haloalkyl, -ORG5, -SRG5, and -N(RG5)2, provided at least one substituent is -N(RG5)2.

[0187] As generally defined herein, each instance of RG7is independently halo, C1-6alkyl, C1-6haloalkyl, -ORG5, -SRG5, or -N(RG5)2.

[0188] In some embodiments, RG7is halo.

[0189] In some embodiments, RG7is F, Cl, Br, or I. In some embodiments, RG7is F, Cl, or Br. In some embodiments, RG7is F or Cl.

[0190] In some embodiments, RG7is F. In some embodiments, RG7is Cl. In some embodiments, RG7is Br. In some embodiments, RG7is I.

[0191] In some embodiments, RG7is C1-6alkyl.

[0192] In some embodiments, RG7is methyl. In some embodiments, RG7is ethyl. In some embodiments, RG7is propyl. In some embodiments, RG7is butyl. In some embodiments, RG7is pentyl. In some embodiments, RG7is hexyl. In some embodiments, RG7is isopropyl. In some embodiments, RG7is isobutyl. In some embodiments, RG7is isopentyl. In some embodiments, RG7is isohexyl. In some embodiments, RG7is secbutyl. In some embodiments, RG7is secpentyl. In some embodiments, RG7is sechexyl. In some embodiments, RG7is tertbutyl.

[0193] In some embodiments, RG7is C1-6haloalkyl.

[0194] In some embodiments, RG7is halomethyl. In some embodiments, RG7is haloethyl. In some embodiments, RG7is halopropyl. In some embodiments, RG7is halobutyl. In some embodiments, RG7is halopentyl. In some embodiments, RG7is halohexyl.

[0195] In some embodiments, RG7is -ORG5.

[0196] In some embodiments, RG7is -SRG5.

[0197] In some embodiments, RG7is -N(RG5)2.

[0198] As generally defined herein, RG1, RG2, RG3, and RG4are each independently selected from the group consisting of hydrogen, halo, C1-6alkyl, C1-6haloalkyl, and -ORG6.

[0199] In some embodiments, RG1is selected from the group consisting of hydrogen, halo, C1-6alkyl, C1-6haloalkyl, and -ORG6.

[0200] In some embodiments, RG1is hydrogen.

[0201] In some embodiments, RG1is halo.

[0202] In some embodiments, RG1is F, Cl, Br, or I. In some embodiments, RG1is F, Cl, or Br. In some embodiments, RG1is F or Cl.

[0203] In some embodiments, RG1is F. In some embodiments, RG1is Cl. In some embodiments, RG1is Br. In some embodiments, RG1is I.

[0204] In some embodiments, RG1is C1-6alkyl.

[0205] In some embodiments, RG1is methyl. In some embodiments, RG1is ethyl. In some embodiments, RG1is propyl. In some embodiments, RG1is butyl. In some embodiments, RG1is pentyl. In some embodiments, RG1is hexyl. In some embodiments, RG1is isopropyl. In some embodiments, RG1is isobutyl. In some embodiments, RG1is isopentyl. In some embodiments, RG1is isohexyl. In some embodiments, RG1is secbutyl. In some embodiments, RG1is secpentyl. In some embodiments, RG1is sechexyl. In some embodiments, RG1is tertbutyl.

[0206] In some embodiments, RG1is C1-6haloalkyl.

[0207] In some embodiments, RG1is halomethyl. In some embodiments, RG1is haloethyl. In some embodiments, RG1is halopropyl. In some embodiments, RG1is halobutyl. In some embodiments, RG1is halopentyl. In some embodiments, RG1is halohexyl.

[0208] In some embodiments, RG1is -ORG6.

[0209] In some embodiments, RG2is selected from the group consisting of hydrogen, halo, C1-6alkyl, C1-6haloalkyl, and -ORG6.

[0210] In some embodiments, RG2is hydrogen.

[0211] In some embodiments, RG2is halo.

[0212] In some embodiments, RG2is F, Cl, Br, or I. In some embodiments, RG2is F, Cl, or Br. In some embodiments, RG2is F or Cl.

[0213] In some embodiments, RG2is F. In some embodiments, RG2is Cl. In some embodiments, RG2is Br. In some embodiments, RG2is I.

[0214] In some embodiments, RG2is C1-6alkyl.

[0215] In some embodiments, RG2is methyl. In some embodiments, RG2is ethyl. In some embodiments, RG2is propyl. In some embodiments, RG2is butyl. In some embodiments, RG2is pentyl. In some embodiments, RG2is hexyl. In some embodiments, RG2is isopropyl. In some embodiments, RG2is isobutyl. In some embodiments, RG2is isopentyl. In some embodiments, RG2is isohexyl. In some embodiments, RG2is secbutyl. In some embodiments, RG2is secpentyl. In some embodiments, RG2is sechexyl. In some embodiments, RG2is tertbutyl.

[0216] In some embodiments, RG2is C1-6haloalkyl.

[0217] In some embodiments, RG2is halomethyl. In some embodiments, RG2is haloethyl. In some embodiments, RG2is halopropyl. In some embodiments, RG2is halobutyl. In some embodiments, RG2is halopentyl. In some embodiments, RG2is halohexyl.

[0218] In some embodiments, RG2is -ORG6.

[0219] In some embodiments, RG3is selected from the group consisting of hydrogen, halo, C1-6alkyl, C1-6haloalkyl, and -ORG6.

[0220] In some embodiments, RG3is hydrogen.

[0221] In some embodiments, RG3is halo.

[0222] In some embodiments, RG3is F, Cl, Br, or I. In some embodiments, RG3is F, Cl, or Br. In some embodiments, RG3is F or Cl.

[0223] In some embodiments, RG3is F. In some embodiments, RG3is Cl. In some embodiments, RG3is Br. In some embodiments, RG3is I.

[0224] In some embodiments, RG3is C1-6alkyl.

[0225] In some embodiments, RG3is methyl. In some embodiments, RG3is ethyl. In some embodiments, RG3is propyl. In some embodiments, RG3is butyl. In some embodiments, RG3is pentyl. In some embodiments, RG3is hexyl. In some embodiments, RG3is isopropyl. In some embodiments,RG3is isobutyl. In some embodiments, RG3is isopentyl. In some embodiments, RG3is isohexyl. In some embodiments, RG3is secbutyl. In some embodiments, RG3is secpentyl. In some embodiments, RG3is sechexyl. In some embodiments, RG3is tertbutyl.

[0226] In some embodiments, RG3is C1-6haloalkyl.

[0227] In some embodiments, RG3is halomethyl. In some embodiments, RG3is haloethyl. In some embodiments, RG3is halopropyl. In some embodiments, RG3is halobutyl. In some embodiments, RG3is halopentyl. In some embodiments, RG3is halohexyl.

[0228] In some embodiments, RG3is -ORG6.

[0229] In some embodiments, RG4is selected from the group consisting of hydrogen, halo, C1-6alkyl, C1-6haloalkyl, and -ORG6.

[0230] In some embodiments, RG4is hydrogen.

[0231] In some embodiments, RG4is halo.

[0232] In some embodiments, RG4is F, Cl, Br, or I. In some embodiments, RG4is F, Cl, or Br. In some embodiments, RG4is F or Cl.

[0233] In some embodiments, RG4is F. In some embodiments, RG4is Cl. In some embodiments, RG4is Br. In some embodiments, RG4is I.

[0234] In some embodiments, RG4is C1-6alkyl.

[0235] In some embodiments, RG4is methyl. In some embodiments, RG4is ethyl. In some embodiments, RG4is propyl. In some embodiments, RG4is butyl. In some embodiments, RG4is pentyl. In some embodiments, RG4is hexyl. In some embodiments, RG4is isopropyl. In some embodiments, RG4is isobutyl. In some embodiments, RG4is isopentyl. In some embodiments, RG4is isohexyl. In some embodiments, RG4is secbutyl. In some embodiments, RG4is secpentyl. In some embodiments, RG4is sechexyl. In some embodiments, RG4is tertbutyl.

[0236] In some embodiments, RG4is C1-6haloalkyl.

[0237] In some embodiments, RG4is halomethyl. In some embodiments, RG4is haloethyl. In some embodiments, RG4is halopropyl. In some embodiments, RG4is halobutyl. In some embodiments, RG4is halopentyl. In some embodiments, RG4is halohexyl.

[0238] In some embodiments, RG4is -ORG6.

[0239] As generally defined herein, RG5and RG6are each independently hydrogen, C1-6alkyl, or C1-6haloalkyl.

[0240] In some embodiments, RG5is hydrogen.

[0241] In some embodiments, RG5is C1-6alkyl.

[0242] In some embodiments, RG5is methyl. In some embodiments, RG5is ethyl. In some embodiments, RG5is propyl. In some embodiments, RG5is butyl. In some embodiments, RG5is pentyl. In some embodiments, RG5is hexyl. In some embodiments, RG5is isopropyl. In some embodiments, RG5is isobutyl. In some embodiments, RG5is isopentyl. In some embodiments, RG5is isohexyl. In some embodiments, RG5is secbutyl. In some embodiments, RG5is secpentyl. In some embodiments,RG5is sechexyl. In some embodiments, RG5is tertbutyl.

[0243] In some embodiments, RG5is C1-6haloalkyl.

[0244] In some embodiments, RG5is halomethyl. In some embodiments, RG5is haloethyl. In some embodiments, RG5is halopropyl. In some embodiments, RG5is halobutyl. In some embodiments, RG5is halopentyl. In some embodiments, RG5is halohexyl.

[0245] In some embodiments, RG6is hydrogen.

[0246] In some embodiments, RG6is C1-6alkyl.

[0247] In some embodiments, RG6is methyl. In some embodiments, RG6is ethyl. In some embodiments, RG6is propyl. In some embodiments, RG6is butyl. In some embodiments, RG6is pentyl. In some embodiments, RG6is hexyl. In some embodiments, RG6is isopropyl. In some embodiments, RG6is isobutyl. In some embodiments, RG6is isopentyl. In some embodiments, RG6is isohexyl. In some embodiments, RG6is secbutyl. In some embodiments, RG6is secpentyl. In some embodiments, RG6is sechexyl. In some embodiments, RG6is tertbutyl.

[0248] In some embodiments, RG6is C1-6haloalkyl.

[0249] In some embodiments, RG6is halomethyl. In some embodiments, RG6is haloethyl. In some embodiments, RG6is halopropyl. In some embodiments, RG6is halobutyl. In some embodiments, RG6is halopentyl. In some embodiments, RG6is halohexyl.

[0250] In some embodiments, Ring A of formula:is a group of Formula (a-1), (a-2), (a-3), (a-4), (a-5), or (a-6):

[0251] In some embodiments, Ring A of formula:is a group of Formula (a-1), (a-2), or (a-4):

[0252] In some embodiments, Ring A is of Formula (a-1), (a-2), (a-3), (a-4), (a-5), or (a-6), wherein R1is C1-6haloalkyl or -ORG5. In some embodiments, Ring A is of Formula (a-1), (a-2), (a-3), (a-4), (a-5), or (a-6), wherein R1is -CF3, -OCF2H, -OCF3, -OCH3, or -CF2H.

[0253] In some embodiments, Ring A is of Formula (a-1), (a-2), or (a-4), wherein R1is C1-6haloalkyl or -ORG5. In some embodiments, Ring A is of Formula (a-1), (a-2), or (a-4), wherein R1is -CF3, - OCF2H, -OCF3, -OCH3, or -CF2H.

[0254] In some embodiments, Ring A is of Formula (a-2), (a-3), (a-4), (a-5), or (a-6), wherein RG1, RG2, RG3, and RG4are each independently selected from the group consisting of halo, C1-6alkyl, C1-6haloalkyl, and -ORG6. In some embodiments, Ring A is of Formula (a-2), (a-3), (a-4), (a-5), or (a-6), wherein at least one of RG1, RG2, RG3, and RG4is fluoro.

[0255] In some embodiments, Ring A is of Formula (a-2) or (a-4), wherein RG1and RG4are each independently halo. In some embodiments, Ring A is of Formula (a-2) or (a-4), wherein RG1and RG4are each fluoro.

[0256] In some embodiments, Ring A is of Formula (a-2-F), (a-4-F), (a-5-F), or (a-6-F):

[0257] In some embodiments, Ring A is of Formula (a-2-F) or (a-4-F):

[0258] In some embodiments, Ring A is a group of formula:

[0259] In some embodiments, Ring A is a group of formula:

[0260] As generally defined herein, R4is hydrogen, C1-3alkyl, C3-4carbocyclyl, or C3-4carbocyclyl- C1-3alkyl-, wherein the alkyl and carbocyclyl are each independently substituted with 0, 1, 2, 3, 4, 5, or 6 halo, and wherein the carbocyclyl is further independently substituted with 0, 1, or 2 C1-3alkyl or C1-3haloalkyl.

[0261] In some embodiments, R4is hydrogen. In other embodiments, R4is not hydrogen.

[0262] In some embodiments, R4is C1-3alkyl.

[0263] In some embodiments, R4is methyl. In some embodiments, R4is ethyl. In some embodiments, R4is propyl. In some embodiments, R4is isopropyl.

[0264] In some embodiments, R4is C1-3alkyl substituted with 0, 1, 2, 3, 4, 5, or 6 halo.

[0265] In some embodiments, R4is methyl substituted with 0, 1, 2, or 3 halo. In some embodiments, R4is ethyl substituted with 0, 1, 2, 3, 4, 5, or 6 halo. In some embodiments, R4is propyl substituted with 0, 1, 2, 3, 4, 5, or 6 halo. In some embodiments, R4is isopropyl substituted with 0, 1, 2, 3, 4, 5, or 6 halo.

[0266] In some embodiments, R4is C1-3alkyl substituted with 1 halo.

[0267] In some embodiments, R4is methyl substituted with 1 halo. In some embodiments, R4is ethyl substituted with 1 halo. In some embodiments, R4is propyl substituted with 1 halo. In some embodiments, R4is isopropyl substituted with 1 halo.

[0268] In some embodiments, R4is C1-3alkyl independently substituted with 2 halo.

[0269] In some embodiments, R4is methyl independently substituted with 2 halo. In some embodiments, R4is ethyl independently substituted with 2 halo. In some embodiments, R4is propyl independently substituted with 2 halo. In some embodiments, R4is isopropyl independently substituted with 2 halo.

[0270] In some embodiments, R4is C1-3alkyl independently substituted with 3 halo.

[0271] In some embodiments, R4is methyl independently substituted with 3 halo. In some embodiments, R4is ethyl independently substituted with 3 halo. In some embodiments, R4is propyl independently substituted with 3 halo. In some embodiments, R4is isopropyl independently substituted with 3 halo.

[0272] In some embodiments, R4is C1-3alkyl independently substituted with 4 halo.

[0273] In some embodiments, R4is ethyl independently substituted with 4 halo. In some embodiments, R4is independently propyl substituted with 4 halo. In some embodiments, R4is isopropyl independently substituted with 4 halo.

[0274] In some embodiments, R4is C1-3alkyl substituted with 5 halo.

[0275] In some embodiments, R4is ethyl independently substituted with 5 halo. In some embodiments, R4is propyl independently substituted with 5 halo. In some embodiments, R4is isopropyl independently substituted with 5 halo.

[0276] In some embodiments, R4is C1-3alkyl substituted with 6 halo.

[0277] In some embodiments, R4is independently propyl substituted with 6 halo. In some embodiments, R4is independently isopropyl substituted with 6 halo.

[0278] In some embodiments, R4is C1-3alkyl substituted with at least one of F, Cl, Br, or I. In some embodiments, R4is C1-3alkyl substituted with at least one of F, Cl, or Br. In some embodiments, R4is C1-3alkyl substituted with at least one of F or Cl.

[0279] In some embodiments, R4is methyl substituted with at least one of F, Cl, Br, or I. In some embodiments, R4is methyl substituted with at least one of F, Cl, or Br. In some embodiments, R4is methyl substituted with at least one of F or Cl.

[0280] In some embodiments, R4is ethyl substituted with at least one of F, Cl, Br, or I. In some embodiments, R4is ethyl substituted with at least one of F, Cl, or Br. In some embodiments, R4is ethyl substituted with at least one of F or Cl.

[0281] In some embodiments, R4is propyl substituted with at least one of F, Cl, Br, or I. In some embodiments, R4is propyl substituted with at least one of F, Cl, or Br. In some embodiments, R4is propyl substituted with at least one of F or Cl.

[0282] In some embodiments, R4is isopropyl substituted with at least one of F, Cl, Br, or I. In someembodiments, R4is isopropyl substituted with at least one of F, Cl, or Br. In some embodiments, R4is isopropyl substituted with at least one of F or Cl.

[0283] In some embodiments, R4is C1-3alkyl substituted with at least one F. In some embodiments, R4is C1-3alkyl substituted with at least one Cl. In some embodiments, R4is C1-3alkyl substituted with at least one Br. In some embodiments, R4is C1-3alkyl substituted with at least one I.

[0284] In some embodiments, R4is methyl substituted with at least one F. In some embodiments, R4is methyl substituted with at least one Cl. In some embodiments, R4is methyl substituted with at least one Br. In some embodiments, R4is methyl substituted with at least one I.

[0285] In some embodiments, R4is ethyl substituted with at least one F. In some embodiments, R4is ethyl substituted with at least one Cl. In some embodiments, R4is ethyl substituted with at least one Br. In some embodiments, R4is ethyl substituted with at least one I.

[0286] In some embodiments, R4is propyl substituted with at least one F. In some embodiments, R4is propyl substituted with at least one Cl. In some embodiments, R4is propyl substituted with at least one Br. In some embodiments, R4is propyl substituted with at least one I.

[0287] In some embodiments, R4is isopropyl substituted with at least one F. In some embodiments, R4is isopropyl substituted with at least one Cl. In some embodiments, R4is isopropyl substituted with at least one Br. In some embodiments, R4is isopropyl substituted with at least one I.

[0288] In some embodiments, R4is C3-4carbocyclyl substituted with 0, 1, 2, 3, 4, 5, or 6 halo and 0, 1, or 2 C1-3alkyl or C1-3haloalkyl.

[0289] In some embodiments, R4is C3carbocyclyl substituted with 0, 1, 2, 3, 4, or 5 halo. In some embodiments, R4is C4carbocyclyl substituted with 0, 1, 2, 3, 4, 5, or 6 halo.

[0290] In some embodiments, R4is unsubstituted C3-4carbocyclyl.

[0291] In some embodiments, R4is unsubstituted C3carbocyclyl. In some embodiments, R4is unsubstituted C4carbocyclyl.

[0292] In some embodiments, R4is C3-4carbocyclyl substituted with 1 halo.

[0293] In some embodiments, R4is C3carbocyclyl substituted with 1 halo. In some embodiments, R4is C4carbocyclyl substituted with 1 halo.

[0294] In some embodiments, R4is C3-4carbocyclyl independently substituted with 2 halo.

[0295] In some embodiments, R4is C3carbocyclyl independently substituted with 2 halo. In some embodiments, R4is C4carbocyclyl substituted with 2 halo.

[0296] In some embodiments, R4is C3-4carbocyclyl independently substituted with 3 halo.

[0297] In some embodiments, R4is C3carbocyclyl independently substituted with 3 halo. In some embodiments, R4is C4carbocyclyl substituted with 3 halo.

[0298] In some embodiments, R4is C3-4carbocyclyl independently substituted with 4 halo.

[0299] In some embodiments, R4is C3carbocyclyl independently substituted with 4 halo. In some embodiments, R4is C4carbocyclyl substituted with 4 halo.

[0300] In some embodiments, R4is C3-4carbocyclyl independently substituted with 5 halo.

[0301] In some embodiments, R4is C3carbocyclyl independently substituted with 5 halo. In some embodiments, R4is C4carbocyclyl substituted with 5 halo.

[0302] In some embodiments, R4is C4carbocyclyl independently substituted with 6 halo.

[0303] In some embodiments, R4is C3-4carbocyclyl substituted with at least one of F, Cl, Br, or I. In some embodiments, R4is C3-4carbocyclyl substituted with at least one of F, Cl, or Br. In some embodiments, R4is C3-4carbocyclyl substituted with at least one of F or Cl.

[0304] In some embodiments, R4is C3carbocyclyl substituted with at least one of F, Cl, Br, or I. In some embodiments, R4is C3carbocyclyl substituted with at least one of F, Cl, or Br. In some embodiments, R4is C3carbocyclyl substituted with at least one of F or Cl.

[0305] In some embodiments, R4is C4carbocyclyl substituted with at least one of F, Cl, Br, or I. In some embodiments, R4is C4carbocyclyl substituted with at least one of F, Cl, or Br. In some embodiments, R4is C4carbocyclyl substituted with at least one of F or Cl.

[0306] In some embodiments, R4is C3-4carbocyclyl substituted with at least one F. In some embodiments, R4is C3-4carbocyclyl substituted with at least one Cl. In some embodiments, R4is C3-4carbocyclyl substituted with at least one Br. In some embodiments, R4is C3-4carbocyclyl substituted with at least one I.

[0307] In some embodiments, R4is C3carbocyclyl substituted with at least one F. In some embodiments, R4is C3carbocyclyl substituted with at least one Cl. In some embodiments, R4is C3carbocyclyl substituted with at least one Br. In some embodiments, R4is C3carbocyclyl substituted with at least one I.

[0308] In some embodiments, R4is C4carbocyclyl substituted with at least one F. In some embodiments, R4is C4carbocyclyl substituted with at least one Cl. In some embodiments, R4is C4carbocyclyl substituted with at least one Br. In some embodiments, R4is C4carbocyclyl substituted with at least one I.

[0309] In some embodiments, R4is C3-4carbocyclyl-C1-3alkyl-, wherein the alkyl and carbocyclyl are each independently substituted with 0, 1, 2, 3, 4, 5, or 6 halo.

[0310] For clarity, the number of substituents provided on the alkyl and the carbocyclyl group should satisfy valency requirements of that group. Additionally, wherein both an alkyl and carbocyclyl are in a variable, either the alkyl or carbocyclyl group may each be independently substituted with up to 6 halo, and carbocyclyl up to 0, 1, or 2 C1-3alkyl or C1-3haloalkyl.

[0311] In some embodiments, R4is C3carbocyclyl-C1-3alkyl, wherein the carbocyclyl is substituted with 0, 1, 2, 3, 4, or 5 halo and 0, 1, or 2 C1-3alkyl or C1-3haloalkyl. In some embodiments, R4is C4carbocyclyl-C1-3alkyl, wherein the carbocyclyl is independently substituted with 0, 1, 2, 3, 4, 5, or 6 halo and 0, 1, or 2 C1-3alkyl or C1-3haloalkyl. In some embodiments, the C1-3alkyl is independently substituted with 0, 1, 2, 3, 4, 5, or 6 halo.

[0312] In some embodiments, R4is C3-4carbocyclyl-C1alkyl, wherein the carbocyclyl is independently substituted with 0, 1, 2, 3, 4, 5, or 6 halo and 0, 1, or 2 C1-3alkyl or C1-3haloalkyl. Insome embodiments, R4is C3-4carbocyclyl-C2alkyl, wherein the carbocyclyl is independently substituted with 0, 1, 2, 3, 4, 5, or 6 halo and 0, 1, or 2 C1-3alkyl or C1-3haloalkyl. In some embodiments, R4is C3-4carbocyclyl-C3alkyl, wherein the carbocyclyl is independently substituted with 0, 1, 2, 3, 4, 5, or 6 halo and 0, 1, or 2 C1-3alkyl or C1-3haloalkyl. In some embodiments, the C1-3alkyl is independently substituted with 0, 1, 2, 3, 4, 5, or 6 halo.

[0313] In some embodiments, R4is unsubstituted C3-4carbocyclyl-C1-3alkyl.

[0314] In some embodiments, R4is unsubstituted C3carbocyclyl-C1-3alkyl. In some embodiments, R4is unsubstituted C4carbocyclyl-C1-3alkyl.

[0315] In some embodiments, R4is unsubstituted C3-4carbocyclyl-C1alkyl. In some embodiments, R4is unsubstituted C3-4carbocyclyl-C2alkyl. In some embodiments, R4is unsubstituted C3-4carbocyclyl-C3alkyl.

[0316] In some embodiments, R4is C3-4carbocyclyl-C1-3alkyl, wherein the carbocyclyl is substituted with 1 halo. In some embodiments, the C1-3alkyl is independently substituted with 0, 1, 2, 3, 4, 5, or 6 halo.

[0317] In some embodiments, R4is C3carbocyclyl-C1-3alkyl, wherein the carbocyclyl is substituted with 1 halo. In some embodiments, R4is C4carbocyclyl-C1-3alkyl, wherein the carbocyclyl is substituted with 1 halo. In some embodiments, the C1-3alkyl is independently substituted with 0, 1, 2, 3, 4, 5, or 6 halo.

[0318] In some embodiments, R4is C3-4carbocyclyl-C1alkyl, wherein the carbocyclyl is substituted with 1 halo. In some embodiments, R4is C3-4carbocyclyl-C2alkyl, wherein the carbocyclyl is substituted with 1 halo. In some embodiments, R4is C3-4carbocyclyl-C3alkyl, wherein the carbocyclyl is substituted with 1 halo. In some embodiments, the C1-3alkyl is independently substituted with 0, 1, 2, 3, 4, 5, or 6 halo.

[0319] In some embodiments, R4is C3-4carbocyclyl-C1-3alkyl, wherein the carbocyclyl is independently substituted with 2 halo. In some embodiments, the C1-3alkyl is independently substituted with 0, 1, 2, 3, 4, 5, or 6 halo.

[0320] In some embodiments, R4is C3carbocyclyl-C1-3alkyl, wherein the carbocyclyl is independently substituted with 2 halo. In some embodiments, R4is C4carbocyclyl-C1-3alkyl, wherein the carbocyclyl is independently substituted with 2 halo. In some embodiments, the C1-3alkyl is independently substituted with 0, 1, 2, 3, 4, 5, or 6 halo.

[0321] In some embodiments, R4is C3-4carbocyclyl-C1alkyl, wherein the carbocyclyl is independently substituted with 2 halo. In some embodiments, R4is C3-4carbocyclyl-C2alkyl, wherein the carbocyclyl is independently substituted with 2 halo. In some embodiments, R4is C3-4carbocyclyl-C3alkyl, wherein the carbocyclyl is independently substituted with 2 halo. In some embodiments, the C1-3alkyl is independently substituted with 0, 1, 2, 3, 4, 5, or 6 halo.

[0322] In some embodiments, R4is C3-4carbocyclyl-C1-3alkyl, wherein the carbocyclyl is independently substituted with 3 halo. In some embodiments, the C1-3alkyl is independentlysubstituted with 0, 1, 2, 3, 4, 5, or 6 halo.

[0323] In some embodiments, R4is C3carbocyclyl-C1-3alkyl, wherein the carbocyclyl is independently substituted with 3 halo. In some embodiments, R4is C4carbocyclyl-C1-3alkyl, wherein the carbocyclyl is independently substituted with 3 halo. In some embodiments, the C1-3alkyl is independently substituted with 0, 1, 2, 3, 4, 5, or 6 halo.

[0324] In some embodiments, R4is C3-4carbocyclyl-C1alkyl, wherein the carbocyclyl is independently substituted with 3 halo. In some embodiments, R4is C3-4carbocyclyl-C2alkyl, wherein the carbocyclyl is independently substituted with 3 halo. In some embodiments, R4is C3-4carbocyclyl-C3alkyl, wherein the carbocyclyl is independently substituted with 3 halo. In some embodiments, the C1-3alkyl is independently substituted with 0, 1, 2, 3, 4, 5, or 6 halo.

[0325] In some embodiments, R4is C3-4carbocyclyl-C1-3alkyl, wherein the carbocyclyl is independently substituted with 4 halo. In some embodiments, the C1-3alkyl is independently substituted with 0, 1, 2, 3, 4, 5, or 6 halo.

[0326] In some embodiments, R4is C3carbocyclyl-C1-3alkyl, wherein the carbocyclyl is independently substituted with 4 halo. In some embodiments, R4is C4carbocyclyl-C1-3alkyl, wherein the carbocyclyl is independently substituted with 4 halo. In some embodiments, the C1-3alkyl is independently substituted with 0, 1, 2, 3, 4, 5, or 6 halo.

[0327] In some embodiments, R4is C3-4carbocyclyl-C1alkyl, wherein the carbocyclyl is independently substituted with 4 halo. In some embodiments, R4is C3-4carbocyclyl-C2alkyl, wherein the carbocyclyl is independently substituted with 4 halo. In some embodiments, R4is C3-4carbocyclyl-C3alkyl, wherein the carbocyclyl is independently substituted with 4 halo. In some embodiments, the C1-3alkyl is independently substituted with 0, 1, 2, 3, 4, 5, or 6 halo.

[0328] In some embodiments, R4is C3-4carbocyclyl-C1-3alkyl, wherein the carbocyclyl is independently substituted with 5 halo. In some embodiments, the C1-3alkyl is independently substituted with 0, 1, 2, 3, 4, 5, or 6 halo.

[0329] In some embodiments, R4is C3carbocyclyl-C1-3alkyl, wherein the carbocyclyl is independently substituted with 5 halo. In some embodiments, R4is C4carbocyclyl-C1-3alkyl, wherein the carbocyclyl is independently substituted with 5 halo. In some embodiments, the C1-3alkyl is independently substituted with 0, 1, 2, 3, 4, 5, or 6 halo.

[0330] In some embodiments, R4is C3-4carbocyclyl-C1alkyl, wherein the alkyl and carbocyclyl are independently substituted with 5 halo. In some embodiments, R4is C3-4carbocyclyl-C2alkyl, wherein the carbocyclyl is independently substituted with 5 halo. In some embodiments, R4is C3-4carbocyclyl-C3alkyl, wherein the carbocyclyl is independently substituted with 5 halo. In some embodiments, the C1-3alkyl is independently substituted with 0, 1, 2, 3, 4, 5, or 6 halo.

[0331] In some embodiments, R4is C4carbocyclyl-C1-3alkyl, wherein the carbocyclyl is independently substituted with 6 halo. In some embodiments, the C1-3alkyl is independently substituted with 0, 1, 2, 3, 4, 5, or 6 halo.

[0332] In some embodiments, R4is C4carbocyclyl-C1alkyl, wherein the carbocyclyl is independently substituted with 6 halo. In some embodiments, R4is C4carbocyclyl-C2alkyl, wherein the carbocyclyl is independently substituted with 6 halo. In some embodiments, R4is C4carbocyclyl- C3alkyl, wherein the carbocyclyl is independently substituted with 6 halo. In some embodiments, the C1-3alkyl is independently substituted with 0, 1, 2, 3, 4, 5, or 6 halo.

[0333] In some embodiments, R4is hydrogen, methyl, ethyl, cyclopropyl, or cyclopropyl-methyl. In some embodiments, R4is methyl or ethyl. In some embodiments, R4is methyl. (b) Ring B, Ring C, n, p, m, R3, R2a, and R2b

[0334] As generally described herein, n is 0 or 1.

[0335] In some embodiments, n is 0 or 1.

[0336] In some embodiments, n is 0. In some embodiments, n is 1.

[0337] As generally described herein, p is 1 or 2.

[0338] In some embodiments, p is 1. In some embodiments, p is 2.

[0339] As generally described herein, m is 0, 1, 2, or 3.

[0340] In some embodiments, m is 1, 2, or 3. In some embodiments, m is 0, 1, or 2. In some embodiments, m is 1 or 2. In some embodiments, m is 2 or 3. In some embodiments, m is 1 or 3.

[0341] In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3.

[0342] As generally described herein, R2aand R2bare each independently hydrogen, halo, C1-6alkyl, C1-6haloalkyl, C3-4carbocyclyl, or 3-4 membered heterocyclyl, wherein the carbocyclyl or heterocyclyl are each independently substituted with 0, 1, 2, or 3 halo, or R2aand R2bare joined to form a C3carbocyclyl independently substituted with 0, 1, 2, or 3 halo.

[0343] In some embodiments, R2ais independently hydrogen, halo, C1-6alkyl, C1-6haloalkyl, C3-4carbocyclyl, or 3-4 membered heterocyclyl.

[0344] In some embodiments, R2ais independently hydrogen.

[0345] In some embodiments, R2ais independently halo.

[0346] In some embodiments, R2ais independently F, Cl, Br, or I. In some embodiments, R2ais independently F, Cl, or Br. In some embodiments, R2ais independently F or Cl.

[0347] In some embodiments, R2ais independently F. In some embodiments, R2ais independently Cl. In some embodiments, R2ais independently Br. In some embodiments, R2ais independently I.

[0348] In some embodiments, R2ais independently C1-6alkyl.

[0349] In some embodiments, R2ais independently methyl. In some embodiments, R2ais independently ethyl. In some embodiments, R2ais independently propyl. In some embodiments, R2ais independently butyl. In some embodiments, R2ais independently pentyl. In some embodiments, R2ais independently hexyl. In some embodiments, R2ais independently isopropyl. In some embodiments, R2ais independently isobutyl. In some embodiments, R2ais independently isopentyl. In someembodiments, R2ais independently isohexyl. In some embodiments, R2ais independently secbutyl. In some embodiments, R2ais independently secpentyl. In some embodiments, R2ais independently sechexyl. In some embodiments, R2ais independently tertbutyl.

[0350] In some embodiments, R2ais independently C1-6haloalkyl.

[0351] In some embodiments, R2ais independently halomethyl. In some embodiments, R2ais independently haloethyl. In some embodiments, R2ais independently halopropyl. In some embodiments, R2ais independently halobutyl. In some embodiments, R2ais independently halopentyl. In some embodiments, R2ais independently halohexyl.

[0352] In some embodiments, R2ais independently C3-4carbocyclyl.

[0353] In some embodiments, R2ais independently C3carbocyclyl. In some embodiments, R2ais independently C4carbocyclyl.

[0354] In some embodiments, R2ais independently 3-4 membered heterocyclyl.

[0355] In some embodiments, R2ais independently 3-membered heterocyclyl. In some embodiments, R2ais independently 4-membered heterocyclyl.

[0356] In some embodiments, each instance of R2bis independently hydrogen, halo, C1-6alkyl, C1-6haloalkyl, C3-4carbocyclyl, or 3-4 membered heterocyclyl.

[0357] In some embodiments, R2bis independently hydrogen.

[0358] In some embodiments, R2bis independently halo.

[0359] In some embodiments, R2bis independently F, Cl, Br, or I. In some embodiments, R2bis independently F, Cl, or Br. In some embodiments, R2bis independently F or Cl.

[0360] In some embodiments, R2bis independently F. In some embodiments, R2bis independently Cl. In some embodiments, R2bis independently Br. In some embodiments, R2bis independently I.

[0361] In some embodiments, R2bis independently C1-6alkyl.

[0362] In some embodiments, R2bis independently methyl. In some embodiments, R2bis independently ethyl. In some embodiments, R2bis independently propyl. In some embodiments, R2bis independently butyl. In some embodiments, R2bis independently pentyl. In some embodiments, R2bis independently hexyl. In some embodiments, R2bis independently isopropyl. In some embodiments, R2bis independently isobutyl. In some embodiments, R2bis independently isopentyl. In some embodiments, R2bis independently isohexyl. In some embodiments, R2bis independently secbutyl. In some embodiments, R2bis independently secpentyl. In some embodiments, R2bis independently sechexyl. In some embodiments, R2bis independently tertbutyl.

[0363] In some embodiments, R2bis independently C1-6haloalkyl.

[0364] In some embodiments, R2bis independently halomethyl. In some embodiments, R2bis independently haloethyl. In some embodiments, R2bis independently halopropyl. In some embodiments, R2bis independently halobutyl. In some embodiments, R2bis independently halopentyl. In some embodiments, R2bis independently halohexyl.

[0365] In some embodiments, R2bis independently C3-4carbocyclyl.

[0366] In some embodiments, R2bis independently C3carbocyclyl. In some embodiments, R2bis independently C4carbocyclyl.

[0367] In some embodiments, R2bis independently 3-4 membered heterocyclyl.

[0368] In some embodiments, R2bis independently 3-membered heterocyclyl. In some embodiments, R2bis independently 4-membered heterocyclyl.

[0369] In some embodiments, R2aand R2bare the same. In some embodiments, R2aand R2bare different. In some embodiments one of R2aand R2bis C1-6alkyl, e.g., -CH3, and one of R2aand R2bis H. In some embodiments one of R2aand R2bis C1-6alkyl, e.g., -CH3, and the other of R2aand R2bis H.

[0370] In some embodiments, R2aand R2bare joined to form a C3carbocyclyl independently substituted with 0, 1, 2, or 3 halo.

[0371] As generally described herein, each instance of R3is independently halo, C1-6alkyl, or C1-6haloalkyl, or two R3groups are joined to form a C1-3alkylene bridging group or C1-3haloalkylene bridging group.

[0372] In some embodiments, R3is halo.

[0373] In some embodiments, R3is F, Cl, Br, or I. In some embodiments, R3is F, Cl, or Br. In some embodiments, R3is F or Cl.

[0374] In some embodiments, R3is F. In some embodiments, R3is Cl. In some embodiments, R3is Br. In some embodiments, R3is I.

[0375] In some embodiments, R3is C1-6alkyl.

[0376] In some embodiments, R3is methyl. In some embodiments, R3is ethyl. In some embodiments, R3is propyl. In some embodiments, R3is butyl. In some embodiments, R3is pentyl. In some embodiments, R3is hexyl. In some embodiments, R3is isopropyl. In some embodiments, R3is isobutyl. In some embodiments, R3is isopentyl. In some embodiments, R3is isohexyl. In some embodiments, R3is secbutyl. In some embodiments, R3is secpentyl. In some embodiments, R3is sechexyl. In some embodiments, R3is tertbutyl.

[0377] In some embodiments, R3is C1-6haloalkyl.

[0378] In some embodiments, R3is halomethyl. In some embodiments, R3is haloethyl. In some embodiments, R3is halopropyl. In some embodiments, R3is halobutyl. In some embodiments, R3is halopentyl. In some embodiments, R3is halohexyl.

[0379] As generally described herein, two R3groups are joined to form a C1-3alkylene bridging group or a C1-3haloalkylene bridging group.

[0380] In some embodiments, two R3groups are joined to form a bridging group are defined as L.

[0381] In some embodiments, two R3groups are joined to form a C1-3alkylene bridging group.

[0382] In some embodiments, two R3groups are joined to form a methylene bridging group. In some embodiments, two R3groups are joined to form an ethylene bridging group. In some embodiments, two R3groups are joined to form a propylene bridging group.

[0383] In some embodiments, two R3groups are joined to form a C1-3haloalkylene bridging group.

[0384] In some embodiments, two R3groups are joined to form a halomethylene bridging group. In some embodiments, two R3groups are joined to form a haloethylene bridging group. In some embodiments, two R3groups are joined to form a halopropylene bridging group.

[0385] As generally described herein, Ring C is a group of Formula (i-O) or (i-N):or a tautomer thereof.

[0386] In some embodiments, Ring C is a group of Formula (i-O):or tautomer thereof.

[0387] In some embodiments, Ring C is a group of Formula (i-N):or tautomer thereof.

[0388] In some embodiments, Ring B of formula:is a group of Formula (b-1-O):or tautomer thereof.

[0389] In some embodiments, Ring B is a group of Formula (b-1-i-O), (b-1-ii-O), (b-1-iii-O), or (b- 1-iv-O):or tautomer thereof. In some embodiments, Ring B is a group of Formula (b-1-i-O). In some embodiments, Ring B is a group of Formula (b-1-ii-O). In some embodiments, Ring B is a group of Formula (b-1-iii-O). In some embodiments, Ring B is a group of Formula (b-1-iv-O).

[0390] In some embodiments, Ring B is a group of Formula (b-1-i-O), (b-1-ii-O), (b-1-iii-O), or (b- 1-iv-O), or tautomer thereof, wherein R2aand R2bis C1-6alkyl, e.g., -CH3.

[0391] In some embodiments, Ring B is a group of Formula (b-1-ii-O) or (b-1-iii-O), or tautomer thereof, wherein R2aand R2bis C1-6alkyl, e.g., -CH3.

[0392] In some embodiments, Ring B is of Formula (b-1-i-O), (b-1-ii-O), (b-1-iii-O), or (b-1-iv-O), or tautomer thereof, wherein two R3groups, together with the atoms to which they are attached, are joined to form a C1-3alkylene bridging group. In some embodiments, the bridging group is -CH2CH2-.

[0393] In some embodiments, Ring B is of Formula (b-1-ii-O) or (b-1-iii-O), or tautomer thereof, wherein two R3groups, together with the atoms to which they are attached, are joined to form a C1-3alkylene bridging group. In some embodiments, the bridging group is -CH2CH2-.

[0394] In some embodiments, Ring B is a group of Formula (b-1-BR-O): or tautomer thereof, wherein L isa C1-3alkylene bridging group. In some embodiments, L is - CH2CH2-.

[0395] In some embodiments, Ring B is a group of Formula (b-1-BR-i-O), (b-1-BR-ii-O), (b-1-BR- iii-O), or (b-1-BR-iv-O):or tautomer thereof, wherein L is a C1-3alkylene bridging group. In some embodiments, L is - CH2CH2-.

[0396] In some embodiments, Ring B is a group of Formula (b-1-BR-i-O), (b-1-BR-ii-O), (b-1-BR- iii-O), or (b-1-BR-iv-O), or tautomer thereof, wherein R2aand R2bis C1-6alkyl, e.g., -CH3.

[0397] In some embodiments, Ring B is a group of Formula (b-1-BR-i-O) or (b-1-BR-iv-O), or tautomer thereof, wherein R2aand R2bis C1-6alkyl, e.g., -CH3

[0398] In some embodiments, Ring B of formula:is a group of Formula (b-1-N):or tautomer thereof.

[0399] In some embodiments, Ring B is a group of Formula (b-1-i-N), (b-1-ii-N), (b-1-iii-N), or (b- 1-iv-N): or tautomer thereof.

[0400] In some embodiments, Ring B is a group of Formula (b-1-i-N), (b-1-ii-N), (b-1-iii-N), or (b- 1-iv-N), or tautomer thereof, wherein R2aand R2bis C1-6alkyl, e.g., -CH3.

[0401] In some embodiments, Ring B is of Formula (b-1-i-N), (b-1-ii-N), (b-1-iii-N), or (b-1-iv-N), or tautomer thereof, wherein two R3groups, together with the atoms to which they are attached, are joined to form a C1-3alkylene bridging group. In some embodiments, the bridging group is -CH2CH2-.

[0402] In some embodiments, Ring B is of Formula (b-1-ii-N) or (b-1-iii-N), or tautomer thereof, wherein two R3groups, together with the atoms to which they are attached, are joined to form a C1-3alkylene bridging group. In some embodiments, the bridging group is -CH2CH2-.

[0403] In some embodiments, Ring B is a group of Formula (b-1-BR-N): or tautomer thereof, wherein L isa C1-3alkylene bridging group. In some embodiments, L is - CH2CH2-.

[0404] In some embodiments, Ring B is a group of Formula (b-1-BR-i-N), (b-1-BR-ii-N), (b-1-BR- iii-N), or (b-1-BR-iv-N): or tautomerthereof, wherein L is a C1-3alkylene bridging group. In some embodiments, L is - CH2CH2-.

[0405] In some embodiments, Ring B is a group of Formula (b-1-BR-i-N), (b-1-BR-ii-N), (b-1-BR- iii-N), or (b-1-BR-iv-N), or tautomer thereof, wherein R2aand R2bis C1-6alkyl, e.g., -CH3.

[0406] In some embodiments, Ring B is a group of Formula (b-1-BR-i-N) or (b-1-BR-iv-N), or tautomer thereof, wherein R2aand R2bis C1-6alkyl, e.g., -CH3. (c) Subgenera

[0407] It is understood that, for a compound of the present disclosure, variables L, Ring A, G1, G2, G3, G4, R1, RG1, RG2, RG3, RG4, RG5, RG6, RG7, Ring B, n, p, m, R3, Ring C, R4, R2a, and R2bcan each be, where applicable, selected from the groups described herein, and any group described herein for any of variables L, Ring A, G1, G2, G3, G4, R1, RG1, RG2, RG3, RG4, RG5, RG6, RG7, Ring B, n, p, m, R3, Ring C, R4, R2a, and R2bcan be combined, where applicable, with any group described herein for one or more of the remainder of variables L, Ring A, G1, G2, G3, G4, R1, RG1, RG2, RG3, RG4, RG5, RG6, RG7, Ring B, n, p, m, R3, Ring C, R4, R2a, and R2b. Additional exemplary combinations of the above described embodiments are further contemplated herein.

[0408] For example, in some embodiments of Formula (I) or (II), or subgenera thereof, as described above and herein, (i) G1is CRG1, G2is CH, G3is CH, and G4is CRG4; (ii) G1is CRG1, G2is CH, G3is CH, and G4is CRG4, RG1is hydrogen or halo, RG4is hydrogen or halo, and R1is C1-3alkyl, C1-3haloalkyl, or -ORG5, wherein RG5is C1-3alkyl or C1-3haloalkyl; (iii) RG1is hydrogen or fluoro; (iv) RG4is hydrogen or fluoro; (v) R1is -CF3, -OCF2H, -OCF3, -OCH3, or -CF2H; (vi) n is 0 and p is 1; (viii) n is 0, p is 1, and R2aor R2bis C1-6alkyl, e.g., -CH3; (ix) n is 0, p is 1, and two R3groups, together with the atoms to which they are attached, join to form a C1-3alkylene, e.g., ethylene (-CH2-CH2-) bridge; (x) n is 0, p is 1, R2aor R2bis -CH3, and two R3groups, together with the atoms to which they are attached, join to form an ethylene (-CH2-CH2-) bridge; and / or (xi) R4is - C1-3alkyl, e.g., -CH3or - CH2CH3.

[0409] In some embodiments, provided is a compound of Formula (I-i-O-Bridge-a) or (I-i-O- Bridge-h): or a pharmaceutically acceptable salt or tautomer thereof. In some embodiments, G1is CRG1, G2is CH, G3is CH, and G4is CRG4. In some embodiments, G1is CRG1, G2is CH, G3is CH, and G4is CRG4, RG1is hydrogen or halo, RG4is hydrogen or halo, and R1is C1-3alkyl, C1-3haloalkyl, or -ORG5, wherein RG5is C1-3alkyl or C1-3haloalkyl. In some embodiments, RG1is hydrogen or fluoro. In some embodiments, RG4is hydrogen or fluoro. In some embodiments, R1is -CF3, -OCF2H, -OCF3, -OCH3, or -CF2H. In some embodiments, n is 0 and p is 1. In some embodiments, n is 0, p is 1, and R2aor R2bis C1-6alkyl, e.g., -CH3. In some embodiments, n is 0, p is 1, and two R3groups, together with the atoms to which they are attached, join to form a C1-3alkylene, e.g., ethylene (-CH2-CH2-) bridge. In some embodiments, n is 0, p is 1, R2aor R2bis -CH3, and two R3groups, together with the atoms to which they are attached, join to form an ethylene (-CH2-CH2-) bridge. In some embodiments, the compound is of Formula (I-i-O-Bridge-a) or a pharmaceutically acceptable salt or tautomer thereof.

[0410] In some embodiments, provided is a compound of Formula (I-i-N-Bridge-a) or (I-i-N- Bridge-h): or a pharmaceutically acceptable salt or tautomer thereof. In some embodiments, G1is CRG1, G2is CH, G3is CH, and G4is CRG4. In some embodiments, G1is CRG1, G2is CH, G3is CH, and G4is CRG4, RG1is hydrogen or halo, RG4is hydrogen or halo, and R1is C1-3alkyl, C1-3haloalkyl, or -ORG5, wherein RG5is C1-3alkyl or C1-3haloalkyl. In some embodiments, RG1is hydrogen or fluoro. In some embodiments, RG4is hydrogen or fluoro. In some embodiments, R1is -CF3, -OCF2H, -OCF3, -OCH3, or -CF2H. In some embodiments, n is 0 and p is 1. In some embodiments, n is 0, p is 1, and R2aor R2bis C1-6alkyl, e.g., -CH3. In some embodiments, n is 0, p is 1, and two R3groups, together with the atoms to which they are attached, join to form a C1-3alkylene, e.g., ethylene (-CH2-CH2-) bridge. In some embodiments, n is 0, p is 1, R2aor R2bis -CH3, and two R3groups, together with the atoms to which they are attached, join to form an ethylene (-CH2-CH2-) bridge. In some embodiments, the compound is of Formula (I-i-N-Bridge-a) or a pharmaceutically acceptable salt or tautomer thereof.

[0411] In some embodiments, provided is a compound of Formula (II-i-O-Bridge-a) or (II-i-O- Bridge-h):or apharmaceutically acceptable salt or tautomer thereof. In some embodiments, G1is CRG1, G2is CH, G3is CH, and G4is CRG4. In some embodiments, G1is CRG1, G2is CH, G3is CH, and G4is CRG4, RG1is hydrogen or halo, RG4is hydrogen or halo, and R1is C1-3alkyl, C1-3haloalkyl, or -ORG5, wherein RG5is C1-3alkyl or C1-3haloalkyl. In some embodiments, RG1is hydrogen or fluoro. In some embodiments, RG4is hydrogen or fluoro. In some embodiments, R1is -CF3, -OCF2H, -OCF3, -OCH3, or -CF2H. In some embodiments, n is 0 and p is 1. In some embodiments, n is 0, p is 1, and R2aor R2bis C1-6alkyl, e.g., -CH3. In some embodiments, n is 0, p is 1, and two R3groups, together with the atoms to which they are attached, join to form a C1-3alkylene, e.g., ethylene (-CH2-CH2-) bridge. In some embodiments, n is 0, p is 1, R2aor R2bis -CH3, and two R3groups, together with the atoms to which they are attached, join to form an ethylene (-CH2-CH2-) bridge. In some embodiments, R4is - C1-3alkyl, e.g., -CH3or -CH2CH3. In some embodiments, R4is -CH3. In some embodiments, the compound is of Formula (II-i-O-Bridge-a) or a pharmaceutically acceptable salt or tautomer thereof.

[0412] In some embodiments, provided is a compound of Formula (II-i-N-Bridge-a) or (II-i-N- Bridge-h):or a pharmaceutically acceptable salt or tautomer thereof. In some embodiments, G1is CRG1, G2is CH, G3is CH, and G4is CRG4. In some embodiments, G1is CRG1, G2is CH, G3is CH, and G4is CRG4, RG1is hydrogen or halo, RG4is hydrogen or halo, and R1is C1-3alkyl, C1-3haloalkyl, or -ORG5, wherein RG5is C1-3alkyl or C1-3haloalkyl. In some embodiments, RG1is hydrogen or fluoro. In some embodiments, RG4is hydrogen or fluoro. In some embodiments, R1is -CF3, -OCF2H, -OCF3, -OCH3, or -CF2H. In some embodiments, n is 0 and p is 1. In some embodiments, n is 0, p is 1, and R2aor R2bis C1-6alkyl, e.g., -CH3. In some embodiments, n is 0, p is 1, and two R3groups, together with the atoms to which they are attached, join to form a C1-3alkylene, e.g., ethylene (-CH2-CH2-) bridge. In some embodiments, n is 0, p is 1, R2aor R2bis -CH3, and two R3groups, together with the atoms to which they are attached, join to form an ethylene (-CH2-CH2-) bridge. In some embodiments, R4is - C1-3alkyl, e.g., -CH3or -CH2CH3. In some embodiments, R4is -CH3. In some embodiments, the compound is of Formula (II-i-N-Bridge-a) or a pharmaceutically acceptable salt or tautomer thereof.

[0413] In some embodiments, the compound of Formula (I) is selected from any one of the compounds of Table 1 or a pharmaceutically acceptable salt or tautomer thereof. In some embodiments, the compound of Formula (I) is a pharmaceutically acceptable salt of any one of the compounds of Table 1 or tautomer thereof. In some embodiments, the compound of Formula (I) is a free base selected from any one of the compounds of Table 1 or tautomer thereof.

[0414] In some embodiments, the compound of Formula (II) is selected from any one of the compounds of Table 2 or a pharmaceutically acceptable salt or tautomer thereof. In some embodiments, the compound of Formula (II) is a pharmaceutically acceptable salt of any one of the compounds of Table 2 or tautomer thereof. In some embodiments, the compound of Formula (II) is a free base selected from any one of the compounds of Table 2 or tautomer thereof.

[0415] The below Tables 1 and 2 also provides the location of the compound in the Examples (Ex) by Example Number (Ex) or as provided in Table B (TA) of the Examples. The Asterix (*) next to the Compound Number (#) signifies that arbitrary stereochemistry has been assigned.(ii) Pharmaceutical Compositions

[0416] Pharmaceutical compositions comprising a compound of Formula (I) or (II), or a pharmaceutically acceptable salt or tautomer thereof, and one or more pharmaceutically acceptable carriers, are further contemplated herein.

[0417] For example, in some aspects, provided is a pharmaceutical composition comprising a compound of Formula (I) or (II), or a pharmaceutically acceptable salt or tautomer thereof, and one ormore pharmaceutically acceptable carriers.

[0418] Exemplary pharmaceutical acceptable carriers may include diluents, e.g., purified water, triglyceride oils, such as hydrogenated or partially hydrogenated vegetable oil, or mixtures thereof, com oil, olive oil, sunflower oil, safflower oil, fish oils, such as EPA or DHA, or their esters or triglycerides or mixtures thereof, omega-3 fatty acids or derivatives thereof, lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, sodium, saccharin, glucose and / or glycine.

[0419] Administration to the subject can be accomplished via any mode of administration, for example, by oral administration, topical administration, or by injection. Depending on the intended mode of administration, the pharmaceutical composition comprising the compound of Formula (I) or (II), or a pharmaceutically acceptable salt or tautomer thereof, can be in solid, semi-solid or liquid dosage form.

[0420] A compound of Formula (I) or (II), or a pharmaceutically acceptable salt or tautomer thereof, may be administered alone in the pharmaceutical composition as the sole therapeutic agent, or may be administered in combination with another therapeutic agent. Combination treatment may be achieved by way of co-administration (e.g., the two agents being administered at the same time) or sequential administration (e.g., one agent being administered first, then the other). In the case of coadministration, the compound of Formula (I) or (II), or a pharmaceutically acceptable salt or tautomer thereof, may be administered in the same pharmaceutical composition as the other therapeutic agent, or may be administered in a separate pharmaceutical composition. The choice of the other therapeutic agent will depend upon the diagnosis of the attending physicians and their judgment of the condition of the subject and the appropriate treatment protocol.(iii) Methods of Treatment and Prevention

[0421] Compounds of Formula (I) or (II), and pharmaceutically acceptable salts and tautomers thereof, have been found useful as inhibitors of NLRP3 activity.

[0422] In some aspects, provided is a method of treating or preventing a disease or disorder in a subject in need thereof, comprising administering to the subject a compound of Formula (I) or (II), or a pharmaceutically acceptable salt or tautomer thereof, or a pharmaceutical composition comprising same. In some embodiments, provided is a method of treating a disease or disorder in a subject in need thereof, comprising administering to the subject a compound of Formula (I) or (II), or a pharmaceutically acceptable salt or tautomer thereof, or a pharmaceutical composition comprising same. In some aspects, provided is a method of treating or preventing a disease or disorder in a subject in need thereof, comprising administering to the subject an effective amount of a compound of Formula (I) or (II), or a pharmaceutically acceptable salt or tautomer thereof, or a pharmaceutical composition comprising same. In some embodiments, provided is a method of treating disease or disorder in a subject in need thereof, comprising administering to the subject an effective amount of a compound of Formula (I) or (II), or a pharmaceutically acceptable salt or tautomer thereof, or apharmaceutical composition comprising same. In some embodiments, the disease or disorder is associated with aberrant NLRP3 activity, and the method comprises inhibiting the aberrant NLRP3 activity such that the subject is treated.

[0423] In some embodiments, the disease or disorder is a disease or disorder of the central nervous system (CNS), a disease or disorder of the peripheral nervous system (PNS), a primary neurological disease of the muscles, an inflammatory disorder, an autoimmune disorder, cancer, an infection, obesity, a metabolic disease, a cardiovascular disease, a respiratory disease, a kidney disease, a liver disease, an ocular disease, a skin disease, a lymphatic disease, a rheumatic disease, a psychological disease, graft versus host disease, pain (including disorders related to pain management), an NLRP3- related disease in a subject that has been determined to carry a germline or somatic non-silent mutation in NLRP3, or obesity.

[0424] In some embodiments, the disease or disorder is a disease or disorder of central nervous system and / or peripheral nervous system (“PNS”), such as dementia, Alzheimer’s disease (“AD”) epilepsy, traumatic brain injury (“TBI”), multiple sclerosis (“MS”), a developmental disturbance, acute disseminated encephalopathy, transverse myelitis, Parkinson’s disease (“PD”), amyotrophic lateral sclerosis (“ALS”), Huntington’s disease (“HD”), spinal cord injury, or obesity related to neuroinflammation .

[0425] In some embodiments, the disease or disorder is a primary neurological disease of the muscle, such as a dystrophy or spinal muscular atrophy.

[0426] In some embodiments, the disease or disorder is a primary neurological disease of the muscle, such as a dystrophy or atrophy. In some embodiments, the atrophy is spinal muscular atrophy.

[0427] In some embodiments, the disease or disorder is an inflammatory disorder, such as gout or anemia of inflammation.

[0428] In some embodiments, the disease or disorder is an autoimmune disease, such as ulcerative colitis.

[0429] In some embodiments, the disease or disorder is cancer, such as skin cancer or colon cancer.

[0430] In some embodiments, the disease or disorder is an infection, such as a neuro-infection.

[0431] In some embodiments, the disease or disorder is a metabolic disease, such as diabetes, e.g., type 2 diabetes.

[0432] In some embodiments, the disease or disorder is obesity. In some embodiments, the obesity is related to neuroinflammation, e.g., hypothalamic inflammation and / or gliosis. In some embodiments, the obesity is related to a metabolic disorder.

[0433] In some embodiments, the disease or disorder is a cardiovascular disease, such as stroke, atherosclerosis or atherosclerotic cardiovascular disease (ASCVD).

[0434] In some embodiments, the disease or disorder is a respiratory disease, such as asthma (e.g., steroid-resistant asthma, severe steroid-resistant asthma) or chronic obstructive pulmonary disease (“COPD”).

[0435] In some embodiments, the disease or disorder is a kidney disease, such as acute kidney disease, a chronic kidney disease, or a rare kidney disease. In some embodiments, the chronic kidney disease is chronic kidney failure.

[0436] In some embodiments, the disease or disorder is a liver disease, such as nonalcoholic fatty liver disease (NAFLD) or non-alcoholic steatohepatitis (NASH, also known as MASH or metabolic dysfunction-associated steatohepatitis) .

[0437] In some embodiments, the disease or disorder is an ocular disease, such as optic neuritis or macular degeneration.

[0438] In some embodiments, the disease or disorder is a skin disease, such as psoriasis, hidradenitis suppurativa (HS), or atopic dermatitis.

[0439] In some embodiments, the disease or disorder is a lymphatic disease.

[0440] In some embodiments, the disease or disorder is a rheumatic disease, such as osteoarthritis, dermatomyositis, Still’s disease, or juvenile idiopathic arthritis.

[0441] In some embodiments, the disease or disorder is a psychological disease, such as a neuropsychiatric condition, including depression, major depressive disorder, or refractory depression.

[0442] In some embodiments, the disease or disorder is a graft versus host disease.

[0443] In some embodiments, the disease or disorder is pain (including disorders related to pain management), such as headache pain, pain management addiction, osteoarthritis pain, or allodynia.

[0444] In some embodiments, the NLRP3 -related disease in a subject that has been determined to carry a germline or somatic non-silent mutation in NLRP3 is cryopyrin-associated autoinflammatory syndrome. In some embodiments, the cryopyrin-associated autoinflammatory syndrome is familial cold autoinflammatory syndrome, Muckle-Wells syndrome, or neonatal onset multisystem inflammatory disease (NOMID).

[0445] In some embodiments, the disease or disorder is dementia, Alzheimer’s disease (“AD”), epilepsy, traumatic brain injury (“TBI”), multiple sclerosis (“MS”), developmental disturbances, acute disseminated encephalopathy, transverse myelitis, Parkinson’s disease (“PD”), amyotrophic lateral sclerosis (“ALS”), spinal muscular atrophy, Huntington’s disease (“HD”), a spinal cord injury, a dystrophy, a neuro-infection, pain (e.g., headache pain, osteoarthritis pain, or allodynia, a pain management addiction), a neuropsychiatric condition (e.g. depression, major depressive disorder, refractory depression), neonatal onset multisystem inflammatory disease (“NOMID”), asthma, osteoarthritis, ulcerative colitis, gout, anemia of inflammation, Still’s disease, chronic obstructive pulmonary disease (“COPD”), osteoarthritis pain, hidradenitis suppurativa, or obesity.

[0446] In other aspects, provided is a method of modulating (e.g., inhibiting) NLRP3 activity (e.g., in vitro or in vivo in a cell, or in a subject), comprising contacting the cell with or administering to the subject a compound of Formula (I) or (II), or a pharmaceutically acceptable salt or tautomer thereof. In some embodiments, the compound or a pharmaceutically acceptable salt or tautomer thereof is administered to the cell or subject in an effective amount.(iv) Methods of Preparation

[0447] Compounds of Formula (I) or (II), and salts and tautomers thereof, may be synthesized following General Schemes A-C, as provided below. The Examples further described non-limiting examples of this general syntheses.

[0448] For example, as depicted in General Scheme A, Step 1, treating a compound of Formula (A), or salt thereof, with hydroxylamine under acidic conditions provides a compound of Formula (B-N), or salt thereof, or with hydroxylamine under neutral or basic conditions provides a compound of Formula (B-O), or salt thereof, wherein PG1is an amino protecting group. As depicted in General Scheme A, Step 2, treating the compound of Formula (B-N) or (B-O), or salt thereof, with phosgene or phosgene equivalent (e.g., diphosgene, triphosgene or carbodiimidazole (CDI)) provides a compound of Formula (C-N) or (C-O), or salt thereof. As depicted in General Scheme A, Step 3, deprotecting the compound of Formula (B-N) or (B-O), or salt thereof, provides a compound (D-N) or (D-O), or salt thereof (collectively referred to as a compound of Formula (D), or salt thereof). General Scheme A

[0449] As depicted in General Scheme B, Step 4, coupling the compound of Formula (D), or salt thereof, with a compound of Formula (E), or salt thereof, wherein R′ is hydrogen, C1-6alkyl, C1-6haloalkyl, or an oxygen protecting group, provide a compound of Formula (I), or salt thereof.General Scheme B

[0450] Likewise, as depicted in General Scheme C, Step 5, coupling the compound of Formula (D), or salt thereof, with a compound of Formula (F), or salt thereof, wherein R′′ is hydrogen, C1-6alkyl, C1-6haloalkyl, or an oxygen protecting group, provide a compound of Formula (II), or salt thereof. General Scheme C(v) Biological Assays

[0451] Various in vitro or in vivo biological assays may be suitable for detecting the effect of the compounds of the present disclosure. These in vitro or in vivo biological assays can include, but are not limited to, binding assays, cellular assays (cell lines, primary cells and whole blood), in vitro cell viability assays, as well as assays for determining NLRP3 potency, unbound clearance, and solubility.

[0452] In some embodiments, the compounds of the instant disclosure may be tested for their human- NLRP3 inhibitory activity using known procedures, such as the methodology reported in Coll et al. Nat Med. (2015) 21(3):248-255. See also the Examples, Assay Methods section.

[0453] In some embodiments, the compounds of the instant disclosure may be tested for unbound clearance (Clu) following known procedures, such as described in Miller et al., J. Med. Chem. (2020) 63:12156-12170. For example, unbound clearance (Clu) may be calculated by dividing total clearance (‘CL’ in mL / min / kg) as measured in blood or plasma by the unbound fraction in plasma (fu).

[0454] In some embodiments, the solubility of compounds of the instant disclosure may be determined following known procedures, such as described in Alsenz and Kansy, Advanced Drug Delivery Reviews (2007) 59:546-567, and Wang et al. J Mass Spectrom. (2000) 35:71-76. For example, the kinetic solubility in physiologically relevant media may be measured using serial dilution and two hour incubation period, followed by filtration, and reported in uM by LC-MS / MS. Thermodynamic solubility in physiologically relevant media may be measured by LC-MS / MS, after a twenty-four hour incubation, followed by filtration, and reported in mg / mL. EXEMPLARY EMBODIMENTS

[0455] Exemplary Embodiment No.1. A compound of Formula (I) or (II): or a pharmaceuticallyacceptable salt or tautomer thereof, wherein: Ring A is a ring system wherein: G1is CRG1or N; G2is CRG2or N; G3is CRG3or N; and G4is CRG4or N; provided no more than two of G1, G2, G3, and G4are N; R1is halo, C1-6alkyl, C1-6haloalkyl, -ORG5, -SRG5, -N(RG5)2, C3-4carbocyclyl, or 3-4 membered heterocyclyl, wherein the carbocyclyl and heterocyclyl are independently substituted with 0, 1, 2, or 3 halo, C1-6alkyl, C1-6haloalkyl, -ORG5, -SRG5, or -N(RG5)2; or R1and G2, together with the atoms to which they are attached, are joined to form a 5- membered heteroaryl ring independently substituted with 0, 1, 2, or 3 RG7; RG1, RG2, RG3, and RG4are each independently selected from the group consisting of hydrogen, halo, C1-6alkyl, C1-6haloalkyl, and -ORG6; RG5and RG6are each independently hydrogen, C1-6alkyl, or C1-6haloalkyl; and each instance of RG7is independently halo, C1-6alkyl, C1-6haloalkyl, -ORG5, -SRG5, or -N(RG5)2; Ring B is a ring system wherein: n is 0 or 1; p is 1 or 2;m is 0, 1, 2, or 3; R2aand R2bare each independently hydrogen, halo, C1-6alkyl, C1-6haloalkyl, C3-4carbocyclyl, or 3-4 membered heterocyclyl, wherein the carbocyclyl or heterocyclyl are each independently substituted with 0, 1, 2, or 3 halo, or R2aand R2bare joined to form a C3carbocyclyl independently substituted with 0, 1, 2, or 3 halo; and each instance of R3is independently halo, C1-6alkyl or C1-6haloalkyl, or two R3groups are joined to form a C1-3alkylene bridging group or C1-3haloalkylene bridging group; R4is hydrogen, C1-3alkyl, C3-4carbocyclyl, or C3-4carbocyclyl-C1-3alkyl-, wherein the alkyl and carbocyclyl are each independently substituted with 0, 1, 2, 3, 4, 5, or 6 halo, and wherein the carbocyclyl is further independently substituted with 0, 1, or 2 C1-3alkyl or C1-3haloalkyl; and Ring C is an oxadiazolone of Formula (i-O) or (i-N):

[0456] Exemplary Embodiment No.2. The compound of Exemplary Embodiment No.1, wherein the compound is of Formula (II-i-O) or (II-i-N): or a pharmaceutically acceptable salt or tautomer thereof.

[0457] Exemplary Embodiment No.3. The compound of Exemplary Embodiment No.1 or Exemplary Embodiment No.2, wherein the compound is of Formula (II-i-O′-b), (II-i-O′′-a), (II-i- N′-b), or (II-i-N′′-a):or a pharmaceutically acceptable salt or tautomer thereof.

[0458] Exemplary Embodiment No.4. The compound of Exemplary Embodiment No.1 or Exemplary Embodiment No.2, wherein the compound is of Formula (II-i-O-Bridge) or (II-i-N- Bridge): or a pharmaceutically acceptable salt or tautomer thereof, wherein L is a C1-3alkylene bridging group.

[0459] Exemplary Embodiment No.5. The compound of any one of Exemplary Embodiment Nos. 1-2 or 4, wherein the compound is of Formula (II-i-N-Bridge-a) or (II-i-N-Bridge-h): or a pharmaceutically acceptable salt or tautomer thereof.

[0460] Exemplary Embodiment No.6. The compound of Exemplary Embodiment No.1, wherein the compound is of Formula (I-i-O) or (I-i-N): or a pharmaceuticallyacceptable salt or tautomer thereof.

[0461] Exemplary Embodiment No.7. The compound of Exemplary Embodiment No.1 or Exemplary Embodiment No.6, wherein the compound is of Formula (I-i-O′-b), (I-i-O′′-a), (I-i-N′- b), or (I-i-N′′-a):or a pharmaceutically acceptable salt or tautomer thereof.

[0462] Exemplary Embodiment No.8. The compound of Exemplary Embodiment No.1 or Exemplary Embodiment No.6, wherein the compound is of Formula (I-i-O-Bridge) or (I-i-N- Bridge): or a pharmaceutically acceptable salt or tautomer thereof, wherein L is a C1-3alkylene bridging group.

[0463] Exemplary Embodiment No.9. The compound of any one of Exemplary Embodiment Nos. 1, 6, or 8, wherein the compound is of Formula (I-i-O-Bridge-a) or (I-i-O-Bridge-h): or a pharmaceutically acceptable salt or tautomer thereof.

[0464] Exemplary Embodiment No.10. The compound of any one of Exemplary Embodiment Nos. 1-5, or a pharmaceutically acceptable salt or tautomer thereof, wherein R4is C1-3alkyl.

[0465] Exemplary Embodiment No.11. The compound of Exemplary Embodiment No.10, or a pharmaceutically acceptable salt or tautomer thereof, wherein R4is -CH3or -CH2CH3.

[0466] Exemplary Embodiment No.12. The compound of any one of Exemplary Embodiment Nos. 1-11, or a pharmaceutically acceptable salt or tautomer thereof, wherein G1is CRG1, G2is CH, G3is CH, and G4is CRG4.

[0467] Exemplary Embodiment No.13. The compound of any one of Exemplary Embodiment Nos. 1-12, or a pharmaceutically acceptable salt or tautomer thereof, wherein RG1is hydrogen or halo.

[0468] Exemplary Embodiment No.14. The compound of Exemplary Embodiment No.13, or a pharmaceutically acceptable salt or tautomer thereof, wherein RG1is hydrogen or fluoro.

[0469] Exemplary Embodiment No.15. The compound of any one of Exemplary Embodiment Nos. 1-14, or a pharmaceutically acceptable salt or tautomer thereof, wherein RG4is hydrogen or halo.

[0470] Exemplary Embodiment No.16. The compound of Exemplary Embodiment No.15, or a pharmaceutically acceptable salt or tautomer thereof, wherein RG4is hydrogen or fluoro.

[0471] Exemplary Embodiment No.17. The compound of any one of Exemplary Embodiment Nos. 1-16, or a pharmaceutically acceptable salt or tautomer thereof, wherein R1is C1-3alkyl, C1-3haloalkyl, or -ORG5.

[0472] Exemplary Embodiment No.18. The compound of any one of Exemplary Embodiment Nos. 1-17, or a pharmaceutically acceptable salt or tautomer thereof, wherein RG5is C1-3alkyl or C1-3haloalkyl.

[0473] Exemplary Embodiment No.19. The compound of Exemplary Embodiment No.17, or a pharmaceutically acceptable salt or tautomer thereof, wherein R1is -CF3, -OCF2H, -OCF3, -OCH3, or -CF2H.

[0474] Exemplary Embodiment No.20. The compound of any one of Exemplary Embodiment Nos. 1-19, or a pharmaceutically acceptable salt or tautomer thereof, wherein n is 0 and p is 1.

[0475] Exemplary Embodiment No.21. The compound of any one of Exemplary Embodiment Nos. 1-20, or a pharmaceutically acceptable salt or tautomer thereof, wherein one of R2aand R2bis C1-6alkyl, and the other of R2aand R2bis H.

[0476] Exemplary Embodiment No.22. The compound of Exemplary Embodiment No.21, or a pharmaceutically acceptable salt or tautomer thereof, wherein one of R2aand R2bis -CH3, and the other of R2aand R2bis H.

[0477] Exemplary Embodiment No.23. The compound of any one of Exemplary Embodiment Nos. 1-22, or a pharmaceutically acceptable salt or tautomer thereof, wherein Ring A is a group of formula:

[0478] Exemplary Embodiment No.24. The compound of Exemplary Embodiment No.23, or apharmaceutically acceptable salt or tautomer thereof wherein Ring A is a group of formula:

[0479] Exemplary Embodiment No. 25. The compound of Exemplary Embodiment Nos. 1-24, wherein the compound is selected from the compounds described in Table 1 and Table 2, or a pharmaceutically acceptable salt or tautomer thereof.

[0480] Exemplary Embodiment No. 26. A pharmaceutical composition comprising the compound of any one of Exemplary Embodiment Nos. 1-25, or a pharmaceutically acceptable salt or tautomer thereof, and one or more pharmaceutically acceptable carriers.

[0481] Exemplary Embodiment No. 27. A method of inhibiting NLRP3, the method comprising administering to the subject the compound of any one of Exemplary Embodiment Nos. 1-25, or a pharmaceutically acceptable salt or tautomer thereof, or the pharmaceutical composition of Exemplary Embodiment No. 26.

[0482] Exemplary Embodiment No. 28. A method of treating or preventing a disease or disorder, the method comprising administering to the subject the compound of any one of Exemplary Embodiment Nos. 1-25, or a pharmaceutically acceptable salt or tautomer thereof, or the pharmaceutical composition of Exemplary Embodiment No. 26.

[0483] Exemplary Embodiment No. 29. The compound of any one of Exemplary Embodiment Nos. 1-25, or a pharmaceutically acceptable salt or tautomer thereof, or the pharmaceutical composition of Exemplary Embodiment No. 26, for use in treating or preventing a disease or disorder.

[0484] Exemplary Embodiment No. 30. Use of the compound of any one of Exemplary Embodiment Nos. 1-25, or a pharmaceutically acceptable salt or tautomer thereof, in the manufacture of a medicament, for the treatment or prevention of a disease or disorder.

[0485] Exemplary Embodiment No. 31. Use of the compound of any one of Exemplary Embodiment Nos. 1-25, or a pharmaceutically acceptable salt or tautomer thereof, for the treatment or prevention of a disease or disorder.

[0486] Exemplary Embodiment No. 32. The method, compound, or use of any one of Exemplary Embodiment Nos. 28-31, wherein the disease or disorder is a disease or disorder of the central nervous system (CNS), a disease or disorder of the peripheral nervous system (PNS), a primary neurological disease of the muscles, an inflammatory disorder, an autoimmune disorder, cancer, an infection, obesity, a metabolic disease, a cardiovascular disease, a respiratory disease, a kidney disease, a liver disease, an ocular disease, a skin disease, a lymphatic disease, a rheumatic disease, a psychological disease, graft versus host disease, pain (including disorders related to pain management), an NLRP3-related disease in a subject that has been determined to carry a germline orsomatic non-silent mutation in NLRP3, or obesity.

[0487] Exemplary Embodiment No.33. A process for preparing the compound of Formula (I) or (II) of any one of Exemplary Embodiment Nos.1-25, or a pharmaceutically acceptable salt or tautomer thereof, wherein the compound is synthesized according to General Schemes A-C. EXEMPLIFICATION

[0488] In order that this disclosure may be more fully understood, the following Examples are set forth. It should be understood that these examples are for illustrative purposes only and are not to be construed as limiting this disclosure in any manner. Analytical Methods

[0489] Nuclear magnetic resonance (NMR) spectra were recorded at 400 MHz as stated and at 300.3 K unless otherwise stated; the chemical shifts (δ) are reported in parts per million (ppm). Spectra were recorded using a Bruker Avance 400 instrument with 8, 16 or 32 scans. Typical NMR solvents include deuterated dimethylsulfoxide (DMSO-d6) and deuterated methanol (CD3OD).

[0490] Gas Chromatography - Mass Spectrometry (GCMS) chromatograms and spectra were recorded using Agilent GCMS 8890-5977 and Detector Channel FID. GC Parameters: DB-5MS, 12m x 0.20mm x 0.33um; Column Oven Temp: 50.0; Injection volume: 0.5µL; Column Flow: 1.2ml / min; Injection temperature: 300°C; Injection Mode: Split; Split Ratio: 20:1; Detector temperature: 300°C; Initial temperature: 50°C for 1 min then 40°C / min to 300°C for 1.75 min. Makeup Gas: He; Makeup Flow: 25.0 mL / min; H2; Flow: 30.0 mL / min; Air Flow: 400.0 mL / min; Final temperature: 300°C. The MS detector of acquisition mode: Start Time: 2.00 min; End Time: 9.00 min; Acquisition Mode: Scan;Interface Type: EI Threshold: 150; Scan Speed: 1562; Start m / z: 50.00; End m / z: 550.00; MS Source: 230.00 °C; MS Quad: 150.00 °C; Solvent Cut Time: 2.00 min.

[0491] Liquid Chromatography - Mass Spectrometry (LCMS) chromatograms and spectra were recorded using a Shimadzu LCMS-2020. Injection volumes were 0.7 - 8.0 µl and the flow rates were typically 0.8 or 1.2 mL / min. Detection methods were diode array (DAD) or evaporative light scattering (ELSD) as well as positive ion electrospray ionization. MS range was 100 - 1000 Da. mobile phases of water and / or acetonitrile (MeCN) may contain a modifier (typically 0.01 - 0.04 %) such as trifluoroacetic acid (TFA), formic acid (FA), or ammonium carbonate. ESI or ES = electrospray ionization; m / z = mass / charge; RT = retention time (minutes).

[0492] Purification / Separation Methods. The Synthetic methods describe purification and / or separation chromatographic methods which have been employed in the purification and / or isolation of the exemplified compounds. RT = retention time (minutes); Prep-HPLC = Preparative High- performance liquid chromatography. Chiral SFC = chiral supercritical fluid chromatography.

[0493] Additional abbreviations used herein are provided in Table A below.Synthetic Methods

[0494] For purposes of the Examples, including the data provided in the Assay Methods section, “Rac-X” signifies a mixture of 2 or more stereoisomers in equal or unequal amounts. Compounds are numbered following the below numbering system.

[0495] If a stereochemical position is arbitrarily assigned, an Asterix (*) is included as part of the Compound number. Future tense (“may be” prepared / synthesized) language signify examples not yet conducted. Example 1. Synthesis of N-((1R,2R,4R,5S)-4-methyl-8-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)- 8-azabicyclo[3.2.1]octan-2-yl)-1-(4-(trifluoromethyl)phenyl)cyclopropane-1-carboxamide(Compound 1A*-O) and N-((1S,2S,4S,5R)-4-methyl-8-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)- 8-azabicyclo[3.2.1]octan-2-yl)-1-(4-(trifluoromethyl)phenyl)cyclopropane-1-carboxamide (Compound 1D*-O)

[0496] Step 1: To a solution of 3-hydroxypyridine (50.0 g, 526 mmol, 1 equiv) in isopropanol (500 mL) was added benzyl bromide (96.2 g, 562 mmol, 1.07 equiv) at room temperature. The reaction was stirred overnight at 80 °C, and the resulting mixture was concentrated under reduced pressure. The residue was triturated in EtOAc (200 mL), filtered, and dried under vacuum, to afford 1-benzyl-3- hydroxypyridin-1-ium bromide (135 g, 97% crude yield). LCMS: m / z [M+H]+= 186.1.

[0497] Step 2: To a stirred solution of 1-benzyl-3-hydroxypyridin-1-ium bromide (25.0 g, 93.9 mmol, 1 equiv), phenyl vinyl sulfone (21.0 g, 125 mmol, 1.33 equiv) and hydroquinone (207 mg, 1.88 mmol, 0.02 equiv) in THF (200 mL), was added triethylamine (14.2 g, 141 mmol, 1.50 equiv) dropwise at room temperature under N2atmosphere. The reaction was stirred overnight at 65 °C, quenched by the addition of water (300 mL) at room temperature, and extracted with EtOAc (3 x 200 mL). The organic phase was concentrated under reduced pressure, and the resulting solid residue was collected and washed with EtOAc (3 x 50 mL) to afford a mixture of assumed (1R,5R,6S)-8-benzyl-6- (phenylsulfonyl)-8-azabicyclo[3.2.1]oct-3-en-2-one and the corresponding enantiomer (20 g, 60% crude yield). LCMS: m / z [M+H]+= 354.1.

[0498] Step 3: To a stirred solution of assumed (1R,5R,6S)-8-benzyl-6-(phenylsulfonyl)-8- azabicyclo[3.2.1]oct-3-en-2-one and of the corresponding enantiomer (20 g, 56.6 mmol, 1 equiv) in 200 mL of THF, was added 0.5 M Me2CuLi in Et2O (170 mL, 84.8 mmol, 1.50 equiv) dropwise at - 78°C under N2atmosphere. The reaction was stirred for 1 hour at room temperature, quenched by the addition of water (500 mL) at 0 °C, and extracted with EtOAc (3 x 500 mL). The combined organic layers were washed with water (2 x 300 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to provide a mixture of assumed (1R,4R,5R,6S)-8-benzyl-4-methyl-6- (phenylsulfonyl)-8-azabicyclo[3.2.1]octan-2-one and the corresponding enantiomer (18.0 g, 86% crude yield). LCMS: m / z [M+H]+= 370.1.

[0499] Step 4: A mixture of assumed (1R,4R,5R,6S)-8-benzyl-4-methyl-6-(phenylsulfonyl)-8- azabicyclo[3.2.1]octan-2-one and the corresponding enantiomer (2.58 g, 6.98 mmol, 1 equiv), hydroxylamine hydrochloride (534 mg, 7.68 mmol, 1.10 equiv) and pyridine (1104 mg, 13.96 mmol, 2.00 equiv) in ethanol (26 mL), was stirred overnight at room temperature, and the reaction wasquenched by the addition of water (100 mL). The resulting mixture was extracted with EtOAc (3 x 100 mL), and the combined organic layers were washed with water (2 x 50 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to provide a mixture of assumed N- ((1R,4R,5R,6S)-6-(benzenesulfonyl)-8-benzyl-4-methyl-8-azabicyclo[3.2.1]octan-2- ylidene)hydroxylamine and the corresponding enantiomer (2.5 g, 93% crude yield). LCMS: m / z [M+H]+= 385.1.

[0500] Step 5: A solution of assumed N-((1R,4R,5R,6S)-6-(benzenesulfonyl)-8-benzyl-4-methyl-8- azabicyclo[3.2.1]octan-2-ylidene)hydroxylamine and the corresponding enantiomer (2.50 g, 6.50 mmol, 1 equiv) in DMF (50 mL) was treated with NaBH3CN (1.63 g, 26.0 mmol, 4 equiv) and NaHSO4(2.34 g, 19.5 mmol, 3.00 equiv) for 5 minutes at room temperature under N2atmosphere, followed by the addition of MoCl5(0.89 g, 3.25 mmol, 0.5 equiv) in portions. The reaction was stirred overnight, quenched by the addition of saturated aqueous NaHCO3(100 mL), and extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with water (2 x 50 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to provide a mixture of assumed (1R,2R,4R,5R,6S)-8-benzyl-4-methyl-6-(phenylsulfonyl)-8-azabicyclo[3.2.1]octan-2-amine and the corresponding enantiomer (1.80 g, 75% crude yield). LCMS: m / z [M+H]+= 371.1.

[0501] Step 6: A solution of a mixture of assumed (1R,2R,4R,5R,6S)-8-benzyl-4-methyl-6- (phenylsulfonyl)-8-azabicyclo[3.2.1]octan-2-amine and the corresponding enantiomer (1 g, 2.69 mmol, 1 equiv) and magnesium chips (treated with 0.5% HCl) (0.52 g, 22 mmol, 7.9 equiv) in methanol (15 mL) was stirred overnight at room temperature, followed by the addition of acetic acid (0.66 mL) and water (10 mL). The reaction was stirred for 1 hour, quenched by the addition of saturated aqueous NaOH (5 mL), and extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with water (3 x 10 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to provide a mixture of assumed (1R,2R,4R,5S)-8-benzyl-4-methyl-8- azabicyclo[3.2.1]octan-2-amine and the corresponding enantiomer (700 mg, 84% crude yield). LCMS: m / z [M+H]+= 231.1.

[0502] Step 7: To a solution of assumed (1R,2R,4R,5S)-8-benzyl-4-methyl-8-azabicyclo[3.2.1]octan- 2-amine and the corresponding enantiomer (700 mg, 3.03 mmol, 1.00 equiv) in methanol (3 mL), was added (Boc)2O (796 mg, 3.64 mmol, 1.20 equiv) at room temperature. The reaction was stirred for 2 hours, and the resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with 15% of EtOAc in petroleum ether, to afford a mixture of assumed tert-butyl ((1R,2R,4R,5S)-8-benzyl-4-methyl-8-azabicyclo[3.2.1]octan-2- yl)carbamate and the corresponding enantiomer (800 mg, 80% yield). LCMS: m / z [M+H]+= 331.1.

[0503] Step 8: To a stirred solution of a mixture of assumed tert-butyl ((1R,2R,4R,5S)-8-benzyl-4- methyl-8-azabicyclo[3.2.1]octan-2-yl)carbamate and the corresponding enantiomer (4.30 g, 13.0 mmol, 1 equiv) in isopropanol (50 mL) was added wet 10% Pd / C (2.76 g, 26.0 mmol, 2 equiv) at room temperature, and the reaction was stirred for 16 hours under H2atmosphere. The resultingmixture was filtered, washed with methanol (3 x 50 mL), and the filtrate was concentrated under reduced pressure to afford a mixture of assumed tert-butyl ((1R,2R,4R,5S)-4-methyl-8- azabicyclo[3.2.1]octan-2-yl)carbamate and the corresponding enantiomer (2.7 g, 86% crude yield). LCMS: m / z [M+H]+= 241.2.

[0504] Step 9: To a stirred solution of a mixture of assumed tert-butyl ((1R,2R,4R,5S)-4-methyl-8- azabicyclo[3.2.1]octan-2-yl)carbamate and the corresponding enantiomer (2.70 g, 11.2 mmol, 1 equiv) and K2CO3(4.69 g, 33.7 mmol, 3.00 equiv) in acetonitrile (30 mL), was added BrCN (4.76 g, 44.9 mmol, 4.00 equiv) at room temperature. The reaction was stirred for 2 hours at 80 °C, quenched with water (50 mL), and extracted with EtOAc (2 x 100 mL). The combined organic layers were washed with brine (1 x 50 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to afford a mixture of assumed tert-butyl ((1R,2R,4R,5S)-8-cyano-4-methyl-8- azabicyclo[3.2.1]octan-2-yl)carbamate and the corresponding enantiomer (2.7 g, 91% yield). LCMS: m / z [M+H]+= 266.2.

[0505] Step 10: A mixture of assumed tert-butyl ((1R,2R,4R,5S)-8-cyano-4-methyl-8- azabicyclo[3.2.1]octan-2-yl)carbamate and the corresponding enantiomer (12.0 g, 45.2 mmol, 1.00 equiv), K2CO3(18.9 g, 136 mmol, 3.00 equiv), hydroxylamine hydrochloride (6.28 g, 90.4 mmol, 2.00 equiv) in ethyl alcohol (120 mL) was stirred for 2 hours at 60 °C. The reaction was quenched by the addition of water (100 mL) at room temperature and extracted with EtOAc (2 x 200 mL). The combined organic layers were washed with brine (1 x 100 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to afford a mixture of assumed tert-butyl ((1R,4R,5S)-8-((E)-N'-hydroxycarbamimidoyl)-4-methyl-8-azabicyclo[3.2.1]octan-2-yl)carbamate and the corresponding enantiomer (11 g, 82% crude yield). LCMS: m / z [M+H]+= 299.2. Reactivity of the nitrogen atom of hydroxylamine (rather than the oxygen atom) with the cyano moiety is favored under basic or neutral conditions. See, e.g., in contrast, Example 3.

[0506] Step 11: A solution of a mixture of assumed tert-butyl ((1R,4R,5S)-8-((E)-N'- hydroxycarbamimidoyl)-4-methyl-8-azabicyclo[3.2.1]octan-2-yl)carbamate and the corresponding enantiomer (6.00 g, 20.1 mmol, 1.00 equiv) and 1,1′-carbonyldiimidazole (CDI) (3.26 g, 20.1 mmol, 1.00 equiv) in THF (60 mL) was stirred for 1 hour at 60 °C. The resulting mixture was concentrated under reduced pressure, and the residue was purified by flash C18 gel chromatography, eluting with 35% to 50% acetonitrile in water (0.1% TFA) over 10 minutes, to afford a mixture of assumed tert- butyl ((1R,4R,5S)-4-methyl-8-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)-8-azabicyclo[3.2.1]octan-2- yl)carbamate and the corresponding enantiomer (4.00 g, 61% yield).

[0507] Step 12: A solution of a mixture of assumed tert-butyl ((1R,4R,5S)-4-methyl-8-(5-oxo-4,5- dihydro-1,2,4-oxadiazol-3-yl)-8-azabicyclo[3.2.1]octan-2-yl)carbamate and the corresponding enantiomer (4 g, 12.33 mmol, 1.00 equiv) in 4 M HCl in 1,4-dioxane (30 mL) was stirred for 1 hour at room temperature, and the resulting mixture was concentrated under reduced pressure to afford a mixture of assumed 3-((1R,2R,4R,5S)-2-amino-4-methyl-8-azabicyclo[3.2.1]octan-8-yl)-1,2,4-oxadiazol-5(4H)-one hydrochloride salt (RRRS-isomer) and 3-((1S,2S,4S,5R)-2-amino-4-methyl-8- azabicyclo[3.2.1]octan-8-yl)-1,2,4-oxadiazol-5(4H)-one hydrochloride salt (SSSR-isomer) (3 g, 93% crude yield). LCMS: m / z [M+H]+= 225.2.

[0508] Step 13: A mixture of 1-(4-(trifluoromethyl)phenyl)cyclopropane-1-carboxylic acid (1.50 g, 6.52 mmol, 1.00 equiv), the mixture of assumed 3-((1R,2R,4R,5S)-2-amino-4-methyl-8- azabicyclo[3.2.1]octan-8-yl)-1,2,4-oxadiazol-5(4H)-one hydrochloride salt (RRRS-isomer) and 3- ((1S,2S,4S,5R)-2-amino-4-methyl-8-azabicyclo[3.2.1]octan-8-yl)-1,2,4-oxadiazol-5(4H)-one (SSSR- isomer) (1.70 g, 6.52 mmol, 1.00 equiv), HOBT (1.06 g, 7.82 mmol, 1.20 equiv), EDCI (1.62 g, 8.47 mmol, 1.30 equiv) and i-Pr2NEt (2.53 g, 19.6 mmol, 3.00 equiv) in DMF (20 mL), was stirred for 2 hours at room temperature, and the reaction was quenched with water (100 mL). The resulting mixture was extracted with EtOAc (3 x 200 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash C18 gel chromatography, eluting with 40% to 60% acetonitrile in water (0.1% TFA) over 30 minutes, to afford 2.0 g of a product that was further purified by Prep-HPLC (XSelect CSH C18 OBD, 30 x 150 mm, 5μm; mobile phase: 5% acetonitrile in water (0.05% TFA) for 2 minutes, 22% to 42% of acetonitrile in water (0.05% TFA) over 15 minutes, and 42% to 50% over 15 minutes; flow rate: 60 mL / min; wavelength: 254 / 220 nm), to afford the N-(-4-methyl-8-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)-8- azabicyclo[3.2.1]octan-2-yl)-1-(4-(trifluoromethyl)phenyl)cyclopropane-1-carboxamide (Compound 1-O, rac-1-O) (RT = 16.5 minutes, 1.38 g, 38% yield) as a mixture of two stereoisomers. LCMS: m / z [M+H]+= 437.1.

[0509] Step 14: Compound 1-O (1.38 g) was purified by Prep-SFC (CHIRALPAK IC, 3 x 25 cm, 5 μm; mobile phase: 25% of methanol in super critical CO2; flow rate: 100 mL / min; sample solvent: methanol; injection volume: 3 mL; number of runs: 15) to afford separation of the two stereoisomers (*absolute stereochemistry arbitrarily assigned):

[0510] Compound 1A*-O: as the first eluting peak at RT (minutes) = 4.6; 589 mg. LCMS: m / z [M+H]+= 437.2.1H NMR (400 MHz, Methanol-d4) δ 7.69 (d, J = 8.0 Hz, 2H), 7.59 (d, J = 8.0 Hz, 2H), 4.20 - 4.09 (m, 1H), 4.05 - 4.00 (m, 1H), 3.87 - 3.81 (m, 1H), 2.06 - 1.93 (m, 1H), 1.82 (t, J = 7.2 Hz, 1H), 1.77 - 1.69 (m, 1H), 1.68 - 1.59 (m, 3H), 1.58 - 1.51 (m, 2H), 1.44 - 1.35 (m, 1H), 1.22 - 1.14 (m, 2H), 1.11 (d, J = 7.2 Hz, 3H).

[0511] Compound 1D*-O: as the second eluting peak at RT (minutes) = 6.3; 648 mg. LCMS: m / z [M+H]+= 437.2.1H NMR (400 MHz, Methanol-d4) δ 7.69 (d, J = 8.0 Hz, 2H), 7.58 (d, J = 8.0 Hz, 2H), 4.18 - 4.08 (m, 1H), 4.05 - 3.96 (m, 1H), 3.87 - 3.80 (m, 1H), 2.08 - 1.93 (m, 1H), 1.83 (t, J = 7.2 Hz, 1H), 1.78 - 1.58 (m, 4H), 1.58 - 1.51 (m, 2H), 1.43 - 1.34 (m, 1H), 1.22 - 1.14 (m, 2H), 1.11 (d, J = 7.2 Hz, 3H). Example 2. Synthesis of 1-(2-fluoro-4-(trifluoromethyl)phenyl)-1-methyl-3-((1R,2R,4R,5S)-4- methyl-8-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)-8-azabicyclo[3.2.1]octan-2-yl)urea(Compound 2A*-O) and 1-(2-fluoro-4-(trifluoromethyl)phenyl)-1-methyl-3-((1S,2S,4S,5R)-4- methyl-8-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)-8-azabicyclo[3.2.1]octan-2-yl)urea (Compound 2D*-O)

[0512] Step 1: Into a 40 mL sealed tube were added 1-bromo-2-fluoro-4-(trifluoromethyl)benzene (2.00 g, 8.23 mmol, 1.00 equiv), 1,4-dioxane (15 mL), tert-butyl carbamate (1.93 g, 16.5 mmol, 2.00 equiv), XPhos (1.18 g, 2.46 mmol, 0.30 equiv), XPhos Pd G3(2.09 g, 2.46 mmol, 0.30 equiv) and Cs2CO3(8.04 g, 24.7 mmol, 3.00 equiv). The reaction was stirred for 2 hours at 100 °C under N2atmosphere, quenched with water (100 mL) at room temperature, and extracted with CH2Cl2(3 x 100 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash C18 gel chromatography, eluting with 0% to 100% acetonitrile in water over 30 minutes, to afford tert-butyl N-(2-fluoro-4- (trifluoromethyl)phenyl)carbamate (2.00 g, 87% yield). GCMS: m / z [M] = 279.1.

[0513] Step 2: To a solution of tert-butyl N-(2-fluoro-4-(trifluoromethyl)phenyl)carbamate (2.00 g, 7.16 mmol, 1.00 equiv) in THF (20 mL) was added 60% NaH in mineral oil (0.34 g, 14.3 mmol, 2.00 equiv) by portion at 0 °C. The reaction was stirred for 40 minutes at room temperature, followed bythe addition of methyl iodide (3.05 g, 21.5 mmol, 3.00 equiv). The mixture was stirred for 1 hour, quenched by the addition of 20% aqueous NH4Cl (100 mL), and extracted with CH2Cl2(3 x 100 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash C18 gel chromatography, eluting with 0% to 100% acetonitrile in water over 30 minutes, to afford tert-butyl N-(2-fluoro-4- (trifluoromethyl)phenyl)-N-methylcarbamate (1.70 g, 81% yield). LCMS: m / z [M+H]+= 294.1.

[0514] Step 3: A solution of tert-butyl N-(2-fluoro-4-(trifluoromethyl)phenyl)-N-methylcarbamate (1.70 g, 5.79 mmol, 1.00 equiv) in 4 M HCl in 1,4-dioxane (10 mL) was stirred for 1 hour at room temperature, and then was concentrated under reduced pressure to afford 2-fluoro-N-methyl-4- (trifluoromethyl)aniline hydrochloride salt (1.10 g, 83% crude yield). LCMS: m / z [M+H]+= 194.1.

[0515] Step 4: To a solution of 2-fluoro-N-methyl-4-(trifluoromethyl)aniline hydrochloride salt (1.10 g, 4.79 mmol, 1.00 equiv) and triethylamine (1.45 g, 14.4 mmol, 3.00 equiv) in CH2Cl2(10 mL) was added diphosgene (1.13 g, 5.74 mmol, 1.20 equiv) at 0 °C. The reaction was stirred for 1 hour at room temperature, quenched by the addition of water (30 mL), and extracted with CH2Cl2(3 x 30 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with 50% EtOAc in petroleum ether, to afford trichloromethyl N-(2-fluoro-4-(trifluoromethyl)phenyl)-N-methylcarbamate (700 mg, 41% yield). LCMS: m / z [M+H]+= 353.9.

[0516] Step 5: A solution of trichloromethyl N-(2-fluoro-4-(trifluoromethyl)phenyl)-N- methylcarbamate (270 mg, 0.76 mmol, 1.00 equiv), the mixture of assumed 3-((1R,2R,4R,5S)-2- amino-4-methyl-8-azabicyclo[3.2.1]octan-8-yl)-1,2,4-oxadiazol-5(4H)-one hydrochloride salt (RRRS- isomer) and 3-((1S,2S,4S,5R)-2-amino-4-methyl-8-azabicyclo[3.2.1]octan-8-yl)-1,2,4-oxadiazol- 5(4H)-one (SSSR-isomer) hydrochloride (products of Example 1, Step 12) (238 mg, 0.91 mmol, 1.20 equiv) and i-Pr2NEt (492 mg, 3.81 mmol, 5.00 equiv) in acetonitrile (3.0 mL), was stirred for 1 hour at room temperature, quenched by the addition of water (20 mL), and extracted with CH2Cl2(3 x 20 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash C18 gel chromatography, eluting with 0% to 100% acetonitrile in water over 30 minutes, to afford a 200 mg of a product that was further purified by Prep-HPLC (XSelect CSH C18 OBD, 30 x 150 mm, 5 μm; mobile phase: 5% acetonitrile in water (0.05% TFA) for 2 minutes, 30% to 50% acetonitrile in water (0.05% TFA) over 15 minutes; flow rate: 60 mL / min; wave length: 254 / 220 nm), to afford 1-(2-fluoro-4-(trifluoromethyl)phenyl)-1- methyl-3-(-4-methyl-8-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)-8-azabicyclo[3.2.1]octan-2-yl)urea (Compound 2-O, rac-2-O) (RT = 13.2 minutes, 140 mg, 41% yield) as a mixture of two stereoisomers. LCMS: m / z [M+H]+= 444.2.1H NMR (400 MHz, Methanol-d4) δ 7.62 - 7.54 (m, 3H), 4.11 - 4.01 (m, 2H), 3.88 - 3.82 (m, 1H), 3.26 (s, 3H), 2.10 - 1.99 (m, 1H), 1.89 - 1.84 (m, 2H), 1.80 - 1.63 (m, 3H), 1.49 - 1.41 (m, 1H), 1.13 (d, J = 7.2 Hz, 3H).

[0517] Step 6: Compound 2-O (140 mg) was purified by Prep-HPLC (CHIRALPAK IC, 2 x 25 cm,5 μm; mobile phase: 50% ethanol (50% CH2Cl2) in hexanes (0.1% TFA) in 7 minutes; flow rate: 20 mL / min; wavelength: 220 / 254 nm) to afford separation of the two stereoisomers (*absolute stereochemistry arbitrarily assigned):

[0518] Compound 2A*-O: as the first eluting peak at RT (minutes) = 4.24; 57.5 mg; LCMS: m / z [M+H]+= 444.1.1H NMR (400 MHz, Methanol-d4) δ 7.62 - 7.53 (m, 3H), 4.10 - 3.82 (m, 3H), 3.26 (s, 3H), 2.09 - 2.00 (m, 1H), 1.94 - 1.64 (m, 5H), 1.48 - 1.44 (m, 1H), 1.13 (d, J = 7.2 Hz, 3H); and

[0519] Compound 2D*-O: as the second eluting peak at RT (minutes) = 5.59; 47.8 mg; LCMS: m / z [M+H]+= 444.1.1H NMR (400 MHz, Methanol-d4) δ 7.65 - 7.54 (m, 3H), 4.05 (t, J = 8.0 Hz, 2H), 3.90 - 3.82 (m, 1H), 3.26 (s, 3H), 2.09 - 2.00 (m, 1H), 1.90 - 1.63 (m, 5H), 1.51 - 1.41 (m, 1H), 1.13 (d, J = 7.2 Hz, 3H). Example 3. Synthesis of 1-(2-fluoro-4-(trifluoromethyl)phenyl)-1-methyl-3-((1R,2R,4R,5S)-4- methyl-8-(3-oxo-2,3-dihydro-1,2,4-oxadiazol-5-yl)-8-azabicyclo[3.2.1]octan-2-yl)urea (Compound 2A*-N) and 1-(2-fluoro-4-(trifluoromethyl)phenyl)-1-methyl-3-((1S,2S,4S,5R)-4- methyl-8-(3-oxo-2,3-dihydro-1,2,4-oxadiazol-5-yl)-8-azabicyclo[3.2.1]octan-2-yl)urea (Compound 2D*-N)

[0520] Step 1: A solution of the mixture of assumed tert-butyl ((1R,2R,4R,5S)-8-cyano-4-methyl-8- azabicyclo[3.2.1]octan-2-yl)carbamate and the corresponding enantiomer (2.50 g, 9.42 mmol, 1.00 equiv) (products of Example 1, Step 9) and hydroxylamine hydrochloride (1.31 g, 18.8 mmol, 2.00 equiv) in methanol (20 mL), was stirred for 2 hours at 60 °C, and then the mixture was concentrated under reduced pressure. The residue was purified by flash C18 gel chromatography, eluting with 30% to 40% acetonitrile in water (0.1% TFA) over 10 minutes, to afford a mixture of assumed tert-butyl ((1R,2R,4R,5S)-8-((aminooxy)(imino)methyl)-4-methyl-8-azabicyclo[3.2.1]octan-2-yl)carbamate and the corresponding enantiomer (1.30 g, 39% yield). LCMS: m / z [M+H]+= 299.2. Reactivity of the oxygen atom of hydroxylamine (rather than the nitrogen atom) with the cyano moiety is favored under acidic conditions. See, e.g., in contrast Examples 1 and 9.

[0521] Step 2: A solution of assumed tert-butyl ((1R,2R,4R,5S)-8-((aminooxy)(imino)methyl)-4- methyl-8-azabicyclo[3.2.1]octan-2-yl)carbamate and the corresponding enantiomer (1.30 g, 4.35 mmol, 1.00 equiv) and 1,1′-carbonyldiimidazole (CDI) (706 mg, 4.35 mmol, 1.00 equiv) in THF (15 mL), was stirred for 2 hours at 60 °C, and then the mixture was concentrated under reduced pressure. The residue was purified by flash C18 gel chromatography, eluting with 30% to 50% acetonitrile in water (0.1% TFA) over 10 minutes, to afford a mixture of assumed tert-butyl ((1R,2R,4R,5S)-4- methyl-8-(3-oxo-2,3-dihydro-1,2,4-oxadiazol-5-yl)-8-azabicyclo[3.2.1]octan-2-yl)carbamate and the corresponding enantiomer (1.00 g, 71% yield). LCMS: m / z [M+H]+= 325.3.

[0522] Step 3: A solution of assumed tert-butyl ((1R,2R,4R,5S)-4-methyl-8-(3-oxo-2,3-dihydro- 1,2,4-oxadiazol-5-yl)-8-azabicyclo[3.2.1]octan-2-yl)carbamate and the corresponding enantiomer (1.00 g, 3.08 mmol, 1.00 equiv) in 4 M HCl in 1,4-dioxane (10 mL) was stirred for 1 hour at room temperature, and then the mixture was concentrated under reduced pressure to afford a mixture of 5- ((1R,2R,4R,5S)-2-amino-4-methyl-8-azabicyclo[3.2.1]octan-8-yl)-1,2,4-oxadiazol-3(2H)-one hydrochloride (RRRS-isomer) and 5-((1S,2S,4S,5R)-2-amino-4-methyl-8-azabicyclo[3.2.1]octan-8- yl)-1,2,4-oxadiazol-3(2H)-one hydrochloride (SSSR-isomer) (800 mg, >99% crude yield). LCMS: m / z [M+H]+= 225.2.

[0523] Step 4: A solution of trichloromethyl N-(2-fluoro-4-(trifluoromethyl)phenyl)-N-methylcarbamate (136 mg, 0.38 mmol, 1.00 equiv), (product of Example 2, Step 4), i-Pr2NEt (148 mg, 1.15 mmol, 3.00 equiv) and the mixture of 5-((1R,2R,4R,5S)-2-amino-4-methyl-8- azabicyclo[3.2.1]octan-8-yl)-1,2,4-oxadiazol-3(2H)-one hydrochloride (RRRS-isomer) and 5- ((1S,2S,4S,5R)-2-amino-4-methyl-8-azabicyclo[3.2.1]octan-8-yl)-1,2,4-oxadiazol-3(2H)-one hydrochloride (SSSR-isomer) hydrochloride (100 mg, 0.38 mmol, 1.00 equiv) in acetonitrile (2 mL), was stirred for 1 hour at room temperature. The reaction was quenched with water (10 mL), and the resulting mixture was extracted with EtOAc (3 x 25 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was then purified by flash C18 gel chromatography, eluting with 30% to 50% acetonitrile in water (0.1% TFA) over 10 minutes, to afford 1-(2-fluoro-4-(trifluoromethyl)phenyl)-1-methyl-3-(-4-methyl-8-(3-oxo- 2,3-dihydro-1,2,4-oxadiazol-5-yl)-8-azabicyclo[3.2.1]octan-2-yl)urea (Compound 2-N, rac-2-N) (82 mg) as a mixture of two stereoisomers.

[0524] Step 5: The racemic Compound 2-N (82 mg) was purified by Prep-HPLC (CHIRAL ART Cellulose-SC, 2 x 25 cm, 5 μm; mobile phase: 40% ethanol (50% CH2Cl2) in hexanes (0.5% 2 M methanolic ammonia); flow rate: 20 mL / min; wavelength: 220 / 254 nm) to afford separation of the two stereoisomers (*absolute stereochemistry arbitrarily assigned):

[0525] Compound 2A*-N: as the first eluting peak at RT (minutes) = 6.73; 19.8 mg. LCMS: m / z [M+H]+= 444.1.1H NMR (400 MHz, Methanol-d4) δ 7.61 - 7.57 (m, 3H), 4.04 (d, J = 6.4 Hz, 2H), 3.86 (d, J = 7.2 Hz, 1H), 3.26 (s, 3H), 2.06 - 2.03 (m, 1H), 1.87 - 1.60 (m, 5H), 1.49 - 1.40 (m, 1H), 1.13 (d, J = 7.0 Hz, 3H); and

[0526] Compound 2D*-N: as the second eluting peak at RT (minutes) = 11.93; 12.4 mg. LCMS: m / z [M+H]+= 444.1.1H NMR (400 MHz, DMSO-d6) δ 12.04 (s, 1H), 7.75 - 7.72 (m, 1H), 7.61 - 7.55 (m, 2H), 6.31 (d, J = 7.4 Hz, 1H), 4.01- 4.00 (m, 1H), 3.95 - 3.90 (m, 1H), 3.77 - 3.75 (m, 1H), 3.16 (s, 3H), 1.89 - 1.47 (m, 6H), 1.33 - 1.24 (m, 1H), 1.02 (d, J = 7.0 Hz, 3H). Example 4. Synthesis of 1-(4-(difluoromethoxy)-2,6-difluorophenyl)-1-methyl-3-((1R,2R,4R,5S)- 4-methyl-8-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)-8-azabicyclo[3.2.1]octan-2-yl)urea (Compound 3A*-O) and 1-(4-(difluoromethoxy)-2,6-difluorophenyl)-1-methyl-3-((1S,2S,4S,5R)- 4-methyl-8-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)-8-azabicyclo[3.2.1]octan-2-yl)urea (Compound 3D*-O)

[0527] Step 1: To a solution of 4-amino-3,5-difluorophenol (2.50 g, 17.2 mmol, 1.00 equiv) in methanol (25 mL) was added (Boc)2O (4.14 g, 19.0 mmol, 1.10 equiv), and the reaction was stirred overnight at room temperature. The resulting mixture was diluted with water (50 mL), the aqueous layer was extracted with EtOAc (3 x 50 mL), and the combined organic layers were concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with 20% EtOAc in petroleum ether, to afford tert-butyl N-(2,6-difluoro-4-hydroxyphenyl)carbamate (3.40 g, 81% yield). LCMS: m / z [M+H]+= 246.1.

[0528] Step 2: To a stirred solution of tert-butyl N-(2,6-difluoro-4-hydroxyphenyl)carbamate (3.35 g, 13.7 mmol, 1.00 equiv) in acetonitrile (110 mL), were added diethyl bromodifluoromethylphosphonate (10.9 g, 41.0 mmol, 3.00 equiv) dropwise at room temperature, followed by KOH (15.3 g, 273 mmol, 20.0 equiv) in water (110 mL) dropwise at 0 °C. The reaction was stirred for 2 hours at room temperature, diluted with water (50 mL), and extracted with CH2Cl2(3 x 80 mL). The combined organic layers were concentrated under reduced pressure, and the residue was purified by silica gel column chromatography, eluting with 25% EtOAc in petroleum ether, to afford tert-butyl N-(4-(difluoromethoxy)-2,6-difluorophenyl)carbamate (3.48 g, 86% yield). LCMS: m / z [M+H]+= 296.1.

[0529] Step 3: To a stirred solution of tert-butyl N-(4-(difluoromethoxy)-2,6- difluorophenyl)carbamate (3.45 g, 11.7 mmol, 1.00 equiv) in THF (35 mL) was added 60% NaH in mineral oil (2.33 g, 58.4 mmol, 5.00 equiv). The reaction was stirred for 30 minutes at 0 °C, followed by the addition of methyl iodide (3.32 g, 23.4 mmol, 2.00 equiv). The mixture was stirred for 2 hoursat room temperature, quenched by the addition of water (100 mL) at 0 °C, and extracted with CH2Cl2(3 x 80 mL). The combined organic layers were concentrated under reduced pressure, and the residue was purified by silica gel column chromatography, eluting with 25% EtOAc in petroleum ether, to afford tert-butyl N-(4-(difluoromethoxy)-2,6-difluorophenyl)-N-methylcarbamate (3.24 g, 90% yield). LCMS: m / z [M+H]+= 309.9.

[0530] Step 4: A solution of tert-butyl N-(4-(difluoromethoxy)-2,6-difluorophenyl)-N- methylcarbamate (3.14 g, 10.2 mmol, 1.00 equiv) and 4 M HCl in 1,4-dioxane (60 mL) was stirred overnight at room temperature, and the resulting mixture was concentrated under reduced pressure to afford 4-(difluoromethoxy)-2,6-difluoro-N-methylaniline hydrochloride (2.80 g, 95% crude yield). LCMS: m / z [M+H]+= 210.0.

[0531] Step 5: To a stirred solution of 4-(difluoromethoxy)-2,6-difluoro-N-methylaniline hydrochloride (500 mg, 2.04 mmol, 1.00 equiv) and triethylamine (618 mg, 6.11 mmol, 3.00 equiv) in CH2Cl2(5.0 mL) was added diphosgene (483 mg, 2.44 mmol, 1.20 equiv) dropwise at 0 °C. The reaction was stirred overnight at room temperature, diluted with water (15 mL), and extracted with EtOAc (4 x 15 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to afford trichloromethyl N-(4-(difluoromethoxy)-2,6- difluorophenyl)-N-methylcarbamate (650.0 mg, 86% crude yield). LCMS: m / z [M+H]+= 370.1.

[0532] Step 6: A solution of trichloromethyl N-(4-(difluoromethoxy)-2,6-difluorophenyl)-N- methylcarbamate (200 mg, 0.54 mmol, 1.00 equiv), the mixture of assumed 3-((1R,2R,4R,5S)-2- amino-4-methyl-8-azabicyclo[3.2.1]octan-8-yl)-1,2,4-oxadiazol-5(4H)-one hydrochloride salt (RRRS- isomer) and 3-((1S,2S,4S,5R)-2-amino-4-methyl-8-azabicyclo[3.2.1]octan-8-yl)-1,2,4-oxadiazol- 5(4H)-one (SSSR-isomer) hydrochloride (281 mg, 1.08 mmol, 2.00 equiv) (product of Example 1, Step 12) and i-Pr2NEt (209 mg, 1.62 mmol, 3.00 equiv) in acetonitrile (4 mL), was stirred overnight at room temperature. The mixture was diluted with water (20 mL), extracted with EtOAc (4 x 20 mL), and the combined organic layers were concentrated under reduced pressure. The residue was purified by flash C18 gel chromatography, eluting with 20% to 30% acetonitrile in water over 15 minutes, to afford 178.0 mg of a product that was further purified by Prep-HPLC (XSelect CSH C18 OBD, 30 x 150 mm, 5 μm; mobile phase: 5% acetonitrile in water (0.05% TFA) for 2 minutes, 26% to 46% acetonitrile in water (0.05% TFA) over 15 minutes; flow rate: 60 mL / min; wavelength: 254 / 220 nm), to afford 1-(4-(difluoromethoxy)-2,6-difluorophenyl)-1-methyl-3-(4-methyl-8-(5-oxo-4,5-dihydro- 1,2,4-oxadiazol-3-yl)-8-azabicyclo[3.2.1]octan-2-yl)urea (Compound 3-O, rac-3-O) (100 mg) as a mixture of two stereoisomers. LCMS: m / z [M+H]+= 460.1.

[0533] Step 7: Compound 3-O (100.0 mg) was purified by Prep-HPLC (CHIRALPAK IC, 2 x 25 cm, 5 μm; mobile phase: 40% ethanol (50% CH2Cl2) in hexanes (0.1% TFA) for 9 minutes; flow rate: 20 mL / min; wavelength: 220 / 254 nm), to afford separation of the two stereoisomers (*absolute stereochemistry arbitrarily assigned):

[0534] Compound 3A*-O: as the first eluting peak at RT (minutes) = 4.90; 36.7 mg. LCMS: m / z[M+H]+= 460.1.1H NMR (400 MHz, Methanol-d4) δ 7.17 - 6.79 (m, 3H), 4.07 - 4.01 (m, 2H), 3.86 (d, J = 7.2 Hz, 1H), 3.18 (s, 3H), 2.08 - 2.00 (m, 1H), 1.85 (d, J = 8.0 Hz, 2H), 1.82 - 1.73 (m, 2H), 1.71 - 1.65 (m, 1H), 1.46 (dd, J = 13.4, 5.2 Hz, 1H), 1.14 (d, J = 6.8 Hz, 3H); and

[0535] Compound 3D*-O: as the second eluting peak at RT (minutes) = 7.05; 38.7 mg. LCMS: m / z [M+H]+= 460.1.1H NMR (400 MHz, Methanol-d4) δ 7.16 - 6.79 (m, 3H), 4.08 - 4.01 (m, 2H), 3.87 - 3.85 (m, 1H), 3.18 (s, 3H), 2.08 - 2.00 (m, 1H), 1.86 (d, J = 7.6 Hz, 2H), 1.81 - 1.75 (m, 2H), 1.74 - 1.65 (m, 1H), 1.46 (dd, J = 13.4, 5.2 Hz, 1H), 1.14 (d, J = 7.0 Hz, 3H). Example 5. Synthesis of 1-(4-(difluoromethoxy)phenyl)-1-ethyl-3-((1R,2R,4R,5S)-4-methyl-8-(3- oxo-2,3-dihydro-1,2,4-oxadiazol-5-yl)-8-azabicyclo[3.2.1]octan-2-yl)urea (Compound 4A*-N) and 1-(4-(difluoromethoxy)phenyl)-1-ethyl-3-((1S,2S,4S,5R)-4-methyl-8-(3-oxo-2,3-dihydro- 1,2,4-oxadiazol-5-yl)-8-azabicyclo[3.2.1]octan-2-yl)urea (Compound 4D*-N)

[0536] Step 1: A mixture of 1-bromo-4-(difluoromethoxy)benzene (2.80 g, 12.57 mmol, 1.00 equiv), tert-butyl carbamate (2.94 g, 25.14 mmol, 2.00 equiv), XPhos (1.80 g, 3.77 mmol, 0.30 equiv),Cs2CO3(12.28 g, 37.70 mmol, 3.00 equiv) and XPhos Pd G3 (3.19 g, 3.77 mmol, 0.30 equiv) in 1,4- dioxane (40 mL), was stirred overnight at 80 °C under N2atmosphere. The reaction was quenched by the addition of water (50 mL) at room temperature and extracted with EtOAc (3 x 40 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash C18 gel chromatography, eluting with 30% to 60% acetonitrile in water (0.1% TFA) over 20 minutes, to afford tert-butyl N-(4- (difluoromethoxy)phenyl)carbamate (3.1 g, 95% yield). LCMS: m / z [M-H]- = 258.3.

[0537] Step 2: To a solution of tert-butyl N-(4-(difluoromethoxy)phenyl)carbamate (3.00 g, 11.57 mmol, 1.00 equiv) in THF (40.0 mL) was added 60% NaH in mineral oil (1.04 g, 17.36 mmol, 1.50 equiv) at 0 °C. The reaction was stirred for 2 hours at 0 °C, followed by the dropwise addition of ethyl iodide (3.61 g, 23.14 mmol, 2.00 equiv). The mixture was stirred for 1 hour at room temperature, quenched by the addition of saturated aqueous NH4Cl (20 mL) at 0 °C, and extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (40 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with 25% EtOAc in petroleum ether, to afford tert-butyl N-(4- (difluoromethoxy)phenyl)-N-ethylcarbamate (2.4 g, 72% yield). LCMS: m / z [M+H]+= 288.2.

[0538] Step 3: A solution of tert-butyl N-(4-(difluoromethoxy)phenyl)-N-ethylcarbamate (1.90 g, 6.61 mmol, 1.00 equiv) and 4 M HCl in 1,4-dioxane (16 mL) was stirred for 2 hours at room temperature, and the mixture was concentrated under reduced pressure to afford 4-(difluoromethoxy)- N-ethylaniline hydrochloride (1.4 g, 95% crude yield). LCMS: m / z [M+H]+= 188.3.

[0539] Step 4: To a solution of 4-(difluoromethoxy)-N-ethylaniline hydrochloride (1.30 g, 5.81 mmol, 1.00 equiv) and triethylamine (1.7 g, 17.44 mmol, 2.3 mL, 3.0 equiv) in CH2Cl2(15.0 mL), was added diphosgene (2.30 g, 11.63 mmol, 2.00 equiv) at 0 °C. The reaction was stirred for 2 hours at room temperature, and then was concentrated under vacuum. The residue was purified by prep-TLC eluting with 25% EtOAc in petroleum ether, to afford trichloromethyl N-(4- (difluoromethoxy)phenyl)-N-ethylcarbamate (400 mg, 20% yield). LCMS: m / z [M+H]+= 348.1.

[0540] Step 5: A solution of trichloromethyl N-(4-(difluoromethoxy)phenyl)-N-ethylcarbamate (534.75 mg, 1.54 mmol, 4.00 equiv), the mixture of 5-((1R,2R,4R,5S)-2-amino-4-methyl-8- azabicyclo[3.2.1]octan-8-yl)-1,2,4-oxadiazol-3(2H)-one hydrochloride (RRRS-isomer) and 5- ((1S,2S,4S,5R)-2-amino-4-methyl-8-azabicyclo[3.2.1]octan-8-yl)-1,2,4-oxadiazol-3(2H)-one hydrochloride (SSSR-isomer) (100 mg, 0.38 mmol, 1.00 equiv) (product of Example 3, Step 3) and i-Pr2NEt (148.72 mg, 1.15 mmol, 3.00 equiv) in acetonitrile (1.0 mL) was stirred for 16 hours at 60 °C. The resulting mixture was concentrated under vacuum, and the residue was purified by flash C18 gel chromatography, eluting with 40% to 60% acetonitrile in water (0.1% TFA) over 20 minutes, to afford 1-(4-(difluoromethoxy)phenyl)-1-ethyl-3-(4-methyl-8-(3-oxo-2,3-dihydro-1,2,4-oxadiazol-5- yl)-8-azabicyclo[3.2.1]octan-2-yl)urea (Compound 4-N, rac-4-N) (60 mg) as a mixture of two stereoisomers. LCMS: m / z [M+H]+= 438.1.

[0541] Step 6: Compound 4-N (60 mg) was purified by Prep-HPLC (CHIRALPAK IC, 2 x 25 cm, 5 μm; mobile phase: 40% ethanol (50% CH2Cl2) in hexanes (0.5% 2 M methanolic ammonia); flow rate: 20 mL / min; wavelength: 220 / 254 nm), to afford separation of the two stereoisomers (*absolute stereochemistry arbitrarily assigned):

[0542] Compound 4A*-N: as the first eluting peak at RT (minutes) = 7.83; 15.3 mg. LCMS: m / z [M+H]+= 438.1.1H NMR (400 MHz, DMSO-d6) δ 7.49 - 6.99 (m, 5H), 5.44 (d, J = 7.6 Hz, 1H), 4.00 (d, J = 6.8 Hz, 1H), 3.90 (d, J = 3.6 Hz, 1H), 3.75 (d, J = 6.4 Hz, 1H), 3.58 (d, J = 7.2 Hz, 2H), 1.93 - 1.67 (m, 3H), 1.64 - 1.42 (m, 3H), 1.25 (d, J = 4.8 Hz, 1H), 1.07 - 0.89 (m, 6H); and

[0543] Compound 4D*-N: as the second eluting peak at RT (minutes) = 14.56; 9.4 mg. LCMS: m / z [M+H]+= 438.2.1H NMR (400 MHz, DMSO-d6) δ 7.56 - 7.00 (m, 5H), 5.22 (d, J = 8.0 Hz, 1H), 3.99 (s, 1H), 3.85 (s, 1H), 3.77 (d, J = 6.8 Hz, 1H), 3.59 (d, J =6.6 Hz, 2H), 1.82 - 1.60 (m, 2H), 1.60 - 1.32 (m, 4H), 1.18 (d, J = 5.4 Hz, 1H), 1.08 - 0.93 (m, 6H). Example 6. Synthesis of 1-(2-fluoro-4-(trifluoromethyl)phenyl)-1-ethyl-3-((1R,2R,4R,5S)-4- methyl-8-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)-8-azabicyclo[3.2.1]octan-2-yl)urea (Compound 6A*-O) and 1-(2-fluoro-4-(trifluoromethyl)phenyl)-1-ethyl-3-((1S,2S,4S,5R)-4- methyl-8-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)-8-azabicyclo[3.2.1]octan-2-yl)urea (Compound 6D*-O)

[0544] Step 1: To a solution of tert-butyl N-(2-fluoro-4-(trifluoromethyl)phenyl)carbamate (4.50 g, 16.11 mmol, 1.00 equiv), (product of Example 2, Step 1) in THF (40 mL), was added 60% NaH in mineral oil (0.77 g, 32.23 mmol, 2.00 equiv) at 0 °C. The reaction was stirred for 30 minutes at room temperature, followed by the addition of ethyl iodide (5.02 g, 32.23 mmol, 2.00 equiv). The mixture was stirred for 16 hours at 60 °C, quenched by the addition of water (100 mL) at room temperature, and extracted with CH2Cl2(3 x 100 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash C18 gel chromatography, eluting with 0% to 100% acetonitrile in water over 30 minutes, to afford tert-butyl N-ethyl-N-(2-fluoro-4-(trifluoromethyl)phenyl)carbamate (4.00 g, 81% yield). LCMS: m / z [M+H]+= 308.1.

[0545] Step 2: A solution of tert-butyl N-ethyl-N-(2-fluoro-4-(trifluoromethyl)phenyl)carbamate (1.00 g, 3.25 mmol, 1.00 equiv) and 4 M HCl in 1,4-dioxane (8.0 mL) was stirred for 1 hour at room temperature, and the reaction was concentrated under reduced pressure to afford N-ethyl-2-fluoro-4- (trifluoromethyl)aniline hydrochloride salt (900 mg, 91% crude yield). LCMS: m / z [M+H]+= 208.2.

[0546] Step 3: To a solution of N-ethyl-2-fluoro-4-(trifluoromethyl)aniline hydrochloride salt (100 mg, 0.41 mmol, 1.00 equiv), and triethylamine (124.61 mg, 1.23 mmol, 0.171 mL, 3.00 equiv) in CH2Cl2(2.0 mL), was added diphosgene (97.44 mg, 0.49 mmol, 0.059 mL, 1.20 equiv) at 0 °C. The reaction was stirred for 1 hour at room temperature, quenched by the addition of water (20 mL) at room temperature, and extracted with CH2Cl2(3 x 20 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to afford trichloromethyl N-ethyl-N-(2-fluoro-4-(trifluoromethyl)phenyl)carbamate (120 mg, 79% crude yield). LCMS: m / z [M+H]+= 367.9.

[0547] Step 4: A solution of trichloromethyl N-ethyl-N-(2-fluoro-4- (trifluoromethyl)phenyl)carbamate (100 mg, 0.27 mmol, 1.00 equiv), a mixture of assumed 3- ((1R,2R,4R,5S)-2-amino-4-methyl-8-azabicyclo[3.2.1]octan-8-yl)-1,2,4-oxadiazol-5(4H)-one hydrochloride salt (RRRS-isomer) and 3-((1S,2S,4S,5R)-2-amino-4-methyl-8-azabicyclo[3.2.1]octan- 8-yl)-1,2,4-oxadiazol-5(4H)-one hydrochloride salt (SSSR-isomer) (73.02 mg, 0.32 mmol, 1.20 equiv) (product of Example 1, Step 12) and i-Pr2NEt (105.21 mg, 0.81 mmol, 3.00 equiv) inacetonitrile (2.0 mL), was stirred overnight at room temperature. The reaction was quenched by the addition of water (10 mL) and extracted with CH2Cl2(3 x 15 mL). The combined organic layers were washed with water (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash C18 gel chromatography, eluting with 0% to 100% acetonitrile in water (0.1% TFA) over 30 minutes, to afford 90 mg of a product that was further purified by Prep-HPLC (XSelect CSH C18 OBD, 30 x 150 mm, 5 μm; mobile phase: 5% acetonitrile in water (0.05% TFA) for 2 minutes, 30% to 55% acetonitrile in water (0.05% TFA) over 15 minutes; flow rate: 60 mL / min; wavelength: 254 nm / 220 nm), to afford 1-(2-fluoro-4-(trifluoromethyl)phenyl)- 1-ethyl-3-(4-methyl-8-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)-8-azabicyclo[3.2.1]octan-2-yl)urea (Compound 6-O, rac-6-O) (55 mg) as a mixture of two stereoisomers. LCMS: m / z [M+H]+= 458.1.

[0548] Step 5: Compound 6-O (55 mg) was purified by Prep-HPLC (CHIRAL ART Cellulose-SC, 2 x 25 cm, 5 μm; mobile phase: 20% methanol: CH2Cl2(1:1) in hexanes (0.1% TFA) for 11 minutes; flow rate: 20 mL / min; wavelength: 220 nm / 254 nm), to afford separation of the two stereoisomers (*absolute stereochemistry arbitrarily assigned):

[0549] Compound 6A*-O: as the first eluting peak at RT (minutes) = 7.9; 24.1 mg. LCMS: m / z [M+H]+= 458.1.1H NMR (400 MHz, Methanol-d4) δ 7.65 - 7.52 (m, 3H), 4.11 - 4.00 (m, 2H), 3.88 - 3.81 (m, 1H), 3.71 (d, J = 7.2 Hz, 2H), 2.10 - 1.96 (m, 1H), 1.86 - 1.60 (m, 5H), 1.45 - 1.35 (m, 1H), 1.18 - 1.09 (m, 6H); and

[0550] Compound 6D*-O: as the second eluting peak at RT (minutes) = 9.67; 22.6 mg. LCMS: m / z [M+H]+= 458.1.1H NMR (400 MHz, Methanol-d4) δ 7.65 - 7.52 (m, 3H), 4.11 - 4.00 (m, 2H), 3.85 (d, J = 7.2 Hz, 1H), 3.71 (d, J = 7.1 Hz, 2H), 2.10 - 1.96 (m, 1H), 1.85 - 1.66 (m, 5H), 1.45 - 1.36 (m, 1H), 1.13 - 1.06 (m, 6H). Example 7. Synthesis of 1-(4-(difluoromethoxy)-2-fluorophenyl)-1-ethyl-3-((1R,2R,4R,5S)-4- methyl-8-(3-oxo-2,3-dihydro-1,2,4-oxadiazol-5-yl)-8-azabicyclo[3.2.1]octan-2-yl)urea (Compound 7A*-N) and 1-(4-(difluoromethoxy)-2-fluorophenyl)-1-ethyl-3-((1S,2S,4S,5R)-4- methyl-8-(3-oxo-2,3-dihydro-1,2,4-oxadiazol-5-yl)-8-azabicyclo[3.2.1]octan-2-yl)urea (Compound 7D*-N)

[0551] Step 1: A mixture of 1-bromo-4-(difluoromethoxy)-2-fluorobenzene (1.00 g, 4.15 mmol, 1.00 equiv), tert-butyl carbamate (972.15 mg, 8.30 mmol, 2.00 equiv), XPhos (395.61 mg, 0.83 mmol, 0.20 equiv), Cs2CO3(4.06 g, 12.45 mmol, 3.00 equiv) and XPhos Pd G3 (351.22 mg, 0.41 mmol, 0.10 equiv) in 1,4-dioxane (10 mL), was stirred for 2 hours at 100 °C under N2atmosphere. The reaction was quenched by the addition of water (50 mL) at room temperature and extracted with EtOAc (3 x 200 mL). The combined organic layers were washed with brine (3 x 50 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with 15% EtOAc in petroleum ether, to afford tert-butyl N-(4- (difluoromethoxy)-2-fluorophenyl)carbamate (930 mg, 77% yield). GCMS: m / z [M+H]+= 278.1.

[0552] Step 2: To a solution of tert-butyl N-(4-(difluoromethoxy)-2-fluorophenyl)carbamate (900 mg, 3.25 mmol, 1.00 equiv) in THF (9 mL) was added 60% NaH in mineral oil (155.81 mg, 6.49 mmol, 2.00 equiv) in portions at 0 °C. The reaction was stirred for 30 minutes, followed by the dropwise addition of ethyl iodide (759.46 mg, 4.87 mmol, 1.50 equiv) at 0 °C. The reaction was stirred for 1 hour at room temperature, quenched with saturated aqueous NH4Cl (50 mL), and extracted with EtOAc (3 x 250 mL). The combined organic layers were washed with water (3 x 50 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with 50% EtOAc in petroleum ether, to afford tert-butyl N-(4-(difluoromethoxy)-2-fluorophenyl)-N-ethylcarbamate (700 mg, 68% yield). GCMS: m / z [M+H]+= 306.1.

[0553] Step 3: A solution of tert-butyl N-(4-(difluoromethoxy)-2-fluorophenyl)-N-ethylcarbamate (700 mg, 2.29 mmol, 1.00 equiv) and 4 M HCl in 1,4-dioxane (7.0 mL) was stirred for 1 hour at room temperature, and the mixture was concentrated under reduced pressure to afford 4-(difluoromethoxy)- N-ethyl-2-fluoroaniline hydrochloride (350 mg, 79% crude yield). LCMS: m / z [M+H]+= 206.1.

[0554] Step 4: To a solution of 4-(difluoromethoxy)-N-ethyl-2-fluoroaniline hydrochloride (350 mg, 1.87 mmol, 1.00 equiv) and Et3N (378.41 mg, 3.74 mmol, 2.00 equiv) in CH2Cl2(3 mL), was added diphosgene (554.81 mg, 2.80 mmol, 1.50 equiv) dropwise at 0 °C. The reaction was stirred for 1 hour at room temperature, quenched with water (50 mL), and extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine (3 x 50 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with 50% EtOAc in petroleum ether, to afford trichloromethyl N-(4- (difluoromethoxy)-2-fluorophenyl)-N-ethylcarbamate (230 mg, 33% yield). LCMS: m / z [M+H]+= 348.0.

[0555] Step 5: A solution of trichloromethyl N-(4-(difluoromethoxy)-2-fluorophenyl)-N- ethylcarbamate (140.59 mg, 0.38 mmol, 1.00 equiv), the mixture of 5-((1R,2R,4R,5S)-2-amino-4- methyl-8-azabicyclo[3.2.1]octan-8-yl)-1,2,4-oxadiazol-3(2H)-one hydrochloride (RRRS-isomer) and 5-((1S,2S,4S,5R)-2-amino-4-methyl-8-azabicyclo[3.2.1]octan-8-yl)-1,2,4-oxadiazol-3(2H)-one hydrochloride (SSSR-isomer) (100 mg, 0.38 mmol, 1.00 equiv) (products of Example 3, Step 3), and i-Pr2NEt (247.87 mg, 1.92 mmol, 5.00 equiv) in acetonitrile (2.0 mL), was stirred for 1 hour at room temperature. The reaction was quenched with water (20 mL), extracted with EtOAc (3 x 20 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash C18 gel chromatography, eluting with 35% to 55% acetonitrile in water (0.1% TFA) over 20 minutes, to afford 90 mg of a product that was further purified by Prep-HPLC (XSelect CSH C18 OBD, 30 x 150 mm, 5 μm; mobile phase: 5% acetonitrile in water (0.05% TFA) for 2 minutes, 30% to 50% acetonitrile in water (0.05% TFA) over 15 minutes; flow rate: 60 mL / min; wavelength: 254 / 220 nm) to afford 1-(4-(difluoromethoxy)-2-fluorophenyl)-1-ethyl-3-(4-methyl-8-(3-oxo-2,3- dihydro-1,2,4-oxadiazol-5-yl)-8-azabicyclo[3.2.1]octan-2-yl)urea (Compound 7-N, rac-7-N) (60 mg) as a mixture of two stereoisomers. LCMS: m / z [M+H]+= 456.2.

[0556] Step 6: Compound 7-N (60 mg) was purified by Prep-HPLC (CHIRAL ART Cellulose-SC, 2 x 25 cm, 5 μm; mobile phase: 30% methanol (50% CH2Cl2) in hexanes (0.1% TFA) in 8 minutes; flow rate: 20 mL / min; wavelength: 220 / 254 nm), to afford separation of the two stereoisomers (*absolute stereochemistry arbitrarily assigned):

[0557] Compound 7A*-N: as the first eluting peak at RT (minutes) = 6.28; 28.7 mg. LCMS: m / z [M+H]+= 456.2.1H NMR (400 MHz, Methanol-d4) δ 7.44 - 7.30 (m, 1H), 7.18 - 6.62 (m, 3H), 4.07 - 3.95 (m, 2H), 3.88 - 3.80 (m, 1H), 3.72 - 3.58 (m, 2H), 2.10 - 1.96 (m, 1H), 1.90 - 1.58 (m, 5H), 1.41 (d, J = 4.8 Hz, 1H), 1.16 - 1.05 (m, 6H); and

[0558] Compound 7D*-N: as the second eluting peak at RT (minutes) = 7.4; 25.9 mg. LCMS: m / z [M+H]+= 456.2.1H NMR (400 MHz, Methanol-d4) δ 7.47 - 7.27 (m, 1H), 7.20 - 6.69 (m, 3H), 4.15 - 3.95 (m, 2H), 3.90 - 3.75 (m, 1H), 3.73 - 3.52 (m, 2H), 2.14 - 1.92 (m, 1H), 1.89 - 1.56 (m, 5H), 1.45 - 1.32 (m, 1H), 1.19 - 1.05 (m, 6H). Example 8. Synthesis of 1-(2-fluoro-4-methoxyphenyl)-N-((1R,2R,4R,5S)-4-methyl-8-(3-oxo-2,3- dihydro-1,2,4-oxadiazol-5-yl)-8-azabicyclo[3.2.1]octan-2-yl)cyclopropane-1-carboxamide (Compound 10A*-N) and 1-(2-fluoro-4-methoxyphenyl)-N-((1S,2S,4S,5R)-4-methyl-8-(3-oxo- 2,3-dihydro-1,2,4-oxadiazol-5-yl)-8-azabicyclo[3.2.1]octan-2-yl)cyclopropane-1-carboxamide (Compound 10D*-N)

[0559] Step 1: Into a 30 mL sealed tube were added 1-bromo-2-fluoro-4-methoxybenzene (400 mg, 1.95 mmol, 1.0 equiv), 0.93 M bromo(1-(methoxycarbonyl)cyclopropyl)zinc in THF (6.98 mL, 5.85 mmol, 3.0 equiv), and Pd(t-Bu3P)2(299.12 mg, 0.58 mmol, 0.30 equiv) in THF (4 mL). The reaction was stirred for 2 hours at 60 °C under N2atmosphere, quenched by the addition of water (100 mL) at room temperature, and extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with water (2 x 50 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash C18 gel chromatography, eluting with 40% to 50% acetonitrile in water over 10 minutes, to afford methyl 1-(2-fluoro-4- methoxyphenyl)cyclopropane-1-carboxylate (340 mg, 78% yield). GCMS: m / z [M] = 224.1.

[0560] Step 2: A solution of methyl 1-(2-fluoro-4-methoxyphenyl)cyclopropane-1-carboxylate (320 mg, 1.42 mmol, 1.0 equiv) and NaOH (285.40 mg, 7.13 mmol, 5.0 equiv) in methanol (3 mL) and water (3 mL), was stirred for 1 hour at 40 °C under N2atmosphere. The mixture was adjusted to pH = 5 with 4 M aqueous HCl, and then was extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with water (3 x 80 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to afford 1-(2-fluoro-4-methoxyphenyl)cyclopropane-1-carboxylic acid (180 mg, 60% crude yield). LCMS: m / z [M+H]+= 211.1.

[0561] Step 3: A solution of 1-(2-fluoro-4-methoxyphenyl)cyclopropane-1-carboxylic acid (88.69 mg, 0.42 mmol, 1.1 equiv), the mixture of 5-((1R,2R,4R,5S)-2-amino-4-methyl-8- azabicyclo[3.2.1]octan-8-yl)-1,2,4-oxadiazol-3(2H)-one hydrochloride (RRRS-isomer) and 5- ((1S,2S,4S,5R)-2-amino-4-methyl-8-azabicyclo[3.2.1]octan-8-yl)-1,2,4-oxadiazol-3(2H)-one hydrochloride (SSSR-isomer) (100 mg, 0.38 mmol, 1.0 equiv) (product of Example 3, Step 3), HOBT (103.66 mg, 0.77 mmol, 2.0 equiv), EDCI (147.05 mg, 0.77 mmol, 2.0 equiv), and i-Pr2NEt (148.72 mg, 1.15 mmol, 3.0 equiv) in DMF (3 mL), was stirred for 2 hours at room temperature. The reaction was quenched with water (10 mL) at 0 °C, extracted with EtOAc (3 x 10 mL), and the combined organic layers were concentrated under reduced pressure. The residue was purified by flash C18 gel chromatography, eluting with 10% to 50% acetonitrile in water over 25 minutes, to afford 100 mg of a product that was further purified by Prep-HPLC (XSelect CSH Prep C18 OBD, 19 x 250 mm, 5 μm; mobile phase: 15% to 25% acetonitrile in water (10 mmol / L NH4HCO3) for 10 minutes; flow rate: 20 mL / min; wavelength: 254 / 220 nm), to afford 1-(2-fluoro-4-methoxyphenyl)-N-(4-methyl-8- (3-oxo-2,3-dihydro-1,2,4-oxadiazol-5-yl)-8-azabicyclo[3.2.1]octan-2-yl)cyclopropane-1-carboxamide (Compound 10-N, rac-10-N) (60 mg) as a mixture of two stereoisomers. LCMS: m / z [M+H]+= 417.2.

[0562] Step 4: Compound 10-N (60 mg) was purified by Prep-HPLC (CHIRALPAK IC, 2 x 25 cm, 5 μm; mobile phase: 50% ethanol (50% CH2Cl2) in hexanes (0.1% TFA) for 9 minutes; flow rate: 20 mL / min; wavelength: 220 / 254 nm), to afford separation of the two stereoisomers (*absolute stereochemistry arbitrarily assigned):

[0563] Compound 10A*-N: as the first eluting peak at RT(minutes) = 5.83; 24.5 mg. LCMS: m / z [M+H]+= 417.1.1H NMR (400 MHz, Methanol-d4) δ 7.36 - 7.27 (m, 1H), 6.83 - 6.73 (m, 2H), 4.10 (d, J = 12.4 Hz, 1H), 3.97 (d, J = 6.8 Hz, 1H), 3.84 (s, 4H), 2.01 (d, J = 13.6 Hz, 1H), 1.83 - 1.48 (m, 7H), 1.37 (d, J = 13.6 Hz, 1H), 1.16 - 1.02 (m, 5H); and

[0564] Compound 10D*-N: as the second eluting peak at RT(minutes) = 7.35; 11.4 mg. LCMS: m / z [M+H]+= 417.1.1H NMR (400 MHz, Methanol-d4) δ 7.31 (d, J = 9.2 Hz, 1H), 6.83 - 6.73 (m, 2H), 4.10 (d, J = 12.4 Hz, 1H), 4.01 - 3.95 (m, 1H), 3.84 (s, 4H), 2.07 - 1.93 (m, 1H), 1.84 - 1.48 (m, 7H), 1.37 (d, J = 13.6 Hz, 1H), 1.16 - 1.00 (m, 5H). Example 9. Synthesis of 1-(4-(difluoromethoxy)phenyl)-N-((1R,2R,4R,5S)-4-methyl-8-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)-8-azabicyclo[3.2.1]octan-2-yl)cyclopropane-1-carboxamide (Compound 13A*-O), 1-(4-(difluoromethoxy)phenyl)-N-((1R,2S,4R,5S)-4-methyl-8-(5-oxo-4,5- dihydro-1,2,4-oxadiazol-3-yl)-8-azabicyclo[3.2.1]octan-2-yl)cyclopropane-1-carboxamide (Compound 13B*-O), 1-(4-(difluoromethoxy)phenyl)-N-((1S,2R,4S,5R)-4-methyl-8-(5-oxo-4,5- dihydro-1,2,4-oxadiazol-3-yl)-8-azabicyclo[3.2.1]octan-2-yl)cyclopropane-1-carboxamide (Compound 13C*-O), and 1-(4-(difluoromethoxy)phenyl)-N-((1S,2S,4S,5R)-4-methyl-8-(5-oxo- 4,5-dihydro-1,2,4-oxadiazol-3-yl)-8-azabicyclo[3.2.1]octan-2-yl)cyclopropane-1-carboxamide (Compound 13D*-O) Scheme 9A.Scheme 9C.Scheme 9D.

[0565] Step 1: A mixture of 1-bromo-4-(difluoromethoxy)benzene (4.00 g, 17.93 mmol, 1.00 equiv), 0.93 M bromo(1-(methoxycarbonyl)cyclopropyl)zinc in THF (56.6 ml, 53.80 mmol, 3.0 equiv), and Pd(t-Bu3P)2(2.75 g, 5.38 mmol, 0.30 equiv) in THF (20 mL), was stirred for 2 hours at 60 °C under N2atmosphere. The reaction was quenched with water (20 ml) at room temperature, and then was extracted with EtOAc (3 x 150 mL). The combined organic layers were washed with water (3 x 30 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with 50% EtOAc in petroleum ether, to afford methyl 1-(4-(difluoromethoxy)phenyl)cyclopropane-1-carboxylate (4.90 g, 93% yield). GCMS: m / z [M]= 242.1.

[0566] Step 2: A solution of methyl 1-(4-(difluoromethoxy)phenyl)cyclopropane-1-carboxylate (1.00 g, 4.12 mmol, 1.0 equiv) and NaOH (0.83 g, 20.64 mmol, 5.0 equiv) in methanol (10 mL) and water (10 mL), was stirred for 2 hours at 40 °C. The mixture was adjusted to pH = 5 with 6 M aqueous HCl, and then was extracted with EtOAc (3 x 150 mL). The combined organic layers were washed with water (3 x 50 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash C18 gel chromatography, eluting with 40% to 50% acetonitrile in water over 12 minutes, to afford 1-(4-(difluoromethoxy)phenyl)cyclopropane-1-carboxylic acid (567.2 mg, 60% yield). LCMS: m / z [M-H]- = 227.

[0567] Step 3: Into a 20 mL vial were added tert-butyl 2-oxo-8-azabicyclo[3.2.1]octane-8- carboxylate (600 mg, 2.66 mmol, 1.00 equiv) and iodoxybenzoic acid (IBX) (2237.27 mg, 7.98 mmol, 3.00 equiv) in DMSO (7 mL) at room temperature. The resulting mixture was stirred for 16 hours at 80°C and monitored by LCMS. The reaction was reduced under vacuum to provide a residue. The reaction was repeated twenty-four times and batches combined. The combined residue was purified byreversed-phase flash chromatography (C18 silica gel; mobile phase, MeCN in water, 30% to 40% gradient in 10 min; detector, UV 254 nm) to provide tert-butyl 4-oxo-8-azabicyclo[3.2.1]oct-2-ene-8- carboxylate (6 g). LCMS (ESI): RT=0.77 min, m / z = 168.1 [M+H]+.

[0568] Step 4: To a stirred solution of tert-butyl 4-oxo-8-azabicyclo[3.2.1]oct-2-ene-8-carboxylate (1 g, 4.47 mmol, 1.00 equiv) in tetrahydrofuran (15 mL) were added Me2CuLi (0.5 M in Et2O, 18 mL, 9.00 mmol, 2.01 equiv) dropwise at -78°C under nitrogen atmosphere. The resulting mixture was stirred for 1 hour at room temperature. The reaction was quenched with water (10 mL) at room temperature. The resulting mixture was extracted with EtOAc (2 x 50 mL). The combined organic layers were washed with brine (1 x 20 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to provide a residue. The reaction was repeated five times and the batches combined. The combined residue was purified by reversed-phase flash chromatography (C18 silica gel; mobile phase, MeCN in Water, 45% to 55% gradient in 10 min; detector, UV 254 nm) to provide tert-butyl 2-methyl-4-oxo-8-azabicyclo[3.2.1]octane-8-carboxylate (4 g) as a mixture of the RRS-isomer* and SSR-isomer*. LCMS (ESI): RT=0.87 min, m / z = 184.2 [M+H]+. *Stereochemistry of the methyl group and the ethylene bridge were assumed trans. Stereochemistry of the -NHBn group comprises a mixture of R and S stereoisomers.

[0569] Step 5: A solution of the tert-butyl 2-methyl-4-oxo-8-azabicyclo[3.2.1]octane-8-carboxylate mixture of Step 4 (1 g, 4.18 mmol, 1.00 equiv) and benzylamine (895.59 mg, 8.37 mmol, 2.00 equiv) in methanol (7 mL) was stirred for 16 h at 60°C. To the above mixture was added NaBH3CN (790.02 mg, 12.54 mmol, 3.00 equiv) at 0°C. The resulting mixture was stirred for additional 1 hour at 60°C. The reaction was monitored by LCMS. The reaction was quenched with water (3 mL) at room temperature. The resulting mixture was extracted with EtOAc (2 x 20 mL). The combined organic layers were washed with brine (1 x 20 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to provide a residue. The reaction was repeated three times and the batches combined. The combined residue was purified by silica gel column chromatography, eluted with CH2Cl2 / petroleum ether (1:1) to afford tert-butyl 2-(benzylamino)-4-methyl-8- azabicyclo[3.2.1]octane-8-carboxylate (3 g) as a mixture of stereoisomers. LCMS (ESI): RT=0.71 min, m / z = 331.2 [M+H]+.

[0570] Step 6: To a solution of the tert-butyl 2-(benzylamino)-4-methyl-8-azabicyclo[3.2.1]octane-8- carboxylate mixture of Step 5 (800 mg, 2.42 mmol, 1.00 equiv) in methanol (15 mL), was added 10% wet Pd / C (258 mg, 9.40 mmol, 3.88 equiv), and the reaction was stirred overnight at room temperature under H2atmosphere. The resulting mixture was filtered, the filter cake was washed with methanol (100 mL), and the filtrate was concentrated under reduced pressure to afford tert-butyl 2- amino-4-methyl-8-azabicyclo[3.2.1]octane-8-carboxylate (550.00 mg, 85% crude yield) as a mixture of stereoisomers. LCMS: m / z [M+H]+= 241.2.

[0571] Step 7: A solution of the tert-butyl 2-amino-4-methyl-8-azabicyclo[3.2.1]octane-8- carboxylate mixture of Step 6 (500 mg, 2.08 mmol, 1.20 equiv), 1-(4-(difluoromethoxy)phenyl)cyclopropane-1-carboxylic acid (395.60 mg, 1.73 mmol, 1.00 equiv) (product of this Example 9, Step 2), HOBT (468.51 mg, 3.46 mmol, 2.00 equiv), EDCI∙HCl (664.66 mg, 3.46 mmol, 2.00 equiv), and i-Pr2NEt (672.19 mg, 5.20 mmol, 3.00 equiv) in DMF (5.0 mL) was stirred for 1 hour at room temperature. The reaction was quenched with water (10 mL), and the resulting mixture was extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash C18 gel chromatography, eluting with 70% to 80% acetonitrile in water (0.1% TFA) over 10 minutes, to afford tert-butyl 2-(1-(4- (difluoromethoxy)phenyl)cyclopropane-1-carboxamido)-4-methyl-8-azabicyclo[3.2.1]octane-8- carboxylate (750 mg, 86% yield) as a mixture of stereoisomers. LCMS: m / z [M+H]+= 451.2.

[0572] Step 8: A solution of the tert-butyl 2-(1-(4-(difluoromethoxy)phenyl)cyclopropane-1- carboxamido)-4-methyl-8-azabicyclo[3.2.1]octane-8-carboxylate mixture of Step 7 (750 mg, 1.66 mmol, 1.00 equiv) and 4 M HCl in 1,4-dioxane (7.5 mL) was stirred for 1 hour at room temperature. The resulting mixture was concentrated under reduced pressure to afford 1-(4- (difluoromethoxy)phenyl)-N-(4-methyl-8-azabicyclo[3.2.1]octan-2-yl)cyclopropane-1-carboxamide hydrochloride (600 mg, 93% crude yield) as a mixture of stereoisomers. LCMS: m / z [M+H]+= 351.2.

[0573] Step 9: To a solution of the 1-(4-(difluoromethoxy)phenyl)-N-(4-methyl-8- azabicyclo[3.2.1]octan-2-yl)cyclopropane-1-carboxamide hydrochloride mixture of Step 8 (600 mg, 1.71 mmol, 1.00 equiv) in acetonitrile (6.0 mL) was added BrCN (362.74 mg, 3.42 mmol, 2.00 equiv) and K2CO3(709.94 mg, 5.13 mmol, 3.00 equiv). The reaction was stirred for 1 hour at 80 °C, quenched with water (10 mL), and the resulting mixture was extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to afford N-(8-cyano-4-methyl-8-azabicyclo[3.2.1]octan-2-yl)-1- (4-(difluoromethoxy)phenyl)cyclopropane-1-carboxamide (680 mg, 95% crude yield) as a mixture of stereoisomers. LCMS: m / z [M+H]+= 376.2.

[0574] Step 10: To a solution of the N-(8-cyano-4-methyl-8-azabicyclo[3.2.1]octan-2-yl)-1-(4- (difluoromethoxy)phenyl)cyclopropane-1-carboxamide mixture of Step 9 (200.00 mg, 0.53 mmol, 1.00 equiv) in ethanol (2.0 mL) were added hydroxylamine hydrochloride (74.04 mg, 1.06 mmol, 2.00 equiv) and K2CO3(220.88 mg, 1.59 mmol, 3.00 equiv). The reaction was stirred for 1 hour at 60 °C, quenched with water (10 mL), and the resulting mixture was extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to afford 1-(4-(difluoromethoxy)phenyl)-N-(8-((E)-N'- hydroxycarbamimidoyl)-4-methyl-8-azabicyclo[3.2.1]octan-2-yl)cyclopropane-1-carboxamide (200 mg, 83% crude yield) as a mixture of stereoisomers. LCMS: m / z [M+H]+= 409.2. Reactivity of the nitrogen atom of hydroxylamine (rather than the oxygen atom) with the cyano moiety is favored under basic or neutral conditions. See, e.g., in contrast Example 3.

[0575] Step 11: To a solution of the 1-(4-(difluoromethoxy)phenyl)-N-(8-((E)-N'- hydroxycarbamimidoyl)-4-methyl-8-azabicyclo[3.2.1]octan-2-yl)cyclopropane-1-carboxamide mixture of Step 10 (200 mg, 0.49 mmol, 1.00 equiv) and i-Pr2NEt (189.86 mg, 1.47 mmol, 3.00 equiv) in CH2Cl2(2.0 mL), was added triphosgene (290.59 mg, 0.98 mmol, 2.00 equiv) dropwise at 0 °C. The reaction was stirred for 1 hour at room temperature, quenched with water (10 mL) at 0 °C, and the resulting mixture was extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with brine (15 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash C18 gel chromatography, eluting with 40% to 50% acetonitrile in water (0.1% TFA) over 10 minutes, to afford 1-(4-(difluoromethoxy)phenyl)-N-(4- methyl-8-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)-8-azabicyclo[3.2.1]octan-2-yl)cyclopropane-1- carboxamide (110 mg, 85% yield) as a mixture of stereoisomers. LCMS: m / z [M+H]+= 435.1.

[0576] Step 12: The 1-(4-(difluoromethoxy)phenyl)-N-(4-methyl-8-(5-oxo-4,5-dihydro-1,2,4- oxadiazol-3-yl)-8-azabicyclo[3.2.1]octan-2-yl)cyclopropane-1-carboxamide mixture from Step 11 (110 mg) was purified by Prep-HPLC (XSelect CSH Fluoro-Phenyl OBD, 19 x 250 mm, 5 μm; mobile phase: 33% to 43% acetonitrile in water (0.05% TFA) over 10 minutes, then 43% acetonitrile in water (0.05% TFA) over an extra 10 minutes; flow rate: 25 mL / min; wavelength: 254 / 309 nm), to afford a mixture of two cis isomers and a mixture of two trans isomers (*absolute stereochemistry arbitrarily assigned).

[0577] 1-(4-(difluoromethoxy)phenyl)-N-((2R,4R)-4-methyl-8-(5-oxo-4,5-dihydro-1,2,4-oxadiazol- 3-yl)-8-azabicyclo[3.2.1]octan-2-yl)cyclopropane-1-carboxamide and the corresponding enantiomer (4,2-trans-isomers*): as the first eluting peak at RT(minutes) = 10.3; 35 mg. LCMS: m / z [M+H]+= 435.1, and

[0578] 1-(4-(difluoromethoxy)phenyl)-N-((2R,4S,)-4-methyl-8-(5-oxo-4,5-dihydro-1,2,4-oxadiazol- 3-yl)-8-azabicyclo[3.2.1]octan-2-yl)cyclopropane-1-carboxamide and the corresponding enantiomer (4,2-cis-isomers*): as the second eluting peak at RT(minutes) = 14.5; 28 mg. LCMS: m / z [M+H]+= 435.1.

[0579] Step 13: The mixture 4,2-trans-isomers* from Step 12 (35 mg) was purified by Prep-HPLC (CHIRALPAK IC, 2 x 25 cm, 5 μm; mobile phase: 25% ethanol (50% CH2Cl2) in hexanes (0.1% TFA) for 10 minutes; flow rate: 20 mL / min; wavelength: 220 / 254 nm) to afford separation of the two stereoisomers (*absolute stereochemistry arbitrarily assigned).

[0580] Compound 13A*-O: as the second eluting peak at RT(min): 8.68.11.2 mg. LCMS: m / z [M+H]+= 435.1.1H NMR (400 MHz, Methanol-d4) δ 7.49 - 7.41 (d, J = 8.4 Hz, 2H), 7.18 - 7.11 (d, J =8.6 Hz, 2H), 6.80 (t, J = 74.0 Hz, 1H), 4.00 - 3.93 (m, 1H), 3.83 - 3.79 (m, 1H), 3.73 (d, J = 5.2 Hz, 1H), 2.11 - 2.03 (m, 1H), 2.02 - 1.95 (m, 2H), 1.81 - 1.70 (m, 3H), 1.58 - 1.48 (m, 2H), 1.32 - 1.21 (m, 1H), 1.16 - 1.08 (m, 2H), 0.76 (d, J = 7.2 Hz, 3H).

[0581] Compound 13D*-O: as the first eluting peak at RT(min): 6.95; 13.50 mg. LCMS: m / z [M+H]+= 435.1.1H NMR (400 MHz, Methanol-d4) δ 7.49 - 7.43 (d, J = 8.8 Hz, 2H), 7.18 - 7.12 (d, J= 8.4 Hz, 2H), 6.80 (t, J = 73.6 Hz, 1H), 3.97 (d, J = 5.8 Hz, 1H), 3.81 (d, J = 4.9 Hz, 1H), 3.74 (s, 1H), 2.13 - 2.02 (m, 1H), 2.02 - 1.94 (m, 2H), 1.82 - 1.70 (m, 3H), 1.59 - 1.49 (m, 2H), 1.27 (t, J = 14.6 Hz, 1H), 1.17 - 1.07 (m, 2H), 0.76 (d, J = 7.2 Hz, 3H), and

[0582] Step 14: The mixture of 4,2-cis-isomers* from Step 12 (28 mg) was purified by Prep-HPLC with the following conditions (CHIRALPAK IE, 2 x 25 cm, 5 μm; mobile phase: 40% ethanol (50% CH2Cl2) in hexanes (0.1% TFA) for 11 minutes; flow rate: 20 mL / min; wavelength: 220 / 254 nm), to afford separation of the two stereoisomers (*absolute stereochemistry arbitrarily assigned):

[0583] Compound 13B*-O: as the first eluting peak at RT(minutes) = 6.76; 10.5 mg. LCMS: m / z [M+H]+= 435.2.1H NMR (400 MHz, Methanol-d4) δ 7.45 (d, J = 8.4 Hz, 2H), 7.18 (d, J = 8.8 Hz, 2H), 6.79 (t, J = 74.0 Hz, 1H), 4.09 (d, J = 9.8 Hz, 1H), 3.98 (s, 1H), 3.82 (d, J = 7.2 Hz, 1H), 2.06 - 1.94 (m, 1H), 1.82 (t, J = 7.2 Hz, 1H), 1.75 - 1.56 (m, 4H), 1.54 - 1.47 (m, 2H), 1.42 - 1.34 (m, 1H), 1.16 - 1.05 (m, 5H); and

[0584] Compound 13C*-O: as the second eluting peak at RT(minutes) = 9.33; 8.2 mg. LCMS: m / z [M+H]+= 435.1.1H NMR (400 MHz, Methanol-d4) δ 7.45 (d, J = 8.8 Hz, 2H), 7.17 (d, J = 8.8 Hz, 2H), 6.86 (t, J = 74.0 Hz, 1H), 4.14 - 4.05 (m, 1H), 3.98 (m, 1H), 3.85 - 3.79 (m, 1H), 2.07 - 1.94 (m, 1H), 1.82 (t, J = 7.2 Hz, 1H), 1.76 - 1.56 (m, 4H), 1.53 - 1.48 (m, 2H), 1.39 (dd, J = 13.6, 5.4 Hz, 1H), 1.17 - 1.05 (m, 5H).

[0585] Compounds provided in the below Table B were prepared, or may be prepared, following the General Procedures and Examples as described above. LC-MS data is provided for each compound prepared according to the described Procedure.Assay Methods Human whole blood (hWB) NLRP3 Assay

[0586] The objective of this assay is to demonstrate if a test compound is able to interfere with human NLRP3 function in a whole blood system.

[0587] Human whole blood is drawn from healthy volunteers after obtaining written informed consent. Heparin lithium coated tubes are used to collect blood from volunteers. Blood samples are distributed on 96 well plates using 90 µl per well.

[0588] Priming procedure: Priming is performed by adding 5 µl of LPS (O26:B6; Sigma L-2654) at a final concentration of 1 µg / ml for 4.5 hours in a humidified incubator with 37 °C, 5 % CO2. Thirty minutes prior to NLRP3 activation, 5 µl of a 20X compound solution or vehicle (2% dimethylsulfoxide (DMSO)) is added to each well and plates were incubated on a shaker (450 rpm) in a humidified incubator with 37 °C, 5 % CO2.

[0589] Alternative priming procedure: Thirty minutes prior to LPS priming, 5 µl of a 20X compound solution or vehicle (2% dimethylsulfoxide (DMSO)) is added to each well and plates were incubated on a shaker (450 rpm) in a humidified incubator with 37 °C, 5 % CO2. Priming is performed by adding 5 µl of LPS (O26:B6; Sigma L-2654) at a final concentration of 1 µg / ml for 5 hours in a humidified incubator with 37 °C, 5 % CO2.

[0590] Activation is then performed by adding 3.3 µl of a 31X ATP solution per well. At the end of the 30 minutes stimulation, the plates are centrifuged (800 g, 10 min, room temperature) and the plasma from each well is frozen at -80 °C. IL-1β levels in the supernatant were analyzed using a mesoscale discovery assay (MSD K151TUK) according to the manufacturers’ instructions. There is no detectable difference in assay results using the priming procedure versus the alternative priming procedure.

[0591] hWB NLRP3 IC50assay results, as a measurement of whole blood potency, are provided in Table C. “A” activity = <1 uM; “B” activity = 1 - 2 uM; “C” activity = >2 - 3 uM; “D” activity = >3 uM. Results

[0592] Compounds described herein were tested according to the above-described assay. Dashed (--) line means no data available.OTHER EMBODIMENTS

[0593] Claims or descriptions that include “or” between one or more members of a group are considered satisfied if one, more than one, or all of the group members are present in, employed in, or otherwise relevant to a given product or process unless indicated to the contrary or otherwise evident from the context. The present disclosure includes embodiments in which exactly one member of the group is present in, employed in, or otherwise relevant to a given product or process. The present disclosure includes embodiments in which more than one, or all of the group members are present in, employed in, or otherwise relevant to a given product or process.

[0594] Furthermore, the present disclosure encompasses all variations, combinations, and permutations in which one or more limitations, elements, clauses, and descriptive terms from one or more of the listed claims or embodiments is introduced into another claim or embodiment. For example, any claim that is dependent on another claim can be modified to include one or more limitations found in any other claim that is dependent on the same base claim. Where the present disclosure recites elements presented as lists, e.g., in Markush group format, each subgroup of the elements is also disclosed, and any element(s) can be removed from the group. It should be further understood that when any variable (e.g., an R group) is present more than one time in a given Markush structure (e.g., 2 or more times), and that variable may be selected from a given list of two or more elements, unless otherwise stated or understood within the context of the present disclosure, that variable (e.g., the R group) at each repeated occurrence (e.g., 2 or more times) is independent of each other, being independently selected from that given list.

[0595] It should also be understood that, in general, where the present disclosure, or aspects of the present disclosure, is / are referred to as comprising particular elements and / or features, certain embodiments of the present disclosure or aspects of the present disclosure also consist, or consist essentially of, such elements and / or features. For purposes of simplicity, those embodiments have notbeen specifically set forth in haec verba herein. It is also noted that the terms “comprising” and “containing” are intended to be open and permits the inclusion of additional elements or steps. Where ranges are given, endpoints are understood to be included. Furthermore, unless otherwise indicated or otherwise evident from the context and understanding of one of ordinary skill in the art, values that are expressed as ranges can assume any specific value or sub-range within the stated ranges in different embodiments of the present disclosure, to the tenth of the unit of the lower limit of the range, unless the context clearly dictates otherwise.

[0596] This application refers to various issued patents, published patent applications, journal articles, and other publications, all of which are incorporated herein by reference. If there is a conflict between any of the incorporated references and the present disclosure, the present disclosure shall control. In addition, any particular embodiment of the present disclosure that falls within the prior art may be explicitly excluded from any one or more of the claims. Because such embodiments are deemed to be known to one of ordinary skill in the art, they may be excluded even if the exclusion is not set forth explicitly herein. Any particular embodiment of the present disclosure can be excluded from any claim, for any reason, whether or not related to the existence of prior art.

[0597] The scope of the present embodiments described herein is not intended to be limited to the above Description, but also includes that as set forth in the appended claims. Those of ordinary skill in the art will appreciate that various changes and modifications to this description may be made without departing from the spirit or scope of the present disclosure, as defined in the following claims.

Claims

CLAIMS What is claimed is:

1. A compound of Formula (I) or (II): or a pharmaceutically acceptable salt or tautomer thereof, wherein: Ring A is a ring system wherein: G1is CRG1or N; G2is CRG2or N; G3is CRG3or N; and G4is CRG4or N; provided no more than two of G1, G2, G3, and G4are N; R1is halo, C1-6alkyl, C1-6haloalkyl, -ORG5, -SRG5, -N(RG5)2, C3-4carbocyclyl, or 3-4 membered heterocyclyl, wherein the carbocyclyl and heterocyclyl are independently substituted with 0, 1, 2, or 3 halo, C1-6alkyl, C1-6haloalkyl, -ORG5, -SRG5, or -N(RG5)2, or R1and G2, together with the atoms to which they are attached, are joined to form a 5- membered heteroaryl ring independently substituted with 0, 1, 2, or 3 RG7; RG1, RG2, RG3, and RG4are each independently selected from the group consisting of hydrogen, halo, C1-6alkyl, C1-6haloalkyl, and -ORG6; RG5and RG6are each independently hydrogen, C1-6alkyl, or C1-6haloalkyl; and each instance of RG7is independently halo, C1-6alkyl, C1-6haloalkyl, -ORG5, -SRG5, or -N(RG5)2; Ring B is a ring system wherein: n is 0 or 1; p is 1 or 2; m is 0, 1, 2, or 3; each instance of R2aand R2bis independently hydrogen, halo, C1-6alkyl, C1-6haloalkyl, C3-4carbocyclyl, or 3-4 membered heterocyclyl, wherein the carbocyclyl or heterocyclyl are each independently substituted with 0, 1, 2, or 3 halo, or R2aand R2bare joined to form a C3carbocyclyl independently substituted with 0, 1, 2, or 3 halo; and each instance of R3is independently halo, C1-6alkyl or C1-6haloalkyl, or two R3groups are joined to form a C1-3alkylene bridging group or C1-3haloalkylene bridging group;R4is hydrogen, C1-3alkyl, C3-4carbocyclyl, or C3-4carbocyclyl-C1-3alkyl-, wherein the alkyl and carbocyclyl are each independently substituted with 0, 1, 2, 3, 4, 5, or 6 halo, and wherein the carbocyclyl is further independently substituted with 0, 1, or 2 C1-3alkyl or C1-3haloalkyl; and Ring C is an oxadiazolone of Formula (i-O) or (i-N):

2. The compound of claim 1, wherein the compound is of Formula: or a pharmaceutically acceptable salt or tautomer of any of the foregoing, wherein L is a C1-3alkylene bridging group.

3. The compound of claim 1 or claim 2, wherein the compound is of Formula:or a pharmaceutically acceptable salt or tautomer of any of the foregoing.

4. The compound of any one of claims 1-3, or a pharmaceutically acceptable salt or tautomer thereof, wherein R4is C1-3alkyl.

5. The compound of any one of claims 1-4, or a pharmaceutically acceptable salt or tautomer thereof, wherein G1is CRG1, G2is CH, G3is CH, and G4is CRG4.

6. The compound of any one of claims 1-5, or a pharmaceutically acceptable salt or tautomer thereof, wherein RG1is hydrogen or halo.

7. The compound of any one of claims 1-6, or a pharmaceutically acceptable salt or tautomer thereof, wherein RG4is hydrogen or halo.

8. The compound of any one of claims 1-7, or a pharmaceutically acceptable salt or tautomer thereof, wherein R1is C1-3alkyl, C1-3haloalkyl, or -ORG5.

9. The compound of any one of claims 1-8, or a pharmaceutically acceptable salt or tautomer thereof, wherein RG5is C1-3alkyl or C1-3haloalkyl.

10. The compound of any one of claims 1-9, or a pharmaceutically acceptable salt or tautomer thereof, wherein n is 0 and p is 1.

11. The compound of any one of claims 1-10, or a pharmaceutically acceptable salt or tautomer thereof, wherein one of R2aand R2bis C1-6alkyl, and the other of R2aand R2bis H.

12. The compound of any one of claims 1-11, or a pharmaceutically acceptable salt or tautomer thereof, wherein Ring A is:

13. The compound of any one of claims 1-12, wherein the compound is selected from the compounds described in Table 1 and Table 2, or a pharmaceutically acceptable salt or tautomer thereof.

14. A pharmaceutical composition comprising the compound of any one of claims 1-13, or a pharmaceutically acceptable salt or tautomer thereof, and one or more pharmaceutically acceptable carriers.

15. A method of inhibiting NLRP3, the method comprising administering to a subject the compound of any one of claims 1-13, or a pharmaceutically acceptable salt or tautomer thereof, or the pharmaceutical composition of claim 14.

16. A method of treating or preventing a disease or disorder, the method comprising administering to a subject the compound of any one of claims 1-13, or a pharmaceutically acceptable salt or tautomer thereof, or the pharmaceutical composition of claim 14.

17. A process for preparing the compound of Formula (I) or (II) of any one of claims 1-13, or a pharmaceutically acceptable salt or tautomer thereof, wherein the compound is synthesized according to General Schemes A-C.

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