Heterocyclic compounds, such as HT-6184, for use in the treatment of pain

Abstract

Described herein are methods of treating pain with NEK7 inhibitors. In some embodiments the method of treatment comprises administering a compound of formula (I): or a pharmaceutically acceptable salt or solvate thereof, wherein the variables are as defined herein.

Description

Attorney Docket No.63243-702.601 METHODS FOR THE TREATMENT OF PAIN CROSS REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of U.S. Provisional Patent Application No.63 / 625,217 filed January 25, 2024, and U.S. Provisional Application No.63 / 743,153 filed January 8, 2025, both of which are incorporated by reference herein in their entirety. BACKGROUND OF THE INVENTION

[0002] It is estimated that 50 million adults are afflicted by chronic pain in the UnitedStates alone. Despite the gravity of the pain problem, many existing pain medications often come with severe risks, including gastrointestinal side effects, risk of dependence, and risk of overdose. Therefore, novel methods for the treatment of pain are needed. SUMMARY OF THE INVENTION

[0003] In one aspect, provided herein is a method of treating pain in a subject with acompound provided herein. The pain may be acute inflammatory pain. The pain may be a symptom of a disease or condition of the subject experiencing pain. For example, the pain may be a symptom of inflammation, arthritis (e.g., osteoarthritis, rheumatoid arthritis, psoriatic arthritis), fibromyalgia, lupus, surgery (e.g., post-surgery pain), peritonitis, cancer, cancer treatment (e.g., chemotherapy), systemic sclerosis, psoriasis, atopic dermatitis, hidradenitis suppurativa, inflammatory bowel disease (IBD, e.g., colitis, Crohn's disease), endometriosis, or complex regional pain syndrome (CRPS), or two or more thereof. The pain may be associated with a disease or condition of the subject experiencing pain. As such, in some instances, the subject experiencing pain also has a disease or condition. Non-limiting example diseases and conditions include, inflammation, arthritis (e.g., osteoarthritis, rheumatoid arthritis, psoriatic arthritis), fibromyalgia, lupus, surgery (e.g., post-surgery pain), peritonitis, cancer, cancer treatment (e.g., chemotherapy), systemic sclerosis, psoriasis, atopic dermatitis, hidradenitis suppurativa, inflammatory bowel disease (IBD, e.g., colitis, Crohn's disease), endometriosis, and complex regional pain syndrome (CRPS).

[0004] In some embodiments, the compound is of Formula (I), or a pharmaceuticallyacceptable salt, stereoisomer, or solvate thereof:Attorney Docket No.63243-702.601wherein: A is C6-C10 aryl, C3-C10 cycloalkyl, 3-10 membered heterocyclyl or 5-6 membered monocyclic heteroaryl, each of which is optionally substituted with one or more R6; X is CH or N; Y is NH; R1is H; R2is C1-C6 alkyl, C3-C4 cycloalkyl, C3-C8 heterocyclyl or 5- or 6-membered heteroaryl, each of which is optionally substituted with one more substituent selected from halo, hydroxyl, cyano, aminyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy and 3- to 8- membered heterocyclyl; R3is H; R4is a heteroaryl selected from oxazolyl, isoxazolyl, 1, 2, 3-oxadiazolyl, 1, 2, 4-oxadiazolyl, 1, 2, 5-oxadiazolyl, 1, 3, 4-oxadiazolyl, 1, 2, 3-triazolyl, 1, 2, 4-triazolyl, thiazolyl, isothiazolyl, 1, 2, 3-thiadiazolyl, 1, 2, 4-thiadiazolyl, 1, 2, 5-thiadiazolyl and 1, 3, 4- thiadiazolyl, each of which is optionally substituted with one more substituents selected from halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, cyano, aminyl, C1-C6 hydroxylalkyl, C1-C6 cyanoalkyl, 3- to 8-membered heterocyclyl, C3-C8 haloalkylcycloalkyl, C3-C8 aminylalkylcycloalkyl, C3-C8 alkylcycloalkyl, 3- to 8-membered heterocyclylalkyl, 3- to 8-membered alkylheterocyclylcycloalkyl, 3- to 8-membered haloheterocyclylalkyl, and C3-C8 halocycloalkyl; R5is H; and each R6is independently halo, C1-C6 alkyl, C1-C6 alkoxy, cyano, C1-C6 hydroxylalkyl or C1- C6 haloalkyl.

[0005] In some embodiments, the compound is of Formula (II). In some embodiments,the compound is of Formula (III). In some embodiments, the compound is of Formula (IV). In some embodiments, the compound is of Formula (V). In some embodiments, the compound is of Formula (VI).

[0006] In some embodiments, the compound is a compound of Table 1A. In someAttorney Docket No.63243-702.601 embodiments, the compound is a compound of Table 1B. In some embodiments, the compound is a compound of Table 1C. In some embodiments, the compound is a compound of Table 1D. In some embodiments, the compound is a compound of Table 1E. In some embodiments, the compound is a compound of Table 1F.

[0007] In some embodiments, the compound (e.g., compound of Formula (I), Formula(II), Formula (III), Formula (IV), Formula (V), Formula (VI), or the pharmaceutically acceptable salt, stereoisomer, or solvate thereof), is an inhibitor of NEK7 kinase. In some embodiments, the compound (e.g., compound of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), or the pharmaceutically acceptable salt, stereoisomer, or solvate thereof), is a modulator of the NLRP3 inflammasome. In some embodiments, the compound (e.g., compound of Formula (I), , Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), or the pharmaceutically acceptable salt, stereoisomer, or solvate thereof), is an inhibitor of the NLRP3 (protein)-NEK7 (protein) interaction. In some embodiments, the compound (e.g., compound of Formula (I), , Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), or the pharmaceutically acceptable salt, stereoisomer, or solvate thereof), is a compound that modulates the priming step of the NLRP3 inflammasome and inhibits the formation of NLRP3 (protein)-NEK7 (protein) interactions.

[0008] In some embodiments, the compound (e.g., compound of Formula (I), , Formula(II), Formula (III), Formula (IV), Formula (V), Formula (VI), or the pharmaceutically acceptable salt, stereoisomer, or solvate thereof), is administered orally. In some embodiments, the compound (e.g., compound of Formula (I), , Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), or the pharmaceutically acceptable salt, stereoisomer, or solvate thereof), is provided in a tablet, a pill, or a capsule. In some embodiments, the compound (e.g., compound of Formula (I), , Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), or the pharmaceutically acceptable salt, stereoisomer, or solvate thereof), is administered in a dose of about 0.5 mg to about 10 mg. In some embodiments, the compound (e.g., compound of Formula (I), , Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), or the pharmaceutically acceptable salt, stereoisomer, or solvate thereof), is administered in a dose of about 0.5 mg to about 5 mg. For example, the compound (e.g., the compound of Formula (I), , Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), or the pharmaceutically acceptable salt, stereoisomer, or solvate thereof), is administered in a dose of about 5 mg, about 4 mg, about 3 mg, about 2 mg, about 0.5 mg.Attorney Docket No.63243-702.601 BRIEF DESCRIPTION OF THE FIGURES

[0009] Exemplary embodiments are illustrated in referenced figures. It is intended that theembodiments and figures disclosed herein are to be considered illustrative rather than restrictive.

[0010] FIGS. 1A-1C depict the modulation of mechanical allodynia (measured by pawwithdrawal threshold: FIG.1A, left, FIG.1B, top, FIG.1C, left) and thermal hyperalgesia (measured by paw withdrawal latency: FIG.1A, right, FIG.1B, bottom, FIG.1C, right) in a rat model of CFA-induced inflammatory pain.

[0011] FIGS. 2A-2B depict the modulation of mechanical allodynia (measured by pawwithdrawal threshold) and thermal hyperalgesia (measured by paw withdrawal latency) by Compound 10 in a rat model of postoperative incisional pain.

[0012] FIGS. 3A-3B depict the modulation of body weight and mechanical allodynia(measured by paw withdrawal threshold) by Compound 10 in a rat model of surgically induced osteoarthritis (anterior cruciate ligament transection combined with partial medial meniscectomy).

[0013] FIG. 4 shows the impact of sufficient exposure to compound 10 on CRP levels (CRP= C-reactive protein; Hr = hour) in a human Phase 2b study of third molar extraction.

[0014] FIG. 5 shows the impact of trough compound 10 exposure on CRP levels in a humanPhase 2b study of third molar extraction. (CRP = C-reactive protein; Hr = hour; FU1 = follow-up visit 1; FU2 = follow-up visit 2; PK = pharmacokinetics Note: The dashed line shows the plasma concentration levels of compound 10 in the compound 10 treatment group at baseline before treatment, at 4 hours, and at 24 hours at FU1.)

[0015] FIG. 6 shows SAP pain intensity by time area under curves (AUCs) Full ANCOVAmodel P-values in a human Phase 2b study of third molar extraction. (ANCOVA = analysis of covariance; AUC = area under the curve; SAP = statistical analysis plan. "SAP" Pain Intensity by Time AUCs are calculated (according to the Statistical Analysis Plan) by first replacing pain intensity ratings after the administration of rescue analgesia with the highest score of 10. P-values are from an ANCOVA model that includes the number of impacted mandibular third molars extracted as a covariate, randomized treatment group and the two- way interaction. Error bars are ±1 standard error.)

[0016] FIG. 7 shows analgesic use in subjects without fully impacted molars in a humanPhase 2b study of third molar extraction. (FU2 = follow-up visit 2.)Attorney Docket No.63243-702.601 DETAILED DESCRIPTION OF THE INVENTION

[0017] In one aspect, provided herein are compounds that are modulators of the NLRP3inflammasome, a multimeric protein complex which acts as an intracellular sensor for a variety of danger signals and responds by initiating an inflammatory response, whichincludes release of the proinflammatory cytokines IL- -18, as well as pyroptotic celldeath.

[0018] In some embodiments, compounds herein demonstrate significant pain control in ratmodels of inflammatory pain, postsurgical incisional pain, and pain secondary to osteoarthritis driven by activation of the NLRP3 inflammas Adjuvant (CFA)-induced inflammatory pain model, treatment with single oral doses of a compound herein at 10 mg / kg and 30 mg / kg resulted in significant dose-dependent improvements in mechanical allodynia and thermal hyperalgesia with peak effect observed 3 daily oral doses of a compound herein at 10 mg / kg and 30 mg / kg resulted in a statistically significant improvement in paw withdrawal threshold (PWT) and paw withdrawal latency (PWL) at all timepoints with overall improvements of 51% and 92% in mechanical allodynia and thermal hyperalgesia, respectively (p<0.01 or better), when compared with the no treatment control group. In a model or surgically induced osteoarthritis involving transection of the anterior cruciate ligament combined with partial medial meniscectomy, treatment with daily of doses of a compound herein at 1 mg / kg resulted in a statistically significant improvement in paw withdrawal threshold (PWT) measured 7, 14, 21, 28, and 35 days post- surgery (p<0.05 or better), culminating in a 18% overall improvement in mechanical allodynia (p<0.01), when compared with the no treatment control group.

[0019] Accordingly, provided herein are methods of treating pain with a compounddisclosed herein. For example, a compound of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), or Formula (VI). Terms

[0020] Unless defined otherwise, all terms of art, notations and other technical andscientific terms or terminology used herein are intended to have the same meaning as is commonly understood by one of ordinary skill in the art to which the claimed subject matter pertains. In some cases, terms with commonly understood meanings are described herein for clarity and / or for ready reference, and the inclusion of such should not necessarily be construed to represent a substantial difference over what is generally understood in the art.

[0021] Attorney Docket No.63243-702.601 includes a plurality of samples, including mixtures thereof.

[0022] Adisclosure and a medium generally accepted in the art for the delivery of compounds of the disclosure to mammals, e.g., humans. Such a medium includes all pharmaceutically acceptable carriers, diluents, or excipients therefore.

[0023] , withoutlimitation any adjuvant, carrier, excipient, glidant, sweetening agent, diluent, preservative, dye / colorant, flavor enhancer, surfactant, wetting agent, dispersing agent, suspending agent, stabilizer, isotonic agent, solvent, or emulsifier.

[0024] refers to the NH2 radical.

[0025] CO2H radical.

[0026] CN radical.

[0027] Hydroxy OH radical.

[0028] NO2 radical.

[0029]

[0030] SH substituent.

[0031] Thioxo

[0032] radicalconsisting solely of carbon and hydrogen atoms, having from one to twelve carbon atoms (C1-C12 alkyl), one to eight carbon atoms (C1-C8 alkyl) or one to six carbon atoms (C1-C6 alkyl), or any value within these ranges, such as C4-C6 alkyl and the like, and which is attached to the rest of the molecule by a single bond, e.g., methyl, ethyl, n-propyl, 1-methylethyl (iso-propyl), n-butyl, n-pentyl, 1,1-dimethylethyl (t-butyl), 3-methylhexyl, 2-methylhexyl and the like. The number of carbons referred to relates to the carbon backbone and carbon branching but does not include carbon atoms belonging to any substituents. Unless stated otherwise specifically in the specification, an alkyl group is optionally substituted.

[0033] straight or branched hydrocarbon chain radicalconsisting solely of carbon and hydrogen atoms, which contains one or more carbon-carbon double bonds, having from two to twelve carbon atoms (C2-C12 alkenyl), two to eight carbonAttorney Docket No.63243-702.601 atoms (C2-C8 alkenyl) or two to six carbon atoms (C2-C6 alkenyl), or any value within these ranges, and which is attached to the rest of the molecule by a single bond, e.g., ethenyl, prop-1-enyl, but-1-enyl, pent-1-enyl, penta-1,4-dienyl, and the like. The number of carbons referred to relates to the carbon backbone and carbon branching but does not include carbon atoms belonging to any substituents. Unless stated otherwise specifically in the specification, an alkenyl group is optionally substituted.

[0034] d straight or branched hydrocarbon radical, having2 to 12 carbon atoms (C2-C12 alkynyl), two to nine carbon atoms (C2-C9 alkynyl), or two to six carbon atoms (C2-C6 alkynyl), or any value within these ranges, and having at least one carbon- carbon triple bond. Examples of alkynyl groups may be selected from the group consisting of ethynyl, propargyl, but-1-ynyl, but-2-ynyl and the like. The number of carbons referred to relates to the carbon backbone and carbon branching but does not include carbon atoms belonging to any substituents. Unless stated otherwise specifically in the specification, an alkynyl group is optionally substituted.

[0035] ORa where Ra is an alkyl radical asdefined above containing one to twelve carbon atoms (C1-C12 alkoxy), one to eight carbon atoms (C1-C8 alkoxy) or one to six carbon atoms (C1-C6 alkoxy), or any value within these ranges. Unless stated otherwise specifically in the specification, an alkoxy group is optionally substituted.

[0036] NRaRb, where Ra and Rb are eachindependently H or C1-C6 alkyl as defined above. When both of Ra and Rb are H, an "aminyl" group is the same as an "amino" group as defined above. The C1-C6 alkyl portion of an aminyl group is optionally substituted unless stated otherwise.

[0037] f the formula RaRbNRcRd where Rais cycloalkyl as defined herein, Rb is C1-C6 alkyl, Rc is H or C1-C6 alkyl and Rd is C1-C6 alkyl as defined above. The cycloalkyl and each C1-C6 alkyl portion of an aminylalkylcycloalkyl group are optionally substituted unless stated otherwise.

[0038] i.e., aradical) with a ring of resonance bonds that exhibits increased stability relative to other connective arrangements with the same sets of atoms. Generally, aromatic rings contain a setof covalently bound co- -electrons (for example,alternating double and single bonds) that is even but not a multiple of 4 (i.e. -electrons, where n = 0, 1, 2, 3, etc.). Aromatic rings include, but are not limited to, phenyl,Attorney Docket No.63243-702.601 naphthenyl, imidazolyl, pyrrolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridonyl, pyridazinyl, pyrimidonyl. Unless stated otherwise specifically in the specification, an "aromatic ring" includes all radicals that are optionally substituted.

[0039] atoms, for example 6 to 10 carbon atoms (C6-C10 aryl) and at least one carbocyclic aromatic ring. For purposes of embodiments of this invention, the aryl radical is a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused or bridged ring systems. Aryl radicals include, but are not limited to, aryl radicals derived from aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, fluoranthene, fluorene, as-indacene, s-indacene, indane, indene, naphthalene, phenalene, phenanthrene, pleiadene, pyrene, and triphenylene. Unless stated otherwise specifically in the specification, an aryl group is optionally substituted.

[0040] The CN substituent may be on a primary, secondary, or tertiary carbon. Unless stated otherwise specifically in the specification, a cyanoalkyl group is optionally substituted.

[0041] "Carbocyclic" or "carbocycle" refers to a ring system, wherein each of the ringatoms are carbon.

[0042] refers to a non-aromatic monocyclic or polycyclic carbocyclicradical consisting solely of carbon and hydrogen atoms, which may include fused or bridged ring systems, having from three to fifteen ring carbon atoms (C3-C15 cycloalkyl), from three to ten ring carbon atoms (C3-C10 cycloalkyl), or from three to eight ring carbon atoms (C3-C8 cycloalkyl), or any value within these ranges such as three to four carbon atoms (C3-C4 cycloalkyl), and which is saturated or partially unsaturated and attached to the rest of the molecule by a single bond. Monocyclic radicals include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic radicals include, for example, adamantyl, norbornyl, decalinyl, 7,7-dimethyl-bicyclo[2.2.1]heptanyl, and the like. Unless otherwise stated specifically in the specification, a cycloalkyl group is optionally substituted.

[0043] Alkylcycloalkyl RaRb where Ra is acycloalkyl group and Rb is an alkyl group as defined above. Unless otherwise stated specifically in the specification, an alkylcycloalkyl group is optionally substituted.

[0044] refers to any ring structure described herein which is fused to anotherring structure.

[0045] "Halo" refers to bromo, chloro, fluoro, or iodo.Attorney Docket No.63243-702.601

[0046] or more halo radicals, as defined above, e.g., trifluoromethyl, difluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, and the like. Unless stated otherwise specifically in the specification, a haloalkyl group is optionally substituted.

[0047] substituted by one or more halo radicals, as defined above, e.g., trifluoromethyl, difluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, and the like. Unless stated otherwise specifically in the specification, a halocycloalkyl group is optionally substituted.

[0048] RaRb where Ra is acycloalkyl group and Rb is a haloalkyl group as defined above. Unless otherwise stated specifically in the specification, a haloalkylcycloalkyl group is optionally substituted.

[0049] one or more hydroxyl radical. The hydroxyalkyl radical is joined at the main chain through the alkyl carbon atom. Unless stated otherwise specifically in the specification, a hydroxylalkyl group is optionally substituted.

[0050] - to 18-membered, for example 3- to 10-membered or3- to 8-membered, non-aromatic ring radical having one to ten ring carbon atoms (e.g., two to ten) and from one to six ring heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. Unless stated otherwise specifically in the specification, the heterocyclyl radical is partially or fully saturated and is a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused, spirocyclic and / or bridged ring systems. Nitrogen, carbon, and sulfur atoms in a heterocyclyl radical are optionally oxidized, and nitrogen atoms may be optionally quaternized. Examples of such heterocyclyl radicals include, but are not limited to, dioxolanyl, thienyl[1,3]dithianyl, decahydroisoquinolyl, furanonyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, hexahydro-1H-pyrrolizine, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, oxiranyl, piperidinyl, piperazinyl, 4-piperidonyl, azetidinyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, and 1,1-dioxo-thiomorpholinyl. Unless stated otherwise specifically in the specification, a heterocyclyl group is optionally substituted.

[0051] s to a radical group of the formula RaRb where Ra isAttorney Docket No.63243-702.601 an alkyl group and Rb is a haloheterocyclyl group as defined herein. Unless otherwise stated specifically in the specification, a haloheterocyclylalkyl group is optionally substituted.

[0052] RaRb where Ra is analkyl group and Rb is a heterocyclyl group as defined herein. Unless otherwise stated specifically in the specification, a heterocyclylalkyl group is optionally substituted.

[0053] - to 18-membered, for example 5- to 6-membered, ringsystem radical comprising one to thirteen ring carbon atoms, one to six ring heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, and at least one aromatic ring. Heteroaryl radicals may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused or bridged ring systems; and the nitrogen, carbon, or sulfur atoms in the heteroaryl radical may be optionally oxidized; the nitrogen atom may be optionally quaternized. Examples include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzodioxolyl, benzofuranyl, benzooxazolyl, benzothiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxepinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl), benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridinyl, carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl, isoxazolyl, naphthyridinyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, 1-oxidopyridinyl, 1-oxidopyrimidinyl, 1-oxidopyrazinyl, 1- oxidopyridazinyl, 1-phenyl-1H-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl, quinoxalinyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, and thiophenyl (i.e., thienyl). Unless stated otherwise specifically in the specification, a heteroaryl group is optionally substituted.

[0054] Oxazolyl, isoxazolyl, 1, 2, 3-oxadiazolyl, 1, 2, 4-oxadiazolyl, 1, 2, 5-oxadiazolyl,1, 3, 4-oxadiazolyl, 1, 2, 3-triazolyl, 1, 2, 4-triazolyl, thiazolyl, isothiazolyl, 1, 2, 3- thiadiazolyl, 1, 2, 4-thiadiazolyl, 1, 2, 5-thiadiazolyl and 1, 3, 4-thiadiazolyl refer to the following structures, respectively:Attorney Docket No.63243-702.601

[0056] wherein the oxazolyl, isoxazolyl, 1, 2, 3-oxadiazolyl, 1, 2, 4-oxadiazolyl, 1, 2, 5-oxadiazolyl, 1, 3, 4-oxadiazolyl, 1, 2, 3-triazolyl, 1, 2, 4-triazolyl, thiazolyl, isothiazolyl, 1, 2, 3-thiadiazolyl, 1, 2, 4-thiadiazolyl, 1, 2, 5-thiadiazolyl, and 1, 3, 4-thiadiazolyl are attached to the remainder of the molecule by a covalent bond to one of the carbon atoms in the ring of the oxazolyl, isoxazolyl, 1, 2, 3-oxadiazolyl, 1, 2, 4-oxadiazolyl, 1, 2, 5-oxadiazolyl, 1, 3, 4- oxadiazolyl, 1, 2, 3-triazolyl, 1, 2, 4-triazolyl, thiazolyl, isothiazolyl, 1, 2, 3-thiadiazolyl, 1, 2, 4-thiadiazolyl, 1, 2, 5-thiadiazolyl, and 1, 3, 4-thiadiazolyl.

[0057] The term "substituted" as used herein means any of the above groups (e.g., alkyl,alkenyl, alkylene, alkylcarbonyl, alkoxy, alkoxyalkyl, aminylalkyl, aryl, cyanoalkyl, cycloalkyl, haloalkyl, heterocyclyl, heterocyclene, heterocyclylalkyl, heteroaryl, heteroarylalkyl and / or hydroxylalkyl) wherein at least one hydrogen atom (e.g., 1, 2, 3 or all hydrogen atoms) is replaced by a bond to a non-hydrogen substituent. Examples of non- hydrogen substituents include, but are not limited to amino, carboxyl, cyano, hydroxyl, halo, nitro, oxo, thiol, thioxo, alkyl, alkenyl, alkylcarbonyl, alkoxy, aryl, cyanoalkyl, cycloalkyl, haloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl and / or hydroxylalkyl substituents, each of which may also be optionally substituted with one or more of the above substituents.

[0058] In some specific embodiments, the optional substitutions are independentlyselected from the group consisting of halo, hydroxyl, cyano, aminyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, C3-C8 halocycloalkyl, C6-C10 aryl, 5- or 6-membered heteroaryl, C1-C6 alkoxy and 3-8 membered heterocyclyl.

[0059] a compound described herein that is sufficient to affect the intended application, including but not limited to pain treatment, as defined below.

[0060] T s to an approach for obtaining beneficial or desiredresults with respect to a disease, disorder or medical condition, including but not limited to, pain.

[0061] Pharmaceutically

[0062] acceptable acid additithe biological effectiveness of the free bases, which are biologically tolerable, or otherwise biologically suitable for administration to the subject.

[0063] those salts which retainthe biological effectiveness of the free acids, which are biologically tolerable, or otherwise biologically suitable for administration to the subject.Attorney Docket No.63243-702.601

[0064] fer toa compound having the ability to inhibit a biological function of a target protein, whether by inhibiting the activity or expression of the protein, such as NLRP3 inflammasome or NEK7 or the association of NLRP3 inflammasome NEK7. Accordingly, the terms "antagonist" and "inhibitors" may be defined in the context of the biological role of the target protein.

[0065] initiate or enhance a biological function of a target protein. Accordingly, the term "agonist" is defined in the context of the biological role of the target polypeptide. While preferred agonists herein specifically interact with (e.g., bind to) the target, compounds that initiate or enhance a biological activity of the target polypeptide by interacting with other members of the signal transduction pathway of which the target polypeptide is a member are also specifically included within this definition.

[0066] uman. Themethods described herein can be useful in both human therapeutics and veterinary applications. In some embodiments, the subject is a mammal, and in some embodiments, the subject is human.

[0067] as laboratoryanimals and household pets (e.g., cats, dogs, swine, cattle, sheep, goats, horses, rabbits), and non-domestic animals such as wildlife and the like.

[0068] Certain embodiments are also meant to encompass the in vivo metabolic productsof the disclosed compounds. Such products may result from, for example, the oxidation, reduction, hydrolysis, amidation, esterification, and the like of the administered compound, primarily due to enzymatic processes. Accordingly, embodiments include compounds produced by a process comprising administering a compound of this disclosure to a mammal for a period of time sufficient to yield a metabolic product thereof. Such products are typically identified by administering a radiolabeled compound of the disclosure in a detectable dose to an animal, such as rat, mouse, guinea pig, monkey, or to human, allowing sufficient time for metabolism to occur, and isolating its conversion products from the urine, blood, or other biological samples.

[0069] Often crystallizations produce a solvate of the compounds disclosed herein. Asof the disclosure with one or more molecules of solvent. In some embodiments, the solvent is water, in which case the solvate is a hydrate. Alternatively, in other embodiments, the solvent is an organic solvent. Thus, the compounds of the present disclosure may exist as aAttorney Docket No.63243-702.601 hydrate, including a monohydrate, dihydrate, hemihydrate, sesquihydrate, trihydrate, tetrahydrate and the like, as well as the corresponding solvated forms. In some aspects, the compounds of the disclosure are a true solvate, while in other cases, the compounds of the disclosure merely retain adventitious water or is a mixture of water plus some adventitious solvent.

[0070] same bonds but having different three-dimensional structures, which are not interchangeable. The present disclosure contemplates various stereoisomers and mixtures thereof and includes "enantiomers", which refers to two stereoisomers whose molecules are non-superimposable mirror images of one another.

[0071] The compounds of the disclosure (compounds of Formula (I), Formula (II),Formula (III), Formula (IV), Formula (V), Formula (VI)) or their pharmaceutically acceptable salts may contain one or more centers of geometric asymmetry and may thus give rise to stereoisomers such as enantiomers, diastereomers, and other stereoisomeric forms that are defined, in terms of absolute stereochemistry, as (R)- or (S)- or, as (D)- or (L)- for amino acids. Embodiments thus include all such possible isomers, as well as their racemic and optically pure forms. Optically active (+) and (-), (R)- and (S)-, or (D)- and (L)- isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques, for example, chromatography and fractional crystallization. Conventional techniques for the preparation / isolation of individual enantiomers include chiral synthesis from a suitable optically pure precursor or resolution of the racemate (or the racemate of a salt or derivative) using, for example, chiral high pressure liquid chromatography (HPLC). When the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, and unless specified otherwise, it is intended that the compounds include both E and Z geometric isomers. Likewise, all tautomeric forms are also intended to be included.

[0072] Embodiments of the present disclosure include all manner of rotamers andconformationally restricted states of a compound of the invention. Atropisomers, which are stereoisomers arising because of hindered rotation about a single bond, where energy differences due to steric strain or other contributors create a barrier to rotation that is high enough to allow for isolation of individual conformers, are also included. As an example, certain compounds of the disclosure may exist as mixtures of atropisomers or purified or enriched for the presence of one atropisomer.

[0073] In some embodiments, the compounds of Formula (I), Formula (I), Formula (II),Attorney Docket No.63243-702.601 Formula (III), Formula (IV), Formula (V), or Formula (VI) are a mixture of enantiomers or diastereomers. In other embodiments, the compounds of Formula (I), Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), or Formula (VI) are substantially one enantiomer or diastereomer.

[0074] of the same molecule. Embodiments thus include tautomers of the disclosed compounds.

[0075] The chemical naming protocol and structure diagrams used herein are a modifiedform of the I.U.P.A.C. nomenclature system, using the ACD / Name Version 9.07 software program and / or ChemDraw Professional Version 17.0.0.206 software naming program (CambridgeSoft). For complex chemical names employed herein, a substituent group is typically named before the group to which it attaches. For example, cyclopropylethyl comprises an ethyl backbone with a cyclopropyl substituent. Except as described below, all bonds are identified in the chemical structure diagrams herein, except for all bonds on some carbon atoms, which are assumed to be bonded to sufficient hydrogen atoms to complete the valency.

[0076] circumstances may or may not occur, and that the description includes instances where said event or circumstance occurs and instances in which it does not. For example, "optionally substituted aryl" means that the aryl radical may or may not be substituted and that the description includes both substituted aryl radicals and aryl radicals having no substitution.

[0077] The disclosure provides that wherever embodiments are provided herein with theous embodiments are not explicitly provided. The disclosure further provides that wherever embodiments are e disclosure also provides that

[0078] embers is intended to includeall members individually and all combination of full or partial list of members. For example, intended to encompass each of the following embodiments: A, B, and C; A, B, or C; A or C; A or B; B or C; A and C; A and B; B and C; A (alone); B (alone); and C (alone).Attorney Docket No.63243-702.601

[0079] The section headings used herein are for organizational purposes only and are notto be construed as limiting the subject matter described. Non-Limiting Compounds Applied in the Method of Treating Pain

[0080] Described herein are methods of treating pain comprising administering to asubject in need thereof a compound of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof. In some embodiments, the compound of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, inhibits NEK7 and / or modulates the activity of the NLRP3 inflammasome. The pain may be acute inflammatory pain. The pain may be a symptom of a disease or condition of the subject experiencing pain. The pain may be associated with a disease or condition of the subject experiencing pain. Non-limiting example diseases and conditions include, inflammation, arthritis (e.g., osteoarthritis, rheumatoid arthritis, psoriatic arthritis), fibromyalgia, lupus, surgery (e.g., post-surgery pain), peritonitis, cancer, cancer treatment (e.g., chemotherapy), systemic sclerosis, psoriasis, atopic dermatitis, hidradenitis suppurativa, inflammatory bowel disease (IBD, e.g., colitis, Crohn's disease), endometriosis, and complex regional pain syndrome (CRPS).

[0081] Embodiments described herein provide a compound having Formula (I):or a pharmaceutically acceptable salt, stereoisomer, or prodrug thereof, wherein: A is C6-C10 aryl, C3-C10 cycloalkyl, 3-10 membered heterocyclyl or 5-6 membered monocyclic heteroaryl, each of which is optionally substituted with one or more R6; Y is NH; R1is H or C1-C6 alkyl; R2is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3-8 membered heterocyclyl or 5- or 6-membered heteroaryl, each of which is optionally substituted with one more substituents selected from halo, hydroxyl, cyano, aminyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy and 3-8 membered heterocyclyl;Attorney Docket No.63243-702.601 R3is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3- to 8-membered heterocyclyl or 5- or 6-membered heteroaryl, each of which is optionally substituted with one more substituent selected from halo, hydroxyl, cyano, aminyl, C1-C6 alkyl, C2-C6 alkenyl, C2- C6 alkynyl and C1-C6 alkoxy; R4is a heteroaryl selected from oxazolyl, isoxazolyl, 1, 2, 3-oxadiazolyl, 1, 2, 4-oxadiazolyl, 1, 2, 5-oxadiazolyl, 1, 3, 4-oxadiazolyl, 1, 2, 3-triazolyl, 1, 2, 4-triazolyl, thiazolyl, isothiazolyl, 1, 2, 3-thiadiazolyl, 1, 2, 4-thiadiazolyl, 1, 2, 5-thiadiazolyl and 1, 3, 4-thiadiazolyl, each of which is optionally substituted with one more substituents selected from halo, C1-C6 alkyl, C2- C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, , cyano, aminyl, C1-C6 hydroxylalkyl, C1-C6 cyanoalkyl, 3- to 8-membered heterocyclyl, C3-C8 haloalkylcycloalkyl, C3-C8 aminylalkylcycloalkyl, C3-C8 alkylcycloalkyl, 3- to 8-membered heterocyclylalkyl, 3- to 8-membered alkylheterocyclylcycloalkyl, 3- to 8-membered haloheterocyclylalkyl, and C3- C8 halocycloalkyl, or combinations thereof; R5is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3- to 8-membered heterocyclyl, C6-C10 aryl or 5- or 6-membered heteroaryl, each of which is optionally substituted with one more substituents selected from halo, hydroxyl, cyano, aminyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl and C1-C6 alkoxy; and R6is, at each occurrence, independently halo, C1-C6 alkyl, cyano, C1-C6 hydroxylalkyl, C1-C6 alkoxy, or C1-C6 haloalkyl.

[0082] In some embodiments of the compound of Formula (I):A is C6-C10 aryl, C3-C10 cycloalkyl, 3-10 membered heterocyclyl or 5-6 membered monocyclic heteroaryl, each of which is optionally substituted with one or more R6; Y is NH; R1is H or C1-C6 alkyl; R2is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3-8 membered heterocyclyl or 5- or 6-membered heteroaryl, each of which is optionally substituted with one more substituents selected from halo, hydroxyl, cyano, aminyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy and 3-8 membered heterocyclyl; R3is H, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C8cycloalkyl, 3- to 8-membered heterocyclyl or 5- or 6-membered heteroaryl, each of which is optionally substituted with one more substituent selected from halo, hydroxyl, cyano, aminyl, C1-C6 alkyl, C2-C6 alkenyl, C2- C6 alkynyl and C1-C6 alkoxy; R4is a heteroaryl selected from oxazolyl, isoxazolyl, 1, 2, 3-oxadiazolyl, 1, 2, 4-oxadiazolyl, 1, 2, 5-oxadiazolyl, 1, 3, 4-oxadiazolyl, 1, 2, 3-triazolyl, 1, 2, 4-triazolyl, thiazolyl, isothiazolyl,Attorney Docket No.63243-702.601 1, 2, 3-thiadiazolyl, 1, 2, 4-thiadiazolyl, 1, 2, 5-thiadiazolyl and 1, 3, 4-thiadiazolyl, each of which is optionally substituted with one more substituents selected from halo, C1-C6 alkyl, C2- C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C3-C8 cycloalkyl and C3-C8 halocycloalkyl; R5is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3- to 8-membered heterocyclyl, C6-C10 aryl or 5- or 6-membered heteroaryl, each of which is optionally substituted with one more substituents selected from halo, hydroxyl, cyano, aminyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl and C1-C6 alkoxy; and R6is, at each occurrence, independently halo, C1-C6 alkyl, or C1-C6 haloalkyl.

[0083] In some embodiments of the compound of Formula (I):A is C6-C10 aryl, C3-C10 cycloalkyl, 3-10 membered heterocyclyl or 5-6 membered monocyclic heteroaryl, each of which is optionally substituted with one or more R6; X is CH or N; Y is NH; R1is H or C1-C6 alkyl; R2is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3-8 membered heterocyclyl or 5- or 6-membered heteroaryl, each of which is optionally substituted with one more substituents selected from halo, hydroxyl, cyano, aminyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy and 3-8 membered heterocyclyl; R3is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3- to 8-membered heterocyclyl or 5- or 6-membered heteroaryl, each of which is optionally substituted with one more substituent selected from halo, hydroxyl, cyano, aminyl, C1-C6 alkyl, C2-C6 alkenyl, C2- C6 alkynyl and C1-C6 alkoxy; R4is a heteroaryl selected from oxazolyl, isoxazolyl, 1, 2, 3-oxadiazolyl, 1, 2, 4-oxadiazolyl, 1, 2, 5-oxadiazolyl, 1, 3, 4-oxadiazolyl, 1, 2, 3-triazolyl, 1, 2, 4-triazolyl, thiazolyl, isothiazolyl, 1, 2, 3-thiadiazolyl, 1, 2, 4-thiadiazolyl, 1, 2, 5-thiadiazolyl and 1, 3, 4-thiadiazolyl, each of which is optionally substituted with one more substituents selected from halo, C1-C6 alkyl, C2- C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, cyano, aminyl, C1-C6 hydroxylalkyl, C1-C6 cyanoalkyl, 3- to 8-membered heterocyclyl, C3-C8 haloalkylcycloalkyl, C3-C8aminylalkylcycloalkyl, C3-C8alkylcycloalkyl, 3- to 8-membered heterocyclylalkyl, 3- to 8-membered alkylheterocyclylcycloalkyl, 3- to 8-membered haloheterocyclylalkyl, and C3- C8 halocycloalkyl; R5is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3- to 8-membered heterocyclyl, C6-C10 aryl or 5- or 6-membered heteroaryl, each of which is optionallyAttorney Docket No.63243-702.601 substituted with one more substituents selected from halo, hydroxyl, cyano, aminyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl and C1-C6 alkoxy; and R6is, at each occurrence, independently halo, C1-C6 alkyl, C1-C6 alkoxy, cyano, C1-C6 hydroxylalkyl or C1-C6 haloalkyl.

[0084] In some embodiments, A is any suitable functional group as described herein. Insome embodiments, A is C6-C10 aryl, C3-C10 cycloalkyl, 3-10 membered heterocyclyl or 5-6 membered monocyclic heteroaryl, each of which is optionally substituted with one or more R6. In some embodiments, A is C6-C10 aryl or 5-6 membered monocyclic heteroaryl, each of which is optionally substituted with one or more R6. In some embodiments, A is C6-C10 aryl optionally substituted with one or more R6. In some embodiments, A is 5-6 membered monocyclic heteroaryl optionally substituted with one or more R6. In some embodiments, A is C3-C10 cycloalkyl. In some embodiments, A is 3-10 membered heterocyclyl optionally substituted with one or more R6.

[0085] In some embodiments, A is a divalent optionally substituted C6-10 aryl. In someembodiments, A is a divalent optionally substituted 3-8 membered saturated or partially unsaturated carbocyclic ring. In some embodiments, A is a divalent optionally substituted 3- 10 membered heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, A is a divalent optionally substituted 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0086] In some embodiments, A is a divalent group selected from phenyl, naphthyl,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, cycloheptyl, adamantyl, cyclooctyl, [3.3.0]bicyclooctanyl, [4.3.0]bicyclononanyl, [4.4.0]bicyclodecanyl, [2.2.2]bicyclooctanyl, fluorenyl, indanyl, tetrahydronaphthyl, acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, NH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, dithiazinyl, tetrahydrofuranyl, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, indolenyl, indolinyl, indolizinyl, indolyl, 3-indolyl, isoindolinyl, isoindolenyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl;- 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolidinyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl,Attorney Docket No.63243-702.601 piperazinyl, piperidinyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole, pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2-pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl, 4H- quinolizinyl, quinoxalinyl, quinuclidinyl, tetrahydro furanyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, thiadiazinyl, 1,2,3- thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4- triazolyl, oxetanyl, azetidinyl, and xanthenyl; each of which is optionally substituted.

[0087] In some embodiments, A is a divalent group selected from phenyl, pyridinyl,cyclohexyl, and cyclohexenyl; each of which is optionally substituted. In other embodiments, A is phenyl. In some embodiments, A is saturated or unsaturated cyclohexyl. In more embodiments, A is pyridinyl.

[0088] In some embodiments, A is pyrimidinyl, which is optionally substituted.

[0089] In some embodiments, X is any suitable atom as described herein. In someembodiments, X is CH or N. In some embodiments, X is CH. In some embodiments, X is N.

[0090] In some embodiments, Y is any suitable linker as described herein. In someembodiments, Y is NH.

[0091] In some embodiments, R1 is any suitable functional group described herein. Insome embodiments, R1is H. In some embodiments, R1is C1-C6 alkyl. In some embodiments, R1is methyl, ethyl, n-propyl, or isopropyl.

[0092] In some embodiments, R2 is any suitable functional group described herein. Insome embodiments, R2is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3-8 membered heterocyclyl or 5- or 6-membered heteroaryl, each of which is optionally substituted with one more substituents selected from halo, hydroxyl, cyano, aminyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy and 3-8 membered heterocyclyl. In some embodiments R2is C1-C6 alkyl, C3-C4 cycloalkyl, C3-C8 heterocyclyl or 5- or 6-membered heteroaryl, each of which is optionally substituted with one more substituent selected from halo, hydroxyl, cyano, aminyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy and 3- to 8-membered heterocyclyl. In some embodiments, R2is butyl, cyclopropyl, cyclobutyl, pyrrolidinyl, piperidinyl, pyridinyl, azetidinyl, or oxetanyl, each of which is optionally substituted with one more substituent selected from halo, hydroxyl, cyano, aminyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy and 3- to 8-membered heterocyclyl. In some embodiments, R2is cyclopropyl, cyclobutyl, pyrrolidinyl, piperidinyl, or oxetanyl, each of which is optionally substituted with one more substituent selected from halo, hydroxyl,Attorney Docket No.63243-702.601 cyano, aminyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy and 3- to 8- membered heterocyclyl. In some embodiments, R2is cyclopropyl or oxetanyl, each of which is optionally substituted with one more substituent selected from halo, hydroxyl, cyano, aminyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy and 3- to 8-membered heterocyclyl. In some embodiments, R2is cyclopropyl. In some embodiments, R2is oxetanyl. In some embodiments, R2is unsubstituted cyclopropyl or oxetanyl. In some embodiments, R2is N-methyl substituted pyrrolidinyl. In some embodiments, R2is unsubstituted cyclobutyl.

[0093] In some embodiments, R2 is:

[0094] In some embodiments, R2 is:

[0095] In some embodiments, R3 is any suitable functional group described herein. Insome embodiments, R3is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3- to 8-membered heterocyclyl or 5- or 6-membered heteroaryl, each of which is optionally substituted with one more substituent selected from halo, hydroxyl, cyano, aminyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl and C1-C6 alkoxy. In some embodiments, R3is H or C1- C6 alkyl, wherein the C1-C6 alkyl is optionally substituted with one or more substituents selected from halo, hydroxyl, cyano, aminyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl and C1-C6 alkoxy. In some embodiments, R3is H. In some embodiments, R3is C1-C6 alkyl. In some embodiments, R3is methyl, ethyl, n-propyl, or isopropyl.

[0096] In some embodiments, R4 is any suitable functional group described herein. Insome embodiments, R4is a heteroaryl selected from oxazolyl, isoxazolyl, 1, 2, 3-oxadiazolyl, 1, 2, 4-oxadiazolyl, 1, 2, 5-oxadiazolyl, 1, 3, 4-oxadiazolyl, 1, 2, 3-triazolyl, 1, 2, 4-triazolyl, thiazolyl, isothiazolyl, 1, 2, 3-thiadiazolyl, 1, 2, 4-thiadiazolyl, 1, 2, 5-thiadiazolyl and 1, 3, 4- thiadiazolyl, each of which is optionally substituted with one more substituents selected from halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, , cyano, aminyl, C1-C6 hydroxylalkyl, C1-C6 cyanoalkyl, 3- to 8-membered heterocyclyl, C3-C8 haloalkylcycloalkyl, C3-C8 aminylalkylcycloalkyl, C3-C8 alkylcycloalkyl, 3- to 8-membered heterocyclylalkyl, 3- to 8-membered alkylheterocyclylcycloalkyl, 3- to 8-membered haloheterocyclylalkyl, and C3-C8 halocycloalkyl, or combinations thereof. In someAttorney Docket No.63243-702.601 embodiments, R4is oxazolyl, isoxazolyl, 1, 2, 3-oxadiazolyl, thiazolyl, isothiazolyl, 1,2,4- thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,4-triazolyl or 1, 3, 4-oxadiazolyl, each of which is optionally substituted with one more substituents selected from halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, cyano, aminyl, C1-C6 hydroxylalkyl, C1-C6 cyanoalkyl, 3- to 8-membered heterocyclyl, C3-C8 haloalkylcycloalkyl, C3-C8 aminylalkylcycloalkyl, C3-C8 alkylcycloalkyl, 3- to 8-membered heterocyclylalkyl, 3- to 8-membered alkylheterocyclylcycloalkyl, 3- to 8-membered haloheterocyclylalkyl, and C3- C8 halocycloalkyl, and combinations thereof.

[0097] In some embodiments, R4 is oxazolyl, isoxazolyl, 1, 2, 3-oxadiazolyl or 1, 3, 4-oxadiazolyl, each of which is optionally substituted with one more substituents selected from halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, cyano, aminyl, C1-C6 hydroxylalkyl, C1-C6 cyanoalkyl, 3- to 8-membered heterocyclyl, C3-C8 haloalkylcycloalkyl, C3-C8 aminylalkylcycloalkyl, C3-C8 alkylcycloalkyl, 3- to 8-membered heterocyclylalkyl, 3- to 8-membered alkylheterocyclylcycloalkyl, 3- to 8-membered haloheterocyclylalkyl, and C3-C8 halocycloalkyl, and combinations thereof. In some embodiments, R4is isoxazolyl optionally substituted with one more substituents selected from halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C3-C8 cycloalkyl and C3-C8 halocycloalkyl.

[0098] In some embodiments, R4 is isoxazolyl optionally substituted with one moresubstituents selected from halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, cyano, aminyl, C1-C6 hydroxylalkyl, C1-C6 cyanoalkyl, 3- to 8-membered heterocyclyl, C3-C8 haloalkylcycloalkyl, C3-C8 aminylalkylcycloalkyl, C3-C8 alkylcycloalkyl, 3- to 8-membered heterocyclylalkyl, 3- to 8-membered alkylheterocyclylcycloalkyl, 3- to 8- membered haloheterocyclylalkyl, and C3-C8 halocycloalkyl, and combinations thereof.

[0099] In some embodiments, R4 is thiazolyl optionally substituted with one moresubstituents selected from halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, cyano, aminyl, C1-C6 hydroxylalkyl, C1-C6 cyanoalkyl, 3- to 8-membered heterocyclyl, C3-C8 haloalkylcycloalkyl, C3-C8 aminylalkylcycloalkyl, C3-C8 alkylcycloalkyl, 3- to 8-membered heterocyclylalkyl, 3- to 8-membered alkylheterocyclylcycloalkyl, 3- to 8- membered haloheterocyclylalkyl, and C3-C8 halocycloalkyl, and combinations thereof.

[0100] In some embodiments, R4 is isothiazolyl optionally substituted with one moresubstituents selected from halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, cyano, aminyl, C1-C6 hydroxylalkyl, C1-C6 cyanoalkyl, 3- to 8-membered heterocyclyl, C3-C8 haloalkylcycloalkyl, C3-C8 aminylalkylcycloalkyl, C3-C8 alkylcycloalkyl,Attorney Docket No.63243-702.601 3- to 8-membered heterocyclylalkyl, 3- to 8-membered alkylheterocyclylcycloalkyl, 3- to 8- membered haloheterocyclylalkyl, and C3-C8 halocycloalkyl, and combinations thereof.

[0101] In some embodiments, R4 is 1,2,4-thiadiazolyl optionally substituted with onemore substituents selected from halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, cyano, aminyl, C1-C6 hydroxylalkyl, C1-C6 cyanoalkyl, 3- to 8- membered heterocyclyl, C3-C8 haloalkylcycloalkyl, C3-C8 aminylalkylcycloalkyl, C3-C8 alkylcycloalkyl, 3- to 8-membered heterocyclylalkyl, 3- to 8-membered alkylheterocyclylcycloalkyl, 3- to 8-membered haloheterocyclylalkyl, and C3-C8 halocycloalkyl, and combinations thereof.

[0102] In some embodiments, R4 is 1,3,4-thiadiazolyl optionally substituted with onemore substituents selected from halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, cyano, aminyl, C1-C6 hydroxylalkyl, C1-C6 cyanoalkyl, 3- to 8- membered heterocyclyl, C3-C8 haloalkylcycloalkyl, C3-C8 aminylalkylcycloalkyl, C3-C8 alkylcycloalkyl, 3- to 8-membered heterocyclylalkyl, 3- to 8-membered alkylheterocyclylcycloalkyl, 3- to 8-membered haloheterocyclylalkyl, and C3-C8 halocycloalkyl, and combinations thereof.

[0103] In some embodiments, R4 is 1,2,4-triazolyl optionally substituted with one moresubstituents selected from halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, cyano, aminyl, C1-C6 hydroxylalkyl, C1-C6 cyanoalkyl, 3- to 8-membered heterocyclyl, C3-C8 haloalkylcycloalkyl, C3-C8 aminylalkylcycloalkyl, C3-C8 alkylcycloalkyl, 3- to 8-membered heterocyclylalkyl, 3- to 8-membered alkylheterocyclylcycloalkyl, 3- to 8- membered haloheterocyclylalkyl, and C3-C8 halocycloalkyl, and combinations thereof.

[0104] In some embodiments, R4 is 1, 3, 4-oxadiazolyl optionally substituted with onemore substituents selected from halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, cyano, aminyl, C1-C6 hydroxylalkyl, 3- to 8-membered heterocyclyl and C3-C8 halocycloalkyl, or combinations thereof.

[0105] In some embodiments, R4 is substituted with C1-C6 alkyl, C1-C6 haloalkyl, C3-C8cycloalkyl, cyano, aminyl, C1-C6 hydroxylalkyl, C1-C6 cyanoalkyl, 3- to 8-membered heterocyclyl, C3-C8haloalkylcycloalkyl, C3-C8aminylalkylcycloalkyl, C3-C8alkylcycloalkyl, 3- to 8-membered heterocyclylalkyl, 3- to 8-membered alkylheterocyclylcycloalkyl, 3- to 8- membered haloheterocyclylalkyl, and C3-C8 halocycloalkyl, and combinations thereof.

[0106] In some embodiments, R4 is:Attorney Docket No.63243-702.601Attorney Docket No.63243-702.601

[0109] In some embodiments, R5 is any suitable functional group described herein. Insome embodiments, R5is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3- to 8-membered heterocyclyl, C6-C10 aryl or 5- or 6-membered heteroaryl, each of which is optionally substituted with one more substituents selected from halo, hydroxyl, cyano, aminyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl and C1-C6 alkoxy. In some embodiments, R5is H or C1-C6 alkyl, wherein C1-C6 alkyl is optionally substituted with one more substituents selected from halo, hydroxyl, cyano, aminyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl and C1-C6 alkoxy. In some embodiments, R5is H. In some embodiments, R5is C1-C6 alkyl. In some embodiments, R5is methyl, ethyl, n-propyl, or isopropyl.

[0110] In some embodiments, each R6 is any suitable functional group described herein.In some embodiments, each R6is independently halo, C1-C6 alkyl, cyano, C1-C6 hydroxylalkyl, C1-C6 alkoxy, or C1-C6 haloalkyl. In some embodiments, each R6is chloro or fluoro. In some embodiments, each R6is fluoro. In some embodiments, each R6is C1-C6Attorney Docket No.63243-702.601 hydroxylalkyl. In some embodiments, each R6is C1-C6 hydroxylalkyl. In some embodiments, each R6is -CH2CH2OH. In other embodiments, each R6is cyano. In some embodiments, each R6is C1-C6 alkoxy. In some embodiments, each R6is methoxy.

[0111] In some embodiments, A is:

[0113] In some embodiments, the compound is a compound of Formula (Ia), or apharmaceutically acceptable salt, stereoisomer, or solvate thereof:wherein: R2ais C3-C4 cycloalkyl optionally substituted with one more substituents selected from halo, hydroxyl, cyano, aminyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy and 3-8 membered heterocyclyl; and R4ais isoxazolyl optionally substituted with one more substituents selected from C1-C6haloalkyl, C3-C8 cycloalkyl or C3-C8 haloalkylcycloalkyl.

[0114] In some embodiments, R2a is a branched C1-C6 alkyl substituted with hydroxyl. InAttorney Docket No.63243-702.601 some embodiments, R2ais C3-C8 cycloalkyl. In some embodiments, R2ais:

[0115] In some embodiments, R4a is isoxazolyl substituted with C3-C8haloalkylcycloalkyl. In some embodiments, R4ais C3-C8 fluoroalkylcycloalkyl. In some embodiments, R4ais fluoroalkylcyclopropyl or fluoroalkylcyclobutyl. In some embodiments, R4ais:

[0116] In some embodiments, the compound is a compound of Formula (Ib), or apharmaceutically acceptable salt, stereoisomer, or solvate thereof:wherein: A is C6-C10 aryl, C3-C10 cycloalkyl, 3-10 membered heterocyclyl or 5-6 membered monocyclic heteroaryl, each of which is optionally substituted with one or more R6; X is CH or N; Y is NH; R1is H or C1-C6alkyl; R2is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3-8 membered heterocyclyl or 5- or 6-membered heteroaryl, each of which is optionally substituted with one more substituents selected from halo, hydroxyl, cyano, aminyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy and 3-8 membered heterocyclyl; R3is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3- to 8-membered heterocyclyl or 5- or 6-membered heteroaryl, each of which is optionally substituted with one more substituent selected from halo, hydroxyl, cyano, aminyl, C1-C6 alkyl, C2-C6 alkenyl, C2- C6 alkynyl and C1-C6 alkoxy;Attorney Docket No.63243-702.601 R4is a heteroaryl selected from oxazolyl, isoxazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, thiazolyl, isothiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl and 1,3,4-thiadiazolyl, each of which is optionally substituted with one more substituents selected from halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, cyano, aminyl, C1-C6 hydroxylalkyl, C1-C6 cyanoalkyl, 3- to 8-membered heterocyclyl, C3-C8 haloalkylcycloalkyl, C3-C8 aminylalkylcycloalkyl, C3-C8 alkylcycloalkyl, 3- to 8-membered heterocyclylalkyl, 3- to 8- membered alkylheterocyclylcycloalkyl, 3- to 8-membered haloheterocyclylalkyl, and C3-C8 halocycloalkyl; R5is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3- to 8-membered heterocyclyl, C6-C10 aryl or 5- or 6-membered heteroaryl, each of which is optionally substituted with one more substituents selected from halo, hydroxyl, cyano, aminyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl and C1-C6 alkoxy; and R6is, at each occurrence, independently halo, C1-C6 alkyl, C1-C6 alkoxy, cyano, C1-C6 hydroxylalkyl or C1-C6 haloalkyl.

[0117] In some embodiments, the compound of Formula (I) is a modulator of the NLRP3inflammasome. In some embodiments, the compound of Formula (I) is an inhibitor of NEK7 in a patient or in a biological sample. In some embodiments, the compound of Formula (I) inhibits NEK7 and / or modulates the activity of the NLRP3 inflammasome. In some embodiments, the compound of Formula (I) is administered to treat pain. The pain may be acute inflammatory pain. The pain may be a symptom of a disease or condition of the subject experiencing pain. The pain may be associated with a disease or condition of the subject experiencing pain. Non-limiting example diseases and conditions include, inflammation, arthritis (e.g., osteoarthritis, rheumatoid arthritis, psoriatic arthritis), fibromyalgia, lupus, surgery (e.g., post-surgery pain), peritonitis, cancer, cancer treatment (e.g., chemotherapy), systemic sclerosis, psoriasis, atopic dermatitis, hidradenitis suppurativa, inflammatory bowel disease (IBD, e.g., colitis, Crohn's disease), endometriosis, and complex regional pain syndrome (CRPS).

[0118] In various different embodiments, the compound has one of the structures set forthin Table 1A below, or a pharmaceutically acceptable salt, stereoisomer, or prodrug thereof.

[0119] Compounds in Table 1A were prepared as described in the Examples or methodsknown in the art and analyzed by mass spectrometry and / or1H NMR.Attorney Docket No.63243-702.601 Table 1A: Representative Compounds of Formula (I)Attorney Docket No.63243-702.601Attorney Docket No.63243-702.601Attorney Docket No.63243-702.601Attorney Docket No.63243-702.601Attorney Docket No.63243-702.601Attorney Docket No.63243-702.601Attorney Docket No.63243-702.601Attorney Docket No.63243-702.601Attorney Docket No.63243-702.601Attorney Docket No.63243-702.601Attorney Docket No.63243-702.601Attorney Docket No.63243-702.601Attorney Docket No.63243-702.601Attorney Docket No.63243-702.601Attorney Docket No.63243-702.601Attorney Docket No.63243-702.601Attorney Docket No.63243-702.601Attorney Docket No.63243-702.601Attorney Docket No.63243-702.601Attorney Docket No.63243-702.601

[0120] Embodiments described herein provide a compound having Formula (II):Attorney Docket No.63243-702.601or a pharmaceutically acceptable salt, stereoisomer, or prodrug thereof, wherein: X is N or CH; A is C6-C10 arylene, C3-C10 cycloalkylene, 3-10 membered heterocyclylene, or 5-6 membered heteroarylene; R1is H, halo, C1-C6 alkyl, C3-C10 cycloalkyl, or 3-10 membered heterocyclyl; R2is H, halo, C1-C6 alkyl, C1-C6 haloalkyl, C3-C10 cycloalkyl, or 3-10 membered heterocyclyl; R3is aminylalkyl, 3-10 membered heterocyclyl, 3-10 membered heterocyclylalkyl, 3- 10 membered heterocyclylcarbonyl, 3-10 membered heterocyclylalkenyl, 3-10 membered N- heterocyclyloxy, or 5-6 membered heteroaryl; or R3 joins with an occurrence of R4 attached to a carbon adjacent to a carbon to which R3 is attached to form a C3-C8 cycloalkyl; R4is, at each occurrence, independently halo, cyano, C1-C6 alkyl, C1-C6 haloalkyl, C1- C6 alkoxy, C1-C6 haloalkoxy, C3-C8 halocycloalkyl, or C3-C8 cycloalkyl; and n is 0, 1, 2, 3, or 4.

[0121] In some embodiments, A is C6-C10 arylene. In certain embodiments, A isphenylene. In some specific embodiments, A is 5-6 membered heteroarylene. In certain specific embodiments, A is pyridinylene. In some more specific embodiments, A is C3-C10 cycloalkylene or 3-10 membered heterocyclylene.

[0122] In certain embodiments, A is substituted with one or more substituents selectedfrom halo, cyano, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, or C3-C8 cycloalkyl. In some embodiments, A is substituted with one or more halo substituents. In some specific embodiments, A is unsubstituted.

[0123] In some embodiments, R1 is H. In certain embodiments, R1 is C1-C6 alkyl. In somespecific embodiments, R1is methyl. In certain embodiments, R1is C3-C10 cycloalkyl, or 3-10 membered heterocyclyl. In some embodiments, R1is halo (e.g., fluoro, chloro, bromo, etc.).

[0124] In certain embodiments, R2 is H. In some more specific embodiments, R2 is halo.In more specific embodiments, R2is chloro or fluoro. In some other embodiments, R2is C3-Attorney Docket No.63243-702.601 C10 cycloalkyl (e.g., cyclopropyl). In some embodiments, R2is C1-C6 alkyl, C1-C6 haloalkyl, or 3-10 membered heterocyclyl. In some embodiments, R2is C1-C6 alkyl (e.g., methyl).

[0125] In some embodiments, X is CH or CR3. In some specific embodiments, thecompound has the following structure (IIa):or a pharmaceutically acceptable salt, stereoisomer, or prodrug thereof.

[0126] In some embodiments, the compound has the following structure (IIb):or a pharmaceutically acceptable salt, stereoisomer, or prodrug thereof.

[0127] In certain embodiments, X is N. In certain more specific embodiments, thecompound has the following structure (IIc):or a pharmaceutically acceptable salt, stereoisomer, or prodrug thereof.

[0128] In some embodiments, the compound has the following structure (IId):Attorney Docket No.63243-702.601or a pharmaceutically acceptable salt, stereoisomer, or prodrug thereof, wherein R3ais, at each occurrence, independently halo, cyano, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, aminylalkyl, C3-C8 cycloalkyl, 3-10 membered heterocyclyl, 3-10 membered heterocyclyl, 3-10 membered heterocyclylalkyl, 3-10 membered heterocyclylcarbonyl, 3-10 membered heterocyclylalkenyl, 3-10 membered N- heterocyclyloxy, or 5-6 membered heteroaryl; and m is 0, 1, 2, 3, or 4.

[0129] In some embodiments, R3a is, at each occurrence, independently halo or 3-10membered heterocyclyl. In some embodiments, m is 0, 1, 2, or 3. In some embodiments, m is 0. In certain embodiments, m is 1. In some embodiments, m is 1. In some embodiments, m is 2. In certain embodiments, m is 3.

[0130] In some embodiments, the compound has the following structure (IId1):or a pharmaceutically acceptable salt, stereoisomer, or prodrug thereof.

[0131] In some embodiments, R3 is substituted. In some embodiments, R3 isunsubstituted. In some embodiments, R3is substituted with alkyl (e.g., C1-C6 alkyl), heterocyclyl, halo, haloalkyl (e.g., C1-C6 haloalkyl), alkylcarbonyl (e.g., -C(=O)CH3), hydroxyalkyl, alkoxyalkyl, cycloalkyl (e.g., C3-C8 cycloalkyl), alkylamino, or combinations thereof.

[0132] In some of the above embodiments, R3 is aminylalkyl. In certain embodiments, R3has the following structure:Attorney Docket No.63243-702.601.

[0133] In some embodiments, R3 is a 3-10 membered heterocyclyl. In someembodiments, R3is morpholino. In certain embodiments, R3is piperazinyl. In some specific embodiments, R3has one of the following structures:

[0134] In certain embodiments, R3 is a 3-10 membered heterocyclylalkyl. In certain morespecific embodiments, R3has one of the following structures:

[0135] In some embodiments, R3 has one of the following structures:Attorney Docket No.63243-702.601

[0136] In some embodiments, R3 is 3-10 membered heterocyclylcarbonyl. In a morespecific embodiment, R3has the following structure:.

[0137] In some embodiments, R3 is a 5-6 membered heteroaryl. For example, in someembodiments, R3has the following structure:.

[0138] In some embodiments, R3 is a 3-10 membered heterocyclylalkenyl. In morespecific embodiments, R3has the following structure:.

[0139] In some embodiments, R3 is a 3-10 membered N-heterocyclyloxy. In morespecific embodiments, R3has one of the following structures:Attorney Docket No.63243-702.601

[0140] In some embodiments, R3 has one of the following structures:

[0141] In some embodiments, n is 1 or 2. In some embodiments, n is 2. In some otherembodiments, n is 1. In some specific embodiments, R4is, at each occurrence, independently chloro, fluoro, cyano, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C3-C8 halocycloalkyl, or C3-C8cycloalkyl. In certain embodiments, R4is, at each occurrence, independently methyl, chloro, fluoro, cyano, trifluoromethyl, methoxy, trifluoromethoxy, 2,2- difluorocyclopropyl, or cyclopropyl. In certain embodiments, R4is, at each occurrence, independently methyl, chloro, fluoro, cyano, trifluoromethyl, difluoromethyl, methoxy, trifluoromethoxy, 2,2-difluorocyclopropyl, or cyclopropyl.

[0142] In some embodiments, X is N and n is 3. In some embodiments, X is N and n is 2.In more specific embodiments, X is N and n is 1. In some other embodiments, X is N and n is 0.

[0143] In some embodiments, X is CH and n is 4. In some other embodiments, X is CHand n is 3. In some embodiments, X is CH and n is 2. In more specific embodiments, X is CH and n is 1. In some other embodiments, X is CH and n is 0.

[0144] In some embodiments, the compound of Formula (II) is a modulator of theNLRP3 inflammasome. In some embodiments, the compound of Formula (II) is an inhibitor of NEK7 in a patient or in a biological sample. In some embodiments, the compound of Formula (II) inhibits NEK7 and / or modulates the activity of the NLRP3 inflammasome. In some embodiments, the compound of Formula (II) is administered to treat pain. The pain mayAttorney Docket No.63243-702.601 be acute inflammatory pain. The pain may be a symptom of a disease or condition of the subject experiencing pain. The pain may be associated with a disease or condition of the subject experiencing pain. Non-limiting example diseases and conditions include, inflammation, arthritis (e.g., osteoarthritis, rheumatoid arthritis, psoriatic arthritis), fibromyalgia, lupus, surgery (e.g., post-surgery pain), peritonitis, cancer, cancer treatment (e.g., chemotherapy), systemic sclerosis, psoriasis, atopic dermatitis, hidradenitis suppurativa, inflammatory bowel disease (IBD, e.g., colitis, Crohn's disease), endometriosis, and complex regional pain syndrome (CRPS).

[0145] In various different embodiments, the compound has one of the structures set forthin Table 1B below, or a pharmaceutically acceptable salt, stereoisomer, or prodrug thereof.

[0146] Compounds in Table 1B were prepared as described in the Examples or methodsknown in the art and analyzed by mass spectrometry and / or1H NMR. Table 1B: Representative Compounds of Formula (II)Attorney Docket No.63243-702.601Attorney Docket No.63243-702.601Attorney Docket No.63243-702.601Attorney Docket No.63243-702.601Attorney Docket No.63243-702.601Attorney Docket No.63243-702.601Attorney Docket No.63243-702.601Attorney Docket No.63243-702.601Attorney Docket No.63243-702.601Attorney Docket No.63243-702.601Attorney Docket No.63243-702.601Attorney Docket No.63243-702.601Attorney Docket No.63243-702.601

[0147] Embodiments described herein provide a compound having Formula (III):or a pharmaceutically acceptable salt, stereoisomer, or prodrug thereof, wherein: A is C6-C10 arylene, C3-C10 cycloalkylene, 3-10 membered heterocyclylene, or 5-6 membered heteroarylene; X is N or CR4; Y is N or CH; R1is C1-C6 alkyl, C1-C6 hydroxylalkyl, C3-C10 cycloalkyl, or 3-10 membered heterocyclyl; R2is a 3-10 membered heterocyclyl, 3-10 membered heterocyclylalkyl, 3-10 membered heterocyclylalkenyl, 3-10 membered heterocyclylcarbonyl, 3-10 membered heterocyclyloxy, or 5-6 membered heteroaryl; or R2joins with an occurrence of R3attached to a carbon adjacent to a carbon to which R2is attached to form a C3-C8 cycloalkyl; R3is, at each occurrence, independently halo, cyano, C1-C6 alkyl, C1-C6 haloalkyl, C1- C6 alkoxy, C1-C6 haloalkoxy, or C3-C8 cycloalkyl; R4is H, C1-C6 alkyl, C1-C6 haloalkyl, or C3-C8 cycloalkyl; and n is 0, 1, 2, 3, or 4.

[0148] In some embodiments, A is C6-C10 arylene. In some specific embodiments, A isphenylene. In certain embodiments, A is 5-6 membered heteroarylene. In certain specific embodiments, A is pyridinylene. In some embodiments, A is C3-C10 cycloalkylene or 3-10 membered heterocyclylene. In more specific embodiments, A is substituted with one or more substituents selected from halo, cyano, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, or C3-C8 cycloalkyl. In certain more specific embodiments, A is substituted with one or more halo substituents. In other embodiments, A is unsubstituted.

[0149] In certain embodiments, X is CR4. In more specific embodiments, R4 is H or C1-C6 alkyl. In some embodiments, R4is H. In certain specific embodiments, X is N.

[0150] In some embodiments, R1 is C1-C6 alkyl. In some more specific embodiments, R1Attorney Docket No.63243-702.601 is methyl or iso-propyl. In certain embodiments, R1is C1-C6 hydroxylalkyl. In certain more specific embodiments, R1has one of the following structures:

[0151] In some embodiments, R1 has one of the following structures:

[0152] In certain embodiments, R1 is C1-C6 carboxyalkyl. In more specific embodiments,R1has one of the following structures:

[0153] In some embodiments, R1 is C1-C6 alkoxyalkyl. In some embodiments, R1 has thefollowing structure:.

[0154] In some embodiments, R1 is C3-C10 cycloalkyl. In more specific embodiments, R1is cyclopropyl or cyclobutyl. In certain embodiments, R1is 3-10 membered heterocyclyl. In certain embodiments, R1is oxetanyl, pyrrolidinyl, or piperidinyl. In certain embodiments, R1is oxetanyl, pyrrolidinyl, azetidinyl, or piperidinyl.

[0155] In some embodiments, R1 is C1-C6 alkynyl. In certain embodiments, R1 has one ofthe following structures:

[0156] In some embodiments, R1 is substituted with one or more substituents selectedfrom halo, cyano, C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy, C1-C6haloalkoxy, or C3-C8cycloalkyl. In some embodiments, R1is substituted with one or more substituents selected from halo, cyano, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -S(O)2CH3, -S(O)2cyclopropyl, or C3-C8 cycloalkyl. In more specific embodiments, R1is substituted withAttorney Docket No.63243-702.601 one or more C1-C6 alkyl substituents. In other embodiments, R1is unsubstituted.

[0157] In certain specific embodiments, R1 has one of the following structures:

[0158] In some embodiments, R1 has one of the following structures:

[0159] In some specific embodiments, the compound has the following Structure (IIIa):or a pharmaceutically acceptable salt, stereoisomer, or prodrug thereof.

[0160] In some embodiments, Y is N. In other embodiments, Y is CH.

[0161] In certain specific embodiments, the compound has the following Structure (IIIb):Attorney Docket No.63243-702.601or a pharmaceutically acceptable salt, stereoisomer, or prodrug thereof.

[0162] In some embodiments, R2 is a 3-10 membered heterocyclyl. In some specificembodiments, R2is morpholino. In other specific embodiments, R2is piperazinyl. In some more specific embodiments, R2has one of the following structures:

[0163] In some embodiments, R2 is a 3-10 membered heterocyclylalkyl. In certain morespecific embodiments, R2has one of the following structures:.

[0164] In some more specific embodiments, R2 has one of the following structures:Attorney Docket No.63243-702.601.

[0165] In some embodiments, R2 is 3-10 membered heterocyclylcarbonyl. In certain morespecific embodiments, R2has the following structure:.

[0166] In some embodiments, R2 is a 5-6 membered heteroaryl. In some more specificembodiments, R2has the following structure:Attorney Docket No.63243-702.601.

[0167] In some embodiments, R2 is 3-10 membered heterocyclyloxy. In certain morespecific embodiments, R2has the following structure:.

[0169] In some more specific embodiments, R2 has the following structure:.

[0170] In some embodiments, n is 0. In some embodiments, n is 1 or 2. In certainembodiments, n is 1. In some embodiments, R3is halo, cyano, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, or C3-C8 cycloalkyl. In certain specific embodiments, R3is methyl, chloro, fluoro, cyano, difluoromethyl, trifluoromethyl, methoxy, trifluoromethoxy, or cyclopropyl. In some specific embodiments, n is 1 or 2 and R3is halo, C1-C6alkyl, C1-C6haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, or C3-C8 cycloalkyl. In some embodiments, n is 1 and R3is halo, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, or C3-C8 cycloalkyl. In some embodiments, n is 1 and R3is methyl, chloro, fluoro, trifluoromethyl, methoxy, trifluoromethoxy, or cyclopropyl.

[0171] In some embodiments, the compound has the following Structure (IIIc):Attorney Docket No.63243-702.601or a pharmaceutically acceptable salt, stereoisomer, or prodrug thereof, wherein: R3ais halo or 3-10 membered heterocyclyl; and n1 is 1, 2, or 3.

[0172] In some embodiments, R3a is fluoro or piperazinyl. In more specific embodiments,the compound has the following Structure (IIIc1):or a pharmaceutically acceptable salt, stereoisomer, or prodrug thereof.

[0173] In some embodiments, the compound of Formula (III) is a modulator of theNLRP3 inflammasome. In some embodiments, the compound of Formula (III) is an inhibitor of NEK7 in a patient or in a biological sample. In some embodiments, the compound of Formula (III) inhibits NEK7 and / or modulates the activity of the NLRP3 inflammasome. In some embodiments, the compound of Formula (III) is administered to treat pain. The pain may be acute inflammatory pain. The pain may be a symptom of a disease or condition of the subject experiencing pain. The pain may be associated with a disease or condition of the subject experiencing pain. Non-limiting example diseases and conditions include, inflammation, arthritis (e.g., osteoarthritis, rheumatoid arthritis, psoriatic arthritis), fibromyalgia, lupus, surgery (e.g., post-surgery pain), peritonitis, cancer, cancer treatment (e.g., chemotherapy), systemic sclerosis, psoriasis, atopic dermatitis, hidradenitis suppurativa, inflammatory bowel disease (IBD, e.g., colitis, Crohn's disease), endometriosis, and complex regional pain syndrome (CRPS).Attorney Docket No.63243-702.601

[0174] In various different embodiments, the compound has one of the structures set forthin Table 1C below, or a pharmaceutically acceptable salt, stereoisomer, or prodrug thereof.

[0175] Compounds in Table 1C were prepared as described in the Examples or methodsknown in the art and analyzed by mass spectrometry and / or1H NMR.Table 1C: Representative compounds of Structure (III)Attorney Docket No.63243-702.601Attorney Docket No.63243-702.601Attorney Docket No.63243-702.601Attorney Docket No.63243-702.601Attorney Docket No.63243-702.601Attorney Docket No.63243-702.601Attorney Docket No.63243-702.601Attorney Docket No.63243-702.601Attorney Docket No.63243-702.601Attorney Docket No.63243-702.601Attorney Docket No.63243-702.601Attorney Docket No.63243-702.601Attorney Docket No.63243-702.601Attorney Docket No.63243-702.601Attorney Docket No.63243-702.601Attorney Docket No.63243-702.601Attorney Docket No.63243-702.601Attorney Docket No.63243-702.601Attorney Docket No.63243-702.601Attorney Docket No.63243-702.601Attorney Docket No.63243-702.601Attorney Docket No.63243-702.601Attorney Docket No.63243-702.601Attorney Docket No.63243-702.601Attorney Docket No.63243-702.601Attorney Docket No.63243-702.601Attorney Docket No.63243-702.601Attorney Docket No.63243-702.601Attorney Docket No.63243-702.601Attorney Docket No.63243-702.601

[0176] Embodiments described herein provide a compound having Formula (IV):or a pharmaceutically acceptable salt, stereoisomer, or prodrug thereof, wherein: A is C6-C10 aryl, C3-C10 cycloalkyl, 3-10 membered heterocyclyl, or 5-6 membered monocyclic heteroaryl, each of which is optionally substituted with one or more R5; X is N or CR1c; Y is N or CR1d; Z is C(R6)(R7) or NR6; R1a, R1b, R1c, and R1dare each independently H, halo, C1-C6 alkyl, or C3-C8 cycloalkyl; R2aand R2bare each independently H, halo, cyano, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C3-C8 cycloalkyl, or C3-C8 halocycloalkyl, provided that R2aand R2bare not both H; R3is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3-10 membered heterocyclyl, heteroaryl, or aryl, each of which is optionally substituted with one or moreAttorney Docket No.63243-702.601 substituents selected from halo, hydroxyl, cyano, aminyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, and C1-C6 alkoxy; R4is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3-8 membered heterocyclyl, C6-C10 aryl, or 5- or 6-membered heteroaryl, each of which is optionally substituted with one more substituents selected from halo, hydroxyl, cyano, aminyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, and C1-C6 alkoxy; R5is, at each occurrence, independently halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or C1-C6 haloalkyl; R6is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or C1-C6 hydroxylalkyl; and R7is H, OH, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or C1-C6 hydroxylalkyl.

[0177] In some embodiments, A is C6-C10 aryl. In certain embodiments, A is C3-C10cycloalkyl. In some specific embodiments, A is 3-10 membered heterocyclyl. In certain specific embodiments, A is 5-6 membered monocyclic heteroaryl. In some more specific embodiments, A is substituted with one or more occurrences of R5. In certain more specific embodiments, A is substituted with one or two occurrences of R5. In some embodiments, A is substituted with substituents selected from the group consisting of halo, C1-C6haloalkyl, and combinations thereof. In certain embodiments, A is substituted with substituents selected from the group consisting of fluoro, trifluoromethyl, and combinations thereof. In more specific embodiments, A is unsubstituted.

[0178] In some embodiments, X is N. In certain embodiments, X is CR1c. In somespecific embodiments, R1cis H. In certain more specific embodiments, R1cis halo (e.g., R1cis chloro). In some other embodiments, R1cis C1-C6 alkyl (e.g., R1cis methyl). In certain embodiments, R1cis C3-C8 cycloalkyl (e.g., R1cis cyclopropyl).

[0179] In some embodiments, Y is N. In other embodiments, Y is CR1d. In someembodiments, R1dis H. In certain specific embodiments, R1dis halo, C1-C6 alkyl, or C3-C8 cycloalkyl.

[0180] In some embodiments, Z is C(R6)(R7). In more specific embodiments, R6 is H. Insome embodiments, R7is -OH, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or C1-C6 hydroxylalkyl. In certain specific embodiments, R6and R7are both H.

[0181] In some other embodiments, Z is NR6. In certain embodiments, R6 is H. In certainother embodiments, R6is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or C1-C6 hydroxylalkyl.Attorney Docket No.63243-702.601

[0182] In certain embodiments, R1a is H. In some embodiments, R1a is C1-C6 alkyl (e.g.,R1ais methyl). In some embodiments, R1ais halo or C3-C8 cycloalkyl.

[0183] In some embodiments, R1b is H. In certain embodiments, R1b is halo, C1-C6 alkyl,or C3-C8 cycloalkyl.

[0184] In certain embodiments, R2a is C1-C6 alkyl (e.g., R2a is tert-butyl or methyl). Insome embodiments, R2ais C3-C8 cycloalkyl. In more specific embodiments, R2ais cyclopropyl. In some embodiments, the cyclopropyl is unsubstituted. In some embodiments, the cyclopropyl is substituted with at least one haloalkyl (e.g., trifluoromethyl). In certain more specific embodiments, R2ahas the following structure:.

[0185] In some embodiments, R2b is H. In certain embodiments, R2b is halo, cyano, C1-C6alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C3-C8 cycloalkyl, or C3-C8 halocycloalkyl.

[0186] In certain specific embodiments, R3 is C1-C6 alkyl (e.g., R3 is methyl).

[0187] In some embodiments, R3 is aryl. For example, in some embodiments, R3 isphenyl. In certain embodiments, the phenyl is substituted with one or more substituents selected from halo, hydroxyl, cyano, aminyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, and C1-C6 alkoxy. In certain other embodiments, the phenyl is unsubstituted.

[0188] In some other embodiments, R3 is 3-10 membered heterocyclyl. In more specificembodiments, R3is piperidinyl. In certain specific embodiments, the piperidinyl is substituted with one or more substituents selected from halo, hydroxyl, cyano, aminyl, C1-C6 alkyl, C2- C6 alkenyl, C2-C6 alkynyl, and C1-C6 alkoxy. In certain embodiments, R3has the following structure:.

[0189] In some embodiments, R4 is H. In more specific embodiments, R4 is C1-C6 alkyl,C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3-8 membered heterocyclyl, C6-C10 aryl, or 5- or 6-membered heteroaryl.Attorney Docket No.63243-702.601

[0190] In some embodiments, the compound of Formula (IV) is a modulator of theNLRP3 inflammasome. In some embodiments, the compound of Formula (IV) is an inhibitor of NEK7 in a patient or in a biological sample. In some embodiments, the compound of Formula (IV) inhibits NEK7 and / or modulates the activity of the NLRP3 inflammasome. In some embodiments, the compound of Formula (IV) is administered to treat pain. The pain may be acute inflammatory pain. The pain may be a symptom of a disease or condition of the subject experiencing pain. The pain may be associated with a disease or condition of the subject experiencing pain. Non-limiting example diseases and conditions include, inflammation, arthritis (e.g., osteoarthritis, rheumatoid arthritis, psoriatic arthritis), fibromyalgia, lupus, surgery (e.g., post-surgery pain), peritonitis, cancer, cancer treatment (e.g., chemotherapy), systemic sclerosis, psoriasis, atopic dermatitis, hidradenitis suppurativa, inflammatory bowel disease (IBD, e.g., colitis, Crohn's disease), endometriosis, and complex regional pain syndrome (CRPS).

[0191] In various different embodiments, the compound has one of the structures set forthin Table 1D below, or a pharmaceutically acceptable salt, stereoisomer, or prodrug thereof.

[0192] Compounds in Table 1D were prepared as described in the Examples or methodsknown in the art and analyzed by mass spectrometry and / or1H NMR. Table 1D: Representative compounds of Structure (IV)Attorney Docket No.63243-702.601Attorney Docket No.63243-702.601Attorney Docket No.63243-702.601Attorney Docket No.63243-702.601Attorney Docket No.63243-702.601Attorney Docket No.63243-702.601

[0193] Embodiments described herein provide a compound having Formula (V):or a pharmaceutically acceptable salt, stereoisomer, or prodrug thereof, wherein: A is C6-C10 aryl, C3-C10 cycloalkyl, 3-10 membered heterocyclyl or 5-6 membered monocyclic heteroaryl, each of which is optionally substituted with one or more R5; X is N or CH; Y is CHOH or NH; R1is H or C1-C6 alkyl; R2is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3-8 membered heterocyclyl or 5- or 6-membered heteroaryl, each of which is optionally substituted with one more substituents selected from halo, hydroxyl, cyano, aminyl, C1-C6 alkyl, C2-C6 alkenyl, C2- C6 alkynyl, C1-C6 alkoxy and 3-8 membered heterocyclyl; R3is a heteroaryl selected from oxazolyl, isoxazolyl, 1, 2, 3-oxadiazolyl, 1, 2, 4- oxadiazolyl, 1, 2, 5-oxadiazolyl, 1, 3, 4-oxadiazolyl, 1, 2, 3-triazolyl, 1, 2, 4-triazolyl, thiazolyl, isothiazolyl, 1, 2, 3-thiadiazolyl, 1, 2, 4-thiadiazolyl, 1, 2, 5-thiadiazolyl and 1, 3, 4- thiadiazolyl, each of which is optionally substituted with one more substituents selected from amino, halo, cyano, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, C3-C8 alkylcycloalkyl, C3-C8 haloalkylcycloalkyl, C3-C8 aminylalkylcycloalkyl,Attorney Docket No.63243-702.601 C1-C6 cyanoalkyl C1-C6 aminyl, C1-C6 hydroxylalkyl, 3-8 membered heterocyclyl, 3-8 membered heterocyclylalkyl, 3-8 membered heterocyclylcycloalkyl, 3-8 membered haloheterocyclyl, 3-8 membered haloheterocyclylalkyl, C3-C8 halocycloalkyl and C3-C8 halocycloalkylalkyl, and combinations thereof; R4is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3-8 membered heterocyclyl, C6-C10 aryl or 5- or 6-membered heteroaryl, each of which is optionally substituted with one more substituents selected from halo, hydroxyl, cyano, aminyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl and C1-C6 alkoxy; and R5is, at each occurrence, independently halo, cyano, C1-C6 alkyl, C1-C6 hydroxylalkyl or C1-C6 haloalkyl.

[0194] In some embodiments of structure (V), A is C6-C10 aryl, C3-C10 cycloalkyl, 3-10membered heterocyclyl or 5-6 membered monocyclic heteroaryl, each of which is optionally substituted with one or more R5; X is N or CH; Y is CHOH or NH; R1is H or C1-C6 alkyl; R2is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3-8 membered heterocyclyl or 5- or 6-membered heteroaryl, each of which is optionally substituted with one more substituents selected from halo, hydroxyl, cyano, aminyl, C1-C6 alkyl, C2-C6 alkenyl, C2- C6 alkynyl, C1-C6 alkoxy and 3-8 membered heterocyclyl; R3is a heteroaryl selected from oxazolyl, isoxazolyl, 1, 2, 3-oxadiazolyl, 1, 2, 4- oxadiazolyl, 1, 2, 5-oxadiazolyl, 1, 3, 4-oxadiazolyl, 1, 2, 3-triazolyl, 1, 2, 4-triazolyl, thiazolyl, isothiazolyl, 1, 2, 3-thiadiazolyl, 1, 2, 4-thiadiazolyl, 1, 2, 5-thiadiazolyl and 1, 3, 4- thiadiazolyl, each of which is optionally substituted with one more substituents selected from halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C3-C8 cycloalkyl and C3-C8 halocycloalkyl; R4is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3-8 membered heterocyclyl, C6-C10 aryl or 5- or 6-membered heteroaryl, each of which is optionally substituted with one more substituents selected from halo, hydroxyl, cyano, aminyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl and C1-C6 alkoxy; and R5is, at each occurrence, independently halo, C1-C6 alkyl, C1-C6 alkyl or C1-C6 haloalkyl.Attorney Docket No.63243-702.601

[0195] One embodiment provides a compound of structure (I) or a pharmaceuticallyacceptable salt, stereoisomer or prodrug thereof, wherein: A is C6-C10 aryl, C3-C10 cycloalkyl, 3-10 membered heterocyclyl or 5-6 membered monocyclic heteroaryl, each of which is optionally substituted with one or more R5; X is N or CH; Y is CHOH or NH; R1is H or C1-C6 alkyl; R2is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3-8 membered heterocyclyl or 5- or 6-membered heteroaryl, each of which is optionally substituted with one more substituents selected from halo, hydroxyl, cyano, aminyl, C1-C6 alkyl, C2-C6 alkenyl, C2- C6 alkynyl, C1-C6 alkoxy and 3-8 membered heterocyclyl; R3is a heteroaryl selected from oxazolyl, isoxazolyl, 1, 2, 3-oxadiazolyl, 1, 2, 4- oxadiazolyl, 1, 2, 5-oxadiazolyl, 1, 3, 4-oxadiazolyl, 1, 2, 3-triazolyl, 1, 2, 4-triazolyl, thiazolyl, isothiazolyl, 1, 2, 3-thiadiazolyl, 1, 2, 4-thiadiazolyl, 1, 2, 5-thiadiazolyl and 1, 3, 4- thiadiazolyl, each of which is optionally substituted with one more substituents selected from amino, halo, cyano, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, C3-C8 alkylcycloalkyl, C3-C8 haloalkylcycloalkyl, C3-C8 aminylalkylcycloalkyl, C1-C6 cyanoalkyl, C1-C6 aminyl, C1-C6 hydroxylalkyl, 3-8 membered heterocyclyl, 3-8 membered heterocyclylalkyl, 3-8 membered heterocyclylcycloalkyl, 3-8 membered haloheterocyclyl, 3-8 membered haloheterocyclylalkyl, C3-C8 halocycloalkyl and C3-C8 halocycloalkylalkyl, and combinations thereof; R4is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3-8 membered heterocyclyl, C6-C10 aryl or 5- or 6-membered heteroaryl, each of which is optionally substituted with one more substituents selected from halo, hydroxyl, cyano, aminyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl and C1-C6 alkoxy; and R5is, at each occurrence, independently halo, cyano, C1-C6 alkyl, C1-C6 hydroxylalkyl, C1-C6 alkoxy, or C1-C6 haloalkyl.

[0196] In certain embodiment, R1 is H. In other embodiments, R1 is C1-C6 alkyl, such asmethyl.

[0197] In one embodiment, compounds of Structure (I) are provided, where R2 isbranched C4-C6 alkyl, C3-C4 cycloalkyl, C3-C8 heterocyclyl or 5- or 6-membered heteroaryl, each of which is optionally substituted with one more substituent selected from halo,Attorney Docket No.63243-702.601 hydroxyl, cyano, aminyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy and 3- to 8-membered heterocyclyl.

[0198] In another embodiment, compounds of Structure (I) are provided, where R2 isbranched C4-C6 alkyl, C3-C4 cycloalkyl, or C3-C8 heterocyclyl, each of which is optionally substituted with one more substituent selected from halo, hydroxyl, cyano, aminyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy and 3- to 8-membered heterocyclyl.

[0199] In specific embodiments, R2 is cyclopropyl, cyclobutyl, cyclopentyl orcyclohexyl, each of which is optionally substituted with one more substituent selected from halo, hydroxyl, cyano, aminyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy and 3- to 8-membered heterocyclyl.

[0200] In different embodiments, R2 is methyl, isopropyl, 2-methylpropyl or allyl, eachof which is optionally substituted with one more substituent selected from halo, hydroxyl, cyano, aminyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy and 3- to 8- membered heterocyclyl.

[0201] In different embodiments, R2 is methyl, ethyl, isopropyl, 2-methylpropyl or allyl,each of which is optionally substituted with one more substituent selected from halo, hydroxyl, cyano, aminyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy and 3- to 8-membered heterocyclyl.

[0202] In other embodiments, R2 is oxetanyl, tetrahydrofuranyl, tetrahydropyranyl,piperidinyl or dioxidotetrahydrothiophenyl, each of which is optionally substituted with one more substituent selected from halo, hydroxyl, cyano, aminyl, C1-C6 alkyl, C2-C6 alkenyl, C2- C6 alkynyl, C1-C6 alkoxy and 3- to 8-membered heterocyclyl.

[0203] In other embodiments, R2 is oxetanyl, tetrahydrofuranyl, tetrahydropyranyl,piperidinyl, azetidinyl or dioxidotetrahydrothiophenyl, each of which is optionally substituted with one more substituent selected from halo, hydroxyl, cyano, aminyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, and 3- to 8-membered heterocyclyl.

[0204] In other embodiments, R2 is oxetanyl, tetrahydrofuranyl, tetrahydropyranyl,piperidinyl, azetidinyl pyrrolidinyl, or dioxidotetrahydrothiophenyl, each of which is optionally substituted with one more substituent selected from halo, hydroxyl, cyano, aminyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, and 3- to 8-membered heterocyclyl.

[0205] In still more embodiments, R2 is pyridinyl optionally substituted with one moreAttorney Docket No.63243-702.601 substituent selected from halo, hydroxyl, cyano, aminyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy and 3- to 8-membered heterocyclyl.

[0206] In any of the foregoing embodiments, R2 is unsubstituted. In other of theforegoing embodiments, R2is substituted with one or more of hydroxyl and fluoro.

[0207] In any of the foregoing embodiments, R2 is unsubstituted. In other of theforegoing embodiments, R2is substituted with one or more of hydroxyl, methyl, methoxy, and fluoro.

[0208] In more specific embodiments, R2 has one of the following structures:

[0209] In further specific embodiments, R2 has one of the following structures:

[0210] In further specific embodiments, R2 has one of the following structures:Attorney Docket No.63243-702.601

[0211] In some embodiments, optionally R2 is substituted with one or more substituentsselected from the group consisting of halo, hydroxyl, cyano, aminyl, C1-C6alkyl, and 3-8 membered heterocyclyl.

[0212] In some embodiments, R2 does not have the following structures:

[0213] In any of the foregoing embodiments, R3 is oxazolyl, isoxazolyl, 1, 2, 3-oxadiazolyl or 1, 3, 4-oxadiazolyl, each of which is optionally substituted with one more substituents selected from halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C3-C8 cycloalkyl and C3-C8 halocycloalkyl. For example, in certain embodiments, R3is isoxazolyl optionally substituted with one more substituents selected from halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C3-C8 cycloalkyl and C3-C8 halocycloalkyl. In further specific embodiments, R3is substituted with C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl or C3-C8 halocycloalkyl.

[0214] In further embodiments, R3 is oxazolyl, isoxazolyl, 1, 2, 3-oxadiazolyl, 1, 3, 4-oxadiazolyl, thiazolyl, isothiazolyl, 1, 2, 4-thiadiazolyl, 1, 3, 4-thiadiazolyl or 1, 2, 4- triazolyl, each of which is optionally substituted with one more substituents selected from halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, cyano, C1-C6 aminyl, C1-C6 hydroxylalkyl, 3-8 membered heterocyclyl and C3-C8 halocycloalkyl, or combinations thereof.

[0215] In certain embodiments, R3 is isoxazolyl optionally substituted with one moresubstituents selected from halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, cyano, C1-C6 aminyl, C1-C6 hydroxylalkyl, 3-8 membered heterocyclyl and C3-C8 halocycloalkyl, or combinations thereof.Attorney Docket No.63243-702.601

[0216] In certain embodiments, R3 is thiazolyl optionally substituted with one moresubstituents selected from halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, cyano, C1-C6 aminyl, C1-C6 hydroxylalkyl, 3-8 membered heterocyclyl and C3-C8 halocycloalkyl, or combinations thereof.

[0217] In certain embodiments, R3 is isothiazolyl optionally substituted with one moresubstituents selected from halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, cyano, C1-C6 aminyl, C1-C6 hydroxylalkyl, 3-8 membered heterocyclyl and C3-C8 halocycloalkyl, or combinations thereof.

[0218] In certain embodiments, R3 is 1,2,4-thiadiazolyl optionally substituted with onemore substituents selected from halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, cyano, C1-C6 aminyl, C1-C6 hydroxylalkyl, 3-8 membered heterocyclyl and C3-C8 halocycloalkyl, or combinations thereof.

[0219] In certain embodiments, R3 is 1,3,4-thiadiazolyl optionally substituted with onemore substituents selected from halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, cyano, C1-C6 aminyl, C1-C6 hydroxylalkyl, 3-8 membered heterocyclyl and C3-C8 halocycloalkyl, or combinations thereof.

[0220] In certain embodiments, R3 is 1,3,4-oxadiazolyl optionally substituted with onemore substituents selected from halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, cyano, C1-C6 aminyl, C1-C6 hydroxylalkyl, 3-8 membered heterocyclyl and C3-C8 halocycloalkyl, or combinations thereof.

[0221] In certain embodiments, R3 is 1,2,4-triazolyl optionally substituted with one moresubstituents selected from halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, cyano, C1-C6 aminyl, C1-C6 hydroxylalkyl, 3-8 membered heterocyclyl and C3-C8 halocycloalkyl, or combinations thereof.

[0222] In further embodiments, R3 is substituted with C1-C6 alkyl, C1-C6 haloalkyl, C3-C8cycloalkyl, cyano, C1-C6 aminyl, C1-C6 hydroxylalkyl, 3-8 membered heterocyclyl or C3-C8 halocycloalkyl, or combinations thereof.

[0223] In various embodiments, R3 has one of the following structures:Attorney Docket No.63243-702.601oneoneAttorney Docket No.63243-702.601

[0226] In other embodiments, R4 is H. In other embodiments, R4 C1-C6 alkyl, such asmethyl.

[0227] In certain embodiments, Y is CHOH. In other embodiments, Y is NH.

[0228] In other embodiments, X is N. In more embodiments, X is CH.

[0229] In various embodiments, A is C6-C10 aryl, C3-C10 cycloalkyl or 5-6 memberedmonocyclic heteroaryl, each of which is optionally substituted with one or more R6. It is understood that A is a divalent radical.

[0230] In certain embodiments, A is a divalent optionally substituted C6-10 aryl. In certainembodiments, A is a divalent optionally substituted 3-8 membered saturated or partiallyAttorney Docket No.63243-702.601 unsaturated carbocyclic ring. In certain embodiments, A is a divalent optionally substituted 3- 10 membered heterocylic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In certain embodiments, A is a divalent optionally substituted 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0231] In certain embodiments, A is a divalent group selected from phenyl, pyridinyl,cyclohexyl, and cyclohexenyl; each of which is optionally substituted.

[0232] In other embodiments, A is phenyl. In different embodiments, A is saturated orunsaturated cyclohexyl. In more embodiments, A is pyridinyl.

[0233] In further embodiments, A is pyrimidinyl, which is optionally substituted.

[0234] In any of the foregoing embodiments, A is unsubstituted. In different of theforegoing embodiments, A is substituted with one or more R5. For example, in some embodiments R5is halo. In other embodiments, R5is fluoro. In other different embodiments, R5is chloro.

[0235] In some embodiments, R5 is cyano. In some embodiments, R5 is C1-C6 alkyl. Incertain embodiments, R5is methyl. In some embodiments, R5is C1-C6 haloalkyl. In certain embodiments R5is difluoromethyl. In further embodiments, R5is C1-C6 hydroxylalkyl. In certain embodiments R5is -CH2OH.

[0236] In certain embodiments, A is a divalent group selected from phenyl, naphthyl,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, cycloheptyl, adamantyl, cyclooctyl, [3.3.0]bicyclooctanyl, [4.3.0]bicyclononanyl, [4.4.0]bicyclodecanyl, [2.2.2]bicyclooctanyl, fluorenyl, indanyl, tetrahydronaphthyl, acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, NH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, dithiazinyl, tetrahydrofuranyl, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, indolenyl, indolinyl, indolizinyl, indolyl, 3-indolyl, isoindolinyl, isoindolenyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl;- 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolidinyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl,Attorney Docket No.63243-702.601 piperazinyl, piperidinyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole, pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2-pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl, 4H- quinolizinyl, quinoxalinyl, quinuclidinyl, tetrahydro furanyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, thiadiazinyl, 1,2,3- thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4- triazolyl, oxetanyl, azetidinyl, and xanthenyl; each of which is optionally substituted.

[0237] In specific embodiments, A has one of the following structures:

[0238] In other specific embodiments, A has one of the following structures:

[0239] In some embodiments, the compound of Formula (V) is a modulator of theNLRP3 inflammasome. In some embodiments, the compound of Formula (V) is an inhibitor of NEK7 in a patient or in a biological sample. In some embodiments, the compound of Formula (V) inhibits NEK7 and / or modulates the activity of the NLRP3 inflammasome. In some embodiments, the compound of Formula (V) is administered to treat pain. The pain may be acute inflammatory pain. The pain may be a symptom of a disease or condition of the subject experiencing pain. The pain may be associated with a disease or condition of the subject experiencing pain. Non-limiting example diseases and conditions include, inflammation, arthritis (e.g., osteoarthritis, rheumatoid arthritis, psoriatic arthritis), fibromyalgia, lupus, surgery (e.g., post-surgery pain), peritonitis, cancer, cancer treatment (e.g., chemotherapy), systemic sclerosis, psoriasis, atopic dermatitis, hidradenitis suppurativa,Attorney Docket No.63243-702.601 inflammatory bowel disease (IBD, e.g., colitis, Crohn's disease), endometriosis, and complex regional pain syndrome (CRPS).

[0240] In various different embodiments, the compound has one of the structures set forthin Table 1E below, or a pharmaceutically acceptable salt, stereoisomer, or prodrug thereof.

[0241] Compounds in Table 1E were prepared as described in the Examples or methodsknown in the art and analyzed by mass spectrometry and / or1H NMR. Table 1E. Representative Compounds of Structure (V)Attorney Docket No.63243-702.601Attorney Docket No.63243-702.601Attorney Docket No.63243-702.601Attorney Docket No.63243-702.601Attorney Docket No.63243-702.601Attorney Docket No.63243-702.601Attorney Docket No.63243-702.601Attorney Docket No.63243-702.601Attorney Docket No.63243-702.601Attorney Docket No.63243-702.601Attorney Docket No.63243-702.601Attorney Docket No.63243-702.601Attorney Docket No.63243-702.601Attorney Docket No.63243-702.601Attorney Docket No.63243-702.601Attorney Docket No.63243-702.601Attorney Docket No.63243-702.601Attorney Docket No.63243-702.601Attorney Docket No.63243-702.601Attorney Docket No.63243-702.601Attorney Docket No.63243-702.601Attorney Docket No.63243-702.601

[0242] Embodiments described herein provide a compound having Formula (VI):or a pharmaceutically acceptable salt, stereoisomer, or prodrug thereof, wherein: represents a double or a single bond such that all valences are satisfied; A is an optionally substituted 5-6-membered heterocyclyl, an optionally substituted 6- membered aryl, or an optionally substituted 5-6-membered heteroaryl; X is N or CR3; Y is C or N;Attorney Docket No.63243-702.601 W is CH or N; Z is CH or N; R1is optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkenyl, optionally substituted C1-C6 alkynyl, optionally substituted C1-C6 hydroxyalkyl, optionally substituted C1-C6 alkoxyalkyl, optionally substituted C1-C6 carboxyalkyl, optionally substituted C1-C6 haloalkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C6-C10 aryl, optionally substituted 3-10 membered heterocyclyl, or optionally substituted 5-10 membered heteroaryl; R2is optionally substituted aryl or optionally substituted heteroaryl; and R3is hydrogen, halo, cyano, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 haloalkyl, optionally substituted C1-C6 alkoxy, optionally substituted C1-C6 haloalkoxy, or optionally substituted C3-C8 cycloalkyl.

[0243] In some embodiments, represents a double bond. In some otherembodiments, represents a single bond.

[0244] In some embodiments, A is a 5-membered heterocyclyl. In certain embodiments,A is a 6-membered heterocyclyl. In some embodiments, A is a 6-membered heteroaryl. In certain embodiments, A is a 5-membered heteroaryl. In some embodiments, A is a 6- membered aryl.

[0245] In some embodiments, Y is N. In some embodiments, A is unsubstituted. Incertain embodiments, A is substituted. In some embodiments, A is substituted with one or more substituents selected from the group consisting of halo, cyano, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 haloalkyl, optionally substituted C1-C6 alkoxy, optionally substituted C1-C6 haloalkoxy, or optionally substituted C3-C8 cycloalkyl.

[0246] In some embodiments, A is substituted with one or more substituents selectedfrom the group consisting of halo, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 haloalkyl, optionally substituted C1-C6 alkoxy, and optionally substituted C1-C6 haloalkoxy.

[0247] In some embodiments, A is substituted with one or more substituents selectedfrom the group consisting of C1-C6 alkyl, halo, and C1-C6 haloalkyl. In some embodiments, A is substituted with one or more substituents selected from the group consisting of methyl, fluoro, and trifluoromethyl.Attorney Docket No.63243-702.601

[0248] In some embodiments,has the following structure:

[0249] In some embodiments, Z is CH. In certain embodiments, Z is N. In certainembodiments, X is N. In some embodiments, X is CR3. In some embodiments, R3is hydrogen or optionally substituted C1-C6 alkyl. In certain embodiments, X is CH.

[0250] In some embodiments, R1 is optionally substituted C1-C6 alkyl, optionallysubstituted C1-C6 alkenyl, optionally substituted C1-C6 alkynyl, optionally substituted C1-C6 hydroxyalkyl, optionally substituted C1-C6 alkoxyalkyl, optionally substituted C1-C6 carboxyalkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted 3-10 membered heterocyclyl, or optionally substituted 5-10 membered heteroaryl. In certain embodiments, R1is optionally substituted C1-C6 alkyl. In some embodiments, R1is methyl, ethyl, or iso-propyl. In certain embodiments, R1is optionally substituted C1-C6 alkenyl or optionally substituted C1-C6 alkynyl. In some more specific embodiments, R1has the following structure:

[0251] In some embodiments, R1 is optionally substituted C1-C6 hydroxyalkyl. In certainembodiments, R1has one of the following structures:Attorney Docket No.63243-702.601

[0252] In some embodiments, R1 is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.In some more specific embodiments, R1has one of the following structures:

[0253] In some embodiments, R1 is optionally substituted 3-10 membered heterocyclyl.In certain embodiments, R1has the following structure:

[0254] In some embodiments, R1 is optionally substituted 5-10 membered heteroaryl. Incertain embodiments, R1is unsubstituted pyridinyl. In some embodiments, R1has one of the following structures:

[0255] In some embodiments, R1 is optionally substituted C1-C6 carboxyalkyl. In certainembodiments, R1has the following structure:.

[0256] In some embodiments, R1 is optionally substituted C1-C6 alkoxyalkyl. In certainAttorney Docket No.63243-702.601 embodiments, R1has the following structure:.

[0257] In certain embodiments, R2 is optionally substituted phenyl or optionallysubstituted 5-membered heteroaryl. In some embodiments, R2is optionally substituted phenyl. In certain embodiments, R2is optionally substituted 5-membered heteroaryl. In certain embodiments, R2is optionally substituted isoxazolyl or optionally substituted pyrazolyl. In some embodiments, R2is optionally substituted with one or more substituents selected from the group consisting of halo, cyano, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 haloalkyl, optionally substituted C1-C6 alkoxy, optionally substituted C1-C6 haloalkoxy, optionally substituted C3-C8 cycloalkyl, optionally substituted 5-10-membered heterocyclylalkyl, optionally substituted 5-10-membered heterocyclyloxy, and optionally substituted C6-C10 aryl.

[0258] In some embodiments, R2 is optionally substituted with one or more substituentsselected from the following structures:

[0259] In some embodiments, R2 has one of the following structures:Attorney Docket No.63243-702.601

[0260] In some embodiments, R2 has one of the following structures:Attorney Docket No.63243-702.601Attorney Docket No.63243-702.601 in Table 1F below, or a stereoisomer, tautomer, or salt thereof. Compounds in Table 1F were prepared as described in the Examples or methods known in the art and analyzed by mass spectrometry and / or1H NMR. In some embodiments, the compound of Formula (VI) is a modulator of the NLRP3 inflammasome. In some embodiments, the compound of Formula (VI) is an inhibitor of NEK7 in a patient or in a biological sample. In some embodiments, the compound of Formula (VI) inhibits NEK7 and / or modulates the activity of the NLRP3 inflammasome. In some embodiments, the compound of Formula (VI) is administered to treat pain. The pain may be acute inflammatory pain. The pain may be a symptom of a disease or condition of the subject experiencing pain. The pain may be associated with a disease or condition of the subject experiencing pain. Non-limiting example diseases and conditions include, inflammation, arthritis (e.g., osteoarthritis, rheumatoid arthritis, psoriatic arthritis), fibromyalgia, lupus, surgery (e.g., post-surgery pain), peritonitis, cancer, cancer treatment (e.g., chemotherapy), systemic sclerosis, psoriasis, atopic dermatitis, hidradenitis suppurativa, inflammatory bowel disease (IBD, e.g., colitis, Crohn's disease), endometriosis, and complex regional pain syndrome (CRPS).

[0262] In various different embodiments, the compound has one of the structures set forthin Table 1F below, or a pharmaceutically acceptable salt, stereoisomer, or prodrug thereof.

[0263] Compounds in Table 1F were prepared as described in the Examples or methodsknown in the art and analyzed by mass spectrometry and / or1H NMR. Table 1F: Representative compounds of Structure (VI)Attorney Docket No.63243-702.601Attorney Docket No.63243-702.601Attorney Docket No.63243-702.601Attorney Docket No.63243-702.601Attorney Docket No.63243-702.601Attorney Docket No.63243-702.601Attorney Docket No.63243-702.601Attorney Docket No.63243-702.601Attorney Docket No.63243-702.601Attorney Docket No.63243-702.601Attorney Docket No.63243-702.601Attorney Docket No.63243-702.601Attorney Docket No.63243-702.601Attorney Docket No.63243-702.601Attorney Docket No.63243-702.601Attorney Docket No.63243-702.601Attorney Docket No.63243-702.601Attorney Docket No.63243-702.601Attorney Docket No.63243-702.601Attorney Docket No.63243-702.601Attorney Docket No.63243-702.601Attorney Docket No.63243-702.601Attorney Docket No.63243-702.601Attorney Docket No.63243-702.601Attorney Docket No.63243-702.601Attorney Docket No.63243-702.601Attorney Docket No.63243-702.601Attorney Docket No.63243-702.601Attorney Docket No.63243-702.601Attorney Docket No.63243-702.601Attorney Docket No.63243-702.601Attorney Docket No.63243-702.601Attorney Docket No.63243-702.601Attorney Docket No.63243-702.601Pharmaceutical Compositions

[0264] In one aspect, compounds provided herein are formulated into pharmaceuticalcompositions that are useful in a variety of applications including, but not limited to, therapeutic methods, such as the treatment of pain. The methods of use may be in vitro, ex vivo, or in vivo methods. In various embodiments, the pharmaceutical compositions are formulated for delivery via oral administration.

[0265] The pharmaceutical compositions may contain any pharmaceutically acceptablecarrier. pharmaceutically acceptable material, composition, or vehicle that is involved in carrying or transporting a compound of interest from one tissue, organ, or portion of the body to another tissue, organ, or portion of the body. For example, the carrier may be a liquid or solid filler, diluent, excipient, solvent, or encapsulating material, or a combination thereof. Each component of the carrier must be formulation. It must also be suitable for use in contact with any tissues or organs with which it may come in contact, meaning that does not carry a risk of toxicity, irritation, allergic response, immunogenicity, or any other complication that excessively outweighs its therapeutic benefits.

[0266] In some embodiments, the pharmaceutical composition comprises about 0.1 mg toAttorney Docket No.63243-702.601 about 10 mg of the compound of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), or Formula (VI). In some embodiments, the pharmaceutical composition comprises about 0.5 mg to about 5 mg of the compound of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), or Formula (VI). In some embodiments, the pharmaceutical composition comprises about 10 mg of the compound of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), or Formula (VI). In some embodiments, the pharmaceutical composition comprises about 5 mg of the compound of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), or Formula (VI). In some embodiments, the pharmaceutical composition comprises about 4 mg of the compound of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), or Formula (VI). In some embodiments, the pharmaceutical composition comprises about 3 mg of the compound of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), or Formula (VI). In some embodiments, the pharmaceutical composition comprises about 2 mg of the compound of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), or Formula (VI). In some embodiments, the pharmaceutical composition comprises about 1 mg of the compound of Formula (I). In some embodiments, the pharmaceutical composition comprises about 0.5 mg of the compound of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), or Formula (VI).

[0267] In some embodiments, pharmaceutical compositions of the compounds ofFormula (I), Formula (II), Formula (III), Formula (IV), Formula (V), or Formula (VI) are modulators of the NLRP3 inflammasome. In some embodiments, pharmaceutical compositions of the compounds of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), or Formula (VI) inhibit NEK7 when administered to a patient or a biological sample.

[0268] In some embodiments, the composition of capsules containing the activeingredient, a compound of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), or Formula (VI) is as given in Table 2. In some embodiments, the composition of capsules containing the active ingredient, a compound of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), or Formula (VI) is as given in Table 3. In some embodiments, the composition of capsules containing the active ingredient, a compound of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), or Formula (VI) is as given in Table 4.

[0269] In some embodiments, the composition comprises a tablet comprising the activeingredient, a compound of Formula (I), Formula (II), Formula (III), Formula (IV), FormulaAttorney Docket No.63243-702.601 (V), or Formula (VI); and one or more excipients of Table 2 (e.g., sodium lauryl sulfate (Kolliphore SLS fine), partially pre-gelatinized maize starch (Starch 1500), microcrystalline cellulose (Avicel PH 101), sodium starch glycolate (type A), HPC LF (Klucel LH Pharma), Aerosil Pharma 200, magnesium stearate). The one or more excipients may be present in the tablet at the amount shown in Table 2. The one or more excipients may be present in the table at the weight percentage shown in Table 2.

[0270] In some embodiments, the composition comprises a tablet comprising the activeingredient, a compound of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), or Formula (VI); and one or more excipients of Table 3 (e.g., sodium lauryl sulfate (Kolliphore SLS fine), partially pre-gelatinized maize starch (Starch 1500), microcrystalline cellulose (Avicel PH 101), sodium starch glycolate (type A), HPC LF (Klucel LH Pharma), Aerosil Pharma 200, magnesium stearate). The one or more excipients may be present in the tablet at the amount shown in Table 3. The one or more excipients may be present in the table at the weight percentage shown in Table 3.

[0271] In some embodiments, the composition comprises a tablet comprising the activeingredient, a compound of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), or Formula (VI); and one or more excipients of Table 3 (e.g., sodium lauryl sulfate (Kolliphore SLS fine), partially pre-gelatinized maize starch (Starch 1500), microcrystalline cellulose (Avicel PH 101), sodium starch glycolate (type A), HPC LF (Klucel LH Pharma), Aerosil Pharma 200, magnesium stearate). The one or more excipients may be present in the tablet at the amount shown in Table 3. The one or more excipients may be present in the table at the weight percentage shown in Table 3.

[0272] In some embodiments, the composition of capsules containing the activeingredient, a compound of Formula (I), is as given in Table 2. In some embodiments, the composition of capsules containing the active ingredient, a compound of Formula (I), is as given in Table 3. In some embodiments, the composition of capsules containing the active ingredient, a compound of Formula (I), is as given in Table 4.

[0273] In some embodiments, the pharmaceutical composition comprises about 0.1 mg toabout 10 mg of the compound of Formula (I). In some embodiments, the pharmaceutical composition comprises about 0.5 mg to about 5 mg of the compound of Formula (I). In some embodiments, the pharmaceutical composition comprises about 10 mg of the compound of Formula (I). In some embodiments, the pharmaceutical composition comprises about 5 mg of the compound of Formula (I). In some embodiments, the pharmaceutical composition comprises about 4 mg of the compound of Formula (I). In some embodiments, theAttorney Docket No.63243-702.601 pharmaceutical composition comprises about 3 mg of the compound of Formula (I). In some embodiments, the pharmaceutical composition comprises about 2 mg of the compound of Formula (I). In some embodiments, the pharmaceutical composition comprises about 1 mg of the compound of Formula (I). In some embodiments, the pharmaceutical composition comprises about 0.5 mg of the compound of Formula (I).

[0274] In some embodiments, pharmaceutical compositions of the compounds ofFormula (I) are modulators of the NLRP3 inflammasome. In some embodiments, pharmaceutical compositions of the compounds of Formula (I) inhibit NEK7 when administered to a patient or a biological sample.

[0275] In some embodiments, the composition of capsules containing the activeingredient, a compound of Formula (I), is as given in Table 2. In some embodiments, the composition of capsules containing the active ingredient, a compound of Formula (I), is as given in Table 3. In some embodiments, the composition of capsules containing the active ingredient, a compound of Formula (I), is as given in Table 4. Table 2. Composition of Capsules containing a Compound of Formula (I), 0.5 mgTable 3. Composition of a Compound of Formula (I) in Capsules, 2 mgAttorney Docket No.63243-702.601Table 4. Composition of Compound 10 Capsules, 5 mgMethods of Treatment

[0276] Provided herein are methods of treating pain in a subject in need thereof byadministering to the subject a compound of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), or Formula (VI). Pain includes, without limitation, acute pain, chronic pain, and breakthrough pain. Pain includes, without limitation, nociceptive pain, neuropathic pain, and radicular pain. Pain includes, without limitation, pain caused by arthritis, osteoarthritis, rheumatoid arthritis, psoriatic arthritis, fibromyalgia, lupus, post-surgical pain, acuate inflammatory pain, peritonitis, and any combination thereof.

[0277] The pain may be a symptom of a disease or condition of the subject experiencingpain. For example, the pain may be a symptom of inflammation, arthritis (e.g., osteoarthritis, rheumatoid arthritis, psoriatic arthritis), fibromyalgia, lupus, surgery (e.g., post-surgery pain), peritonitis, cancer, cancer treatment (e.g., chemotherapy), systemic sclerosis, psoriasis, atopic dermatitis, hidradenitis suppurativa, inflammatory bowel disease (IBD, e.g., colitis, Crohn's disease), endometriosis, or complex regional pain syndrome (CRPS), or two or more thereof.

[0278] The pain may be associated with a disease or condition of the subject experiencingpain. As such, in some instances, the subject experiencing pain also has a disease orAttorney Docket No.63243-702.601 condition. Non-limiting example diseases and conditions include, inflammation, arthritis (e.g., osteoarthritis, rheumatoid arthritis, psoriatic arthritis), fibromyalgia, lupus, surgery (e.g., post-surgery pain), peritonitis, cancer, cancer treatment (e.g., chemotherapy), systemic sclerosis, psoriasis, atopic dermatitis, hidradenitis suppurativa, inflammatory bowel disease (IBD, e.g., colitis, Crohn's disease), endometriosis, and complex regional pain syndrome (CRPS).

[0279] In some embodiments, the compound of Formula (I), or the pharmaceuticallyacceptable salt, stereoisomer, or solvate thereof, is administered in a dose of about 0.5 mg to about 10 mg. In some embodiments, the compound of Formula (I), or the pharmaceutically acceptable salt, stereoisomer, or solvate thereof, is administered in a dose of about 0.5 mg to about 5 mg. In some embodiments, the compound of Formula (I), or the pharmaceutically acceptable salt, stereoisomer, or solvate thereof, is administered in a dose of about 5 mg. In some embodiments, the compound of Formula (I), or the pharmaceutically acceptable salt, stereoisomer, or solvate thereof, is administered in a dose of about 4 mg. In some embodiments, the compound of Formula (I), or the pharmaceutically acceptable salt, stereoisomer, or solvate thereof, is administered in a dose of about 3 mg. In some embodiments, the compound of Formula (I), or the pharmaceutically acceptable salt, stereoisomer, or solvate thereof, is administered in a dose of about 2 mg. In some embodiments, the compound of Formula (I), or the pharmaceutically acceptable salt, stereoisomer, or solvate thereof, is administered in a dose of about 0.5 mg.

[0280] In some embodiments, the compound of Formula (I), or the pharmaceuticallyacceptable salt, stereoisomer, or solvate thereof, described herein can be administered by any suitable dosing schedule described herein. In some embodiments, the compound of Formula (I), or the pharmaceutically acceptable salt, stereoisomer, or solvate thereof, described herein is administered before a surgery and after a surgery.

[0281] In some embodiments, the compound of Formula (I), or the pharmaceuticallyacceptable salt, stereoisomer, or solvate thereof, is administered at least 1 day before surgery.

[0282] In some embodiments, the compound of Formula (I), or the pharmaceuticallyacceptable salt, stereoisomer, or solvate thereof, is administered 1 day before surgery.

[0283] In some embodiments, the compound of Formula (I), or the pharmaceuticallyacceptable salt, stereoisomer, or solvate thereof, is administered the day of surgery.

[0284] In some embodiments, the compound of Formula (I), or the pharmaceuticallyacceptable salt, stereoisomer, or solvate thereof, is administered 1-6 hours before surgery. In some embodiments, the compound of Formula (I), or the pharmaceutically acceptable salt,Attorney Docket No.63243-702.601 stereoisomer, or solvate thereof, is administered 1-3 hours before surgery. In some embodiments, the compound of Formula (I), or the pharmaceutically acceptable salt, stereoisomer, or solvate thereof, is administered 2-4 hours before surgery. In some embodiments, the compound of Formula (I), or the pharmaceutically acceptable salt, stereoisomer, or solvate thereof, is administered 2-5 hours before surgery. In some embodiments, the compound of Formula (I), or the pharmaceutically acceptable salt, stereoisomer, or solvate thereof, is administered 3-6 hours before surgery. In some embodiments, the compound of Formula (I), or the pharmaceutically acceptable salt, stereoisomer, or solvate thereof, is administered 6 hours before surgery. In some embodiments, the compound of Formula (I), or the pharmaceutically acceptable salt, stereoisomer, or solvate thereof, is administered 5 hours before surgery. In some embodiments, the compound of Formula (I), or the pharmaceutically acceptable salt, stereoisomer, or solvate thereof, is administered 4 hours before surgery. In some embodiments, the compound of Formula (I), or the pharmaceutically acceptable salt, stereoisomer, or solvate thereof, is administered 3 hours before surgery. In some embodiments, the compound of Formula (I), or the pharmaceutically acceptable salt, stereoisomer, or solvate thereof, is administered 2 hours before surgery. In some embodiments, the compound of Formula (I), or the pharmaceutically acceptable salt, stereoisomer, or solvate thereof, is administered 1 hour before surgery.

[0285] In some embodiments, the compound of Formula (I), or the pharmaceuticallyacceptable salt, stereoisomer, or solvate thereof, is administered starting 1 day after surgery.

[0286] In some embodiments, the compound of Formula (I), or the pharmaceuticallyacceptable salt, stereoisomer, or solvate thereof, is administered for 1 day after surgery. In some embodiments, the compound of Formula (I), or the pharmaceutically acceptable salt, stereoisomer, or solvate thereof, is administered for 2 days after surgery. In some embodiments, the compound of Formula (I), or the pharmaceutically acceptable salt, stereoisomer, or solvate thereof, is administered for 3 days after surgery. In some embodiments, the compound of Formula (I), or the pharmaceutically acceptable salt, stereoisomer, or solvate thereof, is administered for 4 days after surgery. In some embodiments, the compound of Formula (I), or the pharmaceutically acceptable salt, stereoisomer, or solvate thereof, is administered for 5 days after surgery. In some embodiments, the compound of Formula (I), or the pharmaceutically acceptable salt, stereoisomer, or solvate thereof, is administered for 6 days after surgery. In some embodiments, the compound of Formula (I), or the pharmaceutically acceptable salt,Attorney Docket No.63243-702.601 stereoisomer, or solvate thereof, is administered for 7 days after surgery. In some embodiments, the compound of Formula (I), or the pharmaceutically acceptable salt, stereoisomer, or solvate thereof, is administered for 8 days after surgery. In some embodiments, the compound of Formula (I), or the pharmaceutically acceptable salt, stereoisomer, or solvate thereof, is administered for 9 days after surgery. In some embodiments, the compound of Formula (I), or the pharmaceutically acceptable salt, stereoisomer, or solvate thereof, is administered for 10 days after surgery. In some embodiments, the compound of Formula (I), or the pharmaceutically acceptable salt, stereoisomer, or solvate thereof, is administered for 11 days after surgery. In some embodiments, the compound of Formula (I), or the pharmaceutically acceptable salt, stereoisomer, or solvate thereof, is administered for 12 days after surgery. In some embodiments, the compound of Formula (I), or the pharmaceutically acceptable salt, stereoisomer, or solvate thereof, is administered for 13 days after surgery. In some embodiments, the compound of Formula (I), or the pharmaceutically acceptable salt, stereoisomer, or solvate thereof, is administered for 14 days after surgery. In some embodiments, the compound of Formula (I), or the pharmaceutically acceptable salt, stereoisomer, or solvate thereof, is administered for 15 days after surgery. In some embodiments, the compound of Formula (I), or the pharmaceutically acceptable salt, stereoisomer, or solvate thereof, is administered for 16 days after surgery. In some embodiments, the compound of Formula (I), or the pharmaceutically acceptable salt, stereoisomer, or solvate thereof, is administered for 17 days after surgery. In some embodiments, the compound of Formula (I), or the pharmaceutically acceptable salt, stereoisomer, or solvate thereof, is administered for 18 days after surgery. In some embodiments, the compound of Formula (I), or the pharmaceutically acceptable salt, stereoisomer, or solvate thereof, is administered for 19 days after surgery. In some embodiments, the compound of Formula (I), or the pharmaceutically acceptable salt, stereoisomer, or solvate thereof, is administered for 20 days after surgery. In some embodiments, the compound of Formula (I), or the pharmaceutically acceptable salt, stereoisomer, or solvate thereof, is administered for 21 days after surgery. In some embodiments, the compound of Formula (I), or the pharmaceutically acceptable salt, stereoisomer, or solvate thereof, is administered for 22 days after surgery. In some embodiments, the compound of Formula (I), or the pharmaceutically acceptable salt, stereoisomer, or solvate thereof, is administered for 23 days after surgery. In some embodiments, the compound of Formula (I), or the pharmaceutically acceptable salt,Attorney Docket No.63243-702.601 stereoisomer, or solvate thereof, is administered for 24 days after surgery. In some embodiments, the compound of Formula (I), or the pharmaceutically acceptable salt, stereoisomer, or solvate thereof, is administered for 25 days after surgery. In some embodiments, the compound of Formula (I), or the pharmaceutically acceptable salt, stereoisomer, or solvate thereof, is administered for 26 days after surgery. In some embodiments, the compound of Formula (I), or the pharmaceutically acceptable salt, stereoisomer, or solvate thereof, is administered for 27 days after surgery. In some embodiments, the compound of Formula (I), or the pharmaceutically acceptable salt, stereoisomer, or solvate thereof, is administered for 28 days after surgery. In some embodiments, the compound of Formula (I), or the pharmaceutically acceptable salt, stereoisomer, or solvate thereof, is administered for 29 days after surgery. In some embodiments, the compound of Formula (I), or the pharmaceutically acceptable salt, stereoisomer, or solvate thereof, is administered for 30 days after surgery. In some embodiments, the compound of Formula (I), or the pharmaceutically acceptable salt, stereoisomer, or solvate thereof, is administered for 1-7 days after surgery. In some embodiments, the compound of Formula (I), or the pharmaceutically acceptable salt, stereoisomer, or solvate thereof, is administered for 1-10 days after surgery. In some embodiments, the compound of Formula (I), or the pharmaceutically acceptable salt, stereoisomer, or solvate thereof, is administered for 1-20 days after surgery. In some embodiments, the compound of Formula (I), or the pharmaceutically acceptable salt, stereoisomer, or solvate thereof, is administered for 1-30 days after surgery. In some embodiments, the compound of Formula (I), or the pharmaceutically acceptable salt, stereoisomer, or solvate thereof, is administered for 10-20 days after surgery. In some embodiments, the compound of Formula (I), or the pharmaceutically acceptable salt, stereoisomer, or solvate thereof, is administered for 10-30 days after surgery. In some embodiments, the compound of Formula (I), or the pharmaceutically acceptable salt, stereoisomer, or solvate thereof, is administered for 20-30 days after surgery. In some embodiments, the compound of Formula (I), or the pharmaceutically acceptable salt, stereoisomer, or solvate thereof, is administered for at least 10 days after surgery. In some embodiments, the compound of Formula (I), or the pharmaceutically acceptable salt, stereoisomer, or solvate thereof, is administered for at least 20 days after surgery. In some embodiments, the compound of Formula (I), or the pharmaceutically acceptable salt, stereoisomer, or solvate thereof, is administered for at least 30 days after surgery.

[0287] In some embodiments, the compound of Formula (I), or the pharmaceuticallyAttorney Docket No.63243-702.601 acceptable salt, stereoisomer, or solvate thereof, is administered one day before surgery and for at least 1 day after surgery. In some embodiments, the compound of Formula (I), or the pharmaceutically acceptable salt, stereoisomer, or solvate thereof, is administered one day before surgery and for at least 5 days after surgery. In some embodiments, the compound of Formula (I), or the pharmaceutically acceptable salt, stereoisomer, or solvate thereof, is administered one day before surgery and for at least 10 days after surgery. In some embodiments, the compound of Formula (I), or the pharmaceutically acceptable salt, stereoisomer, or solvate thereof, is administered one day before surgery and for at least 20 days after surgery. In some embodiments, the compound of Formula (I), or the pharmaceutically acceptable salt, stereoisomer, or solvate thereof, is administered one day before surgery and for at least 30 days after surgery.

[0288] In some embodiments, the compound of Formula (I), or the pharmaceuticallyacceptable salt, stereoisomer, or solvate thereof, is administered on the day of surgery and for at least 1 day after surgery. In some embodiments, the compound of Formula (I), or the pharmaceutically acceptable salt, stereoisomer, or solvate thereof, is administered on the day of surgery and for at least 5 days after surgery. In some embodiments, the compound of Formula (I), or the pharmaceutically acceptable salt, stereoisomer, or solvate thereof, is administered on the day of surgery and for at least 10 days after surgery. In some embodiments, the compound of Formula (I), or the pharmaceutically acceptable salt, stereoisomer, or solvate thereof, is administered on the day of surgery and for at least 20 days after surgery. In some embodiments, the compound of Formula (I), or the pharmaceutically acceptable salt, stereoisomer, or solvate thereof, is administered on the day of surgery and for at least 30 days after surgery.

[0289] In some embodiments, the compound of Formula (I), or the pharmaceuticallyacceptable salt, stereoisomer, or solvate thereof, is administered to the subject daily. In some embodiments, the compound of Formula (I), or the pharmaceutically acceptable salt, stereoisomer, or solvate thereof, is administered to the subject once daily.

[0290] In some embodiments, the compound of Formula (I), or the pharmaceuticallyacceptable salt, stereoisomer, or solvate thereof, is administered to the subject every other day. In some embodiments, the compound of Formula (I), or the pharmaceutically acceptable salt, stereoisomer, or solvate thereof, is administered to the subject once every other day.

[0291] In some embodiments, the compound of Formula (I), or the pharmaceuticallyacceptable salt, stereoisomer, or solvate thereof, is administered to the subject every week. In some embodiments, the compound of Formula (I), or the pharmaceutically acceptable salt,Attorney Docket No.63243-702.601 stereoisomer, or solvate thereof, is administered to the subject once every week.

[0292] In some embodiments, the compound of Formula (I), or the pharmaceuticallyacceptable salt, stereoisomer, or solvate thereof, is administered at a dose of about 2 mg. In some embodiments, the compound of Formula (I), or the pharmaceutically acceptable salt, stereoisomer, or solvate thereof, is administered at a dose of about 3 mg. In some embodiments, the compound of Formula (I), or the pharmaceutically acceptable salt, stereoisomer, or solvate thereof, is administered at a dose of about 4 mg. In some embodiments, the compound of Formula (I), or the pharmaceutically acceptable salt, stereoisomer, or solvate thereof, is administered at a dose of about 5 mg. In some embodiments, the compound of Formula (I), or the pharmaceutically acceptable salt, stereoisomer, or solvate thereof, is administered at a dose of about 6 mg. In some embodiments, the compound of Formula (I), or the pharmaceutically acceptable salt, stereoisomer, or solvate thereof, is administered at a dose of about 7 mg. In some embodiments, the compound of Formula (I), or the pharmaceutically acceptable salt, stereoisomer, or solvate thereof, is administered at a dose of about 8 mg. In some embodiments, the compound of Formula (I), or the pharmaceutically acceptable salt, stereoisomer, or solvate thereof, is administered at a dose of about 9 mg. In some embodiments, the compound of Formula (I), or the pharmaceutically acceptable salt, stereoisomer, or solvate thereof, is administered at a dose of about 10 mg. In some embodiments, the compound of Formula (I), or the pharmaceutically acceptable salt, stereoisomer, or solvate thereof, is administered at a dose of about 0.5 mg to about 10 mg. In some embodiments, the compound of Formula (I), or the pharmaceutically acceptable salt, stereoisomer, or solvate thereof, is administered at a dose of about 0.5 mg to about 5 mg.

[0293] In some embodiments, the compound of Formula (I), or the pharmaceuticallyacceptable salt, stereoisomer, or solvate thereof, is administered to the subject for at least 5 days. In some embodiments, the compound of Formula (I), or the pharmaceutically acceptable salt, stereoisomer, or solvate thereof, is administered for at least 10 days. In some embodiments, the compound of Formula (I), or the pharmaceutically acceptable salt, stereoisomer, or solvate thereof, is administered for at least 20 days. In some embodiments, the compound of Formula (I), or the pharmaceutically acceptable salt, stereoisomer, or solvate thereof, is administered for at least 30 days.

[0294] In some embodiments, the compound of Formula (I) is administered to the subjectfor at least 2 weeks. In some embodiments, the compound of Formula (I) is administered for at least 4 weeks. In some embodiments, the compound of Formula (I) is administered for atAttorney Docket No.63243-702.601 least 8 weeks. In some embodiments, the compound of Formula (I) is administered for at least 12 weeks. In some embodiments, the compound of Formula (I) is administered for 16 weeks. In some embodiments, the compound of Formula (I) is administered for 20 weeks. In some embodiments, the compound of Formula (I) is administered for 24 weeks. In some embodiments, the compound of Formula (I) is administered for 28 weeks. In some embodiments, the compound of Formula (I) is administered for 32 weeks. In some embodiments, the compound of Formula (I) is administered for 1 to 12 weeks. In some embodiments, the compound of Formula (I) is administered for more than 12 weeks. EXAMPLES

[0295] The following examples are illustrative of the embodiments described herein andare not to be interpreted as limiting the scope of this disclosure. To the extent that specific materials are mentioned, it is merely for purposes of illustration and is not intended to be limiting. One skilled in the art may develop equivalent means or reactants without the exercise of inventive capacity and without departing from the scope of this disclosure. Example 1: Synthesis Scheme

[0296] The following General Reaction Schemes illustrate examples of compounds ofStructure (I):or pharmaceutically acceptable salts, stereoisomers or prodrug thereof, wherein each of A, X, Y, R1, R2, R3, R4and R5are as defined herein. General Reaction Scheme 1

[0297] The following General Reaction Scheme, wherein X1 and X2 are independentlyhalogens, and X, R1, R2, R3and A have the meanings described herein, illustrates examples of methods of making the amine Intermediate D:Attorney Docket No.63243-702.601As shown in General Reaction Scheme 1, alkylation of the pyrimidine / pyridine pyrrole (i.e., Intermediate A) with a cycloalkyl boronate or an appropriate electrophile in presence of base affords the Intermediate B. This precursor is treated with ammonium hydroxide to form the pyrolopyrimidine / pyridine-4-amine derivative Intermediate C. The resulting Intermediate C can then be subject to palladium catalyzed arylation to form Intermediate D. General Reaction Scheme 2

[0298] The following General Reaction Scheme illustrates examples of methods ofmaking the carbamate Intermediate E:As shown in General Reaction Scheme 2, Intermediate E can be prepared the in presence of base by reaction of phenyl chloroformates and the indicated heteroaryl amine (an amine-substituted analogue of R4). General Reaction Scheme 2 depicts preparation of compounds wherein R5is H; however, compounds wherein R5is other than H can be prepare by similar methods by instilling R5after preparation of Intermediate E, or by using an appropriately substituted heteroaryl amine. General Reaction Scheme 3

[0299] The following General Reaction Scheme illustrates examples of methods ofAttorney Docket No.63243-702.601 making the compounds of Structure (I):Intermediate D and Intermediate E are treated with a base (e.g., trimethylamine, DIPEA, DMAP, and the like) in THF to afford the compounds of Structure (I). General Reaction Scheme 4

[0300] The following General Reaction Scheme illustrates examples of methods ofmaking the compounds of Structure (I):Intermediate D is reacted with the phenyl carbonochloridate shown under appropriate conditions to yield Intermediate E. Intermediate E is then coupled with the amine using a suitable base (e.g., trimethylamine, DIPEA, DMAP, and the like) in THF to afford the compounds of Structure (I).

[0301] Any of the above reaction scheme can be modified at any step to add and / ormodify a substituent may be added or modified as appropriate during any stage of the overall synthesis of desired compounds.

[0302] An intermediate A1 (4-chloro-5-iodo-7h-pyrroloAttorney Docket No.63243-702.601 was prepared as follows: N-iodosuccinimide (1.465 g, 6.51 mmol) was added to a stirred solution of 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (1.000 g, 6.51 mmol) in DMF (10 mL) at 0 °C and the resulting mixture was stirred at 25 °C for 12 h. Following completion of the reaction (as indicated by TLC), the reaction mixture was poured into ice cold water (100 mL) and stirred at 25 °C for 15 min. The resulting solid was filtered, washed with water (2 x 25 mL), and dried to afford the title compound as an off-white solid (1.7 g, 93% yield).1H NMR (400 MHz, DMSO- LCMS: 279.9 [M+H].

[0303] An intermediate B1 (4-chloro-7-cyclopropyl-5-iodo-7h-pyrrolo[2,3-d]pyrimidinewas prepared as follows: Copper (II) acetate (0.650 g, 3.58 mmol), 2,2'- bipyridine (0.559 g, 3.58 mmol), and sodium bicarbonate (0.601 g, 7.16 mmol) were added to a solution of 4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (A1, 1.000 g, 3.58 mmol) and cyclopropylboronic acid (0.615 g, 7.16 mmol) in dichloroethane (10 mL) and the resulting mixture was stirred at 70 °C under oxygen atmosphere for 12 h. Following completion of the reaction (as indicated by TLC), the reaction mixture was filtered through a pad of celite which was then rinsed with DCM (2 x 20 mL). The combined filtrates were washed with water (20 mL) and brine (25 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give crude material which was purified by flash chromatography (silica gel 230-400 mesh, eluting with 15% EtOAc in petroleum ether), affording the title compound as an off-white solid (0.7 g, 61% yield).1H NMR (400 MHz, DMSO- 7.96 (s, 1H), 3.63-3.69 (m, 1H), 1.06-1.10 (m, 4H). LCMS: 319.9 [M+H].

[0304] An intermediate C1 (7-cyclopropyl-5-iodo-7h-pyrrolo[2,3-d]pyrimidin-4-aminewas prepared as follows: A mixture of 4-chloro-7-cyclopropyl-5-iodo-7H- pyrrolo[2,3-d]pyrimidine (B1, 1.00 g, 2.191 mmol) and ammonium hydroxide (25% in water, 5 mL) was subjected to microwave irradiation at 150 °C for 1 h. Following completion of the reaction (as indicated by TLC), the reaction mixture was concentrated under reduced pressureAttorney Docket No.63243-702.601 to afford the title compound as an off-white solid (0.75 g, 80% yield).1H NMR (400 MHz,DMSO- -3.54 (m, 1H), 0.97-1.01 (m,4H). LCMS: 301.0 [M+H].

[0305] An intermediate D1 (5-(4-amino-3-fluorophenyl)-7-cyclopropyl-7h-pyrrolo[2,3-d]pyrimidin-4-aminewas prepared as follows: A mixture of 7-cyclopropyl-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4- amine (C1, 0.160 g, 0.533 mmol), 2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)aniline (0.190 g, 0.800 mmol), and K2CO3 (0.221 g, 1.599 mmol) in 1,4-dioxane (1 mL) and water (0.3 mL) was purged with N2 for 10 min. Pd(PPh3)4 (0.062 g, 0.053 mmol) was then added and the reaction mixture was stirred at 100 °C for 12 h. Following completion of the reaction (as indicated by TLC), the mixture was filtered through a pad celite which was then rinsed with EtOAc (2 x 10 mL). The combined filtrates were concentrated under reduced pressure to yield crude material which was purified by flash chromatography (silica gel 230- 400 mesh, eluting with 3% MeOH in DCM), affording the title compound as a yellow solid(0.110 g, 73% yield). 1H NMR (400 MHz, DMSO- -7.09 (m, 1H), 6.95-6.98 (m, 1H), 6.82-6.86 (m, 1H), 6.10 (bs, 2H), 5.22 (bs, 2H), 3.52-3.58 (m, 1H), 1.00-1.04 (m, 4H). LCMS: 284.1 [M+H].

[0306] Compoundwas prepared following the general procedure for urea formation starting from 5-(4-amino-3- fluorophenyl)-7-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (D1, 0.10 g, 0.35 mmol) and phenyl (5-(1-(trifluoromethyl)cyclopropyl)isoxazol-3-yl)carbamate (0.11 g, 0.35 mmolAttorney Docket No.63243-702.601

[0307] Specifically, triethylamine (2.0 eq.) was added to a mixture of D1 (1.0 eq.) and E1(1.0 eq.) in THF (10 Vol.) and the resulting mixture was stirred at 60 °C for 12 h in a sealed tube. Following completion of the reaction (as indicated by LCMS), the reaction mixture was concentrated under reduced pressure to give crude material which was purified by reverse phase preparative HPLC to afford the desired product. Compound 10 was obtained as an off- white solid (0.010 g, 6% yield).1H NMR (400 MHz, DMSO- 1H), 8.14-8.18 (m, 2H), 7.24-7.36 (m, 3H), 6.90 (s, 1H), 6.15 (bs, 2H), 3.56-3.61 (m, 1H), 1.48-1.57 (m, 4H), 1.02-1.07 (m, 4H). LCMS: 502.2 [M+H]. Example 2: Non-Limiting Formulation Examples

[0308] The free base of compound 10 was formulated as an oral capsule in 0.5 mg, 2 mg,and 5 mg capsule strengths, in similar blends as shown in Table 5. Compound 10 may also be formulated into a tablet. For example, the tablet may comprise the excipients of Table 5. Table 5. Composition of the blend for 0.5, 2, and 5 mg strength capsulesAttorney Docket No.63243-702.601 Example 3: CFA-Induced Inflammatory Pain Model in Rats

[0309] Injection of CFA (a water-in-oil emulsion which contains inactivatedsensitivity to heat and mechanical tactile stimulation.

[0310] In this model, male Wistar rats (n=10 per group, group details in Table 6) weresubjected to CFA injection in the plantar surface of their right hind paw (Day 0). After 24 hours (Day 1, t = 0 h), animals were treated with a single oral dose of compound 10 (10 or 30 mg / kg) or the control drug diclofenac (30 mg / kg) then evaluated for mechanical allodynia using a dynamic plantar aesthesiometer to measure PWT and thermal hyperalgesia using Hargreaves apparatus to measure PWL at 0, 1, 3, 6, 9, 12, and 24 hours post dose. Results are shown in FIGS.1A-1C. Table 6. Group details for CFA-induced inflammatory pain model

[0311] Animals in the no treatment control group exhibited statistically significantdecreases (p<0.0001) in PWT and PWL at all time points compared to the sham control, indicating successful induction of inflammatory pain 24 to 48 hours post CFA injection (0 to 24 hours on Day 1). Treatment with the non-steroidal anti-inflammatory diclofenac (30 mg / kg) resulted in a statistically significant improvement of mechanical allodynia and thermal hyperalgesia with peak effect observed 3 hours post dose (p<0.0001 for both PWT and PWL) and efficacy extending to 12 hours (PWT) or 24 hours (PWL) post dose. When comparing with the no treatment control group, diclofenac treatment resulted in a 39% improvement in mechanical allodynia and a 42% improvement in thermal hyperalgesia over the course of 24 hours (p<0.0001 for both).

[0312] Treatment with compound 10 also resulted in significant dose-dependentimprovements in mechanical allodynia and thermal hyperalgesia with peak effect observed 3 hours post dose (p<0.001 or better). Efficacy against mechanical allodynia was significant in the high-dose group until 9 hours post dose (p<0.01 or better) while efficacy against thermalAttorney Docket No.63243-702.601 hyperalgesia extended to 12 hours post-dose in the low dose group and 24 hours post-dose in the high dose group (p<0.05 or better). Overall, when comparing with the no treatment control group over the course of 24 hours, treatment with low dose compound 10 resulted in a 14% improvement in mechanical allodynia and a 24% improvement in thermal hyperalgesia (p<0.0001) while treatment at high dose resulted in a 30% improvement in mechanical allodynia and a 34% improvement in thermal hyperalgesia (p<0.0001 for both).

[0313] These data suggest that compound 10 can provide durable pain control in a ratmodel of CFA-induced inflammatory pain at oral doses as low as 10 mg / kg. Example 4: Brennan's Incisional Pain Model in Rats

[0314] In this study, male SD rats (n=8 per group, group details in Table 7) wereevaluated for mechanical allodynia and thermal hyperalgesia at baseline (Day -1) and underwent surgery on Day 0 (a 1 cm longitudinal incision was made through the skin, fascia, and plantaris muscle of the right hind paw followed by wound closure). On Days 1 through 3, animals received an oral dose of compound 10 (10 mg / kg) or the control drug indomethacin (30 mg / kg) and, 2 hours post drug administration (at t = 24, 48, and 72 hours post-surgery), were evaluated for mechanical allodynia and thermal hyperalgesia. Results are shown in FIGS.2A-2B. Table 7. Group details for Brennan's incisional pain model

[0315] Animals in the no treatment control group exhibited statistically significantdecreases (p<0.001) in PWT and PWL at all time points (an expected consequence of postoperative pain) while their weight increased slightly over 5 days. Treatment with the non- steroidal anti-inflammatory indomethacin (30 mg / kg PO daily) resulted in a statistically significant improvement in PWT and PWL at all timepoints with overall improvements of 87% and 93% in mechanical allodynia and thermal hyperalgesia, respectively (p<0.001 or better), when comparing with the no treatment control group. However, signs of GI and overall toxicity were observed beginning on Day 2 (after administration of a single dose ofAttorney Docket No.63243-702.601 indomethacin) with discolored feces, weakness, and weight loss, culminating in the death of one animal on Day 3 and an overall 9.1% weight loss (p<0.0001) across the group, suggesting that, while efficacious, daily oral treatment with 30 mg / kg of indomethacin is not tolerable.

[0316] Treatment with compound 10 (10 mg / kg PO daily) also resulted in a statisticallysignificant improvement in PWT and PWL at all timepoints with overall improvements of 51% and 92% in mechanical allodynia and thermal hyperalgesia, respectively (p<0.01 or better), when comparing with the no treatment control group. Rats treated with compound 10 study.

[0317] These data suggest that a 10 mg / kg oral daily dose of compound 10 is welltolerated and efficacious at controlling postoperative incisional pain in rats, essentially restoring full function to the affected limb. Example 5: Surgically Induced Osteoarthritis Model in Rats

[0318] Osteoarthritis can be induced in rats by initiating or accelerating jointdegeneration using surgery. In particular, surgical transection of the anterior cruciate ligament (ACLT) combined with partial medial menisectomy (pMMx) results in time- dependent pathological changes such as articular cartilage degradation, subchondral bone sclerosis, and osteophyte formation as well as inflammatory pain.

[0319] In this model, male Wistar rats (n=8 or 10 per group, group details in Table 8)were subjected to ACLT+pMMx surgery (Day 0) then were treated for 5 weeks with oral doses of compound 10 (1 mg / kg / day) or the control drug dexamethasone (0.1 mg / kg / day). Body weight were collected daily and pain was assessed weekly for 5 weeks post-surgery by measuring mechanical allodynia (using a dynamic plantar aesthesiometer to quantify paw withdrawal threshold PWT). Results are shown in FIGS.3A-3B. Table 8. Group details for surgically induced osteoarthritis rat modelAttorney Docket No.63243-702.601

[0320] Following surgery, animals in the no treatment control group exhibitedstatistically significant decreases (p<0.0001 at all timepoints) in PWT with no recovery over 5 weeks (a consequence of untreated severe joint instability and associated pain following the surgery). After a post-surgical weight loss of 3.9%, animals from the no treatment control recovered their pre-dose weight by Day 13. They experienced a total weight gain comparable to the sham control group (9.4% weight gain vs.13.6%, respectively).

[0321] Animals treated with the potent anti-inflammatory corticosteroid dexamethasone(0.1 mg / kg PO daily) experienced a minor (3%) and statistically insignificant improvement in PWT over 5 weeks compared to the no-treatment group. In addition, weight loss was significant in the dexamethasone group, peaking at 10.9% after 2 weeks with limited recovery during the following 3 weeks, resulting in an average weight loss of 7.1% after 5 weeks (p<0.0001). These data indicate that treatment with dexamethasone (0.1 mg / kg daily) following ACLT+MMx surgery is poorly tolerated in rats and fails to restore function in the affected limb.

[0322] In contrast, animals treated with compound 10 (1 mg / kg PO daily) experiencedsteady and continuous improvements in PWT at each weekly measurement, culminating in an 18% improvement in PWT over 5 weeks when compared to the no-treatment group (p<0.01). In addition, following the post-surgical weight loss, animals in the groups exhibited weight gains like those in the sham control group (12.7% vs 13.6% respectively).

[0323] These data suggest that compound 10 is well tolerated after 5 weeks of daily oraldosing at 1 mg / kg and can provide durable pain control and partially restore function to the affected limb in a rat model of surgically induced osteoarthritis Example 6: Phase I Data Safety Receptor Panel Screening

[0324] Compound 10 was screened against a panel of 44 receptors and enzymes knownto be contributors inhibition (> 50%) was found against 14 of these targets. A follow-up study was conducted to determine the IC50 of compound 10 against these targets. The results are shown in Table 9. Table 9. Receptor panel screening results for Compound 10Attorney Docket No.63243-702.601nd: value not determined

[0325] All the targets except for serotonin receptor 5-HT2B showed IC50 µM, whichisconsidered outside the relevant pharmacological range of compound 10, suggesting that no significant toxicity concerns are to be expected from the observed off-target receptor activities. Effects on hERG Channel Function

[0326] The ability of compound 10 to inhibit transport through the ion channel encodedby the human Ether-à-go-go Related Gene (hERG) was evaluated in vitro. Compound 10 at concentrations 0.78, 3, 10 and 30 µM inhibited hERG current by 12.93%, 19.39%, 40.34%, and 52.95%, respectively, compared to the vehicle control current. The calculated IC50 value of compound 10 is 23.10 µM, making it a low potency inhibitor of hERG current. Central Nervous System

[0327] The effect of compound 10 on the central nervous system of male SpragueDawley rats was evaluated using the Functional Observational Battery (FOB). Following administration of a single oral dose (1, 3, and 10 mg / kg), compound 10 was found not to affect any of the CNS functions tested using FOB. Hence, the No Observed Effect Level (NOEL) of compound 10 for the alteration of neurobehavioral functions following administration of a single oral dose in rats is 10 mg / kg, the highest dose tested. Respiratory System

[0328] The effect of compound 10 on the respiratory functions of conscious maleSprague Dawley rats was evaluated using head-out plethysmography. Following administration of a single oral dose (1, 3, and 10 mg / kg), compound 10 was found not toAttorney Docket No.63243-702.601 affect any of the respiratory functions tested in the study. Hence, the NOEL of compound 10 for the alteration of respiratory functions following administration of a single oral dose in rats is 10 mg / kg, the highest dose tested. Cardiovascular System

[0329] Compound 10 was evaluated for its cardiovascular effects in instrumented malebeagle dogs. The NOEL was found to be 4 mg / kg, the highest dose tested. In Vitro Permeability and Drug Transporter Effects

[0330] The permeability of compound 10 was tested in a bidirectional Caco-2 assay.Compound 10 was found to be moderately permeable in the absorptive direction (Papp 2.55 x 10-6 cm / sec) with an efflux ratio of 2.0. Transporter studies revealed modest active transport by BCRP, and to a lesser extent by P-gp.

[0331] Caco-2 screening studies performed with and without selective P-gp and BCRPinhibitors had revealed moderate permeability with no efflux concerns (ER<2) for compound 10, suggesting that the compound was not a substrate of the P-gp and BCRP transporters. To confirm this finding, bidirectional permeability was evaluated in MCDK-II cells transfected with the MDR1 or MDCK genes. Permeability (A>B) was found to be very low in both cell lines with high efflux ratios, ER = 30.4 in MDR1-MDCK-II cells and ER = 78.0 in BCRP- MDCK-II cells. This suggests that compound 10 is a substrate for both the P-gp and BCRP transporters. Use in Humans

[0332] A phase 1, randomized, placebo-controlled, single-center, single and multipleascending dose study has been initiated and is designed to evaluate the safety, tolerability, PK, and PD of compound 10 in healthy human subjects.48 subjects have been enrolled in this study. Eight (8) subjects were enrolled in each cohort, 2 of which received placebo. Therefore, a total of 36 subjects have received compound 10 in this study. Safety data is available for the 32 subjects enrolled in the single ascending dose (SAD) portion of the study, which was completed 29 October 2022. The multiple ascending dose (MAD) portion of the study is ongoing. To date, compound 10 has been dosed over 6 different dose cohorts [1mg single dose (SD) 2mg SD, 3mg SD, 4mg SD, 1mg QD, 2mg QD]. No serious adverse events (SAEs) have been reported to date and no treatment-emergent AEs CTCAE grade 3 occurred to date. Possible Risks and Side Effects

[0333] Compound 10 has been evaluated in 36 subjects with safety data available in 32Attorney Docket No.63243-702.601 subjects. No SAEs were observed and no treatment-emergent AEs CTCAE grade 3 have occurred to date. Based on animal studies, the possible side effects that can be anticipated include transaminitis (reversible) and gastrointestinal toxicity such as diarrhea. Summary

[0334] In-vivo, compound 10 demonstrates significant pain control in rat models ofinflammatory pain and incisional pain driven by activation of the NLRP3 inflammasome. In a Adjuvant (CFA)-induced inflammatory pain model, treatment with single doses of compound 10 at 10 mg / kg and 30 mg / kg resulted in significant dose-dependent improvements in mechanical allodynia and thermal hyperalgesia with peak effect observed 3 hours post daily doses of compound 10 at 10 mg / kg and 30 mg / kg resulted in a statistically significant improvement in paw withdrawal threshold (PWT) and paw withdrawal latency (PWL) at all timepoints with overall improvements of 51% and 92% in mechanical allodynia and thermal hyperalgesia, respectively (p<0.01 or better), when compared with the no treatment control group. Example 7: Phase II Clinical Trial

[0335] A phase II, randomized, placebo-controlled, double-blind, parallel-group study isperformed to evaluate the ability of compound 10 to attenuate diagnostic biomarkers of post- procedure acute inflammation and manage pain following third molar extraction in adult patients.

[0336] Eighty (80) patients will be enrolled and randomized in a 1:1 ratio to study drug,either compound 10 or matching placebo. One single 4 mg dose of randomized study drug will be administered 3 hours (± 15 minutes) prior to surgery. Rescue analgesia (acetaminophen or ibuprofen) is available if pain persists.

[0337] The primary biomarker endpoint of the study, and primary endpoint overall, is themaximum observed CRP increase from pre-dose Primary safety endpoints are incidence rates of AEs and SAEs. Key secondary efficacy endpoints are levels of ESR, IL-IL-6, and TNF- , area under the categorical painintensity-by-time curve from the first rating of pain intensity to 4, 6, and 8 hours after the end of surgery (AUCe, AUC6, and AUC8, respectively), time to rescue analgesia, proportion of patients who require rescue analgesia within 4, 6, and 8 hours after the end of surgery, patient ratings of pain intensity using an 11-point NPRS at 60, 90, 120, 150 minutes, and 3, 4, 5, 6, 7, and 8 hours after the end of surgery (i.e., the time of the last suture), and overall satisfactionAttorney Docket No.63243-702.601 with study drug. Safety Conclusions

[0338] A total of 14 subjects (34.1%) in the compound 10 group and 13 subjects (32.5%)in the placebo group reported at least 1 TEAE during the study. At least 1 TEAE judged possibly or probably related to study drug was reported in 11 subjects (26.8%) in the compound 10 group and 7 subjects (17.5%) in the placebo group; however, only 1 subject (2.5%) in the placebo group, and none in the compound 10 group, reported at least 1 TEAE treatment group were headache, which occurred in 14.6% of compound 10 subjects and 0% of placebo subjects, and nausea, which occurred in 7.3% of compound 10 subjects and 10.0% of placebo subjects.

[0339] The majority of TEAEs were mild in severity in each treatment group (92.9% ofevents in the compound 10 group, and 76.9% of events in the placebo group). No severe treatment group were mild headache, which occurred in 12.2% of compound 10 subjects and 0% of placebo subjects, and mild nausea, which occurred in 7.3% of compound 10 subjects and 10.0% of placebo subjects.

[0340] Treatment-emergent AEs possibly or probably related to study drug were reportedby 26.8% of compound 10 subjects and 17.5% of placebo subjects. The most common (>2.5% of subjects in any treatment group) PTs of TEAEs considered possibly or probably related to study drug were nausea (7.3% and 5.0% for compound 10 and placebo, respectively), headache (9.8% and 0%, respectively), CRP increased (4.9% and 2.5%), and vomiting (0% and 5.0%).

[0341] There were no reported AEs that led to death, no reported serious AEs, and noreported AEs that led to study drug discontinuation or withdrawal.

[0342] With regard to laboratory parameters, neutrophil and monocyte concentrationsincreased on Day 3 in both groups relative to both screening and pre-surgery, though none of -fold. Amylase concentrations decreased in both groups across thepost- -fold. Additionally,only 1 potentially clinica

[0343] There were no group trends across vital sign measurements or notable differencesbetween groups. In summary, compound 10 was overall safe and well-tolerated when compared with placebo.Attorney Docket No.63243-702.601 Efficacy Conclusions

[0344] All efficacy analyses were conducted on the Safety Population, which consisted of81 subjects (41 compound 10 subjects and 40 placebo subjects).

[0345] The primary efficacy endpoint of maximum observed CRP increase from baselinehad no significant difference between groups (p = 0.815).

[0346] The secondary efficacy endpoints were analyzed in a hierarchical closed testprocedure. The secondary endpoints were not considered for statistical significance because the primary efficacy endpoint was not statistically significant.

[0347] Pain intensity AUCs were also assessed as a secondary efficacy endpoint. Painintensity assessment times were 60, 90, 120, and 150 minutes and hourly at 3 through 8 hours following the end of surgery (i.e., the time of the AUCs were lower in the compound 10 group than the placebo group for all time frames. the compound 10 group than the placebo group for all time frames.

[0348] Time to rescue analgesia and requirement for rescue analgesia were recorded foreach subject during the 8 hours following the end of surgery (i.e., the time of the last suture), and comprised further secondary efficacy endpoints. At 4 hours, more subjects in the compound 10 group had taken no rescue analgesia (43.9%) when compared to the placebo group (30.0%), while more subjects in the placebo group had taken first-tier rescue analgesia (67.5%) when compared to the compound 10 group (51.2%). At 6 hours, more subjects in the compound 10 group had taken no rescue analgesia (29.3%) when compared to the placebo group (17.5%), while more subjects in the placebo group had taken first-tier rescue analgesia (75.0%) when compared to the compound 10 group (61.0%). There were no notable differences between treatment groups in taking second-tier rescue analgesia at 4 hours or 6 hours post-surgery, and there were no notable differences between groups in rescue status at 8 hours post-surgery. Only 2 subjects, both in the compound 10 treatment group, did not require rescue analgesia; in total, 39 / 41 (95%) subjects in the compound 10 group required rescue analgesia, and 40 / 40 (100%) subjects in the placebo group required rescue analgesia.

[0349] For the final secondary efficacy endpoint, subjects rated overall satisfaction withthe study drug using a 5- 29.3%, respectively) than the placebo group (17.5% and 37.5%, respectively); more subjects ) than theAttorney Docket No.63243-702.601 with study drug in the 2 treatment groups (31.7% and 27.5% neutral for compound 10 and placebo, respectively, and 14.6% and 15.0% rather satisfied, respectively). Non-prespecified, Exploratory Analyses Rationale and Objective

[0350] In addition to the predefined primary and secondary endpoints of this clinicalstudy, non-prespecified exploratory analyses were conducted to investigate additional outcomes and potential relationships that may provide further insights into the safety and activity of the investigational treatment. Methods

[0351] The same dataset used for the primary and secondary endpoints was alsoemployed for the non-prespecified exploratory analyses. When possible, the statistical -test being the most common of these methods, were applied to support these exploratory analyses. Sub-stratification of Early vs Late Responses

[0352] Early timepoints were assessed at 4 and 8 hours and late timepoints at 24 and 48hours post-surgery, respectively. C-reactive protein (CRP) levels were reviewed at early time points post dose of compound 10 to align with its expected peak plasma concentration (Cmax), which occurs about 2 to 3 hours after dosing based on early clinical data. To capture and pain assessments at earlier (4 and 8 hour) timepoints was conducted post hoc to explore if a reduction in CRP levels at these time points would offer additional insights into compound 10's role in mitigating the inflammatory response. The observed convergence of results between the treatment and placebo groups at the 24 and 48 hour timepoints would support the hypothesis of a weaning biological effect of compound 10 due to the drug now likely only being present at sub-efficacious levels.

[0353] Data illustrated in Figure 4 showed that CRP levels in the placebo group increasedat the 4 and 8 hour time points, reflecting the expected post-surgery inflammatory response. The compound 10 treatment group showed a suppression of CRP levels at the 4 and 8 hour time points relative to the placebo group. This reduction in CRP levels relative to placebo indicates a suppression of the inflammatory response in the compound 10 treated group (1).

[0354] Figure 5 demonstrates that CRP levels measured at baseline, 4, and 8 hours post-surgery, and at 2 follow-up time points (follow-up visit 1 [FU1] at 24 hours, follow-up visit 2 [FU2] at 48 hours), showed a distinct rise in both groups. This could be indicative of aAttorney Docket No.63243-702.601 transient effect of compound 10 when administered as a single dose only, because the drug's impact on suppressing CRP levels may have declined at the later time points. This was also found to coincide with lower compound 10 plasma concentrations. The Importance of Prognostic Factors for Pain Following Third Molar Extraction

[0355] The randomization schedule for assigning treatment to subjects was stratified by abivariate categorization of the number of partially or fully impacted third molars planned for extraction (1 versus more than 1). The rationale for implementing stratification was to ensure balance between the subjects randomized to compound 10 and those randomized to placebo with respect to an important prognostic factor for pain following third molar extraction surgery. Prophylactic administration of study drug demanded subjects be randomized to study drug prior to the actual surgical procedure, therefore the stratification variable was the randomized in th -way analysis of variance (ANOVA) identified as the primary efficacy analysis model in the protocol and statistical analysis plan (SAP). Therefore, inference was based on a one-way ANOVA with a -test. Unfortunately, the revised method of analysis does not account for imbalances between treatment groups with respect to prognostic factors for pain following oral surgery.

[0356] Randomization failed to produce homogeneous subject constituency between thetreatment groups with respect to important prognostic factors for pain following third molar extraction surgery. For example, the percentage of subjects with a fully impacted left mandibular third molar extracted during the study surgery differed between treatment groups (58.5% [24 out of 41 subjects] for compound 10 versus 40.0% [16 out of 40 subjects]), as did the percentage of subjects with a fully impacted right mandibular third molar (51.2% [21 out of 41 subjects] for compound 10 versus 42.5% [17 out of 40 subjects]).

[0357] Given the observed heterogeneity between treatment arms with respect to thenumbers of fully impacted third molars extracted, an ad hoc statistical comparison using analysis of covariance (ANCOVA) was performed on the pain score areas under the curve (AUCs). The objective of this analysis was to remove the effect of the prognostic factor from the comparison of treatment effect; therefore, the ANCOVA model includes the number of impacted mandibular third molars extracted as a covariate, the randomized treatment group, and the two-way interaction. The covariate is tabulated by treatment in the table below.Attorney Docket No.63243-702.601 Summary of Number of Impacted Molars by Treatment Group

[0358] As seen in Figure 6, the p-value for testing the difference between compound 10and placebo with respect to pain intensity AUCs from 1 through 4 hours following surgery (estimated according to the SAP) is 0.021, which is below the nominal threshold for statistical significance. Low p-values were also observed for pain intensity AUCs from 1 through 6 and 1 through 8 hours following surgery (Figure 6; p-values of 0.053 and 0.137, respectively). It is notable that, as an inverse univariate metric for compound 10 to mitigate acute pain, serial p-values increase further away from the administration of study drug, leading to the hypothesis that increased or longer exposure to compound 10 may increase its analgesic effect and duration. While these results are promising and potentially warrant further investigation, statistical significance cannot be declared due to lack of control for multiple comparisons and the ad hoc nature of this test.

[0359] Given the observed heterogeneity in treatment effects potentially influenced byprognostic factors, we examined whether the absence of fully impacted molars correlates with a reduced need for opioid analgesics post-surgery. Figure 7 presents a comparative analysis of opioid use in the compound 10 and placebo groups, specifically highlighting the frequency reached for within the 8 hour observation period and the entire 48 hour study duration through FU2.

[0360] There are noted trends toward less analgesic use, especially opioids, in thecompound 10 treatment group when subjects did not have a fully impacted third molar removed. This may suggest that the effectiveness of compound 10 in the study may be influenced by the number of impacted molars. This could indicate that a pain threshold effect exists, where the difference between partially impacted and fully impacted molars, irrespective of their quantity, becomes a meaningful contributor to surpass a threshold for enhanced analgesic treatment needed, a threshold that is required to discernibly benefit from the analgesic effects of compound 10. Summary of Findings from Non-prespecified AnalysesAttorney Docket No.63243-702.601

[0361] In summary, the following findings have been drawn from the non-prespecifiedanalyses described above: 1. Pain Levels Post-Procedure: Subjects receiving compound 10 reported lower pain levels at 4 and 8 hours post-surgery compared to those receiving the placebo. The pain scores were consistently lower in the compound 10 group, suggesting enhanced analgesic effects. Importantly, the observed differences in pain levels between the treatment and placebo groups became more pronounced when metrics were stratified by prognostic variables such as severity of the surgical procedure and number of impacted molars removed. 2. Use of Rescue Analgesic Medications: The compound 10 group demonstrated a delayed time to first use of rescue analgesics and a reduced total amount of rescue medications used. This further supports a potential analgesic effect observed with compound 10 treatment. Conclusion

[0362] -prespecified analyses highlightcompound 10's potential anti-inflammatory effects and warrant its further exploration as a potential analgesic agent within the context of third molar extraction. The observed reduction in inflammatory markers and pain levels, alongside a decreased reliance on rescue analgesics, further suggests that compound 10 may impart a biological effect on the mechanisms involved in managing post-operative inflammation and pain. Overall Study Conclusions This phase 2, randomized, single-dose, placebo-controlled, double-blind, parallel-group clinical study evaluated the ability of compound 10 to attenuate diagnostic biomarkers of post procedure acute inflammation and manage pain following third molar extraction.

[0363] The compound 10 treatment group did not have a significantly different maximumCRP increase from baseline compared with the placebo treatment group. Thus, the primary endpoint was not met. Several secondary endpoints (pain intensity AUCs, TTR analgesia, proportion of subjects requiring rescue analgesia, and overall satisfaction with study drug) were not considered for statistical significance because the primary efficacy endpoint was not statistically significant. However, it is noteworthy that pain intensities were lower in the compound 10 treatment group than the placebo group at nearly all time points; although descriptive only, the analysis of overall satisfaction with study drug indicated that subjects who received compound 10 were generally more satisfied with the treatment than placebo subjects. Additionally, a post hoc review of CRP levels at earlier (4 and 8 hour) postAttorney Docket No.63243-702.601 procedure time points was conducted and found a suppression in CRP levels at these earlier time points following only a single compound 10 dose, suggesting a transient drug effect. These post hoc findings point to an emerging hypothesis that increased or longer exposure to compound 10 may strengthen its analgesic effect. This hypothesis is further substantiated by the observed divergence in pain scores for placebo and compound 10, with lower pain levels in compound 10 subjects, as well as the delayed first use of rescue analgesia and lower total amount of rescue analgesics in compound 10 subjects.

[0364] Overall, treatment with compound 10 resulted in an acceptable safety profile forsingle dose exposure in the study population. The incidence of TEAEs was similar between in either treatment group were headache, which occurred in 14.6% of compound 10 subjects and 0% of placebo subjects, and nausea, which occurred in 7.3% of compound 10 subjects and 10.0% of placebo subjects. Most reported TEAEs were mild in severity, and no severe TEAEs were reported. There were no reported AEs that led to death, no reported serious AEs, and no reported AEs that led to study drug discontinuation or withdrawal.

[0365] Clinical laboratory parameters were similar between groups, and only 1potentially clinically significant laboratory value was reported. There were no treatment group trends across vital sign measurements, and no notable differences between groups. In conclusion, while compound 10 was generally safe and well tolerated, measures of the effectiveness of a single 4 mg dose of compound 10 to attenuate diagnostic biomarkers of post-procedure acute inflammation and to manage pain following third molar extraction surgery relative to placebo did not achieve statistical significance; however, based on findings from a non-prespecified analysis, further exploration of compound 10 as a potential analgesic may be warranted. Namely, compound 10 may impart biological effects on the mechanisms involved in managing post-operative inflammation and pain.

[0366] The foregoing description of various embodiments known to the applicant at thistime of filing the application has been presented and is intended for the purposes of illustration and description. The present description is not intended to be exhaustive nor limited to the precise form disclosed and many modifications and variations are possible in the light of the above teachings. The embodiments described serve to explain principles and practical applications, and to enable others skilled in the art to utilize the various embodiments, optionally with various modifications, as are suited to the particular use contemplated. Therefore, it is intended that the disclosure not be limited to the particular embodiments disclosed.

Claims

Attorney Docket No.63243-702.601 CLAIMS WHAT IS CLAIMED IS:

1. A method of treating pain, comprising administering to a subject in need thereof acompound of Formula (I), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof:wherein: A is C6-C10 aryl, C3-C10 cycloalkyl, 3-10 membered heterocyclyl or 5-6 membered monocyclic heteroaryl, each of which is optionally substituted with one or more R6; X is CH or N; Y is NH; R1is H; R2is C1-C6 alkyl, C3-C4 cycloalkyl, C3-C8 heterocyclyl or 5- or 6-membered heteroaryl, each of which is optionally substituted with one more substituent selected from halo, hydroxyl, cyano, aminyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy and 3- to 8- membered heterocyclyl; R3is H; R4is a heteroaryl selected from oxazolyl, isoxazolyl, 1, 2, 3-oxadiazolyl, 1, 2, 4-oxadiazolyl, 1, 2, 5-oxadiazolyl, 1, 3, 4-oxadiazolyl, 1, 2, 3-triazolyl, 1, 2, 4-triazolyl, thiazolyl, isothiazolyl, 1, 2, 3-thiadiazolyl, 1, 2, 4-thiadiazolyl, 1, 2, 5-thiadiazolyl and 1, 3, 4- thiadiazolyl, each of which is optionally substituted with one more substituents selected from halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, cyano, aminyl, C1-C6 hydroxylalkyl, C1-C6 cyanoalkyl, 3- to 8-membered heterocyclyl, C3-C8 haloalkylcycloalkyl, C3-C8 aminylalkylcycloalkyl, C3-C8 alkylcycloalkyl, 3- to 8-membered heterocyclylalkyl, 3- to 8-membered alkylheterocyclylcycloalkyl, 3- to 8-membered haloheterocyclylalkyl, and C3-C8 halocycloalkyl; R5is H; and each R6is independently halo, C1-C6 alkyl, C1-C6 alkoxy, cyano, C1-C6 hydroxylalkyl or C1- C6 haloalkyl.Attorney Docket No.63243-702.6012. The method of claim 1, wherein the compound of Formula (I), or thepharmaceutically acceptable salt, stereoisomer, or solvate thereof, is administered in a dose of about 0.5 mg to about 5 mg.

3. The method of claim 1 or claim 2, wherein the pain is a symptom of and / or associatedwith arthritis.

4. The method of claim 3, wherein the arthritis is rheumatoid arthritis.

5. The method of claim 3, wherein the arthritis is osteoarthritis.

6. The method of claim 3, wherein the arthritis is psoriatic arthritis.

7. The method of claim 1 or claim 2, wherein the pain is a symptom of and / or associatedwith fibromyalgia.

8. The method of claim 1 or claim 2, wherein the pain is a symptom of and / or associatedwith lupus.

9. The method of claim 1 or claim 2, wherein the pain is acute inflammatory pain.

10. The method of claim 1 or claim 2, wherein the pain is a symptom of and / or associatedwith peritonitis.

11. The method of claim 1 or claim 2, wherein the pain is a symptom of and / or associatedwith cancer, or the treatment thereof.

12. The method of claim 1 or claim 2, wherein the pain is a symptom of and / or associatedwith systemic sclerosis.

13. The method of claim 1 or claim 2, wherein the pain is a symptom of and / or associatedwith psoriasis.

14. The method of claim 13, wherein the psoriasis is psoriatic arthritis.

15. The method of claim 1 or claim 2, wherein the pain is a symptom of and / or associatedwith atopic dermatitis or hidradenitis suppurativa.

16. The method of claim 1 or claim 2, wherein the pain is a symptom of and / or associatedwith inflammatory bowel disease (IBD).

17. The method of claim 16, wherein the IBD is colitis.

18. The method of claim 16, wherein the IBD is Crohn's disease.

19. The method of claim 1 or claim 2, wherein the pain is a symptom of and / or associatedwith endometriosis.

20. The method of claim 1 or claim 2, wherein the pain is a symptom of and / or associatedwith complex regional pain syndrome (CRPS).

21. The method of claim 1 or claim 2, wherein the pain is pain that occurs post-surgery.Attorney Docket No.63243-702.60122. The method of any one of claims 1-21, wherein the compound of Formula (I), or thepharmaceutically acceptable salt, stereoisomer, or solvate thereof, is administered orally.

23. The method of any one of claims 1-22, wherein the compound of Formula (I), or thepharmaceutically acceptable salt, stereoisomer, or solvate thereof, is provided in a tablet, a pill, or a capsule.

24. The method of any one of claims 1-23, wherein the compound of Formula (I), or thepharmaceutically acceptable salt, stereoisomer, or solvate thereof, is administered in a dose of about 5 mg.

25. The method of any one of claims 1-23, wherein the compound of Formula (I), or thepharmaceutically acceptable salt, stereoisomer, or solvate thereof, is administered in a dose of about 4 mg.

26. The method of any one of claims 1-23, wherein the compound of Formula (I), or thepharmaceutically acceptable salt, stereoisomer, or solvate thereof, is administered in a dose of about 3 mg.

27. The method of any one of claims 1-23, wherein the compound of Formula (I), or thepharmaceutically acceptable salt, stereoisomer, or solvate thereof, is administered in a dose of about 2 mg.

28. The method of any one of claims 1-23, wherein the compound of Formula (I), or thepharmaceutically acceptable salt, stereoisomer, or solvate thereof, is administered in a dose of about 0.5 mg.

29. The method of any one of claims 1-28, wherein R2 is butyl, cyclopropyl, cyclobutyl,pyrrolidinyl, piperidinyl, pyridinyl, azetidinyl, or oxetanyl, each of which is optionally substituted with one more substituent selected from halo, hydroxyl, cyano, aminyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy and 3- to 8-membered heterocyclyl.

30. The method of any one of claims 1-29, wherein R2 is:

31. The method of any one of claims 1-30, wherein R4 is oxazolyl, isoxazolyl, 1, 2, 3-oxadiazolyl, thiazolyl, isothiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,4-triazolyl or 1, 3, 4-oxadiazolyl, each of which is optionally substituted with one more substituents selected from halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, cyano, aminyl, C1-C6 hydroxylalkyl, C1-C6 cyanoalkyl, 3- to 8-membered heterocyclyl, C3-C8Attorney Docket No.63243-702.601 haloalkylcycloalkyl, C3-C8 aminylalkylcycloalkyl, C3-C8 alkylcycloalkyl, 3- to 8-membered heterocyclylalkyl, 3- to 8-membered alkylheterocyclylcycloalkyl, 3- to 8-membered haloheterocyclylalkyl, and C3-C8 halocycloalkyl, and combinations thereof.

32. The method of any one of claims 1-31, wherein R4 is substituted with C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, cyano, aminyl, C1-C6 hydroxylalkyl, C1-C6 cyanoalkyl, 3- to 8-membered heterocyclyl, C3-C8 haloalkylcycloalkyl, C3-C8 aminylalkylcycloalkyl, C3-C8 alkylcycloalkyl, 3- to 8-membered heterocyclylalkyl, 3- to 8-membered alkylheterocyclylcycloalkyl, 3- to 8-membered haloheterocyclylalkyl, or C3-C8 halocycloalkyl, or combinations thereof.

33. The method of any one of claims 1-32, wherein R4 has one of the followingstructures:

34. The method of any one of claims 1-33, wherein A is C6-C10 aryl, C3-C10 cycloalkyl or5-6 membered monocyclic heteroaryl, each of which is optionally substituted with one or more R6.Attorney Docket No.63243-702.60135. The method of any one of claims 1-34, wherein A is cyclohexyl, cyclohexenyl,phenyl, pyridinyl, or pyrimidinyl.

36. The method of any one of claims 1-35, wherein A is phenyl.

37. The method of any one of claims 1-36, wherein A is unsubstituted.

38. The method of any one of claims 1-36, wherein A is substituted with one or more R6.

39. The method of any one of claims 1-36 or 38, wherein R6 is chloro, fluoro, -CHF2, -CH2CH2OH, cyano, or methoxy.

40. The method of any one of claims 1-35, wherein A is:

41. The method of any one of claims 1-36 or 38-40, wherein the compound is acompound of Formula (Ia), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof:wherein: R2ais C3-C4 cycloalkyl optionally substituted with one more substituents selected from halo, hydroxyl, cyano, aminyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy and 3-8 membered heterocyclyl; and R4ais isoxazolyl optionally substituted with one more substituents selected from C1-C6 haloalkyl, C3-C8 cycloalkyl or C3-C8 haloalkylcycloalkyl.Attorney Docket No.63243-702.60142. The method of claim 41, wherein R2a is cyclopropyl.

43. The method of claim 41 or 42, wherein R4a is:

44. The method of any one of claims 1-28, wherein the compound of Formula (I) is listedin Table 1A, or a pharmaceutically acceptable salt or solvate thereof.

45. The method of any one of claims 1-36 or 38-44, wherein the compound of Formula (I)pharmaceutically acceptable salt or solvate thereof.

46. The method of any one of claims 1-45, wherein the pain is a symptom of and / orassociated with inflammation.

47. The method of any one of claims 1-46, wherein the compound of Formula (I), or thepharmaceutically acceptable salt, stereoisomer, or solvate thereof, is an inhibitor of NEK7 kinase.

48. The method of any one of claims 1-47, wherein the compound of Formula (I), or thepharmaceutically acceptable salt, stereoisomer, or solvate thereof, is a modulator of the NLRP3 inflammasome.

49. The method of any one of claims 1-48, wherein the compound of Formula (I), or thepharmaceutically acceptable salt, stereoisomer, or solvate thereof, is an inhibitor of the NLRP3 (protein)-NEK7 (protein) interaction.

50. The method of any one of claims 1-49, wherein the compound of Formula (I), or thepharmaceutically acceptable salt, stereoisomer, or solvate thereof, is a compound that modulates the priming step of the NLRP3 inflammasome and inhibits the formation of NLRP3 (protein)-NEK7 (protein) interactions.

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